PMID- 29136098 TI - Sequential search leads to faster, more efficient fragment-based de novo protein structure prediction. AB - Motivation: Most current de novo structure prediction methods randomly sample protein conformations and thus require large amounts of computational resource. Here, we consider a sequential sampling strategy, building on ideas from recent experimental work which shows that many proteins fold cotranslationally. Results: We have investigated whether a pseudo-greedy search approach, which begins sequentially from one of the termini, can improve the performance and accuracy of de novo protein structure prediction. We observed that our sequential approach converges when fewer than 20 000 decoys have been produced, fewer than commonly expected. Using our software, SAINT2, we also compared the run time and quality of models produced in a sequential fashion against a standard, non-sequential approach. Sequential prediction produces an individual decoy 1.5-2.5 times faster than non-sequential prediction. When considering the quality of the best model, sequential prediction led to a better model being produced for 31 out of 41 soluble protein validation cases and for 18 out of 24 transmembrane protein cases. Correct models (TM-Score > 0.5) were produced for 29 of these cases by the sequential mode and for only 22 by the non-sequential mode. Our comparison reveals that a sequential search strategy can be used to drastically reduce computational time of de novo protein structure prediction and improve accuracy. Availability and implementation: Data are available for download from: http://opig.stats.ox.ac.uk/resources. SAINT2 is available for download from: https://github.com/sauloho/SAINT2. Contact: saulo.deoliveira@dtc.ox.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29136099 TI - Sex and Aging. PMID- 29136100 TI - Ghrelin is Related to Personality Differences in Reward Sensitivity and Impulsivity. AB - Aims: Ghrelin, a feeding-related peptide mainly produced in the stomach, has been linked to reward mechanisms for food and drugs of abuse in addition to traits of impulsivity. This study is a secondary analysis of an existing data set designed to examine the direct relationships between fasting ghrelin levels and reward sensitivity/impulsivity in healthy social drinkers. Methods: Participants (n = 20) were recruited from an original study examining the subjective effects of alcohol among social drinkers. Fasting ghrelin levels were collected at baseline. Personality measures (Behavioral Inhibition, Behavioral Activation, and Affective Response to Impending Reward and Punishment and Barratt Impulsiveness Scale) were administered at baseline to evaluate sensitivity to reward and punishment, and measure traits of impulsivity, respectively. Results: Fasting ghrelin levels were significantly related to reward sensitivity and impulsivity traits. Specifically, those with higher ghrelin levels were more sensitive to reward and were more impulsive (have lower self-control). Conclusions: The results indicate that individuals with higher levels of ghrelin are more sensitive to reward. In addition, they are less able to exercise self-control and to an extent more likely to act without thinking. This is the first study to report on the direct relationship between fasting ghrelin levels and personality characteristics such as reward sensitivity and aspects of impulsivity among healthy social drinkers. Short summary: Individuals with higher levels of fasting ghrelin are more sensitive to reward, but less sensitive to punishment. Higher ghrelin levels are also related to some aspects of impulsivity such as decreased self-control and increased likelihood of acting without thinking. PMID- 29136101 TI - Identification of topological features in renal tumor microenvironment associated with patient survival. AB - Motivation: As a highly heterogeneous disease, the progression of tumor is not only achieved by unlimited growth of the tumor cells, but also supported, stimulated, and nurtured by the microenvironment around it. However, traditional qualitative and/or semi-quantitative parameters obtained by pathologist's visual examination have very limited capability to capture this interaction between tumor and its microenvironment. With the advent of digital pathology, computerized image analysis may provide a better tumor characterization and give new insights into this problem. Results: We propose a novel bioimage informatics pipeline for automatically characterizing the topological organization of different cell patterns in the tumor microenvironment. We apply this pipeline to the only publicly available large histopathology image dataset for a cohort of 190 patients with papillary renal cell carcinoma obtained from The Cancer Genome Atlas project. Experimental results show that the proposed topological features can successfully stratify early- and middle-stage patients with distinct survival, and show superior performance to traditional clinical features and cellular morphological and intensity features. The proposed features not only provide new insights into the topological organizations of cancers, but also can be integrated with genomic data in future studies to develop new integrative biomarkers. Availability and implementation: https://github.com/chengjun583/KIRP topological-features. Contact: 1271992826@qq.com or kunhuang@iu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29136102 TI - The State of Hypertension in Sub-Saharan Africa: Review and Commentary. PMID- 29136103 TI - Personality and Primary Emotional Traits: Disentangling Multiple Sclerosis Related Fatigue and Depression. AB - Objective: It remains an unresolved research objective to clarify the overlap/association between fatigue (especially its cognitive facet) and depression in People with MS (PwMS). Therefore, in this study the patterns of personality and primary emotional traits (PETs) associated with each (motoric/cognitive fatigue and depression in PwMS) were investigated and compared in order to disentangle the three constructs in PwMS. Additionally, differences in personality and PETs between PwMS and healthy controls (HC) were examined. Method: Associations between motoric/cognitive fatigue, depression, personality and PETs were investigated in 52 PwMS. Personality and PETs were also assessed in a gender matched HC sample (N = 52) and results regarding these were compared between PwMS and HC. Results: Low extraversion was the only significant predictor of MS related motoric fatigue (beta = -.341, p = .013). High neuroticism was a predictor of both MS related cognitive fatigue (beta = .426, p = .002) and depression (beta = .443, p < .001). Whereas neuroticism was the only significant predictor for MS related cognitive fatigue, the cluster of (high) neuroticism, (high) SADNESS (beta = .273, p = .023), and (low) extraversion (beta = -.237, p = .025) predicted MS related depression. PwMS showed significantly higher scores in neuroticism and FEAR compared to HC. Conclusions: MS related motoric/cognitive fatigue and depression in PwMS share variance. But the substantial amount of non shared variance (motoric fatigue, depression: 72%; cognitive fatigue, depression: 66%) together with additional predictors for depression (SADNESS being a predictor of depression only), indicate that MS related motoric/cognitive fatigue and depression are distinguishable. Consequently, we recommend assessing especially SADNESS scores to distinguish between MS related fatigue and depression. PMID- 29136104 TI - Focal Suppression of Distractor Sounds by Selective Attention in Auditory Cortex. AB - Auditory selective attention is required for parsing crowded acoustic environments, but cortical systems mediating the influence of behavioral state on auditory perception are not well characterized. Previous neurophysiological studies suggest that attention produces a general enhancement of neural responses to important target sounds versus irrelevant distractors. However, behavioral studies suggest that in the presence of masking noise, attention provides a focal suppression of distractors that compete with targets. Here, we compared effects of attention on cortical responses to masking versus non-masking distractors, controlling for effects of listening effort and general task engagement. We recorded single-unit activity from primary auditory cortex (A1) of ferrets during behavior and found that selective attention decreased responses to distractors masking targets in the same spectral band, compared with spectrally distinct distractors. This suppression enhanced neural target detection thresholds, suggesting that limited attention resources serve to focally suppress responses to distractors that interfere with target detection. Changing effort by manipulating target salience consistently modulated spontaneous but not evoked activity. Task engagement and changing effort tended to affect the same neurons, while attention affected an independent population, suggesting that distinct feedback circuits mediate effects of attention and effort in A1. PMID- 29136105 TI - Same Genes, Different Brains: Neuroanatomical Differences Between Monozygotic Twins Discordant for Musical Training. AB - Numerous cross-sectional and observational longitudinal studies show associations between expertise and regional brain anatomy. However, since these designs confound training with genetic predisposition, the causal role of training remains unclear. Here, we use a discordant monozygotic (identical) twin design to study expertise-dependent effects on neuroanatomy using musical training as model behavior, while essentially controlling for genetic factors and shared environment of upbringing. From a larger cohort of monozygotic twins, we were able to recruit 18 individuals (9 pairs) that were highly discordant for piano practice. We used structural and diffusion magnetic resonance imaging to analyze the auditory-motor network and within-pair differences in cortical thickness, cerebellar regional volumes and white-matter microstructure/fractional anisotropy. The analyses revealed that the musically active twins had greater cortical thickness in the auditory-motor network of the left hemisphere and more developed white matter microstructure in relevant tracts in both hemispheres and the corpus callosum. Furthermore, the volume of gray matter in the left cerebellar region of interest comprising lobules I-IV + V, was greater in the playing group. These findings provide the first clear support for that a significant portion of the differences in brain anatomy between experts and nonexperts depend on causal effects of training. PMID- 29136106 TI - Cell-Type Specific Burst Firing Interacts with Theta and Beta Activity in Prefrontal Cortex During Attention States. AB - Population-level theta and beta band activity in anterior cingulate and prefrontal cortices (ACC/PFC) are prominent signatures of self-controlled, adaptive behaviors. But how these rhythmic activities are linked to cell-type specific activity has remained unclear. Here, we suggest such a cell-to-systems level linkage. We found that the rate of burst spiking events is enhanced particularly during attention states and that attention-specific burst spikes have a unique temporal relationship to local theta and beta band population-level activities. For the 5-10 Hz theta frequency range, bursts coincided with transient increases of local theta power relative to nonbursts, particularly for bursts of putative interneurons. For the 16-30 Hz beta frequency, bursts of putative interneurons phase synchronized stronger than nonbursts, and were associated with larger beta power modulation. In contrast, burst of putative pyramidal cells showed similar beta power modulation as nonbursts, but were accompanied by stronger beta power only when they occurred early in the beta cycle. These findings suggest that in the ACC/PFC during attention states, mechanisms underlying burst firing are intimately linked to narrow band population-level activities, providing a cell-type specific window into rhythmic inhibitory gating and the emergence of rhythmically coherent network states during goal directed behavior. PMID- 29136107 TI - Contextual Fear Extinction Induces Hippocampal Metaplasticity Mediated by Metabotropic Glutamate Receptor 5. AB - Dysregulated fear memory can lead to a broad spectrum of anxiety disorders. The brain systems underlying fear memory are manifold, with the hippocampus being prominently involved by housing fear-related spatial memories as engrams, which are created and stored through neural changes such as synaptic plasticity. Although metabotropic glutamate (mGlu) receptors contribute significantly to both fear behavior and hippocampal synaptic plasticity, the relationship between these two phenomena has not been fully elucidated. Here, we report that contextual fear extinction induces a novel form of metaplasticity mediated by mGlu5 at the hippocampal SC-CA1 synapse. Further, blockade of mGlu5 prevents both contextual fear extinction and expression of this metaplasticity. This form of metaplasticity was absent in a mouse model of MECP2-duplication syndrome, corresponding to a complete deficit in extinction learning. These findings suggest that mGlu5-dependent metaplasticity within the hippocampus may play a critical role in extinction of contextual fear. PMID- 29136108 TI - Perturbation of GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Induces Trans-regional Metaplasticity at the Medial Prefrontal Cortex. AB - GABAergic synapses in the basolateral amygdala (BLA) play an important role in fear memory generation. We have previously reported that reduction in GABAergic synapses innervating specifically at the axon initial segment (AIS) of principal neurons of BLA, by neurofascin (NF) knockdown, impairs fear extinction. BLA is bidirectionally connected with the medial prefrontal cortex (mPFC), which is a key region involved in extinction of acquired fear memory. Here, we showed that reducing AIS GABAergic synapses within the BLA leads to impairment of synaptic plasticity in the BLA-mPFC pathway, as well as in the ventral subiculum (vSub) mPFC pathway, which is independent of BLA involvement. The results suggest that the alteration within the BLA subsequently resulted in a form of trans-regional metaplasticity in the mPFC. In support of that notion, we observed that NF knockdown induced a severe deficit in behavioral flexibility as measured by reversal learning. Interestingly, reversal learning similar to extinction learning is an mPFC-dependent behavior. In agreement with that, measurement of the immediate-early gene, c-Fos immunoreactivity after reversal learning was reduced in the mPFC and BLA, supporting further the notion that the BLA GABAergic manipulation resulted in trans-regional metaplastic alterations within the mPFC. PMID- 29136109 TI - Using ecological propensity score to adjust for missing confounders in small area studies. AB - Small area ecological studies are commonly used in epidemiology to assess the impact of area level risk factors on health outcomes when data are only available in an aggregated form. However, the resulting estimates are often biased due to unmeasured confounders, which typically are not available from the standard administrative registries used for these studies. Extra information on confounders can be provided through external data sets such as surveys or cohorts, where the data are available at the individual level rather than at the area level; however, such data typically lack the geographical coverage of administrative registries. We develop a framework of analysis which combines ecological and individual level data from different sources to provide an adjusted estimate of area level risk factors which is less biased. Our method (i) summarizes all available individual level confounders into an area level scalar variable, which we call ecological propensity score (EPS), (ii) implements a hierarchical structured approach to impute the values of EPS whenever they are missing, and (iii) includes the estimated and imputed EPS into the ecological regression linking the risk factors to the health outcome. Through a simulation study, we show that integrating individual level data into small area analyses via EPS is a promising method to reduce the bias intrinsic in ecological studies due to unmeasured confounders; we also apply the method to a real case study to evaluate the effect of air pollution on coronary heart disease hospital admissions in Greater London. PMID- 29136110 TI - Meta-Connectomic Analysis Reveals Commonly Disrupted Functional Architectures in Network Modules and Connectors across Brain Disorders. AB - Neuropsychiatric disorders are increasingly conceptualized as disconnection syndromes that are associated with abnormal network integrity in the brain. However, whether different neuropsychiatric disorders show commonly dysfunctional connectivity architectures in large-scale brain networks remains largely unknown. Here, we performed a meta-connectomic study to identify disorder-related functional modules and brain regions by combining meta-analyses of 182 published resting-state functional MRI studies in 11 neuropsychiatric disorders and graph theoretical analyses of 3 independent resting-state functional MRI datasets with healthy and diseased populations (Alzheimer's disease and major depressive disorder [MDD]). Three major functional modules, the default mode, frontoparietal, and sensorimotor networks were commonly abnormal across disorders. Moreover, most of the disorders preferred to target the network connector nodes that were primarily involved in intermodule communications and multiple cognitive components. Apart from these common dysfunctions, different brain disorders were associated with specific alterations in network modules and connector regions. Finally, these meta-connectomic findings were confirmed by two empirical example cases of Alzheimer's disease and MDD. Collectively, our findings shed light on the shared biological mechanisms of network dysfunctions of diverse disorders and have implications for clinical diagnosis and treatment from a network perspective. PMID- 29136111 TI - Corrigendum. PMID- 29136112 TI - Local production of tenascin-C acts as a trigger for monocyte/macrophage recruitment that provokes cardiac dysfunction. AB - Aims: Tenascin-C (TNC) is an endogenous danger signal molecule strongly associated with inflammatory diseases and with poor outcome in patients with cardiomyopathies. Its function within pathological cardiac tissue during pressure overload remains poorly understood. Methods and results: We showed that TNC accumulates after 1 week of transverse aortic constriction (TAC) in the heart of 12-week-old male mice. By cross bone marrow transplantation experiments, we determined that TNC deposition relied on cardiac cells and not on haematopoietic cells. The expression of TNC induced by TAC, or by administration of a recombinant lentivector coding for TNC, triggered a pro-inflammatory cardiac microenvironment, monocyte/macrophage (MO/MPhi) accumulation, and systolic dysfunction. TNC modified macrophage polarization towards the pro-inflammatory phenotype and stimulated RhoA/Rho-associated protein kinase (ROCK) pathways to promote mesenchymal to amoeboid transition that enhanced macrophage migration into fibrillar collagen matrices. The amplification of inflammation and MO/MPhi recruitment by TNC was abrogated by genetic invalidation of TNC in knockout mice. These mice showed less ventricular remodelling and an improved cardiac function after TAC as compared with wild-type mice. Conclusions: By promoting a pro inflammatory microenvironment and macrophage migration, TNC appears to be a key factor to enable the MO/MPhi accumulation within fibrotic hearts leading to cardiac dysfunction. As TNC is highly expressed during inflammation and sparsely during the steady state, its inhibition could be a promising therapeutic strategy to control inflammation and immune cell infiltration in heart disease. PMID- 29136113 TI - The Laminar Organization of Piriform Cortex Follows a Selective Developmental and Migratory Program Established by Cell Lineage. AB - Piriform cortex (PC) is a 3-layer paleocortex receiving primary afferent input from the olfactory bulb. The past decade has seen significant progress in understanding the synaptic, cellular and functional organization of PC, but PC embryogenesis continues to be enigmatic. Here, using birthdating strategies and clonal analyses, we probed the early development and laminar specificity of neurogenesis/gliogenesis as it relates to the organization of the PC. Our data demonstrate a temporal sequence of laminar-specific neurogenesis following the canonical "inside-out" pattern, with the notable exception of PC Layer II which exhibited an inverse "outside-in" temporal neurogenic pattern. Of interest, we found no evidence of a neurogenic gradient along the anterior to posterior axis, although the timing of neuronal migration and laminar development was delayed rostrally by approximately 24 h. To begin probing if lineage affected cell fate in the PC, we labeled PC neuroblasts using a multicolor technique and analyzed their laminar organization. Our results suggested that PC progenitors were phenotypically committed to reach specific layers early in the development. Collectively, these studies shed new light on the determinants of the laminar specificity of neuronal/glial organization in PC and the likely role of subpopulations of committed progenitors in regulating PC embryogenesis. PMID- 29136114 TI - Age-Related Declines in Motor Performance are Associated With Decreased Segregation of Large-Scale Resting State Brain Networks. AB - Aging is typically associated with substantial declines in motor functioning as well as robust changes in the functional organization of brain networks. Previous research has investigated the link between these 2 age-varying factors but examinations were predominantly limited to the functional organization within motor-related brain networks. Little is known about the relationship between age related behavioral impairments and changes in functional organization at the whole brain (i.e., multiple network) level. This knowledge gap is surprising given that the decreased segregation of brain networks (i.e., increased internetwork connectivity) can be considered a hallmark of the aging process. Accordingly, we investigated the association between declines in motor performance across the adult lifespan (20-75 years) and age-related modulations of functional connectivity within and between resting state networks. Results indicated that stronger internetwork resting state connectivity observed as a function of age was significantly related to worse motor performance. Moreover, performance had a significantly stronger association with the strength of internetwork as compared with intranetwork connectivity, including connectivity within motor networks. These findings suggest that age-related declines in motor performance may be attributed to a breakdown in the functional organization of large-scale brain networks rather than simply age-related connectivity changes within motor-related networks. PMID- 29136115 TI - Estradiol Levels Are Altered in Human Immunodeficiency Virus-Infected Pregnant Women Randomized to Efavirenz-Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy. AB - Background: Combination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART. Methods: Three hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay. Results: Estradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases. Conclusions: Combination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority. Clinical Trials Registration: NCT00993031. PMID- 29136116 TI - Prenatal Stress, Glucocorticoids, and Developmental Programming of the Stress Response. AB - The early environment has a major impact on the developing embryo, fetus, and infant. Parental adversity (maternal and paternal) and glucocorticoid exposure before conception and during pregnancy have profound effects on the development and subsequent function of the hypothalamic-pituitary-adrenal axis and related behaviors. These effects are species-, sex-, and age-specific and depend on the timing and duration of exposure. The impact of these early exposures can extend across multiple generations, via both the maternal and paternal lineage, and recent studies have begun to determine the mechanisms by which this occurs. Improved knowledge of the mechanisms by which adversity and glucocorticoids program stress systems will allow development of strategies to ameliorate and/or reverse these long-term effects. PMID- 29136117 TI - Cost-Effectiveness of Community-based Human Immunodeficiency Virus Self-Testing in Blantyre, Malawi. AB - Background: Human immunodeficiency virus self-testing (HIVST) is effective, with scale-up underway in sub-Saharan Africa. We assessed cost-effectiveness of adding HIVST to existing facility-based HIV testing and counseling (HTC) services. Both 2010 (initiate at CD4 <350 cells/MUL) and 2015 (initiate all) World Health Organization (WHO) guidelines for antiretroviral treatment (ART) were considered. Methods: A microsimulation model was developed to evaluate cost-effectiveness, from both health provider and societal perspectives, of an HIVST service implemented in a cluster-randomized trial (CRT; ISRCTN02004005) in Malawi. Costs and health outcomes were evaluated over a 20-year time horizon, using a discount rate of 3%. Probabilistic sensitivity analysis was conducted to account for parameter uncertainty. Results: From the health provider perspective and 20-year time horizon, facility HTC using 2010 WHO ART guidelines was the least costly ($294.71 per person; 95% credible interval [CrI], 270.79-318.45) and least effective (11.64 quality-adjusted life-years [QALYs] per person; 95% CrI, 11.43 11.86) strategy. Compared with this strategy, the incremental cost-effectiveness ratio (ICER) for facility HTC using 2015 WHO ART guidelines was $226.85 (95% CrI, 198.79-284.35) per QALY gained. The strategy of facility HTC plus HIVST, using 2010 WHO ART guidelines, was extendedly dominated. The ICER for facility HTC plus HIVST, using 2015 WHO ART guidelines, was $253.90 (95% CrI, 201.71-342.02) per QALY gained compared with facility HTC and using 2015 WHO ART guidelines. Conclusions: HIVST may be cost-effective in a Malawian population with high HIV prevalence. HIVST is suited to an early HIV diagnosis and treatment strategy. Clinical Trials registration: ISRCTN02004005. PMID- 29136118 TI - Ventricular-arterial and aortic mechanical valve dehiscence evaluated by advanced post-processing techniques in multislice computed tomography. PMID- 29136119 TI - The Bat as a New Model of Cortical Development. AB - The organization of the mammalian cerebral cortex shares fundamental features across species. However, while the radial thickness of grey matter varies within one order of magnitude, the tangential spread of the cortical sheet varies by orders of magnitude across species. A broader sample of model species may provide additional clues for understanding mechanisms that drive cortical expansion. Here, we introduce the bat Carollia perspicillata as a new model species. The brain of C. perspicillata is similar in size to that of mouse but has a cortical neurogenic period at least 5 times longer than mouse, and nearly as long as that of the rhesus macaque, whose brain is 100 times larger. We describe the development of laminar and regional structures, neural precursor cell identity and distribution, immune cell distribution, and a novel population of Tbr2+ cells in the caudal ganglionic eminence of the developing neocortex of C. perspicillata. Our data indicate that unique mechanisms guide bat cortical development, particularly concerning cell cycle length. The bat model provides new perspective on the evolution of developmental programs that regulate neurogenesis in mammalian cerebral cortex, and offers insight into mechanisms that contribute to tangential expansion and gyri formation in the cerebral cortex. PMID- 29136120 TI - T2 mapping cardiovascular magnetic resonance identifies the presence of myocardial inflammation in patients with dilated cardiomyopathy as compared to endomyocardial biopsy. AB - Aims: The aim of this study was to determine the value of T2 mapping for the non invasive assessment of myocardial inflammation in different stages of systolic left ventricular dysfunction in dilated cardiomyopathy (DCM) in comparison with endomyocardial biopsy (EMB). Methods and results: A total of 132 subjects were enrolled between 2013 and 2016 (62 controls and 70 patients with DCM). All patients underwent CMR at 1.5 T and received coronary angiogram and EMB. CMR applied standard protocols including T2 mapping with Gradient And SpinEcho sequence (GRASE). Global T2 relaxation time was significantly increased in patients with DCM compared to the healthy controls (T2 time DCM vs. controls: 65.9 +/- 6.2 vs. 60.0 +/- 4.2 ms; P < 0.001). Of note, patients with the presence of inflammatory cells in EMB exhibited further elevation of T2 values (T2 time in patients with the presence of inflammatory cells vs. T2 time in patients without: 68.8 +/- 5.8 vs. 64.7 +/- 5.9 ms; P = 0.02). Receiver operating characteristic analysis of our data deciphered a global myocardial T2 time >65.3 ms as the best cut-off for distinction between the healthy controls and patients with myocardial inflammation [sensitivity 93%, specificity 90%, P < 0.01, area under the curve (AUC) 0.95]. In patients with DCM, this threshold identified patients with biopsy proven inflammation with a sensitivity of 79% and specificity 58% (AUC 0.72). Conclusion: In patients with DCM and presence of inflammatory cells in the myocardium, myocardial T2 relaxation times may help to non-invasively detect myocardial inflammation. Although there is an overlap of T2 values between patients and healthy controls, T2 mapping may facilitate the identification of patients who may benefit from EMB for therapeutic decision-making. PMID- 29136121 TI - Mechanical Thrombectomy for Acute Ischemic Stroke Secondary to Infective Endocarditis. AB - Intravenous thrombolysis is contraindicated in acute ischemic stroke secondary to infective endocarditis. We report our initial experience in 6 cases of proximal vessel occlusion treated with mechanical thrombectomy, which was safe (no bleeding) and effective (significant early neurological improvement) and might be useful in this clinical setting. PMID- 29136122 TI - Local and Global Spatial Organization of Interaural Level Difference and Frequency Preferences in Auditory Cortex. AB - Despite decades of microelectrode recordings, fundamental questions remain about how auditory cortex represents sound-source location. Here, we used in vivo 2 photon calcium imaging to measure the sensitivity of layer II/III neurons in mouse primary auditory cortex (A1) to interaural level differences (ILDs), the principal spatial cue in this species. Although most ILD-sensitive neurons preferred ILDs favoring the contralateral ear, neurons with either midline or ipsilateral preferences were also present. An opponent-channel decoder accurately classified ILDs using the difference in responses between populations of neurons that preferred contralateral-ear-greater and ipsilateral-ear-greater stimuli. We also examined the spatial organization of binaural tuning properties across the imaged neurons with unprecedented resolution. Neurons driven exclusively by contralateral ear stimuli or by binaural stimulation occasionally formed local clusters, but their binaural categories and ILD preferences were not spatially organized on a more global scale. In contrast, the sound frequency preferences of most neurons within local cortical regions fell within a restricted frequency range, and a tonotopic gradient was observed across the cortical surface of individual mice. These results indicate that the representation of ILDs in mouse A1 is comparable to that of most other mammalian species, and appears to lack systematic or consistent spatial order. PMID- 29136123 TI - Amyloid Network Topology Characterizes the Progression of Alzheimer's Disease During the Predementia Stages. AB - There is increasing evidence showing that the accumulation of the amyloid-beta (Abeta) peptide into extracellular plaques is a central event in Alzheimer's disease (AD). These abnormalities can be detected as lowered levels of Abeta42 in the cerebrospinal fluid (CSF) and are followed by increased amyloid burden on positron emission tomography (PET) several years before the onset of dementia. The aim of this study was to assess amyloid network topology in nondemented individuals with early stage Abeta accumulation, defined as abnormal CSF Abeta42 levels and normal Florbetapir PET (CSF+/PET-), and more advanced Abeta accumulation, defined as both abnormal CSF Abeta42 and Florbetapir PET (CSF+/PET+). The amyloid networks were built using correlations in the mean 18F florbetapir PET values between 72 brain regions and analyzed using graph theory analyses. Our findings showed an association between early amyloid stages and increased covariance as well as shorter paths between several brain areas that overlapped with the default-mode network (DMN). Moreover, we found that individuals with more advanced amyloid accumulation showed more widespread changes in brain regions both within and outside the DMN. These findings suggest that amyloid network topology could potentially be used to assess disease progression in the predementia stages of AD. PMID- 29136124 TI - What is the clinical significance of ventricular mural antagonism? AB - Recent morphological studies provide evidence that the ventricular walls are arranged as a 3D meshwork of aggregated cardiomyocyte chains, exhibiting marked local structural variations. In contrary to previous findings, up to two-fifths of the chains are found to have a partially transmural alignment, thus deviating from the prevailing tangential orientation. Upon contraction, they produce, in addition to a tangential force, a radial force component that counteracts ventricular constriction and aids widening of the ventricular cavity. In experimental studies, we have provided evidence for the existence of such forces, which are auxotonic in nature. This is in contrast to the tangentially aligned myocytes that produce constrictive forces, which are unloading in nature. The ventricular myocardium is, therefore, able to function in an antagonistic fashion, with the prevailing constrictive forces acting simultaneously with a dilatory force component. The ratio of constrictive to dilating force varies locally according to the specific mural architecture. Such antagonism acts according to local demands to preserve the ventricular shape, store the elastic energy that drives the fast late systolic dilation and apportion mural motion to facilitate the spiralling nature of intracavitary flow. Intracavitary pressure and flow dynamics are thus governed concurrently by ventricular constrictive and dilative force components. Antagonistic activity, however, increases deleteriously in states of cardiac disease, such as hypertrophy and fibrosis. beta-blockade at low dosage acts selectively to temper the auxotonic forces. PMID- 29136126 TI - Risk of Subsequent Sepsis Within 90 Days After a Hospital Stay by Type of Antibiotic Exposure. AB - Background: We examined the risk of sepsis within 90 days after discharge from a previous hospital stay by type of antibiotic received during the previous stay. Methods: We retrospectively identified a cohort of hospitalized patients from the Truven Health MarketScan Hospital Drug Database. We examined the association between the use of certain antibiotics during the initial hospital stay, determined a priori, and the risk of postdischarge sepsis controlling for potential confounding factors in a multivariable logistic regression model. Our primary exposure was receipt of antibiotics more strongly associated with clinically important microbiome disruption. Our primary outcome was a hospital stay within 90 days of the index stay that included an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge diagnosis of severe sepsis (ICD-9-CM code 995.92) or septic shock (785.52). Results: Among 516 hospitals, we randomly selected a single stay for eligible patients. In 0.17% of these patients, severe sepsis/septic shock developed within 90 days after discharge. The risk of sepsis associated with exposure to our high-risk antibiotics was 65% higher than in those without antibiotic exposure. Conclusions: Our study identified an increased risk of sepsis within 90 days of discharge among patients with exposure to high-risk antibiotics or increased quantities of antibiotics during hospitalization. Given that a significant proportion of inpatient antimicrobial use may be unnecessary, this study builds on previous evidence suggesting that increased stewardship efforts in hospitals may not only prevent antimicrobial resistance, Clostridium difficile infection, and other adverse effects, but may also reduce unwanted outcomes potentially related to disruption of the microbiota, including sepsis. PMID- 29136127 TI - Risk of Pelvic Inflammatory Disease in Relation to Chlamydia and Gonorrhea Testing, Repeat Testing, and Positivity: A Population-Based Cohort Study. AB - Background: There is uncertainty around whether the risks of pelvic inflammatory disease (PID) differ following Chlamydia trachomatis (chlamydia) and Neisseria gonorrhoeae (gonorrhea) infection. We quantified the risk of PID associated with chlamydia and gonorrhea infection and subsequent repeat infections in a whole population cohort. Methods: A cohort of 315123 Western Australian women, born during 1974-1995, was probabilistically linked to chlamydia and gonorrhea testing records and to hospitalizations and emergency department presentations for PID from 2002 to 2013. Time-updated survival analysis was used to investigate the association between chlamydia and gonorrhea testing, and positivity, and risk of PID. Results: Over 3199135 person-years, 120748 women had pathology test records for both chlamydia and gonorrhea, 10745 chlamydia only, and 653 gonorrhea only. Among those tested, 16778 (12.8%) had >=1 positive chlamydia test, 3195 (2.6%) >=1 positive gonorrhea test, and 1874 (1.6%) were positive for both. There were 4819 PID presentations (2222 hospitalizations, 2597 emergency presentations). Adjusting for age, Aboriginality, year of follow-up, health area, and socioeconomic status, compared to women negative for chlamydia and gonorrhea, the relative risk (adjusted incidence rate ratio) of PID was 4.29 (95% confidence interval [CI], 3.66-5.03) in women who were both chlamydia and gonorrhea positive; 4.54 (95% CI, 3.87-5.33) in those only gonorrhea positive; and 1.77 (95% CI, 1.61-1.94) in those only chlamydia positive. Conclusions: Gonorrhea infection conferred a substantially higher risk than chlamydia of hospitalization or emergency department presentation for PID. The emergence of gonorrhea antimicrobial resistance may have a serious impact on rates of PID and its associated reproductive health sequelae. PMID- 29136125 TI - Effective Connectivity Measured Using Optogenetically Evoked Hemodynamic Signals Exhibits Topography Distinct from Resting State Functional Connectivity in the Mouse. AB - Brain connectomics has expanded from histological assessment of axonal projection connectivity (APC) to encompass resting state functional connectivity (RS-FC). RS FC analyses are efficient for whole-brain mapping, but attempts to explain aspects of RS-FC (e.g., interhemispheric RS-FC) based on APC have been only partially successful. Neuroimaging with hemoglobin alone lacks specificity for determining how activity in a population of cells contributes to RS-FC. Wide field mapping of optogenetically defined connectivity could provide insights into the brain's structure-function relationship. We combined optogenetics with optical intrinsic signal imaging to create an efficient, optogenetic effective connectivity (Opto-EC) mapping assay. We examined EC patterns of excitatory neurons in awake, Thy1-ChR2 transgenic mice. These Thy1-based EC (Thy1-EC) patterns were evaluated against RS-FC over the cortex. Compared to RS-FC, Thy1-EC exhibited increased spatial specificity, reduced interhemispheric connectivity in regions with strong RS-FC, and appreciable connection strength asymmetry. Comparing the topography of Thy1-EC and RS-FC patterns to maps of APC revealed that Thy1-EC more closely resembled APC than did RS-FC. The more general method of Opto-EC mapping with hemoglobin can be determined for 100 sites in single animals in under an hour, and is amenable to other neuroimaging modalities. Opto EC mapping represents a powerful strategy for examining evolving connectivity related circuit plasticity. PMID- 29136128 TI - The Proton-activated Receptor GPR4 Modulates Intestinal Inflammation. AB - Background and Aims: During active inflammation, intraluminal intestinal pH is decreased in patients with inflammatory bowel disease [IBD]. Acidic pH may play a role in IBD pathophysiology. Recently, proton-sensing G-protein coupled receptors were identified, including GPR4, OGR1 [GPR68], and TDAG8 [GPR65]. We investigated whether GPR4 is involved in intestinal inflammation. Methods: The role of GPR4 was assessed in murine colitis models by chronic dextran sulphate sodium [DSS] administration and by cross-breeding into an IL-10 deficient background for development of spontaneous colitis. Colitis severity was assessed by body weight, colonoscopy, colon length, histological score, cytokine mRNA expression, and myeloperoxidase [MPO] activity. In the spontaneous Il-10-/- colitis model, the incidence of rectal prolapse and characteristics of lamina propria leukocytes [LPLs] were analysed. Results: Gpr4-/- mice showed reduced body weight loss and histology score after induction of chronic DSS colitis. In Gpr4-/-/Il-10-/- double knock-outs, the onset and progression of rectal prolapse were significantly delayed and mitigated compared with Gpr4+/+/Il-10-/- mice. Double knock-out mice showed lower histology scores, MPO activity, CD4+ T helper cell infiltration, IFN-gamma, iNOS, MCP-1 [CCL2], CXCL1, and CXCL2 expression compared with controls. In colon, GPR4 mRNA was detected in endothelial cells, some smooth muscle cells, and some macrophages. Conclusions: Absence of GPR4 ameliorates colitis in IBD animal models, indicating an important regulatory role in mucosal inflammation, thus providing a new link between tissue pH and the immune system. Therapeutic inhibition of GPR4 may be beneficial for the treatment of IBD. PMID- 29136129 TI - Comparison of Respirable Mass Concentrations Measured by a Personal Dust Monitor and a Personal DataRAM to Gravimetric Measurements. AB - In 2016, the Mine Safety and Health Administration required the use of continuous monitors to measure respirable dust in mines and better protect miner health. The Personal Dust Monitor, PDM3700, has met stringent performance criteria for this purpose. In a laboratory study, respirable mass concentrations measured with the PDM3700 and a photometer (personal DataRam, pDR-1500) were compared to those measured gravimetrically for five aerosols of varying refractive index and density (diesel exhaust fume, welding fume, coal dust, Arizona road dust (ARD), and salt [NaCl] aerosol) at target concentrations of 0.38, 0.75, and 1.5 mg m-3. For all aerosols except coal dust, strong, near-one-to-one, linear relationships were observed between mass concentrations measured with the PDM3700 and gravimetrically (diesel fume, slope = 0.99, R2 = 0.99; ARD, slope = 0.98, R2 = 0.99; and NaCl, slope = 0.95, R2 = 0.99). The slope deviated substantially from unity for coal dust (slope = 0.55; R2 = 0.99). Linear relationships were also observed between mass concentrations measured with the pDR-1500 and gravimetrically, but one-to-one behavior was not exhibited (diesel fume, slope = 0.23, R2 = 0.76; coal dust, slope = 0.54, R2 = 0.99; ARD, slope = 0.61, R2 = 0.99; NaCl, slope = 1.14, R2 = 0.98). Unlike the pDR-1500, mass concentrations measured with the PDM3700 appear independent of refractive index and density, suggesting that it could have applications in a variety of occupational settings. PMID- 29136130 TI - Distal re-entry closure with neobranching technique after thoracic endovascular aortic repair of Type B aortic dissection. AB - Retrograde false-lumen flow after thoracic endovascular aortic repair of Type B aortic dissection occurs occasionally and may have a negative impact on aortic remodelling and even prevent the decompression of the false lumen. A 67-year-old man with a Type B aortic dissection underwent thoracic endovascular aortic repair for severe compression of the true lumen and visceral malperfusion 7 weeks after the onset. Intraoperative angiography revealed proximal entry tear closure, but the false-lumen flow increased because of retrograde flow through the re-entry tear. Additional intervention including re-entry tear closure was performed with a neobranching technique with covered stent placement in the visceral artery from the aortic true lumen through the distal re-entry tear. We report a case of Type B aortic dissection and discuss the surgical techniques used. PMID- 29136131 TI - Characteristic Increases in EEG Connectivity Correlate With Changes of Structural MRI in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a terminal progressive adult-onset neurodegeneration of the motor system. Although originally considered a pure motor degeneration, there is increasing evidence of disease heterogeneity with varying degrees of extra-motor involvement. How the combined motor and nonmotor degeneration occurs in the context of broader disruption in neural communication across brain networks has not been well characterized. Here, we have performed high-density crossectional and longitudinal resting-state electroencephalography (EEG) recordings on 100 ALS patients and 34 matched controls, and have identified characteristic patterns of altered EEG connectivity that have persisted in longitudinal analyses. These include strongly increased EEG coherence between parietal-frontal scalp regions (in gamma-band) and between bilateral regions over motor areas (in theta-band). Correlation with structural MRI from the same patients shows that disease-specific structural degeneration in motor areas and corticospinal tracts parallels a decrease in neural activity over scalp motor areas, while the EEG over the scalp regions associated with less extensively involved extra-motor regions on MRI exhibit significantly increased neural communication. Our findings demonstrate that EEG-based connectivity mapping can provide novel insights into progressive network decline in ALS. These data pave the way for development of validated cost-effective spectral EEG-based biomarkers that parallel changes in structural imaging. PMID- 29136132 TI - Aortic events and reoperations after elective arch surgery: incidence, surgical strategies and outcomes. AB - OBJECTIVES: The true incidence of aortic events (AEs) and reoperations (REDO) following elective total aortic arch replacement remains unknown. The aim of this study was to review the incidence of AEs and surgical REDO, and its respective outcomes after 1232 elective arch repairs at 11 European aortic centres. METHODS: Retrospective chart review (in the absence of prospective data collection) was performed for statistical analysis. Follow-up was conducted during routine clinical examination or in a telephone interview with patients and/or their respective physicians. RESULTS: One hundred fifty-five (12.6%) patients were identified (median follow-up time 48.7 months). The recorded AEs comprised aortic dilatation (62.6%), rupture (15.5%), endoleak (11%), false aneurysm (3.9%), dissection (3.2%), infection (2.6%) and others (1.3%). REDO (open/endovascular) were performed in 85.8% of patients (n = 133). Intraoperative and in-hospital mortality in the REDO patients were 7.5% and 17.3%, respectively. Postoperative neurological complications comprised paraplegia (6.0%) and stroke (1.5%). Survival rates after REDO at 1, 3 and 5 years were 81.2%, 79.0% and 76.7%, respectively. Univariate analysis identified 'rupture' and 'diameter progression', 'older age at REDO' and the REDO strategies 'frozen elephant trunk' and 'no elephant trunk' as predictors of increased in-hospital mortality. Multivariate analysis identified 'older age at REDO' (P = 0.008) as the only independent risk factor for in-hospital mortality. CONCLUSIONS: AEs after elective arch surgery are not irrelevant and mostly involve the distal aspects of the adjoining aorta. In accordance with the underlying pathology, open or endovascular REDO may be performed with an acceptable outcome. Preparation of an adequate proximal landing zone at the time of primary arch surgery is advisable. PMID- 29136134 TI - Asymptomatic dissection of a giant aorta ascendens aneurysm in Turner syndrome. PMID- 29136133 TI - Representations of Fine Digit Movements in Posterior and Anterior Parietal Cortex Revealed Using Long-Train Intracortical Microstimulation in Macaque Monkeys. AB - The current investigation in macaque monkeys utilized long-train intracortical microstimulation to determine the extent of cortex from which movements could be evoked. Not only were movements evoked from motor areas (PMC and M1), but they were also evoked from posterior parietal (5, 7a, 7b) and anterior parietal areas (3b, 1, 2). Large representations of digit movements involving only the index finger (D2) and thumb (D1), were elicited from areas 1, 2, 7b, and M1. Other movements evoked from these regions were similar to ethologically relevant movements that have been described in other primates. These include combined forelimb and mouth movements and full hand grasps. However, many other movements were much more complex and could not be categorized into any of the previously described ethological categories. Movements involving specific digits, which mimic precision grips, are unique to macaques and have not been described in New World or prosimian primates. We propose that these multiple and expanded motor representations of the digits co-evolved with the emergence of the opposable thumb and alterations in grip type in some anthropoid lineages. PMID- 29136135 TI - Sarin Exposures in A Cohort of British Military Participants in Human Experimental Research at Porton Down 1945-1987. AB - Background: The effects of exposure to chemical warfare agents in humans are topical. Porton Down is the UK's centre for research on chemical warfare where, since WWI, a programme of experiments involving ~30000 participants drawn from the UK armed services has been undertaken. Objectives: Our aim is to report on exposures to nerve agents, particularly sarin, using detailed exposure data not explored in a previous analysis. Methods: In this paper, we have used existing data on exposures to servicemen who attended the human volunteer programme at Porton Down to examine exposures to nerve agents in general and to sarin in particular. Results: Six principal nerve agents were tested on humans between 1945 and 1987. Of all 4299 nerve agent tests recorded, 3511 (82%) were with sarin, most commonly in an exposure chamber, with inhalation being the commonest exposure route (85%). Biological response to sarin exposure was expressed as percentage change in cholinesterase activity and, less commonly, change in pupil size. For red blood cell cholinesterase, median inhibition for inhalation tests was 41% (interquartile range 28-51%), with a maximum of 87%. For dermal exposures the maximum inhibition recorded was 99%. There was a clear association between increasing exposure to sarin and depression of cholinesterase activity but the strength and direction of the association varied by exposure route and the presence of chemical or physical protection. Pupil size decreased with increased exposure but this relationship was less clear when modifiers, such as atropine drops, were present. Conclusions: These results, drawn from high quality experimental data, offer a unique insight into the effects of these chemical agents on humans. PMID- 29136136 TI - A battle in the crusade to understand scimitar syndrome. PMID- 29136137 TI - Copy Number Variation and Expression Analysis Reveals a Nonorthologous Pinta Gene Family Member Involved in Butterfly Vision. AB - Vertebrate (cellular retinaldehyde-binding protein) and Drosophila (prolonged depolarization afterpotential is not apparent [PINTA]) proteins with a CRAL-TRIO domain transport retinal-based chromophores that bind to opsin proteins and are necessary for phototransduction. The CRAL-TRIO domain gene family is composed of genes that encode proteins with a common N-terminal structural domain. Although there is an expansion of this gene family in Lepidoptera, there is no lepidopteran ortholog of pinta. Further, the function of these genes in lepidopterans has not yet been established. Here, we explored the molecular evolution and expression of CRAL-TRIO domain genes in the butterfly Heliconius melpomene in order to identify a member of this gene family as a candidate chromophore transporter. We generated and searched a four tissue transcriptome and searched a reference genome for CRAL-TRIO domain genes. We expanded an insect CRAL-TRIO domain gene phylogeny to include H. melpomene and used 18 genomes from 4 subspecies to assess copy number variation. A transcriptome-wide differential expression analysis comparing four tissue types identified a CRAL-TRIO domain gene, Hme CTD31, upregulated in heads suggesting a potential role in vision for this CRAL-TRIO domain gene. RT-PCR and immunohistochemistry confirmed that Hme CTD31 and its protein product are expressed in the retina, specifically in primary and secondary pigment cells and in tracheal cells. Sequencing of eye protein extracts that fluoresce in the ultraviolet identified Hme CTD31 as a possible chromophore binding protein. Although we found several recent duplications and numerous copy number variants in CRAL-TRIO domain genes, we identified a single copy pinta paralog that likely binds the chromophore in butterflies. PMID- 29136138 TI - Calcific aortic valve stenosis: hard disease in the heart: A biomolecular approach towards diagnosis and treatment. AB - Calcific aortic valve stenosis (CAVS) is common in the ageing population and set to become an increasing economic and health burden. Once present, it inevitably progresses and has a poor prognosis in symptomatic patients. No medical therapies are proven to be effective in holding or reducing disease progression. Therefore, aortic valve replacement remains the only available treatment option. Improved knowledge of the mechanisms underlying disease progression has provided us with insights that CAVS is not a passive disease. Rather, CAVS is regulated by numerous mechanisms with a key role for calcification. Aortic valve calcification (AVC) is actively regulated involving cellular and humoral factors that may offer targets for diagnosis and intervention. The discovery that the vitamin K dependent proteins are involved in the inhibition of AVC has boosted our mechanistic understanding of this process and has opened up novel avenues in disease exploration. This review discusses processes involved in CAVS progression, with an emphasis on recent insights into calcification, methods for imaging calcification activity, and potential therapeutic options. PMID- 29136140 TI - Inaccurate aortic stent graft deployment in the distal landing zone: incidence, reasons and consequences. AB - OBJECTIVES: The aim of this study was to investigate the accuracy of stent graft deployment in the distal landing zone (LZ) during thoracic endovascular aortic repair (TEVAR). Currently, TEVAR focuses on accurate stent graft deployment in the proximal LZ. Data on landing in the distal LZ are lacking. METHODS: Of 195 TEVAR patients (2005-16) with a non-dissected aortic pathology, 59 [median age 73 years (first quartile 68; third quartile 77), 20 women] patients had a distal LZ shorter than 40 mm. In all, the aim was to deploy the stent graft just above the target vessel (coeliac trunk, mesenteric superior or renal artery). Patients were divided into the accurate landing (n = 10) and inaccurate landing (IAL, n = 49) groups according to the distance to the target vessel <= 5 mm or > 5 mm after TEVAR, target vessel coverage and the need for a second stent graft in the distal LZ. We assessed the distal LZ, stent graft distance to the target vessel, apposition, migration and endoleak Ib on computed tomography. Median follow-up period was 23 months (5; 48). RESULTS: Distal LZ anatomy did not differ between groups. Overall stent graft distance to the target vessel was 10.0 mm (6.5 mm; 16.0 mm). Three patients required a second stent graft in the distal LZ, and in 3 others, the target vessel was accidentally covered. In patients of the accurate landing group primary endoleak Ib occurred less frequently than those in the IAL group (0% vs 33%; P = 0.049). Three (30%) accurate landing and 19 (39%) IAL patients (P = 0.73) presented with substantial stent graft wedge apposition. CONCLUSIONS: Accurate stent graft implantation in the distal LZ with the currently available deployment mechanism is often challenging. An inaccurate landing is associated with a higher incidence of endoleak Ib. PMID- 29136139 TI - RAD-Seq Reveals Patterns of Additive Polygenic Variation Caused by Spatially Varying Selection in the American Eel (Anguilla rostrata). AB - The American Eel (Anguilla rostrata) has an exceptional life cycle characterized by panmictic reproduction at the species scale, random dispersal, and selection in a highly heterogeneous habitat extending from subtropical to subarctic latitudes. The genetic consequences of spatially-varying selection in this species have been investigated for decades, revealing subtle clines in allele frequency at a few loci that contrast with complete panmixia on the vast majority of the genome. Because reproduction homogenizes allele frequencies every generation, sampling size, and genomic coverage are critical to reach sufficient power to detect selected loci in this context. Here, we used a total of 710 individuals from 12 sites and 12,098 high-quality single nucleotide polymorphisms to re-evaluate the extent to which local selection affects the spatial distribution of genetic diversity in this species. We used environmental association methods to identify markers under spatially-varying selection, which indicated that selection affects ~1.5% of the genome. We then evaluated the extent to which candidate markers collectively vary with environmental factors using additive polygenic scores. We found significant correlations between polygenic scores and latitude, longitude and temperature which are consistent with polygenic selection acting against maladapted genotypes in different habitats occupied by eels throughout their range of distribution. Gene functions associated with outlier markers were significantly enriched for the insulin signaling pathway, indicating that the trade-offs inherent to occupying such a large distribution range involve the regulation of metabolism. Overall, this study highlights the potential of the additive polygenic scores approach in detecting selective effects in a complex environment. PMID- 29136141 TI - Vaccination policies of immigrants in the EU/EEA Member States-the measles immunization example. AB - Background: In 2015-16, the European Union/European Economic Area Member States (EU/EEA MSs) experienced an unprecedented volume and rate of migration, posing serious challenges to existing national immunization systems and strategies and raising the questions of where, when and who to vaccinate. We assessed existing strategies for vaccinating immigrant populations in the EU/EEA using measles as an example of the most important vaccine-preventable diseases. Methods: In this cross-sectional study, conducted from March to May 2016, an electronic questionnaire was sent to the Heads of National Immunization Technical Advisory Groups (NITAGs) or equivalent policy-making bodies in each of the 31 EU/EEA Member States. Responses were entered into a structured database and validated by survey responders for final analysis. Results: Validated responses from all 31 EU/EEA NITAGs or equivalents showed that there is no common measles immunization policy for European immigrants. Policies vary widely from no policy at all (9 of 31, 29%) to vaccination of all comers (2 of 31, 6%), or vaccination of selected cohorts based on vaccination history (17 of 31, 55%) or serum antibody analysis (2 of 31, 6%). Further, the operational responsibilities for immigrant vaccination and documentation methods are not unified within the EU/EEA region. Conclusions: With some notable exceptions immunization policies to contain spread of infectious diseases through migration are either non-existent or vary widely between countries in the EU/EEA. With freedom of movement within the EU/EEA there ought to be harmonization and a common EU/EEA vaccination strategy to replace national policies for immigrant populations. PMID- 29136142 TI - The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance in myocarditis. AB - Aims: Foxo3 is a transcription factor involved in cell metabolism, survival, and inflammatory disease. However, mechanistic insight in Foxo3 effects is still limited. Here, we investigated the role of Foxo3 on natural killer (NK) cell responses and its effects in viral myocarditis. Methods and results: Effects of Foxo3 on viral load and immune responses were investigated in a model of coxsackie virus B3 myocarditis in wild-type (WT) and Foxo3 deficient mice. Reduced immune cell infiltration, viral titres, and pro-inflammatory cytokines in cardiac tissue were observed in Foxo3-/- mice 7 days post-infection (p.i.). Viral titres were also attenuated in hearts of Foxo3-/- mice at Day 3 while interferon gamma (IFNgamma) and NKp46 expression were up-regulated suggesting early viral control by enhanced NK cell activity. CD69 expression of NK cells, frequencies of CD11b+CD27+ effector NK cells and cytotoxicity of Foxo3-/- mice was enhanced compared to WT littermates. Moreover, microRNA-155 expression, essential in NK cell activation, was elevated in Foxo3-/- NK cells while its inhibition led to diminished IFNgamma production. Healthy humans carrying the longevity-associated FOXO3 single nucleotide polymorphism (SNP) rs12212067 exhibited reduced IFNgamma and cytotoxic degranulation of NK cells. Viral inflammatory cardiomyopathy (viral CMI) patients with this SNP showed a poorer outcome due to less efficient virus control. Conclusion: Our results implicate Foxo3 in regulating NK cell function and suggest Foxo3 playing an important role in the antiviral innate immunity. Thus, enhanced FOXO3 activity such as in the polymorphism rs12212067 may be protective in chronic inflammation such as cancer and cardiovascular disease but disadvantageous to control acute viral infection. PMID- 29136143 TI - Time-varying cycle average and daily variation in ambient air pollution and fecundability. AB - STUDY QUESTION: Does ambient air pollution affect fecundability? SUMMARY ANSWER: While cycle-average air pollution exposure was not associated with fecundability, we observed some associations for acute exposure around ovulation and implantation with fecundability. WHAT IS KNOWN ALREADY: Ambient air pollution exposure has been associated with adverse pregnancy outcomes and decrements in semen quality. STUDY DESIGN, SIZE, DURATION: The LIFE study (2005-2009), a prospective time-to-pregnancy study, enrolled 501 couples who were followed for up to one year of attempting pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Average air pollutant exposure was assessed for the menstrual cycle before and during the proliferative phase of each observed cycle (n = 500 couples; n = 2360 cycles) and daily acute exposure was assessed for sensitive windows of each observed cycle (n = 440 couples; n = 1897 cycles). Discrete-time survival analysis modeled the association between fecundability and an interquartile range increase in each pollutant, adjusting for co-pollutants, site, age, race/ethnicity, parity, body mass index, smoking, income and education. MAIN RESULTS AND THE ROLE OF CHANCE: Cycle-average air pollutant exposure was not associated with fecundability. In acute models, fecundability was diminished with exposure to ozone the day before ovulation and nitrogen oxides 8 days post ovulation (fecundability odds ratio [FOR] 0.83, 95% confidence interval [CI]: 0.72, 0.96 and FOR 0.84, 95% CI: 0.71, 0.99, respectively). However, particulate matter <=10 microns 6 days post ovulation was associated with greater fecundability (FOR 1.25, 95% CI: 1.01, 1.54). LIMITATIONS, REASONS FOR CAUTION: Although our study was unlikely to be biased due to confounding, misclassification of air pollution exposure and the moderate study size may have limited our ability to detect an association between ambient air pollution and fecundability. WIDER IMPLICATIONS OF THE FINDINGS: While no associations were observed for cycle-average ambient air pollution exposure, consistent with past research in the United States, exposure during critical windows of hormonal variability was associated with prospectively measured couple fecundability, warranting further investigation. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Longitudinal Investigation of Fertility and the Environment study contract nos. #N01-HD-3 3355, NO1-HD-#-3356, N01-HD-3-3358 and the Air Quality and Reproductive Health Study Contract No. HHSN275200800002I, Task Order No. HHSN27500008). We declare no conflict of interest. PMID- 29136144 TI - Antioxidants improve IVF outcome and subsequent embryo development in the mouse. AB - STUDY QUESTION: What is the effect of a combination of three antioxidants (Acetyl L-Carnitine, N-Acetyl-L-Cysteine and alpha-Lipoic Acid), present in IVF medium during mouse oocyte and sperm collection, on fertilization and subsequent IVF embryo development? SUMMARY ANSWER: A combination of antioxidants resulted in faster developmental times from the 2-cell stage through to expanded blastocyst stage, accompanied by a significant increase in blastocyst cell number and a reduction of intracellular hydrogen peroxide (H2O2) levels. WHAT IS KNOWN ALREADY: The antioxidant combination Acetyl-L-Carnitine, N-Acetyl-L-Cysteine and alpha-Lipoic Acid, when present in embryo culture media, has a significant beneficial effect on in vitro fertilized mouse pronucleate oocyte development, especially under oxidative stress. STUDY DESIGN, SIZE, DURATION: IVF was conducted with combined antioxidants supplemented in IVF medium that was used for mouse oocyte collection and fertilization (oocyte IVF medium, 4 h exposure) and sperm collection and preparation (sperm IVF medium, 1 h exposure). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: IVF was conducted under 20% oxygen, in the presence or absence of a combination of antioxidants (10 MUM Acetyl-L Carnitine, 10 MUM N-Acetyl-L-Cysteine, 5 MUM alpha-Lipoic Acid) and resultant embryos cultured with and without antioxidants under 20% oxygen. Subsequently, the effects of antioxidants on either oocytes or sperm was evaluated. Embryo development was analysed through time-lapse microscopy followed by differential nuclear staining to determine cell allocation in the blastocyst. Intracellular levels of H2O2 were assessed using an aryl boronate probe after 4 h of incubation with antioxidants. Controls were gametes and embryos that had no antioxidants in the medium. In a separate series of experiments, pronucleate oocytes were collected in handling medium with and without antioxidants for 20 min and subsequent cell numbers analysed. MAIN RESULTS AND THE ROLE OF CHANCE: Antioxidant treatment during both IVF and culture resulted in significantly faster development times to two cell cleavage (P < 0.01), which continued through to the expanded blastocyst stage (P < 0.05). Resultant blastocysts had a significant increase in both trophectoderm (TE) cell numbers, inner cell mass (ICM) and total cell numbers (P < 0.001). The addition of antioxidants to IVF medium or embryo culture media exclusively also resulted in a significant increase in both blastocyst TE and ICM numbers leading to an increase in total cell numbers (P < 0.001). Antioxidant supplementation of either oocyte IVF medium alone, or in both oocyte and sperm IVF medium, lead to significantly faster times to two cell cleavage, which continued through to the expanded blastocyst stage. Blastocyst cell number in both these groups had significantly higher TE cell numbers resulting in an increase in total cell numbers. In contrast, there were no differences in embryo developmental rates and blastocyst cell number when antioxidants were present only in the sperm IVF medium. Levels of H2O2 were significantly reduced in pronucleate oocytes that were cultured in the presence of antioxidants (P < 0.001) compared to control, untreated embryos. Similarly, pronucleate oocytes treated with the combined antioxidants during pronucleate oocyte collection resulted in significantly increased blastocyst ICM numbers compared with controls (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Embryo development was only examined in the mouse. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that supplementation of antioxidants to the IVF medium, as well as to embryo culture media, may further assist in maintaining the viability of human embryos in ART, conceivably through the reduction of oxidative stress. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by a research grant from Vitrolife AB (Sweden). The authors have no conflict of interest to declare. PMID- 29136145 TI - A two-step method for variable selection in the analysis of a case-cohort study. AB - Background: Accurate detection and estimation of true exposure-outcome associations is important in aetiological analysis; when there are multiple potential exposure variables of interest, methods for detecting the subset of variables most likely to have true associations with the outcome of interest are required. Case-cohort studies often collect data on a large number of variables which have not been measured in the entire cohort (e.g. panels of biomarkers). There is a lack of guidance on methods for variable selection in case-cohort studies. Methods: We describe and explore the application of three variable selection methods to data from a case-cohort study. These are: (i) selecting variables based on their level of significance in univariable (i.e. one-at-a time) Prentice-weighted Cox regression models; (ii) stepwise selection applied to Prentice-weighted Cox regression; and (iii) a two-step method which applies a Bayesian variable selection algorithm to obtain posterior probabilities of selection for each variable using multivariable logistic regression followed by effect estimation using Prentice-weighted Cox regression. Results: Across nine different simulation scenarios, the two-step method demonstrated higher sensitivity and lower false discovery rate than the one-at-a-time and stepwise methods. In an application of the methods to data from the EPIC-InterAct case cohort study, the two-step method identified an additional two fatty acids as being associated with incident type 2 diabetes, compared with the one-at-a-time and stepwise methods. Conclusions: The two-step method enables more powerful and accurate detection of exposure-outcome associations in case-cohort studies. An R package is available to enable researchers to apply this method. PMID- 29136146 TI - The ABC death risk score: is it time to start measuring GDF-15? PMID- 29136147 TI - Antibiotic susceptibility of clinical Legionella pneumophila serogroup 1 strains isolated in Germany. PMID- 29136148 TI - Legal but limited? Abortion service availability and readiness assessment in Nepal. AB - The government of Nepal revised its law in 2002 to allow women to terminate a pregnancy up to 12 weeks gestation for any indication on request, and up to 18 weeks if certain conditions are met. We evaluated the readiness of facilities in Nepal to provide three abortion services, manual vacuum aspiration (MVA), medication abortion (MA) and post-abortion care (PAC), using the service availability and readiness assessment (SARA) framework. The framework consists broadly of three domains; service availability, general service readiness and service readiness specific to individual services (i.e. service-specific readiness). We applied the framework to data from the Nepal Health Facility Survey 2015, a nationally representative survey of 992 health facilities. Overall, we find that access to safe abortion remains limited in Nepal. Of the facilities that reported offering delivery services and were thus eligible to provide safe abortion services, 44.5, 36.0 and 25.6% had provided any MVA, MA or PAC services, respectively, in the 3 months prior to the survey, and <2% were 'ready' to provide any abortion service based on our application of the SARA criteria for service-specific readiness. Among only the facilities that reported providing an abortion service in the 3 months prior to the survey, 3.2% of facilities that provided MVA, 1.5% of facilities that provided MA and 1.1% of the facilities that provided PAC had all the components of care required. Although the private sector conducted approximately half of all abortion services provided in the 3 months prior to the survey, no private sector facilities had all the abortion service-specific readiness components. Results suggest that accessing safe abortion services remains a significant challenge for Nepalese women, despite a set of permissive laws. PMID- 29136149 TI - Pesticide use in agriculture and Parkinson's disease in the AGRICAN cohort study. AB - Background and Aim: Epidemiological studies have reported an increased risk of Parkinson's disease (PD) in farmers exposed to pesticides, but no clear conclusion can be drawn on the type of pesticide and duration of use associated with an effect. In the French agricultural cohort AGRICAN, we assessed associations between PD and pesticide use according to the types of livestock and crops grown, including exposure to some active ingredients with duration of use. Methods: Self-reported PD and history of lifetime exposure to 13 crops and 5 types of animals and pesticide use were collected at enrolment (2005-07) among 181 842 participants. Exposure to selected active ingredients and duration of use lifelong were assessed with the crop-exposure matrix PESTIMAT. Associations between pesticide use and PD were estimated by logistic regression according to crops and livestock, adjusted for sex, age, educational level, smoking status and alcohol consumption. Results: PD was reported by 1732 subjects (1.2%) at enrolment in the cohort. Pesticide use lifelong was associated with an increased risk of PD in all types of activities [odds ratio (OR) = 1.31 (cattle) to 1.79 (peas), P < 0.05]. Rotenone, diquat, paraquat and several dithiocarbamates were associated with an increased risk of PD [OR = 1.31 (cuprobam) to 1.57 (rotenone)], especially in farmers with the longest exposure. Conclusions: Our work suggests that the risk of PD is increased in farmers exposed to pesticides on several French crops and livestock, and supports additional evidence of an association of PD with dithiocarbamate fungicides, rotenone and the herbicides diquat and paraquat. PMID- 29136150 TI - Using Value Stream Mapping to improve quality of care in low-resource facility settings. AB - Quality problem or issue: Jacaranda Health (JH) is a Kenya-based organization that attempts to provide affordable, high-quality maternal and newborn healthcare through a chain of private health facilities in Nairobi. Initial assessment: JH needed to adopted quality improvement as an organization-wide strategy to optimize effectiveness and efficiency. Choice of solution: Value Stream Mapping, a Lean Management tool, was used to engage staff in prioritizing opportunities to improve clinical outcomes and patient-centered quality of care. Implementation: Implementation was accomplished through a five-step process: (i) leadership engagement and commitment; (ii) staff training; (iii) team formation; (iv) process walkthrough; and (v) construction and validation. Evaluation: The Value Stream Map allowed the organization to come together and develop an end-to-end view of the process of care at JH and to select improvement opportunities for the entire system. Lessons learned: The Value Stream Map is a simple visual tool that allows organizations to engage staff at all levels to gain commitment around quality improvement efforts. PMID- 29136151 TI - Emergence of multiple carbapenemase-producing organisms in single patients: an increasing threat to treatment of infection. PMID- 29136152 TI - Concomitant thoracoscopic surgery for solitary pulmonary nodule and atrial fibrillation. AB - OBJECTIVES: The incidence of both solitary pulmonary nodules (SPN) and non valvular atrial fibrillation (NVAF) has increased over the past decade. We performed concomitant video-assisted thoracoscopic surgery with modified epicardial radiofrequency ablation procedure for NVAF and SPN resection. METHODS: Sixteen patients (7 men, mean age 62.6 +/- 11.2 years) with SPN and NVAF underwent this procedure. Of these patients, 10 had paroxysmal atrial fibrillation and 6 persistent atrial fibrillation. A modified epicardial radiofrequency ablation combined with pulmonary vein isolation, circumferential left atrial ablation, ganglionic plexus ablation and left atrial appendage resection was performed for all patients. Left pulmonary surgery was carried out subsequently. RESULTS: The mean procedure duration was 203.1 +/- 15.6 (range 177 224) min. All patients successfully underwent this procedure with no conversion to sternotomy or pacemaker implantation. Of the 16 included patients, 13 received lobectomy and 3 received wedge resection. No severe complications occurred postoperatively. The mean length of hospital stay was 9.1 +/- 1.4 (range 7-11) days with a mean follow-up period of 18.7 +/- 6.7 (range 8-32) months. One patient had AF recurrence 6 months postoperatively. No pulmonary vein stenosis was detected at the 3rd postoperative month. There were no deaths or thromboembolic events during follow-up. CONCLUSIONS: This concomitant therapy proved to be safe and yielded good clinical outcomes. Therefore, it deserves to be considered as a treatment for patients with SPN and NVAF. PMID- 29136153 TI - Reverse NCX Attenuates Cellular Sodium Loading in Metabolically Compromised Cortex. AB - In core regions of ischemic stroke, disruption of blood flow causes breakdown of ionic gradients and, ultimately, calcium overload and cell death. In the surrounding penumbra, cells may recover upon reperfusion, but recovery is hampered by additional metabolic demands imposed by peri-infarct depolarizations (PIDs). There is evidence that sodium influx drives PIDs, but no data exist on PID-related sodium accumulations in vivo. Here, we found that PIDs in mouse neocortex are associated with propagating sodium elevations in neurons and astrocytes. Similar transient sodium elevations were induced in acute tissue slices by brief chemical ischemia. Blocking NMDA-receptors dampened sodium and accompanying calcium loads of neurons in tissue slices, while inhibiting glutamate transport diminished sodium influx into astrocytes, but amplified neuronal sodium loads. In both cell types, inhibition of sodium/calcium exchange (NCX) increased sodium transients. Blocking NCX also significantly reduced calcium transients, a result confirmed in vivo. Our study provides the first quantitative data on sodium elevations in peri-infarct regions in vivo. They suggest that sodium influx drives reversal of NCX, triggering a massive secondary calcium elevation while promoting export of sodium. Reported neuroprotective effects of NCX activity in stroke models might thus be related to its dampening of ischemia-induced sodium loading. PMID- 29136154 TI - The number of oocytes retrieved during IVF: a balance between efficacy and safety. AB - STUDY QUESTION: What is the relationship between the number of oocytes collected in fresh IVF treatments and the likelihood of cumulative delivery rate (fresh and frozen) per oocyte aspiration, severe ovarian hyperstimulation syndrome (OHSS) and thromboembolic events? SUMMARY ANSWER: Cumulative delivery rate per aspiration increases up to 20 oocytes retrieved and then evens out while the incidence of severe OHSS increases more rapidly from around 18 oocytes and thromboembolic events, although rare, occurs in particular if 15 or more oocytes are retrieved. WHAT IS KNOWN ALREADY?: Previous studies have shown that the number of oocytes retrieved for IVF is a positive predictor of live birth in fresh cycles. Few studies have investigated cumulative live birth rates and OHSS in relation to the number of aspirated oocytes. STUDY DESIGN, SIZE, DURATION: Retrospective population-based registry study including 39 387 women undergoing 77 956 fresh IVF cycles in the period 2007-2013 and 36 270 consecutive transfers of frozen/thawed embryos in the period 2007-2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from The Swedish National Quality Registry of Assisted Reproduction (Q-IVF) including all IVF cycles with oocyte retrieval performed in public or private infertility clinics during the study period, was cross-linked to the National Patient Register regarding diagnostic codes (ICD 10) for severe (OHSS) and thromboembolic events. Oocyte donation cycles were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth delivery rate in fresh cycles increased up to 11 oocytes retrieved and then evened out, where the live birth rate was 30.3% for a 34-year-old woman. The cumulative delivery rate per aspiration, including fresh transfer and all subsequent transfers of frozen thawed embryos (FET cycles) per oocyte retrieval, increased up to approximately 20 oocytes where it reached 45.8%. The adjusted odds ratio (AOR) for live birth by the number of oocytes was 1.064 (95% CI: 1.061; 1.067). The incidence of severe OHSS increased significantly by the number of oocytes, particularly if more than 18 oocytes were retrieved. The AOR for OHSS by the number of oocytes was 1.122 (95% CI: 1.08; 1.137). Thromboembolic events were rare, a total of 16 events in 14 patients were observed, and occurred in particular if 15 or more oocytes were retrieved. LIMITATIONS, REASONS FOR CAUTION: All FET cycles might not be included. Some embryos cryopreserved between 2010 and 2013 might still result in additional births until 2018. Furthermore the gonadotrophin dose was not included in the Q-IVF Registry in the study period, thus adjustment for dose was not possible. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest a shift at approximately 18-20 oocytes where the cumulative delivery rate per aspiration levels off and, at the same time, the incidence of severe OHSS increases more rapidly. Thromboembolic events, although rare, should also be taken into consideration at stimulation regimes for IVF. Evaluating data taking both efficacy and the most serious safety aspects into account, is a new approach and of crucial importance both for patients undergoing IVF and their physicians. STUDY FUNDING/COMPETING INTEREST: Financial support was received through an agreement relating to research and the education of doctors (ALFGBG-70 940) and grant from the Hjalmar Svensson Research Foundation. None of the authors declares any conflict of interest. PMID- 29136155 TI - A model-informed preclinical approach for prediction of clinical pharmacodynamic interactions of anti-TB drug combinations. AB - Background: Identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting for many reasons. The aim of this work was to develop a model-informed preclinical approach for prediction of clinical pharmacodynamic drug interactions in order to inform early anti-TB drug development. Methods: In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The multistate TB pharmacometric (MTP) model was used to characterize the natural growth and exposure-response relationships of each drug after mono exposure. Pharmacodynamic interactions during combination exposure were characterized by linking the MTP model to the general pharmacodynamic interaction (GPDI) model with successful separation of the potential effect on each drug's potency (EC50) by the combining drug(s). Results: All combinations showed pharmacodynamic interactions at cfu level, where all combinations, except isoniazid plus ethambutol, showed more effect (synergy) than any of the drugs alone. Using preclinical information, the MTP-GPDI modelling approach was shown to correctly predict clinically observed pharmacodynamic interactions, as deviations from expected additivity. Conclusions: With the ability to predict clinical pharmacodynamic interactions, using preclinical information, the MTP-GPDI model approach outlined in this study constitutes groundwork for model-informed input to the development of new and enhancement of existing anti-TB combination regimens. PMID- 29136156 TI - Increase in antimicrobial resistance and emergence of major international high risk clonal lineages in dogs and cats with urinary tract infection: 16 year retrospective study. AB - Objectives: To evaluate temporal trends in antimicrobial resistance, over 16 years, in bacteria isolated from dogs and cats with urinary tract infection (UTI) and the clonal lineages of bacteria harbouring critical antimicrobial resistance mechanisms. Methods: Antimicrobial susceptibility testing was conducted for 948 bacteria isolated from dogs and cats with UTI (1999-2014). Resistance mechanisms were detected by PCR, namely ESBL/AmpC in third-generation cephalosporin (3GC) resistant Escherichia coli and Proteus mirabilis, mecA in methicillin-resistant staphylococci, and aac(6')-Ieaph(2")-Ia and aph(2")-1d in high-level gentamicin resistant (HLGR) enterococci. Resistant bacteria were typed by MLST, and temporal trends in E. coli and Enterobacteriaceae antimicrobial resistance were determined by logistic regression. Results: Enterobacteriaceae had a significant temporal increase in resistance to amoxicillin/clavulanate, 3GCs, trimethoprim/sulfamethoxazole, fluoroquinolones, gentamicin and tetracycline (P < 0.001). An increase in MDR was also detected (P < 0.0001). 3GC resistance was mainly caused by the presence of blaCTX-M-15 and blaCMY-2 in E. coli and the presence of blaCMY-2 in P. mirabilis. Two major 3GC-resistant E. coli clonal lineages were detected: O25b:H4-B2-ST131 and ST648. The mecA gene was detected in 9.2% (n = 11/119) of Staphylococcus spp., including MRSA clonal complex (CC) 5 (n = 2) and methicillin-resistant Staphylococcus epidermidis CC5 (n = 4). A temporal increase in MDR methicillin-resistant Staphylococcus pseudintermedius was detected (P = 0.0069). Some ampicillin-resistant and/or HLGR Enterococcus spp. were found to belong to hospital-adapted CCs, namely Enterococcus faecalis ST6 CC6 (n = 1) and Enterococcus faecium CC17 (n = 8). Conclusions: The temporal increase in antimicrobial resistance and in MDR bacteria causing UTI in dogs and cats creates important therapeutic limitations in veterinary medicine. Furthermore, the detection of MDR high-risk clonal lineages raises public health concerns since companion animals with UTI may contribute to the spread of such bacteria. PMID- 29136157 TI - Depletion of recombination-specific cofactors by the C-terminal mutant of the activation-induced cytidine deaminase causes the dominant negative effect on class switch recombination. AB - Activation-induced cytidine deaminase (AID) is essential for class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes. Studies on in vitro mutagenized AID as well as its mutations in human patients with hyper-IgM (HIGM)-syndrome type II revealed that C-terminal AID mutations were defective in CSR whereas their DNA cleavage and SHM activities remained intact. The C-terminal mutants of AID were speculated to exert the dominant negative effect on wild-type (WT) AID whereas its mechanism remains unknown. We generated the JP41 (R190X) mutation in one allele and a null mutation on the other allele in a mouse B cell line (CH12F3-2A) using CRISPR/Cas9 genome-editing tools and studied the effect of JP41 expression on the function of exogenously introduced WT AID fused with estrogen receptor (AIDER) in AIDJP41/?/AIDER CH12F3 2A cells. We found that JP41 expression strongly suppressed not only CSR but also Igh/c-Myc chromosomal translocations by AIDER. We showed that the dominant negative effect is not evident at the DNA cleavage step but obvious at both deletional and inversional recombination steps. We also confirmed the dominant negative effect of other C-terminal mutants, JP8Bdel (R183X) and P20 (34-aa insertion at residue 182) in AID-deficient spleen B cells. Finally, we showed that the expression of JP41 reduced the binding of AIDER with its cofactors (hnRNP L, SERBP1 and hnRNP U). Together, these data indicate that dominant negative effect of JP41 on CSR is likely due to the depletion of the CSR-specific RNA-binding proteins from WT AID. PMID- 29136158 TI - Corrigendumto: Identifying multi-level culturally appropriate smoking cessation strategies for Aboriginal health staff: a concept mapping approach. PMID- 29136159 TI - Associations between maternal lifestyle factors and neonatal body composition in the Screening for Pregnancy Endpoints (Cork) cohort study. AB - Background: Neonatal body composition likely mediates fetal influences on life long chronic disease risk. A better understanding of how maternal lifestyle is related to newborn body composition could thus inform intervention efforts. Methods: Using Cork participant data (n = 1754) from the Screening for Pregnancy Endpoints (SCOPE) cohort study [ECM5(10)05/02/08], we estimated how pre-pregnancy body size, gestational weight gain, exercise, alcohol, smoking and diet were related to neonatal fat and fat-free mass, as well as length and gestational age at birth, using quantile regression. Maternal factors were measured by a trained research midwife at 15 gestational weeks, in addition to a 3rd trimester weight measurement used to calculate weight gain. Infant body composition was measured using air-displacement plethysmography. Results: Healthy (versus excess) gestational weight gain was associated with lower median fat-free mass [-112 g, 95% confidence interval (CI): -47 to -176) and fat mass (-33 g, 95% CI: -1 to 65) in the offspring; and a 103 g decrease in the 95th centile of fat mass (95% CI: -33 to -174). Maternal normal weight status (versus obesity) was associated with lower median fat mass (-48 g, 95% CI: -12 to -84). At the highest centiles, fat mass was lower among infants of women who engaged in frequent moderate intensity exercise early in the pregnancy (-92 g at the 95th centile, 95% CI: 168 to -16). Lastly, women who never smoked tended to have longer babies with more fat mass and fat-free mass. No other lifestyle factors were strongly related to infant body composition. Conclusions: These results suggest that supporting healthy maternal lifestyles could reduce the risk of excess fat accumulation in the offspring, without adversely affecting fat-free mass development, length or gestational age. PMID- 29136160 TI - Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis. AB - Objectives: To calculate the clavulanic acid exposure of oral amoxicillin/clavulanic acid dosing regimens, to investigate variability using a population pharmacokinetic model and to explore target attainment using Monte Carlo simulations. Methods: Two groups of healthy male volunteers received amoxicillin/clavulanic acid tablets at the start of a standard meal on two separate days 1 week apart. One group (n = 14) received 875/125 mg q12h and 500/125 mg q8h and the other group (n = 15) received 500/125 mg q12h and 250/125 mg q8h. In total, 1479 blood samples were collected until 8-12 h after administration. Concentrations were analysed using non-compartmental (WinNonLin) and population pharmacokinetic (NONMEM) methods. Results: Median Cmax and AUC0-8 were 2.21 mg/L (0.21-4.35) and 4.99 mg.h/L (0.44-8.31), respectively. In 40/58 daily concentration-time profiles, Cmax and AUC0-8 of the morning dose were higher than with later doses. The final population model included a lag time (0.447 h), first-order absorption (3.99 h-1 at 8:00 h, between-subject variability 52.8%, between-occasion variability 48.5%), one distribution compartment (33.0 L, between-subject variability 23.9%) and first-order elimination (24.6 L/h, between-subject variability 26.7%). Bioavailability (fixed at 1 at 8:00 h, between-occasion variability 28.2%) and absorption rate decreased over the day. For 97.5% of the simulated population after 125 mg q12h or q8h, %fT > Ct at 0.5 mg/L was 8.33% (q12h) and 15.2% (q8h), %fT > Ct at 1 mg/L was 0% (q12h + q8h), and fAUC0-24 was 3.61 (q12h) and 5.56 (q8h) mg.h/L. Conclusions: Clavulanic acid absorption in healthy volunteers is highly variable. Bioavailability and absorption rate decrease over the day. The model developed here may serve to suggest clavulanic acid dosing regimens to optimize efficacy and prevent underdosing. PMID- 29136161 TI - Trends and Predictors of Syphilis Prevalence in the General Population: Global Pooled Analyses of 1103 Prevalence Measures Including 136 Million Syphilis Tests. AB - Background: This study assessed levels, trends, and associations of observed syphilis prevalence in the general adult population using global pooled analyses. Methods: A standardized database of syphilis prevalence was compiled by pooling systematically gathered data. Random-effects meta-analyses and meta-regressions were conducted using data from the period 1990-2016 to estimate pooled measures and assess predictors and trends. Countries were classified by World Health Organization region. Sensitivity analyses were conducted. Results: The database included 1103 prevalence measures from 136 million syphilis tests across 154 countries (85% from women in antenatal care). Global pooled mean prevalence (weighted by region population size) was 1.11% (95% confidence interval [CI], .99 1.22). Prevalence predictors were region, diagnostic assay, sample size, and calendar year interacting with region. Compared to the African Region, the adjusted odds ratio (AOR) was 0.42 (95% CI, .33-.54) for the Region of the Americas, 0.13 (95% CI, .09-.19) for the Eastern Mediterranean Region, 0.05 (95% CI, .03-.07) for the European Region, 0.21 (95% CI, .16-.28) for the South-East Asia Region, and 0.41 (95% CI, .32-.53) for the Western Pacific Region. Treponema pallidum hemagglutination assay (TPHA) only or rapid plasma reagin (RPR) only, compared with dual RPR/TPHA diagnosis, produced higher prevalence (AOR >1.26), as did smaller sample-size studies (<500 persons) (AOR >2.16). Prevalence declined in all regions; the annual AORs ranged from 0.84 (95% CI, .79-.90) in the Eastern Mediterranean to 0.97 (95% CI, .97-1.01) in the Western Pacific. The pooled mean male-to-female prevalence ratio was 1.00 (95% CI, .89-1.13). Sensitivity analyses confirmed robustness of results. Conclusions: Syphilis prevalence has declined globally over the past 3 decades. Large differences in prevalence persist among regions, with the African Region consistently the most affected. PMID- 29136162 TI - Differences in Taste Perception and Spicy Preference: A Thai-Japanese Cross cultural Study. AB - Taste perception is influenced by several factors. However, the relation between taste perception and food culture is unclear. This study compared taste thresholds between populations with different food culture, i.e. Thai and Japanese. A matched case-control study was conducted in 168 adults (84 for each; aged between 50 and 90 years). The age, sex, systemic disease, medication, smoking, xerostomia, and oral hygiene of both groups were not different. Recognition thresholds (RTs) of sweet, salty, sour, bitter, and umami were measured using filter paper disc (FPD). Detection taste thresholds were measured using electrogustometry. Spicy preference was measured by calibrated questionnaires. Higher RTs of all tastes and higher detection taste thresholds were found in Thai as compared to those of Japanese (P < 0.0001). Separate analyses of healthy and unhealthy persons confirmed the significant differences between 2 countries. The average thresholds for sweet, salty, sour, and bitter in Thai and Japanese were 4 and 2, respectively. The average threshold for umami in Thai and Japanese was 5 and 3, respectively. Moreover, Thai population had stronger preference for spicy food (P < 0.0001) with 70% mild- or moderate and 10% strong lovers, compared to over 90% non- or mild-spicy lovers in Japanese. In addition, 70% of Thai consumed spicy food weekly, whilst 80% of Japanese consumed it monthly. Our findings suggested that population with stronger spicy preference such as Thai had much poorer taste sensitivity and perception than that with milder preference like Japanese. Extensive international survey is needed to conclude the influence of food culture on taste perception. PMID- 29136163 TI - Ascaris Suum Infection Downregulates Inflammatory Pathways in the Pig Intestine In Vivo and in Human Dendritic Cells In Vitro. AB - Ascaris suum is a helminth parasite of pigs closely related to its human counterpart, A. lumbricoides, which infects almost 1 billion people. Ascaris is thought to modulate host immune and inflammatory responses, which may drive immune hyporesponsiveness during chronic infections. Using transcriptomic analysis, we show here that pigs with a chronic A. suum infection have a substantial suppression of inflammatory pathways in the intestinal mucosa, with a broad downregulation of genes encoding cytokines and antigen-processing and costimulatory molecules. A. suum body fluid (ABF) suppressed similar transcriptional pathways in human dendritic cells (DCs) in vitro. DCs exposed to ABF secreted minimal amounts of cytokines and had impaired production of cyclooxygengase-2, altered glucose metabolism, and reduced capacity to induce interferon-gamma production in T cells. Our in vivo and in vitro data provide an insight into mucosal immune modulation during Ascaris infection, and show that A. suum profoundly suppresses immune and inflammatory pathways. PMID- 29136164 TI - Habitat Heterogeneity, Host Population Structure, and Parasite Local Adaptation. AB - Reciprocal-transplant experiments have proven to be a powerful tool for detecting local adaptation (LA). More recently, reciprocal cross-inoculation experiments have been used to evaluate adaptation by parasites to their local host populations. These experiments are conceptually similar to reciprocal-transplant experiments, except that the "environment" (the host population) may have evolved in response to changes in the parasite population. Here, I use analytical tools and computer simulations to determine when parasites would be expected to be more infective to their local host populations than to allopatric host populations. The models assume that parasites have to genetically "match" their hosts in order to infect. I also assumed that different host clones were favored in different populations. When parasite virulence was low, clonal selection outweighed parasite-mediated selection, leading to low host diversity within populations and strong LA by parasites. At intermediate levels of virulence, parasite-mediated selection maintained high levels of host diversity within populations, which reduced or eliminated parasite LA. The loss of parasite LA was not associated with increased infectivity by parasites on allopatric hosts. Instead, the loss of LA was due to a reduction in infectivity of parasites on sympatric hosts. Finally, at high levels of parasite virulence, parasite-mediated selection led to oscillatory host dynamics and weak local adaption by parasites. Across all levels of virulence, the strength of parasite LA closely tracked the degree of host population structure (GST). PMID- 29136165 TI - Low-dose electron energy-loss spectroscopy using electron counting direct detectors. AB - Since the development of parallel electron energy loss spectroscopy (EELS), charge-coupled devices (CCDs) have been the default detectors for EELS. With the recent development of electron-counting direct-detection cameras, micrographs can be acquired under very low electron doses at significantly improved signal-to noise ratio. In spectroscopy, in particular in combination with a monochromator, the signal can be extremely weak and the detection limit is principally defined by noise introduced by the detector. Here we report the use of an electron counting direct-detection camera for EEL spectroscopy. We studied the oxygen K edge of amorphous ice and obtained a signal noise ratio up to 10 times higher than with a conventional CCD.We report the application of electron counting to record time-resolved EEL spectra of a biological protein embedded in amorphous ice, revealing chemical changes observed in situ while exposed by the electron beam. A change in the fine structure of nitrogen K and the carbon K edges were recorded during irradiation. A concentration of 3 at% nitrogen was detected with a total electron dose of only 1.7 e-/A2, extending the boundaries of EELS signal detection at low electron doses. PMID- 29136166 TI - Diabetes-induced hyperglycemia impairs male reproductive function: a systematic review. AB - BACKGROUND: Hyperglycemia can result from a loss of pancreatic beta-cells or a decline in their function leading to decreased insulin secretion or may arise from insulin resistance and variable degrees of inadequate insulin secretion resulting in diabetes and related comorbidities. To date several reviews have addressed the issue of diabetes-related male infertility but most have focused on how metabolic syndrome causes the decline in male fertility. However, a comprehensive overview as to how diabetes-induced hyperglycemia impairs male fertility is missing. Impaired regulation of glucose and the resultant hyperglycemia are major threats to the health of individuals in modern societies especially given the rapidly rising prevalence affecting an increasing number of men in their reproductive years. Consequently, diabetes-induced hyperglycemia is likely to contribute to a decline in global birth rates especially in those societies with a high diabetic prevalence. OBJECTIVE AND RATIONALE: This systematic review addresses and summarizes the impact of hyperglycemia on male reproductive health with a particular emphasis on the molecular mechanisms that influence the testis and other parts of the male reproductive tract. SEARCH METHODS: A systematic search of the literature published in the MEDLINE-Pubmed database (http://www.ncbi.nlm.nih.gov/pubmed) and Cochrane Library (http://www.cochranelibrary.com) was performed, as well as hand searching reference lists, from the earliest available online indexing year until May 2017, using diabetes- and male fertility-related keywords in combination with other search phrases relevant to the topic of hyperglycemia. Inclusion criteria were: clinical studies on type 1 diabetic (T1D) men and studies on T1D animal models with a focus on reproductive parameters. Case reports/series, observational studies and clinical trials were included. Studies on patients with type 2 diabetes (T2D) or animal models of T2D were excluded to distinguish hyperglycemia from other metabolic effects. OUTCOMES: A total of 890 articles were identified of which 197 (32 clinical, 165 animal studies) were selected for qualitative analysis. While the clinical data from men with hyperglycemia-induced reproductive dysfunction were reported in most studies on T1D, the study designs were variable and lacked complete information on patients. Moreover, only a few studies (and mostly animal studies) addressed the underlying mechanisms of how hyperglycemia induces infertility. Potential causes included impaired function of the hypothalamic-pituitary-gonadal axis, increased DNA damage, perturbations in the system of advanced glycation endproducts and their receptor, oxidative stress, increased endoplasmatic reticulum stress, modulation of cellular pathways, impaired mitochondrial function and disrupted sympathetic innervation. However, intervention studies to identify and confirm the pathological mechanisms were missing: data that are essential in understanding these interactions. WIDER IMPLICATIONS: While the effects of regulating the hyperglycemia by the use of insulin and other modulators of glucose metabolism have been reported, more clinical trials providing high quality evidence and specifically addressing the beneficial effects on male reproduction are required. We conclude that interventions using insulin to restore normoglycemia should be a feasible approach to assess the proposed underlying mechanisms of infertility. PMID- 29136167 TI - Juvenile-Onset Recurrent Respiratory Papillomatosis: The Benefits of Quadrivalent Human Papillomavirus Vaccination Continue to Accrue. PMID- 29136168 TI - A Prospective Study of the Incidence of Juvenile-Onset Recurrent Respiratory Papillomatosis After Implementation of a National HPV Vaccination Program. AB - Background: Recurrent respiratory papillomatosis is a rare but morbid disease caused by human papillomavirus (HPV) types 6 and 11. Infection is preventable through HPV vaccination. Following an extensive quadrivalent HPV vaccination program (females 12-26 years in 2007-2009) in Australia, we established a method to monitor incidence and demographics of juvenile-onset recurrent respiratory papillomatosis (JORRP) cases. Methods: The Australian Paediatric Surveillance Unit undertakes surveillance of rare pediatric diseases by contacting practitioners monthly. We enrolled pediatric otorhinolaryngologists and offered HPV typing. We report findings for 5 years to end 2016. Results: The average annual incidence rate was 0.07 per 100000. The largest number of cases was reported in the first year, with decreasing annual frequency thereafter. Rates declined from 0.16 per 100000 in 2012 to 0.02 per 100000 in 2016 (P = .034). Among the 15 incident cases (60% male), no mothers were vaccinated prepregnancy, 20% had maternal history of genital warts, and 60% were first born; 13/15 were born vaginally. Genotyped cases were HPV-6 (n = 4) or HPV-11 (n = 3). Conclusion: To our knowledge, this is the first report internationally documenting decline in JORRP incidence in children following a quadrivalent HPV vaccination program. PMID- 29136169 TI - Disparagement of health warning labels on cigarette packages and cessation attempts: results from four countries. AB - Health warning labels (HWLs) on cigarette packs that use strong fear appeals may evoke defensive responses including acts of disparaging the warnings. Whether warning disparagement undermines HWL effectiveness remains unclear. We assessed correlates of one type of HWL disparagement and its association with subsequent cessation attempts. Longitudinal data (2012-14) on adult smokers from Australia, Canada, Mexico and the United States (US) were analyzed. HWL disparagement was assessed as the frequency of making fun of HWLs in the past month. Using Generalized Estimating Equation models we estimated correlates of HWL disparagement and whether HWL disparagement predicted subsequent cessation attempts. In each country, across all waves, 24-31% of smokers reported making fun of the warnings at least once in the past month. More frequent disparagement was found among males, younger participants, those with higher education and greater addiction, and those who recently attempted to quit. Attention to, avoidance of and talking to others about HWLs were all positively associated with HWL disparagement. In all countries, except the US, this type of HWL disparagement was an independent predictor of subsequent cessation attempts. HWL disparagement among smokers may indicate greater warning relevance and processing and does not result in counterproductive effects on cessation efforts. PMID- 29136170 TI - Corrigendum: The social determinants of lesbian, gay, bisexual and transgender youth suicidality in England: a mixed methods study. PMID- 29136171 TI - Mating System and Effective Population Size of the Overexploited Neotropical Tree (Myroxylon peruiferum L.f.) and Their Impact on Seedling Production. AB - The reproductive system of a tree species has substantial impact on genetic diversity and structure within and among natural populations. Such information, should be considered when planning tree planting for forest restoration. Here, we describe the mating system and genetic diversity of an overexploited Neotropical tree, Myroxylon peruiferum L.f. (Fabaceae) sampled from a forest remnant (10 seed trees and 200 seeds) and assess whether the effective population size of nursery grown seedlings (148 seedlings) is sufficient to prevent inbreeding depression in reintroduced populations. Genetic analyses were performed based on 8 microsatellite loci. M. peruiferum presented a mixed mating system with evidence of biparental inbreeding (t^m-t^s = 0.118). We found low levels of genetic diversity for M. peruiferum species (allelic richness: 1.40 to 4.82; expected heterozygosity: 0.29 to 0.52). Based on Ne(v) within progeny, we suggest a sample size of 47 seed trees to achieve an effective population size of 100. The effective population sizes for the nursery-grown seedlings were much smaller Ne = 27.54-34.86) than that recommended for short term Ne >= 100) population conservation. Therefore, to obtain a reasonable genetic representation of native tree species and prevent problems associated with inbreeding depression, seedling production for restoration purposes may require a much larger sampling effort than is currently used, a problem that is further complicated by species with a mixed mating system. This study emphasizes the need to integrate species reproductive biology into seedling production programs and connect conservation genetics with ecological restoration. PMID- 29136172 TI - Assessing the contraceptive supply environment in Kinshasa, DRC: trend data from PMA2020. AB - Performance Monitoring and Accountability 2020 (PMA2020) is a population-based and facility-based survey program conducted in 11 countries to track contraceptive use dynamics and the supply environment. Annual data collection provides trend data unavailable from any other source. Two-stage cluster sampling was used to select 58 enumeration areas in Kinshasa; data were collected in 2014, 2015 and 2016 from three to six service delivery points (SDPs) per EA. Of the 228 248 SDPs surveyed each year, only two-thirds reported to offer family planning (FP) services. Of those reporting to offer FP, one-fifth or more did not do so on the day of the survey. As of 2016, only one-half of SDPs offering FP had at least three methods available, a proxy for contraceptive choice; only one in five had at least five methods. Long-acting reversible contraceptives, including implants and IUDs, were less widely offered and more often stocked out than resupply methods, including condoms, pills and injectables. Contraceptive stockouts were rampant: in 2016, over a quarter of the SDPs experienced stockouts of all methods (except condoms) in the previous 3 months, and two of the three most widely used methods-implants and injectables-were also the most likely to be stocked out. The findings documented the inconsistency in pricing of methods across facilities; moreover, less than one quarter of SDPs posted prices. Patterns in the contraceptive supply environment remained relatively unchanged between 2014 and 2016. The PMA2020 SDP module provides timely, actionable information to the DRC government, FP implementing organizations and donors involved in FP service delivery in Kinshasa, DRC. Yet the value of this information will be determined by the ability of the local FP stakeholders to use it in bringing the needed improvements identified by this survey to the contraceptive supply environment. PMID- 29136173 TI - High levels of GSK-3beta signalling reduce osteogenic differentiation of stem cells in osteonecrosis of femoral head. AB - Osteonecrosis of the femoral head (ONFH) is a common but intractable disease. In this study, we investigated the mechanisms regulating alterations in mesenchymal stem cell (MSC) differentiation in ONFH. Five patients who were diagnosed with ONFH were enrolled in this study. Bone MSCs (BMSCs) were isolated from the osteonecrotic zone in the femoral head (FH-pMSCs) and from the normal zone in the pelvis (hMSCs) of the same patient. Morphology, cell proliferation and expression of mediators of the Wnt signalling pathway were evaluated. There were significant differences in cell proliferation and expression of surface markers between the two populations of cells. FH-pMSCs exhibited significantly lower osteogenic differentiation compared with hMSCs (P < 0.0001). Dissection of the Wnt pathway showed that FH-pMSCs had significantly higher GSK3beta expression compared with hMSCs (P < 0.001). Addition of LiCl, a GSK3beta inhibitor, significantly increased osteogenic differentiation in FH-pMSCs, suggesting a relationship between the microenvironment and regulation of stem cell behaviour in ONFH. FH pMSCs also exhibited significant downregulation of other mediators of the Wnt signalling pathway, including runx2 and beta-catenin. Our data suggested that mediators of the Wnt signalling pathway, such as GSK3beta could be important therapeutic targets for early-stage ONFH. PMID- 29136174 TI - Partner switching for Ran during the mitosis dance. PMID- 29136176 TI - Mutations in MetG (methionyl-tRNA synthetase) and TrmD [tRNA (guanine-N1) methyltransferase] conferring meropenem tolerance in Burkholderia thailandensis. AB - Objectives: Although meropenem is widely used to treat Burkholderia infections, the response of Burkholderia pathogens to this antibiotic is largely unexplored. Methods: Burkholderia thailandensis, a model for Burkholderia spp., particularly Burkholderia mallei and Burkholderia pseudomallei, was challenged with a lethal level of meropenem and survivors were isolated. The genomes of two of the isolates were analysed to identify mutated genes and these genes were then specifically examined in more isolates to profile mutation diversity. Mutants were characterized to investigate the biological basis underlying survival against meropenem. Results: One of two genes associated with tRNA metabolism [metG or trmD, encoding methionyl-tRNA synthetase or tRNA (guanine-N1) methyltransferase, respectively] was found to be mutated in the two survivors. A single nucleotide substitution and a frameshift mutation were found in metG and trmD, respectively. Five different substitution mutations affecting methionine- or tRNA-binding sites were found in metG during further screening. The mutants exhibited slowed growth and increased tolerance not only to meropenem but also various other antibiotics. This tolerance required intact RelA, a key stringent response. Conclusions: Specific mutations affecting the tRNA pool, particularly those in metG, play a pivotal role in the B. thailandensis response to meropenem challenge. This mechanism of antibiotic tolerance is important because it can reduce the effectiveness of meropenem and thereby facilitate chronic infection by Burkholderia pathogens. In addition, specific mutations found in MetG will prove useful in the effort to develop new drugs to completely inhibit this essential enzyme, while preventing stringent-response-mediated antibiotic tolerance in pathogens. PMID- 29136175 TI - Structural basis of effector and operator recognition by the phenolic acid responsive transcriptional regulator PadR. AB - The PadR family is a large group of transcriptional regulators that function as environmental sensors. PadR negatively controls the expression of phenolic acid decarboxylase, which detoxifies harmful phenolic acids. To identify the mechanism by which PadR regulates phenolic acid-mediated gene expression, we performed structural and mutational studies of effector and operator recognition by Bacillus subtilis PadR. PadR contains an N-terminal winged helix-turn-helix (wHTH) domain (NTD) and a C-terminal homodimerization domain (CTD) and dimerizes into a dolmen shape. The PadR dimer interacts with the palindromic sequence of the operator DNA using the NTD. Two tyrosine residues and a positively charged residue in the NTD provide major DNA-binding energy and are highly conserved in the PadR family, suggesting that these three residues represent the canonical DNA binding motif of the PadR family. PadR directly binds a phenolic acid effector molecule using a unique interdomain pocket created between the NTD and the CTD. Although the effector-binding site of PadR is positionally segregated from the DNA-binding site, effector binding to the interdomain pocket causes PadR to be rearranged into a DNA binding-incompatible conformer through an allosteric interdomain-reorganization mechanism. PMID- 29136177 TI - Effect of sequential chemoradiotherapy in patients with limited-disease small cell lung cancer who were ineligible for concurrent therapy: a retrospective study at two institutions. AB - Background: The standard treatment for limited-disease small-cell lung cancer (LD SCLC) is a combination of chemotherapy and concurrent thoracic radiotherapy. In selected cases, sequential radiotherapy is preferred because of the need for a large irradiation field, patient age, comorbidities or performance status. Nevertheless, the efficacy of sequential chemoradiotherapy in patients in whom concurrent chemoradiotherapy is contraindicated is not well known. Methods: We retrospectively analyzed 286 patients with LD-SCLC at two institutions in Japan between 2000 and 2014. We compared the clinical characteristics and treatment outcomes of patients undergoing sequential radiotherapy with those undergoing concurrent radiotherapy. Results: One hundred and seventy-five patients received concurrent chemoradiotherapy, 33 received sequential chemoradiotherapy and 46 received chemotherapy only. The median patient age was 64 years (range, 18-82 years) for the concurrent group and 71 years (49-82 years) for the sequential group. Conventional radiotherapy was selected more frequently than accelerated hyperfractionated radiotherapy (27 patients [82%] with conventional radiotherapy, and six patients [18%] with hyperfractionated radiotherapy). The major reasons for the selection of sequential radiotherapy were advanced age (12 patients) and a large irradiation field (11 patients). The median overall survival time was 41.1 months for the sequential group and 38.1 months for the concurrent group. The 5-year survival rates were 36.0% for the sequential group and 41.6% for the concurrent group. Conclusions: In clinical situation, since the treatment outcomes for patients with sequential radiotherapy were comparable to those receiving concurrent radiotherapy, sequential chemoradiotherapy can be a choice for the treatment of patients who are not candidates for concurrent chemoradiotherapy. PMID- 29136178 TI - Identification of Genomic Regions Associated With Sex in Pacific Halibut. AB - Understanding and identifying the genetic mechanisms responsible for sex determination are important for species management, particularly in exploited fishes where sex biased harvest could have implications on population dynamics and long-term persistence. The Pacific halibut (Hippoglossus stenolepis) supports important fisheries in the North Pacific Ocean. The proportion of each sex in the annual harvest is currently estimated using growth curves, but genetic techniques may provide a more accurate method. We used restriction-site associated DNA (RAD) sequencing to identify RAD-tags that were linked to genetic sex, based on differentiation (FST) between the sexes. Identified RAD-tags were aligned to the Atlantic halibut (Hippoglossus hippoglossus) linkage map, the turbot (Scophthalmus maximus) genome, and the half-smooth tongue sole (Cynoglossus semilaevis) genome to identify genomic regions that may be involved in sex determination. In total, 56 RAD-tags (70 single nucleotide polymorphisms) were linked to sex, and 3 RAD-tags were identified in only females. Sex-linked loci aligned to 3 linkage groups in the Atlantic halibut (LG07: 7 loci, LG15: 1 locus, and LG24: 1 locus), 3 chromosomes in the turbot (LG12: 13 loci, LG01: 1 locus, and LG05: 1 locus), and 1 chromosome in the half-smooth tongue sole (ChrZ: 9 loci). Results add support to the hypothesis that Pacific halibut genetic sex is determined in a ZW system. Two sex-linked loci were further developed into sex identification assays, and their efficacy was tested on individuals that had been morphologically sexed. The accuracy of each assay on its own was 97.5% compared to morphological sex. PMID- 29136180 TI - BCNTB bioinformatics: the next evolutionary step in the bioinformatics of breast cancer tissue banking. AB - Here, we present an update of Breast Cancer Now Tissue Bank bioinformatics, a rich platform for the sharing, mining, integration and analysis of breast cancer data. Its modalities provide researchers with access to a centralised information gateway from which they can access a network of bioinformatic resources to query findings from publicly available, in-house and experimental data generated using samples supplied from the Breast Cancer Now Tissue Bank. This in silico environment aims to help researchers use breast cancer data to their full potential, irrespective of any bioinformatics barriers. For this new release, a complete overhaul of the IT and bioinformatic infrastructure underlying the portal has been conducted and a host of novel analytical modules established. We developed and adopted an automated data selection and prioritisation system, expanded the data content and included tissue and cell line data generated from The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia, designed a host of novel analytical modalities and enhanced the query building process. Furthermore, the results are presented in an interactive format, providing researchers with greater control over the information on which they want to focus. Breast Cancer Now Tissue Bank bioinformatics can be accessed at http://bioinformatics.breastcancertissuebank.org/. PMID- 29136179 TI - Fluorescently-tagged human eIF3 for single-molecule spectroscopy. AB - Human translation initiation relies on the combined activities of numerous ribosome-associated eukaryotic initiation factors (eIFs). The largest factor, eIF3, is an ~800 kDa multiprotein complex that orchestrates a network of interactions with the small 40S ribosomal subunit, other eIFs, and mRNA, while participating in nearly every step of initiation. How these interactions take place during the time course of translation initiation remains unclear. Here, we describe a method for the expression and affinity purification of a fluorescently tagged eIF3 from human cells. The tagged eIF3 dodecamer is structurally intact, functions in cell-based assays, and interacts with the HCV IRES mRNA and the 40S IRES complex in vitro. By tracking the binding of single eIF3 molecules to the HCV IRES RNA with a zero-mode waveguides-based instrument, we show that eIF3 samples both wild-type IRES and an IRES that lacks the eIF3-binding region, and that the high-affinity eIF3-IRES interaction is largely determined by slow dissociation kinetics. The application of single-molecule methods to more complex systems involving eIF3 may unveil dynamics underlying mRNA selection and ribosome loading during human translation initiation. PMID- 29136181 TI - Dating and relationship violence among 16-19 year olds in England and Wales: a cross-sectional study of victimization. AB - Background: Dating and relationship violence (DRV) is under-researched in the UK, especially among Further Education (FE) students. This study examines the association between DRV victimization and socio-demographic characteristics, sexual identity and dating and relationship behaviours among 16-19 year olds FE students. Methods: Cross-sectional self-report data were collected from 1751 students aged 16-19 at six FE settings in England and Wales. Factor analysis examined the structure of DRV victimization by gender. Multilevel logistic regression examined the odds ratios of DRV victimization according to socio demographics, sexual identity and dating behaviours. Results: DRV victimization clusters into two categories for females, and three for males. Among females, 46.1% experienced controlling behaviours and 31.6% threatening behaviours; 49.9% of males experienced controlling behaviours, 27.1% threatening behaviours and 5.8% online sexual violence. The odds of DRV victimization were 2-8 times greater for males and 2-4 times greater for females who had ever sent a sexually explicit image. No consistent association was found between DRV and age, spending money per week, educational attainment or meeting partners online. Conclusions: The high prevalence, absence of gender differences and social patterning, suggests DRV victimization may be becoming normalized and is of significant public health importance for young people in England and Wales. PMID- 29136182 TI - Assessing privacy risks in population health publications using a checklist-based approach. AB - Objective: Recent growth in the number of population health researchers accessing detailed datasets, either on their own computers or through virtual data centers, has the potential to increase privacy risks. In response, a checklist for identifying and reducing privacy risks in population health analysis outputs has been proposed for use by researchers themselves. In this study we explore the usability and reliability of such an approach by investigating whether different users identify the same privacy risks on applying the checklist to a sample of publications. Methods: The checklist was applied to a sample of 100 academic population health publications distributed among 5 readers. Cohen's kappa was used to measure interrater agreement. Results: Of the 566 instances of statistical output types found in the 100 publications, the most frequently occurring were counts, summary statistics, plots, and model outputs. Application of the checklist identified 128 outputs (22.6%) with potential privacy concerns. Most of these were associated with the reporting of small counts. Among these identified outputs, the readers found no substantial actual privacy concerns when context was taken into account. Interrater agreement for identifying potential privacy concerns was generally good. Conclusion: This study has demonstrated that a checklist can be a reliable tool to assist researchers with anonymizing analysis outputs in population health research. This further suggests that such an approach may have the potential to be developed into a broadly applicable standard providing consistent confidentiality protection across multiple analyses of the same data. PMID- 29136183 TI - Glyphosate Use and Cancer Incidence in the Agricultural Health Study. AB - Background: Glyphosate is the most commonly used herbicide worldwide, with both residential and agricultural uses. In 2015, the International Agency for Research on Cancer classified glyphosate as "probably carcinogenic to humans," noting strong mechanistic evidence and positive associations for non-Hodgkin lymphoma (NHL) in some epidemiologic studies. A previous evaluation in the Agricultural Health Study (AHS) with follow-up through 2001 found no statistically significant associations with glyphosate use and cancer at any site. Methods: The AHS is a prospective cohort of licensed pesticide applicators from North Carolina and Iowa. Here, we updated the previous evaluation of glyphosate with cancer incidence from registry linkages through 2012 (North Carolina)/2013 (Iowa). Lifetime days and intensity-weighted lifetime days of glyphosate use were based on self-reported information from enrollment (1993-1997) and follow-up questionnaires (1999-2005). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounders, including use of other pesticides. All statistical tests were two sided. Results: Among 54 251 applicators, 44 932 (82.8%) used glyphosate, including 5779 incident cancer cases (79.3% of all cases). In unlagged analyses, glyphosate was not statistically significantly associated with cancer at any site. However, among applicators in the highest exposure quartile, there was an increased risk of acute myeloid leukemia (AML) compared with never users (RR = 2.44, 95% CI = 0.94 to 6.32, Ptrend = .11), though this association was not statistically significant. Results for AML were similar with a five-year (RRQuartile 4 = 2.32, 95% CI = 0.98 to 5.51, Ptrend = .07) and 20-year exposure lag (RRTertile 3 = 2.04, 95% CI = 1.05 to 3.97, Ptrend = .04). Conclusions: In this large, prospective cohort study, no association was apparent between glyphosate and any solid tumors or lymphoid malignancies overall, including NHL and its subtypes. There was some evidence of increased risk of AML among the highest exposed group that requires confirmation. PMID- 29136184 TI - Female Mimicry by Sneaker Males Has a Transcriptomic Signature in Both the Brain and the Gonad in a Sex-Changing Fish. AB - Phenotypic plasticity represents an elegant adaptive response of individuals to a change in their environment. Bluehead wrasses (Thalassoma bifasciatum) exhibit astonishing sexual plasticity, including female-to-male sex change and discrete male morphs that differ strikingly in behavior, morphology, and gonadal investment. Using RNA-seq transcriptome profiling, we examined the genes and physiological pathways underlying flexible behavioral and gonadal differences among female, dominant (bourgeois) male, and female-mimic (sneaker) male blueheads. For the first time in any organism, we find that female mimicry by sneaker males has a transcriptional signature in both the brain and the gonad. Sneaker males shared striking similarity in neural gene expression with females, supporting the idea that males with alternative reproductive phenotypes have "female-like brains." Sneaker males also overexpressed neuroplasticity genes, suggesting that their opportunistic reproductive strategy requires a heightened capacity for neuroplasticity. Bourgeois males overexpressed genes associated with socio-sexual behaviors (e.g., isotocin), but also neuroprotective genes and biomarkers of oxidative stress and aging, indicating a hitherto unexplored cost to these males of attaining the reproductively privileged position at the top of the social hierarchy. Our novel comparison of testicular transcriptomes in a fish with male sexual polymorphism associates greater gonadal investment by sneaker males with overexpression of genes involved in cell proliferation and sperm quality control. We propose that morphological female-mimicry by sneaker male teleosts entails pervasive downregulation of androgenesis genes, consistent with low androgen production in males lacking well-developed secondary sexual characters. PMID- 29136185 TI - Cognitive dysfunction among newly diagnosed older patients with hematological malignancy: frequency, clinical indicators and predictors. AB - Background: Medical staff often overlook or underestimate the presence or severity of cognitive dysfunction. The purpose of this study was to clarify the frequency, clinical indicators and predictors of cognitive dysfunction among newly diagnosed older patients with hematologic malignancy receiving first-line chemotherapy. Methods: Patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were consecutively recruited. Cognitive dysfunction was evaluated using the Mini-Mental State Examination (MMSE) twice: before starting chemotherapy (T1) and 1 month later (T2). Participants also underwent a comprehensive geriatric assessment at T1. Potential clinical indicators that were associated with cognitive dysfunction were explored via cross-sectional analysis at T1. Predictors of cognitive dysfunction at T2 were also investigated among patients without cognitive dysfunction at T1. Results: A total of 145 participants participated in the study; cognitive dysfunction at T1 was present in 20%. Multivariate analysis demonstrated that lower educational attainment and poorer instrumental activities of daily living were significant clinical indicators of cognitive dysfunction. Among 99 patients who did not have cognitive dysfunction at T1 and underwent cognitive assessment at T2, 7% developed dysfunction. Subjective perception of difficulty remembering at T1 was the only factor which significantly predicted new-onset cognitive dysfunction at T2. Conclusions: The prevalence rate of cognitive dysfunction was non-negligible among older patients with hematologic malignancy before and immediately after initial chemotherapy. Attention to the clinical indicators and predictors found in this study may provide facilitate the identification of cognitive dysfunction in patients with cancer. PMID- 29136186 TI - Clonal spread and azole-resistant mechanisms of non-susceptible Candida albicans isolates from vulvovaginal candidiasis patients in three Shanghai maternity hospitals. AB - In our multicenter study, 43 fluconazole non-susceptible and 45 fluconazole susceptible isolates were collected from vulvovaginal candidiasis (VVC) patients from three Shanghai maternity hospitals to analyze their molecular epidemiological features and fluconazole resistant mechanisms. Cross-resistance to fluconazole, itraconazole and voriconazole was observed in 53.5% of the nonsusceptible isolates. Though we acquired 12 clonal complexes (CCs) of diploid sequence types (DSTs) in clinical isolates by a multilocus sequence typing method, fluconazole nonsusceptible isolates all belonged to CC69 with a predominant genotype of DST 79. Increased expressions of efflux pump genes (CDR1, CDR2, and MDR1) were observed only in minor fluconazole non-susceptible isolates by real-time quantitative polymerase chain reaction (PCR). However, ERG11 genes of fluconazole SDD and resistant isolates had significantly higher expression levels than fluconazole-susceptible isolates. Moreover, 13 distinct amino acid substitutions in Erg11p were found in clinical isolates. Three of the substitutions were novel amino acid substitutions (T123I, P98S, and Y286D), which were not in the susceptible isolates. Only two heterozygous amino acid substitutions (A18P/A and R365G/R) in Erg3p were found in two isolates with cross resistance to fluconazole, itraconazole, and voriconazole. Taken together, we observed the clonal spread of CC69 in fluconazole non-susceptible isolates of Candida albicans from VVC patients with the dominant genotype DST79. ERG11 gene mutations and overexpression predominantly contributed to fluconazole resistance instead of the more common increased expressions of efflux pump genes (CDR1, CDR2, and MDR1). PMID- 29136187 TI - A Phase III trial of a single early intravesical instillation of pirarubicin to prevent bladder recurrence after radical nephroureterectomy for upper tract urothelial carcinoma (JCOG1403, UTUC THP Phase III). AB - Observation is the current standard for managing cases of Stage 0a-III upper tract urothelial carcinoma after radical nephroureterectomy. A randomized Phase III trial commenced in Japan during October 2016. The trial is designed to investigate the superiority of a single early intravesical instillation of pirarubicin, compared with observation, in terms of relapse-free survival after radical nephroureterectomy for Stage 0a-III upper tract urothelial carcinoma. During a 5-year period, 310 patients will be recruited from 43 Japanese institutions. The primary endpoint is defined as relapse-free survival, and the secondary endpoints are overall survival, intravesical relapse-free survival, adverse events, and serious adverse events. This trial has been registered in the UMIN Clinical Trials Registry (UMIN000024267, http://www.umin.ac.jp/ctr/index.htm). PMID- 29136188 TI - Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage. PMID- 29136189 TI - Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction. AB - STUDY QUESTION: Are serum polyunsaturated fatty acids (PUFA) concentrations, including omega-3 (omega3-PUFA) and omega-6 (omega6-PUFA), related to ART outcomes? SUMMARY ANSWER: Serum levels of long-chain omega3-PUFA were positively associated with probability of live birth among women undergoing ART. WHAT IS KNOWN ALREADY: Intake of omega3-PUFA improves oocyte and embryo quality in animal and human studies. However, a recent cohort study found no relation between circulating omega3-PUFA levels and pregnancy rates after ART. STUDY DESIGN SIZE, AND DURATION: This analysis included a random sample of 100 women from a prospective cohort study (EARTH) at the Massachusetts General Hospital Fertility Center who underwent 136 ART cycles within one year of blood collection. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum fatty acids (expressed as percentage of total fatty acids) were measured by gas chromatography in samples taken between Days 3 and 9 of a stimulated cycle. Primary outcomes included the probability of implantation, clinical pregnancy and live birth per initiated cycle. Cluster-weighted generalized estimating equation (GEE) models were used to analyze the association of total and specific PUFAs with ART outcomes adjusting for age, body mass index, smoking status, physical activity, use of multivitamins and history of live birth. MAIN RESULTS AND ROLE OF CHANCE: The median [25th, 75th percentile] serum level of omega3-PUFA was 4.7% [3.8%, 5.8%] of total fatty acids. Higher levels of serum long-chain omega3-PUFA were associated with higher probability of clinical pregnancy and live birth. Specifically, after multivariable adjustment, the probability of clinical pregnancy and live birth increased by 8% (4%, 11%) and 8% (95% CI: 1%, 16%), respectively, for every 1% increase in serum long-chain omega3-PUFA levels. Intake of long-chain omega3-PUFA was also associated with a higher probability of life birth in these women, with RR of 2.37 (95% CI: 1.02, 5.51) when replacing 1% energy of long-chain omega3 PUFA for 1% energy of saturated fatty acids. Serum omega6-PUFA, ratios of omega6 and omega3-PUFA, and total PUFA were not associated with ART outcomes. LIMITATIONS REASONS FOR CAUTION: The generalizability of the findings to populations not undergoing infertility treatment may be limited. The use of a single measurement of serum fatty acids to characterize exposure may lead to potential misclassification during follow up. WIDER IMPLICATIONS OF THE FINDINGS: Serum omega3-PUFA are considered biomarkers of dietary intake. The association of higher serum long chain omega3-PUFA levels with improved ART outcomes suggests that increased intake of these fats be may be beneficial for women undergoing infertility treatment with ART. STUDY FUNDING/COMPETING INTERESTS: NIH grants R01 ES009718 from the National Institute of Environmental Health Sciences, P30 DK046200 and T32-DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases, and L50-HD085359 from the National Institute of Child Health and Human Development, and the Early Life Nutrition Fund from Danone Nutricia US. Dr Rueda is involved in a patent 9,295,662, methods for enhancing, improving, or increasing fertility or reproductive function (http://patents.com/us-9295662.html). This patent, however, does not lead to financial gain for Dr Rueda, or for Massachusetts General Hospital. Dr Rueda does not own any part of the company nor does he have any equity in any fertility related company. As Dr Rueda is not a physician, he does not evaluate patients or prescribe medications. All other coauthors have no conflicts of interest to declare. PMID- 29136190 TI - The genotype-phenotype relationships in the light of natural selection. AB - Although any genotype-phenotype relationships are a result of evolution, little is known about how natural selection and neutral drift, two distinct driving forces of evolution, operate to shape the relationships. By analysing ~500 yeast quantitative traits we reveal a basic "supervisor-worker" gene architecture underlying a trait. Supervisors are often identified by "perturbational" approaches (such as gene deletion), while workers, which usually show small and statistically insignificant deletion effects, are tracked primarily by "observational" approaches that examine the correlation between gene activity and trait value across a number of conditions. Accordingly, supervisors provide most of the genetic understandings of the trait while workers provide rich mechanistic understandings. Further analyses suggest that most observed supervisor-worker interactions may evolve largely neutrally, resulting in pervasive between-worker epistasis that suppresses the tractability of workers. In contrast, a fraction of supervisors are recruited/maintained by natural selection to build worker co expression, boosting the tractability of workers. Thus, by revealing a supervisor worker gene architecture underlying complex traits, the opposite roles of natural selection versus neutral drift in shaping the gene architecture, and the complementary strengths of the perturbational and observational research strategies in characterizing the gene architecture, this study may lay a new conceptual foundation for understanding the molecular basis of complex traits. PMID- 29136191 TI - Genome sequence of the small brown planthopper, Laodelphax striatellus. AB - Background: Laodelphax striatellus Fallen (Hemiptera: Delphacidae) is one of the most destructive rice pests. L. striatellus is different from 2 other rice planthoppers with a released genome sequence, Sogatella furcifera and Nilaparvata lugens, in many biological characteristics, such as host range, dispersal capacity, and vectoring plant viruses. Deciphering the genome of L. striatellus will further the understanding of the genetic basis of the biological differences among the 3 rice planthoppers. Findings: A total of 190 Gb of Illumina data and 32.4 Gb of Pacbio data were generated and used to assemble a high-quality L. striatellus genome sequence, which is 541 Mb in length and has a contig N50 of 118 Kb and a scaffold N50 of 1.08 Mb. Annotated repetitive elements account for 25.7% of the genome. A total of 17 736 protein-coding genes were annotated, capturing 97.6% and 98% of the BUSCO eukaryote and arthropoda genes, respectively. Compared with N. lugens and S. furcifera, L. striatellus has the smallest genome and the lowest gene number. Gene family expansion and transcriptomic analyses provided hints to the genomic basis of the differences in important traits such as host range, migratory habit, and plant virus transmission between L. striatellus and the other 2 planthoppers. Conclusions: We report a high-quality genome assembly of L. striatellus, which is an important genomic resource not only for the study of the biology of L. striatellus and its interactions with plant hosts and plant viruses, but also for comparison with other planthoppers. PMID- 29136192 TI - Assessing the hydration status of children with chronic kidney disease and on dialysis: a comparison of techniques. AB - Background: Fluid balance is pivotal in the management of children with chronic kidney disease (CKD) and on dialysis. Although many techniques are available to assess fluid status, there are only a few studies for children, of which none have been comparable against cardiovascular outcome measures. Methods: We performed a longitudinal study in 30 children with CKD5-5D and 13 age-matched healthy controls (71 measurements) to determine a correlation between optimal weight by bioimpedance spectroscopy (Wt-BIS) and clinical assessment (Wt-CA). The accuracy of Wt-BIS [relative overhydration (Rel-OH)] was compared against indicators of fluid status and cardiovascular measures. Results: There was poor agreement between Wt-CA and Wt-BIS in children on dialysis (P = 0.01), but not in CKD5 or control subjects. We developed a modified chart to plot Rel-OH against systolic blood pressure (SBP) z-score for the appropriate representation of volume status and blood pressure (BP) in children. In total, 25% of measurements showed SBP >90th percentile but not with concurrent overhydration. Rel-OH correlated with peripheral pulse pressure (P = 0.03; R = 0.3), higher N-terminal pro-brain natriuretic peptide (P = 0.02; R = 0.33) and left ventricular end diastolic diameter (P = 0.05; R = 0.38). Central aortic mean and pulse pressure significantly associated with the left ventricular end-diastolic diameter (P = 0.03; R = 0.47 and P = 0.01; R = 0.50, respectively), but not with Rel-OH. SBP was positively associated with pulse wave velocity z-score (P = 0.04). In total, 40% of children on haemodialysis and 30% on peritoneal dialysis had increased left ventricular mass index. Conclusions: BIS provides an objective method for the assessment of hydration status in children on dialysis. We noted a marked discrepancy between BP and hydration status in children on dialysis that warrants further investigation. PMID- 29136193 TI - Early first trimester uteroplacental flow and the progressive disintegration of spiral artery plugs: new insights from contrast-enhanced ultrasound and tissue histopathology. AB - STUDY QUESTION: Does the use of a vascular contrast agent facilitate earlier detection of maternal flow to the placental intervillous space (IVS) in the first trimester of pregnancy? SUMMARY ANSWER: Microvascular filling of the IVS was demonstrated by contrast-enhanced ultrasound from 6 weeks of gestation onwards, earlier than previously believed. WHAT IS KNOWN ALREADY: During placental establishment and remodeling of maternal spiral arteries, endovascular trophoblast cells invade and accumulate in the lumen of these vessels to form 'trophoblast plugs'. Prior evidence from morphological and Doppler ultrasound studies has been conflicting as to whether the spiral arteries are completely plugged, preventing maternal blood flow to the IVS until late in the first trimester. STUDY DESIGN, SIZE, DURATION: Uteroplacental flow was examined across the first trimester in human subjects given an intravenous infusion of lipid shelled octofluoropropane microbubbles with ultrasound measurement of destruction and replenishment kinetics. We also performed a comprehensive histopathological correlation using two separately archived uteroplacental tissue collections to evaluate the degree of spiral artery plugging and evaluate remodeling of the upstream myometrial radial and arcurate arteries. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnant women (n = 34) were recruited in the first trimester (range: 6+3 to 13+6 weeks gestation) for contrast-enhanced ultrasound studies with destruction-replenishment analysis of signal intensity for assessment of microvascular flux rate. Histological samples from archived in situ (Boyd Collection, n = 11) and fresh first, second, and third trimester decidual and post-hysterectomy uterine specimens (n = 16) were evaluated by immunohistochemistry (using markers of epithelial, endothelial and T-cells, as well as cell adhesion and proliferation) and ultrastructural analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Contrast agent entry into the IVS was visualized as early as 6+3 weeks of gestation with some variability in microvascular flux rate noted in the 6-7+6 week samples. Spiral artery plug canalization was observed from 7 weeks with progressive disintegration thereafter. Of note, microvascular flux rate did not progressively increase until 13 weeks, which suggests that resistance to maternal flow in the early placenta may be mediated more proximally by myometrial radial arteries that begin remodeling at the end of the first trimester. LIMITATIONS REASONS FOR CAUTION: Gestational age was determined by crown-rump length measurements obtained by transvaginal ultrasound on the day of contrast-enhanced imaging studies, which may explain the variability in the earliest gestational age samples due to the margin of error in this type of measurement. WIDER IMPLICATIONS OF THE FINDINGS: Our comprehensive in situ histological analysis, in combination with the use of an in vivo imaging modality that has the sensitivity to permit visualization of microvascular filling, has allowed us to reveal new evidence in support of increasing blood flow to the IVS from 6 weeks of gestation. Histologic review suggested the mechanism may be blood flow through capillary-sized channels that form through the loosely cohesive 'plugs' by 7 weeks gestation. However, spiral artery remodeling on its own did not appear to explain why there is significantly more blood flow at 13 weeks gestation. Histologic studies suggest it may be related to radial artery remodeling, which begins at the end of the first trimester. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by the Oregon Health and Science University Knight Cardiovascular Institute, Center for Developmental Health and the Struble Foundation. There are no competing interests. PMID- 29136195 TI - Hour-by-hour physical activity patterns of adults aged 45-65 years: a cross sectional study. AB - Background: Limited information exists on hour-by-hour physical activity (PA) patterns among adults aged 45-65 years. Therefore, this study aimed to distinguish typical hour-by-hour PA patterns, and examined which individuals typically adopt certain PA patterns. Methods: Accelerometers measured light and moderate-vigorous PA. GIS-data provided proportions of land use within an 800 and 1600 m buffer around participant's homes. Latent class analyses were performed to distinguish PA patterns and groups of individuals with similar PA patterns. Results: Four PA patterns were identified: a morning light PA pattern, a mid-day moderate-vigorous PA pattern, an overall inactive pattern and an overall active pattern. Groups of individuals with similar PA patterns differed in ethnicity, dog ownership, and the proportion of roads, sports terrain, larger green and blue space within their residential areas. Conclusions: Four typical hour-by-hour PA patterns, and three groups of individuals with similar patterns were distinguished. It is this combination that can substantially contribute to the development of more tailored policies and interventions. PA patterns were only to a limited extent associated with personal and residential characteristics, suggesting that other factors such as work time regimes, family life and leisure may also have considerable impact on the distribution of PA throughout the day. PMID- 29136194 TI - Fast skin dose estimation system for interventional radiology. AB - To minimise the radiation dermatitis related to interventional radiology (IR), rapid and accurate dose estimation has been sought for all procedures. We propose a technique for estimating the patient skin dose rapidly and accurately using Monte Carlo (MC) simulation with a graphical processing unit (GPU, GTX 1080; Nvidia Corp.). The skin dose distribution is simulated based on an individual patient's computed tomography (CT) dataset for fluoroscopic conditions after the CT dataset has been segmented into air, water and bone based on pixel values. The skin is assumed to be one layer at the outer surface of the body. Fluoroscopic conditions are obtained from a log file of a fluoroscopic examination. Estimating the absorbed skin dose distribution requires calibration of the dose simulated by our system. For this purpose, a linear function was used to approximate the relation between the simulated dose and the measured dose using radiophotoluminescence (RPL) glass dosimeters in a water-equivalent phantom. Differences of maximum skin dose between our system and the Particle and Heavy Ion Transport code System (PHITS) were as high as 6.1%. The relative statistical error (2 sigma) for the simulated dose obtained using our system was <=3.5%. Using a GPU, the simulation on the chest CT dataset aiming at the heart was within 3.49 s on average: the GPU is 122 times faster than a CPU (Core i7-7700K; Intel Corp.). Our system (using the GPU, the log file, and the CT dataset) estimated the skin dose more rapidly and more accurately than conventional methods. PMID- 29136197 TI - Mapping VIS-terahertz (<=17 THz) surface plasmons sustained on native and chemically functionalized percolated gold thin films using EELS. AB - Heterogeneous assemblies of molecules (Rhodamine B) adsorbed onto a nano corrugated metallic surface (a percolated Au network) are investigated using electron energy loss spectroscopy in the scanning transmission electron microscope (STEM-EELS). Our first measurements target the native metallic substrate, which consists of a commercial Au thin film atop an ultrathin carbon membrane. The Au film displays a percolated morphology with nanostructures of estimated thickness <=10 nm approximately. We observe a rich plasmonic response from the metallic substrate; one which varies nanometrically and spans the VIS terahertz region. Multiple localized plasmons are detected at individual nanometric integrated areas, while an analysis of their spatial distribution reveals that for each integrated energy range (50 meV integration window) resonances are simultaneously supported at different locations within the film. We record subsequent EEL spectrum images of the hybrid molecular-metallic construct after deposition of Rhodamine B molecules onto the substrate, where plasmons, molecular vibrations and electronic excitations might all be simultaneously detected. A comparison of average signals for both systems is performed and spectral variations within the three spectral regions where molecular signatures may be observed are discussed. Our measurements and their analysis, if applied to the same location before and after molecular deposition, may be used to rationalize optical microscopic and spectroscopic measurements that take advantage of the interplay between molecules and plasmons. PMID- 29136198 TI - Harms and Benefits of Stigmatizing Smoking. PMID- 29136196 TI - Analysis of the natively unstructured RNA/protein-recognition core in the Escherichia coli RNA degradosome and its interactions with regulatory RNA/Hfq complexes. AB - The RNA degradosome is a multi-enzyme assembly that plays a central role in the RNA metabolism of Escherichia coli and numerous other bacterial species including pathogens. At the core of the assembly is the endoribonuclease RNase E, one of the largest E. coli proteins and also one that bears the greatest region predicted to be natively unstructured. This extensive unstructured region, situated in the C-terminal half of RNase E, is punctuated with conserved short linear motifs that recruit partner proteins, direct RNA interactions, and enable association with the cytoplasmic membrane. We have structurally characterized a subassembly of the degradosome-comprising a 248-residue segment of the natively unstructured part of RNase E, the DEAD-box helicase RhlB and the glycolytic enzyme enolase, and provide evidence that it serves as a flexible recognition centre that can co-recruit small regulatory RNA and the RNA chaperone Hfq. Our results support a model in which the degradosome captures substrates and regulatory RNAs through the recognition centre, facilitates pairing to cognate transcripts and presents the target to the ribonuclease active sites of the greater assembly for cooperative degradation or processing. PMID- 29136199 TI - Site-specific dual-color labeling of long RNAs for single-molecule spectroscopy. AB - Labeling of long RNA molecules in a site-specific yet generally applicable manner is integral to many spectroscopic applications. Here we present a novel covalent labeling approach that is site-specific and scalable to long intricately folded RNAs. In this approach, a custom-designed DNA strand that hybridizes to the RNA guides a reactive group to target a preselected adenine residue. The functionalized nucleotide along with the concomitantly oxidized 3'-terminus can subsequently be conjugated to two different fluorophores via bio-orthogonal chemistry. We validate this modular labeling platform using a regulatory RNA of 275 nucleotides, the btuB riboswitch of Escherichia coli, demonstrate its general applicability by modifying a base within a duplex, and show its site-selectivity in targeting a pair of adjacent adenines. Native folding and function of the RNA is confirmed on the single-molecule level by using FRET as a sensor to visualize and characterize the conformational equilibrium of the riboswitch upon binding of its cofactor adenosylcobalamin. The presented labeling strategy overcomes size and site constraints that have hampered routine production of labeled RNA that are beyond 200 nt in length. PMID- 29136200 TI - PRODORIC2: the bacterial gene regulation database in 2018. AB - Bacteria adapt to changes in their environment via differential gene expression mediated by DNA binding transcriptional regulators. The PRODORIC2 database hosts one of the largest collections of DNA binding sites for prokaryotic transcription factors. It is the result of the thoroughly redesigned PRODORIC database. PRODORIC2 is more intuitive and user-friendly. Besides significant technical improvements, the new update offers more than 1000 new transcription factor binding sites and 110 new position weight matrices for genome-wide pattern searches with the Virtual Footprint tool. Moreover, binding sites deduced from high-throughput experiments were included. Data for 6 new bacterial species including bacteria of the Rhodobacteraceae family were added. Finally, a comprehensive collection of sigma- and transcription factor data for the nosocomial pathogen Clostridium difficile is now part of the database. PRODORIC2 is publicly available at http://www.prodoric2.de. PMID- 29136201 TI - Safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as second-line therapy, in Japanese patients with advanced solid malignancies or non-small cell lung cancer. AB - Objective: This Phase I study (NCT01605916) investigated the safety, tolerability and pharmacokinetic profile of selumetinib plus docetaxel as second-line therapy in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), or selumetinib monotherapy in Japanese patients with advanced solid malignancies. Methods: All enrolled patients received single-dose selumetinib 25, 50 or 75 mg, followed by a 3-day washout. Combination therapy cohorts then started a 21-day cycle of docetaxel 60 mg/m2 plus selumetinib 25 or 75 mg twice-daily (BID) on Day 1. Thereafter, selumetinib BID continued for 20 days; patients received <=6 cycles. Following single-dosing, monotherapy cohorts underwent a 21-day cycle of selumetinib 25, 50 or 75 mg BID. Results: Thirty three patients were enrolled and 25 assigned to treatment (combination, n = 8; monotherapy, n = 17). Most frequent adverse events (AEs) included: vomiting, decreased appetite, diarrhea, nausea and stomatitis (combination cohorts); gastrointestinal disorders, skin and subcutaneous tissue disorders (monotherapy cohorts). Grade 3 dose-limiting toxicities: febrile neutropenia, causally related to combination therapy (n = 3); pneumonitis, selumetinib 50 mg monotherapy (n = 1). Selumetinib 75 mg monotherapy and selumetinib 25 mg plus docetaxel 60 mg/m2 were tolerated; selumetinib 75 mg plus docetaxel 60 mg/m2 was not tolerated. Selumetinib pharmacokinetic profile was similar when administered as a monotherapy or in combination with docetaxel. Conclusions: Selumetinib 75 mg monotherapy was tolerated in Japanese patients with NSCLC. Due to the overall selumetinib AE profile, the maximum tolerated dose was not determined for combination therapy or monotherapy. Selumetinib 75 mg BID plus docetaxel 60 mg/m2 was not tolerated in this patient population. PMID- 29136202 TI - A Conceptual Framework for Cell Identity Transitions in Plants. AB - Multicellular organisms develop from a single cell that proliferates to form different cell types with specialized functions. Sixty years ago, Waddington suggested the 'epigenetic landscape' as a useful metaphor for the process. According to this view, cells move through a rugged identity space along genetically encoded trajectories, until arriving at one of the possible final fates. In plants in particular, these trajectories have strong spatial correlates, as cell identity is intimately linked to its relative position within the plant. During regeneration, however, positional signals are severely disrupted and differentiated cells are able to undergo rapid non-canonical identity changes. Moreover, while pluripotent properties have long been ascribed to plant cells, the introduction of induced pluripotent stem cells in animal studies suggests such plasticity may not be unique to plants. As a result, current concepts of differentiation as a gradual and hierarchical process are being reformulated across biological fields. Traditional studies of plant regeneration have placed strong emphasis on the emergence of patterns and tissue organization, and information regarding the events occurring at the level of individual cells is only now beginning to emerge. Here, I review the historical and current concepts of cell identity and identity transitions, and discuss how new views and tools may instruct the future understanding of differentiation and plant regeneration. PMID- 29136203 TI - FreePSI: an alignment-free approach to estimating exon-inclusion ratios without a reference transcriptome. AB - Alternative splicing plays an important role in many cellular processes of eukaryotic organisms. The exon-inclusion ratio, also known as percent spliced in, is often regarded as one of the most effective measures of alternative splicing events. The existing methods for estimating exon-inclusion ratios at the genome scale all require the existence of a reference transcriptome. In this paper, we propose an alignment-free method, FreePSI, to perform genome-wide estimation of exon-inclusion ratios from RNA-Seq data without relying on the guidance of a reference transcriptome. It uses a novel probabilistic generative model based on k-mer profiles to quantify the exon-inclusion ratios at the genome scale and an efficient expectation-maximization algorithm based on a divide-and-conquer strategy and ultrafast conjugate gradient projection descent method to solve the model. We compare FreePSI with the existing methods on simulated and real RNA-seq data in terms of both accuracy and efficiency and show that it is able to achieve very good performance even though a reference transcriptome is not provided. Our results suggest that FreePSI may have important applications in performing alternative splicing analysis for organisms that do not have quality reference transcriptomes. FreePSI is implemented in C++ and freely available to the public on GitHub. PMID- 29136204 TI - Thrombolysis is an Independent Risk Factor for Poor Outcome After Carotid Revascularization. AB - BACKGROUND: Thrombolysis is the standard of care for acute ischemic stroke patients presenting in the appropriate time window. Studies suggest that the risk of recurrent ischemia is lower if carotid revascularization is performed early after the index event. The safety of early carotid revascularization in this patient population is unclear. OBJECTIVE: To evaluate the safety of carotid revascularization in patients who received thrombolysis for acute ischemic stroke. METHODS: The Nationwide Inpatient Sample database was queried for patients admitted through the emergency room with a primary diagnosis of carotid stenosis and/or occlusion. Each patient was reviewed for administration of thrombolysis, carotid endarterectomy, (CEA) or carotid angioplasty and stenting (CAS). Primary endpoints were intracerebral hemorrhage (ICH), postprocedural stroke (PPS), poor outcome, and in-hospital mortality. Potential risk factors were examined using univariate and multivariate analyses. RESULTS: A total of 310 257 patients were analyzed. Patients who received tissue plasminogen activator (tPA) and underwent either CEA or CAS had a significantly higher risk of developing an ICH or PPS than patients who underwent either CEA or CAS without tPA administration. The increased risk of ICH or PPS in tPA-treated patients who underwent carotid revascularization diminished with time, and became similar to patients who underwent carotid revascularization without tPA administration by 7 d after thrombolysis. Patients who received tPA and underwent CEA or CAS also had higher odds of poor outcome and in-hospital mortality. CONCLUSION: Thrombolysis is a strong risk factor for ICH, PPS, poor outcome, and in-hospital mortality in patients with carotid stenosis/occlusion who undergo carotid revascularization. The increased risk of ICH or PPS due to tPA declines with time after thrombolysis. Delaying carotid revascularization in these patients may therefore be appropriate. This delay, however, will expose these patients to the risk of recurrent stroke. Future studies are needed to determine the relative risks of these 2 adverse events. PMID- 29136205 TI - Transcription Factor AsMYC2 Controls the Jasmonate-Responsive Expression of ASS1 Regulating Sesquiterpene Biosynthesis in Aquilaria sinensis (Lour.) Gilg. PMID- 29136206 TI - Calculation, consequences and measurement of the point spread function for low loss inelastic scattering. AB - We have previously derived an analytical formula for the point spread function (PSF) that describes the delocalization of low-loss inelastic scattering. Here, we modify the formula to take account variation of scattered-electron phase. The exponentially attenuated Lorentzian form is retained but its halfwidth at half maximum is chosen to provide better agreement with measurements of the median delocalization distance. For low energy losses, the 1/r2 tails of the PSF extend beyond the region of energy deposition, allowing a small-diameter electron probe to provide energy-loss data from relatively undamaged regions of a beam-sensitive specimen. Alternatively, a core-loss or elastic image can be recorded with less damage by sparse scanning, as in scanned moire imaging. A procedure is proposed for directly measuring the PSF, using a TEM with aberration-corrected lenses and an energy-filtered imaging system. PMID- 29136207 TI - LinkedOmics: analyzing multi-omics data within and across 32 cancer types. AB - The LinkedOmics database contains multi-omics data and clinical data for 32 cancer types and a total of 11 158 patients from The Cancer Genome Atlas (TCGA) project. It is also the first multi-omics database that integrates mass spectrometry (MS)-based global proteomics data generated by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) on selected TCGA tumor samples. In total, LinkedOmics has more than a billion data points. To allow comprehensive analysis of these data, we developed three analysis modules in the LinkedOmics web application. The LinkFinder module allows flexible exploration of associations between a molecular or clinical attribute of interest and all other attributes, providing the opportunity to analyze and visualize associations between billions of attribute pairs for each cancer cohort. The LinkCompare module enables easy comparison of the associations identified by LinkFinder, which is particularly useful in multi-omics and pan-cancer analyses. The LinkInterpreter module transforms identified associations into biological understanding through pathway and network analysis. Using five case studies, we demonstrate that LinkedOmics provides a unique platform for biologists and clinicians to access, analyze and compare cancer multi-omics data within and across tumor types. LinkedOmics is freely available at http://www.linkedomics.org. PMID- 29136208 TI - Mouse Phenome Database: an integrative database and analysis suite for curated empirical phenotype data from laboratory mice. AB - The Mouse Phenome Database (MPD; https://phenome.jax.org) is a widely used resource that provides access to primary experimental trait data, genotypic variation, protocols and analysis tools for mouse genetic studies. Data are contributed by investigators worldwide and represent a broad scope of phenotyping endpoints and disease-related traits in naive mice and those exposed to drugs, environmental agents or other treatments. MPD houses individual animal data with detailed, searchable protocols, and makes these data available to other resources via API. MPD provides rigorous curation of experimental data and supporting documentation using relevant ontologies and controlled vocabularies. Most data in MPD are from inbreds and other reproducible strains such that the data are cumulative over time and across laboratories. The resource has been expanded to include the QTL Archive and other primary phenotype data from mapping crosses as well as advanced high-diversity mouse populations including the Collaborative Cross and Diversity Outbred mice. Furthermore, MPD provides a means of assessing replicability and reproducibility across experimental conditions and protocols, benchmarking assays in users' own laboratories, identifying sensitized backgrounds for making new mouse models with genome editing technologies, analyzing trait co-inheritance, finding the common genetic basis for multiple traits and assessing sex differences and sex-by-genotype interactions. PMID- 29136209 TI - Use of 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of polymyalgia rheumatica-A prospective study of 99 patients. AB - Objective: Previous studies have shown that the majority of patients with PMR have increased 18F-fluorodeoxyglucose (FDG) uptake around the shoulders, hips and processes of the cervical and lumbar spine on PET. The specificity of these findings for PMR is, however, not known. Methods: We prospectively included 99 consecutive patients with a possible clinical diagnosis of PMR. All patients underwent 18F-FDG-PET scanning before treatment with glucocorticoids was started. The clinical suspicion of PMR was quantified by the treating physician on a scale from 1 to 5. FDG uptake was scored visually in 12 articular regions (scores 0-2) and a total skeletal score was calculated reflecting the FDG uptake in these 12 articular regions. Receiver operating characteristics analysis was performed to determine the optimal clinical and total skeletal score for diagnosing PMR. The gold standard for a diagnosis of PMR was the judgement of an experienced clinician after at least 6 months of follow-up. Results: Sixty-seven patients were diagnosed with PMR while 32 patients got another diagnosis. A clinical score of 4 or more had a sensitivity of 67.2%, specificity of 87.5%, positive predictive value (PPV) of 91.8% and a negative predictive value (NPV) of 56.0% for the diagnosis of PMR. A total skeletal score of 16 or more had a sensitivity, specificity, PPV and NPV of, respectively, 85.1, 87.5, 93.4 and 73.7%. Conclusion: 18F-FDG-PET before starting glucocorticoid therapy improves the diagnostic accuracy compared with a clinical scoring system in patients with clinical suspicion of PMR. PMID- 29136210 TI - The effect of sexual maturity and egg production on skeletal muscle (pectoralis major and gastrocnemius) protein turnover in broiler breeder pure lines. AB - A study was conducted to evaluate the effect of sexual maturity on pectoralis major and gastrocnemius muscle protein turnover in broiler breeder pure lines. Protein turnover in skeletal muscle tissue was determined in 4 broiler breeder pure lines (Line A, Line B, Line C and Line D) at 22, 27, 33, 37, 44, and 50 wk of age. A completely randomized design with a factorial arrangement 4 * 6 (4 lines and 6 time periods (ages)) was used. There were 5 replicates per line/time and each hen represented a replicate. Five hens/line at each age were given an intravenous flooding-dose of 15N-phenylalanine (150 mM, 40 atom percent excess (APE) at a dose of 10 mL/kg. After 10 min, birds were euthanized using CO2 asphyxiation and the breast and leg muscle excised and snap frozen in liquid nitrogen for protein turnover analysis. Excreta was collected from each breeder for 3-methyl histidine (3-MH) analysis. There was a significant age effect for the breast muscle fractional synthesis rate (FSR), but no main effects (age and line) for leg muscle FSR. The FSR in breast muscle tissue decreased in hens from wk 22 (first egg) to wk 33 (peak egg production). There was a significant age effect on fractional breakdown rate (FBR) in breast and leg muscle. The FBR in breast muscle increased in hens from wk 22 to wk 33 and remained high through wk 37. Breast muscle FBR significantly decreased in hens from wk 37 to wk 50. The FBR in leg muscle tissue increased in hens from wk 33 to wk 37 and then decreased at wk 50. No line effect was seen for FSR or FBR. There is a large increase in skeletal muscle FBR during the transition for the pullet to sexual maturity with increases in skeletal muscle FBR in the breast and leg muscle through peak egg production. Protein turnover in skeletal muscle tissue is believed to be a source of nutrients for egg production. PMID- 29136211 TI - P3: Phylogenetic Posterior Prediction in RevBayes. AB - Tests of absolute model fit are crucial in model-based inference because poorly structured models can lead to biased parameter estimates. In Bayesian inference, posterior predictive simulations can be used to test absolute model fit. However, such tests have not been commonly practiced in phylogenetic inference due to a lack of convenient and flexible software. Here, we describe our newly implemented tests of model fit using posterior predictive testing, based on both data- and inference-based test statistics, in the phylogenetics software RevBayes. This new implementation makes a large spectrum of models available for use through a user friendly and flexible interface. PMID- 29136212 TI - Neoadjuvant and adjuvant therapy for Stage III non-small cell lung cancer. AB - The treatments for advanced non-small cell lung cancer (NSCLC) should control both local and microscopic systemic disease, because the 5-year survival of patients with Stage III NSCLC who underwent surgical resection alone has been dismal. One way to improve surgical outcome is the administration of chemotherapy before or after the surgical procedure. During the last two decades, many clinical studies have focused on developing optimal adjuvant or neoadjuvant chemotherapy regimens that can be combined with surgical treatment and/or radiotherapy. Based on the results of those clinical studies, multimodality therapy is considered to be an appropriate treatment approach for Stage IIIA NSCLC patients; although, optimal treatment strategies are still evolving. When N2 nodal involvement is discovered postoperatively, adjuvant cisplatin-based chemotherapy confers an overall survival benefit. The addition of postoperative radiotherapy might be considered for patients with nodal metastases. Although definitive chemoradiation remains a standard of care for cN2 NSCLC, alternative approaches such as induction chemotherapy or chemoradiotherapy and surgery can be considered for a selective group of patients. When surgical resection can be performed after induction therapy with low risk and a good chance of complete resection, the outcome may be optimal. The decision to proceed with resection after induction therapy must include a detailed preoperative pulmonary function evaluation as well as a critical intraoperative assessment of the feasibility of complete resection. PMID- 29136213 TI - KNOTTIN: the database of inhibitor cystine knot scaffold after 10 years, toward a systematic structure modeling. AB - Knottins, or inhibitor cystine knots (ICKs), are ultra-stable miniproteins with multiple applications in drug design and medical imaging. These widespread and functionally diverse proteins are characterized by the presence of three interwoven disulfide bridges in their structure, which form a unique pseudoknot. Since 2004, the KNOTTIN database (www.dsimb.inserm.fr/KNOTTIN/) has been gathering standardized information about knottin sequences, structures, functions and evolution. The website also provides access to bibliographic data and to computational tools that have been specifically developed for ICKs. Here, we present a major upgrade of our database, both in terms of data content and user interface. In addition to the new features, this article describes how KNOTTIN has seen its size multiplied over the past ten years (since its last publication), notably with the recent inclusion of predicted ICKs structures. Finally, we report how our web resource has proved usefulness for the researchers working on ICKs, and how the new version of the KNOTTIN website will continue to serve this active community. PMID- 29136214 TI - Effects of dietary supplemental bile acids on performance, carcass characteristics, serum lipid metabolites and intestinal enzyme activities of broiler chickens. AB - The objective of the present study was to evaluate the effect of bile acids derived from swine on the growth performance, carcass traits, serum lipid metabolites and intestinal enzyme activities in broiler chickens. Four hundred thirty-two 1-day-old Arbor Acres male broilers were randomly assigned to 4 treatments with 6 replicates of 18 chicks each for 42 d. The experimental treatments received a corn-soybean basal diet containing lard and were as follows: 0 (control), 40 mg, 60 mg, and 80 mg bile acids/kg of diet. Dietary of inclusion bile acids significantly increased average daily gain and decreased feed to gain ratio from d 21 to d 42 (P < 0.01). However, average daily feed intake was unaffected by dietary supplementation with bile acids. The dressing percentage and the percentage of thigh muscle in the carcass were notably (P < 0.01) higher for broilers fed diets supplemented with 60 and 80 mg/kg bile acids. In contrast, abdominal fat weight was reduced significantly (P < 0.01). In 42-day old broilers, serum triglyceride, high density lipoprotein and low density lipoprotein concentrations were unaffected (P > 0.05) by bile acids supplementation. Supplementation with 60 and 80 mg/kg significantly increased the activity of duodenum lipase and lipoprotein lipase on d 21 and d 42, as well as decreased the activity of hormone sensitive lipase on d 42. Supplementation of diets with 60 and 80 mg/kg of bile acid can effectively enhance the activity of intestinal lipase and lipoprotein lipase and improve growth performance and carcass traits of broilers. PMID- 29136215 TI - MultitaskProtDB-II: an update of a database of multitasking/moonlighting proteins. AB - Multitasking, or moonlighting, is the capability of some proteins to execute two or more biological functions. MultitaskProtDB-II is a database of multifunctional proteins that has been updated. In the previous version, the information contained was: NCBI and UniProt accession numbers, canonical and additional biological functions, organism, monomeric/oligomeric states, PDB codes and bibliographic references. In the present update, the number of entries has been increased from 288 to 694 moonlighting proteins. MultitaskProtDB-II is continually being curated and updated. The new database also contains the following information: GO descriptors for the canonical and moonlighting functions, three-dimensional structure (for those proteins lacking PDB structure, a model was made using Itasser and Phyre), the involvement of the proteins in human diseases (78% of human moonlighting proteins) and whether the protein is a target of a current drug (48% of human moonlighting proteins). These numbers highlight the importance of these proteins for the analysis and explanation of human diseases and target-directed drug design. Moreover, 25% of the proteins of the database are involved in virulence of pathogenic microorganisms, largely in the mechanism of adhesion to the host. This highlights their importance for the mechanism of microorganism infection and vaccine design. MultitaskProtDB-II is available at http://wallace.uab.es/multitaskII. PMID- 29136217 TI - Smoking Cessation Benefit Utilization: Comparing Methodologies for Measurement using New York State's Medicaid Data. AB - Introduction: Pharmacotherapy and counseling for tobacco cessation are evidence based methods that increase successful smoking cessation attempts. Medicaid programs are required to provide coverage for smoking cessation services. Monitoring utilization is desirable for program evaluation and quality improvement. Various methodologies have been used to study utilization. Many factors can influence results, perhaps none more than how smokers are identified. This study evaluated the utilization of smoking cessation services using various methods to estimate the number of smokers within New York State's (NYS's) Medicaid program in 2015. Methods: Estimates of utilization were generated based on Medicaid claims and encounters and four sources of smoking prevalence: two population surveys, one Medicaid enrollee survey, and diagnosis codes. We compared the percentage of (estimated) smokers utilizing cessation services, and the average number of services used, across fee-for-service and managed care populations, and by cessation service category. Results: Statewide, smoking prevalence estimates ranged from 10.9% to 31.5%. Diagnosis codes identified less than 45% of smokers estimated by surveys. A similar number of cessation counseling (199106) and pharmacotherapy services (197728) were used, yet more members utilized counseling (126839) than pharmacotherapy (91433). The estimated percentage of smokers who used smoking cessation services ranged from 15.1% to 43.4%, and the estimated average number of cessation services used ranged from 0.31 to 0.90 per smoker. Conclusion: Smoking prevalence estimates obtained through surveys greatly exceed prevalence observed in diagnosis codes in NYS's Medicaid data. Use of diagnosis codes in the analysis of smoking cessation benefit utilization may result in overestimates. Implications: Selection of a smoking prevalence data source for similar analyses should ultimately be based on completeness of the data and applicability to the population of interest. Evaluation of smoking cessation benefit utilization and the effectiveness of tobacco control campaigns aimed to increase utilization requires a well-defined methodology which ensures reliable baseline data. Comparing utilization estimates across populations or state lines can be misleading, as differences in how estimations were generated can greatly bias observed results. PMID- 29136216 TI - The eukaryotic linear motif resource - 2018 update. AB - Short linear motifs (SLiMs) are protein binding modules that play major roles in almost all cellular processes. SLiMs are short, often highly degenerate, difficult to characterize and hard to detect. The eukaryotic linear motif (ELM) resource (elm.eu.org) is dedicated to SLiMs, consisting of a manually curated database of over 275 motif classes and over 3000 motif instances, and a pipeline to discover candidate SLiMs in protein sequences. For 15 years, ELM has been one of the major resources for motif research. In this database update, we present the latest additions to the database including 32 new motif classes, and new features including Uniprot and Reactome integration. Finally, to help provide cellular context, we present some biological insights about SLiMs in the cell cycle, as targets for bacterial pathogenicity and their functionality in the human kinome. PMID- 29136218 TI - MEASUREMENT OF RADIATION DOSES TO THE EYE LENS DURING ORTHOPEDIC SURGERY USING AN C-ARM X-RAY SYSTEM. AB - The present study aimed to determine doses delivered to the eye lenses of surgeons while using the inverted-C-arm technique and the protective effect of leaded spectacles during orthopedic surgery. The kerma in air was measured at five positions on leaded glasses positioned near the eye lens and on the neck using small optically stimulated luminescence (OSL) dosemeters. The lens equivalent dose was also measured at the neck using an OSL dosemeter. The maximum equivalent dose to the eye lens and the maximum kerma were 0.8 mSv/month and 0.66 mGy/month, respectively. The leaded glasses reduced the exposure by ~60%. Even if the surgeons are exposed to the maximum dose of X-ray radiation for 5 years, the equivalent doses to the eye lens will not exceed the present limit recommended by the ICRP. PMID- 29136220 TI - Interactions of dietary protein and threonine on growth performance in Pekin ducklings from 1 to 14 days of age. AB - The present study was conducted to investigate the effects of dietary crude protein (CP) on threonine requirements by determining the interactions of dietary CP levels (16.0, 17.5, 19.0, 20.5, and 22.0%) and supplemental threonine levels (0, 0.07, 0.14, 0.21, and 0.28%) on growth performance of Pekin ducks from 1 to 14 days of age. A total of 1,200 one-day-old male Pekin ducks was randomly allotted to 1 of 25 dietary treatments with 6 replicate pens of 8 birds per pen for each treatment. The results showed that dietary CP and threonine levels affected the average daily feed intake (ADFI, P < 0.0001), average daily gain (ADG, P < 0.0001), ratio of feed/gain (F/G, P < 0.0001) of Pekin ducks, and had an interactions on the ADFI, ADG, F/G (P < 0.0001). The ADG was increased linearly (P < 0.002) and then reached a plateau as the dietary threonine increased at all CP diets. According to the estimation of broken-line models, the dietary threonine requirements at 16.0, 17.5, 19.0, 20.5, and 22.0% CP diets for optimal ADG of ducks were 0.56, 0.61, 0.60, 0.63, and 0.67% when expressed as percentage of diet, or 44.22, 47.65, 47.50, 48.30, and 50.39% when expressed as percentage of dietary lysine, or 3.45, 3.44, 3.12, 3.27, and 2.98% when expressed as percentage of dietary CP, respectively. Threonine requirements of Pekin ducks from 1 to 14 days of age were affected by dietary CP levels according to the Student t test results, but had no difference among the moderate CP level diets (17.5, 19, and 20.5%) when expressed as a percentage of diet or dietary lysine. It was concluded that dietary CP levels affected the threonine requirements of Pekin ducks from 1 to 14 days of age, but threonine requirements were constant within the limiting CP level range (17.5 to 20.5%) with a good balance of dietary amino acid, and were approximately 0.60 to 0.63% of diet or 47.5 to 48.3% of dietary lysine. PMID- 29136219 TI - MobiDB 3.0: more annotations for intrinsic disorder, conformational diversity and interactions in proteins. AB - The MobiDB (URL: mobidb.bio.unipd.it) database of protein disorder and mobility annotations has been significantly updated and upgraded since its last major renewal in 2014. Several curated datasets for intrinsic disorder and folding upon binding have been integrated from specialized databases. The indirect evidence has also been expanded to better capture information available in the PDB, such as high temperature residues in X-ray structures and overall conformational diversity. Novel nuclear magnetic resonance chemical shift data provides an additional experimental information layer on conformational dynamics. Predictions have been expanded to provide new types of annotation on backbone rigidity, secondary structure preference and disordered binding regions. MobiDB 3.0 contains information for the complete UniProt protein set and synchronization has been improved by covering all UniParc sequences. An advanced search function allows the creation of a wide array of custom-made datasets for download and further analysis. A large amount of information and cross-links to more specialized databases are intended to make MobiDB the central resource for the scientific community working on protein intrinsic disorder and mobility. PMID- 29136222 TI - Erratum. PMID- 29136221 TI - Facial flushing after alcohol intake as a predictor for a high risk of synchronous or metachronous cancer of the upper gastrointestinal tract. AB - Background: In Japan, there has been a lot of reports showing an association between facial flushing after light alcohol consumption and heterozygosity for inactive aldehyde dehydrogenase-2 (ALDH2). Persons with inactive ALDH2 may have a higher risk of alcohol-related oral, pharyngeal and esophageal cancers, compared with those with wild-type ALDH2. The purpose of this study was to examine whether flushers with oral or pharyngeal squamous cell carcinoma have an increased risk of synchronous or metachronous cancer of the upper gastrointestinal (UGI) tract. Methods: A retrospective study was performed by medical chart review and through a questionnaire sent to 285 patients treated for oral and pharyngeal cancer. Responses were obtained from 150 patients (52.6%), who were classified as flushers or non-flushers, smokers (>=20 pack-year; 1 pack-years = number of cigarettes/20 per day) or non-smokers, and drinkers (>=14 units of alcohol consumption per week; 1 unit = 22 g) or non-drinkers. Relationships of these factors with occurrence of second primary cancers (SPCs) in the UGI tract were investigated. Results: In Kaplan-Meier analysis, there was a significantly higher rate of SPC at 5 years in flushers and drinkers, but no relationship with smoking. In multivariate analyses, a history of flushing was significantly associated with SPC in the UGI tract (HR 2.64, 95% CI 1.25-5.52, P = 0.0109), but not with smoking or alcohol consumption. Conclusions: A simple interview on history of facial flushing after alcohol intake can be useful for identifying patients at high risk for synchronous or metachronous cancers of the UGI tract. PMID- 29136223 TI - Baroreceptors in the carotid and hypertension-systematic review and meta-analysis of the effects of baroreflex activation therapy on blood pressure. AB - Activation of baroreceptors in the carotid modulates the autonomic nervous system. Baroreflex activation therapy (BAT), which activates baroreceptors in the carotid, has become available in the treatment of resistant hypertension. Besides this, a carotid implant modulating baroreceptors as well as pharmacological modulation of carotid bodies were quite recently presented. This review will underscore currently available and promising approaches that activate baroreceptors in the carotid, and thereby contribute to beneficial effects in patients with arterial hypertension, and discusses potential organoprotective BAT effects beyond blood pressure (BP) reduction. A systematic review and meta analysis was conducted including observational studies or randomized controlled trials that investigated the effect of BAT on BP in resistant hypertension. Nine studies, seven observational and two randomized, with a total of 444 patients, were included in the evaluation. Analysing the longest follow-up visit from the different studies, there was a significant reduction of systolic BP after BAT of 36 mmHg [95% confidence interval (CI) -42 to -30 mmHg]. Separate meta-analysis of the short-term (1-6 months) and long-term effects (>=12 months) revealed a reduction of -21 mmHg (95% CI -26 to -17 mmHg) and -38 mmHg (95% CI -46 to -30 mmHg), respectively. There are promising data both in the experimental and the clinical application for BAT. Though the present meta-analysis suggests beneficial effects of BAT on BP, the results must be interpreted extremely carefully. Considering that evidence from controlled trials is very limited, it is evident that there is a strong need for further investigation. PMID- 29136224 TI - Reliable Identification of Benign Clinical Course in Aneurysmal Subarachnoid Hemorrhage: A Simple and Qualitative Algorithm. AB - BACKGROUND: A reliable method to specifically identify low vasospasm risk in aneurysmal subarachnoid hemorrhage (aSAH) patients has not been previously proposed. OBJECTIVE: To develop a clinical algorithm using admission aSAH clinical severity and subarachnoid blood distribution to identify patients at low risk of clinical vasospasm. METHODS: Clinical severities, admission noncontrasted head computerized tomography (CT) scan, and incidences of vasospasm among 291 aSAH patients treated at our institution were evaluated. Admission head CTs were assessed for distributions of cisternal and ventricular blood. Patients with the following 4 criteria experienced considerably lower risk of vasospasm: (1) Hunt Hess grade 1 to 2, (2) Lack of thick subarachnoid blood filling 2 adjacent cisterns, (3) Lack of thick interhemispheric blood, and (4) Lack of biventricular intraventricular hemorrhage. RESULTS: One hundred thirty-three patients (45.7%) developed cerebral vasospasm. Hunt Hess grade greater than 2 (odds ratio [OR] 4.52, 95% confidence interval [CI] 2.74-7.46), adjacent cistern blood (OR 4.1, 95% CI 2.51-6.7), interhemispheric thick blood (OR 5.72, 95% CI 3.41-9.59), and biventricular intraventricular hemorrhage (OR 1.92, 95% CI 1.19-3.02) were significant risk factors. Application of our algorithm yielded a sensitivity of 29%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 54.5%, which was superior compared to metrics from current institutional practice criteria. Inter-rater agreement was substantial at mean kappa = 0.75. CONCLUSION: Application of our novel clinical algorithm produced successful identification of aSAH patients who experience zero risk of clinical vasospasm. Our algorithm is simple to apply with high reliability and is superior to currently available clinical and radiographic metrics. PMID- 29136225 TI - Evaluation of EELS spectrum imaging data by spectral components and factors from multivariate analysis. AB - Multivariate analysis is a powerful tool to process spectrum imaging datasets of electron energy loss spectroscopy. Most spatial variance of the datasets can be explained by a limited numbers of components. We explore such dimension reduction to facilitate quantitative analyses of spectrum imaging data, supervising the spectral components instead of spectra at individual pixels. In this study, we use non-negative matrix factorization to decompose datasets from Fe2O3 thin films with different Sn doping profiles on SnO2 and Si substrates. Case studies are presented to analyse spectral features including background models, signal integrals, peak positions and widths. Matlab codes are written to guide microscopists to perform these data analyses. PMID- 29136226 TI - Testing the Financial Capability Framework: Findings from YouthSave-Impact Study Kenya. AB - In sub-Saharan Africa (SSA), youths (23 years or younger)-who account for almost half the population-are particularly vulnerable to poverty and exclusion from financial markets and intermediaries. In addition, a significant factor in the financial instability of the region appears to be the economic functioning of its youths. In recent years, social work interventions throughout the region have focused on investing in the economic functioning of youths. This study looked at baseline data from one such intervention in Kenya (N = 3,965), using the financial capabilities framework to evaluate the factors related to youths' saving behaviors. Authors investigated the association between youths' financial literacy (that is, knowledge, socialization), financial access, and financial capabilities and savings behaviors. Results indicate that adolescents who rate themselves as financially literate and those living in close proximity to a bank are more likely to report higher capabilities. Furthermore, financial capabilities in turn partially mediate the relationship between financial literacy, access, and savings. Overall, the study's findings point to the positive effect of enhanced financial capabilities among youths and offer support for asset-based interventions targeting youths in SSA. PMID- 29136227 TI - Developmental outcome of 9-year-old children born after PGS: follow-up of a randomized trial. AB - STUDY QUESTION: Does Day-3 cleavage-stage PGS affect neurodevelopment of 9-year old IVF offspring? SUMMARY ANSWER: We did not find evidence of adverse consequences of Day-3 cleavage-stage PGS on neurodevelopment of 9-year-old IVF offspring, although children born after IVF with or without PGS often had a non optimal neurological condition. WHAT IS KNOWN ALREADY: Knowledge on long-term sequelae for development and health of children born following PGS is lacking. This is striking as evidence accumulates that IVF itself is associated with increased risk for impaired health and development in the offspring. STUDY DESIGN SIZE, DURATION: This prospective, assessor-blinded, multicentre, follow-up study evaluated development and health of 9-year-old IVF children born to women who were randomly assigned to IVF with PGS (PGS group) or without PGS (control group). The follow-up examination at 9 years took place between March 2014 and May 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 408 women were included and randomly assigned to IVF with or without Day-3 cleavage-stage PGS. This resulted in 52 ongoing pregnancies in the PGS group and 74 in the control group. In the PGS group, 59 children were born alive; in the control group, 85 children were born alive. At the age of 9 years, 43 children born after PGS and 56 control children participated in the study. Our primary outcome was the neurological optimality score, a sensitive measure of neurological condition assessed with a standardized, age-specific test (Touwen test). Secondary outcomes were adverse neurological condition (neurologically abnormal and the complex form of minor neurological dysfunction), cognitive development (intelligence quotient and specific domains), behaviour (parental and teacher's questionnaires), blood pressure and anthropometrics. MAIN RESULTS AND THE ROLE OF CHANCE: Neurodevelopmental outcome of PGS children did not differ from that of controls; the neurological optimality scores (mean values [(95% CI]: PGS children 51.5 [49.3; 53.7], control children 53.1 [50.5; 55.7]) were not significantly different. The prevalences of adverse neurological outcome (in all but one child implying the presence of the complex form of minor neurological dysfunction) did not differ between the groups (PGS group 17/43 [40%], control group 19/56 [34%]), although the prevalence of complex minor neurological dysfunction in both groups was rather high. Also intelligence quotient scores of the two groups were not significantly different (PGS group 114 [108; 120]); control group 117 [109; 125]), and the behaviour, blood pressure and anthropometrics of both groups did not differ. Mean blood pressures of both groups were above the 60th percentile. LIMITATIONS REASONS FOR CAUTION: The power analysis of the study was not based on the number of children needed for the follow-up study, but on the number of women who were needed to detect an increase in ongoing pregnancy rates after PGS. In addition, our study evaluated embryo biopsy in the form of PGS at cleavage stage (Day-3 embryo biopsy), while currently PGS at blastocyst stage (Day-5 embryo biopsy) is recommended and increasingly being used. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that PGS in cleavage stage embryos is not associated with adverse effects on neurological, cognitive and behavioural development, blood pressure and anthropometrics of offspring at 9 years. This is a reassuring finding as embryo biopsy in the forms of PGS and PGD is increasingly applied. However, both groups of IVF offspring showed high prevalences of the clinically relevant form of minor neurological dysfunction, which is a point of concern for the IVF community. In addition, our study confirms findings of others that IVF offspring may be at risk of an unfavourable cardiovascular outcome. These findings are alarming and highlight the importance of research on the underlying mechanisms of unfavourable neurodevelopmental and cardiovascular outcomes in IVF offspring. STUDY FUNDING/COMPETING INTEREST(S): The randomized controlled trial was financially supported by the Organization for Health Research and Development (ZonMw), The Netherlands (Grant number 945-03-013). The follow-up was financially supported by the University Medical Center Groningen (Grant number: 754510), the Cornelia Foundation, and the graduate schools BCN and Share, Groningen, The Netherlands. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: ISRCTN76355836. PMID- 29136228 TI - Opioid Prescription Use in Nursing Home Residents with Advanced Dementia. AB - Background: Although proper pain treatment may require opioids, discussion continues about possible undertreatment or overtreatment in persons with advanced dementia. Objective: To investigate the prevalence of pain, frequency of opioid prescription use, and factors associated with strong opioid prescription use in nursing homes. Design: Cross-sectional study. Setting and Subjects: Eighteen Norwegian nursing homes; 327 persons with advanced dementia and behavioral disturbances participated. Methods: Potential factors associated with strong opioid prescription use were assessed: demographics (age, gender), medical conditions (comorbidity, number of medications), pain (Mobilization-Observation Behaviour-Intensity-Dementia-2 Pain Scale >= 3, pain-related diagnoses, analgesic prescription use), functioning (activities of daily living, Mini-Mental State Examination) and behavior (Neuropsychiatric Inventory-Nursing Home version, Cohen Mansfield Agitation Inventory). Factors with P < 0.10, age, and gender were included in multivariate regression analysis. Results: The prevalence of moderate to severe pain was 62.1%. Of all participants, 19.3% (N = 63) were prescribed opioids, and of these, 79.4% (N = 50) were still in pain; 66.7% of the opioid prescriptions were less than or equal to the lowest dosage of fentanyl patches (12 mcg/h) or buprenorphine (5 or 10 mcg/h). Pain (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.12-1.42), total number of pain-related diagnoses (OR = 1.47, 95% CI = 1.14-1.90), and depression and anxiety (OR = 1.05, 95% CI = 1.01 1.11) were positively associated with an opioid prescription. Stroke was negatively associated (OR = 0.43, 95% CI = 0.19-0.99). Conclusions: Strong opioid prescription use was mainly associated with pain. However, in this population, despite the relatively prevalent use of strong prescription opioids, pain was still prevalent. This emphasizes the challenge of proper pain treatment and need for regular evaluation of pain and pain management. PMID- 29136229 TI - Letter: Sex After Neurosurgery-Is It Safe? PMID- 29136230 TI - High-Dose TL Dosimetry of Reactor Neutrons. AB - Radiation dose was measured with set of TL dosimeters during checkout of neutron radiation hardness of the ORTEC preamplifier type 142A in the experiment at the MARIA nuclear reactor at the National Centre for Nuclear Research (NCBJ), Otwock Swierk, Poland. Different types of LiF-based TL detectors have been used for measurements in order to evaluate neutron and non-neutron components of the radiation field in the reactor channel during exposure and to check their relevancy for dose measurements in the reactor environment. For high-dose evaluation a new Ultra-High-Temperature Ratio (UHTR) method established for highly sensitive LiF:Mg,Cu,P detectors has been applied. Neutron fluence evaluated from TL measurements was in good agreement with one calculated using neutron flux data during the experiment. PMID- 29136231 TI - CHARACTERISATION OF THE PTB THERMAL NEUTRON CALIBRATION FACILITY WITH THE BONNER SPHERE SPECTROMETER NEMUS. AB - The neutron field of the PTB Thermal Neutron Calibration Facility was characterised with the help of the Bonner sphere spectrometer of PTB, NEutron MUltisphere Spectrometer (NEMUS). For the analysis of the Bonner sphere data an analytical model of the neutron energy distribution was used. The unfolding of neutron spectra was performed via the method of Bayesian parameter estimation. Comparison of the results of thermal neutron fluence and thermal ambient dose equivalent with the results of the reference method of gold activation showed a very good agreement. For fast neutrons the results obtained with NEMUS will serve as reference values for this facility. The facility is ready for use as a thermal neutron reference field for calibrations of neutron measuring devices. PMID- 29136232 TI - Trayvon Martin: Racial Profiling, Black Male Stigma, and Social Work Practice. AB - To address a critical gap in the social work literature, this article examines the deleterious effects of racial profiling as it pertains to police targeting of male African Americans. The authors use the Trayvon Martin court case to exemplify how racial profiling and black male stigma help perpetuate social inequality and injustice for black men. A racism-centered perspective is examined historically and contemporarily as a theoretical approach to understanding the role that race plays in social injustice through racial profiling. Implications for social work research design and practice aimed at increasing the social work knowledge base on racial profiling are discussed. The authors call for attention and advocacy by major social work organizations in the reduction of black male stigma and racial profiling. PMID- 29136233 TI - A SIMPLE METHOD FOR CALIBRATING PIXEL VALUES OF THE CT LOCALIZER RADIOGRAPH FOR CALCULATING WATER-EQUIVALENT DIAMETER AND SIZE-SPECIFIC DOSE ESTIMATE. AB - The purpose of this study is to establish the relationship between the pixel value (I) of the CT localizer radiograph and water-equivalent thickness (tw) in a straightforward procedure. We used a body CTDI phantom, which was scanned in the AP and LAT projections. After transformation from the pixel values of the images to tw, water-equivalent diameter (Dw) and size-specific dose estimate were calculated on an anthropomorphic phantom and 30 patients retrospectively. We found a linear correlation between I and tw, with R2 >= 0.980. The Dw values based on the CT localizer radiograph were comparable to those calculated using axial images. The Dw difference for the anthropomorphic phantom between AP projection and axial images was 5.4 +/- 4.2%, and between LAT projection and axial images was 6.7 +/- 5.3%. The Dw differences for the patients between CT localizer radiograph and axial images was 2.3 +/- 3.2%. PMID- 29136234 TI - Non-Apnea Sleep Disorder Increases the Risk of Subsequent Female Infertility-A Nationwide Population-Based Cohort Study. AB - Study Objectives: Non-apnea sleep disorder (NASD) increases the risk of hypertension, type 2 diabetes mellitus, chronic kidney disease, cardiovascular disease, and stroke. However, the risk and the time interval of NASD to female infertility has not been thoroughly understood. Our study aimed to determine whether NASD increases the subsequent risk of female infertility. Methods: This study utilized outpatient and inpatient data from the Longitudinal Health Insurance Database between 2000 and 2010 in Taiwan. We enrolled 50,154 females aged 20 to 45 years old and diagnosed with NASD as outpatients >=2 times or hospitalized, 16,718 of them who matched our criteria were assigned to the study group. For each NASD patient, two comparison patients were frequency matched by age (each 5-year span), index date, and comorbidities as the control cohort with a total of 33,436 patients. We conducted Cox proportional hazard regression analysis to estimate the effects of NASD on female infertility. Results: The NASD cohort had an adjusted hazard ratio (HR) of subsequent female infertility of 3.718-fold higher than that of the cohort without sleep disorders. In the stratified age group, NASD had the highest impact on 26-30 years old, with an adjusted HR of 5.146 followed by 31-35 years old (adjusted HR = 3.356). The Kaplan-Meier analysis also showed that in the sixth year of follow-up, the incidence of female infertility was higher in the NASD cohort than in the general population cohort till the end of the follow-up. Conclusions: Our study demonstrates that NASD patients are at a higher risk of developing female infertility. PMID- 29136235 TI - 241Am-Be(alpha,n) CHARACTERIZATION FOR A NEW LABORATORY FACILITY IN BRAZIL. AB - The Laboratorio de Ciencias Radiologicas is developing an irradiator for neutron survey meters calibration. Part of this work is related to the characterization of the neutron source that will be used in the irradiator. Therefore, a source of 241Am-Be(alpha,n) was characterized according to the following attributes: neutron energy distribution, anisotropy and emission rate. In order to make these values into high-level metrological references traceable by the Bureau International des Poids et Mesures, these measurements were taken at the Neutron Laboratory part of the Laboratorio Nacional de Metrologia das Radiacoes Ionizantes. Results obtained for the source spectrum have strong adherence to the reference spectrum established by ISO 8529-1. The new laboratory for neutron calibration will allow calibration in an approximate ambient dose equivalent ranging 20-4500 MUSv/h. PMID- 29136237 TI - Evaluation of the addition of organic acids in the feed and/or water for broilers and the subsequent recovery of Salmonella Typhimurium from litter and ceca. AB - Three separate broiler Salmonella Typhimurium challenge experiments were conducted evaluating efficacy of formic and propionic acid feed supplements to suppress environmental and cecal Salmonella Typhimurium prevalence. In experiment 1, broilers were provided feed with 1 kg/ton formic acid or 5 kg/ton propionic acid feed additives or a basal control diet. At the day of placement, half of the pens were inoculated with seeder chicks orally challenged with a marker strain of Salmonella Typhimurium and to yield challenged and adjacent nonchallenged pens. No differences in weekly litter samples or cecal Salmonella prevalence at 3 or 6 wk among feeding treatments were detected. In experiment 2, treatments were: 2 kg/ton propionic acid in feed, 1.0 mL/L formic acid in water, both propionic acid in feed and formic acid in water, and a basal control. Every pen was challenged with seeder chicks inoculated with Salmonella Typhimurium. By 6 wk all pens maintained detectable litter Salmonella, and broilers provided both propionic acid in feed and formic acid in water had the lowest cecal recovery (35%), compared to the control (60%). In experiment 3, treatments were: formic acid at 4 or 6 kg/ton from wk 0 to 6 or for only the last wk, propionic acid at 5 or 10 kg/ton for only the last wk, and a basal control. Each pen was challenged with Salmonella Typhimurium inoculated seeder chicks. By 6 wk, broilers fed formic acid (4 kg/ton) for the entire growout had no Salmonella-positive ceca (0/30). All treatments that provided acid supplemented feed for only the last wk had 3 13% Salmonella-positive ceca. These experiments indicate that adding formic acid to broiler feed appears to prevent Salmonella colonization from challenge pens entering into the adjacent nonchallenge pens. Feeding formic acid (4 kg/ton) for 6 wk resulted in no recovery of Salmonella from ceca compared to the control prevalence of 17%. PMID- 29136236 TI - Basic Neuroscience Illuminates Causal Relationship Between Sleep and Memory: Translating to Schizophrenia. AB - Patients with schizophrenia are often plagued by sleep disturbances that can exacerbate the illness, including potentiating psychosis and cognitive impairments. Cognitive dysfunction is a core feature of schizophrenia with learning and memory being particularly impaired. Sleep disruptions often accompanying the illness and may be key mechanism that contribute to these core dysfunctions. In this special translational neuroscience feature, we highlight the role of sleep in mediating cognitive function, with a special focus on learning and memory. By defining dysfunctional sleep architecture and rhythms in schizophrenia, we focus on the disarray of mechanisms critical to learning and memory and postulate an association between sleep disturbances and cognitive impairments in the disorder. Lastly, we review preclinical models of schizophrenia and highlight exciting translational research that may lead to new therapeutic approaches to alleviating sleep disturbances and effectively improving cognitive function in schizophrenia. PMID- 29136238 TI - Regulation of transcriptional silencing and chromodomain protein localization at centromeric heterochromatin by histone H3 tyrosine 41 phosphorylation in fission yeast. AB - Heterochromatin silencing is critical for genomic integrity and cell survival. It is orchestrated by chromodomain (CD)-containing proteins that bind to methylated histone H3 lysine 9 (H3K9me), a hallmark of heterochromatin. Here, we show that phosphorylation of tyrosine 41 (H3Y41p)-a novel histone H3 modification participates in the regulation of heterochromatin in fission yeast. We show that a loss-of-function mutant of H3Y41 can suppress heterochromatin de-silencing in the centromere and subtelomere repeat regions, suggesting a de-silencing role for H3Y41p on heterochromatin. Furthermore, we show both in vitro and in vivo that H3Y41p differentially regulates two CD-containing proteins without the change in the level of H3K9 methylation: it promotes the binding of Chp1 to histone H3 and the exclusion of Swi6. H3Y41p is preferentially enriched on centromeric heterochromatin during M- to early S phase, which coincides with the localization switch of Swi6/Chp1. The loss-of-function H3Y41 mutant could suppress the hypersensitivity of the RNAi mutants towards hydroxyurea (HU), which arrests replication in S phase. Overall, we describe H3Y41p as a novel histone modification that differentially regulates heterochromatin silencing in fission yeast via the binding of CD-containing proteins. PMID- 29136239 TI - Changes in Membrane Lipid Composition and Function Accompanying Chilling Injury in Bell Peppers. AB - Bell peppers are vulnerable to low temperature (<7 degrees C) and subject to chilling injury (CI). To elucidate the relationship between cell membrane lipid composition and CI, a membrane lipidomic approach was taken. In addition, we performed microstructural analysis and low-field nuclear magnetic resonance to better understand CI. We also monitored primary physiological metabolism parameters to explain lipidomics. Our study indicated that cellular structure damage was more serious at 4 degrees C, mostly represented by damage to the plasmalemma and plastid degradation. Membrane lipidomic data analysis reveals monogalactosyldiacylglycerol, phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid as crucial biomarkers during CI. Furthermore, the significant increase in proline, electrolyte leakage and phospholipase D in chilled fruits also proved that membrane lipid metabolism is involved in the response to low temperature stress. To our knowledge, this study is the first attempt to describe the CI mechanisms in bell peppers based on membrane lipidomics. PMID- 29136240 TI - Postmortem Autopsy-Confirmation of Antemortem [F-18]FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy. AB - Currently, only presumptive diagnosis of chronic traumatic encephalopathy (CTE) can be made in living patients. We present a modality that may be instrumental to the definitive diagnosis of CTE in living patients based on brain autopsy confirmation of [F-18]FDDNP-PET findings in an American football player with CTE. [F-18]FDDNP-PET imaging was performed 52 mo before the subject's death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest. Upon death, the brain was examined to identify the topographic distribution of neurodegenerative changes. Correlation between neuropathology and [F-18]FDDNP-PET binding patterns was performed using Spearman rank-order correlation. Mood, behavioral, motor, and cognitive changes were consistent with chronic traumatic myeloencephalopathy with a 22-yr lifetime risk exposure to American football. There were tau, amyloid, and TDP-43 neuropathological substrates in the brain with a differential topographically selective distribution. [F-18]FDDNP-PET binding levels correlated with brain tau deposition (rs = 0.59, P = .02), with highest relative distribution volumes in the parasagittal and paraventricular regions of the brain and the brain stem. No correlation with amyloid or TDP-43 deposition was observed. [F-18]FDDNP-PET signals may be consistent with neuropathological patterns of tau deposition in CTE, involving areas that receive the maximal shearing, angular-rotational acceleration-deceleration forces in American football players, consistent with distinctive and differential topographic vulnerability and selectivity of CTE beyond brain cortices, also involving midbrain and limbic areas. Future studies are warranted to determine whether differential and selective [F-18]FDDNP-PET may be useful in establishing a diagnosis of CTE in at-risk patients. PMID- 29136242 TI - Older Adults' Knowledge of Anxiety Disorders. AB - Objectives: The underuse of mental health services for anxiety disorders is particularly pronounced among older adults and could, in part, be explained by a lack of knowledge on this subject in this population. The purpose of this study was to document senior's knowledge of anxiety. Method: Young adults (n = 64) and older adults (n = 78) completed a sociodemographic questionnaire (including clinical variables), the Beck Anxiety Inventory and a questionnaire measuring their knowledge of the various dimensions of anxiety disorders, including symptoms, risk factors, and treatments. Results: Results show that older adults have less knowledge about anxiety disorders than young adults and that this difference is observable for all dimensions assessed. Low level of education is associated with less knowledge of anxiety disorders. Students and those who were employed scored better that those who were retired and those with incomes below $10,000 scored better than those with higher incomes. Discussion: Results show the importance and the diversity of knowledge needs with regards to anxiety disorders among older adults. A strategy to enhance knowledge about anxiety disorders among older adults should be adapted to this specific population (with regards to its delivery approach) and includes diverse domains of knowledge. PMID- 29136241 TI - WikiPathways: a multifaceted pathway database bridging metabolomics to other omics research. AB - WikiPathways (wikipathways.org) captures the collective knowledge represented in biological pathways. By providing a database in a curated, machine readable way, omics data analysis and visualization is enabled. WikiPathways and other pathway databases are used to analyze experimental data by research groups in many fields. Due to the open and collaborative nature of the WikiPathways platform, our content keeps growing and is getting more accurate, making WikiPathways a reliable and rich pathway database. Previously, however, the focus was primarily on genes and proteins, leaving many metabolites with only limited annotation. Recent curation efforts focused on improving the annotation of metabolism and metabolic pathways by associating unmapped metabolites with database identifiers and providing more detailed interaction knowledge. Here, we report the outcomes of the continued growth and curation efforts, such as a doubling of the number of annotated metabolite nodes in WikiPathways. Furthermore, we introduce an OpenAPI documentation of our web services and the FAIR (Findable, Accessible, Interoperable and Reusable) annotation of resources to increase the interoperability of the knowledge encoded in these pathways and experimental omics data. New search options, monthly downloads, more links to metabolite databases, and new portals make pathway knowledge more effortlessly accessible to individual researchers and research communities. PMID- 29136243 TI - Structure and electrical properties of DNA nanotubes embedded in lipid bilayer membranes. AB - Engineering the synthetic nanopores through lipid bilayer membrane to access the interior of a cell is a long persisting challenge in biotechnology. Here, we demonstrate the stability and dynamics of a tile-based 6-helix DNA nanotube (DNT) embedded in POPC lipid bilayer using the analysis of 0.2 MUs long equilibrium MD simulation trajectories. We observe that the head groups of the lipid molecules close to the lumen cooperatively tilt towards the hydrophilic sugar-phosphate backbone of DNA and form a toroidal structure around the patch of DNT protruding in the membrane. Further, we explore the effect of ionic concentrations to the in solution structure and stability of the lipid-DNT complex. Transmembrane ionic current measurements for the constant electric field MD simulation provide the I V characteristics of the water filled DNT lumen in lipid membrane. With increasing salt concentrations, the measured values of transmembrane ionic conductance of the porous DNT lumen vary from 4.3 to 20.6 nS. Simulations of the DNTs with ssDNA and dsDNA overhangs at the mouth of the pore show gating effect with remarkable difference in the transmembrane ionic conductivities for open and close state nanopores. PMID- 29136245 TI - The Religiosity and Spiritual Beliefs and Practices of Clinical Social Workers: A National Survey. AB - This article describes the religious and spiritual beliefs and practices among a national sample of 426 licensed clinical social workers (LCSWs). Given the significant role LCSWs' intrinsic religiosity plays in whether or not they consider clients' religion and spirituality (RS) as it relates to practice, it is critical that the profession best understands current LCSWs' religious and spiritual beliefs, and in what ways these mirror or contrast those of the clients whom they serve. Findings from this secondary analysis of a recent national survey suggest that compared with the general U.S. population, fewer LCSWs self identify as Protestant or Catholic, fewer engage in frequent prayer, and fewer self-identify as religious. However, more LCSWs engage in meditation and consider themselves to be spiritual. Although it appears that RS is an important area in both LCSWs' and clients' lives, the beliefs, practices, and degree of importance with either differ. This article addresses implications for practice and education, as identifying such differing views calls on the profession to strengthen its training surrounding LCSWs' self-awareness of their RS beliefs and recognizing that their clients may not hold similar beliefs or engage in similar practices. PMID- 29136244 TI - A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma. AB - Background: Clinical trials of therapies directed against nodes of the signaling axis of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin (mTOR) in glioblastoma (GBM) have had disappointing results. Resistance to mTOR inhibitors limits their efficacy. Methods: To determine mechanisms of resistance to chronic mTOR inhibition, we performed tandem screens on patient-derived GBM cultures. Results: An unbiased phosphoproteomic screen quantified phosphorylation changes associated with chronic exposure to the mTOR inhibitor rapamycin, and our analysis implicated a role for glycogen synthase kinase (GSK)3B attenuation in mediating resistance that was confirmed by functional studies. A targeted short hairpin RNA screen and further functional studies both in vitro and in vivo demonstrated that microtubule-associated protein (MAP)1B, previously associated predominantly with neurons, is a downstream effector of GSK3B-mediated resistance. Furthermore, we provide evidence that chronic rapamycin induces microtubule stability in a MAP1B-dependent manner in GBM cells. Additional experiments explicate a signaling pathway wherein combinatorial extracellular signal-regulated kinase (ERK)/mTOR targeting abrogates inhibitory phosphorylation of GSK3B, leads to phosphorylation of MAP1B, and confers sensitization. Conclusions: These data portray a compensatory molecular signaling network that imparts resistance to chronic mTOR inhibition in primary, human GBM cell cultures and points toward new therapeutic strategies. PMID- 29136246 TI - Renal function and urological complications after radical hysterectomy with postoperative radiotherapy and platinum-based chemotherapy for cervical cancer. AB - Background: We aimed to clarify renal functional changes long term and serious urological complications in women with cervical cancer who undergo radical hysterectomy followed by pelvic radiotherapy and/or platinum-based chemotherapy to treat the initial disease. Methods: Data on 380 women who underwent radical hysterectomy at the National Kyushu Cancer Center from January 1997 to December 2013 were reviewed. Main outcome measures were the estimated glomerular filtration rate (eGFR) and monitored abnormal urological findings. Results: Postoperative eGFR was significantly lower than preoperative eGFR in 179 women with surgery alone and in 201 women with additional pelvic radiotherapy and/or chemotherapy (both P < 0.01). Two types of univariate analyses for eGFR reduction in women after treatment showed that older age, advanced stage, pelvic radiotherapy, and platinum-based chemotherapy were significant variables on both analyses. Two types of multivariate analyses showed that platinum-based chemotherapy or pelvic radiotherapy were associated with impaired renal function (odds ratio 1.96, 95% confidence interval 1.08-3.54 and odds ratio 2.85, 95% confidence interval 1.12-7.24, for the respective analyses). There was a higher rate of bladder wall thickening in women with pelvic radiotherapy had than those without it (17.4% vs. 2.7%, P < 0.01). One serious urological complication (intraperitoneal rupture of the bladder) occurred among women who underwent pelvic radiotherapy (0.6% vs. 0%). Conclusions: Surgeons should be aware that eGFR is reduced after platinum-based chemotherapy and/or postoperative pelvic radiotherapy. Serious and life-threatening urological complications are rare, but surgeons should be aware of the possibility during the long follow-up. PMID- 29136247 TI - Behavioral Mental Health: An Emerging Field of Service or an Oxymoron? AB - Proliferation in the use of the terminology around behavioral mental health suggests, on one hand, an emerging field of service that integrates psychiatric, substance abuse, and related services. On the other hand, this development also raises questions about the coherence of this approach. This review explores the history, definitional issues, current trends, and available data on the impact of this field. It considers a variety of critiques of behavioral mental health, such as possibility that the field attempts to integrate fundamentally incompatible domains, that the term "behavioral mental health" is thus an oxymoron, and that it represents a co-optation by the insurance industry of traditional ideals of mental health and of behavioral medicine or as code for the implementation of a medical model that emphasizes short-term, behavioral, and psychopharmacological treatments at the expense of a truly biopsychosocial orientation. Other concerns include the focus on individual change and the effectiveness of behavioral health as a strategy for destigmatizing mental health. Recommendations for addressing the various barriers to realizing the ideals of behavioral mental health include revamping the role of managed care in oversight of treatment decisions, broadening the implementation of evidence-based treatment, and the development of treatment models that build on traditional social work practice models. PMID- 29136248 TI - DETERMINATION OF NATIONAL DIAGNOSTIC REFERENCE LEVELS IN COMPUTED TOMOGRAPHY EXAMINATIONS OF IRAN BY A NEW QUALITY CONTROL-BASED DOSE SURVEY METHOD. AB - National diagnostic reference levels (NDRLs) of Iran were determined for the four most common CT examinations including head, sinus, chest and abdomen/pelvis. A new 'quality control (QC)-based dose survey method', as developed by us, was applied to 157 CT scanners in Iran (2014-15) with different slice classes, models and geographic spread across the country. The NDRLs for head, sinus, chest and abdomen/pelvis examinations are 58, 29, 12 and 14 mGy for CTDIVol and 750, 300, 300 and 650 mGy.cm for DLP, respectively. The 'QC-based dose survey method' was further proven that it is a simple, accurate and practical method for a time and cost-effective NDRLs determination. One effective approach for optimization of the CT examination protocols at the national level is the provision of an adequate standardized training of the radiologists, technicians and medical physicists on the patient radiation protection principles and implementation of the DRL concept in clinical practices. PMID- 29136249 TI - Natural Polyphenol Chlorogenic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Activating ERK/Nrf2 Antioxidative Pathway. AB - Hepatotoxicity due to acetaminophen (APAP) overdose is a leading cause of drug induced acute liver failure in clinic. Chlorogenic acid (CGA), a dietary polyphenol, was reported to prevent APAP-induced liver injury in our previous studies. This study aims to investigate the protection provided by CGA against APAP-induced hepatotoxicity via focusing on nuclear factor erythroid 2-related factor 2 (Nrf2) and extracellular regulated protein kinases (ERK)1/2. CGA prevented APAP-induced oxidative liver injury and enhanced Nrf2 activation in mice and in hepatocytes in vitro. CGA-provided the protection against APAP induced hepatotoxicity was diminished after the application of Nrf2 siRNA in vitro and Nrf2 knockout mice in vivo. CGA enhanced the expression of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1), and their inhibitors reduced the protection provided by CGA against APAP-induced cytotoxicity in hepatocytes. Molecular docking results indicated the potential interaction of CGA with Nrf2 binding site in Kelch-like ECH-associating protein-1 (Keap1). CGA decreased the expression of protein phosphatases including PP2A subunit A (PP2A-A) and PP5, and induced the sustained ERK1/2 phosphorylation. Moreover, ERK1/2 inhibitors (U0126 and PD98059) and ERK2 siRNA abrogated CGA induced Nrf2 phosphorylation and its subsequent transcriptional activation, and also reduced the protection provided by CGA against APAP-induced cytotoxicity in hepatocytes. These results suggest that CGA protects against APAP-induced hepatotoxicity by activating Nrf2 antioxidative signaling pathway via blocking the binding of Nrf2 to its inhibitor protein Keap1, and ERK1/2 plays a critical role in regulating CGA-induced Nrf2 transcriptional activation. CGA is a promising therapeutic agent for the detoxification of APAP-induced hepatotoxicity. PMID- 29136251 TI - C/EBPbeta mediates RNA polymerase III-driven transcription of oncomiR-138 in malignant gliomas. AB - MicroRNA-138 (miR-138) is a pro-survival oncomiR for glioma stem cells. In malignant gliomas, dysregulated expression of microRNAs, such as miR-138, promotes Tumour initiation and progression. Here, we identify the ancillary role of the CCAAT/enhancer binding protein beta (C/EBPbeta) as a transcriptional activator of miR-138. We demonstrate that a short 158 bp DNA sequence encoding the precursor of miR-138-2 is essential and sufficient for transcription of miR 138. This short sequence includes the A-box and B-box elements characteristic of RNA Polymerase III (Pol III) promoters, and is also directly bound by C/EBPbeta via an embedded 'C/EBPbeta responsive element' (CRE). CRE and the Pol III B-box element overlap, suggesting that C/EBPbeta and transcription factor 3C (TFIIIC) interact at the miR-138-2 locus. We propose that this interaction is essential for the recruitment of the RNA Pol III initiation complex and associated transcription of the oncomiR, miR-138 in malignant gliomas. PMID- 29136250 TI - Genetic Overlap Between Schizophrenia and Volumes of Hippocampus, Putamen, and Intracranial Volume Indicates Shared Molecular Genetic Mechanisms. AB - Schizophrenia (SCZ) is associated with differences in subcortical brain volumes and intracranial volume (ICV). However, little is known about the underlying etiology of these brain alterations. Here, we explored whether brain structure volumes and SCZ share genetic risk factors. Using conditional false discovery rate (FDR) analysis, we integrated genome-wide association study (GWAS) data on SCZ (n = 82315) and GWAS data on 7 subcortical brain volumes and ICV (n = 11840). By conditioning the FDR on overlapping associations, this statistical approach increases power to discover genetic loci. To assess the credibility of our approach, we studied the identified loci in larger GWAS samples on ICV (n = 26577) and hippocampal volume (n = 26814). We observed polygenic overlap between SCZ and volumes of hippocampus, putamen, and ICV. Based on conjunctional FDR < 0.05, we identified 2 loci shared between SCZ and ICV implicating genes FOXO3 (rs10457180) and ITIH4 (rs4687658), 2 loci shared between SCZ and hippocampal volume implicating SLC4A10 (rs4664442) and SPATS2L (rs1653290), and 2 loci shared between SCZ and volume of putamen implicating DCC (rs4632195) and DLG2 (rs11233632). The loci shared between SCZ and hippocampal volume or ICV had not reached significance in the primary GWAS on brain phenotypes. Proving our point of increased power, 2 loci did reach genome-wide significance with ICV (rs10457180) and hippocampal volume (rs4664442) in the larger GWAS. Three of the 6 identified loci are novel for SCZ. Altogether, the findings provide new insights into the relationship between SCZ and brain structure volumes, suggesting that their genetic architectures are not independent. PMID- 29136252 TI - Promoting Reentry Well-Being: A Novel Assessment Tool for Individualized Service Assignment in Prisoner Reentry Programs. PMID- 29136253 TI - Fatty Degeneration of the Rotator Cuff Reflects Shoulder Strength Deficits in Patients With Rotator Cuff Tears. AB - Fatty degeneration is an important clinical factor in patients with rotator cuff tears. Goutallier grade, occupation ratio, and tangent sign help identify fatty degeneration; however, little is known about how closely these measurement techniques correlate with actual muscle strength deficits. The authors evaluated each method's ability to determine the correlation between fatty degeneration and muscle strength deficits. The authors included 203 patients who underwent full thickness rotator cuff repair (mean age, 61.29+/-7.92 years). All patients were evaluated with preoperative magnetic resonance imaging to identify fatty degeneration and with an isokinetic test to determine actual shoulder strength. Fatty degeneration was evaluated using Goutallier grade, occupation ratio, and tangent sign. The actual shoulder strength deficit was evaluated by abduction, whereas external and internal rotation were tested using the isokinetic test. More severe fatty degeneration was correlated with lower degrees of abduction, external rotation, and internal rotation. The occupation ratio was more closely correlated with actual muscle strength deficits. However, in patients with massive tears, the correlation between fatty degeneration and muscle strength was less pronounced. Tangent sign (+) findings had a significantly lower strength of external rotation and abduction. The fatty degeneration of the rotator cuff muscle measured by each method was correlated with actual shoulder strength deficits in patients with rotator cuff tears. However, the correlations were less clear in patients with massive rotator cuff tears. Therefore, in cases of massive rotator cuff tears, fatty degeneration was correlated with muscle strength deficits but was not directly proportional to their extent. [Orthopedics. 2018; 41(1):e15-e21.]. PMID- 29136254 TI - Completion of Multiple Fellowships by Orthopedic Surgeons: Analysis of the American Board of Orthopaedic Surgery Certification Database. AB - Orthopedic surgeons have become increasingly subspecialized, and recent studies have shown that American Board of Orthopaedic Surgery (ABOS) Step II applicants are performing a higher percentage of their cases within their chosen subspecialties. However, these studies focused exclusively on surgeons who have completed a single fellowship; little data exist on those who pursue a second fellowship. All applicants to the ABOS Part II examination from 2004 to 2016 were classified by their self-reported fellowship training history using the ABOS Part II examination database. Trends in the number of applicants completing multiple fellowships and the types of fellowships combined were analyzed. In addition, cases performed by applicants who had performed multiple fellowships were analyzed to determine what percentage were within their chosen subspecialties. A total of 9776 applicants to ABOS Part II were included in the database from 2004 to 2016, including 444 (4.5%) applicants who completed more than one fellowship. There were 43 different combinations of fellowships; the most common additional fellowships were trauma (40.1%), sports medicine (38.7%), and joints (30.4%). The most common combinations were joints and sports medicine (10.6%) and foot and ankle and sports medicine (10.1%). A significant increase occurred in physicians training in both pediatric orthopedics and sports medicine (P=.02). The percentage of cases within the applicants' chosen specialties ranged from 91.4% in sports to 73.6% in tumor. Multiple fellowship applicants represent a small percentage of all applicants, and although subspecialization in orthopedics is increasing, no increasing trend toward multiple fellowships within this dataset was observed. However, the significant increase in applicants who combined pediatric orthopedic and sports medicine fellowships suggests an increasing interest in treating this increasing patient population in addition to social and economic factors. [Orthopedics. 2018; 41(1):e33-e37.]. PMID- 29136255 TI - Loss of Internal Tibial Rotation After Anterior Cruciate Ligament Reconstruction. AB - The flexion angle of the knee and the position of the tibia need to be considered during tensioning of the anterior cruciate ligament (ACL) graft to avoid overconstraining the knee. The purpose of this report was to describe 2 cases of loss of tibial internal rotation after single-bundle anatomic ACL reconstruction with graft tensioning in flexion. Retrospective review of each patient's operative chart revealed that the graft was tensioned in flexion and placed in an anatomic position in the femoral tunnel at the time of the index operation. Primary outcome was ACL revision surgery. Secondary outcome data included Lysholm scores and Lachman and pivot shift tests. Two patients underwent revision ACL reconstruction with a more vertical tunnel placed through a transtibial technique. The graft was tensioned in full knee extension and neutral rotation of the tibia. This resulted in restoration of normal tibial internal rotation to 10 degrees . Lysholm scores improved from 35 to 90 in patient 1 and from 12 to 61 in patient 2. Patient 1 returned to college soccer at 6 months postoperatively. Her knee was stable to Lachman and pivot shift tests. Patient 2 has been followed for 12 months and has returned to all normal activities without pain or dysfunction. Anatomic femoral placement of the ACL with improper positioning of the knee during tensioning of the graft may capture the knee and lead to loss of the normal internal rotation. The surgeon should be aware of this complication during primary ACL reconstruction. [Orthopedics. 2018; 41(1):e22-e26.]. PMID- 29136256 TI - Incidence of and Risk Factors for Inpatient Stroke After Hip Fractures in the Elderly. AB - Although uncommon, stroke can be a catastrophic inpatient complication for patients with hip fractures. The current study determines the incidence of inpatient stroke after hip fractures in elderly patients, identifies risk factors associated with such strokes, and determines the association of stroke with short term inpatient outcomes. A retrospective review of all patients aged 65 years or older with isolated hip fractures in the 2011 and 2012 National Trauma Data Bank was conducted. A total of 37,584 patients met inclusion criteria. Of these patients, 162 (0.4%) experienced a stroke during their hospitalization for the hip fracture. In multivariate analysis, a history of prior stroke (odds ratio [OR], 13.24), coronary artery disease (OR, 2.05), systolic blood pressure 180 mm Hg or higher (OR, 1.66), and bleeding disorders (OR, 1.65) were associated with inpatient stroke. Inpatient stroke was associated with increased mortality (OR, 7.17) and inpatient serious adverse events (OR, 6.52). These findings highlight the need for vigilant care of high-risk patients, such as those with a history of prior stoke, and for an understanding that patients who experience an inpatient stroke after a hip fracture are at significantly increased risk of mortality and inpatient serious adverse events. [Orthopedics. 2018; 41(1):e27-e32.]. PMID- 29136257 TI - Risk Factors for Pathological Fracture and Metastatic Epidural Spinal Cord Compression in Patients With Spinal Metastases. AB - Vertebral pathological fracture and metastatic epidural spinal cord compression (MESCC) due to metastatic cancer inevitably cause pain, neurological deficit, impaired function, and decreased quality of life and are indications for surgery. In such cases, earlier surgical intervention has the potential to prevent permanent neurological deficit and disability and to maintain function and quality of life. Therefore, the aim of this study was to identify and evaluate risk factors for pathological fracture and MESCC in patients with spinal metastases. Retrospective assessment of clinical and radiological parameters was undertaken in patients with spinal metastases. Seventy-two patients with spinal metastases underwent decompressive and/or stabilization surgery for pathological fracture and/or MESCC or nerve root compression. The following items were assessed for association with pathological fracture or MESCC: tumor size, location, type, and morphology; disease burden; pain; and function. Pain, tumor size within the vertebral body, vertebral endplate and 3-column involvement, primary tumor growth rate, and multiple vertebral metastases were associated with increased risk for pathological fracture. Vertebral posterior element and costovertebral joint involvement by tumor, primary tumor growth rate, and the presence of visceral metastases were associated with MESCC or nerve root compression. These factors should be considered in the decision-making process for surgery for spinal metastases. Patients with osteolytic spinal metastatic lesions causing pain, greater than 25% occupancy of the vertebral body, and involvement of the vertebral endplate or all 3 columns should be considered for prophylactic or therapeutic decompressive and stabilization surgery. [Orthopedics. 2018; 41(1):e38-e45.]. PMID- 29136258 TI - Ultra-Short Versus Conventional Uncemented Stems for Hip Replacement in Octogenarians. AB - The aim of this study was to determine how an ultra-short anatomic uncemented stem vs a diaphyseal filling five-eighths porous coated uncemented femoral stem (conventional stem) affects the survival of primary total hip arthroplasties in octogenarians. The current study consisted of 52 patients (55 hips) in the ultra short stem group (mean age, 85.5+/-5.3 years) and 61 patients (72 hips) in the diaphyseal (conventional) stem group (mean age, 84.1+/-4.8 years). The predominant diagnosis was osteoarthritis, followed by osteonecrosis of the femoral head, in both groups. Average follow-up was 6.1 years (range, 5-8 years) in the ultra-short stem group and 6.3 years (range, 5-9 years) in the conventional stem group. Pre- (41 vs 39 points) and postoperative (85 vs 86 points) Harris hip scores were similar between groups (P=.131 and .129, respectively). The incidence of thigh pain was 0% (0 of 52 patients) in the ultra short stem group and 15% (9 of 61 patients) in the conventional stem group. The revision rate was 1.8% (1 hip) in the ultra-short stem group and 1.4% (1 hip) in the conventional stem group. Survivorship of the femoral stem was 98.2% in the ultra-short stem group at 6.1 years and 98.6% in the conventional stem group at 6.3 years. Ultra-short anatomic and diaphyseal filling uncemented stems obtained osseointegration in all hips. However, the prevalence of thigh pain and periprosthetic fracture were significantly higher in the patients with a conventional stem than in those with an ultra-short stem. [Orthopedics. 2018; 41(1):28-34.]. PMID- 29136259 TI - Risk Factors for Surgical Site Infections in Dermatological Surgery. AB - Current literature on risk factors for surgical site infection (SSI) in dermatological surgery in the absence of antibiotic prophylaxis is limited. The aim of this study was to retrospectively evaluate patients presenting for dermatological surgery. A total of 1,977 procedures were reviewed. SSI was clinically suspected in 79 (4.0%) patients and confirmed by culture in 38 (1.9%). Using the strictest definition of SSI (clinical symptoms with positive culture) significantly higher risk of SSI was found for location on the ear (odds ratio (OR) 6.03, 95% confidence interval (95% CI) 2.12-17.15), larger defects (OR 1.08 per cm2 increase, 95% CI 1.03-1.14), closure with flaps (OR 6.35, 95% CI 1.33 30.28) and secondary intention (OR 3.01, 95% CI 1.11-8.13). These characteristics were also associated with higher risk of clinically suspected SSI regardless of culture results with slightly lower ORs. In conclusion, the risk of acquiring a SSI is increased in surgeries performed on the ear, in larger wounds and in defects closed with flaps or healed by secondary intention. PMID- 29136260 TI - Localized Scleroderma, Systemic Sclerosis and Cardiovascular Risk: A Danish Nationwide Cohort Study. AB - Recent findings indicate that patients with systemic sclerosis have an increased risk of cardiovascular disease. To determine whether patients with systemic sclerosis or localized scleroderma are at increased risk of cardiovascular disease, a cohort study of the entire Danish population aged >= 18 and <= 100 years was conducted, followed from 1997 to 2011 by individual-level linkage of nationwide registries. Multivariable adjusted Cox regression models were used to estimate the hazard ratios (HRs) for a composite cardiovascular disease endpoint. A total of 697 patients with localized scleroderma and 1,962 patients with systemic sclerosis were identified and compared with 5,428,380 people in the reference population. In systemic sclerosis, the adjusted HR was 2.22 (95% confidence interval 1.99-2.48). No association was seen between patients with localized scleroderma and cardiovascular disease. In conclusion, systemic sclerosis is a significant cardiovascular disease risk factor, while patients with localized scleroderma are not at increased risk of cardiovascular disease. PMID- 29136261 TI - Decrease in Diversity of Propionibacterium acnes Phylotypes in Patients with Severe Acne on the Back. AB - Propionibacterium acnes, a major member of normal skin microbiota, is subdivided into 6 phylotypes: IA1, IA2, IB, IC, II and III. This study investigated P. acnes subgroups on the face and back in patients with severe acne and in healthy controls. In 71.4% of patients with severe acne, P. acnes phylotypes were identical on the face and back, whereas this was the case in only 45.5% of healthy controls. The healthy group carried phylotypes IA1 (39.1%) and II (43.4%), whereas the acne group carried a high predominance of IA1 (84.4%), especially on the back (95.6%). In addition, the single-locus sequence typing (SLST) method revealed A1 to be the predominant type on the back of patients with acne, compared with a wide diversity in the healthy group. We report here that severity of acne on the back is associated with loss of diversity of P. acnes phylotype, with a major predominance of phylotype IA1. The change in balance of cutaneous P. acnes subgroups might be an inducing factor in the activation of P. acnes, which could trigger inflammation. PMID- 29136262 TI - Treatment of Cutaneous Pseudolymphoma: A Systematic Review. AB - Cutaneous pseudolymphoma (CPL) is a reactive polyclonal T- or B-cell lymphoproliferative process. CPL may appear as localized or disseminated skin lesions. While most cases of CPL are idiopathic, they may also occur as a response to, for example, contact dermatitis, arthropod reactions, and bacterial infections. CPL can be classified based on its clinical features, but all variants have similar histopathological patterns of either predominantly B-cell infiltrates, T-cell infiltrates, or mixed T/B-cell infiltrates. The prognosis of CPL is good, but the underlying disease process should be taken into account. If an antigenic stimulus is identified, it should be removed. In patients with idiopathic CPL, a close follow-up control strategy should be adopted. The aim of this systematic review is to summarize all reported treatments for CPL. The review was based on articles from the PubMed database, using the query "skin pseudolymphoma treatment", English and German, about "human" subjects, and published between 1990 and 2015 documenting adequate treatment and/or aetiology. Mainly individual case reports and small case series were found. Treatment options include topical and intralesional agents, systemic agents, and physical modalities. The final part of the review proposes a treatment algorithm for CPL according to each aetiology, based on the literature of the last 25 years. Future research should focus on randomized controlled trials and studies on long-term outcomes, which were not identified in the current review. PMID- 29136263 TI - Treatment of Scleroedema Adultorum Buschke: A Systematic Review. AB - Scleroedema adultorum Buschke is a rare skin disease, which can be divided into 3 subtypes: classic type, occurring after respiratory infections; a type lacking association with infections; and a type associated with diabetes. Scleroedema adultorum Buschke is characterized by thickening and tightening of the skin, which typically starts at the neck. In half of patients, spontaneous remission may occur. The aim of this systematic review is to summarize all reported treatments for scleroedema adultorum Buschke, based on articles from PubMed database, using the query "scleroedema adultorum Buschke treatment", English and German, published between 1970 and 2016 and documenting adequate treatments. The results are based mainly on individual case reports, small case series, and retrospective studies often reporting unsuccessful results. Treatment options include topical as well as systemic treatments, and physical modalities. There is a need for randomized controlled trials and studies on long-term outcomes after treatment. PMID- 29136264 TI - Biological and Clinical Response to Omalizumab in a Patient with Bullous Pemphigoid. PMID- 29136265 TI - Generalized Bullous Fixed Drug Eruption Following Metamizole (Re-)Exposure: A Medical Error-analytic Case Study. PMID- 29136266 TI - Prostanoids and Hair Follicles: Implications for Therapy of Hair Disorders. AB - Prostanoids, including prostaglandins (PGs) and thromboxane A2 (TXA2), are a family of lipid-derived autacoids that modulate many physiological systems and pathological contexts. Prostanoids are generated by sequential metabolism of arachidonic acid, catalysed by cyclo-oxygenase, to PGH2, which is then converted to PGD2, PGE2, PGF2alpha, PGI2 and TXA2, catalysed by their specific synthases. Recent evidence suggests that prostanoids play a role in regulating hair growth. The PGF2alpha analogue is Food and Drug Administration-approved in the US and routinely used to enhance the growth of human eyelashes. PGE2 is reported to protect from radiation-induced hair loss in mice. Conversely, PGD2 inhibits hair growth. This paper reviews the metabolism of prostanoids and the expression pattern of prostanoid receptors in hair follicles, focussing on their different and opposing effects on hair growth and the underlying mechanisms. This has potential clinical relevance in the treatment and prevention of hair disorders. PMID- 29136267 TI - The Regibul Register: A Tool for Monitoring the Distribution and Incidence of Autoimmune Bullous Dermatoses in Three French Regions, 2010 to 2015. PMID- 29136268 TI - Allopurinol Co-prescription Improves the Outcome of Azathioprine Treatment in Chronic Eczema. PMID- 29136269 TI - Earthquake loss estimates help and challenge medical disaster responders. PMID- 29136271 TI - Emergency preparedness training preferences and perceived barriers to training among various healthcare providers and public health practitioners in Massachusetts. AB - INTRODUCTION: Emergency preparedness training is vital to a wide range of healthcare and public health disciplines. Although agencies may try to tailor their training efforts based on perceived need, the topics and methods of instruction may be misguided, resulting in wasted effort and poor participation in training events. OBJECTIVE: The objective of this study was to understand in a rigorous way, the training preferences and barriers to training among practitioners in Massachusetts. METHODS: In August 2013, the Massachusetts Department of Public Health distributed an online survey to health professionals in Massachusetts regarding their emergency preparedness training topic preferences and any perceived barriers and challenges associated with obtaining this training. A total of 796 healthcare and public health professionals responded to the survey and answered some or all of the questions asked. RESULTS: The results of the survey identified important differences in preference for some topics based on a provider's practice location and discipline. However, Community Recovery and Community Preparedness were seen as desirable by all disciplines with more than 80 percent of respondents rating each of these issues as being highly important. Barriers to training were also assessed. Time spent away from work was the most commonly identified barrier (77.41 percent). Travel distance and financial constraints were also rated highly with scores of 65.48 and 63.71 percent, respectively. CONCLUSIONS: This study demonstrates important areas of agreement with respect to desired training topics and points out areas where providers in different disciplines and from different geographic areas may have differing educational preferences. Even within the limitation of this investigation, we expect that this study will be a valuable tool for those attempting to effectively target emergency preparedness training and structure course offerings in ways that minimize the impact of barriers to training. PMID- 29136270 TI - 60 seconds to survival: A pilot study of a disaster triage video game for prehospital providers. AB - INTRODUCTION: Disaster triage training for emergency medical service (EMS) providers is not standardized. Simulation training is costly and time-consuming. In contrast, educational video games enable low-cost and more time-efficient standardized training. We hypothesized that players of the video game "60 Seconds to Survival" (60S) would have greater improvements in disaster triage accuracy compared to control subjects who did not play 60S. METHODS: Participants recorded their demographics and highest EMS training level and were randomized to play 60S (intervention) or serve as controls. At baseline, all participants completed a live school-shooting simulation in which manikins and standardized patients depicted 10 adult and pediatric victims. The intervention group then played 60S at least three times over the course of 13 weeks (time 2). Players triaged 12 patients in three scenarios (school shooting, house fire, tornado), and received in-game performance feedback. At time 2, the same live simulation was conducted for all participants. Controls had no disaster training during the study. The main outcome was improvement in triage accuracy in live simulations from baseline to time 2. Physicians and EMS providers predetermined expected triage level (RED/YELLOW/GREEN/BLACK) via modified Delphi method. RESULTS: There were 26 participants in the intervention group and 21 in the control group. There was no difference in gender, level of training, or years of EMS experience (median 5.5 years intervention, 3.5 years control, p = 0.49) between the groups. At baseline, both groups demonstrated median triage accuracy of 80 percent (IQR 70-90 percent, p = 0.457). At time 2, the intervention group had a significant improvement from baseline (median accuracy = 90 percent [IQR: 80-90 percent], p = 0.005), while the control group did not (median accuracy = 80 percent [IQR:80-95], p = 0.174). However, the mean improvement from baseline was not significant between the two groups (difference = 6.5, p = 0.335). CONCLUSION: The intervention demonstrated a significant improvement in accuracy from baseline to time 2 while the control did not. However, there was no significant difference in the improvement between the intervention and control groups. These results may be due to small sample size. Future directions include assessment of the game's effect on triage accuracy with a larger, multisite site cohort and iterative development to improve 60S. PMID- 29136272 TI - Are you ready? Crisis leadership in a hyper-VUCA environment. AB - The current hyper-volatile, -uncertain, -complex, and -ambiguous (VUCA) threat environment demands a more cohesive support structure for crisis leaders who may be faced with crises of increasing magnitude and frequency and, in some instances, multiple crisis events simultaneously. The project team investigates the perceptions of crisis leaders regarding establishing a crisis leader advisor position for crisis leaders to benefit from their experience while prosecuting crisis response activities. The team linked hyper-VUCA crises, crisis response frameworks, meta-leadership, crisis leader attributes, and advisor attributes. The overall goal of the project is to increase the ability of the crisis leaders to more effectively and efficiently navigate crisis events resulting in more efficient and effective response and recovery. Three research questions were developed to assess the following: thoughts of integrating a crisis leader advisor position; development of a crisis leader advisor certification program; and attributes of crisis leader advisors. A qualitative research methodology using a phenomenological approach was employed. Forty-one participants were purposefully selected and administered a short, online survey consisting of 11 questions. Data were analyzed using percentage analysis, weighted sums, and inductive thematic analysis. The project team found an overwhelming support for the crisis leader advisor position and the crisis leader advisor certification program. Additionally, experience and trustworthiness ranked among the top sought after attributes of a crisis leader advisor. The team recommendations included (1) implement a crisis leaders advisor guide/framework; (2) create a formal crisis leader advisor position in national incident management system; (3) implement a crisis leader advisor certification framework; (4) benchmark established advisor programs; and (5) implement a framework to match leaders and advisors. PMID- 29136273 TI - FOXE3 mutations: genotype-phenotype correlations. AB - Microphthalmia and anophthalmia (MA) are severe developmental eye anomalies, many of which are likely to have an underlying genetic cause. More than 30 genes have been described, each of which is responsible for a small percentage of these anomalies. Among these, is the FOXE3 gene, which was initially described in individuals with dominantly inherited anterior segment dysgenesis and, subsequently, associated with recessively inherited primary aphakia, sclerocornea and microphthalmia. In this work, we describe 8 individuals presenting with an MA phenotype. Among them, 7 are carrying biallelic recessive FOXE3 mutations and 2 of these have novel mutations: p.(Ala78Thr) and p.(Arg104Cys). The last of our patients is carrying in the heterozygous state the recessive p.(Arg90Leu) mutation in the FOXE3 gene. To further understand FOXE3 involvement in this wide spectrum of ocular anomalies with 2 different patterns of inheritance, we reviewed all individuals with ocular abnormalities described in the literature for which a FOXE3 mutation was identified. This review demonstrates that correlations exist between the mutation type, mode of inheritance and the phenotype severity. Furthermore, understanding the genetic basis of these conditions will contribute to overall understanding of eye development, improve the quality of care, genetic counseling and, in future, gene-based therapies. PMID- 29136274 TI - Diagnostic accuracy of magnetic resonance imaging in detecting the severity of abnormal invasive placenta: a systematic review and meta-analysis. AB - INTRODUCTION: Accurate prenatal diagnosis of abnormally invasive placenta (AIP) is fundamental because it significantly reduces maternal morbidities. MATERIAL AND METHODS: Medline, Embase, CINAHL and the Cochrane databases were searched. The primary aim of the present review was to elucidate the diagnostic accuracy of prenatal magnetic resonance imaging (MRI) in recognizing the severity of AIP, defined as the depth and topography of invasion. The secondary aim was to ascertain the strength of association between each MRI sign and the depth of placental invasion and to test their individual predictive accuracy in detecting such invasion. Inclusion criteria were studies on women who had prenatal MRI for ultrasound suspicion or the presence of clinical risk factors for AIP. Estimates of sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratio were calculated using the hierarchical summary receiver characteristics curve model, and individual data random-effect logistic regression was used to calculate OR. RESULTS: Twenty studies (1080 pregnancies undergoing MRI mainly for the ultrasound suspicion of AIP) were included. MRI showed a sensitivity of 94.4% [95% confidence interval (CI) 15.8-99.9], 100% (95% CI 75.3-100) and 86.5% (95% CI 74.2-94.4) for detection of placenta accreta, increta and percreta, respectively; the corresponding values for specificity were 98.8% (95% CI 70.7-100), 97.3% (95% CI 93.3-99.3), 96.8% (95% CI 93.5-98.7). MRI identified 100% of cases with S1 and 100% of those with S2 invasion confirmed at surgery. Among the different MRI signs, intra-placental dark bands showed the best sensitivity for the detection of placenta accreta, increta and percreta; as well as abnormal intra-placental vascularity, uterine bulging was associated with a higher risk of increta and percreta, exophitic mass and bladder tenting with placenta percreta. CONCLUSION: Prenatal MRI has an excellent diagnostic accuracy in identifying the depth and the topography of placental invasion. However, these findings come mainly from studies in which MRI was performed as a secondary imaging tool in women already screened for AIP on ultrasound and might not reflect its actual diagnostic performance in detecting the severity of these disorders. PMID- 29136275 TI - Subterranean flowers of Aspidistra elatior are mainly pollinated by not terrestrial amphipods but fungus gnats. PMID- 29136277 TI - Homozygous XYLT2 variants as a cause of spondyloocular syndrome. AB - Spondyloocular syndrome (SOS) is a rare autosomal recessive, skeletal disorder. Two recent studies have shown that it is the result of biallelic sequence variants in the XYLT2 gene with pleiotropic effects in multiple organs, including retina, heart muscle, inner ear, cartilage, and bone. The XYLT2 gene encodes xylosyltransferase 2, which catalyzes the transfer of xylose (monosaccharide) to the core protein of proteoglycans (PGs) leading to initiating the process of PG assembly. SOS was originally characterized in 2 families A and B of Iraqi and Turkish origin, respectively. Using DNA from affected members of the same 2 families, we performed whole exome sequencing, which revealed 2 novel homozygous missense variants (c.1159C > T, p.Arg387Trp) and (c.2548G > C, p.Asp850His). Our findings extend the body of evidence that SOS is caused by homozygous variants in the XYLT2 gene. In addition, this report has extended the phenotypic description of SOS by adding follow-up data from 5 affected individuals in one of the two families, presented here. PMID- 29136278 TI - A critical appraisal of pharmacogenetic inference. AB - In essence, pharmacogenetic research is aimed at discovering variants of importance to gene-treatment interaction. However, epidemiological studies are rarely set up with this goal in mind. It is therefore of great importance that researchers clearly communicate which assumptions they have had to make, and which inherent limitations apply to the interpretation of their results. This review discusses considerations of, and the underlying assumptions for, utilizing different response phenotypes and study designs popular in pharmacogenetic research to infer gene-treatment interaction effects, with a special focus on those dealing with of clinical effects of drug treatment. PMID- 29136279 TI - Ultrasound in the evaluation of neuromuscular complications of radiation therapy. PMID- 29136276 TI - Targeted Therapies: Immunologic Effects and Potential Applications Outside of Cancer. AB - Two pharmacologic approaches that are currently at the forefront of treating advanced cancer are those that center on disrupting critical growth/survival signaling pathways within tumor cells (commonly referred to as "targeted therapies") and those that center on enhancing the capacity of a patient's immune system to mount an antitumor response (immunotherapy). Maximizing responses to both of these approaches requires an understanding of the oncogenic events present in a given patient's tumor and the nature of the tumor-immune microenvironment. Although these 2 modalities were developed and initially used independently, combination regimens are now being tested in clinical trials, underscoring the need to understand how targeted therapies influence immunologic events. Translational studies and preclinical models have demonstrated that targeted therapies can influence immune cell trafficking, the production of and response to chemokines and cytokines, antigen presentation, and other processes relevant to antitumor immunity and immune homeostasis. Moreover, because these and other effects of targeted therapies occur in nonmalignant cells, targeted therapies are being evaluated for use in applications outside of oncology. PMID- 29136280 TI - TransitQA - A new method for transit dosimetry of Tomotherapy patients. AB - PURPOSE: TransitQA is an innovative method for Tomotherapy transit dosimetry using the on-board detector (OBD). Our previously published model for Tomotherapy treatment plan verification (AirQA) has been enhanced to take into account patient and couch transmission. AirQA estimates the OBD signal during irradiation with nothing in the beam path from the leaf control sinogram, allowing us to check whether the planned treatment is correctly delivered by the machine. TransitQA allows us to check the treatment delivery with the patient on the couch, potentially showing the effects of changes in the patient anatomy and delivery errors. METHODS: Patient and couch transmission have been added to the model using the OBD projections of pretreatment megavoltage computed tomography (MVCT). The difference in the energy spectra between the imaging and treatment beams has been corrected by an exponent from the MVCT projections consisting of the ratio of the mass attenuation coefficients. This exponent has been found to not vary significantly with the atomic number Z, allowing us to apply this procedure to heterogeneous media, such as patients. The attenuated OBD projections acquired during the treatment are compared to the model via a signed global gamma-index analysis. The dose criterion was 5% of the 95th percentile of the dose distribution, and the distance to agreement (DTA) was 4 mm. RESULTS: Our method has been applied to a heterogeneous phantom with 98.1% of the points passing the gamma-evaluation test, showing that the model can predict the attenuated OBD projection. The method has been applied to two representative patients throughout the whole treatment, highlighting variations in the signal transmission and gamma-index. CONCLUSION: This paper establishes the proof-of concept of transit dosimetry for all patients treated by Tomotherapy. Moreover, this method can be used as a surrogate for in vivo dosimetry. PMID- 29136281 TI - Genetic prediction of type 2 diabetes using deep neural network. AB - Type 2 diabetes (T2DM) has strong heritability but genetic models to explain heritability have been challenging. We tested deep neural network (DNN) to predict T2DM using the nested case-control study of Nurses' Health Study (3326 females, 45.6% T2DM) and Health Professionals Follow-up Study (2502 males, 46.5% T2DM). We selected 96, 214, 399, and 678 single-nucleotide polymorphism (SNPs) through Fisher's exact test and L1-penalized logistic regression. We split each dataset randomly in 4:1 to train prediction models and test their performance. DNN and logistic regressions showed better area under the curve (AUC) of ROC curves than the clinical model when 399 or more SNPs included. DNN was superior than logistic regressions in AUC with 399 or more SNPs in male and 678 SNPs in female. Addition of clinical factors consistently increased AUC of DNN but failed to improve logistic regressions with 214 or more SNPs. In conclusion, we show that DNN can be a versatile tool to predict T2DM incorporating large numbers of SNPs and clinical information. Limitations include a relatively small number of the subjects mostly of European ethnicity. Further studies are warranted to confirm and improve performance of genetic prediction models using DNN in different ethnic groups. PMID- 29136282 TI - Principal component reconstruction (PCR) for cine CBCT with motion learning from 2D fluoroscopy. AB - PURPOSE: This work aims to generate cine CT images (i.e., 4D images with high temporal resolution) based on a novel principal component reconstruction (PCR) technique with motion learning from 2D fluoroscopic training images. METHODS: In the proposed PCR method, the matrix factorization is utilized as an explicit low rank regularization of 4D images that are represented as a product of spatial principal components and temporal motion coefficients. The key hypothesis of PCR is that temporal coefficients from 4D images can be reasonably approximated by temporal coefficients learned from 2D fluoroscopic training projections. For this purpose, we can acquire fluoroscopic training projections for a few breathing periods at fixed gantry angles that are free from geometric distortion due to gantry rotation, that is, fluoroscopy-based motion learning. Such training projections can provide an effective characterization of the breathing motion. The temporal coefficients can be extracted from these training projections and used as priors for PCR, even though principal components from training projections are certainly not the same for these 4D images to be reconstructed. For this purpose, training data are synchronized with reconstruction data using identical real-time breathing position intervals for projection binning. In terms of image reconstruction, with a priori temporal coefficients, the data fidelity for PCR changes from nonlinear to linear, and consequently, the PCR method is robust and can be solved efficiently. PCR is formulated as a convex optimization problem with the sum of linear data fidelity with respect to spatial principal components and spatiotemporal total variation regularization imposed on 4D image phases. The solution algorithm of PCR is developed based on alternating direction method of multipliers. RESULTS: The implementation is fully parallelized on GPU with NVIDIA CUDA toolbox and each reconstruction takes about a few minutes. The proposed PCR method is validated and compared with a state-of-art method, that is, PICCS, using both simulation and experimental data with the on-board cone beam CT setting. The results demonstrated the feasibility of PCR for cine CBCT and significantly improved reconstruction quality of PCR from PICCS for cine CBCT. CONCLUSION: With a priori estimated temporal motion coefficients using fluoroscopic training projections, the PCR method can accurately reconstruct spatial principal components, and then generate cine CT images as a product of temporal motion coefficients and spatial principal components. PMID- 29136283 TI - Population PK Analyses of Ubrogepant (MK-1602), a CGRP Receptor Antagonist: Enriching In-Clinic Plasma PK Sampling With Outpatient Dried Blood Spot Sampling. AB - Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin gene related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure-response modeling. The clinical endpoint was a spontaneous event, which generally occurs outside a clinic visit. Thus, an innovative feature of this trial was facilitating DBS in an outpatient setting. In vitro and bioanalytical tests established initial method feasibility and suitability for further evaluations in the clinic. A quantitative relationship was developed between blood and plasma concentrations from concurrently collected samples in a phase 1 (healthy subjects) and phase 2 (target patient population) study using graphical and population PK approaches. This integrated information was presented to the Food and Drug Administration for regulatory input. Following regulatory concurrence, DBS was poised for use in further clinical studies. Population PK modeling was used to dissect sources of variability contributing to DBS collection in the outpatient setting. What has been learned from this program has informed the broader integrated strategy of Merck & Co., Inc. (Kenilworth, NJ) for DBS implementation in clinical trials and research to improve the precision of PK data collected in an outpatient setting. PMID- 29136284 TI - Patient outcomes of genetic counseling: Assessing the impact of different approaches to family history collection. AB - No studies have yet evaluated whether different modalities for the collection of family history data influence patient outcomes of genetic counseling. We retrospectively compared outcomes of genetic counseling between patients whose family history (Fhx) was collected (1) via telephone prior to their appointment (FhxPrior) or (2) during the appointment (FhxDuring). We used a psychiatric genetic counseling clinic database, where information about demographics and Fhx timing is recorded, and patients complete the Genetic Counseling Outcomes Scale (GCOS, measuring empowerment) and Illness Management Self-Efficacy Scale (IMSES) immediately prior to (T1) and 1 month after their appointment (T2). We used ANCOVA to evaluate the effect of the Fhx method on patient outcomes at T2. Complete data were available for 240 patients and were used for analysis (FhxPrior, n = 206; FhxDuring, n = 34). GCOS and IMSES scores increased from T1 to T2 (P < .0005 and P = .004, respectively). Although there was no difference between groups for GCOS (P = .412), T2 IMSES scores were significantly higher for FhxPrior than FhxDuring after controlling for T1 scores (P = .011). Our data suggest that obtaining Fhx via telephone prior to genetic counseling may lead to greater increases in patients' self-efficacy as compared to obtaining Fhx during the genetic counseling appointment. PMID- 29136285 TI - Characterization and oxidative stability of purslane seed oil microencapsulated in yeast cells biocapsules. AB - BACKGROUND: Purslane seed oil, as a potential nutritious source of omega-3 fatty acid, is susceptible to oxidation. Encapsulation in yeast cells is a possible approach for overcoming this problem. In the present study, purslane seed oil was encapsulated in non-plasmolysed, plasmolysed and plasmolysed carboxy methyl cellulose (CMC)-coated Saccharomyces cerevisiae cells and measurements of oil loading capacity (LC), encapsulation efficiency (EE), oxidative stability and the fatty acid composition of oil-loaded microcapsules were made. Furthermore, investigations of morphology and thermal behavior, as well as a Fourier transform infrared (FTIR) analyses of microcapsules, were performed. RESULTS: The values of EE, LC were approximately 53-65% and 187-231 g kg-1, respectively. Studies found that the plasmolysis treatment increased EE and LC and decreased the mean peroxide value (PV) of microencapsulated oil. The presence of purslane seed oil in yeast microcapsules was confirmed by FTIR spectroscopy and differential scanning calorimetry analyses. The lowest rate of oxidation belonged to the oil loaded plasmolysed CMC-coated microcapsules (16.73 meqvO2 kg-1 ), whereas the highest amount of oxidation regardless of native oil referred to the oil-loaded in non-plasmolysed cells (28.15 meqvO2 kg-1 ). CONCLUSION: The encapsulation of purslane seed oil in the yeast cells of S. cerevisiae can be considered as an efficient approach for extending the oxidative stability of this nutritious oil and facilitating its application in food products. (c) 2017 Society of Chemical Industry. PMID- 29136286 TI - Brompheniramine and Chlorpheniramine Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years. AB - Two pediatric studies characterized brompheniramine and chlorpheniramine pharmacokinetics in a total of 72 subjects, aged 2 to 17 years. A single age /weight-based oral dose, ranging from 1 to 4 mg, was administered with 2 to 6 oz of water at least 2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed using high-pressure liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods; relationships with age were assessed using linear regression. Results indicated that for brompheniramine and chlorpheniramine, Cmax was similar across age groups, although it tended to occur earlier in the youngest group. AUC was ~15% to 30% higher in the oldest age group. As expected, CLo and Vz /F increased with age; however, following allometric scaling, no age-related differences existed. Because the increase with age for both parameters was similar, no age-related differences in t1/2,z existed (~15 hours). Overall, the single doses were well tolerated. Sedation was the most common reported AE and appeared to be more prevalent in the 2- to 5-year-old group. Overall, these results indicate that an age/weight dosing nomogram using a 4-fold range of doses achieves similar Cmax and AUC. PMID- 29136288 TI - 28th Regional Congress of the ISBT, Guangzhou, China, November 25-28, 2017. PMID- 29136287 TI - Quantification of MRI visibility and artifacts at 3T of liquid fiducial marker in a pancreas tissue-mimicking phantom. AB - PURPOSE: X-ray-based position verification of the target volume in image-guided radiation therapy (IGRT) of patients with pancreatic ductal adenocarcinoma (PDAC) is currently performed on solid fiducial markers that are implanted under endoscopic ultrasonography. A new biodegradable liquid fiducial marker has recently been introduced. To assess its potential use for magnetic resonance imaging (MRI)-guided photon or proton radiotherapy of PDAC, the MRI visibility and artifacts of this marker were quantified and compared against solid gold markers. MATERIAL AND METHODS: Different spherical volumes (10 MUL, 25 MUL, 50 MUL, and 100 MUL) of a biodegradable liquid fiducial marker as well as seven differently sized and oriented solid gold (0.35 mm diameter; 5 mm and 10 mm length) and iron-gold alloy fiducial markers (0.28 mm diameter; 1 cm and 2 cm length) were implanted in a spherical gel phantom, mimicking the proton spin relaxation properties of healthy pancreatic tissue at 3 Tesla. MR relaxometry was performed to quantify the size and magnitude of the decrease in the effective transversal relaxation time T2* and relative proton density rho(H) as a measure of potential visibility and to quantify the size and magnitude of the increase in magnetic field inhomogeneity DeltaB0 as a measure of potential signal artifacts. The phantom was scanned in a 3.0 T PET/MR scanner with an eight-channel head coil. RESULTS: The solid fiducial markers showed a direct linear relationship between the potentially visible size and artifact size. The liquid fiducial marker showed a tendency toward a potentially visible size at smaller artifacts. Liquid markers from 25 to 100 MUL generated visible volumes comparable to the size of the solid markers. The magnitude of visibility was the highest for the liquid fiducial marker with volumes of 25-100 MUL showing no correlation with the magnitude of artifact. The solid markers showed a strong nonlinear correlation between magnitude of visibility and artifact, whereas the solid marker consisting of a gold-iron alloy induced the strongest artifacts. CONCLUSION: The liquid fiducial marker causes signal voids on MRI due to its absence of water hydrogen atoms without strongly affecting the magnetic field in the surrounding tissue. The alteration of the static magnetic field was found to be the main effect leading to the visibility of the solid fiducial markers. Hence, especially when a low level of image distortion is required, MRI characteristics of the liquid marker surpass those of solid gold markers currently being used for IGRT of PDAC. PMID- 29136289 TI - Extraction of amino acids from aerogel for analysis by capillary electrophoresis. Implications for a mission concept to Enceladus' Plume. AB - Ocean worlds like Europa and Enceladus in the outer solar system are prime targets in the search for life beyond Earth. Enceladus is particularly interesting due to the presence of a water plume ejecting from the south polar region. The recent discovery of H2 in the plume, in addition to the presence of previously observed organic compounds, highlights the possibility of life in this moon. The plume provides materials from the underlying ocean that could be collected simply by flying through it. The presence of the plume means that material from the ocean is available for collection during a flyby, without the need for landing or complex sample handling operations such as scooping or drilling. An attractive approach to preserve the organics in particles collected during flyby encounters would be to utilize silica aerogel, the material used to collect particles at hypervelocity during the Stardust mission. Here we demonstrate amino acids can be extracted from aerogel simply by adding water. This simple liquid extraction method could be implemented during a mission prior to analysis with a liquid-based technique like capillary electrophoresis. PMID- 29136291 TI - GPCR Signaling From Intracellular Membranes - A Novel Concept. PMID- 29136290 TI - The role of Ca2+ -dependent K+ - channels at the rat corticostriatal synapses revealed by paired pulse stimulation. AB - Potassium channels play an important role in modulating synaptic activity both at presynaptic and postsynaptic levels. We have shown before that presynaptically located KV and KIR channels modulate the strength of corticostriatal synapses in rat brain, but the role of other types of potassium channels at these synapses remains largely unknown. Here, we show that calcium-dependent potassium channels BK-type but not SK-type channels are located presynaptically in corticostriatal synapses. We stimulated cortical neurons in rat brain slices and recorded postsynaptic excitatory potentials (EPSP) in medium spiny neurons (MSN) in dorsal neostriatum. By using a paired pulse protocol, we induced synaptic facilitation before applying either BK- or SK-specific toxins. Thus, we found that blockage of BKCa with iberiotoxin (10 nM) reduces synaptic facilitation and increases the amplitude of the EPSP, while exposure to SK-blocker apamin (100 nM) has no effect. Additionally, we induced train action potentials on striatal MSN by current injection before and after the exposure to KCa toxins. We found that the action potential becomes broader when the MSN is exposed to iberiotoxin, although it has no impact on frequency. In contrast, exposure to apamin results in loss of afterhyperpolarization phase and an increase of spike frequency. Therefore, we concluded that postsynaptic SK channels are involved in afterhyperpolarization and modulation of spike frequency while the BK channels are involved on the late repolarization phase of the action potential. Altogether, our results show that calcium-dependent potassium channels modulate both input towards and output from the striatum. PMID- 29136292 TI - Clinical and genetic characteristics of Pseudohypoparathyroidism in the Chinese population. AB - BACKGROUND: Pseudohypoparathyroidism (PHP) is caused by mutations and epimutations in the GNAS locus, and characterized by the possibility of resistance to multiple hormones and Albright's hereditary osteodystrophy. PHP can be classified into the forms 1A/C, sporadic 1B and familial 1B. OBJECTIVES: To obtain an overall view of the clinical and genetic characteristics of the Chinese PHP patient population. METHODS: From 2000 to 2016, 120 patients were recruited and studied using Sanger sequencing, methylation-specific multiple ligation dependent probe amplification (MS-MLPA) and combined bisulfite restriction analysis (COBRA). Of these patients, 104 had positive molecular alterations indicative of certain forms of PHP and were included in data analysis. Clinical and laboratory features were compared between PHP1A/C and PHP1B patients. RESULTS: Ten PHP1A/C, 21 familial PHP1B and 73 sporadic PHP1B patients were identified. Four novel GNAS mutations were discovered in these patients, including c.1038+1G>T, c.530+2T>C, c.880_883delCAAG and c.311_312delAAG, insT. The most common symptoms in this series were recurrent tetany (89.4%) and epilepsy (47.1%). The prevalence of weight excess increased with age for PHP1B (10%-35%) and PHP1A/C (50%-75%). Intracranial calcification had a prevalence of 94.6% and correlated with seizures (r = .227, P = .029). Cataracts occurred in 56.2% PHP patients, and there was a trend towards longer disease duration in patients with cataracts (P = .051). Statistically significant differences (P < .05) were observed when comparing certain clinical characteristics between PHP1B and PHP1A/C patients, including age of onset (10 vs 7 year), short stature (21.3% vs 70%), rounded face (60.6% vs 100%), brachydactyly (25.5% vs 100%), ectopic ossification (1.1% vs 40%) and TSH resistance (44.6% vs 90%), respectively. CONCLUSIONS: This study is the largest single-centre series of PHP patients and summarizes the clinical and genetic features of the Chinese PHP population. While there was substantial clinical overlap between PHP1A/C and PHP1B, differences in disease progression were observed. PMID- 29136294 TI - Reply to is there even such a thing as "idiopathic normal pressure hydrocephalus"? PMID- 29136293 TI - Efficacy and safety of tofacitinib for moderate-to-severe plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials. AB - The effects of tofacitinib in treating moderate-to-severe plaque psoriasis were unclear. We aimed to assess the effects of tofacitinib in treating moderate-to severe plaque psoriasis. We searched PubMed, Cochrane Central Register of Controlled Trials and EMBASE for relevant randomized controlled trials (RCTs) and conducted a systematic review and meta-analysis. Four RCTs with 2724 participants were included. Compared to placebo, tofacitinib significantly improved psoriasis {>=75% reduction in the Psoriasis Area and Severity Index score: 5 mg BID: risk difference (RD) 0.32 [95% confidence interval (CI) 0.28-0.35], 10 mg BID: RD 0.51 (95% CI 0.43-0.58); >=90% reduction in the Psoriasis Area and Severity Index score: 5 mg BID: RD 0.19 (95% CI 0.17-0.22), 10 mg BID: RD 0.36 (95% CI 0.31 0.42); Physician's Global Assessment 0/1: 5 mg BID: RD 0.31 (95% CI 0.27-0.35), 10 mg BID: RD 0.48 (95% CI 0.44-0.53)} and participants' life quality [Dermatology Life Quality Index 0/1: 5 mg BID: RD 0.24 (95% CI 0.20-0.2), 10 mg BID: RD 0.36 (95% CI 0.33-0.40)]. Tofacitinib was associated with an increase in minor adverse events [upper respiratory tract infection: 5 mg BID: RD 0.02 (95% CI 0.00-0.03), 10 mg BID: RD 0.02 (95% CI 0.00-0.04); hypercholesterolaemia: 5 mg BID: RD 0.02 (95% CI 0.01-0.04), 10 mg BID: RD 0.02 (95% CI 0.01-0.04)]. In conclusion, tofacitinib may be a treatment option for moderate-to-severe plaque psoriasis that is unresponsive to other therapies and patients who are intolerable to other therapies or prefer oral medications. PMID- 29136295 TI - Genomewide association study identifies GALC as susceptibility gene for mucous membrane pemphigoid. AB - Mucous membrane pemphigoid (MMP) is a rare, chronic and often aggressive subepidermal autoimmune blistering disease potentially affecting several mucous membranes with blisters and secondary erosions and scars. The pathogenesis of MMP is poorly understood, and the contribution of genetic predispositions, other than HLA class II allele variants to MMP, is unknown. The objective of this study is to identify susceptibility genes for MMP in a British cohort of MMP patients. A GWAS was conducted in a British cohort of 106 MMP patients. Publicly available genotypes of 2900 blood donors of the UK Blood Service and of 6740 individuals of the 1958 British Birth Cohort served as control. Subsequently, putative susceptibility genes were independently replicated in a German cohort of 42 MMP patients. The GWAS found 38 SNPs in 28 haploblocks with an odds ratio >2 reaching genomewide significance (P < 5.7 * 10-7 ). Replication confirmed an association of MMP with SNPs in rs17203398 (OR: 3.9), located intronically in the beta galactocerebrosidase gene (GALC) on chromosome 14 and with recessive polymorphisms in rs9936045 (OR: 3.1) in the intergenic region between CASC16 and CHD9 on chromosome 16. The risk of developing MMP is partially genetically determined. SNPs in GALC enhance the risk for MMP, indicating that beta galactocerebrosidase may be involved in the pathogenesis of MMP. Likewise, impacts of polymorphisms in the intergenic region between CASC16 and CHD9 on the activity of neighbouring genes may facilitate the emergence of MMP. The putative role of both polymorphisms requires functional studies in the future. PMID- 29136296 TI - Scalp melanoma after antihair loss mesotherapy. PMID- 29136297 TI - Is there even such a thing as "idiopathic normal pressure hydrocephalus"? PMID- 29136298 TI - Tuning the Forster Resonance Energy Transfer through a Self-Assembly Approach for Efficient White-Light Emission in an Aqueous Medium. AB - A simple and cost-effective methodology employing environmentally benign substances for the fabrication of white-light emitting materials is important for practical applications in the field of lighting and display devices. Designing purely organic-based white-light-emitting systems with high quantum efficiency in aqueous media is an unmet challenge. With this objective, a new class of pyridoindole-based hydrophobic fluorophore 6,7,8,9-tetrapropylpyrido[1,2-a]indole 10-carbaldehye (TPIC) was introduced. A strategy of self-assembly using nonionic surfactants was employed to enhance the fluorescence of TPIC in an aqueous medium and was exploited as energy donor. The steady-state and time-resolved emission spectra analysis revealed the micelle-mediated energy transfer from TPIC to Nile red (energy acceptor) leading to tunable fluorescence along with white-light emission. The white-light emitting aqueous solution was obtained with the Commission Internationale de l'Eclairage (CIE) chromaticity coordinates of (0.33, 0.36) and significantly high quantum yield of 37 %. Solid-state white-light emission was achieved retaining the assembly of fluorophores in the form of a gel having the high quantum efficiency of 33 % with CIE coordinates of (0.32, 0.36); close to that of pure white light. The bright white luminescence of the inscription prepared using white-light emitting gel on a solid substrate offers promising applications for full-color flat panel displays. PMID- 29136299 TI - Malignancy in Renal Transplant Recipients Exposed to Cyclophosphamide Prior to Transplantation for the Treatment of Native Glomerular Disease. AB - STUDY OBJECTIVE: To evaluate the risk of posttransplantation malignancy in renal transplant recipients exposed to pretransplantation cyclophosphamide for the treatment of glomerular nephropathy (GN). DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center. PATIENTS: Six hundred adult renal transplant recipients were transplanted between 1993 and 2014; 54 patients were exposed to pretransplantation cyclophosphamide for treatment of GN (GN-CYC group), and 546 patients with polycystic kidney disease were not exposed to pretransplantation cyclophosphamide (PKD group). MEASUREMENT AND MAIN RESULTS: Data were collected retrospectively from electronic medical records. The primary outcome was occurrence of posttransplantation malignancy. During a median follow up of 5.5 years, 130 patients developed malignancy (incidence rate 3.5 events per 100 person-yrs). Exposure to cyclophosphamide before transplantation was significantly associated with malignancy after transplantation (adjusted hazard ratio [aHR] 2.20, 95% confidence interval [CI] 1.16-4.22, p=0.02), specifically skin cancer (aHR 2.24, 95% CI 1.09-4.60, p=0.03). Malignancy risk in the GN-CYC group was higher in the setting of lymphocyte-depleting induction (alemtuzumab; aHR 4.53, 95% CI 0.99-20.72, p=0.05) compared with basiliximab induction. Incidences of death-censored graft loss and mortality were similar between the GN CYC and PKD groups. CONCLUSION: In our observational study, renal transplant recipients exposed to pretransplantation cyclophosphamide appeared to have a higher risk of developing a malignancy compared with unexposed renal transplant recipients. Further investigation into the impact of pretransplantation immunosuppression on malignancy, particularly the compounded effect with lymphocyte-depleting induction, is warranted. PMID- 29136300 TI - Comments to : compound heterozygotes for filaggrin gene mutations do not always show severe atopic dermatitis. PMID- 29136301 TI - Ketamine for the Acute Management of Excited Delirium and Agitation in the Prehospital Setting. AB - Traditional first-line therapy in the prehospital setting for the acutely agitated patient includes an antipsychotic in combination with a benzodiazepine. Recently, interest has grown regarding the use of ketamine in the prehospital setting as an attempt to overcome the limitations of the traditional medications and provide a more safe and effective therapy. This review provides an overview of the pharmacology of ketamine, evaluates the literature regarding ketamine use for prehospital agitation, and proposes an algorithm that may be used within the prehospital setting. A literature review was conducted to identify articles utilizing ketamine in the prehospital setting. The review was limited to English language articles identified in Embase (1988-June 2017) and the U.S. National Library of Medicine (1970-June 2017). References of all pertinent articles were also reviewed. Ten articles were identified including 418 patients receiving ketamine for agitation. The most commonly utilized route for administration was intramuscular (IM), with five of the seven IM administration studies using a ketamine dose of 5 mg/kg. Ketamine administered in this fashion was efficacious to achieve proper sedation during transport and did not require repeat dosing. Three studies applied a ketamine protocol to outline dosing and the management of ketamine adverse events. The most common adverse events identified were respiratory-related events and hypersalivation. Ketamine has a role for agitation management in the prehospital setting; however, emergency personnel education and ketamine protocols should be utilized to aid in safe and effective pharmacotherapy and provide guidance on the management of adverse events. Future prospective comparative studies, with protocolized standard ketamine regimens, are needed to further delineate the role of ketamine in agitation management and identify accurate adverse event incidence rates. PMID- 29136302 TI - The sociotype in dermatology. PMID- 29136303 TI - Chromosome 9 mutations reported absent in some patients with basal cell carcinoma nevus syndrome. PMID- 29136304 TI - Reversible Polymerization of Adamantane-type [P4 N10 ]10- Anions to Honeycomb type [P2 N5 ]5- Layers under High-Pressure. AB - The high-pressure polymorph Li5 P2 N5 of Li10 P4 N10 (="2 Li5 P2 N5 ") was synthesized by high-pressure/high-temperature reaction of LiPN2 and Li7 PN4 or beta-Li10 P4 N10 at 9 GPa, using the Li3 N self-flux method in a Walker-type multianvil assembly. Li5 P2 N5 is the first lithium nitridophosphate with a layered structure and is made up of corner sharing PN4 tetrahedra forming a corrugated honeycomb-type layer of linked sechser-rings in chair conformation. The arrangement of the P atoms is analogous to that of black phosphorus. The structure was elucidated from single-crystal X-ray data. To confirm the structure Rietveld refinement, 6 Li, 7 Li and 31 P solid-state NMR spectroscopy were conducted. To corroborate Li5 P2 N5 as the corresponding high-pressure polymorph of beta-Li10 P4 N10 DFT calculations and temperature dependent X-ray powder diffraction were carried out. DFT calculations estimated the transition pressure to 6.5 GPa (without accounting for temperature), which is in line with the synthesis pressure. PMID- 29136305 TI - Neural basis of exertional fatigue in the heat: A review of magnetic resonance imaging methods. AB - The central nervous system, specifically the brain, is implicated in the development of exertional fatigue under a hot environment. Diverse neuroimaging techniques have been used to visualize the brain activity during or after exercise. Notably, the use of magnetic resonance imaging (MRI) has become prevalent due to its excellent spatial resolution and versatility. This review evaluates the significance and limitations of various brain MRI techniques in exercise studies-brain volumetric analysis, functional MRI, functional connectivity MRI, and arterial spin labeling. The review aims to provide a summary on the neural basis of exertional fatigue and proposes future directions for brain MRI studies. A systematic literature search was performed where a total of thirty-seven brain MRI studies associated with exercise, fatigue, or related physiological factors were reviewed. The findings suggest that with moderate dehydration, there is a decrease in total brain volume accompanied with expansion of ventricular volume. With exercise fatigue, there is increased activation of sensorimotor and cognitive brain areas, increased thalamo-insular activation and decreased interhemispheric connectivity in motor cortex. Under passive hyperthermia, there are regional changes in cerebral perfusion, a reduction in local connectivity in functional brain networks and an impairment to executive function. Current literature suggests that the brain structure and function are influenced by exercise, fatigue, and related physiological perturbations. However, there is still a dearth of knowledge and it is hoped that through understanding of MRI advantages and limitations, future studies will shed light on the central origin of exertional fatigue in the heat. PMID- 29136307 TI - Using Electromagnetic Articulography to Measure Denture Micromovement during Chewing with and without Denture Adhesive. AB - PURPOSE: To study the effects of denture adhesive upon denture micromovements in three dimensions during the chewing of hard, sticky, and tough food items observed using a novel method involving an electromagnetic articulograph (EMA) speech research system. MATERIALS AND METHODS: Ten volunteers (mean age 60.9 +/- 10.4 years) with fair- or poor-fitting complete maxillary dentures were enrolled. Chewing experiments were conducted using two treatments (adhesive or no-adhesive control) and three foods: carrots (hard), raisins (sticky), and processed meat stick (tough). Denture micromovement was measured through a novel application of a Northern Digital Wave EMA System. Three-dimensional denture position was captured during mastication using three sensors embedded into a replica denture for each subject. Following individual characterization of a "home" reference position, the Euclidean Distances from Home (DfH) were calculated for each recorded sample of the chewing experiments. The DfH at each sample represented the denture movement for that 1/100th of a second of the activity. The DfH data were then summarized as the mean DfH, the maximum DfH, and total distance traveled by the denture. Several thresholds were also analyzed, including the percent of time that the DfH >=1.5 mm, >=2.0 mm, and >=2.5 mm. RESULTS: With adhesive treatment, the mean DfH of dentures during chewing was reduced by 26.8% for carrot, 30.3% for raisin, and 31.0% for meat stick, when compared with no adhesive treatment (p < 0.001 for all comparisons). Similar results were also seen for the maximum DfH and total distance travelled endpoints across foods. For the threshold endpoints, adhesive treatment was associated with a statistically significant reduction in denture micromovements at all three thresholds across foods. At the threshold of DfH >= 1.5 mm, adhesive treatment was associated with a reduction in micromovement by 61.6%, 56.2%, and 70.0% with carrot, raisin, and meat stick, respectively (p <= 0.004 for all comparisons). CONCLUSIONS: Observations of denture movement using the Wave EMA System were able to differentiate systematically between adhesive treatment and no-adhesive treatment for denture micromovements during different chewing challenges. Use of adhesive was associated with statistically significant reductions in denture micromovements for hard, sticky, and tough foods as measured with both distance and threshold endpoints. PMID- 29136306 TI - Patient and physician satisfaction in an observational study with methyl aminolevulinate daylight photodynamic therapy in the treatment of multiple actinic keratoses of the face and scalp in six European countries. AB - BACKGROUND: Guidelines recommend treating actinic keratoses (AKs) as they are recognized as precursors of invasive squamous cell carcinoma. OBJECTIVE: The objective of this study was to collect real-world clinical data on the use of methyl aminolevulinate daylight photodynamic therapy (MAL DL-PDT) for the treatment of face and scalp AK in Europe. METHODS: A prospective, multicenter, non-interventional study was conducted in six European countries in patients receiving a single treatment of MAL DL-PDT for face and/or scalp AK. Patient reported outcomes were assessed by patient questionnaires at baseline and at 3 months after treatment, efficacy was assessed at 3 months using a 6-point global improvement scale, and adverse events (AE) were recorded at each visit. RESULTS: Overall, 325 patients were enrolled from 52 investigational centres, 314 of whom attended the 3-month visit. Most patients had multiple lesions (58.4% had >10 lesions) with lesions mainly located on the scalp (60.0%) and/or forehead (54.2%). AKs were predominantly grade I (39.4%) or grade II (33.2%), and 10.5% of patients had grade III lesions. The proportions of patients and physicians that were overall satisfied to very satisfied with the MAL DL-PDT treatment were 80.4% and 90.3%, respectively. The vast majority of patients (90.0%) would consider using MAL DL-PDT again if needed. Physician-assessed efficacy at 3 months was at least much improved in 83.5% of patients, with 45.9% of patients requiring no retreatment. Related AEs were reported in 15% of patients. CONCLUSION: Use of MAL DL-PDT for multiple face and/or scalp AKs resulted in high levels of patient and physician satisfaction in clinical practice in Europe, reflecting the good efficacy and high tolerability of this convenient procedure. PMID- 29136308 TI - Author's response to the comment to 'Compound heterozygotes for filaggrin gene mutations do not always show severe atopic dermatitis'. PMID- 29136309 TI - Comparison of Fit of Dentures Fabricated by Traditional Techniques Versus CAD/CAM Technology. AB - PURPOSE: To compare the shrinkage of denture bases fabricated by three methods: CAD/CAM, compression molding, and injection molding. The effect of arch form and palate depth was also tested. MATERIALS AND METHODS: Nine titanium casts, representing combinations of tapered, ovoid, and square arch forms and shallow, medium, and deep palate depths, were fabricated using electron beam melting (EBM) technology. For each base fabrication method, three poly(vinyl siloxane) impressions were made from each cast, 27 dentures for each method. Compression molded dentures were fabricated using Lucitone 199 poly methyl methacrylate (PMMA), and injection molded dentures with Ivobase's Hybrid Pink PMMA. For CAD/CAM, denture bases were designed and milled by Avadent using their Light PMMA. To quantify the space between the denture and the master cast, silicone duplicating material was placed in the intaglio of the dentures, the titanium master cast was seated under pressure, and the silicone was then trimmed and recovered. Three silicone measurements per denture were recorded, for a total of 243 measurements. Each silicone measurement was weighed and adjusted to the surface area of the respective arch, giving an average and standard deviation for each denture. RESULTS: Comparison of manufacturing methods showed a statistically significant difference (p = 0.0001). Using a ratio of the means, compression molding had on average 41% to 47% more space than injection molding and CAD/CAM. Comparison of arch/palate forms showed a statistically significant difference (p = 0.023), with shallow palate forms having more space with compression molding. The ovoid shallow form showed CAD/CAM and compression molding had more space than injection molding. CONCLUSION: Overall, injection molding and CAD/CAM fabrication methods produced equally well-fitting dentures, with both having a better fit than compression molding. Shallow palates appear to be more affected by shrinkage than medium or deep palates. Shallow ovoid arch forms appear to benefit from the use of injection molding compared to CAD/CAM and compression molding. PMID- 29136311 TI - Issue Information-Declaration of Helsinki. PMID- 29136312 TI - On the Performance of Hybrid Functionals for Non-linear Optical Properties and Electronic Excitations in Chiral Molecular Crystals: The Case of Butterfly-Shaped Dicinnamalacetone. AB - Purely organic chiral molecular assemblies in the solid state hold great potential for non-linear optical applications. Herein, a newly synthesised molecular system is reported, namely, dicinnamalacetone, an otherwise planar molecule that crystallises in a disordered non-centrosymmetric form with four different conformations having an overall predominance of a particular helicity. A combined experimental and theoretical approach, including single-crystal X-ray diffraction, Kurtz-Perry and ab initio methods, is employed to characterise the system and benchmark the performance of hybrid functionals for the prediction of non-linear optical properties and electronic excitations. Comparison of experiment and theory points to a particular set of hybrid functionals that provides an optimal description of this molecular system. PMID- 29136313 TI - In Situ Scatheless Cell Detachment Reveals Correlation between Adhesion Strength and Viability at Single-Cell Resolution. AB - Single-cell biology provides insights into some of the most fundamental processes in biology and promotes the understanding of life's mysteries. As the technologies to study single-cells expand, they will require sophisticated analytical tools to make sense of various behaviors and components of single cells as well as their relations in the adherent tissue culture. In this paper, we revealed cell heterogeneity and uncovered the connections between cell adhesion strength and cell viability at single-cell resolution by extracting single adherent cells of interest from a standard tissue culture by using a microfluidic chip-based live single-cell extractor (LSCE). We believe that this method will provide a valuable new tool for single-cell biology. PMID- 29136310 TI - Brain networks of the imaginative mind: Dynamic functional connectivity of default and cognitive control networks relates to openness to experience. AB - Imagination and creative cognition are often associated with the brain's default network (DN). Recent evidence has also linked cognitive control systems to performance on tasks involving imagination and creativity, with a growing number of studies reporting functional interactions between cognitive control and DN regions. We sought to extend the emerging literature on brain dynamics supporting imagination by examining individual differences in large-scale network connectivity in relation to Openness to Experience, a personality trait typified by imagination and creativity. To this end, we obtained personality and resting state fMRI data from two large samples of participants recruited from the United States and China, and we examined contributions of Openness to temporal shifts in default and cognitive control network interactions using multivariate structural equation modeling and dynamic functional network connectivity analysis. In Study 1, we found that Openness was related to the proportion of scan time (i.e., "dwell time") that participants spent in a brain state characterized by positive correlations among the default, executive, salience, and dorsal attention networks. Study 2 replicated and extended the effect of Openness on dwell time in a correlated brain state comparable to the state found in Study 1, and further demonstrated the robustness of this effect in latent variable models including fluid intelligence and other major personality factors. The findings suggest that Openness to Experience is associated with increased functional connectivity between default and cognitive control systems, a connectivity profile that may account for the enhanced imaginative and creative abilities of people high in Openness to Experience. PMID- 29136314 TI - Syncope Prognosis Based on Emergency Department Diagnosis: A Prospective Cohort Study. AB - OBJECTIVE: Relatively little is known about outcomes after disposition among syncope patients assigned various diagnostic categories during emergency department (ED) evaluation. We sought to measure the outcomes among these groups within 30 days of the initial ED visit. METHODS: We prospectively enrolled adult syncope patients at six EDs and excluded patients with presyncope, persistent mental status changes, intoxication, seizure, and major trauma. Patient characteristics, ED management, diagnostic impression (presumed vasovagal, orthostatic, cardiac, or other/unknown) at the end of the ED visit, and physicians' confidence in assigning the etiology were collected. Serious outcomes at 30 days included death, arrhythmia, myocardial infarction, structural heart disease, pulmonary embolism, and hemorrhage. RESULTS: A total of 5,010 patients (mean +/- SD age = 53.4 +/- 23.0 years; 54.8% females) were enrolled; 3.5% suffered serious outcomes-deaths (0.3%), arrhythmias (1.8%), nonarrhythmic cardiac (0.5%), and noncardiac (0.9%) including pulmonary embolism (0.2%). The cause of syncope was presumed as vasovagal among 53.3% and cardiac in 5.4% of patients. The proportion of patients with ED investigations (p < 0.001) and short term serious outcomes (p < 0.01) increased in each diagnostic category in the following order: presumed vasovagal, orthostatic hypotension, other/unknown cause, and cardiac. No deaths occurred in patients with presumed vasovagal syncope. A higher proportion of all serious outcomes occurred among patients suspected of cardiac syncope in the ED (p < 0.01). Confidence was highest among physicians for a presumed vasovagal syncope diagnosis and lowest when the cause was other/unknown. CONCLUSION: Short-term serious outcomes strongly correlated with the etiology assigned in the ED visit. The importance of the physician's clinical judgment should be further studied to determine if it should become incorporated in risk-stratification tools for prognostication and safe management of ED syncope patients. PMID- 29136315 TI - Deficient Pain Modulation in Patients with Chronic Hemiplegic Shoulder Pain. AB - BACKGROUND: Hemiplegic shoulder pain (HSP) following stroke significantly affects the individual's function and quality of life. The mechanism of HSP is not clearly understood; hence, it is unclear why HSP resolves spontaneously or following routine care in some patients, while in others it becomes persistent. The aim was therefore to study whether HSP is associated with deficient pain modulation. METHODS: Thirty post-stroke patients-16 with HSP and 14 without HSP and 20 matched controls participated. Pain adaptation and conditioned pain modulation (CPM) were measured as indicators of pain modulation, in the affected (hemiplegic) and contralateral shoulder as well as in the affected shin among post-stroke patients, and in comparable body regions among controls. Post-stroke patients also underwent functional and physical evaluation of the shoulder. RESULTS: Pain adaptation was absent among HSP patients, in both the painful shoulder and the affected shin, but existed in the 2 control groups. In addition, the affected shoulder and shin among the HSP group had reduced thermal sensibility compared to the contralateral regions. CPM was similar across groups. Shoulder functional status and physical status were similar for the 2 post-stroke groups. CONCLUSIONS: The results suggest that HSP is associated with a lack of pain adaptation, characteristic not only of the painful shoulder but also of the affected side. Although we cannot determine whether lack of pain adaptation precedes the HSP or results from it, interventions that enhance descending pain inhibition may improve management and prevent HSP chronification. PMID- 29136316 TI - Quality of expert medical opinions on occupational skin cancer caused by natural UV light. PMID- 29136318 TI - Orbital fracture with Valsalva manoeuvre causing ciliary artery herniation. PMID- 29136317 TI - IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade-resistant rejection. AB - Kidney transplant patients treated with belatacept without depletional induction experience higher rates of acute rejection compared to patients treated with conventional immunosuppression. Costimulation blockade-resistant rejection (CoBRR) is associated with terminally differentiated T cells. Alemtuzumab induction and belatacept/sirolimus immunotherapy effectively prevent CoBRR. We hypothesized that cells in late phases of differentiation would be selectively less capable than more naive phenotypes of repopulating postdepletion, providing a potential mechanism by which lymphocyte depletion and repopulation could reduce the risk of CoBRR. Lymphocytes from 20 recipients undergoing alemtuzumab-induced depletion and belatacept/sirolimus immunosuppression were studied longitudinally for markers of maturation (CCR7, CD45RA, CD57, PD1), recent thymic emigration (CD31), and the IL-7 receptor-alpha (IL-7Ralpha). Serum was analyzed for IL-7. Alemtuzumab induction produced profound lymphopenia followed by repopulation, during which naive IL-7Ralpha+ CD57- PD1- cells progressively became the predominant subset. This did not occur in a comparator group of 10 patients treated with conventional immunosuppression. Serum from depleted patients showed markedly elevated IL-7 levels posttransplantation. Sorted CD57- PD1- cells demonstrated robust proliferation in response to IL-7, whereas more differentiated cells proliferated poorly. These data suggest that differences in IL-7-dependent proliferation is one exploitable mechanism that distinguishes CoB sensitive and CoB-resistant T cell populations to reduce the risk of CoBRR. (ClinicalTrials.gov - NCT00565773.). PMID- 29136319 TI - Response to laparoscopic ventral rectopexy for rectal prolapse and rectal intussusception using a biological mesh. AB - We read with interest the article by Albayati et al published recently.1 There is a sparsity of long term data in use of biological mesh in laparoscopy rectopexy for the treatment of rectal prolapse. We appreciate the efforts made by Albayati et al in this study and note the homogeneous population in terms of gender, age and BMI. This article is protected by copyright. All rights reserved. PMID- 29136320 TI - N-Heterocyclic Carbene Catalysis via Azolium Dienolates: An Efficient Strategy for Remote Enantioselective Functionalizations. AB - N-heterocyclic carbene (NHC) catalysis has emerged as a powerful strategy in organic synthesis. In recent years a number of reviews have been published on NHC catalyzed transformations involving Breslow intermediates, acyl azoliums, alpha,beta-unsaturated acyl azoliums, homoenolate equivalents, and azolium enolates. However, the azolium dienolate intermediates generated by NHCs have been employed in asymmetric synthesis only very recently, especially in cycloadditions dealing with remote functionalization. This Minireview highlights all the developments and the new advances in NHC-catalyzed asymmetric cycloaddition reactions involving azolium dienolate intermediates. PMID- 29136321 TI - Recalcitrant rash in a six-month-old infant. PMID- 29136324 TI - Proton Transfer Reaction Dynamics of Pyranine in DMSO/Water Mixtures. AB - Photoinduced intermolecular excited-state proton transfer (ESPT) reactions are ubiquitous in chemistry and biology. ESPT reactions are extremely sensitive to the nature of water molecules in its microenvironment and thus serve as a sensitive reporter for the water structure and dynamics in a system. Herein, the photoinduced intermolecular ESPT reaction of 8-hydroxypyrene-1,3,5-trisulfonic acid (HPTS, also known as pyranine) has been investigated in various DMSO/water mixtures by using steady-state and time-resolved emission spectroscopy. The DMSO/water binary mixture yields an interesting and anomalous behavior for the proton transfer reaction dynamics of HPTS at a mole fraction of DMSO (XDMSO ) of 0.41-0.51, which has also been previously investigated and projected as an anomalous region by molecular dynamics simulation and other experimental techniques. The extreme slowdown of the proton transfer reaction observed at XDMSO =0.41-0.51 has been attributed to the slow solvation dynamics, as well as the non-availability of free water molecules at this composition, which are required to solvate the newly generated proton. These observations have been also corroborated by time-resolved area-normalized emission spectra. The dimensionality of the proton diffusion process has been investigated by analyzing the geminate recombination process, and is found to be significantly different in DMSO/water mixtures (XDMSO =0.41-0.51) compared with three-dimensional proton diffusion in neat water. PMID- 29136322 TI - Heme oxygenase-1 regulates sirtuin-1-autophagy pathway in liver transplantation: From mouse to human. AB - Liver ischemia-reperfusion injury (IRI) represents a major risk factor of early graft dysfunction and a key obstacle to expanding the donor pool in orthotopic liver transplantation (OLT). Although graft autophagy is essential for resistance against hepatic IRI, its significance in clinical OLT remains unknown. Despite recent data identifying heme oxygenase-1 (HO-1) as a putative autophagy inducer, its role in OLT and interactions with sirtuin-1 (SIRT1), a key autophagy regulator, have not been studied. We aimed to examine HO-1-mediated autophagy induction in human OLT and in a murine OLT model with extended (20 hours) cold storage, as well as to analyze the requirement for SIRT1 in autophagy regulation by HO-1. Fifty-one hepatic biopsy specimens from OLT patients were collected under an institutional review board protocol 2 hours after portal reperfusion, followed by Western blot analyses. High HO-1 levels correlated with well preserved hepatocellular function and enhanced SIRT1/LC3B expression. In mice, HO 1 overexpression by genetically modified HO-1 macrophage therapy was accompanied by decreased OLT damage and increased SIRT1/LC3B expression, whereas adjunctive inhibition of SIRT1 signaling diminished HO-1-mediated hepatoprotection and autophagy induction. Our translational study confirms the clinical relevance of HO-1 cytoprotection and identifies SIRT1-mediated autophagy pathway as a new essential regulator of HO-1 function in IR-stressed OLT. PMID- 29136323 TI - Increasing canopy photosynthesis in rice can be achieved without a large increase in water use-A model based on free-air CO2 enrichment. AB - Achieving higher canopy photosynthesis rates is one of the keys to increasing future crop production; however, this typically requires additional water inputs because of increased water loss through the stomata. Lowland rice canopies presently consume a large amount of water, and any further increase in water usage may significantly impact local water resources. This situation is further complicated by changing the environmental conditions such as rising atmospheric CO2 concentration ([CO2 ]). Here, we modeled and compared evapotranspiration of fully developed rice canopies of a high-yielding rice cultivar (Oryza sativa L. cv. Takanari) with a common cultivar (cv. Koshihikari) under ambient and elevated [CO2 ] (A-CO2 and E-CO2 , respectively) via leaf ecophysiological parameters derived from a free-air CO2 enrichment (FACE) experiment. Takanari had 4%-5% higher evapotranspiration than Koshihikari under both A-CO2 and E-CO2 , and E-CO2 decreased evapotranspiration of both varieties by 4%-6%. Therefore, if Takanari was cultivated under future [CO2 ] conditions, the cost for water could be maintained at the same level as for cultivating Koshihikari at current [CO2 ] with an increase in canopy photosynthesis by 36%. Sensitivity analyses determined that stomatal conductance was a significant physiological factor responsible for the greater canopy photosynthesis in Takanari over Koshihikari. Takanari had 30% 40% higher stomatal conductance than Koshihikari; however, the presence of high aerodynamic resistance in the natural field and lower canopy temperature of Takanari than Koshihikari resulted in the small difference in evapotranspiration. Despite the small difference in evapotranspiration between varieties, the model simulations showed that Takanari clearly decreased canopy and air temperatures within the planetary boundary layer compared to Koshihikari. Our results indicate that lowland rice varieties characterized by high-stomatal conductance can play a key role in enhancing productivity and moderating heat-induced damage to grain quality in the coming decades, without significantly increasing crop water use. PMID- 29136325 TI - Primary graft dysfunction after heart transplantation: Incidence, trends, and associated risk factors. AB - Changes in heart transplantation (HT) donor and recipient demographics may influence the incidence of primary graft dysfunction (PGD). We conducted a retrospective study to evaluate PGD incidence, trends, and associated risk factors by analyzing consecutive adult patients who underwent HT between January 2009 and December 2014 at our institution. Patients were categorized as having PGD using the International Society for Heart & Lung Transplantation (ISHLT) defined criteria. Variables, including clinical and demographic characteristics of donors and recipients, were selected to assess their independent association with PGD. A time-trend analysis was performed over the study period. Three hundred seventeen patients met inclusion criteria. Left ventricular PGD, right ventricular PGD, or both, were observed in 99 patients (31%). Risk factors independently associated with PGD included ischemic time, recipient African American race, and recipient amiodarone treatment. Over the study period, there was no change in the PGD incidence; however, there was an increase in the recipient pretransplantation use of amiodarone. The rate of 30-day mortality was significantly elevated in those with PGD versus those without PGD (6.06% vs 0.92%, P = .01). Despite recent advancements, incidence of PGD remains high. Understanding associated risk factors may allow for implementation of targeted therapeutic interventions. PMID- 29136326 TI - DNA-based testing in lung transplant recipients with suspected non-viral lower respiratory tract infection: A prospective observational study. AB - BACKGROUND: Non-viral lower respiratory tract infections (LRTI) are common among lung transplant (LTx) recipients with increased mortality. Early pathogen identification is crucial to guide therapy and avoid adverse events. Results from cultures may require up to 72 hours. Multiplex polymerase chain reaction assay (PCR) may allow faster pathogen identification, but its utility in LTx recipients with suspected non-viral LRTI remains unclear. METHODS: In a prospective open label observational trial, LTx recipients presenting with suspected LRTI received bronchoscopy with bronchoalveolar lavage (BAL). Samples were simultaneously analyzed by multiplex PCR (Curetis P55 Pneumonia) and cultures for pathogen identification. Time to result notification for PCR and cultures and time to final diagnosis were recorded. Definition of non-viral LRTI was isolation of a lung-pathogenic non-viral pathogen by either method. RESULTS: Forty-eight patients were included, with 32 (67%) having a lung-pathogenic isolate by conventional cultures. In 17/32 pathogen identification was identical on PCR, in 12/32 (37%) PCR returned negative, and in 3/32 (10%) PCR and culture identified different pathogens. Sensitivity and specificity with 95% confidence intervals for pathogen isolation for PCR were 66% (47-81) and 100% (79-100), respectively. The positive predictive value for PCR was 100% (84-100) and the negative predictive value was 59% (39-78). PCR results were available after 21.2 hours (interquartile range [IQR] 19.3-65.7) vs 23 hours (IQR 21.1-67.4) from cultures (P < .0001). The time to final diagnosis of non-viral LRTI was 22.9 hours (20.4 37.5). CONCLUSION: In LTx recipients with suspected non-viral LRTI, multiplex PCR had a lower sensitivity than cultures. Results were available 2 hours earlier. PMID- 29136327 TI - Long-term follow-up after implantation of a telemetric intraocular pressure sensor in patients with glaucoma: a safety report. AB - IMPORTANCE: To investigate the long-term safety of a novel intraocular telemetric pressure sensor. BACKGROUND: Acquisition of accurate intraocular pressure (IOP) data is vital for sufficient medical care of glaucoma patients. Non-invasive self tonometry with a telemetric IOP sensor can provide important information regarding the individual IOP profile. DESIGN: Retrospective analysis of long-term follow-up data assessed during outpatient visits in a university hospital. PARTICIPANTS: Six patients with open-angle glaucoma were included. Unfortunately, one patient passed away shortly after completion of the original 1-year study. METHODS: Within the scope of a prospective 1-year pilot clinical trial, a telemetric IOP sensor was inserted into the ciliary sulcus after intracapsular lens implantation during planned cataract surgery. Patients were regularly examined as outpatients even beyond the duration of the 1-year study. Data concerning sensor functionality, safety parameters and home self-tonometry were assessed. MAIN OUTCOME MEASURES: Long-term sensor functionality and safety. RESULTS: Sensor measurements were always successful in every patient. Additionally, home self-tonometry was conducted without any problems by every patient. The average follow-up period was 37.5 months (21-50 months). During this period, the average number of IOP measurements performed per patient was 1273 (223-2884 measurements). No severe adverse events were reported. A varying degree of pupillary distortion was observed after 6-12 months in every patient; this remained unchanged thereafter with only one exception. CONCLUSIONS AND RELEVANCE: Telemetric IOP sensors showed good functionality and tolerability during long term follow-up. Non-invasive self-tonometry with a telemetric IOP sensor can provide useful additional data for future monitoring of patients with glaucoma. PMID- 29136328 TI - Organ preservation in rectal cancer: a synopsis of current guidelines. AB - BACKGROUND: The high morbidity associated with radical resection for rectal cancer is an incentive for surgeons to adopt strategies aimed at organ preservation, particularly for early disease. There are a number of different approaches to achieve this. In this study we have collated current national and international guidelines to produce a synopsis to support this changing practice. METHODS: The databases PubMed, Embase, Trip database, national guideline clearinghouse, BMJ Best practice were interrogated. Guidelines published before 2010 were excluded. The AGREE-II tool was used for quality assessment. RESULTS: 24 guidelines were drawn from 2278 potential publications. A consensus exists for local excision for "low risk" T1 rectal cancer but there is no agreement how to stratify the risk of treatment failure. There is a low level of agreement for rectal preservation for more advanced disease but when mentioned is recommended for unfit patients or in th context of a clinical trial. Guidelines are inconsistent with respect to surveillance in node negative disease and after, complete response to chemoradiotherapy CONCLUSION: According to current guidelines and consensus statements organ preservation for rectal cancer beyond low risk T1, is still considered experimental and only indicated in patients unsuitable for radical surgery.. Follow up strategies and cN0 staging deserve attention and highlight the need for high quality clinical trials. This article is protected by copyright. All rights reserved. PMID- 29136330 TI - Keystone flap for covering large soft tissue defects of the dorsum of the hand. PMID- 29136329 TI - Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment. AB - BACKGROUND: The introduction of direct-acting antivirals (DAA) has increased sustained virological response (SVR) rates in patients with advanced liver disease and chronic hepatitis C(CHC)infection. At present, data on clinical outcome and long-term durability of viral eradication after successful DAA therapy are scarce. AIM: To evaluate the long-term success of viral eradication in patients with advanced fibrosis or cirrhosis treated with DAAs. METHODS: Five hundred and fifty-one patients with advanced fibrosis (n = 158) or cirrhosis (CPS A:317,CPS-B/C:76) and SVR after interferon and ribavirin-free DAA therapy treated between October 2013 and April 2016 were studied with a median follow-up of 65.6 (13.0-155.3) weeks. Only patients without hepatocellular carcinoma (HCC) at baseline and without liver transplantation were included. RESULTS: Twelve patients (2.2%) died during follow-up: the mortality rate was 0.6% in F3, 2.2% in CPS-A and 5.3% in CPS-B/C patients (P = .08). During follow-up 36 patients with cirrhosis (9.1%) developed a liver related event, including 16 with de-novo HCC (4.1%). Seven patients were transplanted at a median of 9.7 (range 3.8-21.7) months after EOT. History of decompensation was significantly associated with liver related events during follow-up (HR 7.9; 95% CI 2.7-22.6; P < .001), and with mortality (HR 5.5; 95% CI 1.5-20.2, P = .01). CONCLUSIONS: Eradication of HCV by DAA therapy was durable irrespective of the DAA combination used. Most of the cured patients had an excellent long-term clinical prognosis. Nevertheless, the risk of new occurrence of HCC remains worrisome and thus regular surveillance is obligatory even after clinical stabilization and improvement of the patient. PMID- 29136331 TI - Risk factor management in a contemporary Australian population at increased cardiovascular disease risk. AB - BACKGROUND: Effective management of cardiovascular and chronic kidney disease risk factors offers longer, healthier lives and savings in healthcare. AIM: To examine risk factor management in participants of the SCReening Evaluation of the Evolution of New Heart Failure study, a self-selected population at increased cardiovascular disease risk recruited from members of a health insurance fund in Melbourne and Shepparton, Australia. METHODS: Inclusion criteria were age >= 60 years with one or more self-reported ischaemic or other heart diseases, irregular or rapid heart rhythm, cerebrovascular disease, renal impairment or treatment for hypertension or diabetes for >=2 years. Exclusion criteria were known heart failure or cardiac abnormality on echocardiography or other imaging. Medical history, clinical examination, full blood examination and biochemistry (without lipids and glycated haemoglobin (HbA1c)) were performed for 3847 participants on enrolment, and blood pressure, lipids and HbA1c were measured 1-2 years after enrolment for 3203 participants. RESULTS: Despite 99% of 3294 participants with hypertension receiving antihypertensive medication, half had blood pressures >140/90 mmHg. Approximately 77% of participants were overweight or obese, with one third being obese. Additionally, 74% of participants at high cardiovascular disease risk had low-density lipoprotein cholesterol levels >=2 mmol/L, one third of diabetic participants had HbA1c >7%, 22% had an estimated glomerular filtration rate < 60 mL/min/1.73m2 , and substantial proportions had under utilisation of antiplatelet therapy and anticoagulation for atrial fibrillation and were physically inactive. CONCLUSIONS: This population demonstrated substantial potential to reduce cardiovascular and renal morbidity and mortality and healthcare costs through more effective management of modifiable risk factors. PMID- 29136332 TI - Design considerations for an eHealth decision support tool in inflammatory bowel disease self-management. AB - BACKGROUND: Electronic health (eHealth) decision support tools have the potential to: facilitate inflammatory bowel disease (IBD) self-management, reduce health care utilisation and alleviate the pressure on overburdened outpatient clinics. The purpose of this study was to explore the perspectives of key stakeholders on the potential use of a decision support tool for IBD patients. METHODS: A qualitative study using focus group methodology was conducted at a tertiary IBD centre in Melbourne, Australia in February 2015. Key stakeholders, including physicians, nurses and patients, were included in the study. Two independent reviewers undertook inductive coding and generated themes. RESULTS: In total, 31 participants were included in the study (including 16 males; 11 physicians; 6 nurses). An eHealth decision support tool was thought to be beneficial to facilitate IBD self-management. Four themes emerged: (i) Framework for the decision support tool - the tool should be an adjunct to current models of care and facilitate shared decision-making and patient engagement; (ii) Target population - stable patients with mild to moderate disease; (iii) Functionalities of the intervention - a web-based platform encompassing patient-reported outcomes, objective markers of disease and clinical algorithms based on international guidelines; and (iv) Design and Implementation - patients should be involved in the design. CONCLUSIONS: eHealth interventions are thought to be an important strategy to facilitate self-management for patients with IBD. A multi stage iterative approach should be adopted in the design and implementation process of eHealth interventions. Patient perspectives need to be sought prior to and throughout the development of an eHealth decision support tools for IBD. PMID- 29136333 TI - Role of Bismuth in the Electrokinetics of Silicon Photocathodes for Solar Rechargeable Vanadium Redox Flow Batteries. AB - The ability of crystalline silicon to photoassist the V3+ /V2+ cathodic reaction under simulated solar irradiation, combined with the effect of bismuth have led to important electrochemical improvements. Besides the photovoltage supplied by the photovoltaics, additional decrease in the onset potentials, high reversibility of the V3+ /V2+ redox pair, and improvement in the electrokinetics were attained thanks to the addition of bismuth. In fact, Bi0 deposition has shown to slightly decrease the photocurrent, but the significant enhancement in the charge transfer, reflected in the overall electrochemical performance clearly justifies its use as additive in a photoassisted system for maximizing the efficiency of solar charge to battery. PMID- 29136334 TI - Identification of Plasma Membrane Glycoproteins Specific to Human Glioblastoma Multiforme Cells Using Lectin Arrays and LC-MS/MS. AB - Glioblastoma, also known as glioblastoma multiforme (GBM), is the most malignant type of brain cancer and has poor prognosis with a median survival of less than one year. While the structural changes of tumor cell surface carbohydrates are known to be associated with invasive behavior of tumor cells, the cell surface glycoproteins to differentiate the low- and high-grade glioma cells can be potential diagnostic markers and therapeutic targets for GBMs. In the present study, lectin arrays consisting of eight lectins were employed to explore cell surface carbohydrate expression patterns on low-grade oligodendroglioma cells (Hs683) and GBM cells (T98G). Griffonia simplicifolia I (GS I) was found to selectively bind to T98G cells and not to Hs683 cells. For identification of the glioblastoma-specific cell surface markers, the glycoproteins from each cell type were captured by a GS I lectin column and analyzed by LC-MS/MS. The identified proteins from the two cell types were quantified using label-free quantitative analysis based on spectral counting. Of cell surface glycoproteins showing significant increases in T98G cells, five proteins were selected for verification of both protein and glycosylation level changes using Western blot and GS I lectin-based immunosorbent assay. PMID- 29136335 TI - [Sar1, Ile4, Ile8]-angiotensin II Potentiates Insulin Receptor Signalling and Glycogen Synthesis in Hepatocytes. AB - The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]-angiotensin II (SII Ang II) analogue, that only activate a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance. Here, we studied the effect of SII Ang II on insulin receptor (IR) signalling and glucose metabolism in primary rat hepatocytes. We show that long-term pre-treatment of hepatocytes with SII Ang II increased insulin-stimulated glycogen synthesis, while Ang II and the AT1R antagonist losartan had no effect. Insulin-stimulated suppression of hepatic glucose output was not affected by Ang II or SII Ang II. It is well known that insulin regulates glycogen synthesis and glucose output through Akt-mediated phosphorylation of glycogen synthase kinase alpha/beta (GSK3alpha/beta) and forkhead box protein O1 (FOXO1), respectively. In line with this, we show that SII Ang II potentiated insulin-stimulated phosphorylation of Akt and GSK3alpha/beta, but not FOXO1. Furthermore, we demonstrate that the effect of SII Ang II on insulin-stimulated signalling and glycogen synthesis was dependent on Src and Galphaq, as inhibitors of these proteins abolished the potentiating effect of SII Ang II. Thus, our results demonstrate that SII Ang II may have a positive effect on IR signalling and glucose metabolism in hepatocytes. PMID- 29136336 TI - Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers. AB - Sertraline is a selective serotonin reuptake inhibitor widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P-glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of this study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty-six healthy volunteers (24 men and 22 women) receiving a 100-mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP-binding cassette subfamily B member 1 (ABCB1), solute carrier family 6 member 4 (SLC6A4), 5-hydroxytryptamine receptor 2A (HTR2A) and 5-hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Individuals carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half-life (T1/2 ). Moreover, CYP2C19*17 was related to a decreased AUC and T1/2 . No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate-lowering effect, directly related to maximum concentration (Cmax ) and the presence of ABCB1 minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and individuals with higher AUC of sertraline, such as CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T individuals. PMID- 29136337 TI - Production of Jet Fuel-Range Hydrocarbons from Hydrodeoxygenation of Lignin over Super Lewis Acid Combined with Metal Catalysts. AB - Super Lewis acids containing the triflate anion [e.g., Hf(OTf)4 , Ln(OTf)3 , In(OTf)3 , Al(OTf)3 ] and noble metal catalysts (e.g., Ru/C, Ru/Al2 O3 ) formed efficient catalytic systems to generate saturated hydrocarbons from lignin in high yields. In such catalytic systems, the metal triflates mediated rapid ether bond cleavage through selective bonding to etheric oxygens while the noble metal catalyzed subsequent hydrodeoxygenation (HDO) reactions. Near theoretical yields of hydrocarbons were produced from lignin model compounds by the combined catalysis of Hf(OTf)4 and ruthenium-based catalysts. When a technical lignin derived from a pilot-scale biorefinery was used, more than 30 wt % of the hydrocarbons produced with this catalytic system were cyclohexane and alkylcyclohexanes in the jet fuel range. Super Lewis acids are postulated to strongly interact with lignin substrates by protonating hydroxyl groups and ether linkages, forming intermediate species that enhance hydrogenation catalysis by supported noble metal catalysts. Meanwhile, the hydrogenation of aromatic rings by the noble metal catalysts can promote deoxygenation reactions catalyzed by super Lewis acids. PMID- 29136338 TI - Perspectives of Medical Specialists From Different Disciplines on the Management of Systemic Lupus Erythematosus: An Interview Study. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex autoimmune disease that can affect multiple organ systems, with specialists from many disciplines often involved, which may lead to inconsistent care. We aimed to describe the attitudes and perspectives of specialists from different medical disciplines on the management of people with SLE. METHODS: Face-to-face semistructured interviews were conducted with rheumatologists (n = 16), nephrologists (n = 16), and immunologists (n = 11) providing care to adults with SLE from 19 centers across Australia in 2015. All interviews were transcribed and analyzed thematically. RESULTS: Five themes were identified: uncertainties in judgments (hampered by unknown and unclear etiology, inapplicable evidence, comprehending information dispersion), reflexive responses (anchoring to specialty training, anticipating outcomes, avoiding disaster, empathy for the vulnerable), overarching duty to patients (achieving patient priorities, maximizing adherence, controlling the disease, providing legitimate information, having adequate and relevant expertise), safeguarding professional opportunities (diversifying clinical skills, protecting colleagues' interests), and optimizing access to treatment (capitalizing on multidisciplinary care, acquiring breakthrough therapies). CONCLUSION: Specialists strive to deliver evidence-informed patient centered care, but recognize that they are anchored by their training. To overcome uncertainties in clinical management due to lack of high-quality evidence and specialty silo structures, specialists translated evidence from other disease settings and collaborated with other specialists in routine care. Developing robust evidence, tools to support evidence-informed decisions, and multidisciplinary shared-care pathways may improve the management of people with this complex disease. PMID- 29136339 TI - The imaging definition of bronchiectasis in children: Is it time for a change? PMID- 29136340 TI - Nomenclature of Cutaneous Vasculitis: Dermatologic Addendum to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. AB - OBJECTIVE: To prepare a dermatologic addendum to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012) to address vasculitides affecting the skin (D-CHCC). The goal was to standardize the names and definitions for cutaneous vasculitis. METHODS: A nominal group technique with a facilitator was used to reach consensus on the D-CHCC nomenclature, using multiple face-to-face meetings, e-mail discussions, and teleconferences. RESULTS: Standardized names, definitions, and descriptions were adopted for cutaneous components of systemic vasculitides (e.g., cutaneous IgA vasculitis as a component of systemic IgA vasculitis), skin-limited variants of systemic vasculitides (e.g., skin-limited IgA vasculitis, drug-induced skin limited antineutrophil cytoplasmic antibody-associated vasculitis), and cutaneous single-organ vasculitides that have no systemic counterparts (e.g., nodular vasculitis). Cutaneous vasculitides that were not included in the CHCC2012 nomenclature were introduced. CONCLUSION: Standardized names and definitions are a prerequisite for developing validated classification and diagnostic criteria for cutaneous vasculitis. Accurate identification of specifically defined variants of systemic and skin-limited vasculitides requires knowledgeable integration of data from clinical, laboratory, and pathologic studies. This proposed nomenclature of vasculitides affecting the skin, the D-CHCC, provides a standard framework both for clinicians and for investigators. PMID- 29136341 TI - Photodynamic therapy and nuclear imaging activities of zinc phthalocyanine integrated TiO2 nanoparticles in breast and cervical tumors. AB - In recent years, phthalocyanines (Pcs) have been widely used as photosensitizer in photodynamic therapy applications. Because of their strong absorptions in the near-infrared region (640-700 nm). The integration of phthalocyanine derivatives to a nanoparticle is expected to be efficient way to improve the activity of the photosensitizer on the targeted tissue. It is known that the integrated molecules not only show better accumulation on tumor tissue but also reduce toxicity in healthy tissues. In this study, the ZnPc molecule was synthesized and integrated to the TiO2 nanoparticle, to investigate the potential of PDT and its cytotoxicity. Additionally, ZnPc and ZnPc-TiO2 molecules were labeled with 131 I and it was aimed to put forth the nuclear imaging/therapy potentials of 131 I labeled ZnPc/ZnPc-TiO2 by determining in vitro uptakes in mouse mammary carcinoma (EMT6), human cervical adenocarcinoma (HeLa). In result of our study, it was observed that the radiolabeling yields of the synthesized ZnPc and ZnPc-TiO2 with 131 I were quite high. In vitro uptake studies shown that 131 I-ZnPc-TiO2 could be a potential agent for nuclear imaging/treatment of breast and cervical cancers. According to PDT results, ZnPc-TiO2 might have as to be a potential PDT agent in the treatment of cervical tumor. ZnPc and ZnPc-TiO2 might be used as theranostic agents. PMID- 29136342 TI - Direct intranasal application of the solid phase of ImmunoCAP(r) increases nasal specific immunoglobulin E detection in local allergic rhinitis patients. AB - BACKGROUND: The measurement of nasal specific IgE (NsIgE) in local allergic rhinitis (LAR) patients is challenging and shows variability. The objective of this work was to evaluate a minimally-invasive method of direct detection of NsIgE in patients with LAR to Dermatophagoides pteronyssinus (DP) using an automated immunoassay. METHODS: Fifty patients participated (LAR, n = 14; allergic rhinitis (AR), n = 20; healthy controls [HC], n = 16). Detection of NsIgE was performed by direct application of the solid phase of a commercial DP ImmunoCAP(r) test 24 hours after DP nasal provocation. RESULTS: There was no difference in the median volume of secretion absorbed by the solid phase of the ImmunoCAP test in the 3 studied groups (p = 0.17). According to receiver operating characteristic (ROC) curve analysis, NsIgE >=0.1450 was the optimal cutoff point, obtaining in LAR patients 42.86% sensitivity with the highest specificity (100%), and 75% sensitivity and 100% specificity for AR. CONCLUSION: This study demonstrates the detection of NsIgE to DP in LAR by using a simple, commercial device with high specificity. PMID- 29136343 TI - Pharmacokinetics, Pharmacodynamics, and Safety of a Long-Acting Human Growth Hormone (MOD-4023) in Healthy Japanese and Caucasian Adults. AB - Daily injections of growth hormone (GH) as replacement therapy in GH-deficient (GHD) patients may cause poor compliance and inconvenience. C-terminal peptide modified human GH (MOD-4023) has been developed for once-weekly administration in GHD adults and children. In the present study, the pharmacokinetics (PK) and pharmacodynamics (PD) of a single subcutaneous dose of MOD-4023 were evaluated in healthy Caucasian and Japanese adults, using a phase 1 double-blind, vehicle controlled, randomized study design. The study was conducted in 42 healthy Japanese (n = 21) and Caucasian (n = 21) men receiving either MOD-4023 at a dose of 2.5, 7.5, or 15 mg or vehicle. In the 2.5- and 7.5-mg cohorts, no differences in mean MOD-4023 serum concentration were found between Japanese and Caucasian subjects. A comparison of PK parameters in the 15-mg group suggests a slower absorption rate of MOD-4023 in Japanese subjects. PD analysis showed no apparent differences in IGF-1 and IGFBP-3 plasma concentrations between the Japanese and Caucasian subjects and indicated that a dose of 15 mg achieved the maximal effect in both ethnic groups. MOD-4023 demonstrated a favorable safety profile and local tolerance following single-dose subcutaneous administration. This study provides additional support for the development of MOD-4023 as a long-acting human growth hormone formulation for once-weekly administration. PMID- 29136344 TI - The hypoxic test in preterm neonates reinvestigated. AB - AIM: We currently lack a suitable gold-standard method for implementation on modern equipment to assess peripheral chemoreceptor sensitivity. The aim of the present study was to develop an accurate and reproducible method for assessing peripheral chemoreceptors sensitivity in sleeping preterm neonates. METHODS: A poikilocapnic hypoxic test was performed twice during rapid eye movement sleep (REM sleep) and non-rapid eye movement sleep (nonREM sleep). The infant breathed hypoxic gas (15% O2 ) for 60 s. The ventilatory response to hypoxia was assessed by comparing minute ventilation during the control period (21% O2 ) with successive 4-cycles sequences during hypoxia. We detected the first statistically significant increase in minute ventilation and recorded the corresponding response time. RESULTS: During normoxia, minute ventilation was higher during REM sleep than in nonREM sleep (428.1 mL . min-1 . kg-1 [307.7-633.6]; 388.8 mL . min-1 . kg-1 [264.7-608.0], respectively; P = 0.001). After hypoxia, minute ventilation increased in both REM and nonREM sleep. The response was significantly higher in REM than in nonREM (25.3% [10.8-80.0] and 16.8% [7.5 33.2], respectively; P = 0.005). The intraclass correlation coefficients for all respiratory parameters were above 0.90. CONCLUSION: We have developed a highly reliable method for assessing peripheral chemoreceptors sensitivity at the response time to hypoxia. In the future, researchers could use this method to assess the involvement of peripheral chemoreceptors in infants who experience chronic hypoxia (e.g. in bronchopulmonary dysplasia and recurrent apnea). PMID- 29136345 TI - Regional lung function testing in children using electrical impedance tomography. AB - OBJECTIVE: To evaluate regional lung function in lung-healthy children before and after exercise challenge using electrical impedance tomography (EIT). METHODS: Regional lung function was examined using EIT in 100 lung-healthy children (three age subgroups: 74-121, 122-155, 156-195 months) at baseline and 10 min after exercise. Global lung function was assessed by spirometry using Z-Scores of FEV1 , FVC, FEV1 /FVC, and FEF75 . The same lung function measures were determined in 912 EIT image pixels to enable the spatial and temporal ventilation distribution analysis. Coefficients of variation (CV) of these pixel values were calculated and histograms of pixel FEV1 /FVC and times required to exhale 50% and 75% of pixel FVC (t50 and t75 ) generated. Additionally, we compared the findings of the studied population with three cystic fibrosis (CF) children. FINDINGS: Z-Scores corresponded to the worldwide reference values in all studied age groups at baseline. Global lung function was not affected by exercise, only the youngest group exhibited higher FVC and lower FEF75 , FEV1 /FVC attributable to the training effect. The overall degree of ventilation heterogeneity assessed by CV showed no exercise dependency. The histograms of pixel values of FEV1 /FVC, t50 , and t75 revealed a slight modulating effect of exercise on regional ventilation distribution in all subgroups. EIT identified the distinctly higher ventilation heterogeneity in the CF children. CONCLUSION: Global and regional lung functions were not affected by exercise in lung-healthy children. Exercise did not increase ventilation inhomogeneity. The obtained EIT-derived regional lung parameters can serve as reference values for future studies in children with lung diseases. PMID- 29136346 TI - Can high flow nasal cannula be used in a pediatric patient with tracheomalacia? PMID- 29136347 TI - Pro-inflammatory mediator responses from neonatal airway epithelial cells and early childhood wheeze. AB - BACKGROUND: Airway epithelial cell (AEC) function differs between children with and without asthma. Here, we associated neonatal AEC function with asthma symptoms at 4 years of age. METHODS: Nasal AEC were collected from neonates within 48 h of birth. Cells were cultured and stimulated with tumor necrosis factor alpha/interleukin-1 beta (TNFalpha/IL-1beta), lipopolysaccharide (LPS), or house dust mite (HDM). Absolute concentrations of pro-inflammatory mediators in the culture supernatant were quantified and expressed as median [interquartile range] in pg/mg protein. A parent-completed respiratory questionnaire was returned when the child was 4 years old. RESULTS: AEC were successfully cultured in 139 neonates, of whom 120 were contacted at 4 years and 91 (76%) questionnaires were returned. Sixteen children had wheezed ever and 11 had recent wheeze. At birth, when compared to those with no recent wheeze, supernatants from cultured neonatal AEC from the children with recent wheeze had reduced median IL 8 (CXCL8) release after treatment with culture medium alone (P = 0.049), with TNFalpha/IL-1beta (P < 0.001) and LPS (P = 0.004). Additionally, and when compared to those with no recent wheeze, 4 year olds with recent wheeze had reduced neonatal AEC release of IL-6 (P = 0.013), GMCSF (P = 0.012), and ICAM-1 (P = 0.017) after treatment with TNFalpha/IL-1beta and reduced release of ICAM-1 (P = 0.038) and RANTES (P = 0.042) after treatment with HDM. CONCLUSIONS: Abnormalities in AEC function are present at birth before the onset of childhood wheeze. The relationship between reduced AEC function at birth and wheeze at 4 years was not exclusive, suggesting that post-natal factors are required for the AEC abnormality to translate into symptoms. PMID- 29136348 TI - Outcomes of donation after circulatory death kidneys undergoing hypothermic machine perfusion following static cold storage: A UK population-based cohort study. AB - Evidence is currently lacking regarding the outcomes of kidneys undergoing hypothermic machine perfusion (HMP) in patients in the United Kingdom. Using the National Health Service Blood and Transplant database, the authors compared outcomes for recipients of single-organ donation after circulatory death (DCD) kidneys preserved with HMP with those preserved using only static cold storage (SCS). Between 2007 and 2015, HMP was used in 19.1% (864/4,529) of kidneys. Rates of delayed graft function (DGF) were significantly lower in organs preserved with HMP than for organs preserved with SCS (34.2% vs 42.0%, P < .001), despite a slightly longer cold ischemic time (median: 14.8 vs 14.1 hours, P < .001). Multivariable analysis found the effect of preservation modality to remain significant, with HMP organs having a significantly lower rate of DGF (odds ratio 0.65, 95% confidence interval 0.53-0.80, P < .001) and significantly shorter times to DGF resolution (average: 6.1 vs 7.4 days, P = .003) than SCS organs. The patient (P = .313) and graft (P = .263) survival rates were similar in the 2 preservation groups. HMP was associated with a marginal functional benefit in 1 year creatinine values (P = .044), with adjusted averages of 1.36 mg/dL (HMP) versus 1.40 mg/dL (SCS). This study supports the use of HMP and aids decision making over its instigation, which may improve short-term patient outcomes. PMID- 29136350 TI - Cryptographic Strategy Could Deliver Better Genomic Privacy: Method hides parts of the genome of no specific interest. PMID- 29136351 TI - Study Points to Value of Genetic Testing in Epilepsy: But genetic testing guidelines and insurance coverage are lacking. PMID- 29136349 TI - Clinical delineation of a subtype of frontonasal dysplasia with creased nasal ridge and upper limb anomalies: Report of six unrelated patients. AB - Frontonasal dysplasias are rare congenital malformations of frontonasal process derived structures, characterized by median cleft, nasal anomalies, widely spaced eyes, and cranium bifidum occultum. Several entities of syndromic frontonasal dysplasia have been described, among which, to date, only a few have identified molecular bases. We clinically ascertained a cohort of 124 individuals referred for frontonasal dysplasia. We identified six individuals with a similar phenotype, including one discordant monozygous twin. Facial features were remarkable by nasal deformity with creased ridge and depressed or absent tip, widely spaced eyes, almond-shaped palpebral fissures, and downturned corners of the mouth. All had apparently normal psychomotor development. In addition, upper limb anomalies, frontonasal encephalocele, corpus callosum agenesis, choanal atresia, and congenital heart defect were observed. We identified five reports in the literature of patients presenting with the same phenotype. Exome sequencing was performed on DNA extracted from blood of two individuals, no candidate gene was identified. In conclusion, we report six novel simplex individuals presenting with a specific frontonasal dysplasia entity associating recognizable facial features, limb and visceral malformations, and apparently normal development. The identification of discordant monozygotic twins supports the hypothesis of a mosaic disorder. Although previous patients have been reported, this is the first series, allowing delineation of a clinical subtype of frontonasal dysplasia, paving the way toward the identification of its molecular etiology. PMID- 29136352 TI - Cover Image, Volume 173A, Number 12, December 2017. AB - The cover image, by Isabel Hardee et al., is based on the Clinical Report Defective ciliogenesis in INPP5E-related Joubert syndrome, DOI: 10.1002/ajmg.a.38376. Design Credit: Darryl Leja. PMID- 29136354 TI - "Minimal" holoprosencephaly in a 14q deletion syndrome patient. AB - We report on a patient with terminal deletion of the long arm of chromosome 14 displaying brain interhemispheric fusion limited to the midline anterior frontal cortex associated with hypoplastic corpus callosum and incomplete rotation of the left hippocampus in a clinical setting of motor and intellectual disability with poor language, and social behavior abnormalities with aggressiveness. Some possible correlations between clinical signs and symptoms and various aspects of the complex brain malformation are briefly discussed and compared with other known abnormalities of chromosome 14. The different neuropathology of the most common forms and the new forms of holoprosencephaly recently described is also discussed and leads us to suggest classifying the interhemispheric fusion of this case as a "minimal" form of holoprosencephaly. This appears to be the first description in a 14q deletion patient. PMID- 29136355 TI - Frontiers in Nanointerfaces Research. PMID- 29136356 TI - Age at natural menopause and risk of diabetes in adult women: Findings from the China Kadoorie Biobank study in the Zhejiang area. AB - AIMS/INTRODUCTION: There has been considerable professional debate on the association between age at menopause and diabetes risk, while the findings are controversial. The present study explored the association between late menopause and the prevalence of diabetes in the Chinese population. MATERIAL AND METHODS: The data were part of the baseline survey of China Kadoorie Biobank from Zhejiang Province. A total of 17,076 postmenopausal women were included in the present study. Logistic regression models were used to calculate the adjusted odds ratios and their 95% confidence intervals. RESULTS: Of the participating women, 1,288 (7.54%) had type 2 diabetes. In comparison with those with menopause at 46-52 years, women with menopause at a later age (>=53 years) were 1.21-fold (95% confidence interval 1.03-1.43) more likely to have diabetes. CONCLUSIONS: The present findings suggested that later age at menopause was associated with an increased prevalence of diabetes. PMID- 29136357 TI - Association of cytokine gene polymorphisms with bronchopulmonary dysplasia in Han Chinese newborns. AB - OBJECTIVE: To investigate the association of 14 cytokine gene polymorphisms with bronchopulmonary dysplasia (BPD) among Han Chinese newborns. The 14 polymorphisms investigated were IL18 rs1946519, rs1946518, rs187238, rs360718, and rs360717 polymorphisms, IL10 rs3024493 polymorphism, IL6 rs1800795, rs1800796, and rs1800797 polymorphisms, TNF rs361525 and rs1800629 polymorphisms, and TGFB1 rs1800469, rs1800468, and rs1800471 polymorphisms. WORKING HYPOTHESIS: The polymorphisms could be associated with the risk of BPD among Han Chinese newborns. STUDY DESIGN, PATIENT-SUBJECT SELECTION, AND METHODOLOGY: This is a retrospective study. Genotyping of these polymorphisms were performed on BPD cases (N = 1022) and non-BPD controls (N = 1039) who were ascertained using the established Jobe and Bancalari criteria. The odds ratios (ORs) of polymorphisms whose genotype distribution in the controls fulfilled the Hardy-Weinberg equilibrium (HWE) were calculated to evaluate the strengths of genetic association. RESULTS: Genotype distributions of IL6 rs1800795 and rs1800797 polymorphisms deviated significantly from HWE and were omitted from the analysis. Among the 12 remaining polymorphisms, only TNF rs361525 polymorphism demonstrated a statistically significant association with BPD risk. The heterozygous GA genotype of TNF rs361525 polymorphism showed an OR of 1.932 (1.512-2.470), while the homozygous AA variant genotype showed an OR of 2.927 (1.216-7.048) (P = 0.000 and P = 0.017, respectively). Besides, the allelic OR was also analyzed, and it was found that the variant A allele of TNF rs361525 polymorphism showed an OR of 2.146 (1.718-2.680) (P = 0.000). CONCLUSION: TNF rs361525 polymorphism could influence BPD risk among Han Chinese newborns. PMID- 29136359 TI - When medicine and religion do not mix: Overlooking or misunderstanding the religious and spiritual beliefs of patients can present significant obstacles to cancer care. PMID- 29136358 TI - Is secretion of IFN-gamma in response to Mycobacterium tuberculosis antigens in youngest children sufficient to play a role in TB diagnostics? AB - OBJECTIVES: To assess whether children <=5 years of age, produce sufficient amounts of interferon gamma (IFN-gamma) in response to phytohaemagglutinin (mitogen), and Mycobacterium tuberculosis antigens (TB antigens) in the QuantiFERON-TB Gold in-Tube test (QFT-GIT), (Cellestis Ltd., Australia). WORKING HYPOTHESIS: Is TB-antigen-induced IFN-gamma response in children <=5 years sufficient to consider QFT-GIT a possible tool for TB diagnostics? Study design, patient-subject selection, and methods: We recruited children 0-17 years old suspected of TB infection to this cross-sectional study, in whom QFT-GIT and TST were performed. We analyzed the median IFN-gamma levels in mitogen and TB antigen tubes in children <=5 years and >5 years, and the correlation between IFN-gamma level in both tubes and age. RESULTS: A total of 153 children were enrolled, age median was 7.8 (IQR:8), 45 (29.4%) aged <=5 years (median 3.4, IQR:1.7), 108 > 5 years (median 10.55, IQR:5.93). In the mitogen tubes, the median IFN-gamma level was higher in children >5 years (median 17.87, IQR:2.1 vs 16.77, IQR:7.6), but surprisingly in the TB antigen tubes it was higher in the younger group (median 0.12, IQR:0.21vs 0.06, IQR:0.09, P = 0.04). We proved a positive correlation between IFN-gamma level and age in mitogen tubes (r = 0.18, P = 0.03) and a negative correlation in TB antigen tubes (r = -0.17, P = 0.04). In latent tuberculosis infection patients, the latter correlation was found to be even stronger (r = -0.39, P = 0.01). CONCLUSIONS: The youngest children release sufficient amount of IFN-gamma in response to TB antigens thus QFT-GIT might be a useful tool for TB diagnostics in this age group. PMID- 29136360 TI - Investigating Socioeconomic Position in Dental Caries and Traumatic Dental Injury among Children in Quebec. AB - OBJECTIVES: Socioeconomic position (SEP) is inversely associated with most oral health outcomes, but the patterns of association may vary depending on the specific outcome. We estimated associations between SEP and two oral health outcomes, dental caries and traumatic dental injuries (TDI), in Quebec children. METHODS: We used data from the baseline visit of the QUALITY (QUebec Adipose and Lifestyle Investigation in Youth) Cohort, an ongoing study in Montreal and Quebec, Canada. The analytical sample included 590 children aged 8-10 years. Data on parents' SEP (household income, education) and children's health behaviours and involvement in sports were obtained through questionnaires and interviews. Oral health outcomes (dental caries and TDI in permanent teeth) were assessed by clinical oral exam. Negative binomial regression was used to model dental caries (DMFS index) and number of teeth with TDI adjusting for selected covariates. RESULTS: The mean (SD) DMFS and number of TDI were 0.61 (1.43) and 0.12 (0.43), respectively. Compared to the upper quartile of income, children in the lower quartile had a DMFS approximately 3 times higher (PRR=2.68, 95% CI: 1.43, 5.04). Adjusting for oral health and nutritional behaviours had no effect. Conversely, children in the highest income quartile had a 3 times higher number of teeth with TDI compared to the lowest quartile (PRR=3.14, 95% CI: 1.22, 8.08). Physical activity did not explain this relationship. Parents' education was not associated with dental caries or TDI. CONCLUSION: SEP seems to play a different role in the cause of dental caries and TDI. PMID- 29136361 TI - Dental status in nursing home residents with domiciliary dental care in Sweden. AB - OBJECTIVE: To describe the dental health status of elderly people in nursing homes receiving domiciliary dental care. DESIGN: Case note review. CLINICAL SETTING: Nursing homes in 8 Swedish counties. PARTICIPANTS: Care dependent elderly people (>=65 years). METHODS: Clinical data, including the number of remaining natural teeth, missing and decayed teeth (manifest dental caries) and root remnants, recorded by dentists according to standard practices. Medical and dental risk assessments were performed. RESULTS: Data were available for 20,664 patients. Most were women (69.1%), with a mean age of 87.1 years (SD 7.42, range 65-109). The mean age for men was 83.5 years (SD 8.12, range 65-105). Two or more medical conditions were present in most of the population. A total of 16,210 individuals had existing teeth of whom 10,974 (67.7%) had manifest caries. The mean number of teeth with caries was 5.0 (SD 5.93) corresponding to 22.8% of existing teeth. One in four individuals were considered to have a very high risk in at least one professional dental risk assessment category. CONCLUSIONS: Care dependent elderly in nursing homes have very poor oral health. There is a need to focus on the oral health-related quality of life for this group of frail elderly during their final period of life. PMID- 29136362 TI - Examiner calibration in caries detection for populations and settings where in vivo calibration is not practical. AB - AIM: to compare two methods of in vitro examiner calibration in populations and settings where clinical (in vivo) calibration is not practical. METHODS: Study design was cross-sectional and fully-crossed. The units of analysis were 880 tooth surfaces, from ten children ages 3 to 4 years. The study had three data components: (1) Examiner training and calibration using the International Caries Detection and Assessment System (ICDAS) e-Learning programme (2) In vivo community-based visual examination and (3) Intra-oral digital photographs of the same tooth surfaces from the in vivo visual examination. Kappa and weighted kappa scores were used to study reliability estimates. Systematic differences in caries assessments were determined using the Stuart Maxwell test. Data were analysed using STATA 13.1 and SAS 9.2. RESULTS: Weighted kappa scores for the in vivo component ranged from 0.50 to 0.66 and from 0.64-0.74, for inter- and intraexaminer reliability, respectively. Caries lesions detected in vivo were also detected on photographs, albeit with more false positives when using photographs. For example, of 46 tooth surfaces assessed as being sound in the in vivo examination, 22 (48%) of these were assessed as having caries when photographs were used as the diagnostic method. CONCLUSIONS: From this research it appears that good quality photographs alone may be used for training and calibration among challenging populations or settings without adversely affecting data quality. PMID- 29136363 TI - Dynamic Stabilization of the Ligand-Metal Interface in Atomically Precise Gold Nanoclusters Au68 and Au144 Protected by meta-Mercaptobenzoic Acid. AB - Ligand-stabilized, atomically precise gold nanoclusters with a metal core of a uniform size of just 1-3 nm constitute an interesting class of nanomaterials with versatile possibilities for applications due to their size-dependent properties and modifiable ligand layers. The key to extending the usability of the clusters in applications is to understand the chemical bonding in the ligand layer as a function of cluster size and ligand structure. Previously, it has been shown that monodispersed gold nanoclusters, stabilized by meta-mercaptobenzoic acid (m-MBA or 3-MBA) ligands and with sizes of 68-144 gold atoms, show ambient stability. Here we show that a combination of nuclear magnetic resonance spectroscopy, UV vis absorption, infrared spectroscopy, molecular dynamics simulations, and density functional theory calculations reveals a distinct chemistry in the ligand layer, absent in other known thiol-stabilized gold nanoclusters. Our results imply a low-symmetry C1 ligand layer of 3-MBA around the gold core of Au68 and Au144 and suggest that 3-MBA protects the metal core not only by the covalent S Au bond formation but also via weak pi-Au and O?C-OH...Au interactions. The pi-Au and -OH...Au interactions have a strength of the order of a hydrogen bond and thus are dynamic in water at ambient temperature. The -OH...Au interaction was identified by a distinct carbonyl stretch frequency that is distinct for 3-MBA protected gold clusters, but is missing in the previously studied Au102(p-MBA)44 cluster. These thiol-gold interactions can be used to explain a remarkably low ligand density on the surface of the metal core of these clusters. Our results lay a foundation to understand functionalization of atomically precise ligand stabilized gold nanoclusters via a route where weak ligand-metal interfacial interactions are sacrificed for covalent bonding. PMID- 29136364 TI - Rational Design and Synthesis of Post-Functionalizable Peptide Foldamers as Helical Templates. AB - In this study, we developed post-functionalizable helical peptides composed of Leu, Aib, and Azl residues. We show that the synthesized peptides 1 and 2 form helical structures, and may be modified using specific side chain or several functional groups by the click reaction without influencing their secondary structures. PMID- 29136365 TI - Chiral Molecular Ferroelectrics with Polarized Optical Effect and Electroresistive Switching. AB - Multifunctional properties of chiral molecules arise from the coexistence of mirror-symmetry-induced stereoisomers and optical rotation characteristics in one material. One of these complex phenomena in these molecules is chiral ferroelectricity, providing the coupling between polarized light and the spatial asymmetry induced dipole moment. Herein we describe the chiral polarization and electroresistance in molecular ferroelectric (R)-(-)-3-hydroxyquinuclidinium chloride thin films with a Curie temperature of 340 K. The high transmittance of chiral ferroelectrics is coupled with polarized light for a linear electro-optic effect, which exhibits angle-dependent optical behaviors. The polarization controlled conductance imposes a large on/off ratio (~26.6) of electroresistive switching in molecular ferroelectrics with superior antifatigue endurance. PMID- 29136366 TI - Use of an Efficient Measurement Uncertainty Approach To Compare Room Temperature and Cryogenic Sample Processing in the Analysis of Chemical Contaminants in Foods. AB - In this study, analytical results were compared when using different approaches to bulk food sample comminution, consisting of a vertical chopper (Blixer) at room temperature and dry ice cryogenic conditions, followed by further subsample processing (20 g) using liquid nitrogen cryogenic conditions (cryomill). Analysis of the 43 targeted spiked and incurred contaminants in a food mixture consisting of equal parts orange, apple, kale, salmon, and croaker involved quick, easy, cheap, effective, rugged, and safe (QuEChERS) with automated mini-column solid phase extraction (known as ITSP) cleanup, followed by low-pressure gas chromatography-tandem mass spectrometry (LPGC-MS/MS). Different ambient Blixer test portion sizes of 20, 10, 5, 2, and 1 g were assessed, and for cryogenic Blixer conditions, a 0.5 g test portion was also tested. In the case of the cryomill, test portions were 2, 1, and 0.5 g and all subsamples in all cases entailed five replicates. Determined concentrations and precisions (CV) of the analytes were compared to assess possible differences in systematic and random forms of error. A quality control spike was made before each step in the procedures to isolate that individual step in the uncertainty measurements using the error propagation sum of squares approach. Results indicated that the uncertainty of the sample preparation and LPGC-MS/MS analysis steps were 2-7 and 11% CV, respectively, while uncertainties of sample processing ranged from 6% CV for the cryomill to 12% CV for the ambient Blixer conditions. The common use of internal standards reduced overall method uncertainty from 12-15 to 7-10% CV. For the analytes, matrix, conditions, and tools used in this study, the minimal test sample weight that gave satisfactory recoveries and precision was found to be 1 g in all cases. PMID- 29136367 TI - Heptavalent Actinide Tetroxides NpO4- and PuO4-: Oxidation of Pu(V) to Pu(VII) by Adding an Electron to PuO4. AB - The highest known actinide oxidation states are Np(VII) and Pu(VII), both of which have been identified in solution and solid compounds. Recently a molecular Np(VII) complex, NpO3(NO3)2-, was prepared and characterized in the gas phase. In accord with the lower stability of heptavalent Pu, no Pu(VII) molecular species has been identified. Reported here are the gas-phase syntheses and characterizations of NpO4- and PuO4-. Reactivity studies and density functional theory computations indicate the heptavalent metal oxidation state in both. This is the first instance of Pu(VII) in the absence of stabilizing effects due to condensed phase solvation or crystal fields. The results indicate that addition of an electron to neutral PuO4, which has a computed electron affinity of 2.56 eV, counterintuitively results in oxidation of Pu(V) to Pu(VII), concomitant with superoxide reduction. PMID- 29136368 TI - Split2 Protein-Ligation Generates Active IL-6-Type Hyper-Cytokines from Inactive Precursors. AB - Trans-signaling of the major pro- and anti-inflammatory cytokines Interleukin (IL)-6 and IL-11 has the unique feature to virtually activate all cells of the body and is critically involved in chronic inflammation and regeneration. Hyper IL-6 and Hyper-IL-11 are single chain designer trans-signaling cytokines, in which the cytokine and soluble receptor units are trapped in one complex via a flexible peptide linker. Albeit, Hyper-cytokines are essential tools to study trans-signaling in vitro and in vivo, the superior potency of these designer cytokines are accompanied by undesirable stress responses. To enable tailor-made generation of Hyper-cytokines, we developed inactive split-cytokine-precursors adapted for posttranslational reassembly by split-intein mediated protein trans splicing (PTS). We identified cutting sites within IL-6 (E134/S135) and IL-11 (G116/S117) and obtained inactive split-Hyper-IL-6 and split-Hyper-IL-11 cytokine precursors. After fusion with split-inteins, PTS resulted in reconstitution of active Hyper-cytokines, which were efficiently secreted from transfected cells. Our strategy comprises the development of a background-free cytokine signaling system from reversibly inactivated precursor cytokines. PMID- 29136369 TI - Structure Determination of a Water-Soluble 144-Gold Atom Particle at Atomic Resolution by Aberration-Corrected Electron Microscopy. AB - Structure determination by transmission electron microscopy has revealed the long sought 144-gold atom particle. The structure exhibits deviations from face centered cubic packing of the gold atoms, similar to the solution structure of another gold nanoparticle, and in contrast to a previous X-ray crystal structure. Evidence from analytical methods points to a low number of 3-mercaptobenzoic acid ligands covering the surface of the particle. PMID- 29136370 TI - Ochratoxin A-Induced Apoptosis of IPEC-J2 Cells through ROS-Mediated Mitochondrial Permeability Transition Pore Opening Pathway. AB - With the purpose to explore the mechanisms associated with the intestinal toxicity of Ochratoxin A (OTA), an intestinal porcine epithelial cell line (IPEC J2) was applied in this study as in vitro models for intestinal epithelium. The results confirmed that OTA induced IPEC-J2 cell toxicity by MTT assay and apoptosis by Hoechst 33258 staining and flow cytometer analysis. We also observed that OTA induced the mitochondrial reactive oxygen species (ROS) production and mitochondrial permeability transition pore (mPTP) opening by confocal microscopy. Western blot showed that OTA induced cytochrome c (cyt-c) release and caspase-3 activation, which could be suppressed by inhibition of mPTP opening with cyclosporin A. Treatment with Mito-TEMPO, the mitochondria-targeted ROS scavenger, blocked OTA-induced mitochondrial ROS generation and mPTP opening and prevented cyt-c release, caspase-3 activation, and apoptosis in IPEC-J2 cells. PMID- 29136371 TI - Designing Dendron-Polymer Conjugate Based Targeted Drug Delivery Platforms with a "Mix-and-Match" Modularity. AB - Polymeric micellar systems are emerging as a very important class of nanopharmaceuticals due to their ability to improve pharmacokinetics and biodistribution of chemotherapy drugs, as well as to reduce related systemic toxicities. While these nanosized delivery systems inherently benefit from passive targeting through the enhanced permeation and retention effect leading to increased accumulation in the tumor, additional active targeting can be achieved through surface modification of micelles with targeting groups specific for overexpressed receptors of tumor cells. In this project, nontoxic, biodegradable, and modularly tunable micellar delivery systems were generated using two types of dendron-polymer conjugates. Either an AB type dendron-polymer construct with 2K PEG or an ABA type dendron-polymer-dendron conjugate with 6K PEG based middle block was used as primary construct; along with an AB type dendron-polymer containing a cRGDfK targeting group to actively target cancer cells overexpressing alphaupsilonbeta3/alphaupsilonbeta5 integrins. A set of micelles encapsulating docetaxel, a widely employed chemotherapy drug, were prepared with varying feed ratios of primary construct and targeting group containing secondary construct. Critical micelle concentrations of all micellar systems were in the range of 10-6 M. DLS measurements indicated hydrodynamic size distributions varying between 170 to 200 nm. An increase in docetaxel release at acidic pH was observed for all micelles. Enhanced cellular internalization of Nile red doped micelles by MDA-MB-231 human breast cancer cells suggested that the most efficient uptake was observed with targeted micelles. In vitro cytotoxicity experiments on MDA-MB-231 breast cancer and A549 lung carcinoma cell lines showed improved toxicity for RGD containing micelles. For A549 cell line EC50 values of drug loaded micellar sets were in the range of 10-9 M whereas EC50 value of free docetaxel was around 10-10 M. For MDA-MB-231 cell line EC50 value of free docetaxel was 6 * 10-8 M similar to EC50 of nontargeted AB type docetaxel doped micellar constructs whereas the EC50 value of its targeted counterpart decreased to 5.5 * 10-9 M. Overall, in this comparative study, the targeting group containing micellar construct fabricated with a 2 kDa PEG based diblock dendron polymer conjugate emerges as an attractive drug delivery vehicle due to the ease of synthesis, high stability of the micelles, and efficient targeting. PMID- 29136372 TI - Photochemical Alteration of Dissolved Organic Sulfur from Sulfidic Porewater. AB - Sulfidic sediments are a source of dissolved organic sulfur (DOS) to the ocean but the fate of sedimentary DOS in the oxic, sunlit water column is unknown. We hypothesized that photodegradation after discharge from the dark sedimentary environment results in DOS molecular transformation and decomposition. To test this hypothesis, sulfidic porewater from a saltmarsh was exposed to potential abiotic transformations of dissolved organic matter (DOM) in the water column. We quantitatively investigated DOM transformations via elemental analysis and molecularly via ultrahigh-resolution mass spectrometry. Our study indicated that photoreactivity is dependent on DOM elemental composition as DOS molecular formulas were more photolabile than those without sulfur. Prior to solar irradiation, of the 6451 identified molecular formulas in sulfidic porewater, 39% contained sulfur. After 29 days of irradiation, the DOS concentration was depleted from 13 to 1 MUM, together with a 9% decrease in the number of DOS molecular formulas. Comparing porewater and oceanic DOS molecular formulas, solar irradiation increased the similarity due to the removal of photolabile DOS formulas not present in the ocean. In conclusion, DOS from sulfidic sediments is preferentially photolabile and solar irradiation can be a potential mechanism controlling the stability and fate of porewater DOS. PMID- 29136373 TI - Photocontrol of Antibacterial Activity: Shifting from UV to Red Light Activation. AB - The field of photopharmacology aims to introduce smart drugs that, through the incorporation of molecular photoswitches, allow for the remote spatial and temporal control of bioactivity by light. This concept could be particularly beneficial in the treatment of bacterial infections, by reducing the systemic and environmental side effects of antibiotics. A major concern in the realization of such light-responsive drugs is the wavelength of the light that is applied. Studies on the photocontrol of biologically active agents mostly rely on UV light, which is cytotoxic and poorly suited for tissue penetration. In our efforts to develop photoswitchable antibiotics, we introduce here antibacterial agents whose activity can be controlled by visible light, while getting into the therapeutic window. For that purpose, a UV-light-responsive core structure based on diaminopyrimidines with suitable antibacterial properties was identified. Subsequent modification of an azobenzene photoswitch moiety led to structures that allowed us to control their activity against Escherichia coli in both directions with light in the visible region. For the first time, full in situ photocontrol of antibacterial activity in the presence of bacteria was attained with green and violet light. Most remarkably, one of the diaminopyrimidines revealed an at least 8-fold difference in activity before and after irradiation with red light at 652 nm, showcasing the effective "activation" of a biological agent otherwise inactive within the investigated concentration range, and doing so with red light in the therapeutic window. PMID- 29136374 TI - Saffron against Components of Metabolic Syndrome: Current Status and Prospective. AB - Saffron, the dried stigmas of Crocus sativus L., is mainly used as a food coloring and flavoring agent. This agricultural product is used in traditional medicine for the treatment of several diseases including asthma, liver disease, menstruation disorders, and, of special interest in this review, metabolic syndrome. Saffron and its active components including crocin, crocetin, and safranal are potential therapeutic candidates for attenuating MetS complications including hypertension, hyperglycemia, obesity, and dyslipidemia. This review summarizes the protective role of saffron and its constituents in the pathogenesis of MetS for a better understanding and hence a better management of this disease. PMID- 29136375 TI - Modified Sample Preparation Approach for the Determination of the Phenolic and Humic-Like Substances in Natural Organic Materials By the Folin Ciocalteu Method. AB - A novel modification of the sample preparation procedure for the Folin-Ciocalteu colorimetric assay for the determination of total phenolic compounds in natural solid and semisolid organic materials (e.g., foods, organic solid waste, soils, plant tissues, agricultural residues, manure) is proposed. In this method, the sample is prepared by adding sodium sulfate as a solid diluting agent before homogenization. The method allows for the determination of total phenols (TP) in samples with high solids contents, and it provides good accuracy and reproducibility. Additionally, this method permits analyses of significant amounts of sample, which reduces problems related to heterogeneity. We applied this method to phenols-rich lignocellulosic and humic-like solids and semisolid samples, including rice straw (RS), peat-rich soil (PS), and food waste (FW). The TP concentrations measured with the solid dilution (SD) preparation were substantially higher (increases of 41.4%, 15.5%, and 59.4% in RS, PS and FW, respectively) than those obtained with the traditional method (solids suspended in water). These results showed that the traditional method underestimates the phenolic contents in the studied solids. PMID- 29136376 TI - Mn(OAc)3-Promoted Oxidative Csp3-P Bond Formation through Csp2-Csp2 and P-H Bond Cleavage: Access to beta-Ketophosphonates. AB - The Mn(OAc)3-promoted oxidative phosphonylation of N,N-dimethylenaminones with H phosphonates, involving a chemo- and regioselective Csp2-Csp2 bond cleavage and Csp3-P bond formation in one step, provided successfully functionalized beta ketophosphonates under mild reaction conditions. Oxidative Csp3-H/P-H cross coupling reactions via Csp3-C(C?O) bond cleavage and mechanistic studies are conducted preliminarily, and a possible mechanism is proposed. This novel method proceeds in good to excellent yields, shows operational simplicity, broad substrate scope, and large-scale preparation. PMID- 29136377 TI - Quantifying Missing (Phospho)Proteome Regions with the Broad-Specificity Protease Subtilisin. AB - Despite huge efforts to map the human proteome using mass spectrometry the overall sequence coverage achieved to date is still below 50%. Reasons for missing areas of the proteome comprise protease-resistant domains including the lack/excess of enzymatic cleavage sites, nonunique peptide sequences, impaired peptide ionization/separation and low expression levels. To access novel areas of the proteome the beneficial use of enzymes complementary to trypsin, such as Glu C, Asp-N, Lys-N, Arg-C, LysargiNase has been reported. Here, we present how the broad-specificity protease subtilisin enables mapping of previously hidden areas of the proteome. We systematically evaluated its digestion efficiency and reproducibility and compared it to the gold standard in the field, trypsin. Notably, subtilisin allows reproducible near-complete digestion of cells lysates in 1-5 min. As expected from its broad specificity the generation of overlapping peptide sequences reduces the number of identified proteins compared to trypsin (8363 vs 6807; 1% protein FDR). However, subtilisin considerably improved the coverage of missing and particularly proline-rich areas of the proteome. Along 14 628 high confidence phosphorylation sites identified in total, only 33% were shared between both enzymes, while 37% were exclusive to subtilisin. Notably, 926 of these were not even accessible by additional in silico digestion with either Asp-N, Arg-C, Glu-C, Lys-C, or Lys-N. Thus, subtilisin might be particularly beneficial for system-wide profiling of post-translational modification sites. Finally, we demonstrate that subtilisin can be used for reporter-ion based in depth quantification, providing a precision comparable to trypsin-despite broad specificity and fast digestion that may increase technical variance. PMID- 29136378 TI - Anisotropic Self-Assembly from Isotropic Colloidal Building Blocks. AB - Spherical colloidal particles generally self-assemble into hexagonal lattices in two dimensions. However, more complex, non-hexagonal phases have been predicted theoretically for isotropic particles with a soft repulsive shoulder but have not been experimentally realized. We study the phase behavior of microspheres in the presence of poly(N-isopropylacrylamide) (PNiPAm) microgels at the air/water interface. We observe a complex phase diagram, including phases with chain and square arrangements, which exclusively form in the presence of the microgels. Our experimental data suggests that the microgels form a corona around the microspheres and induce a soft repulsive shoulder that governs the self-assembly in this system. The observed structures are fully reproduced by both minimum energy calculations and finite temperature Monte Carlo simulations of hard core soft shoulder particles with experimentally realistic interaction parameters. Our results demonstrate how complex, anisotropic assembly patterns can be realized from entirely isotropic building blocks by control of the interaction potential. PMID- 29136379 TI - Rotational-Diffusion Propagator of the Intramolecular Proton-Proton Vector in Liquid Water: A Molecular Dynamics Study. AB - The rotational motion of water molecules plays the dominant role in determining NMR spin-relaxation properties of liquid water and many biological tissues. The traditional theory of NMR spin relaxation predominantly uses the assumption that the reorientational dynamics of water molecules is described by a continuous-time rotational-diffusion random walk with a single rotational-diffusion coefficient. However, recent experimental and theoretical studies have demonstrated that water reorientation occurs by large, discrete angular jumps superimposed on a continuous-time rotational-diffusion process. We have investigated the rotational diffusion propagator of the proton-proton (H-H) vector of water molecules in liquid water at 298 K using molecular dynamics (MD) simulations. Analysis of the MD-simulated reorientational trajectories reveals that reorientation of the intramolecular H-H vector occurs through a combination of the two mechanisms: rotational diffusion proper and discrete large-angle jumps. We demonstrate that, empirically, the rotational-diffusion propagator of the intramolecular H-H vector in liquid water can be described in terms of multiple rotational-diffusion coefficients. A model with two rotational-diffusion coefficients was found to provide a reasonable (albeit imperfect) fit of the MD-simulated propagator on the time scales relevant to NMR spin relaxation near room or physiological temperature (picoseconds to nanoseconds). We report the apparent values of the two rotational-diffusion coefficients determined from the propagator analysis at 298 K and discuss their physical meaning. PMID- 29136380 TI - Synchrotron-Based High Angle Resolution and High Lateral Resolution X-ray Diffraction: Revealing Lead White Pigment Qualities in Old Masters Paintings. AB - Microsamples collected on 27 major paintings by Old European Masters dating from the 14th to the late 19th centuries were analyzed using synchrotron-based X-ray diffraction. Two complementary analytical configurations were used at beamlines ID22 (high angle resolution) and ID21 (high lateral resolution), in order to highlight markers of the different grades of the lead white pigments (mixture of cerussite PbCO3 and hydrocerussite Pb3(CO3)2(OH)2). Rietveld analysis and crystalline phases mapping at the microscale revealed the composition and microstructure of the pigments, shedding light on the preparation recipes and pigment choices of the artists through History. PMID- 29136381 TI - Structural and Energetic Properties of Haloacetonitrile-BCl3 Complexes: Computations and Matrix-IR Spectroscopy. AB - The FCH2CN-BCl3 and ClCH2CN-BCl3 complexes were investigated by quantum-chemical computations and low-temperature, matrix-isolation-IR spectroscopy. Theory predicts two stable equilibrium structures, with distinctly different B-N distances, for both complexes. One set of structures, which correspond to the global energy minima, exhibit B-N distances of 1.610 and 1.604 A for FCH2CN-BCl3 and ClCH2CN-BCl3, respectively (via M06-2X/aug-cc-pVTZ). The corresponding binding energies are 5.3 and 6.3 kcal/mol. For the metastable structures, the B-N distances are 2.870 and 2.865 A for FCH2CN-BCl3 and ClCH2CN-BCl3, respectively, and the corresponding binding energies are 3.2 and 3.3 kcal/mol. Also, the barriers between these structures on the B-N distance potentials are 2.5 and 2.8 kcal/mol, respectively, relative to the secondary, long-bond minima. In addition, several IR bands of both FCH2CN-BCl3 and ClCH2CN-BCl3 were observed in nitrogen matrices, but the assigned bands are consistent with M06-2X predictions for the short-bond, minimum-energy structures. None of the observed IR bands could be assigned to the metastable, long-bond structures. PMID- 29136382 TI - A Rhodium-Cyanine Fluorescent Probe: Detection and Signaling of Mismatches in DNA. AB - We report a bifunctional fluorescent probe that combines a rhodium metalloinsertor with a cyanine dye as the fluorescent reporter. The conjugate shows weak luminescence when free in solution or with well matched DNA but exhibits a significant luminescence increase in the presence of a 27-mer DNA duplex containing a central CC mismatch. DNA photocleavage experiments demonstrate that, upon photoactivation, the conjugate cleaves the DNA backbone specifically near the mismatch site on a 27-mer fragment, consistent with mismatch targeting. Fluorescence titrations with the 27-mer duplex containing the CC mismatch reveal a DNA binding affinity of 3.1 * 106 M-1, similar to that of other rhodium metalloinsertors. Fluorescence titrations using genomic DNA extracted from various cell lines demonstrate a clear discrimination in fluorescence between those cell lines that are proficient or deficient in mismatch repair. This differential luminescence reflects the sensitive detection of the mismatchrepair-deficient phenotype. PMID- 29136383 TI - Combined TD-DFT-SOS-CIS(D) Study of BOPHY Derivatives with Potential Application in Biosensing. AB - A set of 13 bis(difluoroboron)-1,2-bis((pyrrol-2-yl)methylene)hydrazine (BOPHY) dyes is studied through a hybrid time-dependent density functional theory (TD DFT)-scaled opposite spin-configuration interaction singles with a double correction [SOS-CIS(D)] approach accounting for solvent effects, to shed light onto the structure-property relationships of these recently developed chromophores. In the first step, we calculate the absorption-fluorescence crossing points with refined TD-DFT models considering the influences of both vibrational and solvent contributions. We found that the systematic overestimation of the 0-0 energies is effectively reduced by combining polarizable continuum model-TD-DFT with a scaled opposite spin-configuration interaction singles with a double correction [SOS-CIS(D)]. Next, for a representative system, the vibrationally resolved spectrum within the harmonic approximation is computed on the basis of TD-DFT vibrational signatures and an excellent match with experiment is found. Finally, the influence of different lateral groups on the spectroscopic properties is rationalized by investigating charge transfer parameters and examining electronic density difference maps. It is found that one can tune the position of the absorption/emission maxima by a judicious choice of the lateral substituents or by using pi-extended segments. The largest absorption and emission wavelengths as well as the largest Stokes shifts are obtained for BOPHYs containing strong electron-donor dimethylaminophenyl groups attached to the alpha-positions of the pyrrole units through vinyl linkers, making these chromophores promising candidates for bioluminescence applications. PMID- 29136384 TI - Field Effect Modulation of Heterogeneous Charge Transfer Kinetics at Back-Gated Two-Dimensional MoS2 Electrodes. AB - The ability to improve and to modulate the heterogeneous charge transfer kinetics of two-dimensional (2D) semiconductors, such as MoS2, is a major challenge for electrochemical and photoelectrochemical applications of these materials. Here we report a continuous and reversible physical method for modulating the heterogeneous charge transfer kinetics at a monolayer MoS2 working electrode supported on a SiO2/p-Si substrate. The heavily doped p-Si substrate serves as a back gate electrode; application of a gate voltage (VBG) to p-Si tunes the electron occupation in the MoS2 conduction band and shifts the conduction band edge position relative to redox species dissolved in electrolyte in contact with the front side of the MoS2. The gate modulation of both charge density and energy band alignment impacts charge transfer kinetics as measured by cyclic voltammetry (CV). Specifically, cyclic voltammograms combined with numerical simulations suggest that the standard heterogeneous charge transfer rate constant (k0) for MoS2 in contact with the ferrocene/ferrocenium (Fc0/+) redox couple can be modulated by over 2 orders of magnitude from 4 * 10-6 to 1 * 10-3 cm/s, by varying VBG. In general, the field effect offers the potential to tune the electrochemical properties of 2D semiconductors, opening up new possibilities for fundamental studies of the relationship between charge transfer kinetics and independently controlled electronic band alignment and band occupation. PMID- 29136385 TI - Elastic Properties of Few Nanometers Thick Polycrystalline MoS2 Membranes: A Nondestructive Study. AB - The performance gain-oriented nanostructurization has opened a new pathway for tuning mechanical features of solid matter vital for application and maintained performance. Simultaneously, the mechanical evaluation has been pushed down to dimensions way below 1 MUm. To date, the most standard technique to study the mechanical properties of suspended 2D materials is based on nanoindentation experiments. In this work, by means of micro-Brillouin light scattering we determine the mechanical properties, that is, Young modulus and residual stress, of polycrystalline few nanometers thick MoS2 membranes in a simple, contact-less, nondestructive manner. The results show huge elastic softening compared to bulk MoS2, which is correlated with the sample morphology and the residual stress. PMID- 29136386 TI - Anisotropic Etching of Hexagonal Boron Nitride and Graphene: Question of Edge Terminations. AB - Chemical vapor deposition (CVD) has been established as the most effective way to grow large area two-dimensional materials. Direct study of the etching process can reveal subtleties of this competing with the growth reaction and thus provide the necessary details of the overall growth mechanism. Here we investigate hydrogen-induced etching of hBN and graphene and compare the results with the classical kinetic Wulff construction model. Formation of the anisotropically etched holes in the center of hBN and graphene single crystals was observed along with the changes in the crystals' circumference. We show that the edges of triangular holes in hBN crystals formed at regular etching conditions are parallel to B-terminated zigzags, opposite to the N-terminated zigzag edges of hBN triangular crystals. The morphology of the etched hBN holes is affected by a disbalance of the B/N ratio upon etching and can be shifted toward the anticipated from the Wulff model N-terminated zigzag by etching in a nitrogen buffer gas instead of a typical argon. For graphene, etched hexagonal holes are terminated by zigzag, while the crystal circumference is gradually changing from a pure zigzag to a slanted angle resulting in dodecagons. PMID- 29136388 TI - European & Developing Countries Clinical Trials Partnership (EDCTP). PMID- 29136389 TI - Factors That Influence FDA Decisions for Postmarketing Requirements and Commitments During Review of Oncology Products. AB - PURPOSE: With the recent use of expedited drug development and approval programs for several oncology products in the United States, the importance of postmarketing plans to confirm clinical benefits and safety is increasing. To discuss postmarketing requirements (PMRs) and postmarketing commitments (PMCs) required for oncology products approved in the United States, we investigated the factors that influenced the US Food and Drug Administration (FDA) decisions for PMR/PMCs during FDA review. METHODS: Characteristics of new drug approvals and PMR/PMCs for oncology products (new molecular entities and new therapeutic biologic products) in the United States between 2008 and 2015 were analyzed. RESULTS: Of the 58 oncology products analyzed, PMR/PMCs were required for 54 products. The proportion of approvals that required confirmatory PMR/PMCs was 100% for accelerated approval (AA) and was 39% for regular approval (RA). Median development times for AA and RA were 7.41 and 7.50 years, respectively. Randomization, number of patients, and end point in pivotal studies were identified as key potential factors that influenced the decision to require PMR/PMCs for both confirmatory and clinical safety studies. CONCLUSION: Robustness of the pivotal study design was identified as one of the key factors for the decision by the FDA to require PMR/PMCs-in particular, significant PMR/PMCs, such as those for confirmatory studies. That is, the FDA approved products with surrogate markers and smaller studies but required PMR/PMCs to fully prove the risk-benefit profile in the postmarketing period. PMID- 29136387 TI - Randomized, Multicenter, Placebo-Controlled Clinical Trial of Duloxetine Versus Placebo for Aromatase Inhibitor-Associated Arthralgias in Early-Stage Breast Cancer: SWOG S1202. AB - Purpose Adherence to aromatase inhibitor (AI) therapy for early-stage breast cancer is limited by AI-associated musculoskeletal symptoms (AIMSS). Duloxetine is US Food and Drug Administration approved for treatment of multiple chronic pain disorders. We hypothesized that treatment of AIMSS with duloxetine would improve average joint pain compared with placebo. Methods This randomized, double blind, phase III trial included AI-treated postmenopausal women with early-stage breast cancer and who had average joint pain score of >= 4 out of 10 that developed or worsened since AI therapy initiation. Patients were randomly assigned 1:1 to duloxetine or placebo for 13 weeks. The primary end point was average joint pain through 12 weeks, examined using multivariable linear mixed models, adjusted for stratification factors (baseline pain score of 4 to 6 v 7 to 10 and prior taxane use). Clinically significant change in average pain was defined as a >= 2-point decrease from baseline. Results Of 299 enrolled patients, 127 patients treated with duloxetine and 128 who received placebo were evaluable for the primary analysis. By 12 weeks, the average joint pain score was 0.82 points lower for patients who received duloxetine compared with those who received placebo (95% CI, -1.24 to -0.40; P = .0002). Similar patterns were observed for worst joint pain, joint stiffness, pain interference, and functioning. Rates of adverse events of any grade were higher in the duloxetine treated group (78% v 50%); rates of grade 3 adverse events were similar. Conclusion Results of treatment with duloxetine for AIMSS were superior to those of placebo among women with early-stage breast cancer, although it resulted in more frequent low-grade toxicities. PMID- 29136390 TI - Assurance of Myeloid Growth Factor Administration in an Infusion Center: Pilot Quality Improvement Initiative. AB - PURPOSE: Four incident reports involving missed doses of myeloid growth factors (MGFs) triggered the need for an outcome-driven initiative. From March 1, 2015, to February 29, 2016, at University of California Irvine Health Chao Infusion Center, 116 of 3,300 MGF doses were missed (3.52%), including pegfilgrastim, filgrastim, and sargramostim. We hypothesized that with the application of Lean Six Sigma methodology, we would achieve our primary objective of reducing the number of missed MGF doses to < 0.5%. METHODS: This quality improvement initiative was conducted at Chao Infusion Center as part of a Lean Six Sigma Green Belt Certification Program. Therefore, Lean Six Sigma principles and tools were used throughout each phase of the project. Retrospective and prospective medical record reviews and data analyses were performed to evaluate the extent of the identified problem and impact of the process changes. Improvements included systems applications, practice changes, process modifications, and safety-net procedures. RESULTS: Preintervention, 24 missed doses (20.7%) required patient supportive care measures, resulting in increased hospital costs and decreased quality of care. Postintervention, from June 8, 2016, to August 7, 2016, zero of 489 MGF doses were missed after 2 months of intervention ( P < .001). Chao Infusion Center reduced missed doses from 3.52% to 0%, reaching the goal of < 0.5%. CONCLUSION: The establishment of simplified and standardized processes with safety checks for error prevention increased quality of care. Lean Six Sigma methodology can be applied by other institutions to produce positive outcomes and implement similar practice changes. PMID- 29136392 TI - Rescue Effect Inherited in Colony Formation Assays Affects Radiation Response. AB - It is well known that nonirradiated cells can exhibit radiation damage (bystander effect), and recent findings have shown that nonirradiated cells may help protect irradiated cells (rescue effect). These findings call into question the traditional view of radiation response: cells cannot be envisioned as isolated units. Here, we investigated traditional colony formation assays to determine if they also comprise cellular communication affecting the radiation response, using colony formation assays with varying numbers of cells, modulated beam irradiation and media transfer. Our findings showed that surviving fraction gradually increased with increasing number of irradiated cells. Specifically, for DU-145 human prostate cancer cells, surviving fraction increased 1.9-to-4.1-fold after 5 12 Gy irradiation; and for MM576 human melanoma cells, surviving fraction increased 1.9-fold after 5 Gy irradiation. Furthermore, increased surviving fraction was evident after modulated beam irradiation, where irradiated cells could communicate with nonirradiated cells. Media from dense cell culture also increased surviving fraction. The results suggest that traditional colony formation assays comprise unavoidable cellular communication affecting radiation outcome and the shape of the survival curve. We also propose that the increased in-field surviving fraction after modulated beam irradiation is due to the same effect. PMID- 29136391 TI - Effects of 1H + 16O Charged Particle Irradiation on Short-Term Memory and Hippocampal Physiology in a Murine Model. AB - Radiation from galactic cosmic rays (GCR) poses a significant health risk for deep-space flight crews. GCR are unique in their extremely high-energy particles. With current spacecraft shielding technology, some of the predominant particles astronauts would be exposed to are 1H + 16O. Radiation has been shown to cause cognitive deficits in mice. The hippocampus plays a key role in memory and cognitive tasks; it receives information from the cortex, undergoes dendritic dependent processing and then relays information back to the cortex. In this study, we investigated the effects of combined 1H + 16O irradiation on cognition and dendritic structures in the hippocampus of adult male mice three months postirradiation. Six-month-old male C57BL/6 mice were irradiated first with 1H (0.5 Gy, 150 MeV/n) and 1 h later with 16O (0.1 Gy, 600 MeV/n) at the NASA Space Radiation Laboratory (Upton, NY). Three months after irradiation, animals were tested for hippocampus-dependent cognitive performance using the Y-maze. Upon sacrifice, molecular and morphological assessments were performed on hippocampal tissues. During Y-maze testing, the irradiated mice failed to distinguish the novel arm, spending approximately the same amount of time in all three arms during the retention trial relative to sham-treated controls. Irradiated animals also showed changes in expression of glutamate receptor subunits and synaptic density-associated proteins. 1H + 16O radiation compromised dendritic morphology in the cornu ammonis 1 and dentate gyrus within the hippocampus. These data indicate cognitive injuries due to 1H + 16O at three months postirradiation. PMID- 29136395 TI - Introduction of Guest Editor Kelly A. Carlson, PhD, PMHNP-BC. PMID- 29136393 TI - Gilbert W. Beebe Symposium on 30 Years after the Chernobyl Accident: Current and Future Studies on Radiation Health Effects. AB - This commentary summarizes the presentations and discussions from the 2016 Gilbert W. Beebe symposium "30 years after the Chernobyl accident: Current and future studies on radiation health effects." The symposium was hosted by the National Academies of Sciences, Engineering, and Medicine (the National Academies). The symposium focused on the health consequences of the Chernobyl accident, looking retrospectively at what has been learned and prospectively at potential future discoveries using emerging 21st Century research methodologies. PMID- 29136396 TI - Building Early Academic Career Capacity Through Mentoring. PMID- 29136397 TI - Psychiatric Inpatient Nurses' Perceptions of Using Motivational Interviewing. AB - BACKGROUND: Motivational interviewing (MI) is an evidence-based intervention that may help inpatient psychiatric nurses understand patient beliefs about medication while simultaneously strengthening the therapeutic alliance. OBJECTIVE: Investigate nurses' perceptions regarding use of motivational interviewing after an educational program. DESIGN: A prospective intervention project. RESULTS: Agreement with consistent use of MI skills declined at one month. Nurses listened and connected with patients and gained self-awareness of their interactions with other providers. CONCLUSIONS: Consistent use of MI was used less often than initially believed but having MI focused conversations were useful. When planning MI training for inpatient psychiatric staff nurses, activities must be timely, realistic, and achievable. Work environment is important to making and sustaining the use of MI. PMID- 29136398 TI - Molecular cloning and epigenetic change detection of Kiss1 during seasonal reproduction in Chinese indigenous sheep. AB - Like most seasonal domesticated species, sheep are short-day breeders, which means that the reproduction axis is activated by short days. The annual photoperiodic cycle affects the amount of daylength information that is transmitted to the hypothalamic-pituitary-gonadal (HPG) axis by regulating pulsatile secretion of gonadotrophin-releasing hormone from the hypothalamus. Kisspeptin, which is encoded by Kiss1, plays a major role in reproductive seasonality. Based on results from our previous Solexa sequencing data obtained from Tan (T) and Small Tail Han (STH) sheep during anoestrus and the breeding season, full-length mRNA information for ovine Kiss1 was obtained; 894bp in T sheep and 1145bp in STH sheep. Both encode 135 amino acids. Additionally, T and STH sheep have different transcription start sites of Kiss1. Kiss1 expression during oestrus was significantly higher than that during dioestrus, both in T and STH sheep (P<0.01). We also found a strong relationship between Kiss1 mRNA levels and histone H3 acetylation status in the 5' promoter region of ovine Kiss1. These data indicated that epigenetic modification occurs during reproduction in sheep, and this is the first report that histone H3 deacetylation occurs in the hypothalamus of seasonal sheep breeders during the transition from dioestrus to oestrus. PMID- 29136399 TI - Proteinaceous sperm motility inhibitory factor from the female Indian garden lizard Calotes versicolor. AB - Female sperm storage is an intriguing adaptation exhibited by a wide array of both vertebrates and invertebrates. The mechanisms underlying female sperm storage have remained elusive. Using the Indian garden lizard Calotes versicolor as a model organism, we investigated the role of low and high molecular weight factors in this phenomenon. Previously, we demonstrated three distinct phases of the reproductive cycle in this animal with live, motile spermatozoa recovered from the uterovaginal region during the reproductive phase. In the present study, we analysed the uterovaginal contents using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and identified an abundant protein band corresponding to ~55 kDa regardless of the phase of the reproductive cycle. Analysis of the purified protein by liquid chromatography-tandem mass spectrometry suggested a unique protein without any homology to the National Center for Biotechnology Information database. Exogenous addition of this protein to washed spermatozoa derived from the epididymis reversibly inhibited sperm motility in a concentration- and time dependent manner, suggesting it plays a key role in sperm storage. These studies are likely to offer new avenues to unravel the secrets of female sperm storage seen across the animal taxa and may have novel applications not only in reproductive biology, but also in general cell storage and preserving endangered animal species. PMID- 29136400 TI - Changes in bone turnover and calcium homeostasis during pregnancy and lactation in mammals: a meta-analysis. AB - Large amounts of calcium are required during pregnancy and lactation to support fetal and neonatal bone growth and calcification. An inadequate supply of calcium during these stages can lead to unsuccessful reproduction or impaired offspring fitness. During reproduction, female mammals undergo numerous physiological changes, including adaptations to allow an adequate supply of calcium. The lack of quantitative studies analysing these physiological changes from a comparative perspective limits our ability to explain and understand these adaptations. Herein, we present our meta-analysis of studies reporting changes in bone turnover and calcium homeostasis during pregnancy and lactation in 14 species of mammals. Our meta-analysis of 60 studies showed that all species have a similar pattern of physiological changes during pregnancy and lactation, which include: (1) decreased serum calcium concentrations; (2) bone tissue loss; (3) decreased serum calcitonin and parathyroid hormone concentrations; and (4) increased serum calcitriol concentration, regardless of changes in parathyroid hormone concentrations. In addition, we found a negative relationship between: (1) serum calcium concentrations and the number of teats; and (2) serum parathyroid hormone concentrations and litter mass. PMID- 29136401 TI - Drugs for Parkinson's disease. PMID- 29136402 TI - Comparison table: drugs for Parkinson's disease. PMID- 29136403 TI - High-grade cervical intraepithelial neoplasia in human papillomavirus self sampling of screening non-attenders. AB - BACKGROUND: Self-sampling for human papillomavirus (HPV) offered to women who do not participate in cervical cancer screening is an increasingly popular method to increase screening coverage. The rationale behind self-sampling is that unscreened women harbour a high proportion of undetected precancer lesions. Here, we compare the cervical intraepithelial neoplasia grade 2 or worse (?CIN2) detection rate between non-attenders who participated in self-sampling and women attending routine screening. METHODS: A total of 23 632 women who were qualified as non-attenders in the Copenhagen Region were invited for HPV-based self sampling. Of these, 4824 women returned a self-sample, and HPV-positive women were referred for cytology and HPV co-testing as follow-up. The entire cohort and a reference cohort (3347 routinely screened women) were followed for histopathology confirmed ?CIN2. Odds ratio (OR) and the relative positive predictive value of ?CIN2 detection between the two populations were estimated. RESULTS: Women participating in self-sampling had a higher ?CIN2 detection than women undergoing routine cytology-based screening (OR=1.83, 95% CI: 1.21-2.77) and a similar detection as routinely screened women tested with cytology and HPV testing (OR=1.03, 95% CI: 0.75-1.40). The positive predictive value for ?CIN2 was higher in screening non-attenders than in routinely HPV- and cytology-screened screened women (36.5% vs 25.6%, respectively). CONCLUSIONS: Self-sampling offered to non-attenders showed higher detection rates for ?CIN2 than routine cytology based screening, and similar detection rates as HPV and cytology co-testing. This reinforces the importance of self-sampling for screening non-attenders in organised cervical cancer screening. PMID- 29136404 TI - Galectin-3 expression is prognostic in diffuse type gastric adenocarcinoma, confers aggressive phenotype, and can be targeted by YAP1/BET inhibitors. AB - BACKGROUND: Overexpression of Galectin-3 (Gal-3), a beta-galactoside binding protein, has been noted in many tumour types but its functional significance and clinical utility in gastric adenocarcinoma (GAC) are not well known. METHODS: We studied 184 GAC patients characterised by histologic grade, sub-phenotypes (diffuse vs intestinal), and ethnicity (Asians vs North Americans). Immunohistochemistry was performed to assess the expression of Gal-3 in human GACs and we correlated it to the clinical outcomes. Cell proliferation, invasion, co-immunoprecipitation and kinase activity assays were done in genetically stable Gal-3 overexpressing GC cell lines and the parental counterparts to delineate the mechanisms of action and activity of inhibitors. RESULTS: Most patients were men, Asian, and had a poorly differentiated GAC. Gal-3 was over-expressed in poorly differentiated (P=0.002) tumours and also in diffuse sub-phenotype (P=0.02). Gal 3 overexpression was associated with shorter overall survival (OS; P=0.026) in all patients. Although, Gal-3 over-expression was not prognostic in the Asian cohort (P=0.337), it was highly prognostic in the North American cohort (P=0.001). In a multivariate analysis, Gal-3 (P=0.001) and N-stage (P=<0.001) were independently prognostic for shorter OS. Mechanistically, Gal-3 induced c MYC expression through increasing RalA activity and an enhanced YAP1/RalA/RalBP complex to confer an aggressive phenotype. YAP1/BET bromodomain inhibitors reduced Gal-3-mediated aggressive phenotypes in GAC cells. CONCLUSIONS: Gal-3 is an independent prognostic marker of shorter OS and a novel therapeutic target particularly in diffuse type GAC in North American patients. PMID- 29136405 TI - Survival outcomes for Australian women receiving trastuzumab for HER2-positive metastatic breast cancer following (neo)adjuvant trastuzumab: a national population-based observational study (2006-2014). AB - BACKGROUND: Patients treated with (neo)adjuvant trastuzumab who relapse and receive trastuzumab for metastatic breast cancer (MBC) are a growing population with little outcome data given their exclusion from most clinical trials. We aim to estimate survival outcomes for this trastuzumab 'pre-treated' population. METHODS: Population-based study of Australian women receiving trastuzumab for HER2-positive MBC between 2006 and 2014, who also received (neo)adjuvant trastuzumab. We used Kaplan-Meier methods to estimate the following: overall survival (OS) from initiation of trastuzumab for MBC; duration of trastuzumab for MBC; and time from last (neo)adjuvant trastuzumab to first trastuzumab for MBC. RESULTS: Of 3199 patients dispensed trastuzumab for MBC, 634 (20%) had received (neo)adjuvant traztuzumab. Pre-treated patients had a median (interquartile range) OS of 21.8 months (10.9-51.6), trastuzumab duration of 12.8 months (4.7 17.5), and time from last (neo)adjuvant trastuzumab to first trastuzumab for MBC of 15.6 months (6.5-28.6). Median OS for patients initiating trastuzumab <12 months and ?12 months from their last (neo)adjuvant trastuzumab were 17.1 months and 24.8 months, respectively. CONCLUSIONS: Patients starting trastuzumab for MBC following (neo)adjuvant trastuzumab had a median treatment duration of 1 year and OS of almost 2 years. These data help inform clinical practice and service planning for this under-researched population. PMID- 29136406 TI - The interaction between androgen receptor and semenogelin I: a synthetic LxxLL peptide antagonist inhibits the growth of prostate cancer cells. AB - BACKGROUND: We previously demonstrated that a seminal plasma protein, semenogelin I (SgI), functioned as an androgen receptor (AR) coactivator. Meanwhile, several short sequence motifs in AR coregulators, such as LxxLL (L=leucine), have been shown to mediate specific interactions with AR. METHODS: We investigated the role of the LxxLL motif within SgI in the interactions with AR and cell growth in prostate cancer lines in vitro. RESULTS: A full-length SgI with mutations in the motif (i.e., LxxAA; A=alanine) failed to significantly increase cell proliferation/migration as well as androgen-mediated AR transcription. Co immunoprecipitation showed no physical interactions between AR and the mutant SgI. In addition, transfection of an 18-amino acid peptide of SgI containing LxxLL, but not LxxAA, resulted in considerable reduction in cell growth and prostate-specific antigen expression in LNCaP and C4-2 lines. CONCLUSIONS: The LxxLL motif of SgI could be a novel therapeutic target for both androgen sensitive and castration-resistant prostate cancers. PMID- 29136408 TI - Fuchs' Endothelial and Myotonic Dystrophies: Corneal Dystrophy in Myotonic Patients. PMID- 29136407 TI - Phospholipase D inhibitors reduce human prostate cancer cell proliferation and colony formation. AB - BACKGROUND: Phospholipases D1 and D2 (PLD1/2) hydrolyse cell membrane glycerophospholipids to generate phosphatidic acid, a signalling lipid, which regulates cell growth and cancer progression through effects on mTOR and PKB/Akt. PLD expression and/or activity is raised in breast, colorectal, gastric, kidney and thyroid carcinomas but its role in prostate cancer (PCa), the major cancer of men in the western world, is unclear. METHODS: PLD1 protein expression in cultured PNT2C2, PNT1A, P4E6, LNCaP, PC3, PC3M, VCaP, 22RV1 cell lines and patient-derived PCa cells was analysed by western blotting. PLD1 protein localisation in normal, benign prostatic hyperplasia (BPH), and castrate resistant prostate cancer (CRPC) tissue sections and in a PCa tissue microarray (TMA) was examined by immunohistochemistry. PLD activity in PCa tissue was assayed using an Amplex Red method. The effect of PLD inhibitors on PCa cell viability was measured using MTS and colony forming assays. RESULTS: PLD1 protein expression was low in the luminal prostate cell lines (LNCaP, VCaP, 22RV1) compared with basal lines (PC3 and PC3M). PLD1 protein expression was elevated in BPH biopsy tissue relative to normal and PCa samples. In normal and BPH tissue, PLD1 was predominantly detected in basal cells as well in some stromal cells, rather than in luminal cells. In PCa tissue, luminal cells expressed PLD1. In a PCa TMA, the mean peroxidase intensity per DAB-stained Gleason 6 and 7 tissue section was significantly higher than in sections graded Gleason 9. In CRPC tissue, PLD1 was expressed prominently in the stromal compartment, in luminal cells in occasional glands and in an expanding population of cells that co expressed chromogranin A and neurone-specific enolase. Levels of PLD activity in normal and PCa tissue samples were similar. A specific PLD1 inhibitor markedly reduced the survival of both prostate cell lines and patient-derived PCa cells compared with two dual PLD1/PLD2 inhibitors. Short-term exposure of PCa cells to the same specific PLD1 inhibitor significantly reduced colony formation. CONCLUSIONS: A new specific inhibitor of PLD1, which is well tolerated in mice, reduces PCa cell survival and thus has potential as a novel therapeutic agent to reduce prostate cancer progression. Increased PLD1 expression may contribute to the hyperplasia characteristic of BPH and in the progression of castrate resistant PCa, where an expanding population of neuroendocrine-like cells express PLD1. PMID- 29136409 TI - Neural representation of form-contingent color filling-in in the early visual cortex. AB - Perceptual filling-in exemplifies the constructive nature of visual processing. Color, a prominent surface property of visual objects, can appear to spread to neighboring areas that lack any color. We investigated cortical responses to a color filling-in illusion that effectively dissociates perceived color from the retinal input (van Lier, Vergeer, & Anstis, 2009). Observers adapted to a star shaped stimulus with alternating red- and cyan-colored points to elicit a complementary afterimage. By presenting an achromatic outline that enclosed one of the two afterimage colors, perceptual filling-in of that color was induced in the unadapted central region. Visual cortical activity was monitored with fMRI, and analyzed using multivariate pattern analysis. Activity patterns in early visual areas (V1-V4) reliably distinguished between the two color-induced filled in conditions, but only higher extrastriate visual areas showed the predicted correspondence with color perception. Activity patterns allowed for reliable generalization between filled-in colors and physical presentations of perceptually matched colors in areas V3 and V4, but not in earlier visual areas. These findings suggest that the perception of filled-in surface color likely requires more extensive processing by extrastriate visual areas, in order for the neural representation of surface color to become aligned with perceptually matched real colors. PMID- 29136410 TI - Salmonella enterica serovar Typhi Producing CTX-M-15 Extended Spectrum beta Lactamase in the Democratic Republic of the Congo. AB - We report a typhoid fever case with a Salmonella enterica serovar Typhi isolate showing extended spectrum beta-lactamase (ESBL) production in the Democratic Republic of the Congo. Whole genome sequencing revealed that the strain carried a plasmid-mediated CTX-M-15 ESBL gene and did not belong to the dominant H58 Salmonella Typhi clade. PMID- 29136411 TI - Shoot apical meristem and plant body organization: a cross-species comparative study. AB - Background and Aims: The shoot apical meristem (SAM) is the key organizing element in the plant body and is responsible for the core of plant body organization and shape. Surprisingly, there are almost no comparative data that would show links between parameters of the SAM and whole-plant traits as drivers of the plant's response to the environment. Methods: Interspecific differences in SAM anatomy were examined in 104 perennial herbaceous angiosperms. Key Results: There were differences in SAM parameters among individual species, their phylogenetic patterns, and how their variation is linked to variation in plant above-ground organs and hence species' environmental niches. SAM parameters were correlated with the size-related traits of leaf area, seed mass and stem diameter. Of the two key SAM parameters (cell size and number), variation in all organ traits was linked more strongly to cell number, with cell size being important only for seed mass. Some of these correlations were due to shared phylogenetic history (e.g. SAM diameter versus stem diameter), whereas others were due to parallel evolution (e.g. SAM cell size and seed mass). Conclusion: These findings show that SAM parameters provide a functional link among sizes and numbers of plant organs, constituting species' environmental responses. PMID- 29136412 TI - Combining Lead Exposure Measurements and Experts' Judgment Through a Bayesian Framework. AB - Objectives: CARcinogen EXposure (CAREX) is a carcinogen-surveillance system employed in many countries. To develop Korean CAREX, the intensity of exposure to lead, as an example, was estimated across industries. Methods: Airborne-lead measurement records were extracted from the work-environment measurement database (WEMD), which is a nationwide workplace-monitoring database. Lead measurements were log-transformed; then, the log-transformed geometric means (LGMs) and log transformed geometric standard deviations (LGSDs) were calculated for each industry. However, the data of many industries was limited. To address this shortcoming, experts' judgments of the lead exposure levels across industries were elicited. Experts provided their estimates of lead exposure levels as the boundary of the 5th and 95th percentiles, and it is assumed that these estimates are based on the log-normal distributions of exposure levels. Estimates of LGM and LGSD were extracted from each expert's response and then combined to quantify the experts' prior distribution. Then, the experts' prior distributions for each industry were updated with the corresponding LGMs and LGSDs calculated from the WEMD data through a Bayesian framework, yielding posterior distributions of the LGM and LGSD. Results: The WEMD contains 83035 airborne-lead measurements that were collected between 2002 and 2007. A total of 17 occupational-hygiene professionals with >20 years of experience provided lead exposure estimates. In industries where measurement data were abundant, the measurement data dominated the posterior exposure estimates. For example, for one industry, 'Manufacture of Accumulator, Primary Cells, and Primary Batteries,' 1152 lead measurements [with a geometric mean (GM) of 14.42 ug m-3 and a geometric standard deviation (GSD) of 3.31] were available and 15 experts' responses (with a GM of 7.06 ug m-3 and a GSD of 4.15) were collected, resulting in a posterior exposure estimate of 14.41ug m-3 as the GM with a GSD of 3.31. For industries with a limited number of measurements available in the WEMD, experts' decisions played a significant role in determining the posterior exposure estimates. For example, for the 'Manufacture of Weapons and Ammunition' industry, 15 lead measurements (with a GM of 6.45 ug m-3 and a GSD of 3.37) were available and seven experts' responses (with a GM of 3.28 ug m-3 and a GSD of 4.54) were obtained, resulting in a posterior exposure estimate of 5.42 ug m-3 as the GM with a GSD of 3.73. Conclusions: The proposed method for estimating the intensity of exposure to carcinogens may introduce an unbiased approach to the development process by simultaneously utilizing both prior knowledge of experts and measurement data. In addition, it supplies a framework for future updates. PMID- 29136413 TI - First Metagenomic Survey of the Microbial Diversity in Bioaerosols Emitted in Waste Sorting Plants. AB - Waste sorting activities are source of occupational bioaerosol exposures that are associated with several health disorders. New analytical tools, based on next generation sequencing (NGS) technologies, provide powerful methods to assess the microbial composition of bioaerosols. The objectives of the study were (i) to assess the feasibility and the repeatability of NGS-based biodiversity measurements and (ii) to study the microbial biodiversity using NGS in bioaerosols emitted in a waste sorting plant (WSP). Three stationary parallel samples were collected in a sorting cabin using closed-face cassettes equipped with polycarbonate membranes. Bacterial and fungal diversity was assessed by sequencing 16S and 18S rDNA genes using either Illumina sequencing or 454 pyrosequencing methods. At sampling point, airborne bacteria were dominated by Proteobacteria, Firmicutes, and Actinobacteria with prevailing genera assigned to unclassified Enterobacteriaceae, Staphylococcus, Acinetobacter, Leuconostoc, Pseudomonas, and Lactobacillus. Airborne fungi were dominated by Ascomycota with prevailing genera assigned to Penicillium, Aspergillus, Rhizopus, Wallemia, and Hemicarpenteles. The NGS biodiversity measurements revealed a higher biodiversity bioaerosols that previously reported for WSP in studies carried out using culture methods followed by identification of microorganisms. These results provide the first survey about taxonomic biodiversity in bioaerosols from WSPs using high throughput sequencing. PMID- 29136414 TI - Quantitative Respirator Fit, Face Sizes, and Determinants of Fit in South African Diagnostic Laboratory Respirator Users. AB - Objectives: Respirators are widely used in health care settings but there is scant information on adequacy of fit and its determinants, particularly in resource-constrained settings. The aim of the study is to describe the proportion of South African diagnostic laboratory respirator users with adequate quantitative respirator fit while wearing their currently selected respirators which were generally supplied without regard to face size, and to identify determinants of fit test pass and fail. Methods: This was a cross-sectional study with 562 participants. Quantitative respirator fit testing was conducted using a PortaCount fit testing machine. Four facial dimensions were taken using callipers and a tape measure. STATA 14 was used to perform descriptive and inferential statistics. The effect of the independent variables including face dimensions, race, smoking, respirator make and size, and age group was explored using multiple logistic regression stratified by sex. Results: Ninety one percent of the respirators supplied were medium-sized. Seventy eight percent of respirator users failed fit testing and were thus probably not protected by their currently supplied respirator. Multiple logistic regression analysis showed that face length in mm (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.00-1.09), nasal root breadth in mm (OR = 1.16, 95% CI = 1.06-1.28), and respirator shape (OR = 0.56, 95% CI = 0.39-0.78) were significant predictors of overall fit for all subjects and for women alone, but these factors explained only a small percentage of fit test outcomes. Conclusion: A large proportion of diagnostic laboratory employees were using poorly fitting respirators. This creates a false impression of protection. Fit testing of respirators is therefore important and recommended. The determinants evaluated described only a small portion of the variability in fit; important determinants were absent from the models. PMID- 29136415 TI - Occupational Noise Exposure and the Risk for Work-Related Injury: A Systematic Review and Meta-analysis. AB - Objectives: Occupational noise exposure has been linked to work-related injuries. Strategies to control occupational hazards often rely on dose-response relationships needed to inform policy, but quantitative synthesis of the relevant literature has not been done so far. This study aimed to systematically review the epidemiological literature and to perform meta-analysis of the risk for work related injury due to occupational noise exposure. Methods: PRISMA and MOOSE guidelines were followed. PubMed, ScienceDirect, and Google Scholar were searched up until 15 December 2016 in English, Russian, and Spanish. Reference lists, grey literature, and expert archives were searched as well. The risk of bias was assessed for each study and incorporated into the meta-analysis weights using the quality effects model. Results: Overall, 21 studies were included at the qualitative review stage: 9 cross-sectional, 6 case-control, 4 cohort, 1 case crossover, and 1 ecological. Noise exposure was assessed objectively in 13 studies. Information on occupational injuries was elicited from medical records/registry in 13 studies. Meta-analyses showed RR = 1.22 (95% CI: 1.15, 1.29) (n = 59028) per 5 dB increase in noise exposure (Cochran's Q = 27.26, P < 0.001, I2 = 67%) and RR = 2.16 (95% CI: 1.61, 2.90) (n = 96023) in the most exposed group (>90-95 dB) compared with the least exposed group (Cochran's Q = 180.46, P < 0.001, I2 = 90%). Subgroup analysis with meta-regression revealed an overall robust pooled risk per 5 dB. Conclusions: There is a dose-response association between occupational noise exposure and work-related injury risk. However, the quality of evidence is 'very low'; therefore, the magnitude of this association should be interpreted with caution. PMID- 29136416 TI - Daily Shoulder Pain Among Flight Baggage Handlers and its Association With Work Tasks and Upper Arm Postures on the Same Day. AB - Objectives: This study of flight baggage handlers aimed at examining the extent to which shoulder pain developed during single work shifts, and whether a possible development was associated with biomechanical exposures and psychosocial factors during the same shift. Methods: Data were collected during, in total, 82 work shifts in 44 workers. Right and left shoulder pain intensity was rated just before and just after the shift (VAS scale 0-100 mm). Objective data on 'time in extreme' and 'time in neutral' upper arm postures were obtained for the full shift using accelerometers, and the baggage handlers registered the number of 'aircrafts handled' in a diary. During half of the shift, workers were recorded on video for subsequent task analysis of baggage handling. 'Influence' at work and 'support' from colleagues were measured by use of Copenhagen Psychosocial Questionnaire (COPSOQ). Associations between exposures and the increase in pain intensity during the shift ('daily pain') were analysed for the right and left shoulder separately using Generalized Estimating Equations (GEE). Results: 'Daily pain' was observed in approximately one third of all shifts. It was significantly associated with the number of 'aircrafts handled' for both the right and left shoulder. In multivariate models including both biomechanical exposures and the psychosocial factors 'influence' at work and 'support' from colleagues, 'aircrafts handled' was still significantly associated with 'daily pain' in both shoulders, and so was 'influence' and 'support', however in opposite directions. Conclusions: 'Daily pain' was, in general, associated with biomechanical exposures during the same shift and with general 'influence' and 'support' in the job. In an effort to reduce pain among flight baggage handlers, it may therefore be justified to consider a reduction of biomechanical exposures during handling of aircrafts, combined with due attention to psychosocial factors at work. PMID- 29136417 TI - Occupational Exposure to Inhalable Manganese at German Workplaces. AB - Due to mounting evidence of neurotoxic effects of manganese (Mn) already at low concentrations, occupational exposure limits (OELs) have been adopted. We analyzed 5771 personal measurements of inhalable manganese (Mn) together with information on sampling conditions and job tasks from the German exposure database Messdaten zur Exposition gegenuber Gefahrstoffen am Arbeitsplatz (MEGA) to assess exposure levels in welders and other occupations between 1989 and 2015. Geometric means (GMs) of exposure to Mn were estimated for various occupational settings adjusted for 2-h sampling duration and analytical method, centered at 2009. Measurements below the limit of quantification (LOQ) were multiply imputed. The median concentration was 74 ug m-3 (inter-quartile range 14-260 ug m-3) in welders and 8 ug m-3 (inter-quartile range =1000 ug m-3. GMs >100 ug m-3 were observed in gas metal and flux-cored arc welders and in shielded metal arc welders using consumables of high Mn content (>5%). Tungsten inert gas welding, laser welding and working in other occupations such as foundry worker, electroplater, or grinder were associated with GMs <10 ug m-3. A shorter sampling duration was associated with higher Mn concentrations. High-emission welding techniques require protective measures to cope with adopted OELs. Results of this study are useful to assess cumulative Mn exposure in community-based studies on neurotoxic effects. PMID- 29136418 TI - Nano-object Release During Machining of Polymer-Based Nanocomposites Depends on Process Factors and the Type of Nanofiller. AB - We tested the nanomaterial release from composites during two different mechanical treatment processes, automated drilling and manual sawing. Polyurethane (PU) polymer discs (1-cm thickness and 11-cm diameter) were created using different nanomaterial fillers: multiwall carbon nanotubes (MWCNT), carbon black (CB), silicon dioxide (SiO2), and an unfilled PU control. Drilling generated far more submicron range particles than sawing. In the drilling experiments, none of the tested nanofillers showed a significant influence on particle number concentrations or sizes, except for the PU/MWCNT samples, from which larger particles were released than from control samples. Higher drilling speed and larger drill bit size were associated with higher particle counts. Differences between composites were observed during sawing: PU/CB released higher number concentrations of micro-sized particles compared to reference samples. When sawing PU/SiO2 more nanoparticle agglomerates were observed. Furthermore, polymer fumes were released during sawing experiments, which was attributed to the process heat. For both drilling and sawing, the majority of the aerosolized particles were polymer matrix materials containing nanofillers (or protruding from their surface), as evidenced by electron microscopic analysis. Results suggest that: (i) processes associated with higher energy inputs are more likely to result in higher particle release in terms of number concentration; (ii) nanofillers may alter release processes; and (iii) other types of released particles, in particular polymer fumes from high-temperature processes, must also be considered in occupational exposure and risk assessments. PMID- 29136419 TI - Occupational Exposure to Manganese and Fine Motor Skills in Elderly Men: Results from the Heinz Nixdorf Recall Study. AB - Objectives: Exposure to manganese (Mn) may cause movement disorders, but less is known whether the effects persist after the termination of exposure. This study investigated the association between former exposure to Mn and fine motor deficits in elderly men from an industrial area with steel production. Methods: Data on the occupational history and fine motor tests were obtained from the second follow-up of the prospective Heinz Nixdorf Recall Study (2011-2014). The study population included 1232 men (median age 68 years). Mn in blood (MnB) was determined in archived samples (2000-2003). The association between Mn exposure (working as welder or in other at-risk occupations, cumulative exposure to inhalable Mn, MnB) with various motor functions (errors in line tracing, steadiness, or aiming and tapping hits) was investigated with Poisson and logistic regression, adjusted for iron status and other covariates. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated for substantially impaired dexterity (errors >90th percentile, tapping hits <10th percentile). Results: The median of cumulative exposure to inhalable Mn was 58 ug m-3 years in 322 men who ever worked in at-risk occupations. Although we observed a partly better motor performance of exposed workers at group level, we found fewer tapping hits in men with cumulative Mn exposure >184.8 ug m-3 years (OR 2.15, 95% CI 1.17-3.94). MnB >= 15 ug l-1, serum ferritin >= 400 ug l-1, and gamma-glutamyl transferase >=74 U l-1 were associated with a greater number of errors in line tracing. Conclusions: We found evidence that exposure to inhalable Mn may carry a risk for dexterity deficits. Whether these deficits can be exclusively attributed to Mn remains to be elucidated, as airborne Mn is strongly correlated with iron in metal fumes, and high ferritin was also associated with errors in line tracing. Furthermore, hand training effects must be taken into account when testing for fine motor skills. PMID- 29136420 TI - Assessment of Environmental Contamination with Pathogenic Bacteria at a Hospital Laundry Facility. AB - Little is known about exposure to pathogenic bacteria among industrial laundry workers who work with soiled clinical linen. To study worker exposures, an assessment of surface contamination was performed at an industrial laundry facility serving hospitals in Seattle, WA, USA. Surface swab samples (n = 240) from the environment were collected during four site visits at 3-month intervals. These samples were cultured for Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE). Voluntary participation of 23 employees consisted of nasal swabs for detection of MRSA, observations during work, and questionnaires. Contamination with all three pathogens was observed in both dirty (laundry handling prior to washing) and clean areas (subsequent to washing). The dirty area had higher odds of overall contamination (>=1 pathogen) than the clean area (odds ratio, OR = 18.0, 95% confidence interval 8.9-36.5, P < 0.001). The odds of contamination were high for each individual pathogen: C. difficile, OR = 15.5; MRSA, OR = 14.8; and VRE, OR = 12.6 (each, P < 0.001). The highest odds of finding surface contamination occurred in the primary and secondary sort areas where soiled linens were manually sorted by employees (OR = 63.0, P < 0.001). The study substantiates that the laundry facility environment can become contaminated by soiled linens. Workers who handle soiled linen may have a higher risk of exposure to C. difficile, MRSA, and VRE than those who handle clean linens. Improved protocols for prevention and reduction of environmental contamination were implemented because of this study. PMID- 29136421 TI - When Does Race Matter? PMID- 29136422 TI - Transmission as a basic process in microbial biology. Lwoff Award Prize Lecture. AB - Transmission is a basic process in biology and evolution, as it communicates different biological entities within and across hierarchical levels (from genes to holobionts) both in time and space. Vertical descent, replication, is transmission of information across generations (in the time dimension), and horizontal descent is transmission of information across compartments (in the space dimension). Transmission is essentially a communication process that can be studied by analogy of the classic information theory, based on 'emitters', 'messages' and 'receivers'. The analogy can be easily extended to the triad 'emigration', 'migration' and 'immigration'. A number of causes (forces) determine the emission, and another set of causes (energies) assures the reception. The message in fact is essentially constituted by 'meaningful' biological entities. A DNA sequence, a cell and a population have a semiotic dimension, are 'signs' that are eventually recognized (decoded) and integrated by receiver biological entities. In cis-acting or unenclosed transmission, the emitters and receivers correspond to separated entities of the same hierarchical level; in trans-acting or embedded transmission, the information flows between different, but frequently nested, hierarchical levels. The result (as in introgressive events) is constantly producing innovation and feeding natural selection, influencing also the evolution of transmission processes. This review is based on the concepts presented at the Andre Lwoff Award Lecture in the FEMS Microbiology Congress in Maastricht in 2015. PMID- 29136423 TI - Beyond Heart Symbolism: Artistic Representation of Narratives of Congenital Heart Disease. PMID- 29136424 TI - Laboratory-on-a-Chip Uses Acoustics to Isolate Tell-Tale Particles in Blood. PMID- 29136425 TI - Functional Brain Imaging Updates on the Horizon. PMID- 29136426 TI - Erythematous Rash Following Hematopoietic Stem Cell Transplantation. PMID- 29136427 TI - Incorrect Statistical Measures and Typographical Errors. PMID- 29136428 TI - Error in Flow Diagram. PMID- 29136429 TI - Prepregnancy Obesity and Severe Maternal Morbidity: What Can Be Done? PMID- 29136430 TI - The "Utility" in Composite Outcome Measures: Measuring What Is Important to Patients. PMID- 29136432 TI - The High Costs of Unnecessary Care. PMID- 29136433 TI - The Method of Experiment in Medicine. PMID- 29136434 TI - Change in Testing, Awareness of Hemoglobin A1c Result, and Glycemic Control in US Adults, 2007-2014. PMID- 29136435 TI - Antipsychotic Drug Prescribing in Nursing Homes. PMID- 29136436 TI - Antipsychotic Drug Prescribing in Nursing Homes. PMID- 29136437 TI - Insulin Analogues and Hypoglycemia in Patients With Type 1 Diabetes. PMID- 29136438 TI - Personal Sound Amplification Products for Hearing Loss. PMID- 29136439 TI - Personal Sound Amplification Products for Hearing Loss-Reply. PMID- 29136440 TI - Insulin Analogues and Hypoglycemia in Patients With Type 1 Diabetes-Reply. PMID- 29136441 TI - Antipsychotic Drug Prescribing In Nursing Homes-Reply. PMID- 29136442 TI - Association Between Prepregnancy Body Mass Index and Severe Maternal Morbidity. AB - Importance: Although high body mass index (BMI) is associated with adverse birth outcomes, the association with severe maternal morbidity is unclear. Objective: To examine the association between prepregnancy BMI and severe maternal morbidity. Design, Setting, and Participants: Retrospective population-based cohort study including all singleton hospital births in Washington State, 2004 2013. Demographic data and morbidity diagnoses were obtained from linked birth certificates and hospitalization files. Exposures: Prepregnancy BMI (weight in kilograms divided by height in meters squared) categories included underweight (<18.5), normal BMI (18.5-24.9), overweight (25.0-29.9), obesity class 1 (30.0 34.9), obesity class 2 (35.0-39.9), and obesity class 3 (>=40). Main Outcomes and Measures: Composite severe maternal morbidity or mortality included life threatening conditions and conditions leading to serious sequelae (eg, amniotic fluid embolism, hysterectomy), complications requiring intensive care unit admission, and maternal death. Logistic regression was used to obtain adjusted odds ratios (ORs) and adjusted rate differences with 95% confidence intervals, adjusted for confounders (eg, maternal age and parity). Results: Overall, 743 630 women were included in the study (mean age, 28.1 [SD, 6.0] years; 41.4% nulliparous). Prepregnancy BMI was distributed as follows: underweight, 3.2%; normal weight, 47.5%; overweight, 25.8%; obesity class 1, 13.1%; obesity class 2, 6.2%; and obesity class 3, 4.2%. Rates of severe maternal morbidity or mortality were 171.5, 143.2, 160.4, 167.9, 178.3 and 202.9 per 10 000 women, respectively. Adjusted ORs were 1.2 (95% CI, 1.0-1.3) for underweight women; 1.1 (95% CI, 1.1 1.2) for overweight women; 1.1 (95% CI, 1.1-1.2) for women with class 1 obesity; 1.2 (95% CI, 1.1-1.3) for women with class 2 obesity; and 1.4 (95% CI, 1.3-1.5) for women with class 3 obesity compared with women with normal BMI. Absolute risk increases (adjusted rate differences per 10 000 women, compared with women with normal BMI) were 28.8 (95% CI, 12.2-47.2) for underweight women, 17.6 (95% CI, 10.5-25.1) for overweight women, 24.9 (95% CI, 15.7-34.6) for women with class 1 obesity, 35.8 (95% CI, 23.1-49.5) for women with class 2 obesity, and 61.1 (95% CI, 44.8-78.9) for women with class 3 obesity. Conclusions and Relevance: Among pregnant women in Washington State, low and high prepregnancy BMI, compared with normal BMI, were associated with a statistically significant but small absolute increase in severe maternal morbidity or mortality. PMID- 29136443 TI - Derivation and External Validation of Prediction Models for Advanced Chronic Kidney Disease Following Acute Kidney Injury. AB - Importance: Some patients will develop chronic kidney disease after a hospitalization with acute kidney injury; however, no risk-prediction tools have been developed to identify high-risk patients requiring follow-up. Objective: To derive and validate predictive models for progression of acute kidney injury to advanced chronic kidney disease. Design, Setting, and Participants: Data from 2 population-based cohorts of patients with a prehospitalization estimated glomerular filtration rate (eGFR) of more than 45 mL/min/1.73 m2 and who had survived hospitalization with acute kidney injury (defined by a serum creatinine increase during hospitalization > 0.3 mg/dL or > 50% of their prehospitalization baseline), were used to derive and validate multivariable prediction models. The risk models were derived from 9973 patients hospitalized in Alberta, Canada (April 2004-March 2014, with follow-up to March 2015). The risk models were externally validated with data from a cohort of 2761 patients hospitalized in Ontario, Canada (June 2004-March 2012, with follow-up to March 2013). Exposures: Demographic, laboratory, and comorbidity variables measured prior to discharge. Main Outcomes and Measures: Advanced chronic kidney disease was defined by a sustained reduction in eGFR less than 30 mL/min/1.73 m2 for at least 3 months during the year after discharge. All participants were followed up for up to 1 year. Results: The participants (mean [SD] age, 66 [15] years in the derivation and internal validation cohorts and 69 [11] years in the external validation cohort; 40%-43% women per cohort) had a mean (SD) baseline serum creatinine level of 1.0 (0.2) mg/dL and more than 20% had stage 2 or 3 acute kidney injury. Advanced chronic kidney disease developed in 408 (2.7%) of 9973 patients in the derivation cohort and 62 (2.2%) of 2761 patients in the external validation cohort. In the derivation cohort, 6 variables were independently associated with the outcome: older age, female sex, higher baseline serum creatinine value, albuminuria, greater severity of acute kidney injury, and higher serum creatinine value at discharge. In the external validation cohort, a multivariable model including these 6 variables had a C statistic of 0.81 (95% CI, 0.75-0.86) and improved discrimination and reclassification compared with reduced models that included age, sex, and discharge serum creatinine value alone (integrated discrimination improvement, 2.6%; 95% CI, 1.1%-4.0%; categorical net reclassification index, 13.5%; 95% CI, 1.9%-25.1%) or included age, sex, and acute kidney injury stage alone (integrated discrimination improvement, 8.0%; 95% CI, 5.1%-11.0%; categorical net reclassification index, 79.9%; 95% CI, 60.9% 98.9%). Conclusions and Relevance: A multivariable model using routine laboratory data was able to predict advanced chronic kidney disease following hospitalization with acute kidney injury. The utility of this model in clinical care requires further research. PMID- 29136444 TI - Effect of Locking Plate Fixation vs Intramedullary Nail Fixation on 6-Month Disability Among Adults With Displaced Fracture of the Distal Tibia: The UK FixDT Randomized Clinical Trial. AB - Importance: The best treatment for fractures of the distal tibia remains controversial. Most such fractures require surgical fixation but outcomes are unpredictable and complications are common. Objective: To assess disability, quality of life, and complications in patients with displaced tibial fracture treated with intramedullary nail fixation vs locking plate fixation. Design, Setting, and Participants: A multicenter randomized trial recruiting 321 patients 16 years or older with an acute, displaced, extra-articular fracture of the distal tibia from April 2013 through April 2016 with final follow-up in February 2017. Exclusion criteria included open fractures, fractures involving the ankle joint, contraindication to nailing, or inability to complete questionnaires. Interventions: Intramedullary nail fixation (nail group; n = 161), a metal rod inserted into the hollow center of the tibia, vs locking plate fixation (plate group; n = 160), a plate attached to the surface of the tibia with fixed-angle screws. Main Outcomes and Measures: Disability Rating Index (DRI; score range, 0 [no disability] to 100 [complete disability]) at 6 months was the primary outcome measure, with a minimal clinically important difference of 8 points. DRI measurement was also collected at 3 and 12 months. Secondary outcomes were the Olerud-Molander Ankle Score (OMAS), quality of life, and complications (such as infection and further surgery). Results: Among 321 randomized patients (mean age, 45 years [SD, 16.2]; men, 197 [61%]; had experienced traumatic injury after a fall, 223 [69%]), 258 completed the study. There was no statistically significant difference in the DRI score at 6 months between groups (mean score, 29.8 in the nail group vs 33.8 in the plate group; adjusted difference, 4.0 [95% CI, -1.0 to 9.0], P = .11). There was a statistically significant difference in the DRI score at 3 months in favor of nail fixation (mean score, 44.2 in the nail group and 52.6 in the plate group; adjusted difference, 8.8 [95% CI, 4.3 to 13.2], P < .001), but not at 12 months (mean score, 23.1 in the nail group and 24.0 in the plate group; adjusted difference, 1.9 [95% CI, -3.2 to 6.9], P = .47). Secondary outcomes showed the same pattern, including a statistically significant difference in mean OMAS at 3 and 6 months in favor of nail fixation. There were no statistically significant differences in complications, including the number of postoperative infections (9% in the nail group vs 13% in the plate group). Further surgery was more common in the plate group at 12 months (8% in nail group vs 12% in plate group). Conclusions and Relevance: Among patients 16 years or older with an acute, displaced, extra-articular fracture of the distal tibia, neither nail fixation nor locking plate fixation resulted in superior disability status at 6 months. Other factors may need to be considered in deciding the optimal approach. Trial Registration: clinicaltrials.gov Identifier: ISRCTN99771224. PMID- 29136446 TI - Acute Mountain Sickness. PMID- 29136445 TI - Effect of Varying Doses of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Exposure Among Patients With Peanut Sensitivity: A Randomized Clinical Trial. AB - Importance: Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials. Objective: To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment. Design, Setting, and Participants: Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein. Interventions: Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 MUg (n = 53), 100 MUg (n = 56), or 250 MUg (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose. Main Outcomes and Measures: The primary efficacy end point was percentage of treatment responders (eliciting dose: >=10-times increase and/or reaching >=1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs). Results: Of 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250 MUg (n = 28; 50.0%) and placebo (n = 14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P = .01). No significant difference was seen between the placebo patch vs the 100-MUg patch. Because of statistical testing hierarchical rules, the 50-MUg patch was not compared with placebo. Interaction by age group was only significant for the 250-MUg patch (P = .04). In the 6- to 11-year stratum, the response rate difference between the 250-MUg (n = 15; 53.6%) and placebo (n = 6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P = .008); adolescents/adults showed no difference between the 250-MUg (n = 13; 46.4%) and placebo (n = 8; 32.0%) patches: 14.4% (95% CI, -11.6% to 40.4%; P = .40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-MUg patch = 100%, 100 MUg patch = 98.2%, 250-MUg patch = 100%, and placebo patch = 92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%. Conclusions and Relevance: In this dose-ranging trial of peanut allergic patients, the 250-MUg peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial. Trial Registration: clinicaltrials.gov Identifier: NCT01675882. PMID- 29136448 TI - The Greatest Gift: How a Patient's Death Taught Me to Be a Physician. PMID- 29136451 TI - Stroke Death Rate Plateaus. PMID- 29136449 TI - Does This Patient Have Acute Mountain Sickness?: The Rational Clinical Examination Systematic Review. AB - Importance: Acute mountain sickness (AMS) affects more than 25% of individuals ascending to 3500 m (11 500 ft) and more than 50% of those above 6000 m (19 700 ft). AMS may progress from nonspecific symptoms to life-threatening high-altitude cerebral edema in less than 1% of patients. It is not clear how to best diagnose AMS. Objective: To systematically review studies assessing the accuracy of AMS diagnostic instruments, including the visual analog scale (VAS) score, which quantifies the overall feeling of sickness at altitude (VAS[O]; various thresholds), Acute Mountain Sickness-Cerebral score (AMS-C; >=0.7 indicates AMS), and the clinical functional score (CFS; >=2 indicates AMS) compared with the Lake Louise Questionnaire Score (LLQS; score of >=5). Data Extraction and Synthesis: Searches of MEDLINE and EMBASE from inception to May 2017 identified 1245 publications of which 91 were suitable for prevalence analysis (66 944 participants) and 14 compared at least 2 instruments (1858 participants) using a score of 5 or greater on the LLQS as a reference standard. To determine the prevalence of AMS for establishing the pretest probability of AMS, a random effects meta-regression was performed based on the reported prevalence of AMS as a function of altitude. Main Outcomes and Measures: AMS prevalence, likelihood ratios (LRs), sensitivity, and specificity of screening instruments. Results: The final analysis included 91 articles (comprising 66 944 study participants). Altitude predicted AMS and accounted for 28% of heterogeneity between studies. For each 1000-m (3300-ft) increase in altitude above 2500 m (8200 ft), AMS prevalence increased 13% (95% CI, 9.5%-17%). Testing characteristics were similar for VAS(O), AMS-C, and CFS vs a score of 5 or greater on the LLQS (positive LRs: range, 3.2-8.2; P = .22 for comparisons; specificity range, 67%-92%; negative LRs: range, 0.30-0.36; P = .50 for comparisons; sensitivity range, 67%-82%). The CFS asks a single question: "overall if you had any symptoms, how did they affect your activity (ordinal scale 0-3)?" For CFS, moderate to severe reduction in daily activities had a positive LR of 3.2 (95% CI, 1.4-7.2) and specificity of 67% (95% CI, 37%-97%); no reduction to mild reduction in activities had a negative LR of 0.30 (95% CI, 0.22-0.39) and sensitivity of 82% (95% CI, 77%-87%). Conclusions and Relevance: The prevalence of acute mountain sickness increases with higher altitudes. The visual analog scale for the overall feeling of sickness at altitude, Acute Mountain Sickness-Cerebral, and clinical functional score perform similarly to the Lake Louise Questionnaire Score using a score of 5 or greater as a reference standard. In clinical and travel settings, the clinical functional score is the simplest instrument to use. Clinicians evaluating high altitude travelers who report moderate to severe limitations in activities of daily living (clinical functional score >=2) should use the Lake Louise Questionnaire Score to assess the severity of acute mountain sickness. PMID- 29136452 TI - "Healing Bracelet" Causes Harm. PMID- 29136453 TI - Randomized phase III trial of adjuvant therapy with locoregional interferon beta versus surgery alone in stage II/III cutaneous melanoma: Japan Clinical Oncology Group Study (JCOG1309, J-FERON). AB - The Dermatologic Oncology Group of Japan Clinical Oncology Group has started a randomized phase III trial to confirm the superiority of adjuvant therapy with locoregional interferon beta in overall survival over surgery alone for patients with pathological stage II/III cutaneous melanoma (JCOG1309). Patients in the interferon beta arm receive intra- or subcutaneous injections of interferon beta directly into the surgical site at a flat dose of 3 million units once per day. Treatment is repeated for 10 consecutive days every 8 weeks for a total of 3 courses during the induction phase, then 1-day injection every 4 weeks for 2.5 years. A total of 240 patients will be accrued from 17 Japanese institutions within 6.5 years. Primary endpoint is overall survival. Secondary endpoints are relapse-free survival, distant metastasis-free survival, pattern of recurrence, and adverse events. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000017494 [http://www.umin.ac.jp/ctr/index.htm]. PMID- 29136454 TI - Immediate Label-Free Ex Vivo Evaluation of Human Brain Tumor Biopsies With Confocal Reflectance Microscopy. AB - Confocal microscopy utilizing fluorescent dyes is widely gaining use in the clinical setting as a diagnostic tool. Reflectance confocal microscopy is a method of visualizing tissue specimens without fluorescent dyes while relying on the natural refractile properties of cellular and subcellular structures. We prospectively evaluated 76 CNS lesions with confocal reflectance microscopy (CRM) to determine cellularity, architecture, and morphological characteristics. A neuropathologist found that all cases showed similar histopathological features when compared to matched hematoxylin and eosin-stained sections. RNA isolated from 7 tissues following CRM imaging retained high RNA integrity, suggesting that CRM does not alter tissue properties for molecular studies. A neuropathologist and surgical pathologist masked to the imaging results independently evaluated a subset of CRM images. In these evaluations, 100% of images reviewed by the neuropathologist and 95.7% of images reviewed by the surgical pathologist were correctly diagnosed as lesional or nonlesional. Furthermore, 97.9% and 91.5% of cases were correctly diagnosed as tumor or not tumor by the neuropathologist and surgical pathologist, respectively, while 95.8% and 85.1% were identified with the correct diagnosis. Our data indicate that CRM is a useful tool for rapidly screening patient biopsies for diagnostic adequacy, molecular studies, and biobanking. PMID- 29136455 TI - LBH589 Inhibits Glioblastoma Growth and Angiogenesis Through Suppression of HIF 1alpha Expression. AB - Glioblastoma (GBM) is an angiogenic malignancy with a highly unfavorable prognosis. Angiogenesis in GBM represents an adaptation to a hypoxic microenvironment and is correlated with tumor growth, invasion, clinical recurrence, and lethality. LBH589 (also called panobinostat) is a histone deacetylase (HDAC) inhibitor with potent antitumor activity. In the current study, we investigated the mechanism and effects of LBH589 on GBM growth and hypoxia-induced angiogenesis in vitro and in vivo. To determine the antitumor and angiogenesis activity and mechanism of LBH589, we used cell proliferations in vitro and GBM xenografts in vivo. To clarify mechanisms of LBH589 on angiogenesis, HDAC assay, RT-PCR, Western blot, and co-immunoprecipitation assays were performed. We found LBH589 displayed significant antitumor effects on GBM as demonstrated by inhibited cell proliferation, slower tumor growth, and decreased microvessel density of subcutaneous xenografts. These actions of LBH589 resulted from the disruption of heat shock protein 90/HDAC6 complex, increased HIF-1alpha instability and degradation, and decreased VEGF expression. Our results indicate the potential antiangiogenic activity of LBH589 in human GBM and provide some preclinical data to warrant further exploration of HDAC inhibitors for the treatment of advanced glioma. Moreover, our study supports the role of HDAC inhibitors as a therapeutic strategy to target tumor angiogenesis. PMID- 29136456 TI - The intimate talk between plants and microorganisms at the leaf surface. AB - The plant epidermis or cuticle is constantly exposed to external and internal environmental factors, including an enriched and diverse community of bacteria, yeast, fungi, viruses, and mites. It is not only where the plant has its first physical barrier, but also where organisms can be recognized and potentially where the plant defense responses can be triggered. The plant cuticle is a polymeric composite formed by an array of structurally and chemically heterogeneous compounds, including cutin and wax. A few studies have shown that cuticular components are essential and important drivers of the structure and size of the bacterial community. On the other hand, cuticular components are also important for both pathogens and plants, to initiate the pre-invasion and infection process and to activate the innate immune response, respectively. In this review, we explore current knowledge on the role of the cuticle during the intimate interactions between plants and microorganisms, in particular pathogenic and non-pathogenic bacteria and fungi. Finally, we propose new perspectives on the potential use of this information for agriculture. PMID- 29136457 TI - The plant cuticle: old challenges, new perspectives. PMID- 29136458 TI - Deficiency of the Stroma-Lamellar Protein LIL8/PSB33 Affects Energy Transfer Around PSI in Arabidopsis. AB - Light-harvesting-like (LIL) proteins are a group of proteins that share a consensus amino acid sequence with light-harvesting Chl-binding (LHC) proteins. We hypothesized that they might be involved in photosynthesis-related processes. In order to gain a better understanding of a potential role in photosynthesis related processes, we examined the most recently identified LIL protein, LIL8/PSB33. Recently, it was suggested that this protein is an auxiliary PSII core protein which is involved in organization of the PSII supercomplex. However, we found that the majority of LIL8/PSB33 was localized in stroma lamellae, where PSI is predominant. Moreover, the PSI antenna sizes measured under visible light were slightly increased in the lil8 mutants which lack LIL8/PSB33 protein. Analysis of fluorescence decay kinetics and fluorescence decay-associated spectra indicated that energy transfer to quenching sites within PSI was partially hampered in these mutants. On the other hand, analysis of the steady-state fluorescence spectra in these mutants indicates that a population of LHCII is energetically disconnected from PSII. Taken together, we suggest that LIL8/PSB33 is involved in the fine-tuning of light harvesting and/or energy transfer around both photosystems. PMID- 29136459 TI - Cesium Uptake by Rice Roots Largely Depends Upon a Single Gene, HAK1, Which Encodes a Potassium Transporter. PMID- 29136460 TI - Graphitic Nitrogen Triggers Red Fluorescence in Carbon Dots. AB - Carbon dots (CDs) are a stable and highly biocompatible fluorescent material offering great application potential in cell labeling, optical imaging, LED diodes, and optoelectronic technologies. Because their emission wavelengths provide the best tissue penetration, red-emitting CDs are of particular interest for applications in biomedical technologies. Current synthetic strategies enabling red-shifted emission include increasing the CD particle size (sp2 domain) by a proper synthetic strategy and tuning the surface chemistry of CDs with suitable functional groups (e.g., carboxyl). Here we present an elegant route for preparing full-color CDs with well-controllable fluorescence at blue, green, yellow, or red wavelengths. The two-step procedure involves the synthesis of a full-color-emitting mixture of CDs from citric acid and urea in formamide followed by separation of the individual fluorescent fractions by column chromatography based on differences in CD charge. Red-emitting CDs, which had the most negative charge, were separated as the last fraction. The trend in the separation, surface charge, and red-shift of photoluminescence was caused by increasing amount of graphitic nitrogen in the CD structure, as was clearly proved by XPS, FT-IR, Raman spectroscopy, and DFT calculations. Importantly, graphitic nitrogen generates midgap states within the HOMO-LUMO gap of the undoped systems, resulting in significantly red-shifted light absorption that in turn gives rise to fluorescence at the low-energy end of the visible spectrum. The presented findings identify graphitic nitrogen as another crucial factor that can red-shift the CD photoluminescence. PMID- 29136461 TI - Enzyme-Free Nucleic Acid Amplification Assay Using a Cellphone-Based Well Plate Fluorescence Reader. AB - Nucleic acids, DNA and RNA, provide important fingerprint information for various pathogens and have significant diagnostic value; however, improved approaches are urgently needed to enable rapid detection of nucleic acids in simple point-of care formats with high sensitivity and specificity. Here, we present a system that utilizes a series of toehold-triggered hybridization/displacement reactions that are designed to convert a given amount of RNA molecules (i.e., the analyte) into an amplified amount of signaling molecules without any washing steps or thermocycling. Fluorescent probes for signal generation were designed to consume products of the catalytic reaction in order to push the equilibrium and enhance the assay fold amplification for improved sensitivity and reaction speed. The system of toehold-assisted reactions is also modeled to better understand its performance and capabilities, and we empirically demonstrate the success of this approach with two analytes of diagnostic importance, i.e., influenza viral RNA and a micro RNA (miR-31). We also show that the amplified signal permits using a compact and cost-effective smartphone-based fluorescence reader, an important requirement toward a nucleic-acid-based point-of-care diagnostic system. PMID- 29136462 TI - On-Surface Annulation Reaction Cascade for the Selective Synthesis of Diindenopyrene. AB - We investigated the thermally induced on-surface cyclization of 4,10-bis(2'-bromo 4'-methylphenyl)-1,3-dimethylpyrene to form the previously unknown, nonalternant polyaromatic hydrocarbon diindeno[1,2,3-cd:1',2',3'-mn]pyrene on Au(111) using scanning tunneling microscopy and spectroscopy. The observed unimolecular reaction involves thermally induced debromination followed by selective ring closure to fuse the neighboring benzene moieties via a five-membered ring. The structure of the product has been verified experimentally as well as theoretically. Our results demonstrate that on-surface reactions give rise to unusual chemical reactivities and selectivities and provide access to nonalternant polyaromatic molecules. PMID- 29136463 TI - Benzo[b]thiophene Fusion Enhances Local Borepin Aromaticity in Polycyclic Heteroaromatic Compounds. AB - This report documents the synthesis, characterization, and computational evaluation of two isomeric borepin-containing polycyclic aromatics. The syntheses of these two isomers involved symmetrical disubstituted alkynes that were reduced to Z-olefins followed by borepin formation either through an isolable stannocycle intermediate or directly from the alkene via the trapping of a transient dilithio intermediate. Comparisons of their magnetic, crystallographic, and computational characterization to literature compounds gave valuable insights about the aromaticity of these symmetrically fused [b,f]borepins. The fusion of benzo[b]thiophene units to the central borepin cores forced a high degree of local aromaticity within the borepin moieties relative to other known borepin based polycyclic aromatics. Each isomer had unique electronic responses in the presence of fluoride anions. The experimental data demonstrate that the local borepin rings in these two compounds have a relatively high amount of aromatic character. Results from quantum chemical calculations provide a more comprehensive understanding of local and global aromatic characters of various rings in fused ring systems built upon boron heterocycles. PMID- 29136464 TI - Predictive Model for Oxidative C-H Bond Functionalization Reactivity with 2,3 Dichloro-5,6-dicyano-1,4-benzoquinone. AB - 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a highly effective reagent for promoting C-H bond functionalization. The oxidative cleavage of benzylic and allylic C-H bonds using DDQ can be coupled with an intra- or intermolecular nucleophilic addition to generate new carbon-carbon or carbon-heteroatom bonds in a wide range of substrates. The factors that control the reactivity of these reactions are well-defined experimentally, but the mechanistic details and the role of substituents in promoting the transformations have not been firmly established. Herein, we report a detailed computational study on the mechanism and substituent effects for DDQ-mediated oxidative C-H cleavage reactions in a variety of substrates. DFT calculations show that these reactions proceed through a hydride transfer within a charge transfer complex. Reactivity is dictated by the stability of the carbocation intermediate, the degree of charge transfer in the transition states, and, in certain cases, secondary orbital interactions between the pi orbital of the forming cation and the LUMO of DDQ. A linear free energy relationship was established to offer a predictive model for reactivity of different types of C-H bonds based on the electronic properties of the substrate. PMID- 29136465 TI - Recent Progress of Small-Molecule Epidermal Growth Factor Receptor (EGFR) Inhibitors against C797S Resistance in Non-Small-Cell Lung Cancer. AB - The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein-797 to serine 790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs. In this Miniperspective, we present key mechanisms of resistance in response to third-generation EGFR TKIs, and emerging reports on novel EGFR TKIs to combat the resistance. Specifically, we analyze the allosteric and ATP-competitive inhibitors in terms of drug discovery, binding mechanism, and their potency and selectivity against EGFR harboring C797S mutations. Lastly, we provide some perspectives on new challenges and future directions in this field. PMID- 29136466 TI - Multiconfiguration Pair-Density Functional Theory and Complete Active Space Second Order Perturbation Theory. Bond Dissociation Energies of FeC, NiC, FeS, NiS, FeSe, and NiSe. AB - We investigate the performance of multiconfiguration pair-density functional theory (MC-PDFT) and complete active space second-order perturbation theory for computing the bond dissociation energies of the diatomic molecules FeC, NiC, FeS, NiS, FeSe, and NiSe, for which accurate experimental data have become recently available [Matthew, D. J.; Tieu, E.; Morse, M. D. J. Chem. Phys. 2017, 146, 144310-144320]. We use three correlated participating orbital (CPO) schemes (nominal, moderate, and extended) to define the active spaces, and we consider both the complete active space (CAS) and the separated-pair (SP) schemes to specify the configurations included for a given active space. We found that the moderate SP-PDFT scheme with the tPBE on-top density functional has the smallest mean unsigned error (MUE) of the methods considered. This level of theory provides a balanced treatment of the static and dynamic correlation energies for the studied systems. This is encouraging because the method is low in cost even for much more complicated systems. PMID- 29136467 TI - Equilibrating (L)FeIII-OOAc and (L)FeV(O) Species in Hydrocarbon Oxidations by Bio-Inspired Nonheme Iron Catalysts Using H2O2 and AcOH. AB - Inspired by the remarkable chemistry of the family of Rieske oxygenase enzymes, nonheme iron complexes of tetradentate N4 ligands have been developed to catalyze hydrocarbon oxidation reactions using H2O2 in the presence of added carboxylic acids. The observation that the stereo- and enantioselectivity of the oxidation products can be modulated by the electronic and steric properties of the acid implicates an oxidizing species that incorporates the carboxylate moiety. Frozen solutions of these catalytic mixtures generally exhibit EPR signals arising from two S = 1/2 intermediates, a highly anisotropic g2.7 subset (gmax = 2.58 to 2.78 and Deltag = 0.85-1.2) that we assign to an FeIII-OOAc species and a less anisotropic g2.07 subset (g = 2.07, 2.01, and 1.96 and Deltag ~ 0.11) we associate with an FeV(O)(OAc) species. Kinetic studies on the reactions of iron complexes supported by the TPA (tris(pyridyl-2-methyl)amine) ligand family with H2O2/AcOH or AcOOH at -40 degrees C reveal the formation of a visible chromophore at 460 nm, which persists in a steady state phase and then decays exponentially upon depletion of the peroxo oxidant with a rate constant that is substrate independent. Remarkably, the duration of this steady state phase can be modulated by the nature of the substrate and its concentration, which is a rarely observed phenomenon. A numerical simulation of this behavior as a function of substrate type and concentration affords a kinetic model in which the two S = 1/2 intermediates exist in a dynamic equilibrium that is modulated by the electronic properties of the supporting ligands. This notion is supported by EPR studies of the reaction mixtures. Importantly, these studies unambiguously show that the g2.07 species, and not the g2.7 species, is responsible for substrate oxidation in the (L)FeII/H2O2/AcOH catalytic system. Instead the g2.7 species appears to be off-pathway and serves as a reservoir for the g2.07 species. These findings will be helpful not only for the design of regio- and stereospecific nonheme iron oxidation catalysts but also for providing insight into the mechanisms of the remarkably versatile oxidants formed by nature's most potent oxygenases. PMID- 29136469 TI - Novel Linear Lipopeptide Paenipeptins with Potential for Eradicating Biofilms and Sensitizing Gram-Negative Bacteria to Rifampicin and Clarithromycin. AB - We report the structure-activity relationship analyses of 17 linear lipopeptide paenipeptin analogues. Analogues 7, 12, and 17 were more potent than the lead compound. Analogue 17 was active against carbapenem-resistant and polymyxin resistant pathogens. This compound at 40 MUg/mL resulted in 3 log and 2.6 log reductions of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, respectively, in catheter-associated biofilms in vitro. Analogue 17 showed little hemolysis at 32 MUg/mL and lysed 11% of red blood cells at 64 MUg/mL. Analogues 9 and 16 were nonhemolytic and retained potent P. aeruginosa specific antimicrobial activity. These two analogues when used alone lacked activity against Acinetobacter baumannii and Klebsiella pneumoniae; however, analogue 9 and 16 at 4 MUg/mL decreased the MIC of rifampicin and clarithromycin against the same pathogens from 16 to 32 MUg/mL to nanomolar levels (sensitization factor: 2048-8192). Therefore, paenipeptins, alone or in combination with rifampicin or clarithromycin, are promising candidates for treating bacterial infections. PMID- 29136468 TI - High-Energy-Resolution Fluorescence-Detected X-ray Absorption of the Q Intermediate of Soluble Methane Monooxygenase. AB - Kalpha high-energy-resolution fluorescence detected X-ray absorption spectroscopy (HERFD XAS) provides a powerful tool for overcoming the limitations of conventional XAS to identify the electronic structure and coordination environment of metalloprotein active sites. Herein, Fe Kalpha HERFD XAS is applied to the diiron active site of soluble methane monooxygenase (sMMO) and to a series of high-valent diiron model complexes, including diamond-core [FeIV2(MU O)2(L)2](ClO4)4] (3) and open-core [(O?FeIV-O-FeIV(OH)(L)2](ClO4)3 (4) models (where, L = tris(3,5-dimethyl-4-methoxypyridyl-2-methyl)amine) (TPA*)). Pronounced differences in the HERFD XAS pre-edge energies and intensities are observed for the open versus closed Fe2O2 cores in the model compounds. These differences are reproduced by time-dependent density functional theory (TDDFT) calculations and allow for the pre-edge energies and intensity to be directly correlated with the local active site geometric and electronic structure. A comparison of the model complex HERFD XAS data to that of MMOHQ (the key intermediate in methane oxidation) is supportive of an open-core structure. Specifically, the large pre-edge area observed for MMOHQ may be rationalized by invoking an open-core structure with a terminal FeIV?O motif, though further modulations of the core structure due to the protein environment cannot be ruled out. The present study thus motivates the need for additional experimental and theoretical studies to unambiguously assess the active site conformation of MMOHQ. PMID- 29136470 TI - Linkage Photoisomerization Mechanism in a Photochromic Ruthenium Nitrosyl Complex: New Insights from an MS-CASPT2 Study. AB - The N -> O linkage photoisomerization mechanism in a ruthenium nitrosyl complex, [RuCl(NO)(py)4]2+, for which a quasicomplete photoconversion between the stable nitrosyl (N-bonded) and metastable isonitrosyl (O-bonded) isomers has been observed under continuous irradiation of the crystal at 473 nm ( Cormary et al. Acta Cryst. B 2009 , 65 , 612 - 623 ), is investigated using multiconfigurational second-order perturbation theory (CASPT2). The results support efficient intersystem crossing pathways from the initially excited singlet states to the lowest triplet excited state of metal-to-ligand charge transfer character (3MLCT). The topology of the involved potential energy surfaces corroborates a complex sequential two-photon photoisomerization mechanism involving nonadiabatic processes in agreement with experimental observations and previous density functional theory calculations. PMID- 29136471 TI - Below-Room-Temperature C-H Bond Breaking on an Inexpensive Metal Oxide: Methanol to Formaldehyde on CeO2(111). AB - Upgrading of primary alcohols by C-H bond breaking currently requires temperatures of >200 degrees C. In this work, new understanding from simulation of a temperature-programmed reaction study with methanol over a CeO2(111) surface shows C-H bond breaking and the subsequent desorption of formaldehyde, even below room temperature. This is of particular interest because CeO2 is a naturally abundant and inexpensive metal oxide. We combine density functional theory and kinetic Monte Carlo methods to show that the low-temperature C-H bond breaking occurs via disproportionation of adjacent methoxy species. We further show from calculations that the same transition state with comparable activation energy exists for other primary alcohols; with ethanol, 1-propanol, and 1-butanol explicitly calculated. These findings indicate a promising class of transition states to search for in seeking low-temperature C-H bond breaking over inexpensive oxides. PMID- 29136472 TI - Thickness-Dependent Phonon Renormalization and Enhanced Raman Scattering in Ultrathin Silicon Nanomembranes. AB - We report on the thickness-dependent Raman spectroscopy of ultrathin silicon (Si) nanomembranes (NMs), whose thicknesses range from 2 to 18 nm, using several excitation energies. We observe that the Raman intensity depends on the thickness and the excitation energy due to the combined effects of interference and resonance from the band-structure modulation. Furthermore, confined acoustic phonon modes in the ultrathin Si NMs were observed in ultralow-frequency Raman spectra, and strong thickness dependence was observed near the quantum limit, which was explained by calculations based on a photoelastic model. Our results provide a reliable method with which to accurately determine the thickness of Si NMs with thicknesses of less than a few nanometers. PMID- 29136473 TI - Structural Investigation of Bulk and Dispersed Inverse Lyotropic Hexagonal Liquid Crystalline Phases of Eicosapentaenoic Acid Monoglyceride. AB - Recent studies demonstrated the potential therapeutic use of newly synthesized omega-3 (omega-3) polyunsaturated fatty acid (PUFA) monoglycerides owing to their beneficial health effects in various disorders including cancer and inflammation diseases. To date, the research was mainly focused on exploring the biological effects of these functional lipids. However, to the best of our knowledge, there is no report on the hydration-mediated self assembly of these lipids that leads to the formation of nanostructures, which are attractive for use as vehicles for the delivery of drugs and functional foods. In the present study, we investigated the temperature-composition phase behaviour of eicosapentaenoic acid monoglyceride (MAG-EPA), which is one of the most investigated omega-3 PUFA monoglycerides, during a heating-cooling cycle in the temperature range of 5-60 degrees C. Experimental synchrotron small-angle X-ray scattering (SAXS) evidence on the formation of a dominant inverse hexagonal (H2) lyotropic liquid crystalline phase and its temperature-induced transition to an inverse micellar solution (L2 phase) is presented for the fully hydrated bulk MAG-EPA system and its corresponding dispersion. We produced colloidal MAG-EPA hexosomes with an internal inverse hexagonal (H2) lyotropic crystalline phase in the presence of F127, a well-known polymeric stabilizer, or citrem, which is a negatively charged food-grade emulsifier. In this work, we report also on the formation of MAG-EPA hexosomes by vortexing MAG-EPA in excess aqueous medium containing F127 at room temperature. This low-energy emulsification method is different than most reported studies in the literature that have demonstrated the need for using a high-energy input during the emulsification step or adding an organic solvent for the formation of such colloidal nonlamellar liquid crystalline dispersions. The designed nanoparticles hold promise for future drug and functional food delivery applications due to their unique structural properties and the potential health promoting effects of MAG-EPA. PMID- 29136474 TI - Characterization of the Submicrometer Hierarchy Levels in the Twist-Bend Nematic Phase with Nanometric Helices via Photopolymerization. Explanation for the Sign Reversal in the Polar Response. AB - Photopolymerization of a reactive mesogen mixed with a mesogenic dimer, shown to exhibit the twist-bend nematic phase (NTB), reveals the complex structure of the self-deformation patterns observed in planar cells. The polymerized reactive mesogen retains the structure formed by liquid crystalline molecules in the twist bend phase, thus enabling its observation by scanning electron microscopy (SEM). Hierarchical ordering scales ranging from tens of nanometers to micrometers are imaged in detail. Submicron features, anticipated from earlier X-ray experiments, are visualized directly. In the self-deformation stripes formed in the NTB phase, the average director field is found tilted in the cell plane by an angle of up to 45 degrees from the cell rubbing direction. This tilt explains the sign inversion being observed in the electro-optical studies. PMID- 29136475 TI - Through-Thickness Vertically Ordered Lamellar Block Copolymer Thin Films on Unmodified Quartz with Cold Zone Annealing. AB - Template-free directed self-assembly of ultrathin (approximately tens of nanometers) lamellar block copolymer (l-BCP) films into vertically oriented nanodomains holds much technological relevance for the fabrication of next generation devices from nanoelectronics to nanomembranes due to domain interconnectivity and high interfacial area. We report for the first time the formation of full through-thickness vertically oriented lamellar domains in 100 nm thin polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) films on quartz substrate, achieved without any PMMA-block wetting layer formation, quartz surface modification (templating chemical, topographical) or system modifications (added surfactant, top-layer coat). Vertical ordering of l-BCPs results from the coupling between a molecular and a macroscopic phenomenon. A molecular relaxation induced vertical l-BCP ordering occurs under a transient macroscopic vertical strain field, imposed by a high film thermal expansion rate under sharp thermal gradient cold zone annealing (CZA-S). The parametric window for vertical ordering is quantified via a coupling constant, C (= v?T), whose range is established in terms of a thermal gradient (?T) above a threshold value, and an optimal dynamic sample sweep rate (v ~ d/tau), where tau is the l-BCP's longest molecular relaxation time and d is the Tg,heat - Tg,cool distance. Real-time CZA-S morphology evolution of vertically oriented l-BCP tracked along ?T using in situ grazing incidence small angle X-ray scattering (GISAXS) exhibited an initial formation phase of vertical lamellae, a polygrain structure formation stage, and a grain coarsening phase to fully vertically ordered l-BCP morphology development. CZA-S is a roll-to-roll manufacturing method, rendering this template-free through-thickness vertical ordering of l-BCP films highly attractive and industrially relevant. PMID- 29136476 TI - Effectiveness of a school-based program focusing on diet and health habits taught through physical exercise. AB - The global rate of obesity in childhood is becoming an epidemic and many authors have established a significant association between childhood obesity and overweight in adulthood. It is therefore necessary to seek effective strategies to reduce these levels of obesity. The aim of this study was to evaluate the impact of the Healthy Habits Program (HHP). The participants comprised 158 children from the fifth and sixth grades (intervention group, n = 82; control group, n = 76). The HHP is a school-based physical activity program focusing on promoting a healthy lifestyle. It lasted for 8 months, and measurements were taken at the beginning and end of the program. Physiological variables (total cholesterol, triglycerides, blood glucose, blood pressure, and maximal oxygen consumption), anthropometric variables (body mass index (BMI)) and behavioral variables (breakfast, quality of diet, meal frequency, physical activity, sedentary behavior, sleep, and perceived health) were evaluated. Repeated measures ANOVA showed significant improvements (p < 0.05) after the intervention for the intervention group in triglycerides, blood glucose and maximal oxygen consumption. Significant improvements were also observed in breakfast habits and quality of diet. Finally, a significant improvement in prevalence of normal levels was observed for total cholesterol, blood pressure, and BMI. It can therefore be stated that the HHP is an innovative and useful school-based program that can help to improve diet and health in childhood. PMID- 29136481 TI - Are We Ready for Mental Health Aging? PMID- 29136482 TI - Impact of an Elementary School-Based Intervention on Physical Activity Time and Aerobic Capacity, Georgia, 2013-2014. AB - OBJECTIVES: The objectives of this study were to (1) determine the impact of a 1 year elementary school physical activity intervention on changes in teacher reported school-based physical activity time and (2) assess the relationship between these changes and changes in student aerobic capacity. METHODS: HealthMPowers, a nonprofit organization, provided a multicomponent physical activity intervention to 3479 students in 39 schools in Georgia during 2013-2014. HealthMPowers administered a survey to faculty members before (August 2013) and after (May 2014) the intervention to measure student physical activity times. The organization collected pre- and post-intervention Progressive Aerobic Cardiovascular Endurance Run (PACER) laps (a measure of aerobic capacity that awards 1 lap for each completed 20-meter lap) for 2342 fourth-grade students. We performed linear regression to determine the relationship between school-level changes in teacher-reported school-based physical activity time and student aerobic capacity. RESULTS: The weekly estimated teacher-reported time in physical activity increased by 39 minutes from pre- to post-intervention: 21 minutes for recess, 17 minutes for classroom, and 1 minute for physical education. The mean number of student PACER laps increased by 3 laps from pre- to post-intervention, and 1515 of 2342 (65%) students increased the number of PACER laps completed. We observed a positive association between school-level changes in school-based physical activity time and school-level changes in PACER laps ( r = 0.38; 95% confidence interval, 0.29-0.46). CONCLUSIONS: These findings highlight the need for more prospective research into multicomponent physical activity interventions. Rigorous testing, including randomized controlled trials of large scale implementations, is needed to examine how these school-based interventions might be used to improve the physical activity and fitness of larger populations of children. PMID- 29136483 TI - Fitness, Sleep-Disordered Breathing, Symptoms of Depression, and Cognition in Inactive Overweight Children: Mediation Models. AB - OBJECTIVES: We used mediation models to examine the mechanisms underlying the relationships among physical fitness, sleep-disordered breathing (SDB), symptoms of depression, and cognitive functioning. METHODS: We conducted a cross-sectional secondary analysis of the cohorts involved in the 2003-2006 project PLAY (a trial of the effects of aerobic exercise on health and cognition) and the 2008-2011 SMART study (a trial of the effects of exercise on cognition). A total of 397 inactive overweight children aged 7-11 received a fitness test, standardized cognitive test (Cognitive Assessment System, yielding Planning, Attention, Simultaneous, Successive, and Full Scale scores), and depression questionnaire. Parents completed a Pediatric Sleep Questionnaire. We used bootstrapped mediation analyses to test whether SDB mediated the relationship between fitness and depression and whether SDB and depression mediated the relationship between fitness and cognition. RESULTS: Fitness was negatively associated with depression ( B = -0.041; 95% CI, -0.06 to -0.02) and SDB ( B = -0.005; 95% CI, -0.01 to 0.001). SDB was positively associated with depression ( B = 0.99; 95% CI, 0.32 to 1.67) after controlling for fitness. The relationship between fitness and depression was mediated by SDB (indirect effect = -0.005; 95% CI, -0.01 to 0.0004). The relationship between fitness and the attention component of cognition was independently mediated by SDB (indirect effect = 0.058; 95% CI, 0.004 to 0.13) and depression (indirect effect = -0.071; 95% CI, -0.01 to -0.17). CONCLUSIONS: SDB mediates the relationship between fitness and depression, and SDB and depression separately mediate the relationship between fitness and the attention component of cognition. PMID- 29136484 TI - Effect of the Strong4Life School Nutrition Program on Cafeterias and on Manager and Staff Member Knowledge and Practice, Georgia, 2015. AB - OBJECTIVES: The goal of the Strong4Life School Nutrition Program is to promote healthy eating in school cafeterias in Georgia by training school nutrition managers and staff members to implement changes in the cafeteria to nudge children to make healthier choices. The objective of our study was to evaluate program effect on (1) school nutrition manager and staff member knowledge of evidence-based strategies and their self-efficacy to make positive changes, (2) the school cafeteria environment, and (3) National School Lunch Program participation. METHODS: We assessed changes in participant knowledge, beliefs, and self-efficacy by administering a survey before and after training (February July 2015); a follow-up survey (3 school months posttraining) assessed changes in the cafeteria. A total of 842 school nutrition managers and staff members were trained and completed pre- and posttraining surveys; 325 managers completed the follow-up survey. We used cafeteria records from a subsample of the first schools trained (40 intervention and 40 control) to assess National School Lunch Program participation. RESULTS: From pretraining to posttraining, we found a significant increase in manager and staff member (n = 842) knowledge of strategies for enhancing taste perception through the use of creative menu item names (from 78% to 95%, P < .001) and understanding that food placement in the lunch line influences food selection (from 78% to 95%, P < .001), and in their self perceived ability to influence the cafeteria environment (from 91% to 96%, P < .001). From pretraining to 3-month follow-up, managers (n = 325) reported increased use of evidence-based serving strategies: visibility (from 84% to 96% for placing healthy options in >2 locations, P < .001), convenience (from 63% to 84% for placing plain milk in front of other beverages, P < .001), sell (from 25% to 38% for branding healthy items with stickers, P < .001), price (from 17% to 27% for using bundle pricing to encourage sales, P < .001), and taste (from 77% to 85% for signage demonstrating the benefits of healthy eating, P = .01). National School Lunch Program participation did not change significantly. CONCLUSIONS: Training cafeteria managers and staff members in Smarter Lunchrooms Movement techniques may be an effective way to make changes in the school cafeteria environment to encourage healthier choices among students. Additional studies allowing time for more complex changes to be implemented are needed to assess the full effect of the program. PMID- 29136485 TI - Evaluating the Impact of Training in Obesity Prevention Methods on the Counseling, Knowledge, and Skills of WIC Nutritionists in Georgia, 2014-2015. AB - OBJECTIVES: Motivational interviewing, a client-centered intervention method focused on enhancing intrinsic motivation for behavior change, shows a positive impact on children's weight status (ie, stabilizing or slowing down weight gain as a child grows). We evaluated the impact of a training program on knowledge and adoption of evidence-based obesity prevention counseling strategies among counselors from Georgia's Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). METHODS: Between July 2014 and September 2015, Children's Healthcare of Atlanta's Strong4Life program provided 388 WIC counselors in Georgia with a 2-hour training session on motivational interviewing, patient-centered counseling, and goal setting for obesity prevention. We evaluated the training using (1) self-administered pre- and post training surveys that assessed knowledge of counseling strategies, (2) post training observation of counseling interactions, and (3) a review of behavior change goal quality pre- and post-training in a random sample of 200 WIC client charts. RESULTS: In a comparison of pre-training knowledge with immediate post training knowledge among 388 counselors, 81% vs 91% ( P < .001) knew that, to be effective, goals must be important to clients, and 66% vs 94% ( P < .001) knew the 5 A's (assess, advise, agree, assist, arrange) of counseling. Knowledge improvements were sustained at 3 months post-training. We observed no improvements in the quality of chart-documented behavior goals. CONCLUSIONS: WIC nutrition counselors in Georgia were aware of evidence-based counseling strategies but did not consistently apply them. The training program was helpful, but time and additional support are needed to adopt new practices. PMID- 29136486 TI - Childhood Obesity in Georgia. PMID- 29136487 TI - The Healthy Fitness Zone Continuum Score as a Measure of Change in Body Mass Index of School-Aged Children and Adolescents, Georgia, 2012-2014. AB - OBJECTIVES: The FitnessGram Healthy Fitness Zone continuum (HFZc) score reflects the relative difference of a person's body mass index (BMI) from the established FitnessGram standard. As such, it may provide added utility for public health programming and research on obesity among school-aged children and adolescents. We used the standard BMI Z (BMIz) score and the alternative HFZc score to describe changes in BMI of school-aged children and adolescents in Georgia over time. METHODS: We compiled 2012-2014 BMI data from the Georgia FitnessGram database. The sample included 162 992 boys and 141 711 girls enrolled in 239 schools from a large urban district in Georgia. We analyzed trends in BMIz and HFZc scores separately for normal-weight, overweight, and obese categories for school-aged children and adolescents using hierarchical linear models. RESULTS: From 2012 to 2014, the BMIz score shifted favorably in up to 40.7% (2052/5047) of normal-weight, 51.0% (758/1485) of overweight, and 52.8% (5430/10 279) of obese students. We also found favorable shifts in HFZc score in up to 69.8% (105 831/151 739) of normal-weight, 78.3% (3605/4603) of overweight, and 80.8% (8305/10 279) of obese students. CONCLUSIONS: Compared with the BMIz score, the HFZc score may be a better indicator of favorable changes in BMI over time among school-aged children and adolescents with different baseline BMI levels, making it potentially valuable for use in individualized assessments, school programs, obesity research, and public health curriculum and policy development. PMID- 29136488 TI - Leading the Way in Preventing Childhood Obesity in Georgia. PMID- 29136489 TI - Like Peas and Carrots: Combining Wellness Policy Implementation With Classroom Education for Obesity Prevention in the Childcare Setting. AB - OBJECTIVES: We evaluated an intervention combining policy training and technical assistance for childcare teachers with a nutrition education curriculum to improve (1) the knowledge and self-efficacy of childcare teachers in implementing obesity prevention policies and practices, (2) the quantity and quality of nutrition and physical activity education, and (3) the childcare wellness environment. METHODS: Thirteen teachers and 8 administrators (2 of whom were also teachers) from 8 childcare programs in Clarke County, Georgia, participated in the Healthy Child Care Georgia intervention during June-October 2015. The intervention included (1) training and technical assistance on obesity prevention policies, systems, and practices and (2) direct education by teachers using the Eat Healthy, Be Active curriculum. We assessed changes in program wellness policy adoption and teacher knowledge and self-efficacy from pre- to post-intervention through self-report questionnaires, interviews, and focus groups. RESULTS: Teachers' knowledge scores (maximum score = 100) rose significantly from a mean (SD) pre-intervention of 67.1 (14.6) to post-intervention of 83.2 (14.3) ( P < .001). The mean score for "teaching nutrition and activity to children" (maximum score = 105) rose significantly from 86.9 (8.2) to 93.5 (5.2) ( P = .011) and for "modeling and supporting children" (maximum score = 63) from 55.8 (5.1) to 59.5 (4.5) ( P = .015). The mean (SD) scores for breastfeeding and infant feeding policy/practice adoption (maximum score = 6) increased significantly from 2.5 (1.8) to 3.7 (1.9) ( P = .043) and for nutrition education policy/practice adoption (maximum score = 4) from 2.0 (1.3) to 3.3 (1.4) ( P = .019). The combined approach enhanced classroom nutrition education and improved the adoption of best practices. CONCLUSION: Future studies should examine the effects of using a combined approach to promote nutrition and physical activity policies and practices in the early care and education setting. PMID- 29136490 TI - Adopting State-Level Policy to Support Physical Activity Among School-Aged Children and Adolescents: Georgia's SHAPE Act. AB - Physical inactivity among children is a public health problem associated with low levels of fitness, obesity, and increased risk of chronic diseases. Public health experts have identified policies targeting physical activity as a promising strategy to address this challenge. Understanding the process by which such policies are adopted may help to facilitate progress nationally. To examine lessons learned from the passage of the Student Health and Physical Education Act in Georgia, we conducted 15 interviews with people engaged in the adoption of the act. We found that several factors were vital to policy adoption: a shifting social and political climate, the organization and mobilization of diverse partners behind a common agenda, and the development of strategies to overcome impediments to legislative progress. These findings suggest that engagement and cooperation with partners, establishment of mutual interests as a basis for collaboration, and grassroots outreach and advocacy can facilitate adoption of policies that promote physical activity. PMID- 29136491 TI - Fitness Trends and Disparities Among School-Aged Children in Georgia, 2011-2014. AB - OBJECTIVES: Although FitnessGram fitness data on aerobic capacity and body mass index (BMI) have been collected in public schools in Georgia since the 2011-2012 school year, the data have not been analyzed. The primary objective of our study was to use these data to assess changes in fitness among school-aged children in Georgia between 2011 and 2014. A secondary objective was to determine if student fitness differed by school size and socioeconomic characteristics. METHODS: FitnessGram classifies fitness into the Healthy Fitness Zone (HFZ) or not within the HFZ for aerobic capacity and BMI. We used data for 3 successive school years (ie, 2011-2012 to 2013-2014) obtained from FitnessGram testing of students in >1600 schools. We calculated the percentage of students who achieved the HFZ for aerobic capacity and BMI. We used growth curve models to estimate the annual changes in these proportions, and we determined the effect of school size and socioeconomic status on these changes. RESULTS: Both elementary school boys (beta = 1.31%, standard error [SE] = 0.23%, P < .001) and girls (beta = 1.53%, SE = 0.26%, P < .001) had significant annual increases in achievement of HFZ for aerobic capacity. Elementary school boys (beta = 3.11%, SE = 0.32%, P < .001) and girls (beta = 3.09%, SE = 0.32%, P < .001) also had significant increases in their BMI HFZ achievement proportions, although these increases occurred primarily between 2011-2012 and 2012-2013. Body mass index HFZ achievement proportions were mixed for middle school students, and we did not observe increases for high school students. Larger school size and higher school socioeconomic status were associated with better aerobic capacity and BMI fitness profiles. CONCLUSIONS: Surveillance results such as these may help inform the process of designing state and local school-based fitness promotion and public health programs and tracking the results of those programs. PMID- 29136492 TI - Bridging Public Health and Education: Results of a School-Based Physical Activity Program to Increase Student Fitness. AB - OBJECTIVE: Power Up for 30 (PU30) is a schoolwide intervention that encourages schools to provide an additional 30 minutes of physical activity during the school day, beyond physical education. The objective of this study was to evaluate the impact of PU30 on Georgia public elementary schools and their students. METHODS: A total of 719 of 1320 public elementary schools in Georgia that were sent a baseline survey about school physical activity during October 2013 to September 2014 completed the survey, 160 of which were asked to complete a second survey. In the interim (March to June 2015), half (80) of these schools implemented the PU30 program. The interim surveys, which were completed during March to June 2015, assessed opportunities for student physical activity and staff member professional development focused on student physical activity. RESULTS: Compared with schools that had not implemented the program, more schools using the PU30 program reported offering before- and after-school physical activity programs. Forty-four of 78 (57%) PU30 schools compared with 20 of 53 (38%) non-PU30 schools offered before-school physical activity programs. Likewise, more PU30 schools than non-PU30 schools offered after-school physical activity programs (35% vs 16%), and a greater proportion of students at PU30 schools compared with non-PU30 schools met fitness benchmarks: recess 5 days per week (91% [288 of 323] vs 80% [273 of 341]), offering >=11 minutes per day of classroom-based physical activity (39% [53 of 136] vs 25% [47 of 189] for kindergarten through second grade; 20% [37 of 187] vs 6% [9 of 152] for grades 3 through 5), and receiving physical activity-related professional development time (42% [136 of 323] vs 14% [48 of 341]). CONCLUSIONS: The surveys provided a statewide picture of the physical activity opportunities offered to students and staff members in Georgia elementary schools and demonstrated the effective use of a comprehensive, multicomponent program to offer more school-based physical activity opportunities and to improve student fitness. PMID- 29136493 TI - Systems Thinking and Simulation Modeling to Inform Childhood Obesity Policy and Practice. AB - OBJECTIVES: In 2007, 31.7% of Georgia adolescents in grades 9-12 were overweight or obese. Understanding the impact of policies and interventions on obesity prevalence among young people can help determine statewide public health and policy strategies. This article describes a systems model, originally launched in 2008 and updated in 2014, that simulates the impact of policy interventions on the prevalence of childhood obesity in Georgia through 2034. METHODS: In 2008, using information from peer-reviewed reports and quantitative estimates by experts in childhood obesity, physical activity, nutrition, and health economics and policy, a group of legislators, legislative staff members, and experts trained in systems thinking and system dynamics modeling constructed a model simulating the impact of policy interventions on the prevalence of childhood obesity in Georgia through 2034. Use of the 2008 model contributed to passage of a bill requiring annual fitness testing of schoolchildren and stricter enforcement of physical education requirements. We updated the model in 2014. RESULTS: With no policy change, the updated model projects that the prevalence of obesity among children and adolescents aged <=18 in Georgia would hold at 18% from 2014 through 2034. Mandating daily school physical education (which would reduce prevalence to 12%) and integrating moderate to vigorous physical activity into elementary classrooms (which would reduce prevalence to 10%) would have the largest projected impact. Enacting all policies simultaneously would lower the prevalence of childhood obesity from 18% to 3%. CONCLUSIONS: Systems thinking, especially with simulation models, facilitates understanding of complex health policy problems. Using a simulation model to educate legislators, educators, and health experts about the policies that have the greatest short- and long-term impact should encourage strategic investment in low-cost, high-return policies. PMID- 29136494 TI - Re: Bilginaylar K: The Use of Platelet Rich Fibrin for Immediate Closure of Acute Oroantral Communications: An Alternative Approach. PMID- 29136495 TI - Agreement between Subjective Global Nutritional Assessment and the nutritional assessment of the World Health Organization. AB - OBJECTIVE: To assess the agreement between the results of the Subjective Global Nutritional Assessment questionnaire, adapted for children and adolescents of the Brazilian population, and the nutritional status assessment method through growth curves and the classification of the World Health Organization in a pediatric hospital service. METHODS: This was an analytical, quantitative, cross-sectional study. During the data collection period, the nutritional status of all patients from 0 to 12 years of age, admitted to the pediatric unit of a university hospital, was concomitantly assessed according to the Subjective Global Nutritional Assessment and World Health Organization curves. To determine the assessment and agreement between these methods, the Kappa and Kendall coefficients were used, respectively, considering a significance level of 5%. RESULTS: Sixty-one children participated, with a predominance of males. It was observed that the highest frequency of equivalent results occurred among the group classified as well nourished, and that only the height/age variable showed a close agreement between the methods. Additionally, there was a good correlation only for the weight/height variable between the assessment tools used. CONCLUSION: Due to the low agreement between the methods, the combination of both may be beneficial for the nutritional assessment of pediatric patients, collaborating with the early diagnosis of nutritional alterations and facilitating the use of adequate dietary therapy. PMID- 29136496 TI - Association between pacifier use and bottle-feeding and unfavorable behaviors during breastfeeding. AB - OBJECTIVE: To investigate the association between pacifier use and bottle-feeding and unfavorable behaviors during breastfeeding. METHOD: A cross-sectional study was conducted with 427 babies/mothers. Socio-demographic, perinatal data, and information about the use of artificial nipples (pacifier and/or bottle) were collected through a questionnaire. The breastfeeding aspects regarding position, affectivity, sucking behavior, baby responses, and breast anatomy were evaluated through observation during breastfeeding. The chi-squared test and the multiple linear regression analysis were used to investigate the association between the variables. RESULTS: The aspects of breastfeeding that showed higher percentages of the category "poor" were sucking behavior (22.5%) and position (22.2%). The group of infants who used pacifiers and/or bottle showed higher percentages in the poor and fair categories when compared with the good category for all five breastfeeding aspects evaluated (p<0.001). The linear regression analysis revealed that the increase in the number of unfavorable behaviors regarding position, affectivity, sucking behavior, and baby responses were independently associated with both pacifier and bottle use (beta positive, p<0.05), while breast anatomy was independently associated only with bottle use. CONCLUSION: The findings suggest that the use of pacifiers and/or bottle-feeding may be associated with unfavorable behaviors during breastfeeding, especially the use of bottle-feeding. PMID- 29136497 TI - Oncogene-Stimulated Congestion at the KEAP1 Stress Signaling Hub Allows Bypass of NRF2 and Induction of NRF2-Target Genes that Promote Tumor Survival. AB - In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif. PMID- 29136498 TI - A Two-Faced mSWI/SNF Subunit: Dual Roles for ARID1A in Tumor Suppression and Oncogenicity in the Liver. AB - In this issue of Cancer Cell, Sun et al. describe context-dependent oncogenic and tumor-suppressive functions for the mammalian SWI/SNF (BAF) complex subunit ARID1A in the development and progression of hepatocellular carcinoma (HCC). PMID- 29136499 TI - Early GalNAc O-Glycosylation: Pushing the Tumor Boundaries. AB - Glycosylation alterations are frequently observed in cancer cells and shape tumor progression. In this issue of Cancer Cell, Nguyen et al. show that GALNT1 relocation from Golgi to endoplasmic reticulum drives liver tumor growth and invasion, due to enhanced glycosylation and consequential activation of the extracellular matrix-degrading metalloproteinase MMP14. PMID- 29136500 TI - Does CSF1R Blockade Turn into Friendly Fire? AB - In this issue of Cancer Cell, Kumar et al. describe how CSF1R blockade induces not only an expected deprivation of tumor-associated macrophages, but also an accumulation of tumor-infiltrating polymorphonuclear mononuclear cells caused by Cxcl-1 released from cancer-associated fibroblasts. PMID- 29136501 TI - Pontine Infantile Glioma Simplified. AB - In this issue of Cancer Cell, Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer. PMID- 29136502 TI - Molecular Landscape of Non-Muscle Invasive Bladder Cancer. AB - In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling. Tumors from female patients have a higher frequency of KDM6A mutations. PMID- 29136503 TI - Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure. AB - Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions. PMID- 29136505 TI - Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts. AB - Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM. PMID- 29136504 TI - Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer. AB - ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context dependent tumor-suppressive and oncogenic roles in cancer. PMID- 29136506 TI - A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia. AB - Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX+ clinical subtype, further underscoring the suppressor role of this pathway. PMID- 29136507 TI - Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis. AB - Cancers grow within tissues through molecular mechanisms still unclear. Invasiveness correlates with perturbed O-glycosylation, a covalent modification of cell-surface proteins. Here, we show that, in human and mouse liver cancers, initiation of O-glycosylation by the GALNT glycosyl-transferases increases and shifts from the Golgi to the endoplasmic reticulum (ER). In a mouse liver cancer model, expressing an ER-targeted GALNT1 (ER-G1) massively increased tumor expansion, with median survival reduced from 23 to 10 weeks. In vitro cell growth was unaffected, but ER-G1 strongly enabled matrix degradation and tissue invasion. Unlike its Golgi-localized counterpart, ER-G1 glycosylates the matrix metalloproteinase MMP14, a process required for tumor expansion. Together, our results indicate that GALNTs strongly promote liver tumor growth after relocating to the ER. PMID- 29136508 TI - Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors. AB - Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2 mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects. PMID- 29136509 TI - An HIF-1alpha/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression. AB - Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1alpha, but not HIF-2alpha, was essential for the effector state in CD8+ T cells. Furthermore, loss of HIF 1alpha in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8+ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1alpha/VEGF-A axis is an essential aspect of tumor immunity. PMID- 29136512 TI - An ethical exploration of standardized testing in nursing education. PMID- 29136511 TI - SnapShot: Chronic Lymphocytic Leukemia. AB - Despite the recent advances in the therapeutic management of Chronic Lymphocytic Leukemia (CLL) patients, this common B cell malignancy still remains incurable. This SnapShot provides an overview of CLL biology and therapy, with a focus on genetics and microenvironmental interactions, which contribute to disease progression and therapy resistance. To view this SnapShot, open or download the PDF. PMID- 29136510 TI - Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency. AB - Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone lysine demethylase KDM6A were present in non-invasive tumors from females than males. PMID- 29136513 TI - Facilitating learning through an international virtual collaborative practice: A case study. AB - BACKGROUND: Internationalisation of higher education involving information and communication technology such as e-learning opens opportunities for innovative learning approaches across nations and cultures. OBJECTIVES: Describe a case in practice of collaborative and transformative learning in relation to 'internationalisation on home grounds' with the broader learning objective of 'becoming aware and knowledgeable'. DESIGN: A mutually developed project established a virtual international collaborative exchange for faculty and students using a course management software (MOODLE) and open access technology (Adobe CONNECT). SETTINGS: Two research universities in Sweden and the United States. PARTICIPANTS: Approximately 90 nursing students from each university per semester over several semesters. METHODS: A collaborative process to develop a joint learning community to construct a virtual module and learning activity involving academics and nursing students in two countries using principles of meaning construction and negotiated learning. RESULTS: Developed possibilities for dealing with the challenges and finding strategies for a future higher education system that opens dialogues worldwide. CONCLUSIONS: Virtual international exchanges open innovative communication and learning contexts across nations and cultures. Internationalisation is so much more than students and teachers' mobility. 'Internationalisation on home grounds' (internationalisation for all) should receive more attention to support faculty and student collaboration, learning, and professional development. PMID- 29136514 TI - Rejection sensitivity, interpersonal rejection, and attention for emotional facial expressions. AB - BACKGROUND AND OBJECTIVES: Rejection sensitivity (RS), attention for depression relevant stimuli, and interpersonal rejection are established risk factors for depression. RS has previously been associated with increased attention for socially threatening faces, but has not been examined in the context of specifically depression-relevant stimuli. The current study examined whether RS influences attention for emotional facial expressions in the context of social rejection or inclusion. METHODS: Participants (n = 180) completed a self-report measure of RS and a free viewing eye tracking task before and after an experimental task (Cyberball) in which participants were randomized to be included or rejected. RESULTS: Hierarchical linear regressions predicting change in attention to emotional faces revealed significant effects only for sad faces. Higher RS was associated with increased attention for sad faces from pre- to post Cyberball. Cyberball condition moderated the effect with participants in the rejection condition demonstrating increased attention for sad faces, but with no significant relationship in the inclusion condition. LIMITATIONS: Our sample had relatively low levels of RS and depression. CONCLUSIONS: Consistent with interpersonal and cognitive models of depression, we found that RS was associated with increased attention for sad faces when participants were interpersonally rejected. Results provide preliminary evidence that rejection sensitivity may contribute to depression vulnerability via increased attention to depression relevant information in the context of interpersonal rejection. Further research including clinically depressed participants and using longitudinal approaches are necessary to confirm this potential relationship. PMID- 29136515 TI - Associations between feelings of social anxiety and emotion perception. AB - BACKGROUND: Abnormally biased perceptual judgment is a feature of many psychiatric disorders. Thus, individuals with social anxiety disorder are biased to recall or interpret social events negatively. Cognitive behavioral therapy addresses such bias by teaching patients, via verbal instruction, to become aware of and change pathological misjudgment. The present study examined whether targeting verbal instruction to specific decision parameters that influence perceptual judgment may affect changes in anger perception. METHOD: We used a signal detection framework to decompose anger perception into three decision parameters (base rate of encountering anger vs. no-anger, payoff for correct vs. incorrect categorization of face stimuli, and perceptual similarity of angry vs. not-angry facial expressions). We created brief verbal instructions that emphasized each parameter separately. Participants with social anxiety disorder, generalized anxiety disorder, and healthy controls, were assigned to one of the three instruction conditions. We compared anger perception pre-vs. post instruction. RESULTS: Base rate and payoff instructions affected response bias over and above practice effects, across the three groups. There was no interaction with diagnosis. DISCUSSION: The ability to target specific decision parameters that underlie perceptual judgment suggests that cognitive behavioral therapy might be improved by tailoring it to patients' individual parameter "estimation" deficits. PMID- 29136516 TI - The order of information processing alters economic gain-loss framing effects. AB - Adaptive decision making requires analysis of available information during the process of choice. In many decisions that information is presented visually - which means that variations in visual properties (e.g., salience, complexity) can potentially influence the process of choice. In the current study, we demonstrate that variation in the left-right positioning of risky and safe decision options can influence the canonical gain-loss framing effect. Two experiments were conducted using an economic framing task in which participants chose between gambles and certain outcomes. The first experiment demonstrated that the magnitude of the gain-loss framing effect was greater when the certain option signaling the current frame was presented on the left side of the visual display. Eye-tracking data during task performance showed a left-gaze bias for initial fixations, suggesting that the option presented on the left side was processed first. Combination of eye-tracking and choice data revealed that there was a significant effect of direction of first gaze (i.e. left vs. right) as well as an interaction between gaze direction and identity of the first fixated information (i.e. certain vs. gamble) regardless of frame. A second experiment presented the gamble and certain options in a random order, with a temporal delay between their presentations. We found that the magnitude of gain-loss framing was larger when the certain option was presented first, regardless of left and right positioning, only in individuals with lower risk-taking tendencies. The effect of presentation order on framing was not present in high risk-takers. These results suggest that the sequence of visual information processing as well as their left-right positioning can bias choices by changing the impact of the presented information during risky decision making. PMID- 29136517 TI - Improving novel motor learning through prior high contextual interference training. AB - The primary objective of the present experiment was to examine the influence of recent practice in a random and blocked format for future motor learning. First, individuals practiced three unique discrete sequence production tasks in either a blocked or random schedule. One day later, all individuals practiced a new motor sequence not previously practiced. On day three, mean total time for the test performance of the original three motor sequences was lower for individuals that practiced in a random format. This emerged as a significant reduction in mean total time from the completion of practice and the test trials implicating offline consolidation as a key contributor to the random practice performance advantage. A novel finding from the present work was that the acquisition of the novel discrete sequence production task practiced on Day 2 was better for individuals that had prior random rather than blocked practice experience. This benefit was robust appearing early during acquisition as significantly lower mean total time. This benefit from random practice experience remained during the delayed test trials administered on Day 3 for the novel motor sequence. PMID- 29136518 TI - Evidence of co-metabolic bentazone transformation by methanotrophic enrichment from a groundwater-fed rapid sand filter. AB - The herbicide bentazone is recalcitrant in aquifers and is therefore frequently detected in wells used for drinking water production. However, bentazone degradation has been observed in filter sand from a rapid sand filter at a waterworks with methane-rich groundwater. Here, the association between methane oxidation and removal of bentazone was investigated with a methanotrophic enrichment culture derived from methane-fed column reactors inoculated with that filter sand. Several independent lines of evidence obtained from microcosm experiments with the methanotrophic enrichment culture, tap water and bentazone at concentrations below 2 mg/L showed methanotrophic co-metabolic bentazone transformation: The culture removed 53% of the bentazone in 21 days in presence of 5 mg/L of methane, while only 31% was removed in absence of methane. Addition of acetylene inhibited methane oxidation and stopped bentazone removal. The presence of bentazone partly inhibited methane oxidation since the methane consumption rate was significantly lower at high (1 mg/L) than at low (1 MUg/L) bentazone concentrations. The transformation yield of methane relative to bentazone normalized by their concentration ratio ranged from 58 to 158, well within the range for methanotrophic co-metabolic degradation of trace contaminants calculated from the literature, with normalized substrate preferences varying from 3 to 400. High-resolution mass spectrometry revealed formation of the transformation products (TPs) 6-OH, 8-OH, isopropyl-OH and di-OH bentazone, with higher abundances of all TPs in the presence of methane. Overall, we found a suite of evidence all showing that bentazone was co-metabolically transformed to hydroxy-bentazone by a methanotrophic culture enriched from a rapid sand filter at a waterworks. PMID- 29136519 TI - Monitoring of uranium concentrations in water samples collected near potentially hazardous objects in North-West Tajikistan. AB - The water contamination near ecologically problematic objects was investigated between 2009 and 2014 in North-West Tajikistan as a part of a joint project between Forschungszentrum Julich and Khujand State University. The main part of this work was the determination of uranium in water samples collected near the Degmay tailings dump, the Taboshar pit lake and the Syr Darya river. More than 130 water samples were collected and analyzed to monitor the uranium concentration near the investigated areas. Two different mass spectrometers and an ion chromatograph were used for element concentration measurements. Based on the results obtained, the uranium influence of the Degmay tailings on the rivers Khoja-Bakyrgan-Say and Syr Darya and surrounding water was not found. The uranium concentration in water samples was monitored for a lengthy period at seven locations Great differences in the uranium concentration in waters collected in 2010, 2011, 2012, 2013 for each location were not observed. Drinking water samples from the region of North-West Tajikistan were analyzed and compared with the World Health Organization's guidelines. Seven out of nine drinking water samples near Taboshar exceeded the WHO guideline value for uranium concentrations (30 MUg/L). The average uranium concentration of water samples from Syr Darya for the period from 2009 to 2014 was determined to be 20.1 (+/-5.2) MUg/L. The uranium contamination of the Syr Darya was determined from the western border to the eastern border and the results are shown in this paper. PMID- 29136520 TI - Characterization of myeloid cell populations in human testes collected after sex reassignment surgery. AB - The testis has been described in animal models as a site of immune privilege, which protects spermatids against tissue damage during inflammation. Myeloid cells, including macrophages and dendritic cells (DC), are defined as key players in the testicular immune privilege in animal models. However, their distribution and frequency in human testis remain poorly described. To overcome the challenges related to tissue sampling, we obtained testicular tissue from men under hormonal therapy who elected to have sex reassignment surgery (SRS). We examined the distribution of myeloid cell populations in tissue sections using immunohistofluorescence and evaluated their relative frequencies in fresh testicular cell suspensions compared with matched blood using multi-parametric flow cytometry. We identified 4.9% of CD45+ leucocytes in testicular cell suspensions, of which 0.4% were B cells, demonstrating a low level of blood contamination. Myeloid cells (Lin-HLA-DR+) were located in the testicular interstitium and represented a median of 23.4% of testicular leucocytes, displaying higher HLA-DR expression compared to their counterparts in blood (p=0.001). The frequency of testicular myeloid cells was not linked with the duration of hormonal therapy. Resident macrophages (CD14+CD163+) constituted the most frequent myeloid cell subset and expressed high levels of CD163. Elevated proportion of myeloid DC (CD14-CD11c+) contrasted with the paucity of plasmacytoid DC (CD14-CD123+) in testis. Myeloid-derived suppressor cells (Lin HLA-DR-CD33hiCD11bhi) were not detected in the testis while constituting 0.5% of blood leucocytes. For the first time, we characterized myeloid cell subsets in human testes collected after SRS, providing a basis to assess their contribution to immune privilege. PMID- 29136521 TI - Toward dynamic urban environmental exposure assessments in mental health research. AB - It is increasingly recognized that mental disorders are affected by both personal characteristics and environmental exposures. The built, natural, and social environments can either contribute to or buffer against metal disorders. Environmental exposure assessments related to mental health typically rely on neighborhoods within which people currently live. In this article, I call into question such neighborhood-based exposure assessments at one point in time, because human life unfolds over space and across time. To circumvent inappropriate exposure assessments and to better grasp the etiologies of mental disease, I argue that people are exposed to multiple health-supporting and harmful exposures not only during their daily lives, but also over the course of their lives. This article aims to lay a theoretical foundation elucidating the impact of dynamic environmental exposures on mental health outcomes. I examine, first, the possibilities and challenges for mental health research to integrate people's environmental exposures along their daily paths and, second, how exposures over people's residential history might affect mental health later in life. To push the borders of scientific inquiries, I stress that only such mobility-based approaches facilitate an exploration of exposure duration, exposure sequences, and exposure accumulation. PMID- 29136522 TI - Ternary composite of TiO2 nanotubes/Ti plates modified by g-C3N4 and SnO2 with enhanced photocatalytic activity for enhancing antibacterial and photocatalytic activity. AB - A series of g-C3N4-SnO2/TiO2 nanotubes/Ti plates were fabricated via simple dipping of TiO2 nanotubes/Ti in a solution containing SnCl2 and g-C3N4 nanosheets and finally annealing of the plates. Synthesized plates were characterized by various techniques. The SEM analysis revealed that the g-C3N4-SnO2 nanosheets with high physical stability have been successfully deposited onto the surface of TiO2 nanotubes/Ti plate. Photocatalytic activity was investigated using two probe chemical reactions: oxidative decomposition of acetic acid and oxidation of 2 propanol under irradiation. Antibacterial activities for Escherichia coli (E. coli) bacteria were also investigated in dark and under UV/Vis illuminations. Detailed characterization and results of photocatalytic and antibacterial activity tests revealed that semiconductor coupling significantly affected the photocatalyst properties synthesized and hence their photocatalytic and antibacterial activities. Modification of TiO2 nanotubes/Ti plates with g-C3N4 SnO2 deposits resulted in enhanced photocatalytic activities in both chemical and microbial systems. The g-C3N4-SnO2/TiO2 nanotubes/Ti plate exhibited the highest photocatalytic and antibacterial activity, probably due to the heterojunction between g-C3N4-SnO2 and TiO2 nanotubes/Ti in the ternary composite plate and thus lower electron/hole recombination rate. Based on the obtained results, a photocatalytic and an antibacterial mechanism for the degradation of E. coli bacteria and chemical pollutants over g-C3N4-SnO2/TiO2 nanotubes/Ti plate were proposed and discussed. PMID- 29136523 TI - The advantages of hypnosis intervention on breast cancer surgery and adjuvant therapy. AB - BACKGROUND: In oncology, hypnosis has been used for pain relief in metastatic patients but rarely for induction of anesthesia. MATERIAL AND METHOD: Between January 2010 and October 2015, 300 patients from our Breast Clinic (Cliniques universitaires Saint-Luc, Universite catholique de Louvain) were included in an observational, non-randomized study approved by our local ethics committee (ClinicalTrials.gov - NCT03003611). The hypothesis of our study was that hypnosis intervention could decrease side effects of breast surgery. 150 consecutive patients underwent breast surgery while on general anesthesia (group I), and 150 consecutive patients underwent the same surgical procedures while on hypnosis sedation (group II). After surgery, in each group, 32 patients received chemotherapy, radiotherapy was administered to 123 patients, and 115 patients received endocrine therapy. RESULTS: Duration of hospitalization was statistically significantly reduced in group II versus group I: 3 versus 4.1 days (p = 0.0000057) for all surgical procedures. The number of post-mastectomy lymph punctures was reduced in group II (1-3, median value n = 1.5) versus group I (2 5, median value n = 3.1) (p = 0.01), as was the quantity of lymph removed (103 ml versus 462.7 ml) (p = 0.0297) in the group of mastectomies. Anxiety scale was also statistically reduced in the postoperative period among the group of patients undergoing surgery while on hypnosis sedation (p = 0.0000000000000002). The incidence of asthenia during chemotherapy was statistically decreased (p = 0.01) in group II. In this group, there was a statistically non-significant trend towards a decrease in the incidence of nausea/vomiting (p = 0.1), and the frequency of radiodermitis (p = 0.002) and post-radiotherapy asthenia (p = 0.000000881) was also reduced. Finally, the incidence of hot flashes (p = 0.0000000000021), joint and muscle pain (p = 0.0000000000021) and asthenia while on endocrine therapy (p = 0.000000022) were statistically significantly decreased in group II. DISCUSSION: Hypnosis sedation exerts beneficial effects on nearly all modalities of breast cancer treatment. CONCLUSION: Benefits of hypnosis sedation on breast cancer treatment are very encouraging and further promote the concept of integrative oncology. PMID- 29136524 TI - Anticancer metal-N-heterocyclic carbene complexes of gold, platinum and palladium. AB - Transition metal compounds are a rich source for anticancer drug development. Judicious application of coordination ligands is a critical success factor in the design of effective anti-tumor compounds. N-heterocyclic carbenes (NHC) are stable ligands that have strong donor strengths in stabilizing metal ions and versatility in structural modifications to provide diverse scaffolds for biological molecular targeting. Remarkable advances have been achieved in the development of metal NHC complexes as anticancer as well as theranostic agents. NHC complexes of gold, platinum and palladium have been designed to elicit potent cancer cell cytotoxicity, effective anti-tumor activities in animal models as well as selective binding to molecular targets (e.g. protein thiols, DNA G quadraplexes, mismatched DNA). The mechanisms of action of some of these complexes have been elucidated. PMID- 29136525 TI - Improving the carbonic anhydrase inhibition profile of the sulfamoylphenyl pharmacophore by attachment of carbohydrate moieties. AB - One of the most successful approaches for designing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was denominated 'the sugar approach'. The sugar approach consists in attaching different carbohydrates to CA inhibiting pharmacophores for modulating the physicochemical properties of these pharmacological agents. In line with this approach, in this paper, we present a new class of C-glycosides incorporating the sulfamoylphenyl moiety. These compounds have been prepared by sulfamoylation of C-glycosyl phenols, which have been synthetized by aldol reaction of glycosyl ketones with the appropriate aromatic aldehydes. The inhibition profile of the new glycomimetics was determined against four human (h) CA isozymes, comprising hCAs I and II (cytosolic, ubiquitous isozymes), hCA IV and hCA IX (tumor associated isozyme). Peracetylated and deprotected C-glycosyl sulfamates showed better inhibition selectivity compared to structurally related phenylsulfamates. In this study, deprotected compound 12 was identified as selective inhibitor of hCA IX. These results confirm that attaching carbohydrate moieties to CA sulfamoylphenyl pharmacophore improves its inhibitory activity. PMID- 29136526 TI - Upbeat nystagmus is a useful sign in the regional diagnosis of trigeminal nerve disorder with multiple sclerosis. AB - Trigeminal nerve disorder is an important neurological sign that is often seen with multiple sclerosis (MS). We investigated eye movements in three MS patients with trigeminal disorder due to pontine lesions near the trigeminal root entry zone (REZ). Upbeat nystagmus was observed in all MS patients with trigeminal REZ lesions. We conjecture that trigeminal nerve disorder and upbeat nystagmus appeared due to simultaneous damage to both the trigeminal nerve and the vestibulo-ocular reflex pathway. If upbeat nystagmus appears in MS patients exhibiting a trigeminal nerve disorder, such as trigeminal neuralgia, and paralysis, pontine lesions near the trigeminal REZ should be considered. Upbeat nystagmus can be understood as a useful sign for the clinical regional diagnosis of trigeminal nerve disorder. PMID- 29136527 TI - Targeting splicing abnormalities in cancer. AB - Recently splicing has been recognized as a key pathway in cancer. Although aberrant splicing has been shown to be a consequence of mutations or the abnormal expression of splicing factors (trans-effect changes) or mutations in the splicing sequences (cis-effect mutations), the connections between aberrant splicing and cancer initiation or progression are still not well understood. Here we review the mutational landscape of splicing factors in cancer and associated splicing consequences, along with the most important examples of the therapeutic approaches targeting the spliceosome currently being investigated in oncology. PMID- 29136528 TI - Role of protein dynamics in transmembrane receptor signalling. AB - Cells are dependent on transmembrane receptors to communicate and transform chemical and physical signals into intracellular responses. Because receptors transport 'information', conformational changes and protein dynamics play a key mechanistic role. We here review examples where experiment and computation have been used to study receptor dynamics. Recent studies on three distinct classes of receptors (G-protein coupled receptors, ligand-gated ion-channels and single-pass receptors) are highlighted to show that conformational changes across a range of time-scales and length-scales are central to function. Because the receptors function in a heterogeneous environment and need to be able to switch between distinct functional states, they may be particularly sensitive to small perturbations that complicate studies linking dynamics to function. PMID- 29136529 TI - YAP-Dependent AXL Overexpression Mediates Resistance to EGFR Inhibitors in NSCLC. AB - The Yes-associated protein (YAP) is a transcriptional co-activator upregulating genes that promote cell growth and inhibit apoptosis. The main dysregulation of the Hippo pathway in tumors is due to YAP overexpression, promoting epithelial to mesenchymal transition, cell transformation, and increased metastatic ability. Moreover, it has recently been shown that YAP plays a role in sustaining resistance to targeted therapies as well. In our work, we evaluated the role of YAP in acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in lung cancer. In EGFR-addicted lung cancer cell lines (HCC4006 and HCC827) rendered resistant to several EGFR inhibitors, we observed that resistance was associated to YAP activation. Indeed, YAP silencing impaired the maintenance of resistance, while YAP overexpression decreased the responsiveness to EGFR inhibitors in sensitive parental cells. In our models, we identified the AXL tyrosine kinase receptor as the main YAP downstream effector responsible for sustaining YAP-driven resistance: in fact, AXL expression was YAP dependent, and pharmacological or genetic AXL inhibition restored the sensitivity of resistant cells to the anti-EGFR drugs. Notably, YAP overactivation and AXL overexpression were identified in a lung cancer patient upon acquisition of resistance to EGFR TKIs, highlighting the clinical relevance of our in vitro results. The reported data demonstrate that YAP and its downstream target AXL play a crucial role in resistance to EGFR TKIs and suggest that a combined inhibition of EGFR and the YAP/AXL axis could be a good therapeutic option in selected NSCLC patients. PMID- 29136530 TI - Microplastic particles cause intestinal damage and other adverse effects in zebrafish Danio rerio and nematode Caenorhabditis elegans. AB - Microplastics have been frequently detected in aquatic environments, and there are increasing concerns about potential effects on biota. In this study, zebrafish Danio rerio and nematode Caenorhabditis elegans were used as model organisms for microplastic exposure in freshwater pelagic (i.e. water column) and benthic (i.e. sediment) environments. We investigated the toxic effects of five common types of microplastics: polyamides (PA), polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) and polystyrene (PS) particles. Results showed no or low lethality in D. rerio after exposure for 10d at 0.001-10.0mgL-1 microplastics. The PA, PE, PP and/or PVC microplastics with ~70MUm size caused intestinal damage including cracking of villi and splitting of enterocytes. Exposure to 5.0mgm-2 microplastics for 2d significantly inhibited survival rates, body length and reproduction of C. elegans. Moreover, exposure to microplastics reduced calcium levels but increased expression of the glutathione S-transferase 4 enzyme in the intestine, which indicates intestinal damage and oxidative stress are major effects of microplastic exposure. Among 0.1, 1.0 and 5.0MUm sizes of fluorescently labeled PS, 1.0MUm particles caused the highest lethality, the maximum accumulation, the lowest Ca2+ level in the intestine and the highest expression of glutathione S-transferase 4 in nematodes. Taken together, these findings suggest that intestinal damage is a key effect of microplastics; and that the toxicity of microplastics is closely dependent on their size, rather than their composition. PMID- 29136531 TI - Long-term effects of contrasting tillage on soil organic carbon, nitrous oxide and ammonia emissions in a Mediterranean Vertisol under different crop sequences. AB - This 2-year study aimed to verify whether the continuous application of no tillage (NT) for over 20years, in comparison with conventional tillage (CT), affects nitrous oxide (N2O) and ammonia (NH3) emissions from a Vertisol and, if so, whether such an effect varies with crop sequence (continuous wheat, WW and wheat after faba bean, FW). To shed light on the mechanisms involved in determining N-gas emissions, soil bulk density, water filled pore space (WFPS), some carbon (C) and nitrogen (N) pools, denitrifying enzyme activity (DEA), and nitrous oxide reductase gene abundance (nosZ gene) were also assessed at 0-15 and 15-30cm soil depth. Tillage system had no significant effect on total NH3 emissions. On average, total N2O emissions were higher under NT (2.45kgN2O-Nha-1) than CT (1.72kgN2O-Nha-1), being the differences between the two tillage systems greater in FW than WW. The higher N2O emissions in NT treatments were ascribed to the increased bulk density, WFPS, and extractable organic C under NT compared to CT, all factors that generally promote the production of N2O. Moreover, compared to CT, NT enhanced the potential DEA (114 vs 16MUgNkg-1h-1) and nosZ gene abundance (116 vs 69 copy number mg-1 dry soil) in the topsoil. Finally, NT compared to CT led to an average annual increase in C stock of 0.70MgCha-1year-1. Though NT can increase the amount os soil organic matter so storing CO2 into soil, some criticisms related to the increase of N2O emission arise, thereby suggesting the need for defining management strategies to mitigate such a negative effect. PMID- 29136532 TI - Spatial and temporal distribution of rainfall and drought characteristics across the Pearl River basin. AB - Understanding rainfall trends as well as drought characteristics plays a key role in watershed development and management. In this study, the spatial and temporal characteristics of rainfall and drought based on temperature and precipitation data observed in 48 meteorological stations from 1959 to 2012 across the Pearl River Basin in China were analyzed. The possible influence of El Nino-Southern Oscillation (ENSO) and El Nino Modoki (ENSO_M) events on seasonal drought based on the Standardized Precipitation-evapotranspiration Index (SPEI) were also investigated. The results show that annual and seasonal rainfall decreased slightly in most areas, annual and seasonal daily precipitation concentration decreased in a few areas, monthly rainfall had an irregular distribution but with no significant trend detected, and rainfall seasonality increased in most areas. Drought tended to worsen during recent years, especially in the upper reaches, and seasonal drought also tended to become serious or occurred frequently across the Pearl River Basin. The drought patterns are not only related to the decreasing trends in rainfall but also to changes in the daily rainfall concentration, monthly rainfall heterogeneity, and rainfall seasonality. Both ENSO and ENSO_M events had an influence on summer drought in the middle-upper reaches. The ENSO events dominated the patterns of autumn drought in the Pearl River Delta, and the ENSO_M events strongly affected the changing patterns of autumn drought in the middle-upper reaches and northern parts of the middle-lower reaches. PMID- 29136533 TI - Removal of phosphate from water by amine-functionalized copper ferrite chelated with La(III). AB - Eutrophication has become a worldwide environmental problem and removing phosphorus from water/wastewater before discharge is essential. The purpose of our present study was to develop an efficient material in terms of both phosphate adsorption capacity and magnetic separability. To this end, we first compared the performances of four spinel ferrites, including magnesium, zinc, nickel and copper ferrites. Then we developed a copper ferrite-based novel magnetic adsorbent, by synthesizing 1,6-hexamethylenediamine-functionalized copper ferrite(CuFe2O4) via a single solvothermal synthesis process followed by LaCl3 treatment. The materials were characterized with X-ray diffraction, transmission electron microscope, vibrating sample magnetometer, Fourier transform infrared spectra and N2 adsorption-desorption. The maximum adsorption capacity of our material, calculated from the Langmuir adsorption isotherm model, attained 32.59mg/g with a saturation magnetization of 31.32emu/g. Data of adsorption kinetics were fitted well to the psuedo-second-order model. Effects of solution pH and coexisting anions (Cl-, NO3-, SO42-) on phosphate adsorption were also investigated, showing that our material had good selectivity for phosphate. But OH- competed efficiently with phosphate for adsorption sites. Furthermore, increasing both NaOH concentration and temperature resulted in an enhancement of desorption efficiency. Thus NaOH solution could be used to desorb phosphate adsorbed on the material for reuse, by adopting a high NaOH concentration and/or a high temperature. PMID- 29136534 TI - Investigating the potential impact of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) on gene biomarker expression and global DNA methylation in loggerhead sea turtles (Caretta caretta) from the Adriatic Sea. AB - Polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) are priority contaminants that bioaccumulate through the food webs and affect the biology of a variety of resident and migratory species, including sea turtles. Few studies have evaluated toxicological biomarkers of exposure to PAHs and PCBs in these animals. The present paper reports the results of an initial field study to quantify the association between plasma concentrations of PAHs/PCBs and whole blood cell expression of gene biomarkers in juvenile loggerhead sea turtles (Caretta caretta) rescued along the Italian coasts of the northern and central areas of the Adriatic Sea. While detectable levels of PAHs were found in all plasma samples examined, only three PCB congeners (PCB52, PCB95, and PCB149) were noted, with detection percentages ranging between 48% and 57%. A significant correlation was found between 3 of the 6 gene biomarkers assessed (HSP60, CYP1A and ERalpha) and plasma levels of some PAH congeners. In contrast, no significant association between PCB burden and gene expression was observed. The global DNA methylation levels were significantly and positively correlated with the concentrations of most of the PAHs and only one of the PCB congeners (PCB52). The relation between PAH concentration and gene expression in whole blood cells suggests that these genes may respond to environmental contaminant exposure and are promising candidates for the development of biomarkers for monitoring sea turtle exposure to persistent organic pollutants (POPs). PMID- 29136535 TI - Urinary reference ranges and exposure profile for lithium among an Italian paediatric population. AB - The aims of the present study were to establish reference values useful in monitoring Lithium (Li) treatment and to trace environmental Li exposure profiles in paediatric age. A cross-sectional study was conducted on a group of healthy Italian children aged 5-11. Data on possible predictors were assessed through a questionnaire, and Li levels in morning and evening urinary samples were determined by ICP-MS technique. The reference intervals for the evening and morning samples were respectively 3.8-51.9MUgL-1 or 5.6-60.6MUgg-1 creatinine and 4.8-71.7MUgL-1 or 4.8-73.2MUgg-1 creatinine. Urinary Li levels showed a significantly inverse correlation with age and a positive correlation with urinary creatinine in both the evening and morning samples. No other studied variables influenced Li urinary excretion. These results, obtained using a readily available matrix as urine, can be useful for both environmental research and Li treatment monitoring. PMID- 29136536 TI - On the bright side of a forest pest-the metabolic potential of bark beetles' bacterial associates. AB - Bark beetles reproduce and overwinter under the bark of trees, and are associated with bacteria that may influence the fitness of their hosts. As regard the aim of this study was to test the metabolic potential of bacterial strains, isolated from the bark beetle species Cryphalus piceae, Ips typographus and Pityophthorus pityophthorus and collected in the Czech Republic from fir, spruce and pine trees, respectively, to degrade plant cell compounds. The bacterial strains were identified as belonging to the genera Curtobacterium, Erwinia, Pantoea, Pseudomonas, Rahnella, Staphylococcus, and Yersinia. Several activities related to the degradation of lignocellulosic materials, such as cellulose, xylan and starch, were found. Moreover, the genomes of three of these strains were sequenced and analyzed, and the presence of the enzymatic machinery required for biomass hydrolysis was discovered. This finding supports the idea that bacteria aid in the provision of nutrients to the beetle from the hydrolysis of tree compounds, results that are relevant for studying the ecological implication of bacterial strains in the bark beetle life cycle. In addition, the activities found in association with the bacterial strains could be useful in biotechnological processes, such as the production of biofuels from biomass, colorant degradation, in the textile industry and for wastewater treatments. Furthermore, the gene sequences of the lignocellulolytic enzymes found within the genomes serve as a basis for future studies regarding the potential application of these bacteria, and their metabolic machinery, in processes such as biomass hydrolysis and bioremediation. PMID- 29136537 TI - New advances in understanding the host immune response to Pneumocystis. AB - Pneumocystis jirovecii causes clinical pneumonia in immunocompromised hosts. Despite this, the inability to cultivate this organism in vitro has likely hindered the field in ascertaining the true impact of Pneumocystis in human infection. However the recent release of the genome as well as in advances in understanding host genetics, and other risk factors for infection and robust experimental models of disease have shed new light on the impact of this fungal pathogen as to better define populations at risk. This review will highlight these recent advances as well as highlight future needed areas of research. PMID- 29136538 TI - The impact of core muscles training on the range of anterior pelvic tilt in subjects with increased stiffness of the hamstrings. AB - The aim of this study is to verify the hypotheses that muscular coordination training of the core region in subjects showing increased hamstring stiffness results in an increase in anterior pelvic tilt and that there is a correlation between hamstring stiffness and anterior pelvic tilt. The two-group, non-blinded experimental controlled trial with three repeated measurements of the dependent variables. The experimental group received muscular coordination training during a period of two weeks, control group - no training. Thirty generally healthy subjects (9 women) were randomly assigned to the two equal groups. Passive knee extension test (hamstring stiffness); the range of anterior pelvic tilt (as measured in neutral standing position and during forward bending of the trunk). A significant decrease in the level of hamstring stiffness was recorded in the experimental group accompanied by an increase in anterior pelvic tilt. No significant changes were observed in the control group. There was a significant, negative, and moderate correlation between hamstring stiffness and anterior pelvic tilt with forward bending of the trunk). PMID- 29136539 TI - An examination of lower limb asymmetry in ankle isometric force control. AB - While asymmetries have been observed between the dominant and non-dominant legs, it is unclear whether they have different abilities in isometric force control (IFC). The purpose of this study was to compare ankle IFC between the legs. IFC is important for stabilization rather than object manipulation, and people typically use their non-dominant leg for stabilization tasks. Additionally, studies suggested that a limb can better acquire a motor task when the control mechanism of the task is related to what the limb is specialized for. We hypothesized that the non-dominant leg would better (1) control ankle IFC with speed and accuracy, and (2) acquire an ankle IFC skill through direct learning and transfer of learning. Two participant groups practiced an IFC task using either their dominant or non-dominant ankle. In a virtual environment, subjects moved a cursor to hit 24 targets in a maze by adjusting the direction and magnitude of ankle isometric force with speed (measured by the time required to hit all targets or movement time) and accuracy (number of collisions to a maze wall). Both groups demonstrated similar movement time and accuracy between the dominant and non-dominant limbs before practicing the task. After practice, both groups showed improvement in both variables on both the practiced and non practiced sides (p < .01), but no between-group difference was detected in the degree of improvement on each side. The ability to control and acquire the IFC skill was similar between the legs, which did not support the brain is lateralized for ankle IFC. PMID- 29136540 TI - The application of in vitro surveillance data for antibacterial dose selection. AB - In vitro surveillance data, which provide key information to interpret the results of pharmacokinetic/pharmacodynamics (PK-PD) target attainment studies, are used to support dose selection decisions and recommendations for in vitro susceptibility testing criteria for antibacterial agents during drug development. Considerations for designing the in vitro surveillance database to support the development of antibacterial agents include the choice of pathogens to study, the sample size of isolate collections needed, and target patient populations from which clinical isolates should be collected. Post-approval, global in vitro surveillance data produced by reference quality antibacterial susceptibility tests together with PK-PD target attainment analyses provide the opportunity to evaluate approved and clinically used antibacterial dosing regimens. These data enable the optimal use of antibacterial agents in an environment in which we face changing and challenging bacterial pathogens. PMID- 29136541 TI - Impact of neonatal morbidity on the risk of developmental delay in late preterm infants. AB - BACKGROUND: Late preterm infants (LPI) have a higher risk of developmental delay (DD) than term-born infants. The association of perinatal complications with specific morbidity is not clear. AIM: (1) To compare the risk of DD at 4years of age between LPI who have presence or absence of any morbidity associated with the prematurity at birth, called complicated (cLPI) or uncomplicated (uLPI), and term born infants, (2) to determine maternal and perinatal factors associated with risk of DD, and (3) to analyze, in LPI, the association between perinatal morbidity and risk of DD. METHODS: A retrospective cohort study including 163 LPI - 47 cLPI and 116 uLPI - and 158 term-born infants (Terms) was conducted. Parents completed the Ages & Stages Questionnaires(r)3rd Spanish version (ASQ3). Risk of DD was defined as the presence of any ASQ3 domain scoring below the mean minus 2 SD. Association between risk of DD and maternal and perinatal factors was analysed using a multivariate logistic model. Incidence of risk of DD was analysed according to specific morbidity. RESULTS: Compared to Terms, cLPI have a higher risk of DD in the communication domain. Respiratory pathology was associated with a higher risk in the communication domain. Caesarean delivery was the only maternal perinatal risk factor for DD, especially in gross motor domain. CONCLUSIONS: At the age of 4years cLPI, especially those with respiratory morbidity, had a higher risk of communication delay. Caesarean delivery was the only perinatal risk factor associated with risk of DD. PMID- 29136542 TI - Cognition and behaviour in children with congenital abdominal wall defects. AB - AIM: To characterise neurodevelopment at age two years and cognition and behaviour at age five years in children born with abdominal wall defects (gastroschisis or exomphalos). STUDY DESIGN: Participants were treated as neonates for gastroschisis or exomphalos and invited for routine clinical follow up at ages two and five years. Thirty-nine two year-olds and 20 five year-olds with gastroschisis and 20 two year-olds and 10 five year-olds with exomphalos returned for age-appropriate assessments of development (two years) and intellectual functioning (IQ), executive function, and behavioural problems. Results were compared with normative data from the tests and published data from local term-born children. RESULTS: For both gastroschisis and exomphalos two year olds, neurodevelopment was in line with the test normative data, but below the level of local normative data for all domains (effect sizes from -0.4 to -1.4 standard deviations). At five years, children with gastroschisis performed similarly to the normative mean for IQ but had high rates of various executive functioning problems on parent report (18-41% compared with 7% expected from norms). There was also a tendency for increased frequency of internalising problems (33% compared with normative expectation of 16%). Five year-olds with exomphalos also performed similarly to the normative mean for IQ and had low rates of executive and behavioural problems. CONCLUSIONS: Survivors of gastroschisis and exomphalos may be at risk of poor neurodevelopment in toddlerhood, depending on the reference group, and children with gastroschisis may be particularly at risk for executive functioning difficulties despite an IQ within normal limits. PMID- 29136543 TI - Graduating student nurses' and student podiatrists' wound care competence - An integrative literature review. AB - The objective of this literature review is to describe graduating student nurses' and student podiatrists' wound care competence. This integrative literature review has been conducted with a systematic search process. Original studies were analysed by qualitative content analysis with the following stages: open coding, creating categories and abstraction. The literature search was conducted on May 2016 and reconducted on October 2016 using the Medline/Pubmed, CINAHL, Cochrane Library, Web of Science, Scopus and National Medic databases and 12 original studies were found. All the studies addressed graduating student nurses' wound care competence. According to original studies, graduating student nurses' wound care competence was inadequate. However, the students showed a positive attitude towards wound care. Subthemes of this literature review were: 1) Wound care knowledge, 2) Attitudes towards wound care, 3) Wound care preparedness and 4) Wound care education which created the main theme Graduating nurses' wound care competence. No studies were found about graduating student podiatrists' wound care competence. Graduating student nurses' wound care knowledge was deficient. Wound care education seemed to have a positive relation to students' wound care competence. The findings indicate that more information about graduating student nurses', and especially graduating podiatrists', wound care competence is needed. PMID- 29136544 TI - Variation of field enhancement factor near the emitter tip. AB - The field enhancement factor at the emitter tip and its variation in a close neighbourhood determines the emitter current in a Fowler-Nordheim like formulation. For an axially symmetric emitter with a smooth tip, it is shown that the variation can be accounted by a costheta~ factor in appropriately defined normalized co-ordinates. This is shown analytically for a hemiellipsoidal emitter and confirmed numerically for other emitter shapes with locally quadratic tips. PMID- 29136545 TI - Removal of tetracycline by Fe/Ni bimetallic nanoparticles in aqueous solution. AB - This study investigated the degradation of tetracycline (TC) by Fe/Ni bimetallic nanoparticles (Fe/Ni BNPs) and nanoscale zero-valent iron (NZVI) in aqueous solution. Results revealed that Fe/Ni BNPs showed much better performance than NZVI. The effects of pH (5, 7 and 9), initial TC concentration and competitive anions (NO3-, H2PO4-, SO42- and HCO3-) on the removal of TC by Fe/Ni BNPs were investigated. The results indicated that the removal of TC was higher under acidic conditions and the reaction reached equilibrium more quickly at lower initial TC concentrations. The presence of NO3- greatly hindered the removal of TC, while the other anions (i.e., H2PO4-, SO42- and HCO3-) exhibited less inhibition. The significant impact of NO3- was due to the fact that Fe/Ni BNPs could be consumed via redox reaction with NO3-. Total organic carbon (TOC) and liquid chromatography-mass spectrometry (LC-MS) analysis shed light on the removal mechanisms of TC by Fe/Ni BNPs. The decrease of TOC in solution and the appearance of intermediate products on the surface of Fe/Ni BNPs indicated that both adsorption and degradation were involved in the reaction process. Based on the results of LC-MS, the detailed pathway of TC degradation by Fe/Ni BNPs was proposed. PMID- 29136546 TI - Multi-component hybrid soft ionogels for photoluminescence tuning and sensing organic solvent vapors. AB - This paper tries to prepare soft ionogels through the carboxyl ion liquid (IM+Br ) as double chemical linker connecting both Bio-MOF-1 (Zn8(ad)4(BPDC)6O.2Me2NH2, BPDC=biphenyl-4,4'-dicarboxylate, Ad = adeninate) and lanthanide complexes. Among anionic Bio-MOF-1 interacts with IM+Br- through cation exchange (IM+) to form BMOF-IM and lanthanide ions are further introduced through the coordination to the carboxylic group of IM+ together with Phen (1,10-phenanthroline) as assistant ligand for Ln3+ (Ln = Eu, Tb or Eu/Tb). The resulting multi-component hybrid ionogels (Phen-Ln-IM@BMOF) are prepared and characterized by PXRD, FTIR, TGA and mechanical properties by compression experiment, respectively. The photophysical properties of these hybrid systems are studied in details. By controlling the composition of different Ln3+ cations in IM@BMOF, the luminescent color of them can be tuned and the white light output can be realized. Furthermore, with careful adjustment of the excitation wavelength, the color of the luminescence can be modulated. Eventually we obtain luminescence trichromatic (Phen-Eu/Tb IM@BMOF) white-light-emitting materials. Moreover, we try to choose Phen-Eu IM@BMOF hybrid system for the detection of organic volatile substances, which shows the apparent luminescence quenching effect on ammonia for high sensitivity of sensing. PMID- 29136547 TI - Natural products used as a chemical library for protein-protein interaction targeted drug discovery. AB - Protein-protein interactions (PPIs), which are essential for cellular processes, have been recognized as attractive therapeutic targets. Therefore, the construction of a PPI-focused chemical library is an inevitable necessity for future drug discovery. Natural products have been used as traditional medicines to treat human diseases for millennia; in addition, their molecular scaffolds have been used in diverse approved drugs and drug candidates. The recent discovery of the ability of natural products to inhibit PPIs led us to use natural products as a chemical library for PPI-targeted drug discovery. In this study, we collected natural products (NPDB) from non-commercial and in-house databases to analyze their similarities to small-molecule PPI inhibitors (iPPIs) and FDA-approved drugs by using eight molecular descriptors. Then, we evaluated the distribution of NPDB and iPPIs in the chemical space, represented by the molecular fingerprint and molecular scaffolds, to identify the promising scaffolds, which could interfere with PPIs. To investigate the ability of natural products to inhibit PPI targets, molecular docking was used. Then, we predicted a set of high-potency natural products by using the iPPI-likeness score based on a docking score-weighted model. These selected natural products showed high binding affinities to the PPI target, namely XIAP, which were validated in an in vitro experiment. In addition, the natural products with novel scaffolds might provide a promising starting point for further medicinal chemistry developments. Overall, our study shows the potency of natural products in targeting PPIs, which might help in the design of a PPI-focused chemical library for future drug discovery. PMID- 29136548 TI - Wavelet coherence analysis: A new approach to distinguish organic and functional tremor types. AB - OBJECTIVE: To distinguish tremor subtypes using wavelet coherence analysis (WCA). WCA enables to detect variations in coherence and phase difference between two signals over time and might be especially useful in distinguishing functional from organic tremor. METHODS: In this pilot study, polymyography recordings were studied retrospectively of 26 Parkinsonian (PT), 26 functional (FT), 26 essential (ET), and 20 enhanced physiological (EPT) tremor patients. Per patient one segment of 20 s in duration, in which tremor was present continuously in the same posture, was selected. We studied several coherence and phase related parameters, and analysed all possible muscle combinations of the flexor and extensor muscles of the upper and fore arm. The area under the receiver operating characteristic curve (AUC-ROC) was applied to compare WCA and standard coherence analysis to distinguish tremor subtypes. RESULTS: The percentage of time with significant coherence (PTSC) and the number of periods without significant coherence (NOV) proved the most discriminative parameters. FT could be discriminated from organic (PT, ET, EPT) tremor by high NOV (31.88 vs 21.58, 23.12 and 10.20 respectively) with an AUC-ROC of 0.809, while standard coherence analysis resulted in an AUC ROC of 0.552. CONCLUSIONS: EMG-EMG WCA analysis might provide additional variables to distinguish functional from organic tremor. SIGNIFICANCE: WCA might prove to be of additional value to discriminate between tremor types. PMID- 29136549 TI - The spectrum of Charcot-Marie-Tooth disease due to myelin protein zero: An electrodiagnostic, nerve ultrasound and histological study. AB - OBJECTIVE: Nerve ultrasound (US) data on myelin protein zero (MPZ)-related Charcot-Marie-Tooth disease (CMT) are lacking. To offer a comprehensive perspective on MPZ-related CMTs, we combined nerve US with clinics, electrodiagnosis and histopathology. METHODS: We recruited 36 patients (12 MPZ mutations), and correlated nerve US to clinical, electrodiagnostic measures, and sural nerve biopsy. RESULTS: According to motor nerve conduction velocity (MNCV) criteria, nine patients were categorized as "demyelinating" CMT1B, 17 as "axonal" CMT2I/J, and 10 as dominant "intermediate" CMTDID. Sural nerve biopsy showed hypertrophic de-remyelinating neuropathy with numerous complex onion bulbs in one patient, de-remyelinating neuropathy with scanty/absent onion bulbs in three, axonal neuropathy in two, mixed demyelinating-axonal neuropathy in five. Electrodiagnosis significantly differed in CMT1B vs. CMT2I/J and CMTDID subgroups. CMT1B had slightly enlarged nerve cross sectional area (CSA) especially at proximal upper-limb (UL) sites. CSA was negatively correlated to UL MNCV and not increased at entrapment sites. Major sural nerve pathological patterns were uncorrelated to UL nerve US and MNCV. CONCLUSIONS: Sural nerve biopsy confirmed the wide pathological spectrum of MPZ-CMT. UL nerve US identified two major patterns corresponding to the CMT1B and CMT2I/J-CMTDID subgroups. SIGNIFICANCE: Nerve US phenotype of MPZ-CMT diverged from those in other demyelinating peripheral neuropathies and may have diagnostic value. PMID- 29136550 TI - Cerebellar transcranial direct current stimulation improves adaptive postural control. AB - OBJECTIVE: Rehabilitation interventions contribute to recovery of impaired postural control, but it remains a priority to optimize their effectiveness. A promising strategy may involve transcranial direct current stimulation (tDCS) of brain areas involved in fine-tuning of motor adaptation. This study explored the effects of cerebellar tDCS (ctDCS) on postural recovery from disturbance by Achilles tendon vibration. METHODS: Twenty-eight healthy volunteers participated in this sham-ctDCS controlled study. Standing blindfolded on a force platform, four trials were completed: 60 s quiet standing followed by 20 min active (anodal tDCS, 1 mA, 20 min, N = 14) or sham-ctDCS (40 s, N = 14) tDCS; three quiet standing trials with 15 s of Achilles tendon vibration and 25 s of postural recovery. Postural steadiness was quantified as displacement, standard deviation and path derived from the center of pressure (COP). RESULTS: Baseline demographics and quiet standing postural steadiness, and backwards displacement during vibration were comparable between groups. However, active-tDCS significantly improved postural steadiness during vibration and reduced forward displacement and variability in COP derivatives during recovery. CONCLUSIONS: We demonstrate that ctDCS results in short-term improvement of postural adaptation in healthy individuals. SIGNIFICANCE: Future studies need to investigate if multisession ctDCS combined with training or rehabilitation interventions can induce prolonged improvement of postural balance. PMID- 29136551 TI - Efficient and relatively safe emulsification microextraction using a deep eutectic solvent for influential enrichment of trace main anti-depressant drugs from complicated samples. AB - In this research work, an efficient, facile, prompt, and relatively safe enrichment procedure, named as air agitated-emulsification microextraction based on a low density-deep eutectic solvent (AA-EME-LD-DES), was applied for the first time to separate trace amounts of the drugs escitalopram, desipramine, and imipramine from complex sample solutions. This bio-degradable and cheap choline chloride-based extracting agent was readily prepared by the easy blending process at the ambient temperature, resulting in a eutectic liquid mixture with distinct features. Also the subsequent usage of an effective proceeding of the current microextraction procedure without a vital requirement for a further purification was adopted as another impressive benefit. Investigation of the main parameters influencing the multivariate technique based on the central composite design (CCD) combined with the desirability function (DF) revealed that pH12.0, 200MUL of the extraction solvent, 430MUL of the emulsifier solvent, and 14 air agitation cycles led to maximum extraction efficiencies with the DF value close to 0.97. Under the optimal experimental conditions, the wide linear dynamic ranges (LDRs) of 10.0-5000, 15.0-8000, and 15.0-6000ngmL-1 for escitalopram, desipramine, and imipramine were accurately obtainable, respectively, with the determination coefficients (R2s) higher than 0.98 and the low limits of detection (LODs) of 3.0 4.5ngmL-1. The percent extraction recoveries and enrichment factors were found to be adequately quantitative in the spans of 42-68% and 25-40, respectively, possessing good relative standard deviations (%RSDs, n=3) in the range of 3.6 5.7%. Finally, accurate analyses at therapeutically low ranges for the human plasma sample and trace levels for the pharmaceutical wastewater sample were successfully obtained, certifying the appropriate pre-concentration and enrichment capabilities of the proposed microextraction approach. PMID- 29136552 TI - Development and validation of modified QuEChERS method coupled with LC-MS/MS for simultaneous determination of cymiazole, fipronil, coumaphos, fluvalinate, amitraz, and its metabolite in various types of honey and royal jelly. AB - Over the past few decades, honey products have been polluted by different contaminants, such as pesticides, which are widely applied in agriculture. In this work, a modified EN - quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction method was developed for the simultaneous quantification of pesticide residues, including cymiazole, fipronil, coumaphos, fluvalinate, amitraz, and its metabolite 2,4-dimethylaniline (2,4-DMA), in four types of honey (acacia, wild, chestnut, and manuka) and royal jelly. Samples were buffered with 0.2M dibasic sodium phosphate (pH 9), and subsequently, acetonitrile was employed as the extraction solvent. A combination of primary secondary amine (PSA) and C18 sorbents was used for purification prior to liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI+/MS-MS) analysis. The estimated linearity measured at six concentration levels presented good correlation coefficients (R2)>=0.99. The recovery, calculated from three different spiking levels, was 62.06-108.79% in honey and 67.58-106.34% in royal jelly, with an RSD<12% for all the tested compounds. The matrix effect was also evaluated, and most of the analytes presented signal enhancement. The limits of quantification (LOQ) ranged between 0.001 and 0.005mg/kg in various samples. These are considerably lower than the maximum residue limits (MRL) set by various regulatory authorities. A total of 43 market (domestic and imported) samples were assayed for method application. Among the tested samples, three samples were tested positive (i.e. detected and quantified) only for cymiazole residues. The residues in the rest of the samples were detected but not quantified. We concluded that the protocol developed in this work is simple and versatile for the routine quantification of cymiazole, 2,4-DMA, fipronil, coumaphos, amitraz, and fluvalinate in various types of honey and royal jelly. PMID- 29136553 TI - Determination of tropane alkaloids by heart cutting reversed phase - Strong cation exchange two dimensional liquid chromatography. AB - Current Chinese Pharmacopoeia (ChP) standards apply liquid extraction combined with one dimensional liquid chromatography (1DLC) method for determining alkaloids in herbal medicines. The complex pretreatments lead to a low analytical efficiency and possible component loss. In this study, a heart cutting reversed phase - strong cation exchange two dimensional liquid chromatography (RP - SCX 2DLC) approach was optimized for simultaneously quantifying tropane alkaloids (anisodine, scopolamine and hyoscyamine) in herbal medicines and herbal medicine tablets without further treatment of the filtered extract. The chromatographic conditions were systematically optimized in terms of column type, mobile phase composition and flow rate. To improve peak capacity and obtain symmetric peak shape of alkaloids, a polar group embedded C18 column combined with chaotropic salts was used in the first dimension. To remove the disturbance of non alkaloids, achieve unique selectivity and acquire symmetric peak shape of alkaloids, an SCX column combined with phosphate buffer was used in the second dimension. Method validation was performed in terms of linearity, precision (0.54 0.82%), recovery (94.1-105.2%), limit of detection (LOD) and limit of quantification (LOQ) of the three analytes varied between 0.067-0.115mgL-1 and 0.195-0.268mgL-1, respectively. The method demonstrated superiority over 1DLC method in respect of resolution (less alkaloid co-eluted), sample preparation (no pretreatment procedure) and transfer rate (minimum component loss). The optimized RP - SCX 2DLC approach was subsequently applied to quantify target alkaloids in five herbal medicines and herbal medicine tablets from three different manufactures. The results demonstrated that the developed heart cutting RP - SCX 2DLC approach represented a new, strategically significant methodology for the quality evaluation of tropane alkaloid in related herbal medicines that involve complex chemical matrix. PMID- 29136554 TI - Separation and purification of four phenolic compounds from persimmon by high speed counter-current chromatography. AB - An efficient method was established by high-speed counter-current chromatography (HSCCC) for preparation of four phenolic compounds from the depolymerization products of persimmon tannin. Using the two solvent systems of n-hexane/ethyl acetate/water (3:17:20, v/v/v) and ethyl acetate/methanol/water (50:1:50, v/v/v), the preparative isolation was successfully performed by a two-step separation. The yields of one run (150mg crude sample) for gallic acid, methyl gallate, and epigallocatechin-3-gallate-(4beta->8, 2beta->O->7)-epigallocatechin-3-gallate dimer (A-type EGCG dimer) were 4.7, 44.2 and 5.9mg, respectively. In addition, 4.6mg epicatechin-3-gallate-(4beta->8, 2beta->O->7)-epicatechin-3-gallate dimer (A-type ECG dimer) was obtained by further preparative high-performance liquid chromatography (prep-HPLC). The purities of these compounds were all above 95.0% and their structures were identified by HPLC/ESI-MS. We found that HSCCC had definite advantages for the preparation of dimeric procyanidins compared with previous methods. Furthermore, it was shown that the four phenolic compounds possessed greater antioxidant activities than Trolox. PMID- 29136555 TI - Non-targeted metabolomics-guided sildenafil metabolism study in human liver microsomes. AB - Metabolomics combined with high-resolution mass spectrometry (HR-MS) and multivariate data analysis has broad applications in the study of xenobiotic metabolism. Although information about xenobiotic metabolism is essential to understand toxic mechanisms, pharmacokinetic parameters and excretion pathways, it is limited to predict all generated metabolites in biological fluids. Here, we revisited sildenafil metabolism in human liver microsomes using a metabolomics approach to achieve a global picture of sildenafil phase 1 metabolism. Finally, 12 phase 1 metabolites were identified in human liver microsomes; M1-M5 were previously known metabolites. The chemical structures of the novel metabolites were elucidated by MS2 fragmentation using an HR-MS system as follows: M6, reduced sildenafil; M7, N,N-deethylation and mono-oxidation; M8, demethanamine, N,N-deethylation and mono-hydroxylation; M9, demethanamine and N,N-deethylation; M10 and M11, mono-oxidation in the piperazine ring after N-demethylation; and M12, mono-oxidation. All metabolites, except M1, were formed by CYP3A4 and CYP3A5. In conclusion, we successfully updated the metabolic pathway of sildenafil in human liver, including 7 novel metabolites using metabolomics combined with HR-MS and multivariate data analysis. PMID- 29136556 TI - Industry interests in gambling research: Lessons learned from other forms of hazardous consumption. AB - Research indicates that the evidential bases for many harm reduction policies targeting hazardous consumptions (including tobacco, alcohol and gambling) have been distorted by commercial industries that derive revenue from such commodities. These distortions are best illustrated by research on tobacco and alcohol, which indicates similar tactics used by industries to determine favourable policy environments through engineering of evidence, among other approaches. Although there is concern that gambling research is similarly vulnerable to commercial interests, the relevant literature lags far behind other fields and the aim of this paper is to increase familiarity with tactics used by industries for influencing research. It summarises the conceptual and empirical bases for expecting conflicts between goals of public health and companies that profit from hazardous consumptions. It also summarises evidence describing practices deployed by tobacco corporations, which include third-party techniques and the selective funding of research to manufacture doubt and deflect attention away from the consequences of smoking. It then reviews both early and emerging evidence indicating similar strategies used by alcohol industry, and uses this literature to view practices of the gambling industry. It argues that parallels regarding selective funding of research and third-party techniques provide grounds for strong concern about commercial influences on gambling research, and implementation of precautionary approaches to management of vested interests. PMID- 29136557 TI - Biological-inorganic hybrid systems as a generalized platform for chemical production. AB - An expanding renewable energy market to supplant petrochemicals has motivated synthesis technologies that use renewable feedstocks, such as CO2. Hybrid biological-inorganic systems provide a sustainable, efficient, versatile, and inexpensive chemical synthesis platform. These systems comprise biocompatible electrodes that transduce electrical energy either directly or indirectly into bioavailable energy, such as H2 and NAD(P)H. In combination, specific bacteria use these energetic reducing equivalents to fix CO2 into multi-carbon organic compounds. As hybrid biological-inorganic technologies have developed, the focus has shifted from phenomenological and proof-of-concept discovery towards enhanced energy efficiency, production rate, product scope, and industrial robustness. In this review, we highlight the progress and the state-of-the-art of this field and describe the advantages and challenges involved in designing bio- and chemo- compatible systems. PMID- 29136558 TI - Autonomous vehicles' disengagements: Trends, triggers, and regulatory limitations. AB - Autonomous Vehicle (AV) technology is quickly becoming a reality on US roads. Testing on public roads is currently undergoing, with many AV makers located and testing in Silicon Valley, California. The California Department of Motor Vehicles (CA DMV) currently mandates that any vehicle tested on California public roads be retrofitted to account for a back-up human driver, and that data related to disengagements of the AV technology be publicly available. Disengagements data is analyzed in this work, given the safety-critical role of AV disengagements, which require the control of the vehicle to be handed back to the human driver in a safe and timely manner. This study provides a comprehensive overview of the fragmented data obtained from AV manufacturers testing on California public roads from 2014 to 2017. Trends of disengagement reporting, associated frequencies, average mileage driven before failure, and an analysis of triggers and contributory factors are here presented. The analysis of the disengagements data also highlights several shortcomings of the current regulations. The results presented thus constitute an important starting point for improvements on the current drafts of the testing and deployment regulations for autonomous vehicles on public roads. PMID- 29136559 TI - Determinants of pedestrian and bicyclist crash severity by party at fault in San Francisco, CA. AB - Pedestrian and bicyclist safety is of growing concern, especially given the increasing numbers of urban residents choosing to walk and bike. Sharing the roads with automobiles, these road users are particularly vulnerable. An intuitive conceptual model is proposed of the determinants of injury severity in crashes between vehicles and nonmotorized road users. Using 10 years of crash data from San Francisco, CA, we estimate logistic regression models to illuminate key determinants of crash severity for both pedestrian and bicyclist collisions. The analyses are separated by party at fault to test the novel hypothesis that environmental factors affecting driver speed and reaction time may be especially important when the driver is not at fault. Pedestrian results are broadly consistent with prior research, and offer considerable support for this hypothesis. The strongest predictors of injury severity include pedestrian advanced age, driver sobriety, vehicle type, and a set of variables that help determine driver speed and reaction time. Bicyclist results were weaker overall, and the distinction by party at fault was less important. PMID- 29136560 TI - Cytoprotective effects of glycyrrhetinic acid liposome against cyclophosphamide induced cystitis through inhibiting inflammatory stress. AB - This study was designed to investigate the pharmacological efficacy of glycyrrhetinic acid liposome (GAL) against female mice with nonbacterial cystitis induced by cyclophosphamide (CPS). Mice in different groups were subjected to tests for lactate dehydrogenase (LD), cytokine contents (IL-6, TNF-alpha) in serum, and histological changes in bladder tissue and to immunoassays. As a result, cyclophosphamide-induced cystitis in mice showed an increased LD level in serum, and the contents of cytokines (IL-6, TNF-alpha) were elevated. Interestingly, GAL-treated mice showed decreased LD and inflammatory cytokines of IL-6 and TNF-alpha in blood. Inflammatory infiltration and cell death in bladder tissue were reduced by GAL treatments. In addition, intravesical mRNAs of NF kappaB and TNF-alpha were lowered dose-dependently in GAL-treated mice. As shown in cytohistological staining, the number of intravesical caspase-3, PARP-positive cells decreased in GAL-treated mice. Furthermore, a GAL-treated bladder showed down-regulated NF-kappaB and TNF-alpha expressions in a dose-dependent manner. In conclusion, our current findings may be the first to provide scientific evidence demonstrating that glycyrrhetinic acid liposomes provide benefits against cyclophosphamide-induced cystitis, which possibly occurs through underlying mechanisms that inhibit cell death and inflammatory stress. PMID- 29136561 TI - Calibrated automated thrombogram values in infants with cardiac surgery before and after cardiopulmonary bypass. AB - INTRODUCTION: Impaired thrombin generation has been associated to increase bleeding after cardiac surgery with cardiopulmonary bypass (CPB), especially in children. The aim of this study was to evaluate standard coagulation assay, thrombin generation by calibrated automated thrombogram (CAT), thromboelastography (TEG) and procoagulant phospholipids (PPL) activity in infants undergoing cardiac surgery with CPB. MATERIALS AND METHODS: Prospective observational study performed in children aged <24months undergoing cardiac surgery with CPB. Exclusion criteria were preoperative coagulopathy or anticoagulant therapy. Coagulation was evaluated by standard coagulation assays (prothrombin time, activated partial thromboplastin time, fibrinogen level, platelet count), TEG, CAT and PPL at anaesthesia induction (T1) and after 12h (T2). Perioperative bleeding management was performed according to the institutional guidelines. RESULTS: Forty-nine children aged <24months were enrolled. At T1 ETP and peak height evaluated by CAT were significantly lower in infants aged <6months. Standard coagulation tests, TEG and PPL did not correlate with age. At T2 platelet count, plasmatic fibrinogen level, all TEG parameters, ETP and peak height by CAT were significantly impaired compared to baseline values (T1), despite allogeneic blood product transfusions. CONCLUSIONS: Thrombin generation is significantly impaired in children affected by congenital heart disease, compared to healthy children and adults. CAT parameters resulted age dependent, and thrombin generation is lower in infants aged <6months. After cardiac surgery with CPB, a coaugulopathy, revealed by CAT, TEG, but not by PT and aPTT assays, is persistent 12h after surgery despite transfusions of blood products. PMID- 29136562 TI - Warfarin resumption following anticoagulant-associated intracranial hemorrhage: A systematic review and meta-analysis. AB - BACKGROUND: This study aims to assess the effect of warfarin resumption in patients who experienced warfarin-associated intracranial hemorrhage (ICH). METHODS: We conducted a systematic review and meta-analysis of studies evaluating the outcomes of adult patients who survived warfarin-associated ICH. We included studies that compared patients who resumed warfarin versus those who did not. RESULTS: Of 3145 studies screened, ten observational studies were included in the final analysis. Death occurred in 181 of 968 patients (18.7%) who resumed warfarin and 834 of 2579 (32.3%) who did not resume warfarin (RR 0.51, 95% CI 0.34 to 0.76, P=0.0009). Ischemic stroke occurred in 32 of 902 (3.5%) patients who resumed warfarin and 172 of 2467 (7.0%) patients who did not resume warfarin (RR 0.56, 95% CI 0.39 to 0.82, P=0.002). Venous thromboembolism occurred in 4 of 224 (1.8%) patients who resumed warfarin and of 33 of 681 (4.8%) patients who did not resume warfarin (RR 0.39, 95% CI, 0.15 to 1.03, P=0.06). Recurrent ICH occurred in 200 of 2994 (6.7%) patients who resumed warfarin and 358 of 4652 (7.7%) patients who did not resume warfarin (RR 0.89, 95% CI 0.65 to 1.23, P=0.49). CONCLUSION: The study suggests that warfarin resumption is associated with significant reduction in ischemic stroke and venous thromboembolism when compared to no warfarin resumption in patients who experience warfarin-associated ICH. Although these results are strongly supportive of restarting anticoagulation, prospective studies are required to confirm our results due to the high likelihood of bias in the included studies. PMID- 29136563 TI - Generation of human iPSC line from a patient with laterality defects and associated congenital heart anomalies carrying a DAND5 missense alteration. AB - A human iPSC line was generated from exfoliated renal epithelial (ERE) cells of a patient affected with Congenital Heart Disease (CHD) and Laterality Defects carrying tshe variant p.R152H in the DAND5 gene. The transgene-free iPSCs were generated with the human OSKM transcription factor using the Sendai-virus reprogramming system. The established iPSC line had the specific heterozygous alteration, a stable karyotype, expressed pluripotency markers and generated embryoid bodies that can differentiate towards the three germ layers in vitro. This iPSC line offers a useful resource to study the molecular mechanisms of cardiomyocyte proliferation, as well as for drug testing. PMID- 29136564 TI - Frustration stress (unexpected loss of alternative reinforcement) increases opioid self-administration in a model of recovery. AB - PURPOSE: Engaging in alternative activities in the context where opioid use had occurred can constrain opioid use and helps to maintain recovery. However, "frustration stress" that occurs when contingencies on these alternative activities unexpectedly change (e.g., job loss or divorce) is thought to threaten recovery by prompting a return to drug use. Yet it remains unclear whether frustration stress can result in a return to drug use, and if so, whether it returns to prior levels or to even greater levels. PROCEDURES: We examine the impact of unsignaled extinction of alternative reinforcement on opioid use. Rats were trained to respond for an etonitazene solution (5MUg/ml, p.o.), then for food in alternating daily sessions. Subsequently, food and etonitazene were made concurrently available. Under concurrent availability conditions, rats were exposed to 1, 2, or 4 sessions of unsignaled food extinction, and effects on responding for etonitazene and food measured. FINDINGS: When etonitazene was the only reinforcer available, rats earned 58.3+/-20.3MUg/kg/session (mean+/-S.E.M.). When food was available in alternating sessions, etonitazene earned was unchanged (65.3+/-19.2MUg/kg/session). Concurrent food availability decreased etonitazene earned (13.5+/-4.5MUg/kg/session). Unsignaled food extinction returned etonitazene earnedto levels similar to (60.5+/-18.4MUg/kg/session), but not greater than, those observed previously when etonitazene alone was available. CONCLUSIONS: Unsignaled extinction of alternative behavior controlling opioid use can result in increased opioid use, but this use does not rise beyond previous levels observed when opioid use is unconstrained by alternative reinforced behavior. PMID- 29136565 TI - Attentional bias toward alcohol stimuli as a predictor of treatment retention in cocaine dependence and alcohol user patients. AB - BACKGROUND: Attentional bias towards substance-related stimuli has shown to be involved in the development and maintenance of cocaine dependence. The relationship between alcohol use and cocaine dependence shown in literature justify the need of study these two substances jointly. METHODS: This paper analyzes patterns of attentional bias in 71 patients with cocaine dependence and compares these patterns according to whether occasional or problematic concurrent alcohol use is taken into account. It also analyzes whether attentional bias towards alcohol and cocaine-related stimuli predicts treatment retention. Attentional bias was evaluated with a visual probe task between 15 and 20days after admission to treatment. Treatment status was recorded at a three-month follow-up. Severity of dependence and cocaine and alcohol craving were also measured. RESULTS: Results show that patients with cocaine dependence and problematic alcohol use show a pattern of approach towards alcohol stimuli (M=8.32, SD=27.01). In contrast, patients with cocaine dependence with occasional consumption of alcohol exhibit a pattern of avoidance of such stimuli (M=-7.23, SD=19.20) (t=2.79, p=0.007). Logistic regression indicates that alcohol attentional bias is the only variable with predictive capacity (OR=1.05, 95% CI=[1.01, 1.09]). It should also be noted that there is a pattern of avoidance of alcohol stimuli in patients who drop out of treatment. CONCLUSION: The results of this study suggest the need to delve into whether therapeutic strategies involving deeper emotional processing or avoidance strategies are more suitable for preventing relapse. PMID- 29136566 TI - Treatment for opioid use and outcomes in older adults: a systematic literature review. AB - BACKGROUND: Historically, issues relating to problem substance use among older people have received little attention, and have only recently been recognised. METHODS: A literature review of relevant material was conducted in November 2015 to assess current outcome research among older adults treated for opioid dependence. Multiple electronic databases were searched and results were supplemented by grey literature, library and online searches, and relevant references within selected articles. Retrieved articles were assessed for relevance against the inclusion and exclusion criteria. Results were reviewed to identify major findings and recommendations. RESULTS: A total of 76 titles were included in the review. Most research conducted on older adults involves alcohol and prescription medications. Older drug users are growing in number and have a unique profile, with many presenting for treatment for the first time aged 50-70 years. Findings reveal (1) opioid treatment numbers are decreasing, however the average age of treatment admissions is increasing, (2) there is no consensus on what old is (3) two distinct types of older opioid substance users exist (early/late onset), (4) older clients achieve better treatment outcomes than younger counterparts, and (5) older women achieve better treatment outcomes than men. CONCLUSIONS: Findings suggest that little is known about treatment outcomes among older people. Problematic drug use (of which opioids make up the largest proportion) had been incorrectly assumed to end as patients age. Defining an age limit for 'older' is important. Addiction and healthcare services must anticipate and prepare for increased demand by this group. PMID- 29136567 TI - Persistent organic pollutants in red- and white-blooded High-Antarctic notothenioid fish from the remote Weddell Sea. AB - It has been suggested that High-Antarctic waters, despite their remoteness from human activities, are impacted by anthropogenic pollution, and that the local biota are accumulating the contaminants. At present, no data exist on persistent organic pollutant (POP) body burdens for notothenioid fish inhabiting the High Antarctic Weddell Sea. We determined the pollutant load in white muscle tissue of red- and white-blooded notothenoids from the Weddell Sea (Trematomus loennbergii and Chionodraco hamatus, respectively), and compared them to our previous measurements of POPs in Low-Antarctic notothenioids. Analytes included various organochlorine pesticides (OCPs), polychlorinated biphenyls (indicator (i) PCBs, dioxine-like (dl) PCBs) and polybrominated diphenyl ethers (PBDEs). The analytical concentrations were converted into 2,3,7,8-TCDD toxic equivalents (TEQs). Compared to T. loennbergii, C. hamatus had lower levels of beta-HCH (0.45 vs. 4.5 ng g-1 lipid weight), and Sigma iPCBs (30 vs. 39 ng g-1 lipid weight), as well as lower levels of Sigma PBDEs (131 vs. 261 ng g-1 fresh weight). POP body burdens and TEQs were mostly similar to those of Low-Antarctic notothenioids analysed previously, and not related to the trophic positions of the species. The variations in POP levels between and within High- and Low-Antarctic notothenioids only marginally corresponded to sampling site, ecological differences or trophic levels of the species, and might rather be related to metabolism or age effects. The present findings suggest that fishes of High-Antarctic waters, although this area is more remote and less influenced by local human activities, do not show lower POP body burdens than fishes from Low-Antarctic waters. PMID- 29136568 TI - Derivation of aquatic predicted no-effect concentration (PNEC) for ibuprofen and sulfamethoxazole based on various toxicity endpoints and the associated risks. AB - For pharmaceuticals, the ecological risk assessment based on traditional endpoints of toxicity could not be properly protective in the long run since the mode of action could vary because they are intended for different therapeutic uses. In this study, the predicted no-effect concentrations (PNECs) of two selected pharmaceuticals, ibuprofen (IBU) and sulfamethoxazole (SMX), were derived based on either traditional endpoints of survival and growth data or some nonlethal endpoints such as reproduction, biochemical and molecular data. The PNECs of IBU based on biochemical-cellular and reproduction data were 0.018 and 0.026 MUg L-1 that were significantly lower than those derived from other endpoints, while the lowest PNEC for SMX derived from growth data with the concentration of 0.89 MUg L-1. Ecological risk assessment was performed for IBU and SMX to the aquatic environment by applying hazard quotient and probabilistic distribution based quotient (DBQs) methods. The results showed that the probability of DBQs of IBU exceeding 0.1 was 11.2%, while for SMX the probability was 0.9% that could be neglected. PMID- 29136569 TI - Unleaded gasoline as a significant source of Pb emissions in the Subarctic. AB - After the phasing out of leaded gasoline, Pb emissions to the atmosphere dramatically decreased, and other sources became more significant. The contribution of unleaded gasoline has not been sufficiently recognized; therefore, we evaluated the impact of Pb from unleaded gasoline in a relatively pristine area in Subarctic NE Norway. The influence of different endmembers (Ni slag and concentrate from the Nikel smelter in Russia, PM10 filters, and traffic) on the overall Pb emissions was determined using various environmental samples (snow, lichens, and topsoils) and Pb isotope tracing. We found a strong relationship between Pb in snow and the Ni smelter. However, lichen samples and most of the topsoils were contaminated by Pb originating from the current use of unleaded gasoline originating from Russia. Historical leaded and recent unleaded gasoline are fully distinguishable using Pb isotopes, as unleaded gasoline is characterized by a low radiogenic composition (206Pb/207Pb = 1.098 and 208Pb/206Pb = 2.060) and remains an unneglectable source of Pb in the region. PMID- 29136570 TI - Fabrication of g-C3N4 and a promising charcoal property towards enhanced chromium(VI) reduction and wastewater treatment under visible light. AB - The visible light driven photoactivity of g-C3N4 can be enhanced using charcoal as a supporter. Charcoal/g-C3N4 composite materials were prepared by the simultaneous thermal condensation of melamine and charcoal. The effect of different atmospheres (O2, air, and argon) on the reaction was investigated. The effect of different weight ratios of charcoal to melamine (1:1 and 1:4 wt%) was also investigated. The physical properties of the charcoal/g-C3N4 materials were analyzed using XRD, SEM, TEM, XPS, BET and FTIR techniques. It was found that an oxidation reaction of charcoal and g-C3N4 during preparation greatly affected the photoactivity. A composite of charcoal:melamine (1:4 wt%) prepared under an air atmosphere provided good photooxidation of methylene blue; whereas a composite of charcoal:melamine (1:4 wt%) prepared under an oxygen atmosphere exhibited good photoreduction of chromium (VI). PMID- 29136571 TI - Heavy metal remediation with Ficus microcarpa through transplantation and its environmental risks through field scale experiment. AB - The phytoremediation efficiency of various metals by Ficus microcarpa was evaluated through a real scale experiment in the present study. The root biomass production of the species varied significantly from 3.68 to 5.43 g because of the spatial heterogeneity of different metals. It would take 4-93 years to purify the excess Cd of the experimental site. Mercury was the most inflexible element which can barely be phytoremediated by F. microcarpa. After the species transplanted from the polluted soil to the clean site, Cd and Cu were transferred to the rhizosphere soil to different extent while the bulk soil was barely influenced. Relative to Cd and Cu, significantly fewer amounts of Pb and Hg were released. The highest concentrations of Cd, Cu, Hg and Pb in the clean soil were far below their corresponding safe thresholds for agricultural land after 3 months of the polluted plants were cultivated and metal concentrations of plant leaves were negligible, both indicated the low ecological risk of transplantation. Results from this study suggested a feasible disposal method for metal rich plants after phytoremediation. PMID- 29136572 TI - Multiple bioanalytical method to reveal developmental biological responses in zebrafish embryos exposed to triclocarban. AB - Triclocarban (TCC) is a well-known antibacterial agent that is frequently detected in environmental, wildlife and human samples. The potential toxicological effects and action mechanism of TCC on vertebrate development has remained unclear. In the present study, we analyzed phenotypic alterations, thyroid hormone levels, thyroid hormone responsive genes, and proteomic profiles of zebrafish embryos after exposure to a series of concentrations of TCC from 6 h post-fertilization (hpf) to 120 hpf. The most nonlethal concentration (MNLC), lethal concentration 10% (LC10) and lethal concentration 50% (LC50) of TCC for exposures of 96 h were 133.3 MUg/L, 147.5 MUg/L and 215.8 MUg/L, respectively. Our results showed that exposure to TCC decreased heart rate, delayed yolk absorption and swim bladder development at MNLC and LC10. Exposure to MNLC of TCC inhibited thyroid hormone and altered expression of thyroid hormone responsive genes. Furthermore, exposure to 1/20 MNLC of TCC altered expression of proteins related to binding and metabolism, skeletal muscle development and function, as well as proteins involved in nervous system development and immune response, indicating TCC has potential health risks in wildlife and humans at low concentration level. PMID- 29136573 TI - Engineered nickel oxide nanoparticles affect genome stability in Allium cepa (L.). AB - Indiscriminate uses of engineered nickel oxide nanoparticles (NiO-NPs) in heavy industries have ushered their introduction into the natural environment, ensuing novel interactions with biotic components of the ecosystem. Though much is known about the toxicity of NiO-NPs on animals, their phytotoxic potential is not well elucidated. NiO-NP hinders intra-cellular homeostasis by producing ROS in excess, having profound effect on the antioxidant profile of exposed animal and plant tissues. In the present study, bulbs of the model plant Allium cepa were treated with varying concentrations of NiO-NP (10 mg L-1 - 500 mg L-1) to study changes in ROS production and potential genotoxic effect. The data generated proved a concomitant upsurge in intracellular ROS accumulation with NiO-NP dosage that could be correlated with increased genotoxicity in A. cepa. Augmented in situ ROS production was revealed through DCFH-DA assay, with highest increase in fluorescence (70% over control) in bulbs exposed to 125 mg L-1 NiO-NP. Effect of NiO-NP on genomic DNA was studied through detailed analyses of RAPD profiles which allows detection of even slightest changes in DNA sequence of treated plants. Significant differences in band intensity, loss and appearance of bands as well as genomic template stability and band sharing indices of treated plants revealed increased vulnerability of genomic DNA to NiO-NP, at even lowest concentration (10 mg L-1). This is the first report of NiO-NP induced genotoxicity on A. cepa, which confirms the nanoparticle as a potent environmental hazard. PMID- 29136574 TI - Are we using the appropriate reference samples to develop juvenile age estimation methods based on bone size? An exploration of growth differences between average children and those who become victims of homicide. AB - The population on which forensic juvenile skeletal age estimation methods are applied has not been critically considered. Previous research suggests that child victims of homicide tend to be from socioeconomically disadvantaged contexts, and that these contexts impair linear growth. This study investigates whether juvenile skeletal remains examined by forensic anthropologists are short for age compared to their normal healthy peers. Cadaver lengths were obtained from records of autopsies of 1256 individuals, aged birth to eighteen years at death, conducted between 2000 and 2015 in Australia, New Zealand, and the U.S. Growth status of the forensic population, represented by homicide victims, and general population, represented by accident victims, were compared using height for age Z scores and independent sample t-tests. Cadaver lengths of the accident victims were compared to growth references using one sample t-tests to evaluate whether accident victims reflect the general population. Homicide victims are shorter for age than accident victims in samples from the U.S., but not in Australia and New Zealand. Accident victims are more representative of the general population in Australia and New Zealand. Different results in Australia and New Zealand as opposed to the U.S. may be linked to socioeconomic inequality. These results suggest that physical anthropologists should critically select reference samples when devising forensic juvenile skeletal age estimation methods. Children examined in forensic investigations may be short for age, and thus methods developed on normal healthy children may yield inaccurate results. A healthy reference population may not necessarily constitute an appropriate growth comparison for the forensic anthropology population. PMID- 29136575 TI - The correlation between concentrations of zolpidem and benzodiazepines in segmental hair samples and use patterns. AB - The aim of this study was to investigate the correlation between histories of zolpidem and benzodiazepines use and their concentrations in hair as determined by segmental hair analysis, that is, by analyzing hair samples taken 0-1, 1-2, 2 3, 3-4, 4-5, and 5-6cm etc. and 0-3cm from the scalp, and whole hair. Of the 23 hair samples examined, 18 were collected from patients in a rehabilitation program and five were from patients that had taken zolpidem only once by prescription. All 23 patients provided written informed consent after reviewing the research plan, described their zolpidem and benzodiazepines use histories accurately, and provided hair samples, which were weighed, washed, cut into lengths of <1mm, and extracted in 100% methanol for 16h (diazepam-d5 was used as an internal standard). Extracts were evaporated under reduced pressure and reconstituted with aqueous methanol (1:1 v/v). These extracts (10MUL) were analyzed by Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS). The method used was validated by determining LOD, LOQ, calibration curves, intra- and inter accuracies, precisions, matrix effects, process efficiencies, extraction efficiencies, and processed sample stabilities. Five hundred and ninety-five 1cm hair segments showed 61.59% positive probability and 86.71% negative probability of quality correlation between zolpidem and benzodiazepines use and concentrations in hair. Good qualitative correlations were observed between drug use and detection in hair. False positivity and false negativity were very low. Of the hair samples taken from patients in a rehabilitation program, subject nos. 4, 5, and 12 had correlation coefficients of 0.68, 0.54 and 0.71, respectively, for relationships between zolpidem use and concentration of zolpidem in hair. For the 5 patients taking only a single dose of zolpidem (10mg), the average zolpidem concentrations in hair were 20, 15 and 40pg/mg after 5, 30 and 60 days, respectively. This study shows a relationship between history of zolpidem and benzodiazepines use and their concentrations in 1cm hair segment. PMID- 29136576 TI - Influence of compost and biochar on microbial communities and the sorption/degradation of PAHs and NSO-substituted PAHs in contaminated soils. AB - Diffusely contaminated soils often remain untreated as classical remediation approaches would be disproportionately expensive. Adding compost can accelerate the biodegradation of organic contaminants and adding biochar can immobilize contaminants through sorption. The combined use of compost and biochar to reduce polycyclic aromatic hydrocarbon (PAH) and NSO-substituted PAH contamination has, however, not previously been systematically investigated. We have therefore investigated the processes involved (i) through sorption batch experiments, (ii) by monitoring changes in bacterial, fungal and archaeal communities using denaturing gradient gel electrophoresis, and (iii) through degradation experiments with fluorene, phenanthrene, pyrene, carbazole, dibenzothiophene, and dibenzofuran. Sorption coefficients for organic contaminants in soils increased tenfold following 10% compost addition and up to a hundredfold with further addition of 5% biochar. The rate of PAH and NSO-PAH degradation increased up to twofold following compost addition despite increased sorption, probably due to the introduction of additional microbial species into the autochthonous soil communities. In contrast, degradation of PAHs and NSO-PAHs in soil-compost biochar mixtures slowed down up to tenfold due to the additional sorption, although some degradation still occurred. The combined use of biochar and compost may therefore provide a strategy for immobilizing PAHs and NSO-PAHs and facilitating degradation of remaining accessible contaminant fractions. PMID- 29136577 TI - Atomic force microscopy study revealed velocity-dependence and nonlinearity of nanoscale poroelasticity of eukaryotic cells. AB - Intracellular network deformation of the cell plays an important role in cellular shape formation. Recent studies suggest that cell reshaping and deformation due to external forces involve cellular volume, pore size, elasticity, and intracellular filaments polymerization degree change. This cell behavior can be described by poroelastic models due to the porous structure of the cytoplasm. In this study, the nanoscale poroelasticity of human mammary basal/claudin low carcinoma cell (MDA-MB-231) was investigated using indentation-based atomic force microscopy. The effects of cell deformation (i.e., indentation) velocity and depth on the poroelasticity of MDA-MB-231 cells were studied. Specifically, the cell poroelastic behavior (i.e., the diffusion coefficient) was quantified at different indenting velocities (0.2, 2, 10, 20, 100, 200 MUm/s) and indentation depths (635, 965, and 1313nm) by fitting the force-relaxation curves using a poroelastic model. Cell treated with cytoskeleton inhibitors (latrunculin B, blebbistatin, and nocodazole) were measured to investigate the effect of the cytoskeletal components on the cell poroelasticity. It was found that in general the MDA-MB-231 cells behaved less poroelastic (i.e., with lower diffusion coefficient) at higher indenting velocities due to the local stiffening up and dramatic pore size reduction caused by faster force load, and the cytoplasm is nonlinear in terms of poroelasticity. The poroelastic relaxation was more pronounced when the local cytoplasm porous structure was stretched by higher indentation. Furthermore, inhibition of cytoskeletal components resulted in pronounced poroelastic relaxation when compared with the control, and affected the nonlinearity of cell poroelasticity at different depth range inside of the cell. The comparison between the diffusion coefficient variation and the Young's modulus change under each indentation/treatment condition suggested that the cytoplasm porous geometry is more dominant than the cell Young's modulus in terms of affecting cell poroelasticity. PMID- 29136578 TI - Deformation mechanisms of prototype composite braided stent-grafts in bending fatigue for peripheral artery application. AB - Stent-grafts in peripheral arteries suffer from complex cyclic loadings in vivo, including pulsatile, axial bending and torsion. Normal fatigue durability evaluation technologies, however, are majorly based on pulsation and thus are short of accuracy under the complicated stress conditions experienced physiologically. While there is a little research focused on the cyclic fatigue of stent-grafts in bending, it remains an almost total lack of deformation or fatigue mechanisms. In this work, composite braided stent-grafts incorporating Nitinol (NiTi) yarns and polyethylene terephthalate (PET) multifilament yarns were cycled in bending by the self-developed testing system to investigate their deformation behaviors. Deformation mechanisms at the yarn level were discussed, and NiTi yarn crossover structure was considered the primary factor affecting the deformation modes. Four yarn-crossover-based deformation modes (accordion buckling, diamond-shaped buckling, neck propagation and microbuckling) revealed the mechanisms of energy absorption of braided stent-grafts on the mesoscopic scale. Further, mechanical modes were applied to help regulate stent designs. PMID- 29136579 TI - The effectiveness and practicality of using simultaneous superglue & iodine fuming method for fingermark development on 'low yield' leather surfaces: A feasibility study. AB - This research successfully demonstrated the first use of simultaneous superglue & iodine fuming on leather surfaces compared to superglue, iodine, superglue-iodine and iodine-superglue fuming methods which typically give low fingermark yields. A novel fuming chamber was developed and used for simultaneous superglue & iodine fuming. Results show that the simultaneous fuming method produced significantly better enhancement for light-coloured leather substrates relative to other processing procedures, but was found to be ineffective on dark-coloured leather. However, superglue, as one of the most common methods in practice, was found to be effective for freshly deposited latent fingermarks on dark-coloured leather. The newly designed chamber for the simultaneous fuming method has proved to be fast, effective and delightfully easy to use. PMID- 29136580 TI - Advancing the large-scale CCS database for metabolomics and lipidomics at the machine-learning era. AB - Metabolomics and lipidomics aim to comprehensively measure the dynamic changes of all metabolites and lipids that are present in biological systems. The use of ion mobility-mass spectrometry (IM-MS) for metabolomics and lipidomics has facilitated the separation and the identification of metabolites and lipids in complex biological samples. The collision cross-section (CCS) value derived from IM-MS is a valuable physiochemical property for the unambiguous identification of metabolites and lipids. However, CCS values obtained from experimental measurement and computational modeling are limited available, which significantly restricts the application of IM-MS. In this review, we will discuss the recently developed machine-learning based prediction approach, which could efficiently generate precise CCS databases in a large scale. We will also highlight the applications of CCS databases to support metabolomics and lipidomics. PMID- 29136581 TI - Honokiol exerts dual effects on browning and apoptosis of adipocytes. AB - BACKGROUND: Induction of brown adipocyte-like phenotype (browning) in white adipocytes and promotion of apoptosis by dietary and pharmacological compounds is considered a novel strategy against obesity. Here, we show that honokiol exerts dual modulatory effects on adipocytes via induction of browning in 3T3-L1 white adipocytes and apoptosis as well as activation of HIB1B brown adipocytes combined with inhibition of apoptosis. METHODS: Honokiol-induced browning and apoptosis were investigated by determining expression levels of brown adipocyte-specific genes and proteins by RT-PCR and immunoblot analysis, respectively. Apoptotic data were validated by immunofluorescence and ROS levels were measured by FACS analysis. RESULTS: Honokiol treatment induced browning by elevating expression levels of brown adipocyte-specific genes such as Cidea, Cox8, Fgf21, Pgc-1alpha, and Ucp1. Honokiol promoted apoptosis of 3T3-L1 white adipocytes and inhibited apoptosis of HIB1B brown adipocytes via opposite regulation of the pro-apoptotic protein BAX and anti-apoptotic protein Bcl-2. Honokiol also significantly increased protein expression levels of ACOX1, CPT1, p-HSL, and p-PLIN and reduced ROS levels, suggesting its possible role in fat oxidation and lipid catabolism. Honokiol-induced browning could be mediated by activation of ERK, as inhibition of ERK by FR180204 abolished expression of PGC-1alpha and UCP1. CONCLUSION: Our findings suggest that honokiol exhibits a modulatory role in adipocytes via induction of browning and apoptosis in white adipocytes, promotion of catabolic lipid metabolism, as well as activation and inhibition of apoptosis in HIB1B brown adipocytes, thereby exhibiting therapeutic potential against obesity. PMID- 29136582 TI - Colorimetric detection of melamine in milk based on Triton X-100 modified gold nanoparticles and its paper-based application. AB - In this study, we have developed a method for rapid, highly efficient and selective detection of melamine. The negatively charged citrate ions form an electrostatic layer on gold nanoparticles (AuNPs) and keep the NPs dispersed and stable. When citrate-capped AuNPs were further modified with Triton X-100, it stabilized the AuNPs against the conditions of high ionic strength and a broad pH range. However, the addition of melamine caused the destabilization and aggregation of NPs. This may be attributed to the interaction between melamine and the AuNPs through the ligand exchange with citrate ions on the surface of AuNPs leading Triton X-100 to be removed. As a result, the AuNPs were unstable, resulting in the aggregation. The aggregation induced a wine red-to-blue color change, and a new absorption peak around 630nm appeared. Triton X-100-AuNPs could selectively detect melamine at the concentration as low as 5.1nM. This probe was successfully applied to detect melamine in milk. Furthermore, paper-based quantitative detection system using this colorimetric probe was also demonstrated by integrating with a smartphone. PMID- 29136583 TI - Heterocyclic Schiff bases as non toxic antioxidants: Solvent effect, structure activity relationship and mechanism of action. AB - Phenolic heterocyclic imine based Schiff bases from Thiophene-2-carboxaldehyde and Pyrrole-2-carboxaldehyde were synthesized and characterized as novel antioxidants. The solvent effects of these Schiff bases were determined and compared with standard antioxidants, BHA employing DPPH assay and ABTS assay. Fixed reaction time and Steady state measurement were used for study. IC50 and EC50 were calculated. Structure-activity relationship revealed that the electron donating group in the phenolic ring increases the activity where as the electron withdrawing moiety decreases the activity. The Schiff base derivatives showed antioxidant property by two different pathways namely SPLET and HAT mechanisms in DPPH assay. While in ABTS method, the reaction between ABTS radical and Schiff bases involves electron transfer followed by proton transfer (ET-PT) mechanism. The cytotoxicity of these compounds has been evaluated by MTT assay. The results showed that all these compounds are non toxic in nature. PMID- 29136584 TI - Unprecedented chemosensing behavior of novel tetra-substituted benzimidazole zinc(II) phthalocynine for selective detection of Bi3+ ion: Synthesis, characterization and ROS generation. AB - In this work, synthesis of novel symmetrical 4-(2-bromo-4-(5-bromo-1H-benzo[d] imidazol-2-yl) phenoxy) tetra substituted zinc phthalocyanine has been reported. The novel benzimidazole zinc phthlocynine compound (3) has been characterized by MALDI-TOF MS, FT-IR, UV-vis, and 1H NMR spectroscopy. This new compound 3 displayed excellent selectivity towards Bi3+ ion in the presence of other competitive ions including Ca2+, Cd2+, Co2+ Cu2+, Fe3+, Hg2+, Sn2+, Mg2+, Na+, Ni2+ and Pb2+ respectively. Upon addition of Bi3+ into the solution of compound 3 in DMSO, dramatic change was observed in the Q- and the B-bands in UV-visible spectra as a result of donor acceptor interactions. Reactive oxygen species (ROS) were also studied using 2,7-dichlorofluorescin diacetate (DCFH-DA) a fluorescent probe which is converted to highly fluorescent dichlorofluorescein (DCF) in the presence of ROS. This property of non-aggregating zinc phthalocyanine is promising as a photosensitizer in photodynamic therapy of cancer. PMID- 29136585 TI - White-emission in single-phase Ba2Gd2Si4O13:Ce3+,Eu2+,Sm3+ phosphor for white LEDs. AB - To develop new white-light-emitting phosphor, a series of Ce3+-Eu2+-Sm3+ doped Ba2Gd2Si4O13 (BGS) phosphors were prepared by the solid-state reaction method, and their photoluminescence properties were studied. The Ce3+ and Eu2+ single doped BGS show broad emission bands around in the region of 350-550 and 420 650nm, respectively. By co-doping Ce3+-Eu2+ into BGS, the energy transfer (ET) from Ce3+ to Eu2+ is inefficient, which could be due to the competitive absorption between the two activator ions. The Sm3+-activated BGS exhibits an orangey-red emission in the region of 550-750nm. To achieve white emission, the BGS:0.06Ce3+,0.04Eu2+,ySm3+ (0<=y<=0.18) phosphors were designed, in which the ET from Ce3+/Eu2+ to Sm3+ was observed. The emission color can be tuned by controlling the Sm3+ concentration, and white emission was obtained in the BGS:0.06Ce3+,0.04Eu2+,0.06Sm3+ sample. The investigation of thermal luminescence stability for the typical BGS:0.06Ce3+,0.04Eu2+,0.06Sm3+ sample reveals that the emission intensities of both Eu2+ and Sm3+ demonstrate continuous decrease but the Ce3+ emission is enhanced gradually with increasing temperature. The corresponding reason has been discussed. PMID- 29136586 TI - Generalised two-dimensional correlation analysis of the Co, Ce, and Pd mixed oxide catalytic systems for methane combustion using in situ infrared spectroscopy. AB - The process of methane combustion over the surface of a catalyst is still not fully understood. The identification of the reaction path and the intermediates created during catalysis is crucial for understanding the transformation of methane molecules. Two-dimensional (2D) correlation spectroscopy was engaged as a tool for the quantitative analysis of a series of temperature-dependent infrared spectra registered in situ during methane combustion. The prepared samples of catalysts were based on a Co, Pd and Ce mixed oxide adsorbed on an aluminium oxide layer deposited on kanthal steel. The registered spectra were transformed into 2D synchronous and asynchronous contour maps. The sequential order of spectral intensity changes was determined, and the resolution enhancement of overlapping IR bands by 2D correlation was demonstrated. The changes in the bands' intensity and information about band position can be correlated with a specific bond, and thus, the possible process intermediates can be identified. The 2DCoS analysis proved to be a powerful tool for band enhancement and revealed the changes occurring within the analysed catalyst systems as responses to increased temperature. PMID- 29136587 TI - Management of eosinophilic esophagitis and celiac disease. AB - Eosinophilic esophagitis (EoE) and celiac disease (CeD) are chronic immune mediated gastrointestinal disorders characterized by mucosal inflammation, both of which are related to food antigens, but with differences in clinical and histopathological features. When untreated, both diseases lead to destruction of the epithelium. While a strict gluten-free diet is the only effective therapy for CeD, several therapeutic options, such as proton pump inhibitors, topical steroids and diet elimination therapy are available for EoE. For EoE patients, all can be efficacious in achieving remission, but the looming question is whether all patients should be on maintenance therapy. New biologic therapies are being studied under study in both diseases, but none are ready for clinical use. PMID- 29136588 TI - A facile way to fabricate manganese phosphate self-assembled carbon networks as efficient electrochemical catalysts for real-time monitoring of superoxide anions released from HepG2 cells. AB - Quantification of superoxide anions (O2*-) is significant in the monitoring of many serious diseases and the design of enzyme-mimic catalysts plays the main role in the development of non-enzymatic O2*- sensors. Herein, we proposed a facile self-assembly process to synthesize manganese phosphate modified carbon networks using three kinds of widely-used carbon materials (MWCNTs, NGS and GO) as pillar connectors. Characterizations demonstrate that manganese phosphate is widely dispersed inside and on the surface of carbon networks without visible morphology. Meanwhile, all three kinds of synthesized catalysts were successfully immobilized on the screen-printed carbon electrodes to evaluate the electrochemical performance of fabricated sensors. The results indicate that sensors based on Mnx(PO4)y modified MWCNTs exhibit high sensitivity with an extremely low detection limit of 0.127MUM (S/N = 3) and a wide liner range of 0 1.817mM (R2 = 0.998). We further employed the recommended sensors in the real time monitoring of HepG2 cells released O2*- under the stimulating of Zymosan (20mg/mL). Noticeably, the proposed sensors exhibit not only sensitive response but also stable current steps upon different addition of Zymosan. The calculated concentrations of cell-released O2*- vary from 6.772 to 24.652pM cell-1 for the Zymosan amount used in this work. The established novel sensors display low background current and signal noises, thus holding unique advantages in the trace analysis of O2*- in biological samples and in vivo environment. PMID- 29136589 TI - Nucleic acid aptamer-based methods for diagnosis of infections. AB - Infectious diseases are a serious global problem, which not only take an enormous human toll but also incur tremendous economic losses. In combating infectious diseases, rapid and accurate diagnostic tests are required for pathogen identification at the point of care (POC). In this review, investigations of diagnostic strategies for infectious diseases that are based on aptamers, especially nucleic acid aptamers, oligonucleotides that have high affinities and specificities toward their targets, are described. Owing to their unique features including low cost of production, easy chemical modification, high chemical stability, reproducibility, and low levels of immunogenicity and toxicity, aptamers have been widely utilized as bio-recognition elements (bio-receptors) for the development of infection diagnostic systems. We discuss nucleic acid aptamer-based methods that have been developed for diagnosis of infections using a format that organizes discussion according to the target pathogenic analytes including toxins or proteins, whole cells and nucleic acids. Also included is, a summary of recent advances made in the sensitive detection of pathogenic bacteria utilizing the isothermal nucleic acid amplification method. Lastly, a nucleic acid aptamer-based POC system is described and future directions of studies in this area are discussed. PMID- 29136590 TI - Ultrasensitive electrochemical immunosensor for quantitative detection of HBeAg using Au@Pd/MoS2@MWCNTs nanocomposite as enzyme-mimetic labels. AB - A sensitive sandwich-type electrochemical immunosensor for the detection of hepatitis B e antigen (HBeAg) was successfully developed based on the gold@palladium nanoparticles (Au@Pd NPs) loaded by molybdenum disulfide functionalized multiwalled carbon nanotubes (Au@Pd/MoS2@MWCNTs). The resultant nanocomposites not only possessed high specific surface area and good biocompatibility, but also exhibited excellent electro-catalytical property. Au NPs functionalized porous graphene oxide (p-GO@Au) were used as sensing platforms and primary antibodies carriers, which can accelerate the electron transfer and improve the load capacity of primary antibodies (Ab1), improving the sensitivity of the immunosensor. Under optimal conditions, the designed immunosensor could detect target HBeAg concentration in the range from 0.1pg/mL to 500pg/mL, with a low detection limit of 26fg/mL (S/N = 3) for HBeAg. Additionally, the designed immunosensor showed excellent specificity, good reproducibility and acceptable stability. The satisfactory results in analysis of human serum samples indicated that it had potential application in clinical monitoring of tumor markers. PMID- 29136591 TI - Direct comparison of low- and mid-frequency Raman spectroscopy for quantitative solid-state pharmaceutical analysis. AB - This study considers the potential of low-frequency (terahertz) Raman spectroscopy in the quantitative analysis of ternary mixtures of solid-state forms. Direct comparison between low-frequency and mid-frequency spectral regions for quantitative analysis of crystal form mixtures, without confounding sampling and instrumental variations, is reported for the first time. Piroxicam was used as a model drug, and the low-frequency spectra of piroxicam forms beta, alpha2 and monohydrate are presented for the first time. These forms show clear spectral differences in both the low- and mid-frequency regions. Both spectral regions provided quantitative models suitable for predicting the mixture compositions using partial least squares regression (PLSR), but the low-frequency data gave better models, based on lower errors of prediction (2.7, 3.1 and 3.2% root-mean square errors of prediction [RMSEP] values for the beta, alpha2 and monohydrate forms, respectively) than the mid-frequency data (6.3, 5.4 and 4.8%, for the beta, alpha2 and monohydrate forms, respectively). The better performance of low frequency Raman analysis was attributed to larger spectral differences between the solid-state forms, combined with a higher signal-to-noise ratio. PMID- 29136592 TI - Human sirtuin 3 (SIRT3) deacetylates histone H3 lysine 56 to promote nonhomologous end joining repair. AB - Human sirtuin 3 (SIRT3) is a conserved NAD+ dependent deacetylase, which functions in important cellular processes including transcription, metabolism, oxidative stress response. It is a robust mitochondrial deacetylase; however, few studies have indicated its nuclear functions. Here we report interaction of SIRT3 with core histones and identified acetylated histone H3 lysine 56 (H3K56ac) as its novel substrate, in addition to known substrates acetylated H4K16 and H3K9. Further, we showed in response to DNA damage SIRT3 localizes to the repair foci colocalizing with gammaH2AX and nonhomologous end joining (NHEJ) marker p53 binding protein 1 (53BP1). However, it does not colocalize with homologous repair (HR) marker BRCA1. By ChIP break assay, we demonstrated the recruitment of SIRT3 at the double strand-break site in response to DNA damage. Additionally, the relocalization of SIRT3 to the nucleus on MMS treatment led to concurrent decrease in H3K56ac, which is an important step in NHEJ. Depletion of SIRT3 by si RNA mediated knock down affected recruitment of 53BP1, resulting in compromised NHEJ efficiency, and survival defect as seen by colony formation assay. Altogether, our results demonstrated that SIRT3 recruits 53BP1 to the site of damage thereby plays a significant role in NHEJ pathway. PMID- 29136593 TI - Polycyclic aromatic hydrocarbons and organochlorine pesticides in surface water from the Yongding River basin, China: Seasonal distribution, source apportionment, and potential risk assessment. AB - The presence of 17 polycyclic aromatic hydrocarbons (PAHs) and 15 persistent organochlorine pesticides (OCPs) in surface water of the Yongding River Basin was analyzed through GC/MS/MS during the spring and summer at 46 sampling sites. The goal was to investigate their seasonal distribution, possible sources, and potential risk. Our results showed that the total PAH concentration in surface water of Yongding River Basin ranged from 41.60 to 1482.60ng/L with a mean value of 137.85ng/L in the spring, and from 53.53 to 506.53ng/L with a mean value of 124.43ng/L in the summer. The total OCP concentration ranged from <0.08 to 197.71ng/L with a mean value of 7.69ng/L in the spring, and from <0.08 to 93.58ng/L with a mean value of 7.92ng/L in the summer. Moreover, the total PAH concentration was slightly lower in the spring than in the summer, whereas the total OCP concentration was similar between seasons. Source analysis indicated that combustion sources and petroleum sources both contributed to the presence of PAHs. Historical environmental residues and long range atmospheric transport were the major sources of HCH and DDT contamination. The concentrations of total PAHs and single PAHs including benz(a)anthracene, benzo(a)pyrene, benz(b)fluoranthene, and benz(k)fluoranthene in surface water at some sampling sites exceeded the water environmental quality standards of China and several other countries or organizations. This indicated a potential threat to human health from the consumption of aquatic organisms due to PAH bioaccumulation. The concentrations of alpha-HCH, p,p'-DDE, and p,p'-DDD at several sampling sites exceeded the limit for human health specified in the ambient water quality criteria developed by the US Environmental Protection Agency, which indicated that these pollutants provide potential hazards to the residents around the sampling sites. PMID- 29136594 TI - Quantitative assessment of human health risks induced by vehicle exhaust polycyclic aromatic hydrocarbons at Zhengzhou via multimedia fugacity models with cancer risk assessment. AB - Traffic-related pollution released a large amount of atmospheric polycyclic aromatic hydrocarbons (PAHs) which have severely influenced environmental safety and human health until now. However, the important issue of polycyclic aromatic hydrocarbon (PAH) emission from vehicle exhaust in urban populated areas has not been sufficiently investigated yet. This study focused on environmental behavior of vehicle exhaust PAHs (VEPAHs) and resultant health risk on local residents in urban populated areas. This study combined the multimedia fugacity models (Level III and Level IV) and the incremental lifetime cancer risk (ILCR) model, for analyzing the VEPAHs' environmental fate and related health risk on local residents in Zhengzhou of the central China. Regression models were applied to explore correlation between atmospheric concentration of VEPAHs and local pulmonary disease mortality rate. Our results demonstrate that the majority of VEPAH was sunk into the soil compartment in 2013, but the calculated BaP equivalent concentrations of total VEPAHs in the air compartment exceeded the annual average standard limit of China (1ng/m3) yet. The human exposure routes of VEPAHs caused cancer risk in the following order: inhalation>dermal contact>ingestion. PMID- 29136595 TI - Modeling the temporal dynamics of intertidal benthic infauna biomass with environmental factors: Impact assessment of land reclamation. AB - Anthropogenic activities such as land reclamation are threatening tidal marshes worldwide. This study's hypothesis is that land reclamation in a semi-enclosed bay alters the seasonal dynamics of intertidal benthic infauna, which is a key component in the tidal marsh ecosystem. Mai Po Tidal Marsh, Deep Bay, Pearl River Estuary, China was used as a case study to evaluate the hypothesis. Ecological models that simulate benthic biomass dynamics with governing environmental factors were developed, and various scenario experiments were conducted to evaluate the impact of reclamations. Environmental variables, selected from the areas of hydrodynamics, meteorology, and water quality based on correlation analysis, were used to generate Bayesian regression models for biomass prediction. The best-performing model, which considered average water age (i.e., a hydrodynamic indicator of estuarine circulation) in the previous month, salinity variation (i.e., standard deviation of salinity), and the total sunny period in the current month, captured well both seasonal and yearly trends in the benthic infauna observations from 2002 to 2008. This model was then used to simulate biomass dynamics with varying inputs of water age and salinity variation from coastal numerical models of different reclamation scenarios. The simulation results suggest that the reclamation in 2007 decreased the spatial and annual average benthic infauna biomass in the tidal marsh by 20%, which agreed with the 28% biomass decrease recorded by field survey. The range of biomass seasonal variation also decreased significantly from 2.1 to 230.5g/m2 (without any reclamation) to 1.2 to 131.1g/m2 (after the 2007 reclamation), which further demonstrates the substantial ecological impact of reclamation. The ecological model developed in this study could simulate seasonal biomass dynamics and evaluate the ecological impact of reclamation projects. It can therefore be applied to evaluate the ecological impact of coastal engineering projects for tidal marsh management, conservation, and restoration. PMID- 29136596 TI - Occurrence of organic UV filters and metabolites in lebranche mullet (Mugil liza) from Brazil. AB - UV filters (UV-Fs) constitute a heterogeneous group of chemicals used as protection against the effects of UV radiation, widely used in all sort of goods and ubiquitous in the environment. The presence of these chemicals in fish is a matter of concern, because many UV-Fs display hormonal activity. In this study, muscle, gills, and liver from 11 Mugil liza individuals from the highly urbanized Guanabara Bay (Rio de Janeiro, Brazil) were analysed in order to detect eight UV Fs and metabolites (4-dihydroxybenzophenone [BP1] (2-hydroxy-4 methoxybenzophenone [BP3], 4-methylbenzylidiene camphor [4MBC], ethylhexyl methoxycinnamate [EHMC], ethylhexyl dimethyl p-aminobenzoic acid [ODPABA], octocrylene [OC], 4-hydroxybenzophenone [4HB], and 4,4'-dihydroxybenzophenone [4DHB]) using liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Results showed that both target UV-Fs and metabolites were ubiquitous in the analysed tissues. Lower concentrations were observed in muscle and gills (3.07 31.6ngg-1 dry weight (dw)), whereas in liver significant amounts of metabolites (5.47-451ngg-1 dw) were present. With the concentrations determined in the fish, an estimation of the daily intake revealed that consumption of muscle in the diet represent from 0.3 to 15.2ng UV-Fs (kg body weight-1) d-1, higher than those reported in fish for selected persistent organic pollutants (POPs). PMID- 29136597 TI - Lead in Egyptian soils: Origin, reactivity and bioavailability measured by stable isotope dilution. AB - The current availability of Pb in Egyptian soils and associated plants were studied in 15 locations (n=159) that had been historically subjected to industrial and automobile Pb emissions. Isotopic dilution with enriched 204Pb was used to estimate the soil Pb labile pool (PbE); results showed that %PbE values were mostly <25% which is likely due to the alkaline nature of the soils. Nonetheless, lability of Pb was significantly higher in urban and industrial locations indicating greater reactivity of anthropogenic Pb in comparison to geogenic-Pb. A plot of 206Pb/207Pb vs 208Pb/207Pb showed that all soils were aligned close to a virtual binary line between two apparent end member signatures (petrol and geogenic-Pb) suggesting that they are the major sources of Pb in the Egyptian environment. Soils with greater Pb concentrations (urban and industrial locations) displayed a significantly greater ratio of labile petrol-Pb to labile geogenic-Pb in comparison to less-contaminated soils. However, this difference was marginal (+/-5%) suggesting that historically emitted petrol-Pb has substantially mixed with geogenic-Pb into a common pool as a result of prolonged contact with soil. The proportion of petrol-Pb in fruits and leaf vegetables was significantly (P<0.005) greater than that of the associated soils suggesting preferential uptake of the more labile petrol-Pb as opposed to the relatively immobile geogenic-Pb. However, it is also possible that the major source of Pb intake by Egyptian consumers is extraneous Pb dust enriched with petrol Pb rather than systematic Pb via roots uptake. PMID- 29136598 TI - Bacterial population and chemicals in bioaerosols from indoor environment: Sludge dewatering houses in nine municipal wastewater treatment plants. AB - Municipal wastewater treatment plants (MWTPs) are regarded as sources of airborne microorganisms. Sludge dewatering house (SDH) is one of the most serious indoor bioaerosol pollution treatment sectors in MWTPs. In this study, properties of bioaerosols from SDHs of nine MWTPs were investigated in China. Results suggested that bioaerosols were generated mainly from the mixed liquor and will be promoted by the mechanical motion of belts of dewatering devices. They will accumulate in the SDHs due to the treatment devices placed inside. Levels of airborne bacteria and chemicals showed regional variations. In Hefei and Yixing, the emissions of total suspended particles (TSP) and airborne bacteria were higher than those in Beijing and Guangzhou. Results of bacterial population showed that bacterial species in bioaerosols from SDHs also presented significant regional disparity; these regional disparities were closely related with the source of bioaerosols in SDHs. Among these identified bacterial species, some common potential pathogens were detected in all SDHs, such as Aeromonas caviae, Flavobacterium sp., and Staphylococcus lentus. Relative humidity (RH) and temperature were the major parameters on bioaerosols to survive. As shown in this study, SDHs in wastewater treatment plants should be provided considerable attention for being an emission source of indoor bioaerosols. PMID- 29136599 TI - The bioavailability of different dissolved organic nitrogen compounds for the freshwater algae Raphidocelis subcapitata. AB - Understanding which factors affect the algal bioavailability of dissolved organic nitrogen (DON) compounds in natural surface waters is important for our understanding of nutrient biogeochemistry and water quality management. We used nitrogen uptake kinetics and algal cell yield to characterize the algal bioavailability of 22 dissolved DON compounds that are commonly found in natural surface waters and wastewater treatment plant effluents, including urea, amino acids, amino sugars, nucleotides, pyrimidines, oraganonitriles, polyacrylamide, EDTA, caffeine, phenolic compounds and humic acids. Twelve of these compounds were highly bioavailable, including urea, dissolved free amino acids, bovine serum albumin, DNA, RNA, ATP, AMP, acetonitrile and caffeine. Four compounds had intermediate bioavailability including two humic acids (Elliott Soil and Pahokee Peat), glycylglycine, RNA and uracil. The remaining six compounds were classified as recalcitrant, i.e., EDTA, 2,3-Dinitrophenol, aminobenzoic acid, polyacrylamide and Aldrich humic acid. For many of the compounds tested, the algal cell yield was only 60-80% of expected relative to DON uptake. These results help explain why some DON compounds are more likely to persist in natural systems, and why the DON pool is often recalcitrant in surface waters. PMID- 29136600 TI - Effects of venlafaxine versus lithium monotherapy on quality of life in bipolar II major depressive disorder: Findings from a double-blind randomized controlled trial. AB - Bipolar disorder is associated with decreased quality of life, especially during depressive episodes. There are few studies that have examined whether quality of life improves following pharmacological treatments of bipolar depression. In this exploratory study, we examined the effects of antidepressant versus mood stabilizer monotherapy on quality of life ratings in bipolar II subjects during acute (12 week) treatment. Data were derived from a randomized double-blind comparison of venlafaxine (n = 65) versus lithium (n = 64) monotherapy. The Quality of Life Index (QLI) was administered at baseline (n = 126; 98%) and again at the end of treatment. We explored treatment differences in continuous changes on the QLI using last-observation carried forward. Additionally, we explored the likelihood of experiencing clinically-significant improvements as well as baseline correlates of QLI and changes in QLIe. Venlafaxine was superior to lithium in reducing symptoms of depression during acute treatment. However, there were no significant differences between treatments in QLI ratings. Changes in symptoms of depression were correlated to, but not redundant, with improvements in QLI ratings. These findings suggest that quality of life may be an important secondary outcome to target and measure as a part of comparative clinical trials of pharmacotherapy for bipolar II depression. PMID- 29136601 TI - No neuronal autoantibodies detected in plasma of patients with a bipolar I disorder. AB - A subpopulation of patients with bipolar disorder type I (BD-I) might suffer from undiagnosed autoimmune encephalitis. We tested plasma of 104 BD-I patients with a current or recent manic episode in the past 2 years for the presence of neuronal autoantibodies using immunohistochemistry, immunocytochemistry and cell-based assay (CBA). Neuronal antibodies were not detected in any of the BD type I. This finding suggests that the frequency of an undiagnosed autoimmune encephalitis in patients with BD I is less than 1%. However, these findings need to be confirmed in cerebrospinal fluid and/or blood of acutely ill manic patients. PMID- 29136602 TI - Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. AB - BACKGROUND: Depression and anxiety are two common mental health problems with high economic and social costs. Currently, a number of treatments are available for patients with depression and anxiety disorders such as psychotherapy, electroconvulsive therapy and antidepressant drugs. Due to safety concerns, adverse effects, limited efficacy and low tolerability associated with many antidepressant and anti-anxiety medications, identification of novel agents with less toxicity and more favorable outcome is warranted. METHODS: The current article provides a non-systematic review of the available in vitro, in vivo and clinical evidence on the efficacy, safety and mechanisms of action of saffron and its active ingredients in the treatment of anxiety, depression and other mental disorders. RESULTS: Several interesting data have been reported about the antidepressant and anti-anxiety properties of saffron, the dried stigmas of Crocus sativus L., in several preclinical and clinical studies. In particular, a number of clinical trials demonstrated that saffron and its active constituents possess antidepressant properties similar to those of current antidepressant medications such as fluoxetine, imipramine and citalopram, but with fewer reported side effects. CONCLUSION: Saffron may exert antidepressant effects and represents an efficacious and safe treatment. PMID- 29136603 TI - Prolonged grief reactions after old age spousal loss and centrality of the loss in post loss identity. AB - BACKGROUND: The loss of a spouse is a major life event. Previous research found that centrality of the loss to one's identity using Centrality of Event Scale (CES) is related to complicated bereavement reactions, such as depression, posttraumatic stress symptoms (PTS), and prolonged grief symptoms (PGS). This study aims to examine loss-centrality in elderly bereaved people up to 4 years post loss, to determine the relation of loss-centrality to complicated bereavement reactions, such as PGS, depression, and PTS, and to identify early predictors of loss-centrality. METHOD: Self-reported data were collected from 208 elderly bereaved people (mean age 72 years, 63.9% women), who completed measures of psychological distress (PTS, depression, PGS) as well as intra- and interpersonal factors (coping-style, crisis support, satisfaction with life, and NEO-PI-R) at 2, 6, and 48 months post spousal loss. CES was measured 48 months post spousal loss. RESULTS: In line with previous findings (Boelen, 2012a), loss centrality 4 years following the loss was significantly related to depression, PTS, and PGS. Additionally, early PGS and gender predicted later loss-centrality. LIMITATIONS: Self-repport data was used rather than clinical interviews. CES was only measured 48 months post loss. PGS was first measured 6 months post. CONCLUSIONS: The results support the link between loss-centrality and post loss psychopathology in a population particularly vulnerable to complicated bereavement reactions. The close link between prolonged grief and CES may be relevant in developing treatments for PGS, especially considering the potential relationship between high CES, high PGS, and possibly lack of acceptance of the loss. PMID- 29136604 TI - Extragenital malignant mixed mesodermal tumor: A case report. AB - INTRODUCTION: Primary malignant mixed mesodermal tumor (MMMt, also called malignant mixed Mullerian tumor and designated in the WHO classification of female genital tract neoplasms as carcinosarcoma) is an infrequent tumor that develops usually in the uterus and more rarely in the ovary. Extragenital tumor, including primary peritoneal MMMt, is an extremely rare and aggressive neoplasm with only few case reported in the literature. PRESENTATION OF CASE: We report a case of a 70-year's old female who presented with nausea and abdominal discomfort for 6 months. Workup revealed an abdominal mass. Patient was treated with surgical removal in a general hospital. DISCUSSION: Most peritoneal carcinosarcomas originate in the pelvic peritoneum, followed by decreasing frequency in the serosal surface of the colon, retroperitoneum, anterolateral abdominal peritoneum, and omentum. Surgical excision is the most effective treatment in carcinosarcomas. A complete cytoreduction, with resection of cancer to a status of no evidence of disease by the surgeon's unaided eye should be attempted. CONCLUSION: Owing to the rarity of the disease, limited data regarding the management of peritoneal MMMT exists. Recommendations for the treatment of MMMT are based on individual cases only. In our case, the patient is alive with a follow-up of 15 months and she did not receive any cycle of chemotherapy. PMID- 29136605 TI - Scalp metastasis as an initial presentation of lung adenocarcinoma : A case report and literature review. AB - INTRODUCTION: Cutaneous metastasis from primary visceral malignancy is a relatively uncommon clinical entity, with a reported incidence of 0.22%-10% among various series. However, the presence of cutaneous metastasis as the first sign of a clinically silent visceral cancer is exceedingly rare. PRESENTATION OF CASE: We describe here a case of an asymptomatic male patient who presented with a solitary scalp metastasis as the initial manifestation of an underlying lung cancer. Diagnostic evaluation revealed advanced disease. DISCUSSION: The report emphasizes that physicians should be aware of this rare clinical entity, and appropriate investigation should be arranged for early diagnosis and initiation of the appropriate treatment. The occurrence of skin lesions in lung cancer announces an ominous prognosis. CONCLUSION: We conclude that the possibility of metastatic skin disease should always be considered in the differential diagnosis in patients with a history of smoking or lung cancer presenting with cutaneous nodules. PMID- 29136606 TI - Heavy metals in soils of Hechuan County in the upper Yangtze (SW China): Comparative pollution assessment using multiple indices with high-spatial resolution sampling. AB - In order to assess heavy metals (HMs) in soils of the upper Yangtze Basin, a very high-spatial-resolution sampling (582 soil samples) was conducted from Hechuan County, an important agricultural practice area in the Southwest China. Multiple indices including geoaccumulation index (Igeo), enrichment factor (EF), sediment pollution index (SPI) and risk index (RI), as well as multivariate statistics were employed for pollution assessment and source identification of HMs in soils. Our results demonstrated that the averages of eight HMs decreased in the following order: Zn (82.8 +/- 15.9) > Cr (71.6 +/- 12.2) > Ni (32.1 +/- 9.89) > Pb (27.6 +/- 13.8) > Cu (25.9 +/- 11.8) > As (5.48 +/- 3.42) > Cd (0.30 +/- 0.077) > Hg (0.082 +/- 0.092). Averages of HMs except Cd were lower than threshold value of Environmental Quality Standard for Soils, while 43% of total samples had Cd concentration exceeding the national standard, 1% of samples for Hg and 5% samples for Ni, moreover, Cd and Hg averages were much higher than their background levels. Igeo and EF indicated that their levels decreased as follows: Cd > Hg > Zn > Pb > Ni > Cu > Cr > As, with moderate enrichments of Cd and Hg. RI indicated that 61.7% of all samples showed moderate risk, while 6.5% of samples with greater than considerable risk due to human activities should be paid more attention. Multivariate analysis showed lithogenic source of Cu, Cr, Ni and Zn, while Cd and Hg were largely contributed by anthropogenic activities such as agricultural practices. Our study would be helpful for improving soil environmental quality in SW, China, as well as supplying modern approaches for other areas with soil HM pollution. PMID- 29136607 TI - Differences in Learning Outcomes in Simulation: The observer role. AB - The objective of the study was to examine differences in learning outcomes, in students in the role of observer, using an observation guide and those without an observation guide during a simulation-based learning experience. The study design was quasi-experimental and included statistical analysis of variance (ANOVA) and independent t-tests to identify differences in learning outcomes. No significant improvement in knowledge, self-confidence, or collaboration was noted between baccalaureate nursing students (n = 121) using an Observation Guide (n = 62). However, students utilizing an Observation Guide were more satisfied with the Simulation-based Learning (SBL) experience (t (117) = 2.518, p = 0.013), although effect size was small (r = 0.05). Challenges such as decreases in clinical placement sites and increased student enrollment, indicate a need for improvements in implementation of SBL for student observers. PMID- 29136608 TI - Variation of the Korotkoff Stethoscope Sounds During Blood Pressure Measurement: Analysis Using a Convolutional Neural Network. AB - Korotkoff sounds are known to change their characteristics during blood pressure (BP) measurement, resulting in some uncertainties for systolic and diastolic pressure (SBP and DBP) determinations. The aim of this study was to assess the variation of Korotkoff sounds during BP measurement by examining all stethoscope sounds associated with each heartbeat from above systole to below diastole during linear cuff deflation. Three repeat BP measurements were taken from 140 healthy subjects (age 21 to 73 years; 62 female and 78 male) by a trained observer, giving 420 measurements. During the BP measurements, the cuff pressure and stethoscope signals were simultaneously recorded digitally to a computer for subsequent analysis. Heartbeats were identified from the oscillometric cuff pressure pulses. The presence of each beat was used to create a time window (1 s, 2000 samples) centered on the oscillometric pulse peak for extracting beat-by beat stethoscope sounds. A time-frequency two-dimensional matrix was obtained for the stethoscope sounds associated with each beat, and all beats between the manually determined SBPs and DBPs were labeled as "Korotkoff." A convolutional neural network was then used to analyze consistency in sound patterns that were associated with Korotkoff sounds. A 10-fold cross-validation strategy was applied to the stethoscope sounds from all 140 subjects, with the data from ten groups of 14 subjects being analyzed separately, allowing consistency to be evaluated between groups. Next, within-subject variation of the Korotkoff sounds analyzed from the three repeats was quantified, separately for each stethoscope sound beat. There was consistency between folds with no significant differences between groups of 14 subjects (P = 0.09 to P = 0.62). Our results showed that 80.7% beats at SBP and 69.5% at DBP were analyzed as Korotkoff sounds, with significant differences between adjacent beats at systole (13.1%, P = 0.001) and diastole (17.4%, P < 0.001). Results reached stability for SBP (97.8%, at sixth beat below SBP) and DBP (98.1%, at sixth beat above DBP) with no significant differences between adjacent beats (SBP P = 0.74; DBP P = 0.88). There were no significant differences at high-cuff pressures, but at low pressures close to diastole there was a small difference (3.3%, P = 0.02). In addition, greater within subject variability was observed at SBP (21.4%) and DBP (28.9%), with a significant difference between both (P < 0.02). In conclusion, this study has demonstrated that Korotkoff sounds can be consistently identified during the period below SBP and above DBP, but that at systole and diastole there can be substantial variations that are associated with high variation in the three repeat measurements in each subject. PMID- 29136609 TI - A Group-Based Image Inpainting Using Patch Refinement in MRF Framework. AB - This paper presents a Markov random field (MRF)-based image inpainting algorithm using patch selection from groups of similar patches and optimal patch assignment through joint patch refinement. In patch selection, a novel group formation strategy based on subspace clustering is introduced to search the candidate patches in relevant source region only. This improves patch searching in terms of both quality and time. We also propose an efficient patch refinement scheme using higher order singular value decomposition to capture underlying pattern among the candidate patches. This eliminates random variation and unwanted artifacts as well. Finally, a weight term is computed, based on the refined patches and is incorporated in the objective function of the MRF model to improve the optimal patch assignment. Experimental results on a large number of natural images and comparison with well-known existing methods demonstrate the efficacy and superiority of the proposed method. PMID- 29136610 TI - Explicit Ringing Removal in Image Deblurring. AB - In this paper, we present a simple yet effective image deblurring method to produce ringing-free deblurred images. Our work is inspired by the observation that large-scale deblurring ringing artifacts are measurable through a multi resolution pyramid of low-pass filtering of the blurred-deblurred image pair. We propose to model such a quantification as a convex cost function and minimize it directly in the deblurring process in order to reduce ringing regardless of its cause. An efficient primal-dual algorithm is proposed as a solution to this optimization problem. Since the regularization is more biased toward ringing patterns, the details of the reconstructed image are prevented from over smoothing. An inevitable source of ringing is sensor saturation which can be detected costlessly contrary to most other sources of ringing. However, dealing with the saturation effect in deblurring introduces a non-linear operator in optimization problem. In this paper, we also introduce a linear approximation as a solution to handling saturation in the proposed deblurring method. As a result of these steps, we significantly enhance the quality of the deblurred images. Experimental results and quantitative evaluations demonstrate that the proposed method performs favorably against state-of-the-art image deblurring methods. PMID- 29136611 TI - Gut Microbiota in Health and Disease. AB - Intestinal regulatory T (Treg) cells are critical to maintaining immune tolerance to dietary antigens and gut microbiota. This paper reviews several papers on this topic that were recently published by Japanese researchers. Specifically, Prof. K. Honda and his group have found that commensal microbiota capable of metabolizing butyrate induces the differentiation of colonic Treg cells. In a separate work, Prof. Y. Yokoyama and his group used a novel, culture-independent analytical method (the Yakult Intestinal Flora-Scan) for detection of bacteria in the bloodstream. Their work revealed that bacteremia in invasive surgery patients was ameliorated by synbiotic supplementation; similar results were reported in pediatric surgical cases by Dr. T. Okazaki and his group. This cutting-edge method may lead to the evolution of an altered disease concept; an example of this change is provided by the description of bacteremia in patients with type 2 diabetes, as reported by Dr. J. Sato and her group. In a similar work, Prof. Y. Yamashiro and his group found that infants born by cesarean (C)-section, who typically have gut dysbiosis, exhibit higher carriage of toxigenic Clostridium perfringens. The finding suggests that C-section-born infants may serve as a potential reservoir of this opportunistic pathogen. Another separate work by the laboratory of Dr. K. Yamashiro has revealed that gut dysbiosis is associated with altered metabolism and systemic inflammation in patients with ischemic stroke. These papers are consistent with a study by Prof. N. Sudo and his group, who have made significant progress in research on interaction among the microbiota, gut, and brain. PMID- 29136612 TI - Biochemical, Anthropometric and Lifestyle Factors Related with Weight Maintenance after Weight Loss Secondary to a Hypocaloric Mediterranean Diet. AB - BACKGROUND/AIMS: The aim of our study was to evaluate the influence of lifestyle factors and molecular biomarkers on the maintenance of the weight lost after a hypocaloric Mediterranean diet. DESIGN: After 3 months on a diet, patients (n = 335) remained with no controlled diet during 3 years and they were revaluated. RESULTS: Using linear regression, in the group of responders, we detected that a positive weight loss at 3 months, serum levels of leptin at 3 months, and each 30 min per week of physical activity were associated with weight loss maintenance. In the model with reduced weight (RW) as dependent variable, a positive weight loss at 3 months was associated with 2.4% RW (95% CI 1.31-8.11; p = 0.015), each unit of serum leptin levels at 3 months with -0.44% RW (95% CI -0.59 to -0.020; p = 0.007), each basal unit homeostasis model assessment for insulin resistance (HOMA-IR) level with -2.32% (95% CI -13.01 to -0.17; p = 0.040), and each 30 min per week of physical activity with 1.58% RW (95% CI 1.08-2.94; p = 0.020). CONCLUSION: Obese subjects who are on maintenance weight loss after a dietary intervention appear to have a better initial response during the 3 months intervention, more physical activity at 3 years, and lower basal HOMA-IR and leptin after weight loss than those who regain weight. PMID- 29136613 TI - Increasing Incidence and Prevalence of Multiple Sclerosis in Puerto Rico (2013 2016). AB - BACKGROUND: The incidence of multiple sclerosis (MS) has been increasing worldwide over the past decades. However, this upward trend has not been examined at the country level in Latin America and the Caribbean (LAC). The aims of this study are to examine trends of MS incidence over 4 years and to provide age- and gender-standardized incidence rate estimates for a Caribbean island. METHODS: Data from the Puerto Rico (PR) MS Foundation's registry was used to identify all newly diagnosed MS cases between 2013 and 2016. MS patients were 18 years and older and met the 2010 revised McDonald criteria. Age- and gender-standardized incidence rates were estimated. RESULTS: A total of 583 new MS cases were diagnosed in PR from 2013 to 2016. The age- and gender-standardized MS incidence rate for PR increased from 6.1/100,000 in 2013 to 6.7/100,000 in 2016. The annual age-standardized MS incidence rates for females rose from 8.4/100,000 in 2013 to 9.8/100,000 in 2016 and were higher than males, which remained around 3.7/100,000. CONCLUSION: Incidence estimates for PR were higher than other LAC countries but consistent with MS increases in other world regions. Our findings tend to rule out several prior potential environmental explanations for high MS incidence rates. PMID- 29136614 TI - Impact of Early Infant Growth, Duration of Breastfeeding and Maternal Factors on Total Body Fat Mass and Visceral Fat at 3 and 6 Months of Age. AB - BACKGROUND: Accelerated gain in fat mass in the first months of life is considered to be a risk factor for adult diseases, given the tracking of infancy fat mass into adulthood. Our objective was to assess the influence of early growth, type of feeding and maternal variables on fat mass in early life. METHODS: In 300 healthy term infants, we longitudinally measured fat mass percentage (FM%) by air-displacement-plethysmography at 1, 3, and 6 months and abdominal visceral and subcutaneous fat measured by ultrasound at 3 and 6 months. RESULTS: Both gain in FM% and weight-for-length in the first 3 months were positively associated with FM% at 6 months of age and visceral fat at 3 months of age. Gain in FM% and weight-for-length between 3 and 6 months were both positively associated with visceral fat at 6 months. Breastfeeding duration associated positively with subcutaneous fat but not with visceral fat at 3 and 6 months. Maternal characteristics did not associate with FM% or visceral fat at 3 or 6 months. CONCLUSION: Higher gain in FM% or in weight-for-length in the first postnatal months leads not only to higher FM% but also more to accumulation of visceral fat. Exclusive breastfeeding appears to promote subcutaneous but not visceral fat in the first 6 months. PMID- 29136615 TI - Videokymographic Visualization of Phonasthenia: A Nonorganic Voice Disorder. AB - BACKGROUND: Phonasthenia is a voice disorder where the larynx looks essentially normal and dysphonia is not heard but felt by the patient. This study aims to use videokymography (VKG) to detect any abnormalities in the vibratory pattern in phonasthenia and to find out whether or not these abnormalities change after vocal loading. METHODS: Thirty-seven phonasthenic patients and 31 normal subjects participated in a detailed protocol, including analysis of subjective complaints and videokymographic quasi-objective parameters (baseline) followed by loading their voices through prolonged loud reading for 45 min. A second evaluation (experimental) was done after loading. RESULTS: Before vocal loading, patients had significantly more symptoms in all questionnaire questions and higher maximum width difference in VKG than controls. When pre- and postloading values were compared, both groups experienced more symptoms after loading (significant in most of the questions), while the pre- and post-VKG parameters did not show significant differences neither in patients nor controls. On comparing their percent change, the only statistically significant difference between the 2 groups was a greater change in the total score of the questionnaire in the control group. CONCLUSION: Patients had more vocal fatigue symptoms and more amplitude asymmetry between left and right vocal folds than normal subjects. PMID- 29136616 TI - No Relapse of Calcineurin Inhibitor-Associated Thrombotic Microangiopathy after Discontinuation of Eculizumab. PMID- 29136617 TI - Prognostic Factors in Patients with an Implanted Pacemaker after 80 Years of Age in a 4-Year Follow-Up. AB - BACKGROUND: The controversy over electrotherapy for patients aged >80 years occurs already at the stage of qualification for this treatment type and concerns optimal device selection, the implantation strategy, and the overall benefit from pacemaker therapy. The group also has a considerable number of cardiovascular risk factors, and the data from the literature on the impact of the pacing mode on the remote prognosis of this group are ambiguous. OBJECTIVE: Assessment of the risk factors for death among patients with implanted pacemakers >80 years of age in a 4-year follow-up. METHODS: The study group consisted of 140 consecutive patients (79 women) aged 84.48 +/- 3.65 years with single- or dual-chamber pacemakers implanted >80 years of age because of symptomatic bradycardia. In univariate and multivariate Cox regression analyses, demographic, echocardiographic, and laboratory parameters, pharmacotherapy, and factors related to the implanted device - i.e., indications, pacemaker type, and the implantation position of the tip of the right ventricular lead - were included. The endpoint was death for any reason in a 4-year follow-up. RESULTS: During follow-up, 68 patients (48.6%) died. Although atrial fibrillation with a slow ventricular response constituted 20% of the indications for implantation, 60.8% of the patients received a single-chamber system (VVI/VVIR). In the whole group, the multivariate Cox regression analysis showed both a favourable prognostic significance of DDD pacing system implantation (HR = 0.507; 95% CI: 0.294-0.876) and coexisting hypertension (HR = 0.520; 95% CI: 0.299-0.902). The risk factors were fasting glycaemia (HR = 1.180; 95% CI: 1.038-1.342) and, potentially, female sex (HR = 1.672; 95% CI: 0.988-2.830; p = 0.056). In the female subgroup a more favourable prognosis was related to the use of angiotensin-converting enzyme inhibitors (HR = 0.435; 95% CI: 0.202-0.933) and DDD pacemaker implantation (HR = 0.381; 95% CI: 0.180-0.806). In the male subgroup a more favourable prognosis was related to concerned patients with coexisting hypertension (HR = 0.349; 95% CI: 0.079-0.689). CONCLUSIONS: DDD mode pacing seems to serve as a factor which decreases mortality among patients aged >80 years in long-term follow-up. The potentially poorer prognosis for the female patients in this group may result from a combination of the dominant VVI pacing mode, potential propagation of atrial fibrillation, a low proportion of antithrombotic therapy, and sex-related predispositions to thromboembolic complications. PMID- 29136618 TI - Hepcidin in Iron Homeostasis: Diagnostic and Therapeutic Implications in Type 2 Diabetes Mellitus Patients. AB - The prevalence of type 2 diabetes is increasing in epidemic proportions worldwide. Evidence suggests body iron overload is frequently linked and observed in patients with type 2 diabetes. Body iron metabolism is based on iron conservation and recycling by which only a part of the daily need is replaced by duodenal absorption. The principal liver-produced peptide called hepcidin plays a fundamental role in iron metabolism. It directly binds to ferroportin, the sole iron exporter, resulting in the internalization and degradation of ferroportin. However, inappropriate production of hepcidin has been shown to play a role in the pathogenesis of type 2 diabetes mellitus and its complications, based on the regulation and expression in iron-abundant cells. Underexpression of hepcidin results in body iron overload, which triggers the production of reactive oxygen species simultaneously thought to play a major role in diabetes pathogenesis mediated both by beta-cell failure and insulin resistance. Increased hepcidin expression results in increased intracellular sequestration of iron, and is associated with the complications of type 2 diabetes. Besides, hepcidin concentrations have been linked to inflammatory cytokines, matriptase 2, and chronic hepatitis C infection, which have in turn been reported to be associated with diabetes by several approaches. Either hepcidin-targeted therapy alone or as adjunctive therapy with phlebotomy, iron chelators, or dietary iron restriction may be able to alter iron parameters in diabetic patients. Therefore, measuring hepcidin may improve differential diagnosis and the monitoring of disorders of iron metabolism. PMID- 29136620 TI - Use of Automated Analysis of Cervical Cytology for the Detection of High-Grade Squamous Intraepithelial Lesions in Human Papillomavirus-Positive Women: A Future Practice? PMID- 29136619 TI - Risk Factor Analysis for AKI Including Laboratory Indicators: a Nationwide Multicenter Study of Hospitalized Patients. AB - BACKGROUND/AIMS: Risk factor studies for acute kidney injury (AKI) in China are lacking, especially those regarding non-traditional risk factors, such as laboratory indicators. METHODS: All adult patients admitted to 38 tertiary and 22 secondary hospitals in China in any one month between July and December 2014 were surveyed. AKI patients were screened according to the Kidney Disease: Improving Global Outcomes' definition of AKI. Logistic regression was used to analyze the risk factors for AKI, and Cox regression was used to analyze the risk of in hospital mortality for AKI patients; additionally, a propensity score analysis was used to reconfirm the risk factors among laboratory indicators for mortality. RESULTS: The morbidity of AKI was 0.97%. Independent risk factors for AKI were advancing age, male gender, hypertension, and chronic kidney disease. All-cause mortality was 16.5%. The predictors of mortality in AKI patients were advancing age, tumor, higher uric acid level and increases in Acute Physiologic Assessment and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores. The hazard ratio (HR) for mortality with uric acid levels > 9.1 mg/dl compared with <= 5.2 mg/dl was 1.78 (95% CI: 1.23 to 2.58) for the AKI patients as a group, and was 1.73 (95% CI: 1.24 to 2.42) for a propensity score-matched set. CONCLUSION: In addition to traditional risk factors, uric acid level is an independent predictor of all-cause mortality after AKI. PMID- 29136621 TI - Evaluation of Nickel Release from Endobronchial Valves as a Possible Cause of Hypersensitivity Pneumonitis in a Patient Treated with Bronchoscopic Lung Volume Reduction. AB - BACKGROUND: Endobronchial valve (EBV) placement is an established lung volume reduction procedure aiming to improve lung function and exercise capacity in patients with severe emphysema. As EBVs consist of silicone and nitinol (a metal alloy of nickel and titanium), there are concerns that nickel ions might be released and could have a clinical impact in patients with a contact allergy to nickel. Based on a case with hypersensitivity pneumonitis (HP) after treatment with EBVs, we aimed to evaluate the in vitro nickel release from EBVs using inductively coupled plasma mass spectrometry (ICP-MS) and scanning electron microscopy (SEM). METHODS: Six EBVs were immersed in artificial saliva for a period of 7 days. At 24-h intervals, the nickel ion concentration was measured using ICP-MS. RESULTS: There was evidence of a significant nickel release from EBV during the first 48 h, which is possibly due to an incomplete silicone layer detected by SEM. The concentration of released nickel was below the toxic limit. CONCLUSIONS: To the best of our knowledge, we report the first case of HP after EBV treatment. Our finding of in vitro release of nickel ions from EBVs may contribute to the current understanding on hypersensitivity reactions after nitinol implants in patients with nickel contact allergy. However, it did not confirm a causative relationship. PMID- 29136622 TI - Serum Transaminase Concentrations and the Presence of Irritable Bowel Syndrome Are Associated with Serum 25-Hydroxy Vitamin D Concentrations in Adolescent Girls Who Are Overweight and Obese. AB - BACKGROUND/AIMS: Vitamin D deficiency has become endemic globally and its etiology is complex. Few studies have investigated the determinants of serum 25 hydroxy vitamin D (25-OH D). The aim of this study was to investigate the association between lifestyle patterns, liver functional tests (LFTs), and the presence of irritable bowel syndrome (IBS) with serum 25-OH D in apparently healthy girls. METHODS: This cross-sectional study was undertaken in 965 adolescent girls aged 12-18 years. IBS was diagnosed using the Rome III questionnaire. An electrochemiluminescence method was used to measure serum 25-OH D. LFTs were measured using commercial kits and an auto analyzer. Linear regression and univariate analyses were performed to determine the association between continuous and categorical variables with serum 25-OH D respectively. RESULTS: Serum 25-OH D was significantly higher in normal weight subjects compared to either overweight or obese subjects (9.5 +/- 7.02 vs. 7.9 +/- 5.7 ng/mL, p = 0.03). Physical activity level was positively associated with serum 25 OH D in overweight and obese subjects (beta = 0.15, p < 0.05). An inverse relationship was found between the presence of IBS and 25-OH D in both normal (beta = -1.95, p < 0.05), overweight and obese subjects (beta = -1.83, p < 0.05). Serum alanine transaminase (ALT; beta = -0.19, p < 0.05) and aspartate transaminase (beta = -0.17, p < 0.05) were inversely associated with serum 25-OH in overweight and obese subjects. CONCLUSIONS: Individuals with IBS had significantly lower serum 25-OH D concentrations. In addition, there was an inverse association between serum ALT and 25-OH D. Prospective studies, and perhaps interventional trials, will be required to clarify these associations. PMID- 29136623 TI - Synergistic Effect of Eicosapentaenoic Acid on Antiproliferative Action of Anticancer Drugs in a Cancer Cell Line Model. AB - BACKGROUND/AIMS: It has been found experimentally and clinically that eicosapentaenoic acid (EPA) exerts an anticancer effect and that it has a minimal adverse event profile relative to other anticancer drugs. Any synergy between EPA and other anticancer drugs could be of therapeutic relevance, especially in elderly or high-risk patients. Therefore, we investigated the synergism between anticancer drugs and EPA experimentally. METHODS: EPA was coadministered in vitro with various anticancer drugs (paclitaxel, docetaxel, 5-fluorouracil and cis diamminedichloridoplatinum[II]) to TE-1 cells, which were derived from human esophageal cancer tumors. Cell proliferation was measured by the water soluble tetrazolium-1 method. RESULT: Sub-threshold concentrations of EPA, which alone produced no anticancer effect, caused a synergistic suppressive effect on TE-1 cell proliferation when combined with other anticancer agents. CONCLUSION: Coadministration of EPA with other anticancer drugs may represent a new therapeutic paradigm offering a reduced side effect profile. PMID- 29136624 TI - Value of Intraoperative Cytological and Pathological Sentinel Lymph Node Diagnosis in Fertility-Sparing Trachelectomy for Early-Stage Cervical Cancer. AB - BACKGROUND AND OBJECTIVES: Trachelectomy, a fertility-sparing surgery for early stage cervical cancer, can be performed only when there is no extrauterine extension present. Therefore, identifying the sentinel lymph nodes (SLNs) and using them to obtain an intraoperative pathologic diagnosis can provide information on the feasibility and safety of trachelectomy. Our aim was to assess the value of an intraoperative SLN diagnosis. METHODS: We retrospectively analyzed the accuracy of intraoperative imprint cytology and frozen-section examination in 201 patients at our institution in whom trachelectomy was planned. RESULTS: All patients could be evaluated for SLNs; a total of 610 SLNs were analyzed. Although the specificity of both imprint cytology and frozen-section examination was 100.0%, the sensitivity was only 58.6 and 65.5%, respectively. The diagnostic sensitivity was higher in 2-mm slices along the short axis than on bisection along the longitudinal axis. Imprint cytology correctly diagnosed 2 patients who had false-negative results on frozen section. The nature of the metastatic foci that caused an intraoperative false-negative diagnosis was either micrometastasis or isolated tumor cells. CONCLUSIONS: The accuracy of intraoperative SLN diagnosis requires improvement, especially when small metastatic foci are present. PMID- 29136625 TI - Caries-Preventive Effect of Salt Fluoridation in Preschool Children in The Gambia: A Prospective, Controlled, Interventional Study. AB - The aim of this study was to investigate the anticaries effect of fluoridated salt in a communal feeding program for preschool children. In the Gambian city of Brikama, drinking water had a low fluoride content (0.1 mg F-/L) and young children did not use toothpaste for oral hygiene. Its 2 preschools served as clusters for the trial. Random allocation of the kindergartens was performed by one person not involved in the study, and the clinical examinations were carried out using the envelope method. Meals were prepared with fluoridated salt (250 mg F-/kg salt) in the intervention group but not in the control group. According to the inclusion criteria (complete primary dentition and informed consent from legal guardian), 441 children aged 3-5 years were enrolled. The children were examined by calibrated persons according to WHO criteria, allowing the calculation of d3mft scores. The primary end point was the mean difference in the incidence of caries cavities (Deltad3/4mft) after 12 months. After 12 months, the mean caries incidence per person was 1.29 d3/4mf teeth (95% CI: 0.96; 1.62) in the test group (n = 304 children) and 3.83 d3/4mf teeth (95% CI: 2.94; 4.72) in the control group (n = 137 children). Thus, the caries-prevented fraction was 66.3%. No signs of harm due to the intervention were observed. The use of fluoridated salt in a communal feeding program and in an environment with negligible availability of fluoride from other sources yields a considerable caries-preventive effect. PMID- 29136626 TI - Comparison of Visual Inspection with Acetic Acid and the Pap Smear for Cervical Cancer Screening. AB - OBJECTIVE: To evaluate the efficacy of visual inspection with acetic acid (VIA) in the early detection of cervical cancer and compare it with the Pap smear. STUDY DESIGN: This was a cross-sectional study conducted over a period of 3 months. A total of 316 patients who attended the Gynecology Outpatient Department of Era's Lucknow Medical College and Hospital, fulfilled the inclusion criteria, and gave their informed consent were included. RESULTS: VIA was found positive in 38 patients (12.6%). Pap smear was positive in 31 patients (10.3%). Twenty-eight patients had a positive VIA and a positive Pap smear, 3 had a negative VIA and a positive Pap smear, 10 had a positive VIA and a negative Pap smear, and 34 had a negative VIA and a negative Pap smear. CONCLUSION: The sensitivity of VIA and the Pap smear was found to be nearly equal, 93.3 and 93.8%, respectively. The Pap smear was found to be more specific than VIA, i.e., 72.9 versus 60%. In terms of test accuracy, the Pap smear was found to have greater test accuracy, i.e., 77.3 versus 66.7% for VIA. PMID- 29136628 TI - Incidence of Multiple Sclerosis in Germany: A Cohort Study Applying Different Case Definitions Based on Claims Data. AB - BACKGROUND: Data on the incidence of multiple sclerosis (MS) on the national level is scarce. We aimed to estimate the incidence of MS in Germany and to compare different MS case definitions based on claims data. METHODS: We conducted a cohort study with the German Pharmacoepidemiological Research Database in 2012 and calculated age- and gender-standardized incidence rates (sIRs) for 3 case definitions. In addition, the effect of stepwise reduction of the look-back period without MS diagnosis on the incidence rate was evaluated. RESULTS: Our cohort comprised 4,175,877 individuals. The first case definition based on ICD-10 diagnoses yielded an sIR of 21.8 (95% CI 20.2-23.5) per 100,000 person years, whereas the second and third case definitions with additional requirements for drug treatment and diagnostic tests resulted in lower sIRs of 10.1 (9.1-11.3) and 6.6 (5.8-7.6) respectively. We observed a higher incidence for shorter look-back periods. CONCLUSION: The incidence of MS in Germany might be substantially higher than suggested in earlier studies. In addition, our study highlights the importance of a look-back period of at least 36 months to identify incident MS cases based on claims data. PMID- 29136627 TI - Toll-Like Receptor 4 Reduces Occludin and Zonula Occludens 1 to Increase Retinal Permeability Both in vitro and in vivo. AB - We reported that beta-adrenergic receptors regulate toll-like receptor 4 (TLR4) signaling in the retina of diabetic mice and in retinal endothelial cells (REC) and Muller cells. We hypothesized that TLR4 regulates retinal permeability both in vitro and in vivo in the retinal vasculature. We used REC cultured in normal and high-glucose conditions and TLR4 siRNA treatments for cell culture studies of permeability and protein analyses of tumor necrosis factor alpha, occludin, and zonula occludens 1 (ZO-1). We used endothelial cell (EC)-specific Cre-Lox TLR4 knockout mice to study retinal permeability and neuronal and vascular changes following exposure to ocular ischemia/reperfusion (I/R) used as a retinal stressor. We found that the loss of TLR4 in the EC led to the reduced permeability following I/R and fewer degenerate capillaries. Retinal permeability was increased in REC grown in high-glucose conditions but was inhibited by TLR4 siRNA treatment. High-glucose culture conditions significantly reduced occludin and ZO-1 levels in REC, and TLR4 siRNA treatment restored levels to baseline. In conclusion, these studies demonstrate that TLR4 in EC strongly regulates retinal permeability and neuronal and vascular changes following exposure to stressors such as I/R. PMID- 29136629 TI - Modified Alcohol-Formalin Cell Block Technique in Head and Neck Pathology Diagnosis. AB - OBJECTIVES: Cell block preparation is a recognized technique in histopathological diagnosis. This technique aids in maintaining an intact architecture and reducing the diagnostic errors associated with fine-needle aspiration cytology. Numerous techniques have been put forth, but the need for an optimal technique for routine use in the laboratory still persists. The aim of our study was to establish a cell block technique which aids in the accurate diagnosis of head and neck pathology. METHODOLOGY: A modified cell block technique was developed using alcohol-formalin as a fixative. Forty fine-needle aspiration fluids from clinically and radiologically diagnosed cases of head and neck pathology were used as samples. The cell block sections were compared with the cytology smears to determine the utility of the technique. RESULTS: The cell blocks presented with better preservation of the architectural framework and enabled a quick diagnosis. Cellular clumping was negligible, and nuclear as well as cellular details were maintained similar to tissue sections. It led to the integration of conventional techniques using 10% neutral buffered formalin with that of the 10% alcohol-formalin technique. CONCLUSION: Modified cell block technique can be used as a simple and effective tool in the routine diagnosis of head and neck pathology. PMID- 29136630 TI - One-to-One Correspondence Locations of Resected Polyps after Endoscopic Resection Using Catcher Tagged Method: A Randomized Prospective Study. AB - BACKGROUND/AIMS: Multiple colorectal polyps with a diameter in the range of 10-19 mm are unable to be retrieved through a 3-mm endoscopic channel by the aspiration method. This study aims to assess the usefulness of Catcher Tag retrieval, which not only allows the accurate identification of the resected location but also enables the easiest retrieval in a short time without any special device. METHODS: One hundred thirty five patients (483 polyps) were diagnosed with colorectal neoplasm, and 64 patients (225 polyps) were enrolled and randomly allocated into the Net forceps group (NET) and the Catcher Tagged group (TAG). In TAG, 3 types of colored ring-threads were used to retrieve resected polyps. After local injection of natural saline, ring-threads were placed close to polyps. The primary outcome was the number of one-to-one correspondence locations (UMIN000020826). RESULTS: There was significant difference in one-to-one correspondence (p = 0.004). The average retrieval procedure time was 13.56 +/- 3.47 (min) in NET and 3.55 +/- 1.68 in TAG (p = 0.006). In NET, 1 polyp in each of 4 cases was lost during endoscopic mucosal resection and 2 polyps were lost in 1 case. In TAG, no polyp was lost (p = 0.016). CONCLUSION: The Catcher Tagged method is very useful for accurate one-to-one correspondence locations and pathological evaluation, and easy-to-retrieve multiple resected specimens. PMID- 29136631 TI - Drug-Induced Pseudoallergy: A Review of the Causes and Mechanisms. AB - Adverse drug reactions occur frequently and can trigger pseudoallergy, which has become a serious threat to public health. Pseudoallergy is a typical non-immune anaphylactic reaction characterized by the independence of antigen-specific immune responses. In the clinic, pseudoallergy is often elicited by the first dose of medication, and here lies its unpredictability and occasional lethal outcome. However, the mechanisms of pseudoallergy are not well understood. This review focusses on the causes and mechanisms of pseudoallergy induced by drugs. Two categories of mechanisms will be considered, namely, (1) complement activation-related pseudoallergy and (2) mast cell activation-related pseudoallergy. The factors that induce pseudoallergy include opioid drugs, complement activation-related pseudoallergenic drugs, nonsteroidal anti inflammatory drugs and traditional Chinese medicine injections. PMID- 29136632 TI - Saturated Fat Intake Is Related to Heart Rate Variability in Women with Polycystic Ovary Syndrome. AB - BACKGROUND/AIMS: There is a heightened risk for cardiovascular diseases in women with polycystic ovary syndrome (PCOS). Alterations in heart rate variability (HRV) may reflect subclinical cardiovascular disease, with a putative association between HRV and dietary fat. This study evaluated HRV in PCOS and control women based on the dietary intake of saturated fatty acid (SFA). METHODS: Biochemical/hormonal profile, resting metabolic rate, physical activity, HRV in response to the Stroop test, and dietary intake were assessed in 84 PCOS and 54 control women stratified by median SFA intake in the PCOS group (8.5% of daily energy intake). RESULTS: Body mass index (p = 0.041), blood pressure (p < 0.01), and HOMA-IR (p = 0.003) were higher in PCOS vs. CONTROLS: PCOS women had higher testosterone (p = 0.001), dehydroepiandrosterone sulfate (p = 0.012), and free androgen index (p = 0.001), and lower sex hormone-binding globulin levels than controls (p = 0.001). In both groups, the clinical profile and calorie intake were similar between SFA categories. In PCOS, testosterone was lower when SFA intake <8.5%. PCOS women with SFA <8.5% consumed more beans, fruits, and vegetables and had better frequency and time domain HRV indices. No differences in HRV were detected between SFA categories in controls. In PCOS, age and SFA intake were independent predictors of HRV. CONCLUSIONS: Lower SFA intake is related to improved cardiovascular autonomic function in PCOS. PMID- 29136633 TI - Impaired Enterohormone Response Following a Liquid Test Meal in Gastrectomized Patients. AB - BACKGROUND: Total gastrectomy (TG) is responsible for symptoms or disturbance of alimentary status (changes in body weight, food intake per meal and frequency of meal per day) which, in turn are responsible for weight loss and malnutrition. The study evaluates the gut hormone responses in totally gastrectomized (TG) patients after a liquid meal test. METHODS: Twenty total gastrectomized cancer free patients (12 M, 8 F, 56.4 +/- 10.2 years, BMI 21.4 +/- 2.2 kg/m2) and 10 healthy volunteers (4 M, 6 F, 48.0 +/- 12.7 years, BMI 26.7 +/- 3.0 kg/m2 ) drank a liquid meal (1.25 kcal/mL) at the rate of 50 mL/5' min for a maximum of 30 min. Satiety score was assessed and blood sample was taken at different time points. RESULTS: The time response course, particularly for insulin, glucose-like pepetide-1, and cholecystokinin, significantly differed between TG patients and controls. CONCLUSIONS: Our results may help to better understand hormone responses triggered by the faster arrival of nutrients in the small bowel and to explain some post-TG symptoms. PMID- 29136634 TI - Treatment and Outcomes of Working Aged Adults with Stroke: Results from a National Prospective Registry. AB - BACKGROUND: Given the potential differences in etiology and impact, the treatment and outcome of younger patients (aged 18-64 years) require examination separately to older adults (aged >=65 years) who experience acute stroke. METHODS: Data from the Australian Stroke Clinical Registry (2010-2015) including demographic and clinical characteristics, provision of evidence-based therapies and health related quality of life (HRQoL) post-stroke was used. Descriptive statistics and multilevel regression models were used for group comparisons. RESULTS: Compared to older patients (age >=65 years) among 26,220 registrants, 6,526 (25%) younger patients (age 18-64 years) were more often male (63 vs. 51%; p < 0.001), born in Australia (70 vs. 63%; p < 0.001), more often discharged home from acute care (56 vs. 38%; p < 0.001), and less likely to receive antihypertensive medication (61 vs. 73%; p < 0.001). Younger patients had a 74% greater odds of having lower HRQoL compared to an equivalent aged-matched general population (adjusted OR 1.74, 95% CI 1.56-1.93, p < 0.001). CONCLUSIONS: Younger stroke patients exhibited distinct differences from their older counterparts with respect to demographic and clinical characteristics, prescription of antihypertensive medications and residual health status. PMID- 29136635 TI - Stroke among Rheumatoid Arthritis Patients: Does Age Matter? A Real-Life Study. AB - BACKGROUND/AIMS: Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease that affects the joints and it is known to be associated with cardiovascular morbidity. However, the association between RA and stroke among different age groups has not been explored. The objective of our study was to evaluate the association between RA and stroke in different age strata. METHODS: Cross-sectional study, utilizing the database of Israel's largest healthcare provider. The proportion of stroke was compared between patients diagnosed with RA and age- and gender-matched controls. The study sample was divided into 2 age groups: young (<=65 years) and elderly (>65 years). Multivariable analysis was performed using logistic regression. RESULTS: The study included 11,782 RA patients and 57,973 age- and gender-matched controls. RA patients, primarily young, had more cardiovascular risk factors than controls. Stroke rates were significantly elevated among young RA patients in comparison with controls (3.74 vs. 2.20%, respectively, p < 0.001). In multivariate analysis, RA was found to be independently associated with stroke (OR 1.18, 95% CI 1.09-1.28). CONCLUSION: RA is independently associated with stroke, especially among RA patients under 65 years, for whom cardiovascular risk factors were more prominent. Physicians should advise RA patients to manage their risk factors strictly. PMID- 29136636 TI - Screening of Skin Lesion-Associated Genes in Patients with Psoriasis by Meta Integration Analysis. AB - AIM: Psoriasis is an inflammatory skin disease, and approximately one quarter of individuals with psoriasis develop painful and debilitating arthritis. As a complex and polygenetic hereditary disease, it is significant to investigate skin lesion-associated genes of psoriasis. METHOD: In the present study, a total of 3,047 differentially expressed genes between lesional and nonlesional skin of psoriasis patients were screened based on 4 data sets in GEO DataSets. In the following, network module analyses were performed. RESULT: After calculating the correlation coefficients between eigenvalues of each module and disease status (psoriatic lesion and nonlesion), it was observed that the genes in black and green modules showed a significant correlation in each data set. Consequently, 58 significant characteristic genes of black modules and 74 of green modules were chosen for further analysis. The interaction network of the candidate feature genes was constructed based on the BioGRID, HPRD, and BIND databases, which contained 310 nodes. The mutual relationships of 70 genes, including 28 genes in the black module and 42 genes in the green module, were summarized, and 5 drug molecules related to these 70 factors were detected. Mepacrine and camptothecin were indicated as 2 drugs negatively related to psoriasis. CONCLUSION: The results suggested a pathogenesis mechanism of psoriasis and indicated novel therapeutic targets for psoriasis. PMID- 29136637 TI - Transcriptional profiling of Toll-like receptor 2-deficient primary murine brain cells during Toxoplasma gondii infection. AB - BACKGROUND: Toxoplasma gondii is capable of persisting in the brain, although it is efficiently eliminated by cellular immune responses in most other sites. While Toll-like receptor 2 (TLR2) reportedly plays important roles in protective immunity against the parasite, the relationship between neurological disorders induced by T. gondii infection and TLR2 function in the brain remains controversial with many unknowns. In this study, primary cultured astrocytes, microglia, neurons, and peritoneal macrophages obtained from wild-type and TLR2 deficient mice were exposed to T. gondii tachyzoites. To characterize TLR2 dependent functional pathways activated in response to T. gondii infection, gene expression of different cell types was profiled by RNA sequencing. RESULTS: During T. gondii infection, a total of 611, 777, 385, and 1105 genes were upregulated in astrocytes, microglia, neurons, and macrophages, respectively, while 163, 1207, 158, and 1274 genes were downregulated, respectively, in a TLR2 dependent manner. Overrepresented Gene Ontology (GO) terms for TLR2-dependently upregulated genes were associated with immune and stress responses in astrocytes, immune responses and developmental processes in microglia, metabolic processes and immune responses in neurons, and metabolic processes and gene expression in macrophages. Overrepresented GO terms for downregulated genes included ion transport and behavior in astrocytes, cell cycle and cell division in microglia, metabolic processes in neurons, and response to stimulus, signaling and cell motility in macrophages. CONCLUSIONS: To our knowledge, this is the first transcriptomic study of TLR2 function across different cell types during T. gondii infection. Results of RNA-sequencing demonstrated roles for TLR2 varied by cell type during T. gondii infection. Our findings facilitate understanding of the detailed relationship between TLR2 and T. gondii infection, and elucidate mechanisms underlying neurological changes during infection. PMID- 29136638 TI - A free-boundary model of a motile cell explains turning behavior. AB - To understand shapes and movements of cells undergoing lamellipodial motility, we systematically explore minimal free-boundary models of actin-myosin contractility consisting of the force-balance and myosin transport equations. The models account for isotropic contraction proportional to myosin density, viscous stresses in the actin network, and constant-strength viscous-like adhesion. The contraction generates a spatially graded centripetal actin flow, which in turn reinforces the contraction via myosin redistribution and causes retraction of the lamellipodial boundary. Actin protrusion at the boundary counters the retraction, and the balance of the protrusion and retraction shapes the lamellipodium. The model analysis shows that initiation of motility critically depends on three dimensionless parameter combinations, which represent myosin-dependent contractility, a characteristic viscosity-adhesion length, and a rate of actin protrusion. When the contractility is sufficiently strong, cells break symmetry and move steadily along either straight or circular trajectories, and the motile behavior is sensitive to conditions at the cell boundary. Scanning of a model parameter space shows that the contractile mechanism of motility supports robust cell turning in conditions where short viscosity-adhesion lengths and fast protrusion cause an accumulation of myosin in a small region at the cell rear, destabilizing the axial symmetry of a moving cell. PMID- 29136639 TI - Structural and kinetic considerations on the catalysis of deoxyarbutin by tyrosinase. AB - Deoxyarbutin, a potent inhibitor of tyrosinase, could act as substrate of the enzyme. Oxytyrosinase is able to hydroxylate deoxyarbutin and finishes the catalytic cycle by oxidizing the formed o-diphenol to quinone, while the enzyme becomes deoxytyrosinase, which evolves to oxytyrosinase in the presence of oxygen. This compound is the only one described that does not release o-diphenol after the hydroxylation step. Oxytyrosinase hydroxylates the deoxyarbutin in ortho position of the phenolic hydroxyl group by means of an aromatic electrophilic substitution. As the oxygen orbitals and the copper atoms are not coplanar, but in axial/equatorial position, the concerted oxidation/reduction cannot occur and the release of a copper atom to bind again in coplanar position, enabling the oxidation/reduction or release of the o-diphenol from the active site to the medium. In the case of deoxyarbutin, the o-diphenol formed is repulsed by the water due to its hydrophobicity, and so can bind correctly and be oxidized to a quinone before being released. Deoxyarbutin has been characterized with: [Formula: see text] = 1.95 +/- 0.06 s-1 and [Formula: see text] = 33 +/- 4 MUM. Computational simulations of the interaction of beta-arbutin, deoxyarbutin and their o-diphenol products with tyrosinase show how these ligands bind at the copper centre of tyrosinase. The presence of an energy barrier in the release of the o-diphenol product of deoxyarbutin, which is not present in the case of beta arbutin, together with the differences in polarity and, consequently differences in their interaction with water help understand the differences in the kinetic behaviour of both compounds. Therefore, it is proposed that the release of the o diphenol product of deoxyarbutin from the active site might be slower than in the case of beta-arbutin, contributing to its oxidation to a quinone before being released from the protein into the water phase. PMID- 29136640 TI - Long-term outcomes of the Atypical Hemolytic Uremic Syndrome after kidney transplantation treated with eculizumab as first choice. AB - INTRODUCTION: The treatment of choice for Atypical Hemolytic Uremic Syndrome (aHUS) is the monoclonal antibody eculizumab. The objective of this study was to assess the efficacy and safety of eculizumab in a cohort of kidney transplant patients suffering from aHUS. METHODS: Description of the prospective cohort of all the patients primarily treated with eculizumab after transplantation and divided into the therapeutic (onset of aHUS after transplantation) and prophylactic use (patients with previous diagnosis of aHUS undergoing kidney transplantation). RESULTS: Seven cases were outlined: five of therapeutic use and two, prophylactic. From the five cases of therapeutic use, there was improvement of the thrombotic microangiopathy in the 48 hours following the start of the drug and no patient experienced relapse during an average follow-up of 21 months in the continuous use of eculizumab (minimum of 6 and maximum of 42 months). One patient died at 6 months, due to Aspergillus infection. From the two cases of prophylactic use, one patient experienced relapsed thrombotic microangiopathy after 4 months and another patient remained asymptomatic after 16 months of follow-up, both on chronic treatment. DISCUSSION: The therapeutic use of eculizumab showed to be effective, with improvement of the microangiopathy parameters and persisting up to the end of the follow-up, without relapses. The additional risk of immunosuppression, leading to opportunistic infections, was well tolerated. The prophylactic use showed to be effective and safe; however, the doses and intervals should be individualized in order to avoid relapsed microangiopathy, especially in patients with factor H mutation. PMID- 29136641 TI - Radioactive contamination in the Tokyo metropolitan area in the early stage of the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident and its fluctuation over five years. AB - Radioactive contamination in the Tokyo metropolitan area in the immediate aftermath of the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident was analyzed via surface soil sampled during a two-month period after the accident. 131I, 134Cs, and 137Cs were detected in these soil samples. The activity and inventory of radioactive material in the eastern part of Tokyo tended to be high. The 134Cs/137Cs activity ratio in soil was 0.978 +/- 0.053. The 131I/137Cs ratio fluctuated widely, and was 19.7 +/- 9.0 (weighted average 18.71 +/- 0.13, n = 14) in the Tokyo metropolitan area. The radioactive plume with high 131I activity spread into the Tokyo metropolitan area and was higher than the weighted average of 6.07 +/- 0.04 (n = 26) in other areas. The radiocesium activity and inventory surveyed in soil from a garden in Chiyoda Ward in the center of Tokyo, fell approximately 85% in the four months after the accident, and subsequently tended to rise slightly while fluctuating widely. It is possible that migration and redistribution of radiocesium occurred. The behavior of radiocesium in Tokyo was analyzed via monitoring of radiocesium in sludge incineration ash. The radiocesium activity in the incineration ash was high at wastewater treatment centers that had catchment areas in eastern Tokyo and low at those with catchment areas in western Tokyo. Similar to the case of the garden soil, even in incineration ash, the radiocesium activity dropped rapidly immediately after the accident. The radiocesium activity in the incineration ash fell steadily from the tenth month after the accident until December 2016, and its half-life was about 500 days. According to frequency analysis, in central Tokyo, the cycles of fluctuation of radiocesium activity in incineration ash and rainfall conformed, clearly showing that radiocesium deposited in urban areas was resuspended and transported by rainfall run-off. PMID- 29136643 TI - Controversy matters: Impacts of topic and solution controversy on the perceived credibility of a scientist who advocates. AB - In this article, we focus on the potential influence of a scientist's advocacy position on the public's perceived credibility of scientists as a whole. Further, we examine how the scientist's solution position (information only, non controversial, and controversial) affects the public's perception of the scientist's motivation for sharing information about specific issues (flu, marijuana, climate change, severe weather). Finally, we assess how perceived motivations mediate the relationship between solution position and credibility. Using data from a quota sample of American adults obtained by Qualtrics (n = 2,453), we found that in some conditions advocating for a solution positively predicted credibility, while in one condition, it negatively predicted scientist credibility. We also found that the influence of solution position on perceived credibility was mediated by several motivation perceptions; most notably through perception that the scientist was motivated to: (a) serve the public and (b) persuade the public. Further results and implications are discussed. PMID- 29136642 TI - Common and distinct structural features of schizophrenia and bipolar disorder: The European Network on Psychosis, Affective disorders and Cognitive Trajectory (ENPACT) study. AB - INTRODUCTION: Although schizophrenia (SCZ) and bipolar disorder (BD) share elements of pathology, their neural underpinnings are still under investigation. Here, structural Magnetic Resonance Imaging (MRI) data collected from a large sample of BD and SCZ patients and healthy controls (HC) were analyzed in terms of gray matter volume (GMV) using both voxel based morphometry (VBM) and a region of interest (ROI) approach. METHODS: The analysis was conducted on two datasets, Dataset1 (802 subjects: 243 SCZ, 176 BD, 383 HC) and Dataset2, a homogeneous subset of Dataset1 (301 subjects: 107 HC, 85 BD and 109 SCZ). General Linear Model analyses were performed 1) at the voxel-level in the whole brain (VBM study), 2) at the regional level in the anatomical regions emerged from the VBM study (ROI study). The GMV comparison across groups was integrated with the analysis of GMV correlates of different clinical dimensions. RESULTS: The VBM results of Dataset1 showed 1) in BD compared to HC, GMV deficits in right cingulate, superior temporal and calcarine cortices, 2) in SCZ compared to HC, GMV deficits in widespread cortical and subcortical areas, 3) in SCZ compared to BD, GMV deficits in insula and thalamus (p<0.05, cluster family wise error corrected). The regions showing GMV deficits in the BD group were mostly included in the SCZ ones. The ROI analyses confirmed the VBM results at the regional level in most of the clusters from the SCZ vs. HC comparison (p<0.05, Bonferroni corrected). The VBM and ROI analyses of Dataset2 provided further evidence for the enhanced GMV deficits characterizing SCZ. Based on the clinical neuroanatomical analyses, we cannot exclude possible confounding effects due to 1) age of onset and medication in BD patients, 2) symptoms severity in SCZ patients. CONCLUSION: Our study reported both shared and specific neuroanatomical characteristics between the two disorders, suggesting more severe and generalized GMV deficits in SCZ, with a specific role for insula and thalamus. PMID- 29136644 TI - Developmentally regulated internal transcription initiation during meiosis in budding yeast. AB - Sporulation of budding yeast is a developmental process in which cells undergo meiosis to generate stress-resistant progeny. The dynamic nature of the budding yeast meiotic transcriptome has been well established by a number of genome-wide studies. Here we develop an analysis pipeline to systematically identify novel transcription start sites that reside internal to a gene. Application of this pipeline to data from a synchronized meiotic time course reveals over 40 genes that display specific internal initiations in mid-sporulation. Consistent with the time of induction, motif analysis on upstream sequences of these internal transcription start sites reveals a significant enrichment for the binding site of Ndt80, the transcriptional activator of middle sporulation genes. Further examination of one gene, MRK1, demonstrates the Ndt80 binding site is necessary for internal initiation and results in the expression of an N-terminally truncated protein isoform. When the MRK1 paralog RIM11 is downregulated, the MRK1 internal transcript promotes efficient sporulation, indicating functional significance of the internal initiation. Our findings suggest internal transcriptional initiation to be a dynamic, regulated process with potential functional impacts on development. PMID- 29136645 TI - A 4-miRNA signature to predict survival in glioblastomas. AB - Glioblastomas are among the most lethal cancers; however, recent advances in survival have increased the need for better prognostic markers. microRNAs (miRNAs) hold great prognostic potential being deregulated in glioblastomas and highly stable in stored tissue specimens. Moreover, miRNAs control multiple genes representing an additional level of gene regulation possibly more prognostically powerful than a single gene. The aim of the study was to identify a novel miRNA signature with the ability to separate patients into prognostic subgroups. Samples from 40 glioblastoma patients were included retrospectively; patients were comparable on all clinical aspects except overall survival enabling patients to be categorized as short-term or long-term survivors based on median survival. A miRNome screening was employed, and a prognostic profile was developed using leave-one-out cross-validation. We found that expression patterns of miRNAs; particularly the four miRNAs: hsa-miR-107_st, hsa-miR-548x_st, hsa-miR-3125_st and hsa-miR-331-3p_st could determine short- and long-term survival with a predicted accuracy of 78%. Heatmap dendrograms dichotomized glioblastomas into prognostic subgroups with a significant association to survival in univariate (HR 8.50; 95% CI 3.06-23.62; p<0.001) and multivariate analysis (HR 9.84; 95% CI 2.93 33.06; p<0.001). Similar tendency was seen in The Cancer Genome Atlas (TCGA) using a 2-miRNA signature of miR-107 and miR-331 (miR sum score), which were the only miRNAs available in TCGA. In TCGA, patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylated tumors and low miR sum score had the shortest survival. Adjusting for age and MGMT status, low miR sum score was associated with a poorer prognosis (HR 0.66; 95% CI 0.45-0.97; p = 0.033). A Kyoto Encyclopedia of Genes and Genomes analysis predicted the identified miRNAs to regulate genes involved in cell cycle regulation and survival. In conclusion, the biology of miRNAs is complex, but the identified 4-miRNA expression pattern could comprise promising biomarkers in glioblastoma stratifying patients into short- and long-term survivors. PMID- 29136646 TI - The effect of interventions aiming to optimise the prescription of antibiotics in dental care-A systematic review. AB - BACKGROUND: Abundant evidence in dentistry suggests that antibiotics are prescribed despite the existence of guidelines aiming to reduce the development of antibiotic resistance. This review investigated (1) which type of interventions aiming to optimise prescription of antibiotics exist in dentistry, (2) the effect of these interventions and (3) the specific strengths and limitations of the studies reporting on these interventions. METHOD: Literature search was based on Medline, Embase, Global Health, Cochrane CENTRAL, ClinicalTrials.gov and Current Controlled Trials. Studies with one of the two primary outcomes were included: (1) The number of antibiotics prescribed and/or (2) the accuracy of the prescription, commonly measured as a percentage of adherence to local clinical guidelines. RESULTS: Nine studies met these inclusion criteria. Five studies reported on the prescription of antibiotics in primary dental care and four studies focused on outpatient dental care. Interventions used in primary dental care included a combination of audit, feedback, education, local consensus, dissemination of guidelines and/or academic detailing. Trials in the outpatient setting made use of expert panel discussions, educational feedback on previous acts of prescribing, the dissemination of guidelines and the establishment of internal guidelines. All studies successfully reduced the number of antibiotics prescribed and/or increased the accuracy of the prescription. However, most studies were confounded by a high risk of selection bias, selective outcome reporting and high variance across study groups. In particular, information relating to study design and methodology was insufficient. Only three studies related the prescriptions to the number of patients treated with antibiotics. CONCLUSIONS: This systematic review was able to offer conclusions which took the limitations of the investigated studies into account. Unfortunately, few studies could be included and many of these studies were confounded by a low quality of scientific reporting and lack of information regarding study methodology. High-quality research with objective and standardised outcome reporting, longer periods of follow-up, rigorous methodology and adequate standard of study reporting is urgently needed. PMID- 29136647 TI - Katanin-like 2 (KATNAL2) functions in multiple aspects of haploid male germ cell development in the mouse. AB - The katanin microtubule-severing proteins are essential regulators of microtubule dynamics in a diverse range of species. Here we have defined critical roles for the poorly characterised katanin protein KATNAL2 in multiple aspects of spermatogenesis: the initiation of sperm tail growth from the basal body, sperm head shaping via the manchette, acrosome attachment, and ultimately sperm release. We present data suggesting that depending on context, KATNAL2 can partner with the regulatory protein KATNB1 or act autonomously. Moreover, our data indicate KATNAL2 may regulate delta- and epsilon-tubulin rather than classical alpha-beta-tubulin microtubule polymers, suggesting the katanin family has a greater diversity of function than previously realised. Together with our previous research, showing the essential requirement of katanin proteins KATNAL1 and KATNB1 during spermatogenesis, our data supports the concept that in higher order species the presence of multiple katanins has allowed for subspecialisation of function within complex cellular settings such as the seminiferous epithelium. PMID- 29136648 TI - Imprinting alterations in sperm may not significantly influence ART outcomes and imprinting patterns in the cord blood of offspring. AB - An increase in imprinting disorders in children conceived though assisted reproductive technologies (ARTs) has been the subject of several reports. The transmission of imprinting errors from the sperm of infertile fathers is believed to be a possible reason for the increased occurrence of these disorders. However, whether the imprinting alterations in sperm affect ART outcomes and the imprinting of offspring is unclear. In the current study, we analyzed the methylation of H19, SNRPN and KCNQ1OT1 by pyrosequencing sperm samples from 97 infertile patients and 31 proven fertile males as well as cord blood samples from 13 infantswho were conceived by infertile parents through intracytoplasmic sperm injection (ICSI) and 30 healthy newborns who were conceived naturally. After four cases were excluded owing to the lack of a sequencing signal, the infertile patients were subgrouped into normal (69 cases) and abnormal (24 cases) imprinting groups according to the reference range set by the control group. Between the groups, there were no significant differences in ART outcomes. Significantly different levels of methylation were detected in H19, but none of the imprinted genes were determined to be outside of the methylation reference range set by the values derived from the naturally conceived controls. Three CpG loci were found to be significantly hypomethylated in the maternally imprinted gene KCNQ1OT1 in two patients from the abnormal imprinting group, none of which were caused by sperm imprinting errors. In addition, the paternal H19 gene exhibited discrepant methylation patterns between the sperm controls and the cord blood controls. Our data suggest that increased imprinting errors in the sperm of infertile patients do not have an obvious influence on ART outcomes or the imprinting of offspring. PMID- 29136649 TI - Discordance between 'actual' and 'scheduled' check-in times at a heart failure clinic. AB - INTRODUCTION: A 2015 Institute Of Medicine statement "Transforming Health Care Scheduling and Access: Getting to Now", has increased concerns regarding patient wait times. Although waiting times have been widely studied, little attention has been paid to the role of patient arrival times as a component of this phenomenon. To this end, we investigated patterns of patient arrival at scheduled ambulatory heart failure (HF) clinic appointments and studied its predictors. We hypothesized that patients are more likely to arrive later than scheduled, with progressively later arrivals later in the day. METHODS AND RESULTS: Using a business intelligence database we identified 6,194 unique patients that visited the Cleveland Clinic Main Campus HF clinic between January, 2015 and January, 2017. This clinic served both as a tertiary referral center and a community HF clinic. Transplant and left ventricular assist device (LVAD) visits were excluded. Punctuality was defined as the difference between 'actual' and 'scheduled' check-in times, whereby negative values (i.e., early punctuality) were patients who checked-in early. Contrary to our hypothesis, we found that patients checked-in late only a minority of the time (38% of visits). Additionally, examining punctuality by appointment hour slot we found that patients scheduled after 8AM had progressively earlier check-in times as the day progressed (P < .001 for trend). In both a Random Forest-Regression framework and linear regression models the most important risk-adjusted predictors of early punctuality were: later in the day appointment hour slot, patient having previously been to the hospital, age in the early 70s, and white race. CONCLUSIONS: Patients attending a mixed population ambulatory HF clinic check-in earlier than scheduled times, with progressive discrepant intervals throughout the day. This finding may have significant implications for provider utilization and resource planning in order to maximize clinic efficiency. The impact of elective early arrival on patient's perceived wait times requires further study. PMID- 29136650 TI - Emerging and reemerging arboviruses: A new threat in Eastern Peru. AB - BACKGROUND: Arboviral diseases are one of the most common causes of acute febrile illness (AFI) and a significant health problem in South America. In Peru, laboratory etiologic identification of these infections occurs in less than 50% of cases, leading to underdiagnoses of important emerging arboviruses. AIM: To assess the prevalence of the Dengue (DENV), Oropouche (OROV), Chikungunya (CHIKV), Mayaro (MAYV) and Zika (ZIKV) viruses in patients with acute febrile illness from Puerto Maldonado (Peru). METHODOLOGY: Serum samples were obtained from patients with AFI during January 2016 to March 2016. A total of 139 specimens were analyzed for the presence of DENV, OROV, CHIKV, MAYV, and ZIKV using polymerase chain reaction (PCR). RESULTS: CHIKV in 9.4% and OROV in 8.6% were the most prevalent arboviruses, followed by DENV and ZIKV, with a prevalence of 6.5% and 5%, respectively. Among all patients, the most common symptoms accompanying fever were headaches 79.9%, muscle pain 65.5% and joint pain 63.3%. CONCLUSIONS: During this short 3-month period, 4 arboviruses were detected by PCR, CHIKV and OROV being the most common arboviruses in Puerto Maldonado (Peru). Thus, it is crucial to include OROV detection in the national health surveillance. Furthermore, the etiologic clinical diagnosis of arboviral infections is not possible due to the low specificity of symptoms; therefore an increase of cases confirmed by molecular diagnostic methods will enhance arboviral surveillance in Peru. PMID- 29136651 TI - Structural basis of glycan specificity of P[19] VP8*: Implications for rotavirus zoonosis and evolution. AB - Recognition of specific cell surface glycans, mediated by the VP8* domain of the spike protein VP4, is the essential first step in rotavirus (RV) infection. Due to lack of direct structural information of virus-ligand interactions, the molecular basis of ligand-controlled host ranges of the major human RVs (P[8] and P[4]) in P[II] genogroup remains unknown. Here, through characterization of a minor P[II] RV (P[19]) that can infect both animals (pigs) and humans, we made an important advance to fill this knowledge gap by solving the crystal structures of the P[19] VP8* in complex with its ligands. Our data showed that P[19] RVs use a novel binding site that differs from the known ones of other genotypes/genogroups. This binding site is capable of interacting with two types of glycans, the mucin core and type 1 histo-blood group antigens (HBGAs) with a common GlcNAc as the central binding saccharide. The binding site is apparently shared by other P[II] RVs and possibly two genotypes (P[10] and P[12]) in P[I] as shown by their highly conserved GlcNAc-interacting residues. These data provide strong evidence of evolutionary connections among these human and animal RVs, pointing to a common ancestor in P[I] with a possible animal host origin. While the binding properties to GlcNAc-containing saccharides are maintained, changes in binding to additional residues, such as those in the polymorphic type 1 HBGAs may occur in the course of RV evolution, explaining the complex P[II] genogroup that mainly causes diseases in humans but also in some animals. PMID- 29136653 TI - drLumi: An open-source package to manage data, calibrate, and conduct quality control of multiplex bead-based immunoassays data analysis. AB - Multiplex bead-based immunoassays are used to measure concentrations of several analytes simultaneously. These assays include control standard curves (SC) to reduce between-plate variability and normalize quantitation of analytes of biological samples. Suboptimal calibration might result in large random error and decreased number of samples with analyte concentrations within the limits of quantification. Suboptimal calibration may be a consequence of poor fitness of the functions used for the SC, the treatment of the background noise and the method used to estimate the limits of quantification. Currently assessment of fitness of curves is largely dependent on operator and that may add additional error. Moreover, there is no software to automate data managing and quality control. In this article we present a R package, drLumi, with functions for managing data, calibrating assays and performing quality control. To optimize the assay the package implements: i) three dose-response functions, ii) four approaches for treating background noise and iii) three methods for estimating limits of quantifications. Other implemented functions are focused on the quality control of the fitted standard curve: detection of outliers, estimation of the confidence or prediction interval, and estimation of summary statistics. With demonstration purpose, we apply the software to 30 cytokines, chemokines and growth factors measured in a multiplex bead-based immunoassay in a study aiming to measure correlates of risk or protection from malaria of the RTS,S malaria vaccine nested in the Phase 3 randomized controlled trial of this vaccine. PMID- 29136652 TI - Tuberculosis transmission in the Indigenous peoples of the Canadian prairies. AB - SETTING: The prairie provinces of Canada. OBJECTIVE: To characterize tuberculosis (TB) transmission among the Indigenous and non-Indigenous Canadian-born peoples of the prairie provinces of Canada. DESIGN: A prospective epidemiologic study of consecutively diagnosed adult (age >= 14 years) Canadian-born culture-positive pulmonary TB cases on the prairies, hereafter termed "potential transmitters," and the transmission events generated by them. "Transmission events" included new positive tuberculin skin tests (TSTs), TST conversions, and secondary cases among contacts. RESULTS: In the years 2007 and 2008, 222 potential transmitters were diagnosed on the prairies. Of these, the vast majority (198; 89.2%) were Indigenous peoples who resided in either an Indigenous community (135; 68.2%) or a major metropolitan area (44; 22.2%). Over the 4.5-year period between July 1st, 2006 and December 31st 2010, 1085 transmission events occurred in connection with these potential transmitters. Most of these transmission events were attributable to potential transmitters who identified as Indigenous (94.5%). With a few notable exceptions most transmitters and their infected contacts resided in the same community type. In multivariate models positive smear status and a higher number of close contacts were associated with increased transmission; adjusted odds ratios (ORs) and 95% confidence intervals (CIs), 4.30 [1.88, 9.84] and 2.88 [1.31, 6.34], respectively. Among infected contacts, being Indigenous was associated with disease progression; OR and 95% CI, 3.59 [1.27, 10.14] and 6.89 [2.04, 23.25] depending upon Indigenous group, while being an infected casual contact was less likely than being a close contact to be associated with disease progression, 0.66 [0.44, 1.00]. CONCLUSION: In the prairie provinces of Canada and among Canadian-born persons, Indigenous peoples account for the vast majority of cases with the potential to transmit as well as the vast majority of infected contacts. Active case finding and preventative therapy measures need to focus on high-incidence Indigenous communities. PMID- 29136654 TI - Vascular surgical stretch injury leads to activation of P2X7 receptors and impaired endothelial function. AB - A viable vascular endothelial layer prevents vasomotor dysfunction, thrombosis, inflammation, and intimal hyperplasia. Injury to the endothelium occurs during harvest and "back table" preparation of human saphenous vein prior to implantation as an arterial bypass conduit. A subfailure overstretch model of rat aorta was used to show that subfailure stretch injury of vascular tissue leads to impaired endothelial-dependent relaxation. Stretch-induced impaired relaxation was mitigated by treatment with purinergic P2X7 receptor (P2X7R) inhibitors, brilliant blue FCF (FCF) and A740003, or apyrase, an enzyme that catalyzes the hydrolysis of ATP. Alternatively, treatment of rat aorta with exogenous ATP or 2'(3')-O-(4-Benzoyl benzoyl)-ATP (BzATP) also impaired endothelial-dependent relaxation. Treatment of human saphenous vein endothelial cells (HSVEC) with exogenous ATP led to reduced nitric oxide production which was associated with increased phosphorylation of the stress activated protein kinase, p38 MAPK. ATP- stimulated p38 MAPK phosphorylation of HSVEC was inhibited by FCF and SB203580. Moreover, ATP inhibition of nitric oxide production in HSVEC was prevented by FCF, SB203580, L-arginine supplementation and arginase inhibition. Finally, L arginine supplementation and arginase inhibition restored endothelial dependent relaxation after stretch injury of rat aorta. These results suggest that vascular stretch injury leads to ATP release, activation of P2X7R and p38 MAPK resulting in endothelial dysfunction due to arginase activation. Endothelial function can be restored in both ATP treated HSVEC and intact stretch injured rat aorta by P2X7 receptor inhibition with FCF or L-arginine supplementation, implicating straightforward therapeutic options for treatment of surgical vascular injury. PMID- 29136655 TI - Socio-behavioral risk factors among older adults living with HIV in Thailand. AB - BACKGROUND: There has been a global increase in HIV infection in persons 50 years of age and older. This group is at risk for development of chronic illness that may be exacerbated by socio-behavioral risk factors such as smoking, unhealthy alcohol use, and sedentary lifestyle. However, socio-behavioral risk factors in this older HIV infected population are not well described. The current study aims to describe and document factors related to alcohol use, tobacco smoking, and physical exercise in older adults living with HIV (OALHIV). METHODS: This cross sectional quantitative study was conducted between August and September 2015, and enrolled HIV-infected participants aged 50 years and older from 12 community hospitals in Chiang Mai Province, Northern Thailand. RESULTS: Of the 364 participants recruited in the study, 57.1% were female, and 67.3% were between 50 59 years of age. Respectively, 15.1%, 59.1%, and 18.7% were current smokers, currently engaged in physical exercises, and reported ever drank alcohol in the past year. 22.1% of those who drank alcohol reported experience of heavy episodic drinking. Male gender was one of the strongest predictors of ever drank alcohol in the past year (AOR, 4.66; CI, 2.28-9.49; P<0.001) and of being a current smoker (AOR, 13.41; CI, 7.23-24.87; P<0.001). Lower household income was associated with increased odds of ever drank alcohol in the past year (household income (1 USD = 35 THB) of <= 5,000 Baht versus > 20,000 Baht: AOR, 5.34; CI, 1.28-22.25; P = 0.021). Lower educational level was associated with decreased odds of physical exercises (no education versus secondary and higher: AOR, 0.22; CI, 0.08-0.55; P = 0.001). CONCLUSION: Smoking and alcohol use is common among OALHIV, with a substantial proportion not engaging in physical exercises. Interventions for OALHIV should particularly target males and those of lower socio-economic status to deter smoking and alcohol use and to promote physical exercises. PMID- 29136656 TI - Genetic diversity, linkage disequilibrium, and association mapping analyses of Gossypium barbadense L. germplasm. AB - Limited polymorphism and narrow genetic base, due to genetic bottleneck through historic domestication, highlight a need for comprehensive characterization and utilization of existing genetic diversity in cotton germplasm collections. In this study, 288 worldwide Gossypium barbadense L. cotton germplasm accessions were evaluated in two diverse environments (Uzbekistan and USA). These accessions were assessed for genetic diversity, population structure, linkage disequilibrium (LD), and LD-based association mapping (AM) of fiber quality traits using 108 genome-wide simple sequence repeat (SSR) markers. Analyses revealed structured population characteristics and a high level of intra-variability (67.2%) and moderate interpopulation differentiation (32.8%). Eight percent and 4.3% of markers revealed LD in the genome of the G. barbadense at critical values of r2 >= 0.1 and r2 >= 0.2, respectively. The LD decay was on average 24.8 cM at the threshold of r2 >= 0.05. LD retained on average distance of 3.36 cM at the threshold of r2 >= 0.1. Based on the phenotypic evaluations in the two diverse environments, 100 marker loci revealed a strong association with major fiber quality traits using mixed linear model (MLM) based association mapping approach. Fourteen marker loci were found to be consistent with previously identified quantitative trait loci (QTLs), and 86 were found to be new unreported marker loci. Our results provide insights into the breeding history and genetic relationship of G. barbadense germplasm and should be helpful for the improvement of cotton cultivars using molecular breeding and omics-based technologies. PMID- 29136657 TI - Contrasts in the marine ecosystem of two Macaronesian islands: A comparison between the remote Selvagens Reserve and Madeira Island. AB - The islands of Madeira and Selvagens are less than 300 km apart but offer a clear contrast between a densely populated and highly developed island (Madeira), and a largely uninhabited and remote archipelago (Selvagens) within Macaronesia in the eastern Atlantic. The Madeira Archipelago has ~260,000 inhabitants and receives over six million visitor days annually. The Selvagens Islands Reserve is one of the oldest nature reserves in Portugal and comprises two islands and several islets, including the surrounding shelf to a depth of 200 m. Only reserve rangers and a small unit of the maritime police inhabit these islands. The benthic community around Selvagens was dominated by erect and turf algae, while the community at Madeira was comprised of crustose coralline and turf algae, sessile invertebrates, and sea urchin barrens. The sea urchin Diadema africanum was 65% more abundant at Madeira than at Selvagens. Total fish biomass was 3.2 times larger at Selvagens than at Madeira, and biomass of top predators was more than 10 times larger at Selvagens. Several commercially important species (e.g., groupers, jacks), which have been overfished throughout the region, were more common and of larger size at Selvagens than at Madeira. Important sea urchin predators (e.g., hogfishes, triggerfishes) were also in higher abundance at Selvagens compared to Madeira. The effects of fishing and other anthropogenic influences are evident around Madeira. This is in stark contrast to Selvagens, which harbors healthy benthic communities with diverse algal assemblages and high fish biomass, including an abundance of large commercially important species. The clear differences between these two island groups highlights the importance of expanding and strengthening the protection around Selvagens, which harbors one of the last intact marine ecosystems in the North Atlantic, and the need to increase management and protection around Madeira. PMID- 29136658 TI - Community ecology in 3D: Tensor decomposition reveals spatio-temporal dynamics of large ecological communities. AB - Understanding spatio-temporal dynamics of biotic communities containing large numbers of species is crucial to guide ecosystem management and conservation efforts. However, traditional approaches usually focus on studying community dynamics either in space or in time, often failing to fully account for interlinked spatio-temporal changes. In this study, we demonstrate and promote the use of tensor decomposition for disentangling spatio-temporal community dynamics in long-term monitoring data. Tensor decomposition builds on traditional multivariate statistics (e.g. Principal Component Analysis) but extends it to multiple dimensions. This extension allows for the synchronized study of multiple ecological variables measured repeatedly in time and space. We applied this comprehensive approach to explore the spatio-temporal dynamics of 65 demersal fish species in the North Sea, a marine ecosystem strongly altered by human activities and climate change. Our case study demonstrates how tensor decomposition can successfully (i) characterize the main spatio-temporal patterns and trends in species abundances, (ii) identify sub-communities of species that share similar spatial distribution and temporal dynamics, and (iii) reveal external drivers of change. Our results revealed a strong spatial structure in fish assemblages persistent over time and linked to differences in depth, primary production and seasonality. Furthermore, we simultaneously characterized important temporal distribution changes related to the low frequency temperature variability inherent in the Atlantic Multidecadal Oscillation. Finally, we identified six major sub-communities composed of species sharing similar spatial distribution patterns and temporal dynamics. Our case study demonstrates the application and benefits of using tensor decomposition for studying complex community data sets usually derived from large-scale monitoring programs. PMID- 29136659 TI - Predicting the distributions of Egypt's medicinal plants and their potential shifts under future climate change. AB - Climate change is one of the most difficult of challenges to conserving biodiversity, especially for countries with few data on the distributions of their taxa. Species distribution modelling is a modern approach to the assessment of the potential effects of climate change on biodiversity, with the great advantage of being robust to small amounts of data. Taking advantage of a recently validated dataset, we use the medicinal plants of Egypt to identify hotspots of diversity now and in the future by predicting the effect of climate change on the pattern of species richness using species distribution modelling. Then we assess how Egypt's current Protected Area network is likely to perform in protecting plants under climate change. The patterns of species richness show that in most cases the A2a 'business as usual' scenario was more harmful than the B2a 'moderate mitigation' scenario. Predicted species richness inside Protected Areas was higher than outside under all scenarios, indicating that Egypt's PAs are well placed to help conserve medicinal plants. PMID- 29136660 TI - Predation risk affects growth and reproduction of an invasive snail and its lethal effect depends on prey size. AB - The behavior of invasive species under predation risk has been studied extensively, but their growth and reproductive responses have rarely been investigated. We conducted experiments with juveniles and adults of the invasive freshwater snail Pomacea canaliculata, and we observed changes in growth and reproduction in response to predation risk from a caged predator (Trachemys scripta elegans). P. canaliculata produced eggs earlier in the presence of predators and injured conspecifics compared with the control group (no risk), although the total number of egg masses laid by per female was exceeded by that of the controls after 15 days. Egg hatching success noticeably decreased under predation risk, and the incubation period was significantly prolonged; however, the oviposition height of the snails was not affected. A lethal effect of predation risk was detected in juvenile snails but not in adults. The growth of juvenile P. canaliculata was inhibited under predation risk, probably due to a reduction in food intake. Adult females exhibited a greater reduction in growth under predation risk than males, which likely resulted in part from the high reproductive investment of females in egg laying. These results indicate that P. canaliculata snails under predation risk face a trade-off between predator avoidance and growth and reproduction, where the lethal effect of predation risk is linked to the size of the prey. PMID- 29136661 TI - Domain learning naming game for color categorization. AB - Naming game simulates the evolution of vocabulary in a population of agents. Through pairwise interactions in the games, agents acquire a set of vocabulary in their memory for object naming. The existing model confines to a one-to-one mapping between a name and an object. Focus is usually put onto name consensus in the population rather than knowledge learning in agents, and hence simple learning model is usually adopted. However, the cognition system of human being is much more complex and knowledge is usually presented in a complicated form. Therefore, in this work, we extend the agent learning model and design a new game to incorporate domain learning, which is essential for more complicated form of knowledge. In particular, we demonstrate the evolution of color categorization and naming in a population of agents. We incorporate the human perceptive model into the agents and introduce two new concepts, namely subjective perception and subliminal stimulation, in domain learning. Simulation results show that, even without any supervision or pre-requisition, a consensus of a color naming system can be reached in a population solely via the interactions. Our work confirms the importance of society interactions in color categorization, which is a long debate topic in human cognition. Moreover, our work also demonstrates the possibility of cognitive system development in autonomous intelligent agents. PMID- 29136662 TI - Protective effect of metformin against retinal vein occlusions in diabetes mellitus - A nationwide population-based study. AB - Previous studies have found that metformin can reduce cardiovascular risk, but its association with retinal vein occlusion (RVO) is unknown. In this population based cohort study using the Taiwan National Health Insurance Research Database (NHIRD), we demonstrated the protective effect of metformin against RVO in diabetes mellitus (DM) and explored the incidence rate and factors associated with RVO development in general and diabetic populations. One million patients were randomly selected from the registry files of the NHIRD, and all their claims data were collected for the 1996-2011 period. Patients with a new diagnosis of central or branch RVO were identified using International Classification of Disease codes. DM was defined for patients with diagnoses and treatments. Factors associated with RVO development in the non-DM and DM cohorts were explored using Cox proportional regression models. In total, 1,018 RVO patients were identified from the database. The average incidence of RVO was 9.93 and 53.5 cases per 100,000 person-years in the non-DM and DM cohorts, respectively. Older age, DM, hypertension, and glaucoma were significant risk factors for RVO, whereas the prescription of anticoagulants was a significant protective factor. In the DM cohort, older age, hypertension, and diabetic retinopathy were significant risk factors for RVO, whereas metformin treatment was a significant protective factor. These results confirmed the risk factors for RVO and demonstrated the protective effect of metformin against RVO in DM patients. Prescribing metformin for DM patients may be beneficial for reducing the incidence of RVO, along with its hypoglycemic action. PMID- 29136668 TI - Endoscopic submucosal dissection of a squamous cell carcinoma of the esophagus developing in the area of a previous Heller's myotomy for achalasia. PMID- 29136669 TI - The endoscopic loop-and-let-go technique for treatment of an exceedingly rare cause of recurrent biliary pain. PMID- 29136663 TI - Phylogenic inference using alignment-free methods for applications in microbial community surveys using 16s rRNA gene. AB - The diversity of microbiota is best explored by understanding the phylogenetic structure of the microbial communities. Traditionally, sequence alignment has been used for phylogenetic inference. However, alignment-based approaches come with significant challenges and limitations when massive amounts of data are analyzed. In the recent decade, alignment-free approaches have enabled genome scale phylogenetic inference. Here we evaluate three alignment-free methods: ACS, CVTree, and Kr for phylogenetic inference with 16s rRNA gene data. We use a taxonomic gold standard to compare the accuracy of alignment-free phylogenetic inference with that of common microbiome-wide phylogenetic inference pipelines based on PyNAST and MUSCLE alignments with FastTree and RAxML. We re-simulate fecal communities from Human Microbiome Project data to evaluate the performance of the methods on datasets with properties of real data. Our comparisons show that alignment-free methods are not inferior to alignment-based methods in giving accurate and robust phylogenic trees. Moreover, consensus ensembles of alignment free phylogenies are superior to those built from alignment-based methods in their ability to highlight community differences in low power settings. In addition, the overall running times of alignment-based and alignment-free phylogenetic inference are comparable. Taken together our empirical results suggest that alignment-free methods provide a viable approach for microbiome-wide phylogenetic inference. PMID- 29136670 TI - Submucosal tunneling endoscopic myotomy of esophageal epiphrenic diverticulum. PMID- 29136671 TI - New indications for fully covered lumen-apposing metal stents: biliary stenting to treat post-sphincterotomy bleeding or ampullary stenosis. PMID- 29136672 TI - Laparoscopic and endoscopic cooperative surgery for difficult resection of posterior esophagogastric junction gastrointestinal stromal tumors. PMID- 29136673 TI - Endoscopic full-thickness resection of gastric stromal tumor: one and done. PMID- 29136674 TI - Familial Hyperparathyroidism - Disorders of Growth and Secretion in Hormone Secretory Tissue. AB - Six syndromes of familial hyperparathyroidism are compared: 1) Familial hypocalciuric hypercalcemia (FHH) expresses primary hyperparathyroidism (PHPT) beginning at birth with lifelong hypercalcemia. There is nonsuppressed PTH secretion from outwardly normal parathyroid glands. It reflects germline heterozygous mutation in CASR, GNA11, or AP2S1. 2) Neonatal severe primary hyperparathyroidism is severest of the six syndromes. It requires urgent total parathyroidectomy in infancy. It usually reflects biallelic inactivation of the CASR. 3) Multiple endocrine neoplasia type 1 (MEN1) is most frequently expressed as PHPT with asymmetric enlargement of 3-4 parathyroids. Benign or malignant tumors may occur among 30 other tissues. It is predisposed by germline inactivation of MEN1 or rarely by inactivation of a cyclin dependent kinase inhibitor, and then termed MEN4. 4) Multiple endocrine neoplasia type 2A from RET activating mutation rarely presents as familial hyperparathyroidism, because medullary thyroid cancer and pheochromocytoma are more prominent. 5) Hyperparathyroidism-jaw tumor syndrome (HPT-JT) has frequent PHPT and benign jaw tumors. Twenty percent develop parathyroid cancer. It is predisposed by inactivating mutation in CDC73. 6) Familial isolated hyperparathyroidism causes multiple parathyroid tumors. It can be an incomplete expression of FHH, MEN1, HPT JT or even of relatives without a shared driver mutation. However, in 20% of families it reflects GCM2 activating mutation. Five of the PHPT syndromes reflect overgrowth of parathyroid tissue; in contrast, familial hypocalciuric hypercalcemia reflects dysregulation of PTH secretion with little or no parathyroid overgrowth. These differences underlie major differences in clinical expression. PMID- 29136675 TI - Only a Rapid Complete Biochemical Remission After 131I-Therapy is Associated with an Unimpaired Life Expectancy in Differentiated Thyroid Cancer. AB - The objective of the work was to investigate the relationship between thyroglobulin doubling time (TgDT) as a marker of speed of response to 131I therapy and the differentiated thyroid cancer (DTC) recurrence rate, DTC specific mortality rate, and relative survival rate in a DTC population followed over a long period of time after 131I-therapy. From our database, data of 1354 patients were reviewed. TgDT could be calculated in 174 patients, however, 376 patients did not have sufficient Tg values available for TgDT calculation and 804 patients reached biochemical remission before a sufficient number of Tg measurements for TgDT calculation was acquired. Main outcome measures were recurrence-free, DTC specific, and relative survival rates. In patients<45 years, TgDT in multivariate analysis was identified as the solitary significant determinant of DTC specific and relative survival. In patients>=45 years of age at diagnosis, TgDT is an independent, but not the only determinant of recurrence free, DTC specific, and relative survival. Importantly, in this age group life expectancy is normal in patients reaching rapid biochemical remission (i. e., before TgDT can be calculated); it was reduced in patients with a negative TgDT, which normally is deemed a marker of response to therapy. Only DTC patients with a rapid biochemical remission have a very good prognosis with a normal life expectancy. If no rapid biochemical remission occurs, both biochemically progressive disease and a slower biochemical remission of disease are associated with a reduced prognosis, especially in older DTC patients. PMID- 29136676 TI - Papillary Thyroid Cancer and Coexisting Autoimmune Thyroiditis. AB - Histological findings often display an association between papillary thyroid carcinomas (PTC) and autoimmune thyroiditis (AIT) and so differ significantly from follicular thyroid carcinomas (FTC). The aim of this interdisciplinary, retrospective study was to evaluate the association of AIT in patients with PTC and FTC and a control group of benign nodular goiters. One hundred thyroidectomies with histologically confirmed differentiated thyroid carcinomas, 67 with PTC and 33 with FTC, were submitted for examination. The two control groups consisted of 60 patients with euthyroid nodular goiter, displaying no signs for malignancy (no surgery) and 100 patients (second control group) with surgery of a benign nodular goiter. Controls were collected to obtain data about the incidence of significantly increased TPOAbs in the first group and of lymphocytic infiltrates (LI) in the second group. High TPOAbs were found in 35% (23/67) of patients with PTC. LI were detected by histology in 48% (32/67) of PTC. Ten patients (10/32) of this group showed the clinical and histological manifestation of a classic AIT with diffuse dense LI as well as diffuse hypoechogeneity in ultrasonography. In 7/32 cases, the histological report described focal dense LI (fAIT) and in 15/32 cases scant scattered LI. AIT and fAIT, together 25% of all PTC (17/67), showed germinal centers and can therefore be characterized as chronic autoimmune thyroiditis. In this group, high TPOAb could be detected in 94% (16/17). Scan scattered LI without germinal centers (15/32) do not represent a fAIT, although TPOAb are high in 47% (7/15). The younger age group (<45 years) showed significantly more often high TPOAbs (p<0.023) in comparison with the age-group older than 60 years. In contrast to PTC, only 4/33 (12%) patients with FTC had high TPOAb levels. We conclude that in contrast to benign euthyroid goiters and to FTC, different degrees of LI are often associated with high TPOAb levels and seem to be significantly increased in PTC, particularly prominent in younger age. There is a high coincidence between LI and high TPOAb levels. In the presence of hypoechoic thyroid nodule, signs of thyroid autoimmunity such as the presence of high TPOAbs, lymphocytic infiltration in cytology, and/or characteristic ultrasonic features, are arguments that might favor the decision for surgery if a cytologically indeterminate thyroid nodule is found and focal autonomy is excluded by szintiscan. PMID- 29136677 TI - Thymus Growth and Fetal Immune Responses in Diabetic Pregnancies. AB - Type 1 diabetes (T1D) during pregnancy possibly affects the development of the thymus and the maturation of the immune system in the offspring. The aim of the ImmunDiabRisk study was to investigate thymus growth and maternal and fetal immune responses in pregnancies with and without T1D. The thymus circumferences of the fetuses of pregnant women with T1D (n=49) and without diabetes (n=59) were measured using ultrasound around the 29th gestational week and standardized for gestational age. Simultaneously, the frequencies and total numbers of cell markers were analyzed by flow cytometry in maternal peripheral blood, and at birth in umbilical cord blood. The standardized circumference of the thymus was similar in fetuses of mothers with and without T1D (p=0.26). We observed higher numbers of FOXP3 Tregs, memory Tregs, erythrocytes, and lymphocytes in the cord blood from T1D pregnancies (p=0.01, p=0.002, p=0.002 and p=0.02, respectively). The frequencies of CD4+/CD8+ T cells correlated positively in maternal blood and umbilical cord blood of mother-child pairs, as did the levels of neutrophils (Spearman's correlation coefficient r=0.43, p=0.02 for CD4+/CD8+ cells; r=0.46, p=0.03 for neutrophils), while no significant correlations were observed between thymus circumference and any cell markers in the child. Parts of the prenatal immune system seem to develop differently in the offspring of mothers with and without T1D. The correlation of Tregs between maternal blood and cord blood may indicate a significant cross-talk between the maternal and fetal immune system. PMID- 29136678 TI - Professor Sotorios Raptis. PMID- 29136679 TI - Current trends and pitfalls in endoscopic treatment of urolithiasis. AB - Current development of endoscopic technology, lithotripters, and stone-retrieval devices has expanded the indications for retrograde and antegrade endoscopic therapy in the management of urolithiasis. This technology has also resulted in minimally invasive therapy. As surgeons' experience of endourological procedures with the newer instruments has become integrated, the surgical technique and indications for urolithiasis have also changed in the past few years. The present review provides an overview of endourological procedures for upper urinary tract stones and the key points related to surgical techniques. PMID- 29136680 TI - Developing prognostic biomarkers in intermediate age-related macular degeneration: their clinical use in predicting progression. AB - Age-related macular degeneration is a common, complex and blinding eye disease. When early and intermediate levels of severity are detected in one or both eyes, there is a wide-ranging 0.4 to 53 per cent risk of progression to advanced disease in five years. In order to maximise visual outcomes for their patients, practising eye-care professionals must be able to stratify patients according to their risk of progression, intervene (for example by recommending smoking cessation or nutritional supplements and Amsler grid self-monitoring in intermediate disease) and monitor accordingly. With the aid of ocular imaging, a range of under-recognised yet meaningful risk factors have been identified. The purpose of this review is to assist the eye-care practitioner in stratifying the risk of progression in intermediate age-related macular degeneration using the range of established and emerging precursory signs that herald loss of vision. PMID- 29136681 TI - Assessment of multiple cytochrome P450 activities in metabolically inactivated human liver microsomes and roles of P450 2C isoforms in reaction phenotyping studies. AB - The fraction of substrate metabolized (fm ) can be used to estimate drug interactions and can be determined by comparison of the intrinsic clearances (CLint ) of victim drugs obtained from inhibited and uninhibited hepatic enzymes. Commercially available human liver microsomes were recently developed in which one cytochrome P450 (P450) isoform is selectively inactivated. These inactivated liver microsomes were used to evaluate the roles of P450 2C isoforms in the depletion and oxidation of probe substrates. Determination of CLint with sets of control and P450 2C9-inactivated liver microsomes yielded fm,P450 2C9 values of 0.69-1.0 for celecoxib, diclofenac and warfarin. Apparent minor contributions of P450 1A2/2C8/3A4 were seen in depletion assays, yielding ~1 for the sum of the fm values. Selectively inactivated liver microsomes were thereby shown to be potentially useful for determining the in vitro fm values for major P450 2C9 contributions to substrate oxidations. Metabolite formations from diclofenac and warfarin were suppressed by 62-84% by the replacement of control liver microsomes with P450 2C9-inactivated liver microsomes. R-, S- and racemic omeprazole and troglitazone oxidation activities by liver microsomes at multiple substrate concentrations were suppressed by 26-36% and 22-50%, respectively, when P450 2C19 and 2C8-inactivated liver microsomes were used in place of control liver microsomes. This study provides important information to help elucidate the different roles of P450 isoforms in metabolite formation at different substrate concentrations. The data obtained allow the fractions metabolized to be calculated for victim drugs. PMID- 29136682 TI - Exploring the cancer caregiver's journey through web-based Meaning-Centered Psychotherapy. AB - OBJECTIVE: Psychosocial interventions are historically underutilized by cancer caregivers, but support programs delivered flexibly over the Internet address multiple barriers to care. We adapted Meaning-Centered Psychotherapy for cancer caregivers, an in-person psychotherapeutic intervention intended to augment caregivers' sense of meaning and purpose and ameliorate burden, for delivery in a self-administered web-based program, the Care for the Cancer Caregiver (CCC) Workshop. The present study evaluated the feasibility, acceptability, and preliminary effects of this program. METHODS: Eighty-four caregivers were randomized to the CCC Workshop or waitlist control arm. Quantitative assessments of meaning, burden, anxiety, depression, benefit finding, and spiritual well being were conducted preintervention (T1), within 2-weeks postintervention (T2), and 2- to 3-month follow-up (T3). In-depth semistructured interviews were conducted with a subset of participants. RESULTS: Forty-two caregivers were randomized to the CCC Workshop. Attrition was moderate at T2 and T3, with caregiver burden and bereavement as key causes of drop-out. At T2 and T3, some observed mean change scores and effect sizes were consistent with hypothesized trends (eg, meaning in caregiving, benefit finding, and depressive symptomatology), though no pre-post significant differences emerged between groups. However, a longitudinal mixed-effects model found significant differential increases in benefit finding in favor of the CCC arm. CONCLUSIONS: The CCC Workshop was feasible and acceptable. Based on effect sizes reported here, a larger study will likely establish the efficacy of the CCC Workshop, which has the potential to address unmet needs of caregivers who underutilize in person supportive care services. PMID- 29136684 TI - [Issues for special attention in pathology field of China]. PMID- 29136683 TI - Why is Meaning-Centered Group Psychotherapy (MCGP) effective? Enhanced sense of meaning as the mechanism of change for advanced cancer patients. AB - OBJECTIVES: Meaning-Centered Group Psychotherapy (MCGP) has been demonstrated to be an effective method for improving advanced cancer patients' quality of life and reducing their depression, hopelessness, and desire for hastened death. To further understand MCGP, this study examined the mechanisms of change in MCGP on these outcomes via advanced cancer patients' changes of sense of meaning and peace in life. METHODS: The sample data were from 2 randomized control trials that compared MCGP (n = 124) to supportive group psychotherapy (n = 94). Mediation effects of treatment status on outcomes (2 months after completion of treatment) via patients' change in sense of meaning and peace (posttreatment minus pretreatment) were tested. The outcome variables used in these analyses were quality of life, depression, hopelessness, and desire for hastened death. RESULTS: Significant mediation effects via change in sense of meaning and peace on these outcomes were found. Consistent results were found using intention-to treated statuses. Weaker, but still significant, mediation effects via change in sense of faith on these outcomes were also found. CONCLUSIONS: Results supported the hypotheses that improvement due to MCGP is mediated by advanced cancer patients' enhanced sense of meaning. These findings highlight the importance of interventions focused on enhancing sense of meaning, as this appears to be a viable route to improve quality of life and decrease psychological distress among patients with advanced cancer. PMID- 29136685 TI - [Heterogeneity and stem cells of gastric cardiac carcinoma: recent discoveries]. PMID- 29136686 TI - [Clinicopathologic and molecular characteristics of malignant gastrointestinal neuroectodermal tumors]. AB - Objective: To investigate the clinicopathologic and molecular characteristics, diagnostic, differential diagnostic and prognostic features of malignant gastrointestinal neuroectodermal tumor. Methods: Two cases of malignant gastrointestinal neuroectodermal tumor were retrieved; the clinical and radiologic features, histomorphology, immunophenotype, molecular genetics and prognosis were analyzed and the relevant literature reviewed. Results: Case 1 was a 57-year-old male, presented with recurrent abdominal pain and melena. Pelvic imaging showed a circumscribed thickening of the wall of a small intestinal segment, and a malignant lymphoma was favored. Case 2 was a 24-year-old male, presented with recurrent small intestinal malignancy. Imaging demonstrated multiple masses in the peritoneal and pelvic cavities, and a malignant gastrointestinal stromal tumor with multiple metastases was suspected. Grossly both tumors were located mainly in the muscularis propria of small intestine. Case 1 showed a single 5.5 cm tumor; and case 2 consisted of two tumors measuring 4 cm and 6 cm respectively. Microscopic examination of both tumors showed small round blue, but focally spindled or clear tumor cells in solid pattern. The tumor cells had scanty cytoplasm, indistinctive nucleoli and brisk mitoses. Osteoclast like giant cells were dispersed within the stroma. In case 1 rosette-like and pseudo-papillary growth patterns were noted, and in case 2 there were variable sized hemorrhagic cysts. By immunohistochemistry, both tumors showed strong and diffuse expression of SOX10 and S-100, and focal to diffuse expression of neuroendocrine markers (CD56 or synaptophysin). Case 2 exhibited focal reactivity to pan-cytokeratin. Both tumors lacked expression of markers associated with gastrointestinal stromal tumor, smooth muscle tumor, melanoma (HMB45 or Melan A), dendritic cell tumor and Ewing sarcoma. Fluorescence in situ hybridization analysis demonstrated EWSR1 rearrangement in both tumors and the next generation sequencing confirmed EWSR1-ATF1 gene fusion in case 2. At follow-up of 16 months, case 1 was recurrence or metastasis free; whereas case 2 showed multiple recurrences and metastases within 19 months although stable disease was transiently achieved when treated with combinations of multidrug and targeted chemotherapy. Conclusions: Malignant gastrointestinal neuroectodermal tumor is a rare and aggressive soft tissue sarcoma with a predilection for small intestine. It has distinctive morphologic, immunohistochemical and molecular characteristics and needs to be distinguished from other small blue round and spindle cell tumors that occur in the gut. Careful attentions to its characteristic histomorphology with the judicious use of immunohistochemistry and molecular genetics can help to distinguish this tumor from its many mimickers. PMID- 29136687 TI - [Gastric glomus tumors expressing synaptophysin: clinicopathologic and immunohistochemical analyses]. AB - Objective: To investigate the clincopathologic and immunohistochemical features of gastric glomus tumors and their differences from gastric neuroendocrine neoplasms. Methods: Six cases of gastric glomus tumors, 8 cases of glomus tumors in other sites and 7 cases of gastric neuroendocrine neoplasms were collected from the Department of Pathology, Taizhou Hospital. The clinicopathological and immunohistochemical characteristics of these tumors were analyzed retrospectively. Results: The gastric glomus tumors were located in the muscularis propria of the antrum and most cases strongly expressed synaptophysin (5/6). However, no synaptophysin expression was seen in glomus tumors of other organs.Most gastric neuroendocrine neoplasms were located in the mucosa or submucosa of the fundus and corpus. In addition to the strong expression of synaptophysin (7/7), CgA (6/7) and CD56(5/7) were strongly positive, although SMA was negative. Conclusions: Gastric glomus tumors and neuroendocrine neoplasms have similar morphological characteristics and both show strongly expression of synaptophysin. However, the location and immunohistochemical characteristics of gastric glomus tumors differ from those of the neuroendocrine neoplasms. PMID- 29136688 TI - [Characteristics of ERG, Fli-1, CD34, CD31 and FVIIIRAg expression in hepatic malignant vascular tumors]. AB - Objective: To investigate the expression of ERG, Fli-1, CD34, CD31 and factor VIII-related antigen(FVIIIRAg) in hepatic malignant vascular tumors. Methods: A retrospective analysis was conducted on 63 cases of primary hepatic malignant vascular tumors and 31 cases of hepatic other malignant spindle cell tumors collected during January 1986 to January 2014. EnVision method was used to detect the expression of ERG, Fli-1, CD34, CD31, FVIIIRAg. Results: Sixty-three cases of malignant vascular tumors, including 24 cases of angiosarcoma, 38 cases of epithelioid hemangioendothelioma and 1 case of hepatic Kaposi's sarcoma. All of the cases were positive for ERG(100.0%, 63/63). Positive rate of Fli-1, CD34, CD31, FVIIIRAg was 96.8% (61/63), 87.3% (55/63), 81.0% (51/63) and 41.3% (26/63), respectively. In other hepatic malignant spindle cell tumors, the positive rate of ERG, Fli-1, CD34, CD31 and FVIIIRAg was 3.2% (1/31), 19.4% (6/31), 19.4% (6/31), 9.7%(3/31) and 3.2%(1/31), respectively.The sensitivity of ERG, Fli-1, CD34, CD31, FVIIIRAg was 100.0%, 96.8%, 87.3%, 81.0% and 41.3%, respectively.The specificity was 96.8%, 80.6%, 80.6%, 90.3% and 96.8%, respectively. Conclusion: ERG is a more sensitive and specific diagnostic marker for hepatic malignant vascular tumors in comparison to Fli-1, CD34, CD31 and FVIIIRAg. PMID- 29136689 TI - [Detection of epidermal growth factor receptor gene mutations in different types of non-small cell lung cancer by droplet digital PCR and amplification refractory mutation system]. AB - Objective: To compare amplification refractory mutation system(ARMS) and droplet digital PCR (ddPCR) in the detection of epidermal growth factor receptor (EGFR) gene mutations in patients with non-small cell lung cancer (NSCLC), and to investigate the clinical value of ddPCR. Methods: A total of 79 specimens of NSCLC, including 22 cases of cell block, 18 cases of surgical specimens, 12 cases of biopsy specimens and 27 cases of plasma samples, were analyzed for the mutation status of EGFR gene by ARMS and droplet digital PCR method. Results: In 18 cases of surgical specimens and 12 cases of biopsy specimens, the detection results by the two methods were identical with positive rates of 9/18 and 5/12, respectively. In 22 cases of effusion cell blocks, ARMS detected 19-del and L858R of EGFR gene in two cases, in which droplet digital PCR detected 19-del+ T790M mutations in one case and L858R+ T790M mutation in another. L858R mutation was detected by droplet digital PCR in one case but ARMS assay was negative. The remaining 19 cases were consistent by the two methods. In blood samples, the positive rate was 33.3%(9/27) by ARMS and 37.0%(10/27) by droplet digital PCR. Two cases showed L858R and 19-del+ T790M mutation by droplet digital PCR but ARMS assay detected only 19-del. The remaining 25 cases were consistent by the two methods. Conclusion: Droplet digital PCR method is more sensitive and accurate than ARMS for the detection of EGFR mutations in pleural fluid and blood samples, can be used in clinical test. PMID- 29136690 TI - [Values of JAZF1 gene rearrangement detected by fluorescence in-situ hybridization in diagnosis of endometrial stromal tumours]. AB - Objective: To investigate the role of JAZF1 gene rearrangement in the diagnosis and differential diagnosis of endometrial stromal sarcomas by fluorescence in situ hybridization (FISH). Methods: JAZF1 gene rearrangement was analyzed by FISH in 129 cases of ESS diagnosed from January 2008 to December 2016 including 105 cases of low-grade endometrial stromal sarcoma (LG-ESS), 21 cases of high-grade endometrial stromal sarcoma (HG-ESS) and 3 cases of undifferentiated uterine sarcoma (UUS). Sixteen cases of the related tumours in uterus were also collected as control group. The results were compared with our previous studies of JAZF1/JJAZ1 fusion gene in ESS by RT-PCR. Results: Detection of JAZF1 gene rearrangement by FISH was successfully analyzed in 144 cases. JAZF1 gene alteration was detected in 63 cases, all of which were LG-ESS, with an overall positivity of 60.6% (63/104), while no JAZF1 gene rearrangement was found in all other cases. JAZF1 gene rearrangement was present in LG-ESS with classic histology (69.3%, 52/75), smooth muscle differentiation (2/10), sex cord-like differentiation (4/5), fibromyxoid change (1/5), clear cell change (0/1), skeletal muscle differentiation (0/1), and schwannoma-like palisading pattern (0/1). The different components in all the cases of LG-ESS with variant histology had the clonal origin, with or without JAZF1 gene alteration. Compared to the results of JAZF1/JJAZ1 fusion gene by RT-PCR, the positive rate of JAZF1 gene rearrangement in LG-ESS by FISH (61.9%, 26/42) was significantly higher than that of RT-PCR (30.0%, 12/40; P<0.01). Conclusions: JAZF1 gene rearrangement is present only in LG-ESS, but not in HG-ESS, UUS or other related tumours in uterus. The frequency of JAZF1 gene rearrangement varies between classic LG-ESS and different morphologic variants. It is frequently, but not consistently, present in classic LG-ESS and less often positive in variant cases. The results of JAZF1 gene alterations in LG-ESS with different morphologic variants support the contention that the endometrial stromal and their variant morphologic components have the same clonal origin. Detection of JAZF1 gene rearrangement by FISH is very useful for the diagnosis and differential diagnosis of ESS. PMID- 29136691 TI - [Tumors of lymphoid and hematopoietic tissue of spleen: a clinicopathologic analysis of 53 cases]. AB - Objective: To study the clinicopathologic features, diagnosis and differential diagnosis of the tumors of lymphoidand hematopoietic tissue of the spleen(TLTS). Methods: Fifty-three cases of TLTS were selected from the pathologic files from Peking University People's Hospital from April 2002 to April 2017. According to WHO classification of tumors of hematopoietic and lymphoid tissues (2008) and its updated classification (2016), the cases were studied by microscopy, immunohistochemistry and in situ hybridization, combined with the bone marrow biopsy and clinical examination. Results: In 53 cases of TLTS, the male to female ratio was 3.4?1.0; the mean age was 55.4 years (range 21-76 years), and all patients presented with variable degree of splenomegaly. Laboratory examination showed increased percentage of lymphocyte in peripheral blood in 22 cases, and elevated serum LDH level in 24 cases. Abnormal blood counts were seen in 26 cases pre-operatively, in which 22 cases showed complete or partial correction of these abnormalities post-operatively (84.6%, 22/26). The clinical symptoms included abdominal pain or distension, fatigue, fever, and weight loss, etc. Seventeen cases presented with lymphadenopathy of abdomen or other sites. Bone marrow biopsy was performed in 30 cases, and 19 cases were involved by tumor (63.3%). Of all 53 cases, 43 were diagnosed as primary splenic lymphoma (PSL), and the remaining 10 cases as secondary TLTS. According to Ann Arbor staging, 14 cases were stages I or II, 6 were stage III and 28 were stage IV. By histopathologic classification, 43 cases of PSL were splenic B-cell marginal zone lymphoma (SMZL; 48.8%, 21/43), diffuse large B cell lymphoma (DLBCL; 23.3%, 10/43), splenic diffuse red pulp small B-cell lymphoma (11.6%, 5/43), mantle cell lymphoma (9.3%, 4/43), follicular lymphoma (4.7%, 2/43), and composite lymphoma (CL, DLBCL and classical Hodgkin lymphoma; 2.3%, 1/43). The remaining 10 cases were chronic lymphocytic leukaemia/small lymphocytic lymphoma (4 cases), hairy cell leukaemia (1 case), hepatosplenic T-cell lymphoma (HSTL; 5 cases), with lesions in other sites. Of the 53 cases of TLTS, 47 were B cell neoplasm (88.7%, 47/53), and the T cell neoplasms were all HSTL(5 cases, 9.4%, 5/53), 1 case was composite lymphoma. In 11 cases of TLTS, EBER in situ hybridization was performed and all cases were negative. Forty eight cases had follow-up data, and the median survival period was 17.0 months(range: 1-96 months). The survival of patients with SMZL and DLBCL were 25.7 and 18.6 months respectively. Thirteen patients died (27.1%, 13/48). The prognosis of those with elevated LDH level, high clinical stage, B symptoms and older than 60 years of age was worse. And the prognosis of DLBCL was worse than that of SMZL. There was no statistically significant difference between these factors and prognosis (P>0.05). Conclusions: Most TLTS cases present with splenomegaly and abnormal blood counts, and complete or partial remission of blood counts isseen after splenectomy. The most common pathologic types of TLTS are SMZL and DLBCL. Definite diagnosis of TLTS could be made by combining clinical features, histopathology, immunophenotype, genetics, bone marrow biopsy and laboratory examination. PMID- 29136693 TI - [Application of clear margins in pathologic diagnosis of cold-knife conization tissues]. PMID- 29136692 TI - [Expression and prognostic values of PD-1, PD-L1 and IDO-1 in sinonasal malignant mucosal melanoma]. AB - Objective: To investigate the correlation between the expression of programmed death-1(PD-1), PD ligand-1(PD-L1), indoleamine 2, 3-dioxygenase 1(IDO-1) and clinical parameters in sinonasal malignant mucosal melanoma (SNM). Methods: Samples from 86 SNM patients who did not receive immune-targeted therapy and radio-chemotherapy were analyzed for PD-1, PD-L1, and IDO-1 expression by immunohistochemistry. Results: High clinical/pathologic staging, brain metastases and advanced age were independent risk factors of poor prognosis. The overall survival rate of SNM without pigment was lower than that with pigment. PD-1, PD L1 and IDO-1 expression was not correlated with tumor pigmentation, but correlated with different primary site.PD-1, PD-L1 and IDO-1 were expressed in 47.6% (41/86), 53.5% (46/86) and 58.1% (50/86)of SNM samples respectively. PD-1 was associated with brain metastasis. Negative expression of PD-1(P=0.031) and IDO-1(P=0.017 9) correlated with worse disease-free survival. No significant association was found between PD-L1 and prognosis. For stages III, IVA and IVB patients, PD-1 expression was associated with better outcome (P=0.025), but PD-L1 negative and IDO-1 positive patients hadworse outcome (P>0.05). PD-1 positive and IDO-1 negative stage IVC patients had poorer overall survival. Conclusions: In SNM patients, clinical/pathologic staging, brain metastases, age and pigmentation were prognostic indicator. IDO-1 and PD-1 can also be used as reference to evaluate prognosis. Anti-IDO-1 targeted therapy may be suitable for middle to late stage patients, while advanced stage patients might benefit from anti-PD-1 targeted therapy. PD-1/PD-L1 and IDO-1 may be considered as joint targeted therapy.The predictive value of PD-L1 requires further study. PMID- 29136694 TI - [Endoscopic full-thickness resection of synaptophysin-positive glomus tumor in gastric body: report of a case]. PMID- 29136695 TI - [Metastatic epithelioid hemangioendothelioma of peritoneum with florid mesothelial hyperplasia mimicking malignant mesothelioma: report of a case]. PMID- 29136696 TI - [Cervical invasive stratified mucin-producing carcinoma: report of a case]. PMID- 29136697 TI - [Occult breast cancer with ipsilateral axillary and cervical lymph node metastasis: report of a case]. PMID- 29136698 TI - [Epithelial-predominant adult Wilms' tumor: report of 2 cases]. PMID- 29136699 TI - [Gastrointestinal hamartomatous polyps]. PMID- 29136700 TI - [Newer antibodies for diagnostic pathology]. PMID- 29136701 TI - [Research progress on the dysfunction of interstitial cells of Cajal in gastrointestinal motlity diseases]. PMID- 29136702 TI - [Research progress of SATB2 in differential diagnosis and malignant tumor]. PMID- 29136704 TI - [Pay attention to the diagnosis and treatment of myeloma-related kidney disease]. PMID- 29136703 TI - [Best wishes to the guidelines for the diagnosis and management of multiple myeloma in China (2017 revision)]. PMID- 29136705 TI - [The guidelines for the diagnosis and management of multiple myeloma in China (2017 revision): interpretation of initial treatment]. PMID- 29136706 TI - [The guidelines for the diagnosis and management of multiple myeloma in China (2017 revision): interpretation of treatment of relapsed/refractory multiple myeloma]. PMID- 29136707 TI - [The guidelines for the diagnosis and management of multiple myeloma in China (2017 revision): interpretation of response criteria]. PMID- 29136708 TI - [Analysis of risk factors related to the prognosis in patients with late-onset severe pneumonia after allogeneic hematopoietic stem cell transplantation]. AB - Objective: To investigate the prognostic factors of late-onset severe pneumonia (LOSP) in patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: From January 2009 to December 2015, 68 patients with LOSP after allo-HSCT at Peking University Institute of Hematology were enrolled. In this retrospective study, univariate and multivariate analysis were used to evaluate the prognostic factors for LOSP after allo-HSCT. Results: The median time from allo-HSCT to the development of LOSP was 213 (90-2 330) days. The overall survival rate was 42.6% (29/68). The median survival time from LOSP to death was 21 days. Early mortality was defined as death within 21 days after LOSP, as late death more than or equal to 21 days. The median oxygenation index was 199.15 (92.21-290.48) mmHg. LOSPs in thirty-two patients (36.8%) were caused by virus, bacteria, fungi or mixed pathogens. The median C-reactive protein (CRP) was 75.65 (0.94-451.00) mg/L. The median procalcitonin (PCT) was 0.66 (0.00-249.00) MUg/L. The higher PCT value indicated an early higher mortality rate by the ROC curve (PCT: cut-off >=0.94 MUg/L). Furthermore, multivariate analysis suggested that PCT more than or equal to 0.94 MUg/L was a risk factor for early death of LOSP (OR=5.77, 95%CI 1.66-20.11, P=0.006). LOSP occurred later or equal to 213 days after allo-HSCT was also a risk factor of early death in LOSP (OR=4.74, 95%CI 1.33-16.89, P=0.017). No previous history of chronic graft versus host disease (GVHD) (OR=4.50, 95%CI 1.58-12.83, P=0.005) and LOSP later or equal to 213 days (OR=4.40, 95%CI 1.61-11.99, P=0.004) were the risk factors of late death in LOSP. Conclusions: PCT more than or equal to 0.94 MUg/L and LOSP later or equal to 213 days are the risk factors of early death in LOSP. No previous chronic GVHD and LOSP later or equal to 213 days are the risk factors of late death in LOSP. PMID- 29136709 TI - [The clinical analysis of frontline nilotinib vs imatinib therapies for newly diagnosed chronic myeloid leukemia in chronic phase]. AB - Objective: To compare the clinical efficacy and safety of nilotinib and imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase(CML-CP). Methods: Until December 31st 2016, 18 patients using nilotinib and 83 using imatinib were recruited in our study. The efficacy and safety of two groups were evaluated. Results: A total of 101 patients with CML-CP included 18 receiving nilotinib and 83 imatinib. The optimal response rates at 3, 6, 12 and 18 months in nilotinib and imatinib group were 88.9% (16/18) vs 57.3% (47/82) (P=0.012), 82.4% (14/17) vs 55.7% (44/79) (P=0.041), 9/12 vs 63.9% (39/61) (P=0.460), 6/9 vs 68.9% (31/45) (P=0.896) respectively. The optimal response rates by 3 months in low sokal risk group on nilotinib and imatinib were 9/9 vs 76.5%(26/34) (P=0.107), in intermediate and high sokal risk group were 7/8 vs 45.2%(14/31) (P=0.032). At the end of follow-up, the rate of major molecular response (MMR) in nilotinib group was 72.2%, which was higher than 56.6% in imatinib group (P=0.021). The rate of complete cytogenetic response (CCyR) in nilotinib group was 100%, which was higher than 71.1% in imatinib group (P = 0.002). Progression free survival (PFS) rates in nilotinib and imatinib groups were 94.4% and 98.8% (P=0.019) respectively; whereas event free survival (EFS) rates were 88.9% and 48.2% (P=0.045). The incidence of drug related adverse reactions in nilotinib and imatinib was similar with only minor proportion of grade 3/4 adverse reactions. Conclusions: Nilotinib achieves a deeper molecular response in a shorter time than imatinib in newly diagnosed patients with CML-CP, especially in patients with high risk outcome. Good safety is obtained in both groups so as to ensure a long-term administration and improving prognosis. PMID- 29136710 TI - [Clinical characteristics of 128 hospitalized patients with syndrome of inappropriate antidiuretics of different etiologies]. AB - Objective: To summarize and analyze the clinical features and etiologies in hospitalized patients with syndrome of inappropriate antidiuretics (SIAD) during the past 25 years. Methods: All data of 128 patients with SIAD admitted to Chinese PLA General Hospital since January 1991 to January 2016 were collected. SIAD was diagnosed based on the 1957 criterion. Results: (1) The most frequent causes of increased inappropriate secretion of vasopressin were malignant tumors, lung diseases (e. g. pneumonia), and central nervous system diseases, in which malignant tumors accounted for 38.28% of the SIAD. (2) During the past 25 years, the proportion of malignant diseases declined from 4/7 to 35.29%, while, the proportion of pulmonary infection increased from 1/7 to 35.29% (P<0.05). (3) The patients with malignant tumors had the lowest serum sodium and serum osmolality among all SIAD patients. (4) CT scan had a high diagnostic value for chest and brain detection. (5) Among three SIAD subjects with unknown reasons at onset, two were diagnosed with small cell lung cancer and one with gastric cancer during follow-up. Conclusion: The etiology of SIAD is complex and it could be attributed to multifarious etiological factors. Malignant tumors account for the largest proportion of all patients, and pulmonary infection was ranked in second place. Cautions on tumors have to be taken when serum sodium of a SIAD patient is below 118.1 mmol/L. PMID- 29136711 TI - [The optimal cutoff value of waist-to-height ratio in Chinese: based on cardiovascular risk and metabolic disease]. AB - Objective: Waist-to-height ratio (WHtR), a measurement of the distribution of body fat, correlated with abdominal obesity indicating that it might be a better predictor of cardiovascular risk and metabolic disease. We, therefore, evaluated optimal WHtR cutoff points according to the risk of framingham risk score (FRS) and metabolic syndrome (MS) in Chinese. Methods: The subjects were from China National Diabetes and Metabolic Disorders Survey during 2007-2008. Receiver operating characteristic analysis was used to examine the optimal cutoff values of WHtR according to the risk of FRS and MS. Results: A total of 27 820 women and 18 419 men were included in the evaluation. The average age was (45.0+/-13.7) years. The proportions of FRS >=10% and MS increased with WHtR both in men and women. The cutoff points of WHtR for the risk of FRS >=10% and MS were 0.51, 0.52 in men, and 0.52, 0.53 in women, respectively. When FRS >=10% and MS were taken into consideration with a certain weights, the pooled cutoffs of WHtR were 0.51 in men, and 0.53 in women, respectively. By using the similar method, the optimized cutoff points were 0.52, 0.51, 0.50 for men and 0.51, 0.53, 0.54 for women in age group 20-39, 40-59 and >=60 years, respectively. Conclusions: The optimal cutoffs of WHtR are 0.51 in men, and 0.53 in women for FRS>=10% in combination with MS indicating that this WHtR cutoff points might be used as indexes to evaluate obesity and risk of obesity-related diseases. PMID- 29136712 TI - [Long-term outcome and prognostic factors in pregnant women with pulmonary arterial hypertension associated with congenital heart disease]. AB - Objective: To investigate the perinatal outcome, risk factors and long-term outcome of pregnancy complicated with pulmonary arterial hypertension(PAH) and congenital heart diseases (CHD). Methods: Clinical data of 110 pregnant women who were diagnosed as PAH-CHD were retrospectively analyzed in the Department of Obstetrics and Gynecology and Surgical Intensive Care Unit at Beijing Anzhen Hospital from 2004 to 2013. The survival and treatment status were followed up. Results: 110 subjects consisted of 11 mild PAH, 33 moderate and 66 severe ones. The incidences of deterioration in New York Heart Association (NYHA) classes (>=2) during pregnancy, respiratory failure, pulmonary hypertension crisis and arrhythmia were 25.5% (28/110), 7.3% (8/110), 10.0% (11/110), 10.0% (11/110) respectively. Among them, the difference of deterioration in NYHA classes (>=2) during pregnancy among the three groups was statistically significant. A total of 8 (7.3%) maternal deaths occurred during hospitalization, all of whom were severe PAH cases. Multivariate analysis showed that pulmonary artery systolic pressure was a risk factor of perioperative death (OR=1.042, P=0.005). There were 55 cases (50.0%) of term delivery, and 35 cases (31.8%) of iatrogenic abortion. The proportion of term delivery in the severe PAH group was significantly lower. The proportion of iatrogenic abortion and small for gestational age infant (SGA) were higher in severe group. The incidence of neonatal malformations was 8.0% (6/75). The follow-up rate was 61.8% (63/102). Sudden death was reported in a parturient a few days after discharge. The remaining 62 patients survived during follow-up, while 53 patients (85.5%) were functional class (FC) I-II, 9 (14.5%) were FC III IV at follow-up. The cardiac function deterioration during pregnancy was not significantly correlated with long-term deterioration (P=0.767). Conclusions: Perinatal mortality and the incidence of maternal and fetal adverse events were high in pregnancy with PAH-CHD. Pulmonary artery systolic pressure is a major risk factor for perioperative mortality in pregnant women. PAH-CHD woman had good overall outcome after puerperium. PMID- 29136713 TI - [The associations between adenosine triphosphate binding cassette subfamily G member-2 single nucleotide polymorphism and hyperuricemia in a Chinese tertiary hospital faculty cohort]. AB - Objective: To investigate gender specific association between single nucleotide polymorphism rs2231142 and hyperuricemia. Method: A matched case-control study was conducted in a faculty cohort of a tertiary hospital in Beijing. The enrollment criteria were faculty member of the hospital with signed consent. The exclusion criteria were tumor, previous renal diseases, renal function damage, pregnancy, currently taking medicines that could increase or decrease serum uric acid level, and those who had gout. Males with serum uric acid>416.4 MUmol/L and females with serum uric acid> 359.6 MUmol/L were enrolled as hyperuricemia group. Subjects with normal serum uric acid were randomly enrolled at 1?2 ratio after matching for gender, age, renal function and body mass index. Rs2231142(C>A) was assayed by amplification refractory mutation system polymerase chain reaction, with common forward primer: 5' GGCTTTGCAGACATCTATGG 3', C specific reverse primer: 5'CGAAGAGCTGCTGAGAAATG 3', and A specific reverse primer: 5' CGAAGAGCTGCTGAGAAATT 3'.Association between rs2231142 and hyperuricemia was analyzed in the general study group, as well as different gender and age groups. Results: A total of 198 subjects with hyperuricemia and 370 controls were enrolled. The A allele frequency of rs2231142 was significantly higher in the hyperuricemia group than control group (38.38% vs 26.62%, P<0.001), with an OR for hyperuricemia of 2.89 (95%CI 1.91-4.37, P<0.001). After adjustment for hypertension, hyperglycemia and dyslipidemia, the OR was 2.99 (95%CI 1.94 - 4.62, P<0.001). Subgroup analysis showed that the ORs were 3.83 (95%CI 2.03-7.24, P<0.001) in male and 2.30 (95%CI 1.32-4.00, P=0.003) in female. In those 55 years or older, the gender differences of ORs were decreased, with ORs of 3.23 (95%CI 1.02-10.29, P=0.047) in male and 3.06 (95%CI 1.37-6.84, P=0.006) in female. While in those less than 55 years, the gender differences of ORs were enlarged, with ORs of 4.11 (95%CI 1.92-8.79, P<0.001) in males and 1.73 (95%CI 0.80-3.76, P=0.165) in females. Interaction study between gender and rs2231142 did not reach significant level in both the gender group and two age groups. Conclusion: Single nucleotide polymorphism rs2231142 A allele is an independent risk factor for hyperuricemia in this tertiary hospital faculty cohort. The ORs are higher in male than those in female, especially in those less than 55 years old. PMID- 29136714 TI - [The prognostic significance of plasma Epstein-Barr virus DNA in patients with diffuse large B cell lymphoma]. AB - To retrospectively analyze the prognostic significance of plasma Epstein-Barr virus (EBV) DNA in 122 patients with diffuse large B cell lymphoma (DLBCL). Plasma EBV DNA positivity was related to advanced disease stage (P=0.030), B symptoms (P=0.004) and elevated serum lactic dehydrogenase (LDH) (P=0.001). Furthermore, univariate analysis indicated that plasma EBV DNA level was associated with worse overall survival (OS) (HR=0.223, 95%CI 0.096-0.518, P<0.001) and worse progression free survival (PFS) (HR=4.417, 95%CI 1.911-10.208, P<0.001), whereas multivariate analysis showed plasma EBV DNA as a probable independent prognostic factor of clinical outcome(HR=0.409, 95%CI 0.166-1.008, P=0.052). PMID- 29136715 TI - [Analysis of the clinical and electrophysiological characteristics of multifocal motor neuropathy]. AB - Ten patients diagnosed with multifocal motor neuropathy (MMN) were recruited in the Department of Neurology at Chinese PLA General Hospital from January 1, 2009 to August 31, 2015. The clinical and electrophysiological features were analyzed retrospectively. All patients complained of progressive asymmetric limb weakness, which was more severe in distal than in proximal. Five presented muscle atrophy. None had sensory disturbances. All suffered diminished or disappeared tendon reflex, whereas Babinski signs were negative. Multi-focal conduction block (CB) was confirmed by nerve conduction studies (NCS) in all patients and 7 showed spontaneous potentials in needle electrode electromyography. Abnormal sensory nerve conduction was seen in 3 patients. Laboratory test revealed anti ganglioside GM1 antibody in cerebrospinal fluid (CSF) in 6 cases and elevated CSF protein in 7 cases. Limb weakness alleviated greatly in 9 cases after intravenous immunoglobulin (IVIg) treatment. But the other one reported poor response, who had long course of disease, serious limb weakness and obvious muscle atrophy. Motor nerve damage is the most important manifestation of MMN and sensory nerve damage may also appear. NCS is essential to the diagnosis of this disease, with CB as the characteristic electrophysiological feature. IVIg is an effective treatment. PMID- 29136716 TI - [The impact of goal directed analgesia on mechanical ventilated patients's outcomes in intensive care unit: a clinical observational study]. AB - To investigate the impact of goal directed analgesia on the outcome of patients with mechanical ventilation in intensive care unit.A total of 126 patients who needed mechanical ventilation were recruited.With a method of before and after paired comparison, they were divided into two group: (1) analgesia with empirical administration or control group; (2) goal directed analgesia based on critical care pain observation tool (CPOT). Compared with the control group, after goal directed analgesia was applied, the consumption of midazolam significantly dropped from (368.47+/-27.41) mg to (151.27+/-29.31) mg(P<0.05), whereas the consumption of dexmedetomidine significantly increased from (623.62+/-20.91) MUg to (812.34+/-22.57) MUg(P<0.05). The median score of Richmond agitation-sedation scale increased from -3 to -1.The incidence of delirium significantly reduced from 23.81% to 17.46%(P<0.05). The mean ventilator duration was significantly shortened from (168.49+/-11.41) h to (142.38+/-13.24) h(P<0.05). ICU length of stay was significantly shortened from (23.64+/-9.26) d to (19.63+/-8.46) d(P<0.05). Due to the mild sedation, patients receiving goal directed analgesia report less delirium, less ventilation time and shorter ICU length of stay, suggesting that the general outcome is improved. PMID- 29136717 TI - [Two cases report of glomus tumor of the trachea]. PMID- 29136718 TI - [A case report of Cushing's syndrome in pregnancy]. PMID- 29136719 TI - [Congenital adrenal hypoplasia combined with hypogonadotropic hypogonadism dued to new DAX-1 mutations: two cases report]. PMID- 29136720 TI - [Psychocardiology medicine: mental stress-induced myocardial damages]. PMID- 29136722 TI - [Endothelial cell specific molecule-1: a novel biomarker for endothelial injury in acute respiratory distress syndrome]. PMID- 29136721 TI - [Advances in immune deregulation mechanisms and immunomodulation therapy in myelodysplastic syndrome]. PMID- 29136723 TI - [The guidelines for the diagnosis and management of multiple myeloma in China (2017 revision)]. AB - Multiple myeloma (MM) is a clonal plasma cell malignancy, mainly in elderly people and still incurable at present. In the ear of novel agents and sensitive laboratory exams, the diagnosis and treatment of MM have been significantly improved. Chinese MM guidelines for the diagnosis and treatment were updated every two years according to the progression of international and domestic research and clinical studies. In this version, we updated the response criteria and new combination regimens in newly diagnosed patients. Monoclonal gammopathy of renal significance (MGRS) was added as a new part of differential diagnosis, meanwhile, relapsed/refractory MM patients should be treated as long as possible. PMID- 29136725 TI - [The China expert consensus of clinical practice for magnetically controlled capsule gastroscopy(2017, Shanghai)]. AB - Gastric diseases are very common in China, especially gastric cancer with a continuous high level of morbidity and mortality. As an important screening method of gastric diseases, magnetically-controlled-capsule-gastroscopy (MCCG) has already been widely used in medical institutions worldwide. Several clinical trials have already showed that MCCG has comparable accuracy in diagnosing gastric diseases compared with conventional gastroscopy. Furthermore, MCCG has the advantages of anesthesia free, no risks of cross infection, and excellent compliance. Thus MCCG could be a potential alternative technique of conventional gastroscopy. Based on the clinical practice of MCCG during recent years, Chinese doctors have gained a lot of experience. In order to standardize and popularize the application of MCCG, the expert consensus for the clinical application of MCCG was developed through several discussions and modifications among Chinese experts in the field of capsule endoscopy. PMID- 29136724 TI - [Expert consensus for the diagnosis and treatment of patients with renal impairment of multiple myeloma]. AB - Renal impairment (RI) is a common complication of multiple myeloma (MM), which is presented as chronic kidney disease (CKD) or acute kidney injury (AKI). The typical pathological feature is cast nephropathy. Presently international system staging (ISS) is used in evaluating MM. Although the classic Durie-Salmon staging system could be still used in clinical practice, it may miss out some patients with renal impairment. For evaluations of RI in MM patients with CKD, it's recommended to assess the estimated glomerular filtration rate (eGFR) by creatinine based formula CKD-epidemiology collaboration (EPI) or modification of diet in renal disease(MDRD) and to stage the renal injuries according to 2013 Kidney Disease Improving Global Outcomes (KDIGO) CKD guidelines. For MM patients with AKI, KDIGO AKI guidelines is recommended for evaluation. Renal biopsy is not a routine procedure in all MM patients. It's necessary for patients presenting with glomerular injuries such as albuminuria > 1 g/24 h to eliminate immunoglobulin associated amyloidosis (AL) and monoclonal immunoglobulin deposition disease (MIDD). The effective treatment of MM can reduce serum light chain concentration and improve renal function. The basis of the RI treatment in MM is bortizomib-based regimen, which does not require dosage adjustment in patients with dialysis or renal insufficiency. Thalidomide and lenalidomide are two major immunomodulators in MM treatment. Thalidomide can be used effectively in RI patients without dosage adjustment while lenalidomide should be used cautiously in patients with mild or moderate RI with dosage adjustment and serum toxicity surveillance. High-dose therapy (HDT) and autologous peripheral blood stem cell transplantation (APBSCT) can be therapeutical options for RI patients younger than 65 y, and they should be considered more prudently in patients with severe renal insufficiency (GFR<30 ml/min). For patients who are not suitable for the treatment mentioned above, they can be treated with conventional chemotherapy, including VAD (vincristine, adriamycin and dexamethasone), MP (mephalan and prednisolone) and high-dose dexamethasone regimen. Adequate hydration (at least 3 litres of fluid intake a day or 2 L.m(-2).d(-1)) and correcting reversible causes of RI are key points for the supportive care. Renal replacement therapy (more often hemodialysis) should be started in patients with severe AKI and end stage renal disease (ESRD). High flux or high cut-off membrane are recommended because routine hemodialysis could not remove the serum free light chain (sFLC) effectively. Plasmapheresis (PE) is recommended for patients with hyperviscosity syndrome or cast nephropathy presented with AKI, which may help to increase the dialysis-independency. PMID- 29136726 TI - [Chinese expert consensus on the diagnosis and treatment of hypertension in the elderly(2017)]. AB - China has stepped into an aging society. Hypertension is an independent risk factor of cardio-cerebrovascular diseases and related to mortality and disability of the elderly. Compared to middle-aged and young patients with similar blood pressure elevation, the risks of cardiovascular and cerebrovascular events significantly increase in the elderly. Since the Chinese expert consensus on the diagnosis and treatment of hypertension in the elderly(2008, 2011 version) were published, many guidelines have been accordingly updated, which further improved the prevention and control strategy of hypertension. In this article, Chinese expert consensus on the diagnosis and treatment of hypertension in the elderly(2017) is revised as to facilitate the prevention and treatment of hypertension in Chinese elderly. The consensus is composed of eight parts, including definition, epidemiology, characteristics, evidence, treatment objectives and measurements of elderly hypertension. The purpose of the consensus is to provide guidance for management of elderly hypertensive patients. PMID- 29136727 TI - [The 459th case: arthralgia, fever, rash, and thrombocytopenia]. AB - The differential diagnoses of reactive arthritis presenting as arthralgia should be considered as diverse disorders, especially when the symptoms cannot be fully explained by some definite diseases. Do not ignore the indication of bone marrow aspiration. We reported a 50-year-old woman who complained of arthralgia, recurrent fever and rash 9 months ago. Laboratory exams showed mild leukopenia, anemia, thrombocytopenia and increased lymphocyte proportion. She was treated with glucocorticoid after the diagnosis of connective tissue disease was suspected. Until platelet count abruptly decreased to very low level, the final diagnosis of acute lymphoblastic leukemia was made through bone marrow morphology, flow cytometry, and chromosome examination. Therefore, a small number of leukemia is not easily diagnosed by routine operations. Thus when diagnoses are not determined with recurrent symptoms, cautious observation and further examination are required to avoid misdiagnoses or missed diagnoses of acute leukemia. PMID- 29136728 TI - [Guidelines on nutritional support in patients with tumor]. AB - Nutritional support for patients with tumor has been considered an important part of multidisciplinary treatment of tumor. It could improve the prognosis and quality of life for tumor patients when performed in a reasonable and effective way. Chinese Society for Parenteral and Enteral Nutrition (CSPEN) convened experts to develop these guidelines after many discussions and revisions according to standard procedures of guideline's development which were used worldwide. In order to develop these guidelines, we systematically reviewed the related global literature published in recent years, referred to other guidelines of national and international nutrition society, considered on expert opinion and their clinical experience in our country, and widely consulted the members of CSPEN and other related professionals. In the guideline, we firstly expounded metabolic characteristics and nutritional requirements in patients with tumor, and then raised 13 common questions existed in the practice of clinical nutrition, and provided 33 recommendations followed by systematic discussion. The guideline will help to standardize the clinical nutrition practice, provide reasonable and effective nutrition support, and further improve the prognosis and quality of life for tumor patients. We hope that the guideline release could provide theoretical guidance for nutritional support in patients with tumor in our country, and also make great contributions to much progress of clinical nutrition and tumor treatment in our country, and strengthen the multidisciplinary cooperation. PMID- 29136729 TI - [Consensus on the establishment of urban trauma rescue system in China]. AB - With the rapid economic development in China, the incidence of all sorts of accidental injury, such as traffic injuries and fall-induced injuries, increased significantly. Trauma, particularly severe trauma, often involves multiple organs and multiple system damage, and needs a scientific, standardized comprehensive multidisciplinary approach for treatment. Due to meticulous sub-division of clinical department sand lack of professional trauma treatment team in general hospitals in China's major cities, the overall level of trauma rescue in China is much lower than the developed countries. So the urgent need is to establish and form an efficient and standardized urban trauma treatment system. In order to further guarantee the establishment of urban trauma rescue system, and to further improve the success rate of trauma rescue in China, nationally well-known trauma experts of China developed the "Expert consensus document on the establishment of urban trauma rescue system in China" based on its previous research results, foreign countries' successful experience and China's national conditions. This document would be an important reference for our local governments at all levels to create urban trauma rescue system. PMID- 29136730 TI - [Application of the descending branch of the lateral circumflex femoral artery in the coronary artery bypass grafting operation]. AB - Objective: To investigate the technical method for harvesting and application of the descending branch of the lateral circumflex femoral artery (DBLCFA) in the coronary artery bypass grafting (CABG) operation. Methods: Between December 2016 and April 2017, 19 patients were arranged to use DBLCFA and got CT angiography (CTA) of pelvic and femoral arteries pre-operative at Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Finally, DBLCFA was harvested in 16 patients (including 2 female patients, with a mean age of (47.4+/ 8.5) years) through the anterior thigh incision (13 cases on the left side, 3 cases on the right side). The CABG operations were performed under the cardiopulmonary bypass support (in 10 cases) or under the beating heart condition (in 6 cases), and the DBLCFA conduit was used combining with bilateral internal thoracic artery (in 12 cases), radial artery (in 7 cases) and saphenpous vein (in 3 cases). Results: Due to anatomical variations such as short length and anomalous branch, or due to silent atherosclerosis stenosis of femoral artery, DBLCFA in 3 patients was considered inappropriate for use and was not harvested after CTA examination. In another 16 patients, DBLCFA was safely and quickly harvested and successfully used. On average, 3.4+/-0.6 anastomosis was built up in CBAG, no adverse effects were exhibited. The length of the harvested DBLCFA was (10.3+/-1.8) cm, with average lumen diameter of (1.9+/-0.5) mm. DBLCFA was used as free graft in 15 patients (7 to the first diagonal branch, 6 to the ramus intermedius branch, 1 to the left anterior descending branch and 1 to the second obtuse marginal branch). In 1 patient, the DBLCFA was firstly implanted end-to side to the internal thoracic artery as a "Y" type composite graft, and then anastomosed to the third obtuse marginal branch. Conclusions: The descending branch of the lateral circumflex femoral artery is an option conduit in CABG. It can be harvested easily and safely. However, pre-operative CTA examination is necessary to exclude the variation and appropriate strategy for graft establishment should be considered during the operation. PMID- 29136731 TI - [The surgical treatment of ovarian cancer metastasis between liver and diaphragm: a report of 83 cases]. AB - Objective: To explore the safety and feasibility of associating diaphragm resection and liver-diaphragmatic metastasis lesions resection for patients with advanced ovarian cancer. Methods: Retrospectively analysis 83 cases(98 times) of advanced ovarian cancer with liver-diaphragmatic metastasis between January 2012 and December 2016 at Department of Liver Surgery, Peking Union Medical College Hospital.The patients were aged from 19 to 75 years.Surgical procedure included metastatic lesions resection(43 times) and stripping(55 times). Operation status, post-operative complications, pathology results and follow-up of the patients were analyzed. Results: Fifteen patients received twice surgical treatment and 68 patients received one time surgical treatment. Postoperative hemorrhage in chest and between liver and diaphragm was not occurred in all cases.Dyspnea and low oxygen saturation were occurred in two cases of stripping patients and 1 case of metastatic lesions resection patients.Results of CT examination indicated that there was medium to large amount of ascites in right chests.The symptoms were relieved after placing thoracic closed drainage.Other patients were recovered smoothly.All patients were diagnosed as ovarian cancer by pathological examination. Conclusion: Associating diaphragm resection is safe and feasible for liver-diaphragmatic metastasis lesions from ovarian cancer. PMID- 29136732 TI - [Prognosis factors for the perineal incision complications after abdominoperineal resection for low rectal cancer]. AB - Objective: To evaluate the prognosis factors affecting perineal incision complications after abdominoperineal resection (APR) for the low rectal cancer. Methods: This was a retrospective analysis of 151 consecutive patients with low rectal cancer undergoing APR between January and December 2013 at Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. The patients were comprised of 95 males and 56 females. The mean age of the patients was (57.3+/-10.9) years (ranging from 31 to 79 years). chi(2) test and Logistic regression analysis were used to identify the prognosis factors of perineum incision complications. Results: In all 151 patients, perineal incision complications were confirmed in 31 patients (20.5%), including 8 cases of incision infection, 22 cases of poor healing of perineal wound, and 1 case of incision fistula formation. In univariate analysis, the factors associated with perineal incision complications were American Society of Anesthesiologists grade (chi(2)=7.116, P=0.008), intraoperative blood loss (chi(2)=9.157, P=0.002), while the protective factors associate with perineal incision complications were the intraperitoneal chemotherapy with fluorouracil sustained release (chi(2)=5.020, P=0.025), pelvic restoration (chi(2)=10.158, P=0.001), operation experience (chi(2)=7.334, P=0.007). The gender, age, body mass index, diabetes, preoperative radiochemtherapy, hemoglobin level, albumin level, distance from distal tumor to anal verge, the procedure of APR, operating time, intraoperative blood transfusion, total drainage volume 3 days after operation, tumor differentiation and the postoperative TNM staging were not associated with perineal incision complications (P>0.05). Multivariable logistic regression analysis showed that the intraoperative pelvic restoration (OR=0.200, 95% CI: 0.045 to 0.894, P=0.035) and intraoperative blood loss (OR=2.953, 95% CI: 1.155 to 7.551, P=0.024) were independent prognosis factors of perineum incision complications. Conclusions: For patients with low rectal cancer undergoing APR procedure, pelvic restoration wound be needed. The operation should be performed by experienced doctors, intraoperative blood loss should be reduced when possible. PMID- 29136733 TI - [Exploratory study of circulating tumor DNA detection in early breast cancer: an analysis of 75 next-generation sequencing results]. AB - Objective: To explore the utility of circulating tumor DNA detection in early breast cancer by using next-generation sequencing. Methods: This exploratory study of circulating tumor DNA detection is for early invasive breast cancer patients treated in Breast Disease Center, Peking University First Hospital from December 2015 to July 2016. Plasma samples were collected and were used to isolate plasma cell-free DNA.Exons or hotspots of 247 cancer related genes were sequenced by next-generation sequencing. Mutations and their correlation with clinic-pathological factors were analyzed. The correlation between mutations and clinic-pathological factors was evaluated by chi(2) test or Fisher's exact test. Results: Seventy-five patients were enrolled in this study. All patients were female and aged from 31 to 88 years with median age of 58 years. All patients' clinic-pathological records were complete. Sixty-four mutations in 18 genes (ALK, BCR, ERBB2, ROS1, PDGFRA, EGFR, FGFR2, CYP1B1, CALR, CASP7, BRAF, FGFR1, FGFR3, MET, NRAS, PTEN, KIT, SOD2) were detected in 47 (62.7%) among all 75 patients.Exons were captured in 10 genes, and mutations in 2 of 3 genes analyzed were clustered. Gene mutations were not correlated with menopausal status, histological type, primary tumor (T), regional lymph nodes (N), TNM stage, histological grade, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, Ki-67 and molecular subtype (all P>0.05). Conclusion: Circulating tumor DNA sequencing by next-generation sequencing was useful for detecting breast cancer-related mutations. PMID- 29136734 TI - [Functional recovery after recurrent laryngeal nerve injury on different electromyography thresholds during thyroid surgery]. AB - Objective: To discuss the functional recovery after recurrent laryngeal nerve injury (RLNI) on different electromyography thresholds during thyroid surgery. Methods: The prospective experimentally were induced in 12 acute recurrent laryngeal traction animals (porcine) from December 2014 to December 2015, the amplitude and latency of electromyography, even time course during RLNI and recovery of 24 recurrent laryngeal nerves(RLN) were continuous intraoperative neuromonitoring(IONM), including 12 RLN releasing traction after 50% amplitude decrease (AD) and other 12 RLN after 70% AD. The IONM data and postoperative laryngoscopy result of 1 119 thyroid cancer patients, involved 237 male and 882 female, aged 45.2 years in average, who underwent thyroidectomy in Department of Thyroid Surgery, China-Japan Union Hospital Affiliated to Jilin University from July to December in 2016 were analyzed retrospectively. Results: The porcine model of traction lesion showed that the time of 50% AD was (59+/-4) s, latency increase (LI) was (8+/- 4)%, was recovered in 10 minutes; the time of 70% AD was (75+/-6)s, LI was (11+/-5)% , was recovered (43+/-23)% of baseline even during 20 minutes. Among the IONM of 1 632 recurrent laryngeal nerves in clinic, the mechanism of 64 RLNI is clear, including traction injury accounted for 62.5% (40/64), thermal injury was 12.5% (8/64), compression injury was 23.4% (15/64), clamp injury was 1.6% (1/64). When 50%<=AD <70% (8.8%), the rate of abnormal vocal fold movement (AVCM) was 8.8% (6/68), while AD>=70% (37.2%), the rate of AVCM was 37.2% (19/51), but LOS was 5/13. Conclusion: Releasing the injury before AD>=50% in surgery, is a more effective indicator to avoid postoperative AVCM and promote nerve function recovery. PMID- 29136735 TI - [Bit1 mediates the malignant behaviors in pancreatic cancer and its potential clinical significance]. AB - Objective: To investigate the potential role of Bit1 in the pathogenesis of pancreatic ductal cancer cells(PDAC) and its potential clinical application value. Methods: Real-time PCR and Western blot were employed to detect the expression of Bit1 in six pancreatic cancer cells, then the tool cells were selected to further study the function of Bit1.PolyHEMA was used to monitor the suspended cell culture condition in vitro.The invasion and migration abilities of pancreatic cancer cells were detected through Transwell assay. Western blot and confocal assay were used to explore the potential mechanism of Bit1 in the process of metastasis.The expression of Bit1 was detected through tissue microarray, the potential relationship between Bit1 and other clinical factors were analyzed. Results: The results of real-time PCR and Western blot indicated that the expression of Bit1 was highest in the PANC1 cells and lowest in the Mia paca2 cells (gene: 3.13+/-0.40 vs. 1.00+/-0.35, protein: 1.77+/-1.00 vs. 0.23+/ 0.45). The shBit1 PANC1 and Bit1-OE(over expression) Mia paca2 cells were successfully constructed.Bit1 over expression could promote the anoikis rate of Mia paca2 cells, and Bit knockdown could inhibit the anoikis incidence.Bit1 over expression suppressed the motility and invasion of Mia paca2 cells, but Bit1 knockdown could accelerate the migration and invasion ability of PANC1 cells.Bit1 could potentially affect pancreatic cancer cells' malignant behaviors through epithelial-mesenchymal transition process.Bit1 expression was significantly associated with pancreatic cancer's neural invasion (P<0.05). Conclusions: Bit1 could affect the anoikis incidence of pancreatic cancer, Bit1 negatively affect the migration and invasion abilities of PDAC, the EMT process was potentially involved in the whole modulation process.Bit1 expression is associated with neural invasion in pancreatic cancer patients. PMID- 29136736 TI - [Expression of B cell transposition gene 3 in pancreatic ductal adenocarcinoma and its prognostic value]. AB - Objective: To detect the expression of B cell transposition gene 3(BTG3) in pancreatic ductal adenocarcinoma(PDAC), and explore its relationship with postoperative recurrence and metastasis of tumor. Methods: Six self-paired frozen PDAC specimens and 3 normal pancreatic tissues from the Second Hospital of Jiaxing Affiliated to Jiaxing University were collected and the expression of BTG3 was detected by qPCR. Ten normal pancreatic tissues and 52 cases of PDAC tumor and paracarcinomatous tissues from the Second Hospital of Jiaxing Affiliated to Jiaxing University were collected from June 2009 to December 2016. The expression of BTG3 and relationship among BTG3 and clinicopathological characteristics of PDAC and patients' prognosis were detected and analyzed using immunohistochemistry.chi(2) test, Kaplan-Meier method and Cox regression model were used to analyzed the data. Results: The results of qPCR showed that expression level of BTG3 in PDAC (0.63+/-0.17) was lower significantly than that in paracarcinomatous (0.96+/-0.04) and normal tissues (1.00)(t=4.673, 5.502; both P<0.05). Immunohistochemistrv showed that BTG3 mainly expressed in the cytoplasm.The high expression rate of BTG3 in PDAC tumor tissues was 25.0%(13/52), which was remarkably lower than that in paracarcinomatous tissues(65.4%) and normal liver tissues(7/10)(chi(2)=17.120 and 5.849, both P<0.05). The low expression of BTG3 in PDAC was correlated with primary tumor, and TNM stage(chi(2)=7.704, P=0.006; U=154.000, P=0.018, respectively). Survival analysis showed that disease free survival rate of patients with low expression of BTG3 was significantly less than that with high expression(chi(2)=192.493, P<0.01). The Cox multivariate analysis demonstrated that low expression of BTG3 was independent risk factors for disease free survival in patients with PDAC after a curative resection(RR=3.366, 95%CI: 1.040-10.889, P=0.043). Conclusion: BTG3 may be involved in the occurence and development of tumor, and its low expression may be associated with poor prognosis in patients with PDAC. PMID- 29136737 TI - [Research progress on early diagnosis, reasonable prevention and treatment of symptomatic spinal epidural hematoma following spinal surgery]. AB - Symptomatic spinal epidural hematoma (SSEH) following spinal surgery is rare but one of the serious complications. SSEH can leave devastating neurological consequences if missing the optimal timing for treatment. The early diagnosis of SSEH is critical to the neurologic recovery, and MRI examination can help to check the location and the scope of the hematoma and provide imaging information for surgical operation. The risk factors of SSEH can be divided into preoperative factors, intraoperative factors and postoperative factors. The occurrence of SSEH can be minimized by controlling the risk factors, exact hemostasis and reasonable perioperative management. Patients with mild paralysis can choose conservative treatment, while patients with severe or progressive nerve injury (manual muscle testing <3) and unendurable nerve root pain should choose to clean the hematoma and decompress the nerve as soon as possible. PMID- 29136738 TI - [Focusing on and strengthening the health research on the elderly, especially the oldest old in China]. PMID- 29136739 TI - [Key strategy of the China Action Plan for the Thirteen Five-Year Plan for Combating and Prevention of AIDS]. PMID- 29136740 TI - [The relationship between core members' individual social capital and performance among HIV/AIDS related community-based organization]. AB - Objective: To investigate the relationship between core members' social capital and performance among HIV/AIDS-related community-based organizations (CBO). Methods: From July to December in 2015, a total of 327 core members from 212 HIV/AIDS-related CBO in 8 provinces were recruited based on the prevalence of HIV/AIDS (e.g., Yunnan, Hunan, and Sichuan are in high epidemic level; Anhui, Hubei, Shandong, and Jilin are in middle epidemic level; and Gansu is in low epidemic level) by multistage stratified cluster sampling and convenient sampling method. A questionnaire was administered in this study, including general demographic information, core members' social capital, individual performance and organizational performance. Multivariate logistic regression model was used to analyze the relationship between core members' social capital and performance among CBO. Results: Among the 327 individuals, the proportion of male was 201(61.47%). The proportion of core members from grassroots CBO was 66.97% (219/327). Core members from non-grassroots organizations were more likely to publish articles, the OR (95%CI) was 2.58 (1.30-5.14); Social network had a positive impact on the AIDS experts, the OR (95%CI) was 2.41(1.47-3.95); Core members from registered CBO were more likely to secure funding for the organization, the OR (95%CI) was 3.42 (1.65-7.10); Social network and the core members from high endemic areas were significantly correlated with the number of HIV/AIDS patients, the OR (95%CI) were 2.79 (1.27-6.14) and 1.99 (1.21-3.27). Conclusions: We should use the core members' social network to establish relationship and communication with organizations and institutions, ultimately accelerating the growth of HIV/AIDS prevention and care. PMID- 29136741 TI - [Characteristics of non-marital and non-commercial heterosexual transmission of HIV infection in Miao-Dong Autonomous prefecture of Qiandongnan]. AB - Objective: The goal of this research was to understand the demographic distribution and related factors of non-marital and non-commercial heterosexual transmission (non-commercial transmission) for HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome). Methods: Data related to HIV/AIDS infected by non-marital heterosexual transmission and whose present address was in Qian Dongnan, were collected from Information System on the HIV/AIDS Prevention and Control. Information included demographic characteristics, the members of non-marital sex partners, transmission path, detection source, CD4(+)T lymphocyte level, et al. cases belong to homosexual history, injective drug use or non-classified non-marital heterosexuality transmission were excluded, totally collect HIV/AIDS 919 cases. Multivariate logistic regressions were used to analyze potential factors associated with non-marital and non-commercial heterosexual transmission. In addition, in March and June 2017, using a convenience sampling, we conducted one-to-one interviews among 10 HIV/AIDS who were infected by non-marital heterosexuality and had non-marital and non commercial heterosexual experience in Kaili Center for Disease Control and Prevention. The content of the interview included basic information, sexual orientation, the main place of making friends and sexual behavior, attitude to commercial heterosexuality and non-martial and non-commercial heterosexuality and so on. Results: Out of the 919 cases, 645 (70.2%) were male, the proportion of non-commercial transmission was 55.06% (506). The proportion of female HIV/AIDS with non-commercial transmission was 84.7% (232), which was higher than male (42.5%(274)) (chi(2)=138.35, P<0.001). The proportion of Han HIV/AIDS with non commercial transmission was 61.5% (275), which was higher than other religion (52.2%(412)) (chi(2)=6.32, P=0.012). The proportion of HIV/AIDS with non commercial transmission who had 0-5 non-marital sexual partners was 58.8% (498), which was higher than who had>5 non-marital sexual partners (11.1%(8)) (chi(2)=61.10, P<0.001). The proportion of HIV/AIDS with non-commercial transmission who lived mobile was 72.9% (94), which was higher than who lived fixedly (52.2%(412)) (chi(2)=19.34, P<0.001). Qualitative interviews results revealed that the age of the respondents were 22-69. Respondents whose ages are in 22-34 were more likely to use mobile phone (4/10) and respondents whose ages are in 35-69 were less likely to look partners through party and the context of working. Conclusion: The proportion of cases being infected by non-marital and non-commercial heterosexual transmission in Qian dongnan was higher than general national levels. The characteristics of sex, marriage status, migration, vocation, the members of non-marital sex partners were significant differed between commercial heterosexual transmission and non-marital and non-commercial heterosexual transmission. PMID- 29136742 TI - [Antiretroviral treatment discontinuation and its influencing factors among HIV infected patients who initiated ART from 2012 to 2015 in Wenshan prefecture, Yunnan Province]. AB - Objective: To understand the antiretroviral treatment (ART) discontinuation rate and its influencing factors among HIV infected patients who initiated ART between 2012 and 2015 in Wenshan prefecture, Yunnan province. Methods: Demographic characteristics, baseline informations of ART, initial treatment regimens and follow-up status of a total of 4 354 patients who initiated ART from 2012 to 2015 in Wenshan prefecture were collected. A historical cohort study was used to describe the discontinuation incidence rate of ART. Life table was used to estimate cumulative retention rate and Cox proportional hazard model was used to determine the influencing factors of ART discontinuation. Results: The percentage and incidence rate of discontinuation were 25.1% (1 092/4 354) and 14.53 per 100 person-years among patients who initiated ART from 2012 to 2015 in Wenshan prefecture. ART retention rates were 88%, 83%, 78%, 74% at 6(th) month, 12(th) month, 18(th) month, 24(th) month, respectively. The multivariate Cox proportional hazard regression model showed that male patients were at a higher risk of discontinuation (HR=1.24, 95%CI: 1.09-1.41) than female patients, patients aged >=50 years were at a higher risk of discontinuation (HR=1.27, 95%CI: 1.06-1.53) than patients aged<30 years, discontinuation hazard among patients who were unmarried or divorced or widowed was 1.30 times (HR:1.30, 95%CI: 1.14-1.48) as patients who were married or cohabitation, discontinuation hazard among patients infected with HIV through injection drug use (IDU) was 1.49 times (HR:1.49, 95%CI: 1.23-1.82) as those infected through heterosexual transmission, patients with a baseline CD4 cell count<350/MUl (HR=1.34, 95%CI: 1.13-1.58) or >=500/MUl (HR=1.36, 95%CI: 1.09-1.71) were at a higher risk of discontinuation than those with a baseline CD4 cell count from 350/MUl to 500/MUl, patients initiating ART in 2014 (HR=1.25, 95%CI: 1.04-1.50) or in 2015 (HR=1.26, 95%CI: 1.02-1.55) were at a higher risk of discontinuation than those initiating ART in 2012. Conclusion: There is an uptrend for ART discontinuation rate in Wenshan prefecture. Male, 50 years or older, unmarried or divorced or widowed, transmission route as IDU, baseline CD4 count <350/MUl or >=500/MUl are risk factors of ART discontinuation. PMID- 29136743 TI - [Drug resistance mutations and its associated factors among 579 HIV/AIDS patients experiencing failure of antiretroviral therapy in Jiangsu Province, China]. AB - Objective: To understand the incidence and related factors of HIV-1 drug resistance among HIV/AIDS patients experiencing treatment failure in Jiangsu province, China. Methods: The HIV/AIDS integrated prevention and control data information management system of China were used to collect the basic data of patients, blood specimens were collected from patients who had antiretroviral therapy (ART) failure with >=12 months and older than 18 years in 2016 in Jiangsu, excluding cases with missing information, 713 cases were enrolled in this study. HIV-1 RNA was extracted, and then pol gene region was amplified and sequenced. The obtain sequences were submitted to Stanford University HIV Drug Resistance Database to interpret and analyse HIV-1 drug resistance and sub-types. Multivariate logistic regression model was used to explore the related factors of drug resistance. Results: A total of 579 subjects were amplified successfully, male accounted for 85.66% (496 cases), and the median age was 39 years old. The main route of infection was sexual transmission (553 cases, 95.51%). A total of 331 patients with drug resistance gene mutation were detected, drug resistance mutation rate was 57.18%. Compared with patients with baseline CD4(+)T cell count >500 cells/MUl, patients with CD4(+)T cell count in 201-500 cells/mm(3) and <=200 cells/MUl had a higher incidence of genetic drug resistance, the odds ratio was 3.33 and 6.87, respectively. Compared with patients with treatment less than 24 months, patients treated for 25-48 months had a higher incidence of drug resistance, the odds ratio was 1.88. Compared with patients infected by CRF07_BC strains, patients infected by CRF01_AE strains were associated with higher incidence of drug resistance, the odds ratio was 2.22 and 3.32, respectively. Protease inhibitor (PI) resistance mutations, nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) were found in 3.80%, 33.16% and 53.37% of patients, respectively. 31.95% of patients harbored NRTI and NNRTI resistance mutations simultaneously. M184V/I and K103N/Q were the highest frequency of NRTI and NNRTI resistance mutation, the prevalence of M184V/I and K103N/Q were 28.15% and 22.28%, respectively. Conclusion: The status of HIV-1 drug resistance mutations are complex and diverse among patients experiencing failure of ART in Jiangsu. Patients with lower baseline CD4(+)T cell count, longer treatment time and HIV-1 CRF01_AE and B strains infection were associated with higher incidence of drug resistance mutation. PMID- 29136744 TI - [Factors associated with syphilis/HIV infection among men who have sex with men in Shenzhen,2011-2016]. AB - : Objective: To investigate the factors associated with syphilis/HIV infection among men who have sex with men (MSM) maintaining a single sexual partner in Shenzhen. Methods: Respondent driven sampling and snowball sampling method were used to recruit MSM receiving voluntary counseling and testing in Shenzhen Rainbow clinic from 2011 to 2016. INCLUSION CRITERIA: aged 18 years and above; reported having one or more anal sexual partners in the recent 6 months. A total of 3 109 men who have sex with men (MSM) were involved in the study. Questionnaire-based interviews were conducted on a one-on-one basis. Data were collected including socio-demographic information, human immunodeficiency virus (HIV) testing history, history of blood donation and drug abuse in the recent two years, self-identified sexual orientation, role in homosexual behavior, ever being money boys (MB) and clients of MB, female sexual partners in the recent 6 months. 5 ml blood samples were taken after questionnaires. Syphilis was screened using toluidine red unheated serum test for the antibody of treponema pallidum and then confirmed by treponema pallidum particle assay. The enzyme-linked immunosorbent assay (ELISA) was used for screening HIV and western blot was used to confirm the HIV screening results. The difference of condom use among MSM between female sexual partners and male sexual partners were compared. Multivariate unconditional stepwise logistic regression model was used to analyze factors associated with syphilis infection and HIV positive among MSM. Results: A total of 3 109 eligible participants with mean (SD) age of 31.49 (8.64) years were enrolled in this study. Among them, 565 cases were infected with syphilis (18.17%), 330 cases were infected with HIV (10.61%), and 165 cases (5.31%) were syphilis co-infected with HIV. 791 (25.44%) reported maintaining a single sexual partners in the recent 6 months. Compared to MSM with multiple sexual partners, the prevalence of syphilis and HIV infection among MSM with a single sexual partner were lower, and the OR (95%CI) were 0.64 (0.51-0.81) and 0.66 (0.49 0.90), respectively. Conclusion: The proportion of fixed single sexual partner was much lower among MSM in Shenzhen. Maintaining a single sexual partners can reduce the risk of syphilis/HIV infection among MSM. PMID- 29136745 TI - [Willingness and influencing factors of using pre-exposure prophylaxis among 301 men have sex with men in Wuhan city, 2015]. AB - Objective: To understand willingness and influencing factors of using pre exposure prophylaxis (Pr-EP) among men who have sex with men (MSM). Methods: Snow ball sampling was employed to recruit MSM in the social spaces (like bars and bathrooms) with focused activities by MSM and internet (QQ and Wechat) in Wuhan between August and November, 2015. 304 MSM were considered eligible when they were self-identified MSM and has had sex with men in the previous 12 months, over the age of 18 and have full civil liability. On-site and online questionnaire surveys were conducted by self-designed questionnaires to collect information including demographic characteristics, sexual risks and practices, awareness of PrEP, and willingness to use PrEP. A total of 301 qualified questionnaires were obtained. Multivariate logistic regression models were constructed to identify factors associated with willingness to use Pr-EP. Results: The mean age of surveyed MSM were (27.51+/-8.31) years, between18-61. 149 on-site survey, online were152; 131 MSM have regular homosexual partners, 170 MSM have not regular homosexual partners. Only 17.28% (52/301) had heard of Pr-EP before this survey, 18.32% (24/130) had heard of Pr-EP among those who had regular homosexual partners and those who had not accounted for 16.47% (28/170). 74.42% (224/301) had willingness to use Pr-EP after they knew Pr-EP was safe and effective through the survey. The proportion among those who had regular homosexual partners was 74.05%(74), and the proportion among those who had not was 74.71% (127); Among those who had regular homosexual partners, results suggested that those who were married/cohabiting were more likely to report a willingness to use PrEP compared to unmarried/divorced or widowed (OR=5.60), compared with homosexual, heterosexuality was associated with decreased odds of willingness to use Pr-EP (OR= 0.22), compared with HIV status of sexual partner was negative or uncertain, positive infection status was associated with increased odds of willingness to use (OR=7.52). Compared with MSM who have not regular homosexual partners, those who were married/cohabiting were more likely to report a willingness to use PrEP compared to unmarried/divorced or widowed (OR=9.09), compared with those who think they have risk of infection, those who do not think they have risk of infection was associated with decreased odds of willingness to use Pr-EP (OR= 0.30), compared with those with a high frequency to seek sexual partners, those not often to seek was associated with decreased odds of willingness to use Pr-EP (OR= 0.27). All above P values were<0.05. Conclusion: The awareness rate of Pr-EP among MSM in Wuhan is low in 2015, but the willingness to use Pr-EP could get a considerable increase after introduction. It is considered that promotion of Pr EP is feasible in China, and there are different influencing factors for the willingness between two MSM subgroups (having regular homosexual partners and having no regular homosexual partners). PMID- 29136746 TI - [Study on handgrip strength of elderly >=60 years old from longevity areas in China]. AB - Objective: To assess the status of handgrip strength of elderly population from longevity areas in China, and to analyze the correlative factors of handgrip strength of elderly people. Methods: Data from Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2012 was used, from which1 967 participants aged >=60 years old with valid data of grip strength value from 8 Chinese longevity areas were included. Information on demographics characteristic, life style and health status was collected using questionnaires. The handgrip strength of both left and right hands were measured by grip dynamometer. The different characteristics of group of participants with different grip strength were compared and then analyzed by adopting the Cumulative odds Logistic regression model to identify main factors associated with hand grip strength. Results: The P(50) (P(25)-P(50)) of hand grip strength of elderly people from the eight longevity areas was 20 (11 28) kg; The hand grip strength of males was 26 (18-34) kg, which was higher than that of females(14 (9-20) kg) (P<0.001). Cumulative odds Logistic regression model showed that the hand grip strength of females was lower than males, whose beta value (95%CI) was-1.22 (-1.43--1.00). The elderly who was at a higher age, smoking, drinking or with anemia, had a comparatively lower handgrip strength, whose beta (95%CI) value were separately-0.08(-0.09~-0.07),-0.29(-0.56~-0.02), 0.54(-0.80~-0.28), and-0.41(-0.62~-0.20). And the elderly who had a higher boby mass index, drinking tea and outdoor activities, had a comparatively higher handgrip strength, whose beta(95%CI) value were separately 0.28 (0.15-0.40), 0.25(0.03-0.47) and 0.51(0.30-0.71). Conclusion: Age and gender were the main correlative factors, lifestyles and physical conditions might also be correlative factors of hand grip strength of the elderly from longevity areas in China. PMID- 29136747 TI - [Association between biomarkers and activities of daily living in the elderly >=65 years old from longevity areas in China]. AB - Objective: To explore the association between biomarkers and activities of daily living (ADL) in the elderly over 65 years old from longevity areas in China. Methods: A total of 2 439 people from 8 longevity areas were included in our baseline survey in 2012. Using questionnaires, body measurements, and blood biochemical examinations, information on demographics characteristic, life style, ADL, blood pressure and biomarkers were collected. Based on these six items of ADL (bathing, dressing, indoor activities, toileting, eating, bowel and bladder control), we constructed a dichotomous indicator for ADL. A respondent was defined as ADL disabled if any difficulty in one or more of the above six activities was reported. Information were collected in the follow-up in 2014 using the same questionnaires and examinations. We excluded information on the elderly who lacked ADL or biomarkers test results or with ADL disability at baseline study. Finally 938 elderly people over 65 years old were included in this analysis. Multivariate logistic regression model was used to analyze the influence factors of ADL disability. Results: During the 2-year follow-up, 100 (10.7%) participants developed into ADL disability, with a rate at 10.7%. Multivariate logistic regression analysis indicated that each year increase in age or each 1 mmHg (1 mmHg=0.133 kPa) increase in systolic blood pressure (SBP) would cause the risk of ADL disability to increase 9% or 1%, whose OR (95%CI) were separately 1.09 (1.06-1.12), 1.01 (1.00-1.02). Han nationality or cognitive impairment increased the risk of ADL disability, whose OR (95%CI) values were separately 4.90 (1.13-21.24), 2.47 (1.44-4.25), while increased lymphocyte count (>1.60*10(9)/L), being married, or participating in recreational activities decreased the risk of ADL disability, whose OR (95%CI) values were separately 0.51 (0.31-0.82), 0.52 (0.28-0.96), 0.43 (0.23-0.80). Conclusion: In the elderly elevated lymphocyte count was associated with lower risk of ADL disability. In addition, incresed age, increased SBP, unmarried, Han nationality or cognitive impairment were associated with the increasing risk of ADL disability in older people, while participating in recreational activities would reduce the risk. PMID- 29136748 TI - [Follow-up study of body mass index and risk of cognitive impairment among elderly adults aged >=65 years old from longevity areas of China]. AB - Objective: To discuss the relationship between body mass index (BMI) and cognitive impairment among elderly adults aged >=65 years old from longevity areas of China. Methods: A total of 2 439 elderly adults from 8 longevity areas were included in our baseline survey by answering questionnaire and taking body measurements and blood biochemical examinations in 2012. In the follow-up study in 2014, we studied the cognitive impairment status among the 1 135 elderly adults aging >=65 years old. Multivariate logistic regression model was used to analyze the relationship between BMI and cognitive impairment risk. Results: 113 participants were defined as cognitive impairment, with a positive rate at 10.0%. The positive rate in group of underweight, normal weight, and overweight and obese elderly were 22.2% (51/230), 7.5% (47/629), 5.4% (15/276). The rate of cognitive impairment in groups of low BMI (<19.7 kg/m(2)), middle BMI (19.7-23.1 kg/m(2)) and high BMI (>23.1 kg/m(2)) were separately 17.7% (66/372), 7.1% (27/379) and 5.2% (20/384) (P<0.001). Every 1.0 kg/m(2) increase in BMI, the risk of cognitive impairment would significantly decreased by 7% (RR(95%CI): 0.93(0.87 0.99)). Compared with participants with middle BMI level, the group of low BMI participants was associated with a significantly increased risk of cognitive impairment (RR (95% CI): 1.98(1.14-3.44)); while there was no significant association was observed in the high BMI group (RR(95%CI): 1.15(0.57-2.32)). Compared with elderly in normal weight, the elderly with under weight was in higher risk of cognitive impairment (RR (95%CI: 2.19(1.31-3.66)) and there was no significant association found between the elderly with overweight (RR(95%CI): 1.18(0.58-2.38)). Conclusion: Among the elderly >=65 years old from longevity area, low BMI level and underweight were associated with the increased risk of cognitive impairment. PMID- 29136749 TI - [Relationship between the successful aging and survival status among the elderly from longevity areas in China]. AB - Objective: To explore the relationship between successful aging (SA) index and the survival status among elderly from longevity areas of China. Methods: A total of 2 296 old people aged >=65 years old from 8 longevity areas were enrolled in our baseline survey in 2012. The information of demographics characteristic, life style, self-assessed health and mood or emotional state, cognitive function, abilities of daily living and physical activity were collected by questionnaire. There were 891 SA people in total, whose SA score was 4-5. 891 SA and 1 396 non SA participated in the follow-up study in 2014. Finally, 860 SA and non-SA people were matched by orientation analysis. A Cox proportional hazards model was used to explore the relationship between successful aging index and survival status. Results: After 2 years of follow-up, a total of 1 442 elderly survived, with an average baseline age at (83.69+/-10.81) years old and 278 elderly people died, with an average baseline age at (93.41+/-9.05) years old. The mortality rate was 16.16% (278/1 720) in total, and it was 13.14% (113/860) in SA group, which was lower than it in non-SA group (19.19%, 165/860), and the difference was statistically significant (P=0.001). The analysis of the multivariate Cox regression showed that SA was the protective factor of the survival of the elderly after age and sex adjusted. Compared to the non-SA group, the risk of mortality rate in SA group decreased by 38%, the HR (95% CI) was 0.62 (0.49 0.79). Conclusion: The mortality rate in the SA group was low in the longevity areas in China; compared with non-SA group, the death rate in SA group reduced by 38%. PMID- 29136750 TI - [A perspective cohort study on influence factors of survival outcome among the elderly aged >=80 years old from longevity areas in China]. AB - Objective: To investigate the influence factors of survival outcome among elderly aged >=80 years old. Methods: In baseline survey in 2009, 930 participants aged >=80 years old were enrolled from 7 longevity areas, to collect the information of socioeconomic factors, life style, cognitive function, activities of daily living and diseases, as well as physical examination to test biomarkers of blood and urine. The survival status was followed up at 2012 and 2014 survey. Stepwise Cox proportional hazards models were used to screen influence factors of 5-year survival. Results: During 5 years of follow-up, 571 participants died, 133 participants were lost to follow up, and the all-cause mortality was 63.4%. In stepwise Cox proportional hazards models, male, unmarried, self-reported poor life quality, disability in daily life, cognitive impairment, cardiovascular and cerebrovascular diseases, chronic kidney diseases were risk factors for elderly survival outcome, with the HR (95%CI) at 1.75 (1.40-2.12), 1.49 (1.10-2.03), 1.40 (1.16-1.69), 1.37 (1.11-1.70), 1.51 (1.22-1.88), 1.62 (1.18-2.23) and 1.48 (1.23 1.77) respectively. Each 1 year increase in age corresponded to 4% increase in mortality risk (HR (95%CI)=1.04 (1.02-1.05)); each 1 kg/m(2) increase in BMI corresponded to 5% increase in mortality risk (HR (95%CI)=0.95 (0.93-0.98)); each 1.0*10(9)/L increase in total lymphocyte count (TLC) corresponded to 13% increase in mortality risk (HR (95%CI)=0.87 (0.76-0.99)). Additionally, the mortality risk decreased 19% (HR (95%CI)=0.81 (0.66-0.98)) in participants with regularly physical exercise compared to those without; and the mortality risk decreased 41% (HR (95% CI)=0.59 (0.40-0.88)) in participants with elevated triglycerides (TG, >=2.26 mmol/L) compared to those without. Conclusion: In Chinese longevity areas, some nutritional and immune indices such as relatively higher level of BMI, TLC and TG were independent protective factors for 5-year survival outcome, which was different from general adults and younger elderly. PMID- 29136751 TI - [Analysis on probability of premature death and cause eliminated life expectancy of major non-communicable diseases in Chongqing Municipality, 2016]. AB - Objective: To analyze the premature death probability and cause-eliminated life expectancy of cardiovascular disease, cancer, chronic respiratory disease and diabetes in Chongqing residents in 2016 so as to provide recommendation for non communicable diseases (NCDs) prevention and control in Chongqing. Methods: Death cases of Chongqing Municipality between January 1(st) and December 31(st), 2016 were reported through death case registry system of national center for disease prevention and control. Death cases were sorted by international classification of disease (ICD-10). Mortality rate, standardized mortality rate, constituent ratio, premature death probability, life expectancy, and cause-eliminated life expectancy of four major NCDs were analyzed. Results: A total of 218 004 death cases were reported in Chongqing, 2016, and the mortality rate was 731.73/100 000. Of them, a total of 179 637 death cases of the four major NCDs including cardiovascular disease, cancer, chronic respiratory disease and diabetes were reported, accounting for 82.40% of all death cases. The mortality rate and standardized mortality rate of four major NCDs was 602.95/100 000 and 455.82/100 000, respectively. The premature death probability of four major NCDs was 15.96%, and males (25.39%) had a higher premature death probability than females (10.78%). The premature death probability of cardiovascular disease, cancer, chronic respiratory disease, and diabetes were 6.01%, 8.32%, 2.05%, and 0.43%, respectively. Life expectancy would increase by 6.02, 3.19, 1.89, and 0.19 years, after eliminating cardiovascular disease, cancer, chronic respiratory disease and diabetes respectively. Conclusion: The premature death probability of major NCDs was high in Chongqing, and males had a higher premature death probability than females did. Intervention and health management of the population should be conducted according to different gender-based risk factors to reduce the premature death probability. PMID- 29136752 TI - [The effect of breast massage at different time in the early period after cesarean section]. AB - Objective: To evaluate the effect of breast massage at different time in the early period on maternal lactation after cesarean section. Methods: 80 women delivered by cesarean section were randomly selected from maternity ward of a hospital in Shandong province during Jan. 2013 to Jan. 2015; which were divided into four groups, with 20 patients in each. Three groups received 3 times of breast massage every 24 hoursbeginning from 2, 12 and 24 h after cesarean section, respectively. The control group didn't receive any breast massage. The starting time and status of lactation were observed and recorded after cesarean section. 5 ml venous blood sample was drawn from each patient respectively at 2 h before cesarean, 6, 12, 24, 48 and 72 h after cesarean to test the level of serum prolactin. The lactation status of each group was compared. Results: The P(50) (P(25)-P(75)) of starting time of lactation of the three massage groups and control group were 3 (2-6) h, 4 (2-8) h, 4 (3-12) h and 4 (2-12) h, respectively, whose differences showed no statistical significance (H=3.32, P=0.345).The number of delivered women with adequate lactation 24 hours after cesarean was 10 in the group who received massage beginning from 2 h after cesarean; while the number was only 2 in the control group. The number of delivered women with adequate lactation 48 hours after cesarean was 18 in the group who received massage beginning from 2 h after cesarean; while the number was 8 in the control group. The differences showed statistical significances (P values were 0.021 and 0.008, respectively). The serum prolactin level in the group of delivered women who received massage from 2 h after cesarean was separately (195.9+/-78.5), (176.0+/ 96.5), (216.4+/-110.0), (190.0+/-56.8) and (184.8+/-69.6) MUg/L at 2, 12, 24, 48 and 72 h after cesarean, which were significantly higher than those in the control group (which were (128.8+/-40.6), (127.3+/-66.8), (162.2+/-58.8), (145.1+/-64.7) and (141.7+/-49.3) MUg/L, respectively) (P=0.007). Conclusion: Breast massage beginning from 2 hours after cesarean section can effectively improve the lactation status of delivered women. PMID- 29136753 TI - [Metabolomics study of tris(2-chloroethyl) phosphate induced hepaotoxicity and nephrotoxicity in Sprague-Dawley rats]. AB - Objective: To discuss the potential toxic target organ and the toxic effects and mechanisms of tris (2-chloroethyl) phosphate (TCEP) on SD rats. Methods: 40 female SD rats weaning from milk for 21 days, weighted (50+/-2.3)g were selected as subjects and marked by the weight. They were randomly divided into 4 groups, namely control group, 50 (L), 100 (M) and 250 (H) mg.kg(-1).d(-1) dose of TCEP group. Each group has 10 rats, and administrated the corresponding dose of drug or vehicle by mouth, quaque die for 60 days. All rats were sacrificed after the last administration. The livers and kidneys were dyed by HE for pathological observation; and the blood samples were collected to analyze the biochemical index. H(1)-Nuclear Magnetic Resonance ((1)H-NMR)-based metabolomics methods coupling with histopathogy examination were used to investigate the toxic effects of TCEP. Results: Inflammatory cell infiltration and hepatic necrosis were observed in the liver of TCEP-treated rats. Inflammatory cells invaded and calcification/ossification foci were also found in renal of TCEP-treated rats and tumor hyperplasia were existed in renal tubule in H group. The level of HDL-C in the L, M and H group were separately (1.7+/-0.09) , (1.5+/-0.07) and (1.3+/-0.1) umol/L, which were all significantly lower than that of control group ( (1.9+/ 0.2) umol/L) (P<0.05) . The activity of cholinesterase (CHE) in the L, M and H group were separately (918+/-14.8) , (828+/-28.6) and (674+/-36.5) U/L, which were all significantly lower than that of control group ((1056+/-28.8) umol/L) (P<0.05). Moreover, The level of creatinine (CRE) in the L, M and H group were separately (29.8+/-4.6) , (28.9+/-5.3) and (25.8+/-6.2) umol/L, which were all significantly lower than that of control group ((30.2+/-3.9) umol/L) (P<0.05). In the H group, the enzyme activities of alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), alkaline phosphatase (ALP) and the contents of total bilirubin (TBIL), glucose (GLU) and uric acid (UA) were all significantly higher than the results in control group. The results of (1)H-NMR metabolomics showed that the contents of lactate, glycine, high-density lipoprotein, low-density lipoprotein and phosphatidylcholine in blood of rats would decrease by TCEP exposure, while N-acetylglycoprotein, acetate, alanine, glucose, lipids, lipoproteins and fatty acids would increase. Conclusion: TCEP caused disorders in endogenous energy metabolism, leading to the pathological changes of inflammatory cells infiltration and necrosis in liver and kidney, caused enzyme activity changes of ALT, ALP and the content changes of other liver and kidney injury-related markers. PMID- 29136754 TI - [Survey on the status of the air pollutants in Lanzhou-Urumuqi high-speed railway carriage]. PMID- 29136755 TI - [Epidemiological characteristics of a cutaneous anthrax outbreak in Huairou District of Beijing]. PMID- 29136756 TI - [The advance of detection technology of HIV self-testing]. AB - At present, China's AIDS testing increased rapidly, but there are still many people living with HIV do not recognize their status, thus postponing the antiviral treatment time. HIV self-testing (HST) is an effective method to expand the testing, not only simple operation, easy to get a result, effectively protect the detection privacy, expand the selection of testers, suit to the entire population, but also the premise and basis of other AIDS comprehensive prevention measures, all over the world are promoting it. Because the HST has controversies in the window period, price and before and after controversial, and our country is in the initial stage of HST, so it is not to develop related policies, but more and more countries are in accordance with their own situations are modified or developed to allow to use rapid detection of AIDS policy to regulate the field. This paper analyzed and summarized the advantage and influence factors of HST promotion, HST believes that in the long term, the advantages outweigh the disadvantages, we need to formulate relevant policies, and improve the sensitivity of the kit, shorten the window period of time, production and promotion of operation standard of video, specification and testing the operating practices, preventing and reporting the possible social harm, investigation and understanding of the needs of the people of the crowd, to maximize the advantages of HST, find more infection, so as to curb the epidemic of AIDS. PMID- 29136757 TI - Muscone exerts protective roles on alcohol-induced osteonecrosis of the femoral head. AB - Long-term alcohol abuse causes musculoskeletal disorders, among of which, alcohol induced osteonecrosis of the femoral head (ONFH) is of concern due to its significant and severe complications. A variety of methods have been attempted to prevent alcohol-induced ONFH, and monomers extracted from Chinese herbs might benefit the disease profoundly. In the current study, muscone, the main ingredient of musk, was used to prevent alcohol-induced ONFH. In vitro, ethanol was used to affect the potential of osteogenesis and proliferation of human bone mesenchymal stem cells (hBMSCs), and beneficial role of muscone was investigated on hBMSCs. In vivo, following the establishment of alcohol-induced ONFH, muscone was employed to treat the diseased rats, which were analyzed by micro-CT scanning and a series of histologic staining. As a result, we found ethanol could significantly suppress osteogenic differentiation of hBMSCs, while muscone held the potential to promote ALP activity and mRNA expressions of COL1 and OCN under ethanol treatment. Meanwhile, imaging analysis revealed muscone could restore BV/TV ratio and bone mineral density of the necrotic femoral head, and the protective role of muscone on alcohol-induced ONFH was further confirmed by histologic examinations. Our study confirmed the protective effect of muscone against alcohol-induced ONFH both in vitro and in vivo. Therefore, muscone may be considered as a valuable therapeutic natural drug for alcohol-induced ONFH in humans. PMID- 29136758 TI - Psychotropic agent thioridazine elicits potent in vitro and in vivo anti-melanoma effects. AB - Psychotropic agents have been shown anti-tumor potential in recent years. In the present study, our in vitro pharmacological data indicated that thioridazine inhibited melanoma cells proliferation. The growth-arresting effect of thioridazine was accompanied by autophagy induction, as shown by immunoblotting of increased LC3II. Besides, certain apoptotic events had also occurred after thioridazine exposure. The in vivo anti-melanoma effect of thioridazine was confirmed by showing that intraperitoneally injection of thioriazine remarkably retarded tumor growth and reduced tumor vasculature. Our results imply that thioridazine might be an available therapeutic agent for melanoma patients with no better options. PMID- 29136759 TI - Novel function of hydroxychloroquine: Down regulation of T follicular helper cells in collagen-induced arthritis. AB - Hydroxychloroquine (HCQ) is an immunosuppressive agent widely used in rheumatoid arthritis (RA). T follicular helper (Tfh) cells play a vital role in the pathogenesis of RA. However, whether HCQ suppresses arthritis development through interfering with Tfh cells have never been reported. To address this issue, we investigated the percent of Tfh cells in newly diagnosed RA patients and found that they were up-regulated in peripheral blood. Importantly, in ex vivo experiments of peripheral blood mononuclear cells (PBMCs) from healthy volunteers, we proved that the percentage of Tfh cells in PBMCs and purified CD4+ T cells were decreased after HCQ treatment. In in vivo experiments of collagen induced arthritis (CIA) model, we discovered that HCQ suppressed the incidence and score of arthritis, reduced the secretion of proinflammatory cytokines in serum. Similar to ex vivo study, the ratio of Tfh cells in HCQ treated CIA mice declined to the level of vehicle-treated group. Further research demonstrated that HCQ inhibited the generation of Tfh cells stimulated by IL-12 and IL-21. In conclusion, our study indicates a previously unrecognized mechanism of HCQ in RA, that HCQ directly suppresses the generation of Tfh cells by blocking IL-12 and IL 21 signaling pathways probably. PMID- 29136760 TI - Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR-193a-5p and regulating mTOR expression. AB - OBJECTIVE: Numerous studies suggested autophagy was involved in temozolomide (TMZ) resistance in glioma. Long non-coding RNA (lncRNA) CASC2 was shown to be downregulated in glioma tissues and cell lines, and was related to the TMZ resistance. However, whether CASC2 affects TMZ resistance through regulating autophagy is unknown. The aim of this study was to assess the role and mechanism of CASC2 in TMZ-induced drug resistance in glioma cells. METHODS: Glioma and the adjacent non-cancerous tissues from 32 patients were collected. The expressions of CASC2 and miR-193a-5p were determined by PCR, and their correlation was analyzed. The correlation between CASC2 expression and the clinical characteristics of patients was also studied. Glioma cells were treated with TMZ to acquire the TMZ-resistant cell lines in which the expressions of CASC2, miR 193a-5p, and mTOR were measured. The regulatory roles of CASC2, miR-193a-5p, and mTOR were defined through the loss of function and luciferase reporter assays. Autophagy was inhibited by autophagy inhibitor 3-MA, CASC2 and mTOR overexpression, or miR-193a-5p inhibitor, and the effect of which on cell viability, apoptosis, and migration of TMZ-resistant glioma cells was evaluated. RESULTS: CASC2 downregulation and miR-193a-5p upregulation was found to be associated with advanced clinical stage and TMZ response in patients with glioma. CASC2 negatively regulates miR-193a-5p expression by direct interaction in glioma cells. Overexpression of CASC2 or inhibition of miR-193a-5p reduced TMZ-induced autophagy via mTOR upregulation, which makes the glioma cells become sensitive to TMZ cytotoxicity. CONCLUSION: CASC2 is downregulated in gliomas, resulting in increased miR-193a-5p level and a decrease in mTOR expression, which further induces protective autophagy, leading to TMZ resistance. Inhibition of autophagy helps to increase the efficacy of TMZ. PMID- 29136761 TI - Galangin inhibits the cell progression and induces cell apoptosis through activating PTEN and Caspase-3 pathways in retinoblastoma. AB - Retinoblastoma is reported as a rare cancer that occurs during childhood. Although several treatments are available for retinoblastoma, there is a need for alternative new treatment modalities for retinoblastoma with better safety and efficacy profile. Galangin (3,5,7-trihydroxyflavone), is a flavonoid compound, which is found in high concentration in lesser galangal. Galangin has been reported to have various bioactivities, including anti-inflammation, anti oxidative stress and anti-cancer through various pathways. The objective of our study was to explore the effects of galangin on the suppression of retinoblastoma in vitro and in vivo. Using MTT analysis, transwell-chamber migration analysis, colony-forming analysis, wound healing analysis, immunofluorescent assay of KI 67, we found that galangin exhibited a suppressive effect on human retinoblastoma cell proliferation and migration. Moreover, PTEN, a tumor-suppressor, was increased by galangin in cancer cells and in tumor tissues isolated from retinoblastoma xenograft models. Additionally, galangin reduced protein kinase B (Akt) phosphorylation, which was associated with PTEN up-regulation. Galangin reduced Akt activation and cell proliferation was abolished by PTEN knockdown, which might be associated with the over-expression of phosphatidylinositol-3,4,5 triphosphate (PIP3)/diphosphate product (PIP2). Furthermore, flow cytometry, Hoechst 33258 staining and western blot assays indicated that galangin could induce apoptosis through promoting Caspase-3 pathway, which was, at least partly, dependent on PTEN expression. Our data illustrated that galangin treatment suppressed the growth of retinoblastoma tumor in vivo by anti-proliferative and apoptogenic mechanisms. Thus, galangin might be a safe and promising non chemotherapeutic drug, which could be useful as an adjuvant against retinoblastoma. PMID- 29136762 TI - TGF-beta signaling regulates DACT1 expression in intestinal epithelial cells. AB - DACT1, was first identified as a Dishevelled-associated antagonist of Wnt signaling pathway. It has been reported that DACT1 functions in embryonic development and tumorigenesis. However, the regulation of DACT1 still remains unclear. We found Wnt signaling has no effect on DACT1, but TGF-beta increases expression of DACT1 in intestinal epithelial cells. In addition, the minimal promoter is located in the region of -500bp to +1bp and the region between 3000bp to +1bp enhanced promoter activity. Site-directed mutation analysis was performed and indicated that potential regulatory elements was near -335bp. Our study provided the basic information for the exploration of DACT1 regulation and expression. Moreover, TGF-beta inhibits Wnt signaling to enhance the function of DACT1 inhibiting Wnt signaling. PMID- 29136763 TI - Amorphous solid dispersions of hecogenin acetate using different polymers for enhancement of solubility and improvement of anti-hyperalgesic effect in neuropathic pain model in mice. AB - Hecogenin acetate (HA) is an acetylated sapogenin that has shown potential antihyperalgesic activity, inhibiting descending pain and acting in opioid receptors. However, HA exhibits poor aqueous solubility, which may limit its application. This study aims to develop amorphous solid dispersions (ASD) using five hydrophilic polymers, to characterize them and to evaluate their antihyperalgesic activity. Physicochemical characterization was performed by X Ray Diffraction (XRD), Scanning Electron Microscopy (SEM) and Fourier Transformed Infrared (FTIR) spectroscopy. In order to evaluate the hyperalgesia of the ASD, sciatic nerve crush injury (NCI) was induced in mice followed by administration of the ASD, where three parameters were evaluated: mechanical and thermal hyperalgesia as well as grip strength. XRD and SEM showed that ASD of HA with HPMC obtained by kneading (KND) presented an amorphous profile, unlike the others polymers, indicating interaction between HA and HPMC. FTIR analysis evidenced the strong interaction between HA and HPMC. Although the results of mechanical hyperalgesia were slightly improved on the groups treated with ASD of HA with HPMC, the thermal hyperalgesia showed that the incorporation of HA into HPMC matrix significantly improved its antinociceptive activity. PMID- 29136764 TI - Cardiac apoptosis induced under high glucose condition involves activation of IGF2R signaling in H9c2 cardiomyoblasts and streptozotocin-induced diabetic rat hearts. AB - The insulin-like growth factor type 2 receptor (IGF2R) overexpression has been implicated in heart disease progression. Unregulated IGF2R signaling triggers cardiac hypertrophy, apoptosis, and cardiomyopathies. The present study investigated the role of IGF2R in cardiomyocyte apoptosis under high glucose (HG) levels and in streptozotocin (STZ) induced diabetic rat hearts. We found that IGF2 and IGF2R protein expression were highly upregulated under high glucose condition in H9c2 cells as well as in STZ induced diabetic rat hearts. Using immunoblotting and TUNEL assay, we found that elevated glucose condition induced IGF2R expression leads to activation of Galphaq mediated calcineurin-dependent signaling pathway, which further leads to downstream activation and expression of cardiac hypertrophy related proteins, ANP and BNP. Further, we found that glucose induced IGF2R expression downregulated survival protein p-Akt, p-Bad (Ser 155) and enhanced the expression of apoptosis-inducing proteins cytochrome c and cleaved Caspase-3. Our results suggested that hyperglycemic condition leads to cellular cardiomyocyte apoptosis both in vitro and in vivo models, via abnormally increased activation of the IGF2R signaling pathway. PMID- 29136766 TI - Behavioral and biochemical evidences for nootropic activity of boldine in young and aged mice. AB - Boldine, a bioactive compound, has been reported to be neuroprotective, but its effect on learning and memory has not been explored. So, the present study was aimed to study the effect of boldine on the learning and memory of the Swiss albino male young and aged mice. Boldine (1.5, 3 and 6mg/kg, po) and physostigmine salicylate (0.1mg/kg, ip) were administered to separate groups of mice for 7 successive days. Morris water maze was utilized as a behavioural model to study the effect of drugs on learning and memory of mice. Boldine and physostigmine significantly improved learning and memory of young as well as aged mice, as indicated by decrease in escape latency time during training session and increase in time spent in target quadrant during retrieval session. No significant effect on locomotor activities of mice was observed due to drug treatments. Memory-enhancing activity of boldine (3mg/kg) was found to be comparable to physostigmine. Boldine significantly reversed scopolamine-, sodium nitrite- and aging-induced amnesia in mice. Moreover, boldine attenuated oxidative stress, as shown by a significant decrease in brain malondialdehyde as well as brain nitrite levels and a significant increase in brain GSH level of young as well as aged mice. Brain acetylcholinesterase activity was also significantly inhibited by boldine in young as well as aged mice. In conclusion boldine administered for 7 successive days exhibited significant improvement of learning and memory of young and aged mice possibly through inhibition of brain acetylcholinesterase activity and alleviation of brain oxidative stress. PMID- 29136765 TI - Panax quinquefolium saponin inhibits endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and attenuates the progression of osteoarthritis in rat. AB - Treatments for osteoarthritis (OA) seek to restore chondrocyte function and inhibit cell apoptosis. Panax quinquefolium saponin (PQS) is the major active ingredient of Radix panacis quinquefolii (American ginseng), and has been demonstrated to exert anti-inflammatory and anti-apoptotic effects in various diseases. However, any potential effect of PQS on the pathological process of OA remains unclear. This work aimed to explore the role of PQS in chondrocytes and to clarify its potential mechanisms. We showed that PQS treatment could protect chondrocytes against endoplasmic reticulum (ER) stress and associated apoptosis induced by interleukin (IL)-1beta. Also, PQS further attenuated triglyceride (TG) induced ER stress and associated apoptosis. Moreover, PQS may inhibit the ER stress-activated NF-kappaB pathway and associated inflammatory response in chondrocytes. Finally, PQS abolished rat cartilage degeneration in an in-vivo OA model of the knee joint. Our results indicate that PQS may be a potential novel treatment for OA. PMID- 29136767 TI - The exposure-effect-toxicity correlation of docetaxel and magnesium isoglycyrrhizinate in non-small cell lung tumor-bearing mice. AB - To take full advantage of combination therapy of Docetaxel (DTX) and Magnesium isoglycyrrhizinate (MGIG), the pharmacokinetic- pharmacodynamic- toxicodynamics (PK-PD-TD) interaction of DTX and MGIG in non-small cell lung tumor-bearing mice was investigated in the present study. A model, an integrated semi-mechanistic PK PD-TD, was established for elucidating the exposure-effect-toxicity relationship between DTX and MGIG. A tumor growth and a transit compartmental system were applied to imitate the growth and death of tumor cell. An indirect model with precursor-dependence was induced to clarify the temporal relationship between liver injury and drug exposure. No PK interaction between DTX and MGIG in plasma, liver and tumor was observed. In PD and TD results, MGIG had no antitumoral activity on non-small cell lung carcinoma, while it showed a strong hepatoprotection on DTX-induced liver injury. The PK-PD parameters of anti-tumor effect were related with the tumor growth characteristics, the kinetics of the tumor death and drug potency. In the PK-TD model, it was estimated about the elevation rate of ALT after DTX challenge in hepatocytes as well as plasma. MGIG reduced the DTX-induced ALT release rate from hepatocyte efficiently. Based on parameters estimated via PK-PD-TD correlation, the model successfully predicted the tumor growth kinetics and hepatoprotection at different dose regimes. Therefore, this prospective model might provide an alternative approache to the optimization of new experiment design. PMID- 29136768 TI - Lipoxin A4 protects against spinal cord injury via regulating Akt/nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 signaling. AB - Spinal cord injury (SCI) is a devastating physical trauma worldwide. The mechanisms of SCI are still not clear and the effective treatment is limited. Lipoxin A4 (LXA4) possesses anti-inflammatory and neuroprotective effects. The present study was designed to further evaluate the molecular mechanisms of LXA4 induced protective effects in a rat model of SCI. We found that LXA4 increased Basso, Beattie and Bresnahan (BBB) scores, increased mechanical paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) to a radiant heat, reduced the lesion volume, decreased Bax mRNA expression and increased Bcl-2 expression after SCI. The phosphorylation of Akt and protein expression of Nrf2 and HO-1 were reduced after SCI. LXA4 treatment significantly inhibited the reduction of Akt phosphorylation and Nrf2 and HO-1 protein expression. Injection of LY294002 notably inhibited the phosphorylation of Akt, and the expression of total Akt and Nrf2 and HO-1 after SCI in LXA4-treated rats. LY294002 prohibited LXA4-induced effects after SCI. shNrf2 injection markedly decreased both Nrf2 and HO-1 expression in LXA4-treated rats after SCI. ZnPP notably decreased HO-1 expression but did not markedly affect Nrf2 expression. shNrf2 and ZnPP prohibited LXA4 induced increase of BBB scores, and PWT and PWL, decrease of lesion volume of spinal cord, reduction of Bax expression and increase of Bcl-2 expression. The results indicate that LXA4 protects against SCI through Akt/Nrf2/HO-1 signaling. The data provide novel insights into the mechanisms of LXA4-mediated neuprotective effects against SCI and suggest that LXA4 may be a potential therapeutic agent for SCI and its associated complications. PMID- 29136769 TI - LncRNA-p21 inhibited the proliferation of osteosarcoma cells via the miR 130b/PTEN/AKT signaling pathway. AB - Osteosarcoma (OS) is the most common type of malignant bone tumor in children and adolescents. However, the molecular mechanism underlying OS development is unclear. Here, we investigated the contribution of lncRNA-p21, a novel long non coding RNA, on OS cell proliferation. Our results demonstrated that the expression of lncRNA-p21 was repressed in OS tissue. Growth curves and the cell colony formation assay showed that lncRNA-p21 significantly inhibited the proliferation of OS cell lines. In addition, the expression of lncRNA-p21 increased the protein levels of proliferation markers, such as Ki-67 and cyclin D1. Subsequently, lncRNA-p21 overexpression up-regulated the protein level of phosphatase and tensin homolog deleted on chromosome ten (PTEN), a well-known inhibitor of AKT signaling. Moreover, our gain and loss function assay showed that the promotion of PTEN by lncRNA-p21 was mediated by miR-130b, an oncogene overexpressed in OS tissue. Our findings may provide a novel lncRNA-targeted therapy for patients with OS. PMID- 29136770 TI - Magnesium valproate ameliorates type 1 diabetes and cardiomyopathy in diabetic rats through estrogen receptors. AB - Estrogen is known to exhibit cardioprotective and antihyperlipidemic action. Valproic acid has been shown to upregulate estrogen receptors (ERs) in breast and prostate cancer tissues. No pharmacological evaluations for magnesium valproate (MgV) so far have been done for diabetic cadio-lipidemic complications. Based on the above context, current study was undertaken to evaluate the therapeutic effectiveness of MgV in cardiac complications associated with type-1 diabetes mellitus in rats wherein diabetes was induced by single tail vein injection of streptozotocin (STZ, 45mg/kg, IV) in female Sprague Dawley rats and treatment of MgV (210mg/kg, PO) was given for eight weeks to diabetic animals, after which, various biochemical and cardiac biomarkers, hypertrophic, hemodynamic and histological parameters along with immunohistochemistry of ERs in the left ventricle (LV) were estimated. MgV treatment significantly controlled hyperglycemia and dyslipidemia, reduced elevated cardiac biomarkers and C reactive protein(CRP), significantly improved hemodynamic functions and increased the rate of pressure development and decay. MgV also significantly reduced left ventricular hypertrophy index and cardiac hypertrophy index, LV wall thickness, LV collagen, cardiomyocyte diameter and prevented the oxidative stress with significant increase in Na+-K+-ATPase activity in LV. Moreover, MgV reversed STZ induced histological alterations and decreased glycogen content in LV and increased the ERbeta expressions in LV as evidenced by immunohistochemistry. The result indicated that MgV prevented disease progression in the early stage of diabetic cardiomyopathy which seems to be mediated by upregulation of estrogen receptors in LV tissue. PMID- 29136771 TI - A review on the chemotherapeutic potential of fisetin: In vitro evidences. AB - During the past five decades, cancer cell lines are being successfully used as an in vitro model to discover the anti-cancer potential of plant secondary metabolites. Fisetin - the most popular polyphenol from fruits and vegetables, exhibits a repertoire of promising pharmacological features. Such versatile properties make fisetin an excellent anticancer agent and its efficacy as a chemotherapeutic agent against tumor heterogeneity from in vitro studies are encouraging. Fisetin is like a Pandora's box, as more research studies are being carried out, it reveals its new molecules within the cancer cells as therapeutic targets. These molecular targets orchestrate processes such as apoptosis, autophagic cell death, cell cycle, invasion, metastasis and angiogenesis in cancer cells. Besides apoptotic elicitation, fisetin's ability to induce autophagic cell death in cancer cells has been reported. This review examines the various molecular mechanisms of action elicited by fisetin leading to apoptosis and autophagic cell death as evidenced from cancer cell lines. In addition, the increased bioavailability and sustained release of fisetin improved through conjugation and enhanced effect of fisetin through synergism on various cancers are also highlighted. PMID- 29136772 TI - Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway. AB - BACKGROUND: Many studies have identified trimethylamine N-oxide (TMAO) as a new risk factor of cardiovascular diseases. It has been suggested that TMAO promotes atherosclerosis development. However, the underlying mechanism is still unclear. METHODS: Apoe-/- mice were fed a high-fat diet and given water with or without TMAO for 8-week. Histological and immunohistological analyses were used to evaluate the atherogenic effect of TMAO in vivo. We also employed peritoneal elicited macrophages and RAW264.7 to assess the role of MAPK/JNK pathway in TMAO induced formation of foam cells. RESULTS: TMAO significantly promoted plaque progression in apoe-/- mice fed with high-fat diet for 8 weeks. Besides, macrophage recruitment, CD36 and proinflammatory cytokine expressions were enhanced by TMAO in plaque lesions. In vitro, TMAO increased the macrophage migration and the expression of TNF-alpha, IL-6 and ICAM1. In addition, CD36 expression and foam cell formation induced by ox-LDL were also enhanced by TMAO, which could be attenuated by siRNA-mediated knockdown of CD36. We additionally used MAPK inhibitor (SB230580) and JNK inhibitor (SP600125) to assess the MAPK/JNK pathway in TMAO-induced CD36 expression. Western blotting showed that both SB230580 and SP600125 could reduce the expression of CD36 induced by ox-LDL and TMAO. Moreover, SB230580 and SP600125 could also reduce the formation of foam cells. CONCLUSIONS: TMAO promotes the atherosclerosis in vivo and in vitro.CD36/MAPK/JNK pathway may play a crucial role in TMAO-induced formation of foam cells. PMID- 29136773 TI - The potential use of melatonin to treat protozoan parasitic infections: A review. AB - Melatonin (N-acetyl-5-methoxytryptamine) is a circadian hormone produced in vertebrates by the pineal gland and other organs. Melatonin is believed to influence immune cells leading to modulation of the proliferative response of stimulated lymphocytes as well as cytokine production. Due to the antioxidant and immunomodulatory effects of melatonin, it is suggested that this molecule could be a therapeutic alternative agent to fight bacterial, viral, and parasitic infections by a variety of mechanisms. Herein, we review the effects of melatonin on the cell biology of protozoan parasites and host's immune response. In toxoplasmosis, African trypanosomiasis and Chagas' disease, melatonin enhances host's immune response against the parasite via regulating the secretion of inflammatory mediators. In amoebiasis, melatonin reduces the amoebic lesions as well as increasing the leukophagocytosis and the number of dead amoebae. In giardiasis, serum melatonin levels are elevated in these patients; this suggests a positive correlation between the level of melatonin and phagocytic activity in the G. duodenalis infected patients, possibly related to melatonin's immunomodulatory effect. In leishmaniasis, melatonin arrests parasite replication accompanied by releasing mitochondrial Ca2+ into the cytosol, increasing the level of mitochondrial nitrites as well as reducing superoxide dismutase (SOD) activity. In malaria, melatonin synchronizes the Plasmodium cell cycle via modulating cAMP-PKA and IP3-Ca2+ pathways. Thus, simultaneous administration of melatonin agonists or giving pharmacological doses of melatonin may be considered a novel approach for treatment of malarial infection. PMID- 29136774 TI - An overview of neuroprotective and cognitive enhancement properties of lignans from Schisandra chinensis. AB - Schisandra chinensis fruits have been traditionally used for thousands of years in Korea, China and Japan to treat various ailments. The fruits contain a variety of bioactive metabolites, especially lignan components have been reported to have various biological activities and have potential in the treatment of numerous neurodegenerative diseases. The lignans from S. chinensis are mainly grouped under dibenzocyclooctadiene lignans. Previous studies have reported that the crude extracts and the isolated pure lignan components effectively protect the neuronal cell damage and significantly enhance the cognitive performances. The experimental findings support the extracts and lignan components from S. chinensis can be used as new therapeutic agents to treat various neurodegenerative diseases. In the current review, we highlight the lignans from S. chinensis as promising resources for the development of natural and effective agents for neuroprotective and cognitive enhancement effects. The lignan extracts and individual compounds from S. chinensis were summarized in relation to their neuroprotective and cognitive enhancement activities. PMID- 29136775 TI - High parathyroid hormone concentration in tenofovir-treated patients are due to inhibition of calcium-sensing receptor activity. AB - Bone health impairment is a common finding in HIV-infected patients on antiretroviral treatment. High serum parathyroid hormone (PTH) concentration in patients on antiretroviral treatment containing tenofovir disoproxil fumarate (TDF) has been reported. Hyperparathyroidism was not always sustained by a reduction in vitamin D concentration. We thus hypothesized a direct inhibitory effect of TDF on the Calcium-sensing receptor (CaSR), leading to hyperparathyroidism. Human embryonic kidney cells were transfected with CASR wild type gene or mutated in different sites (N124K, T1051G, C788T, T888M). Cells were grown in standard conditions and the activity of CaSR was assessed after stimulation with CaCl2 with and without TDF (100 nM-1 MUM). We evaluated by western blot phospho-p44/42 ERK expression levels as a marker of CaSR activity. In silico structure models were obtained for wild-type and N124K mutant. Molecular docking with TDF was also evaluated. The stimulation by CaCl2 and TDF 100 nM led to a decrease of 55% of CaSR activity (P < 0.001), whereas the stimulation by CaCl2 and TDF 1 MUM reduced the activity by 68% (P < 0.001). The decreased CaSR activity was comparable to that observed from known CASR gene inactivating mutations (T1051G, C788T), which inhibit the receptor activity by 56% and 78%, respectively. The TDF inhibits the CaSR activity carrying a gain of function mutation in the intracellular domain (T888M), but it does not influence the activity of the receptor carrying the N124K activating mutation. Our data show that TDF is able to inhibit the activity of CaSR in a dose-dependent manner. Hyperparathyroidism observed in TDF-treated patients may be therefore promoted by the direct effect of the drug on CaSR. PMID- 29136776 TI - Dihydroartemisinin inhibits ER stress-mediated mitochondrial pathway to attenuate hepatocyte lipoapoptosis via blocking the activation of the PI3K/Akt pathway. AB - Alcoholic liver disease (ALD), characterized by accumulation of fatty acids in liver cells, is usually caused by Chronic alcohol consumption. Our previous study has identified that DA protects against alcoholic liver injury in alcohol-fed rats through alleviating hepatocyte steatosis. It has emerged that saturated fatty acids could provoke endoplasmic reticulum (ER) stress and apoptosis in hepatocytes. This study was aimed to explore the impact of DA on ALD and further elaborate the underlying mechanisms. Results demonstrated that DA attenuates alcoholic liver injury in mice. Our results also indicated that DA attenuated lipid accumulation in hepatocytes exposed to ethanol. DA attenuates ethanol induced hepatocyte apoptosis. Results demonstrated that DA dose-dependently ameliorated activation of mitochondrial pathway activation, which plays a critical role in apoptosis attributed to lipotoxicity. Further, DA suppressed the activation of JNK and the expression of CHOP, attributed to the inhibition of ER stress. It has emerged that activation of ER stress-JNK/CHOP-mitochondria cascade is considered as the key mechanisms underlying hepatocyte lipoapoptosis. In addition, DA attenuates PI3K/Akt Pathway in hepatocytes, consistent with our previous finding in HSCs. DA effects were reinforced by PI3K specific inhibitor LY294002. In summary, DA significantly protected hepatocytes against lipoapoptosis via a PI3K/Akt Pathway inhibition-dependent mechanism. PMID- 29136777 TI - Anti-hypertensive and vasodilatory effects of amended Banxia Baizhu Tianma Tang. AB - Although Banxia Baizhu Tianma Tang (BBT) has been long administered for hypertensive treatment in Traditional Chinese Medicine (TCM), the ratio of the herbal components that makes up the formulation has not been optimized with respect to the anti-hypertensive effect that it inherently possesses. A newly amended BBT (ABBT) formulation was developed using the evidence-based approach of orthogonal stimulus-response compatibility model. The ABBT showed enhanced therapeutic effect while maintaining its traditional theoretical approach rooted in TCM. This study was designed to investigate the possible mechanism of actions involved in the vasodilatory activity of ABBT-50 by evaluating its vasodilative effect on isolated Sprague Dawley rats in the presence of absence of various antagonists. When pre-contracted with phenylephrine, relaxation was observed in endothelium intact (EC50=0.027+/-0.003mg/ml, Rmax=109.8+/-2.12%) and denuded aortic rings (EC50=0.409+/-0.073mg/ml, Rmax=63.15+/-1.78%), as well as in endothelium intact aortic rings pre-contracted with potassium chloride (EC50=32.7+/-12.16mg/ml, Rmax=34.02+/-3.82%). Significant decrease in the vasodilative effect of ABBT-50 was observed in the presence of Nomega-nitro-l arginine methyl ester (EC50=0.12+/-0.021mg/ml, Rmax=75.33+/-3.28%), 1H-[1,2,4] Oxadiazolo[4,3-a]quinoxalin-1-one (EC50=0.463+/-0.18mg/ml, Rmax=54.48+/-2.02%), methylene blue (EC50=0.19+/-0.037mg/ml, Rmax=83.69+/-3.19%), indomethacin (EC50=0.313+/-0.046mg/ml, Rmax=71.33+/-4.12%), atropine (EC50=0.146+/-0.013mg/ml, Rmax=77.2+/-3.41%), and 4-aminopyridine (EC50=0.045+/-0.008mg/ml, Rmax=95.55+/ 2.36%). ABBT-50 was also suppressing Ca2+ release from sarcoplasmic reticulum and inhibiting calcium channels. Vasodilatory effects of ABBT-50 are mediated through NO/sGC/cGMP cascade and PGI2, followed by muscarinic pathways and calcium channels. PMID- 29136778 TI - Zuogui Pill improves the dexamethasone-induced osteoporosis progression in zebrafish larvae. AB - The current study was to evaluate the protective effects of Chinese medicine prescription Zuogui Pill (ZGP) on osteoporosis (OP) in zebrafish larvae induced by dexamethasone. Alizarin Red staining, calcium and phosphorus determination were performed to evaluate the effect of ZGP on bone mineralization. Hydroxyproline (HP), Alkaline phosphatase (ALP), and tartrate resistant acid phosphatase (TRAP) were also measured by commercial kits. We found that ZGP had positive effects in increasing bone mineral content (BMC), strengthening bone biomechanical, promoting bone formation, inhibiting bone resorption, and mediating protein levels of TGF-beta1/Smads signaling pathway. The findings demonstrated that ZGP treatments inhibited the phosphorylation of TGF-beta and p Smad 3 as well as the expressions of collagen I and collagen II by western blot. Taken together, we demonstrated that ZGP may prevent osteoporosis via reversing the imbalance of bone fomation/bone resorption and activating the TGF-beta-Smad signal. PMID- 29136779 TI - Juglanin ameliorates LPS-induced neuroinflammation in animal models of Parkinson's disease and cell culture via inactivating TLR4/NF-kappaB pathway. AB - Parkinson's disease (PD) is a common neuro-degenerative disorder, and novel therapeutic targets are required for the treatment of PD. Juglanin is a natural compound extracted from the crude Polygonum aviculare, exhibiting anti inflammatory, anti-oxidant and anti-cancer activities. In our study, PD in mice was induced by systemic LPS treatment as evidenced by enhanced alpha-synuclein and reduced tyrosine hydroxylase (TH), which were reversed by juglanin treatment. Moreover, juglanin administration attenuated LPS-caused behavioral and memory impairments and reduced LPS-induced enhancement of neuro-degenerative markers, including amyloid beta (Abeta) and p-Tau. Additionally, juglanin ameliorated synaptic functionality through promoting the expression of synaptic markers, such as SYP, PSD-95 and SNAP-25. Toll-like receptor 4 (TLR4) signaling in brain regulates neuroinflammation, contributing to neurodegenerative diseases. Furthermore, LPS induced neuroinflammation through the acceleration of various pro-inflammatory cytokines, including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-18 (IL-18) and Cyclooxygenase-2 (COX-2), via activating TLR4/nuclear factor (NF)-kappaB pathway in hippocampus of mice and microglia cells. Juglanin significantly reduced LPS-induced production of pro-inflammatory cytokines and blocked TLR4/NF-kappaB pathway. We also found that LPS-induced astrocytes (AST) activity was prevented by juglanin through down regulating glial fibrillary acidic protein (GFAP) and Iba1 in vivo and in vitro. Together, our results indicated that juglanin ameliorated neuroinflammation related memory impairment, and neurodegeneration through impeding TLR4/NF-kappaB, indicating its potential for PD prevention. PMID- 29136780 TI - CML/CD36 accelerates atherosclerotic progression via inhibiting foam cell migration. AB - Among the various complications of type 2 diabetes mellitus, atherosclerosis causes the highest disability and morbidity. A multitude of macrophage-derived foam cells are retained in atherosclerotic plaques resulting not only from recruitment of monocytes into lesions but also from a reduced rate of macrophage migration from lesions. Nepsilon-carboxymethyl-Lysine (CML), an advanced glycation end product, is responsible for most complications of diabetes. This study was designed to investigate the mechanism of CML/CD36 accelerating atherosclerotic progression via inhibiting foam cell migration. In vivo study and in vitro study were performed. For the in vivo investigation, CML/CD36 accelerated atherosclerotic progression via promoting the accumulation of macrophage-derived foam cells in aorta and inhibited macrophage-derived foam cells in aorta migrating to the para-aorta lymph node of diabetic apoE-/- mice. For the in vitro investigation, CML/CD36 inhibited RAW264.7-derived foam cell migration through NOX-derived ROS, FAK phosphorylation, Arp2/3 complex activation and F-actin polymerization. Thus, we concluded that CML/CD36 inhibited foam cells of plaque migrating to para-aorta lymph nodes, accelerating atherosclerotic progression. The corresponding mechanism may be via free cholesterol, ROS generation, p-FAK, Arp2/3, F-actin polymerization. PMID- 29136781 TI - Andrographolide sulfonate improves Alzheimer-associated phenotypes and mitochondrial dysfunction in APP/PS1 transgenic mice. AB - Alzheimer's disease is a neurodegenerative disorder with Amyloid-beta plaques onset, synaptic damage, and cognitive decline. Abeta deposits cause pathological events including oxidative stress, mitochondrial dysfunction, and neuron death. In this study, APPswe/PSENDelta9 double transgenic mice model was used to imitate Alzheimer's disease and the effect and possible mechanism of Andrographolide sulfonate were examined. Andrographolide sulfonate was given to the mice for 7 months before the onset of Abeta plaque. Spatial memory test showed that Andrographolide sulfonate treatment prevented cognitive decline. Abeta deposits were not affected while hippocampus and synapse damage was significantly alleviated. Mechanism studies showed that oxidative stress and mitochondrial swelling was reduced after Andrographolide sulfonate administration. These findings suggest that Andrographolide sulfonate, which has been applied in clinical medicine, might be a promising therapeutic agent for AD therapy via mitochondria protection. PMID- 29136782 TI - Effect of human umbilical cord blood-derived mononuclear cells on diabetic nephropathy in rats. AB - Diabetic nephropathy (DN) is damage to the kidney which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of adult kidney failure worldwide in the developed world. The current work was designed to elucidate the effect of mononuclear cells (MNCs) injection on reverse DN in rats exposed to streptozotocin (STZ) injection compared to metformin as a known hypoglycemic drug, 40 Male rats were divided equally into 4 groups; normal control group, diabetic control group, MNCs group were diabetic rats treated with MNCs (30*106 MNCs/rat once iv dose) in the tail vein of the rat, and metformin group were diabetic rats treated with metformin (100mg/kg orally daily dose) for four weeks. The results indicated an improvement effect of MNCs and metformin on STZ-induced DN in rats, which was evidenced by significant decrease in urinary albumin/creatinine ratio, N-acetyl-beta-d-glucosaminidase (NAG), urinary kidney injury molecule-1 (KIM-1), serum urea, serum creatinine and fasting blood glucose and significant increase in C- peptide level, compared to diabetic control group. Additionally MNCs treated group exhibited pronounced effects in all previous parameters compared to metformin treated group. It is proved that MNCs treatment was superior to metformin in controlling hyperglycemia, and improving renal function in diabetic rats. PMID- 29136783 TI - Revalidation of the neuroprotective effects of a United States patented polyherbal formulation on scopolamine induced learning and memory impairment in rats. AB - OBJECTIVE: Alzheimer's disease (AD) is the most common cause of dementia yet treatment options are extremely limited. The disease is associated with cognitive impairment as well as structural irregularities, accumulation of plaques and neurofibrillary tangles, diminished levels of acetylcholine, oxidative stress, and inflammation in the brain. We have previously reported on the positive effects of a united states patented (US 7,273,626 B2) poly herbal test formulation, consisting of Bacopa monnieri, Hippophae rhamnoides and Dioscorea bulbifera extracts, on cognitive deficits in AD patients. The present study was conducted to investigate the mechanism(s) of action of the formulation using scopolamine treated rats as an AD model. METHOD: The formulation was administered daily along with scopolamine for a period of 14days following which the elevated plus maze, passive avoidance, and Morris water maze tests were performed to assess learning and memory. Rats treated with scopolamine or vehicle only were also included in the experiment. Acetylcholine levels and activities of acetylcholinesterase (AChE) and anti-oxidant enzymes in the brain were also measured at the end of the treatment period. RESULTS: The study demonstrate that scopolamine treatment resulted in learning and memory deficits which were partially and significantly ameliorated by the formulation. The formulation also counteracted scopolamine-induced decreases in acetylcholine levels, increases in AChE activity, and decreases in activities of the antioxidant enzymes. CONCLUSION: The study demonstrates the ability of the test formulation to reverse scopolamine-induced learning and memory deficits in rats which may at least partially be explained by the reversal of scopolamine-induced reductions in brain acetylcholine levels and antioxidant activities by the test formulation. PMID- 29136784 TI - The alternation of autophagy/apoptosis in CD4+CD25+Foxp3+ Tregs on the developmental stages of atherosclerosis. AB - Naturally regulatory T cells (Tregs) play a critical role in the regulation of T cell-mediated immune responses in atherosclerosis. However, the regulatory mechanism underlying Tregs upon long-term development of atherosclerosis remains unknown. Therefore, in this study, atherosclerotic model was induced in ApoE-/- mice by feeding fat-diet for 10 weeks. Quantification of atherosclerotic lesions was done by calculating the lesion size in the aortic sinus every 2 weeks. The lipid levels and inflammatory mediators were detected in serum sample. The populations of CD4+CD25+Foxp3+ Tregs were compared between ApoE-/- mice (ApoE-/-) and wild type C57BL/6 littermates (WT). The expression levels of autophagy and apoptosis signaling related regulators were determined by flow cytomery, RT-qPCR, and western blot assays in the CD4+CD25+Foxp3+ Tregs isolated from ApoE-/- and WT. We found that the sizes of plaque lesions in atherosclerotic ApoE-/- mice were larger than those in WT group during 10 weeks' detection (all P<0.05); Whereas, flow cytometry assay showed that the populations of CD4+CD25+Foxp3+ Tregs were significantly reduced in atherosclerotic ApoE-/- mice compared with those in corresponding WT group from the 4th weeks' detection (all P<0.05). The lipid accumulation and increased pro-inflammatory mediators were correlated with the developmental progression of atherosclerosis. Furthermore, compared to WT group, the functional properties of CD4+CD25+Foxp3+ Tregs from ApoE-/- mice showed a gradually decreased autophagic activity with aberrant expressions of LC3, Beclin1, ATG5, ATG7, p62 (all P<0.05), and a gradually increased apoptotic activity with abnormal expressions of cleaved caspase 3, Bim, Bcl-2 (all P<0.05) during the 10 weeks' detection period. Taken together, our data demonstrated that the population of CD4+CD25+Foxp3+ Tregs was reversely correlated with plaque forming in atherosclerotic ApoE-/- mice during atherosclerosis development. And the autophagy/apoptosis-dependent Tregs might play a crucial role for the maintenance of CD4 9+CD25+Foxp3+ Tregs survival during atherosclerosis progression. PMID- 29136785 TI - Obestatin prevents H2O2-induced damage through activation of TrkB in RGC-5 cells. AB - BACKGROUD: In the early stage of diabetic retinopathy, the damage of retinal ganglion cells already exists, promoting the development of the disease. The aim of this study was to investigate the protective role and the mechanisms of obestatin against H2O2-induced damage in RGC-5 cells. METHODS: RGC-5 cells were incubated with various concentrations of obestatin for 24h before H2O2 added. The survival rates of RGC-5 were measured by MTT assay. The expression of apoptosis related proteins and TrkB pathway-related proteins were detected by Western blot analysis. RESULTS: Our data showed that H2O2 evidently decreased the survival rate of RGC-5 cells. However, obestatin pretreatment reversed the decreased activity. Moreover, obestatin effectively increased the expression of Bcl-2 and decreased the expression of Bax. In addition, obestatin potentially plays a role in protecting RGC-5 by activating of TrkB. Obestatin notablely increased the phosphorylation of TrkB, AKT and ERK1/2. All these effects of obestatin can be inhibited by GLP-1R antagonist exendin (9-39). CONCLUSIONS: Obestatin prevents H2O2-induced damage in RGC-5 cells by activating TrkB pathway. Moreover, GLP-1R is closely related to the function of obestatin in RGC-5 cells. PMID- 29136786 TI - Poly (methacrylic acid-co-diethenyl-benzene) monolithic microextraction column and its application to simultaneous enrichment and analysis of mycotoxins. AB - A poly (methacrylic acid-co-divinyl-benzene) [poly (MAA-co-DVB)] monolithic column was specially prepared according to the chemical structures of the three mycotoxins of aflatoxin B1, zearalenone and sterigmatocystin, and used for in tube solid-phase microextraction (in-tube SPME) of the selected mycotoxins. The poly (MAA-co-DVB) monolithic column was characterized in detail, and exhibited effective hydrophobic, pi-pi, and hydrogen bonding interactions towards the target analytes. By coupling the poly (MAA-co-DVB) monolithic column-based in tube SPME with high-performance liquid chromatography, a simple, sensitive and matrix effect-free method for determination of mycotoxins was developed. Some important parameters related to extraction efficiency were optimized systematically. Under the optimal conditions, the enrichment factors for the three mycotoxins ranged from 71.9 to 98.7. Recoveries of mycotoxins in rice grains with three spiked concentration levels were in the range of 78.0-102.8%, with satisfactory relative standard deviations (n = 4) of 2.96-4.74%. Good linearity was obtained with correlation coefficients larger than 0.99, and the detection limits (S/N = 3) of the three mycotoxins were between 0.69 and 2.03MUgkg-1. The developed poly (MAA-co-DVB) monolithic column based in-tube SPME HPLC method was successfully used to sensitively determine trace mycotoxins in practical samples of rice grain without interference peaks, indicating that it is promising for the detection of trace mycotoxins in complex grain samples. PMID- 29136787 TI - 1H NMR assisted quantification of glycerol carbonate in the mixture of glycerol and glycerol carbonate. AB - Glycerol carbonate (GLC) is a very important chemical having a variety of application viz., green solvent in organic synthesis, an electrolyte in lithium batteries, wetting agent in cosmetics and precursor in polymer and food industry for the synthesis of 1,3-sn-diglycerides. Hence, it is vital to find out the quick and simple method for the quantification of GLC when it is synthesized via dimethyl carbonate (DMC) assisted transesterification with glycerol (GL). Present study, proposes simple, accurate and non destructive quantitative proton nuclear magnetic resonance (qHNMR) method for the determination of GLC. Based upon the study, two different equations are proposed to calculate the GLC employing the data obtained from the 1H NMR spectra. qHNMR results were also validated by preparing the standard mixtures of varying concentrations of GL and GLC. Further, to conform the developed method for a real application, GLC concentration was also estimated during CaO catalyzed DMC transesterification with GL. The qHNMR assisted GLC quantification were found consistent with those obtained from high performance liquid chromatography analysis (R2 = 0.99). PMID- 29136788 TI - Red-emitting BSA-stabilized copper nanoclusters acted as a sensitive probe for fluorescence sensing and visual imaging detection of rutin. AB - In this article, red-emitting copper nanoclusters (Cu NCs) were prepared in the matrix of bovine serum albumin (BSA) through using N2H4.H2O as a reducing agent and BSA as a stabilizer. In the aqueous suspension of BSA-Cu NCs, the addition of rutin enabled the combination of rutin with BSA around Cu NCs via hydrogen bond and electrostatic interactions between functional groups of BSA and rutin. The approaching of rutin to Cu NCs induced that the fluorescence (FL) of Cu NCs was quenched by rutin due to the electron transfer from Cu NCs to rutin. Under the optimal conditions, the FL of Cu NCs was linearly decreased with the increase of rutin concentration from 0.1 to100 MUM, together with a low detection limit of ca. 0.02MUM. The FL quenching responses of Cu NCs were highly selective and sensitive towards rutin, over potential interferents in real human serum samples. Based on BSA-Cu NCs, this as-proposed FL probe exhibited a superior capability of rutin detection in real human serum samples. Significantly, this probe of rutin could realize the FL sensing of rutin and the naked-eye visual FL imaging detection of rutin in aqueous solution and on filter paper. PMID- 29136789 TI - Application of pseudo-template molecularly imprinted polymers by atom transfer radical polymerization to the solid-phase extraction of pyrethroids. AB - A polymer-based adsorption medium with molecular recognition ability for homologs of pyrethroids was prepared by atom transfer radical polymer iration using a fragment imprinting technique. Phenyl ether-biphenyl eutectic was utilized as a pseudo-template molecule, and the adsorption medium prepared was evaluated by solid-phase extraction and gas chromatography. Selectivity of the medium for pyrethroids was evaluated using it as solid phase extraction packing by Gas Chromatography. The results demonstrated that the absorption amount of bifenthrin, fenpropathrin, permethrin, cypermethrin, fenvalerate, Dursban and pentachloronitrobenzene for molecularly imprinted polymers were 2.32, 2.12, 2.18, 2.20, 2.30, 1.30 and 1.40mgg-1, respectively, while the non-imprinted polymers were 1.20, 1.13, 1.25, 1.05, 1.20, 1.23 and 1.32mgg-1, respectively. The rebinding test based on the molecularly imprinted solid phase extraction column technique showed the recoveries of honey sample spiked with seven insecticides within 88.5-106.2%, with relative standard deviations of 2.38-5.63%. Finally, the method was successfully applied to the analysis of pyrethroids in a honey sample. PMID- 29136790 TI - Paper-based amperometric sensor for determination of acetylcholinesterase using screen-printed graphene electrode. AB - A simple paper-based sensor with electrochemical detection was first developed for rapid, selective, and sensitive determination of acetylcholinesterase (AChE). The screen-printed graphene electrode was used as working electrode providing sensitivity for the sensor. The amperometric detection of AChE is based on the determination of thiocholine (TCh) produced from hydrolysis of acetylthiocholine chloride (ATCh) by AChE. To detect TCh, the ATCh immobilized sheet was stacked onto the detection sheet using double adhesive tape, then samples of AChE were dropped on the back side of an ATCh immobilized sheet with only 1min of incubation time. To avoid interference, glutathione (GSH), the potential of 0.5V vs. Ag/AgCl was applied onto a graphene electrode and the current, which depends on AChE concentration, was measured. Under optimized conditions, the limit of detection (LOD) from the experiment of AChE determination was 0.1U/mL with AChE concentration in range of 0.1-15U/mL. The data correlated well with the data obtained using spectrophotometric method. The developed sensor had been successfully applied to detect AChE in blood samples. PMID- 29136791 TI - A flow injection procedure using Layered Double Hydroxide for on line pre concentration of fluoride. AB - This work showed a flow system designed with solenoid valves for preconcentration of fluoride using SPADNS method in water samples. The analyte was preconcentrated in a mini-column coated with Layered Double Hydroxides (LDH) used as adsorbent. Then, the fluoride ions were eluted with 0.5molL-1 sodium hydroxide and determined by spectrophotometry. The variables that affect the system such adsorbent mass, type of eluent, solutions flow rate, reagent concentration and pH effect were critically evaluated. Under optimized conditions, the detection limit, coefficient of variation, linear range and preconcentration factor were estimated at 15ugL-1 (99.7% confidence level), 0.8% (500ugL-1, n = 10), 50-500ugL 1 and 10, respectively. The accuracy of the method was evaluated by analysis of ALPHA APS 1076 (Simulated Rain Water) certified material, the values were not significantly different at a 95% level of confidence. The method was applied for fluoride determination in water samples and the levels found were below the maximum values established by Brazilian environmental and health legislations. PMID- 29136792 TI - Comparative performances of a bare graphite-polyurethane composite electrode unmodified and modified with graphene and carbon nanotubes in the electrochemical determination of escitalopram. AB - A bare composite graphite-polyurethane electrode (EGPU) and two other modified with graphene (EGPU-GR) and functionalized multi-walled carbon nanotubes (EGPU CNTs) were prepared and compared regarding their voltammetric response to escitalopran (EST). The modifiers were characterized by Raman spectroscopy and the resulting electrode materials by contact angle measurements with a hydrophilicity character in the ascending order for the composites: GPU > GPU-GR > GPU-CNTs and scanning electron microscopy (SEM). The electroactive areas of the EGPU, EGPU-GR, and EGPU-CNTs were 0.065, 0.080, and 0.092cm2, respectively, calculated from the chronocoulometry using K3[Fe(CN)6] as a probe and the Cottrell equation. The cyclic voltammograms obtained for EST indicated irreversible electrochemical behavior, with an anodic peak at ca. +0.80V (nus. SCE). These measurements were carried out with the three electrodes, and comparison of the analytical responses led to the EGPU-GR electrode being selected for use in the subsequent experiments. Under optimal conditions, square wave and differential pulse voltammetry at EGPU-GR presented linear dynamic ranges between 1.5 * 10-6 and 1.2 * 10-5mol L-1, with a detection limit of 2.5 * 10-7molL-1 (SWV) and 1.5 * 10-6 and 1.2 * 10-5molL-1, with a detection limit of 3.2 * 10-7molL-1 (DPV) for EST. The proposed method was applied for the quantification of EST in synthetic urine and cerebrospinal fluid samples, offering advantages including simplicity of fabrication, no requirement for analyte preconcentration and surface renewal, fast response, and selectivity. PMID- 29136793 TI - Electrochemical monitoring of the interaction between anticancer drug and DNA in the presence of antioxidant. AB - The aim of this work is to find out the effect of antioxidant onto the interaction of DNA-anticancer drug, daunorubicin. Daunorubicin (DNR) is an anti cancer drug which is used for the treatment of certain cancers including the treatment of leukemia. The treatments of patients, who suffer from cancer, become generally complicated if they take some antioxidant-containing supplement during chemotherapy. In this study, the interaction performance between DNR and DNA was investigated both in the presence and absence of antioxidant, caffeic acid, as the first time in the literature. Interaction performances were evaluated by observing both guanine (1.0V) and DNR (0.5V) oxidation signal in the same potential window. PMID- 29136794 TI - Determination of neutral diols and carboxylic acids formed during glycerol electrooxidation by capillary electrophoresis with dual C4D. AB - Methods for determination of glycerol and its electrooxidation products (neutral diols and carboxylates) by capillary electrophoresis (CE) with dual capacitively coupled contactless conductivity detectors (C4D) are presented. Glycerol, dihydroxyacetone and glyceraldehyde were detected as anionic borate complexes in less than 3min under counter Electroosmotic Flow (EOF) mode (resolution of the critical pair of 1.8). Limits of detection (LODs) of 15, 15 and 10umolL-1 were obtained for glycerol, dihydroxyacetone and glyceraldehyde, respectively. Two methods of separation were used for the separation of carboxylates. The first one used the same Back Ground Electrolyte (BGE) containing borate, and the second used a BGE (pH 6.1) composed by 2-(N-morpholino)ethanesulfonic acid (MES), L Histidine and a flow modifier. Better separation and LODs for carboxylates were obtained using Mes/Histidine as BGE. However, along with the non-applicability of this BGE to the determination of neutral diols, observation of the C4D signals at two different points of the capillary (10 and 50cm apart from the injection tip) revealed interaction of the flow modifier with some species (mesoxalate and glyoxylate). The electrooxidation of a glycerol sample in alkaline media on an 8cm2 gold working electrode was evaluated by the developed methods. After 16h of electrolysis, 87% of the glycerol had been oxidized and formate, glycolate, hydroxypyruvate and glycerate were detected as the main products. PMID- 29136795 TI - A regenerative and selective electrochemical aptasensor based on copper oxide nanoflowers-single walled carbon nanotubes nanocomposite for chlorpyrifos detection. AB - Chlorpyrifos is a commonly used organophosphorus pesticide in agriculture. However, its neurotoxicity poses a huge threat to human health. To detect trace amounts of chlorpyrifos, we herein developed a regenerative electrochemical aptasensor for the sensitive detection of chlorpyrifos. The nanocomposite consisting of copper oxide nanoflowers (CuO NFs) and carboxyl-functionalized single walled carbon nanotubes (c-SWCNTs) was prepared to improve the sensing performance for chlorpyrifos detection. Various characterization methods such as scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FT IR) and cyclic voltammetry (CV) were used to demonstrate the successful fabrication of biosensor. Differential pulse voltammetry (DPV) was utilized to optimize test conditions and quantify chlorpyrifos. Under optimal conditions, the biosensor obtained a good linearity for chlorpyrifos ranging from 0.1 to 150ng/mL, with a lower detection limit of 70pg/mL. This aptasensor also exhibited high selectivity and outstanding repeatability, and was successfully applied to the determination of chlorpyrifos in spiked apple and celery cabbage with satisfactory recoveries. Furthermore, the sensor can be easily regenerated by urea for continuous application. With all the features, the proposed strategy provides an excellent platform for regenerative and selective detection of chlorpyrifos. PMID- 29136796 TI - A multi-purpose tool for food inspection: Simultaneous determination of various classes of preservatives and biogenic amines in meat and fish products by LC-MS. AB - This paper describes an innovative fast and multipurpose method for the chemical inspection of meat and fish products by liquid chromatography-tandem mass spectrometry. Solid-liquid extraction and low temperature partitioning were applied to 17 analytes, which included large bacteriocins (3.5kDa) and small molecules (organic acids, heterocyclic compounds, polyene macrolides, alkyl esters of the p-hydroxybenzoic acid, aromatic, and aliphatic biogenic amines and polyamines). Chromatographic separation was achieved in 10min, using stationary phase of di-isopropyl-3-aminopropyl silane bound to hydroxylated silica. Method validation was in accordance to Commission Decision 657/2002/CE. Linear ranges were among 1.25-10.0mgkg-1 (natamycin and parabens), 2.50-10.0mgkg-1 (sorbate and nisin), 25.0-200mgkg-1 (biogenic amines, hexamethylenetetramine, benzoic and lactic acids), and 50.0-400mgkg-1 (citric acid). Expanded measurement uncertainty (U) was estimated by single laboratory validation combined to modeling in two calculation approaches: internal (U = 5%) and external standardization (U = 24%). Method applicability was checked on 89 real samples among raw, cooked, dry fermented and cured products, yielding acceptable recoveries. Many regulatory issues were revealed, corroborating the need for enhancement of the current analytical methods. This simple execution method dispenses the use of additional procedures of extraction and, therefore, reduces costs over time. It is suitable for routine analysis as a screening or confirmatory tool for both qualitative and quantitative results, replacing many time consuming analytical procedures. PMID- 29136797 TI - Unparalleled sample treatment throughput for proteomics workflows relying on ultrasonic energy. AB - We report on the new microplate horn ultrasonic device as a powerful tool to speed proteomics workflows with unparalleled throughput. 96 complex proteomes were digested at the same time in 4min. Variables such as ultrasonication time, ultrasonication amplitude, and protein to enzyme ratio were optimized. The "classic" method relying on overnight protein digestion (12h) and the sonoreactor based method were also employed for comparative purposes. We found the protein digestion efficiency homogeneously distributed in the entire microplate horn surface using the following conditions: 4min sonication time and 25% amplitude. Using this approach, patients with lymphoma and myeloma were classified using principal component analysis and a 2D gel-mass spectrometry based approach. Furthermore, we demonstrate the excellent performance by using MALDI-mass spectrometry based profiling as a fast way to classify patients with rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis. Finally, the speed and simplicity of this method were demonstrated by clustering 90 patients with knee osteoarthritis disease (30), with a prosthesis (30, control group) and healthy individuals (30) with no history of joint disease. Overall, the new approach allows profiling a disease in just one week while allows to match the minimalism rules as outlined by Halls. PMID- 29136798 TI - Corrigendum to "Magnetic graphene solid-phase extraction for the determination of carbamate pesticides in tomatoes coupled with high performance liquid chromatography" [Talanta 141 (2015) 212-219]. PMID- 29136799 TI - Ratiometric fluorescence and visual imaging detection of dopamine based on carbon dots/copper nanoclusters dual-emitting nanohybrids. AB - In this article, blue-emitting carbon dots (CDs) were prepared via hydrothermal treatment of sodium citrate and NH4HCO3, and then combined with 3 aminophenylboronic acid (APBA) to prepare APBA modified-CDs. APBA acted as the receptor of dopamine (DA). Using bovine serum albumin (BSA) as a stabilizer and N2H4.H2O as a reducing reagent, BSA-stabilized and red-emitting copper nanoclusters (CuNCs) were prepared. By carbodiimide-activated coupling, novel nanohybrids consisting of CDs and CuNCs were constructed and exhibited dual emitting fluorescence (FL). In the presence of DA, marked FL (at 440nm) quenching of nanohybrids was detected. Specific coupling interactions between boric acid of APBA and cis-glycol of DA induced the combination of DA and APBA on the surface of CDs. As a superior electron receptor, DA triggered the electron transfer from CDs to DA, resulting in the FL quenching of CDs in nanohybrids. The FL (at 640nm) of CuNCs in nanohybrids was almost unchanged after the addition of DA, and so further used for a reference FL to develop a novel ratiometric FL probe for DA detection. In addition to high sensitivity and selectivity, superior analytical performances of this probe were confirmed in applications, including dual-signal FL sensing of DA and naked-eye visual FL imaging of DA in aqueous solution and on filter paper. PMID- 29136800 TI - Polyamidoamine starburst dendrimer-activated chromatography paper-based assay for sensitive detection of telomerase activity. AB - Telomerase is extensively expressed in various cancer cells and recognized as a target for cancer drug discovery. In the present study, a simple and amplification-free fluorescence assay based on polyamidoamine starburst dendrimer (PAMAM dendrimer)-activated paper device is proposed for sensitive detection of telomerase activity through hybridization of Cy5 modified single strand DNA probes with telomerase extension products. The paper substrate is fabricated by hand drawing according to a template, which is low cost, instrument free and easy operation. PAMAM is rich in amino groups on its surface and employed to immobilize the telomerase substrate (TS) primer. Highly sensitive detection of telomerase activity in HeLa cell lysate of 10 cells is achieved since the PAMAM dendrimer-activated paper surface can provide high density of binding sites for immobilization of TS primer. The experimental results also demonstrate that the assay can be employed to evaluate telomerase activity levels of various cell lines and screen telomerase inhibitors. PMID- 29136801 TI - A sensitive label-free electrochemical immunosensor for detection of cytokeratin 19 fragment antigen 21-1 based on 3D graphene with gold nanopaticle modified electrode. AB - Previous studies have confirmed that cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1) serves as a powerful biomarker in non-small cell lung cancer (NSCLC). Herein, we report for the first time a label-free electrochemical immunosensor for sensitive and selective detection of tumor marker CYFRA21-1. In this work, three-dimensional graphene @ gold nanoparticles (3D-G@Au) nanocomposite was modified on the glassy carbon electrode (GCE) surface to enhance the conductivity of immunosensor. The anti-CYFRA21-1 captured and fixed on the modified GCE through the cross-linking of chitosan (CS), glutaraldehyde (GA) and anti-CYFRA21 1. The differential pulse voltammetry (DPV) peak current change due to the specific interaction between anti-CYFRA21-1 and CYFRA21-1 on the modified electrode surface was utilized to detect CYFRA21-1. Under optimized conditions, the proposed electrochemical immunosensor was employed to detect CYFRA21-1 and exhibited a wide linear range of 0.25-800ngmL-1 and low detection limit of 100pgmL-1 (S/N = 3). Moreover, the recovery rates of serum samples were in the range from 95.2% to 108.7% and the developed immunosensor also shows a good correlation (less than 6.6%) with enzyme-linked immunosorbent assay (ELISA) in the detection of clinical serum samples. Therefore, it is expected that the proposed immunosensor based on a 3D-G@Au has great potential in clinical medical diagnosis of CYFRA21-1. PMID- 29136802 TI - Carboxylated carbon nanospheres as solid-phase extraction adsorbents for the determination of perfluorinated compounds in water samples by liquid chromatography-tandem mass spectrometry. AB - This work demonstrates the extraction potential of carboxylated carbon nanospheres (CNSs-COOH) for solid-phase extraction of perfluoroalkyl acids (PFAAs) for the first time. Six PFAAs, including perfluorohexanesulfonate (PFHxS), perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), perfluorooctanoic sulfonic (PFOS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), were quantitatively adsorbed on a CNSs-COOH-packed cartridge; then, the PFAAs retained on the adsorbent were quantitatively eluted with an optimized volume of acetone (pH = 10). Finally, the desorbed PFAAs were determined by liquid chromatography-tandem mass spectrometry. Important relevant factors, such as the eluant and its volume, sample pH, amount of CNSs-COOH, sample flow rate and sample volume were optimized in detail. Under the optimized conditions, low limits of detection (0.01-1.2ngL-1), wide linear range (0.50 200ngL-1) and good repeatability (2.4-5.1%) and good reproducibility (3.7-8.8%) were obtained. The proposed method was applied to analyze the six PFAAs in real environmental water samples, and satisfactory results were achieved. All of these results showed that CNSs-COOH will be a good choice for the pre-concentration and analysis of target PFAAs at trace levels in environmental water samples in the future. PMID- 29136803 TI - Simple and selective paper-based colorimetric sensor for determination of chloride ion in environmental samples using label-free silver nanoprisms. AB - Simple and selective paper-based colorimetric sensors using silver nanoprism (AgNPrs) were conveniently fabricated and developed for the determination of chloride ions (Cl-) contaminated in the environment. Samples containing different concentrations of Cl- were analyzed. The analysis is based on the oxidative etching of the AgNPrs into smaller silver nanospheres (AgNPss) by Cl-. In the presence of Cl-, the distinctive color change of the AgNPrs from dark-violet to red was rapidly visualized by the naked eye in 5min without the requirement of surface modification. For quantitative measurement using image processing, a good linear relationship (R2 = 0.996) between logarithmic of Cl- concentration and the average mean color intensity was obtained in the range of 10-1000mgL-1 with a detection limit of 1.3mgL-1. The developed sensors were investigated for precision, accuracy, and sensitivity and validated by the classical method. Statistical analysis proved that the developed sensors were precise, sensitive and accurate and can be used effectively for the analysis of Cl- in natural waters. PMID- 29136804 TI - An on-line coupling of nanofibrous extraction with column-switching high performance liquid chromatography - A case study on the determination of bisphenol A in environmental water samples. AB - Polyamide 6 nanofiber polymers were used as modern sorbents for on-line solid phase extraction (SPE) coupled with liquid chromatography. The on-line SPE system was tested for the determination of bisphenol A in river water samples. Polyamide nanofibers were prepared using needleless electrospinning, inserted into a mini column cartridge (5 * 4.6mm) and coupled with HPLC. The effect of column packing and the amount of polyamide 6 on extraction efficiency was tested and the packing process was optimized. The proposed method was performed using a 50-uL sample injection followed by an on-line nanofibrous extraction procedure. The influence of the washing mobile phase on the retention of bisphenol A during the extraction procedure was evaluated. Ascentis(r) Express C18 (10cm * 4.6mm) core-shell column was used as an analytical column. Fluorescence detection wavelengths (lambdaex = 225nm and lambdaem = 320nm) were used for identification and quantification of Bisphenol A in river waters. The linearity was tested in the range from 2 to 500ugL-1 (using nine calibration points). The limits of detection and quantification were 0.6 and 2ugL-1, respectively. The developed method was successfully used for the determination of bisphenol A in various samples of river waters in the Czech Republic (The Ohre, Labe, Nisa, Upa, and Opava Rivers). PMID- 29136805 TI - The characterization of natural gemstones using non-invasive FT-IR spectroscopy: New data on tourmalines. AB - Fourteen samples of tourmaline from the Real Museo Mineralogico of Federico II University (Naples) have been characterized through multi-methodological investigations (EMPA-WDS, SEM-EDS, LA-ICP-MS, and FT-IR spectroscopy). The samples show different size, morphology and color, and are often associated with other minerals. Data on major and minor elements allowed to identify and classify tourmalines as follows: elbaites, tsilaisite, schorl, dravites, uvites and rossmanite. Non-invasive, non-destructive FT-IR and in-situ analyses were carried out on the same samples to validate this chemically-based identification and classification. The results of this research show that a complete characterization of this mineral species, usually time-consuming and expensive, can be successfully achieved through non-destructive FT-IR technique, thus representing a reliable tool for a fast classification extremely useful to plan further analytical strategies, as well as to support gemological appraisals. PMID- 29136806 TI - Multivariate analysis of organic acids in fermented food from reversed-phase high performance liquid chromatography data. AB - Multivariate calibration coupled to RP-HPLC with diode array detection (HPLC-DAD) was applied to the identification and the quantitative evaluation of the short chain organic acids (malic, oxalic, formic, lactic, acetic, citric, pyruvic, succinic, tartaric, propionic and alpha-cetoglutaric) in fermented food. The goal of the present study was to get the successful resolution of a system in the combined occurrence of strongly coeluting peaks, of distortions in the time sensors among chromatograms, and of the presence of unexpected compounds not included in the calibration step. Second-order HPLC-DAD data matrices were obtained in a short time (10min) on a C18 column with a chromatographic system operating in isocratic mode (mobile phase was 20mmolL-1 phosphate buffer at pH 2.20) and a flow-rate of 1.0mLmin-1 at room temperature. Parallel factor analysis (PARAFAC) and unfolded partial least-squares combined with residual bilinearization (U-PLS/RBL) were the second-order calibration algorithms select for data processing. The performance of the analytical parameters was good with an outstanding limit of detection (LODs) for acids ranging from 0.15 to 10.0mmolL 1 in the validation samples. The improved method was applied to the analysis of many dairy products (yoghurt, cultured milk and cheese) and wine. The method was shown as an effective means for determining and following acid contents in fermented food and was characterized by reducibility with simple, high resolution and rapid procedure without derivatization of analytes. PMID- 29136807 TI - In situ gold-nanoparticle electrogeneration on gold films deposited on paper for non-enzymatic electrochemical determination of glucose. AB - This work describes the development and evaluation of a new electrochemical platform based on the sustainable generation of gold-nanoparticles on paper-based gold-sputtered electrodes. The disposable porous paper electrode is combined with screen-printed electrodes for ensuring a precise electrogeneration of nanoparticles and also for the evaluation of these simple, versatile and low-cost microfluidic devices. Two types of chromatographic paper with different thicknesses have been evaluated. Paper gold working electrodes modified with gold nanoparticles were characterized by scanning electron microscopy and cyclic voltammetry using potassium ferrocyanide as a common redox probe, showing an improved electrochemical performance when compared to bare gold electrodes. The platform has been applied to the non-enzymatic determination of glucose, molecule of enormous interest. The porous gold structure made by sputtering on paper, modified with electrogenerated nanoparticles allowed precise and accurate determination of the analyte in beverages at low potential. PMID- 29136808 TI - An approach for quantification of platinum distribution in tissues by LA-ICP-MS imaging using isotope dilution analysis. AB - Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been revealed as a convenient technique for trace elemental imaging in tissue sections, providing elemental 2D distribution at a quantitative level. For quantification purposes, in the last years several approaches have been proposed in the literature such as the use of CRMs or matrix matched standards. The use of Isotope Dilution (ID) for quantification by LA-ICP-MS has been also described, being mainly useful for bulk analysis but not feasible for spatial measurements so far. In this work, a quantification method based on ID analysis was developed by printing isotope-enriched inks onto kidney slices from rats treated with antitumoral Pt-based drugs using a commercial ink-jet device, in order to perform an elemental quantification in different areas from bio-images. For the ID experiments 194Pt enriched platinum was used. The methodology was validated by deposition of natural Pt standard droplets with a known amount of Pt onto the surface of a control tissue, where could be quantified even 50pg of Pt, with recoveries higher than 90%. The amount of Pt present in the whole kidney slices was quantified for cisplatin, carboplatin and oxaliplatin-treated rats. The results obtained were in accordance with those previously reported. The amount of Pt distributed between the medullar and cortical areas was also quantified, observing different behavior for the three drugs. PMID- 29136809 TI - Highly selective detection of phosphate ion based on a single-layered graphene quantum dots-Al3+ strategy. AB - Determination of phosphate ion (PO43-) is important in biomedical and environmental arrays because its controlling concentrations are associated with different pathologies or the quality of water. Herein, we report a new type of photoluminescence (PL) probe for highly selective detection of PO43- based on a single-layered graphene quantum dots chelating with aluminium ions (s-GQDs-Al3+) system. The PL of s-GQDs can be enhanced by Al3+ through the aggregation-induced emission enhancement (AIEE) effect. With the addition of PO43-, the PL of the s GQDs-Al3+ system is faded away because PO43- has stronger coordination with Al3+ which results in the elimination of AIEE effect and the decrease in the PL intensity of the s-GQDs-Al3+ system. Therefore, the s-GQDs-Al3+ system can behave as an on-off type PL probe for PO43- detection. It is found that the PL intensity ratio (I/I0) of s-GQDs in the presence of Al3+ at 463nm is proportional to the concentration of PO43- in the range of 0.25-7.5MUM with the limit of detection as low as 0.1MUM. This selective assay has a great application prospect in the complex matrixes owing to its simplicity and specificity for PO43- detection. PMID- 29136810 TI - Prediction of parameters related to grape ripening by multivariate calibration of voltammetric signals acquired by an electronic tongue. AB - An electronic tongue (ET) consisting of two voltammetric sensors, namely a poly ethylendioxythiophene modified Pt electrode and a sonogel carbon electrode, has been developed aiming at monitoring grape ripening. To test the effectiveness of device and measurement procedures developed, samples of three varieties of grapes have been collected from veraison to harvest of the mature grape bunches. The derived musts have been then submitted to electrochemical investigation using Differential Pulse Voltammetry technique. At the same time, quantitative determination of specific analytical parameters for the evaluation of technological and phenolic maturity of each sample has been performed by means of conventional analytical techniques. After a preliminary inspection by principal component analysis, calibration models were calculated both by partial least squares (PLS) on the whole signals and by the interval partial least squares (iPLS) variable selection algorithm, in order to estimate physico-chemical parameters. Calibration models have been obtained both considering separately the signals of each sensor of the ET, and by proper fusion of the voltammetric data selected from the two sensors by iPLS. The latter procedure allowed us to check the possible complementarity of the information brought by the different electrodes. Good predictive models have been obtained for estimation of pH, total acidity, sugar content, and anthocyanins content. The application of the ET for fast evaluation of grape ripening and of most suitable harvesting time is proposed. PMID- 29136811 TI - Electrochemical sensor based on palladium-reduced graphene oxide modified with gold nanoparticles for simultaneous determination of acetaminophen and 4 aminophenol. AB - Herein, a newly developed electrochemical sensor base on the nanohybrid of palladium-reduced graphene oxide modified with gold nanoparticles (Au/Pd/rGO) was established, which was prepared by electrodeposing Au nanoparticles on Pd/rGO modified on a glass carbon electrode. The morphologies and microstructures of the as-prepared nanohybrid were characterized by X-ray photoelectron spectroscopy, Scanning electron microscopy and Infrared spectroscopy. And, experiment results showed that the prepared Au/Pd/rGO nanohybrid exhibited excellent electrocatalytic- activity toward the redox of acetaminophen (PA) and 4 aminophenol (4-AP) simultaneously. The linear detection ranges were 1.00 250.00MUM for PA and 1.00-300.00MUM for 4-AP, with the detection limits of 0.30MUM for PA and 0.12MUM for 4-AP, respectively. Because of the excellent performance of lower detection, wider linear range and better selectivity, the prepared Au/Pd/rGO nanohybrid with more potential applications was a promising candidate for advanced electrode material in electrochemical sensing field. PMID- 29136812 TI - Silica based click-dibenzo-18-crown-6-ether high performance liquid chromatography stationary phase and its application in separation of fullerenes. AB - Crown ether is a type of typical macrocyclic polyether compounds, which can produce strong interactions with cationic species, such as metal ions and protonated amines due to its cavity structure and the strong electronegative effect of heteroatoms on the crown ether ring. In this paper, a type of silica based crown ether stationary phase was prepared by covalently bonding dibenzo-18 crown 6-ether (DBCE) on silica gel via copper (I) catalyzed azide-alkyne 1,3 dipolar cycloaddition (CuAAC). The tetraazido DBCE was rapidly prepared by bromomethylation and subsequent azido substitution of DBCE. Finally, this key intermediate was covalently bonded to silica beads by click chemistry to get click-DBCE. Its structure was confirmed by FT-IR and elemental analysis, and the structures of all related intermediates were confirmed by NMR, IR and MS spectra. The crown ether based stationary phase showed good chromatography characteristics and column efficiency (up to 43,553 plates m-1 theoretical plate number is obtained in the case of fluoranthene) under reverse phase liquid chromatographic (RPLC) model. The primary chromatographic evaluation showed that click-DBCE displayed better chromatography efficiency than commercial C18 stationary phase (THERMO BDS HYPERSIL), when they were applied in the separation of regio-isomers of benzene, polycyclic aromatic hydrocarbons (PAHs) and macrolide pharmaceuticals. Furthermore, this stationary phase could also be used to separate fullerenes under normal phase mode, and in this case, 1 chloronaphthalene was suitable additive for improving chromatographic separation ability. PMID- 29136813 TI - Isolation of 236U and 239,240Pu from seawater samples and its determination by Accelerator Mass Spectrometry. AB - In this work we present and evaluate a radiochemical procedure optimised for the analysis of 236U and 239,240Pu in seawater samples by Accelerator Mass Spectrometry (AMS). The method is based on Fe(OH)3 co-precipitation of actinides and uses TEVA(r) and UTEVA(r) extraction chromatography resins in a simplified way for the final U and Pu purification. In order to improve the performance of the method, the radiochemical yields are analysed in 1 to 10L seawater volumes using alpha spectrometry (AS) and Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Robust 80% plutonium recoveries are obtained; however, it is found that Fe(III) concentration in the precipitation solution and sample volume are the two critical and correlated parameters influencing the initial uranium extraction through Fe(OH)3 co-precipitation. Therefore, we propose an expression that optimises the sample volume and Fe(III) amounts according to both the 236U and 239,240Pu concentrations in the samples and the performance parameters of the AMS facility. The method is validated for the current setup of the 1MV AMS system (CNA, Sevilla, Spain), where He gas is used as a stripper, by analysing a set of intercomparison seawater samples, together with the Laboratory of Ion Beam Physics (ETH, Zurich, Switzerland). PMID- 29136814 TI - Polyaniline-dicationic ionic liquid coated with magnetic nanoparticles composite for magnetic solid phase extraction of polycyclic aromatic hydrocarbons in environmental samples. AB - In this present study, magnetic nanoparticles (MNPs) nanocomposites modified with polyaniline (PANI) coated newly synthesised dicationic ionic liquid (DICAT) forming MNP-PANI-DICAT were successfully synthesised as new generation material for magnetic solid phase extraction (MSPE). MNP-PANI-DICAT was characterised by FT-IR NMR, CHN, BET, SEM, TEM, and VSM techniques and the results were compared with MNP-PANI and native MNP. This new material was applied as a magnetic adsorbent for the pre-concentration and separation of polycyclic aromatic hydrocarbons (PAHs) due to the pi-pi interaction between polyaniline shell and dicationic ionic liquid (DICAT) with PAHs compounds. Under the optimal conditions, the proposed method was evaluated and applied for the analysis of PAHs in environmental samples using gas chromatography-mass spectrometry (GC-MS). The validation method showed good linearity (0.005-500ugL-1) with the coefficient of determination (R2) > 0.999. The limits of detection (LOD) and quantification (LOQ) of the developed method (MNP-PANI-DICAT-MSPE) were in the range of 0.0008 0.2086ugL-1 and 0.0024-0.6320ugL-1, respectively. The enrichment factor (EF) of PAHs on MNP-PANI-DICAT-MSPE were in the range of 7.546-29.632. The extraction recoveries of natural water, sludge, and soil samples were ranged from 80.2% to 111.9% with relative standard deviation (RSD) less than 5.6%. The newly synthesised MNP-PANI-DICAT possess good sensitivity, reusability, and fast extraction of PAHs under the MSPE procedure in various environmental samples. PMID- 29136815 TI - Quantitative study of zinc and metallothioneins in the human retina and RPE cells by mass spectrometry-based methodologies. AB - The retina contains the highest concentration of zinc in the human eye and it is primarily associated with the retinal pigment epithelium (RPE). Metallothioneins (MTs) are the main cytosolic zinc-ion-binding proteins, exerting a tight control in the number of atoms of Zn-bound to the MTs related with their antioxidant and neuroprotective functions. In order to study the Zn-MT system in retina and RPE, we have implemented mass spectrometry (MS)-based technologies: two complementary element detection methodologies (HPLC- and laser ablation (LA)-ICP-MS) have been successfully employed to study metal content in the human eye as well as to perform speciation studies of Zn-MTs. First, Zn-elemental distribution was studied on cryogenic ocular sections by LA-ICP-MS. Quantitative images of Zn along RPE cell layer and the retina were obtained with a laser beam diameter of 25um, showing a preferential distribution in the RPE. We carried out then the quantitative speciation of Zn, Fe, and Cu in the water-soluble protein fractions of RPE and retina to study their protein binding profile using HPLC-ICP-MS, where Zn is mainly associated to low molecular mass proteins (i.e., MTs). Finally, the effect of addition of different inductors, such as metal (i.e., 68ZnSO4), dexamethasone (DEX) and erythropoietin, was investigated in an in vitro cellular model of human RPE cells (HRPEsv), again using HPLC-ICP-MS in combination with stable isotopes and mathematical calculations based on isotope dilution and isotope pattern deconvolution. Exogenous Zn and DEX were found to increase MT proteins synthesis and exerted a stoichiometric transition in MT proteins in HRPEsv cells. PMID- 29136816 TI - Simultaneous determination of tert-butylhydroquinone, propyl gallate, and butylated hydroxyanisole by flow-injection analysis with multiple-pulse amperometric detection. AB - We report the first amperometric method for the simultaneous determination of tert-butylhydroquinone (tBHQ), propyl gallate (PG), and butylated hydroxyanisole (BHA) using flow injection analysis coupled to multiple-pulse amperometry. A sequence of potential pulses was selected in order to detect tBHQ, PG, and BHA separately in a single injection step at a glassy carbon electrode without the need of a preliminary separation. A mixture of methanol and 0.040M Britton Robinson buffer was used both as a carrier solution and for dilution of analyzed solutions before injection. The method is precise (RSD < 5%, n = 10), fast (a frequency of 140 injections h-1), provides sufficiently low quantification limits (2.51, 1.45, and 0.85MUmolL-1 for tBHQ, PG, and BHA, respectively) and can be easily applied without high demands on instrumentation. As a practical application, the determination of these antioxidants contained in commercial chewing gum samples was carried out by applying a simple extraction procedure. PMID- 29136817 TI - Rapid quantification of persulfate in aqueous systems using a modified HPLC unit. AB - Existing analytical techniques used for the quantification of persulfate (PS) in water mostly rely on polarography, reductometry or spectrophotometry. Although acceptable to a certain extent, these methods did not satisfy environmental chemists seeking rapid, reproducible and accurate quantification of PS upon the application of ISCO and AOPs technologies. Accordingly, a novel flow injection/spectroscopy analytical technique is developed via the use of an HPLC coupled to bypass capillary columns and a DAD detector. Special HPLC configuration uses concentrated KI solution as mobile phase to readily reduce PS present in the sample. The reaction takes place inside the capillary columns, under moderate pressure facilitating the production of Iodine suspension (I2), to yield finally the formation of the Triiodide anion (I3-) in the presence of an excess of I-. Triiodide absorbs at 352nm which minimizes interferences from other organic contaminants (OCs). The method was validated by comparison to traditional PS quantification methods and tested on several environmental samples. The new method proved its superiority in terms of time requirement, labor need, material consumption, sample volume and simplicity. It eliminates the inconsistency present in other idiometric methods which is caused by the delay between the PS/I reaction and I3- measurement. The obtained LDR extends from 0.075 to 300mmolL-1 with a LOD of 6.6 * 10-3mmol L-1 and a LOQ of 2.20 * 10-2mmolL-1. The method is successfully implemented in our laboratory to rapidly and automatically monitor the variation in the concentration of PS used in different projects, which facilitates the rapid determination of the reaction stoichiometric efficiency (RSE) of the oxidation reaction, a key factor toward the optimization of the mineralization process and its sustainability. PMID- 29136818 TI - A mitochondria-targeted ratiometric two-photon fluorescent probe for detecting intracellular cysteine and homocysteine. AB - A novel mitochondria-targeted ratiometric two-photon fluorescent probe (Mito-MQ) for detecting intracellular cysteine (Cys) and homocysteine (Hcy) has been designed. Mito-MQ showed the ratiometric fluorescent detection signal (the green to-blue emissionfrom 517nm to 460nm) to cysteine (Cys) and homocysteine (Hcy) over glutathione (GSH), along with the fast response rate (10min). The detection mechanism was illustrated by 1H NMR, ESI-MS and theoretical calculation. The co localization coefficient of 0.87 between Mito-MQ and MitoTracker Red revealed that the probe was predominantly present in mitochondria, therefore, Mito-MQ was successfully applied to detect mitochondrial oxidative stress by detecting the change of Cys/Hcy. Moreover, imaging in fresh tissue slices indicated that Mito MQ could work in deep tissue (ca. 130um) under two-photon excitation. Furthermore, the measurement of Cys/Hcy detection in zebrafish showed that probe can be used in determination of biothiols in vivo. PMID- 29136819 TI - Alteration in the liver metabolome of rats with metabolic syndrome after treatment with Hydroxytyrosol. A Mass Spectrometry And Nuclear Magnetic Resonance - based metabolomics study. AB - Metabolic syndrome (MetS) represents a group of abnormalities that enhances the risk for cardiovascular disease, diabetes and stroke. The Mediterranean diet seems to be an important dietary pattern, which reduces the incidence of MetS. Hydroxytyrosol (HT) - a simple phenol found in olive oil - has received increased attention for its antioxidant activity. Recently, the European Foods Safety Authority (EFSA) claimed that dietary consumption of HT exhibits a protective role against cardiovascular disease. In this study, an experimental protocol has been setup, including isolated HT administration in a diet induced model of MetS in young Wistar rats, in order to find out whether HT has a protective effect against MetS. Rats were randomly divided into two groups nurtured by high carbohydrate high-fat (H) (MetS inducing diet) and high-carbohydrate high-fat + HT (HHT). HT (20mg/kg/d oral gavage, water vehicle) was administered for 8 weeks on the basal diet. Previous pharmacological evaluation of HT showed that hepatic steatosis was reduced and the inflammatory cells into the liver were infiltrated. These indicate that HT shows bioactivity against metabolic syndrome. Therefore, the metabolomics evaluation of liver extracts would indicate the putative biochemical mechanisms of HT activity. Thus, the extracts of liver tissues were analyzed using Ultra Performance Liquid Chromatography - High Resolution Mass Spectrometry (UPLC-HRMS, Orbitrap Discovery) and Nuclear Magnetic Resonance (NMR) spectroscopy (Bruker Avance III 600MHz). Multivariate analysis was performed in order to gain insight on the metabolic effects of HT administration on the liver metabolome. Normalization employing multiple internal standards and Quality Control-based Robust LOESS (LOcally Estimated Scatterplot Smoothing) Signal Correction algorithm (QC-RLSC) was added in the processing pipeline to enhance the reliability of metabolomic analysis by reducing unwanted information. Experimentally, HHT rats were clearly distinguished from H in PLS-DA, showing differences in the liver metabolome between the groups and specific biomarkers were determined supporting the pharmacological findings. More specifically, HT has shown to be effective towards the mobilization of lipids as various lipid classes being differentially regulated between the H and HHT groups. Interestingly branched fatty acid esters of hydroxy oleic acids (OAHSA) lipids have been shown to be up regulated to the HHT group, denoting the alleviation of the MetS to the animals administered with HT. PMID- 29136820 TI - Fluorescent ligand fishing combination with in-situ imaging and characterizing to screen Hsp 90 inhibitors from Curcuma longa L. based on InP/ZnS quantum dots embedded mesoporous nanoparticles. AB - Although ligand fishing has been shown to be an efficient technique for the identification of bioactive components from complex mixtures such as natural products, it cannot be applied to biomedical image processing. Herein, a specific fluorescent ligand fishing combined with in situ imaging approach is presented for the identification of heat shock protein 90 (Hsp 90) inhibitors from complex matrixes, Curcuma longa L., using N-terminus immobilized Hsp 90alpha functionalized InP/ZnS quantum dots embedded mesoporous nanoparticles (i.e. Hsp 90alpha (NT)-FQDNs) as extraction sorbents and fluorescent tracer. The fished ligands were identified by liquid chromatography time-of-flight/mass spectrometry (LC-TOF/MS) and gas chromatography-mass spectrometry (GC-MS). Moreover, in situ imaging by confocal laser scanning microscopy (CLSM) was applied for evaluating the effect of fished-ligands on bioactivity-induced apoptosis morphologically in HeLa cells. MTT assay verified the bioactivity of the ligands and molecular docking results further provided convincing information to verify the feasible binding mode between ligands and protein. Twelve ligands as potential Hsp 90 inhibitors were ultimately fished and identified from Curcuma longa L. crude extracts. The proposed approach based on Hsp 90alpha functionalized nanocomposites is superior in the combination of highly specific screening efficiency and concurrent visual in situ imaging, which could have great promise for the development of other plant-derived Hsp 90 inhibitors, and providing a rapid and reliable platform for discovering biologically active molecules in natural products. PMID- 29136821 TI - Thin-film microextraction coupled to surface enhanced Raman scattering for the rapid detection of benzoic acid in carbonated beverages. AB - Benzoic acid (BA) is widely used as an antimicrobial preservative in carbonated beverages. In this study, silica gel thin-film microextraction (TFME) coupled to surface enhanced Raman scattering (SERS) was applied for the rapid detection of BA in carbonated beverages. The TFME process was performed by placing small pieces of silica gel substrate in a simple homemade device, and then the content of BA was detected using SERS after colloidal gold was uniformly dropped onto the substrate. The obtained SERS signals of BA were strong and of high reproducibility. A good linearity between the concentration of BA and the SERS signal intensity at 994cm-1 in the range of 25-500MUgmL-1 was obtained under optimal experimental conditions. The detection limit value was found to be 3.6MUgmL-1 and the recovery of the spiked BA was in the range 85.0-103.0%. The developed method was successfully applied to detect BA in carbonated beverage samples as the results were consistent with those using high performance liquid chromatography, suggesting that it is a rapid, convenient and sensitive way to achieve BA detection in carbonated beverages. PMID- 29136822 TI - New Ti-IMAC magnetic polymeric nanoparticles for phosphopeptide enrichment from complex real samples. AB - The work describes the preparation of a new magnetic phase for batch enrichment of phosphopeptides. The material exploits the advantages of magnetic solid phase extraction and couples them with the most employed approach for phosphopeptide enrichment, i.e. Ti4+-IMAC. In order to immobilize Ti4+ ions on the surface of the magnetite nanoparticles, they were first covered by a silica shell and then modified to expose at the surface bromine containing groups. Glycidyl methacrylate was subsequently polymerized from these groups using the "grafting from" approach by the activator regenerated by electron transfer-atom transfer radical polymerization (ARGET-ATRP) technique. Finally, the glycidyl groups were reacted with iminodiacetic acid to functionalize the material with moieties suitable for coordination. The prepared material was extensively characterized and subsequently tested for enrichment of a bovine serum albumin mixture with casein to ascertain its potential. With positive results, the new magnetic polymeric material was further employed to set up an enrichment method on yeast protein digest based on shotgun proteomics. The sample to phase ratio was optimized and the best condition compared to a commercial TiO2 spin column. At the end of the comparison, the new material proved better and could enrich a larger total number of phosphopeptides with increased selectivity. All these conclusions and the test performed on a real complex sample within the final shotgun application further support the applicability of the new material in phosphopeptide analysis of real matrices. PMID- 29136823 TI - Use of a small molecule as an initiator for interchain staudinger reaction: A new ATP sensing platform using product fluorescence. AB - We demonstrated that a small molecule induced interchain Staudinger reaction can be employed for highly selective detection of adenosine triphosphate (ATP), an important energy-storage biomolecule. A designed ATP split aptamer (A1) was first functionalized with a weakly fluorescent coumarin derivative due to an azide group (azido-coumarin). The second DNA strand (A2) was covalently linked with triphenylphosphine, which could selectively and efficiently reduce azido to amino group through the Staudinger reaction. The A2 was then hybridized with a half of another designed longer DNA strand (T1). The second half of T1 was a split aptamer and selectively recognized ATP with A1 to form a sandwich structure. The specific interaction between ATP and the aptamers drew the two functionalized DNA strands (A1 and A2) together to initiate the interchain Staudinger reduction at fmol-nmol concentration level, hence produced fluorescent 7-aminocoumarin which could be used as an indicator for the presence of trace ATP. The reaction process had a concentration dependent manner with ATP in a large concentration range. Such a strategy of interchain Staudinger reaction can be extended to construct biosensors for other small functional molecules on the basis of judiciously designed aptamers. PMID- 29136824 TI - Assessment of potential false positives via orbitrap-based untargeted lipidomics from rat tissues. AB - Untargeted lipidomics is increasingly popular due to the broad coverage of lipid species. Data dependent MS/MS acquisition is commonly used in order to acquire sufficient information for confident lipid assignment. However, although lipids are identified based on MS/MS confirmation, a number of false positives are still observed. Here, we discuss several causes of introducing lipid false identifications in untargeted analysis. Phosphotidylcholines and cholesteryl esters generate in-source fragmentation to produce dimethylated phosphotidylethanolamine and free cholesterol. Dimerization of fatty acid results in false identification of fatty acid ester of hydroxyl fatty acid. Realizing these false positives is able to improve confidence of results acquired from untargeted analysis. Besides, thresholds are established for lipids identified using LipidSearch v4.1.16 software to reduce unreliable results. PMID- 29136825 TI - Determining moisture content in pasta by vibrational spectroscopy. AB - Pasta aside from bread is the most consumed cereal-based product in the world. Its taste and cooking ease makes it the basis of many cuisines. The pasta dough formed by mixing flour and water is extruded through an extrusion die to mould the appropriate pasta form and is dried to obtain a stable product. The concentration of moisture in the pasta dough is a one of key parameters determining the final quality of the product. Monitoring the moisture content of pasta after extrusion is also critically important. It enables a selection of suitable drying conditions that ensure the appropriate parameters of pasta, such as texture, color and taste, are met. A method for the quantitative determination of moisture content in pasta dough and in pasta based on the partial least squares treatment of infrared spectra registered using a single-reflection attenuated total reflectance diamond accessory is described. Results of a similar quality were found using models derived from near infrared spectra obtained in a diffuse reflectance mode and slightly worse based on Raman spectra. Relative standard errors of prediction calculated for moisture quantification by ATR/NIR/Raman techniques amounted to 2.54/3.16/5.56% and 2.15/3.32/5.67%, for calibration and validation sets, respectively. The proposed procedures can be used for fast and efficient pasta moisture quantification and may replace the current, more laborious methods used. PMID- 29136826 TI - Preparation and evaluation of magnetic molecularly imprinted polymers for the specific enrichment of phloridzin. AB - In present study, magnetic molecularly imprinted polymers (MMIPs) were successfully prepared for specific recognition and selective enrichment of phloridzin from the leaves of Malus doumeri (Bois) A. Chev and rats' plasma. The magnetic Fe3O4 were prepared by the solvothermal reaction method and followed by the modification of TEOS and functionalization with APTES. Using functionalized Fe3O4 particles as the magnetic cores, phloridzin as template, ethylene glycol dimethacrylate (EGDMA) as cross-linker and 2,2-azobisisobutyonnitrile (AIBN) as initiator, the MMIPs were prepared through APTES to associate the template on the surface of the magnetic substrate. The structural features and morphological characterizations of MMIPs were performed by FT-IR, SEM, TEM, XRD, TGA and VSM. The adsorption experiments revealed that the MMIPs presented high selective recognition property to phloridzin. The selectivity experiment indicated that the adsorption capacity and selectivity of polymers to phloridzin was higher than that of baicalin and 2,3,5,4'-ttrahydroxy stilbene-2-O-beta-D-glucoside. Furthermore, the MMIPs were employed as adsorbents for extraction and enrichment of phloridzin from the leaves of M. doumeri and rats' plasma. The recoveries of phloridzin in the leaves of M. doumeri ranged from 81.45% to 90.27%. The maximum concentration (Cmax) of phloridzin in rats' plasma was detected as 12.19 +/- 0.84MUg/mL at about 15min after oral administration of phloridzin (200mg/kg). These results demonstrate that the prepared MMIPs are suitable for the selective adsorption of phloridzin from complex samples such as natural medical plants and biological samples. PMID- 29136827 TI - Biobarcode assay for the oral anticoagulant acenocoumarol. AB - A novel approach for therapeutic drug monitoring of oral anticoagulants (OA) in clinical samples is reported, based on a NP-based biobarcode assay. The proposed strategy uses specific antibodies for acenocumarol (ACL) covalently bound to magnetic particles (pAb236-MP) and a bioconjugate competitor (hACL-BSA) linked to encoded polystyrene probes (hACL-BSA-ePSP) on a classical competitive immunochemical format. By using this scheme ACL can be detected in low nM range (LOD, 0.96 +/- 0.26, N = 3, in buffer) even in complex samples such as serum or plasma (LOD 4 +/- 1). The assay shows a high reproducibility (%CV 1.1 day-to-day) and is robust, as it is demonstrated by the fact that ACL can be quantified in complex biological samples with a very good accuracy (slope = 0.97 and R2 = 0.91, of the linear regression obtained when analyzing spiked vs measured values). Moreover, we have demonstrated that the biobarcode approach has the potential to overcome one of the main challenges of the multiplexed diagnostic, which is the possibility to measure in a single run biomarker targets present at different concentration ranges. Thus, it has been proven that the signal and the detectability can be modulated by just modifying the oligonucleotide load of the encoded probes. This fact opens the door for combining in the same assay encoded probes with the necessary oligonucleotide load to achieve the detectability required for each biomarker target. PMID- 29136828 TI - Compact detectors made of paired LEDs for photometric and fluorometric measurements on paper. AB - The utility of strikingly simple and cheap optoelectronic detectors operating according to a Paired-Emitter-Detector-Diode (PEDD) principle for microfluidic paper-based analytical devices (MUPAD) has been experimentally confirmed. The prototypes of these compact detectors have been made of only two customary light emitting diodes without any additional optical parts like lens, filters, fibers etc. Moreover, for their operation economic and portable equipment is required (low-power circuit and ordinary voltmeter). Photometric and fluorometric PEDDs for paper devices are developed. In both cases the possibility of their applicability in transmittance and reflectance modes of measurements are presented. In these investigations as model analytes some coloured and fluorescence substances have been handled, but the utility of several developed systems for real chemical analysis has also been demonstrated. The results of photometric determination of hemoglobin in human blood, as well as fluorometric determination of quinine in tonics and calcium ions in mineral waters using various PEDD-MUPAD systems have been shown. PMID- 29136829 TI - Au-Pt bimetallic nanoparticles decorated on sulfonated nitrogen sulfur co-doped graphene for simultaneous determination of dopamine and uric acid. AB - In this work, a novel nanohybrid (AuPtNPs/S-NS-GR) of well-defined Au-Pt bimetallic nanoparticles (Au-PtNPs) decorated on sulfonated nitrogen sulfur co doped graphene (S-NS-GR) was developed. Firstly, nitrogen sulfur co-doped graphene (NS-GR) was synthesized by one-step thermal annealing method. Secondly, phenyl SO3H- group was introduced onto the surface of NS-GR via diazotization reaction, which could provide more binding sites for the formation of metal nanoparticles. Finally, Au-Pt bimetallic nanoparticles were anchored on the surface of S-NS-GR by using electrochemical deposition. The prepared material was characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), energy dispersive X-ray spectroscopy (EDS), Raman spectroscopy and electrochemical impedance spectra (EIS). In addition, the electrocatalytic activity towards dopamine (DA) and uric acid (UA) was systematically studied by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques. Under optimum conditions, the linear ranges for the detection of DA and UA were 1.0*10-8 - 4.0*10-4 M and 1.0*10-6 - 1.0*10-3 M with the limits of detection (LOD, S/N = 3) of 0.006MUM and 0.038MUM, respectively. Furthermore, the modified electrode was applied to real sample analysis. PMID- 29136830 TI - A review of the identification and detection of heavy metal ions in the environment by voltammetry. AB - Currently, environmental pollution by heavy metals is a global problem. Therefore, it is crucial to develop effective detection techniques to determine the levels of heavy metal contamination in various mediums. Voltammetry is a highly sensitive electrochemical method used for the in situ detection of heavy metal ions. This study investigates the current trends related to electrode modification, developments in materials, and optimization of the experimental parameters. We discuss the sensing performance of four kinds of nanomaterials capable of inorganic modification (metal nanoparticles, metal oxides, carbonaceous nanomaterials, and their nanocomposites). The impact of several important factors, such as the deposition potential and time, buffer solution types, and pH on the sensitivity, reproducibility, stability, and anti interference ability of the detection process, especially with regard to the co detection of several heavy metal ions, was reviewed. We noted that in addition to the application of voltammetry to water-related issues, it is suitable for rapid and simple identification and analyses of heavy metals in polluted soil and other mediums. Thus, it is important to conduct additional research on the application of voltammetry to this area. PMID- 29136831 TI - Rapid method for determination of 90Sr in seawater by liquid scintillation counting with an extractive scintillator. AB - A rapid determination method of 90Sr is developed for the monitoring of seawater around the Fukushima Daiichi Nuclear Power Plant (FDNPP). Three ideas of chemical separation and measurements to accelerate 90Sr analysis are investigated. Strontium is co-precipitated in a two-step procedure with hydroxyapatite after the removal of magnesium phosphate in the presence of citric acid. The purification process of strontium is in combination with solid phase extraction disks. One or two sheets of Sr Rad disk and cyclic operations are examined to eliminate interfering substances and secure the exchange capacity. The suitable conditions of adsorption and stripping are determined with a 85Sr tracer. Seawater samples up to 1L can be analyzed within 4h. Additionally, the appropriate pH conditions to extract strontium to the scintillator are studied, and the 90Sr activity is assessed via liquid scintillation counting using an extractive scintillator based on the di-(2-etyl hexyl)-phosphoric acid (HDEHP) extraction method. The new scintillation counting method involves a small quenching effect and a low background compared to the conventional emulsion scintillator method. The minimum detectable activity (MDA) is 35mBq/L of 90Sr in 180min of counting. The proposed method provides analytical results within a day after receipt of the samples. PMID- 29136832 TI - Interleaved incremental association Markov blanket as a potential feature selection method for improving accuracy in near-infrared spectroscopic analysis. AB - The interleaved Incremental Association Markov Blanket (inter-IAMB) is described herein as a feature selection method for the NIR spectroscopic analysis of several samples (diesel, gasoline, and etchant solutions). Although the Markov blanket (MB) has been proven to be the minimal optimal set of features (variables) that does not change the original target distribution, variables selected by the existing IAMB algorithm could be redundant and/or misleading as the IAMB requires an unnecessarily large amount of learning data to identify the MB. Use of the inter-IAMB interleaving the grow phase with the shrink phase to maintain the size of the MB as small as possible by immediately eliminating invalid candidates could overcome this drawback. In this report, a likelihood ratio (LR)-based conditional independence test, able to handle spectroscopic data normally comprising a large number of continuous variables in a small number of samples, was uniquely embedded in the inter-IAMB and its utility was evaluated. The variables selected by the inter-IAMB in complexly overlapped and feature indistinct NIR spectra were used to determine the corresponding sample properties. For comparison, the properties were also determined using the IAMB selected variables as well as the whole variables. The inter-IAMB was more effective in the selection of variables than the IAMB and thus able to improve the accuracy in the determination of the sample properties, even though a smaller number of variables was used. The proposed LR-embedded inter-IAMB could be a potential feature selection method for vibrational spectroscopic analysis, especially when the obtained spectral features are specificity-deficient and extensively overlapped. PMID- 29136833 TI - A cell-penetrating ratiometric probe for simultaneous measurement of lysosomal and cytosolic pH change. AB - A new ratiometric fluorescent probe based on cell-penetrating peptides (CPPs) was constructed for whole-cell pH mapping and simultaneous measurement of pH changes in the cytoplasm and lysosomes. The arginine-rich CPP, R12K worked as linker, carrier and part of the fluorophore. Benefiting from R12K, the fluorescent probe is completely water soluble, membrane permeable and well biocompatible. It shows high selectivity, sensitivity and reversibility to pH fluctuations. The ratio of fluorescence intensities F519/F582 increased from 0.2 to 9.2 over the pH range from 3.3 to 8.1. Intracellular pH mapping was successfully realized owing to the wide distribution of the probe in live cells (even in nucleus). Moreover, cytosolic and lysosomal pH change caused by the stimuli can be simultaneously detected. Compared to other ratiometric pH probes, RhB-R12K-FITC can provide more precise information about H+ redistribution between different cellular compartments. PMID- 29136834 TI - Comparative proteomics of cancer stem cells in osteosarcoma using ultra-high performance liquid chromatography and Orbitrap Fusion mass spectrometer. AB - Osteosarcoma is the most common malignant tumour found in bones, and it has a poor prognosis. For improved therapy, it is significant to have a deep understanding of the proteomics changes in the cancer stem cells (CSCs) of osteosarcoma. Therefore, a comparative proteomics approach based on ultra-high performance liquid chromatography coupled to an Orbitrap Fusion mass spectrometer (UHPLC-Orbitrap Fusion MS) was established to investigate the key molecular changes between CSCs and non-CSCs in human osteosarcoma HOS cells. A proteomic analysis was performed on these samples and a total of more than 6600 proteins were identified in each run. Moreover, most of the correlation coefficients between three biological repeats were more than 0.9 in each group. That finding demonstrated not only that the reproducibility of the test is good but also that the stability of this MS is excellent. A label-free quantitative method was applied to analyse differentially expressed proteins. Using the criteria of greater than 1.5-fold changes and a p value < 0.05, 124 proteins were identified as being significantly different between HOS-CSCs and non-CSCs. A pathway analysis of differentially expressed proteins by Ingenuity Pathway Analysis (IPA) revealed the potential molecular regulatory networks that may regulate CSCs. Selected differential alpha-actinin 4 (ACTN4) proteins were validated by Western blot assay. These findings enhance our understanding of the molecular changes in CSCs and may provide additional improvements in therapy for treating osteosarcoma. Moreover, the UHPLC-Orbitrap Fusion MS-based proteomics method is helpful in cancer research. PMID- 29136835 TI - Design and construction of an injection port for coupling stir-bar sorptive extraction with ion mobility spectrometry. AB - An appropriate injection port was designed and constructed for direct analysis of stir-bar sorptive extractions using an ion mobility spectrometry (IMS). The novel design of the port offers great simplicity in use, high sensitivity, and high thermal and mechanical stability. The sol-gel technique was applied to prepare polydimethylsiloxane absorbent on a stir-bar. The parameters affecting extraction efficiency including stirring rate, extraction temperature, extraction time, salt addition and desorption temperature were optimized. The detection limit of the method was calculated to be 1.5MUgL-1, for diazinon, an organophosphorus pesticide selected as a test compound. The linear dynamic range was obtained to be 5.0-200.0MUgL-1 with a determination coefficient of 0.9991 for the test compound. The intra- and inter-day relative standard deviations were calculated to be 4% and 5%, respectively. Agricultural wastewater, well water, and apple were selected as real samples. The detection limit was calculated to be 1.5MUgL-1 and 7.5MUgkg-1 for the real water samples and the apple sample, respectively. The recovery values (%) were 105 +/- 6, 107 +/- 3 and 96 +/- 6 for the spiked agricultural wastewater, well water and apple samples, respectively. The results revealed that the injection port can be used for direct analysis of samples extracted by any sorbent support, without any further sample preparation. PMID- 29136836 TI - Detection of new emerging type-A trichothecenes by untargeted mass spectrometry. AB - Mycotoxins occur naturally as agricultural contaminants all over the world. The toxic effects of some of their metabolites are known and their presence regulated in food and feed. This paper describes two methods for the detection of toxins of type-A trichothecenes group, and their modified forms, using mass spectrometry. Ultra-performance liquid chromatography coupled to mass spectrometry-ion trap time of flight (UPLC-MS-IT-TOF) was employed to characterize the fragmentation pathways of 10 type-A trichothecenes, and characteristic ions were tentatively identified in scan mode through their accurate masses. Unknown signals were detected in a F. sporotrichioides extract, which afterwards were identified as seven modified forms of neosolaniol (NEO) and T-2 toxin. Then, UPLC coupled to tandem mass spectrometry (MS/MS) was employed to develop a precursor ion scanning method that can be used as a screening tool to detect any modified type-A trichothecenes. PMID- 29136837 TI - Optical molecular analysis using office flatbed photo scanner: New approaches and solutions. AB - The design and operations principles of a prototype of optical device based on an office flatbed photo scanner with a slide adapter are described in the paper. The developed device is intended for the analysis of liquid-phase samples by colorimetry, photometry, fluorimetry and nephelometry. Teflon cassettes designed for fixing cuvettes on glass plate of the scanner. Teflon wedge-shaped inserts for cuvettes have been developed to optimize the conditions of colorimetric analysis. These inserts allow varying the thickness of the absorbing layer of solutions. Multilayer absorption filters with a variable bandwidth are proposed for light monochromatization. Filters are obtained by the method of inkjet printing on polymer films. A violet laser pointer is used as a light source for fluorimetric and nephelometric analysis. The principal possibility of measuring the absorption and fluorescence spectra using photo scanner is shown. The analytical capabilities of the developed prototype of an optical molecular analyzer are demonstrated when determining riboflavin in an injection solution, acetylsalicylic acid and magnesium hydroxide in Cardiomagnyl(r) drug. PMID- 29136838 TI - A robotic magnetic nanoparticle solid phase extraction system coupled to flow batch analyzer and GFAAS for determination of trace cadmium in edible oils without external pretreatment. AB - A lab-made magnetic-mechanical robotic (MMR) system coupled to a flow-batch analyzer (FBA) for magnetic nanoparticles solid phase extraction (MSPE) is presented. As an illustrative application, an NMR-FBA couple was connected to a graphite furnace atomic absorption spectrometer (GFAAS) for quantification of trace cadmium in edible oils. Factors affecting MSPE, such as the amount of adsorbent, the type, concentration and volume of the eluent and elution time were studied. Under the optimized experimental conditions, the interferents studied did not reveal a significant change in the analytical response, indicating that proposed method is selective. The sampling rate, characteristic mass, working linear range, limits of detection (LOD), and sensitivity were 10h-1, 0.18pg, 0.05 1.0MUgkg-1, 0.006MUgL-1, and 0.4197, respectively. An enrichment factor of 9 was achieved using a 2.5mL oil sample. In order to evaluate the accuracy, a certified reference material was analyzed by the proposed and a reference method. The values obtained were compared with the one provided from the manufacturer and no statistically significant differences were observed among three values at a confidence level of 95% using paired t-test. In addition, the precision intra-day and inter day of the proposed method and the robustness were assessed and again no statistically significant differences were observed at a confidence level of 95%. The use of a microcolumn to immobilize the MNPs is not needed with the proposed MMR-FBA-GFAAS system, thus avoiding the well-known problem of non uniform packing of the MNPs presented in previous flow-based automatic methods. Despite a high organic load of edible oils, the method developed is simple, robust and presents satisfactory analytical features when compared with others that have been reported in the literature, suggesting that it is a potentially useful alternative to determine trace analytes in viscous matrices without external pretreatment. PMID- 29136839 TI - ChromiSense: A colourimetric lab-on-a-disc sensor for chromium speciation in water. AB - The development of a centrifugal device for quantitative analysis of both chromium (III) and (VI) species in water is reported. ChromiSense is a colourimetric sensor system that has been applied to the measurement of chromium in spiked river water samples. For analysis, the sample is loaded into a reservoir on the disposable microfluidic disc, along with reagents. A centrifugal force is created by spinning the disc to pump liquids through microchannels, causing them to mix and react to form a coloured product. The coloured product is then presented to a low-cost optical detection system, where absorbance measurements can be recorded. The optical detection system consists of a light emitting diode (LED) and photodiode (PD) couple. Chromium (III) was measured using 2,6-pyridine dicarboxylic acid as a ligand, forming a complex that was measured at 535nm and at 335nm. While measuring at 535nm allowed for the use of a low cost LED, the sensitivity was improved 2.5 times by measuring at 335nm. However, 335nm also yielded a diminished linear range with little improvement in limit of deteciton (LOD), and required a lengthier manufacturing process due to the need for a UV-transparent material. Chromium (VI) was detected using 1,5 diphenyl carbazide (DPC). This standard analysis method was simplified for automation on-disc, and optimised to achieve a low LOD. The LOD for trivalent and hexavalent chromium using this device were 21mgL-1 and 4MUgL-1, respectively. The linear range for quantitative analysis was found to be 69-1000mgL-1 for Cr(III) and 14-1000MUgL-1 for Cr (VI). While this range is high for Cr(III), incorporation of an off-disc pre-concentration method would make this technology suitable for environmental sample analysis. The device is simple to use, low in cost, and could provide rapid on-site measurements, with results comparable to those obtained using a benchtop spectrophotometer. PMID- 29136840 TI - Assessment of cyanide contamination in soils with a handheld mid-infrared spectrometer. AB - We examined the feasibility of using handheld mid-infrared (MIR) Fourier Transform infrared (FT-IR) instrumentation for detecting and analysing cyanide (CN) contamination in field contaminated soils. Cyanide spiking experiments were first carried out, in the laboratory, to test the sensitivity of infrared Fourier transform (DRIFT) spectrometry to ferro- and ferricyanide compounds across a range of reference soils and minerals. Both benchtop and handheld diffuse reflectance infrared spectrometers were tested. Excellent results were obtained for the reference soils and minerals, with the MIR outperforming the near infrared (NIR) range. Spectral peaks characteristic of the -C=N group were observed near 2062 and 2118cm-1 in the MIR region for the ferro- and ferricyanide compounds spiked into soils/minerals, respectively. In the NIR region such peaks were observed near 4134 and 4220cm-1. Cyanide-contaminated samples were then collected in the field and analyzed with the two spectrometers to further test the applicability of the DRIFT technique for soils containing aged CN residues. The prediction of total CN in dry and ground contaminated soils using the handheld MIR instrument resulted in a coefficient of determination (R2) of 0.88 0.98 and root mean square error of the cross-validation (RMSE) of 21-49mgkg-1 for a CN range of 0-611mgkg-1. A major peak was observed in the MIR at about 2092cm-1 which was attributed to "Prussian Blue" (Fe4[Fe(CN)6]3.xH2O). These results demonstrate the potential of handheld DRIFT instrumentation as a promising alternative to the standard laboratory method to predict CN concentrations in contaminated field soils. PMID- 29136841 TI - Miniaturized QuEChERS based methodology for multiresidue determination of pesticides in odonate nymphs as ecosystem biomonitors. AB - The impacts of the modern, agrochemicals based agriculture that threatens the overall systems sustainability, need to be monitored and evaluated. Seeking for agroecosystems monitors, the present article focus in the occurrence and abundance of aquatic macroinvertebrates, that have been frequently used as bioindicators of water quality due to their relationship with land use. Some of these organisms are on the top of the food chain, where bioaccumulation and biomagnification processes can be observed, and they can turn into secondary pollution sources of systems and terrestrial organisms as well. Odonate nymphs, which belong to the functional group of predators, were selected for this study. A methodology to determine 73 pesticide residues in odonate nymphs by LC-MS/MS and GC-MS/MS was developed. A QuEChERS sample preparation strategy was adapted. As it is complex to obtain samples especially in disturbed ecosystems, the method was minimized to a sample size of 200mg of fresh nymphs. The method was validated and good recoveries (71-120%) with RSDs below 20% for the majority of the studied pesticides at least at two of the assayed levels 1, 10 and 50ugkg-1 were obtained. For 32 analytes the limit of quantitation was 1ugkg-1 and 10ugkg-1 for the others. The lineal range was observed between 1-100ugkg-1 in matrix-matched and solvent calibration curves for most of the assessed pesticides. LC-MS/MS matrix effects were evaluated, 40% of the analytes presented low or no signal suppression. Only flufenoxuron presented high matrix effects. The obtained methodology is adequate for pesticide multiresidue analysis in aquatic macroinvertebrates (odonates) aiming to contribute to the ecological state evaluation of freshwater ecosystems. PMID- 29136842 TI - Application of micro X-ray fluorescence and micro computed tomography to the study of laser cleaning efficiency on limestone monuments covered by black crusts. AB - Laser cleaning is widely used to remove black crusts from weathered limestone monuments. The cleaning efficiency is commonly tested using conventional analytical techniques, which do not allow to analyze the same sample before and after the treatment. In this paper, micro computed tomography (MU-CT) and micro X ray fluorescence spectroscopy (MU-XRF) techniques were used for the first time to evaluate the laser cleaning efficiency on two different encrusted quoins collected from a limestone monument. Analyses were carried out non-destructively on the same portion of the two lithotypes before and after the treatment. MU-XRF confirmed the presence of gypsum in the black crust, and showed a marked decrease of S and other typical elements after laser cleaning of both samples. MU-CT clearly showed the different structure of limestone before and after cleaning and the crust portion removed by the laser. The combination of the two techniques allowed to assess that, even if the two samples had a similar chemical composition, their response to laser cleaning was different on dependence of their different fabric/structure. In fact, in one sample calcium sulphate was still partially retained also after the black crust removal, whereas in the other sample the sulphate layer was almost completely ablated due to its more compact structure. In both cases, laser cleaning operation was shown not to cause any structural modification or mechanical damage of the original stone material. In conclusion, the use of these novel techniques appears very promising for studying the effects of laser ablation on rock samples in order to set the best working conditions for their cleaning. PMID- 29136843 TI - Improved assessment of accuracy and performance using a rotational paper-based device for multiplexed detection of heavy metals. AB - In this work, a novel rotational microfluidic paper-based device was developed to improve the accuracy and performance of the multiplexed colorimetric detection by effectively avoiding the diffusion of colorimetric reagent on the detection zone. The integrated paper-based rotational valves were used to control the connection or disconnection between detection zones and fluid channels. Based on the manipulation of the rotational valves, this rotational paper-based device could prevent the random diffusion of colorimetric reagent and reduce the error of quantitative analysis considerably. The multiplexed colorimetric detection of heavy metals Ni(II), Cu(II) and Cr(VI) were implemented on the rotational device and the detection limits could be found to be 4.8, 1.6, and 0.18mg/L, respectively. The developed rotational device showed the great advantage in improving the detection accuracy and was expected to be a low-cost, portable analytical platform for the on-site detection. PMID- 29136844 TI - Physicochemical characterization of Lavandula spp. honey with FT-Raman spectroscopy. AB - This study aimed to evaluate the potential of FT-Raman spectroscopy in the prediction of the chemical composition of Lavandula spp. monofloral honey. Partial Least Squares (PLS) regression models were performed for the quantitative estimation and the results were correlated with those obtained using reference methods. Good calibration models were obtained for electrical conductivity, ash, total acidity, pH, reducing sugars, hydroxymethylfurfural (HMF), proline, diastase index, apparent sucrose, total flavonoids content and total phenol content. On the other hand, the model was less accurate for pH determination. The calibration models had high r2 (ranging between 92.8% and 99.9%), high residual prediction deviation - RPD (ranging between 4.2 and 26.8) and low root mean square errors. These results confirm the hypothesis that FT-Raman is a useful technique for the quality control and chemical properties' evaluation of Lavandula spp honey. Its application may allow improving the efficiency, speed and cost of the current laboratory analysis. PMID- 29136845 TI - Controlled modification of electrochemical microsystems with polyethylenimine/reduced graphene oxide using electrophoretic deposition: Sensing of dopamine levels in meat samples. AB - Microsystems play an important role in many biological and environmental applications. The integration of electrical interfaces into such miniaturized systems provides new opportunities for electrochemical sensing where high sensitivity and selectivity towards the analyte are requested. This can be only achieved upon controlled functionalization of the working electrode, a challenge for compact microsystems. In this work, we demonstrate the benefit of electrophoretic deposition (EPD) of reduced graphene oxide/polyethylenimine (rGO/PEI) for the selective modification of a gold (Au) microelectrode in a microsystem comprising a Pt counter and a Ag/AgCl reference electrode. The functionalized microsystem was successfully applied for the sensing of dopamine with a detection limit of 50nM. Additionally, the microsystem exhibited good performance for the detection of dopamine levels in meat samples. PMID- 29136846 TI - Determination of bisphenols with estrogenic activity in plastic packaged baby food samples using solid-liquid extraction and clean-up with dispersive sorbents followed by gas chromatography tandem mass spectrometry analysis. AB - Bisphenols (BPs) are a family of chemicals with known endocrine disrupting activity. Bisphenol A (BPA) is the most representative prototype of this group of chemicals. Recently, the use of BPA, a prototype of endocrine disruptors, has been reduced and replaced with structural analogs due to its negative effects on both the environment and consumers. In this work, a new method is presented for the determination of seven BPs, with estrogenic activity in ready-to-eat plastic packaged baby foods. The procedure involves the isolation of the analytes using solid-liquid phase extraction with acetonitrile followed by a clean-up step with a mixture of dispersive-SPE sorbents (C18 and PSA) and magnesium sulphate, to reduce matrix effect from proteins, sugars and lipids. Extraction parameters were optimized using multivariate optimization methods. The compounds were detected and quantified by gas chromatography tandem mass spectrometry (GC-MS/MS). The limits of quantification were between 0.1 and 1.2ngg-1 for the studied analytes. The method was validated using matrix-matched calibration and recovery assays with spiked samples. Recovery rates were between 91% and 110% and % RSD was lower than 13% in all cases. The method has been successfully applied for the determination of these endocrine disrupting chemicals (EDCs) in samples of a novel type of food consumed by pre-schoolers. This is the first study to analyze EDCs in plastic packaged foods consumed by this target group. PMID- 29136847 TI - Nitrogen-doped carbon nanotubes decorated poly (L-Cysteine) as a novel, ultrasensitive electrochemical sensor for simultaneous determination of theophylline and caffeine. AB - In present study, a novel and facile electrochemical sensor based on glassy carbon electrode (GCE) modified with nitrogen-doped carbon nanotubes (N-CNT) decorated with poly (L-Cysteine) (PLCY) were fabricated and applied for the simultaneous voltammetric determination of theophylline (THEO) and caffeine (CAF). The morphology and structure of multilayer film modified on the surface of glassy carbon electrode were investigated successfully by Scanning Electron Microscope (SEM), Transmission Electron Microscope (TEM) and Raman Spectroscopy. And the properties of the modified electrode were investigated by Chronocoulometry (CC), Cyclic Voltammetry (CV) and Differential Pulse Voltammetry (DPV) were utilized to investigate the electrochemical behavior of THEO and CAF on the composite film modified electrode. The results showed that the determination towards THEO and CAF can be operated at the same potential window with the oxidation current peak separated and non-interfering respectively. Compared to the bare GCE, the PLCY/N-CNT/GCE can signally meliorate the electrocatalytic activity towards the oxidation of THEO and CAF with a remarkably increase in the anodic peak currents of 495.94% and 465.48%. Under the optimal conditions, the fabrication multilayer film sensor had excellent performances in determination towards THEO and CAF with a wide linear dynamic range from 0.10 to 70.0MUM and 0.40-140.0MUM, low detection limit (S/N = 3) of 0.033MUM and 0.20MUM, respectively. The PLCY/N-CNT/GCE sensor also had advantages as easy-made, high sensitivity, stability and reproducibility. Moreover, it was successfully used to analyze the THEO and CAF in green tee, oral theophylline sustained release tablets and energy drink sample with a satisfactory result. PMID- 29136848 TI - Convertible DNA ends-based silver nanoprobes for colorimetric detection human telomerase activity. AB - Human telomerase is an endogenous ribonucleoprotein that is over-expressed in most types of malignant cancer cells. Sensitive and specific detection of telomerase activity is crucial for better understanding its role in cancer cells and further exploring its function in cancer diagnosis. Here, we develop convertible DNA ends-based silver nanoprobes for sensitive and specific colorimetric detection telomerase activity. Silver nanoprobes are constructed by modifying telomerase binding substrates (TS) that are pre-hybridized with complementary sequences onto silver nanoparticles (AgNPs), via the coordination between consecutive cytosines in TS strand and AgNPs. This forms blunt-end terminated, double-stranded DNA on the surface of AgNPs. Under the action of telomerase, TS on the silver nanoprobes are elongated with telomeric repeats, converting DNA stiff blunt ends to flexible single-stranded dangling ends. The dangling ends enhance the stability of nanoprobes and relieve their salt-induced aggregation, and the solution shows a yellow color. When telomerase is inactive, the blunt end-terminated nanoprobes cannot resist salt-induced aggregation, resulting in a gray color of solution. Based on telomerase-regulated DNA "blunt dangling" ends conversion-induced AgNPs' dispersity and color change, colorimetric detection of the endogenous telomerase with AgNPs is realized. The detection limit is equivalent to 1 cell/MUL of telomerase activity, and extracts from cancer cells and normal cells are visually distinguished through color difference. The proposed strategy will offer a new approach for reliable, convenient quantification of telomerase activity in biochemical research and clinical diagnosis. PMID- 29136849 TI - Simultaneous determination of three estrogens in human saliva without derivatization or liquid-liquid extraction for routine testing via miniaturized solid phase extraction with LC-MS/MS detection. AB - Accurate quantitation of estrogens (i.e, estrone (E1), estradiol (E2) and estriol (E3)) is valuable for clinical assessment of human health and disease. Alterations in estrogen levels have been implicated in numerous pathological conditions. However, inadequacies in sensitivity and specificity, cumbersome sample preparation and invasive specimen collection hamper the usability of available methods for clinical applications. Herein, a simple, rapid, highly sensitive and specific LC-MS/MS method was developed and validated for the simultaneous determination of three estrogens in human saliva providing a non invasive alternative to conventional blood samples. For the first time, a 96-well hydrophilic-lipophilic-balanced (HLB) microplate was employed for clean-up and enrichment of estrogens in a single extraction without the requirements of derivatization, evaporation, liquid-liquid extraction and online extraction. A rapid LC chromatographic separation with a turnaround time of 5.0min was achieved on a BEH C18 XP column. The use of 0.1mM ammonium fluoride (NH4F) as LC additive, and integration of summated and scheduled multiple reaction monitoring (MRM) transitions substantially improved the sensitivity to 1pg/mL, allowing the accurate quantitation of trace levels of three estrogens in one run. The assay was fully validated with good performance for extraction efficiency (67.0-85.6%), matrix effect (89.6-100.2%), linearity (from 1.0pg/mL up to 1000pg/mL), accuracy (98.9-112.4%) and precision (<=7.4%). Additionally, the assay was unaffected by 34 structurally-similar, potentially interfering substances tested at high clinical concentrations. The applicability of the assay was demonstrated by assessing the reference intervals of authentic saliva samples from healthy adult males, pre- and post-menopausal females. The easy sample preparation, fast LC and multi-analyte MS/MS detection utilizing noninvasive saliva as a specimen delivers a simple, practical, sensitive and accurate tool suitable for the high throughput measurement of E1, E2 and E3 in clinical laboratories. PMID- 29136850 TI - Novel generation of deep eutectic solvent as an acceptor phase in three-phase hollow fiber liquid phase microextraction for extraction and preconcentration of steroidal hormones from biological fluids. AB - In this study, a novel generation of deep eutectic solvents (DESs) was used as an acceptor phase in three-phase hollow fiber liquid phase microextraction (HF-LPME) based on two immiscible organic phases. It was compared with other common DESs for extraction and preconcentration of dydrogesterone (DYD) and cyproterone acetate (CPA) from urine and plasma samples. The extracted analytes were analyzed by high performance liquid chromatography with UV-vis detector (HPLC-UV). This phosphonium based DES due to low volatility, low price and multifunctionality introduced itself as worthy next generation of acceptor phase in HF-LPME. The factors affected on extraction efficiency of the analytes were investigated and optimized. The performance of the proposed method was studied in terms of linear ranges (LRs from 1 to 500ugL-1 with R2 >= 0.9946), precision (RSD% <= 6.3) and limits of detection (LODs in the range of 0.5-2ugL-1). Under the optimized conditions, preconcentration factors in the range of 187-428 were obtained. Finally, the method was applied to the analysis of DYD and CPA in human urine and plasma samples and desirable results were obtained. PMID- 29136851 TI - In situ fabrication of cobalt nanoflowers on sulfonated and fluorinated poly (arylene ether ketone-benzimidazole) template film for the electrocatalytic oxidation of glucose. AB - Using sulfonated and fluorinated poly (arylene ether ketone) comprising functional strong coordination group benzimidazole (SPAEK-F-BI) as a template film, a novel fabrication method of cobalt nanoflowers (CoNFs) and non-enzymatic glucose electrochemical sensor was developed in this work. After the precursors Co2+ ions were cooperatively bound by sulfonate and imidazole functionalities contained in SPAEK-F-BI film through ion exchange and strong coordination action, cobalt colloid nuclei were formed and grew to flower-like nanostructures by subsequent in-situ electrochemical reduction on SPAEK-F-BI film modified GCE. Characterization of SPAEK-F-BI film and CoNFs/SPAEK-F-BI film on GCE was performed in detail by FT-IR spectroscopy and scanning electron microscopy (SEM) attached with energy dispersive spectroscopy (EDS), electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The results of SEM showed that beautiful CoNFs constructed by Co colloid nanosheets with just a few nanometers thickness were well dispersed on uniform SPAEK-F-BI film modified GCE, and the density of CoNFs was mainly influenced by the concentration of the precursor solution CoSO4. The CoNFs/SPAEK-F-BI composite modified electrode exhibited good electrocatalytic activity toward glucose oxidation in 0.1M NaOH solution, and the kinetic parameters of glucose oxidation were determined using chronoamperometry. When it was applied for the determination of glucose by amperometry at a potential of 0.6V versus Ag/AgCl, the linear range from 5MUM to 1.14mM and the detection limit of 800nM (S/N = 3) were obtained. Finally, it was successfully employed to detect the glucose in human serum real samples, and the results were agreed closely with those measured in hospital. PMID- 29136852 TI - A robust and effective intact protein fractionation strategy by GO/PEI/Au/PEG nanocomposites for human plasma proteome analysis. AB - Identification of human plasma proteins with deep coverage is considered as a great challenge due to its extreme complexity. In this work, an intact proteins fractionation strategy based on multi-interaction between proteins and GO/PEI/Au/PEG nanocomposites (GPAP strategy) was developed for human plasma proteome deep analysis. Compared with untreated method, the number of identified proteins was increased from 858 to 2023, among which the number of low-abundance proteins (< 100ng/mL) was increased from 2 to 11. The concentration range of the identified proteins was broaden to 9 orders of magnitude. Furthermore, the spectral count of the top three proteins in human plasma (Plasma Albumin, Human IgG, Serotransferrin) were decreased in the range of 37.4-82.6%. An excellent reproducibility of GPAP strategy was verified via stable isotope dimethyl label strategy. The functionalized material was demonstrated to be an efficient method to achieve deep coverage identification of human plasma proteome. PMID- 29136853 TI - Electrochemical strategy for pyrophosphatase detection Based on the peroxidase like activity of G-quadruplex-Cu2+ DNAzyme. AB - A new simple and highly sensitive electrochemical method for pyrophosphatase (PPase) activity detection was developed based on the peroxidase-like activity of G-quadruplex-Cu2+ DNAzyme. In the absence of PPase, Cu2+ could coordinate with pyrophosphate (PPi) to form Cu2+-PPi compound. While in the presence of PPase, it could destroy the coordinate compound because PPase catalyzed the hydrolysis of PPi into inorganic phosphate and produced free Cu2+, which then could be coupled with G-rich DNA to form G-quadruplex-Cu2+ DNAzyme. The formation of a mimic enzyme (G-quadruplex-Cu2+ DNAzyme) was immobilized on the surface of screen printed gold electrode (SPGE). Using 3, 3', 5, 5'-tetramethylbenzidine (TMB) as a redox mediator and H2O2 as an enzyme substrate, the DNAzyme catalyzed the reduction of H2O2 to generate quantitative chronoamperometric signal. The catalytic activity of G-quadruplex-Cu2+ DNAzyme for TMB-H2O2 reaction was proportional to the activity of PPase, based on which, a simple and sensitive turn-on electrochemical method for PPase activity was thus developed for the first time. The chronoamperometric intensity of the system had a linear relationship with the PPase activities in the range of 1.0-50.0mU/mL and the detection limit could be down to 0.6mU/mL (S/N = 3). This proposed method was selective, cost-effective and convenient without any labels or complicated operations, which was furthermore applied to screen the inhibitor for PPase with high efficiency. PMID- 29136854 TI - Disperse magnetic solid phase microextraction and surface enhanced Raman scattering (Dis-MSPME-SERS) for the rapid detection of trace illegally chemicals. AB - The technique of solid phase micro-extraction (SPME) is an important method for sample pretreatment in analytical chemistry, especially for the analysis in micro systems. Surface enhanced Raman scattering (SERS) is an ultra-sensitive and fast detection technique. Both are particularly important in qualitative analysis of trace amount of substance. In this study, combining the magnetic nanoparticles with magnetic SPME device, we develop a high efficient new pretreatment method named as disperse magnetic solid phase micro-extraction (Dis-MSPME). In comparison to the traditional SPME, the proposed Dis-MSPME realizes solid phase micro-extraction from dispersive system, which improved the extraction efficiency largely. Conjunction the advantages both of Dis-MSPME and SERS is proposed as Dis MSPME-SERS as a new detection method, which realize enrichment, magnetic separation and detection all-in-one. Making it a simpler, more efficient and sensitive approach in identifying the illegal additives. Sildenafil citrate (SC) in 500MUL health wine as an example of illegal additive was successfully detected in a LOD of 1.0 * 10-8M. Moreover, comparative study on the extract efficient of Dis-MSPME-SERS with SPME-SERS shows it takes only 10min to detect sildenafil citrate in the health wine, from enrichment to detection by Dis-MSPME-SERS. PMID- 29136855 TI - Molecularly imprinted polymer (MIP) membrane assisted direct spray ionization mass spectrometry for agrochemicals screening in foodstuffs. AB - Paper spray ionization (PSI) has some limitations such as low sensitivity and ionization suppression when complex samples are analyzed. The use of sample preparation devices directly coupled to MS can avoid these restrictions. Molecularly imprinted polymers (MIPs) are materials widely used as adsorbent in sample preparation methods such as solid-phase extraction and solid-phase microextraction, and they can provide specifics cavities with affinity to a target molecule. Here, we introduce a new MIP membrane spray ionization method combining MIP and PSI. MIP was synthesized directly on a cellulose membrane. Monuron and 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) were used as template molecules in MIP synthesis for diuron and 2,4-D (2,4-dichlorophenoxyacetic acid) analyte sequesters, respectively. Apple, banana and grape methanolic extracts were used as matrices. The MIP membrane spray showed signal intensities of diuron and 2,4-D that were much higher compared to those obtained by non-imprinted polymers(NIP). Calibration curves exhibited R2 > 0.99 for diuron and 2,4-D in all fruit extracts analyzed. LODs were found less than 0.60ugL-1 and LLOQs were found less than 2.00ugL-1. The coefficients of variation and relative errors were less than 15% for almost all analyses. The apparent recovery test results ranged between 92,5% and 116.9%. Finally, the MIP membrane spray method was employed for the quantification of diuron and 2,4-D in real samples. Diuron contents were only found in three bananas (4.0, 6.5, and 9.9ugL-1). The proposed MIP membrane spray ionization method was straightforward, fast to carry out and provided satisfactory results for analyses of diuron and 2,4-D in apple, banana and grape samples. PMID- 29136856 TI - Nitrogen dots as reductant and stabilizer for the synthesis of AgNPs/N-dots nanocomposites for efficient surface-enhanced Raman scattering detection. AB - A simple method was developed for the preparation of silver nanoparticles (AgNPs) by using amino-functionalized nitrogen dots (N-dots) as reductant and stabilizer under mild conditions. N-dots were hydrothermal synthesized using 2 azidoimidazole as the precursor in aqueous ammonia. The as prepared N-dots were rich in nitrogen and oxygen-containing functional groups and exhibit strong reducing capacity. Therefore, AgNPs were rapidly synthesized under mild conditions based on N-dots serving as the reducing agent, the reaction time and temperature were 5min and 40 degrees C, respectively. Moreover, owing to the abundant functional groups on the surface of N-dots, the obtained AgNPs/N-dots nanocomposites with the average diameters of 12.9nm were well dispersed and stable at 4 degrees C for at least two months. Furthermore, the synthesized AgNPs/N-dots showed high surface-enhanced Raman scattering (SERS) activity and provided a sensitive SERS sensing ability for malachite green (MG) and crystal violet (CV) in aquaculture water, with the low detection limit (S/N = 3) of 2.7nmol/L and 2.0nmol/L, respectively, corresponding with the wide linear range from 10.0 to 1000.0nmol/L for MG and 5.0-100.0nmol/L for CV. This method offers an easy and low-cost way to prepare AgNPs/N-dots substrates and makes SERS detection more practicable. PMID- 29136857 TI - Solid-supported synergistic twain probes with aggregation-induced emission: A sensing platform for fingerprinting volatile amines. AB - Two solid emitters DMA and HBA were synthetized, showing aggregation-induced emission (AIE) phenomenon. Incorporation of electron donor-acceptor (D-A) pairs endows the solid emitters with both charge transfer (CT) state emission and distinct solvatochromic effect. The compounds undergo a rapid interaction with amines followed by the resulting weakened electron withdrawing ability to yield florescent products with either hypochromatic shift or decrease in the emission intensity. DFT calculations on HOMO and LUMO electronic cloud distribution and energy levels have demonstrated that the transition from CT state to locally excited (LE) state is mainly responsible for the spectral changes. The AIE compounds were thus developed into solid-supported amine sensor and show nice linear relationship. The detection limits of DMA- and HBA-based sensing film to ammonia gas are 2.61Pa and 2.63Pa, respectively. Time-dependent emission spectra upon treating with a variety of amines exhibited differential responses, in which two factors were defined accordingly, including maximum emission wavelength and quenching efficiency. Two-dimensional coordinate system was then built on the basis of the two factors, creating a fingerprint data base for the involved amines. The fingerprint map shows a clear differentiation of the tested amines, making DMA and HBA synergistic twain probes for identification of diverse amines. PMID- 29136858 TI - Monoclonal antibody N-glycosylation profiling using capillary electrophoresis - Mass spectrometry: Assessment and method validation. AB - Characterization of therapeutic proteins represents a major challenge for analytical sciences due to their heterogeneity caused by post-translational modifications (PTM). Among these PTM, glycosylation which is possibly the most prominent, require comprehensive identification because of their major influence on protein structure and effector functions of monoclonal antibodies (mAbs). As a consequence, glycosylation profiling must be deeply characterized. For this application, several analytical methods such as separation-based or MS-based methods, were evaluated. However, no CE-ESI-MS approach has been assessed and validated. Here, we illustrate how the use of CE-ESI-MS method permits the comprehensive characterization of mAbs N-glycosylation at the glycopeptide level to perform relative quantitation of N-glycan species. Validation of the CE-ESI-MS method in terms of robustness and reproducibility was demonstrated through the relative quantitation of glycosylation profiles for ten different mAbs produced in different cell lines. Glycosylation patterns obtained for each mAbs were compared to Hydrophilic Interaction Chromatography of 2-aminobenzamide labelled glycans with fluorescence detector (HILIC-FD) analysis considered as a reference method. Very similar glycoprofiling were obtained with the CE-ESI-MS and HILIC-FD demonstrating the attractiveness of CE-ESI-MS method to characterize and quantify the glycosylation heterogeneity of a wide range of therapeutic mAbs with high accuracy and precision. PMID- 29136859 TI - pH detection in biological samples by 1D and 2D 1H-31P NMR. AB - The chemical shifts of several important endogenous phosphorus compounds under different pH conditions were explored, including adenosine-5'-triphosphate, adenosine-5'-diphosphate, adenosine-5'-monophosphate, phosphorylcholine and phosphorylethanolamine. Their 31P NMR and 1H NMR chemical shifts were all pH sensitive in the similar pH range. Two dimensional (2D) 1H-31P NMR spectra were found helpful to identify these endogenous phosphorus markers in biological samples from rather complicated NMR spectra. Herein, for the first time, a pH sensor based on 2D 1H-31P NMR was established and applied to biological samples analysis with pH values determined in good agreement with those by potentiometric method. Apart from being simple, green, rapid and less sample-consuming, information concerning both the endogenous phosphorus markers and pH status could be attained in a single NMR run, which demonstrated the great potential of this method in rare sample analysis and even disease diagnosis. PMID- 29136860 TI - Scattering measurement of single particle for highly sensitive homogeneous detection of DNA in serum. AB - A highly sensitive homogeneous method for DNA detection has been developed. The system relies on two kinds of gold nanorod (AuNR) probes with complementary DNA sequences to the target DNA. In the presence of the target DNA, two kinds of AuNR probes are assembling into dimers or small aggregates. The target-induced AuNR aggregate has higher scattering intensity than that of a single AuNR because of the plasmonic coupling effect. Dark field microscopy was utilized to image the single particle and measure its scattering intensity. We wrote our own Matlab code and used it to extract the scattering signal of all particles. Difference in distribution of scattering intensity between the single AuNR and its aggregate provides a quantitative basis for the detection of target DNA. A linear dynamic range spanning from 0.1pM to 1nM and a detection limit of ~ 30fM were achieved for the detection of DNA in serum sample. PMID- 29136861 TI - Quality by design approach in the development of an ultra-high-performance liquid chromatography method for Bexsero meningococcal group B vaccine. AB - Bexsero is the first approved vaccine for active immunization of individuals from 2 months of age and older to prevent invasive disease caused by Neisseria meningitidis serogroup B. The active components of the vaccine are Neisseria Heparin Binding Antigen, factor H binding protein, Neisseria adhesin A, produced in Escherichia coli cells by recombinant DNA technology, and Outer Membrane Vesicles (expressing Porin A and Porin B), produced by fermentation of Neisseria meningitidis strain NZ98/254. All the Bexsero active components are adsorbed on aluminum hydroxide and the unadsorbed antigens content is a product critical quality attribute. In this paper the development of a fast, selective and sensitive ultra-high-performance liquid chromatography (UHPLC) method for the determination of the Bexsero antigens in the vaccine supernatant is presented. For the first time in the literature, the Quality by Design (QbD) principles were applied to the development of an analytical method aimed to the quality control of a vaccine product. The UHPLC method was fully developed within the QbD framework, the new paradigm of quality outlined in International Conference on Harmonisation guidelines. Critical method attributes (CMAs) were identified with the capacity factor of Neisseria Heparin Binding Antigen, antigens resolution and peak areas. After a scouting phase, aimed at selecting a suitable and fast UHPLC operative mode for the vaccine antigens separation, risk assessment tools were employed to define the critical method parameters to be considered in the screening phase. Screening designs were applied for investigating at first the effects of vial type and sample concentration, and then the effects of injection volume, column type, organic phase starting concentration, ramp time and temperature. Response Surface Methodology pointed out the presence of several significant interaction effects, and with the support of Monte-Carlo simulations led to map out the design space, at a selected probability level, for the desired CMAs. The selected working conditions gave a complete separation of the antigens in about 5min. Robustness testing was carried out by a multivariate approach and a control strategy was implemented by defining system suitability tests. The method was qualified for the analysis of the Bexsero vaccine. PMID- 29136862 TI - Stimulus-response click chemistry based aptamer-functionalized mesoporous silica nanoparticles for fluorescence detection of thrombin. AB - In most aptamer based stimulus response mesoporous silica nanoparticles (MSN) systems, the aptamer is modified on the MSN via electrostatic interaction, however leakage might exist after a certain time in the system and hence the stability is not good. In this study, the pores of MSN were capped by aptamer through click chemistry reaction for the first time and the system was then employed to develop a fluorescence biosensor. Specifically, the aptamer of the target (thrombin in this study) was hybridized with its complementary DNA (which was initially modified with alkyne at the terminal) to form a double strand DNA (dsDNA) firstly, and then this dsDNA was modified on N3 modified MSN via Cu(I) catalyzed alkyne-azide cycloaddition reaction. The guest molecules (fluorescein) were blocked in the pores of the MSN with high efficiency and nearly no leakage was detected. Upon the introduction of thrombin, thrombin specifically recognized its aptamer, so aptamer released from the MSN; and the single strand DNA(ssDNA) left could not cap the pores of the MSN efficiently and hence caused the releasing of fluorescein into the solution. The enhanced fluorescence intensity of the system has a good linear relationship with the thrombin concentration in the range of 50-1000ngmL-1 with a detection limit of 28.46ngmL-1. The proposed biosensor has been successfully applied to detect thrombin in serum samples with high selectivity. The same strategy can be applied to develop biosensors for different targets by changing the adopted aptamer. PMID- 29136863 TI - The biological acoustic sensor to record the interactions of the microbial cells with the phage antibodies in conducting suspensions. AB - The acoustic biological sensor for the analysis of the bacterial cells in conducting suspension was developed. The sensor represented the two channel delay line based on the piezoelectric plate of Y-X lithium niobate thick of 0.2mm. Two pairs of the interdigital transducers (IDT) for the excitation and reception of shear horizontal acoustic wave of zero order (SH0) in each channel were deposited by the method of photolithography. One channel of the delay line was electrically shorted by the deposition of thin aluminum film between IDTs. The second channel remained as electrically open. The liquid container with the volume of 5ml was fixed on the plate surface between IDTs by the glue, which did not cause the additional insertion loss. For the first time the influence of the conductivity of the cell suspension on the registration of the specific and nonspecific interactions of the bacterial cells with phage-antibodies (phage-Abs) was studied by means of the developed sensor. The dependencies of the change in insertion loss and phase of the output signal on the conductivity of the buffer solution at specific/nonspecific interactions for the electrically open and shorted channels of the delay line were obtained. It was shown that the sensor successfully registered the interactions of microbial cells with phage-Abs in the range of the conductivity of 2-20 MUS/cm on the model samples A. brasilense Sp245 - specific phage-Abs. The sensor in the time regime of the operation fast reacted on the specific/nonspecific interaction and the time of the stabilization of the output parameters did not exceed 10min. PMID- 29136864 TI - Suspect screening of halogenated carboxylic acids in drinking water using ion exchange chromatography - high resolution (Orbitrap) mass spectrometry (IC-HRMS). AB - Retrospective in silico screening of analytical data for the identification of new or emerging disinfection by-products in drinking waters could be useful to assess quality and potential hazards, as well as help implement mitigation procedures more rapidly. Herein, the first study coupling ion exchange chromatography (IC) with high resolution mass spectrometry (HRMS) for the determination of halogenated carboxylic acid disinfectant by-products is reported. Separation was achieved using a Metrohm A Supp 5 column and a Na2CO3/NaHCO3 gradient eluent from 1/0.31 to 10/3.1mM. A variety of solid phase extraction (SPE) sorbents were tested for added selectivity to organic ions and Isolute ENV+ cartridges were selected because of their best overall extraction performance. Method LODs were in the MUgL-1 concentration range, with R2 >= 0.99 for all the analytes, and isobaric ions could be easily discriminated using HRMS. The method was applied to municipal drinking water. Targeted quantitative analysis revealed the presence of 10 haloacetic acids at levels not exceeding the limits set by WHO and USEPA. Furthermore, suspect screening for additional halogenated carboxylic acids via retrospective HRMS data analysis also indicated the presence of other iodinated HAAs and chlorinated propionic acids, of which one (i.e. monochloropropionic acid) is discussed here for the first time. Most importantly, several potential suspects could be eliminated from further consideration through HRMS data analysis alone. To our knowledge, this represents the first time that a retrospective IC-HRMS screen of halogenated carboxylic acids in drinking water has been reported. PMID- 29136865 TI - A catalytic spectrophotometric method for determination of nanomolar manganese in seawater using reverse flow injection analysis and a long path length liquid waveguide capillary cell. AB - A sensitive and precise method for determination of nanomolar manganese in seawater was developed, using reverse flow injection analysis, a long path length liquid waveguide capillary cell, and spectrophotometric detection. The reaction was based on manganese catalyzed oxidation of leucomalachite green with sodium periodate. Various experimental parameters were investigated and optimized. Foreign trace metal ions of iron, copper, zinc, nickel and aluminum did not cause obvious interference with manganese detection. Low manganese seawater was prepared and used as the blank and standards' matrix, to eliminate the seawater matrix effect. The method detection limit was 0.20nmolL-1, and the quantification range was 0.50-10.00nmolL-1, which should be sensitive enough and suitable for open ocean seawater analysis. The seawater certified reference material NASS-6 was used to test the accuracy, and good agreement was obtained. The proposed method was applied to analyze seawater samples collected at the SEATS station in the South China Sea. The vertical profile of the total dissolvable manganese is reported and discussed. PMID- 29136866 TI - Flow-through silica: A potential matrix for fast chromatographic enantioseparation with high enantioselectivity. AB - The demand for fast chromatographic enantioseparation aroused the hot research in stationary phase matrix. In the present study, the flow-through silica, which is characterized by hierarchical pores of through pores in several hundred nanometer range and mesopores about 20nm, was attempted for fast enantioseparation. Thanks to the large surface area and full openness of the through pores, the flow through silica had comparable cellulose derivative loading amount as the commercial wide-pore silica, which was impracticable for most of the core-shell particles and sub-2-MUm fully porous silica. In addition, the backpressure was about two times lower in the case of the flow-through silica of the same particle size to the commercial wide-pore silica, due to the highly porous structure of the former. Another appreciated merit of the flow-through silica in small size (~2um) was the less dependence of column efficiency on the flow rate. All of the above features rendered the flow-through silica a tremendous potential for fast enantioseparation with desired enantioselectivity, especially suitable for the polysaccharide chiral selector. PMID- 29136867 TI - Deep eutectic solvent based advance microextraction method for determination of aluminum in water and food samples: Multivariate study. AB - Preconcentration of aluminum Al3+ was carried out by a novel deep eutectic solvent based ultrasound-assisted liquid phase microextraction (DES-UALPME) method. The deep eutectic solvents (DESs), a green solvent was first time used for enrichment and quantification of very low concentration of Al3+ in water and food samples, prior to analysed by electrothermal atomic absorption spectrometry (ETAAS). In present method it was observed that % recovery of Al-8 hydroxyquinoline chelates efficiently extracted by DES solvent. Pre-enrichment factor and limit of detection were observed to be 50, and 0.032MUgL-1, respectively. Developed procedure was validated with the CRM (SLRS-5 river water) of Al and a good agreement was observed in results of measured value to the certified value. The RSD was calculated as 3.3%. The presented procedure was successfully carried out to different water and food samples. PMID- 29136868 TI - A PCR-free colorimetric strategy for visualized assay of telomerase activity. AB - A simple yet powerful polymerase chain reaction (PCR)-free strategy for visualized assay of human telomerase activity was reported in this work. Gold nanoparticles (AuNPs) based colorimetric strategy was applied with well-designed enzyme-aided cyclic amplification. Briefly, the detection relies on the elongated primers of telomerase substrate (TS) induced by telomerase, which open the hairpin DNA and hybridize with linker DNA, the trigger of AuNPs aggregation. Nicking endonuclease was added in the sensing system, which cleaved linker DNA after hybridization and released complimentary strand for cyclic hybridization with linker DNA, resulted in high sensitivity for the detection of telomerase. Down to 25 HeLa cells with high expression of telomerase could be recognized. The proposed strategy provides a good platform for the determination of telomerase activity, differentiation of cancer cell lines from normal cell line and screening of telomerase-targeted anticancer drugs. PMID- 29136869 TI - Facile synthesis of Fe3O4@PDA core-shell microspheres functionalized with various metal ions: A systematic comparison of commonly-used metal ions for IMAC enrichment. AB - Metal ions differed greatly in affinity towards phosphopeptides, and thus it is essential to systematically compare the phosphopeptides enrichment ability of different metal ions usually used in the IMAC techniques. In this work, for the first time, eight metal ions, including Nb5+, Ti4+, Zr4+, Ga3+, Y3+, In3+, Ce4+, Fe3+, were immobilized on the polydopamine (PDA)-coated Fe3O4 (denoted as Fe3O4@PDA-Mn+), and systematically compared by the real biosamples, in addition to standard phosphopeptides. Fe3O4 microspheres were synthesized via the solvothermal reaction, followed by self-polymerization of dopamine on the surface. Then through taking advantage of the hydroxyl and amino group of PDA, the eight metal ions were easily adhered to the surface of Fe3O4@PDA. After characterization, the resultant Fe3O4@PDA-Mn+ microspheres were applied to phosphopeptides enrichment based on the binding affinity between metal ions and phosphopeptides. According to the results, different metal ions presented diverse phosphopeptides enrichment efficiency in terms of selectivity, sensitivity and the enrichment ability from real complex samples, and Fe3O4@PDA-Nb5+ and Fe3O4@PDA-Ti4+ showed obvious advantages of the phosphopeptides enrichment effect after the comparison. This systematic comparison may provide certain reference for the use and development of IMAC materials in the future. PMID- 29136870 TI - 3D hierarchical bayberry-like Ni@carbon hollow nanosphere/rGO hybrid as a new interesting electrode material for simultaneous detection of small biomolecules. AB - Metal-organic framework derived hierarchical bayberry-like Ni@carbon hollow nanosphere/reduced graphene oxide (Ni@CHS/rGO) hybrid was synthesized by combining a simple solvothermal reaction with a further annealing treatment. 3D hierarchical bayberry-like Ni@CHS/rGO hybrid not only offered a continuous highly conductive Ni metal and graphene matrix to facilitate the charge transfer, but also allowed uptaking and releasing of electrolytes and enchanted adsorbing of targets due to a hollow structure and introduction of graphene. Consequently, such a charming architecture displays preeminent electrocatalytic activity towards the electro-oxidation on ternary mixtures of ascorbic acid (AA), uric acid (UA) and dopamine (DA). For simultaneous detection of three small molecules, the fabricated sensor exhibited good application prospects toward analytes of DA, UA and AA. Furthermore, three well-separated voltammetry peaks were obtained using Ni@CHS/rGO electrode in differential pulse voltammetry (DPV) measurements. The calibration curves for UA, DA and AA were obtained: 0.25-126uM, 0.25-126uM and 2-4000uM, respectively, the detection limits were 0.05uM, 0.05uM, 0.37uM, respectively. This sensor exhibited excellent sensitivity, good stability, outstanding anti-interference ability and acceptable reproducibility. Moreover, the intriguing sensor was triumphantly applied for the quantitative analysis of UA, DA and AA in human urine and vitamin C tablets samples with satisfactory recovery, which manifests its viability application for practical analysis. PMID- 29136871 TI - A novel task specific magnetic polymeric ionic liquid for selective preconcentration of potassium in oil samples using centrifuge-less dispersive liquid-liquid microextraction technique and its determination by flame atomic emission spectroscopy. AB - In the present study a new centrifuge-less dispersive liquid-liquid microextraction technique based on application of a new task specific magnetic polymeric ionic liquid (TSMPIL) as a chelating and extraction solvent for selective preconcentration of trace amounts of potassium from oil samples is developed, for the first time. After extraction, the fine droplets of TSMPIL were transferred into an eppendorf tube and diluted to 500uL using distilled water. Then, the enriched analyte was determined by flame atomic emission spectroscopy (FAES). Several important factors affecting both the complexation and extraction efficiency including extraction time, rate of vortex agitator, amount of carbonyl iron powder, pH of sample solution, volume of ionic liquid as well as effects of interfering species were investigated and optimized. Under the optimal conditions, the limits of detection (LOD) and quantification (LOQ) were 0.5 and 1.6ugL-1 respectively with the preconcentration factor of 128. The precision (RSD %) for seven replicate determinations at 10ugL-1 of potassium was better than 3.9%. The relative recoveries for the spiked samples were in the acceptable range of 95-104%. The results demonstrated that no remarkable interferences are created by other various ions in the determination of potassium, so that the tolerance limits (WIon/WK) of major cations and anions were in the range of 2500-10,000. The purposed method was successfully applied for the analysis of potassium in some oil samples. PMID- 29136872 TI - A novel hybrid flow platform for on-line simultaneous dynamic fractionation and evaluation of mercury lability in environmental solids. AB - A method for the automatic simultaneous assessment of mobility and lability of mercury in environmental solid samples has been developed for the first time. It has been implemented in a hybrid flow system integrating flow-through dynamic sequential extraction and on-line chemical digestion prior to atomic fluorescence detection. The method allows the determination of trace concentrations of labile mercury (HgL) and non-labile mercury (HgNL) in different bioaccessible phases of environmental solid samples thus providing expeditious data not only for Hg exposome studies but also for the selection of suitable environmental remediation techniques. The analytical procedure involves the sequential application of deionized water, 0.01M HNO3 solution, 1M KOH solution and solution containing both Na2S and KOH (1molL-1 each) to a solid sample packed in a column to release four Hg fractions according to their mobilities (i.e. water soluble, exchangeable, organic matter associated, and sulfide bound Hg) followed by the on line determination of the concentrations of HgL and HgNL by flow programming. Apart from obtaining more comprehensive knowledge of risk exposure of Hg-laden solids, important advantages of the newly developed method compared to its batch wise fractionation counterpart include (i) approximately 8-fold reduction in the time for acquisition of the dynamic extraction data, (ii) evaluation of the kinetics of release of Hg, (iii) Hg lability analysis, and (iv) minimization of matrix interferences and potential re-adsorption or transformation of the extracted Hg species. PMID- 29136873 TI - Fabrication of 8-aminocaprylic acid doped UIO-66 as sensitive solid-phase microextraction fiber for nitrosamines. AB - The introduction of functional groups into metal organic frameworks has great potential for enhancement in adsorption performance of nitrosamines using solid phase microextraction (SPME). However, pre-functionalization and post modification generally suffer from the same limitation that the additional functional groups occupy the free volume and thereby decreasing pore volume and special surface area. Herein, we use a modulator-induced defect-formation strategy to prepare the 8-aminocaprylic acid doped UIO-66 (Am-UIO-66) with high adsorption capacity of nitrosamines. Then, the as-synthesized UIO-66 and Am-UIO 66 were fabricated as SPME fibers exhibiting good adsorption capacity towards nitrosoamines. The reason was that the 8-aminocaprylic acid creates structural defects and additional pore spaces of Am-UIO-66, thus increases the specific surface area as well as pore volume. Finally, the Am-UIO-66-coated SPME fiber was successfully applied to the determination of nitrosamines migration from latex gloves and achieved good linearity (20-2000ngL-1), satisfactory recoveries (85.2 112.8%) and rather low LODs (2.61-6.12ngL-1), by coupling with gas chromatography mass spectrometry (GC-MS). PMID- 29136874 TI - A rapid detection method for policy-sensitive amines real-time supervision. AB - Many organic amines that comprise a benzene ring are policy-sensitive because of their toxicity and links to social harm. However, to date, detection of such compounds mainly relies on offline methods. This study proposes an online pptv (parts per trillion by volume) level of detection method for amines, using the recently-built vacuum ultraviolet photoionization mass spectrometer (VUV-PIMS) combined with a new doping technique. Thus, the dichloromethane doping-assisted photoionization mass spectra of aniline, benzylamine, phenethylamine, amphetamine, and their structural isomers were recorded. The dominant characteristic mass peaks for all amines are those afforded by protonated amines and the amino radical-loss. The signal intensities of the amines were enhanced by 60-130 times compared to those recorded without doping assistance. Under 10s detection time, the sensitivities of aniline and benzylamine in the gas phase were determined as 4.0 and 2.7 countspptv-1, with limits of detection (LODs) of 36 and 22 pptv, respectively. Notably, the detection efficiency of this method can be tenfold better in future applications since the ion transmission efficiency of the mass spectrometer was intentionally reduced to ~ 10% in this study. Therefore, dichloromethane doping-assisted photoionization mass spectrometry has proven to be a highly promising on-line approach to amine detection in environmental and judicial supervision and shows great potential for application in the biological field. PMID- 29136875 TI - A turn-on competitive immunochromatographic strips integrated with quantum dots and gold nano-stars for cadmium ion detection. AB - Immunochromatographic strips (ICSs) are inexpensive, simple, portable, and robust, and therefore have many uses in the medicinal, agricultural, and environmental industries. For detection of small molecules, current ICSs are competitive format (competitive ICSs, CICSs), which only offer a turn-off readout mode, and therefore lead to low sensitivity when evaluating results by the naked eye. To overcome this problem, we report a turn-on CICSs that relies on the ability of gold nano-stars (AuNSs) quenching the signal of quantum dots (QDs). This turn-on CICSs device was applied to detect cadmium ions (Cd2+). The linear detection range (LDR) of the turn-on CICSs was 0.25ng/mL-8ng/mL, and the detection of limit (LOD) was 0.18ng/mL. Compared with traditional turn-off CICSs, the sensitivity of the turn-on CICSs was enhanced by 32 times. The turn-on CICSs also has a high specificity and high recovery for the detection of Cd2+ in Pearl River (95-112%) and tap water samples (103.5-116.67%). Therefore, we believe the turn-on CICSs offers great potential for the detection of other small molecules in clinical diagnostics, food safety investigations, and environment pollution monitoring. PMID- 29136876 TI - Capillary electrochromatography using knitted aromatic polymer as the stationary phase for the separation of small biomolecules and drugs. AB - Hypercrosslinked polymers (HCPs) are currently receiving great attention due to their unique characteristics and potential uses in diverse areas. However, the field of HCPs for open-tubular capillary electrochromatography (OT-CEC) separations has not been explored. Here, a knitted aromatic polymer (KAP) was in situ grown on the inner wall of the capillary column for OT-CEC for the first time. The silylating reagent containing phenyl was served as monomer, immobilized on the inner wall of the capillary column, and then KAPs-modified capillary column was prepared through in-situ hypercrosslinking reaction. The surface structure and morphology of KAPs-modified capillary column was characterized by Fourier transform infrared spectra (FT-IR) and scanning electron microscopy (SEM). The prepared capillary columns showed good separation performance for neutral compounds, small biomolecules, such as nucleosides, amino acids, small peptides, and non-steroidal anti-inflammatory drugs, sulfa drugs. In addition, the KAPs-modified capillaries showed good reproducibility, with relative standard deviations for intra-day, inter-day and column-to-column runs less than 1.59%, 2.55%, and 5.19% respectively. The strategy of in-situ immobilization of KAPs provides a new approach for the application of the material in the analytical fields. PMID- 29136877 TI - QSPR in forensic analysis - The prediction of retention time of pesticide residues based on the Monte Carlo method. AB - A method for the prediction of retention indices of pesticides using the Monte Carlo method and with optimal molecular descriptors based on local graph invariants and the SMILES notation of studied compounds has been presented. Quite satisfactory results were obtained with the proposed method, since a robust model with good statistical quality was developed. The predictive potential of the applied approach was tested and the robustness of the model was proven with different methods. The best calculated QSPR model had following statistical parameters: r2 = 0.9182 for the training set and r2 = 0.8939 for the test set. Structural indicators defined as molecular fragments responsible for the increases and decreases of gas chromatographic retention indices activity were calculated. PMID- 29136878 TI - Highly sensitive and selective turn-on fluorescent chemosensors for Hg2+ based on thioacetal modified pyrene. AB - This work reports a facile strategy for the synthesis of water-soluble fluorescent probes Pyr1 and Pyr2, which have carboxyl and hydroxyl group in the side chain of thioacetal moiety, respectively. Pyr1-2 exhibit exclusively selective turn-on fluorescence response towards Hg2+ over other cations, based on intramolecular charge transfer (ICT) mechanism. Upon addition of Hg2+, the thioacetal moiety in Pyr1-2 can be converted to aldehyde group, which is confirmed by 1H NMR titrations. The detection limits for Pyr1-2 are less than 1.80nM in aqueous media, lower than the maximum allowable level of Hg2+ in drinking water by EPA. Moreover, Pyr2 have been successfully used for fluorescence imaging of Hg2+ in living cells, demonstrating potential application in biological science. PMID- 29136879 TI - Development and evaluation of a new diffusive gradients in thin-films technique for measuring organotin compounds in coastal sediment pore water. AB - Organotins present a toxicological risk to biota in the aquatic environment. Understanding the behaviour of these compounds in sediment is challenging, with sophisticated analytical techniques required for their measurement. We investigated the use of silica-bound sorbents for diffusive gradients in thin films (DGT) adsorption gels to pre-concentrate five organotins (monobutlytin (MBT), dibutyltin (DBT), tributyltin (TBT), diphenyltin (DPhT), triphenyltin (TPhT)) found frequently in coastal sediment. C8 sorbent showed optimum performance in uptake and recovery of organotins for pH and ionic strength ranges typical of coastal waters. Recoveries from adsorption gels deployed in filtered sea water were MBT = 123 +/- 20%, DBT = 75 +/- 12%, TBT = 81 +/- 16%, DPhT = 72 +/- 30%, TPhT = 58 +/- 10% respectively. Devices were used to investigate DGT fluxes and pore water concentrations of organotins in coastal sediment collected from a contaminated site. DGT fluxes measured in sediment cores for the five organotins ranged between 4.3 * 10-8 and 1.6 *10-5ngcm2s-1. The depletion of organotin species within pore waters at the interface with DGT devices was measured over a series of deployment times (2, 7, 14, 21 and 28 days) and provided estimates of the concentration of organotins in pore waters at Langstone Harbour, UK, prior to depletion by the DGT device and information on their spatial heterogeneity. The novel in situ DGT device developed can pre-concentrate organotins from pore waters in coastal sediment core samples and allows their detection at low environmental concentrations using conventional gas chromatographic/mass spectrometric instrumentation. Use of the DGT device overcomes many problems associated with the conventional pore water sampling of organotins. Our preliminary data suggests it has potential in the future to be a useful tool in investigating the environmental fate of these pollutants. The use of the C8 gel will also allow for the simultaneous sequestration of other semi- and non-polar analytes present in the pore water. PMID- 29136880 TI - Enhanced electrochemical response of carbon quantum dot modified electrodes. AB - A glassy carbon electrode (GCE) was surface-modified with carbon quantum dots (CQDs) and applied for the effective enhancement of the electrochemical signal for dopamine and uric acid determination. CQDs were prepared from graphite by a green modification of the Hummers method. They were characterized by FTIR-ATR, XPS, solid-state NMR, fluorescence and Raman spectroscopies. TPD-MS analysis was applied to characterize the functionalization of the surface. The CQDs were assembled on the glassy carbon electrode by adsorption because of the large number of carboxy groups on their surface warrants effective adsorption. The modified GCE exhibits a sensitivity that is almost 10 times better than of the bare GCE. The lower limits of detection are 1.3MUM for uric acid and 2.7MUM for dopamine. PMID- 29136881 TI - Monitoring of tablet coating processes with colored coatings. AB - Endpoints of coating processes for colored tablets were determined using in-line Raman spectroscopy. Coatings were performed with six commercially available formulations of pink, yellow, red, beige, green and blue color. The coatings were comprising pigments and/or dyes, some causing fluorescence and interfering the Raman signal. Using non-contact optics, a Raman probe was used as process analytical technology (PAT) tool, and acquired spectra were correlated to the sprayed mass of aqueous coating suspension. Process endpoints were determined using univariate (UV) data analysis and three multivariate analysis methods, namely Projection to Latent Structures (PLS)-regression, Science-Based Calibration (SBC) and Multivariate Curve Resolution (MCR). The methods were compared regarding model performance parameters. The endpoints of all coating experiments could be predicted until a total coating time of 50min corresponding to coating thicknesses between 21 and 38um, depending on the density of the coat formulation. With the exception of SBC, all calibration methods resulted in R2 values higher than 0.9. Additionally, the methods were evaluated regarding their capability for in-line process monitoring. For each color, at least two methods were feasible to do this. Overall, PLS-regression led to best model performance parameters. PMID- 29136882 TI - Growth of Escherichia coli on the GaAs (001) surface. AB - Detection of pathogenic bacteria and monitoring their susceptibility to antibiotics are of great importance in the fields of medicine, pharmaceutical research, as well as water and food industries. In order to develop a photonic biosensor for detection of bacteria by taking advantage of photoluminescence (PL) of GaAs-based devices, we have investigated the capture and growth of Escherichia coli K12 on bare and biofunctionalized surfaces of GaAs (001) - a material of interest for capping different semiconductor microstructures. The results were compared with the capture and growth of Escherichia coli K12 on Au surfaces that have commonly been applied for studying a variety of biological and biochemical reactions. We found that neither GaAs nor Au-coated glass wafers placed in Petri dishes inoculated with bacteria inhibited bacterial growth in nutrient agar, regardless of the wafers being bare or biofunctionalized. However, the capture and growth of bacteria on biofunctionalized surfaces of GaAs and Au wafers kept in a flow cell and exposed to different concentrations of bacteria and growth medium revealed that the initial surface coverage and the subsequent bacterial growth were dependent on the biofunctionalization architecture, with antibody coated surfaces clearly being most efficient in capturing bacteria and offering better conditions for growth of bacteria. We have observed that, as long as the GaAs wafers were exposed to bacterial suspensions at concentrations of at least 105 CFU/mL, bacteria could grow on the surface of wafers, regardless of the type of biofunctionalization architecture used to capture the bacteria. These results provide important insight towards the successful development of GaAs-based devices designed for photonic monitoring of bacterial reactions to different biochemical environments. PMID- 29136883 TI - Programmable Fow Injection. Principle, methodology and application for trace analysis of iron in a sea water matrix. AB - Automation of reagent based assays by Flow Injection is based on sample processing, in which a sample flows continuously towards and through a detector for monitoring of its components. There are three drawbacks to using this approach. The constant continuous forward flow: continually consumes reagents and generates chemical waste and necessitates a compromise when optimizing the performance of the reagent based assay. The reason is that individual steps of an assay protocol, i.e., sample and reagent metering, mixing, incubation, monitoring and efficient washout are carried out most efficiently on different time scales and therefore at different flowrates. Programmable Flow Injection (pFI) eliminates all three drawbacks and permits the execution of optimization of the assay protocol by means of a computer. This paper details this novel approach to method development by optimization of an assay of iron at nanomolar levels and its application to its determination in a sea water matrix. The pFI method was developed in two variants: Stop in Holding Coil (SHC) and Stop in Flow cell (SFC). The SHC method has a Limit of Detection (LOD = 3.1ppb or 55nM Fe, precision of 1.9% r.s.d. at ~ 90nM, and sampling frequency of 90 samples/h. The SFC method had LOD = 0.57ppb or 10nM Fe, precision of 0.8% r.s.d. at ~ 90nM, and sampling frequency of 40 samples/h and its sensitivity is independent of the salinity of the matrix. The SFC method, and its manual equivalent, was used for the determination of dissolved Fe (II) that had been spiked into several samples of seawater that had been diluted with various volumes of deionized water to mimic coastal seawater. The results showed good agreement between both the SFC and the manual methods. PMID- 29136884 TI - Electrooxidation and amperometric determination of vorinostat on hierarchical leaf-like gold nanolayers. AB - Hierarchical leaf-like gold nanolayers were electrodeposited using choline chloride as a shape directing agent and characterized using field emission scanning electron microscopy. The electrooxidation behavior of vorinostat was then studied on the nanolayers and the kinetic parameters of the electrodic process were obtained by voltammetric measurements in a phosphate buffer solution at pH 7.40. Vorinostat was electrooxidized on the nanolayers' surface at a lower potential and with a higher rate, compared to a polycrystalline smooth gold surface, through an irreversible process. Based on the results, an amperometric sensor was designed using the hierarchical leaf-like gold nanolayers for the determination of vorinostat. A linear dynamic range of 4.0-52MUmol L-1 with a calibration sensitivity of 7.7mAmol-1L, and a detection limit of 1.40MUmolL-1 were obtained. The amperometry method was also applied to the analysis of vorinostat capsules. PMID- 29136885 TI - An inorganic boronate affinity in-needle monolithic device for specific capture of cis-diol containing compounds. AB - In this work, inorganic boronate affinity monolith was prepared by in situ synthesis in 0.33mm i.d. stainless steel needle through sol-gel process using tetraethoxysilane and tetrabutyl orthotitanate as the co-precursors. The morphology, structure and composition of the monolith were characterized. In contrast to conventional boronate affinity materials, inorganic boric acid was used as affinity ligand. Different compounds were used for the evaluation of the boronate affinity of this inorganic monolithic material. The monolith exhibited good selectivity towards cis-diol containing compounds. Recovery of greater than 90% was achieved for in-needle extraction of catechol under neutral conditions. Owing to the hydrophilic property of the monolith, the procedure of affinity chromatography could be performed in aqueous solution. This monolithic in-needle device will be useful for boronate affinity extraction of small-volume samples. PMID- 29136886 TI - Determination of terpenoid contents of aromatic plants using NIRS. AB - The method was developed in order to provide a fast, simple and non-destructive analysis of terpenoid compounds of aromatic plants. For this purpose, spectroscopic data were collected on the surface of dried plant samples by using near infrared spectroscopic (NIRS) analysis. Volatile substances were extracted from aromatic plants using hydro-distillation method to determine terpenoid composition by using gas chromatography-mass spectrometry (GC-MS). Multivariate calibration methods namely, partial least squares (PLS) regression, were used for data analysis. The correlation between NIRS spectral data and the concentrations of terpenoid contents were established with coefficient of determination (R2) values in the range of 0.953-0.997. The model validation results showed that the contents of 24 terpenoids were predicted accurately with a satisfactory limit of detection (LOD) values. In this study, 24 terpenoids, the major constituents of volatile compounds, from nine aromatic plants were investigated. PMID- 29136887 TI - Flow injection analysis-flame atomic absorption spectrometry system for indirect determination of sulfite after on-line reduction of solid-phase manganese (IV) dioxide reactor. AB - A new and simple flow injection method followed by atomic absorption spectrometry was developed for indirect determination of sulfite. The proposed method is based on the oxidation of sulfite to sulphate ion using solid-phase manganese dioxide (30% W/W suspended on silica gel beads) reactor. MnO2 will be reduced to Mn(II) by sample injection in to the column under acidic carrier stream of HNO3 (pH 2) with flow rate of 3.5mLmin-1 at room temperature. Absorption measurement of Mn(II) which is proportional to the concentration of sulfite in the sample was carried out by atomic absorption spectrometry. The calibration curve was linear up to 25mgL-1 with a detection limit (DL) of 0.08mgL-1 for 400uL injection sample volume. The presented method is efficient toward sulfite determination in sugar and water samples with a relative standard deviation (RSD) less than 1.2% and a sampling rate of about 60h-1. PMID- 29136888 TI - Urinary metal and metalloid biomarker study of Henoch-Schonlein purpura nephritis using inductively coupled plasma orthogonal acceleration time-of-flight mass spectrometry. AB - To obtain a better understanding as to whether concentration alterations of metals and metalloids in urine were related to Henoch-Schonlein purpura nephritis (HSPN), the profiles of as many as 29 elements in urine were compared among three groups, the Henoch-Schonlein purpura (HSP), HSPN and a healthy control group. To this end, a reliable method has been developed for the simultaneous quantification of multiple elements including Li, Be, B, Al, Sc, Ti, V, Cr, Mn, Fe, Ni, Co, Cu, Zn, Ga, Ge, As, Se, Rb, Sr, Mo, Cd, Sn, Sb, Cs, Ba, Tl, Pb and Bi in urine using inductively coupled plasma orthogonal acceleration time-of-flight mass spectrometry (ICP-oa-TOF-MS). The process of sample pre-treatment used a direct 20-fold dilution method with centrifuged urine. The internal standard element used for quantification was 103Rh, and 1,4-butanediol was chosen as a matrix matching reagent. The method detection limits of these 29 elements were in the range of 0.04-12ngmL-1. Results of statistical analysis revealed that the concentrations of 15 elements and the element homeostasis were significantly different among these three groups. Our study provides a potential method for HSPN metal and metalloid biomarker discovery. PMID- 29136889 TI - Carbon nanostructured films modified by metal nanoparticles supported on filtering membranes for electroanalysis. AB - A novel methodology to prepare sensors based on carbon nanostructures electrodes modified by metal nanoparticles is proposed. As a proof of concept, a novel bismuth nanoparticle/carbon nanofiber (Bi-NPs/CNF) electrode and a carbon nanotube (CNT)/gold nanoparticle (Au-NPs) have been developed. Bi-NPs/CNF films were prepared by 1) filtering a dispersion of CNFs on a polytetrafluorethylene (PTFE) filter, and 2) filtering a dispersion of Bi-NPs chemically synthesized through this CNF/PTFE film. Next the electrode is prepared by sticking the Bi NPs/CNF/PTFE film on a PET substrate. In this work, Bi-NPs/CNF ratio was optimized using a Cd2+ solution as a probe sample. The Cd anodic stripping peak intensity, registered by differential pulse anodic stripping voltammetry (DPASV), is selected as target signal. The voltammograms registered for Cd stripping with this Bi-NPs/CNF/PTFE electrode showed well-defined and highly reproducible electrochemical. The optimized Bi-NPs/CNF electrode exhibits a Cd2+ detection limit of 53.57 ppb. To demonstrate the utility and versatility of this methodology, single walled carbon nanotubes (SWCNTs) and gold nanoparticles (Au NPs) were selected to prepare a completely different electrode. Thus, the new Au NPs/SWCNT/PTFE electrode was tested with a multiresponse technique. In this case, UV/Vis absorption spectroelectrochemistry experiments were carried out for studying dopamine, demonstrating the good performance of the Au-NPs/SWCNT electrode developed. PMID- 29136890 TI - Electro-acoustic sensor for the real-time identification of the bacteriophages. AB - The electro-acoustical sensor for the real-time identification of the bacteriophage FAl-SR65 is described. The polyclonal antibodies specific to the bacteriophage FAl-SR65 were for the first time obtained, and the possibility of their application to the bacteriophage detection by using the electro-acoustical method of analysis was also studied for the first time. The electro-acoustical sensor was based on the lateral electric field excited piezoelectric resonator. The frequency dependences of the real and imaginary parts of the electrical impedance of such a resonator, loaded with the virus-antibody suspension, significantly differed from those measured for the same resonator with the same virus suspension but without antibodies (control). The limit for the reliable bacteriophage detection during their interaction with the antibodies (sensitivity level) was determined to be 106 phages ml-1. The obtained results demonstrate the possibility to record the bacteriophage-antibody interactions and can be used as the basis for the development of the biological sensor for the quantitative virus detection. PMID- 29136891 TI - Detection and quantification of extra virgin olive oil adulteration by means of autofluorescence excitation-emission profiles combined with multi-way classification. AB - Within olive oils, extra virgin olive oil is the highest quality and, in consequence, the most expensive one. Because of that, it is common that some merchants attempt to take economic advantage by mixing it up with other less expensive oils, like olive oil or olive pomace oil. In consequence, the characterization and authentication of extra virgin olive oils is a subject of great interest, both for industry and consumers. This paper reports the potential of front-face total fluorescence spectroscopy combined with second-order chemometric methods for the detection of extra virgin olive oils adulteration with other olive oils. Excitation-emission matrices (EEMs) of extra virgin olive oils and extra virgin olive oils adulterated with olive oils or with olive pomace oils were recorded using front-face fluorescence spectroscopy. The full information content in these fluorescence images was analyzed with the aid of unsupervised parallel factor analysis (PARAFAC), PARAFAC supervised by linear discriminant analysis (LDA-PARAFAC), and discriminant unfolded partial least squares (DA-UPLS). The discriminant ability of LDA-PARAFAC was studied through the tridimensional plots of the canonical vectors, defining a surface separating the established categories. For DA-UPLS, the discriminant ability was established through the bidimensional plots of predicted values of calibration and validation samples, in order to assign each sample to a given class. The models demonstrated the possibility of detecting adulterations of extra virgin olive oils with percentages of around 15% and 3% of olive and olive pomace oils, respectively. Also, UPLS regression was used to quantify the adulteration level of extra virgin olive oils with olive oils or with olive pomace oils. PMID- 29136892 TI - Green synthesis of monolithic column incorporated with graphene oxide using room temperature ionic liquid and eutectic solvents for capillary electrochromatography. AB - In this work, a hybrid monolith incorporated with graphene oxide (GO) was prepared in the first time with binary green porogens of deep eutectic solvents (DESs) and room temperature ionic liquids (RTILs). GO was modified with 3 (trimethoxysilyl) propylmethacrylate (gamma-MPS), and the resultant GO-MPS can be incorporated into poly (methacrylic acid-co-butylmethacrylate-co-ethylene glycol dimethacrylate) monoliths covalently. A hybrid monolithic column with high permeability and homogeneity can be achieved due to good dispersion of GO-MPS in the green solvents. The GO-MPS incorporated monolith was characterized by transmission electron microscopy, scanning electron microscopy, thermogravimetric analysis and nitrogen adsorption tests. The separation of small organic molecules of alkylphenones and alkylbenzenes was used to evaluate the performance of GO-MPS grafted monolith. The GO-MPS grafted monolith displayed the maximum column efficiency of 147,000 plates/m, about twice higher than the GO-free monolith. In addition, all of the retention and selectivity of small molecules of alkylphenones and alkylbenzenes increased due to the addition of GO-MPS. The results demonstrated that the use of DESs and RTILs is a powerful approach for the preparation of GO incorporated polymer monoliths. The monolith was further applied to the separation of tryptic digests from bovine serum albumin, and the result indicated its potential in the analysis of some complex samples. PMID- 29136893 TI - Study on molecularly imprinted nanoparticle modified microplates for pseudo-ELISA assays. AB - Nanosized Molecularly Imprinted Polymers (nanoMIPs) are designed artificial nanoreceptors with a predetermined selectivity and specificity for a given analyte, lately proposed as a replacement to antibodies in immunoassays. The nanoMIP-plate preparation based on nanoparticle adsorption was studied with the aim to rationally identify and discuss the critical points in the nanoMIP-assay development, in an example based on the iron homeostasis biomarker hepcidin and hepcidin-specific nanoMIPs (Kd = 9nM). Plates were prepared by deposition and drying of nanoMIP (0.5-4ug/well), or by nanoMIPs co-depositions (proteins, PVA). Rehydration (> 1h) of dry nanoMIP-plates showed the reconstitution of the imprinted binding sites. NanoMIP-plate mechanical stresses (several washings; pipetting) caused nanoMIP desorption (~90%). After 10 washes the quantity of nanoMIP was 0.2ug/well, the imprinted binding sites were ~270 fmol/well, their accessibility the 92%. Co-depositions resulted in higher amount of adsorbed nanomaterial (1.2ug/well), but low accessibility of the imprinted binding sites (2-47%). Tested in a competitive sequential assay, using as competitor horseradish peroxidase conjugate to hepcidin, the nanoMIP-plate permitted to determine hepcidin in serum samples, yet with a narrow dynamic range of response (0.9-10nM). Critical points in the assay were: the instability of the nanoMIP adsorption, which lead to the progressive loss of binding sites/well, and the affinity of the nanoMIP for the analyte (Kd = 9nM), which corresponds to kinetics dissociation constants on the time-scale of the washing lengths (minutes), thus compatible with the release of the bound hepcidin during the washings. The found limits set the conditions to develop a successful nanoMIP-assay: (i) stable microplate derivatization; (ii) maximized number of imprinted binding sites/well; (iii) nanoMIP/analyte equilibrium not perturbed on the time scale of the minutes (i.e. Kd ~ pM). PMID- 29136894 TI - SI-traceable calibration-free analysis for the active concentration of G2-EPSPS protein using surface plasmon resonance. AB - Active proteins play important roles in the function regulation of human bodies and attract much interest for use in pharmaceuticals and clinical diagnostics. However, the lack of primary methods to analyze active proteins means there is currently no metrology standard for active protein measurement. In recent years, calibration-free concentration analysis (CFCA), which is based on surface plasmon resonance (SPR) technology, has been proposed to determine the active concentration of proteins that have specific binding activity with a binding partner without any higher order standards. The CFCA experiment observes the changes of binding rates at totally different two flow rates and uses the known diffusion coefficient of an analyte to calculate the active concentration of proteins, theoretically required, the binding process have to be under diffusion limited conditions. Measuring the active concentration of G2-EPSPS protein by CFCA was proposed in this study. This method involves optimization of the regeneration buffer and preparation of chip surfaces for appropriate reaction conditions by immobilizing ligands (G2-EPSPS antibodies) on sensor chips (CM5) via amine coupling. The active concentration of G2-EPSPS was then determined by injection of G2-EPSPS protein samples and running buffer over immobilized and reference chip surfaces at two different flow rates (5 and 100MULmin-1). The active concentration of G2-EPSPS was obtained after analyzing these sensorgrams with the 1:1 model. Using the determined active concentration of G2-EPSPS, the association, dissociation, and equilibrium constants of G2-EPSPS and its antibody were determined to be 2.18 +/- 0.03 * 106M-1s-1, 5.79 +/- 0.06 *10-3s-1, and 2.65 +/- 0.06 * 10-9M, respectively. The performance of the proposed method was evaluated. The within-day precisions were from 3.26% to 4.59%, and the between day precision was 8.36%. The recovery rate of the method was from 97.46% to 104.34% in the concentration range of 1.5-8nM. The appropriate concentration range of G2-EPSPS in the proposed method was determined to be 1.5-8nM. The active G2-EPSPS protein concentration determined by our method was only 17.82% of that obtained by isotope dilution mass spectrometry, showing the active protein was only a small part of the total G2-EPSPS protein. The measurement principle of the proposed method can be clearly described by equations and the measurement result can be expressed in SI units. Therefore, the proposed method shows promise to become a primary method for active protein concentration measurement, which can benefit the development of certified reference materials for active proteins. PMID- 29136895 TI - Reactive low temperature plasma ionization mass spectrometry for the determination of organic UV filters in personal care products. AB - Organic UV filters in personal care products (PCPs) have been persistently reported as a potential threat to human health. In order to guarantee consumers' safety, the dose of these compounds in PCPs needs to be monitored. Here, a methodology based on reactive low temperature plasma ionization (LTP) mass spectrometry (MS) has been developed for the determination of common organic UV filters in PCPs including benzophenone-3, ethylhexyl dimethyl p-aminobenzoic acid, ethylhexyl methoxycinnamate, 4-methylbenzylidene camphor, octocrylene, and ethylhexyl salicylate. The experiments were carried out in transmission geometry where the LTP ion source, samples loaded on a stainless steel mesh, and the MS inlet were aligned coaxially. Four chemicals, ammonia, ammonium formate, aniline, and methylamine were considered as reactive additives allowing reactions with the UV filters through different mechanisms. Methylamine-induced reactive LTP-MS showed the most prominent improvement on the detection of UV filter compounds. Compared to direct LTP-MS, the developed method improved the detection limits of UV filters more than 10 fold. Moreover, the method enabled fast semi-quantitative screening of UV filters in authentic PCPs. Concentrations of active ingredients in eight authentic PCPs as determined with reactive LTP-MS were found comparable to values offered by the cosmetic companies and corresponding HPLC data. The methodology provides high throughput analysis (70s per sample) and sensitive identification of organic UV filters. Lowest detectable concentrations ranged from 0.13ug/g for 4-methylbenzylidene camphor to 7.67ug/g for octocrylene in spiked cream. In addition, it shows the potential to be used as a screening tool for legal authentications of these chemicals in the future due to its semi quantitative determination of UV filters in PCPs without tedious sample preparation and time-consuming chromatographic separation. PMID- 29136896 TI - Hollow mesoporous CuCo2O4 microspheres derived from metal organic framework: A novel functional materials for simultaneous H2O2 biosensing and glucose biofuel cell. AB - Hollow mesoporous CuCo2O4 (meso-CuCo2O4) microspheres were successfully synthesized by decomposing metal-organic frameworks (MOFs) as the template. The as-prepared CuCo2O4 microspheres were first simultaneously used for H2O2 biosensing and glucose biofuel cell (GFC) as the enzyme mimic. The resulting of meso-CuCo2O4 displayed not only excellent catalytic performances to H2O2 including a super-fast response time (within 2s), a super-high sensitivity (654.23 MUA mM-1 cm-2) and a super-low detection limit (3nM at S/N = 3) on the sensor, but also great values in GFC as anode material with an open circuit voltage of 0.85V, a maximum power density of 0.33 mWcm-2 and a limiting current density of 1.27 mAcm-2, respectively. The preeminent catalytic abilities to H2O2 and glucose may be attributed to the surpassing intrinsic catalytic activity of CuCo2O4 and large specific area of mesoporous structure. These significant findings deriving from this work not only provided a novel exploration for the fabrication of hollow spherical mesoporous bimetallic oxides, but also promoted the development of the supersensitive detection of H2O2 and non-enzymatic biofuel cell. PMID- 29136897 TI - Cysteamine-capped copper nanoclusters as a highly selective turn-on fluorescent assay for the detection of aluminum ions. AB - A new type of copper nanoclusters was synthesized by a one-pot reaction using cysteamine as a capping agent and reducing agent (Cys-CuNCs). The synthesized CuNCs exhibited a spherical shape and a monodisperse and strong fluorescent emission characteristic peak at 430nm when exciting at 330nm. The Cys-CuNCs were demonstrated as a fluorescent chemodosimeter for the selective detection of Al3+. In the presence of Al3+, the fluorescent emission of the Cys-CuNCs was considerably enhanced, while other studied metal ions did not show this phenomenon. The fluorescent intensity near 380nm linearly increased with an increasing Al3+ concentration. The proposed method provided a working range of 1 7uM with a low detection limit of 26.7nM and was applied to determine Al3+ in drinking water samples with satisfactory results. PMID- 29136898 TI - Aerosol dilution as a simple strategy for analysis of complex samples by ICP-MS. AB - This study investigated the capability of High Matrix Introduction (HMI) strategy for analysis of dialysis solution and urine samples using inductively coupled plasma mass spectrometry. The use of HMI enables the direct introduction of urine samples and dialysis solutions 2-fold diluted with 0.14molL-1 HNO3. Bismuth, Ge, Ir, Li, Pt, Rh, Sc and Tl were evaluated as internal standards for Al, Ag, As, Be, Cd, Cr, Pb, Sb, Se, Tl, and Hg determination in dialysis solution and As, Cd, Hg and Pb determination in urine samples. Helium collision cell mode (4.5mLmin-1) was efficient to overcome polyatomic interferences in As, Se and Cr determinations. Mercury memory effects were evaluated by washing with 0.12molL-1 HCl or an alkaline diluent solution prepared with n-butanol, NH4OH, EDTA, and Triton X-100. This later solution was efficient for avoiding Hg memory effects in 6h of analysis. Linear calibration curves were obtained for all analytes and detection limits were lower than maximum amounts allowed by Brazilian legislations. Recoveries for all analytes in dialysis solutions and urine samples ranged from 82% to 125% and relative standard deviations for all elements and samples were lower than 7%. Analysis of control internal urine samples was in agreement with certified values at 95% confidence level (t-test; p < 0.05). PMID- 29136899 TI - Characterization of mercury-binding proteins in human neuroblastoma SK-N-SH cells with immobilized metal affinity chromatography. AB - Metal-binding proteins play important roles in biological functions of metals. However, only very limited mercury-binding proteins with high abundance were characterized in cells or organisms. Characterization of mercury-binding proteins in proteome-wide is important for elucidating mechanisms of mercury toxicity comprehensively. In this study, a method based on immobilized mercury ion affinity chromatography was developed for identification of putative mercury binding proteins. The method was then successfully applied to profile mercury binding proteins in human neuroblastoma SK-N-SH cells. In total, 38 proteins were identified as mercury-binding proteins, in which most of them were uncharacterized to associate with mercury in cells. The identified mercury binding proteins did not show obvious relevance to protein abundance and were mainly involved in protein processing in endoplasmic reticulum, protein folding, and cytoskeleton organization. The newly built metalloproteomic approach provided valuable information on the possible molecular mechanisms and protein candidates for mercury transport and toxicity. PMID- 29136900 TI - Detection of yeast Saccharomyces cerevisiae with ionic liquid mediated carbon dots. AB - Hydrophobic nitrogen-doped carbon dots are prepared with energetic ionic liquid (1,3-dibutylimidazolium dicyandiamide, BbimDCN) as carbon source. A yield of as high as 58% is obtained for the carbon dots, shortly termed as BbimDCN-OCDs, due to the presence of thermal-instable N(CN)2- moiety. BbimDCN-OCDs exhibit favorable biocompability and excellent imaging capacity for fluorescence labelling of yeast cell Saccharomyces cerevisiae. In addition, chitosan-modified Dy3+-doped magnetic nanoparticles (shortly as Chitosan@Fe2.75Dy0.25O4) with superparamagnetism are prepared. The electrostatic attraction between positively charged magnetic nanoparticles and negatively charged yeast cells facilitates exclusive recognition/isolation of S. cerevisiae. In practice, S. cerevisiae is labelled by BbimDCN-OCDs and adhered onto the Chitosan@Fe2.75Dy0.25O4. The yeast/ BbimDCN-OCDs/Chitosan@Fe2.75Dy0.25O4 composite is then isolated with an external magnet and the fluorescence from BbimDCN-OCDs incorporated in S. cerevisiae is monitored. The fluorescence intensity is linearly correlated with the content of yeast cell, showing a calibration graph of F = 3.01log[C]+11.7, offering a detection limit of 5*102 CFU/mL. S. cerevisiae content in various real sample matrixes are quantified by using this protocol. PMID- 29136901 TI - Biomarker analysis of hemoglobin adducts of acrylamide and glycidamide enantiomers for mid-term internal exposure assessment by isotope dilution ultra high performance liquid chromatography tandem mass spectrometry. AB - Hemoglobin (Hb) adducts of acrylamide (AA) and its oxidative metabolite glycidamide (GA) are important biomarkers for evaluating the mid-term exposure of acrylamide toxicity in vivo. Taking pentafluoro-2-methylphenyl isothiocyanates of N-(2-carbamoylethyl)valine (AAVal-PFPTH) and N-(2-carbamoyl-2-hydroxyethy)valine (GAVal-PFPTH) as target analytes, we developed an isotope dilution ultra-high performance liquid chromatograph tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of AA and GA hemoglobin (Hb) adducts under the electroscopy ionization negative (ESI?) mode in the present work. Among them, the enantiomer pair of GA-Hb adducts was firstly identified and successfully separated at baseline level. The method achieved high sensitivity with the LOD and LOQ ranging 1.43-5.05pmol/g Hb and 4.78-16.82pmol/g Hb, respectively. The recovery rates with low, intermediate and high spiking levels were calculated as 97.0-105.2%, 97.4-106.4% and 100.3-111.2%, respectively. Acceptable within laboratory reproducibility (RSD < 13.7%) substantially supported the robustness of current UHPLC-MS/MS method, which was successfully applied to measure the hemoglobin adducts of acrylamide and glycidamide enantiomers in blood of both rats and humans. A linear exposure assessment model was developed for estimating the daily exposure to acrylamide in humans via considering acrylamide hemoglobin adducts as variables, indicating a novel connect between biomarker-based internal exposure and dietary-based external exposure. Overall, the present instrumental analysis and related internal exposure assessment model provide a substantially methodological support for profiling the internal biological exposure and estimating the external dietary exposure to acrylamide. PMID- 29136902 TI - Nitrone formation: A new strategy for the derivatization of aldehydes and its application on the determination of furfurals in foods by high performance liquid chromatography with fluorescence detection. AB - A nitrone formation method using a novel fluorescent reagent 4 hydroxylaminopropyl-7-methoxylcoumarin (HAMC) has been developed and applied for the determination of furfurals in foods using high performance liquid chromatography with fluorescence detection (HPLC-FLD). Furfurals samples were derivatized by HAMC in aqueous condition at room temperature in less than 30min and were subjected to direct HPLC-FLD analysis without extra purification or extraction. Compared with other conventional methods, nitrone formation method produced single chromatographic peak for each analyte, leading to simpler chromatograms and enhancing the overall sensitivity. Low detection limits at sub nM level (0.08-0.1nM) and high repeatabilities (intra-day RSD <= 4.2% and inter day RSD <= 6.7%) were achieved. The linear range of the calibration curve was 0.2 4000nM with good correlation coefficients (R >= 0.9989). This method was successfully applied for furfurals determination in food samples, including honey and coffee. The accuracy was satisfactory with recoveries ranging from 89.7% to 106.7% Above all, this pre-column derivatization method is simple, reliable and highly sensitive, providing a promising way for future studies of aldehydes from various sources. PMID- 29136903 TI - Multivariate optimization of a procedure employing microwave-assisted digestion for the determination of nickel and vanadium in crude oil by ICP OES. AB - This work presents the optimization of a sample preparation procedure using microwave-assisted digestion for the determination of nickel and vanadium in crude oil employing inductively coupled plasma optical emission spectrometry (ICP OES). The optimization step was performed utilizing a two-level full factorial design involving the following factors: concentrated nitric acid and hydrogen peroxide volumes, and microwave-assisted digestion temperature. Nickel and vanadium concentrations were used as responses. Additionally, a multiple response based on the normalization of the concentrations by the highest values was built to establish a compromise condition between the two analytes. A Doehlert matrix optimized the instrumental conditions of the ICP OE spectrometer. In this design, the plasma robustness was used as chemometric response. The experiments were performed using a digested oil sample solution doped with magnesium(II) ions, as well as a standard magnesium solution. The optimized method allows for the determination of nickel and vanadium with quantification limits of 0.79 and 0.20MUgg-1, respectively, for a digested sample mass of 0.1g. The precision (expressed as relative standard deviations) was determined using five replicates of two oil samples and the results obtained were 1.63% and 3.67% for nickel and 0.42% and 4.64% for vanadium. Bismuth and yttrium were also tested as internal standards, and the results demonstrate that yttrium allows for a better precision for the method. The accuracy was confirmed by the analysis of the certified reference material trace element in fuel oil (CRM NIST 1634c). The proposed method was applied for the determination of nickel and vanadium in five crude oil samples from Brazilian Basins. The metal concentrations found varied from 7.30 to 33.21MUgg-1 for nickel and from 0.63 to 19.42MUgg-1 for vanadium. PMID- 29136904 TI - A light-up fluorescent probe for citrate detection based on bispyridinum amides with aggregation-induced emission feature. AB - Citrate is an important intermediate in the citric acid cycle, a vital metabolic pathway for animals, plants and bacteria. It is of great significance to detect its levels in human beings because several diseases may cause the abnormal of citrate. In this paper, a new turn-on fluorescent sensor (TPE-Py) using the classic tetraphenylethylene (TPE) as the aggregation-induced emission (AIE) fluorophore and bipyridinium-based amides as the recognition receptor has been synthesized for the detection of citrate. The probe exhibits good selectivity and sensitivity to citrate with a relatively low detection limit (1.0 * 10-7M). The enhancement of the fluorescence is relevant with the AIE property based on the complexation of TPE-Py with citrate caused by the hydrogen bonding and electrostatic interactions between the bipyridinium diamides and citrate, which has been proved by 1H NMR and mass spectra titration, scanning electronic microscope and dynamic light scattering analyses. More importantly, the quantification of citrate in artificial urine may develop TPE-Py fluorometric probe for the citrate detection in real biosystems. PMID- 29136905 TI - Evaluation of electrochemical, UV/VIS and Raman spectroelectrochemical detection of Naratriptan with screen-printed electrodes. AB - Naratriptan, active pharmaceutical ingredient with antimigraine activity was electrochemically detected in untreated screen-printed carbon electrodes (SPCEs). Cyclic voltammetry and differential pulse voltammetry were used to carry out quantitative analysis of this molecule (in a Britton-Robinson buffer solution at pH 3.0) through its irreversible oxidation (diffusion controlled) at a potential of +0.75V (vs. Ag pseudoreference electrode). Naratriptan oxidation product is an indole based dimer with a yellowish colour (maximum absorption at 320nm) so UV VIS spectroelectrochemistry technique was used for the very first time as an in situ characterization and quantification technique for this molecule. A reflection configuration approach allowed its measurement over the untreated carbon based electrode. Finally, time resolved Raman Spectroelectrochemistry is used as a powerful technique to carry out qualitative and quantitative analysis of Naratriptan. Electrochemically treated silver screen-printed electrodes are shown as easy to use and cost-effective SERS substrates for the analysis of Naratriptan. PMID- 29136906 TI - Comparison of common components analysis with principal components analysis and independent components analysis: Application to SPME-GC-MS volatolomic signatures. AB - The aim of this work is to compare a novel exploratory chemometrics method, Common Components Analysis (CCA), with Principal Components Analysis (PCA) and Independent Components Analysis (ICA). CCA consists in adapting the multi-block statistical method known as Common Components and Specific Weights Analysis (CCSWA or ComDim) by applying it to a single data matrix, with one variable per block. As an application, the three methods were applied to SPME-GC-MS volatolomic signatures of livers in an attempt to reveal volatile organic compounds (VOCs) markers of chicken exposure to different types of micropollutants. An application of CCA to the initial SPME-GC-MS data revealed a drift in the sample Scores along CC2, as a function of injection order, probably resulting from time-related evolution in the instrument. This drift was eliminated by orthogonalization of the data set with respect to CC2, and the resulting data are used as the orthogonalized data input into each of the three methods. Since the first step in CCA is to norm-scale all the variables, preliminary data scaling has no effect on the results, so that CCA was applied only to orthogonalized SPME-GC-MS data, while, PCA and ICA were applied to the "orthogonalized", "orthogonalized and Pareto-scaled", and "orthogonalized and autoscaled" data. The comparison showed that PCA results were highly dependent on the scaling of variables, contrary to ICA where the data scaling did not have a strong influence. Nevertheless, for both PCA and ICA the clearest separations of exposed groups were obtained after autoscaling of variables. The main part of this work was to compare the CCA results using the orthogonalized data with those obtained with PCA and ICA applied to orthogonalized and autoscaled variables. The clearest separations of exposed chicken groups were obtained by CCA. CCA Loadings also clearly identified the variables contributing most to the Common Components giving separations. The PCA Loadings did not highlight the most influencing variables for each separation, whereas the ICA Loadings highlighted the same variables as did CCA. This study shows the potential of CCA for the extraction of pertinent information from a data matrix, using a procedure based on an original optimisation criterion, to produce results that are complementary, and in some cases may be superior, to those of PCA and ICA. PMID- 29136907 TI - Ultrasonic-based membrane aided sample preparation of urine proteomes. AB - A new ultrafast ultrasonic-based method for shotgun proteomics as well as label free protein quantification in urine samples is developed. The method first separates the urine proteins using nitrocellulose-based membranes and then proteins are in-membrane digested using trypsin. The enzymatic digestion process is accelerated from overnight to four minutes using a sonoreactor ultrasonic device. Overall, the sample treatment pipeline comprising protein separation, digestion and identification is done in just 3h. The process is assessed using urine of healthy volunteers. The method shows that male can be differentiated from female using the protein content of urine in a fast, easy and straightforward way. 232 and 226 proteins are identified in urine of male and female, respectively. From this, 162 are common to both genders, whilst 70 are unique to male and 64 to female. From the 162 common proteins, 13 are present at levels statistically different (p < 0.05). The method matches the analytical minimalism concept as outlined by Halls, as each stage of this analysis is evaluated to minimize the time, cost, sample requirement, reagent consumption, energy requirements and production of waste products. PMID- 29136908 TI - Chiral recognition of tryptophan enantiomers using chitosan-capped silver nanoparticles: Scanometry and spectrophotometry approaches. AB - A new, fast and inexpensive colorimetric sensor was developed for chiral recognition of tryptophan enantiomers using chitosan-capped silver nanoparticles. The function of the sensor was based on scanometry and spectrophotometry of the colored product of a reaction solution containing a mixture of chitosan-capped silver nanoparticles, phosphate buffer and tryptophan enantiomers. The image of the colored solution was taken using the scanometer and the corresponding color values were obtained using Photoshop software which subsequently were used for optimization of the experimental parameters as the analytical signal. Two types of color values system were investigated: RGB (red, green and blue values) and CMYK (cyan, magenta, yellow and black values). The color values indicated that L tryptophan had better interaction than D-tryptophan with chitosan-capped silver nanoparticles. A linear relationship between the analytical signal and the concentration of L-tryptophan was obtained in the concentration range of 1.3 * 10 5-4.6 * 10-4molL-1. Detection limits, were obtained to be 2.1 * 10-6, 2.4 * 10-6 and 3.8 * 10-6molL-1 for L-tryptophan based on R (red), G (green) and B (blue) values, respectively. PMID- 29136909 TI - Simple and selective determination of 6-thioguanine by using polyethylenimine (PEI) functionalized carbon dots. AB - In this work, a new selective and simple fluorescence probe based on polyethylenimine(PEI) functionalized carbon dots (PEI-CDs) for fast determination of 6-thioguanine (6-TG) was developed. We successfully prepared the highly fluorescent PEI-CDs by hydrothermal method, and completed the synthesis and modification processes in one step. The fluorescence quantum yield (QY) of the as synthesized CDs was 38% and higher than that of most previous reports (5-30%). The fluorescence intensity of PEI-CDs decreased obviously with gradually increased concentration of 6-TG. The interference substances caused a negligible effect on the fluorescence intensity of the (PEI-CDs)-6-TG reaction system with the interference ratios all below 2.8%. Under optimum conditions, a great linear relationship between fluorescence intensity function log(F0/F) and concentration of 6-TG in a wide range from 4MUM to 800MUM with a detection limit (S/N = 3) of 1.33MUM was obtained. And this proposed approach was successfully applied for the determination of 6-TG in human serum and urine samples. Furthermore, the PEI-CDs fluorescence probe has superior potential in practical application of detecting 6 TG due to its inexpensive precursors, simple operation, low toxicity and excellent biocompatibility. PMID- 29136910 TI - Low-cost approach to increase the analysis throughput of bar adsorptive microextraction (BAuE) combined with environmentally-friendly renewable sorbent phase of recycled diatomaceous earth. AB - In this study, a novel apparatus for bar adsorptive microextraction (BAuE) using a voltage regulator was proposed as an alternative tool to improve the analysis throughput. In addition, recycled diatomaceous earth obtained as a brewery residue was employed as a biosorbent coating for the determination of methyl paraben, ethyl paraben, benzophenone and triclocarban in water samples by high performance liquid chromatography-diode array detection (HPLC-DAD). The use of the extraction devices, comprised of floating adsorptive bars of 7.5mm length, in the extractions with magnetic stirrers linked to a voltage regulator enabled the analysis of multiple samples, simultaneously. The method optimization was carried out by univariate and multivariate analyses. The optimal conditions for the method were sample solution at pH 5, extraction time of 90min and liquid desorption in 100uL of acetonitrile:methanol (50:50, v/v) for 15min. The total sample preparation time was 17.5min per sample for a simultaneous batch of six extractions. The R2 values for the calibration curves obtained were higher than 0.9985. The limits of detection (LODs) varied from 0.19 to 2MUgL-1 and the limits of quantification (LOQs) ranged from 0.63 to 6.9MUgL-1. The method was applied to freshwater samples collected from Peri Lagoon (Florianopolis, SC, Brazil) and the relative recoveries ranged from 63% to 124% with relative standard deviations (RSDs) of < 20% (n = 2). The RSD values for the reproducibility of the performance of the magnetic stirrers and inter-device extraction efficiency were lower than 14% (n = 3) and 11% (n = 3), respectively. PMID- 29136911 TI - One-step detection for two serological biomarker species to improve the diagnostic accuracy of hepatocellular carcinoma. AB - At present, the accuracy of clinical hepatocellular carcinoma (HCC) diagnosis needs to be further improved. In this work, two kinds of serological biomarker species, microRNA and protein biomarker, have been detected simultaneously to identify HCC. Herein, a dual-aptamer hairpin DNA oligonucleotide is designed as the electrochemical sensing probe (ESP) to achieve this goal. The hairpin structured DNA probe consists microRNA-16 (miR-16) complementary sequence and alpha fetoprotein (AFP) aptamer sequence, so it can both capture miR-16 and AFP. Once it hybridizes with miR-16, the hairpin structure is unlocked so that the terminal modified signal molecule (methylene blue, MB) would give a decreased electrochemical signal. Meanwhile, once it recognizes AFP, concanavalin A (ConA) modified silver nanoparticles (AgNPs) can bind to AFP at the sensing surface. An obvious electrochemical signal of AgNPs can thus be generated for AFP detection. In this way, one-step and simultaneous detection of miRNA-16 and AFP can easily be realized by collecting the two sensitive and non-interfering electrochemical signals. Compared with traditional single biomarker detection methods, this assay strategy can improve the accuracy of HCC by monitoring two kinds of serological biomarkers species. Besides, this novel electrochemical biosensor based on ESP is simple, low-cost and efficient, which make it promising to improve the accuracy and specificity for the diagnosis HCC in the future. PMID- 29136912 TI - A new procedure for high precision isotope ratio determinations of U, Cu and Zn at nanogram levels in cultured human cells: What are the limiting factors? AB - The monitoring of isotopic fractionations in in vitro cultured human cell samples is a very promising and under-exploited tool to help identify the metabolic processes leading to disease-induced isotopic fractionations or decipher metabolic pathways of toxic metals in these samples. One of the limitations is that the analytes are often present at small amounts, ranging from tens to hundreds of ng, thus making challenging low-uncertainty isotope ratio determinations. Here we present a new procedure for U, Cu and Zn purification and isotope ratio determinations in cultured human neuron-like cells exposed to natural U. A thorough study of the influence of the limiting factors impacting the uncertainty of delta238U, delta66Zn and delta65Cu is also carried out. These factors include the signal intensity, which determines the within-day measurement reproducibility, the procedural blank correction and the matrix effects, which determine the accuracy of the mass bias correction models. Given the small Cu and U amounts in the cell samples, 15-30 and 20ng respectively, a highly efficient sample introduction system was employed in order to improve the analyte transport to the plasma and, hence, the signal intensity. With this device, the procedural blanks became the main uncertainty source of delta238U and delta65Cu values, accounting over 65% of the overall uncertainty. The matrix effects gave rise to inaccuracies in the mass bias correction models for samples finally dissolved in the minimal volumes required for the analysis, 100-150uL, leading to biases for U and Cu. We will show how these biases can be cancelled out by dissolving the samples in volumes of at least 300uL for Cu and 450uL for U. Using our procedure, expanded uncertainties (k = 2) of around 0.350/00 for delta238U and 0.150/00 for delta66Zn and delta65Cu could be obtained. The analytical approach presented in this work is also applicable to other biological microsamples and can be extended to other elements and applications. PMID- 29136913 TI - Direct detection of fluoride ions in aquatic samples by surface-enhanced Raman scattering. AB - Given the strong hydration propensity of fluoride ions, it is difficult to detect fluoride, especially inorganic fluoride, in aqueous samples. Resolving the issue of fluoride detection in aqueous samples is a scientific undertaking of great practical significance. Herein, we propose a new method for the sensitive and selective detection of fluoride in aqueous samples without the addition of organic solvents. The method involves surface-enhanced Raman spectroscopy using 1,4-diketo-3,6-diphenylpyrrolo[3,4-c]pyrrole (DPP) compounds and Ag nanoparticles. The method is based on a diketopyrrolopyrrole compound linked to 1 butyl iodide (DPP1), which can sense fluoride sensitively and selectively. When DPP1 was combined with Ag NPs and reacted with tetrabutylammonium fluoride or inorganic fluoride in aqueous samples, an obvious Raman enhancement was obtained at the excitation wavelength of 633nm. This response arises because the introduction of fluoride anions into the system changes the molecular orientation of DPP1 on the Ag NP substrate from horizontal to vertical, inducing a signal enhancement in the Raman spectrum. This system can detect inorganic fluoride at concentrations as low as 1.0MUmolL-1 (0.018ppm), which is far below the public health service recommended levels for drinking water (0.7-1.2ppm). Furthermore, using the proposed method, a linear response for fluoride in the concentration range of 1.0 * 10-3-1.0 * 10-6molL-1 was obtained, which makes fluoride detection possible in practical samples, such as fluoride-containing toothpaste. PMID- 29136914 TI - Copper sulfide nanoplates as nanosensors for fast, sensitive and selective detection of DNA. AB - The present communication reports on a novel high-sensitivity DNA sensor based on cooper sulfide nanoplates (CuS NPs). The CuS NPs are successfully synthesized through a mild one-step hydrothermal method. As an efficient nanosensor for the fluorescent detection of DNA, the CuS NPs possess high sensitivity and selectivity with a detection limit of 25pM. PMID- 29136915 TI - A quantum dot-based lateral flow immunoassay for the sensitive detection of human heart fatty acid binding protein (hFABP) in human serum. AB - We describe the preparation and validation of a novel lateral flow immunoassay test for the detection of human heart fatty acid binding protein (hFABP). Water soluble CdTe quantum dots (QDs) were selected as the fluorescent label and were linked covalently to anti-hFABP antibodies. Upon conjugation, the secondary structure of the anti-hFABP was preserved and the fluorescence quantum yield of the CdTe QDs increased. The labelled antibodies were transferred to the immunoassay test strip and the antigen-antibody reaction was successfully performed. This evidenced the preserved antibody activity of QD-labelled anti hFABP towards hFABP, and provided a rapid means for the quantitation of hFABP in human serum within the range of 0-160ng ? ml-1, with a much lower detection limit of 221pg.? ml-1 compared with other rapid tests based on lateral flow immunoassays. This new immunoassay test has been successfully used for the early detection of acute myocardial infarction. PMID- 29136916 TI - Magnetophoretic separation ICP-MS immunoassay using Cs-doped multicore magnetic nanoparticles for the determination of salmonella typhimurium. AB - In this work, a magnetophoretic separation ICP-MS immunoassay using newly synthesized multicore magnetic nanoparticles (MMNPs) was developed for the determination of salmonella typhimurium (typhi). The uniqueness of this method was the use of MMNPs doped with Cs for both separation and detection, which enable us to achieve fast analysis, high sensitivity, and good reliability. For demonstration, heat-killed typhi in a phosphate buffer solution was determined by ICP-MS after the MMNP-typhi reaction product was separated from unreacted MMNPs in a micropipette tip filled with 25% polyethylene glycol through magnetophoretic separation. The calibration curve obtained by plotting 133Cs intensity vs. the number of synthetic standard, showed a coefficient of determination (R2) of 0.94 with a limit of detection (LOD) of 102 cells/mL without cell culturing. Excellent recoveries, between 98-100%, were obtained from four replicates and compared with a sandwich-type ICP-MS immunoassay for further confirmation. PMID- 29136917 TI - One-step direct immunoassay with horseradish peroxidase as antigen for studying the functionality of antibody surfaces. AB - Antibody-coated surfaces (Ab surfaces) play a key role in bioanalytical tools developed for biosensors and diagnostics. Therefore, a high and well-defined functional activity of the Ab surface is required. The functional activity of the Ab surface depends on its available binding sites i.e. "the active sites" that are able to capture antigen (Ag). The number of active binding sites strongly depends on the immobilization strategy used to fix the Ab on the solid surface. Determination of layer thickness or surface topology are often used to characterize the Ab surfaces but there is no gold standard method for the study of the functionality of the Ab surfaces. For that purpose, we aim at developing an assay allowing to determine the performances of Ab surfaces. In the present study, anti-horseradish peroxidase antibody (anti-HRP Ab) is used as capture Ab covalently bound to the surface and enzyme HRP as Ag. This direct assay permits, in one-step, to generate a signal utilizing the catalytic properties of HRP. The signal is directly proportional to the amount of HRP bound on the Ab surface, and therefore to the active binding sites of immobilized Ab. The HRP/anti-HRP Ab interactions may be a useful indicator to construct accurate and reproducible active Ab surfaces and also to improve their performances in term of stability and sensitivity. Optimization of the assay parameters and quality of the results are presented. A good repeatability and an acceptable inter-day precision (RSD < 10%) are reported. PMID- 29136918 TI - Simultaneous grouping and ranking with combination of SOM and TOPSIS for selection of preferable analytical procedure for furan determination in food. AB - Novel methodology for grouping and ranking with application of self-organizing maps and multicriteria decision analysis is presented. The dataset consists of 22 objects that are analytical procedures applied to furan determination in food samples. They are described by 10 variables, referred to their analytical performance, environmental and economic aspects. Multivariate statistics analysis allows to limit the amount of input data for ranking analysis. Assessment results show that the most beneficial procedures are based on microextraction techniques with GC-MS final determination. It is presented how the information obtained from both tools complement each other. The applicability of combination of grouping and ranking is also discussed. PMID- 29136919 TI - Flow-batch analysis of clenbuterol based on analyte extraction on molecularly imprinted polymers coupled to an in-system chromogenic reaction. Application to human urine and milk substitute samples. AB - A fully automated spectrophotometric method based on flow-batch analysis has been developed for the determination of clenbuterol including an on-line solid phase extraction using a molecularly imprinted polymer (MIP) as the sorbent. The molecularly imprinted solid phase extraction (MISPE) procedure allowed analyte extraction from complex matrices at low concentration levels and with high selectivity towards the analyte. The MISPE procedure was performed using a commercial MIP cartridge that was introduced into a guard column holder and integrated in the analyzer system. Optimized parameters included the volume of the sample, the type and volume of the conditioning and washing solutions, and the type and volume of the eluent. Quantification of clenbuterol was carried out by spectrophotometry after in-system post-elution analyte derivatization based on azo-coupling using N- (1-Naphthyl) ethylenediamine as the coupling agent to yield a red-colored compound with maximum absorbance at 500nm. Both the chromogenic reaction and spectrophotometric detection were performed in a lab-made flow-batch mixing chamber that replaced the cuvette holder of the spectrophotometer. The calibration curve was linear in the 0.075-0.500mgL-1 range with a correlation coefficient of 0.998. The precision of the proposed method was evaluated in terms of the relative standard deviation obtaining 1.1% and 3.0% for intra-day precision and inter-day precision, respectively. The detection limit was 0.021mgL 1 and the sample throughput for the entire process was 3.4h-1. The proposed method was applied for the determination of CLB in human urine and milk substitute samples obtaining recoveries values within a range of 94.0-100.0%. PMID- 29136920 TI - Forensic utility of a nitrogen and oxygen isotope ratio time series of ammonium nitrate and its isolated ions. AB - Ammonium nitrate (AN) based fertilizers are inexpensive and easily obtained, characteristics that often lead to their use in homemade explosive devices. The stable nitrogen and oxygen isotope ratios (15N/14N and 18O/16O, expressed as delta15N and delta18O) of AN have the potential to aid in forensic investigations by providing supplemental properties for sample-to-sample comparison in materials which are otherwise chemically identical. The forensic utility of stable isotope analyses depends on demonstrated variation between different sources and minimal variation within a source. To test the variability within a single manufacturer (here considered a source), a total of 26 samples representing two production time periods and two product lines were analyzed for bulk delta15N and delta18O. Additionally, because AN is known to have a modest isotopic range, a potassium nitrate precipitation method was developed to separate the component ions (NO3- and NH4+) for individual delta15N analysis and increased discriminatory power. The average delta15N and delta18O of bulk AN (- 0.100/00 and + 22.80/00, respectively) is similar to the isotopic signature of atmospheric N2 and O2, the starting reactants in AN production. The bulk delta15N, delta18O, and NO3- delta15N show average values from both product lines that differ by 1.50/00, 2.00/00, and 2.60/00, respectively, between the production periods of June and November 2015. Conversely, the NH4+ delta15N remained relatively consistent over time. Furthermore, whereas samples in the two product lines produced on the same day in June are isotopically similar, there are isotopic differences between samples in the two product lines manufactured within 6h of each other in November. The observed variability could be useful in comparing AN from two or more bombs, or a bomb and a stash of AN in a suspect's possession, but the observed lot-to-lot differences within one manufacturer could complicate attribution efforts. In contrast, the NH4+ delta15N values, which appear to be the most consistent over time within this factory, need to be further explored as a potentially reliable signal. PMID- 29136921 TI - Voltammetric detection of antimony in natural water on cathodically pretreated microcrystalline boron doped diamond electrode: A possibility how to eliminate interference of arsenic without surface modification. AB - Very simple and fast electroanalytical method for the detection Sb(III) on chemically unmodified boron-doped diamond electrode (BDDE) has been developed. Voltammetric behavior of antimony was investigated in various acidic supporting electrolytes and the most suitable medium for the determination of Sb(III) on bare BDDE has been 6molL-1 HClO4 solution. The analytical performance was studied with differential pulse anodic stripping voltammetry (DPASV) with optimized conditions (deposition potential -1V vs. Ag/ AgCl and deposition time 240s). An analysis of possible effects due to the presence of other metal ions (especially As(III)) in the solution was eliminated using NaH2PO4 as supporting electrolyte with addition EDTA as selective complexing agent for Sb(III). Speciation of antimony was also investigated. The detection limit of this analytical strategy achieved value of 1.08 * 10-7molL-1. The proposed method was validated and applied for natural water from former antimony mines as real samples. PMID- 29136922 TI - Immunosensing system for rapid multiplex detection of mastitis-causing pathogens in milk. AB - Mastitis, an inflammation of the mammary gland and udder tissue, is the major endemic disease of dairy cattle. In addition to causing health problems to the animals, mastitis leads to the reduction of milk production and quality, representing a significant economic burden for farmers. To enable timely treatment of infected animals with pathogen-specific antibiotics, the development of automated analytical methods for rapid on-site identification and quantification of mastitis-causing pathogens in milk is particularly important. An immunosensing system for multiplex detection of the two most common mastitis causing pathogens Staphylococcus aureus and Escherichia coli is proposed in the present study. This immunosensor combines Bead Injection Analysis (BIA), attachment of pathogens onto renewable micro-column, biorecognition of bound pathogens by specific antibodies, conjugated with different fluorescence markers and the measurement of fluorescence signals. The analysis takes 20min and exhibits detection limits of < 50 CFU mL-1 for E. coli and 100 CFU mL-1 for S. aureus in milk. The applicability of the immunosensor was demonstrated by analyzing milk samples from cows, who were suffering from acute clinical mastitis. PMID- 29136923 TI - A High Sensitivity Biosensor to detect the presence of perfluorinated compounds in environment. AB - A novel surface plasmon resonance (SPR) optical fiber biosensor, able to bind perfluorooctanoate and perfluorooctanesulfonate compounds, is presented. In the first step, an ad hoc antibody compound has been designed, produced and tested by ELISA, then, in the second step, the gold surface of a plastic optical fiber sensor has been derivatizated and functionalized with this new bio-receptor, able to bind target analytes with high affinity and selectivity. The experimental data have shown that the developed SPR optical fiber biosensor makes it possible to detect these compounds. One advantage of this approach stems from the possibility to monitor the perfluorinated compounds in the environment exploiting the remote sensing capability offered by the optical fibers. The measurements were performed in laboratory, also exploiting matrices mimicking the real environment. The limit of detection of the assay was 0.21ppb, a value that is lower than the maximum residue limit fixed by the European Union regulations. PMID- 29136924 TI - Preparation of GO-COOH/AuNPs/ZnAPTPP nanocomposites based on the pi-pi conjugation: Efficient interface for low-potential photoelectrochemical sensing of 4-nitrophenol. AB - The GO-COOH/AuNPs/ZnAPTPP nanocomposites were constructed using zinc monoamino porphyrin (ZnAPTPP) through pi-pi conjugation with carboxylated graphene oxide (GO-COOH) loaded with Au nanoparticles (AuNPs). Prepared materials were characterized by 1H NMR spectra, UV-vis absorption spectroscopy and electrochemical impedance spectroscopy. ITO electrode surface was modified with the prepared nanocomposites showed a good photocurrent response when the bias potential, -0.1V was applied. Nanocomposites modified ITO electrode exhibited good photo-response to the 4-nitrophenol (4-NP). ZnAPTPP were excited from HOMO to LUMO under light irradiation, the photoexcited electrons injected into the conduction band of GO-COOH, and then transferred to AuNPs further to the ITO. The presence of GO-COOH and AuNPs improved the separation of photogenerated charges due to their synergetic effect and excellent conductivity. Externally added 4-NP scavenges the photogenerated holes i.e. it acts as a sacrificial electron donor thereby it enhances the photocurrent of the system. Based on this interaction, a novel method for photoelectrochemical detection of 4-NP was developed with a linear range from 0.1 to 15nmol/L (r = 0.996) and detection limit of 0.04nmol/L (S/N = 3). Proposed method is simple and sensitive and this was successfully applied for the quantification 4-NP in river water sample matrices. PMID- 29136925 TI - Piezoelectric biosensor for the determination of Tumor Necrosis Factor Alpha. AB - Tumor Necrosis Factor Alpha (TNFalpha) is an important marker of inflammatory processes in human body. In the current healthcare, determination of TNFalpha blood or plasma level is done by Enzyme Linked Immuno-Sorbent Assay (ELISA) as a primary choice method. Piezoelectric immunosensors are analytical platform recording affinity interactions on their surface. It is inferred that the immunosensors would be a functional alternative to the ELISA. In this study, antibody against TNFalpha was immobilized on Quartz Crystal Microbalance (QCM) sensor and the same was made on magnetic particles. Human TNFalpha was measured in a way of interaction with QCM surface and then the particles were applied. The assay exerted sufficient limit of detection equal to 1.62pg/ml and it also fully correlated with standard ELISA tests. No interference by interleukin 6 or albumin was observed. Long term stability of the immunosensors lasting for at least three months was found. The immunosensors appears to be readily for practical performance and it would be an alternative to the standard ELISA especially when diagnoses made in field, homecare conditions or conditions of small hospitals as an emergency test. PMID- 29136926 TI - Simple G-quadruplex-based 2-aminopurine fluorescence probe for highly sensitive and amplified detection of microRNA-21. AB - Based on 2-aminopurine (2-AP) probe in conjunction with a G-quadruplex structure and signal amplification technique, a simple and highly sensitive fluorescence sensor for detecting microRNA (miRNA) is developed for high signal-to-background ratio and wide linear range. The proposed sensor contains two hairpins DNA: H1 and H2. H1 is labeled by 2-AP incorporated into a G-rich sequence. Upon the addition of a target miRNA, H1 is unfolded and forms DNA/RNA complexes that contain a G-quadruplex, thereby significantly enhancing 2-AP fluorescence due to the protection provided by the G-quadruplex. Subsequently, H2 can displace the miRNA from the DNA/RNA complexes and induce signal amplification, resulting in further enhanced fluorescence intensity. Hence, the sensor is highly sensitive and its low limit of detection (L.O.D.) can reach as low as 1.48pM. Furthermore, the proposed sensor is used to detect overexpressed miRNA-21 from human breast cancer cell lysate. The result demonstrates the potential of the proposed sensor to monitor different miRNA biomarkers for the early diagnosis of various cancers. PMID- 29136927 TI - Enantioselective determination of metconazole in multi matrices by high performance liquid chromatography. AB - A reliable and effective HPLC analytical method has been developed to stereoselectively quantify metconazole in soil and flour matrices. Effects of polysaccharide chiral stationary phase, type and content of alcoholic modifier on separation of racemic metconazole have been discussed in detail. Resolution and quantitative determination of metconazole stereoisomers were performed by using an Enantiopak OD column, with the n-hexane-ethanol mixture (97:3, v/v) at the flow rate of 1.0mL/min. Then, extraction and cleanup procedures followed by the modified QuEChERS (quick, easy, cheap, effective, rugged and safe) method were used for metconazole racemate in soil and flour matrices. The residual analysis method was validated. Good linearity (R2 >= 0.9997) and recoveries (94.98 104.89%, RSD <= 2.0%) for four metconazole stereoisomers were obtained. In brief, this proposed method showed good accuracy and precision, which might be applied in enantioselective determination, residual quantitative analysis, and degradation of metconazole in food and environmental matrices. PMID- 29136928 TI - Prediction of 2-EHN content in diesel/biodiesel blends using FTIR and chemometrics. AB - Quantification models based on the processing of FTIR spectra by partial least squares regression (PLS) were created in order to develop a method for the determination of 2-ethylhexyl nitrate (2-EHN) in diesel fuels. The set of standards was prepared using 2-EHN, biodiesel (FAME) and various mineral diesel fuels (2-EHN free). The standards were prepared in the concentration range of 2 EHN of 0-2436mgkg-1. The set of the standards was divided into the calibration, validation and test sets. While the calibration set was used to build the model, validation set was used in order to optimize the model parameters. The test set of the standards was used to assess the predictive ability and repeatability of the model. Several hundreds of various models were developed and compared in order to find a suitable combination of the preprocessing methods and number of latent variables. The most promising model was developed using mean centered spectra in the form of their first derivative and smoothed using Gap-Segment derivative. The model showed quite good predictive ability and repeatability. PMID- 29136929 TI - Ultrasensitive chemiluminescent biosensor for the detection of cholesterol based on synergetic peroxidase-like activity of MoS2 and graphene quantum dots. AB - Developing a novel non-enzyme mimetic in biosensors is of great significance. Here, a synergetic peroxidase-like activity was disclosed for mixed MoS2 quantum dots (MoS2 QDs) and graphene quantum dots (GQDs). The high catalytic effect of this mixture was studied on the chemiluminescence system. It was observed that the simultaneous presence of MoS2 QDs and GQDs had a powerful enhancing effect on the chemiluminescence (CL) emission of rhodamine B (RB)-H2O2 reaction. MoS2 QDs and GQDs mixture (prepared with a ratio of 3:2) showed a superior catalytic activity when compared to each of the constituents. A linear relationship was acquired between the CL emission intensity and H2O2 concentration in the range of 1.5-460nmolL-1. On the other hand, since the enzymatic oxidation of cholesterol leads to the production of H2O2; the offered CL system was examined to detect cholesterol after its oxidation by cholesterol oxidase (ChOx) enzyme. Herein, a further improvement was achieved by MoS2 nanosheets. The MoS2 nanosheets increased the performance of ChOx in cholesterol oxidation process. The obtained results confirmed a highly selective and sensitive determination of cholesterol concentration in a linear dynamic range of 0.08-300umolL-1, with a detection limit (3S) of 35nmolL-1. The developed method was successfully applied for the detection of cholesterol level in human serum samples. PMID- 29136930 TI - Insight into the effect of organic and inorganic draw solutes on the flux stability and sludge characteristics in the osmotic membrane bioreactor. AB - In this study, chloride based (CaCl2 and MgCl2) and acetate based (NaOAc and MgOAc) salts in comparison with NaCl were investigated as draw solutions (DS) to evaluate their viability in the osmotic membrane bioreactor (OMBR). Membrane distillation was coupled with an OMBR setup to develop a hybrid OMBR-MD system, for the production of clean water and DS recovery. Results demonstrate that organic DS were able to mitigate the salinity buildup in the bioreactor as compared to inorganic salts. Prolonged filtration runs were observed with MgCl2 and MgOAc in contrast with other draw solutes at the same molar concentration. Significant membrane fouling was observed with NaOAc while rapid flux decline due to increased salinity build-up was witnessed with NaCl and CaCl2. Improved characteristics of mixed liquor in terms of sludge filterability, particle size, and biomass growth along with the degradation of soluble microbial products (SMP) were found with organic DS. PMID- 29136931 TI - Understanding regulation in substrate dependent modulation of growth and production of alcohols in Clostridium sporogenes NCIM 2918 through metabolic network reconstruction and flux balance analysis. AB - Flux Balance Analysis was performed for Clostridium sporogenes NCIM 2918 grown on sole glucose and glycerol or glucose-glycerol combinations at varied concentrations. During acidogenesis, glucose and glucose-glycerol combinations favored improved growth and butyric acid production. Glycerol fermentation was however marked by reduced growth and predominant ethanol synthesis. Further, with increase of glycerol fraction in glucose-glycerol blend, flux towards ethanol synthesis linearly increased with simultaneous decrease in butanol flux. Elevated ATP demand due to improved growth was satisfied by upregulated carbon flux towards butyric acid synthesis during both glucose and dual substrate fermentations. Possible repression of pyruvate carboxylase by glycerol resulting in downturn of carbon uptake flux towards TCA cycle through anaplerotic reaction may be responsible for reduced growth in glycerol fermentation. Ammonium acetate mediated induction of acetic acid utilization, during acidogenesis, led to excess acetyl-CoA generation and its subsequent metabolism to lesser reduced products, butyric acid or ethanol. PMID- 29136932 TI - Cell immobilization on 3D-printed matrices: A model study on propionic acid fermentation. AB - This study uses three-dimensional (3D) printing technology as a tool for designing carriers for immobilization of microbial cells for bioprocesses. Production of propionic acid from glucose by immobilized Propionibacterium sp. cells was studied as a model system. For cell adsorption, the 3D-printed nylon beads were added to the culture medium during 3 rounds of cell cultivation. Cell adsorption and fermentation kinetics were similar irrespective of the bead size and lattice structure. The cells bound to 15 mm beads exhibited reduced fermentation time as compared to free cell fermentations; maximum productivity and propionic acid titer of 0.46 g/L h and 25.8 g/L, respectively, were obtained. Treatment of the beads with polyethyleneimine improved cell-matrix binding, but lowered the productivity perhaps due to inhibitory effect of the polycation. Scanning electron micrographs revealed the cells to be located in crevices of the beads, but were more uniformly distributed on PEI-coated carrier indicating charge-charge interaction. PMID- 29136933 TI - Alkaline solubilization of excess mixed sludge and the recovery of released phosphorus as magnesium ammonium phosphate. AB - The alkaline solubilization of excess mixed sludge was investigated and subsequently the released phosphorus was recovered as magnesium ammonium phosphate (MAP). Considerable and rapid release of glycogen and protein was encountered after alkaline addition into the sludge. Only 45.0% of sludge cells were destructed after 240 min treatment in R1 while the corresponding ratio was 96.1% in R3 according to the release of DNA. Non-apatite inorganic phosphorus (NAIP) in the alkaline treated sludge decreased due to the dissolution of Al(OH)3 and AlPO4, which was the dominant reason for phosphorus release. Soluble orthophosphate (SOP) in the supernatant of alkaline treated sludge could be recovered quickly with the recovery efficiency of 84.6% within 5 min and about 53 55% of P participated in MAP reaction, producing large amounts of acicular crystals. PMID- 29136934 TI - Differential responses of the green microalga Chlorella zofingiensis to the starvation of various nutrients for oil and astaxanthin production. AB - Chlorella zofingiensis has been proposed as a potential producer of lipids and the high-value carotenoid astaxanthin. In this study, the responses of photoautotrophic C. zofingiensis with respect to growth, lipid profiles and astaxanthin accumulation were investigated upon the starvation of N (NS), P (PS) and S (SS). NS and SS stimulated triacylglycerol (TAG) accumulation, which reached 27% and 21% of dry weight (DW), respectively. Stresses also stimulated astaxanthin accumulation greatly, reaching 3.9 mg/g DW by NS. SS led to the highest TAG productivity (52.4 mg L-1 d-1) while NS gave rise to the highest astaxanthin productivity (0.624 mg L-1 d-1). In combination with transcriptional analysis, a working model for stress-associated TAG and astaxanthin biosynthesis was proposed. Taken together, these detailed data shed light on the elucidation of differential responses to nutrient stresses and may provide insights into future engineering of this promising alga for improving TAG and astaxanthin production. PMID- 29136935 TI - Understanding azo dye anaerobic bio-decolorization with artificial redox mediator supplement: Considering the methane production. AB - Artificial redox mediators (ARM) have been proven to accelerate the azo dye anaerobic bio-reduction (ADAB) but the mechanisms involved are still unclear. Previous studies do seldom focus on the production of methane during the ADAB, particularly if supplemented with ARM. Our studies revealed that the supplement of ARM could significantly accelerate the decolorization rate, recover the inhibited methanogenesis and decrease extracellular polymeric substance secretion in an ADAB system. Supplement of an ARM only enhanced the pre-existing metabolic pathway of the ADAB system. Significant differences in metabolic pathway and microbial community were found between traditional methanogenic system and ADAB system by high-throughput sequencing technique. The ADAB system performed an "over-requirement for electron donor" phenomenon and the requirement amount can be altered by regulating ARM dosage. Response surface methodology was then successfully employed to optimize the dosage of ARM and possible additional electron donor required for ADAB under different conditions. PMID- 29136936 TI - Analysis of a bio-electrochemical reactor containing carbon fiber textiles for the anaerobic digestion of tomato plant residues. AB - A bio-electrochemical system packed with supporting material can promote anaerobic digestion for several types of organic waste. To expand the target organic matters of a BES, tomato plant residues (TPRs), generated year-round as agricultural and cellulosic waste, were treated using three methanogenic reactors: a continuous stirred tank reactor (CSTR), a carbon fiber textile (CFT) reactor, and a bio-electrochemical reactor (BER) including CFT with electrochemical regulation (BER + CFT). CFT had positive effects on methane fermentation and methanogen abundance. The microbial population stimulated by electrochemical regulation, including hydrogenotrophic methanogens, cellulose degrading bacteria, and acetate-degrading bacteria, suppressed acetate accumulation, as evidenced by the low acetate concentration in the suspended fraction in the BER + CFT. These results indicated that the microbial community in the BER + CFT facilitated the efficient decomposition of TPR and its intermediates such as acetate to methane. PMID- 29136937 TI - Deep eutectic solvent and inorganic salt pretreatment of lignocellulosic biomass for improving xylose recovery. AB - Deep eutectic solvents (DESs) have received considerable attention in recent years due to their low cost, low toxicity, and biodegradable properties. In this study, a sequential pretreatment comprising of a DES (choline chloride:urea in a ratio of 1:2) and divalent inorganic salt (CuCl2) was evaluated, with the aim of recovering xylose from oil palm fronds (OPF). At a solid-to-liquid ratio of 1:10 (w/v), DES alone was ineffective in promoting xylose extraction from OPF. However, a combination of DES (120 degrees C, 4h) and 0.4mol/L of CuCl2 (120 degrees C, 30min) resulted in a pretreatment hydrolysate containing 14.76g/L of xylose, remarkably yielding 25% more xylose than the CuCl2-only pretreatment (11.87g/L). Characterization studies such as FE-SEM, BET, XRD, and FTIR confirmed the delignification of OPF when DES was implemented. Thus, the use of this integrated pretreatment system enabled xylose recoveries which were comparable with other traditional pretreatments. PMID- 29136938 TI - Temperature-phased anaerobic digestion of food waste: A comparison with single stage digestions based on performance and energy balance. AB - The temperature-phased anaerobic digestion (TPAD) of food waste was studied for the purpose of comparing with single-stage mesophilic and thermophilic anaerobic digestion. The biogas and methane yields in the TPAD during the steady period were 0.759 +/- 0.115 L/g added VS and 0.454 +/- 0.201 L/g added VS, which were lower than those in the two single-stage anaerobic digestion. The improper sludge retention time may be the reason for the lower biogas and methane production in TPAD. The removal of volatile solids in the TPAD was 78.55 +/- 4.59% and the lowest among the three anaerobic digestion processes. The reaction ratios of the four anaerobic digestion steps in the TPAD were all lower than those in the two single-stage anaerobic digestion. The energy conversion efficiency of the degraded substrate in the TPAD was similar with those in single-stage mesophilic and thermophilic anaerobic digestion systems. PMID- 29136939 TI - Process simulation and economic assessment of hydrothermal pretreatment and enzymatic hydrolysis of multi-feedstock lignocellulose - Separate vs combined processing. AB - Biorefinery based on multi-feedstock lignocellulose can be viable where a sustainable supply of a single substrate is limited, for example in arid regions. Processing of mixed feedstocks has been studied in lab scale, however, its economics are less studied. In this study, an economic comparison was made between separate and combined (mixed) processing approaches for multi-feedstock lignocellulose for the production of monomeric sugars. This modular approach of focusing on sugar platform makes the results applicable for many applications using the sugars as feedstock. Feedstock considered in this study were the green and woody lignocellulose residues: Bermuda grass, Jasmine hedges, and date palm fronds. Results showed that, at an identical total feed rate, combined processing was more advantageous as compared to separate processing. A further sensitivity analysis on mixed combined processing showed that the cellulase enzyme price and feed price are the two major factors affecting the production cost. PMID- 29136940 TI - Accelerated removal of high concentration p-chloronitrobenzene using bioelectrocatalysis process and its microbial communities analysis. AB - p-Chloronitrobenzene (p-CNB) is a persistent refractory and toxic pollutant with a concentration up to 200 mg/L in industrial wastewater. Here, a super-fast removal rate was found at 0.2-0.8 V of external voltage over a p-CNB concentration of 40-120 mg/L when a bioelectrochemical technology is used comparing to the natural biodegradation and electrochemical methods. The reduction kinetics (k) was fitted well according to pseudo-first order model with respect to the different initial concentration, indicating a 1.12-fold decrease from 1.80 to 0.85 h-1 within the experimental range. Meanwhile, the highest k was provided at 0.5 V with the characteristic of energy saving. It was revealed that the functional bacterial (Propionimicrobium, Desulfovibrio, Halanaerobium, Desulfobacterales) was selectively enriched under electro-stimulation, which possibly processed Cl-substituted nitro-aromatics reduction. The possible degradation pathway was also proposed. This work provides the beneficial choice on the rapid treatment of high-concentration p-CNB wastewater. PMID- 29136941 TI - Enhanced granulation and methane recovery at low load by downflow sludge circulation in anaerobic treatment of domestic wastewater. AB - The effects of downflow sludge circulation on granulation and methane recovery at low load were investigated for domestic wastewater treatment in a modified anaerobic reactor. Compared with conventional upflow anaerobic reactors, enhanced granulation with shortened start-up time was achieved and stable granules were successfully cultivated only after 58 days operations. The introduction of downflow sludge circulation resulted in reverse wastewater-sludge flow and uniform sludge distribution in the reaction zone, which contributed to enhanced wastewater-sludge mass transfer and satisfactory performance with a high soluble chemical oxygen demand (SCOD) removal efficiency of 94.8% at hydraulic retention time (HRT) 6 h. Besides, enhanced liquid-to-gas mass transfer caused a lower dissolved CH4 saturation index of 1.11 and a higher CH4 recovery efficiency of 79.48% at HRT 6 h. High throughput sequencing revealed a distinct shift of microbial community during start-up period from Proteobacteria to Bacteroidetes and Chloroflexi in the existence of downflow sludge circulation. PMID- 29136942 TI - Targeted poly(3-hydroxybutyrate-co-3-hydroxyvalerate) bioplastic production from carbon dioxide. AB - A microbial production process was developed to convert CO2 and valeric acid into tailored poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) bioplastics. The aim was to understand microbial PHBV production in mixotrophic conditions and to control the monomer distribution in the polymer. Continuous sparging of CO2 with pulse and pH-stat feeding of valeric acid were evaluated to produce PHBV copolyesters with predefined properties. The desired random monomer distribution was obtained by limiting the valeric acid concentration (below 1 gL-1). 1H-NMR, 13C-NMR and chromatographic analysis of the PHBV copolymer confirmed both the monomer distribution and the 3-hydroxyvalerate (3HV) fraction in the produced PHBV. A physical-based model was developed for mixotrophic PHBV production, which was calibrated and validated with independent experimental datasets. To produce PHBV with a predefined 3HV fraction, an operating diagram was constructed. This tool was able to predict the 3HV fraction with a very good accuracy (2% deviation). PMID- 29136943 TI - ADAM12 induces EMT and promotes cell migration, invasion and proliferation in pituitary adenomas via EGFR/ERK signaling pathway. AB - Pituitary adenomas are the second most common primary brain tumor with invasive properties. We have previously identified that ADAM12 (a disintegrin and metalloprotease 12) overexpression is associated with the tumor invasion of pituitary adenomas, however, the underlying mechanism remains unknown. This study aims to elucidate the mechanistic role of ADAM12 in regulating the tumor invasion of pituitary adenomas. In this study, we first showed that ADAM12 expression was concomitant with epithelial to mesenchymal transition (EMT) process in clinical specimens of human pituitary adenomas. Further functional studies showed that ADAM12 silencing in pituitary adenoma cells significantly inhibited the EMT process and suppressed cell migration, invasion and proliferation without influencing cell apoptosis. Mechanistically, ADAM12 silencing significantly reduced ectodomain shedding of epidermal growth factor receptor (EGFR) ligands and attenuated the EGFR/ERK signaling pathway. Blocking of EGFR signaling resulted in EMT suppression similar to silencing of ADAM12 and reduced cell migration, invasion and proliferation, while EGFR activation abolished the suppression on EMT, proliferation, migration and invasion induced by ADAM12 silencing. Moreover, ADAM12 silencing significantly impaired tumorigenesis and EMT of pituitary adenoma cells in vivo. Taken together, our study provide crucial evidence that ADAM12 induces EMT and promotes cell migration, invasion and proliferation in pituitary adenomas via EGFR/ERK signaling pathway. These finds strongly suggest that ADAM12 might serve as a novel valuable therapeutic target for pituitary adenomas. PMID- 29136944 TI - MIAT promotes proliferation and hinders apoptosis by modulating miR-181b/STAT3 axis in ox-LDL-induced atherosclerosis cell models. AB - BACKGROUND: Plenty of lncRNAs and microRNAs have been identified to be critical mediators in the progression of atherosclerosis (AS). Myocardial infarction associated transcript (MIAT) were aberrantly high expressed and closely associated with the pathogenesis of AS. However, its molecular mechanism has not been well characterized. METHODS: The expression patterns of MIAT and microRNA 181b (miR-181b) in clinical samples and cells were measured by RT-qPCR assays. Luciferase reporter assay and RIP assays were used to manifest the potential interaction between MIAT, miR-181b and signal transducer and activator of transcription 3 (STAT3). Cell Counting Kit-8 (CCK-8), Propidium Iodide (PI) staining, Terminal dexynucleotidyl transferase(TdT)-mediated dUTP nick end labeling (TUNEL) and western blot assays were carried out to detect cell proliferation, cell cycle distribution, apoptosis, and STAT3 protein level, respectively. RESULTS: MIAT expression was up-regulated and miR-181b expression was down-regulated in AS patients serum and oxidized low-density lipoprotein (ox LDL) induced AS cells model. MIAT facilitated cell proliferation, accelerated cell cycle progression and inhibited apoptosis in ox-LDL-induced AS cell lines, while this effect was partly reversed by miR-181b overexpression. Moreover, MIAT enhanced STAT3 expression through sequestering miR-181b as a molecular sponge. Furthermore, MiR-181b hindered cell growth, induced cell cycle arrest and promoted apoptosis by directly targeting STAT3. CONCLUSION: MIAT performed as an induction factor of AS by regulating miR-181b/STAT3 axis in ox-LDL-induced AS cell lines, offering a new insight into the potential application of MIAT in AS treatment. PMID- 29136945 TI - Mitochondria protection as a mechanism underlying the hepatoprotective effects of glycine in cholestatic mice. AB - Cholestasis is the stoppage of bile flow which could lead to serious clinical complications if not managed. Cytotoxic bile acids are involved in the pathogenesis of liver injury during cholestasis. There are no promising pharmacological interventions against cholestasis and its associated complications. This study examined the impact of glycine supplementation on liver mitochondria as a major target of bile acids-induced toxicity during cholestasis. Mice underwent BDL operation and received glycine (0.25% and 1% w:v in drinking water). Blood and liver samples were collected at scheduled time intervals (3, 7, and 14 days after BDL surgery). Plasma biomarkers of liver injury, along with markers of oxidative stress in the liver tissue were evaluated. Furthermore, liver mitochondria were isolated, and several mitochondrial indices were assessed. BDL-induced cholestasis was evident in mice as a significant elevation in plasma biomarkers of liver injury. Markers of oxidative stress were significantly increased in the liver of BDL animals. Liver injury was histopathologically evident by tissue necrosis, bile duct proliferation, hydropic changes, inflammation, and fibrosis. Furthermore, high level of reactive oxygen species, lipid peroxidation, depleted glutathione reservoirs, and impaired tissue antioxidant capacity were also detected in the liver of cholestatic mice. An assessment of liver mitochondrial function in BDL animals revealed an inhibition of mitochondrial dehydrogenases activity, collapse of mitochondrial membrane potential, mitochondrial swelling, and increase of reactive oxygen species (ROS), and lipid peroxidation (LPO). Furthermore, a significant decrease in mitochondrial ATP was detected in the liver mitochondria isolated from cholestatic animals. Glycine supplementation (0.25% and 1%) decreased mitochondrial swelling, ROS, and LPO. Moreover, glycine treatment improved mitochondrial membrane potential and restored liver mitochondrial ATP. On the other hand, it was found that glycine supplementation attenuated oxidative stress markers in the liver of BDL animals. Moreover, liver histopathological changes and collagen deposition were markedly mitigated by glycine treatment. The mechanisms for the beneficial effects of glycine administration in cholestatic animals might be linked to its ability for preserving cellular redox environment, preventing oxidative stress, and maintaining mitochondrial functionality. PMID- 29136946 TI - Neuroprotective effect of hesperetin and nano-hesperetin on recognition memory impairment and the elevated oxygen stress in rat model of Alzheimer's disease. AB - Alzheimer disease (AD) is a progressive dementia affecting a large proportion of the aging population. There is evidence that brain tissue in patients with AD is exposed to oxidative stress during the course of the disease. Hesperetin (Hst) is a natural flavonoid, which has been reported to exert various biological activities such as antioxidant and anti-inflammatory effect. The present study aimed to investigate the effects of hesperetin and nano-hesperetin on neurobehavioral activity and superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRx) and catalase (CAT) enzymes activity, malondialdehyde (MDA) and glutathione (GSH) levels in hippocampal area of rats in an experimental model of AD. The AD was induced in animals by intracerebroventricular injection of STZ (icv-STZ) unilaterally. Animals were treated with the Hst and nano-Hst (10, 20 mg/kg body weight), then after three successive weeks, recognition memory was examined (passive avoidance test and novel object recognition test) and antioxidant parameters were evaluated. In our study behavioral testes showed improvement on memory retrieval and recognition memory consolidation. Furthermore the Hst and nano-Hst increased the activity of antioxidant enzymes (SOD, glutathione GPx, GRx and CAT) and GSH levels and decreased MDA in the hippocampal area. These results suggested that Hst and nano Hst may inhibit STZ-induced oxidative stress, and that it may possess therapeutic potential for the treatment of AD. PMID- 29136947 TI - The effect of the dipeptidyl peptidase-4 inhibitor sitagliptin on gentamicin nephrotoxicity in mice. AB - This study aimed at investigating the possible ameliorative effects of sitagliptin in mice with gentamicin (GEN) nephrotoxicity. Sitagliptin was given to the animals at an oral dose of 10mgkg-1 per day for 10days, and in some of these mice, GEN was injected intraperitoneally at a dose of 100mgkg-1 per day during the last seven days of the treatment. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically by measuring several indices in plasma, urine and renal cortex homogenates. GEN treatment induced nephrotoxicity as evidenced by significantly (P<0.0001) increasing the plasma concentrations of urea, creatinine, circulatory cytokines, cystatin C, sclerostin, and TNFalpha. Treatment with GEN also significantly elevated urinary N-acetyl-beta-d glucosaminidase (NAG) concentration (P<0.0001). Moreover, GEN caused significant increase in oxidative stress in the kidneys (P<0.0001). Histopathological examination revealed massive tubular injury, necrosis, infiltration of inflammatory cells and intraluminal hyaline casts in mice treated with GEN. Sitagliptin alone did not significantly affect any of the indices measured. However, concomitant treatment with sitagliptin and GEN significantly mitigated most of the nephrotoxic actions of GEN. Pending further studies, sitagliptin may potentially be useful as a nephroprotectant agent. PMID- 29136948 TI - Gastroprotective effect and mode of action of methanol extract of Sphenodesme involucrata var. paniculata (C.B. Clarke) Munir (Lamiaceae) leaves on experimental gastric ulcer models. AB - Sphenodesme involucrata var. paniculata (C. B. Clarke) Munir, endemic to South Asia, is used by tribal for alleviation from abdominal disorders, inflammation and body pain. However, the gastroprotective properties of this species have not yet been studied. The leaves of S. involucrata were extracted by Soxhlet extraction using different solvents successively and the extracts were analyzed for antioxidant and anti-Helicobacter pylori activities using different in vitro assays. The chemical composition of methanol extract of S. involucrata (MESi) was analysed by gas chromatography-mass spectrometry (GC-MS). The gastroprotective action of the MESi at the doses of 100, 200, and 400 mg/kg were evaluated in absolute ethanol, acidified ethanol (EtOH/HCl) and nonsteroidal anti-inflammatory drug (NSAID) induced rat experimental models. To elucidate the mode of antiulcerogenic action, the antisecretory parameters (gastric juice volume, pH, and total acidity) and the catalase (CAT) and superoxide dismutase (SOD) enzymes activity and malondialdehyde (MDA) level were evaluated in gastric ulcer tissue. Also the stomachs of the animals were subjected to histological assessment. MESi presented a high antioxidant activity in several oxidants in vitro systems (DPPH*, ABTS*+ and FRAP) and it demonstrated a good spectrum of inhibitory activity against H. pylori growth (MIC, 100 MUg/mL). GC-MS analysis of MESi indicated the presence of twenty one compounds, among them phenol (21.84%), hexadecanoic acid (15.96%), (9E, 12E)-9, 12-octadecadienoyl chloride (11.15%) and palmitic acid-beta-monoglyceride (8.80%) were found higher. MESi (100, 200 and 400 mg/kg, p.o.) produced significant reduction (p < 0.01) of lesion area in the ethanol, acidified ethanol and indomethacin-induced ulcer models. In the pylorus ligation induced ulcer model, the treatment with MESi significantly altered the gastric secretion by decreasing total gastric juice volume and gastric acidity as well as by increasing the gastric pH. MESi pre-treatment significantly (p < 0.05) restored the depleted activity of SOD, CAT enzymes and reduced MDA levels in the gastric tissue as well as the histological analysis of the stomachs of the animals showed that the MESi also prevents local action of offensive factors. Collectively, the present study results suggest that the methanol extract of S. involucrata leaves demonstrates gastroprotective action, supporting the folkloric usage of the plant to treat gastro-intestinal disturbances. PMID- 29136949 TI - Minocycline improves cardiac function after myocardial infarction in rats by inhibiting activation of PARP-1. AB - To investigate whether Minocycline can protect myocardial cells after myocardial infarction and improve myocardial remodeling through inhibiting PARP-1 activity, thus improving cardiac function. 50 male Wistar rats aged 4 months were used to establish the myocardial infarction model. The experimental rats underwent the echocardiography at 3d, 14d and 28d after operation. After 28days, the rats were executed and the myocardial tissues in the infarct-related zone were treated with immumohistochemical staining and molecular biology detection. Our study found Minocycline could improve the cardiac function of rats after myocardial infarction. TUNEL results showed that Minocycline could reduce the apoptosis of myocardial cells after myocardial infarction. Western blotting results showed that Minocycline reduced the expressions of apoptotic proteins. Immunohistochemistry and Western blotting showed that Minocycline reduced the expressions of inflammatory factors, NF-kappaB and IL-1beta, etc., in myocardial cells after myocardial infarction. Besides, it was found in further study that Minocycline could inhibit the PARP-1 activity after myocardial ischemic necrosis. In conclusion, Myocardial remodeling occurs after myocardial infarction, affecting the cardiac function. Minocycline can inhibit the activity of apoptosis and inflammatory factors, reduce the apoptosis, alleviate the inflammation and improve the ventricular remodeling through inhibiting PARP-1, thus protecting the cardiac function. PMID- 29136950 TI - A novel sesquiterpene glycoside from Loquat leaf alleviates oleic acid-induced steatosis and oxidative stress in HepG2 cells. AB - Loquat (Eriobotrya japonica) leaf has displayed beneficial effect on metabolic syndrome. In our previously study, total sesquiterpene glycosides (TSG) isolated from Loquat leaf exhibited therapeutic effect on Non-alcoholic fatty liver disease (NAFLD) in vivo, but the accurate active compound remains unknown. Sesquiterpene glycoside 1 (SG1) is a novel compound, which is exclusively isolated from Loquat leaf, but its biological activity has been rarely reported. The present study was designed to evaluate the pharmacological effect of SG1, the main component of TSG, in oleic acid (OA)-induced HepG2 cell model of NAFLD with its related mechanisms of action. In this study, both SG1 and TSG were found to significantly reduce the lipid deposition in the cell model. They could also decrease total cholesterol (TC), triglyceride (TG) and intracellular free fatty acid (FFA) contents. Compared with OA-treated cells, the superoxide dismutase (SOD) level increased, and the malondialdehyde (MDA) and 4-hydroxynonenal levels respectively decreased after the administration of SG1 or TSG. The high dose of SG1 (140 MUg/mL) displayed a similar therapeutic effect as TSG at 200 MUg/mL. Both SG1 and TSG were found to suppress the expression of cytochrome P450 2E1 (CYP2E1) and the phosphorylation of c-jun terminal kinase (JNK) and its downstream target c-Jun in OA-treated cell. These results demonstrate again that TSG are probably the main responsible chemical profiles of Loquat leaf for the treatment of NAFLD, for which it can effectively improve OA-induced steatosis and reduce oxidative stress, probably by downregulating of CYP2E1 expression and JNK/c-Jun phosphorylation, while SG1 may be the principle compound. PMID- 29136951 TI - Chemopreventive effect of Myricetin, a natural occurring compound, on colonic chronic inflammation and inflammation-driven tumorigenesis in mice. AB - Myricetin is a flavonoids compound extracted from edible myrica rubra. We aimed to evaluate the efficacy of Myricetin on colonic chronic inflammation and inflammation-driven tumorigenesis in mice. Myricetin was administrated by gavage for 4 consecutive weeks. Mice were sacrificed and the number of colonic polyps was counted. Myricetin significantly inhibited AOM/DSS-induced colitis and colorectal tumorigenesis. Myricetin prevented the incidence of colorectal tumorigenesis and reduced the size of colorectal polyps. Histopathologic analysis showed that Myricetin could attenuate the degree of colonic inflammation and colorectal tumorigenesis. Further analysis showed that Myricetin strongly reduced the levels of inflammatory factors TNF-alpha, IL-1beta, IL-6, NF-kappaB, p-NF kappaB, cyclooxygenase-2 (COX-2), PCNA and Cyclin D1 in the colonic tissues as analyzed by the assays of immunohistochemical staining, Western blotting and Q-RT PCR. Our results demonstrated that Myricetin possesses the biological activities of chemoprevention colonic chronic inflammation and inflammation-driven tumorigenesis. We suggest that Myricetin could be developed as a promising chemopreventive drug for reducing the risk of colorectal cancer. PMID- 29136952 TI - Identification and validation of cetuximab resistance associated long noncoding RNA biomarkers in metastatic colorectal cancer. AB - BACKGROUND: Cetuximab is one of the most widely used epidermal growth factor receptor (EGFR) inhibitors to treat patients with metastatic colorectal cancer (mCRC) harboring wild-type of RAS/RAF status. However, primary and acquired resistance to cetuximab is often found during target therapy. METHODS: To gain insights into the functions of long non-coding RNA (lncRNA) in cetuximab resistance, we used a lncRNA-mining approach to distinguish lncRNA specific probes in Affymetrix HG-U133A 2.0 arrays. Then we performed lncRNA expression profiling in a cetuximab treated mCRC cohort from Gene Expression Ominus (GEO). The potential lncRNAs were further validated in acquired cetuximab resistant cell lines and clinical samples of our hospital. The functions and associated pathways of the prognostic lncRNA were predicted by GO and KEGG analyses. RESULTS: 249 lncRNA-specific probe sets (corresponding to 212 lncRNAs) were represented in Affymetrix HG-U133A 2.0 arrays. We found that 9 lncRNAs were differentially expressed between disease control group (DCG) and non-responders, and 5 of these 9 lncRNAs were significantly related with the progression-free survival (PFS) of the patients. Among those 5 lncRNAs, POU5F1P4 was also down-regulated in acquired cetuximab resistant cells, as well as in cetuximab resistant patients. Downregulation of POU5F1P4 decreased the sensitivity of colorectal cancer cells to cetuximab. CONCLUSION: Our findings indicate the potential roles of lncRNAs in cetuximab resistance, and may provide the useful information for discovery of new biomarkers and therapeutic targets. PMID- 29136954 TI - Vaccaria hypaphorine impairs RANKL-induced osteoclastogenesis by inhibition of ERK, p38, JNK and NF-kappaB pathway and prevents inflammatory bone loss in mice. AB - Osteoclasts are sole bone-resorbing cells which exert a profound effect on skeletal metabolism. The search for medicines that affect the differentiation and function of osteoclasts is crucial in developing therapies for osteoclast-based diseases. Vaccaria hypaphorine, the main active compound of the traditionally used Chinese herb Vaccaria segetalis, has anti-inflammatory activity. The present study demonstrated for the first time that vaccaria hypaphorine could significantly inhibit the receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastic differentiation in vitro and alleviate lipopolysaccharide (LPS)-induced bone loss in vivo. Further study showed that vaccaria hypaphorine decreased osteoclastogenesis in a dose-dependent manner. Furthermore, vaccaria hypaphorine was confirmed to inhibit osteoclasts differentiation at early stage but not at later stage. Pit formation assay and F actin ring staining showed that vaccaria hypaphorine inhibited the bone-resorbing activity of osteoclasts. Mechanistically, vaccaria hypaphorine impaired RANKL induced osteoclastogenesis through reduction of extracellular signal-regulated kinases (ERK), p38, c-Jun N-terminal kinase (JNK) and NF-kappaB p65 phosphorylation. Taken together, our results provided evidences that vaccaria hypaphorine might be considered as potential therapeutic agent for treating osteoclast-based bone loss. PMID- 29136953 TI - Antidiarrheal effects of water-soluble proteins from Plumeria pudica latex in mice. AB - The water-soluble protein fraction obtained from Plumeria pudica (LPPp) latex has previously been demonstrated to have anti-inflammatory and antinociceptive effects. In the present study, LPPp was tested for activity against diarrhea induced by castor oil, prostaglandin E2 (PGE2) or cholera toxin. Different doses of LPPp (10, 20 or 40mg/kg) significantly inhibited the percentage of diarrheal stools (31.18%, 42.97% and 59.70%, respectively) induced by castor oil. This event was followed by significant reduction of both intestinal fluid accumulation (31.42%; LPPp 40mg/kg) and intestinal transit (68.4%; LPPp 40mg/kg). The pretreatment of animals with LPPp (40mg/kg) prevented glutathione and malondialdehyde alterations induced by castor oil. The effects of LPPp against diarrhea induced by castor oil were lost when the fraction was submitted to protein denaturing treatment with heat. LPPp (40mg/kg) also inhibited the average volume of intestinal fluid induced by PGE2 (inhibition of 46.0%). Furthermore, LPPp (40mg/kg) prevented intestinal fluid secretion accumulation (37.7%) and chloride ion concentration (50.2%) induced by cholera toxin. In parallel, colorimetric assays demonstrated that proteinases, chitinases and proteinase inhibitors were found in LPPp. Our data suggest that the antidiarrheal effect of LPPp is due to its protein content and is probably associated with its anti inflammatory properties. PMID- 29136955 TI - Eucommia ulmoides leaf (EUL) extract enhances NO production in ox-LDL-treated human endothelial cells. AB - Eucommia ulmoides leaves (EULs), referred to as Du-zhong, are utilized to lower blood pressure and improve liver and kidney tone, and also have been applied to cardiovascular disease in Korea, China, and Japan. Endothelial dysfunction, which is caused by endothelial nitric oxide synthase (eNOS) uncoupling, is an initial step in atherosclerosis. In this study, we investigated the protective effects of EUL aqueous extract against ox-LDL-induced eNOS uncoupling and its possible mechanisms in human umbilical vein endothelial cells (HUVECs). A EUL component, aucubin, was also applied to ox-LDL-exposed HUVECs. Whereas ox-LDL significantly decreased nitric oxide (NO) levels in HUVECs, EUL extract and aucubin led to significant recovery of NO levels. When treated with ox-LDL in the presence of EUL extracts or aucubin, O2- production was markedly reduced in HUVECs compared to treatment with ox-LDL alone. EUL extract and aucubin also led to recovery of phospho-eNOS Thr495 expression, a critical signaling component in eNOS uncoupling, suggesting that EUL has regulatory effects against eNOS uncoupling and might play preventive/regulatory roles against vascular endothelial dysfunction. PMID- 29136956 TI - Antagonistic Effect of Oxytocin and Tacrolimus Combination on Adipose Tissue - Derived Mesenchymal Stem Cells: Antagonistic effect of oxytocin and tacrolimus. AB - Tacrolimus (FK506) is a chemotherapeutic agent, which uses calcineurin pathway via inhibiting the stimulation of T cells to prevent the formation of immune response in the recipient individual in organ transplants. FK506 is mainly metabolized in the liver by cytochrome P450 enzyme system and is known that it has high toxic effects on different cells. Mesenchymal stem cells (MSCs) have recently gained importance since their potential to be used in cellular therapy and tissue regeneration. In some clinical cases, MSCs are transferred into the patient after the organ transplantations in order to support the treatment. Because of their immunomodulatory actions and assistance to the regeneration, popularity of MSCs have been increasing recently. However, since immunosuppressive agents have a potential cytotoxic and apoptotic effect on MSCs, researches have attempted to use it as a combination with an agent that alleviates these effects. Oxytocin (OT) is primarily acting as a neuromodulator in humans and is a peptide hormone secreted by the pituitary gland of the neurohypophysis. OT has such effects on cells as to confer resistance against oxidative stress on cells and to increase the proliferation and help regeneration. Studies on the active substance of FK506 were aimed to investigate the cytotoxic effects on human adipose tissue derived MSCs. The purpose of this study was to determine the cytotoxic, apoptotic and morphological effects of FK506, an immunosuppressive agent, on adipose tissue - derived MSC (ADMSC) which has the potential to be used for immune suppression. In addition, it was aimed to determine whether the agent could reduce the cytotoxic, apoptotic, and morphological effects on ADMSCs when used in combination with OT. For this purpose, the cytotoxic effects of the FK506 and OT on ADMSCs were determined by time and dose dependent manner by the WST-1 test. Isobologram analysis was evaluated using the WST-1 test according to IC50 values of FK506 and OT. The apoptotic effects of the agents on the ADMSCs were determined by the Annexin V method. Immunofluorescence staining was performed to determine morphological changes. Changes in the levels of oxidative stress markers were measured by colorimetric and flourometric methods using lipid peroxidation, superoxide dismutase activity, catalase activity and glutathione peroxidase assays. The IC50 values of FK506 and OT on ADMSCs were calculated as 17.44MUM and 13.43MUM, respectively.FK506 and OT were found to have antagonistic activity on ADMSCs (CI value of the combination was 1.24). The effects of the agents individually and in combination on the levels of apoptosis and oxidative stress markers have been evaluated. When the results obtained from the study are evaluated, the adipose- tissue derived mesenchymal stem cells used with takrolimus and oxytocin combination have a potential for novel treatment approaches. PMID- 29136957 TI - CXCL6 promotes non-small cell lung cancer cell survival and metastasis via down regulation of miR-515-5p. AB - Chemokine plays an important role in lung cancer and CXCL6 is one of chemokine, however, its effect on miRNAs profile and its roles in non-small cell lung cancer cell (NSCLC) is not elucidated. This study is purposed to explore the influence of CXCL6 on miRNA expression profile and found that CXCL6 could reduce the expression of miR-515-5p in NSCLC cells. MiR-515-5p in NSCLC cells could inhibit NSCLC survival and metastasis. MiR-515-5p acted as a tumor suppressor by targeting CXCL6 in NSCLC cells. These data highlighted a novel molecular interaction between miR-515-5p and CXCL6. MiR-515-5p may constitute a potential therapy target for NSCLC. PMID- 29136958 TI - MiR-182-5p regulates BCL2L12 and BCL2 expression in acute myeloid leukemia as a potential therapeutic target. AB - The importance of microRNAs (miRNAs) are shown during various cancers including acute myeloid leukemia (AML). MiR-182-5p functions as an oncogene or a potential suppressive miRNA in cancers, but its expression and function in AML is unknown. The purpose is to investigate the roles of miR-182-5p in AML in this study. MiR 182-5p was examined in the blood samples of AML and it was found that miR-182-5p expression levels were higher in AML tissues than it in their normal controls, so did in the AML cells. BCL2L12 and BCL2 were predicted as target genes of miR-182 5p and verified using luciferase reporter assay. BCL2L12 and BCL2 mRNA and protein levels were up-regulated in the AML cells with miR-182-5p inhibition. Cellular function of miR-182-5p indicated that miR-182-5p suppression in AML cells could decrease cell proliferation and reverse cisplatin (DDP) resistance via targeting BCL2L12 and BCL2 expression. Inhibition of miR-182-5p promoted AML cell apoptosis by targeting BCL2 or BCL2L12. The study demonstrates that high levels of miR-182-5p in AML promotes cell proliferation and suppresses cell apoptosis by targeting BCL2L12 and BCL2. PMID- 29136959 TI - Alterations of biomechanics in cancer and normal cells induced by doxorubicin. AB - Mechanical properties of biological structures play an important role in regulating cellular activities and are critical for understanding metabolic processes in cancerous cells and the effects of drugs. For some cancers, such as acute myeloid leukaemia, chemotherapy is one of preferential methods. However, due to the lack of selectivity to cancer cells, cytostatic agents cause toxicity to normal tissues. Here, we study the effect of doxorubicin (DOX) on the mechanical properties of DNA molecules, leukemic blast cells and erythrocytes, using optical tweezers. In addition, we controlled the subcellular distribution of the drug by confocal microscopy. Our results indicated that doxorubicin affects mechanical properties of cellular structures. In all cases the drug reduced mechanical strength of examined objects. For the leukemic cells the drug subcellular distribution was predominantly nuclear with some particulate cytoplasmic fluorescence. In erythrocytes, doxorubicin showed fluorescence mainly in cytoplasm and plasma membrane. The lowering of blast cells stiffness may be due to the interaction of doxorubicin with nuclear structures, especially with nucleic acids, as our studies with DNA confirmed. In addition, it is known that DOX inhibits the polymerization of actin and thus cytoskeletal modification may also be important in reducing of cell mechanical strength. In the case of erythrocytes - the non-nucleated cells, a significant effect on the decrease of cell stiffness, besides the cytoskeleton, may have the interaction of the drug with the cell membrane. Experiments with model phospholipid membranes confirmed that observed increase in cell elasticity originates, among other things, from the drug incorporation in the lipid membrane itself. The lowering of mechanical strength of leukemic cells may have an significant impact on the effectiveness of chemotherapy. However, the fact that doxorubicin interacts not only with proliferating cancer cells, but also with the health ones may explains the high toxicity of the drug at the therapeutic concentrations. Our observations also suggest that chemotherapy with doxorubicin may decrease the risk of vascular complications in acute leukemia, due to increasing the cell elasticity. PMID- 29136961 TI - Validation of the 2012 International Consensus Guidelines Using CT and MRI: Branch Duct and Main Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas. PMID- 29136962 TI - Impact of Neoadjuvant Chemoradiation on Lymph Node Status in Esophageal Cancer: Post hoc Analysis of a Randomized Controlled Trial. PMID- 29136963 TI - Lymph Node Status After Neoadjuvant Chemoradiotherapy for Esophageal Cancer: Implications for the Extent of Lymphadenectomy. PMID- 29136964 TI - Does Surgical Resection Provide Better Outcomes Than Radiofrequency Ablation in Patients With BCLC Very Early-stage Hepatocellular Carcinoma? PMID- 29136965 TI - Ablation for Hepatocellular Carcinoma: Where Do We Stand? PMID- 29136966 TI - Minimally Invasive Surgery: A Minimally Useful Term? PMID- 29136967 TI - Are We Ready to Perform Fully Minimally Invasive ALPPS? PMID- 29136968 TI - Impact of Bariatric Surgery on Life Expectancy in Severely Obese Patients With Diabetes. PMID- 29136969 TI - Impact of Bariatric Surgery on Life Expectancy in Severely Obese Patients With Diabetes. PMID- 29136970 TI - Bariatric Surgery in Patients With Type 2 Diabetes Mellitus. PMID- 29136971 TI - Letter to the Editor: Laparoscopic Surgery or Conservative Treatment for Appendiceal Abscess in Adults? PMID- 29136972 TI - Reply to Letter: "Laparoscopic Surgery or Conservative Treatment for Appendiceal Abscess in Adults?" PMID- 29136973 TI - Relevance of Postoperative Peak Transaminase After Elective Hepatectomy. PMID- 29136974 TI - Reply to "Relevance of Postoperative Peak Transaminase After Elective Hepatectomy". PMID- 29136975 TI - The Impact of Preoperative Serum Anti-TNFalpha Therapy Levels on Early Postoperative Outcomes in Inflammatory Bowel Disease Surgery. PMID- 29136976 TI - Pancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767): Perioperative and Long-term Results of a Multicenter Randomized Controlled Trial. PMID- 29136977 TI - Reply to "Pancreatogastrostomy versus Pancreatojejunostomy Following Pancreatoduodenectomy: Comments on RECOPANC Study". PMID- 29136978 TI - Evaluation of Quality of Life After Incisional Hernia Repair Using Condition specific Scales and Risk Factors. PMID- 29136979 TI - Reply to Letter "Evaluation of Quality of Life After Incisional Hernia Repair Using Condition-specific Scales and Risk Factors". PMID- 29136980 TI - Letter in response to Singh et al: A Randomized Controlled Study to Evaluate the Role of Video-based Coaching in Training Laparoscopic Skills. PMID- 29136981 TI - Response to Letter From Bookless et al. PMID- 29136982 TI - Does a Multidisciplinary Approach Have a "Compensatory Effect" on Surgeon Experience in Pacreaticoduodenectomy? PMID- 29136983 TI - Association of Postoperative Transfusions With Adverse Outcomes After Noncardiac Surgery. PMID- 29136984 TI - Reply to Letter: Association of Postoperative Transfusions With Adverse Outcomes After Noncardiac Surgery. PMID- 29136985 TI - Improving Surgical Ward Round Quality: Lessons From Studying Communication. PMID- 29136986 TI - Reply to "Improving Surgical Ward Round Quality: Lessons From Studying Communication". PMID- 29136987 TI - Letter to the Editor: What Happened to Surgical Leadership? PMID- 29136988 TI - Renal Function of Patients With Synchronous Bilateral Wilms Tumor. PMID- 29136989 TI - Seasonal Variation in Emergency General Surgery: Why Is February Underrepresented. PMID- 29136990 TI - Reply: Seasonal Variation in Emergency General Surgery: Why is February Underrepresented? PMID- 29136991 TI - FAST Ultrasound Examination as a Predictor of Outcomes After Resuscitative Throacotomy: A Prospective Evaluation. PMID- 29136992 TI - Pretreatment Neutrophil to Lymphocyte Ratio Independently Predicts Disease specific Survival in Patients With Resectable Gastroesophageal Junction and Gastric Cancer. PMID- 29136993 TI - Reply to "Pretreatment Neutrophil to Lymphocyte Ratio Independently Predicts Disease-specific Survival in Patients With Resectable Gastroesophageal Junction and Gastric Cancer". PMID- 29136994 TI - Effect of Laparoscopic Cholecystectomy After Idiopathic Acute Pancreatitis May Be Overestimated. PMID- 29136995 TI - Reply to "Effect of Laparoscopic Cholecystectomy After Idiopathic Acute Pancreatitis May Be Overestimated". PMID- 29136996 TI - Limitations of Preoperative Clinical Staging in Selecting the Enrolled Patients Before Randomization. PMID- 29136997 TI - Early Drain Amylase Value Predicts the Occurrence of Pancreatic Fistula After Pancreaticoduodenectomy. PMID- 29136998 TI - Early Drain Amylase Value Predicts the Occurrence of Pancreatic Fistula After Pancreaticoduodenectomy. PMID- 29136999 TI - Sentinel Node Biopsy in Melanoma: Lessons Learned From Different Positivity Rates From Different Hospitals. PMID- 29137000 TI - Laparoscopic Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma: Time for a Randomized Controlled Trial? Results of an All-inclusive National Observational Study. PMID- 29137001 TI - Reply to the Letter to the Editor "Laparoscopic Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma: time for a Randomized Controlled Trial? Results of an All-inclusive National Observational Study". PMID- 29137002 TI - Cost-effective Decisions in Managing Silent Common Bile Duct Stones Should Include All the Management Options to Help Decision Makers. PMID- 29137003 TI - Segment 4: a Key Point of ALPPS Procedure. PMID- 29137004 TI - The Principle of Preserving Outflow Structures in Partial ALPPS: a commentary on "Segment 4: A Key Point of ALPPS Procedure". PMID- 29137005 TI - Bare-metal stents across the Vater's ampulla is a safe method for patients with lower bile duct obstruction. AB - This study explored the effect of the implant position of stents across the Vater's ampulla on treatment outcomes in patients with lower bile duct obstruction.In the retrospective study, 41 patients with malignant obstruction of the lower bile duct and obstructive jaundice received percutaneous transhepatic biliary placement of bare-metal stents. Basic demographic data on patients, such as sex, age, and primary diseases, and follow-up data, including postoperative complications and jaundice-free survival, were recorded. The follow-up data on patients with an involved ampulla, patients with an uninvolved ampulla, patients with a stent across the ampulla, and patients with a stent at a site other than the ampulla were compared. Furthermore, prognostic factors for jaundice- free survival were investigated using Cox proportional hazards regression analysis.Among the 41 patients, 38 patients experienced subsiding of jaundice, whereas 3 cases had unsuccessful stent patency. Whether or not the ampulla was involved did not influence the incidence rates of postoperative complications and the jaundice-free survival time. Notably, when stents were placed across the ampulla, the jaundice-free survival time was significantly longer than when stents were placed at sites other than across the ampulla (P < .05). Furthermore, placement of the stent across the ampulla or at other sites was an independent prognostic factor (hazard ratio = 0.154, 95% confidence interval 0.042-0.560, P = .005) for jaundice-free survival of patients.The current study revealed that the implant position of a stent across the ampulla resulted in maintenance of stent patency and prolongation of the jaundice-free survival time. PMID- 29137006 TI - Definition of "persistent vomiting" in current medical literature: A systematic review. AB - BACKGROUND AND AIM: Persistent vomiting is mentioned as a symptom of a large variety of systemic disorders. It is commonly used interchangeably with chronic, recurrent, or intractable vomiting and widely used as a warning sign of severe illness in dengue infection. However, it has been poorly defined in the medical literature. Therefore, we aimed to systematically review a definition of persistent vomiting in the medical literature. METHODS: A systematic search was done through; PubMed, Google Scholar, Web of Science, Scopus, VHL, WHO-GHL, Grey Literature Report, POPLINE, and SIGLE for the last 10 years. Consensus on the definition was considered to be reached if at least 50% of studies described the same definition using the Delphi consensus technique. RESULT: Of 2362 abstracts reviewed, 15 studies were selected based on the inclusion criteria. Three studies used the same definition. Another 2 studies defined it as vomiting of all foods and fluid in 24 hours. Three studies defined persistent vomiting in the units of days or weeks. Four studies used the number of episodes: >=2 episodes 15 minutes apart, >3 episodes in 12 hours, and >3 episodes within 24 hours. CONCLUSION: No consensus for the definition was found among authors. This is a point of concern that needs to be addressed by further studies. PMID- 29137008 TI - The sonographic features of neonatal appendicitis: A case report. AB - RATIONALE: Neonatal appendicitis is extremely rare, and preoperative diagnosis is challenging. This study aimed to investigate the utility of ultrasound for the diagnosis of neonatal appendicitis. PATIENT CONCERNS: Four cases of neonatal appendicitis were included in this case series. One was a female infant and the other 3 were male infants; they were aged from 10 to 17 days. DIAGNOSES: Neonatal appendicitis. INTERVENTIONS: Four newborns in our hospital were diagnosed with neonatal appendicitis by abdominal ultrasound. Their sonographic features were summarized and compared with surgical and pathological findings. OUTCOMES: In these infants, abdominal ultrasound demonstrated ileocecal bowel dilatation, intestinal and bowel wall thickening, and localized encapsulated effusion in the right lower quadrant and the abscess area, which was assumed to surround the appendix. LESSONS: Ultrasound is helpful for the diagnosis of neonatal appendicitis. PMID- 29137007 TI - Prognostic role of pretreatment neutrophil to lymphocyte ratio in breast cancer patients: A meta-analysis. AB - BACKGROUND: Inflammation and cancer are closely related to each other. As a parameter that can reflect inflammation and host immune reaction, elevated blood neutrophil to lymphocyte ratio (NLR) has been confirmed to be correlated with poor prognosis in a variety of cancers. However, this remains controversial in breast cancer. Thus, we performed this updated meta-analysis to further clarify whether high NLR could be a predictor of survival in breast cancer patients. METHODS: We searched on PubMed Database and Cochrane Library. Overall survival (OS), disease-free survival (DFS), and cancer-specific survival were used as outcome events, and hazard ratio (HR) was chosen as the parameter to evaluate the correlation. RESULT: Eighteen eligible studies were involved in this meta analysis. The synthesized analysis demonstrated that elevated NLR was associated with poor DFS [HR = 1.72, 95% confidence interval (95% CI) = 1.30-2.27], OS (HR = 1.87, 95% CI = 1.41-2.48), and cancer-specific survival (HR = 2.09, 95% CI = 1.04 4.21). The correlation was stronger in triple-negative breast cancer (TNBC) (OS: HR = 2.58, 95% CI = 1.63-4.06; DFS: HR = 3.51, 95% CI = 1.97-6.24). CONCLUSION: Higher NLR was correlated to poor prognosis of breast cancer patients. As a clinical parameter that we can easily obtain, NLR might be a potential predictor in patients' survival to assist with physicians' treatment decisions. PMID- 29137009 TI - Brain metabolism in patients with freezing of gait after hypoxic-ischemic brain injury: A pilot study. AB - Movement disorders are 1 of the long-term neurological complications that can occur after hypoxic-ischemic brain injury (HIBI). However, freezing of gait (FOG) after HIBI is rare. The aim of this study was to examine the brain metabolism of patients with FOG after HIBI using F-18 fluoro-2-deoxy-D-glucose positron emission tomography (F-18 FDG PET).We consecutively enrolled 11 patients with FOG after HIBI. The patients' overall brain metabolism was measured by F-18 FDG PET, and we compared their regional brain metabolic activity with that from 15 healthy controls using a voxel-by-voxel-based statistical mapping analysis. Additionally, we correlated each patient's FOG severity with the brain metabolism using a covariance analysis.Patients with FOG had significantly decreased brain glucose metabolism in the midbrain, bilateral thalamus, bilateral cingulate gyri, right supramarginal gyrus, right angular gyrus, right paracentral lobule, and left precentral gyrus (PFDR-corrected < .01, k = 50). No significant increases in brain metabolism were noted in patients with FOG. The covariance analysis identified significant correlations between the FOG severity and the brain metabolism in the right lingual gyrus, left fusiform gyrus, and bilateral cerebellar crus I (Puncorrected < 0.001, k = 50).Our data suggest that brain regions in the gait-related neural network, including the cerebral cortex, subcortical structures, brainstem, and cerebellum, may significantly contribute to the development of FOG in HIBI. Moreover, the FOG severity may be associated with the visual cortex and cerebellar regions. PMID- 29137010 TI - Management of and risk factors for regional recurrence in upper lip squamous cell carcinoma. AB - Our goal was to evaluate the risk factors for regional recurrence in upper lip squamous cell carcinoma (SCC).A total of 109 patients with upper lip SCC were retrospectively enrolled. Clinical and pathologic information was collected and analyzed.Fifteen (13.8%) patients had a regional metastasis, 2 patients had parotid node metastasis, and no local or distant metastasis was noted. There was neck level I node metastasis in 15 (100%) patients. In multivariate analysis, invasion depth and degree of differentiation were significantly associated with regional metastasis. The 5- and 10-year disease-specific survival rate was 95.4% and 80.1%, respectively.Invasion depth and degree of differentiation have reliable value for predicting regional metastasis. PMID- 29137011 TI - A prospective observational study evaluating the efficacy of prophylactic internal iliac artery balloon catheterization in the management of placenta previa-accreta: A STROBE compliant article. AB - We studied the efficacy of prophylactic internal iliac artery balloon catheterization for managing severe hemorrhage caused by pernicious placenta previa.This prospective observational study was conducted in Tongji Hospital, Wuhan, China. One hundred sixty-three women past 32-week's gestation with placenta previa-accreta were recruited and managed. Women in the balloon group accepted prophylactic internal iliac artery balloon catheterization before scheduled caesarean delivery and controls had a conventional caesarean delivery. Intraoperative hemorrhage, transfusion volume, radiation dose, exposure time, complications, and neonatal outcomes were discussed.Significant differences were detected in estimated blood loss (1236.0 mL vs 1694.0 mL, P = .01), calculated blood loss (CBL) (813.8 mL vs 1395.0 mL, P < .001), CBL of placenta located anteriorly (650.5 mL vs 1196.0 mL, P = .03), and anterioposteriorly (928.3 mL vs 1680.0 mL, P = .02). Prophylactic balloon catheterization could reduce intraoperative red blood cell transfusion (728.0 mL vs 1205.0 mL, P = .01) and lessen usage of perioperative hemostatic methods. The incidence of hysterectomy was lower in balloon group. Mean radiation dose was 29.2 mGy and mean exposure time was 92.2 seconds. Neonatal outcomes and follow-up data did not have significant difference.Prophylactic internal iliac artery balloon catheterization is an effective method for managing severe hemorrhage caused by placenta previa accreta as it reduced intraoperative blood loss, lessened perioperative hemostatic measures and intraoperative red cell transfusions, and reduce hysterectomies. PMID- 29137012 TI - The relationship between neutrophil-to-lymphocyte ratio and diabetic peripheral neuropathy in Type 2 diabetes mellitus. AB - To explore the relationship between neutrophil-to-lymphocyte ratio (NLR) and diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus.A total of 557 newly diagnosed Type 2 Diabetes Mellitus (T2DM) patients were recruited, including 397 T2DM patients without complication (DM group) as well as 160 T2DM patients complicated with DPN (DPN group). Student t test, Mann-Whitney U test, or chi test was applied to the data of the 2 groups, including the levels of neutrophils and lymphocytes as well as the NLR values of peripheral blood and other biochemistry indexes; Pearson correlation analysis was used to calculate the correlation of NLR and detected factors; risk factors of DPN were estimated via logistic regression analysis and multivariate analysis.The values of triglyceride (TG), neutrophils, fasting insulin, urinary albumin, and 2 hour postglucose in DPN group were significantly higher than those of the DM group, whereas the number of lymphocytes of DPN group was considerably lower than that of the DM group (P < .05 respectively); NLR values were remarkably higher in DPN group compared with those of DM group (2.58 +/- 0.50 vs 2.18 +/- 0.61, P < .001); logistic regression analysis showed that NLR (P = .002, OR = 4.960, 95% CI = 1.843-13.349) was a risk factor of DPN. Multivariate logistic regression analysis showed that DPN was independently related to NLR (P = .002, OR = 4.960, 95% CI = 1.843-13.349). The ROC curve analysis confirmed that the optimal cut-off point, specificity, and sensitivity in diagnosing DPN by NLR were 2.13%, 48.1%, and 81.3% respectively.Our results showed that NLR is significantly correlated with DPN, which suggested that NLR may be an independent risk factor of DPN. PMID- 29137013 TI - Combination of Ewing test, heart rate variability, and heart rate turbulence analysis for early diagnosis of diabetic cardiac autonomic neuropathy. AB - The aim of this study was to compare and analyze Ewing test, heart rate variability (HRV), and heart rate turbulence (HRT) in the diagnosis of cardiac autonomic neuropathy (CAN) in diabetic patients.Ninety diabetic patients (age 18 78) and 20 nondiabetic control subjects were studied. Standard Ewing test and 24 hour Holter was performed in all participants to evaluate CAN. Patients with Ewing score >=2 were classified as CAN+.The rate of CAN+ in diabetic patients [44.4% (40/90)] was higher than that in the controls [5% (1/20)] (P < .05). Using the HRV analysis and HRT analysis, rates of CAN+ in diabetic patients were 56.67% (51/90) and 52.22% (47/90), respectively. SD of all normal-to-normal (NN) intervals (SDNN), SD of the average NN intervals calculated over 5-minute periods of the entire recording (SDANN), low frequency power (LF), and turbulence slope (TS) were significantly correlated negatively with Ewing scores. TS (r = -0.68, P < .05) and SDNN (r = -0.58, P < .05) had the strongest correlation with Ewing scores among relevant factors. Combining TS with SDNN as diagnostic criteria for CAN, the diagnostic sensitivity can be increased to 98%.Parameters used for evaluating parasympathetic functions in Ewing test, HR variability, and HR turbulence were found to significantly decrease in CAN+ group. The combination of SDNN and TS showed greater diagnostic value than Ewing test, HRV analysis, or HRT analysis alone. PMID- 29137014 TI - Radiological manifestations and surgical outcome of combined upper cervical cord compression and cervical ossification of the posterior longitudinal ligament with a minimum 2-year follow-up. AB - Combined upper cervical cord compression associated with cervical ossification of the posterior longitudinal ligament (OPLL) is a rare and under-recognized disorder. The aim of this study was to investigate the radiological manifestations and surgical outcome of this combined disease.Between May 2011 and July 2015, patients who underwent surgery for combined upper cervical cord compression and cervical OPLL in our institution were included in this study. After a minimum 2-year follow-up, radiological and clinical data were collected. The etiology of upper cervical cord compression and radiological features of cervical OPLL was determined. Surgical outcome was evaluated with Visual Analogue Scale (VAS), Japanese Orthopedic Association score (JOA), space available for the spinal cord (SAC) at the cephalad adjacent level, occupying ratio of OPLL and cervical lordosis.In total, 24 patients (11 men and 13 women) with a mean age of 57.9 years old were included. The etiology of upper cervical cord compression included craniovertebral junction deformity (n = 10), atlantoaxial subluxation (n = 5), and OPLL extending to C2 level (n = 9). The extent, type, and thickest level of cervical OPLL varied among the patients. Significant improvement of VAS and JOA score was noted postoperatively and at a minimum 2-year follow-up. The result was satisfactory in SAC at the cephalad level and occupying ratio of OPLL. There were no significant differences in C2/C7 lordotic angle at the preoperative, postoperative and the last follow-up examination.In conclusion, the radiological manifestations of combined upper cervical cord compression and cervical OPLL varied among the patients. Satisfied results can be achieved with adequate surgical treatment a minimum 2-year follow-up. PMID- 29137015 TI - Malignant transformation of a mature teratoma of the adrenal gland: A rare case report and literature review. AB - RATIONALE: Adrenal mature TMT is very rare. So far, only two cases have been reported. PATIENT: We report a rare case of malignant transformation of a mature teratoma in the right adrenal gland of a 36-year-old Chinese female. The patient had been asymptomatic until physical exam identified a palpable mass in the right abdomen. Abdominal non-enhanced computed tomography (CT) scan showed a huge tumor with mixed density in right adrenal region, which had cystic components, fat, calcifications, and separations. Contrast-enhanced CT showed significant enhancement of the cyst wall and septations as well as mural nodules. In addition, the patient had four abnormal laboratory results, including cortisol 773.58 mol/L ? (reference range 118.6 to 618 mol/L), adrenocorticotropic hormone (ACTH) 70.980 pg/ml ? (reference range 7.2 to 63.3 pg/ml), aldosterone 317.84 pg/ml ? (reference range prone: 49.3-175 pg/ml; Standing: 34.7-275 pg/ml; 24h urine 2.84-33.99 ug/d), and vanillyl mandelic acid (VMA) 22.38 mg / 24 h ? (reference range 0-13.6 mg / 24 h) which to our knowledge have not been reported by any adrenal mature teratoma's reference literature. DIGNOSES: It was initially diagnosed as a right adrenal hamartoma by the radiologist. Final pathology confirmed it as malignant transformation of a right adrenal mature teratoma, which is extremely rare. INTERVENTIONS: Laparoscopic resection is usually the treatment of choice for adrenal teratoma and our case report is no exception. OUTCOMES: This article is a case report, no outcomes. LESSONS: Non-enhanced CT findings of a mass with cystic change, fat, calcification and separation are suggestive of a teratoma. If there is significant enhancement of the cyst wall and septations as well as mural nodules in contrast-enhanced CT, then adrenal TMT should be considered. In addition, abnormal levels of hormones including cortisol, ACTH, aldosterone and VMA may also aid in the diagnosis of adrenal TMT. PMID- 29137016 TI - Binding pancreaticogastrostomy anastomosis in central pancreatectomy: A single center experience. AB - A growing number of central pancreatectomies are performed. However, reconstruction of pancreaticoenteral digestive continuity after central pancreatectomy remains debated. This study evaluates the short-term outcomes of binding pancreaticogastrostomy anastomosis in central pancreatectomy.We have reviewed our experience with 52 patients who underwent binding pancreaticogastrostomy following central pancreatectomy from February 2009 to March 2015. Indication includes 6 noninvasive intraductal papillary mucinous neoplasms, 11 neuroendocrine tumors, 12 solid pseudopapillary tumor, 9 serous cystadenoma, 6 mucinous cystadenoma, and 8 focal pancreatic traumas.The mortality rate was nil while the morbidity rate was 34.6%. Eighteen patients experienced complications including 6 pancreatic fistulas, 2 postpancreatectomy hemorrhages, 4 delayed gastric emptying, 1 hypostatic pneumonia, and 5 pancreatitis. The median postoperative length of hospital stay was 12 days (10 days for patients without fistula). None of the 52 patients were found to have pancreatic endocrine or exocrine insufficiency or recurrence of tumors.Central pancreatectomy with binding pancreaticogastrostomy is a useful and practicable surgical procedure for benign or borderline lesions of the pancreatic neck or proximal body. PMID- 29137017 TI - Prognostic value of glucose metabolism for non-ST-segment elevation infarction patients with diabetes mellitus and single concomitant chronic total occlusion following primary percutaneous coronary intervention. AB - Glucose metabolism status may play a predictive role in the severity of the complications among patients with type 2 diabetes mellitus (DM). However, few studies have focused on the prognostic value of glycosylated hemoglobin (HbA1c) and Homeostatic Model Assessment 2 for Insulin Resistance (HOMA2-IR) in patients with DM, non-ST-segment elevation infarction (NSTEMI), and single concomitant chronic total occlusion (CTO) following primary percutaneous coronary intervention (PCI). Short- and long-term prognostic value of HbA1c and HOMA2-IR in patients with DM with NSTEMI and single CTO who received primary percutaneous transluminal coronary intervention (pPCI).Data from 202 patients with NSTEMI and single CTO in nonculprit vessels were included. The incidence of revascularization, cardiogenic shock, ischemic stroke, major bleeding (ie, cerebral hemorrhage or massive hemorrhage of gastrointestinal tract), and cardiac death were combined as composite end points (CEPs). HbA1c was measured on admission and at 12 and 24 weeks after discharge. HOMA2-IR was measured on admission and at 6 and 12 weeks after discharge. The mean value of HbA1c and HOMA2-IR was calculated to determine the impact on 2.5-year CEPs. All patients were assessed during hospitalization and followed for up to 2.5 years after discharge.Mean age was 62.4 +/- 11.8 years and 76% were male. Previous MI, lower left ventricular ejection fraction, and higher HbA1c (hazard ratio [HR] = 1.216; 95% confidence interval [CI] = 1.023-1.445; P = .023) were independently associated with a poor prognosis at 2.5 years. Higher HbA1c and HOMA2-IR on admission was associated with CEPs during hospitalization. Mean HOMA2-IR prior to pPCI was associated with revascularization (HR = 1.129; 95% CI = 1.008-1.265; P = .036) and ischemic stroke (HR = 1.276; 95% CI = 1.044-1.560; P = .017) during the 2.5 years follow-up period.Glucose metabolism status reflected by HbA1c and HOMA2 IR may provide prognostic value to patients with NSTEMI, type 2 DM, and single concomitant CTO following PCI. Therefore, patients with NSTEMI, CTO, and poor glycemic control should be carefully evaluated prior to PCI. PMID- 29137018 TI - Rare metastasis of nasopharyngeal carcinoma to the thyroid gland with subsequent metastatic abdominal lymph nodes: A case report and literature review. AB - RATIONALE: Thyroid metastasis from nasopharyngeal carcinoma is rare. Metastasis of nasopharyngeal carcinoma to the thyroid gland with subsequent metastatic abdominal lymph nodes hasn't been reported before. We want to share our experience about the treatment choice. PATIENT CONCERNS: A 27-year-old man was diagnosed with nasopharyngeal nonkeratinizing carcinoma in August 2004. In March 2013 he underwent a thyroid carcinoma radical operation, and histological examination revealed metastasis to the thyroid gland from nasopharyngeal carcinoma. An 18F-FDG-PET/CT scan and biopsy showed metastatic abdominal lymph nodes of nasopharyngeal carcinoma in April 2015. DIAGNOSES: A 27-year-old man was diagnosed with metastasis of nasopharyngeal carcinoma to the thyroid gland with subsequent metastatic abdominal lymph nodes. INTERVENTIONS: The patient was treated with concurrent chemotherapy and radiotherapy for nasopharyngeal carcinoma and metastasis to the thyroid gland. The metastases to the abdominal lymph nodes received chemotherapy. OUTCOMES: After 6 cycles of chemotherapy with gemcitabine, cisplatin, and 5-fluorouracil for metastasis to the abdominal lymph nodes, the patient is currently asymptomatic with stable disease and improved quality of life. LESSONS: The treatment choice for metastasis of nasopharyngeal carcinoma depends on the clinical disease extent, and surgery and/or chemo radiation therapy must be drafted to the individual patient in order to improve the prognosis and quality of life. PMID- 29137019 TI - Optical coherence tomography angiography in patients with diabetic retinopathy treated with anti-VEGF intravitreal injections: Case report. AB - PURPOSE: To present optical coherence tomography angiography (OCTA) features in patients with diabetic retinopathy (DR) at the baseline and in response to treatment with anti-VEGF intravitreal injections. To investigate the role of OCTA in management of patients with DR. METHODS: Retrospective case series showing primary outcomes of 3 patients with DR and diabetic macular edema. Patients were injected intravitreally a loading phase of 3 monthly 2.0 mg aflibercept, followed by 2 injections bimonthly (5 injections in total). Before each injection OCTA was performed using 3 mm * 3 mm scans (Optovue, XR Avanti). The obtained scans of the macula were analyzed and compared to the image at the baseline. Best-corrected visual acuity (BCVA) was examined at the baseline and before each injection. RESULTS: In the superficial plexus, a rarefaction of capillaries with capillary dropout and nonperfusion areas were present in all eyes. The microaneurysms were good to visualize in 3 mm * 3 mm scans. In deep vascular network, evident microvascular alterations around the small cystoid edema cells were to detect. There were no differences in perfusion density level for the whole macular area in 3 mm * 3 mm scans shown in density maps between injections in all presented cases. After a series of aflibercept intravitreal injections decreased cystic changes were observed. Moreover in all presented cases, the decrease in central retinal thickness that correlated clinically with improvement of visual acuity (BCVA) was observed. All patients achieved a goal of well-controlled diabetes by having a HbA1c level (<8.0%) before each injection. CONCLUSIONS: OCTA is a dyeless, quick, and noninvasive method which allows to detect ischemic changes in DR and might be a useful tool in observing the progress of the disease and the response to anti-VEGF treatment in clinical practice. PMID- 29137020 TI - Alveolar soft part sarcoma occurring in the penis of a 3-year-old boy: A rare case report. AB - RATIONALE: Alveolar soft part sarcoma (ASPS) is a rare, malignant neoplasm, which mostly occurs in the upper and lower extremities. This article presents an unusual case of ASPS involving the penis of a 3-year-old boy. To our knowledge, this is the first case of ASPS in the penis of a child. PATIENT CONCERNS: The patient complained of slight penile pain for 1 year and a soft tissue mass could be palpated in his penis. DIAGNOSES: Imaging was performed on the penis. The pathological feature of the mass was evaluated through biopsy examination. It was found that the mass was an alveolar soft tissue sarcoma, which was then confirmed by immunohistochemistry. INTERVENTIONS: The patient only underwent a partial penectomy because his parents wished to keep the penis. Conventional chemotherapy has been performed for 6 months after the surgery. OUTCOMES: At 28-month follow up the mass did not increase apparently, and no signs of metastasis were found. LESSONS: ASPS may occur originally in the penis. PMID- 29137021 TI - Effect of antitumor treatments on triple-negative breast cancer patients: A PRISMA-compliant network meta-analysis of randomized controlled trials. AB - BACKGROUND: Triple-negative breast cancer (TNBC) lacks the expression of the estrogen receptor, progesterone receptor, and receptor tyrosine-protein kinase erbB-2 (HER2/neu), which renders hormone-related endocrine and targeted therapy essentially futile. OBJECTIVE: We performed a meta-analysis to assess the effects of antitumor regimens in the treatment of TNBC patients. METHODS: We searched electronic databases, including PubMed, Embase, and the Cochrane Library, through January 2017 using the following keywords: "triple negative breast cancer," "TNBC," and "random*" without language restrictions. The major outcome in the present analysis was the overall response rate (ORR), and the secondary outcomes were progression-free survival (PFS) and overall survival (OS). A network meta analysis and multilevel mixed-effects logistic regression were used to compare antitumor regimens. RESULTS: We included 35 articles assessing a total of 8476 TNBC patients in our systematic review. The regimen of Bevacizumab, Carboplatin, and Paclitaxel (78.2%) was the most likely to improve the ORR in TNBC patients, followed by EndoTAG-1 and Paclitaxel (69.7%), Carboplatin and Paclitaxel (65.0%), and Bevacizumab and Paclitaxel (61.8%). In the patients without metastasis, the regimen of Bevacizumab, Carboplatin, and Paclitaxel (74.9%) remained the most likely to improve the ORR. We could not analyze the results for patients with metastasis or outcomes of PFS and OS because no >4 regimens formed a network. In the regression analysis, Bevacizumab (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.43-2.05; P < .001) and Carboplatin (OR, 2.07; 95% CI, 1.62-2.64; P < .001) correlated with superior ORR outcome, and Iniparib (OR, 1.51; 95% CI, 1.11-2.07; P = .009) correlated with superior OS outcome. CONCLUSION: The regimen including Bevacizumab, Carboplatin, and Paclitaxel was the most likely to improve the ORR in TNBC patients and in advanced metastatic TNBC patients. The administration of Bevacizumab and Carboplatin provided greater benefit toward improved patient ORR. PMID- 29137022 TI - The effect of whole-body vibration training on lean mass: A PRISMA-compliant meta analysis. AB - BACKGROUND: Whole-body vibration training (WBVT) confers a continuous vibration stimuli to the body. Although some reports have discussed the effects of whole body vibration (WBV) on bone mineral density and muscle strength, study of WBV effects on lean mass have not been determined. The purpose of the present meta analysis was to evaluate published, randomized controlled trials (RCTs) that investigated the effects of WBVT on lean mass. METHODS: We identified only RCTs by searching databases, including Web of Science, PubMed, Scopus, Embase, and the Cochrane Library from inception to March 2017. Data extraction, quality assessment, and meta-analysis were performed. RESULTS: Ten RCTs with 5 RCTs concentrating on older people, 3 on young adults, and 2 on children and adolescents were included. We additionally explored the effect of WBVT on postmenopausal women (6 trials from the 10 trials). Significant improvements in lean mass with WBVT were merely found in young adults (P = .02) but not in other populations compared to control group. CONCLUSION: The effect of WBVT found in the present meta-analysis may be used in counteracting the loss of muscle mass in younger adults. Moreover, optimal WBVT protocols for greater muscle hypertrophy are expected to be investigated. PMID- 29137023 TI - A case report of Schatzker type VI tibial plateau fracture treated with double reverse traction closed reduction combined with minimally invasive percutaneous plate osteosynthesis technique: A case report. AB - RATIONALE: The knee joint is an important weight-bearing joint, tibial plateau fractures affect knee function and stability. High-energy intra-articular fractures involving the tibial plateau can cause management-related problems such as wound dehiscence; severe comminution leading to malalignment; and delayed complications such as varus collapse, implant failure, and arthritis of the knee joint. The treatment of severe or complex tibial plateau fractures can be quite difficult. Traditional methods of open reduction and plating require extensive exposures, which may further compromise soft tissue and devascularize bone fragments, leading to infection. In this case, a novel device, double reverse traction combined with MIPPO technique, was used and provided the possibility of minimally invasive and personalized orthopedic surgery to treat severe comminuted Schatzker type VI tibial plateau fracture and tibial shaft fracture and got satisfactory results. PATIENT CONCERNS: A previously healthy 56-year-old man presented to the emergency room after a fall from a height, who lost the movement of the left knee with pain and swelling. DIAGNOSES: X-rays showed a tibial plateau comminuted fracture, Schatzker type VI, and tibial shaft fracture. INTERVENTIONS: Applying less extensile exposure and the indirect reduction technique of double reverse traction and closed reduction combined with minimally invasive percutaneous plate osteosynthesis (MIPPO) technique, we got satisfactory recovery of the severe comminuted Schatzker type VI tibial plateau fracture and tibial shaft fracture. OUTCOMES: This severe comminuted fracture and tibial shaft fracture were successfully reduced and got satisfactory recovery of knee joint function. LESSONS: Double reverse traction combined with MIPPO technique can reduce the risk of surgical complications, such as bleeding, oozing, and wound infection. It can be applied in patients with comorbidities such as cardiac disease, hypertension, and heart failure who may otherwise not be candidates for surgery. The cost burden is lower than that of the traditional traction table. PMID- 29137024 TI - Effect of different surgical type of coronary artery bypass grafting on kidney injury: A propensity score analysis. AB - Acute kidney injury (AKI) after coronary artery bypass grafting (CABG) is associated with a less favorable outcome. Off-pump surgery results in lower kidney dysfunction than conventional on-pump arrest surgery. On-pump arrest surgery results in a lower revascularization rate compared with off-pump surgery. On-pump beating heart (OPBH) CABG combines the advantages of beating heart surgery and cardiopulmonary bypass. This study compared the renal outcomes of 3 cardiac surgical methods. From January 2010 to December 2012, 373 patients who underwent on-pump CABG were enrolled. Propensity analysis was performed to compare the postoperative outcomes of postoperative AKI, renal replacement therapy (RRT), intensive care unit (ICU) stay, mortality, and extubating time. In total, 98 patients received conventional on-pump surgery, 160 received OPBH surgery, and 115 received off-pump surgery. The Society of Thoracic Surgeons scores of these 3 groups were 6.1 +/- 13.6, 7.4 +/- 13.6, and 5.6 +/- 10.9, respectively. Propensity analysis revealed lower AKI incidence in the off-pump group than in the on-pump surgery group. No substantial differences were observed in mortality, RRT, and the ICU stay between the off-pump and OPBH surgery groups. Among the 3 surgical methods, off-pump surgery results in lower AKI incidence. The short-term outcome, including kidney function, of OPBH surgery is similar to that of the off-pump group. Therefore, OPBH surgery is a considerable choice for patients with a high surgical risk. PMID- 29137025 TI - Tapentadol versus tramadol in the management of low back pain in the emergency department: Impact of use on the need for reassessments. AB - Nontraumatic musculoskeletal disorders are the main reason for presentation to the emergency department (ED), with rachialgia (back pain) being the most common reason to request medical assessment among them. This also generates the highest demand for reassessments due to poor pain control or onset of adverse reactions to the treatment prescribed in the initial assessment.A retrospective observational study based on usual clinical practice was conducted in patients attending the ED due to low back pain during a period of 24 months. The primary objective was to determine the demand for reassessments in the ED by these patients in the following 30 days, according to the type of therapeutic approach used in the initial assessment.A total of 732 patients who requested medical assessment due to back pain in the ED of our hospital were analyzed, 91 of whom were treated with tapentadol whereas 641 received another treatment. In the first month after the initial assessment, reassessments were less common in the tapentadol group; this difference was significant from days 8 to 15 (P = 0.001, odds ratio [OR] 0.252 with 95% confidence interval [CI] 0.100-0.635) and days 15 to 30 (P < 10, OR 0.277 with 95% CI 0.136-0.563). Patients who received tapentadol also had a better clinical evolution of pain compared to those who did not receive it (P < 10) and to those who received tramadol (P < 10).In this study in patients with back pain, tapentadol shows clear advantages over the other analgesics analyzed, in terms of pain control and less need for reassessments. PMID- 29137026 TI - Implantation of ArtificialIris, a CustomFlex irisprosthesis, in a trauma patient with an Artisan lens: A case report and review. AB - PURPOSE: To evaluate probable complications of ArtificialIris implantation with iris fixated intraocular lens. METHOD: Development of photophobia, glare, and psychological strain during face-to-face communication in a 23-year-old man with a widespread traumatic iris defect terminate to make a decision for performing implantation of an ArtificialIris (Humanoptics, Erlangen, Germany) under the remnant iris without removing the patient's existing Artisan lens. RESULTS: Without any intraoperative or postoperative complications, the patient's visual acuity increased by 1 line, the endothelial cell loss was comparable with the cell loss associated with standard cataract surgery, and the anterior-chamber depth and anterior-chamber anatomy did not change. At the final follow-up examination, the mean intraocular pressure did not differ from baseline, and we achieved high level of patient satisfaction and subjective vision improvement. We discuss the particular importance of considering the patient's expectations, the appropriate measurements, ways to perfect color evaluation, and the types of ArtificialIris products. CONCLUSION: The implantation of the ArtificialIris in patients with aphakic iris-supported lenses (ie, pre-existing Artisan lenses) is a feasible approach and a useful option for patients with thin irises and iris hypoplasia who are at risk of subluxation or the dislocation of the posterior chamber intraocular lens (PCIOL), and also those with sclerally fixed PCIOLs. PMID- 29137027 TI - Morphobiochemical diagnosis of acute trabecular microfractures using gamma correction Tc-99m HDP pinhole bone scan with histopathological verification. AB - We prospectively performed gamma correction pinhole bone scan (GCPBS) and histopathologic verification study to make simultaneous morphobiochemical diagnosis of trabecular microfractures (TMF) occurred in the femoral head as a part of femoral neck fracture.Materials consisted of surgical specimens of the femoral head in 6 consecutive patients. The specimens were imaged using Tc-99m hydroxymethylene diphosphonate (HDP) pinhole scan and processed by the gamma correction. After cleansing with 10% formalin solution, injured specimen surface was observed using a surgical microscope to record TMF. Morphological findings shown in the photograph, naive pinhole bone scan, GCPBS, and hematoxylin-eosin (H&E) stain of the specimen were reciprocally correlated for histological verification and the usefulness of suppression and enhancement of Tc-99m HDP uptake was biochemically investigated in TMF and edema and hemorrhage using gamma correction.On the one hand, GCPBS was able to depict the calcifying calluses in TMF with enhanced Tc-99m HDP uptake. They were pinpointed, speckled, round, ovoid, rod-like, geographic, and crushed in shape. The smallest callus measured was 0.23 mm in this series. On the other hand, GCPBS biochemically was able to discern the calluses with enhanced high Tc-99m HDP uptake from the normal and edema dipped and hemorrhage irritated trabeculae with washed out uptake.Morphobiochemically, GCPBS can clearly depict microfractures in the femoral head produced by femoral neck fracture. It discerns the microcalluses with enhanced Tc-99m HDP uptake from the intact and edema dipped and hemorrhage irritated trabeculae with suppressed washed out Tc-99m HDP uptake. Both conventional pinhole bone scan and gamma correction are useful imaging means to specifically diagnose the microcalluses naturally formed in TMF. PMID- 29137028 TI - Role of positioning posterior cord on coracoid approach brachial plexus block guided by nerve stimulator: Compared with guided by ultrasound. AB - BACKGROUND: Coracoid approach is efficient and safe for brachial plexus block, and is guided by nerve stimulator or ultrasound in general. Many trials have proved that ultrasonic guidance was more efficacious than nerve stimulator guidance. We hypothesized that positioning posterior cord could enhance the anesthesia effect of coracoid approach brachial plexus block (CABPB) guided by nerve stimulator. METHODS: Eighty patients were randomized into 2 groups to receive CABPB with positioning posterior cord guided by nerve stimulator (group A) or CABPB guided by ultrasound (group B). Success rate, procedure time, and onset time of sensory or motor block were recorded. RESULTS: Success rate was similar in 2 groups (89.7% in group A vs 87.5% in group B, P > .05). Procedure time was longer in group A (8 minutes), as compared with group B (4 minutes; P < .05). The difference of onset time of sensory and motor block was not significant between the 2 groups. The onset time of sensory and motor block for musculocutaneous nerve was significantly shorter in group A, as compared with group B (P < .05). CONCLUSION: The 2 technologies are equivalent regarding success rate, safety, and onset time of sensory or motor block. Positioning posterior cord in CABPB guided by nerve stimulator is efficacious for upper extremity surgery.(URL: http://www.chictr.org.cn/listbycreater.aspx ID: ChiCTR INR-16009091 DATE: 25/8/2016). PMID- 29137029 TI - Neural reorganization between injured cingula and the brainstem cholinergic nuclei in a patient with cerebral concussion: A case report. AB - RATIONALE: We report on a patient who showed neural reorganization between injured cingula and the brainstem cholinergic nuclei following cerebral concussion. PATIENT CONCERNS: The main concern of the patient is memory impairment. DIAGNOSES: Cerebral concussion. OUTCOMES: When she visited our hospital at 2 years after onset, cognitive function was evaluated using 2 scales; the Wechsler Intelligence Scale, and the Seoul neuropsychological screening battery: total IQ 97, verbal immediate recall 5.70 percentile, visual immediate recall 30.75 percentile, verbal delayed recall 3.13 percentile, visual delayed recall 11.00 percentile, verbal recognition <0.01 percentile, and visual recognition 13.70 percentile. Conventional brain magnetic resonance imaging did not show any abnormality. On 2-year diffusion tensor tractography for the cingulum, both anterior cingula were discontinued over the genu of the corpus callosum. One neural fiber bundle originating from the middle portion of the left cingulum descended through the left subcortical white matter, and connected to the left pedunculopontine nucleus (Ch 5) in the midbrain and the left laterodorsal tegmental nucleus (Ch 6) in the upper pons. LESSONS: Reorganization of cholinergic innervations between cholinergic nuclei in the basal forebrain and brainstem following injury of the anterior cingulum was demonstrated in a patient with cerebral concussion. PMID- 29137030 TI - Emergency obstetric hysterectomy for life-threatening postpartum hemorrhage: A 12 year review. AB - The aim of the study was to review the operative experiences of emergency hysterectomy for life-threatening postpartum hemorrhage (PPH) performed over a 12 year period at Fujian Provincial Maternity and Children's Hospital; to examine the incidence and risk factors for emergency obstetric hysterectomy; and to evaluate the curative effectiveness and safety of subtotal hysterectomy for life threatening PPH.The records of all cases of emergency obstetric hysterectomy performed at Fujian Maternity and Children Health Hospital between January 2004 and June 2016 were analyzed. The incidence, risk factors, and outcomes of hysterectomy, the peripartum complications, and the coagulation function indices were evaluated.A total of 152,023 of women were delivered. The incidence of emergency postpartum hysterectomy was 0.63 per 1000 deliveries: 96 patients underwent hysterectomy for uncontrolled PPH, 19 (0.2070/00) underwent hysterectomy following vaginal delivery, and 77 (1.280/00) underwent the procedure following cesarean delivery (P < .001). Common risk factors included postpartum prothrombin activity <= 50% (61.5%), placenta accreta (43.76%), uterine atony (37.5%), uterine rupture (17.5%), and grand multiparity > 6 (32.3%). Forty-one patients underwent subtotal abdominal hysterectomy (STH) and 55 patients underwent total abdominal hysterectomy (TH). The mean operation time was significantly shorter for TH (193.59 +/- 83.41 minutes) than for STH (142.86 +/- 78.32 minutes; P = .002). The mean blood loss was significantly greater for TH (6832 +/- 787 mL) than for STH (6329 +/- 893 mL; P = .003). The mean number of red cell units transfusion was higher during TH (16.24 +/- 9.48 units vs 12.43 +/ 7.2, respectively; P = .047). Postoperative prothrombin activity was significantly higher than preoperative levels (56.84 +/- 14.74 vs 44.39 +/- 15.69, respectively; P < .001) in women who underwent TH and in those who underwent STH (57.63 +/- 15.68 vs 47.87 +/- 12.86, respectively; P < .001). There was no significant difference in the maternal complications after TH or STH for PPH.Cesarean deliveries were associated with an increased risk of emergency hysterectomy, and postpartum prothrombin activity < 50% was the greatest risk factor for hysterectomy in most women who underwent hysterectomy. STH was the preferred procedure for emergency obstetric hysterectomy. PMID- 29137031 TI - Subcellular localization of beta-arrestin1 and its prognostic value in lung adenocarcinoma. AB - beta-Arrestins play important roles in cancer progression, and the subcellular localization of beta-arrestin1 has been receiving increasingly more attention. Intriguingly, several studies, including some of our previous work, showed that the effects of beta-arrestin1 on outcomes of cancer patients were controversial.Specimens were obtained from 133 patients with lung adenocarcinoma. Immunohistochemistry was used to detect the expression of beta-arrestin1 and p300 in the collected tissues. The Kaplan-Meier analysis and Cox proportional hazards regression were used to examine the relationship between beta-arrestin1 and patient survival.We found no significant association between beta-arrestin1 and clinicopathological variables. The Kaplan-Meier plot showed that patients with high expression of beta-arrestin1 (especially in the nucleus) had a poorer overall survival (OS) and shorter disease-free survival (DFS) (P = .026, P = .015). Additionally, high p300 expression also resulted in worse OS (P = .039). Following the univariate analysis, high expressions of nuclear beta-arrestin1 and p300 were classed as poor prognostic factors for both OS (P = .016) and DFS (P = .025).The expression of beta-arrestin1 in the nucleus is associated with increased malignant tendency of lung adenocarcinoma, and the predictive value of beta-arrestin1 may be optimized by combining information about the expression of p300 acetyltransferase. PMID- 29137032 TI - Non-Hodgkin lymphoma of multiple extranodal involvement seen on MRI, FDG PET-CT scans: A case report. AB - RATIONALE: Anaplastic large cell lymphoma (ALCL) is a rare type of non-Hodgkin lymphoma (NHL). The most common extranodal sites of ALCL are skin, subcutaneous tissue, bone, lung, and gastrointestinal organs. This study reports a case of ALCL with multiple extranodal involvement, especially the whole body skeletal muscles, with the aim to share the imaging features of the ALCL including magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT). PATIENT CONCERNS: A 54-year-old female patient presented with two-month history of bilateral shoulder pain, which had exacerbated for 6 days prior to admission. MRI scans revealed multiple hyperintense on T2-weighted image (T2WI) and marked inhomogenous diffuse or rim enhancement masses in shoulder muscles. The probable diagnoses must include metastatic carcinoma in the skeletal muscle, purulent abscess, soft-tissue sarcoma and lymphoma. For our patient, however, she did not have a history of cancer or hyperleukocytosis. 18F-FDG PET-CT was made for further evaluation and identified whether there is another related lesion. PET-CT image showed widespread FDG uptake lesions, including cervical/retroperitoneal lymphnodes, subcutaneous tissue, hepar and multiple groups of whole body muscles. DIAGNOSES: An ultrasound-guided tissue biopsy was performed on the left cervical lymphnodes. Histological and immunohistochemical examination showed ALK- ALCL. INTERVENTIONS: Clinicians planned to give our patient systemic chemotherapy. OUTCOMES: Our patient died of multiple organ failure four weeks after her first visit to our hospital. LESSONS: This disease should be considered when patient presented diffuse muscle swelling in particular when a history of cancer and hyperleukocytosis was not supported. The presence of soft tissue masses in skeletal muscles on MRI scans, as well as multiple marked focal tracer uptake on PET-CT and immunohistochemical analysis of the mass, may help the recognition of ALCL and the state of illness evaluation, allowing for the appropriate treatment strategy to be initiated. PMID- 29137033 TI - Prognostic role of C-reactive protein in patients with nasopharyngeal carcinoma: A meta-analysis and literature review. AB - BACKGROUND: C-reactive protein (CRP) has been shown to be associated with several tumors. However, its association with nasopharyngeal carcinoma (NPC) is not well characterized. We performed a literature review and meta-analysis to assess the prognostic relevance of elevated CRP levels in patients with NPC. METHODS: A literature search for relevant studies was performed on PubMed (Medline), the Cochrane Library, and Web of Science databases. Hazard ratios (95% confidence intervals) were calculated to assess the association between elevated CRP levels and survival outcomes. RESULTS: Five studies with a combined study population of 5215 patients with NPC were included. Pooled hazard ratios for overall survival and distant metastasis-free survival were 1.84 (95% CI = 1.57-2.17) and 1.81 (95% CI = 1.53-2.14), respectively. Subgroup analyses showed that types of indicators and treatment before inclusion had no significant impact on the observed association. CONCLUSION: Elevated serum CRP levels in patients with NPC were associated with worse prognosis. PMID- 29137034 TI - Uniparental disomy and prenatal phenotype: Two case reports and review. AB - RATIONALE: Uniparental disomy (UPD) gives a description of the inheritance of both homologues of a chromosome pair from the same parent. The consequences of UPD depend on the specific chromosome/segment involved and its parental origin. PATIENT CONCERNS: We report prenatal phenotypes of 2 rare cases of UPD. DIAGNOSES: The prenatal phenotype of case 1 included sonographic markers such as enlarged nuchal translucency (NT), absent nasal bone, short femur and humerus length, and several structural malformations involving Dandy-Walker malformation and congenital heart defects. The prenatal phenotype of Case 2 are sonographic markers, including enlarged NT, thickened nuchal fold, ascites, and polyhydramnios without apparent structural malformations. INTERVENTIONS: Conventional G-band karyotype appears normal in case 1, while it shows normal chromosomes with a small supernumerary marker chromosome (sSMC) in case 2. Genetic etiology was left unknown until single-nucleotide polymorphism-based array (SNP-array) was performed, and segmental paternal UPD 22 was identified in case 1 and segmental paternal UPD 14 was found in case 2. OUTCOMES: The parents of case 1 chose termination of pregnancy. The neonate of case 2 was born prematurely with a bellshaped small thorax and died within a day. LESSONS: UPD cases are rare and the phenotypes are different, which depend on the origin and affected chromosomal part. If a fetus shows multiple anomalies that cannot be attributed to a common aneuploidy or a genetic syndrome, or manifests some features possibly related to an UPD syndrome, such as detection of sSMC, SNP array should be considered. PMID- 29137035 TI - Enteral nutrition tube placement assisted by ultrasonography in patients with severe acute pancreatitis: A novel method for quality improvement. AB - To evaluate the effect of a novel procedure using real-time ultrasonography to assist nasojejunal tube placement at bedside in patients with severe acute pancreatitis (SAP).Single center, prospective descriptive study in a 15-bed surgery intensive care unit of a university hospital. Thirty SAP patients were enrolled. The whole procedure of placing nasojejunal tube was performed by a single physician, who places nasojejunal tube at the bedside and performs ultrasonography to guide the tube positioning. The final nasojejunal tube position was confirmed by abdominal radiograph. The successful rate of the procedure as well as the time it took, the time from the decision of enteral feeding to commencement of feeding, and complications were recorded.Thirty-six intubations were performed in 30 patients by using ultrasonography-assisted method at bedside. Nasojejunal tubes were successful placed in 28 of 30 patients (93.3%). The average time of successful placement was 22.07 +/- 5.78 minutes. The median time between physician's decision for tube placement and feeding initiation was 5.5 (2, 24) hours. No adverse events occurred in all of patients.This novel method of nasojejunal tube placement under ultrasound guidance is practical, less time consuming and reliable. PMID- 29137036 TI - Attenuation and scatter correction in I-123 FP-CIT SPECT do not affect the clinical diagnosis of dopaminergic system neurodegeneration. AB - The purpose of this study was to assess the influence of different reconstruction factors in N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-I-123 iodophenyl)nortropane (I-123 FP-CIT) single-photon emission computed tomography (SPECT) images for the diagnosis of dopaminergic system neurodegeneration (DSND).Seventy-three patients (38 females, 35 males) suspected of DSND were included in this study. The patients were divided into 3 groups on the basis of their final clinical diagnoses; patients with Parkinson disease (group 1, n = 36), patients with other DSND (group 2, n = 19), patients without DSND (group 3, n = 18). FP-CIT accumulation in the striata was evaluated visually and semiquantitatively. SPECT images were classified visually as normal or abnormal based on the previous report. For semiquantitative analysis, we used DaTView software (Aze Corporation), and specific binding ratios (SBR) and asymmetry indices (AI) were calculated. Visual and semiquantitative evaluations for different reconstruction factors were compared among the 3 groups.In the visual evaluation, there were no differences among DSND diagnostic capabilities of attenuation and scatter correction by computed tomography attenuation correction scatter correction, computed tomography attenuation correction, Chang attenuation correction, and non-attenuation and -scatter correction. In the semiquantitative evaluation, receiver operating characteristic analysis of SBR and AI for clinical DSND diagnostic ability (group 1+2 vs 3) showed no significant difference among the reconstruction factors by multiple comparisons.Although the values of SBR and AI were changed and image quality could be improved when attenuation correction and/or scatter correction were applied, the clinical impact of these reconstruction factors for the diagnosis of DSND was negligible. PMID- 29137037 TI - A case report of recurrent thyroid inflammatory myofibroblastic tumor and its metastasis in soft tissue. AB - RATIONALE: Inflammatory myofibroblastic tumor (IMT) is a neoplasm of low malignant potential. The most frequent site of IMT is in the lung, whereas recurrent and metastasis of thyroid IMT has been seldom reported. PATIENT CONCERNS: A 57-year-old male presented with a 3-year history of painless thyroid mass. The physical examination revealed a diffusely enlarged thyroid which was firm. The thyroid function and antibodies were normal. Thyroid ultrasound revealed a hypoechoic mass in the left lobe and heterogeneous echo in the right lobe. Neck computed tomography showed a diffused enlargement of thyroid with the homogeneously low intensity and the moderate enhancement. DIAGNOSES: A diagnosis of thyroid IMT was made according the postoperative histological and immunohistochemical analysis. INTERVENTIONS: The patient underwent subtotal thyroidectomy. Seventeen months after the surgery, the patients presented with a firm nodule of right adductor magnus and a relapsing mass of thyroid. Needle core biopsy of the thyroid mass suggested the relapsing of thyroid IMT. The mass excision of the right adductor magnus was performed and an IMT was confirmed by histopathology. The patient underwent thyroid radiation therapy and steroid therapy. OUTCOMES: The size of the tumor was smaller than the preradiation size and the patient is now under follow-up. LESSONS: This is the seldom reported patient with recurrent thyroid IMT with metastasis. IMT of the thyroid is an unusual but distinct disease entity. The clinical and radiological features are not specific and its diagnosis is based on the histological features. Although tumor resection and radiation seem to be effective, no standard treatment for such disease has been established. PMID- 29137038 TI - Quantification of STAT3 and VEGF expression for molecular diagnosis of lymph node metastasis in breast cancer. AB - BACKGROUND: Axillary lymph node metastasis is associated with increased risk of regional recurrence, distant metastasis, and poor survival in breast malignant neoplasm. Expression of signal transducer and activator of transcription 3 (STAT3) is significantly associated with tumor formation, migration, and invasion in various cancers. In addition, vascular endothelial growth factor (VEGF) expression could promote angiogenesis and increase the risk of tumorigenesis. To determine correlations among STAT3 expression, VEGF, and clinicopathological data on lymph node involvement in breast cancer patients after surgery. METHODS: The mRNA expression levels of STAT3 and VEGFs were measured in 45 breast invasive ductal carcinoma tissues, 45 peritumoral tissues, and 45 adjacent nontumor tissues by real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Postoperative pathological examination revealed explicit axillary lymph node involvement in all patients. RESULTS: Average mRNA levels of STAT3 and VEGFs were the highest in breast invasive ductal carcinoma tissues, followed by peritumoral tissues. High expression of STAT3 showed significant positive correlation with high axillary lymph node involvement and progesterone receptor (PR), VEGF-C, VEGF-D, and vascular endothelial growth factor receptor (VEGFR)-3 expression. The expression levels of STAT3, VEGF-C, and VEGFR-3 were significantly higher in the tumor tissues of patients with axillary lymph node metastasis than in those of patients without the metastasis. Expression levels of VEGF-C and VEGFR-3 were also significantly higher in peritumoral tissues of patients with axillary lymph node metastasis. Positive correlations were found between STAT3 and VEGF-C/-D mRNA levels. CONCLUSION: These data suggest that STAT3/VEGF-C/VEGFR-3 signaling pathway plays an important role in carcinogenesis and lymph-angiogenesis. Our findings suggest that STAT3 may be a potential molecular biomarker for predicting the involvement of axillary lymph nodes in breast cancer, and therapies targeting STAT3 may be important for preventing breast cancer metastasis. PMID- 29137039 TI - Association of metabolic syndrome and its components with all-cause and cardiovascular mortality in the elderly: A meta-analysis of prospective cohort studies. AB - There is increasing evidence regarding the relationship between metabolic syndrome and mortality. However, previous research examining metabolic syndrome and mortality in older populations has produced mixed results. In addition, there is a clear need to identify and manage individual components of metabolic syndrome to decrease cardiovascular disease (CVD) mortality. In this meta analysis, we searched the MEDLINE databases using PubMed, Cochrane Library, and EMBASE databases. Based on 20 prospective cohort studies, metabolic syndrome was associated with a higher risk of all-cause mortality [relative risk (RR), 1.23; 95% confidence interval (CI), 1.15-1.32; I = 55.9%] and CVD mortality (RR, 1.24; 95% CI, 1.11-1.39; I = 58.1%). The risk estimates of all-cause mortality for single components of metabolic syndrome were significant for higher values of waist circumference or body mass index (RR, 0.94; 95% CI, 0.88-1.00), higher values of blood glucose (RR, 1.19; 95% CI, 1.05-1.34), and lower values of high density lipoprotein (HDL) cholesterol (RR, 1.11; 95% CI, 1.02-1.21). In the elderly population, metabolic syndrome was associated with an increased risk of all-cause and CVD mortality. Among the individual components of metabolic syndrome, increased blood glucose and HDL cholesterol levels were significantly associated with increased mortality. However, older obese or overweight individuals may have a decreased mortality risk. Thus, the findings of the current meta-analysis raise questions about the utility of the definition of metabolic syndrome in predicting all-cause mortality and CVD mortality in the elderly population. PMID- 29137040 TI - A multicenter, open-label, phase III study of Abcertin in Gaucher disease. AB - BACKGROUND: Gaucher disease (GD) is caused by a deficiency in the lysosomal enzyme glucocerebrosidase. Enzyme replacement therapy (ERT) is recommended for clinical improvement. METHODS: The efficacy and safety of a new imiglucerase, Abcertin, were assessed in 7 Egyptian patients with treatment-naive type 1 GD. Each patient was administered a biweekly 60 U/kg dose of Abcertin for 6 months. The primary endpoint was the change in hemoglobin concentration. The secondary endpoints were changes from baseline in platelet counts, spleen and liver volumes, biomarker levels, skeletal parameters, and bone mineral density. RESULTS: The hemoglobin concentration increased by a mean of 1.96 +/- 0.91 g/dL (range 1.11-2.80 g/dL) or 20.6% (P = .001). Statistically significant increases in the platelet count and decreases in the spleen volume and biomarker levels were also observed. There were no severe drug-related adverse events. One patient developed anti-imiglucerase antibodies without neutralizing activity. CONCLUSION: Our study results demonstrate the efficacy and safety of Abcertin in patients with type 1 GD. This suggests that Abcertin can be an alternative ERT option for type 1 GD. PMID- 29137042 TI - Associations among medication regimen complexity, medical specialty, and medication possession ratio in newly diagnosed hypertensive patients: A population-based study. AB - The aim of this study was to explore the associations among the medication regimen complexity index (MRCI), medical specialty, and medication possession ratio (MPR) in newly diagnosed hypertensive patients.Data from 19,859 newly diagnosed hypertensive patients were collected from 2,000,000 random samples of the National Health Insurance Research Database in Taiwan. All study participants were followed for 1 year after the first diagnosis of hypertension. MPR was defined as total days of antihypertensive drugs supplied/365 days. MRCI was calculated on the basis of the type of dosage forms, dosing frequency, and additional directions for use of antihypertensive drugs. Patients were further restricted to those who visited the same medical specialty to examine specialty specific variations in the MRCI and MPR.The mean MPR was 54.83%, and the sample sizes for the low-, medium-, and high-MPR groups were 9806 (49.38%), 4619 (23.26%), and 5434 (27.36%), respectively. More than 50% of the patients visited the same medical specialty during the 1-year follow-up. The mean MRCI was 3.64; the cardiology specialty had the highest MRCI, and the family medicine specialty had the lowest. Multiple linear regression analyses showed that MRCI was negatively associated with MPR (beta = -7.75, P <= .01) whether or not the patients visited the same medical specialty. For the patients who visited the same medical specialty, those treated by endocrinology and metabolism specialists had a significantly higher MPR (beta = 9.87, P <= .01) than that of those treated by family medicine specialists.MRCI and medical specialty were both significantly associated with the MPR of newly diagnosed hypertensive patients. PMID- 29137041 TI - Efficacy of rituximab combined with CHOP for treating patients with diffuse large B-cell lymphoma. AB - BACKGROUND: This study aimed to evaluate the efficacy and safety of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treating patients with diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 144 patients with DLBCL were randomly divided into intervention group and control group, 72 patients in each group. The patients in the control group received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, while the participants in the intervention group received R-CHOP. The primary endpoint was relapse-free survival (RFS) and the secondary endpoints were overall survival rate (OSR) and adverse events (AEs). RESULTS: One hundred thirty-four patients completed the study. The intervention with R-CHOP did not show greater efficacy than CHOP in the estimated median follow-up time (intervention group 33 months vs control group 29 months, P = .15). In addition, no significant differences in the 5-year RFS (intervention group 81% vs placebo group 76%, P = .28) or the 5-year OSR (intervention group 93% vs placebo group 91%, P = .53) were found between the 2 groups. The AEs were also similar between the 2 groups. CONCLUSION: This study demonstrated that R-CHOP, when compared with CHOP alone, could not improve the RFS and OS of patients with DLBCL. Additionally, both groups had similar safety profiles. PMID- 29137043 TI - Portal vein thrombosis before and after transjugular intrahepatic portosystemic shunt placement: An observational study (STROBE compliant). AB - Portal vein thrombosis (PVT) is common in patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS). This study had 3-fold aims: to assess risk factors for PVT; to determine the efficacy of anticoagulant therapy; to investigate the impact of PVT on clinical outcomes in TIPS-treated cirrhosis.Between June 2012 and February 2016, 126 TIPS-treated patients with cirrhosis were enrolled and studied prospectively. Enrolled patients were screened for PVT before TIPS and at 3, 6, 12, and 24 months post-TIPS. All patients received warfarin (1.5-3.0 mg/day) or aspirin (100 mg/day) or clopidogrel (75 mg/day) post-TIPS. Results of patients with and without PVT (baseline and de novo) were compared.White blood cell (WBC) counts (odds ratio (OR): 0.430, 95% confidence interval (CI): 0.251-0.739, P = .002) and Child Turcotte-Pugh (CTP) score (OR: 2.377, 95% CI: 1.045-5.409, P = .039) were significant baseline predictors for PVT in TIPS-treated patients with cirrhosis. Warfarin resulted in markedly greater rates of complete recanalization than aspirin or clopidogrel (P < .05) in patients with PVT. Patients with PVT had markedly higher 2-year cumulative rates of variceal rebleeding, shunt dysfunction, hepatic encephalopathy, and hepatocellular carcinoma, and prominently lower overall survival than those without PVT (P < .05).In TIPS treated patients with cirrhosis, lower WBC count and higher CTP score were independent baseline predictors for PVT; patients with PVT had worse clinical outcomes than those without; warfarin may be more effective in recanalizing PVT than aspirin or clopidogrel. PMID- 29137044 TI - Outcomes of percutaneous coronary intervention in patients with coronary chronic total occlusions with versus without type 2 diabetes mellitus: A systematic review and meta-analysis. AB - BACKGROUND: Nowadays, due to advanced techniques and well-trained interventionists in catheter labs, new scientific research has shown percutaneous coronary intervention (PCI) to be a safe treatment procedure in patients with chronic total occlusion (CTO). However, no study has systematically compared PCI outcomes in CTO patients with versus without type 2 diabetes mellitus (T2DM). Therefore, through this meta-analysis we aimed to systematically solve this issue. METHODS: Between September 2016 and June 2017, the Cochrane Database of Randomized Trials, EMBASE, and MEDLINE databases were carefully searched for publications comparing PCI outcomes in CTO patients with versus without T2DM. Long-term (>=1 year) adverse clinical outcomes were considered the endpoints. Discontinuous data were analyzed by RevMan 5.3 whereby odds ratios (OR) and 95% confidence intervals (CIs) were the statistical parameters. RESULTS: This analysis consisted of 1 randomized trial and 6 observational studies with a total number of 4571 patients with CTO (1915 patients with T2DM and 2656 patients without T2DM). Patients' enrollment was between the years 1998 and 2015.During this long-term follow-up (>=1 year), mortality was significantly higher in CTO patients with T2DM (OR: 1.56, 95% CI: 1.05-2.31; P = .03, I = 0%). Major adverse cardiac events (MACEs) and repeated revascularization were also significantly higher in patients with T2DM (OR: 1.30, 95% CI: 1.06-1.58; P = .01, I = 10%) and (OR: 1.30, 95% CI: 1.06-1.59; P = .01, I = 36%) respectively. However, myocardial infarction was not significantly different (OR: 1.01, 95% CI: 0.61-1.67; P = .96, I = 26%). CONCLUSION: During this longer follow-up period post-PCI, mortality, MACEs and repeated revascularization in CTO patients with T2DM were significantly higher compared with similar patients without T2DM. Nevertheless, whether this hypothesis is relevant or not should be confirmed in larger trials. PMID- 29137045 TI - The significance of uric acid in the diagnosis and treatment of Parkinson disease: An updated systemic review. AB - BACKGROUND: Parkinson disease (PD) is a neurodegenerative disease characterized by chronic and progressive loss of dopaminergic neurons in substansia nigra pars compacta. Oxidative stress is proposed to play a critical role in the pathogenesis of PD. Uric acid (UA), as an important physiological antioxidant, is identified a molecular predictor associated with a decreased risk and a slower disease progression for PD and potential neuroprotectant of PD by increasing epidemiological and clinical evidences. Within this review, we will present a comprehensive overview of the data linking UA to PD in recent years. METHODS: We searched PubMed, EMBASE, Web of Science databases for relevant studies. Any observational or experimental studies that evaluated UA and PD were our goal of searching the electric databases. RESULTS: Twelve studies that evaluated UA and PD were identified in this review. We reviewed the roles of UA in the pathogenesis of PD, the association of UA with morbidity, severity/progression, nonmotor symptoms, motor complications of PD, with an attempt to provide new ideas for diagnosis and treatment in PD. CONCLUSION: Our findings supported that lots of clinical and epidemiological data observed lower UA levels in PD patients. Manipulation of UA or its precursors' concentration could be effective to treat or prevent PD. However, it is still suspectable that higher UA levels are better enough to PD patients. Furthermore, for the complex nature of PD and its heterogeneous genetic and environmental influences, it is inadequate for just manipulating UA in treating the disease. PMID- 29137046 TI - Multiple adverse drug reactions and genetic polymorphism testing: A case report with negative result. AB - RATIONALE: Defects in drug metabolic pathways could explain why some patients have a history of multiple adverse drug reactions (ADR); therefore we aimed to analyze genetic polymorphisms in a patient with multiple ADR related to drugs with a common hepatic metabolic pathway through CYP2D6. PATIENT CONCERNS: We report a patient with psychosis and hypertension related to amitriptyline, tramadol, and duloxetine within a 2-year period. INTERVENTIONS AND OUTCOMES: A pharmacogenetic test was performed to assess the causative role of the CYP2D6 enzyme, but did not demonstrate a metabolic deficiency. LESSONS: Although negative results in the reported case; typing for cytochrome P450 isoenzyme polymorphisms could be a useful diagnostic tool in some patients with a history of multiple ADR. PMID- 29137047 TI - Massive neonatal intracranial hemorrhage caused by bromadiolone: A case report. AB - RATIONALE: Bromadiolone, often called a super-warfarin, is a potent rodenticide with long half-life. Skin and mucosal bleeding is the most common clinical manifestations of its intoxication. Bromadiolone intoxications in adults and children have been reported, but this phenomenon is rarely seen in fetuses. This paper presents a case of neonate with massive intracranial hemorrhage mediated by bromadiolone intoxication, highlighting that the bromadiolone is potentially lethal to the fetus. PATIENT CONCERNS: The male neonate presented with poor respiratory effort, decreased muscle tone, and pallor at birth. He developed generalized seizures on day 1 of life. His mother suffered from bleeding of oral mucosa and the subsequent lab screening for toxicants showed a bromadiolone level of 126 ng/mL. DIAGNOSES: Laboratory tests revealed that prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT). A computed tomography (CT) of his head revealed a severe subdural hematoma, which lead to midline shift, bilateral intraventricular hemorrhage, and subarachnoid hemorrhage. Serum from cord blood was collected and screened for toxicants. The result returned with a bromadiolone level of 94 ng/mL. INTERVENTIONS: The neonate was treated with vitamin K, fresh-frozen plasma, and red blood cells. OUTCOMES: His parents required termination of all treatments, and the neonate unfortunately died shortly after. LESSONS: Through clinical experience from this case, we believe that bromadiolone can be passed down to the fetus via placenta. Neonatal intracranial hemorrhage caused by bromadiolone is rare but potentially lethal. Pregnant women should be informed of the serious side effects of bromadiolone and this poisonous reagent should be avoided in any period during pregnancy. PMID- 29137049 TI - Garcin syndrome caused by parotid gland adenoid cystic carcinoma: A case report. AB - RATIONALE: Garcin syndrome is characterized by the gradual involvement, and ultimately, unilateral paralysis of at least 7 and sometimes all cranial nerves, without intracranial hypertension or any long tract signs. PATIENT CONCERNS: We report the case of a 59-year-old woman who presented with Garcin syndrome, which gradually progressed over a period of 2 years. DIAGNOSIS: A left parotid gland biopsy revealed parotid gland adenoid cystic carcinoma (PGACC) with perineural invasion of a peripheral nerve bundle and lymph node metastasis. INTERVENTIONS: The patient was treated 3 times with local-field palliative radiotherapy. OUTCOMES: She died after several months. LESSONS: To the best of our knowledge, this is the first report of PGACC presenting as Garcin syndrome. PGACC is a rare tumor with a high propensity for perineural spread, and it should be considered as a possible cause of Garcin syndrome. PMID- 29137048 TI - Apatinib for the treatment of pulmonary epithelioid hemangioendothelioma: A case report and literature review. AB - RATIONALE: Pulmonary epithelioid hemangioendothelioma (P-EHE) is a rare tumor, with no established standard treatment. Overexpression of vascular endothelial growth factor receptor 2 (VEGFR-2) has been reported in some P-EHE patients. Apatinib, a new small molecule tyrosine kinase inhibitor that specifically targets VEGFR-2, has therapeutic benefits in some advanced tumors. However, its efficacy in P-EHE cases has not been reported. PATIENT CONCERNS: Herein, we presented a 44-year-old man with recurrent hemoptysis for approximately 9 years. DIAGNOSES: After hospitalization, relevant examinations were conducted. The disease was subsequently diagnosed as P-EHE. INTERVENTIONS: The patient underwent pulmonary lobectomy, but subsequently developed multiple metastases. Within the tumor, CD31, CK, and Vimentin were found to be positive, while CD34 was negative. Apatinib was initially administered 250 mg daily doses and after 1 month was increased to 500 mg daily. OUTCOMES: He showed noticeable symptomatic improvements and positive imaging changes in the first month of treatment. However, the disease progressed in the following month, despite the increased apatinib dose. LESSONS: Apatinib is possibly a new treatment for P-EHE. However, further clinical trials are necessary to confirm an effective dose and the efficacy and safety of apatinib in P-EHE treatment. PMID- 29137050 TI - Uncommon cause of fungemia in a patient with renal cell cancer: A case report of Candida lusitaniae Fungemia. AB - INTRODUCTION: We present an interesting case of Candida lusitaniae infection in a patient diagnosed with renal clear cell carcinoma.An 82-year-old male presented with worsening back pain for 1 week. Physical examination including neurologic examination was normal. A computed tomography scan of the abdomen revealed a mass in the right upper pole of the kidney suggestive of a renal neoplasm. Pathology from a percutaneous biopsy of the kidney revealed clear cell carcinoma. During his hospitalization the patient developed fungemia due to C lusitaniae. He was started on fluconazole, which was later switched to caspofungin due to worsening transaminitis. The patient's clinical status improved and repeat blood cultures were negative for fungal growth. CONCLUSION: To our knowledge, this is the first case of C lusitaniae reported in a patient diagnosed with clear cell carcinoma of the kidney. PMID- 29137051 TI - Neutrophil-to-lymphocyte and aspartate-to-alanine aminotransferase ratios predict hepatocellular carcinoma prognosis after transarterial embolization. AB - The neutrophil-to-lymphocyte ratio (NLR) reflects the systematic inflammatory status, and the aspartate aminotransferase-to-alanine aminotransferase ratio (AAR) is a biomarker of liver fibrosis and cirrhosis. These values can be conveniently obtained from routine blood tests; however, their combined clinical utility has not been extensively studied in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). This study aimed to investigate the prognostic value of NLR-AAR in patients with unresectable HCC undergoing TACE. Data for 760 patients with newly diagnosed HCC were retrospectively evaluated. The NLR-AAR was calculated as follows: patients in whom both the NLR and AAR were elevated according to the receiver operating characteristic (ROC) curve analysis were assigned a score of 2; patients showing an elevation in one or neither of these indicators were assigned a score of 1 or 0, respectively. Univariate and multivariate analyses were performed to identify the clinicopathological variables associated with overall survival. An ROC curve was also generated and the area under the curve (AUC) was calculated to evaluate the discriminatory ability of each index at 1, 3, and 5 years of follow-up, as well as overall. The NLR-AAR consistently had a greater AUC value at 1 year (0.669), 3 years (0.667), and 5 years (0.671) post-TACE compared with either NLR or AAR alone. The median survival times of patients with a NLR-AAR of 0, 1, and 2 were 31.0 (95% confidence interval [CI] 24.0-38.0), 15.0 (95% CI 11.2-18.8), and 5.0 (95% CI 4.0-5.9) months, respectively (P < .001). Multivariate analysis showed that the NLR-AAR, elevated total bilirubin level, and vascular invasion were independently associated with overall survival. NLR and AAR, when combined to produce an inflammation-based index and fibrosis score, is an independent marker of poor prognosis in patients with HCC receiving TACE. PMID- 29137052 TI - Arytenoid cartilage dislocation mimicking bilateral vocal cord paralysis: A case report. AB - RATIONALE: Arytenoid dislocation is very rare and may be misdiagnosed as vocal cord paralysis or a self-limiting sore throat. PATIENT CONCERNS: A 70-year-old male (70 kg, 156 cm) was scheduled for transurethral resection of bladder tumors. A McGrath videolaryngoscope, with a basic cuffed Mallinckrodt oral tracheal tube of 7.5 mm internal diameter, was used to successfully intubate his trachea. The duration of surgery was 25 minutes. In the recovery room, he complained of sore throat and dyspnea with inspiratory stridor, which were not resolved after intravenous injection of 10 mg of dexamethasone. DIAGNOSES: The otolaryngological examination revealed midline fixation of the bilateral vocal folds, suggestive of bilateral arytenoid dislocation or bilateral vocal cord palsy. The latter was ruled out because there was no evidence of recurrent laryngeal nerve injury. INTERVENTIONS: Under general anesthesia, a closed reduction was performed using laryngoscopic forceps to apply posterolateral pressure on the arytenoid joints on both sides. Only the dislocation of the left cricoarytenoid joint could be easily reduced, whereas reduction of the right joint was not possible. OUTCOMES: On postoperative day 7, examination with a rigid laryngoscope showed a medially fixed right vocal fold, with full compensation by the left vocal fold. Computed tomography of the neck showed no pathologic findings. Six weeks after surgery, the patient had regained his normal voice with no complications. LESSONS: Although arytenoid dislocation is a rare complication, it should be considered even in patients with uncomplicated tracheal intubation. Early diagnosis and the optimal therapeutic approach are critical for restoration of the patient's original vocal cord function. PMID- 29137053 TI - Prognostic value of high-resolution magnetic resonance imaging in evaluating carotid atherosclerotic plaque in patients with ischemic stroke. AB - BACKGROUND: Ischemic stroke (IS) is a devastating occurrence affecting millions worldwide. This study aimed to evaluate the prognostic value of high-resolution magnetic resonance imaging (HRMRI) in assessing carotid atherosclerotic plaque in IS patients. METHODS: Between January 2013 and March 2015, 338 IS patients were recruited for the investigative purposes of the study. All participants of the study underwent an HRMRI inspection procedure after being admitted into the hospital. During this study, we systematically analyzed and measured various types of fibrous caps, lipid compositions, and plaque lipid ratios. Univariate and multivariate logistic regression analyses were performed for predicting prognosis of IS patients. A receiver-operating characteristic (ROC) curve was employed to determine the accuracy of the IS prognosis. RESULTS: The percentage of type I fibrous caps exhibited significant decrease, while the percentage of type III fibrous caps, lipid compositions, and lipid ratios all displayed increase. The results of the univariate analysis indicated that age, hypertension, hyperlipidemia, treatment regimens, fibrous cap type, plaque type, lipid composition, and lipid ratio shared a correlation in regards to the poor prognosis of IS patients. Multivariate logistic regression analysis demonstrated that the prognosis of IS patients was not necessarily dependent on fibrous cap type, plaque type, or age. ROC curves revealed that the HRMRI possessed a strong predicative ability in relation to the identification of the prognosis of IS patients through factors such as type of plaque and fibrous caps determination. CONCLUSION: Our study conclusively intimated the promise of HRMRI as an evaluative tool for the determination of carotid atherosclerotic plaques in patients with IS. PMID- 29137054 TI - Case report: middle-aged woman from Ghana with unsteady gait and enlarging cerebellar mass. AB - RATIONALE: Neurosarcoidosis (NS) is an uncommon manifestation of systemic sarcoidosis, with a propensity for middle-agedwomen. Often discovered only at autopsy, rates of neurologic involvement (5%-10%) reported in the literature underscore a lack of sensitivity and specificity in current diagnostic methods. PATIENT CONCERNS: Herein, we describe a 53-year-old woman who presented with gait imbalance and distal extremity muscular weakness. She was known to harbor a brain mass (4 years in duration) that was monitored and recently seemed to enlarge. DIAGNOSIS: A subsequent brain biopsy showed necrotizing granulomatous inflammation suggestive of NS. However, no clinical or radiologic evidence of activity was found in other organs. INTERVENTIONS AND OUTCOMES: Ultimately, endo and transbronchial biopsies were performed, providing histologic confirmation of systemic sarcoidosis. LESSONS: This approach is advised in all instances of suspected NS where systemic involvement is in question. PMID- 29137056 TI - Optic nerve injury-associated blunt cerebrovascular injury: Three case reports. AB - RATIONALE: Blunt cerebrovascular injury (BCVI) is a rare complication that may occur after craniocervical trauma. The current literature is limited to extracranial carotid artery injuries; however, no reports have been published on blunt intracranial carotid injury (BICI), especially those associated with optic nerve injury. PATIENT CONCERNS: Here we report on 3 BICI cases that demonstrated optic nerve injuries after craniofacial injuries. All 3 patients showed post trauma vision loss on the injured side. DIAGNOSES: Optical canal fractures can be found in these patients, and carotid sulcus was compressed by the fragments. Computed tomography angiography (CTA) and digital subtraction angiography (DSA) were performed in all 3 patients. INTERVENTIONS: Case 1 was given no further treatment, except for symptomatic support and rehabilitation therapy. Case 2 was treated with antiplatelet therapy for 3 days, and then a stent was inserted in the injured internal carotid. Case 3 received antiplatelet therapy and a internal carotid compression test was performed simultaneously for 2 weeks, then the injured internal carotid was completely blocked. OUTCOMES: Case 1 developed cerebral infarction that resulted in unilateral hemiplegia. Due to timely treatment, the remaining 2 patients had a better prognosis. LESSONS: CTA should be performed primarily to exclude vascular injury and for CTA-positive patients, a further DSA should be performed to investigate pathological changes and for a definitive diagnosis. At last, the current therapeutic protocols for BCVI are not entirely applicable to intracranial vascular injury, and appropriate protocols for the treatment of BICI should be selected based on the combination of test results and the actual condition of the patient. PMID- 29137055 TI - Efficacy of Tai Chi and qigong for the prevention of stroke and stroke risk factors: A systematic review with meta-analysis. AB - BACKGROUND: This review aims to summarize the evidence of Tai Chi and qigong interventions for the primary prevention of stroke, including the effects on populations with major stroke risk factors. METHODS: A systematic literature search was conducted on January 16, 2017 using the PubMed, Scopus, Cochrane Library, and CINAHL databases. Randomized controlled trials examining the efficacy of Tai Chi or qigong for stroke prevention and stroke risk factors were included. Risk of bias was assessed using the Cochrane Risk of Bias tool. RESULTS: Twenty-one trials with n = 1604 patients with hypertension, hyperlipidaemia, diabetes, overweight or obesity, or metabolic syndrome were included. No trials were found that examined the effects of Tai Chi/qigong on stroke incidence. Meta-analyses revealed significant, but not robust, benefits of Tai Chi/qigong over no interventions for hypertension (systolic blood pressure: 15.55 mm Hg (95% CI: -21.16; -9.95); diastolic blood pressure: -10.66 mm Hg (95% CI: -14.90, -6.43); the homeostatic model assessment (HOMA) index (-2.86%; 95% CI: -5.35, -0.38) and fasting blood glucose (-9.6 mg/dL; 95% CI: -17.28, -1.91), and for the body mass index compared with exercise controls (-1.65 kg/m; 95% CI: 3.11, -0.20). Risk of bias was unclear or high for the majority of trials and domains, and heterogeneity between trials was high. Only 6 trials adequately reported safety. No recommendation for the use of Tai Chi/qigong for the prevention of stroke can be given. CONCLUSION: Although Tai Chi and qigong show some potential more robust studies are required to provide conclusive evidence on the efficacy and safety of Tai Chi and qigong for reducing major stroke risk factors. PMID- 29137058 TI - Anemia and thrombocytopenia as initial symptoms of occult breast cancer with bone marrow metastasis: A case report. AB - RATIONALE: Occult breast cancer (OBC) is a rare type of breast cancer without any symptoms in the breast and is often presented with initial symptoms of axillary lymph node metastasis or other metastases. The low incidence rates of OBC make it a great challenge to diagnose and cure. PATIENT CONCERNS: Our case was a 58-year old female affected by dizziness and fatigue for nearly a month. Blood tests revealed anemia and thrombocytopenia, and pathological results of a bone marrow biopsy confirmed the metastatic carcinoma. DIAGNOSES: It was diagnosed as an OBC based on the positive immunohistochemical staining of cytokeratin (CK) and gross cystic disease fluid protein-15 (GCDFP-15). INTERVENTIONS: Doctor advised her to check whether the bone metastases existed in order to choose an appropriate treatment. It is highly regrettable that the patient gave up all treatments and left the hospital. OUTCOMES: Recently, we conducted a telephone follow-up and received that the patient only took tramadol and other painkilling drugs to alleviate the pain caused by cancer. LESSONS: The current case inferred that symptoms of anemia and thrombocytopenia should not be ignored for the diagnosis of OBC, and bone marrow biopsy is useful in reducing the rates of misdiagnosis and missed diagnosis of OBC. PMID- 29137057 TI - Readability of internet-sourced patient education material related to "labour analgesia". AB - We evaluated the readability of Internet-sourced patient education materials (PEMs) related to "labour analgesia." In addition to assessing the readability of websites, we aimed to compare commercial, personal, and academic websites.We used the most popular search engine (http://www.google.com) in our study. The first 100 websites in English that resulted from a search for the key words "labour analgesia" were scanned. Websites that were not in English, graphs, pictures, videos, tables, figures and list formats in the text, all punctuation, the number of words in the text is less than 100 words, feedback forms not related to education, (Uniform Resource Locator) URL websites, author information, references, legal disclaimers, and addresses and telephone numbers were excluded.The texts included in the study were assessed using the Flesch Reading Ease Score (FRES), Flesch-Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG), and Gunning Frequency of Gobbledygook (FOG) readability formulae. The number of Latin words within the text was determined.Analysis of 300-word sections of the texts revealed that the mean FRES was 47.54 +/- 12.54 (quite difficult), mean FKGL and SMOG were 11.92 +/- 2.59 and 10.57 +/- 1.88 years of education, respectively, and mean Gunning FOG was 14.71 +/- 2.76 (very difficult). Within 300-word sections, the mean number of Latin words was identified as 16.56 +/- 6.37.In our study, the readability level of Internet sourced PEM related to "labour analgesia" was identified to be quite high indicating poor readability. PMID- 29137059 TI - Adherence to gout management recommendations of Chinese patients. AB - Though efficacious and affordable treatments for gout are widely available, gout is still not well controlled in many countries of the world including China.To investigate patient adherence to gout management recommendations and potential barriers in Chinese male gout patients, a survey was carried out by telephone interview in male patients registered in the gout clinic at Peking Union Medical College Hospital. Adherence to dietary and medication recommendations was measured by a food frequency questionnaire and proportion of cumulative time adherent to chemical urate-lowering therapy (ULT), respectively. Dietary adherence was defined as consumption of alcohol, seafood and animal organs less than once per month, and reduced red meat after dietary counseling. Medication adherence was defined as ULT >=80% of time in the past 12 months for patients with indications. Logistic regression models were used to identify patient characteristics associated with management adherence. Reasons for nonadherence were also sought by open-end questions.Dietary and medication adherence were 44.2% and 21.9%, respectively. Older age (odds ratio [OR] 7.90, 95% confidence interval [CI] 2.49-25.04 for age >=60), higher serum uric acid (sUA) levels (OR 3.53, 95% CI 1.42-8.75 for the highest quartile), and tophi (OR 2.31, 95% CI 1.12 4.77) were associated with dietary adherence independently, while tophi (OR 14.05, 95% CI 2.67-74.08) and chronic kidney disease (OR 16.66, 95% CI 2.63 105.37) were associated with medication adherence independently. Reasons that patients reported for nonadherence to medication included remission after treatment (35.3%), concerns for potential side effects (22.7%), insufficient patient education (8.7%), and adverse events (8.2%).Patient adherence to gout management recommendations is poor in China. Older age, increased disease burden, and specific comorbidities were associated with management adherence. PMID- 29137060 TI - A case report of mixed acinar-endocrine carcinoma of the pancreas treated with S 1 chemotherapy: Does it work or induce endocrine differentiation? AB - RATIONALE: Acinar cell carcinomas (ACCs) and mixed acinar-endocrine carcinomas (MAECs) of the pancreas are rare, accounting for only 1% of pancreatic tumors. Although both typically present at an advanced stage, chemotherapeutic regimes have not yet been standardized. PATIENT CONCERNS: A 65-year-old man presented with a large mass in the pancreatic tail with multiple liver metastases. DIAGNOSIS, INTERVENTIONS, OUTCOMES: He was initially treated with gemcitabine for suspected ductal carcinoma of the pancreas, but no response was observed. S-1, administered as second-line chemotherapy, showed an approximately 38% reduction in the size of the primary tumor and metastatic deposits with therapeutic effects being maintained for 12 months. When the tumor progressed again, he underwent a percutaneous liver biopsy, which led to the diagnosis of MAEC. Combination therapy with cisplatin and etoposide targeting the endocrine component was administered, and this was based on the endocrine component potentially being less sensitive to S-1 than the ACC element. However, therapy was stopped due to the development of neutropenia, and the patient is currently receiving best supportive care. LESSONS: Given the previous studies suggested that S-1 is more effective for ACCs than gemcitabine, MAECs may also respond to S-1 chemotherapy, similar to ACCs. Another potential interpretation is that S-1 was effective when the condition was ACC, and eventually showed decreased effectiveness when the condition shifted to MAEC. Future studies are needed to conclude whether S-1 chemotherapy truly works against MAECs or induces endocrine differentiation in ACCs as a part of the drug-resistance process. PMID- 29137061 TI - Low free triiodothyronine levels predict symptomatic intracranial hemorrhage and worse short-term outcome of thrombolysis in patients with acute ischemia stroke. AB - The aim of the study was to determine whether thyroid hormones level on admission in patients with ischemic stroke, treated with intravenous recombinant tissue type plasminogen activator (rtPA), was associated with symptomatic intracranial hemorrhage (sICH) and worse outcomes at 3 months.Patients with acute ischemic stroke (AIS) receiving intravenous rtPA thrombolytic treatment on our stroke unit between January 2015 and June 2016 were included in this study. Serum-free triiodothyronine (fT3), free thyroxine (fT4), total triiodothyronine (tT3), total thyroxine (tT4), and thyroid-stimulating hormone (TSH) were detected on admission. The endpoints were sICH, and poor functional outcomes at 3 and 6 months.In all, 159 patients (106 males; mean age 65.36 +/- 10.02 years) were included. FT3 was independently associated with sICH (odds ratio [OR] 0.204, 95% confidence interval [CI] 0.065-0.642) and poor outcomes at 3 months (OR 0.396, 95% CI 0.180-1.764). The cut-off values of fT3 for sICH was 3.54 pg/mL (sensitivity 83%; specificity 83%; area under the curve 0.88). FT3 values <=3.54 pg/mL increased risk for sICH by 3.16-fold (95% CI 0.75-1.0) compared with fT3 values >3.54 pg/mL.Low fT3 levels at admission were independently associated with sICH and worse outcomes at 3 months in AIS patients receiving rtPA thrombolytic therapy. PMID- 29137062 TI - Postoperative aspartate aminotransferase to lymphocyte ratio index change is an independent predictor of survival in patients with small hepatocellular carcinoma. AB - Elevated preoperative aspartate aminotransferase (AST) to lymphocyte ratio index (ALRI) is reported to be a prognostic factor for patients with hepatocellular carcinoma (HCC) after treatment. However, [DELTA] ALRI which represents the change from postoperative ALRI to preoperative ALRI change has received little attention. The present study was designed to evaluate the prognostic value of [DELTA] ALRI in small HCC patients after liver resection.A retrospective cohort study was performed to analyze 241 patients with small HCC who underwent liver resection. Patients were divided into Group A ([DELTA] ALRI < 0, n = 142) and group B ([DELTA] ALRI >= 0, n = 99) according to postoperative ALRI change. Clinical data, overall survival (OS), and recurrence-free survival (RFS) were compared between the 2 groups, and a multivariate analysis was used to identify prognostic factors.The 1, 3, and 5-year OS rates were 96.5%, 84.9%, and 70.8%, respectively, for group A, and 94.9%, 75.8%, and 59.7%, respectively for group B (P = .014). The corresponding 1, 3, and 5-year RFS rates were 78.2%, 54.6%, and 52.3%, respectively, for group A, and 62.6%, 40.1%, 24.5%, respectively, for group B (P < .001). The results of univariate and multivariate analysis indicated that [DELTA] ALRI was an independent prognostic factor for both RFS (P < .001, hazard ratio [HR] 2.192, 95% confidence interval 1.527-3.147) and OS (P < .001, HR 2.381, 95% confidence interval 1.503-3.771).A positive [DELTA] ALRI after liver resection predicts decreased OS and RFS in patients with small HCC. PMID- 29137063 TI - Gallstone ileus displaying the typical Rigler triad and an occult second ectopic stone: A case report. AB - RATIONALE: Gallstone ileus is a rare complication of cholecystolithiasis. It has a female predominance and can result in high mortality rates. PATIENT CONCERNS: A 71-year-old woman complaining of recurrent vomiting and vague epigastralgia for > 2 weeks presented to our department. DIAGNOSIS: Based on her physical examination, laboratory test results and radiographic findings (the typical Rigler's triad), she was diagnosed with gallstone ileus caused by multiple ectopic stones. INTERVENTIONS: After correction of electrolyte imbalances through parenteral nutrition and fluid management, the patient's condition improved and she underwent enterolithotomy. A 5.3-cm stone located 40 cm from the ligament of Treitz was extracted, and a second ectopic stone, not detected on any imaging modality, was found during laparotomy. Given her comorbidities and overall poor condition, cholecystectomy and fistula repair were not performed. OUTCOMES: The patient gradually recovered postoperatively. LESSONS: Clinical symptoms including epigastralgia with nausea and vomiting, and abdominal CT findings of Rigler's triad (ectopic gallstone, bowel obstruction, and pneumobilia) may lead to early diagnosis of gallstone ileus and enterolithotomy may be the preferred treatment for this condition in the elderly. Laparotomy should involve a systematic and meticulous search for the presence of additional ectopic enteric stones. PMID- 29137064 TI - Clinical features and prognostic factors in patients with intraventricular hemorrhage caused by ruptured arteriovenous malformations. AB - Intraventricular hemorrhage (IVH) was associated with poor outcomes in patients with intracerebral hemorrhage. IVH had a high incidence in patients with ruptured arteriovenous malformations (AVMs). In this study, we aimed to discuss the clinical features and prognostic factors of outcomes in the patients with AVM related IVH.From January 2010 to January 2016, we collected the data of the patients with AVM-related IVH retrospectively. The data, including clinical and radiological parameters, were collected to evaluate the clinical features. Univariate and multivariate logistic regression analyses were used to identify the prognostic factors for clinical outcomes (hydrocephalus, 6-month outcomes measured by the modified Rankin scale) in our cohort.A total of 67 eligible patients were included and 19 patients (28%) only presented with IVH. Thirty three patients (49%) presented hydrocephalus, and 12 patients (18%) presented brain ischemia. Nineteen patients (28%) had a poor outcome after 6 months. In multivariate logistic regression, subarachnoid hemorrhage (SAH) (P = .028) was associated with hydrocephalus and higher Graeb score (P = .080) tended to increase the risk of hydrocephalus. The high Glasgow coma scale (P = .010), large hematoma volume of parenchyma (P = .006), and high supplemented Spetzler-Martin (sup-SM) score (P = .041) were independent factors of the poor outcome.IVH was common in ruptured AVMs and increased the poor outcomes in patients with the ruptured AVMs. The AVM-related IVH patients had a high incidence of hydrocephalus, which was associated with brain ischemia and SAH. Patients with lower Glasgow coma scale, lower sup-SM score, and smaller parenchymal hematoma had better long-term outcomes. PMID- 29137065 TI - Primary leiomyosarcoma of the bone: a case report and a review of the literature. AB - RATIONALE: Leiomyosarcoma (LMS) is a malignant sarcoma that can occur in different anatomic sites, including the bone, showing similar histological characteristics but heterogeneous clinical behavior and prognosis. Primary bone LMS was first described in 1965. It is a very rare sarcoma, accounting for <0.7% of all primary malignant bone tumors. PATIENT CONCERNS: We report the case of a 52-year-old male with primary bone LMS who presented with a solitary osteolytic lesion with focal cortical destruction in the left clavicle, seen on an x-ray and subsequent computed tomography (CT) scan. DIAGNOSIS: The multidisciplinary Osteoncology team of our institute planned a biopsy that revealed the presence of spindle and pleomorphic cells with a positive reaction for smooth muscle actin and desmin at immunohistochemical analysis, without the presence of cartilage or bone matrix. These results were consistent with a high-grade malignant LMS arising from the bone. INTERVENTIONS: Complete surgical resection of the tumor was performed and a decision was made with the patient not to proceed with adjuvant chemotherapy or radiotherapy. OUTCOMES: After more than 1 year of surgery, the patient is well, with no evidence of recurrent or metastatic disease. Follow-up is ongoing. LESSONS: Little is known about the biology and clinical behavior of bone LMS due to its extreme rarity. A multidisciplinary team in a specialized center is needed for the optimal management of the disease. Surgery with a curative intent is the cornerstone of treatment of localized disease. No data are available about chemotherapy in neoadjuvant, adjuvant, or advanced settings. Further research is needed to identify more effective therapies. PMID- 29137066 TI - A coronary artery fistula having connection between 2 coronary arteries and the left ventricle: A case report. AB - RATIONALE: Cases of coronary artery fistula having a connection with the cardiac cavity are rare. Here, we report a case in which 2 coronary arteries empty into the left ventricular cavity together. PATIENT CONCERNS: A 63-year-old woman who was diagnosed as having hypertension 20 years prior presented with dyspnea. DIAGNOSES: The coronary angiography revealed coronary artery fistula. INTERVENTIONS: Chest X-ray showed pulmonary edema. Transthoracic echocardiography revealed moderately decreased left ventricular (LV) function and increased LV end diastolic volume and mass index. Coronary angiography and cardiac computed tomography revealed that 2 coronary arteries joined together at the distal end and directly drained into the left ventricular cavity bypassing the myocardial capillary vessels. We started medical treatment for heart failure with an angiotensin-converting-enzyme inhibitor, loop diuretic, and spironolactone. OUTCOMES: The pulmonary edema improved rapidly. The patient did not experience dyspnea after discharge, and follow-up echocardiography showed improved cardiac function. MAIN LESSON: Coronary artery fistula could be found incidentally on coronary angiography performed for varied reasons. Physicians must decide carefully whether the fistula needs to be treated in view of the clinical context. PMID- 29137067 TI - Harlequin syndrome and Horner syndrome after neck schwannoma excision in a pediatric patient: A case report. AB - RATIONALE: Harlequin syndrome is an extremely rare benign condition characterized by unilateral facial flushing and sweating. PATIENT CONCERN: An 11-year-old boy presented with complaint of a right neck mass of 1-month duration. DIAGNOSIS: The preoperative diagnosis was neurogenic tumor of vagus nerve or sympathetic nerve. INTERVENTIONS: We performed right neck mass removal under general anesthesia. OUTCOMES: We report a case of harlequin syndrome associated with Horner syndrome in an 11-year boy who underwent excision of right neck schwannoma. LESSONS: Clinicians should consider the point that harlequin syndrome could occur as a first sign of more serious conditions. PMID- 29137068 TI - Carnitine-acylcarnitine translocase deficiency with c.199-10 T>G and novel c.1A>G mutation: Two case reports and brief literature review. AB - RATIONALE: Carnitine-acylcarnitine translocate deficiency (CACTD) is a rare and life-threatening, autosomal recessive disorder of fatty acid beta-oxidation characterized by hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy, liver dysfunction, and muscle weakness; culminating in early death. To date, CACTD cases screened from the Chinese mainland population, especially patient with compound heterozygote with c.199-10T>G and a novel c.1A>G mutation in the SLC25A20 gene has never been described. PATIENT CONCERNS: Herein, we report 2 neonatal cases of CACTD identified from the mainland China. These 2 patients were presented with severe metabolic crisis and their clinical conditions deteriorate rapidly and both died of cardiorespiratory collapse in the first week of life. We present the clinical and biochemical features of 2 probands and a brief literature review of previously reported CACTD cases with the c.199-10T>G mutation. DIAGNOSES: The acylcarnitine profiles by tandem-mass-spectrometry and the mutation analysis of SLC25A20 gene confirmed the diagnosis of CACTD in both patients. Mutation analysis demonstrated that patient No. 1 was homozygous for c.199-10T>G mutation, while patient No. 2 was a compound heterozygote for 2 mutations, a maternally-inherited c.199-10T>G and a paternally-inherited, novel c.1A>G mutation. INTERVENTIONS: Both patients were treated with an aggressive treatment regimen include high glucose and arginine infusion, respiratory, and circulatory support. OUTCOMES: The first proband died 3 days after delivery due to sudden cardiac arrest. The second patient's clinical condition, at one time, was improved by high glucose infusion, intravenous arginine, and circulatory support. However, the patient failed to wean from mechanical ventilation. Unfortunately, her parents refused further treatment due to fear of financial burdens. The patient died of congestive heart failure in the 6th day of life. LESSONS: We report the first 2 cases of CACTD identified from the mainland China. Apart from a founder mutation c.199-10T>G, we identified a novel c.1A>G mutation. Patients with CACTD with a genotype of c.199-10T>G mutation usually presents with a severe clinical phenotype. Early recognition and appropriate treatment is crucial in this highly lethal disorder. This case series highlights the importance of screening for metabolic diseases including CACTD in cases of sudden infant death and unexplained abrupt clinical deterioration in the early neonatal period. PMID- 29137069 TI - Graves disease following radioiodine therapy for toxic adenoma: Clinical case report. AB - RATIONALE: There is a low risk of developing Graves disease (GD) with elevated thyrotropin receptor antibodies (TRAbs) in patients undergoing radioiodine therapy for toxic adenoma. PATIENT CONCERNS: An old female patient with a history of Hashimoto thyroiditis was referred to our department due to thyrotoxic symptoms. After the administration of radioiodine, a significant remission was achieved. However, after 4 months, she was referred to our department again due to recurrence of hyperthyroid symptoms. DIAGNOSES: Based on the results of laboratory test, thyroid scan and ultrasound examination, she was diagnosed as thyrotoxicosis induced by toxic adenoma at the first visit. However, 4 months later, she was diagnosed as Graves' disease at the second visit. INTERVENTIONS: She received radioiodine therapy two times with different doses of 15 mCi and 12 mCi. OUTCOMES: After the administration of 15 mCi radioiodine, her thyroid hormones and clinical symptoms showed significant improvement. However, 4 months later, she presented thyrotoxicosis again. After the second radioiodine therapy with a lower dose, her clinical symptoms moved towards normalization during regular follow up. LESSONS: Toxic adenoma and GD are considered as 2 distinct disease entities; however, radioiodine therapy for toxic adenoma may induce GD. We should learn to differentiate these 2 disorders prior to radioiodine therapy because of different treatment strategies and goals. PMID- 29137070 TI - A case report of primary adrenal angiosarcoma as depicted on magnetic resonance imaging. AB - RATIONALE: Angiosarcoma is an extremely rare malignant tumor of endothelial origin. The majority of studies reporting angiosarcoma have been concerned with the clinical and pathological aspects, with limited reporting of their imaging findings. To our knowledge, angiosarcoma of the adrenal gland is very rare. Herein we firstly report a primary adrenal angiosarcoma depicted on magnetic resonance imaging (MRI). PATIENT CONCERNS: A 59-year-old man was referred to our hospital for 1 year left-flank pain that exacerbated in recent 4 months. DIAGNOSIS: A regular mass with clear boundary was revealed on MRI in the region of left adrenal gland. Its signal intensity was inhomogeneous. It mainly showed isointensity with patchy slight hyperintensity on T1-weighted images and marked hyperintensity with patchy hypointensity on T2-weighted images. On contrast enhanced images, it demonstrated significantly heterogeneous enhancement, and the peripheral solid component showed delayed enhancement. Bulky blood vessels and hemorrhage were identified in the tumor. INTERVENTIONS: The mass was surgically excised under a left laparoscopic adrenalectomy. OUTCOMES: Left adrenal angiosarcoma was confirmed by pathological and immunohistochemical examinations. No evidence of recurrence was found 6 months after operation. LESSONS: In conclusion, primary adrenal angiosarcoma has some MRI features corresponding to its pathological nature. It should be included in the differential diagnosis when a mass was detected in the adrenal gland. PMID- 29137071 TI - A comparative study of biological and metabolic biomarkers between healthy individuals and patients with acne vulgaris: A cross-sectional study protocol. AB - Acne is a multifactorial dermatosis, which is influenced not only by hormones but also by the biochemical relationship between them and the pilosebaceous unit. Inflammatory cytokines, chemokines, active oxygen, and zinc are known to be associated with the development of acne. Further, steroid metabolism is known as one of the important factors related to sebum secretion and comedone formation in acne. However, there is a lack of studies comparing these human biomarkers between healthy individuals and patients with acne. In particular, no study has investigated the relationship between human biomarkers and patterns of acne yet.The purpose of this study is to investigate diagnostic human biomarkers in acne by comparing the biological and metabolic biomarkers between healthy individuals and patients with acne and identify the relationship between human biomarkers and patterns of acne.This study is a protocol for a cross-sectional study. Forty healthy participants and 60 patients with acne will be recruited at 1 center. We will collect their blood samples and analyze the molecular biological and metabolic biomarkers (cytokines, chemokines, reactive oxygen species, corticotropin-releasing hormone, zinc, amino acid, 1-carbon metabolite, lipid metabolite, etc.). Further, we will administer questionnaires regarding their diet, sleep, stress, and other factors relating to acne and measure their skin elasticity.The study protocol was approved by the Institutional Review Board of Oriental Medical Hospital at Kyung Hee Medical Center (KOMCIRB-161118-HR-062). Written informed consent will be obtained from all the participants. The trial was registered in the Clinical Research Information Service, Republic of Korea: KCT0002212.This trial will provide evidence regarding diagnostic human biomarkers in acne and the relationship between the human biomarkers and patterns of acne. PMID- 29137072 TI - Volume-based metabolic parameter of breast cancer on preoperative 18F-FDG PET/CT could predict axillary lymph node metastasis. AB - The purpose of our study was to evaluate the association between metabolic parameters on FDG PET/CT and axillary lymph node metastasis (ALNM) in patients with invasive breast cancer.From January 2012 to December 2012, we analyzed 173 patients with invasive ductal carcinoma (IDC) who underwent both initial breast magnetic resonance imaging (MRI) and F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) examinations. All metabolic parameters were measured from the tumor volume segmented by a gradient-based method. Once the primary target lesion was segmented, maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated automatically by the MIMvista software.Mean age of 173 patients was 49 years. Of 173 patients, 45 (26%) showed ALNM. On univariate analysis, larger tumor size (>2.2 cm; P = .002), presence of lymphovascular invasion (P < .001), higher SUVmax (>2.82; P = .038), higher SUVmean (>1.2; P = .027), higher MTV (>2.38; P < .001), and higher TLG (>3.98; P = .007) were associated with a higher probability of ALNM. On multivariate analysis, presence of lymphovascular invasion (adjusted odds ratio [OR], 11.053; 95% CI, 4.403-27.751; P < .001) and higher MTV (>2.38) (adjusted OR, 2.696; 95% CI, 1.079-6.739; P = .034) maintained independent significance in predicting ALNM. In subgroup analysis of T2/T3 breast cancer, lymphovascular invasion (adjusted OR, 20.976; 95% CI, 5.431-81.010; P < .001) and higher MTV (>2.38) (adjusted OR, 4.906; 95% CI, 1.616-14.896; P = .005) were independent predictors of ALNM. However in T1 breast cancer, lymphovascular invasion (adjusted OR, 16.096; 95% CI, 2.517-102.939; P = .003) and larger SUV mean (>1.2) (adjusted OR, 13.275; 95% CI, 1.233-142.908; P = .033) were independent predictors while MTV was not.MTV may be associated with ALNM in patients with invasive breast cancer, particularly T2 and T3 stages. In T1 breast cancer, SUVmean was associated with ALNM. PMID- 29137073 TI - Incidence of C5 nerve root palsy after cervical surgery: A meta-analysis for last decade. AB - PURPOSE: We aim to perform a meta-analysis on incidence of C5 nerve root palsy (C5 palsy) for patients after cervical surgery. METHODS: An extensive search of the literature was performed in PubMed/MEDLINE, Embase, the Cochrane library, CNKI, and WANFANG databases on incidence of C5 palsy from January 2007 to January 2017. Prevalence of C5 palsy related to different surgery methods was calculated and data analysis was conducted with STATA 12.0. RESULTS: A total of 61 studies containing 721 patients with C5 palsy in total 11,481 patients (6.3%) were included in our study. The incidences after anterior cervical discectomy and fusion (ACDF), anterior cervical corpectomy and fusion (ACCF), anterior corpectomy combined with discectomy (ACCDF), laminoplasty (LP) and laminectomy and fusion (LF) were 5.5%, 7.5%, 6%, 4.4%, and 12.2%, respectively. Compared with anterior approaches (5%), female patients (4%) and patients with cervical spondylotic myelopathy (CSM) (4.8%), posterior approaches (6.2%), male patients (5.7%) and patients with ossification of posterior longitudinal ligament (OPLL) (8.1%) have a higher prevalence. In ACDF and LP, patients with OPLL (5.5%, 8.1%, respectively) have a higher incidence than those in patients with CSM (4.7%, 3.1%, respectively); however, in LF, patients with CSM and OPLL have similar incidence of C5 palsy (13% vs 13.1%). In most cases, C5 palsy was unilateral (74.5%). CONCLUSIONS: Based on our meta-analysis, posterior approaches, male patients and patients with OPLL have a higher incidence of C5 palsy. In ACDF and LP, patients with OPLL have a higher incidence of C5 palsy, but in LF, patients with CSM and OPLL have similar result. PMID- 29137074 TI - Refractive state and optical compositions of preterm children with and without retinopathy of prematurity in the first 6 years of life. AB - This study aimed to investigate the refractive state and optical compositions of preterm children with and without mild retinopathy of prematurity (ROP) and explore the influence of prematurity and mild ROP on the development of refractive state and optical compositions.Preterm children who received fundus screening were recruited, and divided into ROP group and non-ROP group. Term children matched in age were also recruited as controls. Several correspondence indicators were measured before and after ciliary muscle paralysis with 1% cyclopentanone.A total of 250 eyes from 126 patients were included for analysis. The incidence of myopia was the highest in ROP group. The incidence of hyperopia was the highest in control group. The incidence of astigmatism was the highest in ROP group. The corneal astigmatism and mean astigmatism in ROP group and non-ROP group were significantly higher than in control group. Corneal refraction in ROP was markedly higher than in non-ROP group and control group; corneal curvature in ROP group increased significantly as compared with non-ROP group and control group (P < .05). The axial eye length in ROP group and non-ROP group reduced significantly as compared with control group (P < .05). Gestational age had negative relationships with corneal astigmatism (P = .019) and astigmatism (P = .001) and positive relationship with axial eye length (P = .005). Birth weight had negative relationships with corneal astigmatism (P = .001), astigmatism (P < .001), corneal refraction (P = .001), and corneal curvature (P = .001) and positive relationships with axial eye length (P = .001) and spherical equivalent refraction (P = .039). The incidence of myopia increased and that of hyperopia reduced in children over age. In children aged 3 to 4 years, the anterior chamber depth, lens thickness, vitreous thickness, and axial eye length significantly increased as compared with those aged 5 years (P < .05); the vitreous thickness and axial eye length in children aged 5 years increased significantly as compared with those aged 6 years (P < .05).This study shows that preterm children with and without mild ROP are more likely to develop myopia and astigmatism, and low birth weight, prematurity, and ROP may simultaneously affect the development of optical compositions, leading to myopia and astigmatism. PMID- 29137076 TI - Test-retest reliability of the Mandarin versions of the Hypertension Self-Care Profile instrument. AB - Self-efficacy in essential hypertension can be measured using scales, such as the "Hypertension Self-Care Profile" (HTN-SCP) questionnaire. It assesses "Behavior", "Motivation", and "Self-efficacy" in 3 domains, respectively. This study aimed to validate the Mandarin version of HTN-SCP instrument (HTN-SCP-Mn) targeted at patients of Chinese ethnicity with hypertension.Our study recruited Chinese patients, aged 40 years and older, with essential hypertension from a public primary healthcare clinic in Singapore. The 60-item HTN-SCP-Mn questionnaire was completed online using a tablet or smartphone on enrolment. A retest was conducted 2 weeks after the initial test. Reliability was assessed by internal consistency and test-retest reliability using Cronbach alpha and intraclass correlation coefficients (ICC). Differences between the overall HTN-SCP-Mn scores of the patients and their self-reported self-management activities were also determined using independent t test.Of the 153 patients who completed the HTN-SCP Mn during the initial test, 79 responded to the test-retest evaluation. Reliability of the 3 domains "Behavior", "Motivation", and "Self-efficacy" obtained high internal consistency (Cronbach alpha = 0.838, 0.929, and 0.927, respectively). The item total correlation ranged from 0.058 to 0.677 for Behavior, 0.374 to 0.798 for Motivation, and 0.326 to 0.767 for self-efficacy. The ICC indicated fair to good test-retest reliability with scores of 0.643, 0.579, and 0.710 for the respective domains.The results showed face validity of the HTN-SCP-Mn instrument, indicating its potential application in mandarin proficient patients. Further study is needed to correlate its scores with objective demonstration of self-efficacy. PMID- 29137075 TI - Influence of neck postural changes on cervical spine motion and angle during swallowing. AB - Occipitocervical (OC) fixation in a neck retraction position could be dangerous due to the risk of postoperative dysphagia. No previous study has demonstrated an association between the cervical posture change and cervical spine motion/angle during swallowing. So, we aimed to analyze the influence of neck posture on the cervical spine motion and angle change during swallowing.Thirty-seven asymptomatic volunteers were recruited for participation this study. A videoflurographic swallowing study was performed in the neutral and retracted neck posture. We analyzed the images of the oral and pharyngeal phases of swallowing and compared the angle and the position changes of each cervical segment.In the neutral posture, C1 and C2 were flexed, while C5, C6, and C7 were extended. C3, C4, C5, C6, and C7 moved posteriorly. All cervical levels, except for C5, moved superiorly. In the retraction posture, C0 and C1 were flexed, while C6 was extended during swallowing. All cervical levels moved posteriorly. C1, C2, C3, and C4 moved superiorly. The comparison between 2 postures shows that angle change is significantly different between C0, C2, and C5. Posterior translation change is significantly different in the upper cervical spine (C0, C1, and C2) and C7. Superior movement is significantly different in C0.C0 segment is most significantly different between neutral and retraction posture in terms of angle and position change. These data suggest that C0 segment could be a critical level of compensation that allows swallowing even in the retraction neck posture regarding motion and angle change. So, it is important not to do OC fixation in retraction posture. Also, sparing C0 segment could provide some degree of freedom for the compensatory movement and angle change to avoid dysphagia after OC fixation. PMID- 29137077 TI - Quality of life and complications at the different stages of bone transport for treatment infected nonunion of the tibia. AB - The aim of this study was to assess Physical Component Summary (PCS), Mental Component Summary (MCS) of the Mos 36-item Short Form Health Survey (SF-36) score, and the virtual Analogue Scale (VAS) of pain during the treatment period and the complication rate associated with infected nonunion of the tibia managed surgically by bone transport.This is a retrospective analysis of prospectively collected data in a consecutive patient cohort. Patients suffering from infected nonunion of the tibia were treated by bone transport from 2012 to 2014. Follow-up was for at least 2 years after complete osseous consolidation. Standardized treatment included bacterial eradication by segmental resection, bone transport using Ilizarov apparatus, and docking maneuver. The main outcome measurements consisted of the quality of life (PCS and MCS scores) and the VAS of pain during the different stages of therapy. In addition, all complications were documented.Our series comprised 12 men and 3 women with an average age of 36.9 years (range: 20-55 years). All patients previously undergone an average of 2.9 operations (range: 1-6 operations). In all patients, bone defects were present with a mean size of 7.5 cm (range: 3-12 cm), and all patients were suffering from soft tissue defects (range: 5-17 cm). The mean external fixator time (EFT) was 48 weeks (range: 30-62 weeks) and the mean external fixation index was 43.1 days/cm (range: 33-62 days/cm). All patients achieved bone union, and no recurrence of infection was observed. According to the Paley classification, patients suffered 15 minor and 13 major complications. The average complication rate per patient comprised of 1.0 minor and 0.9 major complications. Bone grafting was required in 6 cases at the docking site. One patient suffered from equinus deformity, and refused any further surgical procedures. We performed 28 operations in 15 patients (average 1.9 operations per patient). After the period of bone transport, PCS and MCS scores increased continuously. After completed consolidation, the average MCS score was comparable to a normal collective, and the average VAS score was 1.87 (range: 0-3).Bone transport is a safe option for the treatment of infected nonunion of the tibia despite the high complication rate. The arduous and demanding nature of this treatment subjects patient to considerable the pain, mental, and physical stress. The average VAS scores, PCS, and MCS scores significantly improve at final follow-up. It is essential to communicate this fact to the patients and their relatives before the application of the frame in order to increase their compliance with the long and emotionally draining treatment. PMID- 29137078 TI - Successful treatment of ovarian cancer with apatinib combined with chemotherapy: A case report. AB - RATIONALE: The standard treatment for ovarian cancer is chemotherapy with 2 drugs (taxanes and platinum drugs). However, the traditional combination of the 2 drugs has many adverse effects (AEs) and the cancer cells will quickly become resistant to the drugs. Apatinib is a small-molecule antiangiogenic agent which has shown promising therapeutic effects against diverse tumor types, but it still remains unknown whether apatinib has an antitumor effect in patients with ovarian cancer. Herein, we present a successfully treated case of ovarian cancer using chemotherapy and apatinib, in order to demonstrate the effectiveness of this new combined regimen in ovarian cancer. PATIENTS CONCERNS: A 51-year-old Chinese woman presented with ovarian cancer >4.5 years. The disease and the cancer antigen 125 (CA-125) had been controlled well by surgical treatment and following chemotherapy. However, the drugs could not control the disease anymore as the CA 125 level was significantly increasing. DIAGNOSIS: Ovarian cancer. INTERVENTIONS: The patient was treated with apatinib combined with epirubicin. Apatinib was administered orally, at an initial daily dose of 500 mg, and was then reduced to 250 mg qd after the appearance of intolerable hand-foot syndrome (HFS) and oral ulcer. Then, the oral ulcer disappeared and the HFS was controlled by dose adjustment, oral vitamin B6, and hand cream application. OUTCOMES: The CA-125 reverted to the normal value after treatment with the new regimen. Magnetic resonance imaging showed that the original tumor lesions had disappeared. Apatinib monotherapy as maintenance therapy was then used to successfully control the cancer with a complete response. Our study is the first, to our knowledge, to report the therapeutic effects of apatinib and epirubicin on ovarian cancer. LESSONS: Apatinib combined with chemotherapy and apatinib monotherapy as maintenance therapy could be a new therapeutic strategy for ovarian cancer, especially adenocarcinomas. PMID- 29137079 TI - Treatment of hypermyoglobinemia after CRS + HIPEC for patients with peritoneal carcinomatosis: A retrospective comparative study. AB - This retrospective comparative study aims to explore the time courses of serum myoglobin (Mb) changes, and summarize our experience in treating patients with hypermyoglobinemia after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).This study covered 60 patients with peritoneal carcinomatosis treated with CRS + HIPEC as the study group, and another 25 cancer patients treated with conventional extensive surgery without HIPEC as the control group from February to October 2016. In the study group, patients with postoperative hypermyoglobinemia were on a comprehensive treatment regimen consisting intravenous injection of sodium bicarbonate solution according to the Mb level. In the control group, patients were recorded and treated with the same regimen except for special sodium bicarbonate solution. The preoperative and postoperative serum Mb, blood urine nitrogen (BUN), and creatinine (Cr) levels were evaluated.There were no significantly difference between the 2 groups in serum Mb, BUN, and Cr levels before surgery. Postoperative serum Mb levels were elevated in both groups and significantly higher on postoperative 0 to 2 days (P < .05) in the study group than the control group. The peak value of serum Mb levels (426.65 +/- 108.386 MUg/L) occurred on the surgery day. The serum Mb change rate was much bigger in the study group than the control group. Serum BUN levels in both groups revealed a slow increase during the early postoperative period and were significantly lower in the study group than the control group on days 1 and 2. The serum Cr levels were similar and stable between the 2 groups after surgery. The serum Cr change rates changed synchronously with same tendency in both groups, and on postoperative day 1 the increase rate was bigger in the control group than the study group.Hypermyoglobinemia is a common and prominent lab abnormality after CRS + HIPEC, and serum Mb levels could be an early and sensitive indicator for dramatic disturbances in the internal milieu after CRS + HIPEC. Adequate treatment with sodium bicarbonate could accelerate the reduction in serum Mb levels and reduce the risk for major organ damages. PMID- 29137080 TI - A medium-term follow-up of adult lumbar tuberculosis treating with 3 surgical approaches. AB - Surgical intervention is an important option for treating lumbar tuberculosis. Previous studies have reported different surgical intervention procedures. To our knowledge, few studies have compared the clinical results of mid-term follow-up of 3 different surgeries in surgical treatment of spinal tuberculosis. This study's purpose is to evaluate the effectiveness of 3 different surgeries for the treatment of lumbar tuberculosis in adult and analyze the mid-term influence of the surgery on quality of life.Between June 2004 and January 2010, a total of 137 adult patients (54 women and 83 men) with lumbar tuberculosis were recruited for this study. The patients were divided into 3 groups based on administered surgeries: posterior, anterior, and combined posterior-anterior. The trauma index (operation time, blood loss, length of hospital stay, and complications), imaging parameters (segment kyphotic angle, correction rate, loss angle, and bone fusion time), and quality-of-life indicators, including Oswestry Disability Index (ODI), the Frankel grade, visual analog scale (VAS), and Macnab score, were collected.The posterior group experienced the lowest trauma index, whereas the combined group faced the highest trauma index. The anterior group's kyphosis correction rate of (52% +/- 5.45%) was significantly inferior to the posterior group (74% +/- 5.04%) and the combined group (69% +/- 7.95%), whereas the loss of correction in the anterior group (2.5 degrees ) was higher than the losses of correction in the posterior group (0.8 degrees ) and combined group (1.1 degrees ). The mean bone fusion times of the 3 groups were similar. Postsurgery quality of life was markedly improved in all patients. The improvement rates of the ODI, VAS, and the excellent and good rate per the Macnab score were similar among the 3 groups at the final follow-up.Based on a retrospective study, for patients with lumbar tuberculosis, use of the anterior approach should be limited. Although the combined approach produced satisfactory outcomes, it remains more traumatic. Compared with the anterior surgery and the combined surgery, the posterior-only approach is safer and less invasive. PMID- 29137081 TI - Sinonasal undifferentiated carcinoma originating from inverted papilloma: A case report. AB - RATIONALE: Sinonasal inverted papilloma (IP) is a locally aggressive tumor found in the schneiderian membrane, lining the nasal cavity and paranasal sinuses. PATIENT CONCERNS: We report a case of a 63-year-old woman with undifferentiated carcinoma (UC) arising in an IP in the left maxillary sinus. DIAGNOSES: The preoperative diagnosis was IP of the maxillary sinus. INTERVENTIONS: We performed endoscopic medial maxillectomy to remove the remnant mass in the left maxillary sinus. OUTCOMES: Histological examination of the specimen revealed typical area of IP and sinonasal UC. LESSONS: Clinicians should consider sinonasal UC in the differential diagnosis of malignancy arising in the sinonasal IP. PMID- 29137082 TI - Trends in the prevalence of periodontitis in Taiwan from 1997 to 2013: A nationwide population-based retrospective study. AB - Periodontitis is one of the most prevalent oral diseases. In this study, we probed the nationwide registered database to assess the time trends of prevalence of periodontitis in Taiwan.A retrospective study was conducted to analyze the registered database compiled by the National Health Insurance provided by the Department of Health, Taiwan, from 1997 to December 2013.We found that the prevalence of periodontitis significantly increased from 11.5% in 1997 to 19.59% in 2013 (P for trend < .0001). The mean age +/- standard deviation with periodontitis from 1997 to 2013 was 54.46 +/- 14.47 and 45.51 +/- 16.58 years old, respectively. The proportion of individuals with periodontitis in age group >65 years old decreased markedly. The proportion of individuals with periodontitis in age groups <25 and 26 to 35 years old demonstrated an increased pattern. Compared to the reference cohort of 1953 to 1957, the recent birth cohort of 1993 to 1997 revealed the highest relative risk (RR) of periodontitis (male: RR, 67.42, 95% confidence interval [CI], 17.04-266.76; female: RR, 65.85, 95% CI, 16.70-259.70). Both male and female groups showed the similar age-effect pattern in the cross-sectional age curve from age-period-cohort model. There was an upturn with advancing age up to 40 to 50 years old and then a downward trend in both genders. Population dwelling in suburban area (RR, 0.95; 95% CI, 0.94 0.97) and rural area (RR, 0.97; 95% CI, 0.95-0.99) had the lower risk of periodontitis than those who lived in urban area. The higher income group revealed the higher risk of periodontitis compared with lower income group (RR, 1.20; 95% CI, 1.18-1.23).The prevalence of periodontitis significantly increased in Taiwan over past 17 years. The mean age with periodontitis was shown in a decreased pattern. The use of a nationwide population-based database could provide sufficient sample size, generalizability, and statistical power to assess the periodontal status in Taiwan. PMID- 29137083 TI - Indications and outcomes of pediatric keratoplasty in a tertiary eye care center: A retrospective review. AB - To evaluate indications and outcomes of pediatric keratoplasty in a tertiary eye center, and identify factors that affect visual outcomes.We performed a retrospective review of penetrating keratoplasty in children aged 0 to 18 years between 1995 and 2011 in the Asociacion para Evitar la Ceguera en Mexico IAP, Hospital "Dr. Luis Sanchez Bulnes".A total of 574 penetrating keratoplasties were performed during the study interval. Median follow-up was 5.0 years. Main indications included keratoconus (55.58%), postherpetic scarring (9.58%), traumatic opacities (7.49%), and bullous keratopathy (6.09%). Rejection rates at 5 years were 27% overall, and among indications, keratoconus showed the best graft survival at 60-months follow-up (85%). The percentage of patients with best corrected visual acuity (BCVA) posttransplant >20/400 at 5 years in the nonrejection group was 81.25% and 82.74% in < and > 10 years of age (YOA) groups, respectively, versus a BCVA posttransplant > 20/400 at 5 years in the rejection group of 53.68% and 51.72% in < and > 10 YOA groups, respectively. There was a statistically significant reduced rejection rate between genders at 18 months of follow-up, favoring males.Despite being considered a high-risk procedure in children, penetrating keratoplasty can achieve good results, especially in patients with keratoconus. It can achieve significative improvements of visual acuity, provided there is an adequate follow-up and treatment adherence. PMID- 29137084 TI - Vertebral column decortication for the management of sharp angular spinal deformity in Pott disease: Case report. AB - RATIONALE: Extremely sharp angular spinal deformity of healed tuberculosis can be corrected by vertebral column resection (VCR). However, the VCR techniques have many limitations including spinal column instability, greater blood loss, and greater risk of neurologic deficit. PATIENT CONCERNS: We described a new spinal osteotomy technique to collect sharp angular spinal deformity in Pott disease. A 52-year-old woman presented with back pain and gait imbalance. DIAGNOSIS: The kyphosis of healed tuberculosis was diagnosed based on history and imaging examinations. INTERVENTION: A new posterior VCR was designed to treat this disease. OUTCOMES: The neurological function improved from Japanese Orthopedic Association scale 3 to 7. The back pain and neurological function were significantly improved. The Oswestry Disability Index decreased from 92 to 34. There was also a significant decrease in back pain visual analog scale from 9 to 2. LESSONS: For cases with extremely severe Pott kyphotic deformity, the technology of modified VCR offers excellent clinical and radiographic results. PMID- 29137085 TI - Current trends of practical issues concerning micropapillary thyroid carcinoma: The Korean Society of Thyroid-Head and Neck Surgery. AB - Although several thyroid associations have published various guidelines, controversies especially in cases of micropapillary thyroid cancer (MPTC) still exist. This survey was designed to collect information about diagnostic tests and treatments performed on patients with MPTC and help identify current trends in thyroid surgery.We developed questionnaires about the management methods for MPTC, which were used to identify factors related to indications of fine needle aspiration (FNA), type of surgery, and central lymph node dissection (CLND). Active 60 members of the Korean Society of Thyroid-Head and Neck Surgery participated in the study in September 2016.Ultrasound-guided FNA was usually initiated when the tumor was at least 5 mm (60%). All respondents preferred ultrasound-guided FNA and surgery for nodules with extrathyroidal extension (ETE). The preferred treatment option for intraglandular MPTC was lobectomy (92%) rather than active surveillance (8%). Posterolateral ETE increased the respondents' preference for total thyroidectomy (61.7%). Active surveillance was preferred for tumors <5 mm, which was decreased by the presence of ETE. The presence of ETE (73.3%) and its proximity to critical organs (46.7%) were the main determining factors for prophylactic CLND. For multiple metastatic lymph nodes at level III, selective neck dissection including levels IIb (23.3%) and V (78.3%) was preferred in addition to levels IIa, III, VI, and V.Korean head and neck surgeons favored total thyroidectomy and CLND in cases wherein ETE, central lymph node metastasis, or critical organ involvement was suspected. PMID- 29137086 TI - Chorea associated with nonketotic hyperglycemia: A case report with atypical imaging changes. AB - INTRODUCTION: This is a unique case of nonketotic hyperglycemic (NKH) chorea in 84-year-old Asian woman. The patient had a history of type 2 diabetes mellitus more than 30 years, but had a poor control of blood sugar. She complained of acute onset of bilateral limb involuntary activities, and being easy to fall within a week. Laboratory testing disclosed hyperglycemia (669 mg/dL), glycated hemoglobin (14%), and normal ketones. The brain computed tomography scan and magnetic resonance imaging did not disclose any abnormality in the basal ganglion unlike most cases. The patient was then diagnosed with NKH chorea. Her symptoms improved quickly. CONCLUSIONS: NKH chorea with normal imaging may represent a new subtype. PMID- 29137087 TI - Isolated tear of the cord-like middle glenohumeral ligament in Buford complex: A case report. AB - RATIONALE: We describe a rare case of the isolated tear in the cord-like middle glenohumeral ligament (MGHL) in Buford complex. To the best of our knowledge, this is the first report in the English literature about the isolated tear of cord-like MGHL in Buford complex. The present report describes in detail our experience with the diagnosis of isolated tear of the cord-like MGHL in Buford complex and management. PATIENT CONCERNS: A 50-year-old female patient visited our hospital with pain and stiffness in the right shoulder that lasted for 9 months. DIAGNOSES: The clinical impression was frozen shoulder by primary impingement syndrome of right shoulder and the magnetic resonance (MR) images showed tear of cord-like MGHL. INTERVENTIONS: We repaired the torn MGHL with the arthroscopic technique. OUTCOMES: Positive outcome by arthroscopic repair demonstrates that this disease entity is one of spectrum of pathologic condition in shoulder joint. LESSONS: Isolated tear of cord-like MGHL should be restored to the original anatomy for positive outcome. PMID- 29137088 TI - Fixation of comminuted midshaft clavicle fractures with bone fragments separated by soft tissue using a novel double ligature technique: A case report. AB - RATIONALE: Clavicle fractures are common, and mostly occur in the midshaft. Methods for operative treatment of midshaft clavicle fractures are evolving, as they improve clinical outcomes compared with traditional conservative management. However, fixation of comminuted midshaft clavicle fractures with bone fragments separated by soft tissue remains a challenge. PATIENT CONCERNS: Here, we present a case of comminuted midshaft clavicle fracture with a bone fragment separated from the main fracture by soft tissue. DIAGNOSIS: Left comminuted midshaft clavicle fracture. INTERVENTIONS: We treated this patient with a novel double ligature technique using absorbable suturing. OUTCOMES: In the past 7 years, we have treated >50 patients with this technique. We have achieved good clinical outcomes with no complications. LESSONS: We recommend widespread use of our novel double ligature technique for treating comminuted midshaft clavicle fractures with bone fragments separated by soft tissue. PMID- 29137089 TI - A case report of Takayasu arteritis with aortic dissection as initial presentation. AB - RATIONALE: The initial symptoms and signs of Takayasu arteritis vary due to the heterogeneity of affected vessels. Moreover, the vascular lesions are difficult to detect at initial presentation, making diagnosis even more challenging. Although cases of aortic dissection with arteritis history have been reported, Takayasu arteritis in men with aortic dissection as initial presentation is very rare. PATIENT CONCERNS: A 37-year-old man presenting with persistent chest and back pain for 6 days was transferred to our hospital for further treatment. Left hand pulse was absent and right lower limb pulse was feeble. Blood pressure was 144/83 mmHg in the right arm but only 114/62 mmHg in the left arm. DIAGNOSES: Computed tomography angiography revealed aortic dissection (DeBakey type III b) from the descending aorta to the distal abdominal aorta. INTERVENTIONS: High-dose glucocorticoid therapy and immunosuppressive therapy have been used to control inflammatory reaction during acute period of Takayasu arteritis. Endovascular graft exclusion (EVGE) surgery was performed to cover the primary entry tear and re-expand true lumen during inactive stage. OUTCOMES: His pain symptoms improved progressively and he was followed in our outpatient clinic after discharged from hospital, without recurrence. LESSONS: Timely therapy (glucocorticoid and immunosuppressive) and corrective surgery (endovascular graft exclusion) for Takayasu arteritis with aortic dissection at the inactive stage is essential and beneficial. PMID- 29137090 TI - Diabetic and sympathetic influences on the water permeability barrier function of human skin as measured using transepidermal water loss: A case-control study. AB - The presence of long-standing hyperglycemic conditions has been suggested to lead to many skin problems associated with an impaired skin barrier function. However, the relationship between impaired skin barrier status and altered peripheral nervous system function has not yet been determined. The purpose of this study was to investigate the water evaporation rate as a measure of the permeability barrier function of diabetic skin and its relationship to diabetic sensorimotor polyneuropathy (DSPN) and peripheral autonomic neuropathy (PAN) using well controlled confounding variables.This case-control study included 42 participants with chronic diabetes and 43 matched healthy controls. The diabetic group underwent a nerve conduction study and sympathetic skin response (SSR) test to confirm the presence of DSPN and PAN, respectively. Different skin regions were analyzed using the noninvasive Tewameter instrument (Courage + Khazaka Electronic GmbH, Cologne, Germany). The impacts of PAN, DSPN, age, and diabetes duration on the values of transepidermal water loss (TEWL) were each analyzed and compared between the groups.Regardless of the presence of DSPN or PAN, the TEWL values as measured on the distal extremities were significantly lower in the diabetic group than in the control group. In the diabetic group, participants with abnormal SSR test results showed decreased TEWL values in the finger, sole, and first toe, as compared with participants with normal SSR test results. In the control group, age showed a negative correlation with the TEWL values with respect to some measured regions. However, in the diabetic group, there was no significant correlation between either patient age or diabetes duration and TEWL values.The presence of a long-term hyperglycemic state can reduce the permeability barrier function of the skin, a phenomenon that might be related to the presence of an impaired peripheral sympathetic nervous system, rather than peripheral sensorimotor denervation. PMID- 29137091 TI - The effects of hypervolemic infusion on microcirculation perfusion of patients during laparoscopic colorectal surgery. AB - The aim of this study is to assess the effects of hypervolemic infusion with different solutions on microcirculation perfusion during laparoscopic colorectal surgery.Thirty-six patients were randomly divided into Ringer lactate solution [RL] group, succinylated gelatin injection [Gel] group, and hypertonic saline hydroxyethyl starch 40 injection [HS] group. Hypervolemic infusion was performed during the induction period of general anesthesia. Arterial blood-gas parameters, noninvasive hemodynamics, gastric tonometry values, and central venous pressure (CVP) were compared at baseline (T1); the end of hypervolemic infusion (T2); 5 min (T3), 15 min (T4), 30 min (T5), and 60 min (T6) during pneumoperitoneum; 5 min (T7), 15 min (T8), and 25 min (T9) after pneumoperitoneum. Patients were also grouped by age for further comparisons.The hematocrit levels of all groups after T2 decreased. The gastric mucosal-arterial carbon dioxide partial pressure (Pg aCO2) started to decrease after T2 and rebounded after T5. There was no difference in the gastric mucosal perfusion when compared between 3 groups. The blood Na of HS group increased significantly after T2, then gradually restored and returned to baseline by T8. The plasma bicarbonate (HCO3) levels of RL and Gel groups elevated from T2 to T7, after which they started to decrease, but this phenomenon was not significant in HS group. In both RL and Gel groups, blood pressure has a significant fluctuation in elder patients.Hypervolemic infusion of these solutions during the induction of anesthesia can improve gastric mucosal perfusion. HS can maintain a more stable hemodynamic effect when used with caution in patients with preoperative hypernatremia. PMID- 29137092 TI - Circulating 25-hydroxyvitamin D and lung cancer risk and survival: A dose response meta-analysis of prospective cohort studies. AB - Lower serum level of 25-hydroxyvitamin D is associated with several negative outcomes. However, previous studies have indicated that 25-hydroxyvitamin D is associated with lung cancer risk and survival, but presented controversial results.PubMed and Embase databases were searched update to August 2017 to identify and quantify the potential association between 25-hydroxyvitamin D and lung cancer risk and survival.Seventeen eligible studies involving a total of 138,858 participants with 4368 incident cases were included in this meta analysis. Our results showed statistically significant association between 25 hydroxyvitamin D and lung cancer risk and mortality. However, circulating 25 hydroxyvitamin D was not associated with overall lung cancer survival. Furthermore, compared with the lowest circulating 25-hydroxyvitamin D, the highest circulating 25-hydroxyvitamin D is significantly decreased risk of lung cancer risk in male and female. In addition, the highest circulating 25 hydroxyvitamin D was significantly associated with a lower risk in Caucasian and Asian. We also obtained the best fit at an inflection point of 10 nmol/L in piecewise regression analysis, increasing 10 nmol/L dose of circulating 25 hydroxyvitamin D was associated with an 8% reduction in the risk of lung cancer risk and an 7% reduction in the risk of lung cancer mortality. Subgroup meta analyses in study quality, number of participants, and number of cases showed consistent with the primary findings.The highest circulating 25-hydroxyvitamin D was associated with decreased lung cancer risk and mortality but not overall survival. PMID- 29137093 TI - An incidental encounter of a rare high take-off right coronary artery: A case report. AB - RATIONALE: High take-off of the coronary arteries is a rare cardiac anatomic anomaly, which may occur independently or with other congenital heart defects. In the clinical setting, it is noteworthy as a cause of sudden cardiac death. Further, it is vital to identify such anomalies to avoid intraoperative catastrophes in surgeries for congenital heart defects. PATIENT CONCERNS: A II/6 systolic heart murmur on physical examination was incidentally found in a 9-year old boy; he was confirmed to have a secundum-type atrial septal defect on echocardiography. He was referred to our institution for elective surgery. DIAGNOSES: The preoperative echocardiogram confirmed the presence of an atrial septal defect, and during the surgical procedure, a high take-off right coronary artery was found. INTERVENTIONS: The atrial septal defect was closed surgically, and care was taken to avoid clamping the anomalous right coronary artery when placing the aortic cross-clamp. OUTCOMES: Postoperative echocardiogram verified the presence of the high take-off right coronary artery and a satisfactory repair of the atrial septal defect. The postoperative course was uneventful, and the patient was discharged on postoperative day 5. LESSONS: This case suggests that it is critical to perform echocardiography to assess the anatomy of the coronary arteries, especially in pediatric cardiac patients. In addition, multi-detector computed tomography may be considered if appropriate. Care should be taken to assess the coronary anatomy for anomalies during interventional therapy or surgery, especially in congenital cases. PMID- 29137094 TI - A novel non-contrast-enhanced MRA using silent scan for evaluation of brain arteriovenous malformation: A case report and review of literature. AB - RATIONALE: Brain arteriovenous malformations (AVMs) are congenital vascular abnormalities involving abnormal connections between arteries and veins. In clinical practice, imaging studies help evaluate feeding arteries, niduses, draining venous systems, and coexisting complications in patients with brain AVM. They also have an impact on decision-making regarding clinical management. We applied a novel non-contrast-enhanced MR angiography (MRA) technique, termed "silent MRA," for evaluating an incidental brain AVM. Here, we describe the clinical case with radiological review and highlight the technical background and clinical usefulness of silent MRA. PATIENT CONCERNS: A 60-year-old woman underwent neuroimaging study including MRA to evaluate intracranial cause of headache. DIAGNOSES: The brain AVM, including its nidus and draining veins, was conspicuously delineated on silent MRA images; these findings correlated well with conventional angiographic findings. INTERVENTIONS: The patient did not receive interventional or surgical treatment. OUTCOMES: The patient is being followed up regularly at the outpatient department. LESSONS: The silent MRA can be a suitable imaging modality for repeated follow-up evaluation for not only brain AVMs but also various intracranial vascular diseases without the use of contrast materials. PMID- 29137095 TI - Differences in UGT1A1 gene mutations and pathological liver changes between Chinese patients with Gilbert syndrome and Crigler-Najjar syndrome type II. AB - Diagnosis of Crigler-Najjar syndrome type II (CNS-II) and Gilbert syndrome (GS) based on the serum bilirubin concentration is difficult, because this parameter can fluctuate under certain conditions. The aim of this study was to explore differences in UGT1A1 gene mutations, which cause both CNS and GS, and pathological changes between CNS-II and GS.Ninety-five Chinese patients with hereditary unconjugated hyperbilirubinemia were enrolled in this study. Peripheral blood samples obtained from patients were used to evaluate bilirubin levels and for UGT1A1 gene testing. Percutaneous needle biopsy of the liver and staining of tissue samples with hematoxylin and eosin, Masson trichrome, reticulin, and Perl Prussian blue were performed for 59 patients. The Ishak scoring system was used to assess inflammatory activity and the extent of fibrosis.One hundred ninety-two UGT1A1 mutations at 6 sites were detected in the 95 patients; the most common mutation in GS was c.-3279T>G in the phenobarbital response enhancing motif of the UGT1A1 promoter, whereas the most common mutation in CNS-II was p.G71R. The frequency of heterozygous p.G71R mutations in CNS-II was significantly higher than that in GS (P = .001); however, the frequency of homozygous c.-3279T>G mutations in CNS-II was markedly lower than that in GS (P = .032). Among all patients with multiple mutations, the frequency of p.Y486D was significantly higher in CNS-II than in GS (P = .007). The frequency of compound c.-3279T>G, A(TA)7TAA, and p.G71R mutations in CNS-II was significantly higher than that in GS (P = .001). Among the 59 patients who underwent percutaneous needle biopsy, 20 had iron deposition in the liver. The frequency of hepatic iron deposition in CNS-II was significantly higher than that in GS (P = .002).The linked polymorphic mutations, A(TA)7TAA and c.-3279T>G in UGT1A1, were most strongly associated with GS, whereas mutations in the coding region, especially p.G71R and p.Y486D, were more strongly associated with CNS-II. Iron deposition was more common in liver biopsies from patients with CNS-II than in those with GS. PMID- 29137096 TI - Synchronous multiple carcinoma with small intestine and pulmonary neuroendocrine involvement: A case report. AB - RATIONALE: In clinical work, neuroendocrine synchronous multiplicity carcinoma was relatively rare. Most were confirmed by the pathological diagnosis of a certain part of the body combined with the imaging of the whole body, while cases that had both pathological and immunohistochemistry diagnosis were few. PATIENT CONCERNS: A patient who presented with abdominal pain visited our hospital, and was diagnosed with lesions in both the small intestine and lung. DIAGNOSES: Both were considered primary tumors by imaging, and diagnosed as neuroendocrine carcinomas by pathology. INTERVENTIONS: The intestinal lesion was surgically resected, and the lung tumor treated by chemoradiotherapy. OUTCOMES: The survival time of this patient exceeded 24 months. LESSONS: The diagnosis relied on clinical, imaging, pathological, and immunohistochemical features, which confirmed a synchronous multiple carcinoma. Treatment was based on the pathological types. Through this case report, the clinical and pathological data of neuroendocrine synchronous multiplicity carcinoma could be enriched. PMID- 29137097 TI - Prognostic role of neutrophil-lymphocyte ratio in patients with acute ischemic stroke. AB - BACKGROUND: The aim of this study was to evaluate the prognostic role of neutrophil-lymphocyte ratio (NLR) in patients with acute ischemic stroke (AIS). METHODS: PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure were searched for potential eligible literature. The study characteristics and relevant data were extracted. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to estimate the prognostic role of NLR in patients with AIS. Poor functional outcome was defined as modified Rankin Scale >= 3. RESULTS: Nine studies with 2947 patients were included. The pooled OR of higher NLR for poor functional outcome at 3 months was 1.55 (95% CI, 1.21 2.00). The pooled ORs for death at 3 months, poor functional outcome at discharge, and symptomatic intracranial hemorrhage (sICH) were 2.35 (95% CI, 0.40 13.78), 2.38 (95% CI, 0.49-11.69), and 4.32 (95% CI, 2.46-7.61), respectively. CONCLUSION: For patients with AIS, higher NLR was associated with poorer functional outcome at 3 months and may be associated with a higher risk of developing sICH. This readily available and inexpensive marker may be helpful in future clinical and research work. However, due to the limited number of included studies, more well-designed studies are warranted to further clarify this issue. PMID- 29137098 TI - Scrambler therapy for the treatment of neuropathic pain related to leukemia in a pediatric patient: A case report. AB - RATIONALE: Cancer-related neuropathic pain often responds poorly to standard pain treatments. Scrambler therapy has relieved refractory chronic pain in several uncontrolled clinical trials. PATIENT CONCERNS: An 11-year-old female patient was suffering from left groin and medial thigh pain after irradiation to the knee. The girl was diagnosed with precursor B-cell lymphoblastic leukemia 2 years ago. Extramedullary relapse of leukemia developed 1 month ago and pain had started. She was treated with oral medications, but she was continuously complaining of severe pain. DIAGNOSIS: Neuropathic pain caused by obturator nerve involvement in leukemia. INTERVENTION: Scrambler therapy. OUTCOME: Pain reduction. LESSONS: Scrambler therapy is noninvasive, is not associated with any complications, causes minimal discomfort during treatment, and is very effective in a pediatric patient with cancer-related neuropathic pain. PMID- 29137099 TI - Chemoembolization for hepatocellular carcinoma fed by right internal thoracic artery. AB - The purpose of the study was to evaluate the value of transarterial chemoembolization (TACE) via right internal thoracic artery (RITA) for patients with unresectable hepatocellular carcinoma (HCC).From January 2000 to June 2016, a retrospective study was conducted of all patients with unresectable HCC who underwent TACE via RITA across 3 medical centers. The technical success, serum alpha-fetoprotein (AFP) level changes, major complications, disease control rate, and survival were evaluated and analyzed.During the study peroid, in all, 21 patients (men 21; mean age 57.3 +/- 7.1 years) were included in this study. Of the 21 patients, all the tumors were located under the capsule of the liver and adjacent to the diaphragm with median tumor diameter of 8.2 cm in 20 patients, and the tumor was located at the surface of the liver due to incisional site metastasis in 1 remaining patient. Lesions fed by the RITA were demonstrated during initial TACE in 2 patients and during repeat TACE therapy in 19 patients. The technical success rate was 100%. The AFP response 1 month after treatment was complete (n = 4) and partial (n = 9) of 13 patients whose AFP was abnormal before the procedure, and the serum levels of AFP reduced significantly 1 month after treatment (1240.1 +/- 347.1 vs 175.2 +/- 71.8; P < .01). No major complications occurred. The disease control rate was 100% at 3 months after treatment. The median overall survival from the time of TACE therapy via the RITAs was 18.2 months, and 1-year survival after TACE therapy via the RITAs was 76.2%.Chemoembolization via the RITA can improve the therapeutic efficacy of TACE and reduce the presence of residual HCC. PMID- 29137100 TI - Ultrasonic and pathological characteristics of ovarian mucinous cystic tumors with malignant mural nodules: Two cases report. AB - RATIONALE: Sarcomatous or anaplastic carcinoma mural nodules presenting in ovarian mucinous cystic tumors are very rare. Here, we reported the ultrasonic and pathological features of 2 such cases. PATIENT CONCERNS: A 60-year-old woman presented with a complaint of lower abdominal pain. Physical examination revealed a hard, palpable mass in her right lower abdomen with mild tenderness. In addition, a 48-year-old woman presented with left abdominal pain and abdominal fullness. Physical examination revealed a palpable mass in her left lower abdomen. DIAGNOSES: The diagnosis of ovarian mucinous cystic tumor (including mucinous cystadenoma, mucinous cystadenoma of borderline malignancy, and intraepithelial carcinoma) associated with the sarcomatous mural nodule was made for the first patient. The mass of the second patient was mucinous cystic tumor (including mucinous cystadenoma, borderline malignant mucinous cystadenoma, and mucinous cystadenocarcinoma) associated with sarcoma-like mural nodules and multifocal anaplastic carcinoma. INTERVENTIONS: Both patients underwent bilateral salpingo-oophorectomy and omentectomy. In addition, appendectomy was also performed for the younger patient. OUTCOMES: Ultrasonic imaging showed huge pelvic cavity mixed masses with reticular or petaloid fluid sonolucent areas, uneven thickness separation, and multiple various mural nodules. The internal echo of the masses was complex and varied. The ultrasonic features of mural nodules were characteristic, including irregular shape, rough surface, wide basement, and nonuniform internal echogenicity. Pathological examination revealed multiple nodules with obvious atypia and mucinous cystic tumors with different malignancy. Sarcomatous or anaplastic carcinoma mural nodules showed irregular structure, significant cell atypia, and noticeable mitoses. The discovery of vascular invasion has an important role in the diagnosis of sarcomatous mural nodules. Immunohistochemical features of positive cytokeratin and negative vimentin can identify the anaplastic carcinoma component from the bizarre stromal components of the nodule. LESSONS: Ultrasonography was helpful to evaluate the preoperative diagnosis and determining the surgical approach, and pathology was indispensable to the diagnosis of these diseases. PMID- 29137101 TI - Analysis of islet beta cell functions and their correlations with liver dysfunction in patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). AB - Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) primarily manifests in neonates or infants with hepatomegaly, liver dysfunction, and hypoglycemia. This study investigated the functions of islet beta cells and their correlations with liver dysfunction in NICCD patients.We retrospectively analyzed clinical data on liver function and islet beta cell functions for 36 patients diagnosed with NICCD and 50 subjects as the control group. The NICCD group had significantly higher total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate amino transferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and alpha-fetoprotein (AFP) levels and albumin/globulin ratio (A/G) (P < .05), and lower ALB and GLB levels than the control group (P < .05). The differences in fasting blood glucose (FBG), fasting insulin, C-peptide (C-P), the homeostasis model of assessment for the insulin resistance index (HOMA-IR), fasting beta cell function (FBCI), and the HOMA beta cell function index (HBCI) between the NICCD and control groups were not significant (P > .05). A linear correlation was found between FBG and fasting insulin (P < .001) and between FBG and C-P in the NICCD patients (P = .001). Fasting insulin (P = .023), HOMA-IR (P = .023), FBCI (P = .049), and HBCI (P = .048) were positively correlated with increases in the ALT level. There was no difference in islet beta cell functions between the NICCD and control groups. The liver dysfunction may be correlated with islet beta cell functions in NICCD patients. PMID- 29137102 TI - Lateral medullary infarction with similar features of Brown Sequard syndrome caused by vertebrobasilar dysplasia and Klippel-Feil syndrome: A case report. AB - RATIONALE: Patients with Klippel-Feil syndrome (KFS) are always anomaly associated with vertebrobasilar dysplasia. That may present commonly as infarction of brainstem, medulla, and cerebellum. In this article, we reported a rare case of lateral medullary infarction (LMI) with similar features of Brown Sequard syndrome caused by vertebrobasilar dysplasia and KFS, and the 2 rare conditions that are causally related. The case is being reported because of its unusual and rare presentation. PATIENT CONCERNS: A 38-year-old female presented with acute unsteadiness, along with a tendency to lean to the left side while walking or sitting, and paresthesia in the right lower limb and trunk, at 2 days before admission. She had no history of hypertension and diabetes, but had a 20 years history of neck pain and dizziness, which was related to head movement. DIAGNOSES: Brown Sequard syndrome and a lesion of the left thoracic spinal cord were suspected initially. KFS was confirmed by the cervical magnetic resonance imaging (MRI) and computed tomographic angiography (CTA) results. Transcranial Doppler (TCD) results confirmed that there was a causal link between LMI and KFS. INTERVENTIONS: The patient rejected the operation of stabilization of the cervical spine with fusion at appropriate levels. OUTCOMES: No recurrence of stroke, but neck pain and dizziness remained after 6 months of discharge. LESSONS: For such patients, the conventional treatment of cerebral infarction might be ineffective, but stabilization of the cervical spine with fusion at appropriate levels can successfully prevent further episodes of syncope and stroke. PMID- 29137103 TI - Crizotinib resistance overcome by ceritinib in an ALK-positive non-small cell lung cancer patient with brain metastases: A case report. AB - RATIONALE: The treatment of non-small cell lung cancer (NSCLC) has now changed dramatically in recent years and anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitors are developing rapidly. PATIENT CONCERNS: Here we reported a 57 year-old ALK-positive NSCLC man with brain metastases. DIAGNOSES: A case of lung adenocarcinoma with brain metastases. INTERVENTIONS: Crizotinib was administered orally at a dose of 250mg twice a day until the brain metastases were found. Treatment with orally administered ceritinib at a dose of 450mg/d was initiated after crizotinib treatment. OUTCOMES: The patient is currently receiving maintenance ceritinib treatment, with no evidence of extracranial or intracranial tumor progression for 25 months. LESSONS: Ceritinib may be a good choice for ALK positive NSCLC patients with brain metastases who acquire resistance to crizotinib. PMID- 29137104 TI - Tumor and bone marrow uptakes on [18F]fluorodeoxyglucose positron emission tomography/computed tomography predict prognosis in patients with diffuse large B cell lymphoma receiving rituximab-containing chemotherapy. AB - The purpose of this study was to determine the relevance of standardized uptake value (SUV) on [F]fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), focusing on tumor and bone marrow, to disease outcomes based on progression-free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab-containing chemotherapy.We reviewed the records of patients with DLBCL who were diagnosed between September 2009 and January 2013 and underwent pretreatment whole-body FDG PET/CT scans. All patients received rituximab-containing chemotherapy. The maximal SUV of tumor (SUVt) and maximal SUV of sternum (SUVst) were measured. Univariate and multivariate analyses were used to assess the prognostic significance of SUVt, SUVst, gender, age, clinical stage, international prognostic index (IPI), and laboratory tests.There were total 70 patients enrolled in this study. The median follow-up time was 36 months. An SUVt cut-off value of >=19 had the best discriminative yield for PFS (P = .04). An SUVst cut off value of >=1.6 had the best discriminative yield for OS. The 3-year OS rates for patients with maximal SUVst < 1.6 and for those with maximal SUVst >=1.6 were 74.8% and 57.1%, respectively (P = .04). Further forward, multivariate Cox proportional hazards model revealed that maximal SUVst (hazard ratio: 2.62; 95% confidence interval: 1.10-6.28; P = .03) and IPI were significant factors affecting OS.In patients with DLBCL receiving rituximab-containing chemotherapy, elevated maximal SUVt >=19 was an independent predictor for shorter PFS, and maximal SUVst >=1.6 was an independent predictor for shorter OS. It adds the value of pretreatment FDG PET/CT scans. PMID- 29137105 TI - Urgent laparoscopic ureterolithotomy for proximal ureter stones accompanied with obstructive pyelonephritis: Is it safe and effective without preoperative drainage? AB - To evaluate the safety and efficacy of retroperitoneal laparoscopic ureterolithotomy (RLU) in the treatment of proximal ureteral stones accompanied with obstructive pyelonephritis without preoperative drainage.We retrospectively reviewed 21 cases of proximal ureteral stones with infected kidney undergoing RLU between July 2013 and September 2016. Stone-induced obstructive infected hydronephrosis was diagnosed using blood and urine tests and imaging modalities. Empirical effective broad spectrum antibiotic therapy was initiated immediately, and then urgent RLU was performed without preoperative drainage. During the surgical procedure, infected urine was also aspirated before stone was removed. Preoperative, intraoperative, and postoperative clinical data were collected.Operations were performed successfully without open conversion or blood transfusion. The mean operation time was 69.3 +/- 12.33 minutes. For all the patients, the level of plasma procalcitonin decreased after RLU. The mean hospital stay duration was 6.4 +/- 1.54 days. No septic shock or other severe complications occurred. By discharge, the body temperature and hemogram of each patient returned to normal. A 100% stone-free rate was achieved.Our study suggests that RLU is a potentially safe and effective method to treat proximal ureteral stones accompanied with obstructive pyelonephritis without any need of preoperative drainage. PMID- 29137106 TI - Trabecular bone score as a supplementary tool for the discrimination of osteoporotic fractures in postmenopausal women with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a risk factor for bone fragility, and its effect on fracture risk is independent of bone mineral density (BMD). The trabecular bone score (TBS) is a new indirect parameter of bone quality. In this study, BMD and the TBS were compared between female postmenopausal RA patients with and those without vertebral fractures (VFs).This study had a cross-sectional design. Two hundred seventy-nine postmenopausal women with RA aged 50 years or older were included in this study. TBS measurements were performed on the same vertebrae as those for the BMD measurements.Among the 279 subjects, 34 had VFs (12.5%). There was a significant difference in the TBS (P = .005) but not L-spine BMD (P = .142) between the subjects with and those without VFs. The odds ratio (OR) for the TBS per standard deviation decrease was significant, even after adjusting for confounding factors such as age, height, rheumatoid factor positivity, the disease activity score for 28 joints (DAS28), the cumulative dose of glucocorticoids (GCs), the time since menopause and osteoporosis drug use (OR = 2.86; 95% CI, 1.34-6.09), and L-spine BMD (OR = 2.57; 95% CI, 1.19-5.54). The TBS was negatively correlated with the cumulative dose of GCs, but not with the DAS28 or erythrocyte sedimentation rate. However, the correlation was an L-shaped nonlinear relationship.The TBS could be a supplementary tool for discriminating osteoporotic fractures in postmenopausal women with RA, and it may have a nonlinear relationship with the cumulative dose of GCs, but not with RA disease activity. PMID- 29137107 TI - Effect of lanthanum carbonate on coronary artery calcification and bone mineral density in maintenance hemodialysis patients with diabetes complicated with adynamic bone disease: A prospective pilot study. AB - BACKGROUND: The incidence of adynamic bone disease (ABD) is increasing. Coronary artery calcification (CAC) may be severe in patients with ABD on maintenance hemodialysis (MHD). The aim of this study was to evaluate the effect of lanthanum carbonate (LC) on CAC and bone mineral density (BMD) in MHD patients with diabetes complicated with ABD. METHODS: A total of 92 MHD cases were divided into the calcium carbonate (CC) and LC groups. Primary outcome measure was the changes in the degree of CAC score (CACS) and BMD in forearm from baseline to 12 months. Secondary outcomes included changes in serum markers of CKD-MBD and side-effects. RESULTS: After 12 months, serum levels of calcium, phosphate, FGF23, and MGP were decreased significantly, while iPTH, b-ALP, PINP and beta-CTX, and CACS and BMD were increased in LC group compared with those at baseline (P < .05). After 12 months treatment, serum levels of calcium, phosphate, FGF23, and CACS were lowered, while MGP, b-ALP, PINP, beta-CTX, BMD, and iPTH were higher in LC group than in CC group. Pearson correlation analyses revealed that BMD in forearm was positively correlated with iPTH and MGP, while negatively with CACS. CACS was positively correlated with serum calcium, phosphate and FGF23, while negatively with serum MGP. Multivariate linear regression revealed changes of BMD in forearm and femoral neck and changes of serum FGF23 were independent influential factors for changes of CACS (P < .05). CONCLUSIONS: In MHD patients with diabetes complicated with ABD, lanthanum carbonate could delay CAC progress, and improve bone transport and bone density. PMID- 29137108 TI - Tuberculosis presenting as isolated bronchonodal fistula in a patient with systemic lupus erythematosus: Case report. AB - RATIONALE: Lymph node is a preferred site for extrapulmonary tuberculosis (TB). In the thorax, mediastinal tuberculous lymph nodes can erode adjacent structures such as heart, aorta, and esophagus, forming fistula, and causing fatal consequences. However, tuberculous bronchonodal fistula as a complication of lymph node TB in adults is rarely known in terms of imaging or clinical findings. Here, a case of isolated tuberculous bronchonodal fistula appearing as the first presentation of TB in a 74-year-old male with systemic lupus erythematosus (SLE) is reported. PATIENT CONCERN: A 74-year-old male with SLE visited the hospital with dry cough. In family history, his son was treated for pulmonary TB 9 years previously. Laboratory test revealed increased C-reactive protein level and erythrocyte sedimentation rate. Chest computed tomography (CT) scan revealed a necrotic lymph node in the right hilar area connected to the inferior wall of the right upper lobe bronchus and the lateral wall of bronchus intermedius. DIAGNOSES: On bronchoscopy performed under guidance of 3-dimensionally reconstructed CT image, fistula formation between the right hilar lymph node and 2 bronchi (the right upper lobe and intermediate bronchus) was confirmed. Sputum culture revealed growth of Mycobacterium tuberculosis. INTERVENTION: Anti-TB medication with isoniazid, ethambutol, pyrazinamide, and moxifloxacin for 9 months. OUTCOME: The patient's symptom was gradually improved. Follow-up bronchoscopy performed at 3 months after starting the medication revealed decreased size of the fistula. LESSONS: This is a rare case of bronchonodal fistula appearing as the first presentation of TB in a 74-year-old male patient with SLE. CT provided useful information regarding the origin and progress of the disease. PMID- 29137109 TI - Potential Applications and Limitations of Electronic Nose Devices for Plant Disease Diagnosis. AB - Electronic nose technology has recently been applied to the detection of several plant diseases and pests, with promising results. However, in spite of its numerous advantages, including operational simplicity, non-destructivity, and bulk sampling, drawbacks include a low sensitivity and specificity in comparison with microbiological and molecular methods. A critical review of the use of an electronic nose for plant disease diagnosis and pest detection is presented, describing the instrumental and procedural advances of sensorial analysis, for the improvement of discrimination between healthy and infected or infested plants. In conclusion, the use of electronic nose technology is suggested to assist, direct, and optimise traditionally adopted diagnostic techniques. PMID- 29137110 TI - NeoBOMB1, a GRPR-Antagonist for Breast Cancer Theragnostics: First Results of a Preclinical Study with [67Ga]NeoBOMB1 in T-47D Cells and Tumor-Bearing Mice. AB - BACKGROUND: The GRPR-antagonist-based radioligands [67/68Ga/111In/177Lu]NeoBOMB1 have shown excellent theragnostic profiles in preclinical prostate cancer models, while [68Ga]NeoBOMB1 effectively visualized prostate cancer lesions in patients. We were further interested to explore the theragnostic potential of NeoBOMB1 in GRPR-positive mammary carcinoma, by first studying [67Ga]NeoBOMB1 in breast cancer models; Methods: We investigated the profile of [67Ga]NeoBOMB1, a [68Ga]NeoBOMB1 surrogate, in GRPR-expressing T-47D cells and animal models; Results: NeoBOMB1 (IC50s of 2.2 +/- 0.2 nM) and [natGa]NeoBOMB1 (IC50s of 2.5 +/- 0.2 nM) exhibited high affinity for the GRPR. At 37 degrees C [67Ga]NeoBOMB1 strongly bound to the T-47D cell-membrane (45.8 +/- 0.4% at 2 h), internalizing poorly, as was expected for a radioantagonist. [67Ga]NeoBOMB1 was detected >90% intact in peripheral mouse blood at 30 min pi. In mice bearing T-47D xenografts, [67Ga]NeoBOMB1 specifically localized in the tumor (8.68 +/- 2.9% ID/g vs. 0.6 +/ 0.1% ID/g during GRPR-blockade at 4 h pi). The unfavorably high pancreatic uptake could be considerably reduced (206.29 +/- 17.35% ID/g to 42.46 +/- 1.31% ID/g at 4 h pi) by increasing the NeoBOMB1 dose from 10 pmol to 200 pmol, whereas tumor uptake remained unaffected. Notably, tumor values did not decline from 1 to 24 h pi; Conclusions: [67Ga]NeoBOMB1 can successfully target GRPR-positive breast cancer in animals with excellent prospects for clinical translation. PMID- 29137111 TI - Effect of Omega-3 Fatty Acid Supplementation on Plasma Fibroblast Growth Factor 23 Levels in Post-Myocardial Infarction Patients with Chronic Kidney Disease: The Alpha Omega Trial. AB - Fibroblast growth factor 23 (FGF23) is an independent risk factor for cardiovascular mortality in chronic kidney disease. Omega-3 (n-3) fatty acid consumption has been inversely associated with FGF23 levels and with cardiovascular risk. We examined the effect of marine n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and plant-derived alpha-linolenic acid (ALA) on plasma FGF23 levels in post-myocardial infarction patients with chronic kidney disease. In the randomized double-blind Alpha Omega Trial, 4837 patients with a history of myocardial infarction aged 60-80 years (81% men) were randomized to one of four trial margarines supplemented with a targeted additional intake of 400 mg/day EPA and DHA, 2 g/day ALA, EPA-DHA plus ALA, or placebo for 41 months. In a subcohort of 336 patients with an eGFR < 60 mL/min/1.73 m2 (creatinine-cystatin C-based CKD-EPI formula), plasma C-terminal FGF23 was measured by ELISA at baseline and end of follow-up. We used analysis of covariance to examine treatment effects on FGF23 levels adjusted for baseline FGF23. Patients consumed 19.8 g margarine/day on average, providing an additional amount of 236 mg/day EPA with 158 mg/day DHA, 1.99 g/day ALA or both, in the active intervention groups. Over 79% of patients were treated with antihypertensive and antithrombotic medication and statins. At baseline, plasma FGF23 was 150 (128 to 172) RU/mL (mean (95% CI)). After 41 months, overall FGF23 levels had increased significantly (p < 0.0001) to 212 (183 to 241) RU/mL. Relative to the placebo, the treatment effect of EPA-DHA was indifferent, with a mean change in FGF23 (95% CI) of -17 (-97, 62) RU/mL (p = 0.7). Results were similar for ALA (36 (-42, 115) RU/mL) and combined EPA-DHA and ALA (34 (-44, 113) RU/mL). Multivariable adjustment, pooled analyses, and subgroup analyses yielded similar non-significant results. Long-term supplementation with modest quantities of EPA-DHA or ALA does not reduce plasma FGF23 levels when added to cardiovascular medication in post-myocardial patients with chronic kidney disease. PMID- 29137112 TI - Elucidating Direct Photolysis Mechanisms of Different Dissociation Species of Norfloxacin in Water and Mg2+ Effects by Quantum Chemical Calculations. AB - The study of pollution due to combined antibiotics and metals is urgently needed. Photochemical processes are an important transformation pathway for antibiotics in the environment. The mechanisms underlying the effects of metal-ion complexation on the aquatic photochemical transformation of antibiotics in different dissociation forms are crucial problems in science, and beg solutions. Herein, we investigated the mechanisms of direct photolysis of norfloxacin (NOR) in different dissociation forms in water and metal ion Mg2+ effects using quantum chemical calculations. Results show that different dissociation forms of NOR had different maximum electronic absorbance wavelengths (NOR2+ < NOR0 < NOR+) and showed different photolysis reactivity. Analysis of transition states (TS) and reaction activation energies (Ea) indicated NOR+ generally underwent loss of the piperazine ring (C10-N13 bond cleavage) and damage to piperazine ring (N13-C14 bond cleavage). For NOR2+, the main direct photolysis pathways were de-ethylation (N7-C8 bond cleavage) and decarboxylation (C2-C5 bond cleavage). Furthermore, the presence of Mg2+ changed the order of the wavelength at maximum electronic absorbance (NOR+-Mg2+ < NOR0-Mg2+ < NOR2+-Mg2+) and increased the intensities of absorbance peaks of all three dissociation species of NOR, implying that Mg2+ played an important role in the direct photolysis of NOR0, NOR+, and NOR2+. The calculated TS results indicated that the presence of Mg2+ increased Ea for most direct photolysis pathways of NOR, while it decreased Ea for some direct photolysis pathways such as the loss of the piperazine ring and the damage of the piperazine ring of NOR0 and the defluorination of NOR+. PMID- 29137113 TI - Integrated Evaluation of the Potential Health Benefits of Einkorn-Based Breads. AB - Nowadays the high nutritional value of whole grains is recognized, and there is an increasing interest in the ancient varieties for producing wholegrain food products with enhanced nutritional characteristics. Among ancient crops, einkorn could represent a valid alternative. In this work, einkorn flours were analyzed for their content in carotenoids and in free and bound phenolic acids, and compared to wheat flours. The most promising flours were used to produce conventional and sourdough fermented breads. Breads were in vitro digested, and characterized before and after digestion. The four breads having the best characteristics were selected, and the product of their digestion was used to evaluate their anti-inflammatory effect using Caco-2 cells. Our results confirm the higher carotenoid levels in einkorn than in modern wheats, and the effectiveness of sourdough fermentation in maintaining these levels, despite the longer exposure to atmospheric oxygen. Moreover, in cultured cells einkorn bread evidenced an anti-inflammatory effect, although masked by the effect of digestive fluid. This study represents the first integrated evaluation of the potential health benefit of einkorn-based bakery products compared to wheat-based ones, and contributes to our knowledge of ancient grains. PMID- 29137114 TI - Natural Cyclopeptide RA-XII, a New Autophagy Inhibitor, Suppresses Protective Autophagy for Enhancing Apoptosis through AMPK/mTOR/P70S6K Pathways in HepG2 Cells. AB - Liver cancer is a progressive, irreversible and aggressive malignant disease, which has no effective chemotherapeutic drugs. RA-XII, a natural cyclopeptide isolated from the traditional Chinese medicine Rubia yunnanensis, exerts anti cancer and anti-inflammatory activities. This work aimed to investigate the effects of RA-XII on a hepatic tumor and its underlying mechanisms in human hepatoma HepG2 cells. The results showed that RA-XII effectively inhibited the proliferation of HepG2 cells. Consistently, RA-XII significantly induced apoptosis in HepG2 cells by decreasing the expression of caspase 3, 8, 9, and promoting the Cleavage of PARP. Moreover, RA-XII-induced apoptosis was attenuated in the presence of apoptosis inhibitor N-Benzyloxycarbonyl-Val-Ala-Asp (O-Me) fluoromethyl keton, suggesting that RA-XII induced apoptosis-cell-death in HepG2 cells. Furthermore, autophagy-related proteins and mRNA levels were dramatically reduced after RA-XII treatment. Meanwhile, we observed that autophagy inhibitor chloroquine could enhance apoptosis in RA-XII-treated HepG2 cells, indicating that autophagy played a protective role in HepG2 cells and RA-XII might inhibit protective autophagy. Further analysis showed that RA-XII inhibited AMPK phosphorylation and led to the mTOR/P70S6K pathway activation, suggesting that RA XII inhibited autophagy through AMPK/mTOR/P70S6K pathways. This study demonstrated that RA-XII promoted apoptosis and inhibited protective autophagy through AMPK/mTOR/P70S6K pathways in HepG2 cells. In conclusion, these findings suggest that RA-XII might potentially be a candidate as an autophagy inhibitor agent for further therapy of liver cancer. PMID- 29137115 TI - Cost-Effective and Handmade Paper-Based Immunosensing Device for Electrochemical Detection of Influenza Virus. AB - Although many studies concerning the detection of influenza virus have been published, a paper-based, label-free electrochemical immunosensor has never been reported. Here, we present a cost-effective, handmade paper-based immunosensor for label-free electrochemical detection of influenza virus H1N1. This immunosensor was prepared by modifying paper with a spray of hydrophobic silica nanoparticles, and using stencil-printed electrodes. We used a glass vaporizer to spray the hydrophobic silica nanoparticles onto the paper, rendering it super hydrophobic. The super-hydrophobicity, which is essential for this paper-based biosensor, was achieved via 30-40 spray coatings, corresponding to a 0.39-0.41 mg cm-2 coating of nanoparticles on the paper and yielding a water contact angle of 150 degrees +/- 1 degrees . Stencil-printed carbon electrodes modified with single-walled carbon nanotubes and chitosan were employed to increase the sensitivity of the sensor, and the antibodies were immobilized via glutaraldehyde cross-linking. Differential pulse voltammetry was used to assess the sensitivity of the sensors at various virus concentrations, ranging from 10 to 104 PFU mL-1, and the selectivity was assessed against MS2 bacteriophages and the influenza B viruses. These immunosensors showed good linear behaviors, improved detection times (30 min), and selectivity for the H1N1 virus with a limit of detection of 113 PFU mL-1, which is sufficiently sensitive for rapid on-site diagnosis. The simple and inexpensive methodologies developed in this study have great potential to be used for the development of a low-cost and disposable immunosensor for detection of pathogenic microorganisms, especially in developing countries. PMID- 29137116 TI - Altering Residue 134 Confers an Increased Substrate Range of Alkylated Nucleosides to the E. coli OGT Protein. AB - O6-Alkylguanine-DNA alkyltransferases (AGTs) are proteins responsible for the removal of mutagenic alkyl adducts at the O6-atom of guanine and O4-atom of thymine. In the current study we set out to understand the role of the Ser134 residue in the Escherichia coli AGT variant OGT on substrate discrimination. The S134P mutation in OGT increased the ability of the protein to repair both O6 adducts of guanine and O4-adducts of thymine. However, the S134P variant was unable, like wild-type OGT, to repair an interstrand cross-link (ICL) bridging two O6-atoms of guanine in a DNA duplex. When compared to the human AGT protein (hAGT), the S134P OGT variant displayed reduced activity towards O6-alkylation but a much broader substrate range for O4-alkylation damage reversal. The role of residue 134 in OGT is similar to its function in the human homolog, where Pro140 is crucial in conferring on hAGT the capability to repair large adducts at the O6 position of guanine. Finally, a method to generate a covalent conjugate between hAGT and a model nucleoside using a single-stranded oligonucleotide substrate is demonstrated. PMID- 29137117 TI - A Systematic Review and Meta-Analysis of Proteomics Literature on the Response of Human Skeletal Muscle to Obesity/Type 2 Diabetes Mellitus (T2DM) Versus Exercise Training. AB - We performed a systematic review and meta-analysis of proteomics literature that reports human skeletal muscle responses in the context of either pathological decline associated with obesity/T2DM and physiological adaptations to exercise training. Literature was collected from PubMed and DOAJ databases following PRISMA guidelines using the search terms 'proteom*', and 'skeletal muscle' combined with either 'obesity, insulin resistance, diabetes, impaired glucose tolerance' or 'exercise, training'. Eleven studies were included in the systematic review, and meta-analysis was performed on a sub-set (four studies) of the reviewed literature that reported the necessary primary data. The majority of proteins (n = 73) more abundant in the muscle of obese/T2DM individuals were unique to this group and not reported to be responsive to exercise training. The main response of skeletal muscle to exercise training was a greater abundance of proteins of the mitochondrial electron transport chain, tricarboxylic acid cycle and mitochondrial respiratory chain complex I assembly. In total, five proteins were less abundant in muscle of obese/T2DM individuals and were also reported to be more abundant in the muscle of endurance-trained individuals, suggesting one of the major mechanisms of exercise-induced protection against the deleterious effects of obesity/T2DM occurs at complex I of the electron transport chain. PMID- 29137118 TI - Modeling Skin Injury from Hot Spills on Clothing. AB - The present work analyzes scald burns from hot beverages, such as coffee and tea, spilled on the lap, i.e., an incident that may occur in daily life. The Pennes bioheat equation is solved numerically for small spills wetting the clothing, i.e., the fabric prevents the spilled liquid from draining away. Temperatures are analyzed in the wetted fabric and the skin layers and the resulting skin injury is calculated based on the basal layer temperature. Parameters influencing burn severity, such as clothing thickness, liquid temperature, removal of fabric and thermal effects of post scald water cooling are analyzed. The fabric cools the water some but represents a threat since the entrapped water results in a prolonged heat supply. The liquid temperature turned out to be the most important injury parameter, where liquid temperature of about 80-85 degrees C seems to be a limit for developing superficial partial-thickness burns in the present minimum case, i.e., where the liquid just wets the fabric. Spilling water in excess of just wetting the fabric, more severe burns will develop at lower liquid temperatures due to the prolonged heat supply. Higher liquid temperatures will nearly instantly develop more severe burns. It is demonstrated that removal of the clothing within the first seconds after the spill may significantly reduce the scalding severity. The general advice is therefore to avoid excessive heating of beverages and, if the beverage is spilled, to quickly remove the wetted clothing. Prolonged tempered water cooling is advised to improve the healing processes. PMID- 29137119 TI - Dynamic Reorganization of the Cytoskeleton during Apoptosis: The Two Coffins Hypothesis. AB - During apoptosis, cells undergo characteristic morphological changes in which the cytoskeleton plays an active role. The cytoskeleton rearrangements have been mainly attributed to actinomyosin ring contraction, while microtubule and intermediate filaments are depolymerized at early stages of apoptosis. However, recent results have shown that microtubules are reorganized during the execution phase of apoptosis forming an apoptotic microtubule network (AMN). Evidence suggests that AMN is required to maintain plasma membrane integrity and cell morphology during the execution phase of apoptosis. The new "two coffins" hypothesis proposes that both AMN and apoptotic cells can adopt two morphological patterns, round or irregular, which result from different cytoskeleton kinetic reorganization during the execution phase of apoptosis induced by genotoxic agents. In addition, round and irregular-shaped apoptosis showed different biological properties with respect to AMN maintenance, plasma membrane integrity and phagocyte responses. These findings suggest that knowing the type of apoptosis may be important to predict how fast apoptotic cells undergo secondary necrosis and the subsequent immune response. From a pathological point of view, round-shaped apoptosis can be seen as a physiological and controlled type of apoptosis, while irregular-shaped apoptosis can be considered as a pathological type of cell death closer to necrosis. PMID- 29137120 TI - Aspidosperma pyrifolium Has Anti-Inflammatory Properties: An Experimental Study in Mice with Peritonitis Induced by Tityus serrulatus Venom or Carrageenan. AB - Scorpions of the genus Tityus are responsible for the majority of envenomation in Brazil, the Tityus serrulatus species being the most common and dangerous in South America. In this approach, we have investigated the ability of the aqueous extract from the leaves of Aspidosperma pyrifolium in reducing carrageenan induced inflammation and the inflammation induced by T. serrulatus envenomation in mice. We also evaluated the cytotoxic effects of this extract, using the 3 (4,5-dimethythiazol-2-yl)-2,5-diphenyl-2H-tetrazolium (MTT) assay and the results revealed that the extract is safe. Analysis by High Performance Liquid Chromatography coupled with Diode Array Detector (HPLC-DAD) and Liquid Chromatography Coupled with Mass Spectrometry with Diode Array Detection (LC-DAD MS) showed one major chemical component, the flavonoid rutin and phenolics compounds. For in vivo studies in carrageenan-induced peritonitis model, mice received extracts, dexamethasone, rutin or saline, before administration of carrageenan. For venom-induced inflammation model, animals received T. serrulatus venom and were, simultaneously, treated with extracts, antivenom, rutin or saline. The extract and rutin showed a reduction in the cell migration into the peritoneal cavity, and in the same way the envenomated animals also showed reduction of edema, inflammatory cell infiltration and vasodilation in lungs. This is an original study revealing the potential action of A. pyrifolium against inflammation caused by Tityus serrulatus venom and carrageenan, revealing that this extract and its bioactive molecules, specifically rutin, may present potential anti-inflammatory application. PMID- 29137121 TI - Human Mesenchymal Stem Cells Growth and Osteogenic Differentiation on Piezoelectric Poly(vinylidene fluoride) Microsphere Substrates. AB - The aim of this work was to determine the influence of the biomaterial environment on human mesenchymal stem cell (hMSC) fate when cultured in supports with varying topography. Poly(vinylidene fluoride) (PVDF) culture supports were prepared with structures ranging between 2D and 3D, based on PVDF films on which PVDF microspheres were deposited with varying surface density. Maintenance of multipotentiality when cultured in expansion medium was studied by flow cytometry monitoring the expression of characteristic hMSCs markers, and revealed that cells were losing their characteristic surface markers on these supports. Cell morphology was assessed by scanning electron microscopy (SEM). Alkaline phosphatase activity was also assessed after seven days of culture on expansion medium. On the other hand, osteoblastic differentiation was monitored while culturing in osteogenic medium after cells reached confluence. Osteocalcin immunocytochemistry and alizarin red assays were performed. We show that flow cytometry is a suitable technique for the study of the differentiation of hMSC seeded onto biomaterials, giving a quantitative reliable analysis of hMSC associated markers. We also show that electrosprayed piezoelectric poly(vinylidene fluoride) is a suitable support for tissue engineering purposes, as hMSCs can proliferate, be viable and undergo osteogenic differentiation when chemically stimulated. PMID- 29137123 TI - Proteomic Characterization of the Venom of Five Bombus (Thoracobombus) Species. AB - Venomous animals use venom, a complex biofluid composed of unique mixtures of proteins and peptides, to act on vital systems of the prey or predator. In bees, venom is solely used for defense against predators. However, the venom composition of bumble bees (Bombus sp.) is largely unknown. The Thoracobombus subgenus of Bombus sp. is a diverse subgenus represented by 14 members across Turkey. In this study, we sought out to proteomically characterize the venom of five Thoracobombus species by using bottom-up proteomic techniques. We have obtained two-dimensional polyacrylamide gel (2D-PAGE) images of each species' venom sample. We have subsequently identified the protein spots by using matrix assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF MS). We have identified 47 proteins for Bombus humilis, 32 for B. pascuorum, 60 for B. ruderarius, 39 for B. sylvarum, and 35 for B. zonatus. Moreover, we illustrated that intensities of 2DE protein spots corresponding to putative venom toxins vary in a species-specific manner. Our analyses provide the primary proteomic characterization of five bumble bee species' venom composition. PMID- 29137122 TI - Peptide Nucleic Acid-Based Biosensors for Cancer Diagnosis. AB - The monitoring of DNA and RNA biomarkers freely circulating in the blood constitutes the basis of innovative cancer detection methods based on liquid biopsy. Such methods are expected to provide new opportunities for a better understanding of cancer disease at the molecular level, thus contributing to improved patient outcomes. Advanced biosensors can advance possibilities for cancer-related nucleic acid biomarkers detection. In this context, peptide nucleic acids (PNAs) play an important role in the fabrication of highly sensitive biosensors. This review provides an overview of recently described PNA based biosensors for cancer biomarker detection. One of the most striking features of the described detection approaches is represented by the possibility to detect target nucleic acids at the ultra-low concentration with the capability to identify single-base mutations. PMID- 29137124 TI - Asthmatic Patients with Vitamin D Deficiency have Decreased Exacerbations after Vitamin Replacement. AB - BACKGROUND: Intervention studies with vitamin D in asthma are inconclusive for several reasons, such as inadequate dosing or duration of supplementation or uncontrolled baseline vitamin D status. Our aim was to evaluate the benefit of long term vitamin D add-on in asthmatic patients with actual vitamin D deficiency, that is a serum 25-hydroxy vitamin D (25-OHD ) below 20 ng/mL. METHODS: Serum 25-OHD, asthma exacerbations, spirometry and inhaled corticosteroids (CS) dose were evaluated in a cohort of 119 asthmatic patients. Patients with deficiency were evaluated again after one year vitamin supplementation. RESULTS: 25-OHD was low in 111 patients and was negatively related to exacerbations (p < 0.001), inhaled CS dose (p = 0.008) and asthma severity (p = 0.001). Deficiency was found in 90 patients, 55 of whom took the supplement regularly for one year, while 24 discontinued the study and 11 were not adherent. Patients with vitamin D deficiency after 12 months supplementation showed significant decrease of exacerbations (from 2.6 +/- 1.2 to 1.6 +/- 1.1, p < 0.001), circulating eosinophils (from 395 +/- 330 to 272 +/- 212 106/L, p < 0.001), and need of oral CS courses (from 35 to 20, p = 0.007) and improvement of airway obstruction. CONCLUSIONS: Asthma exacerbations are favored by vitamin D deficiency and decrease after long-term vitamin D replacement. Patients who are vitamin D deficient benefit from vitamin D supplementation. PMID- 29137125 TI - New 2-Methoxy Acetylenic Acids and Pyrazole Alkaloids from the Marine Sponge Cinachyrella sp. AB - Three new 2-methoxy acetylenic acids (1-3) and a known derivative (4), in addition to three new natural pyrazole alkaloids (5-7) were isolated from an Indonesian marine sponge of the genus Cinachyrella. Compounds 5 and 6 have previously been reported as synthetic compounds. The structures of the new compounds were established on the basis of one- and two-dimensional NMR spectroscopy as well as by mass spectrometric data. The absolute configuration of the new acetylenic acid derivatives (1-3) was established by ECD spectroscopy. All isolated compounds were evaluated for their cytotoxicity against L5178Y mouse lymphoma cells. Compounds 1-4 exhibited strong activity with an IC50 value of 0.3 uM. A plausible biosynthetic pathway for the pyrazole metabolites 5-7 is proposed. PMID- 29137126 TI - Carbon Nanotubes' Effect on Mitochondrial Oxygen Flux Dynamics: Polarography Experimental Study and Machine Learning Models using Star Graph Trace Invariants of Raman Spectra. AB - This study presents the impact of carbon nanotubes (CNTs) on mitochondrial oxygen mass flux (Jm) under three experimental conditions. New experimental results and a new methodology are reported for the first time and they are based on CNT Raman spectra star graph transform (spectral moments) and perturbation theory. The experimental measures of Jm showed that no tested CNT family can inhibit the oxygen consumption profiles of mitochondria. The best model for the prediction of Jm for other CNTs was provided by random forest using eight features, obtaining test R-squared (R2) of 0.863 and test root-mean-square error (RMSE) of 0.0461. The results demonstrate the capability of encoding CNT information into spectral moments of the Raman star graphs (SG) transform with a potential applicability as predictive tools in nanotechnology and material risk assessments. PMID- 29137127 TI - Physical Activity of German Children and Adolescents 2003-2012: The MoMo-Study. AB - Organized and unorganized physical activity (PA) hold an important role in the daily life of children and adolescents. Regular representative tracking of PA in different settings is important to evaluate social trends and implemented interventions. In this paper, representative PA data of German children and adolescents from the MoMo Baseline-Study (2004, n = 4528) are compared to those of Wave 1 (2010, n = 3994). Participants aged 4-17 were drawn out of 167 sample points in Germany and the data was weighted to ensure representativeness. PA was measured via questionnaire and was differentiated between organized (sports clubs and schools) and unorganized (unorganized sports and playing outside). Organized PA in extracurricular activities and sports clubs increased by eight percent, while unorganized PA decreased by seven percent. In addition to sports clubs, schools became a more prevalent setting for participation in physical activity in Germany. PMID- 29137129 TI - Design and Evaluation of Novel Polymyxin Fluorescent Probes. AB - Polymyxins (polymyxin B and colistin) are cyclic lipopeptide antibiotics that serve as a last-line defence against Gram-negative "superbugs". In the present study, two novel fluorescent polymyxin probes were designed through regio selective modifications of the polymyxin B core structure at the N-terminus and the hydrophobic motif at positions 6 and 7. The resulting probes, FADDI-285 and FADDI-286 demonstrated comparable antibacterial activity (MICs 2-8 mg/L) to polymyxin B and colistin (MICs 0.5-8 mg/L) against a panel of gram-negative clinical isolates of Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. These probes should prove to be of considerable utility for imaging cellular uptake and mechanistic investigations of these important last-line antibiotics. PMID- 29137128 TI - Tactile Evaluation Feedback System for Multi-Layered Structure Inspired by Human Tactile Perception Mechanism. AB - Tactile sensation is one type of valuable feedback in evaluating a product. Conventionally, sensory evaluation is used to get direct subjective responses from the consumers, in order to improve the product's quality. However, this method is a time-consuming and costly process. Therefore, this paper proposes a novel tactile evaluation system that can give tactile feedback from a sensor's output. The main concept of this system is hierarchically layering the tactile sensation, which is inspired by the flow of human perception. The tactile sensation is classified from low-order of tactile sensation (LTS) to high-order of tactile sensation (HTS), and also to preference. Here, LTS will be correlated with physical measures. Furthermore, the physical measures that are used to correlate with LTS are selected based on four main aspects of haptic information (roughness, compliance, coldness, and slipperiness), which are perceived through human tactile sensors. By using statistical analysis, the correlation between each hierarchy was obtained, and the preference was derived in terms of physical measures. A verification test was conducted by using unknown samples to determine the reliability of the system. The results showed that the system developed was capable of estimating preference with an accuracy of approximately 80%. PMID- 29137130 TI - Halogen-Metal Exchange on Bromoheterocyclics with Substituents Containing an Acidic Proton via Formation of a Magnesium Intermediate. AB - A selective and practical bromine-metal exchange on bromoheterocyclics bearing substituents with an acidic proton under non-cryogenic conditions was developed by a simple modification of an existing protocol. Our protocol of using a combination of i-PrMgCl and n-BuLi has not only solved the problem of intermolecular quenching that often occurred when using alkyl lithium alone as the reagent for halogen-lithium exchange, but also offered a highly selective method for performing bromo-metal exchange on dibrominated arene compounds through chelation effect. PMID- 29137131 TI - Fiber-Optic Thermal Sensor for TiN Film Crack Monitoring. AB - The study focuses on the thermal and temperature sensitivity behavior of an optical fiber sensor device. In this article, a titanium nitride (TiN)-coated fiber Bragg grating (FBG) sensor fabricated using an ion beam sputtering system was investigated. The reflection spectra of the FBG sensor were tested using R soft optical software to simulate the refractive index sensitivity. In these experiments, the temperature sensitivity of the TiN FBG was measured at temperatures ranging from 100 to 500 degrees C using an optical spectrum analyzer (OSA). The results showed that the temperature sensitivity of the proposed TiN FBG sensor reached 12.8 pm/ degrees C for the temperature range of 100 to 300 degrees C and 20.8 pm/ degrees C for the temperature range of 300 to 500 degrees C. Additionally, we found that the produced oxidation at temperatures of 400-500 degrees C caused a crack, with the crack becoming more and more obvious at higher and higher temperatures. PMID- 29137133 TI - Reduced Graphene Oxide on Nickel Foam for Supercapacitor Electrodes. AB - The focus of this paper is the investigation of reduced graphene oxide (GO)/nickel foam (RGON) samples for use as supercapacitor electrodes. Nickel foam samples were soaked in a GO suspension and dried before being subjected to two different methods to remove oxygen. Atmospheric pressure annealed (APA) samples were treated with a varying number (10-18) of nitrogen plasma jet scans, where sample temperatures did not exceed 280 degrees C. Furnace annealed (FA) samples were processed in an atmosphere of hydrogen and argon, at temperatures ranging from 600 degrees C to 900 degrees C. Environmental Scanning Electron Microscope (ESEM) data indicated that the carbon to oxygen (C:O) ratio for APA samples was minimized at an intermediate number of plasma scans. Fourier Transform Infrared Spectroscopic (FTIR) and Raman spectroscopic data supported this finding. ESEM analysis from FA samples showed that with increasing temperatures of annealing, GO is transformed to reduced graphene oxide (RGO), with C:O ratios exceeding 35:1. X-ray Photoelectron Spectroscopy (XPS) and X-ray diffraction (XRD) data indicated the formation of RGO with an increasing annealing temperature until 800 degrees C, when oxygen reincorporation in the surface atomic layers becomes an issue. Supercapacitors, constructed using the FA samples, demonstrated performances that correlated with surface atomic layer optimization of the C:O ratio. PMID- 29137132 TI - Maternal Vitamin D Status and the Relationship with Neonatal Anthropometric and Childhood Neurodevelopmental Outcomes: Results from the Seychelles Child Development Nutrition Study. AB - Vitamin D has an important role in early life; however, the optimal vitamin D status during pregnancy is currently unclear. There have been recent calls for pregnant women to maintain circulating 25-hydroxyvitamin D (25(OH)D) concentrations >100 nmol/L for health, yet little is known about the long-term potential benefits or safety of achieving such high maternal 25(OH)D concentrations for infant or child health outcomes. We examined maternal vitamin D status and its associations with infant anthropometric and later childhood neurocognitive outcomes in a mother-child cohort in a sun-rich country near the equator (4.6 degrees S). This study was conducted in pregnant mothers originally recruited to the Seychelles Child Development Nutrition Study. Blood samples (n = 202) taken at delivery were analysed for serum 25-hydroxyvitamin D (25(OH)D) concentrations. Multiple linear regression models assessed associations between maternal 25(OH)D and birth weight, infant head circumference, and neurocognitive outcomes in the children at age 5 years. Mothers were, on average, 27 years of age, and the children's average gestational age was 39 weeks. None of the women reported any intake of vitamin D supplements. Maternal 25(OH)D concentrations had a mean of 101 (range 34-218 nmol/L) and none were deficient (<30 nmol/L). Maternal 25(OH)D concentrations were not associated with child anthropometric or neurodevelopmental outcomes. These findings appear to indicate that a higher vitamin D status is not a limiting factor for neonatal growth or neurocognitive development in the first 5 years of life. Larger studies with greater variability in vitamin D status are needed to further explore optimal cut-offs or non-linear associations (including for maternal health) that might exist among populations with sub-optimal exposure. PMID- 29137135 TI - An Electrochemical Enzyme Biosensor for 3-Hydroxybutyrate Detection Using Screen Printed Electrodes Modified by Reduced Graphene Oxide and Thionine. AB - A biosensor for 3-hydroxybutyrate (3-HB) involving immobilization of the enzyme 3 hydroxybutyrate dehydrogenase onto a screen-printed carbon electrode modified with reduced graphene oxide (GO) and thionine (THI) is reported here. After addition of 3-hydroxybutyrate or the sample in the presence of NAD+ cofactor, the generated NADH could be detected amperometrically at 0.0 V vs. Ag pseudo reference electrode. Under the optimized experimental conditions, a calibration plot for 3-HB was constructed showing a wide linear range between 0.010 and 0.400 mM 3-HB which covers the clinically relevant levels for diluted serum samples. In addition, a limit of detection of 1.0 uM, much lower than that reported using other biosensors, was achieved. The analytical usefulness of the developed biosensor was demonstrated via application to spiked serum samples. PMID- 29137134 TI - An Overview of the Bacterial Carbonic Anhydrases. AB - Bacteria encode carbonic anhydrases (CAs, EC 4.2.1.1) belonging to three different genetic families, the alpha-, beta-, and gamma-classes. By equilibrating CO2 and bicarbonate, these metalloenzymes interfere with pH regulation and other crucial physiological processes of these organisms. The detailed investigations of many such enzymes from pathogenic and non-pathogenic bacteria afford the opportunity to design both novel therapeutic agents, as well as biomimetic processes, for example, for CO2 capture. Investigation of bacterial CA inhibitors and activators may be relevant for finding antibiotics with a new mechanism of action. PMID- 29137136 TI - Incorporation of Fiber Bragg Sensors for Shape Memory Polyurethanes Characterization. AB - Shape memory polyurethanes (SMPUs) are thermally activated shape memory materials, which can be used as actuators or sensors in applications including aerospace, aeronautics, automobiles or the biomedical industry. The accurate characterization of the memory effect of these materials is therefore mandatory for the technology's success. The shape memory characterization is normally accomplished using mechanical testing coupled with a heat source, where a detailed knowledge of the heat cycle and its influence on the material properties is paramount but difficult to monitor. In this work, fiber Bragg grating (FBG) sensors were embedded into SMPU samples aiming to study and characterize its shape memory effect. The samples were obtained by injection molding, and the entire processing cycle was successfully monitored, providing a process global quality signature. Moreover, the integrity and functionality of the FBG sensors were maintained during and after the embedding process, demonstrating the feasibility of the technology chosen for the purpose envisaged. The results of the shape memory effect characterization demonstrate a good correlation between the reflected FBG peak with the temperature and induced strain, proving that this technology is suitable for this particular application. PMID- 29137137 TI - A Comparison of FPGA and GPGPU Designs for Bayesian Occupancy Filters. AB - Grid-based perception techniques in the automotive sector based on fusing information from different sensors and their robust perceptions of the environment are proliferating in the industry. However, one of the main drawbacks of these techniques is the traditionally prohibitive, high computing performance that is required for embedded automotive systems. In this work, the capabilities of new computing architectures that embed these algorithms are assessed in a real car. The paper compares two ad hoc optimized designs of the Bayesian Occupancy Filter; one for General Purpose Graphics Processing Unit (GPGPU) and the other for Field-Programmable Gate Array (FPGA). The resulting implementations are compared in terms of development effort, accuracy and performance, using datasets from a realistic simulator and from a real automated vehicle. PMID- 29137138 TI - Metabolic Profile of the Cellulolytic Industrial Actinomycete Thermobifida fusca. AB - Actinomycetes have a long history of being the source of numerous valuable natural products and medicinals. To expedite product discovery and optimization of biochemical production, high-throughput technologies can now be used to screen the library of compounds present (or produced) at a given time in an organism. This not only facilitates chemical product screening, but also provides a comprehensive methodology to the study cellular metabolic networks to inform cellular engineering. Here, we present some of the first metabolomic data of the industrial cellulolytic actinomycete Thermobifida fusca generated using LC-MS/MS. The underlying objective of conducting global metabolite profiling was to gain better insight on the innate capabilities of T. fusca, with a long-term goal of facilitating T. fusca-based bioprocesses. The T. fusca metabolome was characterized for growth on two cellulose-relevant carbon sources, cellobiose and Avicel. Furthermore, the comprehensive list of measured metabolites was computationally integrated into a metabolic model of T. fusca, to study metabolic shifts in the network flux associated with carbohydrate and amino acid metabolism. PMID- 29137139 TI - Deduction of Novel Genes Potentially Involved in Osteoblasts of Rheumatoid Arthritis Using Next-Generation Sequencing and Bioinformatic Approaches. AB - The role of osteoblasts in peri-articular bone loss and bone erosion in rheumatoid arthritis (RA) has gained much attention, and microRNAs are hypothesized to play critical roles in the regulation of osteoblast function in RA. The aim of this study is to explore novel microRNAs differentially expressed in RA osteoblasts and to identify genes potentially involved in the dysregulated bone homeostasis in RA. RNAs were extracted from cultured normal and RA osteoblasts for sequencing. Using the next generation sequencing and bioinformatics approaches, we identified 35 differentially expressed microRNAs and 13 differentially expressed genes with potential microRNA-mRNA interactions in RA osteoblasts. The 13 candidate genes were involved mainly in cell-matrix adhesion, as classified by the Gene Ontology. Two genes of interest identified from RA osteoblasts, A-kinase anchoring protein 12 (AKAP12) and leucin rich repeat containing 15 (LRRC15), were found to express more consistently in the related RA synovial tissue arrays in the Gene Expression Omnibus database, with the predicted interactions with miR-183-5p and miR-146a-5p, respectively. The Ingenuity Pathway Analysis identified AKAP12 as one of the genes involved in protein kinase A signaling and the function of chemotaxis, interconnecting with molecules related to neovascularization. The findings indicate new candidate genes as the potential indicators in evaluating therapies targeting chemotaxis and neovascularization to control joint destruction in RA. PMID- 29137140 TI - Effect of Relative Humidity on Adsorption Breakthrough of CO2 on Activated Carbon Fibers. AB - Microporous activated carbon fibers (ACFs) were developed for CO2 capture based on potassium hydroxide (KOH) activation and tetraethylenepentamine (TEPA) amination. The material properties of the modified ACFs were characterized using several techniques. The adsorption breakthrough curves of CO2 were measured and the effect of relative humidity in the carrier gas was determined. The KOH activation at high temperature generated additional pore networks and the intercalation of metallic K into the carbon matrix, leading to the production of mesopore and micropore volumes and providing access to the active sites in the micropores. However, this treatment also resulted in the loss of nitrogen functionalities. The TEPA amination has successfully introduced nitrogen functionalities onto the fiber surface, but its long-chain structure blocked parts of the micropores and, thus, made the available surface area and pore volume limited. Introduction of the power of time into the Wheeler equation was required to fit the data well. The relative humidity within the studied range had almost no effects on the breakthrough curves. It was expected that the concentration of CO2 was high enough so that the impact on CO2 adsorption capacity lessened due to increased relative humidity. PMID- 29137142 TI - Characterization and Antibiofouling Performance Investigation of Hydrophobic Silver Nanocomposite Membranes: A Comparative Study. AB - Biofouling is one of the drawbacks restricting the industrial applications of membranes. In this study, different thicknesses of silver nanoparticles with proper adhesion were deposited on poly(vinylidenefluoride) (PVDF) and polyethersulfone (PES) surfaces by physical vapor deposition (PVD). The crystalline and structural properties of modified and pure membranes were investigated by carrying out X-ray diffraction (XRD) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). Scanning electron microscope (SEM) and atomic force microscopy (AFM) analyses were employed to examine the surface morphology and the bacteria anti-adhesion property of the membranes. The morphology measurements confirmed that even though after silver grafting the surface became more hydrophobic, the homogeneity increased and the flux reduction decreased after coating. Moreover a comparison between PVDF and PES revealed that CFU (colony forming units) reduced 64.5% on PVDF surface and 31.1% on PES surface after modification. In conclusion, PVD improved the performance of the membrane antibiofouling, and it is more promising to be used for PVDF rather than PES. PMID- 29137143 TI - Evaluation of a Mass-Media Campaign to Increase the Awareness of the Need to Reduce Discretionary Salt Use in the South African Population. AB - The South African strategic plan to reduce cardiovascular disease (CVD) includes reducing population salt intake to less than 5 g/day. A mass media campaign was undertaken to increase public awareness of the association between high salt intake, blood pressure and CVD, and focused on the reduction of discretionary salt intake. Community based surveys, before and after the campaign, were conducted in a cohort of black women aged 18-55 years. Questions on knowledge, attitudes and beliefs regarding salt use were asked. Current interest in engaging with salt reduction behaviors was assessed using the "stage of change" model. Five hundred fifty women participated in the baseline study and 477 in the follow up survey. Most of the indicators of knowledge, attitudes and behavior change show a significant move towards considering and initiating reduced salt consumption. Post intervention, significantly more participants reported that they were taking steps to control salt intake (38% increased to 59.5%, p < 0.0001). In particular, adding salt while cooking and at the table occurred significantly less frequently. The findings suggest that mass media campaigns may be an effective tool to use as part of a strategy to reduce discretionary consumption of salt among the population along with other methods. PMID- 29137141 TI - Steroid and Xenobiotic Receptor Signalling in Apoptosis and Autophagy of the Nervous System. AB - Apoptosis and autophagy are involved in neural development and in the response of the nervous system to a variety of insults. Apoptosis is responsible for cell elimination, whereas autophagy can eliminate the cells or keep them alive, even in conditions lacking trophic factors. Therefore, both processes may function synergistically or antagonistically. Steroid and xenobiotic receptors are regulators of apoptosis and autophagy; however, their actions in various pathologies are complex. In general, the estrogen (ER), progesterone (PR), and mineralocorticoid (MR) receptors mediate anti-apoptotic signalling, whereas the androgen (AR) and glucocorticoid (GR) receptors participate in pro-apoptotic pathways. ER-mediated neuroprotection is attributed to estrogen and selective ER modulators in apoptosis- and autophagy-related neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, stroke, multiple sclerosis, and retinopathies. PR activation appeared particularly effective in treating traumatic brain and spinal cord injuries and ischemic stroke. Except for in the retina, activated GR is engaged in neuronal cell death, whereas MR signalling appeared to be associated with neuroprotection. In addition to steroid receptors, the aryl hydrocarbon receptor (AHR) mediates the induction and propagation of apoptosis, whereas the peroxisome proliferator-activated receptors (PPARs) inhibit this programmed cell death. Most of the retinoid X receptor-related xenobiotic receptors stimulate apoptotic processes that accompany neural pathologies. Among the possible therapeutic strategies based on targeting apoptosis via steroid and xenobiotic receptors, the most promising are the selective modulators of the ER, AR, AHR, PPARgamma agonists, flavonoids, and miRNAs. The prospective therapies to overcome neuronal cell death by targeting autophagy via steroid and xenobiotic receptors are much less recognized. PMID- 29137146 TI - The Dynamics of Arrivals of Maine Migratory Breeding Birds: Results from a 24 Year Study. AB - This citizen-science project is the first systematic study of patterns of spring migration of Maine migratory birds. A comparison of arrival data from the Maine Ornithological Society from 1899-1911 with the modern data (1994-2017) collected for this study indicated that most species are now not arriving earlier, contrary to the predictions of earlier arrivals in the face of global warming. Arrival was synchronous across the lower two-thirds of the state for most species, although some species showed delayed arrivals along the northeastern coast compared to southern coastal areas. Only thirteen of 81 species are now arriving earlier and seven arriving later. Using quantile regression analysis with three levels of tau, the effect of year, temperature-departure from mean monthly temperature and the North Atlantic Oscillation Index were weak. Most species did not respond to any of these explanatory variables using the modern data. Leaf-gleaners showed the strongest responses. Only four species showed increasing abundance in recent years, an effect that influences detectability and hence could confound interpretation of changes in arrival date. PMID- 29137145 TI - Dietary Pea Fiber Supplementation Improves Glycemia and Induces Changes in the Composition of Gut Microbiota, Serum Short Chain Fatty Acid Profile and Expression of Mucins in Glucose Intolerant Rats. AB - Several studies have demonstrated the beneficial impact of dried peas and their components on glucose tolerance; however, the role of gut microbiota as a potential mediator is not fully examined. In this study, we investigated the effect of dietary supplementation with raw and cooked pea seed coats (PSC) on glucose tolerance, microbial composition of the gut, select markers of intestinal barrier function, and short chain fatty acid profile in glucose intolerant rats. Male Sprague Dawley rats were fed high fat diet (HFD) for six weeks to induce glucose intolerance, followed by four weeks of feeding PSC-supplemented diets. Cooked PSC improved glucose tolerance by approximately 30% (p < 0.05), and raw and cooked PSC diets reduced insulin response by 53% and 56% respectively (p < 0.05 and p < 0.01), compared to HFD (containing cellulose as the source of dietary fiber). 16S rRNA gene sequencing on fecal samples showed a significant shift in the overall microbial composition of PSC groups when compared to HFD and low fat diet (LFD) controls. At the family level, PSC increased the abundance of Lachnospiraceae and Prevotellaceae (p < 0.001), and decreased Porphyromonadaceae (p < 0.01) compared with HFD. This was accompanied by increased mRNA expression of mucin genes Muc1, Muc2, and Muc4 in ileal epithelium (p < 0.05). Serum levels of acetate and propionate increased with raw PSC diet (p < 0.01). These results indicate that supplementation of HFD with PSC fractions can improve glycemia and may have a protective role against HFD-induced alterations in gut microbiota and mucus layer. PMID- 29137147 TI - Development of pGEMINI, a Plant Gateway Destination Vector Allowing the Simultaneous Integration of Two cDNA via a Single LR-Clonase Reaction. AB - Gateway technology has been used to facilitate the generation of a large number of constructs for the modification of plants for research purposes. However, many of the currently available vectors only allow the integration of a single cDNA of interest into an expression clone. The ability to over-express multiple genes in combination is essential for the study of plant development where several transcripts have a role to play in one or more metabolic processes. The tools to carry out such studies are limited, and in many cases rely on the incorporation of cDNA into expression systems via conventional cloning, which can be both time consuming and laborious. To our knowledge, this study reports on the first development of a vector allowing the simultaneous integration of two independent cDNAs via a single LR-clonase reaction. This vector "pGEMINI" represents a powerful molecular tool offering the ability to study the role of multi-cDNA constructs on plant development, and opens up the process of gene stacking and the study of gene combinations through transient or stable transformation procedures. PMID- 29137144 TI - Impact of Labile Zinc on Heart Function: From Physiology to Pathophysiology. AB - Zinc plays an important role in biological systems as bound and histochemically reactive labile Zn2+. Although Zn2+ concentration is in the nM range in cardiomyocytes at rest and increases dramatically under stimulation, very little is known about precise mechanisms controlling the intracellular distribution of Zn2+ and its variations during cardiac function. Recent studies are focused on molecular and cellular aspects of labile Zn2+ and its homeostasis in mammalian cells and growing evidence clarified the molecular mechanisms underlying Zn2+ diverse functions in the heart, leading to the discovery of novel physiological functions of labile Zn2+ in parallel to the discovery of subcellular localization of Zn2+-transporters in cardiomyocytes. Additionally, important experimental data suggest a central role of intracellular labile Zn2+ in excitation-contraction coupling in cardiomyocytes by shaping Ca2+ dynamics. Cellular labile Zn2+ is tightly regulated against its adverse effects through either Zn2+-transporters, Zn2+-binding molecules or Zn2+-sensors, and, therefore plays a critical role in cellular signaling pathways. The present review summarizes the current understanding of the physiological role of cellular labile Zn2+ distribution in cardiomyocytes and how a remodeling of cellular Zn2+-homeostasis can be important in proper cell function with Zn2+-transporters under hyperglycemia. We also emphasize the recent investigations on Zn2+-transporter functions from the standpoint of human heart health to diseases together with their clinical interest as target proteins in the heart under pathological condition, such as diabetes. PMID- 29137148 TI - A Miniaturized Nickel Oxide Thermistor via Aerosol Jet Technology. AB - In this study, a miniaturized thermistor sensor was produced using the Aerosol Jet printing process for temperature sensing applications. A nickel oxide nanoparticle ink with a large temperature coefficient of resistance was fabricated. The thermistor was printed with a circular NiO thin film in between the two parallel silver conductive tracks on a cutting tool insert. The printed thermistor, which has an adjustable dimension with a submillimeter scale, operates over a range of 30-250 degrees C sensitively (B value of ~4310 K) without hysteretic effects. Moreover, the thermistor may be printed on a 3D surface through the Aerosol Jet printing process, which has increased capability for wide temperature-sensing applications. PMID- 29137149 TI - Physiological and Biochemical Changes Reveal Differential Patterns of Docosahexaenoic Acid Partitioning in Two Marine Algal Strains of Isochrysis. AB - The marine microalgae Isochrysis are a good producer of natural docosahexaenoic acid (DHA). To better understand the patterns of DHA accumulation and distribution, two Isochrysis strains, CL153180 and CCMP462, were evaluated in this study. In a batch culture, CL153180 showed a decline in DHA content while CCMP462 exhibited a progressive increase during the late growth period when nitrogen was almost exhausted. In response to nitrogen deficiency (ND), both strains showed a considerable increase in neutral lipids (NL) at the expense of glycolipids (GL) but had little variation in phospholipids (PL). In CL153180, the DHA percentage of NL decreased gradually upon ND, while that in CCMP462 increased progressively to 21.4% after 4 days of ND, which is around 5-fold higher than CL153180. Accordingly, in contrast to CL153180 that stored DHA predominantly in GL, CCMP462 accumulated DHA mainly in NL in late days of ND. Taken together, we proposed a working model for the differential DHA partitioning patterns between two Isochrysis strains: for CCMP462, the degradation of GL released free fatty acids including DHA, which was incorporated into NL upon ND; whereas for CL153180, the released DHA from GL might not be incorporated into NL, and, consequently, might be subject to beta-oxidation for degradation. PMID- 29137150 TI - In Vitro Fermentation Patterns of Rice Bran Components by Human Gut Microbiota. AB - Whole grain rice is a rich source of fiber, nutrients, and phytochemicals that may promote gastrointestinal health, but such beneficial components are typically removed with the bran during polishing. Soluble feruloylated arabinoxylan oligosaccharides (FAXO) and polyphenols (RBPP) isolated from rice bran are hypothesized to have positive impacts on human gut microbiota through a prebiotic function. Using an in vitro human fecal fermentation bioassay, FAXO and RBPP treatments were assessed for short-chain fatty acids (SCFA) production patterns and by evaluating their impacts on the phylogentic composition of human gut microbiota by 16S rRNA gene sequencing. Fresh fecal samples collected from healthy adults (n = 10, 5 males, 5 females) were diluted with anaerobic medium. Each sample received five treatments: CTRL (no substrates), FOS (fructooligosaccharides), FAXO, RBPP, and MIX (FAXO with RBPP). Samples were incubated at 37 degrees C and an aliquot was withdrawn at 0, 4, 8, 12, and 24 h Results showed that SCFA production was significantly increased with FAXO and was comparable to fermentation with FOS, a well-established prebiotic. RBPP did not increase SCFA productions, and no significant differences in total SCFA production were observed between FAXO and MIX, indicating that RBPP does not modify FAXO fermentation. Changes in microbiota population were found in FAXO treatment, especially in Bacteroides, Prevotella, and Dorea populations, indicating that FAXO might modulate microbiota profiles. RBPP and MIX increased Faecalibacterium, specifically F. prausnitzii. Combined FAXO and RBPP fermentation increased abundance of butyrogenic bacteria, Coprococcus and Roseburia, suggesting some interactive activity. Results from this study support the potential for FAXO and RBPP from rice bran to promote colon health through a prebiotic function. PMID- 29137151 TI - The Complete Mitogenome of the Wood-Feeding Cockroach Cryptocercus meridianus (Blattodea: Cryptocercidae) and Its Phylogenetic Relationship among Cockroach Families. AB - In this study, the complete mitochondrial genome of Cryptocercus meridianus was sequenced. The circular mitochondrial genome is 15,322 bp in size and contains 13 protein-coding genes, two ribosomal RNA genes (12S rRNA and 16S rRNA), 22 transfer RNA genes, and one D-loop region. We compare the mitogenome of C. meridianus with that of C. relictus and C. kyebangensis. The base composition of the whole genome was 45.20%, 9.74%, 16.06%, and 29.00% for A, G, C, and T, respectively; it shows a high AT content (74.2%), similar to the mitogenomes of C. relictus and C. kyebangensis. The protein-coding genes are initiated with typical mitochondrial start codons except for cox1 with TTG. The gene order of the C. meridianus mitogenome differs from the typical insect pattern for the translocation of tRNA-SerAGN, while the mitogenomes of the other two Cryptocercus species, C. relictus and C. kyebangensis, are consistent with the typical insect pattern. There are two very long non-coding intergenic regions lying on both sides of the rearranged gene tRNA-SerAGN. The phylogenetic relationships were constructed based on the nucleotide sequence of 13 protein-coding genes and two ribosomal RNA genes. The mitogenome of C. meridianus is the first representative of the order Blattodea that demonstrates rearrangement, and it will contribute to the further study of the phylogeny and evolution of the genus Cryptocercus and related taxa. PMID- 29137153 TI - Halogen Bonding Involving CO and CS with Carbon as the Electron Donor. AB - MP2/aug'-cc-pVTZ calculations have been carried out to investigate the halogen bonded complexes formed when CO and CS act as electron-pair donors through C to ClF, ClNC, ClCl, ClOH, ClCN, ClCCH, and ClNH2. CO forms only complexes stabilized by traditional halogen bonds, and all ClY molecules form traditional halogen bonded complexes with SC, except ClF which forms only an ion-pair complex. Ion pair complexes are also found on the SC:ClNC and SC:ClCl surfaces. SC:ClY complexes stabilized by traditional halogen bonds have greater binding energies than the corresponding OC:ClY complexes. The largest binding energies are found for the ion-pair SC-Cl+:-Y complexes. The transition structures which connect the complex and the ion pair on SC:ClNC and SC:ClCl potential surfaces provide the barriers for inter-converting these structures. Charge-transfer from the lone pair on C to the sigma-hole on Cl is the primary charge-transfer interaction stabilizing OC:ClY and SC:ClY complexes with traditional halogen bonds. A secondary charge-transfer occurs from the lone pairs on Cl to the in-plane and out-of-plane pi antibonding orbitals of ClY. This secondary interaction assumes increased importance in the SC:ClNH2 complex, and is a factor leading to its unusual structure. C-O and C-S stretching frequencies and 13C chemical shieldings increase upon complex formation with ClY molecules. These two spectroscopic properties clearly differentiate between SC:ClY complexes and SC-Cl+:-Y ion pairs. Spin-spin coupling constants 1xJ(C-Cl) for OC:ClY complexes increase with decreasing distance. As a function of the C-Cl distance, 1xJ(C-Cl) and 1J(C-Cl) provide a fingerprint of the evolution of the halogen bond from a traditional halogen bond in the complexes, to a chlorine-shared halogen bond in the transition structures, to a covalent bond in the ion pairs. PMID- 29137152 TI - Synthesis and In Vitro Antiproliferative Activity of 11-Substituted Neocryptolepines with a Branched omega-Aminoalkylamino Chain. AB - Neocryptolepine, which is a kind of tetracyclic indoloquinoline alkaloid, exhibits the inhibition of topoisomerase II and shows antiproliferative activity. The present study describes the synthesis and antiproliferative evaluation of several neocryptolepine analogues carrying a branched, functionalized dibasic side chain at C11. These 2-substituted 5-methyl-indolo[2,3-b]quinoline derivatives were prepared by nucleophilic aromatic substitution (SNAr) of 11 chloroneocryptolepines with appropriate 1,2- and 1,3-diamines. Some of the 11 (omega-aminoalkylamino) derivatives were further transformed into 11-ureido and thioureido analogues. Many of the prepared neocryptolepine derivatives showed submicromolar antiproliferative activity against the human leukemia MV4-11 cell line. Among them, 11-(3-amino-2-hydroxy)propylamino derivatives 2h and 2k were the most cytotoxic with a mean IC50 value of 0.042 MUM and 0.057 MUM against the MV4-11 cell line, 0.197 MUM and 0.1988 MUM against the A549 cell line, and 0.138 MUM and 0.117 MUM against the BALB/3T3 cell line, respectively. PMID- 29137154 TI - Two Sulfur Glycoside Compounds Isolated from Lepidium apetalum Willd Protect NRK52e Cells against Hypertonic-Induced Adhesion and Inflammation by Suppressing the MAPK Signaling Pathway and RAAS. AB - Lepidium apetalum Willd has been used to reduce edema and promote urination. Cis desulfoglucotropaeolin (cis-DG) and trans-desulfoglucotropaeolin (trans-DG) were isolated from Lepidium apetalum Willd, and caused a significant increase in cell viability in a hypertonic model in NRK52e cells. In the hypertonic model, cis-DG and trans-DG significantly promoted the cell viability of NRK52e cells and inhibited the elevation of Na+ in the supernatant, inhibited the renin angiotensin-aldosterone (RAAS) system, significantly reduced the levels of angiotensin II (Ang II) and aldosterone (ALD), and lowered aquaporin-2 (AQP2) and Na+-K+ ATP content in renal medulla. After treatment with cis-DG and trans-DG, expression of calcineurin (CAN) and Ca/calmodulin-dependent protein kinase II (CaMK II) was decreased in renal tissue and Ca2+ influx was inhibited, thereby reducing the secretion of transforming growth factor-beta (TGFbeta), reversing the increase in adhesion and inflammatory factor E-selectin and monocyte chemotactic protein 1 (MCP-1) induced by high NaCl, while reducing oxidative stress status and decreasing the expression of cyclooxygenase-2 (COX2). Furthermore, inhibition of protein kinase C (PKC) expression also contributed to these improvements. The cis-DG and trans-DG reduced the expression of p-p44/42 MAPK, p-JNK and p-p38, inhibited the phosphorylation of the MAPK signaling pathway in NRN52e cells induced by high salt, decreased the overexpression of p p38 and p-HSP27, and inhibited the overactivation of the p38-MAPK signaling pathway, suggesting that the p38-MAPK pathway may play a vital role in the hypertonic-induced adhesion and inflammatory response. From the results of this study, it can be concluded that the mechanism of cis-DG and trans-DG may mainly be through inhibiting the p38-MAPK signaling pathway, inhibiting the excessive activation of the RAAS system, and thereby reducing adhesion and inflammatory factors. PMID- 29137156 TI - Digital Platforms in the Assessment and Monitoring of Patients with Bipolar Disorder. AB - This paper aims to review the application of digital platforms in the assessment and monitoring of patients with Bipolar Disorder (BPD). We will detail the current clinical criteria for the diagnosis of BPD and the tools available for patient assessment in the clinic setting. We will go on to highlight the difficulties in the assessment and monitoring of BPD patients in the clinical context. Finally, we will elaborate upon the impact that diital platforms have made, and have the potential to make, on healthcare, mental health, and specifically the management of BPD, before going on to evaluate the benefits and drawbacks of the use of such technology. PMID- 29137155 TI - Identification, Expression, and Functional Analysis of the Fructokinase Gene Family in Cassava. AB - Fructokinase (FRK) proteins play important roles in catalyzing fructose phosphorylation and participate in the carbohydrate metabolism of storage organs in plants. To investigate the roles of FRKs in cassava tuber root development, seven FRK genes (MeFRK1-7) were identified, and MeFRK1-6 were isolated. Phylogenetic analysis revealed that the MeFRK family genes can be divided into alpha (MeFRK1, 2, 6, 7) and beta (MeFRK3, 4, 5) groups. All the MeFRK proteins have typical conserved regions and substrate binding residues similar to those of the FRKs. The overall predicted three-dimensional structures of MeFRK1-6 were similar, folding into a catalytic domain and a beta-sheet ''lid" region, forming a substrate binding cleft, which contains many residues involved in the binding to fructose. The gene and the predicted three-dimensional structures of MeFRK3 and MeFRK4 were the most similar. MeFRK1-6 displayed different expression patterns across different tissues, including leaves, stems, tuber roots, flowers, and fruits. In tuber roots, the expressions of MeFRK3 and MeFRK4 were much higher compared to those of the other genes. Notably, the expression of MeFRK3 and MeFRK4 as well as the enzymatic activity of FRK were higher at the initial and early expanding tuber stages and were lower at the later expanding and mature tuber stages. The FRK activity of MeFRK3 and MeFRK4 was identified by the functional complementation of triple mutant yeast cells that were unable to phosphorylate either glucose or fructose. The gene expression and enzymatic activity of MeFRK3 and MeFRK4 suggest that they might be the main enzymes in fructose phosphorylation for regulating the formation of tuber roots and starch accumulation at the tuber root initial and expanding stages. PMID- 29137157 TI - In Situ Synthesis of Silver Nanoparticles in a Hydrogel of Carboxymethyl Cellulose with Phthalated-Cashew Gum as a Promising Antibacterial and Healing Agent. AB - Silver nanoparticles have been shown to possess considerable antibacterial activity, but in vivo applications have been limited due to the inherent, but low, toxicity of silver. On the other hand, silver nanoparticles could provide cutaneous protection against infection, due to their ability to liberate silver ions via a slow release mechanism, and their broad-spectrum antimicrobial action. Thus, in this work, we describe the development of a carboxymethyl cellulose based hydrogel containing silver nanoparticles. The nanoparticles were prepared in the hydrogel in situ, utilizing two variants of cashew gum as a capping agent, and sodium borohydride as the reducing agent. This gum is non-toxic and comes from a renewable natural source. The particles and gel were thoroughly characterized through using rheological measurements, UV-vis spectroscopy, nanoparticles tracking analysis, and transmission electron microscopy analysis (TEM). Antibacterial tests were carried out, confirming antimicrobial action of the silver nanoparticle-loaded gels. Furthermore, rat wound-healing models were used and demonstrated that the gels exhibited improved wound healing when compared to the base hydrogel as a control. Thus, these gels are proposed as excellent candidates for use as wound-healing treatments. PMID- 29137158 TI - Chemically Modified Polyvinyl Chloride for Removal of Thionine Dye (Lauth's Violet). AB - The chemical modification of hydrophobic polymer matrices is an alternative way to elchange their surface properties. The introduction of sulfonic groups in the polymer changes the surface properties such as adhesion, wettability, catalytic ability, and adsorption capacity. This work describes the production and application of chemically modified polyvinyl chloride (PVC) as adsorbent for dyes removal. Chemical modification of PVC was evaluated by infrared spectroscopy and elemental analysis, which indicated the presence of sulfonic groups on PVC. The chemically modified PVC (PVCDS) showed an ion exchange capacity of 1.03 mmol-1, and efficiently removed the thionine dye (Lauth's violet) from aqueous solutions, reaching equilibrium in 30 min. The adsorption kinetics was better adjusted for a pseudo second order model. This result indicates that the adsorption of thionine onto PVCDS occurs by chemisorption. Among the models for the state of equilibrium, SIPS and Langmuir exhibited the best fit to the experimental results and PVCDS showed high adsorption capacities (370 mg-1). Thus, it is assumed that the system presents homogeneous characteristics to the distribution of active sites. The modification promoted the formation of surface characteristics favorable to the dye adsorption by the polymer. PMID- 29137159 TI - Linear vs. Nonlinear Extreme Learning Machine for Spectral-Spatial Classification of Hyperspectral Images. AB - As a new machine learning approach, the extreme learning machine (ELM) has received much attention due to its good performance. However, when directly applied to hyperspectral image (HSI) classification, the recognition rate is low. This is because ELM does not use spatial information, which is very important for HSI classification. In view of this, this paper proposes a new framework for the spectral-spatial classification of HSI by combining ELM with loopy belief propagation (LBP). The original ELM is linear, and the nonlinear ELMs (or Kernel ELMs) are an improvement of linear ELM (LELM). However, based on lots of experiments and much analysis, it is found that the LELM is a better choice than nonlinear ELM for the spectral-spatial classification of HSI. Furthermore, we exploit the marginal probability distribution that uses the whole information in the HSI and learns such a distribution using the LBP. The proposed method not only maintains the fast speed of ELM, but also greatly improves the accuracy of classification. The experimental results in the well-known HSI data sets, Indian Pines, and Pavia University, demonstrate the good performance of the proposed method. PMID- 29137160 TI - The Influence of Toothpaste Containing Australian Melaleuca alternifolia Oil and Ethanolic Extract of Polish Propolis on Oral Hygiene and Microbiome in Patients Requiring Conservative Procedures. AB - The study was based on the use of a toothpaste with antiphlogistic activity, containing Australian Melaleuca alternifolia oil (tea tree oil-TTO) and ethanolic extract of Polish propolis (EEP). Fifty-one patients with varying conditions of the gingiva were divided into two groups. The study group received the toothpaste with TTO and EEP, while the control group received the same toothpaste but without TTO and EEP. Approximal plaque index (API), simplified oral hygiene index (OHI-s) and modified sulcus bleeding index (mSBI) were assessed in three subsequent stages. During each examination, swabs were employed for microbiological inoculation. During the period of use of toothpastes with TTO and EEP, a significant reduction of the API was observed, as assessed upon the control visit after 7 days and after 28 days, compared to baseline. A statistically significant reduction of mSBI was observed after 7 and 28 days of using the toothpaste with TTO and EEP, as compared to the value upon the initial visit. Statistically significant differences in the OHI-s value were observed in the study group, which was using the active toothpaste. The use of a toothpaste containing TTO and EEP helps to maintain microbiome balance. The observed stabilisation of bacterial microflora confirms the beneficial activity of toothpaste containing EEP and TTO compared to the control group, where the lack of these substances contributed to the emergence of qualitative and quantitative changes in oral microbiome. PMID- 29137161 TI - Constructing Asymmetric Polyion Complex Vesicles via Template Assembling Strategy: Formulation Control and Tunable Permeability. AB - A strategy for constructing polyion complex vesicles (PICsomes) with asymmetric structure is described. Poly(methylacrylic acid)-block-poly(N isopropylacrylamide) modified gold nanoparticles (PMAA-b-PNIPAm-@-Au NPs) were prepared and then assembled with poly(ethylene glycol)-block-poly[1-methyl-3-(2 methacryloyloxy propylimidazolium bromine)] (PEG-b-PMMPImB) via polyion complex of PMMA and PMMPImB. After removing the Au NPs template, asymmetric PICsomes composed of a PNIPAm inner-shell, PIC wall, and PEG outer-corona were obtained. These PICsomes have low protein absorption and thermally tunable permeability, provided by the PEG outer-corona and the PNIPAm inner-shell, respectively. Moreover, PICsome size can be tailored by using templates of predetermined sizes. This novel strategy for constructing asymmetric PICsomes with well-defined properties and controllable size is valuable for applications such as drug delivery, catalysis and monitoring of chemical reactions, and biomimetics. PMID- 29137164 TI - Highly Efficient Multi Channel Packet Forwarding with Round Robin Intermittent Periodic Transmit for Multihop Wireless Backhaul Networks. AB - Round Robin based Intermittent Periodic Transmit (RR-IPT) has been proposed which achieves highly efficient multi-hop relays in multi-hop wireless backhaul networks (MWBN) where relay nodes are 2-dimensionally deployed. This paper newly investigates multi-channel packet scheduling and forwarding scheme for RR-IPT. Downlink traffic is forwarded by RR-IPT via one of the channels, while uplink traffic and part of downlink are accommodated in the other channel. By comparing IPT and carrier sense multiple access with collision avoidance (CSMA/CA) for uplink/downlink packet forwarding channel, IPT is more effective in reducing packet loss rate whereas CSMA/CA is better in terms of system throughput and packet delay improvement. PMID- 29137162 TI - Structures and Functions of the Envelope Glycoprotein in Flavivirus Infections. AB - Flaviviruses are enveloped, single-stranded RNA viruses that widely infect many animal species. The envelope protein, a structural protein of flavivirus, plays an important role in host cell viral infections. It is composed of three separate structural envelope domains I, II, and III (EDI, EDII, and EDIII). EDI is a structurally central domain of the envelope protein which stabilizes the overall orientation of the protein, and the glycosylation sites in EDI are related to virus production, pH sensitivity, and neuroinvasiveness. EDII plays an important role in membrane fusion because of the immunodominance of the fusion loop epitope and the envelope dimer epitope. Additionally, EDIII is the major target of neutralization antibodies. The envelope protein is an important target for research to develop vaccine candidates and antiviral therapeutics. This review summarizes the structures and functions of ED I/II/III, and provides practical applications for the three domains, with the ultimate goal of implementing strategies to utilize the envelope protein against flavivirus infections, thus achieving better diagnostics and developing potential flavivirus therapeutics and vaccines. PMID- 29137163 TI - Association between Small Fetuses and Puberty Timing: A Systematic Review and Meta-Analysis. AB - Background: Epidemiological studies reporting the effect of small fetuses (SF) on puberty development have shown inconsistent results. Objective: To examine current study evidence and determine the strength and direction of the association between SF and puberty timing. Methods: PubMed, OVID, Web of Science, EBSCO, and four Chinese databases were searched from their date of inception to February 2016. All cohort studies that examined the association between SF and puberty timing in children were identified. Two reviewers independently screened the studies, assessed the quality of included studies, and extracted the data. The quality of the included cohort studies was assessed by the Newcastle-Ottawa Scale. Risk ratio (RR), Weighted Mean Difference (WMD), and 95% confidence intervals (CIs) were calculated and pooled by RevMan5.3 (Cochrane Collaboration, London, UK). Results: A total of 10 cohort studies involving 2366 subjects was included in the final analysis. The pooled estimates showed that SF did not significantly increase the number of pubertal children in boys (RR: 0.97; 95% CI: 0.82 to 1.15), or in girls (RR: 0.91; 95% CI: 0.79 to 1.04). Compared with the control group, the SF group had an earlier onset of puberty in girls (WMD: -0.64; 95% CI: -1.21 to -0.06), and in precocious pubarche (PP) girls (WMD: -0.10; 95% CI: -0.13 to -0.07). There was no difference in the onset of puberty in boys (WMD: -0.48; 95% CI: -1.45 to 0.50) between SF and control groups. The pooled result indicated an earlier age at menarche in girls born small for gestational age (WMD: -0.30; 95% CI: -0.58 to -0.03), but no difference in the age at menarche in the SF group of PP girls. Conclusions: SF may be associated with an earlier age of onset of puberty, especially among girls, as well as earlier age at menarche for girls. Well-designed studies with larger sample sizes and long term follow-up among different countries and ethnicities are needed. PMID- 29137165 TI - ABS-FishCount: An Agent-Based Simulator of Underwater Sensors for Measuring the Amount of Fish. AB - Underwater sensors provide one of the possibilities to explore oceans, seas, rivers, fish farms and dams, which all together cover most of our planet's area. Simulators can be helpful to test and discover some possible strategies before implementing these in real underwater sensors. This speeds up the development of research theories so that these can be implemented later. In this context, the current work presents an agent-based simulator for defining and testing strategies for measuring the amount of fish by means of underwater sensors. The current approach is illustrated with the definition and assessment of two strategies for measuring fish. One of these two corresponds to a simple control mechanism, while the other is an experimental strategy and includes an implicit coordination mechanism. The experimental strategy showed a statistically significant improvement over the control one in the reduction of errors with a large Cohen's d effect size of 2.55. PMID- 29137167 TI - Transmission Dynamics of HIV-1 Drug Resistance among Treatment-Naive Individuals in Greece: The Added Value of Molecular Epidemiology to Public Health. AB - The presence of human immunodeficiency virus type 1 (HIV-1) drug resistance among drug-naive patients remains stable, although the proportion of patients with virological failure to therapy is decreasing. The dynamics of transmitted resistance among drug-naive patients remains largely unknown. The prevalence of non-nucleoside reverse transcriptase inhibitors (NNRTI) resistance was 16.9% among treatment-naive individuals in Greece. We aimed to investigate the transmission dynamics and the effective reproductive number (Re) of the locally transmitted NNRTI resistance. We analyzed sequences with dominant NNRTI resistance mutations (E138A and K103N) found within monophyletic clusters (local transmission networks (LTNs)) from patients in Greece. For the K103N LTN, the Re was >1 between 2008 and the first half of 2013. For all E138A LTNs, the Re was >1 between 1998 and 2015, except the most recent one (E138A_4), where the Re was >1 between 2006 and 2011 and approximately equal to 1 thereafter. K103N and E138A_4 showed similar characteristics with a more recent origin, higher Re during the first years of the sub-epidemics, and a declining trend in the number of transmissions during the last two years. In the remaining LTNs the epidemic was still expanding. Our study highlights the added value of molecular epidemiology to public health. PMID- 29137166 TI - Antimicrobial and Osseointegration Properties of Nanostructured Titanium Orthopaedic Implants. AB - The surface design of titanium implants influences not only the local biological reactions but also affects at least the clinical result in orthopaedic application. During the last decades, strong efforts have been made to improve osteointegration and prevent bacterial adhesion to these surfaces. Following the rule of "smaller, faster, cheaper", nanotechnology has encountered clinical application. It is evident that the hierarchical implant surface micro- and nanotopography orchestrate the biological cascades of early peri-implant endosseous healing or implant loosening. This review of the literature gives a brief overview of nanostructured titanium-base biomaterials designed to improve osteointegration and prevent from bacterial infection. PMID- 29137168 TI - Origin and Evolution of the Neo-Sex Chromosomes in Pamphagidae Grasshoppers through Chromosome Fusion and Following Heteromorphization. AB - In most phylogenetic lineages, the evolution of sex chromosomes is accompanied by their heteromorphization and degradation of one of them. The neo-sex chromosomes are useful model for studying early stages of these processes. Recently two lineages of the neo-sex chromosomes on different stages of heteromorphization was discovered in Pamphagidae family. The neo-sex chromosome heteromorphization was analyzed by generation of DNA probes derived from the neo-Xs and neo-Ys followed with chromosome painting in nineteen species of Pamphagidae family. The homologous regions of the neo-sex chromosomes were determined in closely related species with the painting procedure and image analysis with application of the Visualization of the Specific Signal in Silico software package. Results of these analyses and distribution of C-positive regions in the neo-sex chromosomes revealed details of the heteromorphization of the neo-sex chromosomes in species from both phylogenetic lineages of Pamphagidae grasshoppers. The hypothetical mechanism of the neo-Y degradation was suggested. It includes expansion of different repeats from the proximal neo-Y chromosome region by inversions, spreading them towards distal region. Amplification of these repeats leads to formation of C-positive regions and elimination of the C-negative regions located between them. PMID- 29137169 TI - Pancreatic Exocrine Insufficiency after Bariatric Surgery. AB - Morbid obesity is a lifelong disease, and all patients require complementary follow-up including nutritional surveillance by a multidisciplinary team after bariatric procedures. Pancreatic exocrine insufficiency (PEI) refers to an insufficient secretion of pancreatic enzymes and/or sodium bicarbonate. PEI is a known multifactorial complication after upper gastrointestinal surgery, and might constitute an important clinical problem due to the large number of bariatric surgical procedures in the world. Symptoms of PEI often overlap with sequelae of gastric bypass, making the diagnosis difficult. Steatorrhea, weight loss, maldigestion and malabsorption are pathognomonic for both clinical conditions. Altered anatomy after bypass surgery can make the diagnostic process even more difficult. Fecal elastase-1 (FE1) is a useful diagnostic test. PEI should be considered in all patients after bariatric surgery with prolonged gastrointestinal complaints that are suggestive of maldigestion and/or malabsorption. Appropriate pancreatic enzyme replacement therapy should be part of the treatment algorithm in patients with confirmed PEI or symptoms suggestive of this complication. PMID- 29137170 TI - Design, Synthesis, and Biological Activity of Tetrahydrobenzo[4,5]thieno[2,3 d]pyrimidine Derivatives as Anti-Inflammatory Agents. AB - We designed and synthesized 26 prototype compounds and studied their anti inflammatory activity and underlying molecular mechanisms. The inhibitory effects of the compounds on the production of nitric oxide (NO), cytokines, inflammatory related proteins, and mRNAs in lipopolysaccharide (LPS)-stimulated macrophages were determined by the Griess assay, Enzyme linked immunosorbent assay (ELISA), Western blot analysis, and Reverse transcription-Polymerase Chain Reaction (RT PCR), respectively. Our results indicated that treatment with A2, A6 and B7 significantly inhibited the secretion of NO and inflammatory cytokines in RAW264.7 cells without demonstrable cytotoxicity. It was also found that A2, A6 and B7 strongly suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase enzyme COX-2, and prevented nuclear translocation of nuclear factor kappaB (NF-kappaB) p65 by inhibiting the degradation of p50 and IkappaBalpha. Furthermore, the phosphorylation of mitogen-activated protein kinase (MAPKs) in LPS-stimulated RAW264.7 cells was significantly inhibited by A2, A6 and B7. These findings suggest that A2, A6 and B7 may operate as an effective anti-inflammatory agent through inhibiting the activation of NF-kappaB and MAPK signaling pathways in macrophages. Moreover, rat paw swelling experiments showed that these compounds possess anti-inflammatory activity in vivo, with compound A6 exhibiting similar activities to the reference drug Indomethacin. PMID- 29137171 TI - Regulation of the Rhythmic Emission of Plant Volatiles by the Circadian Clock. AB - Like other organisms, plants have endogenous biological clocks that enable them to organize their metabolic, physiological, and developmental processes. The representative biological clock is the circadian system that regulates daily (24 h) rhythms. Circadian-regulated changes in growth have been observed in numerous plants. Evidence from many recent studies indicates that the circadian clock regulates a multitude of factors that affect plant metabolites, especially emitted volatiles that have important ecological functions. Here, we review recent progress in research on plant volatiles showing rhythmic emission under the regulation of the circadian clock, and on how the circadian clock controls the rhythmic emission of plant volatiles. We also discuss the potential impact of other factors on the circadian rhythmic emission of plant volatiles. PMID- 29137172 TI - Fluorescent Magnetopolymersomes: A Theranostic Platform to Track Intracellular Delivery. AB - We present a potential theranostic delivery platform based on the amphiphilic diblock copolymer polybutadiene-block-poly (ethylene oxide) combining covalent fluorescent labeling and membrane incorporation of superparamagnetic iron oxide nanoparticles for multimodal imaging. A simple self-assembly and labeling approach to create the fluorescent and magnetic vesicles is described. Cell uptake of the densely PEGylated polymer vesicles could be altered by surface modifications that vary surface charge and accessibility of the membrane active species. Cell uptake and cytotoxicity were evaluated by confocal microscopy, transmission electron microscopy, iron content and metabolic assays, utilizing multimodal tracking of membrane fluorophores and nanoparticles. Cationic functionalization of vesicles promoted endocytotic uptake. In particular, incorporation of cationic lipids in the polymersome membrane yielded tremendously increased uptake of polymersomes and magnetopolymersomes without increase in cytotoxicity. Ultrastructure investigations showed that cationic magnetopolymersomes disintegrated upon hydrolysis, including the dissolution of incorporated iron oxide nanoparticles. The presented platform could find future use in theranostic multimodal imaging in vivo and magnetically triggered delivery by incorporation of thermorepsonsive amphiphiles that can break the membrane integrity upon magnetic heating via the embedded superparamagnetic nanoparticles. PMID- 29137173 TI - Psychiatric Disorders Differently Correlate with Physical Self-Rated Health across Ethnic Groups. AB - In this study, we compared 10 ethnic groups for associations between psychiatric disorders and physical self-rated health (SRH) in the United States. Data came from the Collaborative Psychiatric Epidemiology Surveys (CPES), 2001-2003. The study included 7587 non-Latino White, 4746 African American, 1442 Mexican, 1106 other Hispanic, 656 other Asian, 600 Chinese, 577 Cuban, 520 Vietnamese, 508 Filipino, and 495 Puerto Rican individuals. The Composite International Diagnostic Interview (CIDI) was used to measure psychiatric disorders, including major depressive disorder (MDD), general anxiety disorder (GAD), social phobia, panic disorder, post-traumatic stress disorder (PTSD), alcohol abuse, and binge eating disorders. A single-item measure was used to estimate physical SRH. Demographic (age and gender) and socioeconomic (education and income) factors were also measured. Unadjusted and adjusted correlations between psychiatric disorders and physical SRH were calculated. Major ethnic variations were found in the correlation between psychiatric disorders and physical SRH; as well as the role of demographic and socioeconomic status (SES) factors in explaining these associations. non-Hispanic Whites, Cubans, and African Americans showed more correlations between psychiatric disorders and physical SRH than other ethnic groups. In non-Hispanic Whites, the associations between psychiatric disorders and physical SRH were explained by demographic factors. In African Americans, the link between psychiatric disorders and poor physical SRH were explained by SES indicators. In conclusion, although single-item physical SRH measures are traditionally assumed to reflect the physical health needs of populations, they may also indicate psychiatric disorders in some ethnic groups, such as non Hispanic Whites, Cubans, and African Americans. Demographic and socioeconomic factors also have differential roles in explaining the link between psychiatric disorders and physical SRH. Physical SRH does not exclusively reflect physical health, and it may be more biased by mental health across some ethnic groups. PMID- 29137174 TI - HDOMO: Smart Sensor Integration for an Active and Independent Longevity of the Elderly. AB - The aim of this paper is to present the main results of HDOMO, an Ambient Assisted Living (AAL) project that involved 16 Small and Medium Enterprises (SMEs) and 2 research institutes. The objective of the project was to create an autonomous and automated domestic environment, primarily for elderly people and people with physical and motor disabilities. A known and familiar environment should help users in their daily activities and it should act as a virtual caregiver by calling, if necessary, relief efforts. Substantially, the aim of the project is to simplify the life of people in need of support, while keeping them autonomous in their private environment. From a technical point of view, the project provides the use of different Smart Objects (SOs), able to communicate among each other, in a cloud base infrastructure, and with the assisted users and their caregivers, in a perspective of interoperability and standardization of devices, usability and effectiveness of alarm systems. In the state of the art there are projects that achieve only a few of the elements listed. The HDOMO project aims to achieve all of them in one single project effectively. The experimental trials performed in a real scenario demonstrated the accuracy and efficiency of the system in extracting and processing data in real time to promptly acting, and in providing timely response to the needs of the user by integrating and confirming main alarms with different interoperable smart sensors. The article proposes a new technique to improve the accuracy of the system in detecting alarms using a multi-SO approach with information fusion between different devices, proving that this architecture can provide robust and reliable results on real environments. PMID- 29137175 TI - Wireless Energy Harvesting Two-Way Relay Networks with Hardware Impairments. AB - This paper considers a wireless energy harvesting two-way relay (TWR) network where the relay has energy-harvesting abilities and the effects of practical hardware impairments are taken into consideration. In particular, power splitting (PS) receiver is adopted at relay to harvests the power it needs for relaying the information between the source nodes from the signals transmitted by the source nodes, and hardware impairments is assumed suffered by each node. We analyze the effect of hardware impairments [-20]on both decode-and-forward (DF) relaying and amplify-and-forward (AF) relaying networks. By utilizing the obtained new expressions of signal-to-noise-plus-distortion ratios, the exact analytical expressions of the achievable sum rate and ergodic capacities for both DF and AF relaying protocols are derived. Additionally, the optimal power splitting (OPS) ratio that maximizes the instantaneous achievable sum rate is formulated and solved for both protocols. The performances of DF and AF protocols are evaluated via numerical results, which also show the effects of various network parameters on the system performance and on the OPS ratio design. PMID- 29137177 TI - Comprehensive Profiling of lincRNAs in Lung Adenocarcinoma of Never Smokers Reveals Their Roles in Cancer Development and Prognosis. AB - Long intergenic non-coding RNA (lincRNA) is a family of gene transcripts, the functions of which are largely unknown. Although cigarette smoking is the main cause for lung cancer, lung cancer in non-smokers is a separate entity and its underlying cause is little known. Growing evidence suggests lincRNAs play a significant role in cancer development and progression; however, such data is lacking for lung cancer in non-smokers, or those who have never smoked. This study conducted comprehensive profiling of lincRNAs from RNA sequencing (RNA-seq) data of non-smoker patients with lung adenocarcinoma. Both known and novel lincRNAs distinctly segregated tumors from normal tissues. Approximately one third of lincRNAs were differentially expressed between tumors and normal samples and most of them were coordinated with their putative protein gene targets. More importantly, lincRNAs defined two clusters of tumors that were associated with tumor aggressiveness and patient survival. We identified a subset of lincRNAs that were differentially expressed and also associated with patient survival. Very high concordance (R2 = 0.9) was observed for the differentially expressed lincRNAs in the Cancer Genome Atlas (TCGA) validation set of 85 transcriptomes and the lincRNAs associated with survival from the discovery set were similarly predictive in the validation set. These lincRNAs warrant further investigation as potential diagnostic and prognostic markers. PMID- 29137179 TI - Special Issue: Beneficial Microorganisms for Food Manufacturing-Fermented and Biopreserved Foods and Beverages. AB - Food fermentation is an ancient technology, disseminated worldwide, which harness microorganisms and their enzymes to improve and diversify the human diet [...]. PMID- 29137178 TI - Antidepressants and Mood Stabilizers: Novel Research Avenues and Clinical Insights for Bipolar Depression. AB - The concept of the bipolar-spectrum and of mixed features being a bridge between major depressive disorders and bipolar disorders (BDs) has become increasingly important in mood-disorder diagnoses. Under these circumstances, antidepressants (ADs) and mood stabilizers (MSs) should be used with caution in the treatment of major depressive episodes (MDEs) and to obtain long-term stability in BDs. Before treating MDEs, screening tools, specific symptom evaluation and medical history should be used to distinguish between bipolarity and mixed features in patients for whom AD monotherapy may present a risk. In these patients, a combination of ADs plus MSs or atypical antipsychotics is recommended, rather than AD monotherapy. Studies evaluating MSs for bipolar depression suggest that lamotrigine is the most reliable treatment and lithium has modest effects; there is a lack of clear evidence regarding the efficacy of valproate and carbamazepine. Recently, significant progress has been made with respect to the pathophysiology of mood disorders and the application of potential biomarkers. There is an opportunity to study novel drug mechanisms through the rediscovery of fast-acting drugs such as ketamine. It is anticipated that future research developments will involve the discovery of potential targets for new drugs and their application to personalized treatments. PMID- 29137180 TI - Metabolomic Modularity Analysis (MMA) to Quantify Human Liver Perfusion Dynamics. AB - Large-scale -omics data are now ubiquitously utilized to capture and interpret global responses to perturbations in biological systems, such as the impact of disease states on cells, tissues, and whole organs. Metabolomics data, in particular, are difficult to interpret for providing physiological insight because predefined biochemical pathways used for analysis are inherently biased and fail to capture more complex network interactions that span multiple canonical pathways. In this study, we introduce a nov-el approach coined Metabolomic Modularity Analysis (MMA) as a graph-based algorithm to systematically identify metabolic modules of reactions enriched with metabolites flagged to be statistically significant. A defining feature of the algorithm is its ability to determine modularity that highlights interactions between reactions mediated by the production and consumption of cofactors and other hub metabolites. As a case study, we evaluated the metabolic dynamics of discarded human livers using time-course metabolomics data and MMA to identify modules that explain the observed physiological changes leading to liver recovery during subnormothermic machine perfusion (SNMP). MMA was performed on a large scale liver-specific human metabolic network that was weighted based on metabolomics data and identified cofactor-mediated modules that would not have been discovered by traditional metabolic pathway analyses. PMID- 29137176 TI - EBV and Apoptosis: The Viral Master Regulator of Cell Fate? AB - Epstein-Barr virus (EBV) was first discovered in cells from a patient with Burkitt lymphoma (BL), and is now known to be a contributory factor in 1-2% of all cancers, for which there are as yet, no EBV-targeted therapies available. Like other herpesviruses, EBV adopts a persistent latent infection in vivo and only rarely reactivates into replicative lytic cycle. Although latency is associated with restricted patterns of gene expression, genes are never expressed in isolation; always in groups. Here, we discuss (1) the ways in which the latent genes of EBV are known to modulate cell death, (2) how these mechanisms relate to growth transformation and lymphomagenesis, and (3) how EBV genes cooperate to coordinately regulate key cell death pathways in BL and lymphoblastoid cell lines (LCLs). Since manipulation of the cell death machinery is critical in EBV pathogenesis, understanding the mechanisms that underpin EBV regulation of apoptosis therefore provides opportunities for novel therapeutic interventions. PMID- 29137181 TI - Structure and Functional Analysis of Promoters from Two Liver Isoforms of CPT I in Grass Carp Ctenopharyngodon idella. AB - Carnitine palmitoyltransferase I (CPT I) is a key enzyme involved in the regulation of lipid metabolism and fatty acid beta-oxidation. To understand the transcriptional mechanism of CPT Ialpha1b and CPT Ialpha2a genes, we cloned the 2695-bp and 2631-bp regions of CPT Ialpha1b and CPT Ialpha2a promoters of grass carp (Ctenopharyngodon idella), respectively, and explored the structure and functional characteristics of these promoters. CPT Ialpha1b had two transcription start sites (TSSs), while CPT Ialpha2a had only one TSS. DNase I foot printing showed that the CPT Ialpha1b promoter was AT-rich and TATA-less, and mediated basal transcription through an initiator (INR)-independent mechanism. Bioinformatics analysis indicated that specificity protein 1 (Sp1) and nuclear factor Y (NF-Y) played potential important roles in driving basal expression of CPT Ialpha2a gene. In HepG2 and HEK293 cells, progressive deletion analysis indicated that several regions contained cis-elements controlling the transcription of the CPT Ialpha1b and CPT Ialpha2a genes. Moreover, some transcription factors, such as thyroid hormone receptor (TR), hepatocyte nuclear factor 4 (HNF4) and peroxisome proliferator-activated receptor (PPAR) family, were all identified on the CPT Ialpha1b and CPT Ialpha2a promoters. The TRalpha binding sites were only identified on CPT Ialpha1b promoter, while TRbeta binding sites were only identified on CPT Ialpha2a promoter, suggesting that the transcription of CPT Ialpha1b and CPT Ialpha2a was regulated by a different mechanism. Site-mutation and electrophoretic mobility-shift assay (EMSA) revealed that fenofibrate-induced PPARalpha activation did not bind with predicted PPARalpha binding sites of CPT I promoters. Additionally, PPARalpha was not the only member of PPAR family regulating CPT I expression, and PPARgamma also regulated the CPT I expression. All of these results provided new insights into the mechanisms for transcriptional regulation of CPT I genes in fish. PMID- 29137182 TI - Current and Prospective Protein Biomarkers of Lung Cancer. AB - Lung cancer is a malignant lung tumor with various histological variants that arise from different cell types, such as bronchial epithelium, bronchioles, alveoli, or bronchial mucous glands. The clinical course and treatment efficacy of lung cancer depends on the histological variant of the tumor. Therefore, accurate identification of the histological type of cancer and respective protein biomarkers is crucial for adequate therapy. Due to the great diversity in the molecular-biological features of lung cancer histological types, detection is impossible without knowledge of the nature and origin of malignant cells, which release certain protein biomarkers into the bloodstream. To date, different panels of biomarkers are used for screening. Unfortunately, a uniform serum biomarker composition capable of distinguishing lung cancer types is yet to be discovered. As such, histological analyses of tumor biopsies and immunohistochemistry are the most frequently used methods for establishing correct diagnoses. Here, we discuss the recent advances in conventional and prospective aptamer based strategies for biomarker discovery. Aptamers like artificial antibodies can serve as molecular recognition elements for isolation detection and search of novel tumor-associated markers. Here we will describe how these small synthetic single stranded oligonucleotides can be used for lung cancer biomarker discovery and utilized for accurate diagnosis and targeted therapy. Furthermore, we describe the most frequently used in-clinic and novel lung cancer biomarkers, which suggest to have the ability of differentiating between histological types of lung cancer and defining metastasis rate. PMID- 29137183 TI - Lactobacillus plantarum Enhanced IL-22 Production in Natural Killer (NK) Cells That Protect the Integrity of Intestinal Epithelial Cell Barrier Damaged by Enterotoxigenic Escherichia coli. AB - Interleukin (IL)-22-producing Natural Killer (NK) cells protect the gut epithelial cell barrier from pathogens. A strain of probiotics, Lactobacillus plantarum (L. plantarum, LP), was previously found by our laboratory to significantly improve the mucosal barrier integrity and function of the small intestine in pigs. However, it was unclear whether LP benefited the intestinal mucosal barrier via interactions with the intestinal NK cells. The present study, therefore, was focused on the therapeutic effect of NK cells that were stimulated by LP on attenuating enterotoxigenic Escherichia coli (ETEC)-induced the damage to the integrity of the epithelial cell barrier. The results showed that LP can efficiently increase protein levels of the natural cytotoxicity receptor (NCR) family, and the expression levels of IL-22 mRNA and protein in NK cells. Transfer of NK cells stimulated by LP conferred protection against ETEC K88-induced intestinal epithelial barrier damage in NCM460 cells. We found that NK cells stimulated by LP could partially offset the reduction in NCM460 cell monolayers transepithelial electrical resistance (TEER) caused by ETEC K88, and increase ZO 1 and occludin mRNA and protein expressions by ETEC K88-infected NCM460 cells. Furthermore, adding NK cells that were stimulated by LP to ETEC K88-infected NCM460cells, IL-22R1, p-Stat3, and p-Tyk2 expression by NCM460 cells was increased. Mechanistic experiment showed that NK cells stimulated by LP lost the function of maintaining TEER of NCM460 cells challenged with ETEC K88, when polyclonal anti-IL-22 antibody was used to block IL-22 production. Collectively, our results suggested that LP stimulation of NK could enhance IL-22 production, which might be able to provide defense against ETEC-induced damage to the integrity of intestinal epithelial barrier. PMID- 29137184 TI - Cell-Type Specific Metabolic Flux Analysis: A Challenge for Metabolic Phenotyping and a Potential Solution in Plants. AB - Stable isotope labelling experiments are used routinely in metabolic flux analysis (MFA) to determine the metabolic phenotype of cells and tissues. A complication arises in multicellular systems because single cell measurements of transcriptomes, proteomes and metabolomes in multicellular organisms suggest that the metabolic phenotype will differ between cell types. In silico analysis of simulated metabolite isotopomer datasets shows that cellular heterogeneity confounds conventional MFA because labelling data averaged over multiple cell types does not necessarily yield averaged flux values. A potential solution to this problem-the use of cell-type specific reporter proteins as a source of cell type specific labelling data-is proposed and the practicality of implementing this strategy in the roots of Arabidopsis thaliana seedlings is explored. A protocol for the immunopurification of ectopically expressed green fluorescent protein (GFP) from Arabidopsis thaliana seedlings using a GFP-binding nanobody is developed, and through GC-MS analysis of protein hydrolysates it is established that constitutively expressed GFP reports accurately on the labelling of total protein in root tissues. It is also demonstrated that the constitutive expression of GFP does not perturb metabolism. The principal obstacle to the implementation of the method in tissues with cell-type specific GFP expression is the sensitivity of the GC-MS system. PMID- 29137185 TI - A Cross-Sectional Study of Nutrient Intake and Health Status among Older Adults in Yogyakarta Indonesia. AB - Many communities around the world, particularly developing countries including Indonesia, are experiencing population ageing. There is little knowledge regarding the impact of malnutrition, or its prevalence within rural compared to urban areas, on the nutritional, functional and mental status of community-living older residents in these countries. Hence, a cross-sectional study was conducted to determine socio-demographic and anthropometric characteristics, nutritional, mental and functional status, and energy and nutrient intake of community dwelling Indonesians from both rural and urban areas of Yogyakarta. Older individuals were included in the study if they had been living in Yogyakarta for the last year and were aged >=65 years (n = 527; mean +/- SD age of 74 +/- 7 years). Rural compared with urban participants had a lower level of education and income, more hospital admissions, less dietary protein intake, lower cognitive function, poorer nutritional status and grip strength, but faster gait speed while being more dependent on assistance to perform daily activities (all p < 0.05). Cognitive function was more strongly associated than nutritional status with physical function. Rural older Indonesians living in Yogyakarta were more likely than urban older people to be malnourished and cognitively impaired, and to have associated reductions in functional capacity and independence. Strategies to improve cognitive function and nutritional status are therefore important for the wellbeing of Indonesian citizens. PMID- 29137186 TI - Dopaminergic Dysfunction in Mammalian Dopamine Neurons Induced by Simazine Neurotoxicity. AB - Many studies have shown that the pollutant simazine (6-chloro-N,N'-diethyl-1,3,5 triazine-2,4-diamine), which has been overused, inhibits the proliferation of mammalian dopaminergic cells, and affects the developmental differentiation of mammalian dopaminergic neurons. However, few studies have shown the effects of simazine on dopaminergic metabolism in these cells. Therefore, we aim to examine the metabolic effects of simazine exposure in mouse dopaminergic progenitor neurons (MN9D) at different exposure times. The cells were treated with simazine at 0, 150, 300 and 600 uM for 12, 24 and 48 h, respectively. The content of dopamine in these cells was then examined using the enzyme-linked immunosorbent assay (ELISA) kit. Real-time quantitative polymerase chain reaction (PCR) and western blotting were performed to analyze the mRNA and protein expression of aromatic amino acid decarboxylase (AADC), tyrosine hydroxylase (DYT5b), dopamine transporter (DAT), monoamine vesicular transporter 2 (VMAT2), monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). The results showed that simazine influenced the metabolism of dopamine and led to a decrease in dopamine level in these cells which may eventually lead to neurological disorders of the dopaminergic system. PMID- 29137187 TI - Clinical Usefulness of the Platelet-to Lymphocyte Ratio in Patients with Angiosarcoma of the Face and Scalp. AB - Angiosarcoma of the face and scalp (ASFS) is an extremely aggressive tumor that frequently metastasizes, often leading to death. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) are inflammatory markers that predict outcome of various cancers. We aimed to examine the relationship between pretreatment inflammatory markers and ASFS outcome. We included 17 patients with ASFS and a control group of 56 age- and gender-matched healthy individuals. Total white blood counts, neutrophil, lymphocyte, monocyte, and platelet counts were recorded; NLR, PLR, and LMR were calculated. Kaplan-Meier curves were used to calculate overall survival (OS) and distant metastasis-free survival (DMFS). Optimal cut-off values for each inflammatory marker were calculated using receiver operating curve analysis. Median follow-up was 22 months (range, 6-75). There was a statistically significant difference in absolute neutrophil counts and NLR between patient and control groups. Two-year OS and DMFS rates were 41% and 35%, respectively. In patients with tumors < 10 cm, PLR was highly correlated with DMFS, with the 2 year DMFS for those with a high PLR being 50% compared with 100% for those with a low PLR (p = 0.06). This study suggests that PLR is superior to NLR and LMR, and is a clinically useful marker in patients with ASFS with small tumors. PMID- 29137189 TI - Microscopic and Molecular Tracing of Cryptosporidium Oocysts: Identifying a Possible Reservoir of Infection in Red Grouse. AB - Infection by Cryptosporidiumbaileyi causes respiratory cryptosporidiosis in red grouse Lagopuslagopusscotica. First diagnosed in 2010, it has since been detected across half of moors managed for grouse shooting in northern England. We hypothesised that contaminated grouse faeces within communal trays visited by grouse containing grit coated with flubendazole, provided to control Trichostrongylustenuis parasites of grouse, is a reservoir of infection. To establish the basis to this hypothesis, contents of 23 trays from a grouse moor were examined for Cryptosporidium oocysts. Contents were subjected to Immuno Magnetic Separation oocyst concentration techniques prior to examination by Immuno Fluorescence Antibody Test microscopy and molecular analysis on the 18S rRNA gene. Seven of 13 (54%) grit trays known to be used by infected grouse were positive for Cryptosporidium by IMS-IFAT, compared to two of 10 (20%) random background trays. Ten of the 13 (77%) trays used by infected birds amplified positive for Cryptosporidium by Polymerase Chain Reaction and three of the 10 (30%) random trays. All PCR amplified products sequenced matched with C.baileyi, with C.parvum also present in one tray. These data suggest that trays used to "worm" grouse may act as reservoirs of Cryptosporidium infection and their future design may need to be reconsidered to minimise contamination. PMID- 29137188 TI - Physical Localization of a Locus from Agropyron cristatum Conferring Resistance to Stripe Rust in Common Wheat. AB - Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most destructive diseases of wheat (Triticum aestivum L.) worldwide. Agropyron cristatum (L.) Gaertn. (2n = 28, PPPP), one of the wild relatives of wheat, exhibits resistance to stripe rust. In this study, wheat-A. cristatum 6P disomic addition line 4844-12 also exhibited resistance to stripe rust. To identify the stripe rust resistance locus from A. cristatum 6P, ten translocation lines, five deletion lines and the BC2F2 and BC3F2 populations of two wheat-A. cristatum 6P whole-arm translocation lines were tested with a mixture of two races of Pst in two sites during 2015-2016 and 2016-2017, being genotyped with genomic in situ hybridization (GISH) and molecular markers. The result indicated that the locus conferring stripe rust resistance was located on the terminal 20% of 6P short arm's length. Twenty-nine 6P-specific sequence-tagged-site (STS) markers mapped on the resistance locus have been acquired, which will be helpful for the fine mapping of the stripe rust resistance locus. The stripe rust-resistant translocation lines were found to carry some favorable agronomic traits, which could facilitate their use in wheat improvement. Collectively, the stripe rust resistance locus from A. cristatum 6P could be a novel resistance source and the screened stripe rust-resistant materials will be valuable for wheat disease breeding. PMID- 29137190 TI - Spirulina maxima Extract Ameliorates Learning and Memory Impairments via Inhibiting GSK-3beta Phosphorylation Induced by Intracerebroventricular Injection of Amyloid-beta 1-42 in Mice. AB - Spirulina maxima, a microalga containing high levels of protein and many polyphenols, including chlorophyll a and C-phycocyanin, has antioxidant and anti inflammatory therapeutic effects. However, the mechanisms where by Spirulina maxima ameliorates cognitive disorders induced by amyloid-beta 1-42 (Abeta1-42) are not fully understood. In this study, we investigated whether a 70% ethanol extract of Spirulina maxima (SM70EE) ameliorated cognitive impairments induced by an intracerebroventricular injection of Abeta1-42 in mice. SM70EE increased the step-through latency time in the passive avoidance test and decreased the escape latency time in the Morris water maze test in Abeta1-42-injected mice. SM70EE reduced hippocampal Abeta1-42 levels and inhibited amyloid precursor protein processing-associated factors in Abeta1-42-injected mice. Additionally, acetylcholinesterase activity was suppressed by SM70EE in Abeta1-42-injected mice. Hippocampal glutathione levels were examined to determine the effects of SM70EE on oxidative stress in Abeta1-42-injected mice. SM70EE increased the levels of glutathione and its associated factors that were reduced in Abeta1-42 injected mice. SM70EE also promoted activation of the brain-derived neurotrophic factor/phosphatidylinositol-3 kinase/serine/threonine protein kinase signaling pathway and inhibited glycogen synthase kinase-3beta phosphorylation. These findings suggested that SM70EE ameliorated Abeta1-42-induced cognitive impairments by inhibiting the increased phosphorylation of glycogen synthase kinase-3beta caused by intracerebroventricular injection of Abeta1-42 in mice. PMID- 29137192 TI - Influence of KMnO4 Concentrationon Infrared Emissivity of Coatings Formed on TC4 Alloys by Micro-Arc Oxidation. AB - Ceramic coatings with high emissivity were fabricated on TC4 alloys by micro-arc oxidation technique (MAO) in mixed silicate and phosphate electrolytes with varying KMnO4 addition. The microstructure, phase and chemical composition were characterized by scanning electron microscope (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS), and the infrared emissivity of the MAO coatings was measured in a waveband of 5-20 MUm. The results show that the thickness of the coatings increased with the addition of KMnO4, but the roughness of the coatings first decreased and then increased slightly due to the inhibitory effect of KMnO4 on Na2SiO3 deposition. The main phase composition of the coatings was anatase and rutile TiO2, amorphous form of SiO2 and MnO2. The infrared emissivity value of the coatings strongly depended on KMnO4 concentration, the coating formed at the concentration of 0.8 g/L KMnO4 reached the highest and an average of up to 0.87 was observed. PMID- 29137191 TI - Maternal Iodine Intake and Offspring Attention-Deficit/Hyperactivity Disorder: Results from a Large Prospective Cohort Study. AB - Current knowledge about the relationship between mild to moderately inadequate maternal iodine intake and/or supplemental iodine on child neurodevelopment is sparse. Using information from 77,164 mother-child pairs in the Norwegian Mother and Child Cohort Study, this study explored associations between maternal iodine intake and child attention-deficit/hyperactivity disorder (ADHD) diagnosis, registered in the Norwegian Patient Registry and maternally-reported child ADHD symptoms at eight years of age. Pregnant women reported food and supplement intakes by questionnaire in gestational week 22. In total, 1725 children (2.2%) were diagnosed with ADHD. In non-users of supplemental iodine (53,360 mothers), we found no association between iodine intake from food and risk of child ADHD diagnosis (p = 0.89), while low iodine from food (<200 ug/day) was associated with higher child ADHD symptom scores (adjusted difference in score up to 0.08 standard deviation (SD), p < 0.001, n = 19,086). In the total sample, we found no evidence of beneficial effects of maternal use of iodine-containing supplements (n = 23,804) on child ADHD diagnosis or symptom score. Initiation of iodine supplement use in gestational weeks 0-12 was associated with an increased risk of child ADHD (both measures). In conclusion, insufficient maternal iodine intake was associated with increased child ADHD symptom scores at eight years of age, but not with ADHD diagnosis. No reduction of risk was associated with maternal iodine supplement use. PMID- 29137193 TI - Gas Measurement Using Static Fourier Transform Infrared Spectrometers. AB - Online monitoring of gases in industrial processes is an ambitious task due to adverse conditions such as mechanical vibrations and temperature fluctuations. Whereas conventional Fourier transform infrared (FTIR) spectrometers use rather complex optical and mechanical designs to ensure stable operation, static FTIR spectrometers do not require moving parts and thus offer inherent stability at comparatively low costs. Therefore, we present a novel, compact gas measurement system using a static single-mirror Fourier transform spectrometer (sSMFTS). The system works in the mid-infrared range from 650 cm - 1 to 1250 cm - 1 and can be operated with a customized White cell, yielding optical path lengths of up to 120 cm for highly sensitive quantification of gas concentrations. To validate the system, we measure different concentrations of 1,1,1,2-Tetrafluoroethane (R134a) and perform a PLS regression analysis of the acquired infrared spectra. Thereby, the measured absorption spectra show good agreement with reference data. Since the system additionally permits measurement rates of up to 200 Hz and high signal to-noise ratios, an application in process analysis appears promising. PMID- 29137194 TI - Integrated Display and Simulation for Automatic Dependent Surveillance-Broadcast and Traffic Collision Avoidance System Data Fusion. AB - Automatic Dependent Surveillance-Broadcast (ADS-B) is the direction of airspace surveillance development. Research analyzing the benefits of Traffic Collision Avoidance System (TCAS) and ADS-B data fusion is almost absent. The paper proposes an ADS-B minimum system from ADS-B In and ADS-B Out. In ADS-B In, a fusion model with a variable sampling Variational Bayesian-Interacting Multiple Model (VSVB-IMM) algorithm is proposed for integrated display and an airspace traffic situation display is developed by using ADS-B information. ADS-B Out includes ADS-B Out transmission based on a simulator platform and an Unmanned Aerial Vehicle (UAV) platform. This paper describes the overall implementation of ADS-B minimum system, including theoretical model design, experimental simulation verification, engineering implementation, results analysis, etc. Simulation and implementation results show that the fused system has better performance than each independent subsystem and it can work well in engineering applications. PMID- 29137195 TI - Three-Dimensional ZnO Hierarchical Nanostructures: Solution Phase Synthesis and Applications. AB - Zinc oxide (ZnO) nanostructures have been studied extensively in the past 20 years due to their novel electronic, photonic, mechanical and electrochemical properties. Recently, more attention has been paid to assemble nanoscale building blocks into three-dimensional (3D) complex hierarchical structures, which not only inherit the excellent properties of the single building blocks but also provide potential applications in the bottom-up fabrication of functional devices. This review article focuses on 3D ZnO hierarchical nanostructures, and summarizes major advances in the solution phase synthesis, applications in environment, and electrical/electrochemical devices. We present the principles and growth mechanisms of ZnO nanostructures via different solution methods, with an emphasis on rational control of the morphology and assembly. We then discuss the applications of 3D ZnO hierarchical nanostructures in photocatalysis, field emission, electrochemical sensor, and lithium ion batteries. Throughout the discussion, the relationship between the device performance and the microstructures of 3D ZnO hierarchical nanostructures will be highlighted. This review concludes with a personal perspective on the current challenges and future research. PMID- 29137196 TI - High Expression of STAT3 in Subcutaneous Adipose Tissue Associates with Cardiovascular Risk in Women with Rheumatoid Arthritis. AB - Despite the predominance of female patients and uncommon obesity, rheumatoid arthritis (RA) is tightly connected to increased cardiovascular morbidity. The aim of this study was to investigate transcriptional activity in the subcutaneous white adipose tissue (WAT) with respect to this disproportionate cardiovascular risk (CVR) in RA. CVR was estimated in 182 female patients, using the modified Systematic Coronary Risk Evaluation scale, and identified 93 patients with increased CVR. The overall transcriptional activity in WAT was significantly higher in patients with CVR and was presented by higher serum levels of WAT products leptin, resistin and IL-6 (all, p < 0.001). CVR was associated with high WAT-specific transcription of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor NF-kappa-B p65 subunit (RELA), and with high transcription of serine-threonine kinase B (AKT1) in leukocytes. These findings suggest Interleukin 6 (IL-6) and leptin take part in WAT-specific activation of STAT3. The binary logistic regression analysis confirmed an independent association of CVR with IL-6 in serum, and with STAT3 in WAT. The study shows an association of CVR with transcriptional activity in WAT in female RA patients. It also emphasizes the importance of STAT3 regulatory circuits for WAT-related CVR in RA. PMID- 29137197 TI - Effect of Age on Glasgow Coma Scale in Patients with Moderate and Severe Traumatic Brain Injury: An Approach with Propensity Score-Matched Population. AB - Background: The most widely used methods of describing traumatic brain injury (TBI) are the Glasgow Coma Scale (GCS) and the Abbreviated Injury Scale (AIS). Recent evidence suggests that presenting GCS in older patients may be higher than that in younger patients for an equivalent anatomical severity of TBI. This study aimed to assess these observations with a propensity-score matching approach using the data from Trauma Registry System in a Level I trauma center. Methods: We included all adult patients (aged >=20 years old) with moderate to severe TBI from 1 January 2009 to 31 December 2016. Patients were categorized into elderly (aged >=65 years) and young adults (aged 20-64 years). The severity of TBI was defined by an AIS score in the head (AIS 3-4 and 5 indicate moderate and severe TBI, respectively). We examined the differences in the GCS scores by age at each head AIS score. Unpaired Student's t- and Mann-Whitney U-tests were used to analyze normally and non-normally distributed continuous data, respectively. Categorical data were compared using either the Pearson chi-square or two-sided Fisher's exact tests. Matched patient populations were allocated in a 1:1 ratio according to the propensity scores calculated using NCSS software with the following covariates: sex, pre-existing chronic obstructive pulmonary disease, systolic blood pressure, hemoglobin, sodium, glucose, and alcohol level. Logistic regression was used to evaluate the effects of age on the GCS score in each head AIS stratum. Results: The study population included 2081 adult patients with moderate to severe TBI. These patients were categorized into elderly (n = 847) and young adults (n = 1234): each was exclusively further divided into three groups of patients with head AIS of 3, 4, or 5. In the 162 well-balanced pairs of TBI patients with head AIS of 3, the elderly demonstrated a significantly higher GCS score than the young adults (14.1 +/- 2.2 vs. 13.1 +/- 3.3, respectively; p = 0.002). In the 362 well-balanced pairs of TBI patients with head AIS of 4, the elderly showed a significantly higher GCS score than the young adults (13.1 +/- 3.3 vs. 12.2 +/- 3.8, respectively; p = 0.002). In the 89 well-balance pairs of TBI patients with head AIS of 5, no significant differences were observed for the GCS scores. Conclusions: This study demonstrated that elderly patients with moderate TBI present higher GCS score than younger patients. This study underscores the importance of determining of TBI severity in this group of elderly patients based on the GCS score alone. A lower threshold of GCS cutoff should be adopted in the management of the elderly patients with TBI. PMID- 29137198 TI - Water-Based Suspensions of Iron Oxide Nanoparticles with Electrostatic or Steric Stabilization by Chitosan: Fabrication, Characterization and Biocompatibility. AB - Present day biomedical applications, including magnetic biosensing, demand better understanding of the interactions between living systems and magnetic nanoparticles (MNPs). In this work spherical MNPs of maghemite were obtained by a highly productive laser target evaporation technique. XRD analysis confirmed the inverse spinel structure of the MNPs (space group Fd-3m). The ensemble obeyed a lognormal size distribution with the median value 26.8 nm and dispersion 0.362. Stabilized water-based suspensions were fabricated using electrostatic or steric stabilization by the natural polymer chitosan. The encapsulation of the MNPs by chitosan makes them resistant to the unfavorable factors for colloidal stability typically present in physiological conditions such as pH and high ionic force. Controlled amounts of suspensions were used for in vitro experiments with human blood mononuclear leukocytes (HBMLs) in order to study their morphofunctional response. For sake of comparison the results obtained in the present study were analyzed together with our previous results of the study of similar suspensions with human mesenchymal stem cells. Suspensions with and without chitosan enhanced the secretion of cytokines by a 24-h culture of HBMLs compared to a control without MNPs. At a dose of 2.3, the MTD of chitosan promotes the stimulating effect of MNPs on cells. In the dose range of MNPs 10-1000 MTD, chitosan "inhibits" cellular secretory activity compared to MNPs without chitosan. Both suspensions did not caused cell death by necrosis, hence, the secretion of cytokines is due to the enhancement of the functional activity of HBMLs. Increased accumulation of MNP with chitosan in the cell fraction at 100 MTD for 24 h exposure, may be due to fixation of chitosan on the outer membrane of HBMLs. The discussed results can be used for an addressed design of cell delivery/removal incorporating multiple activities because of cell capability to avoid phagocytosis by immune cells. They are also promising for the field of biosensor development for the detection of magnetic labels. PMID- 29137200 TI - A Lab-on-a-Chip-Based Non-Invasive Optical Sensor for Measuring Glucose in Saliva. AB - A lab-on-a-chip (LOC)-based non-invasive optical sensor for measuring glucose in saliva was fabricated. Existing glucose sensors utilizing blood require acquisition of a blood sample by pricking the finger, which is painful and inconvenient. To overcome these limitations, we propose a non-invasive glucose sensor with LOC, micro-electro-mechanical system and optical measurement technology. The proposed sensor for measuring glucose in saliva involves pretreatment, mixing, and measurement on a single tiny chip. Saliva containing glucose and glucose oxidase for glucose oxidation are injected through Inlets 1 and 2, respectively. Next, H2O2 is produced by the reaction between glucose and glucose oxidase in the pretreatment part. The saliva and generated H2O2 are mixed with a colorizing agent injected through Inlet 3 during the mixing part and the absorbance of the colorized mixture is measured in the measurement part. The absorbance of light increases as a function of glucose concentration at a wavelength of 630 nm. To measure the absorbance of the colorized saliva, a light emitting diode with a wavelength of 630 nm and a photodiode were used during the measurement part. As a result, the measured output current of the photodiode decreased as glucose concentration in the saliva increased. PMID- 29137199 TI - Epidemiology of Bone Fracture in Female Trauma Patients Based on Risks of Osteoporosis Assessed using the Osteoporosis Self-Assessment Tool for Asians Score. AB - Background: Osteoporotic fractures are defined as low-impact fractures resulting from low-level trauma. However, the exclusion of high-level trauma fractures may result in underestimation of the contribution of osteoporosis to fractures. In this study, we aimed to investigate the fracture patterns of female trauma patients with various risks of osteoporosis based on the Osteoporosis Self Assessment Tool for Asians (OSTA) score. Methods: According to the data retrieved from the Trauma Registry System of a Level I trauma center between 1 January 2009 and 31 December 2015, a total of 6707 patients aged >=40 years and hospitalized for the treatment of traumatic bone fracture were categorized as high-risk (OSTA < -4, n = 1585), medium-risk (-1 >= OSTA >= -4, n = 1985), and low-risk (OSTA > 1, n = 3137) patients. Two-sided Pearson's, chi-squared, or Fisher's exact tests were used to compare categorical data. Unpaired Student's t-test and Mann-Whitney U-test were used to analyze normally and non-normally distributed continuous data, respectively. Propensity-score matching in a 1:1 ratio was performed with injury mechanisms as adjusted variables to evaluate the effects of OSTA-related grouping on the fracture patterns. Results: High- and medium-risk patients were significantly older, had higher incidences of comorbidity, and were more frequently injured from a fall and bicycle accident than low-risk patients did. Compared to low-risk patients, high- and medium-risk patients had a higher injury severity and mortality. In the propensity-score matched population, the incidence of fractures was only different in the extremity regions between high- and low risk patients as well as between medium- and low-risk patients. The incidences of femoral fractures were significantly higher in high-risk (odds ratio [OR], 3.4; 95% confidence interval [CI], 2.73-4.24; p < 0.001) and medium-risk patients (OR, 1.4; 95% CI, 1.24-1.54; p < 0.001) than in low-risk patients. In addition, high risk patients had significantly lower odds of humeral, radial, patellar, and tibial fractures; however, such lower odds were not found in medium- risk than low-risk patients. Conclusions: The fracture patterns of female trauma patients with high- and medium-risk osteoporosis were different from that of low-risk patients exclusively in the extremity region. PMID- 29137201 TI - Review on SERS of Bacteria. AB - Surface enhanced Raman spectroscopy (SERS) has been widely used for chemical detection. Moreover, the inherent richness of the spectral data has made SERS attractive for use in detecting biological materials, including bacteria. This review discusses methods that have been used to obtain SERS spectra of bacteria. The kinds of SERS substrates employed to obtain SERS spectra are discussed as well as how bacteria interact with silver and gold nanoparticles. The roll of capping agents on Ag/Au NPs in obtaining SERS spectra is examined as well as the interpretation of the spectral data. PMID- 29137203 TI - A First-Principle Theoretical Study of Mechanical and Electronic Properties in Graphene Single-Walled Carbon Nanotube Junctions. AB - The new three-dimensional structure that the graphene connected with SWCNTs (G CNTs, Graphene Single-Walled Carbon Nanotubes) can solve graphene and CNTs' problems. A comprehensive study of the mechanical and electrical performance of the junctions was performed by first-principles theory. There were eight types of junctions that were constituted by armchair and zigzag graphene and (3,3), (4,0), (4,4), and (6,0) CNTs. First, the junction strength was investigated. Generally, the binding energy of armchair G-CNTs was stronger than that of zigzag G-CNTs, and it was the biggest in the armchair G-CNTs (6,0). Likewise, the electrical performance of armchair G-CNTs was better than that of zigzag G-CNTs. Charge density distribution of G-CNTs (6,0) was the most homogeneous. Next, the impact factors of the electronic properties of armchair G-CNTs were investigated. We suggest that the band gap is increased with the length of CNTs, and its value should be dependent on the combined effect of both the graphene's width and the CNTs' length. Last, the relationship between voltage and current (U/I) were studied. The U/I curve of armchair G-CNTs (6,0) possessed a good linearity and symmetry. These discoveries will contribute to the design and production of G-CNT based devices. PMID- 29137204 TI - Optically Controllable Linear-Polarization Rotator Using Chiral-Azobenzene-Doped Liquid Crystals. AB - A linear-polarization rotator based on the optically tunable pitch of chiral azobenzene-doped liquid crystals (CAdLCs) has been investigated. It is shown that the orientation of linearly polarized (LP) light can be optically tuned using CAdLCs and that the transmitted light possesses a good degree of linear polarization (DoLP). Experimental and simulation (4 * 4 Berreman matrix) results show that the rotation angle is dependent on the pitch as well as the number of turns of the cholesteric LC helix. Some causes to affect the DoLP of the output LP lights during photoisomerization are also discussed. Moreover, a calibration term, beta(t), is also introduced to elucidate the behavior of the discontinuous change of the CAdLC pitch in a fixed cell thickness. PMID- 29137202 TI - Differential Gene Expression Analysis of Bovine Macrophages after Exposure to the Penicillium Mycotoxins Citrinin and/or Ochratoxin A. AB - Mycotoxins produced by fungal species commonly contaminate livestock feedstuffs, jeopardizing their health and diminishing production. Citrinin (CIT) and ochratoxin A (OTA) are mycotoxins produced by Penicillium spp. and commonly co occur. Both CIT and OTA can modulate immune response by inhibiting cell proliferation and differentiation, altering cell metabolism, and triggering programmed cell death. The objective of this study was to determine the effects of sublethal exposure (i.e., the concentration that inhibited cell proliferation by 25% (IC25)) to CIT, OTA or CIT + OTA on the bovine macrophage transcriptome. Gene expression was determined using the Affymetrix Bovine Genome Array. After 6 h of exposure to CIT, OTA or CIT + OTA, the number of differentially expressed genes (DEG), respectively, was as follows: 1471 genes (822 up-regulated, 649 down regulated), 5094 genes (2611 up-regulated, 2483 down-regulated) and 7624 genes (3984 up-regulated, 3640 down-regulated). Of these, 179 genes (88 up-regulated, 91 down-regulated) were commonly expressed between treatments. After 24 h of exposure to CIT, OTA or CIT + OTA the number of DEG, respectively, was as follows: 3230 genes (1631 up-regulated, 1599 down-regulated), 8558 genes (4167 up regulated, 4391 down-regulated), and 10,927 genes (6284 up-regulated, 4643 down regulated). Of these, 770 genes (247 up-regulated, 523 down-regulated) were commonly expressed between treatments. The categorization of common biological functions and pathway analysis suggests that the IC25 of both CIT and OTA, or their combination, induces cellular oxidative stress, a slowing of cell cycle progression, and apoptosis. Collectively, these effects contribute to inhibiting bovine macrophage proliferation. PMID- 29137206 TI - Ancient Food Habits Dictate that Food Can Be Medicine but Medicine Cannot Be "Food"!! AB - Background: Extensive surveys of several population settlements in different parts of India-covering plains, mountains, valleys, river banks and deeper areas of forests at different altitudes-between 1968 and 2016 demonstrated that the basic vital need of hunger is being fulfilled since antiquity by plants in the wild. Methods: Based on collections, consultations with local population personnel and literature searches, this paper presents many plants that are commonly used as food and focuses on their products, which are rich in alkaloids, polysaccharides, steroids, terpenoids, flavonoids, aminoacids, fatty acids and antibiotics etc. These complex organic compounds are suitable for the production of drugs for many ailments/diseases, including the prevention of cancers. Results: There are more than 100 families including several hundred plant taxa from various plant groups like angiosperms, bryophytes, pteridophytes, gymnosperms and even fleshy fungi, which have offered essential food items to ever-growing human populations since antiquity. Phytochemicals functioning as antioxidants are exceedingly beneficial to the human body but excess consumption of these compounds, adding higher levels of antioxidants, may even be responsible for chronic diseases including aging, cancer, cardiovascular diseases, rheumatoid arthritis, atherosclerosis, etc. These medicines can obviously be taken in small and prescribed quantities but can never be consumed as "food items." PMID- 29137205 TI - Oleanolic Acid and Its Derivatives: Biological Activities and Therapeutic Potential in Chronic Diseases. AB - The increasing demand for natural products as an alternative therapy for chronic diseases has encouraged research into the pharmacological importance of bioactive compounds from plants. Recently, there has been a surge of interest in the therapeutic potential of oleanolic acid (OA) in the prevention and management of chronic diseases. Oleanolic acid is a pentacyclic triterpenoid widely found in plants, including fruits and vegetables with different techniques and chromatography platforms being employed in its extraction and isolation. Several studies have demonstrated the potential therapeutic effects of OA on different diseases and their symptoms. Furthermore, oleanolic acid also serves as a framework for the development of novel semi-synthetic triterpenoids that could prove vital in finding therapeutic modalities for various ailments. There are recent advances in the design and synthesis of chemical derivatives of OA to enhance its solubility, bioavailability and potency. Some of these derivatives have also been therapeutic candidates in a number of clinical trials. This review consolidates and expands on recent reports on the biological effects of oleanolic acid from different plant sources and its synthetic derivatives as well as their mechanisms of action in in vitro and in vivo study models. This review suggests that oleanolic acid and its derivatives are important candidates in the search for alternative therapy in the treatment and management of chronic diseases. PMID- 29137207 TI - The Interaction between Ambient PM10 and NO2 on Mortality in Guangzhou, China. AB - Air pollution is now a significant environmental issue in China. To better understand the health impacts of ambient air pollution, this study investigated the potential interaction between PM10 and NO2 on mortality in Guangzhou, China. Time series data of daily non-accidental mortality and concentrations of PM10 and NO2 from 2006 to 2010 were collected. Based on generalized additive model, we developed two models (bivariate model and stratified model) to explore the interaction both qualitatively and quantitatively. At lag of 0-2 days, greater interactive effects between PM10 and NO2 were presented in the graphs. Positive modified effects were also found between the two pollutants on total non accidental death and cardiovascular death. When the NO2 concentration was at a high level (>76.14 MUg/m3), PM10 showed the greatest excess relative risk percentage (ERR%) for total non-accidental mortality (0.46, 95% CI: 0.13-0.79) and cardiovascular disease mortality (0.61, 95% CI: 0.06-1.16) for each 10 MUg/m3 increase. During the period of high PM10 concentration (>89.82 MUg/m3), NO2 demonstrated its strongest effect for total non-accidental mortality (ERR%: 0.92, 95% CI: 0.42-1.42) and cardiovascular disease mortality (ERR%: 1.20, 95% CI: 0.38 2.03). Our results suggest a positive interaction between PM10 and NO2 on non accidental mortality in Guangzhou. PMID- 29137209 TI - LIR and APEAR, two distinct Atg8-binding features within Atg4. PMID- 29137210 TI - Intentional weight loss and cancer risk. PMID- 29137208 TI - Asbestos Ban in Italy: A Major Milestone, Not the Final Cut. AB - Background and history: Italy was the main asbestos producer and one of the greatest consumers in 20th century Europe until the asbestos ban was introduced in 1992. Asbestos exposure affected the population in a wide range of working environments, namely mining and marketing of asbestos, asbestos cement production, shipyards and textile industries. This also determined a widespread environmental asbestos exposure affecting the surrounding communities. Methods: To investigate the drivers and difficulties of the process leading to the asbestos ban and its subsequent implementation, we focused on stakeholder involvement, environmental health policies, capacity building and communication. Results: In the past three decades, stakeholder involvement has been instrumental in advancing the industrial asbestos replacement process, prevention and remediation interventions. Furthermore, involvement also contributed to the integration of environmental and health policies at national, regional and local levels, including capacity building and communication. In a global public health perspective, international scientific cooperation has been established with countries using and producing asbestos. Discussion and Conclusions: Key factors and lessons learnt in Italy from both successful and ineffective asbestos policies are described to support the relevant stakeholders in countries still using asbestos contributing to the termination of its use. PMID- 29137211 TI - Community mining of open clinical trial data. PMID- 29137212 TI - Novel function of the tumor suppressor PML at ER-mitochondria sites in the control of autophagy. PMID- 29137213 TI - Taking it up a NOTCH: a novel subgroup of ACC is identified. PMID- 29137214 TI - Eph receptors as oncotargets. PMID- 29137215 TI - 'ILC-poiesis': generating tissue ILCs from naive precursors. PMID- 29137216 TI - Immune-DDR crosstalk in pre-leukemia stem cells. PMID- 29137217 TI - UCB HCT in FLT3+ AML. PMID- 29137218 TI - Importance of FISH genetics in light chain amyloidosis. PMID- 29137219 TI - Functional characterization of lysine-specific demethylase 2 (LSD2/KDM1B) in breast cancer progression. AB - Flavin-dependent histone demethylases govern histone H3K4 methylation and act as important chromatin modulators that are extensively involved in regulation of DNA replication, gene transcription, DNA repair, and heterochromatin gene silencing. While the activities of lysine-specific demethylase 1 (LSD1/KDM1A) in facilitating breast cancer progression have been well characterized, the roles of its homolog LSD2 (KDM1B) in breast oncogenesis are relatively less understood. In this study, we showed that LSD2 protein level was significantly elevated in malignant breast cell lines compared with normal breast epithelial cell line. TCGA- Oncomine database showed that LSD2 expression is significantly higher in basal-like breast tumors compared to other breast cancer subtypes or normal breast tissue. Overexpression of LSD2 in MDA-MB-231 cells significantly altered the expression of key important epigenetic modifiers such as LSD1, HDAC1/2, and DNMT3B; promoted cellular proliferation; and augmented colony formation in soft agar; while attenuating motility and invasion. Conversely, siRNA-mediated depletion of endogenous LSD2 hindered growth of multiple breast cancer cell lines while shRNA-mediated LSD2 depletion augmented motility and invasion. Moreover, LSD2 overexpression in MDA-MB-231 cells facilitated mammosphere formation, enriched the subpopulation of CD49f+/EpCAM- and ALDHhigh, and induced the expression of pluripotent stem cell markers, NANOG and SOX2. In xenograft studies using immune-compromised mice, LSD2-overexpressing MDA-MB-231 cells displayed accelerated tumor growth but significantly fewer lung metastases than controls. Taken together, our findings provide novel insights into the critical and multifaceted roles of LSD2 in the regulation of breast cancer progression and cancer stem cell enrichment. PMID- 29137221 TI - Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP. AB - Pancreatic cancer is chemo-resistant and metastasizes early with an overall five year survival of ~8.2%. First-in-class imipridone ONC201 is a small molecule in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201 analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer cell lines (N=16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4 in-vivo models including ONC201-resistant tumors. ONC212 is active in pancreatic cancer as single agent or in combination with 5-fluorouracil, irinotecan, oxaliplatin or RTK inhibitor crizotinib. Based on upregulation of pro-survival IGF1-R in some tumors, we found an active combination of ONC212 with inhibitor AG1024, including in vivo. We show a rationale for targeting pancreatic cancer using ONC212 combined with targeting the unfolded-protein response and ER chaperones such as GRP78/BIP. Our results lay the foundation to test imipridones, anti-cancer agents, in pancreatic cancer, that is refractory to most drugs. PMID- 29137220 TI - Stromal cyclin D1 promotes heterotypic immune signaling and breast cancer growth. AB - The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that drives cell autonomous cell cycle progression and proliferation. Herein we show cyclin D1 abundance is increased >30-fold in the stromal fibroblasts of patients with invasive breast cancer, associated with poor outcome. Cyclin D1 transformed hTERT human fibroblast to a cancer-associated fibroblast phenotype. Stromal fibroblast expression of cyclin D1 (cyclin D1Stroma) in vivo, enhanced breast epithelial cancer tumor growth, restrained apoptosis, and increased autophagy. Cyclin D1Stroma had profound effects on the breast tumor microenvironment increasing the recruitment of F4/80+ and CD11b+ macrophages and increasing angiogenesis. Cyclin D1Stroma induced secretion of factors that promoted expansion of stem cells (breast stem-like cells, embryonic stem cells and bone marrow derived stem cells). Cyclin D1Stroma resulted in increased secretion of proinflammatory cytokines (CCL2, CCL7, CCL11, CXCL1, CXCL5, CXCL9, CXCL12), CSF (CSF1, GM-CSF1) and osteopontin (OPN) (30-fold). OPN was induced by cyclin D1 in fibroblasts, breast epithelial cells and in the murine transgenic mammary gland and OPN was sufficient to induce stem cell expansion. These results demonstrate that cyclin D1Stroma drives tumor microenvironment heterocellular signaling, promoting several key hallmarks of cancer. PMID- 29137222 TI - PI3Kdelta inhibition causes feedback activation of PI3Kalpha in the ABC subtype of diffuse large B-cell lymphoma. AB - Cell line models of the activated B cell-like (ABC) subtype of diffuse large B cell (DLBCL) depend on both NF-kappaB and phosphatidylinositol 3-kinase (PI3K) signaling pathways for survival, especially those with gain-of-function B cell receptor (BCR) mutations. Here we show that these cells depend specifically on the PI3Kdelta isoform, but that PI3K pathway interruption by PI3Kdelta inhibitors is short-lived due to feedback activation of the PI3Kalpha isoform. PI3Kdelta and PI3Kalpha inhibition cooperated in killing ABC DLBCL lines, and genetic knockdown of PI3Kalpha sensitized cells to PI3Kdelta inhibition and prolonged the interruption of PI3K signaling. PI3Kdelta inhibition evoked feedback activation of proximal BCR signaling, which increased the association of PI3Kalpha with BCAP and CD19 and increased overall PI3K activity. These results support the clinical evaluation of dual PI3Kdelta and PI3Kalpha inhibition in patients with ABC DLBCL. PMID- 29137223 TI - Hormone-induced DNA damage response and repair mediated by cyclin D1 in breast and prostate cancer. AB - Cell cycle control proteins govern events that leads to the production of two identical daughter cells. Distinct sequential temporal phases, Gap 1 (G1), Gap 0 (G0), Synthesis (S), Gap 2 (G2) and Mitosis (M) are negotiated through a series of check points during which the favorability of the local cellular environment is assessed, prior to replicating DNA [1]. Cyclin D1 has been characterized as a key regulatory subunit of the holoenzyme that promotes the G1/S-phase transition through phosphorylating the pRB protein. Cyclin D1 overexpression is considered a driving force in several types of cancers and cdk inhibitors are being used effectively in the clinic for treatment of ERalpha+ breast cancer [1, 2]. Genomic DNA is assaulted by damaging ionizing radiation, chemical carcinogens, and reactive oxygen species (ROS) which are generated by cellular metabolism. Furthermore, specific hormones including estrogens [3, 4] and androgens [5] govern pathways that damage DNA. Defects in the DNA Damage Response (DDR) pathway can lead to genomic instability and cancer. Evidence is emerging that cyclin D1 bind proteins involved in DNA repair including BRCA1 [6], RAD51 [7], BRCA2 [8] and is involved in the DNA damage and DNA repair processes [7, 8]. Because the repair of damaged DNA appears to be an important and unexpected role for cyclin D1, and inhibitors of cyclin D1-dependent kinase activity are being used in the clinic, the latest findings on the role of cyclin D1 in mediating the DDR including the DDR induced by the hormones estrogen [9] and androgen [10, 11] is reviewed. PMID- 29137224 TI - Role of the inflammasome in chronic obstructive pulmonary disease (COPD). AB - Inflammation is central to the development of chronic obstructive pulmonary disease (COPD), a pulmonary disorder characterized by chronic bronchitis, chronic airway obstruction, emphysema, associated to progressive and irreversible decline of lung function. Emerging genetic and pharmacological evidence suggests that IL 1-like cytokines are highly detected in the sputum and broncho-alveolar lavage (BAL) of COPD patients, implying the involvement of the multiprotein complex inflammasome. So far, scientific evidence has focused on nucleotide-binding oligomerization domain-like receptors protein 3 (NLRP3) inflammasome, a specialized inflammatory signaling platform that governs the maturation and secretion of IL-1-like cytokines through the regulation of caspase-1-dependent proteolytic processing. Some studies revealed that it is involved during airway inflammation typical of COPD. Based on the influence of cigarette smoke in various respiratory diseases, including COPD, in this view we report its effects in inflammatory and immune responses in COPD mouse models and in human subjects affected by COPD. In sharp contrast to what reported on experimental and clinical studies, randomized clinical trials show that indirect inflammasome inhibitors did not have any beneficial effect in moderate to severe COPD patients. PMID- 29137225 TI - Circular RNA expression profile and potential function of hsa_circRNA_101238 in human thoracic aortic dissection. AB - Objective: To assess the circular RNAs (circRNAs) expression profile and explore the potential functions in human thoracic aortic dissection (TAD). Methods: The differentially expressed circRNAs profiles of the aortic segments between human type A TAD patients (n=3) and age-matched normal donors (NA; n=3) were analyzed using the Arraystar human circRNAs microarray. Quantitative real-time PCR was used to validate the expression pattern of circRNAs, parental genes, and hsa-miR 320a; Western blotting confirmed MMP9 expression with additional samples. Bioinformatic tools including network analysis, Gene ontology, and KEGG pathway analysis were utilized. Results: Among 8,173 detected circRNA genes, 156 upregulated and 106 downregulated significantly in human TAD as compared to NA (PL0.05). Quantitative real-time PCR showed an elevated expression of the upregulated hsa_circRNA_101238, hsa_circRNA_104634, hsa_circRNA_002271, hsa_circRNA_102771, hsa_circRNA_104349, COL1A1, and COL6A3 and reduced of the downregulated hsa_circRNA_102683, hsa_circRNA_005525, hsa_circRNA_103458, and FLNA. Gene ontology analysis revealed that the parental genes favored several pathological processes, such as negative regulation of cell proliferation and extracellular matrix organization. The circRNA-miRNA co-expression network predicted that 33 circRNAs might interact with at least one target miRNAs altered in TAD. KEGG pathway analysis revealed that 28 altered miRNAs were enriched on focal adhesion and vascular smooth muscle contraction. The hsa_circRNA_101238 miRNA-mRNA network indicated the highest degree of hsa-miR-320a. Quantitative real-time PCR and Western blot manifested the low expression of hsa-miR-320a and high of MMP9 in human TAD tissues, respectively. Conclusions: This study revealed hundreds of differentially expressed circular RNAs in human TAD, suggesting that hsa_circRNA_101238 might inhibit the expression of hsa-miR-320a and increase that of MMP9 in TAD. PMID- 29137226 TI - The neglected avian hepatotropic virus induces acute and chronic hepatitis in ducks: an alternative model for hepatology. AB - Duck Hepatitis A Virus (DHAV) belongs to the Avihepatovirus, which is also classified into Picornaviridae with Hepatovirus, Hepatitis A Virus (HAV). In humans, the pathogenesis of HAV is not well understood because of limited work with animal models. Here, we investigated the progress of duck viral hepatitis caused by DHAV and their potential for dissecting the pathogenesis of HAV. During the course of infection, the duck model had undergone hepatocellular lesions (vacuolation, acidophilic degeneration and steatosis), lymphocytes recruitment (neutrophil granulocytes, heterophilic granulocytes and T cells or plasm cells) and repair (activation of hepatic stellate cells, fibrosis and regeneration). Coincident with liver injury, the serum biomarkers, aspartate aminotransferase and alanine transaminase were significantly increased. Moreover, comparatively lower CD4+ and CD8+ T-cells were recruited to the liver, which might lead to a persistent infection (40 wk). Because DHAV and HAV have similar genomic structure, biological phenotypes and can easily replicate in liver. And half of fibrosis-related genes had high homology between humans and ducks. Considering these similarity in pathological and virological phenotypes, we proposed that the ducks might be an alternatively small animal model that would provide insight into the pathogenesis of viral hepatitis, fibrosis and liver regeneration. PMID- 29137227 TI - Re-balance of memory T cell subsets in peripheral blood from patients with CML after TKI treatment. AB - T cell immune surveillance is considered an important host protection process for inhibiting carcinogenesis. The full capacity of T cell immune surveillance is dependent on T cell homeostasis, particularly for central memory T (TCM) cells and stem cell memory T (TSCM) cells. In this study, distribution of T cell subsets in peripheral blood from 12 patients with chronic myeloid leukemia (CML) and 12 cases with CML in complete remission (CR) was analyzed using a multicolor flow cytometer, and 16 samples from healthy individuals (HIs) served as control. The proportion of CD8+ TSCM and CD4+ and CD8+ TCM cells were lower, while CD4+ effector memory T (TEM) cells and CD4+ and CD8+ terminal effector T (TEF) cells were higher in CML patients compared with HIs. Moreover, the proportion of CD8+CD28- T cells, which were found to have the immune suppressive function, increased in the naive T (TN) cell and TCM subsets in CML patients compared with HIs. Our study reveals that elimination of leukemia cells by treating with tyrosine kinase inhibitors (TKIs) restores the memory T cell distribution from a skewed pattern in CML patients who are under leukemia burden, indicating that leukemia-specific immune responses mediated by T cells might be induced and maintained in CML patients, however, these responsive T cells might gradually become exhausted due to the continued existence of leukemia cells and their environment; therefore, T cell activation using a different approach remains a key point for enhancing global T cell immunity in CML patients, even for those with CR status. PMID- 29137228 TI - A native-like bispecific antibody suppresses the inflammatory cytokine response by simultaneously neutralizing tumor necrosis factor-alpha and interleukin-17A. AB - Anti-tumor necrosis factor (TNF) therapies are successful in the treatment of inflammatory disorders. However, some patients with rheumatoid arthritis (RA) fail to response anti-TNF drugs due to the compensation of other inflammatory signals. In this study, to reduce compensatory responses of interleukin-17A (IL 17A) during TNF-alpha inhibition, we generated an IgG-like bispecific antibodiy (bsAb) against TNF-alpha and IL-17A through a combination method of electrostatic Fc pairing and light chain crossover. This bsAb exhibited relatively high stability comparable to natural IgG antibodies, and retained the unaltered affinities to both of two targets. BsAb significantly decreased not only the expression level of neutrophil or Th17 chemokines, but also the secretion of IL 6/IL-8 on fibroblast-like synoviocytes (FLS) from a patient with RA. Meanwhile, TNF-alpha-mediated cellular cytotoxicity of fibroblasts was neutralized by bsAb. Importantly, we demonstrate that the combined blockade of TNF-alpha and IL-17A is more efficient than inhibition of either factor alone. Our results suggest the IgG-like anti-TNF-alpha/IL-17A bispecific molecule overcome the limited therapeutic responses using anti-TNF drugs. It may be a promising therapeutic agent for the treatment of autoimmune diseases. PMID- 29137229 TI - Activation of VIP signaling enhances immunosuppressive effect of MDSCs on CMV induced adaptive immunity. AB - Vasoactive intestinal peptide (VIP) is recognized as a potent anti-inflammatory factor which affects both the innate and adaptive arms of the immune system. These effects include, but are not limited to, inhibition of T cell proliferation and disruption of immune homeostasis. Myeloid-derived suppressor cells (MDSC) are an immune regulatory cell type that has been described in settings of cancer and infectious disease._Here we demonstrate a reduced circulating monocytic MDSCs in the VIP -/-vs. wild type MCMV. VIP-/- MDSCs secretes less NO upon stimulation with LPS and interferon that relatively lose the ability to suppress T cells activation in vitro compared to wild type MDSCs._Considering the importance of VIP in immunomodulation, the possible effect of VIP in the suppressive function of MDSC populations following CMV infection remains unknown. We describe the possible role of VIP in the regulation of anti-CMV activity of T cells through the activation of MDSCs. PMID- 29137230 TI - Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells. AB - Obesity is involved in tumor progression. However, the corresponding mechanisms remain largely unknown. Here, we report that adipocytes increase the invasive ability of tumor cells by producing exosomes with a high level of MMP3. Compared with 3T3-L1 cells, 3T3-L1 adipocytes are enriched in MMP3 protein and can transfer MMP3 to 3LL lung cancer cells. Then, MMP3 activates MMP9 activity in 3LL cells and promotes invasion in vitro and in vivo via MMP9. Furthermore, MMP3 protein levels in lung tumor tissues from obese patients are increased compared with those of non-obese patients. In addition, MMP3 protein levels are positively correlated with MMP9 activity in tumor tissues. Therefore, our results reveal a novel mechanism in the adipocyte-derived exosome-mediated promotion of lung tumor metastasis, which extends our knowledge regarding obesity and tumor progression. PMID- 29137231 TI - An oral keratinocyte life cycle model identifies novel host genome regulation by human papillomavirus 16 relevant to HPV positive head and neck cancer. AB - Many aspects of the HPV life cycle have been characterized in cervical cell lines (W12, CIN612) and in HPV immortalized primary foreskin keratinocytes. There is now an epidemic of HPV positive oropharyngeal cancers (HPV16 is responsible for 80-90% of these); therefore increased understanding of the HPV16 life cycle in oral keratinocytes is a priority. To date there have been limited reports characterizing the HPV16 life cycle in oral keratinocytes. Using TERT immortalized "normal" oral keratinocytes (NOKs) we generated clonal cell lines maintaining the HPV16 genome as an episome, NOKs+HPV16. Organotypic raft cultures demonstrated appropriate expression of differentiation markers, E1^E4 and E2 expression along with amplification of the viral genome in the upper layers of the epithelium. Using this unique system RNA-seq analysis revealed extensive gene regulation of the host genome by HPV16; many of the changes have not been observed for HPV16 before. The RNA-seq data was validated on a key set of anti viral innate immune response genes repressed by HPV16 in NOKs+HPV16. We show that the behavior of these NOKs+HPV16 lines is identical to HPV16 immortalized human tonsil keratinocytes with regards innate gene regulation. Finally, using The Cancer Genome Atlas (TCGA) data we examined gene expression patterns from HPV positive and negative head and neck cancers and demonstrate this innate immune gene signature set is also downregulated in HPV positive cancers versus negative. Our system provides a model for understanding HPV16 transcriptional regulation of oral keratinocytes that is directly relevant to HPV positive head and neck cancer. PMID- 29137232 TI - Integration of metabolomics, transcriptomics, and microRNA expression profiling reveals a miR-143-HK2-glucose network underlying zinc-deficiency-associated esophageal neoplasia. AB - Esophageal squamous cell carcinoma (ESCC) in humans is a deadly disease associated with dietary zinc (Zn)-deficiency. In the rat esophagus, Zn-deficiency induces cell proliferation, alters mRNA and microRNA gene expression, and promotes ESCC. We investigated whether Zn-deficiency alters cell metabolism by evaluating metabolomic profiles of esophageal epithelia from Zn-deficient and replenished rats vs sufficient rats, using untargeted gas chromatography time-of flight mass spectrometry (n = 8/group). The Zn-deficient proliferative esophagus exhibits a distinct metabolic profile with glucose down 153-fold and lactic acid up 1.7-fold (P < 0.0001), indicating aerobic glycolysis (the "Warburg effect"), a hallmark of cancer cells. Zn-replenishment rapidly increases glucose content, restores deregulated metabolites to control levels, and reverses the hyperplastic phenotype. Integration of metabolomics and our reported transcriptomic data for this tissue unveils a link between glucose down-regulation and overexpression of HK2, an enzyme that catalyzes the first step of glycolysis and is overexpressed in cancer cells. Searching our published microRNA profile, we find that the tumor suppressor miR-143, a negative regulator of HK2, is down-regulated in Zn deficient esophagus. Using in situ hybridization and immunohistochemical analysis, the inverse correlation between miR-143 down-regulation and HK2 overexpression is documented in hyperplastic Zn-deficient esophagus, archived ESCC-bearing Zn-deficient esophagus, and human ESCC tissues. Thus, to sustain uncontrolled cell proliferation, Zn-deficiency reprograms glucose metabolism by modulating expression of miR-143 and its target HK2. Our work provides new insight into critical roles of Zn in ESCC development and prevention. PMID- 29137233 TI - Outcome of patients treated for myelodysplastic syndromes with 5q deletion after failure of lenalidomide therapy. AB - While lenalidomide (LEN) is the standard of care for the lower-risk myelodysplastic syndromes (MDS) patients with deletion 5q, 35% will not respond to or do not tolerate the drug. Moreover, most of the patients will lose their response after a few years. Defining the outcome of patients with LEN failure and determining the impact of subsequent therapies is therefore important to develop alternative strategies. Based on an international collaboration, we were able to compile a total of 392 patient cases of lower-risk MDS patients with 5q deletion and to analyze their outcome after failure of lenalidomide. The median survival following LEN failure was 23 months. We observed a negative impact on survival of advanced age, higher bone marrow blast count at LEN initiation, progression after LEN failure, and unfavorable cytogenetics. Among the treatment strategies, we observed a relatively prolonged survival of patients treated subsequently with hypomethylating agents and only a limited impact on survival of allogeneic transplantation. In conclusion, our work stresses the relatively short survival of this group of patient and defines the expected baseline for the needed future investigations in this group of patients. PMID- 29137234 TI - The AF4-MLL fusion transiently augments multilineage hematopoietic engraftment but is not sufficient to initiate leukemia in cord blood CD34+ cells. AB - The translocation t(4;11)(q21;q23) is the hallmark genetic abnormality associated with infant pro-B acute lymphoblastic leukemia (B-ALL) and has the highest frequency of rearrangement in Mixed-lineage leukemia (MLL) leukemias. Unlike other MLL translocations, MLL-AF4-induced proB-ALL is exceptionally difficult to model in mice/humans. Previous work has investigated the relevance of the reciprocal translocation fusion protein AF4-MLL for t(4;11) leukemia, finding that AF4-MLL is capable of inducing proB-ALL without requirement for MLL-AF4 when expressed in murine hematopoietic stem/progenitor cells (HSPCs). Therefore, AF4 MLL might represent a key genetic lesion contributing to t(4;11)-driven leukemogenesis. Here, we aimed to establish a humanized mouse model by using AF4 MLL to analyze its transformation potential in human cord blood-derived CD34+ HSPCs. We show that AF4-MLL-expressing human CD34+ HSPCs provide enhanced long term hematopoietic reconstitution in primary immunodeficient recipients but are not endowed with subsequent self-renewal ability upon serial transplantation. Importantly, expression of AF4-MLL in primary neonatal CD34+ HSPCs failed to render any phenotypic or hematological sign of disease, and was therefore not sufficient to initiate leukemia within a 36-week follow-up. Species-specific (epi)-genetic intrinsic determinants may underlie the different outcome observed when AF4-MLL is expressed in murine or human HSPCs. PMID- 29137235 TI - The significance of post-translational removal of alpha-DG-N in early stage endometrial cancer development. AB - Endometrial cancer is one of the most common gynecological malignancies affecting post-menopausal women, yet the underlying mechanisms are not well understood. Dystroglycan (DG) is a large glycoprotein, consisting of alpha- and beta-subunits that are non-covalently associated with each other. Modifications to alpha-DG have been linked to a variety of cancers, where the N-terminus of alpha-DG (alpha DG-N) is post-translationally removed by a furin-like enzyme. However, the functional significance of alpha-DG-N removal is unknown. Our previous studies have established that the alpha-DG cleavage enzyme furin is significantly up regulated in endometrial cancer. This study aimed to investigate the importance of alpha-DG-N removal in post-menopausal endometrial cancer. We demonstrated that alpha-DG-N removal predominantly occurred in early stage endometrial cancer tissues, and that the cleaved alpha-DG-N was significantly elevated in the uterine lavage of early grade endometrial cancer patients. Furthermore, alpha-DG N removal significantly decreased the tight junction integrity and polarity of the endometrial epithelial cells, promoting the loss of polarity markers scribble and atypical protein kinase C (aPKC) and reducing the trans-epithelial electrical resistance. The removal of alpha-DG-N also sensitized the cells for estrogen dependent proliferation. These results strongly suggest that alpha-DG-N removal plays an important role in early stage development of endometrial cancer, and that the elevated levels of alpha-DG-N in uterine fluid may provide a biomarker for early detection of endometrial cancer. PMID- 29137236 TI - The nucleocytoplasmic translocation and up-regulation of ING5 protein in breast cancer: a potential target for gene therapy. AB - Here, we found that ING5 overexpression resulted in a lower proliferation, reduced glucose metabolism, S arrest, decreased migration and invasion, apoptotic induction, fat accumulation, autophagy, senescence and mesenchymal-epithelial transition of breast cancer cells. It also suppressed the tumor growth of breast cancer cells by inhibiting proliferation, inducing apoptosis and autophagy. ING5 mediated chemoresistance was positively linked to Akt and NF-kappaB activation, MRP1 and GST-pi overexpression, and FBXW7 hypoexpression. ING5 expression was higher in breast cancer than normal tissue at both mRNA and protein levels. ING5 mRNA expression was positively correlated with relapse- and distant metastasis free survival rates. Nuclear ING5 expression showed gradual decrease from breast normal tissue, fibroadenoma, adenomatosis, primary to metastatic cancers, while versa for cytoplasmic ING5. Nuclear ING5 expression was negatively correlated with distant metastasis and p53 hypoexpression, while cytoplasmic ING5 expression was positively correlated with tumor size and ER expression. These data suggested that up-regulated expression and nucleocytoplasmic translocation of ING5 protein were observed in breast cancer. The higher expression of nuclear ING5 was inversely linked to worse clinicopathological behaviors of breast cancer by in vivo and vitro reversing aggressive phenotypes. Therefore, it should be employed as a biomarker to indicate the tumorigenesis and aggressiveness of breast cancer, and as a potential target for gene therapy. PMID- 29137237 TI - Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer. AB - In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 -15.1months), median progression-free survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer. PMID- 29137238 TI - Significance of NLDA, the commixed index of inflammation, immune responses, hemostasis, and nutrition, for predicting metastatic non-small cell lung cancer prognosis and metastases. AB - Purpose: This study aimed to take a comprehensive review of the hematological indexes and discover a novel, comprehensive, and economical index for prognostic prediction. Results: The predictive prognostic model revealed that an elevated value of NLDA (NLDA = neutrophil count/lymphocyte count * D-dimer count/albumin) was an independent risk factor for one-year adverse prognosis (hazard ratio = 3.038; 95% confidence interval [CI], 1.959-4.712; P < 0.001). The C-indexes of internal and external validation in nomogram were 0.738 (95% CI, 0.686-0.79) and 0.731 (95% CI, 0.631-0.831), respectively. The areas under the curves of the NLDA values in retrospective and prospective studies were 0.700 (95% CI, 0.631-0.769; P < 0.001) and 0.692 (95% CI, 0.535-0.822; P = 0.005), respectively. The cut-off value of NLDA was 0.15. NLDA was positively associated with M stage (P = 0.032), organ metastasis counts (P = 0.006), liver metastases (P = 0.019), and vertebrae metastases (P = 0.013). Materials and Methods: This was a retrospective and prospective study. The clinicopathological characteristics and hematological parameters of stage IV non-small cell lung cancer patients were analyzed retrospectively and prospectively to establish a valid predictive prognostic model. The primary endpoint was the 1-year overall survival. The predictive prognostic model was established and validated by Cox Regression and nomogram. The cut-off and predictive prognostic values of the novel indexes were calculated through the receiver operating characteristic curves. The chi-square test was used to explore the correlation between the new prognostic hematological index and metastatic characteristics. Conclusions: In this study, NLDA, a new, comprehensive and economic parameter, was found to be an independent adverse prognostic factor for stage IV non-small cell lung cancer patients, and was positively associated with organ metastases. PMID- 29137239 TI - Transcriptome profiling in preadipocytes identifies long noncoding RNAs as Sam68 targets. AB - The KH-type RNA binding protein Sam68 is required for adipogenesis. We have previously shown that Sam68-deficient mice have a lean phenotype and are protected against dietary-induced obesity due to defects in mTOR and S6K1 alternative splicing. Herein we profiled the transcriptome of Sam68 wild type and deficient 3T3-L1 mouse preadipocytes. We identified 652 protein-coding genes and 9 ncRNAs that were significantly altered with the loss of Sam68. As expected, downregulated genes were significantly associated with GO terms linked to cell migration, motility, and fat cell differentiation, while upregulated genes were mostly associated with GO terms linked to neurogenesis. Of the lncRNAs, we identified Hotair, Mir155hg, as well as two new lncRNAs (SR-lncRNA-1 and SR lncRNA-2) that were regulated by Sam68, and contained consensus Sam68 binding sites. RNA stability assays showed that Sam68-deficiency decreased the half-life of Hotair, and increased the half-lives of Mir155hg and SR-lncRNA-2, while the stability of SR-lncRNA-1 was unaffected. Depletion of Hotair and SR-lncRNA-1 in wild type 3T3-L1 cells led to defects in adipogenesis, whereas depletion of SR lncRNA-2 in Sam68-deficient 3T3-L1 cells partially rescued the adipogenesis defect observed in these cells. Collectively, our findings define a new role for Sam68 as a regulator of lncRNAs during adipogenic differentiation. PMID- 29137241 TI - ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo. AB - mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415. ERK inhibition (by MEK162/U0126) or knockdown (by targeted ERK1/2 shRNAs) dramatically sensitized CZ415-induced osteosarcoma cell apoptosis. In vivo, CZ415 oral administration efficiently inhibited U2OS tumor growth in mice. Its activity was further potentiated with co-administration of MEK162. Collectively, we demonstrate that ERK inhibition sensitizes CZ415-induced anti osteosarcoma activity in vitro and in vivo. CZ415 could be further tested as a promising anti-osteosarcoma agent, alone or in combination of ERK inhibition. PMID- 29137240 TI - Mutational re-modeling of di-aspartyl intramembrane proteases: uncoupling physiologically-relevant activities from those associated with Alzheimer's disease. AB - The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/PS2) underlie production of beta-amyloid, the key process in Alzheimer's disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the gamma-cleavage activities of PSENs that produce Abeta, but not the epsilon like cleavage activity that release physiologically essential transcription activators, is a potential approach for the development of rational therapies for AD. In order to identify whether different activities of PSEN1 can be dissociated, we designed multiple mutations in the evolutionary conserved sites of PSEN1. We tested them in vitro and in vivo assays and compared their activities with mutant isoforms of presenilin-related intramembrane di-aspartyl protease (IMPAS1 (IMP1)/signal peptide peptidase (SPP)). PSEN1 auto-cleavage was more resistant to the mutation remodeling than the epsilon-like proteolysis. PSEN1 with a G382A or a P433A mutation in evolutionary invariant sites retains functionally important APP epsilon- and Notch S3- cleavage activities, but G382A inhibits APP gamma-cleavage and Abeta production and a P433A elevates Abeta. The G382A variant cannot restore the normal cellular ER Ca2+ leak in PSEN1/PSEN2 double knockout cells, but efficiently rescues the loss-of-function (Egl) phenotype of presenilin in C. elegans. We found that, unlike in PSEN1 knockout cells, endoplasmic reticulum (ER) Ca2+ leak is not changed in the absence of IMP1/SPP. IMP1/SPP with the analogous mutations retained efficiency in cleavage of transmembrane substrates and rescued the lethality of Ce-imp-2 knockouts. In summary, our data show that mutations near the active catalytic sites of intramembrane di-aspartyl proteases have different consequences on proteolytic and signaling functions. PMID- 29137242 TI - Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy. AB - Successful treatment of neurofibromatosis type 1 (NF1)-associated tumors poses a significant clinical challenge. While the primary underlying genetic defect driving RAS signaling is well described, recent evidence suggests immune dysfunction contributes to tumor pathogenesis and malignant transformation. As immunologic characterizations, prognostic and predictive of immunotherapeutic clinical response in other cancers, are not fully described for benign and malignant NF1-related tumors, we sought to define their immunologic profiles. We determined the expression of human leukocyte antigen (HLA)-A/-B/-C, beta-2 microglobulin (B2M), and T cell inhibitory ligands PD-L1 and CTLA-4 by microarray gene analysis and flow cytometry. We examined HLA-A/-B/-C, B2M, and PD-L1 expression on thirty-six NF1-associated tumor samples by immunohistochemistry, and correlated these with tumoral CD4+, CD8+, FOXP3+, CD56+, and CD45RO+ lymphocytic infiltrates. We evaluated several tumors from a single patient, observing trends of increasing immunogenicity over time, even with disease progression. We observed similarly immunogenic profiles for malignant peripheral nerve sheath tumors (MPNST) and nodular and plexiform neurofibromas, contrasting with diffuse neurofibromas. These studies suggest that while immunotherapies may offer some benefit for MPNST and nodular and plexiform neurofibromas, tumor heterogeneity might pose a significant clinical challenge to this novel therapeutic approach. PMID- 29137243 TI - Ionising radiation increases permeability of endothelium through ADAM10-mediated cleavage of VE-cadherin. AB - The association between ionising radiation (IR) exposure and risk of cardiovascular diseases (CVD) is well documented, but the underlying mechanism is still poorly understood. As atherosclerotic plaques are the most common cause of CVD, we investigated the effects of IR on one of the critical parameters for atherosclerotic plaque formation - endothelium permeability to macromolecules. We used endothelial cells from human coronary artery as a model of the endothelial layer. Our results show that exposure of this endothelial layer to IR increased its permeability to macromolecules of various sizes in a dose-dependent manner. Immunofluorescence analysis revealed disruption of cell junctions caused by decreased amounts of two junction proteins, one of which is vascular endothelial cadherin (VE-cadherin). The reduction in the level of this protein was not due to diminished transcription but to protein processing instead. We observed a radiation dose-dependent increase in the cleavage of VE-cadherin by ADAM10. This was not mediated through the canonical VEGF route but was instead accompanied by intra-cellular calcium release. Importantly, inhibition of ADAM10 activity rescued IR-induced permeability. Our observations demonstrate that exposure to IR activates ADAM10 to cleave VE-cadherin leading to augmented endothelium permeability; a feature that can lead to the development of atherosclerotic plaques and increase the risk of cardiovascular disease. PMID- 29137244 TI - MicroRNA-423-5p facilitates hypoxia/reoxygenation-induced apoptosis in renal proximal tubular epithelial cells by targeting GSTM1 via endoplasmic reticulum stress. AB - It has been reported that microRNAs (miRs) can regulate renal response to acute injury and members of them are believed to be important in maintenance of renal function and development of renal injury. We investigated the actions of microRNA 423-5p (miR-423-5p) and glutathione-S-transferase (GST) M1 after acute kidney injury. MiR-423-5p was up-regulated and GSTM1 was down-regulated in human kidney (HK-2) cells subjected to hypoxia/reoxygenation (H/R) and in rat kidneys subjected to ischemia/reperfusion (I/R) injury. Dual luciferase assays revealed miR-423-5p binding to the 3' untranslated region of GSTM1. Proliferation was lower and apoptosis, ER stress and oxidative stress were all higher in H/R treated HK-2 cells transfected with or without miR-423-5p mimics and GSTM1 siRNA than in the same cells transfected with miR-423-5p inhibitors and a GSTM1 expression vector. Increased miR-423-5p and decreased GSTM1 mRNA and protein levels were observed in rat kidneys on days 1, 2 and 7 after I/R. Levels had normalized by days 14 and 21. On day 3 after treatment, rats receiving I/R or I/R plus miR-423-5p mimics exhibited higher serum creatinine and urea nitrogen levels than rats receiving I/R plus a miR-423-5p inhibitor. MiR-423-5p and lower GSTM1 mRNA and protein levels were higher in the I/R and I/R plus miR-423-5p mimic groups than in the I/R plus miR-423-5p inhibitors group. These findings demonstrate that after acute kidney injury, miR-423-5p induces ER stress and oxidative stress by inhibiting GSTM1and suppresses repair. PMID- 29137245 TI - Associations between polymorphisms in the IL-4 gene and renal cell carcinoma in Chinese Han population. AB - Renal cell carcinoma (RCC) is considered to be a kind of cytokine reactive tumor. The research has been suggested that the host immune system can regulate the clinical course of RCC. Therefore, cytokine gene polymorphisms in RCC patients were analyzed was necessary. Our study is purpose to analyzing the interleukin 4(IL-4) polymorphisms associated with RCC risk from Han Chinese population. IL-4 genetic polymorphisms were genotyped using Massarray technology from a total of 291RCC and 463 controls. Unconditional logistic regression analysis was performed to analyze their relationship with risk of RCC. A significant association was found between the rs2243250 "C" allel and decreased risk of RCC (OR=0.75, 95%CI=0.59-0.96, P=0.02). Stratified analysis based on the age, gender, smoking status, drinking status revealed no significant association with RCC in age>55, female, smoking and nodrinking. However, for age<55 group (rs2243250, rs2243267, rs2243270), male group (rs2243250), nonsmoking group (rs2227284), and drinking group (rs2243250, rs2227284, rs2243267, rs2243270) polymorphisms were found obviously associated with RCC. The haplotype analyses showed that the haplotype have a significant decreased risk of RCC in the rs2243250/rs2227284/rs2243267/rs2243270/rs2243283/rs2243289 (CGGACA) (Total, OR=0.73, 95%CI=0.54-0.98, P=0.034; Male, OR=0.59, 95%CI=0.39-0.90, P=0.014). Therefore, the present study suggests that IL-4 may be a candidate gene for assessing the risk of RCC. PMID- 29137246 TI - Apigenin sensitizes BEL-7402/ADM cells to doxorubicin through inhibiting miR 101/Nrf2 pathway. AB - Chemo-resistance is one of the main obstacle in hepatocellular carcinoma therapy. Apigenin as a natural bioflavonoid has been exhibited anti-cancer properties in various malignant cancers. The aim of this study is to evaluate the potential chemo-sensitization effect of apigenin in doxorubicin-resistant hepatocellular carcinoma cell line BEL-7402/ADM and to investigate its possible mechanism. We found that apigenin significantly reversed doxorubicin sensitivity and induced caspase-dependent apoptosis in BEL-7402/ADM cells. Furthermore, apigenin induced miR-101 expression, and overexpression of miR-101 mimicked the doxorubicin sensitizing effect of apigenin. Importantly, we showed that miR-101 was able to target the 3'-UTR of Nrf2. The results suggested that apigenin sensitizes BEL 7402/ADM cells to doxorubicin through miR-101/Nrf2 pathway, which furtherly supports apigenin as a potential chemo-sensitizer for hepatocellular carcinoma. PMID- 29137247 TI - The influence of marital status on survival in patients with oral tongue squamous cell carcinoma. AB - Marital status was found to be an independent prognostic factor for survival in several cancers. However related researches of oral tongue squamous cell carcinoma (OTSCC) are still rare. We explored the Surveillance, Epidemiology, and End Results (SEER) program and finally identified 14,194 patients with OTSCC. Kaplan-Meier analysis and multivariate Cox regression models were used to distinguish risk factors for overall survival (OS) and tumor cause-specific survival (TCSS). Widowed patients had the highest percentage of female, highest average ages and more prevalence with localized SEER Stage significantly, while patients in the single group were younger than other groups. After univariate analysis and multivariate analysis, marital status was demonstrated to be an independent prognostic factor of OS and TCSS. Married patients showed better 5 year OS (65.6%) and 5-year TCSS (89.9%) than other patients. Subgroup survival analysis according to AJCC TNM stage and SEER stage showed that the widowed patients demonstrated worst OS and TCSS compared to other groups. Marital status was an important prognostic factor for survival in patients with OTSCC. Widowed patients exhibited with the highest risk of death compared with other groups. PMID- 29137248 TI - Association of striking life events with primary breast cancer in 265 Chinese women: a case-control study. AB - The current case-control study investigated the relationship between striking life events and breast cancer in Chinese women. A total of 265 primary breast cancer patients and 265 controls were enrolled with matching for age and completed questionnaires. Logistic regression analysis was used. Thirty-nine breast cancer patients reported striking life events and twenty-four of the controls reported striking life events. The number of striking life events was significantly greater in patients (p = 0.04). It indicated a striking life event led to a 1.726-fold increased HR (95% CI 1.005-2.965, p < 0.05) for breast cancer with adjustment for age, and a 1.811-fold increased HR (95% CI 1.021 - 3.212, P < 0.05) with adjustment for age, BMI, and late age at menopause. High BMI (OR: 1.680, 95% CI: 1.258-2.196, p < 0.05) and a family history of breast cancer (OR: 2.244, 95% CI: 1.065-4.729, p < 0.05, respectively) increased the risk of breast cancer, and late age at menopause decreased the risk for breast cancer (OR: 0.513, 95% CI: 0.303-0.868, p < 0.05). Our findings indicate a significant association between striking life events and breast cancer in Chinese women, especially in the subpopulation with high BMI or family history of breast cancer. PMID- 29137249 TI - Endoscopic retrograde cholangiopancreatography versus laparoscopic exploration for common bile duct stones in post-cholecystectomy patients: a retrospective study. AB - Background and Objective: Common bile duct (CBD) stones are common in patients even after cholecystectomy. Besides endoscopic retrograde cholangiography (ERCP), laparoscopic common bile duct exploration (LCBDE) is also applied. This study aims to compare clinical indications, therapeutic benefits and complications for these two managements. Methods: From October 2012 to February 2015, 1072 consecutive patients were diagnosed as choledocholithiasis in our single hospital. Post-cholecystectomy patients who underwent ERCP or LCBDE were included. Clinical data were analyzed, such as success rate, complications, procedure duration, postoperative hospital stay, total cost and recurrence of ductal stones. Prior ERCP, previous biliary anatomic alteration surgeries and lost to follow up were the excluding criteria. Results: 141 patients were included according to the criteria, and 87 cases underwent ERCP and 54 cases underwent LCBDE. Age and sex distribution of patients were comparable between the two groups. The success rate for CBD stones clearance was 97.7% in the ERCP group, compared with 87.0% in the LCBDE group (p=0.03). The mean procedure duration was also significantly shorter in ERCP group (52.0+/-15.8 vs. 102.9+/ 40.1 min; p<0.001). Postoperative hospital stay was similar (5.5+/-2.6 vs. 5.9+/ 2.3 days; p=0.40). And no significant difference for postoperative complications (3.4% vs. 11.1%; p=0.15), total cost ($3787.1+/-1061.5 vs. $3983.54+/-1257.1, p=0.32), and the rate of bile duct stones recurrence (6.9% vs. 7.4%, p=1.00). Conclusions: For clearing CBD stones in patients after cholecystectomy, ERCP was more efficient and might be the first choice, while LCBDE might be beneficial for patients with large stones. PMID- 29137250 TI - Molecular chaperones in the acquisition of cancer cell chemoresistance with mutated TP53 and MDM2 up-regulation. AB - Utilizing the TCGA PANCAN12 dataset we discovered that cancer patients with mutations in TP53 tumor suppressor and overexpression of MDM2 oncogene exhibited decreased survival post treatment. Interestingly, in the case of breast cancer patients, this phenomenon correlated with high expression level of several molecular chaperones belonging to the HSPA, DNAJB and HSPC families. To verify the hypothesis that such a genetic background may promote chaperone-mediated chemoresistance, we employed breast and lung cancer cell lines that constitutively overexpressed heat shock proteins and have shown that HSPA1A/HSP70 and DNAJB1/HSP40 facilitated the binding of mutated p53 to the TAp73alpha protein. This chaperone-mediated mutated p53-TAp73alpha complex induced chemoresistance to DNA damaging reagents, like Cisplatin, Doxorubicin, Etoposide or Camptothecin. Importantly, when the MDM2 oncogene was overexpressed, heat shock proteins were displaced and a stable multiprotein complex comprising of mutated p53-TAp73alpha-MDM2 was formed, additionally amplifying cancer cells chemoresistance. Our findings demonstrate that molecular chaperones aid cancer cells in surviving the cytotoxic effect of chemotherapeutics and may have therapeutic implications. PMID- 29137251 TI - Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration. AB - Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States with a majority of these patients dying from aggressively invasive and metastatic disease. There is growing evidence that suggests an important role for microRNAs (miRNAs) in the pathobiology of aggressive PDAC. In this study, we found that the expression of miR-145 was significantly lower in PDAC cells when compared to normal pancreatic duct epithelial cells. Here we show that inhibition of the nuclear exporter protein exportin 1 (XPO1; also known as chromosome maintenance region 1 [CRM1]) by siRNA knockdown or by the Selective Inhibitor of Nuclear Export (SINE) compound (KPT 330; selinexor) increases miR-145 expression in PDAC cells resulting in the decreased cell proliferation and migration capacities. A similar result was obtained with forced expression of miR-145 in PDAC cells. To this end, SINE compound treatment mediated the down-regulation of known miR-145 targets genes including EGFR, MMP1, MT-MMP, c-Myc, Pak4 and Sox-2. In addition, selinexor induced the expression of two important tumor suppressive miRNAs miR-34c and let 7d leading to the up-regulation of p21WAF1. These results are the first to report that targeted inhibition of the nuclear export machinery could restore tumor suppressive miRNAs in PDAC that warrants further clinical investigations. PMID- 29137252 TI - A novel mutation R190H in the AT-hook 1 domain of MeCP2 identified in an atypical Rett syndrome. AB - Background: Mutations in Methyl-CpG binding protein 2 (MECP2) have been identified as the disease-causing mutations in Rett Syndrome (RTT). However, no mutation in the AT-hook 1 domain of MECP2 has been reported in RTT yet. The function of AT-hook 1 domain of MECP2 has not been described either. Methods: The clinical and radiological features of a girl with progressive hyperactivity and loss of acquired linguistic and motor functions were presented. Next generation sequencing was used to screen the causative gene. Effect of the mutant protein on histone 3 methylation was assessed in vitro experiment. Results: The patient was diagnosed with an atypical RTT at the age of nine. Magnetic resonance imaging revealed a loss of whole-brain volume and abnormal myelination. Genetic analysis identified a de novo novel missense mutation of MECP2 (NM_004992, c.570G->A, p.Arg190His). This mutation is located in the AT-hook 1 domain of MeCP2 protein. Overexpression of the mutant MeCP2 in cultured neuroblastoma cells SH-SY5Y revealed increased level of dimethylated histone 3 lysine 9, a transcriptional repressor marker. Conclusion: A novel missense mutation in AT-hook 1 domain of MeCP2 was identified in a patient with atypical RTT. Clinical data and in vitro experiment result imply that R190H mutation in AT-hook1 may cause dysfunction of MeCP2 and be a pathogenic variant. PMID- 29137253 TI - G-T haplotype established by rs3785889-rs16941382 in GOSR2 gene is associated with coronary artery disease in Chinese Han population. AB - Objectives: The aim of the present study is to assess the association between the human GOSR2 gene and coronary artery disease using a haplotype-based case-control study in Chinese Han population. Methods: A total of 283 coronary artery disease patients and 280 controls were genotyped for the human GOSR2 gene (rs197932, rs3785889, rs197922, rs17608766, and rs16941382). Data were analyzed for three separate groups: the total subjects, men, and women. Results: For the total subjects, the frequency of the G-T haplotype established by rs3785889-rs16941382 was significantly higher in the coronary artery disease patients as compared to the control subjects (P=0.009). Multiple logistic regression analysis also confirmed that the subjects with G-T haplotype established by rs3785889 rs16941382 (homozygote) were found having significantly higher chance suffering from coronary artery disease than the ones without this haplotype (OR=1.887, P=0.007). Conclusions: The G-T haplotype established by rs3785889-rs16941382 may be a risk genetic marker for coronary artery disease patients in Chinese Han population. PMID- 29137254 TI - Quaking-5 suppresses aggressiveness of lung cancer cells through inhibiting beta catenin signaling pathway. AB - Quaking-5 (QKI-5) belongs to the STAR (signal transduction and activation of RNA) family of RNA binding proteins and functions as a tumor suppressor in several human malignancies. In this study, we attempt to elucidate the role of QKI-5 in the pro-metastasis processes of lung cancer (LC) cells and the underlying mechanisms. We confirmed that QKI-5 was decreased in human LC tissues and cell lines, especially in high-metastatic cells. Moreover, QKI expression was positively correlated with LC patients' survival. Functional studies verified that QKI-5 suppressed migration, invasion and TGF-beta1-induced epithelial mesenchymal transition (EMT) of LC cells. Mechanistically, we affirmed that QKI-5 reduced beta-catenin level in LC cells via suppressing its translation and promoting its degradation, whereas QKI-5 promoter hypermethylation suppressed QKI 5 expression. Our findings indicate that QKI-5 inhibits pro-metastasis processes of LC cells through interdicting beta-catenin signaling pathway, and that QKI-5 promoter hypermethylation is a crucial epigenetic regulation reducing QKI-5 expression in LC cells, and reveal that QKI-5 is a potential prognostic biomarker for LC patients. PMID- 29137255 TI - Potential genotoxic and cytotoxicity of emamectin benzoate in human normal liver cells. AB - Pesticide residue inducing cancer-related health problems draw people more attention recently. Emamectin benzoate (EMB) has been widely used in agriculture around the world based on its specificity targets. Although potential risk and the molecular mechanism of EMB toxicity to human liver has not been well characterized. Unlike well-reported toxicity upon central nervous system, potential genotoxic and cytotoxicity of EMB in human liver cell was ignored and very limited. In this study, we identify genotoxicity and cytotoxicity of EMB to human normal liver cells (QSG7701 cell line) in vitro. We demonstrate that EMB inhibited the viability of QSG7701 cells and induced the DNA damage. Established assays of cytotoxicity were performed to characterize the mechanism of EMB toxicity on QSG7701 cells. Typical chromatin condensation and DNA fragmentation indicated the apoptosis of QSG7701 cells induced by EMB. And the intracellular biochemical results demonstrated that EMB-enhanced apoptosis of QSG7701 cells concurrent with generated ROS, a loss of mitochondrial membrane potential, the cytochrome-c release, up regulate the Bax/Bcl-2 and the activation of caspase-9/ 3. Our results of EMB induces the death of QSG7701 cells maybe via mitochondrial mediated intrinsic apoptotic pathways would contribute to promote the awareness of EMB as an extensive used pesticide to human being effects and reveal the underlying mechanisms of potential genotoxic. PMID- 29137256 TI - QiShenYiQi pill attenuates atherosclerosis by promoting regulatory T cells, inhibiting T helper 17 cells and accelerating cholesterol excretion. AB - Objective: The aim of this study was to explore potential immunoregulatory mechanisms underlying the suppressive effect on atherosclerosis of QiShenYiQi pill (QSYQ). Methods and Results: Male ApoE-/- mice were maintained on a Western type diet and QSYQ treatment for eight weeks. Determination of atherosclerosis demonstrated that QSYQ attenuated plaque formation and decreased the level of blood low-density lipoproteins-cholesterol. QSYQ treatment did not affect body weight but reduced the ratio of liver weight and body weight. Western blots of liver showed that QSYQ increased the expression of liver X receptor alpha and ATP binding cassette sub-family G member 5. Western blots of atherosclerotic aorta revealed that QSYQ inhibited the expression of cluster of differentiation 36, promoted the expression of forkhead box P3 and decreased interleukin-17A expression. Western blots of spleen showed that QSYQ decreased the expression of mothers against decapentaplegic homolog 2/3 and forkhead box P3, as well as attenuated the expression of spleen interleukin-6, RAR-related orphan receptor gamma and interleukin-17A. Conclusions: QSYQ exerted an anti-atherosclerosis effect by promoting regulatory T cells in atherosclerotic lesion, inhibiting T helper 17 cells in plaque and spleen and accelerating liver cholesterol excretion. PMID- 29137257 TI - Kaempferol induces hepatocellular carcinoma cell death via endoplasmic reticulum stress-CHOP-autophagy signaling pathway. AB - Kaempferol is a flavonoid compound that has gained widespread attention due to its antitumor functions. However, the underlying mechanisms are still not clear. The present study investigated the effect of kaempferol on hepatocellular carcinoma and its underlying mechanisms. Kaempferol induced autophagy in a concentration- and time-dependent manner in HepG2 or Huh7 cells, which was evidenced by the significant increase of autophagy-related genes. Inhibition of autophagy pathway, through 3-methyladenine or Atg7 siRNA, strongly diminished kaempferol-induced apoptosis. We further hypothesized that kaempferol can induce autophagy via endoplasmic reticulum (ER) stress pathway. Indeed, blocking ER stress by 4-phenyl butyric acid (4-PBA) or knockdown of CCAAT/enhancer-binding protein homologous protein (CHOP) with siRNA alleviated kaempferol-induced HepG2 or Huh7 cells autophagy; while transfection with plasmid overexpressing CHOP reversed the effect of 4-PBA on kaempferol-induced autophagy. Our results demonstrated that kaempferol induced hepatocarcinoma cell death via ER stress and CHOP-autophagy signaling pathway; kaempferol may be used as a potential chemopreventive agent for patients with hepatocellular carcinoma. PMID- 29137258 TI - Aberrantly activated Cox-2 and Wnt signaling interact to maintain cancer stem cells in glioblastoma. AB - Glioblastoma recurrence after aggressive therapy typically occurs within six months, and patients inevitably succumb to their disease. Tumor recurrence is driven by a subpopulation of cancer stem cells in glioblastoma (glioblastoma stem like cells, GSCs), which exhibit resistance to cytotoxic therapies, compared to their non-stem-cell counterparts. Here, we show that the Cox-2 and Wnt signaling pathways are aberrantly activated in GSCs and interact to maintain the cancer stem cell identity. Cox-2 stimulates GSC self-renewal and proliferation through prostaglandin E2 (PGE2), which in turn activates the Wnt signaling pathway. Wnt signaling underlies PGE2-induced GSC self-renewal and independently directs GSC self-renewal and proliferation. Inhibition of PGE2 enhances the effect of temozolomide on GSCs, but affords only a modest survival advantage in a xenograft model in the setting of COX-independent Wnt activation. Our findings uncover an aberrant positive feedback interaction between the Cox-2/PGE2 and Wnt pathways that mediates the stem-like state in glioblastoma. PMID- 29137259 TI - Iron-responsive element-binding protein 2 plays an essential role in regulating prostate cancer cell growth. AB - Iron-responsive element-binding proteins (IRPs) are master regulators of cellular iron homeostasis. Our previous work demonstrated that iron homeostasis is altered in prostate cancer and contributes to prostate cancer progression. Here we report that prostate cancer cells overexpress IRP2 and that overexpression of IRP2 drives the altered iron phenotype of prostate cancer cells. IRP2 knockdown in prostate cancer cell lines reduces intracellular iron and causes cell cycle inhibition and apoptosis. Cell cycle analysis demonstrates that IRP2-depleted prostate cancer cells accumulate in G0/G1 due to induction of p15, p21, and p27. Activation of these pathways is sufficient to significantly reduce the growth of PC3 prostate tumors in vivo. In contrast, IRP1 knockdown does not affect iron homeostasis and only modestly affects cell growth, likely through an iron independent mechanism. These results demonstrate that upregulation of IRP2 in prostate cancer cells co-opts normal iron regulatory mechanisms to facilitate iron retention and drive enhanced tumor growth. PMID- 29137260 TI - Pathologic subtype-defined prognosis is dependent on both tumor stage and status of oncogenic driver mutations in lung adenocarcinoma. AB - Previous studies have shown that the prognosis of lung adenocarcinoma is associated with pathological characterization. In this study, we investigated whether pathology-based prognosis was further influenced by both tumor stage and oncogenic driver mutations. To this end, we recruited a cohort of 465 lung adenocarcinoma patients in China. These patients were classified into 6 pathology defined subtypes i.e., lepidic-predominant adenocarcinoma (LPA), acinar predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary-predominant adenocarcinoma (MPA), solid-predominant adenocarcinoma (SPA), and invasive mucinous adenocarcinoma (IMA). Oncogenic mutations in EGFR, KRAS, ALK, RET, and BRAF genes were determined using fluorescent real-time RT PCR. The associations of pathogenic subtype or oncogenic mutation with clinical characteristics were analyzed using Fisher's exact tests. The interactive effects on overall survival (OS) by pathologic subtype, oncogenic mutations, and tumor stage were also determined. We have found that pathogenic subtype of lung adenocarcinoma correlated with smoking habit and tumor cell differentiation. These pathology-defined subtypes can be regrouped into 3 pathology-based prognostic groups: PPG1 (LPA), PPG2 (IMA+APA+PPA), and PPG3 (MPA+SPA) with a favorable, intermediate, and poor OS, respectively. We further demonstrated that this pathology-determined OS can be affected by both tumor stage and status of oncogenic mutations in EGFR, KRAS, ALK, RET, and BRAF genes. Interestingly, the presence of genetic mutations related to ALK, RET and BRAF had an opposite effect on OS between PPG2 (worsen) and PPG3 (improved) patients, reversing the prognostic favorability for patients within these two groups. In conclusion, prognosis of lung adenocarcinoma was defined interactively by pathologic subtype, tumor stage and oncogenic mutation. PMID- 29137261 TI - Enhanced response of melanoma cells to MEK inhibitors following unbiased IGF-1R down-regulation. AB - Due to its ability to compensate for signals lost following therapeutic MAPK inhibition, insulin-like growth factor type 1 receptor (IGF-1R) co-targeting is a rational approach for melanoma treatment. However IGF-1R conformational changes associated with its inhibition can preferentially activate MAPK-pathway in a kinase-independent manner, through a process known as biased signaling. We explored the impact of biased IGF-1R signaling, on response to MAPK inhibition in a panel of skin melanoma cell lines with differing MAPK and p53 mutation statuses. Specific siRNA towards IGF-1R down-regulates the receptor and all its signaling in a balanced manner, whilst IGF-1R targeting by small molecule Nutlin 3 parallels receptor degradation with a transient biased pERK1/2 activity, with both strategies synergizing with MEK1/2 inhibition. On the other hand, IGF-1R down-regulation by a targeted antibody (Figitumumab) induces a biased receptor conformation, preserved even when the receptor is exposed to the balanced natural ligand IGF-1. This process sustains MAPK activity and competes with the MEK1/2 inhibition. Our results indicate that IGF-1R down-regulation offers an approach to increase the sensitivity of melanoma cells to MAPK inhibition, and highlights that controlling biased signaling could provide greater specificity and precision required for multi-hit therapy. PMID- 29137262 TI - Disease spectrum of abnormal serum free light chain ratio and its diagnostic significance. AB - Objective: To analyze the spectrum of abnormal serum free light chain ratio (sFLC kappa/lambda ratio), and to redefine the range of sFLC kappa/lambda ratio, so as to achieve hierarchical diagnosis of diseases with abnormal sFLC kappa/lambda ratio, resulting in the increased sensitivity and specificity in the diagnosis of monoclonal plasma diseases. Methods: Enrolled 1,340 patients with abnormal sFLC kappa/lambda ratio (<0.26 or >1.65) were grouped: (1) group A: malignant plasma diseases; (2) group B: monoclonal gammopathies of undetermined significance (MGUS); (3) group C: reactive plasma diseases. These patients were further divided by renal function eGFR <60 or >60 ml/min/1.73m2 to eliminate renal diseases influencing the results. Statistical analyses was performed by using SPSS 22 software. Results: When sFLC kappa/lambda ratio >3.49 and eGFR >60ml/min/1.73m2, the sensitivity and specificity of the diagnosis of malignant plasma diseases were 86.1% and 94.0%, respectively. When sFLC kappa/lambda ratio >2.89 and eGFR <60ml/min/1.73m2, the sensitivity and specificity of the diagnosis of malignant plasma diseases were 92.0% and 97.0%, respectively. Conclusion: The sensitivity and specificity of the diagnosis of monoclonal plasma diseases can be significantly improved by redefining the cut-off value of sFLC kappa/lambda ratio and the renal function index of eGFR. PMID- 29137263 TI - Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT mediated HIF-1alpha inactivation. AB - Melatonin is the primary pineal hormone that relays light/dark cycle information to the circadian system. It was recently reported to exert intrinsic antitumor activity in various cancers. However, the regulatory mechanisms underlying the antitumor activity of melatonin are poorly understood. Moreover, a limited number of studies have addressed the role of melatonin in hepatocellular carcinoma (HCC), a major life-threatening malignancy in both sexes in Taiwan. In this study, we investigated the antitumor effects of melatonin in HCC and explored the regulatory mechanisms underlying these effects. We observed that melatonin significantly inhibited the proliferation, migration, and invasion of HCC cells and significantly induced the expression of the transcription factor FOXA2 in HCC cells. This increase in FOXA2 expression resulted in upregulation of lncRNA-CPS1 intronic transcript 1 (CPS1-IT1), which reduced HIF-1alpha activity and consequently resulted in the suppression of epithelial-mesenchymal transition (EMT) progression and HCC metastasis. Furthermore, the results of the in vivo experiments confirmed that melatonin exerts tumor suppressive effects by reducing tumor growth. In conclusion, our findings suggested that melatonin inhibited HCC progression by reducing lncRNA-CPS1-IT1-mediated EMT suppression and indicated that melatonin could be a promising treatment for HCC. PMID- 29137264 TI - Preoperative chemoradiotherapy for rectal cancer: the sensitizer role of the association between miR-375 and c-Myc. AB - Administration of chemoradiation before tumor resection has revolutionized the management of locally advanced rectal cancer, but many patients have proven resistant to this preoperative therapy. Our group recently reported a negative correlation between c-Myc gene expression and this resistance. In the present study, integrated analysis of miRNA and mRNA expression profiles was conducted in 45 pre-treatment rectal tumors in order to analyze the expressions of miRNAs and c-Myc and their relationship with clinicopathological factors and patient survival. Twelve miRNAs were found to be differentially expressed by responders and non-responders to the chemoradiation. Functional classification revealed an association between the differentially expressed miRNAs and c-Myc. Quantitative real-time PCR results showed that miRNA-148 and miRNA-375 levels were both significantly lower in responders than in non-responders. Notably, a significant negative correlation was found between miRNA-375 expression and c-Myc expression. According to these findings, miRNA-375 and its targeted c-Myc may be useful as a predictive biomarker of the response to neoadjuvant treatment in patients with locally advanced rectal cancer. PMID- 29137265 TI - c-Met, CREB1 and EGFR are involved in miR-493-5p inhibition of EMT via AKT/GSK 3beta/Snail signaling in prostate cancer. AB - miR-493-5p downregulation has emerged as a critical player in cancer progression yet, the underlying mechanisms of miR-493-5p expression pattern and its function in prostate cancer remains to be elucidated. Here, we illustrate that miR-493-5p is frequently downregulated in prostate cancer, at least partially due to altered DNA methylation. miR-493-5p functions as a tumor suppressor in prostate cancer cells. c-Met, CREB1 and EGFR are downstream target genes of miR-493-5p. miR-493 5p inhibits EMT via AKT/GSK-3beta/Snail signaling in prostate cancer. Taken together, our study identified c-Met, CREB1, EGFR and miR-493-5p establish a regulatory loop in prostate cancer, which could prove useful in the development of effective and therapies against prostate cancer. PMID- 29137266 TI - Correlation of placental microbiota with fetal macrosomia and clinical characteristics in mothers and newborns. AB - Substantial studies indicated that fetal macrosomia was associated with detrimental pregnancy outcomes, and increased susceptibility to metabolic diseases in later life. However, investigations into the association between placental microbiota and fetal macrosomia are limited. We aimed to profile the placental microbiota of fetal macrosomia and study whether they relate to clinical characteristics. Placenta samples were collected from fetal macrosomias and newborns with normal birth weight. The clinical characteristics, umbilical cord blood parameters were measured, and placental microbiota were sequenced and further analysed. The clinical characteristics of infants and mothers and umbilical cord blood parameters were significantly different between macrosomias and controls. The relative abundance of microbiota sequences revealed that microbial structures of the placenta differed significantly between macrosomia and controls. Regression analysis showed a cluster of key operational taxonomic unit (OTUs), phyla and genera were significantly correlated with body length, ponderal index and placenta weight, body weight increase during pregnancy of mothers, and cord blood IGF-1 and leptin concentrations. In conclusion, our study for the first time explored the relationship between placental microbiota profile and fetal macrosomia. It is novel in showing that a distinct placental microbiota profile is present in fetal macrosomia, and is associated with clinical characteristics of mothers and newborns. PMID- 29137268 TI - Understanding the mechanism of binding between Gab2 and the C terminal SH3 domain from Grb2. AB - Gab2 is a large disordered protein that regulates several cellular signalling pathways and is overexpressed in different forms of cancer. Because of its disordered nature, a detailed characterization of the mechanisms of recognition between Gab2 and its physiological partners is particularly difficult. Here we provide a detailed kinetic characterization of the binding reaction between Gab2 and the C-terminal SH3 domain of the growth factor receptor-bound protein 2 (Grb2). We demonstrate that Gab2 folds upon binding following an induced fit type mechanism, whereby recognition is characterized by the formation of an intermediate, in which Gab2 is primarily disordered. In this scenario, folding of Gab2 into the bound conformation occurs only after binding. However, an alanine scanning of the proline residues of Gab2 suggests that the intermediate contains some degree of native-like structure, which might play a role for the recognition event to take place. The results, which represent a fundamental step forward in the understanding of this functional protein-protein interaction, are discussed on the light of previous structural works on these proteins. PMID- 29137267 TI - Tumacrophage: macrophages transformed into tumor stem-like cells by virulent genetic material from tumor cells. AB - Tumor-associated macrophages are regarded as tumor-enhancers as they have key roles in the subversion of adaptive immunity and in inflammatory circuits that promote tumor progression. Here, we show that cancer cells can subvert macrophages yielding cells that have gained pro-tumor functions. When macrophages isolated from mice or humans are co-cultured with dead cancer cell line cells, induced to undergo apoptosis to mimic chemotherapy, up-regulation of pro-tumor gene expression was identified. Phagocytosis of apoptotic cancer cells by macrophages resulted in their transformation into tumor stem (initiating)-like cells, as indicated by the expression of epithelial markers (e.g., cytokeratin) and stem cell markers (e.g., Oct4) and their capability to differentiate in vitro and self-renew in serum-free media. Moreover, we identified a subset of monocytes/macrophages cells in the blood of cancer (breast, ovarian and colorectal) patients undergoing chemotherapy that harbor tumor transcripts. Our findings uncover a new role for macrophages in tumor development, where they can be transformed into tumor-like cells, potentially by horizontal gene transfer of tumor-derived genes, thus, by taking advantage of chemotherapy, these transformed macrophages promote tumor metastasis by escaping immune surveillance. PMID- 29137269 TI - Local blockage of self-sustainable erythropoietin signaling suppresses tumor progression in non-small cell lung cancer. AB - Functional significance of co-expressed erythropoietin (EPO) and its receptor (EPOR) in non-small cell lung cancer (NSCLC) had been under debate. In this study, co-overexpression of EPO/EPOR was confirmed to be positively associated with poor survival in NSCLC. The serum EPO in 14 of 35 enrolled NSCLC patients were found elevated significantly and decreased to normal level after tumor resection. With primary tumor cell culture and patient-derived tumor xenograft (PDX) mouse model, the EPO secretion from the tumors of these 14 patients was verified. Then, we proved the patient derived serum EPO was functionally active and had growth promotion effect in EPO/EPOR overexpressed but not in EPO/EPOR under-expressed NSCLC cells. We also illustrated EPO promoted NSCLC cell proliferation through an EPOR/Jak2/Stat5a/cyclinD1 pathway. In xenograft mouse model, we proved local application of EPO neutralizing antibody and short hairpin RNA (shRNA) against EPOR effectively inhibited the growth of EPO/EPOR overexpressed NSCLC cells and prolonged survivals of the mice. Finally, EPO/EPOR/Jak2/Stat5a/cyclinD1 signaling was found to be a mediator of hypoxia induced growth in EPO/EPOR overexpressed NSCLC. Our results illustrated a subgroup of NSCLC adapt to hypoxia through self-sustainable EPO/EPOR signaling and suggest local blockage of EPO/EPOR as potential therapeutic method in this distinct NSCLC population. PMID- 29137270 TI - Human mesenchymal stem cells ameliorate experimental pulmonary hypertension induced by maternal inflammation and neonatal hyperoxia in rats. AB - Pulmonary hypertension is a critical problem in infants with bronchopulmonary dysplasia. This study determined the therapeutic effects of human mesenchymal stem cells (MSCs) on pulmonary hypertension in an animal model. Pregnant Sprague Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS, 0.5 mg/kg/day) on gestational days 20 and 21. The pups were randomly assigned to two treatment conditions: room air (RA) or an O2-enriched atmosphere. On postnatal day 5, they were intratracheally transplanted with human MSCs (3 * 105 and 1 * 106 cells) in 0.03 mL of normal saline (NS). Five study groups were examined: normal, LPS+RA+NS, LPS+O2+NS, LPS+O2+MSCs (3 * 105 cells), and LPS+O2+MSCs (1 * 106 cells). On postnatal day 14, the pup lungs and hearts were collected for histological examinations. The LPS+RA+NS and LPS+O2+NS groups exhibited a significantly higher right ventricle (RV):left ventricle (LV) thickness ratio and medial wall thickness (MWT) and higher beta-myosin heavy chain (beta-MHC) and toll-like receptor (TLR) 4 expression than did the normal group. Human MSC transplantation in LPS- and O2-treated rats reduced the MWT, RV:LV thickness ratio, and beta-MHC and TLR4 expression to normal levels. Thus, intratracheal human MSC transplantation ameliorates pulmonary hypertension, probably by suppressing TLR4 expression in newborn rats. PMID- 29137271 TI - Environmental conditions differentially affect neurobehavioral outcomes in a mouse model of sepsis-associated encephalopathy. AB - Brain dysfunction remains a common complication after sepsis development and is an independent risk factor for a poorer prognosis and an increased mortality. Here we tested the hypothesis that the behavioral outcomes after lipopolysaccharides (LPS) administration are exacerbated by an impoverished environment (IE) and alleviated by an enriched environment (EE), respectively. Mice were randomly allocated in a standard environment (SE), an EE, or an IE for 4 weeks after LPS or normal saline (NS) administration. Neurobehavioral alternations were assessed by the open field, novel objective recognition, and fear conditioning tests. The expressions of proinflammatory cytokines (tumor necrosis factor (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-10), ionized calcium-binding adaptor molecule-1 (IBA1)-positive cells as well as glial fibrillary acidic protein (GFAP)-positive cells, brain derived neurotrophic factor (BDNF), 5-bromo-2-deoxyuridine-labeled cells in the dentate gyrus of the hippocampus, and the number of dendritic spines in the hippocampal CA1 were determined. Our results showed that the some of the neurocognitive abnormalities induced by LPS administration can be aggravated by stressful conditions such as IE but alleviated by EE. These neurocognitive alternations were accompanied by significant changes in biomarkers of immune response and hippocampal synaptic plasticity. In summary, our study confirmed the negative impact of IE and the positive effects of EE on the cognitive function after LPS administration, with potential implications to the basis of sepsis-related cognitive impairments in the critically ill patients. PMID- 29137272 TI - Immunological cytokine profiling identifies TNF-alpha as a key molecule dysregulated in autistic children. AB - Recent studies have suggested that the etiology of autism spectrum disorder (ASD) may be caused by immunological factors, particularly abnormalities in the innate immune system. However, it is still unclear which specific cytokines may be of most importance. The current study therefore investigated which cytokines showed altered concentrations in blood in ASD compared with healthy control children and which were also correlated with symptom severity. Our study sample included 32 children diagnosed with ASD and 28 age and sex-matched typically developing children. Autism symptoms were measured using the Autistic Behavior Checklist (ABC) and blood samples were taken from all subjects. We used Milliplex cytokine kits to determine serum concentrations of 11 Th1, Th2 and Th17 related cytokines. Additionally, expression of THRIL (TNFalpha and hnRNPL related immunoregulatory LincRNA), a long non-coding RNA involved in the regulation of tumor necrosis factor- alpha (TNF-alpha), was determined using real-time PCR. Of the 11 cytokines measured only concentrations of TNF-alpha (p=0.002), IL-1beta (p=0.02) and IL-17a (p=0.049) were significantly increased in ASD children compared to typically developing controls, but only TNF-alpha concentrations were positively correlated with severity of ASD symptoms on all 5 different ABC sub-scales and were predictive of an ASD phenotype (area under the curve = 0.74). Furthermore, THRIL RNA expression was significantly decreased in ASD children. Our results provide further support for altered innate immunity being an important autism pathogenic factor, with autistic children showing increased blood TNF-alpha concentrations associated with symptom severity, and decreased expression of the THRIL gene involved in regulating TNF-alpha. PMID- 29137273 TI - Programmed death ligand-1 and MET co-expression is a poor prognostic factor in gastric cancers after resection. AB - Programmed death-ligand 1 (PD-L1) plays an essential protein for immune evasion, contributing to tumor development and progression. Recent studies have reported MET as an upregulator for PD-L1 overexpression through an oncogenic pathway. However, an association between PD-L1 expression with MET has not been reported in gastric cancer.The prognostic significance of PD-L1 and its association with Epstein-Barr virus (EBV), microsatellite instability (MSI), and mucin phenotype remain controversial. We performed in situ hybridization for EBV-encoded RNA and immunohistochemistry in tissue microarrays for 394 gastric cancers. A multiplex polymerase chain reaction with five quasimonomorphic markers was performed for MSI. PD-L1 expression was observed in 123 cases (31.2%), and clinicopathological features such as MET overexpression, high pT stage, and a lack of lymphatic invasion represent significant risk factors associated with PD-L1 overexpression in gastric cancers. No associations of EBV, MSI, or mucin phenotype with PD-L1 expression were statistically significant. PD-L1 expression was a strong indicator for worse overall survival (OS) but borderline significant in disease free survival (DFS). A combined analysis of PD-L1 and MET expression indicated that the PD-L1+/MET+ subgroup showed the worst prognosis when compared to the PD L1-/MET- subgroup, which had the best clinical outcome. Furthermore, PD-L1 overexpression exhibited poor prognosis in terms of both OS and DFS in EBV negative, microsatellite stable, and intestinal mucin phenotype tumors. In conclusion, this is the first study to evaluate the overexpression of MET as a risk factor for PD-L1 positivity in gastric cancer tissue as well as the reliability and prognostic relevance of PD-L1/MET co-expression after surgery. PMID- 29137274 TI - Effective protection against acute respiratory distress syndrome/sepsis injury by combined adipose-derived mesenchymal stem cells and preactivated disaggregated platelets. AB - This study assessed whether combining adipose-derived mesenchymal stem cells (ADMSC) with preactivated, disaggregated shape-changed platelets (PreD-SCP) was superior to either therapy alone for protecting rat lung from acute respiratory distress syndrome (ARDS) complicated by sepsis. ARDS and sepsis were induced through 100% oxygen inhalation and peritoneal administration of 1.5 mg/kg lipopolysaccharide (LPS), respectively. Adult-male Sprague-Dawley rats (n=40) were randomized into sham-control (SC), ARDS-LPS, ARDS-LPS-ADMSC (1.2x106 cells), ARDS-LPS-PreD-SCP (3.0x108, intravenous administration), and ARDS-LPS-ADMS/PreD SCP groups, and were sacrificed 72 h after 48 h ARDS induction. Lung injury scores (LIS) and collagen deposition were highest in ARDS-LPS, lowest in SC, higher in ARDS-LPS+ADMSC than in ARDS-LPS+PreD-SCP and ARDS-LPS+ADMS/PreD-SCP, and higher in ARDS-LPS+PreD-SCP than in ARDS-LPS+ADMS/PreD-SCP (all p<0.0001). Alveolar-sac numbers, oxygen saturation, endothelial marker levels, and mitochondrial cytochrome-C levels exhibited opposite patterns with respect to LIS (all p<0.001). Levels of inflammatory, oxidative-stress, apoptosis, mitochondrial/DNA damage, and MAPK and Akt signaling markers exhibited patterns identical to that of LIS (all p<0.001). Anti-oxidant and anti-inflammatory protein levels increased progressively from SC to ARDS-LPS+ADMS/PreD-SCP (all p<0.0001). These findings indicate combined ADMSC/PreD-SCP was superior to either therapy alone for protecting rat lung from ARDS-sepsis injury. PMID- 29137275 TI - Vinculin and filamin-C are two potential prognostic biomarkers and therapeutic targets for prostate cancer cell migration. AB - Prostate cancer (PCa) is one of the most common diseases for male population, and the effective treatment for metastatic castration-resistant PCa is still lacking. To unravel the underlying mechanism of PCa cell migration, we plan to analyze the related crucial proteins and their roles. In our study, we firstly identify the differentially expressed proteins using quantitative proteomics, and confirm their mRNA expression using quantitative polymerase chain reaction (qPCR). The alterations of these proteins at DNA and mRNA levels are obtained from cBioPortal database. Furthermore, the functions of these proteins are evaluated using wound healing assay. The quantitative proteomics identified vinculin (VCL) and filamin C (FLNC) as two highly expressed proteins in PC3 cells, and the DNA and mRNA of these two proteins were amplified and upregulated in a part of PCa patients. Knockdown of VCL and FLNC gene expression significantly inhibit PCa cell migration. These findings suggest that VCL and FLNC identified by quantitative proteomics are highly expressed in PCa cells with high migration potential, and they could be effective targets for repressing PCa cell migration, paving a new avenue for the prognosis and treatment of advanced PCa. PMID- 29137276 TI - Potential clinical value of PET/CT in predicting occult nodal metastasis in T1 T2N0M0 lung cancer patients staged by PET/CT. AB - We assessed the clinical value of 2-fluoro-2-deoxyglucose (18F-FDG) PET/CT imaging for predicting occult nodal metastasis in non-small cell lung cancer (NSCLC) patients. This retrospective study included 54 patients with T1-2N0M0 NSCLC who had undergone 18F-FDG PET/CT before surgery. Occult nodal metastasis was detected in 25.9% (14/54) of the patients. Immunohistochemical analysis revealed that increased glucose transporter 1 expression was associated with occult nodal metastasis, but hexokinase 2 expression was not. Compared to the negative nodal metastasis group, the positive nodal metastasis group was associated with increased maximum standardized uptake value (SUVmax) and tumor size. Multivariate analysis indicated that SUVmax and tumor size were associated with nodal metastasis. Nodal metastasis could be predicted with a sensitivity of 92.9% and a specificity of 55.0% when the SUVmax cutoff was 4.35. When patients were divided into low-risk (tumor size <= 2.5 cm and SUVmax <= 4.35), moderate risk (tumor size <= 2.5 cm and SUVmax > 4.35 or tumor size > 2.5 cm and SUVmax <= 4.35) and high-risk (tumor size > 2.5 cm and SUVmax > 4.35) groups, the lymph node metastasis rates were 4.3%, 22.7%, and 88.9%, respectively. These results indicate that the combination of SUVmax and tumor size has potential clinical value for predicting occult nodal metastasis in NSCLC patients. PMID- 29137277 TI - Ningnanmycin inhibits tobacco mosaic virus virulence by binding directly to its coat protein discs. AB - Tobacco mosaic virus (TMV) causes severe plant diseases worldwide; however, effective antiviral agents for controlling TMV infections are not available. This lack of effective antiviral agents is mainly due to the poor understanding of potential targets associated with TMV infections. During infection, the coat protein (CP), which is delivered by viral particles into susceptible host cells, provides protection for viral RNA. Here, we found that Ningnanmycin (NNM), a commercially used plant antibacterial agent, inhibits the assembly of the CP by directly binding several residues. These interactions cause the disassembly of the CP from discs into monomers, leading to an almost complete loss of pathogenicity. Substitutions in the involved binding residues resulted in mutants that were significantly less sensitive to NNM. Thus, targeting the binding of viral CPs through small molecular agents offers an effective strategy to study the mechanism of NNM. PMID- 29137278 TI - Comprehensive microRNA-sequencing of exosomes derived from head and neck carcinoma cells in vitro reveals common secretion profiles and potential utility as salivary biomarkers. AB - Exosomes are nano-scale, membrane encapsulated vesicles that are released by cells into the extracellular space and function as intercellular signaling vectors through horizontal transfer of biologic molecules, including microRNA (miRNA). There is evidence that cancer-derived exosomes enable the tumor to manipulate its microenvironment, thus contributing to the capacity of the tumor for immune evasion, growth, invasion, and metastatic spread. The objective of this study was to characterize differential secretion of exosomal miRNA by head and neck squamous cell carcinoma (HNSCC) and identify a set of candidate biomarkers that could be detected in non-invasive saliva samples. We isolated exosomes from conditioned media from 4 HNSCC cell lines and oral epithelial control cells and applied miRNA-sequencing to comprehensively characterize their miRNA cargo and compare transcript levels of each HNSCC cell line to that of oral epithelial control cells. A candidate set of miRNA differentially secreted by all 4 HNSCC cell lines was further evaluated in saliva collected from HNSCC patients and healthy controls. We observed extensive differences in exosomal miRNA content between HNSCC cells when compared to normal oral epithelial control cells, with a high degree of overlap in exosomal miRNA profiles between the 4 distinct HNSCC cell lines. Importantly, several of the exosomal miRNA secreted solely by cancer cells in culture were detected at substantially elevated levels in saliva from HNSCC patients relative to saliva from healthy controls. These findings provide important insight into tumor biology and yields a promising set of candidate HNSCC biomarkers for use with non-invasive saliva samples. PMID- 29137279 TI - Implications of mutational spectrum in myelodysplastic syndromes based on targeted next-generation sequencing. AB - Myelodysplastic syndromes (MDS) are a group of myeloid hematological malignancies, with a high risk of progression to acute myeloid leukemia (AML). To explore the role of acquired mutations in MDS, 111 MDS-associated genes were screened using next-generation sequencing (NGS), in 125 patients. One or more mutations were detected in 84% of the patients. Some gene mutations are specific for MDS and were associated with disease subtypes, and the patterns of mutational pathways could be associated with progressive MDS. The patterns, frequencies and functional pathways of gene mutations are different, but somehow related, between MDS and AML. Multivariate analysis suggested that patients with >= 2 mutations had poor progression-free survival, while GATA1/GATA2, DNMT3A and KRAS/NRAS mutations were associated with poor overall survival. Based on a novel system combining IPSS-R and molecular markers, these MDS patients were further divided into 3 more accurate prognostic subgroups. A panel of 11 target genes was proposed for genetic profiling of MDS. The study offers new insights into the molecular signatures of MDS and the genetic consistency between MDS and AML. Furthermore, results indicate that MDS could be classified by mutation combinations to guide the administration of individualized therapeutic interventions. PMID- 29137280 TI - PPARgamma sumoylation-mediated lipid accumulation in lung cancer. AB - Metabolic reprogramming as a crucial emerging hallmark of cancer is critical for tumor cells to maintain cellular bioenergetics, biosynthesis and reduction/oxidation (REDOX) balance. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor regulating transcription of diverse gene sets involved in inflammation, metabolism, and suppressing tumor growth. Thiazolidinediones (TZDs), as selective PPARgamma ligands, are insulin sensitizing drugs widely prescribed for type 2 diabetic patients in the clinic. Here, we report that sumoylation of PPARgamma couples lipid metabolism to tumor suppressive function of the receptor in lung cancer. We found that ligand activation of PPARgamma dramatically induced de novo lipid synthesis as well as fatty acid beta (beta)-oxidation in lung cancer both in vitro and in vivo. More importantly, it turns out that PPARgamma regulation of lipid metabolism was dependent on sumoylation of PPARgamma. Further biochemical analysis revealed that PPARgamma-mediated lipid synthesis depletes nicotinamide adenine dinucleotide phosphate (NADPH), consequently resulting in increased mitochondrial reactive oxygen species (ROS) level that subsequently disrupted REDOX balance in lung cancer. Therefore, liganded PPARgamma sumoylation is not only critical for cellular lipid metabolism but also induces oxidative stress that contributes to tumor suppressive function of PPARgamma. This study provides an important insight of future translational and clinical research into targeting PPARgamma regulation of lipid metabolism in lung cancer patients accompanying type 2 diabetes. PMID- 29137282 TI - Functional polymorphisms in the promoter region of miR-17-92 cluster are associated with a decreased risk of colorectal cancer. AB - miR-17-92 cluster is identified as a potential oncogenic miRNA. The aim of this study was to investigate the association of polymorphisms in the promoter region of miR-17-92 cluster with the risk of colorectal cancer (CRC). Three polymorphisms (i.e., rs9588884, rs982873 and rs1813389) in the promoter of miR-17 92 were analyzed among 874 cases and 1132 controls using a TaqMan allelic discrimination assay or a polymerase chain reaction-restriction fragment length polymorphism method. Relative expression of miR-17-92 was examined among CRC tumors and noncancerous tissues using quantitative reverse transcription-PCR. Transcriptional activities were measured using dual-luciferase reporter assay. We found a significantly reduced CRC risk with the rs9588884 (GG vs. CC: adjusted OR = 0.46, 95% CI, 0.35-0.62; dominant model: adjusted OR = 0.72, 95% CI, 0.59-0.86; recessive model: adjusted OR = 0.53, 95% CI, 0.40-0.69) and the rs982873 (CC vs. TT: adjusted OR = 0.60, 95%CI, 0.46-0.80; recessive model: adjusted OR = 0.62, 95% CI, 0.49-0.80). Haplotype analysis showed that the GCG haplotype had a decreased risk for CRC compared to the CTA haplotype (adjusted OR = 0.67, 95% CI, 0.57-0.79). The rs9588884 GG displayed a lower level of miR-20a and the rs982873 CC displayed a lower level of miR-17. Additionally, the rare allele of rs9588884 G and the rs982873 C revealed a reduced luciferase activity. These findings indicate that the rs9588884 GG and the rs982873 CC in the promoter of miR-17-92 may protect against CRC, possibly by decreasing transcriptional activity and eventually resulting in lower levels of miR-20a and miR-17. PMID- 29137281 TI - Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFbeta1-independent manner. AB - The molecular basis of epithelial ovarian cancer (EOC) dissemination is still poorly understood. We have previously identified the hydrogen peroxide-inducible clone-5 (Hic-5) gene as hypomethylated in high-grade (HG) serous EOC tumors, compared to normal ovarian tissues. Hic-5 is a focal adhesion scaffold protein and has been primarily studied for its role as a key mediator of TGF-beta-induced epithelial-to-mesenchymal transition (EMT) in epithelial cells of both normal and malignant origin; however, its role in EOC has been never investigated. Here we demonstrate that Hic-5 is overexpressed in advanced EOC, and that Hic-5 is upregulated upon TGFbeta1 treatment in the EOC cell line with epithelial morphology (A2780s), associated with EMT induction. However, ectopic expression of Hic-5 in A2780s cells induces EMT independently of TGFbeta1, accompanied with enhancement of cellular proliferation rate and migratory/invasive capacity and increased resistance to chemotherapeutic drugs. Moreover, Hic-5 knockdown in the EOC cells with mesenchymal morphology (SKOV3) was accompanied by induction of mesenchymal-to-epithelial transition (MET), followed by a reduction of their proliferative, migratory/invasive capacity, and increased drugs sensitivity in vitro, as well as enhanced tumor cell colonization and metastatic growth in vivo. The modulation of Hic-5 expression in EOC cells resulted in altered regulation of numerous EMT-related canonical pathways and was indicative for a possible role of Hic-5 in controlling EMT through a RhoA/ROCK mediated mechanism. To our knowledge, this is the first report examining the role of Hic-5 in EOC, and its role in maintaining the mesenchymal phenotype of EOC cells independently of exogenous TGFbeta1 treatment. PMID- 29137283 TI - C1q/Tumor necrosis factor-related protein-3 protects macrophages against LPS induced lipid accumulation, inflammation and phenotype transition via PPARgamma and TLR4-mediated pathways. AB - Macrophage inflammation and foam cell formation are critical events during the initiation and development of atherosclerosis (AS). C1q/tumor necrosis factor related protein-3 (CTRP3) is a novel adipokine with anti-inflammatory and cardioprotection properties; however, little is known regarding the influence of CTRP3 on AS. As macrophages play a key role in AS, this study investigated the effects of CTRP3 on macrophage lipid metabolism, inflammatory reactions, and phenotype transition, as well as underlying mechanisms, to reveal the relationship between CTRP3 and AS. CTRP3 reduced the number of lipid droplets, lowered cholesteryl ester (CE), total cholesterol (TC), and free cholesterol (FC) levels, reduced the CE/TC ratio, and dose-dependently inhibited TNFalpha, IL-6, MCP-1, MMP-9 and IL-1beta release in lipopolysaccharide (LPS)-stimulated THP-1 macrophages and mouse peritoneal macrophages. Pretreatment with CTRP3 effectively increased macrophage transformation to M2 macrophages rather than M1 macrophages. Western blotting showed that the specific NF-kappaB pathway inhibitor ammonium pyrrolidine dithiocarbamate (PDTC) or siRNA targeting PPARgamma/LXRalpha markedly strengthened or abolished the above-mentioned effects of CTRP3, respectively. These results show that CTRP3 inhibits TLR4-NF-kappaB pro-inflammatory pathways but activates the PPARgamma-LXRalpha-ABCA1/ABCG1 cholesterol efflux pathway. Taken together, CTRP3 participates in anti-lipid accumulation, anti-inflammation and macrophage phenotype conversion via the TLR4-NF-kappaB and PPARgamma-LXRalpha ABCA1/ABCG1 pathways and, thus, may have anti-atherosclerotic properties. PMID- 29137284 TI - Treatment strategy and prognostic factors for Krukenberg tumors of gastric origin: report of a 10-year single-center experience from China. AB - Background: Gastric cancer patient with ovarian metastasis is common in clinical practice, but it is still uncertain whether surgical resection of ovarian metastasis could improve the outcome. This study aimed to explore the survival benefit of metastasectomy plus chemotherapy over chemotherapy alone in the treatment of Krukenberg tumors arising from gastric cancer and to identify prognostic factors. Results: A total of 152 patients were identified, including 93 patients with synchronous ovarian metastasis and 59 patients with metachronous ovarian metastasis. Overall survival (OS) was significantly better in metastasectomy group relative to the non-metastasectomy group for patients with synchronous ovarian metastasis (19.0 months vs. 11.8 months; P < 0.001) and those with metachronous ovarian metastasis (24.6 months vs. 14.3 months; P = 0.02), respectively. Metastasectomy (hazard ration [HR] 0.486; 95% confidence interval [CI] 0.323-0.729; P < 0.001), peritoneal carcinomatosis (HR 1.934; 95% CI 1.230 3.049; P = 0.004), and expression status of ER-beta (HR 0.404; 95% CI 0.251 0.648; P < 0.001) and PR (HR 0.496; 95% CI 0.301-0.817; P < 0.001) were independent predictors of OS. Methods: All patients who were diagnosed with gastric cancer and ovarian metastases between January 2005 and December 2014 were included in the current study. Patients were subdivided according to treatment modality: the metastasectomy group (metastasectomy plus chemotherapy) and the non metastasectomy group (chemotherapy alone). The clinicopathological features and the treatment records were reviewed in detail and their association with survival were analyzed. Conclusion: Metastasectomy plus chemotherapy was associated with survival benefits in patients with Krukenberg tumors from gastric cancer. Metastasectomy, peritoneal carcinomatosis, and expression status of ER-beta and PR were independent prognostic factors for survival. PMID- 29137285 TI - Genetic and immune features of resectable malignant brainstem gliomas. AB - We surveyed common genetic mutations (IDH1, H3F3A, PPM1D, and TP53) and immune features (PD-L1 expression and CD8+ T cell tumor infiltration) in a series of 62 malignant brainstem gliomas that were resected via microsurgery. IDH1 mutations were mutually exclusive with H3F3A mutations. IDH1 mutations appeared only in adults and occurred more frequently in tumors larger than 10cm3 (8/29 vs 1/32, Fisher's exact test, p=0.010). H3F3A mutations occurred more frequently in children and adolescent patients (19/24 vs 18/38, chi-square test, p=0.013), low preoperative Karnofsky Performance Scale (KPS) patients (10/11 vs 20/43, chi square test, p=0.021), and higher grade brainstem gliomas (8/21 in grade II vs 16/24 in grade III vs 13/17 in grade IV; chi-square test, p=0.038). PPM1D mutations clustered in H3F3A-mutated tumors (12/37), whereas were rare in H3F3A wildtype tumors (1/25). MGMT promoter methylations clustered in IDH1-mutated tumors (4/9), but were rare in H3F3A-mutated tumors (1/37). PD-L1 staining was detected in 59.7% of brainstem glioma specimens (37/62). High intra-tumoral CD8+ T cell density was less frequent in the H3F3A-mutated than H3F3A-wild-type tumors (4/37 vs. 11/25, p=0.005). Patients with H3F3A-mutated tumors (13.8 months overall survival) had much worse prognoses than those with IDH1-mutated (54.9 months, p=0.001) or H3F3A-IDH1 co-wildtype tumors (38.4 months, p=0.001). H3F3A mutations independently increased the relative risk of death as much as 4.19-fold according to a multivariate Cox regression model. Taken together, resectable malignant brainstem gliomas can be classified into three subtypes: H3F3A-mutated, IDH1 mutated and H3F3A-IDH1 co-wildtype tumors, which have distinct clinical characteristics, prognoses, genetic and immune features. PMID- 29137286 TI - Fibroblast growth factor modulates mast cell recruitment in a murine model of prostate cancer. AB - Mast cells are important modifiers of prostate tumor microenvironment. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system plays a non-redundant autocrine/paracrine role in the growth, vascularization and progression of prostate tumors. Accordingly, the FGF antagonist long pentraxin-3 (PTX3) and the PTX3-derived small molecule FGF-trap NSC12 have been shown to inhibit the growth and vascularization of different FGF-dependent tumor types, including prostate cancer. In this study, we show that recombinant FGF2 is able to cause mast cell recruitment in vivo in the Matrigel plug assay. Conversely, PTX3 overexpression in transgenic mice or treatment with the FGF inhibitor NSC12 result in a significant inhibition of the growth and vascularization of TRAMP-C2 tumor grafts, a murine model of prostate cancer, that were paralleled by a decrease of mast cell infiltrate into the lesion. These data confirm and extend previous observations about the capacity of mast cells to respond chemotactically to FGF2 stimulation and provide evidence about a relationship among mast cell recruitment, angiogenesis, and tumor growth in human prostate adenocarcinoma. PMID- 29137287 TI - N-myc downstream-regulated gene 1 promotes apoptosis in colorectal cancer via up regulating death receptor 4. AB - The aim of this study was to evaluate the clinical significance of N-myc downstream-regulated gene 1 (NDRG1) in colorectal cancer (CRC) patients and to explore the mechanisms governing the role of NDRG1 in apoptosis of CRC cells. In the current study, we found that NDRG1 was a prognostic marker of CRC patients. Moreover, NDRG1 expression negatively correlated to tumor size and clinical TNM stage, suggesting that NDRG1 might act as a tumor suppressor by inhibiting proliferation or inducing apoptosis in CRC. Consistently, substantial apoptosis was observed in vitro and in vivo in the presence of NDRG1. From a mechanistic standpoint, we discovered that NDRG1 was able to prevent death receptor 4 from degradation induced by MARCH-8, a member of the membrane-associated RING-CH (MARCH) ubiquitin ligase family. As a consequence, CRC cells expressing NDRG1 were more sensitive to reagents targeting death receptors such as tumor necrosis factor-related apoptosis-inducing ligands (TRAIL). Additionally, the pro apoptotic effect of NDRG1 was also validated in mouse xenograft model. In conclusion, our results provided further insights of the pivotal role of NDRG1 in apoptosis initiated by death receptors and demonstrated a novel marker to predict the sensitivity of CRC to TRAIL treatment in future clinical study. PMID- 29137288 TI - Elevated TIMP-1 expression is associated with a prometastatic phenotype, disease relapse, and poor survival in neuroblastoma. AB - Approximately two-thirds of patients with neuroblastoma are found to have metastatic disease at time of diagnosis with frequent skeletal, lymph node, central nervous system, and liver involvement. Using a serial in vivo splenic injection model, we have isolated an aggressive subclone (BE(2)-C/LM2) from MYCN amplified neuroblastomas that demonstrate an enhanced propensity to develop metastatic liver lesions. BE(2)-C/LM2 subclone cells demonstrate increased adherent, soft agar colony and tumorsphere growth in vitro. Components of the tumor microenvironment regulate cancer progression, via networks of cytokines and growth factors. Cytokine array analysis identified increased TIMP-1 in the plasma of mice injected with BE(2)-C/LM2 subclone cells, leading us to hypothesize that TIMP-1 may play a role in our observed prometastatic phenotype. Immunoblotting and ELISA demonstrated enhanced endogenous TIMP-1 expression in our isolated neuroblastoma subclone. Silencing endogenous TIMP-1 successfully blocked in vitro proliferation, soft agar colony formation and tumorsphere formation by BE(2) C/LM2 cells. Stable RNA interference of endogenous TIMP-1 failed to reverse the prometastatic phenotype of our BE(2)-C/LM2 subclone in our liver metastasis model, suggesting that endogenous TIMP-1 levels may not be an essential component of this in vivo behavior. Notably, tissue microarray analysis and Kaplan-Meier by gene expression demonstrates that elevated TIMP-1 expression is correlated with increased disease relapse and mortality in patients with neuroblastoma. Taken together, our study identifies TIMP-1 as a novel soluble factor that is associated with a prometastatic phenotype in our in vivo model and adverse outcomes in patients with neuroblastoma. PMID- 29137289 TI - Lingguizhugan decoction improves non-alcoholic fatty liver disease by altering insulin resistance and lipid metabolism related genes: a whole trancriptome study by RNA-Seq. AB - Lingguizhugan decoction, a classic traditional Chinese medicine formula, has been used to treat non-alcoholic fatty liver disease (NAFLD), however, the underlying mechanisms remains unclear. In the present study, we compared the phenotype of the normal rats (fed with chow diet), high-fat-diet (HFD) induced NAFLD rats and Lingguizhugan decoction (LGZG, comprises four Chinese herbs: Poria, Ramulus Cinnamomi, Rhizoma Atractylodis Macrocephalae, and Radix Glycyrrhizae.) intervened rats, and detected whole genome gene expression by RNA-Seq. Our results demonstrated that LGZG decoction attenuated phenotypic characteristics of NAFLD rats. RNA-Seq data analysis revealed that gene expression profiles exerted differential patterns between different groups. 2690 (1445 up-regulated, 1245 down-regulated) genes in NAFLD versus (vs) normal group, 69 (16 up-regulated, 53 down-regulated) genes in LGZG vs NAFLD group, and 42 overlapped (12 up- regulated, 30 down-regulated) genes between NAFLDvs normal group and LGZG vs NAFLD group were identified as differentially expressed. GO, pathway enrichment and PPI networks analysis of the overlapped genes revealed that LGZG decoction might attenuate NAFLD possibly by affecting insulin resistance and lipid metabolism related pathways (e.g., PI3K-Akt, AMPK). Differentially expressed genes involved in these pathways such as Pik3r1, Foxo1, Foxo3, Scd1, Col3a1 and Fn1 might be candidate targets for treating NAFLD. PMID- 29137290 TI - Expression of protein kinase A and the kappa opioid receptor in selected brain regions and conditioned place aversion in morphine-dependent rats. AB - This study examined adaptive changes in protein kinase A (PKA) and kappa opioid receptor (KOR) in selected addiction-related brain regions before and after conditioned place aversion (CPA). Seventy-two male SD rats were randomly assigned to an experimental group (morphine + naloxone, "MN") and 2 control groups: MS (morphine + saline) and SN (saline + naloxone). MN rats were intraperitoneally injected with morphine twice per day for 6.5 days and naloxone once and trained to establish CPA model. MS and SN rats were injected with equivalent volumes of morphine plus saline and saline plus naloxone, respectively. PKA and KOR in AcbSH, CeA and VTA were measured by immunohistochemistry. Before CPA, there were no significant differences in PKA and KOR expression levels in the AcbSH, CeA and VTA between MN and 2 control groups. After CPA, significant differences in PKA expression were detected in the AcbSH (P<0.001) and VTA (P=0.018) between MN and 2 control groups. The average gray intensity of MN group (109.50+/-4.66) in AcbSH was significantly higher than that of MS (126.50+/-3.70, P<0.001) and MN (133.50+/-6.364, P<0.001) groups. Significant differences in KOR expression were also detected between MN and 2 control groups in CeA (P<0.001). In MN group, PKA and KOR expression levels showed adaptive changes at different points of CPA. These findings demonstrated that neuroadaptation mediated by PKA and KOR may be an important molecular neurobiology basis for CPA. The upregulation of AC-cAMP PKA-CREB signaling pathway in AcbSH and VTA has some role in the neurobiological mechanism of CPA. PMID- 29137291 TI - The clinicopathological significance and prognostic value of EMMPRIN overexpression in cancers: evidence from 39 cohort studies. AB - Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to be associated with tumor formation and invasion in many studies. However, the clinicopathological significance and prognosis of EMMPRIN in cancer patients remains inconclusive. Therefore, we conducted a meta-analysis to assess the predictive potential of EMMPRIN in various cancers. By searching Pubmed, Cochrane library database and web of science comprehensively, 39studies with 5739 cases were included in our meta-analysis. The results indicated that EMMPRIN overexpression was significantly associated with poor outcome of cancers (HR=2.46, 95% CI: 2.21-2.75, P<0.0001). In addition, a significant relation was found between EMMPRIN overexpression and clinicopathological features, such as tumor stage (T3+T4/ T1+T2, OR=1.87, 95% CI:1.64-2.12, P<0.0001), tumor differentiation (poor/ well+ moderate, OR=1.09, 95% CI:1.60-2.23, P<0.0001), clinical stage (III+IV /I +II, OR=1.96, 95% CI:1.69-2.27, P<0.0001) and nodal metastasis (positive/negative, OR=2.37, 95% CI:1.93-2.90, P<0.0001). However, the expression of EMMRIN was not significantly associated with tumor stage in cervical cancer (OR=1.35, 95%CI: 0.73-2.48, P=0.33). In conclusion, EMMPRIN overxepression is significantly associated with clinicopathological characteristics and prognosis of cancers. Thus, EMMPRIN may be regarded as a promising bio-marker in predicting the clinical outcome of patients in cancers and could be used as the therapeutic target during clinical practices. PMID- 29137292 TI - The clinical significance of c-Kit mutations in metastatic oral mucosal melanoma in China. AB - c-Kit mutations are frequently detected in mucosal melanomas, but their clinical significance in metastatic oral mucosal melanomas (OMM) remains unclear. The main purpose of this study was to investigate the clinical and pathological features of metastatic OMMs with c-Kit mutations and the efficiency of the tyrosine kinase inhibitor imatinib in treating metastatic OMMs. We found thatresidual primary lesion and neck lymph nodes could act as independent prognostic factors in metastatic OMM patients. c-Kit mutations were detected in 22 out of 139 (15.8%) metastatic OMM patients. Under chemotherapy, the overall survival (OS) of c-Kit mutant patients was significantly shorter than that of wild-type patients. The Ki67 expression was significantly higher in c-Kit mutant patients than in wild type patients. In distant metastatic OMM patients with c-Kit mutations, the treatment with c-Kit inhibitor resulted in a better OS. In conclusion, residual primary lesion, cervical lymph nodes and c-Kit mutations act as adverse prognostic factors of metastatic OMMs. The Kit inhibitor imatinib could benefit metastatic OMM patients with c-Kit mutations. PMID- 29137293 TI - Identification of novel genetic regulations associated with airway epithelial homeostasis using next-generation sequencing data and bioinformatics approaches. AB - Airway epithelial cells play important roles in airway remodeling. Understanding gene regulations in airway epithelial homeostasis may provide new insights into pathogenesis and treatment of asthma. This study aimed to combine gene expression (GE) microarray, next generation sequencing (NGS), and bioinformatics to explore genetic regulations associated with airway epithelial homeostasis. We analyzed expression profiles of mRNAs (GE microarray) and microRNAs (NGS) in normal and asthmatic bronchial epithelial cells, and identified 9 genes with potential microRNA-mRNA interactions. Of these 9 dysregulated genes, downregulation of MEF2C and MDGA1 were validated in a representative microarray (GSE43696) from the gene expression omnibus (GEO) database. Our findings suggested that upregulated mir-203a may repress MEF2C, a transcription factor, leading to decreased cellular proliferation. In addition, upregulated mir-3065-3p may repress MDGA1, a cell membrane anchor protein, resulting in suppression of cell-cell adhesion. We also found that KCNJ2, a potassium channel, was downregulated in severe asthma and may promote epithelial cell apoptosis. We proposed that aberrant regulations of mir 203a-MEF2C and mir-3065-3p-MDGA1, as well as downregulation of KCNJ2, play important roles in airway epithelial homeostasis in asthma. These findings provide new perspectives on diagnostic or therapeutic strategies targeting bronchial epithelium for asthma. The approach in this study also provides a new aspect of studying asthma. PMID- 29137294 TI - Immunoprevention of KRAS-driven lung adenocarcinoma by a multipeptide vaccine. AB - Lung cancer remains the leading cause of cancer death worldwide. Mutations in KRAS are detected in up to 30% of lung cancer cases. No effective therapies specifically targeting mutant KRAS have been developed. Vaccination against KRAS mutants is one of the venues of active exploration. The present study evaluated both immunogenicity and antitumor efficacy of a newly formulated multipeptide vaccine targeting multiple epitopes of the KRAS molecule. The formulated vaccine contained top four peptides, which elicited the strongest immunologic response and showed 100% sequence homology between human and mouse. The multipeptide KRAS vaccine was tested in an inducible CCSP-TetO-KRASG12D mouse model, where the vaccine was administered prior to activating the mutant KRAS protein. The KRAS peptide vaccine exhibited striking efficacy, reducing tumor number and tumor burden by >80% when compared with adjuvant alone. Splenocytes collected from vaccinated animals showed a robust immunologic response to the immunizing peptides. Furthermore, in vitro stimulation of these splenocytes by the vaccinated peptides resulted in the secretion of cytokines indicative of Th1 responses but with minimal secretion of Th2-related cytokines. The multipeptide KRAS vaccine was immunogenic and efficacious in the primary prevention of KRAS induced lung cancer, indicating that the approach potentially can be used to prevent other KRAS-driven cancers, either alone or in combination with other modalities. PMID- 29137295 TI - Clinical outcome of dynamic hip locking plates and proximal femoral nails anti rotation-Asia for treating intertrochanteric femur fracture with lateral wall fractures in the elder patients. AB - Purpose: To compare the clinical results of DHLP (Dynamic hip locking plates) and PFNA-IIs (proximal femoral nails anti-rotation-Asia) for treating intertrochanteric femur fracture (IFF) with lateral wall fractures in the elder patients and provide a rationale for the clinical practice. Methods: A retrospective analysis of 43 patients of IFF with lateral wall fractures was performed from December 2009 to April 2015. Intraoperative variables and postoperative complications and function were compared between the two groups. Results: 17 cases were treated by DHLPs, and 26 treated by PFNA-IIs. Patients were followed up from 6 to 16 months with an average of 11 months. Both the groups were comparable for demographic data before surgery. The PFNA-II group had less operation time, time of full weight bearing and healing time of fracture, but larger blood loss in comparison with the DHLP group (p<0.05). Additionally, internal fixation failure was significantly more in the DHLP group than in the PFNA-II group. The mean HHS and the rate of good-to-excellent in the PFNA-II group was significantly higher than that in the DHLP group both in third month after surgery (p<0.05). Conclusions: PFNA-IIs treatment should be recommended for the elderly patients of IFF with lateral wall fractures, because of its shorter operation time, faster full weight bearing, faster function recovery, and lower failure rate. However, more attention should be payed to its larger blood loss. PMID- 29137296 TI - Early detection of thymidylate synthase resistance in non-small cell lung cancer with FLT-PET imaging. AB - Introduction: Inhibition of thymidylate synthase (TS) results in a transient compensatory "flare" in thymidine salvage pathway activity measureable with 18F thymidine (FLT)- positron emission tomography (PET) at 2hrs. of therapy which may predict non-small cell lung cancer (NSCLC) sensitivity to TS inhibition. Materials and Methods: Resistance to TS inhibition by pemetrexed was induced in NSCLC cell lines H460 and H1299 through TS overexpression. TS overexpression was confirmed with RT-PCR and Western blotting and pemetrexed resistance confirmed with IC50 assays. The presence of a pemetrexed-induced thymidine salvage pathway "flare" was then measured using 3H-thymidine in both pemetrexed sensitive (H460 and H1299) and resistant (H460R, H1299R, CALU-6, H522, H650, H661, H820, H1838) lines in vitro, and validated with FLT-PET in vivo using H460 and H460R xenografts. Results: Overexpression of TS induced pemetrexed resistance with IC50 for H460, H1299, H460R and H1299R measured as 0.141 MUM, 0.656 MUM, 22.842 MUM, 213.120 MUM, respectively. Thymidine salvage pathway 3H-thymidine "flare" was observed following pemetrexed in H460 and H1299 but not H460R, H1299R, CALU-6, H522, H650, H661, H820 or H1838 in vitro. Similarly, a FLT "flare" was observed in vivo following pemetrexed therapy in H460 but not H460R tumor-bearing xenografts. Conclusions: Imaging of TS inhibition is predictive of NSCLC sensitivity to pemetrexed. PMID- 29137297 TI - Probably less than one-tenth of the genes produce only the wild type protein without at least one additional protein isoform in some human cancer cell lines. AB - To estimate how many genes produce multiple protein isoforms, we electrophoresed proteins from MCF7 and MDA-MB231 (MB231) human breast cancer cells in SDS-PAGE and excised narrow stripes of the gel at the 48kD, 55kD and 72kD. Proteins in these stripes were identified using liquid chromatography and tandem mass spectrometry. A total of 765, 750 and 679 proteins from MB231 cells, as well as 470, 390 and 490 proteins from MCF7 cells, were identified from the 48kD, 55kD and 72kD stripes, respectively. We arbitrarily allowed a 10% technical variation from the proteins' theoretical molecular mass (TMM) and considered those proteins with their TMMs within the 43-53 kD, 49-61 kD and 65-79 kD ranges as the wild type (WT) expected from the corresponding stripe, whereas those with a TMM above or below this range as a smaller- or larger-group, respectively. Only 263 (34.4%), 269 (35.9%) and 151 (22.2%) proteins from MB231 cells and 117 (24.9%), 135 (34.6%) and 130 (26.5%) proteins from MCF7 cells from the 48kD, 55kD and 72kD stripes, respectively, belonged to the WT, while the remaining majority belonged to the smaller- or larger-groups. Only about 3-16%, on average about 10% regardless of the stripe and cell line, of the proteins appeared in only one stripe and within the WT range, while the remaining preponderance appeared also in additional stripe(s) or had a larger or smaller TMM. We conclude that few (fewer than 10%) of the human genes produce only the WT protein without additional isoform(s). PMID- 29137298 TI - ING4 expressing oncolytic vaccinia virus promotes anti-tumor efficiency and synergizes with gemcitabine in pancreatic cancer. AB - With no effective treatments available for most pancreatic cancer patients, pancreatic cancer continues to be one of the most difficult malignancies to treat. Oncolytic virus mediated-gene therapy has exhibited ubiquitous antitumor potential. In this study, we constructed a novel oncolytic vaccinia virus harboring the inhibitor of growth family member 4 gene (VV-ING4) to investigate its therapeutic efficacy alone or in combination with gemcitabine against pancreatic cancer cells in vitro and in vivo. ING4 expression was determined via quantitative real-time polymerase chain reaction (qPCR) and western blot. The cytotoxicity of VV-ING4 was measured using a cell proliferation assay. Both flow cytometry and western blot were applied to analyze the cell cycle and apoptosis. Furthermore, the combination inhibitory effect of VV-ING4 and gemcitabine was assessed using Chou-Talalay analysis in vitro and a BLAB/c mice model in vivo. We found that VV-ING4 significantly increases ING4 expression, displayed greater cytotoxic efficiency, and induced pancreatic cancer cell apoptosis and G2/M phase arrest. Additionally, the combination of VV-ING4 and gemcitabine synergistically effect in vitro and in vivo. Taken together, our data implicate VV-ING4 as a conceivable pancreatic cancer therapeutic candidate alone or in combination with gemcitabine. PMID- 29137299 TI - Tumor-expressed immune checkpoint B7x promotes cancer progression and antigen specific CD8 T cell exhaustion and suppressive innate immune cells. AB - B7x (B7-H4 or B7S1) is a coinhibitory member of the B7 immune checkpoint ligand family that regulates immune function following ligation with its unknown cognate receptors. B7x has limited expression on normal tissues, but is up-regulated on solid human tumors to inhibit anti-tumor immunity and associates with poor clinical prognosis. We assessed the contribution of cytokine stimuli to induce surface B7x expression on cancer cells and the role of tumor-expressed B7x in a murine pulmonary metastasis model, and finally evaluated the potential interaction between B7x and Neuropilin-1, a suggested potential cognate receptor. We showed that pro-inflammatory and anti-inflammatory cytokines IFNgamma, TNFalpha, and IL-10 did not induce expression of B7x on human or murine cancer cells. Following i.v. injection of CT26, a murine colon cancer cell line in the BALB/c background, we observed a significant increase in tumor burden in the lung of B7x-expressing CT26 mice compared to B7x-negative parental CT26 control mice. This was marked by a significant increase in M2 tumor associated macrophages and antigen-specific CD8 T cell exhaustion. Finally, we found through multiple systems that there was no evidence for B7x and Neuropilin-1 direct interaction. Thus, the B7x pathway has an essential role in modulating the innate and adaptive immune cell infiltrate in the tumor microenvironment with its currently unknown cognate receptor(s). PMID- 29137300 TI - PATZ1 knockdown enhances malignant phenotype in thyroid epithelial follicular cells and thyroid cancer cells. AB - This study was designed to examine the involvement of PATZ1 in carcinogenesis and dedifferentiation of thyroid cancer. Immunohistochemistry on clinical specimens indicated nuclear PATZ1 expression in all normal thyroid glands and adenomatous goiter, while nuclear PATZ1 expression decreased along with the dedifferentiation of thyroid cancer. Knockdown of nuclear PATZ1 by siRNA in an immortalized normal follicular epithelial cell line (Nthy-ori 3-1) altered cellular morphology and significantly increased cell proliferation, migration, and invasion. In addition, the expression of urokinase-type plasminogen activator (uPA), matrix metalloproteinase (MMP) 2, MMP9, and MMP11 was increased by PATZ1 knockdown in Nthy-ori 3-1 cells. When PATZ1 was silenced in differentiated thyroid cancer (DTC) cell lines (TPC-1 and FTC-133), proliferation, cellular motility, and expression of uPA and MMPs were significantly increased. Forced expression of exogenous PATZ1 decreased proliferation, cellular motility, and the expression of uPA and MMPs in ATC cell lines (ACT-1 and FRO). In thyroid cancer cell lines, PATZ1 functioned as a tumor suppressor regardless of p53 status. Moreover, the ratio of nuclear PATZ1 positive tumors was significantly decreased in ATC irrespective of p53 status. Our study demonstrates that PATZ1 knockdown enhances malignant phenotype both in thyroid follicular epithelial cells and thyroid cancer cells, suggesting that PATZ1 functions as a tumor suppressor in thyroid follicular epithelial cells and is involved in the dedifferentiation of thyroid cancer. PMID- 29137301 TI - Antitumor efficacy of triple monoclonal antibody inhibition of epidermal growth factor receptor (EGFR) with MM151 in EGFR-dependent and in cetuximab-resistant human colorectal cancer cells. AB - Purpose: We investigated the effect of triple monoclonal antibody inhibition of EGFR to overcome acquired resistance to first generation of anti-EGFR inhibitors. Experimental design: MM151 is a mixture of three different monoclonal IgG1 antibodies directed toward three different, non-overlapping, epitopes of the EGFR. We performed an in vivo study by using human CRC cell lines (SW48, LIM 1215 and CACO2) which are sensitive to EGFR inhibitors, in order to evaluate the activity of MM151 as compared to standard anti-EGFR mAbs, such as cetuximab, as single agent or in a sequential strategy of combination MM151 with irinotecan (induction therapy) followed by MM151 with a selective MEK1/2 inhibitor (MEKi) (maintenance therapy). Furthermore, the ability of MM151 to overcome acquired resistance to cetuximab has been also evaluated in cetuximab-refractory CRC models. Results: MM151 shown stronger antitumor activity as compared to cetuximab. The maintenance treatment with MM151 plus MEKi resulted the most effective therapeutic modality. In fact, this combination caused an almost complete suppression of tumor growth in SW48, LIM 1215 and CACO2 xenografts model at 30 week. Moreover, in this treatment group, mice with no evidence of tumor were more than double as compared to single agent treated mice. Its superior activity has also been demonstrated, in cetuximab-refractory CRC models. Conclusions: These results provide experimental evidence that more efficient and complete EGFR blockade may determine better antitumor activity and could contribute to prevent and/or overcome acquired resistance to EGFR inhibitors. PMID- 29137302 TI - Functional and non-functional pancreatic neuroendocrine tumours: ENETS or AJCC TNM staging system? AB - Background: There are currently 2 Tumour-Node-Metastasis (TNM) staging systems for pancreatic neuroendocrine tumours (p-NETs) - European Neuroendocrine Tumour Society (ENETS) and American Joint Committee on Cancer (AJCC). P-NETs being heterogeneous, we investigated the prognostic value of the 2 systems in p-NETs, as a whole, and more interestingly in functional and non-functional sub-groups separately, with a view to ascertaining any potential clinical benefits of using one system over the other. Methods: Data from patients with surgically resected p NETs were retrospectively reviewed. Kaplan-Meier method and Cox Regression proportional hazards model were used to analyse overall survival (OS) and prognostic predictors respectively. Results: In the whole group of 165 patients, both TNM systems successfully discriminated OS differences when comparing stages I and II with stages III and IV (P<0.05); ENETS stage III patients had a significantly better OS than those in stage IV (P=0.003). Patients with functional p-NETs in ENETS stage II showed a statistically better OS than those in stages III and IV (P<0.05). For non-functional tumours, the AJCC staging system could effectively discriminate between the OS differences of patients in stage I with stages III and IV, or stage II with III and IV (P<0.05). Along with surgical intent and World Health Organisation (WHO) 2010 grade, both ENETS and AJCC staging systems were effective predictors of OS for different function status p-NETs. Conclusions: The ENETS system might have potential advantages when applied to all p-NETs and to the functional sub-group, while the AJCC system might be clinically more practical for non-functional p-NETs. PMID- 29137303 TI - The association between CCR5 Delta32 polymorphism and susceptibility to breast cancer. AB - Background: Chemokine C-C motif receptor 5 (CCR5) gene polymorphisms have been proposed to play important roles in tumors. Delta32 polymorphism of this gene might correlate with breast cancer (BC) susceptibility. Nevertheless, inconsistent conclusions have been achieved as yet. We carried out this meta analysis to draw a more comprehensive and convincing conclusion on this issue. Results: No significant correlation of CCR5 Delta32 polymorphism with individual susceptibility to BC was detected in either total analysis (Delta32 vs. WT: OR=1.12, 95% CI=0.76-1.65; WT/Delta32 vs. WT/WT: OR=1.21, 95% CI=0.81-1.80) or subgroup analyses by ethnicity and control source. Methods: All eligible studies were searched from electronic databases including Chinese National Knowledge Infrastructure (CNKI), PubMed, EMBASE, and Google Scholar Web. Strength of association between CCR5 Delta32 polymorphism and BC susceptibility was evaluated using pooled odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs). To further detect their correlation in specific populations, subgroup analyses were performed based on ethnicity and control source. Sensitivity analysis was conducted in this meta-analysis to test statistical stability of the final results. Publication bias among included studies was inspected with Begg's funnel plot and Egger's test. Conclusion: CCR5 Delta32 polymorphism may not independently affect the risk of BC. PMID- 29137305 TI - miR-93-3p inhibition suppresses clear cell renal cell carcinoma proliferation, metastasis and invasion. AB - miRNA dysregulation is associated with many human diseases, including cancer. This study explored the effects of miR-93-3p on clear cell renal cell carcinoma (ccRCC). We found that miR-93-3p is upregulated an average of 38-fold in 138 ccRCC specimens compared to matched normal kidney tissues, which correlated with poor patient outcome. miR-93-3p inhibition reduced ccRCC cell growth, invasion, and migration in vitro and in a mouse xenograft model. A search of the TargetScan, miRanda, and PicTar databases revealed that miR-93-3p is predicted to regulate pigment epithelium-derived factor (PEDF). A direct PEDF-miR-93-3p interaction was confirmed via dual-luciferase reporter assays. Like miR-93-3p inhibition, PEDF overexpression induced cell apoptosis and inhibited migration and invasion. Additionally, co-transfection with PEDF siRNA reversed the effects of miR-93-3p inhibition in ccRCC cells. Thus, miR-93-3p is a likely ccRCC oncogene that acts by regulating PEDF. These results suggest that miR-93-3p may predict ccRCC patient clinical outcome and serve as a novel anti-ccRCC therapeutic target. PMID- 29137304 TI - Monocarboxylate transporter 1 (MCT1), a tool to stratify acute myeloid leukemia (AML) patients and a vehicle to kill cancer cells. AB - Dysregulation of glucose/lactate dynamics plays a role in cancer progression, and MCTs are key elements in metabolic remodeling. VEGF is a relevant growth factor in the maintenance of bone marrow microenvironment and it is also important in hematological diseases. Our aim was to investigate the role of VEGF in the metabolic adaptation of Acute myeloid leukemia (AML) cells by evaluating the metabolic profiles and cell features according to the AML lineage and testing lactate as a metabolic coin. Our in vitro results showed that AML promyelocytic (HL60) and monocytic (THP1) (but not erythroid- HEL) lineages are well adapted to VEGF and lactate rich environment. Their metabolic adaptation relies on high rates of glycolysis to generate intermediates for PPP to support cell proliferation, and on the consumption of glycolysis-generated lactate to supply biomass and energy production. VEGF orchestrates this metabolic network by regulating MCT1 expression. Bromopyruvic acid (BPA) was proven to be an effective cytotoxic in AML, possibly transported by MCT1. Our study reinforces that targeting metabolism can be a good strategy to fight cancer. MCT1 expression at the time of diagnosis can assist on the identification of AML patients that will benefit from BPA therapy. Additionally, MCT1 can be used in targeted delivery of conventional cytotoxic drugs. PMID- 29137306 TI - MMP9 polymorphism is associated with susceptibility to non-traumatic osteonecrosis of femoral head in a Chinese Han population. AB - Non-traumatic osteonecrosis of femoral head (ONFH) is an orthopedic refractory disease with escalating morbidity in Chinese Han population. In our case-control study, we examined eight previously identified MMP9 single-nucleotide polymorphisms (SNPs) in 585 non-traumatic ONFH patients and 507 healthy individuals from northern China to determine whether these SNPs associated with the risk of developing non-traumatic ONFH. Genetic model and haplotype analyses were used to evaluate the association between SNPs and non-traumatic ONFH. MMP9 rs2274755 (OR, 0.740; 95% CI, 0.578-0.949; p = 0.017) was associated with a reduced risk of non-traumatic ONFH. After adjusting for age and gender, the logistic regression results showed that rs2274755 associated with a lower risk of non-traumatic ONFH in the dominant (OR=0.71, 95% CI: 0.54-0.94, p=0.016), overdominant (OR=0.73, 95% CI: 0.55-0.96, p=0.026) and log-additive (OR=0.74740; 95% CI, 0.578-0.949; p=0.017) models. In addition, the "TGC" haplotype of rs2274755 was associated with a 0.79-fold decrease in risk while the "CTC" haplotype associated with a 0.65-fold decrease risk of the non-traumatic ONFH. These results provide evidence that the MMP9 SNP at the rs2274755 locus is associated with a decreased risk of non-traumatic ONFH in a Chinese Han population. PMID- 29137307 TI - Reversal of 5-fluorouracil resistance by EGCG is mediate by inactivation of TFAP2A/VEGF signaling pathway and down-regulation of MDR-1 and P-gp expression in gastric cancer. AB - The effect of 5-fluorouracil (5-FU) chemotherapy for gastric cancer (GC) is limited by drug-resistance. To conquer this drug-resistance, various treatments including combination therapy have been used, but the overall survival has not been improved yet. In our current study, 5-FU resistant GC cells, SGC7901/FU and MGC803/FU, were established by long term exposure to 5-FU, and the proliferation capability of these resistant cells was verified to be reduced. The drug related proteins, MDR1 and P-gp were up-regulated in resistant cells compared to the parental cells. We further found proliferation and tumor growth suppressed effects of epigallocatechin gallate (EGCG), which is the predominant polyphenolic catechin constituent in green tea, on both the 5-FU resistant cells and the SGC7901/FU xenograft. Furthermore, an interesting results showed that reversal of 5-FU resistance of GC cells by EGCG treatment in vivo and in vitro. In the molecular study, We also found that EGCG suppressed the expression of both MDR-1 and P-gp at mRNA and protein levels in vivo and in vitro. Western blot and ELISA assay revealed that EGCG was able to inhibit VEGF secretion and expression, and its up-stream signal regulator, transcription factor activator protein 2A (TFAP2A) was also down-regulated by EGCG, our results indicated that TFAP2A/VEGF axis is one of the critical pathway inhibited by EGCG for cell proliferation and 5-FU resistance. Taken together, our data suggested that EGCG inhibits GC growth and reverses 5-FU resistance of GC through inactivation of TFAP2A/VEGF pathway and down-regulation of MDR-1 and P-gp expression. PMID- 29137308 TI - MicroRNA-23a promotes pancreatic cancer metastasis by targeting epithelial splicing regulator protein 1. AB - miR-23a plays vital roles in various cancer metastases. Here, we found that miR 23a expression was significantly up-regulated in pancreatic cancer tissues compared with adjacent normal tissues. miR-23a up-regulation was significantly associated with differentiated degree, lymphoid nodal status, tumor invasion and poor survival rate in pancreatic cancer patients. We also found that miR-23a expression was significantly up-regulated in lymph node metastatic tissues and in pancreatic cancer cells that underwent epithelial-mesenchymal transition (EMT). miR-23a down-regulation blocked TGF-beta1-induced EMT and reversed the phenotype of EMT in Panc-1 cells. Furthermore, miR-23a down-regulation inhibited Panc-1 cells migration and invasion in vitro and liver metastases in vivo. But the effect of miR-23a up-regulation in Aspc-1 cells was opposite to that of miR-23a down-regulation in Panc-1 cells. Epithelial splicing regulatory protein 1 (ESRP1) was identified as a direct target of miR-23a. Restoration of ESRP1 rescued the effect of miR-23a on pancreatic cancer cell progression. Moreover, miR-23a up regulation in Aspc-1 cells induced a shift in CD44 expression from variant isoforms (CD44v) to the standard isoform (CD44s) together with increased FGFR2 IIIc mRNA levels, and decreased FGFR2 IIIb expression during EMT. But the effect of miR-23a down-regulation in Panc-1 cells was opposite to that of miR-23a up regulation in Aspc-1 cells. In addition, the effect of miR-23a up-regulation was partly reversed by ESRP1 over-expression. Taken together, our findings indicated that miR-23a functions as an oncogene by regulating ESRP1 in pancreatic cancer. PMID- 29137309 TI - Anti-proliferative and pro-apoptotic effects induced by simultaneous inactivation of HER1 and HER2 through endogenous polyclonal antibodies. AB - The human epidermal growth factor receptor (HER1) and its partner HER2 are extensively described oncogenes and validated targets for cancer therapy. However, the effectiveness of monospecific therapies targeting these receptors is hampered by resistance emergence, which is frequently associated with the upregulation of other members of HER family. Combined therapies using monoclonal antibodies or tyrosine kinase inhibitors have been suggested as a promising strategy to circumvent this resistance mechanism. We propose an alternative approach based on simultaneous inactivation of HER1 and HER2 by multi-epitope blockade with specific polyclonal antibodies induced by vaccination. Elicited antibodies impaired both receptors activation and induced their degradation, which caused the inhibition of down-signaling cascades. This effect was translated into cell cycle arrest and apoptosis induction of human tumor cells. Elicited antibodies were able to reduce the viability of a panel of human tumor lines with differential expression levels of HER1 and HER2. The most significant effects were obtained in the tumor lines with lower expression levels of both receptors. These new insights would contribute to the rational design of HER receptors targeting multivalent vaccines, as an encouraging approach for the treatment of cancer patients. PMID- 29137310 TI - Ex vivo evaluation of tumor cell specific drug responses in malignant pleural effusions. AB - The effect of chemotherapy may be improved by combining the most effective drugs based on testing the sensitivity of the individual tumor ex vivo. Such estimations of tumor cells from effusions have so far not been implemented in the clinical routine as a basis for individualized choice of therapy. One obstacle for such analyses is the admixture of benign cells that might obscure the results. In this paper we test and compare two ways of performing the analysis specifically on tumor cells. First we enrich the tumor cells, using antibody labeled magnetic separation, and measure the effects of subsequent drug exposure with the metabolic activity assays WST-1 and alamar blue. The second way of estimating drug effects specifically on tumor cells employs multi parameter flow cytometry, measuring apoptosis with the propidium iodide / AnnexinV technique and, particularly for pemetrexed, possible effects on cell cycle progression in immunologically identified tumor cells. The two techniques produce similar results, indicating a possible use in personalized medicine. The possible predictive role of the analysis remains to be shown. PMID- 29137311 TI - Crenolanib is a type I tyrosine kinase inhibitor that inhibits mutant KIT D816 isoforms prevalent in systemic mastocytosis and core binding factor leukemia. AB - Activating D816 mutations of the class III receptor tyrosine kinase KIT are associated with the majority of patients with systemic mastocytosis (SM), but also core binding factor (CBF) AML, making KIT mutations attractive therapeutic targets for the treatment of these cancers. Crenolanib is a potent and selective inhibitor of wild-type as well as mutant isoforms of the class III receptor tyrosine kinases FLT3 and PDGFRalpha/beta. Notably, crenolanib inhibits constitutively active mutant-FLT3 isoforms resulting from amino acid substitutions of aspartic acid at codon 835, which is homologous to codon 816 in the KIT gene - suggesting sensitivity against mutant-KIT D816 isoforms as well. Here we demonstrate that crenolanib targets KIT D816 in SM and CBF AML models: crenolanib inhibits cellular proliferation and initiates apoptosis of mastocytosis cell lines expressing these mutations. Target-specificity was confirmed using an isogenic cell model. In addition, we demonstrate that KIT D816 mutations are targetable with clinically achievable doses of crenolanib. Further, a rationale to combine cladribine (2-CDA), the therapeutic standard in SM, with crenolanib is provided. In conclusion, we demonstrate that crenolanib is an inhibitor of mutant-KIT D816 isoforms at clinically achievable concentrations, and thus may be a potential treatment for SM and CBF AML as a monotherapy or in combination approaches. PMID- 29137312 TI - Neurofibromatosis type-1 is a prognostic indicator in human gastric carcinoma. AB - We investigated whether the Neurofibromatosis type-1(NF1) gene was of prognostic relevance to gastric cancer (GC) patients. Immunohistochemical staining of 160 matched GC tumor and adjacent normal tissue samples showed that 58.1% (93/160) of GC samples were NF1-positive as compared to 94.4% (151/160) of normal tissue samples (chi2=58.05, P <0.001). qRT-PCR analysis revealed that NF1 mRNA expression is lower in GC tissues than normal tissues (chi2=34.23, P <0.001). Moreover, NF1 protein and mRNA levels were associated with T stage (P <0.05) and TNM (P <0.001). No association was observed with other clinicopathological parameters, including gender, age, tumor size, lymph-node metastasis, cancer differentiation and distant metastasis (all P >0.05). Kaplan-Meier analysis revealed that negative or low NF1 were associated with poor overall survival (OS) in gastric cancer patients (P<0.001). Further univariate and multivariate cox regression analysis also showed that NF1 expression was an independent risk factor of survival of GC patients. These data show that NF1 has prognostic relevance to clinical outcomes in gastric cancer patients. PMID- 29137313 TI - RNA-seq reveals distinctive RNA profiles of small extracellular vesicles from different human liver cancer cell lines. AB - Liver cancer (LC) is one of the most common cancers and represents the third highest cause of cancer-related deaths worldwide. Extracellular vesicle (EVs) cargoes, which are selectively enriched in RNA, offer great promise for the diagnosis, prognosis and treatment of LC. Our study analyzed the RNA cargoes of EVs derived from 4 liver-cancer cell lines: HuH7, Hep3B, HepG2 (hepato-cellular carcinoma) and HuH6 (hepatoblastoma), generating two different sets of sequencing libraries for each. One library was size-selected for small RNAs and the other targeted the whole transcriptome. Here are reported genome wide data of the expression level of coding and non-coding transcripts, microRNAs, isomiRs and snoRNAs providing the first comprehensive overview of the extracellular-vesicle RNA cargo released from LC cell lines. The EV-RNA expression profiles of the four liver cancer cell lines share a similar background, but cell-specific features clearly emerge showing the marked heterogeneity of the EV-cargo among the individual cell lines, evident both for the coding and non-coding RNA species. PMID- 29137314 TI - Lack of both androgen receptor and forkhead box A1 (FOXA1) expression is a poor prognostic factor in estrogen receptor-positive breast cancers. AB - The present study aimed to examine the associations between androgen receptor (AR) and forkhead box A1 (FOXA1) and to investigate clinicopathological features and survival according to both biomarker status in estrogen receptor (ER) positive breast cancers using in vitro study, patient cohort data, and the cBioPortal for Cancer Genomics and Kaplan-Meier Plotter websites. Experiments using T47D and ZR75-1 demonstrated AR-overexpressing cell lines decreased in cell proliferation through downregulation of ER, but FOXA1 did not change. Knockdown of FOXA1 resulted in a significantly reduced cell viability. Patients with immunohistochemically AR(-)/FOXA1(-) tumor frequently showed node metastasis, high grade, and high Ki-67 proliferation, therefore, significantly worse survival in ER-positive disease. AR and FOXA1 mRNA levels were significantly higher in ER positive than in ER-negative tumors and AR-low/FOXA1-low tumors showed high grade, frequent basal-like subtype and worse disease-free survival in ER-positive cancers of public gene dataset, similarly to patient cohort results. The Kaplan Meier Plotter analysis independently validated patients with both low AR/FOXA1 tumor were significantly associated with worse relapse-free survival in ER positive cancers. This study suggests that distinctive clinicopathological features according to AR and FOXA1 are determined and a lack of both biomarkers is an independent poor prognostic factor in ER-positive tumors. PMID- 29137315 TI - Protective effects of sulforaphane on di-n-butylphthalate-induced testicular oxidative stress injury in male mice offsprings via activating Nrf2/ARE pathway. AB - Di-N-butylphthalate (DBP) is one of the most common endocrine-disrupting chemicals which can disrupt human endocrine system, especially in the male reproductive system. Here, this study was aimed to determine whether sulforaphane (SFN) could protect against testicular oxidative stress injury induced by DBP in male mice offsprings. Wild-type (Nrf2+/+) and Nrf2-deficient (Nrf2-/-) timed pregnant mice were given DBP orally from embryonic day (E)14.5 to E19.5. Subsequently, the oxidative stress markers were evaluated. Besides, Nrf2, NF kappaB, I-kB, HO-1 and NQO-1 expression levels in the testis were measured by immunohistochemical staining or western blot analysis. DBP significantly reduced anogenital distance (AGD) and influenced testes growth in male mice offsprings, while SFN ameliorated these phenotypes. After DBP stimulation, the testicular morphology, testicular cell apoptosis index and the oxidative stress markers exhibited statistical differences compared with Control group, while SFN supplementation showed obvious improvements. In addition, administration of SFN could obviously increase the expression level of Nrf2 and its downstream ARE gene battery, such as HO-1, NQO-1 in the testis. Meanwhile, SFN pretreatment did not confer protection against DBP-induced testicular oxidative stress injury in Nrf2 knockout mice. Therefore, the present findings suggested that SFN could effectively protect against DBP-induced testicular oxidative stress injury through Nrf2/ARE signaling pathways in male mice offsprings. PMID- 29137316 TI - RRS1 silencing suppresses colorectal cancer cell proliferation and tumorigenesis by inhibiting G2/M progression and angiogenesis. AB - Colorectal cancer (CRC) is one of the most common malignancies worldwide. Ribosome biogenesis regulatory protein homolog (RRS1) is an essential factor involved in ribosome biogenesis, while its role in CRC remains largely unclear. Here, we found that RRS1 expression was significantly higher in CRC tissues compared with adjacent normal tissues. RRS1 High expression also predicted poor overall survival of CRC patients. Knockdown of RRS1 induced the G2/M cell cycle arrest, apoptosis and suppressed the proliferation of RKO and HCT-116 CRC cells. Furthermore, angiogenesis was also reduced in CRC cells after RRS1 knockdown. In addition, suppression of RRS1 blunted the tumor formation of CRC cells in nude mice. At the molecular level, silencing of RRS1 decreased the expression of M phase inducer phosphatase 3 (CDC25C), Cyclin-dependent kinase 1 (CDK1), antigen KI-67 (KI67) and increased the protein level of cyclin-dependent kinase inhibitor 1 (CDKN1A) and tumor suppressor p53 (p53). Taken together, our findings provide evidence that RRS1 may promote the development of colon cancer. Therefore, targeting RRS1 may be a promising therapeutic strategy for CRC patients. PMID- 29137317 TI - Mcl-1 stabilization confers resistance to taxol in human gastric cancer. AB - Taxol has been extensively used as an antineoplastic drug to treat human gastric cancer. However, the acquired drug resistance invariably develops and greatly limits the therapeutic efficacy of Taxol. Identification of the underlying resistance mechanisms may inform the development of new therapies of gastric cancers to Taxol treatment. Here we report that upregulation of Mcl-1 (Myeloid cell leukemia-1) confers acquired resistance to Taxol in human gastric cancer. Mcl-1 is shown to be stabilized in Taxol -resistant gastric cancer cells because of the hyper-activation of the PI3K/Akt signaling pathway. The increased Mcl-1 prevents of the permeabilization of the outer mitochondrial membrane, thereby blocking the Taxol-induced apoptosis. Furthermore, inhibition of Mcl-1 or PI3K/Akt pathway significantly reversed the resistant phenotype of Taxol resistant human gastric cancer cells. Taken together, our findings broaden the view of PI3K/Akt pathway as an important regulator in Taxol acquired resistance, and implicate Mcl-1 as a specific therapeutic target for the treatment of Taxol resistant human gastric cancer. PMID- 29137318 TI - miR-27a-3p targeting RXRalpha promotes colorectal cancer progression by activating Wnt/beta-catenin pathway. AB - This study aimed to elucidate how miR-27a-3p modulates the Wnt/beta-catenin signaling pathway to promote colorectal cancer (CRC) progression. Our results showed that the expression of miR-27a-3p was up-regulated in CRC and closely associated with histological differentiation, clinical stage, distant metastasis and CRC patients' survival. miR-27a-3p mimic suppressed apoptosis and promoted proliferation, migration, invasion of CRC cells in vitro and in vivo. Whereas miR 27a-3p inhibitor promoted apoptosis and suppressed proliferation, migration, invasion of CRC cells in vitro and in vivo. Furthermore, RXRalpha was the target gene of miR-27a-3p in CRC. miR-27a-3p expression negatively correlated with RXRalpha expression in CRC tissues. The underlining mechanism study showed that miR-27a-3p/RXRalpha/Wnt/beta-catenin signaling pathway is involved in CRC progression. In conclusion, our findings first demonstrate that miR-27a-3p is a prognostic and/or potential therapeutic biomarker for CRC patients and RXRalpha as miR-27a-3p targeting gene plays an important role in activation of the Wnt/beta-catenin pathway during CRC progression. PMID- 29137319 TI - Effects of growth hormone on cardiac remodeling and soleus muscle in rats with aortic stenosis-induced heart failure. AB - Background: Skeletal muscle wasting is often observed in heart failure (HF). The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis is impaired in HF. In this study, we evaluated the effects of GH on soleus muscle and cardiac remodeling in rats with aortic stenosis (AS)-induced HF. Methods: AS was created by placing a stainless-steel clip on the ascending aorta. After clinically detecting HF, GH (2 mg/kg/day) was subcutaneously injected for 14 days (AS-GH group). Results were compared with those from Sham and non-treated AS groups. Transthoracic echocardiogram was performed before and after treatment. Protein expression was evaluated by Western blot and satellite cells activation by immunofluorescence. Statistical analyzes: ANOVA and Tukey or Kruskal-Wallis and Student-Newman-Keuls. Results: Before treatment both AS groups presented a similar degree of cardiac injury. GH prevented body weight loss and attenuated systolic dysfunction. Soleus cross-sectional fiber areas were lower in both AS groups than Sham (Sham 3,556+/-447; AS 2,882+/-422; AS-GH 2,868+/-591 MUm2; p=0.016). GH increased IGF-1 serum concentration (Sham 938+/-83; AS 866+/-116; AS GH 1167+/-166 ng/mL; p<0.0001) and IGF-1 muscle protein expression and activated PI3K protein. Neural cell adhesion molecule (NCAM) immunofluorescence was increased in both AS groups. Catabolism-related intracellular pathways did not differ between groups. Conclusion: Short-term growth hormone attenuates left ventricular systolic dysfunction in rats with aortic stenosis-induced HF. Despite preserving body weight, increasing serum and muscular IGF-1 levels, and stimulating PI3K muscle expression, GH does not modulate soleus muscle trophism, satellite cells activation or intracellular pathways associated with muscle catabolism. PMID- 29137320 TI - A phase II study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer. AB - Background: Concurrent chemoradiotherapy (CCRT) using conventional platinum-based doublets are often associated with significant incidence of toxic effects in elderly patients with esophageal cancer. We previously reported a phase I trial of CCRT using S-1, an oral 5-fluorouracil derivative, which yielded well safe and active outcomes. Methods: Patients with histologically confirmed esophageal cancer, who were age of 70 years or older with performance status (PS) score of 0 2 or age of 66 to 69 with PS score of 2, were eligible for this Phase II trial. Radiotherapy was delivered in 1.8 Gy per fraction to a total dose of 54 Gy. Concurrently, S-1 was administered at 70 mg/m2 on days 1-14 and 29-42. The primary end point was 2-year overall survival rate. Results: Thirty patients were enrolled, and 28 patients completed the full course of radiotherapy. No grade 4 toxicity or treatment-related death occurred. The grade 3 toxicities included esophagitis (16.7%), leucopoenia (13.3%), neutropenia (10%), anaemia (3.3%), pneumonitis (3.3%) and fatigue (3.3%). The median progression-free survival time and median survival time was 19 and 24 months, respectively. The 2-year overall survival rate was 45.1%, which exceeded the predefined threshold of 2-year OS 35% and met the primary end point of the study. Conclusions: The results suggest that CCRT using S-1 is effective with mild toxicity in elderly patients with esophageal cancer. A phase III trial is needed to further evaluate this regimen. PMID- 29137321 TI - The role of indoxyl sulfate in renal anemia in patients with chronic kidney disease. AB - Renal anemia is a common complication in patients with advanced chronic kidney disease. In vitro studies have shown that indoxyl sulfate decreases erythropoietin production. Whether this effect is seen in vivo remains unclear. Our goal was to explore the role of indoxyl sulfate in renal anemia. We found serum indoxyl sulfate levels are significantly and negatively associated with erythropoietin levels in human. A multiple stepwise linear regression analyses after adjustment for other independent parameters revealed that free indoxyl sulfate, and total indoxyl sulfate were significantly associated with erythropoietin levels. In animal studies, erythropoietin gene and protein expression were markedly inhibited in rats with chronic kidney disease; however, this effect was significantly reversed by lowering serum indoxyl sulfate with AST 120. Indoxyl sulfate may also inhibit erythropoietin expression in animal models with chronic kidney disease. These findings further support the role of indoxyl sulfate in the development of renal anemia. PMID- 29137322 TI - The c-jun N-terminal kinase plays a key role in ocular degenerative changes in a mouse model of Alzheimer disease suggesting a correlation between ocular and brain pathologies. AB - Recently a range of ocular manifestations such as retinal and lens amyloid-beta accumulation and retinal nerve fiber layer loss have been proposed as potential biomarkers in Alzheimer disease (AD). The TgCRND8 mouse model of AD exhibits age dependent amyloid beta (Abeta) oligomers accumulation and cognitive defects, amyloid plaques and hyperphosphorylated Tau deposition and inflammation. We proved the correlation between ocular pathologies and AD, observing increased levels of p-APP and p-Tau, accumulation of Abeta oligomers in the retina, eye, and optic nerve. The accumulation of amyloid markers was significantly stronger in the retinal ganglion cell (RGC) layer, suggesting that RGC might be more susceptible to degeneration. We detected a thinning of the RGC layer as well as RGC death in the retina of TgCRND8 mice, by using a combination of Optical Coherence Tomography (OCT), immunofluorescence, immunohistochemistry and Western blotting techniques. We proved for the first time the key role of C-Jun N terminal Kinase (JNK) in the ocular degeneration. In support of this, the administration of the JNK inhibitor, D-JNKI1, was able to counteract the Abeta and p-Tau accumulation in the retina of TgCRND8 mice, and consequently reduce RGCs loss. These results confirm that degenerative changes in the retina/eye of AD mouse model mirrors the events observed in the brain parenchyma. Ocular changes can be detected by non-invasive imaging techniques, such as OCT, to study and test different therapeutic strategies against degenerative events associated to AD. PMID- 29137323 TI - NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction. AB - NVP-BKM120, a potent and highly selective PI3K inhibitor, is currently being investigated in phase I/II clinical trials. The mechanisms of action of NVP BKM120 in colon cancer cells are unclear. In the present study, we investigated how NVP-BKM120 suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. We found that NVP-BKM120 treatment enhance PUMA induction irrespective of p53 status through the FoxO3a pathway following AKT inhibition. Furthermore, PUMA is required for NVP-BKM120-induced apoptosis in colon cancer cells. In addition, NVP-BKM120 also synergized with 5-Fluorouracil or regorafenib to induce marked apoptosis via PUMA induction. Deficiency of PUMA suppressed apoptosis and antitumor effect of NVP-BKM120 in xenograft model. These results demonstrate a key role of PUMA in mediating the anticancer effects of NVP BKM120 and suggest that PUMA could be used as an indicator of NVP-BKM120 sensitivity, and also have important implications for it clinical applications. PMID- 29137324 TI - Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer. AB - Background: Approximately 20-25% of ovarian cancers are attributable to germline or somatic BRCA1/2 mutations, resulting in defects in the homologous recombination pathway. Inactivation of these genes can also be mediated by epigenetic changes, e.g., hypermethylation of CpG islands in the promoter regions. In such homologous recombination deficient tumors, platinum based chemotherapy is in general effective, however, loss of hypermethylation might lead to refractory disease. The aim of this study was to evaluate the stability of BRCA1 promoter hypermethylation in recurrent disease after platinum based chemotherapy. Methods: Tumor tissue from 76 patients with primary and 48 patients with platinum-sensitive recurrent high-grade ovarian cancer was collected. In a subgroup of 12 patients, 'paired' tumor tissue from primary and recurrent surgery was available. BRCA1 promoter methylation status was assessed using methylation specific polymerase chain reaction and was verified by Sanger Sequencing. Results: 73.7% (56/76) of primary and 20.8% (10/48) of recurrent tumors displayed BRCA1 promoter hypermethylation. BRCA1 promoter methylation status was not associated with progression-free- or overall survival. In the paired subgroup 83.3% (10/12) of the primary vs. 16.7% (2/12) of the recurrent tumors showed hypermethylation. In eight patients loss of BRCA1 hypermethylation was observed, whereas two patients had stable methylation status. Conclusions: Loss of BRCA1 promoter methylation may be a mechanism to restore BRCA1 function in recurrent disease. However, currently the clinical significance is still unclear and should be evaluated in prospective clinical trials. PMID- 29137325 TI - RLIM suppresses hepatocellular carcinogenesis by up-regulating p15 and p21. AB - Hepatocellular carcinogenesis results from dysregulation of oncogenes and tumor suppressors that influence cellular proliferation, differentiation and apoptosis. p15 and p21 are cyclin-dependent kinase inhibitors, which arrest cell proliferation and serve as critical tumor suppressors. Here we report that the E3 ubiquitin ligase RLIM expression is downregulated in hepatocellular carcinoma patients, and correlated with p15 and p21 expression in clinical progression. In addition, we showed that RLIM overexpression suppresses the cell growth and arrests cell cycle progression of hepatocellular carcinoma. Mechanistically, we found that RLIM directly binds to MIZ1, disrupting the interaction between c-MYC and MIZ1, and enhancing p15 and p21 transcription. Our results demonstrate that RLIM is an important suppressor in hepatocellular carcinogenesis. PMID- 29137326 TI - Overexpression of carbonic anhydrase IX induces cell motility by activating matrix metalloproteinase-9 in human oral squamous cell carcinoma cells. AB - Oral cancer is a solid malignant tumor that is prone to occur following hypoxia. There are no clear studies showing a link between hypoxia and oral carcinogenesis. Carbonic anhydrase IX (CAIX), which is a hypoxia-induced transmembrane protein, is highly expressed in various types of human cancer. However, the effects of CAIX on the metastasis of human oral cancer cells and the underlying molecular mechanisms have not been clarified. In this study, we observed that CAIX overexpression increased the migratory and invasive abilities of SCC-9 and SAS cells. In addition, CAIX overexpression increased the mRNA and protein expression of matrix metalloproteinase-9 (MMP-9) and the phosphorylation of focal adhesion kinase (FAK), steroid receptor coactivator (Src), and extracellular signal-regulated kinase 1/2 signaling proteins. CAIX overexpression also increased the binding capacity of nuclear factor-kappaB (NF-kappaB), c-Jun, and c-Fos on the MMP-9 gene promoter. In addition, treatment with MMP-9 short hairpin RNA, an MMP inhibitor (GM6001), an FAK mutant, or an MEK inhibitor (U0126) inhibited CAIX-induced cell motility in SCC-9 cells. Moreover, data sets from The Cancer Genome Atlas demonstrated that CAIX expression was significantly associated with advanced progression and poor survival in oral cancer. In conclusion, it can be inferred that CAIX overexpression induces MMP-9 gene expression, which consequently induces the metastasis of oral cancer cells. PMID- 29137327 TI - Regulation of FBXO4-mediated ICAM-1 protein stability in metastatic breast cancer. AB - Advanced or progressive cancers share common traits such as altered transcriptional modulation, genetic modification, and abnormal post-translational regulation. These processes influence protein stability and cellular activity. Intercellular adhesion molecule-1 (ICAM-1) is involved in the malignant progression of various human cancers, including breast, liver, renal, and pancreatic cancers, but protein stability has not been deal with in metastatic breast cancer. Additionally, the relevance of the stability maintenance of ICAM-1 protein remains obscure. Here, we identified a novel interaction of E3 ligase FBXO4 that is specifically presented to ICAM-1. To understand how FBXO4 modulates ICAM-1 stability, we investigated ICAM-1-overexpressing or knockdown metastatic/non-metastatic breast cancers. ICAM-1 was found to influence tumor progression and metastasis, whereas FBXO4 regulated aggressive tumorigenic conditions. These results demonstrate that FBXO4 is a major regulator of ICAM-1 stability and that alterations in the stability of ICAM-1 can influence therapeutic outcome in metastatic cancer. PMID- 29137328 TI - Trends of long noncoding RNA research from 2007 to 2016: a bibliometric analysis. AB - Purpose: This study aims to analyze the scientific output of long noncoding RNA (lncRNA) research and construct a model to evaluate publications from the past decade qualitatively and quantitatively. Methods: Publications from 2007 to 2016 were retrieved from the Web of Science Core Collection database. Microsoft Excel 2016 and CiteSpace IV software were used to analyze publication outputs, journals, countries, institutions, authors, citation counts, ESI top papers, H index, and research frontiers. Results: A total of 3,008 papers on lncRNA research were identified published by June 17, 2017. The journal, Oncotarget (IF2016, 5.168) ranked first in the number of publications. China had the largest number of publications (1,843), but the United States showed its dominant position in both citation frequency (45,120) and H-index (97). Zhang Y (72 publications) published the most papers, and Guttman M (1,556 citations) had the greatest co-citation counts. The keyword "database" ranked first in research frontiers. Conclusion: The annual number of publications rapidly increased in the past decade. China showed its significant progress in lncRNA research, but the United States was the actual leading country in this field. Many Chinese institutions engaged in lncRNA research but significant collaborations among them were not noted. Guttman M, Mercer TR, Rinn JL, and Gupta RA were identified as good candidates for research collaboration. "Database," "Xist RNA," and "Genome wide association study" should be closely observed in this field. PMID- 29137329 TI - Development of a radiolabeled caninized anti-EGFR antibody for comparative oncology trials. AB - Due to large homology of human and canine EGFR, dogs suffering from spontaneous EGFR+ cancer can be considered as ideal translational models. Thereby, novel immunotherapeutic compounds can be developed for both human and veterinary patients. This study describes the radiolabeling of a canine anti-EGFR IgG antibody (can225IgG) with potential diagnostic and therapeutic value in comparative clinical settings. Can225IgG was functionalized with DTPA for subsequent chelation with the radionuclide 99mTc. Successful coupling of 10 DTPA molecules per antibody on average was proven by significant mass increase in MALDI-TOF spectroscopy, gel electrophoresis and immunoblots. Following functionalization and radiolabeling, 99mTc-DTPA-can225IgG fully retained its binding capacity towards human and canine EGFR in flow cytometry, immuno- and radioblots, and autoradiography. The affinity of radiolabeled can225IgG was determined to KD 0.8 +/-0.0031 nM in a real-time kinetics assay on canine carcinoma cells by a competition binding technique. Stability tests of the radiolabeled compound identified TRIS buffered saline as the ideal formulation for short-term storage with 87.11 +/-6.04% intact compound being still detected 60 minutes post radiolabeling. High stability, specificity and EGFR binding affinity pinpoint towards 99mTc-radiolabeled can225IgG antibody as an ideal lead compound for the first proof-of-concept diagnostic and therapeutic applications in canine cancer patients. PMID- 29137330 TI - Virtual screening approach to identifying influenza virus neuraminidase inhibitors using molecular docking combined with machine-learning-based scoring function. AB - In recent years, an epidemic of the highly pathogenic avian influenza H7N9 virus has persisted in China, with a high mortality rate. To develop novel anti influenza therapies, we have constructed a machine-learning-based scoring function (RF-NA-Score) for the effective virtual screening of lead compounds targeting the viral neuraminidase (NA) protein. RF-NA-Score is more accurate than RF-Score, with a root-mean-square error of 1.46, Pearson's correlation coefficient of 0.707, and Spearman's rank correlation coefficient of 0.707 in a 5 fold cross-validation study. The performance of RF-NA-Score in a docking-based virtual screening of NA inhibitors was evaluated with a dataset containing 281 NA inhibitors and 322 noninhibitors. Compared with other docking-rescoring virtual screening strategies, rescoring with RF-NA-Score significantly improved the efficiency of virtual screening, and a strategy that averaged the scores given by RF-NA-Score, based on the binding conformations predicted with AutoDock, AutoDock Vina, and LeDock, was shown to be the best strategy. This strategy was then applied to the virtual screening of NA inhibitors in the SPECS database. The 100 selected compounds were tested in an in vitro H7N9 NA inhibition assay, and two compounds with novel scaffolds showed moderate inhibitory activities. These results indicate that RF-NA-Score improves the efficiency of virtual screening for NA inhibitors, and can be used successfully to identify new NA inhibitor scaffolds. Scoring functions specific for other drug targets could also be established with the same method. PMID- 29137331 TI - HDAC inhibitors enhance the immunotherapy response of melanoma cells. AB - We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney. Knock down of HDAC1, HDAC3, HDAC8 and HDAC10, but not HDAC6, recapitulated the effects of the HDAC inhibitors on the immunotherapy biomarkers. Using B16 mouse melanoma cells we discovered that pre-treatment with AR42 or sodium valproate enhanced the anti-tumor efficacy of an anti-PD-1 antibody and of an anti-CTLA4 antibody. In the B16 model, both AR42 and sodium valproate enhanced the anti-tumor efficacy of the multi-kinase inhibitor pazopanib. In plasma from animals exposed to [HDAC inhibitor + anti-PD-1], but not [HDAC inhibitor + anti-CTLA4], the levels of CCL2, CCL5, CXCL9 and CXCL2 were increased. The cytokine data from HDAC inhibitor plus anti-PD-1 exposed tumors correlated with increased activated T cell, M1 macrophage, neutrophil and NK cell infiltration. Collectively, our data support the use of pan-HDAC inhibitors in combination with kinase inhibitors or with checkpoint inhibitor antibodies as novel melanoma therapeutic strategies. PMID- 29137332 TI - Long noncoding RNA XIST is a prognostic factor in colorectal cancer and inhibits 5-fluorouracil-induced cell cytotoxicity through promoting thymidylate synthase expression. AB - A major reason for the failure of advanced colorectal cancer (CRC) treatment is the occurrence of chemoresistance to 5-fluorouracil (5FU)-based treatment. Recent studies have shown that long non-coding RNAs (lncRNAs) are critical regulators in chemoresistance. By using the next generation HiSeq sequencing assay, we identified lncRNAs showing differential expression levels in 5FU resistant and non-resistant CRC patients. RT-qPCR was then performed for validation in tissues and serum samples, and lncRNA XIST was verified to be up-regulated in non responding patients and have considerable diagnostic potential to identify responding patients from non-responding patients. In addition, increased serum XIST level was associated with poor response and lower survival rate in CRC patients receiving 5FU-based treatment. Subsequently, the 5FU resistant (5FU-R) cell lines were established, and lncRNA XIST was significantly up-regulated HT29 5FU-R and HCT116 5FU-R cells. Furthermore, knockdown of XIST reversed 5FU resistance while enhanced XIST could restrained the 5FU-induced cell cytotoxcity in both CRC cell lines. Western blotting and immunofluorescence analysis indicated that XIST promoted the expression of thymidylate synthase, a critical 5FU-targetd enzyme. In conclusion, our integrated approach demonstrates that increased expression of lncRNA XIST3 in CRC confers a potent poor therapeutic efficacy, and that lncRNA XIST participated in 5FU resistance through promoting the expression of thymidylate synthase. Thus, specific silence oflncRNA XIST could be a future direction to develop a novel therapeutic strategy to overcome 5FU resistance of CRC patients. PMID- 29137333 TI - Preoperative chronic kidney disease predicts poor oncological outcomes after radical nephroureterectomy in patients with upper urinary tract urothelial carcinoma. AB - Objective: To evaluate the impact of preoperative chronic kidney disease (CKD) on oncological outcomes in patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy. Methods: A total of 426 patients who underwent radical nephroureterectomy at five medical centers between February 1995 and February 2017 were retrospectively examined. Oncological outcomes, including intravesical recurrence-free, visceral recurrence-free, cancer specific, and overall survival rates (intravesical RFS, visceral RFS, CSS, and OS, respectively) stratified by preoperative CKD status (CKD vs. non-CKD) were investigated. Cox proportional hazards regression analysis was performed using inverse probability of treatment weighting (IPTW) to evaluate the impact of preoperative CKD on prognosis and a prognostic factor-based risk stratification nomogram was developed. Results: Of the 426 patients, 250 (59%) were diagnosed with CKD before radical nephroureterectomy. Before the background adjustment, intravesical RFS, visceral RFS, CSS, and OS after radical nephroureterectomy were significantly shorter in the CKD group than in the non-CKD group. Background adjusted IPTW analysis demonstrated that preoperative CKD was significantly associated with poor visceral RFS, CSS, and OS after radical nephroureterectomy. Intravesical RFS was not significantly associated with preoperative CKD. The nomogram for predicting 5-year visceral RFS and CSS probability demonstrated a significant correlation with actual visceral RFS and CSS (c-index = 0.85 and 0.83, respectively). Conclusions: Upper tract urothelial carcinoma patients with preoperative CKD had a significantly lower survival probability than those without CKD. PMID- 29137334 TI - The coffee diterpene kahweol enhances sensitivity to sorafenib in human renal carcinoma Caki cells through down-regulation of Mcl-1 and c-FLIP expression. AB - Sorafenib is approved for the treatment of hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC). However, low tumor response and side effects have been widely reported. Therefore, to improve the efficacy of sorafenib, we investigated whether combined treatment with sorafenib and kahweol, the coffee specific diterpene, has a synergistic effect on apoptotic cell death. Combined treatment with sorafenib and kahweol markedly induced caspase-mediated apoptosis in renal carcinoma Caki cells. Combined treatment with sorafenib and kahweol induced down-regulation of Mcl-1 and c-FLIP expression. We found down-regulation of Mcl-1 and c-FLIP expression was modulated by the ubiquitin-proteasome pathway. Ectopic expression of Mcl-1 inhibited sorafenib plus kahweol-induced apoptosis. Interestingly, combined treatment with sorafenib and kahweol induced apoptotic cell death in c-FLIP overexpressed cells. In addition, combined treatment with sorafenib and kahweol markedly induced apoptosis in human lung carcinoma (A549) and breast carcinoma (MDA-MB-361) cells, but not in human normal mesangial cells and human skin fibroblast cells (HSF). Collectively, our study demonstrates that combined treatment with sorafenib and kahweol induces apoptotic cell death through down-regulation of Mcl-1 expression. PMID- 29137335 TI - Inhibition of cell cycle progression by the hydroxytyrosol-cetuximab combination yields enhanced chemotherapeutic efficacy in colon cancer cells. AB - Hydroxytyrosol (HT), a polyphenol of olive oil, downregulates epidermal growth factor (EGFR) expression and inhibits cell proliferation in colon cancer (CC) cells, with mechanisms similar to that activated by the EGFR inhibitor, cetuximab. Here, we studied whether HT treatment would enhance the cetuximab inhibitory effects on cell growth in CC cells. HT-cetuximab combination showed greater efficacy in reducing cell growth in HT-29 and WiDr cells at concentrations 10 times lower than when used as single agents. This reduction was clearly linked to cell cycle blockade, occurring at G2/M phase. The cell cycle arrest in response to combination treatment is related to cyclins B, D1, and E, and cyclin-dependent kinase (CDK) 2, CDK4, and CDK6 down-regulation, and to the concomitant over-expression of CDK inhibitors p21 and p27. HT and cetuximab stimulated a caspase-independent cell death cascade, promotedtranslocation of apoptosis-inducing factor (AIF) from mitochondria to nucleus and activated the autophagy process. Notably, normal colon cells and keratinocytes were less susceptible to combo-induced cell death and EGFR downregulation. These results suggest a potential role of diet, containing olive oil, during cetuximab chemotherapy of colon tumor. HT may be a competent therapeutic agent in CC enhancing the effects of EGFR inhibitors. PMID- 29137336 TI - Percutaneous laser ablation for benign thyroid nodules: a meta-analysis. AB - Purpose: To evaluate percutaneous laser ablation in treating benign thyroid nodules, we conducted a meta-analysis based on summarizing existing researches. Materials and Methods: A literature search for clinical trial was performed in PubMed, Cochrane Library and Excerpt Medica Database. The qualities of included studies were evaluated. We calculated the indexes with mean difference. Heterogeneity and publication bias were tested and explored. We performed subgroup analyses and sensitivity analysis further. Results: A total of 19 researches and 2137 patients were included in this meta-analysis. The pooled estimates of nodule volume were statistically significant after percutaneous laser ablation for 1 month, 3 month, 6month, 12month, 24month and 36month(P < 0.05). The pooled estimate of thyroid-stimulating hormone was statistically significant after percutaneous laser ablation for 1 and 12 month (P = 0.008 and P = 0.03). The pooled estimate of free triiodothyronine was no statistically significant after percutaneous laser ablation for all follow-up intervals. The pooled estimate of free tetraiodothyronin was statistically significant after percutaneous laser ablation1 month (P = 0.004). The pooled estimate of thyroglobulin was statistically significant after percutaneous laser ablation 24 month (P = 0.04). The heterogeneity was found and the source of heterogeneity was explored in nodule volume for 6 and 12 month. No publication bias was found. Conclusions: This meta-analysis demonstrated that percutaneous laser ablation was safe and useful in shrinking benign thyroid nodules volume, improving thyroid function, relieving symptoms of pressure and esthetic, especial for hyper vascular benign thyroid nodules. Larger number of high-quality prospective studies still needs to be performed. PMID- 29137337 TI - Alcohol consumption and gastric cancer risk: a meta-analysis of prospective cohort studies. AB - We performed this meta-analysis to explore the precise quantification relationship between alcohol consumption and gastric cancer and to provide evidence for preventing gastric cancer. We searched PubMed, Embase, and Web of Science for articles published up to December 2016, and identified 23 cohort studies that included a total population of 5,886,792 subjects. We derived meta analytic estimates using random-effects models, taking into account correlations between estimates. We also investigated the dose-response relationship between gastric cancer risk and alcohol consumption. We found that alcohol consumption increased gastric cancer risk, where the summary risk ratio was 1.17 (95% confidence interval (CI): 1.00-1.34; I2 = 79.6%, p < 0.05. The dose-response analysis showed that every 10 g/d increment in alcohol consumption was associated with 7% increased gastric cancer risk (95% CI 1.02-1.12; I2 = 28.9%, p = 0.002). This meta-analysis provides evidence that alcohol consumption is an important risk factor of the incidence of gastric cancer. PMID- 29137338 TI - Effect of long non-coding RNA highly up-regulated in liver cancer (HULC) on the prognosis of cancer: a meta-analysis. AB - Some studies investigated the association between highly up-regulated in liver cancer (HULC) and the overall survival (OS) of cancer. However, the results were conflicted and inconclusive. Therefore, we performed this meta-analysis to determine the association between HULC and the OS of cancer. A comprehensive online search was conducted on Online electronic databases (PubMed, EMBASE, and Wanfang database) from the earliest date to Aug 30, 2016. The strength of the association was calculated with the HRs and respective 95% CIs. The expression of HULC was significantly associated with OS of cancers (HR = 2.12; 95% CI 1.61 - 2.79; P<0.00001). In the subgroup analysis by ethnicity, the expression of HULC was significantly associated with OS in Chinese patients (HR = 2.04; 95% CI 1.55 2.70; P<0.00001). In the subgroup analysis by cancer type, HULC was associated with OS in osteosarcoma patients (HR = 3.36; 95% CI 1.02 - 11.07; P = 0.05) and in gastric cancer patients (HR = 2.17; 95% CI 1.08 - 4.38; P = 0.03). We performed the sensitivity analysis to assess the stability of the meta-analysis. A significant association was found in studies with adjustment (HR = 2.01; 95% CI 1.35 - 2.99; P= 0.0006). In conclusion, this meta-analysis suggested that high expression of HULC was significantly associated with OS of cancer. PMID- 29137339 TI - Meta-analysis of differences in Constant-Murley scores for three mid-shaft clavicular fracture treatments. AB - There is no consensus on the optimal treatment for mid-shaft clavicular fracture. We conducted a meta-analysis to compare the effectiveness of non-operative treatment, plate fixation, and intramedullary pin fixation in terms of the Constant-Murley Score (CMS) for treatment of mid-shaft clavicular fracture. Comprehensive search of the Embase, Cochrane Library and PubMed was conducted to retrieve relevant randomized controlled trials (RCTs). A random-effect network meta-analysis was conducted within a Bayesian framework using Markov Chain Monte Carlo (MCMC) in OpenBUGS 3.2.2. Differences in CMS among the three treatments analyzed were evaluated with weighted mean difference (WMD) and surface under the cumulative ranking curves (SUCRA). Eleven studies met our inclusion criteria and were included in our network meta-analysis. Our results revealed that in terms of CMS followed-up for six months, the efficacies of plate fixation and intramedullary pin fixation were higher than non-operative treatment (plate fixation: WMD = 4.70, 95% CI = 1.21 ~ 7.83; intramedullary pin fixation: WMD = 6.71, 95% CI = 3.20 ~ 10.39), and intramedullary pin fixation had better efficacy than plate fixation, had better efficacy. However, no differences were found between the efficacies of the three treatments in pairwise comparisons with respect to CMS followed-up for six weeks, three months, 12 months and 24 months. In addition, the cluster analysis showed that intramedullary pin fixation had the best efficacy for patients with mid-shaft CF, followed by plate fixation and non operative treatment. These analyses suggest intramedullary pin fixation may be the optimal therapeutic approach for mid-shaft clavicular fracture patients. PMID- 29137341 TI - Clinicopathological significance of the p16 hypermethylation in multiple myeloma, a systematic review and meta-analysis. AB - It is well known that the loss of function of the p16INK4A gene is mainly caused by the hypermethylation of the p16 gene; however, whether or not the inactivation is associated with the clinical significance of multiple myeloma (MM) remains elusive. A meta-analysis was conducted to quantitatively determine the role of the p16 hypermethylation in the clinical significance of MM. We demonstrated that MM patients show much higher hypermethylation rates on the p16 gene in bone marrow compared to normal individuals, as well as monoclonal gammopathy of undetermined significance (MGUS). The difference of aberrant p16 hypermethylation between MM patients in advanced stage and MM patients in early stage is not statistically significant. Interestingly, the survival rate of MM patients with the p16 hypermethylation is much shorter compared to those without the p16 hypermethylation. Our results demonstrate that hypermethylation status of the p16 gene may play a role in the progression of MGUS to MM, as well as worse survival in MM. The p16 hypermethylation, which induces the loss of function of the p16 gene that plays a critical role in the early tumorigenesis of MM. PMID- 29137340 TI - Prognostic role of tumour-associated macrophages and macrophage scavenger receptor 1 in prostate cancer: a systematic review and meta-analysis. AB - Recent studies suggested that the tumour associated macrophages may be associated with prostate cancer outcome. A meta-analysis was performed to evaluate the prognostic value of tumor associated macrophages and macrophage scavenger receptor 1, marker for a subset of macrophages, by pooled hazard ratio and 95% confidence intervals from qualified studies following a systemic search. The results indicate that higher infiltration of tumor associated macrophages predicts poor overall survival (HR=1.57, 95%CI: 1.15-1.98), but not biochemical recurrence (HR=1.01, 95%CI: 0.98-1.04) or recurrence-free survival (HR=1.03, 95%CI: 0.05-2.01). In contrast, elevated level of macrophage scavenger receptor 1 was significantly associated with better recurrence-free survival (HR=3.26, 95%CI: 1.22-5.29). Thus, our analysis confirmed the prognostic value of these markers in prostate cancer outcome. We also discussed potential causes of the controversies in the literature and future research directions. PMID- 29137342 TI - Incidence and relative risk of cutaneous squamous cell carcinoma with single agent BRAF inhibitor and dual BRAF/MEK inhibitors in cancer patients: a meta analysis. AB - Background: BRAF inhibitor and dual BRAF/MEK inhibitors have been approved for the treatment of BRAF-mutated melanoma. Cutaneous squamous cell carcinoma (cuSCC) is an adverse event associated with these drugs. The contribution of BRAF inhibitor and dual BRAF/MEK inhibitors to cuSCC are still unknown. We performed this meta-analysis to determine the overall incidence and relative risk of cuSCC in cancer patients treated with these drugs. Results: A total of 7,442 patients from 24 primary studies were included. The incidences of all-grade and high-grade cuSCC in cancer patients treated with BRAF inhibitor were 12.5% (95% CI: 10.8 14.6%) and 11.6% (95% CI: 9.8-13.8%), and dual BRAF/MEK inhibitors were 3.0% (95% CI: 2.0-4.5%) and 2.8% (95% CI: 1.9-4.0%), respectively. On subgroup analysis and meta-regression, the incidence of cuSCC did not vary with tumor type, study design and specific drug used. The use of single agent BRAF inhibitor significantly increased the risk of developing cuSCC comparing with dual BRAF/MEK inhibitors for all-grade (RR 4.72, 95% CI: 2.42-9.20) and high-grade (RR 4.92, 95% CI: 2.64-9.16) in cancer patients. Materials and Methods: The databases of PubMed, Embase and abstracts published in ASCO proceedings were searched for relevant studies from January 2000 to June 2017. Summary incidences, relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models according to the heterogeneity of included studies. Conclusions: BRAF inhibitor significantly increases the risk of developing cuSCC compared with dual BRAF/MEK inhibitors in cancer patients. Clinicians should be aware of the risks of cuSCC with the administration of these drugs in cancer patients. PMID- 29137343 TI - Prognostic value of lncRNAs in lung carcinoma: a meta-analysis. AB - Many different long non-coding RNAs (lncRNAs) have been reported to be abnormally expressed in lung carcinoma and may thus serve as prognostic biomarkers for this disease. We conducted this meta-analysis, which included a total of 30 studies identified via searches of PubMed, Embase, Medline, and Web of Science and included 2912 patients from China (28), Germany (1), and Japan (1), to investigate the prognostic value of different lncRNAs in lung carcinoma. The results revealed that lncRNA transcription levels were significantly associated with overall survival in lung cancer patients (HR:1.46, 95% CI: 1.16-1.83, P = 0.000). However, lncRNA transcription levels were not associated with progression free survival (PFS) (HR: 1.55, 95% CI: 0.50-4.80, P = 0.449). Further analysis showed that high lncRNA transcription levels were significantly associated with tumour-node-metastasis (TNM) stage (III/IV vs I/II: RR = 1.339, 95% CI: 1.046 1.716, P = 0.012), lymph node metastasis (positive vs negative: RR = 1.442, 95% CI: 1.103-1.885, P = 0.007), and distant metastasis (yes vs no: RR = 3.187,95% CI: 1.393-7.294, P = 0.006). Taken together, the results of our present meta analysis revealed that lncRNAs may be useful prognostic markers for lung carcinoma and may also have value as biomarkers for TNM stage, lymph node metastasis and distant metastasis. PMID- 29137344 TI - Red and processed meat consumption and colorectal cancer risk: a systematic review and meta-analysis. AB - The associations between red and processed meat consumption and the risk of colorectal cancer types have not been conclusively defined. We performed a systematic review and meta-analysis to analyze these associations. We searched PubMed and EMBASE to identify studies published from inception through September 2016. Dose-response, subgroup and subtype analyses of colorectal cancer (colon cancer, proximal colon cancer, distal colon cancer and rectal cancer) were performed. We ultimately selected 60 eligible studies. Positive associations were observed for colorectal cancer in case-control studies (red meat, P<0.01; processed meat, P<0.01) and cohort studies (red meat, P<0.01; processed meat, P<0.01). However, subtype analyses yielded null results for distal colon cancer in case-control studies (P=0.41) and cohort studies (P=0.18) for red meat and null results for proximal colon cancer in case-control studies (P=0.13) and cohort studies (P=0.39) for processed meat. Additionally, although the results of case-control studies were positive (red meat, P<0.01; processed meat, P=0.04) for rectal cancer, there were no positive associations between red (P=0.34) and processed meat (P=0.06) consumption and the risk in cohort studies. In a systematic review and meta-analysis, we found consumption of red and processed meat was associated with the risk of overall colorectal cancer but not rectal cancer. Additionally, there were no associations between the consumption of red meat and distal colon cancer risk and between the consumption of processed meat and proximal colon cancer risk. PMID- 29137345 TI - The efficacy and safety of adjunctive corticosteroids in the treatment of tuberculous pleurisy: a systematic review and meta-analysis. AB - Purpose: To evaluate the efficacy and safety of adjunctive corticosteroids in the treatment of patients with tuberculous pleurisy. Methods: The PubMed, Cochrane, Medline, Embase, Web of Science and Chinese National Knowledge Infrastructure were searched. Clinical trials of corticosteroids compared with control were eligible for inclusion. Results: Ten studies (6 randomized controlled trials [RCTs] and 4 non-RCTs) with 957 participants met the inclusion criteria. Compared to the controls (placebos or non-steroids), adjunctive corticosteroid use reduced the risk of residual pleural fluid after 4 weeks and the number of days to symptom improvement; however, there was no convincing evidence to support the positive effects of corticosteroids over the long term (8 weeks) on residual pleural fluid, pleural thickening, or pleural adhesions, and there was no statistical difference between the corticosteroid group and control group with respect to 7-days relief of the clinical symptoms or death from any cause. In addition, more adverse events were observed in patients who received corticosteroids than in those in the control group. Conclusions: Our results suggest that adjunctive corticosteroid use did not improve long-term efficacy and might induce more adverse events, although the risk of residual pleural fluid at 4 weeks and the number of days to symptom improvement were reduced. PMID- 29137346 TI - Safety of the neprilysin/renin-angiotensin system inhibitor LCZ696. AB - Objectives: The combined neprilysin/rennin-angiotensin system inhibitor sacubitril/valsartan (LCZ696) has shown its superiority over ACEI/ARB therapy. In view of the existing concern of its adverse effects, we aimed to provide evidence of the safety of the new drug. Results: A total of 6 randomized trials with 11,821 subjects were included in this analysis. No significant differences were found in any adverse effects between LCZ696 and ACEI/ARB or placebo groups. LCZ696 significantly decreased the risks of serious adverse events and death compared with ACEI/ARB. LCZ696 also significantly decrease the risk of discontinuation of treatment for any adverse event no matter compared with ACEI/ARB or a placebo. LCZ696 significantly increased the risk of angioedema and dizziness, while it decreased the risk of renal dysfunction and bronchitis. There was no difference for hypotension, hyperkalemia, cough, upper respiratory tract inflammation, diarrhoea, back pain, nasopharyngitis, headache and influenza between the LCZ696 group and the ACEI/ARB group. Materials and Methods: A meta analysis of eligible studies that used LCZ696 in heart failure and hypertension was performed. Embase, PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) with data on any adverse effects, serious adverse events, discontinuation of treatment for any adverse event, death, angioedema, hypotension, hyperkalemia, and other adverse effects to perform this meta-analysis. Conclusions: In addition to the beneficial effect of LCZ696 on end point events, the available evidences showed that LCZ696 was associated with less drug-risks than a placebo and ACEI/ARB. PMID- 29137347 TI - Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone. AB - Data have demonstrated that COCs, besides offering a satisfactory and safe contraception, offer a variety of non-contraceptive health benefits and therapeutic positive aspects. Many prescribes and users, however, do not realize these positive aspects especially the non-contraceptive health benefits. While the contraceptive use is the primary indication for COC use for most women, these users should be advised in regard of the non-contraceptive benefits when contraception is discussed and prescribed. Using COCs specifically for non contraceptive indications is an off-label use in many clinical situations (only some exceptions as e.g. acne vulgaris in some countries are allowed clinical entities for the use of these drugs). Therefore, appropriate discussions with the patient regarding this fact should performed and documented by the prescribing physicians. Independent of the off-label situation, COCs containing the newer progestogens dienogest and drospirenone with their antiandrogenic and antimineralocorticoid health benefits play an important role in the management of many diseases and their use should therefore be considered by clinician's. This review will focus on the effects of these COCs on the endometrium, the skin, the fat tissue and the premenstrual syndrome. PMID- 29137348 TI - Reverse phase protein array (RPPA) combined with computational analysis to unravel relevant prognostic factors in non- small cell lung cancer (NSCLC): a pilot study. AB - In this work high throughput technology and computational analysis were used to study two stage IV lung adenocarcinoma patients treated with standard chemotherapy with markedly different survival (128 months vs 6 months, respectively) and whose tumor samples exhibit a dissimilar protein activation pattern of the signal transduction. Tumor samples of the two patients were subjected to Reverse Phase Protein Microarray (RPPA) analysis to explore the expression/activation levels of 51 signaling proteins. We selected the most divergent proteins based on the ratio of their RPPA values in the two patients with short (s-OS) and long (l-OS) overall survival (OS) and tested them against a EGFR-IGF1R mathematical model. The model with RPPA data showed that the activation levels of 19 proteins were different in the two patients. The four proteins that most distinguished the two patients were BADS155/136 and c KITY703/719 having a higher activation level in the patient with short survival and p70S6S371/T389 and b-RAFS445 that had a lower activation level in the s-OS patient. The final model describes the interactions between the MAPK and PI3K mTOR pathways, including 21 nodes. According to our model mTOR and ERK activation levels were predicted to be lower in the s-OS patient than the l-OS patient, while the AMPK activation level was higher in the s-OS patient. Moreover, KRAS activation was predicted to be higher in the l-OS KRAS-mutated patient. In accordance with their different biological properties, the Moment Independent Robustness Indicator in s-OS and l-OS predicted the interaction of MAPK and mTOR and the crosstalk AKT with p90RSK as candidates to be prognostic factors and drug targets. PMID- 29137349 TI - Tumor Trp53 status and genotype affect the bone marrow microenvironment in acute myeloid leukemia. AB - The genetic heterogeneity of acute myeloid leukemia (AML) and the variable responses of individual patients to therapy suggest that different AML genotypes may influence the bone marrow (BM) microenvironment in different ways. We performed gene expression profiling of bone marrow mesenchymal stromal cells (BM MSC) isolated from normal C57BL/6 mice or mice inoculated with syngeneic murine leukemia cells carrying different human AML genotypes, developed in mice with Trp53 wild-type or nullgenetic backgrounds. We identified a set of genes whose expression in BM-MSC was modulated by all four AML genotypes tested. In addition, there were sets of differentially-expressed genes in AML-exposed BM-MSC that were unique to the particular AML genotype or Trp53 status. Our findings support the hypothesis that leukemia cells alter the transcriptome of surrounding BM stromal cells, in both common and genotype-specific ways. These changes are likely to be advantageous to AML cells, affecting disease progression and response to chemotherapy, and suggest opportunities for stroma-targeting therapy, including those based on AML genotype. PMID- 29137350 TI - IL2RG, identified as overexpressed by RNA-seq profiling of pancreatic intraepithelial neoplasia, mediates pancreatic cancer growth. AB - Pancreatic ductal adenocarcinoma evolves from precursor lesions, the most common of which is pancreatic intraepithelial neoplasia (PanIN). We performed RNA sequencing analysis of laser capture microdissected PanINs and normal pancreatic duct cells to identify differentially expressed genes between PanINs and normal pancreatic duct, and between low-grade and high-grade PanINs. One of the most highly overexpressed transcripts identified in PanIN is interleukin-2 receptor subunit gamma (IL2RG) encoding the common gamma chain, IL2Rgamma. CRISPR-mediated knockout of IL2RG in orthotopically implanted pancreatic cancer cells resulted in attenuated tumor growth in mice and reduced JAK3 expression in orthotopic tumors. These results indicate that IL2Rgamma/JAK3 signaling contributes to pancreatic cancer cell growth in vivo. PMID- 29137351 TI - MicroRNA-200, associated with metastatic breast cancer, promotes traits of mammary luminal progenitor cells. AB - MicroRNAs are critical regulators of gene networks in normal and abnormal biological processes. Focusing on invasive ductal breast cancer (IDC), we have found dysregulated expression in tumor samples of several microRNAs, including the miR-200 family, along progression from primary tumors to distant metastases, further reflected in higher blood levels of miR-200b and miR-7 in IDC patients with regional or distant metastases relative to patients with primary node negative tumors. Forced expression of miR-200s in MCF10CA1h mammary cells induced an enhanced epithelial program, aldehyde dehydrogenase (ALDH) activity, mammosphere growth and ability to form branched tubuloalveolar structures while promoting orthotopic tumor growth and lung colonization in vivo. MiR-200s also induced the constitutive activation of the PI3K-Akt signaling through downregulation of PTEN, and the enhanced mammosphere growth and ALDH activity induced in MCF10CA1h cells by miR-200s required the activation of this signaling pathway. Interestingly, the morphology of tumors formed in vivo by cells expressing miR-200s was reminiscent of metaplastic breast cancer (MBC). Indeed, the epithelial components of MBC samples expressed significantly higher levels of miR-200s than their mesenchymal components and displayed a marker profile compatible with luminal progenitor cells. We propose that microRNAs of the miR 200 family promote traits of highly proliferative breast luminal progenitor cells, thereby exacerbating the growth and metastatic properties of transformed mammary epithelial cells. PMID- 29137353 TI - Mesenchymal stem cells inhibit RANK-RANKL interactions between osteoclasts and Th17 cells via osteoprotegerin activity. AB - Th17 cells play a critical role in several autoimmune diseases, including psoriasis and psoriatic arthritis (PsA). Psoriasis is a chronic inflammatory skin disease associated with systemic inflammation and comorbidities, such as PsA. PsA develops in nearly 70% of patients with psoriasis, and osteoclasts associated bone erosion is a hallmark of the disease. Thus far, the effect of Th17 cells on osteoclastogenesis via direct cell-to-cell interactions is less understood. In this study, we observed that Th17 cells directly promote osteoclast differentiation and maturation via expression of receptor activator of nuclear factor-kappa beta ligand (RANKL) in vitro. We investigated the impact of conditioned medium obtained from human palatine tonsil-derived mesenchymal stem cells (T-CM) on the interactions between osteoclasts and Th17 cells. T-CM effectively blunted the RANK-RANKL interaction between the osteoclast precursor cell line RAW 264.7 and Th17 cells via osteoprotegerin (OPG) activity. The frequency of tartrate-resistant acid phosphatase (TRAP)-positive cells in the bone marrow of an imiquimod (IMQ)-induced psoriasis mouse model was decreased following T-CM injection. Therefore, our data provide novel insight into the therapeutic potential of tonsil-derived mesenchymal stem cell-mediated therapy (via OPG production) for the treatment of pathophysiologic processes induced by osteoclasts under chronic inflammatory conditions such as psoriasis. PMID- 29137352 TI - Maternal high calorie diet induces mitochondrial dysfunction and senescence phenotype in subcutaneous fat of newborn mice. AB - Mitochondrial dysfunction, inflammation and senescence-like features are observed in adipose depots in aging and obesity. Herein, we evaluated how maternal high calorie diet (HCD) may impact on subcutaneous adipose tissue (sAT) of the newborn mice. Adult C57BL/6J mice were randomly divided in three groups: normal calorie diet (NCD), HCD and HCD supplemented with niacin 8 weeks before mating. Mothers and pups were then sacrificed and metabolic and molecular analyses were carried out on sAT. HCD induced mitochondria dysfunction in mothers without inflammation and senescence, whereas in pups we also revealed the occurrence of senescent phenotype. The mitochondrial dysfunction-associated senescence in pups was accompanied by a drop in NAD+/NADH ratio and alteration in the NAD+-dependent enzymes PARP1 and SIRT1. Importantly, maternal dietary supplementation with niacin during gestation and lactation restrained NAD+/NADH decrease imposed by HCD limiting inflammatory cytokine production and senescence phenotype in newborn sAT. Given the fundamental role of sAT in buffering nutrient overload and avoiding pathogenic ectopic fat accumulation, we suggest that NAD+ boosting strategies during maternal HCD could be helpful in limiting sAT dysfunction in newborn. PMID- 29137354 TI - ERpS294 is a biomarker of ligand or mutational ERalpha activation and a breast cancer target for CDK2 inhibition. AB - ERalpha phosphorylation at hinge site S294 (pS294) was recently shown to be essential for ER-dependent gene transcription and mediated by an unknown cyclin dependent kinase (CDK). This study was undertaken to identify the exact CDK pathway mediating pS294 formation, and to determine if this phosphorylation event occurs with, and can be targeted to treat, the ligand-independent growth of breast cancers expressing endocrine-refractory ESR1 mutations. Using a newly developed anti-pS294 monoclonal antibody, a combination of CDK specific siRNA knockdown studies and a broad panel of CDK selective inhibitors against ligand (E2)-stimulated MCF7 cells, we first identified CDK2 as the primary mediator of pS294 formation and showed that CDK2-selective inhibitors like Dinaciclib, but not CDK4/6 inhibitors like Palbociclib, can selectively prevent pS294 formation and repress ER-dependent gene expression. We then expressed the ER-activating mutations ERmut(Y537S) and ERmut(D538G) in MCF7 cells, and demonstrated their ability to induce ligand-independent and tamoxifen-resistant growth, associated with constitutive and CDK2-dependent pS294 expression. Following robust growth of E2-independent and TAM-resistant MCF7mutER(Y537S) tumors in vivo, nude mice were also treated with either Dinaciclib or Palbociclib at doses and injection schedules unable to retard tumor growth as single agents; the TAM plus Palbociclib combination arrested further tumor growth without affecting pS294 formation, while the TAM plus Dinaciclib combination produced tumor regression associated with loss of pS294 expression. These findings, and our proposed mechanistic model, provide new rationale for the clinical evaluation of CDK2 inhibitors given in combination with endocrine agents as a new treatment strategy against ESR1 mutation expressing breast cancers. PMID- 29137355 TI - A pilot study evaluating concordance between blood-based and patient-matched tumor molecular testing within pancreatic cancer patients participating in the Know Your Tumor (KYT) initiative. AB - Recent improvements in next-generation sequencing (NGS) technology have enabled detection of biomarkers in cell-free DNA in blood and may ultimately replace invasive tissue biopsies. However, a better understanding of the performance of blood-based NGS assays is needed prior to routine clinical use. As part of an IRB approved molecular profiling registry trial of pancreatic ductal adenocarcinoma (PDA) patients, we facilitated blood-based NGS testing of 34 patients from multiple community-based and high-volume academic oncology practices. 23 of these patients also underwent traditional tumor tissue-based NGS testing. cfDNA was not detected in 9/34 (26%) patients. Overall concordance between blood and tumor tissue NGS assays was low, with only 25% sensitivity of blood-based NGS for tumor tissue NGS. Mutations in KRAS, the major PDA oncogene, were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies. The presence of mutations in circulating DNA was associated with reduced overall survival (54% in mutation-positive versus 90% in mutation-negative). Our results suggest that in the setting of previously treated, advanced PDA, liquid biopsies are not yet an adequate substitute for tissue biopsies. Further refinement in defining the optimal patient population and timing of blood sampling may improve the value of a blood-based test. PMID- 29137356 TI - Disruption of STAT3-DNMT1 interaction by SH-I-14 induces re-expression of tumor suppressor genes and inhibits growth of triple-negative breast tumor. AB - Epigenetic regulation of gene expression is an emerging target to treat several human diseases including cancers. In cancers, expressions of many tumor suppressor genes are suppressed by hyper-methylation in their regulatory regions. Herein, we describe a novel carbazole SH-I-14 that decreased the level of the acetyl-STAT3 at the K685 residue. Mutation analysis revealed that SH-I-14 disrupted STAT3-DNMT1 interaction by removing acetyl group from K685 of STAT3. Finally, the inhibition of STAT3-DNMT1 interaction by SH-I-14 resulted in re expression of tumor suppressor genes such as VHL and PDLIM4 through de methylation of their promoter regions. In addition, SH-I-14 showed anti proliferative effect in triple-negative breast cancer (TNBC) cell lines in vitro and anti-tumor effect in a mouse xenograft model of MDA-MB-231 tumor. Taken together, our results suggest that targeting acetyl-STAT3 (K685) provides potential therapeutic opportunity to treat a subset of human cancers. PMID- 29137357 TI - AKR7A3 suppresses tumorigenicity and chemoresistance in hepatocellular carcinoma through attenuation of ERK, c-Jun and NF-kappaB signaling pathways. AB - Hepatocellular carcinoma (HCC), which accounts for 85-90% of primary liver cancer, is now the second leading cause of cancer-related mortality worldwide. Here we reported that Aldo-Keto Reductase family 7A isoform 3 (AKR7A3) is frequently down-regulated in HCC, associating with poor overall survival rate, elevated serum alpha-fetoprotein (AFP) and poor differentiation of HCC. The promoter region of AKR7A3 was detected to be hypermethylated. Loss of heterozygosity (LOH) was also detected in AKR7A3. Functional assays on both AKR7A3 overexpressed and knockdown cells, including foci formation, colony formation in soft agar, migration, invasion and tumor formation in nude mice, demonstrated the strong tumor suppressive functions of AKR7A3. In addition, treatment of chemotherapy drug cisplatin showed that AKR7A3 sensitizes tumor cells to apoptosis. Mechanistically, western blot analysis showed that overexpression of AKR7A3 inhibits the activation of ERK, c-Jun and NF-kappaB. In summary, we found that AKR7A3 functions as a tumor suppressor gene in HCC through attenuating c-Jun, ERK and NF-kappaB signaling pathways. PMID- 29137358 TI - TM4SF5 promotes metastatic behavior of cells in 3D extracellular matrix gels by reducing dependency on environmental cues. AB - Transmembrane 4 L six family member 5 (TM4SF5) is highly expressed in hepatocellular carcinoma tissues and enhances migration in two-dimensional environments. Here, we investigated how TM4SF5 is involved in diverse pro metastatic phenotypes in in vivo-like three-dimensional (3D) extracellular matrix gels. TM4SF5-positive cells aggressively formed invasive foci in 3D Matrigel, depending on TM4SF5-mediated signaling activity, cytoskeletal organization, and matrix metallopeptidase (MMP) 2-mediated extracellular remodeling, whereas TM4SF5 null cells did not. The TM4SF5-null cells did, however, form invasive foci in 3D Matrigel following inhibition of Rho-associated protein kinase or addition of collagen I, suggesting that collagen I compensated for TM4SF5 expression. Similarly, TM4SF5-positive cells expressing vascular endothelial-cadherin formed network-like vasculogenic mimicry in 3D Matrigel and collagen I mixture gels, whereas TM4SF5-negative cells in the mixture gels displayed the network structures only upon further treatment with epidermal growth factor. The foci formation also required MMP2-mediated remodeling of the extracellular matrix. Co cultures exhibited TM4SF5-positive or cancer-associated fibroblasts at the outward edges of TM4SF5-null cell clusters. Compared with TM4SF5-null cells, TM4SF5-positive cells in 3D collagen gels showed a more invasive outgrowth with dramatic invadopodia. These observations suggest that TM4SF5 plays roles in the promotion of diverse metastatic properties with fewer environmental requirements than TM4SF5-negative cells. PMID- 29137359 TI - Granulysin expressed in a humanized mouse model induces apoptotic cell death and suppresses tumorigenicity. AB - Granulysin (GNLY) is a cytolytic and proinflammatory protein expressed in activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Conventional mouse models cannot adequately address the triggering mechanism and immunopathological pathways in GNLY-associated diseases due to lack of the GNLY gene in the mouse genome. Therefore, we generated a humanized immune system (HIS) mouse model by transplanting human umbilical cord blood mononuclear cells into NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice after sublethally irradiation. We examined the GNLY expression and its effects on tumor growth using this system. Our HIS mice expressed human CD45+, CD4+, CD8+ and CD56+ cells in the peripheral blood and spleen. A high expression level of human Th1/Th2 and NK cytokines was detected, indicating the activation of both T and NK cells. Importantly, we found an elevated level of GNLY in the serum and it was produced by human CTLs and NK cells obtained from the peripheral blood mononuclear cells and spleen cells in the HIS mice. The serum level of GNLY was negatively correlated with the proliferation of transplanted tumor cells in HIS mice. Collectively, our findings strongly supported that HIS mouse as a valuable model for studying human cancer under an intact immune system and the role of GNLY in tumorigenesis. PMID- 29137360 TI - Novel mechanisms for crotonaldehyde-induced lung edema. AB - Background: Crotonaldehyde is a highly noxious alpha,beta-unsaturated aldehyde in cigarette smoke that causes edematous acute lung injury. Objective: To understand how crotonaldehyde impairs lung function, we examined its effects on human epithelial sodium channels (ENaC), which are major contributors to alveolar fluid clearance. Methods: We studied alveolar fluid clearance in C57 mice and ENaC activity was examined in H441 cells. Expression of alpha- and gamma-ENaC was measured at protein and mRNA levels by western blot and real-time PCR, respectively. Intracellular ROS levels were detected by the dichlorofluorescein assay. Heterologous alphabetagamma-ENaC activity was observed in an oocyte model. Results: Our results showed that crotonaldehyde reduced transalveolar fluid clearance in mice. Furthermore, ENaC activity in H441 cells was inhibited by crotonaldehyde dose-dependently. Expression of alpha- and gamma-subunits of ENaC was decreased at the protein and mRNA level in H441 cells exposed to crotonaldehyde, which was probably mediated by the increase in phosphorylated extracellular signal-regulated protein kinases 1 and 2. ROS levels increased time dependently in cells exposed to crotonaldehyde. Heterologous alphabetagamma-ENaC activity was rapidly eliminated by crotonaldehyde. Conclusion: Our findings suggest that crotonaldehyde causes edematous acute lung injury by eliminating ENaC activity at least partly via facilitating the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 signal molecules. Long term exposure may decrease the expression of ENaC subunits and damage the cell membrane integrity, as well as increase the levels of cellular ROS products. PMID- 29137361 TI - Downregulation of miR-199a-5p promotes prostate adeno-carcinoma progression through loss of its inhibition of HIF-1alpha. AB - Hypoxia-inducible factor-1 alpha (HIF-1alpha) plays key roles in cell survival under both hypoxia and normoxia conditions. Regulation of HIF-1alpha is complex and involves numerous molecules and pathways, including post-transcriptional regulation by microRNAs (miRNAs). Although upregulation of HIF-1alpha has been shown to promote prostate adenocarcinoma (PCa) progression, the mechanism by which miRNAs modulate HIF-1alpha in prostate cancer has not been clarified. Here, we show that miR-199a-5p is underexpressed in prostate adenocarcinoma. Artificial overexpression of miR-199a-5p decreased cell proliferation, motility, and tumor angiogenesis and increased apoptosis in PCa cell liness PC-3 and DU145 by directly targeting the 3'-untranslated region (UTR) of HIF-1alpha mRNA, which reduced HIF-1alpha levels as well as downstream genes transactivated by HIF 1alpha (such as VEGF, CXCR4, BNIP3 and BCL-xL). Abnormalities of miR-199a-HIF regulation may contribute significantly to PCa pathogenesis and progression. PMID- 29137362 TI - An optimized HMGB1 expressed by recombinant rabies virus enhances immunogenicity through activation of dendritic cells in mice. AB - Rabies remains an important public health threat, killing approximately 59,000 people worldwide annually, most of which are from the developing countries of Africa and Asia where dog rabies are endemic. Therefore, developing an affordable and efficacious vaccine for dog-mediated rabies control is needful in these countries. Our previous studies indicated that over-expression of granulocyte macrophage colony stimulating factor (GM-CSF) or macrophage inflammatory protein 1 (MIP-1alpha or CCL3) by recombinant rabies virus (rRABV) could enhance the immunogenicity by activating dendritic cells (DCs). In this study, to further characterize the role of activating DCs in RABV immunogenicity, High mobility group box 1 (HMGB1), a highly conserved and non-histone chromosomal protein that can promote DCs maturation and activation, were investigated. The wild-type HMGB1 (HMGB1wt) and an optimized HMGB1 (HMGB1mut) were individually inserted into the genome of the rRABV strain LBNSE (designated as LBNSE-HMGB1wt and LBNSE-HMGB1mut, respectively), and the effect of over-expression of HMGB1 on the immunogenicity of RABV was investigated. The results demonstrated that LBNSE-HMGB1mut could promote significantly more DCs activation, and the recruitment of follicular helper T, germinal center B and plasma cells in vaccinated mice than those immunized with LBNSE-HMGB1wt or parent virus LBNSE. Further investigations suggested that mice vaccinated with LBNSE-HMGB1mut produced significantly higher level of RABV-neutralizing antibodies and offered a better protection than those vaccinated with LBNSE or LBNSE-HMGB1wt. Taken together, these data provides a better understanding of the mechanism for HMGB1 as a potential adjuvant in enhancing the immunogenicity of RABV, which would contribute to developing more efficacious rabies vaccines. PMID- 29137363 TI - Comparison of the 7th and 8th editions of the American joint committee on cancer TNM classification for patients with stage III gastric cancer. AB - Background and Objectives: The eighth TNM edition for gastric cancer was released in 2016 and included major revisions, especially of stage III. The purpose of this study was to evaluate the prognostic value of the new AJCC TNM classification in comparison with the 7th edition for stage III gastric cancer. Methods: Clinical and histopathological data on 1,496 patients operated on for stage III GC according to the seventh edition between 2005 and 2013 were analyzed and compared using 7th and 8th classifications. The 2 systems were compared in terms of prognostic performance. Results: The stage shifted for 650 (43.45%) patients: from IIIA to IIIB (2 patient, 0.13%), from IIIB to IIIA (214 patients, 14.30%), from IIIB to IIIC (99 patients, 6.62%), and from IIIC to IIIB (335 patients, 22.39%). Cox regression multivariate analysis showed both the 8th and 7th TNM classification were independent prognostic factors. The 8th edition system had higher linear trend and likelihood ratio chi2 scores, and smaller AIC values compared with those for the 7th edition. However, the performance of the eighth edition did not reveal significant improvement compared to the seventh edition (c-index 0.625 vs. c-index 0.616, p=0.085). Conclusion: The eighth TNM edition may not provide significantly better accuracy in predicting the prognosis of stage III GC. However, to confirm our findings, further studies are warranted. PMID- 29137364 TI - Association between MMP3 and TIMP3 polymorphisms and risk of osteoarthritis. AB - Osteoarthritis (OA) is the most commonly occurring degenerative joint disease worldwide, and its incidence has increased in recent years. We evaluated whether there is the association between MMP-3 and TIMP-3 variants and susceptibility to OA in a Chinese population. Venous blood samples were collected from 431 female participants (200 cases and 231 controls) at Hong Hui Hospital, Xi'an Jiaotong University College of Medicine between 2015 and 2016. After genotyping the samples using standard protocols, the association between MMP-3 and TIMP-3 single nucleotide polymorphisms and risk of OA was assessed by calculating odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression analysis. The minor G allele of rs650108 was associated with OA risk in a recessive model (p = 0.034, OR = 1.82, 95%CI = 1.04-3.18), while the minor A allele of rs715572 was associated with OA risk in a recessive model (p = 0.030, OR = 1.88, 95%CI = 1.05-3.34). Thus a suggestive association was observed in a discovery case-control study between OA and two common SNPs, rs650108 in MMP-3 and rs715572 in TIMP-3. PMID- 29137365 TI - Longitudinal serum metabolomics evaluation of trastuzumab and everolimus combination as pre-operative treatment for HER-2 positive breast cancer patients. AB - The mammalian target of rapamycin complex 1 (mTORC1) is an attractive target for HER-2 positive breast cancer therapy because of its key role in protein translation regulation, cell growth and metabolism. We present here a metabolomic investigation exploring the impact of mTOR inhibition on serum metabolic profiles from patients with non-metastatic breast cancer overexpressing HER-2. Baseline, treatment-related and post-treatment serum samples were analyzed for 79 patients participating in the French clinical trial RADHER, in which randomized patients with HER-2 positive breast cancer received either trastuzumab alone (arm T) or a trastuzumab and everolimus combination (arm T+E). Longitudinal series of NMR serum metabolic profiles were exploited to investigate treatment effects on the patients metabolism over time, in both group. Trastuzumab and everolimus combination induces faster changes in patients metabolism than trastuzumab alone, visible after only one week of treatment as well as a residual effect detectable up to three weeks after ending the treatment. These metabolic fingerprints highlight the involvement of several metabolic pathways reflecting a systemic effect, particularly on the liver and visceral fat. Comparison of serum metabolic profiles between the two arms shows that everolimus, an mTORC1 inhibitor, is responsible for host metabolism modifications observed in arm T+E. In HER-2 positive breast cancer, our metabolomic approach confirms a fast and persistent host metabolism modification caused by mTOR inhibition. PMID- 29137366 TI - P-, but not E- or L-, selectin-mediated rolling adhesion persistence in hemodynamic flow diverges between metastatic and leukocytic cells. AB - The ability of leukocytic cells to engage selectins via rolling adhesion is critical to inflammation, but selectins are also implicated in mediating metastatic dissemination. Using a microfluidic- and flow-based cell adhesion chromatography experimental and analytical technique, we interrogated the cell subtype differences in engagement and sustainment of rolling adhesion on P-, E-, and L-selectin-functionalized surfaces in physiological flow. Our results indicate that, particularly at low concentrations of P-selectin, metastatic but not leukocytic cells exhibit reduced rolling adhesion persistence, whereas both cell subtypes exhibited reduced persistence on L-selectin and high persistence on E-selectin, differences not revealed by flow cytometry analysis or reflected in the extent or velocity of rolling adhesion. Conditions under which adhesion persistence was found to be significantly reduced corresponded to those exhibiting the greatest sensitivity to a selectin-antagonist. Our results suggest that potentially therapeutically exploitable differences in metastatic and leukocytic cell subtype interactions with selectins in physiological flow are identifiable through implementation of functional assays of adhesion persistence in hemodynamic flow utilizing this integrated, flow-based cell adhesion chromatography analytical technique. PMID- 29137367 TI - Glycolytic reprogramming through PCK2 regulates tumor initiation of prostate cancer cells. AB - Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein acetylation. Our data suggest PCK2 promotes tumor initiation by lowering acetyl-CoA level through reducing the mitochondrial tricarboxylic acid (TCA) cycle. Thus, PCK2 is a potential therapeutic target for aggressive prostate tumors. PMID- 29137368 TI - The protective effects of carboxyhemoglobin during the resuscitation from hemorrhagic shock in rats. AB - Aim: This study was aimed to explore the effects of carboxyhemoglobin on reperfusion injury in hemorrhagic shock, as well as its action time and related mechanisms. Results: CO-RBC group showed milder oxidative injury than O2-RBC group. CO reperfusion did not show advantages in functions of kidney and lung during resuscitation. The level of Bax was decreased in CO-RBC group, especially in early CO-RBC group. Moreover, the autophay-related gene Beclin-1 was down regulated in CO-RBC and early CO-RBC groups. The inflammation was severer in CO RBC resuscitation group. Materials and Methods: The hemorrhagic shock model rats were randomly divided into: the hemorrhagic shock group (n = 6); the O2-red blood cells (O2-RBC) group (n = 6), perfused with O2-RBC 1 h after ischemia; CO-RBC group (n = 12), perfused with CO-RBC 1 h after ischemia; and early CO-RBC group (n = 12), perfused with CO-RBC 30 min after ischemia. The reperfusion injuries were evaluated through anti-reactive oxygen species (ROS), inflammatory action, organ function, cell apoptosis and autophagy. Conclusions: Carboxyhemoglobin not only relieves the oxidative injury and inhibites apoptosis and autophagy, but also aggravates inflammatory reactions during reperfusion. The action time of carboxyhemoglobin may be an influencing factor for reperfusion outcomes. PMID- 29137369 TI - LRH-1 expression patterns in breast cancer tissues are associated with tumour aggressiveness. AB - The significance and regulation of liver receptor homologue 1 (LRH-1, NR5A2), a tumour-promoting transcription factor in breast cancer cell lines, is unknown in clinical breast cancers. This study aims to determine LRH-1/NR5A2 expression in breast cancers and relationship with DNA methylation and tumour characteristics. In The Cancer Genome Atlas breast cancer cohort NR5A2 expression was positively associated with intragenic CpG island methylation (1.4-fold expression for fully methylated versus not fully methylated, p=0.01) and inversely associated with promoter CpG island methylation (0.6-fold expression for fully methylated versus not fully methylated, p=0.036). LRH-1 immunohistochemistry of 329 invasive carcinomas and ductal carcinoma in situ (DCIS) was performed. Densely punctate/coarsely granular nuclear reactivity was significantly associated with high tumour grade (p<0.005, p=0.033 in invasive carcinomas and DCIS respectively), negative estrogen receptor status (p=0.008, p=0.038 in overall cohort and invasive carcinomas, respectively), negative progesterone receptor status (p=0.003, p=0.013 in overall cohort and invasive carcinomas, respectively), HER2 amplification (overall cohort p=0.034) and non-luminal intrinsic subtype (p=0.018, p=0.038 in overall cohort and invasive carcinomas, respectively). These significant associations of LRH-1 protein expression with tumour phenotype suggest that LRH-1 is an important indicator of tumour biology in breast cancers and may be useful in risk stratification. PMID- 29137370 TI - Comparative efficacy and safety of immune checkpoint inhibitor-related therapies for advanced melanoma: a Bayesian network analysis. AB - Objectives: We aimed to compare and rank the effects of 9 immune checkpoint inhibitor-related therapies for treating advanced melanoma. Methods: We searched Pubmed, Cochrane databases, Web of Science, and ClinicalTrials.gov for randomized controlled trials of the immune checkpoint inhibitor-related treatments for advanced melanoma. Analysis was done on a Bayesian framework. Results: Twelve trials including 5413 patients were identified. Ipilimumab plus nivolumab, nivolumab, and pembrolizumab were significantly more efficacious for progression free survival (PFS) than ipilimumab (hazard ratio [HR], 0.38, 0.50, and 0.58, respectively), ipilimumab plus chemotherapy (0.45, 0.60, and 0.70, respectively), or ipilimumab plus sargramostim (0.44, 0.57, and 0.67, respectively). Ipilimumab plus gp100 was significantly less efficacious for PFS than the remaining eight immune checkpoint inhibitor-related strategies. Pembrolizumab was significantly more efficacious than ipilimumab and ipilimumab plus gp100 (HR, 0.66, and 0.64, respectively) in improving overall survival (OS). Nivolumab significantly improved OS over tremelimumab (HR, 0.48). Ipilimumab plus sargramostim was ranked the second most effective strategy in terms of OS and well tolerated. Nivolumab and pembrolizumab showed the best profile of acceptability, with significantly less high-grade adverse events than ipilimumab (odds ratio [OR], 0.49 and 0.50, respectively), tremelimumab (0.21 and 0.21, respectively), ipilimumab plus chemotherapy (0.13 and 0.13, respectively), or ipilimumab plus nivolumab (0.15 and 0.15, respectively). Conclusions: Nivolumab, pembrolizumab and ipilimumab plus sargramostim might be optimum treatments for advanced melanoma because they have the most favorable balance between benefits and acceptability. Ipilimumab plus nivolumab is the most effective in prolonging PFS, but is far more toxic than nivolumab and pembrolizumab. PMID- 29137371 TI - Peripheral CD4+ naive/memory ratio is an independent predictor of survival in non small cell lung cancer. AB - Background: To investigate the clinical significance of naive T cells, memory T cells, CD45RA+CD45RO+ T cells, and naive/memory ratio in non-small cell lung cancer (NSCLC) patients. Methods: Pretreatment peripheral blood samples from 76 NSCLC patients and 28 age- and sex-matched healthy volunteers were collected and tested for immune cells by flow cytometry. We compared the expression of these immune cells between patients and healthy controls and evaluated their predictive roles for survival in NSCLC by cox proportional hazards model. Results: Decreased naive CD4+ T cells, naive CD8+ T cells, CD4+ naive/memory ratios and CD4+CD45RA+CD45RO+ T cells, and increased memory CD4+ T cells, were observed in 76 NSCLC patients compared to healthy volunteers. Univariate analysis revealed that elevated CD4+ naive/memory ratio correlated with prolonged progression-free survival (P=0.013). Multivariate analysis confirmed its predictive role with a hazard ratio of 0.35 (95% confidence interval, 0.19-0.75, P=0.012). Conclusions: Peripheral CD4+ naive/memory ratio can be used as a predictive biomarker in NSCLC patients and used to optimize personalized treatment strategies. PMID- 29137372 TI - microRNA-33a-5p increases radiosensitivity by inhibiting glycolysis in melanoma. AB - Glycolysis was reported to have a positive correlation with radioresistance. Our previous study found that the miR-33a functioned as a tumor suppressor in malignant melanoma by targeting hypoxia-inducible factor1-alpha (HIF-1alpha), a gene known to promote glycolysis. However, the role of miR-33a-5p in radiosensitivity remains to be elucidated. We found that miR-33a-5p was downregulated in melanoma tissues and cells. Cell proliferation was downregulated after overexpression of miR-33a-5p in WM451 cells, accompanied by a decreased level of glycolysis. In contrast, cell proliferation was upregulated after inhibition of miR-33a-5p in WM35 cells, accompanied by increased glycolysis. Overexpression of miR-33a-5p enhanced the sensitivity of melanoma cells to X radiation by MTT assay, while downregulation of miR-33a-5p had the opposite effects. Finally, in vivo experiments with xenografts in nude mice confirmed that high expression of miR-33a-5p in tumor cells increased radiosensitivity via inhibiting glycolysis. In conclusions, miR-33a-5p promotes radiosensitivity by negatively regulating glycolysis in melanoma. PMID- 29137373 TI - CEACAM6 is a prognostic biomarker and potential therapeutic target for gastric carcinoma. AB - This study aims to investigate the prognostic power of carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6) in gastric cancer (GC) and its potential role in cancer development and progression. Data mining results show that CEACAM6 is overexpressed in gastric cancer and is correlated with lymph node metastasis. Subsequently, immunohistochemical staining was performed to determine CEACAM6 protein levels in paraffin gastric tumor specimens. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was conducted to detect CEACAM6 mRNA levels in fresh GC samples. CEACAM6 protein and mRNA levels were significantly up regulated in GC compared with paired normal mucosa. The IHC staining intensity of CEACAM6 was positively correlated with tumor size, Lauren's classification, vascular invasion, lymph node metastasis, distant metastasis, and TNM stage. CEACAM6 expression was inversely correlated with the five-year survival rate of GC patients. Cox multivariate analysis results demonstrated that the overall survival was independently correlated with CEACAM6 expression. A significant association was observed between CEACAM6 and distant metastases. Network analysis of downstream gene signatures revealed several hub genes such as SRC and DNM1L etc. which may mediating tumor promoting functions of CEACAM6. Further data mining discovered that Tamoxifen etc. could be therapeutic alternatives for gastric patients with CEACAM6 overexpression. Collectively, CEACAM6 overexpression is a common characteristic of GC and is associated with poor 5 year survival rate in GC. Besides, potential molecular mechanisms and treatment options were also provided. PMID- 29137374 TI - Hypoxia favors myosin heavy chain beta gene expression in an Hif-1alpha-dependent manner. AB - The potentiation of the naturally limited regenerative capacity of the heart is dependent on an understanding of the mechanisms that are activated in response to pathological conditions such as hypoxia. Under these conditions, the expression of genes suggested to support cardiomyocyte survival and heart adaptation is triggered. Particularly important are changes in the expression of myosin heavy chain (MHC) isoforms. We propose here that alterations in the expression profiles of MHC genes are induced in response to hypoxia and are primarily mediated by hypoxia inducible factor (HIF). In in vitro models of mouse embryonic stem cell derived cardiomyocytes, we showed that hypoxia (1% O2) or the pharmacological stabilization of HIFs significantly increased MHCbeta (Myh7) gene expression. The key role of HIF-1alpha is supported by the absence of these effects in HIF-1alpha deficient cells, even in the presence of HIF-2alpha. Interestingly, ChIP analysis did not confirm the direct interaction of HIF-1alpha with putative HIF response elements predicted in the MHCalpha and beta encoding DNA region. Further analyses showed the significant effect of the mTOR signaling inhibitor rapamycin in inducing Myh7 expression and a hypoxia-triggered reduction in the levels of antisense RNA transcripts associated with the Myh7 gene locus. Overall, the recognized and important role of HIF in the regulation of heart regenerative processes could be highly significant for the development of novel therapeutic interventions in heart failure. PMID- 29137375 TI - Impact of tumor size and cirrhotic background for differentiating HCC and ICC with CEUS: does it matter for patients undergoing hepatectomy? AB - Objectives: The aim of this study was to investigate the role of contrast enhanced ultrasound (CEUS) in differentiating hepatocellular carcinoma (HCC) vs. intrahepatic cholangiocarcinoma (ICC) and primary liver cancer vs. benign liver lesions for surgical decision making. Methods: Data from 328 patients (296 primary liver cancer patients: 232 HCC and 64 ICC patients and 32 benign hepatic lesion patients) who underwent hepatectomy at our center were retrospectively collected from 2010 to 2015. Conventional ultrasound (US) and CEUS were performed for all patients before hepatectomy. Enhancement patterns in CEUS were classified and compared for HCC vs. ICC and for primary liver cancer vs. benign lesions. Results: Primary liver cancer and hepatic benign lesions could be distinguished by CEUS in different phases. The most obvious differences were in the portal and delayed phases, in which benign lesions could still show hyperenhancement (46.9% vs. 0.0% and p < 0.001 in the portal phase; 43.7% vs. 0.0% and p < 0.001 in the delayed phase). For differentiating HCC and ICC, our results revealed that HCC and ICC displayed different enhancement patterns in the arterial phase (p < 0.001) and the portal phase (p < 0.001). In the subgroup analyses, both HCC and ICC showed a high rate of homogeneous hyperenhancement during the arterial phase when tumors were <=5 cm (87.2% vs. 64.0% and p = 0.008) or the Ishak score was >=5 (75.8% vs. 42.9% and p = 0.023), although there was statistical difference. However, during the portal phase, ICC > 5 cm showed significantly more frequent hypoenhancement (92.3% vs. 54.5% and p < 0.001) and less isoenhancement (7.7% vs. 45.5% and p < 0.001) than HCC; additionally, during the portal phase, there was no statistical difference in the enhancement patterns of ICC with different hepatic backgrounds. Conclusions: Tumor size and hepatic background should be taken into consideration when distinguishing HCC and ICC before surgery. However, CEUS is a helpful tool for differentiating malignant and benign hepatic lesions. For patients who require surgical treatment, CEUS may help with surgical decision making. PMID- 29137376 TI - Impact of VEGFA polymorphisms on glioma risk in Chinese. AB - Several single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor A (VEGFA) gene have been previously reported to be associated with glioma susceptibility, but individual studies have demonstrated inconclusive results. In the current study, a meta-analysis was performed to derive a more precise estimation of the involvement of VEGFA polymorphisms in glioma development. A comprehensive literature search conducted in PubMed, Embase, the Cochrane Library, and OVID databases through February 25, 2017 yielded 4 eligible studies consisting of 2,275 cases and 2,475 controls. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated under allele contrast, dominant, recessive, homozygous, and heterozygous models. In general, minor alleles of polymorphisms rs3025039, rs2010963, and rs3025030 were associated with increased glioma risk. In contrast, a significant correlation was found between the minor allele of polymorphism rs3024994 and decreased susceptibility to glioma. Moreover, statistically significant associations with glioma risk were observed for polymorphisms rs1413711 and rs3025035 in the meta analysis although positive associations were not observed in any of the included studies individually. No significant correlations with glioma susceptibility were identified for polymorphisms rs3025010 or rs833069 except in the recessive model. Finally, stratified analysis on the basis of genotyping method and Hardy-Weinberg equilibrium (HWE) in controls revealed no significant difference between subgroups. Our results indicated that several VEGFA polymorphisms might be risk factors for glioma in Chinese. More studies with larger sample sizes using different ethnicities are needed to provide additional evidence. PMID- 29137377 TI - An evaluation of nutrition intervention during radiation therapy in patients with locoregionally advanced nasopharyngeal carcinoma. AB - Purpose: To evaluate the effectiveness of nutrition intervention during radiation for patients with locoregionally advanced (III-IVa) nasopharyngeal carcinoma (NPC). Materials and Methods: We retrospectively reviewed 117 patients with locoregionally advanced (III-IVa) NPC treated between December 2015 and March 2016 in Zhejiang Cancer Hospital. All the patients underwent radical chemo radiotherapy. First, all the patients were divided into the nutrition intervention group and the control group, depending on whether they accepted nutrition intervention. Repeated measures were used to analyze the change of nutritional indicators before, during, and after radiation therapy and to simultaneously compare the difference in nutritional status between the two groups at the same time point. Subsequently, the 117 patients were divided into the malnourished group (weight loss > 5%) and the non-malnourished group (weight loss <= 5%) according to whether their weight loss was over 5% of their body weight during radiotherapy. Chi-square tests and logistic regression analysis were used to explore the influence factors for the weight loss. Results: The repeated measures showed that all indicators including weight, body mass index (BMI), albumin, pre-albumin(PA), and prognostic nutritional index (PNI) dramatically declined in both groups compared with their levels before radiation therapy (All p < 0.001). However, there was no significant difference between the intervention and non-intervention groups regarding the mean values of nutritional indicators at the same time point, that before, during, and after radiation therapy, except BMI (All p > 0.05). Logistic regression analysis revealed grade >= 3 radiation-induced oral mucositis as the prognostic factor for a poor nutrition status (odds ratio, OR = 3.232, p = 0.021, confidence interval, CI [1.198, 8.820]). Besides this, patients with a decrease of >15% in pre-albumin level were more likely to be malnourished (OR = 2.442, p = 0.041, CI [1.036, 5.757]). Similar to that observed in our former analysis, we did not find that existing nutrition intervention can significantly improve nutritional status (OR = 1.217, p = 0.704, CI [0.042, 3.348]). Conclusions: Our study shows that the nutritional status of the patients gradually declined during treatment. We concluded that grade >= 3 radiation-induced oral mucositis would aggravate the extent of malnutrition during radiation therapy in patients with locoregionally advanced NPC. Pre-albumin level was a predictive marker for weight loss in patients with NPC. However, current nutrition intervention during radiation therapy can't significantly reverse nutritional status. PMID- 29137378 TI - Trastuzumab distribution in an in-vivo and in-vitro model of brain metastases of breast cancer. AB - Background: Drug and antibody delivery to brain metastases has been highly debated in the literature. The blood-tumor barrier (BTB) is more permeable than the blood-brain barrier (BBB), and has shown to have highly functioning efflux transporters and barrier properties, which limits delivery of targeted therapies. Methods: We characterized the permeability of 125I-trastuzumab in an in-vivo, and fluorescent trastuzumab-Rhodamine123 (t-Rho123) in a novel microfluidic in-vitro, BBB and BTB brain metastases of breast cancer model. In-vivo: Human MDA-MB-231 HER2+ metastatic breast cancer cells were grown and maintained under static conditions. Cells were harvested at 80% confluency and prepped for intra-cardiac injection into 20 homozygous female Nu/Nu mice. In-vitro: In a microfluidic device (SynVivo), human umbilical vein endothelial cells were grown and maintained under shear stress conditions in the outer compartment and co-cultured with CTX-TNA2 rat brain astrocytes (BBB) or Met-1 metastatic HER2+ murine breast cancer cells (BTB), which were maintained in the central compartment under static conditions. Results: Tissue distribution of 125I-trastuzumab revealed only ~3% of injected dose reached normal brain, with ~5% of injected dose reaching brain tumors. No clear correlation was observed between size of metastases and the amount of 125I-trastuzumab localized in-vivo. This heterogeneity was paralleled in-vitro, where the distribution of t-Rho123 from the outer chamber to the central chamber of the microfluidic device was qualitatively and quantitatively analyzed over time. The rate of t-Rho123 linear uptake in the BBB (0.27 +/- 0.33 * 104) and BTB (1.29 +/- 0.93 * 104) showed to be significantly greater than 0 (p < 0.05). The BTB devices showed significant heterogenetic tendencies, as seen in in-vivo. Conclusions: This study is one of the first studies to measure antibody movement across the blood-brain and blood-tumor barriers, and demonstrates that, though in small and most likely not efficacious quantities, trastuzumab does cross the blood-brain and blood-tumor barriers. PMID- 29137379 TI - Diagnostic potential of serum exosomal colorectal neoplasia differentially expressed long non-coding RNA (CRNDE-p) and microRNA-217 expression in colorectal carcinoma. AB - In this study, we investigated the diagnostic potential of serum exosomal colorectal neoplasia differentially expressed (CRNDE-p) long coding RNA and microRNA-217 in colorectal carcinoma (CRC). We detected high CRNDE-p and low miR 217 levels in exosomes released by multiple CRC cell lines into culture media as well as in sera from CRC xenograft mice and CRC patients. Conversely, we observed lower CRNDE-p and higher miR-217 levels in serum exosomes from post-chemotherapy than from pre-chemotherapy patient samples. The area under curve (AUC) value for the serum exosomal CRNDE-p and miR-217 combination was higher than CRNDE-p or miR 217 alone. Moreover, high CRNDE-p and low miR-217 serum exosomal levels correlated with advanced clinical stages (III/IV), tumor classification (T3/T4), and lymph node or distant metastasis. Thus combined evaluation of serum exosomal CRNDE-p and miR-217 levels show diagnostic and prognostic potential for CRC patients. PMID- 29137380 TI - Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells. AB - Imetelstat (GRN163L) is a potent and selective inhibitor of telomerase. We have previously reported that GRN163L could shorten telomeres and limit the lifespan of CD18/HPAF and CAPAN1 pancreatic cancer cells. Here, we examined the effects of GRN163L on two other pancreatic cancer cell lines: AsPC1 and L3.6pl. In both lines, chronic exposure to GRN163L led to an initial shortening of telomeres followed by a stabilization of extremely short telomeres. In AsPC1 cells, telomere attrition eventually led to the induction of crisis and the loss of the treated population. In L3.6pl cells, crisis was transient and followed by the emergence of GRN163L-resistant cells, which could grow at increasing concentrations of GRN163L. The Shelterin complex is a telomere-associated complex that limits the access of telomerase to telomeres. The telomerase inhibitory function of this complex can be enhanced by drugs that block the poly(ADP ribosyl)ation of its TRF1 and/or TRF2 subunits. Combined treatment of the GRN163L resistant L3.6pl cells with GRN163L and 3-aminobenzamide (3AB), a general inhibitor of poly(ADP-ribose) polymerases, led to additional telomere shortening and limited the lifespan of the resistant cells. Results from this work suggest that inhibitors of telomerase and poly(ADP-ribose) polymerases can cooperate to limit the lifespan of pancreatic cancer cells. PMID- 29137381 TI - Gene expression and molecular pathway activation signatures of MYCN-amplified neuroblastomas. AB - Neuroblastoma is a pediatric cancer arising from sympathetic nervous system. Remarkable heterogeneity in outcomes is one of its widely known features. One of the traits strongly associated with the unfavorable subtype is the amplification of oncogene MYCN. Here, we performed cross-platform biomarker detection by comparing gene expression and pathway activation patterns from the two literature reports and from our experimental dataset, combining profiles for the 761 neuroblastoma patients with known MYCN amplification status. We identified 109 / 25 gene expression / pathway activation biomarkers strongly linked with the MYCN amplification. The marker genes/pathways are involved in the processes of purine nucleotide biosynthesis, ATP-binding, tetrahydrofolate metabolism, building mitochondrial matrix, biosynthesis of amino acids, tRNA aminoacylation and NADP linked oxidation-reduction processes, as well as in the tyrosine phosphatase activity, p53 signaling, cell cycle progression and the G1/S and G2/M checkpoints. To connect molecular functions of the genes involved in MYCN amplified phenotype, we built a new molecular pathway using known intracellular protein interaction networks. The activation of this pathway was highly selective in discriminating MYCN-amplified neuroblastomas in all three datasets. Our data also suggest that the phosphoinositide 3-kinase (PI3K) inhibitors may provide new opportunities for the treatment of the MYCN-amplified neuroblastoma subtype. PMID- 29137382 TI - Circulating long-chain n-3 polyunsaturated fatty acid and incidence of stroke: a meta-analysis of prospective cohort studies. AB - Background: Circulating long-chain (LC) n-3 polyunsaturated fatty acid (PUFA) can provide objective measures that reflect both dietary consumption and relevant biological processes. Nevertheless, prospective cohort studies on circulating LC n-3 PUFA in relation to incidence of stroke have yielded inconsistent results. We therefore conducted a meta-analysis to quantitatively evaluate the association. Results: A total of 2,836 stroke events occurred among 20,460 individuals aged 35 79 yr from 10 prospective cohort studies. Circulating LC n-3 PUFA was significantly associated with reduced risk of stroke (RR: 0.86; 95% CI: 0.76, 0.98; I2 = 0.00%), especially 22:5n-3 (RR: 0.74; 95% CI: 0.60, 0.92) and 22:6n-3 (RR: 0.78; 95% CI: 0.65, 0.94). The associations were more pronounced with ischemic stroke (RR: 0.81; 95% CI: 0.68, 0.96), but not with hemorrhagic stroke (RR: 0.95; 95% CI: 0.60, 1.49). A 1% increment of 22:5n-3 and 22:6n-3 proportions in circulating blood was associated with 25% (RR: 0.75; 95% CI: 0.64, 0.87) and 11% (RR: 0.89; 95% CI: 0.83, 0.95) reduced risk of stroke, respectively. Materials and Methods: Pertinent studies were identified from Cochrane Library, PubMed and EMBASE database through June 2017. Multivariate-adjusted risk ratios (RRs) with 95% confidence interval (CI) for incident stroke when comparing the top with the bottom tertiles of baseline LC n-3 PUFA proportions in blood were pooled using a random-effect model. Conclusions: Circulating LC n-3 PUFAs were linearly associated with reduced risk of stroke, especially 22:5n-3 and 22:6n-3. Such findings highlight the importance of circulating LC n-3 PUFA in the development of ischemic stroke. PMID- 29137383 TI - Oral administration of Ginsenoside Rg1 prevents cardiac toxicity induced by doxorubicin in mice through anti-apoptosis. AB - Although Ginsenoside Rg1 has been reported to have protective cardiac effects, its effects on cardiac toxicity induced by doxorubicin needs to be studied. The present study investigated the effects of oral administration of Rg1 on the heart in mice treated with doxorubicin and found improved fractional shortening and ejection fraction of the heart and decreased cardiac apoptosis in mice treated with doxorubicin. The underlying mechanisms include increased phosphorylation of Akt and Erk by Rg1, increased ratio of Bcl-2 and Bax, and decreased release of cytochrome c from mitochondria, thereby protecting the heart from doxorubicin induced apoptosis. This phenotype suggested that the oral administration of Rg1 may be a potential method preventing the cardiac toxicity caused by doxorubicin in clinical practice. PMID- 29137384 TI - MiR-324-5p assists ultrasonography in predicting lymph node metastasis of unifocal papillary thyroid microcarcinoma without extracapsular spread. AB - Ultrasonography is the first choice of lymph node metastasis (LNM) detection which is crucial for therapeutic options of papillary thyroid cancer (PTC). However, the sensitivity of ultrasonography in detecting LNM of PTC is relatively low; especially in central LNM. MiR-324-5p has been reported to play important roles in the metastasis of various cancers. To explore the relationship between miR-324-5p and LNM in PTC, quantitative real-time polymerase chain reaction was performed in PTC tissue and fine needle aspiration (FNA) washout successively. Its correlation with LNM of PTC was analyzed. The clinicopathological and sonographic factors relating to LNM were also studied. Additionally, the function assay of miR-324-5p in PTC cells was conducted. Current study demonstrated that age was an independent protective factor and multifocality, advanced TNM stage, increased transverse diameter of thyroid nodule, ultrasound suspected LNM were independent risk factors of LNM. MiR-324-5p promoted proliferation, migration and invasion of PTC cell line. MiR-324-5p could serve as a candidate predictor along with ultrasonography in predicting LNM, especially central LNM of unifocal papillary thyroid microcarcinoma without extracapsular spread. PMID- 29137385 TI - Improved outcome of haploidentical transplantation in severe aplastic anemia using reduced-intensity fludarabine-based conditioning. AB - Significant improvements in hematopoietic stem cell transplantation (HSCT) with haploidentical family donors (HFD) have confirmed its therapeutic role in severe aplastic anemia (SAA) and led to the evolution of treatment algorithms. However, the optimal conditioning regimen for HFD-HSCT remains undefined, especially the dosage of cyclophosphamide (Cy). A total of 77 patients with SAA from two research centers, who received HFD-HSCT with reduced-intensity fludarabine + cyclophosphamide + thymoglobulin +/- busulfan conditioning regimen plus third party cells infusion were included in this study, of which 67 pairs had 4-5 loci mismatched. We were particularly interested in whether the dosage of Cy significantly impacted graft failure (GF) and overall survival (OS). All patients showed sustained hematopoietic engraftment without any increase in severe aGVHD and transplantation-related mortality (TRM). The incidences of grade II-IV aGVHD, grade III-IV aGVHD and extensive cGVHD were 18%, 10% and 7%, respectively. The probabilities of 1-year and 5-year OS were 93.1% and 87.9%, respectively. Furthermore, patient age <15 years, MNC cells >8*108/kg and donor age <45 years were associated with better survival (P=0.043, P=0.023, and P=0.037, respectively) and engraftment (P=0.019, P=0.008, and P=0.001, respectively). Our findings indicated that SAA patients lack MSD benefited the most if HFD-HSCT was performed with reduced-intensity fludarabine-based conditioning regimen. Improved outcomes with HFD-HSCT may lead to a salvaged therapy and an expanded direct role for SAA in the future. PMID- 29137386 TI - Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect. AB - Background: A shift from oxygen phosphorylation to aerobic glycolysis was known as the Warburg effect and a characteristic of cancer cell metabolism facilitating metastasis. Mitochondrial calcium uniporter (MCU), a key ion channel that mediates Ca2+ uptake into mitochondria, was found to promote cancer progression and metastasis. However, its explicit role in shifting metabolism of breast cancer cells has not been defined. Methods: We evaluated MCU overexpression or knock-down on migration, invasion and glucose metabolismin breast cancer cells. Mitochondrial Ca2+ dynamics were monitored with Rhod-2 fluorescence imaging. Luciferase reporter assay was used to confirm the interaction between miR-340 and 3'-untranslated region (3'-UTR) of MCU gene. Mouse models of lung metastasis were used to determine whether gain-/loss-of-MCU impacts metastasis. MCU expression was assessed in 60 tumor samples from breast cancer patients by immunohistochemistry (IHC). Results: Knockdown of MCU in MDA-MB-231 cells significantly reduced cell migration and invasion in vitro and lung metastasis in vivo; whereas overexpression of MCU in MCF-7 cells significantly increased migration and invasion in vitro and lung metastasis in vivo. Overexpression of MCU promoted lung metastasis by enhancing glycolysis, whereas suppression of MCU abolished this effect. Moreover, a novel mechanism was identified that MCU was a direct target of microRNA-340, which suppressed breast cancer cell motility by inhibiting glycolysis. Consistently, significantly increased MCU protein was found in metastatic breast cancer patients. Conclusions: We identified a novel mechanism that upregulated MCU promotes breast cancer metastasis via enhancing glycolysis, and that this process is posttranscriptionally and negatively regulated by microRNA-340. PMID- 29137387 TI - Infrequently expressed miRNAs influence survival after diagnosis with colorectal cancer. AB - Half of miRNAs expressed in colorectal tissue are expressed < 50% of the population. Many infrequently expressed miRNAs have low levels of expression. We hypothesize that less frequently expressed miRNAs, when expressed at higher levels, influence both disease stage and survival after diagnosis with colorectal cancer (CRC); low levels of expression may be background noise. We examine 304 infrequently expressed miRNAs in 1893 population-based cases of CRC with paired carcinoma and normal mucosa miRNA profiles. We evaluate miRNAs with disease stage and survival after adjusting for age, study center, sex, MSI status, and AJCC stage. These miRNAs were further evaluated with RNA-Seq data to identify miRNA::mRNA associations that may provide insight into the functionality of miRNAs. Eleven miRNAs were associated with advanced disease stage among colon cancer patients (Q value = 0.10). Eight infrequently expressed miRNAs influenced survival if highly expressed in overall CRC. Of these, five increased likelihood of dying if they were highly expressed, i.e. miR-124-3p, miR-143-5p, miR-145-3p, miR31-5p, and miR-99b-5p, while three were associated with better survival if highly expressed, i.e. miR-362-5p, miR-374a-5p, and miR-590-5p. Thirteen miRNAs infrequently expressed in colon-specific carcinoma tissue were associated with CRC survival if highly expressed. Evaluation of miRNAs::mRNA associations showed that mRNA expression influenced by infrequently expressed miRNA contributed to networks and pathways shown to influence disease progression and prognosis. Our large study enabled us to examine the implications of infrequently expressed miRNAs after removal of background noise. These results require replication in other studies. Confirmation of our findings in other studies could lead to important markers for prognosis. PMID- 29137388 TI - Rapid and accurate detection of KRAS mutations in colorectal cancers using the isothermal-based optical sensor for companion diagnostics. AB - Although KRAS mutational status testing is becoming a companion diagnostic tool for managing patients with colorectal cancer (CRC), there are still several difficulties when analyzing KRAS mutations using the existing assays, particularly with regard to low sensitivity, its time-consuming, and the need for large instruments. We developed a rapid, sensitive, and specific mutation detection assay based on the bio-photonic sensor termed ISAD (isothermal solid phase amplification/detection), and used it to analyze KRAS gene mutations in human clinical samples. To validate the ISAD-KRAS assay for use in clinical diagnostics, we examined for hotspot KRAS mutations (codon 12 and codon 13) in 70 CRC specimens using PCR and direct sequencing methods. In a serial dilution study, ISAD-KRAS could detect mutations in a sample containing only 1% of the mutant allele in a mixture of wild-type DNA, whereas both PCR and direct sequencing methods could detect mutations in a sample containing approximately 30% of mutant cells. The results of the ISAD-KRAS assay from 70 clinical samples matched those from PCR and direct sequencing, except in 5 cases, wherein ISAD KRAS could detect mutations that were not detected by PCR and direct sequencing. We also found that the sensitivity and specificity of ISAD-KRAS were 100% within 30 min. The ISAD-KRAS assay provides a rapid, highly sensitive, and label-free method for KRAS mutation testing, and can serve as a robust and near patient testing approach for the rapid detection of patients most likely to respond to anti-EGFR drugs. PMID- 29137389 TI - Targeting Src attenuates peritoneal fibrosis and inhibits the epithelial to mesenchymal transition. AB - Src has been reported to mediate tissue fibrosis in several organs, but its role in peritoneal fibrosis remains unknown. In this study, we evaluated the therapeutic effect of KX2-391, a highly selective inhibitor of Src, on the development of peritoneal fibrosis in a rat model. Daily intraperitoneal injections of chlorhexidine gluconate induced peritoneal fibrosis, as indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts. This was accompanied by time-dependent phosphorylation of Src at tyrosine 416. Administration of KX2-391 attenuated peritoneal fibrosis and abrogated increased phosphorylation of Src and multiple signaling molecules associated with tissue fibrosis, including epidermal growth factor receptor, Akt, Signal transducer and activator of transcription 3 and nuclear factor-kappaB in the injured peritoneum. KX2-391 also inhibited the production of proinflammatory cytokines and the infiltration of macrophages into the injured peritoneum. In cultured human peritoneal mesothelial cells, inhibition of Src by KX2-391 or siRNA resulted in decreased expression of alpha smooth muscle actin (alpha-SMA), fibronectin and collagen I, the hallmarks of epithelial to mesenchymal transition. These results suggest that Src is a critical mediator of peritoneal fibrosis and the epithelial to mesenchymal transition. Thus, Src could be a potential therapeutic target in the treatment of peritoneal fibrosis. PMID- 29137390 TI - A cocktail of p16INK4a and Ki-67, p16INK4a and minichromosome maintenance protein 2 as triage tests for human papillomavirus primary cervical cancer screening. AB - Most human papillomavirus (HPV) infections are transient and additional triage approaches should be built after HPV-based primary cervical cancer screening. We evaluated the accuracy of p16/Ki-67 and p16/mcm2 dual staining as biomarkers for triaging HPV positive women in China. 4070 participants aged 35 to 64 years attending ongoing cervical cancer screening were enrolled in 2015-2016. Cervical exfoliated cells were collected for HPV DNA analysis and the residual positive specimens were tested for liquid-based cytology and biomarkers. Women infected with HPV 16/18 type or other 12 high-risk HPV types with abnormal cytology results received colposcopy. We found the positive rates of both biomarkers increased significantly with histology severity. p16/Ki-67 positivity in HPV16/18 group, other 12 high-risk HPV group and HPV negative group was 50.0%, 33.7% and 8.9%, respectively. The corresponding p16/mcm2 positivity was 70.0%, 56.3% and 6.7%, respectively. The sensitivity and specificity of p16/Ki-67 for CIN2+ in all HPV-positive women were 91.7% and 63.5%, with a referral rate of 36.2%, while p16/mcm2 were 87.5% and 42.1%, with a referral rate of 58.4%, respectively. The sensitivity of p16/Ki-67 increased to 95.8% for CIN2+ and 100% for CIN3+ when combined with high-grade cytology, without decrease in specificity. Our studies suggest that p16/Ki-67 is an efficient triaging biomarker for HPV-positive women and could reduce colposcopy workload. p16/mcm2 is more sensitive compared with cytology for identifying cervical lesions. PMID- 29137391 TI - Activated spleen tyrosine kinase promotes malignant progression of oral squamous cell carcinoma via mTOR/S6 signaling pathway in an ERK1/2-independent manner. AB - Spleen tyrosine kinase (SYK), a non-receptor cytoplasmic tyrosine enzyme, is well known for its ability in certain pathways through immune receptors. Recently, SYK role in cancer has been widely studied. SYK plays a dual role as a tumor suppressor and tumor promoter. Nevertheless, its role in oral squamous cell carcinoma (OSCC) has not been fully investigated. In the current study, samples from OSCC tumors and adjacent normal counterparts were collected and SYK expression was evaluated by real-time qPCR. SYK mRNA expression in tumors was higher than the normal tissues. And high SYK expression was confirmed by immunohistochemistry analysis and closely related to worse overall survival. The expression of SYK mRNA and protein was detected in 2 of 4 OSCC cell lines. SYK pharmacological suppression and RNAi-mediated knockdown inhibited proliferation, migration, and invasion of SYK-positive cells by reducing phosphorylated ERK1/2 and mTOR levels. One inhibitor of MEK, PD98059, also suppressed the same cancer associated phenotypes of SYK-positive cells by decreasing phosphorylated ERK1/2 but increasing phosphorylated mTOR. Piceatannol, one pharmacological inhibitor of SYK, attenuated tumor growth in vivo. Overall, our results revealed a novel mechanism triggered by SYK to increase OSCC tumoriogenesis and tumor progression. PMID- 29137392 TI - Selective secretion of microRNAs from lung cancer cells via extracellular vesicles promotes CAMK1D-mediated tube formation in endothelial cells. AB - Extracellular vesicles (EVs) are key signaling mediators between cancer cells and their supporting stroma, and regulate critical processes such as invasion, metastases, and angiogenesis. We have identified a subset of miRNAs (miR-142-3p, miR-143-3p, miR-145-5p, miR-150-5p, miR-223-3p, miR-451a, miR-486-5p, miR-605-5p) that are enriched in lung adenocarcinoma extracellular vesicles compared to the donor cells from which they were derived. Two well-known tumor suppressors, miR 143-3p and miR-145-5p, were also enriched in serum samples collected during surgery from blood vessels draining directly from lung adenocarcinoma tumor beds. Recently, both miRNAs were found to promote neoangiogenesis in endothelial cells in mouse models of lung adenocarcinoma through targeting of CAMK1D, an inhibitory kinase that can impair angiogenesis when over-expressed. We show that the transfer of miR-143-3p and miR-145-5p within extracellular vesicles from lung adenocarcinoma cells to endothelial cells reduces the levels of CAMK1D and increases tube formation by endothelial cells. This finding suggests that transfer of miRNAs within extracellular vesicles is a method of communication between cancer and endothelial cells which promotes angiogenesis while simultaneously removing tumor suppressive miRNAs within the tumor cells, thus driving tumorigenesis. PMID- 29137393 TI - Synergistic effect of eribulin and CDK inhibition for the treatment of triple negative breast cancer. AB - Activation of CDK2 in triple negative breast cancer (TNBC) can contribute to non canonical phosphorylation of a TGFbeta signaling component, Smad3, promoting cell proliferation and migration. Inhibition of CDK2 was shown to decrease breast cancer oncogenesis. Eribulin chemotherapy was used effectively in the treatment of TNBC. To this end, we tested therapeutic efficacy of a novel CDK2/9 inhibitor, CYC065, eribulin, and the combination of CYC065 and eribulin in 3 different TNBC cell lines, and an in vivo xenograft model. Specifically, we characterized cell proliferation, apoptosis, migration, cell cycle associated protein expression, treatment-related transcription factor activity, and tumor growth in TNBC. Treatment with CYC065 and eribulin in combination had a superior effect on decreasing cell proliferation, inducing apoptosis, and inhibiting migration in TNBC cell lines in vitro. Combination therapy inhibited non-canonical Smad3 phosphorylation at the T179 site in the protein linker region, and resulted in increased p15 and decreased c-myc expression. In a transcription factor array, combination treatment significantly increased activity of AP1 and decreased activity of factors including NFkappaB, SP1, E2F, and SMAD3. In an in vivo xenograft model of TNBC, individual and combination treatments resulted in a decrease in both tumor volume and mitotic indices. Taken together, these studies highlight the potential of this novel drug combination, CYC065 and eribulin, to suppress the growth of TNBC cells in vitro and in vivo, warranting further clinical investigation. PMID- 29137394 TI - Measuring plasma levels of three microRNAs can improve the accuracy for identification of malignant breast lesions in women with BI-RADS 4 mammography. AB - A BI-RADS category of 4 from a mammogram indicates suspicious breast lesions, which require core biopsies for diagnosis and have an approximately one third chance of being malignant. Human plasma contains many circulating microRNAs, and variations in their circulating levels have been associated with pathologies, including cancer. Here, we present a novel methodology to identify malignant breast lesions in women with BI-RADS 4 mammography. First, we used the miRNome array and qRT-PCR to define circulating microRNAs that were differentially represented in blood samples from women with breast tumor (BI-RADS 5 or 6) in comparison to controls (BI-RADS 1 or 2). Next, we used qRT-PCR to quantify the level of this circulating microRNAs in patients with mammograms presenting with BI-RADS category 4. Finally, we developed a machine learning method (Artificial Neural Network - ANN) that receives circulating microRNA levels and automatically classifies BI-RADS 4 breast lesions as malignant or benign. We identified a minimum set of three circulating miRNAs (miR-15a, miR-101 and miR-144) with altered levels in patients with breast cancer. These three miRNAs were quantified in plasma from 60 patients presenting biopsy-proven BI-RADS 4 lesions. Finally, we constructed a very efficient ANN that could correctly classify BI-RADS 4 lesions as malignant or benign with approximately 92.5% accuracy, 95% specificity and 88% sensibility. We believe that our strategy of using circulating microRNA and a machine learning method to classify BI-RADS 4 breast lesions is a non invasive, non-stressful and valuable complementary approach to core biopsy in women with BI-RADS 4 lesions. PMID- 29137395 TI - Lithium chloride inhibits titanium particle-induced osteoclastogenesis by inhibiting the NF-kappaB pathway. AB - Osteoclast over-activation and inflammation responses promote peri-implant osteolysis (PIO), which is the leading cause of aseptic artificial joint loosening. We examined the effect of lithium chloride (LiCl) on wear debris induced osteoclastogenesis and inflammation. Fifty-Six C57BL/6J male mice were randomly distributed into four groups: sham control (sham, treated with phosphate buffered saline [PBS]), vehicle (treated with titanium/PBS), low-LiCl (L-LiCl, titanium: 50 mg/kg LiCl) and high-LiCl (H-LiCl, titanium: 200 mg/kg LiCl). After 14 days, mouse calvaria were harvested for micro-computed tomography and histomorphological and molecular analyses. Bone marrow-derived macrophages (BMMs) were extracted to examine osteoclast differentiation, and the RAW264.7 cell line was used to investigate osteoclastogenesis mechanisms. LiCl reduced the number of osteoclasts, debris-induced osteolysis, and the expression of inflammatory factors, thereby preventing bone loss in vivo. In vitro, LiCl inhibited osteoclastogenesis and osteoclastic bone resorption by inhibiting the RANKL induced NF-kappaB signaling pathway. LiCl's activation of the canonical Wnt/beta catenin signaling pathway was not associated with LiCl's inhibition of osteoclastogenesis. These results suggest that LiCl may be an effective agent for treatment of osteolytic diseases caused by chronic inflammation and over activation of osteoclasts. PMID- 29137396 TI - TGFBR-IDH1-Cav1 axis promotes TGF-beta signalling in cancer-associated fibroblast. AB - TGF-beta signalling plays an important role in fibroblasts activation and tumour progression. Here, we report that the TGFBR-IDH1-Cav1 axis promotes TGF- beta signalling in fibroblasts. Our data demonstrated that IDH1 was downregulated by TGF-beta signalling in fibroblasts, and downregulation of IDH1 increased cellular concentration of alpha-ketoglutarate (alpha-KG) by accelerating glutamine metabolization. Interestingly, alpha-KG suppressed Cav1 expression through reducing the trimethylation of histone H3K4. Furthermore, Cav1 downregulation inhibited TGFBR protein degradation. In turn, the activated TGFBR promoted TGF beta signalling. These findings demonstrated that metabolic enzyme IDH1 regulates TGF-beta signalling by feedback mechanism through alpha-KG and TGFBR-IDH1-Cav1 axis is important for TGF-beta signalling. PMID- 29137397 TI - DNA mismatch repair protein Mlh1 is required for tetravalent chromium intermediate-induced DNA damage. AB - Hexavalent chromium (Cr[VI]) is associated with occupational lung cancer and poses a significant public health concern. When exposed to Cr[VI], cells rapidly internalize this compound and metabolize it to Cr[III]. Byproducts of Cr[VI] metabolism include unstable Cr[V] and Cr[IV] intermediates that are believed to be directly responsible for the genotoxicity and carcinogenicity caused by Cr[VI] exposure; however, the carcinogenic potential of the Cr intermediates and the mechanisms of Cr-induced carcinogenesis remain to be further defined. Utilizing synthetic Cr[IV] and Cr[V] compounds, we demonstrate here that Cr[IV] or Cr[V] exposure induces DNA double-strand breaks; however, of the two compounds, mammalian cells only respond to Cr[V]-induced DNA damage. Exposure to Cr[V], but not Cr[IV], results in initiation of cell cycle checkpoints and activates the ATM kinase, a critical regulator of the DNA damage response. Furthermore, cells exposed to Cr[IV] have significantly increased mutation frequencies in the HPRT gene compared to cells exposed to Cr[V], indicating that Cr[IV] possesses a higher mutagenic potential than Cr[V]. We also find that MLH1, a critical mismatch repair (MMR) protein, is required for activation of the G2/M cell cycle checkpoint in response to Cr[VI] exposure and to limit Cr-induced mutagenesis. Our results provide evidence for Cr[IV] as the ultimate mutagenic intermediate produced during Cr[VI] metabolism and indicate that functional MMR is crucial in the cellular response to chromium exposure. PMID- 29137398 TI - Prognostic significance of PD-L1 expression and tumor infiltrating lymphocyte in surgically resectable non-small cell lung cancer. AB - Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early stage resectable NSCLC remains unclear. Here, we studied PD-L1 expression and tumor infiltrating lymphocytes (TILs) in surgically resectable NSCLC and correlate the finding with clinicopathological features and patient outcomes. Total of 170 archival samples of resectable NSCLC were probed for PD-L1 expression using the clone 22C3 pharmDx kit. The PD-L1 expression was determined by the Tumor Proportion Score (TPS) and classified into TPS <1%, TPS 1 to 49% and TPS >=50%. The scoring of TILs was from hematoxylin & eosin stained tissue sections using a system for standardized evaluation of TILs in breast cancer. PD-L1 expression was compared with clinical pathological characteristics and survival outcome. Expression of PD-L1 scores of TPS >=50%, TPS 1 to 49% and TPS <1% were observed in 10.6%, 24.7% and 64.7% of the 170 archival samples, respectively. Positive PD L1 expression was significantly higher in patients with squamous carcinoma, in those with higher TNM stage and with the presence of TILs. Neither the PD-L1 expression, TIL status, nor their combination was an independent prognosis biomarker of survival when the data was subjected to either univariate or multivariate analysis. The incidence of PDL1 expression appears to be lower in patient with early stage resectable lung cancer. PD-L1 expression and TILs are not prognostic indicators of survival outcome in this population. PMID- 29137399 TI - Molecular characteristics and serodiagnostic potential of chitinase-like protein from Sarcoptes scabiei. AB - Scabies, caused by the mite Sarcoptes scabiei, is an allergic skin disease that affects millions of people and other mammals worldwide. This highly contagious parasitic disease is among the top 50 epidemic disease and is regarded as a neglected tropical disease. Diagnosis of scabies is difficult in the early stage, and the pathogenesis of scabies is not currently clear. Here, we expressed, identified and located the chitinase-like protein of S. scabiei (SsCLP), and evaluated its potential as an early-stage diagnostic antigen for rabbit scabies. Indirect ELISA using recombinant SsCLP (rSsCLP) exhibited diagnostic sensitivity of 94.4% (17/18) and specificity of 86.7% (26/30). Early diagnostic test after artificial infection of rabbits with S. scabiei for 1 week showed a positive detection rate of 96.7% (29/30). Immunolocalization assays showed that fluorescence signals were localized on the surface of mites and, in infected rabbits, were observed in keratinized skin and embedded mites. Intradermal skin tests of rabbits by injecting rSsCLP showed a wheal, flare and erythema reaction. These results suggest that S. scabiei chitinase-like protein is conducive to host invasion, participates in inducing the allergic response of the host, and is an effective antigen for the diagnosis of S. scabiei. PMID- 29137400 TI - Downregulation of the Sonic Hedgehog/Gli pathway transcriptional target Neogenin 1 is associated with basal cell carcinoma aggressiveness. AB - Basal Cell Carcinoma (BCC) is one of the most diagnosed cancers worldwide. It develops due to an unrestrained Sonic Hedgehog (SHH) signaling activity in basal cells of the skin. Certain subtypes of BCC are more aggressive than others, although the molecular basis of this phenomenon remains unknown. We have previously reported that Neogenin-1 (NEO1) is a downstream target gene of the SHH/GLI pathway in neural tissue. Given that SHH participates in epidermal homeostasis, here we analyzed the epidermal expression of NEO1 in order to identify whether it plays a role in adult epidermis or BCC. We describe the mRNA and protein expression profile of NEO1 and its ligands (Netrin-1 and RGMA) in human and mouse control epidermis and in a broad range of human BCCs. We identify in human BCC a significant positive correlation in the levels of NEO1 receptor, NTN-1 and RGMA ligands with respect to GLI1, the main target gene of the canonical SHH pathway. Moreover, we show via cyclopamine inhibition of the SHH/GLI pathway of ex vivo cultures that NEO1 likely functions as a downstream target of SHH/GLI signaling in the skin. We also show how Neo1 expression decreases throughout BCC progression in the K14-Cre:Ptch1lox/lox mouse model and that aggressive subtypes of human BCC exhibit lower levels of NEO1 than non aggressive BCC samples. Taken together, these data suggest that NEO1 is a SHH/GLI target in epidermis. We propose that NEO1 may be important in tumor onset and is then down-regulated in advanced BCC or aggressive subtypes. PMID- 29137401 TI - Hormone receptors expression in ovarian cancer taking into account menopausal status: a retrospective study in Chinese population. AB - Ovarian cancer is a major gynaecological cancer with different subtypes and studies have suggested that estrogen receptor (ER) or progesterone receptor (PR) positivity are associated with better clinical outcomes. Furthermore, the clinical outcomes of ovarian cancer are better in Asian compared to Caucasian. To date, studies investigating the ER or PR positivity in all subtypes of ovarian cancer, including borderline epithelial, are limited. In this retrospective study we investigated ER and PR positivity in Chinese women with malignant epithelial ovarian cancer (n=577), sex cord-stromal tumor (n=26) and borderline epithelial ovarian cancer (n=98) taking into account menopausal status. The positivity of ER (>85%) or PR (>58%) was higher in serous and endometrioid carcinoma of malignant epithelial ovarian cancer than that in mucinous and clear-cell carcinoma (<19% of ER or 24% of PR). The majority of serous carcinomas of borderline epithelial ovarian cancerwere ER or PR positive, but in contrast less than 33% of mucinous carcinomas of borderline epithelial ovarian cancerswere ERor PR positive.Furthermore, there was no association between the ER or PR positivity and menopausal status in both malignant and borderline epithelial ovarian cancer. We also found that the age at diagnosis with ovarian cancer was younger in Chinese women. Our data suggest that ER or PR positivity in Chinese women with ovarian cancer is similar to that of other ethnicities reported in literature, suggesting that the better clinical outcomes seen in Asian may be associated with other factors such as age at diagnosis of ovarian cancer. PMID- 29137402 TI - BDNF/TrkB signaling mediates the anorectic action of estradiol in the nucleus tractus solitarius. AB - Although compelling evidence indicates that estradiol (E2) acts in the nucleus tractus solitarius (NTS) to reduce food intake, the underlying mechanisms are largely unknown. We now report that estrogen's anorectic action occurs through enhancing the strength of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase (TrkB) signaling in the NTS. Intra-4th-ventricular administration of a low dose of BDNF reduced food intake to a greater extent in ovariectomized (OVX) rats cyclically treated with E2 than in vehicle-treated OVX rats, implying that cyclic E2 replacement increases BDNF's satiating potency. OVX significantly decreased bdnf gene expression in the NTS, and this was reversed by cyclic replacement of E2. Treatment of cultured primary neuronal cells from embryonic rat brainstem with E2 or PPT (ERalpha agonist), but not with DPN (ERbeta agonist), significantly increased bdnf mRNA levels, indicating that ERalpha is the primary receptor mediating E2's stimulatory effect on bdnf gene expression. Administration of the selective TrkB antagonist, ANA-12, directly into the NTS significantly attenuated E2-induced reductions of food intake and body weight gain in OVX rats, indicating that TrkB receptor activation is necessary for E2's anorectic effect. Finally, relative to controls, OVX mice with bdnf gene knockdown specifically in the NTS had a blunted feeding response to E2. These data collectively imply that BDNF/TrkB receptor signaling in the NTS is a downstream mediator of E2 in the control of energy intake. PMID- 29137403 TI - Chicken CCDC152 shares an NFYB-regulated bidirectional promoter with a growth hormone receptor antisense transcript and inhibits cells proliferation and migration. AB - The chicken coiled-coil domain-containing protein 152 (CCDC152) recently has been identified as a novel one implicated in cell cycle regulation, cellular proliferation and migration by us. Here we demonstrate that CCDC152 is oriented in a head-to-head configuration with the antisense transcript of growth hormone receptor (GHR) gene. Through serial luciferase reporter assays, we firstly identified a minimal 102 bp intergenic region as a core bidirectional promoter to drive basal transcription in divergent orientations. And site mutation and transient transfected assays showed that nuclear transcription factor Y subunit beta (NFYB) could bind to the CCAAT box and directly transactivate this bidirectional promoter. SiRNA-mediated NFYB depletion could significantly down regulate the expression of both GHR-AS-I6 and CCDC152. Additionally, the expression of GHR-AS-I6 was significantly up-regulated after CCDC152 overexpression. Overexpression of CCDC152 remarkably reduced cell proliferation and migration through JAK2/STAT signaling pathway. Thus, the GHR-AS-I6-CCDC152 bidirectional transcription unit, as a novel direct target of NFYB, is possibly essential for the accelerated proliferation and motility of different cells. PMID- 29137404 TI - The role of TFPI2 hypermethylation in the detection of gastric and colorectal cancer. AB - Gastrointestinal cancer is a prevalent disease with high morbidity and mortality. Tissue factor pathway inhibitor 2 (TFPI2) gene could protect the extracellular matrix of cancer cells from degradation and tumor invasion. The goal of our study was to estimate the diagnostic value of TFPI2 hypermethylation in gastric cancer (GC) and colorectal cancer (CRC). TFPI2 methylation was measured by quantitative methylation-specific polymerase chain reaction (qMSP) method in 114 GC and 80 CRC tissues and their paired non-tumor tissues. Our results showed that TFPI2 methylation was significantly higher in tumor tissues (GC: 29.940% vs. 12.785%, P < 0.001; CRC: 26.930% vs. 5.420%, P < 0.001). The methylation level of TFPI2 in colorectal tumor tissues was significantly higher than that in colorectal normal tissues (26.930% versus 0.002%, P < 0.00001). In GC, TFPI2 hypermethylation yielded an area under the curve (AUC) of 0.762 (95% CI: 0.696-0.828) with a sensitivity of 68% and a specificity of 83%. In CRC, TFPI2 hypermethylation yielded an AUC of 0.759 (95% CI: 0.685-0.834) with a sensitivity of 61% and a specificity of 84%. Similarly, TCGA data also supported TFPI2 hypermethylation was a promising diagnostic marker for GC and CRC. Moreover, the dual-luciferase reporter assay showed TFPI2 fragment could upregulate gene expression (fold change = 5, P = 0.005). Data mining further indicated that TFPI2 expression in CRC cell lines was significantly increased after 5'-AZA-deoxycytidine treatment (fold change > 1.37). In conclusion, TFPI2 hypermethylation might be a promising diagnostic biomarker for GC and CRC. PMID- 29137405 TI - Necroptosis regulated proteins expression is an early prognostic biomarker in patient with sepsis: a prospective observational study. AB - Background and aim: Increasing researchers indicate that necroptosis is playing an important role in the regulation of systemic inflammatory response syndrome. The current study was to investigate the prognostic biomarker of the regulated proteins of necroptosis in sepsis patients. Results: One hundred and twenty-four patients were divided into three groups: 43 patients (34.68%) with sepsis, 39 patients (31.45%) with severe sepsis, and 42 patients (33.87%) with septic shock. The RIPK3 levels in the severe sepsis and septic shock groups were notably higher than those in sepsis group at various time points (all p < 0.05), and the RIPK3 levels had positive association with the Sequential Organ Failure Assessment (SOFA) score as well as procalcitonin (PCT) level (all p < 0.05). The RIPK3 level like the SOFA score and PCT level could be a prognostic biomarker of sepsis patients. Materials and Methods: We prospectively recruited the eligible patients with sepsis, severe sepsis, or septic shock who were treated in our hospital from January 2014 to May 2016. The dynamic changes in infectious variables and blood plasma receptor interacting protein kinase 1 (RIPK1) and receptor interacting protein kinase 3 (RIPK3) levels were determined from measurements taken in a double-blinded fashion at 24, 48, 72, and 120 hours later. Conclusions: These results suggested that dynamic monitoring of RIPK3 levels can contribute to the prediction of outcome of sepsis and might be of particular value in identifying patients who would benefit from specific treatments. PMID- 29137406 TI - The forkhead box C1 (FOXC1) transcription factor is downregulated in acute promyelocytic leukemia. AB - Forkhead box (FOX) genes encode transcription factors, which regulate embryogenesis and play an important role in hematopoietic differentiation and in mesenchymal niche maintenance. Overexpression of the family member FOXC1 has been reported in solid tumors and acute myeloid leukemia (AML). We studied FOXC1 expression and function in acute promyelocytic leukemia (APL) and normal hematopoietic progenitors. FOXC1 mRNA and protein levels were significantly lower in primary marrow samples from 27 APL patients, as compared to samples obtained from 27 patients with other AML subtypes, and 5 normal CD34+ hematopoietic cells. FOXC1 expression significantly increased in APL samples at the time of remission following consolidation treatment. In cell lines overexpressing PML-RARA, and in the NB4 t(15;17)-positive cell line, FOXC1 expression was lower than in other non APL cell lines, and increased following treatment with all-trans retinoic acid (ATRA), due to functional binding of ATRA to the FOXC1 promoter region. Reduced FOXC1 expression was also associated to DNA hypermethylation of the +354 to +568 FOXC1 region, both in primary APL, and in NB4 cells. Treatment of NB4 cells with decitabine demethylated FOXC1 and upregulated its expression. Our findings indicate that FOXC1 is consistently repressed in APL due to hypermethylation and the presence of the PML-RARA rearrangement. A potential role of hypomethylating treatment in advanced APL remains to be established. PMID- 29137407 TI - LncRNA SNHG12 contributes to multidrug resistance through activating the MAPK/Slug pathway by sponging miR-181a in non-small cell lung cancer. AB - Small nucleolar RNA host gene 12 (SNHG12), as one of the long non-coding RNAs (lncRNAs), plays an oncogenic role in various cancers, however, its role in the chemoresistance of non-small cell lung cancer (NSCLC) is unclear. In this study, we investigated the effect of SNHG12 on multidrug resistance (MDR) in NSCLC. The results showed that SNHG12 was high-expressed and miR-181a was low-expressed in NSCLC tumor tissues and cell lines. Knockdown of SNHG12 reversed the resistance to cisplatin, paclitaxel and gefitinib in A549/DDP, A549/PTX and PC9/AB2 cells through inducing cell apoptosis. Moreover, SNHG12 silencing suppressed MAPK1 and MAP2K1 expression by upregulating miR-181a, leading to inhibition of the MAPK/Slug pathway through decreasing phosphorylated MAPK1 (p-MAPK1), phosphorylated MAP2K1 (p-MAP2K1) and Slug levels. Furthermore, downregulation of SNHG12 enhanced the sensitivity of NSCLC cells to cisplatin in nude mice. Overall, our study is the first to identify a SNHG12-miR-181a-MAPK/Slug axis to elucidate in part how SNHG12 exert functions in NSCLC MDR, providing a novel therapeutic target to overcome MDR in NSCLC. PMID- 29137408 TI - Incidence and risk of regorafenib-induced hepatotoxicity. AB - Regorafenib, an oral multi-kinase inhibitor, has been approved for the treatments of several malignancies. Unlike traditional cytotoxic chemotherapeutic agents, regorafenib therapy often induces a distinct profile of adverse events (AEs) including hepatotoxicity. Here we conducted an up-to-date meta-analysis to assess the incidence and risk of regorafenib related hepatic toxicities. PubMed and Embase database were reviewed from inception to June 2017 for relevant trials. Eligible studies include subjects with solid tumors treated with 160 mg of regorafenib daily during the first three week of each four-week cycle, and adequate safety data reporting the elevation of aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin. Statistical analyses were conducted to calculate the summary incidence and relative risk (RR). A total of 2,213 subjects from 14 trials were included. The incidences of regorafenib-associated all-grade and high-grade hepatotoxicity were: bilirubin elevation: 23% and 5%; AST elevation: 32% and 6%; ALT elevation: 27% and 5%; ALP elevation: 31% and 2%. Regorafenib-treated subjects had a significant increased risk of all-grade (RR = 3.10; 95% CI, 2.22-4.34) and high grade (RR = 1.74; 95% CI, 1.09-2.80) bilirubin elevation; all-grade (RR = 1.51; 95% CI, 1.13-2.00) and high-grade (RR = 1.79; 95% CI, 1.00-3.22) AST elevation; all-grade (RR = 1.82; 95% CI, 1.25-2.64) and high-grade (RR = 3.07; 95% CI, 1.30 7.22) ALT elevation; and all-grade (RR = 2.11; 95% CI, 1.01-4.40) ALP elevation. Our results suggest that regorafenib is associated with an increased risk of hepatic toxicities. Hepatotoxicity examination at regular intervals should be advised to clinicians. PMID- 29137409 TI - Overexpression of CTEN relates to tumor malignant potential and poor outcomes of adenocarcinoma of the esophagogastric junction. AB - Background: To detect a novel treatment target for adenocarcinoma of the esophagogastric junction (AEG), we tested whether C-terminal tensin-like (CTEN), a member of the tensin gene family and frequently overexpressed in various cancers, acts as a cancer-promoting gene through overexpression in AEG. Materials and Methods: We analyzed 5 gastric adenocarcinoma (GC) cell lines and 104 primary AEG tumors curatively resected in our hospital between 2000 and 2010. Results: CTEN overexpression was detected in GC cell lines (2/5 cell lines; 40%) and primary AEG tumor samples (35/104 cases; 34%). CTEN knockdown using several specific siRNAs inhibited the proliferation, migration, and invasion of CTEN overexpressing cells. CTEN overexpression was significantly correlated with more aggressive venous and lymphatic invasion, deeper tumor depth, and higher rates of lymph node metastasis and recurrence. Patients with CTEN-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors (P < 0.0001, log-rank test) in an expression-dependent manner. CTEN positivity was independently associated with a worse outcome in the multivariate analysis (P = 0.0423, hazard ratio 3.54 [1.04-16.4]). Conclusions: CTEN plays a crucial role in tumor cell proliferation, migration, and invasion through its overexpression, which highlights its usefulness as a prognosticator and potential therapeutic target in AEG. PMID- 29137410 TI - LINC00461, a long non-coding RNA, is important for the proliferation and migration of glioma cells. AB - An increasing number of reports have revealed that long non-coding RNAs are important players in tumorigenesis. Here we showed that long non-coding RNA LINC00461 is highly expressed in glioma tissues compared to non-neoplastic brain tissues. The knockdown of LINC00461 suppressed cyclinD1/A/E expression which led to G0/G1 cell cycle arrest and inhibited cell proliferation in glioma cells. LINC00461 suppression also inhibited glioma cell migration and invasion. The function of LINC00461 in glioma cells is partially mediated by MAPK/ERK and PI3K/AKT signaling pathways as down-regulation of LINC00461 expression suppressed ERK1/2 and AKT activities. Moreover, LINC00461 knockdown decreased expression levels of microRNA miR-9 and flanking genes MEF2C and TMEM161B. Taken together, our results demonstrate that LINC00461 is important for glioma progression affecting cell proliferation, migration and invasion via MAPK/ERK, PI3K/AKT, and possibly other signaling pathways. PMID- 29137411 TI - A novel polyamine blockade therapy activates an anti-tumor immune response. AB - Most tumors maintain elevated levels of polyamines to support their growth and survival. This study explores the anti-tumor effect of polyamine starvation via both inhibiting polyamine biosynthesis and blocking the upregulated import of polyamines into the tumor. We demonstrate that polyamine blockade therapy (PBT) co-treatment with both DFMO and a novel polyamine transport inhibitor, Trimer PTI, significantly inhibits tumor growth more than treatment with DFMO or the Trimer PTI alone. The anti-tumor effect of PBT was lost in mice where CD4+ and CD8+ T cells were antibody depleted, implying that PBT stimulates an anti-tumor immune effect that is T-cell dependent. The PBT anti-tumor effect was accompanied by an increase in granzyme B+, IFN-gamma+ CD8+ T-cells and a decrease in immunosuppressive tumor infiltrating cells including Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs), CD4+CD25+ Tregs, and CD206+F4/80+ M2 macrophages. Stimulation with tumor-specific peptides elicited elevated antigen-specific IFN gamma secretion in splenocytes from PBT-treated mice, indicating that PBT treatment stimulates the activation of T-cells in a tumor-specific manner. These data show that combined treatment with both DFMO and the Trimer PTI not only deprives polyamine-addicted tumor cells of polyamines, but also relieves polyamine-mediated immunosuppression in the tumor microenvironment, thus allowing the activation of tumoricidal T-cells. PMID- 29137413 TI - Abnormal neural activities of directional brain networks in patients with long term bilateral hearing loss. AB - The objective of the study is to provide some implications for rehabilitation of hearing impairment by investigating changes of neural activities of directional brain networks in patients with long-term bilateral hearing loss. Firstly, we implemented neuropsychological tests of 21 subjects (11 patients with long-term bilateral hearing loss, and 10 subjects with normal hearing), and these tests revealed significant differences between the deaf group and the controls. Then we constructed the individual specific virtual brain based on functional magnetic resonance data of participants by utilizing effective connectivity and multivariate regression methods. We exerted the stimulating signal to the primary auditory cortices of the virtual brain and observed the brain region activations. We found that patients with long-term bilateral hearing loss presented weaker brain region activations in the auditory and language networks, but enhanced neural activities in the default mode network as compared with normally hearing subjects. Especially, the right cerebral hemisphere presented more changes than the left. Additionally, weaker neural activities in the primary auditor cortices were also strongly associated with poorer cognitive performance. Finally, causal analysis revealed several interactional circuits among activated brain regions, and these interregional causal interactions implied that abnormal neural activities of the directional brain networks in the deaf patients impacted cognitive function. PMID- 29137412 TI - Long non-coding RNA SNHG15 inhibits P15 and KLF2 expression to promote pancreatic cancer proliferation through EZH2-mediated H3K27me3. AB - Long non-coding RNA (lncRNA) is emerging as an critical regulator in multiple cancers, including pancreatic cancer (PC). Recently, lncRNA SNHG15 was found to be up-regulated in gastric cancer and hepatocellular carcinoma, exerting oncogenic effects. Nevertheless, the biological function and regulatory mechanism of SNHG15 remain unclear in pancreatic cancer (PC). In this study, we reported that SNHG15 expression was also upregulated in PC tissues, and its overexpression was remarkably associated with tumor size, tumor node metastasis (TNM) stage and lymph node metastasis in patients with PC. SNHG15 knockdown inhibited proliferative capacities and suppressed apoptotic rate of PC cells in vitro, and impaired in-vivo tumorigenicity. Additionally, RNA immunoprecipitation (RIP) assays showed that SNHG15 epigenetically repressed the P15 and Kruppel-like factor 2 (KLF2) expression via binding to enhancer of zeste homolog 2 (EZH2), and chromatin immunoprecipitation assays (CHIP) assays demonstrated that EZH2 was capable of binding to promoter regions of P15 and KLF2 to induce histone H3 lysine 27 trimethylation (H3K27me3). Furthermore, rescue experiments indicated that SNHG15 oncogenic function partially involved P15 and KLF2 repression. Consistently, an inverse correlation between the expression of SNHG15 and traget genes were found in PC tissues. Our results reported that SNHG15 could act as an oncogene in PC, revealing its potential value as a biomarker for early detection and individualized therapy. PMID- 29137414 TI - Salvage lymph node dissection after 68Ga-PSMA or 18F-FEC PET/CT for nodal recurrence in prostate cancer patients. AB - The management of patients with biochemical recurrence (BCR) after definitive treatment for prostate cancer remains controversial. Our aim was to determine survival rates and complications of salvage lymph node dissection (sLND) in patients with recurrent prostate cancer after radical prostatectomy, while evaluating biochemical response (BR) with two different positron emission tomography/computed tomography (PET/CT) tracers used for preoperative imaging. sLND was performed in 104 patients diagnosed with isolated nodal recurrence on either 18F-fluoroethylcholine (18F-FEC) or 68Ga-PSMA-HBED-CC (68Ga-PSMA) PET/CT. Surgical complications, BR, clinical recurrence (CR), and cancer-specific survival (CSS) were evaluated. Logistic regression was used to determine predictors of complete BR (cBR) and CR after sLND and survival rates were assessed. Median follow-up was 39.5 months. Median patient age and prostate specific antigen (PSA) at sLND were 64 years and 4.1 ng/mL. Median number of lymph nodes (LNs) removed was 13; median number of positive LNs was 3 per patient. Rate of Clavien-Dindo Grade III complications was low (4.8%). 29.8% of patients developed cBR (PSA < 0.2 ng/mL), and 56.7% partial BR (PSA postoperative < PSA preoperative) after sLND. Patients with LN metastases diagnosed on 68Ga PSMA PET/CT showed a higher rate of cBR compared to 18F-FEC PET/CT (45.7 vs. 21.7%, p = 0.040). PSA at sLND (p = 0.031) and choice of PET tracer (p = 0.048) were independent predictors of cBR. The 5-year BCR-free, CR-free and CSS rates were 6.2%, 26.0%, and 82.8%, respectively. While preoperative staging with 68Ga PSMA seems superior, only a limited number of patients developed cBR after surgery. Most patients experienced BCR and CR during follow-up. PMID- 29137415 TI - Ubiquitin conjugating enzyme E2 L3 promoted tumor growth of NSCLC through accelerating p27kip1 ubiquitination and degradation. AB - The molecular pathogenesis of human lung cancer has not been completely clarified. Here, we reported that UBE2L3, a member of the ubiquitin-conjugating enzymes (E2s), were overexpressed in non-small-cell lung cancer (NSCLC) tissues compared with the non-tumor tissues. High expression of UBE2L3 was correlated with advanced tumor stage and adverse outcomes. Knockdown of UBE2L3 inhibited NSCLC cell growth while ectopic expression of UBE2L3 promoted NSCLC cell growth in a cell cycle dependent manner. The results of subcutaneous tumor xenograft studies revealed that knockdown of UBE2L3 attenuated the in vivo tumor growth. Mechanistically, we observed that UBE2L3 could interact with F-box protein Skp2, a member of the SCF (Skp2) ubiquitin ligase complex, and thus promoted the ubiquitination and proteasomal degradation of p27kip1. Furthermore, NSCLC cases with high level of UBE2L3 and low level of p27kip1 had worst prognosis, suggesting that combination of UBE2L3 and p27kip1 is a more powerful prognostic marker for NSCLC patients. Taken together, the current study presented a novel marker for predicting prognosis and a potential therapeutic target for NSCLC patients. PMID- 29137416 TI - Analysis of clinical and neurological outcomes in patients with cauda equina syndrome caused by acute lumbar disc herniation: a retrospective-prospective study. AB - Objectives: In this research we analyzed the results of surgical treatment of cauda equina syndrome (CES) caused by acute lumbar disc herniation. We emphasize the early treatment for good neurological recovery. Methods: A retrospective prospective, non randomized, clinical study was performed between Jan 2010 and Dec 2014. We retrospectively collected medical records of 18 patients who suffered from CES due to acute lumbar disc herniation and followed up them regularly. Visual analogue scale (VAS) score, lumbar JOA score (29 points), RR (recovery rate) and Oswestry disability index (ODI) questionnaire were used to evaluate clinical outcomes. Results: All patients were followed up for at least two years. Lumbar disc herniation is located at L2-3 level in 2 cases, L3-4 level in 2 cases, L4-5 level in 9 cases, L5-S1 level in 5 cases. VAS score is 6+/-2.5 preoperatively and 1.5+/-1.0 postoperatively at last follow-up (P<0.001). JOA score is 5+/-3.5 preoperatively, while it is 20+/-7 postoperatively at last follow-up (P<0.001). RR >= 50% was found in 12 cases. ODI is 75%+/-25% preoperatively, while it becomes 28%+/-16% postoperatively at last follow-up (P<0.001). It also shows that advanced age (>=45 years) may act as a risk factor for poor RR(<50%), while early operation (duration before surgery, <48 h) proves to be a protective factor. Conclusions: Early operations are mandatory and closely relevant to final outcomes for CES patients. However, elder patients are more likely to have poor clinical effect after surgery. PMID- 29137417 TI - Inhibition of retinoic acid receptor beta signaling confers glycolytic dependence and sensitization to dichloroacetate in melanoma cells. AB - Dysregulation of metabolism during melanoma progression is tightly associated with the acquisition of genetic and epigenetic alterations in regulators of metabolic pathways. Retinoic acid receptor beta (RARbeta) is epigenetically silenced in a large proportion of melanomas, but a link between RARbeta and metabolic rewiring of melanoma has not been established. Here, we show that in primary human melanocytes, all-trans retinoic acid (a RARbeta agonist) induced growth inhibition accompanied by a decrease in both glycolytic and oxidative metabolism, whereas selective inhibition of RARbeta led to an increase in the basal glycolytic rate and increased sensitivity to inhibition of glycolysis. In melanoma cells, inhibition of RARbeta promoted lower mitochondrial respiration and higher glycolytic activity, which led to energetic stress and activation of the energy sensor AMP-activated protein kinase. This metabolic shift increased the sensitivity to both glycolytic inhibition and stimulation of mitochondrial metabolism with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase. In melanoma cells harboring the BRAFV600E mutation, RARbeta activation antagonized the effect of the BRAF inhibitor PLX4032 (vemurafenib). Collectively, these data suggest that RARbeta signaling is involved in regulating cellular metabolism in melanoma and may provide a potential target in combination treatment strategies. PMID- 29137418 TI - A randomized phase II study of aromatase inhibitors plus metformin in pre-treated postmenopausal patients with hormone receptor positive metastatic breast cancer. AB - Background: Everolimus significantly improves progression-free survival (PFS) and has been approved to use in aromatase inhibitor pretreated patients with hormone receptor positive advanced breast cancer. Metformin has been shown to inhibit mTOR pathway, with more favorable safety profile, leading to this hypothesis generating trial to assess whether metformin enhances the efficacy of aromatase inhibitors. Methods: 60 postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer were randomly assigned 1:1 to aromatase inhibitor (exemestane 25mg/d or letrozole 2.5mg/d depending on the most recent treatment) plus metformin (0.5g bid, orally) or placebo. The primary endpoint was PFS, and secondary endpoints were objective response rate, clinical benefit rate, overall survival and safety. Results: Median PFS was 4.7 months in the combination group and 6.0 months in the control group (hazard ratio, 1.2; 95% confidence interval [CI], 0.7 to 2.1; P =0.48). ORR was 6.7% in the combination group and 0% in the control group (odds ratio for ORR not available; P =0.99), and CBR was 33.3% and 50.0%, respectively (OR for CBR 0.5; 95% CI, 0.2 to 1.4; P=0.15). No significant difference in overall survival was observed between the combination and control groups (median OS, 30.9 vs. 32.4 months; P = 0.81). Subgroup analyses didn't find any specific population favoring the combination treatment. No substantial difference in incidence or severity of adverse events was seen between the two treatment groups. Conclusion: This randomized phase II clinical trial failed to show an improved efficacy with the addition of metformin to endocrine therapy, although with excellent tolerability. PMID- 29137419 TI - Caspase-3 expression in tumorigenesis and prognosis of buccal mucosa squamous cell carcinoma. AB - Buccal mucosa squamous cell carcinoma (BMSCC) is the most common oral cancer in Southeast Asia. Caspase-3, a key molecule in regulating apoptosis, promotes the malignancy of various cancers. However, its role in BMSCC is unknown. Herein, we evaluated the association of caspase-3 expression with tumorigenesis and prognosis in BMSCC patients. Immunohistochemical staining indicated that the expression levels of cleaved caspase-3 (p<0.001) and caspase-3 (p<0.001) in 185 BMSCC tissues were significantly higher compared to those in the tumor adjacent normal tissues. Moreover, the high expression of caspase-3 was associated with poor pathological outcomes [advanced pathological stage (p=0.029) and larger tumor size (p=0.002)] and poor disease-free survival in patients receiving postoperative radiotherapy (p=0.030). Moreover, the low co-expression of cleaved caspase-3 and caspase-3 was associated with better disease-specific survival in patients with early pathological stage (I + II, p=0.018) or without lymph node invasion (p=0.043) compared to the positive/high expression of either or both cleaved caspase-3 and caspase-3. Taken together, cleaved caspase-3 and caspase-3 could be biomarkers for tumorigenesis in BMSCC patients. Cleaved caspase-3 and/or caspase-3 might be prognostic biomarkers for certain stages of BMSCC. PMID- 29137420 TI - Anti-angiogenic and anti-tumor effects of metronomic use of novel liposomal zoledronic acid depletes tumor-associated macrophages in triple negative breast cancer. AB - Zoledronic acid (ZOL) has been used as an adjuvant therapy for breast cancer. It is suggested that ZOL might be associated with inhibition of macrophages, which in turn reduces tumor growth, metastasis and tumor angiogenesis. Moreover, metronomic therapy can inhibit tumor angiogenesis and tumor immune cells. Previously we developed ZOL based cationic liposomes that allowed a higher intratumor delivery of drug compared with free ZOL in vivo. Therefore, in this study, Asn-Gly-Arg (NGR) and PEG2000 were used as ligands to modify the surface of liposomes (NGR-PEG-LP-ZOL) in metronomic therapy to clear the tumor-associated macrophages (TAMs) and inhibit the formation of tumor angiogenesis, achieving the purpose of anti-tumor growth. Our data showed that NGR-PEG-LP-ZOL metronomic therapy has the strongest inhibitory effect on tumor growth. Further, NGR-PEG-LP ZOL metronomic therapy could significantly impair TAMs by inhibiting the expression of CD206 antibody in tumor tissues, decreasing the expression of cytokine related gene expression of TAMs, as well as reducing the percentage of TAMs in tumor tissues. In addition, NGR-PEG-LP-ZOL metronomic therapy could significantly inhibit the expression of tumor neovascular specific antibody CD31 and reduce the microvessel density. In conclusion, our study demonstrated that NGR-PEG-LP-ZOL metronomic therapy could impair TAMs by inhibiting tumor angiogenesis and enhance the antitumor effect of ZOL. PMID- 29137421 TI - GPER mediates differential effects of estrogen on colon cancer cell proliferation and migration under normoxic and hypoxic conditions. AB - The estrogen receptor ERbeta is the predominant ER subtype expressed in normal well-differentiated colonic epithelium. However, ERbeta expression is lost under the hypoxic microenvironment as colorectal cancer (CRC) malignancy progresses. This raises questions about the role of signalling through other estrogen receptors such as ERalpha or G-protein coupled estrogen receptor (GPER, GPR30) by the estrogen 17beta-estradiol (E2) under hypoxic conditions after ERbeta is lost in CRC progression. We tested the hypothesis that E2 or hypoxia can act via GPER to contribute to the altered phenotype of CRC cells. GPER expression was found to be up-regulated by hypoxia and E2 in a panel of CRC cell lines. The E2-modulated gene, Ataxia telangiectasia mutated (ATM), was repressed in hypoxia via GPER signalling. E2 treatment enhanced hypoxia-induced expression of HIF1-alpha and VEGFA, but repressed HIF1-alpha and VEGFA expression under normoxic conditions. The expression and repression of VEGFA by E2 were mediated by a GPER-dependent mechanism. E2 treatment potentiated hypoxia-induced CRC cell migration and proliferation, whereas in normoxia, cell migration and proliferation were suppressed by E2 treatment. The effects of E2 on these cellular responses in normoxia and hypoxia were mediated by GPER. In a cohort of 566 CRC patient tumor samples, GPER expression significantly associated with poor survival in CRC Stages 3-4 females but not in the stage-matched male population. Our findings support a potentially pro-tumorigenic role for E2 in ERbeta-negative CRC under hypoxic conditions transduced via GPER and suggest a novel route of therapeutic intervention through GPER antagonism. PMID- 29137422 TI - Pkm2 can enhance pluripotency in ESCs and promote somatic cell reprogramming to iPSCs. AB - Aerobic glycolysis is one of the most important common characteristics in both cancer cells and stem cells. Metabolism switch has been discovered as an important early event in the process of reprogramming somatic cells to induced pluripotent stem cells (iPSCs). As a rate limiting kinase in glycolysis, Pkm2 has been reported playing critical roles in many tumors, yet its role in stem cells and iPSCs induction is poorly defined. In the present study, we showed that Pkm2 is a predominant pyruvate kinase in embryonic stem cells (ESCs), and its expression increases many pluripotent genes. During somatic cell reprogramming, up-regulation of Pkm2 can be observed and over-expression of Pkm2 can facilitate iPSCs induction, while Pkm1 or a mutant form of Pkm2 (Pkm2K422R) showed no enhancement role in iPSCs induction. Therefore, our data demonstrated that Pkm2 enhances the pluripotency maintenance in ESCs and promotes the pluripotency acquisition during somatic cell reprogramming. PMID- 29137423 TI - Expression of the beta3 subunit of Na+/K+-ATPase is increased in gastric cancer and regulates gastric cancer cell progression and prognosis via the PI3/AKT pathway. AB - ATP1B3 encodes the beta3 subunit of Na+/K+-ATPase and is located in the q22-23 region of chromosome 3. Na+/K+-ATPase participates in normal cellular activities but also plays a crucial role in carcinogenesis. In the present study, we found that expression of the beta3 subunit of Na+/K+-ATPase was increased in human gastric cancer tissues compared with that in normal matched tissues and that this increased expression predicted a poor outcome. ATP1B3 expression was elevated at both the mRNA and protein levels in gastric cancer cell lines relative to those in a normal gastric epithelial cell line. Interestingly, ATP1B3 knockdown significantly inhibited cell proliferation, colony-formation ability, migration, and invasion and increased apoptosis in human gastric carcinoma cell lines. Additionally, knockdown induced cell cycle arrest at the G2/M phase. Furthermore, we demonstrated that ATP1B3 silencing decreased the expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and phosphorylated AKT (p-AKT), indicating that ATP1B3 regulates gastric cancer cell progression via the PI3K/AKT signalling pathway. Hence, the beta3 subunit of Na+/K+-ATPase plays an essential role in the tumourigenesis of gastric cancer and may be a potential prognostic and therapeutic target for the treatment of gastric cancer. PMID- 29137424 TI - Septicemia is associated with increased risk for dementia: a population-based longitudinal study. AB - Background: Systemic infection has been linked to cognitive impairment. We hypothesized that patients with septicemia are predisposed to increased risks for developing dementia in a long-term setting. Methods: This observational, retrospective, longitudinal, nation-wide population-based study was conducted using the data deduced from Longitudinal Health Insurance Database (LHID) in Taiwan. All patients with septicemia hospitalized for the first time from 2001 to 2011 without prior dementia were included. The development of Alzheimer's disease (AD) or non-Alzheimer dementias (NAD) in relation to the development of septicemia for each patient was recorded. An age- and sex-matched cohort without septicemia and without prior dementia served as the control. Septicemia, dementia, and other confounding factors were defined according to International Classification of Diseases Clinical Modification Codes. Cox proportional-hazards regressions were utilized to analyze adjusted hazard ratios. Results: Patients with septicemia had a higher risk for developing dementia based on hazard ratios (HRs) (p<0.001). Patients with septicemia in the younger age groups had a greater dementia risk (p<0.01). Septicemia was associated with subsequent NAD (p<0.001), whereas the increased risk of AD was statistically insignificant (p>0.05). Furthermore, higher severity of septicemia was associated with increased risk of developing dementia. Conclusions: Our findings suggest that septicemia is associated with an increased risk in developing NAD but not AD. A likely causal role of septicemia in increasing the risk of NAD is suggested, according to the findings that patients with higher severity of septicemia carried greater risk of sustaining dementia. PMID- 29137425 TI - A fatal case of mitochondrial DNA depletion syndrome with novel compound heterozygous variants in the deoxyguanosine kinase gene. AB - The deoxyguanosine kinase (DGUOK) gene controls mitochondrial DNA (mtDNA) maintenance, and variation in the gene can alter or abolish the anabolism of mitochondrial deoxyribonucleotides. A Chinese female infant, whose symptoms included weight stagnation, jaundice, hypoglycemia, coagulation disorders, abnormal liver function, and multiple abnormal signals in the brain, died at about 10 months old. Genetic testing revealed a compound heterozygote of alleles c.128T>C (p.I43T) and c.313C>T (p.R105*) of the DGUOK gene. c.128T>C (p.I43T) is a novel variant located in exon 1 (NM_080916) in the first beta sheet of DGUOK. Her mother was an allele c.313C>T (p.R105*) heterozygote, which is located in DGUOK exon 2 (NM_080916) between the third and fourth alpha helixes. c.313C>T (p.R105*) is predicted to result in a 173 amino acid residue truncation at the C terminus of DGUOK. There are as many as 112 infantile mtDNA depletion syndrome (MDS) cases in the literature related to DGUOK gene variants. These variants include missense mutations, nucleotide deletion, nucleotide insertion, and nucleotide duplication. Integrated data showed that mutations affected both conserved and non-conserved DGUOK amino acids and are associated with patient deaths. PMID- 29137426 TI - Therapeutic implications of tumor free margins in head and neck squamous cell carcinoma. AB - Objectives: The resection status is one of the most important prognostic factors for patients with head and neck squamous cell carcinoma (HNSCC) concerning overall survival (OS) and recurrence free interval (RFI). To assess whether therapy concepts changed depending on different resection margins and extracapsular extension, OS and RFI data were set into clinical context. Methods: All HNSCC patients who underwent head and neck surgery with/without adjuvant therapy (n=534) were selected over a ten-year period (2001-2011). Clinical parameters and survival data were collected retrospectively and histopathological analysis of tumor free margins and extracapsular extension were done. Results: Patients with microscopic in-sano resection showed mean OS/RFI of 95/96 months. OS/RFI decreased in microscopic non-in-sano and macroscopic non-in-sano (56/58 and 35/39 months) as well as in unclear resection margins (63/60 months). Patients with extracapsular extension, microscopic non-in-sano resection as well as patients with in-sano resection after follow up resection demonstrated therapy escalation by adjuvant (chemo-) radiation. Conclusions: Insufficient surgical margins and extracapsular extension are main risks for a reduced overall and recurrence free survival. Although there is no measure to prevent positive extracapsular extension, clear margins at first pass protect patients from adjuvant therapy escalation. PMID- 29137427 TI - Association of opioid receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) with nicotine dependence. AB - Background and Object: Whether opioid-receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) is associated with nicotine dependence is controversial. We analyzed the combined results from published studies of this possibility. Methods: Literature reviews were performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Web of Science, Chinese National Science Infrastructure (CNKI), PubMed, Embase and Google Scholar database searches using MeSH terms were conducted to find all relevant researches up to October 2016. Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated in allele, homozygote, heterozygote, dominant and recessive models. Ethnicity-specific subgroup meta-analysis, heterogeneity, sensitivity analysis and publication bias were considered. Results: Seven eligible studies with 3313 patients were included. The ORs in the five genetic models mentioned above were 1.000 (95% CI: 0.906, 1.104; p = 0.999), 1.032 (95% CI: 0.771, 1.381; p = 0.834), 0.963 (95% CI: 0.799, 1.162; p = 0.696), 1.006 (95% CI: 0.916, 1.104; p = 0.907), 0.967 (95% CI: 0.715, 1.309; p = 0.830), respectively. Only in dominant model is the association significant. Upon ethnicity-specific subgroup analysis, there is no statistical significance. Conclusion: OPRM1-A118G polymorphism (A>G) is not associated with nicotine dependence. PMID- 29137428 TI - PTEN loss is associated with prostate cancer recurrence and alterations in tumor DNA methylation profiles. AB - Background: Prostate cancer (PCa) with loss of the tumor suppressor gene PTEN has an unfavorable prognosis. DNA methylation profiles associated with PTEN loss may provide further insights into the mechanisms underlying these more aggressive, clinically relevant tumors. Methods: The cohort included patients with clinically localized PCa. Samples taken from the primary tumor were used to determine PTEN genomic deletions using FISH, and to analyze epigenome-wide DNA methylation profiles. Patients were followed for PCa recurrence on average for 8 years after diagnosis. Results: The study included 471 patients with data on PTEN loss, and the frequency of hemi- and homozygous PTEN loss was 10.0% and 4.5%, respectively. Loss of PTEN was associated with a significantly higher risk of recurrence (any vs. no PTEN loss; HR = 1.74; 95% CI: 1.03-2.93). Hazard ratios for hemi- and homozygous loss were 1.39 (95% CI: 0.73-2.64) and 2.84 (95% CI: 1.30-6.19), respectively. Epigenome-wide methylation profiling identified 4,208 differentially methylated CpGs (FDR Q-value < 0.01) in tumors with any versus no PTEN loss. There were no genome-wide significant differentially methylated CpGs in homo- versus hemizygous deleted tumors. Tumor methylation data were used to build a methylation signature of PTEN loss in our cohort, which was confirmed in TCGA, and included CpGs in ATP11A, GDNF, JAK1, JAM3, and VAPA. Conclusion: Loss of PTEN was positively associated with PCa recurrence. Prostate tumors with PTEN loss harbor a distinct methylation signature, and these aberrantly methylated CpG sites may mediate tumor progression when PTEN is deleted. PMID- 29137429 TI - Survival rate variation with different histological subtypes of poor prognostic male anal squamous cell carcinoma: a population-based study. AB - Background and objective: The prognosis of male anal squamous cell carcinoma (MASCC) and female anal squamous cell carcinoma (FASCC) is variable. The influence of tumor subtype on the survival rate and gender is poorly known. Our study is the largest population-based study and aims to outline the difference in survival between MASCC and FASCC patients. Methods: A retrospective population based study was performed to compare the disease-specific mortalities (DSMs) between genders related to the tumor subtypes. The Surveillance, Epidemiology, and End Results (SEER) program database was employed to obtain the data from January 1988 to December 2014. Results: A total of 4,516, (3,249 males and 1,267 females), patients with anal squamous cell carcinomas (ASCC) were investigated. The 5-year DSMs were 24.18% and 18.08% for men and women, respectively. The univariate analysis of the male basaloid squamous cell carcinoma (BSCC) and cloacogenic carcinoma (CC) patients demonstrated higher DSMs (P <0.001). Moreover, in the multivariate analysis, BSCC and CC were associated with soaring DSMs in male patients (P < 0.05). Conclusions: In the cohort of BSCC and CC patients, male patients demonstrated a considerable decrease in survival rate compared to females. A more precise classification of ASCC and individualized management for MASCC are warranted. PMID- 29137430 TI - Genome-wide analysis and functional prediction of long non-coding RNAs in mouse uterus during the implantation window. AB - Establishment of the receptive uterus is a crucial step for embryo implantation. In this study, the expression profiles and characterization of long non-coding RNAs (lncRNAs) in pregnant mouse uteri on day 4, day 5 at implantation sites and inter-implantation sites were conducted using RNA-seq. A total of 7,764 putative lncRNA transcripts were identified, including 6,179 known lncRNA transcripts and 1,585 novel lncRNA transcripts. Bioinformatics analysis of the cis and trans lncRNA targets showed that the differentially expressed lncRNAs were mainly involved in tissue remodelling, immune response and metabolism-related processes, indicating that lncRNAs could be involved in the regulation of embryo implantation. We also discovered that differentially expressed lncRNAs might regulate multiple signalling pathways that play an important role in the regulation of embryo implantation. In addition, nine known lncRNAs and four novel lncRNAs were randomly selected and validated by qRT-PCR. The expression of Tug1, Neat1, Gas5, Malat1, H19 and Rmst were significantly regulated in the mouse uterus during the implantation window. Our results are the first to systematically identify lncRNAs in the mouse uterus and provide a catalogue of lncRNAs for further understanding their functions in pregnant mouse uteri during the implantation window. PMID- 29137431 TI - Mitochondrial DNA depletion, mitochondrial mutations and high TFAM expression in hepatocellular carcinoma. AB - We investigated the role of mitochondrial genetic alterations in hepatocellular carcinoma by directly comparing the mitochondrial genomes of 86 matched pairs of HCC and non-tumor liver samples. Substitutions in 637 mtDNA sites were detected, comprising 89.80% transitions and 6.60% transversions. Forty-six somatic variants, including 15 novel mutations, were identified in 40.70% of tumor tissues. Of those, 21 were located in the non-coding region and 25 in the protein coding region. Twenty-two somatic nonsynonymous changes were identified as putative pathogenic variants, including 4 truncating mutations produced by three frameshifts (MT-ATP6 8628 insC; MT-ND5 13475 T-del, and MT-CYB 14984 insA) and 1 nonsense mutation in MT-CO3 9253 G>A. Among the somatic variants, only m.13676 A>G (MT-ND5), found in only 1 tumor, was heteroplasmic. Both inherited and somatic variants were predominately located in the D-loop region and the MT-ND5 gene. Tumor/non-tumor paired analysis showed that 69% of HCC samples contained significantly reduced mtDNA, compared with 49.0% of non-tumor counterparts. In 81.40% of HCC samples, mitochondrial transcription factor A (TFAM) was enriched in tumor cells but not in adjacent non-tumor cells. Neither mtDNA depletion nor TFAM overexpression correlated with the degree of cell differentiation, though TFAM expression correlated with tumor size. PMID- 29137432 TI - MiR-143 inhibits endometrial cancer cell proliferation and metastasis by targeting MAPK1. AB - Endometrial cancer (EC) is one of the most commonly diagnosed gynecologic malignancies in the world, with the morbidity rate of over 7%. The mechanism of the pathogenesis has not been specifically elucidated to date, which is imperative for EC treatment. The aim of our study was to investigate the target relationship between miR-143 and mitogen-activated protein kinase 1 (MAPK1) and explore the effect of miR-143 on the endometrial cancers (EC) cells through targeting MAPK1. We collected EC tissues and adjacent tissues, and transfected miR-143 mimics and MAPK1 siRNA into EC cells with lipofectamine. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to examine the expression of miR-143 and MAPK1 mRNA and the protein expression of MAPK1. Cell counting kit-8, wound healing assay, flow cytometry and transwell assay were applied to examining the alteration of the proliferation, migration, cell cycle and invasion ability of EC cells. We predicted the targeting gene of miR-143 through bioinformatics analysis. MiR-143 was found under-expressed in EC tissues and cells. Overexpression of miR-143 or knockdown of MAPK1 in human EC cell line HEC-1B inhibited the EC cell proliferation, migration and invasion and induced apoptosis. MAPK1 was verified to be a target gene of miR-143. MiR-143 overexpression could effectively inhibit mRNA and protein expression of MAPK1 in HEC-1B cells. Collectively, miR-143 might inhibit the proliferation, migration and invasion of EC cells, and promote the apoptosis of EC cells by suppressing MAPK1. These findings provided a view for new and potential therapeutic method for the clinical treatment of EC. PMID- 29137433 TI - Upregulation of homeobox gene is correlated with poor survival outcomes in cervical cancer. AB - HOX family members encode transcription factors crucial for embryogenesis and may be associated with carcinogenesis. Here, we evaluated the expression of 39 HOX genes in cervical cancer by using clinicopathological information and gene expression data of 308 patients from The Cancer Genome Atlas (TCGA) database. Correlations between mRNA expression of HOX family members and clinicopathological variables were explored. Seventy-three (23.7%) patients died during the follow-up period (median, 22.0 months). Overall mortality was significantly associated with advanced FIGO stage, lymph node metastasis, lymphovascular invasion, and increased HOXA1, HOXA5, HOXA6, and HOXC11 mRNA expression. Kaplan-Meier survival analysis revealed that overall survival was significantly shorter in patients with high HOXA rather than low HOXA expression (HOXA1, P = 0.012; HOXA5, P = 0.008; and HOXA6, P = 0.006). Upregulated HOXA1, HOXA5, and HOXA6 expression are significantly correlated with unfavorable overall survival and increased mortality in cervical cancer patients. Therefore, HOXA expression is a potential cervical cancer prognostic indicator. PMID- 29137434 TI - Involment of RAS/ERK1/2 signaling and MEF2C in miR-155-3p inhibition-triggered cardiomyocyte differentiation of embryonic stem cell. AB - MicroRNAs (miRNAs) are short, noncoding RNAs that regulate post-transcriptional gene expression by targeting messenger RNAs (mRNAs) for cleavage or translational repression. Growing evidence indicates that miR-155 expression changes with the development of heart and plays an important role in heart physiopathology. However, the role of miR-155 in cardiac cells differentiation is unclear. Using the well-established embryonic stem cell (ESC), we demonstrated that miR-155-3p expression was down-regulated during cardiogenesis from mouse ESC. By contrast, the myogenic enhance factor 2C (MEF2C), a predicted target gene of miR-155-3p, was up-regulated. We further demonstrated that miR-155-3p inhibition increased the percentage of embryoid bodies (EB) beating and up-regulated the expression of cardiac specific markers, GATA4, Nkx2.5, and cTnT mRNA and protein. Notably, miR 155-3p inhibition caused upregulation of MEF2C, KRAS and ERK1/2. ERK1/2 inhibitor, PD98059 significantly decreased the expression of MEF2C protein. These findings indicate that miR-155-3p inhibition promotes cardiogenesis, and its mechanisms are involved in the RAS-ERK1/2 signaling and MEF2C. PMID- 29137435 TI - Recurrent mutations in a SERPINC1 hotspot associate with venous thrombosis without apparent antithrombin deficiency. AB - Despite the essential anticoagulant function of antithrombin and the high risk of thrombosis associated with its deficiency, the prevalence of antithrombin deficiency among patients with venous thromboembolism (VTE) is very low. However, increasing evidence suggests that antithrombin deficiency may be underestimated. The analysis of SERPINC1, the gene encoding antithrombin, in 1,304 consecutive Chinese VTE patients and 1,334 healthy controls revealed a hotspot involving residues 294 and 295 that severely increases the risk of VTE. We detected the c.883G>A (p.Val295Met) (rs201381904) mutation in 11 patients and just one control (OR = 13.6; 95% CI: 1.7-107.1); c.881G>T (p.Arg294Leu) (rs587776397) in six patients but no controls; and c.880C>T (p.Arg294Cys) (rs747142328) in two patients but no controls. In addition, c.881G>A (p.Arg294His) (rs587776397) was identified in one control. These mutations were absent in a Caucasian cohort. Carriers of these mutations had normal antithrombin levels and anticoagulant activity, consistent with results obtained in a recombinant model. However, mutation carriers had a significantly increased endogenous thrombin potential. Our results suggest the existence in the Chinese population of a hotspot in SERPINC1 that significantly increases the risk of VTE by impairing the anticoagulant capacity of the hemostatic system. This effect is not revealed by current antigen or in vitro functional antithrombin assays. PMID- 29137436 TI - Tumor-biopsy stratification based on mTOR-pathway activity and functional mutations in the upstream genes PIK3CA and PTEN. AB - The mechanistic target of the rapamycin (mTOR) pathway is frequently activated in human cancers. Our objective was to evaluate relationships between mTOR-pathway activity and functional mutations in the upstream genes PIK3CA and PTEN in solid tumor biopsies from a broad selection of cancer types. Formalin-fixed paraffin embedded (FFPE) tumor samples were analyzed by immunohistochemistry (IHC) and next-generation sequencing (NGS). TOR-pathway activation was identified by expression (by IHC) of the downstream effector p-4E-BP1. Activating PIK3CA mutations and null PTEN mutations were identified by NGS, and for PTEN, confirmed by IHC. Overall, mTOR-pathway activation was identified in 444/538 (83%) samples representing 40 different cancer types. Functional mutations in either or both PIK3CA and PTEN genes were identified in 173/538 (32%) samples. PIK3CA mutations were identified in 60/538 (11%) samples, PTEN mutations were identified in 155/538 (29%) samples and mutations in both PIK3CA and PTEN were identified in 18/538 (3%) samples. Overall, mTOR-pathway activation was not significantly associated with the PIK3CA and PTEN genotypes. However, all 18 samples with both PIK3CA and PTEN mutations also displayed mTOR-pathway activation (chi2p=0.0471). Also, out of a total of 95 breast cancer samples, there were 5 breast-cancer samples which did not have mTOR-pathway activation, and all 5 (100%) of these had PIK3CA and PTEN mutations compared to 51/90 (57%) in the breast-cancer samples with mTOR-pathway activation (chi2p=0.0134). Finally, the percentages of PIK3CA mutations were higher in colorectal-cancer samples which had mTOR-pathway activation (9/27, 33%) than in colorectal-cancer samples without mTOR-pathway activation (6/44; 14%; chi2 p=0.0484). Therefore, tumor-biopsy analyses based on combined mTOR-pathway biomarkers (and combined NGS and IHC assessments) could potentially provide treatment-informative stratification for particular cancer types. PMID- 29137437 TI - DNA hypermethyation and silencing of PITX1 correlated with advanced stage and poor postoperative prognosis of esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is associated with the accumulation of genetic and epigenetic changes in the background mucosa. Dysregulated DNA methylation is known to lead to the inactivation of tumor suppressor genes and the activation of oncogenes. To identify the genes whose expression is perturbed by abnormal DNA methylation in ESCC, integrative transcriptomics by serial analysis of gene expression (SAGE) and methylome sequencing by methyl-DNA immunoprecipitation (MeDIP) analysis were performed. We found 159 genes with significantly decreased expression in ESCC compared to that in noncancerous esophageal mucosa. MeDIP-seq analysis identified hypermethylation in the promoter region of 56 of these genes. Using surgically resected tissues of 40 cases, we confirmed that the paired-like homeodomain 1 (PITX1) gene was hypermethylated in ESCC compared to that in normal tissues (P < 0.0001) by pyrosequencing. PITX1 overexpression in ESCC cell lines inhibited cell growth and colony formation, whereas PITX1 knockdown accelerated cell growth. A PITX1-transfected ESCC cell line, KYSE30, formed smaller tumors in nude mice than in mock-transfected cells. Hypermethylation of PITX1 was associated with tumor depth (P = 0.0011) and advanced tumor stage (P = 0.0052) and predicted poor survival in ESCC (hazard ratio, 0.1538; 95% confidence interval, 0.03159-0.7488; P = 0.0169). In this study, we found a novel tumor suppressor gene of ESCC, PITX1, which is silenced by DNA hypermethylation. Downregulation of PITX1 contributes to the growth and progression of ESCC. Hypermethylation of the PITX1 in ESCC correlated with tumor progression and advanced stage cancer, and may predict a poor prognosis. PMID- 29137438 TI - Prognostic value of bone scan index as an imaging biomarker in metastatic prostate cancer: a meta-analysis. AB - Background: The prognostic value of the bone scan index (BSI) in metastatic prostate cancer (mPCa) remained controversial. Therefore, we performed a meta analysis to determine the predictive value of BSI and survival in patients with mPCa. Materials and Methods: A literature search was performed in PubMed, Embase, Web of Science and Cochrane library databases. Hazard ratios (HRs), concordance indices (C-indices) were extracted to estimate the relationship between BSI and survival in patients with mPCa. Subgroup analyses were conducted on different types of mPCa, ethnics, cut-off values and sample sizes. Results: 14 high quality studies involving 1295 patients with mPCa were included in this meta-analysis. The pooled results indicated that high basline BSI and elevated BSI change on treatment (DeltaBSI) were significantly predictive of poor overall survial (HR = 1.29, P < 0.001; HR = 1.27, P < 0.001, respectively). Baseline BSI was also significantly related to cancer specific survival (HR = 1.65, P = 0.019) and prostate specific antigen recurrence survival (HR = 2.26, P < 0.001). Subgroup analysis supported main results. Moreover, BSI could increase the C-indices of predictive models. Conclusions: Baseline BSI and DeltaBSI may be beneficial to mPCa prognosis in clinical monitor and treatment. Further high quality studies with larger sample size are required in the future. PMID- 29137439 TI - Association between alcohol consumption and the risk of gastric cancer: a meta analysis of prospective cohort studies. AB - Alcohol consumption is inconsistently associated with the risk of gastric cancer morbidity and mortality. The aim of this study was to systematically evaluate the association between alcohol consumption on gastric cancer risk. The PubMed, Embase, and Cochrane Library databases were searched from inception through April 2017. Prospective cohort studies evaluating the association between alcohol consumption and risk of gastric cancer which report its effect estimates with 95% confidence intervals (CIs) were included. The results summary was performed using the random-effect model. Twenty-two cohort studies involving 22,545 cases of gastric cancer and 5,820,431 participants were identified and included in our data analysis. Overall, drinking had little or no effect on gastric cancer as compared with non-drinkers. Furthermore, light and moderate alcohol consumption had no significant effect on gastric cancer risk when compared with non-drinkers. However, heavy alcohol consumption was associated with a greater risk of gastric cancer when compared with non-drinkers. The findings of the subgroup analyses indicated that light alcohol consumption was associated with a lower risk of gastric cancer in women, while heavy alcohol consumption was associated with an increased risk of gastric cancer regardless of country, gender, whether the study reported gastric cancer incidence, or whether the study adjusted for body mass index, educational attainment, or physical activity. The findings of this study suggest that light alcohol consumption might play a protective effect on gastric cancer in women, while heavy alcohol consumption is associated with a significantly increased risk of gastric cancer in all subgroups. PMID- 29137440 TI - Comparison of DWI and 18F-FDG PET/CT for assessing preoperative N-staging in gastric cancer: evidence from a meta-analysis. AB - The diagnostic values of diffusion weighted imaging (DWI) and 18F fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for N-staging of gastric cancer (GC) were identified and compared. After a systematic search to identify relevant articles, meta-analysis was used to summarize the sensitivities, specificities, and areas under curves (AUCs) for DWI and PET/CT. To better understand the diagnostic utility of DWI and PET/CT for N staging, the performance of multi-detector computed tomography (MDCT) was used as a reference. Fifteen studies were analyzed. The pooled sensitivity, specificity, and AUC with 95% confidence intervals of DWI were 0.79 (0.73-0.85), 0.69 (0.61 0.77), and 0.81 (0.77-0.84), respectively. For PET/CT, the corresponding values were 0.52 (0.39-0.64), 0.88 (0.61-0.97), and 0.66 (0.62-0.70), respectively. Comparison of the two techniques revealed DWI had higher sensitivity and AUC, but no difference in specificity. DWI exhibited higher sensitivity but lower specificity than MDCT, and 18F-FDG PET/CT had lower sensitivity and equivalent specificity. Overall, DWI performed better than 18F-FDG PET/CT for preoperative N staging in GC. When the efficacy of MDCT was taken as a reference, DWI represented a complementary imaging technique, while 18F-FDG PET/CT had limited utility for preoperative N-staging. PMID- 29137442 TI - Prognostic value of long noncoding RNA ZFAS1 in various carcinomas: a meta analysis. AB - A number of studies have revealed that zinc finger antisense 1 (ZFAS1), a long noncoding RNA (lncRNA), is aberrantly regulated in various cancers, and high ZFAS1 expression is associated with poor prognosis and increased risk of lymph node metastasis (LNM). This meta-analysis was conducted to identify the potential value of ZFAS1 as a biomarker for cancer prognosis. We searched electronic database PubMed, Web of Science, and China Wanfang Data (up to June 1, 2017) to collect all relevant studies and explore the association of ZFAS1 expression with overall survival (OS) and LNM. The results showed that cancer patients with high ZFAS1 expression had a worse OS than those with low ZFAS1 expression (HR: 1.94, 95% confidence interval [CI]: 1.41-2.47, P < 0.001), and high ZFAS1 expression was significantly associated with LNM (OR: 2.60, 95% CI: 1.54-4.42, P < 0.001). Subgroup analysis revealed that high ZFAS1 expression was significantly related to high incidence of LNM in subgroups of sample size more than 88 (OR: 3.16, 95% CI: 2.06-4.86, P < 0.001), non-digestive system malignancies (OR: 4.05, 95% CI: 2.49-6.60, P < 0.001), and studies reported in 2017 (OR: 4.86, 95% CI: 2.67-8.84, P < 0.001) without significant heterogeneity. Further meta-regression by the covariates showed that tumor type, sample size, quality score, cut off value and publication year did not result in the inter-study heterogeneity. In conclusion, the present meta-analysis demonstrates that high ZFAS1 expression may potentially serve as a reliable biomarker for poor clinical outcome in various cancers. PMID- 29137441 TI - Aberrations in circulating inflammatory cytokine levels in patients with Down syndrome: a meta-analysis. AB - Evidence suggests that immune system alterations in Down syndrome (DS) may be early events that drive neuropathological and cognitive changes of Alzheimer's disease. The primary objective of this meta-analysis was to investigate whether there is an abnormal cytokine profile in DS patients when compared with healthy control (HC) subjects. A systematic search of Pubmed and Web of Science identified 19 studies with 957 DS patients and 541 HC subjects for this meta analysis. Random effects meta-analysis demonstrated that patients with DS had significantly increased circulating tumor necrosis factor-alpha (Hedges' g = 1.045, 95% confidence interval (CI) = 0.192 to 1.898, p = 0.016), interleukin (IL)-1beta (Hedges' g = 0.696, 95% confidence CI = 0.149 to 1.242, p = 0.013), interferon-gamma (Hedges' g = 0.978, 95% CI = 0.417 to 1.539, p = 0.001) and neopterin (Hedges' g = 0.815, 95% CI = 0.423 to 1.207, p < 0.001) levels compared to HC subjects. No significant differences were found between patients with DS and controls for concentrations of IL-4, IL-6, IL8 and IL-10. In addition, most of the cytokine data in this meta-analysis were from children with DS and HC, and subgroup analysis showed that children with DS had elevated tumor necrosis factor alpha, IL-1beta and interferon-gamma levels when compared with controls. Taken together, these results demonstrated that patients (children) with DS are accompanied by increased circulating cytokine tumor necrosis factor-alpha, IL 1beta and interferon-gamma levels, strengthening the clinical evidence that patients (children) with DS are accompanied by an abnormal inflammatory response. PMID- 29137443 TI - The clinical use of the platelet to lymphocyte ratio and lymphocyte to monocyte ratio as prognostic factors in renal cell carcinoma: a systematic review and meta analysis. AB - Conflicting evidence exists regarding the effect of platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) on the prognosis of renal cell carcinoma (RCC) patients. Here we quantify the prognostic impact of these biomarkers and assess their consistency in RCC. Eligible studies were retrieved from the PubMed, Embase and Web of Science databases. Pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Sixteen studies containing 6,223 patients met criteria for inclusion. Overall, elevated PLR was associated with poorer overall survival (OS, HR 1.76, 95% CI 1.41-2.19, P < 0.001), progression-free survival (PFS, HR 2.81, 95% CI 1.40-5.63, P = 0.004) and recurrence-free survival (RFS, HR 2.64, 95% CI 1.35-5.14, P = 0.004). Conversely, high LMR was correlated with more favorable OS (HR 0.62, 95% CI 0.51 0.77, P < 0.001) and RFS (HR 0.53, 95% CI 0.42-0.67, P < 0.001). Moreover, low LMR was significantly associated with some clinicopathological characteristics that are indicative of poor prognosis and disease aggressiveness. By these results, elevated PLR was associated with poor outcomes, while high LMR correlated with more favorable survival in RCC patients. Pretreatment PLR and LMR can serve as prognostic factors in RCC patients. PMID- 29137444 TI - Impact of splenic hilar lymph node metastasis on prognosis in patients with advanced gastric cancer. AB - Background: Impact of splenic hilar LN dissection during total gastrectomy for proximal advanced gastric cancer is controversial. The objective of this study was to assess the impact on prognosis of splenic hilar lymph node(LN) metastasis compared to that of metastasis to other regional LN groups. Study Design: Patients who underwent total gastrectomy with D2 LN dissection from 2000 to 2010 were reviewed retrospectively. The clinicopathologic characteristics and long term results of patients with splenic hilar LN metastasis were compared to those of patients with only metastasis to other extraperigastric LNs (stations #8a, #9, #11, or #12a). To investigate the survival benefit of performing splenic hilar LN dissection, the estimated therapeutic index for the procedure was calculated by multiplying the incidence of metastases in the hilar region by the survival rates for individuals with nodal involvement in that region. Results: Of 602 patients, 87(14.5%) had hilar LN metastasis. The 5-year overall and relapse-free survival rates for patients with hilar LN metastasis were 24.1% and 12.1%, respectively. These rates were similar to those for patients with metastasis to other extraperigastric LNs (P > 0.05), with similar recurrence patterns. Overall survival in the hilar LN metastasis group was better than that for patients with distant metastasis(P < 0.05). The estimated therapeutic index of splenic hilar LN dissection was 3.5, which was similar to index values for LN dissection at other extraperigastric LNs. Conclusions: Dissection of splenic hilar LNs during total gastrectomy for advanced gastric cancer allows for a prognosis similar to that achieved with dissection of extraperigastric LNs. PMID- 29137445 TI - Altered resting-state functional activity in isolated pontine infarction patients with pathological laughing and crying. AB - We used resting-state functional magnetic resonance imaging to investigate the global spontaneous neural activity involved in pathological laughing and crying after stroke. Twelve pathological laughing and crying patients with isolated pontine infarction were included, along with 12 age- and gender-matched acute isolated pontine infarction patients without pathological laughing and crying, and 12 age- and gender-matched healthy controls. We examined both the amplitude of low-frequency fluctuation and the regional homogeneity in order to comprehensively evaluate the intrinsic activity in patients with post-stroke pathological laughing and crying. In the post-stroke pathological laughing and crying group, changes in these measures were observed mainly in components of the default mode network (medial prefrontal cortex/anterior cingulate cortex, middle temporal gyrus, inferior temporal gyrus, superior frontal gyrus, middle frontal gyrus and inferior parietal lobule), sensorimotor network (supplementary motor area, precentral gyrus and paracentral lobule), affective network (medial prefrontal cortex/anterior cingulate cortex, parahippocampal gyrus, middle temporal gyrus and inferior temporal gyrus) and cerebellar lobes (cerebellum posterior lobe). We therefore speculate that when disinhibition of the volitional system is lost, increased activation of the emotional system causes pathological laughing and crying. PMID- 29137446 TI - Suspected cancer diagnoses made by general practitioners in a population with subsequently confirmed cancer diagnoses in Germany: a retrospective study of 31,628 patients. AB - The goal of the present study was to analyze the prevalence and risk factors of suspected cancer diagnoses made by general practitioners (GP) in a population with subsequently confirmed cancer diagnoses in Germany. This study included patients aged 18 years or older who received an initial documentation of a confirmed cancer diagnosis from 1,262 German GP between January and December 2016 (index date). The main outcome measure of the study was the rate of suspected cancer diagnoses made by GP within one year prior to the index date. A multivariate logistic regression model was used to estimate the relationship between defined demographic and clinical variables and suspected cancer diagnoses. This study included 31,628 individuals. Within the year prior to the confirmed cancer diagnosis, 5% of the population received suspected cancer diagnoses. Patients in the age groups 41-50, 51-60, and 61-70 years were more likely to receive a suspected cancer diagnosis from a GP than those in the age group > 80 years (OR ranging from 1.30 to 1.38). Lung cancer, skin cancer, prostate cancer, and leukemia were associated with an increase in such odds when compared to cancers of the digestive organs (OR ranging from 1.56 to 2.26), whereas female genital organ cancers were associated with decreased odds (OR = 0.63). Overall, approximately 5% of patients received suspected diagnoses of cancer prior to their confirmed diagnoses. Suspected cancer diagnoses were associated with age and several types of cancer. PMID- 29137447 TI - Thrombospondin-1 is a multifaceted player in tumor progression. AB - Thrombospondins are a family of extracellular matrix (ECM) proteins. Thrombospondin-1 (TSP1) was the first member to be identified and is a main player in tumor microenvironment. The diverse functions of TSP1 depend on the interactions between its structural domains and multiple cell surface molecules. TSP1 acts as an angiogenesis inhibitor by stimulating endothelial cell apoptosis, inhibiting endothelial cell migration and proliferation, and regulating vascular endothelial growth factor bioavailability and activity. In addition to angiogenesis modulation, TSP1 also affects tumor cell adhesion, invasion, migration, proliferation, apoptosis and tumor immunity. This review discusses the multifaceted and sometimes opposite effects of TSP1 on tumor progression depending on the molecular and cellular composition of the microenvironment. Clinical implications of TSP1-related compounds are also discussed. PMID- 29137448 TI - Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. AB - The development of multidrug resistance (MDR) is one of the major challenges to the success of traditional chemotherapy treatment in cancer patients. Most studies to date have focused on strategies to reverse MDR following its development. However, agents utilizing this approach have proven to be of limited clinical use, failing to demonstrate an improvement in therapeutic efficacy with almost no significant survival benefits observed in cancer clinical trials. An alternative approach that has been applied is to prevent or delay MDR prior or early in its development. Recent investigations have shown that preventing the emergence of MDR at the onset of chemotherapy treatment, rather than reversing MDR once it has developed, may assist in overcoming drug resistance. In this review, we focus on a number of novel strategies used by small-molecule inhibitors to prevent the development of MDR. These agents hold great promise for prolonging the efficacy of chemotherapy treatment and improving the clinical outcomes of patients with cancers that are susceptible to MDR development. PMID- 29137449 TI - Differential side effects profile in patients with mCRPC treated with abiraterone or enzalutamide: a meta-analysis of randomized controlled trials. AB - Background: Abiraterone and enzalutamide are currently approved for mCRPC patients. Both drugs have distinct mechanisms of action and may have different toxicity profile. There are limited data comparing the side effects of abiraterone and enzalutamide. We performed a meta-analysis of randomized controlled trials (RCT) to better characterize the risk of adverse events associated with both drugs. Methods: We performed a literature search on MEDLINE for studies reporting abiraterone and enzalutamide side effects from January 1966 to July 31, 2015. Abstracts presented at ASCO meetings from 2004 to 2015 were selected manually. Phase III RCT were included in analysis. We assessed the risk of adverse events reported in RCT by performing two meta-analyses: abiraterone prednisone vs. placebo-prednisone (2,283 pts) and enzalutamide vs. placebo (2,914 pts). Summary of incidence, relative-risks (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: Overall, enzalutamide was not associated with all-grade (RR 1.06 - 95% CI 0.67-1.65) or grade >=3 (RR 0.81 - 95% CI 0.28-2.33) cardiovascular events, but was associated with increased risk of all-grade fatigue (RR 1.29 - 95% CI 1.15-1.44). On the other hand, abiraterone was associated with increased risk of all-grade (RR 1.28 - 95% CI 1.06-1.55) and grade >=3 (RR 1.76 - 95% CI 1.12-2.75) cardiovascular events, but was not associated with all-grade (RR 0.85 - 95% CI 0.58-1.23) or grade >=3 (RR 1.07 - 95% CI 0.97-1.19) fatigue. Conclusions: In this meta-analysis, abiraterone was associated with an increased risk of cardiovascular events, while enzalutamide was associated with an increased risk of fatigue. PMID- 29137452 TI - Pathologic basis of the sonographic differences between thyroid cancer and noninvasive follicular thyroid neoplasm with papillary-like nuclear features. AB - Ultrasonography is pivotal in triage thyroid biopsy in the era after the identification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This pictorial essay illustrates the pathologic basis of the sonographic features that distinguish NIFTP from thyroid cancers. In this study, we present the correlations of ultrasonography to *1 histopathology to assess shape and margin characteristics. Markedly hypoechoic nodules correlate to microfollicular/solid nodules, while isoechoic/hyperechoic thyroid nodules correlate to normofollicular/macrofollicular nodules. The ultrasound findings of NIFTP and minimally invasive encapsulated thyroid cancers are similar. Both are well-circumscribed, oval-to-round nodules with regular margins. Blurred or microlobulated margins indicate infiltrating tumors, while lobulated margins are characteristic of expansile tumors. Overtly invasive encapsulated tumors are characterized by oval-to-round nodules with irregular or lobulated margins. The ultrasound findings for infiltrative thyroid cancers show at least one of the following malignant features: marked hypoechoicity, taller-than-wide shape, microcalcifications, and blurred or microlobulated margins. PMID- 29137453 TI - Instantaneous Colorimetric and Fluorogenic Detection of Phosgene with a meso Oxime-BODIPY. AB - The meso-oxime-substituted-1,3,5,7-tetramethyl BODIPY (1-oxime) was developed into a colorimetric and fluorogenic probe to selectively detect and quantify phosgene. The fast (<10 s) and sensitive (LOD = 0.09 ppb) phosgene detection is achieved by the conversion of the meso-oxime to the meso-nitrile, resulting in a large fluorescence turn-on response. The utility of 1-oxime was established for the visual detection of phosgene in solution and in a practical solid-state platform, making it a suitable candidate for on-site monitoring of phosgene gas exposure in the workplace. PMID- 29137451 TI - The transcription factor ATF5: role in cellular differentiation, stress responses, and cancer. AB - Activating transcription factor 5 (ATF5) is a cellular prosurvival transcription factor within the basic leucine zipper (bZip) family that is involved in cellular differentiation and promotes cellular adaptation to stress. Recent studies have characterized the oncogenic role of ATF5 in the development of several different types of cancer, notably glioblastoma. Preclinical assessment of a systemically deliverable dominant-negative ATF5 (dnATF5) biologic has found that targeting ATF5 results in tumor regression and tumor growth inhibition of glioblastoma xenografts in mouse models. In this review, we comprehensively and critically detail the current scientific literature on ATF5 in the context of cellular differentiation, survival, and response to stressors in normal tissues. Furthermore, we will discuss how the prosurvival role of ATF5 aides in cancer development, followed by current advances in targeting ATF5 using dominant negative biologics, and perspectives on future research. PMID- 29137450 TI - Moving forward with actionable therapeutic targets and opportunities in endometrial cancer: NCI clinical trials planning meeting report on identifying key genes and molecular pathways for targeted endometrial cancer trials. AB - The incidence and mortality rates from endometrial cancer are increasing. There have been no new drugs approved for the treatment of endometrial cancer in decades. The National Cancer Institute, Gynecologic Cancer Steering Committee identified the integration of molecular and/or histologic stratification into endometrial cancer management as a top strategic priority. Based on this, they convened a group of experts to review the molecular data in this disease. Here we report on the actionable opportunities and therapeutic directions identified for incorporation into future clinical trials. PMID- 29137454 TI - Determination of Cancer Cell-Based pH-Sensitive Fluorescent Carbon Nanoparticles of Cross-Linked Polydopamine by Fluorescence Sensing of Alkaline Phosphatase Activity on Coated Surfaces and Aqueous Solution. AB - The tumor-specific sensitive fluorescence sensing of cellular alkaline phosphatase (ALP) activity on the basis of host-guest specific and pH sensitivity was conducted on coated surfaces and aqueous states. Cross-linked fluorescent nanoparticles (C-FNP) consisting of beta-cyclodextrin (beta-CD)/boronic acid (BA) and fluorescent hyaluronic acid [FNP(HA)] were conjugated to fluorescent polydopamine [FNP(pDA)]. To determine the quenching effect of this system, hydrolysis of 4-nitrophenyl phosphate (NPP) to 4-nitrophenol (NP) was performed in the cavity of beta-CD in the presence of ALP activated photoinduced electron transfer (PET) between NP and C-FNP. At an ALP level of 30-1000 U/L, NP caused off-emission of C-FNP because of their specific host-guest recognition. Fluorescence can be recovered under pH shock due to cleavage of the diol bond between beta-CD and BA, resulting in release of NP from the fluorescent system. Sensitivity of the assays was assessed by confocal imaging not only in aqueous states, but also for the first time on coated surfaces in MDAMB-231 and MDCK cells. This novel system demonstrated high sensitivity to ALP through generation of good electron donor/acceptor pair during the PET process. Therefore, this fluorescence sensor system can be used to enhance ALP monitoring and cancer diagnosis on both coated surfaces and in aqueous states in clinical settings. PMID- 29137455 TI - Metal/Ion Interactions Induced p-i-n Junction in Methylammonium Lead Triiodide Perovskite Single Crystals. AB - Hybrid perovskites, as emerging multifunctional semiconductors, have demonstrated dual electronic/ionic conduction properties. We report a metal/ion interaction induced p-i-n junction across slightly n-type doped MAPbI3 single crystals with Au/MAPbI3/Ag configuration based on interface dependent Seebeck effect, Hall effect and time-of-flight secondary ion mass spectrometry analysis. The organic cations (MA+) interact with Au atoms, forming positively charged coordination complexes at Au/MAPbI3 interface, whereas iodine anions (I-) can react with Ag contacts, leading to interfacial ionic polarization. Such metal/ion interactions establish a p-doped region near the Au/MAPbI3 interface due to the formation of MA+ vacancies, and an n-doped region near the Ag/MAPbI3 interface due to formation of I- vacancies, consequently forming a p-i-n junction across the crystal in Au/MAPbI3/Ag configuration. Therefore, the metal/ion interaction plays a role in determining the surface electronic structure and semiconducting properties of hybrid perovskites. PMID- 29137456 TI - Highly Stretchable Conductors Based on Expanded Graphite Macroconfined in Tubular Rubber. AB - Highly stretchable and durable conductors are significant to the development of wearable devices, robots, human-machine interfaces, and other artificial intelligence products. Although many respectable methods have been reported, it is still a challenge to fabricate stretchable conductors with a large elastic limit, high conductivity, and excellent reliability in rapid, effective, and economic ways. Herein, a facile method is offered to fabricate high-performance stretchable tubular conductors (TCs) based on a macroconfined structure of expanded graphite (EG) in rubber tubing by simply physical packing. The maximum original electrical conductivity of TCs reached a high value of 160.6 S/cm. Meanwhile, TCs showed more insensitive response of conductivity to increasing tensile strain compared to the TCs encapsulated with liquid metal or ionic liquid. The conductivity and effective stretchability of TCs can be adjusted by varying the packing density of EG. A low gauge factor below 3 was reached even under 400% stretching for TCs with a packing density of 1.233 g/cm3. The excellent resilience and good stability of conductivity of TCs during dynamic stretching-releasing cycles are attributed to the stable and rapid reconstruction of the percolation network of EG particles. The combination of high conductivity, tunable stretchability, and good reliability renders potential applications to TCs, such as highly stretchable interconnects or strain sensors, in human motion detection. PMID- 29137458 TI - Microfluidics Fabrication of Self-Oscillating Microgel Clusters with Tailored Temperature-Responsive Properties Using Polymersomes as "Microreactors". AB - Poly(N-isopropylacrylamide)-based microgel clusters were successfully prepared using polymersomes as "microreactors", which were fabricated through microfluidics. The clusters were formed from the cross-linking reaction between ruthenium/amino group dual functionalized poly(N-isopropylacrylamide) microgels and linear poly(N-isopropylacrylamide)-r-(N-acryloxysuccinimide)-based polymer linkers under neutral pH conditions. By simply adjusting the ratio of N isopropylacrylamide to N-acryloxysuccinimide in the polymer cross-linkers, the internal structures of the clusters can be controlled; hence, the temperature response of the clusters can be regulated. It was demonstrated that these different microgel clusters showed various degrees of chemomechanical oscillations when the clusters were exposed to a catalyst-free solution containing Belousov-Zhabotinsky reaction substrates. PMID- 29137460 TI - Feeling Rejected? ACS Chemical Neuroscience Can Help Get Your Science to the Neuroscience Community As Quickly As Possible. PMID- 29137457 TI - Monoclonal Antibody That Recognizes Diethoxyphosphotyrosine-Modified Proteins and Peptides Independent of Surrounding Amino Acids. AB - Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are irreversibly inhibited by organophosphorus pesticides through formation of a covalent bond with the active site serine. Proteins that have no active site serine, for example albumin, are covalently modified on tyrosine and lysine. Chronic illness from pesticide exposure is not explained by inhibition of AChE and BChE. Our goal was to produce a monoclonal antibody that recognizes proteins diethoxyphosphorylated on tyrosine. Diethoxyphosphate-tyrosine adducts for 13 peptides were synthesized. The diethoxyphosphorylated (OP) peptides cross-linked to four different carrier proteins were used to immunize, boost, and screen mice. Monoclonal antibodies were produced with hybridoma technology. Monoclonal antibody depY was purified and characterized by ELISA, western blotting, Biacore, and Octet technology to determine binding affinity and binding specificity. DepY recognized diethoxyphosphotyrosine independent of the amino acid sequence around the modified tyrosine and independent of the identity of the carrier protein or peptide. It had an IC50 of 3 * 10-9 M in a competition assay with OP tubulin. Kd values measured by Biacore and OctetRED96 were 10-8 M for OP-peptides and 1 * 10 12 M for OP-proteins. The limit of detection measured on western blots hybridized with 0.14 MUg/mL of depY was 0.025 MUg of human albumin conjugated to YGGFL-OP. DepY was specific for diethoxyphosphotyrosine (chlorpyrifos oxon adduct) as it failed to recognize diethoxyphospholysine, phosphoserine, phosphotyrosine, phosphothreonine, dimethoxyphosphotyrosine (dichlorvos adduct), dimethoxyphosphoserine, monomethoxyphosphotyrosine (aged dichlorvos adduct), and cresylphosphoserine. In conclusion, a monoclonal antibody that specifically recognizes diethoxyphosphotyrosine adducts has been developed. The depY monoclonal antibody could be useful for identifying new biomarkers of OP exposure. PMID- 29137461 TI - Embarking on a 5 Year Journey to Highlight Genetic and Rare Diseases of the Central Nervous System. PMID- 29137463 TI - Normalized Weight of Iranian Newborns According to Gestational Age: A Nationwide Study. AB - BACKGROUND: By organizing birth weights according to gestational age at birth, reference weight values for different sex-gestational ages are provided. METHODS: Data of 1,090,779 mothers and their neonates were gathered from 30 provinces of Iran. Pregnancy complications, maternal risk factors, type of delivery, maternal outcome, neonatal sex and APGAR score were determined. Birth weights were quantified into 3rd, 50th and 97th centile. Regression analysis was used to estimate birth weight of neonates. RESULTS: Birth weight showed an enhancing trend with age; boys weighed more, multiparous women had higher neonatal birth weight, mothers with cardiovascular disease and diabetes mellitus had heavier infants, and mothers aged below 20 years had lower estimated infant birth weight. Gestational age (beta = 147.3) and male sex (beta = 114.9) were the most important independent variables, respectively for predicting birth weight (R square = 0.512 and P < 0.001). In other words, with each unit increase in gestational age, birth weight would increase by 147.3 grams. Male fetuses were also 114.9 grams heavier than females of the same gestational age. Value of R square shows relatively acceptable goodness of this statistical model. CONCLUSION: A national reference for fetal growth patterns and related factors was determined in this study. PMID- 29137464 TI - Zero and Five End-Digit Preference and Blood Pressure Quality of Care Revisited. AB - BACKGROUND: To determine the rate of zero and five end-digit preference (EDP) for systolic and diastolic blood pressures (SBP and DBP, respectively) and risk factors amongst a representative sample of Iranian adults in the year 2011. METHODS: Data gathered from 7997 Iranian adults aged 25-70 were extracted from the database of the sixth Survey of Surveillance of Risk Factors of Non communicable Diseases, which surveyed a total of 11,864 individuals aged 6 to 70 years. Multilevel multiple logistic regression was used to identify the independent factors associated with zero or five EDP. RESULTS: The prevalence of three serial zero or five EDP for SBP and DBP were 18.5% (95% CI: 11.3%-25.7%). SBP >=140 mmHg (OR = 0.78; 95% CI: 0.65-0.95), DBP >=90 mmHg (OR = 0.71; 95% CI: 0.58-0.88), and a positive family history of diabetes (OR = 0.77; 95% CI: 0.66 0.9) were found as protective factors against zero or five EDP in blood pressure recording the male gender (OR = 1.18; 95% CI: 1.04-1.35) was found to be its independent risk factor. CONCLUSION: Sex, SBP, DBP and family history of diabetes were found to be the main independent determinants of EDP in our country which underscores the importance of assessing the many patient-related factors in the studies involving EDP as part of BP monitoring in public health care. PMID- 29137465 TI - A Trial on The Effects of Magnesium-Zinc-Calcium-Vitamin D Co-Supplementation on Glycemic Control and Markers of Cardio-Metabolic Risk in Women with Polycystic Ovary Syndrome. AB - BACKGROUND: There is scarce data on the effects of magnesium-zinc-calcium-vitamin D co-supplementation on glycemic control and markers of cardio-metabolic risk among women with polycystic ovary syndrome (PCOS). The objective of this study was to assess the effects of magnesium-zinc-calcium-vitamin D co-supplementation on glycemic control and markers of cardio-metabolic risk in women with PCOS. METHODS: Sixty PCOS women were randomized into two groups and treated with 100 mg of magnesium, 4 mg of zinc, 400 mg of calcium plus 200 IU of vitamin D supplements (n = 30) or placebo (n = 30) twice a day for 12 weeks. Glycemic control and markers of cardio-metabolic risk were assessed at baseline and at the end of trial. RESULTS: After the 12-week intervention, compared with the placebo, magnesium-zinc-calcium-vitamin D co-supplementation supplementation resulted in significant reductions in serum insulin levels (-1.9 +/- 4.6 vs. +0.4 +/- 2.8 uIU/mL, P = 0.01), and homeostatic model of assessment for insulin resistance ( 0.4 +/- 1.0 vs. +0.1 +/- 0.6, P = 0.02), as well as a significant increase in quantitative insulin sensitivity check index (+0.01 +/- 0.02 vs. -0.0003 +/- 0.01, P = 0.02). In addition, magnesium-zinc-calcium-vitamin D co-supplementation significantly decreased serum triglycerides (-26.5 +/- 42.9 vs. +8.9 +/- 17.9 mg/dL, P < 0.001), VLDL-cholesterol concentrations (-5.3 +/- 8.6 vs. +1.8 +/- 3.6 mg/dL, P < 0.001), total cholesterol (-4.2 +/- 30.7 vs. +11.1 +/- 28.4 mg/dL, P = 0.04) and total-/HDL-cholesterol ratio (-0.04 +/- 0.6 vs. +0.3 +/- 0.9, P = 0.04) compared with the placebo. CONCLUSION: Overall, the results of this study demonstrated that magnesium-zinc-calcium-vitamin D co-supplementation for 12 weeks among patients with PCOS had beneficial effects on insulin metabolism and markers of cardio-metabolic risk. PMID- 29137466 TI - Evaluation of Extremity Injuries Presented to Emergency Department. AB - OBJECTIVE: In this study, we aimed to review cases with firearms injury of extremities presented to our hospital. METHODS: After approval by Institutional Board, electronic database was retrospectively screened for firearms injury of extremities between 2012 and 2015. Overall, 600 cases with firearms injury of extremities were included in the study. Cases were assessed for demographic and clinical characteristics, Mangled extremity severity score (MESS), Glasgow Coma Scale (GCS), costs and outcomes. RESULTS: Totally, 552 (92.0%) cases were men and 48 (8.0%) were women. Mean age was 29.97 +/- 10.40 years (range: 5-64 years). A significant difference was detected in gender distribution. Of the cases, 96.6% (n = 580) were Syrian war casualties. Lower extremity injury was the most frequently seen injury (n = 312; 52.0%). Mean MESS score was 4.71 +/- 1.32 (range: 2-9). GCS score was <8 in 3 fatal cases (0.5%) whereas it was 15 in 597 cases (99.5%). It was found that 66 cases (11.0%) underwent amputation after they arrived in the hospital as a result of crush injury due to mine and blast. In cases who underwent amputation, a positive correlation was detected in MESS scores (P = 0.00). Mean cost was estimated to be 6,936 TL (280-32,232 TL). CONCLUSION: Young male and lower extremity injuries were most commonly encountered. Amputation was performed in the early period in cases with highest MESS scores. It was seen that amputation was common in crush injuries due to mine and blast. It was found that patient volume at emergency department and hospital and costs were increased due to war. PMID- 29137467 TI - Evaluation of Serum Copper Level in Naswar (Smokeless Tobacco) Addicts Using Flame Atomic Absorption Spectroscopy. AB - BACKGROUND: Substance abuse and its consequences are a matter of great concern in South-East Asian countries, especially Pakistan and Afghanistan. Due to contamination of Naswar with copper, or by any other physiological mechanism, there is a great chance of copper poisoning in addicts. Keeping in view the literature, there is no comparative study on serum copper levels (SCuL) in Naswar addicts. Therefore, it is very important to evaluate SCuL in this population. METHODS: The current study was performed in September 2016 where a total of 75 volunteers (selected from villages near the University of Peshawar, Pakistan) were grouped as Naswar addicts (n = 45) and the control group (n = 30). The addicts were compared to controls for age, weight, BMI, FBS and creatinine clearance. For serum analysis, about 3mL of blood was collected from which the serum was separated, digested, and then evaluated for SCuL using flame atomic absorption spectroscopy at the Department of Pharmacy and Centralized Resource Laboratory of University of Peshawar. RESULTS: The SCuL in addicts had a range of 2.6 to 11.1 ug/dL with a mean of 5.1 +/- 2.4 ug/dL. In the healthy control group, SCuL was between 1.7 to 3.9 ug/dL with a mean of 2.6 +/-0.1 ug/dL. The mean difference between the two study groups was statistically significant (P = 0.005); the duration of addiction and quantity of drug consumptions per day correlated positively with SCuL. CONCLUSION: Serum level of copper in Naswar addicts is elevated compared to the Control group. The exact cause of SCuL elevations and the mechanisms involved must be studied in large group samples. PMID- 29137468 TI - Epidemiology of Neuroendocrine Tumors in an Iranian Population. AB - Neuroendocrine tumors (NETs) are a rare and heterogeneous group of malignancies most commonly found in the gastrointestinal system. In this study, we examined the epidemiology of NETs in an Iranian population. The incident NET cases diagnosed between January 1, 2009 and December 31, 2014 were collected from databases of three hospitals in Tehran (Shoada-e-Tajrish Hospital, Imam Hossein Hospital and Pars Hospital). A total of 291 cases with NET diagnosis were identified. The most common NET location was gastrointestinal (71.4%), followed by Bronchopulmonary (7.2%) and Genitourinary (7.2%). The total number of identified NETs in our study increased from 25 cases in 2009 to 66 cases in 2014. In conclusion, our data suggests that the incidence of NETs is increasing slowly. Thus, etiologic studies for NETs are needed to help plan future preventive strategies. The authors declare no conflicts of interests. PMID- 29137469 TI - Photoclinic. PMID- 29137470 TI - Controversies in Management of Hyperthyroidism during Pregnancy. PMID- 29137471 TI - Serum levels of spexin and kisspeptin negatively correlate with obesity and insulin resistance in women. AB - Spexin (SPX) and kisspeptin (KISS) are novel peptides relevant in the context of regulation of metabolism, food intake, puberty and reproduction. Here, we studied changes of serum SPX and KISS levels in female non-obese volunteers (BMI<25 kg/m(2)) and obese patients (BMI>35 kg/m(2)). Correlations between SPX or KISS with BMI, McAuley index, QUICKI, HOMA IR, serum levels of insulin, glucagon, leptin, adiponectin, orexin-A, obestatin, ghrelin and GLP-1 were assessed. Obese patients had lower SPX and KISS levels as compared to non-obese volunteers (SPX: 4.48+/-0.19 ng/ml vs. 6.63+/-0.29 ng/ml; p<0.001, KISS: 1.357+/-0.15 nmol/l vs. 2.165+/-0.174 nmol/l; p<0.01). SPX negatively correlated with BMI, HOMA-IR, insulin, glucagon, active ghrelin and leptin. Positive correlations were found between SPX and QUICKI index, McAuley index, serum levels of obestatin, GLP-1 and adiponectin and orexin-A Serum KISS negatively correlated with BMI, HOMA-IR, serum levels of insulin, glucagon, active ghrelin and leptin. KISS positively correlated with QUICKI index, McAuley index and adiponectin. In summary, SPX and KISS show negative correlations with obesity, insulin resistance indices, and hormones known to affect insulin sensitivity in females. Both, SPX and KISS could be therefore relevant in the pathophysiology of obesity and insulin resistance. PMID- 29137472 TI - Changes in transcription pattern lead to a marked decrease in COX, CS and SQR activity after the developmental point of the 22(nd) gestational week. AB - Tissue differentiation and proliferation throughout fetal development interconnect with changes in the oxidative phosphorylation system (OXPHOS) on the cellular level. Reevaluation of the expression data revealed a significant increase in COX4 and MTATP6 liver transcription levels after the 22(nd) gestational week (GW) which inspired us to characterize its functional impact. Specific activities of cytochrome c oxidase (COX), citrate synthase (CS), succinate-coenzyme Q reductase (SQR) and mtDNA determined by spectrophotometry and RT-PCR were studied in a set of 25 liver and 18 skeletal muscle samples at 13(th) to 29(th) GW. Additionally, liver hematopoiesis (LH) was surveyed by light microscopy. The mtDNA content positively correlated with the gestational age only in the liver. The activities of COX, CS and SQR in both liver and muscle isolated mitochondria significantly decreased after the 22(nd) GW in comparison with earlier GW. A continuous decline of LH, not correlating with the documented OXPHOS-specific activities, was observed from the 14(th) to the 24(th) GW indicating their exclusive reflection of liver tissue processes. Two apparently contradictory processes of increasing mtDNA transcription and decreasing OXPHOS specific activities seem to be indispensable for rapid postnatal adaptation to high energy demands. The inadequate capacity of mitochondrial energy production may be an important factor in the mortality of children born before the critical developmental point of the 22(nd) GW. PMID- 29137473 TI - Effect of short- and long-term administration of baclofen on spatial learning and memory in rats. AB - Baclofen is the only clinically available metabotropic GABA(B) receptor agonist. In our experiment, we tested the hypothesis that long-term baclofen administration can impair learning and memory in rats. The experiment consisted of three parts. In the first part of the study the drug was administered simultaneously with the beginning of the behavioral tests. In the second and third part of the experiment baclofen was administered daily for 14 days and for one month before the tests. In each part of the experiment, adult rats were randomly divided into four treatment groups. Three groups were given an injection of baclofen at doses of 1 mg/kg, 5 mg/kg, 10 mg/kg, while the fourth group was injected with saline. The injections were given after each session. Spatial learning and memory were tested using the Morris water maze, involving three types of tests: Acquisition, Probe, and Re-acquisition. This work reveals that baclofen did not affect spatial learning at any of the tested doses and regardless of the length of administration. Memory was observed to be affected, but only at the highest dose of baclofen and only temporarily. This conclusion is in line with previously published clinical cases. PMID- 29137474 TI - Ontogenetic development of sensitivity of the cerebral cortex to an antagonist of GABA(A) receptor bicuculline. AB - Local application of four concentrations of bicuculline methiodide (a specific antagonist of GABA(A) receptors) was used to study a sensitivity of somatosensory cortex in four age groups of immature rats with implanted electrodes. Presence and latencies of two epileptic phenomena (focal discharges and seizures) were evaluated. Focal discharges exhibited moderate tendency to a decrease of sensitivity to bicuculline methiodide with maturation. Concentration-effect relation of incidence of focal discharges was observed only in 7- and 12-day-old but not in older animals. Results with incidence and latencies of seizures did not show relations to age or concentration of bicuculline. Neither of the epileptic phenomena can be used as a reliable index of cortical maturation. PMID- 29137475 TI - Metformin attenuates myocardium dicarbonyl stress induced by chronic hypertriglyceridemia. AB - Reactive dicarbonyls stimulate production of advanced glycation endproducts, increase oxidative stress and inflammation and contribute to the development of vascular complications. We measured concentrations of dicarbonyls - methylglyoxal (MG), glyoxal (GL) and 3-deoxyglucosone (3-DG) - in the heart and kidney of a model of metabolic syndrome - hereditary hypertriglyceridemic rats (HHTg) and explored its modulation by metformin. Adult HHTg rats were fed a standard diet with or without metformin (300 mg/kg b.w.) and dicarbonyl levels and metabolic parameters were measured. HHTg rats had markedly elevated serum levels of triacylglycerols (p<0.001), FFA (p<0.01) and hepatic triacylglycerols (p<0.001) along with increased concentrations of reactive dicarbonyls in myocardium (MG: p<0.001; GL: p<0.01; 3-DG: p<0.01) and kidney cortex (MG: p<0.01). Metformin treatment significantly reduced reactive dicarbonyls in the myocardium (MG: p<0.05, GL: p<0.05, 3-DG: p<0.01) along with increase of myocardial concentrations of reduced glutathione (p<0.01) and glyoxalase 1 mRNA expression (p<0.05). Metformin did not have any significant effect on dicarbonyls, glutathione or on glyoxalase 1 expression in kidney cortex. Chronically elevated hypertriglyceridemia was associated with increased levels of dicarbonyls in heart and kidney. Beneficial effects of metformin on reactive dicarbonyls and glyoxalase in the heart could contribute to its cardioprotective effects. PMID- 29137476 TI - Acute glycemic changes in brain and subcutaneous tissue measured by continuous glucose monitoring system in hereditary hypertriglyceridemic rat. AB - Parallel glucose measurements in blood and other different tissues give us knowledge about dynamics of glycemia changes, which depend on vascularization, distribution space and local utilization by tissues. Such information is important for the understanding of glucose homeostasis and regulation. The aim of our study was to determine the time-lag between blood, brain, and adipose tissue during rapid glucose changes in a male hHTG rat (n=15). The CGMS sensor Guardian RT (Minimed/Medtronic, USA) was inserted into the brain and into the abdominal subcutaneous tissue. Fixed insulin and variable rate of glucose infusion was used to maintain euglycemia during sensor calibration period. At 0 min, 0.5 g/kg of bolus of glucose was administered, and at 50 min, 5 IU/kg of bolus of insulin was administered. Further glucose and insulin infusion was stopped at this time. The experiment was finished at 130 min and animals were euthanized. The time-shift between glycemia changes in blood, brain, and subcutaneous tissue was calculated by identification of the ideal correlation function. Moreover, the time to achieve 90 % of the maximum glucose excursion after intervention (T90) was measured to compare our data with the literature. The time-lag blood vs. brain and blood vs. subcutaneous tissue was 10 (10; 15) min and 15 (15; 25) min, respectively. The difference was statistically significant (P=0.01). T90 after glucose bolus in brain and subcutaneous tissue was 10 min (8.75; 15) and 15 min (13.75; 21.25), respectively. T90 after insulin bolus in brain and subcutaneous tissue was 10 min (10; 15) and 20 min (20; 27.5), respectively. To the contrary, with literature, our results showed earlier glucose level changes in brain in comparison with subcutaneous tissue after glucose and insulin boluses. Our results suggest that glucose dynamics is different within monitored tissues under rapid changing glucose level and we can expect similar behavior in humans. Improved knowledge about glucose distribution and dynamics is important for avoiding hypoglycemia. PMID- 29137477 TI - Circulating lipopolysaccharide-binding protein and carotid intima-media thickness in obstructive sleep apnea. AB - Circulating lipopolysaccharide-binding protein (LBP), a metabolic endotoxemia marker, was identified as an independent predictor of atherosclerosis. Although increases in carotid intima-media thickness (CIMT) were repeatedly reported in obstructive sleep apnea (OSA), neither the role of OSA in metabolic endotoxemia nor of LBP in early atherosclerosis were explored in patients with OSA. At a tertiary university hospital we investigated the relationships between OSA, LBP and CIMT in 117 men who underwent full polysomnography and CIMT assessment by B mode ultrasound. Circulating LBP concentrations and average CIMT increased from patients without OSA to those with mild-moderate and severe OSA (from 32.1+/-10.3 to 32.3+/-10.9 to 38.1+/-10.3 microg.ml(-1), p=0.015; from 0.52+/-0.09 to 0.58+/ 0.06 to 0.62+/-0.10 mm, p=0.004, respectively). Oxygen desaturation index (ODI) was a predictor of serum LBP levels independent of age, waist-to-hip ratio (WHR), smoking, hypertension, HDL cholesterol, triglycerides and fasting glucose [p (ANOVA)=0.002, r(2)=0.154], with no independent effect of the ODI*WHR interaction term on LBP. Furthermore, serum LBP predicted CIMT independently of known risk factors of atherosclerosis including obesity (p<0.001, r(2)=0.321). Our results suggest that OSA severity contributes to metabolic endotoxemia in patients with OSA independently of obesity, and that LBP might represent a contributing factor promoting early atherosclerosis in such patients. PMID- 29137478 TI - Effects of increased myocardial tissue concentration of myristic, palmitic and palmitoleic acids on the course of cardiac atrophy of the failing heart unloaded by heterotopic transplantation. AB - The present experiments were performed to evaluate if increased heart tissue concentration of fatty acids, specifically myristic, palmitic and palmitoleic acids that are believed to promote physiological heart growth, can attenuate the progression of unloading-induced cardiac atrophy in rats with healthy and failing hearts. Heterotopic abdominal heart transplantation (HT(x)) was used as a model for heart unloading. Cardiac atrophy was assessed from the ratio of the native- to-transplanted heart weight (HW). The degree of cardiac atrophy after HT(x) was determined on days 7, 14, 21 and 28 after HT(x) in recipients of either healthy or failing hearts. HT(x) of healthy hearts resulted in 23+/-3, 46+/-3, 48+/-4 and 46+/-4 % HW loss at the four time-points. HT(x) of the failing heart resulted in even greater HW losses, of 46+/-4, 58+/-3, 66+/-2 and 68+/-4 %, respectively (P<0.05). Activation of "fetal gene cardiac program" (e.g. beta myosin heavy chain gene expression) and "genes reflecting cardiac remodeling" (e.g. atrial natriuretic peptide gene expression) after HT(x) was greater in failing than in healthy hearts (P<0.05 each time). Exposure to isocaloric high sugar diet caused significant increases in fatty acid concentrations in healthy and in failing hearts. However, these increases were not associated with any change in the course of cardiac atrophy, similarly in healthy and post-HT(x) failing hearts. We conclude that increasing heart tissue concentrations of the fatty acids allegedly involved in heart growth does not attenuate the unloading-induced cardiac atrophy. PMID- 29137479 TI - The role of the carbohydrates in plasmatic membrane. AB - In the following paper, authors describe glycans present on cell membranes as they affect the folding, the spatial arrangement, the behavior and the interaction with the substrate of some membrane proteins. Authors describe the synthesis and assembly of a glycan on a protein, the formation of N-glycans, the maturation of an N-glycan in different cellular compartments, the structure of the glycocalyx and how it interacts with any pathogens. The study of the E cadherin and the potassium channel to demonstrate how glycans affect the spatial arrangement, the stability and activity of the glycoproteins on the membranes. Subsequently, authors analyze the correlation between disorder glycosylation and human health. Authors define glycosylation disorders as a genetic defect that alter the structure or biosynthesis of glycans (sugar chains) in one or more biosynthetic pathways. Human glycosylation disorders reflect the disruption of early steps in the pathways of glycan biosynthesis. More in details, authors analyze the role of glycoprotein in tumor cell adhesion, in particular, in cells MCF-7 and MDA-MB-231 on zeolite scaffold. In the same time, the role of metalloproteinase is described in the mobilization of cancer cells and in metastasis. PMID- 29137480 TI - Akt substrate of 160 kDa dephosphorylation rate is reduced in insulin-stimulated rat skeletal muscle after acute exercise. AB - Because greater Akt substrate of 160 kDa (AS160) phosphorylation has been reported in insulin-stimulated skeletal muscles without improved Akt activation several hours post-exercise, we hypothesized that prior exercise would result in attenuated AS160 dephosphorylation in insulin-stimulated rat skeletal muscle. Epitrochlearis muscles were isolated from rats that were sedentary (SED) or exercised 3 h earlier (3 h post-exercise; 3hPEX). Paired muscles were incubated with [(3)H]-2-deoxyglucose (2-DG) without insulin or with insulin. Lysates from other insulin-stimulated muscles from SED or 3hPEX rats were evaluated using AS160(Thr642) and AS160(Ser588) dephosphorylation assays. Prior exercise led to greater 2-DG uptake concomitant with greater AS160(Thr642) phosphorylation and a non-significant trend (P=0.087) for greater AS160(Ser588). Prior exercise also reduced AS160(Thr642) and AS160(Ser588) dephosphorylation rates. These results support the idea that attenuated AS160 dephosphorylation may favor greater AS160 phosphorylation post-exercise. PMID- 29137481 TI - Effects of pioglitazone on ventricular myocyte shortening and Ca(2+) transport in the Goto-Kakizaki type 2 diabetic rat. AB - Pioglitazone (PIO) is a thiazolidindione antidiabetic agent which improves insulin sensitivity and reduces blood glucose in experimental animals and treated patients. At the cellular level the actions of PIO in diabetic heart are poorly understood. A previous study has demonstrated shortened action potential duration and inhibition of a variety of transmembrane currents including L-type Ca(2+) current in normal canine ventricular myocytes. The effects of PIO on shortening and calcium transport in ventricular myocytes from the Goto-Kakizaki (GK) type 2 diabetic rat have been investigated. 10 min exposure to PIO (0.1-10 microM) reduced the amplitude of shortening to similar extents in ventricular myocytes from GK and control rats. 1 microM PIO reduced the amplitude of the Ca(2+) transients to similar extents in ventricular myocytes from GK and control rats. Caffeine-induced Ca(2+) release from the sarcoplasmic reticulum and recovery of Ca(2+) transients following application of caffeine and myofilament sensitivity to Ca(2+) were not significantly altered in ventricular myocytes from GK and control rats. Amplitude of L-type Ca(2+) current was not significantly decreased in myocytes from GK compared to control rats and by PIO treatment. The negative inotropic effects of PIO may be attributed to a reduction in the amplitude of the Ca(2+) transient however, the mechanisms remain to be resolved. PMID- 29137482 TI - Uphill running excessive training increases gastrocnemius glycogen content in C57BL/6 mice. AB - The main aim of the present investigation was to verify the effects of three overtraining (OT) protocols performed in downhill (OTR/down), uphill (OTR/up) and without inclination (OTR) on the protein levels of Akt (Ser473), AMPKalpha (Thr172), PGC-1alpha, plasma membrane GLUT-1 and GLUT-4 as well as on the glycogen contents in mice gastrocnemius. A trained (TR) protocol was used as positive control. Rodents were divided into naive (N, sedentary mice), control (CT, sedentary mice submitted to the performance evaluations), TR, OTR/down, OTR/up and OTR groups. At the end of the experimental protocols, gastrocnemius samples were removed and used for immunoblotting analysis as well as for glycogen measurements. There was no significant difference between the experimental groups for the protein levels of pAkt (Ser473), pAMPKalpha (Thr172), PGC-1alpha, plasma membrane GLUT-1 and GLUT-4. However, the OTR/up protocol exhibited higher contents of glycogen compared to the CT and TR groups. In summary, the OTR/up group increased the gastrocnemius glycogen content without significant changes of pAkt (Ser473), pAMPKalpha (Thr172), PGC-1alpha, plasma membrane GLUT-1 and GLUT 4. PMID- 29137483 TI - Molecular profiling in IgA nephropathy and focal and segmental glomerulosclerosis. AB - The aim of the study was to characterize by molecular profiling two glomerular diseases: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) and to identify potential molecular markers of IgAN and FSGS progression. The expressions of 90 immune-related genes were compared in biopsies of patients with IgAN (n=33), FSGS (n=17) and in controls (n=11) using RT-qPCR. To identify markers of disease progression, gene expression was compared between progressors and non-progressors in 1 year follow-up. The results were verified on validation cohort of patients with IgAN (n=8) and in controls (n=6) using laser-capture microdissection, that enables to analyze gene expression separately for glomeruli and interstitium. In comparison to controls, patients with both IgAN and FSGS, had lower expression of BAX (apoptotic molecule BCL2-associated protein) and HMOX 1 (heme oxygenase 1) and higher expression of SELP (selectin P). Furthermore, in IgAN higher expression of PTPRC (protein-tyrosine phosphatase, receptor-type C) and in FSGS higher expression of BCL2L1 (regulator of apoptosis BCL2-like 1) and IL18 compared to control was observed. Validation of differentially expressed genes between IgAN and controls on another cohort using laser-capture microdissection confirmed higher expression of PTPRC in glomeruli of patients with IgAN. The risk of progression in IgAN was associated with higher expression EDN1 (endothelin 1) (AUC=0.77) and FASLG (Fas ligand) (AUC=0.82) and lower expression of VEGF (vascular endothelial growth factor) (AUC=0.8) and in FSGS with lower expression of CCL19 (chemokine (C-C motif) ligand 19) (AUC=0.86). Higher expression of EDN1 and FASLG along with lower expression of VEGF in IgAN and lower expression of CCL19 in FSGS at the time of biopsy can help to identify patients at risk of future disease progression. PMID- 29137484 TI - The role of endogenous reactive oxygen species in cardiac myocyte autophagy. AB - Autophagy is implicated in the maintenance of cardiac homeostasis. Autophagy is activated in heart failure, in which reactive oxygen species (ROS) are increased. Exogenous ROS have been shown to induce cardiomyocyte autophagy alterations. However, little is known about the influences of physiological levels of endogenous ROS on cardiomyocyte autophagy. In the present study, we tested the hypothesis that endogenous ROS in cardiomyocytes play an important role in inducing autophagy. Cultured H9C2 cardiomyocytes or Sprague-Dawley rats were treated with the antioxidant N-acetyl-cysteine (NAC) or the superoxide dismutase mimic tempol under the basal or nutrient deprivation conditions. The autophagic flux was assessed by the lysosomal inhibitor chloroquine. In H9C2 cardiomyocytes, under a basal condition, NAC or tempol increased the ratio of LC3 II/I proteins and reduced LC3 II autophagic flux. Under nutrient deprivation, NAC increased the LC3 II/I ratio and reduced LC3 II autophagic flux. In vivo studies in rats, NAC treatment increased the LC3 II/I ratio and p-Akt protein expression in myocardium. We concluded that the antioxidants reduced autophagic flux in cardiomyocytes under the basal or nutrient deprivation conditions, suggesting that endogenous ROS promote autophagy flux under physiological conditions, and this effect is mediated, at least in part, through Akt inhibition. PMID- 29137485 TI - Heat stress prevents the decrease in succinate dehydrogenase activity in the extensor digitorum longus of streptozotocin-induced diabetic rats. AB - This study aimed to investigate whether heat stress (HS) prevents a decrease in succinate dehydrogenase (SDH) activity and heat shock protein 60 (HSP60) and superoxide dismutase 2 (SOD2) contents in the extensor digitorum longus of streptozotocin (STZ)-induced diabetic rats. Twelve-week-old male Wistar rats were assigned to one of the four groups (n=6/group): control (Con), HS, diabetes mellitus (DM), and diabetes mellitus and heat stress (DM+HS). Diabetes was induced by the administration of STZ (50 mg/kg). HS was initiated 7 days after STZ treatment and performed at 42 degrees C for 30 min 5 times a week for 3 weeks. SDH activity was decreased in the DM and DM+HS groups. However, SDH activity was greater in the DM+HS group than in the DM group. Although HSP60 content was lower in the DM group than in the Con group, it was maintained in the DM+HS groups and was higher than that in the DM group. SOD2 content was decreased only in the DM group. These findings suggest that HS prevents the decrease in SDH activity in the skeletal muscle induced by DM. According to this mechanism, the maintenance of SOD2 and HSP60 by HS may suppress the increase in oxidative stress. PMID- 29137486 TI - The arteriolar glycocalyx plays a role in the regulation of blood flow in the iliac of the anaesthetised pig. AB - The role of the glycocalyx of arterial resistance vessels in regulating blood flow in vivo is not fully understood. Therefore, the effect of glycocalyx damage using two separate compounds, hyaluronidase and N-Formylmethionyl-leucyl phenylalanine (fMLP), was evaluated in the iliac artery vascular bed of the anaesthetised pig. Blood flow and pressure were measured in the iliac, an adjustable snare was applied to the iliac above the pressure and flow measurement site to induce step decreases (3 occlusions at 3-4 min intervals were performed for each infusion) in blood flow, and hence iliac pressure, and vascular conductance (flow/pressure) was calculated. Saline, hyaluronidase (14 and 28 microg/ml/min), and fMLP (1 microM/min) were infused separately, downstream of the adjustable snare and their effect on arterial conductance assessed. Hyaluronidase at the higher infusion rate and fMLP both caused a reduction in arterial conductance, and hence an increase in blood flow resistance. In conclusion, the results show that glycocalyx damage causes an increase in resistance to blood flow in the iliac artery vascular bed. PMID- 29137487 TI - Emergence of fosfomycin resistance among isolates of Escherichia coli harboring extended-spectrum and AmpC beta-lactamases. AB - Urinary tract infection (UTI) is a common type of infectious disease globally. The aim of this study was to detect the frequency of fosA3 and fosC2 genes in extended-spectrum beta-lactamases (ESBL) and blaDHA, blaCMY-2, and blaCMY-42 genes in AmpC beta-lactamases-producing isolates of Escherichia coli. In total, 120 isolates of E. coli were collected from three teaching hospitals between March 2014 and February 2015. Antibiotic susceptibility tests were carried out by disk diffusion method. The presence of blaCMY-2, blaCMY-42, blaDHA, fosA3, and fosC2 genes was detected by polymerase chain reaction (PCR) and sequencing. Of the 120 strains, 92 (76.6%) were identified as ESBL producers, 30 (25%) were determined as AmpC beta-lactamase producers, and 24 (20%) had both ESBL and AmpC beta-lactamase enzymes. Imipenem, fosfomycin, and nitrofurantoin had the best effect against isolates of E. coli. PCR assay demonstrated that the frequency of blaCMY-2, blaCMY-42, and blaDHA genes among AmpC beta-lactamases-producing strains were 39%, 1%, and 17.5%, respectively. This study reports the first detection of fosfomycin resistance in Iran. This study indicated the increasing prevalence of UTI isolates of E. coli-harboring ESBL and AmpC beta-lactamases genes in Iran. Therefore, due to the high rate of blaDHA and blaCMY genes and emergence of fosfomycin-resistant E. coli isolates, we recommend continuous monitoring of antibiotic resistance as well as attention to guidelines of infection controls. PMID- 29137488 TI - Things fall apart with hepatocellular carcinoma and direct-acting antivirals. PMID- 29137489 TI - Androgen deprivation therapy for the treatment of prostate cancer: a focus on pharmacokinetics. AB - INTRODUCTION: Medical therapy has undergone many changes as our understanding of prostate cancer cell biology has improved. Androgen deprivation therapy (ADT) remains the mainstay of therapy for metastatic disease. Metastatic castrate resistant prostate cancer (CRPC) is an important concern since we are unable to stop progression with currently available agents. Areas covered: Pharmacologic ADT is the most commonly used treatment for metastatic prostate cancer. Multiple agents are available for both first-line and second-line use: antiandrogens, estrogens, luteinizing hormone-releasing hormone agonists/antagonists, and CYP17 inhibitors. With adoption of these drugs, it is important to consider their pharmacokinetic and pharmacodynamic properties. Many undergo metabolism through cytochrome P450. Levels may be altered with co-administration of drugs acting as enzyme inhibitors or inducers. Understanding mechanism of action, metabolism, and excretion of these drugs allows clinicians to provide the best therapeutic care while minimizing adverse events. Expert opinion: Many men with metastatic prostate cancer will progress to castration resistance. An understanding of resistance mechanisms at the cellular level has revealed new drug targets with hopes of halting or reversing progression of metastatic disease. Second-line agents, traditionally reserved for CRPC, are being studied in metastatic castrate sensitive prostate cancer, and may offer practice-changing evidence supporting their use. PMID- 29137490 TI - Recent developments concerning the application of the Mannich reaction for drug design. AB - INTRODUCTION: The versatile multicomponent Mannich reaction occupies a salient position in organic chemistry and drug design. Sound knowledge of its scope and variations and of the biological activities of Mannich bases is crucial for the development and improvement of drugs for various diseases. Areas covered: The following article provides an overview of the latest developments in the field of drugs based on the Mannich reaction. Web-based literature searching tools such as PubMed and SciFinder were applied to obtain useful articles. In addition, pertinent literature that was recently published by the authors is discussed in this manuscript. The chemical structures of bioactive Mannich bases are also given. Expert opinion: The Mannich reaction represents a feasible and cost effective procedure with great potential for drug development. Several newly discovered Mannich bases exhibit sound activities against various human diseases as well as favorable pharmacokinetics. Thus, scientific research about Mannich bases is prospering and appears very attractive both for chemists and for clinicians. PMID- 29137491 TI - Characterization of biochemical traits of dog rose (Rosa canina L.) ecotypes in the central part of Iran. AB - Dog rose (Rosa canina L.) is a wild native species in Iran, with a significant genetic diversity. This plant serves as a rich source of vitamin C, anthocyanins, phenolic contents and carotenoids. Rose hips have been used in several food products, as well as perfumery and cosmetics industries. In this research, we investigate biochemical characteristics of five dog rose ecotypes (Kopehjamshid, Zarneh, Miyankish, Aghcheh and Sadeghiyeh), that were collected from the central part of Iran (Isfahan province). Amounts of vitamin C, total carotenoids, total phenolic contents, total anthocyanins, macro and micro minerals were measured. Seed oil are extracted by soxhlet method and analysed by gas chromatography. The macro and micro minerals levels in the fruit vary significantly among these regions. The results of this study demonstrate that dog rose have great diversity and can be used in breeding programmes in order to increase nutrient values as a food resource additive. PMID- 29137492 TI - A Guide to Topical Vehicle Formulations. AB - Adherence to topical treatment for a variety of chronic skin conditions, such as psoriasis, acne, and atopic dermatitis, is known to be very poor. A number of factors contribute to this phenomenon, including lack of treatment efficacy and patient concerns regarding side effects, among others. At the forefront of barriers facing optimal patient adherence to topical treatment is choosing the ideal topical vehicle formulation. Medical professionals have demonstrated a lack of understanding with respect to the composition and nomenclature of the various topical formulations. In this review, we clarify the properties and definitions of the following topical formulations: ointments, creams, lotions, topical solutions, topical suspensions, gels, foams, and sprays. We also provide suggested areas of application for the aforementioned formulations and a succinct, patient-geared summary of their advantages and disadvantages. This review hopes to deliver a clear and concise practical summary of the most commonly encountered topical formulations for the treatment of cutaneous disease for medical professionals. This will allow clinicians to provide their patients with accurate information to facilitate informed choice of topical formulation, which may serve to improve treatment adherence. PMID- 29137493 TI - Tolerance in Internet gaming disorder: A need for increasing gaming time or something else? AB - Background and aims The criterion of tolerance in DSM-5 Internet gaming disorder (IGD) refers to a need for increasing time spent gaming. However, this focus on "need for gaming time" may overlook some of the broader motivations, outcomes, or effects of gaming that underlie excessive play. This study aimed to explore regular and problematic gamers' experiences and perceptions of tolerance in IGD. Methods An online survey of 630 adult gamers yielded 1,417 text responses to open ended questions. A thematic analysis of 23,373 words was conducted to extract dominant themes. Results Participants reported that they increasingly desired game items, status, or story progress as they became more involved or invested in games. As players develop higher standards of play in games, an increasing number of potential reward outcomes may have diminishing mood-modifying effects. None of the participants, including those with self-reported IGD, explicitly referred to a need for increasing time spent gaming. Discussion and conclusions These results suggest that players may be motivated by preferences for specific goals or reinforcers in games rather than wanting an amount of time spent gaming. Thus, problematic gaming may involve a need for completion of increasingly intricate, time-consuming, or difficult goals to achieve satisfaction and/or reduce fears of missing out. Further research is needed to determine whether these cognitive and motivational factors related to gaming stimuli should extend or replace the concept of tolerance in IGD or be considered as separate but related processes in disordered gaming. PMID- 29137494 TI - TRH receptor mobility in the plasma membrane is strongly affected by agonist binding and by interaction with some cognate signaling proteins. AB - OBJECTIVES: Extensive research has been dedicated to elucidating the mechanisms of signal transduction through different G protein-coupled receptors (GPCRs). However, relatively little is known about the regulation of receptor movement within the cell membrane upon ligand binding. In this study we focused our attention on the thyrotropin-releasing hormone (TRH) receptor that typically couples to Gq/11 proteins. METHODS: We monitored receptor diffusion in the plasma membrane of HEK293 cells stably expressing yellow fluorescent protein (YFP) tagged TRH receptor (TRHR-YFP) by fluorescence recovery after photobleaching (FRAP). RESULTS: FRAP analysis indicated that the lateral movement of the TRH receptor was markedly reduced upon TRH binding as the value of its diffusion coefficient fell down by 55%. This effect was prevented by the addition of the TRH receptor antagonist midazolam. We also found that siRNA-mediated knockdown of Gq/11alpha, Gbeta, beta-arrestin2 and phospholipase Cbeta1, but not of Gialpha1, beta-arrestin1 or G protein-coupled receptor kinase 2, resulted in a significant decrease in the rate of TRHR-YFP diffusion, indicating the involvement of the former proteins in the regulation of TRH receptor behavior. The observed partial reduction of the TRHR-YFP mobile fraction caused by down-regulation of Gialpha1 and beta-arrestin1 suggests that these proteins may also play distinct roles in THR receptor-mediated signaling. CONCLUSION: These results demonstrate for the first time that not only agonist binding but also abundance of some signaling proteins may strongly affect TRH receptor dynamics in the plasma membrane. PMID- 29137495 TI - Development of chondrocyte-seeded electrosprayed nanoparticles for repair of articular cartilage defects in rabbits. AB - Due to limited self-healing capacity in cartilages, there is a rising demand for an innovative therapy that promotes chondrocyte proliferation while maintaining its biofunctionality for transplantation. Chondrocyte transplantation has received notable attention; however, the tendencies of cell de-differentiation and de-activation of biofunctionality have been major hurdles in its development, delaying this therapy from reaching the clinic. We believe it is due to the non stimulative environment in the injured cartilage, which is unable to provide sustainable physical and biological supports to the newly grafted chondrocytes. Therefore, we evaluated whether providing an appropriate matrix to the transplanted chondrocytes could manipulate cell fate and recovery outcomes. Here, we proposed the development of electrosprayed nanoparticles composed of cartilage specific proteins, namely collagen type II and hyaluronic acid, for implantation with pre-seeded chondrocytes into articular cartilage defects. The fabricated nanoparticles were pre-cultured with chondrocytes before implantation into injured articular cartilage. The study revealed a significant potential for nanoparticles to support pre-seeded chondrocytes in cartilage repair, serving as a protein delivery system while improving the survival and biofunctionality of transplanted chondrocytes for prolonged period of time. PMID- 29137496 TI - Preoperative quantitative dynamic contrast-enhanced MRI and diffusion-weighted imaging predict aggressive disease in endometrial cancer. AB - Background Quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) and diffusion-weighted imaging (DWI) may yield preoperative tumor biomarkers relevant for prognosis and therapy in cancer. Purpose To explore the value of preoperative DCE-MRI and DWI for the prediction of aggressive disease in endometrial cancer patients. Material and Methods Preoperative MRI (1.5-T) from 177 patients were analyzed and imaging parameters reflecting tumor microvasculature (from DCE-MRI) and tumor microstructure (from DWI) were estimated. The derived imaging parameters were explored in relation to clinico pathological stage, histological subtype and grade, molecular markers, and patient outcome. Results Low tumor blood flow (Fb) and low rate constant for contrast agent intravasation (kep) were associated with high-risk histological subtype ( P <= 0.04 for both) and tended to be associated with poor prognosis ( P <= 0.09). Low tumor apparent diffusion coefficient (ADC) value and large tumor volume were both significantly associated with deep myometrial invasion ( P < 0.001 for both) and were also unfavorable prognostic factors ( P = 0.05 and P < 0.001, respectively). Conclusion DCE-MRI and DWI represent valuable supplements to conventional MRI by providing preoperative imaging biomarkers that predict aggressive disease in endometrial cancer patients. PMID- 29137497 TI - Optimization of T2-weighted imaging for shoulder magnetic resonance arthrography by synthetic magnetic resonance imaging. AB - Background Synthetic magnetic resonance imaging (MRI) allows reformatting of various synthetic images by adjustment of scanning parameters such as repetition time (TR) and echo time (TE). Optimized MR images can be reformatted from T1, T2, and proton density (PD) values to achieve maximum tissue contrast between joint fluid and adjacent soft tissue. Purpose To demonstrate the method for optimization of TR and TE by synthetic MRI and to validate the optimized images by comparison with conventional shoulder MR arthrography (MRA) images. Material and Methods Thirty-seven shoulder MRA images acquired by synthetic MRI were retrospectively evaluated for PD, T1, and T2 values at the joint fluid and glenoid labrum. Differences in signal intensity between the fluid and labrum were observed between TR of 500-6000 ms and TE of 80-300 ms in T2-weighted (T2W) images. Conventional T2W and synthetic images were analyzed for diagnostic agreement of supraspinatus tendon abnormalities (kappa statistics) and image quality scores (one-way analysis of variance with post-hoc analysis). Results Optimized mean values of TR and TE were 2724.7 +/- 1634.7 and 80.1 +/- 0.4, respectively. Diagnostic agreement for supraspinatus tendon abnormalities between conventional and synthetic MR images was excellent (kappa = 0.882). The mean image quality score of the joint space in optimized synthetic images was significantly higher compared with those in conventional and synthetic images (2.861 +/- 0.351 vs. 2.556 +/- 0.607 vs. 2.750 +/- 0.439; P < 0.05). Conclusion Synthetic MRI with optimized TR and TE for shoulder MRA enables optimization of soft-tissue contrast. PMID- 29137498 TI - Core needle biopsy of thyroid nodules: outcomes and safety from a large single center single-operator study. AB - Background There currently remains a debate over the use of core needle biopsy (CNB) or fine needle aspiration (FNA) for diagnosis of thyroid nodules. The major drawbacks of previous CNB studies include heterogeneity of the study population, variable techniques, devices, and operator experience affecting the outcome of the procedure. Purpose To assess the diagnostic performance and safety of CNB of thyroid nodules performed by a single experienced operator in consecutive patients. Material and Methods From January 2012 to December 2012, 538 thyroid nodules that underwent CNB were retrospectively evaluated. All CNB procedures were performed by a single operator with 18 years of experience. The histopathology of the surgical specimens was considered as the standard reference for malignancy. A final diagnosis of benignity was made by surgery, one benign lesion on FNA and/or CNB with no change on follow-up examinations (>1 year) or benign lesion on >=2 FNA and/or CNB. The diagnostic performance, incidence of technical failure, unnecessary surgery, and complication were evaluated. Results The diagnostic accuracy, sensitivity, and specificity of CNB for malignancy were 92.0%, 85.3%, and 100%, respectively. The non-diagnostic result rate of CNB was 4.8% (26/538) and the inconclusive result rate was 24.3% (131/538). The incidence of technical failure was 0.6% (3/541) and unnecessary surgery was 0.6%. The complication rate was 0.2%, without life-threatening complications. The sensitivity, specificity, and accuracy were 85.3% (156/183), 100.0% (154/154), and 92.0% (310/337), respectively. Conclusion CNB shows a high diagnostic performance for detection of thyroid malignancy and follicular neoplasm, with low rates of technical failure and complications. PMID- 29137499 TI - Improving Care And Lowering Costs: Evidence And Lessons From A Global Analysis Of Accountable Care Reforms. AB - Policy makers and providers are under increasing pressure to find innovative approaches to achieving better health outcomes as efficiently as possible. Accountable care, which holds providers accountable for results rather than specific services, is emerging in many countries to support such care innovations. However, these reforms are challenging and complex to implement, requiring significant policy and delivery changes. Despite global interest, the evidence on how to implement accountable care successfully remains limited. To improve the evidence base and increase the likelihood of success, we applied a comprehensive framework for assessing accountable care implementation to three promising reforms outside the United States. The framework relates accountable care policy reforms to the competencies of health care organizations and their health policy environments to facilitate qualitative comparisons of innovations and factors that influence success. We present emerging lessons to guide future implementation and evaluation of accountable care reforms to improve access to and the quality and affordability of care. PMID- 29137500 TI - Mentor Mothers Program Improved Child Health Outcomes At A Relatively Low Cost In South Africa. AB - In light of South Africa's high prenatal HIV prevalence and infant mortality rate, a cluster randomized controlled trial was conducted to evaluate an intervention called Philani+, which used community health workers (known as Mentor Mothers) to deliver pre- and postnatal home visits in Cape Town, South Africa, to improve maternal and child health. We assessed the costs and benefits of this intervention and made comparisons with other scenarios that depicted increased capacity and provision of nurse-delivered care. The recurrent cost of the twenty-four-month intervention was US$80,001. The major health outcomes analyzed were differences in the proportion of infants who were low birthweight, stunted, and suboptimally breastfed between intervention and control groups. Each case of low birthweight averted cost US$2,397; of stunted growth, US$2,454; and of suboptimal breastfeeding, US$1,618. Employment of community health workers was cost saving compared to that of nurses. Philani+ improved child health at a relatively low cost, considering the health system costs associated with low birthweight and undernutrition. The model could be suitable for replication in low-resource settings to improve child health in other countries. PMID- 29137501 TI - ParkinsonNet: A Low-Cost Health Care Innovation With A Systems Approach From The Netherlands. AB - ParkinsonNet, a low-cost innovation to optimize care for patients with Parkinson disease, was developed in 2004 as a network of physical therapists in several regions in the Netherlands. Since that time, the network has achieved full national reach, with 70 regional networks and around 3,000 specifically trained professionals from 12 disciplines. Key elements include the empowerment of professionals who are highly trained and specialized in Parkinson disease, the empowerment of patients by education and consultation, and the empowerment of integrated multidisciplinary teams to better address and manage the disease. Studies have found that the ParkinsonNet approach leads to outcomes that are at least as good as, if not better than, outcomes from usual care. One study found a 50 percent reduction in hip fractures and fewer inpatient admissions. Other studies suggest that ParkinsonNet leads to modest but important cost savings (at least US$439 per patient annually). These cost savings outweigh the costs of building and maintaining the network. Because of ParkinsonNet's success, the program has now spread to several other countries and serves as a model of a successful and scalable frugal innovation. PMID- 29137502 TI - Innovative Product Development Partnership Reduced Neonatal Mortality In Nepal Through Improved Umbilical Cord Care. AB - Approximately 40 percent of all newborn deaths in Nepal are attributable to neonatal infections. A randomized controlled trial conducted in Nepal in the period 2002-05 on the application of a solution of the disinfectant chlorhexidine to umbilical cord stumps of newborns showed a reduced risk of infections and death. In response to these results, the Government of Nepal and various partners mobilized to deliver this simple, low-cost intervention on a national scale. We describe the design, development, and maturation of a partnership among the government, technical assistance agencies, and a local pharmaceutical company to create a suitable, commercially available gel product to reduce newborn infections. Essential contributors to the partnership's effectiveness included having a for-profit pharmaceutical company as a fully engaged partner; having responsive, flexible relationships among the partners that evolved over time; and paying attention to competition within the private sector. A less formalized arrangement among partners allowed them to build trust in each other over time. Government stewardship of the program throughout the scale-up process ensured that policy and systems integration were aligned as the program matured. PMID- 29137503 TI - Global Lessons In Frugal Innovation To Improve Health Care Delivery In The United States. AB - In a 2015 global study of low-cost or frugal innovations, we identified five leading innovations that scaled successfully in their original contexts and that may provide insights for scaling such innovations in the United States. We describe common themes among these diverse innovations, critical factors for their translation to the United States to improve the efficiency and quality of health care, and lessons for the implementation and scaling of other innovations. We highlight promising trends in the United States that support adapting these innovations, including growing interest in moving care out of health care facilities and into community and home settings; the growth of alternative payment models and incentives to experiment with new approaches to population health and care delivery; and the increasing use of diverse health professionals, such as community health workers and advanced practice providers. Our findings should inspire policy makers and health care professionals and inform them about the potential for globally sourced frugal innovations to benefit US health care. PMID- 29137504 TI - Avoidable Hospital Admissions From Diabetes Complications In Japan, Singapore, Hong Kong, And Communities Outside Beijing. AB - Improving the quality of primary care may reduce avoidable hospital admissions. Avoidable admissions for conditions such as diabetes are used as a quality metric in the Health Care Quality Indicators of the Organization for Economic Cooperation and Development (OECD). Using the OECD indicators, we compared avoidable admission rates and spending for diabetes-related complications in Japan, Singapore, Hong Kong, and rural and peri-urban Beijing, China, in the period 2008-14. We found that spending on diabetes-related avoidable hospital admissions was substantial and increased from 2006 to 2014. Annual medical expenditures for people with an avoidable admission were six to twenty times those for people without an avoidable admission. In all of our study sites, when we controlled for severity, we found that people with more outpatient visits in a given year were less likely to experience an avoidable admission in the following year, which implies that primary care management of diabetes has the potential to improve quality and achieve cost savings. Effective policies to reduce avoidable admissions merit investigation. PMID- 29137505 TI - Choosing Wisely: How To Fulfill The Promise In The Next 5 Years. AB - Low-value care-the use of unnecessary and potentially harmful health care services-accounted for roughly $200 billion in wasteful spending in the United States in 2011. In 2012 the ABIM Foundation and Consumer Reports launched the Choosing Wisely(r) campaign, inspired by the idea that professional societies and health care providers should take the lead in defining and motivating efforts to reduce the use of low-value care. But decreases in that use have been slow in coming. We discuss the campaign's significant accomplishments in the past five years and summarize the work that is needed to fulfill the promise of Choosing Wisely. We focus on innovations in three main areas: identifying high-priority clinical targets, developing theory-based interventions, and evaluating interventions in ways that are clinically meaningful. PMID- 29137506 TI - Measuring The Impact Of Cash Transfers And Behavioral 'Nudges' On Maternity Care In Nairobi, Kenya. AB - Many patients in low-income countries express preferences for high-quality health care but often end up with low-quality providers. We conducted a randomized controlled trial with pregnant women in Nairobi, Kenya, to analyze whether cash transfers, enhanced with behavioral "nudges," can help women deliver in facilities that are consistent with their preferences and are of higher quality. We tested two interventions. The first was a labeled cash transfer (LCT), which explained that the cash was to help women deliver where they wanted. The second was a cash transfer that combined labeling and a commitment by the recipient to deliver in a prespecified desired facility as a condition of receiving the final payment (L-CCT). The L-CCT improved patient-perceived quality of interpersonal care but not perceived technical quality of care. It also increased women's likelihood of delivering in facilities that met standards for routine and emergency newborn care but not the likelihood of delivering in facilities that met standards for obstetric care. The LCT had fewer measured benefits. Women preferred facilities with high technical and interpersonal care quality, but these quality measures were often negatively correlated within facilities. Even with cash transfers, many women still used poor-quality facilities. A larger study is warranted to determine whether the L-CCT can improve maternal and newborn outcomes. PMID- 29137507 TI - Nationwide Mortality Studies To Quantify Causes Of Death: Relevant Lessons From India's Million Death Study. AB - Progress toward the United Nations 2030 Sustainable Development Goals requires improved information on mortality and causes of death. However, causes of many of the fifty million annual deaths in low- and middle-income countries remain unknown, as most of the deaths occur at home without medical attention. In 2001 India began the Million Death Study in 1.3 million nationally representative households. Nonmedical staff conduct verbal autopsies, which are structured interviews including a half-page narrative in local language of the family's story of the symptoms and events leading to death. Two physicians independently assess each death to arrive at an underlying cause of death. The study has thus far yielded information that substantially altered previous estimates of cause specific mortality and risk factors in India. Similar robust studies are feasible at low cost in other low- and middle-income countries, particularly if they adopt electronic data management and ensure high quality of fieldwork and physician coding. Nationwide mortality studies enable the quantification of avoidable premature mortality and key risk factors for disease, and provide a practicable method to monitor progress toward the Sustainable Development Goals. PMID- 29137508 TI - Health Professional Education And Universal Health Coverage: A Summary Of Challenges And Selected Case Studies. AB - Low- and middle-income countries are experiencing serious shortages in meeting health workforce requirements for universal health coverage. We examine how national-level policies can address these deficiencies and support the development of an appropriately skilled health workforce in line with population needs. We discuss three innovative, government-led solutions that are designed to align health workforce training with the demands of universal health coverage. Specifically, we discuss two initiatives to train and retain doctors in rural areas of Thailand, the large-scale training of community health workers within multidisciplinary primary health care teams in Brazil, and the introduction of a postgraduate diploma program in primary care for nurses in India. Several positive outcomes have been associated with these initiatives, including improvements in the rural retention of doctors in Thailand and reductions in infant and child mortality rates in Brazil. However, further research is needed to assess the impact of such initiatives on the long-term retention of workers particularly doctors-and the adequacy of the training offered to lower-skilled workers to effectively plug medical personnel gaps. Systematic monitoring of program affordability and cost-effectiveness over time must be prioritized, alongside efforts to disseminate lessons learned. PMID- 29137509 TI - Explicit Bias Toward High-Income-Country Research: A Randomized, Blinded, Crossover Experiment Of English Clinicians. AB - Unconscious bias may interfere with the interpretation of research from some settings, particularly from lower-income countries. Most studies of this phenomenon have relied on indirect outcomes such as article citation counts and publication rates; few have addressed or proven the effect of unconscious bias in evidence interpretation. In this randomized, blinded crossover experiment in a sample of 347 English clinicians, we demonstrate that changing the source of a research abstract from a low- to a high-income country significantly improves how it is viewed, all else being equal. Using fixed-effects models, we measured differences in ratings for strength of evidence, relevance, and likelihood of referral to a peer. Having a high-income-country source had a significant overall impact on respondents' ratings of relevance and recommendation to a peer. Unconscious bias can have far-reaching implications for the diffusion of knowledge and innovations from low-income countries. PMID- 29137510 TI - Accountable Care Reforms Improve Women's And Children's Health In Nepal. AB - Over the past decade the Ministry of Health of Nepal and the nonprofit Possible have partnered to deliver primary and secondary health care via a public-private partnership. We applied an accountable care framework that we previously developed to describe the delivery of their integrated reproductive, maternal, newborn, and child health services in the Achham district in rural Nepal. In a prospective pre-post study, examining pregnancies at baseline and 541 pregnancies in follow-up over the course of eighteen months, we found an improvement in population-level indicators linked to reducing maternal and infant mortality: receipt of four antenatal care visits (83 percent to 90 percent), institutional birth rate (81 percent to 93 percent), and the prevalence of postpartum contraception (19 percent to 47 percent). The intervention cost $3.40 per capita (at the population level) and $185 total per pregnant woman who received services. This study provides new analysis and evidence on the implementation of innovative care and financing models in resource-limited settings. PMID- 29137511 TI - In British Columbia, The Supply Of Primary Care Physicians Grew, But Their Rate Of Clinical Activity Declined. AB - Reports of a primary care shortage are ubiquitous in Canada and the United States. We used a population-based, retrospective cohort study to examine the extent to which the feminization and aging of the primary care physician workforce and secular trends may contribute to changes in the availability of primary care services. We used billing data for all primary care physicians in British Columbia for the period 2005-12. We used multivariate linear mixed effects models to study physician remuneration and activity levels. We found limited change in per physician remuneration over the study period. However, numbers of patient contacts and practice sizes (numbers of unique patients) declined by 14 percent and 10 percent, respectively. Although the feminization of the workforce-and, to a lesser extent, its aging-contributed to this decline, the primary driver appears to be a broad trend toward reduced clinical activity over time. To the extent that similar trends are occurring in the United States, the implications of our study for the availability of primary care services beyond Canada are potentially significant. PMID- 29137512 TI - Microfinance Institutions' Successful Delivery Of Micronutrient Powders: A Randomized Trial In Rural Haiti. AB - Globally, two-thirds of child deaths could be prevented by increased provision of health interventions such as vaccines, micronutrient supplements, and water purification tablets. We report the results from a randomized controlled trial in Haiti during 2012 that tested whether microfinance institutions-which reach 200 million households worldwide-can effectively deliver health products. These institutions provide loans to underserved entrepreneurs, primarily poor women in rural areas. In the intervention group, micronutrient powders to improve the nutrition of young children were distributed at regularly occurring microfinance meetings by a trained borrower. In both the control and the intervention groups, nurses led seminars on nutrition and extended breastfeeding during microfinance meetings. At three-month follow-up, the mean difference in hemoglobin concentration between children in the intervention group and those in the control group was 0.28 grams per deciliter (g/dL)-with a subsample of younger children (under two years of age) showing greater relative improvement (0.46 g/dL)-and the odds ratio for children in the intervention group meeting the diagnostic criteria for anemia was 0.64. The results are similar to those of previous studies that evaluated micronutrient powder distribution through dedicated health institutions. Our findings suggest that microfinance institutions are a promising platform for the large-scale delivery of health products in low-income countries. PMID- 29137513 TI - Trends In The Alignment And Harmonization Of Reproductive, Maternal, Newborn, And Child Health Funding, 2008-13. AB - Donor financing to low- and middle-income countries for reproductive, maternal, newborn, and child health increased substantially from 2008 to 2013. However, increased spending by donors might not improve outcomes, if funds are delivered in ways that undermine countries' public financial management systems and incur high transaction costs for project implementation. We combined quantitative and qualitative methods to examine the quality of funding for reproductive, maternal, newborn, and child health globally and in Tanzania, based on two principles of aid effectiveness: the alignment of donor financing with the recipient country's public health financial management systems, and donor harmonization for coordinated, transparent, and collectively effective actions. We found that alignment of donor financing deteriorated throughout the period, with the proportion of funds channeled through governments decreasing from 47 percent to 39 percent. Tanzania-based donors attributed the change to the pressure donors were under to achieve and show results. Donor harmonization was low overall and remained relatively constant, although it increased in sub-Saharan Africa and decreased in South Asia. Bilateral funding agencies were the most harmonized donors. We recommend that future assessments of Sustainable Development Goals financing include measures of harmonization and alignment of funding. PMID- 29137514 TI - Lower-Income Countries That Face The Most Rapid Shift In Noncommunicable Disease Burden Are Also The Least Prepared. AB - Demographic and epidemiological changes are shifting the disease burden from communicable to noncommunicable diseases in lower-income countries. Within a generation, the share of disease burden attributed to noncommunicable diseases in some poor countries will exceed 80 percent, rivaling that of rich countries, but this burden is likely to affect much younger people in poorer countries. The health systems of lower-income countries are unprepared for this change. We examined the shift to noncommunicable diseases and estimated preparedness for the shift by ranking 172 nations using a health system capacity index for noncommunicable disease. We project that the countries with the greatest increases in the share of disease burden attributable to noncommunicable disease over the next twenty-five years will also be the least prepared for the change, as they ranked low on our capacity index and are expected to have the smallest increases in national health spending. National governments and donors must invest more in preparing the health systems of lower-income countries for the dramatic shift to noncommunicable diseases and in reducing modifiable noncommunicable disease risks. PMID- 29137515 TI - Choosing Wisely Campaign: Valuable For Providers Who Knew About It, But Awareness Remained Constant, 2014-17. AB - Together with physician specialty societies, the Choosing Wisely(r) campaign has codified recommendations of which health care services' use should be questioned and discussed with patients. The ABIM Foundation administered surveys in 2014 and 2017 to examine physicians' attitudes toward and awareness of the use of low value care. The surveys included questions on the factors driving that use, physicians' comfort in having conversations with patients about that use, and physicians' exposure to the Choosing Wisely campaign. Despite continued publicity and physician outreach efforts, there were no significant changes between 2014 and 2017 in awareness of the campaign among physicians (awareness increased from 21 percent to 25 percent) or physician-reported difficulty in talking to patients about avoiding a low-value service (42 percent reported that such conversations had gotten harder in 2014, and 46 percent did so in 2017). Barriers to the adoption of recommendations included malpractice concerns, patient demand and satisfaction, and physicians' desire for more information to reduce uncertainty. Multifaceted interventions that reinforce guidelines through personalized education, follow-up, and feedback, as well as aligned financial incentives, should be pursued to reduce the use of low-value services. PMID- 29137516 TI - To Reduce Neonatal Mortality, Nigeria Is Taking A Simple Treatment Nationwide. PMID- 29137523 TI - Foundations' Efforts To Improve Rural Health Care. PMID- 29137524 TI - Making The Most Of Microfinance Networks. AB - Together, data scientists and microfinance institutions are bringing vital health products to Haiti's rural communities. PMID- 29137525 TI - Global Health Policy. PMID- 29137526 TI - Tools To Reduce Newborn Deaths In Africa. AB - An engineering team designs a breathing device specifically for premature babies born in low-resource health care settings. PMID- 29137527 TI - Binding modes of Bcl-2 homology 3 (BH3) peptides with anti-apoptotic protein A1 and redesign of peptide inhibitors: a computational study. AB - The interaction between protein and peptide ligand is a challenging problem in molecular biology and drug design. The binding of the Bcl-2 homology 3 (BH3) peptide to the anti-apoptotic protein A1 was revealed as a critical step in the regulation of apoptosis. These BH3 peptides hold high structural similarity, but are diverse in their regulation abilities. Based on molecular simulations and MM P(G)BSA methods, this work presented a detailed analysis on binding mechanism of the BH3 peptides derived from PUMA and BMF. Residue-level energy decomposition showed that the core regions of BH3 peptides maintain in stable helical conformations and the four conserved hydrophobic residues together with an invariant aspartic acid contribute the major driving force for binding, whereas their two terminal segments exhibit obvious flexibility and various binding modes. Such kind of behavior was suggested as the reason for binding diversity and selectivity of BH3 peptides. As a further step, several BH3-mimetic peptides have been redesigned by computational mutation. Those new peptides showed not only stronger affinities when binding to protein A1, as well transferable binding patterns at some specific positions. A long-range coupling effect was disclosed for BH3 peptides, side-chain orientation and binding contribution of terminal residues were even affected by mutations at large sequence interval. Overall, this work reports that the binding modes of BH3 peptides are primarily dependent on its two terminal segments. The computational methods applied herein are also demonstrated to be of great assistance in the rational design of peptide inhibitors. PMID- 29137528 TI - Scrub typhus reinfection. PMID- 29137529 TI - Disorderly Households, Self-Presentation, and Mortality: Evidence From a National Study of Older Adults. AB - This article examines whether disorderly household conditions and bodily self presentation predict mortality, above and beyond four sets of variables conceptually linked to both death and disorder. Data come from 2005/2006 and 2010/2011 waves of the National Social Life, Health, and Aging Project. We used naturalistic observation of respondents' homes and bodies, along with a diverse range of additional covariates, to predict probability of death. Older adults living in disorderly households were at highest risk of death over 5 years, primarily because they confronted high levels of frailty. Disorderly bodily self presentation was also related to mortality risk, but this association could be only partially explained by demographic factors, health conditions, frailty, and low social connectedness. Findings suggest that disorder in the residential context-dress and hygiene in particular-is a strong predictor of mortality. Support providers should be mindful of changes in bodily presentation among community-dwelling older adults. PMID- 29137530 TI - Neuroanatomical substrates involved in unrelated false facial recognition. AB - Identifying faces is a process central for social interaction and a relevant factor in eyewitness theory. False recognition is a critical mistake during an eyewitness's identification scenario because it can lead to a wrongful conviction. Previous studies have described neural areas related to false facial recognition using the standard Deese/Roediger-McDermott (DRM) paradigm, triggering related false recognition. Nonetheless, misidentification of faces without trying to elicit false memories (unrelated false recognition) in a police lineup could involve different cognitive processes, and distinct neural areas. To delve into the neural circuitry of unrelated false recognition, we evaluated the memory and response confidence of participants while watching faces photographs in an fMRI task. Functional activations of unrelated false recognition were identified by contrasting the activation on this condition vs. the activations related to recognition (hits) and correct rejections. The results identified the right precentral and cingulate gyri as areas with distinctive activations during false recognition events suggesting a conflict resulting in a dysfunction during memory retrieval. High confidence suggested that about 50% of misidentifications may be related to an unconscious process. These findings add to our understanding of the construction of facial memories and its biological basis, and the fallibility of the eyewitness testimony. PMID- 29137531 TI - "I Honestly Would Not Have Known What to Do": An Exploratory Study of Perspectives on Client Suicide Among Vocational Rehabilitation Support Staff. AB - Despite the high prevalence of suicide both overall and among people with disabilities in particular, little research has explored suicide in the context of the vocational rehabilitation (VR) system or in counseling support staff in general. We analyzed the responses of 14 VR support staff who responded to an open-ended qualitative prompt regarding their experiences with suicide training and competency. Key themes included a perceived lack of and desire for more training regarding suicide, seeking and receiving suicide training outside of VR, and a perceived lack of resources for working with suicidal clients. Responses also underscored the heavy emotional impact of working with these clients, especially when one feels unprepared to do so. These results suggest that it is important to provide VR support staff with resources and training for addressing suicide in their client populations. PMID- 29137532 TI - On the intrinsic propensity of the Asn-Gly sequence to fold into type I' beta turn: molecular dynamics simulations of Asn-Gly beta-turn containing peptide sequences. PMID- 29137533 TI - ? PMID- 29137534 TI - [CME: Non-ST-Elevation Myocardial Infarction (NSTEMI) - Definition, Risk Stratification and Management.] PMID- 29137535 TI - ? PMID- 29137537 TI - ? PMID- 29137536 TI - ? PMID- 29137538 TI - ? PMID- 29137539 TI - ? PMID- 29137540 TI - ? PMID- 29137541 TI - [CME Rheumatology 13: Shoulder Pain, Muscle Weakness and Skin Rash]. PMID- 29137542 TI - ? PMID- 29137543 TI - ? PMID- 29137544 TI - Effect of Aerobic Training on Peak Oxygen Uptake Among Seniors Aged 70 or Older: A Meta-Analysis of Randomized Controlled Trials. AB - Older adults undergo a progressive decline in cardiorespiratory fitness and functional capacity. This lower peak oxygen uptake (VO2peak) level is associated with increased risk of frailty, dependency, loss of autonomy, and mortality from all causes. Regular physical activity and particularly aerobic training (AT) have been shown to contribute to better and healthy aging. We conducted a meta analysis to measure the exact benefit of AT on VO2peak in seniors aged 70 years or older. A comprehensive, systematic database search for articles was performed in Embase, Medline, PubMed Central, Science Direct, Scopus, and Web of Science using key words. Two reviewers independently assessed interventional studies for potential inclusion. Ten randomized controlled trials (RCTs) were included totaling 348 seniors aged 70 years or older. Across the trials, no high risk of bias was measured and all considered open-label arms for controls. With significant heterogeneity between the RCTs (all p < 0.001), pooled analyses were computed for VO2peak. Not only was VO2peak found significantly higher in the training group compared to controls (mean difference [MD] = 1.56; 95% confidence interval [CI]: 0.90-2.23) in pooled analysis of the 10 RCTs but also when the analysis was adjusted on the participants' health statuses. MD among healthy and unhealthy seniors were, respectively, 1.72 (95% CI: 0.34-3.10) and 1.47 (95% CI: 0.60-2.34). This meta-analysis confirms the AT-associated benefits on VO2peak in healthy and unhealthy seniors. PMID- 29137545 TI - Exploring the perceived health benefits of singing in a choir: an international cross-sectional mixed-methods study. AB - AIM: This mixed-methods exploratory study investigates the perceived health benefits of singing in a choir from an international sample of choristers. METHOD: An online questionnaire including demographic information, 28 quantitative statements and two qualitative questions relating to the perceived health benefits of singing in a choir was distributed via email and social media over a period of 4 months to a sample of 1,779 choristers. Basic descriptives and comparisons between subgroups of the sample are presented along with thematic analysis of qualitative comments. RESULTS: Basic descriptives suggest an overwhelmingly positive response. Females scored significantly higher than males on physical benefits, social benefits and emotional benefits. Professional singers reported significantly more physical, social and spiritual benefits than amateur singers. Bias may be present in these findings as the results were entirely self-reported by people who already sing in choirs. Qualitative thematic analysis identified six key themes which may counter this bias by providing deeper understanding of the perceived benefits for choir singers. These include social connection, physical and physiological benefits (specifically respiratory health), cognitive stimulation, mental health, enjoyment and transcendence. CONCLUSION: Choral singing elicits a positive response in the chorister across a plethora of domains. This research confirms previous findings on the health benefits of singing but offers evidence from the largest sample of singers to date. However, results are based on self-perceptions of choristers, and findings are, therefore, limited. Results may be used as a base on which to develop further research in this area. It also provides confirmatory evidence to support choral singing as a means of improving wellbeing in many populations, including but not limited to workplaces, schools, nursing homes, communities and churches. PMID- 29137547 TI - Developing a framework of behaviours before suicides at railway locations. AB - Better knowledge of behaviours of people at railway property could help with identifying those at risk of suicide. Literature has been reviewed from a range of disciplines on what is known about studying behaviour in this type of public location. Secondary analysis has been carried out on descriptions of behaviour from structured exercises with experts and other pre-existing sources. A framework has been produced with five main classes (display of emotion, appearance, posture/movements, activities and interactions) and associated sub classes. Commentary has been provided on factors that influence identification of suspicious behaviours, how to distinguish these from normal behaviours and the circumstances that inhibit timely reactions to the behaviour amidst the complexity of the operational railway. Opportunities to develop and use the framework are discussed, including using this to prompt collection of additional behavioural data from wider resources, enhancing staff training and developing requirements for effective use of surveillance technologies. Practitioner Summary: Many railway suicides could be prevented with better understanding of behaviours before events. Pre-existing data sources have been analysed, producing a framework highlighting five aspects of behaviour. This can prompt the collection of better evidence on pre-suicidal behaviours, with future applications in developing surveillance technologies, training staff and public awareness. PMID- 29137548 TI - Exploring organisational competences in Human Factors and UX project work: managing careers, project tactics and organisational strategy. AB - Organisational competence in Human Factors and UX (user experience) has not been looked at before despite its relevance to project success. We define organisational competence as the collective competence of the individuals, bringing together their complementary abilities to deliver an outcome that is typically more than the sum of its parts. Twenty-two UX and Human Factors practitioners were interviewed about their project work in two contrasting domains: web design and safety-critical systems to explore organisational competences. Through doing a FRAM analysis, 29 functions and 6 main areas of competences were identified: the central project process; the process of learning about the problem; maintaining and developing client relations; staff development; evolving practices; and the management of documentation for audit and quality control. These dynamic and situated competences form a web of interactions. Managing competences is essential for project success. Implications for managing careers, project tactics and organisational strategy are discussed. Practitioner Summary: Organisational competences impact how routine and non routine project work is performed, but these have received little attention in the literature. Six key areas of competences in Human Factors and UX project work were identified from practitioner interviews. Managing combinations of adaptive competences is important for developing careers, project tactics and organisational strategies. PMID- 29137549 TI - The Impact of a Long-Acting Oral Sphingosine-1-Phosphate Analogue on Ovarian Aging in a Rat Model. AB - In animal studies, intravenous continuous infusion or peritoneal injection of sphingosine-1-phosphate (S1P) has been shown to decrease chemotherapy- and radiotherapy-induced apoptosis on primordial follicles. Although a long-acting oral form of an S1P analogue (FTY720, fingolimod) has been recently developed and utilized in women with multiple sclerosis, there are no data exploring its ability to avoid spontaneous follicle apoptosis. Thirty 10-month-old female rats were randomly assigned to 3 groups to investigate whether fingolimod would be able to decrease the spontaneous ovarian follicle apoptosis ratio. An oral analogue form of S1P was administered for 60 days at a dose of 0.1 mg/kg (n = 10) or dose of 1 mg/kg (n = 10) per day. The control group (n = 10) received physiological serum via an orogastric feeding tube. The main outcome measures were anti-Mullerian hormone (AMH) level and nonapoptotic follicle ratio. While low-dose S1P group had comparable AMH levels to high-dose S1P group and controls, high-dose S1P group had higher mean levels of AMH, reaching marginal significance with controls (5.72 +/- 0.61 vs 4.81 +/- 0.85 ng/mL, P = .050). For the nonapoptotic primordial follicle ratio, both low-dose S1P group (67.0% +/- 16.4% vs 29.9% +/- 19.5%, P < .001) and high-dose S1P group (51.1% +/- 11.5% vs 29.9% +/- 19.5%, P = .023) had superior rates when compared with controls. Interestingly, low-dose S1P groups also had a statistically higher nonapoptotic primordial follicle ratio than high-dose S1P group ( P = .047). Our findings suggest that a long-acting oral analogue of S1P might decrease spontaneous follicular apoptosis based on the nonapoptotic primordial follicle ratio and AMH levels when compared with placebo. PMID- 29137550 TI - Reengineering Electronic Fetal Monitoring Interpretation: Using the Fetal Reserve Index to Anticipate the Need for Emergent Operative Delivery. AB - OBJECTIVE: The near-ubiquitous use of electronic fetal monitoring has failed to lower the rates of both cerebral palsy and emergency operative deliveries (EODs). Its performance metrics have low sensitivity, specificity, and predictive values for both. There are many EODs, but the vast majority have normal outcomes. The EODs, however, cause serious disruption in the delivery suite routine with increased complications, anxiety, and concern for all. METHODS: We developed the fetal reserve index (FRI) as multicomponent algorithm including 4 FHR components (analyzed individually), uterine activity, and maternal, obstetrical, and fetal risk factors to assess risk of cerebral palsy and EOD. Scores were categorized into green, yellow, and red zones. Here, we studied 300 patients by the FRI, all of whom had normal neonatal outcomes. We attempted to distinguish the clinical course of those cases which required an EOD versus controls which did not. RESULTS: 51 cases with EOD had FRIs much lower than 249 non-EOD cases. The red zone was reached more frequently ( P < .001) and lasted longer (1.06 vs 0.05 hours; P < .001). Reaching the red zone had a sensitivity of 92% for EOD, with a positive predictive value of 64% and a false positive rate of 10.4%. CONCLUSIONS: Our data suggest the FRI can significantly lower the incidence of EODs by identifying the opportunity for intrauterine resuscitation. Our approach can reduce the disruptive effects of EODs and their concomitant increased risks of complications. The FRI may provide a metric that can refine labor management to reduce CP and EODs. PMID- 29137551 TI - Environmental Manipulations as an Effective Alternative Treatment to Reduce Endometriosis Progression. AB - Treatments for endometriosis include pharmacological or surgical procedures that produce significant side effects. We aimed to determine how environmental enrichment (EE) could impact the progression of endometriosis using the autotransplantation rat model. Female rats were exposed to EE (endo-EE: toys and nesting materials, 4 rats per cage, larger area enclosure) or no enrichment (endo NE: 2 rats per cage) starting on postnatal day 21. After 8 weeks, sham surgery or surgical endometriosis was induced by suturing uterine horn tissue next to the intestinal mesentery, then allowed to progress for 60 days during which EE or NE continued. At the time of killing, we measured anxiety behaviors, collected endometriotic vesicles and uterus, and processed for quantitative real-time polymerase chain reaction for corticotropin-releasing hormone (CRH), urocortin-1, CRH receptors type 1 and type 2, and glucocorticoid receptor (GR). Endometriosis did not affect anxiety-like behaviors, yet rats in enriched conditions showed lower basal anxiety behaviors than the nonenriched group. Importantly, the endo EE group showed a 28% reduction in the number of endometriosis vesicles and the vesicles were significantly smaller compared to the endo-NE group. Endometriosis increased CRH and GR only in the vesicles of endo-NE, and this increase was dampened in the endo-EE. However, urocortin 1 was increased in the vesicles of the endo-EE group, suggesting different pathways of activation of CRH receptors in this group. Our results suggest that the use of multimodal complementary therapies that reduce stress in endometriosis could be an effective and safe treatment alternative, with minimal side effects. PMID- 29137552 TI - Clinical governance breakdown: Australian cases of wilful blindness and whistleblowing. AB - BACKGROUND: After their attempts to have patient safety concerns addressed internally were ignored by wilfully blind managers, nurses from Bundaberg Base Hospital and Macarthur Health Service felt compelled to 'blow the whistle'. Wilful blindness is the human desire to prefer ignorance to knowledge; the responsibility to be informed is shirked. OBJECTIVE: To provide an account of instances of wilful blindness identified in two high-profile cases of nurse whistleblowing in Australia. RESEARCH DESIGN: Critical case study methodology using Fay's Critical Social Theory to examine, analyse and interpret existing data generated by the Commissions of Inquiry held into Bundaberg Base Hospital and Macarthur Health Service patient safety breaches. All data was publicly available and assessed according to the requirements of unobtrusive research methods and secondary data analysis. Ethical considerations: Data collection for the case studies relied entirely on publicly available documentary sources recounting and detailing past events. FINDINGS: Data from both cases reveal managers demonstrating wilful blindness towards patient safety concerns. Concerns were unaddressed; nurses, instead, experienced retaliatory responses leading to a 'social crisis' in the organisation and to whistleblowing. CONCLUSION: Managers tasked with clinical governance must be aware of mechanisms with the potential to blind them. The human tendency to favour positive news and avoid conflict is powerful. Understanding wilful blindness can assist managers' awareness of the competing emotions occurring in response to ethical challenges, such as whistleblowing. PMID- 29137553 TI - Relationship Between Pregnancy Complications and Psychiatric Disorders: A Population-Based Study With a Matched Control Group. AB - OBJECTIVES: This study sought to identify whether pregnancy complications differ between women with and without a psychiatric disorder diagnosis prior to pregnancy. METHODS: Women who gave birth between 2007 and 2009 in Pennsylvania and were enrolled in Medicaid from one year prior to their pregnancy until their delivery were included (N=9,930); those with psychiatric disorders were compared with a matched control group (N=4,965 for each). Logistic regression analysis estimated the odds of having a pregnancy complication among those with a psychiatric diagnosis prior to pregnancy, adjusting for demographic characteristics and chronic general medical conditions. RESULTS: Compared with the control group, women with a psychiatric disorder prior to pregnancy had greater odds of having at least one pregnancy complication (odds ratio=1.48, 95% confidence interval=1.37-1.61). Compared with the control group, their odds of antepartum hemorrhage were 1.50 times higher, their odds of preterm labor were 1.45 times higher, and their odds of preterm birth were 1.61 times higher. CONCLUSIONS: Women with psychiatric disorders prior to pregnancy were more likely to experience pregnancy complications, including pregnancy hemorrhage, preterm labor, and preterm birth, after the analysis controlled for age, race-ethnicity, and chronic illness status before and during pregnancy. The finding of an association between psychiatric disorders and a higher complication risk suggests the importance of population-based preconception interventions for women with psychiatric disorders and prenatal monitoring to reduce the risk of pregnancy complications in this group. PMID- 29137555 TI - Impact of ACA Health Reforms for People With Mental Health Conditions. AB - OBJECTIVE: This brief report explores the impact of health reform for people with mental illness. METHODS: The Health Reform Monitoring Survey was used to examine health insurance, access to care, and employment for 1,550 people with mental health conditions pre- and postimplementation of the Affordable Care Act (ACA) and by state Medicaid expansion status. Multivariate logistic regressions with predictive margins were used. RESULTS: Post-ACA reforms, people with mental health conditions were less likely to be uninsured (5% versus 13%; t=-6.89, df=50, p<.001) and to report unmet need due to cost of mental health care (17% versus 21%; t=-3.16, df=50, p=.002) and any health services (46% versus 51%; t= 3.71, df=50, p<.001), and they were more likely to report a usual source of care (82% versus 76%; t=3.11, df=50, p=.002). These effects were experienced in both Medicaid expansion and nonexpansion states. CONCLUSIONS: Findings underscore the importance of ACA improvements in the quality of health insurance coverage. PMID- 29137554 TI - The Alternative Quality Contract: Impact on Service Use and Spending for Children With ADHD. AB - In 2009, Blue Cross-Blue Shield of Massachusetts (BCBSMA) implemented the alternative quality contract (AQC), which pays provider organizations a global payment for all services used by enrollees. BCBSMA claims for 2006-2011 were used to compare youths enrolled in provider organizations participating in the AQC (7,407 person-years [PYs]) with those not participating (45,398 PYs). Difference in-differences models estimated changes in mental health and substance abuse treatment service utilization and spending attributable to the AQC. The AQC was associated with small increases in the probability of any outpatient visits and in the probability and number of medication management visits among children with attention-deficit hyperactivity disorder (ADHD). Spending did not change, and there was no evidence of reductions in service utilization or spending for children with ADHD in the first three years of AQC implementation. PMID- 29137556 TI - All-Cause, 30-Day Readmissions Among Persons With Intellectual and Developmental Disabilities and Mental Illness. AB - OBJECTIVE: Early hospital readmissions within 30 days of discharge are common and costly. This research describes predictors of all-cause, 30-day hospital readmissions among persons with intellectual and developmental disabilities (IDD), a group known to experience high rates of hospitalization. METHODS: A cohort of 66,484 adults with IDD from Ontario, Canada, was used to create two subgroups: individuals with IDD only and those with IDD and mental illness. The rates of hospital readmission were determined and contrasted with a comparison subgroup of people without IDD who have mental illness. RESULTS: Compared with those with mental illness only, individuals with IDD and mental illness were 1.7 times more likely to experience a hospital readmission within 30 days. Predictors of their readmission rates included being a young adult and having high morbidity levels. CONCLUSIONS: The high rate of hospital readmission suggests that individuals with IDD and mental illness need attention regarding discharge planning and outpatient follow-up. PMID- 29137557 TI - The Impact of a State Medicaid Peer-Review Authorization Program on Pediatric Use of Antipsychotic Medications. AB - OBJECTIVE: This cross-sectional study assessed the impact of a peer-review program on the prevalence of pediatric antipsychotic use among Medicaid-insured youths in a Mid-Atlantic state. METHODS: Medicaid claims (2010-2014) were assessed among continuously enrolled youths in the 12 months before and after implementation of peer review. The study identified children ages zero to four preimplementation (N=118,815) and postimplementation (N=121,431), ages five to nine preimplementation (N=98,681) and postimplementation (N=107,872), and ages 10 to 17 preimplementation (N=154,696) and postimplementation (N=161,370). (Age ranges are inclusive of the final number). In each age group, multivariable logistic regression models with generalized estimating equations assessed the change in annual prevalence of antipsychotic use pre- to postimplementation. Use of other leading psychotropic classes and antipsychotic prescribing by medical specialty were also examined. RESULTS: The annual pre- to postimplementation prevalence of antipsychotic use decreased significantly, from .07% to .03% (adjusted odds ratio [AOR]=.41) among children ages zero to four, from 1.57% to .86% (AOR=.54) among those ages five to nine, and from 3.28% to 2.40% (AOR=.72) among those ages 10 to 17. With the exception of alpha-agonist use, which increased postimplementation (AOR=1.30) among those ages zero to four, no clinically significant pre-post change was noted in other leading psychotropic classes among children ages zero to four and 10 to 17. By contrast, postimplementation use of other psychotropic medications decreased among those ages five to nine (AOR=.73). CONCLUSIONS: A state Medicaid peer-review program resulted in decreased antipsychotic use across all age groups, particularly among children younger than ten. No notable substitution of other psychotropic classes for antipsychotics was observed. PMID- 29137558 TI - Testing a Web-Based, Trained-Peer Model to Build Capacity for Evidence-Based Practices in Community Mental Health Systems. AB - OBJECTIVE: Use of expert-led workshops plus consultation has been established as an effective strategy for training community mental health (CMH) clinicians in evidence-based practices (EBPs). Because of high rates of staff turnover, this strategy inadequately addresses the need to maintain capacity to deliver EBPs. This study examined knowledge, competency, and retention outcomes of a two-phase model developed to build capacity for an EBP in CMH programs. METHODS: In the first phase, an initial training cohort in each CMH program participated in in person workshops followed by expert-led consultation (in-person, expert-led [IPEL] phase) (N=214 clinicians). After this cohort completed training, new staff members participated in Web-based training (in place of in-person workshops), followed by peer-led consultation with the initial cohort (Web-based, trained peer [WBTP] phase) (N=148). Tests of noninferiority assessed whether WBTP was not inferior to IPEL at increasing clinician cognitive-behavioral therapy (CBT) competency, as measured by the Cognitive Therapy Rating Scale. RESULTS: WBTP was not inferior to IPEL at developing clinician competency. Hierarchical linear models showed no significant differences in CBT knowledge acquisition between the two phases. Survival analyses indicated that WBTP trainees were less likely than IPEL trainees to complete training. In terms of time required from experts, WBTP required 8% of the resources of IPEL. CONCLUSIONS: After an initial investment to build in-house CBT expertise, CMH programs were able to use a WBTP model to broaden their own capacity for high-fidelity CBT. IPEL followed by WBTP offers an effective alternative to build EBP capacity in CMH programs, rather than reliance on external experts. PMID- 29137559 TI - Factors Influencing Receipt of Mental Health Services Among Medicaid Beneficiaries With Breast Cancer. AB - OBJECTIVE: This study examined associations of state-level Medicaid reimbursement and other policies and patient characteristics with receipt of mental health diagnostic and treatment services for beneficiaries with cancer. METHODS: Data (2006-2008) from Medicaid beneficiaries with breast cancer were analyzed to examine predictors of receiving mental health diagnostic services and mental health treatment services. Independent variables included state-level Medicaid policies for reimbursements for mental health services and consultations (requests from one health care provider to another for advice regarding evaluation or management of a specific problem), required patient copayments, and requirements governing the timing of Medicaid eligibility recertification (eligibility recertification period). Generalized estimating equations were used to assess factors influencing receipt of mental health services while controlling for clustering by state. RESULTS: The analysis of diagnostic services included 7,441 Medicaid beneficiaries, and the analysis of treatment services included 7,511 beneficiaries. Medicaid reimbursements for mental health services were not associated with receiving these services. However, increased Medicaid reimbursement for consultations significantly increased the likelihood of receiving mental health diagnostic and treatment services. Increased comorbidities were also associated with increased likelihood of receiving mental health services. CONCLUSIONS: The association of higher Medicaid reimbursements for consultations with receipt of mental health services suggests that consultation reimbursement has a "gatekeeper" effect-after a patient received an initial consultation, lower reimbursements for mental health services were not barriers to subsequent mental health care. Increased Medicaid reimbursement for consultations with a mental health professional may increase willingness of health care providers to provide mental health care services for Medicaid beneficiaries. PMID- 29137560 TI - Randomized Trial of Interventions for Smoking Cessation Among Medicaid Beneficiaries With Mental Illness. AB - OBJECTIVE: Medicaid beneficiaries with severe mental illnesses are a financially disadvantaged group with high rates of smoking and poor cessation outcomes. This study examined whether abstinence-contingent monetary incentives improved outcomes when added to cessation treatments at community mental health centers: prescriber visit for pharmacotherapy only (PV only), prescriber visit and facilitated quitline (PV+Q), and prescriber visit and telephone cognitive behavioral therapy (PV+CBT). METHODS: During 2012-2015, a total of 1,468 adult, daily smoking Medicaid beneficiaries with mental illnesses received Web-based motivational tobacco education. Eligible participants who wanted cessation treatment (N=661) were randomly assigned to treatment with or without abstinence contingent incentives for four weeks after a quit attempt and assessed for biologically verified abstinence at three, six, nine, and 12 months. To examine intervention effect on abstinence over time, logistic generalized linear models estimated with generalized estimating equations were used, with missing observations imputed as smoking. RESULTS: Participants included smokers with schizophrenia disorders (N=148), bipolar disorder (N=150), major depressive disorder (N=158), and anxiety and other disorders (N=205). There was no significant effect of intervention (PV only, PV+Q, and PV+CBT). However, participants who received monetary incentives were more likely to be abstinent from smoking over time (adjusted odds ratio [AOR]=1.77, p=.009). Post hoc comparisons indicated greater abstinence at 12 months in PV+Q with incentives than in PV+Q without incentives (14% versus 4% abstinent, AOR=3.94, p=.014). Treatment participation and cessation outcomes did not differ significantly between diagnostic groups. CONCLUSIONS: Abstinence-contingent incentives improved cessation outcomes among financially disadvantaged smokers with mental illness receiving tobacco treatment at community mental health centers. PMID- 29137562 TI - Beware the Educational Fix: Limitations of Efforts to Promote Mental Health Literacy. AB - Public health professionals seek to promote health literacy through education. In the mental health arena, such approaches have included teaching primary care gatekeepers to screen for early identification of suicide risk and teaching members of the general public to engage peers in need of mental health treatment and guide them into evidence-based care. Educational positivism is the belief that this pedagogic enterprise is unlimited, leading to a "more is better" approach. Despite its promise, however, educational approaches may have muted effects. Students in discrete training programs are often overwhelmed by too much information. Moreover, the effects of distributed training programs, which usually involve repeated training over longer periods, compete with already existing schemes of health action as well as the cacophony of other channels of information. Strategies to address these concerns are described. PMID- 29137561 TI - Mental Health Spending and Intensity of Service Use Among Individuals With Diagnoses of Eating Disorders Following Federal Parity. AB - OBJECTIVE: The Mental Health Parity and Addiction Equity Act (MHPAEA) was intended to eliminate differences in insurance coverage for mental health and substance use disorder services and medical-surgical care. No studies have examined mental health service use after federal parity implementation among individuals with diagnoses of eating disorders, for whom financial access to care has often been limited. This study examined whether MHPAEA implementation was associated with changes in use of mental health services and spending in this population. METHODS: Using Truven Health MarketScan data from 2007 to 2012, this study examined trends in mental health spending and intensity of use of specific mental health services (inpatient days, total outpatient visits, psychotherapy visits, and medication management visits) among individuals ages 13-64 with a diagnosis of an eating disorder (N=27,594). RESULTS: MHPAEA implementation was associated with a small increase in total mental health spending ($1,271.92; p<.001) and no change in out-of-pocket spending ($112.99; p=.234) in the first year after enforcement of the parity law. The law's implementation was associated with an increased number of outpatient mental health visits among users, corresponding to an additional 5.8 visits on average during the first year (p<.001). This overall increase was driven by an increase in psychotherapy use of 2.9 additional visits annually among users (p<.001). CONCLUSIONS: MHPAEA implementation was associated with increased intensity of outpatient mental health service use among individuals with diagnoses of eating disorders but no increase in out-of-pocket expenditures, suggesting improvements in financial protection. PMID- 29137563 TI - Stem anteversion mismatch to the anatomical anteversion causes loss of periprosthetic bone density after THA. AB - The short tapered-wedge stem is popular worldwide because it potentially preserves more bone stock during total hip arthroplasty (THA). However, stem version mismatch may affect physiological stress distribution. In this study, we analyzed the correlations between periprosthetic bone mineral density (BMD) changes and anteversion mismatch in patients who underwent THA using a short tapered-wedge stem. The study included 44 patients (44 joints) who underwent THA with a Tri-Lock stem. At baseline and at 6 and 24 months postoperatively, the BMDs in the seven Gruen zones were evaluated using dual-energy X-ray absorptiometry. BMD changes and stem alignment, that is, anteversion and stem anteversion mismatch to the anatomical canal anteversion, were analyzed. Significant negative correlations were found between BMD changes and absolute anteversion error in Gruen zones 1 and 7 at 6 and 24 months postoperatively (zone 1, 6M; RR= -0.48, p < 0.001) (zone 7, 6M; RR= -0.46, p = 0.002) (zone 1, 24M; RR= -0.47, p = 0.001) (zone 7, 24M; RR= -0.40, p = 0.007). We further demonstrated that excessive stem anteversion mismatch to the anatomical canal anteversion causes stem point contact with the cortical bone in the distal portion and affected proximal periprosthetic BMD loss after THA. We recommend that the native anatomical anteversion angle should be used as a reference for inserting the tapered-wedge stems. PMID- 29137564 TI - Muscle atrophy and recovery of individual thigh muscles as measured by magnetic resonance imaging scan during treatment with cast for ankle or foot fracture. AB - PURPOSE: We aimed to longitudinally investigate individual thigh muscle changes using magnetic resonance imaging (MRI) during treatment with cast of ankle or foot fracture. Moreover, we aimed to demonstrate whether measurements of muscle cross-sectional area (CSA) are sensitive to muscle changes, contributing to simpler methods in clinical application . METHODS: Ten patients undergoing treatment with cast of acute ankle or foot fractures were studied. Axial MRI (1.5 T) was conducted around the affected mid-thigh region after the injury (Pre), after maintaining a nonweight-bearing (NWB) period (approximately 28 days), and after finishing rehabilitation (recovery). Regarding individual thigh muscles, the total CSAs corresponding to 40% of the femoral length (FL) and the CSAs at 5% interval of the FL were longitudinally measured. Standardized response means (SRMs) were accessed for sensitivity in the muscle changes. RESULTS: The total CSAs at NWB were significantly lower than those at Pre in vastus lateralis (10.9% +/- 5.4%), vastus intermedius (8.4% +/- 6.7%), and vastus medialis (11.2% +/- 6.9%) ( p < 0.01 for all). In contrast, at recovery, the only significant muscle atrophy relative to that at Pre was observed in the semitendinosus of the proximal 15% and 10% CSAs ( p < 0.01 and p = 0.01, respectively). In all muscles, SRM using a single-slice CSA at or near the muscle belly was high. CONCLUSION: Thigh muscle changes differ according to the variations in individual muscles. CSA measurements at or near the muscle belly are simple methods and sensitive indicators of these muscle changes. PMID- 29137565 TI - MRI evaluation of the ACL remnant tissue in ACL-deficient knee. AB - PURPOSE: To clarify the relationship between anterior cruciate ligament (ACL) remnant tissue at the time of surgery and preoperative evaluation of ACL-injured knee. METHODS: A total of 123 patients were enrolled and classified into four groups based on the classification of ACL remnant tissue. To quantify the signal noise quotient (SNQ), five regions of interest (ROIs), such as tibial, mid, femoral ACL remnant, tendon of quadriceps femoris to normalize the signal intensity of ACL remnant tissue, and background measurements, were measured. Preoperative side-to-side difference (SSD) and SNQ were analyzed. RESULTS: Significant differences were observed in preoperative SSD of the four groups ( p = 0.021), and a post hoc analysis revealed that SSD in Crain type 2 was significantly smaller than that in Crain type 4 ( p = 0.014). SSD in Crain type 3 was also significantly smaller than that in Crain type 4 ( p = 0.0030). There were significant differences in SNQ at the tibial, mid, and femoral portion in Crain types 2 and 3 ( p < 0.001); SNQ at the tibial portion in Crain type 2 was significantly lower than that at the mid portion ( p = 0.024); and SNQ at the tibial portion in Crain type 3 was significantly lower than that at the mid portion ( p = 0.016). Furthermore, significant differences were observed in SNQ at the tibial portions in the four groups ( p = 0.034), and SNQ at the tibial portions in Crain type 2 was significantly lower than that in Crain type 1 ( p = 0.044). Also, SNQ at the tibial portions in Crain type 3 was significantly lower than that in Crain type 1 ( P = 0.035). CONCLUSION: The femoral attachment of the ACL remnant tissue may influence the SNQ of the tibial remnant tissue and the stability of the ACL-injured knee. PMID- 29137566 TI - A novel exercise device for venous thromboembolism prophylaxis improves venous flow in bed versus ankle movement exercises in healthy volunteers. AB - PURPOSE: Venous thromboembolism prophylaxis is crucial. To facilitate active ankle movement in postoperative and bedridden patients, we developed a novel leg exercise apparatus (LEX). We investigated the effect of the LEX by comparing increases in lower extremity venous flow during different modes of exercise using the LEX. METHODS: In eight healthy participants, we measured venous flow volume and velocity in the femoral vein using duplex ultrasonography at 1, 10, 20, and 30 min after completing three modes of 1-min LEX exercises. The exercises involved (1) rapid single motion (ankle dorsi-plantar flexion; 60 cycles/min); (2) slow single motion (30 cycles/min); and (3) slow combined leg motion. RESULTS: Flow volumes after modes 1, 2, and 3 were 1.63-, 1.39-, and 1.53-fold above baseline at 30 min, respectively. Short periods of rapid single motion, with the LEX, improved postexercise lower extremity venous flow volumes at 30 min and mean venous flow velocity at 20 min, compared to slow single motion exercise. Even at slow speeds, combined-motion improved flow volume compared to single motion. CONCLUSION: Short periods of rapid single motion exercise, with the LEX, improved postexercise venous flow volumes in the lower extremities at 30 min and mean venous flow velocity at 20 min. These effects were greater than those produced by slow single motion exercises. However, even at slow speeds, combined motion exercises improved flow volume compared to single motion. Therefore, LEX may prove effective at preventing thromboembolism in postoperative and bedridden patients. PMID- 29137567 TI - Primary repair of Achilles tendon avulsions: Presentation of a novel technique and its comparison with suture anchor repair. AB - PURPOSE: We aimed to present our novel technique in the surgical treatment of Achilles tendon avulsions and compare the clinical results of such technique with the repair method using suture anchors. METHODS: A retrospective study was made of patients with Achilles tendon sleeve avulsion and patients where distal portion of the tear prohibited primary repair, surgically treated between January 2009 and January 2013. Twenty-one patients who met the criteria were examined and called for final examination: 9 patients were treated with the novel technique (group 1) and 12 patients were treated with suture anchor repair (group 2). Data were gathered from patient registry and final evaluation. The patients of both groups were compared in respect of mean age, follow-up, gender and AOFAS and VAS scores at final evaluation. RESULTS: There was no significant difference between two groups in terms of follow-up period ( p = 0.478) and mean age ( p = 0.274). Three of 9 patients in group 1 and 4 of 12 patients in group 2 were female. A significant clinical difference was determined between two groups according to the AOFAS and VAS scores ( p = 0.034 and p = 0.043, respectively). CONCLUSIONS: Both techniques are beneficial in the treatment of avulsion injuries of Achilles tendon. Better clinical results can be obtained with the presented novel technique and such technique can be considered for the surgical fixation of Achilles tendon avulsions. PMID- 29137568 TI - First dorsal metatarsal artery perforator flap to cover great toe defect. AB - BACKGROUND: There were very few options available for distal foot and toe defects that required a vascularized flap for coverage. As such, the use of a free flap was often justified in this region of the foot. The use of perforator flaps has created a new subset of local tissue transfer alternatives that increases the potential that the difficulties associated with microvascular tissue transfers could be avoided. The first dorsal metatarsal artery (FDMA) perforator flap was one variant of this new type of tissue transfer. The aim of this report was to describe our experience using FDMA perforator flap to cover great toe defect. METHODS: A standard FDMA flap from the dorsum of the foot was raised in reversed fashion based on the distal communicating branch or "perforator" from plantar foot circulation in two patients with great toe defect. RESULTS: Salvage of the great toe was achieved in both patients. FDMA perforator flap achieved both reconstructive goals, and the donor site closure can be successfully performed without tension. Donor site healing was achieved in both patients with no associated complications by the 1-year follow-up. CONCLUSIONS: FDMA flap can be successfully used as a local flap to cover distal foot and toe wounds. However, direct donor site closure can be problematic and may need skin graft. PMID- 29137570 TI - Description and evaluation of a peracetic acid air sampling and analysis method. AB - Peracetic acid (PAA) is a corrosive chemical with a pungent odor, which is extensively used in occupational settings and causes various health hazards in exposed workers. Currently, there is no US government agency recommended method that could be applied universally for the sampling and analysis of PAA. Legacy methods for determining airborne PAA vapor levels frequently suffered from cross reactivity with other chemicals, particularly hydrogen peroxide (H2O2). Therefore, to remove the confounding factor of cross-reactivity, a new viable, sensitive method was developed for assessment of PAA exposure levels, based on the differential reaction kinetics of PAA with methyl p-tolylsulfide (MTS), relative to H2O2, to preferentially derive methyl p-tolysulfoxide (MTSO). By quantifying MTSO concentration produced in the liquid capture solution from an air sampler, using an internal standard, and utilizing the reaction stoichiometry of PAA and MTS, the original airborne concentration of PAA is determined. After refining this liquid trap high-performance liquid chromatography (HPLC) method in the laboratory, it was tested in five workplace settings where PAA products were used. PAA levels ranged from the detection limit of 0.013 parts per million (ppm) to 0.4 ppm. The results indicate a viable and potentially dependable method to assess the concentrations of PAA vapors under occupational exposure scenarios, though only a small number of field measurements were taken while field testing this method. However, the low limit of detection and precision offered by this method makes it a strong candidate for further testing and validation to expand the uses of this liquid trap HPLC method. PMID- 29137569 TI - The neuro-ophthalmological effects related to long-term occupational exposure to organic solvents in painters. AB - PURPOSE: Organic solvents are widely used in many industries, and usually, exposure occurs with mixtures of solvents. Organic solvent mixtures are known for their ability to affect tissues of high lipid content including the myelin sheath in the nervous system. The purpose of this work was to study the evidence that long-term (more than 10 years) exposure to organic solvent mixtures among painters can induce neuro-ophthalmological effects on the function of retinal ganglion cells and the optic tract. METHODS: Twenty workers with long-term occupational exposure to mixed organic solvents were compared to 40 control subjects. The controls were matched for age, gender, and demographic characteristics but were not occupationally exposed to any known organic solvents, using the following comparators: visual evoked potential (VEP), electroretinogram (ERG), color vision (CV), and contrast sensitivity (CS) testing. Environmental monitoring was done in the work environment with consideration to the American Conference of Governmental Industrial Hygienists Threshold Limit Values (ACGIH-TLVs). RESULTS: The exposed group had significantly longer latency and higher amplitude of VEP waves especially P100, higher Color Confusion Index (CCI), especially affecting the blue-yellow spectrum, and lower Log CS. There was no significant difference between exposed and nonexposed groups in full-field flash ERG response; however, in the pattern ERG, the exposed group had significantly longer latency of P50, which reflects changes in the retinal ganglion cell. CONCLUSION: Long-term occupational exposure to mixed organic solvents appeared to affect the optic tract functions in the form of increasing latency of VEP response, affecting the quality of CV and decreasing CS. It also affects the retinal ganglion cell layer with increased latency of P50 of the pattern ERG response. PMID- 29137571 TI - Genotoxic evaluation of common commercial pesticides in human peripheral blood lymphocytes. AB - This study aims to evaluate the genotoxic potential of four commercial pesticides with diverse health categorizations by different world associations currently in use. We tested the fungicide mancozeb and the insecticides pirimicarb, monocrotophos and permethrin. The research was done with in vitro human peripheral blood lymphocytes using the DNA single gel electrophoresis assay and the cytokinesis-block micronucleus (MN) test, where we analysed common parameters such as the tail moment and the frequency of MN formation. We also measured other parameters like frequency of nucleoplasmic bridges, nuclear buds, apoptosis and necrosis with the MN test. Each pesticide induced significant differences in all of these parameters when compared with the negative control and showed different behaviours in the concentration-dependent response. This could be attributed to their genotoxic potential where mancozeb and monocrotophos induced the highest genetic damage, permethrin caused mainly cell death and pirimicarb had the least impact upon cells. This research provides valuable data about the harmful effects of these pesticides on human cells and may be an important contribution in the construction of a unique international classification of health and to reinforce the use of genotoxic analyses to regulate the use of pesticides. PMID- 29137572 TI - Intravenous crystalloids in the late 19th and early 20th century. PMID- 29137573 TI - Can we reduce the prevalence of persistent opioid use after surgery by predicting the future? PMID- 29137574 TI - Understanding the lives of anaesthesia trainees. PMID- 29137575 TI - Effect of hypocaloric normoprotein or trophic feeding versus target full enteral feeding on patient outcomes in critically ill adults: a systematic review. AB - Uncertainty surrounds the optimal approach to feeding the critically ill, with increasing interest in the concept of intentional underfeeding to reduce metabolic stress while maintaining gut integrity. Conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, this systematic review evaluates clinical outcomes reported in studies comparing hypocaloric normonitrogenous or trophic feeding (collectively 'intentional underfeeding') targeted full energy feeding administered via enteral nutrition to adult critically ill patients. Electronic databases including PubMed, CINAHL, EMBASE and CENTRAL were searched up to September 2017 for trials evaluating intentional underfeeding versus targeted energy feeding interventions on clinical outcomes (mortality, length of stay, duration of ventilation, infective complications, feeding intolerance and glycaemic control) among critically ill adult patients. Bias of included studies was assessed using the Cochrane risk of bias tool. Of the 595 articles identified, seven studies (six randomised controlled trials, one non-randomised trial) met the inclusion criteria, representing 2,684 patients (hypocaloric normonitrogenous n=668; trophic n=681; full energy feeding n=1335). Across the studies, there was considerable heterogeneity in study methodology, population, feeding strategy and outcomes and their timepoints. We observed no evidence that intentional underfeeding, when compared to targeting full energy feeding, reduced mortality or duration of ventilation or length of stay. However, limited trial evidence is available on the impact of intentional underfeeding on post-discharge functional and quality of life outcomes. PMID- 29137576 TI - Perioperative assessment of older surgical patients using a frailty index feasibility and association with adverse post-operative outcomes. AB - This study aimed to examine the feasibility of using a frailty index (FI) based on comprehensive geriatric assessment (CGA), to assess the level of frailty in older surgical patients preoperatively and to evaluate the association of FI-CGA with poorer postoperative outcomes. Two hundred and forty-six patients aged >=70 years undergoing intermediate- to high-risk surgery in a tertiary hospital were recruited. Frailty was assessed using a 57-item FI-CGA form, with fit, intermediate frail, and frail patients defined as FI <=0.25, >0.25 to 0.4, and >0.4, respectively. Adverse outcomes were ascertained at 30 days and 12 months post-surgery. Logistic regression models assessed the relationship between FI and adverse outcomes, adjusting for age, gender and acuity of surgery. The mean age of the participants was 79 years (standard deviation [SD] 6.5%), 52% were female, 91% were admitted from the community, 43% underwent acute surgery, and 19% were assessed as frail. The FI-CGA form was reported as being easy to apply, with a low patient refusal rate (2.2%). The majority of items were easy to rate, although inter-rater reliability was not tested. In relation to outcomes, greater frailty was associated with increased 12-month mortality (6.4%, 15.6%, and 23% for fit, intermediate frail, and frail patients respectively, P=0.01) and 12-month hospital readmissions (33.9%, 48.9%, and 60% respectively, P=0.004). There were no statistically significant differences between fit, intermediate frail, and frail groups in perioperative adverse events (17.4%, 23.3%, and 19.1% respectively, P=0.577) or 30-day postoperative complications (35.8%, 47.8%, and 46.8% respectively, P=0.183). Our findings suggest that it is feasible to use the FI-CGA to assess frailty preoperatively, and that using the FI-CGA may identify patients at high risk of adverse long-term outcomes. PMID- 29137577 TI - Postoperative troponin measurement as a screening tool for adverse cardiac events in adult patients undergoing moderate or major non-cardiac surgery. AB - Elevated troponin levels within three days of surgery are strongly linked to major adverse cardiac events (MACE). However, the value of screening with troponin measurements is controversial. The extent to which this is done in routine practice is uncertain. We examined the medical records of all patients >=45 years of age undergoing moderate or major non-cardiac surgery in our tertiary referral hospital over a six-month period. We determined how many patients had a troponin (TnT) measurement recorded in the first three days postoperatively, how many of these were abnormal, and the occurrence of MACE within 30 days. Two thousand and two hundred patients underwent 2,577 operations that met the study criteria. A postoperative TnT was measured after 4.5% of operations. Thirty-eight percent of patients with a recorded TnT measurement, and 44% of those with an abnormal measurement, experienced a MACE within 30 days. The sensitivity of an abnormal TnT to detect MACE was 86%. The specificity was low at 32% with a false positive rate of 56%. Patients with an abnormal TnT result had an increased risk of MACE (23%). The 'number needed to measure' to detect one patient with MACE was 4.4. In our institution, postoperative TnT levels were rarely measured and were used as a diagnostic rather than as a screening tool. The high false positive rate for MACE prediction limits its potential value as a screening tool. The test could be considered useful if it leads to further investigation, and may be best considered as one component of a multivariate approach to cardiac risk evaluation and diagnosis. PMID- 29137578 TI - Predictive value of quick Sepsis-Related Organ Failure Scores following sepsis related Medical Emergency Team calls: a retrospective cohort study. AB - We conducted a cohort study of adult ward patients who had a Medical Emergency Team (MET) call triggered by confirmed or suspected sepsis in an Australian tertiary centre to assess the predictive utility of systemic inflammatory response syndrome (SIRS) and quick Sepsis-Related Organ Failure Assessment (qSOFA) scores for 28-day mortality over a 12-month period. Sepsis was the causative aetiology in 970 MET calls for 646 patients with a mean age of 68 years and median Charlson Comorbidity score (CCS) of 3.0. Four hundred and seven (63%) patients had microbiological identification of a causative organism with 35 (9%) demonstrating multi-drug resistance. The 28-day mortality rate was 22%. Independent risk factors for 28-day mortality included age (incidence rate ratio [IRR] 1.038; P <0.001) and CCS (IRR 1.102; P <0.001). qSOFA positive patients had a three-fold risk of 28 day mortality compared to those who were negative (IRR 3.15; P=0.02). Both the SIRS and qSOFA score had poor sensitivity (86% versus 62%, respectively) for mortality as a sole diagnostic tool and should be investigated as part of a multiparameter panel within a large prospective study. PMID- 29137579 TI - Assessment of the reliability of intubation and ease of use of the Cook Staged Extubation Set-an observational study. AB - The Staged Extubation Set has recently been introduced by Cook Medical for the management of difficult airway patients who potentially require reintubation; however, its reliability for intubation and ease of use is not reported in the literature. The set contains a wire and reintubation catheter with a central lumen for the wire and oxygenation if required. Reintubation is by a two-stage Seldinger-like technique. After induction of general anaesthesia, 23 low-risk elective surgical patients had the Staged Extubation Wire from the Cook set inserted into their trachea under direct laryngoscopy. The intubation was subsequently completed using the rest of the Staged Extubation Set as designed. Difficult intubation was simulated by intentionally decreasing the laryngeal view. Simulated reintubation failed in 8.3% and significant technical difficulty in simulated reintubation was noted in another 17.3% of intubation sequences. The latter represent probable failures in a clinical difficult reintubation setting. The mean time taken to intubate was 109 seconds. Using the Cook Staged Extubation Set may be inferior to using an airway exchange catheter for reintubation. PMID- 29137580 TI - Prevalence and predictors of persistent post-surgical opioid use: a prospective observational cohort study. AB - Post-surgical opioid prescribing intended for the short-term management of acute pain may lead to long-term opioid use. This study was undertaken to determine the prevalence of persistent post-surgical opioid use and patient-related factors associated with post-surgical opioid use. One thousand and thirteen opioid-naive patients awaiting elective surgery in a tertiary private hospital in Sydney were enrolled. Preoperatively, patients completed a questionnaire comprising potential predictors of persistent post-surgical opioid use. Patients underwent surgery with routine perioperative care, and were followed up at 90 to 120 days after surgery to determine opioid use. Factors associated with opioid use were assessed with logistic regression. We had an overall response rate of 95.8% (n=970) of patients, of whom 10.5% (n=102) continued to use opioids at >90 days after surgery. On surgical subtype analysis, the prevalence of persistent opioid use was 23.6% after spinal surgery, and 13.7% after orthopaedic surgery. Four factors were independently associated with persistent post-surgical opioid use in a multivariate model: having orthopaedic (odds ratio [OR] 4.6, 95% confidence interval [CI] 2.0 to 10.8, P <0.001) or spinal surgery (OR 4.0, 95% CI 1.7 to 9.2, P <0.001), anxiety (OR 2.1, 95% CI 1.1 to 4.1, P=0.03), attending pre-admission clinic (OR 3.7, 95% CI 1.6 to 8.6, P=0.002), and higher self-reported pain score at >90 days after surgery (P <0.001). More than 10% of opioid-naive patients undergoing elective surgery experience persistent post-surgical opioid use. Identification of factors associated with persistent post-surgical opioid use may allow development of a risk stratification tool to predict those at highest risk. PMID- 29137581 TI - Evidence of malignant hyperthermia in patients administered triggering agents before malignant hyperthermia susceptibility identified: missed opportunities prior to diagnosis. AB - Malignant hyperthermia (MH) is a hypermetabolic disorder of skeletal muscle triggered almost exclusively by potent inhalational agents and suxamethonium. Signs of an MH reaction are non-specific and may be confused with the presentation of other problems such as sepsis and overheating of a patient. A high index of suspicion is needed to be aware of an early presentation of MH. Nine patients are presented who showed abnormal signs with an earlier anaesthetic where the possible diagnosis of an MH reaction was missed. These patients either presented later with an MH reaction, confirmed by DNA analysis and in some cases in vitro contracture testing, or were diagnosed by the identification of a causative mutation confirming MH susceptibility. The MH clinical grading scale is helpful in determining the likelihood that clinical indicators indicate a possible MH reaction. Masseter muscle rigidity is a known sign of MH, confirmed in this report by positive in vitro contracture testing and DNA analysis. Several uncommon muscle disorders have a high association with MH, and postoperative myalgia unrelated to suxamethonium can be a sign which is associated with MH. These reports emphasise the importance of a thorough family history (as the MH status was known by the family in four patients), a high index of suspicion for MH, and documentation of the possibility of MH susceptibility in the anaesthesia record. PMID- 29137582 TI - The effectiveness of regional anaesthesia before and after the introduction of a dedicated regional anaesthesia service incorporating a block room. AB - Dedicated regional anaesthesia services incorporating block rooms and/or block teams may facilitate theatre efficiency and improve training in regional anaesthesia. Currently, it is unknown if a dedicated regional anaesthesia service improves the effectiveness of regional anaesthesia. In November 2013, the Royal Brisbane and Women's Hospital established a dedicated regional anaesthesia service comprising a block team and a block room. Pre-intervention (conventional model of care) registry data was retrospectively compared with post-intervention (dedicated regional anaesthesia service) audit data, with regard to pain and opioid requirement in the post-anaesthesia care unit (PACU). The primary outcome was inadequate analgesia, defined as a numerical rating scale (NRS; 0, no pain; 10, worst pain imaginable) for pain >5 in the PACU. Pre- and post-intervention, 43.7% and 27.7% of patients respectively reported a NRS >5 (P <0.001). A difference in the type of blocks and surgery performed may have accounted for the improved outcome seen post-intervention. After adjustment for American Society of Anesthesiologists physical status, block type and surgery type, the odds ratio of having inadequate analgesia (NRS >5) was 0.54 (95% confidence interval 0.39 to 0.76) for post-intervention compared to pre-intervention. Secondary outcomes examined pre- and post-intervention were the absence of pain (39.3% and 55.1% of patients, respectively, P <0.001), systemic opioid analgesia requirement (48.6% and 30.5% of patients respectively, P <0.001) and median maximum NRS (4 [interquartile range (IQR) 0 to 8] and 0 [IQR 0 to 6] respectively, P <0.001). A dedicated regional anaesthesia service was associated with improved effectiveness of regional anaesthesia. PMID- 29137583 TI - The effect of intensive care unit admission on smokers' attitudes and their likelihood of quitting smoking. AB - We sought to estimate the proportion of patients admitted to a metropolitan intensive care unit (ICU) who were current smokers, and the relationships between ICU survivors who smoked and smoking cessation and/or reduction six months post ICU discharge. We conducted a prospective cohort study at a metropolitan level III ICU in Melbourne, Victoria. One hundred consecutive patients who met the inclusion criteria were included in the study. Inclusion criteria consisted of patients who were smokers at time of ICU admission, had an ICU length of stay greater than one day, survived to ICU discharge, and provided written informed consent. A purpose-designed questionnaire which included the Fagerstrom test for nicotine dependence and evaluation of patients' attitude towards smoking cessation was completed by participants following ICU discharge and prior to hospital discharge. Participants were re-interviewed over the phone at six months post-ICU discharge. Of the 1,062 patients admitted to ICU, 253 (23%) were current smokers and 100 were enrolled. Six months post-ICU discharge, 28 (33%) of the 86 participants who were alive and contactable had quit smoking and 35 (41%) had reduced smoking. The median number of reported cigarettes smoked per day reduced by 40%. Participants who initially believed their ICU admission was smoking related were more likely to have quit six months post-ICU discharge (odds ratio 2.98; 95% confidence interval 1.07 to 8.26; P=0.036). Six months post-ICU discharge, 63/86 (74%) of participants had quit or reduced their smoking. Further research into targeted smoking cessation counselling for ICU survivors is indicated. PMID- 29137584 TI - Dexmedetomidine-associated hyperthermia: a retrospective cohort study of intensive care unit admissions between 2009 and 2016. AB - Dexmedetomidine-associated hyperthermia has not been previously studied. Analysis is warranted to determine whether this potentially dangerous complication is more prevalent than previously realised. We aimed to examine the association between dexmedetomidine and temperature >=39.5 degrees C, including patient characteristics, temporality and potential risk factors. We conducted a retrospective cohort study of all intensive care unit (ICU) admissions between 1 July 2009 and 31 May 2016 in a tertiary ICU in Australia. Temperature data was available for 9,782 ICU admissions. Dexmedetomidine was given intravenously to 611 (6.3%) patients at a dose of 0 to 1.5 g/kg/hour. Temperatures >=39.5 degrees C were recorded in 341 (3.5%) patients. Overall hospital mortality was 10.8% for all admissions and 29.3% for patients with temperatures >=39.5 degrees C. Dexmedetomidine exposure was more frequent in patients with temperature recordings >=39.5 degrees C compared to those with temperatures <39.5 degrees C, 11.94% versus 2.94% (odds ratio [OR] 4.49; 95% confidence intervals [CI] 3.37, 5.92; P <0.001). The association was stronger for patients post-open heart surgery (OHS) with temperatures >=39.5 degrees C (OR 12.9; 95% CI 5.01, 31.62; P <0.001). Multivariate analysis showed an independent association between dexmedetomidine and a temperature >=39.5 degrees C in two particular patient groups: OHS (OR 2.72; 95% CI 1.1, 6.9; P <0.001), and obesity (OR 3.44; 95% CI 1.5, 7.9; P <0.001). Dexmedetomidine exposure is associated with an increased risk of hyperthermia. Possible risk factors are open heart surgery and obesity. PMID- 29137585 TI - Association of positive fluid balance and mortality in sepsis and septic shock in an Australian cohort. AB - In patients with septic shock, a correlation between positive fluid balance and worsened outcomes has been reported in multiple observational studies worldwide. No published data exists in an Australasian cohort. We set out to explore this association in our institution. We conducted a retrospective audit of patient records from August 2012 to May 2015 in a single-centre, 24-bed surgical and medical intensive care unit (ICU) in Sydney, Australia. All patients with septic shock were included. Exclusion criteria included length of stay less than 24 hours or vasopressors needed for less than six hours. Data was gathered on fluid balance for the first seven days of ICU admission, biochemical data and other clinical indices. The primary outcome measure was survival to hospital discharge. One hundred and eighty-six patients with septic shock were included, with an overall hospital mortality of 23.7%. Seventy-five percent of patients required mechanical ventilation, and 27.4% required haemodialysis. The mean daily fluid balance on the first day of admission was positive 1,424 ml and 1,394 ml for ICU and hospital survivors, respectively. On average, the daily fluid balance for non survivors was higher than the survivors: ICU non-survivors were 602 (95% confidence intervals 230, 974) ml (P=0.0015) and hospital non-survivors were 530 [95% confidence intervals 197, 863] ml (P=0.0017) more than the survivors. In line with other recently published data, after adjustment for confounders (severity of illness based on the Acute Physiology and Chronic Health Evaluation score) we found a correlation between positive fluid balance and worsened hospital mortality in critically ill patients with sepsis and septic shock. Further research investigating rational use of fluids in this patient group is needed. PMID- 29137586 TI - Burnout and the learning environment of anaesthetic trainees. AB - Burnout has a high prevalence among healthcare workers and is increasingly recognised as an environmental problem rather than reflecting a personal inability to cope with work stress. We distributed an electronic survey, which included the Maslach Burnout Inventory Health Services Survey and a previously validated learning environment instrument, to 281 Victorian anaesthetic trainees. The response rate was 50%. We found significantly raised rates of burnout in two of three subscales. Ninety-one respondents (67%) displayed evidence of burnout in at least one domain, with 67 (49%) reporting high emotional exhaustion and 57 (42%) reporting high depersonalisation. The clinical learning environment tool demonstrated a significant negative correlation with burnout (r=-0.56, P <0.001). Burnout was significantly more common than when previously measured in Victoria in 2008 (62% versus 38%). Trainees rated examination preparation the most stressful aspect of the training program. There is a high prevalence of burnout among Victorian anaesthetic trainees. We have shown a significant correlation exists between the clinical learning environment measure and the presence of burnout. This correlation supports the development of interventions to improve the clinical learning environment, as a means to improve trainee wellbeing and address the high prevalence of burnout. PMID- 29137587 TI - A lung model to demonstrate dynamic gas trapping and intrinsic positive end expiratory pressure at realistic ventilation settings. AB - Intrinsic positive end-expiratory pressure (PEEP) and gas trapping are recognised hazards during ventilation of patients with airflow obstruction. Demonstration of these phenomena on conventional lung models using realistic ventilation settings is difficult. We describe an Intrinsic PEEP Model that is able to demonstrate dynamic gas trapping and intrinsic PEEP at realistic ventilation settings, and demonstrate its ability to develop intrinsic PEEP in a timeframe useful for teaching. The model uses a Heimlich valve to permit a lower resistance on inspiration than expiration. The model was tested using a series of typical ventilation settings which, when applied in a clinical setting on patients with airflow obstruction issues, would result in prolonged low expiratory flow and the development of intrinsic PEEP of 10 to 20 cmH2O, and ultimately significant gas trapping. The IPM can be used to demonstrate this effect and the ventilator adjustments required to minimise these problems. PMID- 29137588 TI - Sodium-glucose linked transporter 2 inhibitor-associated perioperative euglycaemic diabetic ketoacidosis: a case for a perioperative guideline. PMID- 29137589 TI - Gastric decompression before laparoscopic entry via Palmer's point. PMID- 29137590 TI - A Closing Chapter: Hepatitis C Genotype 3 Elimination in Liver Transplant; Sofosbuvir/Daclatasvir in a Hard-to-Treat Population. AB - OBJECTIVES: Historically, hepatitis C virus genotype 3 infection has not been as hard to treat as genotype 1 using interferon-based therapy. Now, genotype 3 infection can be treated using interferon-free regimes such as the combination of sofosbuvir and daclatasvir, which is a highly successful and reliable therapeutic option before liver transplant. However, real world data are rather limited regarding the use of antivirals (sofosbuvir/daclatasvir) for hepatitis C virus genotype 3 recurrence after liver transplant. Here, we present the results of antiviral treatment with sofosbuvir and daclatasvir in patients with genotype 3 recurrence after liver transplant and also viewed published data, to finally close the chapter on genotype 3 elimination. MATERIALS AND METHODS: We analyzed 11 patients who received liver transplants due to hepatitis C virus genotype 3 associated cirrhosis at our center. Two patients were nadve for any antiviral therapy. All patients received antiviral treatment with sofosbuvir/daclatasvir for 12 weeks after liver transplant, with 1 patient also having ribavirin. The endpoint was hepatitis C virus RNA-free survival after 12 weeks of therapy. Secondary endpoints were preservation of renal and liver function and incidence of adverse events. RESULTS: All patients were free of hepatitis C virus RNA by at least 8 weeks after therapy initiation. Elevated transaminases and gamma glutamyltransferase at the beginning of therapy normalized quickly during treatment. Synthesis and excretion were stable at all dates. Patients displayed no severe adverse effects, especially regarding renal function and blood counts. Sustained virologic response rates at week 12 were achieved in all 11 patients. CONCLUSIONS: Hepatitis C virus could be eliminated in all patients after liver transplant with 12-week sofosbuvir/daclatasvir therapy. Sofosbuvir combined with daclatasvir is safe and reliable for recurrent hepatitis C virus genotype 3 infection. Our results have closed the chapter on genotype 3 recurrence after liver transplant in our outpatient clinic. PMID- 29137591 TI - Surgical Anatomy and Microvascular Surgical Technique Relevant to Experimental Renal Transplant in Rat Employing Aortic and Inferior Venacaval Conduits. AB - OBJECTIVES: Rat models of renal transplant are used to investigate immunologic processes and responses to therapeutic agents before their translation into routine clinical practice. In this study, we have described details of rat surgical anatomy and our experiences with the microvascular surgical technique relevant to renal transplant by employing donor inferior vena cava and aortic conduits. MATERIALS AND METHODS: For this study, 175 rats (151 Lewis and 24 Fisher) were used to establish the Fisher-Lewis rat model of chronic allograft injury at our institution. Anatomic and technical details were recorded during the period of training and establishment of the model. RESULTS: A final group of 12 transplanted rats were studied for an average duration of 51 weeks for the Lewis-to-Lewis isografts (5 rats) and 42 weeks for the Fisher-to-Lewis allografts (7 rats). Functional measurements and histology confirmed the diagnosis of chronic allograft injury. CONCLUSIONS: Mastering the anatomic details and microvascular surgical techniques can lead to the successful establishment of an experimental renal transplant model. PMID- 29137592 TI - Isolated V-Lesion in an ABO-Incompatible Kidney Transplant Recipient Receiving Rituximab. AB - We report an ABO-incompatible kidney transplant performed on a 69-year-old female patient, whose donor was her 69-year-old husband. The patient received an immunosuppressive protocol using rituximab without splenectomy. Renal biopsy was done on posttransplant day 8 due to poor early graft function, and an isolated v lesion was found, which responded to steroid pulse therapy and gusperimus hydrochloride administration. Our results indicate that isolated v-lesions can occur in ABO-incompatible kidney transplant recipients receiving rituximab and that this finding should be treated as acute rejection. To our knowledge, this is the first report of an isolated v-lesion in an ABO-incompatible kidney transplant recipient who had been administered rituximab. PMID- 29137593 TI - Central Pontine Myelinolysis After Living-Donor Liver Transplant: A Report of 2 Cases. AB - Here, we present 2 patients who developed central pontine myelinolysis after living-donor liver transplant. Both patients had abnormal sodium level before living-donor liver transplant. Patient 1 presented with severe hyponatremia on admission. After administration of 3% saline, her sodium level during the first 24 hours was kept at 100 mEq/L and then increased to 116 mEq/L during the next 24 hours. The level increased 5.8 mEq/L during the 4- to 5-hour transplant procedure. Patient 2 was admitted to the hospital with an unprovoked seizure. The serum sodium concentration was 111 mEq/L, which was treated with 3% saline infusion. Serum sodium concentration escalated to 118 mEq/L over an 8-hour period. Intraoperatively, both patients received large amounts of replacement fluids (0.9% normal saline and albumin), blood transfusion, and sodium bicarbonate during the anhepatic phase, all of which carry high sodium load. Variations in sodium levels changed rapidly in patient 1 during transplant surgery. After they underwent liver transplant, patient 1 had clear mental status and patient 2 demonstrated worsened mental status. On approximately day 14 and day 4 after liver transplant, magnetic resonance imaging showed diffuse abnormalities of the pons, resulting in diagnosis of central pontine myelinolysis. Although both patients survived, 1 remains in a vegetative state and the other continues to present with mild balance and swallowing abnormalities. To reduce the chance of inadvertent overcorrection in patients with hyponatremia, it is therefore important that sodium concentrations should be monitored frequently and fluids and electrolytes titrated carefully. PMID- 29137594 TI - Fractures in Kidney Transplant Recipients: A Comparative Study Between England and New York State. AB - OBJECTIVES: Fractures are associated with high morbidity and are a major concern for kidney transplant recipients. No comparative analysis has yet been conducted between countries in the contemporary era to inform future international prevention trials. MATERIALS AND METHODS: Data were obtained from the Hospital Episode Statistics and the Statewide Planning and Research Cooperative databases on all adult kidney transplants performed in England and New York State from 2003 to 2013, respectively, and on posttransplant fracture-related hospitalization from 2003 to 2014. RESULTS: Our analysis included 18 493 English and 11 602 New York State kidney transplant recipients. Overall, 637 English recipients (3.4%) and 398 New York State recipients (3.4%) sustained a fracture, giving an unadjusted event rate of 7.0 and 5.9 per 1000 years, respectively (P = .948). Of these, 147 English (0.8%) and 101 New York State recipients (0.9%) sustained a hip fracture, giving an unadjusted event rate of 1.6 and 1.5 per 1000 years, respectively (P = .480). There were no differences in the cumulative incidence of all fractures or hip fractures. One-year mortality rates after any fracture (9% and 11%) or after a hip fracture (15% and 17%) were not different between cohorts. CONCLUSIONS: Contemporaneous English and New York State kidney transplant recipients have similar fracture rates and mortality rates postfracture. PMID- 29137595 TI - Study of Bacterial Infections Among Patients Receiving Kidney Transplant in Mashhad, Iran. AB - OBJECTIVES: Over the past 2 decades, significant advances have been made in the management of infections after transplant; however, transplant recipients are still at high risk of infectious complications. This study aimed to evaluate the prevalence of bacterial infections and antimicrobial resistance patterns in kidney transplant recipients. MATERIALS AND METHODS: This cross-sectional study included 356 patients who received kidney transplants, regardless of the underlying disease, from 2013 to 2015 at the Montaserieh Transplant Hospital (Mashhad, Iran). Clinical samples collected from patients were sent to the microbiology laboratory for culture processing. Typing of bacteria was conducted, and susceptibility testing was performed according to the Clinical and Laboratory Standards Institute guideline by use the of disk diffusion agar method. Data were then analyzed by SPSS software (SPSS: An IBM Company, IBM Corporation, Armonk, NY, USA) using chi-square test. RESULTS: Among 356 kidney recipients (206 men and 150 women), 115 (32.3%) received transplants from living donors and 241 (67.7%) received transplants from deceased donors. Of 356 total patients, 112 patients (31.5%) had an infection at various times after transplant. The most common gram negative and gram-positive isolated bacteria were Escherichia coli and coagulase negative Staphylococcus, with prevalence rates of 66.1% and 48.6%. Most of the isolates were resistant against selected antibiotics. CONCLUSIONS: Because of the high prevalence of infection among transplant patients, infection prevention should receive more attention, and antibiotic susceptibility should be determined before treatment. PMID- 29137596 TI - Analysis of breast cancer subtypes by AP-ISA biclustering. AB - BACKGROUND: Gene expression profiling has led to the definition of breast cancer molecular subtypes: Basal-like, HER2-enriched, LuminalA, LuminalB and Normal like. Different subtypes exhibit diverse responses to treatment. In the past years, several traditional clustering algorithms have been applied to analyze gene expression profiling. However, accurate identification of breast cancer subtypes, especially within highly variable LuminalA subtype, remains a challenge. Furthermore, the relationship between DNA methylation and expression level in different breast cancer subtypes is not clear. RESULTS: In this study, a modified ISA biclustering algorithm, termed AP-ISA, was proposed to identify breast cancer subtypes. Comparing with ISA, AP-ISA provides the optimized strategy to select seeds and thresholds in the circumstance that prior knowledge is absent. Experimental results on 574 breast cancer samples were evaluated using clinical ER/PR information, PAM50 subtypes and the results of five peer to peer methods. One remarkable point in the experiment is that, AP-ISA divided the expression profiles of the luminal samples into four distinct classes. Enrichment analysis and methylation analysis showed obvious distinction among the four subgroups. Tumor variability within the Luminal subtype is observed in the experiments, which could contribute to the development of novel directed therapies. CONCLUSIONS: Aiming at breast cancer subtype classification, a novel biclustering algorithm AP-ISA is proposed in this paper. AP-ISA classifies breast cancer into seven subtypes and we argue that there are four subtypes in luminal samples. Comparison with other methods validates the effectiveness of AP-ISA. New genes that would be useful for targeted treatment of breast cancer were also obtained in this study. PMID- 29137597 TI - Reduction of pluripotent gene expression in murine embryonic stem cells exposed to mechanical loading or Cyclo RGD peptide. AB - BACKGROUND: Self-renewal and differentiation of embryonic stem cells (ESCs) is directed by biological and/or physical cues that regulate multiple signaling cascades. We have previously shown that mESCs seeded in a type I collagen matrix demonstrate a loss of pluripotent marker expression and differentiate towards an osteogenic lineage. In this study, we examined if this effect was mediated in part through Arginylglycylaspartic acid (RGD) dependent integrin activity and/or mechano-transduction. RESULTS: The results from this study suggest that mESC interaction with the local microenvironment through RGD dependent integrins play a role in the regulation of mESC core transcription factors (TF), Oct-4, Sox 2 and Nanog. Disruption of this interaction with a cyclic RGD peptide (cRGDfC) was sufficient to mimic the effect of a mechanical stimulus in terms of pluripotent gene expression, specifically, we observed that supplementation with cRGDfC, or mechanical stimulus, significantly influenced mESC pluripotency by down regulating core transcription factors. Moreover, our results indicated that the presence of the cRGDfC peptide inhibited integrin expression and up-regulated early lineage markers (mesoderm and ectoderm) in a Leukemia inhibitory factor (LIF) dependent manner. When cRGDfC treated mESCs were injected in Severe combined immunodeficiency (SCID) mice, no tissue growth and/or teratoma formation was observed, suggesting that the process of mESC tumor formation in vivo is potentially dependent on integrin interaction. CONCLUSIONS: Overall, the disruption of cell-integrin interaction via cRGDfC peptide can mimic the effect of mechanical stimulation on mESC pluripotency gene expression and also inhibit the tumorigenic potential of mESCs in vivo. PMID- 29137598 TI - GFF3sort: a novel tool to sort GFF3 files for tabix indexing. AB - BACKGROUND: The traditional method of visualizing gene annotation data in JBrowse is converting GFF3 files to JSON format, which is time-consuming. The latest version of JBrowse supports rendering sorted GFF3 files indexed by tabix, a novel strategy that is more convenient than the original conversion process. However, current tools available for GFF3 file sorting have some limitations and their sorting results would lead to erroneous rendering in JBrowse. RESULTS: We developed GFF3sort, a script to sort GFF3 files for tabix indexing. Specifically designed for JBrowse rendering, GFF3sort can properly deal with the order of features that have the same chromosome and start position, either by remembering their original orders or by conducting parent-child topology sorting. Based on our test datasets from seven species, GFF3sort produced accurate sorting results with acceptable efficiency compared with currently available tools. CONCLUSIONS: GFF3sort is a novel tool to sort GFF3 files for tabix indexing. We anticipate that GFF3sort will be useful to help with genome annotation data processing and visualization. PMID- 29137599 TI - Neonatal outcomes of deliveries in occiput posterior position when delayed pushing is practiced: a cohort study. AB - BACKGROUND: To examine the impact of occiput posterior position, compared to occiput anterior position, on neonatal outcomes in a setting where delayed pushing is practiced. The specific aim was to estimate the risk of acidaemia. METHODS: Cohort study from a university hospital in Sweden between 2004 and 2012. Information was collected from a local database of 35,546 births. Umbilical artery sampling was routine. Outcomes were: umbilical artery pH < 7.00 and <7.10 and short-term neonatal morbidity. The association between occiput posterior position and neonatal outcomes was examined using logistic regression analysis, presented as adjusted odds ratio (AOR) with 95% confidence interval (CI). RESULTS: Of 27,648 attempted vaginal births, 1292 (4.7%) had occiput posterior position. Compared with occiput anterior, there was no difference in pH < 7.00 (0.4% vs. 0.5%) but a higher rate of pH < 7.10 in occiput posterior births (3.8 vs. 5.5%). Logistic regression analysis showed no increased risk of pH < 7.10 (AOR 1.28 95% CI 0.93-1.74) when occiput posterior was compared with occiput anterior births but, an increased risk of Apgar score < 7 at 5 min (AOR 1.84, 95% CI 1.11-3.05); neonatal care admission (AOR 1.68, 95% CI 1.17-2.42) and composite morbidity (AOR 1.66, 95% CI 1.19-2.31). CONCLUSIONS: With delayed pushing, birth in occiput posterior compared with anterior position is not associated with acidaemia. The higher risk of neonatal morbidity is of concern and any long-term consequences need to be investigated in future studies. PMID- 29137600 TI - Perioperative blood transfusion does not affect recurrence-free and overall survivals after curative resection for intrahepatic cholangiocarcinoma: a propensity score matching analysis. AB - BACKGROUND: Whether perioperative blood transfusions (PBTs) adversely influence oncological outcomes for intrahepatic cholangiocarcinoma (ICC) patients after curative resection remains undetermined. METHODS: Of the 605 patients who underwent curative liver resection for ICC between 2000 and 2012, 93 received PBT. We conducted Cox regression and variable selection logistic regression analyses to identify confounding factors of PBT. Propensity score matching (PSM) and Cox regression analyses were used to compare the overall survival (OS) and disease-free survival (DFS) between the patients with or without PBT. RESULTS: After exclusion, 93 eligible patients (15.4%) received PBT, compared with 512 (84.6%) who did not receive PBT; the groups were highly biased in terms of the propensity score (PS) analysis (0.096 +/- 0.104 vs. 0.479 +/- 0.372, p < 0.001). PBT was associated with an increased risk of OS (HR: 1.889, 95% CI: 1.446-2.468, p < 0.001) and DFS (HR: 1.589, 95% CI: 1.221-2.067, p < 0.001) in the entire cohort. After propensity score matching (PSM), no bias was observed between the groups (PS,0.136 +/- 0.117 VS. 0.193 +/- 0.167, p = 0.785). In the multivariate Cox analysis, PBT was not associated with increased risks of OS (HR: 1.172, 95% CI: 0.756-1.816, p = 0.479) and DFS (HR: 0.944, 95% CI: 0.608-1.466, p = 0.799). After propensity score adjustment, PBT was still not associated with OS or DFS after ICC curative resection. CONCLUSIONS: The present study found that PBT did not affect DFS and OS after curative resection of ICC. PMID- 29137602 TI - Behaviour change interventions to reduce second-hand smoke exposure at home in pregnant women - a systematic review and intervention appraisal. AB - BACKGROUND: Second-hand smoke (SHS) exposure during pregnancy is associated with poor pregnancy and foetal outcomes. Theory-based behaviour change interventions (BCI) have been used successfully to change smoking related behaviours and offer the potential to reduce exposure of SHS in pregnant women. Systematic reviews conducted so far do not evaluate the generalisability and scalability of interventions. The objectives of this review were to (1) report the BCIs for reduction in home exposure to SHS for pregnant women; and (2) critically appraise intervention-reporting, generalisability, feasibility and scalability of the BCIs employed. METHODS: Standard methods following PRISMA guidelines were employed. Eight databases were searched from 2000 to 2015 in English. The studies included used BCIs on pregnant women to reduce their home SHS exposure by targeting husbands/partners. The Workgroup for Intervention Development and Evaluation Research (WIDER) guidelines were used to assess intervention reporting. Generalisability, feasibility and scalability were assessed against criteria described by Bonell and Milat. RESULTS: Of 3479 papers identified, six studies met the inclusion criteria. These studies found that BCIs led to increased knowledge about SHS harms, reduction or husbands quitting smoking, and increased susceptibility and change in level of actions to reduce SHS at home. Two studies reported objective exposure measures, and one reported objective health outcomes. The studies partially followed WIDER guidelines for reporting, and none met all generalisability, feasibility and scalability criteria. CONCLUSIONS: There is a dearth of literature in this area and the quality of studies reviewed was moderate to low. The BCIs appear effective in reducing SHS, however, weak study methodology (self-reported exposure, lack of objective outcome assessment, short follow-up, absence of control group) preclude firm conclusion. Some components of the WIDER checklist were followed for BCI reporting, scalability and feasibility of the studies were not described. More rigorous studies using biochemical and clinical measures for exposures and health outcomes in varied study settings are required. Studies should report interventions in detail using WIDER checklist and assess them for generalisability, feasibility and scalability. TRIAL REGISTRATION: CRD40125026666. PMID- 29137601 TI - Random walks on mutual microRNA-target gene interaction network improve the prediction of disease-associated microRNAs. AB - BACKGROUND: MicroRNAs (miRNAs) have been shown to play an important role in pathological initiation, progression and maintenance. Because identification in the laboratory of disease-related miRNAs is not straightforward, numerous network based methods have been developed to predict novel miRNAs in silico. Homogeneous networks (in which every node is a miRNA) based on the targets shared between miRNAs have been widely used to predict their role in disease phenotypes. Although such homogeneous networks can predict potential disease-associated miRNAs, they do not consider the roles of the target genes of the miRNAs. Here, we introduce a novel method based on a heterogeneous network that not only considers miRNAs but also the corresponding target genes in the network model. RESULTS: Instead of constructing homogeneous miRNA networks, we built heterogeneous miRNA networks consisting of both miRNAs and their target genes, using databases of known miRNA-target gene interactions. In addition, as recent studies demonstrated reciprocal regulatory relations between miRNAs and their target genes, we considered these heterogeneous miRNA networks to be undirected, assuming mutual miRNA-target interactions. Next, we introduced a novel method (RWRMTN) operating on these mutual heterogeneous miRNA networks to rank candidate disease-related miRNAs using a random walk with restart (RWR) based algorithm. Using both known disease-associated miRNAs and their target genes as seed nodes, the method can identify additional miRNAs involved in the disease phenotype. Experiments indicated that RWRMTN outperformed two existing state-of-the-art methods: RWRMDA, a network-based method that also uses a RWR on homogeneous (rather than heterogeneous) miRNA networks, and RLSMDA, a machine learning-based method. Interestingly, we could relate this performance gain to the emergence of "disease modules" in the heterogeneous miRNA networks used as input for the algorithm. Moreover, we could demonstrate that RWRMTN is stable, performing well when using both experimentally validated and predicted miRNA-target gene interaction data for network construction. Finally, using RWRMTN, we identified 76 novel miRNAs associated with 23 disease phenotypes which were present in a recent database of known disease-miRNA associations. CONCLUSIONS: Summarizing, using random walks on mutual miRNA-target networks improves the prediction of novel disease-associated miRNAs because of the existence of "disease modules" in these networks. PMID- 29137603 TI - ClusterTAD: an unsupervised machine learning approach to detecting topologically associated domains of chromosomes from Hi-C data. AB - BACKGROUND: With the development of chromosomal conformation capturing techniques, particularly, the Hi-C technique, the study of the spatial conformation of a genome is becoming an important topic in bioinformatics and computational biology. The Hi-C technique can generate genome-wide chromosomal interaction (contact) data, which can be used to investigate the higher-level organization of chromosomes, such as Topologically Associated Domains (TAD), i.e., locally packed chromosome regions bounded together by intra chromosomal contacts. The identification of the TADs for a genome is useful for studying gene regulation, genomic interaction, and genome function. RESULTS: Here, we formulate the TAD identification problem as an unsupervised machine learning (clustering) problem, and develop a new TAD identification method called ClusterTAD. We introduce a novel method to represent chromosomal contacts as features to be used by the clustering algorithm. Our results show that ClusterTAD can accurately predict the TADs on a simulated Hi-C data. Our method is also largely complementary and consistent with existing methods on the real Hi-C datasets of two mouse cells. The validation with the chromatin immunoprecipitation (ChIP) sequencing (ChIP-Seq) data shows that the domain boundaries identified by ClusterTAD have a high enrichment of CTCF binding sites, promoter-related marks, and enhancer-related histone modifications. CONCLUSIONS: As ClusterTAD is based on a proven clustering approach, it opens a new avenue to apply a large array of clustering methods developed in the machine learning field to the TAD identification problem. The source code, the results, and the TADs generated for the simulated and real Hi-C datasets are available here: https://github.com/BDM Lab/ClusterTAD . PMID- 29137604 TI - Varicella zoster virus-associated morbidity and mortality in Africa - a systematic review. AB - BACKGROUND: Varicella zoster virus (VZV) causes varicella and herpes zoster. These vaccine preventable diseases are common globally. Most available data on VZV epidemiology are from industrialised temperate countries and cannot be used to guide decisions on the immunization policy against VZV in Africa. This systematic review aims to review the published data on VZV morbidity and mortality in Africa. METHODS: All published studies conducted in Africa from 1974 to 2015 were eligible. Eligible studies must have reported any VZV epidemiological measure (incidence, prevalence, hospitalization rate and mortality rate). For inclusion in the review, studies must have used a defined VZV case definition, be it clinical or laboratory-based. RESULTS: Twenty articles from 13 African countries were included in the review. Most included studies were cross-sectional, conducted on hospitalized patients, and half of the studies used varying serological methods for diagnosis. VZV seroprevalence was very high among adults. Limited data on VZV seroprevalence in children showed very low seropositivity to anti-VZV antibodies. Co-morbidity with VZV was common. CONCLUSION: There is lack of quality data that could be used to develop VZV control programmes, including vaccination, in Africa. TRIAL REGISTRATION: PROSPERO 2015: CRD42015026144 . PMID- 29137605 TI - Effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs on the incidence of recurrent colorectal adenomas: a systematic review with meta analysis and trial sequential analysis of randomized clinical trials. AB - BACKGROUND: Beneficial effects of aspirin and non-aspirin nonsteroidal anti inflammatory drugs (NSAIDs) against recurrent colorectal adenomas have been documented in systematic reviews; however, the results have not been conclusive. Uncertainty remains about the appropriate dose of aspirin for adenoma prevention. The persistence of the protective effect of NSAIDs against recurrent adenomas after treatment cessation is yet to be established. METHODS: Our objective was to update and systematically evaluate the evidence for aspirin and other NSAIDs on the incidence of recurrent colorectal adenomas taking into consideration the risks of random error and to appraise the quality of evidence using GRADE (The Grading of Recommendations, Assessment, Development and Evaluation) approach. Retrieved trials were evaluated using Cochrane risk of bias instrument. Meta analytic estimates were calculated with random-effects model and random errors were evaluated with trial sequential analysis (TSA). RESULTS: In patients with a previous history of colorectal cancer or adenomas, low-dose aspirin (80-160 mg/day) compared to placebo taken for 2 to 4 years reduces the risk of recurrent colorectal adenomas (relative risk (RR), 0.80 [95% CI (confidence interval), 0.70 0.92]). TSA indicated a firm evidence for this beneficial effect. The evidence indicated moderate GRADE quality. Low-dose aspirin also reduces the recurrence of advanced adenomas (RR, 0.66 [95% CI, 0.44-0.99]); however, TSA indicated lack of firm evidence for a beneficial effect. High-dose aspirin (300-325 mg/day) did not statistically reduce the recurrent adenomas (RR, 0.90 [95% CI, 0.68-1.18]). Cyclooxygenase-2 (COX-2) inhibitors (e.g. celecoxib 400 mg/day) were associated with a significant decrease in the recurrence of both adenomas (RR, 0.66 [95% CI, 0.59-0.72]) and advanced adenomas (RR, 0.45 [95% CI, 0.33-0.57]); however, this association did not persist and there was a trend of an increased risk of recurrent adenomas observed 2 years after the withdrawal. CONCLUSION: Our findings confirm the beneficial effect of low-dose aspirin on recurrence of any adenomas; however, effect on advanced adenomas was inconclusive. COX-2 inhibitors seem to be more effective in preventing recurrence of adenomas; however, there was a trend of an increased risk of recurrence of adenomas observed after discontinuing regular use. PMID- 29137606 TI - Outbreak of caliciviruses in the Singapore military, 2015. AB - BACKGROUND: From 31 August to 9 September 2015, a total of 150 military personnel at a military institution in Singapore were infected with acute gastroenteritis (AGE) with an attack rate of approximately 3%. This study aimed to determine the epidemiology of the outbreak, investigate its origins, and discuss measures to prevent future occurrences. METHODS: After the AGE outbreak was declared on 31 August 2015, symptom surveys, hygiene inspections, and the testing of water, food, and stool samples were initiated. We collected 86 stool samples from AGE cases and 58 samples from food-handlers during the course of the outbreak and these stool samples were tested for 8 bacterial pathogens and 2 viral pathogens (i.e., norovirus and sapovirus). RESULTS: We detected Sapovirus (SaV), group I Norovirus (NoV GI) and group II Norovirus (NoV GII) from the stool samples of AGE cases. Further sequence analyses showed that the AGE outbreak in August was caused mainly by three rarely reported calicivirus novel genotypes: NoV GI.7, NoV GII.17 and SaV GII.3. Control measures implemented focused on the escalation of personal and environmental hygiene, which included the separation of affected and unaffected soldiers, enforcement of rigorous hand-washing and hygiene, raising awareness of food and water safety, and disinfection of communal areas with bleach. CONCLUSIONS: This study identified both NoV and SaV as the causative agents for an AGE outbreak at a Singapore military camp in August 2015. This study is also the first to report SaV as one of the main causative agents, highlighting the importance of caliciviruses as causative agents of AGE outbreaks in the Singapore military. As there are no commercially available vaccines against caliciviruses, strict personal hygiene and proper disinfection of environmental surfaces remain crucial to prevent calicivirus outbreak and transmission. PMID- 29137607 TI - Improved referral and survival of newborns after scaling up of intensive care in Suriname. AB - BACKGROUND: Scaling up neonatal care facilities in developing countries can improve survival of newborns. Recently, the only tertiary neonatal care facility in Suriname transitioned to a modern environment in which interventions to improve intensive care were performed. This study evaluates impact of this transition on referral pattern and outcomes of newborns. METHODS: A retrospective chart study amongst newborns admitted to the facility was performed and outcomes of newborns between two 9-month periods before and after the transition in March 2015 were compared. RESULTS: After the transition more intensive care was delivered (RR 1.23; 95% CI 1.07-1.42) and more outborn newborns were treated (RR 2.02; 95% CI 1.39-2.95) with similar birth weight in both periods (P=0.16). Mortality of inborn and outborn newborns was reduced (RR 0.62; 95% CI 0.41-0.94), along with mortality of sepsis (RR 0.37; 95% CI 0.17-0.81) and asphyxia (RR 0.21; 95% CI 0.51-0.87). Mortality of newborns with a birth weight <1000 grams (34.8%; RR 0.90; 95% CI 0.43-1.90) and incidence of sepsis (38.8%, 95% CI 33.3-44.6) and necrotizing enterocolitis (NEC) (12.5%, 95% CI 6.2-23.6) remained high after the transition. CONCLUSIONS: After scaling up intensive care at our neonatal care facility more outborn newborns were admitted and survival improved for both in- and outborn newborns. Challenges ahead are sustainability, further improvement of tertiary function, and prevention of NEC and sepsis. PMID- 29137608 TI - The pennycress (Thlaspi arvense L.) nectary: structural and transcriptomic characterization. AB - BACKGROUND: Pennycress [Thlaspi arvense L (Brassicaceae)] is being domesticated as a renewable biodiesel feedstock that also provides crucial ecosystems services, including as a nutritional resource for pollinators. However, its flowers produce significantly less nectar than other crop relatives in the Brassicaceae. This study was undertaken to understand the basic biology of the pennycress nectary as an initial step toward the possibility of enhancing nectar output from its flowers. RESULTS: Pennycress flowers contain four equivalent nectaries located extrastaminally at the base of the insertion sites of short and long stamens. Like other Brassicaceae, the nectaries have open stomates on their surface, which likely serve as the sites of nectar secretion. The nectaries produce four distinct nectar droplets that accumulate in concave structures at the base of each of the four petals. To understand the molecular biology of the pennycress nectary, RNA was isolated from 'immature' (pre-secretory) and 'mature' (secretory) nectaries and subjected to RNA-seq. Approximately 184 M paired-end reads (368 M total reads) were de novo assembled into a total of 16,074 independent contigs, which mapped to 12,335 unique genes in the pennycress genome. Nearly 3700 genes were found to be differentially expressed between immature and mature nectaries and subjected to gene ontology and metabolic pathway analyses. Lastly, in silico analyses identified 158 pennycress orthologs to Arabidopsis genes with known enriched expression in nectaries. These nectary enriched expression patterns were verified for select pennycress loci by semi quantitative RT-PCR. CONCLUSIONS: Pennycress nectaries are unique relative to those of other agriculturally important Brassicaceae, as they contain four equivalent nectaries that present their nectar in specialized cup-shaped structures at the base of the petals. In spite of these morphological differences, the genes underlying the regulation and production of nectar appear to be largely conserved between pennycress and Arabidopsis thaliana. These results provide a starting point for using forward and reverse genetics approaches to enhance nectar synthesis and secretion in pennycress. PMID- 29137609 TI - A comparative content analysis of media reporting of sports betting in Australia: lessons for public health media advocacy approaches. AB - BACKGROUND: Harmful gambling is a significant public health issue. There has been widespread discussion in the Australian media about the extent and impact of sports betting on the Australian community, particularly relating to young men and children. Given the role that the media plays in influencing policy change and political agendas, and the acknowledgement that media based advocacy is a fundamental component of successful advocacy campaigns, this research aimed to investigate how different stakeholder groups discuss sports betting within the Australian print media. The study uses this information to provide recommendations to guide public health media advocacy approaches. METHODS: A quantitative content analysis of print media articles was conducted during two significant Parliamentary Inquiries about sports betting - (1) The Joint Select Committee Inquiry into the Advertising and Promotion of Gambling Services in Sport (2012/2013), and (2) 'The Review of Illegal Offshore Wagering (2015/2016). A total of 241 articles from 12 daily Australian newspapers were analysed. Statistical analysis was used to compare frequency of, and changes in, themes, voices and perspectives over time. RESULTS: Discussions about the marketing and communication of sports betting was a main theme in media reporting (n = 165, 68.5%), while discussions about gambling reform decreased significantly across the two time periods (p < 0.0001). The presence of sports betting industry (p < 0.0001), sporting code (p < 0.0001) and public health expert (p = 0.001) voices all increased significantly across the two time periods. There were very few (n = 11, 4.6%) voices from those who had experienced gambling harm. Finally, while there were significantly fewer articles taking the perspective that regulation changes were needed to protect vulnerable sub-populations (p < 0.0001), articles that had a neutral perspective about the need for regulation change increased significantly across the two time periods (p < 0.0001). DISCUSSION AND CONCLUSIONS: Mapping the media reporting of sports betting is important in developing effective public health advocacy approaches. This study indicates that discussions about the marketing strategies utilised by the sports betting industry was still a main theme in media articles. However, discussions relating to sports betting reforms, in particular to protect individuals who may be vulnerable to the harm associated with these products and their promotional strategies (for example children and young men) decreased during the time periods. Public health advocates may seek to address the decrease in media reports about reform by developing clear evidence-based messages about why regulatory reform is needed, as well as the potential consequences of not implementing reforms. Working with organisations to build capacity for people who have experienced gambling harm may help ensure that individuals with a lived experience of harm have an increased voice in the media. PMID- 29137610 TI - Hemoglobin stimulates the expression of ADAMTS-5 and ADAMTS-9 by synovial cells: a possible cause of articular cartilage damage after intra-articular hemorrhage. AB - BACKGROUND: ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteins play an important pathological role in matrix degeneration. Aggrecan degradation is a significant and critical event in early-stage osteoarthritis. To determine the effect of hemoglobin (Hb) on the ability of synovial tissues to produce ADAMTS family members, we examined the influence of Hb by synovial cells in an in vitro experimental system. METHODS: Synovial tissues were obtained from five young patients with meniscal injury under arthroscopic surgery. Primary cultures of human knee synovial cells were treated with different doses of human Hb (0, 25, 50, 100 MUg/ml). The culture media were collected 24 h after Hb treatment. In the time-course studies, cells were treated with and without 100 MUg/ml Hb, and culture media were taken at 6, 12, and 24 h. To identify the proteins responsible for aggrecanase activity, Western blot analysis using antibodies against human ADAMTS-5, -8, -9, and -10; enzyme-linked immunosorbent assay (ELISA); and gene expression for ADAMTS-5 and -9 were examined. Statistical comparisons between each group were performed using paired t-tests. RESULTS: Western blot analysis revealed that Hb-treatment resulted in the expression of ADAMTS-5 and -9. Neither control group nor Hb-treated medium showed immunoreactivity against ADAMTS-8 or -10. In a dose-dependency study, the Hb treated group showed significantly higher levels of ADAMTS-5 and -9 compared with the control (p < 0.05). There was no significant difference between 25, 50, and 100 MUg/ml Hb-treated groups. In a time-course study, the ADAMTS-5 and -9 levels in the conditioned medium had significantly increased expression at 6, 12, and 24 h in the Hb-treated group (p < 0.05). Hb evoked significant expression of ADAMTS 9 mRNA at 12 and 24 h (p < 0.05). CONCLUSIONS: These findings indicate that Hb induces the expression of ADAMTS-5 and -9 by synovial cells at low doses, even at an acute phase, and suggests a possible role for Hb in cartilage damage after intra-articular hemorrhage. The results also suggest a new potential therapeutic target by inhibiting the activities of ADAMTS-5 and -9 to prevent cartilage damage after intra-articular hemorrhage. PMID- 29137612 TI - Comparison of semi-quantitative and quantitative dynamic contrast-enhanced MRI evaluations of vertebral marrow perfusion in a rat osteoporosis model. AB - BACKGROUND: This study aims to investigate the technical feasibility of semi quantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the assessment of longitudinal changes of marrow perfusion in a rat osteoporosis model, using bone mineral density (BMD) measured by micro computed tomography (micro-CT) and histopathology as the gold standards. METHODS: Fifty rats were randomly assigned to the control group (n=25) and ovariectomy (OVX) group whose bilateral ovaries were excised (n=25). Semi-quantitative and quantitative DCE-MRI, micro-CT, and histopathological examinations were performed on lumbar vertebrae at baseline and 3, 6, 9, and 12 weeks after operation. The differences between the two groups in terms of semi-quantitative DCE-MRI parameter (maximum enhancement, Emax), quantitative DCE-MRI parameters (volume transfer constant, Ktrans; interstitial volume, Ve; and efflux rate constant, Kep), micro-CT parameter (BMD), and histopathological parameter (microvessel density, MVD) were compared at each of the time points using an independent sample t test. The differences in these parameters between baseline and other time points in each group were assessed via Bonferroni's multiple comparison test. A Pearson correlation analysis was applied to assess the relationships between DCE-MRI, micro-CT, and histopathological parameters. RESULTS: In the OVX group, the Emax values decreased significantly compared with those of the control group at weeks 6 and 9 (p=0.003 and 0.004, respectively). The Ktrans values decreased significantly compared with those of the control group from week 3 (p<0.05). However, the Ve values decreased significantly only at week 9 (p=0.032), and no difference in the Kep was found between two groups. The BMD values of the OVX group decreased significantly compared with those of the control group from week 3 (p<0.05). Transmission electron microscopy showed tighter gaps between vascular endothelial cells with swollen mitochondria in the OVX group from week 3. The MVD values of the OVX group decreased significantly compared with those of the control group only at week 12 (p=0.023). A weak positive correlation of Emax and a strong positive correlation of Ktrans with MVD were found. CONCLUSIONS: Compared with semi-quantitative DCE-MRI, the quantitative DCE-MRI parameter Ktrans is a more sensitive and accurate index for detecting early reduced perfusion in osteoporotic bone. PMID- 29137613 TI - Preoperative T staging using CT colonography with multiplanar reconstruction for very low rectal cancer. AB - BACKGROUND: Preoperative T staging of lower rectal cancer is an important criterion for selecting intersphincteric resection (ISR) or abdominoperineal resection (APR) as well as selecting neoadjuvant therapy. The aim of this study was to evaluate the accuracy of preoperative T staging using CT colonography (CTC) with multiplanar reconstruction (MPR), in which with the newest workstation the images can be analyzed with a slice thickness of 0.5 mm. METHODS: Between 2011 and 2013, 45 consecutive patients with very low rectal adenocarcinoma underwent CTC with MPR. The accuracy of preoperative T staging using CTC with MPR was evaluated. The accuracy of preoperative T staging using MRI in the same patient population (34 of 45 patients) was also examined. RESULTS: Overall accuracy of T staging was 89% (41/45) for CTC with MPR and 71% (24/34) for MRI. CTC with MPR was particularly sensitive for pT2 tumors (82%; 14/17), whereas MRI tended to overstage pT2 tumors and its sensitivity for pT2 was 53% (8/15). CONCLUSIONS: CTC with MPR, with an arbitrary selection, could be aligned to the tumor axis and better demonstrated tumor margins consecutively including the deepest section of the tumor. The accuracy of T2 and T3 staging using CTC with MPR seemed to surpass that of MRI, suggesting a potential role of CTC with MPR in preoperative T staging for very low rectal cancer. PMID- 29137611 TI - Diagnostic validity and triage concordance of a physiotherapist compared to physicians' diagnoses for common knee disorders. AB - BACKGROUND: Emergence of more autonomous roles for physiotherapists warrants more evidence regarding their diagnostic capabilities. Therefore, we aimed to evaluate diagnostic and surgical triage concordance between a physiotherapist and expert physicians and to assess the diagnostic validity of the physiotherapist's musculoskeletal examination (ME) without imaging. METHODS: This is a prospective diagnostic study where 179 consecutive participants consulting for any knee complaint were independently diagnosed and triaged by two evaluators: a physiotherapist and one expert physician (orthopaedic surgeons or sport medicine physicians). The physiotherapist completed only a ME, while the physicians also had access to imaging to make their diagnosis. Raw agreement proportions and Cohen's kappa (k) were calculated to assess inter-rater agreement. Sensitivity (Se) and specificity (Sp), as well as positive and negative likelihood ratios (LR+/-) were calculated to assess the validity of the ME compared to the physicians' composite diagnosis. RESULTS: Primary knee diagnoses included anterior cruciate ligament injury (n = 8), meniscal injury (n = 36), patellofemoral pain (n = 45) and osteoarthritis (n = 79). Diagnostic inter-rater agreement between the physiotherapist and physicians was high (k = 0.89; 95% CI:0.83-0.94). Inter-rater agreement for triage recommendations of surgical candidates was good (k = 0.73; 95% CI:0.60-0.86). Se and Sp of the physiotherapist's ME ranged from 82.0 to 100.0% and 96.0 to 100.0% respectively and LR+/- ranged from 23.2 to 30.5 and from 0.03 to 0.09 respectively. CONCLUSIONS: There was high diagnostic agreement and good triage concordance between the physiotherapist and physicians. The ME without imaging may be sufficient to diagnose or exclude common knee disorders for a large proportion of patients. Replication in a larger study will be required as well as further assessment of innovative multidisciplinary care trajectories to improve care of patients with common musculoskeletal disorders. PMID- 29137615 TI - Advance directives, proxy opinions, and treatment restrictions in patients with severe stroke. AB - BACKGROUND: Patients with severe stroke often do not have the capacity to participate in discussions on treatment restrictions because of a reduced level of consciousness, aphasia, or another cognitive disorder. We assessed the role of advance directives and proxy opinions in the decision-making process of incapacitated patients. METHODS: Sixty patients with severe functional dependence (Barthel Index <=6) at day four after ischemic stroke or intracerebral hemorrhage were included in a prospective two-center cohort study. The decision-making process with respect to treatment restrictions was assessed by means of a semi structured questionnaire administered to the treating physician at the day of inclusion. RESULTS: Forty-nine patients (82%) did not have the capacity to participate in the decision-making process. In eight patients, there was no discussion on treatment restrictions and full care was installed. In 41 patients, the decision whether to install treatment restrictions was discussed with proxies. One patient had a written advance directive. In the remaining 40 patients, proxies based their opinion on previously expressed wishes of the patient (18 patients) or advised in the best interest of the patient (22 patients). In 36 of 41 patients, treatment restrictions were installed after agreement between physician and proxy. At six months, 23 of 49 patients had survived. In only three of them the decision on treatment restrictions was based on previously expressed wishes. Remarkably, two of these survivors could not recall any of their alleged previously expressed wishes. CONCLUSIONS: Treatment restrictions were installed in the majority of incapacitated patients after stroke. Proxy opinions frequently served as the best way to respect the patients' autonomy, but their accuracy remains unclear. PMID- 29137614 TI - Safety classification of herbal medicines used among pregnant women in Asian countries: a systematic review. AB - BACKGROUND: High prevalence of herbal medicines used in pregnancy and the lack of information on their safety is a public concern. Despite this, no significant research has been done regarding potential adverse effects of using herbal medicines during pregnancy, especially among developing Asian countries. METHODS: Cross-sectional studies were searched up to year 2016 on PubMed/Medline and EMBASE, the data were extracted and quality of studies was assessed using the quality appraisal tool. The findings are reported in accordance to the PRISMA checklist (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Classification on safety of identified herbal medicines was done based on current scientific literature. RESULTS: This study included eight cross-sectional studies (2729 participants) from seven different Asian countries, of which 1283 (47.01%) women used one or more herbal medicines during pregnancy. Peppermint (22.8%), aniseed (14.7%), olibanum (12.9%), flixweed seed (12.2%) and ginger (11.5%) were the most frequently used herbal medicines. Out of the 33 identified herbal medicines, 13 were classified as safe to use, five as use with caution, eight were potentially harmful to use in pregnancy and information on seven herbal medicines was not available in the current literature. CONCLUSIONS: Several herbal medicines identified in this review were classified to be potentially harmful or the information regarding safety in pregnancy was missing. It is recommended that contraindicated herbal medicines should be avoided and other herbals should be taken under supervision of a qualified health care practitioner. The classification regarding safety of herbal medicines in pregnancy can be utilized to create awareness on prevention of adverse effects. PMID- 29137616 TI - Foraging dispersion of Ryukyu flying-foxes and relationships with fig abundance in East-Asian subtropical island forests. AB - BACKGROUND: Figs are widely distributed key resources to many tropical subtropical animals, and flying-foxes are major consumers and seed dispersers of figs. Bat-fig interrelationships, however, may vary among species differing in fruiting traits, i.e., bat- versus bird-dispersed figs. We examined Ryukyu flying fox foraging dispersion and the relationships with tree species composition and fig abundance in forests of Iriomote Island. RESULTS: Bat foraging dispersion showed no spatial patterns with respect to different areas of the island, and was not explained by heterogeneity, density, or basal area (BA) of total trees, nor by relative density or BA of fruiting trees or total fruiting figs among sites. Instead, bat densities were positively dependent on the relative density of total figs, and particularly the relative BA of bat-dispersed figs Ficus septica and F. variegata. Both species were dominant figs in forests, fruiting asynchronously with long crop seasons, and were used as predominant foods. Bats foraged mostly solitarily and the mean density was in a hump-shaped relationship with crop sizes of the dominant bat-figs. These two species and Ficus benguetensis are larger sized bat-figs, all contained more seeds, higher dry-pulp mass and water mass, but not necessarily water content. By approximate estimation, higher proportions of seeds of these bat-figs would have been removed from fruits through the bat consumption, than that of small-sized bird-figs like F. virgata, F. superba, and F. microcarpa. CONCLUSIONS: The foraging dispersion of Ryukyu flying-foxes in forests depends on the availability of the most abundant bat-figs that serve as predominant foods. Intermediate levels of crop sizes of theses figs appear most fit with their solitary foraging. Our results suggest that as density and BA coverage of these dominant bat-figs are below a certain level, their effectiveness to attract bats may dwindle and so would their chance of dispersal by bats. PMID- 29137617 TI - Surgical treatment for diffused-type giant cell tumor (pigmented villonodular synovitis) about the ankle joint. AB - BACKGROUND: Diffused-type giant cell tumor(Dt-GCT) is a rare, aggressive disorder of the joint synovium, bursa and tendon sheaths. Osseous erosions and subchondral cysts may develop as the result of synovium infiltration in Dt-GCT. We present a retrospective study of a series of patients who are diagnosed with Dt-GCT about the ankle joint, there clinical outcome is evaluated in this study. MATERIAL AND METHOD: Fifteen patients with radiologically and histologically confirmed Dt-GCT about the ankle joint were identified in our foot and ankle department. Patients were managed with open synovectomy for the tumor tissue and bone grafting for bony erosions. X-rays and MRI scans were used for evaluation of the tumor and bony erosions pre- and post-operatively. Pre- and post-operative ankle function was assessed using the American Orthopedic Foot and Ankle Society -Ankle and Hindfoot (AOFAS-AH) score and the Muscularskeletal Tumor Society (MSTS) score. RESULTS: The mean follow-up duration was 37.4 months (range 25 to 50 months). There were 6 males and 9 females, with a mean age of 35 years old (range 18 to 65 years). All patients had talar erosion with the average size of 10.1*9.1*8.2 mm, distal tibia was affected in 5 patients with the average size of 6.2*5.6*5.8 mm. 7 patients had tendon involvement, 2 patients had recurrence and progression of ankle osteoarthritis. Both of them underwent ankle fusion. At the time of last follow-up, the mean AOFAS-AH score increased from 49 to 80 points (p < 0.05), the MSTS score increased from 12 to 22 points (p < 0.05). CONCLUSION: For Dt-GCT with bony erosions, open synovectomy combined with bone grafting seems to be a safe and effective operation for the salvage of ankle joint. Fusion is recommended for failed and severe cartilage destruction of the ankle joint. PMID- 29137618 TI - AFEAP cloning: a precise and efficient method for large DNA sequence assembly. AB - BACKGROUND: Recent development of DNA assembly technologies has spurred myriad advances in synthetic biology, but new tools are always required for complicated scenarios. Here, we have developed an alternative DNA assembly method named AFEAP cloning (Assembly of Fragment Ends After PCR), which allows scarless, modular, and reliable construction of biological pathways and circuits from basic genetic parts. METHODS: The AFEAP method requires two-round of PCRs followed by ligation of the sticky ends of DNA fragments. The first PCR yields linear DNA fragments and is followed by a second asymmetric (one primer) PCR and subsequent annealing that inserts overlapping overhangs at both sides of each DNA fragment. The overlapping overhangs of the neighboring DNA fragments annealed and the nick was sealed by T4 DNA ligase, followed by bacterial transformation to yield the desired plasmids. RESULTS: We characterized the capability and limitations of new developed AFEAP cloning and demonstrated its application to assemble DNA with varying scenarios. Under the optimized conditions, AFEAP cloning allows assembly of an 8 kb plasmid from 1-13 fragments with high accuracy (between 80 and 100%), and 8.0, 11.6, 19.6, 28, and 35.6 kb plasmids from five fragments at 91.67, 91.67, 88.33, 86.33, and 81.67% fidelity, respectively. AFEAP cloning also is capable to construct bacterial artificial chromosome (BAC, 200 kb) with a fidelity of 46.7%. CONCLUSIONS: AFEAP cloning provides a powerful, efficient, seamless, and sequence-independent DNA assembly tool for multiple fragments up to 13 and large DNA up to 200 kb that expands synthetic biologist's toolbox. PMID- 29137619 TI - Percutaneous medial hemi-epiphysiodesis using a transphyseal screw for caput valgum associated with developmental dysplasia of the hip. AB - BACKGROUND: The purpose of this study was to evaluate the radiologic outcome of percutaneous medial hemi-epiphysiodesis using a transphyseal screw for the management of caput valgum associated with developmental dysplasia of the hip (DDH). METHODS: Eighteen hips (18 patients) having caput valgum treated with screw hemi-epiphysiodesis were followed for more than 2 years, and were included in this study. The mean age at the time of the index operation was 8.3 years (range, 4.3 to 10.7 years) and age at the latest follow-up was 12.2 years (range, 9.4 to 16.4 years). The screw in 5 hips was changed into a longer one at postoperative 21.8 months (range, 14 to 29 months) because the proximal femur outgrew the screw. The screws in 11 hips were removed at the mean age of 10.9 years (range, 8.0 to 14.5 years). We retrospectively analyzed the change in various radiologic parameters over time. RESULTS: The mean Hilgenreiner epiphyseal angle (HEA) of the operated side was 5.1 +/- 11.3 degrees preoperatively, and increased to 20.6 +/- 11.3 degrees at the latest follow-up (p = 0.001). The mean difference of the HEA between the operated and contralateral sides was 16.9 +/- 15.1 degrees preoperatively, which decreased to 2.4 +/- 12.4 degrees at the latest follow-up (p = 0.008). The mean articulo trochanteric distance of the operated side, which was 3.2 +/- 5.5 mm longer than that of the contralateral side preoperatively, became 5.6 +/- 9.1 mm shorter at the latest follow-up (p = 0.001). The ratio of femoral neck length of the operated side to that of the contralateral side decreased over the follow-up period. Acetabular shape as measured by the Sharp angle and acetabular roof angle and femoral head coverage as measured by lateral center-edge angle did not change significantly by the index operation. The ratio of medial joint space width of the operated side to that of the contralateral side did not change significantly. CONCLUSIONS: Screw medial hemi-epiphysiodesis can effectively correct caput valgum associated with DDH. However, this technique remains coxa brevis and does not seem to significantly affect acetabular morphology or reduce subluxation. PMID- 29137620 TI - Isocitrate dehydrogenase mutation in Vibrio anguillarum results in virulence attenuation and immunoprotection in rainbow trout (Oncorhynchus mykiss). AB - BACKGROUND: Vibrio anguillarum is an extracellular bacterial pathogen that is a causative agent of vibriosis in finfish and crustaceans with mortality rates ranging from 30% to 100%. Mutations in central metabolism (glycolysis and the TCA cycle) of intracellular pathogens often result in attenuated virulence due to depletion of required metabolic intermediates; however, it was not known whether mutations in central metabolism would affect virulence in an extracellular pathogen such as V. anguillarum. RESULTS: Seven central metabolism mutants were created and characterized with regard to growth in minimal and complex media, expression of virulence genes, and virulence in juvenile rainbow trout (Oncorhynchus mykiss). Only the isocitrate dehydrogenase (icd) mutant was attenuated in virulence against rainbow trout challenged by either intraperitoneal injection or immersion. Further, the icd mutant was shown to be immunoprotective against wild type V. anguillarum infection. There was no significant decrease in the expression of the three hemolysin genes detected by qRT-PCR. Additionally, only the icd mutant exhibited a significantly decreased growth yield in complex media. Growth yield was directly related to the abundance of glutamate. A strain with a restored wild type icd gene was created and shown to restore growth to a wild type cell density in complex media and pathogenicity in rainbow trout. CONCLUSIONS: The data strongly suggest that a decreased growth yield, resulting from the inability to synthesize alpha-ketoglutarate, caused the attenuation despite normal levels of expression of virulence genes. Therefore, the ability of an extracellular pathogen to cause disease is dependent upon the availability of host-supplied nutrients for growth. Additionally, a live vaccine strain could be created from an icd deletion strain. PMID- 29137621 TI - COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA. AB - BACKGROUND: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance. CASE PRESENTATION: Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein. CONCLUSIONS: This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome. PMID- 29137622 TI - Genome-wide scan for runs of homozygosity identifies potential candidate genes associated with local adaptation in Valle del Belice sheep. AB - BACKGROUND: Because very large numbers of single nucleotide polymorphisms (SNPs) are now available throughout the genome, they are particularly suitable for the detection of genomic regions where a reduction in heterozygosity has occurred and they offer new opportunities to improve the accuracy of inbreeding ([Formula: see text]) estimates. Runs of homozygosity (ROH) are contiguous lengths of homozygous segments of the genome where the two haplotypes inherited from the parents are identical. Here, we investigated the occurrence and distribution of ROH using a medium-dense SNP panel to characterize autozygosity in 516 Valle del Belice sheep and to identify the genomic regions with high ROH frequencies. RESULTS: We identified 11,629 ROH and all individuals displayed at least one ROH longer than 1 Mb. The mean value of [Formula: see text] estimated from ROH longer than1 Mb was 0.084 +/- 0.061. ROH that were shorter than 10 Mb predominated. The highest and lowest coverages of Ovis aries chromosomes (OAR) by ROH were on OAR24 and OAR1, respectively. The number of ROH per chromosome length displayed a specific pattern, with higher values for the first three chromosomes. Both number of ROH and length of the genome covered by ROH varied considerably between animals. Two hundred and thirty-nine SNPs were considered as candidate markers that may be under directional selection and we identified 107 potential candidate genes. Six genomic regions located on six chromosomes, corresponding to ROH islands, are presented as hotspots of autozygosity, which frequently coincided with regions of medium recombination rate. According to the KEGG database, most of these genes were involved in multiple signaling and signal transduction pathways in a wide variety of cellular and biochemical processes. A genome scan revealed the presence of ROH islands in genomic regions that harbor candidate genes for selection in response to environmental stress and which underlie local adaptation. CONCLUSIONS: These results suggest that natural selection has, at least partially, a role in shaping the genome of Valle del Belice sheep and that ROH in the ovine genome may help to detect genomic regions involved in the determinism of traits under selection. PMID- 29137623 TI - Analysis of factors influencing molecular testing at diagnostic of colorectal cancer. AB - BACKGROUND: The aim of the study was to evaluate the current rate of molecular testing prescription (KRAS codons 12/13, BRAF and microsatellite instability (MSI)) in newly diagnosed colorectal cancer (CRC) patients and to determine which factors influence testing. METHODS: All incident CRC cases in 2010 were identified in the Poitou-Charentes General Cancer Registry. The exhaustive molecular testing performed was accessed in the French molecular genetics platform. Factors influencing prescription were analyzed using logistic regression. RESULTS: Among the 1269 CRCs included in the study, KRAS, BRAF and MSI testing accounted for 35.1%, 10.5% and 10.9%, respectively. KRAS testing was carried out in 65.5% of metastatic CRCs, and 26.1% of non-metastatic CRCs. Among metastatic CRCs, age (<60 years), site of primary tumour (left colon) and geographical area of treatment were factors related to KRAS testing. BRAF testing was contemporary to KRAS testing for 92.5% of patients. Factors related to MSI testing were age (<60 years), TNM stage (stage IV) and geographical area of treatment. Among CRC patients under 60 years old, only 37.5% had MSI testing. CONCLUSION: These results underscore the need to reduce disparities in CRC molecular testing and highlight the limited application of the French guidelines, especially concerning MSI testing. PMID- 29137624 TI - Compression-rate-dependent nonlinear mechanics of normal and impaired porcine knee joints. AB - BACKGROUND: The knee joint performs mechanical functions with various loading and unloading processes. Past studies have focused on the kinematics and elastic response of the joint with less understanding of the rate-dependent load response associated with viscoelastic and poromechanical behaviors. METHODS: Forty-five fresh porcine knee joints were used in the present study to determine the loading rate-dependent force-compression relationship, creep and relaxation of normal, dehydrated and meniscectomized joints. RESULTS: The mechanical tests of all normal intact joints showed similar strong compression-rate-dependent behavior: for a given compression-magnitude up to 1.2 mm, the reaction force varied 6 times over compression rates. While the static response was essentially linear, the nonlinear behavior was boosted with the increased compression rate to approach the asymptote or limit at approximately 2 mm/s. On the other hand, the joint stiffness varied approximately 3 times over different joints, when accounting for the maturity and breed of the animals. Both a loss of joint hydration and a total meniscectomy greatly compromised the load support in the joint, resulting in a reduction of load support as much as 60% from the corresponding intact joint. However, the former only weakened the transient load support, but the latter also greatly weakened the equilibrium load support. A total meniscectomy did not diminish the compression-rate-dependence of the joint though. CONCLUSIONS: These findings are consistent with the fluid-pressurization loading mechanism, which may have a significant implication in the joint mechanical function and cartilage mechanobiology. PMID- 29137625 TI - Variations in sagittal locations of anterior cruciate ligament tibial footprints and their association with radiographic landmarks: a human cadaveric study. AB - BACKGROUND: This cadaveric study aimed to demonstrate variation of the anterior cruciate ligament (ACL) tibial attachment in the sagittal plane, and to analyze the radiographic landmarks which predict the sagittal location of the ACL tibial attachment. METHODS: In 20 cadaveric knees, native ACLs were removed and the centers of the ACL tibial and femoral attachments were marked with metal pins. Full extension lateral radiographs were then obtained in each cadaveric knee. Using the full extension lateral radiographs, the sagittal location of the ACL tibial footprint center was estimated as a percentage in the Amis and Jakob's line. Several radiographic landmarks including the geometry of Blumensaat's line and the apex of the tibial eminence were measured. Then, the relationship between the variation of the sagittal location of the ACL tibial footprint and several radiographic landmarks were analyzed using Pearson's correlation analysis. RESULTS: The average sagittal position of the native ACL tibial footprint was 40.9% (range: 38.0-45.0%). The line connecting the centers of the ACL footprint was nearly parallel to Blumensaat's line, with an average angle of 1.7 degrees (range: 0-4.1 degrees ). In addition, the distance from the point where Blumensaat's line meets the tibial articular surface to the center of the ACL tibial footprint was almost consistent, at 7.6 mm on average (range: 6.4-8.7 mm). The correlation analysis revealed that the geometry of Blumensaat's line was significantly correlated with the sagittal location of the ACL tibial footprint. CONCLUSION: The radiographic landmark that showed a significant correlation with the ACL tibial footprint in the full extension lateral radiographs was Blumensaat's line. PMID- 29137626 TI - Treatment outcomes of MDR-tuberculosis patients in Brazil: a retrospective cohort analysis. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a threat for the global TB epidemic control. Despite existing evidence that individualized treatment of MDR-TB is superior to standardized regimens, the latter are recommended in Brazil, mainly because drug-susceptibility tests (DST) are often restricted to first-line drugs in public laboratories. We compared treatment outcomes of MDR-TB patients using standardized versus individualized regimens in Brazil, a high TB burden, low resistance setting. METHODS: The 2007-2013 cohort of the national electronic database (SITE-TB), which records all special treatments including drug-resistance, was analysed. Patients classified as MDR-TB in SITE-TB were eligible. Treatment outcomes were classified as successful (cure/treatment completed) or unsuccessful (failure/relapse/death/loss to follow-up). The odds for successful treatment according to type of regimen were controlled for demographic and clinical variables. RESULTS: Out of 4029 registered patients, we included 1972 recorded from 2010 to 2012, who had more complete outcome data. The overall success proportion was 60%. Success was more likely in non-HIV patients, sputum-negative at baseline, with unilateral disease and without prior DR-TB. Adjusted for these variables, those receiving standardized regimens had 2.7-fold odds of success compared to those receiving individualized treatments when failure/relapse were considered, and 1.4-fold odds of success when death was included as an unsuccessful outcome. When loss to follow-up was added, no difference between types of treatment was observed. Patients who used levofloxacin instead of ofloxacin had 1.5-fold odds of success. CONCLUSION: In this large cohort of MDR-TB patients with a low proportion of successful outcomes, standardized regimens had superior efficacy than individualized regimens, when adjusted for relevant variables. In addition to the limitations of any retrospective observational study, database quality hampered the analyses. Also, decision on the use of standard or individualized regimens was possibly not random, and may have introduced bias. Efforts were made to reduce classification bias and confounding. Until higher-quality evidence is produced, and DST becomes widely available in the country, our findings support the Brazilian recommendation for the use of standardized instead of individualized regimens for MDR-TB, preferably containing levofloxacin. Better quality surveillance data and DST availability across the country are necessary to improve MDR-TB control in Brazil. PMID- 29137627 TI - Prevalence of current patterns and predictive trends of multidrug-resistant Salmonella Typhi in Sudan. AB - BACKGROUND: Enteric fever has persistence of great impact in Sudanese public health especially during rainy season when the causative agent Salmonella enterica serovar Typhi possesses pan endemic patterns in most regions of Sudan - Khartoum. OBJECTIVES: The present study aims to assess the recent state of antibiotics susceptibility of Salmonella Typhi with special concern to multidrug resistance strains and predict the emergence of new resistant patterns and outbreaks. METHODS: Salmonella Typhi strains were isolated and identified according to the guidelines of the International Standardization Organization and the World Health Organization. The antibiotics susceptibilities were tested using the recommendations of the Clinical Laboratories Standards Institute. Predictions of emerging resistant bacteria patterns and outbreaks in Sudan were done using logistic regression, forecasting linear equations and in silico simulations models. RESULTS: A total of 124 antibiotics resistant Salmonella Typhi strains categorized in 12 average groups were isolated, different patterns of resistance statistically calculated by (y = ax - b). Minimum bactericidal concentration's predication of resistance was given the exponential trend (y = n ex) and the predictive coefficient R2 > 0 < 1 are approximately alike. It was assumed that resistant bacteria occurred with a constant rate of antibiotic doses during the whole experimental period. Thus, the number of sensitive bacteria decreases at the same rate as resistant occur following term to the modified predictive model which solved computationally. CONCLUSION: This study assesses the prediction of multi-drug resistance among S. Typhi isolates by applying low cost materials and simple statistical methods suitable for the most frequently used antibiotics as typhoid empirical therapy. Therefore, bacterial surveillance systems should be implemented to present data on the aetiology and current antimicrobial drug resistance patterns of community-acquired agents causing outbreaks. PMID- 29137628 TI - Hypertonic saline for prevention of delirium in geriatric patients who underwent hip surgery. AB - BACKGROUND: Postoperative delirium (POD) is a common disorder in the elderly patients, and neuroinflammation is the possible underlying mechanism. This study is designed to determine whether or not hypertonic saline (HS) pre-injection can alleviate POD in aged patients. METHODS: This prospective study recruited 120 geriatric patients who underwent hip surgery. The patients were randomly divided into two groups: control group (NS group) and HS group. Patients in the NS group were pre-injected with 4 mL/kg isotonic saline, and those in the HS group were pre-injected with 4 mL/kg 7.5% HS. All 120 patients were then subjected to general anesthesia. Blood samples were extracted to detect the concentration of inflammatory factors, namely, IL-1beta, IL-6, IL-10, and TNF-alpha, and the nerve injury factor S100beta. Flow cytometry was used to detect the number of monocytes in peripheral venous blood and evaluate the relationship of inflammation to delirium. The nursing delirium screening scale (Nu-DESC) was used to determine cognitive function 1 to 3 days postoperatively. RESULTS: Analysis using random effect multivariable logistic regression indicated that HS administration before anesthesia was associated with a low risk of POD (odds ratio [OR], 0.13; 95% CI, 0.04 to 0.41; P = 0.001) and few CD14 + CD16+ monocytes (beta = - 0.61; 95% CI, - 0.74 to - 0.48; P = 0.000) the following day. When the association between HS and delirium was controlled for CD14 + CD16+ monocytes, the effect size became nonsignificant (odds ratio [OR], 0.86; 95% CI, 0.14 to 5.33; P = 0.874). TNF alpha was significantly associated with POD (odds ratio [OR], 1.10; 95% CI, 1.05 to 1.16; P = 0.000). However, IL-1beta, IL-6, IL-10, and S100beta were not significantly related to POD. CONCLUSION: HS can alleviate POD in geriatric patients and may inhibit the secretion of inflammatory factors by monocytes. PMID- 29137629 TI - Correction to: Molecular surveillance of pfhrp2 and pfhrp3 deletions in Plasmodium falciparum isolates from Mozambique. AB - After publication of the article [1], it has been brought to our attention that two of the authors have had their names spelt incorrectly in the original publication. The eighth author should be "N. Regina Rabinovich" but was previously spelt as "N. Regina Rabinovitch". The tenth author should be "Francisco Saute" but was previously spelt as "Franciso Saute". The original version of this article has now been revised to include these corrections. PMID- 29137630 TI - DIET@NET: Best Practice Guidelines for dietary assessment in health research. AB - BACKGROUND: Dietary assessment is complex, and strategies to select the most appropriate dietary assessment tool (DAT) in epidemiological research are needed. The DIETary Assessment Tool NETwork (DIET@NET) aimed to establish expert consensus on Best Practice Guidelines (BPGs) for dietary assessment using self report. METHODS: The BPGs were developed using the Delphi technique. Two Delphi rounds were conducted. A total of 131 experts were invited, and of these 65 accepted, with 48 completing Delphi round I and 51 completing Delphi round II. In all, a total of 57 experts from North America, Europe, Asia and Australia commented on the 47 suggested guidelines. RESULTS: Forty-three guidelines were generated, grouped into the following four stages: Stage I. Define what is to be measured in terms of dietary intake (what? who? and when?); Stage II. Investigate different types of DATs; Stage III. Evaluate existing tools to select the most appropriate DAT by evaluating published validation studies; Stage IV. Think through the implementation of the chosen DAT and consider sources of potential biases. CONCLUSIONS: The Delphi technique consolidated expert views on best practice in assessing dietary intake. The BPGs provide a valuable guide for health researchers to choose the most appropriate dietary assessment method for their studies. These guidelines will be accessible through the Nutritools website, www.nutritools.org . PMID- 29137632 TI - Descriptive study of interprofessional collaboration between physicians and osteopaths for the pediatric population in Quebec, Canada. AB - BACKGROUND: Osteopathy is an increasingly popular healthcare approach that uses a wide variety of therapeutic manual techniques to address pain and somatic dysfunction. In Quebec, Canada, osteopathy is the complementary medicine most often recommended by family physicians. However, factors fostering the development of interprofessional collaboration (IPC) between physicians and osteopaths are unknown. This study aimed to describe the current situation in terms of IPC among practitioners working with pediatric patients. METHODS: A self administered questionnaire was sent to osteopaths, family physicians, and pediatricians involved with pediatric patients in the province of Quebec. The postal questionnaire captured general knowledge about osteopathy and its practice parameters and role, sources of information, communication aspects including having a professional relationship and referrals, and influence of the upcoming government regulation. Quantitative data from the questionnaires were analyzed using descriptive statistics. Logistic regression model for factors associated with osteopathic referrals and multiple linear regression analyses for the number of correct answers about general osteopathic practice parameters were performed. RESULTS: A total of 274 physicians (155 family physicians (response rate 13%) and 119 pediatricians (17%)) and 297 osteopaths (42%) completed the survey. According to physicians, osteopathy was most appropriate for musculoskeletal pain (241; 91%) and plagiocephaly (235; 88%). Osteopathic referral was positively associated with having a professional relationship (odds ratio [OR] 4.10 (95% confidence interval [CI] 2.12; 7.95), p < 0.001), personal consultation (OR 2.58 (95% CI 1.35; 4.93), p = 0.004), community-based practice (OR 1.89 (95% CI 1.03; 3.47), p = 0.040), and belief in the active role of osteopathy for pediatric conditions (OR 1.22 (95% CI 1.01; 1.47), p = 0.042). The majority of physicians (72%) and osteopaths (62%) considered the upcoming government regulation of osteopathy a positive factor for collaboration. CONCLUSION: Some collaboration already exists among these practitioners, including mutual referrals, but optimizing this collaboration still poses some challenges. PMID- 29137631 TI - Synthetic oleanane triterpenoids enhance blood brain barrier integrity and improve survival in experimental cerebral malaria. AB - BACKGROUND: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection associated with high mortality and neurocognitive impairment in survivors. New anti-malarials and host-based adjunctive therapy may improve clinical outcome in CM. Synthetic oleanane triterpenoid (SO) compounds have shown efficacy in the treatment of diseases where inflammation and oxidative stress contribute to pathogenesis. METHODS: A derivative of the SO 2-cyano-3,12 dioxooleana-1,9-dien-28-oic acid (CDDO), CDDO-ethyl amide (CDDO-EA) was investigated for the treatment of severe malaria in a pre-clinical model. CDDO-EA was evaluated in vivo as a monotherapy as well as adjunctive therapy with parenteral artesunate in the Plasmodium berghei strain ANKA experimental cerebral malaria (ECM) model. RESULTS: CDDO-EA alone improved outcome in ECM and, given as adjunctive therapy in combination with artesunate, it significantly improved outcome over artesunate alone (p = 0.009). Improved survival was associated with reduced inflammation, enhanced endothelial stability and blood-brain barrier integrity. Survival was improved even when administered late in the disease course after the onset of neurological symptoms. CONCLUSIONS: These results indicate that SO are a new class of immunomodulatory drugs and support further studies investigating this class of agents as potential adjunctive therapy for severe malaria. PMID- 29137633 TI - Bi-directional exosome-driven intercommunication between the hepatic niche and cancer cells. AB - BACKGROUND: Our understanding of the multiple roles exosomes play during tumor progression is still very poor and the contribution of the normal tissue derived exosomes in distant seeding and tumor outgrowth has also not been widely appreciated. METHODS: Using our all-human liver microphysiological system (MPS) platform as a model to closely recapitulate the early metastatic events, we isolated exosomes from both tumor cells and liver microenvironment. RESULTS: We observed that while priming of the hepatic niche (HepN) with MDA-231 breast cancer derived exosomes facilitated seeding of the cancer cells in the liver, subsequent tumor outgrowth was diminished; this was consistent with increased entry into dormancy. We found that hepatic niche (HepN) derived exosomes contribute significantly to the exosome pool and are distinguished from cancer derived exosomes based on their size, protein and miRNA content. By Ingenuity Pathway Analysis (IPA) of the miRNA content of the HepN, MDA-231/HepN and MDA-231 cells we showed that the HepN derived exosomes affect the breast cancer cells by suppressing pathways involved in cancer cell proliferation and invasion. More importantly exposure of MDA-231 and MDA-468 cells to purified normal HepN derived exosomes, induced changes in the cells consistent with a Mesenchymal to Epithelial reverting Transition (MErT). miRNA arrays performed on MDA-231 treated with Hum Hep/NPC derived exosomes showed significant changes in the levels of a select number of miRNAs involved in epithelial cell differentiation and miRNAs, such as miR186, miR23a and miR205, from our top and bottom bins have previously been reported to regulate E-cadherin transcription and MErT induction in various cancer types. Consistently HepN derived exosome treatment of breast and prostate cancer lines lead to a transient induction of E-cadherin and ZO-1 at the protein level and a more epithelial-like morphology of the cells. CONCLUSIONS: Collectively our data revealed a novel mechanism of regulation of the metastatic cascade, showing a well-orchestrated, timely controlled crosstalk between the cancer cells and the HepN and implicating for the first time the normal tissue/HepN derived exosomes in enabling seeding and entry into dormancy of the cancer cells at the metastatic site. PMID- 29137634 TI - Profiling of Saccharomyces cerevisiae transcription factors for engineering the resistance of yeast to lignocellulose-derived inhibitors in biomass conversion. AB - BACKGROUND: Yeast transcription factors (TFs) involved in the regulation of multidrug resistance (MDR) were investigated in experiments with deletion mutants, transformants overexpressing synthetic genes encoding TFs, and toxic concentrations of lignocellulose-derived substances added to cultures as complex mixtures or as specific compounds, viz. coniferyl aldehyde, 5 hydroxymethylfurfural, and furfural. RESULTS: In the presence of complex mixtures of toxic substances from spruce wood, transformants overexpressing YAP1 and STB5, TFs involved in oxidative stress response, exhibited enhanced relative growth rates amounting to 4.589 +/- 0.261 and 1.455 +/- 0.185, respectively. Other TFs identified as important for resistance included DAL81, GZF3, LEU3, PUT3, and WAR1. Potential overlapping functions of YAP1 and STB5 were investigated in experiments with permutations of deletions and overexpression of the two genes. YAP1 complemented STB5 with respect to resistance to 5-hydroxymethylfurfural, but had a distinct role with regard to resistance to coniferyl aldehyde as deletion of YAP1 rendered the cell incapable of resisting coniferyl aldehyde even if STB5 was overexpressed. CONCLUSIONS: We have investigated 30 deletion mutants and eight transformants overexpressing MDR transcription factors with regard to the roles the transcription factors play in the resistance to toxic concentrations of lignocellulose-derived substances. This work provides an overview of the involvement of thirty transcription factors in the resistance to lignocellulose derived substances, shows distinct and complementary roles played by YAP1 and STB5, and offers directions for the engineering of robust yeast strains for fermentation processes based on lignocellulosic feedstocks. PMID- 29137635 TI - The association between serum 25-hydroxyvitamin D3 concentration and serum lipids in the rural population of China. AB - BACKGROUND: Vitamin D deficiency is implicated in some diseases, including cardiovascular. Few studies have assessed the correlation between 25 hydroxyvitamin D3 [25(OH) D3] and serum lipids. In this study, we explored the correlation between serum 25(OH) D3 concentrations and serum lipids with a typical sample of the rural population in China. METHODS: Face-to-face research was used to gather some basic information. Fasting serum concentrations of 25 (OH) D3, total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C) and, LDL cholesterol (LDL-C) tested in the laboratory. RESULTS: The mean of serum 25(OH) D3 level was 28.71 +/- 29.29 ng/mL. The results showed that the dyslipidemia was strongly associated with gender (P = 0.031), drinking (P = 0.043), high-fat diet intake (P = 0.017), HDL-C (P<0), TG (P<0), body mass index (BMI) (P<0) and serum 25(OH)D3 levels (P = 0.002). There was a positive correlation between serum 25(OH)D3 and HDL-C (P<0) in all groups. The relationship between 25(OH) D3 and LDL-C (P = 0.024) was discovered only in normal lipid group. The multivariable adjusted odds ratio (95%CI) of hypoalphalipoproteinemia/HDL and dyslipidemia by comparing the sufficiency vs. the deficiency serum 25-(OH) D3 level were 0.31 (0.192, 0.499) (P = 0.001) and 0.52 (0.36, 0.73) (P = 0.005), respectively. CONCLUSIONS: Serum 25(OH) D3 concentrations were associated with the serum lipids level and the association was different in normal serum lipid group and dyslipidemia group. With the increase of serum 25(OH) D3 levels, the incidence of dyslipidemia decreased. PMID- 29137636 TI - Structure-based antigenic epitope and PEGylation improve the efficacy of staphylokinase. AB - Staphylokinase (Sak) holds promise for use in thrombolytic therapy for acute myocardial infarction. However, its immunogenicity is a major disadvantage under clinical conditions. PEGylation has become a sophisticated method to decrease that immunogenicity. In this report, according predicted epitope from the active center, five residues, including Gly79, Leu82, Lys84, Ala97, and Arg104 have been mutant as cysteine for mono PEGylation, respectively. According to the relative immunogenicity of Sak or its PEGylation derivatives, the amount of specific anti Sak IgG antibodies elicited by PEGylation proteins, including C79G, C82L, C84K, C97A, and C104R in BALB/c mice decreased by approximately 15-75% each. PEGylated Sak derivatives showed a decrease of up to 75% in the immune reactivity in PEG Sak-C104R. Thrombelastography experiments showed that two PEG-conjugated derivatives, PEG-Sak-C97A (Ly30, 68.14 +/- 2.51%) and PEG-Sak-C104R (Ly30, 66.49 +/- 5.97%), the LY30 of PEG-Sak-C97A, and PEG-Sak-C104R produced values very similar to those of wild-type Sak. The fibrin plate assays showed the bioactivity of PEG-Sak-C104R to exhibit the most activity approximately as much as urokinase (diameter of halo pattern, 18.6 +/- 1.06 mm) and tPA (diameter of halo pattern, 17.2 +/- 0.49 mm). The Sak PEGylation derivative PEG-Sak-C104R was also selected for further in vivo activity experimentation. The thrombolytic ability of PEG-Sak C104R is a little lower than wild-type Sak, whereas, this PEGylated protein retained high activity suitable for thrombolytic therapy. Collectively, with the in vivo and in vitro experiments, the present study suggests that site mutant PEGylation, PEG-Sak-C104R, is a suitable type of PEGylation for clinical applications. Further optimization would help maintain the bioactivity and decrease the immunogenicity of staphylokinase. PMID- 29137637 TI - Molecular evolution of HIV-1 integrase during the 20 years prior to the first approval of integrase inhibitors. AB - BACKGROUND: Detailed knowledge of the evolutionary potential of polymorphic sites in a viral protein is important for understanding the development of drug resistance in the presence of an inhibitor. We therefore set out to analyse the molecular evolution of the HIV-1 subtype B integrase at the inter-patient level in Germany during a 20-year period prior to the first introduction of integrase strand inhibitors (INSTIs). METHODS: We determined 337 HIV-1 integrase subtype B sequences (amino acids 1-278) from stored plasma samples of antiretroviral treatment-naive individuals newly diagnosed with HIV-1 between 1986 and 2006. Shannon entropy was calculated to determine the variability at each amino acid position. Time trends in the frequency of amino acid variants were identified by linear regression. Direct coupling analysis was applied to detect covarying sites. RESULTS: Twenty-two time trends in the frequency of amino acid variants demonstrated either single amino acid exchanges or variation in the degree of polymorphy. Covariation was observed for 17 amino acid variants with a temporal trend. Some minor INSTI resistance mutations (T124A, V151I, K156 N, T206S, S230 N) and some INSTI-selected mutations (M50I, L101I, T122I, T124 N, T125A, M154I, G193E, V201I) were identified at overall frequencies >5%. Among these, the frequencies of L101I, T122I, and V201I increased over time, whereas the frequency of M154I decreased. Moreover, L101I, T122I, T124A, T125A, M154I, and V201I covaried with non-resistance-associated variants. CONCLUSIONS: Time-trending, covarying polymorphisms indicate that long-term evolutionary changes of the HIV-1 integrase involve defined clusters of possibly structurally or functionally associated sites independent of selective pressure through INSTIs at the inter patient level. Linkage between polymorphic resistance- and non-resistance associated sites can impact the selection of INSTI resistance mutations in complex ways. Identification of these sites can help in improving genotypic resistance assays, resistance prediction algorithms, and the development of new integrase inhibitors. PMID- 29137639 TI - Proactive Ethical Design for Neuroengineering, Assistive and Rehabilitation Technologies: the Cybathlon Lesson. AB - BACKGROUND: Rapid advancements in rehabilitation science and the widespread application of engineering techniques are opening the prospect of a new phase of clinical and commercial maturity for Neuroengineering, Assistive and Rehabilitation Technologies (NARTs). As the field enters this new phase, there is an urgent need to address and anticipate the ethical implications associated with novel technological opportunities, clinical solutions, and social applications. MAIN IDEA: In this paper we review possible approaches to the ethics of NART, and propose a framework for ethical design and development, which we call the Proactive Ethical Design (PED) framework. CONCLUSION: A viable ethical framework for neuroengineering, assistive and rehabilitation technology should be characterized by the convergence of user-centered and value-sensitive approaches to product design through a proactive mode of ethical evaluation. We propose four basic normative requirements for the realization of this framework: minimization of power imbalances, compliance with biomedical ethics, translationality and social awareness. The aims and values of the CYBATHLON competition provide an operative model of this ethical framework and could drive an ethical shift in neuroengineering and rehabilitation. PMID- 29137638 TI - Virus-triggered exacerbation in allergic asthmatic children: neutrophilic airway inflammation and alteration of virus sensors characterize a subgroup of patients. AB - BACKGROUND: Viruses are important triggers of asthma exacerbations. They are also detected outside of exacerbation. Alteration of anti-viral response in asthmatic patients has been shown although the mechanisms responsible for this defect remain unclear. The objective of this study was to compare in virus-infected and not-infected allergic asthmatic children, aged 6 to 16 years, admitted to hospital for a severe exacerbation, the innate immune response and especially the expression of pattern recognition receptor (PRR) and their function. METHODS: Virus identification was performed both during the exacerbation and at steady state (eight weeks later). Data assessed at both periods included clinical features, anti-viral response and inflammation (in sputum and plasma), and PRR expression/function in blood mononuclear cells. RESULTS: Viruses were identified in 46 out of 72 children (median age 8.9 years) during exacerbation, and among them, in 17 at steady state. IFN-beta, IFN-gamma and IL-29 levels in sputum and plasma were similar between infected and not infected patients at both times, as well as the expression of TLR3, RIG-I and MDA5 in blood monocytes and dendritic cells. Airway inflammation in infected patients was characterized by significantly higher IL-5 concentration and eosinophil count. Compared to patients only infected at exacerbation, the re-infected children significantly exhibited lower levels of IFN-gamma in plasma and sputum at exacerbation associated with modifications in PRR expression and function in blood mononuclear cells. These re-infected patients also presented an airway neutrophilic inflammation at steady state. CONCLUSION: Our results reports in asthmatic children that impaired anti-viral response during virus-induced exacerbation is more pronounced in a subgroup of patients prone to re-infection by virus. This subgroup is characterized by altered PRR function and a different pattern of airway inflammation. TRIAL REGISTRATION: This multicenter prospective study was approved by the regional investigational review board (ref: 08/07). PMID- 29137640 TI - Direct reprogramming of mouse fibroblasts into neural cells via Porphyra yezoensis polysaccharide based high efficient gene co-delivery. AB - BACKGROUND: The cell source for transplantation therapy is always a prerequisite question to be solved in clinical applications. Neural cells are considered non regenerable, which highly restrict their application in the treatment for nerve injury. Therefore, neural trans-differentiation based on gene transfection provides a new solution to this issue. Compared to viral strategy, non-viral gene delivery systems are considered as a more promising way to achieve this aim. This study centers on a novel application of Porphyra yezoensis polysaccharide as a non-viral gene carrier for the neural trans-differentiation of mouse fibroblasts. RESULTS: Ethanediamine modified P. yezoensis polysaccharide (Ed-PYP) served as a gene carrier and a group of plasmids that encode Ascl1, Brn4, and Tcf3 (pABT) self-assembled into nanoparticles. Results demonstrated that Ed-PYP-pABT nanoparticles at Ed-PYP: pABT weight ratio of 40:1 was the optimal candidate for gene delivery. ELISA assay revealed the highest expression levels of NGF, BDNF and SHH at 14 days after last transfection. Immunofluorescence and western blot assays also showed robust expression of neural markers including Nestin, GFAP, beta-3tubulin, NF200, GAP43 and MAP2, in induced 3T6 cells at this time point. CONCLUSION: Overall, these findings indicated that the P. yezoensis polysaccharide-based non-viral gene co-delivery system is a promising strategy for the generation of neural cells, which might facilitate the developments in the recovery of neural injuries. PMID- 29137641 TI - Improving E. coli growth performance by manipulating small RNA expression. AB - Efficient growth of E. coli, especially for production of recombinant proteins, has been a challenge for the biotechnological industry since the early 1970s. By employing multiple approaches, such as different media composition, various growth strategies and specific genetic manipulations, it is now possible to grow bacteria to concentrations exceeding 100 g/L and to achieve high concentrations of recombinant proteins. Although the growth conditions are carefully monitored and maintained, it is likely that during the growth process cells are exposed to periodic stress conditions, created by fluctuations in pH, dissolved oxygen, temperature, glucose, and salt concentration. These stress circumstances which can occur especially in large volume bioreactors, may affect the growth and production process. In the last several years, it has been recognized that small non-coding RNAs can act as regulators of bacterial gene expression. These molecules are found to be specifically involved in E. coli response to different environmental stress conditions; but so far, have not been used for improving production strains. The review provides summary of small RNAs identified on petri dish or in shake flask culture that can potentially affect growth characteristics of E. coli grown in bioreactor. Among them MicC and MicF that are involved in response to temperature changes, RyhB that responds to iron concentration, Gady which is associated with lower pH, Sgrs that is coupled with glucose transport and OxyS that responds to oxygen concentration. The manipulation of some of these small RNAs for improving growth of E. coli in Bioreactor is described in the last part of the review. Overexpression of SgrS was associated with improved growth and reduced acetate expression, over expression of GadY improved cell growth at acidic conditions and over expression of OxyS reduced the effect of oxidative stress. One of the possible advantages of manipulating sRNAs for improving cell growth is that the modifications occur at a post-translational level. Therefore, the use of sRNAs may exert minimal effect on the overall bacterial metabolism. The elucidation of the physiological role of newly discovered sRNAs will open new possibilities for creating strains with improved growth and production capabilities. PMID- 29137642 TI - Effects of mRNA secondary structure on the expression of HEV ORF2 proteins in Escherichia coli. AB - BACKGROUND: Viral protein expression in Escherichia coli (E. coli) is a powerful tool for structural/functional studies as well as for vaccine and diagnostics development. However, numerous factors such as codon bias, mRNA secondary structure and nucleotides distribution, have been indentified to hamper this heterologous expression. RESULTS: In this study, we combined computational and biochemical methods to analyze the influence of these factors on the expression of different segments of hepatitis E virus (HEV) ORF 2 protein and hepatitis B virus surface antigen (HBsAg). Three out of five HEV antigens were expressed while all three HBsAg fragments were not. The computational analysis revealed a significant difference in nucleotide distribution between expressed and non expressed genes; and all these non-expressing constructs shared similar stable 5' end mRNA secondary structures that affected the accessibility of both Shine Dalgarno (SD) sequence and start codon AUG. By modifying the 5'-end of HEV and HBV non-expressed genes, there was a significant increase in the total free energy of the mRNA secondary structures that permitted the exposure of the SD sequence and the start codon, which in turn, led to the successful expression of these genes in E. coli. CONCLUSIONS: This study demonstrates that the mRNA secondary structure near the start codon is the key limiting factor for an efficient expression of HEV ORF2 proteins in E. coli. It describes also a simple and effective strategy for the production of viral proteins of different lengths for immunogenicity/antigenicity comparative studies during vaccine and diagnostics development. PMID- 29137643 TI - Efficient gene editing in Corynebacterium glutamicum using the CRISPR/Cas9 system. AB - BACKGROUND: Corynebacterium glutamicum (C. glutamicum) has traditionally been used as a microbial cell factory for the industrial production of many amino acids and other industrially important commodities. C. glutamicum has recently been established as a host for recombinant protein expression; however, some intrinsic disadvantages could be improved by genetic modification. Gene editing techniques, such as deletion, insertion, or replacement, are important tools for modifying chromosomes. RESULTS: In this research, we report a CRISPR/Cas9 system in C. glutamicum for rapid and efficient genome editing, including gene deletion and insertion. The system consists of two plasmids: one containing a target specific guide RNA and a homologous sequence to a target gene, the other expressing Cas9 protein. With high efficiency (up to 100%), this system was used to disrupt the porB, mepA, clpX and Ncgl0911 genes, which affect the ability to express proteins. The porB- and mepA-deletion strains had enhanced expression of green fluorescent protein, compared with the wild-type stain. This system can also be used to engineer point mutations and gene insertions. CONCLUSIONS: In this study, we adapted the CRISPR/Cas9 system from S. pyogens to gene deletion, point mutations and insertion in C. glutamicum. Compared with published genome modification methods, methods based on the CRISPR/Cas9 system can rapidly and efficiently achieve genome editing. Our research provides a powerful tool for facilitating the study of gene function, metabolic pathways, and enhanced productivity in C. glutamicum. PMID- 29137644 TI - Functional resonance magnetic imaging (fMRI) in adolescents with idiopathic musculoskeletal pain: a paradigm of experimental pain. AB - BACKGROUND: Studies on functional magnetic resonance imaging (fMRI) have shown that adults with musculoskeletal pain syndromes tolerate smaller amount of pressure (pain) as well as differences in brain activation patterns in areas related to pain.The objective of this study was to evaluate, through fMRI, the brain activation in adolescents with idiopathic musculoskeletal pain (IMP) while performing an experimental paradigm of pain. METHODS: The study included 10 consecutive adolescents with idiopathic musculoskeletal pain (average age 16.3+/ 1.0) and 10 healthy adolescents age-matched. fMRI exams were performed in a 3 T scanner (Magnetom Trio, Siemens) using an event-related design paradigm. Pressure stimuli were performed in the nondominant hand thumb, divided into two stages, fixed pain and variable pain. The two local Research Ethics Committees (Ethics Committee from Universidade Federal de Sao Paulo- Brazil, process number 0688/11, on July 1st, 2011 and Ethics Committee from Hospital Israelita Albert Einsten - Brazil, process number 1673, on October 19th, 2011) approved the study. RESULTS: The idiopathic musculoskeletal pain (IMP) group showed a reduced threshold for pain (3.7 kg/cm2 versus 4.45 kg/cm2, p = 0.005). Control group presented increased bain activation when compared to IMP group in the following areas: thalamus (p = 0.00001), precentral gyrus (p = 0.0004) and middle frontal gyrus (p = 0.03). In intragroup analysis, IMP group showed greater brain activation during the unpredictable stimuli of the variable pain stage, especially in the lingual gyrus (p = 0.0001), frontal lobe (p = 0.0001), temporal gyrus (p = 0.0001) and precentral gyrus (p = 0.03), when compared to predictable stimulus of fixed pain. The same intragroup analysis with the control group showed greater activation during the unpredictable stimuli in regions of the precentral gyrus (p = 0.0001), subcallosal area (p = 0.0001), right and left occipital fusiform gyrus (p = 0.0001; (p = 0.0007), middle gyrus (p = 0.01) and precuneus p = (0.02). CONCLUSION: Adolescents with idiopathic musculoskeletal pain (IMP) tend to request higher brain function in cognitive-emotional areas when interpreting unpredictable sensory-perceptual situations. Therefore, it is assumed that this difference in pain processing in adolescents with IMP make the subjective experience of pain something more intense and unpleasant. PMID- 29137645 TI - Distribution of essential medicines to primary care institutions in Hubei of China: effects of centralized procurement arrangements. AB - BACKGROUND: Poor distribution of essential medicines to primary care institutions has attracted criticism since China adopted provincial centralized regional tendering and procurement systems. This study evaluated the impact of new procurement arrangements that limit the number of distributors at the county level in Hubei province, China. METHODS: Procurement ordering and distribution data were collected from four counties that pioneered a new distribution arrangement (commencing September 2012) compared with six counties that continued the existing arrangement over the period from August 2011 to September 2013. The new arrangement allowed primary care institutions and/or suppliers to select a local distributor from a limited panel (from 3 to 5) of government nominated distributors. Difference-in-differences analyses were performed to assess the impact of the new arrangements on delivery and receipt of essential medicines. RESULTS: Overall, the new distribution arrangement has not improved distribution of essential medicines to primary care institutions. On the contrary, we found a 7.78-19.85 percentage point (p < 0.01) decrease in distribution rates to rural primary care institutions. Similar results were demonstrated using the indicator of received rates, with a 7.89-19.65 percentage point (p < 0.01) decrease. CONCLUSIONS: Simply limiting the number of distributors does not offer a solution to the poor performance of delivery of essential medicines for primary care institutions, especially those located in rural areas. Procurement arrangements need to consider the special characteristics of rural facilities. In a county, there are more rural primary care institutions than urban ones. On average, rural primary care institutions demand more and are more geographically dispersed compared to their urban counterparts, which may impose increased distribution costs. PMID- 29137646 TI - The potential of interleukin-37 as an effective therapeutic agent in asthma. AB - Interleukin (IL)-37 belongs to the IL-1 cytokine family. It binds to IL-18Ralpha and recruits the orphan decoy IL-1R8. Emerging evidence shows that IL-37 is a key player in the regulation of inflammation, cellular differentiation, and proliferation. Altered IL-37 expression has been demonstrated in many inflammatory disease conditions, including asthma. In rheumatoid arthritis, IL-37 is involved in the regulation of proliferation, production of inflammatory mediators, and activation of inflammatory cells. Furthermore, this cytokine acts as a negative regulator of inflammation in inflammatory bowel disease. Similarly, IL-37 also appears to suppress allergic inflammation in asthma. In a murine model of asthma, local administration of IL-37 markedly reduced the degree of inflammatory cell infiltration and airway hyper-responsiveness. IL-37 has also been shown to be involved in a number of aspects of allergic inflammation, such as eosinophil and neutrophil recruitment, as well as inhibition of Th1/Th2/Th17 inflammatory mediators. However, the exact molecular mechanisms underlying the function of IL-37 in human asthma have yet to be fully elucidated. This review describes the current evidence regarding the role of IL-37 in the pathophysiology of asthma and evaluates both the potential of IL-37 as a biomarker for airway inflammation and a therapeutic target for the treatment of asthma. PMID- 29137647 TI - New eight genes identified at the clinical multidrug-resistant Acinetobacter baumannii DMS06669 strain in a Vietnam hospital. AB - BACKGROUND: Acinetobacter baumannii is an important nosocomial pathogen that can develop multidrug resistance. In this study, we characterized the genome of the A. baumannii strain DMS06669 (isolated from the sputum of a male patient with hospital-acquired pneumonia) and focused on identification of genes relevant to antibiotic resistance. METHODS: Whole genome analysis of A. baumannii DMS06669 from hospital-acquired pneumonia patients included de novo assembly; gene prediction; functional annotation to public databases; phylogenetics tree construction and antibiotics genes identification. RESULTS: After sequencing the A. baumannii DMS06669 genome and performing quality control, de novo genome assembly was carried out, producing 24 scaffolds. Public databases were used for gene prediction and functional annotation to construct a phylogenetic tree of the DMS06669 strain with 21 other A. baumannii strains. A total of 18 possible antibiotic resistance genes, conferring resistance to eight distinct classes of antibiotics, were identified. Eight of these genes have not previously been reported to occur in A. baumannii. CONCLUSIONS: Our results provide important information regarding mechanisms that may contribute to antibiotic resistance in the DMS06669 strain, and have implications for treatment of patients infected with A. baumannii. PMID- 29137648 TI - LesR is a novel upstream regulator that controls downstream Clp expression to modulate antibiotic HSAF biosynthesis and cell aggregation in Lysobacter enzymogenes OH11. AB - BACKGROUND: Heat-stable antifungal factor (HSAF) is a polycyclic tetramate macrolactam secondary metabolite that exhibits broad-spectrum inhibitory activities against filamentous fungal pathogens. The native yield of this chemical is low. It is also a great challenge to synthesize HSAF artificially, due to its complex structure. Understanding the regulatory mechanism underlying HSAF biosynthesis could provide genetic basis for engineering high HSAF-producing strain. The transcription factor Clp is a global regulator that controls bacterial pathogenicity and the expression of one hundred related genes in the phytopathogenic bacterium Xanthomonas campestris pv. campestris (Xcc). Diffusible signal factor (DSF) chemical signaling is the only well-characterized upstream regulatory pathway that involves downstream Clp regulation in Xcc. Such a regulatory hierarchy between DSF signaling and Clp is also conserved in the Gram negative biological control agent Lysobacter enzymogenes, where the DSF signaling system controls antifungal antibiotic HSAF biosynthesis via Clp. RESULTS: Here, using LLysobacter enzymogenes OH11 as a working organism, we examined a novel upstream regulator, LesR, a LuxR solo that controls Clp expression to modulate HSAF biosynthesis as well as cell aggregation. We found that the overexpression of lesR in strain OH11 almost entirely shut down HSAF production and accelerated cell aggregation. These changed phenotypes could be rescued by the introduction of plasmid-borne clp in the lesR overexpression background. Consistent with findings, we further found that overexpression of lesR led to a decrease in the Clp level. CONCLUSIONS: These results collectively have shown that LesR could exert its function, i.e., HSAF biosynthesis, via downstream Clp. These findings were subsequently validated by a comparative transcriptome analysis, where the regulatory action of LesR was found to largely overlap with that of Clp. Therefore, in addition to the well-known DSF signaling system, the present study reveals that LesR functions as a new upstream regulatory factor of Clp in L. enzymogenes. The key factor was important for the production of HSAF. The strains with high HSAF yield can presumably be constructed by deletion of the negative regulators or overexpression of the positive regulators by genetic engineering. PMID- 29137649 TI - Exploring the factors affecting the implementation of tobacco and substance use interventions within a secondary school setting: a systematic review. AB - BACKGROUND: The aim of this mixed-methods, systematic literature review was to develop an understanding of the factors affecting the implementation of tobacco and substance use intervention programmes in the secondary school setting using NPT as an analytical framework. METHODS: A search strategy was developed that combined implementation, school and intervention search terms. Literature searches were conducted in MEDLINE, Embase, PsycHINFO, Scopus, ERIC, CINAHL, Web of Science and the Cochrane Library. PROSPERO was also searched for similar systematic reviews and a grey literature search of policy documents and relevant material was also conducted. Papers were eligible for inclusion if they were based in a secondary school and focused on the implementation of a tobacco or substance use programme. Both quantitative and qualitative methodologies were considered for inclusion. Normalisation Process Theory (NPT) was used as a conceptual framework to identify facilitators and barriers of implementation and to structure the synthesis. RESULTS: Inclusion criteria were met by 15 papers. The included papers were both quantitative and qualitative and focused on a range of tobacco and substance use interventions, delivered by differing providers. Key facilitating factors for implementation were positive organisational climate, adequate training and teacher's and pupil's motivation. Barriers to implementation included heavy workloads, budget cuts and lack of resources or support. Quality appraisal identified papers to be of moderate to weak quality, as papers generally lacked detail. CONCLUSION: NPT highlighted the need for studies to extend their focus to include reflexive monitoring around appraisal and the evaluation processes of implementing new tobacco or substance use programs. Future research should also focus on employing implementation theory as a tool to facilitate bridging the gap between school health research and practice. PMID- 29137650 TI - Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism. AB - BACKGROUND: Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency. RESULTS: A G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic. CONCLUSIONS: These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes. PMID- 29137652 TI - Characterization of Streptococcus pneumoniae isolates from Austrian companion animals and horses. AB - BACKGROUND: The aim of the present study was to investigate the genetic relatedness and the antimicrobial resistance profiles of a collection of Austrian Streptococcus pneumoniae isolates from companion animals and horses. A total of 12 non-repetitive isolates presumptively identified as S. pneumoniae were obtained during routinely diagnostic activities between March 2009 and January 2017. RESULTS: Isolates were confirmed as S. pneumoniae by bile solubility and optochin susceptibility testing, matrix-assisted laser desorption-ionization-time of flight (MALDI-TOF) mass spectrometry and sequence analysis of a part recA and the 16S rRNA genes. Isolates were further characterized by pneumolysin polymerase chain reaction (PCR) and genotyped by multilocus sequence typing (MLST). Antimicrobial susceptibility testing was performed and resistance genes were detected by specific PCR assays. All isolates were serotyped. Four sequence types (ST) (ST36, ST3546, ST6934 and ST6937) and four serotypes (3, 19A, 19F and 23F) were detected. Two isolates from twelve displayed a multidrug-resistance pheno- and genotype. CONCLUSIONS: This study represents the first comprehensive investigation on characteristics of S. pneumoniae isolates recovered from Austrian companion animals and horses. The obtained results indicate that common human sero- (23F) and sequence type (ST36) implicated in causing invasive pneumococcal disease (IPD) may circulate in dogs. Isolates obtained from other examined animals seem to be host-adapted. PMID- 29137651 TI - Abnormal dendritic calcium activity and synaptic depotentiation occur early in a mouse model of Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid deposition, tangle formation as well as synapse loss. Synaptic abnormalities occur early in the pathogenesis of AD. Identifying early synaptic abnormalities and their underlying mechanisms is likely important for the prevention and treatment of AD. METHODS: We performed in vivo two-photon calcium imaging to examine the activities of somas, dendrites and dendritic spines of layer 2/3 pyramidal neurons in the primary motor cortex in the APPswe/PS1dE9 mouse model of AD and age-matched wild type control mice. We also performed calcium imaging to determine the effect of Abeta oligomers on dendritic calcium activity. In addition, structural and functional two-photon imaging were used to examine the link between abnormal dendritic calcium activity and changes in dendritic spine size in the AD mouse model. RESULTS: We found that somatic calcium activities of layer 2/3 neurons were significantly lower in the primary motor cortex of 3-month old APPswe/PS1dE9 mice than in wild type mice during quiet resting, but not during running on a treadmill. Notably, a significantly larger fraction of apical dendrites of layer 2/3 pyramidal neurons showed calcium transients with abnormally long duration and high peak amplitudes during treadmill running in AD mice. Administration of Abeta oligomers into the brain of wild type mice also induced abnormal dendritic calcium transients during running. Furthermore, we found that the activity and size of dendritic spines were significantly reduced on dendritic branches with abnormally prolonged dendritic calcium transients in AD mice. CONCLUSION: Our findings show that abnormal dendritic calcium transients and synaptic depotentiation occur before amyloid plaque formation in the motor cortex of the APPswe/PS1dE9 mouse model of AD. Dendritic calcium transients with abnormally long durations and high amplitudes could be induced by soluble Abeta oligomers and contribute to synaptic deficits in the early pathogenesis of AD. PMID- 29137653 TI - Prognostic value of PAM50 and risk of recurrence score in patients with early stage breast cancer with long-term follow-up. AB - BACKGROUND: The aim of this study was to investigate the prognostic value of the PAM50 intrinsic subtypes and risk of recurrence (ROR) score in patients with early breast cancer and long-term follow-up. A special focus was placed on hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) pN0 patients not treated with chemotherapy. METHODS: Patients with early breast cancer (n = 653) enrolled in the observational Oslo1 study (1995 1998) were followed for distant recurrence and breast cancer death. Clinicopathological parameters were collected from hospital records. The primary tumors were analyzed using the Prosigna(r) PAM50 assay to determine the prognostic value of the intrinsic subtypes and ROR score in comparison with pathological characteristics. The primary endpoints were distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS). RESULTS: Of 653 tumors, 52.2% were classified as luminal A, 26.5% as luminal B, 10.6% as HER2 enriched, and 10.7% as basal-like. Among the HR+/HER2- patients (n = 476), 37.8% were categorized as low risk by ROR score, 22.7% as intermediate risk, and 39.5% as high risk. Median follow-up durations for BCSS and DDFS were 16.6 and 7.1 years, respectively. Multivariate analysis showed that intrinsic subtypes (all patients) and ROR risk classification (HR+/HER2- patients) yielded strong prognostic information. Among the HR+/HER2- pN0 patients with no adjuvant treatment (n = 231), 53.7% of patients had a low ROR, and their prognosis at 15 years was excellent (15-year BCSS 96.3%). Patients with intermediate risk had reduced survival compared with those with low risk (p = 0.005). In contrast, no difference in survival between the low- and intermediate-risk groups was seen for HR+/HER2- pN0 patients who received tamoxifen only. Ki-67 protein, grade, and ROR score were analyzed in the unselected, untreated pT1pN0 HR+/HER2- population (n = 171). In multivariate analysis, ROR score outperformed both Ki-67 and grade. Furthermore, 55% of patients who according to the PREDICT tool ( http://www.predict.nhs.uk/ ) would be considered chemotherapy candidates were ROR low risk (33%) or luminal A ROR intermediate risk (22%). CONCLUSIONS: The PAM50 intrinsic subtype classification and ROR score improve classification of patients with breast cancer into prognostic groups, allowing for a more precise identification of future recurrence risk and providing an improved basis for adjuvant treatment decisions. Node-negative patients with low ROR scores had an excellent outcome at 15 years even in the absence of adjuvant therapy. PMID- 29137656 TI - How Brunei trainee teachers cope with distress: counseling implications. AB - OBJECTIVE: This study investigated the strategies used by student teachers when dealing with distress during training. Specifically, this study addressed the following research goals: (1) identify Ways of Coping that predict achievement on a quantitative reasoning test; (2) determine participants' coping differences per sex, age, and ability in quantitative reasoning; and (3) reveal coping strategies that work best for each and both sexes in fostering academic achievement in quantitative reasoning. The data used in this study was from a single observation. RESULTS: Confrontive coping, planful problem solving, and self control were significant main effect predictors of achievement. Two separate sex interaction variables (male with accepting responsibility and female versus accepting responsibility) were also significant predictors of achievement. Accepting responsibility was therefore helpful to both sexes in achievement. Younger participants aged 22-24 years scored significantly higher on the accepting responsibility subscale than older peers aged 25-26 years. In addition, low scorers on the quantitative reasoning test scored significantly higher on the escape avoidance coping subscale than their more-able counterparts. These findings have counseling implications for students with high support needs. A large-scale study with interview probes is recommended to learn more about this issue. PMID- 29137654 TI - Conventional fractionation should not be the standard of care for T2 glottic cancer. AB - BACKGROUND: The aim of this study was to report outcomes and late toxicity following hypofractionated accelerated radiotherapy for T2 glottic cancers. We highlight the importance of hypofractionated treatments with shorter overall treatment times, in improving outcomes for T2 glottic cancers. We also compare the biologically effective dose of hypofractionated regimes, with conventional fractionation. METHODS: One hundred twelve patients with T2 glottic cancer were treated between January 1999 and December 2005. All patients were prescribed a hypofractionated accelerated radiotherapy dose of 52.5 Gray in 3.28 Gray per fraction, delivered over 22 days. Radiobiological calculations were used to assess the relationship of fraction size and overall treatment time on local control outcomes and late toxicity. RESULTS: The 5-year overall survival was 67%, the 5-year local control was 82%, and the 5-year disease-specific survival was 90%. The respective 5-year local control for T2a and T2b disease was 88.8 and 70.8% (p = 0.032). Severe late toxicity occurred in two patients (1.8%). Radiobiological calculations showed an increase in local control of nearly 12%, with a 10 Gray increase in biologically effective dose. CONCLUSION: This study has demonstrated that accelerated hypofractionated regimes have improved local control and similar late toxicity compared with conventional fractionation schedules. This supports the use of hypofractionated regimes as the standard of care for early glottic laryngeal cancers. PMID- 29137655 TI - Can integrating the Memory Support Intervention into cognitive therapy improve depression outcome? Study protocol for a randomized controlled trial. AB - BACKGROUND: The Memory Support Intervention was developed in response to evidence showing that: (1) patient memory for treatment is poor, (2) poor memory for treatment is associated with poorer adherence and poorer outcome, (3) the impact of memory impairment can be minimized by the use of memory support strategies and (4) improved memory for treatment improves outcome. The aim of this study protocol is to conduct a confirmatory efficacy trial to test whether the Memory Support Intervention improves illness course and functional outcomes. As a "platform" for the next step in investigating this approach, we focus on major depressive disorder (MDD) and cognitive therapy (CT). METHOD/DESIGN: Adults with MDD (n = 178, including 20% for potential attrition) will be randomly allocated to CT + Memory Support or CT-as-usual and will be assessed at baseline, post treatment and at 6 and 12 months' follow-up (6FU and 12FU). We will compare the effects of CT + Memory Support vs. CT-as-usual to determine if the new intervention improves the course of illness and reduces functional impairment (aim 1). We will determine if patient memory for treatment mediates the relationship between treatment condition and outcome (aim 2). We will evaluate if previously reported poor treatment response subgroups moderate target engagement (aim 3). DISCUSSION: The Memory Support Intervention has been developed to be "transdiagnostic" (relevant to a broad range of mental disorders) and "pantreatment" (relevant to a broad range of types of treatment). This study protocol describes a "next step" in the treatment development process by testing the Memory Support Intervention for major depressive disorder (MDD) and cognitive therapy (CT). If the results are promising, future directions will test the applicability to other kinds of interventions and disorders and in other settings. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01790919 . Registered on 6 October 2016. PMID- 29137657 TI - p53 aberrations in low grade endometrioid carcinoma of the endometrium with nodal metastases: possible insights on pathogenesis discerned from immunohistochemistry. AB - BACKGROUND: TP53 mutations are rarely identified in low grade endometrioid carcinoma of the endometrium, and their pathogenic significance in such tumors is evidenced by the fact that TP53 aberrations have been associated with reduced recurrence-free survival in this subset of tumors. However, TP53 aberrations may not always represent a driving molecular event in a given endometrial cancer with a mutation. In this case study, the immunophenotype of a distinctive low grade endometrioid adenocarcinoma with an unusual pattern of lymph node metastases is used to explore the possible roles for underlying TP53-related molecular events in its pathogenesis. CASE PRESENTATION: A low grade endometrioid carcinoma, 9 cm in greatest dimension, with 35% invasion of the myometrial wall thickness, focal lymphovascular invasion, and metastases to 2 of 16 pelvic lymph nodes, was diagnosed in a 52-year-old woman. The endometrial tumor showed a p53-mutation (aberrant)-type immunohistochemical pattern in 40% of the tumor, but the rest of the tumor, as well as the foci of myometrial and lymphovascular invasion, were p53-wild type. Both lymph nodes with metastatic disease showed a distinct biphasic pattern, comprised of both p53-wild type and p53-aberrant areas in tumoral foci that were spatially apposed but not intermixed. Most p53-aberrant areas (at both the lymph nodes and the endometrium) showed a higher mitotic index and increased atypia as compared to the p53-wild type areas; both showed squamous differentiation. The p53-aberrant areas at both locations were also p16-diffusely positive, vimentin-positive, and estrogen/progesterone receptor-positive, whereas the p53-wild type areas showed an identical immunophenotype with the exception of being p16-mosaic positive. All components of the tumor at both the primary and metastatic sites showed loss of MSH2 and MSH6 and retained MLH/PMS2 expression. CONCLUSIONS: The presence of p53-mutant and wild-type areas in multiple lymph nodes, coupled with the absence of a p53-aberrant immunophenotype in the myometrium-invasive or lymphovascular-invasive portions of the tumor, argues against the possibility that the TP53 mutation in this tumor is a driving event in its pathogenesis, at least regarding the metastatic process. This case illustrates how routine immunohistochemistry can provide important insights into underlying molecular events in cancers, exemplifies an uncommon co-existence of DNA mismatch repair protein deficiency and p53-aberrant immunophenotype in low grade endometrioid carcinoma, illustrates morphologic differences between p53 aberrant and p53-wild type areas within in the same tumor, and is an exemplar of the emerging theory that lymph node metastases of endometrial cancer may be comprised of different subclones of the primary tumor. PMID- 29137658 TI - Comparison of three different fixation constructs for radial neck fractures: a biomechanical study. AB - BACKGROUND: Fixation of radial neck fractures can be achieved with a plate and screw construct or with two screws. This study evaluated the biomechanical properties of three different fixation methods following radial neck fractures. METHODS: Twenty-four fourth-generation composite radii were sawed to simulate an unstable radial neck fracture. They were then instrumented with a plate and screw construct or two different orientations (crossed and parallel) of screw fixation. Implants were tested under bending and torsional loads via a tension torsion composite test system. Bending and torsional failure loads were added to the remaining implant-radius constructs if they did not fail during the previous tests. RESULTS: During the bending loading test, the crossed-screw group showed the greatest stiffness, followed by the parallel-screw group, the plate group demonstrating the weakest stiffness. There was no significant difference between the crossed- and the parallel-screw groups. However, there was a significant difference between the two screw groups and the plate group. During the bending failure test, the largest stiffness was found for the crossed-screw group, while the plate group exhibited the smallest stiffness. There was a significant difference between the three groups. During the torsion loading test, the highest stiffness was observed for the crossed-screw group, while the plate group showed the lowest stiffness. In the torsion failure test, the failure torques were 11.97 +/- 2.659, 8.531 +/- 1.768, and 7.079 +/- 1.666 N m respectively for the crossed screw, parallel-screw, and plate groups. There was a significant difference between the crossed-screw group and the two other groups. CONCLUSIONS: Crossed screws and plate fixation are commonly used in clinical practice to treat simple radial neck fractures. While the present study shows that the parallel-screw method results in similar biomechanical strength as the two other techniques, it has the advantages of reaching limited wound exposure and having the implant buried. Therefore, it may be widely used in clinical practice. PMID- 29137660 TI - Optimising the value of the evidence generated in implementation science: the use of ontologies to address the challenges. AB - Implementing research findings into healthcare practice and policy is a complex process occurring in diverse contexts; it invariably depends on changing human behaviour in many parts of an intricate implementation system. Questions asked with the aim of improving implementation are multifarious variants of 'What works, compared with what, how well, with what exposure, with what behaviours (for how long), for whom, in what setting and why?'. Relevant evidence is being published at a high rate, but its quantity, complexity and lack of shared terminologies present challenges. The achievement of efficient, effective and timely synthesis of evidence is facilitated by using 'ontologies' to systematically structure and organise the evidence about constructs and their relationships, using a controlled, well-defined vocabulary. PMID- 29137659 TI - The effectiveness of research implementation strategies for promoting evidence informed policy and management decisions in healthcare: a systematic review. AB - BACKGROUND: It is widely acknowledged that health policy and management decisions rarely reflect research evidence. Therefore, it is important to determine how to improve evidence-informed decision-making. The primary aim of this systematic review was to evaluate the effectiveness of research implementation strategies for promoting evidence-informed policy and management decisions in healthcare. The secondary aim of the review was to describe factors perceived to be associated with effective strategies and the inter-relationship between these factors. METHODS: An electronic search was developed to identify studies published between January 01, 2000, and February 02, 2016. This was supplemented by checking the reference list of included articles, systematic reviews, and hand searching publication lists from prominent authors. Two reviewers independently screened studies for inclusion, assessed methodological quality, and extracted data. RESULTS: After duplicate removal, the search strategy identified 3830 titles. Following title and abstract screening, 96 full-text articles were reviewed, of which 19 studies (21 articles) met all inclusion criteria. Three studies were included in the narrative synthesis, finding policy briefs including expert opinion might affect intended actions, and intentions persisting to actions for public health policy in developing nations. Workshops, ongoing technical assistance, and distribution of instructional digital materials may improve knowledge and skills around evidence-informed decision-making in US public health departments. Tailored, targeted messages were more effective in increasing public health policies and programs in Canadian public health departments compared to messages and a knowledge broker. Sixteen studies (18 articles) were included in the thematic synthesis, leading to a conceptualisation of inter-relating factors perceived to be associated with effective research implementation strategies. A unidirectional, hierarchal flow was described from (1) establishing an imperative for practice change, (2) building trust between implementation stakeholders and (3) developing a shared vision, to (4) actioning change mechanisms. This was underpinned by the (5) employment of effective communication strategies and (6) provision of resources to support change. CONCLUSIONS: Evidence is developing to support the use of research implementation strategies for promoting evidence-informed policy and management decisions in healthcare. The design of future implementation strategies should be based on the inter-relating factors perceived to be associated with effective strategies. TRIAL REGISTRATION: This systematic review was registered with Prospero (record number: 42016032947). PMID- 29137661 TI - Applying tuberculosis management time to measure the tuberculosis infectious pool at a local level in Ethiopia. AB - BACKGROUND: Measuring the size of the infectious pool of tuberculosis (TB) is essential to understand the burden and monitor trends of TB control program performance. This study applied the concept of TB management time to estimate and compare the size of the TB infectious pool between 2009 and 2014 in West Gojjam Zone of Amhara Region, Ethiopia. METHODS: New sputum smear-positive and smear negative pulmonary TB (PTB) and retreatment cases who attended 30 randomly selected public health facilities in West Gojjam Zone from October 2013 to October 2014 were consecutively enrolled in the study. In order to determine the infectious period, the TB management time (number of days from the onset of cough until start of anti-TB treatment) was computed for each patient category. The number of undiagnosed TB cases was estimated and hence the TB management time for the undiagnosed category was calculated. The total size of the TB infectious pool during the study period for the study zone was estimated as the annual number of infectious person days. RESULTS: New smear-positive and smear-negative PTB cases contributed 25,050 and 12,931 infectious person days per year to the TB infectious pool, respectively. The retreatment and presently undiagnosed cases contributed 8840 and 34,310 infectious person days per year, respectively. The total size of the TB infectious pool in West Gojjam Zone during the study period was estimated at 81,131 infectious person days per year or 3405 infectious person days per 100,000 population per year. Compared to a similar study done in 2009 in the study area, the current study showed reduction of the TB infectious pool by 244,279 infectious person days. CONCLUSIONS: TB management time is a simple and practical tool that may help to estimate and compare the changes in the size of the TB infectious pool at local level. It may also be used as an indicator to monitor the changes in TB control program performance. PMID- 29137662 TI - Peer assisted learning among Sri Lankan medical undergraduates: a cross sectional study. AB - OBJECTIVE: The objectives of this study were to; (a) evaluate the current practices of peer assisted learning among second year and final year medical students of Faculty of Medicine, University of Colombo, Sri Lanka; (b) identify reasons for engaging in peer assisted learning; (c) identify perceived weaknesses in current learning activities; and (d) determine student characteristics associated with engaging in peer assisted learning. RESULTS: This cross sectional study interviewed two hundred and eighty-four eligible students. Average number of hours spent on peer assisted learning during a week was significantly greater among second year students compared to final year students (15.1 vs. 7.1 h, p < 0.05). Overall, female students were more likely to engage in peer assisted learning than male students. In second year, most common method of peer assisted learning was mass lectures offered by batch mates or seniors, while in final year it was group discussions. This reflected a transition to more focused, interactive, active learning among senior students. PMID- 29137663 TI - Patent landscape of neglected tropical diseases: an analysis of worldwide patent families. AB - BACKGROUND: "Neglected Tropical Diseases" (NTDs) affect millions of people in Africa, Asia and South America. The two primary ways of strategic interventions are "preventive chemotherapy and transmission control" (PCT), and "innovative and intensified disease management" (IDM). In the last 5 years, phenomenal progress has been achieved. However, it is crucial to intensify research effort into NTDs, because of the emerging drug resistance. According to the World Health Organization (WHO), the term NTDs covers 17 diseases, namely buruli ulcer, Chagas disease, dengue, dracunculiasis, echinococcosis, trematodiasis, human African trypanosomiasis, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, rabies, schistosomiasis, soil-transmitted helminthes, taeniasis, trachoma, and yaws. The aim of this study is to map out research and development (R&D) landscape through patent analysis of these identified NTDs. To achieve this, analysis and evaluation have been conducted on patenting trends, current legal status of patent families, priority countries by earliest priority years and their assignee types, technological fields of patent families over time, and original and current patent assignees. MAIN BODY: Patent families were extracted from Patseer, an international database of patents from over 100 patent issuing authorities worldwide. Evaluation of the patents was carried out using the combination of different search terms related to each identified NTD. In this paper, a total number of 12,350 patent families were analyzed. The main countries with sources of inventions were identified to be the United States (US) and China. The main technological fields covered by NTDs patent landscape are pharmaceuticals, biotechnology, organic fine chemistry, analysis of biological materials, basic materials chemistry, and medical technology. Governmental institutions and universities are the primary original assignees. Among the NTDs, leishmaniasis, dengue, and rabies received the highest number of patent families, while human African trypanosomiasis (sleeping sickness), taeniasis, and dracunciliasis received the least. The overall trend of patent families shows an increase between 1985 and 2008, and followed by at least 6 years of stagnation. CONCLUSION: The filing pattern of patent families analyzed undoubtedly reveals slow progress on research and development of NTDs. Involving new players, such as non-governmental organizations may help to mitigate and reduce the burden of NTDs. PMID- 29137664 TI - Therapeutic efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Ethiopia: a systematic review and meta-analysis. AB - BACKGROUND: As Ethiopia is one of the sub-Saharan countries with a great burden of malaria the effectiveness of first line anti-malarial drugs is the major concern. The aim of this study was to synthesize the available evidence on the efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Ethiopia. This was done by performing a meta-analysis of recent studies conducted in the country on this topic. METHODS: Studies published between January 2010 and January 2017 that reported on the efficacy of artemether lumefantrine in the treatment of P. falciparum malaria in Ethiopian patients were searched for using the PubMed and Google Scholar databases. Ten prospective single-arm cohort studies that followed patients for 28-42 days were included in this analysis. All of the included studies were deemed to be of high quality. RESULTS: Ten studies involving 1179 patients that were eligible for meta-analysis were identified. At recruitment, the average parasite count per patient was 1 2981/MUl of blood. On the third day of treatment, 96.7% and 98.5% of the study subjects become fever-free and parasite-free, respectively. Based on the per protocol analysis, the cure rate after use of artemether-lumefantrine was 98.2% (polymerase chain reaction corrected) and 97.01% (polymerase chain reaction uncorrected) after 28 days of follow-up. The reinfection rate within 28 days was 1.1% and the recrudescence rate was 1.9%. CONCLUSIONS: This review found that the cure rate for uncomplicated P. falciparum malaria using artemether-lumefantrine in Ethiopia is still high enough to recommend the drug as a first-line agent. There should be careful periodic monitoring of the efficacy of this drug, as treatment failure may occur due to resistance, sub-therapeutic levels that may occur due to non-adherence, or inadequate absorption. PMID- 29137665 TI - Treatment for lateral patellar impingement syndrome with arthroscopic lateral patelloplasty: a bidirectional cohort study. AB - BACKGROUND: Anterior knee pain is one of the most common musculoskeletal complaints of young patients. We notice that some patients had normal femoral trochlear, medial and lateral patellar retinaculum, and special patellar morphology, which resulted in a series of symptoms in the flexion of the knee due to the impingement of the lateral articular surface of the patella with the femur. We firstly termed this pathologic process as lateral patellar impingement syndrome (LPIS). This ambispective cohort study was to explore the curative effect of arthroscopic lateral patelloplasty for early LPIS. METHODS: Thirty-five early LPIS patients which underwent arthroscopic lateral patelloplasty were enrolled in our study. Evaluations consisted of pre- and postoperative symptoms, physical examinations, radiographs, and questionnaires. The Lysholm score, patellar suitable angle, patellar tilt angle, and patellar lateral shift were measured with the CT scan and Merchant X-ray film. The efficacy was graded as excellent, good, fair, and poor according to the patient's subjective evaluation. RESULTS: The patients were followed up for an average of 41.1 +/- 18.6 months. The efficacy results were excellent in 6, good in 26, fair in 2, and poor in 1. There were statistical differences in pre- and postoperative Lysholm scores (80.66 +/- 5.51 vs 81.91 +/- 6.21) (P < 0.05). The pre- and postoperative congruence angle, patellar tilt angle, and patellar lateral shift were significantly different (P < 0.05). CONCLUSIONS: Arthroscopic lateral patelloplasty is an effective and minimal-invasive method for patients with lateral patellar impingement syndrome. PMID- 29137666 TI - Utilization of the Behavior Change Wheel framework to develop a model to improve cardiometabolic screening for people with severe mental illness. AB - BACKGROUND: Individuals with severe mental illness (e.g., schizophrenia, bipolar disorder) die 10-25 years earlier than the general population, primarily from premature cardiovascular disease (CVD). Contributing factors are complex, but include systemic-related factors of poorly integrated primary care and mental health services. Although evidence-based models exist for integrating mental health care into primary care settings, the evidence base for integrating medical care into specialty mental health settings is limited. Such models are referred to as "reverse" integration. In this paper, we describe the application of an implementation science framework in designing a model to improve CVD outcomes for individuals with severe mental illness (SMI) who receive services in a community mental health setting. METHODS: Using principles from the theory of planned behavior, focus groups were conducted to understand stakeholder perspectives of barriers to CVD risk factor screening and treatment identify potential target behaviors. We then applied results to the overarching Behavior Change Wheel framework, a systematic and theory-driven approach that incorporates the COM-B model (capability, opportunity, motivation, and behavior), to build an intervention to improve CVD risk factor screening and treatment for people with SMI. RESULTS: Following a stepped approach from the Behavior Change Wheel framework, a model to deliver primary preventive care for people that use community mental health settings as their de facto health home was developed. The CRANIUM (cardiometabolic risk assessment and treatment through a novel integration model for underserved populations with mental illness) model focuses on engaging community psychiatrists to expand their scope of practice to become responsible for CVD risk, with significant clinical decision support. CONCLUSION: The CRANIUM model was designed by integrating behavioral change theory and implementation theory. CRANIUM is feasible to implement, is highly acceptable to, and targets provider behavior change, and is replicable and efficient for helping to integrate primary preventive care services in community mental health settings. CRANIUM can be scaled up to increase CVD preventive care delivery and ultimately improve health outcomes among people with SMI served within a public mental health care system. PMID- 29137667 TI - Selective medial soft tissue release combined with tibial reduction osteotomy in total knee arthroplasty. AB - BACKGROUND: To obtain the correct coronal alignment and balancing in flexion and extension, we established a selective medial release technique and investigated the effectiveness and safety of the technique during primary total knee arthroplasty (TKA). METHODS: Four hundred sixty-six primary TKAs with varus deformity were prospectively evaluated between June 2013 and June 2015. A knee joint position similar to Patrick's sign was used to release the medial structure. The medial release technique consisted of release of the capsule and the deep medial collateral ligament (dMCL) (step1), selective release of superficial medial collateral ligament (sMCL) or posterior oblique ligament (POL) (step 2), and selective tibial reduction osteotomy (step 3). Improvement of medial joint gap at each step and other clinical outcomes were evaluated. RESULTS: Among the 466 knees, symmetrical gaps could be achieved by the limited release of the capsule and the dMCcL in 276 (59%) knees. One hundred fifty-two (33%) required additional sMCL release with 2-5 cm from the joint line distally or POL release. Thirty-eight (8%) necessitated an additional tibial reduction osteotomy. Anterior-medial release and 4-mm medial osteotomy contributed to more improvement of medial gap in flexion than in extension (each p < 0.01). Posteromedial release and posteromedial osteotomy contributed to more improvement in extension than in flexion (each p < 0.01). No specific complication related to our technique was identified. CONCLUSION: The technique of the tibial reduction osteotomy combined with medial soft structure release using Patrick's sign is effective, safe, and minimally invasive to obtain balanced mediolateral and extension-flexion gaps in primary TKA. PMID- 29137668 TI - Advancing theory development: exploring the leadership-climate relationship as a mechanism of the implementation of cultural competence. AB - BACKGROUND: Leadership style and specific organizational climates have emerged as critical mechanisms to implement targeted practices in organizations. Drawing from relevant theories, we propose that climate for implementation of cultural competence reflects how transformational leadership may enhance the organizational implementation of culturally responsive practices in health care organizations. METHODS: Using multilevel data from 427 employees embedded in 112 addiction treatment programs collected in 2013, confirmatory factor analysis showed adequate fit statistics for our measure of climate for implementation of cultural competence (Cronbach's alpha = .88) and three outcomes: knowledge (Cronbach's alpha = .88), services (Cronbach's alpha = .86), and personnel (Cronbach's alpha = .86) practices. RESULTS: Results from multilevel path analyses indicate a positive relationship between employee perceptions of transformational leadership and climate for implementation of cultural competence (standardized indirect effect = .057, bootstrap p < .001). We also found a positive indirect effect between transformational leadership and each of the culturally competent practices: knowledge (standardized indirect effect = .006, bootstrap p = .004), services (standardized indirect effect = .019, bootstrap p < .001), and personnel (standardized indirect effect = .014, bootstrap p = .005). CONCLUSIONS: Findings contribute to implementation science. They build on leadership theory and offer evidence of the mediating role of climate in the implementation of cultural competence in addiction health service organizations. PMID- 29137669 TI - Blocked expression of key genes of the angiogenic pathway in JSRV-induced pulmonary adenocarcinomas. AB - JSRV (Jaagsiekte Sheep Retrovirus) is a retrovirus inducing a transmissible lung adenocarcinoma in sheep and goats with predominantly lepidic and papillary lesions. This naturally occurring lung cancer in large animals shares many features with human pneumonic-type lung adenocarcinomas with predominant lepidic growth. The metastatic spread is rare in both human and animal cancers. This unique feature prompted us to decipher the angiogenesis pathway in these cancers. We focused on the levels of mRNA and proteins of genes implicated in the extension of JSRV-induced lung adenocarcinomas by studying their expression in lung cancers (n = 10) and normal lungs (n = 10) and in primary epithelial alveolar type II cells derived from cancers (n = 10) or normal lungs (n = 6). In parallel, we evaluated the levels of expression of key genes in lung tissues collected from lepidic (n = 13) or papillary (n = 5) human adenocarcinomas and, when available, adjacent normal lungs (n = 11). We measured the expression of the same key genes implicated in angiogenesis, lymphangiogenesis and degradation of the extracellular matrix. In ovine adenocarcinomas, VEGFR2 and VEGFD mRNA were downregulated in cancers; MMP9, TIMP1 and FGFR2 mRNA were overexpressed as compared to normal lungs. Importantly, VEGFA and VEGFR2 proteins were not expressed in JSRV-induced cancers. In human lepidic adenocarcinomas, VEGFA and VEGFR2 mRNA were weakly expressed and no VEGFR2 protein was detectable. Downregulation of key angiogenic players may contribute to the control of extra thoracic invasion of cancer cells in human and ovine pneumonic-type adenocarcinoma with predominant lepidic growth. PMID- 29137670 TI - Modelling and mapping tick dynamics using volunteered observations. AB - BACKGROUND: Tick populations and tick-borne infections have steadily increased since the mid-1990s posing an ever-increasing risk to public health. Yet, modelling tick dynamics remains challenging because of the lack of data and knowledge on this complex phenomenon. Here we present an approach to model and map tick dynamics using volunteered data. This approach is illustrated with 9 years of data collected by a group of trained volunteers who sampled active questing ticks (AQT) on a monthly basis and for 15 locations in the Netherlands. We aimed at finding the main environmental drivers of AQT at multiple time scales, and to devise daily AQT maps at the national level for 2014. METHOD: Tick dynamics is a complex ecological problem driven by biotic (e.g. pathogens, wildlife, humans) and abiotic (e.g. weather, landscape) factors. We enriched the volunteered AQT collection with six types of weather variables (aggregated at 11 temporal scales), three types of satellite-derived vegetation indices, land cover, and mast years. Then, we applied a feature engineering process to derive a set of 101 features to characterize the conditions that yielded a particular count of AQT on a date and location. To devise models predicting the AQT, we use a time-aware Random Forest regression method, which is suitable to find non linear relationships in complex ecological problems, and provides an estimation of the most important features to predict the AQT. RESULTS: We trained a model capable of fitting AQT with reduced statistical metrics. The multi-temporal study on the feature importance indicates that variables linked to water levels in the atmosphere (i.e. evapotranspiration, relative humidity) consistently showed a higher explanatory power than previous works using temperature. As a product of this study, we are able of mapping daily tick dynamics at the national level. CONCLUSIONS: This study paves the way towards the design of new applications in the fields of environmental research, nature management, and public health. It also illustrates how Citizen Science initiatives produce geospatial data collections that can support scientific analysis, thus enabling the monitoring of complex environmental phenomena. PMID- 29137671 TI - Herpes simplex virus-1 entrapped in Candida albicans biofilm displays decreased sensitivity to antivirals and UVA1 laser treatment. AB - BACKGROUND: Recently, we published data suggesting a mutualistic relationship between HSV-1 and Candida. albicans; in particular: (a) HSV-1 infected macrophages are inhibited in their anti-Candida effector function and (b) Candida biofilm protects HSV-1 from inactivation. The present in vitro study is aimed at testing the effects of Candida biofilm on HSV-1 sensitivity to pharmacological and physical stress, such as antiviral drugs (acyclovir and foscarnet) and laser UVA1 irradiation. We also investigated whether fungus growth pattern, either sessile or planktonic, influences HSV-1 sensitivity to antivirals. METHODS: Mature Candida biofilms were exposed to HSV-1 and then irradiated with laser light (UVA1, 355 lambda). In another set of experiments, mature Candida biofilm were co-cultured with HSV-1 infected VERO cells in the presence of different concentrations of acyclovir or foscarnet. In both protocols, controls unexposed to laser or drugs were included. The viral yield of treated and untreated samples was evaluated by end-point titration. To evaluate whether this protective effect might occur in relation with a different growth pattern, HSV-1 infected cells were co-cultured with either sessile or planktonic forms of Candida and then assessed for susceptibility to antiviral drugs. RESULTS: UVA1 irradiation caused a 2 Log reduction of virus yield in the control cultures whereas the reduction was only 1 Log with Candida biofilm, regardless to the laser dose applied to the experimental samples (50 or 100 J/cm2). The presence of biofilm increased the IC90 from 18.4-25.6 J/cm2. Acyclovir caused a 2.3 Log reduction of virus yield in the control cultures whereas with Candida biofilm the reduction was only 0.5 Log; foscarnet determined a reduction of 1.4 Log in the controls and 0.2 Log in biofilm cultures. Consequently, the ICs50 for acyclovir and foscarnet increased by 4- and 12-folds, respectively, compared to controls. When HSV-1 was exposed to either sessile or planktonic fungal cells, the antiviral treatments caused approximately the same weak reduction of virus yield. CONCLUSIONS: These data demonstrate that: (1) HSV-1 encompassed in Candida biofilm is protected from inactivation by physical (laser) and pharmacological (acyclovir or foscarnet) treatments; (2) the drug antiviral activity is reduced at a similar extent for both sessile or planktonic Candida. PMID- 29137672 TI - The primary health care in the emirate of Abu Dhabi: are they aligned with the chronic care model elements? AB - BACKGROUND: Abu Dhabi is the capital of the United Arab Emirates (UAE) and the largest of the seven emirates in terms of land mass and population. Abu Dhabi emirate has three different geographical regions: the Central Capital District, the Eastern Region, and the Western Region. The health system has been regulated by the Health Authority - Abu Dhabi (HAAD), and has been provided by the Abu Dhabi Health Services Company (SEHA), since 2007. The UAE has a high population burden of morbidity and mortality related to chronic diseases. This paper aims to characterize the Primary Health Care (PHC) public services in Abu Dhabi using the Chronic Care Model (CCM) as a framework. METHODS: Officially published data from HAAD, SEHA and the UAE Ministry of Health and Prevention was reviewed and abstracted. The Preferred Reporting Items Systematic Reviews and Meta-Analysis (PRISMA) statement was used as a baseline to review the PHC services through the CCM approach and to identify potential opportunities for improvement. RESULTS: There are 38 SEHA Ambulatory Healthcare Centers (AHS) that provide PHC, from which 20 are located in the Eastern Region and the other 18 in the Central Capital District. The AHS adopted the principles of the patient-centered medical home model, aiming at providing structured, proactive and coordinated care. Implementation of the CCM elements aligns with those standards and is positively associated with the use of interventions targeting high-risk behaviors. CONCLUSION: The UAE has a strong foundation in place for addressing the growing problem of chronic diseases. The CCM has been shown to have beneficial effects on clinical outcomes reinforcing the PHC procedures and processes of care and should continue to inform systematic efforts to improve the care that lead to better lives for the Abu Dhabi community. PMID- 29137673 TI - A cheap and open HIV viral load technique applicable in routine analysis in a resource limited setting with a wide HIV genetic diversity. AB - BACKGROUND: HIV infection in Cameroon is characterized by a great viral diversity with all HIV-1 groups (M, N, O, and P) and HIV-2 in circulation. HIV group determination is very important if tailored viral load analysis and treatments are to be applied. In our laboratory, HIV viral load is carried out using two platforms; Biocentric and Abbott depending on the HIV group identified. Biocentric which quantifies HIV-1 group M is a cheap and open system useful in resource limited settings. The objective of this study was to compare the viral load analyses of serologically group-indeterminate HIV samples using the two platforms with the view of reducing cost. METHODS: Consecutive samples received between March and May 2014, and between August and September 2014 in our laboratory for HIV viral load analysis were included. All these samples were analyzed for their HIV groups using an in-house ELISA serotyping test. All HIV-1 group M samples were quantified using the Biocentric test while all other known atypical samples (HIV-1 groups N, O and P) were analyzed using the Abbott technique. HIV group-indeterminate samples (by serotyping) were quantified with both techniques. RESULTS: Among the 6355 plasma samples received, HIV-1 group M was identified in 6026 (94.82%) cases; HIV-1 group O, in 20 (0.31%); HIV-1 group M + O, in 3 (0.05%) and HIV-2, in 3 (0.05%) case. HIV-group indeterminate samples represented about 4.76% (303/6355) and only 231 of them were available for analysis by Abbott Real-Time HIV-1 and Generic HIV Viral Load techniques. Results showed that 188 (81.39%) samples had undetectable viral load in both techniques. All the detectable samples showed high viral load, with a mean of 4.5 log copies/ml (range 2.1-6.5) for Abbott Real-Time and 4.5 log copies/ml (range 2 6.4) for Generic HIV Viral Load. The mean viral load difference between the two techniques was 0.03 log10 copies/ml and a good correlation was obtained (r 2 = 0.89; P < 0.001). CONCLUSION: Our results suggest that cheaper and open techniques such as Biocentric could be useful alternatives for HIV viral load follow-up quantification in resource limited settings like Cameroon; even with its high viral diversity. PMID- 29137674 TI - The development of the PARENTS: a tool for parents to assess residents' non technical skills in pediatric emergency departments. AB - BACKGROUND: Parents can assess residents' non-technical skills (NTS) in pediatric emergency departments (EDs). There are no assessment tools, with validity evidence, for parental use in pediatric EDs. The purpose of this study was to develop the Parents' Assessment of Residents Enacting Non-Technical Skills (PARENTS) educational assessment tool and collect three sources of validity evidence (i.e., content, response process, internal structure) for it. METHODS: We established content evidence for the PARENTS through interviews with physician educators and residents, focus groups with parents, a literature review, and a modified nominal group technique with experts. We collected response process evidence through cognitive interviews with parents. To examine the internal structure evidence, we administered the PARENTS and performed exploratory factor analysis. RESULTS: Initially, a 20-item PARENTS was developed. Cognitive interviews led to the removal of one closed-ended item, the addition of resident photographs, and wording/formatting changes. Thirty-seven residents and 434 parents participated in the administration of the resulting 19-item PARENTS. Following factor analysis, a one-factor model prevailed. CONCLUSIONS: The study presents initial validity evidence for the PARENTS. It also highlights strategies for potentially: (a) involving parents in the assessment of residents, (b) improving the assessment of NTS in pediatric EDs, and PMID- 29137675 TI - Human hyaluronic acid synthase-1 promotes malignant transformation via epithelial to-mesenchymal transition, micronucleation and centrosome abnormalities. AB - BACKGROUND: Human hyaluronic acid (HA) molecules are synthesized by three membrane spanning Hyaluronic Acid Synthases (HAS1, HAS2 and HAS3). Of the three, HAS1 is found to be localized more into the cytoplasmic space where it synthesizes intracellular HA. HA is a ubiquitous glycosaminoglycan, mainly present in the extracellular matrix (ECM) and on the cell surface, but are also detected intracellularly. Accumulation of HA in cancer cells, the cancer surrounding stroma, and ECM is generally considered an independent prognostic factors for patients. Higher HA production also correlates with higher tumor grade and more genetic heterogeneity in multiple cancer types which is known to contribute to drug resistance and results in treatment failure. Tumor heterogeneity and intra-tumor clonal diversity are major challenges for diagnosis and treatment. Identification of the driver pathway(s) that initiate genomic instability, tumor heterogeneity and subsequent phenotypic/clinical manifestations, are fundamental for the diagnosis and treatment of cancer. Thus far, no evidence was shown to correlate intracellular HA status (produced by HAS1) and the generation of genetic diversity in tumors. METHODS: We tested different cell lines engineered to induce HAS1 expression. We measured the epithelial traits, centrosomal abnormalities, micronucleation and polynucleation of those HAS1-expressing cells. We performed real-time PCR, 3D cell culture assay, confocal microscopy, immunoblots and HA-capture methods. RESULTS: Our results demonstrate that overexpression of HAS1 induces loss of epithelial traits, increases centrosomal abnormalities, micronucleation and polynucleation, which together indicate manifestation of malignant transformation, intratumoral genetic heterogeneity, and possibly create suitable niche for cancer stem cells generation. CONCLUSIONS: The intracellular HA produced by HAS1 can aggravate genomic instability and intratumor heterogeneity, pointing to a fundamental role of intracellular HA in cancer initiation and progression. PMID- 29137676 TI - A medium invasiveness multi-level patient's specific template for pedicle screw placement in the scoliosis surgery. AB - BACKGROUND: Several methods including free-hand technique, fluoroscopic guidance, image-guided navigation, computer-assisted surgery system, robotic platform and patient's specific templates are being used for pedicle screw placement. These methods have screw misplacements and are not always easy to be applied. Furthermore, it is necessary to expose completely a large portions of the spine in order to access fit entirely around the vertebrae. METHODS: In this study, a multi-level patient's specific template with medium invasiveness was proposed for pedicle screw placement in the scoliosis surgery. It helps to solve the problems related to the soft tissues removal. After a computer tomography (CT) scan of the spine, the templates were designed based on surgical considerations. Each template was manufactured using three-dimensional printing technology under a semi-flexible post processing. The templates were placed on vertebras at four points-at the base of the superior-inferior articular processes on both left right sides. This helps to obtain less invasive and more accurate procedure as well as true-stable and easy placement in a unique position. The accuracy of screw positions was confirmed by CT scan after screw placement. RESULTS: The result showed the correct alignment in pedicle screw placement. In addition, the template has been initially tested on a metal wire series Moulage (height 70 cm and material is PVC). The results demonstrated that it could be possible to implement it on a real patient. CONCLUSIONS: The proposed template significantly reduced screw misplacements, increased stability, and decreased the sliding & the intervention invasiveness. PMID- 29137677 TI - Angiotensin II in vasodilatory shock: lights and shadows. PMID- 29137678 TI - Disentangling regional trade agreements, trade flows and tobacco affordability in sub-Saharan Africa. AB - BACKGROUND: In principle, trade and investment agreements are meant to boost economic growth. However, the removal of trade barriers and the provision of investment incentives to attract foreign direct investments may facilitate increased trade in and/or more efficient production of commodities considered harmful to health such as tobacco. We analyze existing evidence on trade and investment liberalization and its relationship to tobacco trade in Sub-Saharan African countries. METHODS: We compare tobacco trading patterns to foreign direct investments made by tobacco companies. We estimate and compare changes in the Konjunkturforschungsstelle (KOF) Economic Globalization measure, relative price measure and cigarette prices. RESULTS: Preferential regional trade agreements appear to have encouraged the consolidation of cigarette production, which has shaped trading patterns of tobacco leaf. Since 2002, British American Tobacco has invested in tobacco manufacturing facilities in Nigeria, Kenya and South Africa strategically located to serve different regions in Africa. Following this, British America Tobacco closed factories in Ghana, Rwanda, Uganda, Mauritius and Angola. At the same time, Malawi and Tanzania exported a large percentage of tobacco leaf to European countries. After 2010, there was an increase in tobacco exports from Malawi and Zambia to China, which may be a result of preferential trade agreements the EU and China have with these countries. Economic liberalization has been accompanied by greater cigarette affordability for the countries included in our analysis. However, only excise taxes and income have an effect on cigarette prices within the region. CONCLUSIONS: These results suggest that the changing economic structures of international trade and investment are likely heightening the efficiency and effectiveness of the tobacco industry. As tobacco control advocates consider supply-side tobacco control interventions, they must consider carefully the effects of these economic agreements and whether there are ways to mitigate them. PMID- 29137679 TI - Trial of Acute Femoral Fracture Fixation (TrAFFix): study protocol for a randomised controlled feasibility trial. AB - BACKGROUND: Distal femoral fractures are a source of considerable morbidity and best treatment is currently uncertain. The Trial of Acute Femoral Fracture Fixation (TrAFFix) is a randomised, parallel-group feasibility study designed to inform the design of a later, definitive clinical trial comparing intramedullary nails and locking plates for the treatment of distal femoral fractures. METHODS/DESIGN: Patients aged 50 years and older with a femoral fracture within the distal two Muller squares are potentially eligible for inclusion. Participants are randomly allocated to receive fixation with either an intramedullary nail or a distal locking plate. Measurements (EuroQol 5 Dimensions, Dementia Quality of Life, Disability Rating Index) are collected at baseline, 6 weeks and 4 months. The recruitment rate will be assessed across seven participating centres over a total of 52 centre-months which is expected after 10 months of recruitment. Objectives are - feasibility phase, to assess recruitment rate and completion rate of the primary outcome measure; process evaluation, to assess the generalisability and likely success of a future trial; definitive trial, quantify and draw inferences on observed differences in health related quality of life at 4 months between the study intervention groups (nail versus plate). A favourable opinion was granted by the Wales Research Ethics Committee (16/WA/0225), study-wide NHS approval was given by the Health Research Authority (IRAS 206745), and participating NHS trusts provided local approvals. This study was funded by the National Institute for Health Research Health Technology Assessment (HTA 15/59/22). DISCUSSION: This is the protocol for a feasibility study conducted prior to any future definitive trial. The estimates of participant recruitment rate and proportion of data completion will be coupled with outputs from the process evaluation to make a final decision regarding feasibility TRIAL REGISTRATIONS: The study is registered with the National Institute for Health Research Portfolio (CPMS ID: 32536) and the ISRCTN registry ( ISRCTN92089567 ) on 26 May 2016. PMID- 29137680 TI - Correction to: Development of molecular confirmation tools for swift and easy rabies diagnostics. AB - CORRECTION: After publication of the article [1], it has been brought to our attention that an incorrect genetic sequence has been cited. On page 4, paragraph 1 the following sequence is cited "ATG GAT GCC GAC AAG ATT GTM TTY AAA GTY AAT A 3". This is an error and the correct sequence should be "GGG GGC TTT YCC TAG GGT KAT ACW GGG CTT T 3". PMID- 29137681 TI - Influence of tourniquet use in primary total knee arthroplasty with drainage: a prospective randomised controlled trial. AB - BACKGROUND: We aimed to compare the effect of tourniquet use or lack of it on recovery following uncomplicated primary total knee arthroplasty (TKA). METHODS: In a prospective randomised double-blinded study, 150 patients undergoing primary TKA were assigned to either a tourniquet or non-tourniquet group. At the early phase, 3 and 6 months after surgery, an independent observer assessed the primary outcome measure (i.e. total blood loss) and secondary outcome measures (i.e. wound complications, visual analogue scale pain score and knee range of motion). RESULTS: The tourniquet group exhibited reduced intraoperative blood loss (215.7 +/- 113.7 ml vs. 138.6 +/- 93.9 ml, P < 0.001) and shorter operating time (77.2 +/- 14.5 min vs. 82.0 +/- 12.7 min, P = 0.038). However, the non-tourniquet group showed less postoperative blood loss (180.2 +/- 117.0 ml vs. 253.7 +/- 144.2 ml, P = 0.001) and drainage volume (89.2 +/- 66.3 ml vs. 164.5 +/- 97.8 ml, P = 0.004), less thigh pain (all P < 0.001) in the initial 3 weeks, better knee range of motion (ROM) in the initial 3 days (day 1 81.6 +/- 17.1 vs. 75.95 +/- 14.55, P = 0.036; day 3 99.8 +/- 13.7 vs. 93.95 +/- 11.15, P = 0.005) and fewer wound tension vesicles (10.3 vs. 29.2%, P = 0.005). Earlier straight-leg raising (4.6 +/- 3.8 h vs. 6.4 +/- 4.3 h, P = 0.01) and shorter length of stay (6.3 +/- 1.7 days vs. 7.1 +/- 1.9 days, P = 0.001) were found in the non-tourniquet group. Similar total blood loss and blood transfusion rate were observed for both groups. All other parameters revealed no significant differences. CONCLUSIONS: Our study suggests that a non-tourniquet TKA would lead to early rehabilitation without increasing side effects. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR-IOR-16007851 , 1/29/2016. PMID- 29137682 TI - Cefepime-induced neurotoxicity: a systematic review. AB - BACKGROUND: Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood-brain barrier and exhibit concentration-dependent Upsilon-aminobutyric acid (GABA) antagonism. Neurotoxic symptoms include depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. Data suggest that up to 15% of ICU patients treated with cefepime may experience these adverse effects. Risk factors include renal dysfunction, excessive dosing, preexisting brain injury, and elevated serum cefepime concentrations. We aimed to characterize the clinical course of cefepime neurotoxicity and response to interventions. METHODS: A librarian-assisted search identified publications describing cefepime-associated neurotoxicity from January 1980 to February 2016 using the CINAHL and MEDLINE databases. Search terms included cefepime, neurotoxicity, encephalopathy, seizures, delirium, coma, non-convulsive status epilepticus, myoclonus, confusion, aphasia, agitation, and death. Two reviewers independently assessed identified articles for eligibility and used the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) for data reporting. RESULTS: Of the 123 citations identified, 37 (representing 135 patient cases) were included. Patients had a median age of 69 years, commonly had renal dysfunction (80%) and required intensive care (81% of patients with a reported location). All patients exhibited altered mental status, with reduced consciousness (47%), myoclonus (42%), and confusion (42%) being the most common symptoms. All 98 patients (73% of cohort) with electroencephalography had abnormalities, including non-convulsive status epilepticus (25%), myoclonic status epilepticus (7%), triphasic waves (40%), and focal sharp waves (39%). As per Food and Drug Administration (FDA)-approved dosing guidance, 48% of patients were overdosed; however, 26% experienced neurotoxicity despite appropriate dosing. Median cefepime serum and cerebrospinal fluid (CSF) concentrations were 45 mg/L (n = 21) and 13 mg/L (n = 4), respectively. Symptom improvement occurred in 89% of patients, and 87% survived to hospital discharge. The median delay from starting the drug to symptom onset was 4 days, and resolution occurred a median of 2 days after the intervention, which included cefepime discontinuation, antiepileptic administration, or hemodialysis. CONCLUSIONS: Cefepime-induced neurotoxicity is challenging to recognize in the critically ill due to widely varying symptoms that are common in ICU patients. This adverse reaction can occur despite appropriate dosing, usually resolves with drug interruption, but may require additional interventions such as antiepileptic drug administration or dialysis. PMID- 29137683 TI - Tanshinone I alleviates motor and cognitive impairments via suppressing oxidative stress in the neonatal rats after hypoxic-ischemic brain damage. AB - Neonatal hypoxia-ischemia is one of the main reasons that cause neuronal damage and neonatal death. Several studies have shown that tanshinone I (TsI), one of the major ingredients of Danshen, exerts potential neuroprotective effect in adult mice exposed to permanent left cerebral ischemia. However, it is unclear whether administration of TsI has neuroprotective effect on neonatal hypoxic ischemic brain damage (HIBD), and if so, the potential mechanisms also remain unclear. Here, we reported that treatment with TsI (5 mg/kg, i.p.) significantly alleviated the deficits of myodynamia and motor functions as well as the spatial learning and memory in the rat model of HIBD. These behavioral changes were accompanied by a significant decrease in the number of neuronal loss in the CA1 area of hippocampus. Moreover, ELISA assay showed that TsI significantly increased the production of antioxidants including total antioxidant capacity (T AOC), glutathione (GSH), total superoxide dismutase (T-SOD) and catalase (CAT), and reduced the production of pro-oxidants including hydrogen peroxide (H2O2), total nitric oxide synthase (T-NOS) and inducible nitric oxide synthase (iNOS). Taken together, these results indicate that TsI presents potential neuroprotection against neuronal damage via exerting significantly antioxidative activity and against pro-oxidant challenge, thereby ameliorating hypoxia-ischemia induced motor and cognitive impairments in the neonatal rats, suggesting that TsI may be a potential therapeutic agent against HIBD. PMID- 29137684 TI - Use of an intraoperative navigation system and piezoelectric surgery for styloidectomy in a patient with Eagle's syndrome: a case report. AB - BACKGROUND: Elongated styloid process syndrome (Eagle's syndrome) is the term given to the symptomatic elongation of the styloid process or the mineralization of the stylohyoid or stylomandibular ligament. The two commonly used approaches for the surgical treatment of this syndrome are the transcervical and transoral approaches. Both have their limitations and specific intraoperative risks. Here, we report the treatment of a patient with Eagle's syndrome using the transoral approach in conjunction with piezoelectric surgery, surgical planning, and intraoperative navigation to reduce the risk of complications. CASE PRESENTATION: The elongated styloid process was resected in a 45-year-old Japanese man using a minimally invasive approach with an intraoperative navigation system. Preoperative preparation involved the use of a custom interocclusal splint to produce the mouth opening conditions required during surgery. Using the three dimensional position of the navigation probe, the location of the elongated styloid process was identified. After confirmation of the resection spot via the transoral approach, the styloid process was dissected by piezoelectric surgery. Follow-up examination showed an uneventful recovery with no associated complications. CONCLUSION: The resection of the styloid process using an intraoperative navigation system and a custom interocclusal splint during a transoral approach, together with a piezoelectric cutting device, is safe and effective for the treatment of Eagle's syndrome. PMID- 29137685 TI - Nutrition research in cognitive impairment/dementia, with a focus on soya and folate. AB - Observational studies and treatment trials investigating nutrition and cognitive function, with a focus on folate and soya and dementia, were reviewed. Data suggested that effects of folic acid based interventions may only be shown before cognitive decline is evident and/or if people are folate deficient. In older people in Indonesia, Hawai'i and China, tofu, which can contain high levels of phytoestrogens, was found to increase dementia risk. This association was not mediated by a vegetarian diet, socioeconomic status, formaldehyde, thyroid function, or loss of teeth. On the other hand, human observational and animal treatment studies suggested that tempe, a fermented soya product containing phytoestrogens and folate, reduced dementia risk and improved memory. High oestrogen levels were found to increase dementia risk in older women. However, in women with adequate serum folate, high oestrogen levels did not confer additional dementia risk and may protect ageing neurons. In conclusion, reviews seem to suggest that folic acid interventions are only effective on cognitive outcomes in people who are folate deficient and do not have cognitive impairment. Frequent consumption of tofu may have detrimental effects on memory and increase dementia risk in older East Asian people, while tempe may reduce these risks. Possibly folate in tempe offsets the potential negative effects of oestrogenic compounds on ageing neurons. PMID- 29137686 TI - The food multimix concept: harnessing and promoting local composite complementary diets. AB - Over the past two decades, increasing efforts have been made to find suitable nutritional products for managing particularly moderate forms of malnutrition following acute phase treatment, including the adoption of ready-to-use therapeutic foods. The challenge in meeting nutrient needs of normal growing young children and other vulnerable population groups with scant food supply has led us to explore the use of local, traditional and culturally adaptable food based complementary foods employing the food multimix (FMM) concept. The present paper examined FMM as a concept to demonstrate how locally available composite complementary recipes were used to create highly nutritious recipes at low cost and improve nutrition among vulnerable individuals. The method employed a food-to food fortification approach for recipe development making use of the 'nutrient strengths' of candidate ingredients. A range of different food recipes had been developed using a stepwise approach and combinations of foods from different populations and communities and packaged as 100 g recipe powders. Proximate and micronutrient analyses have been undertaken, optimised and the nutrient compositions compared with reference nutrient intakes for target groups. Examples of recipes and their nutrient profiles had been highlighted for different formulations showing different ingredients. Theoretical nutrient values were translated into practice based on data from intervention studies. The FMM approach using locally available food has held promise, and published evidence did indicate that the concept can contribute significantly to long-term food based solutions to meeting nutrient needs of vulnerable groups in poor communities. PMID- 29137688 TI - The Long Noncoding RNA HOTAIR Promotes Colorectal Cancer Progression by Sponging miR-197. AB - The long noncoding RNA HOX transcript antisense RNA (HOTAIR) has been found to be overexpressed in many human malignancies and involved in tumor progression and metastasis. Although the downstream target through which HOTAIR modulates tumor metastasis is not well known, evidence suggests that microRNA-197 (miR-197) might be involved in this event. In the present study, the significance of HOTAIR and miR-197 in the progression of colorectal cancer was detected in vitro and in vivo. We found that HOTAIR expression was significantly increased in colorectal cancer cells and tissues. In contrast, the expression of miR-197 was obviously decreased. We further demonstrated that HOTAIR knockdown promoted apoptosis and inhibited cell proliferation, migration, and invasion in vitro and in vivo. Moreover, HOTAIR modulated the progression of colorectal cancer by competitively binding miR-197. Taken together, our study has identified a novel pathway through which HOTAIR exerts its oncogenic role and provided a molecular basis for potential applications of HOTAIR in the prognosis and treatment of colorectal cancer. PMID- 29137687 TI - Combining traditional dietary assessment methods with novel metabolomics techniques: present efforts by the Food Biomarker Alliance. AB - FFQ, food diaries and 24 h recall methods represent the most commonly used dietary assessment tools in human studies on nutrition and health, but food intake biomarkers are assumed to provide a more objective reflection of intake. Unfortunately, very few of these biomarkers are sufficiently validated. This review provides an overview of food intake biomarker research and highlights present research efforts of the Joint Programming Initiative 'A Healthy Diet for a Healthy Life' (JPI-HDHL) Food Biomarkers Alliance (FoodBAll). In order to identify novel food intake biomarkers, the focus is on new food metabolomics techniques that allow the quantification of up to thousands of metabolites simultaneously, which may be applied in intervention and observational studies. As biomarkers are often influenced by various other factors than the food under investigation, FoodBAll developed a food intake biomarker quality and validity score aiming to assist the systematic evaluation of novel biomarkers. Moreover, to evaluate the applicability of nutritional biomarkers, studies are presently also focusing on associations between food intake biomarkers and diet-related disease risk. In order to be successful in these metabolomics studies, knowledge about available electronic metabolomics resources is necessary and further developments of these resources are essential. Ultimately, present efforts in this research area aim to advance quality control of traditional dietary assessment methods, advance compliance evaluation in nutritional intervention studies, and increase the significance of observational studies by investigating associations between nutrition and health. PMID- 29137690 TI - Avoiding the Perils of Self-Plagiarism: The Importance of Acknowledging Your Original Scholarly Project. PMID- 29137689 TI - MicroRNA-433 Represses Proliferation and Invasion of Colon Cancer Cells by Targeting Homeobox A1. AB - The aberrant expression of miR-433 has been validated in some types of cancers. However, the expression profile and the biological function of miR-433 on colon cancer are still elusive. This study was designed to investigate the function of miR-433 on the proliferation and invasion of colon cancer cells. We detected the expression of miR-433 in colon cancer tissues, adjacent normal tissues, and cell lines. CCK8 and Transwell assays were performed to explore the impact of miR-433 on colon cancer cell proliferation and invasion. The luciferase reporter assay was applied to identify the direct target of miR-433. The results demonstrated that miR-433 was downregulated in colon cancer tissues and cell lines when compared with the control. Overexpression of miR-433 significantly suppressed the ability of colon cancer cell proliferation and invasion, whereas knockdown of miR 433 remarkably enhanced cell proliferation and invasion. Homeobox A1 (HOXA1) was identified as a target of miR-433, and it mediated the functions of miR-433 on colon cancer cells. To conclude, we revealed that miR-433 was downregulated in colon cancer, and it inhibited colon cancer cell proliferation and invasion by directly targeting HOXA1. PMID- 29137691 TI - Goodbye Theory-Practice Gap: Highlighting the Neuman Systems Model. PMID- 29137692 TI - Attitudes, Social Norms, Perceived Behavioral Control, and Intention Toward Methicillin-Resistant Staphylococcus aureus Screening Among Health Care Workers. AB - BACKGROUND: Screening for methicillin-resistant Staphylococcus aureus (MRSA) represents a worldwide public health priority. Screening patients to detect colonization is considered an essential pillar of any MRSA control program. PURPOSE: To (a) assess health care workers' (HCWs) attitudes, social norms, perceived behavioral control toward MRSA screening, and intention to perform the screening; (b) examine the predictors of HCWs intentions to perform screening; (c) identify HCWs' perception of barriers to and benefits of screening; and (d) identify HCWs' information sources about screening. METHODS: Data obtained from 870 HCWs using the MRSA Screening Survey (MRSASS) were analyzed. The MRSASS was divided into three parts. Part 1 assessed sociodemographic variables. Part 2 contained the following six sections: (a) attitudes and perceived risk of MRSA screening, (b) perceived social norms of screening, (c) perceived behavioral control factors, (d) intention, (e) barriers to screening, and (f) benefit of screening. Part 3 assessed HCWs' source of information about MRSA screening. RESULTS: HCWs had positive attitudes toward the intention to screen for MRSA. Many HCWs felt that they had little influence on policy makers to conduct MRSA screening. The most reported barriers for MRSA screening were a lack of isolation facilities and increased workload. Only 5.2% (n = 45) of respondents indicated that they had been given MRSA screening training. CONCLUSION: Attitude was the only predictor for the intention to screen for MRSA. HCWs believed that the barriers to MRSA screening were inadequate facilities, primarily the lack of isolation facilities, and increased workload. PMID- 29137693 TI - Another Chance at Life: Jordanian Patients' Experience of Going Through a Myocardial Infarction. AB - BACKGROUND AND PURPOSE: Myocardial infarction (MI) is a life-threatening health condition that has physical, spiritual, emotional, and social changes. Understanding feelings and thoughts of patients who suffered MI attacks is essential to recovery. Among Jordanian patients who suffered an acute attack of MI, the aim of the study was to describe the experiences and the varied meanings that they assign to their experiences. METHODS: A qualitative hermeneutic phenomenological research design was used. Five participants were engaged in in depth semistructured interviews. The participants were identified using a purposeful sampling technique, after being admitted at a coronary care unit in a university hospital located in Amman, the capital city of Jordan. The hospital provides a full range of cardiovascular medical and surgical care for patients admitted from different socioeconomic levels. Transcribed data were analyzed following inductive qualitative content analysis method. RESULTS: The experience of MI was a traumatizing event characterized by life-threatening symptoms, and participants feared they would not come back home. However, cultural values and religiosity among the Jordanian patients played a major role in facilitating their positive coping during and after the MI attack. The participants' recount of their experience was summed-up into 5 major themes: frightening experience, needed support, religiosity, experiencing changes, and lifestyle modifications. After the MI attack, most of the participants felt that they had given another chance to live, showing a pressing need to make healthier lifestyle modifications to avoid another MI attack. IMPLICATIONS FOR PRACTICE: Health care workers should need not only pay attention on physical and physiological caring aspects but should also consider other patients' needs, while supporting the patients and their family members. PMID- 29137694 TI - Construct Validity and Reliability of the Beliefs Toward Mental Illness Scale for American, Japanese, and Korean Women. AB - PURPOSE: The aim of this study was to evaluate the psychometric properties of the Beliefs Toward Mental Illness Scale (BMI) across women from the United States, Japan, and South Korea. METHODS: A cross-sectional study design was employed. The sample was 564 women aged 21-64 years old who were recruited in the United States and Korea (American = 127, Japanese immigrants in the United States = 204, and Korean = 233). We carried out item analysis, construct validity by confirmatory factor analysis (CFA), and internal consistency using SPSS Version 22 and AMOS Version 22. RESULTS: An acceptable model fit for a 20-item BMI (Beliefs Toward Mental Illness Scale-Revised [BMI-R]) with 3 factors was confirmed using CFA. Construct validity of the BMI-R showed to be all acceptable; convergent validity (average variance extracted [AVE] >=0.5, construct reliability [CR] >=0.7) and discriminant validity (r = .65-.89, AVE >.79). The Cronbach's alpha of the BMI-R was .92. CONCLUSION: These results showed that the BMI was a reliable tool to study beliefs about mental illness across cultures. Our findings also suggested that continued efforts to reduce stigma in culturally specific contexts within and between countries are necessary to promote help-seeking for those suffering from psychological distress. PMID- 29137695 TI - Career Commitment of Nurse Faculty. AB - BACKGROUND: A nurse faculty shortage exists, and it is predicted to continue in the United States (American Association of Colleges of Nursing [AACN], 2016). Several factors that have been identified as contributing to this shortage include aging faculty, lack of doctoral-prepared faculty, and the economic cost of pursuing an academic career (AACN, 2016). However, there is a need to explore subtle factors. This study was conducted to examine the interaction of career commitment to education, faculty satisfaction, and teacher efficacy on developing qualified and retaining committed faculty. PURPOSE: The purpose of this study was to investigate relationships among education, teacher self-efficacy, and career satisfaction of nurse faculty to career commitment. METHODS: A cross-sectional design was used to survey a convenience sample of nurse faculty (N = 470). An online survey contained three scales (Career Satisfaction, Teacher Self-Efficacy Beliefs, and Career Commitment) to obtain data. Descriptive data, Pearson's correlations, and path analysis were used to analyze data. RESULTS: Teacher self efficacy and career satisfaction predicted career commitment. Education measured by credit hours significantly predicted teacher self-efficacy. The relationship between career satisfaction and career commitment was significant and statistically positive. Model fit indices confirm the career commitment for nurse faculty model fits the data. IMPLICATIONS FOR PRACTICE: The study highlights the importance of teacher self-efficacy, career satisfaction, and career commitment among nurse faculty. The results provide valuable insight to the factors that may influence attraction or retention of nurse faculty. PMID- 29137696 TI - Effects of Self-Knee Massage With Ginger Oil in Patients With Osteoarthritis: An Experimental Study. AB - BACKGROUND AND PURPOSE: The purpose of our study was to assess the effects of self-knee massage with ginger oil on pain and daily living activities in patients with knee osteoarthritis. METHODS: Participants (N = 68) were asked about their sociodemographic characteristics, pain level in the last week using the Visual Analog Scale (VAS), and functionality in activities of daily living with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Standard treatment prescribed by a physician was given to the patients with osteoarthritis. In addition to the standard treatment, self-knee massage with ginger oil twice a week was recommended to the intervention group (n = 34). At the end of the first and fifth week, participants in both groups were assessed regarding pain and functional state. RESULTS: The mean VAS Pain scores of the intervention group were significantly lower at the end of the first and fifth weeks (p< .05). The mean total scores and mean Function subscale scores of the WOMAC were significantly lower in massage group in the first- and fifth-week assessments (p < .05). IMPLICATIONS FOR PRACTICE: Self-massage of the knee with ginger oil may be used as a complementary method to standard medical treatment. Nurses can easily train patients and their caregivers on knee massage, and the intervention can be implemented by patients at home without any restrictions on location. PMID- 29137697 TI - The Readiness to Change for Bariatric Surgery Assessment Tool: Validity, Factor Structure, and Reliability. AB - BACKGROUND AND PURPOSE: Currently, there is no guideline or standard of practice for performing the psychiatric/psychological evaluation that is a requirement for approval for bariatric surgery. The Readiness to Change for Bariatric Surgery Assessment Tool (RCB-SAT) establishes a means for psychiatric evaluators to objectively assess the patient's cognition, beliefs, and motivation around the bariatric diet and lifestyle changes. Development of a clinical decision-making tool for assessing readiness to change in bariatric patients will be useful regarding The Strategic Plan for NIH Obesity Research. The strategic plan outlines 6 overarching themes, with the last 3 centering around creation of such a clinical decision-making tool to assess a bariatric patient's readiness to change: evaluate promising strategies for obesity prevention and treatment in realworld settings and diverse populations, harness technology and tools to advance obesity research and improve health care delivery, and facilitate integration of research results into community programs and medical practice (National Institutes of Health, 2011). METHODS: The pilot tool was administered to 153 potential bariatric patients, with 61 patients completing the survey a second time. Face and content validity of the items were established through an expert review process. RESULTS: Principle axis factoring by means of varimax rotation with Kaiser normalization identified 15 items loading on 3 factors associated with Prochaska and DiClemente's transtheoretical model of health behavior change: precontemplation, contemplation, and action (DiClemente & Prochaska, 1998). Test-retest reliability was also established for the tool. IMPLICATIONS FOR PRACTICE: The proposed RCB-SAT demonstrates potential for assessing a patient's readiness to change regarding the bariatric diet and lifestyle. PMID- 29137698 TI - Understanding the Work of Nurse Theorists: A Creative Beginning, Third Edition. PMID- 29137699 TI - Determination of Sulfite in Food by Liquid Chromatography Tandem Mass Spectrometry: Collaborative Study. AB - Sulfites are added to a wide range of food and beverage products to prevent browning or oxidation. Although most of the population do not experience side effects from consuming sulfites, a small subset has been shown to experience an "allergic-like" response. For this reason, the U.S. Food and Drug Administration requires that sulfites be labeled on all products that contain more than 10 mg/kg (parts per million) sulfur dioxide. The current regulatory method, optimized Monier-Williams (OMW) Official Method 990.28, has been successful in quantifying sulfites in most matrixes, but is time-consuming and has a method detection limit at the regulatory-labeling threshold. Recently, an LC-tandem MS (MS/MS) method was published that was applicable to a wide range of sulfite-containing matrixes. This method converts free and reversibly bound sulfite to the formaldehyde adduct hydroxymethylsulfonate, which could then be separated from matrix constituents using a hydrophilic interaction LC analytical column and subsequently be detected with tandem MS (MS/MS). In this study, multilaboratory validation was conducted with 11 laboratories in the United States and Canada. Four matrixes were spiked at varying concentrations and three additional commercially sulfited matrixes were included. An abbreviated comparison study between the LC-MS/MS and OMW methods was conducted for select samples. Average recoveries for all matrixes ranged from 86 to 114% with RSDr and RSDR values of 4.5-17.5 and 8.6-22.5%, respectively. Further comparisons will be necessary to draw comparisons between the two methods. This method proved to be a faster and more sensitive way to determine sulfites in food and beverages, showing promise for the continuing improvement of enforcement of sulfite labeling requirements to protect individuals who have sulfite sensitivity. PMID- 29137700 TI - Limitation of therapeutic effort in patients hospitalised in departments of internal medicine. AB - INTRODUCTION: There is little information on the limitation of therapeutic effort (LTE) in patients admitted to hospital internal medicine units. OBJECTIVES: To describe the indicated LTE regimens in the departments of internal medicine and the characteristics of the patients who undergo them. PATIENTS AND METHODS: An observational, descriptive retrospective study was conducted on 4 hospitals of the Community of Madrid. The study collected demographic and comorbidity data and the LTE orders prescribed for all patients who died during a period of 6 months. RESULTS: The study included 382 patients with a mean age of 85+/-10 years; 204 were women (53.4%) and 222 (58.1%) came from their homes. Some 51.1% of the patients were terminal, 43.2% had moderate to severe dementia, and 95.5% presented at least moderate comorbidity. Some type of LTE was performed in 318 patients (83.7%); the most common orders were "No cardiopulmonary resuscitation" (292 patients, 76.4%; 95% CI 72.1-80.8), "Do not use aggressive measures" (113 patients, 16.4%; 95% CI 13.7-19.4) and "Do not transfer to an intensive care unit" (102 cases, 14.8%, 95% CI 12.3-17.7). Some type of LTE was performed in 318 patients (83.7%); the most common orders were "No cardiopulmonary resuscitation" (292 patients, 76.4%; 95% CI 72.1-80.8), "Do not use aggressive measures" (113 patients, 16.4%; 95% CI 13.7-19.4) and "Do not transfer to an intensive care unit" (102 cases, 14.8%, 95% CI 12.3-17.7). CONCLUSIONS: LTE is common among patients who die in Internal Medicine. The most widely used regimens were "No CPR" and the unspecific statement "Do not use aggressive measures". The patients were elderly and had significant comorbidity, terminal illness and advanced dementia. PMID- 29137701 TI - The correlation between ATLS and junior doctors' anatomical knowledge of central venous catheter insertion at a major trauma centre in South Africa. AB - OBJECTIVE: To review the ability of junior doctors (JDs) in identifying the correct anatomical site for central venous catheterization (CVC) and whether prior Advanced Trauma Life Support (ATLS) training influences this. DESIGN: We performed a prospective, observational study using a structured survey and asked a group of JDs (postgraduate year 1 [PGY1] or year 2 [PGY2]) to indicate on a photograph the exact site for CVC insertion via the internal jugular (IJV) and the subclavian (SCV) approach. This study was conducted in a large metropolitan university hospital in South Africa. RESULTS: A total of 139 JDs were included. Forty-four per cent (61/139) were males and the mean age was 25 years. There were 90 PGY1s (65%) and 49 PGY2s (35%). Overall, 32% (45/139) were able to identify the correct insertion site for the IJV approach and 60% (84/139) for the SCV approach. Of the 90 PGY1s, 34% (31/90) correctly identified the insertion site for the IJV approach and 59% (53/90) for the SCV approach. Of the 49 PGY2s, 29% (14/49) correctly identified the insertion site for the IJV approach and 63% (31/49) for the SCV approach. No significant difference between PGY1 and 2 were identified. Those with ATLS provider training were significantly more likely to identify the correct site for the IJV approaches [OR=4.3, p=0.001]. This was marginally statistically significant (i.e. p>0.05 but <0.1) for the SCV approach. CONCLUSIONS: The majority of JDs do not have sufficient anatomical knowledge to identify the correct insertion site CVCs. Those who had undergone ATLS training were more likely to be able to identify the correct insertion site. PMID- 29137702 TI - Review of recent developments in determining volatile organic compounds in exhaled breath as biomarkers for lung cancer diagnosis. AB - Lung cancer is the most common cause of cancer deaths, its global incidence is rising, and continuing rises are predicted. The potential to diagnose lung cancers based on the determination of volatile organic compounds (VOCs) in human breath has been attracting increasing attention with the development of new techniques and methodologies. However, despite many reports of VOC profiling in lung cancer patients, little is known about how specific biomarkers relate to the biochemical pathways involved in lung cancer development, and there is still no reliable method for diagnosing lung cancer at the early stages. This review summarizes some of the latest methods used for monitoring biomarkers in lung cancer patients, which could be applicable for clinical diagnosis. Techniques for capturing and pre-concentrating biomarkers, and the technologies used for subsequently determining them, are also discussed. PMID- 29137703 TI - Fabrication of a novel aptasensor based on three-dimensional reduced graphene oxide/polyaniline/gold nanoparticle composite as a novel platform for high sensitive and specific cocaine detection. AB - In the present research, we have developed a novel label free aptasensor based on screen printed carbon electrode (SPCE) modified with three-dimensional magnetic reduced graphene oxide(3D-MRGO)/polyaniline(PA)/gold nanoparticle(AuNP) nanocomposite for impedimetric determination of cocaine. To achieve this goal, a specific thiolated cocaine aptamer was immobilized onto the surface of synthesized nanocomposite. The signaling mechanism of the proposed aptasensor was based on increase in the [Fe(CN)6]3-/4- charge transfer resistance (RCT) as an electrochemical probe in the presence of target analyte. In order to collect of 3D-MRGO/PA/AuNP/aptamer on the surface of working electrode easily, a new electrochemical cell was fabricated. The advantages of the new electrochemical cell configuration can be counted as reusing SPCE for several times, obtaining repeatable responses, reducing required volume of electrolyte and probe solution and making proposed method more user-friendly. Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR) were used for the characterization of synthesized nanocomposite and modified electrode surface. Under optimized condition, cocaine was determined in a linear concentration range from 0.09 to 85 nM with a detection limit of 0.029 nM by EIS. Also, in order to test applicability of the proposed aptasensor, it was applied to determine cocaine in urine and serum samples and satisfactory results were obtained. PMID- 29137704 TI - High throughput screening of phenoxy carboxylic acids with dispersive solid phase extraction followed by direct analysis in real time mass spectrometry. AB - A high throughput, low environmental impact methodology for rapid determination of phenoxy carboxylic acids (PCAs) in water samples was developed by combing dispersive solid phase extraction (DSPE) using velvet-like graphitic carbon nitride (V-g-C3N4) and direct analysis in real time mass spectrometry (DART-MS). Due to the large surface area and good dispersity of V-g-C3N4, the DSPE of PCAs in water was completed within 20 s, and the elution of PCAs was accomplished in 20 s as well using methanol. The eluents were then analyzed and quantified using DART ionization source coupled to a high resolution mass spectrometer, where an internal standard was added in the samples. The limit of detection ranged from 0.5 ng L-1 to 2 ng L-1 on the basis of 50 mL water sample; the recovery 79.9 119.1%; and the relative standard deviation 0.23%-9.82% (>=5 replicates). With the ease of use and speed of DART-MS, the whole protocol can complete within mere minutes, including sample preparation, extraction, elution, detection and quantitation. The methodology developed here is simple, fast, sensitive, quantitative, requiring little sample preparation and consuming significantly less toxic organic solvent, which can be used for high throughput screening of PCAs and potentially other contaminants in water. PMID- 29137705 TI - Novel approach to high-throughput determination of endocrine disruptors using recycled diatomaceous earth as a green sorbent phase for thin-film solid-phase microextraction combined with 96-well plate system. AB - A sustainable approach to TF-SPME is presented using recycled diatomaceous earth, obtained from a beer purification process, as a green sorbent phase for the determination of bisphenol A (BPA), benzophenone (BzP), triclocarban (TCC), 4 methylbenzylidene camphor (4-MBC) and 2-ethylhexyl-p-methoxycinnamate (EHMC) in environmental water samples. TF-SPME was combined with a 96-well plate system allowing for high-throughput analysis due to the simultaneous extraction/desorption up to 96 samples. The proposed sorbent phase exhibited good stability in organic solvents, as well as satisfactory analytical performance. The optimized method consisted of 240 min of extraction at pH 6 with the addition of NaCl (15% w/v). A mixture of MeOH:ACN (50:50 v/v) was used for the desorption the analytes, using a time of 30 min. Limits of detection varied from 1 MUg L-1 for BzP and TCC to 8 MUg L-1 for the other analytes, and R2 ranged from 0.9926 for 4-MBC to 0.9988 for BPA. This novel and straightforward approach offers an environmentally-friendly and very promising alternative for routine analysis. . The total sample preparation time per sample was approximately 2.8 min, which is a significant advantage when a large number of analytical run is required. PMID- 29137706 TI - Accurate phosphorylation site localization using phospho-brackets. AB - Phosphorylation is one of the most important and widely studied protein post translational modifications. Tandem mass spectrometry using higher-energy collisional dissociation has evolved into a state-of-the-art analytical platform for both phosphorylation identification and site localization. Tens of thousands of phosphopeptides can now be routinely identified from a single shotgun proteomics study; site localization, however, is much more complicated and many challenges still exist. Here, we report our development of P-bracket using direct experimental evidence of phospho-containing site-determining product ions for accurate site localization without the need for additional FLR control. A P bracket is defined as a complementary product ion pair that forms a bracket to confine a phosphorylation event to a unique site. P-bracket has been successfully benchmarked with a set of six synthetic phosphopeptides with a single phosphorylation event, a set of 96 synthetic peptides and phosphopeptide reference libraries, and two HeLa phosphopeptide LC-MS/MS (HCD) datasets; Accurate phosphosite localization by P-bracket will greatly enhance identification confidence of phosphopeptides and contribute to structural and functional studies of phosphoproteins. PMID- 29137707 TI - Use of chemical conversion for determination of nitrated aromatic hydrocarbons using femtosecond ionization mass spectrometry. AB - A sample containing nitrated aromatic hydrocarbons (NPAHs) was injected into the sample inlet port of a gas chromatograph (GC), along with hydrazine, a reducing reagent. The analytes that eluted from the GC column were measured by mass spectrometry (MS) using an ultraviolet femtosecond laser as the ionization source. When no reducing reagent was used, large numbers of polycyclic aromatic hydrocarbons (PAHs) including NPAHs were observed in the two-dimensional GC/MS display. In contrast, when hydrazine was present, reduced forms of NPAHs, which included amino PAHs, were detected. When a palladium or platinum catalyst was placed in the GC inlet port, the compounds were further reduced to non-aromatic hydrocarbons. The present approach would be useful for studies to evaluate the chemical reaction that converts the constituents contained in exhaust emitted from a diesel engine. PMID- 29137708 TI - Smartphone based non-invasive salivary glucose biosensor. AB - The present work deals with the development of a non-invasive optical glucose biosensor using saliva samples and a smartphone. The sensor was fabricated with a simple methodology by immobilization of Glucose oxidase enzyme along with a pH responsive dye on a filter paper based strip. The strip changes color upon reaction with glucose present in saliva and the color changes were detected using a smartphone camera through RGB profiling. This standalone biosensor showed good sensitivity and low interference while operating within 20 s response time. We used various means for improvements such as the use of slope method instead of differential response; use of a responsive pH indicator and made numerous tweaks in the smartphone app. Calibration with spiked saliva samples with slopes for (R + G + B) pixels revealed an exponentially increasing calibration curve with a linear detection range of 50-540 mg/dL, sensitivity of 0.0012 pixels sec-1/mg dL 1 and LOD of 24.6 mg/dL. The biosensor was clinically validated on both healthy and diabetic subjects divided into several categories based on sex, age, diabetic status etc. and correlation between blood and salivary glucose has been established for better standardization of the sensor. Correlation of 0.44 was obtained between blood and salivary glucose in healthy individuals whereas it was 0.64 and 0.94 in case of prediabetic and diabetic patients respectively. The developed biosensor has the potential to be used for mass diagnosis of diabetes especially in such areas where people remain prohibited from routine analysis due to high healthcare cost. Apart from that, a smartphone would be the only device the user needs for this measurement, along with a disposable low cost test strip. PMID- 29137709 TI - Simultaneous detection of folic acid and methotrexate by an optical sensor based on molecularly imprinted polymers on dual-color CdTe quantum dots. AB - In this work, molecularly imprinted polymers (MIPs) were used on the surface of cadmium telluride quantum dots (CdTe QDs) for the simultaneous determination of folic acid (FA) and methotrexate (MTX). For this purpose, two different sizes of CdTe QDs with emission peaks in the yellow (QDY) and orange (QDO) spectral regions were initially synthesized and capped with MIPs. FA and MTX were used as templates for the synthesis of the two composites and designated as QDY-MIPs and QDO-MIPs, respectively. Fourier transform infrared spectroscopy, transmission electron microscopy, and fluorescence spectroscopy were employed to characterize the composites. QDY-MIPs and QDO-MIPs were then mixed (to form QDs-MIPs) and excited at identical excitation wavelengths; they emitted two different emission wavelengths without any spectral overlap. The fluorescence signals of QDY-MIPs and QDO-MIPs diminished in intensity with increasing concentration of the corresponding template molecules. Under optimal conditions, the dynamic range was 0.5-20 MUmol L-1 for FA and MTX, and the detection limits for FA and MTX were 32.0 nmol L-1 and 34.0 nmol L-1, respectively. The reproducibility of the method was checked for 12.5 MUmol L-1 of FA and MTX to find RSD values of 4.2% and 6.3%, respectively. Finally, the applicability of the method was checked using human blood plasma samples. Results indicated the successful application of the method as a fluorescent probe for the rapid and simultaneous detection of FA and MTX in real samples. PMID- 29137710 TI - Loop-mediated isothermal amplification using self-avoiding molecular recognition systems and antarctic thermal sensitive uracil-DNA-glycosylase for detection of nucleic acid with prevention of carryover contamination. AB - Loop-mediated isothermal amplification (LAMP) is the most popular technique to amplify nucleic acid sequence without the use of temperature cycling. However, LAMP is often confounded by false-positive results, arising from interactions between (hetero-dimer) or within (self-dimerization) primers, off-target hybrids and carryover contaminants. Here, we devised a new LAMP technique that is self avoiding molecular recognition system (SAMRS) components and antarctic thermal sensitive uracil-DNA-glycosylase (AUDG) enzyme-assisted, termed AUDG-SAMRS-LAMP. Incorporating SAMRS components into 3'-ends of LAMP primers can improve assay's specificity, which completely prevents the non-specific amplification yielding from off-target hybrids and undesired interactions between or within primers. Adding AUDG into reaction mixtures can effectively eliminate the false-positive results arising from carryover contamination, thus the genuine positive reactions are generated from the amplification of target templates. Furthermore, AUDG-SAMRS LAMP results are confirmed using a new analysis strategy, which is developed for detecting LAMP amplicons by lateral flow biosensor (LFB). Only a single labeled primer is required in the analysis system, thus the false positive results arising from hybridization (the labeled primer and probe, or between two labeled primers) are avoided. Hence, the SAMRS components, AUDG and LFB convert traditional LAMP from a technique suited for the research laboratory into one that has practical value in the field of diagnosis. Human Tuberculosis (TB) is caused by infection with members of Mycobacterium tuberculosis complex (MTC), which are detected by the AUDG-SAMRS-LAMP technique to demonstrate the availability of target analysis. The proof-of-concept method can be reconfigured to detect various nucleic acids by redesigning the specific primers. PMID- 29137712 TI - Hydrophilic interaction liquid chromatography of hydroxy aromatic carboxylic acid positional isomers. AB - Hydrophilic interaction liquid chromatography (HILIC) has become increasingly popular as an alternative to reversed phase LC due to its ease of separating complex polar compound mixtures and the compatibility of the mobile phase with mass spectrometry (MS). Using a plain silica column (150 mm * 4.6 mm), we have shown a mixture containing three hydroxybenzoic acid isomers plus syringic and vanillic acid and three hydroxycinnamic acid isomers plus ferulic and sinapic acid can be separated using a mobile phase comprised of 90% acetonitrile (MeCN) and 10% 20 mM ammonium acetate at pH 6 in under 45 min. This method is appropriate when using UV detection at 275 nm. However, for improved MS compatibility, a buffer concentration of 10 mM is recommended but this greatly decreases the analyte retention factors. A second more nonpolar organic solvent component in the mobile phase (particularly pentane which has not been previously considered for HILIC) is found to offset this loss in retention. The optimum mobile phase is found to be 90% MeCN, 5% 10 mM ammonium acetate pH 6, and 5% pentane with resolution of eight of the ten compounds with a separation time of 30 min. Using UV detection, we have shown that detection limits range from 36 to 133 pmole and quantitation limits are spread from 94 to 376 pmole for six of the analytes. Upon testing this method on two other silica columns from different manufacturers, it is found that while resolution is similar, further optimization of the mobile phase is recommended. PMID- 29137711 TI - Novel free-radical mediated lipid peroxidation biomarkers in newborn plasma. AB - Oxidative stress derived from perinatal asphyxia appears to be closely linked to neonatal brain damage and lipid peroxidation biomarkers have shown to provide predictive power of oxidative stress related pathologies in situations of hypoxia and reoxygenation in the newborn. The objective of this work was to develop and validate of a comprehensive liquid chromatography tandem mass spectrometry approach for the quantitative profiling of 28 isoprostanoids in newborn plasma samples covering a broad range of lipid peroxidation product classes. The method was developed taking into account the specific requirements for its use in neonatology (i.e. limited sample volumes, straightforward sample processing and high analytical throughput). The method was validated following stringent FDA guidelines and was then applied to the analysis of 150 plasma samples collected from newborns. Information obtained from the quantitative analysis of isoprostanoids was critically compared to that provided by a previously developed approach aiming at the semi-quantitative detection of total parameters of fatty acid derived lipid peroxidation biomarkers. PMID- 29137713 TI - TRPV1: A Potential Therapeutic Target in Type 2 Diabetes and Comorbidities? AB - With an estimated 422 million affected patients worldwide in 2016, type 2 diabetes (T2D) has reached pandemic proportions and represents a major unmet medical need. T2D is a polygenic disease with a chronic, low-grade inflammatory component. Second-generation transient receptor potential vanilloid-1 (TRPV1) antagonists are potent anti-inflammatory agents with proven clinical safety. In rodent models of T2D, TRPV1 blockade was shown to halt disease progression and improve glucose metabolism. Thus, we propose that TRPV1 antagonists merit further study as novel therapeutic approaches to potentially treat T2D and its comorbidities. PMID- 29137714 TI - Checkpoint Blockade Plus Oncolytic Virus: A Hot Therapeutic Cancer Strategy. AB - How can we transform an immune desert into a 'hot tumor' that is prone to respond to anti-programmed death (PD)-1 immunotherapy? This might be possible by injecting an oncolytic virus, engineered to induce local immune stimulation, prior to anti-PD-1 therapy. A recent study demonstrated that this combination - evaluated in a Phase Ib metastatic melanoma clinical study - yields promising results. PMID- 29137715 TI - A summary to say goodbye and express thanks for 12 years at Radiologia. PMID- 29137716 TI - (A)phantasia and severely deficient autobiographical memory: Scientific and personal perspectives. AB - I address two interlinked aspects of the diversity in our experiences of memory and the mind's eye. I summarise the long-appreciated role of imagery in mathematics and the physical sciences, and contrast it with the evidence that some scientists have had limited or zero imagery. I then recount the story of how I became aware of my own lack of mental imagery, and the accompanying deficit in my episodic memory, how I have sought scientific understanding of these conditions, and how they have affected my life. PMID- 29137717 TI - An autistic-like profile of attention and perception in synaesthesia. AB - Synaesthesia and autism are two neurodevelopmental conditions that have been shown to co-occur more than expected by chance. The studies reported here test the hypothesis that increased sensory sensitivity and enhanced Attention-to detail are core cognitive features that are shared between them. In Study 1, we administer self-report measures of sensory sensitivity and autistic traits (the Autism Spectrum Quotient, AQ) to a large heterogeneous sample of synaesthetes. Both sensory sensitivity and the Attention-to-detail subscale of the AQ show a "dose-like" relationship with synaesthesia: namely, more kinds of synaesthesia is related to a greater shift up the autistic spectrum. Study 2 uses two objective measures of visual perception/attention linked to autistic traits: Change Blindness and detection of local embedded figures. Both measures are shown here to be sensitive to the Attention-to-detail subscale of the AQ, and synaesthetes outperformed controls on both tasks. Synaesthetes appear to occupy a specific cognitive niche of having autistic-like traits linked to enhanced perception and attention. Whilst these typically occur in the absence of the traditional impairments that define autism, they may carry the cost of increased vulnerability to clinical levels of autism (Odds Ratio = 2.07). PMID- 29137718 TI - Telavancin for the treatment of methicillin-resistant Staphylococcus aureus bone and joint infections. AB - This retrospective, case series describes our experience with the use of telavancin in patients with methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis and prosthetic joint infection. The primary objectives were clinical outcomes and adverse events (AEs), and a secondary outcome described microbiological susceptibility. Fourteen patients were enrolled. Median duration of therapy was 58 days, and four patients had concurrent bacteremia. End-of treatment outcomes were available in 78% of patients, with a clinical success rate of 91%. Thirty-day and 12-month outcomes were also obtained. Seven patients experienced AEs. Infusion-related reactions were most common, and three AEs required discontinuation of therapy. All MRSA isolates had a telavancin MIC <=0.06MUg/ml, which is susceptible. This study indicates that telavancin may have a role in treatment of MRSA osteomyelitis and prosthetic joint infection. Our study describes clinical success and adverse events for long duration of therapy, up to 8 weeks. PMID- 29137719 TI - Impact of patient age on clinical features, serologic test reactivity and long term outcome of culture-confirmed early Lyme disease. AB - Whether age at time of diagnosis impacts the clinical presentation or long-term outcome of early Lyme disease is unknown. Subjects enrolled in this study had culture-confirmed early Lyme disease and were followed up annually in a long-term prospective study. Subjects <=50years of age were compared with those who were >=51years of age at time of study entry. Of the 283 enrolled subjects, the >=51year old age group was significantly more likely to be female (P=0.0095) and to be compliant with long-term follow-up of at least 11years duration (P=0.0119). There were no significant differences between the two age groups with regard to any of the other variables assessed at presentation. For the 128 subjects who were followed up for 11-20years, there was no significant difference between the two age groups in the frequency, number or type of residual symptoms. The older age group at study entry, however, was significantly more likely to develop an intercurrent comorbidity (P=0.0017), and there was a trend toward a greater likelihood of having an intercurrent hospitalization (P=0.0311). Among the 128 subjects followed up for 11-20years, the older age group at study entry returned for a significantly greater number of follow-up visits (P=0.0129). In conclusion, older age at the time of diagnosis of early Lyme disease did not impact the initial clinical features or long-term outcome of this infection. Not unexpectedly, older patients had more comorbidities during long-term follow-up. PMID- 29137720 TI - Improving surgical residents' communication in disclosing complications: A qualitative analysis of simulated physician and patient surrogate conversations. AB - BACKGROUND: In this study, we explore surgical resident communication with simulated patient surrogates (SPs), in an Objective Structured Clinical Examination (OSCE). METHODS: We use discourse analysis (DA), a qualitative approach to analyzing language, to evaluate our residents' interactions with simulated patient surrogates. After identifying problematic communication patterns, we apply communication theory to discuss our findings and provide suggestions for improvement. RESULTS: Residents consistently use bluntness, defined as delivering the news abruptly and without adequate preface, and evasiveness, defined as avoiding giving the news, to deliver difficult information. In addition, some residents use neutral language when empathetic language is warranted; and some try to direct the response of SPs, who then become defensive. Residents use evasiveness most frequently, followed by bluntness. These delivery methods often result in poor communication. CONCLUSIONS: We recommend further research in barriers to effective resident communication with patients, as well as future research on the positive effects of good communication on patient perception. Learning these skills will help residents to convey support and empathy to patients, thereby enhancing care. PMID- 29137721 TI - Current robotic curricula for surgery residents: A need for additional cognitive and psychomotor focus. AB - BACKGROUND: Current robot surgery curricula developed by industry were designed for expert surgeons. We sought to identify the robotic curricula that currently exist in general surgery residencies and describe their components. METHODS: We identified 12 residency programs with robotic curricula. Using a structured coding form to identify themes including sequence, duration, emphasis and assessment, we generated a descriptive summary. RESULTS: Curricula followed a similar sequence: learners started with online modules and simulation exercises, followed by bedside experience during R2-R3 training years, and then operative opportunities on the console in the final years of training. Consistent portions of the curricula reflect a device-dependent training paradigm; they defined the sequence of instruction. Most curricula lacked specifics on duration and content of training activities. None clearly described cognitive or psychomotor skills needed by residents and none required a proficiency assessment before graduation. CONCLUSIONS: Resident-specific robotic curricula remain grounded in initial industrial efforts to train experienced surgeons, are non-specific regarding the type and nature of hands on experience, and do not include discussion of operative technique and surgical concepts. PMID- 29137722 TI - Why teach? Why ASE? PMID- 29137723 TI - The promise and problems of non-physician practitioners in general surgery education: Results of a multi-center, mixed-methods study of faculty. AB - BACKGROUND: Nurse Practitioners and Physician Assistants - called non-physician practitioners or NPPs - are common, but little is known about their educational promise and problems. METHODS: General surgery faculty in 13 residency programs were surveyed (N = 279 with a 71% response rate) and interviewed (N = 43) about experiences with NPPs. The survey documents overall patterns and differences by program type and primary service; interviews point to deeper rationales and concerns. RESULTS: NPPs reduce faculty and resident workloads and teach residents. NPPs also reduce resident exposure to educationally valuable activities, and faculty sometimes round, make decisions, and operate with NPPs instead of residents. Interviews indicate that NPPs can overly reduce resident involvement in patient care, diminish resident responsibility and decision making, disrupt team dynamics, and compete for procedures. CONCLUSIONS: NPPs both enhance and hinder surgical education and highlight the need to more clearly articulate learning outcomes for residents and activities necessary to achieve those outcomes. PMID- 29137724 TI - Simplified boundary conditions alter cortical-trabecular load sharing at the distal radius; A multiscale finite element analysis. AB - High-resolution peripheral quantitative computed tomography (HR-pQCT) derived micro-finite element (FE) modeling is used to evaluate mechanical behavior at the distal radius microstructure. However, these analyses typically simulate non physiologic simplified platen-compression boundary conditions on a small section of the distal radius. Cortical and trabecular regions contribute uniquely to distal radius mechanical behavior, and various factors affect these regions distinctly. Generalized strength predictions from standardized platen-compression analyses may not adequately capture region specific responses in bone. Our goal was to compare load sharing within the cortical-trabecular compartments between the standardized platen-compression BC simulations, and physiologic BC simulations using a validated multiscale approach. Clinical- and high-resolution images were acquired from nine cadaveric forearm specimens using an HR-pQCT scanner. Multiscale FE models simulating physiologic BCs, and micro-FE only models simulating platen-compression BCs were created for each specimen. Cortical and trabecular loads (N) along the length of the distal radius micro-FE section were compared between BCs using correlations. Principal strain distributions were also compared quantitatively. Cortical and trabecular loads from the platen compression BC simulations were strongly correlated to the physiologic BC simulations. However, a 30% difference in cortical loads distally, and a 53% difference in trabecular loads proximally was observed under platen BC simulations. Also, distribution of principal strains was clearly different. Our data indicated that platen-compression BC simulations alter cortical-trabecular load sharing. Therefore, results from these analyses should be interpreted in the appropriate mechanical context for clinical evaluations of normal and pathologic mechanical behavior at the distal radius. PMID- 29137725 TI - A gait retraining system using augmented-reality to modify footprint parameters: Effects on lower-limb sagittal-plane kinematics. AB - Improving lower-limb flexion/extension angles during walking is important for the treatment of numerous pathologies. Currently, these gait retraining procedures are mostly qualitative, often based on visual assessment and oral instructions. This study aimed to propose an alternative method combining motion capture and display of target footprints on the floor. The second objectives were to determine the error in footprint modifications and the effects of footprint modifications on lower-limb flexion/extension angles. An augmented-reality system made of an optoelectronic motion capture device and video projectors displaying target footprints on the floor was designed. 10 young healthy subjects performed a series of 27 trials, consisting of increased and decreased amplitudes in stride length, step width and foot progression angle. 11 standard features were used to describe and compare lower-limb flexion/extension angles among footprint modifications. Subjects became accustomed to walk on target footprints in less than 10 min, with mean (+/- SD) precision of 0.020 +/- 0.002 m in stride length, 0.022 +/- 0.006 m in step width, and 2.7 +/- 0.6 degrees in progression angle. Modifying stride length had significant effects on 3/3 hip, 2/4 knee and 4/4 ankle features. Similarly, step width and progression angle modifications affected 2/3 and 1/3 hip, 2/4 and 1/4 knee as well as 3/4 and 2/4 ankle features, respectively. In conclusion, this study introduced an augmented-reality method allowing healthy subjects to modify their footprint parameters rapidly and precisely. Walking with modified footprints changed lower-limb sagittal-plane kinematics. Further research is needed to design rehabilitation protocols for specific pathologies. PMID- 29137726 TI - Mineralized collagen fibril network spatial arrangement influences cortical bone fracture behavior. AB - Bone is a hierarchical material exhibiting different fracture mechanisms at each length scale. At the submicroscale, the bone is composed of mineralized collagen fibrils (MCF). At this scale, the fracture processes in cortical bone have not been extensively studied in the literature. In this study, the influence of MCF size and orientation on the fracture behavior of bone under both transverse and longitudinal loading was investigated using novel 3D models of MCF networks with explicit representation of extra-fibrillar matrix. The simulation results showed that separation between MCFs was the main cause of damage and failure under transverse loading whereas under longitudinal loading, the main damage and failure mechanism was MCF rupture. When the MCF network was loaded in the transverse direction the mechanical properties increased as the orientation of fibrils deviated farther from the main fibril orientation whereas the opposite trend was observed under longitudinal loading. The fracture energy was much larger in longitudinal than transverse loading. MCF diameter variation did not affect the mechanical properties under longitudinal loading but led to higher mechanical properties with increasing MCF diameter under transverse loading. The new modeling framework established in this study generate unique information on the effect of MCF network spatial arrangement on the fracture behavior of bone at the submicroscale which is not currently possible to measure via experiments. This unique information may improve the understanding of how structural alterations at the submicroscale due to disease, age-related changes, and treatments affect the fracture processes at larger length scales. PMID- 29137728 TI - A computational model for false lumen thrombosis in type B aortic dissection following thoracic endovascular repair. AB - Thoracic endovascular repair (TEVAR) has recently been established as the preferred treatment option for complicated type B dissection. This procedure involves covering the primary entry tear to stimulate aortic remodelling and promote false lumen thrombosis thereby restoring true lumen flow. However, complications associated with incomplete false lumen thrombosis, such as aortic dilatation and stent graft induced new entry tears, can arise after TEVAR. This study presents the application and validation of a recently developed mathematical model for patient-specific prediction of thrombus formation and growth under physiologically realistic flow conditions. The model predicts thrombosis through the evaluation of shear rates, fluid residence time and platelet distribution, based on convection-diffusion-reaction transport equations. The model was applied to 3 type B aortic dissection patients: two TEVAR cases showing complete and incomplete false lumen thrombosis respectively, and one medically treated dissection with no signs of thrombosis. Predicted thrombus growth over time was validated against follow-up CT scans, showing good agreement with in vivo data in all cases with a maximum difference between predicted and measured false lumen reduction below 8%. Our results demonstrate that TEVAR-induced thrombus formation in type B aortic dissection can be predicted based on patient-specific anatomy and physiologically realistic boundary conditions. Our model can be used to identify anatomical or stent graft related factors that are associated with incomplete false lumen thrombosis following TEVAR, which may help clinicians develop personalised treatment plans for dissection patients in the future. PMID- 29137727 TI - The quantitative evaluation of the relationship between the forces applied to the palm and carpal tunnel pressure. AB - Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy occurring in upper limbs. The etiology, however, has not been fully understood yet. Median nerve could be compressed by either increase of carpal tunnel pressure (CTP) or direct impingement when it is forced toward to carpal ligament especially in wrist flexion leading to CTS development. Thus, the increase of carpal tunnel pressure is considered an important role in CTS development. It has been identified that forces applied to the palm would affect the CTP. However, the quantitative relationship between palmar contact force and CTP is not known. The purpose of this study was to quantitatively evaluate the relationship between palmar contact force and CTP. Eight human cadaveric hands were used. The CTP was measured with a diagnostic catheter-based pressure transducer inserted into the carpal tunnel. A custom made device was used to apply forces to the palm for the desired CTP. Palmar contact forces corresponding to the determined CTP level were recorded respectively. The testing was repeated with different ranges of tension applied to the flexor digitorum superficialis tendon of the third finger. The tensions were constant at 50 g for the other flexor tendons and median nerve. The results showed that CTP increased linearly with the force applied to the palm. When CTP was 30 mmHg, mean values of the contact force to the palm was 293 g (SD: 15.2) including all tensions. These results would help to understand the effect of daily activities with hands on CTP. PMID- 29137729 TI - The shear wave elastic modulus and the increased nuclear factor kappa B (NF kB/p65) and cyclooxygenase-2 (COX-2) expression in the area of myofascial trigger points activated in a rat model by blunt trauma to the vastus medialis. AB - We aimed to elucidate the increased inflammatory cytokines expression such as nuclear factor kappa B (NF-kB/p65), cyclooxygenase-2 (COX-2), and voltage-gated calcium channels (VGCC) in the area of activated myofascial trigger points (MTrPs) in a rat model by blunt trauma to the vastus medialis and to evaluate the feasibility of a quantitative analysis of muscle elastic modulus using shear wave elastography (SWE). Twelve 7-week-old male SD rats were divided into normal (NM, n = 6) and model groups (MO, n = 6). In the MO group, MTrPs were activated with a blunt strike to the left vastus medialis and subsequent eccentric exercise for 8 weeks. After 4 weeks of rest, the elastic modulus in the focal site was evaluated using SWE. Electromyography (EMG) data were collected at MTrPs and muscle tissues were evaluated for expression of nuclear factor kappa B (NF-kB/p65), cyclooxygenase-2 (COX-2) protein, and voltage-gated calcium channels (VGCC). The number of the palpable taut bands; EMG frequency and amplitude; elastic modulus values; and NFkB/p65, COX-2, and VGCC expression levels were significantly higher for the left focal area in the MO group compared to those for the NM group (p's < 0.05). These findings suggest that elastic modulus measurement using ultrasound SWE may be effective in evaluating MPS. In addition, increased COX-2, NFkB/p65, and VGCC expression may expand the integrated hypothesis of trigger points. PMID- 29137730 TI - The influence of bovine serum albumin-modified silica on the physicochemical properties of poly(vinyl alcohol) nanocomposites synthesized by ultrasonication technique. AB - In this study, for the first time polymeric nanocomposite (NC) films of poly(vinyl alcohol)/SiO2@bovine serum albumin (PVA/SiO2@BSA) were synthesized by solution casting method under facile and fast method of sonication. In this regard, SiO2 nanoparticles (NPs) were modified by BSA, at room temperature by using phosphate buffer and ultrasonic-assisted method. Then, PVA/SiO2@BSA NCs were prepared by insertion of variant amount (3, 6 and 9wt%) of SiO2@BSA into the PVA matrix, under ultrasonic irradiation. The morphological traits of the NCs were surveyed by Fourier transform infrared spectroscopy, transmission electron microscopy, X-ray diffraction and field emission scanning electron microscopy. It was detected that NPs incorporation didn't remarkably affect the crystallinity and morphology of the NCs. TEM images indicated that the inserted NPs have good diffusions in the PVA matrix, and their embedment in the matrix significantly upgraded its thermal, optical and mechanical behaviors. The tensile strength showed more than 2-fold increase and the thermal stability exhibited about 37% enhancement that was higher, in comparison with those of the similar NCs. This showed that the prepared NCs can have potential application in food packaging.***. PMID- 29137731 TI - Combined effects of phase-shift and power distribution on efficiency of dual-high frequency sonochemistry. AB - In an effort to increase the efficiency of sonochemical reactors, this study investigates a single-source, dual-high-frequency ultrasound reactor. Experiments were conducted with a variety of piezoelectric crystals and reactor components, and for each reactor design a range of power distributions and phase shifts between the two frequencies were evaluated. Certain dual-frequency configurations produced up to a threefold increase in sonochemical efficiency, while others yeilded no improvement over a single frequency. These results led to two significant findings. First, phase-shift had a strong effect on sonochemical efficiency for both harmonic and non-harmonic frequency combinations. Second, the most efficient dual-harmonic-frequency waveforms had a single peak per half cycle, rather than two unique peaks. If dual-frequency, single-source ultrasound reactors are to become more efficient they must be able to consistently control the phase angle of and power distribution between harmonic waves to create an optimal waveform. PMID- 29137732 TI - Ultrasound-assisted biosynthesis of CuO-NPs using brown alga Cystoseira trinodis: Characterization, photocatalytic AOP, DPPH scavenging and antibacterial investigations. AB - This contribution reports the biosynthesis of CuO NPs via ultrasound method using the Cystoseira trinodis extracts as an eco friendly and time saving process. The characterization of cupric oxide NPs was performed using XRD, FE-SEM, EDX, TEM, AFM, photoluminescence, UV-Vis, Raman and FT-IR spectroscopy investigations. SEM images show the spherical structure with the average crystallite size 6nm to 7.8nm of CuO. XRD analysis approved the formation of pure monoclinic crystallite structures of CuO NPs. These observations were confirmed by TEM analysis. The photocatalytic studies reveal the activity of the prepared CuO NPs as an efficient catalyst for the degradation of methylene blue (MB) in the presence of UV and Sunlight. CuO NPs under varying experimental parameters such as dye concentration, catalytic load, pH. The results of the in vitro biological screening effect of CuO NPs (zone of growth inhibition and minimal inhibitory concentrations) in comparison with cephalexin (as a standard compound) using the disc diffusion method was demonstrated the significant bactericidal activity against some bacteria strain including Escherichia coli (E. coli), Enterococcus faecalis (E. faecalis), Salmonella typhimurium (S. typhimurium), Staphylococcus aureus (S. aureus), Bacillus subtilis (B. subtilis), and Streptococcus faecalis (S. faecalis). Furthermore, the Nps found to inhibit the activity of 1,1-Diphenyl 2-picrylhydrazyl (DPPH) free radicals effectively. This study introduces a facile, green and low coast method for the synthesis of monoclinic CuO NPs with catalytic, antioxidant and antibacterial properties. PMID- 29137733 TI - Three-dimensional organometallic thallium(I) supramolecular polymer nanostructures synthesized with sonochemical process. AB - A new three-dimensional thallium(I) supramolecular polymer, [Tl2(MU2-ATA)]n (1), [H2ATA=2-aminoterephthalic acid], has been synthesized and characterized. The single-crystal X-ray data of compound 1 shows one type of TlI ion with a low coordination number. Compound 1 was self-assembled from Tl?C, Tl?O and Tl?N secondary interactions in thallium(I) coordination and the active lone pair on TlI in this compound may be involved in donor bonding. Two sides of the aromatic ring of ATA2- anion have been involved in two types of secondary Tl?C approaches. Three samples of 1 were synthesized with three different concentrations of initial reagents under ultrasonic irradiation. The thermal stability of compound 1 samples were studied by thermo gravimetric (TG) and differential thermal analyses (DTA). These nano-structures were characterized by X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). PMID- 29137734 TI - Ultrasound irradiation promoted enzymatic alcoholysis for synthesis of monoglyceryl phenolic acids in a solvent-free system. AB - Monoglyceryl phenolic acids (MPAs) were known as the natural hydrophilic antioxidants which could be used in different fields such as food, pharmaceutical, cosmetic etc. A novel enzymatic route of MPAs synthesis by the alcoholysis of phenolic acid ethyl esters with glycerol under ultrasound irradiation in solvent free system was developed. Optimization of reaction parameters shows that a high conversion of above 97.4% can be obtained under the following conditions: phenolic acid ethyl esters to glycerol molar ratio of 1:10, with 6% catalyst (Novozym 435), at 60 degrees C and 200rpm, with ultrasound input of 250W, at 20kHz frequency. Compared to the conventional stirring method, the activation energy for phenolic acid ethyl esters conversion was decreased from 65.0kJ/mol to 32.1kJ/mol under ultrasound promotion; the apparent kinetic constant (Vm/Km) increased above 1.2-folds; the lipase amount decreased to 50%; the time required for the maximum conversion reduced up to 3-folds without damaging the lipase activity, which is the fastest report for enzymatic synthesis of MPAs. PMID- 29137735 TI - Superiority of sonochemical processing method for the synthesis of barium titanate nanocrystals in contrast to the mechanochemical approach. AB - The results indicated that the ultrasonic sonochemistry which brings into play the acoustic cavitation phenomenon is more powerful and feasible in synthesizing the mixed oxides in contrast to the conventional solid-state approaches. The obtained results demonstrated that the sonochemical approach is able to obtain highly pure powder product at a much lower processing temperature of about 323K (50 degrees C) in contrast to 1173K (900 degrees C) which is essential for the synthesis by the mechanochemical approach. Sonochemical synthesis benefits from homogenous ordering the reactant ions (which have been dissolved in the solution mixture) into perovskite structure using ultrasonication. This indicates that the acoustic cavitation phenomenon is much more powerful and cost-effective than high energy ball milling in synthesizing nanopowders of the mixed oxide materials. Moreover, the sonochemical processing method is able to prepare the final powder products in a much shorter time by a one-step synthesis approach without the need for the successive calcination in contrast to the solid-state approach. PMID- 29137736 TI - Non-innocent probes in direct sonication: Metal assistance in oxidative radical CH functionalization. AB - Direct sonication by means of ultrasound horns constitutes a widely used technique in chemical process technology. However, the direct contact between the metal probe and the reaction mixture does not always leave the chemical system unaffected. In this report, we study the tert-butyl hydroperoxide-mediated trifluoromethylation of heterocyclic structures, and the influence of sonication thereon. Metal leaching is observed during the process and further examined, showing that several metals can interfere significantly with the chemical reaction under study. Notably, vanadium metal was found to increase the reaction rate exceptionally well, rendering it a useful additive for this type of reactions. Ultimately, some mechanistic considerations are offered, to provide more insight into the nature of the catalytic effect of leached metals. PMID- 29137737 TI - Acoustic cavitation in 1-butyl-3-methylimidazolium bis(triflluoromethyl sulfonyl)imide based ionic liquid. AB - In this work, a comparison between the temperatures/pressures within acoustic cavitation bubble in an imidazolium-based room-temperature ionic liquid (RTIL), 1 butyl-3-methylimidazolium bis(triflluoromethyl-sulfonyl)imide ([BMIM][NTf2]), and in water has been made for a wide range of cavitation parameters including frequency (140-1000kHz), acoustic intensity (0.5-1Wcm-2), liquid temperature (20 50 degrees C) and external static pressure (0.7-1.5atm). The used cavitation model takes into account the liquid compressibility as well as the surface tension and the viscosity of the medium. It was found that the bubble temperatures and pressures were always much higher in the ionic liquid compared to those predicted in water. The valuable effect of [BMIM][NTf2] on the bubble temperature was more pronounced at higher acoustic intensity and liquid temperature and lower frequency and external static pressure. However, confrontation between the predicted and the experimental estimated temperatures in ionic liquids showed an opposite trend as the temperatures measured in some pure ionic liquids are of the same order as those observed in water. The injection of liquid droplets into cavitation bubbles, the pyrolysis of ionic liquids at the bubble-solution interface as well as the lower number of collapsing bubbles in the ionic liquid may be the responsible for the lower measured bubble temperatures in ionic liquids, as compared with water. PMID- 29137739 TI - Employment of ultrasonic irradiation for production of poly(vinyl pyrrolidone)/modified alpha manganese dioxide nanocomposites: Morphology, thermal and optical characterization. AB - This work explains the production, morphology, and features of novel nanocomposite (NC) established on poly(vinyl pyrrolidone) (PVP) as polymer background and modified alpha manganese dioxide (alpha-MnO2) nanorod (NR) asan efficient filler. At first, one-dimensional alpha-MnO2 nanorods (NRs) were produced by a hydrothermal technique and then they were amended with stearic acid (SA) by a solvothermal process. In following, the NCs were made by adding different volumes of alpha-MnO2-SA NR (1, 3 and 5wt%) in the PVP matrix through ultrasonic irradiation as a green, low-cost, fast, and useful technique. Structural and morphological descriptions confirm crystallinity of alpha-MnO2-SA NRs and showed that NRs have been separately dispersed in PVP matrix with rod like morphology and diameter of about 40-60nm. The use of modifier and ultrasonic waves is accountable for good homogeneities of NRs. Thermogravimetric analysis revealed that thermal permanency of the obtained NCs has grown with increasing the alpha-MnO2-SA content. Also, the UV-vis absorption of NCs was enhanced with the incorporation of the modified alpha-MnO2 NR in PVP matrix. The substantial perfections in NCs properties are associated to compatible intermolecular relations between the surface modifying groups of the alpha-MnO2-SA and PVP chain. PMID- 29137738 TI - Ultrasound-assisted leaching of rare earths from the weathered crust elution deposited ore using magnesium sulfate without ammonia-nitrogen pollution. AB - The in situ leaching process of China's unique ion-adsorption rare earth ores has caused severe environmental damages due to the use of (NH4)2SO4 solution. This study reports that magnesium sulfate (MgSO4) as a leaching agent would replace (NH4)2SO4 by ultrasonically assisted leaching to deal with the ammonia-nitrogen pollution problem and enhance leaching process. At leaching conditions of 3wt% MgSO4 concentration, 3:1L/S ratio and 30min, the total rare earth leaching efficiency reaches 75.5%. Ultrasound-assisted leaching experiments show that the leaching efficiency of rare earths is substantially increased by introducing ultrasound, and nearly completely leached out after two stage leaching process. Thus, ultrasonic-assisted leaching process with MgSO4 is not only effective but also environmentally friendly, and beneficial to leach rare earths at laboratory scale. PMID- 29137740 TI - Morphology-dependent sensing performance of dihydro-tetrazine functionalized MOF toward Al(III). AB - A pillared MOF, [Zn(OBA)(H2DPT)0.5].DMF (TMU-34), based on dihydro tetrazine functionalized pillar spacer (H2DPT=3,6-di(pyridin-4-yl)-1,4-dihydro-1,2,4,5 tetrazine) and V-shape dicarboxylate linker (H2OBA=4,4'-oxybis(benzoic acid)) was synthesized by reflux and ultrasonic methods. The effects of sonication time, initial concentration of reagents and sonication power on size and morphology have been optimized. This MOF has been characterized by scanning electron microscopy, FT-IR spectra, X-ray powder diffraction and N2 adsorption at 77K. Bulk and nano samples of TMU-34 have been applied in cation sensing for detection of Al(III) in presence of other cations (Na(I), Mg(II), Sr(II), Al(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Pb(II), Hg(II),Cr(III), Li(I), Fe(III), K(I)). The results show that nano powder of TMU-34 with uniform separated plate-like morphology (TMU-34-F) has higher detection limit and short response time compared to bulk material. So, in this work we show the application of luminescent metal organic frameworks synthesized by sonochemistry approach in effective cation detection. PMID- 29137741 TI - Sonochemical synthesis, characterization, thermal and semiconducting behavior of nano-sized azidopentaamminecobalt(III) complexes containing anion, CrO42- or Cr2O72. AB - New nano-sized cobalt(III) coordination complexes, [Co(NH3)5N3]CrO4 (1N) and [Co(NH3)5N3]Cr2O7 (2N) were synthesized using an innovative sonochemical methodology based on reaction between [Co(NH3)5N3]Cl2 and potassium salt of CrO42 or Cr2O72- in aqueous medium. These complexes were also compared with their respective bulks which were synthesized under identical conditions in the absence of sonicaion. All the complexes were characterized by elemental analysis and spectroscopic techniques (UV-visible and IR). Morphology and particle size of nano-sized complexes was determined by SEM and Zeta-sizer respectively. TGA was used for comparative thermal stability and XRD to identify the phase difference between nano structures and bulk complexes. Furthermore, the electrical property was investigated and all complexes were found to be electrical semiconducting materials and 2N shows better result than others. The single crystals X-ray structure study of new [Co(NH3)5N3]Cr2O7 revealed the presence of discrete ions, [Co(NH3)5N3]2+ and Cr2O72-, crystallizes in monoclinic, space group Pc, with R=0.0636 in the solid state. PMID- 29137742 TI - Ultrasound coupled with supercritical carbon dioxide for exfoliation of graphene: Simulation and experiment. AB - Ultrasound coupled with supercritical CO2 has become an important method for exfoliation of graphene, but behind which a peeling mechanism is unclear. In this work, CFD simulation and experiment were both investigated to elucidate the mechanism and the effects of the process parameters on the exfoliation yield. The experiments and the CFD simulation were conducted under pressure ranging from 8MPa to 16MPa, the ultrasonic power ranging from 12W to 240W and the frequency of 20kHz. The numerical analysis of fluid flow patterns and pressure distributions revealed that the fluid shear stress and the periodical pressure fluctuation generated by ultrasound were primary factors in exfoliating graphene. The distribution of the fluid shear stress decided the effective exfoliation area, which, in turn, affected the yield. The effective area increased from 5.339cm3 to 8.074cm3 with increasing ultrasonic power from 12W to 240W, corresponding to the yield increasing from 5.2% to 21.5%. The pressure fluctuation would cause the expansion of the interlayers of graphite. The degree of the expansion increased with the increase of the operating pressure but decreased beyond 12MPa. Thus, the maximum yield was obtained at 12MPa. The cavitation might be generated by ultrasound in supercritical CO2. But it is too weak to exfoliate graphite into graphene. These results provide a strategy in optimizing and scaling up the ultrasound-assisted supercritical CO2 technique for producing graphene. PMID- 29137743 TI - Sonochemical synthesis of amide-functionalized metal-organic framework/graphene oxide nanocomposite for the adsorption of methylene blue from aqueous solution. AB - Graphene oxide-[Zn2(oba)2(bpfb)].(DMF)5 metal-organic framework nanocomposite (GO TMU-23; H2oba=4,4'-oxybisbenzoic acid, bpfb=N,N'-bis-(4-pyridylformamide)-1,4 benzenediamine, DMF=N,N-dimethylformamide) is prepared through a simple and large scale sonochemical preparation method at room temperature. The obtained nanocomposite is characterized by Field Emission Scanning Electron Microscopy (FE SEM), powder X-ray diffraction (PXRD) and FT-IR spectroscopy. Additionally, the absorption ability of GO-TMU-23 nanocomposite toward cationic dye methylene blue was also performed. Significantly, GO-TMU-23 nanocomposite exhibits remarkably accelerated adsorption kinetics for methylene blue in comparison with the parent materials. The adsorption process shows that 90% of the dye has been removed and the equilibrium status has been reached in 2min by using the nanocomposites as the adsorbent. PMID- 29137745 TI - Intensification of heat transfer during mild thermal treatment of dry-cured ham by using airborne ultrasound. AB - The application of power ultrasound (PuS) could be used as a novel technology with which to intensify thermal treatments using hot air. Mild thermal treatments have been applied to improve the soft texture of dry-cured ham caused by defective processing. In this regard, the aim of this study was to assess the kinetic intensification linked to the application of airborne PuS in the mild thermal treatment using hot air of dry-cured ham. For this purpose, vacuum packed cylindrical samples (2.52+/-0.11cm in diameter and 1.90+/-0.14cm in height) of dry-cured ham were heated using hot air at different temperatures (40, 45, 50 degrees C) and air velocities (1, 2, 3, 4, 6m/s) with (22.3kHz, 50W) and without PuS application. Heat transfer was analyzed by considering that it was entirely controlled by conduction and the apparent thermal diffusivity was identified by fitting the model to the heating kinetics. The obtained results revealed that PuS application sped up the heat transfer, showing an increase in the apparent thermal diffusivity (up to 37%). The improvement in the apparent thermal diffusivity produced by PuS application was greater at high temperatures (50 degrees C) but negligible at high air velocities (6m/s). Heating caused an increase in the hardness and elasticity of dry-cured ham, which would correct ham pastiness defects, while the influence of PuS on such textural parameters was negligible. PMID- 29137744 TI - Luminescence, electrochemical and photocatalytic properties of sub-micron nickel(II) and cobalt(II) coordination polymers synthesized by sonochemical process. AB - Submicron structures of NiII/CoII-based coordination polymers (CPs) [Ni(L1)(mip).H2O]n (1) and {[Co(L2)(mip)].0..5H2O}n(2) (L1=1,6-bis(5,6 dimethylbenzimidazole)hexane, L2=1,6-bis(benzimidazole)hexane, H2mip=5 methylisophthalic acid) were obtained by ultrasonic irradiation and structurally characterized by elemental analysis, powder X-ray diffraction and scanning electron microscopy. Structural analysis show that two CPs feature uninodal 3 connected 2D hcb layer, whilst CP 2 is further extended into a 3D complicated supramolecular network by C14-H14?O2 hydrogen bonds. Ultrasonic time and power influencing morphology of sub-micron sized CPs, were also discussed. Besides that, thermal stability, luminescence, electrochemical properties and photocatalytic activity of sub-micron sized 1 and 2 were presented in detail. Moreover, sub-micron sized 1 manifests the higher photocatalytic activity than sub-micron sized 2 for decomposition of methylene blue (MB) under UV irradiation. PMID- 29137746 TI - Ultrasonically tailored, chemically engineered and "QbD" enabled fabrication of agomelatine nanoemulsion; optimization, characterization, ex-vivo permeation and stability study. AB - The objective of present study was to develop a nanoemulsion formulation of agomelatine (BCS class II drug) for the solubility enhancement. Capmul MCM, Tween 80 and PEG-400 were selected as oil, surfactant and co-surfactant respectively. The high energy ultrasonication method was used for the preparation of nanoemulsion. Three-factor three-level central composite design was employed to get the best formulation. The independent variables selected for the optimization were % oil, %Smix and sonication time (second). Based on the constraints applied to independent and dependent variables, the optimized formulation was selected with 2% oil, 10% Smix and 45s sonication time. The experimental values for dependent variables such as hydrodynamic diameter (nm), % transmittance and % CDR were found to be 73.72+/-2.53nm, 98.2+/-0.42%, 84.71+/-4.05% respectively. TEM and AFM-assisted morphological characterization of optimized Ago-NE was done and it was found with a spherical shape. The PDI, Zeta potential and the refractive index of optimized Ago-NE were found to be 0.137+/-0.016, -7.40+/-0.12mV and 1.423+/-0.045 respectively. The viscosity, pH and drug content of optimized Ago NE were found as 25.12+/-0.67cP, 6.4+/-0.17 and 97.83+/-1.03% respectively. The ex-vivo permeation profile of optimized Ago-NE and agomelatine suspension through goat nasal mucosa were compared till 12h and % cumulative drug permeated was found to be 90% and 40% respectively. The higher drug permeation profile of optimized Ago-NE confirmed that the solubility of agomelatine has been improved. PMID- 29137747 TI - Effect of sonochemical scouring on the surface morphologies, mechanical properties, and dyeing abilities of wool fibres. AB - Ultrasonics has the potential to reduce the cost and environmental impact of textile processing. This work investigates the effects of ultrasonic irradiation during wool scouring on fibre surface morphologies, fibre mechanical properties, and fibre dyeing abilities. A range of ultrasonic frequencies were used in the scouring bath to examine the forms of fibre cuticle damage. It is observed that wool fibres underwent ultrasonic irradiation at a low frequency have severe modifications of the fibre surface structure. Despite some visible disruptions to the fibre scale structure however, ultrasonic irradiation has shown a negligible impact on the fibre mechanical properties, especially bending abrasion resistance which depends largely on the fibre surface conditions, and is responsible for the handle and pilling propensity of the resultant fabrics. Dyeing abilities were investigated on wool samples using commercially available acid dye and reactive dye. It is found that ultrasonically scoured wool has a quicker dye uptake in the early stage of low temperature dyeing for both acid dye and reactive dye, than the conventionally scoured wool. PMID- 29137748 TI - A novel synthesis of a new thorium (IV) metal organic framework nanostructure with well controllable procedure through ultrasound assisted reverse micelle method. AB - Reverse micelle (RM) and ultrasound assisted reverse micelle (UARM) were applied to the synthesis of novel thorium nanostructures as metal organic frameworks (MOFs). Characterization with different techniques showed that the Th-MOF sample synthesized by UARM method had higher thermal stability (354 degrees C), smaller mean particle size (27nm), and larger surface area (2.02*103m2/g). Besides, in this novel approach, the nucleation of crystals was found to carry out in a shorter time. The synthesis parameters of UARM method were designed by 2k-1 factorial and the process control was systematically studied using analysis of variance (ANOVA) and response surface methodology (RSM). ANOVA showed that various factors, including surfactant content, ultrasound duration, temperature, ultrasound power, and interaction between these factors, considerably affected different properties of the Th-MOF samples. According to the 2k-1 factorial design, the determination coefficient (R2) of the model is 0.999, with no significant lack of fit. The Fvalue of 5432, implied that the model was highly significant and adequate to represent the relationship between the responses and the independent variables, also the large R-adjusted value indicates a good relationship between the experimental data and the fitted model. RSM predicted that it would be possible to produce Th-MOF samples with the thermal stability of 407 degrees C, mean particle size of 13nm, and surface area of 2.20*103m2/g. The mechanism controlling the Th-MOF properties was considerably different from the conventional mechanisms. Moreover, the MOF sample synthesized using UARM exhibited higher capacity for nitrogen adsorption as a result of larger pore sizes. It is believed that the UARM method and systematic studies developed in the present work can be considered as a new strategy for their application in other nanoscale MOF samples. PMID- 29137749 TI - Exceptionally high cavitation erosion and corrosion resistance of a high entropy alloy. AB - Cavitation erosion and corrosion of structural materials are serious concerns for marine and offshore industries. Durability and performance of marine components are severely impaired due to degradation from erosion and corrosion. Utilization of advanced structural materials can play a vital role in limiting such degradation. High entropy alloys (HEAs) are a relatively new class of advanced structural materials with exceptional properties. In the present work, we report on the cavitation erosion behavior of Al0.1CoCrFeNi HEA in two different media: distilled water with and without 3.5wt% NaCl. For comparison, conventionally used stainless steel SS316L was also evaluated in identical test conditions. Despite lower hardness and yield strength, the HEA showed significantly longer incubation period and lower erosion-corrosion rate (nearly 1/4th) compared to SS316L steel. Enhanced erosion resistance of HEA was attributed to its high work-hardening behavior and stable passivation film on the surface. The Al0.1CoCrFeNi HEA showed lower corrosion current density, high pitting resistance and protection potential compared to SS316L steel. Further, HEA showed no evidence of intergranular corrosion likely due to the absence of secondary precipitates. Although, the degradation mechanisms (formation of pits and fatigue cracks) were similar for both the materials, the damage severity was found to be much higher for SS316L steel compared to HEA. PMID- 29137750 TI - Intensification of ion exchange desorption of thiamine diphosphate by low-powered ultrasound. AB - The process of ultrasound-assisted ion-exchange desorption of cocarboxylase (thiamine diphosphate (TDP)) from a strong acidic cation resin was studied. Kinetics studies revealed that ultrasound accelerates TDP desorption by 3 times. The optimal desorption parameters, viz. US power input, sonication time, eluent/resin ratio and the eluent (ammonium acetate buffer) concentration were established which were 15mW/cm3, 20min, 1:1 and 1M, respectively. The resin stability studies showed that the optimal ultrasonic power was less by the order than the resin degradation threshold which ensures durable and efficient resin exploitation during production. The resin sorption capacity remained unchanged even after 20 cycles of TDP sorption, ultrasonic desorption and resin regeneration. The recovery ratio of TDP was shown to increase non-linearly with decreasing the resin saturation factor, which can be attributed to diffusion limitations occurring during desorption. The optimal resin loading corresponding to more than 90 per cent of TDP recovery was found to be at the level of 10 per cent of the maximal sorption capacity. The study revealed 4-5-fold increase in concentrations of the recovered solutions, which together with process times shortening should result in considerable energy saving in downstream operations on production scale. PMID- 29137751 TI - Enhanced sonocatalytic degradation of organic dyes from aqueous solutions by novel synthesis of mesoporous Fe3O4-graphene/ZnO@SiO2 nanocomposites. AB - Fe3O4-graphene/ZnO@mesoporous-SiO2 (MGZ@SiO2) nanocomposites was synthesized via a simple one pot hydrothermal method. The as-obtained samples were investigated using various techniques, as follows: scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and specific surface area (BET) vibrating sample magnetometer (VSM), among others. The sonocatalytic activities of the catalysts were tested according to the oxidation for the removal of methylene blue (MB), methyl orange (MO), and rhodamine B (RhB) under ultrasonic irradiation. The optimal conditions including the irradiation time, pH, dye concentration, catalyst dosage, and ultrasonic intensity are 60min, 11, 50mg/L, 1.00g/L, and 40W/m2, respectively. The MGZ@SiO2 showed the higher enhanced sonocatalytic degradation from among the three dyes; furthermore, the sonocatalytic-degradation mechanism is discussed. This study shows that the MGZ@SiO2 can be applied asa novel-design catalyst for the removal of organic pollutants from aqueous solutions. PMID- 29137752 TI - Microwave and ultrasound-assisted synthesis of poly(vinyl chloride)/riboflavin modified MWCNTs: Examination of thermal, mechanical and morphology properties. AB - This study focused on the preparation and investigation of physicochemical features of new poly(vinyl chloride) (PVC) nanocomposites (NCs) including different amounts of carboxylated multi-walled carbon nanotubes (MWCNTs-COOH) functionalized with riboflavin (RIB). Firstly, to increase the hydrophilicity of MWCNTs, the surface of them was functionalized by incorporating and formation of ester groups with RIB as a low cost and environmentally friendly biomolecule through ultrasound and microwave irradiations. Afterwards, PVC/RIB-MWCNTs NCs were fabricated via the solution casting and ultrasonic dispersion methods. Prepared NCs were examined by X-ray diffraction, thermogravimetric analysis, field emission scanning electron microscopy, transmission electron micrograph, and Raman spectroscopy. The PVC/RIB-MWCNTs NCs (12wt%) showed the higher mechanical and thermal behavior as compared to other concentration of MWCNTs. PMID- 29137753 TI - Synthesis of nanocomposites of iron oxide/gold (Fe3O4/Au) loaded on activated carbon and their application in water treatment by using sonochemistry: Optimization study. AB - This paper focuses on the finding best operational conditions using response surface methodology (RSM) for Rhodamine123 (R123) and Disulfine blue (DSB) dyes removal by ultrasound assisted adsorption onto Au-Fe3O4 nanoparticles loaded on activated carbon (Au-Fe3O4 NPs-AC). The influences of variables such as initial R123 (X1) and DSB concentration (X2), pH (X3), adsorbent mass (X4) and sonication time (X5) on their removal were investigated by small central composite design (CCD) under response surface methodology. The significant variables and the possible interactions among variables were investigated and estimated accordingly. The best conditions were set as: 4min, 4.0, 0.025g, 13.5 and 26.5mgL 1 for sonication time, pH, adsorbent weight, initial R123 and DSB concentration, respectively. At above conditions, the adsorption equilibrium and kinetic follow the Langmuir isotherm and pseudo-second-order kinetic model, respectively. The maximum monolayer capacity (Qmax) of 71.46 and 76.38mgg-1 for R123 and DSB show sufficiency of model for well presentation of experimental data. PMID- 29137754 TI - Proteinaceous microspheres as a delivery system for carvacrol and thymol in antibacterial applications. AB - There is an urgent need for new materials with antimicrobial activity. Phenolic essential oil (EO) compounds with Generally Recognized As Safe (GRAS) status are attractive candidates, but they need suitable delivery systems to overcome specific drawbacks. Core-shell microspheres (MSs) of Bovine Serum Albumin (BSA) or Human Serum Albumin (HSA) encapsulating such active compounds in the oil phase are a delivery system that is novel in combination with phenolic EO compounds. Moreover, the EO compounds can also be assembled in an oil shell around a protein core by choosing an appropriate oil phase. A facile sonochemical fabrication method, which can be easily scaled-up, is developed with full characterization of the resulting EO-containing MSs by optical and electron microscopy. Bacterial growth experiments with E. coli including TEM of treated cells confirm antibacterial activity. In the case of carvacrol, the corresponding MSs are found to be both more bioactive and more stable than the free biocide. PMID- 29137755 TI - Development of photocatalyst coated fluoropolymer based microreactor using ultrasound for water remediation. AB - Formation of thin layers of photocatalyst in photo-microreactor is a challenging work considering the properties of both catalyst and the microchannel material. The deposition of semiconductor materials on fluoropolymer based microcapillary requires the use of economical methods which are also less energy dependent. The current work introduces a new method for depositing nanoparticles of TiO2 on the inner walls of a hexafluoropropylene tetrafluoroethylene microtube under mild conditions using ultrasound technique. During the ultrasonication process, changes in the polymer surface were observed and characterized using Attenuated Total Reflectance spectroscopy, Scanning Electron Microscopy and Confocal Microscopy. The rough patches form sites for catalyst deposition resulting in the formation of thin layer of TiO2 nanoparticles in the inner walls of the microtube. The photocatalytic activity of the TiO2 coated fluoropolymer based microcapillary was evaluated for removal of phenol present in water. PMID- 29137756 TI - The effects and mechanism of phycocyanin removal from water by high-frequency ultrasound treatment. AB - The effects and mechanism of phycocyanin removal from water by high-frequency ultrasound treatment were studied. The efficiency of sonication treatment in removing proteins derived from algal cells was investigated, and the factors influencing the process, including the effects of coagulation, were also studied. In addition, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE), the three-dimensional fluorescence spectrum, and mass spectrum were used to illustrate the removal mechanism. The results indicated that phycocyanin can be degraded to the point where it is barely detectable in water samples after 180min of high-frequency sonication. While the total nitrogen (TN) concentration remained consistent during the entire sonication process (240min), about 78.9% of the dissolved organic nitrogen (DON) was oxidized into inorganic nitrogen. The sonication effect was greatly influenced by the ultrasound frequency, with 200kHz having the highest removal performance due to the large production of hydroxyl (HO) radicals. Coagulation was adversely influenced by sonication in the first 60min due to the cross-linking reaction between protein molecules caused by the sonication. The influence of sonication weakened with sonication time due to the further degradation of the proteins by ultrasound. The variation of the TN, DON, and inorganic nitrogen indicated that the main mechanism occurring during the high-frequency sonication of the phycocyanin was the direct oxidation of the radicals, which was totally different from of the mechanism occurring during ultrasound with low frequency. PMID- 29137757 TI - Improved crystallization of ammonium sulphate using ultrasound assisted approach with comparison with the conventional approach. AB - In chemical processing industries, crystallization is one of the most important operations to obtain solid products with desired purity and characteristics. With distinct processing problems for the conventional approaches for crystallization, research into alternate approaches such as ultrasound assisted crystallization has been on the forefront. The present work deals with comparison of the conventional approach and ultrasound assisted approach for crystallization of ammonium sulphate followed by detailed understanding into the effect of important operating parameters (initial concentration, pH, agitation speed, depth of horn, and cooling approach) on the metastable zone width and average crystal size. Ultrasound assisted crystallization has been investigated using both ultrasonic bath and ultrasonic horn to understand the effect of type of irradiation. It has been observed that the maximum reduction in the MSZW was obtained using ultrasonic horn under conditions of optimized initial concentration. The order of average crystal size obtained for ammonium sulphate was conventional cooling crystallization>ultrasonic bath>ultrasonic horn. The average crystal size obtained was in the range of 411-450um for conventional approach of cooling crystallization, 350-400um using ultrasonic bath and 200-250um using ultrasonic horn. The analysis of crystal size distribution and surface characteristics using the SEM analysis was also performed under set of optimized parameters established using the particle size analysis. Overall the work has clearly established that the ultrasound assisted crystallization gave better results as compared to the conventional cooling crystallization in terms of reduced metastable zone width, better crystal characteristics and less agglomeration. PMID- 29137758 TI - Droplets banding characteristics of water-in-oil emulsion under ultrasonic standing waves. AB - Droplets banding is critical to emulsion separation under ultrasonic irradiation as it can greatly improve the separation efficiency. In this paper, the formation process of droplets banding under ultrasonic standing waves was precisely captured by high-speed microscopic photography; by processing the images, the droplets banding characteristics, including the banding formation time and banding interval, were extracted. Then the effects of acoustic intensity, frequency, droplet size, and physical properties of oil and water on the droplets banding characteristics were discussed in details. The results show that the range of acoustic intensities, within which the droplets banding can form, increases with the increase of the frequency; a maximum allowable acoustic intensity exists for banding formation, which also increases with the frequency. The banding formation time, which increases with increasing oil viscosity but decreases with droplet size, is found to be hardly affected by the oil-water interfacial tension. In addition, the banding interval is only related to the frequency, which closely corresponds to the half wavelength. PMID- 29137759 TI - Ultrasonic assisted production of starch nanoparticles: Structural characterization and mechanism of disintegration. AB - In this paper, the disintegration of starch (waxy and standard starch) granules into nanosized particles under the sole effect of high power ultrasonication treatment in water/isopropanol is investigated, by using wide methods of analysis. The present work aims at a fully characterization of the starch nanoparticles produced by ultrasonication, in terms of size, morphology and structural properties, and the proposition of a possible mechanism explaining the top-down generation of starch nanoparticles (SNPs) via high intensity ultrasonication. Dynamic light scattering measurements have indicated a leveling of the particle size to about 40nm after 75min of ultrasonication. The WAXD, DSC and Raman have revealed the amorphous character of the SNPs. FE-SEM. AFM observations have confirmed the size measured by DLS and suggested that SNPs exhibited 2D morphology of platelet-like shapes. This morphology is further supported by SAXS. On the basis of data collected from the different characterization techniques, a possible mechanism explaining the disintegration process of starch granules into NPs is proposed. PMID- 29137760 TI - A novel high performance nano chemosensor for copper (II) ion based on an ultrasound-assisted synthesized diphenylamine-based Schiff base: Design, fabrication and density functional theory calculations. AB - A novel high selective colorimetric chemosensor was introduced based on a nano diphenyl-based Schiff base (H2L), 2,2'-((1E,1'E)-(((hexylazanediyl)bis(4,1 phenylene))bis(methanylylidene))bis(azanylylidene))bis(4-methylphenol) that synthesized using sonochemical method. H2L was characterized by FT-IR, MS, TGA, 1H NMR, 13C NMR, SEM and elemental analysis techniques, then fabricated as the portable strips for sensing copper (II) ions in aqueous media. The binding interaction between H2L and various metal ions was investigated by UV-Vis spectroscopic that showed favorable coordination toward Cu2+ ion. H2L exhibited binding-induced color changes from yellow to pink and practically no interference in the presence of other metal ions, i.e., Cr2+, Mn2+, Fe2+, Co2+, Ni2+, Zn2+, Cd2+, Hg2+, Pb2+, Mg2+ and Ca2+. The chemsensor showd the color change from yellow to pink in presence of copper (II) ion in aqueous media due to binging of H2L and Cu (II). This sensor can determine the copper (II) at in the rang of 7.5 * 10-8-1.8 * 10-5 mol L-1 with a correlation equation: Absorbance = 0.0450[Cu2+] * 10-6 + 0.71 and R2 = 0.975 and low detection limit of 1.89 * 10-8 mol L-1. Density functional theory (DFT) calculations were carried out at the B3LYP levels of theory with B3LYP/6-311+G(d,p) and LANL2DZ/6-311+G(d,p) basis sets for chemosensor and its copper complex respectively. The optimized geometry, harmonic vibrational frequencies, 1H NMR and 13C NMR chemical, Molecular orbital (M.O.), Mulliken population analysis (MPA), contour of Electrostatic Potential (ESP) and Molecular Electrostatic Potential (MEP) map of H2L were calculated which show good agreement with behavior of sensor for detection of Cu2+ ion. PMID- 29137762 TI - Ultrasonic-promoted rapid preparation of PVC/TiO2-BSA nanocomposites: Characterization and photocatalytic degradation of methylene blue. AB - In the present project in order to prevent agglomeration and better dispersion of TiO2 nanoparticles (NPs) in the poly(vinyl chloride) (PVC) matrix, initially, the surface of TiO2 NPs was covered by bovine serum albumin protein (BSA) via sonication method. Then, the TiO2-BSA powders were embedded into the PVC matrix using ultrasonic irradiations. With mechanical and magnetic stirring homogenous mixture was not obtained. So sonication process was very essential and vital. Physical, chemical and structural properties of the samples were investigated with various tools. Morphology studies showed the well distribution of spherical TiO2 NPs in the PVC matrix. TGA analysis showed that nanocomposites (NCs) have higher thermal stability than the pristine polymer. The photocatalytic activity tests by destroying the methylene blue dye on the pristine TiO2 NPs, TiO2-BSA NPs and PVC/TiO2-BSA NC 6 wt% were examined. The results showed that the photocatalytic activity of TiO2 NPs was reduced in the presence of BSA and PVC. It can be concluded that the TiO2-BSA NPs and PVC/TiO2-BSA NC 6 wt% have UV shielding properties and can protect film from degradation by UV. PMID- 29137761 TI - Ultrasound-assisted surface treatment of ZrO2 with BSA and incorporating in PVC to improve the properties of the obtained nanocomposites: Fabrication and characterization. AB - This paper describes the preparation of poly(vinyl chloride) (PVC) nanocomposites (NCs) reinforced with modified zirconia (ZrO2) nanoparticles (NPs). The ZrO2 NPs were defined as efficient filler for PVC NCs. For achieving the best dispersion and improvement of properties, the surface of ZrO2 NPs was modified by Bovine Serum Albumin (BSA). Carboxylic acids and amines are important functional groups of BSA which handle the grafting BSA on the surface of ZrO2 NPs. The PVC/ZrO2-BSA NCs were fabricated by incorporation of various amounts of the ZrO2-BSA NPs (3, 6 and 9wt%) into PVC matrix. All the above processes were accomplished by ultrasonication asa green and environmentally-friendly method. Also, the magnetic and mechanical stirrer was used for the preparation of samples but the results are not suitable and the aggregation was observed which indicated the use of ultrasonic irradiation is the best method for the preparation of NC. The products were characterized by Fourier transform infrared spectroscopy, Transmission electron microscopy, Field emission scanning electron microscopy, X-ray diffraction, Thermogravimetric analysis, Ultraviolet-visible spectroscopy, photoluminescence spectroscopy, energy dispersive X-ray spectroscopy, wettability, and mechanical tests. The achieved PVC/ZrO2-BSA NCs showed high thermal stability, good mechanical, optical and wettability properties compared to the pure PVC. In addition, among the obtained NCs, the PVC/ZrO2-BSA NC 6wt% showed the best improvement. PMID- 29137763 TI - MWCNT/TiO2 hybrid nano filler toward high-performance epoxy composite. AB - In this work, multi-walled carbon nanotubes (MWCNTs) are decorated by TiO2 nanoparticles and formed a new hybrid structure of filler (MWCNT/TiO2 hybrid filler). The MWCNT/TiO2 hybrid filler is reinforced in epoxy matrix and studied the mechanical and anti-corrosion properties of epoxy. The morphology of newly formed MWCNT/TiO2 hybrid nano filler has been studied using transmission electron microscopy (TEM). Field Emission Scanning Electron Microscope (FESEM) images of tensile fracture surface confirmed the superior dispersion of MWCNT/TiO2 in the epoxy matrix. The resultant MWCNT/TiO2 hybrid-epoxy nanocomposite exhibits superior anti-corrosion and mechanical performance than the nanocomposite produced by loading of only MWCNTs or TiO2 nanoparticles as well as neat epoxy. For example, tensile strength and storage modulus of epoxy increased by 61% and 43% respectively on loading of MWCNT/TiO2 hybrid nano filler. Furthermore, the coating of MWCNT/TiO2 hybrid-epoxy nanocomposite on mild steel reduces the corrosion rate upto 0.87*10-3MPY from 16.81MPY. PMID- 29137764 TI - Ultra-low temperature sintering of Cu@Ag core-shell nanoparticle paste by ultrasonic in air for high-temperature power device packaging. AB - Sintering of low-cost Cu nanoparticles (NPs) for interconnection of chips to substrate at low temperature and in atmosphere conditions is difficult because they are prone to oxidation, but dramatically required in semiconductor industry. In the present work, we successfully synthesized Cu@Ag NPs paste, and they were successfully applied for joining Cu/Cu@Ag NPs paste/Cu firstly in air by the ultrasonic-assisted sintering (UAS) at a temperature of as low as 160 degrees C. Their sintered microstructures featuring with dense and crystallized cells are completely different from the traditional thermo-compression sintering (TCS). The optimized shear strength of the joints reached to 54.27 MPa, exhibiting one order of magnitude higher than TCS at the same temperature (180 degrees C) under the UAS. This ultra-low sintering temperature and high performance of the sintered joints were ascribed to ultrasonic effects. The ultrasonic vibrations have distinct effects on the metallurgical reactions of the joints, resulting in the contact and growth of Cu core and the stripping and connection of Ag shell, which contributes to the high shear strength. Thus, the UAS of Cu@Ag NPs paste has a great potential to be applied for high-temperature power device packaging. PMID- 29137765 TI - Effect of ultrasound treatments on functional properties and structure of millet protein concentrate. AB - In this study, the effect of high power ultrasound (US) probe in varying intensities and times (18.4, 29.58, and 73.95 W/cm2 for 5, 12.5 and 20 min respectively) on functional properties of millet protein concentrate (MPC) was investigated, and also the structural properties of best modified treatment were evaluated by FTIR, DSC, Zeta potential and SDS-PAGE techniques. The results showed the solubility in all US treated MPC was significantly (p < .05) higher than those of the native MPC. Foaming capacity of native MPC (271.03 +/- 4.51 ml) was reduced after US treatments at low intensities (82.37 +/- 5.51 ml), but increased upon US treatments at high intensities (749.7 +/- 2 ml). In addition, EAI and ES increased after US treatments. One of the best US treatments that can improve the functional properties of MPC was 73.95 W/cm2 for 12.5 min that resulted in reduction of molecular weight and increase nearly 36% in the negative surface charge that was confirmed by SDS-page and Zeta potential results, respectively. PMID- 29137766 TI - Mild synthesis of a Zn(II) metal organic polymer and its hybrid with activated carbon: Application as antibacterial agent and in water treatment by using sonochemistry: Optimization, kinetic and isotherm study. AB - In this work, a room temperature and short method (30min) for synthesis of nanosized rod-like metal organic polymer (MOP) has been described. Reaction of 1,4-phenylenedioxy diacetic acid with zinc salt leads to the formation of [Zn(C10H8O6)(H2O)4]n and subsequently was loaded on activated carbon following sonication and structurally characterized by FTIR, SEM, EDX and XRD analysis. The combination of this new composite with sonication was applied for rapid and efficient adsorption of Bromocresol Purple (BCP). Effects of initial BCP concentration, mass of adsorbent and sonication time on response were investigated and optimized by central composite design (CCD). Analysis of variation (ANOVA) was adapted to experimental data to find best optimum conditions which was set at 15.22mgL-1, 2.41min, 0.02g and 0.009mg for initial BCP concentration, sonication time and adsorbent mass, respectively. Conduction of similar experiments at specified condition permit achievement of 98.69% removal percentage. 1,4-phenylenedioxy diacetic acid and Zn(NO3)2.4H2O which have applied for preparation of MOP are interesting antibacterial properties and accordingly MOP was screened in vitro for their antibacterial actively against Proteus vulgaris bacteria and experimental results reveal this MOP was able to inhibit growth of the tested bacteria. The experimental data were best fitted by pseudo-second order and Langmuir for kinetic model and the adsorption equilibrium isotherm, respectively. PMID- 29137767 TI - Sonochemistry of aqueous NaAuCl4 solutions with C3-C6 alcohols under a noble gas atmosphere. AB - The effect of the type of C3-C6 alcohol, solution temperature, and dissolved gas on the rate of Au(III) reduction was investigated in NaAuCl4 aqueous alcohol solution with a 200-kHz ultrasound irradiation system. It was confirmed in the presence of C3-C6 alcohol that more highly hydrophobic alcohols more effectively accumulated at the argon bubble interface region, and the reducing radicals formed here. To avoid changes in the bubble temperature during collapsing bubble, the effects of the solution temperature on the rate of Au(III) reduction and on the rate of formation of the gaseous compounds (CO, CO2, CH4, C2H2, C2H4, C2H6) were investigated in the presence of low concentration (1.0-mM) of 1-hexanol. Both of the rates showed a good relationship with the gas solubility: the amount of dissolved gas at different solution temperatures affected the number of high temperature bubbles formed. The changes in the concentrations of the gaseous compounds formed from 1-hexanol degradation suggested that CO and the pyrolysis radicals acted as reductants. Finally, the effect of the type of dissolved gas was investigated in the presence of 1.0-mM Au(III) and 1.0-mM 1-hexanol. The rates of 1-hexanol degradation, Au(III) reduction, and gaseous compound formation increased in the order He96% yield). The ZnO-NLs shows an excellent thermal stability even at a higher temperature (900 degrees C) and high surface area. The high antibacterial activity of ZnO-NLs against diseases causing Gram-positive bacteria Staphylococcus aureus shows a reduction in CFU, morphological changes like eight times reduction in cell size, cell burst, and cellular leakage at 200ug/mL concentration. This study provides an efficient, cost-effective and an environmental friendly approach for the synthesis of ZnO-NLs at industrial scale as well as new technique to increase the efficiency of the existing sonochemical method. We envisage that this method can be applied to various fields where ZnO is significantly consumed like rubber manufacturing, ceramic industry and medicine. PMID- 29137778 TI - The use of ultrasound to reduce internal concentration polarization in forward osmosis. AB - Unlike reverse osmosis (RO) that is dominated by the hydraulic pressure differential, forward osmosis (FO) uses the osmotic pressure gradient as the driving force between a dilute feed solution and a concentrated draw solution across a membrane. High pressure is not required in FO, which means that FO can be used as an alternative to RO as an energy-saving separation process in desalination technology. However, a major limiting factor of the FO process is the internal concentration polarization (ICP). Because of the stagnant environment inside the porous supporting layer of a FO membrane, it is difficult to mitigate the ICP by simply increasing the shear stress or promoting turbulence. In this study, the ICP is reduced by ultrasound. The effect of the ultrasound frequency and output power on the ICP coefficient is investigated in a flat-sheet FO membrane module with counter-current flow. The ultrasound frequency and output power are varied between 25, 45, and 72 kHz and over the range of 10 70 W, respectively. NaCl solution is used as both the feed and draw solution. The results illustrate that moderate ultrasonic irradiation is effective for reducing the ICP in a FO process. A modified solution-diffusion model based on film theory is used to assess the effect of ultrasound on the ICP in a FO process. The ICP coefficient is estimated using this model. PMID- 29137779 TI - Physicochemical properties of germinated dehulled rice flour and energy requirement in germination as affected by ultrasound treatment. AB - Limited data are published regarding changes in the physicochemical properties of rice flours from germinated de-hulled rice treated by ultrasound. This work was undertaken to evaluate the effect of ultrasound treatment (25 kHz, 16 W/L, 5 min) on starch hydrolysis and functional properties of rice flours produced from ultrasound-treated red rice and brown rice germinated for up to 36 h. Environmental Scanning Electron Microscopy (ESEM) microimages showed that the ultrasound treatment altered the surface microstructure of rice, which helped to improve moisture transfer during steam-cooking. The flours from sonicated germinated de-hulled rice exhibited significantly (p < .05) enhanced starch hydrolysis, increased the glucose content, and decreased falling number values and viscosities determined by a Rapid Visco Analyzer. The amylase activity of the germinating red rice and brown rice displayed different sensitivity to ultrasonic treatment. The ultrasonic pre-treatment resulted in a significant reduction in energy use during germination with a potential to further reduce energy use in germinated rice cooking process. The present study indicated that ultrasound could be a low-power consumption method to modify the rheological behavior of germinated rice flour, as well as an efficient approach to improve the texture, flavor, and nutrient properties of steam-cooked germinated rice. PMID- 29137780 TI - Sonication affects the quantity and the morphology of ZnO nanostructures synthesized on the mild steel and changes the corrosion protection of the surface. AB - The several types of sonication methods were applied to access the different morphologies of ZnO nanostructures on the surface of mild steel. To achieve this goal, a sonictor equipped with the probe extender was used as a high intensity ultrasonic apparatus for direct sonication. Furthermore, an ultrasonic bath (low intensity) and a cup-horn system (high intensity) were applied for indirect sonication. To find the effect of the acoustic waves on the ZnO morphology, the micrographs of obtained surfaces were compared to the sample prepared by the conventional method using scanning electron microscopy (SEM). In this work, the beneficial effects of sonication were subjected on the breaking down the agglomerates to smaller size particles, metal surface activation, and on the facile approach to nanostructures synthesis. The influence of the resulting ZnO structures over the corrosion protection of the electroless Ni-P alloy coatings was evaluated by the potentiodynamic polarization technique (Tafel extrapolation). PMID- 29137781 TI - Preparation of novel CeO2-biochar nanocomposite for sonocatalytic degradation of a textile dye. AB - The sonocatalytic performance of CeO2 nanoparticles synthesized by a hydrothermal method (CeO2-H) and CeO2@biochar (CeO2-H@BC) nanocomposite, were evaluated for the degradation of Reactive Red 84 (RR84) under ultrasonic irradiation. For comparison purposes the corresponding performance of bare biochar (BC) and commercial CeO2 (CeO2-C) samples were also assessed. A complementary characterization study, involving scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), Transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray diffraction (XRD), N2 adsorption at -196 degrees C (Brunauer-Emmett-Teller (BET) method) and Fourier transform infrared spectroscopy (FT-IR) was undertaken to gain insight into the structure performance relationships. The effect of various parameters such as initial RR84 concentration, solution pH, catalyst amount and ultrasonic power on the sonodegradation of RR84 was studied in detail. The results indicated that the CeO2-H@BC nanocomposite exhibited the best RR84 degradation efficiency, which is enhanced with the increase of CeO2-H@BC amount and ultrasonic power but diminished with the increment in RR84 concentration and pH value. A 98.5% degradation was obtained with a CeO2-H@BC amount of 1g/L, ultrasonic power of 450 W, pH of 6.5 and initial RR84 concentration of 10mg/L. The quenching effects of various scavengers proposed that OH radical plays the key role in the process. Analyses of intermediates by Gas chromatography-Mass spectroscopy (GC-MS) identified several by-products and accordingly the main pathway was proposed. PMID- 29137782 TI - Compensating effect of ultrasonic waves on retarding action of nanoparticles in drops liquid-liquid extraction. AB - The influence of ultrasonic waves on liquid-liquid extraction of circulating drops and in the presence of magnetite nanoparticles was investigated. Experiments were conducted in a column equipped with an ultrasound transducer. The frequency and intensity of received waves, measured by the hydrophone standard method, were 35.40 kHz and 0.37 mW/cm2, respectively. The recommended chemical system of cumene-isobutyric acid-water was used in which mass transfer resistance lies in the aqueous phase. Nanoparticles, within concentration range of (0.0003-0.0030) wt%, were added to the aqueous continuous phase. The presence of nanoparticles and ultrasonic waves provided no sensible change in drop size (within 2.49-4.17 mm) and measured terminal velocities were close to Grace model. However, presence of nanoparticles, caused mass transfer to decrease. This undesired effect was significantly diminished by using ultrasonic waves so that mass transfer coefficient increased from (73.0-178.2) to (130.2-240.2) um/s, providing a 55.6% average enhancement. It is presumably due to disturbing the accumulated nanoparticles around the drops. The current innovative study highlights the fact that using ultrasonic waves is an interesting way to improve liquid-liquid extraction in the presence and absence of nanoparticles. PMID- 29137783 TI - Probing the radical chemistry and the reaction zone during the sono-degradation of endocrine disruptor 2-phenoxyethanol in water. AB - Sonochemical degradation at 600 kHz of 2-phenoxyethanol (PhE), an endocrine disrupting compound, was performed in the presence of several organic additives, namely: 2-propanol, Triton X-100 and sucrose, of different volatilities to obtain detailed information on the reaction zone and the oxidation pathway of this priority emerging water contaminate. It was found that sonication at 600 kHz and 120 W completely remove PhE (10 mg L-1) from aerated solutions within 100 min of irradiation. Very little removal of PhE (~7%) and low accumulation of H2O2 took place in the presence of adequate amount of 2-propanol, indicating that reaction with OH radical outside the bubble is the major degradation pathway of PhE. Addition of the hydrophobic surfactant Triton X-100, as an OH-probe for the interfacial region, at 10 and 100 mM reduced the degradation event by 57% and 72% and resulted in more than 50% decrease in the yield of H2O2, confirming that PhE degradation occurs mainly at the bubble/solution interface with hydroxyl radical attack. Addition of the hydrophilic substrate glucose at high doses decreased slightly (~7%) the degradation of PhE and the formation rate of H2O2, meaning that the bulk of the solution participate marginally in the degradation of the pollutant. Finally, analyzing the degradation rates at various initial PhE concentrations (2-400 mg L-1) with a heterogeneous Langmuir type mechanism underlined the predominance of interfacial radical reactions during the oxidation of PhE, particularly at high initial pollutant concentrations. PMID- 29137784 TI - Surface modified SiO2 nanoparticles by thiamine and ultrasonication synthesis of PCL/SiO2-VB1 NCs: Morphology, thermal, mechanical and bioactivity investigations. AB - The influence of silica (SiO2) nanoparticles (NPs) on the properties of polycaprolactone (PCL) was investigated. Due to the intense tendency of SiO2 NPs to aggregation and their high surface energy, the surface of SiO2 NPs was treatment via Vitamin B1 (VB1) as a biosafe coupling agent. Novel PCL/SiO2-VB1 nanocomposites (NC) films by variety of percentage of SiO2-VB1 NPs were prepared under ultrasonic irradiation as an eco-friendly and fast procedure following by casting method. Fourier transform infrared spectroscopy and energy dispersive X ray analysis exposed the presence of SiO2 NPs into the polymer matrix. A good distribution of the silica into the polymer matrix was detected by microscopic observations and EDX testing. According to the UV-Vis spectra, the absorption of prepared NCs was improved via increasing the amount of SiO2 NPs. PCL/SiO2-VB1 NCs showed more thermal stability compared to the pure polymer. The tensile test was investigated and good arrangement among the experimental data and the predicted flexibility of NCs was obtained. Moreover, PCL/SiO2-VB1 6wt% had noticeable increase values for tensile strength. Finally, in vitro bioactivity investigation designated that by rising SiO2 contents in the NCs, the amount of the hydroxyapatite formed was increased and NC films are bioactive and have a potential to be utilized in bone tissue engineering. PMID- 29137785 TI - Synthesis and characterization of polyester bionanocomposite membrane with ultrasonic irradiation process for gas permeation and antibacterial activity. AB - Optically active bionanocomposite membranes composed of polyester (PE) and cellulose/silica bionanocomposite (BNCs) prepared with simple, green and inexpensive ultrasonic irradiation process. It is a novel method to enhance the gas separation performance. The novel optically active diol containing functional trifluoromethyl groups was prepared in four steps reaction and it was fully characterized by different techniques. Commercially available silica nanoparticles were modified with biodegradable nanocellulose through ultrasonic irradiation technique. Transmission electron microscopy (TEM) analyses showed that the cellulose/silica composites were well dispersed in the polymer matrix on a nanometer scale. The mechanical properties nanocomposite films were improved by the addition of cellulose/silica. Thermo gravimetric analysis (TGA) data indicated an increase thermal stability of the PE/BNCs in compared to the pure polymer. The results obtained from gas permeation experiments showed that adding cellulose/silica to the PE membrane structure increased the permeability of the membranes. The increase in the permeability of the gases was as follows: PCH4 (38%) 10% was predictive of needing ECMO (AUC: 0.92; sensitivity: 85%; and specificity: 100%). The algorithm predicted need for ECMO within the first 12h of life and at least 6h prior to the clinical decision for ECMO with 88% sensitivity and 100% specificity. CONCLUSION: This computational algorithm of cerebral NIRS predicts the need for ECMO in neonates with CDH. LEVEL OF EVIDENCE: II. PMID- 29137807 TI - Mapping the mechanical gradient of human dentin-enamel-junction at different intratooth locations. AB - OBJECTIVES: The local structures and mechanical properties within tooth dentin enamel-junction (DEJ) regions have been focused for numerous studies. The reported results, however, remain inconsistent particularly on the functional width and gradient architecture of the DEJ. The current study aims at systematically determining the mechanical gradient of the DEJ at different intratooth locations such that a clearer understanding on the tooth properties and the potential correlations with the tooth function could be obtained. METHODS: We re-examined how mechanical properties such as elastic modulus and hardness transitioned from those of dentin to those of enamel using combined static and dynamic nanoindentation mapping techniques. A new mapping method and associated image processing procedures were developed to improve the measurement accuracy and resolution. RESULTS: A thin, sigmoidally-transitioned interphase layer of the DEJ was identified with an accurate functional width of 2-3MUm. The DEJ width and gradient architecture were found intratooth location-dependent, with the DEJ at the occlusal sites being wider and transitioning smoother than that at the cervical sites. Such different widths and architectures of the interphase layer at sites subjected to different types and magnitudes of loadings during mastication could promote more efficient stress transferring between enamel and dentin without compromising the overall stiffness of the tooth. SIGNIFICANCE: The presented study not only adds our understanding in the local mechanical properties within tooth DEJ regions, it could also further advance the development of DEJ-mimetic, functional gradient interphase for strong and ultra durable jointing between dissimilar materials. PMID- 29137808 TI - Geometric and dosimetric accuracy of dynamic tumor tracking during volumetric modulated arc therapy using a gimbal mounted linac. AB - PURPOSE: The aim was to examine the feasibility of a dynamic tumor-tracking volumetric modulated arc therapy (DTT-VMAT) technique using a gimbal-mounted linac and assess its positional, mechanical and dosimetric accuracy. MATERIALS AND METHODS: DTT-VMAT was performed using a surrogated signal-based technique. The positional tracking accuracy was evaluated as the difference between the predicted and detected target positions for various wave patterns. Mechanical accuracy measurements included gantry, multileaf collimator (MLC) and gimbal positions. The differences between the command and the measured positions were evaluated for various wave patterns. Dosimetric verification was performed using Gafchromic EBT3 films in the benchmark phantom and two clinical cases. RESULTS: The root mean square error (RMSE) of the positional accuracy was within 0.31 mm. The RMSE of mechanical accuracy was within 0.14 degrees for the gantry, 0.11 +/- 0.02 mm for the MLC and 0.13 mm for the gimbal positions. The passing rate of the 3%/3 mm gamma index was greater than 83.3% and 91.2% for the benchmark phantom and two clinical cases, respectively. CONCLUSIONS: The positional, mechanical and dosimetric accuracy of DTT-VMAT were evaluated. DTT-VMAT with a gimbal-mounted linac had sufficient accuracy and presents a new strategy for treatment of several tumors with respiratory motion. PMID- 29137809 TI - Prognostic factors for local recurrence of squamous cell carcinoma of the vulva: A systematic review. AB - BACKGROUND: In patients treated for early-stage squamous cell vulvar carcinoma local recurrence is reported in up to 40% after ten years. Knowledge on prognostic factors related to local recurrences should be helpful to select high risk patients and/or to develop strategies to prevent local recurrences. OBJECTIVE: This systematic review aims to evaluate the current knowledge on the incidence of local recurrences in vulvar carcinoma related to clinicopathologic and cell biologic variables. DATA SOURCES: Relevant studies were identified by an extensive online electronic search in July 2017. STUDY ELIGIBILITY CRITERIA: Studies reporting prognostic factors specific for local recurrences of vulvar carcinoma were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Two review authors independently performed data selection, extraction and assessment of study quality. The risk difference was calculated for each prognostic factor when described in two or more studies. RESULTS: Twenty-two studies were included; most of all were retrospective and mainly reported pathologic prognostic factors. Our review indicates an estimated annual local recurrence rate of 4% without plateauing. The prognostic relevance for local recurrence of vulvar carcinoma of all analyzed variables remains equivocal, including pathologic tumor free margin distance <8mm, presence of lichen sclerosus, groin lymph node metastases and a variety of primary tumor characteristics (grade of differentiation, tumor size, tumor focality, depth of invasion, lymphovascular space invasion, tumor localization and presence of human papillomavirus). CONCLUSIONS: Current quality of data on prognostic factors for local recurrences in vulvar carcinoma patients does not allow evidence-based clinical decision making. Further research on prognostic factors, applying state of the art methodology is needed to identify high-risk patients and to develop alternative primary and secondary prevention strategies. PMID- 29137810 TI - Technique for precaval and laterocaval nodes excision at extraperitoneal paraaortic lymphadenectomy. AB - STUDY OBJECTIVE: To describe our technique for excision of the pre-caval and laterocaval nodes using an extraperitoneal approach. This technique was developed to make the dissection and excision of the less accessible nodes in an easier and safer way by minimizing the risk of great vessels injury and bleeding. DESIGN: Step-by-step description of the surgical procedure using video (Canadian Task Force classification III). SETTING: The procedure was performed at a teaching hospital, Hospital Universitario Donostia (Spain). PATIENTS: A 52-year-old woman with a body mass index of 33 underwent endoscopic extraperitoneal paraaortic lymphadenectomy for advanced high grade cervical adenocarcinoma FIGO IIB. INTERVENTIONS: The patient underwent an endoscopic extraperitoneal para-aortic lymphadenectomy. An anatomical dissection is being performed being the upper limit of the dissection the left renal vein. Focus of the video involves the challenging dissection of the right nodes. MEASUREMENTS AND MAIN RESULTS: Firstly we complete a dissection of all the anatomical aortic limits until the renal vein and exeresis of aortic nodes. A plane just above the cava vein is carefully developed by pushing all the lymph nodes to the roof of the dissection. Special care must be taken close to the aortic bifurcation due to the perforating vessels that can be found more frequently in this location. Once all this space is dissected, nodes attached to the roof are easily pushed down. It is useful to use a clip in the upper part, close to the renal vein, to prevent lymphorrhea. Nodes are excised in four blocks, supramesenteric and inframesenteric aortic and precaval nodes. The proximity to the peritoneal roof and the chance for a peritoneal hole and loss of pneumoperitoneum can be less problematic if the right dissection is performed at the end of the procedure. CONCLUSION: A complete para aortic retroperitoneal dissection can be achieved with this extraperitoneal approach. Benefits of this technique are based on the absence of the bowel or other intraperitoneal structures invading the operative field given the barrier free nature of the retroperitoneal space. Despite the challenge of the access to the right nodes in a retroperitoneal paraaortic lymphadenectomy they can be successfully excised reaching the renal vein including obese patients. PMID- 29137811 TI - Improving the safety of metal-based drugs by tuning their metabolism with chemoprotective agents. AB - Metal-based drugs remain a tiny minority of all drugs that are on the market. The success story of the quintessential metal-based drug cisplatin (CP), which is intravenously administered to 70% of all cancer patients, however, demonstrates the inherent potential of metal-based drugs. A distinct disadvantage of CP is the dose-limiting severe toxic-side effects that it exerts in patients. To better understand the biomolecular basis for its toxicity, we employed a metallomics method to observe all platinum metabolites that are formed in blood plasma. These investigations revealed that a highly toxic CP-derived hydrolysis product - the highly toxic monoaqua hydrolysis complex (MHC) - is formed within 5min. More importantly, the application of this research tool has unraveled the mechanisms by which the chemoprotective agents sodium thiosulfate, d-methionine, N-acetyl cysteine and l-glutathione modulate the metabolism of CP in plasma, namely by rapidly reacting with the MHC to form platinum-sulfur complexes. Since CP remained in plasma for a considerable time, the possibility of 'tuning' its metabolism with chemoprotective agents in a desirable way has emerged. These observations are highly relevant because these chemoprotective agents were previously shown to significantly reduce the toxicity of CP in animal models, often without appreciably affecting its anticancer efficiency. Collectively, these results suggest that the toxicity of other metal-based drugs may be overcome if their metabolism in the bloodstream is adequately tuned with a suitable chemoprotective agent. This principle strategy has considerable potential in terms of harnessing the full potential of bringing more metal-based drugs to the market. PMID- 29137812 TI - Crowdsourcing conservation: The role of citizen science in securing a future for seagrass. AB - Seagrass meadows are complex social-ecological systems. Understanding seagrass meadows demands a fresh approach integrating "the human dimension". Citizen science is widely acknowledged for providing significant contributions to science, education, society and policy. Although the take up of citizen science in the marine environment has been slow, the need for such methods to fill vast information gaps is arguably great. Seagrass meadows are easy to access and provide an example of where citizen science is expanding. Technological developments have been pivotal to this, providing new opportunities for citizens to engage with seagrass. The increasing use of online tools has created opportunities to collect and submit as well as help process and analyse data. Citizen science has helped researchers integrate scientific and local knowledge and engage communities to implement conservation measures. Here we use a selection of examples to demonstrate how citizen science can secure a future for seagrass. PMID- 29137813 TI - Reasons for seagrass optimism: Local ecological knowledge confirms presence of dugongs. AB - Dugongs (Dugong dugon) depend on seagrass meadows for food. As such seagrass and dugong conservation should go hand in hand. Assessing dugong populations is notoriously challenging. In the most resource dependent communities Local Ecological Knowledge (LEK) is generally high and can provide an alternative to the use of expensive ecological surveys to understand dugong populations and support associated resource management decisions. Residents of the Wakatobi National Park (WNP), SE Sulawesi, Indonesia are highly dependent on marine resources for livelihoods and correspondingly LEK is high. Here LEK documents the presence of D. dugon in the WNP and infers changes in population size. Interviews with local residents in 2012-2013 revealed 99 sightings of dugongs since 1942, 48 of which occurred between 2002 and 2012, with 79.82% of respondents having seen a dugong. Declines in the frequency of sightings within the lifetime of several respondents were reported, respondents speculating that populations are reduced. This information can guide further cooperative research and conservation efforts for the protection of a vulnerable species and the seagrass habitat on which it depends. PMID- 29137814 TI - Biofabrication: A Guide to Technology and Terminology. AB - Biofabrication holds the potential to generate constructs that more closely recapitulate the complexity and heterogeneity of tissues and organs than do currently available regenerative medicine therapies. Such constructs can be applied for tissue regeneration or as in vitro 3D models. Biofabrication is maturing and growing, and scientists with different backgrounds are joining this field, underscoring the need for unity regarding the use of terminology. We therefore believe that there is a compelling need to clarify the relationship between the different concepts, technologies, and descriptions of biofabrication that are often used interchangeably or inconsistently in the current literature. Our objective is to provide a guide to the terminology for different technologies in the field which may serve as a reference for the biofabrication community. PMID- 29137815 TI - Local injection of d-lys-3-GHRP-6 in the rat amygdala, dentate gyrus or ventral tegmental area impairs memory consolidation. AB - It is well known that the hormone ghrelin affects learning and memory in different experimental models of learning. Though, the effect of antagonism of ghrelin receptor type 1a (GHS-R1a) in various regions of the brain and on different stages of learning has not been examined. In this study the effect of injection of a GHS-R1a selective antagonist (d-Lys-3-GHRP-6) into the basolateral amygdala, dentate gyrus or ventral tegmental area was examined on memory consolidation in the passive avoidance task. Adult male Wistar rats weighing 230 280g were used. Animals underwent stereotaxic surgery and cannulated in their amygdala, dentate gyrus or ventral tegmental area. One week after surgery, the rats received different doses of d-Lys-3-GHRP-6 (0.08, 0.8, and 8nM), immediately after training. The control groups received solvent of the drug. Twenty four hours later in the test day, memory retrieval was assessed. In all groups, post training injection of d-Lys-3-GHRP-6 decreased step-through latency and increased entries into the dark compartment and time spent in the dark compartment, significantly and in a dose-dependent manner. The results indicate that antagonism of the GHS-R1a in the rat amygdala, dentate gyrus or ventral tegmental area impairs memory consolidation and show that the ghrelin signaling has a widespread influence on cognitive performance. PMID- 29137816 TI - Resuscitation for the specialty of nephrology: is cardionephrology the answer? AB - The specialty of nephrology faces major fellowship recruitment challenges, with ongoing declining interest among internal medicine residents. The field of Cardionephrology can help instill new interest and enthusiasm in choosing nephrology as a career amongst trainee physicians. PMID- 29137817 TI - Beyond ALS and FTD: the phenotypic spectrum of TBK1 mutations includes PSP-like and cerebellar phenotypes. AB - Mutations in the TANK-binding kinase 1 gene (TBK1) are a rare, but recurrent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the complete phenotypic spectrum of syndromes associated with TBK1 mutations remains to be elucidated. Using next-generation panel-sequencing of neurodegenerative disease genes, we identified a TBK1 index patient presenting with a progressive supranuclear palsy-like syndrome. Consecutively, we screened the whole-exome sequencing data of 439 index subjects presenting with various neurodegenerative syndromes outside the ALS-FTD spectrum for TBK1 mutations. Based on this genetic screen, we identified another TBK1 index patient presenting with progressive cerebellar ataxia. Both index patients carried the established p.Glu643del TBK1 mutation (c.1928_1930delAAG). In the index patients' families, we identified mesencephalic and cerebellar atrophy as recurrent imaging findings of TBK1-associated neurodegeneration, with cerebellar atrophy occurring even in presymptomatic mutation carriers. Our findings demonstrate that the phenotypic spectrum of TBK1 mutations extends beyond ALS and FTD to include also progressive supranuclear palsy-like and cerebellar syndromes, with mesencephalon and cerebellum representing recurrent sites of TBK1-associated neurodegeneration. PMID- 29137818 TI - Molecular Imaging for the diagnosis of infective endocarditis: A systematic literature review and meta-analysis. AB - BACKGROUND: Infective endocarditis (IE) is a serious, potentially life threatening condition. Currently, the modified Duke criteria is used to assist with the diagnosis of IE, but it can still remain difficult. Growing data supports the potential use of molecular imaging to assist in the diagnosis of IE. Our objective was to understand the potential utility of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT), 67Ga citrate and radiolabeled white blood cell (WBC) scintigraphy in the diagnosis of IE. METHODS AND RESULTS: A systematic review of the literature and meta-analysis on the use of all 3 modalities in IE was conducted. The literature search identified 2753 articles. A total of 14 studies met the inclusion criteria (10 for 18F-FDG, 3 for WBC and 1 for both modalities). No 67Ga citrate study met the inclusion criteria. Pooled sensitivity of 18F-FDG studies with adequate cardiac preparation for the diagnosis of IE was 81% (95% CI, 73%-86%) and pooled specificity was 85% (95% CI, 78%-91%). There was good overall accuracy with an area under the curve (AUC) of 0.897. Pooled sensitivity of WBC for the diagnosis of IE was 86% (95% CI, 77%-92%) and pooled specificity was 97% (95% CI, 92%-99%). The overall accuracy of WBC was excellent with an AUC of 0.957. CONCLUSIONS: Both 18F-FDG and WBC have good sensitivity, specificity and accuracy for the diagnosis of IE. Both modalities are useful in the investigation of IE, and should be considered in cases where the diagnosis is uncertain. PMID- 29137819 TI - Vascular response and healing profile of everolimus-eluting bioresorbable vascular scaffolds for percutaneous treatment of chronic total coronary occlusions: A one-year optical coherence tomography analysis from the GHOST-CTO registry. AB - BACKGROUND: Bioresorbable vascular scaffolds (BVS) have been heralded with potential benefits that are especially desired in long lesions, including chronic total occlusions (CTOs). Procedural feasibility and mid-term outcomes of BVS in CTOs have been reported. However, there is still a paucity of data regarding the vascular and healing response to BVS in CTOs evaluated by optical coherence tomography (OCT). METHODS: This study included prospectively 21 patients who had a CTO lesion treated with a BVS. Angiography and OCT scan were recorded at either post-implantation and 1-year follow-up. Quantitative coronary angiography and OCT analyses were performed by an independent core laboratory. RESULTS: The angiographic analysis showed a significant increase in the percentage of in segment diameter stenosis at 1year (11.89+/-9.5% vs. 21.84+/-11.7%; p=0.002). The OCT analysis showed a trend (p=0.07) towards increased mean scaffold area and significant reductions in mean lumen diameter (3.1+/-0.36mm vs. 2.85+/-0.47mm; p=0.0046), mean lumen area (7.8+/-1.73mm2 vs. 6.76+/-2mm2; p=0.0082) and minimal lumen area (5.26+/-1.86mm2 vs. 3.56+/-1.52mm2; p<0.0001). Malapposition area and volume decreased from 0.26+/-0.17mm2 to 0.08+/-0.1mm2 (p=0.0003) and from 14.17+/ 12.92mm3 to 3.99+/-4.46mm3 (p=0.0014), respectively. The rate of uncovered or malapposed struts, measured at the frame level, was 5.29+/-6.48% at 1year. CONCLUSIONS: In a small series of CTO patients treated with BVS implantation, OCT outcomes at 1year displayed an overall favorable vascular response and healing profile. PMID- 29137820 TI - Does acute care for the elderly (ACE) unit decrease the incidence of falls? AB - To determine whether acute care for the elderly (ACE) units decrease the incidence of patient falls compared to general medical and surgical (GMS) units, a non-concurrent prospective study included individuals aged 65 and older admitted to ACE or GMS units over a 2-year span was done. There were 7069 admissions corresponded to 28,401 patient-days. A total of 149 falls were reported for an overall incidence rate (IR) of 5.2 falls per 1000 patient-days, 95% CI, 4.4/1000-6.1/1000 patient-days. The falls IR ratio for patients in ACE unit compared to those in non-ACE units after adjusting for age, sex, prescribed psychotropics and hypnotics, and Morse Fall Score was 0.27/1000 patient-days; 95% CI, 0.13-0.54; p < 0.001. So, an estimated 73% reduction in patient falls between ACE unit and non-ACE units. Hospitals may consider investing in ACE units to decrease the risk of falls and the associated medical and financial costs. PMID- 29137821 TI - Equination (inoculation of horsepox): An early alternative to vaccination (inoculation of cowpox) and the potential role of horsepox virus in the origin of the smallpox vaccine. AB - For almost 150 years after Edward Jenner had published the "Inquiry" in 1798, it was generally assumed that the cowpox virus was the vaccine against smallpox. It was not until 1939 when it was shown that vaccinia, the smallpox vaccine virus, was serologically related but different from the cowpox virus. In the absence of a known natural host, vaccinia has been considered to be a laboratory virus that may have originated from mutational or recombinational events involving cowpox virus, variola viruses or some unknown ancestral Orthopoxvirus. A favorite candidate for a vaccinia ancestor has been the horsepox virus. Edward Jenner himself suspected that cowpox derived from horsepox and he also believed that "matter" obtained from either disease could be used as preventative of smallpox. During the 19th century, inoculation with cowpox (vaccination) was used in Europe alongside with inoculation with horsepox (equination) to prevent smallpox. Vaccine-manufacturing practices during the 19th century may have resulted in the use of virus mixtures, leading to different genetic modifications that resulted in present-day vaccinia strains. Horsepox, a disease previously reported only in Europe, has been disappearing on that continent since the beginning of the 20th century and now seems to have become extinct, although the virus perhaps remains circulating in an unknown reservoir. Genomic sequencing of a horsepox virus isolated in Mongolia in 1976 indicated that, while closely related to vaccinia, this horsepox virus contained additional, potentially ancestral sequences absent in vaccinia. Recent genetic analyses of extant vaccinia viruses have revealed that some strains contain ancestral horsepox virus genes or are phylogenetically related to horsepox virus. We have recently reported that a commercially produced smallpox vaccine, manufactured in the United States in 1902, is genetically highly similar to horsepox virus, providing a missing link in this 200-year-old mystery. PMID- 29137823 TI - Red-eyed-tatoo: An unusual red eye of tuberculous etiology. PMID- 29137822 TI - DNMT1 is associated with cell cycle and DNA replication gene sets in diffuse large B-cell lymphoma. AB - Dysregulation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) is associated with the pathogenesis of various types of cancer. It has been previously shown that DNMT1 is frequently expressed in diffuse large B-cell lymphoma (DLBCL), however its functions remain to be elucidated in the disease. In this study, we gene expression profiled (GEP) shRNA targeting DNMT1(shDNMT1)-treated germinal center B-cell-like DLBCL (GCB-DLBCL)-derived cell line (i.e. HT) compared with non silencing shRNA (control shRNA)-treated HT cells. Independent gene set enrichment analysis (GSEA) performed using GEPs of shRNA-treated HT cells and primary GCB DLBCL cases derived from two publicly-available datasets (i.e. GSE10846 and GSE31312) produced three separate lists of enriched gene sets for each gene sets collection from Molecular Signatures Database (MSigDB). Subsequent Venn analysis identified 268, 145 and six consensus gene sets from analyzing gene sets in C2 collection (curated gene sets), C5 sub-collection [gene sets from gene ontology (GO) biological process ontology] and Hallmark collection, respectively to be enriched in positive correlation with DNMT1 expression profiles in shRNA-treated HT cells, GSE10846 and GSE31312 datasets [false discovery rate (FDR) <0.05]. Cell cycle progression and DNA replication were among the significantly enriched biological processes (FDR <0.05). Expression of genes involved in the activation of cell cycle and DNA replication (e.g. CDK1, CCNA2, E2F2, PCNA, RFC5 and POLD3) were highly correlated (r>0.8) with DNMT1 expression and significantly downregulated (log fold-change <-1.35; p<0.05) following DNMT1 silencing in HT cells. These results suggest the involvement of DNMT1 in the activation of cell cycle and DNA replication in DLBCL cells. PMID- 29137824 TI - Future perspectives in glaucoma medical therapy. PMID- 29137825 TI - Polyphemus and stereopsis. PMID- 29137826 TI - The blindness of Rosalba Carriera. An artist in the darkness. PMID- 29137827 TI - The Graeae sisters, the sisters who shared a single eye. PMID- 29137828 TI - Differentiating between clinical and behavioral phenotypes in first-episode psychosis during maintenance of visuospatial working memory. AB - INTRODUCTION: We probed the neural basis of working memory in individuals with first episode of psychosis (FEP) and assessed how these neural abnormalities are associated with behavioral performance and/or core to psychosis pathophysiology. METHODS: FEP (N=35) and matched controls (N=25) performed a visuospatial working memory task during fMRI acquisition. We isolated neural activity during the maintenance period and examined neural activity within regions typically engaged during a working memory task. Functional connectivity estimates were derived using psychophysiological interaction analysis. We examined correlations between brain function and behavioral performance and clinical symptomatology. RESULTS: FEP had reduced accuracy and slower reaction times compared to controls (p<0.05, q<0.05). During the maintenance period, FEP exhibited reduced right dorsolateral prefrontal cortex (DLPFC) activation compared to controls (p=0.007, q=0.01), even when behavioral performance was matched between groups (p=0.01, q=0.03). Unlike controls, FEP failed to show increased dorsal anterior cingulate (dACC) activity with increased load level (p=0.02, q=0.06). Compared to controls, FEP showed increased negative DLPFC-dACC coupling during the maintenance period (p=0.05). Increased DLPFC activation was significantly associated with greater negative symptoms (p<0.005, q=0.02), while greater dACC activation was significantly associated with better performance in FEP (p<0.05, q<0.17). CONCLUSION: WM impairment in psychosis may be specific to abnormalities in the ability of frontal systems processing executive commands (DLPFC) and monitoring performance (dACC) during the maintenance of information. Our results add to accumulating evidence indicating that DLPFC abnormalities may be core to psychosis psychopathology. We also provide new insights regarding how DLPFC abnormalities may undermine dACC processing during the maintenance of information. PMID- 29137829 TI - Effects of Removal and Reinsertion of Headless Compression Screws. AB - PURPOSE: This study investigates the loss of compression when 3 commonly used headless compression screws are backed out (reversed), and assesses the ability to re-establish compression with screws of greater diameter. METHODS: Two investigators tested 3 screw designs (Acutrak 2, Synthes HCS, Medartis SpeedTip CCS) in 2 diameters and lengths. Each design had 10 test cycles in a polyurethane foam bone model with compression recorded using a washer load cell. A 28-mm screw of the narrower diameter was inserted until 2 mm recessed and then reversed 30 degrees , 60 degrees , 90 degrees , 180 degrees , 270 degrees , 360 degrees , and 720 degrees . After this the screw was removed completely and a 24-mm screw of greater diameter inserted until recessed 2 mm with the compressive force again recorded. RESULTS: All screws showed an immediate, statistically significant loss of compression at 30 degrees of reversing. The Acutrak 2 Micro screw demonstrated not only the greatest mean compressive force, but also the fastest compressive loss. Insertion of the shorter screw of greater diameter was associated with re-establishment of compression to levels comparable with the original screw. CONCLUSIONS: This study reaffirms the importance of establishing the correct screw length before insertion due to the immediate loss of compression with reversal of these devices. CLINICAL RELEVANCE: If a headless compression screw penetrates the far joint surface, the screw should be completely removed and replaced with a shorter screw of greater diameter. PMID- 29137831 TI - Monitour: Tracking global routes of electronic waste. AB - Many nations seek to control or prevent the inflow of waste electronic and electrical equipment, but such flows are difficult to track due to undocumented, often illegal global trade in e-waste. We apply wireless GPS location trackers to this problem, detecting potential cases of non-compliant recycling operations in the United States as well as the global trajectories of exported e-waste. By planting hidden trackers inside discarded computer monitors and printers, we tracked dozens of devices being sent overseas to various ports in Asia, flows likely unreported in official trade data. We discuss how location tracking enables new ways to monitor, regulate, and enforce rules on the international movement of hazardous electronic waste materials, and the limitations of such methods. PMID- 29137830 TI - Efficacy and Safety of Tamsulosin in Medical Expulsive Therapy for Distal Ureteral Stones with Renal Colic: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial. AB - BACKGROUND: Recent large high-quality trials have questioned the clinical effectiveness of medical expulsive therapy using tamsulosin for ureteral stones. OBJECTIVE: To evaluate the efficacy and safety of tamsulosin for distal ureteral stones compared with placebo. DESIGN, SETTING, AND PARTICIPANTS: We conducted a double-blind, placebo-controlled study of 3296 patients with distal ureteral stones, across 30 centers, to evaluate the efficacy and safety of tamsulosin. INTERVENTION: Participants were randomly assigned (1:1) into tamsulosin (0.4mg) or placebo groups for 4 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point of analysis was the overall stone expulsion rate, defined as stone expulsion, confirmed by negative findings on computed tomography, over a 28 d surveillance period. Secondary end points included time to stone expulsion, use of analgesics, and incidence of adverse events. RESULTS AND LIMITATIONS: Among 3450 patients randomized between September 1, 2011, and August 31, 2013, 3296 (96%) were included in the primary analysis. Tamsulosin benefits from a higher stone expulsion rate than the placebo (86% vs 79%; p<0.001) for distal ureteral stones. Subgroup analysis identified a specific benefit of tamsulosin for the treatment of large distal ureteral stones (>5mm). Considering the secondary end points, tamsulosin-treated patients reported a shorter time to expulsion (p<0.001), required lower use of analgesics compared with placebo (p<0.001), and significantly relieved renal colic (p<0.001). No differences in the incidence of adverse events were identified between the two groups. CONCLUSIONS: Our data suggest that tamsulosin use benefits distal ureteral stones in facilitating stone passage and relieving renal colic. Subgroup analyses find that tamsulosin provides a superior expulsion rate for stones >5mm, but no effect for stones <=5mm. PATIENT SUMMARY: In this report, we looked at the efficacy and safety of tamsulosin for the treatment of distal ureteral stones. We find that tamsulosin significantly facilitates the passage of distal ureteral stones and relieves renal colic. PMID- 29137832 TI - Response to a letter to the editor. PMID- 29137833 TI - The role of corticosteroid in septic shock patients. PMID- 29137834 TI - Response to the letter by Sion Jo et al. PMID- 29137835 TI - Venous thromboembolism risk and prophylaxis in the Portuguese hospital care setting: The ARTE study. AB - INTRODUCTION: Venous thromboembolism (VTE) is a relatively common complication during hospital stay and determination of VTE risk is critical to choosing the best prophylactic strategy for each patient. OBJECTIVES: In the present study we studied the risk profile for VTE in hospitalized patients in a group of hospitals in Portugal. METHODS: Based on an open cohort of 4248 patients hospitalized in surgical, internal medicine, orthopedic or oncology departments, we determined thromboembolic risk at admission by applying a new score, modified from the Caprini and Khorana scores. Thrombotic, embolic and bleeding events and death were assessed during hospital stay and at three and six months after discharge. RESULTS: The median duration of hospital stay was five days and thromboembolic prophylaxis was implemented in 67.2% (n=2747) of the patients. A low molecular weight heparin was used as prophylaxis in the majority of cases (88.3%). Most patients were classified as high (68%) or intermediate risk (27%). The overall incidence of thromboembolic events was 1.5%. Major bleeding events were recorded in 3.89% of patients and all-cause mortality was 3.4%. CONCLUSIONS: In this study, we propose a modified VTE risk score that effectively risk-stratifies a mixed inpatient population during hospital stay. The use of this score may result in improvement of thromboprophylaxis practices in hospitals. PMID- 29137836 TI - How participatory action research changed our view of the challenges of shared decision-making training. AB - OBJECTIVE: This paper aims to demonstrate how the use of participatory action research (PAR) helped us identify ways to respond to communication challenges associated with shared decision-making (SDM) training. METHODS: Patients, relatives, researchers, and health professionals were involved in a PAR process that included: (1) two theatre workshops, (2) a pilot study of an SDM training module involving questionnaires and evaluation meetings, and (3) three reflection workshops. RESULTS: The PAR process revealed that health professionals often struggled with addressing existential issues such as concerns about life, relationships, meaning, and ability to lead responsive dialogue. Following the PAR process, a communication programme that included communication on existential issues and coaching was drafted. CONCLUSION: By involving multiple stakeholders in a comprehensive PAR process, valuable communication skills addressing a broader understanding of SDM were identified. A communication programme aimed to enhance skills in a mindful and responsive clinical dialogue on the expectations, values, and hopes of patients and their relatives was drafted. PRACTICAL IMPLICATIONS: Before integrating new communication concepts such as SDM in communication training, research methods such as PAR can be used to improve understanding and identify the needs and priorities of both patients and health professionals. PMID- 29137837 TI - Online, game-based education for melanoma recognition: A pilot study. AB - OBJECTIVE: To evaluate the effectiveness of a game-based learning (GBL) intervention, Tapamole, in improving recognition of the features of melanoma (MM) compared to a written education intervention. METHODS: Tapamole, an online education intervention, was developed using GBL. Participants were voluntarily recruited from the Dermatology waiting room and randomized to three groups: game, pamphlet, and no intervention. Participants completed a pre-intervention survey, post-intervention survey, and test on MM recognition. Clustered binary data equations were used to calculate sensitivity, specificity, and accuracy for each group and GEE model with log link was used to compare measures between groups. RESULTS: Sixty participants were recruited. The sensitivity for MM recognition in the game group was 100% compared to 95% for the pamphlet group. The specificity (40.8% vs 53.3%) and accuracy (60.6% vs 67.2%) of the game and pamphlet groups were similar. Participants in the game group reported higher enjoyment than those in the pamphlet group. CONCLUSION: GBL was as effective as the written intervention in identifying features of MM. PRACTICE IMPLICATIONS: With increasing use of the Internet for health information, it is critical to have effective online education interventions. GBL education tools are effective, enjoyable, and should be used to improve MM patient education. PMID- 29137838 TI - Fusion of fMRI and non-imaging data for ADHD classification. AB - Resting state fMRI has emerged as a popular neuroimaging method for automated recognition and classification of different brain disorders. Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common brain disorders affecting young children, yet its underlying mechanism is not completely understood and its diagnosis is mainly dependent on behavior analysis. This paper addresses the problem of classification of ADHD based on resting state fMRI and proposes a machine learning framework with integration of non-imaging data with imaging data to investigate functional connectivity alterations between ADHD and control subjects (not diagnosed with ADHD). Our aim is to apply computational techniques to (1) automatically classify a subject as ADHD or control, (2) identify differences in functional connectivity of these two groups and (3) evaluate the importance of fusing non-imaging with imaging data for classification. In the first stage of our framework, we determine the functional connectivity of brain regions by grouping brain activity using clustering algorithms. Next, we employ Elastic Net based feature selection to select the most discriminant features from the dense functional brain network and integrate non-imaging data. Finally, a Support Vector Machine classifier is trained to classify ADHD subjects vs. control. The proposed framework was evaluated on a public ADHD-200 dataset, and our results suggest that fusion of non-imaging data improves the performance of the framework. Classification results outperform the state-of-the-art on some subsets of the data. PMID- 29137839 TI - Predictors of Intention of Reporting Child Abuse among Emergency Nurses. AB - PURPOSE: The current study investigates predictors of intention of reporting child abuse among emergency nurses in Korea. DESIGN AND METHODS: A descriptive cross-sectional design was used. Data were collected from 200 emergency nurses in eight general hospitals in Korea through a questionnaire that asked about their general characteristics, knowledge about child abuse, perceived behavioral control, experiences of child abuse cases and reporting, and attitude toward child abuse. RESULTS: Multiple regression analysis indicated that attitude toward child abuse was the most influential predictor of the intention of reporting child abuse among Korea's emergency nurses. Knowledge about child abuse, and perceived behavioral control were also significant influencing predictors of reporting intention. These variables explained 22.1% of the variances in the intention of reporting child abuse among emergency nurses. CONCLUSIONS: Reporting child abuse has not yet been established as a professional responsibility among Korea's emergency nurses. Increasing the level of awareness of the characteristics of child abuse and encouraging communication among nurses about the responsibility to report suspected child abuse will increase nurses' confidence to report. PRACTICE IMPLICATIONS: Training for reporting child abuse should be implemented in the near future to improve emergency nurses' understanding of child abuse. A support program is also needed to help emergency nurses build confidence in reporting child abuse as a professional responsibility. PMID- 29137840 TI - Resolvin D1 attenuates imiquimod-induced mice psoriasiform dermatitis through MAPKs and NF-kappaB pathways. AB - BACKGROUND: Resolvin D1 (RvD1), a pro-resolution lipid mediator derived from docosahexaenoic acid (DHA), has been described to promote several kinds of inflammatory resolution. However, the effects and anti-inflammatory mechanisms of RvD1 on psoriasis have not been previously reported. OBJECTIVE: The present study aimed to determine the protective effects and the underlying mechanisms of RvD1 on imiquimod (IMQ)-induced psoriasiform dermatitis. METHODS: Mice were topically treated with IMQ to develop psoriasiform dermatitis on their shaved back, pretreated intraperitoneally (i.p.) with or without RvD1 or tert-butoxycarbonyl Met-Leu-Phe peptide (Boc), a lipoxin A4 (ALX) receptor antagonist. The severity was monitored and graded using a modified human scoring system, the Psoriasis Area and Severity Index (PASI), histopathology, and the signature cytokines of psoriasis (IL-23, IL-17, IL-22 and TNF-alpha). The mRNA and protein levels of inflammatory cytokines were quantified by quantitative real-time PCR (QRT-PCR) and ELISA. The expressions of signaling proteins MAPKs and NF-kappaB p65 were analyzed using western blotting. Electrophoretic mobility shift assay (EMSA) was used to check NF-kappaB p65 DNA binding activity. RESULTS: Our study showed that RvD1 alleviated IMQ-induced psoriasiform dermatitis and improved skin pathological changes. RvD1 markedly inhibited IMQ-induced activation of ERK1/2, p38, JNK (c-Jun N-terminal protein kinase, a subfamily of MAPKs), and NF-kappaB. Furthermore, pretreatment with Boc, would not exacerbate skin inflammation of IMQ induced mice, but significantly reversed the beneficial effects of RvD1 on IMQ induced psoriasiform inflammation. CONCLUSION: RvD1 can obviously improve skin inflammation in IMQ-induced mice psoriasiform dermatitis. The protective mechanisms might be related to its selective reaction with lipoxin A4 receptor/Formyl-peptide receptor 2 (ALX/FPR2), by downregulating relevant cytokines of the IL-23/IL-17 axis expression, the inhibition of MAPKs and NF kappaB signaling transduction pathways. Thus, these results show that RvD1 could be a possible candidate for psoriasis therapy. PMID- 29137841 TI - Using ecological momentary assessment to assess the temporal relationship between sleep quality and cravings in individuals recovering from substance use disorders. AB - INTRODUCTION: The causal direction of the relationship between sleep disturbance and drug cravings is unknown. Based on resource depletion literature, we hypothesized that sleep difficulties lead to cravings. We tested whether sleep quality predicts craving at the within- or between-person level, with perceived willpower as a multilevel mediator. METHODS: We used ecological momentary assessments (EMA) to compare two models of temporal precedence. Participants in addiction treatment (N=122) were sent four surveys each day for three weeks. Participants rated previous night's sleep quality and level of cravings and willpower. RESULTS: The between- (beta=-0.18, SE=0.06) and within-person (beta= 0.02, SE=0.02) effects of maximum daily craving on sleep quality were significant, as were the between- (beta=-0.33, SE=0.08) and within-person (beta= 0.08; SE=0.03) effects of daily sleep quality on maximum daily cravings. In the mediation analysis of the indirect effect of sleep quality on cravings via willpower, both the indirect effect for the between-person pathway (beta=-0.27, SE=0.07) and the indirect within-person pathway (beta=-0.01, SE=0.01) were significant. CONCLUSIONS: EMA methodology allowed for disentanglement of the temporal relationship between sleep and cravings. We found support for the resource depletion hypothesis, operationalized by linking sleep quality to cravings via willpower. However, the magnitude of the association between sleep quality and cravings was stronger at the between-person level, suggesting a potentially cumulative effect of poor sleep on cravings. These results suggest that clinicians should ask patients about chronic sleep problems, as these may pose a risk for relapse. PMID- 29137843 TI - [Blood pressure in a native Tzotzil population from the state of Chiapas, Mexico]. AB - OBJECTIVE: To determine the blood pressure in a native Tzotzil population from the state of Chiapas, Mexico. METHODOLOGY: Cross-sectional study on a Chenalho Tzotzil population from Chiapas, Mexico, from August to December 2015, aged between 20 to 60 years-old. Patients with diabetes mellitus and hypertension were excluded, as well as pregnant patients. The sample size was 205, using as sample basis, the list of patients that went to the healthy patient wellness clinic. The systolic and diastolic pressures were measured by the same person. The measurement was performed on the right arm with the patient seated, five minutes after coming into the clinic, without performing any physical activity beforehand. It was measured with an AdexTM mercury column sphygmomanometer. The statistical analysis includes mean and percentages, as well as their confidence intervals. RESULTS: The mean diastolic blood pressure found was 68.73mmHg (95% CI,-67.63-69.69), with a diastolic of 103.65mmHg (95% CI; 102.24-105.06) and a mean arterial pressure 80.37mmHg (95% CI, 79.35-81.39). CONCLUSION: The arterial blood pressure in a Tzotzil native population of Chiapas, Mexico is lower than that reported in the scientific literature. PMID- 29137842 TI - Comparison of pharmacokinetics of newly discovered aromatase inhibitors by a cassette microdosing approach in healthy Japanese subjects. AB - The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 MUg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 MUg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 +/- 7.1 mL/min/kg and 34.9 +/- 32.3% for cetrozole, and 16.8 +/- 3.5 mL/min/kg and 18.4 +/- 12.2% for TMD-322, respectively. The area under the plasma concentration-time curves of cetrozole and TMD-322 after oral administration was markedly lower than that of anastrozole because of their high hepatic clearance. Two subjects out of six exhibited 4- and 17-fold larger exposure of cetrozole than the others following intravenous and oral administration, respectively. Such variation was not observed for TMD-322 and anastrozole. Extensive metabolism of cetrozole and TMD-322 was observed in the CYP2C19 expression system among the test CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). We report the first clinical investigation of our aromatase inhibitors by a cassette microdose strategy in healthy Japanese subjects. This strategy offers an optional approach for candidate selection as a phase zero study in drug development. PMID- 29137844 TI - Occult gastrointestinal disease unmasked by direct oral anticoagulants used for the prevention of atrial fibrillation. PMID- 29137845 TI - Enumeration of bone marrow plasmacytoid dendritic cells by multiparameter flow cytometry as a prognostic marker following allogeneic hematopoietic stem cell transplantation. AB - Plasmacytoid dendritic cells (pDCs) promote tolerance in solid organ transplants and hematopoietic stem cell transplantation (HSCT). pDCs originate from CD34+ hematopoietic progenitors. Following allogeneic hematopoietic stem cell transplant (allo-HSCT), pDC reconstitution in the BM and PB gradually attain levels similar to those in healthy individuals. We have investigated the recovery of pDC following allo-HSCT as a means to predict successful marrow engraftment. We retrospectively studied immune reconstitution of pDC in the BM of 48 patients following allo-HSCT for initial diagnoses of leukemia or other malignancies. Multi-parameter flow cytometry was used to detect the CD45+CD123bright HLA-DR+ CD4low pDCs in BM aspirates at 2-14months (median 6months) post allo-HSCT. Percentages of pDCs were analyzed along with engraftment, acute graft-versus-host disease (aGVHD), event-free survival, relapse and death over a period of up to 39months (median 30) following HSCT. We report that higher levels of pDCs in the BM post-HSCT are associated with successful engraftment, less severity of aGVHD, lower relapse rate, higher event-free survival and overall survival (P value <0.05 for all). pDC levels detected at a shorter time interval 2-8months (median 5months) following HSCT also showed similar results. We conclude that pDC numbers are associated with HSCT engraftment and overall survival. Flow cytometry offers rapid quantification of pDCs as an early predictor of outcome following HSCT. PMID- 29137846 TI - Commentary on "Popliteal Artery Aneurysms in Women". PMID- 29137848 TI - Evaluating the association between household air pollution and oral cancer. PMID- 29137847 TI - Comparison Between Radiological Semantic Features and Lung-RADS in Predicting Malignancy of Screen-Detected Lung Nodules in the National Lung Screening Trial. AB - RATIONALE: Lung computed tomography (CT) Screening Reporting and Data System (lung-RADS) has standardized follow-up and management decisions in lung cancer screening. To date, little is known how lung-RADS classification compares with radiological semantic features in risk prediction and diagnostic discrimination. OBJECTIVES: To compare the performance of radiological semantic features and lung RADS in predicting nodule malignancy in lung cancer screening. METHODS: We used data and low-dose CT (LDCT) images from the National Lung Screening Trial (NLST). The training cohort contained 60 patients with screen-detected incident lung cancers who had a positive baseline screen (T0) that was not diagnosed and then was diagnosed at second follow-up (T2), and 139 nodule-positive controls who had 3 consecutive positive screens (T0 to T2) that were not diagnosed as lung cancer. The testing cohort included 40 patients with incident lung cancers that were diagnosed at first follow-up (T1) and 40 nodule-positive controls. Twenty-four semantic features were scored on a point scale from the LDCT images. Multivariable linear predictor model was built on the semantic features and the performances were compared with lung-RADS in 3 screening rounds. We also combined non-size-based semantic features with lung-RADS to improve malignancy detection. RESULTS: At T0, the average area under the receiver operating characteristic curve (AUROC) for border definition in risk prediction was 0.72. The average AUROC for contour at T1 in risk prediction and T2 in diagnostic discrimination was 0.82 and 0.88, respectively. By comparison, the average AUROC of lung-RADS at T0, T1 and T2 were 0.60, 0.76 and 0.87, respectively. The combined model of the semantic features and lung-RADS shows improvement with AUROCs of 0.74, 0.88 and 0.96 at T0, T1, and T2, respectively, achieved by adding border definition (at T0) or contour (at T1 and T2). CONCLUSION: We find semantic features defined by border definition and contour performed similar to lung-RADS at follow-up time point and outperformed lung-RADS at baseline. These semantics alongside of lung RADS shows improved performance to detect malignancy. PMID- 29137849 TI - Genera, evolution, and botanists in 1940: Edgar Anderson's "Survey of Modern Opinion". PMID- 29137850 TI - The importance of subclinical left ventricular dysfunction and blood pressure pattern in asymptomatic type-2 diabetic patients: the diagnostic and prognostic significance of Tissue Doppler parameters, left ventricular global longitudinal strain, and nighttime blood pressure during sleep. AB - : The primary aims of this study have been to explore the diagnostic and prognostic significance of Tissue Doppler parameters (TDI), global longitudinal strain (GLS), and blood pressure (BP) pattern in normotensive diabetic patients. METHODS: The study consisted of 121 diabetic patients and 41 healthy subjects. Conventional and TDI echocardiography were performed on all patients, including E/Em (ratio of diastolic velocities). GLS was derived from two-dimensional speckle-tracking. Ambulatory BP monitoring (ABPM) was obtained over 24h. Over the three year follow up, the end points were cardiac events (myocardial infarction, coronary revascularization procedures, new-onset angina, heart failure). RESULTS: GLS was found to be significantly lower (-17.5+/-2.1vs-24.4+/-2.4; p<0.001), while E/Em was significantly higher (10.3+/-2.24vs7.4+/-1.8; p<0.001) in diabetic patients. A non-dipping pattern of BP was observed in 38 diabetic patients (31.4%); 14 diabetic patients had an increase in their nocturnal BP. Significant predictors of an adverse cardiac event: a reduction of GLS value (-17%,p=0.05) increase in E/Em (>15, p=0.002) and systolic BP during nocturnal sleep (>119mmHg,p=0.020). CONCLUSION: Early detection of nocturnal hypertension and subclinical LV dysfunction by TDI and 2D spackle tracking are of significant clinical and prognostic importance. PMID- 29137851 TI - Evaluation of positional plagiocephaly: Conventional anthropometric measurement versus laser scanning method. AB - BACKGROUND: The incidence of plagiocephaly has increased in the 25 years since the "Back to Sleep" campaign in 1991 to prevent sudden infant death. Plagiocephaly is not considered to be a pathological condition. It is more of an esthetic impairment and could have potentially negative psychological or psychosocial consequences; therefore, treatment is recommended. The aim of this study is to compare conventional anthropometry and laser scanning - two different measurement methods - as diagnostic instruments for plagiocephaly. The present study also tests the measurement time of both methods and whether one method is easier on the patient than the other. MATERIAL AND METHODS: A total of 44 children (21 girls, 23 boys) with a mean age of 8.8 months were involved in the present study. Of all patients, the following parameters were routinely evaluated using a standard protocol with the conventional anthropometric method and the scan method: head circumference, head length, head width, head diagonals, and distances ex-t. Furthermore, the time required to obtain measurements and the behavior of the children during measurement were documented. For statistical analysis, a t-test and a Wilcoxon test were used to analyze differences between the two methods. RESULTS: The results for head circumference showed a mean of 441.5 mm for the anthropometric measurements and 441.6 mm for the scan method, with no significant difference between the two methods. A significant difference was found regarding the head width, head length, diagonals, and distance ex-t. The measurement process using the scan method needed a mean of 579.6 s in contrast to the manual anthropometric method, which required a mean time of 180.5 s. DISCUSSION: In comparison with the conventional anthropometric method, measurements made with a 3D laser scanner yield inconsistent results. Moreover, the current state of technology of 3D cephalometry has no advantages compared with the conventional anthropometric method. Disadvantages worth mentioning appear to be the higher technical outlay and the considerable acquisition, service, and maintenance costs. PMID- 29137852 TI - Dysarthria in pallidal Deep Brain Stimulation in dystonia depends on the posterior location of active electrode contacts: a pilot study. AB - BACKGROUND: Pallidal Deep Brain Stimulation (GPi-DBS) is an efficient treatment for primary dystonia. We investigated stimulation-induced dysarthria, which is the most frequent side-effect of GPi-DBS. METHODS: Speech was recorded while reading a standard text, and performing rapid syllable repetitions ON and OFF DBS in ten dystonia patients (6 men; 3 cervical, 4 segmental, 3 generalized, unselected for DBS-related speech impairments). Speech and articulation rate, pauses, and syllable repetition rates were extracted via acoustic analysis. Locations of active stimulation contacts and volumes of tissue activated (VTA) were calculated. RESULTS: The number of pauses increased significantly ON vs. OFF stimulation (Wilcoxon test, p < 0.05). More posteriorly localized active contacts were associated with slower syllable repetition (Pearson correlation, p < 0.05). VTA size did not correlate with any measure of dysarthria. CONCLUSION: Using quantitative acoustic signal analysis, this study demonstrates that GPi-DBS alters motor aspects of speech. Both inadvertent stimulation of parts of the internal capsule, or interference with GPi function and outflow are possible causes. Understanding causes of GPi-DBS-induced speech changes can improve DBS programming. PMID- 29137853 TI - Antidiabetic, antihyperlipidemic activities and herb-drug interaction of a polyherbal formulation in streptozotocin induced diabetic rats. AB - BACKGROUND: Ojamin (OJ), a polyherbal antidiabetic formulation, is extensively used as a food supplement to control diabetes alone or along with synthetic antidiabetic agents. However, it's phytochemical and pharmacological investigations are lacking. OBJECTIVE: The present study was undertaken to study antidiabetic and antihyperlipidemic potentials of OJ and its interaction with Metformin in streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Diabetes was induced in Wistar rats by single intraperitoneal (i.p.) injection of streptozotocin (60 mg/kg). Antidiabetic, antihyperlipidemic activities of OJ were evaluated at dose of 0.28 ml/kg by estimating biochemical changes in urine, serum and liver tissue homogenate and histological changes in liver and pancreatic tissues. Metformin (100 mg/kg, p.o.) was used as reference standard drug. RESULTS: Results indicate that STZ administration caused hyperglycemia, increased serum glycosylated hemoglobin content, altered serum lipid profile, polyuria, decreased liver glycogen content and histological changes in liver and pancreatic tissues. This elevated serum glucose level and urine volume was significantly decreased by OJ. Supplementation with OJ produced significant improvement in serum lipid profile and glycosylated hemoglobin content along with significant increase in the liver glycogen content. OJ treatment also restored histological changes in liver and pancreatic tissue near to the normal. The observed antidiabetic and hypolipidemic effects of OJ were superior to Metformin. Co treatment of diabetic rats with OJ and Metformin failed to control blood glucose levels. CONCLUSION: It is concluded that the OJ possesses significant antidiabetic and antihyperlipidemic activities in rats. However, co administration of OJ and Metformin is cautioned. PMID- 29137854 TI - [Inclusion of patient safety into the Medical degree electives: Description of the experience and student perception]. AB - INTRODUCTION: One of the factors identified to reduce medical errors has been the organisational culture. Education is proposed as a tool for its modification, but this does not have a unique way of being achieved. This paper sought to describe a patient safety elective for medical students and to determine their perceptions on the subject. MATERIALS AND METHODS: A descriptive study was performed in the Center of Medical Education and Clinical Investigations, in Argentina. Every student who participated in the elective was included, and there were no exclusion criteria. An online survey was conducted on all participants, and individual interviews were conducted on a convenience sample. RESULTS: The subject was chosen by 54 students out of a total of 274 students between 2011 and 2014. All (100%) of the students completed the course and passed the exam, and stated that they would recommend the elective. Most of the students (n=26) agreed that patient safety content should be mandatory, that its content was novel, and that the subject's structure seemed appropriate, with 21 saying that it was the first time they had been talked about these issues. From the individual interviews, students emphasised the novelty of the subject, and that their perception on patient safety issues had increased. DISCUSSION: The proposed elective had a good reception among students. The methodology planned for its teaching seemed appropriate. Inter-professional education in patient safety should be implemented to improve student competencies in the subject. PMID- 29137855 TI - Improving the quality of surgical care: The American College of Surgeons National Surgical Quality Improvement Program. PMID- 29137856 TI - [From paper to new technologies in communication with our patients]. PMID- 29137858 TI - Human Papillomavirus E6 and E7 oncoproteins affect the cell microenvironment by classical secretion and extracellular vesicles delivery of inflammatory mediators. AB - The connection between chronic inflammation and risk of cancer has been supported by several studies. The development of cancer might be a process driven by the presence of a specific combination of inflammatory mediators, including cytokines, chemokines and enzymes, in the tumor microenvironment. Virus-induced tumors, like HPV-induced Squamous Cell Carcinomas, represent a paradigmatic example of the interplay between inflammation, as integral part of the innate antiviral response, and malignant transformation. Here, the role of inflammatory microenvironment in the HPV-induced carcinogenesis is addressed, with a specific focus on the involvement of the immune molecules as well as their delivery through the microvesicle cargo possibly correlated to the different HPV genotype. The expression of the inflammatory mediators in HPV positive cells has been analyzed in primary human foreskin keratinocytes and keratinocytes transduced by E6 and E7 from mucosal HPV-16 or cutaneous HPV-38 genotypes. HPV E6 and E7 proteins can modulate the expression of immune mediators in HPV-infected cells and can affect the levels of immune molecules, mainly chemokines, in the extracellular milieu. HPV-16 E6 and E7 oncoproteins have been silenced to confirm the specificity of the modulation of the inflammatory microenvironment. Our results suggest that the expression of HPV oncoproteins allows the modification of the tumor milieu through the synthesis and release of specific pro inflammatory cytokines and chemokines, affecting the efficacy of the immune response. The microenvironment can also be conditioned by an altered mRNA cargo delivered by extracellular vesicles, thereby efficiently affecting the surrounding cells with possible implication for tumorigenesis and tumor diagnosis. PMID- 29137857 TI - Matricellular proteins and survival in patients with pancreatic cancer: A systematic review. AB - Extracellular matrix (ECM) plays a fundamental role in tissue architecture and homeostasis and modulates cell functions through a complex interaction between cell surface receptors, hormones, several bioeffector molecules, and structural proteins like collagen. These components are secreted into ECM and all together contribute to regulate several cellular activities including differentiation, apoptosis, proliferation, and migration. The so-called "matricellular" proteins (MPs) have recently emerged as important regulators of ECM functions. The aim of our review is to consider all different types of MPs family assessing the potential relationship between MPs and survival in patients with pancreatic ductal adenocarcinoma (PDAC). A systematic computer-based search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) Statement issued in 2009 was conducted through Ovid interface, and literature review was performed in May 2017. The search text words were identified by means of controlled vocabulary, such as the National Library of Medicine's MESH (Medical Subject Headings) and Keywords. Collected data showed an important role of MPs in carcinogenesis and in PDAC prognosis even though the underlying mechanisms are still largely unknown and data are not univocal. Therefore, a better understanding of MPs role in regulation of ECM homeostasis and remodeling of specific organ niches may suggest potential novel extracellular targets for the development of efficacious therapeutic strategies. PMID- 29137859 TI - Dynamics and control of infections on social networks of population types. AB - Random mixing in host populations has been a convenient simplifying assumption in the study of epidemics, but neglects important differences in contact rates within and between population groups. For HIV/AIDS, the assumption of random mixing is inappropriate for epidemics that are concentrated in groups of people at high risk, including female sex workers (FSW) and their male clients (MCF), injecting drug users (IDU) and men who have sex with men (MSM). To find out who transmits infection to whom and how that affects the spread and containment of infection remains a major empirical challenge in the epidemiology of HIV/AIDS. Here we develop a technique, based on the routine sampling of infection in linked population groups (a social network of population types), which shows how an HIV/AIDS epidemic in Can Tho Province of Vietnam began in FSW, was propagated mainly by IDU, and ultimately generated most cases among the female partners of MCF (FPM). Calculation of the case reproduction numbers within and between groups, and for the whole network, provides insights into control that cannot be deduced simply from observations on the prevalence of infection. Specifically, the per capita rate of HIV transmission was highest from FSW to MCF, and most HIV infections occurred in FPM, but the number of infections in the whole network is best reduced by interrupting transmission to and from IDU. This analysis can be used to guide HIV/AIDS interventions using needle and syringe exchange, condom distribution and antiretroviral therapy. The method requires only routine data and could be applied to infections in other populations. PMID- 29137860 TI - Quality of anthropometric measurements in Spanish Intensive Care Units (The CAMIES Study). AB - INTRODUCTION: Real body weight and height are essential data to be obtained in all critically ill patients (CIP), due to their influence in the designing of therapies and monitoring. Visual estimation is a very inaccurate practice. No precise descriptions of anthropometric measurements among CIP are available in the clinical practice guides. OBJECTIVE: To describe anthropometric quality in CIP, health professional perception of such quality, and its influencing factors. DESIGN: Computer-assisted telephone or self-interviewing. SETTING: Doctors and nurses of all Spanish Intensive Care Units (ICU) attending adults. RELEVANT VARIABLES: Anthropometric practices were described in detail, along with the proclivity to obtain real measurements, and the influence of professional experience, the number of ICU beds, and the health professional group involved. RESULTS: A total of 481 questionnaires were collected from 176 hospitals (36.8% from physicians). The availability of measuring tools is limited (weight 68.7% - height 76.7%), with no relation to the number of ICU beds (weight P=.343, height P=.61). Visual estimation was the most frequent way of obtaining measurements (weight 65.9% - height 64.8%), even when measuring tools were available. Willingness to take real measurements was very low, especially among physicians, and professional experience was associated to increased rejection (P<.001). CONCLUSIONS: Visually estimated measurements exceed real measurements in the routine practice of Spanish ICUs. Measurement tools are not widely available in the ICU, and even when available, their use is not guaranteed. The surveyed population does not view anthropometric measures as being important for clinical practice. An effort should be made by scientific societies to promote reliable anthropometric practice in Spanish ICUs. PMID- 29137861 TI - Renal replacement therapy in severe phenobarbital poisoning: Another brick in the wall. PMID- 29137862 TI - Fastrach TM Intubating Laryngeal Mask for traumatic cervical spinal cord injury. PMID- 29137863 TI - Results and functional outcomes of acute ischemic stroke patients who underwent mechanical thrombectomy admitted to intensive care unit. AB - PURPOSE: To study the results and complications of endovascular treatment (EVT) in acute ischemic stroke patients admitted to Intensive Care Unit (ICU). To analyse the possible factors related to mortality and level of disability at ICU discharge and one year after stroke. DESIGN: Observational prospective study. SETTING: Mixed ICU. Third level hospital. PATIENTS: Sixty adult patients. Consecutive sample. INTERVENTIONS: None. VARIABLES OF INTEREST: Epidemiological data, time from symptom onset to EVT, angiographic result, length of stay, days on mechanical ventilation, neurological complications, National Institutes of Health Stroke Scale (NIHSS) at ICU admission and discharge, modified Rankin scale score (mRS) at one year. RESULTS: Mean age 68,90+/-8,84years. Median time from symptom onset to EVT: 180minutes. Median NIHSS at admission: 17,5; at discharge: 3. Distal flow was achieved in 90% of cases. Median ICU stay: 3 days. Mechanical ventilation: 81,7.%. Functional independence (mRS<=2) 50% at one year. Deaths: 22 (36,6%) of which 8 (13,3%) died during UCI stay and the rest during the first year. CONCLUSIONS: The factors relating to a worse functional outcome were symptomatic hemorrhage transformation, lack of recanalization and complications during EVT. The factors relating to mortality were symptomatic hemorrhage and hydrocephalus. Distal flow was achieve in most cases with a low complication rate. Half of the patients presented functional independence one year after the stroke. PMID- 29137864 TI - Synthesis, molecular docking, and QSAR study of sulfonamide-based indoles as aromatase inhibitors. AB - Thirty four of indoles bearing sulfonamides (11-44) were synthesized and evaluated for their anti-aromatase activities. Interestingly, all indole derivatives inhibited the aromatase with IC50 range of 0.7-15.3 MUM. Indoles (27 36) exerted higher aromatase inhibitory activity than that of ketoconazole. The phenoxy analogs 28 and 34 with methoxy group were shown to be the most potent compounds with sub-micromolar IC50 values (i.e., 0.7 and 0.8 MUM, respectively) without affecting to the normal cell line. Molecular docking demonstrated that the indoles 28, 30 and 34 could occupy the same binding site on the aromatase pocket and share several binding residues with those of the natural substrate (androstenedione), which suggested the competitive binding could be the mode of inhibition of the compounds. The most potent analog 28 could mimic H-bond interactions of the natural androstenedione with MET374 and ASP309 residues on the aromatase. QSAR model also revealed that the para-phenoxy indole (28) affords the higher value of electronegativity descriptor MATS6e as well as the higher inhibitory activity compared with that of the ortho-phenoxy compound (34). The study highlighted a series of promising indoles to be potentially developed as novel aromatase inhibitors for therapeutics. PMID- 29137865 TI - Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives. AB - A series of 4-aminomethyl derivatives of heliomycin 1 was prepared using the Mannich reaction. The modification significantly improved aqueous solubility of the initially poorly soluble antibiotic. Testing the antiproliferative efficacy revealed a potent activity of heliomycin as well as its new derivatives on a panel of mammalian tumor cells including drug resistant variants. In contrast to 1 the new derivatives 7a, 7l, 7p generated a high level of ROS associated with induction of apoptosis in T24 bladder cancer cells. Introduction of 4-aminomethyl moiety increased the affinity to DNA and the ability to inhibit topoisomerase 1 making 7p the most promising candidate for further preclinical evaluation. Thus, aminomethylation is the first-in-class successful transformation of the antibiotic 1 resulting in an improved water solubility of derivatives and promising properties in search of novel anticancer drug candidates. PMID- 29137866 TI - Development of noviomimetics that modulate molecular chaperones and manifest neuroprotective effects. AB - Heat shock protein 90 (Hsp90) is a chaperone under investigation for the treatment of cancer and neurodegenerative diseases. Neuroprotective Hsp90 C terminal inhibitors derived from novobiocin (novologues) include KU-32 and KU 596. These novologues modulate molecular chaperones and result in an induction of Heat Shock Protein 70 (Hsp70). "Noviomimetics" replace the synthetically complex noviose sugar with a simple cyclohexyl moiety to maintain biological efficacy as compared to novologues KU-596 and KU-32. In this study, we further explore the development of noviomimetics and evaluate their efficacy using a luciferase refolding assay, immunoblot analysis, a c-jun assay, and an assay measuring mitochondrial bioenergetics. These new noviomimetics were designed and synthesized and found to induce Hsp70 and improve biological activity. Noviomimetics 39e and 40a were found to induce Hsp70 and exhibit promising effects in cellular assays. PMID- 29137867 TI - Functionalized 2,1-benzothiazine 2,2-dioxides as new inhibitors of Dengue NS5 RNA dependent RNA polymerase. AB - Over recent years, many RNA viruses have been "re-discovered", including life threatening flaviviruses, such as Dengue, Zika, and several encephalitis viruses. Since no specific inhibitors are currently available to treat these infections, there is a pressing need for new therapeutics. Among the flaviviral proteins, NS5 RNA-dependent RNA polymerase (RdRp) represents a validated target being essential for viral replication and it has no human analog. To date, few NS5 RdRp inhibitor chemotypes have been reported and no inhibitors are currently in clinical development. In this context, after an in vitro screening against Dengue 3 NS5 RdRp of our in-house HCV NS5B inhibitors focused library, we found that 2,1 benzothiazine 2,2-dioxides are promising non-nucleoside inhibitors of flaviviral RdRp with compounds 8 and 10 showing IC50 of 0.6 and 0.9 MUM, respectively. Preliminary structure-activity relationships indicated a key role for the C-4 benzoyl group and the importance of a properly functionalized C-6 phenoxy moiety to modulate potency. Compound 8 acts as non-competitive inhibitor and its proposed pose in the so-called N pocket of the RdRp thumb domain allowed to explain the key contribution of the benzoyl and the phenoxy moieties for the ligand binding. PMID- 29137868 TI - What works in inclusion health: overview of effective interventions for marginalised and excluded populations. AB - Inclusion health is a service, research, and policy agenda that aims to prevent and redress health and social inequities among the most vulnerable and excluded populations. We did an evidence synthesis of health and social interventions for inclusion health target populations, including people with experiences of homelessness, drug use, imprisonment, and sex work. These populations often have multiple overlapping risk factors and extreme levels of morbidity and mortality. We identified numerous interventions to improve physical and mental health, and substance use; however, evidence is scarce for structural interventions, including housing, employment, and legal support that can prevent exclusion and promote recovery. Dedicated resources and better collaboration with the affected populations are needed to realise the benefits of existing interventions. Research must inform the benefits of early intervention and implementation of policies to address the upstream causes of exclusion, such as adverse childhood experiences and poverty. PMID- 29137870 TI - Inclusion health: addressing the causes of the causes. PMID- 29137869 TI - Morbidity and mortality in homeless individuals, prisoners, sex workers, and individuals with substance use disorders in high-income countries: a systematic review and meta-analysis. AB - BACKGROUND: Inclusion health focuses on people in extremely poor health due to poverty, marginalisation, and multimorbidity. We aimed to review morbidity and mortality data on four overlapping populations who experience considerable social exclusion: homeless populations, individuals with substance use disorders, sex workers, and imprisoned individuals. METHODS: For this systematic review and meta analysis, we searched MEDLINE, Embase, and the Cochrane Library for studies published between Jan 1, 2005, and Oct 1, 2015. We included only systematic reviews, meta-analyses, interventional studies, and observational studies that had morbidity and mortality outcomes, were published in English, from high-income countries, and were done in populations with a history of homelessness, imprisonment, sex work, or substance use disorder (excluding cannabis and alcohol use). Studies with only perinatal outcomes and studies of individuals with a specific health condition or those recruited from intensive care or high dependency hospital units were excluded. We screened studies using systematic review software and extracted data from published reports. Primary outcomes were measures of morbidity (prevalence or incidence) and mortality (standardised mortality ratios [SMRs] and mortality rates). Summary estimates were calculated using a random effects model. FINDINGS: Our search identified 7946 articles, of which 337 studies were included for analysis. All-cause standardised mortality ratios were significantly increased in 91 (99%) of 92 extracted datapoints and were 11.86 (95% CI 10.42-13.30; I2=94.1%) in female individuals and 7.88 (7.03 8.74; I2=99.1%) in men. Summary SMR estimates for the International Classification of Diseases disease categories with two or more included datapoints were highest for deaths due to injury, poisoning, and other external causes, in both men (7.89; 95% CI 6.40-9.37; I2=98.1%) and women (18.72; 13.73 23.71; I2=91.5%). Disease prevalence was consistently raised across the following categories: infections (eg, highest reported was 90% for hepatitis C, 67 [65%] of 103 individuals for hepatitis B, and 133 [51%] of 263 individuals for latent tuberculosis infection), mental health (eg, highest reported was 9 [4%] of 227 individuals for schizophrenia), cardiovascular conditions (eg, highest reported was 32 [13%] of 247 individuals for coronary heart disease), and respiratory conditions (eg, highest reported was 9 [26%] of 35 individuals for asthma). INTERPRETATION: Our study shows that homeless populations, individuals with substance use disorders, sex workers, and imprisoned individuals experience extreme health inequities across a wide range of health conditions, with the relative effect of exclusion being greater in female individuals than male individuals. The high heterogeneity between studies should be explored further using improved data collection in population subgroups. The extreme health inequity identified demands intensive cross-sectoral policy and service action to prevent exclusion and improve health outcomes in individuals who are already marginalised. FUNDING: Wellcome Trust, National Institute for Health Research, NHS England, NHS Research Scotland Scottish Senior Clinical Fellowship, Medical Research Council, Chief Scientist Office, and the Central and North West London NHS Trust. PMID- 29137872 TI - [Atelectasis in patients undergoing bariatric surgery without any previous pulmonary alterations: comments from the prevalence study]. PMID- 29137871 TI - [Anesthesia and Alzheimer disease - Current perceptions]. AB - BACKGROUND AND OBJECTIVES: It has been speculated that the use of anesthetic agents may be a risk factor for the development of Alzheimer disease. The objective of this review is to describe and discuss pre-clinical and clinical data related to anesthesia and this disease. CONTENT: Alzheimer disease affects about 5% of the population over 65 years old, with age being the main risk factor and being associated with a high morbidity. Current evidence questions a possible association between anesthesia, surgery, and long-term cognitive effects, including Alzheimer disease. Although data from some animal studies suggest an association between anesthesia and neurotoxicity, this link remains inconclusive in humans. We performed a review of the literature in which we selected scientific articles in the PubMed database, published between 2005 and 2016 (one article from 1998 due to its historical relevance), in English, which address the possible relationship between anesthesia and Alzheimer disease. 49 articles were selected. CONCLUSION: The possible relationship between anesthetic agents, cognitive dysfunction, and Alzheimer disease remains to be clarified. Prospective cohort studies or randomized clinical trials for a better understanding of this association will be required. PMID- 29137873 TI - [Validity time of normal results of preoperative tests for surgical reintervention and the impact on postoperative outcomes]. AB - BACKGROUND AND OBJECTIVE: There are few data defining the period of time in which preoperative tests can be considered valid. The purpose of this study was to determine the likelihood of changes in the results of preoperative tests previously normal in relation to time, and the impact of these changes on postoperative outcomes. METHODS: A total of 970 patients with normal preoperative tests before the first surgery and who required a new intervention were included. The preoperative tests performed for the first procedure were compared with those performed for the second procedure. The following variables were assessed regarding their potential to induce changes in test results: sex, age, surgical risk, previous chemotherapy or radiotherapy, and presence of comorbidities. In hospital outcomes were analyzed. RESULTS: The median time between procedures was 27 months (6-84). The probability of change in at least one of the preoperative exams was 1.7% (95% CI: 0.5-2.9), 3.6% (95% CI: 1.8-5.4), and 6.4% (95% CI: 3.9 8.9) during the 12, 24, and 36-month intervals, respectively, for patients aged <50 years and 2.1% (95% CI: 0.7-3.5), 9.2% (95% CI: 5.9-12.5), and 13.4% (95% CI: 9.3-17.5), respectively, for patients >= 50 years of age. Age (p=0.009), surgical risk (p <0.001), chemotherapy (p=0.001), radiotherapy (p=0.012), and comorbidities (p <0.001) were associated with the likelihood of changes in test results. Test changes were not significantly associated with in-hospital adverse outcomes (p=0.426). CONCLUSION: For patients undergoing a second surgical procedure, the probability of change in previously normal preoperative tests is low during the first years after the first surgical intervention, and when changes occurred, they did not adversely affect the in-hospital postoperative outcomes. PMID- 29137874 TI - Investigating antenatal nutrition education preferences in South-East Queensland, including Maori and Pasifika women. AB - BACKGROUND: Little is reported about the nutrition-related needs and preferences of women seeking maternity services, particularly Maori and Pasifika (M&P) women who have higher chronic disease rates in Queensland. AIM: Nutrition-related knowledge, needs, behaviours and education preferences were compared between women of M&P ancestry and non-Maori and Pasifika women (NMP). METHOD: Women (>=18 years) admitted to the postnatal ward were surveyed. Anthropometry, dietary quality, nutrition education preferences, country of birth and ancestry were collected. Analysis included chi-squared and t-tests. FINDINGS: The survey was completed by 399 eligible women. Country of birth data suggested 4% of respondents were Pasifika and failed to separately identify New Zealand Maori, whereas 18% of respondents (n=73) reported M&P ancestry. Descriptors were similar between groups (28+/-5 years; 91% any breastfeeding; 18% gestational diabetes mellitus; p>0.05). However M&P women were less often university educated (M&P:6(9%); NMP:71(22%), p<0.01) and more likely had >2 children (M&P: 30(54%); NMP:70(30%), p<0.01). M&P women reported heavier weight at conception (M&P:79.0+/ 20.2kg, 29.2+/-7.5kg/m2; NMP:71.3+/-18.9kg, 26.3+/-6.5kg/m2, p<0.01), and were more likely to report excess gestational weight gain (M&P:30(56%), NMP:96(36%), p<0.05). Most (>75%) women did not know their recommended weight gain. Many respondents reported inadequate intake of vegetables (95%), fruit (29%) and dairy (69%) during pregnancy. Two-fifths (38-41%) reported interest in perinatal nutrition education, with topics including healthy eating postpartum. DISCUSSION: Findings enable targeted service delivery according to women's preferences. CONCLUSION: Collecting ancestral and maternal data to facilitate the provision of appropriate nutrition education may be critical for achieving optimal maternal outcomes in Maori and Pasifika women. PMID- 29137875 TI - Contribution of 11C-Choline PET/CT in prostate carcinoma biochemical relapse with serum PSA level below 1 ng/ml. AB - OBJECTIVE: 11C-choline PET/CT has demonstrated good results in the restaging of prostate cancer (PCa) with high serum prostate specific antigen (PSA), but its use in patients with low serum PSA is controversial. Our aim was to evaluate the contribution of 11C-choline PET/CT in patients with PCa, biochemical relapse and PSA <1 ng/ml. MATERIAL AND METHOD: Fifty consecutive patients (mean age: 65.9+/ 5.6 years) with biochemical relapse of PCa and serum PSA <1ng/ml were evaluated retrospectively. PET/CT was performed 20min after intravenous administration of 555-740 MBq of 11C-choline. Minimum follow up time was 30 months. RESULTS: Twenty one out of 50 patients (42%) had an abnormal 11C-choline PET/CT. In 7 out of 21 patients (14%) tumor was confirmed (4 in prostatic bed, 4 in pelvic lymph nodes, 2 in mediastinal lymph nodes and one synchronous sigmoid carcinoma), and in all cases the initial therapeutic planning was modified. In 2 patients (4%) subsequent tests diagnosed a benign disease (one sarcoidosis, one tuberculosis sequelae) and in 3 patients (6%) they ruled out pathology. The other 9 patients (18%) had no further assessment (7 mediastinal and 4 pelvic lymph nodes). Twenty nine out of 50 patients (58%) had a normal PET/CT. At 30 months, follow up recurrence was confirmed only in 2 of these patients. CONCLUSIONS: 11C-choline PET/CT proved its usefulness in demonstrating tumor in 14% of patients with BR of PCa and serum PSA <1ng/ml, with therapeutic implications. In 4% of patients a benign condition was detected. A normal 11C-choline PET/CT was associated with a very low rate of recurrence at 30 months. PMID- 29137876 TI - New approaches in radioguided surgery. PMID- 29137877 TI - Immune Analysis of Radium-223 in Patients With Metastatic Prostate Cancer. AB - BACKGROUND: Radium223 (Ra223) delivers high-energy radiation to osteoblastic metastasis of prostate cancer, resulting in irreparable double-stranded DNA damage. The effects of Ra223 on CD8+ T cell subsets in patients with prostate cancer is unknown. PATIENTS AND METHODS: Fifteen men with metastatic prostate cancer with clinical indication for Ra223 without any autoimmune or immune deficiency conditions were enrolled. Patients received a course of Ra223 50 kBq/kg. Concurrent use of prednisone <= 10 mg a day was allowed. Peripheral blood samples were collected before and 3 to 4 weeks after the first dose of Ra223 50 kBq/kg. Peripheral blood mononuclear cells were purified and analyzed for the phenotypic and functional characteristics of CD8+ T cells using flow cytometry. RESULTS: One Ra223 treatment did not result in significant change in the overall frequencies of CD8+ T cells and their subsets including naive, central memory, and effect memory cells. However, the mean frequency of programmed cell death protein 1-expressing EM CD8+ T cells decreased after 1 Ra223 treatment from 20.6% to 14.6% (P = .020), whereas no significant change was observed in the frequencies of CD27-, CD28-, or CTLA4-expressing T cells. One Ra223 treatment was not associated with any significant change in the frequencies of CD8+ T cells producing IFN-gamma, TNF-alpha, and IL-13. CONCLUSION: One Ra223 treatment is associated with a decreased mean frequency of programmed cell death protein 1 expressing effect memory CD8+ T cell without affecting other immune checkpoint molecules or cytokine production. Further investigations are warranted to elucidate the immunologic and clinical significance of our observations and its long-term effects after multiple treatments. PMID- 29137878 TI - Integration of Medicare and Medicaid for dually eligible beneficiaries: A focus group study examining beneficiaries' early experiences in California's dual financial alignment demonstration. AB - BACKGROUND: In 2014 California implemented a federal dual alignment demonstration used a capitated managed healthcare model called Cal MediConnect (CMC) to integrate medical care and long term services and supports (LTSS) for beneficiaries with both Medicare and Medicaid. These beneficiaries often have complex care needs, including multiple chronic conditions and disabilities. By 2016, 120,000 eligible beneficiaries were enrolled in the program. OBJECTIVES: Focus groups with enrolled beneficiaries were conducted to gather rich data about their early experiences with quality of care, access to care, and coordination of care in CMC plans and to identify recommendations for program improvement. METHODS: Evaluators conducted 14 focus groups with 104 beneficiaries enrolled in CMC plans in 6 demonstration counties. RESULTS: The passive enrollment process did not provide adequate information about certain aspects of CMC, leaving many beneficiaries unaware of new benefits such as care coordination, transportation, and managed LTSS. Most beneficiaries who were using the CMC care coordination benefit reported increased access to specialty care, medical equipment, and other LTSS. Changing providers and having trouble with authorization for specialty services, prescriptions, or medical equipment were common reasons for dissatisfaction. Many beneficiaries reported that early disruptions in care due to the transition of delivery system improved with time. CONCLUSION: Similar to other studies that examine beneficiaries' experiences with delivery system change, participants were confused about the passive enrollment process and demonstrated a lack of understanding of many aspects of Cal MediConnect. Analysis identified areas where beneficiaries noted improvement in their quality of care, access, and coordination of care, but also areas for improvement. Streamlining the authorization processes and extending continuity of care provisions would improve access to providers. Increasing beneficiaries' awareness of CMC plans' role in LTSS is key to improving their access to home- and community-based services. PMID- 29137880 TI - Microbioma and probiotics: from gut to Mars. PMID- 29137879 TI - Identification and management of inverted or everted edges of traumatic tympanic membrane perforations. AB - INTRODUCTION: Most of traumatic tympanic membrane perforations have inverted or everted edges, however, the effects of inverted and everted edges on the spontaneous healing of the eardrum remain controversial. OBJECTIVE: We investigated the influence of inverted or everted edges on the spontaneous healing of traumatic tympanic membrane perforations. METHODS: The clinical records of patients with a traumatic tympanic membrane perforations who met the study criteria were retrieved and categorized into two groups, based on whether the eardrum was inverted or everted. The features along the edge of each inverted or everted eardrum were described using 30 degrees and 70 degrees endoscopes. RESULTS: In total, 196 patients (196 ears) met the inclusion criteria; of these, 148 had inverted or everted eardrums while 48 did not. Of the 148 patients with inverted or everted eardrums, the perforation edges were everted in 77 patients, inverted in 44 patients, drooping in 17 patients, and both inverted and everted in 10 patients. The perforation shape was triangular in 18.9% of patients, sector shaped in 11.5%, kidney-shaped in 14.2%, ovoid in 20.3%, and irregularly shaped in 35.1% of patients. The difference was not significant between the with and without inverted/everted eardrum edges groups in terms of the closure rate or closure time. Similarly, the difference was not significant between the with and without edge approximation groups in terms of the closure rate or closure time at the end of the 12-month follow-up period. CONCLUSION: This study suggests that endoscopic inspection can clearly identify inverted/everted eardrum edges using 30 degrees and 70 degrees endoscopes. The edge is glossy in inverted/everted eardrums, whereas the edge is rough and irregular in non-inverted/everted cases. The inverted/everted eardrums gradually became necrotic, but this did not affect the healing process. Additionally, edge approximation did not improve the healing outcome of traumatic tympanic membrane perforations. PMID- 29137881 TI - Comparison between chloral hydrate and propofol-ketamine as sedation regimens for pediatric auditory brainstem response testing. AB - INTRODUCTION: The use of diagnostic auditory brainstem response testing under sedation is currently the "gold standard" in infants and young children who are not developmentally capable of completing the test. OBJECTIVE: The aim of the study is to compare a propofol-ketamine regimen to an oral chloral hydrate regimen for sedating children undergoing auditory brainstem response testing. METHODS: Patients between 4 months and 6 years who required sedation for auditory brainstem response testing were included in this retrospective study. Drugs doses, adverse effects, sedation times, and the effectiveness of the sedative regimens were reviewed. RESULTS: 73 patients underwent oral chloral hydrate sedation, while 117 received propofol-ketamine sedation. 12% of the patients in the chloral hydrate group failed to achieve desired sedation level. The average procedure, recovery and total nursing times were significantly lower in the propofol-ketamine group. Propofol-ketamine group experienced higher incidence of transient hypoxemia. CONCLUSION: Both sedation regimens can be successfully used for sedating children undergoing auditory brainstem response testing. While deep sedation using propofol-ketamine regimen offers more efficiency than moderate sedation using chloral hydrate, it does carry a higher incidence of transient hypoxemia, which warrants the use of a highly skilled team trained in pediatric cardio-respiratory monitoring and airway management. PMID- 29137882 TI - Foreword. PMID- 29137883 TI - The significance of changes in pupil size during straylight measurement and with varying environmental illuminance. AB - PURPOSE: In this work, we investigated the pupillary conditions during straylight measurement, and the potential effect this might have on the measured straylight. METHODS: Five young (26-29-years-old) and 15 older (50-68-years-old) individuals participated in this study. First, the pupil diameter of both eyes was measured at three room illuminances. Next, straylight was assessed at two room illuminances. Simultaneously, the change in pupil size of the fellow eye was registered by a camera. RESULTS: Pupil size decreased with room illuminance and with age (both p<0.05). The dependency of pupil size on age decreased as room illuminance increased (0.018mm/year at 4 lux, 0.014mm/year at 40 lux, and 0.008mm/year at 400 lux illuminances). However, during straylight measurement, pupil sizes hardly differed between 4 and 40 lux illuminances. Respective pupil sizes corresponded with 399 and 451 lux adaptation on average. No statistically significant difference was found between the straylight under the two illuminances with average R2=0.85, p<0.05. CONCLUSION: We conclude that the illuminance of the examination room during straylight assessment does not affect the outcome in normal eyes. In fact, under mesopic and scotopic conditions, the luminance of the test field is so much higher than that of the room so that it determines the pupil size. Regardless of the lighting level, straylight measured in a laboratory, is valid for photopic pupils at an adaptation level corresponding with about 400 lux room illuminance. PMID- 29137884 TI - Uptake and Effectiveness of FOLFIRINOX for Advanced Pancreatic Cancer: a Population-based Study. AB - AIMS: Although FOLFIRINOX is a standard treatment option for advanced pancreas cancer, there are few data describing utilisation and effectiveness in routine clinical practice. Here we report practice patterns and outcomes in the general population of Ontario, Canada. MATERIALS AND METHODS: Using the Ontario Cancer Registry and New Drug Funding Program, we identified all patients with pancreas cancer treated with palliative intent gemcitabine or FOLFIRINOX in Ontario during 2006-2014. FOLFIRINOX became available in Ontario's single-payer health system in November 2011. Gemcitabine cases were classified as pre-FOLFIRINOX era (2006 2010) or post-FOLFIRINOX era (2011-2014). Cases treated with perioperative chemotherapy were excluded. Comparisons of proportions between study groups were made using the chi-square test. Overall survival was measured from the date of chemotherapy initiation. RESULTS: During 2006-2014, 3826 patients in Ontario were treated with gemcitabine (n = 3042) or FOLFIRINOX (n = 784) chemotherapy for advanced pancreas cancer. Uptake of FOLFIRINOX increased from 41% (206/505) of treated cases in 2012 to 56% (274/486) of treated cases in 2014. The median overall survival of patients treated with gemcitabine was 5.0 months in 2006-2010 and 4.8 months in 2011-2014. The median overall survival of FOLFIRINOX patients treated in 2011-2014 was 8.2 months. CONCLUSION: The use of FOLFIRINOX in the general population has increased since 2011. Survival outcomes show a substantial efficacy-effectiveness gap between the pivotal Prodige 4/ACCORD 11 clinical trial and routine practice. PMID- 29137885 TI - In-situ examination of graphene and graphene oxide impact on the depuration of phenanthrene and fluoranthene adsorbed onto spinach (Spinacia oleracea L.) leaf surfaces. AB - To further assess the human being's exposure to polycyclic aromatic hydrocarbons (PAHs) through the dietary pathway, understanding the partitioning of these chemicals co-existed with nanomaterials in edible vegetable systems deserves specific consideration. In this study, the fiber-optic fluorimetry was applied to in situ examine the effects of graphene (GNS) and graphene oxide (GO) nanosheets on the quantification and depuration of three-ringed phenanthrene (Phe) and four ringed fluoranthene (Fla) adsorbed individually onto the living spinach (Spinacia oleracea L.) surfaces. When the GNS and GO dosages separately increased to the maximum values: a respective red-shift of 4-5 nm and blue-shift of 2-3 nm occurred for the optimal detection emission wavelengths (lambdaem) of the two PAHs, indicating that individual GNS and GO resulted in different changes to the epicuticular wax (ECW) polarity; GNS-inducing fluorescence quenching for the PAHs was about two times greater than GO, owing to the stronger pi-pi interactions between PAH molecules and GNS relative to GO; the volatilization coefficients (kC1) were reduced by 31.1% versus 26.7% for Phe, and 51.6% versus 34.4% for Fla, mainly via providing an additional adsorbent and promoting the accessibility of the leaf cuticle; respective photolysis coefficients (kP2) of Phe and Fla decreased by 42.9% and 50.0% with GNS, primarily owing to the enhancement of the ECW light-adsorption capacity, but increased by 33.3% and 40.0% with GO due to its photocatalytic activities; overall, total depuration coefficients (kT1, kT2) of the two PAHs decreased by 11.1-55.6%. These findings demonstrate that GNS and GO significantly alter the depuration behavior of PAHs in vegetable systems, potentially posing a threat to the safety of edible vegetables. PMID- 29137886 TI - Diesel exhaust inhalation exposure induces pulmonary arterial hypertension in mice. AB - Diesel exhaust (DE) is one of the main sources of urban air pollution. An increasing number of evidence showed the association of air pollution with cardiovascular diseases. Pulmonary arterial hypertension (PAH) is one of the most disastrous vascular diseases, which results in right ventricular failure and death. However, the relationship of DE inhalation exposure with PAH is still unknown. In this study, male adult mice were exposed by inhalation to filtered ambient air (negative control), 10% O2 hypoxia (PAH-phenotype positive control), 350 MUg/m3 particulate matter whole DE, or the combination of DE and hypoxic condition. DE inhalation induced PAH-phenotype accompanied with increased right ventricular systolic pressure (RVSP), right ventricle hypertrophy and pulmonary arterial thickening in a mouse model. DE exposure induced the proliferation of vascular smooth muscle cells (VSMCs) and apoptosis of endothelial cells in pulmonary artery. DE inhalation exposure induced an accumulation of CD45+ lymphocytes and CD68+ macrophages surrounding and infiltrating pulmonary arteriole. The levels of pro-inflammatory cytokines tumor necrosis factor (TNF alpha), interleukin-6 (IL-6) and IL-13 produced by T helper 17 (Th17) and Th2 cells were markedly elevated in lung tissues of mice after DE inhalation exposure. Our findings suggest DE exposure induces PAH by activating Th17-skewed and Th2-droved responses, stimulating VSMCs proliferation and inducing endothelial cell apoptosis by the production of multifunctional pro-inflammatory cytokines, especially IL-6 and TNF-alpha. Considering the adverse impact of air pollution on health care, it is imperative to understand air pollution-induced susceptibility of progressive cardiopulmonary disease, such as PAH, and also elucidate critical mechanistic pathways which mediate pulmonary artery vascular remodeling and may serve as targets for preventive measures. PMID- 29137887 TI - Effects of chlortetracycline on the fate of multi-antibiotic resistance genes and the microbial community during swine manure composting. AB - Excessive use of antibiotics in breeding industry leads to accumulation of antibiotic residuals and antibiotic resistance genes (ARGs) in environment from improperly treated livestock excrements. Four commonly used veterinary antibiotics including chlortetracycline (CTC), sulfamerazine (SMZ), enrofloxacin (ENR) and erythromycin (ERY) were monitored in the swine manure composting. Co resistance and cross-resistance effects among relative ARGs, correlations between ARGs and bacterial community under multiple antibiotics residual during the composting were investigated in this research. With CTC addition up to 20 mg/kg, more than 99% of CTC removal was achieved after composting, and most of the other antibiotics can be thoroughly removed as well. The variations in ARGs during the composting were strongly correlated to the compositions of the microbial community, Bacteroides and Sporosarcina were main ARGs carriers in the thermophlic phase. Clostridium XI, Clostridium sensu stricto, and Pseudoxanthomonas, might spread ARGs in cooling and maturing stage. Most of the tested ARGs in swine manure can be effectively reduced through composting, thus makes the compost products safe for soil fertilization. PMID- 29137888 TI - Comparative effects of graphene and graphene oxide on copper toxicity to Daphnia magna: Role of surface oxygenic functional groups. AB - Although the risk of graphene materials to aquatic organisms has drawn wide attention, the combined effects of graphene materials with other contaminants such as toxic metals, which may bring about more serious effects than graphene materials alone, have seldom been explored. Herein, the effects of graphene (GN) and graphene oxide (GO, an important oxidized derivative of graphene) on copper (Cu) toxicity to Daphnia magna were systematically investigated. The results indicated that GN remarkably increased the Cu accumulation in D. magna and enhanced the oxidative stress injury caused by Cu, whereas did not significantly alter D. magna acute mortality within the tested Cu concentrations (0-200 MUg L 1). On the contrary, GO significantly decreased the Cu accumulation in D. magna and alleviated the oxidative stress injury caused by Cu. Meanwhile, the presence of GO significantly reduced the mortality of D. magna when Cu concentration exceeded 50 MUg L-1. The different effects of GN and GO on Cu toxicity were possibly dependent on the action of surface oxygenic functional group. Because of the introduction of surface oxygenic functional groups, the adsorption ability to metal ions, stability in water and interaction mode with organisms of GO are quite different from that of GN, causing different effects on Cu toxicity. This study provides important information on the bioavailability and toxicity of heavy metals as affected by graphene materials in natural water. PMID- 29137889 TI - Modeling of the transport and deposition of polydispersed particles: Effects of hydrodynamics and spatiotemporal evolution of the deposition rate. AB - A time-distance-dependent deposition model is built to investigate the effects of hydrodynamic forces on the transport and deposition of polydispersed particles and the evolution of deposition rates with time and distance. Straining and the heterogeneity of the particle population are considered to play important roles in the decreasing distribution of deposition rates. Numerical simulations were applied in a series of sand column experiments at different fluid velocities for three different porous media. The effects of hydrodynamics forces are elaborated with the systematic variations of deposition dynamic parameters of the proposed model. With retention distributions with particle size as well as temporal and spatial evolutions of deposition rates, the transport and deposition mechanisms of polydispersed particles will be elucidated through the interplay of the variation of the particle size distribution of mobile particle populations and the geometrical change of the porous medium due to retention (straining and blocking). PMID- 29137890 TI - Exposure to the fungicide propamocarb causes gut microbiota dysbiosis and metabolic disorder in mice. AB - Propamocarb (PM) is a widely used fungicide with property of affecting fatty acid and phospholipid biosynthesis in funguses. In this study, we explored its effects on mice gut microbiota and metabolism by exposing mice to 3, 30, and 300 mg/L PM through drinking water for a duration of 28 days. We observed that the transcription of hepatic genes related to regulate lipid metabolism were perturbed by PM exposure. The microbiota in the cecal contents and feces changed during or after PM exposure at phylum or genus levels. 16S rRNA gene sequencing for the cecal content revealed shifted in overall microbial structure after PM exposure, and operational taxonomic unit (OTU) analysis indicated that 32.2% of OTUs changed by 300 mg/mL PM exposure for 28 days. In addition, based on 1H NMR analysis,a total of 20 fecal metabolites mainly including succinate, short chain fatty acids, bile acids and trimethylamine were found to be significantly influenced by exposure to 300 mg/L PM.,. These metabolites were tightly correlated to host metabolism. Our findings indicated that high doses of PM exposure could disturb mice metabolism through, or partly through, altering the gut microbiota and microbial metabolites. PMID- 29137891 TI - Human Leukocyte Antigen (HLA) and Gulf War Illness (GWI): HLA-DRB1*13:02 Spares Subcortical Atrophy in Gulf War Veterans. AB - BACKGROUND: Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-91 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. We reported previously on the protective role of six Human Leukocyte Antigen (HLA) alleles in GWI (Georgopoulos et al., 2016) and their association with regional brain function (James et al., 2016). More recently, we reported on the presence of subcortical brain atrophy in GWI (Christova et al., 2017) and discussed its possible relation to immune mechanisms. Here we focused on one of the six HLA GWI-protective HLA alleles, DRB1*13:02, which has been found to have a protective role in a broad range of autoimmune diseases (Furukawa et al., 2017), and tested its effects on brain volumes. METHODS: Seventy-six Gulf War veterans (55 with GWI and 21 healthy controls) underwent a structural Magnetic Resonance Imaging (sMRI) scan to measure the volumes of 9 subcortical brain regions to assess differences between participants with (N=11) and without (N=65) HLA class II allele DRB1*13:02. FINDINGS: We found that DRB1*13:02 spared subcortical brain atrophy in Gulf War veterans; overall subcortical volume was 6.6% higher in carriers of DRB1*13:02 (P=0.007). The strongest effect was observed in the volume of cerebellar gray matter which was 9.6% higher (P=0.007) in carriers of DRB1*13:02 than in non-carriers. By contrast, DRB1*13:01 had no effect. INTERPRETATION: These findings document the protective effect of DRB1*13:02 on brain atrophy in Gulf War veterans and are in keeping with recent results documenting sharing of brain mechanisms between GWI and other immune related diseases (Georgopoulos et al., 2017). We hypothesize that the protective role of DRB1*13:02 is due to its successful elimination of external antigens to which Gulf War veterans were exposed, antigens that otherwise would persist causing low-grade inflammation and possibly leading to autoimmunity. FUNDING SOURCE: U.S. Department of Defense (W81XWH-15-1-0520), Department of Veterans Affairs, American Legion Brain Sciences Chair, and University of Minnesota. PMID- 29137892 TI - Role of pyrophosphate in vascular calcification in chronic kidney disease. AB - Vascular calcification is a pathology characterized by the deposition of calcium phosphate in cardiovascular structures, mainly in the form of hydroxyapatite crystals, resulting in ectopic calcification. It is correlated with increased risk of cardiovascular disease and myocardial infarction in diabetic patients and in those with chronic kidney disease (CKD). Vascular smooth muscle cells are sensitive to changes in inorganic phosphate (Pi) levels. They are able to adapt and modify some of their functions and promote changes which trigger calcification. Pi is regulated by parathyroid hormone and 1,25-dihydroxyvitamin D. Changes in the transport of Pi are the primary factor responsible for the regulation of Pi homeostasis and the calcification process. Synthesis of calcification inhibitors is the main mechanism by which cells are able to prevent vascular calcification. Extracellular pyrophosphate (PPi) is a potent endogenous inhibitor of calcium-phosphate deposition both in vivo and in vitro. Patients with CKD show lower levels of PPi and increased activity of the enzyme alkaline phosphatase. Numerous enzymes implicated in the metabolism of PPi have been associated with vascular calcifications. PPi is synthesized from extracellular ATP by nucleotide pyrophosphatase/phosphodiesterase from extracellular ATP hydrolysis. PPi is hydrolyzed into Pi by tissue-nonspecific alkaline phosphatase. ATP can be hydrolyzed to Pi via the ectonucleoside triphosphate diphosphohydrolase family. All these enzymes must be in balance, thereby preventing calcifications. However, diseases like CKD or diabetes induce alterations in their levels. Administration of PPi could open up new treatment options for these patients. PMID- 29137893 TI - Advances in the evaluation of bone health in kidney transplant patients. AB - Bone disease related to chronic kidney disease and, particularly, to kidney transplant patients is a common cause or morbidity and mortality, especially due to a higher risk of osteoporotic fractures. Despite the fact that this has been known for decades, to date, an appropriate diagnostic strategy has yet to be established. Apart from bone biopsy, which is invasive and scarcely used, no other technique is available to accurately establish the risk of fracture in kidney patients. Techniques applied to the general population, such as bone densitometry, have not been subjected to sufficient external validation and their use is not systematic. This means that the identification of patients at risk of fracture and therefore those who are candidates for preventive strategies is an unmet need. Bone strength, defined as the ability of the bone to resist fracture, is determined by bone mineral density (measured by bone densitometry), trabecular architecture and bone tissue quality. The trabecular bone score estimates bone microarchitecture, and low values have been described as an independent predictor of increased fracture risk. Bone microindentation is a minimally invasive technique that measures resistance of the bone to micro-cracks (microscopic separation of mineralised collagen fibres), and therefore bone tissue biomechanical properties. The superiority over bone densitometry of the correlation between the parameters measured by trabecular bone score and microindentation with the risk of fracture in diverse populations led us to test its feasibility in chronic kidney disease and kidney transplant patients. PMID- 29137894 TI - Beyond the traditional lipid parameters in chronic kidney disease. PMID- 29137895 TI - A Four-kallikrein Panel and beta-Microseminoprotein in Predicting High-grade Prostate Cancer on Biopsy: An Independent Replication from the Finnish Section of the European Randomized Study of Screening for Prostate Cancer. AB - BACKGROUND: A panel of four kallikrein markers (total, free, and intact prostate specific antigen [PSA] and human kallikrein-related peptidase 2 [hK2]) improves predictive accuracy for Gleason score >=7 (high-grade) prostate cancer among men biopsied for elevated PSA. A four-kallikrein panel model was originally developed and validated by the Dutch center of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The kallikrein panel is now commercially available as 4KscoreTM. OBJECTIVE: To assess whether these findings could be replicated among participants in the Finnish section of ERSPC (FinRSPC) and whether beta microseminoprotein (MSP), a candidate prostate cancer biomarker, adds predictive value. DESIGN, SETTING, AND PARTICIPANTS: Among 4861 biopsied screening-positive participants in the first three screening rounds of FinRSPC, a case-control subset was selected that included 1632 biopsy-positive cases matched by age at biopsy to biopsy-negative controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The predictive accuracy of prespecified prediction models was compared with biopsy outcomes. RESULTS AND LIMITATIONS: Among men with PSA of 4.0-25ng/ml, 1111 had prostate cancer, 318 of whom had high-grade disease. Total PSA and age predicted high-grade cancer with an area under the curve of 0.648 (95% confidence interval [CI] 0.614-0.681) and the four-kallikrein panel increased discrimination to 0.746 (95% CI 0.717-0.774). Adding MSP to the four-kallikrein panel led to a significant (Wald test; p=0.015) but small increase (0.003) in discrimination. Limitations include a risk of verification bias among men with PSA of 3.0 3.99ng/ml and the absence of digital rectal examination results. CONCLUSIONS: These findings provide additional evidence that kallikrein markers can be used to inform biopsy decision-making. Further studies are needed to define the role of MSP. PATIENT SUMMARY: Four kallikrein markers and beta-microseminoprotein in blood improve discrimination of high-grade prostate cancer at biopsy in men with elevated prostate-specific antigen. PMID- 29137896 TI - Higher triglyceride level predicts hyperuricemia: A prospective study of 6-year follow-up. AB - BACKGROUND: Despite abundant evidence indicating that higher triglyceride (TG) levels are associated with increased risks of hyperuricemia (HUA), it is unclear whether TG levels can independently predict the incidence of HUA. OBJECTIVE: The aim of the study was to investigate whether TG is an independent risk factor of HUA in a cohort study. METHODS: We explored the relationship between TG levels and HUA in a dynamic cohort established in 2009. During the 6 years of follow-up, 5442 subjects without HUA were studied. We divided subjects into 4 groups based on baseline TG levels and used the Cox hazard regression model to estimate HUA risk by TG quartile, after adjustment for potential confounding factors. Kaplan Meier survival analysis compared the risk of HUA incidence among individuals in each TG quartile. RESULTS: The incidence of HUA in this cohort was 25.9%. The hazard ratios (95% confidence intervals) for HUA in the second, third, and fourth TG quartiles, compared with the first quartile, were 1.19 (1.01-1.40), 1.33 (1.13 1.57), and 1.62 (1.37-1.92), respectively. The Kaplan-Meier survival analysis suggested that higher TG levels predicted higher incidences of HUA in a dose dependent relationship. Stratification analyses showed that the association between TG levels and the presence of HUA was more pronounced in individuals aged <50 years, of obese, with normal estimated glomerular filtration rate, and with hypertension. CONCLUSION: Our findings suggest that TG level is a significant and independent risk factor for HUA. PMID- 29137897 TI - Elevated serum levels of endothelin-1 in patients with chronic inflammatory demyelinating polyneuropathy. AB - INTRODUCTION: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, or non-hereditary, chronic demyelinating neuropathy. Currently, there is no reliable molecular biomarker that can identify CIDP patients as well as monitor disease severity. MATERIAL AND METHODS: We measured serum levels of endothelin-1 (ET-1), a factors involved in vasoconstrictive, inflammatory and nerve regenerative processes, in 20 CIDP, 21 acute inflammatory demyelinating polyneuropathy (AIDP), 37 multiple sclerosis (MS), and 10 Alzheimer's disease (AD) patients, as well as 26 healthy control (HC) subjects. RESULTS: Patients with CIDP demonstrated higher serum levels of ET-1 (2.07+/-1.07pg/mL) than those with AIDP (0.75+/-0.62ng/mL, P<0.001), AD (0.78+/-0.49pg/mL, P<0.001), as well as HCs (1.16+/-0.63pg/mL, P=0.002), while levels of ET-1 in patients with MS (2.10+/ 0.81pg/mL) and CIDP were similar. Furthermore, the serum ET-1 levels significantly correlated with Inflammatory Neuropathy Cause And Treatment (INCAT) disability scale in CIDP patients. Receiver operating characteristic (ROC) curve showed good discrimination ability for ET-1 to distinguish CIDP patients from AIDP (AUC=0.883) or HCs (AUC=0.763). CONCLUSION: This study discloses the potential of serum ET-1 as a biomarker for CIDP. PMID- 29137898 TI - Antiseptics Commonly Used in Total Joint Arthroplasty Interact and May Form Toxic Products. AB - BACKGROUND: Multiple antiseptics have been described for use in total joint arthroplasty infection, and the use of multiple antiseptic solutions during a single operation has been described. Our clinical experience is that chlorhexidine (CHX) and Dakin's solution (NaOCl) interact and form a precipitate. The purpose of this study is to determine whether this reaction could be replicated in a laboratory setting, and to determine if other commonly used antiseptics also visibly react when mixed. METHODS: Four percent chlorhexidine gluconate (CHX), 0.5% sodium hypochlorite (NaOCl), 3% hydrogen peroxide (H2O2), and 10% povidone-iodine (BTD) solutions were obtained and all possible combinations were mixed. Any visible reactions were noted and recorded, and a literature search was performed to characterize the reaction and products. RESULTS: CHX and NaOCl, CHX and H2O2, and CHX and BTD reacted instantly, forming a precipitate. NaOCl and H2O2 reacted to produce a gas. NaOCl and BTD reacted and produced a color change. The literature review revealed that at least 2 of the reactions tested (CHX + NaOCl and NaOCl + H2O2) could result in byproducts toxic to humans. CONCLUSION: Surgeons must be aware of these interactions when using antiseptic solutions during procedures. Caution should be used combining or mixing antiseptics, and we recommend against concomitant introduction in a surgical wound. PMID- 29137899 TI - Joint Gap in Mid-Flexion Is Not a Predictor of Postoperative Flexion Angle After Total Knee Arthroplasty. AB - BACKGROUND: Postoperative knee flexion angle is one of the most important outcomes of total knee arthroplasty (TKA). Intraoperative ligament balancing may affect the postoperative range of motion of the knee. However, the relationship between intraoperative ligament balancing and postoperative flexion angle was still controversial. The purpose of this study was to determine whether intraoperative joint gap affects postoperative knee flexion angle or not. METHODS: Prospective multicenter study of 246 knees with varus osteoarthritis undergoing a posterior-stabilized, mobile-bearing TKA was performed. The joint gap before implantation and after implantation was measured. The joint gap after implantation was measured using a specially designed tensor device with the same shape of a total knee prosthesis at 0 degrees , 30 degrees , 60 degrees , 90 degrees , 120 degrees , and 145 degrees of flexion with the reduction of the patellofemoral joint. Stepwise multiple regression analysis was conducted to determine the predictors of the flexion angle of the knee after the operation. RESULTS: Predictors were identified in the following 3 categories: (1) preoperative flexion angle, (2) intraoperative flexion angle, and (3) joint gap looseness at 120 degrees of flexion (joint gap after implantation at 120 degrees of flexion - joint gap after implantation at 0 degrees of flexion) (R = 0.472, P < .01). CONCLUSION: Flexion angle after TKA was not affected by the flexion joint gap looseness before implantation and the joint gap looseness after implantation from 30 degrees to 90 degrees of flexion. Surgeons should notice that joint gap looseness in mid-flexion range did not increase the postoperative knee flexion angle. PMID- 29137900 TI - The Posterior Capsular Ligamentous Complex Contributes to Hip Joint Stability in Distraction. AB - BACKGROUND: Laxity of soft tissues after total hip arthroplasty is considered to be a cause of accelerated wear of bearing surfaces and dislocation. The purpose of this study is to assess the contribution of the anterior and posterior capsular ligamentous complexes and the short external rotators, except the quadratus femoris, on the stability of the hip against axial traction. METHODS: The study subjects comprised 7 fresh cadavers with 12 normal hip joints. In 6 hips, soft tissues surrounding the hip joint were resected in the following order to simulate the anterior approach: anterior capsule, posterior capsule, piriformis, conjoined tendon, and external obturator. In the remaining 6 hips, soft tissues were resected in the following order to simulate the posterior approach: piriformis, conjoined tendon, external obturator, posterior capsule, and anterior capsule. Soft tissue tension was measured by applying traction amounting to 250 N with joints in the neutral position. RESULTS: The separation distance between the femoral head and acetabulum during axial leg traction significantly increased from 4.0 to 14.5 mm on average after circumferential resection of the capsule via the anterior approach. Subsequent resection of the short external rotators increased the separation distance up to 19.0 mm, but the differences did not reach statistical significance. Resection of the short external rotators via the posterior approach did not significantly increase the separation distance; it significantly increased from 6.0 to 11.4 mm after the resection of the anterior capsule and further to 20.5 mm after the resection of the posterior capsule. CONCLUSION: The posterior capsule, in addition to the anterior capsule, significantly contributes to hip joint stability in distraction regardless of whether the short external rotators, except the quadratus femoris, were preserved or resected. PMID- 29137901 TI - Impact of Femoral Stem Design on Failure After Anterior Approach Total Hip Arthroplasty. AB - BACKGROUND: An increased rate of complications related to femoral component failure has been described with less invasive total hip arthroplasty (THA). This study evaluated the incidence of femoral complications associated with the direct anterior approach for THA. METHODS: Retrospective review was performed of the initial 1120 consecutive patients who underwent direct anterior THA by 2 surgeons. RESULTS: A total of 899 patients (80.3%) had a 2-year follow-up (range, 2-8 years). Complications within 90 days occurred in 20 patients (1.8%): 10 calcar fractures, 1 greater trochanter fracture, 1 canal perforation, 3 hematomas, 2 dislocations, 2 superficial, and 1 deep infection. Nine patients (1%) underwent revision: 5 for aseptic femoral loosening (0.55%), 1 for periprosthetic joint infection, 1 for dislocation, 1 for hip flexor irritation, and 1 for a damaged polyethylene liner. Of the 5 patients with aseptic femoral loosening, 3 had a short, mediolateral tapered stem, 1 cemented stem, and 1 S-ROM stem placed to bypass a canal perforation. There were no revisions for aseptic loosening in the collared, fully hydroxyapatite (HA)-coated compaction broached or triple tapered proximal fit and fill stem designs (70.6% of all stems). Revision rate for femoral loosening was significantly higher for tapered wedge over HA-coated, compaction broached stems (P < .005). CONCLUSION: Pain and function improved predictably with a 0.55% rate of femoral loosening at 2-year follow-up. Among collared, fully HA-coated and triple taper fit and fill femoral stems, there were no instances of revision for aseptic loosening vs 3 in the short stem, collarless mediolateral tapered group. PMID- 29137902 TI - Effects of opioid medications on cognitive skills among Emergency Department patients. AB - INTRODUCTION: Treatment for pain and related conditions has been identified as the most common reason for Emergency Department (ED) visits. Concerns exist regarding the effects of opioid pain medications on cognition and patient ability to consent for procedures, hospital admission, or to refuse recommended medical interventions. This study was undertaken to identify cognitive skills before and after opioid pain medication in the ED setting. METHODS: This was a prospective study comparing performance on the Mini-Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA) before and after administration of opioid pain medications. Eligible participants included ED patients with pain, who received opioid treatment. Participants were randomized to receive either the MMSE before pain medication and the MoCA after medication, or the reverse. MoCA scores were converted to MMSE equivalent scores for comparison. RESULTS: Among 65 participants, the median age was 36 and median triage pain score was 8. 35% of patients were considered cognitively impaired based on their MMSE score prior to any opioid medication (MMSE<27). There was a median decrease in pain scores of 1 point following pain medication, p-value<0.001. There was a median decrease in MMSE scores of 1 point following pain medication, p-value=0.003. The range of change in scores (post minus pre) on the MMSE-equivalent was -7 to 3. 35 patients (56%) had a decrease in scores, 6 (10%) had no change, and 21 (34%) had an increase. After medication, 31 (48%) were abnormal (MMSE score<27). No differences in MMSE scores were identified by gender, ethnicity, mode of arrival, insurance, age, triage pain scores, opioid agent given, or ED diagnosis. CONCLUSIONS: There is an association between opioid pain medication and decrease in cognitive performance on the MMSE. Because of the wide range of cognitive performance following opioid pain medication, assessment of individual patients' cognitive function is indicated. PMID- 29137903 TI - Implementation of Alere i Influenza A & B point of care test for the diagnosis of influenza in an ED. AB - STUDY OBJECTIVE: This study aimed to evaluate the impact of implementing rapid point-of-care testing (POCT) with the Alere i Influenza A & B in an emergency department (ED) during an influenza epidemic. METHODS: Direct nasal swabs were prospectively collected following the physical examination of patients aged >18years who presented to the ED of a tertiary hospital in France with influenza like illness (ILI) symptoms (N=301) between February 1st and March 31st, 2016, which coincided with an influenza epidemic. Laboratory-based testing (standard of care) was used to obtain a diagnosis in February 2016 (pre-POCT cohort) and positive results were confirmed using polymerase chain reaction. The primary endpoint was patient time in the ED. RESULTS: A total of 169 and 132 patients participated in the pre-POCT phase and POCT phase respectively. A significantly higher proportion of patients received a positive diagnosis in the POCT cohort compared with the pre-POCT cohort (31% versus 5.3%, P<0.01). Mean time spent in the ED and hospitalization rate were significantly lower in the POCT cohort (6.06h versus 4.15h, P=0.03, and 44.4% versus 9.7%, P=0.02, respectively). Despite similar rates in the prescription of antibiotics and antiviral therapies, the proportion of patients who were referred for additional tests was significantly lower in the POCT cohort (78.1% versus 62.1%, P=0.003, and 80.5% versus 63.6%, P=0.01, respectively). CONCLUSIONS: The Alere i Influenza A & B POCT reduced the length of stay in ED, the hospitalization rates, and the number of additional diagnostic tests compared with standard of care testing. PMID- 29137905 TI - ED chest radiography for children with asthma exacerbation is infrequently associated with change of management. AB - BACKGROUND: Acute asthma exacerbations (AAE) account for many Pediatric Emergency Department (PED) visits. Chest radiography (CXR) is often performed in these patients to identify practice-changing findings such as pneumonia (PNA). Limited knowledge exists to balance the cost and radiation dose of CXR with expected yield of clinically meaningful information. OBJECTIVE: To determine in children with AAE with CXR, whether patient characteristics are associated with radiographic PNA; and significant practice change by initiation of antibiotic. DESIGN/METHODS: Retrospective chart review of AAE patients with CXR performed in a PED in 2014. We examined univariate associations between patient characteristics and PNA on CXR and administration of antibiotic. Multiple logistic regression models then subsequently examined adjusted associations between patient characteristics and both outcomes. RESULTS: Of 288 patients, 43 (15%) had PNA on CXR and 51 (17.8%) received antibiotics. There were no statistically significant univariate associations between either outcome and age, race, gender, insurance status, mode of PED arrival, fever or hypoxia (all p>0.11). Crackles were associated with antibiotic administration (p=0.03), but not PNA on CXR (p=0.07). Only previous antibiotic use within 7days had both significant univariate associations (p=0.002) and adjusted associations with both PNA on CXR (aOR 3.6) and antibiotic administration (aOR 3.3). CONCLUSION: CXR infrequently adds valuable information in children with AAE. Patients treated with antibiotic within 7days are more likely to have PNA identified on CXR and receive antibiotics. A larger study is needed to examine potential significance of hypoxia and crackles. PMID- 29137904 TI - Implications of iodinated contrast media extravasation in the emergency department. AB - PURPOSE: To characterize the management, outcomes, and emergency department (ED) length of stay (LOS) following iodinated contrast media extravasation events in the ED. METHODS: All ED patients who developed iodinated contrast media extravasation following contrast-enhanced CT (CECT) from October 2007-December 2016 were retrospectively identified. Medical records were reviewed and management, complications, frequency of surgical consultation, and ED LOS were quantified using descriptive statistics. The Wilcoxon rank sum test was used to compare ED LOS in patients who did and did not receive surgical consultation. RESULTS: A total of 199 contrast extravasation episodes occurred in ED patients during the 9-year study period. Of these, 42 patients underwent surgical consultation to evaluate the contrast extravasation event. No patient developed progressive symptoms, compartment syndrome, or tissue necrosis, and none received treatment beyond supportive care (warm/cold packs, elevation, compression). Median ED LOS for patients who did and did not receive surgical consultation was 11.3h versus 9.0h, respectively (p<0.01). CONCLUSION: Close observation and supportive care are sufficient for contrast extravasation events in the ED without concerning symptoms (progressive pain/swelling, altered tissue perfusion, sensory changes, or blistering/ulceration). Routine surgical consultation is likely unnecessary in the absence of these symptoms - concordant with the current American College of Radiology guidelines - and may be associated with longer ED LOS without impacting management. PMID- 29137906 TI - Can different physicians providing urgent and non-urgent treatment improve patient flow in emergency department? AB - BACKGROUND: Emergency Department (ED) overcrowding is a worldwide problem, and it might be caused by prolonged patient stay in the ED. This study tried to analyze if different practice models influence patient flow in the ED. MATERIALS AND METHODS: A retrospective, 1-year cohort study was conducted across two EDs in the largest healthcare system in Taiwan. A total of 37,580 adult non-trauma patients were involved in the study. The clinical practice between two ED practice models was compared. In one model, urgent and non-urgent patients were treated by different emergency physicians (EPs) separately (separated model). In the other, EPs treated all patients assigned randomly (merged model). The ED length of stay (LOS), diagnostic tool use (including laboratory examinations and computed tomography scans), and patient dispositions (including discharge, general ward admission, intensive care unit (ICU) admissions, and ED mortality) were selected as outcome indicators. RESULT: Patients discharged from ED had 0.4h shorter ED LOS in the separated model than in merged model. After adjusting for the potential confounding factors through regression model, there was no difference of patient disposition of the two practice models. However, the separated model showed a slight decrease in laboratory examination use (adjusted odds ratio, 0.9; 95% confidence interval, 0.83-0.96) compared with the merged model. CONCLUSION: The separated model had better patient flow than the merged model did. It decreased the ED LOS in ED discharge patients and laboratory examination use. PMID- 29137907 TI - Primary aortoesophageal fistula: A fatal outcome. AB - Aortoesophageal fistula is a rare but life-threatening cause of massive gastrointestinal bleeding. We reported a case of primary aortoesophageal fistula associated with thoracic aortic pseudoaneurysm. Esophagogastroduodenoscopy demonstrated a bulging erosive lesion coated with fibrin. The patient was therefore diagnosed as malignant esophageal mesenchymoma initially. An emergency contrast-enhanced computed tomography revealed an out-pouching saccular aneurysm protruding toward the esophagus at the level of T8-9. The patient expired rapidly due to intractable massive bleeding. Assumptive diagnosis of esophageal malignancy leads to a loss of the most optimal time-point for operation thus negatively affecting the patient survival. PMID- 29137908 TI - No evidence found for an association between prednisone dose and FVC change in newly-treated pulmonary sarcoidosis. AB - BACKGROUND: Prednisone is used as first-line therapy for pulmonary sarcoidosis. What dosing strategy has the best balance between effect and side-effects is largely unknown. We analyzed change in forced vital capacity (FVC) and weight during different prednisone doses used in daily practice for treatment naive pulmonary sarcoidosis patients. METHODS: Multilevel models were used to describe FVC and weight change over time. Correlations were calculated using linear regression models. RESULTS: Fifty-four patients were included. FVC changed over time (p < 0.001), with an average increase of 9.6% predicted (95% CI: 7.2 to 12.1) at 12 months. Weight changed significantly over time (p < 0.001), with an average increase of 4.3 kg (95% CI: 3.0 to 5.6) at 12 months. Although FVC and weight changed significantly over time, there was little correlation between prednisone dose and FVC change, while weight increase correlated significantly with cumulative prednisone dose at 24 months. In patients treated with a high cumulative prednisone dose, baseline FVC was on average lower (p = 0.001) compared to low dose treated patients, while no significant differences were observed in need for second/third-line therapy or number of exacerbations. A strategy leading to a low cumulative dose at 12 months was defined by rapid dose tapering to 10 mg/day within 3.5 months. CONCLUSIONS: These results suggest that prednisone therapy aimed at improving or preserving FVC in newly- treated pulmonary sarcoidosis can often be reduced in dose, using a treatment regimen that is characterized by early dose tapering. PMID- 29137909 TI - Use of Expired Air Carbon Monoxide Testing in Clinical Tobacco Treatment Settings. AB - Carbon monoxide (CO) testing is considered an easy, noninvasive, and objective contribution to the assessment of smoking behavior, as CO is rapidly absorbed into the bloodstream when lit cigarettes or cigars are inhaled. CO testing is a medically important billable outpatient service that can contribute to sustainability of face to face tobacco use treatment services by clinicians. This article reviews research on the clinical use of CO testing to provide biomedical feedback in assessing smoking behavior, educating smokers on tobacco health effects, assisting with treatment planning, and as a motivational tool to encourage people to become tobacco free. Further research can focus on how to best incorporate CO testing into clinical practice, including more research on outcomes and methods to ensure that insurers reimburse for testing and improved ways to use CO testing to initiate attempts to quit tobacco use, to maintain cessation, and to prevent relapse. PMID- 29137910 TI - Tamponade: Hemodynamic and Echocardiographic Diagnosis. AB - Cardiac tamponade is a medical emergency that can be readily reversed with timely recognition and appropriate intervention. The clinical diagnosis of cardiac tamponade requires synthesis of a constellation of otherwise nonspecific features based on an understanding of the underlying pathophysiological characteristics. Although echocardiographic examination is a central component of diagnosis, alone it is insufficient to establish the physiological diagnosis of hemodynamically significant cardiac tamponade. The hemodynamic diagnosis of cardiac tamponade requires clinical evidence of low cardiac output and stroke volume in the setting of elevated cardiac filling pressures, with evidence of increased sympathetic tone (eg, tachycardia, peripheral vasoconstriction), and exclusion of other causes of shock as the primary problem (particularly cardiogenic shock). The hemodynamic features of tamponade are revealed by considering the effects of pericardial constraint. Pulsus paradoxus and loss of the normal "y" descent of a jugular venous pressure waveform may be appreciated on clinical examination. When a pulmonary artery catheter is placed, equalization of diastolic pressures across all chambers is observed. Echocardiographic examination confirms the size, location, and other characteristics of the causal pericardial collection. Several echocardiographic features support the hemodynamic diagnosis of tamponade, including early diastolic collapse of the right ventricle, late diastolic collapse of the right atrium, respiratory variation in mitral valve inflow (akin to pulsus paradoxus), and decreased early filling (E wave) of mitral valve inflow (related to loss of the y descent). Echocardiographic examination then supports decisions about the early treatment and drainage of the tamponading effusion. PMID- 29137911 TI - Effect of supplementing a diet with monensin sodium and Saccharomyces Cerevisiae on reproductive performance of Ghezel ewes. AB - Effect of supplementing a diet, in an attempt to enhance reproduction, with monensin sodium and Saccharomyces cerevisiae yeast on reproductive performance was investigated during the breeding season using 44 Ghezel ewes (body weight 56.97+/-7.47kg, age 2-5 years and body condition score (BCS) 2.5) which were allocated randomly in equal numbers to the four dietary treatments as follows: 1) Basal diet plus supplemental feed (450g/ewe/d) plus monensin sodium (30mg/ewe/d) (MS); 2) Basal diet plus supplemental feed (450 g/ewe/d) plus Saccharomyces cerevisiae yeast (4*109CFU/ewe/d) (SC); 3) Basal diet plus supplemental feed (450g/ewe/d) (FG); 4) Basal diet (only grazing on pasture, Control; G). Estrous synchronization of all ewes was done using controlled internal drug release (CIDR) and all ewes were mated with purebred Ghezel rams after CIDR removal. The results indicated that MS and SC treatments with 15 lambs had greater number of lambs than ewes of the other two treatment groups. Ewes in MS group with 50% twining rate had the greatest value followed by the FG, SC and G treatment groups (P<0.05). The lambs from ewes in MS and SC groups were heavier in weight than those in FG and G treatments (P<0.01). Blood sample analysis provided evidence that ewes in MS and SC groups had greater concentrations of 17beta-estradiol (E2), progesterone (P4), blood urea nitrogen (P<0.05), insulin, glucose, cholesterol and total protein (P<0.01) than ewes of the other groups. These results indicated that using a diet for enhancing reproduction, including monensin sodium and Saccharomyces cerevisiae yeast in the breeding season could have beneficial effects on reproductive performance of Ghezel ewes. PMID- 29137912 TI - Nonalcoholic fatty liver disease increases risk of incident chronic kidney disease: A systematic review and meta-analysis. AB - BACKGROUND: Recent studies examined the prognostic impact of nonalcoholic fatty liver disease (NAFLD) on the risk of incident chronic kidney disease (CKD). However, the extent to which NAFLD may confer risk of incident CKD is uncertain. We performed a meta-analysis of relevant studies to quantify the magnitude of the association between NAFLD and risk of incident CKD. METHODS: We searched PubMed, Scopus and Web of Science from January 1, 2000 to August 31, 2017 using pre defined keywords to identify large observational cohort studies with a follow-up duration of at least 1year, in which NAFLD was diagnosed by biochemistry, fatty liver index or ultrasonography. No studies with biopsy-proven NAFLD were available for the analysis. Data from selected studies were extracted, and meta analysis was performed using random-effects modeling. RESULTS: A total of 9 observational studies with 96,595 adult individuals (34.1% with NAFLD) of predominantly Asian descent, and 4653 cases of incident CKD stage >=3 (i.e., defined as occurrence of estimated glomerular filtration rate<60ml/min/1.73m2, with or without accompanying overt proteinuria) over a median period of 5.2years were included in the final analysis. Patients with NAFLD had a significantly higher risk of incident CKD than those without NAFLD (random-effects hazard ratio [HR] 1.37, 95% CI 1.20-1.53; I2=33.5%). Patients with more 'severe' NAFLD (according to ultrasonography and non-invasive fibrosis markers) were also more likely to develop incident CKD (n=2 studies; random-effects HR 1.50, 95% CI 1.25 1.74; I2=0%); this risk appeared to be even greater among those with ultrasound diagnosed NAFLD and a high-intermediate NAFLD fibrosis score (n=1 study; random effects HR 1.59, 95% CI 1.31-1.93). Sensitivity analyses did not alter these findings. Funnel plot and Egger's test did not reveal significant publication bias. CONCLUSIONS: This largest and most updated meta-analysis to date shows that NAFLD (detected by biochemistry, fatty liver index or ultrasonography) is associated with a nearly 40% increase in the long-term risk of incident CKD. However, the observational nature of the eligible studies does not allow for proving causality. Our findings pave the way for future large, prospective, histologically-based studies. PMID- 29137913 TI - Neutrophil CD16b crosslinking induces lipid raft-mediated activation of SHP-2 and affects cytokine expression and retarded neutrophil apoptosis. AB - Two different types of FcRs for IgG are constitutively expressed on the surface of human neutrophils, namely, FcgammaRIIA (CD32a) and FcgammaRIIIB (CD16b). Unlike FcgammaRIIA, FcgammaRIIIb is GPI anchored to the cell membrane and its signal transduction is still ambiguous. To further understand the signal transduction of CD16b, we compared neutrophil cytokine expression and apoptosis by the cross-linking of CD32a and CD16b respectively. We found that both CD32a and CD16b crosslinking can activate neutrophils, but did not exactly share cytokine expression profiles. On the other hand, CD16b cross-linking retarded neutrophil apoptosis while CD32a promoted it. By interrupting the lipid raft with methyl-beta-cyclodextrin (MbetaCD) and inhibiting the ITAM-SYK pathway with an SYK inhibitor (piceatannol), we found reduced apoptosis was at least partially mediated by lipid raft structure, but not the ITAM-SYK pathway. Additionally, CD16b but not CD32a cross-linking triggered SHP-2 phosphorylation and led to its translocation into lipid rafts. SHP-2 phosphorylation and translocation were inhibited by MbetaCD. Moreover, pre-inhibition of SHP-2 by a specific inhibitor (SHP099) converted IL-10 and SOCS3 expression level and promoted neutrophil apoptosis after CD16b crosslinking. In conclusion, these results, for the first time, collectively indicate that SHP-2 is activated by CD16b crosslinking in neutrophils and functions as a component of the raft-mediated signaling pathway. PMID- 29137915 TI - First line direct access for transarterial embolization of a dural arteriovenous fistula: Case report and literature review. AB - Intracranial dural arteriovenous fistulae (DAVF) are complex vascular malformations consisting of a pathological shunt located between meningeal arteries and drainage to dural venous sinuses and/or cerebral veins. We report an unusual anatomical variation, resulting in a DAVF forming between the superior sagittal sinus and an anomalous origin of the middle meningeal artery (MMA) arising from the left ophthalmic artery. We present an atypical case requiring mini-craniotomy for catheter access, as well as cannulation of extracranial arterial supply prior to embolization of a Cognard type IIa+b fistula. Due to structural variation, transarterial endovascular embolization was deemed too high risk owing to risk of permanent blindness. We present a technical note and literature review on the first documented case of combined endovascular and surgical intervention as first line treatment for embolization of an anomalous middle meningeal artery related fistula. Our approach provided adequate obliteration of the DAVF and may be an alternative way to treat DAVF, when traditional transarterial or transvenous approaches are deemed high risk for neurological deficit. PMID- 29137914 TI - Orthogonal potency analysis of mesenchymal stromal cell function during ex vivo expansion. AB - Adult bone marrow mesenchymal stromal cells (MSCs) have cross-functional, intrinsic potency that is of therapeutic interest. Their ability to regenerate bone, fat, and cartilage, modulate the immune system, and nurture the growth and function of other bone marrow hematopoietic stem/progenitor cells have all been evaluated by transplant applications of MSCs. These applications require the isolation and expansion scaled cell production. To investigate biophysical properties of MSCs that can be feasibly utilized as predictors of bioactivity during biomanufacturing, we used a low-density seeding model to drive MSCs into proliferative stress and exhibit the hallmark characteristics of in vitro aging. A low-density seeding method was used to generate MSCs from passages 1-7 to simulate serial expansion of these cells to maximize yield from a single donor. MSCs were subjected to three bioactivity assays in parallel to ascertain whether patterns in MSC age, size, and shape were associated with the outcomes of the potency assays. MSC age was found to be a predictor of adipogenesis, while cell and nuclear shape was strongly associated to hematopoietic-supportive potency. Together, these data evaluate morphological changes associated with cell potency and highlight new strategies for purification or alternatives to assessing MSC quality. PMID- 29137916 TI - Analysis on the risk factors of medication-overuse headache in Chinese patients. AB - OBJECTIVE: The purpose of this study was to analyze the risk factors of medication-overuse headache in patients with chronic migraine in China. MATERIALS AND METHODS: 157 patients who were diagnosed as chronic migraine were chosen from headache outpatients of Shandong Provincial Hospital affiliated to Shandong University. Based on a standardized questionnaire, a database was developed and analyzed with 45 indexes. RESULTS: The independent risk factors of medication overuse headache identified in this study included the frequency of medicine overuse (OR = 9.575, 95%CI, 3.573-35.659), Allodynia Symptom Checklist scores (OR = 5.846, 95%CI, 2.065-22.856), anxiety disorder (OR = 2.902, 95%CI, 1.601-7.476) and lack or non- standardized preventive treatment (OR = 1.173, 95%CI, 1.073 3.826). CONCLUSIONS: The frequency of medicine overuse, Allodynia Symptom Checklist scores, anxiety disorder and lack or non-standardized preventive therapy were the independent risk factors for medication-overuse headache in patients with chronic migraine. PMID- 29137917 TI - Radiation exposure with hybrid image-guidance-based minimally invasive transforaminal lumbar interbody fusion. AB - The transforaminal lumbar interbody fusion (TLIF) is used for the treatment of back and leg pain secondary to spinal stenosis, degenerative disc disease, and spondylolisthesis. Minimally invasive surgery (MIS) is associated with less estimated blood loss (EBL), decreased length of stay, lower infection rates, and similar outcomes compared to the traditional TLIF. Fluoroscopy time has been reported with MIS-TLIF, but there are limited data on specific radiation dosages. We performed a retrospective analysis of a prospectively acquired cohort of patients undergoing MIS-TLIF. A total of 50 patients were included. Mean age was 53 years with 60% women and mean BMI of 30 (range 21-41). Diagnoses were as follows: 45 stenosis (90%), 29 spondylolisthesis (58%), 5 facet cysts (10%), 3 scoliosis (6%), and 1 cauda equina syndrome (2%). A single level was fused in 33 cases (66%), two levels in 15 (30%), three levels in 2 (4%). Average cage height was 10 mm with mean EBL of 80 ml and operative time of 240 min. The average radiation doses from intraoperative CT scan and fluoroscopy were 35.3 and 26.5 mGy, respectively. Average CT scan and fluoroscopy times were 5.2 and 37.1 s, respectively, for a total of 42.2 s. Average length of stay was 3 days (range 1-7 days). Although these data represent a preliminary experience, by streamlining the timing of intraoperative CT scan and minimizing the amount of intraoperative fluoroscopy, this protocol has the potential for decreasing operative time and radiation exposure. PMID- 29137918 TI - Spinobulbar muscular atrophy combined with atypical hereditary neuropathy with liability to pressure palsy. AB - Spinobulbar muscular atrophy (SBMA) is an X-linked recessive disease, presenting motor weakness and wasting of facial, bulbar and limb muscles. Hereditary neuropathy with liability to pressure palsy (HNPP) is autosomal dominant disorder characterized by recurrent neuropathies at common entrapment sites. We report a case of co-existence of SBMA and atypical HNPP with genetic confirmation of CAG expansion in the androgen receptor (AR) gene and deletion of the peripheral myelin protein 22 (PMP22) gene. A 62-year-old man presented with progressive muscle weakness, fasciculations in upper and lower limbs and dysesthesia predominantly in the distal regions. No family members, including his children, experienced similar symptoms. The electrodiagnostic examination was compatible with demyelinating sensorimotor polyneuropathy. Simultaneous hereditary polyneuropathy and motor neuron disease were suspected and relevant genetic testing was confirmed HNPP and SBMA. This case presented with 2 rare genetic neuromuscular disorders and the atypical HNPP phenotype. This case highlight the importance of detailed patient histories, as well as neurological and electrophysiological examinations for diagnosis of atypical and combination of rare genetic disorders. PMID- 29137919 TI - Neurenteric cyst at the dorsal craniocervical junction in a child: Case report. AB - Neurenteric cysts, also known as enterogenous cysts, are uncommon, benign, congenital lesions that usually occur in the posterior mediastinum but can be seen at any level of the neuraxis. Here, we report a pediatric patient with a neurenteric cyst in the dorsal craniocervical junction as the only third reported pediatric case in the literature in this rare location, and describe the clinical course and pathologic findings with a review of the literature on this rare entity. PMID- 29137920 TI - Serum anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder presenting as acute eosinophilic encephalomyelitis. AB - We report the case of a 57-year-old man with neuromyelitis optica spectrum disorder (NMOSD) presenting as acute eosinophilic encephalomyelitis. Magnetic resonance imaging revealed central nervous system lesions typical of NMOSD and anti-aquaporin-4 antibodies in the serum were identified; however, eosinophilia was evident in the cerebrospinal fluid (CSF) at the early stage of the disease. The number of eosinophils in the CSF decreased subsequently. Although activation of eosinophils is known to be an important factor in the development of NMOSD lesions, prominent eosinophilia in the CSF at the early stage of the disease has never been reported in patients with NMOSD. PMID- 29137921 TI - Intraoperative definition of bottom-of-sulcus dysplasia using intraoperative ultrasound and single depth electrode recording - A technical note. AB - Bottom of sulcus dysplasias (BOSDs) are localized focal cortical dysplasias (FCDs) centred on the bottom of a sulcus that can be highly epileptogenic, but difficult to delineate intraoperatively. We report on a patient with refractory epilepsy due to a BOSD, successfully resected with the aid of a multimodal surgical approach using neuronavigation based on MRI and PET, intraoperative ultrasound (iUS) and electrocorticography (ECoG) using depth electrodes. The lesion could be visualized on iUS showing an increase in echogenicity at the grey white matter junction. IUS demonstrated the position of the depth electrode in relation to the lesion. Depth electrode recording showed almost continuous spiking. Thus, intraoperative imaging and electrophysiology helped confirm the exact location of the lesion. Post-resection ultrasound demonstrated the extent of the resection and depth electrode recording did not show any epileptiform activity. Thus, both techniques helped assess completeness of resection. The patient has been seizure free since surgery. Using a multimodal approach including iUS and ECoG is a helpful adjunct in surgery for BOSD and may improve seizure outcome. PMID- 29137922 TI - Extracellular vesicles in neurodegenerative diseases. AB - Extracellular vesicles (EVs) are released by all neural cells, including neurons, oligodendrocytes, astrocytes, and microglia. The lack of adequate technology has not halted neuroscientists from investigating EVs as a mean to decipher neurodegenerative disorders, still in search of comprehensible pathogenic mechanisms and efficient treatment. EVs are thought to be one of ways neurodegenerative pathologies spread in the brain, but also one of the ways the brain tries to displace toxic proteins, making their meaning in pathogenesis uncertain. EVs, however do reach biological fluids where they can be analyzed, and might therefore constitute clinically decisive biomarkers for neurodegenerative diseases in the future. Finally, if they constitute a physiological inter-cell communication system, they may represent also a very specific drug delivery tool for a difficult target such as the brain. We try to resume here available information on the role of EVs in neurodegeneration, with a special focus on Alzheimer's disease, progressive multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. PMID- 29137923 TI - The PDGF/PDGFR pathway as a drug target. AB - Platelet-derived growth factors (PDGF) promotes cell proliferation, survival and migration, primarily of cells of mesenchymal origin. Dysfunction of PDGF signaling has been observed in a wide array of pathological conditions, such as cancer, fibrosis, neurological conditions and atherosclerosis. Reported abnormalities of the PDGF pathway include overexpression or amplification of PDGF receptors (PDGFRs), gain of function point mutations or activating chromosomal translocations. Current development of therapeutic drugs often aims at producing compounds that specifically target interaction between PDGFs and their receptors by specific DNA aptamers and ligand traps, or downregulate PDGFRs with blocking antibodies, or inhibit tyrosine kinase activity of PDGFRs with small molecules. In this review, we discuss some of the approaches taken to interfere with PDGF signaling, review a panel of existing therapeutic drugs, and consider clinically successful cases and remaining challenges. PMID- 29137924 TI - Nasal and otic placode specific regulation of Sox2 involves both activation by Sox-Sall4 synergism and multiple repression mechanisms. AB - Transcription factor gene Sox2 is expressed throughout sensory development, but the enhancers that regulate the gene vary depending on the developmental stages and tissues. To gain new insights into the gene regulatory network in sensory placode specification, regulation of the nasal-otic bispecific NOP1 enhancer of Sox2 was investigated in chicken embryos. Deletion and mutational analyses using electroporation showed that transcriptional repression mechanisms in combination with activation mechanisms determine placodal specificity. Activation of the NOP1 enhancer involves synergistic action by Sall4 and SoxB1/SoxE factors that bind to the adjacent sites. Deletion of repressive elements resulted in widening of the tissue area for enhancer activity to a region where the expression of Sall4 and SoxB1/E overlaps, e.g., the CNS and neural crest. Among multiple repressive elements that contribute to the placodal confinement of the NOP1 enhancer activity, CACCT/CACCTG motifs bound by Zeb/Snail family repressors play important roles. Overexpression of deltaEF1 (Zeb1) or Snail2 (Slug) strongly inhibited NOP1 activity. These data indicate that both activation by Sall4-Sox synergism and multiple repression mechanisms involving Zeb/Snail factors are essential for Sox2 regulation to be confined to the nasal and otic placodes. PMID- 29137925 TI - Polycomb repression complex 2 is required for the maintenance of retinal progenitor cells and balanced retinal differentiation. AB - Polycomb repressive complexes maintain transcriptional repression of genes encoding crucial developmental regulators through chromatin modification. Here we investigated the role of Polycomb repressive complex 2 (PRC2) in retinal development by inactivating its key components Eed and Ezh2. Conditional deletion of Ezh2 resulted in a partial loss of PRC2 function and accelerated differentiation of Muller glial cells. In contrast, inactivation of Eed led to the ablation of PRC2 function at early postnatal stage. Cell proliferation was reduced and retinal progenitor cells were significantly decreased in this mutant, which subsequently caused depletion of Muller glia, bipolar, and rod photoreceptor cells, primarily generated from postnatal retinal progenitor cells. Interestingly, the proportion of amacrine cells was dramatically increased at postnatal stages in the Eed-deficient retina. In accordance, multiple transcription factors controlling amacrine cell differentiation were upregulated. Furthermore, ChIP-seq analysis showed that these deregulated genes contained bivalent chromatin (H3K27me3+ H3K4me3+). Our results suggest that PRC2 is required for proliferation in order to maintain the retinal progenitor cells at postnatal stages and for retinal differentiation by controlling amacrine cell generation. PMID- 29137926 TI - Effect of water activity and temperature on the growth of Eurotium species isolated from animal feeds. AB - BACKGROUND: Xerophilic fungi represent a serious problem due to their ability to grow at low water activities causing the spoiling of low and intermediate moisture foods, stored goods and animal feeds, with the consequent economic losses. AIMS: The combined effect of water activity and temperature of four Eurotium species isolated from animal feeds was investigated. METHODS: Eurotium amstelodami, Eurotium chevalieri, Eurotium repens and Eurotium rubrum were grown at 5, 15, 25, 37 and 45 degrees C on malt extract agar adjusted with glycerol in the range 0.710-0.993 of water activities. RESULTS: The cardinal model proposed by Rosso and Robinson (2001) was applied to fit growth data, with the variable water activity at fixed temperatures, obtaining three cardinal water activities (awmin, awmax, awopt) and the specific growth rate at the optimum aw (MUopt). A probabilistic model was also applied to define the interface between growth and no-growth. The cardinal model provided an adequate estimation of the optimal aw to grow and the maximum growth rate. The probabilistic model showed a good performance to fit growth/no-growth cases in the predicted range. CONCLUSIONS: The results presented here could be applied to predict Eurotium species growth in animal feeds. PMID- 29137927 TI - The cholesterol-lowering effect of statins is potentiated by whole grains intake. The Polish Norwegian Study (PONS). AB - BACKGROUND: Hypercholesterolemia treatment guidelines emphasize an adequate whole grains (WG) intake, alone or complementary to pharmacological treatment. We conducted this study to compare the prevalence of adequate WG intake and levels of blood lipids according to the statin/WG intake status. METHODS: This cross sectional analysis of a community-based study included 12,754 men and women, age 45-64. Statin use over past 30days was recorded by trained nurses. Food intake over past 12months was assessed by a validated food-frequency questionnaire. Adequate WG intake was defined as >=3oz-equivalents/day, representing >=3WGservings/day. RESULTS: The prevalence of an adequate WG intake was marginally superior in statin users (26.79%) than non-users (21.51%). This superiority was attenuated after multiple covariates adjustment (PR 1.12, 95%CI 1.02-1.22). Statin users with an adequate WG intake had lower multivariable adjusted mean blood total cholesterol (185.14mg/dL vs. 190.14mg/dL) and LDL cholesterol (103.30mg/dL vs. 108.19mg/dL) than those with an inadequate WG intake. Statin users with an adequate WG intake had lower odds (OR, 95% CI) of having TC>=240mg/dL (OR 0.67, 95% CI 0.46-0.98) and lower odds of having LDL>=100mg/dL (OR 0.72, 95% CI 0.58-0.89), compared to statin users with inadequate WG intake. A subgroup analysis restricted to those with prevalent CVD yielded similar results. CONCLUSIONS: In this community based sample of middle aged adults, only one in four statin users had adequate whole grain intake. Statin users with adequate WG intake had statistically and clinically significant lower levels of blood total- and LDL-cholesterol. PMID- 29137929 TI - Enhanced performance and kinetics of marine anammox bacteria (MAB) treating nitrogen-rich saline wastewater with Mn(II) and Ni(II) addition. AB - A sequencing batch reactor (SBR) was used to study nitrogen removal performance of marine anammox bacteria (MAB) with Mn(II) and Ni(II) addition. The reactor was operated at 25 +/- 0.5 degrees C with influent pH of 7.5 +/- 0.1. Optimal ammonium removal efficiencies (AREs) were 93.95% and 93.18% with 0.05 mM Mn(II) and 0.025 mM Ni(II), respectively. Both Mn(II) and Ni(II) played key roles in treating nitrogen-rich saline wastewater. However, the effect resulting from Ni(II) was far stronger than Mn(II). With optimal Ni(II) addition (0.025 mM), maximal nitrogen removal rate (NRR) and specific anammox activity (SAA) increased by 14.64% and 57.88%, respectively. Modified Boltzmann model was appropriate to describe nitrogen removal at low Mn(II) and Ni(II) concentrations while remodified Logistic model could be used at high Mn(II) and Ni(II) concentrations. Mn(II) and Ni(II) dosage should be controlled within 0.075 mM to achieve good nitrogen removal in nitrogen-rich saline wastewater treatment. PMID- 29137930 TI - Mitigating external and internal cathode fouling using a polymer bonded separator in microbial fuel cells. AB - Microbial fuel cell (MFC) cathodes rapidly foul when treating domestic wastewater, substantially reducing power production over time. Here a wipe separator was chemically bonded to an activated carbon air cathode using polyvinylidene fluoride (PVDF) to mitigate cathode fouling and extend cathode performance over time. MFCs with separator-bonded cathodes produced a maximum power density of 190 +/- 30 mW m-2 after 2 months of operation using domestic wastewater, which was ~220% higher than controls (60 +/- 50 mW m-2) with separators that were not chemically bonded to the cathode. Less biomass (protein) was measured on the bonded separator surface than the non-bonded separator, indicating chemical bonding reduced external bio-fouling. Salt precipitation that contributed to internal fouling was also reduced using separator-bonded cathodes. Overall, the separator-bonded cathodes showed better performance over time by mitigating both external bio-fouling and internal salt fouling. PMID- 29137928 TI - CaMKIIalpha expression in a mouse model of NMDAR hypofunction schizophrenia: Putative roles for IGF-1R and TLR4. AB - Schizophrenia (SCZ) is a neuropsychiatric disorder that is linked to social behavioral deficits and other negative symptoms associated with hippocampal synaptic dysfunction. Synaptic mechanism of schizophrenia is characterized by loss of hippocampal N-Methyl-d-Aspartate Receptor (NMDAR) activity (NMDAR hypofunction) and dendritic spines. Previous studies show that genetic deletion of hippocampal synaptic regulatory calcium-calmodulin dependent kinase II alpha (CaMKIIalpha) cause synaptic and behavioral defects associated with schizophrenia in mice. Although CaMKIIalpha is involved in modulation of NMDAR activity, it is equally linked to inflammatory and neurotropin signaling in neurons. Based on these propositions, we speculate that non-neurotransmitter upstream receptors associated with neurotropic and inflammatory signaling activities of CaMKIIalpha may alter its synaptic function. Besides, how these receptors (i.e. inflammatory and neurotropic receptors) alter CaMKIIalpha function (phosphorylation) relative to hippocampal NMDAR activity in schizophrenia is poorly understood. Here, we examined the relationship between toll-like receptor (TLR4; inflammatory), insulin-like growth factor receptor 1 (IGF-1R; neurotropic) and CaMKIIalpha expression in the hippocampus of behaviorally deficient schizophrenic mice after we induced schizophrenia through NMDAR inhibition. Schizophrenia was induced in WT (C57BL/6) mice through intraperitoneal administration of 30mg/Kg ketamine (NMDAR antagonist) for 5days (WT/SCZ). Five days after the last ketamine treatment, wild type schizophrenic mice show deficiencies in sociability and social novelty behavior. Furthermore, there was a significant decrease in hippocampal CaMKIIalpha (p<0.001) and IGF-1R (p<0.001) expression when assessed through immunoblotting and confocal immunofluorescence microscopy. Additionally, WT schizophrenic mice show an increased percentage of phosphorylated CaMKIIalpha in addition to upregulated TLR4 signaling (TLR4, NF-kappaB, and MAPK/ErK) in the hippocampus. To ascertain the functional link between TLR4, IGF-1R and CaMKIIalpha relative to NMDAR hypofunction in schizophrenia, we created hippocampal-specific TLR4 knockdown mouse using AAV-driven Cre-lox technique (TLR4 KD). Subsequently, we inhibited NMDAR function in TLR4 KD mice in an attempt to induce schizophrenia (TLR4 KD SCZ). Interestingly, IGF-1R and CaMKIIalpha expressions were preserved in the TLR4 KD hippocampus after attenuation of NMDAR function. Furthermore, TLR4 KD SCZ mice showed no prominent defects in sociability and social novelty behavior when compared with the control (WT). Our results show that a sustained IGF-1R expression may preserve the synaptic activity of CaMKIIalpha while TLR4 signaling ablates hippocampal CaMKIIalpha expression in NMDAR hypofunction schizophrenia. Together, we infer that IGF-1R depletion and increased TLR4 signaling are non-neurotransmitter pro schizophrenic cues that can reduce synaptic CaMKIIalpha activity in a pharmacologic mouse model of schizophrenia. PMID- 29137931 TI - Secondary effluent purification by a large-scale multi-stage surface-flow constructed wetland: A case study in northern China. AB - Assessment of treatment performance in the large-scale constructed wetland (CW) for secondary effluent purification remains limited. The aim of this case study was to therefore to investigate the long-term treatment capacity of organics and ammonium pollutants in a large-scale multi-stage surface-flow (SF) CW fed with secondary effluents from the wastewater treatment plants (WWTPs) in northern China. The results for two-and-half-year study period indicated that the water quality parameters including chemical oxygen demand (COD) and ammonium (NH4+-N) met the Chinese Grade III of Environmental Quality Standards. The mass reductions of COD and NH4+-N were 53% (4032 kg ha-1 y-1) and 72% (511 kg ha-1 y-1), respectively. However, there was a significant positive correlation between influent loads and treatment performance. The optimal loading of 2.5 g m-2 d-1 for COD and 0.3 g m-2 d-1 for NH4+-N could be recommended for designing the sustainable large-scale multi-stage SF CW wastewater treatments. PMID- 29137932 TI - The tibial nerve compression test for the diagnosis of lumbar spinal canal stenosis-A simple and reliable physical examination for use by primary care physicians. AB - OBJECTIVES: In the present study, we aimed to evaluate the diagnostic accuracy and suitability of the 'Tibial Nerve Compression Test (TNCT)' as a screening tool for lumbar spinal canal stenosis (LSS). METHODS: A total of 108 consecutive patients admitted to our hospital for surgical treatment or diagnosis of LSS were included in this study. Fifty healthy volunteers were examined as a control group. The severity of tenderness was scored (tenderness score) and measured on a visual analogue scale (P-VAS score). These scores were compared between the LSS and control groups. Moreover, they were compared before and after the operation among operated patients. RESULTS: The positive tenderness rate was significantly higher (92.6% [100/108]) in the LSS group than in the control group (30% [15/50]). The sensitivity and specificity of TNCT (95% confidence interval) were 0.93 (0.88-0.96) and 0.70 (0.61-0.77), respectively. Positive tenderness rates and P-VAS scores were significantly higher in the LSS group (p < 0.0001). Scores on all measures significantly improved post-operatively in operated patients (p < 0.0001). CONCLUSION: The Tibial Nerve Compression Test is a useful screening tool for LSS diagnosis in a primary care setting. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 29137934 TI - The notch pathway is activated in neoplastic progression in esophageal squamous cell carcinoma. AB - The Notch signaling pathway is integral to normal human development and homeostasis and has a deterministic function on cell differentiation. Recent studies suggest aberrant Notch signaling may contribute to neoplastic progression by an increase in stem cell survival, chemoresistance, and the promotion of epithelial-to-mesenchymal transition. The goals of our study were to determine, utilizing quantitative technologies, the expression of activated Notch 1 in esophageal squamous cell carcinoma (SCC) and to determine the relationship between Notch 1 expression and various clinicopathologic parameters. Immunohistochemical staining for Notch intracellular domain (NICD) was performed on 60 consecutive cases of esophageal squamous cell carcinoma, 42 cases of benign esophageal squamous epithelium, and 13 cases of eosinophilic esophagitis diagnosed in our department from 2007 through 2015, and exact nuclear staining and nuclear characteristics were graded using the Vectra imaging system. Clinicopathologic data (gender, age at diagnosis, smoking status, tumor grade, tumor stage, tumor location, and survival) were collected for each SCC case and these were correlated with NICD staining. Cases of esophageal SCC demonstrated significantly higher NICD staining compared to cases of benign and reactive esophageal epithelium (P=.003 and .005, respectively). Among cases of esophageal SCC, nuclear NICD staining was significantly correlated with both tumor grade and stage. Following classification and regression tree analysis, esophageal SCC patients with increased NICD expression were found to be more likely to die from their disease than those with lower levels of expression. Taken together, the findings suggest that increased Notch 1 may contribute to the development and aggressiveness of esophageal SCC. PMID- 29137935 TI - Prostatic adenocarcinoma in the setting of persistent mullerian duct syndrome: a case report. AB - Persistent mullerian duct syndrome (PMDS) is a form of disordered sex development in which rudimentary mullerian structures are identified in phenotypically and genotypically normal males. It is caused by defects in the anti-mullerian hormone (AMH) system. Since patients with PMDS present with undescended testes, testosterone production by Leydig cells later in life is often decreased. The role of androgens in prostate cancerogenesis is well known. Cryptorchid testes and diminished testosterone levels in post-pubertal life in patients with PMDS play a protective role against prostate cancer, and hence, prostate cancer is a rare event in patients with PMDS. Herein, we present a patient who underwent prostatectomy for high-grade prostatic adenocarcinoma with persistent mullerian structures (such as rudimentary uterus, fallopian tubes, and cervix) identified during surgery. To our knowledge, this is the second case reported in the English language literature where PMDS was associated with prostate cancer. PMID- 29137933 TI - CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective. AB - CD4+ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4+ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable T helper type (Th)1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4+ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8+ T cells as well. In this review, we discuss what is known about CD4+ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host-pathogen interaction. PMID- 29137936 TI - The field of medical anthropology in Social Science & Medicine. AB - Conceptually and methodologically, medical anthropology is well-positioned to support a "big-tent" research agenda on health and society. It fosters approaches to social and structural models of health and wellbeing in ways that are critically reflective, cross-cultural, people-centered, and transdisciplinary. In this review article, we showcase these four main characteristics of the field, as featured in Social Science & Medicine over the last fifty years, highlighting their relevance for an international and interdisciplinary readership. First, the practice of critical inquiry in ethnographies of health offers a deep appreciation of sociocultural viewpoints when recording and interpreting lived experiences and contested social worlds. Second, medical anthropology champions cross-cultural breadth: it makes explicit local understandings of health experiences across different settings, using a fine-grained, comparative approach to develop a stronger global platform for the analysis of health-related concerns. Third, in offering people-centered views of the world, anthropology extends the reach of critical enquiry to the lived experiences of hard-to-reach population groups, their structural vulnerabilities, and social agency. Finally, in developing research at the nexus of cultures, societies, biologies, and health, medical anthropologists generate new, transdisciplinary conversations on the body, mind, person, community, environment, prevention, and therapy. As featured in this journal, scholarly contributions in medical anthropology seek to debate human health and wellbeing from many angles, pushing forward methodology, social theory, and health-related practice. PMID- 29137937 TI - Design, synthesis and evaluation of 3-arylidene azetidin-2-ones as potential antifungal agents against Alternaria solani Sorauer. AB - A new concise and facile method was explored to synthesize a collection of new 3 arylidene azetidin-2-ones, which could be regarded as the derivatives of the hybrid scaffold of bioactive natural cinnamamide and heterocycle azetidi-2-one. The structures of the synthesized compounds were characterized by 1H, 13C NMR, and MS; and their antifungal activity were evaluated against Alternaria solani Sorauer. These antifungal data were subjected to a quantitative structure activity relationship (QSAR) analysis using Codessa software on the basis of the results from B3LYP/6-31G(d,p) quantum calculations. The best regressive model revealed that potentially more active compounds should have low dipole moments and QC-min (minimal net atomic charge for a C atom), and high QO-max (maximal net atomic charge for an O atom) and QN-min (minimal net atomic charge for an N atom). The most potent compound 7k could lead to intracellular accumulation of reactive oxygen species, dissipation of mitochondrial transmembrane potential, and an autophagy-like cell death process in A. solani Sorauer. Taken together, these results laid the foundation for further design of improved crop-protection agents based on this hybrid scaffold. PMID- 29137938 TI - Discovery of imidazo[1,2-a]pyridine-based anthelmintic targeting cholinergic receptors of Haemonchus contortus. AB - We report the synthesis of a series of imidazo[1,2-a]pyridine-based molecules as anthelmintic against the livestock parasite Haemonchus contortus. The molecules were tested by using Larval Paralysis Test (LPT), in order to target ionic channels, as most of the prominent marketed anthelminthics present such mechanism of action. The most active compound (5e) displayed paralysis on H. contortus stage 3 larvae until 31.25 uM. Effect of 5e on H. contortus cholinergic receptors (L-AChR1 and 2) was characterized via electrophysiological measurement and a rare antagonist mode of action was unveiled. PMID- 29137939 TI - In silico identification and in vivo characterization of small molecule therapeutic hypothermia mimetics. AB - Hypothermia has been proved to have a beneficial effect on several pathologies. CIRBP is one of the so termed cold-shock proteins involved in this process. In this work, we have detected small molecules capable of modulating the activity of CIRBP in the absence of a cold stimulus, by High Throughput Virtual Screening (HTVS) of the Diversity Set IV of the NCI and 15 compounds of our in-house data base. Fifteen compounds were selected from the HTVS to carry out a second screening through a cell-based Western blot assay. This assay, together with molecular modeling studies allowed us to select compound zr17-2 for an in vivo experiment, which showed an interesting increase of CIRBP expression in several organs of experimental animals. Therefore, we have demonstrated that the effect of hypothermia can be mimicked by small molecules, which can be developed as first-in-class new drugs for the treatment of several diseases. PMID- 29137940 TI - Autoamplificatory singlet oxygen generation sensitizes tumor cells for intercellular apoptosis-inducing signaling. AB - : Tumor cells express NADPH oxidase-1 (NOX1) in their membrane and control NOX1 based intercellular reactive oxygen and nitrogen species (ROS/RNS)-dependent apoptosis-inducing signaling through membrane-associated catalase and superoxide dismutase. TREATMENT: of tumor cells with high concentrations of H2O2, peroxnitrite, HOCl, or increasing the concentration of cell-derived NO causes initial generation of singlet oxygen and local inactivation of membrane associated catalase. As a result, free peroxynitrite and H2O2 interact and generate secondary singlet oxygen. Inactivation of further catalase molecules by secondary singlet oxygen leads to auto-amplification of singlet oxygen generation and catalase inactivation. This allows reactivation of intercellular ROS/RNS signaling and selective apoptosis induction in tumor cells. The initial singlet oxygen generation seems to be the critical point in this complex biochemical multistep mechanism. Initial singlet oxygen generation requires the interaction between distinct tumor cell-derived ROS and RNS and may also depend on either the induction of NO synthase expression or NOX1 activation through the FAS receptor. FAS receptor activation can be achieved by singlet oxygen. Autoamplificatory generation of singlet oxygen through the interaction between peroxynitrite and hydrogen peroxide inherits a rich potential for the establishment of synergistic effects that may be instrumental for novel approaches of tumor therapy with high selectivity towards malignant cells. PMID- 29137941 TI - Acute and sub-acute oral toxicity studies of the aqueous extract from radix, radix with cortex and cortex of Psammosilene tunicoides in mice and rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Psammosilene tunicoides is one of the important ingredients of a famous Chinese traditional medicine formulation "Yunnan Baiyao". Also, this plant is commonly used as an anodyne and hemostatic agent in southwest China. Currently, little toxicological information is available on its safety following prolonged use. AIM OF THE STUDY: In this study, we sought to evaluate the toxicity of the three different parts of Psammosilene tunicoides: Psammosilenes Radix (PR), Psammosilenes Radix with Cortex (PRC) and Psammosilenes Cortex (PC) by acute and sub-acute toxicity studies. MATERIALS AND METHODS: In the acute toxicity study, mice were orally administrated with different doses of PR, PRC and PC. General behavior and mortality were observed up to 14 days. In sub-acute toxicity study, these aqueous extracts were given orally as a single administration to rats at doses of 0.3, 0.6 and 1.2g/kg/day, respectively, for 28 days. General behavior, body weight, biochemical, hematological, organ coefficients and pathological morphology parameters were detected. RESULTS: In acute study, single oral administration of the aqueous extract of PR, PRC and PC caused dose-dependent general behavior adverse effects and mortality. The LD50 values of PR, PRC and PC were 4.64g/kg, 4.85g/kg and 6.40g/kg, respectively. In sub-acute study, the administration of the extract of PR, PRC and PC during 28 days at all doses reduced spontaneous activities with both genders. Occasional nasal secretion with blood at high doses (1.2g/kg) of PR, PRC and PC were observed. Daily single oral administration provoked varying degrees of growth retardation in female rats. The relative heart and spleen weight in the female rats were reduced after the administration. On the hematological and biochemical analyses, the administration of the extract of PR, PRC and PC during 28 days mainly caused variation of indexes in female rats. Histopathological analysis has shown vascular congestion in heart, thickened alveolar wall and emphysema in lung, and vascular congestion in kidney of rats after sub-acute oral administrations. CONCLUSIONS: As shown in the results, Psammosilene tunicoides has a toxic potential in acute and sub-acute oral administrations. However, there is no direct relationship between toxicity and the cortex. Daily oral administration of three different parts from Psammosilene tunicoides (PR, PRC and PC) may cause damages to heart, lung and kidney in rats. Thus these extracts should be used with caution. PMID- 29137942 TI - Response to commentary re 'Reduction and standardization of surgical instruments in pediatric inguinal hernia repair'. PMID- 29137943 TI - Cystoscopic-assisted laparoscopic excision of prostatic utricle. AB - We present a video of our technique for resection of a large prostatic utricle (PU) in a patient who presented initially with disordered sexual development. His karyotype was 46XY, and phenotypically had penoscrotal hypospadias, bifid scrotum, and retractile right testis. An initial micturating cystourethrogram (MCUG) demonstrated the utricle but failed to cannulate the bladder. Being asymptomatic, we carried out staged repair of his hypospadias. Later, he started to have recurrent epididymo-orchitis with resistance to multiple antibiotics. Examination under anaesthesia was done and ruled out meatal or neo-urethral strictures. A subsequent MCUG demonstrated the large utricle and its relation to the bladder. We carried out a cystoscopic-assisted laparoscopic excision. There has been no consensus about the best surgical approach to resect a PU and most known procedures involved extensive pelvic dissection and carried a significant risk of damage to the pelvic nerves. The laparoscopic approach seems to be promising in this field as it provides proper view of the deep pelvis with reasonable magnification, less dissection and shorter postoperative pain and scarring. Cystoscopic assistance in this technique was a great addition to provide counter-traction movement and facilitate proper dissection. PMID- 29137944 TI - Reproductive factors, nutritional status and serum 25(OH)D levels in women with breast cancer: A case control study. AB - The study was conducted with an objective to investigate the association between reproductive factors, nutritional status and serum 25(OH)D levels among women diagnosed with breast cancer (BC). A total of 200 women with BC attending a tertiary healthcare institute of Delhi, India matched with 200 healthy women for age (+/-2years) and socio economic status were included in the study. Data was collected on socio-demographic profile, reproductive factors, physical activity and dietary intake (24h dietary recall and food frequency questionnaire) using interviewer administered structured questionnaires and standard tools. Non fasting blood samples (5ml) were collected for the biochemical estimation of serum 25(OH)D and calcium levels by chemiluminescent immunoassay and colorimetric assay technique. Data was analyzed by univariable conditional logistic regression and significant variables with (p<0.05), were analyzed in final model by conditional multivariable logistic regression analysis. The mean age of patients at diagnosis of BC was 45+/-10years. Results of multivariable conditional logistic regression analysis revealed significantly higher odds of BC for reproductive factors like age at marriage (more than 23 years), number of abortions, history or current use of oral contraceptive pills (OCP), with [OR (95% CI)] of [2.4 (1.2-4.9)], [4.0 (1.6-12.6)], [2.4 (1.2-5.0)]. Women with physically light activities and occasional consumption of eggs were found to have higher odds of BC [4.6 (1.6-13.0)] and [3.2 (1.6-6.3)]. Women with serum 25(OH)D levels less than 20ng/ml and calcium levels less than 10.5mg/dl had higher odds of having BC [2.4 (1.2-5.1)] and [3.7 (1.5-8.8)]. A protective effect of urban areas as place of residence and energy intake greater than 50% of Recommended Dietary Allowance (RDA) per day against BC was observed (p<0.05). The findings of the present study revealed a significant association of reproductive and dietary factors in addition to sedentary physical activity and low serum 25(OH)D levels in women diagnosed with BC. PMID- 29137945 TI - The effects of local microinjection of selective dopamine D1 and D2 receptor agonists and antagonists into the dorsal raphe nucleus on sleep and wakefulness in the rat. AB - The effects of the dopamine (DA) D1 and D2 receptor agonists SKF38393, bromocriptine and quinpirole, respectively, on spontaneous sleep were analyzed in adult rats prepared for chronic sleep recordings. Local administration of the DAergic agonists into the dorsal raphe nucleus (DRN) during the light phase of the light-dark cycle induced a significant reduction of rapid-eye movement sleep (REMS) and the number of REM periods. Additionally, bromocriptine and quinpirole significantly increased wakefulness (W). Opposite, the microinjection into the DRN of the DA D1 and D2 receptor antagonists SCH23390 and sulpiride, respectively, significantly augmented REMS and the number of REM periods. Pretreatment with SCH23390 and sulpiride prevented the effects of SKF38393 and bromocriptine, respectively, on sleep variables. Our results tend to indicate that DAergic neurons located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) contribute to the regulation of predominantly W and REMS by DRN serotonergic neurons. PMID- 29137946 TI - Distinct environmental enrichment protocols reduce anxiety but differentially modulate pain sensitivity in rats. AB - Environmental enrichment (EE) can alter anxiety as well as perception of nociceptive stimuli, suggesting a relationship between well-being and analgesia. Considering that, we aimed to evaluate the influence of different EE types on anxiety and peripheral pain sensitivity of male Wistar rats. Animals were submitted to two different types of EE: On the first one, animals were housed in standard size cages after weaning and received three different objects, one type per week, on a regular basis (simple EE - sEE). On the second one, animals were born in an already enriched environment and, after five weeks, were housed in larger cages and received five different objects, three of each type per week, on a regular basis (improved EE - iEE). Control group remained in standard cages and did not receive objects. Within 7 weeks of life, anxiety and thermal sensibility were evaluated using elevated plus maze and tail flick tests, respectively. Mechanical hyperalgesia was analyzed in the presence of acute and chronic noxious stimuli by paw pressure test. Both EE protocols tested were effective in diminish anxiety but they did not alter thermal sensibility. On the other hand, sEE protocol did not alter acute and chronic induced mechanical hypersensitivity, whereas iEE completely abolished such pain behavior, even without exercise wheel as part of the enrichment. Our results show that specific parameters (anxiety and pain sensitivity) can be differentially modulated depending on EE protocol used, making possible the implementation of welfare to experimental animals in pain research. PMID- 29137947 TI - Low-dose vitamin D supplementation and incident frailty in older people: An eight year longitudinal study. AB - Hypovitaminosis D is associated with frailty, but if vitamin D supplementation may prevent the onset of frailty is poorly known. Therefore, we aimed to investigate whether vitamin D supplementation is associated with a lower risk of frailty. In this longitudinal study, 4,421 individuals at high risk or having knee osteoarthritis free from frailty at baseline (mean age: 61.3, females=58.0%) were followed for 8 years. Details regarding vitamin D supplementation were captured by asking whether the participant took vitamin D during the previous year, at least once per month. Frailty was defined using the Study of Osteoporotic Fracture (SOF) index as the presence of at least two of the following criteria: (i) weight loss>=5% between baseline and any subsequent follow-up visit; (ii) inability to do five chair stands; (iii) low energy level according to the SOF definition. Multivariable Cox's regression analyses, calculating hazard ratios (HRs) with 95% confidence intervals (CIs), were undertaken. At baseline 69.7% took vitamin D supplements in the previous year, with a mean dose of 384+/-157 IU per day. During the 8-year follow-up, no difference in the incidence of frailty was evident by vitamin D supplementation status at baseline, even after adjusting for 13 baseline confounders (HR=0.95; 95% CI: 0.72-1.25). Similar results were obtained using the propensity score (HR=0.95; 95% CI: 0.71-1.25) or age- and sex-matched controls (HR=1.00; 95% CI: 0.75-1.33). In conclusion, low-dose vitamin D supplementation was not associated with any decreased risk of frailty during eight years of follow-up in a large cohort of North American people. Future large-scale trials with high doses of oral vitamin D and longer follow-up are needed to confirm/refute our findings. PMID- 29137949 TI - The Science of Cancer Health Disparities: A Young Discipline with an Old Heritage. AB - This Guest Editorial highlights the reviews in the Race in Cancer Health Disparities Theme Issue that improve our understanding of the complex role of race in disparities in cancer frequency and outcome. PMID- 29137948 TI - Analysis of Tumor Biology to Advance Cancer Health Disparity Research. AB - Cancer mortality rates in the United States continue to decline. Reductions in tobacco use, uptake of preventive measures, adoption of early detection methods, and better treatments have resulted in improved cancer outcomes for men and women. Despite this progress, some population groups continue to experience an excessive cancer burden when compared with other population groups. One of the most prominent cancer health disparities exists in prostate cancer. Prostate cancer mortality rates are highest among men of African ancestry when compared with other men, both in the United States and globally. This disparity and other cancer health disparities are largely explained by differences in access to health care, diet, lifestyle, cultural barriers, and disparate exposures to carcinogens and pathogens. Dietary and lifestyle factors, pathogens, and ancestry related factors can modify tumor biology and induce a more aggressive disease. There are numerous examples of how environmental exposures, like tobacco, chronic stress, or dietary factors, induce an adverse tumor biology, leading to a more aggressive disease and decreased patient survival. Because of population differences in the exposure to these risk factors, they can be the cause of cancer disparities. In this review, we will summarize recent advances in our understanding of prostate and breast cancer disparities in the United States and discuss how the analysis of tumor biology can advance health disparity research. PMID- 29137951 TI - Triple-Negative Breast Cancer, Stem Cells, and African Ancestry. AB - Triple-negative breast cancers (TNBCs) are more common among African-ancestry populations, such as African Americans and western, sub-Saharan Africans, compared with European-ancestry populations. This phenotype prevalence contributes to disparities in breast cancer outcomes between African Americans and White Americans. Breast cancer stem cells represent the tumor subpopulation involved in metastatic virulence, and ongoing research seeks to characterize the extent to which TNBC versus non-TNBC stem cells may differ. This review summarizes the existing literature regarding TNBCs and stem cells as they pertain to the burden of breast cancer among African-ancestry populations. Additional research related to variations in somatic tumor genomics between the African American and White-American populations is also summarized. This review furthermore explores the history of insights regarding breast cancer disparities related to racial/ethnic identity, socioeconomic status, and tumor biology. PMID- 29137950 TI - Linking Race, Cancer Outcomes, and Tissue Repair. AB - The burden of cancer in the United States is unevenly spread across its different populations, with stark differences in both disease prevalence and outcome on the basis of race and ethnicity. Although a large portion of these differences can be explained by a variety of sociobehavioral and socioeconomic factors, even after these exposures are taken into consideration, considerable disparities persist. In this review, we explore a conceptual framework of biological theories and unifying concepts, based on an evolutionary perspective, that may help better define common guiding principles for exploration of underlying causes of cancer health disparities. The ultimate goal of this conceptual perspective is to outline approaches that may aid in establishing integrated pathway and processes analyses to provide useful insights to guide the development of future interventions. These interventions will improve outcome, increase prevention, and ultimately eliminate all disparities. PMID- 29137953 TI - The benefits of the concomitant use of antidepressants and acetyl-l-carnitine in the treatment of moderate depression. PMID- 29137952 TI - Neural EGFL-Like 1 Regulates Cartilage Maturation through Runt-Related Transcription Factor 3-Mediated Indian Hedgehog Signaling. AB - The pro-chondrogenic function of runt-related transcription factor 2 (Runx2) was previously considered to be dependent on direct binding with the promoter of Indian hedgehog (Ihh)-the major regulator of chondrocyte differentiation, proliferation, and maturation. The authors' previous studies identified neural EGFL like 1 (Nell-1) as a Runx2-responsive growth factor for chondrogenic differentiation and maturation. In this study, it was further revealed that the pro-chondrogenic activities of Nell-1 also rely on Ihh signaling, by showing: i) Nell-1 significantly elevated Ihh signal transduction; ii) Nell-1 deficiency markedly reduced Ihh activation in chondrocytes; and iii) Nell-1-stimulated chondrogenesis was significantly reduced by the specific hedgehog inhibitor cyclopamine. Importantly, the authors demonstrated that Nell-1-responsive Ihh signaling and chondrogenic differentiation extended to Runx2-/- models in vitro and in vivo. In Runx2-/- chondrocytes, Nell-1 stimulated the expression and signal transduction of Runx3, another transcription factor required for complete chondrogenic differentiation and maturation. Furthermore, knocking down Runx3 in Runx2-/- chondrocytes abolished Nell-1's stimulation of Ihh-associated molecule expression, which validates Runx3 as a major mediator of Nell-1-stimulated Ihh activation. For the first time, the Runx2->Nell-1->Runx3->Ihh signaling cascade during chondrogenic differentiation and maturation has been identified as an alternative, but critical, pathway for Runx2 to function as a pro-chondrogenic molecule via Nell-1. PMID- 29137954 TI - The trouble with apples and oranges. PMID- 29137955 TI - The cost-effectiveness of arthroscopic partial meniscectomy: comparing apples and oranges. PMID- 29137956 TI - Pattern of relapse and dose received by the recurrent intraprostatic nodule in low- to intermediate-risk prostate cancer treated with single fraction 19 Gy high dose-rate brachytherapy. AB - PURPOSE: The purposes of this study were to investigate the pattern of relapse in patients with low- or intermediate-risk prostate cancer treated with 19-Gy high dose-rate brachytherapy (HDR-BT) and to calculate the dose received by the area of recurrence. METHODS AND MATERIALS: Patients included in this analysis were treated under a Phase II randomized trial that evaluated the role of 19-Gy HDR-BT monotherapy in low- and intermediate-risk prostate cancers. Multiparametric prostate MRI and prostate biopsy were performed in patients with suspicious local recurrence. The site of local relapse was compared with the initial site of disease. The dose received by the site of recurrence was investigated through registration of the posttreatment multiparametric prostate MRI with the HDR-BT treatment plan. RESULTS: Eight of 87 treated patients were found to have local recurrence after 19-Gy HDR-BT. Seven of the eight recurrences were at the site of initial bulk disease. Seven patients were found to have a more aggressive histology in the posttreatment biopsy. The mean volume of prostate that had received 100% of prescription dose was 97%. Mean dose to area of recurrence was 29.1 Gy, whereas dose to 98% and dose to 90% of the recurrence were 21.6 Gy and 23.2 Gy, respectively. CONCLUSIONS: The relapse pattern after a single 19-Gy HDR BT is predominantly associated with the site of initial disease. This lends some rationale to future strategies of further focused dose escalation to initial site of disease, notwithstanding the fact that the calculated biologically equivalent dose using linear-quadratic assumptions is already very high. PMID- 29137957 TI - Phylogenetic analyses of transcriptome data resolve familial assignments for genera of the red-algal Acrochaetiales-Palmariales Complex (Nemaliophycidae). AB - Phylogenetic analyses of transcriptome data for representatives of the red algal Acrochaetiales-Palmariales Complex provided robust support for the assignment of genera to the constituent families. In the Acrochaetiales, the genera Acrochaetium, Grania, and an unnamed genus-level lineage (Acrochaetiac sp._1Aus) were assigned to the Acrochaetiaceae, while Audouinella is placed in a resurrected Audouinellaceae and Rhodochorton and Rhododrewia constitute the resurrected Rhodochortonaceae. For the Palmariales, transcriptome data solidly support the inclusion of Camontagnea and Rhodothamniella in the Rhodothamniellaceae, Meiodiscus and Rubrointrusa in the Meiodiscaceae, Rhodonematella and Rhodophysema in the Rhodophysemataceae, while Devaleraea and Palmaria remained in the Palmariaceae. These analyses, however, questioned the monophyly of Palmaria, which prompted a second round of analyses using eight common red algal phylogenetic markers and including a broader sampling of red algal genera in our analyses. These results supported transfer of Palmaria callophylloides and P. mollis to the genus Devaleraea necessitating new combinations, and further added the genus Halosaccion to the Palmariaceae and the genera Kallymenicola and Rhodophysemopsis to the Meiodiscaceae. Finally, DNA barcode (mitochondrial COI-5P) and ITS data were explored and supported the continued recognition of Palmaria palmata as a single species in the North Atlantic. PMID- 29137958 TI - Knowledge and information sources on standard precautions and infection control of health sciences students at King Saud bin Abdulaziz University for Health Sciences, Saudi Arabia, Riyadh. AB - BACKGROUND: Only one study has been conducted in Saudi Arabia to assess medical students' knowledge of standard precautions (SPs) and infection control (IC). In this study, we examined knowledge of SPs and IC among clinical students attending the King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. METHODS: In this cross-sectional study, we targeted clinical students from the following five colleges: Medicine (fifth and sixth years); Dentistry (second semester of the third, fourth, fifth, and sixth years); Applied Medical Sciences (third and fourth years); Nursing (third and fourth years); and Pharmacy (third, fourth, and fifth years). The data collection instrument was an adopted 41-item questionnaire that measured knowledge of SPs and IC in five domains. A score of >=24 (60%) indicated sufficient knowledge. RESULTS: The participants comprised 129 students (67 men). The proportions of participants from each college were: Medicine, 58.1% (n=75); Dentistry, 14% (n=18); Applied Medical Sciences, 13.2% (n=17); Nursing, 10.9% (n=14); and Pharmacy, 3.9% (n=5). Most students (73.6%) demonstrated sufficient knowledge (men, 67.2% and women, 80.6%). The highest scores were obtained for the domains "general concept of SPs", "hand hygiene", and "personal protective equipment", whereas the lowest scores were obtained for "disposal of and injuries from sharp objects" and "health-care providers' care". The main information source was formal curricular teaching. CONCLUSIONS: In Saudi Arabia, students' knowledge of SPs and IC is satisfactory, with no significant differences between the sexes or between colleges. Thus, formal curricular teaching is an effective way to increase students' knowledge of SPs and IC. PMID- 29137959 TI - Moving From Clinic to Home: What the Future Holds for Ophthalmic Telemedicine. AB - PURPOSE: To describe the expanding role of telemedicine in healthcare, the key criteria required for a successful device and program implementation, and the current and future role of home monitoring in ophthalmology. DESIGN: Expert perspective. METHODS: Analysis with real-world interpretation of home monitoring technologies, including current adoption barriers and expanded future demands based on demographic and market forces. RESULTS: Remote patient monitoring represents a paradigm shift in the way physicians care for patients. Success depends on meeting several criteria, among which are a recognized value proposition to the physician, robust device performance validation, ease of use for the patient, reliability of connectivity, safe and secure data transmission, and economic feasibility. Ophthalmic diseases, such as age-related macular degeneration, glaucoma, and diabetic retinopathy, are ideal candidates for home monitoring practice integration. Established home monitoring technology is already facilitating early detection and improved visual outcomes for patients with age-related macular degeneration. Future innovation currently underway or on the horizon will continue to evolve and expand the footprint of telemedicine within ophthalmology. CONCLUSION: Home monitoring has the potential to enhance the patient-physician relationship and to positively impact visual acuity outcomes in ophthalmic diseases. Advances in technology, demographic shifts, market changes, and patient demand for personalized medicine will require physicians to embrace technology in new and diverse ways, perhaps facilitating widespread adoption of home monitoring technology platforms. PMID- 29137960 TI - AMPA receptor translocation and phosphorylation are induced by transcranial direct current stimulation in rats. AB - Over the last decade, the interest in transcranial direct current stimulation (tDCS) has continued to increase, along with consideration of how it affects neuroplasticity mechanisms in the brain. Both human and animal studies have demonstrated numerous benefits and, although its application has increased, the neurophysiological mechanisms underlying tDCS' beneficial effects remain largely unknown. Recent studies have shown that long-term potentiation (LTP) increases following tDCS. In this work, we utilized a rodent model of tDCS to directly assess changes in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, a critical protein for enhancing synaptic transmission. Animals were subjected to 250 MUA of direct current (DC) stimulation for 30 min with immediate tissue collection. Translocation and phosphorylation of AMPA receptors were examined using protein immunoblot analysis following a subcellular fractionation method. Our findings show that a single application of in vivo tDCS can affect both the translocation and phosphorylation of AMPA receptors in the hippocampus while increasing AMPA receptor phosphorylation in the hypothalamus. In the hippocampus, tDCS increased AMPA translocation to the synapse and increased the phosphorylation of the S831 site on GluA1. In the hypothalamus, no statistically significant changes were observed in AMPA translocation while an increase in the phosphorylation of the S831 site was observed. No changes in the phosphorylation of GluA1 at the S845 site were detected in either brain region. In sum, our findings identify specific AMPA receptor changes induced by tDCS, thereby providing further details on the mechanisms by which tDCS could affect the establishment of LTP and modulate neuroplasticity. PMID- 29137961 TI - Adrenal insufficiency in critical patients: New ethiopathogenic concepts and therapeutic implications. AB - Recently, there have been advances in understanding of the changes that occur in the hypothalamic-pituitary-adrenal axis during the different stages of critical disease. Such advances have led to a paradigm change, so that the aforementioned adaptations are no longer considered the result of adrenal axis activation, but a consequence of decreased cortisol metabolism illness. Knowledge of this new pathophysiological bases should lead to reconsider the diagnosis and treatment of adrenal insufficiency in critically ill patients, a condition poorly understood to date. PMID- 29137962 TI - Reference values for serum thyroglobulin in healthy individuals. PMID- 29137963 TI - Failure of a second temozolomide cycle in a patient with a prolactin-secreting pituitary carcinoma. PMID- 29137964 TI - Oral glucose tolerance test and continuous glucose monitoring to assess diabetes development in cystic fibrosis patients. AB - INTRODUCTION: Patients with cystic fibrosis (CF) undergo a slow and progressive process toward diabetes. Oral glucose tolerance test (OGTT) is recommended to diagnose impaired glucose levels in these patients. Continuous glucose monitoring (CGM) measures glucose profiles under real-life conditions. OBJECTIVE: To compare OGTT and CGM results in CF patients. METHODS: Paired OGTT and 6-day CGM profiles (146.2+/-9.1h/patient) were performed in 30 CF patients aged 10-18 years. RESULTS: According to OGTT, 14 patients had normal glucose tolerance (NGT), 14 abnormal glucose tolerance (AGT), and two cystic fibrosis-related diabetes (CFRD). In 27 patients (13 NGT, 13 AGT, 1 CFRD), CGM showed glucose values ranging from 140 to 200mg/dL during similar monitoring times (2%-14% with NGT, 1% 16.9% with AGT, and 3% with CFRD). Glucose peak levels >=200mg/dL were seen in seven patients (3 NGT, 3 AGT, 1 CFRD). According to CGM, two patients had all glucose values under 140mg/dL (1 NGT, 1 AGT). Seventeen patients had glucose levels ranging from 140 to 200mg/dL (10 NGT, 6 AGT, 1 CFRD). Ten patients (3 NGT, 7 AGT) had glucose values >=200mg/dL for <=1% of the monitoring time and one (CFRD) for >1% of the monitoring time. CONCLUSIONS: OGTT results did not agree with those of the CGM. CGM allows for diagnosis of glucose changes not detected by OGTT. Such changes may contribute to optimize pre-diabetes management in CF patients. PMID- 29137965 TI - A novel bagging C4.5 algorithm based on wrapper feature selection for supporting wise clinical decision making. AB - From the perspective of clinical decision-making in a Medical IoT-based healthcare system, achieving effective and efficient analysis of long-term health data for supporting wise clinical decision-making is an extremely important objective, but determining how to effectively deal with the multi-dimensionality and high volume of generated data obtained from Medical IoT-based healthcare systems is an issue of increasing importance in IoT healthcare data exploration and management. A novel classifier or predicator equipped with a good feature selection function contributes effectively to classification and prediction performance. This paper proposes a novel bagging C4.5 algorithm based on wrapper feature selection, for the purpose of supporting wise clinical decision-making in the medical and healthcare fields. In particular, the new proposed sampling method, S-C4.5-SMOTE, is not only able to overcome the problem of data distortion, but also improves overall system performance because its mechanism aims at effectively reducing the data size without distortion, by keeping datasets balanced and technically smooth. This achievement directly supports the Wrapper method of effective feature selection without the need to consider the problem of huge amounts of data; this is a novel innovation in this work. PMID- 29137966 TI - Clinical outcomes of complex real-world diabetic patients treated with amphilimus sirolimus-eluting stents or zotarolimus-eluting stents: A single-center registry. AB - OBJECTIVE: To assess clinical outcomes of Amphilimus Sirolimus-Eluting Stents (A SES) as compared to Zotarolimus-Eluting Stents (ZES) in complex real-world diabetic patients. BACKGROUND: Patients with diabetes mellitus represent one of the most challenging scenarios with high rates of restenosis and stent thrombosis in the current era of drug-eluting stents. Hence, we assessed the safety of A-SES versus ZES in complex diabetic patients. METHODS: In this observational study, we analyzed all consecutive patients with diabetes mellitus referred to our center from November 2012 to November 2014. The primary outcome was target-lesion failure at 1-year follow-up. RESULTS: A total of 165 consecutive diabetic patients underwent percutaneous coronary intervention with A-SES or ZES for stable coronary artery disease in our tertiary center. Using the Kaplan Meier method the cumulative incidence of target-lesion failure was 6.7% (5.9% A-SES versus 7.5% ZES, p=0.19) at 1-year follow-up. Event-free survival at 1year follow up was similar (89.4% A-SES vs. 83.3% ZES, p=0.29). Interestingly, we did not find any cases of definite-, and only one case of probable stent thrombosis in this high risk cohort. CONCLUSION: In this real-world registry, A-SES and ZES seems to be associated with promising 1-year clinical safety outcomes following PCI in a contemporary cohort of high-risk diabetic patients. Our results should be considered hypothesis generating, as the clinical safety of A-SES has to be confirmed in a large trial. PMID- 29137967 TI - Procedural and thirty-day outcomes following transfemoral implantation of the fully repositionable and retrievable Lotus valve without routine pre-dilatation in a consecutive patient cohort: a single-center experience. AB - BACKGROUND / PURPOSE: The Lotus valve (Boston Scientific, Natick, MA, USA) is a contemporary transcatheter aortic valve implantation (TAVI) device that is fully repositionable and retrievable to aid implantation and optimise procedural results. The ability to implant the device without routine pre-dilatation is another possible advantage reducing associated risks and procedure times. The aim of this study is to report procedural and 30-day outcomes following TAVI in a consecutive patient group presenting with severe symptomatic aortic stenosis with the Lotus valve system without routine pre-dilatation. METHODS / MATERIALS: 146 consecutive patients that underwent TAVI at the John Radcliffe Hospital, Oxford between January 2015 - December 2016 were retrospectively analysed. RESULTS: The mean age was 81.1+/-7.4 years and the mean logistic EuroSCORE was 14.6+/-10. 134 (91.8%) of patients were treated under conscious sedation. 144 (98.6%) of procedures were successful. Two patients (1.4%) died during the follow-up period. None or mild residual aortic regurgitation was achieved in 98.6% of patients. The mean and peak transvalvular gradients were 8.6+/-3.6mmHg and 16.6+/-6.6mmHg respectively. Eight patients (5.5%) suffered a stroke. Over time, there was a reduction in major vascular complications (14.3% vs. 2.2%, p=0.03) and a trend toward shorter procedure times (97.6+/-44.3 vs. 86.8+/-31.4 minutes, p=0.14) and the administration of less contrast (104.4+/-45.2 vs. 91.7+/-37.6 millilitres, p=0.16). The overall new pacemaker implantation rate was 36.3%. CONCLUSIONS: The use of the Lotus valve as a 'workhorse' device without routine pre-dilatation is safe and efficacious and is associated with a very low incidence of residual aortic regurgitation and acceptable transvalvular haemodynamics. PMID- 29137968 TI - Food bundling as a health nudge: Investigating consumer fruit and vegetable selection using behavioral economics. AB - Displaying bundles of healthy foods at the grocery store is a health nudge that simplifies shopping and may have the potential for increasing fruit and vegetable (F&V) purchasing. To evaluate the impact of food bundling, we conduct an artefactual field experiment with community participants in a laboratory set up as a grocery store. Dual-self theory suggests that food choices may differ depending on whether shoppers are under cognitive load - in our experiment, we exogenously vary whether bundles are displayed (with and without a price discount) and whether shoppers are under cognitive load. Our findings align with prior studies that suggest unhealthy options are more likely to be selected when cognitive resources are constrained. When bundles are displayed, we observe increased F&V purchasing. We also observe a significant interaction between cognitive load and price discounting. We find discounted bundles are more effective in the absence of cognitive load, but non-discounted bundles are more effective when shoppers are under cognitive load. Although more research is warranted, our findings suggest that when shopping under cognitive load, it is possible that discounts impose additional cognitive strain on the shopping experience. For retailers and policymakers, our results point to the potential power of bundling as a strategy for increasing healthy food purchasing. PMID- 29137969 TI - Healthier vending machines in a university setting: Effective and financially sustainable. PMID- 29137970 TI - Dietary patterns in Mexican children and adolescents: Characterization and relation with socioeconomic and home environment factors. AB - BACKGROUND: Eating habits in children and adolescents are influenced by multiple determinants, which include socioeconomic and home environmental factors. OBJECTIVE: To characterize the dietary patterns in Mexican children and adolescents and to assess its association with socioeconomic and home environmental factors. METHODS: A cross-sectional study was conducted in 878 children and adolescents aged 5-15 years, unrelated, selected randomly from Morelos Sports Unit at north of Mexico City. Dietary, anthropometric, family, and socioeconomic information was obtained from each participant. Dietary patterns were identified through cluster analysis. The association between dietary patterns with socioeconomic and home environmental factors was assessed by a multivariate multinomial logistic regression model. RESULTS: Three major dietary patterns were identified: diverse dietary pattern (D), high fat dietary pattern (HF), and high sugar dietary pattern (HS). 87% of the participants followed the HF or HS dietary patterns (36% & 51%, respectively). Mother's occupation and the child's screen time was associated with a significant likelihood of following a HF and HS dietary patterns. CONCLUSION: A high percentage of children and adolescents reported following a HS or HF dietary pattern, which in turn were associated with socioeconomic and home environmental factors. These results suggests priority groups for prevention and control actions. PMID- 29137971 TI - Clearance of schistosome parasites by resistant genotypes at a single genomic region in Biomphalaria glabrata snails involves cellular components of the hemolymph. AB - Schistosomiasis is one of the most detrimental neglected tropical diseases. Controlling the spread of this parasitic illness requires effective sanitation, access to chemotherapeutic drugs, and control over populations of the freshwater snails, such as Biomphalaria glabrata, that are essential intermediate hosts for schistosomes. Effectively controlling this disease, while minimising ecological implications of such control, will require an extensive understanding of the immunological interactions between schistosomes and their molluscan intermediate hosts. Here we histologically characterise the clearance of schistosome larvae by snails that exhibit allelic variation at a single genomic region, the Guadeloupe resistance complex. We show that snails with a resistant Guadeloupe resistance complex genotype clear schistosomes within the first 24-48 h, and that this resistance can be transferred to susceptible snails via whole hemolymph but not cell-free plasma. These findings imply that Guadeloupe resistance complex-coded proteins help to coordinate hemocyte-mediated immune responses to schistosome infections in Guadeloupean snails. PMID- 29137973 TI - Exposure to polybrominated diphenyl ethers (PBDEs) and child behavior: Current findings and future directions. AB - Polybrominated diphenyl ethers (PBDEs) are recognized neurotoxicants, but the extent to which PBDEs influence various domains of behavior in children is not fully understood. As such, we reviewed epidemiologic studies published to date to provide an overview of the current state of knowledge on PBDEs' potential role in behavioral development. We identified 19 epidemiologic studies reporting on associations of prenatal and childhood concentrations of PBDEs with behaviors assessed in children from 1 to 12years, including executive function, attention, externalizing and internalizing behaviors, adaptive skills, and social behaviors/Autism Spectrum Disorder (ASD). While the mechanisms of PBDE neurotoxicity in humans are still not clearly elucidated, findings from this review indicate that PBDE exposure during fetal development is associated with impairments in executive function and poorer attentional control in children. Results from large prospective cohorts demonstrate that prenatal and postnatal PBDE exposure adversely impacts externalizing behavior (e.g., hyperactivity and conduct problems). Additional studies are needed to determine whether PBDEs are associated with internalizing problems, adaptive skills, and social behaviors/ASD in children. Future studies will help better understand the potential neurotoxic effects of PBDE exposures during adolescence, possible sex-dependent effects, and the impact of exposure to BDE-209 and alternative flame retardants. Future studies should also examine chemical mixtures to capture real-world exposures when examining PBDEs and their impact on various behavioral domains in the context of multiple chemical exposures. PMID- 29137972 TI - Circulating tumoral DNA: Preanalytical validation and quality control in a diagnostic laboratory. AB - We present the results of our technical validation process in establishing the analysis of circulating tumor DNA (ctDNA) as a diagnostic tool. Like most cells in our body, tumor cells shed DNA in the blood flow. Analysis of ctDNA mutational content can provide invaluable information on the genetic makeup of a tumor, and assist oncologists in deciding on therapy, or in following residual disease. However, low absolute amounts of circulating DNA and low tumor fraction constitute formidable analytical challenges. A key step is to avoid contamination with genomic DNA from cell lysis. Several brands of specialized blood collection tubes are available to prevent leukocyte lysis. We show that they are not equally efficient, depending on storage temperature and time before plasma preparation. We report our analysis of preanalytical factors pertaining to ctDNA analysis (tubes, transportation time, temperature) and our conclusions in terms of instructions to prescribing physicians. We also stress the importance of proper DNA quality control and compare several methods, including a differential amplicon length PCR technique which allows determination of multiple QC parameters from minimal amounts of DNA. Altogether, these data provide useful practical information to diagnostic laboratories wishing to implement the assay of ctDNA in clinical practice. PMID- 29137974 TI - Effects and mechanisms of matrix metalloproteinase2 on neural differentiation of induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) possess the potential to differentiate into neural lineage cells. Matrix metalloproteinase 2 (MMP2), an endopeptidase in the extracellular matrix, has been shown to protect neural cells from injury. However, the mechanisms and effects of MMP2 on neural differentiation of iPSCs remain poorly understood. Here, we demonstrated a role for MMP2 in the differentiation of iPSCs to neurons via the AKT pathway. Treatment of iPSCs with MMP2 promoted their proliferation and differentiation into neural stem cells (NSCs), and then into neurons. The transcript and protein expression of Nestin and microtubule-associated protein 2 (MAP2) increased. Moreover, MMP2 markedly induced the expression of phospho-AKT (pAKT) during these differentiation stages. Consistently, silencing MMP2 using siRNA attenuated the expression of Nestin, MAP2 and pAKT, compared with the control group. In addition, the increasing levels of Nestin, MAP2 and pAKT in the MMP2 group were declined by pretreatment with the phosphoinositide 3-kinase (PI3K)/AKT inhibitor, LY294002. Furthermore, the study detected that TrkA and TrkB were perhaps the potential receptors for these effects of MMP2 on neural differentiation through PI3K/AKT signaling pathway. Taken together, these results suggest that MMP2 induces the differentiation of iPSCs into neurons by regulating the AKT signaling pathway. PMID- 29137975 TI - Microarray analysis of an synthetic alpha-synuclein induced cellular model reveals the expression profile of long non-coding RNA in Parkinson's disease. AB - Long non-coding RNAs (lncRNAs) are a new research focus that are reported to influence the pathogenetic process of neurodegenerative disorders. To uncover new disease-associated genes and their relevant mechanisms, we carried out a gene microarray analysis based on a Parkinson's disease (PD) in vitro model induced by alpha-synuclein oligomers. This cellular model induced by 25 MUmol/L alpha synuclein oligomers has been confirmed to show the stable, transmissible neurotoxicity of alpha-synuclein, a typical PD pathological marker. And several differentially expressed lncRNAs and mRNAs were identified in this model, such as G046036, G030771, AC009365.4, RPS14P3, CTB-11I22.1, and G007549. Subsequent ceRNA analysis determined the potential relationships between these lncRNAs and their associated mRNAs and microRNAs. The results of the present study widen our horizon of PD susceptibility genes and provide new pathways towards efficient diagnostic biomarkers and therapeutic targets for PD. PMID- 29137976 TI - Proteomic analysis of CHO cell lines producing high and low quantities of a recombinant antibody before and after selection with methotrexate. AB - High levels of recombinant protein production in Chinese hamster ovary (CHO) cells can be achieved by amplification of transgenes using the dihydrofolate reductase/methotrexate (DHFR/MTX) system. With the aim to identify predictive markers enabling the preselection of suitable high producing clones we investigated the impact of MTX-based gene amplification on two CHO cells lines producing different levels of a human monoclonal antibody by carrying out a comparative proteome analysis. The difference in antibody yield between the high and low producer was 15-fold before and 245-fold after MTX selection. Difference in-gel electrophoresis of samples from before and after MTX selection revealed 17 unique proteins that were differentially expressed between the high and low productivity lines. Of these, five proteins were differently expressed before MTX selection, representing potential markers for productivity prior to selection and for engineering processes to generate novel CHO cell line with the desirable high productivity phenotype. Fifteen proteins were differently expressed between high and low producer after MTX selection. We further found that MTX selection induced more changes in the proteome of the low producer compared to the high producer. PMID- 29137977 TI - Downregulation of caveolin-1 increased EGFR-TKIs sensitivity in lung adenocarcinoma cell line with EGFR mutation. AB - Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have shown notable effects in lung adenocarcinoma patients harboring EGFR mutations, there are significant differences between individual patients in the degree of benefits provided by EGFR-TKIs. Some evidence supports a role for caveolin-1 (Cav-1) in modulating drug sensitivity. This study aimed to investigate whether Cav-1 plays an important role in sensitivity to EGFR-TKIs in lung adenocarcinoma cells. Downregulation of Cav-1 in PC-9 cells were performed to investigate changes in sensitivity to EGFR-TKIs in vitro and in vivo. Knockdown of Cav-1 dramatically enhanced sensitivity to EGFR-TKIs by down-regulating phosphorylation of EGFR. These results suggest that Cav-1 may be a predictor of the poor efficacy of EGFR TKIs treatment in lung adenocarcinoma with EGFR mutations. PMID- 29137978 TI - Endothelial Robo4 regulates IL-6 production by endothelial cells and monocytes via a crosstalk mechanism in inflammation. AB - Roundabout4 (Robo4) is an endothelial cell-specific receptor that stabilizes vasculature in pathological angiogenesis. Previous studies have shown that Robo4 is a potential therapeutic target for inflammatory diseases, but its precise roles in inflammation remain unclear. To investigate physiological Robo4 functions in inflammation, we performed a loss-of-function study in vitro and in vivo using lipopolysaccharide (LPS)-induced endotoxemia models. Subcutaneous injection of LPS into Robo4-knockout mice reduced circulating IL-6 levels. siRNA mediated Robo4 knockdown suppressed IL-6 production induced by LPS, IL-1beta, and TNFalpha, in human umbilical vein endothelial cells (HUVECs). Coculture experiments with HUVECs and a monocytic cell line, U937 cells, demonstrated that Robo4 knockdown suppresses IL-6 production by both endothelial cells and U937 cells. Further coculture experiments demonstrated that Robo4 knockdown inhibited a novel IL-6 amplification mechanism mediated by crosstalk between endothelial cells and U937 cells via direct interactions and two mediators, GM-CSF and IL 1beta. Taken together, we demonstrated novel Robo4 functions in inflammation, i.e., it promotes IL-6 production by endothelial cells and immune cells via crosstalk. PMID- 29137979 TI - Acute and chronic cadmium telluride quantum dots-exposed human bronchial epithelial cells: The effects of particle sizes on their cytotoxicity and carcinogenicity. AB - Quantum dots (QDs) are semiconducting nanocrystals with unique optical properties. When coated with shell/capping, QDs are not deleterious to cells and organisms. However, when QDs are retained in the cellular environment for a certain period of time, their coatings may be degraded, yielding "naked" QDs. Although some studies have documented the acute effects of cadmium telluride (CdTe) QDs in various cell lines, however, to our knowledge, there are no published studies on the chronic effects of CdTe QDs in normal lung cells. In this study, we therefore sought to study the effects of CdTe QDs of various particle sizes on their cytotoxicity and carcinogenicity in normal human bronchial epithelial cells (BEAS-2B). A total of three particle sizes of CdTe QD with emission maximum at 520, 580, and 730 nm were employed (abbreviated as 520Q, 580Q, and 730Q, respectively). Our results indicated that acute exposure to 520Q (~2.04 nm in diameter) and 580Q (~3.24 nm in diameter) elicited dose-dependent cytotoxicity; while acute exposure to 730Q (~5.40 nm in diameter) elicited negligible cytotoxicity in BEAS-2B cells. Notably, chronic exposure to CdTe QD of all three tested particle sizes induced BEAS-2B cell transformation as evidenced by enhanced cell migration and anchorage-independent growth on soft agar. Taken together, our findings suggest that CdTe QDs are potent human lung carcinogens. PMID- 29137980 TI - Interaction of Alpha-synuclein with Cytogaligin, a protein encoded by the proapoptotic gene GALIG. AB - GALIG, an internal gene to the human galectin-3 gene, encodes two distinct proteins, Mitogaligin and Cytogaligin through translation of a unique mRNA in two overlapping alternative reading frames. When overexpressed GALIG induces apoptosis. In cultured cells, Mitogaligin destabilizes mitochondria membranes through interaction with cardiolipin. Little is known regarding the role of Cytogaligin. This protein displays multiple subcellular localizations; cytosol, nucleus, and mitochondria. We illustrate here that Cytogaligin is also secreted in the extracellular medium. Cytogaligin is shown to interact with alpha Synuclein, the major component of Lewy bodies in Parkinson's disease. Overexpression of Cytogaligin reduces alpha-Synuclein dimerization raising a possible role in the evolution of alpha-Synuclein aggregation, a key molecular event underlying the pathogenesis of Parkinson's disease. PMID- 29137981 TI - Umbilical cord-derived mesenchymal stem cells alleviated inflammation and inhibited apoptosis in interstitial cystitis via AKT/mTOR signaling pathway. AB - Interstitial cystitis (IC) is a bladder syndrome characterized by pelvic pain and urinary frequency without infection or other identifiable pathology. There are no effective treatments to cure IC. This study investigated the effects of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) injection on IC rat model. Furthermore, we used a coculture system to find the possible molecular mechanism on the human uroepithelial cells (SV-HUC-1), which was the cell model of IC. A rat model of IC was established via systemic injection with cyclophosphamide (CYP) and a cell model of IC was induced by being exposed to tumor necrosis factor (TNF)-alpha (10 ng/ml). After one week, UC-MSCs injection significantly ameliorated the bladder voiding function in IC rat model. And the Histo- and immunohistochemical analyses showed that UC-MSCs can repair impaired bladder, reduce mast cell infiltration and inhibit apoptosis of urothelium. ELISA results showed that UC-MSCs can decrease IL-1beta, IL-6 and TNF-alpha in bladder. In the coculture system, UC-MSCs can promote proliferation of impaired SV-HUC-1 cells, and inhibit apoptosis. However, while knocked down EGF secreted by UC-MSCs with siRNA, the effects would be weaken. Western blot showed that UC-MSCs increase protein expression levels of p-AKT and p-mTOR in SV-HUC-1 cells, and decrease the levels of cleaved caspase-3. Taken together, we provide evidence that UC-MSCs therapy can successfully alleviate IC in a preclinical animal Model and cell model by alleviating inflammation, promoting proliferation and inhibiting apoptosis. In addition, we demonstrate that the AKT/mTOR signaling pathway was activated. PMID- 29137982 TI - Adipose tissue complement factor B promotes adipocyte maturation. AB - OBJECTIVES: It is well-known that the complement system plays an essential role in host immunity. Observational studies have indicated that complement system related molecules such as complement factor B (CfB) and other components are correlated with obesity and/or insulin resistance parameters. In this study, we investigated the role of adipocyte-derived CfB in adipose tissue metabolism. METHODS: We investigated the expression level of complement system-related genes in adipocytes. To understand the role of CfB in adipocyte, we performed Cfb overexpression in 3T3-L1 preadipocytes and generated adipocyte-specific Cfb transgenic mice. RESULTS: Cfb expression was markedly enhanced in 3T3-L1 adipocytes co-cultured with macrophages following endotoxin stimulation. In Cfb overexpressing cells, the expression of adipocyte differentiation/maturation related genes encoding peroxisome proliferator-activated receptor gamma (Ppargamma), adipocyte Protein 2 and perilipin was significantly enhanced. Cfb transgenic mice showed a marked increase in the expression of genes encoding Ppargamma, perilipin, sterol regulatory element-binding protein 1 c, and Cd36 in the subcutaneous adipose tissue. CONCLUSIONS: CfB plays a crucial role in late phase of adipocyte differentiation and subsequent lipid droplet formation. PMID- 29137983 TI - Transcriptional regulation of acetoacetyl-CoA synthetase by Sp1 in neuroblastoma cells. AB - Acetoacetyl-CoA synthetase (AACS) is the enzyme responsible for cholesterol and fatty acid synthesis in the cytosol. We have previously shown that AACS has an important role in normal neuronal development and that knockdown of SREBP-2, which orchestrates cholesterol synthesis, resulted in the downregulation of AACS mRNA levels. In this study, we investigated the transcriptional mechanism of AACS in Neuro-2a, neuroblastoma cells. Luciferase assay showed that the minimal core promoter of the mouse AACS gene is located in a region with 110 bps upstream from the transcription start site. Mutagenesis studies showed that the Sp1 binding site was crucial for AACS promoter activity. ChIP assay and DNA affinity precipitation assay showed that Sp1 binds to the Sp1 binding site on the promoter region of AACS. Moreover, overexpression of Sp1 increased AACS mRNA levels. Knockdown of AACS resulted in a decrease in histone deacetylase 9, associated with gene silencing. These results suggest that Sp1 regulates gene expression of AACS in Neuro-2a cells and ketone body utilization affects the balance of histone acetylation. PMID- 29137984 TI - Recombinant human GLP-1(rhGLP-1) alleviating renal tubulointestitial injury in diabetic STZ-induced rats. AB - GLP-1-based treatment improves glycemia through stimulation of insulin secretion and inhibition of glucagon secretion. Recently, more and more findings showed that GLP-1 could also protect kidney from diabetic nephropathy. Most of these studies focused on glomeruli, but the effect of GLP-1 on tubulointerstitial and tubule is not clear yet. In this study, we examined the renoprotective effect of recombinant human GLP-1 (rhGLP-1), and investigated the influence of GLP-1 on inflammation and tubulointerstitial injury using diabetic nephropathy rats model of STZ-induced. The results showed that rhGLP-1 reduced urinary albumin without influencing the body weight and food intake. rhGLP-1 could increased the serum C peptide slightly but not lower fasting blood glucose significantly. In diabetic nephropathy rats, beside glomerular sclerosis, tubulointerstitial fibrosis was very serious. These lesions could be alleviated by rhGLP-1. rhGLP-1 decreased the expression of profibrotic factors collagen I, alpha-SMA, fibronectin, and inflammation factors MCP-1 and TNFalpha in tubular tissue and human proximal tubular cells (HK-2 cells). Furthermore, rhGLP-1 significantly inhibited the phosphorylation of NF-kappaB, MAPK in both diabetic tubular tissue and HK-2 cells. The inhibition of the expression of TNFalpha, MCP-1, collagen I and alpha SMA in HK-2 cells by GLP-1 could be mimicked by blocking NF-kappaB or MAPK. These results indicate that rhGLP-1 exhibit renoprotective effect by alleviation of tubulointerstitial injury via inhibiting phosphorylation of MAPK and NF-kappaB. Therefore, rhGLP-1 may be a potential drug for treatment of diabetic nephropathy. PMID- 29137985 TI - The effect of surface charge on the thermal stability and ice recrystallization inhibition activity of antifreeze protein III (AFP III). AB - The aim of this study was to examine the effect of chemical cationization on the structure and function of antifreeze protein III (AFP III) over an extreme temperature range (-40 degrees C to +90 degrees C) using far-UV synchrotron radiation circular dichroism (SRCD) and ice recrystallization inhibition (IRI) assays. Chemical cationization was able to produce a modified AFP III with a net cationic charge at physiological pH that had enhanced resistance to denaturation at elevated temperatures, with no immediate negative impact on protein structure at subzero temperatures. Furthermore, cationized AFP III retained an IRI activity similar to that of native AFP III. Consequently, chemical cationization may provide a pathway to the development of more robust antifreeze proteins as supplementary cryoprotectants in the cryopreservation of clinically relevant cells. PMID- 29137986 TI - Long-range stress transmission guides endothelial gap formation. AB - In endothelial gap formation, local tractions exerted by the cell upon its basal adhesions are thought to exceed balancing tensile stresses exerted across the cell-cell junction, thus causing the junction to rupture. To test this idea, we mapped evolving tractions, intercellular stresses, and corresponding growth of paracellular gaps in response to agonist challenge. Contrary to expectation, we found little to no relationship between local tensile stresses and gap formation. Instead, we discovered that intercellular stresses were aligned into striking multi-cellular domains punctuated by defects in stress alignment. Surprisingly, gaps emerged preferentially not at stress hotspots, as predicted, but rather at stress defects. This unexpected behavior is captured by a minimal model of the cell layer as a jammed assembly of cohesive particles undergoing plastic rearrangements under tension. Together, experiments and model suggest a new physical picture in which gap formation, and its consequent effect on endothelial permeability, is determined not by a local stress imbalance at a cell-cell junction but rather by emergence of non-local, cooperative stress reorganization across the cellular collective. PMID- 29137987 TI - Degree of pectin methyl esterification in endosperm cell walls is involved in embryo bending in Arabidopsis thaliana. AB - The endosperm is a transitory structure involved in proper embryo elongation. The cell walls of mature seed endosperm are generally composed of a uniform distribution of cellulose, unesterified homogalacturonans, and arabinans. Recent studies suggest that changes in cell wall properties during endosperm development could be related to embryo growth. The degree of methyl esterification of homogalacturonans may be involved in this endosperm tissue remodelling. The relevance of the degree of homogalacturonan methyl esterification during seed development was determined by immunohistochemical analyses using a panel of probes with specificity for homogalaturonans with different degrees of methyl esterification. Low-esterified and un-esterified homogalacturonans were abundant in endosperm cells during embryo bending and were also detected in mature embryos. BIDXII (BDX) could be involved in seed development, because bdx-1 mutants had misshapen embryos. The methyl esterification pattern described for WT seeds was different during bdx-1 seed development; un-esterified homogalacturonans were scarcely present in the cell walls of endosperm in bending embryos and mature seeds. Our results suggested that the degree of methyl esterification of homogalacturonans in the endosperm cell wall may be involved in proper embryo development. PMID- 29137988 TI - TMS-EEG reveals hemispheric asymmetries in top-down influences of posterior intraparietal cortex on behavior and visual event-related potentials. AB - Clinical data and behavioral studies using transcranial magnetic stimulation (TMS) suggest right-hemisphere dominance for top-down modulation of visual processing in humans. We used concurrent TMS-EEG to directly test for hemispheric differences in causal influences of the right and left intraparietal cortex on visual event-related potentials (ERPs). We stimulated the left and right posterior part of intraparietal sulcus (IPS1) while the participants were viewing and rating the visibility of bilaterally presented Gabor patches. Subjective visibility ratings showed that TMS of right IPS shifted the visibility toward the right hemifield, while TMS of left IPS did not have any behavioral effect. TMS of right IPS, but not left one, reduced the amplitude of posterior N1 potential, 180 220ms after stimulus-onset. The attenuation of N1 occurred bilaterally over the posterior areas of both hemispheres. Consistent with previous TMS-fMRI studies, this finding suggests that the right IPS has top-down control on the neural processing in visual cortex. As N1 most probably reflects reactivation of early visual areas, the current findings support the view that the posterior parietal cortex in the right hemisphere amplifies recurrent interactions in ventral visual areas during the time-window that is critical for conscious perception. PMID- 29137989 TI - Does TMS on V3 block conscious visual perception? AB - Primary visual cortex (V1) and extrastriate V2 are necessary for the emergence of visual consciousness, but the effects of involvement of extrastriate V3 on visual consciousness is unclear. The objective of this study was to examine the causal role of V3 in visual consciousness in humans. We combined neuronavigated transcranial magnetic stimulation (TMS) with a computational model of the TMS induced electric field to test whether or not the intact processing of visual input in V3, like in V1 and V2, is necessary for conscious visual perception. We targeted the stimulation both to V2 and to V3. If TMS of V3 blocks conscious visual perception of stimuli, then activation in V3 is a causally necessary prerequisite for conscious perception of stimuli. According to the alternative hypothesis, TMS of V3 will not block the conscious visual perception of stimuli, because the pathways from V1 to the higher cortical areas that go around V3 provide sufficient visual input for the emergence of conscious visual perception. The results showed that TMS interfered with conscious perception of features, detection of stimulus presence and the ability to discriminate the letter stimuli both when TMS was targeted either to V3 or to V2. For the conscious detection of stimulus presence, the effect was significantly stronger when V2 was stimulated than when V3 was stimulated. The results of the present study suggest that in addition to the primary visual cortex and V2, also V3 causally contributes to the generation of the most basic form of visual consciousness. Importantly, the results also indicate that V3 is necessary for visual perception in general, not only for visual consciousness. PMID- 29137990 TI - Affective blindsight in the absence of input from face processing regions in occipital-temporal cortex. AB - Previous research suggests that the implicit recognition of emotional expressions may be carried out by pathways that bypass primary visual cortex (V1) and project to the amygdala. Some of the strongest evidence supporting this claim comes from case studies of "affective blindsight" in which patients with V1 damage can correctly guess whether an unseen face was depicting a fearful or happy expression. In the current study, we report a new case of affective blindsight in patient MC who is cortically blind following extensive bilateral lesions to V1, as well as face and object processing regions in her ventral visual stream. Despite her large lesions, MC has preserved motion perception which is related to sparing of the motion sensitive region MT+ in both hemispheres. To examine affective blindsight in MC we asked her to perform gender and emotion discrimination tasks in which she had to guess, using a two-alternative forced choice procedure, whether the face presented was male or female, happy or fearful, or happy or angry. In addition, we also tested MC in a four-alternative forced-choice target localization task. Results indicated that MC was not able to determine the gender of the faces (53% accuracy), or localize targets in a forced choice task. However, she was able to determine, at above chance levels, whether the face presented was depicting a happy or fearful (67%, p = .006), or a happy or angry (64%, p = .025) expression. Interestingly, although MC was better than chance at discriminating between emotions in faces when asked to make rapid judgments, her performance fell to chance when she was asked to provide subjective confidence ratings about her performance. These data lend further support to the idea that there is a non-conscious visual pathway that bypasses V1 which is capable of processing affective signals from facial expressions without input from higher-order face and object processing regions in the ventral visual stream. PMID- 29137991 TI - Spectrally decomposed dark-to-light transitions in a PSI-deficient mutant of Synechocystis sp. PCC 6803. AB - Cyanobacterial thylakoid membranes are known to host photosynthetic and respiratory complexes. This hampers a straight forward interpretation of the highly dynamic fluorescence originating from photosynthetic units. The present study focuses on dark-to-light transitions in whole cells of a PSI-deficient mutant of the cyanobacterium Synechocystis sp. PCC 6803. The time-dependent cellular fluorescence spectrum has been measured, while having previously exposed the cells to different conditions that affect respiratory activity. The analysis method used allows the detected signal to be decomposed in a few components that are then assigned to functional emitting species. Additionally, we have worked out a minimal mathematical model consisting of sensible postulated species to interpret the recorded data. We conclude that the following two functional complexes play a major role: a phycobilisome antenna complex coupled to a PSII dimer with either two or no closed reaction centers. Crucially, we present evidence for an additional species capable of strongly quenching fluorescence, whose formation requires the presence of oxygen. PMID- 29137992 TI - IR spectroscopy analysis of pancreatic lipase-related protein 2 interaction with phospholipids: 3. Monitoring DPPC lipolysis in mixed micelles. AB - Usual methods for the continuous assay of lipolytic enzyme activities are mainly based on the titration of free fatty acids, surface pressure monitoring or spectrophotometry using substrates labeled with specific probes. These approaches only give a partial information on the chemistry of the lipolysis reaction and additional end-point analyses are often required to quantify both residual substrate and lipolysis products. We used transmission infrared (IR) spectroscopy to monitor simultaneously the hydrolysis of phospholipids by guinea pig pancreatic lipase-related protein 2 (GPLRP2) and the release of lipolysis products. The substrate (DPPC, 1,2-Dipalmitoyl phosphatidylcholine) was mixed with sodium taurodeoxycholate (NaTDC) to form mixed micelles in D2O buffer at pD 6 and 8. After hydrogen/deuterium exchange, DPPC hydrolysis by GPLRP2 (100nM) was monitored at 35 degrees C in a liquid cell by recording IR spectra and time course variations in the CO stretching region. These changes were correlated to variations in the concentrations of DPPC, lysophospholipids (lysoPC) and palmitic acid (Pam) using calibration curves established with these compounds individually mixed with NaTDC. We were thus able to quantify each compound and its time-course variations during the phospholipolysis reaction and to estimate the enzyme activity. To validate the IR analysis, variations in residual DPPC, lysoPC and Pam were also quantified by thin-layer chromatography coupled to densitometry and similar hydrolysis profiles were obtained using both methods. IR spectroscopy can therefore be used to monitor the enzymatic hydrolysis of phospholipids and obtain simultaneously chemical and physicochemical information on substrate and all reaction products (H-bonding, hydration, acyl chain mobility). PMID- 29137993 TI - Characterization of cold adapted and ethanol tolerant beta-glucosidase from Bacillus cellulosilyticus and its application for directed hydrolysis of cellobiose to ethanol. AB - A beta-glucosidase gene from Bacillus cellulosilyticus was expressed in Escherichia coli BL21 and characterized. The recombinant enzyme (BcBgl1A) showed the optimal activity at 40 degrees C, and the half-life of BcBgl1A activity at 40 degrees C was 24h. BcBgl1A was sensitive to heat and exhibited obvious cold adapted activity, retained 27.2% and 46.5% of the optimal activity at 4 and 20 degrees C, respectively. The best activity was observed at pH 7.0 and stable over the range of pH 6.0-8.0. The activity was significantly enhanced by Fe2+, Fe3+ and Mn2+, also showed a high level of NaCl tolerance. BcBgl1A exhibited high activity using both pNPG and cellobiose as substrates, the Vmax for pNPG and cellobiose was 66.2 and 151.5U/mg of protein, respectively, and its Km values were 2.97 and 10.4mM, respectively. Catalysis efficiency (Kcat/Km) of 45.8s-1 (cellobiose) and 70.3s-1 (pNPG). It displayed high tolerance to glucose and ethanol, the Ki and IC50 value was 200mM and 15% (v/v), respectively. Additionally, the BcBgl1A was found to be highly efficient for conversion of cellobiose (100g/L) to ethanol by simultaneous saccharification and fermentation process, achieved an ethanol content of 47.2g/l corresponding to 87.9% of the theoretical ethanol yield. The results suggest that BcBgl1A has a potential for biotechnological applications in the bioconversion of lignocellulosic materials. PMID- 29137994 TI - WITHDRAWN: Role of osmolytes in protein folding and aggregation in cells and its applications in biotechnology. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 29137995 TI - New starch ester/gelatin based films: Developed and physicochemical characterization. AB - A new starch-based ester Starch-EDTAD-NHS (SEN) was successful prepared firstly and used to modify gelatin films by amidation. 1H NMR, FTIR spectra, XRD curves, elemental analysis and Van Slyke method verified the synthesis and confirmed the crosslinking procedure. The properties of the composite SEN-Gel film, such as mechanical test, surface hydrophobicity, light barrier performance, water uptake studies, morphology and solubility behavior were studied. The results of water contact angle showed the hydrophobicity of the films, and the obtained transparency values indicated that the films were opaque. Finally, the modified films with better surface hydrophobicity, more flexible and pliable, improved light barrier performances and low solubility were obtained. All the results above illustrated that the composite films obtained in this work maybe have potential applications in many fields. PMID- 29137996 TI - Mitochondrial genome of Diaphania indica(saunders) (Lepidoptera: Pyraloidea) and implications for its phylogeny. AB - The cucumber moth, Diaphania indica (Saunders) (Lepipdoptera: Pyralidae) is an economically important insect pest of cucurbits and is widely distributed in tropical and sub-tropical regions. Herein, we obtained entire mitochondrial genome (mitogenome) sequence of D. indica using polymerase chain reaction amplification and sequencing method. The complete mitogenome of D. indica is 15,367bp long, including 13 protein coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs) and an A+T rich element. Both the AT skew and GC skew are slightly negative in the newly sequenced mitogenome. All of the 12 PCGs initiate with canonical start codon (ATN), except for coxI that initiate with CGA. The A+T rich element of D. indica is 467bp long and contains many features common to Pyraloidea insects. In addition, we reconstructed phylogenetic relationships among the eight superfamiles of lepidopterans by employing Neighbor joining (NJ) and Maximum likelihood (ML) methods, and both yielded identical topologies. The phylogeny results supported the monophyly of lepidopteran superfamilies. Furthermore, phylogenetic tree showed that D. indica belongs to the Pyraloidea superfamily. PMID- 29137997 TI - Alginic acid: A mild and renewable bifunctional heterogeneous biopolymeric organocatalyst for efficient and facile synthesis of polyhydroquinolines. AB - Alginic acid, a widely used naturally occurring carbohydrate which is generally derived from brown seaweeds, can be considered as a bifunctional heterogeneous and green biopolymeric organocatalyst. Alginic acid, without any post modification with active Bronsted or Lewis acid centers, was found to be a highly active, cost-effective, commercially-available, renewable and recoverable heterogeneous biopolymeric organocatalyst for the expeditious synthesis of polyhydroquinolines (PHQs). Polyhydroquinolines were synthesized from the four component Hantzsch reaction of ethyl acetoacetate, different aldehydes, ammonium acetate and cyclic 1,3-diones under mild conditions in high to quantitative yields, 75-97%, using alginic acid. Furthermore, alginic acid was found to be reusable for at least 6 consecutive cycles without considerable loss of its catalytic activity. PMID- 29137998 TI - Effect of temperature and selected sugars on dilute solution properties of two hairless canary seed starches compared with wheat starch. AB - In this paper, influence of temperature (25, 35, 45 and 55 degrees C) and sugars (sucrose and lactose) at different concentrations (0, 5, 10 and 15%) on some molecular parameters of starches from two canary seed varieties (C05041 and CDC Maria) in the dilute regime were investigated in comparison to wheat starch (WS). The results indicated that the intrinsic viscosity ([eta]) values of C05041, CDC Maria and WS samples were 1.42, 1.46 and 1.70dl/g at 25 degrees C, respectively. Intrinsic viscosity of selected starches decreased with an increase in temperature, but the effect of high temperatures were somewhat unnoticeable. By increasing the sugar concentration, intrinsic viscosity of each starch solution significantly decreased in comparison with the value determined for sugar free solution. Lactose had more pronounced effect on the intrinsic viscosity reduction of CDC Maria starch and WS at 25 degrees C and 35 degrees C compared with sucrose (P<0.05). But at 55 degrees C, the effect of increasing sucrose on decreasing of [eta] of CDC Maria and WS samples were more considerable. The shape factor of starch samples at 25 degrees C were spherical, but increasing temperature from 25 degrees C to 55 degrees C, CSSs and WS samples took an ellipsoidal shape. The interaction between starches and solvent/cosolutes is the predominant factors determining their functional properties in food systems. One of the aspects can help to understand the characteristic of biopolymers such as starches is determination of their dilute solution properties as a function of common additives which are used in food systems. As a matter of fact, dilute solution properties can help to understand the potential applications of biopolymers in food and non-food application. Attentively, dilute solution properties would give some priceless information about molecular properties, biopolymer behavior and its interaction with copolymers. For instance, intrinsic viscosity provides deep insight into fundamental properties of the solute and its interaction with the solvent and/or cosolutes, conformation of flexible chains. There are many studies which investigated the effect of different parameters such as temperature, salts and sugars on dilute solution properties of hydrocolloids, especially gums. Regrettably, few researches scrutinized the influence of various cosolutes on dilute solution properties of starch. Then in this paper, we studied the dilute solution properties of starches from two canary seed varieties (C05041 and CDC Maria), as a new potential source of starch, (CSSs), in comparison to wheat starch at different experimental conditions (temperatures and sugars at different concentrations) in order to shed light on its behavior in real system in comparison to wheat starch. Because of the unique properties of wheat starch, comparison of canary seed starch with wheat starch in dilute regime can help to having better vision of this new starch source. Overall, the intrinsic viscosity, coil dimensions (Rcoil and Vcoil), swollen specific volume, shape function, and hydration parameter of selected starches were determined affected by temperature and sugars concentration treatments. The importance of these results will be cleared when taking into account the influence of crucial additives generally used in food systems, for instance, different sugars and/or frequent processing parameters such as temperature on rheological and functional properties. PMID- 29137999 TI - Structural and functional changes of fibrinogen due to aging. AB - Different factors affect coagulation process. Since fibrinogen is the main coagulation factor, the influence of aging on fibrinogen structure and function was investigated in this study. Fibrinogen was isolated from plasma obtained from healthy persons in the age range 21-83 and examined. Lectin microarray analysis demonstrated increased glycosylation of fibrinogen due to aging, with predominant increase in high-mannose or hybrid type N-glycans, as well as tri-/tetraantennary complex N-glycans with greater content of galactose and N-acetylglucosamine residues. Spectrofluorimetric analysis indicated that fibrinogen molecules have more densely packed structure, but there are no additional advanced glycation end products with increasing age. According to the results of functional analysis, fibrinogen molecules isolated from older persons exhibited reduced clotting time, with significant positive correlation with age, but there were no differences in clotting speed, maximal optical density of fibrin clot, diameter of fibrin fibres, fibrin porosity or reactivity with the insulin-like growth factor binding protein 1. Glycosylation changes of fibrinogen in healthy aging most likely affect its structure and function, namely clotting time. Structural and functional studies of proteins in relation to healthy aging contribute to deeper understanding of mechanisms responsible for longevity. PMID- 29138000 TI - Physiometabolic effects of Agave salmiana fructans evaluated in Wistar rats. AB - A prospective completely randomized experimental study was conducted using 48 animals to evaluate the physiometabolic effects of Agave salmiana fructans as a dietary supplement in healthy Wistar rats. Five fructans concentrations from 5 to 20% (w/w) and one control were used in the rats' diet and were divided into six groups (n=8 rats/group). The treatments were carried out for 35days, during which glucose, cholesterol, triglycerides, body-weight gain, food intake, fecal excretion, organ weights, renal and hepatic functions and a histological analysis of the cecum were evaluated. Glucose, cholesterol, triglycerides, renal and hepatic functions were not significantly affected by any treatment. Body-weight gain and food intake were lower in the rat groups fed fructans than in the control group. Increased fecal excretion (p<0.05) was observed only in animals fed 12.5 and 20% fructans. Mice supplemented with fructans exhibited increased weight and length (p<0.05) in the cecum and colon. A histological analysis of the cecum showed cellular proliferation with a dose of 12.5% and membrane lysis at doses of 15 and 20%. In conclusion, the inclusion of 12.5% of Agave salmiana fructans in the animals' diets exerts beneficial physiometabolic effects after the seventh treatment day. PMID- 29138001 TI - PDZ Ligand Binding-Induced Conformational Coupling of the PDZ-SH3-GK Tandems in PSD-95 Family MAGUKs. AB - Discs large (DLG) MAGUKs are abundantly expressed in glutamatergic synapses, crucial for synaptic transmission, and plasticity by anchoring various postsynaptic components including glutamate receptors, downstream scaffold proteins and signaling enzymes. Different DLG members have shared structures and functions, but also contain unique features. How DLG family proteins function individually and cooperatively is largely unknown. Here, we report that PSD-95 PDZ3 directly couples with SH3-GK tandem in a PDZ ligand binding-dependent manner, and the coupling can promote PSD-95 dimerization and multimerization. Aided by sortase-mediated protein ligation and selectively labeling, we elucidated the PDZ3/SH3-GK conformational coupling mechanism using NMR spectroscopy. We further demonstrated that PSD-93, but not SAP102, can also undergo PDZ3 ligand binding-induced conformational coupling with SH3-GK and form homo-oligomers. Interestingly, PSD-95 and PSD-93 can also form ligand binding induced hetero-oligomers, suggesting a cooperative assembly mechanism for the mega-N-methyl-d-aspartate receptor synaptic signaling complex. Finally, we provide evidence showing that ligand binding-induced conformational coupling between PDZ and SH3-GK is a common feature for other MAGUKs including CASK and PALS1. PMID- 29138002 TI - The Mechanism of HdeA Unfolding and Chaperone Activation. AB - HdeA is a periplasmic chaperone that is rapidly activated upon shifting the pH to acidic conditions. This activation is thought to involve monomerization of HdeA. There is evidence that monomerization and partial unfolding allow the chaperone to bind to proteins denatured by low pH, thereby protecting them from aggregation. We analyzed the acid-induced unfolding of HdeA using NMR spectroscopy and fluorescence measurements, and obtained experimental evidence suggesting a complex mechanism in HdeA's acid-induced unfolding pathway, as previously postulated from molecular dynamics simulations. Counterintuitively, dissociation constant measurements show a stabilization of the HdeA dimer upon exposure to mildly acidic conditions. We provide experimental evidence that protonation of Glu37, a glutamate residue embedded in a hydrophobic pocket of HdeA, is important in controlling HdeA stabilization and thus the acid activation of this chaperone. Our data also reveal a sharp transition from folded dimer to unfolded monomer between pH3 and pH 2, and suggest the existence of a low populated, partially folded intermediate that could assist in chaperone activation or function. Overall, this study provides a detailed experimental investigation into the mechanism by which HdeA unfolds and activates. PMID- 29138003 TI - Serine/Threonine Protein Kinases from Bacteria, Archaea and Eukarya Share a Common Evolutionary Origin Deeply Rooted in the Tree of Life. AB - The main family of serine/threonine/tyrosine protein kinases present in eukarya was defined and described by Hanks et al. in 1988 (Science, 241, 42-52). It was initially believed that these kinases do not exist in bacteria, but extensive genome sequencing revealed their existence in many bacteria. For historical reasons, the term "eukaryotic-type kinases" propagated in the literature to describe bacterial members of this protein family. Here, we argue that this term should be abandoned as a misnomer, and we provide several lines of evidence to support this claim. Our comprehensive phylostratigraphic analysis suggests that Hanks-type kinases present in eukarya, bacteria and archaea all share a common evolutionary origin in the lineage leading to the last universal common ancestor (LUCA). We found no evidence to suggest substantial horizontal transfer of genes encoding Hanks-type kinases from eukarya to bacteria. Moreover, our systematic structural comparison suggests that bacterial Hanks-type kinases resemble their eukaryal counterparts very closely, while their structures appear to be dissimilar from other kinase families of bacterial origin. This indicates that a convergent evolution scenario, by which bacterial kinases could have evolved a kinase domain similar to that of eukaryal Hanks-type kinases, is not very likely. Overall, our results strongly support a monophyletic origin of all Hanks-type kinases, and we therefore propose that this term should be adopted as a universal name for this protein family. PMID- 29138004 TI - Development of an empirical model to predict malaria outbreaks based on monthly case reports and climate variables in Hefei, China, 1990-2011. AB - Malaria remains a significant public health concern in developing countries. Drivers of malaria transmission vary across different geographical regions. Climatic variables are major risk factor in seasonal and secular patterns of P. vivax malaria transmission along Anhui province. The study aims to forecast malaria outbreaks using empirical model developed in Hefei, China. Data on the monthly numbers of notified malaria cases and climatic factors were obtained for the period of January 1st 1990 to December 31st 2011 from the Hefei CDC and Anhui Institute of Meteorological Sciences, respectively. Two logistic regression models with time series seasonal decomposition were used to explore the impact of climatic and seasonal factors on malaria outbreaks. Sensitivity and specificity statistics were used for evaluating the predictive power. The results showed that relative humidity (OR = 1.171, 95% CI = 1.090-1.257), sunshine (OR = 1.076, 95% CI = 1.043-1.110) and barometric pressure (OR = 1.051, 95% CI = 1.003-1.100) were significantly associated with malaria outbreaks after adjustment for seasonality in Hefei area. The validation analyses indicated the overall agreement of 70.42% (sensitivity: 70.52%; specificity: 70.30%). The research suggested that the empirical model developed based on disease surveillance and climatic conditions may have applications in malaria control and prevention activities. PMID- 29138005 TI - Distinct hypoxic regulation of preadipocyte factor-1 (Pref-1) in preadipocytes and mature adipocytes. AB - Preadipocyte factor-1 (Pref-1) is a secretory soluble protein, which exerts pleiotropic effects on maintenance of cancer stem cell characteristics and commitment of mesenchymal stem cell lineages by inhibiting adipogenesis. Observations that obesity renders the microenvironment of adipose tissues hypoxic and that hypoxia inhibits adipogenesis lead us to investigate whether hypoxia increases the expression of anti-adipogenic Pref-1 in preadipocytes, mature adipocytes, and adipose tissues from obese mouse. In 3T3-L1 preadipocytes, hypoxia induces Pref-1 by a hypoxia-inducible factor 1 (HIF-1)-dependent mechanism accompanied by increase in the levels of the active histone mark, acetylated H3K9/14 (H3K9/14Ac). Adipogenesis increased the levels of the heterochromatin histone mark, trimethylated H3K27 (H3K27me3), whereas it decreased the levels of H3K4me3 and H3K9/14Ac euchromatin marks of the mouse Pref 1 promoter. However, differently from preadipocytes, in mature adipocytes hypoxia failed to reverse the repressive epigenetic changes of Pref-1 promoter and to increase its expression. Short term (8weeks) high fat diet (HFD) increased HIF 1alpha protein in subcutaneous and epididymal adipose tissues, but did not increase Pref-1 expression. Unlike in 3T3-L1 preadipocytes, HIF-1alpha did not increase Pref-1 expression in adipose tissues in which mature adipocytes constitute the main population. Interestingly, long term (35weeks) HFD increased Pref-1 in serum but not in obese adipose tissues. This study suggests that Pref-1 is an endocrine factor which is synergistically increased by obesity and age. PMID- 29138006 TI - Distorted leukocyte migration, angiogenesis, wound repair and metastasis in Tspan8 and Tspan8/CD151 double knockout mice indicate complementary activities of Tspan8 and CD51. AB - The tetraspanin Tspan8 supports via associated integrins and proteases tumor progression and angiogenesis. To shed light on its activities in non-transformed cells, we generated a Tspan8 knockout (ko) mouse, comparing leukocyte migration, angiogenesis, wound healing and tumor growth with wild type, CD151ko and Tspan8/CD151ko (dbko) mice. CD151ko mice were included as CD151 activities resemble that of Tspan8, and dbko mice to exclude mutual substitution. Tspan8ko and dbko mice show no pathological phenotype. However, delayed type hypersensitivity reactions are mitigated in Tspan8ko mice, angiogenesis is severely impaired in Tspan8ko, CD151ko and dbko mice, with Tspan8 mostly affecting lymphangiogenesis. Distinct contributions of CD151 and Tspan8 to skin wound healing rely on preferentially CD151 anchoring basal keratinocytes and Tspan8 promoting motility. Proliferation of wounded skin keratinocytes is not affected. Metastasis formation of a melanoma and a Tspan8-expressing pancreatic cancer line was impaired in Tspan8ko and dbko mice, pointing towards a contribution of host Tspan8 to tumor progression. In line with the importance of tetraspanins in exosome-mediated intercellular communication, defects became mitigated by Tspan8/CD151-competent serum exosomes, which offers a most promising therapeutic option for chronic wounds and arteriosclerosis. PMID- 29138007 TI - RBM4-SRSF3-MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell. AB - Alternative splicing (AS) of pre-messenger (m)RNA is a pivotal mechanism in expanding proteomic diversity, which determines the functions of mammalian cells. By conducting transcriptome analyses to profile splicing events in human colorectal cancer (CRC) tissues compared to adjacent normal counterparts, we noted differential splicing profiles of serine/arginine-rich splicing factor 3 (SRSF3) and mitogen-activated protein 4 kinase 4 (MAP4K4) in cancerous tissues of CRC compared to adjacent normal tissues. In addition to SRSF3-mediated autoregulation, RNA-binding motif protein 4 (RBM4) constituted another mechanism in reprogramming the splicing profile of SRSF3. Upregulated expressions of SRSF3 in CRC cells modulated utilization of MAP4K4 exon 16 in a sequence-dependent manner. Alternatively spliced MAP4K4 variants exhibited differential effects on the phosphorylation of c-Jun N-terminal protein kinase 1 (JNK1) which subsequently modulated expression profiles of E-cadherin, N-cadherin, and vimentin, all of which are involved in the migration and invasion of CRC cells. Collectively, RBM4-SRSF3-MAP4K4 constitutes a novel mechanism for manipulating the metastasis of CRC cells through the JNK1 signaling pathway. PMID- 29138008 TI - G-quadruplex structure at intron 2 of TFE3 and its role in Xp11.2 translocation and splicing. AB - Transcription Factor E3 (TFE3) translocation is found in a group of different type of cancers and most of the translocations are located in the 5' region of TFE3 which may be considered as Breakpoint Region (BR). In our In silico study by QGRS mapper and non BdB web servers we found a Potential G-quadruplex forming Sequence (PQS) in the intron 2 of TFE3 gene. In vitro G-quadruplex formation was shown by native PAGE in presence of Pyridostatin(PDS), which with inter molecular secondary structure caused reduced mobility to migrate slower. G-quadruplex formation was mapped at single base resolution by Sanger sequencing and Circular Dichroism showed the formation of parallel G-quadruplex. FRET analysis revealed increased and decreased formation of G-quadruplex in presence of PDS and antisense oligonucleotide respectively. PCR stop assay, transcriptional and translational inhibition by PQS showed stable G-quadruplex formation affecting the biological processes. TFE3 minigene splicing study showed the involvement of this G-quadruplex in TFE3 splicing too. Therefore, G-quadruplex is evident to be the reason behind TFE3 induced oncogenesis executed by translocation and also involved in the mRNA splicing. PMID- 29138009 TI - Human papillomavirus infection in females with normal cervical cytology: Genotyping and phylogenetic analysis among women in Punjab, Pakistan. AB - BACKGROUND: Globally, cervical cancer is the fourth most common cancer in women and the seventh most common cancer overall, accounting for an estimated 300 000 annual deaths. Human papillomavirus (HPV) is the second most common cause of cervical cancer worldwide. HPV screening is not a common practice in Pakistan. The aim of this study was to determine the prevalence of HPV and HPV types in women with a normal cytology of the cervix living in the upper and lower regions of Punjab, Pakistan, and to analyze the risk factors for HPV in this region. METHODS: PCR analysis was performed for 1011 female patients with a normal cytology of the cervix from various districts of Punjab Province, Pakistan. Risk factors for the acquisition of HPV were studied. High-risk HPV types (HPV16 and HPV18) were detected using the Abbott Real Time HR HPV test. To determine the genotype, partial L1 region sequences of HPV-positive samples were subjected to sequencing using MY/09/MY11 primers, and a phylogenetic tree was constructed using CLC software. RESULTS: The study found a 4.74% prevalence of HPV, with the most frequent HPV type found being the low-risk HPV6 (in 25% of infected individuals), followed by HPV55 (22.9%), HPV11 (20.8%), and high-risk types HPV45 (12.5%), HPV33 (8.33%), HPV18 (6.25%), and HPV16 (4.16%). Phylogenetic analysis of all HPV types in this study showed 80-99% nucleotide identity with types related to the same species. The sequences were clustered with China, India, Mexico, Iran, Slovenia, and Germany, showing the diversity in origin of the various genotypes prevalent in Pakistan. CONCLUSIONS: In this population with a normal cervical cytology, the prevalence of high-risk HPV types was very low. The major prevalent HPV genotype in Punjab Province of Pakistan was the low-risk HPV type 6, followed by HPV type 55. Sequencing of the partial L1 region suggested that the region was highly conserved in all reported sequences. This study highlights the need to conduct robust epidemiological studies in the region and to develop regular HPV screening so that the situation does not reach an alarming stage resulting in cervical cancer. PMID- 29138010 TI - Interest in the monitoring of eosinophil count as a marker of the response to antimicrobial therapy: In response to Karakonstantis and Dimitra. PMID- 29138011 TI - Worrisome high frequency of extended-spectrum beta-lactamase-producing Escherichia coli in community-acquired urinary tract infections: A case-control study; methodological issues. PMID- 29138012 TI - Systematic review on the reporting quality of randomized controlled trials in patients with hepatitis B or C in China. AB - BACKGROUND: The numbers of articles reporting randomized controlled trials (RCTs) on viral hepatitis in China have been increasing, but there have been few systematic studies evaluating the reporting quality of RCTs in this field. This study was performed to assess the reporting quality of RCTs on the treatment of hepatitis B and C in China from 1991 to 2015. METHODS: Articles published between January 1991 and December 2015 were identified via the PubMed, MEDLINE, and Embase databases using the key words "randomized clinical trials", "treatment", "therapy", "hepatitis B", "HBV", "hepatitis C", "HCV", "China", and "Chinese". The reporting quality was assessed against the Consolidated Standards of Reporting Trials (CONSORT) checklist. RESULTS: In total, 211 RCTs on the treatment of hepatitis B or C were included. The number of articles focusing on these RCTs increased rapidly over time, while the reporting quality improved steadily over time. Overall, compliance with the key components of the CONSORT checklist was low, with only 8.5%, 3.8%, and 11.4% of the articles fulfilling the reporting requirements of randomization, allocation concealment, and blinding, respectively. CONCLUSIONS: Both the number and the quality of RCT articles were found to have increased steadily over the last two decades. However, compliance with the key components of the CONSORT checklist still needs improvement. It is hoped that the results of this study will lead to improvements in the reporting quality of clinical trials on hepatitis B and C in China. PMID- 29138013 TI - Correspondence regarding "Changes in eosinophil count during bacterial infection: revisiting an old marker to assess the efficacy of antimicrobial therapy". PMID- 29138014 TI - Be cautious for exceptional results in evaluating the effect of adolescent booster of hepatitis B vaccine. PMID- 29138015 TI - Anti-phase synchronization of influenza A/H1N1 and A/H3N2 in Hong Kong and countries in the North Temperate Zone. AB - OBJECTIVES: Influenza affects 10% of the global population annually. Hong Kong is a subtropical city close to the North Temperate Zone (NTZ). Influenza-associated mortality rates in Hong Kong were 27.53, 79.55, 36.94, and 48.72 per one million person-years in 2014, 2015, 2016, and January to July 2017, respectively. The aim of this study was to explore the temporal patterns of influenza A subtypes in both Hong Kong and the NTZ. METHODS: Weekly reported cases of influenza A/H1N1 and A/H3N2 from January 2010 to July 2017 were downloaded from the Centre for Health Protection in Hong Kong and FluNet (provided by the World Health Organization). The spatio-temporal patterns of A/H1N1 and A/H3N2 in Hong Kong and the NTZ were explored. Anti-phase synchronization between A/H1N1 and A/H3N2 is indicated by a high for A/H1N1 coinciding with a low for A/H3N2, and vice versa. RESULTS: Anti-phase synchronization was evident in both Hong Kong and the NTZ. It was found that A/H3N2 clearly dominated in the 2011/2012, 2014/2015, and 2016/2017 influenza seasons. CONCLUSIONS: These results are novel in identifying anti-phase synchronization in influenza A subtypes in Hong Kong and the NTZ. These findings should inform public health preparedness for future epidemics of A/H3N2, which are typically more severe than those of A/H1N1. PMID- 29138016 TI - The challenges of detecting and responding to a Lassa fever outbreak in an Ebola affected setting. AB - OBJECTIVES: Lassa fever (LF), a priority emerging pathogen likely to cause major epidemics, is endemic in much of West Africa and is difficult to distinguish from other viral hemorrhagic fevers, including Ebola virus disease (EVD). Definitive diagnosis requires laboratory confirmation, which is not widely available in affected settings. The public health action to contain a LF outbreak and the challenges encountered in an EVD-affected setting are reported herein. METHODS: In February 2016, a rapid response team was deployed in Liberia in response to a cluster of LF cases. Active case finding, case investigation, contact tracing, laboratory testing, environmental investigation, risk communication, and community awareness raising were undertaken. RESULTS: From January to June 2016, 53 suspected LF cases were reported through the Integrated Disease Surveillance and Response system (IDSR). Fourteen cases (26%) were confirmed for LF, 14 (26%) did not have a sample tested, and 25 (47%) were classified as not a case following laboratory analysis. The case fatality rate in the confirmed cases was 29%. One case of international exportation was reported from Sweden. Difficulties were identified in timely specimen collection, packaging, and transportation (in confirmed cases, the time from sample collection to sample result ranged from 2 to 64 days) and a lack of response interventions for early cases. CONCLUSIONS: The delay in response to this outbreak could have been related to a number of challenges in this EVD-affected setting: a need to strengthen the IDSR system, develop preparedness plans, train rapid response teams, and build laboratory capacity. Prioritizing these actions will aid in the timely response to future outbreaks. PMID- 29138017 TI - Angiotensin converting enzyme inhibitors enhance the hypotensive effects of propofol by increasing nitric oxide production. AB - Propofol anesthesia is usually accompanied by hypotension. Studies have shown that the hypotensive effects of propofol increase in patients treated with angiotensin-converting enzyme inhibitors (ACEi). Given that both propofol and ACEi affect nitric oxide (NO) signaling, the present study tested the hypothesis that ACEi treatment induces pronounced hypotensive responses to propofol by increasing NO bioavailability. In this study we evaluated 65 patients, divided into three groups: hypertensive patients chronically treated with ACEi (HT-ACEi; n = 21), hypertensive patients treated with other antihypertensive drugs instead of ACEi, such as angiotensin II receptor blockers, beta-blockers or diuretics (HT; n = 21) and healthy normotensive subjects (NT; n = 23). Venous blood samples were collected at baseline and after 10min of anesthesia with propofol 2mg/kg administrated intravenously by bolus injection. Hemodynamic parameters were recorded at each blood sample collection. Nitrite levels were determined by using an ozone-based chemiluminescence assay, while NOx (nitrites+nitrates) levels were measured by using the Griess reaction. Additionally, experimental approaches were used to validate our clinical findings. Higher decreases in blood pressure after propofol anesthesia were observed in HT-ACEi group as compared with those found in NT and HT groups. Consistently, rats treated with the ACEi enalapril showed more intense hypotensive responses to propofol. The hypotensive effects of propofol were associated with increased NO production in both clinical and experimental approaches. Enhanced increases in nitrite levels after propofol anesthesia were observed in HT-ACEi patients compared with NT and HT groups. Accordingly, rats treated with enalapril showed increased vascular NO formation after propofol anesthesia compared with rats receiving vehicle. Our data show that ACEi enhance the hypotensive responses to propofol anesthesia and increase nitrite concentrations. These findings suggest that increased NO bioavailability may account for the enhanced hypotensive effects of propofol in ACEi-treated patients. PMID- 29138018 TI - Anti-tumor effects of cold atmospheric pressure plasma on vestibular schwannoma demonstrate its feasibility as an intra-operative adjuvant treatment. AB - Vestibular schwannoma (VS), although a benign intracranial tumor, causes morbidities by brainstem compression. Since chemotherapy is not very effective in most Nf2-negative schwannomas, surgical removal or radiation therapy is required. However, depending on the size and site of the tumor, these approaches may cause loss of auditory or vestibular functions, and severely decrease the post-surgical wellbeing. Here, we examined the feasibility of cold atmospheric pressure plasma (CAP) as an intra-operative adjuvant treatment for VS after surgery. Cell death was efficiently induced in both human HEI-193 and mouse SC4 VS cell lines upon exposure to CAP for seven minutes. Interestingly, both apoptosis and necroptosis were simultaneously induced by CAP treatment, and cell death was not completely inhibited by pan-caspase and receptor-interacting serine/threonine-protein kinase 1 (RIK1) inhibitors. Upon CAP exposure, cell death phenotype was similarly observed in patient-derived primary VS cells and tumor mass. In addition, CAP exposure after the surgical removal of primary tumor efficiently inhibited tumor recurrence in SC4-grafted mouse models. Collectively, these results strongly suggest that CAP should be developed as an efficient adjuvant treatment for VS after surgery to eliminate the possible remnant tumor cells, and to minimize the surgical area in the brain for post-surgical wellbeing. PMID- 29138019 TI - A patient with severe fever with thrombocytopenia syndrome and hemophagocytic lymphohistiocytosis-associated involvement of the central nervous system. AB - Severe fever with thrombocytopenia syndrome (SFTS), a severe infectious disease caused by novel bunyavirus, SFTS virus (SFTSV), is endemic to China, Korea, and Japan. Most SFTS patients show abnormalities in consciousness. Pathological findings in the central nervous system (CNS) of SFTS patients are not reported. A 53-year-old Japanese man was admitted to Uwajima City Hospital with an 8-day history of fever and diarrhea. Laboratory tests revealed leukopenia, thrombocytopenia, and liver enzyme elevation. He was diagnosed as having severe fever with thrombocytopenia syndrome (SFTS) following detection of the SFTSV genome in his blood. Bone marrow aspiration revealed hemophagocytic lymphohistiocytosis. He suffered progressive CNS disturbance and died on day 13 from onset of first symptoms. The SFTSV genome load in blood and levels of certain cytokines increased over the disease course. Necrotizing lymphadenitis with systemic lymphoid tissues positive for nucleocapsid protein (NP) of SFTSV was revealed by immunohistochemical (IHC) analysis. SFTSV-NP-positive immunoblasts were detected in all organs examined, including the CNS, and in the vascular lumina of each organ. Parenchymal cells of all organs examined were negative for SFTSV-NP on IHC analysis. Microscopic examination of the pons showed focal neuronal cell degeneration with hemosiderin-laden macrophages around extended microvessels with perivascular inflammatory cell infiltration and intravascular fibrin deposition. Autopsy confirmed this patient with SFTS was positive for systemic hemophagocytic lymphohistiocytosis including in the CNS. This patient's neurological abnormalities may have been caused by both functional and organic abnormalities. These novel findings provide important insights into the pathophysiology of SFTS. PMID- 29138020 TI - Moyamoya syndrome in a pediatric patient with congenital human immunodeficiency virus type 1 infection resulting in intracranial hemorrhage. AB - In the era of Antiretroviral Therapy (ART) in which human immunodeficiency virus type 1 (HIV-1) infection affected children can expect a better prognosis, the importance of careful follow up of pediatric HIV-1 cases for neurological complications has been growing. We present a case of hemorrhagic Moyamoya syndrome in a child with congenital HIV-1 infection. A 10-year-old girl was referred to our hospital for the treatment of Pneumocystis Jirovecii Pneumonia (PCP: Pneumocystis pneumonia). Her HIV-1 control was poor and Moyamoya syndrome was found during the opportunistic infection screening at admission. Despite subsequent successful treatment of PCP and HIV-1 infection, we could not save her life due to the intracranial hemorrhage caused by Moyamoya syndrome. A few reported cases of Moyamoya syndrome associated with HIV-1 infection have shown negative outcomes when the control of HIV-1 infection is unsuccessful. Recently "HIV-associated vasculopathy" has been used to describe the cerebrovascular disorder related to HIV-1 infection that is caused by the endothelial dysfunction induced from chronic inflammation and cytokine imbalances due to HIV-1 infection. We assumed that "HIV-associated vasculopathy" may have contributed to the development of collateral vessels impairment related to the bleeding, although the mechanism of vascular damage with HIV-1 infection is not yet well defined. Therefore proper management of the HIV-1 infection is crucial for Moyamoya syndrome with HIV-1 cases. Furthermore it is better to take into account the risk of intracerebral hemorrhage when considering the indication and timing of the revascularization surgery, although generally hemorrhaging is rare in Moyamoya disease in children. PMID- 29138021 TI - GyrA and/or ParC alterations of Haemophilus influenzae strains isolated from the urethra of men with acute urethritis. AB - Of 73 clinical strains of Haemophilus influenzae isolated from the urethra of men with urogenital infections, we enrolled 6 strains (8.2%) with levofloxacin (LVFX) minimum inhibitory concentrations (MICs) of >=0.03 MUg/ml in this study. All the strains were isolated from non-gonococcal urethritis (NGU). We amplified the quinolone resistance-determining region of the gyrA gene and the analogous region of the parC gene from bacterial DNAs by PCR and sequenced the PCR products. Two strains with a LVFX MIC of 0.03 MUg/ml had an amino acid change of Asp88 to Gly in GyrA. One with a LVFX MIC of 0.06 MUg/ml had a change of Asp88 to Tyr in GyrA. Two with respective LVFX MICs of 0.12 and 0.25 MUg/ml had a change of Ser84 to Leu in GyrA. One with a LVFX MIC of 1 MUg/ml had changes of Ser84 to Leu in GyrA and of Ser84 to Ile in ParC. Multilocus sequence typing showed two strains with a change of Asp88 to Gly in GyrA had the same sequence type, but the others had sequence types different from each other. Single amino acid changes in GyrA alone or single changes in both GyrA and ParC could contribute to decreased susceptibility to fluoroquinolones in H. influenzae isolates from NGU. Most of the isolates with GyrA and/or ParC alterations would be multiclonal. The prevalence of such isolates would be relatively low, and they would still be susceptible to fluoroquinolones commonly prescribed for treatment of NGU. PMID- 29138022 TI - To which mixtures are French pregnant women mainly exposed? A combination of the second French total diet study with the EDEN and ELFE cohort studies. AB - Pregnant women and their unborn child are exposed to a large number of substances during pregnancy. Some of these substances may cross the placenta, resulting in exposure of the foetus. There is growing evidence that certain substances could interact to produce a mixture effect. It is therefore essential to identify the main mixtures mothers are exposed to. This study aimed to identify the major mixtures French pregnant women included in EDEN and ELFE cohorts were exposed to, on the basis of the 441 substances analysed in the second French total diet study. Exposure systems and the composition of substances were identified from co exposures using sparse non-negative matrix under-approximation to generate the main mixtures. Individuals were clustered to define clusters with similar co exposure profiles. Six clusters associated with eight mixtures were identified. For example in ELFE, cluster 2 comprising 10% of the population was characterised by mixtures "Pest-1" mainly contains pesticides and "TE-F-PAH" contains trace elements, furans and polycyclic aromatic hydrocarbons. Five other clusters were also described with their associated mixtures. Similar results were observed for EDEN. This study helps to prioritise mixtures for which it is crucial to investigate possible toxicological effects and to recommend epidemiological studies concerning health effects. PMID- 29138023 TI - Oleanonic acid ameliorates pressure overload-induced cardiac hypertrophy in rats: The role of PKCzeta-NF-kappaB pathway. AB - It has been reported that inflammation is closely related with cardiac hypertrophy. Some inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 directly induce cardiac hypertrophy, which is associated with the activation of nuclear factorkappa B (NF-kappaB). Thus, NF kappaB is an attractive target for cardiac hypertrophy. In the present study, oleanonic acid inhibited the elevation of transcriptional activity of NF-kappaB and reduced the mRNA expressions of hypertrophic genes such as atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) in a concentration-dependent manner in phenylephrine (PE)-treated cardiomyocytes. Furthermore, we found that oleanonic acid inhibited the phosphorylation of protein kinase C zeta (PKCzeta) at Thr410 site and then reduced the activation of NF-kappaB using gain- and loss of-function approaches in PE-treated cardiomyocytes. In vivo, similar results were observed in abdominal aortic constriction (AAC) rats that were intragastrically administered with oleanonic acid, and the pathological changes accompanying cardiac hypertrophy were relieved. In conclusion, oleanonic acid can effectively ameliorate cardiac hypertrophy by inhibiting PKCzeta-NF-kappaB signaling pathway. PMID- 29138024 TI - (E)-3-(3,4,5-Trimethoxyphenyl)-1-(pyridin-4-yl)prop-2-en-1-one, a heterocyclic chalcone is a potent and selective CYP1A1 inhibitor and cancer chemopreventive agent. AB - The overexpression of CYP1 family of enzymes is reported to be associated with development of human carcinomas. It has been well reported that CYP1A1 specific inhibitors prevents carcinogenesis. Herein, thirteen pyridine-4-yl series of chalcones were synthesized and screened for inhibition of CYP1 isoforms 1A1, 1B1 and 1A2 in SacchrosomesTM and live human HEK293 cells. The structure-activity relationship analysis indicated that chalcones bearing tri-alkoxy groups (8a and 8k) on non-heterocyclic ring displayed selective inhibition of CYP1A1 enzyme, with IC50 values of 58 and 65 nM, respectively. The 3,4,5-trimethoxy substituted derivative 8a have shown >10-fold selectivity towards CYP1A1 with respect to other enzymes of the CYP1 sub-family and >100-fold selectivity with respect to CYP2 and CYP3 family of enzymes. The potent and selective CYP1A1 inhibitor 8a displayed antagonism of B[a]P mediated activation of aromatic hydrocarbon receptor (AhR) in yeast cells, and also protected human cells from CYP1A1 mediated B[a]P toxicity in human cells. This potent and selective inhibitor of CYP1A1 enzyme have a potential for development as cancer chemopreventive agent. PMID- 29138025 TI - Novel all-hydrocarbon stapled p110alpha[E545K] peptides as blockers of the oncogenic p110alpha[E545K]-IRS1 interaction. AB - To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i + 4]-stapled p110alpha[E545K] peptide 1 that was shown to potently block the intracellular p110alpha[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110alpha[E545K]) and the growth of the xenograft tumors formed by cancers harboring this mutation, in the current study we prepared and examined six derivatives of 1, i.e. stapled peptides 2-A, 2 B, 3-A, 3-B, 4-A, 4-B. We found that 2-A, 2-B, 4-A, and 4-B had higher % alpha helicity than 1; moreover, the enhanced % alpha-helicity also led to an enhanced proteolytic stability. When compared with 1, the structurally simplified 14-amino acid 4-A and 4-B were found to more potently deactivate the AKT phosphorylation at Ser473 in the p110alpha[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110alpha[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110alpha[E545K] peptides newly identified in the current study. PMID- 29138026 TI - Hybrid DNA i-motif: Aminoethylprolyl-PNA (pC5) enhance the stability of DNA (dC5) i-motif structure. AB - This report describes the synthesis of C-rich sequence, cytosine pentamer, of aep PNA and its biophysical studies for the formation of hybrid DNA:aep-PNAi-motif structure with DNA cytosine pentamer (dC5) under acidic pH conditions. Herein, the CD/UV/NMR/ESI-Mass studies strongly support the formation of stable hybrid DNA i-motif structure with aep-PNA even near acidic conditions. Hence aep-PNA C rich sequence cytosine could be considered as potential DNA i-motif stabilizing agents in vivo conditions. PMID- 29138027 TI - Imidazo[1,2-a]pyridines linked with thiazoles/thiophene motif through keto spacer as potential cytotoxic agents and NF-kappaB inhibitors. AB - A series of new imidazo[1,2-a]pyridine linked with thiazole/thiophene motif through a keto spacer were synthesized and tested for their cytotoxic potential against three human cancer cell lines including A549, HeLa and U87-MG using MTT assay. Compounds A2, A3, A4, C1 and C2 showed cytotoxicity against all the three cell lines. The selectivity index for compound A4 for A549 and HeLa cells was comparable to that of doxorubicin. Among the synthesized compounds, B5 showed the maximum inhibition of NF-kappaB activity as ascertained by NF-kappaB reporter assay (IC50 = 6.5 +/- 0.6 uM). Treatment of NCI-H23 cells (EGFR overexpressed, KRAS G12V mutant) with erlotinib and gefitinib along with compounds A4 and B5 indicated synergistic and additive potential of combination therapy. PMID- 29138028 TI - Synthesis and evaluation of C2 functionalized analogs of the alpha-tubulin binding natural product pironetin. AB - Pironetin is an alpha-tubulin-binding natural product with potent antiproliferative activity against several cancer cell lines that inhibits cell division by forming a covalent adduct with alpha-tubulin via a Michael addition into the natural product's alpha,beta-unsaturated lactone. We designed and prepared analogs carrying electron-withdrawing groups at the alpha-position (C2) of the alpha,beta-unsaturated lactone with the goal to generate potent and selective binding analogs. We prepared derivatives containing halogens, a phenyl, and a methyl group at the C2 position to evaluate the structure-activity relationship at this position. Testing of the analogs in ovarian cancer cell lines demonstrated 100-1000-fold decreased antiproliferative activity. PMID- 29138029 TI - Synthesis and antidepressant activity of a series of arylalkanol and aralkyl piperazine derivatives targeting SSRI/5-HT1A/5-HT7. AB - A series of arylalkanol and aralkyl piperazine derivatives have been synthesized and evaluated for 5-HT reuptake inhibitory abilities and binding affinities at the 5-HT1A/5-HT7 receptors. Antidepressant activities of the compounds in vivo were screened using the forced swimming test (FST). The results indicated that the compound 8j exhibited high affinities for the 5-HT1A/5-HT7 receptors (5-HT1A, ki = 0.84 nM; 5-HT7, ki = 12 nM) coupling with moderate 5-HT reuptake inhibitory activity (RUI, IC50 = 100 nM) and showed a marked antidepressant-like activity in the FST model. PMID- 29138030 TI - Aspergillus candidus is a newly recognized source of sphaeropsidin A: Isolation, semi-synthetic derivatization and anticancer evaluation. AB - This report details a search for alternative strains that produce the diterpenoid sphaeropsidin A (SphA) among A. candidus strains from the USDA Northern Regional Research Laboratories Culture Collection. We identified two strains that produced SphA using a limited set of test media. An initial scaled-up fermentation of NRRL 313 and isolation effort led to the procurement of sufficient quantities of SphA to prepare five semi-synthetic analogues (1-5) and evaluate their anticancer effects against glioblastoma cells D423 and Gli56 grown in 2D and 3D cultures. Although, the effectiveness of the synthetic analogues varied depending on the cell line and the type of cell culture, compound 5, bearing an aromatic ring at C16, displayed a stronger toxicity towards both D423 and Gli56 cell lines in 2D cultures and D423 spheroids in 3D culture than either SphA or compounds 1-4. PMID- 29138032 TI - Better Reporting Needed for Cosmetics and Women's Health. PMID- 29138031 TI - Mortality and pulmonary outcomes of extremely preterm infants exposed to antenatal corticosteroids. AB - BACKGROUND: Antenatal corticosteroids are given primarily to induce fetal lung maturation but results from meta-analyses of randomized controlled trials have not shown mortality or pulmonary benefits for extremely preterm infants although these are the infants most at risk of mortality and pulmonary disease. OBJECTIVE: We sought to determine if exposure to antenatal corticosteroids is associated with a lower rate of death and pulmonary morbidities by 36 weeks' postmenstrual age. STUDY DESIGN: Prospectively collected data on 11,022 infants 22 0/7 to 28 6/7 weeks' gestational age with a birthweight of >=401 g born from Jan. 1, 2006, through Dec. 31, 2014, were analyzed. The rate of death and the rate of physiologic bronchopulmonary dysplasia by 36 weeks' postmenstrual age were analyzed by level of exposure to antenatal corticosteroids using models adjusted for maternal variables, infant variables, center, and epoch. RESULTS: Infants exposed to any antenatal corticosteroids had a lower rate of death (2193/9670 [22.7%]) compared to infants without exposure (540/1302 [41.5%]) (adjusted relative risk, 0.71; 95% confidence interval, 0.65-0.76; P < .0001). Infants exposed to a partial course of antenatal corticosteroids also had a lower rate of death (654/2520 [26.0%]) compared to infants without exposure (540/1302 [41.5%]); (adjusted relative risk, 0.77; 95% confidence interval, 0.70-0.85; P < .0001). In an analysis by each week of gestation, infants exposed to a complete course of antenatal corticosteroids had lower mortality before discharge compared to infants without exposure at each week from 23-27 weeks' gestation and infants exposed to a partial course of antenatal corticosteroids had lower mortality at 23, 24, and 26 weeks' gestation. Rates of bronchopulmonary dysplasia in survivors did not differ by antenatal corticosteroid exposure. The rate of death due to respiratory distress syndrome, the rate of surfactant use, and the rate of mechanical ventilation were lower in infants exposed to any antenatal corticosteroids compared to infants without exposure. CONCLUSION: Among infants 22-28 weeks' gestational age, any or partial antenatal exposure to corticosteroids compared to no exposure is associated with a lower rate of death while the rate of bronchopulmonary dysplasia in survivors did not differ. PMID- 29138033 TI - Randomized trial of high- and low-fidelity simulation to teach intrauterine contraception placement. AB - BACKGROUND: High-fidelity simulation creates conditions that resemble real circumstances, and can help teach procedures such as intrauterine contraception placement. Its impact on skill retention has not been studied. OBJECTIVE: We sought to evaluate novice learners' skills, attitudes, and knowledge on placement of intrauterine contraception when trained using a high-fidelity commercially available simulator compared with a low-fidelity simulator. STUDY DESIGN: We recruited senior nurse practitioner students and interns in obstetrics and gynecology and family medicine inexperienced with intrauterine contraception placement. In this unblinded, randomized controlled trial, participants were assigned to practice within a high-fidelity simulator group or a coasterlike model group. We evaluated intrauterine contraception placement skills, self perceived comfort and competence, and knowledge before and after simulation, as well as at 3 months. Our primary outcome was the change in scores for intrauterine contraception placement skills before and after practice. Assuming a standard deviation of 15 points, we needed 10 participants per group to detect a 20-point difference in scores with 80% power. RESULTS: From June through July 2014, 60 participants enrolled; 59 completed the initial study visit and 1 withdrew. In all, 48 (80%) completed the second study visit at 3 months. Demographic characteristics were similar for the randomization groups. We observed an improvement in intrauterine contraception placement skills for both groups following practice on simulators (P < .01); the proportion that improved was similar (20% for the high-fidelity simulator group and 15% for the coaster group, P = .55). Increases in self-perceived comfort and competence with placing copper, levonorgestrel 52-mg, and levonorgestrel 13.5-mg devices were similar (all P >= .11). Knowledge assessment scores were comparable between the 2 groups postsimulation (73% for the high-fidelity simulator group and 80% for the coaster group, P = .29) and at 3 months (87% for both groups, P = 1.0). CONCLUSION: Trainees' knowledge, intrauterine contraception placement skills, and self perceived comfort and competence were comparable whether they used high- or low fidelity simulators. PMID- 29138034 TI - Understanding cosmetic product regulation could help reduce disparities. PMID- 29138036 TI - Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. AB - OBJECTIVE DATA: Metaanalyses of randomized controlled trials have reported contradictory results about the effect of aspirin in the prevention of preeclampsia, both in terms of the gestational age at the onset of treatment and the dose of the drug. The controversy may be resolved by a metaanalysis that includes several recently published trials and particularly the large Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence based Preeclampsia Prevention trial and by examination of whether there is a difference of the effect of aspirin on preterm vs term preeclampsia. STUDY: We performed a systematic review and metaanalysis that evaluated the prophylactic effect of aspirin during pregnancy. STUDY APPRAISAL AND SYNTHESIS METHODS: We completed a literature search through PubMed, Cinhal, Embase, Web of Science, and Cochrane library from 1985 to June 2017. Relative risks with random effect were calculated with their 95% confidence intervals. RESULTS: Sixteen trials that included 18,907 participants provided data for preterm and term preeclampsia. Eight of the included studies were evaluated as being of good quality, and the other 8 studies were deemed to be of poor or uncertain quality. There was high heterogeneity within studies (I2 >50%) for preterm and term preeclampsia, but no heterogeneity was found in the subgroup of preterm preeclampsia when the onset of treatment was <=16 weeks of gestation and the daily dose of aspirin was >=100 mg (I2=0%). Administration of aspirin was associated with reduction in the risk of preterm preeclampsia (relative risk, 0.62; 95% confidence interval, 0.45-0.87), but there was no significant effect on term preeclampsia (relative risk, 0.92; 95% confidence interval, 0.70-1.21). The reduction in preterm preeclampsia was confined to the subgroup in which aspirin was initiated at <=16 weeks of gestation and at a daily dose of >=100 mg (relative risk, 0.33; 95% confidence interval, 0.19-0.57). This effect was also observed in the high-quality studies. The reduction in preterm preeclampsia that was observed in the largest trial (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention; n=1620; relative risk, 0.38; 95% confidence interval, 0.20-0.72) was similar to that in the 5 smaller trials in which aspirin was initiated at <=16 weeks of gestation and at a daily dose of >=100 mg (n=639; relative risk, 0.22; 95% confidence interval, 0.07-0.66). CONCLUSION: Aspirin reduces the risk of preterm preeclampsia, but not term preeclampsia, and only when it is initiated at <=16 weeks of gestation and at a daily dose of >=100 mg. PMID- 29138039 TI - Is This Urgency an Emergency?...Sometimes. PMID- 29138037 TI - Genetic predisposition to preeclampsia is conferred by fetal DNA variants near FLT1, a gene involved in the regulation of angiogenesis. AB - Preeclampsia risk is influenced by both the mother's genetic background and the genetics of her fetus; however, the specific genes responsible for conferring preeclampsia risk have largely remained elusive. Evidence that preeclampsia has a genetic predisposition was first detailed in the early 1960s, and overall preeclampsia heritability is estimated at ~55%. Many traditional gene discovery approaches have been used to investigate the specific genes that contribute to preeclampsia risk, but these have largely not been successful or reproducible. Over the past decade, genome-wide association studies have allowed for significant advances in the understanding of the genetic basis of many common diseases. Genome-wide association studies are predicated on the idea that the genetic basis of many common diseases are complex and polygenic with many variants, each with modest effects that contribute to disease risk. Using this approach in preeclampsia, a large genome-wide association study recently identified and replicated the first robust fetal genomic region associated with excess risk. A screen of >7 million genetic variants in 2658 offspring from preeclamptic women and 308,292 population controls identified a single association signal close to the Fms-like tyrosine kinase 1 gene, on chromosome 13. Fms-like tyrosine kinase 1 encodes soluble Fms-like tyrosine kinase 1, a splice variant of the vascular endothelial growth factor receptor that exerts antiangiogenic activity by inhibiting signaling of proangiogenic factors. The Fms like tyrosine kinase 1 pathway is central in preeclampsia pathogenesis because excess circulating soluble Fms-like tyrosine kinase 1 in the maternal plasma leads to the hallmark clinical features of preeclampsia, including hypertension and proteinuria. The success of this landmark fetal preeclampsia genome-wide association study suggests that well-powered, larger maternal and fetal genome wide association study will be fruitful in identifying additional common variants that implicate causal preeclampsia genes and pathways. Such efforts will rely on the continued development of large preeclampsia consortia focused on preeclampsia genetics to obtain adequate sample sizes, detailed clinical phenotyping, and matched maternal-fetal samples. In summary, the fetal preeclampsia genome-wide association study represents an exciting advance in preeclampsia biology, suggesting that dysregulation at the Fms-like tyrosine kinase 1 locus in the fetal genome (likely in the placenta) is a fundamental molecular defect in preeclampsia. PMID- 29138035 TI - Defining failed induction of labor. AB - BACKGROUND: While there are well-accepted standards for the diagnosis of arrested active-phase labor, the definition of a "failed" induction of labor remains less certain. One approach to diagnosing a failed induction is based on the duration of the latent phase. However, a standard for the minimum duration that the latent phase of a labor induction should continue, absent acute maternal or fetal indications for cesarean delivery, remains lacking. OBJECTIVE: The objective of this study was to determine the frequency of adverse maternal and perinatal outcomes as a function of the duration of the latent phase among nulliparous women undergoing labor induction. STUDY DESIGN: This study is based on data from an obstetric cohort of women delivering at 25 US hospitals from 2008 through 2011. Nulliparous women who had a term singleton gestation in the cephalic presentation were eligible for this analysis if they underwent a labor induction. Consistent with prior studies, the latent phase was determined to begin once cervical ripening had ended, oxytocin was initiated, and rupture of membranes had occurred, and was determined to end once 5-cm dilation was achieved. The frequencies of cesarean delivery, as well as of adverse maternal (eg, postpartum hemorrhage, chorioamnionitis) and perinatal (eg, a composite frequency of seizures, sepsis, bone or nerve injury, encephalopathy, or death) outcomes, were compared as a function of the duration of the latent phase (analyzed with time both as a continuous measure and categorized in 3-hour increments). RESULTS: A total of 10,677 women were available for analysis. In the vast majority (96.4%) of women, the active phase had been reached by 15 hours. The longer the duration of a woman's latent phase, the greater her chance of ultimately undergoing a cesarean delivery (P < .001, for time both as a continuous and categorical independent variable), although >40% of women whose latent phase lasted >=18 hours still had a vaginal delivery. Several maternal morbidities, such as postpartum hemorrhage (P < .001) and chorioamnionitis (P < .001), increased in frequency as the length of latent phase increased. Conversely, the frequencies of most adverse perinatal outcomes were statistically stable over time. CONCLUSION: The large majority of women undergoing labor induction will have entered the active phase by 15 hours after oxytocin has started and rupture of membranes has occurred. Maternal adverse outcomes become statistically more frequent with greater time in the latent phase, although the absolute increase in frequency is relatively small. These data suggest that cesarean delivery should not be undertaken during the latent phase prior to at least 15 hours after oxytocin and rupture of membranes have occurred. The decision to continue labor beyond this point should be individualized, and may take into account factors such as other evidence of labor progress. PMID- 29138040 TI - Ultrasound Finding of Ischiofemoral Impingement Syndrome and Novel Treatment With Botulinum Toxin Chemodenervation: A Case Report. AB - : Ischiofemoral impingement syndrome (IFIS) is a rare and poorly understood condition that leads to deep gluteal pain, groin, and/or medial thigh pain. It has unique diagnostic challenges, with limited nonoperative treatment options. It is caused by the impingement of the quadratus femoris by the lesser trochanter and the ischium. Currently, there are no validated physical examination maneuvers for IFIS, and the value of ischiofemoral interval for establishing IFIS is also uncertain. Ultrasound-guided corticosteroid injections have been reported. Here, we present a case of novel treatment of IFIS with botulinum chemodenervation that led to long-term symptomatic and functional improvement in this patient, with the unique ultrasound findings of the "eruption sign." LEVEL OF EVIDENCE: IV. PMID- 29138038 TI - Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep. AB - BACKGROUND: Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure. OBJECTIVE: The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone acetate in preterm fetal sheep. STUDY DESIGN: Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours. RESULTS: All betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg. CONCLUSION: A single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus. PMID- 29138041 TI - Attendance at Prescribed Pelvic Floor Physical Therapy in a Diverse, Urban Urogynecology Population. AB - BACKGROUND: Pelvic floor physical therapy (PFPT) is a common and effective treatment for several pelvic floor disorders, but there is limited knowledge about adherence to the therapy or what factors influence attendance. OBJECTIVE: To determine rates of PFPT attendance (initiation and completion) as well as correlates of PFPT attendance. DESIGN: Retrospective cohort analysis. SETTING: Urban outpatient clinics at a tertiary medical center treating women with pelvic floor disorders. PARTICIPANTS: Patients prescribed PFPT during the time period January 1, 2014, through January 1, 2015. MAIN OUTCOME MEASUREMENTS: Number of PFPT visits recommended and attended; diagnoses associated with PFPT referral. RESULTS: Two-thirds of participants (66%; 118/180) initiated PFPT but less than one-third (29%; 52/180) completed the full treatment course. On univariate analysis, age, body mass index, diagnosis requiring PFPT treatment, marital or employment status, insurance type, number of comorbidities, incontinence status on examination, and stage of prolapse did not differ between PFPT initiators and noninitiators. Those who self-identified as Hispanic were less likely to initiate PFPT when compared with non-Hispanic patients, although this only trended toward significance (odds ratio 0.40, 95% confidence interval 0.14-1.09; exact P = .078). CONCLUSIONS: Two-thirds (66%) of patients initiated PFPT but less than one third (29%) completed the treatment course. There appears to be an opportunity to augment PFPT attendance, as well as explore racial disparities in attendance. LEVEL OF EVIDENCE: II. PMID- 29138042 TI - Tibial bone lengthening via external fixation: Comparative study of the traditional technique and a technique with intramedullary nail assistance. AB - OBJECTIVE: To compare outcomes and complications when performing bone lengthening with two different techniques: isolated external fixation versus external fixation combined with intramedullary nail. MATERIAL AND METHOD: Comparative retrospective study of thirty cases of tibial lengthening divided in two symmetrical groups. Cases were matched based on several variables to maximise homogeneity between the groups. Variables used for comparison were external fixation time, external fixation index, rate of consolidation, clinical outcomes, complications and range of joint motion. RESULTS: Mean external fixation time was 2.08 months in the group lengthened with nail while the standard group showed 5.85 months (P<.0001). Mean external fixation index was 0.42 months per centimetre in the nail group compared with 1.15 in the group without nail (P<.0001). There were no significant differences in the rate of consolidation (1.23 months per centimetre against 1.15) or in terms of clinical outcomes. We found differences in the rate of complications (1.2 per patient to 2.6) in favour of the technique with nail. There were no differences in the range of motion of ankle joint. DISCUSSION AND CONCLUSIONS: Lengthening over an intramedullary nail is more effective than using external fixation alone for tibial lengthening with regard to time of external fixation, index of external fixation and complication rate. We found no advantages in terms of consolidation and joint mobility. PMID- 29138043 TI - Non-traumatic limping in Paediatric Emergencies: Epidemiology, evaluation and results. AB - INTRODUCTION: Non-traumatic limping is a common reason for consultation in paediatric emergencies. Although transient synovitis of the hip (TS) is the most frequent diagnosis, there are cases of limping secondary to serious pathologies. The aim of this review is to describe the variables related to non-traumatic limp that come to the paediatric emergency department to establish the best management protocol, making the most of resources and speeding up emergency care. MATERIAL AND METHOD: A prospective study was conducted, selecting all children less than 15 years old who consulted aspaediatric emergencies for non-traumatic limping during the 2014. Clinical variables, complementary examinations and diagnoses were collected in the emergency room consultation and 6 months after the consultation RESULTS: During 2014, 146 patients (0.69% of the emergencies) were included in the non-traumatic limping study. Four cases of severe limping were diagnosed: 2 leukaemias, 1 septic arthritis and 1 acetabular bone tumour. The most frequent diagnosis was TS (53.16%). At 6 months, 135 children (92.4%) had resolved lameness. The diagnosis was changed in 9 children (6.1%). Children with TS had fewer days of evolution, and 77% were between 3 and 10 years old. Children with a final diagnosis of severe pathology had a limp for longer, fever and did not weight bear on ambulation. CONCLUSIONS: In limping of probable hip origin, at the ages of between 3 and 10, without fever or systemic symptoms and of less than one week's onset, it is possible to make a clinical diagnosis of TS limiting the use of complementary examinations. PMID- 29138044 TI - New insight into the RNA aquatic virosphere via viromics. AB - RNA viruses that infect microbes are now recognized as an active, persistent and important component of the aquatic microbial community. While some information about the diversity and dynamics of the RNA virioplankton has been derived from culture-based and single gene approaches, research based on viromic and metatransciptomic methods has generated unprecedented insight into this relatively understudied class of microbes. Here, the relevant literature is summarized and discussed, including viromic studies of extracellular aquatic RNA viral assemblages, and transcriptomic studies of active and associated RNA viruses from aquatic environments followed by commentary on the present challenges and future directions of this field of research. PMID- 29138045 TI - Cyclodextrins: structure, physicochemical properties and pharmaceutical applications. AB - Since their discovery over 100 years ago cyclodextrins (CDs) have been the subject of numerous scientific publications. In 2016 alone CDs were the subject of over 2200 research articles published in peer-reviewed journals and mentioned in over 2300 patents and patent applications, many of which were on pharmaceutical applications. Natural CDs and their derivatives are used as enabling pharmaceutical excipients that enhance aqueous solubility of poorly soluble drugs, increase drug permeability through biological membranes and improve drug bioavailability. Unlike conventional penetration enhancers, their hydrophilic structure and high molecular weight prevents them from penetrate into lipophilic membranes leaving biological membranes intact. The natural CDs and some of their derivatives have monographs in pharmacopeias and are also commonly used as food additives and in toiletry products. CDs form inclusion complexes with lipophilic moieties of hydrophobic drugs. Furthermore, CDs are able to form non-inclusion complexes and self-assembled aggregates; small and large complex aggregates with micellar-like structures that can enhance drug solubility. Excipients commonly used in pharmaceutical formulations may have additive or inhibiting effect on the CD solubilization. Here various methods used to investigate CD aggregate formation are reviewed as well as techniques that are used to increase the solubilizing effects of CDs; methods that enhance the apparent intrinsic solubility of drugs and/or the complexation efficacy and decrease the amount of CD needed to develop CD-containing pharmaceutical formulations. It will be explained how too much or too little CD can hamper drug bioavailability, and the role of CDs in solid dosage forms and parenteral formulations, and examples given on how CDs can enhance drug delivery after ocular, nasal and pulmonary administration. PMID- 29138046 TI - Novel cremochylomicrons for improved oral bioavailability of the antineoplastic phytomedicine berberine chloride: Optimization and pharmacokinetics. AB - Berberine chloride (BER) is an antineoplastic phytomedicine that combat non Hodgkin lymphoma. BER suffers from low oral bioavailability due to p-glycoprotein efflux and first-pass metabolism. Lymphatic drug targeting recently gained a profound attention due to circumventing hepatic first-pass metabolism and targeting lymph diseases. Therefore, novel BER-loaded cremochylomicrons were elaborated to mitigate BER drawbacks and enhance its lymphatic targeting and bioavailability. Optimized cremochylomicron was prepared with 2.5%w/v Cremophor El and 12.5% w/w berberine content. Promising in vitro characteristics (particle size = 175.6 nm and entrapment efficiency = 95.5%) were obtained. Lyophilized system showed high colloidal stability over 6 months. In addition in vivo pharmacokinetics study demonstrated significant enhancement (>2fold) in the rate and extent of absorption in cremochylomicron over free BER. Moreover, cremochylomicrons demonstrated in significant increase in mean residence time and volume of distribution with decreased intestinal drug clearance as a result of efflux inhibition. In another avenue, a significant reduction in BER absorption (43%) in presence of cycloheximide inhibitor was obtained confirming the lymphatic targeting ability of cremochylomicrons. In conclusion, berberine-loaded cremochylomicron could be considered as a promising nanoplatform for targeting lymphatic system and improving BER oral bioavailability with lower dose and side effects. PMID- 29138047 TI - Antibacterial effect and DNA delivery using a combination of an arsonium containing lipophosphoramide with an N-heterocyclic carbene-silver complex - Potential benefits for cystic fibrosis lung gene therapy. AB - Cystic Fibrosis (CF), the most common chronic genetic disorder among the Caucasian population, is a life-threatening disease mainly due to respiratory failures resulting from chronic infections and inflammation. Although research in the pharmacological field has recently made significant progress, gene therapy still remains a promising strategy to cure CF, especially because it should be applicable to any patient whatever the mutation profile. Until now, little attention has been paid to bacterial lung infections with regard to gene delivery to the airways; yet, this could greatly impact on the success of gene therapy. Previously, we have reported arsonium-containing lipophosphoramides as poly functional nanocarriers capable of simultaneous antibacterial action against Gram positive bacteria and gene transfer into eukaryotic cells. In the present work, we show that such nanoparticles can also be combined with an N-heterocyclic carbene-silver complex in order to extend the spectrum of antibacterial activity, including towards the Gram-negative Pseudomonas aeruginosa. Importantly, this is demonstrated not only using standard in vitro protocols but also a clinically relevant aerosol delivery method. Furthermore, antibacterial effects are compatible with efficient and safe gene delivery into human bronchial epithelial cells. The poly-functionality of combinations of such chemical compounds may thus show benefits for CF lung gene therapy. PMID- 29138048 TI - In-vitro and in-vivo cytotoxicity and efficacy evaluation of novel glycyl-glycine and alanyl-alanine conjugates of chitosan and trimethyl chitosan nano-particles as carriers for oral insulin delivery. AB - PURPOSE: The aim of this research work was to explore the possibility of providing multifunctional oral insulin delivery system by conjugating several types of dipeptides on chitosan and trimethyl chitosan to be used as drug carriers. METHOD: Conjugates of Glycyl-glycine and alanyl-alanine of chitosan and trimethyl chitosan (on primary alcohol group of polymer located on carbon 6) were synthesized and nanoparticles containing insulin were prepared for oral delivery. Preparation conditions of nanoparticles were optimized and their performance to enhance the permeability of insulin as well as cytotoxicity of nanoparticles in Caco-2 cell line was evaluated. To evaluate the efficacy of orally administered nanoparticles, nanoparticles with the most permeability enhancing ability were studied in male Wistar rats as animal model by measuring insulin and glucose Serum levels. RESULT: Structural study of all the conjugates by infrared spectroscopy and nuclear magnetic resonance confirmed the successful formation of the conjugates with the desirable substitution degree. By optimizing preparation conditions, nanoparticles with expected size (157.3-197.7 nm), Zeta potential (24.35-34.37 mV), polydispersity index (0.365-0.512), entrapment efficiency (70.60-86.52%) and loading capacity (30.92-56.81%), proper morphology and desirable release pattern were obtained. Glycyl-glycine and alanyl-alanine conjugate nanoparticles of trimethyl chitosan showed 2.5-3.3 folds more effective insulin permeability in Caco-2 cell line than their chitosan counterparts. In animal model, oral administration of glycyl-glycine and alanyl-alanine conjugate nanoparticles of trimethyl chitosan demonstrated reasonable increase in Serum insulin level with relative bioavailability of 17.19% and 15.46% for glycyl glycine and alanyl-alanine conjugate nanoparticles, respectively, and reduction in Serum glucose level compared with trimethyl chitosan nanoparticles (p < 0.05). CONCLUSION: It seems that glycyl-glycine and alanyl-alanine conjugate nanoparticles of trimethyl chitosan have met the aim of this research work and have been able to orally deliver insulin with more than one mechanism in animal model. Hence, they are promising candidates for further research studies. PMID- 29138049 TI - Pain Neurophysiology Education and Therapeutic Exercise for Patients With Chronic Low Back Pain: A Single-Blind Randomized Controlled Trial. AB - OBJECTIVE: To assess the effect of a pain neurophysiology education (PNE) program plus therapeutic exercise (TE) for patients with chronic low back pain (CLBP). DESIGN: Single-blind randomized controlled trial. SETTING: Private clinic and university. PARTICIPANTS: Patients with CLBP for >=6 months (N=56). INTERVENTIONS: Participants were randomized to receive either a TE program consisting of motor control, stretching, and aerobic exercises (n=28) or the same TE program in addition to a PNE program (n=28), conducted in two 30- to 50-minute sessions in groups of 4 to 6 participants. MAIN OUTCOMES MEASURES: The primary outcome was pain intensity rated on the numerical pain rating scale which was completed immediately after treatment and at 1- and 3-month follow-up. Secondary outcome measures were pressure pain threshold, finger-to-floor distance, Roland Morris Disability Questionnaire, Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia, and Patient Global Impression of Change. RESULTS: At 3-month follow-up, a large change in pain intensity (numerical pain rating scale: -2.2; 2.93 to -1.28; P<.001; d=1.37) was observed for the PNE plus TE group, and a moderate effect size was observed for the secondary outcome measures. CONCLUSIONS: Combining PNE with TE resulted in significantly better results for participants with CLBP, with a large effect size, compared with TE alone. PMID- 29138050 TI - Systematic Review on the Effects of Serious Games and Wearable Technology Used in Rehabilitation of Patients With Traumatic Bone and Soft Tissue Injuries. AB - OBJECTIVE: To assess the effects on functional outcomes and treatment adherence of wearable technology and serious games (ie, interactive computer applications with specific purposes useful in the "real world") currently used in physical rehabilitation of patients after traumatic bone and soft tissue injuries. DATA SOURCES: PubMed, EMBASE, Cochrane Library, and Current Index to Nursing and Allied Health Literature were searched without publication date restrictions for the terms wearable, serious game, videogame or mobile application, and rehabilitation, exercise therapy, and physiotherapy. STUDY SELECTION: The search yielded 2704 eligible articles, which were screened by 2 independent reviewers. Studies comparing serious games to standard therapy were included. DATA EXTRACTION: Methodology and results of the studies were critically appraised in conformity with Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. DATA SYNTHESIS: Twelve articles were included, all of which tested "off-the-shelf" games. No studies on "wearable-controlled" games or games specifically developed for rehabilitation could be included. Medical conditions included postoperative rehabilitation and acute traumatic injuries. All studies were of low to moderate quality. Only 2 studies found beneficial effects of serious games compared to conventional therapy. One of 3 studies reporting pain scores found beneficial effects of serious games compared to physiotherapy. One of 5 trials reporting treatment adherence found a statistically significant advantage in the game group compared to conventional physiotherapy. Because of heterogeneity in study design and outcome measures, pooling of data was not possible. CONCLUSIONS: Serious games seem a safe alternative or addition to conventional physiotherapy after traumatic bone and soft tissue injuries. Future research should determine their validity and effectiveness in rehabilitation therapy, next to their cost-effectiveness and effect on treatment adherence. PMID- 29138052 TI - Intra- and Interfamilial Phenotype Variability Associated with Mutations in gamma Secretase Subunit-Encoding PSENEN. PMID- 29138051 TI - Sarcopenia in Peripheral Arterial Disease: Prevalence and Effect on Functional Status. AB - OBJECTIVES: (1) To determine the prevalence of sarcopenia in older men with peripheral arterial disease (PAD); (2) to compare a subgroup of the group with age-, race-, sex-, and body mass index (BMI)-matched non-PAD control counterparts, and (3) to compare the functional status of those with PAD with and without sarcopenia. DESIGN: Cohort study. SETTING: Medical center. PARTICIPANTS: Sedentary community-dwelling men (N=108; age, >50y) with a confirmed diagnosis of PAD (44% blacks; BMI, 27.8+/-0.4kg/m2; ankle-brachial index, .62+/-.01). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Dual-energy x-ray absorptiometry scans were used to assess appendicular lean mass and determine the prevalence of sarcopenia by/height2. Treadmill tests were used to determine claudication onset time, peak walking time, and claudication recovery time. 6 Minute walk distance was also measured. RESULTS: Sarcopenia prevalence in our PAD cohort was 25%. The PAD subgroup (n=42) matched with control counterparts in terms of race, sex, age, and BMI had higher prevalence rates than did their non PAD counterparts (23.8% vs 2.4%; P<.05). Individuals with sarcopenia (n=28) had a shorter 6-minute walk distance (326+/-18.8m vs 380+/-9.7m; P<.05) and higher claudication recovery time (592+/-98s vs 395+/-29s; P<.05) than did individuals with PAD but without sarcopenia (n=80). There was no difference in claudication onset time or peak walking time between the PAD groups. CONCLUSIONS: Men with PAD demonstrate a high prevalence of sarcopenia. Those with sarcopenia and PAD demonstrate decreased mobility function. PMID- 29138053 TI - Recessive Mutation in FAM83G Associated with Palmoplantar Keratoderma and Exuberant Scalp Hair. PMID- 29138054 TI - Keratinocyte Sonic Hedgehog Upregulation Drives the Development of Giant Congenital Nevi via Paracrine Endothelin-1 Secretion. AB - Giant congenital nevi are associated with clinical complications such as neurocutaneous melanosis and melanoma. Virtually nothing is known about why some individuals develop these lesions. We previously identified the sonic hedgehog (Shh) pathway regulator Cdon as a candidate nevus modifier gene. Here we validate this by studying Cdon knockout mice, and go on to establishing the mechanism by which Shh exacerbates nevogenesis. Cdon knockout mice develop blue nevi without the need for somatic melanocyte oncogenic mutation. In a mouse model carrying melanocyte NRASQ61K, we found that strain backgrounds that carry genetic variants that cause increased keratinocyte Shh pathway activity, as measured by Gli1 and Gli2 expression, develop giant congenital nevi. Shh components are also active adjacent to human congenital nevi. Mechanistically, this exacerbation of nevogenesis is driven via the release of the melanocyte mitogen endothelin-1 from keratinocytes. We then suppressed nevus development in mice using Shh and endothelin antagonists. Our work suggests an aspect of nevus development whereby keratinocyte cytokines such as endothelin-1 can exacerbate nevogenesis, and provides potential therapeutic approaches for giant congenital nevi. Furthermore, it highlights the notion that germline genetic variation, in addition to somatic melanocyte mutation, can strongly influence the histopathological features of melanocytic nevi. PMID- 29138055 TI - Merkel Cells Sense Cooling with TRPM8 Channels. AB - In the skin, Merkel cells connect with keratinocytes and Abeta nerve fibers to form a touch receptor that functions as a slow adapting mechanoreceptor (slow adapting type 1). In human and mouse Merkel cells, we observed an increased concentration of intracellular Ca2+ ions in response to cold temperature and transient receptor potential melastatine 8 (TRPM8) ion channel agonists. A reduction in the response to cooling and TRPM8 agonists occurred after the addition of TRPM8 antagonists, as well as in TRPM8 knockout mice. Cold temperature and TRPM8 agonists also induced a current that was inhibited by a TRPM8 antagonist. Our results indicate that Merkel cells sense cooling through TRPM8 channels. We hypothesized that cooling modulates the slow adapting type 1 receptor response. Cooling mouse skin to 22 degrees C reduced the slow adapting type 1 receptor discharge frequency. Interestingly, we observed no such reduction in TRPM8 knockout mice. Similarly, in human skin, a temperature of 22 degrees C applied to the slow adapting type 1 receptive field reduced the spiking discharge. Altogether, our results indicate that Merkel cells are polymodal sensory cells that respond to mild cold stimuli through the activation of TRPM8 channels. Thermal activation of Merkel cells, and possibly other TRPM8-expressing non-neuronal cells, such as keratinocytes, potentially adapts the discharge of slow adapting type 1 receptors during cooling. PMID- 29138056 TI - Skin-Specific CD301b+ Dermal Dendritic Cells Drive IL-17-Mediated Psoriasis-Like Immune Response in Mice. AB - Conventional dendritic cells (cDCs) are composed of heterogeneous subsets commonly arising from dendritic cell (DC)-committed progenitors. A population of CD301b-expressing DCs has recently been identified in non-lymphoid barrier tissues such as skin. However, whether CD301b+ DCs in the skin represent an ontogenetically unique subpopulation of migratory cDCs has not been fully addressed. Here, we demonstrated that CD301b+ dermal DCs were distinct subpopulation of FMS-like tyrosine kinase 3 ligand (FLT3L)-dependent CD11b+ cDC2 lineage, which required an additional GM-CSF cue for the adequate development. Although the majority of lymphoid-resident cDC2 lacked CD301b expression, dermal migratory cDC2 contained a substantial fraction of CD301b+ subset. Similar to CD301b- population, CD301b+ dermal DC development was closely regulated by FLT3 signaling, suggesting their common origin from FLT3L-responsive cDC progenitors. However, FLT3L-driven cDC progenitor culture was not sufficient, but additional GM-CSF treatment was required to produce CD301b+ cDC2. In vivo development of CD301b+ cDC2 was significantly augmented by exogenous GM-CSF, while the repopulation of CD301b+ dermal cDC2 was abrogated by GM-CSF neutralization. Functionally, CD301b+ cDC2 was capable of producing a high level of IL-23, and the depletion of CD301b+ cDC2 effectively prevented IL-17-mediated psoriasiform dermatitis. Therefore, our findings highlight the differentiation program of a distinct CD301b+ dermal cDC2 subset in the skin and its involvement in psoriatic inflammation. PMID- 29138057 TI - Hidradenitis Suppurativa-Like Lesions Associated with Pharmacologic Inhibition of Gamma-Secretase. PMID- 29138058 TI - The diagnostic value and histologic correlate of distinct patterns of shiny white streaks for the diagnosis of melanoma: A retrospective, case-control study. AB - BACKGROUND: Shiny white streaks (SWSs) are best visualized with polarized dermoscopy and correlate with dermal fibroplasia histopathologically. SWSs have been described at higher frequencies in melanomas than in benign nevi. OBJECTIVE: We assessed the diagnostic value of different patterns of SWSs and their histologic correlate in melanocytic lesions. METHODS: Polarized dermoscopic images of 1507 histopathologically diagnosed melanocytic neoplasms were analyzed for presence and pattern of SWSs. Histology was also reviewed for correlation. RESULTS: Among 1507 melanocytic neoplasms, SWSs were observed in 31 of 144 melanomas (22%) and 22 of 1363 benign neoplasms (1.6%) (P < .001). The sensitivity and specificity of SWSs for melanoma were 22% and 98%, respectively. Diffuse SWSs exhibited the greatest diagnostic value for melanoma, with sensitivity of 11.8% and specificity of 99.5%. Focal central and peripheral SWSs were comparable in diagnostic significance. The presence of SWSs was highly uncommon in dysplastic nevi, whereas in certain benign subgroups of nevi such as Spitz nevi and atypical genital special site nevi, SWSs were not uncommon. Diffuse SWSs correlated with greater breadth of deep fibroplasia than focal SWSs (P = .009), and SWSs correlated with greater Breslow depth among melanomas (P = .007). LIMITATIONS: This study was retrospective. CONCLUSION: Polarized dermoscopy is a valuable diagnostic tool in the identification of SWSs, a feature that is highly specific for melanoma. PMID- 29138059 TI - Pityrosporum folliculitis: A retrospective review of 110 cases. AB - BACKGROUND: Pityrosporum folliculitis is an under-recognized eruption of the face and upper portion of the trunk that may be confused with, or occur simultaneously with, acne vulgaris. OBJECTIVE: We sought to characterize risk factors for Pityrosporum folliculitis, its clinical presentation, and its response to treatment. METHODS: A retrospective chart review was performed on all patients age 0 to 21 years seen at our facility from 2010 to 2015 with Pityrosporum folliculitis confirmed by a potassium hydroxide preparation. RESULTS: Of 110 qualifying patients, more than 75% had acne that had recently been treated with antibiotics, and when recorded, 65% reported pruritus. Clinical examination demonstrated numerous 1- to 2-mm monomorphic papules and pustules that were typically on the forehead extending into the hairline and on the upper portion of the back. The most common treatment was ketoconazole shampoo, which led to improvement or resolution in most cases. Some patients required oral azole antifungals. LIMITATIONS: This study was retrospective and relied on providers describing and interpreting the clinical findings and potassium hydroxide preparations. No standard grading system was used. CONCLUSION: Unlike classic acne vulgaris, Pityrosporum folliculitis was more common after antibiotic use. It presented as fine monomorphic, pruritic papules and pustules along the hairline and on the upper portion of the back, and it improved with topical or oral azole antifungal therapy. PMID- 29138060 TI - Racial disparities and insurance status: An epidemiological analysis of Ohio melanoma patients. PMID- 29138061 TI - Determining the impact of intraoperative smoke evacuation on the patient experience during outpatient surgery: A randomized controlled trial. PMID- 29138062 TI - Topical calcipotriol before ablative fractional laser-assisted photodynamic therapy enhances treatment outcomes for actinic keratosis in Fitzpatrick grades III-V skin: A prospective randomized clinical trial. PMID- 29138063 TI - Polyrotaxane-based systemic delivery of beta-cyclodextrins for potentiating therapeutic efficacy in a mouse model of Niemann-Pick type C disease. AB - Niemann-Pick type C (NPC) disease is a fatal metabolic disorder characterized by the lysosomal accumulation of cholesterol. Although 2-hydroxypropyl beta cyclodextrin (HP-beta-CD) promotes the excretion of cholesterol and prolongs the life span in animal models of NPC disease, it requires extremely high dose. We developed acid-labile beta-CD-based polyrotaxanes (PRXs) comprising multiple beta CDs threaded along a polymer chain capped with acid-cleavable stopper molecules for potentiating therapeutic efficacy of beta-CD in NPC disease. The acid-labile PRXs dissociate under the acidic lysosomes and release threaded beta-CDs in lysosomes, which promotes cholesterol excretion in NPC disease model cells at lower concentration than HP-beta-CD. In this study, the therapeutic effect of the PRXs in a mouse model of NPC disease was investigated. Weekly administration of the PRXs significantly prolonged the life span and suppressed neurodegeneration in mice, even at a dose of 500mg/kg, a markedly lower dose than previously reported for HP-beta-CD. Detailed analysis of tissue cholesterol revealed that PRX treatment markedly suppressed the tissue accumulation of cholesterol in the NPC mouse model, but did not alter cholesterol content in wild-type mice. Acid labile PRX is therefore a promising candidate for potentiating the efficacy of beta-CD in the treatment of NPC disease. PMID- 29138064 TI - Bicontinuous microemulsions as a biomembrane mimetic system for melittin. AB - Antimicrobial peptides effectively kill antibiotic-resistant bacteria by forming pores in prokaryotes' biomembranes via penetration into the biomembranes' interior. Bicontinuous microemulsions, consisting of interdispersed oil and water nanodomains separated by flexible surfactant monolayers, are potentially valuable for hosting membrane-associated peptides and proteins due to their thermodynamic stability, optical transparency, low viscosity, and high interfacial area. Here, we show that bicontinuous microemulsions formed by negatively-charged surfactants are a robust biomembrane mimetic system for the antimicrobial peptide melittin. When encapsulated in bicontinuous microemulsions formed using three-phase (Winsor III) systems, melittin's helicity increases greatly due to penetration into the surfactant monolayers, mimicking its behavior in biomembranes. But, the threshold melittin concentration required to achieve these trends is lower for the microemulsions. The extent of penetration was decreased when the interfacial fluidity of the microemulsions was increased. These results suggest the utility of bicontinuous microemulsions for isolation, purification, delivery, and host systems for antimicrobial peptides. PMID- 29138066 TI - Modification of membrane properties and fatty acids biosynthesis-related genes in Escherichia coli and Staphylococcus aureus: Implications for the antibacterial mechanism of naringenin. AB - In this work, modifications of cell membrane fluidity, fatty acid composition and fatty acid biosynthesis-associated genes of Escherichia coli ATCC 25922 (E. coli) and Staphylococcus aureus ATCC 6538 (S. aureus), during growth in the presence of naringenin (NAR), one of the natural antibacterial components in citrus plants, was investigated. Compared to E. coli, the growth of S. aureus was significantly inhibited by NAR in low concentrations. Combination of gas chromatography-mass spectrometry with fluorescence polarization analysis revealed that E. coli and S. aureus cells increased membrane fluidity by altering the composition of membrane fatty acids after exposure to NAR. For example, E. coli cells produced more unsaturated fatty acids (from 18.5% to 43.3%) at the expense of both cyclopropane and saturated fatty acids after growth in the concentrations of NAR from 0 to 2.20mM. For S. aureus grown with NAR at 0 to 1.47mM, the relative proportions of anteiso-branched chain fatty acids increased from 37.2% to 54.4%, whereas iso branched and straight chain fatty acids decreased from 30.0% and 33.1% to 21.6% and 23.7%, respectively. Real time q-PCR analysis showed that NAR at higher concentrations induced a significant down-regulation of fatty acid biosynthesis associated genes in the bacteria, with the exception of an increased expression of fabA gene. The minimum inhibitory concentration (MIC) of NAR against these two bacteria was determined, and both of bacteria underwent morphological changes after exposure to 1.0 and 2.0 MIC. PMID- 29138067 TI - The Prognostic Effect of Changes in Tumor Stage and Nodal Status After Neoadjuvant Chemotherapy in Each Primary Breast Cancer Subtype. AB - BACKGROUND: Although the prognostic value of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) depends on the intrinsic subtype of breast cancer, it is not clear whether chemosensitivity itself, shown by a decreasing tumor burden after NAC, contributes to improved prognosis in primary breast cancer patients, especially in patients with non-pCR. The aim of this study was to assess the prognostic effect of changes in tumor stage or nodal status after NAC in each primary breast cancer subtype. PATIENTS AND METHODS: We assessed 719 consecutive patients with primary breast cancer who underwent surgical resection after NAC between 2001 and 2010. The patients were divided into 5 subtypes according to their hormone receptor (HR) status, HER2 status, and nuclear grade (NG; 1/2 = low, and 3 = high). RESULTS: In patients with HR-positive (HR+)/HER2 /NG-low tumors, regardless of change in tumor size, the loss of node positivity after NAC significantly improved disease-free survival (DFS). In patients with HR+/HER2-/NG-high tumors, achievement of tumor downstaging as well as the loss of node positivity improved their DFS. In patients with HR-/HER2- tumors, tumor downstaging and the loss of node positivity significantly improved DFS, despite a non-pCR. In contrast, in patients with HER2+ tumors, changes in tumor stage or nodal status were not associated with prognosis unless pCR was achieved. CONCLUSION: Our results revealed that changes in tumor stage and nodal status after NAC might be prognostic markers in patients with HR+/HER2-/NG-high tumors or HR-/HER2- tumors, even if there are residual tumors in the breast. PMID- 29138065 TI - Comparison of lipid-dependent bilayer insertion of pHLIP and its P20G variant. AB - The ability of the pH-Low Insertion Peptide (pHLIP) to insert into lipid membranes in a transbilayer conformation makes it an important tool for targeting acidic diseased tissues. pHLIP can also serve as a model template for thermodynamic studies of membrane insertion. We use intrinsic fluorescence and circular dichroism spectroscopy to examine the effect of replacing pHLIP's central proline on the pH-triggered lipid-dependent conformational switching of the peptide. We find that the P20G variant (pHLIP-P20G) has a higher helical propensity than the native pHLIP (pHLIP-WT), in both water:organic solvent mixtures and in the presence of lipid bilayers. Spectral shifts of tryptophan fluorescence reveal that with both pHLIP-WT and pHLIP-P20G, the deeply penetrating interfacial form (traditionally called State II) is populated only in pure phosphocholine bilayers. The presence of either anionic lipids or phosphatidylethanolamine leads to a much shallower penetration of the peptide (referred to here as State IIS, for "shallow"). This novel state can be differentiated from soluble state by a reduction in accessibility of tryptophans to acrylamide and by FRET to vesicles doped with Dansyl-PE, but not by a spectral shift in fluorescence emission. FRET experiments indicate free energies for interfacial partitioning range from 6.2 to 6.8kcal/mol and are marginally more favorable for pHLIP-P20G. The effective pKa for the insertion of both peptides depends on the lipid composition, but is always higher for pHLIP-P20G than for pHLIP-WT by approximately one pH unit, which corresponds to a difference of 1.3kcal/mol in free energy of protonation favoring insertion of pHLIP-P20G. PMID- 29138068 TI - Scenario Planning: Playing the Expectations Game in Spine Surgery. PMID- 29138069 TI - Traumatic Fractures of the Cervical Spine: Analysis of Changes in Incidence, Cause, Concurrent Injuries, and Complications Among 488,262 Patients from 2005 to 2013. AB - OBJECTIVE: The causes and epidemiology of traumatic cervical spine fracture have not been described with sufficient power or recency. Our goal is to describe demographics, incidence, cause, spinal cord injuries (SCIs), concurrent injuries, treatments, and complications of traumatic cervical spine fractures. METHODS: A retrospective review was carried out of the Nationwide Inpatient Sample. International Classification of Disease, Ninth Revision E-codes identified trauma cases from 2005 to 2013. Patients with cervical fracture were isolated. Demographics, incidence, cause, fracture levels, concurrent injuries, surgical procedures, and complications were analyzed. t tests elucidated significance for continuous variables and chi2 for categorical variables. Level of significance was P < 0.05. RESULTS: A total of 488,262 patients were isolated (age, 55.96 years; male, 60.0%; white, 77.5%). Incidence (2005, 4.1% vs. 2013, 5.4%), Charlson Comorbidity Index (2005, 0.6150 vs. 2013, 1.1178), and total charges (2005, $71,228.60 vs. 2013, $108,119.29) have increased since 2005, whereas length of stay decreased (2005, 9.22 vs. 2013, 7.86) (all P < 0.05). The most common causes were motor vehicle accident (29.3%), falls (23.7%), and pedestrian accidents (15.7%). The most frequent fracture types were closed at C2 (32.0%) and C7 (20.9%). Concurrent injury rates have significantly increased since 2005 (2005, 62.3% vs. 2013, 67.6%). Common concurrent injuries included fractures to the rib/sternum/larynx/trachea (19.6%). Overall fusion rates have increased since 2005 (2005, 15.7% vs. 2013, 18.0%), whereas decompressions and halo insertion rates have decreased (all P < 0.05). SCIs have significantly decreased since 2005, except for upper cervical central cord syndrome. Complication rates have significantly increased since 2005 (2005, 31.6% vs. 2013, 36.2%). Common complications included anemia (7.7%), mortality (6.6%), and acute respiratory distress syndrome (6.6%). CONCLUSIONS: Incidence, complications, concurrent injuries, and fusions have increased since 2005. Length of stay, SCIs, decompressions, and halo insertions have decreased. Indicated trends should guide future research in management guidelines. PMID- 29138070 TI - Posterior Cervical Laminectomy Results in Better Radiographic Decompression of Spinal Cord Compared with Anterior Cervical Discectomy and Fusion. AB - BACKGROUND: Cervical spondylitic myelopathy is a degenerative condition resulting from chronic spinal cord compression and a leading cause of nontraumatic spinal cord dysfunction. The chief surgical goal in the management of cervical spondylitic myelopathy is adequate spinal cord decompression with or without fusion to slow or prevent further neurologic decline. We conducted a radiographic analysis of canal parameters preoperatively and postoperatively for patients undergoing either anterior or posterior cervical decompression. METHODS: Preoperative and postoperative radiographic analysis was performed using midsagittal and axial magnetic resonance imaging at the level of the disc space for 37 patients who underwent anterior or posterior cervical decompression. Statistical comparisons between anterior and posterior groups were performed using independent t test and Mann-Whitney U test where appropriate. RESULTS: Both postoperative anteroposterior canal diameter and posterior cerebrospinal fluid (CSF) space were greater in patients undergoing posterior decompression (P = 0.011 and P < 0.001, respectively), although postoperative anterior CSF space was comparable between both groups. Both anterior and posterior approaches to decompression resulted in a statistically significant improvement in anteroposterior diameter, anterior CSF space, and posterior CSF space (P < 0.001). Posterior decompression yielded significantly greater change in anteroposterior diameter and posterior CSF space compared with the anterior approach (P < 0.001). CONCLUSIONS: In this quantitative radiographic study, we found that although both posterior cervical laminectomy and anterior cervical discectomy yielded significant decompression, laminectomy yielded a greater degree of decompression of the posterior CSF space. PMID- 29138071 TI - Mathematic Network of Seizure Activity: How Presurgical Simulation Can Predict Postsurgical Success. PMID- 29138072 TI - Preoperative Assessment of Craniopharyngioma Adherence: Magnetic Resonance Imaging Findings Correlated with the Severity of Tumor Attachment to the Hypothalamus. AB - BACKGROUND AND OBJECTIVE: Craniopharyngioma (CP) adherence represents a heterogeneous pathologic feature that critically influences the potentially safe and radical resection. The aim of this study was to define the magnetic resonance imaging (MRI) predictors of CP adherence severity. METHODS: This study retrospectively investigated a cohort of 200 surgically treated CPs with their corresponding preoperative conventional MRI scans. MRI findings related to the distortions of anatomic structures along the sella turcica-third ventricle axis caused by CPs, in addition to the tumor's shape and calcifications, were analyzed and correlated with the definitive type of CP adherence observed during the surgical procedures. RESULTS: CP adherence is defined by 3 components, as follows: 1) the specific structures attached to the tumor, 2) the adhesion's extent, and 3) its strength. Combination of these 3 components determines 5 hierarchical levels of adherence severity with gradually increasing surgical risk of hypothalamic injury. Multivariate analysis identified 4 radiologic variables that allowed a correct overall prediction of the levels of CP adherence severity in 81.5% of cases: 1) the position of the hypothalamus in relation to the tumor the most discriminant factor; 2) the type of pituitary stalk distortion; 3) the tumor shape; and 4) the presence of calcifications. A binary logistic regression model including the first 3 radiologic variables correctly identified the CPs showing the highest level of adherence severity (severe/critical) in almost 90% of cases. CONCLUSIONS: A position of the hypothalamus around the middle portion of the tumor, an amputated or infiltrated appearance of the pituitary stalk, and the elliptical shape of the tumor are reliable predictors of strong and extensive CP adhesions to the hypothalamus. PMID- 29138073 TI - Comparison of Results Between Posterior Fossa Decompression with and without Duraplasty for the Surgical Treatment of Chiari Malformation Type I: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Posterior fossa decompression without (PFD) or with duraplasty (PFDD) for the treatment of type 1 Chiari malformation (CM-1) is controversial. We thus performed a systematic review and meta-analysis of studies to assess the effect on clinical and imaging improvement, operative time, complications, and recurrence rate between PFD and PFDD in patients with CM-1. METHODS: We systematically searched PubMed, Embase, Cochrane, Web of Knowledge, and ClinicalTrials.gov for retrospective or prospective studies comparing PFD with PFDD. Our main end points were clinical and imaging improvement, operative time, complications, and recurrence rate. We assessed pooled data by use of a fixed effects or random-effects model according to the between-study heterogeneity. RESULTS: Of 214 identified studies, 13 were eligible and were included in our analysis (N = 3481 patients). Compared with PFD, PFDD led to a mean greater increase in operative time than did PFD [standardized mean difference, -2.35; 95% confidence interval [CI], (-2.70 to -1.99)], a higher likelihood of clinical improvement in patients with syringomyelia (relative risk [RR], 0.70; 95% CI, 0.49-0.98), no increased RR of clinical improvement in patients without syringomyelia, no increased RR of imaging improvement, but an increased RR of cerebrospinal fluid-related complications (RR, 0.29; 95% CI, 0.15-0.58), cerebrospinal fluid leak, aseptic meningitis, pseudomeningocele, and a decreased likelihood of recurrence rate. CONCLUSIONS: PFDD can be an optimal surgical strategy because of its higher clinical improvement and lower recurrence rate in the patients with syringomyelia. In patients without syringomyelia, PFD can be a preferred choice because of its similar clinical improvement and lower costs. Future randomized studies with large numbers and the power to provide illumination for surgical decision making in CM-1 are warranted. PMID- 29138074 TI - Outcome of Transforaminal Epidural Steroid Injection According to Severity of Cervical Foraminal Stenosis. AB - BACKGROUND: Cervical transforaminal epidural steroid injection (TFESI) is considered one of the most effective treatments for radicular pain induced by cervical foraminal stenosis. PURPOSE AND DESIGN: We sought to evaluate the treatment outcome of TFESI according to the severity of cervical foraminal stenosis. In our retrospective study there were 53 patients with cervical radiculopathy due to cervical foraminal stenosis. OUTCOME MEASURES: Pain intensity was evaluated using a numeric rating scale (NRS) at pretreatment, 2 weeks, and 1, 2, and 3 months after TFESI. METHODS: Patients were divided into 2 groups according to the severity of stenosis by cervical axial magnetic resonance imaging findings. Twenty-two patients were assigned to group A (nonsevere stenosis), and 31 patients were assigned to group B (severe stenosis). RESULTS: Thirty-seven (69.8%) of 53 patients showed successful treatment outcome (>50% reduction in the NRS score at 3 months). The patients in both groups showed a significant decrease in NRS scores at 2 weeks and at 1, 2, and 3 months after TFESI. However, the effect of TFESI was not significantly different between patients with nonsevere cervical foraminal stenosis and those with severe cervical foraminal stenosis. CONCLUSIONS: The treatment outcome of cervical TFESI did not different according to the severity of cervical foraminal stenosis. However, on the basis of our results, we suggest that TFESI can be a beneficial clinical option for managing radicular pain due to cervical foraminal stenosis. PMID- 29138075 TI - WITHDRAWN: The Optimal Treatment Options of Septated Chronic Subdural Hematoma: A Retrospective Comparison of Craniotomy Versus Endoscopic-Assisted Burr-Hole Craniostomy. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 29138076 TI - The Effect of Obesity on Clinical Outcomes After Minimally Invasive Surgery of the Spine: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Obesity is associated with increasing morbidity and mortality in many prevalent diseases, especially lumbar degenerative disease. The relationship between minimally invasive surgery (MIS) of the spine and perioperative adverse events in obese patients with lumbar degenerative disease has not been well evaluated. METHODS: We conducted a systematic review and meta-analysis to identify relevant studies involving obese patients with spine MIS in electronic databases up to June 2017, including Web of Science, Embase, PubMed, the Cochrane Controlled Trials Register, and the Cochrane Library. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system, and Cochrane Handbook were applied to assess the quality of the results published in all included studies. RESULTS: No significant difference was found in postoperative complications between obese and nonobese patients, according to the Oswestry Disability Index, and visual analog scale. However, there were significant differences between the 2 groups in surgery time, blood loss, and length of hospital stay. CONCLUSIONS: There does not seem to be an increased risk of developing perioperative complications in obese patients undergoing spine MIS. Spine MIS was a safe and effective technique for obese patients. However, according to our pooled data, longer surgery time was observed in obese patients. PMID- 29138077 TI - Central Nervous System Lymphatics and Impact on Neurologic Disease. PMID- 29138078 TI - Is There an Indication for Intraoperative MRI in Subtotal Resection of Glioblastoma? A Multicenter Retrospective Comparative Analysis. AB - OBJECTIVE: Surgery in patients with highly eloquent glioblastoma (GB) remains challenging. The aim of this study was to evaluate influence of use of intraoperative magnetic resonance imaging (iMRI) on extent of resection (EOR), clinical outcome, and survival in patients with preoperatively intended subtotal resection of GB. METHODS: Retrospective assessment was performed in 3 neurosurgical centers (2008-2013). All patients with primary GB, unilocular growth, and adjuvant radiochemotherapy in whom subtotal resection was intended were included. Imaging data were pseudonymized and volumetrically assessed by a central reviewer. Clinical outcome was evaluated based on complications, new permanent neurologic deficits, and survival. Based on subtraction of potential EOR (as defined by reviewer) from effective EOR, EOR change (DeltaEOR) was calculated for each case. We calculated multivariate linear regressions to assess influence on effective EOR and DeltaEOR, binary regressions to assess influence on complications and new permanent neurologic deficits, and Cox regression models to assess survival. RESULTS: Assessment included 70 patients. In iMRI group, a significantly lower DeltaEOR (4% vs. 22%, P = 0.008) was found. In linear regression model controlling for age, tumor volume, neurophysiologic mapping, and iMRI, only iMRI influenced DeltaEOR significantly (P = 0.03, odds ratio 0.27). In binary regression model controlling for age, tumor volume, effective EOR, neurophysiologic mapping, and iMRI, none of the variables showed a significant difference concerning complications and new permanent neurologic deficits. Overall survival was significantly influenced by age (P = 0.03, odds ratio 1.02) and iMRI (P = 0.026, odds ratio 0.51). CONCLUSIONS: Maximum safe resection is an important prognostic factor for patients with eloquent GBs. iMRI seems to be a relevant tool to achieve this goal. PMID- 29138079 TI - Genetic structure and phenotypic variation of Anopheles darlingi in northwest Colombia. AB - This study evaluated the influence of environmental heterogeneity on Anopheles darlingi genetic and morphometric traits at a microgeographic level. Specimens of An. darlingi collected from multiple municipalities in the Colombian malaria endemic region Uraba-Bajo Cauca and Alto Sinu (UCS) were analyzed using 13 microsatellite loci. Spatial genetic structure, population variation and wing geometric morphometric analyses were performed. Microsatellite results showed low genetic differentiation and high gene flow among populations; four highly admixed subpopulations were detected with no particular association to the municipalities. Wing geometric morphometrics analysis showed a subtle but significant difference in wing shape for El Bagre vs. Mutata populations, possibly influenced by geographical distance. Discrimination among populations in the morphospace showed a slight separation of the Tierralta population. There was no significant correlation between the genetic and geographic or genetic and environmental distances. We hypothesize that environmental heterogeneity in the UCS region does not reach a threshold to affect population structure of An. darlingi. Another possibility is that microsatellites are not sensitive enough to detect existing structure. It remains to be determined which local factors govern phenotypic variation among these populations and how, or whether these may affect mosquito biology and transmission capacity. PMID- 29138080 TI - Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer's disease. AB - Muscarinic acetylcholine receptors (mAChRs) are G proteincoupled receptors (GPCRs) that mediate the metabotropic actions of acetylcholine (ACh). There are five subtypes of mAChR, M1 - M5, which are expressed throughout the central nervous system (CNS) on numerous cell types and represent promising treatment targets for a number of different diseases, disorders, and conditions of the CNS. Although the present review will focus on Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), a number of conditions such as Parkinson's disease (PD), schizophrenia, and others represent significant unmet medical needs for which selective muscarinic agents could offer therapeutic benefits. Numerous advances have been made regarding mAChR localization through the use of subtype selective antibodies and radioligand binding studies and these efforts have helped propel a number of mAChR therapeutics into clinical trials. However, much of what we know about mAChR localization in the healthy and diseased brain has come from studies employing radioligand binding with relatively modest selectivity. The development of subtype-selective small molecule radioligands suitable for in vitro and in vivo use, as well as robust, commercially-available antibodies remains a critical need for the field. Additionally, novel genetic tools should be developed and leveraged to help move the field increasingly towards a systems-level understanding of mAChR subtype action. Finally, functional, proteomic, and genetic data from ongoing human studies hold great promise for optimizing the design and interpretation of studies examining receptor levels by enabling patient stratification. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'. PMID- 29138081 TI - Regulation and trafficking of muscarinic acetylcholine receptors. AB - Fidelity of signal transduction relies on cells expressing the appropriate number of functional receptors. Fluctuation in the total number of muscarinic acetylcholine receptors has been implicated in a range of physiological and pathophysiological processes, and the mechanisms responsible for this regulation represent potential molecular targets for therapeutic intervention. This article will review the current literature on the endocytic trafficking of muscarinic receptors and how knowledge of the trafficking of related receptors might influence future studies. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'. PMID- 29138082 TI - Synthesis of chitosan-alginate microspheres with high antimicrobial and antibiofilm activity against multi-drug resistant microbial pathogens. AB - The successful treatment of multi-drug resistant microbial pathogens represents a major challenge for public health management. Here, chitosan-alginate (CS/ALG) microspheres with narrow size distribution were fabricated by ionically cross linking method using Ca2+ ions as agents for polymer solidification. The physicochemical properties of CS/ALG microspheres, such as surface morphology and size, were studied by SEM. The functional group interactions were confirmed by Fourier transform infrared (FTIR) spectroscopy. SEM revealed that the CS/ALG microspheres were spherical in shape with smooth surfaces, size was 50-100 MUm. The synthesized CS/ALG microspheres showed antibacterial and antibiofilm activity on bacteria of public health relevance. CS/ALG microspheres exhibited antibacterial activity at the concentration of 5-20 MUg, with significant inhibitory zones on multiple antibiotic resistant pathogens, including Gram positive Staphylococcus aureus, Enterococcus faecalis, and Gram negative Pseudomonas aeruginosa and Proteus vulgaris. Furthermore, in situ light microscopy and confocal laser scanning microscopy (CLSM) showed that CS/ALG microspheres inhibited the bacterial biofilm formation in S. aureus, E. faecalis P. aeruginosa and P. vulgaris after a single treatment with 40 MUg. Overall, our findings underlined that chemically synthesized CS/ALG biomaterial has high antibacterial and antibiofilm activity against a number of microbial pathogens of interest for human health, thus this synthesis route can be further exploited for drug development in current biomedical science. PMID- 29138083 TI - Adaptations in the physiological heterogeneity and viability of Shigella dysenteriae, Shigella flexneri and Salmonella typhimurium, after exposure to simulated gastric acid fluid. AB - Stomach acidity is an important barrier of the human body to protect itself from microbial pathogens entering the small intestine and causing infection. This study examined the survival adaptations of non-acid adapted diarrheal Shigella and Salmonella strains in an environment mimicking the human stomach. The bacterial responses to the challenge of acidic simulated gastric fluid were studied using flow cytometry physiological heterogeneity, membrane integrity and survival (culturability) respectively. Flow cytometry showed that bacterial cells, when exposed to gastric fluid, transformed distinctly, into physiologically heterogeneous sub-populations: intact, stressed and damaged cells, when stained with propidium iodide and thiazole orange. Shigella and Salmonella cells became membrane compromised during initial acid shock (0-30 min), and 80% of these cells shifted to the stressed state throughout gastric fluid exposure. Approximately 10-30% of bacterial strains remained culturable after 60 min of gastric fluid exposure at pH 2.5-4.5, with the percentage increasing with an inoculum size of 102 CFU/ml. This ability of non-acid adapted Shigella and Salmonella sp. to adapt and survive low pH gastric fluid, even though the bacterial numbers decreased or changed to a stressed state, further supports the possible risk of infection when consumed. PMID- 29138084 TI - Determination immunogenic property of truncated MrpH.FliC as a vaccine candidate against urinary tract infections caused by Proteus mirabilis. AB - Proteus mirabilis is common cause of urinary tract infections (UTIs) especially in complicated UTIs which are resistant to antibiotic therapy, Consequently, an ideal vaccine is inevitably required. The N-terminal domain of MrpH (Truncated form of MrpH) lies between the most critical antigens of P. mirabilis to consider as vaccine candidate. FliC of Salmonella typhimurium induces several pathways of immunity system, which leads to produce antibody and cytokines. In this study, adjuvant properties of FliC and efficacy of truncated MrpH as important antigen, in tMrpH.FliC were determined in in vitro and in vivo circumstances. Three proteins including: FliC, MrpH and tMrpH.FliC were injected to mice and subsequently sera and supernatant of cell culture were collected to evaluate different immune responses. According to our findings, tMrpH.FliC could stimulate both humoral and cellular immune responses, so that serum IgG, urine IgA, IL.4, IFN-gamma and IL.17 were increased significantly in comparison to MrpH and FliC alone, this augmentation was considerable. Results showed significant decrease of bacterial load in all of the challenged groups compared to the control group, although this protective effect was the highest in mice vaccinated with tMrpH.FliC. Our results showed truncated MrpH, without an unwanted domain is an ideal vaccine target and FliC, as adjuvant, increases its immunogenic property. Thus, fusion protein tMrpH.FliC can be considered as promising vaccine against P. mirabilis. PMID- 29138085 TI - In silico design, cloning, expression and immunologic evaluation of ED fusion protein of NT H. influenzae. AB - Infections due to nontypeable Haemophilus influenzae (NTHi) are important causes of child mortality throughout the world. Given the lack of effective vaccines for these strains and the spread and prevalence of these infections in the world, it is necessary to design novel vaccine candidates against these strains. D and E proteins are conserved membrane-specific lipoproteins among encapsulated and non encapsulated H. influenza strains, which, according to the exposure surface and conservation degree between both strains, can be considered as vaccine candidates suitable for studies. This research was conducted to design a recombinant truncated fusion protein ED. Vaccination of BALB/c mice with recombinant truncated fusion protein ED showed high level of protective responses against NTHi. There were also strong responses of IgG and its subclasses (especially IgG1) as well as high titer levels of IL-4. A mixture of responses was observed considering IgG2a and INF-gamma antibody titers, but the dominant response was toward Th2. According to the obtained results and the importance of humoral immunity in the immune system and vaccines production, it could be concluded that the produced recombinant construct can be used as a suitable vaccine candidate against NTHi or together with other carrier proteins. PMID- 29138086 TI - Eugenol derivatives prospectively inhibit l-asparaginase: A heady target protein of Salmonella typhimurium. AB - Salmonella typhimurium is the causative agent of severe human infections and mortality throughout the world. Pacing advent of new resistance mechanisms in this microorganism exists, rendering treatment of infectious disease difficult. Ciprofloxacin is no longer considered the first choice of antimicrobial agent due to the emergence of resistance. Therefore, the need for scenario is to find out novel drug target and its potential inhibitor to fight against this pathogen. The present study was undertaken to find out a novel drug target and its inhibitor for improving the current therapeutic methods for treating Salmonella infections. It is found that l-asparaginase is exploited by the pathogen for its survival benefit. Therefore, it could be targeted to fight against lethality caused by Salmonella infections. In the present in silico study, the 3-D structure of the enzyme l-asparaginase was modelled by using homology modeling technique. Thereafter, molecular docking studies and ADMET prediction to assess pharmacokinetic profiles of test ligands (eugenol and its derivative) was performed. The results show that eugenol and its derivative are capable of inhibiting the Salmonella virulent protein l-asparaginase. There were 18 ligands including ciprofloxacin (used as reference) were docked. The lowest binding energy was observed with eugenol derivative 8 i.e -5.836 kcal/mol while for ciprofloxacin was -4.661 kcal/mol. The docking of the eugenol derivative 8 with l asparaginase revealed a strong interaction between them with two hydrogen bonds. Thr 35 and Asp 116 residues are actively participating in this interaction. The result of ADMET profiling suggests the potency of eugenol and its derivatives against Salmonellal-asparaginase-II as a compelling drug candidate. These findings provide useful information on the biological role, structure-based drug design and potent inhibitor of l-asparaginase for the development of effective therapeutic molecule against Salmonella infection. PMID- 29138087 TI - Beyond modularity: Fine-scale mechanisms and rules for brain network reconfiguration. AB - The human brain is in constant flux, as distinct areas engage in transient communication to support basic behaviors as well as complex cognition. The collection of interactions between cortical and subcortical areas forms a functional brain network whose topology evolves with time. Despite the nontrivial dynamics that are germane to this networked system, experimental evidence demonstrates that functional interactions organize into putative brain systems that facilitate different facets of cognitive computation. We hypothesize that such dynamic functional networks are organized around a set of rules that constrain their spatial architecture - which brain regions may functionally interact - and their temporal architecture - how these interactions fluctuate over time. To objectively uncover these organizing principles, we apply an unsupervised machine learning approach called non-negative matrix factorization to time-evolving, resting state functional networks in 20 healthy subjects. This machine learning approach automatically groups temporally co-varying functional interactions into subgraphs that represent putative topological modes of dynamic functional architecture. We find that subgraphs are stratified based on both the underlying modular organization and the topographical distance of their strongest interactions: while many subgraphs are largely contained within modules, others span between modules and are expressed differently over time. The relationship between dynamic subgraphs and modular architecture is further highlighted by the ability of time-varying subgraph expression to explain inter-individual differences in module reorganization. Collectively, these results point to the critical role that subgraphs play in constraining the topography and topology of functional brain networks. More broadly, this machine learning approach opens a new door for understanding the architecture of dynamic functional networks during both task and rest states, and for probing alterations of that architecture in disease. PMID- 29138088 TI - Comparing multilayer brain networks between groups: Introducing graph metrics and recommendations. AB - There is an increasing awareness of the advantages of multi-modal neuroimaging. Networks obtained from different modalities are usually treated in isolation, which is however contradictory to accumulating evidence that these networks show non-trivial interdependencies. Even networks obtained from a single modality, such as frequency-band specific functional networks measured from magnetoencephalography (MEG) are often treated independently. Here, we discuss how a multilayer network framework allows for integration of multiple networks into a single network description and how graph metrics can be applied to quantify multilayer network organisation for group comparison. We analyse how well-known biases for single layer networks, such as effects of group differences in link density and/or average connectivity, influence multilayer networks, and we compare four schemes that aim to correct for such biases: the minimum spanning tree (MST), effective graph resistance cost minimisation, efficiency cost optimisation (ECO) and a normalisation scheme based on singular value decomposition (SVD). These schemes can be applied to the layers independently or to the multilayer network as a whole. For correction applied to whole multilayer networks, only the SVD showed sufficient bias correction. For correction applied to individual layers, three schemes (ECO, MST, SVD) could correct for biases. By using generative models as well as empirical MEG and functional magnetic resonance imaging (fMRI) data, we further demonstrated that all schemes were sensitive to identify network topology when the original networks were perturbed. In conclusion, uncorrected multilayer network analysis leads to biases. These biases may differ between centres and studies and could consequently lead to unreproducible results in a similar manner as for single layer networks. We therefore recommend using correction schemes prior to multilayer network analysis for group comparisons. PMID- 29138089 TI - Rapid two-step dipole inversion for susceptibility mapping with sparsity priors. AB - Quantitative susceptibility mapping (QSM) is a post-processing technique of gradient echo phase data that attempts to map the spatial distribution of local tissue magnetic susceptibilities. To obtain these maps, an ill-posed field-to source inverse problem must be solved to remove non-local magnetic field perturbations. Current state-of-the-art algorithms which aim to solve the dipole inversion problem are plagued by the trade-off between reconstruction speed and accuracy. A two-step dipole inversion algorithm is proposed to bridge this gap. Our approach first addresses the well-conditioned k-space region, which is reconstructed using a Krylov subspace solver. Then the ill-conditioned k-space region is reconstructed by solving a constrained l1-minimization problem. The proposed pipeline does not incorporate a priori information, but utilizes sparsity constraints in the second step. We compared our method to well established QSM algorithms with respect to COSMOS in in vivo volunteer datasets. Compared to MEDI and HEIDI the proposed algorithm produces susceptibility maps with a lower root-mean-square error and a higher coefficient of determination, with respect to COSMOS, while being 50 times faster. Our two-step dipole inversion algorithm without a priori information yields improved QSM reconstruction quality at reduced computation times compared to current state-of the-art methods. PMID- 29138090 TI - Novel, de novo dysferlin gene mutations in a patient with Miyoshi myopathy. AB - Miyoshi myopathy (MM) is an autosomal recessive distal muscular dystrophy caused by mutations in the dysferlin gene (DYSF), a 150-kb gene on chromosome 2p13 that contains 55 coding exons. Many patients with MM harbour mutations in the DYSF gene, and most of these mutations are inherited from the patients' parents. Recently, we encountered novel, de novo mutations in the DYSF gene in a patient with MM. DYSF gene analysis was performed by targeted next-generation sequencing, and we found that the patient had compound heterozygous mutations, including a de novo mutation (c.613C > T) in exon 6 and a novel missense mutation (c.968T > C) in exon 11. The novel missense mutation, predicted to be a disease-causing mutation or affecting protein function by MutationTaster and Polyphen2, confirmed the diagnosis. These findings provide important insights into the pathogenesis and inheritance of MM. PMID- 29138091 TI - Longitudinal electrophysiological changes after cervical hemi-contusion spinal cord injury in rats. AB - OBJECTIVE: To evaluate the longitudinal somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) characterization from acute to chronic injury following cervical hemi-contusion spinal cord injury (SCI) in rats, and correlate the MEPs & SEPs to the behavioral outcomes. METHODS: Fifteen adult male Sprague Dawley rats were subjected to the hemi-contusion spinal cord injury at C5. Forelimb MEPs & SEPs were applied to 5 animals before injury and 3h, 1d, 3d, 1w, 2w, 4w and 8w after injury respectively. Forelimb functional assessments, including Montoya staircase task and cylinder rearing test, were conducted on another 10 animals before injury and at 2w, 4w and 8w after injury respectively, as well as histological analysis of the cord at 8w after injury. A group correlation was performed between the MEPs & SEPs and behavioral outcomes. RESULTS: The hemi-contusion injury resulted in unilateral tissue damage at the epicenter with loss of the ventral horns and lateral funiculus. Both ipsilateral and contralateral forelimb MEPs showed latency prolongation and amplitude reduction at 3h after injury. The MEPs amplitude increased with time after injury, but the ipsilateral amplitude was persistently lower than the contralateral amplitude. The ipsilateral MEPs latency increased with time after injury and was significantly longer than the contralateral MEPs latency. The ipsilateral SEPs amplitude dropped after injury and stayed at a lower level up to 8 weeks. There was no difference in the SEPs latency among time points and between sides. At 8 weeks after injury, the ipsilateral forelimb grasped 30% pellets while the contralateral forelimb close to 81%. An obvious decreased usage of the ipsilateral paw and increased usage of the contralateral paw were observed in rearing test after injury. The MEPs latency and amplitude correlated significantly with the forelimb motor function. CONCLUSION: Cervical hemi contusion SCI led to persistent changes in MEPs & SEPs of the ipsilateral forelimb, ipsilateral impairment in motor function and unilateral cord tissue damage. Reliable electrophysiology assessment was obtained in chronic phase due to unstable MEPs & SEPs of bilateral forelimb immediately after injury, which might reflect the underlying pathological processes. The present study further confirmed the link of the MEPs to the behavioral outcomes, supporting the longitudinal electrophysiology assessment for neurological impairment after SCI. PMID- 29138092 TI - Abnormal cortical neuroplasticity induced by paired associative stimulation after traumatic spinal cord injury: A preliminary study. AB - We aimed at assessing in this pilot study whether patients with spinal cord injury (SCI) show alterations of sensorimotor plasticity within the primary motor cortex (M1). Since learning in human M1 occurs through LTP-like mechanisms, we employed the paired associative stimulation (PAS) protocol by transcranial magnetic stimulation (TMS), which is able to induce LTP-like effects in M1, in subjects with chronic SCI. We found that PAS protocol significantly increased corticospinal excitability as long as 30min in healthy subjects and in SCI patients with good motor recovery, while it was followed by a non-significant increase of MEP amplitude in the SCI patients with poor functional recovery. These findings suggest that the level of LTP-like phenomena is correlated with long term recovery and support the correlation between the ability of inducing excitability changes using TMS and the process of motor recovery. Increased cortical plasticity might imply greater capability for neuromodulation. PMID- 29138093 TI - Electrophysiological correlates of performance monitoring under social observation in patients with social anxiety disorder and healthy controls. AB - Previous research suggests that electrophysiological correlates of performance monitoring, in particular the error-related negativity (ERN), vary according to psychopathology and context factors. The present study examined the effect of social context on behavioral and electrophysiological correlates of performance monitoring in healthy adult subjects and in patients with social anxiety disorder (SAD). Participants performed two runs of a Go/NoGo flanker task in different social conditions: in the observation condition, they were observed by a confederate while performing the task, whereas there was no observation in the control condition. Behavioral data showed that accuracy and response times were not modulated by social observation and also did not systematically differ between groups. Post-error slowing was more pronounced in patients, independent of observation condition. ERN amplitudes were generally increased under social observation as compared to the control condition regardless of group (patients, controls). No effects of social context or group were found for PE, NoGo-N2, and NoGo-P3. Exploratory analysis revealed a late sustained parietal negativity to errors in patients as compared to controls. Taken together, the present findings emphasize the importance of social context for the processes underlying performance monitoring. However, the notion of altered error monitoring reflected in an altered ERN in SAD is not supported by our data. PMID- 29138094 TI - FOXO1/3: Potential suppressors of fibrosis. AB - Fibrosis is a universally age-related disease that involves nearly all organs. It is typically initiated by organic injury and eventually results in organ failure. There are still few effective therapeutic strategy targets for fibrogenesis. Forkhead box proteins O1 and O3 (FOXO1/3) have been shown to have favorable inhibitory effects on fibroblast activation and subsequent extracellular matrix production and can ameliorate fibrosis levels in numerous organs, including the heart, liver, lung, and kidney; they are therefore promising targets for anti fibrosis therapy. Moreover, we can develop appropriate strategies to make the best use of FOXO1/3's anti-fibrosis properties. The information reviewed here should be significant for understanding the roles of FOXO1/3 in fibrosis and should contribute to the design of further studies related to FOXO1/3 and the fibrotic response and shed light on a potential treatment for fibrosis. PMID- 29138095 TI - Kinetics and thermodynamics of the thermal inactivation and chaperone assisted folding of zebrafish dihydrofolate reductase. AB - The maintenance of thermal stability is a major issue in protein engineering as many proteins tend to form inactive aggregates at higher temperatures. Zebrafish DHFR, an essential protein for the survival of cells, shows irreversible thermal unfolding transition. The protein exhibits complete unfolding and loss of activity at 50 degrees C as monitored by UV-Visible, fluorescence and far UV-CD spectroscopy. The heat induced inactivation of zDHFR follows first-order kinetics and Arrhenius law. The variation in the value of inactivation rate constant, k with increasing temperatures depicts faster inactivation at elevated temperatures. We have attempted to study the chaperoning ability of a shorter variant of GroEL (minichaperone) and compared it with that of conventional GroEL GroES chaperone system. Both the chaperone system prevented the aggregation and assisted in refolding of zDHFR. The rate of thermal inactivation was significantly retarded in the presence of chaperones which indicate that it enhances the thermal stability of the enzyme. As minichaperone is less complex, and does not require high energy co-factors like ATP, for its function as compared to conventional GroEL-GroES system, it can act as a very good in vitro as well as in vivo chaperone model for monitoring assisted protein folding phenomenon. PMID- 29138096 TI - One single salt bridge explains the different cytolytic activities shown by actinoporins sticholysin I and II from the venom of Stichodactyla helianthus. AB - Sticholysins I and II (StnI and StnII), alpha-pore forming toxins from the sea anemone Stichodactyla helianthus, are water-soluble toxic proteins which upon interaction with lipid membranes of specific composition bind to the bilayer, extend and insert their N-terminal alpha-helix, and become oligomeric integral membrane structures. The result is a pore that leads to cell death by osmotic shock. StnI and StnII show 93% of sequence identity, but also different membrane pore-forming activities. The hydrophobicity profile along the first 18 residues revealed differences which were canceled by substituting StnI amino acids 2 and 9. Accordingly, the StnID9A mutant, and the corresponding StnIE2AD9A variant, showed enhanced hemolytic activity. They also revealed a key role for an exposed salt bridge between Asp9 and Lys68. This interaction is not possible in StnII but appears conserved in the other two well-characterized actinoporins, equinatoxin II and fragaceatoxin C. The StnII mutant A8D showed that this single replacement was enough to transform StnII into a version with impaired pore-forming activity. Overall, the results show the key importance of this salt bridge linking the N terminal stretch to the beta-sandwich core. A conclusion of general application for the understanding of salt bridges role in protein design, folding and stability. PMID- 29138097 TI - Gastric microbiota: An emerging player in Helicobacter pylori-induced gastric malignancies. AB - The complex diversity of nonpathogenic microbes that colonize the human body, known as microbiota, exert considerable effects on physiological homeostasis, and immune regulation. Helicobacter pylori (H. pylori) is a bacterium that frequently colonizes human stomach and is a major pathogenic agent for peptic ulcer diseases, gastric cancer, and mucosa-associated lymphoid tissue (MALT) lymphoma. Due to its acidic pH and peristaltic movements, the stomach has been considered a hostile environment for most microorganisms, however various commensal microorganisms are capable of colonizing the stomach to form a stomach niche. Recent pieces of evidence indicate that commensal gastric microbes or their metabolites influence the capability of H. pylori to colonize the stomach and directly modulate its pathogenicity and carcinogenic potential. In this article, we present an overview of recent advances in the understanding of H. pylori commensal interactions in the pathogenesis and clinical evolution of H. pylori associated gastric malignancies. PMID- 29138098 TI - Cytotoxic activity of Holothuria tubulosa (Echinodermata) coelomocytes. AB - The immune system of marine invertebrates, in particular that of holothurians, still requires further study. Our research showed that coelomocyte cells contained in the coelomic fluid of the sea cucumber, Holothuria tubulosa, are able to lyse, in vitro, red blood cells in rabbits and sheep. A plaque-forming assay showed spherule cells to be the effector cells, able to release cytotoxic molecules after xenogenic cell contact. The coelomocyte lysate supernatant, analysed by polyacrylamide gel electrophoresis overlay technique, using rabbit and sheep erythrocytes, showed two different haemolytic protein patterns: one calcium dependent and the other calcium independent. The fractions of each pattern were resolved on a polyacrylamide gel and calcium-dependent and independent coelomocyte lysate patterns were compared. PMID- 29138099 TI - Effect of an antimicrobial stewardship programme on antimicrobial utilisation and costs in patients with leukaemia: a retrospective controlled study. AB - OBJECTIVES: To examine the effectiveness of an antimicrobial stewardship programme on utilization and cost of antimicrobials in leukaemia patients in Canada. METHODS: We conducted a multisite retrospective observational time series study from 2005 to 2013. We implemented academic detailing as the intervention of an antimicrobial stewardship programme in leukaemia units at a hospital, piloted February-July 2010, then fully implemented December 2010-March 2013, with no intervention in August-November 2010. Internal control was the same hospital's allogeneic haematopoietic stem-cell transplantation unit. External control was the combined leukaemia-haematopoietic stem-cell transplantation unit at another hospital. Primary outcome was antimicrobial utilization (antibiotics and antifungals) in defined daily dose per 100 patient-days (PD). Secondary outcomes were antimicrobial cost (Canadian dollars per PD); cost and utilization by drug class; length of stay; 30-day inpatient mortality; and nosocomial Clostridium difficile infection. We used autoregressive integrated moving average models to evaluate the impact of the intervention on outcomes. RESULTS: The intervention group included 1006 patients before implementation and 335 during full implementation. Correspondingly, internal control had 723 and 264 patients, external control 1395 and 864 patients. Antimicrobial utilization decreased significantly in the intervention group (p <0.01, 278 vs. 247 defined daily dose per 100 PD), increased in external control (p = 0.02, 237.4 vs. 268.9 defined daily dose per 100 PD) and remained stable in internal control (p = 0.66). Antimicrobial cost decreased in the intervention group (p = 0.03; $154.59 per PD vs. $128.93 per PD), increased in external control (p = 0.01; $109.4 per PD vs. $135.97 per PD) but was stable in internal control (p = 0.27). Mortality, length of stay and nosocomial C. difficile rate in intervention group remained stable. CONCLUSIONS: The antimicrobial stewardship programme reduced antimicrobial use in leukaemia patients without affecting inpatient mortality and length of stay. PMID- 29138100 TI - Amphotericin B for treatment of visceral leishmaniasis: systematic review and meta-analysis of prospective comparative clinical studies including dose-ranging studies. AB - OBJECTIVES: To evaluate the evidence for use of different formulations of amphotericin B (AmB), minimum effective dose for each formulation and its comparative efficacy against other drugs in achieving definitive cure of visceral leishmaniasis. METHODS: This systematic review and meta-analysis included following data sources: PubMed, Embase, Scopus, Web of Science and CINAHL. Controlled prospective clinical trials (randomized or nonrandomized, including dose-ranging studies) conducted between 1996 and 2017 with at least one treatment group receiving AmB were included (published data only). The primary outcome was definitive cure at 6 months. Adverse events and mortality were assessed as secondary outcomes. The PROSPERO registration number for this review is CRD42017067488. RESULTS: Thirty-one studies (26 from India) that enrolled 6903 patients into 84 study groups met the selection criteria. In India, liposomal AmB was not inferior to AmB deoxycholate (relative risk 1.00, 95% confidence interval (CI) 0.96-1.03, two randomized controlled trials (RCTs), 514 participants, high quality evidence), and a single dose of the earlier formulation as low as 3.75 mg/kg achieved a cure rate of over 89% (95% CI 70.6-97.2). AmB deoxycholate was as effective as miltefosine (relative risk 0.99, 95% CI 0.95-1.03, two trials, 523 participants, high-quality evidence) and may be better than paromomycin (relative risk 1.04, 95% CI 1.02-1.07, one trial, 667 participants, low-quality evidence) in achieving definitive cure. CONCLUSIONS: AmB is an efficacious drug in the Indian subcontinent. Further evidence is needed from prospective clinical trials in other endemic geographical regions. PMID- 29138102 TI - Citation analysis may well have a role to play in study identification, but more evaluation and system development are required. PMID- 29138103 TI - Citation analysis is also useful to assess the eligibility of biomedical research works for inclusion in living systematic reviews. PMID- 29138101 TI - Primary antibiotic resistance of Helicobacter pylori in Chinese patients: a multiregion prospective 7-year study. AB - OBJECTIVES: To explore the characteristics of Helicobacter pylori resistance in China and the association between antibiotic resistance and several clinical factors. METHODS: H. pylori strains were collected from patients in 13 provinces or cities in China between 2010 and 2016. Demographic data including type of disease, geographic area, age, gender and isolation year were collected to analyse their association with antibiotic resistance. Antibiotic resistance was detected using the Etest test and the Kirby-Bauer disc diffusion method. RESULTS: H. pylori were successfully cultured from 1117 patients. The prevalence of metronidazole, clarithromycin (CLA), azithromycin, levofloxacin (LEV), moxifloxacin, amoxicillin (AMO), tetracycline and rifampicin resistance was 78.2, 22.1, 23.3, 19.2, 17.2, 3.4, 1.9 and 1.5%, respectively. No resistance to furazolidone was observed. The resistance rates to LEV and moxifloxacin were higher in strains isolated from patients with gastritis compared to those with duodenal ulcer and among women. Compared to patients >=40 years old, younger patients exhibited lower resistance rates to CLA, azithromycin, LEV and moxifloxacin. The resistance rates to CLA and AMO were higher in strains isolated more recently, and we also found that the prevalence of resistance to metronidazole, CLA, azithromycin and AMO were significantly different among different regions of China. CONCLUSIONS: The resistance rates to metronidazole, CLA and LEV were high in China. Patient age, gender, disease and location were associated with the resistance of H. pylori to some antibiotics. Furazolidone, AMO and tetracycline are better choices for H. pylori treatment in China. PMID- 29138104 TI - Novel mixed vesicles containing lactobacilli biosurfactant for vaginal delivery of an anti-Candida agent. AB - The purpose of this work was to prepare and characterize an innovative formulation for vaginal delivery of econazole nitrate, commonly used for the treatment of Candida infections. A novel biosurfactant isolated from a vaginal Lactobacillus strain was used to prepare phosphatidylcholine based mixed vesicles. Biosurfactant was produced by Lactobacillus gasseri BC9, isolated from the vagina of a healthy premenopausal woman, and was chemically characterized by FT-IR and ESI-MS. Mixed vesicles, obtained through film rehydration and extrusion method, were characterized in terms of size, zeta potential, encapsulation efficiency, mucoadhesion properties and econazole release. Moreover, the antimicrobial activity of the mixed vesicles was tested towards both planktonic cultures and biofilms of Candida albicans. Biosurfactant produced by L. gasseri BC9 was composed by peptide-like molecules containing hydrocarbon chains and possessed a high surface activity together with a low critical micelle concentration. All the mixed vesicles presented optimal diameter range (226 337nm) for topical vaginal administration. Econazole-loaded mixed vesicles containing biosurfactant showed higher encapsulation efficiency and mucoadhesion ability with respect to vesicles containing Tween 80. Further, they allowed a sustained release of econazole nitrate, maintaining the antifungal activity against C. albicans planktonic culture. Notably, biosurfactant-based vesicles were significantly more active than free econazole in the eradication of Candida biofilm. In conclusion, mixed vesicles are promising new vaginal delivery systems for the potential employment in the treatment of chronic infections. PMID- 29138105 TI - Adrenergic Receptor Agonists' Modulation of Dopaminergic and Non-dopaminergic Neurons in the Ventral Tegmental Area. AB - The ventral tegmental area (VTA) neuronal population consists of dopaminergic (DAergic) and non-DAergic neurons (mainly GABAergic), the activity of which is intertwined with VTA behavioral functions. Both DAergic and GABAergic neurons in the VTA have been shown to express adrenergic receptors (ARs) and respond to AR stimulation. The aim of the present study was to demonstrate the effects of selective AR agonists on DAergic and non-DAergic neuronal activity in the central and lateral parts of the VTA using in vivo electrophysiological recording combined with microiontophoretic drug application in anaesthetized rats. Administration of phenylephrine, a selective alpha1-AR agonist, while having an inhibitory effect on putative DAergic neurons (11% decrease in firing rate), induced a clear excitatory effect (59% increase in firing rate) on putative non DAergic neurons. In contrast, application of clonidine, a selective alpha2-AR agonist, or isoprenaline, a selective beta-adrenergic receptor agonist, did not change the firing rate of either DAergic or non-DAergic neurons but influenced the firing pattern of non-DAergic cells only. Our results suggest that noradrenaline modulates activity of VTA neurons in vivo primarily via alpha1, but also via beta- and alpha2-AR to a lesser extent. Furthermore, we show that alpha1 AR activation has contrasting effects on putative DAergic and non-DAergic neurons. We hypothesize that the phenylephrine-induced inhibition of putative DAergic neurons results from activation of GABAergic terminals present at the site of drug application. Such a mechanism is further supported by the observed alpha1-AR-induced excitation of putative GABAergic VTA neurons. PMID- 29138106 TI - The Subthalamic Neurons are Activated by Both Orexin-A and Orexin-B. AB - : The subthalamic nucleus is an important nucleus in the indirect pathway of the basal ganglia circuit and therefore is involved in motor control under both normal and pathological conditions. Morphological studies reveal that the subthalamic nucleus receives relatively dense orexinergic projections originating from the hypothalamus. Both orexin-1 (OX1) and orexin-2 (OX2) receptors are expressed in the subthalamic nucleus. To explore the functions of orexinergic system in the subthalamic nucleus, extracellular electrophysiological recordings and behavioral tests were performed in the present study. Exogenous application of orexin-A significantly increased the spontaneous firing rate from 5.70 +/- 0.66 Hz to 9.87 +/- 1.18 Hz in 64.00% subthalamic neurons recorded. OX1 receptors are involved in orexin-A-induced excitation. Application of orexin-B increased the firing rate from 7.47 +/- 0.92 Hz to 11.85 +/- 1.39 Hz in 80.95% subthalamic neurons recorded, entirely through OX2 receptors. Both OX1 and OX2 receptor antagonists decreased the firing rate in 43.75% and 62.50% subthalamic neurons recorded respectively, suggesting the involvement of endogenous orexinergic system in the control of spontaneous firing activity. Further elevated body swing test revealed that microinjection of orexins and the receptor antagonists into the subthalamic nucleus induced contralateral-biased swing and ipsilateral-biased swing, respectively. Taken together, the present study suggests that orexins play important roles in the subthalamic nucleus which may provide further evidence for the involvement of subthalamic orexinergic tone in Parkinson's disease. SIGNIFICANCE: Previous morphological studies indicate that the subthalamic nucleus receives orexinergic innervation and expresses both OX1 and OX2 receptors. Using in vivo multibarrel electrophysiological recordings, the present study revealed that exogenous application of orexin-A and orexin-B increased the spontaneous firing rate of the subthalamic neurons through OX1 and OX2 receptors. Endogenous orexinergic system was involved in the control of spontaneous firing of the subthalamic neurons. Further behavioral test revealed that intrasubthalamic application of orexins and the receptor antagonists induced biased swing behavior. The present study may provide further evidence for the involvement of subthalamic orexinergic tone in Parkinson's disease. PMID- 29138107 TI - Effect of Low-Frequency Electrical Stimulation on the High-K+-Induced Neuronal Hyperexcitability in Rat Hippocampal Slices. AB - Low-frequency electrical stimulation (LFS) is a potential therapeutic method for epilepsy treatment. However, the effect of different LFS characteristics including the number of pulses, intensity and the time of application on its antiepileptic action has not been completely determined. In the present study, epileptiform activity (EA) was induced in hippocampal slices by high-K+ solution which was washed out after 20 min. The changes in the electrophysiological properties of CA1 pyramidal neurons were measured during and 30 min after EA using whole-cell patch-clamp recording. EA occurrence resulted in neuronal hyperexcitability. Application of 1-Hz LFS to the Schaffer collaterals at 600 and 900 pulses and two intensities (equal and 1.5 times more than an intensity sufficient to elicits a 5-mV EPSP) at the beginning of EA showed that 900-pulse LFS at high intensity had stronger preventing effect on high-K+-induced neuronal hyperexcitability by increasing the rheobase current, utilization time, first spike latency, delay to first-rebound action potential and decreasing the number of rebound action potential. In addition, application of high-intensity 900-pulse LFS had better inhibitory effect on the neuronal hyperexcitability when applied at the beginning of EA compared to its administration before or at 8-10 min after EA. Therefore, it may suggest the inhibitory action of LFS on the neuronal hyperexcitability is augmented by increasing its number of pulses and intensity. In addition, there is a time window for LFS application so that its application at the beginning of EA has better inhibitory effect. PMID- 29138108 TI - Analysis of Social Process in Two Inbred Strains of Male Mice: A Predominance of Contact-Based Investigation in BALB/c Mice. AB - Developing mouse models for social communication deficits requires a better understanding of the nature of social investigatory processes between mice. Mice use different investigatory strategies based on a possibility of contacts with social sources. A detailed investigation of contact distance revealed strain differences in behavioral strategy between two male inbred C57BL/6 (B6) and BALB/c (BALB) mouse strains. When direct physical contact with stimulus mice was restricted, BALB mice displayed lower social approaches than B6 mice, accompanied by heightened innate anxiety in an unfamiliar environment. However, both BALB and B6 mice expressed distinct object and social recognition in the habituation/dishabituation paradigm. When allowed direct contact with stimulus mice, both B6 and BALB mice showed approach and discrimination of strain differences in the stimulus mice. Furthermore, BALB mice discriminated individuals of the same strain among cagemates and showed a discrete aversion to the anogenital but not facial region of the stranger mice. This anogenital aversion disappeared when the stranger mice received a buspirone injection that reduced anxiety or when familiar cagemates were exposed. These strain differences in investigatory strategies illustrate that B6 mice are able to respond to and process social cues in a vicinity, which does not require physical contact with the source, while BALB mice predominantly process social cues by direct contact with the source. Although BALB mice exhibit marked anxiety and defensive responses to unfamiliarity, there is no evidence of any defect in sociability in BALB mice as a possible autism model. PMID- 29138109 TI - Mesopontine Neurons Implicated in Anesthetic Loss-of-consciousness have Either Ascending or Descending Axonal Projections, but Not Both. AB - The MPTA (mesopontine tegmental anesthesia area) is a key node in a network of axonal pathways that collectively engage the key components of general anesthesia: immobility and atonia, analgesia, amnesia and loss-of-consciousness. In this study we have applied double retrograde tracing to analyze MPTA connectivity, with a focus on axon collateralization. Prior tracer studies have shown that collectively, MPTA neurons send descending projections to spinal and medullary brain targets associated with atonia and analgesia as well as ascending projections to forebrain structures associated with amnesia and arousal. Here we ask whether individual MPTA neurons collateralize broadly as might be expected of modulatory circuitry, sending axonal branches to both caudal and to rostral targets, or whether connectivity is more selective. Two distinguishable retrograde tracers were microinjected into pairs ("dyads") of known synaptic targets of the MPTA, one caudal and one rostral. We found that neurons that were double-labeled, and hence project to both targets were rare, constituting <0.5% on average of all MPTA neurons that project to these targets. The large majority sent axons either caudally, presumably to mediate mobility and/or antinociception, or rostrally, presumably to mediate mnemonic and/or arousal/cognitive functions. MPTA neurons with descending vs ascending projections also differed in size and shape, supporting the conclusion that they constitute distinct neuronal populations. From these and prior observations we conclude that the MPTA has a hybrid architecture including neurons with heterogeneous patterns of connectivity, some highly collateralized and some more targeted. PMID- 29138110 TI - Neuronal Loss in the Developing Cerebral Cortex of Normal and Bax-Deficient Mice: Effects of Ethanol Exposure. AB - Fetal alcohol spectrum disorder is associated with defects in neuronal generation, migration, and differentiation. The present study tested the hypothesis that ethanol exposure during the period of naturally occurring neuronal death causes a time- and Bax-dependent neuronal loss. Wild-type and Bax knockout mice were given a pair of injections (two hours apart) of ethanol (2.5 g/kg) or saline on postnatal day (P) 4, P7, P10, or P13. Mean blood ethanol concentration was 435 mg/dl one hour after the second injection. The total numbers of neurons in individual layers of somatosensory cortex were stereologically determined in 30-day-old mice and the expressions of active caspase 3 immunopositivity and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were determined 2-36 h after the first injection. On P30, ethanol caused up to 36% neuronal loss in cortical laminae of wild-type mice. In contrast, no ethanol-induced loss was detected in Bax knockout mice. Ethanol also caused an acute bilaminar (layers II/III and V) increase in caspase 3 immunoexpression and TUNEL in wild-type mice. The changes in the expression of these markers were age- and lamina-dependent. No ethanol-induced expression of caspase 3 or TUNEL was detected in Bax knockout animals. Thus, ethanol-induced death of cortical neurons is Bax-dependent, occurs concurrently in all layers, but does not correspond to lamina- and age-dependent expression of DNA fragmentation. Both ethanol-induced and naturally occurring death of cortical neurons rely on caspase 3-dependent and independent mechanisms. PMID- 29138111 TI - Recent advances in melanoma research via "omics" platforms. AB - Melanoma has a high mortality rate and metastatic melanoma is highly resistant to conventional therapies. "Omics" fields such as proteomics and microRNA and exosome studies have provided new knowledge to complement the information generated by genomic studies. This work aimed to review the current status of biomarker discovery for melanoma through multi-"omics" platforms. A few sets of novel microRNAs and proteins are described, some of them with important implications in suppressing melanoma at different stages. Upregulation of genes involved in angiogenesis, immunosuppressive factors, modification of stroma, capture of melanoma cells in lymph nodes and factors responsible for tumour cell recruitment have been identified in exosomes, among molecules with other functions. A remarkable series of proteins involved in epithelial mesenchymal/mesenchymal-epithelial transitions, inflammation, motility, proliferation and progression processes, centrosome amplification, aneuploidy, inhibition of CD8+ effector T-cells, and metastasis in general were identified. Genomic and protein-protein interactions or metabolome levels were not analysed. Proteomics tools such as Orbitrap shotgun mass spectrometry or deep mining proteomic analysis utilizing high-resolution reversed phase nanoseparation in combination with mass spectrometry are also discussed. The application of these tools together with bioinformatics approaches applied to the clinical setting will enable the implementation of personalized medicine in the near future. PMID- 29138112 TI - Dentists' decision strategies for suspicious occlusal caries lesions in a National Dental PBRN study. AB - OBJECTIVE: Case presentations (vignettes) were completed by dentists in the National Dental Practice-Based Research Network study "Decision Aids for the Management of Suspicious Occlusal Caries Lesions (SOCLs)". The objective was to determine dentists' decision strategies for SOCLs. METHODS: 107 dentists viewed a series of 16 vignettes that represented all combinations of 4 clinical cues: color, luster, lesion roughness, and patient-level caries risk. Each vignette included a patient description and a photograph of a tooth presenting the 4 cues. Dentists were asked to decide the likelihood that a suspected lesion extended into dentin. A lens model analysis was used to examine how dentists use these cues in making their decisions. RESULTS: 86% of dentists had a consistent pattern of cue use that defined their decision strategy. On average, 70% of the variance in their decisions was accounted for by their use of the 4 cues. However, there was considerable variability in the individual cues used by each dentist. The percentages of dentists who used the different cues consistently were: luster (58%), color (48%), roughness (36%), and risk (35%). 14% of dentists reliably used only color, 7% used only luster, 4% used only roughness, and 1% used only risk when making SOCL decisions. CONCLUSIONS: The online vignette system suggests that clinical SOCL decision strategies are highly individualized and dentists do not use all cues available to them to make these decisions. CLINICAL SIGNIFICANCE: Prior to this study, there has been little evidence about how dentists use these cues (either individually or in combination) when judging the extent of caries progression. Such knowledge would be valuable when designing interventions to help dentists maximize the likelihood of appropriate treatment decisions. PMID- 29138113 TI - Prevalence of extended-spectrum beta-lactamase- and carbapenemase-encoding genes in poultry faeces from Algeria and Marseille, France. AB - OBJECTIVES: The aim of this study was to evaluate the prevalence of extended spectrum beta-lactamase (ESBL)- and carbapenemase-encoding genes in poultry from Algeria and Marseille, France. METHODS: Samples consisted of faeces collected from broilers in France and Algeria between 2014 and 2015. DNA extraction and quantitative PCR were performed on 833 faecal samples to screen for the presence of genes encoding ESBLs (blaTEM, blaSHV and blaCTX-M) and carbapenemases (blaNDM, blaVIM, blaKPC, blaOXA-23, blaOXA-24, blaOXA-48 and blaOXA-58). To characterise bacteria carrying antimicrobial resistance genes, positive results were simultaneously sequenced. RESULTS: All chicken faeces from Marseille were negative for ESBL- and carbapenemase-encoding genes. However, of the 503 faecal samples collected in Algeria, 128 (25.4%) were positive for blaTEM, 83 (16.5%) for blaSHV, 46 (9.1%) for blaCTX-M and 132 (26.2%) for blaOXA-58. Using a sequencing reaction, a high diversity of ESBL genes was observed throughout the sites studied. CONCLUSIONS: This study shows a high prevalence and diversity of ESBL and carbapenemase genes in poultry faeces from Algeria, whereas none of the samples from Marseille were positive for these genes. The high prevalence of ESBLs in Algeria is in contrast to the observation that no chickens were found to be positive in France. PMID- 29138114 TI - The alpha1,3-fucosyltransferase FUT7 regulates IL-1beta-induced monocyte endothelial adhesion via fucosylation of endomucin. AB - Monocyte-endothelial adhesion is a hallmark feature of atherosclerosis at early stage and emerging evidence suggests that the glycosylation of vascular adhesive molecules and its ligands is involved in this process. Nevertheless, the mechanism underlying this process remains incompletely elucidated. In this study, we reported that treatment with inflammatory factors interleukin-1beta (IL-1beta) pronouncedly upregulated alpha1,3-fucosyltransferase VII gene (FUT7) mRNA and protein expression level in EA.hy926 endothelial cells. Moreover, FUT7 overexpression significantly promoted monocyte-endothelial adhesion, while FUT7 knockdown obviously inhibited IL-1beta-induced monocyte-endothelial adhesion. Further analysis demonstrated that fucosylation of selectin ligand endomucin was directly involved in IL-1beta-induced monocyte-endothelial adhesion. Finally, we demonstrated that p38 and extracellular signal-regulated kinase (ERK) MAPK signaling pathway was activated by IL-1beta, while inhibition of p38/ERK signaling pathway decreased FUT7 expression level and IL-1beta-induced monocyte endothelial adhesion. In summary, these results provide a novel insight that FUT7 mediated fucosylation contribute to the initiation and progression of atherosclerosis. PMID- 29138115 TI - Active forms of Akt and ERK are dominant in the cerebral cortex of newborn pigs that are unaffected by asphyxia. AB - AIMS: Perinatal asphyxia (PA) often results in hypoxic-ischemic encephalopathy (HIE) in term neonates. Introduction of therapeutic hypothermia improved HIE outcome, but further neuroprotective therapies are still warranted. The present study sought to determine the feasibility of the activation of the cytoprotective PI-3-K/Akt and the MAPK/ERK signaling pathways in the subacute phase of HIE development in a translational newborn pig PA/HIE model. MAIN METHODS: Phosphorylated and total levels of Akt and ERK were determined by Western blotting in brain samples obtained from untreated naive, time control, and PA/HIE animals at 24-48h survival (n=3-3-6,respectively). PA (20min) was induced in anesthetized piglets by ventilation with a hypoxic/hypercapnic (6%O220%CO2) gas mixture. Furthermore, we studied the effect of topically administered specific Akt1/2 and MAPK/ERK kinase inhibitors on Akt and ERK phosphorylation (n=4-4) in the cerebral cortex under normoxic conditions. KEY FINDINGS: PA resulted in significant neuronal injury shown by neuropathology assessment of haematoxylin/eosin stained sections. However, there were no significant differences among the groups in the high phosphorylation levels of both ERK and Akt in the cerebral cortex, hippocampus and subcortical structures. However, the Akt1/2 and MAPK/ERK kinase inhibitors significantly reduced cerebrocortical Akt and ERK phosphorylation within 30min. SIGNIFICANCE: The major finding of the present study is that the PI-3-K/Akt and the MAPK/ERK signaling pathways appear to be constitutively active in the piglet brain, and this activation remains unaltered during HIE development. Thus, neuroprotective strategies aiming to activate these pathways to limit apoptotic neuronal death may offer limited efficacy in this translational model. PMID- 29138116 TI - In silico identification of genes involved in chronic metabolic acidosis. AB - AIMS: Chronic metabolic acidosis (CMA) refers to increased plasma acidity due to disturbed acid-base equilibrium in human body. CMA leads to many dysfunctions including disorders of intestinal metabolism and barrier functions. The human body responds to these intestinal dysfunctions by creating a compensatory mechanism at genomic level in intestinal epithelial cells. This study was to identify the molecular pathways involved in metabolic dysfunction and compensatory adaptations in intestinal epithelium during CMA. MAIN METHODS: In silico approaches were utilized to characterize a set of 88 differentially expressed genes (DEGs) from intestinal cells of rat CMA model. Interaction networks were constructed for DEGs by GeneMANIA and hub genes as well as enriched clusters in the network were screened using GLay. Gene Ontology (GO) was used for enriching functions in each cluster. KEY FINDINGS: Four gene hubs, i.e., trefoil factor 1, 5-hydroxytryptamine (serotonin) receptor 5a, solute carrier family 6 (neurotransmitter transporter), member 11, and glutamate receptor, ionotropic, n methyl d-aspartate 2b, exhibiting the highest node degree were predicted. Six biologically related gene clusters were also predicted. Functional enrichment of GO terms predicted neurological processes such as neurological system process regulation and nerve impulse transmission which are related to negative and positive regulation of digestive system processes., intestinal motility and absorption and maintenance of gastrointestinal epithelium. SIGNIFICANCE: The study predicted several important genomic pathways that potentially play significant roles in metabolic disruptions or compensatory adaptations of intestinal epithelium induced by CMA. The results provide a further insight into underlying molecular mechanisms associated with CMA. PMID- 29138117 TI - Melatonin protects against behavioral deficits, dopamine loss and oxidative stress in homocysteine model of Parkinson's disease. AB - AIM: Hyperhomocysteinemia and homocysteine (Hcy) mediated dopaminergic neurotoxicity is a matter of concern in the pathophysiology of Parkinson's disease (PD). Our previous study established the involvement of oxidative stress in the substantia nigra (SN) of Hcy rat model of PD; however, the role of antioxidants, such as melatonin, was not tested in this model. MAIN METHODS: Melatonin (10, 20 and 30mg/kg, i.p.) was administered to rats injected with Hcy in right SN (1.0MUmol in 2MUl saline) to investigate its potency in attenuating the behavioral abnormalities, dopamine depletion and oxidative stress prompted by Hcy. KEY FINDINGS: Treatment of melatonin protected against nigral dopamine loss and replenished the striatal dopamine loss that resulted in amelioration of rotational behavioral bias in Hcy denervated animals. Melatonin administration significantly improved mitochondrial complex-I activity and protected the SN neurons from the toxic insults of oxidative stress induced by Hcy. Amelioration of oxidative stress by melatonin in Hcy-infused SN was bought by dose-dependently scavenging of hydroxyl radicals, restoration of glutathione level and elevation in the activity of antioxidant enzymes. SIGNIFICANCE: The observations bring into light the significant neuroprotective potentials of melatonin in Hcy model of PD which is attributed to the attenuation of oxidative stress in SN. PMID- 29138118 TI - 8-Cetylberberine inhibits growth of lung cancer in vitro and in vivo. AB - AIMS: This study is aimed at detecting the anti-tumor efficacy of a new berberine (BBR) derivative 8-cetylberberine (HBBR), which has a significant improvement in hydrophobicity and pharmacological effects compared to BBR. MAIN METHODS: The human non-small lung cancer cell line A549 and normal human lung epithelial cells (MRC-5) were cultured to observe inhibition in vitro. Cell viability was analyzed via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effect of HBBR on cell cycle arrest and apoptosis were assessed by flow cytometry and western blotting. In animal studies, BALB/c nude mice were subcutaneously injected with A549 cells in the armpit and administrated with different dose of HBBR and BBR. The body weight, organ coefficient and tumor inhibitory rate were recorded to evaluate the effect of HBBR in vivo. KEY FINDINGS: The data showed that HBBR induced G1-phase cycle arrest by interfering with the expression of Cyclins D1 and Cyclin E1, increased apoptosis by inducing caspase pathway, and probably inhibited the PI3K/Akt pathway in A549 cells. In addition, animal experiments proved that oral administration of HBBR at a dose of 10mg/kg could significantly inhibit tumor growth, which is stronger than the 120mg/kg dose of BBR treatment. SIGNIFICANCE: Our results suggest that HBBR showed a significantly higher anti-tumor efficacy than BBR in vitro and in vivo and could be a potential therapy for lung cancers. PMID- 29138121 TI - Eosinophilic peripheral arteritis: peripheral arterial occlusion with eosinophilia. PMID- 29138120 TI - Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy. AB - Epidermolysis bullosa (EB) is caused by mutations in as many as 19 distinct genes. We have developed a next-generation sequencing (NGS) panel targeting genes known to be mutated in skin fragility disorders, including tetraspanin CD151 expressed in keratinocytes at the dermal-epidermal junction. The NGS panel was applied to a cohort of 92 consanguineous families of unknown subtype of EB. In one family, a homozygous donor splice site mutation in CD151 (NM_139029; c.351+2T>C) at the exon 5/intron 5 border was identified, and RT-PCR and whole transcriptome analysis by RNA-seq confirmed deletion of the entire exon 5 encoding 25 amino acids. Immunofluorescence of proband's skin and Western blot of skin proteins with a monoclonal antibody revealed complete absence of CD151. Transmission electron microscopy showed intracellular disruption and cell-cell dysadhesion of keratinocytes in the lower epidermis. Clinical examination of the 33-year old proband, initially diagnosed as Kindler syndrome, revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures. The patient also had history of nephropathy with proteinuria. Collectively, the results suggest that biallelic loss-of-function mutations in CD151 underlie an autosomal recessive mechano-bullous disease with systemic features. Thus, CD151 should be considered as the 20th causative, EB-associated gene. PMID- 29138119 TI - Thrombospondin-4 in tissue remodeling. AB - Thrombospondin-4 (TSP-4) belongs to the thrombospondin protein family that consists of five highly homologous members. A number of novel functions have been recently assigned to TSP-4 in cardiovascular and nervous systems, inflammation, cancer, and the motor unit, which have attracted attention to this extracellular matrix (ECM) protein. These newly discovered functions set TSP-4 apart from other thrombospondins. For example, TSP-4 promotes angiogenesis while other TSPs either prevent it or have no effect on new blood vessel growth; TSP-4 reduces fibrosis and collagen production while TSP-1 and TSP-2 promote fibrosis in several organs; unlike other TSPs, TSP-4 appears to have some structural functions in ECM. The current information about TSP-4 functions in different organs and physiological systems suggests that this evolutionary conserved protein is a major regulator of the extracellular matrix (ECM) organization and production and tissue remodeling during the embryonic development and response to injury. In this review article, we summarize the properties and functions of TSP-4 and discuss its role in tissue remodeling. PMID- 29138122 TI - A novel mutation in TRPS1 in a patient with tricho-rhino-phalangeal syndrome type 1, accompanied by vesicoureteral reflux. PMID- 29138123 TI - Two cases of sarcoidosis presenting as diffuse facial erythema, successfully treated with minocycline. PMID- 29138124 TI - Comparison of allergen responses based on the TRUE Test and IQ Chamber system in Korean patients. AB - A comparison between responses to allergens based on the TRUE Test(r)(TT) and IQ(r) Chamber (IQC) in Europeans has been previously reported, however, no such study has been performed in Asians. To compare allergen responses using the TT and IQC (using the Korean standard series) in order to gather more information regarding the positive response rates for each allergen and the clinical value of IQC. Suspected contact dermatitis patients were enrolled and tested with 18 allergens using the TT and IQC. The test was performed in 214 patients. Simultaneous positive results for both tests were recorded in 242 cases (positive concordance rate: 66.7%). IQC yielded more positive results. Allergens with a high positive concordance rate were nickel sulphate (82.1%), thimerosal (78.6%), and p-phenylenediamine (73.3%). IQC mostly showed similar or higher positive rates than TT, with high concordance. We recommend the IQC method as a screening test in patients with suspected contact dermatitis. To compensate for possible false positive results, careful history taking and a different patch test should be performed when appropriate. PMID- 29138125 TI - Palmar erythema: inaugural manifestation of HIV infection. PMID- 29138126 TI - Promoting Secondary Analysis of Electronic Medical Records in China: Summary of the PLAGH-MIT Critical Data Conference and Health Datathon. AB - Electronic health records (EHRs) have been widely adopted among modern hospitals to collect and track clinical data. Secondary analysis of EHRs could complement the traditional randomized control trial (RCT) research model. However, most researchers in China lack either the technical expertise or the resources needed to utilize EHRs as a resource. In addition, a climate of cross-disciplinary collaboration to gain insights from EHRs, a crucial component of a learning healthcare system, is not prevalent. To address these issues, members from the Massachusetts Institute of Technology (MIT) and the People's Liberation Army General Hospital (PLAGH) organized the first clinical data conference and health datathon in China, which provided a platform for clinicians, statisticians, and data scientists to team up and address information gaps in the intensive care unit (ICU). PMID- 29138127 TI - Exploring Working Relationships in Mental Health Care via an E-Recovery Portal: Qualitative Study on the Experiences of Service Users and Health Providers. AB - BACKGROUND: The quality of working relationships between service users and health providers is fundamental in the processes of recovery in mental health. How Internet-based interventions will influence these relationships for persons with long-term care needs, and the measures that can be taken to maintain and enhance working relationships through Internet, is still not well understood. OBJECTIVE: The aim of this study was to gain insights into how service users and health providers experience their working relationships when they are offered the option of supplementing ongoing collaboration with an e-recovery portal. METHODS: In this exploratory and descriptive study, an e-recovery portal was used by service users and their health providers in 2 mental health communities in Norway for at least 6 months and at most 12 months (2015-2016). The portal consists of secure messaging, a peer support forum, and a toolbox of resources for working with life domains including status, goals and activities, network map, crisis plan, and exercises. The portal was owned and managed by the service user while health providers could remotely access parts of the service user-generated content. The participants could use the portal in whatever way they wished, to suit their collaboration. Data from 6 focus groups, 17 individual interviews, and an interview with 1 dyad about their experiences of use of the portal over the study period were inductively coded and thematically analyzed. RESULTS: The thematic analysis resulted in 2 main themes: (1) new relational avenues and (2) out of alignment, illustrated by 8 subthemes. The first main theme is about dyads who reported new and enriching ways of working together through the portal, particularly related to written communication and use of the goal module. Illustrative subthemes are ownership, common ground, goals and direction, and sense of presence and availability. The second main theme illuminates the difficulties that arose when service users' and health providers' expectations for portal use were not aligned, and the consequences of not addressing these difficulties. Illustrative subthemes are initiative and responsibility, waiting for the other, feeling overwhelmed, and clarifications and agreements. CONCLUSIONS: The degree to which dyads benefited from using the e-recovery portal appeared to be mainly associated with the degree to which the dyads' relations were open and flexible before the portal was introduced. For those who experienced frustrations, the portal may have both exposed and added to suboptimal working relationships. Use of the goal module appeared to strengthen the person-centered nature of collaboration. A key question is how health providers balance between enabling service users' greater control over their care, without relinquishing responsibility for the quality of the working relationship, also when using an e-recovery portal. Implications for implementation are discussed. PMID- 29138128 TI - Will Participatory Syndromic Surveillance Work in Latin America? Piloting a Mobile Approach to Crowdsource Influenza-Like Illness Data in Guatemala. AB - BACKGROUND: In many Latin American countries, official influenza reports are neither timely nor complete, and surveillance of influenza-like illness (ILI) remains thin in consistency and precision. Public participation with mobile technology may offer new ways of identifying nonmedically attended cases and reduce reporting delays, but no published studies to date have assessed the viability of ILI surveillance with mobile tools in Latin America. We implemented and assessed an ILI-tailored mobile health (mHealth) participatory reporting system. OBJECTIVE: The objectives of this study were to evaluate the quality and characteristics of electronically collected data, the user acceptability of the symptom reporting platform, and the costs of running the system and of identifying ILI cases, and to use the collected data to characterize cases of reported ILI. METHODS: We recruited the heads of 189 households comprising 584 persons during randomly selected home visits in Guatemala. From August 2016 to March 2017, participants used text messages or an app to report symptoms of ILI at home, the ages of the ILI cases, if medical attention was sought, and if medicines were bought in pharmacies. We sent weekly reminders to participants and compensated those who sent reports with phone credit. We assessed the simplicity, flexibility, acceptability, stability, timeliness, and data quality of the system. RESULTS: Nearly half of the participants (47.1%, 89/189) sent one or more reports. We received 468 reports, 83.5% (391/468) via text message and 16.4% (77/468) via app. Nine-tenths of the reports (93.6%, 438/468) were received within 48 hours of the transmission of reminders. Over a quarter of the reports (26.5%, 124/468) indicated that at least someone at home had ILI symptoms. We identified 202 ILI cases and collected age information from almost three-fifths (58.4%, 118/202): 20 were aged between 0 and 5 years, 95 were aged between 6 and 64 years, and three were aged 65 years or older. Medications were purchased from pharmacies, without medical consultation, in 33.1% (41/124) of reported cases. Medical attention was sought in 27.4% (34/124) of reported cases. The cost of identifying an ILI case was US $6.00. We found a positive correlation (Pearson correlation coefficient=.8) between reported ILI and official surveillance data for noninfluenza viruses from weeks 41 (2016) to 13 (2017). CONCLUSIONS: Our system has the potential to serve as a practical complement to respiratory virus surveillance in Guatemala. Its strongest attributes are simplicity, flexibility, and timeliness. The biggest challenge was low enrollment caused by people's fear of victimization and lack of phone credit. Authorities in Central America could test similar methods to improve the timeliness, and extend the breadth, of disease surveillance. It may allow them to rapidly detect localized or unusual circulation of acute respiratory illness and trigger appropriate public health actions. PMID- 29138129 TI - Patient Portal Utilization Among Ethnically Diverse Low Income Older Adults: Observational Study. AB - BACKGROUND: Patient portals can improve patient communication with providers, provide patients with greater health information access, and help improve patient decision making, if they are used. Because research on factors facilitating and limiting patient portal utilization has not been conceptually based, no leverage points have been indicated for improving utilization. OBJECTIVE: The primary objective for this analysis was to use a conceptual framework to determine potentially modifiable factors affecting patient portal utilization by older adults (aged 55 years and older) who receive care at clinics that serve low income and ethnically diverse communities. The secondary objective was to delineate how patient portal utilization is associated with perceived usefulness and usability. METHODS: Patients from one urban and two rural clinics serving low income patients were recruited and completed interviewer-administered questionnaires on patient portal utilization. RESULTS: A total of 200 ethnically diverse patients completed questionnaires, of which 41 (20.5%) patients reported utilizing portals. Education, social support, and frequent Internet utilization improve the odds of patient portal utilization; receiving health care at a rural clinic decreases the odds of portal utilization. CONCLUSIONS: Leverage points to address disparities in patient portal utilization include providing training for older adults in patient portal utilization, involving spouses or other care partners in this training, and making information technology access available at public places in rural and urban communities. PMID- 29138130 TI - Check and Report Ebola (CARE) Hotline: The User Perspective of an Innovative Tool for Postarrival Monitoring of Ebola in the United States. AB - BACKGROUND: The response to the 2014-2016 Ebola epidemic included an unprecedented effort from federal, state, and local public health authorities to monitor the health of travelers entering the United States from countries with Ebola outbreaks. The Check and Report Ebola (CARE) Hotline, a novel approach to monitoring, was designed to enable travelers to report their health status daily to an interactive voice recognition (IVR) system. The system was tested with 70 Centers for Disease Control and Prevention (CDC) federal employees returning from deployments in outbreak countries. OBJECTIVE: The objective of this study was to describe the development of the CARE Hotline as a tool for postarrival monitoring and examine the usage characteristics and user experience of the tool during a public health emergency. METHODS: Data were obtained from two sources. First, the CARE Hotline system produced a call log which summarized the usage characteristics of all 70 users' daily health reports. Second, we surveyed federal employees (n=70) who used the CARE Hotline to engage in monitoring. A total of 21 (21/70, 30%) respondents were included in the survey analytic sample. RESULTS: While the CARE Hotline was used for monitoring, 70 users completed a total of 1313 calls. We found that 94.06% (1235/1313) of calls were successful, and the average call time significantly decreased from the beginning of the monitoring period to the end by 32 seconds (Z score=-6.52, P<.001). CARE Hotline call log data were confirmed by user feedback; survey results indicated that users became more familiar with the system and found the system easier to use, from the beginning to the end of their monitoring period. The majority of the users were highly satisfied (90%, 19/21) with the system, indicating ease of use and convenience as primary reasons, and would recommend it for future monitoring efforts (90%, 19/21). CONCLUSIONS: The CARE Hotline garnered high user satisfaction, required minimal reporting time from users, and was an easily learned tool for monitoring. This phone-based technology can be modified for future public health emergencies. PMID- 29138132 TI - The Little Prince: a glimpse into the world of autism? PMID- 29138131 TI - Reducing Symptom Distress in Patients With Advanced Cancer Using an e-Alert System for Caregivers: Pooled Analysis of Two Randomized Clinical Trials. AB - BACKGROUND: Symptom distress in patients toward the end of life can change rapidly. Family caregivers have the potential to help patients manage those symptoms, as well as their own stress, if they are equipped with the proper resources. Electronic health (eHealth) systems may be able to provide those resources. Very sick patients may not be able to use such systems themselves to report their symptoms but family caregivers could. OBJECTIVE: The aim of this paper was to assess the effects on cancer patient symptom distress of an eHealth system that alerts clinicians to significant changes in the patient's symptoms, as reported by a family caregiver. METHODS: A pooled analysis from two randomized clinical trials (NCT00214162 and NCT00365963) compared outcomes at 12 months for two unblinded groups: a control group (Comprehensive Health Enhancement Support System [CHESS]-Only) that gave caregivers access to CHESS, an online support system, and an experimental group (CHESS+CR [Clinician Report]), which also had CHESS but with a CR that automatically alerted clinicians if symptoms exceeded a predetermined threshold of severity. Participants were dyads (n=235) of patients with advanced lung, breast, or prostate cancer and their respective family caregivers from 5 oncology clinics in the United States of America. The proportion of improved patient threshold symptoms was compared between groups using area-under-the-curve analysis and binomial proportion tests. The proportion of threshold symptoms out of all reported symptoms was also examined. RESULTS: When severe caregiver-reported symptoms were shared with clinicians, the symptoms were more likely to be subsequently reported as improved than when the symptoms were not shared with clinicians (P<.001). Fewer symptom reports were completed in the group of caregivers whose reports went to clinicians than in the CHESS-Only group (P<.001), perhaps because caregivers, knowing their reports might be sent to a doctor, feared they might be bothering the clinician. CONCLUSIONS: This study suggests that an eHealth system designed for caregivers that alerts clinicians to worrisome changes in patient health status may lead to reduced patient distress. TRIAL REGISTRATION: Clinicaltrials.gov NCT00214162; https://clinicaltrials.gov/ct2/show/NCT00214162 (Archived by WebCite at http://www.webcitation.org/6nmgdGfuD) and Clinicaltrials.gov NCT00365963; https://clinicaltrials.gov/ct2/show/NCT00365963 (Archived by WebCite at http://www.webcitation.org/6nmh0U8VP). PMID- 29138134 TI - Half of doctors from other EEA countries working in UK may leave, poll shows. PMID- 29138133 TI - Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis. AB - Objective To assess whether weight loss interventions for adults with obesity affect all cause, cardiovascular, and cancer mortality, cardiovascular disease, cancer, and body weight.Design Systematic review and meta-analysis of randomised controlled trials (RCTs) using random effects, estimating risk ratios, and mean differences. Heterogeneity investigated using Cochran's Q and I2 statistics. Quality of evidence assessed by GRADE criteria.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, and full texts in our trials' registry for data not evident in databases. Authors were contacted for unpublished data.Eligibility criteria for selecting studies RCTs of dietary interventions targeting weight loss, with or without exercise advice or programmes, for adults with obesity and follow-up >=1 year.Results 54 RCTs with 30 206 participants were identified. All but one trial evaluated low fat, weight reducing diets. For the primary outcome, high quality evidence showed that weight loss interventions decrease all cause mortality (34 trials, 685 events; risk ratio 0.82, 95% confidence interval 0.71 to 0.95), with six fewer deaths per 1000 participants (95% confidence interval two to 10). For other primary outcomes moderate quality evidence showed an effect on cardiovascular mortality (eight trials, 134 events; risk ratio 0.93, 95% confidence interval 0.67 to 1.31), and very low quality evidence showed an effect on cancer mortality (eight trials, 34 events; risk ratio 0.58, 95% confidence interval 0.30 to 1.11). Twenty four trials (15 176 participants) reported high quality evidence on participants developing new cardiovascular events (1043 events; risk ratio 0.93, 95% confidence interval 0.83 to 1.04). Nineteen trials (6330 participants) provided very low quality evidence on participants developing new cancers (103 events; risk ratio 0.92, 95% confidence interval 0.63 to 1.36).Conclusions Weight reducing diets, usually low in fat and saturated fat, with or without exercise advice or programmes, may reduce premature all cause mortality in adults with obesity.Systematic review registration PROSPERO CRD42016033217. PMID- 29138136 TI - Simon Stevens speaks out over NHS funding. PMID- 29138135 TI - Comparative clinical effectiveness and cost effectiveness of endovascular strategy v open repair for ruptured abdominal aortic aneurysm: three year results of the IMPROVE randomised trial. AB - Objective To assess the three year clinical outcomes and cost effectiveness of a strategy of endovascular repair (if aortic morphology is suitable, open repair if not) versus open repair for patients with suspected ruptured abdominal aortic aneurysm.Design Randomised controlled trial.Setting 30 vascular centres (29 in UK, one in Canada), 2009-16.Participants 613 eligible patients (480 men) with a clinical diagnosis of ruptured aneurysm, of whom 502 underwent emergency repair for rupture.Interventions 316 patients were randomised to an endovascular strategy (275 with confirmed rupture) and 297 to open repair (261 with confirmed rupture).Main outcome measures Mortality, with reinterventions after aneurysm repair, quality of life, and hospital costs to three years as secondary measures.Results The maximum follow-up for mortality was 7.1 years, with two patients in each group lost to follow-up by three years. After similar mortality by 90 days, in the mid-term (three months to three years) there were fewer deaths in the endovascular than the open repair group (hazard ratio 0.57, 95% confidence interval 0.36 to 0.90), leading to lower mortality at three years (48% v 56%), but by seven years mortality was about 60% in each group (hazard ratio 0.92, 0.75 to 1.13). Results for the 502 patients with repaired ruptures were more pronounced: three year mortality was lower in the endovascular strategy group (42% v 54%; odds ratio 0.62, 0.43 to 0.88), but after seven years there was no clear difference between the groups (hazard ratio 0.86, 0.68 to 1.08). Reintervention rates up to three years were not significantly different between the randomised groups (hazard ratio 1.02, 0.79 to 1.32); the initial rapid rate of reinterventions was followed by a much slower mid-term reintervention rate in both groups. The early higher average quality of life in the endovascular strategy versus open repair group, coupled with the lower mortality at three years, led to a gain in average quality adjusted life years (QALYs) at three years of 0.17 (95% confidence interval 0.00 to 0.33). The endovascular strategy group spent fewer days in hospital and had lower average costs of -L2605 (95% confidence interval -L5966 to L702) (about ?2813; $3439). The probability that the endovascular strategy is cost effective was >90% at all levels of willingness to pay for a QALY gain.Conclusions At three years, compared with open repair, an endovascular strategy for suspected ruptured abdominal aortic aneurysm was associated with a survival advantage, a gain in QALYs, similar levels of reintervention, and reduced costs, and this strategy was cost effective. These findings support the increasing use of an endovascular strategy, with wider availability of emergency endovascular repair.Trial registration Current Controlled Trials ISRCTN48334791; ClinicalTrials NCT00746122. PMID- 29138138 TI - Should UK training programmes base doctors on one site for two years? PMID- 29138137 TI - The Next Frontier: Head and Neck Cancer Immunoprevention. AB - Restoring T cell-mediated antitumor immunity by targeting immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) results in immunomodulation and durable remissions. However, the overall response rate to these immunotherapies in HNSCC is only approximately 20%. This raises the possibility that immunologic intervention earlier in the HNSCC continuum, such as in oral premalignant lesions (OPL) could elicit an increased therapeutic response. New experimental studies suggest that immune therapies can be used for HNSCC prevention rather than therapy. Given the current excitement for precision medicine, these findings support the future development of multimodality approaches for preventive immune oncology. Cancer Prev Res; 10(12); 681-3. (c)2017 AACRSee related article by Jin Wang, et al., p. 684. PMID- 29138139 TI - GP avoids prosecution over circumcision of 3 month old baby. PMID- 29138140 TI - David Oliver: Supervision and clinical autonomy for junior doctors-have we gone too far? PMID- 29138141 TI - WHO downgrades status of oseltamivir. PMID- 29138142 TI - Catheter Ablation of Idiopathic Left Posterior Fascicular Ventricular Tachycardia: Predicting the Site of Origin via Mapping and Electrocardiography. AB - BACKGROUND: We report the 12-lead ECG morphology of left posterior fascicular ventricular tachycardia (LPF-VT) and the relationship between His-ventricular (HV) interval and site of origin in LPF-VT. METHODS AND RESULTS: We studied 41 patients who underwent successful catheter ablation of LPF-VT with HV interval >0 ms (n=8; proximal-LPF group), HV interval 0 to -15 ms (n=15; middle-LPF group), and HV interval <-15 ms (n=18; distal-LPF group). The earliest mapped presystolic potential (PP)-QRS interval was 34.1+/-4.2, 24.5+/-3.2, and 19.4+/-2.8 ms in proximal-, middle-, and distal-LPF groups. The earliest PP ratio (PP-QRS interval during VT/HV interval during sinus rhythm) was 0.59+/-0.05, 0.45+/-0.07, and 0.31+/-0.05 in the proximal-, middle-, and distal-LPF groups. There were statistically significant differences between the 3 groups in earliest PP ratio, and there was close correlation between the HV interval during LPF-VT and earliest PP ratio. The QRS duration in the proximal-LPF group (114+/-6 ms) was significantly narrower compared with the middle-LPF group (128+/-5 ms) and distal LPF group (140+/-6 ms). In leads I and V6, the ratio of R/S tended to be greater in the proximal-LPF group compared with the other 2 groups. QRS duration, the ratio of R/S in leads V6, and lead I could predict a proximal or distal origin site of LPF-VT with high sensitivity and specificity. CONCLUSION: The HV interval and 12-lead ECG morphology of LPF-VT may help predict the successful site of origin and prove useful in guiding an effective ablation strategy. PMID- 29138144 TI - Successful Minimally Invasive Surgical Ablation of Atrial Fibrillation: A Call to Do Better. PMID- 29138143 TI - Minimally Invasive Stand-Alone Cox Maze Procedure for Persistent and Long Standing Persistent Atrial Fibrillation: Perioperative Safety and 5-Year Outcomes. AB - BACKGROUND: Rhythm control is challenging in patients with extended atrial fibrillation (AF) duration and persistent/long-standing persistent AF. Among surgical approaches to treat AF, the Cox maze procedure performed using alternative energy sources remains superior to other beating heart techniques. We examined permanence of safety and success for the on-pump, minimally invasive, stand-alone Cox maze procedure 5 years after surgery. METHODS AND RESULTS: Stand alone, right 5 cm minithoracotomy, Cox maze III/IV procedure for nonparoxysmal AF was conducted in 133 patients (mean follow-up=65+/-34 months). Data collected prospectively at 3, 6, 9, 12, 18, 24 months and yearly thereafter and reported per Heart Rhythm Society Guidelines. Paired-samples t tests evaluated quality of life changes. Mean age was 57.3+/-9.2 years, mean LA size was 4.9+/-1.1 cm, median AF duration was 51 months, and 78% had long-standing persistent AF. All procedures performed with no conversion to midsternotomy, no renal failure, strokes, or operative mortality (<30 days), transient ischemic attack in 1 patient, reoperation for bleeding in 2 patients, and median length of stay was 4 days [3-5.5 days]. At 5 years, 73% were in sinus rhythm off antiarrhythmic medications after single intervention, 1 stroke (718 patient-years) with 81% off anticoagulation, catheter ablation reinterventions in 13 patients for atrial arrhythmia, and cardioversions in 15 patients. Quality of life scores improved significantly by 12 months after surgery. CONCLUSIONS: Successful ablation for nonparoxysmal AF is challenging. Therefore, periprocedural safety and long-term efficacy of minimally invasive Cox maze procedures should be noted. Continued refinement of decision-making techniques is warranted to improve patient selection for the appropriate intervention to treat AF. PMID- 29138145 TI - Purkinje Arrhythmia Origin Made Easy. PMID- 29138146 TI - Five minutes with . . . Charlie Auld. PMID- 29138147 TI - Communicating with relatives is a double edged sword. PMID- 29138148 TI - Incremental heroes. PMID- 29138149 TI - ? PMID- 29138151 TI - Using disease-specific mortality in discussions with patients. PMID- 29138150 TI - Periodic preventive health visits: a more appropriate approach to delivering preventive services: From the Canadian Task Force on Preventive Health Care. PMID- 29138152 TI - Response. PMID- 29138153 TI - Deprescribing antihyperglycemic agents in older persons: Evidence-based clinical practice guideline. AB - OBJECTIVE: To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper, stop, or switch antihyperglycemic agents in older adults. METHODS: We focused on the highest level of evidence available and sought input from primary care professionals in guideline development, review, and endorsement processes. Seven clinicians (2 family physicians, 3 pharmacists, 1 nurse practitioner, and 1 endocrinologist) and a methodologist comprised the overall team; members disclosed conflicts of interest. We used a rigorous process, including the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, for guideline development. We conducted a systematic review to assess evidence for the benefits and harms of deprescribing antihyperglycemic agents. We performed a review of reviews of the harms of continued antihyperglycemic medication use, and narrative syntheses of patient preferences and resource implications. We used these syntheses and GRADE quality-of-evidence ratings to generate recommendations. The team refined guideline content and recommendation wording through consensus and synthesized clinical considerations to address common front-line clinician questions. The draft guideline was distributed to clinicians and stakeholders for review and revisions were made at each stage. A decision-support algorithm was developed to accompany the guideline. RECOMMENDATIONS: We recommend deprescribing antihyperglycemic medications known to contribute to hypoglycemia in older adults at risk or in situations where antihyperglycemic medications might be causing other adverse effects, and individualizing targets and deprescribing accordingly for those who are frail, have dementia, or have a limited life expectancy. CONCLUSION: This guideline provides practical recommendations for making decisions about deprescribing antihyperglycemic agents. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients. PMID- 29138155 TI - Knowledge translation tools in preventive health care. PMID- 29138156 TI - Return to learn after concussion in children. AB - Question Despite recent interest in the pathophysiology and management of concussion in children, as well as the ongoing concern about return to activity, advice regarding the type and length of cognitive rest has been inconsistent. What should I recommend to the children and adolescents in my clinic regarding cognitive rest following mild concussion? Answer Strict cognitive rest is not needed in those with mild concussion. Evidence suggests a decrease in usual activity to a level that allows children to remain asymptomatic, followed by a gradual return to learning, is appropriate. It is clear that either too little or too much activity is disadvantageous to recovery and can worsen outcomes. PMID- 29138154 TI - Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement. AB - OBJECTIVE: To provide family physicians with a practical clinical summary of the Canadian Pain Society (CPS) revised consensus statement on the pharmacologic management of neuropathic pain. QUALITY OF EVIDENCE: A multidisciplinary interest group within the CPS conducted a systematic review of the literature on the current treatments of neuropathic pain in drafting the revised consensus statement. MAIN MESSAGE: Gabapentinoids, tricyclic antidepressants, and serotonin norepinephrine reuptake inhibitors are the first-line agents for treating neuropathic pain. Tramadol and other opioids are recommended as second-line agents, while cannabinoids are newly recommended as third-line agents. Other anticonvulsants, methadone, tapentadol, topical lidocaine, and botulinum toxin are recommended as fourth-line agents. CONCLUSION: Many pharmacologic analgesics exist for the treatment of neuropathic pain. Through evidence-based recommendations, the CPS revised consensus statement helps guide family physicians in the management of patients with neuropathic pain. PMID- 29138157 TI - Intwosusception: Case report of 2 sisters presenting simultaneously with intussusception. PMID- 29138158 TI - Does evidence support supervised injection sites? PMID- 29138159 TI - Preconception Health Care Tool: One-stop shop for preconception care. PMID- 29138160 TI - The family physician as fifth business. PMID- 29138161 TI - The ideals of balance and harmony: How to measure performance in family practice. PMID- 29138163 TI - Value of family physicians. PMID- 29138162 TI - Encouraging trainees. PMID- 29138164 TI - ? PMID- 29138165 TI - ? PMID- 29138166 TI - Personal learning plan: an update. PMID- 29138167 TI - ? PMID- 29138168 TI - ? PMID- 29138169 TI - ? PMID- 29138170 TI - Choosing Wisely Canada recommendations. PMID- 29138171 TI - ? PMID- 29138172 TI - Framework for building primary care capacity to address the social determinants of health. AB - PROBLEM ADDRESSED: Family physicians have long understood that social factors influence the health of individuals and communities; however, most primary care organizations have yet to develop the capacity to specifically address these social determinants of health (SDOH). OBJECTIVE OF PROGRAM: To support SDOH interventions and foster an organizational culture in which addressing SDOH is considered part of high-quality primary care. PROGRAM DESCRIPTION: An academic family health team in Toronto, Ont, established a committee comprising a diverse group of health professionals focused on the SDOH. The committee analyzes how social factors affect patients and supports the development and implementation of interventions. The committee's current interventions include the following: collecting and analyzing detailed sociodemographic data to identify health inequities; launching an income security health promotion service; establishing a medical-legal partnership; implementing a child literacy program in its clinics; and developing an advocacy and service program to improve access to decent work. Each intervention includes a rigorous evaluation plan to assess implementation and effect. Next steps include developing tools to enable organizations to "move upstream" and adopt a health equity approach to all work, including joining in advocacy. CONCLUSION: Primary care providers are well situated to address SDOH. This article provides a framework that can assist every large primary care organization in establishing a similar committee dedicated to SDOH, which could help build a network across Canada to share lessons learned and support joint advocacy. PMID- 29138173 TI - Cardiovascular preventive care for patients with serious mental illness. AB - OBJECTIVE: To determine whether patients with serious mental illness (SMI) are receiving preventive care for cardiovascular disease at the same rate as those without SMI in an interprofessional practice with a mandate to care for persons with barriers to access to the health care system. DESIGN: Quality improvement exercise using a case-matched retrospective chart review. SETTING: Somerset West Community Health Centre in downtown Ottawa, Ont. PARTICIPANTS: All patients with SMI were adult, current primary care patients from the Somerset West Community Health Centre with a recorded diagnosis of SMI (bipolar affective disorder, schizophrenia, or other psychosis) during the 2-year period from June 1, 2013, to May 31, 2015. Two control patients (current primary care patients without SMI and matched for age and sex) were randomly chosen for each patient with SMI. MAIN OUTCOME MEASURES: They had at least 1 record in their electronic chart during the 2-year study period of measurement of blood pressure, weight, body mass index, smoking status, lipid screening results, or diabetes screening results. Prevention score was calculated as the number of preventive tests documented out of the possible 6. Secondary measures included age, sex, comorbidities (diabetes, hypertension, or hyperlipidemia), mental illness diagnosis, involvement of a psychiatrist, and involvement of a mental health case worker. RESULTS: Patients with SMI had higher rates of diabetes, hypertension, and dyslipidemia. Screening rates for the 6 outcome measures were very similar between patients with and without SMI. Patients with SMI who were under the care of a psychiatrist or who had a case worker had more complete screening results than those who had neither provider. CONCLUSION: As expected, patients with SMI had higher rates of metabolic comorbidities than control patients had. Screening rates for cardiovascular risk factors were similar in the 2 groups. Involvement of mental health case workers and psychiatrists in the patients' care might be linked to more complete preventive screening. PMID- 29138174 TI - First Nations hepatitis C virus infections: Six-year retrospective study of on reserve rates of newly reported infections in northwestern Ontario. AB - OBJECTIVE: To document rates of newly reported hepatitis C virus (HCV) cases from 2010 to 2015 in remote First Nations communities. DESIGN: Retrospective analysis of aggregate data of newly reported HCV antibody-positive (Ab+) cases. SETTING: Northwestern Ontario. PARTICIPANTS: A total of 31 First Nations communities (an on-reserve population of 20 901) supported in health care by the Sioux Lookout First Nations Health Authority. MAIN OUTCOME MEASURES: The aggregate characteristic data included year of notification, age range, and sex for a 6 year period (2010 to 2015). RESULTS: There were 267 HCV Ab+ cases in the 6-year study period. The incidence in 2015 was 324.2 per 100 000 population. This is 11 times the rate for all of Ontario. The most common associated risk factor was sharing of intravenous drug use equipment. Women made up 52% of patients with newly reported HCV Ab+ cases. More than 45% of cases were in patients between 20 and 29 years of age. CONCLUSION: This high burden of newly reported HCV Ab+ cases in geographically remote First Nations communities is concerning, and prevention and treatment resources are needed. This burden of disease might pose more urgent health and social challenges than can be generalized from the experience of the rest of Canada. PMID- 29138176 TI - ? PMID- 29138175 TI - Statin-prescribing trends for primary and secondary prevention of cardiovascular disease. AB - OBJECTIVE: To determine the proportion of patients receiving statins for primary or secondary prevention of cardiovascular disease (CVD), as well as to describe lipid-screening trends. DESIGN: Retrospective chart review using the Manitoba Primary Care Research Network repository. SETTING: Manitoba. PARTICIPANTS: A total of 149 262 patients. MAIN OUTCOME MEASURES: Proportion of patients who were taking statins for primary or secondary prevention of cardiovascular disease (CVD), who did not have evidence of CVD recorded in their charts, and who underwent lipid screening; distribution of statins among age groups; and the proportion of patients eligible for lipid screening when the age cutoffs of the 2012 and 2016 Canadian Cardiovascular Society guidelines were applied. RESULTS: Of the 149 262 patients, 139 025 (93%) did not have CVD recorded in their electronic medical records and made up the primary prevention group; of these 139 025 patients, 5955 (4%) were taking statins. Also in the primary prevention group, 14 814 (11%) patients were 75 years of age and older; of these patients, 1374 (9%) were taking statins. A total of 10 237 of the 149 262 (7%) patients had CVD recorded in their charts (secondary prevention group); 3013 (29%) of these patients were taking statins. When the 2016 Canadian Cardiovascular Society guidelines age cutoffs were applied, 56% of patients (83 119 of 149 262) were eligible for lipid screening, and 31% (26 024 of 83 119) of them had evidence of screening in the past 5 years. Of the total population of those aged 75 and older, 28% (5597 of 20 188) had undergone lipid screening. Of the total population taking statins, 28% (2481 of 8968) had undergone lipid testing while taking statins. CONCLUSION: In Manitoba, less than 5% of the primary prevention population and less than 30% of the secondary prevention population had received repeat statin prescriptions from their primary care providers. This represents a possible practice gap that warrants future research, as statins offer considerable morbidity and mortality benefits in these patients. PMID- 29138177 TI - ? PMID- 29138178 TI - GPs to seek legal advice over smartphone appointment service. PMID- 29138179 TI - Association Between Leukocyte Telomere Length and the Risk of Incident Atrial Fibrillation: The Framingham Heart Study. AB - BACKGROUND: Advancing age is a prominent risk factor for atrial fibrillation (AF). Shorter telomere length is a biomarker of biological aging, but the link between shorter telomere length and increased risk of AF remains unclear. We examined the association between shorter leukocyte telomere length (LTL) and incident AF. METHODS AND RESULTS: We included AF-free participants from the observational Framingham Heart Study Offspring cohort from 1995 to 1998, who had LTL measurements. We examined the association between baseline LTL and incident AF with multivariable Cox models adjusted for age, sex, current smoking, height, weight, systolic and diastolic blood pressure, use of antihypertensive medication, diabetes mellitus, history of myocardial infarction, and history of heart failure. The study sample comprised 1143 AF-free participants (52.8% women), with mean age of 60+/-8 years. The mean LTL at baseline was 6.95+/-0.57 kb. During 15.1+/-4.2 years mean follow-up, 184 participants (64 women) developed AF. Chronological age was associated with increased risk of AF (hazard ratio per 10-year increase, 2.16; 95% confidence interval, 1.71-2.72). There was no significant association between LTL and incident AF (hazard ratio per 1 SD decrease LTL, 1.01; 95% confidence interval, 0.86-1.19). Our study was observational in nature; hence, we could not exclude residual confounding and we were unable to establish causal pathways. CONCLUSIONS: In our moderate-sized community-based cohort, we did not find evidence for a significant association between LTL and risk of incident AF. PMID- 29138180 TI - Inhibition of Vascular c-Jun N-Terminal Kinase 2 Improves Obesity-Induced Endothelial Dysfunction After Roux-en-Y Gastric Bypass. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) reduces obesity-associated comorbidities and cardiovascular mortality. RYGB improves endothelial dysfunction, reducing c-Jun N-terminal kinase (JNK) vascular phosphorylation. JNK activation links obesity with insulin resistance and endothelial dysfunction. Herein, we examined whether JNK1 or JNK2 mediates obesity-induced endothelial dysfunction and if pharmacological JNK inhibition can mimic RYGB vascular benefits. METHODS AND RESULTS: After 7 weeks of a high-fat high-cholesterol diet, obese rats underwent RYGB or sham surgery; sham-operated ad libitum-fed rats received, for 8 days, either the control peptide D-TAT or the JNK peptide inhibitor D-JNKi-1 (20 mg/kg per day subcutaneous). JNK peptide inhibitor D-JNKi 1 treatment improved endothelial vasorelaxation in response to insulin and glucagon-like peptide-1, as observed after RYGB. Obesity increased aortic phosphorylation of JNK2, but not of JNK1. RYGB and JNK peptide inhibitor D-JNKi-1 treatment blunted aortic JNK2 phosphorylation via activation of glucagon-like peptide-1-mediated signaling. The inhibitory phosphorylation of insulin receptor substrate-1 was reduced, whereas the protein kinase B/endothelial NO synthase pathway was increased and oxidative stress was decreased, resulting in improved vascular NO bioavailability. CONCLUSIONS: Decreased aortic JNK2 phosphorylation after RYGB rapidly improves obesity-induced endothelial dysfunction. Pharmacological JNK inhibition mimics the endothelial protective effects of RYGB. These findings highlight the therapeutic potential of novel strategies targeting vascular JNK2 against the severe cardiovascular disease associated with obesity. PMID- 29138181 TI - One-Year Outcome of Intensive Insulin Therapy Combined to Glucose-Insulin Potassium in Acute Coronary Syndrome: A Randomized Controlled Study. AB - BACKGROUND: A number of factors may offset the cardioprotective effects of glucose-insulin-potassium (GIK) on outcome of patients with acute coronary syndrome, such as hyperglycemia induced by this cocktail infusion. We performed a study to evaluate the effect of intensive insulin therapy in association with GIK on 1-year outcome in patients hospitalized for acute coronary syndrome. METHODS AND RESULTS: In a randomized prospective controlled trial we included 772 patients with non-ST-segment elevation acute coronary syndrome. Patients were randomized into 3 groups: GIKI2 group, who received GIK with intensive insulin therapy for 24 hours; GIK group, who received GIK with nonintensive insulin therapy; and control group, who received usual care. The primary outcome criteria were the rates of major cardiovascular events combining death, reinfarction, and stroke rate at 1 year. In addition, we measured platelet function assay-100 and plasminogen activator inhibitor-1 at admission and 24 hours later. Based on an intention-to-treat analysis, major cardiovascular events at 1 year was 12.8% in the GIKI2 group, 15.5% in the GIK group, and 20.5% in the placebo group; the difference was significant between the GIK2 and control groups (P=0.01). Platelet function assay-100 at 24 hours decreased significantly from baseline in the control group but not in the GIKI2 group. Plasminogen activator inhibitor-1 decreased significantly in the GIKI2 group but significantly increased in the control group. Minor hypoglycemic events were more frequent in the GIKI2 group compared with other groups. CONCLUSIONS: GIKI2 led to improvement of 1-year outcome rates in patients with non-ST-segment elevation acute coronary syndrome. This beneficial effect was associated with a decrease in platelet reactivity and an increase on fibrinolysis tests. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00965406. PMID- 29138182 TI - Disparities in the Quality of Cardiovascular Care Between HIV-Infected Versus HIV Uninfected Adults in the United States: A Cross-Sectional Study. AB - BACKGROUND: Cardiovascular disease is emerging as a major cause of morbidity and mortality among patients with HIV. We compared use of national guideline recommended cardiovascular care during office visits among HIV-infected versus HIV-uninfected adults. METHODS AND RESULTS: We analyzed data from a nationally representative sample of HIV-infected and HIV-uninfected patients aged 40 to 79 years in the National Ambulatory Medical Care Survey/National Hospital Ambulatory Medical Care Survey, 2006 to 2013. The outcome was provision of guideline recommended cardiovascular care. Logistic regressions with propensity score weighting adjusted for clinical and demographic factors. We identified 1631 visits by HIV-infected patients and 226 862 visits by HIV-uninfected patients with cardiovascular risk factors, representing ~2.2 million and 602 million visits per year in the United States, respectively. The proportion of visits by HIV-infected versus HIV-uninfected adults with aspirin/antiplatelet therapy when patients met guideline-recommended criteria for primary prevention or had cardiovascular disease was 5.1% versus 13.8% (P=0.03); the proportion of visits with statin therapy when patients had diabetes mellitus, cardiovascular disease, or dyslipidemia was 23.6% versus 35.8% (P<0.01). There were no differences in antihypertensive medication therapy (53.4% versus 58.6%), diet/exercise counseling (14.9% versus 16.9%), or smoking cessation advice/pharmacotherapy (18.8% versus 22.4%) between HIV-infected versus HIV-uninfected patients, respectively. CONCLUSIONS: Physicians generally underused guideline-recommended cardiovascular care and were less likely to prescribe aspirin and statins to HIV infected patients at increased risk-findings that may partially explain higher rates of adverse cardiovascular events among patients with HIV. US policymakers and professional societies should focus on improving the quality of cardiovascular care that HIV-infected patients receive. PMID- 29138183 TI - Endovascular or open repair for ruptured abdominal aortic aneurysm? PMID- 29138184 TI - Major 2012 NHS reform failed to deliver on promises, finds study. PMID- 29138187 TI - Roundup from LMC conference. PMID- 29138186 TI - Allowing patients and relatives access to their medical data. PMID- 29138188 TI - Air pollution, diet, and obesity pose growing threats to health in India, analysis finds. PMID- 29138189 TI - GPs in Scotland to vote on contract offering partners guaranteed minimum income. PMID- 29138190 TI - Prevalence of non-communicable disease risk factors among poor shantytown residents in Dhaka, Bangladesh: a community-based cross-sectional survey. AB - OBJECTIVES: This study aims to describe the prevalence of non-communicable disease (NCD) risk factors among the urban poor in Bangladesh. DESIGN: We conducted a community-based cross-sectional epidemiological study. SETTING: The study was conducted in a shantytown in the city of Dhaka. There were 8604 households with 34 170 residents in the community. Those households were categorised into two wealth strata based on the housing structure. PARTICIPANTS: The study targeted residents aged 18-64 years. A total of 2986 eligible households with one eligible individual were selected by simple random sampling stratified by household wealth status. A total of 2551 residents completed the questionnaire survey, and 2009 participated in the subsequent physical and biochemical measurements. OUTCOME MEASURES: A modified WHO survey instrument was used for assessing behavioural risk factors and physical and biochemical measurements, including glycated haemoglobin (HbA1c). The prevalence of NCD risk factors, such as tobacco use, fruit and vegetable intake, overweight/obesity, hypertension, diabetes (HbA1c >=6.5%) and dyslipidaemia, was described according to household wealth status and gender differences. RESULTS: The prevalence of current tobacco use was 60.4% in men and 23.5% in women. Most of them (90.8%) consumed more than 1 serving of fruits and vegetables per day; however, only 2.1% consumed more than 5 servings. Overweight/obesity was more common in women (39.2%) than in men (18.9%), while underweight was more common in men (21.0%) than in women (7.1%). The prevalence of hypertension was 18.6% in men and 20.7% in women. The prevalence of diabetes was 15.6% in men and 22.5% in women, which was much higher than the estimated national prevalence (7%). The prevalence of raised total cholesterol (>=190 mg/dL) was 25.7% in men and 34.0% in women. CONCLUSION: The study identified that tobacco use, both overweight and underweight, diabetes, hypertension and dyslipidaemia were prevalent among the urban poor in Bangladesh. PMID- 29138191 TI - Evaluation of guidelines regarding surgical treatment of breast cancer using the AGREE Instrument: a systematic review. AB - OBJECTIVES: Many clinical practice guidelines and consensus statements (CPGs/consensus statements) have been developed for the surgical treatments for breast cancer. This study aims to evaluate the quality of these CPGs/consensus statements. METHODS: We systematically searched the PubMed and EMBASE databases, as well as four guideline repositories, to identify CPGs and consensus statements regarding surgical treatments for breast cancer between January 2009 and December 2016. We used the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument to assess the quality of the CPGs and consensus statements included. The overall assessment scores from the AGREE instrument and radar maps were used to evaluate the overall quality. We also evaluated some factors that may affect the quality of CPGs and consensus statements using the Mann-Whitney U test or Kruskal-Wallis H test. All analyses were performed using SPSS V.19.0. This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A total of 19 CPGs and four consensus statements were included. In general, the included CPGs/consensus statements (n=23) performed well in the 'Scope and Purpose' and 'Clarity and Presentation' domains, but performed poorly in the 'Applicability' domain. The American Society of Clinical Oncology (ASCO), National Institute for Health and Care Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN), New Zealand Guidelines Group (NZGG) and Belgium Health Care Knowledge Centre (KCE) guidelines had the highest overall quality, whereas the Saskatchewan Cancer Agency, Spanish Society of Medical Oncology (SEOM), Japanese Breast Cancer Society (JBCS) guidelines and the D.A.C.H and European School of Oncology (ESO) consensus statements had the lowest overall quality. The updating frequency of CPGs/consensus statements varied, with the quality of consensus statements generally lower than that of CPGs. A total of six, eight and five CPGs were developed in the North American, European and Asian/Pacific regions, respectively. However, geographic region was not associated with overall quality. CONCLUSIONS: The ASCO, NICE, SIGN, NZGG and KCE guidelines had the best overall quality, and the quality of consensus statements was generally lower than that of CPGs. More efforts are needed to identify barriers and facilitators for CPGs/consensus statement implementation and to improve their applicability. PMID- 29138192 TI - Prospective daily diary study reporting of any and all symptoms in healthy adults in Pakistan: prevalence and response. AB - OBJECTIVES: Prevalence of symptoms in everyday life and how people respond to these symptoms is little studied outside Western culture and developed countries. We sought to use modified diary methods to explore the prevalence of and responses to symptoms in Pakistan. DESIGN: Prospective daily survey of symptoms and response. SETTING: 8 cities across four provinces in Pakistan. PARTICIPANTS: Stratified intercept in each city to recruit 153 participants of which 151 completed. PRIMARY AND SECONDARY OUTCOME MEASURES: Each day for 30 days, participants were prompted by text message (short message service (SMS)) to complete a symptom diary. On days where symptoms were experienced, participants also reported how they responded. Prevalence was adjusted to population age and gender distributions. RESULTS: 92% of participants experienced symptoms (adjusted prevalence 94%, 95% CI 91% to 97%), with musculoskeletal pain (83%, adj. 84%, 95% CI 84% to 90%) and respiratory symptoms (75%, adj. 77%, 95% CI 71% to 84%) the most prevalent types of symptoms. Self-medication and use of home remedies and traditional medicines were the most common responses. Seeking professional help or using conventional medicine were less common, and self-medication responses included the use of antibiotics without prescription. The range of home remedies and traditional medicines was very diverse. CONCLUSIONS: While symptom experience in Pakistan was similar to Western countries, home remedies were much more frequently used to respond to symptoms. Understanding how people respond and manage their experience of symptoms outside formal healthcare is important for designing effective policy and interventions, and this needs to be understood within the broader context including the cultural and economic setting, the health system and other structural determinants of health. PMID- 29138193 TI - Stoic beliefs and health: development and preliminary validation of the Pathak Wieten Stoicism Ideology Scale. AB - INTRODUCTION: We developed and validated a new parsimonious scale to measure stoic beliefs. Key domains of stoicism are imperviousness to strong emotions, indifference to death, taciturnity and self-sufficiency. In the context of illness and disease, a personal ideology of stoicism may create an internal resistance to objective needs, which can lead to negative consequences. Stoicism has been linked to help-seeking delays, inadequate pain treatment, caregiver strain and suicide after economic stress. METHODS: During 2013-2014, 390 adults aged 18+ years completed a brief anonymous paper questionnaire containing the preliminary 24-item Pathak-Wieten Stoicism Ideology Scale (PW-SIS). Confirmatory factor analysis (CFA) was used to test an a priori multidomain theoretical model. Content validity and response distributions were examined. Sociodemographic predictors of strong endorsement of stoicism were explored with logistic regression. RESULTS: The final PW-SIS contains four conceptual domains and 12 items. CFA showed very good model fit: root mean square error of approximation (RMSEA)=0.05 (95% CI 0.04 to 0.07), goodness-of-fit index=0.96 and Tucker-Lewis Index=0.93. Cronbach's alpha was 0.78 and ranged from 0.64 to 0.71 for the subscales. Content validity analysis showed a statistically significant trend, with respondents who reported trying to be a stoic 'all of the time' having the highest PW-SIS scores. Men were over two times as likely as women to fall into the top quartile of responses (OR=2.30, 95% CI 1.44 to 3.68, P<0.001). ORs showing stronger endorsement of stoicism by Hispanics, Blacks and biracial persons were not statistically significant. DISCUSSION: The PW-SIS is a valid and theoretically coherent scale which is brief and practical for integration into a wide range of health behaviour and outcomes research studies. PMID- 29138194 TI - The costs of functional gastrointestinal disorders and related signs and symptoms in infants: a systematic literature review and cost calculation for England. AB - OBJECTIVES: To estimate the cost of functional gastrointestinal disorders (FGIDs) and related signs and symptoms in infants to the third party payer and to parents. STUDY DESIGN: To estimate the cost of illness (COI) of infant FGIDs, a two-stage process was applied: a systematic literature review and a COI calculation. As no pertinent papers were found in the systematic literature review, a 'de novo' analysis was performed. For the latter, the potential costs for the third party payer (the National Health Service (NHS) in England) and for parents/carers for the treatment of FGIDs in infants were calculated, by using publicly available data. In constructing the calculation, estimates and assumptions (where necessary) were chosen to provide a lower bound (minimum) of the potential overall cost. In doing so, the interpretation of the calculation is that the true COI can be no lower than that estimated. RESULTS: Our calculation estimated that the total costs of treating FGIDs in infants in England were at least L72.3 million per year in 2014/2015 of which L49.1 million was NHS expenditure on prescriptions, community care and hospital treatment. Parents incurred L23.2 million in costs through purchase of over the counter remedies. CONCLUSIONS: The total cost presented here is likely to be a significant underestimate as only lower bound estimates were used where applicable, and for example, costs of alternative therapies, inpatient treatments or diagnostic tests, and time off work by parents could not be adequately estimated and were omitted from the calculation. The number and kind of prescribed products and products sold over the counter to treat FGIDs suggest that there are gaps between treatment guidelines, which emphasise parental reassurance and nutritional advice, and their implementation. PMID- 29138195 TI - Current status of postnatal depression smartphone applications available on application stores: an information quality analysis. AB - OBJECTIVES: It is the aim of the current research to identify some common functionalities of postnatal application, and to determine the quality of the information content of postnatal depression application using validated scales that have been applied for applications in other specialties. SETTINGS AND PARTICIPANTS: To determine the information quality of the postnatal depression smartphone applications, the two most widely used smartphone application stores, namely Apple iTunes as well as Google Android Play store, were searched between 20May and 31 May. No participants were involved. The inclusion criteria for the application were that it must have been searchable using the keywords 'postnatal', 'pregnancy', 'perinatal', 'postpartum' and 'depression', and must be in English language. INTERVENTION: The Silberg Scale was used in the assessment of the information quality of the smartphone applications. PRIMARY AND SECONDARY OUTCOMES MEASURE: The information quality score was the primary outcome measure. RESULTS: Our current results highlighted that while there is currently a myriad of applications, only 14 applications are specifically focused on postnatal depression. In addition, the majority of the currently available applications on the store have only disclosed their last date of modification as well as ownership. There remain very limited disclosures about the information of the authors, as well as the references for the information included in the application itself. The average score for the Silberg Scale for the postnatal applications we have analysed is 3.0. CONCLUSIONS: There remains a need for healthcare professionals and developers to jointly conceptualise new applications with better information quality and evidence base. PMID- 29138196 TI - Cross-sectional study evaluating data quality of the National Cancer Registration and Analysis Service (NCRAS) prostate cancer registry data using the Cluster randomised trial of PSA testing for Prostate cancer (CAP). AB - OBJECTIVES: To compare the completeness and agreement of prostate cancer data recorded by the National Cancer Registration and Analysis Service (NCRAS) with research-level data specifically abstracted from medical records from the Cluster randomised triAl of prostate specific antigen (PSA) testing for Prostate cancer (CAP) trial. DESIGN: Cross-sectional comparison study. PARTICIPANTS: We included 1356 men from the CAP trial cohort who were linked to the NCRAS registry. PRIMARY AND SECONDARY OUTCOME MEASURES: Completeness of prostate cancer data in NCRAS and CAP and agreement for tumour, node, metastases (TNM) stage (T1/T2; T3; T4/N1/M1) and Gleason grade (4-6; 7; 8-10), measured by differences in proportions and Cohen's kappa statistic. Data were also stratified by year and pre-2010 versus post-2010, when NCRAS reporting standards changed. RESULTS: Compared with CAP, completeness was lower in NCRAS for Gleason grade (41.2% vs 76.7%, difference 35.5, 95% CI 32.1 to 39.0) and TNM stage (29.9% vs 67.6%, difference 37.6, 95% CI 34.1 to 41.1). NCRAS completeness for Gleason grade (pre-2010 vs post-2010 31.69% vs 64%; difference 32.31, 95% CI 26.76 to 37.87) and TNM stage (19.31% vs 55.50%; difference 36.19, 95% CI 30.72 to 41.67) improved over time. Agreement for Gleason grade was high (Cohen's kappa, kappa=0.90, 95% CI 0.88 to 0.93), but lower for TNM stage (kappa=0.41, 95% CI 0.37 to 0.51) overall. There was a trend towards improved agreement on Gleason grade, but not TNM stage, when comparing pre-2010 and post-2010 data. CONCLUSION: NCRAS case identification was very high; however, data on prostate cancer grade was less complete than CAP, and agreement for TNM stage was modest. Although the completeness of NCRAS data has improved since 2010, the higher completeness rate in CAP demonstrates that gains could potentially be achieved in routine registry data. This study's findings highlight a need for improved recording of stage and grade data in the source medical records. PMID- 29138197 TI - Incidence of shoulder dislocations in the UK, 1995-2015: a population-based cohort study. AB - OBJECTIVE: This cohort study evaluates the unknown age-specific and gender specific incidence of primary shoulder dislocations in the UK. SETTING: UK primary care data from the Clinical Practice Research Datalink (CPRD) were used to identify patients aged 16-70 years with a shoulder dislocation during 1995 2015. Coding of primary shoulder dislocations was validated using the CPRD general practitioner questionnaire service. PARTICIPANTS: A cohort of 16 763 patients with shoulder dislocation aged 16-70 years during 1995-2015 were identified. PRIMARY OUTCOME MEASURE: Incidence rates per 100 000 person-years and 95% CIs were calculated. RESULTS: Correct coding of shoulder dislocation within CPRD was 89% (95% CI 83% to 95%), and confirmation that the dislocation was a 'primary' was 76% (95% CI 67% to 85%). Seventy-two percent of shoulder dislocations occurred in men. The overall incidence rate in men was 40.4 per 100 000 person-years (95% CI 40.4 to 40.4), and in women was 15.5 per 100 000 person years (95% CI 15.5 to 15.5). The highest incidence was observed in men aged 16-20 years (80.5 per 100 000 person-years; 95% CI 80.5 to 80.6). Incidence in women increased with age to a peak of 28.6 per 100 000 person-years among those aged 61 70 years. CONCLUSIONS: This is the first time the incidence of shoulder dislocations has been studied using primary care data from a national database, and the first time the results for the UK have been produced. While most primary dislocations occurred in young men, an unexpected finding was that the incidence increased in women aged over 50 years, but not in men. The reasons for this are unknown. Further work is commissioned by the National Institute for Health Research to examine treatments and predictors for recurrent shoulder dislocation. STUDY REGISTRATION: The design of this study was approved by the Independent Scientific Advisory Committee (15_260) for the Medicines & Healthcare products Regulatory Agency. PMID- 29138198 TI - Norwegian trends in numbers of lower extremity revascularisations and amputations including regional trends in endovascular treatments for peripheral arterial disease: a retrospective cross-sectional registry study from 2001 to 2014. AB - OBJECTIVE: The numbers of lower extremity revascularisations and amputations are insufficiently reported in Norway. To support future policy decisions regarding the provision of vascular treatment, knowledge of such trends is important. METHODS: This retrospective cross-sectional study from 2001 to 2014 used data from the Norwegian Patient Registry. The revascularisation treatments were categorised in multilevel, aortoiliac, femoral to popliteal and popliteal to foot levels and sorted as open, endovascular and hybrid. The sessions in amputations were divided in major (thigh and below knee) and minor (ankle, foot or digit). Incidence rates were assessed per 100 000 for patients in the age group >60 years. The diabetic prevalence was calculated and the endovascular numbers at the South-Eastern, Western, Central and Northern Norway Regional Health Authority were compared. RESULTS: The overall revascularisation rates increased from 308.7 to 366.8 (p=0.02). Open revascularisations decreased from 158.9 to 98.7 (p<0.01) while endovascular revascularisations increased from 142.2 to 243.4 (p<0.01). Hybrid revascularisations increased from 7.4 to 24.8 (p<0.01). Major amputation rates decreased from 87.8 to 48.7 (p<0.01) while minor amputations increased from 12.3 to 19.6 (p=0.01). The diabetic percentages increased from 12.2 to 22.3 (p<0.01) in revascularisations, from 26.5 to 30.8 (p=0.02) in major amputations and from 43.0 to 49.3 (p=0.13) in minor. (p values refer to average annual changes.) The regional trends in endovascular treatments varied within and between the vascular groups. CONCLUSION: From 2001 to 2014, the revascularisation rates increased due to the rise in endovascular procedures. Open revascularisations and major amputation rates decreased, minor increased. The regional variances in endovascular treatments indicate that the availability of this technology differed between the health regions of Norway. The increase in patients with diabetes requires continued awareness of diabetes and its complications. PMID- 29138199 TI - Electrosclerotherapy for capillary malformations: study protocol for a randomised within-patient controlled pilot trial. AB - INTRODUCTION: The current state-of-the-art treatment modality for hypertrophic capillary malformations (CMs), laser therapy, has a considerable rate of non responders and recurrence. Intralesional bleomycin injections (or 'sclerotherapy') are commonly used to treat venous and lymphatic malformations with an excellent effect, but these intravascular injections are not possible in CMs due to the small diameter of the vessels. Electroporation-an electric field applied to the tissue-could increase the permeability of endothelial cells, which could theoretically facilitate targeted localised bleomycin delivery. We therefore hypothesise that bleomycin injections in combination with electroporation-'electrosclerotherapy' (EST), also known as 'electrochemotherapy' could potentially be a novel alternative treatment option for CMs. METHODS AND ANALYSIS: In this randomised within-patient controlled pilot trial, 20 patients with hypertrophic CMs will be enrolled. Three regions of interest (ROIs) within the CM will be randomly allocated for treatment with (A) EST, (B) bleomycin sclerotherapy without electroporation and (C) no treatment. Patients and outcome assessors are blinded for the treatment allocation. Treatment outcome for each ROI will be measured approximately 7 weeks after the treatment procedure, using patient-reported and physician-reported global assessment scores, colorimetry, laser speckle imaging and reporting of adverse events. ETHICS AND DISSEMINATION: The study protocol is approved by the ethics review committee of the Academic Medical Center, Amsterdam. Results will be published in peer-reviewed medical journals and will be presented at international conferences and scientific meetings. Study results will be fed back to the patient population through website and social media notifications. TRIAL REGISTRATION NUMBER: NCT02883023;Pre-results. NTR6169. PMID- 29138200 TI - Assessing the consequences of gestational diabetes mellitus on offspring's cardiovascular health: MySweetHeart Cohort study protocol, Switzerland. AB - INTRODUCTION: Gestational diabetes mellitus (GDM) is a state of glucose intolerance with onset during pregnancy. GDM carries prenatal and perinatal risks as well as long-term risks for the mother and her child. GDM may be involved in the foetal programming of long-term cardiovascular health. However, evidence is sparse and the effect of GDM on cardiovascular health is unknown. To address these issues, we will conduct MySweetHeart Cohort study. The objectives are to assess the effect of GDM on offspring's cardiovascular health early in life by using surrogate markers of cardiovascular disease and atherosclerosis. METHODS AND ANALYSIS: This is a cohort study of 100 offspring of women with GDM and 100 offspring of women without GDM. At inclusion, a baseline assessment of the mothers will be conducted through means of self-report questionnaires, a researcher-administrated interview, blood pressure and anthropometric measurements, and a maternal blood sampling. Between the 30th and 34th weeks of gestation, a foetal echography will be performed to assess the foetal cardiac structure and function, the fetomaternal circulation and the hepatic volume. At birth, maternal and neonatal characteristics will be assessed. An echocardiography will be performed to assess cardiac structure and function 2-7 days after birth; carotid intima-media thickness will be also measured to assess vascular structure. MySweetHeart Cohort is linked to MySweetHeart Trial (clinicaltrials.gov/ct2/show/NCT02890693), a randomised controlled trial assessing the effect of a multidimensional interdisciplinary lifestyle and psychosocial intervention to improve the cardiometabolic and mental health of women with GDM and their offspring. A long-term follow-up of children is planned. ETHICS AND DISSEMINATION: Ethical approval has been obtained through the state Human Research Ethics Committee of the Canton de Vaud (study number 2016-00745). We aim to disseminate the findings through regional, national and international conferences and through peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (clinicaltrials.gov/ct2/show/NCT02872974). PMID- 29138201 TI - Effect of iron and zinc-biofortified pearl millet consumption on growth and immune competence in children aged 12-18 months in India: study protocol for a randomised controlled trial. AB - INTRODUCTION: Biofortified crops represent a sustainable agricultural solution for the widespread micronutrient malnutrition in India and other resource-limited settings. This study aims to investigate the effect of the consumption of foods prepared with iron- and zinc-biofortified pearl millet (FeZn-PM) by children on biomarkers of iron and zinc status, growth, and immune function. METHODS AND ANALYSIS: We will conduct a randomised controlled feeding trial in identified slums of Mumbai, India among 200 children aged between 12 and 18 months. Children will be randomised to receive foods prepared with the biofortified PM (FeZn-PM, ICTP8203-Fe) or non-biofortified PM. Anthropometric and morbidity data will be gathered every month for 9 months. Biological samples will be collected at baseline, midline and endline to assess iron and zinc status, including haemoglobin, serum ferritin, serum transferrin receptor, serum zinc, C-reactive protein and alpha-1 acid glycoprotein. Biological samples will be archived for future analyses. The midline measurement will be a random serial sample between baseline and endline. Immune function will be assessed at each time point by the measurement of T cell counts and vaccine responses in a subset, respectively. ETHICS AND DISSEMINATION: This study has obtained clearance from the Health Ministry Screening Committee of the Indian Council of Medical Research. Ethical clearance has been obtained from Cornell University's Institutional Review Board, the Inter System Biomedica Ethics Committee and St John's Research Institute's Institutional Ethics Review Board. The results of this study will be disseminated at several research conferences and as published articles in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Clinical trial registration number NCT02233764. CTRI registration number REF/2014/10/007731. PMID- 29138202 TI - Development of a discussion tool to enable well-being by providing choices for people with dementia: a qualitative study incorporating codesign and participatory action research. AB - OBJECTIVE: To codesign a discussion tool to facilitate negotiation of risk between health professionals, people with dementia and carers. METHODS: A qualitative approach using codesign. Thematic analysis was used to analyse interviews and focus groups with people with dementia, carers, healthcare staff and healthy older people exploring the issue of risk in dementia, the acceptability and development of a discussion tool. RESULTS: Sixty-one participants identified the breadth, depth and complexity of risk in dementia care and the need for individualised solutions. They also deemed a discussion tool to facilitate negotiation of risk was acceptable and responses informed the tool development. Twenty-two participants provided feedback that was used to refine the final version. CONCLUSION: Our discussion tool enables choices for people with dementia by focusing on abilities rather than deficits and assists health professionals to deliver person-centred care. Flash cards prompt concerns and the tool provides a range of strategies to address these issues. PMID- 29138203 TI - Does the impact of a plant-based diet during pregnancy on birth weight differ by ethnicity? A dietary pattern analysis from a prospective Canadian birth cohort alliance. AB - OBJECTIVE: Birth weight is an indicator of newborn health and a strong predictor of health outcomes in later life. Significant variation in diet during pregnancy between ethnic groups in high-income countries provides an ideal opportunity to investigate the influence of maternal diet on birth weight. SETTING: Four multiethnic birth cohorts based in Canada (the NutriGen Alliance). PARTICIPANTS: 3997 full-term mother-infant pairs of diverse ethnic groups who had principal component analysis-derived diet pattern scores-plant-based, Western and health conscious-and birth weight data. RESULTS: No associations were identified between the Western and health-conscious diet patterns and birth weight; however, the plant-based dietary pattern was inversely associated with birth weight (beta= 67.6 g per 1-unit increase; P<0.001), and an interaction with non-white ethnicity and birth weight was observed. Ethnically stratified analyses demonstrated that among white Europeans, maternal consumption of a plant-based diet associated with lower birth weight (beta=-65.9 g per 1-unit increase; P<0.001), increased risk of small-for-gestational age (SGA; OR=1.46; 95% CI 1.08 to 1.54;P=0.005) and reduced risk of large-for-gestational age (LGA; OR=0.71; 95% CI 0.53 to 0.95;P=0.02). Among South Asians, maternal consumption of a plant-based diet associated with a higher birth weight (beta=+40.5 g per 1-unit increase; P=0.01), partially explained by cooked vegetable consumption. CONCLUSIONS: Maternal consumption of a plant-based diet during pregnancy is associated with birth weight. Among white Europeans, a plant-based diet is associated with lower birth weight, reduced odds of an infant born LGA and increased odds of SGA, whereas among South Asians living in Canada, a plant-based diet is associated with increased birth weight. PMID- 29138204 TI - Health literacy in Italy: a cross-sectional study protocol to assess the health literacy level in a population-based sample, and to validate health literacy measures in the Italian language. AB - INTRODUCTION: Health literacy (HL) concerns the knowledge and competences necessary for people to meet complex health demands. The aims of this study are to assess the level of HL in a sample using the Italian version of the Newest Vital Sign and the association of HL and selected antecedents with health outcomes, and to develop and validate the Italian version of the three Brief Health Literacy Screeners, two subjective numeracy items and the short form and the short-short form of the European Health Literacy Survey Questionnaire. METHODS AND ANALYSIS: The study adopts a cross-sectional design and is being conducted in Florence, with information collected through telephone interviews. The population-based sample has been randomly selected using the registries of eight general practitioners (GPs). Based on a power calculation, 480 subjects will be included. Participants have been randomly offered two different questionnaires, each containing different HL measures. Data on sociodemographics and important antecedents and consequences of HL will be collected and the distribution of HL levels calculated. The mediating role of HL will be assessed using Preacher and Hayes' model. To assess the concurrent validity of the HL scales, correlation and receiver operating characteristic analyses will be performed. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of the Area Vasta Centro. Results will be disseminated via scientific journals and conference presentations, and individual data made available to the GPs. PMID- 29138205 TI - Long-term prognosis of young breast cancer patients (<=40 years) who did not receive adjuvant systemic treatment: protocol for the PARADIGM initiative cohort study. AB - INTRODUCTION: Currently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient's prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged <=40 years. METHODS AND ANALYSIS: All young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle. ETHICS AND DISSEMINATION: Observational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a 'non-WMO' declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals. PMID- 29138206 TI - MONITOR-IC study, a mixed methods prospective multicentre controlled cohort study assessing 5-year outcomes of ICU survivors and related healthcare costs: a study protocol. AB - INTRODUCTION: Due to advances in critical care medicine, more patients survive their critical illness. However, intensive care unit (ICU) survivors often experience long-term physical, cognitive and mental problems, summarised as post intensive care syndrome (PICS), impacting their health-related quality of life (HRQoL). In what frequency PICS occurs, and to what extent this influences ICU survivors' HRQoL, is mostly unknown. The aims of this study are therefore to study the: (1) 5-year patient outcomes, (2) predictors for PICS, (3) ratio between HRQoL of ICU survivors and healthcare-related costs, and (4) care and support needs. METHODS: The MONITOR-IC study is a multicentre prospective controlled cohort study, carried out in ICUs in four Dutch hospitals. Patients will be included between July 2016 and July 2021 and followed for 5 years. We estimated to include 12000 ICU patients. Outcomes are the HRQoL, physical, cognitive and mental symptoms, ICU survivors' care and support needs, healthcare use and related costs. A control cohort of otherwise seriously ill patients will be assembled to compare long-term patient-reported outcomes. We will use a mixed methods design, including questionnaires, medical data from patient records, cost data from health insurance companies and interviews with patients and family members. ETHICS AND DISSEMINATION: Insights from this study will be used to inform ICU patients and their family members about long-term consequences of ICU care, and to develop prediction and screening instruments to detect patients at risk for PICS. Subsequently, tailored interventions can be developed and implemented to prevent and mitigate long-term consequences. Additionally, insights into the ratio between HRQoL of ICU patients and related healthcare costs during 5 years after ICU admission can be used to discuss the added value of ICU care from a community perspective. The study has been approved by the research ethics committee of the Radboud University Medical Center (2016-2724). CLINICAL TRIAL REGISTRATION: NCT03246334. PMID- 29138207 TI - Impact of improved insulation and heating on mortality risk of older cohort members with prior cardiovascular or respiratory hospitalisations. AB - OBJECTIVES: We carried out an evaluation of a large-scale New Zealand retrofit programme using administrative data that provided the statistical power to assess the effect of insulation and/or heating retrofits on cardiovascular and respiratory-related mortality in people aged 65 and over with prior respiratory or circulatory hospitalisations. DESIGN: Quasi-experimental cohort study based on administrative data. SETTING: New Zealand. PARTICIPANTS: From a larger study cohort of over 900 000 people, we selected two subcohorts: 3287 people who were aged 65 and over and had experienced pretreatment period cardiovascular-related hospitalisation (ICD-10 chapter 9), and 1561 people aged 65 and over who had experienced pretreatment respiratory-related hospitalisation (ICD-10 chapter 10). INTERVENTIONS: Treatment group individuals lived in a home that received insulation and/or heating retrofits under the Warm Up New Zealand: Heat Smart programme. Control group individuals lived in a home that was matched to a treatment home based on physical characteristics and location. PRIMARY AND SECONDARY OUTCOME MEASURES: HR for all-cause mortality for treatment with insulation, heating, or insulation and heating relative to control group. RESULTS: People with pretreatment circulatory hospitalisation who occupied a household that received only insulation had an HR for all-cause mortality of 0.673 (95% CI 0.535 to 0.847) (p<0.001) relative to control group members. Individuals with a pretreatment respiratory hospitalisation who occupied a household that received only an insulation retrofit had an HR for all-cause mortality of 0.830 (95% CI 0.655 to 1.051) (p=0.122) relative to control group members. There was no evidence of an additional benefit from receiving heating. CONCLUSIONS: We interpret the hazard rate observed for cardiovascular subcohort individuals who received insulation as evidence of a protective effect, reducing the risk of mortality for vulnerable older adults. There is suggestive evidence of a protective effect of insulation for the respiratory subcohort. PMID- 29138208 TI - Validation of the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale Dutch language version in patients with hindfoot fractures. AB - OBJECTIVES: The American Orthopaedic Foot and Ankle Society (AOFAS) Ankle Hindfoot Scale is among the most used questionnaires for measuring functional recovery after a hindfoot injury. Recently, this instrument was translated and culturally adapted into a Dutch version. In this study, the measurement properties of the Dutch language version (DLV) were investigated in patients with a unilateral hindfoot fracture. DESIGN: Multicentre, prospective observational study. SETTING: This multicentre study was conducted in three Dutch hospitals. PARTICIPANTS: In total, 118 patients with a unilateral hindfoot fracture were included. Three patients were lost to follow-up. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients were asked to complete the AOFAS-DLV, the Foot Function Index and the Short Form-36 on three occasions. Descriptive statistics (including floor and ceiling effects), reliability (ie, internal consistency), construct validity, reproducibility (ie, test-retest reliability, agreement and smallest detectable change (SDC)) and responsiveness were determined. RESULTS: Internal consistency was inadequate for the AOFAS-DLV total scale (alpha=0.585), but adequate for the function subscale (alpha=0.863). The questionnaire had adequate construct validity (82.4% of predefined hypotheses were confirmed), but inadequate longitudinal validity (70.6%). No floor effects were found, but ceiling effects were present in all AOFAS-DLV (sub)scales, most pronounced from 6 to 24 months after trauma onwards. Responsiveness was only adequate for the pain and alignment subscales, with a SDC of 1.7 points. CONCLUSIONS: The AOFAS Ankle-Hindfoot Scale DLV has adequate construct validity and is reliable, making it a suitable instrument for cross-sectional studies investigating functional outcome in patients with a hindfoot fracture. The inadequate longitudinal validity and responsiveness, however, hamper the use of the questionnaire in longitudinal studies and for assessing long-term functional outcome. TRIAL REGISTRATION NUMBER: NTR5613; Post-results. PMID- 29138209 TI - Healthcare providers' gestational weight gain counselling practises and the influence of knowledge and attitudes: a cross-sectional mixed methods study. AB - OBJECTIVE: To understand current gestational weight gain (GWG) counselling practices of healthcare providers, and the relationships between practices, knowledge and attitudes. DESIGN: Concurrent mixed methods with data integration: cross-sectional survey and semistructured interviews. PARTICIPANTS: Prenatal healthcare providers in Canada: general practitioners, obstetricians, midwives, nurse practitioners and registered nurses in primary care settings. RESULTS: Typically, GWG information was provided early in pregnancy, but not discussed again unless there was a concern. Few routinely provided women with individualised GWG advice (21%), rate of GWG (16%) or discussed the risks of inappropriate GWG to mother and baby (20% and 19%). More routinely discussed physical activity (46%) and food requirements (28%); midwives did these two activities more frequently than all other disciplines (P<0.001). Midwives interviewed noted a focus on overall wellness instead of weight, and had longer appointment times which allowed them to provide more in-depth counselling. Regression results identified that the higher priority level that healthcare providers place on GWG, the more likely they were to report providing GWG advice and discussing risks of GWG outside recommendations (beta=0.71, P<0.001) and discussing physical activity and food requirements (beta=0.341, P<0.001). Interview data linked the priority level of GWG to length of appointments, financial compensation methods for healthcare providers and the midwifery versus medical model of care. CONCLUSIONS: Interventions for healthcare providers to enhance GWG counselling practices should consider the range of factors that influence the priority level healthcare providers place on GWG counselling. PMID- 29138210 TI - What Happens After Menopause? (WHAM): protocol for a prospective, multicentre, age-matched cohort trial of risk-reducing bilateral salpingo-oophorectomy in high risk premenopausal women. AB - INTRODUCTION: Women at high inherited risk of ovarian cancer are advised to undergo risk-reducing bilateral salpingo-oophorectomy (RRBSO) at age 40-45 years or when their families are complete. Most women are premenopausal at this age, so RRBSO will induce surgical menopause. Despite the clear benefits of RRBSO for cancer risk reduction, much less is known about the impact on non-cancer outcomes that contribute to health and well-being and inform surveillance and management strategies. METHODS AND ANALYSIS: This will be a multicentre, prospective cohort study of 105 premenopausal high-risk women undergoing RRBSO and an age-matched comparison group of 105 premenopausal women not planning oophorectomy or pregnancy in the next 2 years. The aim of this study is to measure the impact of RRBSO on sexual function (primary outcome) at 24 months in high-risk premenopausal women compared with the comparison group. Secondary outcomes include menopausal symptoms and menopause-related quality of life, mood, sleep quality, markers of cardiovascular disease and pre-diabetes, bone density and markers of bone turnover, and the impact of hormone replacement therapy use on these outcomes. Data analysis methods will include logistic and linear regression using general estimating equations accounting for the repeated outcome measurements within each participant. ETHICS AND DISSEMINATION: The study has been approved by institutional ethics committees at each participating centre. Findings will be disseminated through peer-reviewed publications and conference presentations, and national and international networks of centres managing high risk women, and will inform national and international clinical guidelines. TRIAL REGISTRATION NUMBER: The pre-results protocol for this trial is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; registration no: ACTRN12615000082505). PMID- 29138211 TI - Transcriptome sequencing of the naked mole rat (Heterocephalus glaber) and identification of hypoxia tolerance genes. AB - The naked mole rat (NMR; Heterocephalus glaber) is a small rodent species found in regions of Kenya, Ethiopia and Somalia. It has a high tolerance for hypoxia and is thus considered one of the most important natural models for studying hypoxia tolerance mechanisms. The various mechanisms underlying the NMR's hypoxia tolerance are beginning to be understood at different levels of organization, and next-generation sequencing methods promise to expand this understanding to the level of gene expression. In this study, we examined the sequence and transcript abundance data of the muscle transcriptome of NMRs exposed to hypoxia using the Illumina HiSeq 2500 system to clarify the possible genomic adaptive responses to the hypoxic underground surroundings. The RNA-seq raw FastQ data were mapped against the NMR genome. We identified 2337 differentially expressed genes (DEGs) by comparison of the hypoxic and control groups. Functional annotation of the DEGs by gene ontology (GO) analysis revealed enrichment of hypoxia stress-related GO categories, including 'biological regulation', 'cellular process', 'ion transport' and 'cell-cell signaling'. Enrichment of DEGs in signaling pathways was analyzed against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database to identify possible interactions between DEGs. The results revealed significant enrichment of DEGs in focal adhesion, the mitogen-activated protein kinase (MAPK) signaling pathway and the glycine, serine and threonine metabolism pathway. Furthermore, inhibition of DEGs (STMN1, MAPK8IP1 and MAPK10) expression induced apoptosis and arrested cell growth in NMR fibroblasts following hypoxia. Thus, this global transcriptome analysis of NMRs can provide an important genetic resource for the study of hypoxia tolerance in mammals. Furthermore, the identified DEGs may provide important molecular targets for biomedical research into therapeutic strategies for stroke and cardiovascular diseases. PMID- 29138212 TI - Bax-inhibiting peptide attenuates bleomycin-induced lung injury in mice. AB - Bax is a pro-apoptotic member of the Bcl-2 family of proteins, and plays a central role in mitochondria-dependent apoptosis. Several lines of evidence have implied that Bax is involved in both epithelial apoptosis and fibroblast proliferation in idiopathic pulmonary fibrosis; however, the mechanisms remain unknown. Bax-inhibiting peptide V5 (BIP-V5) exhibits membrane permeability and inhibits the activation of Bax.The purpose of this study was to investigate whether the control of Bax activity by BIP-V5 reduces the degree of bleomycin induced lung injury. C57BL/6J mice were administered bleomycin and BIP-V5 intratracheally on day 0. Bronchoalveolar lavage fluid and lung tissue were obtained on day 7. Human pulmonary alveolar epithelial cells (A549 cells) and mouse pulmonary alveolar epithelial cells (LA-4 cells) were stimulated with bleomycin to induce apoptosis.Administration of BIP-V5 improved the survival rate and degree of bleomycin-induced lung injury by suppressing Bax activation in mice. BIP-V5 treatment decreased bleomycin-induced apoptosis of alveolar epithelial cell lines (A549 cells and LA-4 cells) by suppressing Bax activation. These results indicate that administration of BIP-V5 may constitute a novel therapeutic strategy against lung injury. PMID- 29138213 TI - Whether we know it or not, our educational perceptions and decisions are shaped by "race". PMID- 29138214 TI - Sport science internships for learning: a critical view. AB - Sport science has gained vast popularity with students who have an interest in both physiology and the underpinning mechanisms of exercise concerning performance and health. The high numbers of graduates each year, coupled with the low number of graduate positions working in sports, has led to a high level of competition between students. To stand out from the crowd, sport science students may undertake an internship placement as part of their course, designed to enhance theoretical, practical, and soft skills in an applied setting. In the present article, we highlight some of the positives and negatives of sport science internships and ways in which they can be implemented and facilitated. Suggestions have also been provided to make students more aware of the reality of working in professional sports, which includes awareness of the potential for long and unsociable hours of work. PMID- 29138215 TI - Physiology undergraduate degree requirements in the U.S. AB - Course-level learning objectives and core concepts for undergraduate physiology teaching exist. The next step is to consider how these resources fit into generalizable program-level guidelines for Bachelor of Science (BS) degrees in Physiology. In the absence of program-level guidelines for Physiology degree programs, we compiled a selective internal report to review degree requirements from 18 peer BS programs entitled "Physiology" in the United States (U.S.). There was a range of zero to three required semesters of math, physics, physics laboratory, general biology, biology laboratory, general chemistry, chemistry laboratory, organic chemistry, organic chemistry laboratory, biochemistry, biochemistry laboratory, anatomy, anatomy laboratory, core systems physiology, and physiology laboratory. Required upper division credits ranged from 11 to 31 and included system-specific, exercise and environmental, clinically relevant, pathology/disease-related, and basic science options. We hope that this information will be useful for all programs that consider themselves to be physiology, regardless of name. Reports such as this can serve as a starting point for collaboration among BS programs to improve physiology undergraduate education and best serve our students. PMID- 29138217 TI - Effectiveness of interprofessional education in renal physiology curricula for health sciences graduate students. AB - The primary purpose of conducting an interprofessional education (IPE) experience during the renal physiology block of a graduate-level course was to provide basic science, physical therapy, and physician assistant graduate students with an opportunity to work as a team in the diagnosis, treatment, and collaborative care of a patient with acute kidney injury. The secondary purpose was to enhance the understanding of basic renal physiology principles with a patient case presentation of renal pathophysiology. The overall purpose was to assess the value of IPE integration within a basic science course by examining student perceptions and program evaluation. Graduate-level students operated in interprofessional teams while working through an acute kidney injury patient case. The following Interprofessional Education Collaborative subcompetencies were targeted: Roles/Responsibilities (RR) Behavioral Expectations (RR1, RR4) and Interprofessional Communication (CC) Behavioral Expectations (CC4). Clinical and IPE stimulus questions were discussed both within and between teams with assistance provided by faculty facilitators. Students were given a pre- and postsurvey to determine their knowledge of IPE. There were statistically significant increases from pre- to postsurvey scores for all six IPE questions for all students. Physical therapy and physician assistant students had a statistically significant increase in pre- to postsurvey scores, indicating a more favorable perception of their interprofessional competence for RR1, RR4, and CC4. No changes were noted in pre- to postsurvey scores for basic science graduate students. Incorporating planned IPE experiences into multidisciplinary health science courses represents an appropriate venue to have students learn and apply interprofessional competencies. PMID- 29138216 TI - Autonomic regulation of the immune system in cardiovascular diseases. AB - The autonomic nervous system is a powerful regulator of circulatory adjustments to acute hemodynamic stresses. Here we focus on new concepts that emphasize the chronic influence of the sympathetic and parasympathetic systems on cardiovascular pathology. The autonomic neurohumoral system can dramatically influence morbidity and mortality from cardiovascular disease through newly discovered influences on the innate and adaptive immune systems. Specifically, the end-organ damage in heart failure or hypertension may be worsened or alleviated by pro- or anti-inflammatory pathways of the immune system, respectively, that are activated through neurohumoral transmitters. These concepts provide a major new perspective on potentially life-saving therapeutic interventions in the deadliest of diseases. PMID- 29138218 TI - Lecture attendance improves success in medical physiology. AB - The educators have underlined the importance of lecture attendance for decades. Nowadays, students have ample online educational sources, which began a debate on the necessity of in-class lectures. In the present study, we investigated the influence of lecture attendance on the exam success. To this aim, we adopted a novel approach and matched second-year medicine students' answers in three interim exams with the lectures related to those questions. Thereby, we were able to evaluate if attending lectures increases the chance of giving a correct answer to the exam question generated from the attended lecture. Furthermore, we examined students who had never taken the course before (first-time takers) and students who had failed and repeated the course (repeat takers) separately, since repeat takers may have attended a lecture previously. We found that first-time takers attended more lectures and gained higher total scores than repeat takers. Lecture-matched correct answers were significantly higher for attended lectures than for skipped lectures in all interim exams. Moreover, the correlation analyses revealed that the number of correct answers increases by lecture attendance in both first-time and repeat takers. These results indicate that in class lectures still should be considered as an essential part of the medical physiology education, even in the internet era. PMID- 29138219 TI - Developing a tool for observing group critical thinking skills in first-year medical students: a pilot study using physiology-based, high-fidelity patient simulations. AB - Most assessments of physiology in medical school use multiple choice tests that may not provide information about a student's critical thinking (CT) process. There are limited performance assessments, but high-fidelity patient simulations (HFPS) may be a feasible platform. The purpose of this pilot study was to determine whether a group's CT process could be observed over a series of HFPS. An instrument [Critical Thinking Skills Rating Instrument CTSRI)] was designed with the IDEAS framework. Fifteen groups of students participated in three HFPS that consisted of a basic knowledge quiz and introduction, HFPS session, and debriefing. HFPS were video recorded, and two raters reviewed and scored all HFPS encounters with the CTSRI independently. Interrater analysis suggested good reliability. There was a correlation between basic knowledge scores and three of the six observations on the CTSRI providing support for construct validity. The median CT ratings significantly increased for all observations between the groups' first and last simulation. However, there were still large percentages of video ratings that indicated students needed substantial prompting during the HFPS. The data from this pilot study suggest that it is feasible to observe CT skills in HFPS using the CTSRI. Based on the findings from this study, we strongly recommend that first-year medical students be competent in basic knowledge of the relevant physiology of the HFPS before participating, to minimize the risk of a poor learning experience. PMID- 29138220 TI - Antibodies targeting surface membrane antigens in patients with chronic graft versus-host disease. AB - Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplant reflects a complex immune response resulting in chronic damage to multiple tissues. Previous studies indicated that donor B cells and the antibodies they produce play an important role in the development of cGVHD. To understand the pathogenic role of antibodies in cGVHD, we focused our studies on posttransplant production of immunoglobulin G antibodies targeting cell surface antigens expressed in multiple cGVHD affected tissues, due to their potential functional impact on living cells in vivo. Using plate-bound cell membrane proteins as targets, we detected a significantly higher level of antibodies reactive with these membrane antigens in patients who developed cGVHD, compared with those who did not and healthy donors. Plasma-reactive antibody levels increased significantly prior to the clinical diagnosis of cGVHD and were reduced following cGVHD therapies including prednisone, interleukin-2, or extracorporeal photophoresis. Using cell-based immunoprecipitation with plasma from cGVHD patients and mass spectrometry, we identified 43 membrane proteins targeted by these antibodies. The presence of antibodies in cGVHD patients' plasma that specifically target 6 of these proteins was validated. Antibodies reactive with these 6 antigens were more frequently detected in patients with cGVHD compared with patients without cGVHD and healthy donors. These results indicate that antibodies that target membrane antigens of living cells frequently develop in cGVHD patients and further support a role for B cells and antibodies in the development of cGVHD. PMID- 29138221 TI - Immature CML cells implement a BMP autocrine loop to escape TKI treatment. AB - The BCR-ABL specific tyrosine kinase inhibitors (TKI) changed the outcome of chronic myeloid leukemia (CML), turning a life-threatening disease into a chronic illness. However, TKI are not yet curative, because most patients retain leukemic stem cells (LSC) and their progenitors in bone marrow and relapse following treatment cessation. At diagnosis, deregulation of the bone morphogenetic protein (BMP) pathway is involved in LSC and progenitor expansion. Here, we report that BMP pathway alterations persist in TKI-resistant patients. In comparison with patients in complete cytogenetic remission, TKI-resistant LSC and progenitors display high levels of BMPR1b expression and alterations of its cellular localization. In vitro treatment of immature chronic phase CML cells with TKI alone, or in combination with interferon-alpha, results in the preferential survival of BMPR1b+ cells. We demonstrated persistent and increasing BMP4 production by patients' mesenchymal cells with resistance. Patient follow-up revealed an increase of BMPR1b expression and in BMP4 expression in LSC from TKI resistant patients in comparison with diagnosis, while remaining unchanged in sensitive patients. Both leukemic and nonleukemic cells exhibit higher BMP4 levels in the bone marrow of TKI-resistant patients. Exposure to BMP2/BMP4 does not alter BCR-ABL transcript expression but is accompanied by the overexpression of TWIST-1, a transcription factor highly expressed in resistant LSC. By modulating BMP4 or BMPR1b expression, we show that these elements are involved in TKI resistance. In summary, we reveal that persistence of BMP alterations and existence of an autocrine loop promote CML-primitive cells' TKI resistance. PMID- 29138222 TI - Decitabine enhances targeting of AML cells by CD34+ progenitor-derived NK cells in NOD/SCID/IL2Rgnull mice. AB - Combining natural killer (NK) cell adoptive transfer with hypomethylating agents (HMAs) is an attractive therapeutic approach for patients with acute myeloid leukemia (AML). However, data regarding the impact of HMAs on NK cell functionality are mostly derived from in vitro studies with high nonclinical relevant drug concentrations. In the present study, we report a comparative study of azacitidine (AZA) and decitabine (DAC) in combination with allogeneic NK cells generated from CD34+ hematopoietic stem and progenitor cells (HSPC-NK cells) in in vitro and in vivo AML models. In vitro, low-dose HMAs did not impair viability of HSPC-NK cells. Furthermore, low-dose DAC preserved HSPC-NK killing, proliferation, and interferon gamma production capacity, whereas AZA diminished their proliferation and reactivity. Importantly, we showed HMAs and HSPC-NK cells could potently work together to target AML cell lines and patient AML blasts. In vivo, both agents exerted a significant delay in AML progression in NOD/SCID/IL2Rgnull mice, but the persistence of adoptively transferred HSPC-NK cells was not affected. Infused NK cells showed sustained expression of most activating receptors, upregulated NKp44 expression, and remarkable killer cell immunoglobulin-like receptor acquisition. Most importantly, only DAC potentiated HSPC-NK cell anti-leukemic activity in vivo. Besides upregulation of NKG2D- and DNAM-1-activating ligands on AML cells, DAC enhanced messenger RNA expression of inflammatory cytokines, perforin, and TRAIL by HSPC-NK cells. In addition, treatment resulted in increased numbers of HSPC-NK cells in the bone marrow compartment, suggesting that DAC could positively modulate NK cell activity, trafficking, and tumor targeting. These data provide a rationale to explore combination therapy of adoptive HSPC-NK cells and DAC in patients with AML. PMID- 29138223 TI - Effect of maternal high-fat diet on key components of the placental and hepatic endocannabinoid system. AB - Maternal obesity in pregnancy has been linked to a spectrum of adverse developmental changes. Involvement of eCBs in obesity is well characterized. However, information regarding eCB physiology in obesity associated with pregnancy is sparse. This study evaluated fetomaternal hepatic, systemic, and placental eCB molecular changes in response to maternal consumption of a HFD. From >=9 mo before conception, nonpregnant baboons ( Papio spp.) were fed a diet of either 45 (HFD; n = 11) or 12% fat or a control diet (CTR; n = 11), and dietary intervention continued through pregnancy. Maternal and fetal venous plasma samples were evaluated using liquid chromatography-mass spectrometry to quantify AEA and 2-AG. Placental, maternal and fetal hepatic tissues were analyzed using RT-PCR, Western blot, and immunohistochemistry. mRNA and protein expression of endocannabinoid receptors (CB1R and CB2R), FAAH, DAGL, MAGL, and COX-2 were determined. Statistical analyses were performed with the nonparametric Scheirer-Ray-Hare extension of the Kruskal-Wallis test to analyze the effects of diet (HFD vs. CTR), fetal sex (male vs. female), and the diet * sex interaction. Fetal weight was influenced by fetal sex but not by maternal diet. The increase in maternal weight in animals fed the HFD vs. the CTR diet approached significance ( P = 0.055). Maternal circulating 2-AG concentrations increased, and fetal circulating concentrations decreased in the HFD group, independently of fetal sex. CB1R receptor expression was detected in syncytiotrophoblasts (HFD) and the fetal endothelium (CTR and HFD). Placental CB2R protein expression was higher in males and lower in female fetuses in the HFD group. Fetal hepatic CB2R, FAAH, COX-2 (for both fetal sexes), and DAGLalpha (in male fetuses) protein expression decreased in the HFD group compared with the CTR group. We conclude that consumption of a HFD during pregnancy results in fetal systemic 2-AG and hepatic eCB deficiency. PMID- 29138225 TI - Androgen signaling expands beta-cell mass in male rats and beta-cell androgen receptor is degraded under high-glucose conditions. AB - A deficient pancreatic beta-cell mass increases the risk of type 2 diabetes mellitus. Here, we investigated the effects of testosterone on the development of pancreatic beta-cell mass in male rats. The beta-cell mass of male rats castrated at 6 wk of age was reduced to ~30% of that of control rats at 16 wk of age, and castration caused glucose intolerance. Loss of beta-cell mass occurred because of decreases in islet density per pancreas and beta-cell cluster size. Castration was negatively associated with the number of Ki-67-positive beta-cells and positively associated with the number of TUNEL-positive beta-cells. These beta cell changes could be prevented by testosterone treatment. In contrast, castration did not affect beta-cell mass in male mice. Androgen receptor (AR) localized differently in mouse and rat beta-cells. Testosterone enhanced the viability of INS-1 and INS-1 #6, which expresses high levels of AR, in rat beta cell lines. siRNA-mediated AR knockdown or AR antagonism with hydroxyflutamide attenuated this enhancement. Moreover, testosterone did not stimulate INS-1 beta cell viability under high d-glucose conditions. In INS-1 beta-cells, d-glucose dose dependently (5.5-22.2 mM) downregulated AR protein levels both in the presence and absence of testosterone. The intracellular calcium chelator (BAPTA AM) could prevent this decrease in AR expression. AR levels were also reduced by a calcium ionophore (A23187), but not by insulin, in the absence of the proteasome inhibitor MG132. Our results indicate that testosterone regulates beta cell mass, at least in part, by AR activation in the beta-cells of male rats and that the beta-cell AR is degraded under hyperglycemic conditions. PMID- 29138224 TI - Short-term metformin and exercise training effects on strength, aerobic capacity, glycemic control, and mitochondrial function in children with burn injury. AB - Severely burned children experience a chronic state of sympathetic nervous system activation that is associated with hypermetabolic/cardiac stress and muscle wasting. Metformin, a diabetes medication, helps control hyperglycemia in obese diabetic populations, and exercise has been shown to improve exercise strength and aerobic exercise capacity after severe burns. However, whether exercise improves glycemic control in burned children and whether combining exercise and metformin improves outcomes to a greater degree than exercise alone are unknown. We tested the hypothesis that a 6-wk exercise program combined with short-term metformin administration (E + M) improves aerobic and strength exercise capacity to a greater degree than exercise and placebo (E), while improving glucose tolerance and muscle metabolic function. We found that, before exercise training, the metformin group compared with the placebo group had attenuated mitochondrial respiration (pmol.s-1.mg-1) for each state: state 2 (-22.5 +/- 3), state 3 (-42.4 +/- 13), and oxphos (-58.9 +/- 19) ( P <= 0.02, M vs. E + M group for each state). However, in the E + M group, exercise increased mitochondrial respiration in each state ( P <= 0.05), with respiration being comparable to that in the E group (each P > 0.05). In both groups, exercise induced comparable improvements in strength (change from preexercise, Delta1.6 +/- 0.6 N-M.kgLBM) and Vo2peak (Delta9 +/- 7 mlO2.kgLBM) as well as fasting glucose (Delta19.3 +/- 13 mg.dl) and glucose AUC (Delta3402 +/- 3674 mg.dl-1.min-1), as measured by a 75-g OGTT (all P <= 0.03). Exercise reduced resting energy expenditure in E + M (Delta539 +/- 480 kcal/24 h, P < 0.01) but not E subjects ( P = 0.68). Both groups exhibited reduced resting heart rate (Delta30 +/- 23 beats/min, P <= 0.02). These data indicate that short-term metformin combined with exercise provides no further improvement beyond that of exercise alone for strength, exercise capacity, and glycemic control. PMID- 29138226 TI - Insulin secretory effect of sitagliptin: assessment with a hyperglycemic clamp combined with a meal challenge. AB - Sitagliptin, a dipeptidyl peptidase-IV inhibitor (DPP-4), sustains activity of the incretin hormones GLP-1 and GIP and improves hyperglycemia in Type 2 diabetes mellitus (T2DM). It has however proven challenging to quantify the effect of sitagliptin on rates of insulin secretion (ISR) during a prandial challenge. The tight feedback governance of ISR by plasma glucose means that in the face of treatment-related lowering of postprandial glycemia, corresponding stimulation of ISR is lessened. We postulated that sustaining a stable level of moderate hyperglycemia before and during a meal challenge (MC) would be a platform that enables greater clarity to assess the effect of sitagliptin on ISR and an approach that could be valuable to evaluate novel targets that increase insulin secretion directly and by augmenting incretins. A hyperglycemic clamp (HGC) at 160 mg/dl was conducted in 12 healthy volunteers (without diabetes) for 6 h; 3 h into the HGC, MC was administered while maintaining stable hyperglycemia of the HGC for an additional 3 h. Modeling of C-peptide response was used to calculate ISR. In crossover design of three periods (sitagliptin twice and placebo once), the effect of sitagliptin vs. placebo on ISR and the reproducibility of the response to sitagliptin were assessed. Sitagliptin increased ISR compared with placebo by 50% and 20% during the HGC alone and the HGC-MC phases, respectively ( P < 0.001 for both). There was an associated significant treatment-based increase in circulating insulin, as well as active levels of GLP-1. Robust reproducibility of the sitagliptin-mediated ISR response was observed; the intraclass correlation value was 0.94. The findings delineate the effect of sitagliptin to stimulate insulin secretion, and these benchmark data also demonstrate that an HGC-MC can be a useful platform for interrogating therapeutic targets that could potentially modulate ISR via direct action on beta-cells as well as by augmenting release or action of incretins. PMID- 29138227 TI - The hepatokines fetuin-A and fetuin-B are upregulated in the state of hepatic steatosis and may differently impact on glucose homeostasis in humans. AB - The liver is a central regulator of whole body glucose, and lipid homeostasis and hepatokines, like fetuin-A, have been identified as markers and mediators of fatty liver-induced cardiometabolic risk. The closely related protein fetuin-B was shown to be upregulated in the fatty liver and to impact on glucose homeostasis in mice. In the present study we aimed to test the relevance of these findings in humans. In 55 subjects, hepatic mRNA expression of both hepatokines, fetuin-A and fetuin-B, associated positively with liver triglyceride content, whereas only fetuin-A expression associated with the homeostatic model assessment of insulin resistance. In 220 subjects who underwent precise metabolic phenotyping, circulating fetuin-A, but not fetuin-B, associated positively with liver fat content, and negatively with insulin sensitivity, measured during the oral glucose tolerance test (OGTT) and during the euglycemic, hyperinsulinemic clamp. Both circulating fetuin-A and fetuin-B correlated positively with the glucose area under the curve during the OGTT, but after additional adjustment for insulin sensitivity this relationship remained significant only for fetuin-B. In conclusion, despite the fact that the two hepatokines, fetuin-A and fetuin-B, are upregulated in the state of hepatic steatosis in humans, it appears that they differently impact on glucose homeostasis. Our data are in agreement with observations that fetuin-A can alter insulin signaling and that fetuin-B may regulate glucose homeostasis via so far unknown effects, possibly on glucose effectiveness. PMID- 29138228 TI - Low-protein diet-induced hyperphagia and adiposity are modulated through interactions involving thermoregulation, motor activity, and protein quality in mice. AB - Low protein (LP)-containing diets can induce overeating in rodents and possibly in humans in an effort to meet protein requirement, but the effects on energy expenditure (EE) are unclear. The present study evaluated the changes induced by reducing dietary protein from 20% to 6%-using either soy protein or casein-on energy intake, body composition, and EE in mice housed at 22 degrees C or at 30 degrees C (thermal neutrality). LP feeding increased energy intake and adiposity, more in soy-fed than in casein-fed mice, but also increased EE, thus limiting fat accumulation. The increase in EE was due mainly to an increase in spontaneous motor activity related to EE and not to thermoregulation. However, the high cost of thermoregulation at 22 degrees C and the subsequent heat exchanges between nonshivering thermogenesis, motor activity, and feeding induced large differences in adaptation between mice housed at 22 degrees C and at 30 degrees C. PMID- 29138231 TI - Myocardial Strain: Still a Long Way to Go. PMID- 29138229 TI - Genomic structural variations lead to dysregulation of important coding and non coding RNA species in dilated cardiomyopathy. AB - The transcriptome needs to be tightly regulated by mechanisms that include transcription factors, enhancers, and repressors as well as non-coding RNAs. Besides this dynamic regulation, a large part of phenotypic variability of eukaryotes is expressed through changes in gene transcription caused by genetic variation. In this study, we evaluate genome-wide structural genomic variants (SVs) and their association with gene expression in the human heart. We detected 3,898 individual SVs affecting all classes of gene transcripts (e.g., mRNA, miRNA, lncRNA) and regulatory genomic regions (e.g., enhancer or TFBS). In a cohort of patients (n = 50) with dilated cardiomyopathy (DCM), 80,635 non-protein coding elements of the genome are deleted or duplicated by SVs, containing 3,758 long non-coding RNAs and 1,756 protein-coding transcripts. 65.3% of the SV-eQTLs do not harbor a significant SNV-eQTL, and for the regions with both classes of association, we find similar effect sizes. In case of deleted protein-coding exons, we find downregulation of the associated transcripts, duplication events, however, do not show significant changes over all events. In summary, we are first to describe the genomic variability associated with SVs in heart failure due to DCM and dissect their impact on the transcriptome. Overall, SVs explain up to 7.5% of the variation of cardiac gene expression, underlining the importance to study human myocardial gene expression in the context of the individual genome. This has immediate implications for studies on basic mechanisms of cardiac maladaptation, biomarkers, and (gene) therapeutic studies alike. PMID- 29138230 TI - Head-to-Head Comparison of Global and Regional Two-Dimensional Speckle Tracking Strain Versus Cardiac Magnetic Resonance Tagging in a Multicenter Validation Study. AB - BACKGROUND: Despite widespread use to characterize and refine prognosis, validation data of two-dimensional (2D) speckle tracking (2DST) echocardiography myocardial strain measurement remain scarce. METHODS AND RESULTS: Global and regional subendocardial peak-systolic Lagrangian longitudinal (LS) and circumferential strain (CS) by 2DST and 2D-tagged (2DTagg) cardiac magnetic resonance imaging were compared against sonomicrometry in a dynamic heart phantom and among each other in 136 patients included prospectively at 2 centers. The ability of regional LS and CS 2DST and 2DTagg to identify late gadolinium enhancement was compared using receiver operating characteristics curves. In vitro, both LS-2DST and 2DTagg highly agreed with sonomicrometry (intraclass correlation coefficient [ICC], 0.89 and ICC, 0.90, both P<0.001 with -3+/-2.8% and 0.34+/-4.35% bias, respectively). In patients, both global LS and global CS 2DST agreed well with 2DTagg (ICC, 0.89 and ICC, 0.80; P<0.001); however, they provided systematically greater values (relative bias of -37+/-27% and -25+/-37% for global LS and global CS, respectively). On regional basis, however, ICC (from 0.17 to 0.81) and relative bias (from -9 to -98%) between 2DST and 2DTagg varied strongly among segments. Ability to discriminate infarcted versus noninfarcted segments by late gadolinium enhancement was similarly good for regional LS 2DTagg and 2DST (area under the curve, 0.66 versus 0.59; P=0.08), while it was lower for CS 2DST than 2DTagg (area under the curve, 0.61 versus 0.75; P<0.001). CONCLUSIONS: The high accuracy against sonomicrometry and good agreement of global LS and global CS by 2DST and 2DTagg confirm the overall validity of 2DST strain measurement. Yet, higher intertechnique segmental variability and lower ability for detecting infarct suggest that 2DST strain estimates may be less performant on regional than on global basis. PMID- 29138233 TI - Do We Finally Have the A to Z of Z Scores? PMID- 29138234 TI - Mesalazine induced myopericarditis in a patient with ulcerative colitis. AB - A 25-year-old male with a background of ulcerative colitis presented with a two week history of central chest pain. His ECG on presentation showed global T wave inversion with a peak troponin I of 165 ng/ml. Clinical diagnosis of myopericarditis/myocarditis was made. Echocardiography and cardiac MR confirmed the diagnosis. On detailed assessment of his medication history, mesalazine was suspected as an aetiological factor, with discontinuation resulting in an improvement in symptoms, inflammatory markers and cardiac enzymes. This is a unique case of mesalazine induced myopericarditis on a background of inflammatory bowel disease. PMID- 29138232 TI - Relationship of Echocardiographic Z Scores Adjusted for Body Surface Area to Age, Sex, Race, and Ethnicity: The Pediatric Heart Network Normal Echocardiogram Database. AB - BACKGROUND: Published nomograms of pediatric echocardiographic measurements are limited by insufficient sample size to assess the effects of age, sex, race, and ethnicity. Variable methodologies have resulted in a wide range of Z scores for a single measurement. This multicenter study sought to determine Z scores for common measurements adjusted for body surface area (BSA) and stratified by age, sex, race, and ethnicity. METHODS AND RESULTS: Data collected from healthy nonobese children <=18 years of age at 19 centers with a normal echocardiogram included age, sex, race, ethnicity, height, weight, echocardiographic images, and measurements performed at the Core Laboratory. Z score models involved indexed parameters (X/BSAalpha) that were normally distributed without residual dependence on BSA. The models were tested for the effects of age, sex, race, and ethnicity. Raw measurements from models with and without these effects were compared, and <5% difference was considered clinically insignificant because interobserver variability for echocardiographic measurements are reported as >=5% difference. Of the 3566 subjects, 90% had measurable images. Appropriate BSA transformations (BSAalpha) were selected for each measurement. Multivariable regression revealed statistically significant effects by age, sex, race, and ethnicity for all outcomes, but all effects were clinically insignificant based on comparisons of models with and without the effects, resulting in Z scores independent of age, sex, race, and ethnicity for each measurement. CONCLUSIONS: Echocardiographic Z scores based on BSA were derived from a large, diverse, and healthy North American population. Age, sex, race, and ethnicity have small effects on the Z scores that are statistically significant but not clinically important. PMID- 29138235 TI - BRIP1 overexpression is correlated with clinical features and survival outcome of luminal breast cancer subtypes. AB - In Oman, breast cancer is most common, representing approximately more than 25% of all cancers in women. Relatively younger populations of patients (25-40 years) present surprisingly with an aggressive phenotype and advanced tumor stages. In this study, we investigated differential gene expressions in Luminal A, Luminal B, triple-negative and Her2+ breast cancer subtypes and compared data to benign tumor samples. We identified a potential candidate gene BRIP1, showing differential expression in the four breast cancer subtypes examined, suggesting that BRIP1 has the profile of a useful diagnostic marker, suitable for targeted therapeutic intervention. RT-qPCR and Western blotting analysis showed higher BRIP1 expression in luminal samples as compared to triple-negative subtype patient's samples. We further screened BRIP1 for eventual mutations/SNPs/deletions by sequencing the entire coding region. Four previously identified polymorphisms were detected, one within the 5'-UTR region (c.141-64G > A) and three in the BRCA-binding domain (c.2755T > C, c.2647G > A and c.3411T > C). Kaplan-Meier analysis revealed that patients with overexpression of BRIP1 displayed a poor survival rate (P < 0.05). BRIP1 has a dual function of an oncogene and a tumor suppressor gene in addition to its role as a potential biomarker to predict survival and prognosis. Data obtained in this study suggest that BRIP1 can plausibly have an oncogenic role in sporadic cancers. PMID- 29138236 TI - A kinase-dependent role for Haspin in antagonizing Wapl and protecting mitotic centromere cohesion. AB - Sister-chromatid cohesion mediated by the cohesin complex is fundamental for precise chromosome segregation in mitosis. Through binding the cohesin subunit Pds5, Wapl releases the bulk of cohesin from chromosome arms in prophase, whereas centromeric cohesin is protected from Wapl until anaphase onset. Strong centromere cohesion requires centromeric localization of the mitotic histone kinase Haspin, which is dependent on the interaction of its non-catalytic N terminus with Pds5B. It remains unclear how Haspin fully blocks the Wapl-Pds5B interaction at centromeres. Here, we show that the C-terminal kinase domain of Haspin (Haspin-KD) binds and phosphorylates the YSR motif of Wapl (Wapl-YSR), thereby directly inhibiting the YSR motif-dependent interaction of Wapl with Pds5B. Cells expressing a Wapl-binding-deficient mutant of Haspin or treated with Haspin inhibitors show centromeric cohesion defects. Phospho-mimetic mutation in Wapl-YSR prevents Wapl from binding Pds5B and releasing cohesin. Forced targeting Haspin-KD to centromeres partly bypasses the need for Haspin-Pds5B interaction in cohesion protection. Taken together, these results indicate a kinase-dependent role for Haspin in antagonizing Wapl and protecting centromeric cohesion in mitosis. PMID- 29138237 TI - Natural Variation in SER1 and ENA6 Underlie Condition-Specific Growth Defects in Saccharomyces cerevisiae. AB - Despite their ubiquitous use in laboratory strains, naturally occurring loss-of function mutations in genes encoding core metabolic enzymes are relatively rare in wild isolates of Saccharomyces cerevisiae Here, we identify a naturally occurring serine auxotrophy in a sake brewing strain from Japan. Through a cross with a honey wine (white tecc) brewing strain from Ethiopia, we map the minimal medium growth defect to SER1, which encodes 3-phosphoserine aminotransferase and is orthologous to the human disease gene, PSAT1 To investigate the impact of this polymorphism under conditions of abundant external nutrients, we examine growth in rich medium alone or with additional stresses, including the drugs caffeine and rapamycin and relatively high concentrations of copper, salt, and ethanol. Consistent with studies that found widespread effects of different auxotrophies on RNA expression patterns in rich media, we find that the SER1 loss-of-function allele dominates the quantitative trait locus (QTL) landscape under many of these conditions, with a notable exacerbation of the effect in the presence of rapamycin and caffeine. We also identify a major-effect QTL associated with growth on salt that maps to the gene encoding the sodium exporter, ENA6 We demonstrate that the salt phenotype is largely driven by variation in the ENA6 promoter, which harbors a deletion that removes binding sites for the Mig1 and Nrg1 transcriptional repressors. Thus, our results identify natural variation associated with both coding and regulatory regions of the genome that underlie strong growth phenotypes. PMID- 29138238 TI - A Resource for the Allele-Specific Analysis of DNA Methylation at Multiple Genomically Imprinted Loci in Mice. AB - Genomically imprinted loci are expressed mono-allelically, dependent upon the parent of origin. Their regulation not only illuminates how chromatin regulates gene expression but also how chromatin can be reprogrammed every generation. Because of their distinct parent-of-origin regulation, analysis of imprinted loci can be difficult. Single nucleotide polymorphisms (SNPs) are required to accurately assess these elements allele specifically. However, publicly available SNP databases lack robust verification, making analysis of imprinting difficult. In addition, the allele-specific imprinting assays that have been developed employ different mouse strains, making it difficult to systemically analyze these loci. Here, we have generated a resource that will allow the allele-specific analysis of many significant imprinted loci in a single hybrid strain of Mus musculus This resource includes verification of SNPs present within 10 of the most widely used imprinting control regions and allele-specific DNA methylation assays for each gene in a C57BL/6J and CAST/EiJ hybrid strain background. PMID- 29138239 TI - Expanding the chondroitin glycoproteome of Caenorhabditis elegans. AB - Chondroitin sulfate proteoglycans (CSPGs) are important structural components of connective tissues in essentially all metazoan organisms. In vertebrates, CSPGs are involved also in more specialized processes such as neurogenesis and growth factor signaling. In invertebrates, however, knowledge of CSPGs core proteins and proteoglycan-related functions is relatively limited, even for Caenorhabditis elegans. This nematode produces large amounts of non-sulfated chondroitin in addition to low-sulfated chondroitin sulfate chains. So far, only nine core proteins (CPGs) have been identified, some of which have been shown to be involved in extracellular matrix formation. We recently introduced a protocol to characterize proteoglycan core proteins by identifying CS-glycopeptides with a combination of biochemical enrichment, enzymatic digestion, and nano-scale liquid chromatography MS/MS analysis. Here, we have used this protocol to map the chondroitin glycoproteome in C. elegans, resulting in the identification of 15 novel CPG proteins in addition to the nine previously established. Three of the newly identified CPGs displayed homology to vertebrate proteins. Bioinformatics analysis of the primary protein sequences revealed that the CPG proteins altogether contained 19 unique functional domains, including Kunitz and endostatin domains, suggesting direct involvement in protease inhibition and axonal migration, respectively. The analysis of the core protein domain organization revealed that all chondroitin attachment sites are located in unstructured regions. Our results suggest that CPGs display a much greater functional and structural heterogeneity than previously appreciated and indicate that specialized proteoglycan-mediated functions evolved early in metazoan evolution. PMID- 29138241 TI - Decorin, a growth hormone-regulated protein in humans. AB - CONTEXT: Growth hormone (GH) stimulates connective tissue and muscle growth, an effect that is potentiated by testosterone. Decorin, a myokine and a connective tissue protein, stimulates connective tissue accretion and muscle hypertrophy. Whether GH and testosterone regulate decorin in humans is not known. OBJECTIVE: To determine whether decorin is stimulated by GH and testosterone. DESIGN: Randomized, placebo-controlled, double-blind study. PARTICIPANTS AND INTERVENTION: 96 recreationally trained athletes (63 men, 33 women) received 8 weeks of treatment followed by a 6-week washout period. Men received placebo, GH (2 mg/day), testosterone (250 mg/week) or combination. Women received either placebo or GH (2 mg/day). MAIN OUTCOME MEASURE: Serum decorin concentration. RESULTS: GH treatment significantly increased mean serum decorin concentration by 12.7 +/- 4.2%; P < 0.01. There was a gender difference in the decorin response to GH, with greater increase in men than in women (? 16.5 +/- 5.3%; P < 0.05 compared to ? 9.4 +/- 6.5%; P = 0.16). Testosterone did not significantly change serum decorin. Combined GH and testosterone treatment increased mean decorin concentration by 19.5 +/- 3.7% (P < 0.05), a change not significantly different from GH alone. CONCLUSION: GH significantly increases circulating decorin, an effect greater in men than in women. Decorin is not affected by testosterone. We conclude that GH positively regulates decorin in humans in a gender-dimorphic manner. PMID- 29138240 TI - Kinetics of H2O2-driven degradation of chitin by a bacterial lytic polysaccharide monooxygenase. AB - Lytic polysaccharide monooxygenases (LPMOs) catalyze the oxidative cleavage of glycosidic bonds in recalcitrant polysaccharides, such as cellulose and chitin, and are of interest in biotechnological utilization of these abundant biomaterials. It has recently been shown that LPMOs can use H2O2, instead of O2, as a cosubstrate. This peroxygenase-like reaction by a monocopper enzyme is unprecedented in nature and opens new avenues in chemistry and enzymology. Here, we provide the first detailed kinetic characterization of chitin degradation by the bacterial LPMO chitin-binding protein CBP21 using H2O2 as cosubstrate. The use of 14C-labeled chitin provided convenient and sensitive detection of the released soluble products, which enabled detailed kinetic measurements. The kcat for chitin oxidation found here (5.6 s-1) is more than an order of magnitude higher than previously reported (apparent) rate constants for reactions containing O2 but no added H2O2 The kcat/Km for H2O2-driven degradation of chitin was on the order of 106 m-1 s-1, indicating that LPMOs have catalytic efficiencies similar to those of peroxygenases. Of note, H2O2 also inactivated CBP21, but the second-order rate constant for inactivation was about 3 orders of magnitude lower than that for catalysis. In light of the observed CBP21 inactivation at higher H2O2 levels, we conclude that controlled generation of H2O2in situ seems most optimal for fueling LPMO-catalyzed oxidation of polysaccharides. PMID- 29138242 TI - Role of ECMO in congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) is typified morphologically by failure of diaphragmatic development with accompanying lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). Patients who have labile physiology and low preductal saturations despite optimal ventilatory and inotropic support may be considered for extracorporeal membrane oxygenation (ECMO). Systematic reviews into the benefits of ECMO in CDH concluded that any benefit is unclear. Few randomised trials exist to demonstrate clear benefit and guide management. However, ECMO may have its uses in those that have reversibility of their respiratory disease. A few centres and networks have demonstrated an increase in survival rate by post hoc analysis (based on a difference in referral patterns with the availability of ECMO) in their series. One issue may be that of careful patient selection with regard to reversibility of pathophysiology. At present, there is no single test or prognostication that predicts reversibility of PPHN and criteria for referral for ECMO is undergoing continued refinement. Overall survival is similar between cannulation modes. There is no consensus on the time limit for ECMO runs. The optimal timing of surgery for patients on ECMO is difficult to definitively establish, but it seems that repair at an early stage (with careful perioperative management) is becoming less of a taboo, and may improve outcome and help with either coming off ECMO or decisions on withdrawal later. The provision of ECMO will continue to be evaluated, and prospective randomised trial are needed to help answer question of patient selection and management. PMID- 29138244 TI - Correction. PMID- 29138243 TI - Congenital erosive and vesicular dermatosis with reticulated supple scarring. PMID- 29138246 TI - Letter by Fadahunsi et al Regarding Article, "Clinical and Echocardiographic Outcomes Following Permanent Pacemaker Implantation After Transcatheter Aortic Valve Replacement Meta-Analysis and Meta-Regression". PMID- 29138245 TI - Clinical Impact of Diabetes Mellitus on Outcomes After Transcatheter Aortic Valve Replacement: Insights From the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. AB - BACKGROUND: Diabetes mellitus (DM) adversely affects morbidity and mortality for cardiovascular diseases and procedures. Data evaluating the outcomes of transcatheter aortic valve replacement (TAVR) in diabetic patients are limited by small sample size and contradictory results. We aimed to establish the magnitude of risk and the incremental influence of insulin dependency by examining short- and long-term adverse outcomes according to DM status and therapy in the world's largest TAVR registry. METHODS AND RESULTS: We analyzed data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. In-hospital mortality, 30-day mortality, and 1-year mortality after TAVR in patients with and without DM were evaluated using multivariate modeling. Among 47 643 patients treated with TAVR from November 2011 through September 2015 at 394 US hospitals, there were 17 849 (37.5%) patients with DM. Overall, 6600 of the diabetic patients were insulin treated (IT). Thirty-day mortality was 5.0% in patients with DM (6.1% in IT DM and 4.4% in non-IT DM; P<0.001) versus 5.9% in patients without DM (P<0.001). Overall, 1-year mortality was 21.8% in patients with DM (24.8% in IT DM and 20.1% in non-IT DM; P<0.001) versus 21.2% in patients without DM (P=0.274). In a multivariable model, DM was associated with increased 1-year mortality (hazard ratio, 1.30; 95% confidence interval, 1.13-1.49; P<0.001). Subgroup multivariable analysis showed stronger mortality association in IT diabetics (hazard ratio, 1.57; 95% confidence interval, 1.28-1.91; P<0.001) than in non-IT diabetics (hazard ratio, 1.17; 95% confidence interval, 1.00-1.38; P=0.052). CONCLUSIONS: Our data establish the magnitude of short- and long-term risk conferred by DM and the incremental risk conferred by insulin dependency in the performance of TAVR. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01737528. PMID- 29138247 TI - Response by Mohananey et al to Letter Regarding Article, "Clinical and Echocardiographic Outcomes Following Permanent Pacemaker Implantation After Transcatheter Aortic Valve Replacement: Meta-Analysis and Meta-Regression". PMID- 29138249 TI - Waiting Period Before Implantable Cardioverter-Defibrillator Implantation in Newly Diagnosed Heart Failure With Reduced Ejection Fraction: A Window of Opportunity. PMID- 29138248 TI - USP1-UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses. AB - Optimal activation of TANK-binding kinase 1 (TBK1) is crucial for initiation of innate antiviral immunity and maintenance of immune homeostasis. Although several E3 ubiquitin ligases have been reported to regulate TBK1 activation by mediating its polyubiquitination, the functions of deubiquitinase on TBK1 activity remain largely unclear. Here, we identified a deubiquitinase complex, which is formed by ubiquitin specific peptidase 1 (USP1) and USP1-associated factor 1 (UAF1), as a viral infection-induced physiological enhancer of TBK1 expression. USP1-UAF1 complex enhanced TLR3/4 and RIG-I-induced IFN regulatory factor 3 (IRF3) activation and subsequent IFN-beta secretion. Mechanistically, USP1 and UAF1 bound to TBK1, removed its K48-linked polyubiquitination, and then reversed the degradation process of TBK1. Furthermore, we found that ML323, a specific USP1 UAF1 inhibitor, attenuated IFN-beta expression and enhanced viral replication both in vitro and in vivo. Therefore, our results outline a novel mechanism for the control of TBK1 activity and suggest USP1-UAF1 complex as a potential target for the prevention of viral diseases. PMID- 29138250 TI - Pulses and waves of contractility. AB - The nature of signal transduction networks in the regulation of cell contractility is not entirely clear. In this study, Graessl et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201706052) visualized and characterized pulses and waves of Rho activation in adherent cells and proposed excitable Rho signaling networks underlying cell contractility. PMID- 29138252 TI - Apical polarization and lumenogenesis: The apicosome sheds new light. AB - Establishment of apico-basal polarity is critical for the lumenal epiblast-like morphogenesis of human pluripotent stem cells (hPSCs). In this issue, Taniguchi et al. (2017. J Cell Biol. https://doi.org/10.1083.jcb201704085) describe a structure called the apicosome, generated in single hPSCs, that allows them to self-organize and form the lumenal epiblast-like stage. PMID- 29138251 TI - Mitochondrial inner-membrane protease Yme1 degrades outer-membrane proteins Tom22 and Om45. AB - Mitochondria are double-membraned organelles playing essential metabolic and signaling functions. The mitochondrial proteome is under surveillance by two proteolysis systems: the ubiquitin-proteasome system degrades mitochondrial outer membrane (MOM) proteins, and the AAA proteases maintain the proteostasis of intramitochondrial compartments. We previously identified a Doa1-Cdc48-Ufd1-Npl4 complex that retrogradely translocates ubiquitinated MOM proteins to the cytoplasm for degradation. In this study, we report the unexpected identification of MOM proteins whose degradation requires the Yme1-Mgr1-Mgr3i-AAA protease complex in mitochondrial inner membrane. Through immunoprecipitation and in vivo site-specific photo-cross-linking experiments, we show that both Yme1 adapters Mgr1 and Mgr3 recognize the intermembrane space (IMS) domains of the MOM substrates and facilitate their recruitment to Yme1 for proteolysis. We also provide evidence that the cytoplasmic domain of substrate can be dislocated into IMS by the ATPase activity of Yme1. Our findings indicate a proteolysis pathway monitoring MOM proteins from the IMS side and suggest that the MOM proteome is surveilled by mitochondrial and cytoplasmic quality control machineries in parallel. PMID- 29138253 TI - Ragulator-a multifaceted regulator of lysosomal signaling and trafficking. AB - The lysosomal Ragulator complex regulates cell metabolism and growth by coordinating the activities of metabolic signaling pathways with nutrient availability. In this issue, Filipek et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201703061) and Pu et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201703094) introduce a role for Ragulator in growth factor- and nutrient-regulated lysosomal trafficking. PMID- 29138254 TI - Estimating Realized Heritability in Panmictic Populations. AB - Narrow sense heritability [Formula: see text] is a key concept in quantitative genetics, as it expresses the proportion of the observed phenotypic variation that is transmissible from parents to offspring. [Formula: see text] determines the resemblance among relatives, and the rate of response to artificial and natural selection. Classical methods for estimating [Formula: see text] use random samples of individuals with known relatedness, as well as response to artificial selection, when it is called realized heritability. Here, we present a method for estimating realized [Formula: see text] based on a simple assessment of a random-mating population with no artificial manipulation of the population structure, and derive SE of the estimates. This method can be applied to arbitrary phenotypic segments of the population (for example, the top-ranking p parents and offspring), rather than random samples. It can thus be applied to nonpedigreed random mating populations, where relatedness is determined from molecular markers in the p selected parents and offspring, thus substantially saving on genotyping costs. Further, we assessed the method by stochastic simulations, and, as expected from the mathematical derivation, it provides unbiased estimates of [Formula: see text] We compared our approach to the regression and maximum-likelihood approaches utilizing Galton's dataset on human heights, and all three methods provided identical results. PMID- 29138255 TI - Complex History and Differentiation Patterns of the t-Haplotype, a Mouse Meiotic Driver. AB - The t-haplotype, a mouse meiotic driver found on chromosome 17, has been a model for autosomal segregation distortion for close to a century, but several questions remain regarding its biology and evolutionary history. A recently published set of population genomics resources for wild mice includes several individuals heterozygous for the t-haplotype, which we use to characterize this selfish element at the genomic and transcriptomic level. Our results show that large sections of the t-haplotype have been replaced by standard homologous sequences, possibly due to occasional events of recombination, and that this complicates the inference of its history. As expected for a long genomic segment of very low recombination, the t-haplotype carries an excess of fixed nonsynonymous mutations compared to the standard chromosome. This excess is stronger for regions that have not undergone recent recombination, suggesting that occasional gene flow between the t and the standard chromosome may provide a mechanism to regenerate coding sequences that have accumulated deleterious mutations. Finally, we find that t-complex genes with altered expression largely overlap with deleted or amplified regions, and that carrying a t-haplotype alters the testis expression of genes outside of the t-complex, providing new leads into the pathways involved in the biology of this segregation distorter. PMID- 29138257 TI - Clinical Juvenile Arthritis Disease Activity Score proves to be a useful tool in treat-to-target therapy in juvenile idiopathic arthritis. AB - OBJECTIVES: To assess if the Juvenile Arthritis Disease Activity Score (JADAS71) could be used to correctly identify patients with juvenile idiopathic arthritis (JIA) in need of antitumour necrosis factor therapy (anti-TNF) therapy 3 and 6 months after start of methotrexate (MTX). METHODS: Monocentric retrospective cohort study from 2011 to 2015 analysing all patients with oligoarticular JIA (OJIA) (n=39) and polyarticular course JIA (PJIA) (n=74) first starting MTX. Three and 6 months after MTX start, clinical and laboratory features and the 2011 American College of Rheumatology (ACR) JIA treatment recommendations (ACR clinical practice guideline (ACR-CPG)) were compared between groups starting and not starting anti-TNF therapy. The sensitivity and specificity of the ACR-CPG, JADAS71 and the clinical JADAS to identify non-responders after 12 months were calculated. RESULTS: Physicians escalated patients with significantly higher physician global assessment, clinical JADAS (cJADAS) and patient Visual Analogue Scale (VAS). The decision not to escalate was correct in 70%-75% as shown by MTX response. The implementation of the ACR-CPG would increase the current anti-TNF use from 12% to 65%. The use of (c)JADAS in identifying patients in need of anti TNF therapy outperformed the ACR-CPG with a much higher sensitivity, specificity and accuracy. The cJADAS threshold for treatment escalation at month 3 and 6 was >5 and >3 for OJIA and >7 and >4 for PJIA, respectively. The performance of the cJADAS decreased when the patient VAS contribution to the total score was restricted and overall did not improve by adding the erythrocyte sedimentation rate. CONCLUSIONS: The cJADAS identifies patients in need of anti-TNF and is a user-friendly tool ready to be used for treat to target in JIA. The patient VAS is a critical item in the cJADAS for the decision to escalate to anti-TNF. PMID- 29138258 TI - Challenges in delivering computed tomography coronary angiography as the first line test for stable chest pain. AB - OBJECTIVE: The National Institute for Health and Care Excellence (NICE) clinical guidelines 'chest pain of recent onset: assessment and diagnosis' (update 2016) state CT coronary angiography (CTCA) should be offered as the first-line investigation for patients with stable chest pain. However, the current provision in the UK is unknown. We aimed to evaluate this and estimate the requirements for full implementation of the guidelines including geographical variation. Ancillary aims included surveying the number of CTCA-capable scanners and accredited practitioners in the UK. METHODS: The number of CTCA scans performed annually was surveyed across the National Health Service (NHS). The number of percutaneous coronary interventions performed for stable angina in the NHS in 2015 was applied to a model based on SCOT-HEART (CTCA in patients with suspected angina due to coronary heart disease: an open-label, parallel-group, multicentre trial) data to estimate the requirement for CTCA, for full guideline implementation. Details of CTCA-capable scanners were obtained from manufacturers and formally accredited practitioner details from professional societies. RESULTS: An estimated 42 340 CTCAs are currently performed annually in the UK. We estimate that 350 000 would be required to fully implement the guidelines. 304 CTCA-capable scanners and 198 accredited practitioners were identified. A marked geographical variation between health regions was observed. CONCLUSIONS: This study provides insight into the scale of increase in the provision of CTCA required to fully implement the updated NICE guidelines. A small specialist workforce and limited number of CTCA capable scanners may present challenges to service expansion. PMID- 29138256 TI - Low Neonatal Plasma n-6/n-3 PUFA Ratios Regulate Offspring Adipogenic Potential and Condition Adult Obesity Resistance. AB - Adipose tissue expansion progresses rapidly during postnatal life, influenced by both prenatal maternal factors and postnatal developmental cues. The ratio of omega-6 (n-6) relative to n-3 polyunsaturated fatty acids (PUFAs) is believed to regulate perinatal adipogenesis, but the cellular mechanisms and long-term effects are not well understood. We lowered the fetal and postnatal n-6/n-3 PUFA ratio exposure in wild-type offspring under standard maternal dietary fat amounts to test the effects of low n-6/n-3 ratios on offspring adipogenesis and adipogenic potential. Relative to wild-type pups receiving high perinatal n-6/n-3 ratios, subcutaneous adipose tissue in 14-day-old wild-type pups receiving low n 6/n-3 ratios had more adipocytes that were smaller in size; decreased Ppargamma2, Fabp4, and Plin1; several lipid metabolism mRNAs; coincident hypermethylation of the PPARgamma2 proximal promoter; and elevated circulating adiponectin. As adults, offspring that received low perinatal n-6/n-3 ratios were diet-induced obesity (DIO) resistant and had a lower positive energy balance and energy intake, greater lipid fuel preference and non-resting energy expenditure, one half the body fat, and better glucose clearance. Together, the findings support a model in which low early-life n-6/n-3 ratios remodel adipose morphology to increase circulating adiponectin, resulting in a persistent adult phenotype with improved metabolic flexibility that prevents DIO. PMID- 29138259 TI - Spectroscopic and calorimetric characterization of spermine oxidase and its association forms. AB - Spermine oxidase (SMOX) is a flavin-containing enzyme that oxidizes spermine to produce spermidine, 3-aminopropanaldehyde, and hydrogen peroxide. SMOX has been shown to play key roles in inflammation and carcinogenesis; indeed, it is differentially expressed in several human cancer types. Our previous investigation has revealed that SMOX purified after heterologous expression in Escherichia coli actually consists of monomers, covalent homodimers, and other higher-order forms. All association forms oxidize spermine and, after treatment with dithiothreitol, revert to SMOX monomer. Here, we report a detailed investigation on the thermal denaturation of SMOX and its association forms in native and reducing conditions. By combining spectroscopic methods (circular dichroism, fluorescence) and thermal methods (differential scanning calorimetry), we provide new insights into the structure, the transformation, and the stability of SMOX. While the crystal structure of this protein is not available yet, experimental results are interpreted also on the basis of a novel SMOX structural model, obtained in silico exploiting the recently solved acetylspermine oxidase crystal structure. We conclude that while at least one specific intermolecular disulfide bond links two SMOX molecules to form the homodimer, the thermal denaturation profiles can be justified by the presence of at least one intramolecular disulfide bond, which also plays a critical role in the stabilization of the overall three-dimensional SMOX structure, and in particular of its flavin adenine dinucleotide-containing active site. PMID- 29138260 TI - Chloroplast division protein ARC3 acts on FtsZ2 by preventing filament bundling and enhancing GTPase activity. AB - Chloroplasts evolved from cyanobacterial endosymbiotic ancestors and their division is a complex process initiated by the assembly of cytoskeletal FtsZ (Filamentous temperature sensitive Z) proteins into a ring structure at the division site (Z-ring). The cyanobacterial Z-ring positioning system (MinCDE proteins) is also conserved in chloroplasts, except that MinC was lost and replaced by the eukaryotic ARC3 (accumulation and replication of chloroplasts). Both MinC and ARC3 act as negative regulators of FtsZ assembly, but ARC3 bears little sequence similarity with MinC. Here, light scattering assays, co sedimentation, GTPase assay and transmission electron microscopy in conjunction with single-particle analysis have been used to elucidate the structure of ARC3 and its effect on its main target in chloroplast division, FtsZ2. Analysis of FtsZ2 in vitro assembly reactions in the presence and absence of GMPCPP showed that ARC3 promotes FtsZ2 debundling and disassembly of existing filaments in a concentration-dependent manner and requires GTP hydrolysis. Three-dimensional reconstruction of ARC3 revealed an almost circular molecule in which the FtsZ binding N-terminus and the C-terminal PARC6 (paralog of ARC6)-binding MORN (Membrane Occupation and Recognition Nexus) domain are in close proximity and suggest a model for PARC6-enabled binding of ARC3 to FtsZ2. The latter is corroborated by in vivo data. PMID- 29138261 TI - Hindsight and moving the needle forwards on rehabilitation trial design. PMID- 29138262 TI - A big beautiful wall against infection. PMID- 29138263 TI - SREBP-1c as a molecular bridge between lipogenesis and cell cycle progression of clear cell renal carcinoma. AB - Sterol regulatory element binding protein 1c (SREBP-1c) promotes lipogenesis and tumor growth in various cancers. It is well known that clear cell renal cell carcinoma (ccRCC), a major subtype of the kidney cancers, exhibits elevated lipid accumulation. However, it has not been fully understood how lipid metabolism might be associated with cell cycle regulation in ccRCC. In a recent issue, Lee et al. (Molecular and Cellular Biology (2017) pii: MCB.00265-17) demonstrate that SREBP-1c is up-regulated in ccRCC by ring finger protein 20 (RNF20) down regulation, leading to aberrant lipid storage and pituitary tumor transforming gene 1 (PTTG1)-dependent cell cycle progression. These findings suggest that SREBP-1c serves as a molecular bridge between lipid metabolism and cell cycle control in ccRCC tumorigenesis. PMID- 29138265 TI - Targeted Delivery of STAT-3 Modulator to Breast Cancer Stem-Like Cells Downregulates a Series of Stemness Genes. AB - Cancer stem cells are known to be controlled by pathways that are dormant in normal adult cells, for example, PTEN, which is a negative regulator of transcription factor STAT3. STAT3 regulates genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of enormous clinical significance. Studies on breast cancer stem cells (BCSC) have been also significantly correlated with STATs. We describe here for the first time a novel strategy to selectively target CSCs and to induce downregulation of STAT3 downstream target genes reducing expression of series of "stem-ness genes" in treated tumors. In vitro and in vivo experiments were performed to evaluate functional activity with gene and protein expression studies. The results of the study indicate that this targeted delivery approach deactivates STAT3 causing a reduction of CD44+/CD24- CSC populations with aptly tracked gene and protein regulations of "stemness" characteristics. Mol Cancer Ther; 17(1); 119-29. (c)2017 AACR. PMID- 29138266 TI - Postoperative hypoxaemia: telebrix aspiration. PMID- 29138264 TI - Comprehensive investigation of cytokine- and immune-related gene variants in HBV associated hepatocellular carcinoma patients. AB - Host genotype may be closely related to the different outcomes of Hepatitis B virus (HBV) infection. To identify the association of variants and HBV infection, we comprehensively investigated the cytokine- and immune-related gene mutations in patients with HBV associated hepatocellular carcinoma (HBV-HCC). Fifty-three HBV-HCC patients, 53 self-healing cases (SH) with HBV infection history and 53 healthy controls (HCs) were recruited, the whole exon region of 404 genes were sequenced at >900* depth. Comprehensive variants and gene levels were compared between HCC and HC, and HCC and SH. Thirty-nine variants (adjusted P<0.0001, Fisher's exact test) and 11 genes (adjusted P<0.0001, optimal unified approach for rare variant association test (SKAT-O) gene level test) were strongly associated with HBV-HCC. Thirty-four variants were from eight human leukocyte antigen (HLA) genes that were previously reported to be associated with HBV-HCC. The novelties of our study are: five variants (rs579876, rs579877, rs368692979, NM_145007:c.*131_*130delTG, NM_139165:exon5:c.623-2->TT) from three genes (REAT1E, NOD-like receptor (NLR) protein 11 (NLRP11), hydroxy-carboxylic acid receptor 2 (HCAR2)) were found strongly associated with HBV-HCC. We found 39 different variants in 11 genes that were significantly related to HBV-HCC. Five of them were new findings. Our data implied that chronic hepatitis B patients who carry these variants are at a high risk of developing HCC. PMID- 29138267 TI - An atypical CaV1.1 mutation reveals a common mechanism for hypokalemic periodic paralysis. PMID- 29138268 TI - N-Acyl Amino Acids (Elmiric Acids): Endogenous Signaling Molecules with Therapeutic Potential. AB - The subject of N-acyl amino acid conjugates has been rapidly growing in recent years, especially with regard to their analgesic and anti-inflammatory actions. The field comprises a large family of lipid signaling molecules whose importance is only now being fully realized. The most widely studied member is N arachidonoyl glycine (NAGly), which differs structurally from the endocannabinoid anandamide (N-arachidonoyl ethanolamide) by a single oxygen atom even as the two are metabolically related. Topics that are covered in this minireview are: biosynthetic pathways for N-acyl amino acids, receptors for N-acyl amino acids, physiologic actions of N-acyl amino acids, pharmacological effects of N-acyl amino acids, and molecular mechanisms believed to be responsible for their effects. On the subject of mechanisms, we propose several possibilities whose basis is the currently available information. Four putative pathways can be suggested: 1) inhibition of fatty acid amide hydrolase-induced increases in anandamide or 2-arachidonoyl glycerol (2-AG) levels, resulting in analgesic activity; 2) binding to GPR18, initiating the production of anti-inflammatory eicosanoids (specifically, the data suggest roles for 15-deoxy-Delta12,14 prostaglandin-J2 and lipoxin A4, both of which are potent inflammation-resolving molecules); 3) inactivation of T-type Cav3 channels; and 4) inhibition of the GLYT2 glycine transporter. Each pathway would produce analgesic effects. Also, the N-acyl amino acids do not bind to either cannabinoid or opioid receptors, thus reducing adverse actions and making them good templates for novel drug candidate molecules. PMID- 29138269 TI - Irreversible Activation and Stabilization of Soluble Guanylate Cyclase by the Protoporphyrin IX Mimetic Cinaciguat. AB - Belonging to the class of so-called soluble guanylate cyclase (sGC) activators, cinaciguat and BAY 60-2770 are interesting therapeutic tools for the treatment of various cardiovascular pathologies. The drugs are supposed to preferentially stimulate oxidized or heme-depleted, but not native sGC. Since this concept has been challenged by studies demonstrating complete relaxation of nondiseased vessels, this study was designed to reinvestigate the mode of action in greater detail. To this purpose, the effect of cinaciguat was studied on vessel tone of porcine coronary arteries and rat thoracic aortas. Organ bath studies showed that the compound caused time- and concentration-dependent relaxation of precontracted vessels with a maximal effect observed at 90 minutes. The dilatory response was not affected by extensive washout of the drug. Cinaciguat-induced vasodilation was associated with a time- and concentration-dependent increase of cGMP levels. Experiments with purified sGC in the presence of Tween 20 showed that cinaciguat activates the heme-free enzyme in a concentration-dependent manner with an EC50 value of ~0.2 uM and maximal cGMP formation at 10 uM. By contrast, the effect of cinaciguat on 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one-oxidized (ferric) sGC was moderate, reaching ~10%-15% of maximal activity. Dilution experiments of cinaciguat/Tween 20-preincubated sGC revealed the irreversible character of the drug. Assuming a sensitive balance between heme-free, ferric, and nitric oxide sensitive ferrous sGC in cells and tissues, we propose that cinaciguat by virtue of its irreversible mode of action is capable of shifting this equilibrium toward the heme-free apo-sGC species. PMID- 29138270 TI - Low- and High-renin Heart Failure Phenotypes with Clinical Implications. AB - BACKGROUND: Blockade of the renin-angiotensin system (RAS) represents a main strategy in the therapy of heart failure with reduced ejection fraction (HFrEF), but the role of active renin concentration (ARC) for guiding therapy in the presence of an RAS blockade remains to be established. This study assessed angiotensin profiles of HFrEF patients with distinct RAS activations as reflected by ARC. METHODS: Two cohorts of stable chronic HFrEF patients on optimal medical treatment (OMT) were enrolled. We assessed ARC and all known circulating angiotensin metabolites, including AngI and AngII, by mass spectrometry to investigate the effect of different therapy modalities. Low- and high-renin HFrEF patients were identified by ARC screening and subsequently characterized by their angiotensin profiles. RESULTS: Although different modes of RAS blockade resulted in typical AngII/AngI ratios, concentrations of (AngI+AngII) strongly correlated with ARC [r = 0.95, P < 0.001] independent of therapy mode. Despite RAS blocker treatment with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II type 1 receptor blockers (ARB), which anticipated ARC upregulation, about 30% of patients showed lower/normal range ARC values. ARC did not correlate with N terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations and New York Heart Association (NYHA) stages. Angiotensin concentrations were profoundly diminished for the low-ARC group compared with the high-ARC group: AngI [6.4 ng/L (IQR: 2.1-12.5) vs 537.9 ng/L (IQR: 423.1-728.4), P < 0.001 for ACE-I; and 4.5 ng/L (IQR: 1.4-11.2) vs 203.0 ng/L (IQR: 130.2-247.9), P = 0.003 for ARB] and AngII [<1.4 ng/L (IQR: <1.4-1.5) vs 6.1 ng/L (IQR: 2.0-11.1), P = 0.002 for ACE-I and 4.7 ng/L (IQR: <1.4-12.3) vs 206.4 ng/L (IQR: 142.2-234.4), P < 0.001 for ARB]. CONCLUSIONS: In addition to NT-proBNP and NYHA stages, ARC enables classification of HFrEF patients receiving OMT into more distinguished neurohumoral HFrEF phenotypes, offering a rationale for adaptive therapeutic interventions. PMID- 29138271 TI - Addressing the Perfect Storm: Biomarkers in Obesity and Pathophysiology of Cardiometabolic Risk. AB - BACKGROUND: The worldwide rise of obesity has provoked intensified research to better understand its pathophysiology as a means for disease prevention. Several biomarkers that may reflect various pathophysiological pathways that link obesity and cardiometabolic diseases have been identified over the past decades. CONTENT: We summarize research evidence regarding the role of established and novel obesity-related biomarkers, focusing on recent epidemiological evidence for detrimental associations with cardiometabolic diseases including obesity-related cancer. The reviewed biomarkers include biomarkers of glucose-insulin homeostasis (insulin, insulin-like growth factors, and C-peptide), adipose tissue biomarkers (adiponectin, omentin, apelin, leptin, resistin, and fatty-acid-binding protein 4), inflammatory biomarkers (C-reactive protein, interleukin 6, tumor necrosis factor alpha), and omics-based biomarkers (metabolites and microRNAs). SUMMARY: Although the evidence for many classical obesity biomarkers, including adiponectin and C-reactive protein (CRP), in disease etiology has been initially promising, the evidence for a causal role in humans remains limited. Further, there has been little demonstrated ability to improve disease prediction beyond classical risk factors. In the era of "precision medicine," there is an increasing interest in novel biomarkers, and the extended list of potentially promising biomarkers, such as adipokines, cytokines, metabolites, and microRNAs, implicated in obesity may bring new promise for improved, personalized prevention. To further evaluate the role of obesity-related biomarkers as etiological and early-disease-prediction targets, well-designed studies are needed to evaluate temporal associations, replicate findings, and test clinical utility of novel biomarkers. In particular, studies to determine the therapeutic implications of novel biomarkers beyond established metabolic risk factors are highly warranted. PMID- 29138272 TI - The Role of Peers for Diabetes Management in Adolescents and Emerging Adults With Type 1 Diabetes: A Longitudinal Study. AB - OBJECTIVE: The increasing importance of peers in adolescence and emerging adulthood has been widely acknowledged. However, longitudinal research linking the peer context to diabetes management and outcomes is scarce. The present longitudinal study in a large sample of youths with type 1 diabetes related both positive and negative peer variables to diabetes outcomes over a time interval of 1 year. RESEARCH DESIGN AND METHODS: Our sample consisted of 467 adolescents (14 17 years of age) and emerging adults (18-25 years of age) with type 1 diabetes who participated in a two-wave longitudinal study. Questionnaires tapped into peer support, extreme peer orientation, parental responsiveness, diabetes-related distress, and treatment adherence. HbA1c values were obtained from the treating physicians of patients. Cross-lagged analysis from a structural equation modeling approach was performed to assess the directionality of effects. RESULTS: Peer support negatively predicted diabetes-related distress over time. Extreme peer orientation positively predicted treatment distress over time. Parental responsiveness negatively predicted food distress over time. Treatment adherence negatively predicted extreme peer orientation, treatment distress, and HbA1c values over time. For emerging adults specifically, there was a reciprocal relationship between HbA1c values and extreme peer orientation because they positively predicted each other. CONCLUSIONS: This study highlights the importance of peers in predicting the functioning of youths with type 1 diabetes. Additionally, treatment adherence at baseline was found to negatively predict extreme peer orientation, treatment distress, and worse glycemic control over time. In sum, the current study underscores the importance of the peer context for adolescents and emerging adults with type 1 diabetes. PMID- 29138274 TI - Five-Year Effectiveness of the Multidisciplinary Risk Assessment and Management Programme-Diabetes Mellitus (RAMP-DM) on Diabetes-Related Complications and Health Service Uses-A Population-Based and Propensity-Matched Cohort Study. AB - OBJECTIVE: To evaluate the 5-year effectiveness of a multidisciplinary Risk Assessment and Management Programme-Diabetes Mellitus (RAMP-DM) in primary care patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A 5-year prospective cohort study was conducted with 121,584 Chinese primary care patients with type 2 DM who were recruited between August 2009 and June 2011. Missing data were dealt with multiple imputations. After excluding patients with prior diabetes mellitus (DM)-related complications and one-to-one propensity score matching on all patient characteristics, 26,718 RAMP-DM participants and 26,718 matched usual care patients were followed up for a median time of 4.5 years. The effect of RAMP DM on nine DM-related complications and all-cause mortality were evaluated using Cox regressions. The first incidence for each event was used for all models. Health service use was analyzed using negative binomial regressions. Subgroup analyses on different patient characteristics were performed. RESULTS: The cumulative incidence of all events (DM-related complications and all-cause mortality) was 23.2% in the RAMP-DM group and 43.6% in the usual care group. RAMP DM led to significantly greater reductions in cardiovascular disease (CVD) risk by 56.6% (95% CI 54.5, 58.6), microvascular complications by 11.9% (95% CI 7.0, 16.6), mortality by 66.1% (95% CI 64.3, 67.9), specialist attendance by 35.0% (95% CI 33.6, 36.4), emergency attendance by 41.2% (95% CI 39.8, 42.5), and hospitalizations by 58.5% (95% CI 57.2, 59.7). Patients with low baseline CVD risks benefitted the most from RAMP-DM, which decreased CVD and mortality risk by 60.4% (95% CI 51.8, 67.5) and 83.6% (95% CI 79.3, 87.0), respectively. CONCLUSIONS: This naturalistic study highlighted the importance of early optimal DM control and risk factor management by risk stratification and multidisciplinary, protocol-driven, chronic disease model care to delay disease progression and prevent complications. PMID- 29138275 TI - Enhanced Predictive Capability of a 1-Hour Oral Glucose Tolerance Test: A Prospective Population-Based Cohort Study. AB - OBJECTIVE: To examine whether the 1-h blood glucose measurement would be a more suitable screening tool for assessing the risk of diabetes and its complications than the 2-h measurement. RESEARCH DESIGN AND METHODS: We conducted a prospective population-based cohort study of 4,867 men, randomly selected from prespecified birth cohorts between 1921 and 1949, who underwent an oral glucose tolerance test with blood glucose measurements at 0, 1, and 2 h. Subjects were followed for up to 39 years, with registry-based recording of events. Discriminative abilities of elevated 1-h (>=8.6 mmol/L) versus 2-h (>=7.8 mmol/L) glucose for predicting incident type 2 diabetes, vascular complications, and mortality were compared using Kaplan-Meier analysis, Cox proportional hazards regression, and net reclassification improvement. RESULTS: Median age was 48 years (interquartile range [IQR] 48-49). During follow-up (median 33 years [IQR 24-37]), 636 (13%) developed type 2 diabetes. Elevated 1-h glucose was associated with incident diabetes (hazard ratio 3.40 [95% CI 2.90-3.98], P < 0.001) and provided better risk assessment than impaired glucose tolerance (Harrell concordance index 0.637 vs. 0.511, P < 0.001). Addition of a 1-h measurement in subjects stratified by fasting glucose provided greater net reclassification improvement than the addition of a 2-h measurement (0.214 vs. 0.016, respectively). Finally, the 1-h glucose was significantly associated with vascular complications and mortality. CONCLUSIONS: The 1-h blood glucose level is a stronger predictor of future type 2 diabetes than the 2-h level and is associated with diabetes complications and mortality. PMID- 29138277 TI - Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence. AB - Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A We developed an innovative approach that integrates single-cell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates. Our data unveiled regulation of senescence as a novel way by which mechanistic target of rapamycin (mTOR) influences reprogramming. On one hand, mTOR inhibition blunts the induction of cyclin-dependent kinase (CDK) inhibitors (CDKIs), including p16INK4a, p21CIP1, and p15INK4b, preventing OSKM-induced senescence. On the other hand, inhibition of mTOR blunts the senescence-associated secretory phenotype (SASP), which itself favors reprogramming. These contrasting actions contribute to explain the complex effect that mTOR has on reprogramming. Overall, our study highlights the advantage of combining functional screens with scRNA-seq to accelerate the discovery of pathways controlling complex phenotypes. PMID- 29138278 TI - A cytoplasmic COMPASS is necessary for cell survival and triple-negative breast cancer pathogenesis by regulating metabolism. AB - Mutations and translocations within the COMPASS (complex of proteins associated with Set1) family of histone lysine methyltransferases are associated with a large number of human diseases, including cancer. Here we report that SET1B/COMPASS, which is essential for cell survival, surprisingly has a cytoplasmic variant. SET1B, but not its SET domain, is critical for maintaining cell viability, indicating a novel catalytic-independent role of SET1B/COMPASS. Loss of SET1B or its unique cytoplasmic-interacting protein, BOD1, leads to up regulation of expression of numerous genes modulating fatty acid metabolism, including ADIPOR1 (adiponectin receptor 1), COX7C, SDC4, and COQ7 Our detailed molecular studies identify ADIPOR1 signaling, which is inactivated in both obesity and human cancers, as a key target of SET1B/COMPASS. Collectively, our study reveals a cytoplasmic function for a member of the COMPASS family, which could be harnessed for therapeutic regulation of signaling in human diseases, including cancer. PMID- 29138276 TI - Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade. AB - There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5 Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage. PMID- 29138279 TI - The secreted neurotrophin Spatzle 3 promotes glial morphogenesis and supports neuronal survival and function. AB - Most glial functions depend on establishing intimate morphological relationships with neurons. Significant progress has been made in understanding neuron-glia signaling at synaptic and axonal contacts, but how glia support neuronal cell bodies is unclear. Here we explored the growth and functions of Drosophila cortex glia (which associate almost exclusively with neuronal cell bodies) to understand glia-soma interactions. We show that cortex glia tile with one another and with astrocytes to establish unique central nervous system (CNS) spatial domains that actively restrict glial growth, and selective ablation of cortex glia causes animal lethality. In an RNAi-based screen, we identified alphaSNAP (soluble NSF [N-ethylmalemeide-sensitive factor] attachment protein alpha) and several components of vesicle fusion and recycling machinery as essential for the maintenance of cortex glial morphology and continued contact with neurons. Interestingly, loss of the secreted neurotrophin Spatzle 3 (Spz3) phenocopied alphaSNAP phenotypes, which included loss of glial ensheathment of neuron cell bodies, increased neuronal cell death, and defects in animal behavior. Rescue experiments suggest that Spz3 can exert these effects only over very short distances. This work identifies essential roles for glial ensheathment of neuronal cell bodies in CNS homeostasis as well as Spz3 as a novel signaling factor required for maintenance of cortex glial morphology and neuron-glia contact. PMID- 29138281 TI - A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo. AB - The microtubule binding protein tau is strongly implicated in multiple neurodegenerative disorders, including frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which is caused by mutations in tau. In vitro, FTDP-17 mutant versions of tau can reduce microtubule binding and increase the aggregation of tau, but the mechanism by which these mutations promote disease in vivo is not clear. Here we take a combined biochemical and in vivo modeling approach to define functional properties of tau driving neurotoxicity in vivo We express wild-type human tau and five FTDP-17 mutant forms of tau in Drosophila using a site-directed insertion strategy to ensure equivalent levels of expression. We then analyze multiple markers of neurodegeneration and neurotoxicity in transgenic animals, including analysis of both males and females. We find that FTDP-17 mutations act to enhance phosphorylation of tau and thus promote neurotoxicity in an in vivo setting. Further, we demonstrate that phosphorylation-dependent excess stabilization of the actin cytoskeleton is a key phosphorylation-dependent mediator of the toxicity of wild-type tau and of all the FTDP-17 mutants tested. Finally, we show that important downstream pathways, including autophagy and the unfolded protein response, are coregulated with neurotoxicity and actin cytoskeletal stabilization in brains of flies expressing wild-type human and various FTDP-17 tau mutants, supporting a conserved mechanism of neurotoxicity of wild-type tau and FTDP-17 mutant tau in disease pathogenesis.SIGNIFICANCE STATEMENT The microtubule protein tau aggregates and forms insoluble inclusion bodies known as neurofibrillary tangles in the brain tissue of patients with a variety of neurodegenerative disorders, including Alzheimer's disease. The tau protein is thus widely felt to play a key role in promoting neurodegeneration. However, precisely how tau becomes toxic is unclear. Here we capitalize on an "experiment of nature" in which rare missense mutations in tau cause familial neurodegeneration and neurofibrillary tangle formation. By comparing the biochemical activities of different tau mutations with their in vivo toxicity in a well controlled Drosophila model system, we find that all mutations tested increase phosphorylation of tau and trigger a cascade of neurotoxicity critically impinging on the integrity of the actin cytoskeleton. PMID- 29138282 TI - Trajectory Analysis Unveils Reelin's Role in the Directed Migration of Granule Cells in the Dentate Gyrus. AB - Reelin controls neuronal migration and layer formation. Previous studies in reeler mice deficient in Reelin focused on the result of the developmental process in fixed tissue sections. It has remained unclear whether Reelin affects the migratory process, migration directionality, or migrating neurons guided by the radial glial scaffold. Moreover, Reelin has been regarded as an attractive signal because newly generated neurons migrate toward the Reelin-containing marginal zone. Conversely, Reelin might be a stop signal because migrating neurons in reeler, but not in wild-type mice, invade the marginal zone. Here, we monitored the migration of newly generated proopiomelanocortin-EGFP-expressing dentate granule cells in slice cultures from reeler, reeler-like mutants and wild type mice of either sex using real-time microscopy. We discovered that not the actual migratory process and migratory speed, but migration directionality of the granule cells is controlled by Reelin. While wild-type granule cells migrated toward the marginal zone of the dentate gyrus, neurons in cultures from reeler and reeler-like mutants migrated randomly in all directions as revealed by vector analyses of migratory trajectories. Moreover, live imaging of granule cells in reeler slices cocultured to wild-type dentate gyrus showed that the reeler neurons changed their directions and migrated toward the Reelin-containing marginal zone of the wild-type culture, thus forming a compact granule cell layer. In contrast, directed migration was not observed when Reelin was ubiquitously present in the medium of reeler slices. These results indicate that topographically administered Reelin controls the formation of a granule cell layer.SIGNIFICANCE STATEMENT Neuronal migration and the various factors controlling its onset, speed, directionality, and arrest are poorly understood. Slice cultures offer a unique model to study the migration of individual neurons in an almost natural environment. In the present study, we took advantage of the expression of proopiomelanocortin-EGFP by newly generated, migrating granule cells to analyze their migratory trajectories in hippocampal slice cultures from wild-type mice and mutants deficient in Reelin signaling. We show that the compartmentalized presence of Reelin is essential for the directionality, but not the actual migratory process or speed, of migrating granule cells leading to their characteristic lamination in the dentate gyrus. PMID- 29138280 TI - Foxp1 regulation of neonatal vocalizations via cortical development. AB - The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 are not fully understood. To elucidate the contribution of FOXP1-mediated signaling to brain development and, in particular, neocortical development, we generated forebrain-specific Foxp1 conditional knockout mice. We show that deletion of Foxp1 in the developing forebrain leads to impairments in neonatal vocalizations as well as neocortical cytoarchitectonic alterations via neuronal positioning and migration. Using a genomics approach, we identified the transcriptional networks regulated by Foxp1 in the developing neocortex and found that such networks are enriched for downstream targets involved in neurogenesis and neuronal migration. We also uncovered mechanistic insight into Foxp1 function by demonstrating that sumoylation of Foxp1 during embryonic brain development is necessary for mediating proper interactions between Foxp1 and the NuRD complex. Furthermore, we demonstrated that sumoylation of Foxp1 affects neuronal differentiation and migration in the developing neocortex. Together, these data provide critical mechanistic insights into the function of FOXP1 in the developing neocortex and may reveal molecular pathways at risk in ASD. PMID- 29138283 TI - Frequency of and reasons for paroxysmal nocturnal haemoglobinuria screening in patients with unexplained anaemia. AB - Referral to hematology for anemia is common. In paroxysmal nocturnal hemoglobinuria (PNH), cells deficient in the glycosylphosphatidyl inositol (GPI) anchor are lysed by complement. Eculizumab improves overall survival and quality of life while reducing hemolysis, transfusion requirements, and thrombosis. We evaluated the frequency of screening for PNH in patients with unexplained anemia. Key clinical features, laboratory data, and investigations were recorded for patients referred for anemia since 2010, without a specific cause found. PNH testing was done by flow cytometry. 540 patients had: anemia not yet diagnosed (NYD, n=318 (including unexplained iron deficiency, n=92; DAT-negative hemolysis, n=9)); anemia of chronic disease, n=173; and pancytopenia NYD, n=49. 82.4% had LDH testing done; 85.0% total bilirubin; 78.7% reticulocyte counts; and 40.6% haptoglobin level; 131 (24.2%) had possible hemolysis. PNH testing was done in 56 (10.4%). Those screened for PNH were more likely to have: younger age (P=0.04); a history of thrombosis (P<0.001); undergone a BMBx (P<0.001); received RBC transfusions (P=0.0018); or evidence of DAT-negative hemolysis (P<0.001). In summary, PNH was tested for in a minority of patients with unexplained anemia (10.4%) despite potential indicators of hemolysis in 24.2%. Increased screening could identify patients who would benefit from treatment and should be considered. PMID- 29138273 TI - Impact of Excessive Weight Gain on Cardiovascular Outcomes in Type 1 Diabetes: Results From the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. AB - OBJECTIVE: Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS: Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS: The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1-3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1-3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1-3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS: For the first 13 years after DCCT, INT for type 1 diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events. PMID- 29138284 TI - Rapid diagnosis of pulmonary tuberculosis and detection of drug resistance by combined simultaneous amplification testing and reverse dot blot. AB - AIMS: Making a correct and rapid diagnosis is essential for managing pulmonary tuberculosis (PTB), particularly multidrug-resistant tuberculosis. We aimed to evaluate the efficacy of the combination of simultaneous amplification testing (SAT) and reverse dot blot (RDB) for the rapid detection of Mycobacterium tuberculosis (MTB) and drug-resistant mutants in respiratory samples. METHODS: 225 suspected PTB and 32 non-TB pulmonary disease samples were collected. All sputum samples were sent for acid-fast bacilli smear, SAT, culture and drug susceptibility testing (DST) by the BACTECTM MGITTM 960 system. 53 PTB samples were tested by both RDB and DNA sequencing to identify drug resistance genes and mutated sites. RESULTS: The SAT positive rate (64.9%) was higher than the culture positive rate (55.1%), with a coincidence rate of 83.7%. The sensitivity and specificity of SAT for diagnosing PTB were 66.7% and 100%, respectively, while those for culture were 53.9% and 84.2%, respectively. RDB has high sensitivity and specificity in identifying drug resistance genes and mutated sites. The results of RDB correlated well with those of DST and DNA sequencing, with coincidence rates of 92.5% and 98.1%, respectively. CONCLUSIONS: The combination of SAT and RDB is promising for rapidly detecting PTB and monitoring drug resistance in clinical laboratories. PMID- 29138285 TI - Expression and prognostic significance of human epidermal growth factor receptors 1, 2 and 3 in oesophageal and gastric adenocarcinomas preneoadjuvant and postneoadjuvant treatment. AB - AIMS: Neoadjuvant treatment has now become the standard of care for oesophageal and gastric cancer. The aim of this study was to investigate the influence of neoadjuvant therapy on the expression of human epidermal growth factor receptor 1 (HER1/EGFR), HER2 and HER3, in oesophageal and gastric adenocarcinoma. METHODS: Immunohistochemical expression of EGFR, HER2 and HER3 was examined and compared in pretreatment biopsies, post-treatment surgical resection specimens and metastases in a retrospective cohort of 166 patients with adenocarcinoma of the oesophagus or stomach. The relationship between expression of the investigative markers and histopathological response to neoadjuvant treatment, overall survival (OS) and recurrence free survival (RFS) was analysed. RESULTS: Conversion of protein expression between pretreatment biopsy and post-treatment surgical resection was seen in 4.6% of the cases for EGFR, 5.9% for HER2% and 19.4% for HER3. Histopathological response to neoadjuvant treatment was significantly and stepwise associated with OS and RFS . High HER3 protein expression in post treatment surgical resection specimens was significantly associated with a prolonged OS in univariable analysis (HR=0.39; 95% CI 0.17 to 0.93), but did not remain significant in multivariable analysis. Expression of EGFR and HER2 in post treatment surgical resection specimens was not prognostic. No correlation between pretreatment HER-protein expression and histopathological response was seen. CONCLUSIONS: The results from this study underscore the need for further studies on the influence of neoadjuvant treatment on biomarker expression, as this may influence treatment strategy as well as prognosis. Histopathological response is validated as a useful prognostic factor. PMID- 29138287 TI - Clopidogrel Carboxylic Acid Glucuronidation is Mediated Mainly by UGT2B7, UGT2B4, and UGT2B17: Implications for Pharmacogenetics and Drug-Drug Interactions . AB - The antiplatelet drug clopidogrel is metabolized to an acyl-beta-d-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl-beta-d-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLMs and HIMs, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers. UGT2B7 and UGT2B17 exhibited the greatest level of clopidogrel carboxylic acid glucuronidation activities, with a CLint,u of 2.42 and 2.82 ul?min-1?mg-1, respectively. Of other enzymes displaying activity (UGT1A3, UGT1A9, UGT1A10-H, and UGT2B4), UGT2B4 (CLint,u 0.51 ul?min-1?mg-1) was estimated to contribute significantly to the hepatic clearance. Nonselective UGT2B inhibitors strongly inhibited clopidogrel acyl-beta-d-glucuronide formation in HLMs and HIMs. The UGT2B17 inhibitor imatinib and the UGT2B7 and UGT1A9 inhibitor mefenamic acid inhibited clopidogrel carboxylic acid glucuronidation in HIMs and HLMs, respectively. Incubation of clopidogrel carboxylic acid in HLMs with UDPGA and NADPH resulted in strong inhibition of CYP2C8 activity. In healthy volunteers, the UGT2B17*2 deletion allele was associated with a 10% decrease per copy in the plasma clopidogrel acyl-beta-d-glucuronide to clopidogrel carboxylic acid area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4) ratio (P < 0.05). To conclude, clopidogrel carboxylic acid is metabolized mainly by UGT2B7 and UGT2B4 in the liver and by UGT2B17 in the small intestinal wall. The formation of clopidogrel acyl-beta-d-glucuronide is impaired in carriers of the UGT2B17 deletion. These findings may have implications regarding the intracellular mechanisms leading to CYP2C8 inactivation by clopidogrel. PMID- 29138288 TI - Fibroblast growth factors: key players in regeneration and tissue repair. AB - Tissue injury initiates a complex repair process, which in some organisms can lead to the complete regeneration of a tissue. In mammals, however, the repair of most organs is imperfect and results in scar formation. Both regeneration and repair are orchestrated by a highly coordinated interplay of different growth factors and cytokines. Among the key players are the fibroblast growth factors (FGFs), which control the migration, proliferation, differentiation and survival of different cell types. In addition, FGFs influence the expression of other factors involved in the regenerative response. Here, we summarize current knowledge on the roles of endogenous FGFs in regeneration and repair in different organisms and in different tissues and organs. Gaining a better understanding of these FGF activities is important for appropriate modulation of FGF signaling after injury to prevent impaired healing and to promote organ regeneration in humans. PMID- 29138286 TI - Transporter Expression in Noncancerous and Cancerous Liver Tissue from Donors with Hepatocellular Carcinoma and Chronic Hepatitis C Infection Quantified by LC MS/MS Proteomics. AB - Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs, and P-gp) in cancerous (C, n = 8) and adjacent noncancerous (NC, n = 33) liver tissues obtained from patients with chronic hepatitis C with hepatocellular carcinoma (HCV-HCC) were quantified by LC-MS/MS proteomics. Herein, we compare our results with our previous data from noninfected, noncirrhotic (control, n = 36) and HCV-cirrhotic (n = 30) livers. The amount of membrane protein yielded from NC and C HCV-HCC tissues decreased (31%, 67%) relative to control livers. In comparison with control livers, with the exception of NTCP, MRP2, and MATE1, transporter expression decreased in NC (38%-76%) and C (56%-96%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP expression increased (113%), MATE1 expression decreased (58%), and MRP2 expression was unchanged relative to control livers. In C HCV-HCC tissues, NTCP and MRP2 expression decreased (63%, 56%) and MATE1 expression was unchanged relative to control livers. Compared with HCV-cirrhotic livers, aside from NTCP, OCT1, BSEP, and MRP2, transporter expression decreased in NC (41%-71%) and C (54%-89%) HCV HCC tissues. In NC HCV-HCC tissues, NTCP and MRP2 expression increased (362%, 142%), whereas OCT1 and BSEP expression was unchanged. In C HCV-HCC tissues, OCT1 and BSEP expression decreased (90%, 80%) relative to HCV-cirrhotic livers, whereas NTCP and MRP2 expression was unchanged. Expression of OATP2B1, BSEP, MRP2, and MRP3 decreased (56%-72%) in C HCV-HCC tissues in comparison with matched NC tissues (n = 8), but the expression of other transporters was unchanged. These data will be helpful in the future to predict transporter mediated hepatocellular drug concentrations in patients with HCV-HCC. PMID- 29138289 TI - The evolution of cortical development: the synapsid-diapsid divergence. AB - The cerebral cortex covers the rostral part of the brain and, in higher mammals and particularly humans, plays a key role in cognition and consciousness. It is populated with neuronal cell bodies distributed in radially organized layers. Understanding the common and lineage-specific molecular mechanisms that orchestrate cortical development and evolution are key issues in neurobiology. During evolution, the cortex appeared in stem amniotes and evolved divergently in two main branches of the phylogenetic tree: the synapsids (which led to present day mammals) and the diapsids (reptiles and birds). Comparative studies in organisms that belong to those two branches have identified some common principles of cortical development and organization that are possibly inherited from stem amniotes and regulated by similar molecular mechanisms. These comparisons have also highlighted certain essential features of mammalian cortices that are absent or different in diapsids and that probably evolved after the synapsid-diapsid divergence. Chief among these is the size and multi-laminar organization of the mammalian cortex, and the propensity to increase its area by folding. Here, I review recent data on cortical neurogenesis, neuronal migration and cortical layer formation and folding in this evolutionary perspective, and highlight important unanswered questions for future investigation. PMID- 29138291 TI - Correction: The many faces of hematopoietic stem cell heterogeneity. Development doi: 10.1242/dev.114231. PMID- 29138292 TI - Impact of Regionalization of ST-Segment-Elevation Myocardial Infarction Care on Treatment Times and Outcomes for Emergency Medical Services-Transported Patients Presenting to Hospitals With Percutaneous Coronary Intervention: Mission: Lifeline Accelerator-2. AB - BACKGROUND: Regional variations in reperfusion times and mortality in patients with ST-segment-elevation myocardial infarction are influenced by differences in coordinating care between emergency medical services (EMS) and hospitals. Building on the Accelerator-1 Project, we hypothesized that time to reperfusion could be further reduced with enhanced regional efforts. METHODS: Between April 2015 and March 2017, we worked with 12 metropolitan regions across the United States with 132 percutaneous coronary intervention-capable hospitals and 946 EMS agencies. Data were collected in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network)-Get With The Guidelines Registry for quarterly Mission: Lifeline reports. The primary end point was the change in the proportion of EMS-transported patients with first medical contact to device time <=90 minutes from baseline to final quarter. We also compared treatment times and mortality with patients treated in hospitals not participating in the project during the corresponding time period. RESULTS: During the study period, 10 730 patients were transported to percutaneous coronary intervention-capable hospitals, including 974 in the baseline quarter and 972 in the final quarter who met inclusion criteria. Median age was 61 years; 27% were women, 6% had cardiac arrest, and 6% had shock on admission; 10% were black, 12% were Latino, and 10% were uninsured. By the end of the intervention, all process measures reflecting coordination between EMS and hospitals had improved, including the proportion of patients with a first medical contact to device time of <=90 minutes (67%-74%; P<0.002), a first medical contact to device time to catheterization laboratory activation of <=20 minutes (38%-56%; P<0.0001), and emergency department dwell time of <=20 minutes (33%-43%; P<0.0001). Of the 12 regions, 9 regions reduced first medical contact to device time, and 8 met or exceeded the national goal of 75% of patients treated in <=90 minutes. Improvements in treatment times corresponded with a significant reduction in mortality (in-hospital death, 4.4% 2.3%; P=0.001) that was not apparent in hospitals not participating in the project during the same time period. CONCLUSIONS: Organization of care among EMS and hospitals in 12 regions was associated with significant reductions in time to reperfusion in patients with ST-segment-elevation myocardial infarction as well as in in-hospital mortality. These findings support a more intensive regional approach to emergency care for patients with ST-segment-elevation myocardial infarction. PMID- 29138290 TI - Developing a sense of touch. AB - The sensation of touch is mediated by mechanosensory neurons that are embedded in skin and relay signals from the periphery to the central nervous system. During embryogenesis, axons elongate from these neurons to make contact with the developing skin. Concurrently, the epithelium of skin transforms from a homogeneous tissue into a heterogeneous organ that is made up of distinct layers and microdomains. Throughout this process, each neuronal terminal must form connections with an appropriate skin region to serve its function. This Review presents current knowledge of the development of the sensory microdomains in mammalian skin and the mechanosensory neurons that innervate them. PMID- 29138293 TI - ICare-ACS (Improving Care Processes for Patients With Suspected Acute Coronary Syndrome): A Study of Cross-System Implementation of a National Clinical Pathway. AB - BACKGROUND: Efforts to safely reduce length of stay for emergency department patients with symptoms suggestive of acute coronary syndrome (ACS) have had mixed success. Few system-wide efforts affecting multiple hospital emergency departments have ever been evaluated. We evaluated the effectiveness of a nationwide implementation of clinical pathways for potential ACS in disparate hospitals. METHODS: This was a multicenter pragmatic stepped-wedge before-and after trial in 7 New Zealand acute care hospitals with 31 332 patients investigated for suspected ACS with serial troponin measurements. The implementation was a clinical pathway for the assessment of patients with suspected ACS that included a clinical pathway document in paper or electronic format, structured risk stratification, specified time points for electrocardiographic and serial troponin testing within 3 hours of arrival, and directions for combining risk stratification and electrocardiographic and troponin testing in an accelerated diagnostic protocol. Implementation was monitored for >4 months and compared with usual care over the preceding 6 months. The main outcome measure was the odds of discharge within 6 hours of presentation RESULTS: There were 11 529 participants in the preimplementation phase (range, 284-3465) and 19 803 in the postimplementation phase (range, 395-5039). Overall, the mean 6-hour discharge rate increased from 8.3% (range, 2.7%-37.7%) to 18.4% (6.8%-43.8%). The odds of being discharged within 6 hours increased after clinical pathway implementation. The odds ratio was 2.4 (95% confidence interval, 2.3-2.6). In patients without ACS, the median length of hospital stays decreased by 2.9 hours (95% confidence interval, 2.4-3.4). For patients discharged within 6 hours, there was no change in 30-day major adverse cardiac event rates (0.52% versus 0.44%; P=0.96). In these patients, no adverse event occurred when clinical pathways were correctly followed. CONCLUSIONS: Implementation of clinical pathways for suspected ACS reduced the length of stay and increased the proportions of patients safely discharged within 6 hours. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au/ (Australian and New Zealand Clinical Trials Registry). Unique identifier: ACTRN12617000381381. PMID- 29138294 TI - Isolation of isoform-specific binding proteins (Affimers) by phage display using negative selection. AB - Some 30 years after its discovery, phage display remains one of the most widely used methods of in vitro selection. Initially developed to revolutionize the generation of therapeutic antibodies, phage display is now the first choice for screening artificial binding proteins. Artificial binding proteins can be used as reagents to study protein-protein interactions, target posttranslational modifications, and distinguish between homologous proteins. They can also be used as research and affinity reagents, for diagnostic purposes, and as therapeutics. However, the ability to identify isoform-specific reagents remains highly challenging. We describe an adapted phage display protocol using an artificial binding protein (Affimer) for the selection of isoform-selective binding proteins. PMID- 29138295 TI - Generation of specific inhibitors of SUMO-1- and SUMO-2/3-mediated protein protein interactions using Affimer (Adhiron) technology. AB - Because protein-protein interactions underpin most biological processes, developing tools that target them to understand their function or to inform the development of therapeutics is an important task. SUMOylation is the posttranslational covalent attachment of proteins in the SUMO family (SUMO-1, SUMO-2, or SUMO-3), and it regulates numerous cellular pathways. SUMOylated proteins are recognized by proteins with SUMO-interaction motifs (SIMs) that facilitate noncovalent interactions with SUMO. We describe the use of the Affimer system of peptide display for the rapid isolation of synthetic binding proteins that inhibit SUMO-dependent protein-protein interactions mediated by SIMs both in vitro and in cells. Crucially, these synthetic proteins did not prevent SUMO conjugation either in vitro or in cell-based systems, enabling the specific analysis of SUMO-mediated protein-protein interactions. Furthermore, through structural analysis and molecular modeling, we explored the molecular mechanisms that may underlie their specificity in interfering with either SUMO-1-mediated interactions or interactions mediated by either SUMO-2 or SUMO-3. Not only will these reagents enable investigation of the biological roles of SUMOylation, but the Affimer technology used to generate these synthetic binding proteins could also be exploited to design or validate reagents or therapeutics that target other protein-protein interactions. PMID- 29138296 TI - The genetics of PKMzeta and memory maintenance. AB - Elucidating the molecular mechanisms that maintain long-term memory is a fundamental goal of neuroscience. Accumulating evidence suggests that persistent signaling by the atypical protein kinase C (PKC) isoform protein kinase Mzeta (PKMzeta) might maintain synaptic long-term potentiation (LTP) and long-term memory. However, the role of PKMzeta has been challenged by genetic data from PKMzeta-knockout mice showing intact LTP and long-term memory. Moreover, the PKMzeta inhibitor peptide zeta inhibitory peptide (ZIP) reverses LTP and erases memory in both wild-type and knockout mice. Data from four papers using additional isoform-specific genetic approaches have helped to reconcile these conflicting findings. First, a PKMzeta-antisense approach showed that LTP and long-term memory in PKMzeta-knockout mice are mediated through a compensatory mechanism that depends on another ZIP-sensitive atypical isoform, PKCiota/lambda. Second, short hairpin RNAs decreasing the amounts of individual atypical isoforms without inducing compensation disrupted memory in different temporal phases. PKCiota/lambda knockdown disrupted short-term memory, whereas PKMzeta knockdown specifically erased long-term memory. Third, conditional PKCiota/lambda knockout induced compensation by rapidly activating PKMzeta to preserve short-term memory. Fourth, a dominant-negative approach in the model system Aplysia revealed that multiple PKCs form PKMs to sustain different types of long-term synaptic facilitation, with atypical PKM maintaining synaptic plasticity similar to LTP. Thus, under physiological conditions, PKMzeta is the principal PKC isoform that maintains LTP and long-term memory. PKCiota/lambda can compensate for PKMzeta, and because other isoforms could also maintain synaptic facilitation, there may be a hierarchy of compensatory mechanisms maintaining memory if PKMzeta malfunctions. PMID- 29138297 TI - MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia. AB - Activating mutations in the gene encoding the cell-cell contact signaling protein Notch1 are common in human T cell acute lymphoblastic leukemias (T-ALLs). However, expressing Notch1 mutant alleles in mice fails to efficiently induce the development of leukemia. We performed a gain-of-function screen to identify proteins that enhanced signaling by leukemia-associated Notch1 mutants. The transcription factors MAFB and ETS2 emerged as candidates that individually enhanced Notch1 signaling, and when coexpressed, they synergistically increased signaling to an extent similar to that induced by core components of the Notch transcriptional complex. In mouse models of T-ALL, MAFB enhanced leukemogenesis by the naturally occurring Notch1 mutants, decreased disease latency, and increased disease penetrance. Decreasing MAFB abundance in mouse and human T-ALL cells reduced the expression of Notch1 target genes, including MYC and HES1, and sustained MAFB knockdown impaired T-ALL growth in a competitive setting. MAFB bound to ETS2 and interacted with the acetyltransferases PCAF and P300, highlighting its importance in recruiting coactivators that enhance Notch1 signaling. Together, these data identify a mechanism for enhancing the oncogenic potential of weak Notch1 mutants in leukemia models, and they reveal the MAFB ETS2 transcriptional axis as a potential therapeutic target in T-ALL. PMID- 29138298 TI - First Insights into the Diverse Human Archaeome: Specific Detection of Archaea in the Gastrointestinal Tract, Lung, and Nose and on Skin. AB - Human-associated archaea remain understudied in the field of microbiome research, although in particular methanogenic archaea were found to be regular commensals of the human gut, where they represent keystone species in metabolic processes. Knowledge on the abundance and diversity of human-associated archaea is extremely limited, and little is known about their function(s), their overall role in human health, or their association with parts of the human body other than the gastrointestinal tract and oral cavity. Currently, methodological issues impede the full assessment of the human archaeome, as bacteria-targeting protocols are unsuitable for characterization of the full spectrum of Archaea The goal of this study was to establish conservative protocols based on specifically archaea targeting, PCR-based methods to retrieve first insights into the archaeomes of the human gastrointestinal tract, lung, nose, and skin. Detection of Archaea was highly dependent on primer selection and the sequence processing pipeline used. Our results enabled us to retrieve a novel picture of the human archaeome, as we found for the first time Methanobacterium and Woesearchaeota (DPANN superphylum) to be associated with the human gastrointestinal tract and the human lung, respectively. Similar to bacteria, human-associated archaeal communities were found to group biogeographically, forming (i) the thaumarchaeal skin landscape, (ii) the (methano)euryarchaeal gastrointestinal tract, (iii) a mixed skin gastrointestinal tract landscape for the nose, and (iv) a woesearchaeal lung landscape. On the basis of the protocols we used, we were able to detect unexpectedly high diversity of archaea associated with different body parts.IMPORTANCE In summary, our study highlights the importance of the primers and data processing pipeline used to study the human archaeome. We were able to establish protocols that revealed the presence of previously undetected Archaea in all of the tissue samples investigated and to detect biogeographic patterns of the human archaeome in the gastrointestinal tract and on the skin and for the first time in the respiratory tract, i.e., the nose and lungs. Our results are a solid basis for further investigation of the human archaeome and, in the long term, discovery of the potential role of archaea in human health and disease. PMID- 29138299 TI - Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent. AB - Although viruses and viral capsids induce rapid immune responses, little is known about viral pathogen-associated molecular patterns (PAMPs) that are exhibited on their surface. Here, we demonstrate that the repeating protein subunit pattern common to most virus capsids is a molecular pattern that induces a Toll-like receptor-2 (TLR2)-dependent antiviral immune response. This early antiviral immune response regulates the clearance of subsequent bacterial superinfections, which are a primary cause of morbidities associated with influenza virus infections. Utilizing this altered susceptibility to subsequent bacterial challenge as an outcome, we determined that multiple unrelated, empty, and replication-deficient capsids initiated early TLR2-dependent immune responses, similar to intact influenza virus or murine pneumovirus. These TLR2-mediated responses driven by the capsid were not dependent upon the capsid's shape, size, origin, or amino acid sequence. However, they were dependent upon the multisubunit arrangement of the capsid proteins, because unlike intact capsids, individual capsid subunits did not enhance bacterial clearance. Further, we demonstrated that even a linear microfilament protein built from repeating protein subunits (F-actin), but not its monomer (G-actin), induced similar kinetics of subsequent bacterial clearance as did virus capsid. However, although capsids and F-actin induced similar bacterial clearance, in macrophages they required distinct TLR2 heterodimers for this response (TLR2/6 or TLR2/1, respectively) and different phagocyte populations were involved in the execution of these responses in vivo Our results demonstrate that TLR2 responds to invading viral particles that are composed of repeating protein subunits, indicating that this common architecture of virus capsids is a previously unrecognized molecular pattern.IMPORTANCE Rapid and precise pathogen identification is critical for the initiation of pathogen-specific immune responses and pathogen clearance. Bacteria and fungi express common molecular patterns on their exteriors that are recognized by cell surface-expressed host pattern recognition receptors (PRRs) prior to infection. In contrast, viral molecular patterns are primarily nucleic acids, which are recognized after virus internalization. We found that an initial antiviral immune response is induced by the repeating subunit pattern of virus exteriors (capsids), and thus, induction of this response is independent of viral infection. This early response to viral capsids required the cell surface expressed PRR TLR2 and allowed for improved clearance of subsequent bacterial infection that commonly complicates respiratory viral infections. Since the repeating protein subunit pattern is conserved across viral capsids, this suggests that it is not easy for a virus to change without altering fitness. Targeting this vulnerability could lead to development of a universal antiviral vaccine. PMID- 29138300 TI - High Zika Virus Seroprevalence in Salvador, Northeastern Brazil Limits the Potential for Further Outbreaks. AB - During 2015 to 2016, Brazil reported more Zika virus (ZIKV) cases than any other country, yet population exposure remains unknown. Serological studies of ZIKV are hampered by cross-reactive immune responses against heterologous viruses. We conducted serosurveys for ZIKV, dengue virus (DENV), and Chikungunya virus (CHIKV) in 633 individuals prospectively sampled during 2015 to 2016, including microcephaly and non-microcephaly pregnancies, HIV-infected patients, tuberculosis patients, and university staff in Salvador in northeastern Brazil using enzyme-linked immunosorbent assays (ELISAs) and plaque reduction neutralization tests. Sera sampled retrospectively during 2013 to 2015 from 277 HIV-infected patients were used to assess the spread of ZIKV over time. Individuals were georeferenced, and sociodemographic indicators were compared between ZIKV-positive and -negative areas and areas with and without microcephaly cases. Epidemiological key parameters were modeled in a Bayesian framework. ZIKV seroprevalence increased rapidly during 2015 to 2016, reaching 63.3% by 2016 (95% confidence interval [CI], 59.4 to 66.8%), comparable to the seroprevalence of DENV (75.7%; CI, 69.4 to 81.1%) and higher than that of CHIKV (7.4%; CI, 5.6 to 9.8%). Of 19 microcephaly pregnancies, 94.7% showed ZIKV IgG antibodies, compared to 69.3% of 257 non-microcephaly pregnancies (P = 0.017). Analyses of sociodemographic data revealed a higher ZIKV burden in low socioeconomic status (SES) areas. High seroprevalence, combined with case data dynamics allowed estimates of the basic reproduction number R0 of 2.1 (CI, 1.8 to 2.5) at the onset of the outbreak and an effective reproductive number Reff of <1 in subsequent years. Our data corroborate ZIKV-associated congenital disease and an association of low SES and ZIKV infection and suggest that population immunity caused cessation of the outbreak. Similar studies from other areas will be required to determine the fate of the American ZIKV outbreak.IMPORTANCE The ongoing American Zika virus (ZIKV) outbreak involves millions of cases and has a major impact on maternal and child health. Knowledge of infection rates is crucial to project future epidemic patterns and determine the absolute risk of microcephaly upon maternal ZIKV infection during pregnancy. For unknown reasons, the vast majority of ZIKV-associated microcephaly cases are concentrated in northeastern Brazil. We analyzed different subpopulations from Salvador, a Brazilian metropolis representing one of the most affected areas during the American ZIKV outbreak. We demonstrate rapid spread of ZIKV in Salvador, Brazil, and infection rates exceeding 60%. We provide evidence for the link between ZIKV and microcephaly, report that ZIKV predominantly affects geographic areas with low socioeconomic status, and show that population immunity likely caused cessation of the outbreak. Our results enable stakeholders to identify target populations for vaccination and for trials on vaccine efficacy and allow refocusing of research efforts and intervention strategies. PMID- 29138301 TI - Genomic Variation and Evolution of Vibrio parahaemolyticus ST36 over the Course of a Transcontinental Epidemic Expansion. AB - Vibrio parahaemolyticus is the leading cause of seafood-related infections with illnesses undergoing a geographic expansion. In this process of expansion, the most fundamental change has been the transition from infections caused by local strains to the surge of pandemic clonal types. Pandemic clone sequence type 3 (ST3) was the only example of transcontinental spreading until 2012, when ST36 was detected outside the region where it is endemic in the U.S. Pacific Northwest causing infections along the U.S. northeast coast and Spain. Here, we used genome wide analyses to reconstruct the evolutionary history of the V. parahaemolyticus ST36 clone over the course of its geographic expansion during the previous 25 years. The origin of this lineage was estimated to be in ~1985. By 1995, a new variant emerged in the region and quickly replaced the old clone, which has not been detected since 2000. The new Pacific Northwest (PNW) lineage was responsible for the first cases associated with this clone outside the Pacific Northwest region. After several introductions into the northeast coast, the new PNW clone differentiated into a highly dynamic group that continues to cause illness on the northeast coast of the United States. Surprisingly, the strains detected in Europe in 2012 diverged from this ancestral group around 2000 and have conserved genetic features present only in the old PNW lineage. Recombination was identified as the major driver of diversification, with some preliminary observations suggesting a trend toward a more specialized lifestyle, which may represent a critical element in the expansion of epidemics under scenarios of coastal warming.IMPORTANCEVibrio parahaemolyticus and Vibrio cholerae represent the only two instances of pandemic expansions of human pathogens originating in the marine environment. However, while the current pandemic of V. cholerae emerged more than 50 years ago, the global expansion of V. parahaemolyticus is a recent phenomenon. These modern expansions provide an exceptional opportunity to study the evolutionary process of these pathogens at first hand and gain an understanding of the mechanisms shaping the epidemic dynamics of these diseases, in particular, the emergence, dispersal, and successful introduction in new regions facilitating global spreading of infections. In this study, we used genomic analysis to examine the evolutionary divergence that has occurred over the course of the most recent transcontinental expansion of a pathogenic Vibrio, the spreading of the V. parahaemolyticus sequence type 36 clone from the region where it is endemic on the Pacific coast of North America to the east coast of the United States and finally to the west coast of Europe. PMID- 29138302 TI - Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology. AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus responsible for several significant outbreaks of debilitating acute and chronic arthritis and arthralgia over the past decade. These include a recent outbreak in the Caribbean islands and the Americas that caused more than 1 million cases of viral arthralgia. Despite the major impact of CHIKV on global health, viral determinants that promote CHIKV-induced disease are incompletely understood. Most CHIKV strains contain a conserved opal stop codon at the end of the viral nsP3 gene. However, CHIKV strains that encode an arginine codon in place of the opal stop codon have been described, and deep-sequencing analysis of a CHIKV isolate from the Caribbean identified both arginine and opal variants within this strain. Therefore, we hypothesized that the introduction of the arginine mutation in place of the opal termination codon may influence CHIKV virulence. We tested this by introducing the arginine mutation into a well-characterized infectious clone of a CHIKV strain from Sri Lanka and designated this virus Opal524R. This mutation did not impair viral replication kinetics in vitro or in vivo Despite this, the Opal524R virus induced significantly less swelling, inflammation, and damage within the feet and ankles of infected mice. Further, we observed delayed induction of proinflammatory cytokines and chemokines, as well as reduced CD4+ T cell and NK cell recruitment compared to those in the parental strain. Therefore, the opal termination codon plays an important role in CHIKV pathogenesis, independently of effects on viral replication.IMPORTANCE Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes significant outbreaks of viral arthralgia. Studies with CHIKV and other alphaviruses demonstrated that the opal termination codon within nsP3 is highly conserved. However, some strains of CHIKV and other alphaviruses contain mutations in the opal termination codon. These mutations alter the virulence of related alphaviruses in mammalian and mosquito hosts. Here, we report that a clinical isolate of a CHIKV strain from the recent outbreak in the Caribbean islands contains a mixture of viruses encoding either the opal termination codon or an arginine mutation. Mutating the opal stop codon to an arginine residue attenuates CHIKV-induced disease in a mouse model. Compared to infection with the opal-containing parental virus, infection with the arginine mutant causes limited swelling and inflammation, as well as dampened recruitment of immune mediators of pathology, including CD4+ T cells and NK cells. We propose that the opal termination codon plays an essential role in the induction of severe CHIKV disease. PMID- 29138303 TI - CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram Negative Pathogens. AB - The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae and colistin-resistant members of the family Enterobacteriaceae that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine modified lipid A. Colistin-resistant K. pneumoniae isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing 4-amino-4-deoxy-l-arabinose modified lipid A were also found to be susceptible to chemokine-mediated antimicrobial activity. However, loss of PhoP/PhoQ autoregulatory control, caused by disruption of the gene encoding the negative regulator MgrB, limited the bactericidal effects of CXCL9 and CXCL10 in a variable, strain-specific manner. Cumulatively, these findings provide mechanistic insight into chemokine-mediated antimicrobial activity, highlight disparities amongst determinants of colistin resistance, and suggest that chemokine-mediated bactericidal effects merit additional investigation as a therapeutic avenue for treating infections caused by multidrug-resistant pathogens.IMPORTANCE As bacterial pathogens become resistant to multiple antibiotics, the infections they cause become increasingly difficult to treat. Carbapenem antibiotics provide an essential clinical barrier against multidrug-resistant bacteria; however, the dissemination of bacterial enzymes capable of inactivating carbapenems threatens the utility of these important antibiotics. Compounding this concern is the global spread of bacteria invulnerable to colistin, a polymyxin antibiotic considered to be a last line of defense against carbapenem-resistant pathogens. As the effectiveness of existing antibiotics erodes, it is critical to develop innovative antimicrobial therapies. To this end, we demonstrate that the chemokines CXCL9 and CXCL10 kill the most concerning carbapenem- and colistin-resistant pathogens. Our findings provide a unique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant "superbugs." PMID- 29138304 TI - Refactoring the Genetic Code for Increased Evolvability. AB - The standard genetic code is robust to mutations during transcription and translation. Point mutations are likely to be synonymous or to preserve the chemical properties of the original amino acid. Saturation mutagenesis experiments suggest that in some cases the best-performing mutant requires replacement of more than a single nucleotide within a codon. These replacements are essentially inaccessible to common error-based laboratory engineering techniques that alter a single nucleotide per mutation event, due to the extreme rarity of adjacent mutations. In this theoretical study, we suggest a radical reordering of the genetic code that maximizes the mutagenic potential of single nucleotide replacements. We explore several possible genetic codes that allow a greater degree of accessibility to the mutational landscape and may result in a hyperevolvable organism that could serve as an ideal platform for directed evolution experiments. We then conclude by evaluating the challenges of constructing such recoded organisms and their potential applications within the field of synthetic biology.IMPORTANCE The conservative nature of the genetic code prevents bioengineers from efficiently accessing the full mutational landscape of a gene via common error-prone methods. Here, we present two computational approaches to generate alternative genetic codes with increased accessibility. These new codes allow mutational transitions to a larger pool of amino acids and with a greater extent of chemical differences, based on a single nucleotide replacement within the codon, thus increasing evolvability both at the single gene and at the genome levels. Given the widespread use of these techniques for strain and protein improvement, along with more fundamental evolutionary biology questions, the use of recoded organisms that maximize evolvability should significantly improve the efficiency of directed evolution, library generation, and fitness maximization. PMID- 29138305 TI - Manipulating the Bacterial Cell Cycle and Cell Size by Titrating the Expression of Ribonucleotide Reductase. AB - Understanding how bacteria coordinate growth with cell cycle events to maintain cell size homeostasis remains a grand challenge in biology. The period of chromosome replication (C period) is a key stage in the bacterial cell cycle. However, the mechanism of in vivo regulation of the C period remains unclear. In this study, we found that titration of the expression of ribonucleotide reductase (RNR), which changes the intracellular deoxynucleoside triphosphate (dNTP) pools, enables significant perturbations of the C period, leading to a substantial change in cell size and DNA content. Our work demonstrates that the intracellular dNTP pool is indeed an important parameter that controls the progression of chromosome replication. Specially, RNR overexpression leads to a shortened C period compared with that of a wild-type strain growing under different nutrient conditions, indicating that the dNTP substrate levels are subsaturated under physiological conditions. In addition, perturbing the C period does not significantly change the D period, indicating that these two processes are largely independent from each other. Overall, titration of ribonucleotide reductase expression can serve as a standard model system for studying the coordination between chromosome replication, cell division, and cell size.IMPORTANCE Bacteria must coordinate growth with cell cycle progression to maintain cell size hemostasis. Cell cycle and cell size regulation is a fundamental concern in biology. The period required for chromosome replication (the C period) is a key stage in the bacterial cell cycle. However, how the C period is controlled in vivo remains largely an open question in this field of bacterial cell cycle regulation. Through introducing a genetic circuit into Escherichia coli for titrating the expression of ribonucleotide reductase, we achieve substantial perturbation of the C period and cell size. Our work demonstrates that the intracellular dNTP pool is an important parameter that controls the progression of chromosome replication. Moreover, our work indicates that bacterial cells manage to maintain subsaturated dNTP levels under different nutrient conditions, leading to a submaximal speed of DNA replication fork movement. PMID- 29138306 TI - Key Metabolites and Mechanistic Changes for Salt Tolerance in an Experimentally Evolved Sulfate-Reducing Bacterium, Desulfovibrio vulgaris. AB - Rapid genetic and phenotypic adaptation of the sulfate-reducing bacterium Desulfovibrio vulgaris Hildenborough to salt stress was observed during experimental evolution. In order to identify key metabolites important for salt tolerance, a clone, ES10-5, which was isolated from population ES10 and allowed to experimentally evolve under salt stress for 5,000 generations, was analyzed and compared to clone ES9-11, which was isolated from population ES9 and had evolved under the same conditions for 1,200 generations. These two clones were chosen because they represented the best-adapted clones among six independently evolved populations. ES10-5 acquired new mutations in genes potentially involved in salt tolerance, in addition to the preexisting mutations and different mutations in the same genes as in ES9-11. Most basal abundance changes of metabolites and phospholipid fatty acids (PLFAs) were lower in ES10-5 than ES9 11, but an increase of glutamate and branched PLFA i17:1omega9c under high salinity conditions was persistent. ES9-11 had decreased cell motility compared to the ancestor; in contrast, ES10-5 showed higher cell motility under both nonstress and high-salinity conditions. Both genotypes displayed better growth energy efficiencies than the ancestor under nonstress or high-salinity conditions. Consistently, ES10-5 did not display most of the basal transcriptional changes observed in ES9-11, but it showed increased expression of genes involved in glutamate biosynthesis, cation efflux, and energy metabolism under high salinity. These results demonstrated the role of glutamate as a key osmolyte and i17:1omega9c as the major PLFA for salt tolerance in D. vulgaris The mechanistic changes in evolved genotypes suggested that growth energy efficiency might be a key factor for selection.IMPORTANCE High salinity (e.g., elevated NaCl) is a stressor that affects many organisms. Salt tolerance, a complex trait involving multiple cellular pathways, is attractive for experimental evolutionary studies. Desulfovibrio vulgaris Hildenborough is a model sulfate-reducing bacterium (SRB) that is important in biogeochemical cycling of sulfur, carbon, and nitrogen, potentially for bio-corrosion, and for bioremediation of toxic heavy metals and radionuclides. The coexistence of SRB and high salinity in natural habitats and heavy metal-contaminated field sites laid the foundation for the study of salt adaptation of D. vulgaris Hildenborough with experimental evolution. Here, we analyzed a clone that evolved under salt stress for 5,000 generations and compared it to a clone evolved under the same condition for 1,200 generations. The results indicated the key roles of glutamate for osmoprotection and of i17:1omega9c for increasing membrane fluidity during salt adaptation. The findings provide valuable insights about the salt adaptation mechanism changes during long-term experimental evolution. PMID- 29138308 TI - Sex Reporting in Preclinical Microbiological and Immunological Research. AB - Both sex (i.e., biological construct of male and female) and gender (i.e., social construct of masculine and feminine) impact the pathogenesis of diseases, including those caused by microbial infections. Following the 2015 NIH policy for consideration of sex as a biological variable in preclinical research, in 2018, authors of papers published in primary-research American Society for Microbiology (ASM) journals will be asked to report the sex of the research subjects and animals and of materials derived directly from them. To address the need for sex reporting in ASM journals, we systematically reviewed 2,928 primary-research articles published in six primary-research ASM journals (Antimicrobial Agents and Chemotherapy, Clinical and Vaccine Immunology, Infection and Immunity, Journal of Bacteriology, Journal of Virology, and mBio) in 2016. Approximately 37% of animal studies and 9% of primary cell culture papers published in 2016 would have been affected by the new sex-reporting policy. For animal studies (i.e., studies with any nonhuman vertebrate hosts), most published papers either did not report the sex of the animals or used only female animals, and a minority used only males or both sexes. For published studies using primary cells from diverse animal species (i.e., humans and nonhuman vertebrates), almost all studies failed to report the sex of donors from which the cells were isolated. We believe that reporting the sex of animals and even of the donors of derived cells could improve the rigor and reproducibility of research conducted in microbiology and immunology and published in ASM journals. PMID- 29138307 TI - Microdiversity of an Abundant Terrestrial Bacterium Encompasses Extensive Variation in Ecologically Relevant Traits. AB - Much genetic diversity within a bacterial community is likely obscured by microdiversity within operational taxonomic units (OTUs) defined by 16S rRNA gene sequences. However, it is unclear how variation within this microdiversity influences ecologically relevant traits. Here, we employ a multifaceted approach to investigate microdiversity within the dominant leaf litter bacterium, Curtobacterium, which comprises 7.8% of the bacterial community at a grassland site undergoing global change manipulations. We use cultured bacterial isolates to interpret metagenomic data, collected in situ over 2 years, together with lab based physiological assays to determine the extent of trait variation within this abundant OTU. The response of Curtobacterium to seasonal variability and the global change manipulations, specifically an increase in relative abundance under decreased water availability, appeared to be conserved across six Curtobacterium lineages identified at this site. Genomic and physiological analyses in the lab revealed that degradation of abundant polymeric carbohydrates within leaf litter, cellulose and xylan, is nearly universal across the genus, which may contribute to its high abundance in grassland leaf litter. However, the degree of carbohydrate utilization and temperature preference for this degradation varied greatly among clades. Overall, we find that traits within Curtobacterium are conserved at different phylogenetic depths. We speculate that similar to bacteria in marine systems, diverse microbes within this taxon may be structured in distinct ecotypes that are key to understanding Curtobacterium abundance and distribution in the environment.IMPORTANCE Despite the plummeting costs of sequencing, characterizing the fine-scale genetic diversity of a microbial community-and interpreting its functional importance-remains a challenge. Indeed, most studies, particularly studies of soil, assess community composition at a broad genetic level by classifying diversity into taxa (OTUs) defined by 16S rRNA sequence similarity. However, these classifications potentially obscure variation in traits that result in fine-scale ecological differentiation among closely related strains. Here, we investigated "microdiversity" in a highly diverse and poorly characterized soil system (leaf litter in a southern Californian grassland). We focused on the most abundant bacterium, Curtobacterium, which by standard methods is grouped into only one OTU. We find that the degree of carbohydrate usage and temperature preference vary within the OTU, whereas its responses to changes in precipitation are relatively uniform. These results suggest that microdiversity may be key to understanding how soil bacterial diversity is linked to ecosystem functioning. PMID- 29138309 TI - Loss of PopZ At activity in Agrobacterium tumefaciens by Deletion or Depletion Leads to Multiple Growth Poles, Minicells, and Growth Defects. AB - Agrobacterium tumefaciens grows by addition of peptidoglycan (PG) at one pole of the bacterium. During the cell cycle, the cell needs to maintain two different developmental programs, one at the growth pole and another at the inert old pole. Proteins involved in this process are not yet well characterized. To further characterize the role of pole-organizing protein A. tumefaciens PopZ (PopZ At ), we created deletions of the five PopZ At domains and assayed their localization. In addition, we created a popZAt deletion strain (DeltapopZAt ) that exhibited growth and cell division defects with ectopic growth poles and minicells, but the strain is unstable. To overcome the genetic instability, we created an inducible PopZ At strain by replacing the native ribosome binding site with a riboswitch. Cultivated in a medium without the inducer theophylline, the cells look like DeltapopZAt cells, with a branching and minicell phenotype. Adding theophylline restores the wild-type (WT) cell shape. Localization experiments in the depleted strain showed that the domain enriched in proline, aspartate, and glutamate likely functions in growth pole targeting. Helical domains H3 and H4 together also mediate polar localization, but only in the presence of the WT protein, suggesting that the H3 and H4 domains multimerize with WT PopZ At , to stabilize growth pole accumulation of PopZ AtIMPORTANCEAgrobacterium tumefaciens is a rod shaped bacterium that grows by addition of PG at only one pole. The factors involved in maintaining cell asymmetry during the cell cycle with an inert old pole and a growing new pole are not well understood. Here we investigate the role of PopZ At , a homologue of Caulobacter crescentus PopZ (PopZ Cc ), a protein essential in many aspects of pole identity in C. crescentus We report that the loss of PopZ At leads to the appearance of branching cells, minicells, and overall growth defects. As many plant and animal pathogens also employ polar growth, understanding this process in A. tumefaciens may lead to the development of new strategies to prevent the proliferation of these pathogens. In addition, studies of A. tumefaciens will provide new insights into the evolution of the genetic networks that regulate bacterial polar growth and cell division. PMID- 29138310 TI - Sparsity enables estimation of both subcortical and cortical activity from MEG and EEG. AB - Subcortical structures play a critical role in brain function. However, options for assessing electrophysiological activity in these structures are limited. Electromagnetic fields generated by neuronal activity in subcortical structures can be recorded noninvasively, using magnetoencephalography (MEG) and electroencephalography (EEG). However, these subcortical signals are much weaker than those generated by cortical activity. In addition, we show here that it is difficult to resolve subcortical sources because distributed cortical activity can explain the MEG and EEG patterns generated by deep sources. We then demonstrate that if the cortical activity is spatially sparse, both cortical and subcortical sources can be resolved with M/EEG. Building on this insight, we develop a hierarchical sparse inverse solution for M/EEG. We assess the performance of this algorithm on realistic simulations and auditory evoked response data, and show that thalamic and brainstem sources can be correctly estimated in the presence of cortical activity. Our work provides alternative perspectives and tools for characterizing electrophysiological activity in subcortical structures in the human brain. PMID- 29138311 TI - Intrusion and extrusion of water in hydrophobic nanopores. AB - Heterogeneous systems composed of hydrophobic nanoporous materials and water are capable, depending on their characteristics, of efficiently dissipating (dampers) or storing ("molecular springs") energy. However, it is difficult to predict their properties based on macroscopic theories-classical capillarity for intrusion and classical nucleation theory (CNT) for extrusion-because of the peculiar behavior of water in extreme confinement. Here we use advanced molecular dynamics techniques to shed light on these nonclassical effects, which are often difficult to investigate directly via experiments, owing to the reduced dimensions of the pores. The string method in collective variables is used to simulate, without artifacts, the microscopic mechanism of water intrusion and extrusion in the pores, which are thermally activated, rare events. Simulations reveal three important nonclassical effects: the nucleation free-energy barriers are reduced eightfold compared with CNT, the intrusion pressure is increased due to nanoscale confinement, and the intrusion/extrusion hysteresis is practically suppressed for pores with diameters below 1.2 nm. The frequency and size dependence of hysteresis exposed by the present simulations explains several experimental results on nanoporous materials. Understanding physical phenomena peculiar to nanoconfined water paves the way for a better design of nanoporous materials for energy applications; for instance, by decreasing the size of the nanopores alone, it is possible to change their behavior from dampers to molecular springs. PMID- 29138312 TI - Correlating cell shape and cellular stress in motile confluent tissues. AB - Collective cell migration is a highly regulated process involved in wound healing, cancer metastasis, and morphogenesis. Mechanical interactions among cells provide an important regulatory mechanism to coordinate such collective motion. Using a self-propelled Voronoi (SPV) model that links cell mechanics to cell shape and cell motility, we formulate a generalized mechanical inference method to obtain the spatiotemporal distribution of cellular stresses from measured traction forces in motile tissues and show that such traction-based stresses match those calculated from instantaneous cell shapes. We additionally use stress information to characterize the rheological properties of the tissue. We identify a motility-induced swim stress that adds to the interaction stress to determine the global contractility or extensibility of epithelia. We further show that the temporal correlation of the interaction shear stress determines an effective viscosity of the tissue that diverges at the liquid-solid transition, suggesting the possibility of extracting rheological information directly from traction data. PMID- 29138313 TI - T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire. AB - Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing ~2.5-fold greater density of T cells and higher clonality compared with normal breast. The clonal structure of T cells in blood and normal breast is more similar than between blood and tumor, and could be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T cell sequences overlap between tissue and blood from the same patient, including ~50% of T cells between tumor and normal breast. Both tumor and normal breast contain high-abundance "enriched" sequences that are absent or of low abundance in the other tissue. Many of these T cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T cells in both tumor and normal breast. Enriched T cell sequences are typically unique to each patient, but a subset is shared between many different patients. We show that many of these are commonly generated sequences, and thus unlikely to play an important role in the tumor microenvironment. PMID- 29138314 TI - Imaging and quantifying ganglion cells and other transparent neurons in the living human retina. AB - Ganglion cells (GCs) are fundamental to retinal neural circuitry, processing photoreceptor signals for transmission to the brain via their axons. However, much remains unknown about their role in vision and their vulnerability to disease leading to blindness. A major bottleneck has been our inability to observe GCs and their degeneration in the living human eye. Despite two decades of development of optical technologies to image cells in the living human retina, GCs remain elusive due to their high optical translucency. Failure of conventional imaging-using predominately singly scattered light-to reveal GCs has led to a focus on multiply-scattered, fluorescence, two-photon, and phase imaging techniques to enhance GC contrast. Here, we show that singly scattered light actually carries substantial information that reveals GC somas, axons, and other retinal neurons and permits their quantitative analysis. We perform morphometry on GC layer somas, including projection of GCs onto photoreceptors and identification of the primary GC subtypes, even beneath nerve fibers. We obtained singly scattered images by: (i) marrying adaptive optics to optical coherence tomography to avoid optical blurring of the eye; (ii) performing 3D subcellular image registration to avoid motion blur; and (iii) using organelle motility inside somas as an intrinsic contrast agent. Moreover, through-focus imaging offers the potential to spatially map individual GCs to underlying amacrine, bipolar, horizontal, photoreceptor, and retinal pigment epithelium cells, thus exposing the anatomical substrate for neural processing of visual information. This imaging modality is also a tool for improving clinical diagnosis and assessing treatment of retinal disease. PMID- 29138315 TI - Dual function for Tango1 in secretion of bulky cargo and in ER-Golgi morphology. AB - Tango1 enables ER-to-Golgi trafficking of large proteins. We show here that loss of Tango1, in addition to disrupting protein secretion and ER/Golgi morphology, causes ER stress and defects in cell shape. We find that the previously observed dependence of smaller cargos on Tango1 is a secondary effect. If large cargos like Dumpy, which we identify as a Tango1 cargo, are removed from the cell, nonbulky proteins reenter the secretory pathway. Removal of blocking cargo also restores cell morphology and attenuates the ER-stress response. Thus, failures in the secretion of nonbulky proteins, ER stress, and defective cell morphology are secondary consequences of bulky cargo retention. By contrast, ER/Golgi defects in Tango1-depleted cells persist in the absence of bulky cargo, showing that they are due to a secretion-independent function of Tango1. Therefore, maintenance of ER/Golgi architecture and bulky cargo transport are the primary functions for Tango1. PMID- 29138317 TI - Reviewer bias in single- versus double-blind peer review. AB - Peer review may be "single-blind," in which reviewers are aware of the names and affiliations of paper authors, or "double-blind," in which this information is hidden. Noting that computer science research often appears first or exclusively in peer-reviewed conferences rather than journals, we study these two reviewing models in the context of the 10th Association for Computing Machinery International Conference on Web Search and Data Mining, a highly selective venue (15.6% acceptance rate) in which expert committee members review full-length submissions for acceptance. We present a controlled experiment in which four committee members review each paper. Two of these four reviewers are drawn from a pool of committee members with access to author information; the other two are drawn from a disjoint pool without such access. This information asymmetry persists through the process of bidding for papers, reviewing papers, and entering scores. Reviewers in the single-blind condition typically bid for 22% fewer papers and preferentially bid for papers from top universities and companies. Once papers are allocated to reviewers, single-blind reviewers are significantly more likely than their double-blind counterparts to recommend for acceptance papers from famous authors, top universities, and top companies. The estimated odds multipliers are tangible, at 1.63, 1.58, and 2.10, respectively. PMID- 29138316 TI - Germline Cas9 expression yields highly efficient genome engineering in a major worldwide disease vector, Aedes aegypti. AB - The development of CRISPR/Cas9 technologies has dramatically increased the accessibility and efficiency of genome editing in many organisms. In general, in vivo germline expression of Cas9 results in substantially higher activity than embryonic injection. However, no transgenic lines expressing Cas9 have been developed for the major mosquito disease vector Aedes aegypti Here, we describe the generation of multiple stable, transgenic Ae. aegypti strains expressing Cas9 in the germline, resulting in dramatic improvements in both the consistency and efficiency of genome modifications using CRISPR. Using these strains, we disrupted numerous genes important for normal morphological development, and even generated triple mutants from a single injection. We have also managed to increase the rates of homology-directed repair by more than an order of magnitude. Given the exceptional mutagenic efficiency and specificity of the Cas9 strains we engineered, they can be used for high-throughput reverse genetic screens to help functionally annotate the Ae. aegypti genome. Additionally, these strains represent a step toward the development of novel population control technologies targeting Ae. aegypti that rely on Cas9-based gene drives. PMID- 29138318 TI - SNARE priming is essential for maturation of autophagosomes but not for their formation. AB - Autophagy, a unique intracellular membrane-trafficking pathway, is initiated by the formation of an isolation membrane (phagophore) that engulfs cytoplasmic constituents, leading to generation of the autophagosome, a double-membrane vesicle, which is targeted to the lysosome. The outer autophagosomal membrane consequently fuses with the lysosomal membrane. Multiple membrane-fusion events mediated by SNARE molecules have been postulated to promote autophagy. alphaSNAP, the adaptor molecule for the SNARE-priming enzyme N-ethylmaleimide-sensitive factor (NSF) is known to be crucial for intracellular membrane fusion processes, but its role in autophagy remains unclear. Here we demonstrated that knockdown of alphaSNAP leads to inhibition of autophagy, manifested by an accumulation of sealed autophagosomes located in close proximity to lysosomes but not fused with them. Under these conditions, moreover, association of both Atg9 and the autophagy-related SNARE protein syntaxin17 with the autophagosome remained unaffected. Finally, our results suggested that under starvation conditions, the levels of alphaSNAP, although low, are nevertheless sufficient to partially promote the SNARE priming required for autophagy. Taken together, these findings indicate that while autophagosomal-lysosomal membrane fusion is sensitive to inhibition of SNARE priming, the initial stages of autophagosome biogenesis and autophagosome expansion remain resistant to its loss. PMID- 29138319 TI - Frequent nonallelic gene conversion on the human lineage and its effect on the divergence of gene duplicates. AB - Gene conversion is the copying of a genetic sequence from a "donor" region to an "acceptor." In nonallelic gene conversion (NAGC), the donor and the acceptor are at distinct genetic loci. Despite the role NAGC plays in various genetic diseases and the concerted evolution of gene families, the parameters that govern NAGC are not well characterized. Here, we survey duplicate gene families and identify converted tracts in 46% of them. These conversions reflect a large GC bias of NAGC. We develop a sequence evolution model that leverages substantially more information in duplicate sequences than used by previous methods and use it to estimate the parameters that govern NAGC in humans: a mean converted tract length of 250 bp and a probability of [Formula: see text] per generation for a nucleotide to be converted (an order of magnitude higher than the point mutation rate). Despite this high baseline rate, we show that NAGC slows down as duplicate sequences diverge-until an eventual "escape" of the sequences from its influence. As a result, NAGC has a small average effect on the sequence divergence of duplicates. This work improves our understanding of the NAGC mechanism and the role that it plays in the evolution of gene duplicates. PMID- 29138320 TI - Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein. AB - Acquired resistance against antimalarial drugs has further increased the need for an effective malaria vaccine. The current leading candidate, RTS,S, is a recombinant circumsporozoite protein (CSP)-based vaccine against Plasmodium falciparum that contains 19 NANP repeats followed by a thrombospondin repeat domain. Although RTS,S has undergone extensive clinical testing and has progressed through phase III clinical trials, continued efforts are underway to enhance its efficacy and duration of protection. Here, we determined that two monoclonal antibodies (mAbs 311 and 317), isolated from a recent controlled human malaria infection trial exploring a delayed fractional dose, inhibit parasite development in vivo by at least 97%. Crystal structures of antibody fragments (Fabs) 311 and 317 with an (NPNA)3 peptide illustrate their different binding modes. Notwithstanding, one and three of the three NPNA repeats adopt similar well-defined type I beta-turns with Fab311 and Fab317, respectively. Furthermore, to explore antibody binding in the context of P. falciparum CSP, we used negative stain electron microscopy on a recombinant shortened CSP (rsCSP) construct saturated with Fabs. Both complexes display a compact rsCSP with multiple Fabs bound, with the rsCSP-Fab311 complex forming a highly organized helical structure. Together, these structural insights may aid in the design of a next generation malaria vaccine. PMID- 29138322 TI - Structures of the type I DNA restriction enzymes. PMID- 29138323 TI - Reply to Liu et al.: Yin and yang of PTEN regulation. PMID- 29138321 TI - In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection. AB - Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release d-aminoluciferin for selective reactivity-based detection of Fe2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology. PMID- 29138324 TI - Transcription start site-associated small RNAs in the PTEN gene. PMID- 29138325 TI - Reply to Mafessoni and Prufer: Inferences with and without singleton site patterns. PMID- 29138326 TI - Better support for a small effective population size of Neandertals and a long shared history of Neandertals and Denisovans. PMID- 29138327 TI - Highly Efficacious Novel Vaccine, Humoral Immunity, and Ocular Herpes Simplex Virus 1: Reality or Myth? PMID- 29138328 TI - Reply to "Highly Efficacious Novel Vaccine, Humoral Immunity, and Ocular Herpes Simplex Virus 1: Reality or Myth?" PMID- 29138329 TI - Correction for Avey et al., "Discovery of a Coregulatory Interaction between Kaposi's Sarcoma-Associated Herpesvirus ORF45 and the Viral Protein Kinase ORF36". PMID- 29138330 TI - Correction for Ansari et al., "Constitutive Interferon-Inducible Protein 16 Inflammasome Activation during Epstein-Barr Virus Latency I, II, and III in B and Epithelial Cells". PMID- 29138331 TI - Correction for Wang et al., "Mitogen-Activated Protein Kinase Kinase 2, a Novel E2-Interacting Protein, Promotes the Growth of Classical Swine Fever Virus via Attenuation of the JAK-STAT Signaling Pathway". PMID- 29138332 TI - Correction for Perez et al., "A Short cis-Acting Motif in the M112-113 Promoter Region Is Essential for IE3 To Activate M112-113 Gene Expression and Is Important for Murine Cytomegalovirus Replication". PMID- 29138333 TI - Correction for Yoon et al., "p53-Derived Host Restriction of HIV-1 Replication by Protein Kinase R-Mediated Tat Phosphorylation and Inactivation". PMID- 29138334 TI - Correction for Cousins et al., "Human Herpesvirus 8 Viral Interleukin-6 Signaling through gp130 Promotes Virus Replication in Primary Effusion Lymphoma and Endothelial Cells". PMID- 29138335 TI - Classic Spotlight, 2012 and 2013: Articles of Significant Interest Selected from the Journal of Virology Archives by the Editors. PMID- 29138336 TI - Correction for Dixit et al., "FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53". PMID- 29138337 TI - Correction for Gutierrez et al., "Ets-1 Is Required for the Activation of VEGFR3 during Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells". PMID- 29138338 TI - Correction for Gjyshi et al., "Activated Nrf2 Interacts with Kaposi's Sarcoma Associated Herpesvirus Latency Protein LANA-1 and Host Protein KAP1 To Mediate Global Lytic Gene Repression". PMID- 29138340 TI - Phase I Study of Chimeric Antigen Receptor-Modified T Cells in Patients with EGFR Positive Advanced Biliary Tract Cancers. AB - Purpose: This study is an expanded and parallel clinical trial of EGFR-specific chimeric antigen receptor-engineered autologous T (CART) cell immunotherapy (NCT01869166) to assess the safety and activity of CART-EGFR cell therapy in EGFR positive advanced unresectable, relapsed/metastatic biliary tract cancers (BTC).Experimental Design: Patients with EGFR-positive (>50%) advanced unresectable, relapsed/metastatic BTCs were enrolled. Well-produced CART-EGFR cells were infused in a manner of dose escalation after the conditioning treatment with nab-paclitaxel (100-250 mg/m2) and cyclophosphamide (15-35 mg/kg).Results: A total of 19 patients (14 cholangiocarcinomas and 5 gallbladder carcinomas) received one to three cycles of CART-EGFR cell infusion (median CART cell dose, 2.65 * 106/kg; range, 0.8-4.1 * 106/kg) within 6 months. The CART-EGFR cell infusion was tolerated, but 3 patients suffered grade >=3 acute fever/chill. Grade 1/2 target-mediated toxicities including mucosal/cutaneous toxicities and acute pulmonary edema and grade >=3 lymphopenia and thrombocytopenia related to the conditioning treatment were observed. Of 17 evaluable patients, 1 achieved complete response and 10 achieved stable disease. The median progression-free survival was 4 months (range, 2.5-22 months) from the first cycle of treatment. Analysis of data indicated that the enrichment of central memory T cells (Tcm) in the infused CART-EGFR cells improved the clinical outcome.Conclusions: The CART EGFR cell immunotherapy was a safe and active strategy for EGFR-positive advanced BTCs. The enrichment of Tcm in the infused CART-EGFR cells could predict clinical response. Clin Cancer Res; 24(6); 1277-86. (c)2017 AACRSee related commentary by Kalos, p. 1246. PMID- 29138341 TI - Long Noncoding RNA NEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/beta-Catenin Pathway by Scaffolding EZH2. AB - Purpose: Long noncoding RNAs have been implicated in gliomagenesis, but their mechanisms of action are mainly undocumented. Through public glioma mRNA expression data sets, we found that NEAT1 was a potential oncogene. We systematically analyzed the clinical significance and mechanism of NEAT1 in glioblastoma.Experimental Design: Initially, we evaluated whether NEAT1 expression levels could be regulated by EGFR pathway activity. We subsequently evaluated the effect of NEAT1 on the WNT/beta-catenin pathway and its target binding gene. The animal model supported the experimental findings.Results: We found that NEAT1 levels were regulated by EGFR pathway activity, which was mediated by STAT3 and NFkappaB (p65) downstream of the EGFR pathway. Moreover, we found that NEAT1 was critical for glioma cell growth and invasion by increasing beta-catenin nuclear transport and downregulating ICAT, GSK3B, and Axin2. Taken together, we found that NEAT1 could bind to EZH2 and mediate the trimethylation of H3K27 in their promoters. NEAT1 depletion also inhibited GBM cell growth and invasion in the intracranial animal model.Conclusions: The EGFR/NEAT1/EZH2/beta catenin axis serves as a critical effector of tumorigenesis and progression, suggesting new therapeutic directions in glioblastoma. Clin Cancer Res; 24(3); 684-95. (c)2017 AACR. PMID- 29138342 TI - Immunotherapy of Hepatocellular Carcinoma: Facts and Hopes. AB - Treatment of patients with hepatocellular carcinoma (HCC) in the advanced stage remains a great challenge, with very few drugs approved. After decades of failure of immune therapies, immune checkpoint inhibitors have emerged as potentially effective treatments for patients with HCC in the advanced stage. Immune checkpoints, including human cancer, cytotoxic T-lymphocyte protein 4 (CTLA-4), and programmed cell death protein 1 (PD-1), are surface proteins expressed in a variety of immune cells and mostly provide immunosuppressive signals. Monoclonal antibodies able to block these molecules have shown antitumor activity against a wide spectrum of human cancers. Clinical experience with checkpoint inhibitors in HCC includes early trials with the anti-CTLA-4 agent tremelimumab and a large phase II trial with the anti-PD-1 agent nivolumab. The latter has shown strong activity particularly as second-line therapy, both in terms of tumor response and patient survival. At least three topics should be the focus of future research: (i) the search for activity in patients at less-advanced stages, including the adjuvant treatment of patients with resectable or ablatable tumors; (ii) the enhanced efficacy of combination therapies, including particularly the combination with those targeted and locoregional therapies that may have a synergistic effect or act upon mechanisms of primary or acquired resistance to checkpoint inhibitors; and (iii) the identification of clinical features and serum or tissue biomarkers that would allow a better patient selection for individual treatments. Hopefully, ongoing trials will help to design better treatments in the future. Clin Cancer Res; 24(7); 1518-24. (c)2017 AACR. PMID- 29138343 TI - A Phase I Clinical Trial of the Poly(ADP-ribose) Polymerase Inhibitor Veliparib and Weekly Topotecan in Patients with Solid Tumors. AB - Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome.Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1-3, 8-10, and 15-17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST.Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1-3, 8-10, and 15-17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1-26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles).Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation. Clin Cancer Res; 24(4); 744-52. (c)2017 AACR. PMID- 29138344 TI - Targeting the MYCN-PARP-DNA Damage Response Pathway in Neuroendocrine Prostate Cancer. AB - Purpose: We investigated MYCN-regulated molecular pathways in castration resistant prostate cancer (CRPC) classified by morphologic criteria as adenocarcinoma or neuroendocrine to extend the molecular phenotype, establish driver pathways, and identify novel approaches to combination therapy for neuroendocrine prostate cancer (NEPC).Experimental Design and Results: Using comparative bioinformatics analyses of CRPC-Adeno and CRPC-Neuro RNA sequence data from public data sets and a panel of 28 PDX models, we identified a MYCN PARP-DNA damage response (DDR) pathway that is enriched in CRPC with neuroendocrine differentiation (NED) and CRPC-Neuro. ChIP-PCR assay revealed that N-MYC transcriptionally activates PARP1, PARP2, BRCA1, RMI2, and TOPBP1 through binding to the promoters of these genes. MYCN or PARP1 gene knockdown significantly reduced the expression of MYCN-PARP-DDR pathway genes and NED markers, and inhibition with MYCNsi and/or PARPsi, BRCA1si, or RMI2si significantly suppressed malignant activities, including cell viability, colony formation, and cell migration, in C4-2b4 and NCI-H660 cells. Targeting this pathway with AURKA inhibitor PHA739358 and PARP inhibitor olaparib generated therapeutic effects similar to those of gene knockdown in vitro and significantly suppressed tumor growth in both C4-2b4 and MDACC PDX144-13C subcutaneous models in vivoConclusions: Our results identify a novel MYCN-PARP-DDR pathway that is driven by N-MYC in a subset of CRPC-Adeno and in NEPC. Targeting this pathway using in vitro and in vivo CRPC-Adeno and CRPC-Neuro models demonstrated a novel therapeutic strategy for NEPC. Further investigation of N-MYC-regulated DDR gene targets and the biological and clinical significance of MYCN-PARP-DDR signaling will more fully elucidate the importance of the MYCN-PARP-DDR signaling pathway in the development and maintenance of NEPC. Clin Cancer Res; 24(3); 696-707. (c)2017 AACR. PMID- 29138346 TI - Inner Workings: Special relationship between fungi and plants may have spurred changes to ancient climate. PMID- 29138345 TI - Novel Predictors of Breast Cancer Survival Derived from miRNA Activity Analysis. AB - Purpose: Breast cancer is among the leading causes of cancer-related death; discovery of novel prognostic markers is needed to improve outcomes. Combining systems biology and epidemiology, we investigated miRNA-associated genes and breast cancer survival in a well-characterized population-based study.Experimental Design: A recently developed algorithm, ActMiR, was used to identify key miRNA "activities" corresponding to target gene degradation, which were predictive of breast cancer mortality in published databases. We profiled miRNA-associated genes in tumors from our well-characterized population-based cohort of 606 women with first primary breast cancer. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CI), after 15+ years of follow-up with 119 breast cancer-specific deaths.Results: miR-500a activity was identified as a key miRNA for estrogen receptor-positive breast cancer mortality using public databases. From a panel of 161 miR-500a-associated genes profiled, 73 were significantly associated with breast cancer-specific mortality (FDR < 0.05) in our population, among which two clusters were observed to have opposing directions of association. For example, high level of SUSD3 was associated with reduced breast cancer-specific mortality (HR = 0.3; 95% CI, 0.2 0.4), whereas the opposite was observed for TPX2 (HR = 2.7; 95% CI, 1.8-3.9). Most importantly, we identified set of genes for which associations with breast cancer-specific mortality were independent of known prognostic factors, including hormone receptor status and PAM50-derived risk-of-recurrence scores. These results are validated in independent datasets.Conclusions: We identified novel markers that may improve prognostic efficiency while shedding light on molecular mechanisms of breast cancer progression. Clin Cancer Res; 24(3); 581-91. (c)2017 AACR. PMID- 29138347 TI - Core Concept: Tissue resident memory cells emerging as key player in health and disease. PMID- 29138349 TI - Diffuse Growth of Plant Cell Walls. PMID- 29138350 TI - The DEAD-box RNA Helicase RH50 Is a 23S-4.5S rRNA Maturation Factor that Functionally Overlaps with the Plastid Signaling Factor GUN1. AB - DEAD-box RNA helicases (DBRHs) modulate RNA secondary structure, allowing RNA molecules to adopt the conformations required for interaction with their target proteins. RH50 is a chloroplast-located DBRH that colocalizes and is coexpressed with GUN1, a central factor in chloroplast-to-nucleus signaling. When combined with mutations that impair plastid gene expression (prors1-1, prpl11-1, prps1-1, prps21-1, prps17-1, and prpl24-1), rh50 and gun1 mutations evoke similar patterns of epistatic effects. These observations, together with the synergistic growth phenotype of the double mutant rh50-1 gun1-102, suggest that RH50 and GUN1 are functionally related and that this function is associated with plastid gene expression, in particular ribosome functioning. However, rh50-1 itself is not a gun mutant, although-like gun1-102-the rh50-1 mutation suppresses the down regulation of nuclear genes for photosynthesis induced by the prors1-1 mutation. The RH50 protein comigrates with ribosomal particles, and is required for efficient translation of plastid proteins. RH50 binds to transcripts of the 23S 4.5S intergenic region and, in its absence, levels of the corresponding rRNA processing intermediate are strongly increased, implying that RH50 is required for the maturation of the 23S and 4.5S rRNAs. This inference is supported by the finding that loss of RH50 renders chloroplast protein synthesis sensitive to erythromycin and exposure to cold. Based on these results, we conclude that RH50 is a plastid rRNA maturation factor. PMID- 29138351 TI - Phytochromes and Phytochrome Interacting Factors. AB - The basic helix-loop-helix domain-containing transcription factors that interact physically with the red and far-red light photoreceptors, phytochromes, are called PHYTOCHROME INTERACTING FACTORS (PIFs). In the last two decades, the phytochrome-PIF signaling module has been shown to be conserved from Physcomitrella patens to higher plants. Exciting recent studies highlight the discovery of at least four distinct kinases (PPKs, CK2, BIN2, and phytochrome itself) and four families of ubiquitin ligases (SCFEBF1/2, CUL3LRB, CUL3BOP, and CUL4COP1-SPA) that regulate PIF abundance both in dark and light conditions. This review discusses these recent discoveries with a focus on the central phytochrome signaling mechanisms that have a profound impact on plant growth and development in response to light. PMID- 29138352 TI - Fission and Fusion of Plant Mitochondria, and Genome Maintenance. PMID- 29138354 TI - Efficient ER Fusion Requires a Dimerization and a C-Terminal Tail Mediated Membrane Anchoring of RHD3. AB - The endoplasmic reticulum (ER) is a network of tubules and sheets stretching throughout the eukaryotic cells. The formation of the ER requires homotypic membrane fusion, which is mediated by a family of Dynamin-like Atlastin GTPase proteins. The Arabidopsis (Arabidopsis thaliana) member ROOT HAIR DEFECTIVE3 (RHD3) has been demonstrated to mediate ER membrane fusion, but how exactly RHD3 is involved in the process is still unknown. Here we conducted systemic structure function analyses of roles of different RHD3 domains in mediating ER fusion. We showed that efficient ER membrane fusion mediated by RHD3 requires a proper dimerization of RHD3 through the GTPase domain (GD) and the first and second three helix bundles (3HBs) in the middle domain. RHD3 has a 3HB-enriched middle domain longer than that of Atlastins, and we revealed that the third and fourth 3HBs are required for the stability of RHD3. The transmembrane segments of RHD3 are essential for targeting and retention of RHD3 in the ER and can also facilitate an oligomerization of RHD3. Furthermore, we showed that an amphipathic helix in the C-terminal cytosolic tail of RHD3 has a membrane anchoring ability that is required for efficient ER membrane fusion mediated by RHD3. This work contributes to a better understanding of a coordinated action of RHD3 in the fusion of ER membranes. PMID- 29138355 TI - The complexities of lithium. PMID- 29138353 TI - Interplay between Ions, the Cytoskeleton, and Cell Wall Properties during Tip Growth. PMID- 29138356 TI - The soluble (Pro) renin receptor does not influence lithium-induced diabetes insipidus but does provoke beiging of white adipose tissue in mice. AB - Earlier we reported that the recombinant soluble (pro) renin receptor sPRR-His upregulates renal aquoporin-2 (AQP2) expression, and attenuates polyuria associated with nephrogenic diabetes insipidus (NDI) induced by vasopressin type 2 receptor (V2R) antagonism. Patients that receive lithium therapy develop polyuria associated NDI that might be secondary to downregulation of renal AQP2. We hypothesized that sPRR-His attenuates indices of NDI associated with lithium treatment. Eight-week-old male C57/BL6 mice consumed chow supplemented with LiCl (40 mmol/kg diets) for 14 days. For the last 7 days mice received either sPRR-His [30 MUg/(kg day), i.v.; sPRR] or vehicle (Veh) via minipump. Control (Con) mice consumed standard chow for 14 days. Compared to Con mice, 14-d LiCl treatment elevated water intake and urine volume, and decreased urine osmolality, regardless of sPRR-His or Veh administration. These data indicate that sPRR-His treatment does not attenuate indices of NDI evoked by lithium. Unexpectedly, epididymal fat mass was lower, adipocyte UCP1 mRNA and protein expression were higher, and multilocular lipid morphology was enhanced, in LiCl-fed mice treated with sPRR-His versus vehicle. The beiging of white adipose tissue is a novel metabolic benefit of manipulating the sPRR in the context of lithium-induced NDI. PMID- 29138357 TI - Tadalafil, a long acting phosphodiesterase inhibitor, promotes bone marrow stem cell survival and their homing into ischemic myocardium for cardiac repair. AB - : The aim was to evaluate the tadalafil-mediated effects at molecular level on bone marrow-derived mesenchymal stem cells (MSCs) survival and their homing into the infarcted hearts to promote cardiac repair and improve function. MSCs were pretreated in vitro with inhibitors of PKG, MAPK, FasL, nitric oxide synthase (NOS) (L-NAME), CXCR4 (AMD3100), or miR-21 inhibitors (+/-luciferase construction +/-Fas) prior to tadalafil treatment for 2 h. These MSCs were then subjected to H2O2 stress to assess their injury. Rats were subjected to acute myocardial infarction (AMI), and then followed by injection of saline or 1.5 x 106 MSCs treated +/- tadalafil into infarcted and peri-infarcted area. In another group, AMI was performed in 1-month post-myelo-ablated rats and were injected intraperitoneally (IP) with tadalafil +/- AMD3100 or L-NAME for 5 days. Also, in another group, AMI mice were treated with IP +/- tadalafil before intravenous injection with 111In-oxine-MSCs followed by CT/SPECT imaging to locate mobilized MSCs. Cardiac function was assessed by echocardiography. MSCs and heart extracts were analyzed by molecular bioassays. Tadalafil-treated MSCs had higher expression of cGMP, NOS, SDF-1alpha, p-VASP, p-Erk1/2, p-STAT3, p-Akt, PKG1 and Bcl-xl; expression of these molecules was reduced with PKG1, MAPK, NOS or FasL inhibitors. Tadalafil inhibited apoptosis through increased miR-21 expression and improved cell survival by inhibiting Fas (restored by PKG1, MAPK or miR-21 inhibitors). In vivo, heart function, grafted cell survival, MSCs mobilization and homing were improved in tadalafil-treated AMI animals versus controls. CONCLUSIONS: Tadalafil prolonged MSCs survival via up-regulation of miR-21 dependent suppression of Fas, and increased MSCs mobilization and their homing into infarcted myocardium resulting in improved cardiac repair and function. PMID- 29138360 TI - Defang ACEs: End Toxic Stress by Developing Resilience Through Physician Community Partnerships. PMID- 29138358 TI - Epileptic pilocarpine-treated rats exhibit aberrant hippocampal EPSP-spike potentiation but retain long-term potentiation. AB - Hippocampal neuron plasticity is strongly associated with learning, memory, and cognition. In addition to modification of synaptic function and connectivity, the capacity of hippocampal neurons to undergo plasticity involves the ability to change nonsynaptic excitability. This includes altering the probability that EPSPs will generate action potentials (E-S plasticity). Epilepsy is a prevalent neurological disorder commonly associated with neuronal hyperexcitability and cognitive dysfunction. We examined E-S plasticity in chronically epileptic Sprague-Dawley rats 3-10 weeks after pilocarpine-induced status epilepticus CA1 neurons in hippocampal slices were assayed by whole-cell current clamp to measure EPSPs evoked by Schaffer collateral stimulation. Using a weak spike-timing dependent protocol to induce plasticity, we found robust E-S potentiation in conjunction with weak long-term potentiation (LTP) in saline-treated rats. In pilocarpine-treated rats, a similar degree of LTP was found, but E-S potentiation was reduced. Additionally, the degree of E-S potentiation was not correlated with the degree of LTP for either group, suggesting that they independently contribute to neuronal plasticity. E-S potentiation also differed from LTP in that E-S plasticity could be induced solely from action potentials generated by postsynaptic current injection. The calcium chelating agent BAPTA in the intracellular solution blocked LTP and E-S potentiation, revealing the calcium dependence of both processes. These findings suggest that LTP and E-S potentiation have overlapping but nonidentical mechanisms of inducing neuronal plasticity that may independently contribute to cognitive disruptions observed in the chronic epileptic state. PMID- 29138359 TI - Comparative effects of intraduodenal amino acid infusions on food intake and gut hormone release in healthy males. AB - In contrast to the many studies of the effects of individual amino acids (AAs) on eating, no studies have compared the effects of different AAs on eating and underlying preabsorptive gastrointestinal mechanisms. To compare the effects of intraduodenal infusions of l-tryptophan (TRP), l-leucine (LEU), l-phenylalanine (PHE) and l-glutamine (GLN) on appetite, gastrointestinal hormone responses (including ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 [GLP-1]), glycemia (glucagon, insulin and glucose) and test meal size in healthy males, we retrospectively analyzed data from four published independent, randomized, double-blind, placebo-controlled studies of 90-min intraduodenal infusions of the individual AAs. The designs of the studies were identical, except the dose of TRP (0.15 kcal/min) was lower than that of the other AAs (0.45 kcal/min) because higher doses of this AA were not well tolerated. TRP and LEU decreased intake more than PHE (reductions relative to control, ~219 +/- 68, ~170 +/- 48 and ~12 +/- 57 kcal, respectively), and TRP decreased intake more than GLN (~31 +/- 82 kcal). These effects of TRP and LEU versus GLN, but not versus PHE, were paralleled by greater decreases in plasma ghrelin, and increases in CCK, concentrations. TRP increased PYY more than GLN or LEU, but not PHE. LEU increased PYY less than PHE. No significant differences were detected for GLP-1. PHE increased glucagon more than TRP or LEU, and increased insulin more than TRP. Under our experimental conditions, intraduodenal TRP and LEU were more satiating than PHE and GLN. The greater satiating efficacy of LEU versus PHE was significantly dissociated from the effects of these AAs on PYY, while the greater satiating potency of TRP versus PHE was significantly dissociated from the effects of these AAs on insulin and glucagon. In contrast, ghrelin and CCK, and potentially other mechanisms, including central sensing of individual AAs, appear to be stronger candidate mechanisms for the relative satiating effects obtained. PMID- 29138361 TI - Rethinking the Definition of Evidence-Based Interventions to Promote Early Childhood Development. PMID- 29138362 TI - Infant Neuromotor Development and Childhood Problem Behavior. AB - BACKGROUND: Research of adults and school-aged children suggest a neurodevelopmental basis for psychiatric disorders. We examined whether infant neuromotor development predicted internalizing and externalizing problems in young children. METHODS: In Generation R, a population-based cohort in the Netherlands (2002-2006), trained research assistants evaluated the neuromotor development of 4006 infants aged 2 to 5 months by using an adapted version of Touwen's Neurodevelopmental Examination (tone, responses, and senses and other observations). We defined nonoptimal neuromotor development as scores in the highest tertile. Mothers and fathers rated their children's behavior at ages 1.5, 3, 6, and 10 years with the Child Behavior Checklist (n = 3474, response: 86.7%). The associations were tested with generalized linear mixed models. RESULTS: Overall, neuromotor development predicted internalizing scores, but no association was observed with externalizing scores. Nonoptimal muscle tone was associated with higher internalizing scores (mothers' report: beta = .07; 95% confidence interval [CI]: 0.01 to 0.13; fathers' report: beta = .09, 95% CI: 0.00 to 0.16). In particular, nonoptimal low muscle tone was associated with higher internalizing scores (mothers' report: beta = .11; 95% CI: 0.05 to 0.18; fathers' report: beta = .13; 95% CI: 0.04 to 0.22). We also observed an association between senses and other observations with internalizing scores. There was no relationship between high muscle tone or reflexes and internalizing scores. CONCLUSIONS: Common emotional problems in childhood have a neurodevelopmental basis in infancy. Neuromotor assessment in infancy may help identify vulnerability to early internalizing symptoms and offer the opportunity for targeted interventions. PMID- 29138363 TI - Primary Care Interventions for Early Childhood Development: A Systematic Review. AB - CONTEXT: The pediatric primary care setting offers a platform to promote positive parenting behaviors and the optimal development of young children. Many new interventions have been developed and tested in this setting over the past 2 decades. OBJECTIVE: To summarize the recent published evidence regarding the impact of primary care-based interventions on parenting behaviors and child development outcomes; to provide recommendations for incorporation of effective interventions into pediatric clinics. DATA SOURCES: A literature search of PubMed and PsycINFO was conducted from January 1, 1999, to February 14, 2017. STUDY SELECTION: Publications in which primary care-based interventions and reported outcomes regarding the child's development or parenting behaviors associated with the promotion of optimal child development are described. DATA EXTRACTION: Forty eight studies in which 24 interventions were described were included. Levels of evidence and specific outcome measures are reported. RESULTS: Included interventions were categorized as general developmental support, general behavioral development, or topic-specific interventions. Two interventions resulted in reductions in developmental delay, 4 improved cognitive development scores, and 6 resulted in improved behavioral intensity or reduction in behavioral problems. Interventions used a variety of theory-based behavior change strategies such as modeling, group discussion, role play, homework assignment, coaching, and video-recorded interactions. Three interventions report the cost of the intervention. LIMITATIONS: Community or home-based interventions were excluded. CONCLUSIONS: Although several interventions resulted in improved child development outcomes for children aged 0 to 3 years, comparison across studies and interventions is limited by use of different outcome measures, time of evaluation, and variability of results. PMID- 29138364 TI - Retrograde CTO-PCI of Native Coronary Arteries Via Left Internal Mammary Artery Grafts: Insights From a Multicenter U.S. Registry. AB - BACKGROUND: Retrograde percutaneous coronary intervention (PCI) of native coronary artery chronic total occlusion (CTO) via left internal mammary artery (LIMA) graft has received limited study. METHODS AND RESULTS: We compared the clinical and procedural characteristics and outcomes of retrograde CTO-PCI through LIMA grafts vs other conduits in a contemporary multicenter CTO registry. The LIMA was used as the collateral channel in 20 of 990 retrograde CTO-PCIs (2.02%) performed at 18 United States centers. The mean age of the study patients was 69 +/- 7 years and 95% were men. The most common CTO target vessel was the right coronary artery (55%). The mean J-CTO score in the LIMA group was high (3.45 +/- 0.76). The technical success rates were 70% for retrograde PCI via LIMA graft vs 81.05% for retrograde via other conduits (P=.25), while procedural success rates were 70% for retrograde PCI via LIMA graft and 78.19% for retrograde via other conduits (P=.41). The incidence of major in-hospital complications was also similar between the LIMA and non-LIMA retrograde groups (5% vs 6%; P>.99). Use of guide-catheter extensions (40% vs 28%; P=.22), intravascular ultrasound (45% vs 31%; P=.20), and left ventricular assist devices (24% vs 10%; P=.08) was numerically higher in retrograde CTO-PCIs via LIMA grafts. CONCLUSIONS: Retrograde CTO-PCI is infrequently performed via LIMA grafts and is associated with similar success and major in-hospital complication rates as retrograde CTO-PCI performed via other conduits. PMID- 29138365 TI - One-Year Clinical Outcomes of the Hybrid CTO Revascularization Strategy After Hospital Discharge: A Subanalysis of the Multicenter RECHARGE Registry. AB - OBJECTIVES: Percutaneous coronary intervention (PCI) of chronic total occlusion (CTO) has historically been associated with higher event rates during follow-up. The hybrid algorithm and contemporary wiring and dissection re-entry (DR) techniques can potentially improve long-term outcomes after CTO-PCI. This study assessed the long-term clinical outcomes of the hybrid CTO practice, when applied by operators with varying experience levels. METHODS: We examined the 1-year clinical events after hospital discharge of the RECHARGE population, according to technical outcome and final technique. The primary endpoint was major adverse cardiac event (MACE) rate. Centers that provided >=90% complete 12-month follow up were included. RESULTS: Follow-up data of 1067 out of 1165 patients (92%) were provided by 13 centers. Mean follow-up duration was 362.8 +/- 0.9 days. One-year MACE-free survival rate was 91.3% (974/1067). MACE included death (1.9%; n = 20), myocardial infarction (1.4%; n = 15), target-vessel failure (5.9%; n = 63), and target-vessel revascularization (TVR) (5.5%; n = 59). Non-TVR was performed in 6.7% (n = 71). MACE was significantly in favor of successful CTO-PCI (8.0% vs 13%; P=.04), even after adjusting for baseline differences (adjusted hazard ratio, 0.59; 95% confidence interval, 0.36-0.98; P=.04). Other events, including individual MACE components, were comparable with respect to technical outcome and final technique (DR vs non-DR techniques). CONCLUSIONS: The use of the hybrid algorithm with contemporary techniques by moderate to highly experienced operators for CTO-PCI is safe and associated with a low 1-year event rate. Successful procedures are associated with a better MACE rate. DR techniques can be used as first-line strategies alongside intimal wiring techniques without compromising clinical outcomes. PMID- 29138366 TI - Lower Repeat Revascularization Rates Among Patients With Prior Coronary Artery Bypass Graft Surgery are Due to Lack of Adequate Target Vessels. AB - BACKGROUND: Studies comparing percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery in patients with multivessel coronary artery disease (CAD) have shown lower repeat revascularization rates in patients who undergo CABG. The reason remains unclear. METHODS: We identified patients with multivessel CAD who received CABG or PCI enrolled in the Duke Databank for Cardiovascular Disease (2003 to 2012). We compared the incidence of major adverse cardiovascular and cerebrovascular events (MACCE) between the two groups. Clinically performed follow-up angiograms for CABG patients were reviewed to determine adequacy of intervenable targets. RESULTS: A total of 1555 patients were included: 861 underwent PCI and 694 underwent CABG. Patients with index PCI were more often female, African-American, presented with ST-elevation myocardial infarction (MI), and had previous MI; they were less often diabetic and had less heart failure or proximal left anterior descending disease. The adjusted hazard ratio of MACCE for CABG vs PCI was 0.68 (95% confidence interval, 0.58-0.80; P<.001). The adjusted odds ratio for repeat revascularization for CABG vs PCI was 0.45 (95% confidence interval, 0.28-0.72; P<.001). Fifty-seven patients with index CABG were found to have >=1 occluded graft on subsequent angiography without repeat revascularization; 48 patients (6.9%) had inadequate targets for intervention. CONCLUSION: Among patients with multivessel CAD, repeat revascularization rates are lower among CABG patients compared with PCI patients. However, a high proportion of CABG patients with occluded grafts on repeat angiography lack targets for repeat revascularization. This may partially explain the disparity in repeat revascularization rates and suggests that future comparison studies should additionally assess angiographic outcomes. PMID- 29138367 TI - [The Framework of the Amended Cancer Control Act]. AB - The Cancer Control Act approved in 2006 was amended in December 2016 by the nonpartisan federation of the National Assembly, while meeting the requests from cancer patient groups. In the chapter on the basic ideas, it is said that cancer control needs to advance the development ofthe social environment that enables cancer patients to run a smooth social life and employment support for cancer patients and promotion of cancer education are newly stated. In the chapter on the basic measures, palliative care, rehabilitation, the research on rare cancer and intractable cancer, the treatment ofchildhood cancer patients and the improvement of educational environment for those patients, and the support for private organizations and cancer patient groups are newly stated. Regarding cancer genome medical care, new legislation is expected. PMID- 29138368 TI - [Regulatory Mechanisms of PD-L1 Expression and Its Role in Immune Evasion]. AB - Immune checkpoint blockade therapy using anti-PD-1 or anti-PD-L1 antibodies can unleash anti-tumor immunity and induce durable remission in a variety ofhuman cancers. However, the regulatory mechanisms of PD-L1 expression mediating immune evasion ofcancer cells have not been fully elucidated, including the genetic alterations causing PD-L1 overexpression. Recently, we have reported a novel genetic mechanism ofimmune evasion associated with structural variations(SVs)disrupting the 3'-untranslated region(UTR)ofthe PD-L1 gene in various malignancies, such as aggressive lymphomas and gastrointestinal cancers. Despite a heterogenous nature ofthese SVs, they are closely associated with a marked upregulation of PD-L1 expression, which augments tumor growth and escape from anti-tumor immunity. Here we present an overview of the regulatory mechanisms of PD-L1 expression in cancer cells, highlighting the genetic mechanisms of PD-L1 constitutive activation, with specific focus on PD-L1 3'-UTR disruption. PMID- 29138369 TI - [Metabolic Competition in Tumor Microenvironment]. AB - Metabolic pathways tightly regulate T cell response in host defense against infection and cancer. Glycolysis plays a key role in effector T cell differentiation and its function. More recent studies have demonstrated that tumor microenvironment forms hypoxia and metabolic disadvantage of immune cells. These environmental attributions impair the effector T cell survival, proliferation and function. Therefore repurposing of metabolic drugs might develop a novel cancer immunotherapy based on the targeting of T cell immunometabolism. In this review, we abridge basis of cancer cell and T cell metabolism and discuss recent advances elucidating "metabolic competition" exerted on tumor-infiltrating T cells that drive their dysfunction in tumor microenvironment. PMID- 29138370 TI - [Development of Holistic Cancer Treatment Centering Cancer Patients - From the Standpoint of Hypoxia and Hedgehog Signaling]. AB - Recently, hypoxia that is one of cancer microenvironments, takes much attention. Because circumstance that we usually perform experiment is 20% O2 condition, it is likely that different signaling pathways may be activated in vivo cancer. We focused Hedgehog(Hh)signaling as one of activated pathways under hypoxia. It has been shown that Hh signaling is activated under hypoxia, followed by inducing malignant phenotypes in pancreatic cancer. Therefore, Hh signaling inhibitor should elicit anti-tumor effect. However, if we consider "whole-person therapy" we should confirm how Hh signaling affects the function of immune cells. In the present study, we describe hypoxia/Hh signaling/functions of cancer cells and immune cells focusing our previous results. PMID- 29138371 TI - [Adaptation of Anti-PD-1/Anti-PD-L1 Antibody from the Viewpoint of Analysis of Tumor Microenvironment]. AB - The response rate of anti-PD-1/anti-PD-L1antibody alone is about 20 to 30%and the development of biomarker for them is important to know their indication. Based on previous reports and our research results, we suggested that basic candidates of biomarker for anti-PD-1/anti-PD-L1antibody are the expression of PD-L1and HLA class I on cancer cells and the invasion of CD8 positive T cells in tumor microenvironment. Furthermore, in addition to these conditions, regulatory T cells and immune cells expressing PD-L1in tumor microenvironment, and microsatellite instability of cancer cells will be considered in the future. PMID- 29138372 TI - [Lower G. I./Colon and Rectum Cancer Updated Japanese Guidelines in Colon and Rectum Cancer]. PMID- 29138373 TI - [I. Key Points of the Guidelines for Clinical Practice of Hereditary Colorectal Cancer]. PMID- 29138374 TI - [II. Clinical Guidelines of Molecular Testing for Colorectal Cancer]. PMID- 29138375 TI - [III. The Review of JSCCR Guidelines 2016 for the Treatment of Colorectal Cancer]. PMID- 29138376 TI - [The Changes in the Neutrophil-to-Lymphocyte Ratio Can Predict the Timing of Chemotherapeutic Regimen Alteration in Patients with Metastatic Colorectal Cancer]. AB - AIM: In order to determine if the changes in the neutrophil-to-lymphocyte ratio(NLR)can predict the timingof regimen alteration, the outcome of chemotherapy for metastatic colorectal cancer was analyzed retrospectively. METHODOLOGY: Thirty patients with unresectable metastatic colorectal cancer were administered chemotherapy from January 2005 to December 2015 at the Niitsu Medical Center Hospital. The NLR was calculated from complete blood counts obtained prior to administration of chemotherapy and at the time of the best response. We defined the period with an NLR<=2.5 as the total interval of an NLR<=2.5. The role of the NLR in overall survival was determined by univariate and multivariate Cox regression models. RESULTS: The median overall survival was 27 months in patients with an NLR<=2.5(n=22)and 11 months in those with an NLR>2.5 (n=8)at the best response(p<0.001). The period with an NLR<=2.5 was found to correlate with overall survival(p<0.001). The patients who survived for more than 3 years were introduced to a second-line treatment prior to achievingan NLR>2.5. The period with an NLR<=2.5(p=0.001)and prechemotherapy CA19 9(p<0.0001)were independent, significant predictors of better survival in multivariate analysis. CONCLUSION: The introduction of a new chemotherapeutic regimen prior to achievingan NLR>2.5 predicted better survival in patients with mCRC. PMID- 29138377 TI - [Safety Evaluation of Paclitaxel Injection NK in Tri-Weekly Administration of Paclitaxel plus Carboplatin(TC Therapy) for Gynecological Cancers]. AB - Paclitaxel is a key drug used for the treatment of gynecological cancers, breast cancer, and gastric cancer. While there is a great deal of safety information on the weekly administration of generic paclitaxel NK(paclitaxel injection NK)and proprietary paclitaxel(Taxol(r)injection), little is known about their safety when administered tri-weekly, partly due to a small sample size. Therefore, to gain more information and to validate the safety of using generic paclitaxel NK in a tri-weekly regimen, we investigated the incidences of adverse events in response to it in a larger number of patients. The incidence of constipation was found to be higher in response to all grades of generic paclitaxel NK, with significant differences between the various grades. The profiles of other adverse events, however, were not significantly different. Thus, generic paclitaxel NK is as safe as the proprietary paclitaxel for tri-weekly administration. PMID- 29138378 TI - [Body Surface Area Formulas for the Calculation of the Chemotherapy Dosage]. AB - Body surface area(BSA)is a parameter frequently used to calculate the chemotherapy dosage. Several different equations for predicting BSA have been developed. We examined the formula suggested for BSA calculation for 62 chemotherapy drugs where the recommended dosage was based on patient BSA. We found that the description of the formula to be used for BSA calculation was not provided in the package inserts or in the drug interview forms in the majority of cases; the BSA formula was mentioned in the guide for appropriate use of medication in only 8 of 62 chemotherapy drugs. Furthermore, we observed that the choice of formula used to calculate patient BSA caused differences in the dosage of drugs administered to patients undergoing certain oral anti-cancer drug therapies. The results ofour study indicate that clinical oncologists should pay careful attention to the formula used to calculate BSA. PMID- 29138379 TI - [A Case of Advanced Gastric Cancer Responding to Neoadjuvant Chemotherapy with Docetaxel, Cisplatin, and 5-Fluorouracil, Leading to a Pathological Complete Response]. AB - We report a 72-year-old woman who was initially diagnosed with locally advanced gastric cancer with involvement of the esophagus and pancreas. She received 3 courses of neoadjuvant chemotherapy(NAC)with docetaxel, cisplatin, and 5- fluorouracil(the DCF regimen)and achieved an excellent response. She underwent total gastrectomy with distal pancreatectomy, splenectomy, and D2 lymphadenectomy. Histological examination confirmed a pathological complete response. NAC chemotherapy can down stage/down size the disease and allow some patients to undergo curative radical surgery. PMID- 29138380 TI - [Three Patients with Gastric Cancer Who Underwent Surgery during Ramucirumab Treatment]. AB - According to the REGARD and RAINBOW trials, ramucirumab(RAM)was introduced as second-line therapy for advanced or metastatic gastric cancer. RAM may impair wound healing due to the inhibition of angiogenesis; details on the postoperative course of patients who underwent surgery during RAM treatment remain unclear. Between 2011 and 2016, 93 patients with incurable gastric cancer were treated with RAM in our institute. Among them, 3 patients underwent surgery after RAM treatment. Case 1: A 74-year-old man with liver metastasis from gastric cancer was treated with a paclitaxel(PTX)plus RAM regimen. Perforation of the stomach was observed 3 days after final RAM administration. He was successfully treated with omental repair and discharged 19 days after surgery. Case 2: A 31-year-old woman with peritoneal recurrence after total gastrectomy received the PTX plus RAM regimen as second-line treatment. Stenting was performed for rectal stenosis. Perforation of the rectum just proximal of the stent was observed 5 days after final RAM administration. Ileostomy was performed. Closure of the perforation was not obtained until the patient died 210 days after surgery. Case 3: A 60-year-old man with remnant gastric cancer received the PTX plus RAM regimen. Accidentally, the enteral feeding tube was removed. Six weeks after the cessation of RAM administration, the enteral feeding tube was inserted under general anesthesia. He was discharged 4 days after surgery. If surgery is required in patients receiving RAM treatment, sufficient drug withdrawal is desirable. If emergency surgery is needed, less invasive procedures should be selected to the maximum extent possible. PMID- 29138381 TI - [A Case of Lung Cancer Associated with Drug-Induced Immune Thrombocytopenia]. AB - A Stage IV lung adenocarcinoma was diagnosed in the left upper lobe of an 81-year old man 2.5 years ago. Following another form of chemotherapy, he then received docetaxel as fourth-line therapy. After 21 days of therapy, although his white blood cell count recovered, his platelet count decreased to 20,000/mL and continued to decrease. Subsequently, he was closely monitored without therapy, and eventually, his platelet count returned within the normal range after 112 days. Blood biochemistry and bone marrow paracentesis findings suggested the presence of paraneoplastic syndrome, idiopathic thrombocytopenic purpura, and drug-induced immune thrombocytopenia. It was difficult to distinguish between the presence of myelosuppression, carcinoma with bone marrow invasion, and paraneoplastic syndrome. This is believed to have resulted from a docetaxel induced immune thrombocytopenia because, although the platelet count decreased after docetaxel chemotherapy, it eventually returned to normal levels without therapy. PMID- 29138382 TI - [A Case of Retroperitoneal Abscess Due to Acute Appendicitis during Neo-Adjuvant Chemotherapy for Breast Cancer]. AB - When acute appendicitis occurs in patients treated with chemotherapy, neutropenia and abdominal complaints caused by chemotherapy can contribute to the diagnostic difficulty, masking the increase in white blood cell(WBC)counts and physical findings of acute appendicitis. A 43-year-old premenopausal woman who was diagnosed with stage IIIA left breast cancer was scheduled for neoadjuvant chemotherapy includingfluorouracil plus epirubicin plus cyclophosphamide(FEC), followed by docetaxel and trastuzumab(DOC plus HER). The patient developed fever and lower abdominal pain on day 17 of DOC plus HER cycle 1, and was diagnosed with acute gastroenteritis in the emergency room. These symptoms were almost improved 4 days later, and then cycle 2 was performed as scheduled. WBC counts decreased to 1,530 cells/mL due to DOCinduced myelosuppression on day 8 of cycle 2 when the patient developed lower abdominal pain again. However, WBC counts increased to 21,680 cells/mL on day 13 of cycle 2. Computed tomography scans revealed an intraperitoneal abscess due to acute appendicitis, and consequently urgent operation was performed. It is necessary to understand that patients with acute appendicitis duringchemotherapy can present less clinical findings. PMID- 29138383 TI - [A Case of Locally Advanced Breast Cancer Successfully Treated with Local Control That Achieved a Pathological Complete Response after Bevacizumab and Paclitaxel Combination Chemotherapy]. AB - A 68-year-old woman with a 5-year history of an untreated left breast tumor presented to our hospital. She was admitted for untreated diabetes and severe anemia. The cause of the anemia was bleeding from the tumor, and she was referred to our department. She was diagnosed with T4bN0M0, stage IIIb breast cancer. First, we initiated hormonal therapy. However, the tumor did not decrease in size. We then administered chemotherapy. The tumor markedly decreased in size, and mastectomy and axillary lymph node dissection were performed. The response was a pathological complete response. She is currently undergoing hormonal therapy at the time of this writing. PMID- 29138384 TI - [A Case of Biopsy Confirmed Unresectable Retroperitoneal Seminoma Successfully Treated with Chemotherapy]. AB - We herein report a case of a retroperitoneal tumor of unknown origin that was diagnosed as a seminoma after tumor biopsy and was successfully treated with chemotherapy containing bleomycin, etoposide, and cisplatin(BEP). A 47-year old man visited our hospital with left abdominal pain. An endoscopic examination revealed an ulcer lesion on the third part of the duodenum. Abdominal CT scan revealed a retroperitoneal tumor invading the abdominal aorta with the tumor thrombus in the inferior vena cava(IVC). An endoscopic biopsy could not identify the tumor's origin because of the negative staining of various surface markers on immunohistochemistry. Surgical biopsy of the unresectable retroperitoneal tumor that was finally diagnosed as a seminoma was performed. The patient was treated with BEP according to the International Germ Cell Consensus Classification(IGCCC)for risks, and orchiectomy was performed. He has been alive for 7 months with progressive shrinkage of the retroperitoneal tumor, in which 18F-fluorodeoxyglucose(FDG)positron emission tomography(PET)has shown a dramatic reduction of the maximum standardized uptake value(SUV)during chemotherapy. PMID- 29138385 TI - Parameters for Contrast-Enhanced Ultrasound (CEUS) of Enlarged Superficial Lymph Nodes for the Evaluation of Therapeutic Response in Lymphoma: A Preliminary Study. AB - BACKGROUND The aims of this preliminary study were to evaluate contrast-enhanced ultrasound (CEUS) imaging and the therapeutic response of enlarged superficial lymph nodes in patients with lymphoma before and after chemotherapy and to determine the most useful CEUS response parameters. MATERIAL AND METHODS Forty three patients with lymphoma, with 43 enlarged superficial lymph nodes, underwent CEUS and conventional ultrasound (US), before treatment and after the first three cycles of chemotherapy. Clinical responses included overall response (OR) and no response (NR). Imaging parameters by time-intensity curve (TIC) included basic intensity (B), wash-out slope and/or decent slope (K), wash-in slope or rise slope (C), time to peak (TTP), area under the gamma curve (Area), arrive time(ATM), peak intensity (PI), change of peak intensity (I) were compared. And receiver operating characteristic (ROC) curve analysis was operated. RESULTS Quantitative parameters of CEUS before and after the first three cycles of chemotherapy showed a significant difference in the AreaDelta, PID, and IDelta in the OR group compared with NR group (P<0.05). There was a significant difference in the Cpre, Areain, PIin, Iin, AreaDelta, PIDelta, and IDelta in the OR group compared with NR group (P<0.05). The effectiveness of the therapeutic response was predicted by the CEUS parameters of IDelta (P<0.05). And DeltaArea has the highest diagnostic performance of ineffectiveness. CONCLUSIONS The findings of this study have shown that quantitative analysis by CEUS may be a useful, and objective, imaging method for the evaluation of the therapeutic response of enlarged superficial lymph nodes in lymphoma before and after chemotherapy. PMID- 29138386 TI - Reverse Less Invasive Stabilization System (LISS) Plating for Proximal Femur Fractures in Poliomyelitis Survivors: A Report of Two Cases. AB - BACKGROUND Poliomyelitis is a neuromuscular disease which causes muscle atrophy, skeletal deformities, and disabilities. Treatment of hip fractures on polio affect limbs is unique and difficult, since routine fixation methods like nailing may not be suitable due to abnormal skeletal structures. CASE REPORT We report one femoral neck fracture and one subtrochanteric fracture in polio survivors successfully treated with reverse less invasive stabilization system (LISS) plating technique. Both fractures were on polio-affected limbs with significant skeletal deformities and low bone density. A contralateral femoral LISS plate was applied upside down to the proximal femur as an internal fixator after indirect or direct reduction. Both patients had uneventful bone union and good functional recovery. CONCLUSIONS Reverse LISS plating is a safe and effective technique to treat hip fractures with skeletal deformities caused by poliomyelitis. PMID- 29138387 TI - Strategies for feeding the world more sustainably with organic agriculture. AB - Organic agriculture is proposed as a promising approach to achieving sustainable food systems, but its feasibility is also contested. We use a food systems model that addresses agronomic characteristics of organic agriculture to analyze the role that organic agriculture could play in sustainable food systems. Here we show that a 100% conversion to organic agriculture needs more land than conventional agriculture but reduces N-surplus and pesticide use. However, in combination with reductions of food wastage and food-competing feed from arable land, with correspondingly reduced production and consumption of animal products, land use under organic agriculture remains below the reference scenario. Other indicators such as greenhouse gas emissions also improve, but adequate nitrogen supply is challenging. Besides focusing on production, sustainable food systems need to address waste, crop-grass-livestock interdependencies and human consumption. None of the corresponding strategies needs full implementation and their combined partial implementation delivers a more sustainable food future. PMID- 29138388 TI - Correspondence: Reply to 'Challenges with dating weathering products to unravel ancient landscapes'. PMID- 29138389 TI - Phage display and selection of lanthipeptides on the carboxy-terminus of the gene 3 minor coat protein. AB - Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an emerging class of natural products with drug-like properties. To fully exploit the potential of RiPPs as peptide drug candidates, tools for their systematic engineering are required. Here we report the engineering of lanthipeptides, a subclass of RiPPs characterized by multiple thioether cycles that are enzymatically introduced in a regio- and stereospecific manner, by phage display. This was achieved by heterologous co-expression of linear lanthipeptide precursors fused to the widely neglected C-terminus of the bacteriophage M13 minor coat protein pIII, rather than the conventionally used N-terminus, along with the modifying enzymes from distantly related bacteria. We observe that C terminal precursor peptide fusions to pIII are enzymatically modified in the cytoplasm of the producing cell and subsequently displayed as mature cyclic peptides on the phage surface. Biopanning of large C-terminal display libraries readily identifies artificial lanthipeptide ligands specific to urokinase plasminogen activator (uPA) and streptavidin. PMID- 29138390 TI - Estimation of Ground PM2.5 Concentrations using a DEM-assisted Information Diffusion Algorithm: A Case Study in China. AB - When estimating national PM2.5 concentrations, the results of traditional interpolation algorithms are unreliable due to a lack of monitoring sites and heterogeneous spatial distributions. PM2.5 spatial distribution is strongly correlated to elevation, and the information diffusion algorithm has been shown to be highly reliable when dealing with sparse data interpolation issues. Therefore, to overcome the disadvantages of traditional algorithms, we proposed a method combining elevation data with the information diffusion algorithm. Firstly, a digital elevation model (DEM) was used to segment the study area into multiple scales. Then, the information diffusion algorithm was applied in each region to estimate the ground PM2.5 concentration, which was compared with estimation results using the Ordinary Kriging and Inverse Distance Weighted algorithms. The results showed that: (1) reliable estimate at local area was obtained using the DEM-assisted information diffusion algorithm; (2) the information diffusion algorithm was more applicable for estimating daily average PM2.5 concentrations due to the advantage in noise data; (3) the information diffusion algorithm required less supplementary data and was suitable for simulating the diffusion of air pollutants. We still expect a new comprehensive model integrating more factors would be developed in the future to optimize the interpretation accuracy of short time observation data. PMID- 29138391 TI - Maternal impulse control disability and developmental disorder traits are risk factors for child maltreatment. AB - Previous work has suggested that maternal developmental disorder traits related to autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) are significantly associated with child maltreatment. However, there may be other important maternal characteristics that contribute to child maltreatment. We hypothesized that maternal impulse control disability may also affect child maltreatment in addition to maternal developmental disorder traits. We aimed to test this hypothesis via a cohort study performed in Tokyo (n = 1,260). Linear regression analyses using the Behavioural Inhibition/Behavioural Activation Scales, the self-administered short version of the Pervasive Developmental Disorders Autism Society Japan Rating Scale, the short form of the Adult Attention-Deficit Hyperactivity Disorder Self-Report Scale, and the Child Maltreatment Scale, revealed that excessive inhibition of behaviour and affect, which is impulse control disability, is significantly associated with child maltreatment (b = 0.031, p = 0.018) in addition to maternal developmental disorder traits (ASD: b = 0.052, p = 0.004; ADHD: b = 0.178, p < 0.001). Logistic regression analyses revealed that ASD (adjusted odds ratio [AOR] = 1.083, p = 0.014) and high behavioural inhibition (AOR = 1.068, p = 0.016) were significantly associated with moderate child maltreatment, while ADHD was associated (AOR = 1.034, p = 0.022) with severe child maltreatment. These maternal characteristics may inform the best means for prevention and management of child maltreatment cases. PMID- 29138392 TI - Bay-Region Functionalisation of Ar-BIAN Ligands and Their Use Within Highly Absorptive Cationic Iridium(III) Dyes. AB - We report the synthesis, UV-vis absorption, electrochemical characterisation, and DFT studies of five panchromatic, heteroleptic iridium complexes (four of which are new) supported by Ar-BIAN ligands. In particular, the synthesis of an ester functionalised Ar-BIAN ligand was carried out by a mechanochemical milling approach, which was advantageous over conventional metal templating solution methods in terms of reaction time and product purity. The introduction of ester and carboxylate functionalities at the bay region of the acenaphthene motif increases each ligand's pi-accepting capacity and imparts grafting capabilities to the iridium complexes. These complexes have absorption profiles that surpass the renowned N3 dye [Ru(dcbpy)2(NCS)2] (dcbpy = 4,4'-dicarboxy-2,2'-bipyridine), making them of interest for solar-energy-harvesting applications. PMID- 29138393 TI - Dogs and humans respond to emotionally competent stimuli by producing different facial actions. AB - The commonality of facial expressions of emotion has been studied in different species since Darwin, with most of the research focusing on closely related primate species. However, it is unclear to what extent there exists common facial expression in species more phylogenetically distant, but sharing a need for common interspecific emotional understanding. Here we used the objective, anatomically-based tools, FACS and DogFACS (Facial Action Coding Systems), to quantify and compare human and domestic dog facial expressions in response to emotionally-competent stimuli associated with different categories of emotional arousal. We sought to answer two questions: Firstly, do dogs display specific discriminatory facial movements in response to different categories of emotional stimuli? Secondly, do dogs display similar facial movements to humans when reacting in emotionally comparable contexts? We found that dogs displayed distinctive facial actions depending on the category of stimuli. However, dogs produced different facial movements to humans in comparable states of emotional arousal. These results refute the commonality of emotional expression across mammals, since dogs do not display human-like facial expressions. Given the unique interspecific relationship between dogs and humans, two highly social but evolutionarily distant species sharing a common environment, these findings give new insight into the origin of emotion expression. PMID- 29138394 TI - Critical Mutation Rate has an Exponential Dependence on Population Size for Eukaryotic-length Genomes with Crossover. AB - The critical mutation rate (CMR) determines the shift between survival-of-the fittest and survival of individuals with greater mutational robustness ("flattest"). We identify an inverse relationship between CMR and sequence length in an in silico system with a two-peak fitness landscape; CMR decreases to no more than five orders of magnitude above estimates of eukaryotic per base mutation rate. We confirm the CMR reduces exponentially at low population sizes, irrespective of peak radius and distance, and increases with the number of genetic crossovers. We also identify an inverse relationship between CMR and the number of genes, confirming that, for a similar number of genes to that for the plant Arabidopsis thaliana (25,000), the CMR is close to its known wild-type mutation rate; mutation rates for additional organisms were also found to be within one order of magnitude of the CMR. This is the first time such a simulation model has been assigned input and produced output within range for a given biological organism. The decrease in CMR with population size previously observed is maintained; there is potential for the model to influence understanding of populations undergoing bottleneck, stress, and conservation strategy for populations near extinction. PMID- 29138397 TI - Author Correction: Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway. AB - The original version of this Article contained an error in the spelling of the author Nobuhiko Ohno, which was incorrectly given as Noubuhiko Ohno. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29138395 TI - Myokine mediated muscle-kidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys. AB - Kidney injury initiates metabolic reprogramming in tubule cells that contributes to the development of chronic kidney disease (CKD). Exercise has been associated with beneficial effects in patients with CKD. Here we show that the induction of a myokine, irisin, improves kidney energy metabolism and prevents kidney damage. In response to kidney injury, mice with muscle-specific PGC-1alpha overexpression (mPGC-1alpha) exhibit reduced kidney damage and fibrosis. Metabolomics analysis reveals increased ATP production and improved energy metabolism in injured kidneys from mPGC-1alpha mice. We identify irisin as a serum factor that mediates these metabolic effects during progressive kidney injury by inhibiting TGF-beta type 1 receptor. Irisin depletion from serum blunts the induction of oxygen consumption rate observed in tubule cells treated with mPGC-1alpha serum. In mice, recombinant irisin administration attenuates kidney damage and fibrosis and improves kidney functions. We suggest that myokine-mediated muscle-kidney crosstalk can suppress metabolic reprograming and fibrogenesis during kidney disease. PMID- 29138398 TI - Characterization of macrophages from schizophrenia patients. AB - Genetic, epidemiological and post mortem studies have described an association between schizophrenia (SCZ) and the immune system. Microglia, the tissue-resident macrophages of the brain, not only play an essential role in inflammatory processes, but also in neurodevelopment and synapse refinement. It has therefore been hypothesized that aberrant functioning of these myeloid immune cells is involved in SCZ pathogenesis. Until now cellular research into the role of myeloid cells in SCZ has been limited to monocytes and functional assays are lacking. In this study we used monocyte-derived macrophages (mo-MPhis) as a model for macrophages and microglia in the CNS and examined two main functions: Inflammatory responses and expression and regulation of synapse refinement molecules. The expression of 24 genes involved in these key functions was assessed. Mo-MPhis were generated from 15 SCZ patients and 15 healthy controls. The cells were exposed to pro-inflammatory and anti-inflammatory stimuli (LPS, R848, IL-4 and dexamethasone), and the response was measured by qPCR and ELISA analyses. One of the genes of interest, P2RX7 that is associated with psychiatric diseases, was significantly reduced in expression after LPS stimulation in SCZ patients. None of the other assessed characteristics were different in this functional screen between mo-MPhis from SCZ patients compared to controls. Although these data suggest that overall the function of macrophages in SCZ is not impaired, further studies with larger groups that enable the possibility to study clinical subgroups and perform additional screenings to asses the full phenotype of the mo-MPhis are needed to strengthen this conclusion. PMID- 29138396 TI - Polo-like kinase 1 coordinates biosynthesis during cell cycle progression by directly activating pentose phosphate pathway. AB - Two hallmarks for cancer cells are the accelerated cell cycle progression as well as the altered metabolism, however, how these changes are coordinated to optimize the growth advantage for cancer cells are still poorly understood. Here we identify that Polo-like kinase 1 (Plk1), a key regulator for cell mitosis, plays a critical role for biosynthesis in cancer cells through activating pentose phosphate pathway (PPP). We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules. Importantly, we further demonstrate that Plk1-mediated activation of G6PD is critical for its role to promote cell cycle progression and cancer cell growth. Collectively, these findings establish a critical role for Plk1 in regulating biosynthesis in cancer cells, exemplifying how cell cycle progression and metabolic reprogramming are coordinated for cancer progression. PMID- 29138399 TI - The industrial anaerobe Clostridium acetobutylicum uses polyketides to regulate cellular differentiation. AB - Polyketides are an important class of bioactive small molecules valued not only for their diverse therapeutic applications, but also for their role in controlling interesting biological phenotypes in their producing organisms. While numerous polyketides are known to be derived from aerobic organisms, only a single family of polyketides has been identified from anaerobic organisms. Here we uncover a family of polyketides native to the anaerobic bacterium Clostridium acetobutylicum, an organism well-known for its historical use as an industrial producer of the organic solvents acetone, butanol, and ethanol. Through mutational analysis and chemical complementation assays, we demonstrate that these polyketides act as chemical triggers of sporulation and granulose accumulation in this strain. This study represents a significant addition to the body of work demonstrating the existence and importance of polyketides in anaerobes, and showcases a strategy of manipulating the secondary metabolism of an organism to improve traits relevant for industrial applications. PMID- 29138400 TI - Accessibility of the histone H3 tail in the nucleosome for binding of paired readers. AB - Combinatorial polyvalent contacts of histone-binding domains or readers commonly mediate localization and activities of chromatin-associated proteins. A pair of readers, the PHD fingers of the protein CHD4, has been shown to bivalently recognize histone H3 tails. Here we describe a mechanism by which these linked but independent readers bind to the intact nucleosome core particle (NCP). Comprehensive NMR, chemical reactivity, molecular dynamics, and fluorescence analyses point to the critical roles of intra-nucleosomal histone-DNA interactions that reduce the accessibility of H3 tails in NCP, the nucleosomal DNA, and the linker between readers in modulating nucleosome- and/or histone binding activities of the readers. We show that the second PHD finger of CHD4 initiates recruitment to the nucleosome, however both PHDs are required to alter the NCP dynamics. Our findings reveal a distinctive regulatory mechanism for the association of paired readers with the nucleosome that provides an intricate balance between cooperative and individual activities of the readers. PMID- 29138402 TI - Impacts of hemispheric solar geoengineering on tropical cyclone frequency. AB - Solar geoengineering refers to a range of proposed methods for counteracting global warming by artificially reducing sunlight at Earth's surface. The most widely known solar geoengineering proposal is stratospheric aerosol injection (SAI), which has impacts analogous to those from volcanic eruptions. Observations following major volcanic eruptions indicate that aerosol enhancements confined to a single hemisphere effectively modulate North Atlantic tropical cyclone (TC) activity in the following years. Here we investigate the effects of both single hemisphere and global SAI scenarios on North Atlantic TC activity using the HadGEM2-ES general circulation model and various TC identification methods. We show that a robust result from all of the methods is that SAI applied to the southern hemisphere would enhance TC frequency relative to a global SAI application, and vice versa for SAI in the northern hemisphere. Our results reemphasise concerns regarding regional geoengineering and should motivate policymakers to regulate large-scale unilateral geoengineering deployments. PMID- 29138401 TI - Imaging the transient heat generation of individual nanostructures with a mechanoresponsive polymer. AB - Measuring the localized transient heat generation is critical for developing applications of nanomaterials in areas of photothermal therapy (PTT), drug delivery, optomechanics and biological processes engineering. However, accurate thermometry with high spatiotemporal resolution is still a challenge. Here we develop a thermosensitive polymer-capped gold nanorod (AuNRs@pNIPAAm), which has temperature-dependent local surface plasmon resonance spectra due to the submolecular conformational change of pNIPAAm molecules. We measure the conformational dynamics on individual gold nanorods at the milliseconds level by the developed spatiotemporal resolution plasmonic spectroscopy (SRPS) and find that it has a fast (<4 ms), linear and reversible mechanoresponse to temperature changes as small as 80 mK. The rapid and highly sensitive thermosensitive AuNRs@pNIPAAm opens a new way to achieve spatiotemporal thermometry for potential applications in PTT and other biological research. PMID- 29138403 TI - Correspondence: Challenges with dating weathering products to unravel ancient landscapes. PMID- 29138404 TI - Neonicotinoid pesticide limits improvement in buzz pollination by bumblebees. AB - Neonicotinoid pesticides have been linked to global declines of beneficial insects such as bumblebees. Exposure to trace levels of these chemicals causes sub-lethal effects, such as reduced learning and foraging efficiency. Complex behaviours may be particularly vulnerable to the neurotoxic effects of neonicotinoids. Such behaviours may include buzz pollination (sonication), in which pollinators, usually bees, use innate and learned behaviours to generate high-frequency vibrations to release pollen from flowers with specialised anther morphologies. This study assesses the effect of field-realistic, chronic exposure to the widely-used neonicotinoid thiamethoxam on the development of sonication buzz characteristics over time, as well as the collection of pollen from buzz pollinated flowers. We found that the pollen collection of exposed bees improved less with increasing experience than that of unexposed bees, with exposed bees collecting between 47% and 56% less pollen by the end of 10 trials. We also found evidence of two distinct strategies for maximising pollen collection: (1) extensions to the duration of individual buzzes and (2) extensions of the overall time spent buzzing. We find new complexities in buzz pollination, and conclude that the impacts of field-realistic exposure to a neonicotinoid pesticide may seriously compromise this important ecosystem service. PMID- 29138405 TI - Ca2+ signals initiate at immobile IP3 receptors adjacent to ER-plasma membrane junctions. AB - IP3 receptors (IP3Rs) release Ca2+ from the ER when they bind IP3 and Ca2+. The spatial organization of IP3Rs determines both the propagation of Ca2+ signals between IP3Rs and the selective regulation of cellular responses. Here we use gene editing to fluorescently tag endogenous IP3Rs, and super-resolution microscopy to determine the geography of IP3Rs and Ca2+ signals within living cells. We show that native IP3Rs cluster within ER membranes. Most IP3R clusters are mobile, moved by diffusion and microtubule motors. Ca2+ signals are generated by a small population of immobile IP3Rs. These IP3Rs are licensed to respond, but they do not readily mix with mobile IP3Rs. The licensed IP3Rs reside alongside ER plasma membrane junctions where STIM1, which regulates store-operated Ca2+ entry, accumulates after depletion of Ca2+ stores. IP3Rs tethered close to ER-plasma membrane junctions are licensed to respond and optimally placed to be activated by endogenous IP3 and to regulate Ca2+ entry. PMID- 29138406 TI - Activating cobalt(II) oxide nanorods for efficient electrocatalysis by strain engineering. AB - Designing high-performance and cost-effective electrocatalysts toward oxygen evolution and hydrogen evolution reactions in water-alkali electrolyzers is pivotal for large-scale and sustainable hydrogen production. Earth-abundant transition metal oxide-based catalysts are particularly active for oxygen evolution reaction; however, they are generally considered inactive toward hydrogen evolution reaction. Here, we show that strain engineering of the outermost surface of cobalt(II) oxide nanorods can turn them into efficient electrocatalysts for the hydrogen evolution reaction. They are competitive with the best electrocatalysts for this reaction in alkaline media so far. Our theoretical and experimental results demonstrate that the tensile strain strongly couples the atomic, electronic structure properties and the activity of the cobalt(II) oxide surface, which results in the creation of a large quantity of oxygen vacancies that facilitate water dissociation, and fine tunes the electronic structure to weaken hydrogen adsorption toward the optimum region. PMID- 29138407 TI - Spirometry is not enough to diagnose COPD in epidemiological studies: a follow-up study. AB - A hallmark of the diagnosis of chronic obstructive pulmonary disease (COPD) is the measurement of post-bronchodilator (post-BD) airflow obstruction (AO) by spirometry, but spirometry is not enough for the provision of a clinical diagnosis. In the majority of previous epidemiological studies, COPD diagnosis has been based on spirometry and a few clinical characteristics. The aim of our study was to identify outcomes in patients newly diagnosed with airflow obstruction (AO) based on a diagnostic work-up conducted as part of a population based cross-sectional study in North-Western Russia. Spirometry was performed before (pre-BD) and after BD administration, and AO was defined using the FEV1/FVC <0.70 and FEV1/FVC 120 ms or aberrant conduction), heart failure, valvular heart disease, chronic pulmonary disease, and obesity were excluded. Ventricular arrhythmias from the left ventricle had an increased S1 complexity score and S1 duration in comparison to adjacent sinus beats. On the other hand, ventricular arrhythmia from right ventricle had decreased S1 complexity score and S1 duration in comparison to adjacent sinus beats. The difference of S1 (DeltaS1) parameters between premature ventricular complex and sinus beat was significantly smaller in right ventricular arrhythmia group compared with and left ventricular arrhythmia group. For predicting the origin of ventricular arrhythmia, the DeltaS1 duration provide better predictive accuracy (sensitivity: 100%, specificity: 100%, cutoff value: -1.28 ms) in comparison to DeltaS1 complexity score (sensitivity 71.4%, specificity 75.0%, cutoff value: -0.13). The change of S1 complexity and duration determined from acoustic cardiography could accurately predict the ventricular arrhythmia origin. PMID- 29138410 TI - PLA2-like proteins myotoxic mechanism: a dynamic model description. AB - Phospholipase A2-like (PLA2-like) proteins contribute to the development of muscle necrosis in Viperidae snake bites and are not efficiently neutralized by current antivenom treatments. The toxic mechanisms of PLA2-like proteins are devoid of catalytic activity and not yet fully understood, although structural and functional experiments suggest a dimeric assembly and that the C-terminal residues are essential to myotoxicity. Herein, we characterized the functional mechanism of bothropic PLA2-like structures related to global and local measurements using the available models in the Protein Data Bank and normal mode molecular dynamics (NM-MD). Those measurements include: (i) new geometric descriptions between their monomers, based on Euler angles; (ii) characterizations of canonical and non-canonical conformations of the C-terminal residues; (iii) accessibility of the hydrophobic channel; (iv) inspection of ligands; and (v) distance of clustered residues to toxin interface of interaction. Thus, we described the allosteric activation of PLA2-like proteins and hypothesized that the natural movement between monomers, calculated from NM MD, is related to their membrane disruption mechanism, which is important for future studies of the inhibition process. These methods and strategies can be applied to other proteins to help understand their mechanisms of action. PMID- 29138411 TI - Divide-and-conquer Tournament on Social Networks. AB - In social gaming networks, previous studies extensively investigated the influence of a variety of strategies on reciprocal behaviors in the prisoner's dilemma game. The studied frameworks range from the case that an individual uniformly cooperates or defects with all social contacts, to the recently reported divide-and-conquer games, where an individual can choose a particular move to play with each neighbor. In this paper, we investigate a divide-and conquer tournament among 14 well-known strategies on social gaming networks. In the tournament, an individual's fitness is measured by accumulated and average payoff aggregated for a certain number of rounds. On the base of their fitness, the evolution of the population follows a local learning mechanism. Our observation indicates that the distribution of individuals adopting a strategy in degree ranking fundamentally changes the frequency of the strategy. In the divide and-conquer gaming networks, our result suggests that the connectivity in social networks and strategy are two key factors that govern the evolution of the population. PMID- 29138412 TI - Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies. AB - The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning. PMID- 29138413 TI - Oscillators that sync and swarm. AB - Synchronization occurs in many natural and technological systems, from cardiac pacemaker cells to coupled lasers. In the synchronized state, the individual cells or lasers coordinate the timing of their oscillations, but they do not move through space. A complementary form of self-organization occurs among swarming insects, flocking birds, or schooling fish; now the individuals move through space, but without conspicuously altering their internal states. Here we explore systems in which both synchronization and swarming occur together. Specifically, we consider oscillators whose phase dynamics and spatial dynamics are coupled. We call them swarmalators, to highlight their dual character. A case study of a generalized Kuramoto model predicts five collective states as possible long-term modes of organization. These states may be observable in groups of sperm, Japanese tree frogs, colloidal suspensions of magnetic particles, and other biological and physical systems in which self-assembly and synchronization interact. PMID- 29138414 TI - Potential Application of 1H NMR for Routine Serum Lipidome Analysis -Evaluation of Effects of Bariatric Surgery. AB - Routine laboratory lipid assays include simple measurements of total cholesterol, triacylglycerols and HDL. However, lipids are a large group of compounds involved in many metabolic pathways, and their alterations may have serious health consequences. In this study, we used 1H NMR to analyze lipids extracted from sera of 16 obese patients prior to and after bariatric surgeries. We observed a post surgery decrease in serum concentrations of lipids from various groups. The hereby presented findings imply that 1H NMR is suitable for rapid, simple and non invasive detection of lipids from 30 structural groups, among them triacylglycerols, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, total phospholipids, total, free and esterified cholesterol, total and unsaturated fatty acids. NMR-based analysis of serum lipids may contribute to a substantial increase in the number of routinely determined markers from this group; therefore, it may find application in clinical assessment of obese subjects prior to and after bariatric surgeries, as well as in the examination of patients with other metabolic diseases. PMID- 29138415 TI - Determining phase coherence time of stored light in warm atomic vapor. AB - In quantum memory based on an atomic medium, we may have a question about whether all information on the stored light is preserved. In particular, the phase coherence between the stored and retrieval light pulses is very interesting, because it can indicate the relationship between the coherence time and storage time of the light. In this paper, we investigate the phase coherence time of light stored in a warm atomic vapor, by examining the beat-note interference between the retrieval light pulse and a reference light beam optically delayed using an optical fiber. The beat-note interference fringes are measured for different reference-light optical delays. The observed retrieval-light phase indicates that the phase of the input probe light is preserved in the medium. However, we further confirm that the retrieval-light phase coherence depends on the phase coherence of the coupling light used for retrieval in the storage process. PMID- 29138416 TI - Plant-to-plant communication triggered by systemin primes anti-herbivore resistance in tomato. AB - Plants actively respond to herbivory by inducing various defense mechanisms in both damaged (locally) and non-damaged tissues (systemically). In addition, it is currently widely accepted that plant-to-plant communication allows specific neighbors to be warned of likely incoming stress (defense priming). Systemin is a plant peptide hormone promoting the systemic response to herbivory in tomato. This 18-aa peptide is also able to induce the release of bioactive Volatile Organic Compounds, thus also promoting the interaction between the tomato and the third trophic level (e.g. predators and parasitoids of insect pests). In this work, using a combination of gene expression (RNA-Seq and qRT-PCR), behavioral and chemical approaches, we demonstrate that systemin triggers metabolic changes of the plant that are capable of inducing a primed state in neighboring unchallenged plants. At the molecular level, the primed state is mainly associated with an elevated transcription of pattern -recognition receptors, signaling enzymes and transcription factors. Compared to naive plants, systemin primed plants were significantly more resistant to herbivorous pests, more attractive to parasitoids and showed an increased response to wounding. Small peptides are nowadays considered fundamental signaling molecules in many plant processes and this work extends the range of downstream effects of this class of molecules to intraspecific plant-to-plant communication. PMID- 29138417 TI - Association of predicted pathogenic mutations in mitochondrial ND genes with distant metastasis in NSCLC and colon cancer. AB - Cancer cells have more mutations in their mitochondrial DNA (mtDNA) than do normal cells, and pathogenic mutations in the genes encoding mitochondrial NADH dehydrogenase (ND) subunits have been found to enhance the invasive and metastatic ability of various tumour cells in animal experiments. However, it is unknown whether single-nucleotide variants (SNVs) of the ND genes that decrease complex I activity are involved in distant metastasis in human clinical samples. Here, we demonstrated the enhancement of the distant metastasis of Lewis lung carcinoma cells by the ND6 13885insC mutation, which is accompanied by the overexpression of metastasis-related genes, metabolic reprogramming, the enhancement of tumour angiogenesis and the acquisition of resistance to stress induced cell death. We then sequenced ND genes in primary tumour lesions with or without distant metastases as well as metastatic tumour lesions from 115 patients with non-small cell lung cancer (NSCLC) and colon cancer, and we subsequently selected 14 SNVs with the potential to decrease complex I activity. Intriguingly, a significant correlation was observed (P < 0.05 by Chi-square test) between the incidence of the selected mutations and distant metastasis. Thus, these results strongly suggest that pathogenic ND gene mutations participate in enhancing distant metastasis in human cancers. PMID- 29138418 TI - Spiral Modes and the Observation of Quantized Conductance in the Surface Bands of Bismuth Nanowires. AB - When electrons are confined in two-dimensional materials, quantum-mechanical transport phenomena and high mobility can be observed. Few demonstrations of these behaviours in surface spin-orbit bands exist. Here, we report the observation of quantized conductance in the surface bands of 50-nm Bi nanowires. With increasing magnetic fields oriented along the wire axis, the wires exhibit a stepwise increase in conductance and oscillatory thermopower, possibly due to an increased number of high-mobility spiral surface modes based on spin-split bands. Surface high mobility is unexpected since bismuth is not a topological insulator and the surface is not suspended but in contact with the bulk. The oscillations enable us to probe the surface structure. We observe that mobility increases dramatically with magnetic fields because, owing to Lorentz forces, spiral modes orbit decreases in diameter pulling the charge carriers away from the surface. Our mobility estimates at high magnetic fields are comparable, within order of magnitude, to the mobility values reported for suspended graphene. Our findings represent a key step in understanding surface spin-orbit band electronic transport. PMID- 29138419 TI - IVIG activates FcgammaRIIB-SHIP1-PIP3 Pathway to stabilize mast cells and suppress inflammation after ICH in mice. AB - Following intracerebral hemorrhage (ICH), the activation of mast cell contributes to brain inflammation and brain injury. The mast cell activation is negatively regulated by an inhibitory IgG-receptor. It's signals are mediated by SHIP (Src homology 2-containing inositol 5' phosphatase), in particular SHIP1, which activation leads to hydrolyzation of PIP3 (Phosphatidylinositol (3,4,5) trisphosphate (PtdIns(3,4,5)P3, leading to the inhibition of calcium mobilization and to the attenuation of mast cell activation. Intravenous immunoglobulin (IVIG) is a FDA-approved drug containing IgG. We hypothesized that IVIG will attenuate the ICH-induced mast cell activation via FcgammaRIIB/SHIP1 pathway, resulting in a decrease of brain inflammation, protection of the blood-brain-barrier, and improvement of neurological functions after ICH. To prove this hypothesis we employed the ICH collagenase mouse model. We demonstrated that while ICH induced mast cell activation/degranulation, IVIG attenuated post-ICH mast cell activation. Mast cell deactivation resulted in reduced inflammation, consequently attenuating brain edema and improving of neurological functions after ICH. Furthermore using siRNA-induced in vivo knockdown approach we demonstrated that beneficial effects of IVIG were mediated, at least partly, via SHIP1/PIP3 pathway. We conclude that IVIG treatment represents a promising therapeutic approach potentially able to decrease mortality and morbidity after ICH in experimental models. PMID- 29138420 TI - Expression of both poly r(C) binding protein 1 (PCBP1) and miRNA-3978 is suppressed in peritoneal gastric cancer metastasis. AB - The expression of legumain which has been shown overexpressed in patients with metastatic gastric cancer is positively correlated to both disease progression and outcome, and negatively correlated to microRNA (miR)-3978 expression. The RNA binding protein, poly r(C) binding protein 1 (PCBP1) was the most downregulated protein in the metastatic tissue specimens. Quantitative real-time PCR showed that PCBP1 expression is transcriptionally downregulated in peritoneal metastasis tissues. RNA immunoprecipitation experiments showed that PCBP1 and miR-3978 are sequestered in normal peritoneal tissue, but the complex is disrupted following metastatic progression. PCBP1 expression mimicked miR-3978 expression across gastric cancer patients. Finally, replenishment of PCBP1 or miR-3978 expression in the peritoneal metastasis cell line MKN45 decreased legumain protein expression and chemosensitized the cells to treatment with docetaxel. However, replenishment of one and concomitant depletion of the other failed to induce chemosensitivity to docetaxel. Replenishment of miR-3978 also resulted in induction of PCBP1 protein expression, potentially indicating that miR-3978 expression might downregulate a negative regulator targeting PCBP1. Our current study reveals PCBP1 as an additional biomarker in peritoneal metastasis. PCBP1 and miR-3978 expression were correlated and suggests a potential interplay of differential miRNA biogenesis and RNA binding protein during metastatic progression. PMID- 29138421 TI - mPeriod2 Brdm1 and other single Period mutant mice have normal food anticipatory activity. AB - Animals anticipate the timing of food availability via the food-entrainable oscillator (FEO). The anatomical location and timekeeping mechanism of the FEO are unknown. Several studies showed the circadian gene, Period 2, is critical for FEO timekeeping. However, other studies concluded that canonical circadian genes are not essential for FEO timekeeping. In this study, we re-examined the effects of the Per2 Brdm1 mutation on food entrainment using methods that have revealed robust food anticipatory activity in other mutant lines. We examined food anticipatory activity, which is the output of the FEO, in single Period mutant mice. Single Per1, Per2, and Per3 mutant mice had robust food anticipatory activity during restricted feeding. In addition, we found that two different lines of Per2 mutant mice (ldc and Brdm1) anticipated restricted food availability. To determine if FEO timekeeping persisted in the absence of the food cue, we assessed activity during fasting. Food anticipatory (wheel-running) activity in all Period mutant mice was also robust during food deprivation. Together, our studies demonstrate that the Period genes are not necessary for the expression of food anticipatory activity. PMID- 29138422 TI - FAM19A5, a brain-specific chemokine, inhibits RANKL-induced osteoclast formation through formyl peptide receptor 2. AB - Osteoclasts can be differentiated from bone marrow-derived macrophages (BMDM). They play a key role in bone resorption. Identifying novel molecules that can regulate osteoclastogenesis has been an important issue. In this study, we found that FAM19A5, a neurokine or brain-specific chemokine, strongly stimulated mouse BMDM, resulting in chemotactic migration and inhibition of RANKL-induced osteoclastogenesis. Expression levels of osteoclast-related genes such as RANK, TRAF6, OSCAR, TRAP, Blimp1, c-fos, and NFATc1 were markedly decreased by FAM19A5. However, negative regulators of osteoclastogenesis such as MafB and IRF-8 were upregulated by FAM19A5. FAM19A5 also downregulated expression levels of RANKL induced fusogenic genes such as OC-STAMP, DC-STAMP, and Atp6v0d2. FAM19A5-induced inhibitory effect on osteoclastogenesis was significantly reversed by a formyl peptide receptor (FPR) 2 antagonist WRW4 or by FPR2-deficiency, suggesting a crucial role of FPR2 in the regulation of osteoclastogenesis. Collectively, our results suggest that FAM19A5 and its target receptor FPR2 can act as novel endogenous ligand/receptor to negatively regulate osteoclastogenesis. They might be regarded as potential targets to control osteoclast formation and bone disorders. PMID- 29138423 TI - The photocycle of orange carotenoid protein conceals distinct intermediates and asynchronous changes in the carotenoid and protein components. AB - The 35-kDa Orange Carotenoid Protein (OCP) is responsible for photoprotection in cyanobacteria. It acts as a light intensity sensor and efficient quencher of phycobilisome excitation. Photoactivation triggers large-scale conformational rearrangements to convert OCP from the orange OCPO state to the red active signaling state, OCPR, as demonstrated by various structural methods. Such rearrangements imply a complete, yet reversible separation of structural domains and translocation of the carotenoid. Recently, dynamic crystallography of OCPO suggested the existence of photocycle intermediates with small-scale rearrangements that may trigger further transitions. In this study, we took advantage of single 7 ns laser pulses to study carotenoid absorption transients in OCP on the time-scale from 100 ns to 10 s, which allowed us to detect a red intermediate state preceding the red signaling state, OCPR. In addition, time resolved fluorescence spectroscopy and the assignment of carotenoid-induced quenching of different tryptophan residues derived thereof revealed a novel orange intermediate state, which appears during the relaxation of photoactivated OCPR to OCPO. Our results show asynchronous changes between the carotenoid- and protein-associated kinetic components in a refined mechanistic model of the OCP photocycle, but also introduce new kinetic signatures for future studies of OCP photoactivity and photoprotection. PMID- 29138425 TI - Timescale Separation of Positive and Negative Signaling Creates History-Dependent Responses to IgE Receptor Stimulation. AB - The high-affinity receptor for IgE expressed on the surface of mast cells and basophils interacts with antigens, via bound IgE antibody, and triggers secretion of inflammatory mediators that contribute to allergic reactions. To understand how past inputs (memory) influence future inflammatory responses in mast cells, a microfluidic device was used to precisely control exposure of cells to alternating stimulatory and non-stimulatory inputs. We determined that the response to subsequent stimulation depends on the interval of signaling quiescence. For shorter intervals of signaling quiescence, the second response is blunted relative to the first response, whereas longer intervals of quiescence induce an enhanced second response. Through an iterative process of computational modeling and experimental tests, we found that these memory-like phenomena arise from a confluence of rapid, short-lived positive signals driven by the protein tyrosine kinase Syk; slow, long-lived negative signals driven by the lipid phosphatase Ship1; and slower degradation of Ship1 co-factors. This work advances our understanding of mast cell signaling and represents a generalizable approach for investigating the dynamics of signaling systems. PMID- 29138424 TI - Structure-function relationships in ABCG2: insights from molecular dynamics simulations and molecular docking studies. AB - Efflux pumps of the ATP-binding cassette transporters superfamily (ABC transporters) are frequently involved in the multidrug-resistance (MDR) phenomenon in cancer cells. Herein, we describe a new atomistic model for the MDR related ABCG2 efflux pump, also named breast cancer resistance protein (BCRP), based on the recently published crystallographic structure of the ABCG5/G8 heterodimer sterol transporter, a member of the ABCG family involved in cholesterol homeostasis. By means of molecular dynamics simulations and molecular docking, a far-reaching characterization of the ABCG2 homodimer was obtained. The role of important residues and motifs in the structural stability of the transporter was comprehensively studied and was found to be in good agreement with the available experimental data published in literature. Moreover, structural motifs potentially involved in signal transmission were identified, along with two symmetrical drug-binding sites that are herein described for the first time, in a rational attempt to better understand how drug binding and recognition occurs in ABCG2 homodimeric transporters. PMID- 29138426 TI - Broadband mixing of [Formula: see text]-symmetric and [Formula: see text]-broken phases in photonic heterostructures with a one-dimensional loss/gain bilayer. AB - Combining loss and gain components in one photonic heterostructure opens a new route to efficient manipulation by radiation, transmission, absorption, and scattering of electromagnetic waves. Therefore, loss/gain structures enabling [Formula: see text]-symmetric and [Formula: see text]-broken phases for eigenvalues have extensively been studied in the last decade. In particular, translation from one phase to another, which occurs at the critical point in the two-channel structures with one-dimensional loss/gain components, is often associated with one-way transmission. In this report, broadband mixing of the [Formula: see text]-symmetric and [Formula: see text]-broken phases for eigenvalues is theoretically demonstrated in heterostructures with four channels obtained by combining a one-dimensional loss/gain bilayer and one or two thin polarization-converting components (PCCs). The broadband phase mixing in the four channel case is expected to yield advanced transmission and absorption regimes. Various configurations are analyzed, which are distinguished in symmetry properties and polarization conversion regime of PCCs. The conditions necessary for phase mixing are discussed. The simplest two-component configurations with broadband mixing are found, as well as the more complex three-component configurations wherein symmetric and broken sets are not yet mixed and appear in the neighbouring frequency ranges. Peculiarities of eigenvalue behaviour are considered for different permittivity ranges of loss/gain medium, i.e., from epsilon-near-zero to high-epsilon regime. PMID- 29138427 TI - Laser Thinning and Patterning of MoS2 with Layer-by-Layer Precision. AB - The recently discovered novel properties of two dimensional materials largely rely on the layer-critical variation in their electronic structure and lattice symmetry. Achieving layer-by-layer precision patterning is thus crucial for junction fabrications and device engineering, which hitherto poses an unprecedented challenge. Here we demonstrate laser thinning and patterning with layer-by-layer precision in a two dimensional (2D) quantum material MoS2. Monolayer, bilayer and trilayer of MoS2 films are produced with precise vertical and lateral control, which removes the extruding barrier for fabricating novel three dimensional (3D) devices composed of diverse layers and patterns. By tuning the laser fluence and exposure time we demonstrate producing MoS2 patterns with designed layer numbers. The underlying physics mechanism is identified to be temperature-dependent evaporation of the MoS2 lattice, verified by our measurements and calculations. Our investigation paves way for 3D device fabrication based on 2D layered quantum materials. PMID- 29138429 TI - Brain Network Correlates of Emotional Aging. AB - Physical and cognitive functions typically decline with aging while emotional stability is relatively conserved. The current proof-of-concept study is the first to report of the brain mechanisms underlying emotional aging from a brain network perspective. Two hundred eighty-six healthy subjects aged 20-65 were classified into three groups of the emotionally young, intermediate-aged, and old (E-young, E-intermediate, and E-old, respectively) based on the cluster analysis of the emotion recognition task data. As subjects get emotionally older, performance on happiness recognition improved, while that on recognition of negative emotions declined. On the brain network side, there was a significant linear decreasing trend in intra-network functional connectivity of the visual and sensorimotor networks with emotional aging (E-young > E-intermediate > E-old) as well as chronological aging (C-young > C-intermediate > C-old). Intra-network functional connectivity of the executive control network (ECN), however, steadily increased with emotional aging (E-young < E-intermediate < E-old) but not with chronological aging. Furthermore, the inter-network functional connections between the ECN and default mode network were also greater in the E-old group relative to the E-young group. This suggests that the top-down integration of self-referential information during emotional processing becomes stronger as people get emotionally older. PMID- 29138428 TI - Structural disorder and induced folding within two cereal, ABA stress and ripening (ASR) proteins. AB - Abscisic acid (ABA), stress and ripening (ASR) proteins are plant-specific proteins involved in plant response to multiple abiotic stresses. We previously isolated the ASR genes and cDNAs from durum wheat (TtASR1) and barley (HvASR1). Here, we show that HvASR1 and TtASR1 are consistently predicted to be disordered and further confirm this experimentally. Addition of glycerol, which mimics dehydration, triggers a gain of structure in both proteins. Limited proteolysis showed that they are highly sensitive to protease degradation. Addition of 2,2,2 trifluoroethanol (TFE) however, results in a decreased susceptibility to proteolysis that is paralleled by a gain of structure. Mass spectrometry analyses (MS) led to the identification of a protein fragment resistant to proteolysis. Addition of zinc also induces a gain of structure and Hydrogen/Deuterium eXchange Mass Spectrometry (HDX-MS) allowed identification of the region involved in the disorder-to-order transition. This study is the first reported experimental characterization of HvASR1 and TtASR1 proteins, and paves the way for future studies aimed at unveiling the functional impact of the structural transitions that these proteins undergo in the presence of zinc and at achieving atomic resolution conformational ensemble description of these two plant intrinsically disordered proteins (IDPs). PMID- 29138430 TI - Extracellular vesicles derived from MSCs activates dermal papilla cell in vitro and promotes hair follicle conversion from telogen to anagen in mice. AB - Hair loss is a common medical problem. In this study, we investigated the proliferation, migration, and growth factor expression of human dermal papilla (DP) cells in the presence or absence of treatment with mesenchymal stem cell extracellular vesicles (MSC-EVs). In addition, we tested the efficacy of MSC-EV treatment on hair growth in an animal model. MSC-EV treatment increased DP cell proliferation and migration, and elevated the levels of Bcl-2, phosphorylated Akt and ERK. In addition; DP cells treated with MSC-EVs displayed increased expression and secretion of VEGF and IGF-1. Intradermal injection of MSC-EVs into C57BL/6 mice promoted the conversion from telogen to anagen and increased expression of wnt3a, wnt5a and versican was demonstrated. The first time our results suggest that MSC-EVs have a potential to activate DP cells, prolonged survival, induce growth factor activation in vitro, and promotes hair growth in vivo. PMID- 29138431 TI - Modelling the effect of beliefs about asthma medication and treatment intrusiveness on adherence and preference for once-daily vs. twice-daily medication. AB - People with asthma who do not adhere to their maintenance medication may experience poorer asthma control and need more healthcare support than those who adhere. People (N = 1010) aged 18-55 years with self-reported asthma, taking one or more asthma maintenance medication(s), from five European countries, participated in a survey using validated scales (Medication Adherence Report Scale [MARS], Asthma Control TestTM [ACT], Beliefs about Medicine Questionnaire [BMQ] and the Asthma Treatment Intrusiveness Questionnaire [ATIQ]). We performed a post hoc evaluation of adherence to maintenance medication, asthma control, beliefs about medication, preferences for once-daily vs. twice-daily asthma maintenance medication and treatment intrusiveness, using structural equation modelling to investigate the relationships between these factors. Most participants reported potential problems with asthma control (ACT < 19: 76.8% [n = 776]), low adherence (median MARS = 3.40) and preferred once-daily medication (73.5% [n = 742/1010]). Non-adherence was associated with worse asthma control (r = 0.262 [P < 0.001]) and a expressed preference for once-daily medication over a "twice daily medication that works slightly better" (test statistic [T] = 2.970 [P = 0.003]). Participants reporting non-adherence/preferring once-daily medication had negative beliefs about their treatment (BMQ necessity-concerns differential: r = 0.437 [P < 0.001]/T = 6.886 [P < 0.001]) and found medication intrusive (ATIQ: r = -0.422 [P < 0.001]/T = 2.689[P = 0.007]). Structural equation modelling showed complex relationships between variables, including: (1) high concerns about treatment associated with increased perceived treatment intrusiveness and reduced adherence, which influenced asthma control; (2) high concerns about treatment and healthcare seeking behaviour, which were predictive of preferring twice-daily asthma medication. Concerns about medication and perceived treatment intrusiveness were predictive of poor adherence, and were associated with preference for once-daily asthma medication. Confirm the utility of the PAPA model and NCF in explaining nonadherence linked to poor asthma control. PMID- 29138432 TI - Social Support as a Key Protective Factor against Depression in HIV-Infected Patients: Report from large HIV clinics in Hanoi, Vietnam. AB - Depression is the most common mental health issue among people living with HIV/AIDS (PLWHA). This study explored how different types and sources of social support are associated with depression among HIV-infected patients in Vietnam. We carried out a cross-sectional survey on 1,503 HIV-infected patients receiving antiretroviral therapy at two HIV clinics in Hanoi in 2016. Depression was prevalent in 26.2% of participants. Higher score of social support, especially emotional/informational support and positive social interaction, showed significant association with lower depression rate. Although family was primary source of all types of social support, receiving emotional/informational support not only from family but also from outside of family correlated with a lower proportion of depression. In countries with constrained social resources and/or with family-oriented social structures, as in Vietnam, expanding social networks between HIV populations and society is a potentially important option for reducing depression. PMID- 29138434 TI - Generating Localized Plasmonic Fields on an Integrated Photonic Platform using Tapered Couplers for Biosensing Applications. AB - A theoretical design and analysis of a tapered-coupler structure on a silicon nitride integrated-photonic platform for coupling optical energy from a dielectric waveguide to a plasmonic tip is presented. The proposed design can be considered as a hybrid photonic-plasmonic structure that generally supports hybrid symmetric and asymmetric modes. Along the taper, one of the hybrid modes approaches the cut-off, while the other approaches the short-range surface plasmon mode that generates localized fields. Potential use of the proposed novel tapered-coupler plasmonic structure for highly sensitive biosensing applications using surface enhanced Raman scattering (SERS) and metal enhanced fluorescence (MEF) techniques is discussed. For SERS, a theoretical electromagnetic enhancement factor as high as 1.23 * 106 is deduced for taper tip widths as small as 20 nm. The proposed tapered-coupler sets up interesting possibilities towards moving to an all-integrated on-chip SERS and MEF based bio-sensor platform - away from traditional free-space based illumination strategies. PMID- 29138433 TI - Transcriptomic analysis of the regulation of stalk development in flowering Chinese cabbage (Brassica campestris) by RNA sequencing. AB - Flowering Chinese cabbage is a stalk vegetable whose quality and yield are directly related to stalk development. However, no comprehensive investigations on stalk development have been performed. To address this issue, the present study used RNA sequencing to investigate transcriptional regulation at three key stages (seedling, bolting, and flowering) of stalk development in flowering Chinese cabbage. Anatomical analysis revealed that cell division was the main mode of stalk thickening and elongation at all key stages. Among the 35,327 genes expressed in shoot apices, 34,448 were annotated and 879 were identified as novel transcripts. We identified 11,514 differentially expressed genes (DEGs) among the three stages of stalk development. Functional analysis revealed that these DEGs were significantly enriched in 'ribosome' and 'plant hormone signal transduction' pathways and were involved in hormone signal transduction, cell cycle progression, and the regulation of flowering time. The roles of these genes in stalk development were explored, and a putative gene-regulation network for the stalk flowering time was established. These findings provide insight into the molecular mechanisms of stalk development in flowering Chinese cabbage that provides a new theoretical basis for stalk vegetable breeding. PMID- 29138435 TI - Effects of GSM and UMTS mobile telephony signals on neuron degeneration and blood brain barrier permeation in the rat brain. AB - Blood-brain barrier (BBB) permeation and neuron degeneration were assessed in the rat brain following exposure to mobile communication radiofrequency (RF) signals (GSM-1800 and UMTS-1950). Two protocols were used: (i) single 2 h exposure, with rats sacrificed immediately, and 1 h, 1, 7, or 50 days later, and (ii) repeated exposures (2 h/day, 5 days/week, for 4 weeks) with the effects assessed immediately and 50 days after the end of exposure. The rats' heads were exposed at brain-averaged specific absorption rates (BASAR) of 0.026, 0.26, 2.6, and 13 W/kg. No adverse impact in terms of BBB leakage or neuron degeneration was observed after single exposures or immediately after the end of repeated exposure, with the exception of a transient BBB leakage (UMTS, 0.26 W/kg). Fifty days after repeated exposure, the occurrence of degenerating neurons was unchanged on average. However, a significant increased albumin leakage was detected with both RF signals at 13 W/kg. In this work, the strongest, delayed effect was induced by GSM-1800 at 13 W/kg. Considering that 13 W/kg BASAR in the rat head is equivalent to 4 times as much in the human head, deleterious effects may occur following repeated human brain exposure above 50 W/kg. PMID- 29138436 TI - The M25 gene products are critical for the cytopathic effect of mouse cytomegalovirus. AB - Cell rounding is a hallmark of the cytopathic effect induced by cytomegaloviruses. By screening a panel of deletion mutants of mouse cytomegalovirus (MCMV) a mutant was identified that did not elicit cell rounding and lacked the ability to form typical plaques. Altered cell morphology was assigned to the viral M25 gene. We detected an early 2.8 kb M25 mRNA directing the synthesis of a 105 kDa M25 protein, and confirmed that a late 3.1 kb mRNA encodes a 130 kDa M25 tegument protein. Virions lacking the M25 tegument protein were of smaller size because the tegument layer between capsid and viral envelope was reduced. The DeltaM25 mutant did not provoke the rearrangement of the actin cytoskeleton observed after wild-type MCMV infection, and isolated expression of the M25 proteins led to cell size reduction, confirming that they contribute to the morphological changes. Yields of progeny virus and cell-to-cell spread of the DeltaM25 mutant in vitro were diminished and replication in vivo was impaired. The identification of an MCMV gene involved in cell rounding provides the basis for investigating the role of this cytopathic effect in CMV pathogenesis. PMID- 29138437 TI - Photosensitized INA-Labelled protein 1 (PhIL1) is novel component of the inner membrane complex and is required for Plasmodium parasite development. AB - Plasmodium parasites, the causative agents of malaria, possess a distinctive membranous structure of flattened alveolar vesicles supported by a proteinaceous network, and referred to as the inner membrane complex (IMC). The IMC has a role in actomyosin-mediated motility and host cell invasion. Here, we examine the location, protein interactome and function of PhIL1, an IMC-associated protein on the motile and invasive stages of both human and rodent parasites. We show that PhIL1 is located in the IMC in all three invasive (merozoite, ookinete-, and sporozoite) stages of development, as well as in the male gametocyte and locates both at the apical and basal ends of ookinete and sporozoite stages. Proteins interacting with PhIL1 were identified, showing that PhIL1 was bound to only some proteins present in the glideosome motor complex (GAP50, GAPM1-3) of both P. falciparum and P. berghei. Analysis of PhIL1 function using gene targeting approaches indicated that the protein is required for both asexual and sexual stages of development. In conclusion, we show that PhIL1 is required for development of all zoite stages of Plasmodium and it is part of a novel protein complex with an overall composition overlapping with but different to that of the glideosome. PMID- 29138438 TI - Network-based analysis of diagnosis progression patterns using claims data. AB - In recent years, several network models have been introduced to elucidate the relationships between diseases. However, important risk factors that contribute to many human diseases, such as age, gender and prior diagnoses, have not been considered in most networks. Here, we construct a diagnosis progression network of human diseases using large-scale claims data and analyze the associations between diagnoses. Our network is a scale-free network, which means that a small number of diagnoses share a large number of links, while most diagnoses show limited associations. Moreover, we provide strong evidence that gender, age and disease class are major factors in determining the structure of the disease network. Practically, our network represents a methodology not only for identifying new connectivity that is not found in genome-based disease networks but also for estimating directionality, strength, and progression time to transition between diseases considering gender, age and incidence. Thus, our network provides a guide for investigators for future research and contributes to achieving precision medicine. PMID- 29138439 TI - ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments. AB - Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identified the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity. This compound efficiently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite. ABMA provokes Rab7-positive late endosomal compartment accumulation in mammalian cells without affecting other organelles (early endosomes, lysosomes, the Golgi apparatus, the endoplasmic reticulum or the nucleus). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. ABMA may represent a novel class of broad spectrum compounds with therapeutic potential against diverse severe infectious diseases. PMID- 29138440 TI - Structural Basis for DNA Recognition of a Single-stranded DNA-binding Protein from Enterobacter Phage Enc34. AB - Modern DNA sequencing capabilities have led to the discovery of a large number of new bacteriophage genomes, which are a rich source of novel proteins with an unidentified biological role. The genome of Enterobacter cancerogenus bacteriophage Enc34 contains several proteins of unknown function that are nevertheless conserved among distantly related phages. Here, we report the crystal structure of a conserved Enc34 replication protein ORF6 which contains a domain of unknown function DUF2815. Despite the low (~15%) sequence identity, the Enc34 ORF6 structurally resembles the gene 2.5 protein from bacteriophage T7, and likewise is a single-stranded DNA (ssDNA)-binding protein (SSB) that consists of a variation of the oligosaccharide/oligonucleotide-binding (OB)-fold and an unstructured C-terminal segment. We further report the crystal structure of a C terminally truncated ORF6 in complex with an ssDNA oligonucleotide that reveals a DNA-binding mode involving two aromatic stacks and multiple electrostatic interactions, with implications for a common ssDNA recognition mechanism for all T7-type SSBs. PMID- 29138441 TI - Screening based approach and dehydrogenation kinetics for MgH2: Guide to find suitable dopant using first-principles approach. AB - First-principles based calculations are performed to investigate the dehydrogenation kinetics considering doping at various layers of MgH2 (110) surface. Doping at first and second layer of MgH2 (110) has a significant role in lowering the H2 desorption (from surface) barrier energy, whereas the doping at third layer has no impact on the barrier energy. Molecular dynamics calculations are also performed to check the bonding strength, clusterization, and system stability. We study in details about the influence of doping on dehydrogenation, considering the screening factors such as formation enthalpy, bulk modulus, and gravimetric density. Screening based approach assist in finding Al and Sc as the best possible dopant in lowering of desorption temperature, while preserving similar gravimetric density and Bulk modulus as of pure MgH2 system. The electron localization function plot and population analysis illustrate that the bond between Dopant-Hydrogen is mainly covalent, which weaken the Mg-Hydrogen bonds. Overall we observed that Al as dopant is suitable and surface doping can help in lowering the desorption temperature. So layer dependent doping studies can help to find the best possible reversible hydride based hydrogen storage materials. PMID- 29138443 TI - Local Reasons to Give Globally: Identity Extension and Global Cooperation. AB - Recent political events across the world suggest a retrenchment from globalization and a possible increase in parochialism. This inward-looking threat from parochialism occurs just as the global community faces growing challenges that require trans-national cooperation. In this research, we question if strong identification with an in-group necessarily leads to parochialism and ultimately is detrimental to global cooperation. Building on research on global social identification, we explore whether strong local identification can expand in inclusiveness to global identification, and among whom this is likely to happen. The results of our global public goods study - conducted in South Korea and the United States - show that high levels of social identification with a local group can extend to the global collective, particularly for individuals who are also high in concern-for-others. Furthermore, this identification translates into behavior that benefits the global, anonymous group at a cost to oneself. These results shed light on how to avoid the trap of parochialism and instead engender cooperative behavior with the broader global community. PMID- 29138442 TI - UV irradiation to mouse skin decreases hippocampal neurogenesis and synaptic protein expression via HPA axis activation. AB - The skin senses external environment, including ultraviolet light (UV). Hippocampus is a brain region that is responsible for memory and emotion. However, changes in hippocampus by UV irradiation to the skin have not been studied. In this study, after 2 weeks of UV irradiation to the mouse skin, we examined molecular changes related to cognitive functions in the hippocampus and activation of the hypothalamic-pituitary-adrenal (HPA) axis. UV exposure to the skin decreased doublecortin-positive immature neurons and synaptic proteins, including N-methyl-D-aspartate receptor 2 A and postsynaptic density protein-95, in the hippocampus. Moreover, we observed that UV irradiation to the skin down regulated brain-derived neurotrophic factor expression and ERK signaling in the hippocampus, which are known to modulate neurogenesis and synaptic plasticity. The cutaneous and central HPA axes were activated by UV, which resulted in significant increases in serum levels of corticosterone. Subsequently, UV irradiation to the skin activated the glucocorticoid-signaling pathway in the hippocampal dentate gyrus. Interestingly, after 6 weeks of UV irradiation, mice showed depression-like behavior in the tail suspension test. Taken together, our data suggest that repeated UV exposure through the skin may negatively affect hippocampal neurogenesis and synaptic plasticity along with HPA axis activation. PMID- 29138444 TI - The Elusive Evidence of Volcanic Lightning. AB - Lightning strikes are known to morphologically alter and chemically reduce geologic formations and deposits, forming fulgurites. A similar process occurs as the result of volcanic lightning discharge, when airborne volcanic ash is transformed into lightning-induced volcanic spherules (LIVS). Here, we adapt the calculations used in previous studies of lightning-induced damage to infrastructure materials to determine the effects on pseudo-ash samples of simplified composition. Using laboratory high-current impulse experiments, this research shows that within the lightning discharge channel there is an ideal melting zone that represents roughly 10% or less of the total channel radius at which temperatures are sufficient to melt the ash, regardless of peak current. The melted ash is simultaneously expelled from the channel by the heated, expanding air, permitting particles to cool during atmospheric transport before coming to rest in ash fall deposits. The limited size of this ideal melting zone explains the low number of LIVS typically observed in volcanic ash despite the frequent occurrence of lightning during explosive eruptions. PMID- 29138445 TI - Inhibition activity of a traditional Chinese herbal formula Huang-Lian-Jie-Du Tang and its major components found in its plasma profile on neuraminidase-1. AB - Huang-Lian-Jie-Du-Tang (HLJDT), a traditional formula with four TCM herbs, has been used for hundred years for different diseases. The current study aimed to assess the inhibitory activity of HLJDT against H1N1 neuraminidase (NA-1), and identify potent NA-1 inhibitors from its plasma profile. The in vitro NA-1 study has shown that the water extract of HLJDT potently inhibited NA-1 (IC50 = 112.6 MUg/ml; Ki = 55.6 MUg/ml) in a competitive mode. The IC50 values of the water extracts of its four herbs were as follows: Coptidis Rhizoma, 96.1 MUg/ml; Phellodendri Chinensis Cortex, 108.6 MUg/ml; Scutellariae Radix, 303.5 MUg/ml; Gardeniae Fructus, 285.0 MUg/ml. Thirteen compounds found in the plasma profile of HLJDT were also identified as potent NA-1 inhibitors, which included jatrorrhizine, palmatine, epiberberine, geniposide, oroxylin A, berberine, coptisine, baicalein, wogonoside, phellodendrine, wogonin, oroxylin A-7-O glucuronide and baicalin (sorted in ascending order by their IC50 values). Their inhibitory activities were consistent with molecular docking analysis when considering crystallographic water molecules in the ligand-binding pocket of NA 1. Our current findings suggested that HLJDT can be used as a complementary medicine for H1N1 infection and its potent active compounds can be developed as NA-1 inhibitors. PMID- 29138446 TI - Antimicrobial resistance and genetic diversity in ceftazidime non-susceptible bacterial pathogens from ready-to-eat street foods in three Taiwanese cities. AB - Bacterial contamination of ready-to-eat (RTE) street foods is a major concern worldwide. Dissemination of antibiotic resistant pathogens from food is an emerging public-health threat. To investigate the prevalence of antibiotic resistance genes and ceftazidime resistance-associated efflux pumps in foodborne pathogens, 270 RTE street foods samples were collected in three densely populated Taiwanese cities. Among 70 ceftazidime non-susceptible isolates, 21 Stenotrophomonas maltophilia, 12 Pseudomonas spp., 22 Acinetobacter spp., and 15 Enterobacteriaceae isolates were identified. Phylogenetic analyses revealed high levels of genetic diversity between all of the different strains. Multi-drug resistance was observed in 86.4% (19/22) of Acinetobacter spp., 100% (12/12) of Pseudomonas spp., 71.4% (15/21) of S. maltophilia, and 93.3% (14/15) of Enterobacteriaceae. Of 70 ceftazidime non-susceptible isolates, 13 contained ESBLs or plasmid-mediated ampC genes and 23 contained ceftazidime resistance associated efflux pumps, with Acinetobacter spp. identified as predominant isolate (69.6%; 16/23). AdeIJK pump RNA expression in Acinetobacter isolates was 1.9- to 2-fold higher in active efflux strains. Nine clinically resistant genes were detected: catIII and cmlA (chloramphenicol); aacC1, aacC2, aacC3, and aacC4 (gentamicin); tet(A), tet(C), and tet(D) (tetracycline). The scope and abundance of multidrug-resistant bacteria described in this report underscores the need for ongoing and/or expanded RTE monitoring and control measures. PMID- 29138447 TI - The Semaphorin 3A inhibitor SM-345431 preserves corneal nerve and epithelial integrity in a murine dry eye model. AB - Dry eye disease (DED) is a common disorder causing discomfort and ocular fatigue. Corneal nerves are compromised in DED, which may further cause loss of corneal sensation and decreased tear secretion. Semaphorin 3A (Sema3A) is expressed by the corneal epithelium under stress, and is known as an inhibitor of axonal regeneration. Using a murine dry eye model, we found that topical SM-345431, a selective Sema3A inhibitor, preserved corneal sensitivity (2.3 +/- 0.3 mm versus 1.4 +/- 0.1 mm in vehicle control, p = 0.004) and tear volume (1.1 +/- 0.1 mm versus 0.3 +/- 0.1 mm in vehicle control, p < 0.001). Fluorescein staining area of the cornea due to damage to barrier function was also reduced (4.1 +/- 0.9% in SM-345431 group versus 12.9 +/- 2.2% in vehicle control, p < 0.001). The incidence of corneal epithelial erosions was significantly suppressed by SM 345431 (none in SM-345431 group versus six (21%) in vehicle control, p = 0.01). Furthermore, sub-epithelial corneal nerve density and intraepithelial expression of transient receptor potential vanilloid receptor 1 (TRPV1) were significantly preserved with SM-345431. Our results suggest that inhibition of Sema3A may be an effective therapy for DED. PMID- 29138449 TI - Haemodynamic Recovery Properties of the Torsioned Testicular Artery Lumen. AB - Testicular artery torsion (twisting) is one such severe vascular condition that leads spermatic cord injury. In this study, we investigate the recovery response of a torsioned ram testicular artery in an isolated organ-culture flow loop with clinically relevant twisting modes (90 degrees , 180 degrees , 270 degrees and 360 degrees angles). Quantitative optical coherence tomography technique was employed to track changes in the lumen diameter, wall thickness and the three dimensional shape of the vessel in the physiological pressure range (10-50 mmHg). As a control, pressure-flow characteristics of the untwisted arteries were studied when subjected to augmented blood flow conditions with physiological flow rates up to 36 ml/min. Both twist and C-shaped buckling modes were observed. Acute increase in pressure levels opened the narrowed lumen of the twisted arteries noninvasively at all twist angles (at ~22 mmHg and ~35 mmHg for 360 degrees -twisted vessels during static and dynamic flow experiments, respectively). The association between the twist-opening flow rate and the vessel diameter was greatly influenced by the initial twist angle. The biomechanical characteristics of the normal (untwisted) and torsioned testicular arteries supported the utilization of blood flow augmentation as an effective therapeutic approach to modulate the vessel lumen and recover organ reperfusion. PMID- 29138448 TI - Antimicrobial peptides in frog poisons constitute a molecular toxin delivery system against predators. AB - Animals using toxic peptides and proteins for predation or defense typically depend on specialized morphological structures, like fangs, spines, or a stinger, for effective intoxication. Here we show that amphibian poisons instead incorporate their own molecular system for toxin delivery to attacking predators. Skin-secreted peptides, generally considered part of the amphibian immune system, permeabilize oral epithelial tissue and enable fast access of cosecreted toxins to the predator's bloodstream and organs. This absorption-enhancing system exists in at least three distantly related frog lineages and is likely to be a widespread adaptation, determining the outcome of predator-prey encounters in hundreds of species. PMID- 29138450 TI - Quantifying quantum coherence with quantum Fisher information. AB - Quantum coherence is one of the old but always important concepts in quantum mechanics, and now it has been regarded as a necessary resource for quantum information processing and quantum metrology. However, the question of how to quantify the quantum coherence has just been paid the attention recently (see, e.g., Baumgratz et al. PRL, 113. 140401 (2014)). In this paper we verify that the well-known quantum Fisher information (QFI) can be utilized to quantify the quantum coherence, as it satisfies the monotonicity under the typical incoherent operations and the convexity under the mixing of the quantum states. Differing from most of the pure axiomatic methods, quantifying quantum coherence by QFI could be experimentally testable, as the bound of the QFI is practically measurable. The validity of our proposal is specifically demonstrated with the typical phase-damping and depolarizing evolution processes of a generic single qubit state, and also by comparing it with the other quantifying methods proposed previously. PMID- 29138451 TI - Improvement on lipid production by Scenedesmus obliquus triggered by low dose exposure to nanoparticles. AB - Carbon nanotubes (CNTs), alpha-Fe2O3 nanoparticles (nano Fe2O3) and MgO nanoparticles (nano MgO) were evaluated for the effects on algae growth and lipid production. Nano Fe2O3 promoted cell growth in the range of 0-20 mg.L-1. CNTs, nano Fe2O3 and nano MgO inhibited cell growth of Scenedesmus obliquus at 10, 40 and 0.8 mg.L-1 respectively. Neutral lipid and total lipid content increased with the increasing concentration of all tested nanoparticles. The maximum lipid productivity of cultures exposed to CNTs, nano Fe2O3 and nano MgO was observed at 5 mg.L-1, 5 mg.L-1 and 40 mg.L-1, with the improvement by 8.9%, 39.6% and 18.5%. High dose exposure to nanoparticles limited increase in lipid productivity, possibly due to the repression on cell growth caused by nanoparticles-catalyzed reactive oxygen species (ROS) generation, finally leading to reduction in biomass and lipid production. Reduced accumulation of fatty acids of C18:3n3, C18:3n6 and C20:2 was observed in cells exposed to nanoparticles. PMID- 29138452 TI - Excessive fuel availability amplifies the FTO-mediated obesity risk: results from the TUEF and Whitehall II studies. AB - Variation in FTO is the most important common genetic determinant of body weight. Altered energy metabolism could underlie this association. We hypothesized that higher circulating glucose or triglycerides can amplify the FTO impact on BMI. In 2671 subjects of the TUEF study, we investigated the interaction effect of fasting glucose and triglyceride levels with rs9939609 in FTO on BMI. We analysed the same interaction effect by longitudinally utilizing mixed effect models in the prospective Whitehall II study. In TUEF, we detected an interaction effect between fasting glucose and fasting triglycerides with rs9939609 on BMI (p = 0.0005 and p = 5 * 10-7, respectively). The effect size of one risk allele was 1.4 +/- 0.3 vs. 2.2 +/- 0.44 kg/m2 in persons with fasting glucose levels below and above the median, respectively. Fasting triglycerides above the median increased the per-allele effect from 1.4 +/- 0.3 to 1.7 +/- 0.4 kg/m2. In the Whitehall II study, body weight increased by 2.96 +/- 6.5 kg during a follow-up of 13.5 +/- 4.6 yrs. Baseline fasting glucose and rs9939609 interacted on weight change (p = 0.009). Higher fasting glucose levels may amplify obesity-risk in FTO carriers and lead to an exaggerated weight gain over time. Since weight gain perpetuates metabolic alterations, this interplay may trigger a vicious circle that leads to obesity and diabetes. PMID- 29138453 TI - The prognostic value of AGR2 expression in solid tumours: a systematic review and meta-analysis. AB - The prognostic value of anterior gradient-2 (AGR2) in tumours remains inconclusive. Here, we systematically reviewed the literature evidence and assessed the association between AGR2 expression and prognosis in solid tumours. The primary outcomes were overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS)/recurrence-free survival (RFS)/progression-free survival (PFS). All analyses were performed by STATA 12.0, with the hazard ratio (HR) or odds ratios (OR), and 95% confidence interval (CI) as the effect size estimate. A total of 20 studies containing 3285 cases were included. Pooled analyses revealed that AGR2 overexpression had an unfavourable impact on OS (HR 1.93, 95% CI 1.32-2.81) and time to tumour progression (TTP) (DFS/RFS/PFS) (HR 1.60 95% CI 1.06-2.40) in solid tumour patients. Subgroup analyses indicated that AGR2 overexpression in breast cancer patients was significantly associated with poor OS (HR 3.02, 95% CI 1.03-8.81) and TTP (HR 1.93, 95% CI 1.17-3.20). Excluding breast cancer, AGR2 overexpression was also found to have a significant correlation with poor OS in the remaining solid tumour patients (HR 1.51, 95% CI 1.04-2.19). Overall, AGR2 might be a potential biomarker to predict prognosis in solid tumour patients. PMID- 29138454 TI - Differences in mitochondrial function and morphology during cooling and rewarming between hibernator and non-hibernator derived kidney epithelial cells. AB - Hibernators show superior resistance to ischemia and hypothermia, also outside the hibernation season. Therefore, hibernation is a promising strategy to decrease cellular damage in a variety of fields, such as organ transplantation. Here, we explored the role of mitochondria herein, by comparing epithelial cell lines from a hibernator (hamster kidney cells, HaK) and a non-hibernator (human embryonic kidney cells, HEK293) during cold preservation at 4 degrees C and rewarming. Cell survival (Neutral Red), ATP and MDA levels, mitochondrial membrane potential (MMP), mitochondrial morphology (using fluorescent probes) and metabolism (seahorse XF) were assessed. Hypothermia induced dispersion of the tubular mitochondrial network, a loss of MMP, increased oxygen radical (MDA) and decreased ATP production in HEK293. In contrast, HaK maintained MMP and ATP production without an increase in oxygen radicals during cooling and rewarming, resulting in superior cell survival compared to HEK293. Further, normothermic HaK showed a dispersed mitochondrial network and higher respiratory and glycolysis capacity compared to HEK293. Disclosing the mechanisms that hibernators use to counteract cell death in hypothermic and ischemic circumstances may help to eventually improve organ preservation in a variety of fields, including organ transplantation. PMID- 29138455 TI - A scale to measure MRI contrast agent sensitivity. AB - Magnetic resonance imaging (MRI) provides superior resolution of anatomical features and the best soft tissue contrast, and is one of the predominant imaging modalities. With this technique, contrast agents are often used to aid discrimination by enhancing specific features. Over the years, a rich diversity of such agents has evolved and with that, so has a need to systematically sort contrast agents based on their efficiency, which directly determines sensitivity. Herein, we present a scale to rank MRI contrast agents. The scale is based on analytically determining the minimum detectable concentration of a contrast agent, and employing a ratiometric approach to standardize contrast efficiency to a benchmark contrast agent. We demonstrate the approach using several model contrast agents and compare the relative sensitivity of these agents for the first time. As the first universal metric of contrast agent sensitivity, this scale will be vital to easily assessing contrast agent efficiency and thus important to promoting use of some of the elegant and diverse contrast agents in research and clinical practice. PMID- 29138456 TI - Prep1 prevents premature adipogenesis of mesenchymal progenitors. AB - Transcriptional regulators are crucial in adipocyte differentiation. We now show that the homeodomain-containing transcription factor Prep1 is a repressor of adipogenic differentiation since its down-regulation (DR) in both ex vivo bone marrow-derived mesenchymal stromal cells (MSC) and in vitro 3T3-L1 preadipocytes significantly increases their adipogenic differentiation ability. Prep1 acts at a stage preceding the activation of the differentiation machinery because its DR makes cells more prone to adipogenic differentiation even in the absence of the adipogenic inducers. Prep1 DR expands the DNA binding landscape of C/EBPbeta (CCAAT enhancer binding protein beta) without affecting its expression or activation. The data indicate that Prep1 normally acts by restricting DNA binding of transcription factors to adipogenic enhancers, in particular C/EBPbeta. PMID- 29138457 TI - Functional annotation of structural ncRNAs within enhancer RNAs in the human genome: implications for human disease. AB - Enhancer RNAs (eRNAs) are a novel class of non-coding RNA (ncRNA) molecules transcribed from the DNA sequences of enhancer regions. Despite extensive efforts devoted to revealing the potential functions and underlying mechanisms of eRNAs, it remains an open question whether eRNAs are mere transcriptional noise or relevant biologically functional species. Here, we identified a catalogue of eRNAs in a broad range of human cell/tissue types and extended our understanding of eRNAs by demonstrating their multi-omic signatures. Gene Ontology (GO) analysis revealed that eRNAs play key roles in human cell identity. Furthermore, we detected numerous known and novel functional RNA structures within eRNA regions. To better characterize the cis-regulatory effects of non-coding variation in these structural ncRNAs, we performed a comprehensive analysis of the genetic variants of structural ncRNAs in eRNA regions that are associated with inflammatory autoimmune diseases. Disease-associated variants of the structural ncRNAs were disproportionately enriched in immune-specific cell types. We also identified riboSNitches in lymphoid eRNAs and investigated the potential pathogenic mechanisms by which eRNAs might function in autoimmune diseases. Collectively, our findings offer valuable insights into the function of eRNAs and suggest that eRNAs might be effective diagnostic and therapeutic targets for human diseases. PMID- 29138458 TI - Low-intensity pulsed ultrasound improves behavioral and histological outcomes after experimental traumatic brain injury. AB - The purpose of this study was to investigate the neuroprotective effects of low intensity pulsed ultrasound (LIPUS) on behavioral and histological outcomes in a mouse model of traumatic brain injury (TBI). Mice subjected to controlled cortical impact injury were treated with LIPUS in the injured region daily for a period of 4 weeks. The effects of LIPUS on edema were observed by MR imaging in the mouse brain at 1 and 4 days following TBI. Brain water content, blood-brain barrier permeability, histology analysis, and behavioral studies were performed to assess the effects of LIPUS. Two-way analysis of variance and Student t test were used for statistical analyses, with a significant level of 0.05. Treatment with LIPUS significantly attenuated brain edema, blood-brain barrier permeability, and neuronal degeneration beginning at day 1. Compared with the TBI group, LIPUS also significantly improved functional recovery and reduced contusion volumes up to post-injury day 28. Post-injury LIPUS treatment reduced brain edema and improved behavioral and histological outcomes following TBI. The neuroprotective effects of LIPUS may be a promising new technique for treating TBI. PMID- 29138459 TI - The genomic landscape of Nepalese Tibeto-Burmans reveals new insights into the recent peopling of Southern Himalayas. AB - While much research attention has focused on demographic processes that enabled human diffusion on the Tibetan plateau, little is known about more recent colonization of Southern Himalayas. In particular, the history of migrations, admixture and/or isolation of populations speaking Tibeto-Burman languages, which is supposed to be quite complex and to have reshaped patterns of genetic variation on both sides of the Himalayan arc, remains only partially elucidated. We thus described the genomic landscape of previously unsurveyed Tibeto-Burman (i.e. Sherpa and Tamang) and Indo-Aryan communities from remote Nepalese valleys. Exploration of their genomic relationships with South/East Asian populations provided evidence for Tibetan admixture with low-altitude East Asians and for Sherpa isolation. We also showed that the other Southern Himalayan Tibeto-Burmans derived East Asian ancestry not from the Tibetan/Sherpa lineage, but from low altitude ancestors who migrated from China plausibly across Northern India/Myanmar, having experienced extensive admixture that reshuffled the ancestral Tibeto-Burman gene pool. These findings improved the understanding of the impact of gene flow/drift on the evolution of high-altitude Himalayan peoples and shed light on migration events that drove colonization of the southern Himalayan slopes, as well as on the role played by different Tibeto-Burman groups in such a complex demographic scenario. PMID- 29138460 TI - Global Sequestration Potential of Increased Organic Carbon in Cropland Soils. AB - The role of soil organic carbon in global carbon cycles is receiving increasing attention both as a potentially large and uncertain source of CO2 emissions in response to predicted global temperature rises, and as a natural sink for carbon able to reduce atmospheric CO2. There is general agreement that the technical potential for sequestration of carbon in soil is significant, and some consensus on the magnitude of that potential. Croplands worldwide could sequester between 0.90 and 1.85 Pg C/yr, i.e. 26-53% of the target of the "4p1000 Initiative: Soils for Food Security and Climate". The importance of intensively cultivated regions such as North America, Europe, India and intensively cultivated areas in Africa, such as Ethiopia, is highlighted. Soil carbon sequestration and the conservation of existing soil carbon stocks, given its multiple benefits including improved food production, is an important mitigation pathway to achieve the less than 2 degrees C global target of the Paris Climate Agreement. PMID- 29138461 TI - Overexpression of a disintegrin and metalloproteinase 21 is associated with motility, metastasis, and poor prognosis in hepatocellular carcinoma. AB - Cell motility plays an important role in intrahepatic metastasis of hepatocellular carcinoma (HCC), and predicts poor prognosis in patients. The present study investigated the role of a disintegrin and metalloproteinases (ADAMs) in HCC, since these proteins are known to be associated with cell motility. We confirmed the expression of 12 ADAMs with putative metalloproteinase activity in HCC cells, and established a KYN-2 HCC cell line stably expressing short interfering RNA against ADAM21 to investigate the effect of ADAM21 deficiency on HCC cell motility and metastasis in vitro and in vivo. We also examined ADAM21 expression in a cohort of 119 HCC patients by immunohistochemistry. ADAM21 was overexpressed in KYN-2 cells, and its knockdown reduced invasion, migration, proliferation, and metastasis relative to controls. In clinical specimens, ADAM21 positivity was associated with vascular invasion, large tumor size, high histological grade, and lower overall and recurrence-free survival as compared to cases that were negative for ADAM21 expression. A multivariate analysis revealed that ADAM21 positivity was an independent risk factor for overall (P = 0.003) and recurrence-free (P = 0.001) survival. These results suggest that ADAM21 plays a role in HCC metastasis and can serve as a prognostic marker for disease progression. PMID- 29138462 TI - The Antibacterial and Anti-inflammatory Activity of Chicken Cathelicidin-2 combined with Exogenous Surfactant for the Treatment of Cystic Fibrosis Associated Pathogens. AB - Cystic fibrosis (CF) is characterized by recurrent airway infections with antibiotic-resistant bacteria and chronic inflammation. Chicken cathelicin-2 (CATH-2) has been shown to exhibit antimicrobial activity against antibiotic resistant bacteria and to reduce inflammation. In addition, exogenous pulmonary surfactant has been suggested to enhance pulmonary drug delivery. It was hypothesized that CATH-2 when combined with an exogenous surfactant delivery vehicle, bovine lipid extract surfactant (BLES), would exhibit antimicrobial activity against CF-derived bacteria and downregulate inflammation. Twelve strains of CF-pathogens were exposed to BLES+CATH-2 in vitro and killing curves were obtained to determine bactericidal activity. Secondly, heat-killed bacteria were administered in vivo to elicit a pro-inflammatory response with either a co administration or delayed administration of BLES+CATH-2 to assess the antimicrobial-independent, anti-inflammatory properties of BLES+CATH-2. CATH-2 alone exhibited potent antimicrobial activity against all clinical strains of antibiotic-resistant bacteria, while BLES+CATH-2 demonstrated a reduction, but significant antimicrobial activity against bacterial isolates. Furthermore, BLES+CATH-2 reduced inflammation in vivo when either co-administered with killed bacteria or after delayed administration. The use of a host-defense peptide combined with an exogenous surfactant compound, BLES+CATH-2, is shown to exhibit antimicrobial activity against antibiotic-resistant CF bacterial isolates and reduce inflammation. PMID- 29138463 TI - TALEN-mediated shift of mitochondrial DNA heteroplasmy in MELAS-iPSCs with m.13513G>A mutation. AB - Induced pluripotent stem cells (iPSCs) are suitable for studying mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations. Here, we generated iPSCs from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with the m.13513G>A mutation. The patient's dermal fibroblasts were reprogrammed, and we established two iPSC clones with and without mutant mtDNA. Furthermore, we tried to decrease mutant mtDNA level in iPSCs using transcription activator-like effector nucleases (TALENs). We originally engineered platinum TALENs, which were transported into mitochondria, recognized the mtDNA sequence including the m.13513 position, and preferentially cleaved G13513A mutant mtDNA (G13513A-mpTALEN). The m.13513G>A heteroplasmy level in MELAS-iPSCs was decreased in the short term by transduction of G13513A mpTALEN. Our data demonstrate that this mtDNA-targeted nuclease would be a powerful tool for changing the heteroplasmy level in heteroplasmic iPSCs, which could contribute to elucidation of the pathological mechanisms of mitochondrial diseases caused by mtDNA mutations. PMID- 29138464 TI - Bone regeneration is associated with the concentration of tumour necrosis factor alpha induced by sericin released from a silk mat. AB - To understand the osteogenic effect of the middle layer of the silk cocoon, sericin was examined for its cellular effects associated with tumor necrosis factor-alpha (TNF-alpha) signaling in this study. The fragmented sericin proteins in the silk mat were evaluated for the TNF-alpha expression level in murine macrophages. The concentration of protein released from silk mats was higher in the outermost and the innermost layers than in the middle layers, and the protein released from the silk mat was identified as sericin. The level of TNF-alpha in murine macrophages was dependent on the applied concentration of sericin, and the expression of genes associated with osteogenesis in osteoblast-like cells was dependent on the applied concentration of TNF-alpha. In animal experiments, silk mats from the middle layers led to a higher regenerated bone volume than silk mats from the innermost layer or the outermost layer. If TNF-alpha protein was incorporated into the silk mats from the middle layers, bone regeneration was suppressed compared with unloaded silk mats from the middle layers. Accordingly, silk mats from the silk cocoon can be considered to be a fragmented sericin secreting carrier, and the level of sericin secretion is associated with TNF alpha induction and bone regeneration. PMID- 29138465 TI - Fine Tuning the Energy Barrier of Molecular Nanomagnets via Lattice Solvent Molecules. AB - Solvents play important roles in our lives, they are also of interest in molecular materials, especially for molecular magnets. The solvatomagnetic effect is generally used for trigger and/or regulation of magnetic properties in molecule-based systems, however, molecular nanomagnets showing solvatomagnetic effects are very difficult to obtain. Here we report four 3d-4f heterometallic cluster complexes containing ROH lattice solvent molecules, [Cu3Tb2(H3L)2(OAc)2(hfac)4]?2ROH {H6L = 1,3 Bis[tris(hydroxymethyl)methylamino]propane, hfac- = hexafluoroacetylacetonate; R = CH3, 1; R = C2H5, 2; R = C3H7, 3; R = H, 4}. Single-molecule magnet (SMM) properties of these four complexes were observed to be dependent on the ROH lattice solvent molecule. There is an interesting magneto-structural correlation: the larger the R group, the higher the energy barrier. For the first time, the solvatomagnetic effect is used for the continuous fine adjustment of the energy barrier of 0D molecular nanomagnets. Additionally, [Cu3Dy2(H3L)2(OAc)2(hfac)4]?2MeOH (5), an analogue of [Cu3Tb2(H3L)2(OAc)2(hfac)4]?2MeOH (1), is also reported for comparison. PMID- 29138466 TI - Manganese availability is negatively associated with carbon storage in northern coniferous forest humus layers. AB - Carbon sequestration below ground depends on organic matter input and decomposition, but regulatory bottlenecks remain unclear. The relative importance of plant production, climate and edaphic factors has to be elucidated to better predict carbon storage in forests. In Swedish forest soil inventory data from across the entire boreal latitudinal range (n = 2378), the concentration of exchangeable manganese was singled out as the strongest predictor (R2 = 0.26) of carbon storage in the extensive organic horizon (mor layer), which accounts for one third of the total below ground carbon. In comparison, established ecosystem models applied on the same data have failed to predict carbon stocks (R2 < 0.05), and in our study manganese availability overshadowed both litter production and climatic factors. We also identified exchangeable potassium as an additional strong predictor, however strongly correlated with manganese. The negative correlation between manganese and carbon highlights the importance of Mn peroxidases in oxidative decomposition of recalcitrant organic matter. The results support the idea that the fungus-driven decomposition could be a critical factor regulating humus carbon accumulation in boreal forests, as Mn-peroxidases are specifically produced by basidiomycetes. PMID- 29138467 TI - Bacillus Classification Based on Matrix-Assisted Laser Desorption Ionization Time of-Flight Mass Spectrometry-Effects of Culture Conditions. AB - Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a reliable and rapid technique applied widely in the identification and classification of microbes. MALDI-TOF MS has been used to identify many endospore-forming Bacillus species; however, endospores affect the identification accuracy when using MALDI-TOF MS because they change the protein composition of samples. Since culture conditions directly influence endospore formation and Bacillus growth, in this study we clarified how culture conditions influence the classification of Bacillus species by using MALDI-TOF MS. We analyzed members of the Bacillus subtilis group and Bacillus cereus group using different incubation periods, temperatures and media. Incubation period was found to affect mass spectra due to endospores which were observed mixing with vegetative cells after 24 hours. Culture temperature also resulted in different mass spectra profiles depending on the temperature best suited growth and sporulation. Conversely, the four common media for Bacillus incubation, Luria Bertani agar, nutrient agar, plate count agar and brain-heart infusion agar did not result in any significant differences in mass spectra profiles. Profiles in the range m/z 1000-3000 were found to provide additional data to the standard ribosomal peptide/protein region m/z 3000-15000 profiles to enable easier differentiation of some highly similar species and the identification of new strains under fresh culture conditions. In summary, control of culture conditions is vital for Bacillus identification and classification by MALDI-TOF MS. PMID- 29138468 TI - Increasing frequency and spatial extent of concurrent meteorological droughts and heatwaves in India. AB - The impacts of concurrent droughts and heatwaves could be more serious compared to their individual occurrence. Meteorological drought condition is generally characterized by low rainfall, but impact of such an event is amplified with simultaneous occurrence of heatwaves. Positive feedback between these two extremes can worsen the rainfall deficit situation to serious soil moisture depletion due to enhanced evapotranspiration. In this study, the concurrence of meteorological droughts and heatwaves is investigated in India using Indian Meteorological Department (IMD) high resolution gridded data over a period of 60 years. Significant changes are observed in concurrent meteorological droughts and heatwaves defined at different percentile based thresholds and durations during the period 1981-2010 relative to the base period 1951-1980. There is substantial increase in the frequency of concurrent meteorological droughts and heatwaves across whole India. Statistically significant trends in the spatial extent of droughts are observed in Central Northeast India and West Central India; however, the spatial extent affected by concurrent droughts and heatwaves is increasing across whole India. Significant shifts are identified in the distribution of spatial extent of concurrent drought and heatwaves in India compared to the base period. PMID- 29138469 TI - Adoptive Transfer of Ceramide Synthase 6 Deficient Splenocytes Reduces the Development of Colitis. AB - Sphingolipids regulate critical cellular processes including inflammation. Ceramide, which serves a central role in sphingolipid metabolism, is generated by six ceramide synthases (CerS) that differ in substrate specificity. CerS6 preferentially generates C16-ceramide and its mRNA is highly expressed in immune tissues. In this study we analyzed how deficiency of CerS6 impacts on the development of colitis using an adoptive transfer model. Adoptive transfer of CerS6-deficient splenocytes, which have significantly decreased levels of C16 ceramide, showed that CerS6-deficiency protected against the development of colitis. However, adoptively transferred cells isolated from the lamina propria of the large intestine from wild type or CerS6-deficient groups showed no differences in the percentages of immune-suppressive regulatory T cells, pro inflammatory Th17 cells, or their ability to express IL-17. In vitro polarization of wild type or CerS6-deficient splenocytes also revealed no defects in the development of T cell subsets. Our data suggest that protection from colitis following adoptive transfer of CerS6-deficient splenocytes maybe related to their ability to migrate and proliferate in vivo rather than subset development or cytokine expression. PMID- 29138470 TI - Obesity-promoting and anti-thermogenic effects of neutrophil gelatinase associated lipocalin in mice. AB - Neutrophil gelatinase-associated lipocalin (NGAL, lipocalin 2 or LCN2) is an iron carrier protein whose circulating level is increased by kidney injury, bacterial infection and obesity, but its metabolic consequence remains elusive. To study physiological role of LCN2 in energy homeostasis, we challenged female Lcn2 knockout (KO) and wild-type (WT) mice with high fat diet (HFD) or cold exposure. Under normal diet, physical constitutions of Lcn2 KO and WT mice were indistinguishable. During HFD treatment, Lcn2 KO mice exhibited larger brown adipose tissues (BAT), consumed more oxygen, ate more food and gained less body weights as compared to WT mice. When exposed to 4 degrees C, KO mice showed higher body temperature and more intense 18F-fluorodeoxyglucose uptake in BAT, which were cancelled by beta3 adrenergic receptor blocker or iron-loaded (but not iron-free) LCN2 administration. These findings suggest that circulating LCN2 possesses obesity-promoting and anti-thermogenic effects through inhibition of BAT activity in an iron-dependent manner. PMID- 29138471 TI - alpha subunits in GABAA receptors are dispensable for GABA and diazepam action. AB - The major isoform of the GABAA receptor is alpha1beta2gamma2. The binding sites for the agonist GABA are located at the beta2+/alpha1- subunit interfaces and the modulatory site for benzodiazepines at alpha1+/gamma2-. In the absence of alpha1 subunits, a receptor was formed that was gated by GABA and modulated by diazepam similarly. This indicates that alternative subunits can take over the role of the alpha1 subunits. Point mutations were introduced in beta2 or gamma2 subunits at positions homologous to alpha1- benzodiazepine binding and GABA binding positions, respectively. From this mutation work we conclude that the site for GABA is located at a beta2+/beta2- subunit interface and that the diazepam site is located at the beta2+/gamma2- subunit interface. Computational docking leads to a structural hypothesis attributing this non-canonical interaction to a binding mode nearly identical with the one at the alpha1+/gamma2- interface. Thus, the beta2 subunit can take over the role of the alpha1 subunit for the formation of both sites, its minus side for the GABA binding site and its plus side for the diazepam binding site. PMID- 29138473 TI - Effects of discrete dynamic-conductivity fractures on the transient pressure of a vertical well in a closed rectangular reservoir. AB - With the extraction of hydrocarbons from reservoirs, fractures will gradually close and their permeabilities will be reduced. Therefore, fracture conductivity will change dynamically during hydrocarbon extraction. The main objective of this study is to develop a new semi-analytical model to simulate the flow inside a homogenous porous medium containing discretely distributed fractures with dynamic conductivities. Based on a dynamic-conductivity model, the pressure and pressure derivative characteristics of a well on or near discrete dynamic-conductivity fractures were simulated. The results show that four flow regimes can be identified for a well near a dynamic-conductivity fracture. Dips in the pressure derivative curves in the transitional flow period were observed as soon as pressure disturbances reached a fracture. In addition, humps caused by the effects of dynamic conductivity were observed after the transitional flow period. Wider and deeper dips were found on the pressure/pressure-derivative curves of a well surrounded by multiple fractures. The novel model presented here can provide a tool for elucidating the flow mechanisms of fluids in closed rectangular reservoirs with discretely dynamic-conductivity fractures. PMID- 29138472 TI - Functional characterization of the Ucp1-associated oxidative phenotype of human epicardial adipose tissue. AB - Brown fat presence and metabolic activity has been associated with lower body mass index, higher insulin sensitivity and better cardiometabolic profile in humans. We, and others, have previously reported the presence of Ucp1, a marker of brown adipocytes, in human epicardial adipose tissue (eAT). Characterization of the metabolic activity and associated physiological relevance of Ucp1 within eAT, however, is still awaited. Here, we validate the presence of Ucp1 within human eAT and its 'beige' nature. Using in-vitro analytical approaches, we further characterize its thermogenic potential and demonstrate that human eAT is capable of undergoing enhanced uncoupling respiration upon stimulation. Direct biopsy gene expression analysis reveals a negative association between thermogenic markers and oxidative stress-related genes in this depot. Consistently, isoproterenol (Iso) stimulation of eAT leads to a downregulation of secreted proteins included in the GO terms 'cell redox homeostasis' and 'protein folding'. In addition, cardiac endothelial cells exhibit a downregulation in the expression of adhesion markers upon treatment with Iso-stimulated eAT derived conditioned media. Overall, these observations suggest that Ucp1- associated metabolic activity plays a significant role in local tissue homeostasis within eAT and can plausibly alter its communication with neighboring cells of the cardiovascular system. PMID- 29138474 TI - Phagocytosis of environmental or metabolic crystalline particles induces cytotoxicity by triggering necroptosis across a broad range of particle size and shape. AB - In crystallopathies, crystals or crystalline particles of environmental and metabolic origin deposit within tissues, induce inflammation, injury and cell death and eventually lead to organ-failure. The NLRP3-inflammasome is involved in mediating crystalline particles-induced inflammation, but pathways leading to cell death are still unknown. Here, we have used broad range of intrinsic and extrinsic crystal- or crystalline particle-sizes and shapes, e.g. calcium phosphate, silica, titanium dioxide, cholesterol, calcium oxalate, and monosodium urate. As kidney is commonly affected by crystallopathies, we used human and murine renal tubular cells as a model system. We showed that all of the analysed crystalline particles induce caspase-independent cell death. Deficiency of MLKL, siRNA knockdown of RIPK3, or inhibitors of necroptosis signaling e.g. RIPK-1 inhibitor necrostatin-1s, RIPK3 inhibitor dabrafenib, and MLKL inhibitor necrosulfonamide, partially protected tubular cells from crystalline particles cytotoxicity. Furthermore, we identify phagocytosis of crystalline particles as an upstream event in their cytotoxicity since a phagocytosis inhibitor, cytochalasin D, prevented their cytotoxicity. Taken together, our data confirmed the involvement of necroptosis as one of the pathways leading to cell death in crystallopathies. Our data identified RIPK-1, RIPK3, and MLKL as molecular targets to limit tissue injury and organ failure in crystallopathies. PMID- 29138475 TI - The rises and falls of opsin genes in 59 ray-finned fish genomes and their implications for environmental adaptation. AB - We studied the evolution of opsin genes in 59 ray-finned fish genomes. We identified the opsin genes and adjacent genes (syntenies) in each genome. Then we inferred the changes in gene copy number (N), syntenies, and tuning sites along each phylogenetic branch during evolution. The Exorh (rod opsin) gene has been retained in 56 genomes. Rh1, the intronless rod opsin gene, first emerged in ancestral Actinopterygii, and N increased to 2 by the teleost-specific whole genome duplication, but then decreased to 1 in the ancestor of Neoteleostei fishes. For cone opsin genes, the rhodopsin-like (Rh2) and long-wave-sensitive (LWS) genes showed great variation in N among species, ranging from 0 to 5 and from 0 to 4, respectively. The two short-wave-sensitive genes, SWS1 and SWS2, were lost in 23 and 6 species, respectively. The syntenies involving LWS, SWS2 and Rh2 underwent complex changes, while the evolution of the other opsin gene syntenies was much simpler. Evolutionary adaptation in tuning sites under different living environments was discussed. Our study provides a detailed view of opsin gene gains and losses, synteny changes and tuning site changes during ray-finned fish evolution. PMID- 29138476 TI - Visuospatial attention in the lateralised brain of pigeons - a matter of ontogenetic light experiences. AB - The ontogenetic mechanisms leading to complementary hemispheric specialisations of the two brain halves are poorly understood. In pigeons, asymmetrical light stimulation during development triggers the left-hemispheric dominance for visuomotor control but light effects on right-hemispheric specialisations are largely unknown. We therefore tested adult pigeons with and without embryonic light experience in a visual search task in which the birds pecked peas regularly scattered on an area in front of them. Comparing the pecking pattern of both groups indicates that the embryonic light conditions differentially influence biased visuospatial attention under mono- and binocular seeing conditions. When one eye was occluded, dark-incubated pigeons peck only within the limits of the visual hemifield of the seeing eye. Light-exposed pigeons also peck into the contralateral field indicating enlarged monocular visual fields of both hemispheres. While dark-incubated birds evinced an attentional bias to the right halfspace when seeing with both eyes, embryonic light exposure shifted this to the left. Thus, embryonic light experience modifies processes regulating biased visuospatial attention of the adult birds depending on the seeing conditions during testing. These data support the impact of light onto the emergence of functional dominances in both hemispheres and point to the critical role of interhemispheric processes. PMID- 29138477 TI - The Exact Curve Equation for Majorana Stars. AB - Majorana stars are visual representation for a quantum pure state. For some states, the corresponding majorana stars are located on one curve on the Block sphere. However, it is lack of exact curve equations for them. To find the exact equations, we consider a superposition of two bosonic coherent states with an arbitrary relative phase. We analytically give the curve equation and find that the curve always goes through the North pole on the Block sphere. Furthermore, for the superpositions of SU(1,1) coherent states, we find the same curve equation. PMID- 29138478 TI - Magnetic Bragg dip and Bragg edge in neutron transmission spectra of typical spin superstructures. AB - Neutron diffractometry has been a critical tool for clarifying spin structures. In contrast, little attention has been paid to neutron transmission spectroscopy, even though they are different types of the same phenomenon. Soon, it will be possible to measure the wavelength dependence of transmissions easily using accelerator-driven neutron facilities. Therefore, we have started studying the potential of spectroscopy in magnetism, and in this paper, we report the first observation of a magnetic Bragg dip and Bragg edge in the neutron transmission spectra of a typical spin superstructure; clear antiferromagnetic Bragg dips and Bragg edges are found for a single crystal and powder of nickel oxide, respectively. The obtained results show that transmission spectroscopy is a promising tool for measurements under multi-extreme conditions and for the precise analyses of spin structures, not only in MW-class pulsed spallation source facilities but also in compact neutron source facilities. PMID- 29138479 TI - Yes-Associated Protein (YAP) Promotes Tumorigenesis in Melanoma Cells Through Stimulation of Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1). AB - YAP is a critical protein in cancer development and can induce transformative phenotypes in mammary epithelial cells. Previous studies have provided evidence that YAP can contribute to the metastatic behavior of melanoma, since specific knockdown of YAP leads to reduced metastatic and invasive capacity in vitro. However, the mechanism by which YAP regulates the function of melanoma is unknown. Here, we identified that YAP has a positive impact on the expression of LRP1, which also plays critical roles in cancer. Mechanically, knockdown of YAP resulted in a significant down-regulation of LRP1 at both the protein and mRNA levels. Tissue microarray analysis (TMA) also showed a positive correlation between YAP and LRP1 expression. In addition, reduction of YAP-impaired pro carcinogenic phenotypes could be partially reversed by simultaneous overexpression of LRP1, suggesting that LRP1 is functionally important in YAP induced melanoma tumorigenesis. Furthermore, we found that LRP1 was regulated by YAP through a transcription- and promoter-dependent mechanism. Taken together, our results suggest that YAP regulates LRP1 through stimulation of the LRP1 promoter and that LRP1 may be an important target for influencing YAP in melanoma. PMID- 29138480 TI - Nitric oxide contributes to high-salt perception in a blood-sucking insect model. AB - In all organisms, salts produce either appetitive or aversive responses depending on the concentration. While low-salt concentration in food elicits positive responses to ingest, high-salt triggers aversion. Still the mechanisms involved in this dual behavior have just started to be uncovered in some organisms. In Rhodnius prolixus, using pharmacological and behavioral assays, we demonstrated that upon high-salt detection in food a nitric oxide (NO) dependent cascade is activated. This activation involves a soluble guanylate cyclase (sGC) and the production of cyclic guanosine monophosphate (cGMP). Thus, appetitive responses to low-salt diets turn to aversion whenever this cascade is activated. Conversely, insects feed over aversive high-salt solutions when it is blocked by reducing NO levels or by affecting the sGC activity. The activation of NO/sGC/cGMP cascade commands the avoidance feeding behavior in R. prolixus. Investigations in other insect species should examine the possibility that high salt aversion is mediated by NO/sSG/cGMP signaling. PMID- 29138481 TI - Quadoctomycin, a 48-membered macrolide antibiotic from Streptomyces sp. MM168 141F8. AB - Drug-resistant bacteria are still emerging, and screening of new skeletal antibiotics is important. During our continuous screening for antimicrobial agents, we discovered a new antimicrobial, named quadoctomycin, from solid culture of Streptomyces sp. MM168-141F8. The substance was purified by solvent extraction, silica gel chromatography and HPLC. Structural elucidation of quadoctomycin was performed by MS and NMR analyses and chemical degradation. Quadoctomycin possesses a 48-membered polyol macrolide skeleton in which an alpha D-mannoside is connected to C-22 by an O-glycosidic linkage. The structure of quadoctomycin was found to be related to that of monazomycin A based on the analyses of NMR spectra in the same solvent (pyridine-d5). Quadoctomycin showed potent antibacterial activity against Staphylococcus aureus, including methicillin-resistant S. aureus, and other Gram-positive pathogenic bacteria such as Enterococcus faecalis and E. faecium (including drug-resistant strains), but did not show activity toward Gram-negative bacteria or Candida albicans.The Journal of Antibiotics advance online publication 15 November 2017; doi:10.1038/ja.2017.140. PMID- 29138482 TI - Valgamicin C, a novel cyclic depsipeptide containing the unusual amino acid cleonine, and related valgamicins A, T and V produced by Amycolatopsis sp. ML1 hF4. AB - In the course of optimizing pargamicin A production in Amycolatopsis sp. ML1-hF4, we discovered novel cyclic depsipeptide compounds in the broth and designated them valgamicins A, C, T and V. The structures of these molecules were determined by spectroscopic studies, advanced Marfey's method and X-ray crystal structural analysis. Valgamicin C contains the extremely rare amino acid cleonine. To our knowledge, this is the first report of a cleonine-containing metabolite from a naturally isolated microorganism without any breeding or mutation treatment. None of the valgamicins showed potent antibacterial activity against either Gram positive or -negative bacteria. Valgamicins A, C and T exhibited moderate cytotoxicity against human tumor cell lines.The Journal of Antibiotics advance online publication, 15 November 2017; doi:10.1038/ja.2017.135. PMID- 29138483 TI - Macroscale multimodal imaging reveals ancient painting production technology and the vogue in Greco-Roman Egypt. AB - Macroscale multimodal chemical imaging combining hyperspectral diffuse reflectance (400-2500 nm), luminescence (400-1000 nm), and X-ray fluorescence (XRF, 2 to 25 keV) data, is uniquely equipped for noninvasive characterization of heterogeneous complex systems such as paintings. Here we present the first application of multimodal chemical imaging to analyze the production technology of an 1,800-year-old painting and one of the oldest surviving encaustic ("burned in") paintings in the world. Co-registration of the data cubes from these three hyperspectral imaging modalities enabled the comparison of reflectance, luminescence, and XRF spectra at each pixel in the image for the entire painting. By comparing the molecular and elemental spectral signatures at each pixel, this fusion of the data allowed for a more thorough identification and mapping of the painting's constituent organic and inorganic materials, revealing key information on the selection of raw materials, production sequence and the fashion aesthetics and chemical arts practiced in Egypt in the second century AD. PMID- 29138484 TI - Non-canonical activation of OmpR drives acid and osmotic stress responses in single bacterial cells. AB - Unlike eukaryotes, bacteria undergo large changes in osmolality and cytoplasmic pH. It has been described that during acid stress, bacteria internal pH promptly acidifies, followed by recovery. Here, using pH imaging in single living cells, we show that following acid stress, bacteria maintain an acidic cytoplasm and the osmotic stress transcription factor OmpR is required for acidification. The activation of this response is non-canonical, involving a regulatory mechanism requiring the OmpR cognate kinase EnvZ, but not OmpR phosphorylation. Single cell analysis further identifies an intracellular pH threshold ~6.5. Acid stress reduces the internal pH below this threshold, increasing OmpR dimerization and DNA binding. During osmotic stress, the internal pH is above the threshold, triggering distinct OmpR-related pathways. Preventing intracellular acidification of Salmonella renders it avirulent, suggesting that acid stress pathways represent a potential therapeutic target. These results further emphasize the advantages of single cell analysis over studies of population averages. PMID- 29138485 TI - Evaluating the impact of domestication and captivity on the horse gut microbiome. AB - The mammal gut microbiome, which includes host microbes and their respective genes, is now recognized as an essential second genome that provides critical functions to the host. In humans, studies have revealed that lifestyle strongly influences the composition and diversity of the gastrointestinal microbiome. We hypothesized that these trends in humans may be paralleled in mammals subjected to anthropogenic forces such as domestication and captivity, in which diets and natural life histories are often greatly modified. We investigated fecal microbiomes of Przewalski's horse (PH; Equus ferus przewalskii), the only horses alive today not successfully domesticated by humans, and herded, domestic horse (E. f. caballus) living in adjacent natural grasslands. We discovered PH fecal microbiomes hosted a distinct and more diverse community of bacteria compared to domestic horses, which is likely partly explained by different plant diets as revealed by trnL maker data. Within the PH population, four individuals were born in captivity in European zoos and hosted a strikingly low diversity of fecal microbiota compared to individuals born in natural reserves in France and Mongolia. These results suggest that anthropogenic forces can dramatically reshape equid gastrointestinal microbiomes, which has broader implications for the conservation management of endangered mammals. PMID- 29138486 TI - The impact of a specialized spinal cord injury center as compared with non specialized centers on the acute respiratory management of patients with complete tetraplegia: an observational study. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To compare the proportion of tracheostomy placement and duration of mechanical ventilation (MV) in patients with a complete cervical spinal cord injury (SCI) that were managed early or lately in a specialized acute SCI-center. The second objective was to determine the impact of the timing of admission to the SCI-center on the MV support duration. SETTING: A single Level-1 trauma center specialized in SCI care in Quebec (Canada). METHODS: A cohort of 81 individuals with complete tetraplegia over a 6-years period was included. Group 1 (N = 57- early group-) was admitted before surgical management in one specialized acute SCI-center, whereas Group 2 (N = 24 -late group-) was surgically managed in a non-specialized center and transferred to the SCI-center for post-operative management only. The proportion of tracheostomy placement and MV duration were compared. Multivariate regression analysis was used to assess the impact of the timing of admission to the SCI center on the MV duration during the SCI-center stay. RESULTS: Patients in Group 2 had a higher proportion of tracheostomy (70.8 vs. 35.1%, p = 0.004) and a higher mean duration of MV support (68.0 +/- 64.2 days vs. 21.8 +/- 29.7 days, p = 0.006) despite similar age, trauma severity (ISS), neurological level of injury and proportion of pneumonia. Later transfer to the specialized acute SCI-center was the main predictive factor of longer MV duration, with a strong impact factor (s = 946.7, p < 0.001). CONCLUSIONS: Early admission to a specialized acute SCI center for surgical and peri-operative management after a complete tetraplegia is associated with lower occurrence of tracheostomy and shorter mechanical ventilation duration support. SPONSORSHIP: MENTOR Program of the Canadian Institute of Health Research and US Department of Defense Spinal Cord Injury Research Program. PMID- 29138487 TI - Associations between Th17-related inflammatory cytokines and asthma in adults: A Case-Control Study. AB - Chronic airway inflammation is recognized as an essential process in the pathogenesis of asthma. Cytokine profiles derived from immune and inflammation cells such as T-helper (Th) cells, eosinophilia and neutrophilia are not limited to the Th2 type in asthma. However, little is understood about associations between Th2-low inflammatory cytokine profiles and risk of asthma in adults. A case-control study of 910 adult asthma and 881 healthy controls was conducted. Inflammatory cytokines screening was undertaken by high-throughput protein microarray technology, and Th17-related inflammatory cytokines (IL17A, IL-9, adipsin and CCL11) were finally selected. Associations between these four cytokines and adult asthma risk were analyzed by multivariate logistic regression models. We observed that plasma IL-17A and IL-9 levels were significantly increased in asthmatics when compared with controls. However, the plasma expressions of adipsin and CCL11 in asthmatics were significantly lower than that in health controls. The adjusted ORs (95%CI) of association between IL-17A, IL-9, adipsin and CCL11 expressions and adult asthma were 3.08 (1.91, 4.97), 1.93 (1.41, 2.64), 10.02 (6.99, 14.37) and 3.29 (2.36, 4.59), respectively (all P trend < 0.0001). Our results suggested that elevated IL-17A and IL-9 expressions and decreased levels of adipsin and CCL11 were positively associated with adult asthma. PMID- 29138488 TI - Structural basis of adaptor-mediated protein degradation by the tail-specific PDZ protease Prc. AB - Peptidoglycan (PG) is a highly cross-linked, protective mesh-like sacculus that surrounds the bacterial cytoplasmic membrane. Expansion of PG is tightly coupled to growth of a bacterial cell and requires hydrolases to cleave the cross-links for insertion of nascent PG material. In Escherichia coli, a proteolytic system comprising the periplasmic PDZ-protease Prc and the lipoprotein adaptor NlpI contributes to PG enlargement by regulating cellular levels of MepS, a cross-link specific hydrolase. Here, we demonstrate how NlpI binds Prc to facilitate the degradation of its substrate MepS by structural and mutational analyses. An NlpI homodimer binds two molecules of Prc and forms three-sided MepS-docking cradles using its tetratricopeptide repeats. Prc forms a monomeric bowl-shaped structure with a lid-like PDZ domain connected by a substrate-sensing hinge that recognizes the bound C terminus of the substrate. In summary, our study reveals mechanistic details of protein degradation by the PDZ-protease Prc bound to its cognate adaptor protein. PMID- 29138489 TI - A dual-channel endoscope for quantitative imaging, monitoring, and triggering of doxorubicin release from liposomes in living mice. AB - Doxorubicin (Dox) is approved for use in liposomal form for the treatment of ovarian cancer. We previously developed a long-circulating Dox formulation in liposomes containing small amounts of porphyrin-phospholipid, which enables on demand drug release with near-infrared irradiation. In this study, we present and evaluate a dual-modal, dual-channel light endoscope that allows quantitative reflectance and fluorescence imaging for monitoring of local Dox concentrations in target areas. The endoscope consists of two flexible imaging fibers; one to transmit diagnostic and therapeutic light to the target, and the other to detect fluorescent and reflected light. Thus, the endoscope serves for imaging, for light delivery to trigger drug release, and for monitoring drug concentration kinetics during drug release. We characterized the performance of this endoscope in tissue phantoms and in an in vivo model of ovarian cancer. This study demonstrates the feasibility of non-invasive, quantitative mapping of Dox distribution in vivo via endoscopic imaging. PMID- 29138490 TI - Bidirectional modulation of hippocampal synaptic plasticity by Dopaminergic D4 receptors in the CA1 area of hippocampus. AB - Long-term potentiation (LTP) is the persistent increase in the strength of the synapses. However, the neural networks would become saturated if there is only synaptic strenghthening. Synaptic weakening could be facilitated by active processes like long-term depression (LTD). Molecular mechanisms that facilitate the weakening of synapses and thereby stabilize the synapses are also important in learning and memory. Here we show that blockade of dopaminergic D4 receptors (D4R) promoted the formation of late-LTP and transformed early-LTP into late-LTP. This effect was dependent on protein synthesis, activation of NMDA-receptors and CaMKII. We also show that GABAA-receptor mediated mechanisms are involved in the enhancement of late-LTP. We could show that short-term plasticity and baseline synaptic transmission were unaffected by D4R inhibition. On the other hand, antagonizing D4R prevented both early and late forms of LTD, showing that activation of D4Rs triggered a dual function. Synaptic tagging experiments on LTD showed that D4Rs act as plasticity related proteins rather than the setting of synaptic tags. D4R activation by PD 168077 induced a slow-onset depression that was protein synthesis, NMDAR and CaMKII dependent. The D4 receptors, thus exert a bidirectional modulation of CA1 pyramidal neurons by restricting synaptic strengthening and facilitating synaptic weakening. PMID- 29138491 TI - SUMOylation regulates the localization and activity of Polo-like kinase 1 during cell cycle in the silkworm, Bombyx mori. AB - Polo-like kinase 1 (Plk1) is a crucial cell cycle regulator by its specific localization and activity during cell cycle. It has been shown that the phosphorylation and ubiquitylation of Plk1 are required for its own activation and localization. Here, we report that SUMOylation regulates the activity of Plk1 in the lepidopteran insect of Bombyx mori. In the absence of SUMOylation, it causes the lost localization of Plk1 on centrosomes and kinetochores, as well as an uneven distribution in midzone. We further identify that the putative SUMOylation site of Bombyx Plk1 at lysine 466 is required for its localization on centrosomes, and K466 mutation in Plk1 could influence its interaction with Smt3/Ubc9 complex. These findings are also confirmed by Drosophila Polo and human Plk1, which together reveals a conserved role of Plk1 SUMOylation in mammals. Moreover, conjugation of Smt3 to Plk1 SUMOylation mutant promotes its localization on centrosomes and kinetochores, and rescues functional defects of chromosome alignment in cells depleted of endogenous Plk1. Altogether, the present data indicate that the SUMOylation of Plk1 could participate in proper chromosome alignment and segregation during mitosis, and provides a novel layer for the regulation of Plk1 localization and activity throughout cell cycle. PMID- 29138492 TI - The antigenic variability of HCV in viral HLA-Ag binding is related to the activation of the host immune response. AB - Our previous data show that hepatitis C virus (HCV) genotype 1 patients expressing the HLA-DQB1 * 0301 allele have a combined response probability of 69%, while the remaining 31% do not respond, probably because the HCV immunodominant epitope (IE) against the DQB1 * 0301 allele is mutated. HCV IE (region sequenced in NS3 is a region encoding aa 1253-1272) from 37 patients (21 Sustained Virological Response, SVR; 16 non-SVR) HLA-DQB1 * 0301+, were analysed by pyrosequencing. In vitro cultures were also determined by CD4+ proliferation, using non-mutated IE (wild-type synthetic peptide) and synthetic mutated peptide. The pyrosequencing study revealed 34 different haplotypes. The SVR patients had fewer haplotypes (P = 0.07), mutations/haplotypes (P = 0.01) and polymorphic sites (P = 0.02) than non-SVR. Three polymorphic sites were associated with the non-SVR patients: haplotype 7 (L5P); haplotype 11 (L7P); and haplotype 15, (L15S) (P = 0.02). The in vitro study (n = 7) showed that in 4/7 patients (Group 1) the CD4+ proliferation obtained with wild-type synthetic peptide was higher than that obtained with the negative control and with the synthetic mutated peptide (P = 0.039). However, in the remaining 3/7 patients (Group 2) this pattern was not observed (P = 0.7). Our findings suggest that HLA-DQB1 * 0301+ patients with high antigenic variability in HCV IE (NS31253-1272) have a lower SVR rate, due to reduced CD4+ proliferation as a result of incorrect viral HLA-Ag binding. PMID- 29138495 TI - Thermoelectric effects in graphene at high bias current and under microwave irradiation. AB - We use a split top gate to induce doping of opposite signs in different parts of a graphene field-effect transistor, thereby effectively forming a graphene thermocouple. The thermocouple is sensitive to the electronic temperature in graphene, which can be several hundred kelvin higher than the ambient one at sufficiently high bias current. Combined with the high thermoelectric power of graphene, this allows for i) simple measurements of the electronic temperature and ii) building thermoelectric radiation detectors. A simple prototype graphene thermoelectric detector shows a temperature-independent optical responsivity of around 400 V/W at 94 GHz at temperatures of 4-50 K. PMID- 29138494 TI - Drying in a microfluidic chip: experiments and simulations. AB - We present an experimental micro-model of drying porous media, based on microfluidic cells made of arrays of pillars on a regular grid, and complement these experiments with a matching two-dimensional pore-network model of drying. Disorder, or small-scale heterogeneity, was introduced into the cells by randomly varying the radii of the pillars. The microfluidic chips were filled with a volatile oil and then dried horizontally, such that gravitational effects were excluded. The experimental and simulated drying rates and patterns were then compared in detail, for various levels of disorder. The geometrical features were reproduced well, although the model under-predicted the formation of trapped clusters of drying fluid. Reproducing drying rates proved to be more challenging, but improved if the additional trapped clusters were added to the model. The methods reported can be adapted to a wide range of multi-phase flow problems, and allow for the rapid development of high-precision micro-models containing tens of thousands of individual elements. PMID- 29138493 TI - Suppression of SRCAP chromatin remodelling complex and restriction of lymphoid lineage commitment by Pcid2. AB - Lymphoid lineage commitment is an important process in haematopoiesis, which forms the immune system to protect the host from pathogen invasion. However, how multipotent progenitors (MPP) switch into common lymphoid progenitors (CLP) or common myeloid progenitors (CMP) during this process remains elusive. Here we show that PCI domain-containing protein 2 (Pcid2) is highly expressed in MPPs. Pcid2 deletion in the haematopoietic system causes skewed lymphoid lineage specification. In MPPs, Pcid2 interacts with the Zinc finger HIT-type containing 1 (ZNHIT1) to block Snf2-related CREBBP activator protein (SRCAP) activity and prevents the deposition of histone variant H2A.Z and transcription factor PU.1 to key lymphoid fate regulator genes. Furthermore, Znhit1 deletion also abrogates H2A/H2A.Z exchange in MPPs. Thus Pcid2 controls lymphoid lineage commitment through the regulation of SRCAP remodelling activity. PMID- 29138496 TI - Designing Ecofriendly Bionanocomposite Assembly with Improved Antimicrobial and Potent on-site Zika Virus Vector Larvicidal Activities with its Mode of Action. AB - Dialyzed natural polymer, fibroin, from Bombyx mori was used to synthesize biocompatible silver and gold nanoparticles in-situ in dispersion form. The films of pure fibroin (PF), fibroin-silver nanocomposite (FSNC) and fibroin-gold nanocomposite (FGNC) were fabricated by drop casting method. The characterization of the resultant dispersion and films was performed by visual color change, UV Vis spectroscopy and atomic force microscopy. The dispersions of PF, FSNC and FGNC were tested for antibacterial activity against E. coli NCIM 2065, S. aureus NCIM 5021, K. pneumoniae NCIM 2957, P. aeruginosa ATCC 9027 and antifungal activity against A. fumigatus NCIM 902. FSNC dispersion exhibited an effective antimicrobial action against all the tested microbes as compared to FGNC dispersion. The mechanism of action for FSNC and FGNC against these microorganisms is proposed. Additionally, the larvicidal activity of the films was investigated against the larvae of Aedes aegypti. The films of FSNC exhibited 100% mortality while the films of FGNC revealed 86-98% mortality against all the larval instars and pupae of A. aegypti. The phytotoxicity study of the nanocomposite films was also carried out to confirm the reusability of water. This is first noble metal nanocomposite based report on larvicidal activity of zika virus vector. PMID- 29138497 TI - Rapid Purification of Human Bispecific Antibodies via Selective Modulation of Protein A Binding. AB - Methods to rapidly generate high quality bispecific antibodies (BsAb) having normal half-lives are critical for therapeutic programs. Here, we identify 3 mutations (T307P, L309Q, and Q311R or "TLQ") in the Fc region of human IgG1 which disrupt interaction with protein A while enhancing interaction with FcRn. The mutations are shown to incrementally alter the pH at which a mAb elutes from protein A affinity resin. A BsAb comprised of a TLQ mutant and a wild-type IgG1 can be efficiently separated from contaminating parental mAbs by differential protein A elution starting from either a) purified parental mAbs, b) in supernatant crossed parental mAbs, or c) co-transfected mAbs. We show that the Q311R mutation confers enhanced FcRn interaction in vitro, and Abs harboring either the Q311R or TLQ mutations have serum half-lives as long as wild-type human IgG1. The mutant Abs have normal thermal stability and Fcgamma receptor interactions. Together, the results lead to a method for high-throughput generation of BsAbs suitable for in vivo studies. PMID- 29138498 TI - Glutaredoxin 1 mediates the protective effect of steady laminar flow on endothelial cells against oxidative stress-induced apoptosis via inhibiting Bim. AB - Endothelial cell apoptosis induced by oxidative stress is an early event in the development of atherosclerosis. Several antioxidant enzymes which can cope with oxidative stress are up-regulated by the anti-atherogenic laminar blood flow often seen in straight or unbranched regions of blood vessels. However, the molecular mechanism responsible for flow-induced beneficial effects is incompletely understood. Here we report the role of glutaredoxin 1 (Grx1), an antioxidant enzyme, in flow-mediated protective effect in endothelial cells. Specifically, we found that Grx1 is markedly up-regulated by the steady laminar flow. Increasing Grx1 reduces the pro-apoptotic protein Bim expression through regulating Akt-FoxO1 signaling and also attenuates H2O2-induced Bim activation via inhibiting JNK phosphorylation, subsequently preventing the apoptosis of endothelial cells. Grx1 knockdown abolishes the inhibitory effect of steady laminar flow on Bim. The inhibitory effect of Grx1 on Bim is dependent on Grx1's thioltransferase activity. These findings indicate that Grx1 induction plays a key role in mediating the protective effect of laminar blood flow and suggest that Grx1 may be a potential therapeutic target for atherosclerosis. PMID- 29138499 TI - Effect of titanium implants with strontium incorporation on bone apposition in animal models: A systematic review and meta-analysis. AB - This systematic review aims to assess the efficacy of titanium (Ti) implant surfaces with or without strontium (Sr) incorporation on osseointegration in animal experimental studies. An electronic search was conducted using databases of PubMed and EMBASE up to November 2016 to identify studies focusing on osseointegration of strontium-modified titanium implants following PRISMA criteria. The primary outcome was the percentage of bone-to-implant contact (BIC) around the implants with or without strontium-modified surface. Of the 1320 studies, 17 studies fulfilling the inclusion criteria were finally included. A random effect meta-analysis was conducted based on BIC in 17 studies, and the results demonstrated considerable heterogeneity (I2 = 79%). A sensitivity analysis found that three studies using the same surface modification method were the major source of the heterogeneity. Therefore, exploratory subgroup analysis was performed. Subgroup one including 14 studies showed a standard mean differences (SMD) of 1.42 (95% CI, 1.13-1.71) with no heterogeneity (I2 = 0.0%), while subgroup two including the other three studies showed a SMD of 9.49.95% CI, 7.51-11.47) with low heterogeneity (I2 = 0.1%). Sr-modified implants in both subgroups showed significantly higher BIC than unmodified implants (P < 0.01). The results showed a statistically significant effect of Sr-modified titanium implant surfaces on osseointegration and bone apposition in animal models. PMID- 29138500 TI - Circulating androgen receptor combined with 18F-fluorocholine PET/CT metabolic activity and outcome to androgen receptor signalling-directed therapies in castration-resistant prostate cancer. AB - The association between choline uptake and androgen receptor (AR) expression is suggested by the upregulation of choline kinase-alpha in prostate cancer. Recently, detection of AR aberration in cell-free DNA as well as early 18F fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) were associated with outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone and enzalutamide. We aimed to make a direct comparison between circulating AR copy number (CN) and choline uptake at FCH-PET/CT. We analysed 80 mCRPC patients progressing after docetaxel treated with abiraterone (n = 47) or enzalutamide (n = 33). We analysed AR CN from plasma samples using digital PCR and Taqman CN assays and total lesion activity (TLA) and metabolic tumor volume (MTV) on FCH-PET/CT at baseline. A meaningful correlation was showed among AR gain and TLA/MTV compared to AR non-gained cases (P = 0.001 and P = 0.004, respectively), independently from type of treatment. Multivariate analysis revealed that AR CN and only TLA were associated with both shorter PFS (P < 0.0009 and P = 0.026, respectively) and OS (P < 0.031 and P = 0.039, respectively). AR gain appeared significantly correlated with choline uptake represented mainly by TLA. Further prospective studies are warranted to better address this pathway of AR-signalling and to identify multiplex biomarker strategies including plasma AR and FCH-PET/CT in mCRPC patients. PMID- 29138501 TI - Targeting SxIP-EB1 interaction: An integrated approach to the discovery of small molecule modulators of dynamic binding sites. AB - End binding protein 1 (EB1) is a key element in the complex network of protein protein interactions at microtubule (MT) growing ends, which has a fundamental role in MT polymerisation. EB1 is an important protein target as it is involved in regulating MT dynamic behaviour, and has been associated with several disease states, such as cancer and neuronal diseases. Diverse EB1 binding partners are recognised through a conserved four amino acid motif, (serine-X-isoleucine proline) which exists within an intrinsically disordered region. Here we report the use of a multidisciplinary computational and experimental approach for the discovery of the first small molecule scaffold which targets the EB1 recruiting domain. This approach includes virtual screening (structure- and ligand-based design) and multiparameter compound selection. Subsequent studies on the selected compounds enabled the elucidation of the NMR structures of the C-terminal domain of EB1 in the free form and complexed with a small molecule. These structures show that the binding site is not preformed in solution, and ligand binding is fundamental for the binding site formation. This work is a successful demonstration of the combination of modelling and experimental methods to enable the discovery of compounds which bind to these challenging systems. PMID- 29138502 TI - Crystal structures of the mitochondrial deacylase Sirtuin 4 reveal isoform specific acyl recognition and regulation features. AB - Sirtuins are evolutionary conserved NAD+-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptosis. In contrast to the mitochondrial deacetylase Sirt3 and desuccinylase Sirt5, no prominent deacylase activity and structural information are available for Sirt4. Here we describe acyl substrates and crystal structures for Sirt4. The enzyme shows isoform-specific acyl selectivity, with significant activity against hydroxymethylglutarylation. Crystal structures of Sirt4 from Xenopus tropicalis reveal a particular acyl binding site with an additional access channel, rationalizing its activities. The structures further identify a conserved, isoform-specific Sirt4 loop that folds into the active site to potentially regulate catalysis. Using these results, we further establish efficient Sirt4 activity assays, an unusual Sirt4 regulation by NADH, and Sirt4 effects of pharmacological modulators. PMID- 29138503 TI - Dihydrotestosterone levels at birth associate positively with higher proportions of circulating immature/naive CD5+ B cells in boys. AB - Boys present with higher proportions of immature/naive CD5+ B cells than girls up to 3 years of age. Boys also have higher fractions of regulatory T cells (Tregs) in early infancy, but the mechanisms for these sex-related differences are unknown. In the prospective FARMFLORA follow-up study of 23 boys and 25 girls, we investigated if these immunological differences remained at 8 years of age. We also examined if testosterone or dihydrotestosterone (DHT) levels at birth and at 8 years of age were associated with immune maturation. Immunological variables and androgen levels were examined and measured in blood samples obtained at birth, 3-5 days and at 8 years of age. Boys had higher proportions of CD5+ and immature/transitional CD24hiCD38hi B cells, whereas girls had higher fractions of B cells with a memory phenotype at 8 years of age. School-aged boys also presented with higher frequencies of Tregs, and a greater capacity to produce T cell-associated cytokines. Among boys, higher cord blood DHT levels were associated with higher proportions of CD5+ B cells in early infancy and at 8 years of life. These results suggest that DHT actions in utero might be involved in the mechanism for delayed peripheral B-cell maturation in boys. PMID- 29138504 TI - Facilitation of information processing in the primary somatosensory area in the ball rotation task. AB - Somatosensory input to the brain is known to be modulated during voluntary movement. It has been demonstrated that the response in the primary somatosensory cortex (SI) is generally gated during simple movement of the corresponding body part. This study investigated sensorimotor integration in the SI during manual movement using a motor task combining movement complexity and object manipulation. While the amplitude of M20 and M30 generated in the SI showed a significant reduction during manual movement, the subsequent component (M38) was significantly higher in the motor task than in the stationary condition. Especially, that in the ball rotation task showed a significant enhancement compared with those in the ball grasping and stone and paper tasks. Although sensorimotor integration in the SI generally has an inhibitory effect on information processing, here we found facilitation. Since the ball rotation task seems to be increasing the demand for somatosensory information to control the complex movements and operate two balls in the palm, it may have resulted in an enhancement of M38 generated in the SI. PMID- 29138505 TI - Increased Complement 3a Receptor is Associated with Behcet's disease and Vogt Koyanagi-Harada disease. AB - Behcet's disease (BD) and Vogt-Koyanagi-Harada disease (VKH) are systemic and recurrent autoimmune diseases associated with abnormal T cell immune response. Complement 3a receptor (C3aR) and complement 5a receptor (C5aR) have been reported to be involved in T cell mediated autoimmune disease. This study aimed to investigate the role of C3aR and C5aR in these two diseases. The C3aR expression in PBMCs was increased in patients with active BD (aBD) and active VKH (aVKH). No statistical difference was found concerning the expression of C5aR in PBMCs between patients with aBD or aVKH and normal controls. After the intraocular inflammation in BD and VKH patients was controlled, the C3aR expression returned back to normal levels. The serum from patients with aBD and aVKH significantly induced C3aR expression by PBMCs. C3a induced IL-6, IL-1beta and TNF-alpha secretion, while inhibited the production of IL-10 by monocytes. Activation of C3aR in CD4+T cells could upregulate IL-17 production and inhibit IL-10 production, but had no detectable influence on IFN-gamma production. Our data indicates that increased C3aR expression may lead to over activation of the Th17 cell response and may therefore contribute to the pathogenesis of BD and VKH disease. PMID- 29138506 TI - Diagnostic performance of susceptibility-weighted magnetic resonance imaging for the detection of calcifications: A systematic review and meta-analysis. AB - Since its introduction, susceptibility-weighted-magnetic resonance imaging (SW MRI) has shown the potential to overcome the insensitivity of MRI to calcification. Previous studies reporting the diagnostic performance of SW-MRI and magnetic resonance imaging (MRI) for the detection of calcifications are inconsistent and based on single-institution designs. To our knowledge, this is the first meta-analysis on SW-MRI, determining the potential of SW-MRI to detect calcifications. Two independent investigators searched MEDLINE, EMBASE and Web of Science for eligible diagnostic accuracy studies, which were published until March 24, 2017 and investigated the accuracy of SW-MRI to detect calcifications, using computed tomography (CT) as a reference. The QUADAS-2 tool was used to assess study quality and methods for analysis were based on PRISMA. A bivariate diagnostic random-effects model was applied to obtain pooled sensitivities and specificities. Out of the 4629 studies retrieved by systematic literature search, 12 clinical studies with 962 patients and a total of 1,032 calcifications were included. Pooled sensitivity was 86.5% (95%-confidence interval (CI): 73.6-93.7%) for SW-MRI and 36.7% (95%-CI:29.2-44.8%) for standard MRI. Pooled specificities of SW-MRI (90.8%; 95%-CI:81.0-95.8%) and standard MRI (94.2; 95%-CI:88.9-96.7%) were comparable. Results of the present meta-analysis suggest, that SW-MRI is a reliable method for detecting calcifications in soft tissues. PMID- 29138507 TI - Systems pathology by multiplexed immunohistochemistry and whole-slide digital image analysis. AB - The paradigm of molecular histopathology is shifting from a single-marker immunohistochemistry towards multiplexed detection of markers to better understand the complex pathological processes. However, there are no systems allowing multiplexed IHC (mIHC) with high-resolution whole-slide tissue imaging and analysis, yet providing feasible throughput for routine use. We present an mIHC platform combining fluorescent and chromogenic staining with automated whole slide imaging and integrated whole-slide image analysis, enabling simultaneous detection of six protein markers and nuclei, and automatic quantification and classification of hundreds of thousands of cells in situ in formalin-fixed paraffin-embedded tissues. In the first proof-of-concept, we detected immune cells at cell-level resolution (n = 128,894 cells) in human prostate cancer, and analysed T cell subpopulations in different tumour compartments (epithelium vs. stroma). In the second proof-of-concept, we demonstrated an automatic classification of epithelial cell populations (n = 83,558) and glands (benign vs. cancer) in prostate cancer with simultaneous analysis of androgen receptor (AR) and alpha-methylacyl-CoA (AMACR) expression at cell-level resolution. We conclude that the open-source combination of 8-plex mIHC detection, whole-slide image acquisition and analysis provides a robust tool allowing quantitative, spatially resolved whole-slide tissue cytometry directly in formalin-fixed human tumour tissues for improved characterization of histology and the tumour microenvironment. PMID- 29138508 TI - Fetal cardiac cine magnetic resonance imaging in utero. AB - Fast magnetic resonance imaging (MRI) led to the emergence of 'cine MRI' techniques, which enable the visualization of the beating heart and the assessment of cardiac morphology and dynamics. However, established cine MRI methods are not suitable for fetal heart imaging in utero, where anatomical structures are considerably smaller and recording an electrocardiogram signal for synchronizing MRI data acquisition is difficult. Here we present a framework to overcome these challenges. We use methods for image acquisition and reconstruction that robustly produce images with sufficient spatial and temporal resolution to detect the heart contractions of the fetus, enabling a retrospective gating of the images and thus the generation of images of the beating heart. To underline the potential of our approach, we acquired in utero images in six pregnant patients and compared these with their echocardiograms. We found good agreement in terms of diameter and area measurements, and low inter- and intra- observer variability. These results establish MRI as a reliable modality for fetal cardiac imaging, with a substantial potential for prenatal evaluation of congenital heart defects. PMID- 29138509 TI - Non-thermal atmospheric plasma ameliorates imiquimod-induced psoriasis-like skin inflammation in mice through inhibition of immune responses and up-regulation of PD-L1 expression. AB - Plasma medicine is an emerging novel therapeutic field. It has been reported that plasma can kill bacteria, promote wound healing and induce apoptosis of tumor cells. However, the effects of plasma on immune cells and immune related skin diseases have not been well studied. In this study, we demonstrated that non thermal atmospheric plasma (NTP) treatment could inhibit psoriasis-like skin inflammation in mice. NTP treatment in imiquimod-induced psoriasis-like mouse skin inhibited increases in epithelial cell thickness and expression of pro inflammatory molecules compared to ones without the NTP treatment. In addition, differentiation of Th17 cells, an important cell type for pathogenesis of psoriasis, was inhibited in the NTP-treated mouse lymph nodes. It was also demonstrated that liquid type plasma (LTP), which is also known as indirect plasma, inhibited Th17 cell differentiation in vitro. Other in vitro experiments showed that LTP inhibited bone marrow-derived dendritic cell activation. Interestingly, LTP enhanced PD-L1 expression in HaCaT cells, suggesting that NTP may inhibit unwanted over-activation of T cells through increased PD-L1 expression. Taken together, these results suggest that NTP may be used in treatment of CD4+ T cell-mediated autoimmune diseases such as psoriasis. PMID- 29138510 TI - High-fat diet-induced obesity and insulin resistance are characterized by differential beta oscillatory signaling of the limbic cortico-basal ganglia loop. AB - The concept of brain circuit disorders has been proposed for a variety of neuropsychiatric diseases, characterized by pathological disturbances of neuronal networks including changes in oscillatory signaling of re-entrant cortico subcortical loops in the basal ganglia system. Parts of this circuitry play a pivotal role in energy homeostasis. We therefore investigated whether high-fat diet (HFD) induced obesity is associated with changes in oscillatory signaling in the limbic cortico-basal ganglia loop. We performed multi-site in-vivo electrophysiological recordings of local field potentials within this network under urethane anesthesia in adult rats after 4 weeks of HFD feeding compared to age-matched controls. Recordings were performed at baseline and during systemic glucose challenge. Our analysis demonstrates increased oscillatory beta power in the nucleus accumbens (NAC) associated with decreased beta coherence between cortex and NAC in animals fed a HFD. Spontaneous beta oscillatory power strongly correlated with endocrine markers of obesity. The glucose challenge increased beta oscillations in control animals but not in animals receiving the HFD. Furthermore direct intracerebroventricular insulin injection increased beta oscillations in the NAC. The present study provides evidence for aberrant oscillatory signaling in the limbic cortico-basal ganglia loop that might contribute to the dysfunctional information processing in obesity. PMID- 29138511 TI - Intrinsic and extrinsic factors drive ontogeny of early-life at-sea behaviour in a marine top predator. AB - Young animals must learn to forage effectively to survive the transition from parental provisioning to independent feeding. Rapid development of successful foraging strategies is particularly important for capital breeders that do not receive parental guidance after weaning. The intrinsic and extrinsic drivers of variation in ontogeny of foraging are poorly understood for many species. Grey seals (Halichoerus grypus) are typical capital breeders; pups are abandoned on the natal site after a brief suckling phase, and must develop foraging skills without external input. We collected location and dive data from recently-weaned grey seal pups from two regions of the United Kingdom (the North Sea and the Celtic and Irish Seas) using animal-borne telemetry devices during their first months of independence at sea. Dive duration, depth, bottom time, and benthic diving increased over the first 40 days. The shape and magnitude of changes differed between regions. Females consistently had longer bottom times, and in the Celtic and Irish Seas they used shallower water than males. Regional sex differences suggest that extrinsic factors, such as water depth, contribute to behavioural sexual segregation. We recommend that conservation strategies consider movements of young naive animals in addition to those of adults to account for developmental behavioural changes. PMID- 29138512 TI - Proteome-wide identification of lysine 2-hydroxyisobutyrylation reveals conserved and novel histone modifications in Physcomitrella patens. AB - Protein lysine 2-hydroxyisobutyrylation (Khib) is a newly identified post translational modification found in animal and yeast cells. Previous research suggested that histone Khib is involved in male cell differentiation and plays a critical role in the regulation of chromatin functions in animals. However, information regarding protein Khib in plants is still limited. In this study, using a specific antibody and LC-MS/MS methods, we identified 11,976 Khib sites in 3,001 proteins in Physcomitrella patens. The bioinformatics analysis indicated that these Khib-modified proteins were involved in a wide range of molecular functions and cellular processes, and showed diverse subcellular localizations. Furthermore, an comparism of Khib sites in histone proteins among human, mouse and P. patens found conserved sites in the H3 and H4 histone proteins and novel sites in H1, H2A and H2B histone proteins in P. patens. This is the first report on Khib post-translational modifications in plants, and the study provides a comprehensive profile of Khib sites in histone and non-histone proteins in Physcomitrella patens. PMID- 29138513 TI - FOXA2 alleviates CCl4-induced liver fibrosis by protecting hepatocytes in mice. AB - The liver-enriched transcription factor Forkhead Box A2 (FOXA2) has been reported to be involved in bile acid homeostasis and bile duct development. However, the role of FOXA2 in liver fibrogenesis remains undefined. In this study, we found that the abundance of FOXA2 was significantly lower in fibrotic livers of patients and mice treated with CCl4 than in controls. Interestingly, the expression level of FOXA2 decreased in hepatocytes, whereas FOXA2 was elevated in hepatic stellate cells (HSCs) of mouse fibrotic livers. Hepatocyte-specific ablation of FOXA2 in adult mice exacerbated liver fibrosis induced by CCl4. Either lentivirus LV-CMV-FOXA2 mediated FOXA2 overexpression in the liver or adeno-associated virus AAV8-TBG-FOXA2-mediated hepatocyte-specific upregulation of FOXA2 alleviated hepatic fibrosis. Overexpression of FOXA2 in HSCs did not obviously affect hepatic fibrogenesis. Additionally, FOXA2 knockout in hepatocytes resulted in aberrant transcription of metabolic genes. Furthermore, hepatocyte-specific knockout of FOXA2 enhanced endoplasmic reticulum stress (ER stress) and the apoptosis of hepatocytes, whereas FOXA2 overexpression in hepatocytes suppressed ER stress and hepatocyte apoptosis in mouse fibrotic livers. In conclusion, our findings suggested that FOXA2-mediated hepatocyte protection has a therapeutic role in hepatic fibrosis, and thus may be a new, promising anti-fibrotic option for treating chronic liver diseases. PMID- 29138514 TI - Changing trends in the prevalence of H. pylori infection in Japan (1908-2003): a systematic review and meta-regression analysis of 170,752 individuals. AB - Changing trends in the prevalence of H. pylori infection in the general population over time are thought to be the main driving force behind the declining gastric cancer mortality in Japan. However, whether the prevalence of H. pylori infection itself shows a birth-cohort pattern needs to be corroborated. We performed a systematic review of studies that reported the prevalence of H. pylori infection among Japanese individuals. Meta-regression was conducted in the framework of a generalized additive mixed model (GAMM) to account for heterogeneity in the prevalence of H. pylori infection as a function of birth year. The prevalence of H. pylori infection confirmed a clear birth cohort pattern: the predicted prevalence (%, 95% CI) was 60.9 (56.3-65.4), 65.9 (63.9 67.9), 67.4 (66.0-68.7), 64.1 (63.1-65.1), 59.1 (58.2-60.0), 49.1 (49.0-49.2), 34.9 (34.0-35.8), 24.6 (23.5-25.8), 15.6 (14.0-17.3), and 6.6 (4.8-8.9) among those who were born in the year 1910, 1920, 1930, 1940, 1950, 1960, 1970, 1980, 1990, and 2000, respectively. The present study demonstrated a clear birth-cohort pattern of H. pylori infection in the Japanese population. The decreased prevalence of H. pylori infection in successive generations should be weighed in future gastric cancer control programs. PMID- 29138515 TI - Targeting a non-oncogene addiction to the ATR/CHK1 axis for the treatment of small cell lung cancer. AB - Small cell lung cancer (SCLC) is a difficult to treat subtype of lung cancer. One of the hallmarks of SCLC is its almost uniform chemotherapy sensitivity. However, chemotherapy response is typically transient and patients frequently succumb to SCLC within a year following diagnosis. We performed a transcriptome analysis of the major human lung cancer entities. We show a significant overexpression of genes involved in the DNA damage response, specifically in SCLC. Particularly CHEK1, which encodes for the cell cycle checkpoint kinase CHK1, is significantly overexpressed in SCLC, compared to lung adenocarcinoma. In line with uncontrolled cell cycle progression in SCLC, we find that CDC25A, B and C mRNAs are expressed at significantly higher levels in SCLC, compared to lung adenocarcinoma. We next profiled the efficacy of compounds targeting CHK1 and ATR. Both, ATR- and CHK1 inhibitors induce genotoxic damage and apoptosis in human and murine SCLC cell lines, but not in lung adenocarcinoma cells. We further demonstrate that murine SCLC tumors were highly sensitive to ATR- and CHK1 inhibitors, while Kras G12D driven murine lung adenocarcinomas were resistant against these compounds and displayed continued growth under therapy. Altogether, our data indicate that SCLC displays an actionable dependence on ATR/CHK1-mediated cell cycle checkpoints. PMID- 29138517 TI - Hypertension: Device therapy for uncontrolled hypertension: new approaches to an old problem. PMID- 29138518 TI - Predicted molecular targets and pathways for germacrone, curdione, and furanodiene in the treatment of breast cancer using a bioinformatics approach. AB - Germacrone, curdione, and furanodiene have been shown to be useful in the treatment of breast cancer but the pharmacological mechanism of action is unclear. In this paper, we explored a new method to study the molecular network and function of Traditional Chinese Medicine (TCM) herbs and their corresponding ingredients with bioinformatics tools, including PubChem Compound Database, BATMAN-TCM, SystemsDock, Coremine Medical, Gene ontology, and KEGG. Eleven targeted genes/proteins, 4 key pathways, and 10 biological processes were identified to participate in the mechanism of action in treating breast cancer with germacrone, curdione, and furanodiene. The information achieved by the bioinformatics tools was useful to interpretation the molecular mechanism for the treatment of germacrone, curdione, and furanodiene on breast cancers. PMID- 29138516 TI - The functions and unique features of long intergenic non-coding RNA. AB - Long intergenic non-coding RNA (lincRNA) genes have diverse features that distinguish them from mRNA-encoding genes and exercise functions such as remodelling chromatin and genome architecture, RNA stabilization and transcription regulation, including enhancer-associated activity. Some genes currently annotated as encoding lincRNAs include small open reading frames (smORFs) and encode functional peptides and thus may be more properly classified as coding RNAs. lincRNAs may broadly serve to fine-tune the expression of neighbouring genes with remarkable tissue specificity through a diversity of mechanisms, highlighting our rapidly evolving understanding of the non-coding genome. PMID- 29138519 TI - Time-to-delivery and delivery outcomes comparing three methods of labor induction in 7551 nulliparous women: a population-based cohort study. AB - OBJECTIVE: Determine time-to-delivery and mode-of-delivery in labor induction among women with unripe cervix. STUDY DESIGN: 7551 nulliparous women with singleton deliveries, ?37 weeks, Bishop Score ?6, induced with dinoprostone, misoprostol or transcervical single balloon catheter. Linear regression analysis was used to estimate mean time-to-delivery with beta-estimates and 95% confidence intervals with adjustments. Multivariable logistic regression analysis was used to calculate odds of cesarean delivery, instrumental vaginal delivery, maternal and neonatal outcomes. RESULTS: Adjusted mean time-to-delivery was 6.9 and 1.5 h shorter, respectively, when inducing labor with balloon catheter (mean 18.3 h, beta -6.9, 95% confidence intervals; -7.6 to -6.3) or misoprostol (mean 23.7 h, beta -1.5, 95% confidence intervals; -2.3 to -0.8) compared with dinoprostone (mean 25.2 h). There were no significant differences in adverse maternal or infant outcomes between induction methods. CONCLUSIONS: Balloon catheter is the most effective induction method with respect to time-to-delivery in nulliparous women at term compared with prostaglandin methods. PMID- 29138520 TI - Prenatal (non)treatment decisions in extreme prematurity: evaluation of decisional conflict and regret among parents. AB - This corrects the article DOI: 10.1038/jp.2017.90. PMID- 29138521 TI - Systematic reviews and meta-analysis: why might more clinical trials yield no greater precision? PMID- 29138522 TI - Complications of prematurity: an infographic. PMID- 29138523 TI - Estimates of perinatal death: a global initiative! PMID- 29138524 TI - Effect of interpregnancy interval on the success rate of trial of labor after cesarean. AB - OBJECTIVE: The objective of this study is to investigate the association between interpregnancy interval and success of vaginal birth after cesarean. STUDY DESIGN: Retrospective 10-year cohort study of pregnant women with one prior cesarean, who opted for trial of labor (n=36 653). Interpregnancy interval is the time between cesarean and next conception. Vaginal birth success rates were compared between six interval groups. Analysis was performed pooled as well as stratified for induction of labor. Adjusted odds ratios were calculated. RESULTS: Success rate in the reference group (12 to 24 months) was 72%. Success rates were similar among those with an interval of less than 24 months. Intervals of 24 months or more showed a decrease in success rate; 70% in 24- to 35-month intervals (adjusted odds ratio 0.92 (0.87 to 0.98)), 67% in 36- to 59-month intervals (adjusted odds ratio 0.87 (0.81 to 0.94)) and 62% in intervals of more than 60 months (adjusted odds ratio 0.77 (0.67 to 0.88)). CONCLUSION: An interpregnancy interval of <24 months is not associated with a decreased success of vaginal birth after cesarean. Success rates decrease when interval increases. PMID- 29138525 TI - Visualizing the GPCR Network: Classification and Evolution. AB - In this study, we delineate an unsupervised clustering algorithm, minimum span clustering (MSC), and apply it to detect G-protein coupled receptor (GPCR) sequences and to study the GPCR network using a base dataset of 2770 GPCR and 652 non-GPCR sequences. High detection accuracy can be achieved with a proper dataset. The clustering results of GPCRs derived from MSC show a strong correlation between their sequences and functions. By comparing our level 1 MSC results with the GPCRdb classification, the consistency is 87.9% for the fourth level of GPCRdb, 89.2% for the third level, 98.4% for the second level, and 100% for the top level (the lowest resolution level of GPCRdb). The MSC results of GPCRs can be well explained by estimating the selective pressure of GPCRs, as exemplified by investigating the largest two subfamilies, peptide receptors (PRs) and olfactory receptors (ORs), in class A GPCRs. PRs are decomposed into three groups due to a positive selective pressure, whilst ORs remain as a single group due to a negative selective pressure. Finally, we construct and compare phylogenetic trees using distance-based and character-based methods, a combination of which could convey more comprehensive information about the evolution of GPCRs. PMID- 29138526 TI - Stimulation of primordial follicle assembly by estradiol-17beta requires the action of bone morphogenetic protein-2 (BMP2). AB - Primordial follicle (PF) pool determines the availability of follicles for ovulation in all mammals. Premature depletion of the PF reserve leads to subfertility or infertility. Bone morphogenetic protein 2 (BMP2) promotes PF formation by facilitating oocyte and granulosa cell development. Estradiol-17beta (E2) upregulates PF formation in developing hamster ovaries. However, if BMP2 mediates E2 effect is not known. We hypothesize that E2 facilitates the effect of BMP2 on somatic to granulosa cell transition. BMP2 and E2 together significantly upregulated the percentage of PFs in hamster fetal ovaries in vitro compared with either of the treatments alone. E2 also promoted BMP2 expression in vivo. Inhibition of BMP2 receptors suppressed E2-stimulation of PF formation while knockdown of BMP2 in vitro significantly suppressed the E2 effect. In contrast, estrogen receptor blocker did not affect BMP2 action. Inhibition of the activity of E2 or BMP2 receptors, either alone or combined during the last two days of the culture (C6-C8) resulted in a significant decrease in PF formation by C8, suggesting that both BMP2 and E2 action is essential for somatic cell differentiation for PF formation. Together, the results suggest that E2 activates BMP2-BMPR system leading to the formation of primordial follicles. PMID- 29138527 TI - Longitudinal Analysis of Mouse SDOCT Volumes. AB - Spectral-domain optical coherence tomography (SDOCT), in addition to its routine clinical use in the diagnosis of ocular diseases, has begun to find increasing use in animal studies. Animal models are frequently used to study disease mechanisms as well as to test drug efficacy. In particular, SDOCT provides the ability to study animals longitudinally and non-invasively over long periods of time. However, the lack of anatomical landmarks makes the longitudinal scan acquisition prone to inconsistencies in orientation. Here, we propose a method for the automated registration of mouse SDOCT volumes. The method begins by accurately segmenting the blood vessels and the optic nerve head region in the scans using a pixel classification approach. The segmented vessel maps from follow-up scans were registered using an iterative closest point (ICP) algorithm to the baseline scan to allow for the accurate longitudinal tracking of thickness changes. Eighteen SDOCT volumes from a light damage model study were used to train a random forest utilized in the pixel classification step. The area under the curve (AUC) in a leave-one-out study for the retinal blood vessels and the optic nerve head (ONH) was found to be 0.93 and 0.98, respectively. The complete proposed framework, the retinal vasculature segmentation and the ICP registration, was applied to a secondary set of scans obtained from a light damage model. A qualitative assessment of the registration showed no registration failures. PMID- 29138528 TI - The Predictive Value of PITX2 DNA Methylation for High-Risk Breast Cancer Therapy: Current Guidelines, Medical Needs, and Challenges. AB - High-risk breast cancer comprises distinct tumor entities such as triple-negative breast cancer (TNBC) which is characterized by lack of estrogen (ER) and progesterone (PR) and the HER2 receptor and breast malignancies which have spread to more than three lymph nodes. For such patients, current (inter)national guidelines recommend anthracycline-based chemotherapy as the standard of care, but not all patients do equally benefit from such a chemotherapy. To further improve therapy decision-making, predictive biomarkers are of high, so far unmet, medical need. In this respect, predictive biomarkers would permit patient selection for a particular kind of chemotherapy and, by this, guide physicians to optimize the treatment plan for each patient individually. Besides DNA mutations, DNA methylation as a patient selection marker has received increasing clinical attention. For instance, significant evidence has accumulated that methylation of the PITX2 (paired-like homeodomain transcription factor 2) gene might serve as a novel predictive and prognostic biomarker, for a variety of cancer diseases. This review highlights the current understanding of treatment modalities of high-risk breast cancer patients with a focus on recommended treatment options, with special attention on the future clinical application of PITX2 as a predictive biomarker to personalize breast cancer management. PMID- 29138529 TI - Matrix Metalloproteinases Polymorphisms as Prognostic Biomarkers in Malignant Pleural Mesothelioma. AB - Background: Malignant pleural mesothelioma (MPM) is a rare disease with a relatively short overall survival (OS). Metalloproteinases (MMPs) have a vast biological effect on tumor progression, invasion, metastasis formation, and apoptosis. MMP expression was previously associated with survival in MPM. Our aim was to evaluate if genetic variability of MMP genes could also serve as a prognostic biomarker in MPM. Methods: We genotyped 199 MPM patients for ten polymorphisms: rs243865, rs243849 and rs7201, in MMP2; rs17576, rs17577, rs20544, and rs2250889 in MMP9; and rs1042703, rs1042704, and rs743257 in MMP14. We determined the influence on survival using Cox regression. Results: Carriers of polymorphic MMP9 rs2250889 allele had shorter time to progression (TTP) (6.07 versus 10.03 months, HR = 2.45, 95% CI = 1.45-4.14, p = 0.001) and OS (9.23 versus 19.2 months, HR = 2.39, 95% CI = 1.37-4.18, p = 0.002). In contrast, carriers of at least one polymorphic MMP9 rs20544 allele had longer TTP (10.93 versus 9.40 months, HR = 0.57, 95% CI = 0.38-0.86 p = 0.007) and OS (20.67 versus 13.50 months, HR = 0.56, 95% CI = 0.37-0.85, p = 0.007). MMP14 rs1042703 was associated with nominally shorter TTP (8.7 versus 9.27 months, HR = 2.09, 95% CI = 1.06-4.12, p = 0.032). Conclusions: Selected MMP SNPs were associated with survival and could be used as potential genetic biomarkers in MPM. PMID- 29138530 TI - Group 2 Innate Lymphoid Cells Are Involved in Skewed Type 2 Immunity of Gastric Diseases Induced by Helicobacter pylori Infection. AB - H. pylori induces a complicated local and systematic immune response and contributes to the carcinogenesis of gastric cancer. A primary type 1 immune response is evoked by H. pylori since its occurrence. However, it is not unusual that an inhibitory immunity is dominant in H. pylori-associated diseases, which are promoted by the formation of immunosuppressive microenvironment. But whether group 2 innate lymphoid cells (ILC2s) plays a critical role in H. pylori-induced skewed type 2 immunity is still unclear. In the present study, firstly, we confirmed that type 1 immunity was inhibited and type 2 immunity were undisturbed or promoted after H. pylori infection in vitro and in vivo. Secondly, GATA-3 was firstly found to be increased in the interstitial lymphocytes from H. pylori associated gastric cancer, among them, Lin-GATA-3+ cells and Lin+GATA-3+ cells were also found to be enhanced, which indicated an important role for ILC2s in H. pylori infection. More importantly, ILC2s were found to be increased after H. pylori infection in clinical patients and animal models. In conclusion, our results indicated that ILC2-mediated innate immune response might play a potential role in dominant type 2 phenotype and immunosuppressive microenvironment in H. pylori infection. PMID- 29138531 TI - Anti-Inflammatory Strategy for M2 Microglial Polarization Using Retinoic Acid Loaded Nanoparticles. AB - Inflammatory mechanisms triggered by microglial cells are involved in the pathophysiology of several brain disorders, hindering repair. Herein, we propose the use of retinoic acid-loaded polymeric nanoparticles (RA-NP) as a means to modulate microglia response towards an anti-inflammatory and neuroprotective phenotype (M2). RA-NP were first confirmed to be internalized by N9 microglial cells; nanoparticles did not affect cell survival at concentrations below 100 MUg/mL. Then, immunocytochemical studies were performed to assess the expression of pro- and anti-inflammatory mediators. Our results show that RA-NP inhibited LPS-induced release of nitric oxide and the expression of inducible nitric oxide synthase and promoted arginase-1 and interleukin-4 production. Additionally, RA NP induced a ramified microglia morphology (indicative of M2 state), promoting tissue viability, particularly neuronal survival, and restored the expression of postsynaptic protein-95 in organotypic hippocampal slice cultures exposed to an inflammatory challenge. RA-NP also proved to be more efficient than the free equivalent RA concentration. Altogether, our data indicate that RA-NP may be envisioned as a promising therapeutic agent for brain inflammatory diseases. PMID- 29138532 TI - Ubiquitin-Specific Protease 2 Modulates the Lipopolysaccharide-Elicited Expression of Proinflammatory Cytokines in Macrophage-like HL-60 Cells. AB - We investigated the regulatory roles of USP2 in mRNA accumulation of proinflammatory cytokines in macrophage-like cells after stimulation with a toll like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). Human macrophage-like HL 60 cells, mouse macrophage-like J774.1 cells, and mouse peritoneal macrophages demonstrated negative feedback to USP2 mRNA levels after LPS stimulation, suggesting that USP2 plays a significant role in LPS-stimulated macrophages. USP2 knockdown (KD) by short hairpin RNA in HL-60 cells promoted the accumulation of transcripts for 25 of 104 cytokines after LPS stimulation. In contrast, limited induction of cytokines was observed in cells forcibly expressing the longer splice variant of USP2 (USP2A), or in peritoneal macrophages isolated from Usp2a transgenic mice. An ubiquitin isopeptidase-deficient USP2A mutant failed to suppress LPS-induced cytokine expression, suggesting that protein ubiquitination contributes to USP2-mediated cytokine repression. Although USP2 deficiency did not accelerate TNF receptor-associated factor (TRAF) 6-nuclear factor-kappaB (NF kappaB) signaling, it increased the DNA binding ratio of the octamer binding transcription factor (Oct)-1 to Oct-2 in TNF, CXCL8, CCL4, and IL6 promoters. USP2 decreased nuclear Oct-2 protein levels in addition to decreasing the polyubiquitination of Oct-1. In summary, USP2 modulates proinflammatory cytokine induction, possibly through modification of Oct proteins, in macrophages following TLR4 activation. PMID- 29138533 TI - Comparison of visual outcomes after bilateral implantation of a diffractive trifocal intraocular lens and blended implantation of an extended depth of focus intraocular lens with a diffractive bifocal intraocular lens. AB - Purpose: The purpose of this study was to compare the visual outcomes and subjective visual quality between bilateral implantation of a diffractive trifocal intraocular lens, Alcon Acrysof IQ(r) PanOptix(r) TNFT00 (group A), and blended implantation of an extended depth of focus lens, J&J Tecnis Symfony(r) ZXR00 with a diffractive bifocal intraocular lens, J&J Vision Tecnis(r) ZMB00 (group B). Methods: This prospective, nonrandomized, consecutive, comparative study included the assessment of 40 eyes in 20 patients implanted with multifocal intraocular lens. Exclusion criteria were existence of any corneal, retina, or optic nerve disease, previous eye surgery, illiteracy, previous refractive surgery, high axial myopia, expected postoperative corneal astigmatism of >1.00 cylindrical diopter (D), and intraoperative or postoperative complications. Binocular visual acuity was tested in all cases. Ophthalmological evaluation included the measurement of uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), uncorrected near visual acuity (UNVA), and uncorrected intermediate visual acuity (UIVA), with the analysis of contrast sensitivity (CS), and visual defocus curve. Results: Postoperative UDVA was 0.01 and -0.096 logMAR (p<0.01) in groups A and B, respectively; postoperative CDVA was -0.07 and -0.16 logMAR (p<0.01) in groups A and B, respectively; UIVA was 0.14 and 0.20 logMAR (p<0.01) in groups A and B, respectively; UNVA was -0.03 and 0.11 logMAR (p<0.01) in groups A and B, respectively. Under photopic conditions group B had better CS at low frequencies with and without glare. Conclusion: Both groups promoted good quality of vision for long, intermediate, and short distances. Group B exhibited a better performance for very short distances and for intermediate and long distances >=-1.50 D of vergence. Group A exhibited a better performance for UIVA at 60 cm and for UNVA at 40 cm. PMID- 29138534 TI - Vitamin D levels in systemic sclerosis patients: a meta-analysis. AB - Purpose: This study aimed to investigate the association between vitamin D and systemic sclerosis (SSc) by meta-analysis. Methods: A comprehensive search was performed through June 12, 2017. Pooled standardized mean difference (SMD) was used to estimate the mean vitamin D difference between case and control groups (or between diffused- and limited-type SSc). Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were used to assess the impact of vitamin D level on clinical characteristics of SSc patients. All statistical analyses were performed using Revman 5.0 software. Results: The search yielded six studies with a total of 554 SSc patients and 321 healthy controls. The meta-analysis showed that SSc patients suffered from decreased vitamin D levels (SMD =-8.72 ng/mL; 95% CI: 10.11 to -7.32) compared with healthy controls. The meta-analysis results of three studies with 240 SSc patients (93 diffused-type and 147 limited-type SSc patients) showed that diffused-type SSc patients exhibited lower vitamin D levels (SMD =-4.71 ng/mL; 95% CI: -8.98 to -0.44) compared with limited-type SSc patients. However, vitamin D level was not found to be associated with Rodnan score (SMD =-2.29 ng/mL, 95% CI: -8.49 to 3.91, P=0.47), systolic pulmonary pressure (SMD =-1.68 ng/mL, 95% CI: -10.79 to 7.43, P=0.72), gastrointestinal ulcer (RR =1.01, 95% CI: 0.53-1.93, P=0.98), or pulmonary involvement (RR =1.01, 95% CI: 0.36-2.86, P=0.99) in SSc patients. Conclusion: SSc patients exhibited lower vitamin D levels compared with healthy controls. Vitamin D levels in diffused-type SSc patients were significantly lower than those in limited-type SSc patients. The severity of clinical features was not associated with the extent of vitamin D deficit. Therefore, we hypothesize that SSc patients, especially diffused type, have lower vitamin D levels, and that the decrease of vitamin D levels might not be an accelerating factor of SSc severity. PMID- 29138535 TI - Comparable pharmacokinetics and pharmacodynamics of two epoetin alfa formulations Eporon(r) and Eprex(r) following a single subcutaneous administration in healthy male volunteers. AB - Purpose: This study aimed to assess and compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties following a single subcutaneous injection of epoetin alfa (Eporon(r)) with those of the comparator (Eprex(r)) in healthy male subjects. Subjects and methods: A randomized, double-blind, two-sequence, crossover study was conducted. Subjects were randomly assigned to receive a single dose, that is, 4,000 IU, of the test or comparator epoetin alfa. After 4 weeks, all subjects received the alternative formulation. The primary PK parameters, maximum observed concentration (Cmax) and area under the curve extrapolated to infinity (AUCinf), were calculated with the serum erythropoietin (EPO) concentrations from blood samples collected for 144 h after dosing. The reticulocyte, hematocrit, hemoglobin and red blood cell counts were measured up to 312 h as PD markers. The primary PD parameters, maximum observed effect (Emax) and area under the effect curve (AUEC), were obtained from the baseline-corrected reticulocyte count. The serum EPO concentration and the reticulocyte count were used to assess the concentration-response relationship. The tolerability and immunogenicity profiles were assessed together. Results: Forty-two subjects completed the study. The mean EPO concentration-time profiles were comparable between the two formulations. The geometric mean ratios (90% CI) of the Cmax and AUCinf were 0.908 (0.843-0.978) and 1.049 (0.999-1.101), respectively, both of which were within the regulatory range of 0.80-1.25. Additionally, the PD and tolerability profiles were similar between the two formulations. The time-matched serum EPO concentration and PD markers presented a counterclockwise hysteresis, suggesting a time delay between the measured concentration and the response. Both formulations were well tolerated, and production of anti-drug antibodies was not observed. Conclusion: The two epoetin alfa formulations had similar PK, PD and tolerability profiles. Furthermore, both formulations had a similar time-matched serum EPO concentration and erythropoietic response profile. Thus, the two formulations are expected to be used interchangeably in clinical settings. PMID- 29138536 TI - Spotlight on siponimod and its potential in the treatment of secondary progressive multiple sclerosis: the evidence to date. AB - Siponimod (BAF312) is a synthetic molecule belonging to the sphingosine-1 phosphate (S1P) modulator family, which has putative neuroprotective properties and well-characterized immunomodulating effects mediated by sequestration of B and T cells in secondary lymphoid organs. Compared to fingolimod (ie, precursor of the S1P modulators commercially available for the treatment of relapsing remitting [RR] multiple sclerosis [MS]), siponimod exhibits selective affinity for types 1 and 5 S1P receptor, leading to a lower risk of adverse events that are mainly induced by S1P3 receptor activation, such as bradycardia and vasoconstriction. In addition, S1P1 and S1P5 receptors are expressed by neurons and glia and could mediate a possible neuroprotective effect of the drug. A Phase II clinical trial of siponimod for RR MS showed a significant effect of the active drug compared to placebo on reducing gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) after 3 months of treatment. In a recently completed Phase III trial, treatment with siponimod was associated with a significant reduction in disability progression in secondary progressive (SP) MS patients compared to placebo. In this article, current evidence supporting siponimod efficacy for SP MS is reviewed. PMID- 29138537 TI - Development of novel ultrashort antimicrobial peptide nanoparticles with potent antimicrobial and antibiofilm activities against multidrug-resistant bacteria. AB - Conventional antibiotics are facing strong microbial resistance that has recently reached critical levels. This situation is leading to significantly reduced therapeutic potential of a huge proportion of antimicrobial agents currently used in clinical settings. Antimicrobial peptides (AMPs) could provide the medical community with an alternative strategy to traditional antibiotics for combating microbial resistance. However, the development of AMPs into clinically useful antibiotics is hampered by their relatively low stability, toxicity, and high manufacturing costs. In this study, a novel in-house-designed potent ultrashort AMP named RBRBR was encapsulated into chitosan-based nanoparticles (CS-NPs) based on the ionotropic gelation method. The encapsulation efficacy reported for RBRBR into CS-NPs was 51.33%, with a loading capacity of 10.17%. The release kinetics of RBRBR from the nanocarrier exhibited slow release followed by progressive linear release for 14 days. The antibacterial kinetics of RBRBR-CS-NPs was tested against four strains of Staphylococcus aureus for 4 days, and the developed RBRBR CS-NPs exhibited a 3-log decrease in the number of colonies when compared to CS NP and a 5-log decrease when compared to control bacteria. The encapsulated peptide NP formulation managed to limit the toxicity of the free peptide against both mammalian cells and human erythrocytes. Additionally, the peptide NPs demonstrated up to 98% inhibition of biofilm formation when tested against biofilm-forming bacteria. Loading RBRBR into CS-NPs could represent an innovative approach to develop delivery systems based on NP technology for achieving potent antimicrobial effects against multidrug-resistant and biofilm-forming bacteria, with negligible systemic toxicity and reduced synthetic costs, thereby overcoming the obstructions to clinical development of AMPs. PMID- 29138538 TI - Interpretability of the European Heart Failure Self-care Behaviour scale. AB - Objective: The European Heart Failure Self-care Behaviour scale (EHFScBs) is a valid patient-reported questionnaire to measure self-care behavior of heart failure (HF) patients. We assessed the interpretability of the EHFScBs. Methods: We used data of 1,023 HF patients. Interpretability refers to the clinical meaning of the score and its changes over time. We operationalized interpretability by evaluating distributions of EHFScBs scores across relevant HF subgroups by eyeballing, by testing the risk on hospitalizations and mortality of a plausible threshold, and by determining a clinically relevant minimal important change (MIC). The scale score ranged from 0 to 100, with a higher score meaning better self-care. A threshold of >=70 was defined as adequate and <70 as inadequate self-care. Results: The EHFScBs scores were similarly normally distributed among the subgroups with a mean between 57.8 (SD 19.4) and 72.0 (SD 18.0). The 464 HF patients with adequate self-care had significantly less all cause hospitalizations than the 559 patients with inadequate self-care. Conclusion: The degree of self-care showed to be independent of relevant HF subgroups. A single threshold of 70 accurately discriminated between patients with adequate and inadequate self-care. Practice implications: The threshold of 70 can be used in designing studies and informing health policy makers. PMID- 29138539 TI - Patient-reported benefits from patient organization magazines and Internet-based peer support in Meniere's disease. AB - Objectives: To facilitate self-help, the Finnish Meniere's Federation (FMF) provides various kinds of support to persons with Meniere's disease (MD), which includes patient magazines (PM) and Internet-based peer support (iPS). The current study aimed to evaluate the benefits reported by MD patients in terms of PM and iPS. Method: The study used a cross-sectional survey design with a mixture of structured and open-ended questions administered online. A sample of 185 patients from the FMF membership database provided complete data. Results: Ninety two percent of the respondents rated PM as useful, or very useful. The main benefits of PM included: information on the disease and complaints, information about elements of peer support program, patient's experience with useful positive case studies, relevant news on MD, and information of activity of the FMF. Of the 185 persons, 68 reported that they did not have a need for peer support as their disease was either in silent phase or did not cause any annoyance. The main reasons for nonuse were: mild disease, personal reasons, and problems in using. Regarding the benefits of iPS, 75% of recent and 64% of chronic MD patients said that they would benefit from such a program. The main benefits of iPS included: reliable information on the disease and its management, peer support useful for coping with the disease, information about managing MD symptoms, information about managing attitude, and information about therapy. Moreover, the study identified different groups of individuals, which included: nonusers of support from patient organizations, those who used the support but did not feel they benefited, and those who used and also benefited from such programs. Conclusion: The current study results provide some information about the preferences of MD patients regarding different forms of support and could certainly prove helpful while developing wider support strategies. PMID- 29138540 TI - A qualitative study exploring issues related to medication management in residential aged care facilities. AB - Background: Globally, the population of older people is on the rise. As families are burdened with the high cost of care for aging members, demand is increasing for medical care and nursing homes. Thus, medication management is crucial to ensure that residents in a care center benefit and assist the management of the care center in reducing the burden of health care. This study is aimed to qualitatively explore issues related to medication management in residential aged care facilities (RACFs). Participants and methods: A total of 11 stakeholders comprising health care providers, administrators, caretakers and residents were recruited from a list of registered government, nongovernmental organization and private RACFs in Malaysia from September 2016 to April 2017. An exploratory qualitative study adhering to Consolidated Criteria for Reporting Qualitative Studies was conducted. In-depth interview was conducted with consent of all participants, and the interviews were audio recorded for later verbatim transcription. Observational analysis was also conducted in a noninterfering manner. Results and discussion: Three themes, namely medication use process, personnel handling medications and culture, emerged in this study. Medication use process highlighted an unclaimed liability for residents' medication by the RACFs, whereas personnel handling medications were found to lack sufficient training in medication management. Culture of the organization did affect the medication safety and quality improvement. The empowerment of the residents in their medication management was limited. There were unclear roles and responsibility of who manages the medication in the nongovernment-funded RACFs, although they were well structured in the private nursing homes. Conclusion: There are important issues related to medication management in RACFs which require a need to establish policy and guidelines. PMID- 29138541 TI - The effect of peer support in adults with insulin pump-treated type 1 diabetes: a pilot study of a flexible and participatory intervention. AB - Aim: The aim of this study was to explore the effects of a flexible and participatory peer support intervention in a clinical setting for adults with type 1 diabetes treated with an insulin pump, focusing on enhancing diabetes specific social capital. The key questions were as follows: 1) what effects are appropriate to expect, according to participants? and 2) to what extent did these effects occur? Methods: Two peer support intervention programs were conducted in a diabetes specialist clinic (N=30). A participatory and adaptable approach allowed flexibility in the content of peer support meetings, which were facilitated by a diabetes nurse. Individual interviews explored participants' perception of effects of the intervention. Interview data were analyzed qualitatively. Participants (n=27) completed a baseline and postintervention questionnaire that included items assessing diabetes empowerment, diabetes distress, diabetes-specific social support, and diabetes loneliness. HbA1c levels were compared before and after the intervention. Results: Participants experienced enhanced diabetes-specific social capital, diabetes motivation, awareness of personal diabetes practices, and serenity and openness in life with diabetes. They also became more aware of treatment and support possibilities. Negative effects included feeling sad or upset after the meetings or feeling different than and not as well-controlled as other participants. Quantitative analyses showed enhanced social support, decreased eating distress and trends toward enhanced diabetes empowerment, decreased diabetes loneliness, and decreased diabetes distress (powerlessness). We found fewer positive and/or negative outcomes among participants who felt no need for peer support or felt that the group was not a unit or that important issues were not addressed. Conclusion: The study indicated that flexible and participatory peer support can strengthen diabetes-specific social capital and improve participants' well-being and diabetes empowerment. Awareness of participants' incentives for attending peer support, as well as the risk of people feeling isolated within peer support groups, is essential to creating effective diabetes-specific social support. PMID- 29138542 TI - Validation of Chinese version of the 4-item Trust in Nurses Scale in patients with cancer. AB - Objective: This study was designed to examine the internal consistency, test retest reliability, construct, and concurrent validity of the Trust in Nurses Scale (TNS) in hospitalized patients with cancer in China. Methods: Between October and December 2016, the Chinese version of TNS and Nurse-Patient Trust Scale were applied to assess 190 patients with cancer in a general hospital. A subsample of 70 patients completed the TNS again 1 week later. Results: The Chinese version of the TNS had good internal consistency (alpha=0.817), fair test retest reliability (r=0.866), and confirmatory factor analysis demonstrated good fit for a four-item version of the TNS. Conclusion: The Chinese TNS exhibited sufficient validity and reliability in hospitalized patients with cancer. PMID- 29138543 TI - Location of submacular hemorrhage as a predictor of visual outcome after intravitreal ranibizumab for age-related macular degeneration. AB - Purpose: To evaluate the anatomical and functional outcomes in patients with submacular hemorrhage (SMH) due to age-related macular degeneration (AMD) treated with ranibizumab, and to evaluate the potential role of the SMH location in the final outcome after treatment. Methods: Participants in this study were 12 treatment-naive patients with SMH due to neovascular AMD who were treated with intravitreal ranibizumab and had at least 12 months' follow-up. All patients underwent best-corrected visual acuity measurement and optical coherence tomography at baseline and at every visit posttreatment, while fluorescein angiography was done at baseline and at the discretion of the physician thereafter. Results: Of the patients, 83.4% showed improvement or stabilization in best-corrected visual acuity after treatment at the 12-month follow-up, with a mean number of 7.3+/-2.9 injections. Patients with SMH surrounding the foveal area in 360 degrees presented worse anatomical and functional outcomes compared to those with SMH adjacent to the fovea. Conclusion: Intravitreal ranibizumab seems to be safe and effective, either improving or stabilizing visual acuity, in patients with SMH due to wet AMD. The location of the SMH may predict the final outcome after treatment. PMID- 29138544 TI - Early postoperative delirium after hemiarthroplasty in elderly patients aged over 70 years with displaced femoral neck fracture. AB - Purpose: Postoperative delirium is a risk factor for worse outcome after hip fracture surgery in elderly patients. Postoperative delirium is associated with anesthesia, postoperative pain, and patient factors. We investigated the incidence, predictors, and prognostic implications of post-operative delirium after hemiarthroplasty (HA) in elderly patients with femoral neck fracture. Patients and methods: A total of 356 consecutive patients aged >70 years who underwent HA for femoral neck fracture were enrolled. Diagnosis of delirium was made by a psychiatrist based on patient status and an objective scoring system. The patients were divided into 2 categories according to the HA onset time (immediate [<=24 h after surgery] vs delayed delirium [>24 h after surgery]) and its incidence, predictors and mortality were evaluated. Results: Postoperative delirium was diagnosed in 110 patients (30.9%) during hospitalization. Immediate and delayed delirium occurred in 59 (53.6%), and 51 (46.4%) patients, respectively. The independent predictors of immediate delirium included age (odds ratio [OR] 1.47, 95% CI 0.98-2.23, p=0.066), and general anesthesia (OR 2.25, 95% CI 1.17-4.43, p=0.015). The independent predictors of delayed delirium were parkinsonism (OR 5.75, 95% CI 1.66-19.96, p=0.006), intensive care unit stay (OR 1.85, 95% CI 0.97-3.56, p=0.064), and higher American Society of Anesthesiologists grade (OR 2.33, 95% CI 0.90-6.07, p=0.083). On Kaplan-Meier survival analysis, the 2-year survival rate was significantly lower in the immediate delirium group than those in the delayed and control groups (71.0% vs 83.6% vs 87.8%, respectively; p=0.031). Conclusion: Immediate and delayed delirium after HA for femoral neck fracture had different predictors and immediate delirium was associated with worse prognosis. PMID- 29138545 TI - Activation of Notch1 signaling alleviates dysfunction of bone marrow-derived mesenchymal stem cells induced by cigarette smoke extract. AB - Bone marrow-derived mesenchymal stem cells (BM-MSCs) are considered attractive therapeutic agents for the treatment of COPD. However, little is known about the impact of Notch on the proliferation, migration, and survival of MSCs in a cigarette smoke (CS) microenvironment. Here, we used CS extract to mimic the CS microenvironment in vitro, with the intention to investigate the effect of Notch in regulating proliferation, migration, and survival of BM-MSCs. Rat bone marrow mesenchymal stem cells were infected with lentivirus vector containing the intracellular domain of Notch1 (N1ICD) and challenged with CS extract. Cell proliferation was detected by Ki67 staining and expression of cell cycle-related proteins. A transwell assay was used to measure cell migration and the expression of apoptotic proteins was examined. The proliferation of BM-MSCs overexpressing N1ICD significantly increased. Consistently, levels of cyclin D1, p-Rb, and E2F-1 increased in N1ICD overexpressing cells. N1ICD overexpression also increased cell migration compared with the control group. N1ICD overexpression equilibrated the expression of Bax and Bcl-2, and blocked caspase-3 cleavage, contributing to the inhibition of apoptosis. Moreover, blockade of the PI3K/Akt pathway suppressed the aforementioned cytoprotective effects of N1ICD. In conclusion, activation of Notch signaling improved proliferation, migration, and survival of BM-MSCs in a CS microenvironment partly through the PI3K/Akt pathway. PMID- 29138546 TI - Prediction models for exacerbations in different COPD patient populations: comparing results of five large data sources. AB - Background and objectives: Exacerbations are important outcomes in COPD both from a clinical and an economic perspective. Most studies investigating predictors of exacerbations were performed in COPD patients participating in pharmacological clinical trials who usually have moderate to severe airflow obstruction. This study was aimed to investigate whether predictors of COPD exacerbations depend on the COPD population studied. Methods: A network of COPD health economic modelers used data from five COPD data sources - two population-based studies (COPDGene(r) and The Obstructive Lung Disease in Norrbotten), one primary care study (RECODE), and two studies in secondary care (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoint and UPLIFT) - to estimate and validate several prediction models for total and severe exacerbations (= hospitalization). The models differed in terms of predictors (depending on availability) and type of model. Results: FEV1% predicted and previous exacerbations were significant predictors of total exacerbations in all five data sources. Disease-specific quality of life and gender were predictors in four out of four and three out of five data sources, respectively. Age was significant only in the two studies including secondary care patients. Other significant predictors of total exacerbations available in one database were: presence of cough and wheeze, pack years, 6-min walking distance, inhaled corticosteroid use, and oxygen saturation. Predictors of severe exacerbations were in general the same as for total exacerbations, but in addition low body mass index, cardiovascular disease, and emphysema were significant predictors of hospitalization for an exacerbation in secondary care patients. Conclusions: FEV1% predicted, previous exacerbations, and disease-specific quality of life were predictors of exacerbations in patients regardless of their COPD severity, while age, low body mass index, cardiovascular disease, and emphysema seem to be predictors in secondary care patients only. PMID- 29138547 TI - Efficacy of tiotropium and indacaterol monotherapy and their combination on dynamic lung hyperinflation in COPD: a random open-label crossover study. AB - Background and objective: The difference in efficacy of long-acting muscarinic antagonists (LAMAs) and long-acting beta2-agonists (LABAs) for dynamic lung hyperinflation (DLH) in COPD is unclear. The purpose of this study was to elucidate the difference in efficacy of LAMA and LABA alone and the combination thereof for DLH. Subjects and methods: Thirty stable patients were enrolled and randomly divided into two groups following baseline measurements. One group was treated with 5 MUg tiotropium (Respimat inhaler) for 4 weeks following a 4-week treatment with 150 MUg indacaterol, while the other group was treated with indacaterol for 4 weeks following a 4-week treatment with tiotropium. For both groups, these treatments were followed by a combination of the two drugs for 4 weeks. Pulmonary function tests, including DLH evaluated by metronome-paced incremental hyperventilation and exercise tolerance evaluated by the shuttle-walk test, were performed at the end of each treatment period. Results: In total, 23 patients completed this study. Both tiotropium and indacaterol alone significantly increased forced expiratory volume in 1 second, exercise tolerance, and improved health status. Tiotropium significantly improved DLH, but indacaterol did not. The combination therapy resulted in further improvements in lung function and exercise tolerance, but not in DLH. Conclusion: The efficacy of tiotropium in inhibiting DLH following metronome-paced incremental hyperventilation may be superior to that of 150 MUg indacaterol, although the effects on airflow obstruction were the same, and the combination therapy showed further improvement in airflow obstruction, but not in DLH. PMID- 29138548 TI - E-cigarettes in patients with COPD: current perspectives. AB - Conventional cigarette smoking is known to result in significant COPD morbidity and mortality. Strategies to reduce and/or stop smoking in this highly vulnerable patient group are key public health priorities to reduce COPD morbidity and mortality. Unfortunately, smoking cessation efforts in patients with COPD are poor and there is a compelling need for more efficient approaches to cessation for patients with COPD. Electronic cigarettes (ECs) are devices that use batteries to vaporize nicotine. They may facilitate quit attempts and cessation in many smokers. Although they are not risk free, ECs are much less harmful than tobacco smoking. Hence, the use of ECs in vulnerable groups and in patients with challenges to abstain or multiple relapses to this habit may be promising. To date, little is known about health consequences of EC use among COPD smokers and whether their regular use has any effects on subjective and objective COPD outcomes. In the current review, we discuss the current perspectives and literature on the role of ECs in abstaining from conventional smoking and the effects of ECs on the respiratory tract in patients with COPD. PMID- 29138550 TI - Overlaps and uncertainties of smoking-related idiopathic interstitial pneumonias. AB - Smoking-related interstitial lung disease (ILD) consists of a heterogeneous group of disorders that are considered a distinct entity. The 2013 American Thoracic Society and European Respiratory Society recommendations classified respiratory bronchiolitis (RB)/RB-ILD and desquamative interstitial pneumonia (DIP) as smoking-related idiopathic interstitial pneumonias (IIPs). The overlapping histopathological and radiological patterns of smoking-related IIPs must be considered. Overlap patterns of smoking-related IIPs are not easily classified as a single disorder. The initial radiological manifestation and follow-up changes are heterogeneous, even when diagnosed pathologically as RB or DIP. Therefore, a clinical-radiological-pathological consensus is important in the diagnosis of smoking-related IIPs, and long-term evaluation is essential to monitor the morphological changes in these patients. In this article, we reviewed the clinical, radiological, and pathological findings, and also the changes in radiological manifestations of smoking-related IIPs over time. PMID- 29138549 TI - Inflammation and chronic colonization of Haemophilus influenzae in sputum in COPD patients related to the degree of emphysema and bronchiectasis in high-resolution computed tomography. AB - The presence of bacteria in the lower airways in COPD results in inflammation, further airway structural damage, and might lead to repeated exacerbations. We have previously shown that chronic colonization of Haemophilus influenzae during stable disease is related to increased inflammation, and we now aimed to relate previous findings of bacterial colonization and inflammation to the degree of radiological findings of bronchiectasis and emphysema. Thirty-nine patients with COPD were included in their stable state, and a high-resolution computed tomography of the lung was performed. They were followed-up monthly for up to a maximum of 6 months or until exacerbation, and they answered questionnaires, performed spirometry, and induced sputum at every visit. Thirty-five patients had emphysema with an emphysema degree of median 20% (interquartile range 10-50), and five patients had bronchiectasis, of which only four could expectorate sputum. The degree of emphysema correlated with several inflammatory mediators in sputum, such as interleukin-8 concentration, myeloperoxidase activity, and Leukotriene B4 concentration. Ten patients were chronically colonized with H. influenzae (ie, had a positive culture for H. influenzae at all visits). The four sputum patients with bronchiectasis were chronically colonized with H. influenzae and showed higher degree of H. influenzae growth compared to patients without bronchiectasis. During exacerbation, there was no longer any correlation between emphysema degree and inflammation, but patients with bronchiectasis showed higher sputum purulence score than patients without bronchiectasis. Emphysema and bronchiectasis in COPD patients show different clinical features. The presence of emphysema is more related to inflammation, while bronchiectasis is associated with bacterial colonization. We believe that both emphysema and bronchiectasis are therefore COPD phenotypes of highest impact and need evaluation to prevent further disease progression. PMID- 29138551 TI - COPD depicted - patients drawing their lungs. AB - Background: Given the increasing importance of patient-reported outcomes (PRO) in quality medical care, we examined the value and feasibility of an innovative method for assessing patients' illness perceptions, represented in drawings made by patients with COPD of their lungs. Aim: The aim of our study was: to study patients' representation of COPD as reflected in their drawings of their lungs; and to examine scores on a validated measure that assesses illness perceptions (ie, Brief Illness Perception Questionnaire [B-IPQ]). Patients and methods: One hundred outpatients with COPD, mean age 70 years, selected from a pharmacy database, participated and 98 filled out the B-IPQ. Eighty-seven patients completed the drawing task. Results: The illness perceptions as reflected in the responses to the B-IPQ scales represented a quite optimistic view of COPD and its consequences. The drawings of the lungs reflected a considerable discordance between patients' representations and medically accepted representations of lungs of a person with COPD. Conclusion: Assessing illness perceptions in clinical care and research about COPD offers opportunities to identify goals for patient education and self-management. Inviting patients to draw their illness is an innovative and promising approach to assessing PRO. PMID- 29138552 TI - SIRT1 and FOXO1 mRNA expression in PBMC correlates to physical activity in COPD patients. AB - Background: Physical activity (PA) is considered as one of the most important prognostic predictors in chronic obstructive pulmonary disease (COPD) patients. Longevity gene, SIRT1, is reported to be involved in the pathogenesis of COPD by regulating the signaling pathways of oxidative stress, inflammation, and aging. We hypothesize that SIRT1 and related genes are also associated with the benefits of PA in COPD patients. Methods: Eighteen COPD outpatients were enrolled in this study, and their PA level was assessed with an accelerometer. We assessed the SIRT1 and related genes mRNA expression levels in the peripheral blood mononuclear cells (PBMCs) of the subjects. We carried out respiratory function testing, blood gas analysis, the 6-minute walk test, and measurement of the cross sectional area of the erector spinae muscles (ESMCSA) by chest computed tomography. We analyzed the association of PA with the results of each of the examinations. Results: The mean age was 72+/-9 years, and the mean forced expiratory volume in 1 second was 1.4+/-0.56 L (52%+/-19% predicted). Our findings revealed a correlation between the daily PA and ESMCSA. The SIRT1 and Forkhead box O (FOXO)1 mRNA expression levels in PBMCs were positively correlated with moderate-PA time (r=0.60, p=0.008 for SIRT1 and r=0.59, p=0.01 for FOXO1). PMID- 29138554 TI - Characteristics of COPD patients according to GOLD classification and clinical phenotypes in the Russian Federation: the SUPPORT trial. AB - Background: The high prevalence of COPD in the Russian Federation has been demonstrated in several epidemiological studies. However, there are still no data on the clinical characteristics of these patients according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups and phenotypes, which could provide additional understanding of the burden of COPD, routine clinical practice, and ways to improve the treatment of patients with COPD in Russia. Patients and methods: SUPPORT was an observational multicenter study designed to obtain data about the distribution of patients with previously diagnosed COPD according to the severity of bronchial obstruction, symptom severity, risk of exacerbation, COPD phenotypes, and treatment of COPD. We included patients with a previous diagnosis of COPD who visited one of 33 primary-care centers for any reason in 23 cities in Russia. Results: Among the 1,505 patients with a previous diagnosis of COPD who attended the primary-care centers and were screened for the study, 1,111 had a spirometry-confirmed diagnosis and were included in the analysis. Up to 53% of the patients had severe or very severe COPD (GOLD stages III-IV), and 74.3% belonged to the GOLD D group. The majority of patients were frequent exacerbators (exacerbators with chronic bronchitis [37.3%], exacerbators without chronic bronchitis [14%]), while 35.8% were nonexacerbators and 12.9% had asthma-COPD overlap. Among the GOLD D group patients, >20% were treated with only short-acting bronchodilators. Conclusion: COPD is still misdiagnosed in primary care in Russia. COPD patients in primary care are usually GOLD D with frequent exacerbations and are often treated with only short-acting bronchodilators. PMID- 29138555 TI - The efficacy of extrafine beclomethasone dipropionate-formoterol fumarate in COPD patients who are not "frequent exacerbators": a post hoc analysis of the FORWARD study. AB - The GOLD 2017 strategy document recommends that the pharmacological management of COPD patients be based on the risk of future exacerbations and the severity of symptoms. A threshold of two moderate exacerbations or one hospitalization is used to define high-risk patients. The FORWARD study was a randomized, double blind, parallel-group trial that compared 48 weeks' treatment with extrafine beclomethasone dipropionate plus formoterol fumarate (BDP-FF) versus FF in severe COPD patients with a history of one or more exacerbations in the previous year. The new GOLD 2017 recommendations mean that many patients in the FORWARD study are now reclassified as GOLD B. We conducted a post hoc analysis of the FORWARD study, in order to investigate the effects of extrafine BDP/FF in patients with one exacerbation in the previous year, focusing on those categorized as group B using the GOLD 2017 definition. The analysis showed a 35% reduction in exacerbation rate with an inhaled corticosteroid (ICS) + long-acting beta-agonist (LABA) versus LABA. We propose that ICS-LABA treatment is a therapeutic option for COPD patients with one exacerbation in the previous year. PMID- 29138553 TI - The protective effect of PRMT6 overexpression on cigarette smoke extract-induced murine emphysema model. AB - Background: Cigarette smoke exposure is the most common risk factor for emphysema, which is one of the major pathologies of COPD. Protein arginine methyltransferase 6 (PRMT6) is a nuclear enzyme that specially catalyzes dimethylation of R2 in histone H3 (H3R2me2a). H3R2me2a prevents trimethylation of H3K4 (H3K4me3), which is located in the transcription start sites of genes in mammalian genomes. We attempted to determine the expression of PRMT6 in human samples, and investigate whether the upregulation of PRMT6 expression can attenuate the development of cigarette smoke extract (CSE)-induced emphysema. Further experiments were performed to elucidate the molecular mechanisms involved. Materials and methods: Human lung tissues were obtained from patients undergoing pneumonectomy for benign pulmonary lesions. BALB/c mice were treated with lentiviral vectors intratracheally and injected with CSE three times. The protein expression of PRMT6, H3R2me2a, and H3K4me3 in human and mouse samples, as well as B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and endothelial nitric oxide synthase (eNOS) in mice were detected in lung homogenates by Western blotting. The mRNA expression of cyclooxygenase-2, interleukin-6, Bcl-2, Bax, and eNOS in mice was measured by quantitative real time polymerase chain reaction. Results: The expression of PRMT6 was significantly downregulated in the pulmonary parenchyma in smokers with COPD as well as in mice treated with CSE. Overexpression of PRMT6 was detected in the CSE + Lenti-PRMT6 group of mice, which reversed the expression of H3R2me2a and H3K4me3. Inflammation, apoptosis, and oxidative stress levels were severe in the CSE-treated emphysema mice compared with the control group, which was inhibited by the overexpression of PRMT6. Conclusion: The overexpression of PRMT6 might inhibit inflammation, apoptosis, and oxidative stress in CSE-induced emphysema mediated by H3R2me2a. PMID- 29138556 TI - Photoactivatable RNAi for cancer gene therapy triggered by near-infrared irradiated single-walled carbon nanotubes. AB - The efficacy of RNA interference (RNAi)-based cancer gene therapy is limited by its unexpected side effects, thus necessitating a strategy to precisely trigger conditional gene knockdown. In this study, we engineered a novel photoactivatable RNAi system, named as polyetherimide-modified single-wall carbon nanotube (PEI SWNT)/pHSP-shT, that enables optogenetic control of targeted gene suppression in tumor cells. PEI-SWNT/pHSP-shT comprises a stimulus-responsive nanocarrier (PEI SWNT), and an Hsp70B'-promoter-driven RNAi vector (pHSP-shT). In response to near infrared (NIR) light irradiation, heating of PEI-SWNT in breast MCF-7 cells triggered gene knockdown targeting human telomerase reverse transcriptase through RNAi, with the gene-knockdown activity capable of being switched off by extinguishing the NIR. Furthermore, we demonstrated that the photoactivatable RNAi system exhibited higher antitumor activity by combining gene therapy and photothermal therapy, both in vitro and in vivo. Optogenetic control of RNAi based on an NIR-activated nanocarrier will potentially facilitate improved understanding of molecular-targeted gene therapy in human malignant tumors. PMID- 29138557 TI - Improving intestinal absorption and oral bioavailability of curcumin via taurocholic acid-modified nanostructured lipid carriers. AB - The expression of multiple receptors on intestinal epithelial cells enables an actively targeted carrier to significantly enhance the oral delivery of payloads. Conjugating the receptors' ligands on the surfaces of a particulate-delivery system allows site-specific targeting. Here, we used taurocholic acid (TCA) as a ligand for uptake of nanostructured lipid carriers (NLCs) mediated by a bile-acid transporter to improve oral bioavailability of curcumin (Cur). First, synthesis of TCA-polyethylene glycol 100-monostearate (S100-TCA) was carried out. Then, the physical and chemical properties of S100-TCA-modified Cur-loaded NLCs (Cur-TCA NLCs) with varying levels of S100-TCA modifications were investigated. Small particle size (<150 nm), high drug encapsulation (>90%), drug loading (about 3%), negative zeta-potential (-7 to -3 mV), and sustained release were obtained. In situ intestinal perfusion studies demonstrated improved absorption rate and permeability coefficient of Cur-TCA NLCs. Depending on the degree of modification, Cur-TCA NLCs displayed about a five- to 15-fold higher area under the curve in rats after oral administration than unmodified Cur NLCs, which established that the addition of S100-TCA to the NLCs boosted absorption of Cur. Further investigations of TCA NLCs might reveal a bright future for effective oral delivery of poorly bioavailable drugs. PMID- 29138558 TI - alphavbeta3 integrin-targeted micellar mertansine prodrug effectively inhibits triple-negative breast cancer in vivo. AB - Antibody-mertansine (DM1) conjugates (AMCs) are among the very few active targeting therapeutics that are approved or clinically investigated for treating various cancers including metastatic breast cancer. However, none of the AMCs are effective for the treatment of triple-negative breast cancers (TNBCs). Here, we show that cRGD-decorated, redox-activatable micellar mertansine prodrug (cRGD MMP) can effectively target and deliver DM1 to alphavbeta3 integrin overexpressing MDA-MB-231 TNBC xenografts in nude mice, resulting in potent tumor growth inhibition. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that cRGD-MMP had obvious targetability to MDA-MB-231 cells with a low half-maximal inhibitory concentration (IC50) of 0.18 MUM, which was close to that of free DM1 and 2.2-fold lower than that of micellar mertansine prodrug (MMP; nontargeting control). The confocal microscopy studies demonstrated that cRGD-MMP mediated a clearly more efficient cellular uptake and intracellular release of doxorubicin (used as a fluorescent anticancer drug model) in MDA-MB 231 cells. Notably, cRGD-MMP loaded with 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide (DiR; a hydrophobic near-infrared dye) was shown to quickly accumulate in the MDA-MB-231 tumor with strong DiR fluorescence from 2 to 24 h post injection. MMP loaded with DiR could also accumulate in the tumor, although significantly less than cRGD-MMP. The biodistribution studies revealed a high DM1 accumulation of 8.1%ID/g in the tumor for cRGD-MMP at 12 h post injection. The therapeutic results demonstrated that cRGD-MMP effectively suppressed MDA-MB-231 tumor growth at 1.6 mg DM1 equiv./kg without causing noticeable side effects, as shown by little body weight loss and histological analysis. This MMP has appeared as a promising platform for potent treatment of TNBCs. PMID- 29138559 TI - Human mesenchymal stem cell-derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia. AB - Magnetic hyperthermia, or the heating of tissues using magnetic materials, is a promising approach for treating cancer. We found that human mesenchymal stem cells (MSCs) isolated from various tissues and MSCs expressing the yeast cytosine deaminase?uracil phosphoribosyl transferase suicide fusion gene (yCD?UPRT) can be labeled with Venofer, an iron oxide carbohydrate nanoparticle. Venofer labeling did not affect cell proliferation or the ability to home to tumors. All Venofer labeled MSCs released exosomes that contained iron oxide. Furthermore, these exosomes were efficiently endocytosed by tumor cells. Exosomes from Venofer labeled MSCs expressing the yCD?UPRT gene in the presence of the prodrug 5 fluorocytosine inhibited tumor growth in a dose-dependent fashion. The treated tumor cells were also effectively ablated following induction of hyperthermia using an external alternating magnetic field. Cumulatively, we found that magnetic nanoparticles packaged into MSC exosomes are efficiently endocytosed by tumor cells, facilitating targeted tumor cell ablation via magnetically induced hyperthermia. PMID- 29138560 TI - Biodistribution of gold nanoparticles in BBN-induced muscle-invasive bladder cancer in mice. AB - Bladder-sparing options are being developed for muscle-invasive bladder cancer in place of radical cystectomy, including the combination of chemotherapy and radiation therapy. We reasoned that improving the radiotherapy component of chemoradiation could improve the control of locally advanced disease. Previously, we showed that gold nanoparticles (AuNPs) are potent enhancers of radiation therapy. We hypothesized that if AuNPs were to preferentially localize to bladder tumors, they may be used to enhance the radiation component of muscle-invasive bladder tumor therapy. Mice were treated with the carcinogen N-butyl-N-(4 hydroxybutyl)nitrosamine (BBN) for 17, 20, and 22 weeks - long enough to induce muscle-invasive tumors. Mice were then anesthetized and injected intravenously with 1.9 nm AuNPs of which most were rapidly cleared from the blood and excreted after a 30-50 minute residence time in the bladder. We found AuNPs distributed throughout the bladder wall, but most of the AuNPs were associated with the stroma surrounding the tumor cells or extracellular keratin produced by the tumor cells. There were relatively few AuNPs in the tumor cells themselves. The AuNPs therefore localized to tumor-associated stroma and this tumor specificity might be useful for specific X-ray dose enhancement therapy of muscle-invasive bladder carcinomas. PMID- 29138561 TI - A simple reduction-sensitive micelles co-delivery of paclitaxel and dasatinib to overcome tumor multidrug resistance. AB - Multidrug resistance (MDR) is one of the major obstacles in successful chemotherapy. The combination of chemotherapy drugs and multidrug-resistant reversing agents for treating MDR tumor is a good strategy to overcome MDR. In this work, we prepared the simple redox-responsive micelles based on mPEG-SS-C18 as a co-delivery system to load the paclitaxel (PTX) and dasatinib (DAS) for treatment of MCF-7/ADR cells. The co-loaded micelles had a good dispersity and a spherical shape with a uniform size distribution, and they could quickly disassemble and rapidly release drugs under the reduction environment. Compared with MCF-7 cells, the DAS and PTX co-loaded redox-sensitive micelle (SS-PDNPs) showed stronger cytotoxicity and a more improving intracellular drug concentration than other drug formulations in MCF-7/ADR cells. In summary, the results suggested that the simple co-delivery micelles of PTX and DAS possessed significant potential to overcome drug resistance in cancer therapy. PMID- 29138562 TI - Dual UV irradiation-based metal oxide nanoparticles for enhanced antimicrobial activity in Escherichia coli and M13 bacteriophage. AB - Metal oxide (MO) nanoparticles have been studied as nano-antibiotics due to their antimicrobial activities even in antibiotic-resistant microorganisms. We hypothesized that a hybrid system of dual UV irradiation and MO nanoparticles would have enhanced antimicrobial activities compared with UV or MO nanoparticles alone. In this study, nanoparticles of ZnO, ZnTiO3, MgO, and CuO were selected as model nanoparticles. A dual UV collimated beam device of UV-A and UV-C was developed depending upon the lamp divided by coating. Physicochemical properties of MO nanoparticles were determined using powder X-ray diffractometry (PXRD), Brunauer-Emmett-Teller analysis, and field emission-scanning electron microscopy with energy-dispersive X-ray spectroscopy. Atomic force microscopy with an electrostatic force microscopy mode was used to confirm the surface topology and electrostatic characteristics after dual UV irradiation. For antimicrobial activity test, MO nanoparticles under dual UV irradiation were applied to Escherichia coli and M13 bacteriophage (phage). The UV-A and UV-C showed differential intensities in the coated and uncoated areas (UV-A, coated = uncoated; UV-C, coated ? uncoated). MO nanoparticles showed sharp peaks in PXRD patterns, matched to pure materials. Their primary particle sizes were less than 100 nm with irregular shapes, which had an 8.6~25.6 m2/g of specific surface area with mesopores of 22~262 nm. The electrostatic properties of MO nanoparticles were modulated after UV irradiation. ZnO, MgO, and CuO nanoparticles, except ZnTiO3 nanoparticles, showed antibacterial effects on E. coli. Antimicrobial effects on E. coli and phages were also enhanced after cyclic exposure of dual UV and MO nanoparticle treatment using the uncoated area, except ZnO nanoparticles. Our results demonstrate that dual UV-MO nanoparticle hybrid system has a potential for disinfection. We anticipate that it can be developed as a next generation disinfection system in pharmaceutical industries and water purification systems. PMID- 29138563 TI - Squarticles as the nanoantidotes to sequester the overdosed antidepressant for detoxification. AB - The increasing death rate caused by drug overdose points to an urgent demand for the development of novel detoxification therapy. In an attempt to detoxify tricyclic antidepressant overdose, we prepared a lipid nanoemulsion, called squarticles, as the nanoantidote. Squalene was the major lipid matrix of the squarticles. Here, we present the animal study to investigate both the pharmacokinetic and pharmacodynamic effects of squarticles on amitriptyline intoxication. The anionic and cationic squarticles had average diameters of 97 and 122 nm, respectively. Through the entrapment study, squarticles could intercept 40%-50% of the amitriptyline during 2 h with low leakage after loading into the nanoparticles. The results of isothermal titration calorimetry demonstrated greater interaction of amitriptyline with the surface of anionic squarticles (Ka =28,700) than with cationic ones (Ka =5,010). Real-time imaging showed that intravenous administration of anionic squarticles resulted in a prolonged retention in the circulation. In a rat model of amitriptyline poisoning, anionic squarticles increased the plasma drug concentration by 2.5 fold. The drug uptake in the highly perfused organs was diminished after squarticle infusion, indicating the lipid sink effect of bringing the entrapped overdosed drug in the tissues back into circulation. In addition, the anionic nanosystems restored the mean arterial pressure to near normal after amitriptyline injection. The survival rate of overdosed amitriptyline increased from 25% to 75% by treatment with squarticles. Our results show that the adverse effects of amitriptyline intoxication could be mitigated by administering anionic squarticles. This lipid nanoemulsion is a potent antidote to extract amitriptyline and eliminate it. PMID- 29138565 TI - Erratum: Bypassing the EPR effect with a nanomedicine harboring a sustained release function allows better tumor control [Corrigendum]. AB - [This corrects the article on p. 2485 in vol. 10, PMID: 25848266.]. PMID- 29138566 TI - Studies on the use of recombinant spider silk protein/polyvinyl alcohol electrospinning membrane as wound dressing. AB - A series of wound membranes of polyvinyl alcohol and recombinant spider silk protein (pNSR16) was prepared by electrospinning. The membrane was analyzed by scanning electron microscopy, atomic force microscopy, and Fourier transform infrared spectroscopy. The result showed that the three factors that affected average fiber diameter from high to low were, voltage, flow speed, and solidification distance; and the three factors that affected fiber uniformity from high to low were, flow speed, solidification distance, and voltage. The fibers adhered together after being dealt with alcohol. pNSR16 transformed from random coil into beta-sheet after being immersed in alcohol. Additionally, the porosity of the electrospun membrane was 84.85%, which was higher than that of cast membrane prepared with the same composition. Experiments of applying electrospun membranes as wound dressing for Sprague Dawley rat wound healing showed that it could promote wound healing and basic fibroblast growth factor expression. PMID- 29138564 TI - Zinc oxide nanoparticles induce toxic responses in human neuroblastoma SHSY5Y cells in a size-dependent manner. AB - Due to the widespread applications of zinc oxide nanoparticles (ZnO NPs), the potential exposure of workers, consumers, and scientists to these particles has increased. This potential for exposure has attracted extensive attention in the science community. Many studies have examined the toxicological profile of ZnO NPs in the immune system, digestive system, however, information regarding the toxicity of ZnO NPs in the nervous system is scarce. In this study, we detected the cytotoxicity of two types of ZnO NPs of various sizes - ZnOa NPs and ZnOb NPs - and we characterized the shedding ability of zinc ions within culture medium and the cytoplasm. We found that reactive oxygen species played a crucial role in ZnO NP-induced cytotoxicity, likely because zinc ions were leached from ZnO NPs. Apoptosis and cytoskeleton changes were also toxic responses induced by the ZnO NPs, and ZnOb NPs induced more significant toxic responses than ZnOa NPs in SHSY5Y cells. In conclusion, ZnO NPs induced toxic responses in SHSY5Y cells in a size-dependent manner, which can probably be attributed to their ion-shedding ability. PMID- 29138567 TI - Resveratrol ameliorates chronic unpredictable mild stress-induced depression-like behavior: involvement of the HPA axis, inflammatory markers, BDNF, and Wnt/beta catenin pathway in rats. AB - Classic antidepressant drugs are modestly effective across the population and most are associated with intolerable side effects. Recently, numerous lines of evidence suggest that resveratrol (RES), a natural polyphenol, possesses beneficial therapeutic activity for depression. The aim of the present study was to explore whether RES exhibits an antidepressant-like effect in a depression model and to explore the possible mechanism. A depression model was established via chronic unpredictable mild stress (CUMS), after which the model rats in the RES and fluoxetine groups received a daily injection of RES or fluoxetine, respectively. The sucrose preference test, open field test, and forced swimming test were used to explore the antidepressant-like effects of RES. The activity of the hypothalamic-pituitary-adrenal (HPA) axis was evaluated by detecting the plasma corticosterone concentration and hypothalamic mRNA expression of corticotrophin-releasing hormone. The plasma interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured by enzyme-linked immunosorbent assay. Hippocampal protein expression of brain-derived neurotrophic factor (BDNF) and the Wnt/beta-catenin pathway were analyzed by western blot. The results showed that RES relieved depression-like behavior of CUMS rats, as indicated by the increased sucrose preference and the decreased immobile time. Rats that received RES treatment exhibited reduced plasma corticosterone levels and corticotrophin-releasing hormone mRNA expression in the hypothalamus, suggesting that the hyperactivity of the HPA axis in CUMS rats was reversed by RES. Moreover, after RES treatment, the rats exhibited increased plasma IL-6, CRP, and TNF-alpha concentrations. Furthermore, RES treatment upregulated the hippocampal protein levels of BDNF and the relative ratio of p-beta-catenin/beta-catenin while downregulating the relative ratio of p GSK-3beta/GSK-3beta. Our findings suggest that RES improved depressive behavior in CUMS rats by downregulating HPA axis hyperactivity, increasing BDNF expression and plasma IL-6, CRP, and TNF-alpha concentrations, and regulating the hippocampal Wnt/beta-catenin pathway. PMID- 29138568 TI - Epidemiology and costs of multiple sclerosis in Switzerland: an analysis of health-care claims data, 2011-2015. AB - Background: Medical therapy for multiple sclerosis (MS) is expensive. Quantifying the burden of MS is fundamental for health-care planning and the allocation of resources for the management of MS. This study provides current national estimates of prevalence, incidence, mortality, and costs of MS in Switzerland using claims data between 2011 and 2015. Methods: We analyzed health insurance claims of adult persons enrolled with a large health insurance group covering about 13% of the Swiss population between 2011 and 2015. The identification of patients with MS was based on prescription data of MS-specific medication using the Anatomical Therapeutic Chemical Classification system as proxy for clinical diagnosis. We estimated prevalence, mortality, and costs of basic health insurance between 2011 and 2015. Furthermore, incidence of MS was calculated for 2015. All results were weighted with census data to achieve an extrapolation to the Swiss general population level. Cost of illness was estimated as direct medical cost from the perspective of a Swiss health insurance using multivariate linear regression analysis. Results: Of the 943,639 subjects in the year 2015, 1,606 were identified as MS patients resulting in a prevalence of 190 per 100,000 (95% CI: 180-190 per 100,000). Incidence was 16 per 100,000 (95% CI: 13-19 per 100,000). According to regression analysis, the total cost of illness for basic mandatory health insurance was 26,710 Swiss Francs (CHF) (95% CI: 26,100-27,300) per person per year with the cost of medication being almost identical 26,960 CHF (95% CI: 26,170-27,800). Conclusions: MS affects 10,000-15,000 persons in Switzerland, and the prevalence has increased over the last 22 years. These persons have high need and demand for health care. High costs are primarily due to expenses for medication. Given the imbalance of MS medication therapy from the perspective of basic health insurance on the disposable resources, it is crucial to increase transparency related to the volume, type, and allocation of expenses. PMID- 29138569 TI - Post-marketing observational program of the effectiveness of fluvoxamine for the treatment of depression in patients with neurological disorders: the FRIENDS study. AB - In a prospective, non-blinded, uncontrolled, multicenter, post-marketing, observational study (FRIENDS; NCT02043197), fluvoxamine (50-300 mg/day for 90 days) was effective for the treatment of depression in 299 adult patients (age >=18 years) with neurological disorders at baseline. The therapeutic effect of fluvoxamine was measured by means of changes in the Hospital Anxiety and Depression Scale depression and anxiety scores (HADS-D and HADS-A, respectively), global severity of illness, and clinical condition (measured using the Clinical Global Improvement [CGI] scale). The mean HADS-D subscale score at baseline in the per-protocol cohort (n=296) was 11.7+/-3.1 points and the corresponding mean HADS-A score was 12.6+/-3.2. Significant (P<0.0001) improvements in both scores were recorded during fluvoxamine treatment and later follow-up. Most patients (>85%) recorded reductions versus baseline in both indices. In the CGI-based assessment, most evaluated patients (>200) experienced moderate to very substantial clinical improvement, with no or limited side effects. Significant improvements were also recorded in the exploratory outcomes of sleep quality, assessed using the Insomnia Severity Index, and cognitive function, assessed using the Montreal Cognitive Assessment (P<0.0001 vs baseline for both). No death or serious adverse drug reactions were reported during the study. The results of this observational study affirm that fluvoxamine is effective and well tolerated for the treatment of depression in the context of neurological disorders. The effects on the exploratory endpoints of this research merit evaluation in controlled trials. PMID- 29138570 TI - Erratum: Quick reference guide to apixaban [Corrigendum]. AB - [This corrects the article on p. 263 in vol. 13, PMID: 28744136.]. PMID- 29138571 TI - Timed up and go test combined with self-rated multifactorial questionnaire on falls risk and sociodemographic factors predicts falls among community-dwelling older adults better than the timed up and go test on its own. AB - Background: Early detection of falls risk among older adults using simple tools may assist in fall prevention strategies. The aim of this study was to identify the best parameters associated with previous falls, either the timed up and go (TUG) test combined with sociodemographic factors and a self-rated multifactorial questionnaire (SRMQ) on falls risk or the TUG on its own. Falls risk was determined based on parameters associated with previous falls. Design: This was a retrospective cohort study. Setting: The study was conducted in a community setting. Participants: The participants were 1,086 community-dwelling older adults, with mean age of 69.6+/-5.6 years. Participants were categorized into fallers and nonfallers based on their history of falls in the past 12 months. Method: Participants' sociodemographic data was taken, and SRMQ consisting of five falls-related questions was administered. Participants performed the TUG test twice, and the mean was taken as the result. Results: A total of 161 participants were categorized as fallers (14.8%). Multivariate logistic regression analysis showed that the model (chi2(6)=61.0, p<0.001, Nagelkerke R2=0.10) consisting of the TUG test, sociodemographic factors (gender, cataract/glaucoma and joint pain), as well as the SRMQ items "previous falls history" (Q1) and "worried of falls" (Q5), was more robust in terms of falls risk association compared to that with TUG on its own (chi2(1)=10.3, p<0.001, Nagelkerke R2=0.02). Conclusion: Combination of sociodemographic factors and SRMQ with TUG is more favorable as an initial falls risk screening tool among community-dwelling older adults. Subsequently, further comprehensive falls risk assessment may be performed in clinical settings to identify the specific impairments for effective management. PMID- 29138572 TI - Current status of poly(ADP-ribose) polymerase inhibitors and future directions. AB - Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA-mutant ovarian cancer. Clinical trials of various combinations of PARP inhibitors with cytotoxic or molecular-targeted agents are also underway. In particular, expanded applications of PARP inhibitors are anticipated following recent reports that defects in homologous recombination repair (HRR) are associated with mutations in repair genes other than BRCA1/BRCA2, such as ATM, ATR, PALB2, RAD51, CHEK1 and CHEK2, as well as with epigenetic loss of BRCA1 function through promoter methylation or overexpression of the BRCA2-interacting transcriptional repressor EMSY. Current topics of interest include selection of the best agent in each clinical context, identification of new treatment targets for HRR-proficient cases, and development of PARP inhibitor-based regimens that are less toxic and that prolong overall survival as well as progression-free survival. In addition, potential long-term side effects and suitable biomarkers for predicting efficacy and mechanisms of clinical resistance are in discussion. This review summarizes representative preclinical and clinical data for PARP inhibitors and discusses their potential for future applications to treat various malignancies. PMID- 29138573 TI - Matrine suppresses the migration and invasion of NSCLC cells by inhibiting PAX2 induced epithelial-mesenchymal transition. AB - Non-small cell lung cancer (NSCLC) is the major cause of deaths among all the cancer types worldwide. Most of the NSCLC is diagnosed at an advanced stage and the 5-year overall survival rate is low. The reason for the low survival rate of patients with NSCLC is mainly due to distant metastasis. Matrine, a traditional Chinese medicine, has been shown a significant anti-proliferation and anti invasive effect in tumors. However, little is known on the anti-invasive mechanism of matrine in lung cancer. Therefore, we tried to investigate the molecular mechanism of matrine on the invasive ability of NSCLC cells in vitro. Cell Counting Kit-8 assay was used to evaluate the cell viability. Transwell assay was used to detect the migration and invasion abilities. Microarray assay was used to analyze the differentiated expression genes with or without matrine treatment. Western blotting and real-time polymerase chain reaction were applied to detect the expressions of PAX2, E-cadherin and N-cadherin. Our study showed that matrine could suppress the proliferative activity of NSCLC cells in a dose- and time-dependent manner. Further investigation discovered that the migration and invasion of NSCLC cells were significantly inhibited by treatment with different concentrations of matrine. Microarray assay, real-time polymerase chain reaction and western blotting showed that matrine could significantly decrease the expression of PAX2. In addition, epithelial-mesenchymal transition and related proteins were decreased. In conclusion, matrine may block PAX2 expression to interfere with epithelial-mesenchymal transition signaling pathway that ultimately inhibit the migration and invasion of NSCLC cells in vitro. Matrine might serve as a potential agent for NSCLC treatment. PMID- 29138575 TI - MicroRNAs as a novel class of diagnostic biomarkers for the detection of osteosarcoma: a meta-analysis. AB - MicroRNAs (miRNAs) have been considered as promising diagnostic biomarkers for many diseases, especially for cancers. Numerous studies have reported the value of miRNAs in the diagnosis of osteosarcoma (OS), but the results vary greatly across different studies. Therefore, we conducted this meta-analysis to assess the prospective diagnostic value of miRNAs in diagnosing OS. All relevant articles from prior to July 28, 2017 were selected from PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, and Wan fang databases. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS 2) was performed to assess the quality of each article. A random-effects model was used to pool the sensitivity and specificity of the positive likelihood ratio (PLR), negative likelihood ratio (NLR) and, diagnostic odds ratio (DOR) together with the area under the curve (AUC) to evaluate diagnostic values. Seventeen studies comprising 2,214 OS patients and 1,534 healthy humans were included in our meta-analysis. The pooled estimations indicated that the miRNAs had a high accuracy for diagnosing OS, with a sensitivity of 0.82, specificity of 0.88, PLR of 10.96, NLR of 0.20, DOR of 54.55, and AUC of 0.93. Twenty-five miRNAs were differentially expressed in OS, including 17 upregulated and 8 downregulated. These miRNAs were correlated with survival time, tumor size, cell differentiation, tumor node metastasis staging, metastasis, tumor/cell invasion, pathological type, and response to radiotherapy and chemotherapy. Several different miRNAs are expressed in OS, and some of them might be potential biomarkers for the early diagnosis of OS. PMID- 29138574 TI - Cancer cell dormancy: mechanisms and implications of cancer recurrence and metastasis. AB - More recently, disease metastasis and relapse in many cancer patients several years (even some decades) after surgical remission are regarded as tumor dormancy. However, the knowledge of this phenomenon is cripplingly limited. Substantial quantities of reviews have summarized three main potential models that can be put forth to explain such process, including angiogenic dormancy, immunologic dormancy, and cellular dormancy. In this review, newly uncovered mechanisms governing cancer cell dormancy are discussed, with an emphasis on the cross talk between dormant cancer cells and their microenvironments. In addition, potential mechanisms of reactivation of these dormant cells in certain anatomic sites including lymph nodes and bone marrow are discussed. Molecular mechanism of cellular dormancy in head and neck cancer is also involved. PMID- 29138576 TI - Progression-free survival of up to 8 months of an advanced intrahepatic cholangiocarcinoma patient treated with apatinib: a case report. AB - Intrahepatic cholangiocarcinoma (ICC) arises from the biliary epithelium and is a relatively rare and highly fatal neoplasm. The prognosis is poor, and survival is limited to a few months. Here, we report a case of advanced ICC that was successfully treated with apatinib, a new oral tyrosine kinase inhibitor that targets the intracellular domain of vascular endothelial growth factor receptor 2. To the best of our knowledge, this is the first case report of the successful use of apatinib for advanced ICC; this treatment has demonstrated fewer toxic effects than traditional cytotoxic chemotherapy. The progression-free survival time was 8 months. The only toxicity observed was mild hand-foot syndrome. Therefore, apatinib may be an additional option for the treatment of advanced ICC, but further prospective studies are needed to optimize the treatment. PMID- 29138577 TI - Identification and validation of potential prognostic gene biomarkers for predicting survival in patients with acute myeloid leukemia. AB - Background: Molecular analysis is a promising source of clinically useful prognostic biomarkers. The aim of this investigation was to identify prognostic biomarkers for patients with acute myeloid leukemia (AML) by using the gene expression profile dataset from public database. Methods: The gene expression profile dataset and corresponding overall survival (OS) information of three cohorts of AML patients from GSE12417 and The Cancer Genome Atlas AML project (TCGA-LAML) were included in the present study. Prognostic gene screening was performed by using a survival package, whereas time-dependent receiver operating characteristic (ROC) curve analysis was performed using the survivalROC package. Results: In the three cohorts, 11 genes were identified that were significantly associated with AML OS. A linear prognostic model of the 11 genes was constructed and weighted by regression coefficient (beta) from the multivariate Cox regression analyses of GSE12417 HG-U133A cohort to divide patients into high- and low-risk groups. GSE12417 HG-U133 plus 2.0 and TCGA-LAML were validation cohorts. Patients assigned to the high-risk group exhibited poor OS compared to patients in the low-risk group. The 11-gene signature is a prognostic marker of AML and demonstrates good performance for predicting 1-, 3-, and 5-year OS as evaluated by survivalROC in the three cohorts. Conclusion: Our study has identified an mRNA signature including 11 genes, which may serve as a potential prognostic marker of AML. PMID- 29138578 TI - Prognostic value of the C-reactive protein to albumin ratio: a novel inflammation based prognostic indicator in osteosarcoma. AB - The prognostic role of the C-reactive protein to albumin ratio (CRP/Alb ratio) in patients with osteosarcoma has not been investigated. A total of 216 osteosarcoma patients were enrolled in the study. Univariate and multivariate survival analyses between the groups were performed and Kaplan-Meier analysis was conducted to plot the survival curves. Receiver operating characteristic curves were generated and areas under the curve (AUCs) were compared to assess the discriminatory ability of the inflammation-based indicators, including CRP/Alb ratio, Glasgow prognostic score (GPS), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR). The optimal cutoff value was 0.210 for CRP/Alb ratio with a Youden index of 0.319. Higher values of CRP/Alb ratio were significantly associated with poorer overall survival in univariate (HR =2.62, 95% CI =1.70-4.03; P<0.001) and multivariate (HR =2.21, 95% CI =1.40-3.49; P=0.001) analyses. In addition, the CRP/Alb ratio had significantly higher AUC values compared with GPS (P=0.003), NLR (P<0.001), and PLR (P<0.001). The study demonstrated that the CRP/Alb ratio is an effective inflammation-based prognostic indicator in osteosarcoma, which potentially has a discriminatory ability superior to that of other inflammatory indicators including GPS, NLR, and PLR. PMID- 29138579 TI - Association of GEMIN4 gene polymorphism and the risk of cancer: a meta-analysis. AB - Gem-associated protein 4 (GEMIN4) gene is a key regulator for the miRNA biogenesis processes. Recent studies have demonstrated that some single nucleotide polymorphisms (SNPs) in GEMIN4 gene are associated with the risk of cancer, but the results are still controversial. Therefore, we conducted a meta analysis to analyze the association between three major SNPs (rs2740348, rs7813, and rs3744741) in the GEMIN4 gene and the risk of cancer. Relevant articles were searched in Web of Science, PubMed, Cochrane Library, Chinese Wan Fang, and Chinese National Knowledge Infrastructure databases. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to quantitatively estimate the association. Publication bias and sensitivity analyses were undertaken to evaluate the stability of the results. Overall, the pooled results showed that rs2740348 involving 3,604 cases and 3,770 controls was significantly associated with increased cancer risk (GG vs GC/CC: OR =1.16, 95% CI =1.05-1.29, P=0.004) and rs7813 involving 4,729 cases and 4,562 controls was also related to increased cancer risk (TT vs TC/CC: OR =1.12, 95% CI =1.03-1.22, P=0.009). However, there was no significant association between rs3744741 and cancer risk under overall genetic models. In conclusion, our study has demonstrated that rs2740348 and rs7813 are associated with increased risk of cancer, and they may be new biomarkers for predicting cancer risk. PMID- 29138580 TI - S100A16, a promising candidate as a prognostic marker for platinum-based adjuvant chemotherapy in resected lung adenocarcinoma. AB - Purpose: Although cisplatin-based adjuvant chemotherapy improves the survival of patients with resected non-small-cell lung cancer, not all patients show a survival benefit, and some patients experience severe toxicity. Therefore, identifying biomarkers is important for selecting subgroups of patients who may show improved survival with platinum-based adjuvant chemotherapy. S100A16 is thought to play key roles during different steps of tumor progression. The aim of this study was to evaluate the use of S100A16 expression as a prognostic marker in patients with completely resected lung adenocarcinoma receiving platinum-based adjuvant chemotherapy. Methods: S100A16 expression was immunohistochemically studied in 65 consecutive lung adenocarcinoma patients who underwent complete resection and received platinum-based adjuvant chemotherapy. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of S100A16 expression on disease-free survival (DFS) and overall survival (OS). Results: S100A16 expression was detected in 26 of the 65 (40.0%) lung adenocarcinoma patients. Although S100A16 expression was not correlated with DFS (P=0.062), it was significantly correlated with OS (P=0.009). In addition, multivariable analysis revealed that S100A16 expression independently predicted a poorer survival (HR =4.79; 95% CI =1.87-12.23; P=0.001). Conclusion: The present study revealed that S100A16 is a promising candidate as a prognostic marker for platinum-based adjuvant chemotherapy in resected lung adenocarcinoma. A further large-scale study is needed to confirm the present results. PMID- 29138581 TI - PUMA mediates the anti-cancer effect of osimertinib in colon cancer cells. AB - Osimertinib, an irreversible EGFR/HER2 inhibitor, has been found to be effective in the cancer cell with EGFR gene mutations in preclinical lung cancer models. However, the effect of osimertinib in colorectal cancer (CRC) cells is unclear. In the present study, we investigated how osimertinib suppresses CRC cells growth and potentiates effects of other chemotherapeutic drugs. We found that p73 mediated osimertinib-induced p53 upregulated modulator of apoptosis (PUMA) expression irrespective of p53 status following PI3K/AKT pathway inhibition in CRC cells. Furthermore, PUMA is required for osimertinib-induced apoptosis. In addition, osimertinib also synergized with 5-FU to induce significant apoptosis via PUMA in CRC cells. These results demonstrated a critical role of PUMA in mediating the anticancer effects of osimertinib and suggest that PUMA induction can be used as an indicator of osimertinib sensitivity. PMID- 29138582 TI - Once-daily intramuscular amikacin for outpatient treatment of lower urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli in children. AB - Background: The rise in community-acquired urinary tract infections (UTIs) with extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli strains raises the question of how to treat these infections effectively in pediatric outpatients. Amikacin has shown promising in vitro activity against ESBL producing urinary isolates of E. coli; however, clinical data are limited. Objective: To investigate the clinical and microbiological outcomes of community acquired lower UTIs caused by ESBL-producing E. coli treated with outpatient amikacin in children. Materials and methods: A retrospective cohort study was performed on pediatric patients aged >=2 to 18 years treated as outpatients with intramuscular amikacin (given at a dose of 15 mg/kg/day once daily) for community acquired lower UTIs caused by ESBL-producing E. coli, between January 2015 and December 2016. Results: A total of 53 pediatric patients (38 females) were enrolled in this study. The median age was 4.7 years (range 3-12 years). All E. coli isolates were susceptible to amikacin with minimum inhibitory concentrations of <=4 mg/L. The median duration of amikacin treatment was 6 days (range 3-7 days). Favorable clinical and bacteriological responses were observed in 51 of 53 (96%) patients. Development of resistance during treatment with amikacin was seen in only 1 patient (2%), who failed to respond to amikacin treatment and developed acute pyelonephritis with bacteremia. Relapsed lower UTI after initial treatment response occurred in 1 patient (2%) 2 weeks after completion of amikacin treatment. All patients had normal serum creatinine values at baseline, and no significant nephrotoxicity or ototoxicity was observed in any of the patients. Conclusion: Our study suggests that once-daily intramuscular amikacin could be an alternative option for outpatient treatment of community-acquired lower UTIs caused by amikacin-susceptible ESBL-producing E. coli in pediatric patients with normal renal function, when there are no suitable oral antibiotics. PMID- 29138583 TI - Efficacy of intravenous tigecycline in patients with Acinetobacter complex infections: results from 14 Phase III and Phase IV clinical trials. AB - Background: Acinetobacter infections, especially multidrug-resistant (MDR) Acinetobacter infections, are a global health problem. This study aimed to describe clinical outcomes in patients with confirmed Acinetobacter spp. isolates who were treated with tigecycline in randomized clinical trials. Materials and methods: Data from 14 multinational, randomized (open-label or double-blind), and active-controlled (except one) Phase III and IV studies were analyzed using descriptive statistics. Results: A total of 174 microbiologically evaluable patients with Acinetobacter spp. infections (including MDR infections) were identified, and 95 received tigecycline to treat community-acquired pneumonia (CAP), diabetic foot infections (DFIs), hospital-acquired pneumonia (HAP), complicated intra-abdominal infections (cIAIs), infections with resistant pathogens (RPs), or complicated skin and skin-structure infections. The rate of cure of tigecycline for most indications was 70%-80%, with the highest (88.2%) in cIAIs. The rate of cure of the comparators was generally higher than tigecycline, but within each indication the 95% CIs for clinical cure for each treatment group overlapped. For most Acinetobacter isolates, the minimum inhibitory concentration of tigecycline was 0.12-2 MUg/mL, with seven at 4 MUg/mL and one at 8 MUg/mL. The cure rate by tigecycline was 50% (95% CI 12.5%-87.5% in CAP) to 88.2% (95% CI 66.2%-97.1% in cIAIs) for all Acinetobacter, and 72.7% (95% CI 54.5%-93.2% in HAP) to 100% (95% CI 25%-100.0% in cIAIs) for MDR Acinetobacter. For the comparators, it was 83.8% (95% CI 62.8%-95.9% in HAP) to 100% (95% CI 75%-100% in cIAIs and 25%-100.0% in RPs) and 88% (95% CI 66%-97% in HAP) to 100% (95% CI 25% 100% in cIAIs and 75%-100% in DFIs), respectively. Conclusion: These findings suggest that with appropriate monitoring, tigecycline may be a useful consideration for Acinetobacter infections alone or in combination with other anti-infective agents when other therapies are not suitable. PMID- 29138584 TI - Repeated intermittent ulipristal acetate in the treatment of uterine fibroids: a cost-effectiveness analysis. AB - There are limited treatment options available for women with moderate to severe symptoms of uterine fibroids (UFs) who wish to avoid surgery. For these women, treatment with standard pharmaceuticals such as contraceptives is often insufficient to relieve symptoms, and patients may require surgery despite their wish to avoid it. Clinical trials demonstrate that ulipristal acetate 5 mg (UPA) is an effective treatment for this patient group, but its cost-effectiveness has not been assessed in this population. A decision-analytic model was developed to simulate a cohort of patients in this population under treatment with UPA followed by surgery as needed compared to treatment with iron and non-steroidal anti-inflammatory drug (NSAID) followed by surgery as needed (best supportive care, BSC). The analysis took the perspective of the National Health Service (NHS) in England, UK, and was based on the published UPA clinical trials. Results were calculated for the long-term costs and quality-adjusted life years (QALYs) for each treatment arm and combined into an incremental cost-effectiveness ratio (ICER) as the primary outcome. The impact of parameter uncertainty on the results was assessed using scenario, deterministic, and probabilistic sensitivity analyses. The results show that treating patients with the UPA strategy, instead of the BSC strategy, results in an additional cost of L1,115 and a gain of 0.087 QALYs, resulting in an ICER of L12,850. Given commonly accepted cost effectiveness thresholds in England, the use of UPA as a repeated, intermittent treatment for women with moderate to severe symptoms of UF wishing to avoid surgery is likely to be a cost-effective intervention when compared to BSC. PMID- 29138585 TI - A comparative analysis of clinical outcomes and disposable costs of different catheter ablation methods for the treatment of atrioventricular nodal reentrant tachycardia. AB - Background: Catheter ablation of atrioventricular nodal reentrant tachycardia (AVNRT) is a commonly performed electrophysiology (EP) procedure. Few data exist comparing conventional (CONV) versus novel ablation strategies from both clinical and direct cost perspectives. We sought to investigate the disposable costs and clinical outcomes associated with three different ablation methodologies used in the ablation of AVNRT. Methods: We performed a retrospective review of AVNRT ablations performed at Augusta University Medical Center from 2006 to 2014. A total of 183 patients were identified. Three different ablation techniques were compared: CONV manual radiofrequency (RF) (n=60), remote magnetic navigation (RMN)-guided RF (n=67), and cryoablation (CRYO) (n=56). Results: Baseline demographics did not differ between the three groups except for a higher prevalence of cardiomyopathy in the RMN group (p<0.01). The clinical end point of interest was recurrent AVNRT following the index ablation procedure. A significantly higher number of recurrent AVNRT cases occurred in the CRYO group as compared to CONV and RMN (p=0.003; OR =7.75) groups. Cost-benefit analysis showed both CONV and RMN to be dominant compared to CRYO. Cost-minimization analysis demonstrated the least expensive ablation method to be CONV (mean disposable catheter cost = CONV US$2340; CRYO US$3515; RMN US$5190). Despite comparable clinical outcomes, the incremental cost of RMN over CONV averaged US$3094 per procedure. Conclusion: AVNRT ablation using either CONV or RMN techniques is equally effective and associated with lower AVNRT recurrence rates than CRYO. CONV ablation carries significant disposable cost savings as compared to RMN, despite similar efficacy. PMID- 29138586 TI - Association between metabolic syndrome and sensorineural hearing loss: a cross sectional study of 11,114 participants. AB - Background/objectives: Hearing loss (HL) is associated with certain diseases and affects health, resulting in a low quality of life. Some components of the metabolic syndrome (MetS) coincide with the risk factors for sensorineural hearing loss (SNHL). To date, very few studies have examined the link between MetS and HL. The aim of the current study was to try to understand the potential association between MetS and HL. Methods: Using Iranian health surveys of professional drivers, we enrolled 11,114 individuals aged 20-60 years, whose main job is to operate a motor vehicle. We examined participants for the presence and absence of SNHL and the components of the MetS. Additionally, we investigated the relationship between MetS and the pure tone air conduction hearing thresholds of participants with SNHL, including low-frequency and high-frequency thresholds. Results: This cross-sectional study consisted of 11,114 participants: 3202 (28.81%) diagnosed with MetS and 7911 (71.18%) without and 2772 (24.94%) with SNHL and 8432 (75.86%) without. Participants with SNHL had a higher number of components of MetS (P<0.001 for all components). Conclusion: Our results demonstrated that an association possibly exists between different components of MetS (obesity, hypertension, hypertriglyceridemia, high fasting glucose levels, and waist circumference) and SNHL in a population of West Azerbaijan drivers. Therefore, it is important to schedule periodic checkups for drivers to detect and avoid the increase in MetS components at an early stage in this population. PMID- 29138587 TI - Primary sclerosing cholangitis: diagnostic and management challenges. AB - Primary sclerosing cholangitis (PSC) is a chronic immune-mediated disease affecting intra- and extrahepatic bile ducts, primarily the large biliary ducts. Clinical manifestations are broad, and the spectrum encompasses asymptomatic cholestasis, icteric cholangitis with pruritis, cirrhosis, and cholangiocarcinoma. Though rare, PSC has a propensity to affect young to middle aged males and is strongly associated with inflammatory bowel disease. There is an unmet need for effective medical treatments for PSC, and to date, the only curative therapy is liver transplantation reserved for those with end-stage liver disease. This article addresses the diagnostic and management challenges of PSC, with a succinct analysis of existing therapies, their limitations, and a glimpse into the future of the management of this multifaceted pathologic entity. PMID- 29138589 TI - Clinical characteristics and outcome of toxicity from Amanita mushroom poisoning. AB - Objective: To describe and analyze the clinical characteristics and outcome of amatoxin poisoning cases. Methods: We performed a retrospective cohort study of amatoxin poisoning cases from Ramathibodi Poison Center Toxic Exposure Surveillance System, from May 2013 to August 2015. Results: There were 30 consultations with a total of 55 poisoning cases. Most cases were male and from the north-east region. Hepatitis, acute kidney injury, jaundice, and coagulopathy accounted for 74%, 46.3%, 44.7%, and 52.8% of the cases, respectively. Almost all of the patients were admitted to the hospital, and the median duration of hospital stay was found to be 4 days. Mortality rate was found to be 27.3%. Most patients (73%) received the treatment including multiple-dose activated charcoal (67.5%), intravenous N-acetylcysteine (87.5%), and benzylpenicillin (45%). In 60% of the cases, the treatment was initiated within 24 h after eating mushrooms. Exchange transfusion and liver transplantation were performed in one severe case. However, this patient died eventually. Because intravenous silybinin is not available in Thailand during the study period, 8 patients received oral silymarin instead. All 8 patients had hepatitis and were treated with high dosage of oral silymarin (5 patients with 4.48 g/day, 2 patients with 1.68 g/day, and 1 patient with 1.4 g/day) for a couple of days. One of these patients died as she received treatment very late; she was treated with silymarin at 1.68 g/day dosage. Thus, the fatality in oral silymarin treatment group was 12.5%. We performed the analysis between the dead and survival groups. We found that in hepatitis, initial and maximum serum aspartate transaminase, initial and maximum serum alanine transaminase, and acute kidney injury were significantly different between the two groups. Conclusion: Amanita mushroom poisoning caused high fatalities. Serum transaminase and creatinine were the factors associated with death. Treatment with oral high dose silymarin should be investigated further as one of the principal therapies in amatoxin poisoning. PMID- 29138588 TI - RAI1 gene mutations: mechanisms of Smith-Magenis syndrome. AB - Smith-Magenis syndrome (SMS; OMIM #182290) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions, encompassing multiple genes and including the retinoic acid induced 1 gene (RAI1), or by mutations in RAI1 itself. About 10% of all the SMS patients, in fact, carry an RAI1 mutation responsible for the phenotype. RAI1 (OMIM *607642) is a dosage-sensitive gene expressed in many tissues and highly conserved among species. Over the years, several studies have demonstrated that RAI1 (or its homologs in animal models) acts as a transcriptional factor implicated in embryonic neurodevelopment, neuronal differentiation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucose metabolisms, behavioral functions, and circadian activity. Patients with RAI1 pathogenic variants show some phenotypic differences when compared to those carrying the typical deletion. They usually have lower incidence of hypotonia and less cognitive impairment than those with 17p11.2 deletions but more frequently show the behavioral characteristics of the syndrome and overeating issues. These differences reflect the primary pathogenetic role of RAI1 without the pathogenetic contribution of the other genes included in the typical 17p11.2 deletion. The better comprehension of physiological roles of RAI1, its molecular co-workers and interactors, and its contribution in determining the typical SMS phenotype will certainly open a new path for therapeutic interventions. PMID- 29138590 TI - The prevalence of probable neuropathic pain in the US: results from a multimodal general-population health survey. AB - Background: The prevalence of neuropathic pain (NeP) has been estimated within specific health conditions; however, there are no published data on its broad prevalence in the US. The current exploratory study addresses this gap using the validated PainDetect questionnaire as a screener for probable NeP in a general population health survey conducted with a multimodal recruitment strategy to maximize demographic representativeness. Materials and methods: Adult respondents were recruited from a combination of Internet panels, telephone lists, address lists, mall-based interviews, and store-receipt invitations using a random stratified-sampling framework, with strata defined by age, sex, and race/ethnicity. Older persons and minorities were oversampled to improve prevalence estimates. Results were weighted to match the total adult US population using US Census data. Demographic information was collected, and respondents who experienced physical pain in the past 12 months completed the PainDetect and provided additional pain history. A cutoff score of 19 or greater on the PainDetect was used to define probable NeP. Results: A total of 24,925 respondents (average response rate 2.5%) provided demographic data (52.2% female, mean age 51.5 years); 15,751 respondents reported pain (63.7%), of which 2,548 (15.7%, 95% confidence interval 14.9%-16.5%) had probable NeP based on the PainDetect, which was 10% (95% confidence interval 9.5%-10.5%) of all respondents. Among those reporting pain, the prevalence of probable NeP among Blacks and Hispanics was consistently higher than Whites in each age- and sex group. The highest prevalence among those with pain was among male Hispanics 35 44 years (32.4%) and 45-54 years (24.2%) old. The most commonly used medications reported by those with probable NeP were nonsteroidal anti-inflammatory drugs (44.2%), followed by weak opioids (31.7%), antiepileptics (10.9%), and strong opioids (10.9%). Conclusion: This is the first study to provide an estimate of the prevalence of probable NeP in the US, showing significant variation by age and ethnicity. PMID- 29138591 TI - Anatomical etiology of "pseudo-sciatica" from superior cluneal nerve entrapment: a laboratory investigation. AB - Objective: The superior cluneal nerve (SCN) may become entrapped where it pierces the thoracolumbar fascia over the iliac crest; this can cause low back pain (LBP) and referred pain radiating into the posterior thigh, calf, and occasionally the foot, producing the condition known as "pseudo-sciatica." Because the SCN was thought to be a cutaneous branch of the lumbar dorsal rami, originating from the dorsal roots of L1-L3, previous anatomical studies failed to explain why SCN causes "pseudo-sciatica". The purpose of the present anatomical study was to better elucidate the anatomy and improve the understanding of "pseudo-sciatica" from SCN entrapment. Materials and methods: SCN branches were dissected from their origin to termination in subcutaneous tissue in 16 cadavers (5 male and 11 female) with a mean death age of 88 years (range 81-101 years). Special attention was paid to identify SCNs from their emergence from nerve roots and passage through the fascial attachment to the iliac crest. Results: Eighty-one SCN branches were identified originating from T12 to L5 nerve roots with 13 branches passing through the osteofibrous tunnel. These 13 branches originated from L3 (two sides), L4 (six sides), and L5 (five sides). Ten of the 13 branches showed macroscopic entrapment in the tunnel. Conclusion: The majority of SCNs at risk of nerve entrapment originated from the lower lumbar nerve. These anatomical results may explain why patients with SCN entrapment often evince leg pain or tingling that mimics sciatica. PMID- 29138592 TI - Dose-related beneficial and harmful effects of gabapentin in postoperative pain management - post hoc analyses from a systematic review with meta-analyses and trial sequential analyses. AB - Background: During the last 15 years, gabapentin has become an established component of postoperative pain treatment. Gabapentin has been employed in a wide range of doses, but little is known about the optimal dose, providing the best balance between benefit and harm. This systematic review with meta-analyses aimed to explore the beneficial and harmful effects of various doses of gabapentin administered to surgical patients. Materials and methods: Data in this paper were derived from an original review, and the subgroup analyses were predefined in an International Prospective Register of Systematic Reviews published protocol: PROSPERO (ID: CRD42013006538). The methods followed Cochrane guidelines. The Cochrane Library's CENTRAL, PubMed, EMBASE, Science Citation Index Expanded, Google Scholar, and FDA database were searched for relevant trials. Randomized clinical trials comparing gabapentin versus placebo were included. Four different dose intervals were investigated: 0-350, 351-700, 701-1050, and >1050 mg. Primary co-outcomes were 24-hour morphine consumption and serious adverse events (SAEs), with emphasis put on trials with low risk of bias. Results: One hundred and twenty-two randomized clinical trials, with 8466 patients, were included. Sixteen were overall low risk of bias. No consistent increase in morphine-sparing effect was observed with increasing doses of gabapentin from the trials with low risk of bias. Analyzing all trials, the smallest and the highest dose subgroups demonstrated numerically the most prominent reduction in morphine consumption. Twenty-seven trials reported 72 SAEs, of which 83% were reported in the >1050 mg subgroup. No systematic increase in SAEs was observed with increasing doses of gabapentin. Conclusion: Data were sparse, and the small number of trials with low risk of bias is a major limitation for firm conclusions. Taking these limitations into account, we were not able to demonstrate a clear relationship between the dosage of gabapentin and opioid-sparing or harmful effects. These subgroup analyses are exploratory and hypothesis-generating for future trialists. PMID- 29138593 TI - Intrathecal pain management: a team-based approach. AB - Objective: Physician assistants (PAs), nurse practitioners (NPs), and registered nurses (RNs) provide professional services on pain management teams. This review provides an overview of the practical management of chronic pain with intrathecal (IT) therapy using an interprofessional approach (eg, physicians and other health care professionals), with a focus on the contributions of PAs, NPs, and RNs. Methods: Narrative review based on literature searches of the Medline database and treatment guidelines on the use of IT therapy in the management of patients with chronic pain. Results: The specific roles and responsibilities of PAs, NPs, and RNs in the management of patients receiving IT therapy vary by practice. In many pain treatment centers, PAs, NPs, and RNs are responsible for patient education, postimplant maintenance, and ongoing supportive care of patients receiving IT therapy. Topics that we address include patient selection, patient expectations and goal setting, medication selection, outcome assessment, and treatment adjustment. Currently, morphine and ziconotide (a nonopioid, selective N-type calcium channel blocker) are the only agents approved by the US Food and Drug Administration for IT analgesia. We provide relevant information on the dosing, titration, and adverse effect management of these medications for PAs, NPs, and RNs responsible for administering IT therapy. Conclusion: PAs, NPs, and RNs are valuable members of IT pain management teams. Treatment success requires ongoing monitoring of efficacy and adverse effects, with corresponding adjustments to medication selection and dosing, in addition to good communication among the health care professionals involved in patient care. PMID- 29138594 TI - Prevention and treatment of acute and chronic radiodermatitis. AB - More than half the number of patients with cancer, who are treated with radiotherapy, will have radiodermatitis at some point during their treatment. Radiodermatitis either occurs early on in the treatment period or appears months or up to several years later. Acute radiodermatitis is a burn injury that varies in severity according to both treatment and inherent patient factors. Most acute radiodermatitis reactions resolve after several weeks but some reactions persist and can cause complications. Late-onset radiodermatitis is characterized by telangiectasia that forms on atrophic and fragile skin. These radiodermatitis reactions can have a significant negative impact on concomitant and subsequent therapeutic protocols and most particularly on the patient's quality of life. Today, treatment of radiodermatitis reactions is in its infancy. Although there is insufficient evidence available to form recommendations that would prevent or reduce radiodermatitis, some advances have been made using low level light therapy (LLLT) or vascular lasers to control the symptoms. Some recent preclinical and clinical research suggests that LLLT has biostimulating properties which allow the tissues to regenerate and heal faster, reduce inflammation, and prevent fibrosis. Also, in late-onset radiodermatitis pulsed dye laser treatment has been shown to be beneficial in clearing radiation-induced telangiectasia. In the absence of evidence-based recommendations, the objective of this paper is to review how to prevent or manage the symptoms of radiodermatitis reactions. PMID- 29138595 TI - Clinical aspects of foot health and their influence on quality of life among breast cancer survivors: a case-control study. AB - Purpose: The aim of this study was to analyze and compare foot health and general health in a sample of women divided into two groups: 1) those with breast cancer and undergoing chemotherapy treatment and 2) healthy women without breast cancer and with normalized reference values. Methods: A case-control observational study was performed. Two-hundred women with a mean age of 51.00+/-8.75 years were recruited from podiatric medicine and surgery clinics from the University of Extremadura (Plasencia, Spain) and the Hospital Infanta Cristina (Badajoz, Spain). The women were divided into case and control groups (undergoing chemotherapy treatment and healthy women, respectively). The Foot Health Status Questionnaire was used to assess foot health domain scores. Results: Significant differences between both groups were seen for foot pain (P=0.003), foot function (P<0.001), physical activity (P<0.001), social capacity (P<0.001), and vigor (P=0.001). The remaining domains (footwear, general health, and foot health) did not show significant differences between the two groups (P>=0.01). Conclusion: Women with breast cancer presented a lower foot health-related quality of life. Clinical aspects with emphasis on foot pain and disability were increased. Furthermore, physical activity, social capacity, and vigor were affected. Therefore, general health care and foot problem prevention for breast cancer survivors should be given more consideration. PMID- 29138596 TI - Nifuratel, a novel STAT3 inhibitor with potent activity against human gastric cancer cells. AB - Activation of the signal transducer and activator of transcription 3 (STAT3) is observed in multiple cancer types, including gastric cancer, and represents a potential drug target for chemotherapy. Currently, clinically available small molecule inhibitors targeting STAT3 are lacking. Here, we report that nifuratel, an antiprotozoal and antifungal drug, is a potent inhibitor of STAT3. We found that nifuratel significantly suppressed proliferation and induced apoptosis of gastric cancer cells. Studies of the mechanism of action of nifuratel indicated that it acts by inhibiting the constitutive and interleukin-6-induced STAT3 activation. Taken together, our findings demonstrate that nifuratel may be a novel, clinically accessible STAT3 inhibitor in gastric cancer cells. PMID- 29138597 TI - Characteristics and prognostic factors of colorectal mucinous adenocarcinoma with signet ring cells. AB - Background: Colorectal signet ring cell (SRC) carcinoma occurs rarely with a poor prognosis. The present study assessed the prognostic factors and predictive value of SRC ratio in colorectal mucinous adenocarcinoma (MAC) with SRCs (MAC-SRC). Patients and methods: A total of 95 consecutive colorectal MAC-SRC patients, confirmed pathologically from February 1987 to December 2015, were analyzed retrospectively in our institute. Clinical characteristics, pathological grade, TNM staging, and SRC ratio were assessed to identify the prognostic factors related to progression-free survival (PFS) and overall survival (OS). SPSS 22.0 was used for statistical analyses. Results: The median follow-up time was 29.7 months (range 0.8-165). Meanwhile, 5-year PFS and OS rates were 25.6% (95% confidence interval [CI] 16.192-35.008%) and 40.5% (95% CI 29.524-51.476%), respectively. Among the 81 patients who underwent surgery, 78 (96.3%) were diagnosed as stage T3 or T4; 74 (91.4%) showed lymph node involvement, and 27 (29.3%) presented distant metastasis. Metastases of the peritoneal cavity and ovaries were observed commonly in colorectal MAC-SRC. In the multivariate Cox regression model, SRC ratio >=35%, absence of preoperative radiotherapy, and distant metastasis were independent predictors of PFS. Furthermore, SRC ratio >=35%, absence of preoperative chemotherapy (pre-CT), and distant metastasis were independent risk factors for poor prognosis. Conclusion: A long-term follow-up of colorectal MAC-SRC reveals that it is a rare subtype of colorectal MAC with a dismal prognosis. Furthermore, SRC ratio, pre-CT, and M stage seem to affect OS independently. PMID- 29138598 TI - Familial aggregation of myasthenia gravis in affected families: a population based study. AB - Introduction: Myasthenia gravis (MG) is clinically heterogeneous and can be life threatening if bulbar or respiratory muscles are involved. However, relative contributions of genetic, shared, and nonshared environmental factors to MG susceptibility remain unclear. The aim of this study was to examine the familial aggregation and heritability of MG and the relative risks (RRs) of other autoimmune diseases in the relatives of patients with MG. Methods: A population based family study using the Taiwan National Health Insurance (NHI) Database was conducted. Participants included all individuals (N=23,422,955) who were actively registered in the NHI Database in 2013, 15,066 of whom had at least one first degree relative with MG. We identified 8,638 parent-child relationships, 3,279 with an affected offspring, 3,134 with affected siblings, and 26 with affected twins. Prevalence and RRs of MG and other autoimmune diseases in the relatives of patients as well as the relative contributions of heritability, shared, and nonshared environmental factors to MG susceptibility were measured. Results: RRs (95% confidence intervals [CIs]) for MG were 17.85 (8.71-36.56) for patients' siblings, 5.33 (2.79-10.18) for parents, 5.82 (3.03-11.16) for offspring, and 1.42 (0.20-10.10) for spouses without genetic similarities. RRs (95% CIs) in individuals with a first-degree relative with MG were 2.18 (1.53-3.12) for systemic lupus erythematosus, 1.73 (1.09-2.74) for primary Sjogren's syndrome, 1.90 (1.66-2.18) for autoimmune thyroid disease, and 1.68 (1.22-2.30) for rheumatoid arthritis. Accountability for the phenotypic variance of MG was 82.1% for familial transmission and 17.9% for nonshared environmental factors. Conclusion: Individual risks of MG and other autoimmune diseases are increased in the relatives of patients with MG. Familial transmission of MG was estimated to be 82.1%. PMID- 29138599 TI - Mortality in adults with and without diabetes: is the gap widening? AB - Objective: We aimed to assess if the gap in mortality between adults with and without diabetes has widened over time in US adults. Methods and study design: This cohort study included 44,041 adults with diabetes from the US National Health Interview Survey between 1986 and 2009 linked to the National Mortality Index data up to 2011. Each participant with diabetes was matched to two participants without diabetes by age, sex, race, survey year, and region of residence (88,082 persons without diabetes). Mortality differences and hazard ratios were calculated for different time periods defined by three methods, according to 1) survey years with original follow-up durations, 2) follow-up calendar years, and 3) survey years with a fixed 3-year follow-up duration. Results: Different methods of defining time periods produced substantially different mortality rates and changing patterns over time. The decline in mortality was higher when time periods were defined according to survey years with original follow-up durations than with the fixed 3-year duration. Different time periods had comparable baseline and attained ages only when the fixed duration was used. With this method, the gap between adults with and without diabetes progressively decreased from 224 (95% confidence interval 188-260) in 1992-1994 to 99 (65-132) per 10,000 person-years in 2007-2009. Hazard ratios declined significantly from 2.12 (1.88-2.38) in 1995-1997 to 1.70 (1.44-2.00) in 2007-2009. Conclusion: The decline in mortality over time was greater among adults with diabetes than those without diabetes. The gap in mortality between adults with diabetes and those without diabetes significantly narrowed in recent years, and was more than halved over the last 15 years. PMID- 29138600 TI - Effects of chronic exposure of hydroxychloroquine/chloroquine on the risk of cancer, metastasis, and death: a population-based cohort study on patients with connective tissue diseases. AB - Background: Hydroxychloroquine and chloroquine may reduce the risk of cancer as they inhibit autophagy, in particular, in people with connective tissue diseases. Methods: The hazard ratios of cancers, metastases, and death were assessed in adults with connective tissue diseases prescribed hydroxychloroquine/chloroquine for at least 1 year in comparison with unexposed individuals with the same underlying conditions. A competing risk survival regression analysis was performed. Data were extracted from the Health Improvement Network UK primary care database. Results: Eight thousand nine hundred and ninety-nine individuals exposed to hydroxychloroquine (98.6%) or chloroquine (1.4%) and 24,118 unexposed individuals were included in the study (median age: 56 [45-66] years, women: 76.8%). When compared to the unexposed group, individuals exposed to hydroxychloroquine/chloroquine were not at lower risk of non-skin cancers (adjusted sub-distribution hazard ratio [sHR]: 1.04 [0.92-1.18], p=0.54), hematological malignancies (adjusted sHR: 1.00 [0.73-1.38], p=0.99), or skin cancers (adjusted sHR: 0.92 [0.78-1.07], p=0.26). The risk of metastasis was not significantly different between the two groups. However, it was significantly lower during the exposure period when compared with the unexposed (adjusted sHR: 0.64 [0.44-0.95] for the overall population and 0.61 [0.38-1.00] for those diagnosed with incident cancers). The risk of death was also significantly lower in those exposed to hydroxychloroquine/chloroquine (adjusted HR: 0.90 [0.81-1.00] in the overall population and 0.78 [0.64-0.96] in those diagnosed with incident cancer). Conclusion: Individuals on long-term exposure to hydroxychloroquine/chloroquine are not at lower risk of cancer. However, hydroxychloroquine/chloroquine may lower the risk of metastatic cancer and death. PMID- 29138601 TI - Zinc phosphate as a definitive cement for implant-supported crowns and fixed dentures. AB - Implant-supported dental prostheses can be retained by a screw or cement. Implant supported fixed partial dentures have a passive fit. A passive fit means there is an internal gap between the abutment surface and the intaglio of the retainer to insure that there is no lateral pressure on the supporting implants or friction upon seating of the prosthesis. This gap is filled with cement for retention of the prosthesis. Any lateral pressure may cause marginal bone loss or periimplantitis. Also, there is usually a microscopic gap at the margin of a crown retainer that exposes the cement to oral fluids. The solubility of zinc phosphate (ZOP) cement is a definite liability due to the risk for cement dissolution. In fixed prostheses, the dissolution of the cement of one or more retainers would cause a transfer of the occlusal load to the retained unit(s). The resulting rotation and lifting of the cement-retained implants from occlusal and parafunctional loads could cause loss of osseointegration of the abutment retained implant(s). ZOP cement may not be indicated for implant-supported fixed partial dentures or splints. Cement dissolution in single unit probably only involves re-cementation, if the patient does not swallow or aspirate the crown. PMID- 29138602 TI - Improved adequacy of endometrial tissue sampled from postmenopausal women using the MyoSure Lite hysteroscopic tissue removal system versus conventional curettage. AB - Objective: To compare the diagnostic suitability of endometrial tissues obtained from postmenopausal women using the MyoSure Lite tissue removal system versus conventional curettage. Materials and methods: Endometrial tissue was sampled in hysteroscopically normal extirpated uteri from seven postmenopausal women (65.9+/ 6.6 years old) using both hysteroscopicguided morcellation and curettage (two quadrants/uterus with each method). Endometrial sampling was performed immediately after hysterectomy for benign reasons unrelated to uterine pathology. Retrieved endometrial tissue samples were evaluated for volume and diagnostic suitability by a pathologist who was masked to the sampling technique used. Results: Endometrial tissue sampling times were similar for morcellation (44+/-23 s) and curettage (47+/-38 s). Mean tissue volume retrieved with MyoSure (1,411+/ 775 mm3) was significantly greater than with curettage (1+/-2 mm3; p=0.0004, two tailed t-test), with larger intact tissue fragments retrieved with morcellation. Both specimen volume and quality obtained by MyoSure Lite were deemed to be significantly better for histologic assessment than the tissues obtained with curettage (p=0.0006 by Fisher's exact test and p=0.0137 by chi-square test, respectively). With dilation and curettage, samples were frequently too scanty for evaluation. Diagnostic concurrence between MyoSure Lite/dilation and curettage samples and histopathology of full-thickness samples taken afterward was also significantly better with MyoSure Lite than with curettage (p=0.0210). Conclusion: Endometrial tissue sampling using the minimally invasive MyoSure Lite hysteroscopic tissue removal system may provide larger volumes of higher-quality endometrial tissue specimens for pathology assessment compared to specimens obtained using conventional curettage, in postmenopausal women. PMID- 29138603 TI - Fatal collapse due to autonomic dysreflexia during manual self-evacuation of bowel in a tetraplegic patient living alone: lessons to learn. AB - Background: To identify areas for improvement, the National Health Service in England mandates the review of case reports of patients who have died, which should be translated into improved care for other patients. Case report: A 49 year-old Caucasian man sustained C-7 tetraplegia in a motorcycle accident in 1992. In 2009, he developed seizures and collapsed in the lavatory on a number of occasions during manual self-evacuation of his bowel. A 24-hour electrocardiogram recording at that time showed sinus rhythm with a maximum heart rate of 97 and a minimum of 39 beats per minute; there were no significant arrhythmias that could have contributed to his episodes of collapse. In 2015, the patient again collapsed while performing manual evacuation of his bowel; on this occasion, he did not suffer a seizure. He was found unresponsive in the bathroom by his daughter, who contacted the emergency services. He recovered consciousness on arrival at the Accident and Emergency Department. A noncontrast computed tomography scan of his head revealed no acute intracranial pathology. In 2016, he suffered a fatal collapse in the lavatory, again while performing manual bowel evacuation. At autopsy, no other significant disease was found that might have caused death, and given the clinical history, the cause of death was recorded as autonomic dysreflexia. Conclusion: There were delays in 1) recognizing that his episodes of collapse in the lavatory were due to autonomic dysreflexia induced by manual bowel evacuation; 2) recommending the prior application of topical 2% lidocaine jelly to prevent or limit autonomic dysreflexia occurring during manual bowel evacuation; and 3) considering alternative bowel management such as stimulant laxatives, transanal irrigation, or colostomy, which could have prevented the occurrence of autonomic dysreflexia caused by manual evacuation. PMID- 29138604 TI - Sport-related anxiety: current insights. AB - To date, much research has been devoted to understanding how anxiety can affect sport performance, both in practice and in competitive settings. It is well known that sport has the potential for high levels of stress and anxiety, and that practicing and employing a range of psychological strategies can be beneficial in anxiety management. Equally, growing evidence also suggests that anxiety can play a role in sport injury prevention, occurrence, rehabilitation, and the return to sport process. The purpose of this paper is to provide current insights into sport-related anxiety. More specifically, it will provide the reader with definitions and theoretical conceptualizations of sport-related anxiety. This will be followed by making a case for considering the term "performance" to be broader than activities associated with sport-related performance in practice and competition, by including performance activities associated with sport injury prevention, rehabilitation, and the return to sport process. The paper will then highlight the importance of recognizing early signs and symptoms of anxiety, and the potential need for referral. Finally, the conclusions will emphasize the need for appropriate, client-specific, and practitioner competent care for athletes experiencing sport-related anxiety. PMID- 29138605 TI - Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: a meta-analysis. AB - The loss of muscle mass and strength with aging results in significant functional impairment. Creatine supplementation has been used in combination with resistance training as a strategy for increasing lean tissue mass and muscle strength in older adults, but results across studies are equivocal. We conducted a systematic review and meta-analysis of randomized controlled trials of creatine supplementation during resistance training in older adults with lean tissue mass, chest press strength, and leg press strength as outcomes by searching PubMed and SPORTDiscus databases. Twenty-two studies were included in our meta-analysis with 721 participants (both men and women; with a mean age of 57-70 years across studies) randomized to creatine supplementation or placebo during resistance training 2-3 days/week for 7-52 weeks. Creatine supplementation resulted in greater increases in lean tissue mass (mean difference =1.37 kg [95% CI =0.97 1.76]; p<0.00001), chest press strength (standardized mean difference [SMD] =0.35 [0.16-0.53]; p=0.0002), and leg press strength (SMD =0.24 [0.05-0.43]; p=0.01). A number of mechanisms exist by which creatine may increase lean tissue mass and muscular strength. These are included in a narrative review in the discussion section of this article. In summary, creatine supplementation increases lean tissue mass and upper and lower body muscular strength during resistance training of older adults, but potential mechanisms by which creatine exerts these positive effects have yet to be evaluated extensively. PMID- 29138606 TI - Mortality in Italian patients with rheumatoid arthritis: evidence for a low mortality rate from cancer and infections in patients followed up at a tertiary center. AB - Objectives: Mortality in patients with rheumatoid arthritis (RA) has never been investigated in Italy. This study is devoted to investigating all the distinct causes of mortality in Italian RA patients. Methods: Clinical charts of patients consecutively admitted to an Italian tertiary center, from January 1, 2008 to December 31, 2014, were reviewed. Mortality rates (incidence mortality rate [IMR] and standardized mortality rate [SMR]) and causes of death as assessed at December 31, 2015, were registered. Mortality rates detected in our series were compared to those reported in other European cohorts and in the general Italian population. Results: Six hundred and eight patients were observed for a median of 3.51 years. Overall IMR was 0.79 deaths/100 person-years. No significant difference between our IMR and that reported in Italian population by the National Institute of Statistics was observed. All-cause and neoplasm IMRs in our series were found to be significantly lower than that reported in the Norfolk Arthritis Registry, while no difference was detected in cardiovascular (CV) mortality. On the other hand, all causes and CV SMRs in our series were found to be higher than that reported in the general Italian population, while cancer and infectious SMRs were found to be lower. Conclusion: In our series, RA patients had an increased all-cause mortality, and in particular an increased death rate due to CV. However, a lower death rate due to cancer and infections was observed. This figure might be due to the careful follow-up of RA patients in tertiary centers, and the results underlines the need to improve the management of CV risk. PMID- 29138607 TI - Evaluation of sleep profile in schizophrenia patients treated with extended release paliperidone: an open-label prospective study in Southeast Asia. AB - Objective: To evaluate the effect of 6 months of treatment with paliperidone extended-release (ER) tablets on the sleep profile of patients with schizophrenia. Methods: A total of 984 patients meeting the The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia who switched their antipsychotic to paliperidone ER were recruited from 61 sites in five countries in Southeast Asia. We recorded patient demographics and assessed sleep quality and daytime drowsiness using visual analog scales. Results: Approximately 70% of patients completed the 6-month study. After the use of paliperidone ER, patients reported significantly better sleep quality (76.44 vs 65.48; p<0.001) and less daytime drowsiness compared with their baseline value (23.18 vs 34.22; p<0.001). Factors predicting sleep profile improvement were completion of the study and higher baseline Positive and Negative Syndrome Scale scores. Conclusion: Paliperidone ER can help schizophrenia patients to improve sleep quality and reduce daytime drowsiness; this was seen especially in the patients who completed the 6-month treatment period and had higher baseline Positive and Negative Syndrome Scale scores. PMID- 29138608 TI - Sleep positions and nocturnal body movements based on free-living accelerometer recordings: association with demographics, lifestyle, and insomnia symptoms. AB - Background: In order to establish normative values for body positions and movements during sleep, the objective of this study was to explore the distribution of sleep positions and extent of nocturnal body moments and the association with sex, age, body-mass index (BMI), smoking, alcohol consumption, and insomnia symptoms. Materials and methods: This cross-sectional study comprised data on a working population (363 men and 301 women) who participated in the Danish Physical Activity Cohort with Objective Measurements (DPHACTO). Measures of body position and movements were obtained from actigraph accelerometers on the thigh, upper back, and upper arm. Linear regression was used to estimate adjusted mean differences in movements among categories of demographic and lifestyle characteristics. Results: During their time in bed, participants spent 54.1% (SD 18.1%) in the side position, 37.5% (SD 18.2%) in the back position, and 7.3% (SD 12.3%) in the front position. Increasing age and BMI were associated with increased time in the side position and a proportional reduction in time in the back position. There were on average 1.6 (SD 0.7) position shifts per hour. Compared to males, females had fewer position shifts ( 0.37, 95% CI -0.48 to -0.24) and fewer arm, thigh, and upper-back movements. Participants aged 20-34 years had more arm, thigh, and upper-back movements compared to participants >=35 years. Obese participants had fewer shifts in body position (-0.15, 95% CI -0.27 to 0), but more arm, thigh, and upper-back movements compared to normal-weight participants. Smokers had fewer shifts in body position than nonsmokers (-0.27, 95% CI -0.4 to -0.13). Conclusion: The predominant sleep position in adults is on the side. This preference increases with age and BMI. The extent of nocturnal body movements is associated with sex, age, BMI, and smoking. PMID- 29138609 TI - Non-valvular atrial fibrillation: impact of apixaban on patient outcomes. AB - Atrial fibrillation is the most common arrhythmia worldwide, and carries a significantly increased risk of thromboembolic stroke. Initially, vitamin K antagonists were used as stroke prophylaxis; but more recently, a group of drugs known as novel oral anticoagulants have been developed. Apixaban belongs to this group of drugs, and is a factor Xa inhibitor that has emerged as a popular pharmacological agent worldwide. In this review, we will provide an overview of the pivotal trials in the development of apixaban, while also critically evaluating the new emerging real-world data, and discussing the effectiveness, safety, economic viability and future prospects of apixaban and how it impacts on patient outcomes in those with non-valvular atrial fibrillation. PMID- 29138610 TI - nab-paclitaxel/carboplatin induction in squamous NSCLC: longitudinal quality of life while on chemotherapy. AB - Background: Longitudinal data on the impact of treatment on quality of life (QoL) in advanced non-small cell lung cancer (NSCLC) are limited. In this palliative setting, treatment that does not deteriorate QoL is key. Here we report longitudinal QoL in patients with squamous NSCLC, receiving <=4 cycles of nab paclitaxel/carboplatin combination chemotherapy. Methods: Patients received nab paclitaxel 100 mg/m2 days 1, 8, 15 + carboplatin area under the curve 6 mg*min/mL day 1 (q3w) for four cycles. QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) at baseline and each cycle (day 1). Results: Two-hundred and six lesion-response-evaluable patients completed baseline + >=1 postbaseline QoL assessment and were QoL evaluable. LCSS average total score and symptom burden index improved from baseline throughout four cycles. In the LCSS pulmonary symptoms score, 46% of patients reported clinically meaningful improvement (>=10 mm visual analog scale) from baseline. Individual EQ-5D-5L dimensions remained stable/improved in >=83% of patients; ~33% reported complete resolution of baseline problems at least once during four cycles. Generally, responders (unconfirmed complete/partial response) had higher scores vs nonresponders. Conclusion: In patients with squamous NSCLC, four cycles of nab-paclitaxel/carboplatin demonstrated clinically meaningful QoL improvements, with greater benefits in responders vs nonresponders. PMID- 29138611 TI - Volunteer patients and small groups contribute to abdominal examination's success. AB - Background: Prior to 2007, we taught the abdominal examination in a hospital based group to 40 students, at one hospital. We used volunteer patients, small groups, repetition, and required faculty development sessions. In 2007, our medical school changed its "Introduction to Physical Examination" session so that the entire class was to be taught in a geographically central session. Our hospital was selected to lead the abdominal examination portion of the session. Aim: Our aim was to answer three questions. First, could we quadruple the recruitment of volunteer patients, and faculty? Second, was it volunteer patients, small groups, repetition, or faculty training that was most valued by the students? Third, would volunteer patients and/or faculty agree to participate a second time? Methods: A total of 43-46 patients and 43-46 faculty were recruited and 43-46 examining rooms were obtained for each of the 5 years of this study. Teachers were required to attend a 1-hour faculty development session. The class of about 170 students was divided into 43-46 groups each year. The teacher demonstrated the abdominal examination and each student practiced the examination on another student. Each student then repeated the full abdominal examination on a volunteer patient. Results: Over the 5-year time period (2008-2012), the abdominal examination ranked first among all organ systems' "Introductory Sessions". The abdominal examination ratings had the best mean score (1.35) on a Likert scale where 1 is excellent and 5 is poor. The students gave the most positive spontaneous comments to having volunteer patients, with small groups coming in as the second most appreciated educational element. Conclusion: We successfully quadrupled the number of faculty, patients, and examining rooms and created a highly rated educational program as measured by anonymous student evaluations, patient and faculty participation, and the medical school's selecting the abdominal examination methods as an "Advanced Examination" for the Pathways Curriculum. PMID- 29138612 TI - Improving undergraduate medical student involvement in research. PMID- 29138613 TI - Medical student involvement in health policy roles. AB - Objectives: A teaching curriculum in health policy may be well established in medical school; however, an emphasis on applying taught principles via participation in health policy roles is less defined. We undertook a study to explore medical student participation in health policy roles. Design and setting: An anonymous online survey via convenience sampling was conducted in the UK. Participants: A total of 112 students from six medical schools participated in the study. Outcome measures: The outcome measures were as follows: medical students' beliefs about their current knowledge of health policy and their desire to learn more; their current, past and future involvement in a health policy role, and perceived barriers to involvement. Results: Forty-seven percent of participants reported previous teaching on health policy, with the majority scoring themselves 2 out of 5 for knowledge about the topic (38%). Seventy-seven percent of participants expressed a desire to be taught health policy while 73% agreed with compulsory teaching. Ninety-six percent of participants reported no current or previous activity in a health policy role, with 61% willing to undertake a role in the future. The three main barriers to student involvement were: a lack of knowledge about health policy (57%), an unawareness of opportunities available (56%), and a lack of time (43%). Conclusion: In addition to already established teaching programs within medical school, implementation of community-based experiences could improve knowledge of health policy, while providing an opportunity for students to gain experience in health policy committee roles. PMID- 29138614 TI - Development of a health care systems curriculum. AB - Background: There is currently no gold standard for delivery of systems-based practice in medical education, and it is challenging to incorporate into medical education. Health systems competence requires physicians to understand patient care within the broader health care system and is vital to improving the quality of care clinicians provide. We describe a health systems curriculum that utilizes problem-based learning across 4 years of systems-based practice medical education at a single institution. Methods: This case study describes the application of a problem-based learning approach to system-based practice medical education. A series of behavioral statements, called entrustable professional activities, was created to assess student health system competence. Student evaluation of course curriculum design, delivery, and assessment was provided through web-based surveys. Results: To meet competency standards for system-based practice, a health systems curriculum was developed and delivered across 4 years of medical school training. Each of the health system lectures and problem-based learning activities are described herein. The majority of first and second year medical students stated they gained working knowledge of health systems by engaging in these sessions. The majority of the 2016 graduating students (88.24%) felt that the course content, overall, prepared them for their career. Conclusion: A health systems curriculum in undergraduate medical education using a problem-based learning approach is feasible. The majority of students learning health systems curriculum through this format reported being prepared to improve individual patient care and optimize the health system's value (better care and health for lower cost). PMID- 29138615 TI - Factors associated with late ANC initiation among pregnant women in select public health centers of Addis Ababa, Ethiopia: unmatched case-control study design. AB - Background: Although Ethiopia has shown remarkable achievements in reducing maternal mortality in the last 10 years, the prevalence of late antenatal care (ANC) initiation is still high in the country. Objective: The primary purpose of this study was to identify the factors related to late ANC initiation among pregnant women in selected public health centers in Addis Ababa, Ethiopia. Subjects and methods: A total of 402 pregnant women (cases=134, controls=268) were recruited using multistage sampling. The design selected for the study was unmatched case-control. EpiData version 3.02 and SPSS version 20.0 were used for data entry and statistical analysis, respectively. Binary logistic regression model was used to model the odds of late ANC initiation. Results: The odds of attending ANC late were significantly higher for mothers with a monthly household income of $8.50 to start the ANC service (AOR=3.04; 95% CI: 1.98, 4.67). Conclusion: Low educational level, low income of the household, unplanned pregnancy, stay for <5 years in Addis Ababa, not getting advice from health extension workers or local TV/radio and higher cost associated with initiation of the first ANC service were the main predictors of late ANC initiation. Therefore, any intervention which would need to improve early ANC initiation should focus on economic empowerment of women, and tailored health education for migrant women should be strengthened. PMID- 29138616 TI - Bipolaris marantae sp. nov., A Novel Helminthosporoid Species Causing Foliage Blight of the Garden Plant Maranta leuconeura in Brazil. AB - A severe leaf spot, turning to foliage blight, was observed on leaves of Maranta leuconeura growing in a garden in Brazil (state of Rio de Janeiro) in 2015. A dematiaceous hyphomycete bearing a morphology typical of a helminthosporoid fungi was regularly found in association with diseased tissues. The fungus was isolated and pathogenicity was demonstrated through the completion of Koch's postulates. A morphology and molecular analysis led to the conclusion that the fungus belonged to the genus Bipolaris, which is characterized by having fusiform conidia, externally thickened and truncate hila and a bipolar pattern of germination. Additionally, homology of internal transcribed spacer and GAPDH sequences with sequences of other Bipolaris species, confirmed its generic placement. A phylogenetic study also indicated clearly that the fungus on M. leuconeura is phylogenetically distinct from related species of this genus, leading to the proposal of the new species Bipolaris marantae. PMID- 29138617 TI - Phylogenetic Placement and Morphological Characterization of Sclerotium rolfsii (Teleomorph: Athelia rolfsii) Associated with Blight Disease of Ipomoea batatas in Korea. AB - In this study, we aimed to characterize fungal samples from necrotic lesions on collar regions observed in different sweetpotato growing regions during 2015 and 2016 in Korea. Sclerotia appeared on the root zone soil surface, and white dense mycelia were observed. At the later stages of infection, mother roots quickly rotted, and large areas of the plants were destroyed. The disease occurrence was monitored at 45 and 84 farms, and 11.8% and 6.8% of the land areas were found to be infected in 2015 and 2016, respectively. Fungi were isolated from disease samples, and 36 strains were preserved. Based on the cultural and morphological characteristics of colonies, the isolates resembled the reference strain of Sclerotium rolfsii. Representative strains were identified as S. rolfsii (teleomorph: Athelia rolfsii) based on phylogenetic analysis of the internal transcribed spacer and large subunit genes along with morphological observations. To test the pathogenicity, sweetpotato storage roots were inoculated with different S. rolfsii strains. 'Yulmi' variety displayed the highest disease incidence, whereas 'Pungwonmi' resulted in the least. These findings suggested that morphological characteristics and molecular phylogenetic analysis were useful for identification of S. rolfsii. PMID- 29138618 TI - Diversity, Phylogeny, and Host-Specialization of Hyaloperonospora Species in Korea. AB - The genus Hyaloperonospora (Peronosporaceae; Oomycota) is an obligate biotrophic group that causes downy mildew disease on the Brassicaceae and allied families of Brassicales, including many economically relevant crops, such as broccoli, cabbage, radish, rape, and wasabi. To investigate the diversity of Hyaloperonospora species in northeast Asia, we performed a morphological analysis for the dried herbarium specimens collected in Korea, along with molecular phylogenetic inferences based on internal transcribed spacer rDNA and cox2 mtDNA sequences. It was confirmed that 14 species of Hyaloperonospora exist in Korea. Of these, three species, previously classified under the genus Peronospora, were combined to Hyaloperonospora: H. arabidis-glabrae comb. nov. (ex Arabis glabra), H. nasturtii-montani comb. nov. (ex Rorippa indica), and H. nasturtii-palustris comb. nov. (ex Rorippa palustris). In addition, finding two potentially new species specific to northeast Asian plants is noteworthy in support of the view that the species abundance of Hyaloperonospora has been underestimated hitherto. PMID- 29138619 TI - Distribution, Characterization, and Diversity of the Endophytic Fungal Communities on Korean Seacoasts Showing Contrasting Geographic Conditions. AB - This study analyzed the distribution of endophytic fungi in 3 coastal environments with different climatic, geographical, and geological characteristics: the volcanic islands of Dokdo, the East Sea, and the West Sea of Korea. The isolated fungal endophytes were characterized and analyzed with respect to the characteristics of their host environments. For this purpose, we selected common native coastal halophyte communities from three regions. Molecular identification of the fungal endophytes showed clear differences among the sampling sites and halophyte host species. Isolates were also characterized by growth at specific salinities or pH gradients, with reference to previous geographical, geological, and climate studies. Unlike the East Sea or West Sea isolates, some Dokdo Islands isolates showed endurable traits with growth in high salinity, and many showed growth under extremely alkaline conditions. A smaller proportion of West Sea coast isolates tolerate compared to the East Sea or Dokdo Islands isolates. These results suggest that these unique fungal biota developed through a close interaction between the host halophyte and their environment, even within the same halophyte species. Therefore, this study proposes the application of specific fungal resources for restoring sand dunes and salt damaged agricultural lands and industrialization of halophytic plants. PMID- 29138620 TI - Cutaneous Microflora from Geographically Isolated Groups of Bradysia agrestis, an Insect Vector of Diverse Plant Pathogens. AB - Larvae of Bradysia agrestis, an insect vector that transports plant pathogens, were sampled from geographically isolated regions in Korea to identify their cutaneous fungal and bacterial flora. Sampled areas were chosen within the distribution range of B. agrestis; each site was more than 91 km apart to ensure geographical segregation. We isolated 76 microbial (fungi and bacteria) strains (site 1, 29; site 2, 29; site 3, 18 strains) that were identified on the basis of morphological differences. Species identification was molecularly confirmed by determination of universal fungal internal transcribed spacer and bacterial 16S rRNA gene sequences in comparison to sequences in the EzTaxon database and the NCBI GenBank database, and their phylogenetic relationships were determined. The fungal isolates belonged to 2 phyla, 5 classes, and 7 genera; bacterial species belonged to 23 genera and 32 species. Microbial diversity differed significantly among the geographical groups with respect to Margalef's richness (3.9, 3.6, and 4.5), Menhinick's index (2.65, 2.46, and 3.30), Simpson's index (0.06, 0.12, and 0.01), and Shannon's index (2.50, 2.17, and 2.58). Although the microbial genera distribution or diversity values clearly varied among geographical groups, common genera were identified in all groups, including the fungal genus Cladosporium, and the bacterial genera Bacillus and Rhodococcus. According to classic principles of co-evolutionary relationship, these genera might have a closer association with their host insect vector B. agrestis than other genera identified. Some cutaneous bacterial genera (e.g., Pseudomonas) displaying weak interdependency with insect vectors may be hazardous to agricultural environments via mechanical transmission via B. agrestis. This study provides comprehensive information regarding the cutaneous microflora of B. agrestis, which can help in the control of such pests for crop management. PMID- 29138621 TI - Influence of the Culture Media and the Organic Matter in the Growth of Paxillus ammoniavirescens (Contu & Dessi). AB - The genus Paxillus is characterized by the difficulty of species identification, which results in reproducibility problems, as well as the need for large quantities of fungal inoculum. In particular, studies of Paxillus ammoniavirescens have reported divergent results in the in vitro growth while little is known of its capacity to degrade organic matter. For all the above, and assuming that this variability could be due to an inappropriate culture media, the aim of this study was to analyse growth in different culture media (MMN, MS, and 1/2 MS) and in the case of MMN in presence/absence of two types of organic matter (fresh litter and senescence litter) to probe the saprophytic ability of P. ammoniavirescens . We also evaluated the effects of pH changes in the culture media. Growth kinetics was assessed by weekly quantification of the area of growth in solid culture media over 5 wk, calculating the growth curves and inflection points of each culture media. In addition, final biomass after 5 wk in the different culture media was calculated. Results showed that best culture media are MS and 1/2 MS. Moreover, an improvement in growth in culture media containing decomposing fall litter was observed, leading to confirm differences in the culture media of this species with others of the same genus. Further, we established that all growth media suffered a significant acidification after fungal growth. PMID- 29138622 TI - Antimicrobial Efficacy of Penicillium amestolkiae elv609 Extract Treated Cotton Fabric for Diabetic Wound Care. AB - Diabetes mellitus is a chronic disorder which affects millions of population worldwide. Global estimates published in 2010 reported the world diabetic prevalence as 6.4%, affecting 285 million adults. Foot ulceration and wound infection are major forms of disabilities arising from diabetic diseases. This study was aimed to develop a natural antimicrobial finishing on medical grade textile that meets American Association of Textiles Chemists and Colorists (AATCC) standard. The textile samples were finished with the ethanolic extract of Penicillium amestolkiae elv609, an endophytic fungus isolated from Orthosiphon stamineus Benth (common name: cat's whiskers). Endophyte is defined as microorganism that reside in the living plant tissue, without causing apparent disease symptom to the host. The antimicrobial efficacy of the ethanolic extract of P. minioluteum was tested on clinical pathogens isolated from diabetic wound. The extract exhibited significant inhibitory activity against 4 bacteria and 1 yeast with the minimal inhibitory concentration ranged from 6.25 to 12.5 mg/mL. The results indicate different susceptibility levels of the test microorganism to the ethanolic extract. However, the killing activity of the extract was concentration-dependent. The finished medical textile showed excellent antimicrobial efficacy on AATCC test assays. All the microbial cultures treated with the textile sample displayed a growth reduction of 99.9% on Hoheinstein Challenge Test. The wash durability of the finished textile was found good even after 50 washes with commercial detergent. Besides, the gas chromatography mass spectrometry analysis showed that 6-octadecenoic acid and diethyl phthalate were the main bioactive constituents of the extract. In conclusion, the developed medical textile showed good antimicrobial efficacy on laboratory tests. This work can be extended to in vivo trials for developing healthcare textile products for antimicrobial applications. PMID- 29138623 TI - Characterization and Pathogenicity of New Record of Anthracnose on Various Chili Varieties Caused by Colletotrichum scovillei in Korea. AB - The anthracnose disease caused by Colletotrichum species is well-known as a major plant pathogen that primarily causes fruit rot in pepper and reduces its marketability. Thirty-five isolates representing species of Colletotrichum were obtained from chili fruits showing anthracnose disease symptoms in Chungcheongnam do and Chungcheongbuk-do, South Korea. These 35 isolates were characterized according to morphological characteristics and nucleotide sequence data of internal transcribed spacer, glyceraldehyde-3-phosphate-dehydrogenase, and beta tubulin. The combined dataset shows that all of these 35 isolates were identified as C. scovillei and morphological characteristics were directly correlated with the nucleotide sequence data. Notably, these isolates were recorded for the first time as the causes of anthracnose caused by C. scovillei on pepper in Korea. Forty cultivars were used to investigate the pathogenicity and to identify the possible source of resistance. The result reveals that all of chili cultivars used in this study are susceptible to C. scovillei. PMID- 29138624 TI - Entomopathogenic Fungi as Dual Control Agents against Both the Pest Myzus persicae and Phytopathogen Botrytis cinerea. AB - The green peach aphid (Myzus persicae), a plant pest, and gray mold disease, caused by Botrytis cinerea, affect vegetables and fruit crops all over the world. To control this aphid and mold, farmers typically rely on the use of chemical insecticides or fungicides. However, intensive use of these chemicals over many years has led to the development of resistance. To overcome this problem, there is a need to develop alternative control methods to suppress populations of this plant pest and pathogen. Recently, potential roles have been demonstrated for entomopathogenic fungi in endophytism, phytopathogen antagonism, plant growth promotion, and rhizosphere colonization. Here, the antifungal activities of selected fungi with high virulence against green peach aphids were tested to explore their potential for the dual control of B. cinerea and M. persicae. Antifungal activities against B. cinerea were evaluated by dual culture assays using both aerial conidia and cultural filtrates of entomopathogenic fungi. Two fungal isolates, Beauveria bassiana SD15 and Metarhizium anisopliae SD3, were identified as having both virulence against aphids and antifungal activity. The virulence of these isolates against aphids was further tested using cultural filtrates, blastospores, and aerial conidia. The most virulence was observed in the simultaneous treatment with blastospores and cultural filtrate. These results suggest that the two fungal isolates selected in this study could be used effectively for the dual control of green peach aphids and gray mold for crop protection. PMID- 29138625 TI - Production and Its Anti-hyperglycemic Effects of gamma-Aminobutyric Acid from the Wild Yeast Strain Pichia silvicola UL6-1 and Sporobolomyces carnicolor 402-JB-1. AB - This study was done to produce gamma-aminobutyric acid (GABA) from wild yeast as well as investigate its anti-hyperglycemic effects. Among ten GABA-producing yeast strains, Pichia silvicola UL6-1 and Sporobolomyces carnicolor 402-JB-1 produced high GABA concentration of 134.4 ug/mL and 179.2 ug/mL, respectively. P. silvicola UL6-1 showed a maximum GABA yield of 136.5 ug/mL and 200.8 ug/mL from S. carnicolor 402-JB-1 when they were cultured for 30 hr at 30C in yeast extract peptone-dextrose medium. The cell-free extract from P. silvicola UL6-1 and S. carnicolor 402-JB-1 showed very high anti-hyperglycemic alpha-glucosidase inhibitory activity of 72.3% and 69.9%, respectively. Additionally, their cell free extract-containing GABA showed the anti-hyperglycemic effect in streptozotocin-induced diabetic Sprague-Dawley rats. PMID- 29138626 TI - Efficient Method for the Rapid Purification of Nosema ceranae Spores. AB - Nosema ceranae is an obligate intracellular fungal parasite that causes mortality in honey bees and enhances the susceptibility of honey bees to other pathogens. Efficient purification of Nosema spores from the midgut of infected honey bees is very important because Nosema is non-culturable and only seasonably available. To achieve a higher yield of spores from honey bees, in this study, we considered that the initial release of spores from the midgut tissues was the most critical step. The use of 2 mm beads along with enzymatic treatment with collagenase and trypsin enhanced the homogenization of tissues and the yield of released spores by approximately 2.95 times compared with the use of common 3 mm beads alone. The optimal time for the enzyme treatment was determined to be 1 hr as measured by the yield and viability of the spores. A one-step filtration using a filter paper with an 8-11 um pore size was sufficient for removing cell debris. This method may be useful to purify not only N. ceranae spores but also other Nosema spp. spores. PMID- 29138627 TI - The Fungicolous Ascomycetes Genus Hypomyces in Korea. AB - The genus Hypomyces contains fungi that grow on mushrooms, including agarics, boletes, and Aphyllophorales. While 53 Hypomyces species have been reported worldwide, only one was in Korea. In this study, two new Korean species were identified as H. luteovirens and H. tubariicola based on morphology and internal transcribed spacer sequencing. PMID- 29138628 TI - Biocontrol Activity of Volatile-Producing Bacillus megaterium and Pseudomonas protegens against Aspergillus flavus and Aflatoxin Production on Stored Rice Grains. AB - In our previous study, three bacterial strains, Bacillus megaterium KU143, Microbacterium testaceum KU313, and Pseudomonas protegens AS15, were selected as effective biocontrol agents against Aspergillus flavus on stored rice grains. In this study, we evaluated the inhibitory effects of the volatiles produced by the strains on A. flavus growth and aflatoxin production on stored rice grains. The three strains significantly reduced mycelial growth of A. flavus in dual-culture assays compared with the negative control strain, Sphingomonas aquatilis KU408, and an untreated control. Of these tested strains, volatiles produced by B. megaterium KU143 and P. protegens AS15 markedly inhibited mycelial growth, sporulation, and conidial germination of A. flavus on agar medium and suppressed the fungal populations in rice grains. Moreover, volatiles produced by these two strains significantly reduced aflatoxin production in the rice grains by A. flavus. To our knowledge, this is the first report of the suppression of A. flavus aflatoxin production in rice grains using B. megaterium and P. protegens volatiles. PMID- 29138629 TI - The Effect of Fungicides on Mycelial Growth and Conidial Germination of the Ginseng Root Rot Fungus, Cylindrocarpon destructans. AB - Ginseng root rot caused by Cylindrocarpon destructans is the most destructive disease of ginseng. Six different fungicides (thiophanate-methyl, benomyl, prochloraz, mancozeb, azoxystrobin, and iprodione) were selected to evaluate the inhibitory effect on the mycelial growth and conidial germination of C. destructans isolates. Benomyl and prochloraz were found to be the most effective fungicides in inhibiting mycelial growth of all tested isolates, showing 64.7% to 100% inhibition at a concentration of 10 ug/mL, whereas thiophanate-methyl was the least effective fungicide, showing less than 50% inhibition even at a higher concentration of 100 ug/mL. The tested fungicides exhibited less than 20% inhibition of conidium germination at concentrations of 0.01, 0.1, and 1 ug/mL. However, the inhibition effect of mancozeb on condium germination of C. destructans was significantly increased to 92% to 99% at a higher concentration of 100 ug/mL, while the others still showed no higher than 30% inhibition. PMID- 29138630 TI - Proteomic Analysis of Coprinopsis cinerea under Conditions of Horizontal and Perpendicular Gravity. AB - Coprinopsis cinerea was employed to investigate the fungal response to gravity. Mycelium growth revealed a consistent growth pattern, irrespective of the direction of gravity (i.e., horizontal vs. perpendicular). However, the fruiting body grew in the direction opposite to that of gravity once the primordia had formed. For the proteomic analysis, only curved-stem samples were used. Fifty-one proteins were identified and classified into 13 groups according to function. The major functional groups were hydrolases and transferases (16%), signal transduction (15%), oxidoreductases and isomerases (11%), carbohydrate metabolism (9%), and transport (5%). To the best of our knowledge, this is the first report on a proteomic approach to evaluate the molecular response of C. cinerea to gravity. PMID- 29138631 TI - SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors. AB - Background: Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported. Methods: We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two stage design was used (target response rate 40%). Results: 34 NF1 (median age 33 years) and 14 sporadic (median age 40 years) MPNST patients enrolled. Five of 28 (17.9%) evaluable NF1 MPNST patients had a partial response (PR), as did 4 of 9 (44.4%) patients with sporadic MPNST. Stable disease (SD) was achieved in 22 NF1 and 4 sporadic MPNST patients. In both strata, results in the initial stages met criteria for expansion of enrollment. Only 1 additional PR was observed in the expanded NF1 stratum. Enrollment was slower than expected and the trial closed before full accrual. Conclusions: This trial was not powered to detect differences in response rates between NF1 and sporadic MPNST. While the OR rate was lower in NF1 compared to sporadic MPNST, qualitative responses were similar, and disease stabilization was achieved in most patients. PMID- 29138632 TI - The "e-Generation": The Technological Usage and Experiences of Medical Students from a Developing Country. AB - Background: The medical community is increasingly using Portable Electronic Devices (PEDs). We evaluated usage of PEDs and medical apps among medical students from Sri Lanka. Methods: This descriptive cross-sectional study was conducted at Faculty of Medicine, University of Colombo. Medical students from 2nd to 5th year were invited for the study. A self-administered questionnaire was used to collect details of PEDs availability, accessibility, and usage, perceived advantages/barriers of PEDs, and availability, accessibility, and usage of medical apps. Results: Sample size was 505 (response rate, 61.8%). Mean age was 23.2 +/- 1.3 years and majority were females (60.4%, n = 305). Majority (87.5%, n = 442) of students owned a PED. Nonaffordability was the most common reason for having not owning a PED (46%). Nonaffordability and lack of knowledge were key determinants of the usage of PEDs and medical "apps." Doubts about reliability and lack of knowledge regarding reliable electronic sources of information were other significant barriers. Conclusions: Our results show that a significant majority of students owned a PED, a higher percentage than what is reported elsewhere. Considering barriers identified, it is important for institutions to promote usage of PEDs and medical apps by providing financial support, training, and knowledge to build confidence in technology. PMID- 29138633 TI - Influence of SPK with Enteric Drainage on the Pancreatic Exocrine Function in Diabetic Patients with Uremia. AB - Objective: This study aimed to determine the use of fecal elastase in evaluating the effect of simultaneous pancreas-kidney transplantation with enteric drainage on the pancreatic exocrine function of diabetic patients with uremia. Methods: A total of 19 patients with simultaneous pancreas-kidney transplantation (SPK) with enteric drainage, 31 diabetic patients with uremia (chronic renal failure (CRF)), 22 diabetic patients with uremia who underwent renal transplantation (RT), and 20 normal individuals (CON) were included in the study. Pancreatic exocrine insufficiency was determined using fecal elastase. Results. The fecal pancreatic elastase level in SPK patients with enteric drainage was 479 MUg/g, which was significantly higher than 229 MUg/g in CRF patients and 197 MUg/g in RT patients. Using 200 MUg/g as the established threshold, a reduced fecal pancreatic elastase level was found in 14/31 of CRF patients, 12/22 of RT patients, 1/19 of SPK patients with enteric drainage, and 1/20 of CON patients. The correlation analysis revealed a significant association between fecal elastase and glycosylated hemoglobin. Conclusions: The present study indicated that SPK with enteric drainage improves pancreatic endocrine and exocrine functions. Fecal elastase may be a clinically relevant means to determine the therapeutic effects. PMID- 29138635 TI - NMR Confirmation and HPLC Quantification of Javamide-I and Javamide-II in Green Coffee Extract Products Available in the Market. AB - Javamide-I/javamide-II are phenolic amides found in coffee. Recent reports suggested that they may contain several biological activities related to human health. Therefore, there is emergent interest about their quantities in coffee related products. Green coffee extract is a powder extract made of unroasted green coffee beans, available as a dietary supplement. However, there is little information about the amounts of javamide-I/javamide-II in green coffee extract products in the market. Therefore, in this paper, javamide-I/javamide-II were extracted from green coffee extract products and their identifications were confirmed by NMR. After that, the amounts of javamide-I/javamide-II were individually quantified from seven different green coffee extract samples using the HPLC method coupled to an electrochemical detector. The HPLC method provided accurate and reliable measurement of javamide-I/javamide-II with excellent peak resolution and low detection limit. In all seven green coffee extract samples, javamide-II was found to be between 0.28 and 2.96 mg/g, but javamide-I was detected in only five samples in the concentration levels of 0.15-0.52 mg/g, suggesting that green coffee extract products contain different amounts of javamide-I/javamide-II. In summary, javamide-I/javamide-II can be found in green coffee extract products sold in the market, but their amounts are likely to be comparatively different in between green coffee extract brands. PMID- 29138634 TI - The Synergistic Interplay between Vitamins D and K for Bone and Cardiovascular Health: A Narrative Review. AB - Vitamins D and K are both fat-soluble vitamins and play a central role in calcium metabolism. Vitamin D promotes the production of vitamin K-dependent proteins, which require vitamin K for carboxylation in order to function properly. The purpose of this review is to summarize available evidence of the synergistic interplay between vitamins D and K on bone and cardiovascular health. Animal and human studies suggest that optimal concentrations of both vitamin D and vitamin K are beneficial for bone and cardiovascular health as supported by genetic, molecular, cellular, and human studies. Most clinical trials studied vitamin D and K supplementation with bone health in postmenopausal women. Few intervention trials studied vitamin D and K supplementation with cardiovascular-related outcomes. These limited studies indicate that joint supplementation might be beneficial for cardiovascular health. Current evidence supports the notion that joint supplementation of vitamins D and K might be more effective than the consumption of either alone for bone and cardiovascular health. As more is discovered about the powerful combination of vitamins D and K, it gives a renewed reason to eat a healthy diet including a variety of foods such as vegetables and fermented dairy for bone and cardiovascular health. PMID- 29138636 TI - Stem Cell Tracking Technologies for Neurological Regenerative Medicine Purposes. AB - The growing field of stem cell therapy is moving toward clinical trials in a variety of applications, particularly for neurological diseases. However, this translation of cell therapies into humans has prompted a need to create innovative and breakthrough methods for stem cell tracing, to explore the migration routes and its reciprocity with microenvironment targets in the body, to monitor and track the outcome after stem cell transplantation therapy, and to track the distribution and cell viability of transplanted cells noninvasively and longitudinally. Recently, a larger number of cell tracking methods in vivo were developed and applied in animals and humans, including magnetic resonance imaging, nuclear medicine imaging, and optical imaging. This review has been intended to summarize the current use of those imaging tools in tracking stem cells, detailing their main features and drawbacks, including image resolution, tissue penetrating depth, and biosafety aspects. Finally, we address that multimodality imaging method will be a more potential tracking tool in the future clinical application. PMID- 29138637 TI - Regulation of Osteogenic Differentiation of Placental-Derived Mesenchymal Stem Cells by Insulin-Like Growth Factors and Low Oxygen Tension. AB - Placental mesenchymal stem cells (PMSCs) are multipotent cells that can differentiate in vitro to multiple lineages, including bone. Insulin-like growth factors (IGFs, IGF-1 and IGF-2) participate in maintaining growth, survival, and differentiation of many stem cells, including osteoprogenitors. Low oxygen tension (PO2) can maintain stem cell multipotency and impede osteogenic differentiation. In this study, we investigated whether PMSC osteogenic differentiation is influenced by low PO2 and by IGFs. Our results indicated that low PO2 decreased osteogenic markers RUNX2 and OPN; however, re-exposure to higher oxygen tension (room air) restored differentiation. IGFs, especially IGF 1, triggered an earlier expression of RUNX2 and enhanced OPN and mineralization. RUNX2 was phosphorylated in room air and augmented by IGFs. IGF-1 receptor (IGF 1R) was increased in low PO2 and reduced by IGFs, while insulin receptor (IR) was increased in differentiating PMSCs and enhanced by IGF-1. Low PO2 and IGFs maintained higher IR-A which was switched to IR-B in room air. PI3K/AKT was required for osteogenic differentiation, while MEK/ERK was required to repress an RUNX2 and OPN increase in low PO2. Therefore, IGFs, specifically IGF-1, trigger the earlier onset of osteogenic differentiation in room air, whereas, reversibly, low PO2 impedes complete differentiation by maintaining higher multipotency and lower differentiation markers. PMID- 29138638 TI - Tissue Source and Cell Expansion Condition Influence Phenotypic Changes of Adipose-Derived Stem Cells. AB - Stem cells derived from the subcutaneous adipose tissue of debrided burned skin represent an appealing source of adipose-derived stem cells (ASCs) for regenerative medicine. Traditional tissue culture uses fetal bovine serum (FBS), which complicates utilization of ASCs in human medicine. Human platelet lysate (hPL) is one potential xeno-free, alternative supplement for use in ASC culture. In this study, adipogenic and osteogenic differentiation in media supplemented with 10% FBS or 10% hPL was compared in human ASCs derived from abdominoplasty (HAP) or from adipose associated with debrided burned skin (BH). Most (95-99%) cells cultured in FBS were stained positive for CD73, CD90, CD105, and CD142. FBS supplementation was associated with increased triglyceride content and expression of adipogenic genes. Culture in hPL significantly decreased surface staining of CD105 by 31% and 48% and CD142 by 27% and 35% in HAP and BH, respectively (p < 0.05). Culture of BH-ASCs in hPL also increased expression of markers of osteogenesis and increased ALP activity. These data indicate that application of ASCs for wound healing may be influenced by ASC source as well as culture conditions used to expand them. As such, these factors must be taken into consideration before ASCs are used for regenerative purposes. PMID- 29138639 TI - Involvement of WNT Signaling in the Regulation of Gestational Age-Dependent Umbilical Cord-Derived Mesenchymal Stem Cell Proliferation. AB - Mesenchymal stem cells (MSCs) are a heterogeneous cell population that is isolated initially from the bone marrow (BM) and subsequently almost all tissues including umbilical cord (UC). UC-derived MSCs (UC-MSCs) have attracted an increasing attention as a source for cell therapy against various degenerative diseases due to their vigorous proliferation and differentiation. Although the cell proliferation and differentiation of BM-derived MSCs is known to decline with age, the functional difference between preterm and term UC-MSCs is poorly characterized. In the present study, we isolated UC-MSCs from 23 infants delivered at 22-40 weeks of gestation and analyzed their gene expression and cell proliferation. Microarray analysis revealed that global gene expression in preterm UC-MSCs was distinct from term UC-MSCs. WNT signaling impacts on a variety of tissue stem cell proliferation and differentiation, and its pathway genes were enriched in differentially expressed genes between preterm and term UC MSCs. Cell proliferation of preterm UC-MSCs was significantly enhanced compared to term UC-MSCs and counteracted by WNT signaling inhibitor XAV939. Furthermore, WNT2B expression in UC-MSCs showed a significant negative correlation with gestational age (GA). These results suggest that WNT signaling is involved in the regulation of GA-dependent UC-MSC proliferation. PMID- 29138640 TI - Prevalence of Soil-Transmitted Helminthiases and Schistosomiasis in Preschool Age Children in Mwea Division, Kirinyaga South District, Kirinyaga County, and Their Potential Effect on Physical Growth. AB - Intestinal parasitic infections can significantly contribute to the burden of disease, may cause nutritional and energetic stress, and negatively impact the quality of life in low income countries of the world. This cross-sectional study done in Mwea irrigation scheme, in Kirinyaga, central Kenya, assessed the public health significance of soil-transmitted helminthiases (STH), schistosomiasis, and other intestinal parasitic infections, among 361 preschool age children (PSAC) through fecal examination, by measuring anthropometric indices, and through their parents/guardians, by obtaining sociodemographic information. Both intestinal helminth and protozoan infections were detected, and, among the soil-transmitted helminth parasites, there were Ascaris lumbricoides (prevalence, 3%), Ancylostoma duodenale (<1%), and Trichuris trichiura (<1%). Other intestinal helminths were Hymenolepis nana (prevalence, 3.6%) and Enterobius vermicularis (<1%). Schistosoma mansoni occurred at a prevalence of 5.5%. Interestingly, the protozoan, Giardia lamblia (prevalence, 14.7%), was the most common among the PSAC. Other protozoans were Entamoeba coli (3.9%) and Entamoeba histolytica (<1). Anthropometric indices showed evidence of malnutrition. Intestinal parasites were associated with hand washing behavior, family size, water purification, and home location. These findings suggest that G. lamblia infection and malnutrition may be significant causes of ill health among the PSAC in Mwea, and, therefore, an intervention plan is needed. PMID- 29138641 TI - Naturally Acquired Antibody Responses to a Synthetic Malaria Antigen AS202.11. AB - Background: A major challenge to malaria vaccine development is identification of protective epitopes and respective protective immune responses. Objective: To characterize naturally acquired Immunoglobulin G (IgG) responses to the synthetic peptide AS202.11, a malaria vaccine candidate. Methodology: This community based cross-sectional study enrolled 320 participants aged 1 year and above. Demographic information was recorded through interviews. Detection of P. falciparum infection was done by microscopy, malaria rapid diagnostic test, and polymerase chain reaction. ELISA was used to detect IgG antibody. Data was analyzed using STATA. Results: The overall AS202.11 IgG seropositivity was 78.8% (73.9-82.9). Seropositivity by age categories was <=12 years [74.3% (67.4-80.2)], 13-40 years [85.3% (76.5-91.1)], and >40 years [82.6% (68.7-91.1)]. Compared to the <= 12-year-old group, aORs for the other groups were 2.22 (1.14-4.32), p = 0.019, and 1.87 (0.81-4.35), p = 0.143, for the 13-40-year-old and >40-year-old groups, respectively. The 13-40-year-old group had more seropositive individuals compared to the <= 12-year-old group. Conclusion: We report a high degree of recognition of AS202.11 by IgG elicited by field P. falciparum strains, suggesting its close similarity to native P. falciparum antigens and possible suitability of the peptide as a future malaria vaccine candidate. PMID- 29138642 TI - Observation of Blood Donor-Recipient Malaria Parasitaemia Patterns in a Malaria Endemic Region. AB - Background: Asymptomatic malaria parasitaemia has been documented in donor blood in West Africa. However, donated blood is not routinely screened for malaria parasites (MPs). The present study therefore aimed to document the frequency of blood transfusion-induced donor-recipient malaria parasitaemia patterns, in children receiving blood transfusion in a tertiary health-centre. Methodology: A cross-sectional, observational study involving 140 children receiving blood transfusion was carried out. Blood donor units and patients' blood samples were obtained, for the determination of malaria parasites (MPs). Giemsa staining technique was used to determine the presence of malaria parasitaemia. Results: Malaria parasites were detected in 7% of donor blood and in 8.3% of the recipients' pretransfusion blood. The incidence of posttransfusion MPs was 3%, but none of these were consistent with blood transfusion-induced malaria, as no child with posttransfusion parasitaemia was transfused with parasitized donor blood. Majority of the blood transfusions (89.4%) had no MPs in either donors or recipients, while 6.8% had MPs in both donors and recipients, with the remaining 3.8% showing MPs in recipients alone. Conclusion: In conclusion, the incidence of posttransfusion malaria parasitaemia appears low under the prevailing circumstances. PMID- 29138643 TI - Interactions of Desmethoxyyangonin, a Secondary Metabolite from Renealmia alpinia, with Human Monoamine Oxidase-A and Oxidase-B. AB - Renealmia alpinia (Zingiberaceae), a medicinal plant of tropical rainforests, is used to treat snakebites and other injuries and also as a febrifuge, analgesic, antiemetic, antiulcer, and anticonvulsant. The dichloromethane extract of R. alpinia leaves showed potent inhibition of human monoamine oxidases- (MAOs-) A and B. Phytochemical studies yielded six known compounds, including pinostrobin 1, 4'-methyl ether sakuranetin 2, sakuranetin 3, pinostrobin chalcone 4, yashabushidiol A 5, and desmethoxyyangonin 6. Compound 6 displayed about 30-fold higher affinity for MAO-B than MAO-A, with Ki values of 31 and 922 nM, respectively. Kinetic analysis of inhibition and equilibrium-dialysis dissociation assay of the enzyme-inhibitor complex showed reversible binding of desmethoxyyangonin 6 with MAO-A and MAO-B. The binding interactions of compound 6 in the active site of the MAO-A and MAO-B isoenzymes, investigated through molecular modeling algorithms, confirmed preferential binding of desmethoxyyangonin 6 with MAO-B compared to MAO-A. Selective reversible inhibitors of MAO-B, like desmethoxyyangonin 6, may have important therapeutic significance for the treatment of neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease. PMID- 29138644 TI - Acupotomy Therapy for Chronic Nonspecific Neck Pain: A Systematic Review and Meta Analysis. AB - Objective: This review is to assess the efficacy and safety of acupotomy therapy in chronic nonspecific neck pain. Methods: We searched six computerised databases. Randomized controlled trials incorporating acupotomy therapy alone or combined with other conventional treatments for chronic nonspecific neck pain were included. Two reviewers screened each literature and extracted data independently according to Cochrane Reviews' Handbook (5.1). The Cochrane Collaboration's RevMan 5.3 software was applied for meta-analysis. Results: A total of ten trials involving 433 patients were enrolled. The pooled analysis indicated that acupotomy therapy showed a significant improving short-term and long-term effect on effective rate and cure rate. Meta-analysis demonstrated that acupotomy therapy group was superior to control group in restoring cervical lordosis and debasing VAS score. The result of continuous data did not support statistical significance of acupotomy therapy in adjusting clinical symptom score. For adverse events, acupotomy group did not reveal obvious superiority compared to control group. Conclusions: Acupotomy therapy may be beneficial to chronic nonspecific neck pain patients. To strengthen supportive evidence, future, more rigorously designed clinical trials, adequate adverse events, and follow-up project are recommended. PMID- 29138645 TI - Chinese Classical Formula Sijunzi Decoction and Chronic Atrophic Gastritis: Evidence for Treatment Approach? AB - Objective: This aim is to evaluate the effect of Sijunzi decoction (SJZD) treating chronic atrophic gastritis (CAG). Methods: We performed searches in seven databases. The randomized controlled trials (RCTs) comparing SJZD with standard medical care or inactive intervention for CAG were enrolled. Combined therapy of SJZD plus conventional therapies compared with conventional therapies alone was also retrieved. The primary outcome included the incidence of gastric cancer and the improvement of atrophy, intestinal metaplasia, and dysplasia based on the gastroscopy and pathology. The secondary outcomes were Helicobacter pylori clearance rate, quality of life, and adverse event/adverse drug reaction. Results: Six RCTs met the inclusion criteria. The research quality was low in the trials. For the overall effect rate, pooled analysis from 4 trials showed that modified SJZD plus conventional medications exhibited a significant improvement (OR = 4.86; 95% CI: 2.80 to 8.44; P < 0.00001) and without significant heterogeneity compared with the conventional medications alone. None reported the adverse effect. Conclusions: Modified SJZD combined with conventional western medicines appears to have benefits for CAG. Due to the limited number and methodological flaw, the beneficial and harmful effects of SJZD for CAG could not be identified. More high-quality clinical trials are needed to confirm the results. PMID- 29138646 TI - The Characteristics of TCM Clinical Trials: A Systematic Review of ClinicalTrials.gov. AB - Objective: The aim of this review is to characterize current status of global TCM clinical trials registered in ClinicalTrials.gov. Methods: We examined all the trials registered within ClinicalTrials.gov up to 25 September 2015, focusing on study interventions to identify TCM-related trials, and extracted 1,270 TCM trials from the data set. Results: Overall, 691 (54.4%) trials were acupuncture, and 454 (35.8%) trials were herbal medicines. Differences in TCM trial intervention types were also evident among the specific therapeutic areas. Among all trials, 55.7% that were small studies enrolled <100 subjects, and only 8.7% of completed studies had reported results of trials. As for the location, the United States was second to China in conducting the most TCM trials. Conclusion: This review is the first snapshot of the landscape of TCM clinical trials registered in ClinicalTrials.gov, providing the basis for treatment and prevention of diseases within TCM and offering useful information that will guide future research on TCM. PMID- 29138647 TI - Nodding syndrome (NS) and Onchocerca Volvulus (OV) in Northern Uganda. AB - Nodding Syndrome (NS) is a childhood neurological disorder characterized by atonic seizures, cognitive decline, school dropout, muscle weakness, thermal dysfunction, wasting and stunted growth. There are recent published information suggesting associations between Nodding Syndrome (NS) with cerebrospinal fluid (CSF) VGKC antibodies and serum leiomidin-1 antibody cross reacting with Onchocerca Volvulus (OV). These findings suggest a neuro-inflammatory cause of NS and they are important findings in the search for the cause of Nodding Syndrome. These observations perhaps provide further, the unique explanation for the association between Nodding Syndrome and Onchocerca Volvulus. Many clinical and epidemiological studies had shown a significant correlation between NS and infestation with a nematode, Onchocerca volvulus which causes a disease, Onchocerciasis, some of which when left untreated can develop visual defect ("River Blindness"). While these studies conducted in Northern Uganda and Southern Sudan indicate a statistically significant association with (OV infection (using positive skin snips), we observe that (OV is generally endemic in many parts of Sub Saharan Africa and Latin America and that to date, no NS cases have been recorded in those regions. This letter to the Editor is to provide additional information on the current view about the relationship between Nodding Syndrome and Onchocerca Volvulus as seen in Northern Uganda. PMID- 29138648 TI - Vascular hyperreactivity in black Cameroonian hypertensive and normotensive patients: a comparative study. AB - Introduction: Vascular hyperreactivity is a risk factor and a factor predicting hypertension (high blood pressure). Unlike other continents where several studies were carried out, it has rarely been studied in black Africa in general and in Cameroon in particular. Methods: Vascular reactivity was measured by the cold test. Vascular hyperreactivity was defined as an increase in blood pressure > 20 mmHg for systolic and/or > 15 mmHg for diastolic. Khi2, Man-Withney, Wilcoxon's signed ranks and logistic regression tests were used for statistical analysis. Results: A total of 31 hypertensive and 31 normotensive patients matched by age and sex participated in this study. Vascular hyperreactivity was present in 77.4% hypertensive patients and 51.6% normotensive patients. There was a significant association between vascular hyperreactivity and hypertension [OR = 3.2 (1.07 - 9.63), p = 0.034]. The median arterial pressure was higher in responders compared to non-responders in the normotensive group. Age > 45 years, female sex, obesity and family history of hypertension appeared to be associated with vascular hyperreactivity, but only in normotensive patients. Conclusion: Vascular hyperreactivity appears to be a risk factor for high blood pressure in black Cameroonians. It appeared to be associated with low blood pressure, age, sex, obesity and family history of hypertension but this was only in the normotensive. PMID- 29138649 TI - [Clinical and electrocardiographic aspect of pulmonary embolism masking aortic dissection revealed by thoracic CT angiography]. AB - We here report the case of a 52-year old hypertensive, obese woman (BMI 32,46 kg/m2) with a past history of smoking and without evidence-based risk factors of venous thromboembolism, hospitalized for left chest pain radiating to the dorsolumbar region associated with dyspnoea. Clinical examination on hopitalization showed left blood pressure 100/60 mmHg, tachycardia 100/min, oxygen desaturation index at 88% with the patient breathing ambient air, normal cardiopulmonary auscultation, peripheral pulses palpable and no symptoms of phlebitis of the lower limbs. The ECG showed right axis deviation, S1Q3 pattern, right ventricular hypertrophy and right bundle branch block (A, B, C). The patient underwent emergency thoracic CT angiography objectifying aortic dissection from the origin of the aorta to the iliac bifurcation (Stanford A). Our patient received medical care based on blood pressure and heart rate control as well as on analgesics, with good evolution in the absence of surgical means. PMID- 29138650 TI - Evaluation of antibiotic self-medication among outpatients of the state university hospital of Port-Au-Prince, Haiti: a cross-sectional study. AB - In Haiti, where all drugs are available over the counter, self-medication with antibiotics appears as a common practice. Inappropriate use of beta-lactams and macrolides is likely to contribute to the development of antimicrobial resistance. This study aimed to (i) assess the extent of self-medication with antibiotics, (ii) explore the contributing factors (age, gender and educational background) and (iii) identify specific antibiotic drug classes used among patients attending the outpatient clinic of the State University Hospital of Port au-Prince. A cross-sectional survey among 200 outpatients of the State University Hospital of Port-au-Prince was conducted in December 2014. Face-to-face interviews were conducted using a standardized questionnaire. Parents of pediatric patients were allowed to answer to questions on their behalf. Among the study sample, 45.5% practiced self-medication with antibiotics. It was less prevalent among patients with the highest education level (23.1%; OR: 0.89 (0.5 1.75), p = 0.001). Mild symptoms (28.6%) and vaginal itching (44.4%) were the main reasons for self-medication with antibiotics. Self-medication using amoxicillin was reported by 67.0%. Self-medication with antibiotics is a common practice among Haitian patients and is more common among the less educated. Amoxicillin for urinary tract infections is the most commonly used medication. It is crucial to raise awareness on the dangers of the practice in the population and inforce the current law regarding the use of over the counter antibiotics. PMID- 29138651 TI - Melanotic neuroectodermal tumor of infancy: a rare presentation of an extremely rare neoplasm and diagnostic implications in Gombe, Nigeria. AB - Melanotic neuro-ectodermal tumor of infancy is very rare. A unique neoplasm of the formative years, it typically involves the face or cranium; possesses rapid, expansile growth; presents as a firm swelling and displays a high rate of recurrence. Its rarity and unique features make diagnosis and management quite challenging. This challenge is increased in resource-limited settings like ours and with atypical presentation, such as was seen at our center, where patient presented with a bony hard swelling. PMID- 29138652 TI - Trauma: a major cause of death among surgical inpatients of a Nigerian tertiary hospital. AB - Introduction: Trauma presents a significant global health burden. Death resulting from trauma remains high in low income countries despite a steady decrease in developed countries. Analysis of the pattern of death will enable intervention to reduce these deaths from trauma in developing countries. This study aims to present the pattern of trauma-related deaths in the surgical wards of University of Port Harcourt Teaching Hospital (UPTH). Methods: This was a retrospective study of all patients who died from trauma during admission into the surgical wards of UPTH from 2007 to 2012. Data on demography and traumatic events leading to death were collected from surgical wards, the emergency unit, and theatre records and analyzed using SPSS version 16.0. Results: Trauma accounted for 219 (42.4%) of the 527 mortalities recorded. Most of the deaths (62.6 %) occurred between 20 and 59 years. There were 148 males (67.6 %). The yearly mortality rates were as follows: 2007(12.3 %); 2008 (16.9%); 2009 (9.1%), 2010 (12.8 %), 2011 (23.3%) and 2012 (25.6%). Most of the patients (91.3%) died within 1 month of admission. The major events leading to deaths were burns 105(47.9%), traumatic brain injuries were 63(28.8%), and spinal cord injuries 21(9.6%). The secondary causes of death were mainly septic shock 112(51.1%); Respiratory failure 60(27.4%); and Multiple organ dysfunction 44(20.1%). Conclusion: Trauma is a leading cause of mortality in the surgical wards of our hospital. Trauma -related deaths continues to increase over the years. Safe keeping of petroleum products and adherence to traffic rules will reduce these avoidable deaths. PMID- 29138653 TI - The incidence of first-line antiretroviral treatment changes and related factors among HIV-infected sex workers in Nairobi, Kenya. AB - Introduction: In many settings, several factors including adverse drug reactions and clinical failure can limit treatment choices for combined antiretroviral therapy (cART). The aim of the study was to describe the incidence of first-line cART changes and associated factors in a cohort of Kenyan sex workers. Methods: This was a retrospective review of medical records collected from 2009 to 2013. The review included records of HIV-infected patients aged >= 18 years, who received either stavudine or zidovudine or tenofovir disoproxil fumarate-based regimens. Using systematic random sampling, the study selected 1 500 records and censoring targeted the first incident of a drug change from the first-line cART. Results: The overall incidence rate of cART changes was 11.1 per 100 person-years within a total follow-up period of 3 427.9 person-years. Out of 380 patients who changed cART, 370 (97%) had a drug substitution and 10 (3%) switched regimens. The most commonly cited reasons for changing cART were adverse drug reactions (76%). Tenofovir disoproxil fumarate had a lower drug change rate (1.9 per 100 person years) compared to stavudine (27 per 100 person years). Using zidovudine as the reference group, stavudine-based regimens were significantly associated with an increased hazard of drug changes (adjusted hazards ratio 10.2; 95% CI: 6.02-17.2). Conclusion: These findings suggest a moderate incidence of cART changes among sex workers in Nairobi, Kenya. Individuals using stavudine were at a higher risk of experiencing a change in their cART, mostly presenting within 20 months, and primarily due to adverse drug reactions. PMID- 29138654 TI - Syphilis and HIV infections among pregnant women attending antenatal clinics in Republic of Congo. AB - Introduction: HIV and syphilis during pregnancy remain a public health concern especially in developing countries. Pregnant women attending antenatal clinics sites for the first time between September and December 2011 and who accepted to participate in the study were enrolled. The objective was to estimate the syphilis and HIV infection rate in this population. Methods: A study was conducted in 44 selected ANCs from 12 departments (5 urban and 7 rural). Pregnant women who accepted to participate in the study, attending selected sentinel ANCs sites for the first time between September and December 2011 were enrolled. To detect HIV antibodies, two consecutive ELISA assays were used (Genscreen Ultra HIV Ag/Ac, (BioRad, France) and Enzygnostic Intergral II (Siemens, GMBH, Marbug Germany). In case of discordant results, the Western blot test II, HIV1 and 2 (Bio-Rad, Marne la Coquette, France) was used as the reference method. The RPR (Bio-Scan, Karnataka, India) test was performed to detect syphilis infection. The RPR positive results were confirmed using the TPHA test (Biotech, Cambridge, UK). Data were analyzed using SPSS 17.0 software. Results: A total of 2979 pregnant women attending ANCs were enrolled. The global HIV infection rate was estimated to be 3.6% (CI: 95%; 3.0-4.4). As expected, HIV prevalence was significantly higher in women aged above 25 years (4.4% (3.4-5.6), p = 0.026) and those attending urban ANCs (5.04%, p < 0.01). Also, women living in the urban area are more at risk to be infected (5.04 VS 2.38, p < 0.01). The RPR test was positive in 117 pregnant women (3.92%). The risk for syphilis occurrence was significantly higher among the single women compared to the married ones (4.4% VS 2.7%; p < 0.01). It was also estimated that the HIV and syphilis coinfection occurred in 22 cases (0.73%). Conclusion: The prevalence's of syphilis and HIV were relatively low. Marital status and sentinel site location were a risk factor associated with HIV and syphilis infections respectively. Therefore, substantial effort is needed to reinforce prevention strategies in this population to prevent mother-to-child and further horizontal transmissions of these infections. PMID- 29138655 TI - Endobronchial localization of Hodgkin's disease. AB - The endobronchial localization of Hodgkin's disease is a rare entity which is often confused with endobronchial tuberculosis in our setting. We report the case of a 16 years old female who presented with 6 months history of dry cough, hemoptysis, dyspnea, dysphagia and dysphonia. The chest radiography showed a mediastinal and pulmonary opacity. The chest CT scan found enlarged mediastinal lymph nodes. The bronchial biopsy and peripheral lymph node biopsy confirmed Hodgkin's disease with endobronchial localization. The patient received chemotherapy (ABVD protocol) and radiotherapy with a favorable follow up. PMID- 29138656 TI - [Hyperthyroidism in children at the University Hospital in Dakar (Senegal)]. AB - Introduction: Hyperthyroidism in children is rare and constitutes a problem because of its psychosomatic impact. This study aimed to present an overview of the state of knowledge on these aspects in children from Dakar. Methods: We conducted a multicenter, descriptive study over a period of 15 years. We evaluated the epidemiological, clinical and etiologic aspects of hyperthyroidism in children. Results: 239 patients were included in the study with a prevalence of 2.4%, a sex ratio (M/F) of 0.36 and an average age of 10.8 years. The inclusion criteria were being the eldest son in a family(26.3%), being advanced (36.9%) or delayed (12.5%) in maturation, having short stature (40.1%). It was caused by Graves' disease in 90.3% of cases with psychoaffective factor in 22.1%. On a clinical point of view tachycardia (92.4%), goiter (91.1%), exophthalmia (81.8%), weight loss (69.8%) prevailed but with bed-wetting (30.2%) and psychic manifestations (3.1%). Cardiovascular and cutaneous manifestations were positively associated with age (p < 0.05). Goiter was associated with female sex (p = 0.005), cardiovascular (p = 0.02), neuropsychic (p = 0.03), skin (p = 0.03) signs and diarrhea (p = 0.03). Free T4 was correlated with age (p = 0.007), diarrhea (p = 0.021), anxiety (p = 0.024), heart rate (p = 0.00) and Graves' disease (p = 0.04). More voluminous the goiter, higher the free T4 (p = 0.007). Conclusion: Hyperthyroidism in children differs from that in adults because of induction factors, growth disturbances and enuresis. Age and sex seem to favor the clinical picture of thyrotoxicosis and its associated signs. PMID- 29138657 TI - Community health worker interventions are key to optimal infant immunization coverage, evidence from a pretest-posttest experiment in Mwingi, Kenya. AB - Introduction: Immunization is a powerful and cost-effective health intervention which averts an estimated 2 to 3 million deaths every year. Kenya has a high infant and under five mortality and morbidity rates. Increasing routine child immunization coverage is one way of reducing child morbidity and mortality rates in Kenya. Community Health Workers (CHWs) have emerged as critical human resources for health in developing countries. The Community Strategy (CS) is one of the CHW led interventions promoting Maternal and Child Health (MCH) in Kenya. This study sought to establish the effect of CS on infant vaccination Coverage (IVC) in Mwingi west sub-county; Kenya. Methods: This was a pretest - posttest experimental study design with 1 pretest and 2 post-test surveys conducted in intervention and control sites. Mwingi west and Mwingi north sub-counties where intervention and control sites respectively. Sample size in each survey was 422 households. Women with a child aged 9-12 months were main respondents. Results: Intervention site end-term evaluation indicated that; the CS increased IVC by 10.1% (Z =6.0241, P <0.0001), from a suboptimal level of 88.7% at baseline survey to optimal level of 98.8% at end term survey. Infants in intervention site were 2.5 times more likely to receive all recommended immunizations within their first year of life [(crude OR= 2.475, P<0.0001; 95%CI: 1.794-3.414) (adj. OR=2.516, P<0.0001; 95%CI: 1.796-3.5240)]. Conclusion: CS increased IVC in intervention site to optimal level (98.8%). To improve child health outcomes through immunization coverage, Kenya needs to fast-track nationwide implementation of the CS intervention. PMID- 29138658 TI - [Femoral varising osteotomy by external opening for the treatment of lateral femorotibial gonarthroses associated with idiopathic genu valgum: a retrospective a study of 10 cases]. AB - Femoral varus osteotomy is a conservative treatment for external single compartment gonarthrosis. This surgical procedure is little used and outcomes are little studied.This study aimed to assess the clinical and radiological results of femoral varising osteotomy in subjects with external femorotibial gonarthrosis associated with idiopathic genu valgum whose data were recorded over a period of 21 years (1992- 2013) in the Department of Orthopedics at Sahloul University Hospital, Sousse. The clinical evaluation of patients was performed using the IKS score (International Knee Society). Radiological assessment was based on pre operative work-up and final follow-up assessment. We here report a case series of 9 patients (and 10 knees) whose average age was 45.2 years, with a sex ratio of 0.5. Mean follow-up was 99-months. Average knee score ranged from 48.4 points preoperatively to 73.5 points at the final follow-up assessment, with a statistically significant improvement (p<10-3). Medium functional score significantly improved, with a preoperative value of 49.5 points and a value of 72 points at the final follow-up assessment. Final correction helped to reduce valgus condition with an average of 3.7 degrees and a preoperative value of 14 degrees . This study, as well as the analysis of literature, indicates that femoral varising osteotomy is the treatment of choice for invalidating genu valgum of femoral origin, without any rheumatoid arthritis, overweight, internal femorotibial nor severe femoropatellar arthritis. PMID- 29138659 TI - [Lymphangioma of the breast: about a case]. AB - Lymphangioma is a benign lesion of the lymphatic vessels. It is a rare paediatric condition and it is exceptional among adults. It mainly occurs in the neck, armpit and abdomen. It rarely occurs in the breast. We report the case of a 18 year-old female patient seen in consultation for a mass in her left breast, which had evolved over the last 23 months. Management was based on surgery. The patient underwent complete tumor resection. Anatomopathological examination showed lymphangioma of the breast. Patient's evolution was favorable and the patient had a median 10 months follow-up with no recurrences identified. PMID- 29138660 TI - Use of cellular phone contacts to increase return rates for immunization services in Kenya. AB - Introduction: In Kenya, failure to complete immunization schedules by children who previously accessed immunization services is an obstacle to ensuring that children are fully immunized. Home visit approaches used to track defaulting children have not been successful in reducing the drop-out rate. Methods: This study tested the use of phone contacts as an approach for tracking immunization defaulters in twelve purposively-selected facilities in three districts of western Kenya. For nine months, children accessing immunization services in the facilities were tracked and caregivers were asked their reasons for defaulting. Results: In all of the facilities, caregiver phone ownership was above 80%. In 11 of the 12 facilities, defaulter rates between pentavalent1 and pentavalent3 vaccination doses reduced significantly to within the acceptable level of < 10%. Caregivers provided reliable contact information and health workers positively perceived phone-based defaulter communications. Tracking a defaulter required on average 2 minutes by voice and Ksh 6 ($ 0.07). Competing tasks and concerns about vaccinating sick children and side-effects were the most cited reasons for caregivers defaulting. Notably, a significant number of children categorised as defaulters had been vaccinated in a different facility (and were therefore "false defaulters"). Conclusion: Use of phone contacts for follow-up is a feasible and cost-effective method for tracking defaulters. This approach should complement traditional home visits, especially for caregivers without phones. Given communication-related reasons for defaulting, it is important that immunization programs scale-up community education activities. A system for health facilities to share details of defaulting children should be established to reduce "false defaulters". PMID- 29138661 TI - Intra-articular knee arborescent lipoma: a case treated with arthroscopic synoviectomy. AB - Arborescent lipoma is an unusual intra-articular lesion that typically develops in the knee and has to be evoked before chronic effusion. It corresponds to hyperplasia of mature fatty tissue and hypertrophy of synovial villi, developing within a joint. The reference treatment is synovectomy by arthrotomy. The rare forms localized to the anterior compartment of the knee can benefit from an arthroscopic synovectomy. The authors report a case of arborescent knee lipoma in a 47-year-old patient who received arthroscopic synoviectomy. To our knowledge, only a few cases of arborescent lipoma treated by arthroscopic synoviectomy have been reported in the literature. PMID- 29138662 TI - ST-segment elevation after blunt chest trauma: myocardial contusion with normal coronary arteries or myocardial infarction following coronary lesions. AB - Cardiac lesions secondary to blunt chest trauma vary from insignificant arrhythmias to fatal cardiac rupture. Of these, a distinction remains difficult; face to ST-segment elevation on ECG with positive cardiac biomarkers, is it a myocardial contusion or a genuine myocardial infarction (MI) secondary to coronary lesions? We report the case of a patient admitted for multiple trauma. Initial assessment showed an ST segment elevation on ECG, along with multiple fractures and abdominal injuries. We would like to discuss, through this case, the similarities and the differences between myocardial infarction due to coronary lesions and myocardial contusion in a traumatic context, but also emphasize the difficulty of striking the right balance between thrombotic and bleeding risks in this situation, and insist on the importance of a multidisciplinary and collegial reflexion so we can offer these patients the best care there is. PMID- 29138663 TI - Toluidine blue: rapid and simple malaria parasite screening and species identification. AB - Malaria, a febrile illness mostly confined to the tropical countries is transmitted by bite of infected female Anopheles mosquito. In 2015 alone, 88% of the malaria burden and 90% deaths due to malaria were confined to the African and Asian countries. Although number of tests are available for rapid diagnosis and screening for malaria, peripheral blood smear examination remains the gold standard. Leishman stain is recommended by WHO however herein we evaluate one of the alternative methods of staining which is simple and rapid. Fifty patients attending the various outpatient departments of the tertiary care hospital with fever and suspected to have malaria were selected. Two thin-air dried smears prepared from the peripheral venous blood from these subjects were stained by Leishman and Toluidine blue method. The findings of the slides by two independent qualified professionals were noted and the results were analyzed. A total of 14% (7/50) cases were diagnosed to have malaria. All the malaria cases which were positive in Leishman stain were also detected in Toluidine blue stain. Malarial parasites were clearly visible against the homogenously light green background in Toluidine blue. The detection of malarial parasite by Toluidine blue was quick, easy and confirmative. Toluidine blue stained peripheral blood smear allows for easy identification and speciation of malarial parasite at low magnification and in shorter period of time. PMID- 29138664 TI - Tuberculosis of the scalp: the tubercle bacilli has not ceased to surprise us. PMID- 29138665 TI - [Epidemiological profile of uropathogenic enterobacteria producing extended spectrum beta-lactamases]. AB - Urinary tract infections due to enterobacteria producing extended spectrum beta lactamases (ESBL-E) constitute a infectious risk, a major therapeutic challenge and can even lead, in some cases, to a deadlock beacuse of their multi-resistance to antibiotics. This study aimed to determine the epidemiological profile of uropathogenic ESBL-E and to describe their current level of resistance to antibiotics for a better patient management according to local data. We conducted a retrospective study of all ESBL-E strains isolated from all cytobacteriogical testing of urine (CBEU) treated in the Microbiology Laboratory at the Military Hospital of Moulay Ismail, Meknes over a period of three years (from 1 January 2013 to 31 December 2015). Culture was performed according to conventional techniques and antibiogram was performed using Mueller-Hinten agar disk diffusion susceptibility test according to the recommendations from the Committee on Antimicrobial Susceptibility of the French Society for Microbiology (CA-SFM), year 2013/2014. This study allowed to report a significant overall prevalence of isolation of ESBL-E (12.2%), particularly among hospitalized patients (54.8%). The greater prevalence (72%) was registered in the Department of Urology. Among these, ESBL-E Escherichia coli constitutes the majority (61%) of the isolates, however Klebsiella pneumoniae is the major ESBL producer (25.8%) within the same species. The analysis of ESBL-E antibioresistance conducted during these three years revealed some co-resistances to ciprofloxacin (92.5%), sulfametoxazole trimethoprim (88.4%), gentamycin (67.2%). Globally, our results are compliant with the data from the other Mediterranean countries, except for amikacin whose resistance was very low (6.1%) in our study. This study shows that the prevalence of ESBL-E in hospital is high and that its diffusion in community setting is a matter of concern. These ESBL-E are generally resistant to antibiotics, including molecules useful in urology. PMID- 29138666 TI - Extensive pyomyositis of vastus muscles. AB - We report a case study on a patient who presented with low back and thigh pain of one month duration. He was eventually diagnosed with left thigh pyomyositis. Tissue from thigh grew Staphylococcus aureus. With commencement of antibiotics and surgical drainage, patient made recovery despite prolonged hospital stay. The underlying mechanism of the extensive abscess accompanied by lack of systemic symptoms; is related to relative immunocompromised state of having underlying diabetes mellitus. PMID- 29138667 TI - [Senile scleral plaques]. PMID- 29138668 TI - [Left paraduodenal hernia: a rare cause of bowel obstruction]. AB - We here report two cases of acute bowel obstruction. Emergency intervention showed left obstructive paraduodenal hernia causing volvulus with necrosis of the incarcerated intestinal loops in one patient who underwent one-time anastomosis resection and suffering but viable small bowel in the second patient treated by incarcerated intestinal loop reduction and obturation of the orifice of the hernial canal. We here highlight the diagnostic and therapeutic features of this rare condition. PMID- 29138669 TI - Medical and dental students' attitude and practice of prevention strategies against hepatitis B virus infection in a Nigerian university. AB - Introduction: Medical and dental students are a high-risk group for hepatitis B virus (HBV) infection which is an occupational hazard for them and a leading cause of death globally. Prevention strategies include vaccination and observance of standard precaution. However, available reports claim utilization of the prevention strategies is low. This study evaluated the attitude of the students towards HBV vaccine and cross-infection practices. Methods: This study was a cross-sectional study carried out at the College of Health Sciences, Obafemi Awolowo University, Nigeria. Using the convenience sampling method, anonymous self-administered questionnaires were distributed to the first 120 participants that volunteered to participate in the study. Data analysis was done using IBM's Statistical Package (SPSS) version 20 software. Statistical level of significance was set at p < 0.05. Results: Over eighty percent (83.2%) of the participants had at least a dose of the HBV vaccine while 79.65% completed the three doses. Majority (94.7%) of the students that did not receive the vaccine cited their busy schedule as the reason for their failure to be vaccinated. Taking every patient as a contagious disease risk (86.5%), washing hands after contact with patients' body fluids (82.1%) and wearing gloves before touching mucous membranes and non-intact skin (74.1%) were the most practiced universal standard precaution items. Conclusion: The uptake rate of HBV vaccination and practice of standard precaution among the students are commendable. However, there is need for improvement considering the level of HBV infection in Nigeria. PMID- 29138670 TI - Simvastatin Ameliorates Diabetic Cardiomyopathy by Attenuating Oxidative Stress and Inflammation in Rats. AB - Simvastatin is a lipid-lowering agent used to treat hypercholesterolemia and to reduce the risk of heart disease. This study scrutinized the beneficial effects of simvastatin on experimental diabetic cardiomyopathy (DCM), pointing to the role of hyperglycemia-induced oxidative stress and inflammation. Diabetes was induced by intraperitoneal injection of streptozotocin and both control and diabetic rats received simvastatin for 90 days. Diabetic rats showed significant cardiac hypertrophy, body weight loss, hyperglycemia, and hyperlipidemia. Serum creatine kinase MB (CK-MB) and troponin I showed a significant increase in diabetic rats. Simvastatin significantly improved body weight, attenuated hyperglycemia and hyperlipidemia, and ameliorated CK-MB and troponin I. Simvastatin prevented histological alterations and deposition of collagen in the heart of diabetic animals. Lipid peroxidation and nitric oxide were increased in the heart of diabetic rats whereas antioxidant defenses were decreased. These alterations were significantly reversed by simvastatin. In addition, simvastatin decreased serum inflammatory mediators and expression of NF-kappaB in the diabetic heart. Cardiac caspase-3 was increased in the diabetic heart and decreased following treatment with simvastatin. In conclusion, our results suggest that simvastatin alleviates DCM by attenuating hyperglycemia/hyperlipidemia-induced oxidative stress, inflammation, and apoptosis. PMID- 29138671 TI - High Circulating Levels of ANGPTL2: Beyond a Clinical Marker of Systemic Inflammation. AB - Angiopoietin-like 2 (ANGPTL2) is a proinflammatory protein belonging to the angiopoietin-like family. ANGPTL2 is secreted and detected in the systemic circulation. Different observational clinical studies reported that circulating levels of ANGPTL2 increase significantly in various chronic inflammatory diseases and showed associations between ANGPTL2 levels and diagnosis and/or prognosis of cardiovascular diseases, diabetes, chronic kidney disease, and various types of cancers. However, these studies did not address the following questions: (a) what are the sources of circulating ANGPTL2? (b) How and by which mechanisms an increase in circulating ANGPTL2 contributes to the pathogenesis of chronic inflammatory diseases? (c) Does an increase in circulating levels of ANGPTL2 measured in a well-defined chronic medical condition originate from a specific cell type? Mechanistic hypotheses have been proposed based on studies performed in mice and cultured cells, and proinflammatory, prooxidative, proangiogenic, proliferative, and antiapoptotic properties of ANGPTL2 have been reported. The aim of this review is to propose answers concerning the potential sources of circulating ANGPTL2 and its common pathological properties associated with various chronic inflammatory diseases and death in humans. We believe that high circulating ANGPTL2 levels are more than an inflammatory marker and may reflect the senescent cellular load of an individual. PMID- 29138672 TI - Testosterone Upregulates the Expression of Mitochondrial ND1 and ND4 and Alleviates the Oxidative Damage to the Nigrostriatal Dopaminergic System in Orchiectomized Rats. AB - Testosterone deficiency, as a potential risk factor for aging and aging-related neurodegenerative disorders, might induce mitochondrial dysfunction and facilitate the declines of the nigrostriatal dopaminergic system by exacerbating the mitochondrial defects and increasing the oxidative damage. Thus, how testosterone levels influence the mitochondrial function in the substantia nigra was investigated in the study. The present studies showed that testosterone deficiency impaired the mitochondrial function in the substantia nigra and induced the oxidative damage to the substantia nigra as well as the deficits in the nigrostriatal dopaminergic system. Of four mitochondrial respiratory chain complexes, castration of male rats reduced the activity of mitochondrial complex I and downregulated the expression of ND1 and ND4 of 7 mitochondrial DNA- (mtDNA ) encoded subunits of complex I in the substantia nigra. Supplements of testosterone propionate to castrated male rats ameliorated the activity of mitochondrial complex I and upregulated the expression of mitochondrial ND1 and ND4. These results suggest an important role of testosterone in maintaining the mitochondrial function in the substantia nigra and the vulnerability of mitochondrial complex I to testosterone deficiency. Mitochondrial ND1 and ND4, as potential testosterone targets, were implicated in the oxidative damage to the nigrostriatal dopaminergic system. PMID- 29138674 TI - Exercise Training Restores Cardiac MicroRNA-1 and MicroRNA-29c to Nonpathological Levels in Obese Rats. AB - We previously reported that aerobic exercise training (AET) consisted of 10 weeks of 60-min swimming sessions, and 5 days/week AET counteracts CH in obesity. Here, we evaluated the role of microRNAs and their target genes that are involved in heart collagen deposition and calcium signaling, as well as the cardiac remodeling induced by AET in obese Zucker rats. Among the four experimental Zucker groups: control lean rats (LZR), control obese rats (OZR), trained lean rats (LZR + TR), and trained obese rats (OZR + TR), heart weight was greater in the OZR than in the LZR group due to increased cardiac intramuscular fat and collagen. AET seems to exert a protective role in normalizing the heart weight in the OZR + TR group. Cardiac microRNA-29c expression was decreased in OZR compared with the LZR group, paralleled by an increase in the collagen volumetric fraction (CVF). MicroRNA-1 expression was upregulated while the expression of its target gene NCX1 was decreased in OZR compared with the LZR group. Interestingly, AET restored cardiac microRNA-1 to nonpathological levels in the OZR-TR group. Our findings suggest that AET could be used as a nonpharmacological therapy for the reversal of pathological cardiac remodeling and cardiac dysfunction in obesity. PMID- 29138673 TI - The Beneficial Effects of Quercetin, Curcumin, and Resveratrol in Obesity. AB - Over the past two decades, obesity has been one of the major public health concerns in most countries. In the search for new molecules that could be used for the treatment of obesity, good perspectives have been opened up for polyphenols, a class of natural bioactive phytochemicals. Experimental and limited clinical trial evidence supports that some polyphenols such as quercetin, curcumin, and resveratrol have potential benefit functions on obesity treatment. This brief review focuses on the main functions of the above-named polyphenols on adipose tissue. These polyphenols may play beneficial effects on adipose tissue under obese condition by alleviating intracellular oxidative stress, reducing chronic low-grade inflammation, inhibiting adipogenesis and lipogenesis, and suppressing the differentiation of preadipocytes to mature adipocytes. PMID- 29138675 TI - Benign Effect of Extremely Low-Frequency Electromagnetic Field on Brain Plasticity Assessed by Nitric Oxide Metabolism during Poststroke Rehabilitation. AB - Nitric oxide (NO) is one of the most important signal molecules, involved in both physiological and pathological processes. As a neurotransmitter in the central nervous system, NO regulates cerebral blood flow, neurogenesis, and synaptic plasticity. The aim of our study was to investigate the effect of the extremely low-frequency electromagnetic field (ELF-EMF) on generation and metabolism of NO, as a neurotransmitter, in the rehabilitation of poststroke patients. Forty-eight patients were divided into two groups: ELF-EMF and non-ELF-EMF. Both groups underwent the same 4-week rehabilitation program. Additionally, the ELF-EMF group was exposed to an extremely low-frequency electromagnetic field of 40 Hz, 7 mT, for 15 min/day. Levels of 3-nitrotyrosine, nitrate/nitrite, and TNFalpha in plasma samples were measured, and NOS2 expression was determined in whole blood samples. Functional status was evaluated before and after a series of treatments, using the Activity Daily Living, Geriatric Depression Scale, and Mini-Mental State Examination. We observed that application of ELF-EMF significantly increased 3-nitrotyrosine and nitrate/nitrite levels, while expression of NOS2 was insignificantly decreased in both groups. The results also show that ELF-EMF treatments improved functional and mental status. We conclude that ELF-EMF therapy is capable of promoting recovery in poststroke patients. PMID- 29138676 TI - Resveratrol Modulation of Protein Expression in parkin-Mutant Human Skin Fibroblasts: A Proteomic Approach. AB - In this study, we investigated by two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) analysis the effects of resveratrol treatment on skin primary fibroblasts from a healthy subject and from a parkin-mutant early onset Parkinson's disease patient. Parkin, an E3 ubiquitin ligase, is the most frequently mutated gene in hereditary Parkinson's disease. Functional alteration of parkin leads to impairment of the ubiquitin-proteasome system, resulting in the accumulation of misfolded or aggregated proteins accountable for the neurodegenerative process. The identification of proteins differentially expressed revealed that resveratrol treatment can act on deregulated specific biological process and molecular function such as cellular redox balance and protein homeostasis. In particular, resveratrol was highly effective at restoring the heat-shock protein network and the protein degradation systems. Moreover, resveratrol treatment led to a significant increase in GSH level, reduction of GSSG/GSH ratio, and decrease of reduced free thiol content in patient cells compared to normal fibroblasts. Thus, our findings provide an experimental evidence of the beneficial effects by which resveratrol could contribute to preserve the cellular homeostasis in parkin-mutant fibroblasts. PMID- 29138678 TI - Febuxostat Modulates MAPK/NF-kappaBp65/TNF-alpha Signaling in Cardiac Ischemia Reperfusion Injury. AB - Xanthine oxidase and xanthine dehydrogenase have been implicated in producing myocardial damage following reperfusion of an occluded coronary artery. We investigated and compared the effect of febuxostat and allopurinol in an experimental model of ischemia-reperfusion (IR) injury with a focus on the signaling pathways involved. Male Wistar rats were orally administered vehicle (CMC) once daily (sham and IR + control), febuxostat (10 mg/kg/day; FEB10 + IR), or allopurinol (100 mg/kg/day; ALL100 + IR) for 14 days. On the 15th day, the IR control and treatment groups were subjected to one-stage left anterior descending (LAD) coronary artery ligation for 45 minutes followed by a 60-minute reperfusion. Febuxostat and allopurinol pretreatment significantly improved cardiac function and maintained morphological alterations. They also attenuated oxidative stress and apoptosis by suppressing the expression of proapoptotic proteins (Bax and caspase-3), reducing TUNEL-positive cells, and increasing the level of antiapoptotic proteins (Bcl-2). The MAPK-based molecular mechanism revealed suppression of active JNK and p38 proteins concomitant with the rise in ERK1/ERK2, a prosurvival kinase. Additionally, a reduction in the level of inflammatory markers (TNF-alpha, IL-6, and NF-kappaB) was also observed. The changes observed with febuxostat were remarkable in comparison with those observed with allopurinol. Febuxostat protects relatively better against IR injury than allopurinol by suppressing inflammation and apoptosis mediating the MAPK/NF-kappaBp65/TNF-alpha pathway. PMID- 29138677 TI - Oxidative Stress in Hemodialysis Patients: A Review of the Literature. AB - Hemodialysis (HD) patients are at high risk for all-cause mortality and cardiovascular events. In addition to traditional risk factors, excessive oxidative stress (OS) and chronic inflammation emerge as novel and major contributors to accelerated atherosclerosis and elevated mortality. OS is defined as the imbalance between antioxidant defense mechanisms and oxidant products, the latter overwhelming the former. OS appears in early stages of chronic kidney disease (CKD), advances along with worsening of renal failure, and is further exacerbated by the HD process per se. HD patients manifest excessive OS status due to retention of a plethora of toxins, subsidized under uremia, nutrition lacking antioxidants and turn-over of antioxidants, loss of antioxidants during renal replacement therapy, and leukocyte activation that leads to accumulation of oxidative products. Duration of dialysis therapy, iron infusion, anemia, presence of central venous catheter, and bioincompatible dialyzers are several factors triggering the development of OS. Antioxidant supplementation may take an overall protective role, even at early stages of CKD, to halt the deterioration of kidney function and antagonize systemic inflammation. Unfortunately, clinical studies have not yielded unequivocal positive outcomes when antioxidants have been administered to hemodialysis patients, likely due to their heterogeneous clinical conditions and underlying risk profile. PMID- 29138680 TI - Enhancement of Antioxidant Mechanisms and Reduction of Oxidative Stress in Chickens after the Administration of Drinking Water Enriched with Polyphenolic Powder from Olive Mill Waste Waters. AB - The aim of the study was to examine the effects of a polyphenolic powder from olive mill wastewater (OMWW) administered through drinking water, on chickens' redox status. Thus, 75 chickens were divided into three groups. Group A was given just drinking water, while groups B and C were given drinking water containing 20 and 50 MUg/ml of polyphenols, respectively, for 45 days. The antioxidant effects of the polyphenolic powder were assessed by measuring oxidative stress biomarkers in blood after 25 and 45 days of treatment. These markers were total antioxidant capacity (TAC), protein carbonyls (CARB), thiobarbituric acid reactive species (TBARS) and superoxide dismutase activity (SOD) in plasma, and glutathione (GSH) and catalase activity in erythrocytes. The results showed that CARB and TBARS were decreased significantly in groups B and C, and SOD decreased in group B compared to that in group A. TAC was increased significantly in group C and GSH was increased in group B, while catalase activity was increased in groups B and C compared to that in group A. In conclusion, this is the first study showing that supplementation of chickens with polyphenols from OMWW through drinking water enhanced their antioxidant mechanisms and reduced oxidative stress-induced damage. PMID- 29138679 TI - Modulatory Mechanism of Polyphenols and Nrf2 Signaling Pathway in LPS Challenged Pregnancy Disorders. AB - Early embryonic loss and adverse birth outcomes are the major reproductive disorders that affect both human and animals. The LPS induces inflammation by interacting with robust cellular mechanism which was considered as a plethora of numerous reproductive disorders such as fetal resorption, preterm birth, teratogenicity, intrauterine growth restriction, abortion, neural tube defects, fetal demise, and skeletal development retardation. LPS-triggered overproduction of free radicals leads to oxidative stress which mediates inflammation via stimulation of NF-kappaB and PPARgamma transcription factors. Flavonoids, which exist in copious amounts in nature, possess a wide array of functions; their supplementation during pregnancy activates Nrf2 signaling pathway which encounters pregnancy disorders. It was further presumed that the development of strong antioxidant uterine environment during gestation can alleviate diseases which appear at adult stages. The purpose of this review is to focus on modulatory properties of flavonoids on oxidative stress-mediated pregnancy insult and abnormal outcomes and role of Nrf2 activation in pregnancy disorders. These findings would be helpful for providing new insights in ameliorating oxidative stress-induced pregnancy disorders. PMID- 29138681 TI - Cell Signaling with Extracellular Thioredoxin and Thioredoxin-Like Proteins: Insight into Their Mechanisms of Action. AB - Thioredoxins are small thiol-oxidoreductase enzymes that control cellular redox homeostasis. Paradoxically, human thioredoxin (TXN1) was first identified as the adult T cell leukemia-derived factor (ADF), a secreted protein. ADF has been implicated in a wide variety of cell-to-cell communication systems acting as a cytokine or a chemokine. TRX80 is a truncated TXN1 protein with cytokine activity. The unconventional secretion mechanism of these extracellular thioredoxins is unknown. The thioredoxin system is relying on glucose metabolism through the pentose phosphate pathway that provides reducing power in the form of NADPH, the cofactor of thioredoxin reductase (TXNRD). While a complete extracellular TXN system is present in the blood in the form of circulating TXN1 and TXNDR1, the source of extracellular NADPH remains a mystery. In the absence of redox regenerating capacity, extracellular thioredoxins may rather be prooxidant agents. Rod-derived cone viability factor (RdCVF) is the product of intron retention of the nucleoredoxin-like 1 (NXNL1) gene, a secreted truncated thioredoxin-like protein. The other product encoded by the gene, RdCVFL, is an enzymatically active thioredoxin. This is a very singular example of positive feedback of a superthioredoxin system encoded by a single gene likely emerging during evolution from metabolic constraints on redox signaling. PMID- 29138684 TI - Know your patients' history; spleno-renal infarction as a presentation of infective endocarditis. PMID- 29138682 TI - miR-128 Is Implicated in Stress Responses by Targeting MAFG in Skeletal Muscle Cells. AB - MAFG (v-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog G) is a bZIP type transcriptional regulator that belongs to the small MAF (sMAFs) protein family. By interacting with other bZIP transcription factors, sMAFs can form homo and heterodimers governing either repressive or activating transcriptional functions. As heterodimeric partner of Nrf2, MAFG positively influences the ARE dependent antioxidant/xenobiotic pathways, at least in condition of a correct MAFG:Nrf2 balance. MicroRNAs (miRs) participate to different regulatory networks being involved as fine-tuning regulators of gene expression. However, the connections between cellular surveillance to stresses mediated by MAFG:Nrf2 and miR regulations are not well understood. Here, we explored the impact of miR-128 in expression of genes related to stress response. Bioinformatic predictions coupled with functional analysis revealed the presence of miR-128 binding site in the 3'UTR of MAFG. Ectopic miR-128 expression correlated with reduced expression of endogenous MAFG-dependent genes and negatively affected ARE-mediated molecular phenotype based on Nrf2 activity. Indeed, miR-128 impairs redox-dependent pathways induced in response to oxidative stress. Moreover, in condition of hypoxia, MAFG induction correlated with reduced levels of miR-128. This lead to increased mRNA levels of HMOX-1 and x-CT for blunting stress. Overall, these findings identify MAFG as novel direct target of miR-128. PMID- 29138683 TI - The Evaluation of Oxidative Stress Parameters in Serum Patients with Relapsing Remitting Multiple Sclerosis Treated with II-Line Immunomodulatory Therapy. AB - Objectives: The assessment of oxidative stress (OS) in serum relapsing-remitting multiple sclerosis patients treated with II-line immunomodulatory therapy (fingolimod, natalizumab) compared to newly diagnosed patients (de novo group) treated with interferon (IFN) beta and controls. The relationship between OS parameters and gender, age, disease duration, Expanded Disability Status Scale, annualized relapse rate, MRI lesions in patients treated with II-line. Materials and Methods: One hundred and twenty-one patients with RRMS were enrolled in the study. Patients were divided into groups: de novo group, IFN, fingolimod (FG), natalizumab (NT), and controls. Lipid hydroperoxides (LHP), malondialdehyde (MDA), lipofuscin (LPS), and total oxidative status (TOS) were determined. Results: LHP, MDA, and TOS were lower in NT and FG groups compared to the de novo group. Levels of OS were different between NT and FG patients and the IFN group. Women treated with FG and NT had lower MDA, LPH, and TOS than women who were not treated while in men only LPH was lowered. Positive correlations were found between MDA, LHP, TOS, and ARR in the NT group. Conclusion: The II-line immunomodulatory treatment decreased OS particularly among women. No difference in OS levels was observed between II-line therapy and IFN beta. PMID- 29138685 TI - Paraneoplastic edematous dermatomyositis: A rare syndrome observed in a case of small cell lung cancer. PMID- 29138686 TI - Insights into the pathogenesis and clinicopathological spectrum of oral vegetable granuloma. Case series with literature review. PMID- 29138687 TI - Analysis of the Biceps Brachii Muscle by Varying the Arm Movement Level and Load Resistance Band. AB - Biceps brachii muscle illness is one of the common physical disabilities that requires rehabilitation exercises in order to build up the strength of the muscle after surgery. It is also important to monitor the condition of the muscle during the rehabilitation exercise through electromyography (EMG) signals. The purpose of this study was to analyse and investigate the selection of the best mother wavelet (MWT) function and depth of the decomposition level in the wavelet denoising EMG signals through the discrete wavelet transform (DWT) method at each decomposition level. In this experimental work, six healthy subjects comprised of males and females (26 +/- 3.0 years and BMI of 22 +/- 2.0) were selected as a reference for persons with the illness. The experiment was conducted for three sets of resistance band loads, namely, 5 kg, 9 kg, and 16 kg, as a force during the biceps brachii muscle contraction. Each subject was required to perform three levels of the arm angle positions (30 degrees , 90 degrees , and 150 degrees ) for each set of resistance band load. The experimental results showed that the Daubechies5 (db5) was the most appropriate DWT method together with a 6-level decomposition with a soft heursure threshold for the biceps brachii EMG signal analysis. PMID- 29138688 TI - Effect on Chest Deformation of Simultaneous Correction of Pectus Excavatum with Scoliosis. AB - Objective: This paper is to understand the effect of simultaneous correction of pectus excavatum with scoliosis and to provide some useful information for clinical orthopedic surgery design. Methods: The method of a three-dimensional reconstruction has been used to the reconstruction of the chest model of pectus excavatum with scoliosis, and the numerical stimulation has been conducted to the process of minimally invasive correction. Three kinds of correction methods have been considered in the numerical simulation, stretch spine, stretch spine and minimally invasive correction at the same time, and release stretch spine after stretch spine and minimally invasive correction of pectus excavatum at the same time. Results: It is found that stretch spine may help to correction of scoliosis but aggravate the sternum collapse, and release stretch spine after stretch spine and minimally invasive correction at the same time could not only be good at scoliosis but also improve the collapse of the sternum, which could help to improve the heartbeat and breath of the patients. Conclusion: Among the three kinds of correction methods, release stretch spine after stretch spine and minimally invasive correction at the same time could help to improve both the scoliosis and the collapse of the sternum. PMID- 29138689 TI - Clarifying sub-genomic positions of QTLs for flowering habit and fruit quality in U.S. strawberry (Fragaria*ananassa) breeding populations using pedigree-based QTL analysis. AB - The cultivated strawberry (Fragaria*ananassa) is consumed worldwide for its flavor and nutritional benefits. Genetic analysis of commercially important traits in strawberry are important for the development of breeding methods and tools for this species. Although several quantitative trait loci (QTL) have been previously detected for fruit quality and flowering traits using low-density genetic maps, clarity on the sub-genomic locations of these QTLs was missing. Recent discoveries in allo-octoploid strawberry genomics led to the development of the IStraw90 single-nucleotide polymorphism (SNP) array, enabling high-density genetic maps and finer resolution QTL analysis. In this study, breeder-specified traits were evaluated in the Eastern (Michigan) and Western (Oregon) United States for a common set of breeding populations during 2 years. Several QTLs were validated for soluble solids content (SSC), fruit weight (FWT), pH and titratable acidity (TA) using a pedigree-based QTL analysis approach. For fruit quality, a QTL for SSC on linkage group (LG) 6A, a QTL for FWT on LG 2BII, a QTL for pH on LG 4CII and two QTLs for TA on LGs 2A and 5B were detected. In addition, a large effect QTL for flowering was detected at the distal end of LG 4A, coinciding with the FaPFRU locus. Marker haplotype analysis in the FaPFRU region indicated that the homozygous recessive genotype was highly predictive of seasonal flowering. SNP probes in the FaPFRU region may help facilitate marker-assisted selection for this trait. PMID- 29138690 TI - Factor XI gene variants in factor XI-deficient patients of Southern Italy: identification of a novel mutation and genotype-phenotype relationship. AB - Congenital Factor XI (FXI) deficiency shows a high variability in clinical phenotype. To date, many allele variants have been shown to cause this bleeding disorder. However, the genotype-phenotype relationship is difficult to establish. This report provides insights into this bleeding disorder. Sixteen unrelated Italian index cases with congenital FXI deficiency and their relatives were investigated. After the identification of the deficiency, we obtained DNA from each subject and analyzed the FXI gene using direct sequencing. We identified 5 and 11 individuals with severe and moderate deficiency of FXI activity, respectively. Most patients (8/16) carried mutations in the Apple 2 domain and 4 patients showed c.403G>T (p.Glu135*; type II mutation). Four novel compound heterozygosities were identified. Bleeding symptoms were present in two severely deficient subjects carrying the combinations c.901T>C (p.Phe301Leu)/c.1556G>A (p.Trp519*) and c.943G>A (p.Glu315)/c.1556G>A (p.Trp519*), respectively. Bleeding episodes were also observed in the presence of a moderate deficiency in two individuals heterozygous for c.449C>T (p.Thr150Met) and c.1253G>T (p.Gly418Val), respectively. One novel mutation, c.1682C>A (p.Ala561Asp), was identified as potentially deleterious in an asymptomatic individual. We confirm an unclear prediction of phenotype from mutational data. The FXI levels should be coupled with FXI analysis for a more comprehensive prediction of the bleeding phenotype in FXI deficiency. PMID- 29138691 TI - A novel DARS2 mutation in a Japanese patient with leukoencephalopathy with brainstem and spinal cord involvement but no lactate elevation. AB - The mitochondrial aspartyl-tRNA synthetase 2 gene (DARS2) is responsible for leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). A Japanese patient with LBSL showed compound heterozygous DARS2 mutations c.358_359delinsTC (p.Gly120Ser) and c.228-15C>G (splicing error). This provides further evidence that most patients with LBSL show compound heterozygous mutations in DARS2 in association with a common splicing mutation in the splicing acceptor site of intron 2. PMID- 29138693 TI - Investigations on the Occurrence and Associated Risk Factors of Avian Coccidiosis in Osun State, Southwestern Nigeria. AB - Avian coccidiosis is one of the most important diseases of poultry and it is responsible for a large number of poultry mortalities worldwide. This study was carried out to investigate the occurrence and associated risk factors of avian coccidiosis in Osun State, Nigeria. Fecal samples were collected and examined from 5,544 avian species that were brought for treatment at the state veterinary hospitals over a 10-year period. Parameters such as age, sex, season, and species of birds were determined. Also, the months of the year were taken into consideration. Overall prevalence of 41.3% was recorded. The year specific rate for avian coccidiosis was highest in 2007 (97.9%) and lowest in 2006 (0.4%), while the month-specific rate was highest in November (85.7%) and lowest in July 2006 (13.3%). There was a significantly (P < 0.05) higher prevalence in young birds compared to adults, in males compared to females, and during the wet season compared to the dry season. Broilers (99.8%) and cockerels (81.0%) were the bird types with the highest prevalence rate. The high prevalence of avian coccidiosis in the study area shows that the disease is endemic and there is need to embark on a radical preventive measure to curtail the disease. PMID- 29138692 TI - Transcriptomics-driven lipidomics (TDL) identifies the microbiome-regulated targets of ileal lipid metabolism. AB - The gut microbiome and lipid metabolism are both recognized as essential components in the maintenance of metabolic health. The mechanisms involved are multifactorial and (especially for microbiome) poorly defined. A strategic approach to investigate the complexity of the microbial influence on lipid metabolism would facilitate determination of relevant molecular mechanisms for microbiome-targeted therapeutics. E. coli is associated with obesity and metabolic syndrome and we used this association in conjunction with gnotobiotic models to investigate the impact of E. coli on lipid metabolism. To address the complexities of the integration of the microbiome and lipid metabolism, we developed transcriptomics-driven lipidomics (TDL) to predict the impact of E. coli colonization on lipid metabolism and established mediators of inflammation and insulin resistance including arachidonic acid metabolism, alterations in bile acids and dietary lipid absorption. A microbiome-related therapeutic approach targeting these mechanisms may therefore provide a therapeutic avenue supporting maintenance of metabolic health. PMID- 29138694 TI - Impact of Topically Administered Steroids, Antibiotics, and Sodium Hyaluronate on Bleb-Related Infection Onset: The Japan Glaucoma Society Survey of Bleb-Related Infection Report 4. AB - Purpose: To investigate the impact of topically administered ophthalmic medications on the onset and severity of bleb-related infections. Methods: Data obtained from 104 eyes of 104 patients with bleb-related infections were analyzed. We assigned an infection stage to each eye (stage 1-4) and analyzed the onset severity. Results: Steroids and antibiotics were routinely administered to 13 (12.5%) and 42 (40.4%) eyes, respectively. The median stage of steroid administered eyes was 3 versus 1 for eyes without steroid administration (P = 0.012). The median duration from surgery to infection for the steroid administered eyes was 2.0 years versus 5.8 years for eyes without steroid administration (P = 0.030). The median duration from surgery to infection for the antibiotic-administered eyes was 6.4 years versus 3.9 years for eyes without antibiotic administration (P = 0.025). Multiple logistic regression analysis revealed that infections were severe in the steroid-administered eyes (odds ratio: 4.57). No infections developed within 16 weeks postoperatively. No relationship was detected between sodium hyaluronate and the analyzed factors. Conclusions: Topical steroid administration beyond the immediate postoperative period may affect severe and earlier onset bleb-related infections. Conversely, topical antibiotic administration may be effective in suppressing earlier onset bleb-related infections. PMID- 29138695 TI - Risk Factors of Malignant Glaucoma Occurrence after Glaucoma Surgery. AB - Purpose: The aim of this study was twofold: first, to evaluate the predisposing factors for occurrence of malignant glaucoma and second, to compare frequency of malignant glaucoma depending on the type of primary glaucoma surgery. Methods: Retrospective analysis was performed in 1689 consecutive patients who underwent glaucoma surgery alone or combined with phacoemulsification. Data collected included the type of surgery, width of the filtration angle, presence or absence of malignant glaucoma in the postoperative period, and time from the primary surgery to malignant glaucoma occurrence. Results: Malignant glaucoma occurred in 22 eyes that amounted to 1.3% of cases among all surgery performed. Mean time from glaucoma surgery to malignant glaucoma occurrence was 61.4 +/- 190.5 days. Among patients with penetrating surgery, malignant glaucoma occurred in 2.3% of patients, whereas after nonpenetrating operations, such complication was not found (p = 0.00004). Malignant glaucoma occurred more often in patients with shallow iridocorneal angle (p = 0.0013). Conclusions: The risk of malignant glaucoma development is associated with penetrating characteristic of glaucoma surgery, after which this complication appears and its occurrence is higher in eyes with shallow iridocorneal angle. The risk of malignant glaucoma after trabeculectomy compared to iridencleisis as well as after phacotrabeculectomy compared to phacoiridencleisis is equivalent. PMID- 29138696 TI - Use of Common Inflammatory Markers in the Long-Term Screening of Total Hip Arthroprosthesis Infections: Our Experience. AB - Orthopedic implants have become essential components of modern medicine. The risk of infection of total hip arthroplasty (THA) is 1.5%-2%. Are the C-reactive protein (CRP), the erythrocyte sedimentation rate (ESR), and procalcitonin (PCT) good markers for THA infection screenings? From February 2009 to December 2012 at our Department of Orthopedics and Traumatology, 1248 patients were treated with THA. No prosthesis was cemented. All patients received antibiotic prophylaxis. All patients were discharged approximately 7.4 days after surgery with this clinical and radiographic follow-up program at 15 days and 1, 3, 6, 12, 24, and 36 months after surgery. Blood samples to determine ESR, CRP, and PCT values were taken at 1 hour before surgery and 15 days and 1, 3, 6, 12, 24, and 36 months after surgery. During follow-ups there were 22 cases of THA infections; according the Widmer classification, infections are hematogenous ones in 16 cases, late chronic ones in 5 cases, and early postoperative ones in 1 case. In all cases the three markers were considered positive; in 6 cases there were no radiological signs of septic loosening. ESR, CRP, and PCT proved to have a greater diagnostic accuracy than X-rays in predicting late chronic and early postoperative infections. These markers are valuable support for the surgeon in monitoring the prosthetic implant lifespan. PMID- 29138697 TI - Following Spinal Cord Injury Transected Reticulospinal Tract Axons Develop New Collateral Inputs to Spinal Interneurons in Parallel with Locomotor Recovery. AB - The reticulospinal tract (RtST) descends from the reticular formation and terminates in the spinal cord. The RtST drives the initiation of locomotion and postural control. RtST axons form new contacts with propriospinal interneurons (PrINs) after incomplete spinal cord injury (SCI); however, it is unclear if injured or uninjured axons make these connections. We completely transected all traced RtST axons in rats using a staggered model, where a hemisection SCI at vertebra T10 is followed by a contralateral hemisection at vertebra T7. In one group of the animals, the T7 SCI was performed 2 weeks after the T10 SCI (delayed; dSTAG), and in another group, the T10 and T7 SCIs were concomitant (cSTAG). dSTAG animals had significantly more RtST-PrIN contacts in the grey matter compared to cSTAG animals (p < 0.05). These results were accompanied by enhanced locomotor recovery with dSTAG animals significantly outperforming cSTAG animals (BBB test; p < 0.05). This difference suggests that activity in neuronal networks below the first SCI may contribute to enhanced recovery, because dSTAG rats recovered locomotor ability before the second hemisection. In conclusion, our findings support the hypothesis that the injured RtST forms new connections and is a key player in the recovery of locomotion post-SCI. PMID- 29138698 TI - Soluble Epoxide Hydrolase Inhibitor and 14,15-Epoxyeicosatrienoic Acid Facilitated Long-Term Potentiation through cAMP and CaMKII in the Hippocampus. AB - Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid and metabolized by soluble epoxide hydrolase (sEH). The role of EETs in synaptic function in the central nervous system is still largely unknown. We found that pharmacological inhibition of sEH to stabilize endogenous EETs and exogenous 14,15-EET significantly increased the field excitatory postsynaptic potential (fEPSP) response in the CA1 area of the hippocampus, while additionally enhancing high-frequency stimulation- (HFS-) induced long-term potentiation (LTP) and forskolin- (FSK-) induced LTP. sEH inhibitor (sEHI) N-[1-(oxopropyl)-4 piperidinyl]-N'-[4-(trifluoromethoxy) phenyl)-urea (TPPU) and exogenous 14,15-EET increased HFS-LTP, which could be blocked by an N-methyl-D-aspartate (NMDA) receptor subunit NR2B antagonist. TPPU- or 14,15-EET-facilitated FSK-mediated LTP can be potentiated by an A1 adenosine receptor antagonist and a phosphodiesterase inhibitor, but is prevented by a cAMP-dependent protein kinase (PKA) inhibitor. sEHI and 14,15-EET upregulated the activation of extracellular signal-regulated kinases (ERKs) and Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII). Phosphorylation of synaptic receptors NR2B and alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor subunit GluR1 was increased by TPPU and 14,15-EET administration. These results indicated that EETs increased NMDAR- and FSK-mediated synaptic potentiation via the AC-cAMP-PKA signaling cascade and upregulated the ERKs and CaMKII, resulting in increased phosphorylation of NR2B and GluR1 in the hippocampus. PMID- 29138700 TI - Retroperitoneal Solitary Fibrous Tumor: A "Patternless" Tumor. AB - Introduction: Solitary fibrous tumor is a rare type of mesenchymal, spindle-cell tumor reported mostly in the pleura. Retroperitoneal occurrence is rare and histopathological diagnosis is challenging. Case Presentation: A 55-year-old woman with nonspecific abdominal pain was found to have a retroperitoneal/pelvic mass adjacent to the upper rectum. The patient underwent surgical resection in clear margins of this pelvic tumor, entering the total mesenteric excision surgical plane. Final histopathology revealed a solitary fibrous tumor and the case is presented herein. Discussion: Solitary fibrous tumor in the retroperitoneum is rarely found in the literature and to the best of our knowledge less than a hundred cases are described so far. Histopathological diagnosis is mostly based on a "patternless pattern" on microscopic examination, which is a storiform arrangement of spindle cells combined with a "hemangiopericytoma-like appearance" and increased vascularity of the lesion. Surgery is the mainstay of treatment and recurrence rates are generally low. PMID- 29138699 TI - For Better or Worse: The Effect of Prismatic Adaptation on Auditory Neglect. AB - Patients with auditory neglect attend less to auditory stimuli on their left and/or make systematic directional errors when indicating sound positions. Rightward prismatic adaptation (R-PA) was repeatedly shown to alleviate symptoms of visuospatial neglect and once to restore partially spatial bias in dichotic listening. It is currently unknown whether R-PA affects only this ear-related symptom or also other aspects of auditory neglect. We have investigated the effect of R-PA on left ear extinction in dichotic listening, space-related inattention assessed by diotic listening, and directional errors in auditory localization in patients with auditory neglect. The most striking effect of R-PA was the alleviation of left ear extinction in dichotic listening, which occurred in half of the patients with initial deficit. In contrast to nonresponders, their lesions spared the right dorsal attentional system and posterior temporal cortex. The beneficial effect of R-PA on an ear-related performance contrasted with detrimental effects on diotic listening and auditory localization. The former can be parsimoniously explained by the SHD-VAS model (shift in hemispheric dominance within the ventral attentional system; Clarke and Crottaz-Herbette 2016), which is based on the R-PA-induced shift of the right-dominant ventral attentional system to the left hemisphere. The negative effects in space-related tasks may be due to the complex nature of auditory space encoding at a cortical level. PMID- 29138701 TI - Valsalva-Related Subretinal Hemorrhage as a Presenting Symptom of Polypoidal Choroidal Vasculopathy. AB - Purpose: To describe a case of Valsalva-related subretinal hemorrhage as a presenting symptom of polypoidal choroidal vasculopathy (PCV). The patient refrained from treatment against our best advice, and thus this is also a rare case of the natural course of an untreated PCV. Methods: Case report. Results: A 66-year-old female with a respiratory infection coughed intensely until exhaustion, after which she developed visual symptoms on the right eye. Primary care ophthalmologist examined the patient on the same day of the onset of symptoms and referred her to our tertiary medical retinal service for detailed retinal diagnosis including fluorescein and indocyanine green angiography. The right eye had a large subretinal hemorrhage and pigment epithelium detachment in the lower temporal arcade with foveal involvement. Against our best advice, the patient refused treatment. In the following 9 months, the BCVA decreased from 68 to 55 ETDRS letters, the subretinal hemorrhage almost regressed, pigment epithelium detachments persisted, and macular edema, intraretinal cysts, and subretinal fibrosis developed. Conclusions: Although classic Valsalva retinopathy with preretinal hemorrhage in most cases can be managed by careful observation and no treatment, this case demonstrates that Valsalva-related subretinal hemorrhage needs different attention and approach. PMID- 29138702 TI - A Case of C5 Vertebral Chordoma in a 73-Year-Old Patient with More Than 8 Years of Follow-Up after Total Piecemeal Spondylectomy. AB - Chordoma arising from the cervical spine is rare and the traditional long-term prognosis is typically poor. Total en bloc spondylectomy with a wide margin is generally accepted to be the most appropriate management for thoracic and lumbar malignant tumors. However, this method is still challenging for the cervical spine because of the proximity of the tumor to the vertebral arteries and neural elements. Here, we report a 73-year-old man with a C5 vertebral chordoma treated with total piecemeal spondylectomy. Histological examination revealed pathognomonic physaliphorous cells with mucus-filled cytoplasm in the tumor, and the ratio of Ki-67-positive cells within the tumor was high (19.0%), showing active proliferation rate. Local recurrences were found at 9 months, 4 years and 2 months, and 6 years after the initial surgery. All the recurrences were encapsulated and isolated and treated with an additional en bloc resection successfully at each stage. Eight years after the initial total piecemeal spondylectomy, the patient maintained his intact neurological status without local recurrence or metastasis. The prognosis of cervical chordoma depends on the patient's age, surgical procedures, and histological features. In this report, we present that piecemeal spondylectomy is an alternative management for aged patients with cervical chordoma, even for those with high MIB-1 index. PMID- 29138703 TI - Malignant Peripheral Nerve Sheath Tumor of the Inguinum and Angiosarcoma of the Scalp in a Child with Neurofibromatosis Type 1. AB - Benign and malignant tumors are common in the setting of neurofibromatosis type 1 (NF1). Malignant peripheral nerve sheath tumor (MPNST) and angiosarcoma are rare tumors in children and adolescents and mostly occur in young patients in relation to NF1. Both histological types can be present in the same tumor mass in patients with NF1. We present a case of 12.5-year-old girl with NF1 who first presented with MPNST of the right inguinal region and 1.5 years later with unrelated angiosarcoma of the scalp. PMID- 29138704 TI - Caudal Regression and Encephalocele: Rare Manifestations of Expanded Goldenhar Complex. AB - Oculoauriculovertebral spectrum, or Goldenhar Syndrome, is a condition characterized by variable degrees of uni- or bilateral involvement of craniofacial structures, ocular anomalies, and vertebral defects. Its expressivity is variable; therefore, the term "expanded Goldenhar complex" has been coined. The Goldenhar Syndrome usually involves anomalies in craniofacial structures, but it is known that nervous system anomalies, including encephalocele or caudal regression, may, rarely, occur in this condition. We report two rare cases of infants affected by Goldenhar Syndrome, associated with neural tube defects, specifically caudal regression syndrome and nasal encephaloceles, to underline the extremely complex and heterogeneous clinical features of this oculoauriculovertebral spectrum. These additional particular cases could increase the number of new variable spectrums to be included in the "expanded Goldenhar complex." PMID- 29138705 TI - Physiotherapy and Rehabilitation in a Child with Joubert Syndrome. AB - Objective: Joubert syndrome (JS) is a rare autosomal recessive genetic disorder characterized by brain malformation, hypotonia, breathing abnormalities, ataxia, oculomotor apraxia, and developmental delay. The purpose of this study was to report the efficiency of the physiotherapy and rehabilitation program in a child with JS. Materials and Methods: Our case is a 19-month-old female child with mild clinical signs of JS. The pretreatment and posttreatment motor functioning level of the case was evaluated through the Gross Motor Function Measure (GMFM), whereas the independence level was evaluated through the Pediatric Functional Independence Measure (WeeFIM). The case was included in the rehabilitation program by the physiotherapist for one hour for five days a week throughout the period of 13 months in accordance with the neurodevelopmental treatment principles. Results: The case was able to turn around from the supine position to the reverse direction by oneself, and she was able to rise on her forearms facedown and was able to sit, crawl, and walk independently. The GMFM score was 210, whereas WeeFIM score was 65. Discussion: In the direction of those findings, in Joubert Syndrome, physiotherapy and rehabilitation can be effective in coping with the symptoms causing developmental delay. PMID- 29138706 TI - Radiological Diagnosis of a Rare Premature Aging Genetic Disorder: Progeria (Hutchinson-Gilford Syndrome). AB - Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare disease with a combination of short stature, bone abnormalities, premature ageing, and skin changes. Though the physical appearance of these patients is characteristic, there is little emphasis on the characteristic radiological features. In this paper, we report a 16-year-old boy with clinical and radiological features of this rare genetic disorder. He had a characteristic facial appearance with a large head, large eyes, thin nose with beaked tip, small chin, protruding ears, prominent scalp veins, and absence of hair. PMID- 29138707 TI - Jejunojejunal Intussusception due to Metastatic Melanoma Seven Years after the Primer. AB - Intestinal intussusception in adults is a rare medical condition accounting for less than 5% of all intussusceptions. Herein we present a 45-year-old patient with a history of abdominal pain and loss of weight. CT scan revealed jejunojejunal intussusceptions. The patient was subjected to exploratory operation and small intestine resection due to a mass causing intestinal intussusception. Pathology confirmed suspected diagnosis of metastatic melanoma to small intestine secondary to melanoma, 7 years after the initial manifestation. Postoperative evaluation with 18FDG-PET/CT revealed increased uptake in the thyroid gland. Subsequent total thyroidectomy revealed severe Hashimoto thyroiditis and no signs of metastasis. The patient received adjuvant immunotherapy and is healthy with no signs of recurrence 3 years after the initial diagnosis and treatment. PMID- 29138708 TI - Chondroma of the Bladder: An Atypical Localization. AB - Chondroma is a benign tumour of mesenchymal origin that is composed of cartilage and rarely located in soft tissues, being described so far only in four cases, as located in the bladder, according to our knowledge. We describe the fifth case of a 67-year-old woman who consulted for microscopic haematuria, with an endoscopic finding of submucosal nodular image in the anterior wall of the bladder, which after resection and the histologic study shows cartilage and fibroconnective tissue, in part hyalinised, and positive immunohistochemical staining of cells with vimentin and S-100; this fact can support the diagnosis of bladder chondroma. PMID- 29138709 TI - Asymptomatic Bacteriuria in Pregnant Women in Outpatient Facilities. AB - Urinary tract morbidity has increased by 7% in Kazakhstan between 2007 to 2011. Pregnant women with extragenital pathologies or kidney diseases had the greatest prevalence of morbidity. Asymptomatic bacteriuria (AB) is one of the most important risk factors of pyelonephritis development in pregnant women, and it can affect the course and outcome of pregnancy, delivery, and postnatal period. AB prevention requires prevention of pregnancy complications including early diagnostic of urinary tract infections, timely optimization of therapy at outpatient facilities, and dynamic follow-up. PMID- 29138710 TI - Studies of Health Effects from Nuclear Testing near the Semipalatinsk Nuclear Test Site, Kazakhstan. AB - The nuclear bomb testing conducted at the Semipalatinsk nuclear test site in Kazakhstan is of great importance for today's radiation protection research, particularly in the area of low dose exposures. This type of radiation is of particular interest due to the lack of research in this field and how it impacts population health. In order to understand the possible health effects of nuclear bomb testing, it is important to determine what studies have been conducted on the effects of low dose exposure and dosimetry, and evaluate new epidemiologic data and biological material collected from populations living in proximity to the test site. With time, new epidemiological data has been made available, and it is possible that these data may be linked to biological samples. Next to linking existing and newly available data to examine health effects, the existing dosimetry system needs to be expanded and further developed to include residential areas, which have not yet been taken into account. The aim of this paper is to provide an overview of previous studies evaluating the health effects of nuclear testing, including some information on dosimetry efforts, and pointing out directions for future epidemiologic studies. PMID- 29138711 TI - Prevalence of hypertension and associated factors in Jalalabad City, Nangarhar Province, Afghanistan. AB - Background: Hypertension affects an estimated one billion people, worldwide. It is a public health challenge characterized by increased morbidity, mortality, as well as cost to the community and health systems. The goal of this study is to determine the prevalence of hypertension and characterize associated risk factors in an urban setting in Afghanistan. Methods: A cross-sectional study of adults aged 25-65 years was conducted in Jalalabad city from May to June 2013 using the World Health Organization STEPwise approach to surveillance (WHO STEPS). A multistage technique was used to enroll 1,200 participants in the study. Demographic and socio-economic variables were collected via individual interviews using the WHO STEPS survey, after which blood samples were collected using a locally developed standard operating procedure (SOP). Bivariate and multivariable analyses were performed to explore the association between hypertension and associated factors. Results: A total of 1,180 adults (40% males, 60% females) of 25-65 years of age were surveyed. The response rate was 98.5 % and the prevalence of hypertension was 28.4. Independent risk factors of hypertension were found to be: age >= 50 (AOR = 3.42, 95% CI: 2.50 - 4.76); sex (AOR = 0.58, 95% CI: 0.38 - 0.88); obesity (AOR = 2.1, 95% CI 1.49 - 2.94); and diabetes (AOR = 1.75, 95% CI: 1.10 - 2.79). Independent protective factors were physically demanding occupations (AOR = 0.55, 95% CI: 0.36 - 0.85); physical activity itself (AOR = 0.69, 95% CI: 0.47 - 0.99) and consuming more vegetables (AOR = 0.59, 95% CI: 0.38 - 0.93). Conclusion: This urban setting in Afghanistan evidenced a high prevalence of hypertension; age, obesity, and diabetes were identified as risk factors and physical activity and consuming more vegetables were protective. These findings have implications for future public health intervention and clinical efforts. PMID- 29138712 TI - Prevalence of Psychiatric Disorders among the Rural Geriatric Population: A Pilot Study in Karnataka, India. AB - Background: Increasing life expectancy around the world, an outstanding achievement of our century, has brought with it new public health challenges. India is the second most populous country in the world, with over 72 million inhabitants above 60 years of age as of 2001. The life expectancy in India increased from 32 years in 1947 to over 66 years in 2010, with 8.0% of the population now reaching over 60 years of age. Few studies in India target the health, especially mental health, of this geriatric population. This study aims to estimate the current prevalence of psychiatric disorders in the geriatric population of the rural area of Singanodi,Karnataka, India. Methods: This cross sectional, epidemiological, community-based study was conducted in a rural health training area of Singanodi, Raichur District, Karnataka, India.The General Health Questionnaire-12, Mini Mental State Examination, and Geriatric Depression Scale were administered to 366 participants. Chi square tests with Yates correction were utilized for statistical analysis using SPSS 19.0 software. Results: We found that 33.9% of the geriatric population in the selected province were above the threshold for mental illness based on the GHQ-12 questionnaire. Females had a higher prevalence of mental disorder at 77.6% (152 out of 196) as compared to males who had a prevalence of 42.4% (72 out of 170). The most common psychiatric disorder was depression (21.9%), and generalized anxiety was present in 10.7% of the study population. Prevalence of cognitive impairment was 16.3%, with a significantly higher percentage of affected individuals in 80+ age group. Conclusion: Mental disorders are common among elderly people, but they are not well documented in rural India. The assessment of psychiatric disorder prevalence will help strengthen psycho-geriatric services and thus improve the quality of life of the elderly. A system that ensures comprehensive health care will have to be developed for this purpose as part of our future efforts. PMID- 29138713 TI - One Health and Zoonoses: The Evolution of One Health and Incorporation of Zoonoses. AB - Introduction: Zoonotic disease outbreaks have surged in the last two decades. These include severe acute respiratory syndrome (SARS), Hendra virus, Nipah virus, influenza viruses, Middle East Respiratory Syndrome (MERS) coronavirus, and ebola. One Health is the initiative of an inclusive collaboration linking human, animal, and environmental health. One Health is advocated through an intersectoral coordination to combat zoonoses, and the term has evolved over centuries. The primary aim of this literature review was to examine the change in the definition of the term One Health over time, particuarly following the the introduction of the latest definition in 2007 by the American Medical Association and the American Veterinary Medical Association. Methods: This review was conducted in four phases. The first phase consisted of a general PubMed search for the phrase "One Health" for every literature published up to December 2014. Then an advanced search was carried out using "One Health" in conjunction with the terms "zoonosis" and "zoonoses" in PubMed for the time period between January 2007 and December 2014. The articles found were then categorized based on the type of journals in which the articles were published. For the second phase, "One Health" was searched as a Medical subject heading (MeSH) term, which is the National Library of Medicine controlled vocabulary thesaurus used for indexing articles. In the third phase, One Health advocate organizations were found using Google search engine. During the final phase, One Health was searched in Google scholar, examined by Google trends, and analyzed by Google ngram. Results: Before 2007, One Health had many connotations to health in the medical literature with an incomplete adherence to the usage of One Health linking zoonoses. The Google trends analysis shows an overal steady increase of the search of One Health from 2007 to 2014, which is consistent with the findings of articles from Pubmed. Discussion: Our results indicate that the linkage between the terms One Health and zoonoses started in 2007, which correlates with the joint declaration made by the American Medical Association and the American Veterinary Medical Association in 2007. We suggest creating a MeSH term for One Health in the PubMed database to support more specific research on zoonoses, and exploring the possibility of a patent of the term One Health to support global health and evidence based public health. PMID- 29138714 TI - Alcohol and Tobacco Use Among Undergraduate and Postgraduate Medical Students in India: A Multicentric Cross-sectional Study. AB - Background: Substance use among medical fraternity is a well-known phenomenon among both undergraduate (UG) and postgraduate (PG) medical students. Yet, there have been very few multi-centric studies to estimate the actual burden of this problem in this important population group in India. This study was conducted to estimate the prevalence of alcohol and tobacco use, assess the knowledge and attitudes towards this issue, and identify factors associated with substance use among UG and PG medical students in India. Methods: A pre-tested, self-report, anonymous questionnaire was administered to medical undergraduates and post graduate medical residents of eight medical colleges across India. This study used a convenience sample of medical colleges with random selection of study participants within each college for each group, UG and PG. Results: Prevalence of alcohol and tobacco use among UG students was 16.6%, 95% CI [14.5, 18.9] and 8.0%, 95% CI [6.4, 9.6], respectively, whereas prevalence was 31.5%, 95% CI [26.3, 37.0] and 14.5%, 95% CI [10.7, 18.9], respectively for PGs. For both substances, males had a higher prevalence of use compared to females in both groups (p < 0.001). Positive family history of substance use (p < 0.001 for both groups) and early age of initiation (p = 0.011 for tobacco; p > 0.05 for alcohol) were associated with a greater difficulty to quit the habit. Over 90% of study participants felt that substance use adversely affected their skills and reported not using substances prior to managing their patients. Conclusions: Since substance use is a relatively common phenomenon among UG and PG medical students in India, future prospective studies and interventions are required to better understand the pattern of substance use and reduce its prevalence. PMID- 29138715 TI - Do People with Type 2 Diabetes Think They are Unhealthy?: A Cross-Sectional Study in Celaya, Mexico. AB - Background: Type 2 diabetes is a chronic disease that presents a significant burden on health care systems in many countries. With the rise of obesity, the incidence of Type 2 diabetes has also been steadily increasing. A healthy lifestyle and understanding of diabetes management are important factors for delaying the onset of comorbidities associated with Type 2 diabetes. The objective of this study was to evaluate the self-perception of health in individuals with Type 2 diabetes as it relates to BMI status, which has important implications for the implementation of preventive programs. Methods: A cross sectional lifestyle survey was implemented in the region of Celaya, Guanajuato, Mexico, targeting 100 participants diagnosed with Type 2 diabetes. Anthropometric measurements and participant characteristics were also obtained. Fisher's exact test was used to determine if the proportions of lifestyles perceptions differed by BMI status. Results: Participants had a mean age of 56.12 +/- 10.26, a mean BMI of 29.13 +/- 5.48 kg/m2, were mostly married (67.0%), and female (70.0%). None of the normal weight participants perceived themselves as unhealthy. 95% of overweight/obese participants perceived themselves to be healthy, despite a diagnosis of diabetes and being overweight/obese, while only 5% perceived themselves to be unhealthy. However, these differences in the perceptions of health classified by BMI status were not statistically significant (p = 0.42). Conclusion: Our findings indicate that overweight and obese persons with Type 2 diabetes in Celaya, Mexico may have misperceptions about their own health, even though these findings were not statistically significant. These preliminary data highlight the importance of implementing prevention and educational programs among those with diabetes, in order to combat health misperceptions and raise awareness about the dangers of diabetes and obesity. Furthermore, more research with larger sample sizes is needed in order to fully understand the effects of perception of health on actual health. PMID- 29138716 TI - Family Medicine as a Model of Primary Health Services Delivery: A Pilot Study in Almaty, Kazakhstan. AB - Introduction: Advanced models of delivering primary health care are being implemented in various countries of the world. This is especially true for countries undergoing a healthcare transition in Central Asia, such as Kazakhstan, which obtained independence from Soviet Union in 1991. The Kazakhstan National Program of Health Reform, implemented between 2005-2010, aimed to create an effective system of primary care. One of the key directions of healthcare reform implemented in Kazakhstan included the development of family medicine, which has become cutting-edge agenda for Kazakhstan Health Ministry over the past 10 years. While many papers have been published about the importance of family medicine and primary healthcare models, few have focused on analyzing family medicine effectiveness in Kazakhstan and its impact on access to family doctor services and patient satisfaction. The key aims of this pilot investigation were 1) to assess the model's impact on access to primary care and patients' satisfaction, and 2) to explore the model's effectiveness in some Central Asian and transitional countries in the literature. Methods: This pilot study was based on semi-structured interviews and questionnaires about the perception and impact of the primary care model to 86 respondents aged 19-51 (54% females, 46% males). The majority of respondents were Almaty city residents (71%), while the rest were Almaty Province rural residents (22%) and residents of other Kazakhstan regions (7%). Results: Respondents from rural areas associated general practitioners, or family doctors, with community clinics (also referred to as feldsher posts). Even though urban area respondents use family doctor services, they were more likely to get those services in private rather than public clinics. Rural residents appear to have better access to primary care providers than urban residents participating in our study. Also, respondents from rural areas were more satisfied with services provided by family doctors than respondents from urban areas. Conclusions: This pilot study helped to improve our understanding of primary health care reforms implemented in Kazakhstan, a topic that is not traditionally covered in international literature. This pilot study suggests that primary care is more effectively implemented in rural areas of Kazakhstan (Almaty Province); however, future full-scale research in this area is needed to fully understand the complexity of primary healthcare access in Kazakhstan. PMID- 29138717 TI - Kainar Syndrome: History of the First Epidemiological Case-control Study of the Effect of Radiation and Malnutrition. PMID- 29138718 TI - Comparing the Use of Uterine Artery Embolization to Gonadotropin-Releasing Hormone Agonists in Shrinking Fibroid Size: A Pilot Study in Kazakhstan. AB - Introduction: Uterine fibroids are the most common benign tumor in women in Kazakhstan. In the past two decades, endoscopic surgery has played an important role in the development of gynecologic surgery, particularly in the treatment of uterine fibroids. The goal of this paper is to evaluate whether uterine artery embolization (UAE) or gonadotropin-releasing hormone agonists (GnRHa) prior to myomectomy was more effective in decreasing fibroid size and improving surgical outcomes in a pilot study of women in Kazakhstan. Methods: This pilot investigation included 24 patients separated into 2 groups: medication group (pre treatment with GnRHa - 13 patients) and embolization group (pre-treatment with UAE - 11 patients). All patients had uterine fibroids, 3-10 cm in diameter, and were treated with myomectomy at the National Research Center for Maternal and Child Health, Astana, Kazakhstan. All patient data were obtained by a retrospective medical records review. Descriptive statistics were utilized to characterize participant demographics data. Independent t-tests were used to analyze continuous variables, and Chi-square and Fisher's exact tests were used where appropriate for count data. Results: The group treated with GnRHa had an operating time of 40+/-10 minutes longer than the group treated with UAE, due to the peri-operative difficulties encountered by surgeons in detecting the layer between the myometrium and fibroid capsule. The group treated with UAE experienced better patient outcomes (less blood loss, less surgical time, and reduced use of anesthesia) and was a technically easier surgery due to visible differences in uterine layers. Conclusions: Despite the fact that both treatments (GnRHa and UAE) were effective for fibroid shrinking, embolization resulted in more optimal surgical time and improved patient outcomes. Results of this pilot study need to be confirmed in a randomized clinical trial, specifically focused on Kazakhstan and the Central Asian Region. PMID- 29138720 TI - Challenges of NGO-to-state Referral in the Delivery of HIV Prevention Programs in Ukraine Supported by the Global Fund. AB - Background: Ukraine has one of the world's fastest growing HIV rates and was one of the largest recipients of funding from the Global Fund to Fight AIDS, Tuberculosis and Malaria (GF). The objective of this study was to close the gaps in the literature on the delivery of HIV prevention services by NGOs and the perceptions of NGO delivered services, using as an example HIV prevention programs in Ukraine funded by the GF. Methods: The aim of this qualitative study was to determine how NGO-based services were implemented in the context of a state-owned healthcare system of Ukraine. An ethnographic study, which included 50 participant interviews, was conducted in three oblasts in Ukraine and in the capital, Kyiv, between 2011 and 2013. This article presents some of the findings that emerged from the analysis. Results: Participants reported that NGOs were focused more on reporting numbers of rapid tests, and less on motivating clients to continue onto treatment. The role division between NGOs and the state in HIV services was largely perceived by participants as unclear and challenging. Overall, lack of clarity on the role of government healthcare providers and NGOs in providing HIV services compromised the process of finding, referring, and retaining HIV patients in care. Conclusions: Gaps in linking HIV patients to the HIV care continuum have been identified as a potentially problematic issue in delivery of HIV prevention services by GF funded NGOs. With an anticipated GF exit from Ukraine, the lack of clearly defined NGO-to-state referrals of HIV patients complicates the transition of NGO run services into state funding. Further steps to improve referral systems are necessary to ensure a smooth transition and enable Ukraine to fight its HIV epidemic effectively. PMID- 29138719 TI - Public Health and Social Desirability in Kazakhstan: Methodological Considerations. AB - Background: As the Republic of Kazakhstan undertakes new public health efforts to promote healthy lifestyles among its citizens, the local perceptions of health and health behaviors need to be examined and understood from the sociocultural and historical perspectives. The primary aim of this study is to examine the association between perception of control on one's health and engagement in good and bad health behaviors. Methods: Students enrolled in a health communication course surveyed 310 citizens of Kazakhstan on their perceptions of control over their own health and multiple health behaviors (i.e. smoking status, physical activity, etc.). Twenty-seven students were divided into groups and approached every third passerby as a potential participant during common shopping hours in nine popular marketplaces in Astana, Kazakhstan. Perception of control on one's health was measured using a validated measure of health control: the multidimensional health locus of control scale (MHLC), developed by Wallston and colleagues. The MHLC measures three separate loci of control: internal, chance, and powerful others. Results: Participants perceived themselves as having highest control over their health (MHLC subscale internal: 29.70+/-0.64), powerful others had second highest control (MHLC subscale power others: 23.72+/-0.77), and chance had the lowest but still some control on their health (MHLC subscale chance: 20.82+/-0.85). Most participants rated their current health as very good (18.1%), good (45.0%), or moderate (32.3%). Approximately 23.4% of participants were smokers, and 22.2% consumed alcohol. Physical activity averaged 3.63 days in the past week, and fruit and vegetable consumption averaged 2 servings of each per day. Tobacco and the powerful others subscale were significantly negatively correlated (r=-0.17, p<0.05). Conclusions: Participant reports regarding personal health behaviors and lifestyle did not reflect the national reports regarding lifestyle behaviors. The relationship between powerful others subscale and tobacco smoking indicate that using healthcare providers may open up avenues to lowering tobacco use through patient education; however, social desirability is a notable concern for public health interventions. More importantly, the surveys uncovered future questions for conducting public health research with the general public, including issues of trust in the healthcare system and social desirability bias. Additional factors such as distrust in healthcare and government also may play a role in the public's participation in social scientific research. The students who conducted the surveys reported a general skepticism from the public ranging from unfamiliarity with survey research to explicit distrust in the intentions and purpose of the research itself. PMID- 29138721 TI - Energy Drink Consumption Practices of Young People in Bahrain. AB - Background: Energy drink (ED) consumption is becoming increasingly popular among young Bahrainis, who may be unaware of the health risks associated with ED consumption. To date, there have been few publications on the consumption of ED in Bahrain, particularly among adolescents. This study seeks to fill a gap in the literature on energy drink consumption practices of Bahraini adolescents. Methods: Data were collected using a previously established European Food Safety Authority questionnaire. Cross-sectional analyses were conducted on a convenience sample of 262 Bahraini students aged 10 to 18 years. Results: Most participants consumed energy drinks 2 to 3 times per week and consumed two or more cans at a time. Eighty percent of partcipants preferred energy drinks with sugar. Participants in the older age group and higher educational level consumed more ED. The majority (57%) consumed ED at home with friends as part of socialization. Notably, 60% of the parents of the respondents have not consumed energy drinks. Prominent reasons for consumption of energy drinks included: taste (40%), energy (30%), stay awake (13%), augment concentration (4%), and enhance sports performance (6%). Conclusion: Energy drink consumption is a popular socialization activity among adolescents of Bahrain. The potential health risks necessitates the need for novel health promotion strategies and advocacy efforts for healthy hydration practices. PMID- 29138722 TI - Quantifying Socioeconomic and Lifestyle Related Health Risks: Burden of Cardiovascular Disease Among Indian Males. AB - Background: Non-communicable diseases account for a significant disease burden in the South East Asia region. India is facing an increased incidence of lifestyle related diseases, such as cardiovascular disease. Socioeconomic and lifestyle risk factors for cardiovascular disease (CVD) have been under investigated in India. This study was designed to explore risk factors contributing to the development of cardiovascular disease among Indian males. Methods: A population based cross-sectional study was conducted among 2,235 males in the age group of 18-60 years across three states of India. A household survey was used to collect demographic and socioeconomic status information in addition to lifestyle-related attributes such as smoking, alcohol consumption, diet, and physical activity. Descriptive statistics and logistic regression were performed to identify the role of various factors that may be associated with the development of cardiovascular disease in this population. Results: The prevalence of cardiovascular disease among the male respondents contacted through a household survey was reported to be 9.8%. Logistic regression revealed that males with higher education and higher income were more likely to report CVD. With age as a strong predictor of CVD, the risk of CVD was found to be five times higher in the older age group. Current smokers were 1.3 times more likely to have CVD compared to those who never smoked. Those who were engaged in physical activity were less likely to have CVD; however, the adverse effects of smoking and excessive consumption of red meat showed a stronger association with CVD than the protective effects of physical activity. Conclusion: In developing countries, where the increase in earning capacity and change in lifestyle has been found to be accompanied by substantial risk of heart disease for males, public health measures like health promotion programs need to be implemented to decrease CVD burden. PMID- 29138723 TI - Risk for Disability and Poverty Among Central Asians in the United States. AB - Understanding the disability-poverty relationship among minority groups within the United States (US) populations may help inform interventions aimed at reducing health disparities. Limited information exists on risk factors for disability and poverty among "Central Asians" (immigrants born in Kazakhstan, Uzbekistan, and other Central Asian regions of the former Soviet Union) in the US. The current cross-sectional analysis used information on 6,820 Central Asians to identify risk factors for disability and poverty. Data from the 2009-2013 Public Use Microdata Sample (PUMS) file from the American Community Survey (ACS) indicate that being married, non-Latino-white, and having higher levels of educational attainment are protective against disability and poverty. In contrast, older age, residing in the Middle Atlantic geographic division, and having limited English language ability are risk factors for both disability and poverty. Research should continue to develop risk profiles for understudied immigrant populations. Expanding knowledge on the well-being of Central Asians in the US may help impact public health interventions and inform health policies. PMID- 29138724 TI - HIV Risks, Testing, and Treatment in the Former Soviet Union: Challenges and Future Directions in Research and Methodology. AB - Background: The dissolution of the USSR resulted in independence for constituent republics but left them battling an unstable economic environment and healthcare. Increases in injection drug use, prostitution, and migration were all widespread responses to this transition and have contributed to the emergence of an HIV epidemic in the countries of former Soviet Union. Researchers have begun to identify the risks of HIV infection as well as the barriers to HIV testing and treatment in the former Soviet Union. Significant methodological challenges have arisen and need to be addressed. The objective of this review is to determine common threads in HIV research in the former Soviet Union and provide useful recommendations for future research studies. Methods: In this systematic review of the literature, Pubmed was searched for English-language studies using the key search terms "HIV", "AIDS", "human immunodeficiency virus", "acquired immune deficiency syndrome", "Central Asia", "Kazakhstan", "Kyrgyzstan", "Uzbekistan", "Tajikistan", "Turkmenistan", "Russia", "Ukraine", "Armenia", "Azerbaijan", and "Georgia". Studies were evaluated against eligibility criteria for inclusion. Results: Thirty-nine studies were identified across the two main topic areas of HIV risk and barriers to testing and treatment, themes subsequently referred to as "risk" and "barriers". Study design was predominantly cross-sectional. The most frequently used sampling methods were peer-to-peer and non-probabilistic sampling. The most frequently reported risks were condom misuse, risky intercourse, and unsafe practices among injection drug users. Common barriers to testing included that testing was inconvenient, and that results would not remain confidential. Frequent barriers to treatment were based on a distrust in the treatment system. Conclusion: The findings of this review reveal methodological limitations that span the existing studies. Small sample size, cross-sectional design, and non-probabilistic sampling methods were frequently reported limitations. Future work is needed to examine barriers to testing and treatment as well as longitudinal studies on HIV risk over time in most-at-risk populations. PMID- 29138725 TI - External Quality Assessment of Sputum Smear Microscopy in Tuberculosis Laboratories in Sughd, Tajikistan. AB - Introduction: Tajikistan has a laboratory network with three levels of tuberculosis (TB) laboratories. The external quality assessment (EQA) of sputum smear microscopy was implemented in 2007. The objective of this study was to evaluate the EQA system and identify potential performance improvement strategies in TB microscopic laboratories in Sughd, Tajikistan. Methods: This is a cross sectional study based on retrospective record review and secondary data analyses on Acid-Fast Bacilli (AFB) microscopy data and EQA reading results collected between the first quarter of 2011 and the fourth quarter of 2013. Descriptive analyses were conducted to examine the overview of microscopy laboratories activities, EQA results, and laboratory performance. Result: Of the 123,874 smears examined between 2011 and 2013, 11,522 (9.30%) were re-checked by the EQA system. The population TB screening rate rose from 0.46% in 2011 to 0.57% in 2013, and the case positivity rate decreased from 6.98% to 4.80%. The regional EQA results showed a reduction in high false-positive, high false-negative, and low false-negative errors. False-positive errors had decreased from 0.13% in 2011 to 0.07% in 2013, and false-negative errors from 0.91% in 2011 to 0.15% in 2013. Regional sensitivity of smear microscopy, when compared to re-checking controller, increased from 88.2% in 2011 to 97.2% in 2013. The regional specificity level remained relatively stable at above 99%. Conclusion: Our study found that a decreasing trend of case positivity rate from 2011 to 2013 in Sughd, though the overall laboratory workload was on the rise. In addition, EQA results showed an overall error reduction and an improved sensitivity of smear microscopy in the region. The overview of microscopic laboratory activities and the actual evaluation of the EQA system on sputum smear microscopy complement each other in providing a better picture on the progress of TB laboratory strengthening. We recommend similar approaches to be adapted by future evaluations on TB microscopic laboratories, particularly among countries of high burden. Interactive training and feedback loops are crucial to improving TB surveillance in Tajikistan. PMID- 29138726 TI - Erratum to: Quantifying Socioeconomic and Lifestyle Related Health Risks: Burden of Cardiovascular Disease Among Indian Males. AB - [This corrects the article on p. 2 in vol. 4.]. PMID- 29138727 TI - Correlation between Reproductive Hormonal Level and Osteoporosis among Women in Mongolia. AB - Background: Postmenopausal osteoporosis is the most common bone metabolic disease associated with low bone mineral density (BMD) and osteopathic fragility fractures, which can lead to significant morbidity. The objective of this study was to investigate the relationship between serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) levels and bone mineral density (BMD) across the stages of menopause in Mongolian women. Methods: Two hundred sixty participants aged 50.1+/-4.4 years were enrolled in the study. Blood samples were obtained from each participant and analyzed using ELISA. Data were first stratified and analyzed by bone mineral density status (osteoporotic, osteopenic, and normal) and then by menopause status. Between group differences were analyzed using t-tests, and correlations were assessed using the Spearman rank order test, with Bonferonni correction. The data were analyzed using Statistical Package Statistical Software version 20.0 (SPSS Inc., Chicago, IL). Significance was set at p<0.05. Results: The mean menopausal age was 48.4+/-3.4, which is comparable to the Mongolian population mean menopausal age. The mean serum estradiol level in the normal BMD group was 18.3+/-13.1 pg/ml and 15.8+/ 10.7 pg/ml in the osteoporotic group. The mean serum FSH in the normal BMD group was 54.5+/-44.1 pg/ml and 81.3+/-34.2 pg/ml in the osteoporotic group. The mean serum LH level in the normal BMD group was 53.1+/-41.2 and 75.1+/-26.1 pg/ml in the osteoporotic group. The mean T and Z score were lower in the osteoporotic group. FSH and LH levels significantly differed across menopause stages in that those who were post-menopausal had higher levels compared to those who were pre- or peri-menopausal. Both hormones, FSH and LH, showed weak negative correlations with BMD level, but not E2. There were significant negative correlations between FSH and Speed of Sound (SOS) (r=-0.16; p<0.01), and between osteoporosis with age (r=-0.30, p<0.05) and number of childbirths (r=-0.14 p<0.05). Discussion: Osteoporosis is a significant problem with associations to hormone levels in post menopausal women. In our study, mean serum estradiol levels decreased with age, and the mean FSH and LH levels were higher in women of later menopausal stage. Further study is warranted to investigate the bone related studies to establish better statistical references among Mongolian women. PMID- 29138728 TI - Dietary and Lifestyle Factors Associated with Dyspepsia among Pre-clinical Medical Students in Ajman, United Arab Emirates. AB - Introduction: Dyspepsia is a common gastrointestinal diseases worldwide with a prevalence ranging from 7 to 40%. Dyspepsia, more commonly known as heartburn or indigestion, is defined as one or more of the following symptoms: postprandial fullness, early satiation (the inability to finish a normal size meal), or epigastric pain or burning for at least 3 months in the past year. Dyspepsia has been studied extensively, but little is known of factors associated with dyspepsia among medical students. Objectives: The purpose of this study was to analyze the prevalence of dyspepsia and to evaluate the association between lifestyle and dietary factors associated with dyspepsia among pre-clinical medical students in Ajman, United Arab Emirates. Methods: A cross-sectional survey study was conducted among pre-clinical medical students at Gulf Medical University, Ajman and collected basic demographic data, dyspepsia prevalence, dietary factors, and lifestyle factors. Data was analyzed using Microsoft Excel and SPSS software. Descriptive statistics were used to summarize the participant characteristics. Chi-square tests were used to test the association between dietary and lifestyle factors and dyspepsia. Logistic regression was used to measure the association of predictors (dietary and lifestyle factors) on the odds of having dyspepsia, independently. Multinomial logistic regression was used to examine the full association of predictors on the odds of having dyspepsia. Results: The resulting sample was 176 pre-clinical medical students, with a mean age of 20.67 +/- 2.57 years. A total of 77 (43.8%) respondents reported having dyspepsia while 99 (56.2%) did not. There was a significant association between smoking and dyspepsia (p<0.05), as well as a marginally significant association between inadequate sleep and dyspepsia (p<0.10). There was no significant association with alcohol or analgesic use on dyspesia. Dietary habits showed no association with dyspepsia. Conclusion: Dyspepsia was reported by 43.8% of the repondents. These findings emphasize the importance of improving lifestyle and dietary factors associated with dyspepsia and raising awareness of reducing risk factors associated with dyspepsia. Further studies are needed on dyspepsia in a larger cohort of students in order to fully understand the complexity of this problem and be able to generalize the findings to other cohorts. PMID- 29138729 TI - Association of rs2294008 and rs9297976 Polymorphisms in PSCA Gene with Gastric Cancer Susceptibility in Uzbekistan. AB - Introduction: Genetic factors play an important role in the development of gastric cancer (GC), a prevalent malignancy in Central Asia. Recent studies have shown that single-nucleotide polymorphisms (SNPs) in several genes are associated with increased GC risk, indicating that genetic variation contributes to gastric carcinogenesis. Located on chromosome 8q24.2, the prostate stem cell antigen (PSCA) gene encodes a 123-amino acid glycoprotein related to the cell proliferation inhibition and cell-death induction activity. SNPs in PSCA gene have been found to be associated with gastric cancer risk in a genome-wide association study, but results were not conclusive. This study aimed to investigate the association between two polymorphic variants of PSCA gene (rs2294008 and rs9297976) and the susceptibility to gastric cancer in Uzbekistan. Methods: Two hundred sixty eight patients with gastric cancer and a control group of 248 healthy individuals were included in this study. DNA samples isolated from these groups were genotyped using PCR-RFLP method. Comparative analysis of resulting genotypes showed a statistically significant association between CT genotype and gastric cancer (p=0.03, additive model of inheritance, Cochran Armitage trend test). Results: Comparative analysis of the distribution of genotypes of rs2976392 polymorphism did not show a statistically significant difference; however, analysis of the distribution of the rs2976392 genotypes in a subgroup of young women revealed a statistically significant (p = 0.04, additive model of inheritance, Cochran-Armitage trend test) increase in the incidence of AA (38%) and AG (56%) genotypes in patients with GC, compared to the controls (20% and 40%). Conclusion: Our findings support that PSCA rs2294008 and rs9297976 polymorphism may contribute to the susceptibility to gastric cancer. Genotyping of these polymorphisms can potentially be recommended as one of the criteria for identification of high risk groups for gastric cancer development in Uzbekistan. PMID- 29138730 TI - The Potential Contribution of BRCA Mutations to Early Onset and Familial Breast Cancer in Uzbekistan. AB - Introuduction: Breast cancer is the most common malignancy in women and affects approximately 1 out of 8 females in the US. Risk of developing breast cancer is strongly influenced by genetic factors. Germ-line mutations in BRCA1 and BRCA2 genes are associated with 5-10% of breast cancer incidence. To reduce the risk of developing cancer and to increase the likelihood of early detection, carriers of BRCA1 or BRCA2 mutations are offered surveillance programs and effective preventive medical interventions. Identification of founder mutations of BRCA1/2 in high risk communities can have a significant impact on the management of hereditary cancer at the level of the national healthcare systems, making genetic testing more affordable and cost-effective. BRCA1 and BRCA2 mutations in breast cancer patients have not been characterized in the Uzbek population. This pilot study aimed to investigate the contribution of BRCA1 and BRCA2 mutation to early onset and familial cases of breast cancer in Uzbekistan. Methods: A total of 67 patients with breast cancer and 103 age-matched disease free controls were included in this study. Utilizing SYBR Green based real-time allele-specific PCR, we have analyzed DNA samples of patients with breast cancer and disease free controls to identify the following BRCA1 and BRCA2 mutations: BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, BRCA2 6174delT. Results: Three unrelated samples (4.5%) were found to be positive for the heterozygous 5382insCBRCA1 mutation, representing a possible founder mutation in the Uzbek population, supporting the need for larger studies examining the contribution of this mutation to breast cancer incidence in Uzbekistan. We did not find BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, and BRCA2 6174delT mutations. Conclusion: This preliminary evidence suggests a potential contribution of BRCA1 5382insC mutation to breast cancer development in Uzbek population. Taking into account a high disease penetrance in carriers of BRCA1 mutation, it seems reasonable to recommend inclusion of the 5382insC mutation test in future research on the development of screening programs for breast cancer prevention in Uzbekistan. PMID- 29138731 TI - The Universal Non-Neuronal Nature of Parkinson's Disease: A Theory. AB - Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet the etiology of the majority of its cases remains unknown. In this manuscript, relevant published evidence is interpreted and integrated into a comprehensive hypothesis on the nature, origin, and inter-cellular mode of propagation of sporadic PD. We propose to characterize sporadic PD as a pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. A universal cell-generic state, the PD state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why ageing associated accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We propose that hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species homeostasis that arises with age in the hematopoietic stem-cell niche. We argue that cellular ageing is nevertheless unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of cellular propagation of the PD-state. We highlight recently published findings on the inter-cellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the inter-cellular transmission of the PD-state. PMID- 29138733 TI - Scientific Banana Republics: Do They Exist? PMID- 29138732 TI - Honey: A Therapeutic Agent for Disorders of the Skin. AB - Problems with conventional treatments for a range of dermatological disorders have led scientists to search for new compounds of therapeutic value. Efforts have included the evaluation of natural products such as honey. Manuka honey, for example, has been scientifically recognised for its anti-microbial and wound healing properties and is now used clinically as a topical treatment for wound infections. In this review, scientific evidence for the effectiveness of honey in the treatment of wounds and other skin conditions is evaluated. A plethora of in vitro studies have revealed that honeys from all over the world have potent antimicrobial activity against skin relevant microbes. Moreover, a number of in vitro studies suggest that honey is able to modulate the skin immune system. Clinical research has shown honey to be efficacious in promoting the healing of partial thickness burn wounds while its effectiveness in the treatment of non burn acute wounds and chronic wounds is conflicted. Published research investigating the efficacy of honey in the treatment of other types of skin disorders is limited. Nevertheless, positive effects have been reported, for example, kanuka honey from New Zealand was shown to have therapeutic value in the treatment of rosacea. Anti-carcinogenic effects of honey have also been observed in vitro and in a murine model of melanoma. It can be concluded that honey is a biologically active and clinically interesting substance but more research is necessary for a comprehensive understanding of its medicinal value in dermatology. PMID- 29138734 TI - Publication Productivity in Central Asia and Countries of the Former Soviet Union. AB - Introduction: Despite the significant number of research institutions and rich scientific heritage, published research from Central Asia (Kazakhstan, Uzbekistan, Kyrgyzstan, Tajikistan, and Turkmenistan) is traditionally underrepresented in international scientific literature. The goal of this paper was to analyze publication patterns in Central Asian countries, and to explore the factors that contributed to the publication productivity in Kazakhstan. Methods: Publication productivity was evaluated using data generated by the SCImago Journal & Country Rank over the period of 1996-2014 for all of the 15 former Soviet Union Republics for all subject categories. Country specific data, including total population, gross domestic product (GDP) per capita, research and development (R&D) expenditure (% of GDP), number of reserchers (per million people), was abstracted from World Bank data. ANOVA and ANCOVA analyses compared the mean number of publications among Central Asian countries. Separate analyses was done for publication patterns in the health sciences. Multiple comparisons were performed using Tukey method. Results: The analysis of publication productivity showed significant discrepancies in the number of published documents among the Central Asian countries. Kazakhstan demonstrated a significant increase in the number of published documents in the period of 1996 2014, mainly in the areas of natural and multidisciplinary sciences. Our analyses also showed that the number of publications are siginicantly associated with GDP and population size. Conclusions: We identified large gaps in publication productivity among the Central Asian countries. The association between publication rate with GDP and population size indicates there is a need to adjust for these factors when planning research policy. PMID- 29138735 TI - Social Determinants of Maternal Health in Afghanistan: A Review. AB - Introduction: Afghanistan has a high maternal mortality rate of 400 per 100,000 live births. Although direct causes of maternal morbidity and mortality in Afghanistan include hemorrhage, obstructed labor, infection, high blood pressure, and unsafe abortion, the high burden of diseases responsible for maternal mortality arises in large part due to social determinants of health. The focus of this literature review is to examine the impact of various social determinants of health on maternal health in Afghanistan, filling an important gap in the existing literature. Methods: This narrative review was conducted using Arksey and O'Malley's framework of (1) defining the question, (2) searching the literature, (3) assessing the studies, (4) synthesizing selected evidence in context, and (5) summarizing potential programmatic implication of the context. We searched Medline, CABI global health database, and Google Scholar for relevant publications. Results: A total of 38 articles/reports were included in this review. We found that social determinants such as maternal education, sociocultural practices, and social infrastructure have a significant impact on maternal health. Health care may be the immediate determinant, but it is influenced by other determinants that must be addressed in order to alleviate the burden on health care, as well as to achieve long-term reduction in maternal mortality. Conclusion: Because of the importance of social factors for maternal health outcomes, committed involvement of multiple government sectors (i.e. education, labor and social affairs, information and culture, transport and rural development among others, alongside health care) is the long-term solution to the maternal health problems in Afghanistan. National and international organizations' long-term commitment to social investment such as education, local economy, cultural change, and social infrastructure is recommended for Afghanstan and globally. PMID- 29138736 TI - Prevalence of Tobacco Smoking and Factors Associated with the Initiation of Smoking among University Students in Dhaka, Bangladesh. AB - Introuduction: Tobacco smoking is considered to be the key preventable risk factor for morbidity and mortality at the global level. The aim of this study was to determine the prevalence of tobacco smoking and factors associated with the initiation of smoking among university students in Dhaka, Bangladesh. Methods: A cross-sectional survey study was conducted with 264 students of Jahangirnagar University, Dhaka, Bangladesh in 2015. A standard, self-administered questionnaire consisting of questions on socio-demographic variables, tobacco smoking status, family and peer tobacco smoking history, attitudes and beliefs about tobacco smoking, as well as knowledge about the negative health consequences of tobacco smoking was administered to participants. Data were analyzed using logistic regression models, chi square, and Fisher exact tests. Results: The overall prevalence of tobacco smoking was 60.2%, where males smoked at higher rates than females (68.81% and 19.56%, respectively). The influence of friends was the most significant reason for initiating tobacco smoking (OR: 0.862; CI: 0.810-0.917). Perception regarding tobacco smoking was significantly related to continuing tobacco use. Logistic regression models identified that smoking-related attitudes, potential health problems, and family members dying from cardiovascular disease and cancer were significantly associated with tobacco smoking. Conclusion: The current tobacco smoking prevalence among university students in Bangladesh is over 60%. We suggest adopting WHO Framework Convention on Tobacco Control (FCTC) policies, especially for university students. PMID- 29138737 TI - Diabetes Mellitus Among Adults in Herat, Afghanistan: A Cross-Sectional Study. AB - Introduction: Diabetes is reaching epidemic levels in Afghanistan. This study identifies the risk factors associated with diabetes in Herat City, Afghanistan, and explores the prevalence of previously undiagnosed diabetes. Methods: A cross sectional study was conducted using multistage cluster sampling by adopting the World Health Organization's (WHO) STEPwise approach to Surveillance (STEPS). We enrolled 1129 participants aged 25-70 years between May and June of 2015 (47.4% males, 52.6% females). A structured questionnaire was used for data collection of demographic, socioeconomic, and behavioral factors. Investigators collected anthropometric measurements and blood samples from study participants. A multivariable logistic regression model was used to identify factors associated with diabetes prevalence. Results: We found that the prevalence of diabetes in Herat City was 9.9% (9.8% in males and 10.1% in females). Of the 1129 respondents, only 3.3% were previously diagnosed with diabetes or were under treatment, whereas 6.6% of respondents were previously undiagnosed. The multivariable analyses showed that age, frequency of rice consumption, type of cooking oil, and systolic blood pressure were associated with diabetes. Conclusions: This is one of the first studies to discuss the high prevalence of undiagnosed diabetes in Herat, Afghanistan. This study found several modifiable factors that were associated with diabetes in Herat, Afghanistan. Future reduction of disease burden should focus on these factors in the development of the most optimal diabetes prevention programs. PMID- 29138738 TI - Spatial Distribution and Trends of Waterborne Diseases in Tashkent Province. AB - Introduction: The cumulative effect of limited investment in public water systems, inadequate public health infrastructure, and gaps in infectious disease prevention increased the incidence of waterborne diseases in Uzbekistan. The objectives of this study were: (1) to spatially analyze the distribution of the diseases in Tashkent Province, (2) to identify the intensity of spatial trends in the province, (3) to identify urban-rural characteristics of the disease distribution, and (4) to identify the differences in disease incidence between pediatric and adult populations of the province. Methods: Data on four major waterborne diseases and socio-demographics factors were collected in Tashkent Province from 2011 to 2014. Descriptive epidemiological methods and spatial temporal methods were used to investigate the distribution and trends, and to identify waterborne diseases hotspots and vulnerable population groups in the province. Results: Hepatitis A and enterobiasis had a high incidence in most of Tashkent Province, with higher incidences in the eastern and western districts. Residents of rural areas, including children, were found to be more vulnerable to the waterborne diseases compared to other populations living in the province. Conclusions: This pilot study calls for more scientific investigations of waterborne diseases and their effect on public health in the region, which could facilitate targeted public health interventions in vulnerable regions of Uzbekistan. PMID- 29138739 TI - The Euclid Statistical Matrix Tool. PMID- 29138740 TI - Pediatric Pulmonary Hemorrhage vs. Extrapulmonary Bleeding in the Differential Diagnosis of Hemoptysis. AB - Introduction: Hemoptysis is an important symptom which causes a major concern, and warrants immediate diagnostic attention. The authors compared a group of patients with pediatric pulmonary hemorrhage with pediatric patients diagnosed with extrapulmonary bleeding focusing on differences in etiology, outcome and differential diagnosis of hemoptysis. Methods: We performed the retrospective analysis of medical charts of 134 pediatric patients admitted to the Emergency Department because of pulmonary and extrapulmonary hemorrhage and were diagnosed with suspected hemoptysis or developed hemoptysis (ICD10-CM code R04.2). The cases with pulmonary hemorrhage (Group 1) were compared with cases of extrapulmonary bleeding (Group 2) using the Fisher Exact test or Pearson's chi2 test for categorical variables. The t-test was used to assess differences between continuous variables of the patients in the two groups. Results: Bloody cough was the presenting symptom in 73.9% of cases. 30 patients had pulmonary hemorrhage (Group 1), while 104 patients had extrapulmonary bleeding (Group 2). The underlying causes of bleeding in Group 2 included epistaxis, inflammatory diseases of nasopharynx and larynx, foreign bodies, gingivitis, and hypertrophy of adenoids. Mortality rate was 10% in Group 1, whereas Group 2 did not have any mortality outcomes during the observation period. Etiologycal factors were significantly different between hemoptysis and extrapulmonary bleeding in children. Conclusions: Our research suggested that pulmonary and extrapulmonary bleeding are two conditions that differ significantly and cannot be unified under one diagnostic code. It is important to differentiate between focal and diffuse cases, and between pulmonary and extrapulmonary hemorrhage due to the diversity of clinical courses and outcomes. PMID- 29138741 TI - Challenges to Global Implementation of Infrared Thermography Technology: Current Perspective. AB - Medical infrared thermography (IT) produces an image of the infrared waves emitted by the human body as part of the thermoregulation process that can vary in intensity based on the health of the person. This review analyzes recent developments in the use of infrared thermography as a screening and diagnostic tool in clinical and nonclinical settings, and identifies possible future routes for improvement of the method. Currently, infrared thermography is not considered to be a fully reliable diagnostic method. If standard infrared protocol is established and a normative database is available, infrared thermography may become a reliable method for detecting inflammatory processes. PMID- 29138742 TI - Hysterectomy Pathway as the Global Engine of Practice Change: Implications for Value in Care. AB - Introduction: In 2012, University of Pittsburgh Medical Center (UPMC) introduced a hysterectomy clinical pathway to reduce the number of total abdominal hysterectomies performed for benign gynecological indications. This study focused on exploring physician and patient factors impacting the utilization of hysterectomy clinical pathways. Methods: An online survey with 24 questions was implemented to explore physicians' attitudes and perceived barriers toward implementing the pathway. A survey consisting of 27 questions was developed for patients to determine the utility of a pathway-based educational tool for making surgery decisions and to measure satisfaction with the information provided. Descriptive statistics were used to describe survey results, while thematic analysis was performed on verbal feedback submitted by respondents. Results: Physician respondents found the clinical pathway to be practical, beneficial to patients, and up-to-date with the latest evidence-based literature. Key barriers to the use of the pathway that were identified by physicians included perceived waste of time, inappropriateness for some of the patient groups, improper incentive structure, and excessive bureaucracy surrounding the process. Overall, patient respondents were satisfied with the tool and found it to be helpful with the decision-making process of choosing a hysterectomy route. Conclusions: Physicians and patients found the developed tools to be practical and beneficial. Findings of this study will help to use pathways as a unifying framework to shape future care of patients needing hysterectomy and add value to their care. PMID- 29138743 TI - Renal adenocarcinoma-associated erythrocytosis in a cat: clinicopathological features and immunohistochemical results. AB - This report documents a case of secondary inappropriate erythrocytosis in a cat with renal cell adenocarcinoma, its stabilization through manual erythrocytapheresis, and the EPO-immunostaining on the affected kidney. An 11 year-old cat was presented with lethargy, weight loss and polyuria/polydipsia. An abdominal mass was detected upon physical examination. Clinicopathological work up revealed marked erythrocytosis (HCT value 64.8%), renal azotemia and decreased urine specific gravity (USG). An abdominal ultrasound was performed, localizing the mass in the right kidney. Serum erythropoietin (EPO) was above the reference interval (RI), and the cytology of the mass was indicative of renal carcinoma. Manual erythrocytapheresis was performed in order to stabilize the patient before surgery, improving the cat's clinical and clinicopathological condition. After nephrectomy, EPO and creatinine concentrations returned within the RI, while the USG markedly increased. Histopathology confirmed the diagnosis of renal adenocarcinoma. Immunohistochemistry with anti-EPO antibody revealed diffuse and strong cytoplasmatic positivity in tumor cells. PMID- 29138744 TI - Multiple myeloma in an Amur tiger (Panthera tigris altaica). AB - The Amur tiger (Panthera tigris altaica) is an endangered tiger subspecies. An adult zoo-bred female was found collapsed, and died despite supportive treatment. Hematology and biochemistry showed pancytopenia and hyperglobulinemia, and serum protein electrophoresis revealed a monoclonal band in the beta-globulin region. Necropsy demonstrated hemoabdomen, multifocal lytic bone marrow lesions, splenomegaly, and hemorrhagic hepatic nodules, with left medial lobe rupture. There were mutifocal hemorrhages in the subcutis, lung, epicardium, and intestinal mucosa. Histopathology demonstrated plasmacytoid cells infiltrating the bone marrow, liver and spleen, and circulating within blood vessels. On immunohistochemistry, cell infiltrates of the three tissues were positive for lambda light chains, bone marrow infiltrates were positive for MUM-1 and bone marrow and spleen infiltrates were positive for CD20. These findings indicate that this animal died of hemoabdomen subsequent to multiple myeloma. This is the first time this disease has been reported in a tiger. PMID- 29138746 TI - A novel encephalopathy in a thiamine-deficient dog resembling human Wernicke's disease with atypical MRI pattern. AB - Thiamine is a water-soluble vitamin, which participates in several vital metabolic pathways involved in energy metabolism and neurotransmitter synthesis of mammals. In companion animals thiamine deficiency is classically associated with signs of diffuse encephalopathy and lesions on brainstem nuclei and mesencephalic colliculi evident on magnetic resonance imaging. This paper describes a novel clinical presentation in a thiamine-deficient dog showing multifocal, central and peripheral nervous and cardiovascular system alterations. Brain MRI showed bilateral caudate nuclei damage, with necrotic-malacic evolution, similar to the atypical MRI pattern found in Wernicke's encephalopathy in humans. Detection of bilateral symmetrical lesions of the caudate nuclei in dogs should prompt consideration of a thiamine deficiency among the differential diagnoses. PMID- 29138745 TI - Spontaneous nervous system concussion in dogs: a description of two cases and a review of terminology in veterinary medicine. AB - In human medicine, central nervous system (CNS) concussion is defined as a transient neurological dysfunction following a traumatic event, without evidence of structural abnormalities of the affected region on advanced diagnostic imaging. Depending on the anatomical region involved, three forms of concussive syndromes are described: brain concussion, spinal concussion and cerebellar concussion. Although major textbooks of veterinary neurology admit the existence of canine brain concussion, spontaneous cases of this pathological condition have not been reported in small animals so far. This report describes two cases of concussion in dogs: a 9-month-old, intact male, shih-tzu with brain concussion; and a 10-month-old, intact male, poodle with cerebellar concussion. In addition, a brief review of the definition of the term "concussion" in the veterinary medical literature is provided, in comparison to its meaning in the human medical literature. Finally, this paper proposes an appropriate definition of "concussion" in dogs, that may facilitate clinicians in the recognition of such an elusive syndrome. PMID- 29138747 TI - Seroprevalence of Toxoplasma gondii and Neospora caninum infections in goats from two Argentinean provinces. AB - The aim of this study was to compare the seroprevalence of Toxoplasma gondii and Neospora caninum in goats from two Argentinean provinces raised under different management conditions. A total of 2922 serum samples from adult goats of Cordoba (n=2187) and Buenos Aires provinces (n= 735), Argentina, were assayed by indirect fluorescence antibody test (IFAT, cut-off 1:100) for antibodies to T. gondii and N. caninum. Seroprevalence was 40.8% (CI 39.0%-42.6%) and 5.5% (CI 4.7%-6.4%) for T. gondii and N. caninum, respectively. The seropositivity for both infections was higher in goats from dairy farms, resulting as follows: for T. gondii 32.7% (CI 30.8%-34.8%) in extensive farms and 59.3% (CI 56.1%-62.6%) in dairy farms and for N. caninum 4.1% (CI 3.2%-4.9%) in extensive farms and 8.8% (CI 6.9%-10.7%) in dairy farms. This is the first extensive seroepidemiology investigation for T. gondii and N. caninum in goats in Argentina. PMID- 29138749 TI - Auris System: Providing Vibrotactile Feedback for Hearing Impaired Population. AB - Deafness, an issue that affects millions of people around the globe, is manifested in different intensities and related to many causes. This impairment negatively affects different aspects of the social life of the deaf people, and music-centered situations (concerts, religious events, etc.) are obviously not inviting for them. The Auris System was conceived to provide the musical experimentation for people who have some type of hearing loss. This system is able to extract musical information from audio and create a representation for music pieces using different stimuli, a new media format to be interpreted by other senses than the hearing. In addition, the system defines a testing methodology based on a noninvasive brain activity recording using an electroencephalographic (EEG) device. The results of the tests are being used to better understand the human musical cognition, in order to improve the accuracy of the Auris musical representation. PMID- 29138748 TI - Identifying Novel Glioma-Associated Noncoding RNAs by Their Expression Profiles. AB - Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play a significant role in cancer development as regulators of protein-coding genes. Their dysregulation was in some extent already associated with glioma, the most aggressive primary brain tumours in adults. The correct diagnosis and treatment selection due to high tumour heterogeneity might be difficult and inadequate, resulting in poor prognosis. Studies of expression patterns of noncoding RNAs (ncRNAs) could provide useful insight in glioma molecular development. We used the qPCR approach to screen and investigate the expression of lncRNAs that were previously deregulated in other cancer types. The study showed altered expression levels for numerous lncRNAs across histologically different glioma samples. Validation of few lncRNAs showed association of expression levels with histological subtype and/or malignancy grade. We also observed deregulated and subtype-distinctive expression for four lncRNA-associated miRNAs. Expression of few lncRNAs and miRNA was also associated with patients' survival, showing potential prognostic value. Several ncRNAs, some already related to glioma and some, to the best of our knowledge, investigated for the first time, might be of greater importance in glioma molecular development and progression. Finding the subtype-specific lncRNA and/or miRNA expression patterns may contribute additional information for a more objective classification. PMID- 29138750 TI - Markers of Alzheimer's Disease in Primary Visual Cortex in Normal Aging in Mice. AB - Aging is the principal risk factor for the development of Alzheimer's disease (AD). The hallmarks of AD are accumulation of the amyloid-beta peptide 1-42 (Abeta42) and abnormal hyperphosphorylation of Tau (p-Tau) protein in different areas of the brain and, more recently reported, in the visual cortex. Recently, Abeta42 peptide overproduction has been involved in visual loss. Similar to AD, in normal aging, there is a significant amyloid deposition related to the overactivation of the aforementioned mechanisms. However, the mechanisms associated with visual loss secondary to age-induced visual cortex affectation are not completely understood. Young and aged mice were used as model to analyze the presence of Abeta42, p-Tau, glial-acidic fibrillary protein (GFAP), and presenilin-2, one of the main enzymes involved in Abeta42 production. Our results show a significant increase of Abeta42 deposition in aged mice in the following cells and/or tissues: endothelial cells and blood vessels and neurons of the visual cortex; they also show an increase of the expression of GFAP and presenilin-2 in this region. These results provide a comprehensive framework for the role of Abeta42 in visual loss due to inflammation present with aging and offer some clues for fruitful avenues for the study of healthy aging. PMID- 29138751 TI - Expression of MicroRNA-29a Regulated by Yes-Associated Protein Modulates the Neurite Outgrowth in N2a Cells. AB - Yes-associated protein (YAP) is proved to increase miR-29a in the present study, but the relevant molecular mechanism is not clear. Also, growing evidence indicates that the high-level miR-29a promotes the neurite outgrowth by decreasing PTEN (phosphatase and tensin homologue deleted on chromosome 10). Results show that the expression of miR-29a increases but the PTEN decreases during transfecting the N2a cells with the YAP plasmid. Meanwhile, the advancement of neurite outgrowth is presented via using multiple methods to detect the expression of GAP-43 and NF-200, which have a strong association with neurite outgrowth. The expression of miR-29a, GAP-43, and NF-200 shows an opposite tendency compared to the PTEN when YAP is downregulated. By treating N2a cells with miR-29a mimic and inhibitor, we also find the same conclusion. For in silico analysis of miR-29a, its promoter may have a binding site for YAP. Based on a luciferase reporter assay and a chromatin immunoprecipitation (ChIP) experiment, we demonstrate that YAP could increase the expression of miR-29a by targeting the promoter of miR-29a. In conclusion, the results identify that YAP promotes the neurite outgrowth via targeting the promoter of miR-29a, and it may be an effective therapeutic medicine for the neural disease. PMID- 29138752 TI - The Effect of Granulocyte Colony-Stimulating Factor on the Progression of Atherosclerosis in Animal Models: A Meta-Analysis. AB - Background: Atherosclerosis is a common inflammatory disease. Stem cell and endothelial progenitor cell treatments can improve cardiac function after myocardial infarction. Granulocyte colony-stimulating factor (G-CSF) is a mobilisation agent, mobilising stem cells from the bone marrow to circulation in the blood. G-CSF may constitute a treatment of atherosclerosis. We have conducted meta-analysis to evaluate the current evidence for the effect of G-CSF on the progression of atherosclerosis in animal models and to provide reference for preclinical experiments and future human clinical trials of atherosclerosis treatment. Methods: We searched several databases and conducted a meta-analysis across seven articles using a random-effect model. All statistical analyses were performed using Review Manager Version 5.2 and Stata 12.0. Results: We found that G-CSF therapy was associated with reduced atherosclerotic lesion area (weighted mean difference (WMD): 7.29%; 95% confidence interval (CI): 2.06-12.52%; P = 0.006). No significant differences in total serum cholesterol (P = 0.54) and triglyceride levels (P = 0.95) were noted in G-CSF treatment groups compared with controls. Multivariable metaregression analysis revealed that the animal type (rabbit, P = 0.022) and frequency of G-CSF administration (>20, P = 0.007) impacted the atherosclerotic lesion area changes. Conclusion: The meta-analysis suggested that G-CSF treatment might inhibit the progression of atherosclerosis in animal models. PMID- 29138753 TI - Lesion Pattern, Mechanisms, and Long-Term Prognosis in Patients with Monoparetic Stroke: A Comparison with Nonmonoparetic Stroke. AB - Background: Monoparetic stroke is rare but could be misdiagnosed as peripheral neuropathy. We investigated the prevalence, lesion pattern, stroke mechanism, and long-term prognosis in patients with monoparetic stroke. Methods: 586 acute ischemic stroke patients (including 31 with monoparesis) were studied. Monoparetic stroke was defined as a motor deficit in either an arm or a leg but without facial weakness or speech disturbance. Median follow-up period was 32.0 months. Kaplan-Meier survival curves, log-rank tests, logistic regressions, and Cox proportional hazards models were used for clinical outcome analyses. Results: The mean age (313 men and 273 women) was 67.6 years. Among monoparetic patients, most had cortical (80.6%) and multiple (64.5%) lesions. The main stroke mechanisms were cardioembolism (38.7%) and large artery atherosclerosis (29.0%). Precentral gyrus with additional regions was most frequently involved in monoparesis (45.2%). Upper motor neuron signs were found in only 11 patients (35.5%). Compared with the nonmonoparetic group, these patients had better functional outcomes (6-month modified Rankin scale <=2) and long-term survival but had comparable risks for further vascular events, including stroke recurrences. Conclusions: Although monoparetic stroke may have a better functional outcome, the risk of the further vascular event seems similar to nonmonoparetic stroke. PMID- 29138754 TI - The Relation between Periodontopathogenic Bacterial Levels and Resistin in the Saliva of Obese Type 2 Diabetic Patients. AB - This study aims to investigate the relation between resistin and periodontopathogenic bacterial levels in the saliva of obese adults compared to healthy control and to examine whether salivary resistin can serve as a biomarker of type 2 diabetes in obese patients. A total of 78 saliva samples were collected from patients attending to the University Dental Hospital, Sharjah, UAE. The patients were divided into three equal groups: obese diabetics, obese nondiabetics, and nonobese nondiabetic control. Salivary resistin was measured using ELISA. The levels of bacterial species associated with periodontitis (Treponema denticola, Porphyromonas gingivalis, Tannerella forsythia, and Actinobacillus actinomycetemcomitans) and gingivitis (Fusobacterium spp.) were measured using real-time PCR. Both salivary resistin and periodontopathogenic bacteria including Fusobacterium spp., P. gingivalis, and T. forsythia were detected in significantly higher quantities in the obese patients (diabetics and nondiabetics) than nonobese nondiabetic control. Resistin concentrations were significantly correlated with BMI; however, its level was not correlated with the blood glucose. In this study, high salivary resistin was associated with obesity, which is a major predisposing factor for type 2 diabetes and also a risk factor for oral diseases. The high levels of salivary periodontopathogenic bacteria could upregulate the local release of salivary resistin in obese people. PMID- 29138755 TI - Paraneoplastic Hepatopathy Associated with Gastrointestinal Carcinoid. AB - Paraneoplastic hepatopathy has been reported with various malignancies, most commonly with renal cell cancer. This non-metastatic hepatic dysfunction in such malignancies is known as Stauffer syndrome. We describe a 61-year-old man who presented with symptoms of bowel obstruction with marked cholestasis and high levels of alkaline phosphatase and bilirubin. Imaging revealed an unremarkable liver and a mass in the ileocecal valve with mesenteric lymphadenopathy. Biopsies were consistent with a carcinoid tumor. Liver dysfunction gradually resolved after surgical resection of the tumor. Paraneoplastic syndrome should be considered in the differential diagnosis for patients with carcinoid tumors who present with cholestasis. PMID- 29138756 TI - Sarcina ventriculi as an Unknown Culprit for Esophageal Stricturing. PMID- 29138757 TI - Effects of Marathon Running on Aerobic Fitness and Performance in Recreational Runners One Week after a Race. AB - It is not clear whether or not recreational runners can recover aerobic fitness and performance within one week after marathon running. This study aimed to investigate the effects of running a marathon race on aerobic fitness and performance one week later. Eleven recreational runners (six men, five women) completed the race in 3 h 36 min 20 s +/- 41 min 34 s (mean +/- standard deviation). Before and 7 days after the race, they performed a treadmill running test. Perceived muscle soreness was assessed before the race and for the following 7 days. The magnitude of changes in the treadmill running test was considered possibly trivial for maximal oxygen uptake ([Formula: see text]O2max) (mean difference -1.2 ml/kg/min; +/-90% confidence limits 2 ml/kg/min), unclear for %[Formula: see text]O2max at anaerobic threshold (AT) (-0.5; +/-4.1%) and RE (0.2; +/-3.5 ml/kg/km), and likely trivial for both velocity at AT and peak ( 0.2; +/-0.49 km/h and -0.3; +/-0.28 km/h). Perceived muscle soreness increased until 3 days after the race, but there were no clear differences between the values before the race and 4-7 days after it. These results show that physiological capacity associated with marathon running performance is recovered within 7 days after a marathon run. PMID- 29138758 TI - Vaginoscopy in Ewes Utilizing a Laparoscopic Surgical Port Device. AB - Vaginoscopy allows for diagnostic evaluation and treatment of the vaginal vault. A laparoscopic surgical port device and rigid telescope were utilized for serial vaginoscopy in 8 healthy anesthetized ewes. Vaginoscopy examinations were performed in each ewe at days 1, 14, and 28. This technique was well-tolerated and facilitated carbon dioxide vaginal inflation, complete vaginal examination, identification of the cervix, and targeted biopsy collection. No complications were encountered during or following the vaginoscopy procedures. The laparoscopic port device was well-suited to the ewe vulvar size. This technique could be applied to clinical evaluation in ewes for the purposes of examination, biopsy, culture, foreign body removal, and minor surgical procedures. PMID- 29138759 TI - Identification of Persistent and Resurgent Sodium Currents in Spiral Ganglion Neurons Cultured from the Mouse Cochlea. AB - In spiral ganglion neurons (SGNs), the afferent single units of the auditory nerve, high spontaneous and evoked firing rates ensure preservation of the temporal code describing the key features of incoming sound. During postnatal development, the spatiotemporal distribution of ion channel subtypes contributes to the maturation of action potential generation in SGNs, and to their ability to generate spike patterns that follow rapidly changing inputs. Here we describe tetrodotoxin (TTX)-sensitive Na+ currents in SGNs cultured from mice, whose properties may support this fast spiking behavior. A subthreshold persistent Na+ current (INaP) and a resurgent Na+ current (INaR) both emerged prior to the onset of hearing and became more prevalent as hearing matured. Navbeta4 subunits, which are proposed to play a key role in mediating INaR elsewhere in the nervous system, were immunolocalized to the first heminode where spikes are generated in the auditory nerve, and to perisomatic nodes of Ranvier. ATX-II, a sea anemone toxin that slows classical Na+ channel inactivation selectively, enhanced INaP five-fold and INaR three-fold in voltage clamp recordings. In rapidly-adapting SGNs under current clamp, ATX-II increased the likelihood of firing additional action potentials. The data identify INaP and INaR as novel regulators of excitability in SGNs, and consistent with their roles in other neuronal types, we suggest that these nonclassical Na+ currents may contribute to the control of refractoriness in the auditory nerve. PMID- 29138760 TI - Cardiac Surgery After Heart Transplantation: Elective Operation or Last Exit Strategy? AB - Background: Because of improved long-term survival after heart transplantation (HTx), late graft pathologies such as valvular disease or cardiac allograft vasculopathy (CAV) might need surgical intervention to enhance longer survival and ensure quality of life. To this date, there exist no guidelines for indication of cardiac surgery other than retransplantation after HTx. Methods: In this retrospective, single-center study, we evaluated patients who underwent cardiac surgery after HTx at our institution. Results: Between March 1984 and October 2016, 17 (1.16%) of 1466 HTx patients underwent cardiac surgery other than retransplantation after HTx. Indication were valvular disease (n = 7), CAV (n = 6), and other (n = 4). Of these, 29.4% (n = 5) were emergency procedures and 70.6% were elective cases. Median age at time of surgery was 61 years (interquartile range, 52-66 years); 82.4% (n = 14) were male. Median time to surgery after HTx was 9.3 years (2.7-11.1 years). In-hospital, mortality was 11.8% (n = 2); later need of retransplantation was 11.8% (n = 2) due to progressing CAV 3 to 9 months after surgery. One-year survival was 82.35%; overall survival was 47.1% (n = 8) with a median follow-up of 1477 days (416-2135 days). Overall survival after emergency procedures was 209 days (36-1119.5 days) whereas, for elective procedures, it was 1583.5 days (901.5-4319 days). Conclusions: Incidence of cardiac surgery after HTx in our cohort was low (1.16%) compared with that of other studies. In elective cases, long-term survival was good. PMID- 29138762 TI - Identifying Cu(ii)-amyloid peptide binding intermediates in the early stages of aggregation by resonance Raman spectroscopy: a simulation study. AB - The aggregation of amyloid beta (Abeta) peptides plays a crucial role in the pathology and etiology of Alzheimer's disease. Experimental evidence shows that copper ion is an aggregation-prone species with the ability to coordinately bind to Abeta and further induce the formation of neurotoxic Abeta oligomers. However, the detailed structures of Cu(ii)-Abeta complexes have not been illustrated, and the kinetics and dynamics of the Cu(ii) binding are not well understood. Two Cu(ii)-Abeta complexes have been proposed to exist under physiological conditions, and another two might exist at higher pH values. By using ab initio simulations for the spontaneous resonance Raman and time domain stimulated resonance Raman spectroscopy signals, we obtained the characteristic Raman vibronic features of each complex. These signals contain rich structural information with high temporal resolution, enabling the characterization of transient states during the fast Cu-Abeta binding and interconversion processes. PMID- 29138763 TI - Light-promoted metal-free cross dehydrogenative couplings on ethers mediated by NFSI: reactivity and mechanistic studies. AB - Cross dehydrogenative couplings on ethers occur very effectively using N fluorobis(phenyl)sulfonimide (NFSI) as oxidizing agent under UVA irradiation in the presence of 2 mol% benzophenone. The reaction was shown to proceed first by fast radical fluorination of the alpha-C-H bond of ethers, followed by HF elimination to yield the highly electrophilic oxocarbenium ion as a key intermediate. PMID- 29138761 TI - A metastasis biomarker (MetaSite BreastTM Score) is associated with distant recurrence in hormone receptor-positive, HER2-negative early-stage breast cancer. AB - Metastasis is the primary cause of death in early-stage breast cancer. We evaluated the association between a metastasis biomarker, which we call "Tumor Microenviroment of Metastasis" (TMEM), and risk of recurrence. TMEM are microanatomic structures where invasive tumor cells are in direct contact with endothelial cells and macrophages, and which serve as intravasation sites for tumor cells into the circulation. We evaluated primary tumors from 600 patients with Stage I-III breast cancer treated with adjuvant chemotherapy in trial E2197 (NCT00003519), plus endocrine therapy for hormone receptor (HR)+ disease. TMEM were identified and enumerated using an analytically validated, fully automated digital pathology/image analysis method (MetaSite BreastTM), hereafter referred to as MetaSite Score (MS). The objectives were to determine the association between MS and distant relapse free interval (DRFI) and relapse free interval (RFI). MS was not associated with tumor size or nodal status, and correlated poorly with Oncotype DX Recurrence Score (r = 0.29) in 297 patients with HR+/HER2 disease. Proportional hazards models revealed a significant positive association between continuous MS and DRFI (p = 0.001) and RFI (p = 0.00006) in HR+/HER2- disease in years 0-5, and by MS tertiles for DRFI (p = 0.04) and RFI (p = 0.01), but not after year 5 or in triple negative or HER2+ disease. Multivariate models in HR+/HER- disease including continuous MS, clinical covariates, and categorical Recurrence Score (<18, 18-30, > 30) showed MS is an independent predictor for 5 year RFI (p = 0.05). MetaSite Score provides prognostic information for early recurrence complementary to clinicopathologic features and Recurrence Score. PMID- 29138764 TI - Correction: The generalized maximum hardness principle revisited and applied to atoms and molecules. AB - Correction for 'The generalized maximum hardness principle revisited and applied to atoms and molecules' by Wojciech Grochala, Phys. Chem. Chem. Phys., 2017, DOI: . PMID- 29138765 TI - Sizing sub-diffraction limit electrosprayed droplets by structured illumination microscopy. AB - Electrosprayed droplets are widely studied for their role in the formation of ions at atmospheric pressure. Most droplet measurement methods used today employ light scattering to infer information about an electrosprayed droplet's size. However, these methods fail to measure droplets smaller than about 400 nm in diameter due to constraints imposed by the diffraction limit of light. To overcome this limitation, a super resolution fluorescence microscopy-based method for determining the sizes of electrosprayed droplets has been developed. Solutions containing rhodamine B and different amounts of glycerol were paper sprayed and nanoelectrosprayed onto conductive microscope coverslips using a single, high voltage pulse. Images of the deposited droplets were collected using a super resolution microscope operating in 3D structured illumination microscopy mode (3D-SIM). The sizes of droplets were measured using a modified circular Hough transformation program in Matlab. On average, the diameters of paper sprayed droplets were between 500 nm and 2 MUm while almost all nanoelectrosprayed droplets were smaller than 1 MUm. The center of a paper spray plume exhibited larger droplets than those at the periphery, likely due to greater Coulombic repulsive forces acting on the smaller droplets to drive them outwards. The periphery also likely contained progeny droplets in addition to smaller parent droplets. It was possible to alter the sizes of nanoelectrosprayed droplets in several ways, including by changing the solvent composition and voltage applied to the emitter. Droplets consisting of high concentrations of glycerol were larger than droplets containing high concentrations of methanol, presumably due to the high surface tension of glycerol. Correspondingly, droplets became smaller when the voltage applied to the emitter was increased, likely due to the ability to overcome the surface tension of the solvent more easily. The smallest detectable droplets confidently measured with this method were 200 nm in diameter. This method demonstrates a new way of measuring the sizes of electrosprayed droplets with half the diameter of conventional droplet size measurement methods. Through further optimization, it may be possible to measure the sizes of electrosprayed droplets as small as the theoretical resolution limit of SIM (~100 nm). PMID- 29138766 TI - Imidazole-stabilized, electron-deficient boron cations. AB - The borenium cations [(C7H5N2Ad)B(C6F5)2][AlCl4/Al2Cl7] 2a, and [(C7H5N2Me)B(C6F5)2][B(C6F5)4] 2b were prepared and are shown to feature a high Lewis acidity, the capability to activate hydrogen and to effect the 1,1 carborations of terminal and internal alkynes under mild conditions. PMID- 29138767 TI - A facile method for urinary phenylalanine measurement on paper-based lab-on-chip for PKU therapy monitoring. AB - A miniaturized paper-based lab-on-chip (LoC) was developed for the facile measurement of urinary Phe (phenylalanine) level on PKU (Phenylketonuria) treated patient. This system permits the monitoring of Phe in a dynamic range concentration of 20-3000 MUM. PMID- 29138768 TI - The role of trinuclear species in a palladium acetate/trifluoroacetic acid catalytic system. AB - Reactions catalyzed by palladium(ii) acetate and trifluoroacetic acid (TFA) have a clear preactivation phase. However, the structure of real catalytic species remains unclear. We show that the key species are cyclic trinuclear complexes of composition [Pd3(OAc)6-x(OTFA)x] (x = 1-6) formed by a sequential ligand exchange from [Pd3(OAc)6]. Furthermore, we prove that the trinuclear palladium backbone of the precatalyst remains preserved during the first phase of the C-H activation reaction of acetanilides. In other words, the reaction pathway including the trinuclear species should be taken into account in discussion about mechanisms of the reactions catalyzed by palladium acetates. PMID- 29138769 TI - Structure of in cell protein crystals containing organometallic complexes. AB - The molecular structures of in cell protein crystals containing organometallic Pd(allyl) complexes were determined by performing microfocus X-ray diffraction experiments. The coordination sites in a polyhedrin mutant with deletion of selected amino acid residues located at the interface of the polyhedrin trimer are dramatically altered compared to those of the wild-type composite. PMID- 29138770 TI - Interdiffusion and crystallization of oppositely charged colloids. AB - The aggregation of oppositely charged colloids, usually denoted as heteroaggregation, is often used in colloidal processing, for which a precise control of the basic mechanisms of aggregate formation is of crucial importance. A promising way to achieve a better degree of control is to guide heteroaggregation by imposing geometric constraints. Here, we consider this possibility by simulating the heteroaggregation of two oppositely charged suspensions which are initially separated and then put into contact through a planar interface. Our Brownian dynamics simulations show that this type of heteroaggregation allows the formation of mixed films whose thickness can be controlled by tuning the interactions between the particles or by changing the colloidal concentration in the initial suspensions. The dependence of the type of crystalline order in these films on these parameters is also analyzed. PMID- 29138771 TI - Near-infrared aza-BODIPY fluorescent probe for selective Cu2+ detection and its potential in living cell imaging. AB - A near-infrared (NIR) fluorescent sensor 1 composed of an aza-boron dipyrromethene (aza-BODIPY) core covalently bound to two di-2-picolylamine moieties was conceived for Cu2+ detection in aqueous solutions. Spectroscopic properties and binding abilities with several metal ions were investigated in phosphate buffered saline (pH 7.4): acetonitrile (95 : 5 v/v) with Triton X-100 via fluorometric titrations. The fluorescence of sensor 1 was quenched selectively by cupric ions in the presence of alkali- and transition-metal-ions. A detection limit of 13 ppb was measured for this system, and this is significantly lower than permissible levels of Cu2+ in drinking water according to the guidelines described by the U.S. Environmental Protection Agency (EPA) and by the World Health Organization (WHO). Application of the sensor in detecting Cu2+ in HepG2 cells was demonstrated. PMID- 29138772 TI - Mesoporous silica nanoparticles incorporating squaraine-based photosensitizers: a combined experimental and computational approach. AB - Squaraine dyes, that exhibit intense absorption in the red/near infrared region, have been successfully introduced into mesoporous silica nanoparticles (MSNs) to obtain a nanoplatform for photodynamic therapy. Three brominated squaraine dyes which exhibited good PS performance in solution but a different behaviour in vitro due to cell permeability issues were used as photosensitizers. The effects of the adsorption within the pores of MSNs on the overall UV-Vis-NIR absorption and emission properties as well as on the PS performance was evaluated via a combined experimental and computational physico-chemical approach, which allowed us to correlate the unusual optical properties of two out of three systems with the dimerization of squaraines on the silica surface, with detrimental effects on the PS performance. Conversely, the nanoplatform where the squaraine molecules are adsorbed as monomers on the silica surface exhibited the best activity in singlet oxygen generation. PMID- 29138773 TI - Cooperating dipole-dipole and van der Waals interactions driven 2D self-assembly of fluorenone derivatives: ester chain length effect. AB - Two-dimensional supramolecular assemblies of a series of 2,7-bis(10-n alkoxycarbonyl-decyloxy)-9-fluorenone derivatives (BAF-Cn, n = 1, 3-6) consisting of polar fluorenone moieties and ester alkoxy chains were investigated by scanning tunneling microscopy on highly oriented pyrolytic graphite surfaces. The chain-length effect was observed in the self-assembly of BAF-Cn. Self-assembly of BAF-C1 was composed of a linear I pattern, where the side chains adopted a fully interdigitated arrangement. As the length of side chains increased, the coexistence of a linear I pattern and a cyclic pattern for the self-assembly of BAF-C3 was observed. Upon increasing the length of the alkoxy chain even further (n = 4-6), another linear II structure was observed in the BAF-Cn monolayer, in which the side chains in adjacent rows were arranged in a tail-to-tail configuration. It is reasonable to conclude that not only the van der Waals forces but also the dipole-dipole interactions from both the fluorenone cores and the ester alkoxy chains play critical roles in the self-assemblies of BAF-Cn. Our work provides detailed insights into the effect of intermolecular dipole-dipole and van der Waals interactions on the monolayer morphology of fluorenone derivatives. PMID- 29138775 TI - Microsecond resolved single-molecule FRET time series measurements based on the line confocal optical system combined with hybrid photodetectors. AB - Single-molecule (sm) fluorescence time series measurements based on the line confocal optical system are a powerful strategy for the investigation of the structure, dynamics, and heterogeneity of biological macromolecules. This method enables the detection of more than several thousands of fluorescence photons per millisecond from single fluorophores, implying that the potential time resolution for measurements of the fluorescence resonance energy transfer (FRET) efficiency is 10 MUs. However, the necessity of using imaging photodetectors in the method limits the time resolution in the FRET efficiency measurements to approximately 100 MUs. In this investigation, a new photodetector called a hybrid photodetector (HPD) was incorporated into the line confocal system to improve the time resolution without sacrificing the length of the time series detection. Among several settings examined, the system based on a slit width of 10 MUm and a high speed counting device made the best of the features of the line confocal optical system and the HPD. This method achieved a time resolution of 10 MUs and an observation time of approximately 5 ms in the sm-FRET time series measurements. The developed device was used for the native state of the B domain of protein A. PMID- 29138774 TI - Exploring the effect of substituent in the hydrazone ligand of a family of MU oxidodivanadium(v) hydrazone complexes on structure, DNA binding and anticancer activity. AB - The reaction of 2-hydroxybenzoylhydrazine (H2bh) separately with equimolar amounts of [VIVO(aa)2] and [VIVO(ba)2] in CHCl3 afforded the complexes [VO3(HL1)2] (1) and [VO3(HL2)2] (2) respectively in good to excellent yield ((HL1)2- and (HL2)2- represent respectively the dianionic form of 2 hydroxybenzoylhydrazones of acetylacetone (H3L1) and benzoylacetone (H3L2) (general abbreviation H3L)). From X-ray structure analysis, the VV-O-VV angle was found to be ~115 degrees and 180 degrees in 1 and 2 respectively. Upon one electron reduction selectively at one V centre at an appropriate potential, each of 1 and 2 generated mixed-valence [(HL)VVO-(MU-O)-OVIV(HL)]- species 1A and 2A respectively, which showed valence delocalization at room temperature and localization at 77 K, and the VIV-O-VV bond angles were calculated to be 177.5 degrees and 180 degrees respectively. The intercalative mode of binding of the two complexes 1 and 2 with CT DNA has been suggested by UV-visible spectroscopy (Kb = 7.31 * 105 M-1 and 8.71 * 105 M-1 respectively for 1 and 2), fluorescence spectroscopy (Ksv = 6.85 * 105 M-1 and 8.53 * 105 M-1 respectively for 1 and 2) and circular dichroism spectroscopy. Such intercalative mode of binding of these two complexes with CT DNA and HPV DNA has also been confirmed by molecular docking study. Both complexes 1 and 2 exhibited promising anti-cancer activity against SiHa cervical cancer cells with IC50 values of 28 +/- 0.5 MUM and 25 +/- 0.5 MUM respectively for 24 h which is significantly better than that of widely used cisplatin (with IC50 value of 63.5 MUM). Nuclear staining experiments reveal that these complexes kill the SiHa cells through apoptotic mode. It is interesting to note that these two complexes are non-toxic to normal T293 cell line. Complex 2 showed higher DNA binding ability with CT DNA and HPV DNA as well as better anti-cancer properties towards SiHa cervical cancer cells in comparison to complex 1, a fact which can be explained by considering the lower energy of LUMO (which favours electron transition from DNA to the metal complex) and also the higher surface area of complex 2 in comparison to complex 1 due to the presence of one extra electron-withdrawing phenyl group in the former. PMID- 29138776 TI - Photoelectron spectroscopy and density functional theory studies of (fructose + (H2O)n)- (n = 1-5) anionic clusters. AB - Photoelectron spectroscopy (PES) and density functional theory (DFT) based calculations are executed to characterize gas phase, isolated (fructose + (H2O)n) (n = 1-5) anionic species produced using a matrix assisted laser desorption ionization (MALDI) method. Gas phase, isolated (fructose + (H2O)n)- (n = 1-5) cluster anions mainly exist as open chain structures with conformational and positional isomers in the present experiments. Some cyclic structures of (fructose + (H2O)n)- (n = 3, 4) are apparently present in the experiments and their VDEs can contribute to the lower energy shoulders of PES features observed for (fructose + (H2O)n)- (n = 3, 4). Cyclic (fructose + (H2O)n)- (n = 1-5) clusters have the added electron as dipole bound, whereas open chain structures have the added electron in a valence orbital. Water molecules in open chain anions predominantly interact with the (1)C side (including (1)OH, (2)O, and (3)OH) of fructose-: they finally form a quasi-cubic structure with OH groups and carbonyl O in the most stable structures for (fructose + (H2O)4)- and (fructose + (H2O)5)- cluster anions. Water molecules solvating cyclic anions form water-water hydrogen bond networks that preferentially interact with OH groups at the (1), (2), and (3) positions of fructose pyranose anions, and the (3), (4), and (6) positions of fructose furanose anions. Structures of neutral (fructose + (H2O)n) (n = 1-5) have pyranose structures as the lower energy isomers rather than open chain structures: this observation is consistent with the fructose solution tautomeric equilibrium with neutral fructose pyranose being the preponderant species. Water molecules also tend to form water-water hydrogen bond networks, interacting with OH groups at (1), (2), and (3) positions for neutral pyranose conformations. PMID- 29138777 TI - Expanding the structural analysis capabilities on an Orbitrap-based mass spectrometer for large macromolecular complexes. AB - Native mass spectrometry can provide insight into the structure of macromolecular biological systems. As analytes under investigation get larger and more complex, instrument capabilities need to be advanced. Herein, modifications to an Orbitrap Q Exactive Plus mass spectrometer that increase signal intensity, mass resolution, and maximum m/z measurable are described. PMID- 29138778 TI - Dual phosphorescence emission of dinuclear platinum(ii) complex incorporating cyclometallating pyrenyl-dipyridine-based ligand and its application in near infrared solution-processed polymer light-emitting diodes. AB - Two novel mono- and binuclear cyclometalated platinum(ii) complexes of (BuPyrDPy)Pt(dpm) and (BuPyrDPy)[Pt(dpm)]2 incorporating a pyrenyl-dipyridine based cyclometalated ligand were synthesized and characterized, respectively. Single-crystal X-ray diffraction of the two materials revealed each complex's coordination mode; their photophysical, electrochemical as well as electroluminescent properties were also investigated. Both complexes exhibited good solubility and excellent thermal stability. (BuPyrDPy)[Pt(dpm)]2 presented dual phosphorescence emissive character at room-temperature and showed an increased quantum efficiency compared to that of (BuPyrDPy)Pt(dpm). Density functional theory (DFT) calculations were carried out to model their photophysical process, and found a significant contribution of the second Pt center to the LUMO plot, giving the T1 and T2 states considerable LMCT nature, which is quite rare in metallic complexes. A device with the structure of ITO/PEDOT (40 nm)/PVK : 30 wt% OXD-7 : 16 wt% (BuPyrDPy)[Pt(dpm)]2 (60 nm)/TPBI (30 nm)/Ba (4 nm)/Al (100 nm) showed a stable NIR emission peak at 695 nm accompanied by two shoulders at 599 nm and 762 nm, with a maximum external quantum efficiency (EQE) of 0.31% and a radiance of 26.9 mW cm-2, which are about 2 and 1.4 times higher than those of (BuPyrDPy)Pt(dpm)-doped devices. This study provides an efficient strategy to simultaneously design novel biluminescent materials and achieve NIR emission through adjusting the emissive triplet states by introducing a second metal into an asymmetric bimetallic system. PMID- 29138779 TI - Ion-solvation structure and battery electrode characteristics of nonflammable organic electrolytes based on tris(trifluoroethyl)phosphate dissolving lithium salts. AB - The structure and properties of lithium salt solutions based on tris(2,2,2 trifluoroethyl)phosphate (TFEP) solvent have been studied to design a safer electrolyte system for large-sized lithium-ion battery applications. Influences of the ionic structure on the polarization behavior of the LiCoO2 (LCO) positive electrode were investigated. The ionic conductivity and viscosity of the solution consisting of lithium salts dissolved in TFEP, LiX/TFEP (X = PF6, BF4 and TFSA) (TFSA = (CF3SO2)2N), were measured. The results suggest that the ion-solvation structure greatly depends on the anionic species in the salt. Spectroscopic measurements also support the conclusion that the Li+-solvation structure varies with the lithium salts. The differences in the ionic structure of LiX/TFEP influence the electrochemical oxidation potential of the solution and the polarization behavior of the LCO electrode. The overvoltage for Li desertion/insertion from/into LCO in LiX/TFEP, being much higher than that observed in conventional LIB electrolyte solutions, shows the order of BF4 < PF6 < TFSA. The addition of ethylene carbonate (EC) to LiX/TFEP increases the ionic conductivity, which is probably caused by changes in the Li+-solvation structure in TFEP. The overvoltage for the Li-desertion/insertion of LCO is much lowered by the addition of EC to LiX/TFEP. PMID- 29138780 TI - Biological network border detection. AB - Complex networks have been widely used to model biological systems. The concept of accessibility has been proposed recently as a means to organize the nodes of complex networks as belonging to its border or center. Such an approach paves the way to investigating how the functional and structural properties of nodes vary with their respective position in the networks. In this work, we approach such a problem in a biological context applying border detection to Protein-Protein Interaction networks from four organisms of the Mycoplasma genus. We found evidence that the borderness of proteins bears a relation with their spatial organization and molecular function specificity. PMID- 29138782 TI - Vasorelaxant activity of twenty-one physiologically relevant (poly)phenolic metabolites on isolated mouse arteries. AB - Polyphenols are beneficial for health, but are metabolised after consumption. We compared the vasorelaxant capacity of twenty-one physiologically relevant polyphenol metabolites in isolated mouse arteries. Hesperetin, urolithins and ferulic acid-4-O-sulfate - not their glucuronidated forms or ferulic acid - caused vasorelaxation. Therefore, we advise the use of relevant conjugates in future mechanistic research. PMID- 29138785 TI - Microstructural metrology of tobacco mosaic virus nanorods during radial compression and heating. AB - We determined stress-induced deformations and the thermal stability of nanorod shaped tobacco mosaic virus (TMV) capsids in coffee-ring structures by X-ray nanodiffraction. The hexagonal capsids lattice transforms under compression in the outer boundary zone of the coffee-ring into a tetragonal lattice. The helical pitch of the nanorods increases by about 2.5% across the outer boundary zone while the lateral distance between nanorods decreases continuously across the whole coffee-ring structure by about 2% due to compressive forces. The diffraction patterns show a mixture of helical scattering and Bragg peaks attributed to a lattice of nanorods interlocked by their helical grooves. Thermo nanodiffraction reveals water loss up to about 100 degrees C resulting in a reduction of the helical pitch by about 6% with respect to its maximum value and a reduction of the nanorods separation by about 0.5 nm. Up to about 200 degrees C the pitch is increasing again by about 2%. Secondary crystallization in the bulk reaches a maximum at 150-160 degrees C. At higher temperatures the crystallinity is continuously decreasing up to about 220 degrees C. Above about 200 degrees C and depending on the heating history, the nanorods start disintegrating into small, randomly oriented aggregates. PMID- 29138786 TI - Electroconvection of pure nematic liquid crystals without free charge carriers. AB - We consider electroconvection as a response of nematic liquid crystals to an external electric AC field, in the absence of free charge carriers. Previous experimental and theoretical results emphasized charge carriers as a necessary precondition of electroconvection because free-charges in the fluid can respond to an external electric field. Therefore, ionized molecules are considered as responsible for the driving of electroconvective flows. In experiments, finite conductivity is achieved by adding charge-carrying dye molecules or in non-dyed liquid crystals by impurities of the samples. The phenomenon of electroconvection is explained by the Carr-Helfrich theory, supported by numerical simulations. In the present paper, we show that electroconvection may occur also in pure nematic liquid crystals. By means of particle-based numerical simulations we found that bound charges emerge by alignment of polarized liquid crystal molecules in response to the external electric field. In our simulations we could reproduce the characteristic features of electroconvection, such as director-flow patterns, the phase-transition in the voltage-frequency diagram, and dislocation climb/glide motion, which are well known from experiments and hydrodynamic simulations under the assumption of free charge carriers. PMID- 29138787 TI - Super-resolution imaging by metamaterial-based compressive spatial-to-spectral transformation. AB - We present a new far-field super-resolution imaging approach called compressive spatial to spectral transformation microscopy (CSSTM). The transformation encodes the high-resolution spatial information to a spectrum through illuminating sub diffraction-limited and wavelength-dependent patterns onto an object. The object is reconstructed from scattering spectrum measurements in the far field. The resolution of the CSSTM is mainly determined by the materials used to perform the spatial to spectral transformation. As an example, we numerically demonstrate sub 15 nm resolution by using a practically achievable Ag/SiO2 multilayer hyperbolic metamaterial. PMID- 29138788 TI - 3D-TEM study on the novel bicontinuous microdomain structure. AB - An ordered bicontinuous double-diamond (OBDD) morphology was found in polystyrene block-(poly-4-vinylphenyldimethylvinylsilane-graft-polyisoprene), PS-b-(PVS-g PI), block-graft copolymer. We obtained a 3D image of the microdomain structure formed in PS-b-(PVS-g-PI) using 3D-TEM. The 3D image shows that the polystyrene (PS) phase consists of two independent and interwoven networks. The structures of the two networks are identical and include tetrapod units that form planar six membered rings. The features of the networks agree with those in the OBDD morphology, indicating that PS-b-(PVS-g-PI) exhibits ordered three-dimensional OBDD networks with the PS phase in the polyisoprene (PI) matrix phase. The grafted PI chains induce the frustration of the PS chains; thus, the effects of the specific interface are more dominant than those of packing frustration in the formation of the morphology, and the OBDD phase is stabilized. PMID- 29138789 TI - Preferential S/Se occupation in an anisotropic ReS2(1-x)Se2x monolayer alloy. AB - Band structure engineering of two-dimensional (2D) metal dichalcogenides (TMDs) is crucial for their light-matter interaction and optoelectronic applications. Alloying of different metal or chalcogen elements with different stoichiometries in TMDs provides a versatile and efficient approach for modulating the electronic structure and properties of 2D materials. In 2D alloys, quantification of spatial distribution and local coordination of atoms facilitates the establishment of the structure-property relationship at the atomic scale. Here, we have imaged and analyzed the atomic configuration of sulfur and selenium atoms in anisotropic ReS1.4Se0.6 by scanning transmission electron microscopy (STEM). In Z-contrast images, we have realized the identification and quantification of Re, Se and S at different coordination sites. Different from the random distribution of metal and chalcogen elements in MoS2(1-x)Se2x and Mo1-xWxS2, we find that Se atoms preferentially locate inside of Re4 diamonds in ReS2(1-x)Se2x. Further density function theory (DFT) calculations reveal electronic structure modulation for Se occupation at different sites. PMID- 29138790 TI - High-efficiency single cell encapsulation and size selective capture of cells in picoliter droplets based on hydrodynamic micro-vortices. AB - Single cell analysis has emerged as a paradigm shift in cell biology to understand the heterogeneity of individual cells in a clone for pathological interrogation. Microfluidic droplet technology is a compelling platform to perform single cell analysis by encapsulating single cells inside picoliter nanoliter (pL-nL) volume droplets. However, one of the primary challenges for droplet based single cell assays is single cell encapsulation in droplets, currently achieved either randomly, dictated by Poisson statistics, or by hydrodynamic techniques. In this paper, we present an interfacial hydrodynamic technique which initially traps the cells in micro-vortices, and later releases them one-to-one into the droplets, controlled by the width of the outer streamline that separates the vortex from the flow through the streaming passage adjacent to the aqueous-oil interface (dgap). One-to-one encapsulation is achieved at a dgap equal to the radius of the cell, whereas complete trapping of the cells is realized at a dgap smaller than the radius of the cell. The unique feature of this technique is that it can perform 1. high efficiency single cell encapsulations and 2. size-selective capturing of cells, at low cell loading densities. Here we demonstrate these two capabilities with a 50% single cell encapsulation efficiency and size selective separation of platelets, RBCs and WBCs from a 10* diluted blood sample (WBC capture efficiency at 70%). The results suggest a passive, hydrodynamic micro-vortex based technique capable of performing high-efficiency single cell encapsulation for cell based assays. PMID- 29138791 TI - A new heteropolysaccharide from the seed husks of Plantago asiatica L. with its thermal and antioxidant properties. AB - A new heteropolysaccharide (PMH) with a molecular weight of 1.4 * 103 kDa was isolated from the seed husks of Plantago asiatica L. The monosaccharide composition of PMH was determined as glucose, xylose, arabinose, rhamnose, galactose and galacturonic acid with a molar ratio of 1.0 : 1.8 : 2.4 : 3.8 : 4.9 : 8.5. The backbone of PMH consisted of 1,4-beta-d-GalpA with the side chains mainly composed of 1,3-alpha-d-Galp and 1,2-alpha-d-Galp which were attached to the O-3 of GlapA. The thermal analysis using the Flynn-Wall-Ozawa (FWO) method revealed that PMH had an apparent activation energy (Ea) of 173.1 kJ mol-1. PMH experienced a major decomposition during the heating process at a temperature of 91.1 degrees C with a dry weight loss of 31.1%. Moreover, PMH exhibited stronger antioxidant ability than commercial psyllium, partially due to its higher content of uronic acid. The results suggested that PMH could be used in functional foods due to its structural, thermal and antioxidant characteristics. PMID- 29138792 TI - Reviewers Who Completed a Review During 2011. PMID- 29138793 TI - Acute Chest Pain in the Emergency Department. PMID- 29138794 TI - Noninvasive Cardiac Testing vs Clinical Evaluation Alone in Acute Chest Pain: A Secondary Analysis of the ROMICAT-II Randomized Clinical Trial. AB - Importance: The incremental benefit of noninvasive testing in addition to clinical evaluation (history, physical examination, an electrocardiogram [ECG], and biomarker assessment) vs clinical evaluation alone for patients who present to the emergency department (ED) with acute chest pain is unknown. Objective: To examine differences in outcomes with clinical evaluation and noninvasive testing (coronary computed tomographic angiography [CCTA] or stress testing) vs clinical evaluation alone. Design, Setting, and Participants: This study was a retrospective analysis of data from the randomized multicenter Rule Out Myocardial Ischemia/Infarction by Computer Assisted Tomography (ROMICAT-II) trial. Data for 1000 patients who presented with chest pain to the EDs at 9 hospitals in the United States were evaluated. Interventions: Clinical evaluation plus noninvasive testing (CCTA or stress test) vs clinical evaluation alone. Main Outcomes and Measures: Primary outcome was length of stay (LOS). Secondary outcomes included hospital admission, direct ED discharge, downstream testing, rates of invasive coronary angiography, revascularization, major adverse cardiac events (MACE), repeated ED visit or hospitalization for recurrent chest pain at 28 days, and cost. Safety end points were missed acute coronary syndrome (ACS) and cumulative radiation exposure during the index visit and follow-up period. Results: Of the 1000 patients randomized, 118 patients (12%) (mean [SD] age, 53.2 [7.8]; 49 [42%] were female) did not undergo noninvasive testing, whereas 882 (88%) (mean [SD] age, 54.4 [8.14] years; 419 [48%] were female) received CCTA or stress testing. There was no difference in baseline characteristics or clinical presentation between groups. Patients who underwent clinical evaluation alone experienced a shorter LOS (20.3 vs 27.9 hours; P < .001), lower rates of diagnostic testing (P < .001) and angiography (2% vs 11%; P < .001), lower median costs ($2261.50 vs $2584.30; P = .009), and less cumulative radiation exposure (0 vs 9.9 mSv; P < .001) during the 28-day study period. Lack of testing was associated with a lower rate of diagnosis of ACS (0% vs 9%; P < .001) and less coronary angiography and percutaneous coronary intervention (PCI) during the index visit (0% vs 10%; P < .001, and 0% vs 4%; P = .02, respectively). There was no difference in rates of PCI (2% vs 5%; P = .15), coronary artery bypass surgery (0% vs 1%; P = .61), return ED visits (5.8% vs 2.8%; P = .08), or MACE (2% vs 1%; P = .24) in the 28-day follow-up period. Conclusions and Relevance: In patients presenting to the ED with acute chest pain, negative biomarkers, and a nonischemic ECG result, noninvasive testing with CCTA or stress testing leads to longer LOS, more downstream testing, more radiation exposure, and greater cost without an improvement in clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01084239. PMID- 29138795 TI - Hesperidin induces apoptosis and G0/G1 arrest in human non-small cell lung cancer A549 cells. AB - Lung cancer has high incidence and mortality rates worldwide. In the present study, the mechanisms by which hesperidin decreases the viability and induces the apoptosis of human non-small cell lung cancer (NSCLC) A549 cells were investigated. Initially, MTT and flow cytometric assays were performed to evaluate the effects of hesperidin on the viability and apoptosis of A549 cells and human normal lung epithelial BEAS-2B cells. The results revealed that hesperidin has no negative effects on the human normal lung epithelial BEAS-2B cells and the viability of cells treated with various concentrations of hesperidin was inhibited in a time- and dose-dependent manner compared with the control groups. Subsequently, the expression levels of proteins involved in the mitochondria-associated apoptotic pathway were studied by western blot analysis. Hesperidin was identified to induce A549 cell apoptosis by downregulating the levels of B-cell lymphoma-2 (Bcl-2) and Bcl extra large protein and simultaneously upregulating the levels of Bcl-2-associated X protein, BH3 interacting-domain death agonist (Bid), tBid, cleaved caspase-9, cleaved caspase 3 and cleaved poly(adenosine diphosphate ribose)polymerase. The effect of hesperidin on the cell cycle was assessed by flow cytometry. Hesperidin was observed to cause G0/G1 arrest of A549 cells by decreasing the expression of cyclin D1 and increasing the expression of p21 and p53. In summary, it was demonstrated that hesperidin induced apoptosis through the mitochondrial apoptotic pathway and induced G0/G1 arrest in human NSCLC A549 cells. Therefore, hesperidin may be developed as a potential therapeutic drug for the treatment of NSCLC. PMID- 29138796 TI - Reactive oxygen species induce injury of the intestinal epithelium during hyperoxia. AB - Long-term therapeutic hyperoxia may exert serious toxic effects on intestinal epithelial cells in vitro and in vivo. The aim of the present study was to investigate the cause of this intestinal injury under conditions of hyperoxia. Caco-2 cells were treated with different concentrations of hydrogen peroxide (H2O2) and 85% hyperoxia for 24 h. higher rates of injury of Caco-2 cells were observed in the hyperoxia and H2O2 groups compared with the control group. The reactive oxygen species (ROS) level of the hyperoxia group was significantly higher compared with that of the 400 uM H2O2 group. The protein and gene levels of RelA, RelB, hypoxia-inducible factor-1alpha, tumor necrosis factor-alpha and apoptosis signal-regulating kinase 1 were significantly higher in the hyperoxia and H2O2 groups compared with those in the control group. In conclusion, during hyperoxia, intestinal epithelial cells were destroyed and the levels of ROS were increased. Therefore, ROS may play an important role in intestinal injury in a hyperoxic environment. PMID- 29138797 TI - Activation of adrenergic receptor beta2 promotes tumor progression and epithelial mesenchymal transition in tongue squamous cell carcinoma. AB - Tongue squamous cell carcinoma (TSCC) is more aggressive than other cancers in the head and neck region because of its potential for metastasis. Recently, beta2 adrenergic receptor (beta2-AR) has been reported to be a potential promoter in various types of solid cancer. However, the role of beta2-AR and its effect on TSCC is not well documented. Histological staining, western blot analysis, migration and invasion assay were used. In this study, the expression of beta2-AR was increased in TSCC tissue compared with adjacent non-cancerous epithelium. Further analysis demonstrated that increased expression of beta2-AR was correlated with differentiation, lymph node metastasis and reduced overall survival rate in patients with TSCC. In vitro studies confirmed that activation of beta2-AR can promote epithelial mesenchymal transition in TSCC by initiating an interleukin-6/Stat3/Snail1 pathway. These results suggest that beta2-AR has an oncogenic role in TSCC and may be a potential therapeutic target in TSCC. PMID- 29138798 TI - Hey1 functions as a positive regulator of odontogenic differentiation in odontoblast-lineage cells. AB - Substantial evidence has indicated that Notch and bone morphogenetic protein (BMP) signaling may regulate odontoblastic differentiation. Hairy/enhancer-of split related with YRPW motif 1 (Hey1), a downstream target gene of Notch and BMP signaling, is expressed in dental pulp tissues and has been demonstrated to be responsible for osteoblast mineralization. The aim of this study was to investigate the effects of Hey1 on odontoblast differentiation. The results of the study demonstrated that Hey1 expression in odontoblast-lineage cells (OLCs) was upregulated by stimulation of osteoblastic/odontoblastic differentiation medium containing ascorbic acid, beta-glycerol phosphate and dexamethasone. Furthermore, stable Hey1-overexpressing cells expressed higher levels of dentin sialophosphoprotein (DSPP) and exhibited higher mineralization capabilities following stimulation by differentiation medium. Furthermore, RNA interference mediated knockdown of Hey1 downregulated the expression levels of DSPP in OLCs stimulated by differentiation medium. Taken together, the findings indicate that Hey1 may be a positive regulator of odontoblastic differentiation. The present study broadens the understanding of odontoblast differentiation and biomineralization. PMID- 29138799 TI - Lychee seed extract protects against neuronal injury and improves cognitive function in rats with type II diabetes mellitus with cognitive impairment. AB - Lychee seed is a traditional Chinese medicine and has many beneficial effects such as modulation of blood sugar and lipids, antioxidation, antivirus and antitumor. Studies have indicated that type II diabetes mellitus (T2DM) and Alzheimer's disease (AD) share common biological mechanisms including insulin resistance, impaired glucose metabolism, beta-amyloid (Abeta) formation, oxidative stress and presence of advanced glycation end products (AGEs). The present study investigated the effects of lychee seed extract (LSE) on neuroprotection, cognitive function improvement and possible underlying mechanisms in a rat model of T2DM with cognitive impairment. We analyzed the chemical profile of LSE using a UHPLC-SPD chromatogram and evaluated its effect on the improvement of spatial learning and memory of rats by a Morris water maze. The levels of glucose, insulin, Abeta, AGEs, Tau protein and acetylcholinesterase in the blood and/or hippocampus of rats were determined by blood-glucose meter, radioimmunoassay, chemical chromatometry, enzyme-linked immunosorbent assay (ELISA) and immunohistochemical analysis, respectively. Results demonstrated that LSE consists of eight major and around 20 minor ingredients, and it remarkably prevents neuronal injury and improves cognitive functions in T2DM rats. The levels of glucose, insulin, Abeta, AGEs and Tau protein were significantly increased in the blood and/or hippocampus of T2DM rats, while LSE remarkably decreased their levels compared to vehicle treatment (P<0.01). The possible mechanisms may be associated with IR improvement and decreased formations of Abeta, AGEs and Tau protein in the hippocampus of T2DM rats. LSE may be developed as the agent for the treatment of T2DM and/or AD clinically. PMID- 29138800 TI - Broadleaf Mahonia attenuates granulomatous lobular mastitis-associated inflammation by inhibiting CCL-5 expression in macrophages. AB - Granulomatous lobular mastitis (GLM) is a type of chronic mammary inflammation with unclear etiology. Currently systematic corticosteroids and methitrexate are considered as the main drugs for GLM treatment, but a high toxicity and risk of recurrence greatly limit their application. It is therefore an urgent requirement that safe and efficient natural drugs are found to improve the GLM prognosis. Broadleaf Mahonia (BM) is a traditional Chinese herb that is believed to have anti-inflammatory properties according to ancient records of traditional Chinese medicine. The present study investigated this belief and demonstrated that BM significantly inhibited the expression of interleukin-1beta (IL-1beta), IL-6, cyclooxygenase-2 and inducible nitric oxide synthase in RAW264.7 cells, but had little influence on the cell viability, cell cycle and apoptosis. Meanwhile, the lipopolysaccharide-induced elevation of reactive oxygen species and nitric oxide was also blocked following BM treatment, accompanied with decreased activity of nuclear factor-kappaB and MAPK signaling. A cytokine array further validated that BM exhibited significant inhibitory effects on several chemoattractants, including chemokine (C-C motif) ligand (CCL)-2, CCL-3, CCL-5 and secreted tumor necrosis factor receptor 1, among which CCL-5 exhibited the highest inhibition ratio in cell and clinical GLM specimens. Collectively, the results show that BM is a novel effective anti-inflammatory herb in vitro and ex vivo, and that CCL-5 may be closely associated with GLM pathogenesis. PMID- 29138801 TI - Vitamin D receptor activation influences the ERK pathway and protects against neurological deficits and neuronal death. AB - Previous studies have demonstrated that global cerebral ischemia (GCI) causes neurological deficits and neuronal cell apoptosis. Calcitriol, a biologically active metabolite of vitamin D, exerts its endocrinological influence via nuclear vitamin D receptor. It is being assessed as an emerging therapeutic strategy in models of various medical conditions, including acute brain injury. The purpose of the present study was to investigate the neuroprotective effects of calcitriol on GCI and further refine the potential underlying mechanisms. A total of 145 male rats were assigned to 5 groups as follows: Sham group, GCI group, calcitriol treatment group, PD98059 treatment group and vehicle-treated group. Brain water content and neurologic severity score were assessed to evaluate the brain edema and neurological deficits of rats. Histopathological changes and ultrastructures of cells were observed via hematoxylin and eosin stain and transmission electron microscopy, respectively. Immunofluorescent staining and western blot analysis were used to assess the expression of proteins and their co-localization at the molecular level. The results demonstrated that post-GCI administration of calcitriol attenuated brain edema and improved neurological function in rats. Calcitriol also caused marked extracellular signal-regulated kinase 1/2 pathway activation, and thereby attenuated neuronal apoptosis. The present study provided novel clues for understanding the mechanisms by which calcitriol exerts its neuroprotective activity in a rat model of GCI. PMID- 29138802 TI - In vitro investigation of the mechanism underlying the effect of ginsenoside on the proliferation and differentiation of neural stem cells subjected to oxygen glucose deprivation/reperfusion. AB - The present study comprised a series of experiments to investigate the mechanism underlying the effect of ginsenoside on the self-renewal, proliferation and differentiation of neural stem cells (NSCs) undergoing oxygen-glucose deprivation/reperfusion (OGD/R) in vitro. The NSCs, which were isolated from the hippocampus of embryonic day 17 embryo rats, were subjected to OGD/R to establish an in vitro model of brain ischemia-reperfusion, following which different doses of ginsenoside were administered to the model. The proliferation of the NSCs was determined using MTT colorimetry and nestin/bromodeoxyuridine (BrdU) immunofluorescent double-labeling. The NSCs were identified by measuring the expression of nestin, and the differentiation of NSCs was assessed through the immunofluorescent double-labeling of nestin/vimentin and nestin/neuron-specific class III beta-tubulin (tuj-1). The protein levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1alpha (HIF-1alpha) were detected to investigate the function and mechanism of ginsenoside on ischemic stroke using an enzyme-linked immunosorbent assay. Marked increases in the optical density, area density and numbers of nestin/BrdU-, nestin/vimentin- and nestin/tuj-1-positive cells were found in the ginsenoside-treated group. Compared with the control group, enhanced expression levels of BrdU, tuj-1 and vimentin were found in the ginsenoside-treated group, suggesting that ginsenoside may significantly promote the proliferation and differentiation of NSCs. The results of the present study also showed that ginsenoside significantly increased the protein level of HIF 1alpha (P<0.05) in the NSCs exposed to OGD/R. These results indicated that ginsenoside may maintain NSC replication, promote NSC proliferation and promote NSC differentiation into neurons and astrocytes. Ginsenoside may initiate the expression of downstream VEGF, which is involved in promoting the survival, self renewal and differentiation of NSCs. PMID- 29138803 TI - Toll like receptors TLR1/2, TLR6 and MUC5B as binding interaction partners with cytostatic proline rich polypeptide 1 in human chondrosarcoma. AB - Metastatic chondrosarcoma is a bone malignancy not responsive to conventional therapies; new approaches and therapies are urgently needed. We have previously reported that mTORC1 inhibitor, antitumorigenic cytostatic proline rich polypeptide 1 (PRP-1), galarmin caused a significant upregulation of tumor suppressors including TET1/2 and SOCS3 (known to be involved in inflammatory processes), downregulation of oncoproteins and embryonic stem cell marker miR 302C and its targets Nanog, c-Myc and Bmi-1 in human chondrosarcoma. To understand better the mechanism of PRP-1 action it was very important to identify the receptor it binds to. Nuclear pathway receptor and GPCR assays indicated that PRP-1 receptors are not G protein coupled, neither do they belong to family of nuclear or orphan receptors. In the present study, we have demonstrated that PRP 1 binding interacting partners belong to innate immunity pattern recognition toll like receptors TLR1/2 and TLR6 and gel forming secreted mucin MUC5B. MUC5B was identified as PRP-1 receptor in human chondrosarcoma JJ012 cell line using Ligand receptor capture technology. Toll like receptors TLR1/2 and TLR6 were identified as binding interaction partners with PRP-1 by western blot analysis in human chondrosarcoma JJ012 cell line lysates. Immunocytochemistry experiments confirmed the finding and indicated the localization of PRP-1 receptors in the tumor nucleus predominantly. TLR1/2, TLR6 and MUC5B were downregulated in human chondrosarcoma and upregulated in dose-response manner upon PRP-1 treatment. Experimental data indicated that in this cellular context the mentioned receptors had tumor suppressive function. PMID- 29138804 TI - Cucurbitacin B and cancer intervention: Chemistry, biology and mechanisms (Review). AB - Cancer is one of the most important healthcare matters, with the worst prognosis but the best possibilities for scientific development. It is likely to increase in the future and cause global havoc designating it as an epidemic. Cancer development requires urgent intervention. Past few decades have witnessed extensive research to challenge carcinogenesis. Treatment involving synthetic discipline is often associated with severe adverse effects, or even worsened prognosis. Accordingly, newer economic and patient friendly molecules are warranted. Many natural substances have proved their potential so far. Cucurbitacin B against cancer and other diseases has achieved towering popularity among the researchers around the world, as detailed in the below sections with summarized tables. In line with the fascinating role of cucurbitacin B against various types of cancers, through various molecular signaling pathways, it is justifiable to propose cucurbitacin B as a mainline chemotherapy before the onset and after the diagnosis of cancer. PMID- 29138807 TI - Role of LASP-1, a novel SOX9 transcriptional target, in the progression of lung cancer. AB - Lung cancer accounts for most cancer-related deaths worldwide. However, the underlying mechanism by which it mediates the progression of lung cancer remains unclear. Expression of LASP-1 (LIM and SH3 protein 1) was evaluated in lung cancer tissues and tumor-adjacent normal tissues using immunohistochemistry and western blotting. Functional studies have shown that siRNA-mediated silencing of LASP-1 in human lung cancer cells and reduced cell proliferation, migration, and invasion. Flow cytometry and immunofluorescence staining also revealed that rate of cell apoptosis was increased after knockdown of expression of LASP-1, thereby suggesting that LASP-1 may function as an oncogene during lung cancer progression. SOX9 is an important transcription factor, which is involved in the development of several types of human cancer. Further analysis has showed the presence of a consensus-binding site of SOX9 in the promoter region of LASP-1. Mechanistic investigations showed that LASP-1 was transcriptionally activated by SOX9. Through luciferase reporter and ChIP assays, we demonstrated that LASP-1 was a direct target gene of sex determining region Y-box 9 (SOX9). Knockdown of SOX9 expression by RNA interference reduces cell proliferation and induces apoptosis of lung cancer cells, which was consistent with the results obtained from silencing the expression of LASP-1 in NCI-H1650 cells. Together, these findings indicated that LASP-1, as a downstream target of SOX9, may act as a novel biomarker for lung cancer and plays an important role in cell proliferation, migration, and invasion. PMID- 29138806 TI - Effect of bis(hydroxymethyl) alkanoate curcuminoid derivative MTH-3 on cell cycle arrest, apoptotic and autophagic pathway in triple-negative breast adenocarcinoma MDA-MB-231 cells: An in vitro study. AB - Curcumin has been shown to exert potential antitumor activity in vitro and in vivo involved in multiple signaling pathways. However, the application of curcumin is still limited because of its poor hydrophilicity and low bio availability. In the present study, we investigated the therapeutic effects of a novel and water soluble bis(hydroxymethyl) alkanoate curcuminoid derivative, MTH 3, on human breast adenocarcinoma MDA-MB-231 cells. This study investigated the effect of MTH-3 on cell viability, cell cycle and induction of autophagy and apoptosis in MDA-MB-231 cells. After 24-h treatment with MTH-3, a concentration dependent decrease in MDA-MB-231 cell viability was observed, and the IC50 value was 5.37+/-1.22 uM. MTH-3 significantly triggered G2/M phase arrest and apoptosis in MDA-MB-231 cells. Within a 24-h treatment, MTH-3 decreased the CDK1 activity by decreasing CDK1 and cyclin B1 protein levels. MTH-3-induced apoptosis was further confirmed by morphological assessment and annexin V/PI staining assay. Induction of apoptosis caused by MTH-3 was accompanied by an apparent increase of DR3, DR5 and FADD and, as well as a marked decrease of Bcl-2 and Bcl-xL protein expression. MTH-3 also decreased the protein levels of Ero1, PDI, PERK and calnexin, as well as increased the expression of IRE1alpha, CHOP and Bip that consequently led to ER stress and MDA-MB-231 cell apoptosis. In addition, MTH-3 treated cells were involved in the autophagic process and cleavage of LC3B was observed. MTH-3 enhanced the protein levels of LC3B, Atg5, Atg7, Atg12, p62 and Beclin-1 in MDA-MB-231 cells. Finally, DNA microarray was carried out to investigate the level changes of gene expression modulated by MTH-3 in MDA-MB-231 cells. Taken together, our results suggest that MTH-3 might be a novel therapeutic agent for the treatment of triple-negative breast cancer in the near future. PMID- 29138805 TI - Extracellular polysaccharides purified from Aureobasidium pullulans SM-2001 (Polycan) inhibit dexamethasone-induced muscle atrophy in mice. AB - The present study assessed the beneficial skeletal muscle-preserving effects of extracellular polysaccharides from Aureobasidium pullulans SM-2001 (Polycan) (EAP) on dexamethasone (DEXA)-induced catabolic muscle atrophy in mice. To investigate whether EAP prevented catabolic DEXA-induced muscle atrophy, and to examine its mechanisms of action, EAP (100, 200 and 400 mg/kg) was administered orally, once a day for 24 days. EAP treatment was initiated 2 weeks prior to DEXA treatment (1 mg/kg, once a day for 10 days) in mice. Body weight alterations, serum biochemistry, calf thickness, calf muscle strength, gastrocnemius muscle thickness and weight, gastrocnemius muscle antioxidant defense parameters, gastrocnemius muscle mRNA expression, histology and histomorphometry were subsequently assessed. After 24 days, DEXA control mice exhibited muscle atrophy according to all criteria indices. However, these muscle atrophy symptoms were significantly inhibited by oral treatment with all three doses of EAP. Regarding possible mechanisms of action, EAP exhibited favorable ameliorating effects on DEXA-induced catabolic muscle atrophy via antioxidant and anti-inflammatory effects; these effects were mediated by modulation of the expression of genes involved in muscle protein synthesis (AKT serine/threonine kinase 1, phosphatidylinositol 3-kinase, adenosine A1 receptor and transient receptor potential cation channel subfamily V member 4) and degradation (atrogin-1, muscle RING-finger protein-1, myostatin and sirtuin 1). Therefore, these results indicated that EAP may be helpful in improving muscle atrophies of various etiologies. EAP at 400 mg/kg exhibited favorable muscle protective effects against DEXA-induced catabolic muscle atrophy, comparable with the effects of oxymetholone (50 mg/kg), which has been used to treat various muscle disorders. PMID- 29138808 TI - The biology and function of extracellular vesicles in nasopharyngeal carcinoma (Review). AB - Extracellular vesicles are a heterogeneous group of membrane-enclosed vesicles, which play an important role in intercellular communication. Increasing number of studies have shown that tumor-derived extracellular vesicles might be involved in the transfer of oncogenic cargo (proteins, lipids, messenger RNA, microRNA, non coding RNAs and DNA) through which cancer cells could shape the tumor microenvironment and influence tumor progression. Nasopharyngeal carcinoma derived extracellular vesicles have also reported to facilitate tumor proliferation, metastasis and immune escape. Moreover, nasopharyngeal carcinoma derived extracellular vesicles might serve as biomarkers for early diagnosis and therapeutic targets. The present review provides information on the biological and clinical significance of extracellular vesicles in tumors, especially in nasopharyngeal carcinoma. PMID- 29138810 TI - Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-kappaB pathway. AB - The aim of the present study was to investigate the role of the angiotensin converting enzyme (ACE)2-angiotensin-(Ang)-(1-7)-Mas axis in the pathogenesis of pancreatitis and the association between this axis and the p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor (NF-kappaB) signaling pathway in pancreatic acinar cells. Mouse pancreatic acinar cancer (MPC-83) cells were stimulated with 10 nM caerulein (CAE) to create an in vitro model of acute pancreatitis, and collected for analysis at 2, 6, 12, 24 and 48 h post stimulation. In addition, cells were pretreated with different concentrations of Ang-(1-7), Ang-(1-7) antagonist A779, p38 MAPK inhibitor SB203580 or ACE2 inhibitor DX600 for 30 min, and then stimulated with CAE for 24 h. The ACE2, Mas receptor, p38 MAPK, phosphorylated (p)-p38 MAPK and NF-kappaB expression levels were evaluated using western blotting and immunofluorescence. p38 MAPK, NF kappaB, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-8 and IL-10 mRNA expression levels were assessed using reverse transcription quantitative polymerase chain reaction. The results of the immunofluorescence assay demonstrated that ACE2 and p38 MAPK were present mainly in the cytoplasm, while the Mas receptor was located mainly in the cell membrane. ACE2, p38 MAPK and p-p38 MAPK protein levels were significantly increased (P<0.05) following stimulation with CAE compared with those in the control group and peaked at 24 h. Mas receptor protein levels were significantly upregulated (P<0.05) between 6 and 24 h, peaking at 12 h. Ang-(1-7) and SB203580 downregulated p-p38 MAPK and NF kappaB expression and the mRNA levels of inflammatory factors IL-6, TNF-alpha and IL-8, but upregulated the mRNA level of inflammatory factor IL-10 compared with those treated with CAE alone. These results were supported by the opposite outcomes observed for cells treated with A779 or DX600. Therefore, it was concluded that the ACE2-Ang-(1-7)-Mas axis significantly inhibits pancreatitis by inhibition of the p38 MAPK/NF-kappaB signaling pathway. PMID- 29138809 TI - MicroRNA expression profiles in non-epithelial ovarian tumors. AB - Ovarian germ cell tumors (OGCTs) and sex cord stromal tumors (SCSTs) are rare gynecologic tumors that are derived from germ and stromal cells, respectively. Unlike their epithelial counterparts, molecular pathogenesis of these tumor types is still poorly understood. Here, we characterized microRNA (miRNA) expression profiles of 9 OGCTs (2 malignant and 7 benign) and 3 SCSTs using small RNA sequencing. We observed significant miRNA expression variations among the three tumor groups. To further demonstrate the biological relevance of our findings, we selected 12 miRNAs for validation in an extended cohort of 16 OGCTs (9 benign and 7 malignant) and 7 SCSTs by reverse transcription-quantitative polymerase chain reaction. Higher expression of miR-373-3p, miR-372-3p and miR-302c-3p and lower expression of miR-199a-5p, miR-214-5p and miR-202-3p were reproducibly observed in malignant OGCTs as compared to benign OGCTs or SCSTs. Comparing with benign OGCTs, miR-202c-3p and miR-513c-5p were more abundant in SCSTs. Additionally, we examined Beclin 1 (BECN1), a target of miR-199a-5p, in the clinical samples using western blot analysis. Our results show that BECN1 expression was higher in malignant OGCTs than benign OGCTs, which is concordant with their lower miR-199a 5p expression. This study suggests that these miRNAs may have potential value as tumor markers and implications for further understanding the molecular basis of these tumor types. PMID- 29138811 TI - High expression of MAGE-A9 contributes to stemness and malignancy of human hepatocellular carcinoma. AB - MAGE-A9, a well-characterized cancer testis antigen (CTA), belongs to a member of melanoma antigen gene (MAGE) family. In human malignancies, aberrant expression of MAGE genes correlated with poor clinical prognosis, increased tumor growth, metastases, and enrichment in stem cell populations of certain cancers. Cancer stem cells (CSCs) have been proposed to contribute to the major malignant phenotypes of liver cancer, including recurrence, metastasis and chemoresistance. However, expression and potential role of MAGE-A9 in liver cancer stem cells (LCSCs) still remain unclear. In the present study, we first analyzed the expression profiling of MAGE family genes in EpCAM+ and EpCAM- human hepatocellular carcinoma (HCC), based on public Gene Expression Omnibus (GEO) database. Among these examined MAGE members, MAGE-A9 is the only one with significantly higher expression in EpCAM+ HCC specimens as compared with EpCAM- HCC. Quantitative PCR analysis further confirmed that MAGE-A9 expression significantly elevated in a subtype of HCC patients that had features of hepatic stem/progenitor cells with high-level expression of EpCAM and alpha-fetoprotein (AFP). Moreover, MAGE-A9 displayed remarkably enriched expression in EpCAM+ HCC cells that were sorted by fluorescence-activated cell sorting and cultured HCC cell spheroids with characteristics of stem/progenitor cells. Functional experiments further revealed that MAGE-A9 overexpression promoted cell proliferation, colony formation, migration, chemoresistance, and tumorigenicity in the context of EpCAM+ HCC cells, whereas MAGE-A9 knockdown significantly inhibited anchorage-dependent and spheroid colony formation and in vivo tumorigenicity. Collectively, these data demonstrate that MAGE-A9 functions as an important regulator of LCSCs, and MAGE-A9 may serve as a potential therapeutic target against HCC stem/progenitor cells. PMID- 29138812 TI - Expression and regulation of the ERK1/2 and p38 MAPK signaling pathways in periodontal tissue remodeling of orthodontic tooth movement. AB - The present study aimed to investigate the expression and regulation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) signaling pathways in periodontal tissue remodeling of orthodontic tooth movement. Sprague Dawley rats with orthodontic tooth movement were generated. After tension stress for 1, 3, 5, 7 and 14 days, the protein and mRNA expression levels of ERK1/2 and p38 in periodontal tissue were determined by western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively. Primary human periodontal ligament cells (hPDLCs) were separated and characterized. Following exposure to centrifugal force for 1, 2, 6, 8 and 12 h, the protein expression levels of ERK1/2 and p38 MAPK, and the mRNA expression levels of ERK1/2, p38 and osteogenesis associated-genes [including alkaline phosphatase (ALP), osteopontin (OPN), collagen I (Col I), osteocalcin (OCN) and bone sialoprotein (BSP)] were measured. The protein expression levels of ERK1/2 and p38 MAPK in periodontal tissue and hPDLCs treated with stress were similar to those in the control groups. However, compared with the control, the phosphorylation and mRNA expression levels of the genes encoding ERK1/2 and p38 MAPK in orthodontic periodontal tissue and forced hPDLCs were elevated. These increases reached a peak at 5 days for orthodontic periodontal tissue and at 6 h for forced hPDLCs. In forced hPDLCs, the mRNA expression levels of ALP, OPN, Col I, OCN and BSP were notably and continuously upregulated in a time-dependent manner. In addition, hPDLCs were treated with the ERK1/2 inhibitor, PD098059, and the p38 MAPK inhibitor, SB203580, and the mRNA expression levels of the osteogenesis associated-genes were then measured using RT-qPCR. Following treatment with the ERK1/2 inhibitor and p38 MAPK inhibitor, the mRNA expression levels of ALP, OPN, Col I, OCN and BSP were significantly downregulated. In conclusion, ERK1/2 and p38 MAPK signaling pathways may be positively and closely associated with periodontal tissue remodeling of orthodontic tooth movement. PMID- 29138813 TI - Reduced miRNA-214 expression in oral mucosa contributes to the pathogenesis of oral lichen planus by targeting CD44. AB - The present study aimed to investigate the role of miRNAs during the pathogenesis of oral lichen planus (OLP). OLP is a chronic inflammatory disorder, which involves T-cell mediated autoimmunity and affects the skin, scalp, nails and mucosa. Abundant T lymphocytes have been demonstrated to infiltrate the oral mucosa, in which the activated T cells trigger apoptosis of oral epithelial cells. Overexpression of osteopontin (OPN) and CD44 has been observed in the mucosa of patients with OLP, and it has been confirmed that OPN suppresses the apoptosis of activated CD8+ T cells via CD44. The present study initially detected the protein and mRNA expression of CD44 and OPN in the mucosa of patients with OLP by western blot analysis and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and confirmed the previously reported overexpression of CD44 and OPN in patients with OLP. The current study demonstrated, by RT-qPCR, that the expression of microRNA-214 (miR-214), miR-216a and miR-216b was significantly reduced in patients with OLP. By analyzing the association between the protein level of CD44 and the expression of microRNAs (miRNAs), the present study identified a negative correlation between the expression of miR-214 and CD44 in the mucosa samples of patients with OLP. Subsequently, the present study confirmed that miR-214 represses endogenous CD44 expression by targeting the 3'untranslated region in HeLa, Raji and Jurkat cells. The current study indicates that reduced miR-214 may be associated with OLP and, therefore, may be a candidate for drug development. PMID- 29138814 TI - Grape seed proanthocyanidin extract attenuates varicocele-induced testicular oxidative injury in rats by activating the Nrf2-antioxidant system. AB - The present study investigated whether grape seed proanthocyanidin extract (GSPE) can attenuate varicocele-induced testicular oxidative injury through the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant pathway. A varicocele model in rats was established by partial ligation of the left renal vein. Following 4 weeks of GSPE administration, the decreased sperm count and motility and other pathological changes caused by varicocele were significantly alleviated, as indicated by the results of computer-assisted sperm analysis and hematoxylin and eosin staining. In addition, the decreased antioxidant enzyme (superoxide dismutase and glutathione peroxidase) activity and elevated oxidative stress level were partially reversed by administration of GSPE. Furthermore, the apoptotic level of the testis induced by varicocele was decreased by the GSPE treatment, according to terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Additionally, the expression of apoptosis-related proteins, including B-cell lymphoma 2 (Bcl-2), Bcl-2-like protein 4 and cleaved caspase-3, were also affected by GSPE. GSPE activated Nrf2, which is a key antioxidative transcription factor, with elevation of the downstream factor hemeoxygenase-1. These findings suggest that GSPE can ameliorate abnormal spermatogenesis and testicular injury in varicocele rats, potentially due to its antioxidative activity and ability to activate the Nrf2 pathway. PMID- 29138815 TI - Curcumin reverses tobacco smoke-induced epithelial-mesenchymal transition by suppressing the MAPK pathway in the lungs of mice. AB - Tobacco smoke is a major risk factor for lung cancer. Epithelial-mesenchymal transition (EMT) is decisive in cancer invasion and metastasis, and therefore promotes cancer progression. Mitogen-activated protein kinase (MAPK) pathways are implicated in various aspects of cancer development and progression, including the EMT process. The chemopreventive effect of curcumin on carcinogenesis has been reported in vivo and in vitro. The present study investigated tobacco smoke induced alterations in the MAPK/activator protein-1 (AP-1) pathways, and pulmonary EMT changes in the lungs of mice, and further observed the chemopreventive effect of curcumin. The protein expression levels analyzed by western blot analysis demonstrated that 12 weeks of tobacco smoke exposure activated extracellular-signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK) and p38 MAPK pathways, in addition to AP-1, in the lungs of mice, while reducing the activation of ERK5/MAPK pathways. The results also indicated that the mRNA and protein levels of the epithelial markers E-cadherin and zona occludens-1 were reduced following tobacco smoke exposure. Conversely, the expression levels of mRNA and protein for the mesenchymal markers vimentin and N cadherin were increased. Curcumin treatment inhibited tobacco smoke-induced MAPK/AP-1 activation, including ERK1/2, JNK and p38 MAPK pathways, and AP-1 proteins, and reversed EMT alterations in lung tissue. The results of the present study provide new insights into the molecular mechanisms of tobacco smoke associated lung cancer and may open up new avenues in the search for potential therapeutic targets in lung tumorigenesis. PMID- 29138816 TI - Protective effects of fucoidan against hyperoxic lung injury via the ERK signaling pathway. AB - High oxygen mechanical ventilation is widely used to treat various lung diseases; however, it may result in hyperoxia, which induces inflammation and lung injury. Fucoidan is an extract of the seaweed Fucus vesiculosus, which has previously been reported to exert effects against diabetic nephropathy. The present study is the first, to the best of our knowledge, to investigate the protective effects of fucoidan against hyperoxic lung injury. Balb/c mice were ventilated with 100% oxygen, with or without the atomization inhalation of fucoidan, for 36 h. Hyperoxia reduced the body weight and increased the relative lung weight of the mice. In addition, cell quantity and differentiation were determined using a hemocytometer, hyperoxia increased the total number of cells, and the number of macrophages, neutrophils and lymphocytes in the bronchoalveolar lavage fluid. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) demonstrated that hyperoxia also increased the mRNA expression levels of cluster of differentiation (CD)68, F4/80, CD64 and CD19 in lung tissue, and induced lung morphological alterations. Furthermore, western blotting assay demonstrated that hyperoxia increased the expression levels of interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha, and the phosphorylation of extracellular signal regulated kinase (ERK)1/2. Conversely, hyperoxia-induced inflammation and morphological alterations were significantly attenuated in the mice treated with fucoidan. Atomization inhalation of fucoidan also reduced the hyperoxia-induced expression of IL-1, IL-6 and TNF-alpha, and the phosphorylation of ERK1/2. These findings suggested that fucoidan may attenuate hyperoxic lung injury via the ERK1/2 signaling pathway. PMID- 29138817 TI - Reduced triglyceride accumulation due to overactivation of farnesoid X receptor signaling contributes to impaired liver regeneration following 50% hepatectomy in extra-cholestatic liver tissue. AB - The aim of the present study was to investigate the role of triglyceride metabolism in the effect of obstructive cholestasis on liver regeneration following 50% partial hepatectomy (PH). Obstructive cholestatic rat models were achieved via ligation of the common bile duct (BDL). Following comparisons between hepatic pathological alterations with patients with perihilar cholangiocarcinoma, rats in the 7 day post-BDL group were selected as the BDL model for subsequent experiments. Liver weight restoration, proliferating cell nuclear antigen labeling index, cytokine and growth factor expression levels, and hepatic triglyceride content were evaluated to analyze liver regeneration post-PH within BDL and control group rats. The results of the present study revealed that obstructive cholestasis impaired liver mass restoration, which occurred via inhibition of early stage hepatocyte proliferation. In addition, reduced triglyceride content and inhibited expression of fatty acid beta-oxidation associated genes, peroxisome proliferator activated receptor alpha and carnitine palmitoyltransferase, were associated with an insufficient energy supply within the BDL group post-PH. Notably, the expression levels of fatty acid synthesis associated genes, including sterol-regulatory element-binding protein-1c, acetyl coA carboxylase 1 and fatty acid synthase were also reduced within the BDL group, which accounted for the reduced triglyceride content and fatty acid utilization. Further investigation revealed that overactivated farnesoid X receptor (FXR) signaling may inhibit fatty acid synthesis within BDL group rats. Collectively, the role of triglycerides in liver regeneration following PH in extra-cholestatic livers was identified in the present study. Additionally, the results indicated that overactivated FXR signaling-induced triglyceride reduction is associated with insufficient energy supply and therefore contributes to the extent of impairment of liver regeneration following PH within extra-cholestatic livers. PMID- 29138818 TI - beta-Ecdysterone promotes autophagy and inhibits apoptosis in osteoporotic rats. AB - Osteoporosis is an aging process of skeletal tissues with characteristics of reductions in bone mass and microarchitectural deterioration of bone tissue. The present study aimed to investigate the effects of glucocorticoid-induced osteoporosis on osteoblasts and to examine the roles of beta-ecdysterone (beta Ecd) involved. In the present study, an in vivo model of osteoporosis was established through the subcutaneous implantation of prednisolone (PRED) into Sprague-Dawley rats, with or without a subcutaneous injection of beta-Ecd (5 or 10 mg/kg body weight). Expression of Beclin-1 and microtubule-associated protein 1A/1B-light chain 3I/II and apoptosis in lumbar vertebrae tissues was measured by immunofluorescence and TUNEL assays, respectively. Serum concentration of calcium and phosphorus, and the activity of tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP) were measured by biochemical assay. Reverse transcription-quantitative polymerase chain reaction and western blotting was used for detect the expression of related genes and proteins. PRED treatment inhibited bone formation by decreasing bone mineral density, and suppressing the expression of Runt-related transcription factor 2 and bone morphogenetic protein 2, while enhancing the activity of alkaline phosphatase, upregulating the expression of receptor activator of nuclear factor-kappaB ligand, and increasing the serum content of calcium, phosphorus and tartrate-resistant acid phosphatase in rats. Additionally, PRED was revealed to inhibit autophagy through the downregulation of Beclin-1, autophagy protein 5 and microtubule-associated protein 1A/1B-light chain 3I/II expression, whereas it induced the apoptosis, through the activation of caspase-3 and the suppression of apoptosis regulator BCL2 expression. Notably, the PRED-induced alterations in bone formation, autophagy and apoptosis were revealed to be attenuated by beta-Ecd administration. In conclusion, the findings of the present study suggested that beta-Ecd may be a promising candidate for the development of therapeutic strategies for the treatment of osteoporosis, through the induction of autophagy and the inhibition of apoptosis in vivo. PMID- 29138819 TI - Beneficial effect of resveratrol on alpha-naphthyl isothiocyanate-induced cholestasis via regulation of the FXR pathway. AB - Cholestasis is defined as a functional impairment of bile secretion which results in the accumulation of bile acids (BAs) and other toxic molecules in the blood and liver, however, there are very few effective therapies for cholestasis. The farnesoid X receptor (FXR), as a nuclear receptor for BAs, is important in the regulation of BA levels in enterohepatic circulation. It has previously been demonstrated that activation of the FXR pathway may be a useful strategy with which to treat cholestasis. Resveratrol, one of the important ingredients from grape skins and Chinese medicine Polygonum cuspidatum, resulted in FXR-activated effects in vitro and exhibited a protective effect against alpha naphthylisothiocyanate (ANIT)-induced cholestasis through FXR regulation in vivo. The underlying mechanisms of resveratrol against ANIT-induced cholestasis may be due to the regulation of BA homeostasis, improvement of liver injury and attenuation of the inflammatory response, which were regulated in a FXR-dependent manner and in turn contributed to overall cholestasis alleviation. Overall, resveratrol as a FXR agonist may act as a potential compound for the treatment of drug-induced cholestasis. PMID- 29138820 TI - Matrine suppresses cardiac fibrosis by inhibiting the TGF-beta/Smad pathway in experimental diabetic cardiomyopathy. AB - Cardiac fibrosis is one of the pathological characteristics of diabetic cardiomyopathy (DbCM). Matrine treatment has proven to be effective in cases of organ fibrosis and cardiovascular diseases. In the present study, the anti fibrosis-associated cardioprotective effects of matrine on DbCM were investigated. Rats with experimental DbCM were administered matrine orally. Cardiac functions were evaluated using invasive hemodynamic examinations. Cardiac compliance was assessed in isolated hearts. Using Sirius Red and fluorescence staining, the collagen in diabetic hearts was visualized. MTT assay was used to select non-cytotoxic concentrations of matrine, which were subsequently used to treat isolated cardiac fibroblasts incubated under various conditions. Western blotting was performed to assess activation of the transforming growth factor beta1 (TGF-beta1)/Smad signaling pathway. Rats with DbCM exhibited impaired heart compliance and left ventricular (LV) functions. Excessive collagen deposition in cardiac tissue was also observed. Furthermore, TGF-beta1/R-Smad (Smad2/3) signaling was revealed to be markedly activated; however, the expression of inhibitory Smad (I-Smad, also termed Smad7) was reduced in DbCM. Matrine administration led to a marked recovery in LV function and heart compliance by exerting inhibitory effects on TGF-beta1/R-Smad signaling pathway-induced fibrosis without affecting I-Smad. Incubation with a high concentration of glucose triggered the TGF-beta1/R-Smad (Smad2/3) signaling pathway and suppressed I-Smad signaling transduction in cultured cardiac fibroblasts, which led to an increase in the synthesis of collagen. After cardiac fibroblasts had been treated with matrine at non-cytotoxic concentrations without affecting I-Smad, matrine blocked TGF-beta1/R-Smad signaling transduction to repress collagen production and deposition. In conclusion, the results of the present study demonstrated that TGF-beta1/Smad signaling-associated cardiac fibrosis is involved in the impairment of heart compliance and LV dysfunction in DbCM. By exerting therapeutic effects against cardiac fibrosis via its influence on TGF-beta1/Smad signaling, matrine exhibited cardioprotective effects in DbCM. PMID- 29138821 TI - Protective effects of oxymatrine against lipopolysaccharide/D-galactosamine induced acute liver failure through oxidative damage, via activation of Nrf2/HO-1 and modulation of inflammatory TLR4-signaling pathways. AB - Oxymatrine has a variety of pharmacological functions, including anti-viral, anti liver fibrotic, anti-cancer, anti-bacterial, anti-epidemic, analgesic, anti allergy and anti-inflammatory properties. The present study aimed to investigate the protective effects of oxymatrine against lipopolysaccharide (LPS)/D galactosamine (D-GalN)-induced acute liver failure and the associated underlying mechanisms. Mice were administrated 4 mg/kg LPS and 600 mg/kg D-GalN. Then, mice in the Oxymatrine group were treated with 120 mg/kg of oxymatrine for 4 weeks. Oxymatrine treatment increased survival rate, decreased plasma aspartate transaminase and alanine aminotransferase activity, increased superoxide dismutase and glutathione peroxidase and decreased malondialdehyde, tumor necrosis factor- and myeloperoxidase activities in mice with LPS/D-GalN-induced liver failure. Furthermore, Oxymatrine activated nuclear factor erythroid 2 related factor (Nrf) 2 and heme oxygenase (HO)-1 protein expression, and suppressed Toll like receptor (TLR)4, myeloid differentiation primary response 88 and nuclear factor-kappaB protein expression in mice LPS/D-GalN mice. Overall, the present study suggests that oxymatrine effectively attenuates LPS/D-GalN induced acute liver failure by oxidative damage via activation of Nrf2/HO-1 and modulation of TLR4-dependent inflammatory signaling pathways. PMID- 29138822 TI - Fucoidan inhibits Ca2+ responses induced by a wide spectrum of agonists for G protein-coupled receptors. AB - Fucoidan, a sulfated polysaccharide extracted from brown seaweed, has been used in traditional Chinese herbal medicine to treat thyroid tumors for many years. Although a number of its cellular effects have been investigated, the role of fucoidan in molecular signaling, particularly in Ca2+ signaling, remains largely unknown. In the present study, the effects of fucoidan on Ca2+ responses in HeLa cells, human umbilical vein endothelial cells and astrocytes were investigated using a wide range of receptor agonists. Fucoidan inhibited the increase in intracellular free calcium concentration that was induced by histamine, ATP, compound 48/80 and acetylcholine. The responses induced by the same agonists in the absence of extracellular Ca2+ were also markedly suppressed by fucoidan. Reverse transcription-polymerase chain reaction demonstrated that 0.5 and 1.0 mg/ml fucoidan treatment for 3 h decreased histamine receptor 1 expression in HeLa cells. Similarly, the expressions of purinergic receptor P2Y, G-protein coupled (P2YR)1, P2YR2 and P2YR11 were significantly downregulated within cells pretreated with 1.0 mg/ml fucoidan for 3 h, and 0.5 mg/ml fucoidan significantly inhibited P2YR1 and P2YR11 expression. The results demonstrated that fucoidan may exert a wide spectrum of inhibitory effects on Ca2+ responses and that fucoidan may inhibit a number of different G-protein coupled receptors associated with Ca2+ dynamics. PMID- 29138823 TI - Mechanical strain promotes osteogenic differentiation of bone mesenchymal stem cells from ovariectomized rats via the phosphoinositide 3-kinase/Akt signaling pathway. AB - Osteoporosis has become an overwhelming public health problem worldwide. As an elementary physiological factor to regulate bone formation and regeneration, mechanical strain may be used as a non-invasive intervention in osteoporosis prevention and treatment. However, little is known regarding the underlying mechanism. The aim of the current study was to investigate the effect of continuous mechanical strain (CMS) on osteogenic differentiation of bone mesenchymal stem cells (BMSCs) from ovariectomized rats (OVX BMSCs). In addition, involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in biomechanical signal transduction and its function were evaluated. The results demonstrated that OVX BMSCs subjected to CMS exhibited higher alkaline phosphatase (ALP) activity and deeper staining at 24 and 48 h. In addition, CMS upregulated the mRNA expression levels of ALP, collagen type I, runt related transcription factor 2 (Runx2), as well as the protein expression level of Runx2 in a time-dependent manner. The PI3K/Akt signaling pathway was rapidly activated by CMS, with its phosphorylation level reaching its maximum in a short duration and a large quantity of phosphorylated-Akt remaining in the nucleus. Pre treatment with a selective blocker significantly blocked the strain-induced activation of PI3K/Akt and reduced the commitment of OVX BMSCs into osteoblasts, demonstrating a dominated regulative effect of PI3K/Akt signaling in strain induced osteogenesis. These results indicated that CMS induced the early differentiation of OVX BMSCs towards an osteogenic phenotype by activating the PI3K/Akt signaling pathway. PMID- 29138824 TI - Genetic mutational testing of Chinese children with familial hematuria with biopsy-proven FSGS. AB - Focal segmental glomerulosclerosis (FSGS) is a pathological lesion rather than a disease, with a diverse etiology. FSGS may result from genetic and non-genetic factors. FSGS is considered a podocyte disease due to the fact that in the majority of patients with proven-FSGS, the lesion results from defects in the podocyte structure or function. However, FSGS does not result exclusively from podocyte-associated genes, however also from other genes including collagen IV associated genes. Patients who carry the collagen type IVA3 chain (COL4A3) or COL4A4 mutations usually exhibit Alport Syndrome (AS), thin basement membrane neuropathy or familial hematuria (FH). Previous studies revealed that long-time persistent microscopic hematuria may lead to FSGS. A case of a family is presented here where affected individuals exhibited FH with FSGS-proven, or chronic kidney disease. Renal biopsies were unhelpful and failed to demonstrate glomerular or basement membrane defects consistent with an inherited glomerulopathy, and therefore a possible underlying genetic cause for a unifying diagnosis was pursued. Genomic DNA of the siblings affected by FH with biopsy proven FSGS was analyzed, and their father was screened for 18 gene mutations associated with FSGS [nephrin, podocin, CD2 associated protein, phospholipase C epsilon, actinin alpha 4, transient receptor potential cation channel subfamily C member 6, inverted formin, FH2 and WH2 domain containing, Wilms tumor 1, LIM homeobox transcription factor 1 beta, laminin subunit beta 2, laminin subunit beta 3, galactosida alpha, integrin subunit beta 4, scavenger receptor class B member 2, coenzyme Q2, decaprenyl diphosphate synthase subunit 2, mitochondrially encoded tRNA leucine 1 (UUA/G; TRNL1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1] using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technology. Then whole exome sequencing (WES) was performed in the two probands to ascertain whether there were other known or unknown gene mutations that segregated with the disease. Using mass array technology, a TRNL1 missense homozygous mutation (m. 3290T>C) was identified in the probands diagnosed with FH and manifested as FSGS on biopsy. In addition, a COL4A4 missense mutation c. 4195A>T (p. M1399L) in heterozygous pattern was identified using WES. None of these variants were detected in their father. In the present study, a mutation in TRNL1 (m. 3290T>C) was identified, which was the first reported variant associated with FSGS. The COL4A4 (c. 4195A>T) may co-segregate with FSGS. Screening for COL4A mutations in familial FSGS patients is suggested in the present study. Genetic investigations of families with similar clinical phenotypes should be a priority for nephrologists. The combination of mass array technology and WES may improve the detection rate of genetic mutation with a high level of accuracy. PMID- 29138826 TI - miR-660-5p is associated with cell migration, invasion, proliferation and apoptosis in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system with poor prognosis. microRNAs (miRNAs) are a class of small, non-coding RNA molecules that serve important roles in biological and pathological processes in several types of human tumors. miRNA (miR)-660-5p is dysregulated in many human cancers; however, its role in renal cell carcinoma is currently unclear. In the present study, reverse transcription-quantitative polymerase chain reaction was performed to examine the expression levels of miR-660-5p in RCC tissues and paired normal adjacent tissues (NATs). To determine the function of miR-660-5p in RCC cells, wound-healing and Matrigel assays were performed to determine the effects of miR 660-5p on cell migration and invasion, respectively. MTT and Cell Counting kit-8 assays were performed to determine the effects of miR-660-5p on RCC cell proliferation. In addition, flow cytometric analysis was performed to validate the effects of miR-660-5p on apoptosis. The results indicated that miR-660-5p expression was downregulated in RCC tissues compared with NATs. Restoration of miR-660-5p expression using synthetic mimics may suppress cell migration, invasion and proliferation, and induce cell apoptosis, while using synthetic inhibitors may promote cell migration, invasion and proliferation, and suppress cell apoptosis. These results suggested that miR-660-5p may serve a tumor suppressive role in RCC tumorigenesis. PMID- 29138825 TI - Utility of miR-133a-3p as a diagnostic indicator for hepatocellular carcinoma: An investigation combined with GEO, TCGA, meta-analysis and bioinformatics. AB - Increasing evidence has demonstrated that microRNA (miR)-133a-3p is an important regulator of hepatocellular carcinoma (HCC). In the present study, the diagnostic role of miR-133a-3p in HCC, and the potential functional pathways, were both explored based on publicly available data. Eligible microarray datasets were collected from NCBI Gene Expression Omnibus (GEO) database and ArrayExpress database. The data related to HCC and matched adjacent normal tissues were also downloaded from The Cancer Genome Atlas (TCGA). Published studies reporting the association between miR-133a-3p expression and HCC were reviewed from multiple databases. By combining the data derived from three sources (GEO, TCGA and published studies), the authors analyzed the comprehensive relationship between miR-133a-3p expression and clinicopathological features of HCC. Eventually, putative targets of miR-133a-3p in HCC were selected for further bioinformatics prediction. A total of eight published microarray datasets were gathered, and the pooled results demonstrated that the expression of miR-133a-3p in the tumor group was lower than that in normal groups [standardized mean difference (SMD)=-0.54; 95% confidence interval (CI), -0.74 to -0.35; P<0.001]. Consistently, the level of miR-133a-1 in HCC was reduced markedly compared to normal tissues (P<0.001) based on TCGA data, and the AUC value of low miR-133a-1 expression for HCC diagnosis was 0.670 (P<0.001). Furthermore, the combined SMD of all datasets (GEO, TCGA and literature) suggested that significant difference was observed between the HCC group and the normal control group, and lower miR-133a-3p expression in HCC group was noted (SMD=-0.69; 95% CI, -1.10 to -0.29; P=0.001). In addition, the authors discovered five key genes of the calcium signaling pathway (NOS1, ADRA1A, ADRA1B, ADRA1D and TBXA2R) that may probably be targeted by miR-133a-3p in HCC. The study reveals that miR-133a-3p may function as a tumor suppressor in HCC. The prospective novel pathways and key genes of miR-133a-3p could offer potential biomarkers for HCC; however, the predictions require further confirmation. PMID- 29138827 TI - Gambogic acid inhibits spinal cord injury and inflammation through suppressing the p38 and Akt signaling pathways. AB - Gamboge is the dry resin secreted by Garcinia hanburyi Hook.f, with the function of promoting blood circulation, detoxification, hemostasis and killing insects, used for the treatment of cancer, brain edema and other diseases. Gambogic acid is the main effective constituent of Gamboge. The present study investigated the protective effects of gambogic acid on spinal cord injury (SCI) and its anti inflammatory mechanism in an SCI model in vivo. Basso, Beattie and Bresnahan (BBB) testing was used to detect the protective effects of gambogic acid on nerve function of SCI rats. The water content of the spinal cord was used to analyze the protective effects of gambogic acid on the damage of SCI. Treatment with gambogic acid effectively improved BBB scores and inhibited water content of the spinal cord in SCI rats. Also, gambogic acid significantly reduced inflammatory cytokines levels of [tumor necrosis factor-alpha, interleukin (IL)-6, IL-12 and IL-1beta] and oxidative stress (malondialdehyde, superoxide dismutase, glutathione and glutathione-peroxidase) factors, and suppressed receptor activator of nuclear factor kappaB ligand, phosphorylated p38 protein expression and toll-like receptor 4/nuclear factor-kappaB pathway activation, and increased phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway activation in SCI rats. These results provide evidence that gambogic acid inhibits SCI and inflammation through suppressing the p38 and Akt signaling pathways. PMID- 29138828 TI - Identification of risk genes associated with myocardial infarction based on the recursive feature elimination algorithm and support vector machine classifier. AB - The aim of the present study was to identify risk genes in myocardial infarction. Microarray data GSE34198, containing data from the peripheral blood of 49 myocardial infarction samples and 48 corresponding control samples, were downloaded from the Gene Expression Omnibus database to screen the differentially expressed genes (DEGs). The DEGs were used to construct a protein-protein interaction (PPI) network of patient samples, from which the feature genes were identified using the neighboring score method. The recursive feature elimination (RFE) algorithm was employed to select the risk genes among feature genes, which were subsequently applied to perform a support vector machine (SVM) classifier to identify the specific signature in myocardial infarction samples. Another dataset, GSE61144, was also downloaded to verify the efficacy of the classifier. A total of 724 downregulated and 483 upregulated DEGs were screened in patient samples compared with control samples in the GSE34198 dataset. The PPI network of myocardial infarction was comprised of 1,083 nodes (genes) and 46,363 lines (connections). Using the neighborhood scoring method, the top 100 feature genes in myocardial infarction samples were identified as the disease feature genes, which distinguish the myocardial infarction samples from the control samples. The RFE algorithm screened 15 risk genes, which were employed to construct a SVM classifier with an average precision of 88% to the patient sample following visualization by a confusion matrix. The predictive precision of the classifier on another microarray dataset, GSE61144, was 0.92, with an average true positive of 0.9278 and an average false positive of 0.2361. A-kinase-anchoring protein 12 (AKAP12) and glycine receptor alpha2 (GLRA2) were two risk genes in the SVM classifier. Therefore, AKAP12 and GLRA2 exert potential roles in the development of myocardial infarction, potentially by influencing cardiac contractility and protecting against ischemia-reperfusion injury, which may provide clues in developing potential diagnostic biomarkers or therapeutic targets for myocardial infarction. PMID- 29138829 TI - Resveratrol ameliorates inflammatory damage and protects against osteoarthritis in a rat model of osteoarthritis. AB - Resveratrol is a non-flavonoid polyphenol compound with a stilbene structure. As a type of phytoalexin produced under stress in plants, it improves the plant's resistance against pathogens and environment deterioration, and performs important functions beneficial to human health, such as anti-cancer, anti oxidation, regulating blood lipid levels and prolonging life span. The effects of resveratrol were examined in a rat model of osteoarthritis (OA) and observed to ameliorate inflammatory damage and protect against OA. In the present study, resveratrol significantly inhibited the induction of clinical scores in rats with OA. Resveratrol inhibited tumor necrosis factor-alpha, interleukin (IL)-1beta, IL 6 and IL-18 expression levels, and decreased caspase-3/9 activity in rats with OA. Inducible nitric oxide synthase, nuclear factor (NF)-kappaB, phosphorylated (p)-AMP-activated protein kinase and sirtuin 1 protein expression were significantly suppressed and heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) protein expression was stimulated in rats with OA treated with resveratrol. The current results indicate that resveratrol ameliorates inflammatory damage and protects against OA in a rat model of OA via NF-kappaB and HO-1/Nrf-2 signaling. PMID- 29138830 TI - miR-185 inhibits non-small cell lung cancer cell proliferation and invasion through targeting of SOX9 and regulation of Wnt signaling. AB - SRY-box 9 (SOX9) is an important transcription factor required for development, which has additionally been reported to be an independent prognostic indicator for the survival of patients with non-small cell lung cancer (NSCLC). Accumulating evidence has indicated that dysregulation of microRNAs (miRNAs/miRs) may contribute to the initiation and progression of cancer. SOX9 may be regulated by a number of miRNAs in different types of cancer, including in NSCLC. The present study sought to identify novel candidate miRNAs associated with SOX9 in NSCLC using online tools, and investigated the detailed functions of miR-185, which suppressed SOX9 mRNA expression most strongly out of the candidate miRNAs. It was observed that ectopic miR-185 expression significantly suppressed NSCLC cell proliferation, invasion and migration. Using luciferase reporter gene and RNA immunoprecipitation assays, SOX9 was confirmed to be a direct target of miR 185. In addition, the downstream Wnt signaling-associated factors beta-catenin and c-Myc proto-oncogene protein (Myc) were demonstrated to be inhibited by miR 185 overexpression. SOX9, beta-catenin and c-Myc mRNA expression was significantly upregulated in NSCLC tissues, and was inversely correlated with miR 185 expression. The results of the present study demonstrated that rescuing miR 185 expression in NSCLC, thereby inhibiting SOX9 expression and the downstream Wnt signaling, and leading to the suppression of NSCLC cell proliferation, invasion and migration, may be a promising strategy for the treatment of NSCLC. PMID- 29138831 TI - Anti-inflammatory effect of Migri-Heal(r) in an in vitro inflammatory model of primary mixed glial cells. AB - Migri-Heal(r), is a novel herbal remedy that was introduced for the treatment of migraine headaches. Previous studies revealed that this drug may reduce nitric oxide (NO) in an in vitro inflammatory model. The aim of the present study was to investigate the anti-inflammatory effect of Migri-Heal(r) on primary mix glial cells stimulated with LPS. In the current study, neonatal rat primary mix glial cells were isolated from the mixed glial cultures via shaking, and cultured in Dulbecco's' modified Eagle's medium supplemented with 10% fetal bovine serum. Following pretreatment with Migri-Heal(r) (25, 75, 100, 150, 200 and 300 ug/ml) and cells were treated with LPS (10 ug/ml) for 1 h, and incubated for 48 h. The present study determined that 150 ug/ml Migri-Heal(r) significantly reduced the production of NO in rat mix glial cells stimulated with 10 ug/ml LPS. Migri Heal(r) also suppressed mRNA expression level of LPS-induced inducible nitric oxide synthase and tumor necrosis factor alpha, which was accompanied by inhibition of the transcription factor nuclear factor-kappaB. Additionally, MTT assay determined that Migri-Heal(r) was not cytotoxic, suggesting that the anti inflammatory effects of Migri-Heal(r) observed were not due to cell death. In conclusion, the findings of the present study demonstrated that Migri-Heal(r) may be useful as a potential anti-inflammatory agent in inflammatory diseases. However, additional studies are required to confirm these findings. PMID- 29138832 TI - Effect of moesin phosphorylation on high-dose sphingosine-1-phosphate-induced endothelial responses. AB - It was previously reported that low-dose sphingosine-1-phosphate (S1P) enhanced endothelial barrier integrity, whereas high-dose S1P induced endothelial monolayer hyperpermeability responses. A number of studies have revealed the underlying molecular mechanisms of the physiological-dose of S1P on barrier protective effect. However, little work has been performed to determine the effect of S1P-induced endothelial barrier responses. In the present study, the role of moesin phosphorylation in excessive S1P-induced endothelial hyperpermeability was investigated by western blotting, fluorescence staining and transendothelial electrical resistance detection. It was revealed that S1P induced moesin phosphorylation in a time- and concentration-dependent manner. In addition, it was confirmed that high-dose S1P-induced moesin phosphorylation occurred via S1P receptor 2 (S1PR2). Moesin phosphorylation was required for S1P induced F-actin rearrangement and endothelial barrier disruption. The results suggested that the S1PR2-moesin axis is involved in high-dose S1P-induced endothelial barrier responses. The results of the present study may provide novel therapeutic targets for endothelial injury-associated vascular disorders. PMID- 29138833 TI - miR-16 mimics inhibit TGF-beta1-induced epithelial-to-mesenchymal transition via activation of autophagy in non-small cell lung carcinoma cells. AB - Autophagy is critical for the metastasis of cancer cells through induction of epithelial-to-mesenchymal transition (EMT). Activation of TGF-beta signaling plays a key role in regulating autophagy. miR-16 may be associated with non-small cell lung carcinoma (NSCLC) progression. However, the role of miR-16 in NSCLC cell autophagy in the presence of TGF-beta and the underlying mechanism are still unclear. To test whether miR-16 targets ATG3 which is involved in autophagy of NSCLC cells, we studied the expression levels of miR-16 and ATG3 in NSCLC patients, verified the targeting of ATG3 by miR-16 by luciferase reporter gene system, and investigated the role of miR-16 in the autophagy of NSCLC cells. Results revealed that miR-16 was significantly downregulated, and ATG3 was significantly upregulated in NSCLC patient tissue samples. ATG3 was found to be a direct target of miR-16. TGF-beta1 significantly downregulated the expression of miR-16 and ATG3 mRNA. Using transmission electron microscopy, we observed that TGF-beta1 treatment reduced autophagosomes in the A549 cells, and miR-16 mimics increased the autophagosomes in the presence of TGF-beta1. Acridine orange (AO) staining and expression of LC3B II/I and p62 confirmed the inhibition of autophagy by TGF-beta1, and the recovery of TGF-beta1-mediated inhibition of autophagy by miR-16 mimics. Finally, miR-16 mimics inhibited TGF-beta1-induced EMT, and this effect was attenuated by autophagy inhibitor 3-MA. Taken together, miR-16 mimics inhibited TGF-beta1-induced EMT via activation of autophagy. PMID- 29138834 TI - Mechanism of free radical generation in platelets and primary hepatocytes: A novel electron spin resonance study. AB - Oxygen free radicals have been implicated in the pathogenesis of toxic liver injury and are thought to be involved in cardiac dysfunction in the cirrhotic heart. Therefore, direct evidence for the electron spin resonance (ESR) detection of how D-galactosamine (GalN), an established experimental hepatotoxic substance, induced free radicals formation in platelets and primary hepatocytes is presented in the present study. ESR results demonstrated that GalN induced hydroxyl radicals (OH*) in a resting human platelet suspension; however, radicals were not produced in a cell free Fenton reaction system. The GalN-induced OH* formation was significantly inhibited by the cyclooxygenase (COX) inhibitor indomethasin, though it was not affected by the lipoxygenase (LOX) or cytochrome P450 inhibitors, AA861 and 1-aminobenzotriazole (ABT), in platelets. In addition, the present study demonstrated that baicalein induced semiquinone free radicals in platelets, which were significantly reduced by the COX inhibitor without affecting the formed OH*. In the mouse primary hepatocytes, the formation of arachidonic acid (AA) induced carbon-centered radicals that were concentration dependently enhanced by GalN. These radicals were inhibited by AA861, though not affected by indomethasin or ABT. In addition, GalN did not induce platelet aggregation prior to or following collagen pretreatment in human platelets. The results of the present study indicated that GalN and baicalein may induce OH* by COX and LOX in human platelets. GalN also potentiated AA induced carbon-centered radicals in hepatocytes via cytochrome P450. The present study presented the role of free radicals in the pathophysiological association between platelets and hepatocytes. PMID- 29138835 TI - Mesenchymal stem cells overexpressing adrenomedullin improve heart function through antifibrotic action in rats experiencing heart failure. AB - Previous studies of the authors have indicated that the transplantation of mesenchymal stem cells (MSCs) can attenuate cardiac fibrosis through the secretion of antifibrotic factors, such as adrenomedullin (ADM). Therefore, the authors addressed the hypothesis that ADM overexpression could enhance the antifibrotic effect of MSCs transplantation in a rat model of heart failure. The results of the present study demonstrated that, compared with the group that received the GFP-MSCs, the transplantation of ADM-MSCs significantly improved heart function and decreased the percentage of fibrotic area and the expression of matrix metalloproteinase 2. In addition, fluorescence microscopy indicated that the survival of transplanted MSCs also increased significantly in the ADM MSCs-treated group. Furthermore, the expression of fibrosis-related genes, such as ADM and hepatocyte growth factor, were significantly influenced in the ADM MSCs-treated group. Based on these findings, it may be concluded that, compared with MSCs, MSCs overexpressing ADM can further improve heart function in rats experiencing heart failure through enhanced antifibrotic activity. PMID- 29138836 TI - GATA4 protects against hyperglycemia-induced endothelial dysfunction by regulating NOX4 transcription. AB - Endothelial dysfunction is one of the most common complications associated with diabetes and may lead to atherosclerosis. Conflicting reports indicate that NADPH oxidase 4 (NOX4) induces hydrogen peroxide production and cytotoxicity, but also has a protective effect on endothelial dysfunction. The present study aimed to identify the transcription factor responsible for NOX4 expression using a transcription factor activation profiling plate array and chromatin immunoprecipitation. Data from these analyses indicated that GATA-binding protein 4 (GATA4) was able to mediate NOX4 transcription and is downregulated in human umbilical vein endothelial cells (HUVECs) that were exposed to hyperglycemic conditions as well as in the endothelial cells of a mouse diabetes model. Overexpression of GATA4 was demonstrated to lead to increased expression of NOX4 mRNA and protein. Furthermore, GATA4 overexpression resulted in increased nitric oxide (NO) production through the upregulation of endothelial NO synthase phosphorylation. Treatment with simvastatin, a drug known to preserve endothelial function through an unknown mechanism, improved endothelial cell function by upregulating GATA4 expression in HUVECs exposed to hyperglycemia. Results from these experiments demonstrated that GATA4 may inhibit diabetes-induced endothelial dysfunction by acting as a transcription factor for NOX4 expression and increasing NO production. Thus, the present study revealed a novel molecular mechanism underlying endothelial dysfunction in diabetes and identified GATA4 as a potential therapeutic target. PMID- 29138837 TI - VEGF secreted by mesenchymal stem cells mediates the differentiation of endothelial progenitor cells into endothelial cells via paracrine mechanisms. AB - Stem cell therapy is a promising treatment strategy for ischemic diseases. Mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) adhere to each other in the bone marrow cavity and in in vitro cultures. We have previously demonstrated that the adhesion between MSCs and EPCs is critical for MSC self renewal and their multi-differentiation into osteoblasts and chondrocytes. In the present study, the influence of the indirect communication between EPCs and MSCs on the endothelial differentiation potential of EPCs was investigated, and the molecular mechanisms underlying MSC-mediated EPC differentiation were explored. The effects of vascular endothelial growth factor (VEGF), which is secreted by MSCs, on EPC differentiation via paracrine mechanisms were examined via co culturing MSCs and EPCs. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the expression of genes and proteins of interest. The present results demonstrated that co-culturing EPCs with MSCs enhanced the expression of cluster of differentiation 31 and von Willebrand factor, which are specific markers of an endothelial phenotype, thus indicating that MSCs may influence the endothelial differentiation of EPCs in vitro. VEGF appeared to be critical to this process. These findings are important for the understanding of the biological interactions between MSCs and EPCs, and for the development of applications of stem cell-based therapy in the treatment of ischemic diseases. PMID- 29138838 TI - Effects of SCN9A gene modification on Na+ channel and the expression of nerve growth factor in a rat model of diarrhea-predominant irritable bowel syndrome. AB - The aim of the present study was to identify whether the sodium voltage-gated channel alpha subunit 9 (SCN9A) gene modification is a potential treatment for diarrhea-predominant irritable bowel syndrome (D-IBS), via regulating the Na+ channel and the expression of nerve growth factor (NGF). The recombinant adenovirus vector of the SCN9A gene was established, and rat colon cells were isolated for SCN9A gene modification. All subjects were divided into four groups: i) The SCN9A-modified (D-IBS rat model implanted with SCN9A-modified colon cells), ii) negative control (NC; D-IBS rat model implanted with colon cells without SCN9A gene modification), iii) blank (D-IBS rat model without any treatment) and iv) normal (normal rats without any treatment). Western blotting and reverse transcription-quantitative polymerase chain reaction were used to detect the protein and mRNA expression levels of SCN9A, NGF and voltage gated sodium channels (Nav)1.8 and Nav1.9 in rat colon tissues. Compared with the normal group, the rats in the SCN9A, NC and blank groups had significantly elevated mRNA and protein expression levels of NGF, SCN9A, Nav1.8 and Nav1.9. The rats in the SCN9A group demonstrated significantly increased mRNA and protein expression levels of NGF, SCN9A, Nav1.8 and Nav1.9 compared with the NC group and the blank group (all P<0.05). SCN9A gene modification can promote the expression of Nav1.8 and Nav1.9 channels, in addition to NGF which may provide a novel therapeutic basis for treating of D-IBS. PMID- 29138839 TI - SUMO1/UBC9-decreased Nox1 activity inhibits reactive oxygen species generation and apoptosis in diabetic retinopathy. AB - Diabetic retinopathy (DR) is an increasing global health concern that causes vision loss and blindness. Reactive oxygen species (ROS) are considered to be a principal cause of DR. An important source of ROS is the oxidization of NADPH. In the present study, NADPH oxidase 1 (Nox1)-expressing human retinal epithelial cell (HREC) lines were generated and infected with small ubiquitin-like modifier 1 (SUMO1) and/or ubiquitin conjugating enzyme E2 I (UBC9) lentiviral pGMLV constructs. The viabilities, apoptotic capacities and ROS production levels of the HREC lines were quantified using Hoechst 33258, annexin V/propidium iodide and dichlorodihydrofluorescein diacetate assays, respectively. Additionally, rat DR models were established. From these models, the apoptotic capacities of retinal tissues were visualized using terminal deoxynucleotidyl transferase dUTP nick end labeling assays, and the pathologies were evaluated. The mRNA and protein expression levels of SUMO1, UBC9 and Nox1 were analyzed using reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. Compared with controls, the relative mRNA levels of SUMO1 and UBC9 were significantly upregulated, and the Nox1 levels significantly downregulated, in cells infected with SUMO1 or UBC9 alone or in combination. The ROS production and apoptosis rates of cells and retinal tissues were decreased. In addition, pathological symptoms in DR tissues improved when they were simultaneously transfected with SUMO1 and UBC9 via intraocular injection. In conclusion, the SUMO1/UBC9 axis may regulate Nox1-mediated DR by inhibiting ROS generation and apoptosis in rat and cellular model systems. PMID- 29138840 TI - Low dosage of arsenic trioxide inhibits vasculogenic mimicry in hepatoblastoma without cell apoptosis. AB - Hepatoblastoma (HB) is the most common type of pediatric liver malignancy, which predominantly occurs in young children (aged <5 years), and continues to be a therapeutic challenge in terms of metastasis and drug resistance. As a new pattern of tumor blood supply, vasculogenic mimicry (VM) is a channel structure lined by tumor cells rather than endothelial cells, which contribute to angiogenesis. VM occurs in a variety of solid tumor types, including liver cancer, such as hepatocellular carcinoma. The aim of the present study was to elucidate the effect of arsenic trioxide (As2O3) on VM. In vitro experiments identified that HB cell line HepG2 cells form typical VM structures on Matrigel, and the structures were markedly damaged by As2O3 at a low concentration before the cell viability significantly decreased. The western blot results indicated that As2O3 downregulated the expression level of VM-associated proteins prior to the appearance of apoptotic proteins. In vivo, VM has been observed in xenografts of HB mouse models and identified by periodic acid-Schiff+/CD105- channels lined by HepG2 cells without necrotic cells. As2O3 (2 mg/kg) markedly depresses tumor growth without causing serious adverse reactions by decreasing the number of VM channels via inhibiting the expression level of VM-associated proteins. Thus, the present data strongly indicate that low dosage As2O3 reduces the formation of VM in HB cell line HepG2 cells, independent of cell apoptosis in vivo and in vitro, and may represent as a candidate drug for HB targeting VM. PMID- 29138841 TI - Enhanced activated T cell subsets in prostate cancer patients receiving iodine 125 low-dose-rate prostate brachytherapy. AB - Radiotherapy (RT) is one of the most important treatments for prostate cancer. Although RT can kill cancer cells through direct and indirect effects of radiation, it occasionally induces an abscopal effect whereby localized radiation treatment is associated with elimination of metastatic cancer at a distance from the irradiated area. Thus, RT may induce an effective antitumor immune response, although the mechanism involved has remained unclear. The present was designed to evaluate this effect of RT in 36 patients with prostate cancer who provided informed consent prior to enrollment in this clinical trial. Peripheral blood samples were collected periodically after low-dose-rate (LDR) prostate brachytherapy, and lymphocyte subsets were analyzed by flow cytometry. The proportion of activated T cells (CD3+HLA-DR+, CD4+HLA-DR+ and CD8+HLA-DR+) in peripheral blood revealed a gradual and bimodal increase after LDR brachytherapy, whereas memory CD8+ T cells bimodally decreased after treatment. The ratios of activated T cells and regulatory T cells gradually increased after the treatment. Thus, LDR brachytherapy was demonstrated to induce effective immune responses in patients. This increase of activated T cells may contribute to maintenance of remission and reduction of relapse rates. PMID- 29138842 TI - Placenta-specific protein 1 promotes cell proliferation and invasion in non-small cell lung cancer. AB - Pulmonary carcinoma-associated proteins have emerged as crucial players in governing fundamental biological processes such as cell proliferation, apoptosis and metastasis in human cancers. Placenta-specific protein 1 (PLAC1) is a cancer related protein, which is activated and upregulated in a variety of malignant tissues, including prostate cancer, gastric adenocarcinoma, colorectal, epithelial ovarian and breast cancer. However, its biological role and clinical significance in non-small cell lung cancer (NSCLC) development and progression are still unknown. In the present study, we found that PLAC1 was significantly upregulated in NSCLC tissues, and its expression level was associated with advanced pathological stage and it was also correlated with shorter progression free survival of lung cancer patients. Furthermore, knockdown of PLAC1 expression by siRNA inhibited cell proliferation, induced apoptosis and impaired invasive ability in NSCLC cells partly via regulation of epithelial-mesenchymal transition (EMT)-related protein expression. Our findings present that increased PLAC1 could be identified as a negative prognostic biomarker in NSCLC and regulate cell proliferation and invasion. Thus, we conclusively demonstrated that PLAC1 plays a key role in NSCLC development and progression, which may provide novel insights on the function of tumor-related gene-driven tumorigenesis. PMID- 29138844 TI - The -alpha3.7 deletion in alpha-globin genes increases the concentration of fetal hemoglobin and hemoglobin A2 in a Saudi Arabian population. AB - The regions of Al-Qatif and Al-Ahssa in the Eastern Province of Saudi Arabia are known for their high prevalence of hemoglobinopathies, including beta-thalassemia and sickle cell anemia. Previously, the alpha-gene deletion has been demonstrated as highly prevalent among populations residing in these two regions. The present study was conducted in order to investigate the implications of the alpha-globin gene deletion on fetal hemoglobin (HbF) and hemoglobin alpha2 (HbA2) concentrations in patients with transfusion-dependent beta-thalassemia. A total of 166 Saudi patients with transfusion-dependent beta-thalassemia and 337 healthy Saudi patients were included in the study. The -alpha3.7, -alpha4.2, --FIL, - SEA, --MED and --(20.5) gene deletions were identified using multiplex alpha globin deletion polymerase chain reaction. The present study revealed that the alpha3.7 gene deletion is the most prevalent (43.5%) in the Saudi populations that were analyzed and is characterized by the deletion of 3,804 base pairs. Numerous genotypes, namely -3.7alpha2/alpha1alpha2, -3.7alpha2/alpha1alpha12, 3.7alpha2/-3.7alpha2, -3.7alpha2HphI/alpha1alpha2HphI, -3.7alpha2/alpha1-4.2, 3.7alpha2/alpha1polyA-1alpha2, -3.7alpha12/alpha1alpha12, --FIL/-3.7alpha2 and 3.7alpha2/-3.7alpha2Hb Villiers le Bel were also identified in the investigated population. Furthermore, a gradual increase in the concentration of HbF and HbA2 in patients with beta-thalassemia and the number of alpha-gene deletions was demonstrated; whereas in healthy patients the level of HbA2 was demonstrated to decrease as the number of alpha-gene deletions increased. Therefore, it can be concluded that the high HbF concentration in the present study is predominantly associated with other mutations associated with beta-thalassemia rather than alpha-globin deletions. Furthermore, the results of the present study also revealed novel alpha-gene deletion genotypes prevalent in the population studied, namely alpha1alpha2/alpha1alpha2HphI, alpha1alpha2HphI/alpha1alpha2HphI, alpha1alpha2/alpha1alpha2Hb Handsworth, -3.7alpha2HphI/alpha1alpha2HphI, 3.7alpha2/-3.7alpha2Hb Villiers le Bel and --MED/alpha1alpha2HphI. PMID- 29138843 TI - Investigation of candidate genes and mechanisms underlying postmenopausal osteoporosis using bioinformatics analysis. AB - The present study aimed to determine candidate genes, chemicals and mechanisms underlying postmenopausal osteoporosis (PMOP). A gene expression profile (accession no. GSE68303), which included 12 tissue samples from ovariectomized mice (OVX group) and 11 normal tissue samples from sham surgery mice (control group), was downloaded from the Gene Expression Omnibus database. The identification of differentially expressed genes (DEGs), and Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses, was performed, followed by an investigation of protein-protein interactions (PPI), PPI modules, transcription factors (TFs) and chemicals. A total of 784 upregulated and 729 downregulated DEGs between the two groups were identified. Furthermore, 2 upregulated modules and 6 downregulated modules were determined. The upregulated DEGs in modules were enriched in 'sensory perception of smell' function and 'olfactory transduction' pathway, and a number of genes belonging to the olfactory receptor (OLFR) family were identified in upregulated modules. The downregulated DEGs in modules were enriched in 'DNA replication initiation' function and 'cell cycle' pathway. A total of 8 TFs, including SP1 TF (SP1) and protein C-ets-1 (ETS1), were associated with PMOP. Furthermore, estradiol and resveratrol were identified as key chemicals in the chemical-gene interaction network. Therefore, TFs, including SP1 and ETS1, in addition to members of the OLFR gene family, may be employed as novel targets for treatment of PMOP. Furthermore, functions including 'sensory perception of smell' and 'replication initiation', and 'olfactory transduction' and 'cell cycle' pathways, may serve roles in PMOP. In addition, based on the chemical-gene interaction network, estradiol and resveratrol may also be considered for the treatment PMOP. PMID- 29138845 TI - Long noncoding RNA Lnc-EGFR promotes cell proliferation and inhibits cell apoptosis via regulating the expression of EGFR in human tongue cancer. AB - Tongue cancer remains a difficult disease to overcome. Long noncoding RNAs (LncRNAs) have been shown to serve significant roles in the diagnosis and treatment of tongue cancer. Herein, the present study aimed to investigate the role of a newly-discovered Lnc, Lnc-EGFR in tongue cancer. The results showed that the transcript level of Lnc-EGFR was upregulated in patients with tongue cancer and in cultured tongue cancer cell lines. Consistently, expression of EGFR was also elevated selectively in cancerous tissues and malignant cell lines. Knockdown of Lnc-EGFR inhibited the clonogenic ability and cell viability of human tongue cancer cell lines UM1 and CAL-27, as evidenced by colony formation assays, and cell proliferation assays. Furthermore, depletion of Lnc-EGFR in UM1 and CAL-27 cells increased cell apoptosis by upregulating the activities of caspase-3, and caspase-9, but not caspase-8. Lnc-EGFR knockdown-mediated inhibition of clonogenic ability and cell viability was rescued by overexpression of EGFR by adding EGFR recombinant protein into both cell lines. Likewise, Lnc EGFR knockdown-induced cell apoptosis was reversed by co-treatment with recombinant EGFR protein in UM1 and CAL-27 cells. All of these results suggested the oncogenic potential of Lnc-EGFR, which was achieved by positive regulation of EGFR in human tongue cancer. PMID- 29138846 TI - ITR-284 modulates cell differentiation in human chronic myelogenous leukemia K562 cells. AB - ITR-284 is a carboxamide analog that can inhibit proliferation in human promyelocytic leukemia HL-60 cells. To understand the effects and molecular mechanisms of ITR-284 in human erythromyeloblastoid leukemia, we treated K562 cells with different concentrations of ITR-284 (0, 2, 4, 6, 8 and 10 nM) and all trans retinoic acid (ATRA) (0, 0.1, 0.5, 1, 5 and 10 uM) for 24 h. The IC50 of ITR-284 was ~10 nM in K562 cells treated for 24 h as determined by MTT assay. May Grunwald-Giemsa staining and nitro blue tetrazolium (NBT) assays were used to determine cell morphology changes and differentiation after ITR-284 and ATRA treatment. In addition, mRNA expression levels of hematopoietic factors, including GATA-1, NF-E2 and GATA-2, were elevated, while expression levels of BCR ABL were downregulated in K562 cells after 24 h of treatment with ITR-284 as determined by quantitative reverse transcription polymerase chain reaction. In addition, western blot analyses showed that FOXM1, GLI 1 and c-MYC protein levels were decreased by ITR-284. Taken together, our data show that ITR-284 induced K562 cell differentiation, which led to decreased tumorigenesis. Our findings suggest that ITR-284 could be a potential candidate for treating chronic myelogenous leukemia. PMID- 29138847 TI - SRPK1-siRNA suppresses K562 cell growth and induces apoptosis via the PARP caspase3 pathway. AB - Serine-arginine protein kinase 1 (SRPK1) has been used as an important signal mediator, and is associated with cancer development. However, studies have yet to determine whether SRPK1 suppresses leukemia cell growth and induces apoptosis. Studies have also yet to reveal the underlying mechanisms. In the present study, the effects of downregulating SRPK1 gene expression on chronic myeloid leukemia cell lines (K562 cells) were investigated through RNA interference (RNAi) and the proliferation inhibition and apoptosis induction of SRPK1 in K562 cells were analyzed. K562 cells were transfected with two different concentrations of siRNA, and the transfection efficiency was detected via flow cytometry. The expression of SRPK1 was detected via reverse transcription-quantitative polymerase chain reaction. K562 cell proliferation and apoptosis were analyzed using MTT and flow cytometry respectively. The roles of caspase-3, poly (ADP-ribose) polymerase (PARP), p53 and B-cell lymphoma (Bcl)-2/Bcl-2 associated X, apoptosis regulator (Bax) proteins in the apoptosis of human K562 cells were further examined through western blot analysis. The SRPK1 expression was lower in the K562 cells transfected with SRPK1-siRNA compared with untransfected cells. The inhibition rate in the transfected groups was increased compared with the untransfected groups. Compared with control groups, the number of apoptotic cells in the SRPK1 silenced groups increased. The number of early apoptotic cells also increased. The cleaved caspase-3, cleaved PARP and p53 expression levels were significantly increased in the RNAi groups compared with control groups. Conversely, the Bcl 2/Bax rate was significantly lower. In conclusion, the knockdown of the SRPK1 gene by RNAi inhibited the proliferation of K562 cells and induced their apoptosis. Apoptosis was induced by the activation of the PARP-caspase3 pathway. PMID- 29138848 TI - Fli-1 promotes metastasis by regulating MMP2 signaling in hepatocellular carcinoma. AB - Friend leukemia virus integration 1 (Fli-1) is a newly identified ETS protein, and has critical roles in many malignancies. However, the physiological characters and potential mechanisms of Fli-1 in hepatocellular carcinoma (HCC) progression remains unclear. In the present study, Fli-1 was highly expressed in HCC samples and tumor cell lines. knockdown of Fli-1 with small interfering (si)RNAs significantly reduced the colony formation and metastasis capacity of HCC cell lines in vitro. Subsequent investigation identified that Fli-1 functioned as an oncogene in HCC carcinogenesis and it exerted its promoting metastatic effect primarily by modulating the matrix metalloproteinase (MMP)2 signaling pathway. Collectively, these data provide a novel insight into the mechanism of Fli-1/MMP2 signaling pathway in the pathogenesis of HCC, and Fli-1 may serve as a novel therapeutic target for HCC. PMID- 29138849 TI - Elevated serum levels of lipoprotein-associated phospholipase A2 predict mortality rates in patients with sepsis. AB - Sepsis remains one of the leading contributors to mortality rates in the intensive care unit (ICU) and emergency intensive care unit (EICU). Therefore, any treatments against the agents which produce sepsis in a medical emergency, are welcome. Elevated serum levels of lipoprotein-associated phospholipase A2 (Lp PLA2) have been reported in a small cohort of patients with inflammation. The present study evaluated serum levels of Lp-PLA2 in patients with sepsis and investigated the role of Lp-PLA2 in sepsis. The investigation involved the selection of 151 patients with sepsis admitted to the emergency department of the Affiliated Hospital of Nantong University (Nantong, China) and 30 healthy controls. All patients (39 with sepsis, 55 with severe sepsis and 57 with septic shock) were examined on admission to the EICU. A complete blood count was performed, and serum levels of Lp-PLA2, C-reactive protein, procalcitonin, and interleukin 6, sequential organ failure (SOFA) scores and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were determined on hospital admission. The EICU and overall mortality rates were evaluated at baseline. The present study also assessed various laboratory parameters, clinical data and inflammatory cytokines. The patient follow up duration was 90 days. The data suggested that the serum levels of Lp-PLA2 on admission to the EICU in patients with sepsis were elevated, compared with those in healthy controls. The concentrations of Lp-PLA2 were correlated with the severity of disease, and were significantly associated with experimental markers of inflammation and established prognostic scores. In the total cohort, persistently elevated levels of Lp-PLA2 on admission for EICU treatment was a predictor of poor prognosis, and provided superior diagnostic use, compared with the prognostic scoring systems, including SOFA or APACHE II scores. Taken together, the results suggested that Lp PLA2, with respect to other markers of inflammation, may have a role as a prognostic marker in sepsis, and provide background evidence for further trials to evaluate the clinical and pathophysiologic roles of Lp-PLA2 in sepsis. Persistently elevated serum concentrations of Lp-PLA2 indicated an unfavorable outcome in patients with sepsis. In addition, the results indicated the potential role of Lp-PLA2 as a prognostic biomarker in patients with sepsis during the early course of EICU treatment. PMID- 29138850 TI - Role of mitochondrial function in the invasiveness of human colon cancer cells. AB - We investigated the role of mitochondrial function in the invasiveness of human colorectal cancer (CRC) cell lines, using paired primary SW480 and metastatic SW620 cells, and appraised the clinical relevance of the alteration of mtDNA copy number in 33 pairs of CRC specimens after surgical resection. Suppression of mitochondrial function was achieved by the exposure of cells to oligomycin A (OA) or by knockdown of mitochondrial transcriptional factor A (TFAM) to evaluate their effects on energy metabolism, reactive oxygen species, protein expression levels of epithelial-mesenchymal transition (EMT) markers and invasive activity of CRC cells. We found that SW620 cells expressed higher levels of TFAM and mitochondrial DNA (mtDNA)-encoded NADH dehydrogenase subunit 6 (ND6) and cytochrome c oxidase subunit II (COX-II) and nuclear DNA-encoded NADH ubiquinone oxidoreductase subunit A9 (NDUFA9), iron-sulfur protein subunit B of succinate dehydrogenase (SDHB), ubiquinol-cytochrome c reductase core protein I/II (UQCRC1/2) and cytochrome c oxidase subunit IV (COX-IV) when compared with the SW480 cells. The mtDNA copy number, ADP-triggered oxygen consumption rate (OCR) and respiratory control ratio (RCR) of succinate-supported respiration in the SW620 cells were higher than those noted in the SW480 cells. The intracellular levels of H2O2 and O2-* in the SW620 cells were lower than levels noted in the SW480 cells. Moreover, SW620 cells displayed lower protein levels of hexokinase II (HK-II), glucose 6-phosphate isomerase (GPI) and lactate dehydrogenase (LDH), and lower lactate production rate, and expressed higher levels of EMT markers N cadherin, vimentin and Snail, and showed higher Transwell migration and invasion activities as compared with the SW480 cells. After OA treatment, SW620 cells exhibited a decrease in OCR and RCR of succinate-supported respiration, an increase in lactate production rate and intracellular levels of H2O2 and O2-*. Moreover, the level of vimentin and Transwell migration activity of the SW620 cells were decreased. After TFAM knockdown, the protein levels of TFAM, ND6 and COX-II, and mtDNA copy number, OCR and RCR of succinate-supported respiration in the SW620-KD#4 and SW620-KD#5 cells were all lower than those noted in the SW620 Control cells. By contrast, the protein level of HK-II, lactate production rate, the intracellular levels of H2O2 and O2-* in the SW620-KD#4 and SW620-KD#5 cells were all higher than those noted in the SW620-Control cells. Subsequently, both SW620-KD#4 and SW620-KD#5 cells had lower Transwell invasion activity than did the SW620-Control cells. Furthermore, we found that deeper invasion (P=0.025) and longer tumor length (P=0.069) were associated with higher mtDNA copy ratios in the 33 pairs of CRC specimens obtained from surgical resection. Taken together, we conclude that higher mtDNA copy number and mitochondrial function may confer an invasive advantage to CRCs. PMID- 29138851 TI - NRP1-positive lung cancer cells possess tumor-initiating properties. AB - Tumor-initiating cells possess the capacity for self-renewal and to create heterogeneous cell lineages within a tumor. Therefore, the identification and isolation of cancer stem cells is an essential step in the analysis of their biology. The aim of the present study was to determine whether the cell surface protein neuropilin 1 (NRP1) can be used as a biomarker of stem-like cells in lung cancer tumors. For this purpose, NRP1-negative (NRP1-) and NRP1-positive (NRP1+) cell subpopulations from two lung cancer cell lines were sorted by flow cytometry. The NRP1+ cell subpopulation showed an increased expression of pluripotency markers OCT-4, Bmi-1 and NANOG, as well as higher cell migration, clonogenic and self-renewal capacities. NRP1 gene knockdown resulted not only in a decreased expression of stemness markers but also in a decrease in the clonogenic, cell migration and self-renewal potential. In addition, the NRP1+ cell subpopulation exhibited dysregulated expression of epithelial-to-mesenchymal transition-associated genes, including the DeltaNp63 isoform protein, a previously reported characteristic of cancer stem cells. Notably, a genome-wide expression analysis of NRP1-knockdown cells revealed a potential new NRP1 pathway involving OLFML3 and genes associated with mitochondrial function. In conclusion, we demonstrated that NRP1+ lung cancer cells have tumor-initiating properties. NRP1 could be a useful biomarker for tumor-initiating cells in lung cancer tumors. PMID- 29138852 TI - Anti-IL-39 (IL-23p19/Ebi3) polyclonal antibodies ameliorate autoimmune symptoms in lupus-like mice. AB - The interleukin (IL)-12 family cytokines have been examined as therapeutic targets in the treatment of several autoimmune diseases. Our previous study showed that a novel IL-12 family cytokine, IL-39 (IL-23p19/Ebi3) mediates inflammation in lupus-like mice. In the present study, the effect of anti-mouse IL-39 polyclonal antibodies on autoimmune symptoms in lupus-like mice was investigated. Rabbit anti-mouse IL-39 polyclonal antibodies were produced by immunization with recombinant mouse IL-39, and purified using protein A chromatography. These antibodies were subsequently used to treat lupus-like mice. Flow cytometry, captured images, ELISA and H&E staining were used to determine the effect of anti-IL-39 polyclonal antibodies on inflammatory cells, autoantibody titers, proteinuria, infiltrating inflammatory cells and the structure of the glomerular region. The anti-IL-39 polyclonal antibodies effectively reduced the numbers of inflammatory cells, splenomegaly, autoantibody titers, proteinuria, infiltrating inflammatory cells, and restored the structure of the glomerular region in MRL/lpr mice. Taken together, these results suggested that anti-IL-39 polyclonal antibodies ameliorated autoimmune symptoms in lupus like mice. Therefore, IL-39 may be used as a possible target for the treatment of systemic lupus erythematosus. PMID- 29138854 TI - NG25, an inhibitor of transforming growth factor-beta-activated kinase 1, ameliorates neuronal apoptosis in neonatal hypoxic-ischemic rats. AB - Transforming growth factor (TGF)-beta-activated kinase 1 (TAK1) was found to be activated by TGF-beta and acts as a central regulator of cell death in various types of disease. However, the expression and function of TAK1 in the neonatal brain following hypoxia-ischemia (HI) remains unclear. In the present study, western blotting and immunofluorescence were employed to determine the expression and distribution of TAK1 in the brain cortex of a perinatal HI rat model. In addition, the specific inhibitor of TAK1, NG25 was administered via intracerebroventricular injection, prior to insult of the neonatal rat brains, for neuroprotection. Western blotting and double immunofluorescence indicated that an increased expression level of phosphorylated-TAK1 was observed, and was localized with neurons and astrocytes, compared with the sham group. Further study demonstrated that injection of NG25 prior to insult significantly inhibited TAK1/c-Jun N-terminal kinases activity and dramatically ameliorated acute hypoxic ischemic cerebral injury by inhibiting cell apoptosis in perinatal rats. Thus, NG25 ameliorates neuronal apoptosis in neonatal HI rats by inhibiting TAK1 expression and cell apoptosis. In addition, NG25 may serve as a promising novel neuroprotective inhibitor for perinatal cerebral injury. PMID- 29138853 TI - Role of innate lymphoid cells in obesity and metabolic disease (Review). AB - The immune system has previously been demonstrated to be associated with the pathophysiological development of metabolic abnormalities. However, the mechanisms linking immunity to metabolic disease remain to be fully elucidated. It has previously been suggested that innate lymphoid cells (ILCs) may be involved in the progression of numerous types of metabolic diseases as these cells act as suppressors and promoters for obesity and associated conditions, and are particularly involved in adipose tissue inflammation, which is a major feature of metabolic imbalance. Group 2 ILCs (ILC2s) have been revealed as anti obese immune regulators by secreting anti-inflammatory cytokines and promoting the polarization of M2 macrophages, whereas group 1 ILCs (ILC1s), including natural killer cells, may promote adipose tissue inflammation via production of interferon-gamma, which in turn polarizes macrophages toward the M1 type. The majority of studies to date have demonstrated the pathological association between ILCs and obesity in the context of adipose tissue inflammation, whereas the roles of ILCs in other organs which participate in obesity development have not been fully characterized. Therefore, identifying the roles of all types of ILCs as central components mediating obesity-associated inflammation, is of primary concern, and may lead to the discovery of novel preventative and therapeutic interventions. PMID- 29138855 TI - Integrated bioinformatics analysis of the osteoarthritis-associated microRNA expression signature. AB - Numerous studies have focused on osteoarthritis (OA) cartilage injuries, with observations of abnormalities in microRNA (miRNA) expression levels. The aim of the present study was to consolidate and assess the results of these studies to identify potential miRNA biomarkers of OA. A comprehensive meta-analysis of eight independent miRNA expression studies in OA was performed using the robust rank aggregation method (RRA), which contained a total of 82 OA and 39 normal cartilage samples. The targets of meta-signature miRNA were predicted using TargetScan v6.2, PicTar, miRDB, TarBase v7.0 and starBase databases. In addition, pathway enrichment analysis was performed to establish the biologically and functionally relevant genes involved in meta-signature miRNA regulation. Six dysregulated miRNAs were identified, including four up regulated (miR-23b-3p, miR 27b-3p, miR-211-5p and miR-16-5p) and two down regulated (miR-25-3p and miR-149 5p). The enrichment of Kyoto Encyclopedia of Genes and Genomes and Panther signaling pathways were predominantly associated with cell signaling and cell regulation. In the present study, the meta-signature miRNA identified may be used to develop a series of diagnostic and prognostic biomarkers for OA specifically for use in a clinical setting. PMID- 29138856 TI - Differentially expressed proteins in the human esophageal cancer cell line Eca 109, in the presence and absence of gemcitabine. AB - The present study aimed to screen and study the roles of differentially expressed proteins in the human esophageal cancer cell line Eca-109, in the presence and absence of gemcitabine (GEM). The 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di phenytetrazoliumromide (MTT) method was used to assay the vitality of the Eca-109 cells following treatment with GEM (1-16 ug/ml). The cell apoptosis was measured by using fluorescence activated cell sorting. The proteins in the treated Eca-109 cells were extracted, validated, and assayed via two-dimensional gel electrophoresis combined with matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). The differentially expressed proteins were then determined by western blotting. Furthermore, alterations in mitochondrial ultrastructure of the treated cells were observed under a transmission electron microscope. GEM significantly inhibited the growth of the Eca-109 cells in a concentration- and time-dependent manner, and the 50% inhibition concentration (IC50) value was 3.87 ug/ml. The MALDI-TOF-MS analysis revealed that there were three differentially expressed proteins following the GEM treatment, compared with the control. The differential proteins were verified to be B cell lymphoma-2 associated X, apoptosis regulator (Bax)-alpha, apoptosis associated speck-like protein containing a CARD (ASC) and myeloid cell leukemia sequence (Mcl)-1. Western blotting revealed that the expression levels of ASC and Bax-alpha proteins in the treated cancer cells were significantly upregulated, whereas the Mcl-1 protein expression was markedly downregulated compared with the control. Furthermore, the GEM treatment destroyed the mitochondrial ultrastructure of the cancer cells, leaving swelled mitochondria, a fading matrix and destroyed the mitochondrial cristae. GEM significantly inhibits the growth and promotes apoptosis of the Eca-109 cells, due to the alterations in the expression levels of the differential proteins, including ASC, Mcl-1 and Bax alpha. PMID- 29138857 TI - miR-218 inhibits the proliferation of human glioma cells through downregulation of Yin Yang 1. AB - Malignant glioma is the most common cancer type of the nervous system and the mechanisms driving the occurrence and development remain unclear, preventing effective treatment of this disease. Therefore, novel and efficient therapies for glioma are required. MicroRNAs (miRNAs) are small non-coding RNAs that act as oncogenes or tumor suppressors in human cancer. In the present study, it was confirmed that Yin Yang-1 (YY1), a transcription factor that is part of the polycomb group protein (PcG) family, is a direct target of miR-218 in human glioma cells. It was demonstrated that YY1 promoted glioma cell proliferation and miR-218 could inhibit glioma cell proliferation by targeting YY1, and indirectly reduced the degradation of p53. Together the results indicate that miR-218 functions as a tumor suppressor in human glioma and suggest that overexpression of miR-218 may be a potential strategy for the treatment of human glioma in the future. PMID- 29138858 TI - Downregulation of miR-19a-3p promotes invasion, migration and bone metastasis via activating TGF-beta signaling in prostate cancer. AB - Constitutive activation of TGF-beta signaling pathway is a well-documented mechanism responsible for the bone metastasis of prostate cancer (PCa). MicroRNAs (miRNAs) have been reported to be crucial for the activation of TGF-beta signaling via targeting downstream components of TGF-beta signaling pathway. Here, we report that miR-19a-3p is downregulated in bone metastatic PCa tissues and cells. Upregulation of miR-19a-3p suppresses invasion, migration in vitro and inhibits bone metastasis in vivo in PCa cells. Conversely, silencing miR-19a-3p yields the opposite effect. Our results further demonstrate that miR-19a-3p inhibits invasion and migration abilities of PCa cells via targeting downstream effectors of TGF-beta signaling, SMAD2 and SMAD4, resulting in the inactivation of TGF-beta signaling. Therefore, our results uncover a novel mechanistic understanding of miR-19a-3p-induced suppressive role in bone metastasis of PCa, which will facilitate the development of effective cancer therapy methods against PCa. PMID- 29138859 TI - 17beta-estradiol attenuates ovariectomy-induced bone deterioration through the suppression of the ephA2/ephrinA2 signaling pathway. AB - The present study aimed to investigate whether 17beta-estradiol (E2) exerts protective effects on bone deterioration induced by ovariectomy (OVX) through the ephA2/ephrinA2 signaling pathway in rats. Female rats were subjected to OVX, sham surgeryor OVX+E2 treatment. Levels of biomarkers were measured in serum and urine. Hematoxylin and eosin staining was performed on paraffin-embedded bone sections. Expression of genes and proteins was analyzed by reverse transcription quantitative polymerase chain reaction and western blotting, respectively. Bone mineral density (BMD) was analyzed by dual-energy X-ray absorptiometry. Trabecular bone microarchitecture was also evaluated. Osteoclastogenesis was induced by in vitro culturing with mouse receptor activator of nuclear factor kappaB ligand (RANKL) and macrophage colony-stimulating factor 1. small interfering RNA was designed to knockdown ehpA2 receptor and its ligand ephrinA2. Results of the present study demonstrated that E2 had suppressive effects on OVX induced body weight gain and bone turnover factors in serum and urine. E2 inhibited the bone resorption function of osteoclasts by inhibiting the production of tartrate-resistant acid phosphatase-5b and RANKL, and induced bone formation function of osteoblasts by prompting runt-related transcription factor 2, Sp7 transcription factor and collagen alpha-1(I) chain expression in bone marrow cells. E2 treatment significantly increased the tibia BMD and prevented the deterioration of trabecular microarchitecture compared with the OVX group. Moreover, E2 significantly decreased the OVX-stimulated expression of ephA2 and ephrinA2. EphA2 or ephrin A2 knockdown significantly suppressed osteoclastogenesis in vitro. In conclusion, E2 can attenuate OVX-induced bone deterioration partially through the suppression of the ephA2/ephrinA2 signaling pathway. Therefore EphA2/ephrinA2 signaling pathway may be a potential target for osteoporosis treatment. PMID- 29138860 TI - An RNA-sequencing study identifies candidate genes for angiotensin II-induced cardiac remodeling. AB - The present study aimed to reveal the underlying mechanism of angiotensin II (AngII)-induced cardiac remodeling and to identify potential therapeutic targets for prevention. Rat cardiac fibroblasts (CFs) were cultured with 10 nM AngII for 12 h, and CFs without AngII were used as the control. Following RNA isolation from AngII treated and control CFs, RNA-sequencing was performed to detect gene expression levels. Differentially-expressed genes (DEGs) were identified using the linear models for microarray analysis package in R software, and their functions and pathways were examined via enrichment analysis. In addition, potential associations at the protein level were revealed via the construction of a protein-protein interaction (PPI) network. The expression levels of genes of interest were validated via reverse transcription-quantitative polymerase chain reaction analysis. In total, 126 upregulated and 140 downregulated DEGs were identified. According to the enrichment analysis, acetyl coA carboxylase beta (ACACB), interleukin 1beta (IL1B), interleukin 1alpha (IL1A), nitric oxide synthase 2 (NOS2) and matrix metallopeptidase 3 (MMP3) were associated with the immune response, regulation of angiogenesis, superoxide metabolic process and carboxylic acid binding biological processes. Among them, ACACB and MPP3 were two predominant nodes in the PPI network. In addition, IL1B and MMP3 were demonstrated to be upregulated. These five genes, particularly IL1B and MMP3, may be used as candidate markers for the prevention of AngII-induced cardiac remodeling. PMID- 29138861 TI - Immunogenic tumor cell death induced by chemotherapy in patients with breast cancer and esophageal squamous cell carcinoma. AB - It has been reported that chemo-radiotherapy can induce immunogenic tumor cell death (ICD), which triggers T-cell immunity mainly mediated by high-mobility group box 1 protein (HMGB1) and calreticulin. However, there is still limited information to support this theory relating to chemotherapy alone. In the present study, the expression of HMGB1 and calreticulin was evaluated by immunohistochemistry in pre-treatment biopsy specimens and surgically resected specimens, which were obtained from patients with breast cancer (n=52) and esophageal squamous cell carcinoma (ESCC) (n=8) who had been treated with neoadjuvant chemotherapy (NAC). We also analyzed HMGB1 and calreticulin expression in breast cancer cell lines treated with chemotherapeutic drugs. As a result, both HMGB1 and calreticulin expression levels were significantly upregulated after NAC in both breast cancer and ESCC tissues. However, no significant correlation was observed between HMGB1 expression and pathological response after NAC or between HMGB1 expression and patient survival. Furthermore, although overall survival in the high infiltration group of CD8-positive T cells was significantly superior to that in the low infiltration group in breast cancer patients, there were no correlations between the number of CD8-positive T cells and HMGB1 or calreticulin expression levels. In addition, chemotherapeutic drugs induced upregulation of HMGB1 and calreticulin in all tested cell lines. Our findings indicate that chemotherapy alone can significantly induce ICD regardless of the degree of pathological response after chemotherapy. PMID- 29138862 TI - Liver kinase B1 restoration promotes exosome secretion and motility of lung cancer cells. AB - Liver kinase B1 (LKB1) regulates a variety of cellular functions, including cell polarity, energy metabolism and cell growth, by targeting multiple signaling pathways such as AMPK/mTOR and p53. LKB1 functions as a tumor suppressor in sporadic cancers including lung cancer. Extracellular vesicles such as exosomes secreted by cancer cells modulate the tumor microenvironment and progression by targeting both tumor cells (autocrine actions) and other types of cells associated with tumors (paracrine actions). While the roles of LKB1 in cellular signaling in general is well-studied, its specific role in exosome-mediated signaling remains to be explored. To this purpose, we reintroduced LKB1 into H460 and A549 lung cancer cells that are endogenously deficient in LKB1 expression. Notably, we found that while restoration of LKB1 significantly reduced lung cancer cell growth as expected, it greatly promoted cell motility and enhanced the release of exosomes. In addition, exosomes isolated from H460 cells with stable restoration of LKB1 had much higher ability in stimulating lung cancer cell migration than did those from H460 cells lacking LKB1. Mechanistically, restoration of LKB1 in H460 cells inhibited cellular expression and exosomal secretion of migration-suppressing microRNAs (miRNAs), including miR-125a, miR 126 and let7b. Taken together, the present study revealed a new role for LKB1 in promoting cell motility by downregulating migration-suppressing miRNA expression and exosome secretion. PMID- 29138863 TI - Therapeutic effect of ulinastatin on pulmonary fibrosis via downregulation of TGF beta1, TNF-alpha and NF-kappaB. AB - Pulmonary fibrosis is a chronic, progressive, lethal lung disease characterized by alveolar cell necrosis and dysplasia of interstitial fibrotic tissue, resulting in loss of lung function and eventual respiratory failure. Previously, glucocorticoid drugs were used to treat this lung disorder. However, positive responses were recorded in less than half of treated patients and the cytotoxicity caused by high dosage treatment is still a concern. The present study investigated whether ulinastatin, a typical urinary trypsin inhibitor that mitigates numerous inflammatory responses, could be a treatment option for lung fibrosis. The results demonstrated that ulinastatin had the ability to ameliorate interstitial fibrosis and alveolar exudates and to protect against lung diseases induced by smoke, irradiation or silica particles. The mechanism of ulinastatin resulted in the downregulation of inflammatory cascades: Transforming growth factor-beta1, tumor necrosis factor-alpha and nuclear factor-kappaB, as demonstrated by western blotting and ELISA. Ulinastatin treatment with a high dose (100,000 U/kg body weight/day) resulted in an attenuated inflammatory response, and inhibited fibrosis formation in lungs, suggesting that ulinastatin may become a part of a clinical therapeutic strategy. PMID- 29138864 TI - Expression level of microRNA-200c is associated with cell morphology in vitro and histological differentiation through regulation of ZEB1/2 and E-cadherin in gastric carcinoma. AB - Scirrhous type gastric cancer is characterized by diffuse infiltration of poorly differentiated adenocarcinoma cells and poor prognosis. Although association of poorly differentiated histology with reduction in E-cadherin expression, as well as association of microRNA (miR)-200c with E-cadherin through regulation of ZEB1/2, has been reported, participation of miR-200c in gastric carcinogenesis is not fully understood. We used 6 cell lines originating from gastric cancers, and investigated levels of miR-200c along with its target mRNAs ZEB1/2 and E-cadherin by qRT-PCR. ZEB1 and E-cadherin protein expression was also assessed via western blotting. Furthermore, we investigated the expression levels of miR-200c by in situ hybridization, along with the expression of ZEB1 and E-cadherin by immunohistochemistry, in 97 gastric adenocarcinoma tissues. Inverse correlation between miR-200c and ZEB1 levels were obtained by qRT-PCR in cell lines (P<0.05). Cell lines with low miR-200c and high ZEB1 exhibited low E-cadherin expression in both qRT-PCR and western blotting, and exhibited spindle-shaped morphology, in contrast to round cell morphology in those cell lines with high miR-200c levels. Inverse correlations were also obtained between miR-200c and ZEB1 as well as between ZEB1 and E-cadherin levels in tissue samples (P<0.001). Cancer tissues with low miR-200c, high ZEB1, and low E-cadherin expression were associated with poorly differentiated histology, in contrast to tubular form in cancers with high miR-200c expression levels (P<0.001). Our data revealed that downregulation of miR-200c primarily regulated cell morphology by downregulation of E-cadherin through upregulation of ZEB1, leading to poorly differentiated histology in gastric cancer. PMID- 29138865 TI - Silencing of vacuolar ATPase c subunit ATP6V0C inhibits the invasion of prostate cancer cells through a LASS2/TMSG1-independent manner. AB - Vacuolar ATPase (V-ATPase), widespread in eukaryotic cells, is extensively expressed in many highly metastatic tumors, of which the V-ATPase c subunit ATP6V0C is particularly associated with the invasion and metastasis of cancer. ATP6V0C was directly found to interact with LASS2/TMSG1 which is a new tumor metastasis inhibitory gene identified by our laboratory in 1999. In order to study the role of ATP6V0C, we generated small interference RNA (siRNA) targeting ATP6V0C and investigated its function on the invasion of human prostate cancer cell line PC-3M-1E8 with high metastatic potential and its interplay with LASS2/TMSG1. We found that the expression of ATP6V0C was higher in prostate cancer cell lines PC-3M-1E8 and PC-3M with high metastatic potential than that from cell lines PC-3M-2B4 and PC-3 with low metastatic potential, indicating that ATP6V0C enhanced metastatic capacity in prostate cancer cells. Furthermore, silencing of ATP6V0C in PC-3M-1E8 cells inhibited V-ATPase activity (by ~5-fold), decreased extracellular hydrogen ion concentration and successively decreased activation of secreted MMP-9 (by ~3.6-fold), which coincided with the inhibition of cell migration and invasion in vitro, as well as a marked decrease in the expression of LASS2/TMSG1 probably through positive feedback. Thus we concluded that silencing of the ATP6V0C gene effectively suppressed the migration and invasion of prostate carcinoma cells through the inhibition of the function of V ATPase, not through a LASS2/TMSG1-dependent manner. Therefore ATP6V0C inhibitors are promising therapeutic targets for advanced prostate cancer. PMID- 29138866 TI - HMGA2 facilitates epithelial-mesenchymal transition in renal cell carcinoma by regulating the TGF-beta/Smad2 signaling pathway. AB - High-mobility group AT-hook 2 (HMGA2), a member of the high mobility group family, has been reported to correlate with cancer progression. However, there is no report concerning the correlation between HMGA2 and metastasis in renal cell carcinoma. In the present study, we found that HMGA2 was highly expressed in five renal cell carcinoma cell lines compared with that in the normal renal tubular epithelial HK2 cell line. Additionally, HMGA2 facilitated cell migration and invasion of renal cell carcinoma cells, as evidenced by wound healing and Transwell assays. Subsequently, our results revealed that the E-cadherin level was upregulated, while N-cadherin, Twist1 and Twist2 expression were downregulated in HMGA2-depleted ACHN cells. In contrast, overexpression of HMGA2 in 786-O cells enhanced epithelial-mesenchymal transition (EMT). In addition, analysis of the database Cancer Browser further validated the positive correlation between HGMA2 and Twist1 or Twist2 in renal cell carcinoma. Meanwhile, Kaplan-Meier analysis indicated that low HMGA2 expression was closely associated with an increased overall survival in renal cell carcinoma patients. To confirm the underlying mechanism of HMGA2-regulated EMT, our results revealed that silencing of HMGA2 downregulated the mRNA and protein levels of TGF-beta and Smad2, while HMGA2 overexpression had the opposite effect. Furthermore, TGF-beta overexpression could partially reverse the anti-metastatic effect and mesenchymal epithelial transition (MET) by HMGA2 loss, while TGF-beta deficiency impeded the pro-metastatic phenotype and high expression of EMT markers induced by HMGA2 overexpression. In summary, our results demonstrated that HMGA2 facilitated a metastatic phenotype and the EMT process in renal cell carcinoma cells in vitro through a TGF-beta-dependent pathway. In addition, these data strongly suggest that HGMA2 may serve as a potential therapeutic target and prognostic biomarker against renal cell carcinoma in the future. PMID- 29138867 TI - Effect of xanthohumol on Th1/Th2 balance in a breast cancer mouse model. AB - Xanthohumol (XN), a prenylflavonoid found in the hop plant, Humulus lupulus, exhibits a variety of biological activities. Numerous studies have reported that XN inhibits the growth of many types of cancer cells, but the effects of XN on tumor immunity have not yet been studied. We explored the effect of XN on Th1/Th2 balance and the underlying mechanism based on a BALB/c-4T1 breast cancer mouse model. The results showed that XN significantly slowed down tumor growth and inhibited expression of antitumor proliferation protein Ki-67 as well as breast cancer-specific marker cancer antigen 15-3 (CA15-3). Flow cytometric analysis revealed that XN enhanced the secretion of perforin, granzyme B and increased the ratio of CD8+/CD25+. ELISA analysis of cytokine results demonstrated that XN obviously upregulated Th1 cytokines, while downregulated Th2 cytokines. Th1/Th2 ratio analysis by flow cytometry illustrated that XN regulated the balance drift to Th1 polarization. Western blotting and immunohistochemistry (IHC) results manifested that XN induced expression of T-bet, a Th1-specific transcription factor. Furthermore, we found that XN significantly promoted the phosphorylation of signal transducer and activator of transcription (STAT)4. Our results demonstrated that XN promoted Th1/Th2 balance towards Th1 polarization, and STAT4 may play a positive role in the regulation of Th1/Th2 cytokines by XN. PMID- 29138868 TI - HDAC inhibitor LMK-235 promotes the odontoblast differentiation of dental pulp cells. AB - The role of dental pulp cells (DPCs) in hard dental tissue regeneration had received increasing attention because DPCs can differentiate into odontoblasts and other tissue-specific cells. In recent years, epigenetic modifications had been identified to serve an important role in cell differentiation, and histone deacetylase (HDAC) inhibitors have been widely studied by many researchers. However, the effects of HDAC4 and HDAC5 on the differentiation of DPCs and the precise molecular mechanisms remain unclear. The present study demonstrated that LMK-235, a specific human HDAC4 and HDAC5 inhibitor, increased the expression of specific odontoblastic gene expression levels detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in dental pulp cells, and did not reduce cell proliferation tested by MTT assay after 3 days in culture at a low concentration. In addition, the mRNA and protein expression levels of dentin sialophosphoprotein, runt-related transcription factor 2, alkaline phosphatase (ALP) and osteocalcin were evaluated by RT-qPCR and western blotting, respectively. The increased gene and protein expression of specific markers demonstrated, indicating that LMK-235 promoted the odontoblast induction of DPCs. ALP activity and mineralised nodule formation were also enhanced due to the effect of LMK-235, detected by an ALP activity test and Alizarin Red S staining, respectively. Additionally, the vascular endothelial growth factor (VEGF)/RAC gamma serine/threonine-protein kinase (AKT)/mechanistic target of rapamycin (mTOR) signalling pathway was tested to see if it takes part in the differentiation of DPCs treated with LMK-235, and it was demonstrated that the mRNA expression levels of VEGF, AKT and mTOR were upregulated. These findings indicated that LMK-235 may serve a key role in the proliferation and odontoblast differentiation of DPCs, and could be used to accelerate dental tissue regeneration. PMID- 29138869 TI - Cepharanthine exhibits a potent anticancer activity in p53-mutated colorectal cancer cells through upregulation of p21Waf1/Cip1. AB - Cepharanthine (CEP), a biscoclurine alkaloid isolated from Stephania cepharantha Hayata, has demonstrated anticancer activity in several different types of cancer cells. Colorectal cancer (CRC) is one of the most common cancers in both men and women. Mutated p53 in CRC was reported to be associated with resistance to commonly used chemotherapeutic agents including, 5-fluorouracil, oxaliplatin and irinotecan. Many studies reported that mutation of p53 induced chemoresistance through several mechanisms, including induction of drug efflux, disruption of cell cycle regulation, evasion of apoptosis and upregulation of DNA repair. This study aimed to evaluate the anticancer activity of CEP in p53 mutant versus p53 wild-type colorectal cancer cells and determine its underlying mechanisms of action. Our results showed that CEP induced colorectal cancer cell death in a concentration-dependent manner. Remarkably, CEP was more effective in controlling the growth of the p53 mutant colorectal cancer cell lines, HT-29 and SW-620, than the p53 wild-type colorectal cancer cell lines, COLO-205 and HCT-116. Further studies on the underlying mechanisms revealed that CEP could induce cell cycle arrest and apoptosis in both HT-29 and COLO-205 cells. Treatment with CEP dramatically increased p21Waf1/Cip1 expression levels of the p53 mutant cell line HT-29 and to a lesser extent, the p53 wild-type cell line COLO-205. In addition, cyclin A and Bcl-2 expression levels of both cell lines were significantly downregulated following treatment with CEP. CEP also induced ROS formation in colorectal cancer cells. Taken together, we concluded that CEP effectively induced cell cycle arrest and apoptosis which may be mediated through upregulation of p21Waf1/Cip1, downregulation of cyclin A and Bcl-2 and induction of ROS production in colorectal cancer cells. These findings suggested that CEP could potentially be a novel anticancer agent for p53 mutant colorectal cancer cells which are often resistant to current chemotherapeutic agents. PMID- 29138871 TI - Revision shoulder arthroplasty with a reverse shoulder prosthesis : Use of structural allograft for glenoid bone loss. AB - INTRODUCTION: Revision shoulder arthroplasty presents many unique and complex challenges when glenoid bone loss is involved. A distorted and medialized anatomy prevents the proper mechanics of the reverse prosthesis with regard to deltoid tension and ultimate function. This paper highlights one surgeon's experience using structural allograft for glenoid bone loss. PATIENTS AND METHODS: In all, 20 patients for a total of 24 surgeries with a medialized glenoid and/or substantial glenoid bone loss of grade IIB or higher were evaluated in this retrospective study. The allograft surgeries were performed as a one-stage procedure except for three patients. Recombinant human bone morphogenetic protein 2 (BMP2) was added to supplement incorporation in all cases. Four patients had two separate allograft procedures. Eight of the allograft procedure were femoral shaft, eleven of the allografts were femoral neck/head, and five of the allograft procedures were from proximal humerus. A graft was considered a success if they had at least 12 months of clinical and radiographic follow-up without subsequent removal of the graft or radiographic failure. Patients with less than 12 months of follow-up were included if the graft was removed or had early failure. RESULTS: All femoral shaft allografts except one failed, and during revision surgery it was often noted that the graft was cracked where the peripheral screws had been drilled. In nine patients the graft was still in place at last follow up, seven of these were femoral neck/head allografts. Five grafts were removed secondary to infection. Average follow-up was 24 months (range 5-45 months). CONCLUSIONS: Femoral neck allografts are an option in patients with substantial bone loss. The authors do not recommend use of femoral shaft allografts. PMID- 29138870 TI - INSIG2 rs7566605 single nucleotide variant and global DNA methylation index levels are associated with weight loss in a personalized weight reduction program. AB - Single nucleotide polymorphisms associated with lipid metabolism and energy balance are implicated in the weight loss response caused by nutritional interventions. Diet-induced weight loss is also associated with differential global DNA methylation. DNA methylation has been proposed as a predictive biomarker for weight loss response. Personalized biomarkers for successful weight loss may inform clinical decisions when deciding between behavioral and surgical weight loss interventions. The aim of the present study was to investigate the association between global DNA methylation, genetic variants associated with energy balance and lipid metabolism, and weight loss following a non-surgical weight loss regimen. The present study included 105 obese participants that were enrolled in a personalized weight loss program based on their allelic composition of the following five energy balance and lipid metabolism-associated loci: Near insulin-induced gene 2 (INSIG2); melanocortin 4 receptor; adrenoceptor beta2; apolipoprotein A5; and G-protein subunit beta3. The present study investigated the association between a global DNA methylation index (GDMI), the allelic composition of the five energy balance and lipid metabolism-associated loci, and weight loss during a 12 month program, after controlling for age, sex and body mass index (BMI). The results demonstrated a significant association between the GDMI and near INSIG2 locus, after adjusting for BMI and weight loss, and significant trends were observed when stratifying by gender. In conclusion, a combination of genetic and epigenetic biomarkers may be used to design personalized weight loss interventions, enabling adherence and ensuring improved outcomes for obesity treatment programs. Precision weight loss programs designed based on molecular information may enable the creation of personalized interventions for patients, that use genomic biomarkers for treatment design and for treatment adherence monitoring, thus improving response to treatment. PMID- 29138872 TI - Cognitively and socially induced stress affects postural control. AB - Postural control is an adaptive process that can be affected by many aspects of human behavior, including emotional contexts. The main emotional contexts that affect postural control are postural threat and passive viewing of aversive or threatening images, both of which produce a reduction in postural sway. The aim of the present study was to assess whether similar stress-related changes in postural sway can be observed using stress induced by social evaluative threat (SET) while performing arithmetic tasks. Twelve young adults performed an arithmetic and a postural control task separately, concurrently, and concurrently with added time pressure in the arithmetic task. In the final condition, participants were given negative feedback about their performance in the arithmetic task and performed it again while being observed (SET condition). Results showed that stress increased linearly with task demand. Postural sway and reaction times were not affected by the first two conditions; however, when time pressure was introduced, reaction times became faster and sway amplitude increased. Finally, introduction of SET caused the predicted reduction in postural sway and an increase in reaction times relative to the time pressure condition. Our results suggest that stress induced using a combination of arithmetic tasks and social evaluative threat leads to systematic changes in postural control. The paradigm developed in the present study would be very useful in assessing interactions between cognition, stress, and postural control in the context of postural instability and falls in older adults. PMID- 29138873 TI - Effects of cognitive load on the amount and temporal structure of postural sway variability in stroke survivors. AB - This study aimed to investigate the variability in postural sway patterns during quiet standing in stroke survivors. The postural sway was measured in 19 stroke survivors, as well as 19 healthy demographically matched participants, at 3 levels of postural difficulty (rigid surface with closed and open eyes, and foam surface with closed eyes), and 3 levels of cognitive difficulty (without a cognitive task, easy and difficult cognitive tasks). Both linear analyses (the amount of postural sway variability, including the standard deviation of the COP velocity in both the anteroposterior (AP) and mediolateral (ML) directions), as well as non-linear analyses [the temporal structure of the COP variability, including % Recurrence, % Determinism, Shannon Entropy, Trend and the maximum diagonal line (D max)] were employed. The results revealed that the amount of variability of the postural sway of stroke survivors was significantly greater than that of healthy participants, along both the ML and AP directions, with the highest obtained during standing on foam with closed eyes. All measures of the temporal structure of the COP variability were significantly greater in stroke survivors, as compared to the control group, along the ML direction, but not along the AP direction. The cognitive error was significantly higher during difficult cognitive tasks, although it was neither affected by postural difficulty nor by group. The different results obtained for the amount and temporal structure of the COP variability in the AP and ML directions shed light on the intricate mechanisms employed by the CNS in post-stroke balance control, and suggest that effective rehabilitative and therapeutic strategies should be patient-specific, taking both the environment/surface as well as the specific protocols into consideration. PMID- 29138874 TI - Using IL-6 concentrations in the first 24 h following trauma to predict immunological complications and mortality in trauma patients: a meta-analysis. AB - PURPOSE: In previous studies, interleukin-6 (IL-6) has been shown to have a high predictive value for the development of complications and mortality after trauma; however, there is some uncertainty around these results. The aim of this meta analysis was to assess the value of early IL-6 levels (within the first 24 h after trauma) for predicting post-traumatic complications [acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), sepsis, multiple organ failure (MOF), and multiple organ dysfunction syndrome (MODS)] and mortality. METHODS: A systemic literature review (from January 01, 1990, to June 03, 2017) of English-language articles was carried out using Pubmed, the Cochrane Central Register of Controlled Trials, Embase, and Web of Science. The search terms used were IL-6 (IL6, IL-6, interleukin 6, or interleukin-6); trauma (trauma*, polytrauma*, multitrauma*, injury, or injury severity score); complications (complication*, ARDS, SIRS, sepsis, MOF, or MODS); and mortality (survival, death). Eleven publications (775 patients) out of 1812 fulfilled the criteria. Fixed-effective models were used for data analysis. Statistical heterogeneity was estimated by a Chi-squared Q test and I 2 statistics, and publication bias was assessed with Egger's test. RESULTS: Results showed that the concentrations of IL-6 within the first 24 h after trauma were significantly higher in the group of patients who had complications or who died [standardized mean difference (SMD) = 0.399; 95% confidence interval (CI) 0.217, 0.580; I 2 = 0.0%; P(heterogeneity) = 0.489]. Subgroup results showed a significant correlation for mortality [SMD = 0.610; 95% CI 0.322, 0.898; I 2 = 0.0%; P(heterogeneity) = 0.708] and MOF/MODS [SMD = 0.334; 95% CI 0.028, 0.639; I 2 = 0.0%; P(heterogeneity) = 0.512] with IL-6, but not for sepsis [SMD = 0.194; 95% CI - 0.095, 0.484; I 2 = 0.0%; P(heterogeneity) = 0.512]. Significance was also found in both ISS >= 9 [SMD = 0.461, 95% CI 0.131, 0.791, I 2 = 5.6%, P(heterogeneity) = 0.365] and ISS >= 16 [SMD = 0.372, 95% CI 0.155, 0.588, I 2 = 1.5%, P(heterogeneity) = 0.413]. CONCLUSION: In conclusion, this meta-analysis showed that serum concentration of IL-6 within the first 24 h after trauma could be useful for the prediction of post-traumatic complications, particularly MOF/MODS and mortality. PMID- 29138875 TI - Variant course of extensor pollicis brevis tendon in the third extensor compartment. AB - INTRODUCTION: According to the anatomical literature, the extensor pollicis brevis (EPB) tendon passes through the first compartment and enters the base of the proximal phalanx of the thumb. There have been a few reports on the different types of supernumerary EPB tendons; however, an unusual course of the EPB tendon is extremely rare. MATERIALS AND METHODS: During routine cadaveric dissection in the Department of Gross Anatomy, we detected an variant EPB muscle in a 96-year old fresh female cadaver. RESULTS: The EPB muscle originated from the posterior surface of the radius and interosseous membrane. However, the EPB tendon passed through the third compartment instead of the first compartment. It ran parallel to the extensor pollicis longus (EPL) tendon and entered the base of the thumb proximal phalanx. The EPL tendon was attached to the base of the first distal phalanx, as normally observed. Both EPB and EPL muscles were innervated by the posterior interosseous nerve. CONCLUSIONS: We report a case of a variant course of the EPB tendon appearing in the third extensor compartment of the wrist with the EPL tendon. The knowledge of this anatomic variation will be helpful for accurate diagnosis and surgical planning. PMID- 29138876 TI - Lower risk of dementia with pioglitazone, compared with other second-line treatments, in metformin-based dual therapy: a population-based longitudinal study. AB - AIMS/HYPOTHESIS: The effect of pioglitazone was compared with that of other second-line glucose-lowering drugs on the risk of dementia among individuals with type 2 diabetes receiving metformin-based dual therapy. METHODS: A total of 204,323 individuals with type 2 diabetes aged >=18 years who were stable metformin users and dementia-free before the initiation of second-line glucose lowering medication were identified in the period 2000-2011 from Taiwan's National Health Insurance Research Database and followed to the end of 2013. Primary analyses included 51,415 individuals aged >=65 years without dementia events in the first year of second-line glucose-lowering treatment. Study subjects were classified into mutually exclusive groups according to various second-line glucose-lowering drugs to metformin. Cox proportional hazards models were applied to assess the time-to-event between propensity score-matched glucose lowering treatment groups. RESULTS: Individuals aged >=65 years on metformin + pioglitazone had a significantly lower risk of dementia compared with those on metformin + sulfonylurea (HR 0.56; 95% CI 0.34, 0.93), and a lower, but insignificant, risk of dementia compared with those on other metformin-based dual regimens (i.e. metformin + acarbose, metformin + meglitinide, metformin + insulin or metformin + dipeptidyl peptidase 4 inhibitors). Among individuals aged >=18 years, there was also a decreased risk of dementia in those taking pioglitazone compared with those taking other second-line glucose-lowering drugs. A lower incidence of dementia was found in users of metformin + pioglitazone compared with users of metformin + rosiglitazone. CONCLUSIONS/INTERPRETATION: Pioglitazone as a second-line treatment after metformin might provide a protective effect on dementia risk among individuals with type 2 diabetes. PMID- 29138877 TI - Delta9-Tetrahydrocannabinol-like discriminative stimulus effects of five novel synthetic cannabinoids in rats. AB - RATIONALE AND OBJECTIVES: Novel synthetic cannabinoid compounds continue to appear in the market advertised as legal alternatives to marijuana and the older synthetic cannabinoid compounds which are now controlled substances. Most of these newer compounds have been found to act at CB1 receptors, so the purpose of this study was to study the abuse liability of these compounds. METHODS: Five of these compounds (BB-22, FUB-PB-22, 5F-AMB, NM2201, and MAB-CHMINACA) were tested for their ability to produce discriminative stimulus effects similar to Delta9 tetrahydrocannabinol (Delta9-THC) in rats. The ability of the CB1 receptor inverse agonist rimonabant to antagonize the discriminative stimulus effects of the five test compounds was also tested. RESULTS: All five of the test compounds fully substituted for the discriminative stimulus effects of Delta9-THC at some dose, although MAB-CHMINACA produced an inverted U-shaped dose effect. Rimonabant fully antagonized the Delta9-THC-like discriminative stimulus effects of BB-22, 5F-AMB, NM2201, and MAB-CHMINACA but only reduced the effects of FUB-PB-22 to 40 50 % of Delta9-THC-appropriate responding. CONCLUSIONS: These findings suggest that all five of the test compounds produced Delta9-THC-like effects and will likely have abuse liability similar to that of the controlled cannabinoid compounds. PMID- 29138878 TI - Higher Cost of Hospitalizations for Non-cardiac Diagnoses in Adults with Congenital Heart Disease. AB - Adults with congenital heart disease (CHD) are a rapidly increasing population and their impact on healthcare resources is not fully understood. The purpose of this study was to describe the costs of hospitalizations for non-cardiac disease for adults with CHD. We conducted a retrospective review of hospital discharge data from the University HealthSystem Consortium Clinical Data Base/Resource Manager from January 2011 through December 2013. Patients were >= 18 years old at admission with any ICD-9 code for moderate or high severity CHD; cardiac surgical admissions were excluded. The comparison group consisted of patients >= 18 years old with no ICD-9 codes for any severity CHD. There were 9,169,700 non-CHD, 28,224 moderate CHD, and 3045 high severity CHD hospital admissions. Total length of stay was longer for acute kidney injury, depressive disorder, esophageal reflux, and obstructive sleep apnea for any severity CHD; ICU admission rates were higher for all diagnoses with any severity CHD. Mean observed direct costs were higher for all diagnoses for moderate CHD and all diagnoses except dehydration, type 2 diabetes, obesity, and obstructive sleep apnea for high severity CHD. This review identified significantly increased hospitalization costs for adults with moderate and high severity CHD who are admitted for non cardiac medical conditions not associated with concomitant cardiac surgical procedures. Admissions with CHD diagnoses had higher ICU admission rates, longer lengths of stay, and higher mortality for most non-cardiac admission diagnoses. These data will add to our understanding of the economic impact of adults with CHD. PMID- 29138879 TI - Predictive Factors for Patients Undergoing ASD Device Occlusion Who "Crossover" to Surgery. AB - The aim of this study was to define characteristics of those patients who are referred for device closure of an Atrial septal defect (ASD), but identified to "crossover" surgery. All patients who underwent surgical and device (Amplatzer or Helex occluder) closures of secundum ASDs from 2001 to 2010 were reviewed and organized into three groups: surgical closure, device closure, and "crossover" group. 369 patients underwent ASD closure (265 device, 104 surgical). 42 of the 265 patients referred for device closure "crossed over" to the surgical group at various stages of the catheterization procedure. The device group had defect size measuring 14.2 mm (mean) and an ASD index (Defect Size (mm)/BSA) of 14.0 compared to the corresponding values in the surgical group (20.1 mm, ASD index 25.9) (P < 0.001) and in the "crossover" group (20.7 mm, 22.6 ASD index) (P < 0.001). 79 patients in the device group had a deficient rim, and 86% were located in the retroaortic region. 33 patients in the "crossover" group had deficient rims with 70% deficiency in the posterior/inferior rim. The device group with deficient rims had an ASD index of 14.7 compared with the crossover group ASD index of 23.8 (P < 0.001). Comparing the device and "crossover" groups, an ASD index greater than 23.7 had a 90% specificity in "crossing over" to surgery. The crossover and surgical groups had statistically larger ASD defect size indexes compared with the device group. Deficient rim in the posterior/inferior rim is associated with a large ASD size index which is a predictive factor for crossing over to surgery. Catheterization did not negatively impact surgical results in the "crossover" group. PMID- 29138880 TI - Morphological classification of intraductal papillary neoplasm of the bile duct. AB - OBJECTIVES: To investigate the morphological classification of intraductal papillary neoplasm of the bile duct (IPNB), as well as morphological differences between IPNB without mucin secretion (IPNB-NM) and IPNB with mucin secretion (IPMN-B). METHODS: Eighty-one patients with IPNB were retrospectively analysed. Imaging examinations included computed tomography (CT), magnetic resonance imaging (MRI), gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB DTPA)-enhanced MRI and positron emission tomography-computed tomography (PET-CT). According to the morphology of tumours and extent of bile duct dilations, IPNB was classified into seven types: I, upstream-ductectatic type; II, typical type; III, superficial-spreading type; IV, no-mass-forming type; V, intrahepatic-cystic type; VI, extrahepatic-cystic type; and VII, infiltrating type. RESULTS: Thirteen IPNB-NM patients comprised type I (11 cases), type II (1 case) and type VII (1 case); 68 IPMN-B patients comprised type I (2 cases), type II (30 cases), type III (6 cases), type IV (11 cases), type V (13 cases), type VI (2 cases) and type VII (4 cases). Bile duct dilations were more severe in IPMN-B than in IPNB-NM. PET-CT and Gd-EOB-DTPA-enhanced MRI clearly demonstrated the extension of infiltrating IPNB. CONCLUSIONS: IPNB can be classified into seven morphological types. IPNB-NM and IPMN-B have different morphological features. KEY POINTS: * IPNB can be classified into seven morphological types. * IPNB-NM and IPMN-B have different morphological features. * Enhanced CT and MRI can display different types of IPNB. * Morphological classification of IPNB facilitates management of the disease. PMID- 29138881 TI - A harmonized immunoassay with liquid chromatography-mass spectrometry analysis in egg allergen determination. AB - Food allergy is a serious health issue worldwide. Implementing allergen labeling regulations is extremely challenging for regulators, food manufacturers, and analytical kit manufacturers. Here we have developed an "amino acid sequence immunoassay" approach to ELISA. The new ELISA comprises of a monoclonal antibody generated via an analyte specific peptide antigen and sodium lauryl sulfate/sulfite solution. This combination enables the antibody to access the epitope site in unfolded analyte protein. The newly developed ELISA recovered 87.1%-106.4% ovalbumin from ovalbumin-incurred model processed foods, thereby demonstrating its applicability as practical egg allergen determination. Furthermore, the comparison of LC-MS/MS and the new ELISA, which targets the amino acid sequence conforming to the LC-MS/MS detection peptide, showed a good agreement. Consequently the harmonization of two methods was demonstrated. The complementary use of the new ELISA and LC-MS analysis can offer a wide range of practical benefits in terms of easiness, cost, accuracy, and efficiency in food allergen analysis. In addition, the new assay is attractive in respect to its easy antigen preparation and predetermined specificity. Graphical abstract The ELISA composing of the monoclonal antibody targeting the amino acid sequence conformed to LC-MS detection peptide, and the protein conformation unfolding reagent was developed. In ovalbumin determination, the developed ELISA showed a good agreement with LC-MS analysis. Consequently the harmonization of immunoassay with LC-MS analysis by using common target amino acid sequence was demonstrated. PMID- 29138882 TI - Further improvements in pesticide residue analysis in food by applying gas chromatography triple quadrupole mass spectrometry (GC-QqQ-MS/MS) technologies. AB - Nowadays, the control of pesticide residues in food is well established. The capacity of triple quadrupole technology to satisfy the current food regulations has been demonstrated. However, the permanent high demand of consumers for more sensitive and faster testing is driving the development of improved analytical methodologies that increase the performances of sensitivity and robustness and reduce the analysis time. In this work, the feasibility of decreasing the run time to 12.4 min by modifying the oven temperature program, for a multiresidue method covering 203 pesticides, was evaluated. Satisfactory sensitivity results were achieved by reaching a limit of quantitation of 2 MUg kg-1 for a great variety of fruits and vegetables. The validated method based on updated GC-QqQ MS/MS has confirmed the abovementioned challenges with adequate robustness by its application to routine analyses for 69 real samples. The proposed method can represent great benefit for laboratories as it allows increasing samples throughput. It is also very useful for risk assessment studies, where the needs of low reporting limits and very wide analytical scope are necessary. PMID- 29138884 TI - [Pilomatrixoma in a tattoo]. AB - A 31-year-old man developed a fast-growing tumor on the right upper arm within a black tattoo, which could be classified histologically as pilomatrixoma. While the age of the patient and the rapid growth of the tumor cannot be regarded as typical findings of pilomatrixomas, the localization on the upper arm is one of their predilection points. Despite the wide spread use of tattoos in the last few decades, tumor development in tattooed skin is rarely reported. It is still controversial whether the ingredients of the tattoo agents can be responsible for tumor induction. PMID- 29138883 TI - Hallmarks of Bone Metastasis. AB - Breast cancer bone metastasis develops as the result of a series of complex interactions between tumor cells, bone marrow cells, and resident bone cells. The net effect of these interactions are the disruption of normal bone homeostasis, often with significantly increased osteoclast and osteoblast activity, which has provided a rational target for controlling tumor progression, with little or no emphasis on tumor eradication. Indeed, the clinical course of metastatic breast cancer is relatively long, with patients likely to experience sequential skeletal related events (SREs), often over lengthy periods of time, even up to decades. These SREs include bone pain, fractures, and spinal cord compression, all of which may profoundly impair a patient's quality-of-life. Our understanding of the contributions of the host bone and bone marrow cells to the control of tumor progression has grown over the years, yet the focus of virtually all available treatments remains on the control of resident bone cells, primarily osteoclasts. In this perspective, our focus is to move away from the current emphasis on the control of bone cells and focus our attention on the hallmarks of bone metastatic tumor cells and how these differ from primary tumor cells and normal host cells. In our opinion, there remains a largely unmet medical need to develop and utilize therapies that impede metastatic tumor cells while sparing normal host bone and bone marrow cells. This perspective examines the impact of metastatic tumor cells on the bone microenvironment and proposes potential new directions for uncovering the important mechanisms driving metastatic progression in bone based on the hallmarks of bone metastasis. PMID- 29138886 TI - Clinical predictors of Stenotrophomonas maltophilia bacteremia in adult patients with hematologic malignancy. AB - Stenotrophomonas maltophilia (SM) has emerged as an important nosocomial pathogen with high morbidity and mortality. Because of its unique antimicrobial susceptibility pattern, appropriate antimicrobial therapy for SM bacteremia is still challenging, especially in immunocompromised patients. The present study was performed to assess clinical predictors of SM bacteremia in adult patients with hematologic malignancy. From 2006 through 2016, a case-control study was performed at a tertiary-care hospital. Case patients were defined as SM bacteremia in patients with hematologic malignancy. Date- and location-matched controls were selected from among patients with gram-negative bacteremia (GNB) other than SM. A total of 118 cases of SM bacteremia were identified and compared to 118 controls. While pneumonia was the most common source of SM bacteremia, centralline-associated infection was most common in the controls. The overall 30 day mortality rate of cases with SM bacteremia was significantly higher than that of the controls (61.0 and 32.2%, respectively; P < 0.001). A multivariable analysis showed that polymicrobial infection, previous SM isolation, the number of antibiotics previously used >= 3, and breakthrough bacteremia during carbapenem therapy were significantly associated with SM bacteremia (all P < 0.01). Previous use of trimethoprim/sulfamethoxazole (TMP/SMX) was negatively association with SM bacteremia (P = 0.002). Our data suggest that SM is becoming a significant pathogen in patients with hematologic malignancy. Several clinical predictors of SM bacteremia can be used for appropriate antimicrobial therapy in hematologic patients with suspected GNB. PMID- 29138885 TI - Delayed recovery of serum immunoglobulin G is a poor prognostic marker in patients with follicular lymphoma treated with rituximab maintenance. AB - Clinical trials involving various treatment schedules for rituximab maintenance have been conducted for patients with follicular lymphoma (FL) and have not confirmed their impact on serum immunoglobulin (sIg) levels until the completion of maintenance. However, the long-term use of rituximab is a concern because of circulating plasma cell-depletion risk, suggesting that the mechanism of change in sIg levels after RM has not been determined. Additionally, the relationship between host humoral immunity and the prognosis of patients with B cell malignancies has not been determined. We retrospectively investigated data from 213 patients with FL from a single institute who achieved at least a partial response with rituximab, cyclophosphamide, vincristine, and prednisolone with or without doxorubicin. Of these, 166 patients underwent RM with a median period of 1.6 years. A significantly delayed recovery of sIgG levels was observed in the maintenance group until 3 years after RM in comparison to the observation group. A multivariate analysis showed that a sIgG level of < 718 mg/dl 1 year after RM was an independent predictor for poor progression-free survival (PFS) (hazard ratio, 2.3; P = 0.04). Therefore, the sIgG levels scarcely recovered and were significantly delayed after RM, leading to shorter PFS in patients with FL. PMID- 29138887 TI - [Developments in dysphagia diagnostics : Presentation of an interdisciplinary concept]. AB - Demographic developments and medical progress will cause the already high prevalence of swallowing disorders to increase further in the future. With the same number of specialists and economic resources, it is necessary to improve the efficiency of dysphagia diagnostics and continue to offer patients a treatment concept tailored to their needs. Manifold and often co-existing causes of dysphagia require interdisciplinary cooperation in this area. Endoscopic swallowing diagnostics play a prominent role in dysphagia diagnostics and should always contain thorough endoscopy of the upper aerodigestive tract-the domain of the ENT specialist and phoniatrician. The concept of a dysphagia day clinic under phoniatric leadership presented here allows for complete and efficient evaluation of swallowing disorders, and offers the patient a comprehensive treatment concept. Technical innovations such as the use of narrow band imaging (NBI) to significantly enhance visualization of the bolus in an endoscopic swallowing examination, as well as special methods like the "dipping maneuver" to allow a close-up examination of the subglottis and trachea were able to improve endoscopic dysphagia diagnosis even further. The examination procedure and the selection of test consistencies and placebo tablets should be tailored individually to the patient, and not follow strict procedures. The task of the ENT specialist or phoniatrician should be to assess and advise each patient individually, depending on underlying illnesses, prognosis, living conditions, and their own wishes. An interdisciplinary team of physicians and therapists permits individual counseling and therapy planning. PMID- 29138888 TI - [You can't be serious, GRC: care after resuscitation without an intensive care physician?] PMID- 29138889 TI - [Hypothermia-induced ECG changes: characteristic, but not specific]. AB - Hypothermia-induced J- or so-called Osborn waves can be detected under therapeutic hypothermia in approximately 20-40% of cases. The occurrence of J waves in the context of the targeted temperature management after cardiopulmonary resuscitation is characteristic, but not pathognomonic for hypothermia. An electrocardiographic diagnosis under hypothermia after cardiac arrest should always be done with caution due to the various hypothermia-associated electromechanical changes of the myocardium. PMID- 29138890 TI - Role of rapid kV-switching dual-energy CT in assessment of post-surgical local recurrence of pancreatic adenocarcinoma. AB - PURPOSE: The purpose of this study is to evaluate the performance of material specific iodine (MS-I) images generated by rapid kV-switching single-source dual energy computed tomography (rsDECT) for distinguishing post-operative changes from local tumor recurrence in patients on follow-up for pancreatic adenocarcinoma after surgical resection. METHODS: In this IRB-approved HIPPA compliant study, retrospective review of 51 patients who underwent surgical resection of pancreatic adenocarcinoma was conducted and were followed up using contrast-enhanced rsDECT (Discovery CT 750HD, GE Healthcare, Milwaukee, WI). Independent qualitative assessment for presence of local tumor recurrence was performed by two radiologists who evaluated 65 keV (single-energy CT-equivalent interpretation) and 65 keV with MS-I (rsDECT interpretation) in separate sessions. Quantitative analysis of Hounsfield unit (HU, on 65 keV) and normalized iodine concentration (NIC on MS-I images; iodine concentration ratio in post operative tissue to aorta) was measured. Follow-up imaging, temporal change of CEA and CA 19-9 or biopsy served as reference standard for presence and absence of local recurrence. Sensitivity and specificity of readers and quantitative parameters was calculated and receiver operating characteristic curves and Fisher's exact test were generated. A p value < 0.05 was considered statistically significant. RESULTS: A total of 51 patients (27 females, 24 males) with mean age of 64 years built the final cohort. Local recurrence was absent in 23 (Group A) and present in 28 (Group B) patients. The follow-up imaging was performed within 7 months of rsDECT. For both readers, the addition of MS-I increased the specificity for tissue characterization and improved reader confidence as compared to 65 keV (specificity: 80% and 56%, respectively) images alone. Quantitative analysis revealed a significantly lower NIC (0.28 vs. 0.35; p < 0.05) for non-recurrent tissue. However, HU was not significantly different for non-recurrent and recurrent tissue (0.63 vs. 0.70; p > 0.05). CONCLUSION: In inherently complex cases of post-operative pancreatic adenocarcinoma, MS-I images from rsDECT can be a useful adjunct to conventional scans in characterizing loco regional soft tissue. PMID- 29138891 TI - 'Sliced bread' or 'club sandwich' appearance. PMID- 29138892 TI - [Partial and complete joint transplantation with fresh osteochondral allografts the FLOCSAT concept]. AB - Cartilage defects in adult patients do not heal well. Fresh osteochondral allograft (OCA) transplantation is based on mature, living, mechanically sound hyaline cartilage attached to a bone interface, which is brought into an osteochondral defect, where it becomes osseointegrated. According to current knowledge, intact hyaline cartilage tissue is immune privileged and does not, in contrast to bone, meniscus or ligaments, cause an immune reaction. The technique has the unique advantage of transplanting viable, mature and mechanically stable hyaline cartilage into the affected area. An OCA is the only biological surgical technique for chondral and osteochondral lesions after failed cell-based techniques or autologous osteochondral transplantation.Fresh osteochondral allografts with mainly small cylindrical transplants show survival of 20 years and more. Based on this experience the FLOCSAT (fresh large [> 10 cm2] osteochondral shell allograft transplantation) concept with the thinnest possible (< 6-8 mm) bone thickness has been developed. Cells survive in special media at 4 degrees C for 4 weeks or more and are transplanted with a minimum of 70% living cells in a live/dead assay and cell density > 200 cells/mm2.FLOCSATs can replace parts or entire joints as uniplanar or multiplanar(n-planar)-FLOCSAT, as unipolar, bipolar or tripolar(n-polar)-FLOCSAT, and in combination with meniscus and/or ligaments (nMnL)-FLOCSAT (n number of structures).The FLOCSAT concept was applied successfully to knee, ankle and elbow joints. All transplants showed sound osseointegration. Cartilage failure was the reason for unsuccessful outcome. Challenges remain regarding graft availability, precise size matching, complex logistics, demanding surgical technique in complex geometries, and open questions in immunology and chimerism. PMID- 29138895 TI - [Cavovarus foot]. PMID- 29138893 TI - Standardization of pediatric uroradiological terms: a multidisciplinary European glossary. AB - To promote the standardization of nephro-uroradiological terms used in children, the European Society of Paediatric Radiology uroradiology taskforce wrote a detailed glossary. This work has been subsequently submitted to European experts in pediatric urology and nephrology for discussion and acceptance to improve the quality of radiological reports and communication between different clinicians involved in pediatric urology and nephrology. PMID- 29138894 TI - Injustice at work affects work ability and role functioning: findings of a cohort study. AB - OBJECTIVES: The aim was to analyze the longitudinal effects of organizational injustice (OIJ) and effort-reward imbalance (ERI) on work ability, emotional role functioning and physical role functioning. METHODS: Longitudinal data with a two year follow-up of people previously receiving sickness absence benefits were used for analyses. OIJ and ERI were included separately and mutually in logistic regression models. Effects were tested for additivity. All analyses were additionally performed stratified by sex. All models were adjusted for sociodemographics and neuroticism. RESULTS: 1886 participants (44.5% men, mean age: 48 years) were included. When mutually adjusted, OIJ and ERI affected work ability, and OIJ affected emotional role functioning. In stratified analyses, OIJ affected all outcomes in women, and ERI affected work ability in men. Additive effects of OIJ and ERI were not identified. CONCLUSIONS: OIJ and ERI are important risk factors of limited participation. People with experiences of health-related and work-related impairments are in need of reliable structures and just working conditions. PMID- 29138896 TI - [Metabolomics and Cancer]. PMID- 29138900 TI - [Intergenerational mobility and health inequalities in East and West Germany : A trend analysis from 1992 to 2012]. AB - BACKGROUND: Social mobility processes, i. e. the movement of a person from one social position to another, are central mechanisms for explaining health inequalities. Social differences in health status or behaviour may also change with changes in social status. This article examines the importance of intergenerational mobility, i. e. the rise and fall of social status in relation to parental social position, for subjective health in East and West Germany and whether this relationship has changed over 20 years. MATERIAL AND METHODS: The data basis is the socio-economic panel from 1992-2012. Employees aged between 25 and 59 were taken into account. Different mobility paths were determined by comparing their current occupational positions with those of their parents. For these, prevalence and logistic regression of subjective health were calculated. RESULTS: Those in low occupational positions rated their health more often as being worse in all periods. Upwardly mobile individuals had a lower risk of poorer health (OR 0.72) compared to those who remained in their original position. Persons affected by downward mobility had a similarly worse self-rated health (OR 1.55 or OR 1.86). Significant differences in gender or region of origin (East-West Germany) could not be determined. Education and income contribute to explaining the relationship. CONCLUSION: The results suggest that social advancement has a positive effect on health, whereas social decline is negative - regardless of gender, region of origin or time. It is therefore important to reinforce political efforts aimed at increasing the mobility opportunities of all social groups in a positive sense and thus reducing social inequalities. PMID- 29138901 TI - [Which factors are associated with the use of potentially inadequate medications (PIM) in the elderly? : Results from the German health interview and examination survey (DEGS1)]. AB - BACKGROUND: Recent studies demonstrate a relationship between the prescription of potentially inappropriate medications (PIM) for patients 65 years or older and an increased risk for adverse events, in particular hospitalisations. The RKI conducted DEGS1-Survey ("German health interview and examination survey for adults") provides a representative sample of the target population to identify determinants for PIM use. OBJECTIVE: The aim of this study was to determine characteristics of older persons in Germany, who currently use PIM, and if there are subpopulations among older persons with a particularly high PIM use. METHODS: Within the DEGS1-Survey a total of 175 variables regarding health and social aspects were documented from 1392 community-dwelling persons between 65 and 79 years of age, and medication intake during the last seven days was recorded. PIM drugs were identified according to the PRISCUS list. Associations between PIM use and variables recorded were evaluated by means of multivariate statistical models. RESULTS: Within seven days before the survey PIM drugs were used by 13.0% (95%-CI: 10.7-15.6) of the respondents. The following factors significantly increase the risk for receiving a PIM: number of drugs taken in the last seven days; number of visits to different physician specialists during the last 12 months; sleep disorders; psychiatric condition, and diseases affecting the musculoskeletal system. The majority of PIMs were antidepressants and anxiolytics/sedatives. Elderly women with depression, sleep disorders, and a need for analgesics are particularly affected by increased PIM use. They deserve special attention in this regard. PMID- 29138897 TI - Correction to: Imported falciparum malaria in adults: host- and parasite-related factors associated with severity. The French prospective multicenter PALUREA cohort study. AB - The members of the Palurea Study Group were provided in such a way that they could not be indexed as collaborators on PubMed. The publisher apologizes for this error and is pleased to list the members of the group here. PMID- 29138902 TI - [Use of E-cigarettes as an additional tool in a smoking cessation group intervention : Results after 12 months]. AB - BACKGROUND: E-cigarettes are considerably safer regarding health issues than conventional cigarettes, but there is uncertainty concerning its use for smoking cessation. OBJECTIVES: How and to what extent are E-cigarettes used by smokers willing to quit? Are E-cigarettes a useful intervention for smokers attending a group intervention for smoking cessation? MATERIALS AND METHODS: One year after attending a group intervention for smoking cessation in Germany, 637 attendants were assessed by telephone. The interview topics were the use of E-cigarettes and tobacco abstinence. RESULTS: Of the attendants that could be interviewed, 12.6% had used E-cigarettes during or after the smoking cessation intervention. At the beginning of the intervention these smokers smoked significantly more cigarettes and were more addicted to cigarettes than the other attendants. After one year significantly less E-cigarette users were abstinent compared to participants that used nicotine replacement therapy or no additional smoking cessation aids. CONCLUSIONS: The application of E-cigarettes is counterproductive for smokers looking for help in an abstinence oriented smoking cessation group. The lack of distinct, easy to follow instructions on the use of E-cigarettes as a cessation tool may impair the process of cessation. Without good guidance smokers may get distracted in their motivation and willingness to stop smoking. PMID- 29138898 TI - Correction to: The Intensive Care Global Study on Severe Acute Respiratory Infection (IC-GLOSSARI): a multicenter, multinational, 14-day inception cohort study. AB - In both the original publication (DOI 10.1007/s00134-015-4206-2) and the first erratum (DOI 10.1007/s00134-016-4317-4), the members of the IC-GLOSSARI Investigators and the ESICM Trials Group were provided in such a way that they could not be indexed as collaborators on PubMed. The publisher apologizes for these errors and is pleased to list the members of the groups here. PMID- 29138903 TI - Next-generation sequencing to identify candidate genes and develop diagnostic markers for a novel Phytophthora resistance gene, RpsHC18, in soybean. AB - KEY MESSAGE: A novel Phytophthora sojae resistance gene RpsHC18 was identified and finely mapped on soybean chromosome 3. Two NBS-LRR candidate genes were identified and two diagnostic markers of RpsHC18 were developed. Phytophthora root rot caused by Phytophthora sojae is a destructive disease of soybean. The most effective disease-control strategy is to deploy resistant cultivars carrying Phytophthora-resistant Rps genes. The soybean cultivar Huachun 18 has a broad and distinct resistance spectrum to 12 P. sojae isolates. Quantitative trait loci sequencing (QTL-seq), based on the whole-genome resequencing (WGRS) of two extreme resistant and susceptible phenotype bulks from an F2:3 population, was performed, and one 767-kb genomic region with DeltaSNP-index >= 0.9 on chromosome 3 was identified as the RpsHC18 candidate region in Huachun 18. The candidate region was reduced to a 146-kb region by fine mapping. Nonsynonymous SNP and haplotype analyses were carried out in the 146-kb region among ten soybean genotypes using WGRS. Four specific nonsynonymous SNPs were identified in two nucleotide-binding sites-leucine-rich repeat (NBS-LRR) genes, RpsHC18-NBL1 and RpsHC18-NBL2, which were considered to be the candidate genes. Finally, one specific SNP marker in each candidate gene was successfully developed using a tetra-primer ARMS-PCR assay, and the two markers were verified to be specific for RpsHC18 and to effectively distinguish other known Rps genes. In this study, we applied an integrated genomic-based strategy combining WGRS with traditional genetic mapping to identify RpsHC18 candidate genes and develop diagnostic markers. These results suggest that next-generation sequencing is a precise, rapid and cost-effective way to identify candidate genes and develop diagnostic markers, and it can accelerate Rps gene cloning and marker-assisted selection for breeding of P. sojae-resistant soybean cultivars. PMID- 29138904 TI - Rice diversity panel provides accurate genomic predictions for complex traits in the progenies of biparental crosses involving members of the panel. AB - KEY MESSAGE: Rice breeding programs based on pedigree schemes can use a genomic model trained with data from their working collection to predict performances of progenies produced through rapid generation advancement. So far, most potential applications of genomic prediction in plant improvement have been explored using cross validation approaches. This is the first empirical study to evaluate the accuracy of genomic prediction of the performances of progenies in a typical rice breeding program. Using a cross validation approach, we first analyzed the effects of marker selection and statistical methods on the accuracy of prediction of three different heritability traits in a reference population (RP) of 284 inbred accessions. Next, we investigated the size and the degree of relatedness with the progeny population (PP) of sub-sets of the RP that maximize the accuracy of prediction of phenotype across generations, i.e., for 97 F5-F7 lines derived from biparental crosses between 31 accessions of the RP. The extent of linkage disequilibrium was high (r 2 = 0.2 at 0.80 Mb in RP and at 1.1 Mb in PP). Consequently, average marker density above one per 22 kb did not improve the accuracy of predictions in the RP. The accuracy of progeny prediction varied greatly depending on the composition of the training set, the trait, LD and minor allele frequency. The highest accuracy achieved for each trait exceeded 0.50 and was only slightly below the accuracy achieved by cross validation in the RP. Our results thus show that relatively high accuracy (0.41-0.54) can be achieved using only a rather small share of the RP, most related to the PP, as the training set. The practical implications of these results for rice breeding programs are discussed. PMID- 29138906 TI - Influence of polyaluminum chloride on microbial characteristics in anaerobic membrane bioreactors for sludge digestion. AB - In this study, two parallel lab-scale anaerobic membrane bioreactors (AnMBRs), one of which was dosed with polyaluminum chloride (PAC) for membrane fouling control, were operated for treating excess activated sludge collected from a wastewater treatment plant (WWTP). The AnMBRs were inoculated with anaerobic digested sludge collected from an anaerobic digester of another WWTP. The microbial community of digested sludge and cake layer in AnMBRs, as well as that of excess sludge, was analyzed through polymerase chain reaction coupled with denaturing gradient gel electrophoresis (PCR-DGGE) and Illumina MiSeq. The dynamic variation of archaeal community in AnMBRs was not as obvious as that of bacterial community based on the PCR-DGGE results. Under the circumstance of stable operation, Cloacimonetes, Chloroflexi, Bacteroidetes, Proteobacteria, Firmicutes, and Ignavibacteriae were observed as the predominant phyla in digested sludge based on the Illumina results. In addition to that, the cake layer possessed similar predominant phyla with the digested sludge but owned a higher diversity. Furthermore, overlapping bacterial communities were discovered between the excess sludge and digested sludge. However, the abundance of aerobic bacteria was substantially reduced, while the abundance of anaerobic microorganisms like phylum Cloacimonetes and Smithella was enriched in digested sludge over time. Additional PAC dosing, on the one hand, affected the bioavailable substrate, thus further changing the microbial community structure; on the other hand, aluminum itself also affected specific microbial communities. Besides, PAC dosing indirectly influenced the bacterial diversity in AnMBR as well. PMID- 29138905 TI - Fatigue in familial Mediterranean fever and its relations with other clinical parameters. AB - Fatigue is a common problem in patients with rheumatic disease. It may cause disability and poor quality of life. The aim of this study is to investigate fatigue in FMF patients as a disabling symptom and its associations with clinical and demographic variables. FMF patients were recruited into the study according to FMF Tel Hashomer criteria. Control group is composed of healthy individuals. Demographic and clinical features of the patients including PRAS scores were noted. Visual analogue score of pain (VAS-pain) and VAS-fatigue were used as clinical parameters. Pittsburgh Sleep Quality Index (PSQI), Multidimensional Assessment of Fatigue (MAF), Nottingham Health Profile (NHP), Fatigue Severity Scale (FSS), Fatigue Impact Scale (FIS) and Hospital Anxiety and Depression Scale (HADS) were filled out by both control and study group. Sixty-one FMF patients and 61 age and gender (44 female, 17 male in each group)-matched controls were enrolled into the study. Mean age of FMF and control group were 35.5 +/- 11.8 and 35.8 +/- 11.7 years, respectively. The mean disease duration was 82.5 +/- 81.7 months. Difference between mean of VAS-pain, VAS-fatigue, PSQI total score, MAF, all subsets of NHP, FSS, FIS, and HADS scores of FMF patients was significantly higher than of control group (p = 0.0001). This study has shown that fatigue in FMF is associated with a number of psychological, sleep, quality of life and disease-related factors. FMF group had increased pain, fatigue, sleep disturbance and decreased quality of life compared to control group. FMF patients with fatigue may benefit from pharmacological and psychological interventions which target these factors. PMID- 29138907 TI - Integrating metabolic modeling and population heterogeneity analysis into optimizing recombinant protein production by Komagataella (Pichia) pastoris. AB - The methylotrophic yeast Komagataella (Pichia) pastoris has become one of the most utilized cell factories for the production of recombinant proteins over the last three decades. This success story is linked to its specific physiological traits, i.e., the ability to grow at high cell density in inexpensive culture medium and to secrete proteins at high yield. Exploiting methanol metabolism is at the core of most P. pastoris-based processes but comes with its own challenges. Co-feeding cultures with glycerol/sorbitol and methanol is a promising approach, which can benefit from improved understanding and prediction of metabolic response. The development of profitable processes relies on the construction and selection of efficient producing strains from less efficient ones but also depends on the ability to master the bioreactor process itself. More specifically, how a bioreactor processes could be monitored and controlled to obtain high yield of production. In this review, new perspectives are detailed regarding a multi-faceted approach to recombinant protein production processes by P. pastoris; including gaining improved understanding of the metabolic pathways involved, accounting for variations in transcriptional and translational efficiency at the single cell level and efficient monitoring and control of methanol levels at the bioreactor level. PMID- 29138908 TI - Amine-modified magnetic iron oxide nanoparticle as a promising carrier for application in bio self-healing concrete. AB - Self-healing mechanisms are a promising solution to address the concrete cracking issue. Among the investigated self-healing strategies, the biotechnological approach is distinguished itself by inducing the most compatible material with concrete composition. In this method, the potent bacteria and nutrients are incorporated into the concrete matrix. Once cracking occurs, the bacteria will be activated, and the induced CaCO3 crystals will seal the concrete cracks. However, the effectiveness of a bio self-healing concrete strictly depends on the viability of bacteria. Therefore, it is required to protect the bacteria from the resulted shear forces caused by mixing and drying shrinkage of concrete. Due to the positive effects on mechanical properties and the high compatibility of metallic nanoparticles with concrete composition, for the first time, we propose 3-aminopropyltriethoxy silane-coated iron oxide nanoparticles (APTES-coated IONs) as a biocompatible carrier for Bacillus species. This study was aimed to investigate the effect of APTES-coated IONs on the bacterial viability and CaCO3 yield for future application in the concrete structures. The APTES-coated IONs were successfully synthesized and characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). The results show that the presence of 100 MUg/mL APTES coated IONs could increase the bacterial viability. It was also found that the CaCO3-specific yield was significantly affected in the presence of APTES-coated IONs. The highest CaCO3-specific yield was achieved when the cells were decorated with 50 MUg/mL of APTES-coated IONs. This study provides new insights for the application of APTES-coated IONs in designing bio self-healing strategies. PMID- 29138909 TI - Improvement of biosynthesis and accumulation of bioactive compounds by elicitation in adventitious root cultures of Polygonum multiflorum. AB - We examined the effects of abiotic (methyl jasmonate [MeJA] and salicylic acid [SA]) and biotic (yeast extract and chitosan) elicitors for improvement of bioactive compounds production on adventitious root cultures in Polygonum multiflorum. The application of yeast extract resulted in significantly (p <= 0.05) higher dry root biomass (9.98 g/L) and relative growth rate versus the control. Cultures treated with abiotic elicitors showed higher percentage of dry weight than the other samples. Low concentrations of all elicitors (50 MUM MeJA and SA, and 50 mg/L yeast extract) improved secondary metabolite production except for chitosan, whose performance was worse than that of the control. HPLC analysis of various bioactive compounds revealed significantly higher elicitation efficiency for MeJA than for the other treatments, with an approximately 2-fold increase in root dry weight (22.08 mg/g DW) under 50 MUM MeJA treatment versus the control (10.35 mg/g DW). We also investigated the feasibility of scaling up the production process by comparing shake flask cultures with 3- and 5-L balloon type bubble bioreactors (BTBB) using 50 MUM MeJA as an elicitor. Growth and metabolite accumulation increased in BTBB compared with shake flask cultures. We detected a non-significant difference in biomass productivity between 3 and 5-L BTBB, but the efficiency of bioactive compound accumulation decreased with increasing volume. These findings will be useful for developing a pilot-scale P. multiflorum adventitious root cultivation process for high biomass and bioactive compound production to meet the demands for natural ingredients by the pharmaceutical and cosmetic industries without affecting the natural habitat of this plant. PMID- 29138910 TI - Metabolic synergies in the biotransformation of organic and metallic toxic compounds by a saprotrophic soil fungus. AB - The saprotrophic fungus Penicillium griseofulvum was chosen as model organism to study responses to a mixture of hexachlorocyclohexane (HCH) isomers (alpha-HCH, beta-HCH, gamma-HCH, delta-HCH) and potentially toxic metals (vanadium, lead) in solid and liquid media. The P. griseofulvum FBL 500 strain was isolated from polluted soil containing high concentrations of HCH isomers and potentially toxic elements (Pb, V). Experiments were performed in order to analyse the tolerance/resistance of this fungus to xenobiotics and to shed further light on fungal potential in inorganic and organic biotransformations. The aim was to examine the ecological and bioremedial potential of this fungus verifying the presence of mechanisms that allow it to transform HCH isomers and metals under different extreme test conditions. To our knowledge, this work is the first to provide evidence on the biotransformation of HCH mixtures, in combination with toxic metals, by a saprotrophic non-white-rot fungus and on the metabolic synergies involved. PMID- 29138911 TI - Yonsei Experience of 5000 Gasless Transaxillary Robotic Thyroidectomies. PMID- 29138912 TI - Long-Term Follow-Up After Non-operative Management of Blunt Splenic and Liver Injuries: A Questionnaire-Based Survey. AB - BACKGROUND: Non-operative management (NOM) of blunt splenic or liver injuries (solid organ injury, SOI) has become the standard of care in hemodynamically stable patients. However, the incidence of long-term symptoms in these patients is currently not known. The aim of this study was to assess long-term symptoms in patients undergoing successful NOM (sNOM) for SOI. METHODS: Long-term posttraumatic outcomes including chronic abdominal pain, irregular bowel movements, and recurrent infections were assessed using a specifically designed questionnaire and analyzed by univariable analysis. RESULTS: Eighty out of 138 (58%) patients with SOI undergoing sNOM) responded to the questionnaire. Median (IQR) follow-up time was 48.8 (28) months. Twenty-seven (34%) patients complained of at least one of the following symptoms: 17 (53%) chronic abdominal pain, 13 (41%) irregular bowel movements, and 8 (25%) recurrent infections. One female patient reported secondary infertility. No significant association between the above-mentioned symptoms and the Injury Severity Score, amount of hemoperitoneum, or high-grade SOI was found. Patients with chronic pain were significantly younger than asymptomatic patients (32.1 +/- 14.5 vs. 48.3 +/- 19.4 years, p = 0.002). Irregular bowel movements were significantly more frequent in patients with severe pelvic fractures (15.4 vs. 0.0%, p = 0.025). A trend toward a higher frequency of recurrent infections was found in patients with splenic injuries (15.9 vs. 2.8%, p = 0.067). CONCLUSION: A third of patients with blunt SOI undergoing sNOM reported long-term abdominal symptoms. Younger age was associated with chronic abdominal symptoms. More studies are warranted to investigate long term outcomes immunologic sequelae in patients after sNOM for SOI. PMID- 29138913 TI - Postoperative Albumin-Bilirubin Grade Change Predicts the Prognosis of Patients with Hepatitis B-Related Hepatocellular Carcinoma Within the Milan Criteria. AB - OBJECTIVE: Albumin-bilirubin (ALBI) grade has been validated as a simple, evidence-based, and objective prognostic tool for patients with hepatocellular carcinoma (HCC). However, minimal information is available concerning postoperative ALBI grade changes in HCC. This study aimed to investigate the prognostic value of postoperative ALBI grade changes in patients with hepatitis B virus (HBV)-related HCC within the Milan criteria after liver resection. METHODS: Patients with HBV-related HCC within the Milan criteria who underwent liver resection between 2010 and 2016 at West China Hospital were reviewed (N = 258). A change in ALBI grade was defined as first postoperative month ALBI grade preoperative ALBI grade. If the value was >0, postoperative worsening of ALBI grade was considered; otherwise, stable ALBI grade was considered. Cox proportional hazard regression analyses were used to determine the factors that influence recurrence and survival. RESULTS: During the follow-up, 130 patients experienced recurrence and 47 patients died. Multivariate analyses revealed that postoperative worsening of ALBI grade (HR 1.541, 95% CI 1.025-2.318, P = 0.038), microvascular invasion (MVI, HR 1.802, 95% CI 1.205-2.695, P = 0.004), and multiple tumors (HR 1.676, 95% CI 1.075-2.615, P = 0.023) were associated with postoperative recurrence, whereas MVI (HR 2.737, 95% CI 1.475-5.080, P = 0.001), postoperative worsening of ALBI grade (HR 2.268, 95% CI 1.227-4.189, P = 0.009), high alpha-fetoprotein level (HR 2.055, 95% CI 1.136-3.716, P = 0.017), and transfusion (HR 2.597, 95% CI 1.395-4.834, P = 0.003) negatively influenced long term survival. Patients with postoperative worsening of ALBI grade exhibited increased incidence of recurrence and worse long-term survival. CONCLUSION: Postoperative worsening of ALBI grade was associated with increased recurrence and poorer overall survival for patients with HBV-related HCC within the Milan criteria. We should pay attention to liver function changes in HCC patients after liver resection. PMID- 29138914 TI - Impact of "Tailored" Parathyroidectomy for Treatment of Primary Hyperparathyroidism in Patients with Multiple Endocrine Neoplasia Type 1. AB - BACKGROUND: Whether total parathyroidectomy (TPTX) or subtotal parathyroidectomy (SPTX) should be performed for primary hyperparathyroidism (PHPT) in patients with multiple endocrine neoplasia type 1 (MEN1) is controversial. At our institution, the parathyroidectomy strategy is based on the number of enlarged intraoperative parathyroid glands. We retrospectively analyzed our parathyroidectomy procedures. METHODS: Data of PHPT treatment in patients with MEN1 who underwent parathyroidectomy from 1982 to 2012 at our department were retrospectively collected. The data were grouped according to the surgical procedure: TPTX, SPTX, and less than SPTX (LPTX). TPTX or SPTX was selected based on the preoperative examination findings and number of enlarged intraoperative parathyroid glands. The outcomes were the disease-free survival (DFS) rate and postoperative calcium replacement rate based on Kaplan-Meier analysis for each type of surgical procedure. RESULTS: Forty-five patients were analyzed. The overall 5- and 10-year DFS was 91.7 and 55.8%, respectively. The 5- and 10-year DFS in each subgroup was 100.0 and 85.7% in the TPTX group, 89.4 and 57.3% in the SPTX group, and 91.6 and 57.3% in the LPTX group, respectively. The postoperative calcium replacement rate at 1 and 12 months was 91.7 and 58.3% in the TPTX group, 21.1 and 7.0% in the SPTX group, and 30.0 and 0.0% in the LPTX group, respectively. CONCLUSIONS: Although LPTX was not satisfactory as a standard procedure, both SPTX and TPTX are effective treatment methods for PHPT in patients with MEN1. The parathyroidectomy strategy should be based on intraoperative evaluation of the parathyroid glands. PMID- 29138915 TI - Anatomic double bundle ACL reconstruction outperforms any types of single bundle ACL reconstructions in controlling dynamic rotational laxity. AB - PURPOSE: To compare the different types of ACL reconstructions in terms of knee dynamic laxity evaluated by acceleration. METHODS: Sixteen fresh frozen cadaveric knees were used. Pivot shift test was manually performed while monitoring the tibial acceleration by use of a triaxial accelerometer. The test was repeated before and after the ACL resection and reconstruction. Three types of ACL reconstruction were tested: (1) Anatomic Single-Bundle reconstruction (n = 8), the graft was placed at the center of the ACL footprint for the both femoral and tibial sides (tunnel diameter: 8mm); (2) Conventional Single-Bundle reconstruction (n = 8), the graft was placed from the tibial PL footprint to femoral high AM position (tunnel diameter: 8mm) and (3) Anatomic Double-Bundle reconstruction (n = 8). The acceleration in each of three x-y-z directions and the overall magnitude of acceleration was calculated to evaluate dynamic rotational laxity and compared between different ACL reconstructions. RESULTS: The overall magnitude of acceleration was significantly different between ACL intact and deficient knees (p < 0.0001). The acceleration was reduced by the DB ACL reconstruction to the intact level (n.s.), but the two SB ACL reconstruction failed to achieve the intact level of the acceleration (p = 0.0002non-anatomic SB, p < 0.0001 anatomic SB). CONCLUSION: The anatomic DB reconstruction better restores dynamic rotational laxity when compared to the SB ACL reconstructions no matter if the tunnel placement was anatomic. The anatomic DB reconstruction better restores dynamic rotational laxity when compared to both anatomic and non anatomic SB ACL reconstruction. For this reason anatomic DB ACL reconstruction is recommended for cases where rotational laxity is an issue. PMID- 29138916 TI - Lateral retinaculum plasty instead of lateral retinacular release with concomitant medial patellofemoral ligament reconstruction can achieve better results for patellar dislocation. AB - PURPOSE: To elucidate the outcomes of lateral retinaculum plasty versus lateral retinacular release with concomitant medial patellofemoral ligament (MPFL) reconstruction. METHODS: In a prospective study, 59 patients treated at our institution from 2012 to 2014 were included. The 59 patients were randomly divided into two groups. Group I included 27 patients who underwent lateral retinacular release and MPFL reconstruction. Group II included 32 patients who underwent lateral retinaculum plasty and MPFL reconstruction. All patients were followed up for at least 2 years and all assessments were performed both pre- and post-operation. Clinical evaluation consisted of the Kujala score, patellar medial glide test, and patellar tilt angle, patellar lateral shift, and congruence angle, measured on CT scan. RESULTS: Significant improvement was seen after surgery in both groups. The group of lateral retinaculum plasty achieved better results than the group of lateral retinacular release. No statistically significant differences were found in lateral patellar shift (ns) or congruence angle (ns) between the groups. There were significant differences in Kujala score (P < 0.05) patellar tilt angle (P < 0.05), and patellar medial glide test (P < 0.05) between the groups. CONCLUSIONS: MPFL reconstruction with lateral retinaculum plasty yielded better results than MPFL with lateral retinacular release. Postoperatively, medial and lateral function were restored, and patellar tracking was normal. Lateral retinaculum plasty is a new method that reduces the complications of lateral retinacular release for patellar dislocation. LEVEL OF EVIDENCE: II. PMID- 29138917 TI - Level of evidence and authorship trends of clinical studies in knee surgery, sports traumatology, arthroscopy, 1995-2015. AB - PURPOSE: There is increasing emphasis on publication quality and internationalization of author groups in orthopaedic literature. The purpose of this review was to evaluate the type of studies and the level of evidence (LOE) published in knee surgery, sports traumatology, arthroscopy (KSSTA) from 1995 to 2015. The secondary aim was to analyze trends in authorship characteristics in KSSTA. METHODS: Two reviewers reviewed the table of contents of KSSTA and identified original papers from 1995, 2000, 2005, 2010, and 2015. The reviewers graded LOE from Levels I to IV using guidelines from the University of Oxford's Centre for Evidence-Based Medicine. For each article, the total number of authors and country of author group were also analyzed. RESULTS: A total of 880 papers were analyzed. The proportions in LOE have stayed consistent throughout the study period (n.s.). There has been a significant increase in the number of published articles and the number of Level I and II studies (P < 0.01). Therapeutic articles were the most common type. The mean number of authors per KSSTA article significantly increased from 3.9 to 5.7 over the 20-year period (P < 0.01). The number of represented countries increased yearly and academic institutions from 40 different nationalities published articles in the Journal. Of the examined years, the percent of articles with international collaboration was 17.6%. CONCLUSION: The proportion of LOE I and II articles published in KSSTA remains consistently high. Therapeutic studies are the most frequently published articles. There is an increase in international groups publishing in KSSTA. LEVEL OF EVIDENCE: IV. PMID- 29138918 TI - Anatomic stabilization techniques provide superior results in terms of functional outcome in patients suffering from chronic ankle instability compared to non anatomic techniques. AB - PURPOSE: To determine the best surgical treatment for chronic ankle instability (CAI) a systematic review was performed to compare the functional outcomes between various surgical stabilization methods. METHODS: A systematic search was performed from 1950 up to April 2016 using PubMed, EMBASE, Medline and the Cochrane Library. Inclusion criteria were a minimum age of 18 years, persistent lateral ankle instability, treatment by some form of surgical stabilization, described functional outcome measures. Exclusion criteria were case reports, (systematic) reviews, articles not published in English, description of only acute instability or only conservative treatment, medial ankle instability and concomitant injuries, deformities or previous surgical treatment for ankle instability. After inclusion, studies were critically appraised using the Modified Coleman Methodology Score. RESULTS: The search resulted in a total of 19 articles, including 882 patients, which were included in this review. The Modified Coleman Methodology Score ranged from 30 to 73 points on a scale from 0 to 90 points. The AOFAS and Karlsson Score were the most commonly used patient reported outcome measures to assess functional outcome after surgery. Anatomic repair showed the highest post-operative scores [AOFAS 93.8 (SD +/- 2.7; n = 119); Karlsson 95.1 (SD +/- 3.6, n = 121)], compared to anatomic reconstruction [AOFAS 90.2 (SD +/- 10.9, n = 128); Karlsson 90.1 (SD +/- 7.8, n = 35)] and tenodesis [AOFAS 86.5 (SD +/- 12.0, n = 10); Karlsson 85.3 (SD +/- 2.5, n = 39)]. Anatomic reconstruction showed the highest score increase after surgery (AOFAS 37.0 (SD +/- 6.8, n = 128); Karlsson 51.6 (SD +/- 5.5, n = 35) compared to anatomic repair [AOFAS 31.8 (SD +/- 5.3, n = 119); Karlsson 40.9 (SD +/- 2.9, n = 121)] and tenodesis [AOFAS 19.5 (SD +/- 13.7, n = 10); Karlsson 29.4 (SD +/- 6.3, n = 39)] (p < 0.005). CONCLUSION: Anatomic reconstruction and anatomic repair provide better functional outcome after surgical treatment of patients with CAI compared to tenodesis reconstruction. These results further discourage the use of tenodesis reconstruction and other non-anatomic surgical techniques. Future studies may be required to indicate potential value of tenodesis reconstruction when used as a salvage procedure. Not optimal, but the latter still provides an increase in functional outcome post-operatively. Anatomic reconstruction seems to give the best results, but may be more invasive than anatomic repair. This has to be kept in mind when choosing between reconstruction and repair in the treatment of CAI. LEVEL OF EVIDENCE: IV. PMID- 29138919 TI - Low re-rupture rate with BPTB autograft and semitendinosus gracilis autograft with preserved insertions in ACL reconstruction surgery in sports persons. AB - PURPOSE: To compare the results of bone-patellar tendon-bone graft (BPTB), semitendinosus-gracilis graft with preserved insertions (STGPI) and semitendinosus-gracilis-free graft (STGF) in terms of graft failure, objective mechanical stability, functional outcome, and return to sports in elite and recreational sports persons. It was hypothesized that the STGPI graft provided superior outcome as compared to the other two grafts. METHODS: Two hundred and forty-nine elite and recreational players who underwent ACL reconstruction surgery, with BPTB graft (N = 80), STGPI graft (N = 85), and STGF graft (N = 84) with a minimum follow-up of 2 years, were assessed using clinical tests, knee arthrometer (KT 1000TM), single-leg hop test, Lysholm knee score, Tegner's activity scale, and return to sports. Groups were matched in terms of age, gender, mode of injury, side involved, the level of sports, associated injuries, and mean follow-up. RESULTS: The median age of the patients was 24 years (range 16-46 years), with 227 males and 22 females, with a mean follow-up of 61.8 +/- 25.9 months. At the final follow-up, the mean side-to-side difference by KT 1000TM was significantly superior in BPTB group (1.4 +/- 2.1 mm) as compared to STGPI (1.9 +/- 2.0 mm) and STGF group (2.5 +/- 2.0 mm) (p = 0.002). The mean Lysholm knee score, Limb symmetry index (LSI) using single-leg hop test and the mean difference in pre-injury and post-surgery level of Tegner's activity scale were not significantly different. The rate of graft failure was significantly higher in STGF group (7.1%) as compared to BPTB (1.2%) and STGPI (1.2%) groups (p = 0.043). CONCLUSION: BPTB graft is a better graft in terms of mechanical stability than STGPI and STGF grafts. STGPI graft and BPTB graft are superior to STGF graft in terms of graft failure rate. However, there is no statistically significant difference amongst the three grafts in terms of return to sports and clinical tests of instability. STGPI graft is another option in the clinical setting with low graft failure rate like that of BPTB graft and with the added advantage of not having significant donor site morbidity. LEVEL OF EVIDENCE: III. PMID- 29138920 TI - Concurrent arthroscopic osteochondral lesion treatment and lateral ankle ligament repair has no substantial effect on the outcome of chronic lateral ankle instability. AB - PURPOSE: The purpose of the study was to evaluate the effect of concurrent arthroscopic osteochondral lesion (OCL) treatment and lateral ankle ligament repair on the outcome of chronic lateral ankle instability. It was hypothesized that the arthroscopic OCL treatment might have some negative effect on the outcome of chronic lateral ankle instability (CLAI) by compromising the rehabilitation program. METHODS: Ankle arthroscopy and anatomic lateral ankle ligament repair with suture anchors were performed for 70 patients with CLAI between 2010 and 2012. Thirty-four patients (group A), 20 males and 14 females with a median age of 30(14-54) years, received arthroscopic abrasion, curettage, drilling, or microfracture for OCLs. The splint was removed daily for joint motion exercises beginning at post-operative 2 weeks and full weight bearing was allowed between post-operative week 8 and 12. The other 36 patients (group B) with no combined OCL were followed up as controls. Pre-operative and post operative visual analog scale (VAS) scores, American Orthopaedic Foot and Ankle Society (AOFAS) scores, Tegner scores, sprain recurrence, ankle stability, and range of motion (ROM) were evaluated and compared. RESULTS: The median follow-up was 46.5 (38-55) months and 44.5 (38-56) months for group A and group B, respectively. The median post-operative VAS score, AOFAS score, and Tegner score were improved from the pre-operative level for both groups with good-to-excellent results for more than 90% patients. No significant difference was found between the two groups for the subjective scores and satisfaction rate (n.s.). Recurrent sprain was found among nine patients(26.5%) of the group A and five patients (13.9%) of the group B (n.s.). The incidence of the ROM restriction of group A was significantly higher than in group B (23.5 vs 5.6%, P = 0.043). CONCLUSIONS: The concurrent arthroscopic treatment of OCL with lateral ankle ligament repair demonstrated no substantial negative effect on the overall mid-term outcome of the patients with CLAI except for a potential risk of ROM restriction. LEVEL OF EVIDENCE: III. PMID- 29138899 TI - Correction to: Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study. AB - Correction to: Intensive Care Med (2016) 42:1865-1876 DOI 10.1007/s00134-016-4571 5. PMID- 29138922 TI - Extraspinal sacrococcygeal ependymoma masquerading as sacrococcygeal teratoma in the pediatric patient. PMID- 29138921 TI - World trends for H. pylori eradication therapy and gastric cancer prevention strategy by H. pylori test-and-treat. AB - Helicobacter pylori-associated gastritis leads to the development of gastric cancer. Kyoto global consensus report on H. pylori gastritis recommended H. pylori eradication therapy to prevent gastric cancer. To manage H. pylori infection, it is important to choose the appropriate regimen considering regional differences in resistance to clarithromycin and metronidazole. Quinolones and rifabutin-containing regimens are useful as third- and fourth-line rescue therapies. PMID- 29138924 TI - Minimal-invasive revision of adjacent level disease after MIS deformity surgery. PMID- 29138923 TI - Hippocampal-caudate nucleus interactions support exceptional memory performance. AB - Participants of the annual World Memory Championships regularly demonstrate extraordinary memory feats, such as memorising the order of 52 playing cards in 20 s or 1000 binary digits in 5 min. On a cognitive level, memory athletes use well-known mnemonic strategies, such as the method of loci. However, whether these feats are enabled solely through the use of mnemonic strategies or whether they benefit additionally from optimised neural circuits is still not fully clarified. Investigating 23 leading memory athletes, we found volumes of their right hippocampus and caudate nucleus were stronger correlated with each other compared to matched controls; both these volumes positively correlated with their position in the memory sports world ranking. Furthermore, we observed larger volumes of the right anterior hippocampus in athletes. Complementing these structural findings, on a functional level, fMRI resting state connectivity of the anterior hippocampus to both the posterior hippocampus and caudate nucleus predicted the athletes rank. While a competitive interaction between hippocampus and caudate nucleus is often observed in normal memory function, our findings suggest that a hippocampal-caudate nucleus cooperation may enable exceptional memory performance. We speculate that this cooperation reflects an integration of the two memory systems at issue-enabling optimal combination of stimulus-response learning and map-based learning when using mnemonic strategies as for example the method of loci. PMID- 29138926 TI - Disease management programs in heart failure: half a century of an unmet need. PMID- 29138925 TI - Efficacy of self-monitoring blood glucose as a key component of a chronic care model versus usual care in type 2 diabetes patients treated with oral agents: results of a randomized trial. PMID- 29138927 TI - ASGE EndoVators Summit: defining the role and value of endoscopic therapies in obesity management. PMID- 29138928 TI - Mechanisms of Drug Binding to Voltage-Gated Sodium Channels. AB - Voltage-gated sodium (Na+) channels are expressed in virtually all electrically excitable tissues and are essential for muscle contraction and the conduction of impulses within the peripheral and central nervous systems. Genetic disorders that disrupt the function of these channels produce an array of Na+ channelopathies resulting in neuronal impairment, chronic pain, neuromuscular pathologies, and cardiac arrhythmias. Because of their importance to the conduction of electrical signals, Na+ channels are the target of a wide variety of local anesthetic, antiarrhythmic, anticonvulsant, and antidepressant drugs. The voltage-gated family of Na+ channels is composed of alpha-subunits that encode for the voltage sensor domains and the Na+-selective permeation pore. In vivo, Na+ channel alpha-subunits are associated with one or more accessory beta subunits (beta1-beta4) that regulate gating properties, trafficking, and cell surface expression of the channels. The permeation pore of Na+ channels is divided in two parts: the outer mouth of the pore is the site of the ion selectivity filter, while the inner cytoplasmic pore serves as the channel activation gate. The cytoplasmic lining of the permeation pore is formed by the S6 segments that include highly conserved aromatic amino acids important for drug binding. These residues are believed to undergo voltage-dependent conformational changes that alter drug binding as the channels cycle through the closed, open, and inactivated states. The purpose of this chapter is to broadly review the mechanisms of Na+ channel gating and the models used to describe drug binding and Na+ channel inhibition. PMID- 29138929 TI - Safety and feasibility study of holmium laser enucleation of the prostate (HOLEP) on patients receiving dual antiplatelet therapy (DAPT). AB - OBJECTIVE: To evaluate the safety and feasibility of Holmium laser enucleation of the prostate (HoLEP) in patients receiving dual antiplatelet therapy (DAPT). METHODS: From March 2013 to August 2016, we retrospectively analyzed 1124 benign prostatic hyperplasia (BPH) patients undergoing HoLEP and divided into four groups: 56 cases receiving DAPT therapy (group A); 72 patients treated with continuous single antiplatelet (AP) therapy (group B); 41 patients treated with single AP therapy but intermittent during preoperative time (group C) and 955 cases had no AP therapy (group D). Patients' baseline characteristics, 1-year clinical outcomes, rates of postoperative bleeding and complications were presented in this study. RESULTS: All patients received successful operations and no severe postoperative complications occurred. Only one patient in Group D required transfusion. The enucleation time and catheterization time for the DAPT patients were the longest among four groups (p < 0.001, respectively). The overall complications rates within 30 days were 23.2% (13/56) in Group A, 27.8% (20/72) in Group B, 19.5% (8/41) in Group C, and 27.0% (258/955) in Group D, respectively (p = 0.678). By the 12 months, the international prostate symptom scores (IPSS), quality of life scores (QOL) and residual urine volume (RUV) in all groups have been significantly improved. CONCLUSION: HoLEP in patients receiving DAPT after coronary artery stunting showed similar results to those achieved in patients receiving single AP therapy or non-AP therapy. It can be a good option, which the urologists can offer to those patients with symptomatic benign prostatic hyperplasia refractory to medical treatment. PMID- 29138930 TI - Identifying a breeding habitat of a critically endangered fish, Acheilognathus typus, in a natural river in Japan. AB - Freshwater biodiversity has been severely threatened in recent years, and to conserve endangered species, their distribution and breeding habitats need to be clarified. However, identifying breeding sites in a large area is generally difficult. Here, by combining the emerging environmental DNA (eDNA) analysis with subsequent traditional collection surveys, we successfully identified a breeding habitat for the critically endangered freshwater fish Acheilognathus typus in the mainstream of Omono River in Akita Prefecture, Japan, which is one of the original habitats of this species. Based on DNA cytochrome B sequences of A. typus and closely related species, we developed species-specific primers and a probe that were used in real-time PCR for detecting A. typus eDNA. After verifying the specificity and applicability of the primers and probe on water samples from known artificial habitats, eDNA analysis was applied to water samples collected at 99 sites along Omono River. Two of the samples were positive for A. typus eDNA, and thus, small fixed nets and bottle traps were set out to capture adult fish and verify egg deposition in bivalves (the preferred breeding substrate for A. typus) in the corresponding regions. Mature female and male individuals and bivalves containing laid eggs were collected at one of the eDNA positive sites. This was the first record of adult A. typus in Omono River in 11 years. This study highlights the value of eDNA analysis to guide conventional monitoring surveys and shows that combining both methods can provide important information on breeding sites that is essential for species' conservation. PMID- 29138931 TI - RNA-Seq analysis reveals the distinctive adaxial-abaxial polarity in the asymmetric one-theca stamen of Canna indica. AB - Proper establishment of adaxial-abaxial polarity is essential for the development of lateral organs, while former researches were mostly focused on the polarity regulation in leaves, and little is known in stamens, especially in the asymmetric ones. Canna indica (Zingiberales: Cannaceae) is a widely cultivated ornamental plant and the representative species to study the evolutionary development of Zingiberales. The androecium of Canna indica comprises 3-4 petaloid staminodes and a fertile stamen (FS), which consists of a one-theca anther and a petaloid appendage. The partially petaloid stamen is considered as an intermediate state organ from a two-thecae stamen to a completely petaloid staminode. Using RNA-Seq, we quantified the expressions of the transcripts in anther and petaloid appendage, and detected 64,430 and 57,041 unigenes in these two organs, respectively. 4574 unigenes were down-regulated, and 3525 were up regulated in petaloid appendage compared with those in anther. GO enrichment analysis indicated that the function of cytokinin is more related to cell differentiation in anther, while auxin is more to cell division in petaloid appendage. B- and C-class floral homeotic genes were expressed in these two androecium parts. Most of the class III HD-ZIP family members, which specify adaxial identity, were expressed lower in petaloid appendage than in anther; while KANADIs and YABBYs, which promote abaxial identity, exhibited opposite expression patterns. In situ hybridization showed that the adaxial marker gene was mainly expressed in the region between the two protrusions of the anther, while the abaxial marker was mainly expressed in petaloid appendage. We hypothesize that the adaxial-abaxial polarity participates in the distinctive anther-petaloid appendage patterning within the asymmetric FS of Canna indica. PMID- 29138932 TI - Soybean (Glycine max) WRINKLED1 transcription factor, GmWRI1a, positively regulates seed oil accumulation. AB - Soybean is the world's most important leguminous crop producing high-quality protein and oil. Elevating oil accumulation in soybean seed is always many researchers' goal. WRINKLED1 (WRI1) encodes a transcription factor of the APETALA2/ethylene responsive element-binding protein (AP2/EREBP) family that plays important roles during plant seed oil accumulation. In this study, we isolated and characterized three distinct orthologues of WRI1 in soybean (Glycine max) that display different organ-specific expression patterns, among which GmWRI1a was highly expressed in maturing soybean seed. Electrophoretic mobility shift assays and yeast one-hybrid experiments demonstrated that the GmWRI1a protein was capable of binding to AW-box, a conserved sequence in the proximal upstream regions of many genes involved in various steps of oil biosynthesis. Transgenic soybean seeds overexpressing GmWRI1a under the control of the seed specific napin promoter showed the increased total oil and fatty acid content and the changed fatty acid composition. Furthermore, basing on the activated expressions in transgenic soybean seeds and existence of AW-box element in the promoter regions, direct downstream genes of GmWRI1a were identified, and their products were responsible for fatty acid production, elongation, desaturation and export from plastid. We conclude that GmWRI1a transcription factor can positively regulate oil accumulation in soybean seed by a complex gene expression network related to fatty acid biosynthesis. PMID- 29138933 TI - Population-based screening improves histopathological prognostic factors in colorectal cancer. AB - INTRODUCTION: Diagnosis of colorectal cancer (CRC) based on clinical symptoms is usually established in its advanced stages. One strategy for reducing mortality is the early detection and removal of preneoplastic and initial neoplastic lesions, even before the first symptoms appear, by means of population-based screening campaigns. The aim of the present study is to determine whether CRC diagnosed via a screening campaign has more favourable histopathological prognostic factors than when diagnosed in the symptomatic phase. MATERIAL AND METHODS: The prospective study of all the patients undergoing programmed CRC surgery at the JM Morales Meseguer Hospital (Spain) is between 2004 and 2010. The patients were divided into two groups: one diagnosed from clinical symptoms and one through a screening campaign. The following factors were compared: tumour size; degree of tumour invasion of the wall; lymph node, perineural and lymphovascular involvement; tumour stage; and grade of differentiation. RESULTS: Compared to the symptomatic group, the screen-detected patients had smaller-sized tumours (lesions of less than 5 cm in 84 vs 69.55%, p < 0.001), a lower degree of colorectal wall invasion (T0-1 in 36 vs 9.02%, p < 0.001), less lymph node involvement (N0 in 72 vs 58.76%, p > 0.05), less vascular invasion (7.20 vs 15.22%, p = 0.79) and less perineural invasion (6.4 vs 20.70%, p < 0.001). The TNM staging in the screening group was lower than in the symptomatic group (stage 0-1 in 50.40 vs 18.58%, p < 0.001). CONCLUSIONS: CRC diagnosed through a population-based screening programme presents more favourable histopathological characteristics than that diagnosed from the appearance of symptoms. PMID- 29138935 TI - Recurrent bacterial meningitis-devil is in the details. PMID- 29138934 TI - Habitat quality affects stress responses and survival in a bird wintering under extremely low ambient temperatures. AB - Animals normally respond to stressful environmental stimuli by releasing glucocorticoid hormones. We investigated whether baseline corticosterone (CORT), handling-induced corticosterone concentration(s), and body condition indices of members of willow tit (Poecile montanus) groups differed while wintering in old growth forests and managed young forests in mild weather conditions and during cold spells. Willow tits spend the winter season in non-kin groups in which dominant individuals typically claim their priority to access resources, while subordinate individuals may experience greater levels of stress and higher mortality, especially during cold spells. We captured birds to measure baseline CORT and levels of handling-induced CORT secretion after 20 min of capture. Willow tits in the young forests had higher baseline CORT and a smaller increase in CORT in response to capture than individuals in the old forests. Baseline CORT was higher in females and juvenile birds compared to adult males, whereas handling-induced CORT secretion did not differ between birds of different ages. During cold spells, baseline CORT of willow tits increased and handling-induced CORT secretion decreased, especially in birds in young forests. Willow tits' survival was higher in the old forests, with dominant individuals surviving better than subordinates. Our results show that changes in CORT secretion reflect responses to habitat quality and climate harshness, indicating young managed coniferous forests as a suboptimal habitat for the willow tit. PMID- 29138936 TI - Working hours and depressive symptoms over 7 years: evidence from a Korean panel study. AB - PURPOSE: This study aims to examine how working hours influence depressive symptoms and the association between working hours and depressive symptoms differently across genders. METHOD: The sample consists of salaried workers aged 25-64 years who participated in two consecutive waves of the seven-wave Korean Welfare Panel Study (2007-2013) (n = 6813 individuals, 27,986 observations) which is a survey of a nationally representative sample of the South Korean population. I apply logit regression and fixed-effects logit regression to examine the causal relation between (intra-)individual changes of working hours and depressive symptoms over a 7-year period. RESULTS: Results from logit model and fixed effects logit model show that less than 30 h of work per week and more than 60 h of work per week are associated with significantly higher levels of depressive symptoms. Sex-stratified analyses reveal that women who worked over 60 h per week were at increased risk of showing depressive symptoms compared with women who worked 30-40 h per week. No significant increase in depressive symptoms was seen in men who worked more than 60 h per week. However, men working less than 30 h per week are more likely to report higher levels of depressive symptoms. CONCLUSIONS: These results suggest that work arrangement affects the mental health of men and women differently. PMID- 29138937 TI - Effects of propofol sedation on pacing thresholds : Results from an observational cohort study. AB - BACKGROUND: Propofol is one of the most commonly used intravenous anaesthetic drugs for surgical procedures. The use of propofol for sedation is also common practice during endoscopic procedures, electrophysiology studies, and ablation procedures, as well as pacemaker and defibrillator implantation. It was found that propofol alters the electrophysiologic properties of the heart and its conduction system. The effects of propofol on pacing thresholds are unknown and could have implications for pacemaker (PM) and defibrillator (ICD) implantation procedures, as well as sedation and anaesthesia in PM and ICD patients in general. OBJECTIVES: We sought to investigate the effects of propofol sedation on atrial and right ventricular pacing thresholds in PM and ICD patients. MATERIALS AND METHODS: A total of 50 patients with PM, ICD, or cardiac resynchronization therapy (CRT) undergoing propofol sedation for electrophysiology (EP) investigation, transesophageal echocardiography (TEE), electrocardioversion (ECV), or bronchoscopy were included prospectively. Pacing thresholds, impedance, and sensing were assessed by device interrogation immediately prior to sedation and after the desired sedation depth was achieved by the administration of propofol. RESULTS: Mean atrial (0.68 V vs 0.77 V, p = 0.136) and mean right ventricular thresholds (0.90 V vs 0.93 V, p = 0.274) remained unchanged. Impedances and sensing remained unaffected in all patients. CONCLUSIONS: Propofol sedation did not affect pacing thresholds of atrial and right ventricular leads in this cohort of PM and ICD patients. PMID- 29138938 TI - Jasmonic acid-induced NO activates MEK1/2 in regulating the metabolism of ascorbate and glutathione in maize leaves. AB - This study investigated the relationship between MEK1/2 and nitric oxide (NO) in jasmonic acid (JA)-regulated metabolism of ascorbate and glutathione in maize leaves. The results showed that JA increased the activities of APX, GR, MDHAR, DHAR, GalLDH, and gamma-ECS; the contents of AsA and GSH; and the production of NO. Above increases except for gamma-ECS activity and NO production were all suppressed by pre-treatments with MEK1/2 inhibitors PD98059 and U0126. Above increases were all suppressed by pre-treatments with nitric oxide synthase (NOS) inhibitor L-NAME and NO scavenger cPTIO. The results of western blot showed that JA enhanced the phosphorylation level of MEK1/2. Pre-treatments with L-NAME and cPTIO suppressed JA-induced phosphorylation level of MEK1/2. Our results suggested that JA-induced NO activated MEK1/2 by increasing the phosphorylation level, which, in turn, resulted in the upregulation of ascorbate and glutathione metabolism in maize leaves. PMID- 29138939 TI - Responses of He-Ne laser on agronomic traits and the crosstalk between UVR8 signaling and phytochrome B signaling pathway in Arabidopsis thaliana subjected to supplementary ultraviolet-B (UV-B) stress. AB - UV-B acclimation effects and UV-B damage repair induced by a 632.8-nm He-Ne laser were investigated in Arabidopsis thaliana plants in response to supplementary UV B stress. There was an increasing trend in growth parameters in the combination treated plants with He-Ne laser and UV-B light compared to those stressed with enhanced UV-B light alone during different developmental stages of plants. The photosynthetic efficiency (Pn) and survival rates of seedlings were significantly higher in the combination treatments than UV-B stress alone. The expression of UVR8, phytochrome B (PhyB), and their mediated signal responsive genes such as COP1, HY5, and CHS were also significantly upregulated in plants with the laser irradiation compared with other groups without the laser. Levels of flavonol accumulation in leaves and capsule yield of He-Ne laser-treated plants were increased. The phyB-9 mutants were more sensitive to enhanced UV-B stress and had no obvious improvements in plant phenotypic development and physiological damage caused by enhanced UV-B stress after He-Ne laser irradiation. Our results suggested that UVR8 and its mediated signaling pathway via interaction with COP1 can be induced by He-Ne laser, and these processes were dependent on cytoplasmic PhyB levels in plant cells, which might be one of the most important mechanisms of He-Ne laser on UV-B protection and UV-B damage repair. These current data have also elucidated that the biostimulatory effects of He-Ne laser on Arabidopsis thaliana plants would happen not only during the early growth stage but also during the entire late developmental stage. PMID- 29138941 TI - Differential timing and latitudinal variation in sex ratio of Aquatic Warblers during the autumn migration. AB - Differential migration has been extensively reported in spring, but less so in autumn, particularly in relation to sex in monomorphic bird species. Here, we analysed the autumn passage of a monomorphic, globally threatened passerine, the Aquatic Warbler Acrocephalus paludicola throughout Western Europe, with regard to age and sex. We showed that, overall, adults migrated earlier than first-year birds, and males migrated earlier than females during the autumn migration. This may be caused by an overall social dominance of adults over immatures, and differentiated migration strategy of males and females. In addition, we found male-skewed sex proportions, with a tendency to an equalised ratio in more southern stopover sites. This may indicate a male bias in the global population or different migration strategies of the sexes. Differential migration may cause the age and sex classes to be exposed differently to various threats affecting demographic structure of the species. PMID- 29138940 TI - Silk fibroin-Pellethane(r) cardiovascular patches: Effect of silk fibroin concentration on vascular remodeling in rat model. AB - Life-threatening cardiovascular anomalies require surgery for structural repair with cardiovascular patches. The biomaterial patch, derived from Bombyx mori silk fibroin (SF), is used as an alternative material due to its excellent tissue affinity and biocompatibility. However, SF lacks the elastomeric characteristics required for a cardiovascular patch. In order to overcome this shortcoming, we combined the thermoplastic polyurethane, Pellethane(r) (PU) with SF to develop an elastic biocompatible patch. Therefore, the purpose of this study was to investigate the feasibility of the blended SF/PU patch in a vascular model. Additionally, we focused on the effects of different SF concentrations in the SF/PU patch on its biological and physical properties. Three patches of different compositions (SF, SF7PU3 and SF4PU6) were created using an electrospinning method. Each patch type (n = 18) was implanted into rat abdominal aorta and histopathology was assessed at 1, 3, and 6 months post-implantation. The results showed that with increasing SF content the tensile strength and elasticity decreased. Histological evaluation revealed that inflammation gradually decreased in the SF7PU3 and SF patches throughout the study period. At 6 months post implantation, the SF7PU3 patch demonstrated progressive remodeling, including significantly higher tissue infiltration, elastogenesis and endothelialization compared with SF4PU6. In conclusion, an increase of SF concentration in the SF/PU patch had effects on vascular remodeling and physical properties. Moreover, our blended patch might be an attractive alternative material that could induce the growth of a neo-artery composed of tissue present in native artery. PMID- 29138942 TI - Calculation of left ventricular volumes and ejection fraction from dynamic cardiac-gated 15O-water PET/CT: 5D-PET. AB - BACKGROUND: Quantitative measurement of myocardial blood flow (MBF) is of increasing interest in the clinical assessment of patients with suspected coronary artery disease (CAD). 15O-water positron emission tomography (PET) is considered the gold standard for non-invasive MBF measurements. However, calculation of left ventricular (LV) volumes and ejection fraction (EF) is not possible from standard 15O-water uptake images. The purpose of the present work was to investigate the possibility of calculating LV volumes and LVEF from cardiac-gated parametric blood volume (V B) 15O-water images and from first pass (FP) images. Sixteen patients with mitral or aortic regurgitation underwent an eight-gate dynamic cardiac-gated 15O-water PET/CT scan and cardiac MRI. V B and FP images were generated for each gate. Calculations of end-systolic volume (ESV), end-diastolic volume (EDV), stroke volume (SV) and LVEF were performed with automatic segmentation of V B and FP images, using commercially available software. LV volumes and LVEF were calculated with surface-, count-, and volume based methods, and the results were compared with gold standard MRI. RESULTS: Using V B images, high correlations between PET and MRI ESV (r = 0.89, p < 0.001), EDV (r = 0.85, p < 0.001), SV (r = 0.74, p = 0.006) and LVEF (r = 0.72, p = 0.008) were found for the volume-based method. Correlations for FP images were slightly, but not significantly, lower than those for V B images when compared to MRI. Surface- and count-based methods showed no significant difference compared with the volume-based correlations with MRI. The volume-based method showed the best agreement with MRI with no significant difference on average for EDV and LVEF but with an overestimation of values for ESV (14%, p = 0.005) and SV (18%, p = 0.004) when using V B images. Using FP images, none of the parameters showed a significant difference from MRI. Inter-operator repeatability was excellent for all parameters (ICC > 0.86, p < 0.001). CONCLUSION: Calculation of LV volumes and LVEF from dynamic 15O-water PET is feasible and shows good correlation with MRI. However, the analysis method is laborious, and future work is needed for more automation to make the method more easily applicable in a clinical setting. PMID- 29138943 TI - Contaminants of emerging concern in surface waters in Barbados, West Indies. AB - Contaminants of emerging concern (CECs), including pharmaceuticals, artificial sweeteners, steroid hormones, and current-use pesticides have been detected in surface waters around the world, but to date, there have been no reports in the peer-reviewed literature on the levels of these classes of contaminants in freshwater resources in the Caribbean region. In the present study, multi-residue solid phase extraction (SPE) and liquid chromatography with tandem mass spectroscopy (LC-MS/MS) were used to analyze grab samples of surface waters collected from five different watersheds in Barbados, West Indies. The artificial sweeteners (AS), acesulfame, cyclamate, saccharin, and sucralose were widely detected in the watersheds, indicating contamination from domestic wastewater, and the concentrations of these chemical tracers in water were correlated with the concentrations of the non-prescription pharmaceutical, ibuprofen (R 2 values of 0.4-0.6). Surprisingly, the concentrations of another chemical tracer of domestic wastewater, caffeine were not correlated with ibuprofen or AS concentrations. Several other prescription pharmaceuticals and the steroid hormones, estrone and androstenedione, were detected in selected watersheds at low ng/L concentrations. The fungicide, chlorothalonil was widely detected in surface waters at low (< 10 ng/L) concentrations, but the levels of this pesticide were not correlated with the concentrations of the other target analytes, indicating that the source of this pesticide is not domestic wastewater. An informal survey of disposal practices for out of date or unused drugs by pharmacies in Barbados indicated that disposal into trash destined for the landfill and flushing down the sink might be significant sources of contamination of water resources by pharmaceuticals. PMID- 29138944 TI - Design, synthesis, conformational and molecular docking study of some novel acyl hydrazone based molecular hybrids as antimalarial and antimicrobial agents. AB - BACKGROUND: Acyl hydrazones are an important class of heterocyclic compounds promising pharmacological characteristics. Malaria is a life-threatening mosquito borne blood disease caused by a plasmodium parasite. In some places, malaria can be treated and controlled with early diagnosis. However, some countries lack the resources to do this effectively. RESULTS: The present work involves the design and synthesis of some novel acyl hydrazone based molecular hybrids of 1,4 dihydropyridine and pyrazole (5a-g). These molecular hybrids were synthesised by condensation of 1,4-dihydropyridin-4-yl-phenoxyacetohydrazides with differently substituted pyrazole carbaldehyde. The final compound (5) showed two conformations (the major, E, s-cis and the minor, E, s-trans) as revealed by NMR spectral data and further supported by the energy calculations (MOPAC2016 using PM7 method). All the synthesised compounds were screened for their in vitro antimalarial activities against chloroquine-sensitive malaria parasite Plasmodium falciparum (3D7) and antimicrobial activity against Gram positive bacteria i.e. Bacillus cereus, Gram negative bacteria i.e. Escherichia coli and antifungal activity against one yeast i.e. Aspergillus niger. All these compounds were found more potent than chloroquine and clotrimazole, the standard drugs. CONCLUSIONS: In vitro antiplasmodial IC50 value of the most potent compound 5d was found to be 4.40 nM which is even less than all the three reference drugs chloroquine (18.7 nM), pyrimethamine (11 nM) and artimisinin (6 nM). In silico binding study of compound 5d with plasmodial cysteine protease falcipain-2 indicated the inhibition of falcipain-2 as the probable reason for the antimalarial potency of compound 5d. All the compounds had shown good to excellent antimicrobial and antifungal activities. PMID- 29138945 TI - Glioblastoma in neurofibromatosis 1 patients without IDH1, BRAF V600E, and TERT promoter mutations. AB - Pilocytic astrocytomas and low-grade gliomas are more common compared with glioblastomas in patients with neurofibromatosis 1 (NF1). A recent genome-wide analysis has shown frequent NF1 gene alterations in the mesenchymal subtype of a glioblastoma; however, little is known about clinicopathological features of glioblastomas in NF1 patients (NF1 glioblastomas). We analyzed four NF1 glioblastomas. Radiographical and intraoperative findings showed well circumscribed tumors from surrounding brain. Pathological analysis presented a paucity of processes with an eosinophilic cytoplasm, bizarre nuclei, xanthomatous like appearance, multinucleated giant cells, and histiocytoid appearance. During the follow-up period, one patient died at 49 months and others remained alive for 60, 87, and 106 months; thus, patients with NF1 glioblastoma presented a relatively favorable survival. None of the NF1 glioblastomas harbored isocitrate dehydrogenase 1 (IDH1) gene mutation, v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene mutation, and telomerase reverse transcriptase (TERT) gene promoter mutation. We identified that NF1 glioblastoma is a unique subset of glioblastoma. PMID- 29138946 TI - Semiotic systems with duality of patterning and the issue of cultural replicators. AB - Two major works in recent evolutionary biology have in different ways touched upon the issue of cultural replicators in language, namely Dawkins' Selfish Gene and Maynard Smith and Szathmary's Major Transitions in Evolution. In the latter, the emergence of language is referred to as the last major transition in evolution (for the time being), a claim we argue to be derived from a crucial property of language, called Duality of Patterning. Prima facie, this property makes natural language look like a structural equivalent to DNA, and its peer in terms of expressive power. We will argue that, if one takes seriously Maynard Smith and Szathmary's outlook and examines what has been proposed as linguistic replicators, amongst others phonemes and words, the analogy meme-gene becomes problematic. A key issue is the fact that genes and memes are assumed to carry and transmit information, while what has been described as the best candidate for replicatorhood in language, i.e. the phoneme, does by definition not carry meaning. We will argue that semiotic systems with Duality of Pattering (like natural languages) force us to reconsider either the analogy between replicators in the biological and the cultural domain, or what it is to be a replicator in linguistics. PMID- 29138947 TI - A posteriori metadata from automated provenance tracking: integration of AiiDA and TCOD. AB - In order to make results of computational scientific research findable, accessible, interoperable and re-usable, it is necessary to decorate them with standardised metadata. However, there are a number of technical and practical challenges that make this process difficult to achieve in practice. Here the implementation of a protocol is presented to tag crystal structures with their computed properties, without the need of human intervention to curate the data. This protocol leverages the capabilities of AiiDA, an open-source platform to manage and automate scientific computational workflows, and the TCOD, an open access database storing computed materials properties using a well-defined and exhaustive ontology. Based on these, the complete procedure to deposit computed data in the TCOD database is automated. All relevant metadata are extracted from the full provenance information that AiiDA tracks and stores automatically while managing the calculations. Such a protocol also enables reproducibility of scientific data in the field of computational materials science. As a proof of concept, the AiiDA-TCOD interface is used to deposit 170 theoretical structures together with their computed properties and their full provenance graphs, consisting in over 4600 AiiDA nodes. PMID- 29138948 TI - Correction to: S-1 and irinotecan plus bevacizumab as second-line chemotherapy for patients with oxaliplatin-refractory metastatic colorectal cancer: a multicenter phase II study in Japan (KSCC1102). AB - In the original publication, in Abstract, the sentence that reads as, "Oral S-1 at a dose of 80 mg/m2 was............. drug-free interval" should read as, "Oral S-1 at a dose of 40 mg/m2 was administered twice daily for 2 weeks, followed by a 1-week drug-free interval. PMID- 29138949 TI - Multiple high-grade gliomas: epidemiology, management, and outcome. A systematic review and meta-analysis. AB - Multiple high-grade gliomas (M-HGGs) are well--separated tumors, differentiated as multifocal (MF) and multicentric (MC) by their MRI features. The authors performed a systematic review and meta-analysis of literature examining epidemiology, clinical and radiological characteristics, management, and the overall survival from M-HGGs. According to PRISMA guidelines, a comprehensive review of studies published between January 1990 and January 2017 was carried out. The authors identified studies that examined the prevalence rate, clinical and radiological characteristics, treatment, and overall survival from M-HGGs in patients with HGG. Data were analyzed using a random-effects meta-analysis model. Finally, we systematically reviewed demographic characteristics, lesion location, and surgical and adjuvant treatments. Twenty-three studies were included in this systematic review. The M-HGGs prevalence rate was 19% (95% CI 13-26%) and the hazard ratio of death from M-HGGs in the HGGs population was 1.71 (95% CI 1.49 1.95, p < 0.0001). The MC prevalence rate was 6% (CI 95% 4-10%), whereas MF prevalence rate was 11% (CI 95% 6-20%) (p < 0.0001). There were no statistically significant differences between MF and MC HGGs in gender, lesion location, histological type, and surgical treatment. Survival analysis of MC tumors showed that surgical resection (gross total resection or subtotal resection) is an independent predictor of improved outcome (HR 7.61 for biopsy subgroup, 95% CI 1.94-29.78, p = 0.004). The prevalence of M-HGGs is approximately 20% of HGGs. The clinical relevance of separating M-HGGs in MF and MC tumors remains questionable and its prognostic significance is unclear. When patient status and lesion characteristics make it safe and feasible, cytoreduction should be attempted in patients with M-HGGs because it improves overall survival. PMID- 29138950 TI - Improvement of amperometric transducer selectivity using nanosized phenylenediamine films. AB - In this work, we studied the conditions of deposition of a semipermeable polyphenylenediamine (PPD)-based membrane on amperometric disk platinum electrodes. Restricting an access of interfering substances to the electrode surface, the membrane prevents their impact on the sensor operation. Two methods of membrane deposition by electropolymerization were compared-at varying potential (cyclic voltammetry) and at constant potential. The cyclic voltammetry was shown to be easier in performing and providing better properties of the membrane. The dependence of PPD membrane effectiveness on the number of cyclic voltammograms and phenylenediamine concentration was analyzed. It was shown that the impact of interfering substances (ascorbic acid, dopamine, cysteine, uric acid) on sensor operation could be completely avoided using three cyclic voltammograms in 30 mM phenylenediamine. On the other hand, when working with diluted samples, i.e., at lower concentrations of electroactive substances, it is reasonable to decrease the phenylenediamine concentration to 5 mM, which would result in a higher sensitivity of transducers to hydrogen peroxide due to a thinner PPD layer. The PPD membrane was tested during continuous operation and at 8-day storage and turned out to be efficient in sensor and biosensors. PMID- 29138951 TI - Chronic Diarrhea in Common Variable Immunodeficiency: a Case Series and Review of the Literature. AB - Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by reduced immunoglobulin serum levels and absent or impaired antibody production. Clinical manifestations, including infections, inflammatory and autoimmune diseases, and malignancies, also involve various segments of the gastrointestinal tract. Chronic diarrhea is one of the most common gastrointestinal symptoms and may cause a wide spectrum of potentially life threatening conditions as malabsorption and protein-energy malnutrition. We describe three female CVID adult patients presenting with chronic diarrhea, weight loss, and protein-energy malnutrition due to different underlying conditions. Our review of the literature explores the various gastrointestinal involvements in CVID and points out several histopathological findings proper of the disease, thus highlighting the relevance of the endoscopic and histological assessment in CVID patients presenting with chronic diarrhea. PMID- 29138952 TI - Age estimation by assessment of pulp chamber volume: a Bayesian network for the evaluation of dental evidence. AB - PURPOSE: The present study aimed to investigate the performance of a Bayesian method in the evaluation of dental age-related evidence collected by means of a geometrical approximation procedure of the pulp chamber volume. Measurement of this volume was based on three-dimensional cone beam computed tomography images. METHODS: The Bayesian method was applied by means of a probabilistic graphical model, namely a Bayesian network. Performance of that method was investigated in terms of accuracy and bias of the decisional outcomes. Influence of an informed elicitation of the prior belief of chronological age was also studied by means of a sensitivity analysis. RESULTS: Outcomes in terms of accuracy were adequate with standard requirements for forensic adult age estimation. Findings also indicated that the Bayesian method does not show a particular tendency towards under- or overestimation of the age variable. Outcomes of the sensitivity analysis showed that results on estimation are improved with a ration elicitation of the prior probabilities of age. PMID- 29138954 TI - Identification of compounds from Palicourea rigida leaves with topical anti inflammatory potential using experimental models. AB - Palicourea rigida Kunth is traditionally used for the treatment of skin diseases, kidney pains and ovarian inflammation. Based on these traditional uses, this study evaluated the topical anti-inflammatory activity of the ethanol extract from P. rigida leaves (EEPR) and identified bioactive compounds. Ear edema was induced in Swiss mice by the topical application of Croton oil, arachidonic acid, phenol and capsaicin. Histopathological analysis and myeloperoxidase and N-acetyl beta-D-glucosaminidase activities were determined. EEPR was characterized by UHPLC-UV-MS HPLC and the isolated compound was identified through 1H and 13C nuclear magnetic resonance and mass fragmentation. Interaction profiles between quercetin 3-O-beta-D-glucoside and cyclooxygenase-1 and -2 were established by molecular docking. EEPR significantly inhibited ear edema induced by Croton oil (p < 0.001), arachidonic acid (p < 0.01), phenol (p < 0.001) and capsaicin (p < 0.01 or p < 0.001). Histopathological analysis showed a reduction of edema, inflammatory cell infiltration and vasodilation. Additionally, the myeloperoxidase and N-acetyl-beta-D-glucosaminidase activities were decreased (p < 0.001). From spectroscopic data, quercetin 3-O-beta-D-glucoside was the identified compound. This compound can to interact with cyclooxygenase-1 and -2 through van der Waals interactions and dipole-dipole and hydrogen bonding's, demonstrating inhibition of these enzymes. The results indicate that EEPR is a source of active compounds with topical anti-inflammatory activity, justifying the traditional use of P. rigida and showing that this species has a therapeutic potential to treat skin inflammatory processes. PMID- 29138955 TI - The impact of palliative care training for oncologists and integrative palliative service in a public-funded hospital cluster-a retrospective cohort study. AB - PURPOSE: Oncological care of advanced cancer patients was provided by multiple departments in Hong Kong. One of these departments, the clinical oncology department (COD), introduced systematic palliative care training for its oncologists since 2002. The COD was recognized as a European Society for Medical Oncology (ESMO) Designated Centre of Integrated Oncology and Palliative Care since 2009. This retrospective cohort study aims to review the impact of integrative training and service on palliative care coverage and outcome. METHODS: Clinical information, palliative service provision, and end-of-life outcomes of patients who passed away from lung, colorectal, liver, stomach, or breast cancer in the Hong Kong West public hospital network during July 2015 to December 2015 were collected. RESULTS: A total of 307 patients were analyzed. Around half (49.2%) were attended primarily by COD, and 68.9% received palliative service. There are significantly fewer patients referred to palliative care from other departments (p < 0.001), with only 19.9% of this patient group receiving palliative referral. COD patients had longer palliative coverage before death (median 65 days versus 24 days, p < 0.001), higher chance of receiving end-of life care at hospice units (36.4 versus 21.2%, p = 0.003), lower ICU admission (0.66 versus 5.1%, p = 0.02), and higher percentage of receiving strong opioid in the last 30 days of life (51.0 versus 28.9%, p < 0.001) compared to other departments. In multivariable analysis, COD being the primary care team (odds ratio 12.2, p < 0.001) was associated with higher palliative care coverage. CONCLUSION: The study results suggested that systematic palliative care training of oncologists and integrative palliative service model was associated with higher palliative service coverage and improved palliative care outcomes. PMID- 29138956 TI - Nurses attitudes and practices towards provision of survivorship care for people with a haematological cancer on completion of treatment. AB - PURPOSE: The purpose of this study is to assess cancer nurses' perceptions of responsibility, confidence levels and practice in relation to survivorship care for people with a haematological malignancy on completion of treatment. METHODS: A prospective cross-sectional survey was conducted. An online survey was distributed to members of two Australian professional bodies. RESULTS: A total of 310 cancer nurses participated in the study, representing a response rate of 28%. The participants generally agreed that all survivorship care items were part of their role. Of the 17 survivorship care items, the three items receiving the lowest confidence scores were discussing fertility issues, discussing employment and financial issues and discussing how to identify signs of cancer recurrence. The least performed survivorship care items were discussing fertility issues, communicating survivorship care with primary healthcare team (i.e. general practitioners) and discussing sexuality issues. Older age, more years of experience, having a post-graduate qualification and working in non-metropolitan area were associated with higher levels of perception of responsibilities and confidence (p < 0.05). The top ranked barriers to survivorship care were reported to be lack of end-of-treatment consultation dedicated to survivorship care, time and an appropriate physical space for delivering care. CONCLUSIONS: Cancer nurses perceive key aspects of survivorship care to be part of their role, however there remains variations in practice and confidence with respect to implementation of survivorship care practices. IMPLICATIONS FOR CANCER SURVIVORS: Interventions that focus on enhancing the capability of cancer nurses and eliminating barriers identified in this study have the potential to improve quality survivorship care provision. PMID- 29138957 TI - The Most Important Recommended Times of Hand Washing with Soap and Water in Preventing the Occurrence of Acute Diarrhea Among Children Under Five Years of Age in Slums of Addis Ababa, Ethiopia. AB - Adequate hand washing with soap at five recommended times is particularly important in urban slums in developing countries, but which of the recommended times are the most important in the prevention of diarrhea among children under five years of age living in these areas remains unclear. To address this gap, a community-based cross-sectional study was undertaken in the slums of Addis Ababa, Ethiopia between September and November 2014. Data were collected using a pre tested structured questionnaire and an observational checklist. Multivariable logistic regression with 95% confidence interval (CI) was used for data analysis. Only 4.4% of the households had hand washing facilities within or near a latrine with soap and water access. The average prevalence of hand washing with soap at the five recommended times was 19.8%. One quarter (24.8%) of caregivers washed their hands with soap before feeding a child, 23.8% before preparing food, and 17.1% after defecation. The most important recommended times in preventing acute diarrhea were before preparing food [adjusted odds ratio (AOR) 0.2; 95% CI 0.1 0.7] and after defecation (AOR 0.3; 95% CI 0.1-0.9). Household size of six or more persons (AOR 2.3; 95% CI 1.4-3.9) and low monthly household income (AOR 2.4; 95% CI 1.4-4.0) were significantly associated with acute diarrhea. Promoting hand washing with soap and advocacy programs at the five recommended times, especially before preparing food and after defecation, and implementation of socioeconomic development programs targeting poor households are essential for increasing the prevalence of hand washing with soap and preventing acute diarrhea in the slums of Addis Ababa. PMID- 29138958 TI - Predictors of Depression in Iranian Women with Polycystic Ovarian Syndrome. AB - Depression is a major complication of polycystic ovarian syndrome (PCOS). Lifestyle modification can prevent it. This study aimed to determine the predictors of depression in women with PCOS. This cross-sectional study was conducted on 174 women who attended in infertility clinics in Urmia-Iran, 2015. The data were collected through socio-demographic, Beck Depression Inventory-II and Health Promoting Lifestyle Profile-2 questionnaires. The mean (standard deviation) of total score of the depression was obtained 27.4 (10.5) in the range 0-63. The mean (SD) of total score of the health promoting lifestyle was obtained 2.2 (0.3) out of 4. Based on multivariate linear regression, the variables of nutrition, interpersonal relationships, spiritual growth, stress management, BMI, the perceived stress of the disease, the first supporter and menstrual bleeding were predictors of the depression. Given the high prevalence of depression in PCOS patients and its relationship with health-promoting behaviors, lifestyle modification to reduce depression is necessary. PMID- 29138959 TI - Body Image Assessment Among Community Mental Health Providers. AB - Although research suggests an association between body image and mental health, with poor body image related to several mental illnesses, there is no research exploring mental health clinicians' body image screening practices. This study aims to fill this gap among a sample of community mental health providers (N = 216). Using a cross-sectional design, clinicians in Community Health Centers were recruited through email using purposeful and snowball sampling in a Midwest state. The majority of participants identified as women (88.4%) and White (88.4%). Additionally, the mean age of the sample was 36.66 years and participants reported working an average of 8.44 years as a mental health provider. We ran descriptive and Chi square analyses. Results suggest a relationship between viewing body image screening as important and level of preparedness as well as level of preparedness and actual assessment. Training and assessment tools may be warranted to increase clinician's preparedness. Additional clinical and policy recommendations are discussed. PMID- 29138960 TI - Probable Post-traumatic Stress Disorder and Self-harming Behaviour: Potential Barriers to Employment? AB - The current study screened for post-traumatic stress disorder (PTSD) and self harming behaviours, often related to borderline personality disorder (BPD), among individuals in a job centre considered unemployable primarily for psychological reasons. Participants (N = 112) filled in questionnaires on PTSD symptoms (n = 62) and self-harming behaviours (n = 59) as part of participating in team meetings providing the individuals with a return-to-work plan. Differences in demographic variables between individuals with and without valid protocols were small to moderate. Of the individuals filling in the PTSD questionnaire 40% fulfilled criteria for probable PTSD and 31% of the individuals filling in the questionnaire on self-harming behaviours reported five or more types of self harming behaviours. Only a minority of these individuals had PTSD or BPD respectively mentioned in their case records. Further investigation of the prevalence of PTSD and self-harming behaviour among individuals considered unemployable is warranted as well as an enhanced focus in jobcentres and other institutions supporting employability on detection and treatment of PTSD and early signs of BPD. PMID- 29138962 TI - Obituary. PMID- 29138961 TI - Blastocystis subtypes isolated from irritable bowel syndrome patients and co infection with Helicobacter pylori. AB - Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disease presenting clinically by abdominal pain with alteration of bowel habits. Although IBS has uncertain etiology, chronic gut inflammation due to persistent exposure to an infectious agent including Blastocystis sp. was proposed. The aim of this study was to detect the prevalence of Blastocystis sp. subtype (ST) isolated from stool of IBS patients and to assess Blastocystis sp. and H. pylori co-infection in IBS patients from Beni-Suef Governorate, Egypt. Stool samples were collected from 115 IBS patients, following Rome III criteria. All stool samples were microscopically examined by wet mount and permanent trichrome stain, cultured on Jones' medium with further sequencing of positive Blastocystis isolates and screened for detection of H. pylori coproantigen. Blastocystis sp. was the predominant parasite in IBS patients; it had statistical significant association with both rural residence (OR = 10) and flatulence (OR = 8.2). There was a predominance of Blastocystis sp. ST3 (81%) followed by ST1 (19%). Blastocystis culture results (19.1%) were superior than microscopy (16.5%). The majority of Blastocystis-positive IBS patients (72.7%) were co-infected with H. pylori with statistical significance; however, H. pylori was higher in Blastocystis-negative IBS patients (47/64) than in Blastocystis-positive IBS patients (17/64). Interestingly, IBS is usually associated with gut dysbiosis, while the most prevalent parasite in our IBS patients was Blastocystis sp., which is frequently found in asymptomatic individuals. Whether Blastocystis sp. is a cause or a consequence of IBS still needs further investigation, with a particular focus on correlation of IBS with different Blastocystis sp. subtypes and gut microbiomes. PMID- 29138963 TI - Synthesis of novel tetrazole containing hybrid ciprofloxacin and pipemidic acid analogues and preliminary biological evaluation of their antibacterial and antiproliferative activity. AB - A series of 1-substituted-1H-tetrazole-5-thiol building blocks were synthesized and introduced to the N-4 piperazinyl group at C-7 position of the quinolone core, and these novel compounds (5a-g and 8a-g) were screened for their antibacterial and antiproliferative activities. Bioactive assay studies manifested that most of new compounds exhibited significant antibacterial activity against the tested strains, including multi-drug-resistant MRSA in comparison with reference drugs ciprofloxacin, streptomycin B and pipemidic acid. Among the synthesized compounds, only ciprofloxacin (5a-g) derivatives displayed significant activity ([Formula: see text]) compared to reference drugs. In addition, these compounds were evaluated for their in vitro inhibition of human cancer cell lines viz human cervical carcinoma cell line (SiHA), breast adenocarcinoma (MDA-MB-235) and human pancreas carcinoma (PANC-1) cell lines by using the SRB assay method. Most of the target compounds showed broad potent growth inhibition activity ([Formula: see text]) against all the tested cancer cell lines compared with reference drug. The most promising active compounds in this series were 5c, 5d, 8c, 8d and 8f endowed with excellent antiproliferative activity. A new class of compounds was designed rationally by introducing tetrazole building block on N-4 piperazinyl group at C-7 position of quinolones core. The titled compounds were evaluated for their preliminary antibacterial and antiproliferative activities. PMID- 29138964 TI - Recent trends in ring opening of epoxides with sulfur nucleophiles. AB - Thiolysis of epoxides offers an efficient and simple synthetic approach to access [Formula: see text]-hydroxy sulfides which are valuable scaffold in the synthesis of various important molecules in medicinal chemistry. This review article presents a recent compilation of the synthetic approaches developed after 2000 for the thiolysis of epoxides. PMID- 29138965 TI - Molecular dynamics and integrated pharmacophore-based identification of dual [Formula: see text] inhibitors. AB - Despite increase in the understanding of the pathogenesis of rheumatoid arthritis (RA), it remains a tough challenge. The advent of kinases involved in key intracellular pathways in pathogenesis of RA may provide a new phase of drug discovery for RA. The present study is aimed to identify dual JAK3/[Formula: see text] inhibitors by developing an optimum pharmacophore model integrating the information revealed by ligand-based pharmacophore models and structure-based pharmacophore models (SBPMs). For JAK3 inhibitors, the addition of an aromatic ring feature and for [Formula: see text] the addition of a hydrophobic feature proposed by SBPMs lead to five-point pharmacophore (i.e., AADHR.54 (JAK3)) and six-point pharmacophore (i.e., AAAHRR.45 ([Formula: see text])). The obtained pharmacophores were validated and used for virtual screening and then for docking based screening. Molecules were further evaluated for ADME properties, and their docked protein complexes were subjected to MM-GBSA energy calculations and molecular dynamic simulations. The top two hit compounds with novel scaffolds 2 oxo-1,2-dihydroquinoline and benzo[d]oxazole showed inhibitory activity for JAK3 and [Formula: see text]. PMID- 29138966 TI - Postnatal nutrition influences male attractiveness and promotes plasticity in male mating preferences. AB - Poor early-life nutrition could reduce adult reproductive success by negatively affecting traits linked to sexual attractiveness such as song complexity. If so, this might favor strategic mate choice, allowing males with less complex songs to tailor their mating tactics to maximize the reproductive benefits. However, this possibility has been ignored in theoretical and empirical studies. By manipulating the micronutrient content of the diet (e.g., low or high) during the postnatal period of male zebra finches, we show for the first time (1) that males reared on a poor (low) micronutrient diet had less complex songs as adults; (2) that these males, in contrast to the high micronutrient diet group, were more selective in their mating strategies, discriminating against those females most likely to reduce their clutch size when paired with males having less complex songs; and (3) that by following different mating strategies, males reared on the contrasting diets obtained similar reproductive benefits. These results suggest that early-life dietary conditions can induce multiple and long-lasting effects on male and female reproductive traits. Moreover, the results seem to reflect a previously unreported case of adaptive plasticity in mate choice in response to a nutritionally mediated reduction in sexual attractiveness. PMID- 29138967 TI - Mice Lacking EGR1 Have Impaired Clock Gene (BMAL1) Oscillation, Locomotor Activity, and Body Temperature. AB - Early growth response transcription factor 1 (EGR1) is expressed in the suprachiasmatic nucleus (SCN) after light stimulation. We used EGR1-deficient mice to address the role of EGR1 in the clock function and light-induced resetting of the clock. The diurnal rhythms of expression of the clock genes BMAL1 and PER1 in the SCN were evaluated by semi-quantitative in situ hybridization. We found no difference in the expression of PER1 mRNA between wildtype and EGR1-deficient mice; however, the daily rhythm of BMAL1 mRNA was completely abolished in the EGR1-deficient mice. In addition, we evaluated the circadian running wheel activity, telemetric locomotor activity, and core body temperature of the mice. Loss of EGR1 neither altered light-induced phase shifts at subjective night nor affected negative masking. Overall, circadian light entrainment was found in EGR1-deficient mice but they displayed a reduced locomotor activity and an altered temperature regulation compared to wild type mice. When placed in running wheels, a subpopulation of EGR1-deficient mice displayed a more disrupted activity rhythm with no measurable endogenous period length (tau). In conclusion, the present study provides the first evidence that the circadian clock in the SCN is disturbed in mice deficient of EGR1. PMID- 29138969 TI - Effects of neonicotinoids on Bees: an invalid experiment. PMID- 29138968 TI - Mitochondrial dysfunctions contribute to energy deficits in rodent model of hepatic encephalopathy. AB - Perturbations in the cerebral energy metabolism are anticipated to be an important factor by which ammonia may exert its toxic effects on the central nervous system. The present study was designed to investigate the role of impaired mitochondrial functions and cerebral energy metabolism in the development hepatic encephalopathy (HE) induced by of bile duct ligation (BDL). After four weeks of BDL, a significant increase in hepatic hydroxyproline and collagen content was observed which confirmed biliary fibrosis. Brain regions viz. cortex, hippocampus, striatum and cerebellum of BDL rats had impaired activity of mitochondrial respiratory chain enzymes. This was accompanied by increase in mitochondrial reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl levels in the brain. Mitochondrial redox ratio was significantly reduced in the brain of BDL rats. In addition, mitochondria from brain of BDL rats were depolarized and swollen compared to the sham controls. Ultrastructure analysis of mitochondria from cortex and hippocampus of BDL animals revealed aberrant cristae, ruptured membranes and non-dense matrix. Further, a significant decrease was observed in creatine kinase activity, glucose uptake and CO2 production in the brain regions of BDL rats. ATP/ADP ratio, a critical parameter of cellular energy status, was also significantly reduced in brain regions of rats with HE. Overall, the findings clearly demonstrate that BDL induced HE involves mitochondrial respiratory chain dysfunctions, mitochondrial depolarization and swelling that accentuates oxidative stress which in turn leads to compromise in cerebral energy metabolism thereby contributing to the pathophysiology of chronic HE. PMID- 29138970 TI - Development of an acute toxicity test with the tropical marine amphipod Parhyale hawaiensis. AB - There is a lack of suitable tropical marine species for ecotoxicity tests. An attractive model organism for ecotoxicology is the marine amphipod Parhyale hawaiensis, which is already a model for genetic and developmental studies. This species is widespread, can tolerate changes in salinity, is easy to handle and is representative of circumtropical regions. The aim of this work was to describe standardized procedures for laboratory husbandry, define conditions for acute toxicity tests, and to provide acute toxicity test results for some reference toxicants. Culturing conditions for the organism in the laboratory were established in reconstituted seawater (30 +/- 2 salinity), 24 +/- 2 degrees C, photoperiod 12/12 h light/dark. Acute toxicity test procedures were developed for 96 h-exposure time, and organisms at ages <7 days. The miniaturized version of the test, based on 96-well microplates and 200 uL of exposure media provided consistent results compared to larger exposure volumes (80-mL vials protocol). Acute toxicity of Ag, Cd, Cu, Zn and ammonia determined for P. hawaiensis were consistent to previous results for other marine amphipods. We conclude that P. hawaiensis can be successfully cultured in standardized conditions and be effectively used in acute toxicity testing. Further development and use of this model will enable standardized and reproducible ecotoxicology investigations in understudied and vulnerable tropical marine ecosystems. PMID- 29138972 TI - Stable isotope labeling and 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D glucopyranoside biosynthetic pathway characterization in Fallopia multiflora. AB - MAIN CONCLUSION: The THSG biosynthetic pathway in F. multiflora was characterized, and enzymatic activities responsible for the resveratrol synthesis, hydroxylation, and glycosylation reactions involved in THSG biosynthesis were confirmed in vitro. The biosynthetic origin of 2,3,5,4' tetrahydroxystilbene-2-O-beta-D-glucopyranoside (THSG) and the enzymes involved in THSG biosynthesis in Fallopia multiflora were studied using stable isotope labeling and biocatalytic methods. UPLC-MS-based analyses were used to unravel the isotopologue composition of the biosynthetic intermediates and products, as well as to detect the products of the enzyme assay experiments. In this study, 13C-labeled L-phenylalanine (L-PHE), sodium pyruvate (SP), and sodium bicarbonate (SB) were used as putative precursors in the feeding experiment. Labeling of polydatin (PD) and THSG using [13C9]L-PHE and [13C1]L-PHE confirmed that the p coumaric moiety of PD and THSG was derived from PHE. The results of the feeding experiments with [13C] SB and [2, 3-13C2] SP suggested that PD and THSG were derivatives of resveratrol that were synthesized by glycosylation and hydroxylation. We developed methods using total crude protein extracts (soluble and microsomal) for comprehensive and simultaneous analysis of resveratrol synthase, glycosyltransferase, and hydroxylase activities in various tissue types of wild F. multiflora and callus cultures. The activity of each tested enzyme was confirmed in one or more tissue types or cell cultures in vitro. The results of the enzyme activity experiments and the distributions of PD and THSG were used to determine the main site and pathway of THSG biosynthesis in F. multiflora. PMID- 29138973 TI - Surgical ligation of spinal dural arteriovenous fistula. AB - BACKGROUND: Spinal dural arteriovenous fistulas (SDAVFs) are abnormal arteriovenous shunts between a radicular artery and the radicular vein, located in the dorsal surface of the dura sleeve, which drains in a retrograde manner into the coronal venous plexus of the spinal cord without an interposed capillary network. This result is a venous hypertension that reduces spinal cord perfusion and leads to ischemia and edema. Spontaneous resolution is extremely rare and, once symptomatic, the typical course is further progression with increased neurological impairment. Therefore, once a fistula is diagnosed, treatment is recommended. METHOD: The fistula is placed at the level of intervertebral foramen and surgical ligation is performed through a laminectomy. After dural opening, the area is inspected, and the arterialized vein is identified and ligated. CONCLUSIONS: Laminectomy and arteriovenous fistula ligation is a safe and reliable approach for accessing and treating spinal dural arteriovenous fistulas. PMID- 29138971 TI - Carbon source-sink relationship in Arabidopsis thaliana: the role of sucrose transporters. AB - MAIN CONCLUSION: The regulation of source-to-sink sucrose transport is associated with AtSUC and AtSWEET sucrose transporters' gene expression changes in plants grown hydroponically under different physiological conditions. Source-to-sink transport of sucrose is one of the major determinants of plant growth. Whole plant carbohydrates' partitioning requires the specific activity of membrane sugar transporters. In Arabidopsis thaliana plants, two families of transporters are involved in sucrose transport: AtSUCs and AtSWEETs. This study is focused on the comparison of sucrose transporter gene expression, soluble sugar and starch levels and long distance sucrose transport, in leaves and sink organs (mainly roots) in different physiological conditions (along the plant life cycle, during a diel cycle, and during an osmotic stress) in plants grown hydroponically. In leaves, the AtSUC2, AtSWEET11, and 12 genes known to be involved in phloem loading were highly expressed when sucrose export was high and reduced during osmotic stress. In roots, AtSUC1 was highly expressed and its expression profile in the different conditions tested suggests that it may play a role in sucrose unloading in roots and in root growth. The SWEET transporter genes AtSWEET12, 13, and 15 were found expressed in all organs at all stages studied, while differential expression was noticed for AtSWEET14 in roots, stems, and siliques and AtSWEET9, 10 expressions were only detected in stems and siliques. A role for these transporters in carbohydrate partitioning in different source-sink status is proposed, with a specific attention on carbon demand in roots. During development, despite trophic competition with others sinks, roots remained a significant sink, but during osmotic stress, the amount of translocated [U-14C] sucrose decreased for rosettes and roots. Altogether, these results suggest that source-sink relationship may be linked with the regulation of sucrose transporter gene expression. PMID- 29138974 TI - Medical complications and mortality in octogenarians undergoing elective spinal fusion surgeries. AB - BACKGROUND: The consequences of suffering postoperative complications in elderly undergoing spinal surgeries may be different compared to younger patients. The primary objective of this study was to identify the types and frequency of medical complications and mortality rates in patients 80 years of age or older undergoing elective spinal fusion surgeries for degenerative spinal disease. METHODS: A prospective observational study with a retrospective chart review was performed, which included all consecutive patients >=80 years old undergoing elective spinal fusion surgeries from May 2012 to August 2015. We identified a total of 95 patients, of which 39 cervical and 56 lumbar surgeries were performed. There were 41 female and 54 male patients with the mean age of 82.8 years (range, 80-91). The perioperative complications were allocated into the following categories: infection, pulmonary, cardiac, gastrointestinal, hematologic, urologic, neurovascular, thromboembolic, and other. Baseline and postoperative clinical outcome scores were compared to evaluate efficacy. RESULTS: The mean follow-up time was 14.8 months (range, 5 days to 37 months) with an overall mortality rate of 8.4%. The 30-day, 90-day, and 1-year mortality rates were 2.1, 2.1, and 4.2%, respectively. There were 53.9 and 71.4% patients with complications in the cervical and lumbar patient groups, respectively. The presence of general comorbidities and the number of intervertebral levels predicted the occurrence of perioperative complications. Also, longer OR times were associated with a higher number of complications per patient and the occurrence of a UTI. Dysphagia was a significant predictor in developing pneumonia and atelectasis. CONCLUSIONS: The incidence of perioperative medical complications and mortality rates in octogenarians undergoing elective spinal surgeries are quite high. The benefits of having surgery must be weighed against the risks of not only surgical but also adverse medical events. An informed decision-making process should include discussion of potential postoperative morbidity specific to this patient population in order to guide patient's acceptance of higher risks and expectations postoperatively. It is also important to identify potential complications and adapt preventive measures in order to help minimize them in this patient population. PMID- 29138975 TI - Distal transsylvian keyhole approach for unruptured anterior circulation small aneurysms. AB - BACKGROUND: To reduce complications associated with conventional pterional craniotomy, a transsylvian keyhole approach for unruptured small anterior circulation aneurysms is proposed. METHODS: A 7-cm linear scalp incision is made along the hairline, beginning at the zygoma, followed by minimal temporal muscle dissection. Two burr holes are drilled out at McCarty's point and the temporal bone, and a 3-cm equilateral triangle bone flap is made, whose apex is located above the sylvian point. After the sphenoid ridge is drilled off, aneurysms are exposed and clipped with conventional microsurgical instruments. CONCLUSIONS: This approach permits access to aneurysms via the transsylvian corridor with a smaller area of potential injury of superficial structures. PMID- 29138976 TI - [Eyeball perforation of a 7-year-old girl caused by the "Must-Have Office Toy 2017" : The potential risk of injury by a spinning toy (fidget spinner)]. AB - A 7-year-old girl presented to the emergency department of the eye clinic with an eyeball perforation with iris prolapse and corneal as well as scleral wounds of the left eye caused by a spinning toy (fidget spinner). A surgical wound inspection with iris reposition and corneal and scleral suture were performed without delay. This case report demonstrates the potential risk of this popular toy. PMID- 29138977 TI - [Reasons for delayed and discontinued therapy in age-related macular degeneration]. AB - BACKGROUND: Critical prerequisites for successful therapy of neovascular age related macular degeneration (nvAMD) are an early initiation and continuous monitoring; however, delays in starting therapy and non-medically indicated discontinuation of therapy are frequent, which limits therapy efficacy and, thus, visual outcomes. OBJECTIVE: To identify the reasons for delay in therapy and non medically indicated termination of therapy. MATERIAL AND METHODS: Patients who had started a new therapy (starters) and those who independently terminated therapy (dropouts) were interviewed by telephone with a specific, standardized questionnaire. Results were summarized descriptively. RESULTS: A total of 100 starters and 55 dropouts were interviewed. The mean therapy delay was 22 (+/-28 SD) days. This was mainly due to the time until the decision to see an ophthalmologist was made. Main reasons for dropping out were: transportation issues (27%), poor general health (25%) and the assumption that there is no benefit from therapy (11%). Of the patients who dropped out 63% would have liked to continue therapy. CONCLUSION: There is potential for improvement in nvAMD management regarding therapy start as well as therapy maintenance. Sensitizing for initial nvAMD symptoms is important as is reduction of barriers to therapy maintenance, since most therapy dropouts would like to continue the therapy. PMID- 29138978 TI - [Morphology of the vitreoretinal interface in fellow eyes of patients with full thickness macular holes]. AB - PURPOSE: We performed a retrospective, observational clinical study to evaluate the vitreoretinal interface (VRI) in fellow eyes of patients with full thickness macular holes (FTMH) based on spectral domain optical coherence tomography (SD OCT) examinations. METHODS: The VRI in fellow eyes of 38 patients with idiopathic FTMH, 6 of which had concomitant vitreomacular traction (VMT) and the VRI of 32 patients with FTMH with complete resolution of VMT were examined by SD-OCT for the presence of vitreomacular adhesion (VMA), VMT and the formation of FTMH, lamellar macular holes (LMH), macular pseudoholes (MPH) or epiretinal membranes (ERM). Patients underwent complete ophthalmic evaluation, including SD-OCT at baseline and follow-up visits. To classify the morphology of the VRI, we used the international vitreomacular traction study classification system by Duker et al. (Ophthalmology 2013), evaluating the baseline SD-OCT data for significant classification parameters, including size of VMA, macular thickness and volume and structural changes of retinal layers. RESULTS: Of the 38 eyes with FTMH, 2 (5.3%) fellow eyes also showed evidence of FTMH, 5 (13.2%) had isolated VMT while 5 (13.2%) showed formation of ERM, of which 2 demonstrated MPH. In 5 patients (13.2%) showing evidence of VMA and 17 patients (44.7%) with an unremarkable VRI, 22 fellow eyes (57.9%) showed no pathological morphology. Altogether, 16 fellow eyes (42.1%) of patients with FTMH showed pathological changes of the vitreoretinal interface. CONCLUSION: This high-resolution SD-OCT-based retrospective study showed that fellow eyes of patients with VMT or FTMH were at increased risk of demonstrating pathological changes in the morphology of the VRI. PMID- 29138979 TI - Autoantibodies binding to stathmin-4: new marker for polyneuropathy in primary Sjogren's syndrome. PMID- 29138980 TI - CD28neg. T lymphocytes of a melanoma patient harbor tumor immunity and a high frequency of germline-encoded and public TCRs. AB - Increased numbers of CD8+CD28neg. T cells have been detected in the peripheral blood of patients with several types of malignancies. However, the role of these cells in anticancer immunity are not yet clear and CD8+CD28neg. T cells are a controversially discussed subpopulation reported both as immunosuppressive and cytotoxic. In this study, we examined the T cell receptor (TCR) repertoire and complementarity-determining region 3 sequences of CD28neg. T cells in a melanoma patient with recurrent disease who achieved long-term disease-free status. As a result, the patient's oligoclonal CD8+CD28neg. T cell compartment holds TCRs that are public and specific for Melan-A as well as several public TCRs reported for common viral antigens. While over 80% of his CD8+CD28neg. T cells expressed a cytotoxicity marker, CD57, only 0.01% of CD8+ CD28neg. T cells were positive for Foxp3. In conclusion, our results demonstrate that besides virus-specific also tumor-associated self-antigen targeting T cells accumulate in the CD28neg. compartment of the immunological memory. Since the patient is in ongoing complete remission for more than 9 years, CD8+CD28neg. T cells with the Melan-A-specific TCR might contribute to antitumor immunity in this patient. PMID- 29138981 TI - Young Men Who Have Sex with Men at High Risk for HIV, Bangkok MSM Cohort Study, Thailand 2006-2014. AB - High HIV incidence has been reported in young men who have sex with men (YMSM) in North America and Western Europe, but there are limited data from Southeast Asia suggesting MSM may be the driver of the HIV epidemic in this region. We described HIV incidence and risk factors among 494 YMSM enrolled in a cohort study in Bangkok, Thailand. The HIV incidence was 7.4 per 100 person-years. In multivariable analysis, reporting use of an erectile dysfunction drug in combination with club drugs, having receptive or both insertive and receptive anal intercourse with men, having hepatitis A infection, having rectal Chlamydia trachomatis, having hepatitis B infection prior to HIV seroconversion, and reporting not always using condoms with male steady partners were significantly associated with HIV incidence in YMSM. Reduction in new HIV infections in YMSM are critical to reach targets set by Thailand and the region. PMID- 29138982 TI - Characterizing the HIV Prevention and Care Continua in a Sample of Transgender Youth in the U.S. AB - In the U.S., transgender and other gender minority (TG) youth are an at-risk group understudied in HIV prevention and treatment. This study sought to characterize the HIV prevention and care continua in a diverse sample of 181 sexually-active TG ages 16-24 years (mean age = 20.7 years; 76.8% trans feminine; 69.1% youth of color) recruited July-December 2015 in 14 U.S. cities. Overall, 30.9% reported living with HIV, of which 71.4% were on antiretroviral therapy (ART) and 55.0% were medication adherent; 65.6% were known to be virally suppressed. In multivariable models, medical gender affirmation was associated with lower odds of viral suppression. Medical gender affirmation and stigma in HIV care were each independently associated with elevated odds of having missed HIV care appointments. Among at-risk TG youth not living with HIV, only 8.2% had accessed pre-exposure prophylaxis (PrEP). Early biobehavioral prevention and treatment interventions are needed for TG youth. PMID- 29138983 TI - Cloning, Expression Analysis and Enzyme Activity Assays of the alpha-Carbonic Anhydrase Gene from Chlamydomonas sp. ICE-L. AB - The alpha-carbonic anhydrase (alpha-CA) is a zinc ion-containing enzyme that catalyzes the hydration of carbon dioxide. In this paper, a full-length alpha-CA gene was cloned from Chlamydomonas sp. ICE-L using RT-PCR and RACE-PCR for bioinformatic analysis. The alpha-CA open reading frame obtained by PCR was cloned into a vector and transformed into Escherichia coli to generate alpha-CA producing bacteria. The alpha-CA was highly expressed upon induction with isopropyl-beta-d-thiogalactoside (IPTG) at a final concentration of 0.8 mM. A single band with a molecular weight of approximate 40 kDa expressed in the recombinant E. coli strain harboring the alpha-CA vector was observed in SDS-PAGE analysis. The carbon dioxide hydration activity and esterase activity of alpha-CA expressed by the recombinant strain were 0.404 U/mg and 0.319 U, respectively. In addition, three conditions, temperature, salinity and UVB radiation exposure, were selected to analyze alpha-CA transcription levels by qRT-PCR. The results suggested UVB exposure increased the expression of relative mRNA; meanwhile, the alpha-CA mRNA expression was rapidly induced by temperature and salinity stress, indicating that Chlamydomonas sp. ICE-L might modulate the alpha-CA mRNA expression to adapt to the extreme environments. PMID- 29138985 TI - Effects of microRNA-708 on Epithelial-Mesenchymal Transition, Cell Proliferation and Apoptosis in Melanoma Cells by Targeting LEF1 through the Wnt Signaling Pathway. AB - This study was conducted in order to elucidate the role microRNA-708 (miR-708) plays between proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) involving melanoma cells by targeting using LEF1 through the Wnt signaling pathway. Male Kunming mice were selected and subsequently divided into normal and model groups to take part in this study. Following cell line selection, the B16 cells with the highest miR-708 expression were selected and assigned into the control, blank, negative control (NC), miR-708 mimic, miR-708 inhibitor, siRNA-LEF1, and miR-708 inhibitor + siRNA-LEF1 groups. A Bioinformatics Web service and dual-luciferase reporter assay were conducted in order to determine the relationship between LEF1 and miR-708. The RT-qPCR method was performed in order to detect the miR-708 expression and mRNA expressions of LEF1, beta-catenin, Wnt3a, N-cadherin, Bcl-2, Bax, Caspase3, E-cadherin, and western blotting was used in order to detect the protein expressions of these genes. MTT assay, scratch test, Transwell assay, and flow cytometry were all conducted in order to detect the cell proliferation, migration, invasion, and cycle/apoptosis, respectively. LEF1 was verified as the target gene of miR-708. In comparison with the normal group, the model group had reduced expressions of miR-708, Bax, Caspase3, and E-cadherin, while showing elevated expressions of LEF1, beta-catenin, Bcl-2, Wnt3a, and N-cadherin. In comparison to the blank and control groups, the miR-708, mimic, and siRNA-LEF1 groups had elevated expressions of Bax, Caspase3, and E-cadherin, while also showing enhanced cell apoptosis. The miR-708, mimic, and siRNA-LEF1 groups also had decreased expressions of LEF1, beta-catenin, Bcl-2, Wnt3a, and N-cadherin, and reduced optical density value 48 h and 72 h after transfection. Besides, these two groups showed declined cell migration and invasion, as well as lengthened G0/G1 phase (increased cell number) and shortened S phase (decreased cell number). Our findings demonstrated that an overexpressed miR-708 inhibits the proliferation, invasion, migration, and EMT, but also promotes the apoptosis of melanoma cells by targeting LEF1 through the suppression of the Wnt signaling pathway. PMID- 29138984 TI - 11beta-Hydroxysteroid Dehydrogenases and Hypertension in the Metabolic Syndrome. AB - The metabolic syndrome describes a clustering of risk factors-visceral obesity, dyslipidaemia, insulin resistance, and salt-sensitive hypertension-that increases mortality related to cardiovascular disease, type 2 diabetes, cancer, and non alcoholic fatty liver disease. The prevalence of these concurrent comorbidities is ~ 25-30% worldwide, and metabolic syndrome therefore presents a significant global public health burden. Evidence from clinical and preclinical studies indicates that glucocorticoid excess is a key causal feature of metabolic syndrome. This is not increased systemic in circulating cortisol, rather increased bioavailability of active glucocorticoids within tissues. This review examines the role of covert glucocorticoid excess on the hypertension of the metabolic syndrome. Here, the role of the 11beta-hydroxysteroid dehydrogenase enzymes, which exert intracrine and paracrine control over glucocorticoid signalling, is examined. 11betaHSD1 amplifies glucocorticoid action in cells and contributes to hypertension through direct and indirect effects on the kidney and vasculature. The deactivation of glucocorticoid by 11betaHSD2 controls ligand access to glucocorticoid and mineralocorticoid receptors: loss of function promotes salt retention and hypertension. As for hypertension in general, high blood pressure in the metabolic syndrome reflects a complex interaction between multiple systems. The clear association between high dietary salt, glucocorticoid production, and metabolic disorders has major relevance for human health and warrants systematic evaluation. PMID- 29138986 TI - Secukinumab in Active Rheumatoid Arthritis after Anti-TNFalpha Therapy: A Randomized, Double-Blind Placebo-Controlled Phase 3 Study. AB - INTRODUCTION: 'REASSURE' (NCT01377012), a phase 3 study, evaluated the efficacy and safety of secukinumab in patients with active rheumatoid arthritis (RA) who had an inadequate response to, or intolerance of, tumor necrosis factor inhibitors (TNF-inhibitors). METHODS: A total of 637 patients were randomized (1:1:1) to receive intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous secukinumab 150 mg or 75 mg every 4 weeks (starting from week 8) or placebo at the same dosing schedule. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) at week 24. Other predefined hierarchical endpoints included Health Assessment Questionnaire Disability Index, van der Heijde modified total Sharp score (vdH-mTSS) at week 24, and major clinical response (MCR; continuous 6 month period of ACR70 response) at 1 year. RESULTS: The primary efficacy endpoint was met with both secukinumab dose groups: ACR20 response rate at week 24 was 35.2% for both secukinumab dose groups (P = 0.0009) vs 19.6% for placebo. The improvements in secondary endpoints were greater in the secukinumab dose groups vs placebo but did not meet statistical significance. The overall safety profile was similar across all treatment groups. CONCLUSION: Secukinumab demonstrated efficacy in reducing disease activity over placebo as measured by ACR20 in patients with active RA who had an inadequate response to TNF-inhibitors. Secukinumab demonstrated a safety profile similar to other biologics currently approved for RA. FUNDING: Novartis Pharma AG. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01377012. PMID- 29138987 TI - Optimized Ciclopirox-Based Eudragit RLPO Nail Lacquer: Effect of Endopeptidase Enzyme as Permeation Enhancer on Transungual Drug Delivery and Efficiency Against Onychomycosis. AB - The aims of our investigation were to develop and optimize ciclopirox (CPX) nail lacquer using nonbiodegradable Eudragit RLPO (E-RLPO) as a film former and to assess its penetration efficiency across the human nail plate. Preliminary trials such as hydration enhancement factor (HEF), a retained drug in the nail plate, and SEM were studied to select the optimized permeation enhancer to be incorporated in the optimized lacquer formulation. A 33 full factorial design was built up to study the effect of three different factors, concentration of E-RLPO (10, 20, and 30%), Tween 80 (0.25, 0.5, and 1%), and triacetin (0, 10, and 30% of polymer weight). The studied responses were the drying time, water resistance, viscosity, and drug release up to 4 h. An ex vivo permeation study for the optimized formulations was carried out. The preliminary study aided the selection of 5% papain (endopeptidase enzyme) as a penetration enhancer; it showed the highest HEF of 15.27%, the highest amount of drug retained in the nail plate (886.2 MUg/g). An ex vivo permeation study guided the selection of F4B (flux value of 3.79 MUg/cm2/h) as optimized formulation. The optimized lacquer formula showed threefold increases in the permeation than the marketed CPX lacquer (Batrafen(r)). Confocal laser scanning microscopy revealed the higher intensity of the Rhodamine B dye across the nail plate in the case of the formula containing papain than the marketed formula without papain. Conclusively, an efficient and stable nail lacquer was developed for potential transungual delivery of CPX to target the drug to the nail bed and ensure efficiency against onychomycosis. PMID- 29138988 TI - Irreversible electroporation of the uterine cervix in a rabbit model. AB - The aim of this study was to evaluate the effects of irreversible electroporation (IRE) on the uterine cervix in a rabbit model. IRE ablation was performed in the cervices of 48 New Zealand rabbits, with one ablation lesion in each animal. Gross pathology, transmission electron microscopy, hematoxylin and eosin (H&E), Masson's trichrome (MT) stain, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed at pre-set time points (0 h, 12 h, 1 d, 2 d, 4 d, 7 d, 14 d, and 28 d post-IRE). All the rabbits tolerated the IRE ablation without serious complications. IRE caused complete cell death of the ablated cervix via cell apoptosis. However, fast recovery of the cervix was observed from 7 d post-IRE, with the signs of collagen fibers hyperplasia, the disappearance of the necrotic cells and muscle fibers, and regeneration and extension of the cervical epithelium. At 28 d post-IRE, the ablated cervices recovered to almost normal. Our study suggested that IRE might be an efficient and safe technology to treat cervical tumors, without causing serious cervical damage. PMID- 29138989 TI - Sexual function and sex hormones in breast cancer patients. AB - PURPOSE: Breast cancer patients (BCP) are at risk of female sexual dysfunction (FSD). Our aim was to clarify the effects of treatment strategies, and steroid hormones levels on FSD. METHODS: We enrolled 136 BCP (46.9 +/- 0.8 years), and 122 completed questionnaires. BCP were divided into four groups: 22 women with advanced breast cancer on neoadjuvant therapy (NAT), 48 on adjuvant therapy (AT), 30 taking hormonal therapy (HT) and 22 with metastatic cancer on first line chemotherapy (FLT). Fifty-eight healthy women (43 +/- 2.8 years) were enrolled as controls. FSD was evaluated by FSFI, and sexual distress was assessed with FSDS R. We have collected demographic data, laboratory values, and LH, FSH, total testosterone (T), and estradiol (E2) levels. RESULTS: BCP showed a prevalence of FSD of 69%, total FSFI score was 17. FSDS-R was 8.3. FSD had a prevalence of 72 % in NAT, 65% in AT, 77% in metastatic BCP under FLT, 67% in HT, compared with a prevalence of 20% in controls. BCP showed lower E2 than normal values, as well as T. LH and FSH were significantly elevated than normal values. Total FSFI score was positively correlated with T in 122 BCP, no significant correlation was found between E2 and FSFI. Significant differences were found between NAT and HT in lubrication, pain domains and total FSDS-R score, AT and HT in pain domain, AT and NAT in lubrication domain. CONCLUSIONS: BCP are at high risk of developing FSD both for treatment choice and hormonal status, but they have not sexually related personal distress. PMID- 29138990 TI - Non-IgE-mediated Adverse Food Reactions. AB - PURPOSE OF REVIEW: The purpose of this review is to update what is currently known about the major non-IgE-mediated food allergies: food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). These conditions are similar in that symptoms are regulated to the gastrointestinal tract; therefore understanding their specific features is important for diagnosis and management. RECENT FINDINGS: The most progress has been made in understanding FPIES with several recent large cohorts being described. The first international consensus guidelines for FPIES were published in 2017 and propose specific diagnostic criteria for acute FPIES as well as guidance for diagnosing chronic FPIES. Recent studies in FPIAP have challenged our thinking about the recommended duration of food avoidance and that cow's milk avoidance is the primary management with reports of self-resolution without dietary management. FPE continues to appear to be on the decline. FPIES, FPIAP, and FPE are distinguished from one another by their main clinical features: delayed repetitive vomiting in FPIES, benign blood in stool in FPIAP, and chronic diarrhea in FPE. Due to the risk of nutritional deficiencies with food avoidance in both infant and maternal diets if breastfeeding, confirmation of diagnosis with challenges is encouraged. Additional studies are needed for these conditions to elucidate pathophysiology, search for diagnostic markers, and understand natural history. PMID- 29138992 TI - Use of Ketamine in Elderly Patients with Treatment-Resistant Depression. AB - PURPOSE OF REVIEW: The purpose of this paper is to provide a review of the use of ketamine as an antidepressant for treatment-resistant depression (TRD) in the geriatric population. Available treatment options for late-life treatment resistant depression are limited and include electroconvulsive therapy and transcranial magnetic stimulation as well as possible pharmacologic augmentation. Ketamine has been shown to be a promising treatment in TRD; however, data regarding the use of ketamine in the elderly includes only five case reports. RECENT FINDINGS: We discuss the use of ketamine for late-life TRD and present two cases where ketamine led to a significant and sustained improvement in depressive symptoms. Ketamine is a promising treatment for geriatric patients with TRD. Further studies in the elderly will provide valuable insights into the use of ketamine for a population much in need of safe and effective treatments for TRD. PMID- 29138991 TI - Test-Retest Reliability and Interpretation of Common Concussion Assessment Tools: Findings from the NCAA-DoD CARE Consortium. AB - BACKGROUND: Concussion diagnosis is typically made through clinical examination and supported by performance on clinical assessment tools. Performance on commonly implemented and emerging assessment tools is known to vary between administrations, in the absence of concussion. OBJECTIVE: To evaluate the test retest reliability of commonly implemented and emerging concussion assessment tools across a large nationally representative sample of student-athletes. METHODS: Participants (n = 4874) from the Concussion Assessment, Research, and Education Consortium completed annual baseline assessments on two or three occasions. Each assessment included measures of self-reported concussion symptoms, motor control, brief and extended neurocognitive function, reaction time, oculomotor/oculovestibular function, and quality of life. Consistency between years 1 and 2 and 1 and 3 were estimated using intraclass correlation coefficients or Kappa and effect sizes (Cohen's d). Clinical interpretation guidelines were also generated using confidence intervals to account for non normally distributed data. RESULTS: Reliability for the self-reported concussion symptoms, motor control, and brief and extended neurocognitive assessments from year 1 to 2 ranged from 0.30 to 0.72 while effect sizes ranged from 0.01 to 0.28 (i.e., small). The reliability for these same measures ranged from 0.34 to 0.66 for the year 1-3 interval with effect sizes ranging from 0.05 to 0.42 (i.e., small to less than medium). The year 1-2 reliability for the reaction time, oculomotor/oculovestibular function, and quality-of-life measures ranged from 0.28 to 0.74 with effect sizes from 0.01 to 0.38 (i.e., small to less than medium effects). CONCLUSIONS: This investigation noted less than optimal reliability for most common and emerging concussion assessment tools. Despite this finding, their use is still necessitated by the absence of a gold standard diagnostic measure, with the ultimate goal of developing more refined and sound tools for clinical use. Clinical interpretation guidelines are provided for the clinician to apply with a degree of certainty in application. PMID- 29138993 TI - Adverse Drug Events and Medication Errors in African Hospitals: A Systematic Review. AB - BACKGROUND: Medication errors and adverse drug events are universal problems contributing to patient harm but the magnitude of these problems in Africa remains unclear. OBJECTIVE: The objective of this study was to systematically investigate the literature on the extent of medication errors and adverse drug events, and the factors contributing to medication errors in African hospitals. METHODS: We searched PubMed, MEDLINE, EMBASE, Web of Science and Global Health databases from inception to 31 August, 2017 and hand searched the reference lists of included studies. Original research studies of any design published in English that investigated adverse drug events and/or medication errors in any patient population in the hospital setting in Africa were included. Descriptive statistics including median and interquartile range were presented. RESULTS: Fifty-one studies were included; of these, 33 focused on medication errors, 15 on adverse drug events, and three studies focused on medication errors and adverse drug events. These studies were conducted in nine (of the 54) African countries. In any patient population, the median (interquartile range) percentage of patients reported to have experienced any suspected adverse drug event at hospital admission was 8.4% (4.5-20.1%), while adverse drug events causing admission were reported in 2.8% (0.7-6.4%) of patients but it was reported that a median of 43.5% (20.0-47.0%) of the adverse drug events were deemed preventable. Similarly, the median mortality rate attributed to adverse drug events was reported to be 0.1% (interquartile range 0.0-0.3%). The most commonly reported types of medication errors were prescribing errors, occurring in a median of 57.4% (interquartile range 22.8-72.8%) of all prescriptions and a median of 15.5% (interquartile range 7.5-50.6%) of the prescriptions evaluated had dosing problems. Major contributing factors for medication errors reported in these studies were individual practitioner factors (e.g. fatigue and inadequate knowledge/training) and environmental factors, such as workplace distraction and high workload. CONCLUSION: Medication errors in the African healthcare setting are relatively common, and the impact of adverse drug events is substantial but many are preventable. This review supports the design and implementation of preventative strategies targeting the most likely contributing factors. PMID- 29138994 TI - Molecular characterization and recombination analysis of porcine reproductive and respiratory syndrome virus emerged in southwestern China during 2012-2016. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an important swine pathogen causing tremendous economic losses to the swine industry. To investigate the prevalence of PRRSV of genotype 2 (North American type, NA-type) in southwestern China, the Nsp2 hypervariable region (Nsp2 HV) and ORF5 of 61 PRRS viruses collected during 2012-2016 were sequenced and analyzed. All the virus detected clustered into the JXA1-like (52/61), VR-2332-like (7/61), and NADC30 like (2/61) sub-genotypes. Five deletions in Nsp2 HV were detected in addition to the typical 30aa discontinuous deletion in HP-PRRSV, and two of these five were not reported previously. Strikingly, two PRRS virus (SCnj16 and SCcd16) isolated in 2016 contained the classic HP-PRRSV molecular marker in the Nsp2-coding region, but belonged to the NADC30-like sub-genotype on the ORF5 gene. Further recombination and phylogenetic analysis on the two complete genomic sequences revealed that they may have originated from recombination events between the NADC30 and Chinese HP-PRRSV strains. The present study suggests that the endemic PRRSVs in the region have continuously evolved and new vaccine strategies are necessary for more efficient control of the virus. PMID- 29138995 TI - Optimization of chromium and tannic acid bioremediation by Aspergillus niveus using Plackett-Burman design and response surface methodology. AB - A chromium and tannic acid resistance fungal strain was isolated from tannery effluent, and identified as Aspergillus niveus MCC 1318 based on its rDNA gene sequence. The MIC (minimum inhibitory concentration) of the isolate against chromium and tannic acid was found to be 200 ppm and 5% respectively. Optimization of physiochemical parameters for biosorption of chromium and tannic acid degradation was carried out by Plackett-Burman design followed by response surface methodology (RSM). The maximum chromium removal and tannic acid degradation was found to be 92 and 68% respectively by A. niveus. Chromium removal and tannic acid degradation was increased up to 11 and 6% respectively after optimization. Scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) was used to investigate biosorption phenomena. PMID- 29138996 TI - Ichthyosiform Pityriasis Rubra Pilaris-Like Eruption Secondary to Ponatinib Therapy: Case Report and Literature Review. AB - Tyrosine kinase inhibitors have revolutionized the chemotherapy arena as targeted therapies for a multitude of malignancies. They are more selective than conventional chemotherapy, and often elicit fewer systemic adverse events, however toxicities still exist. Cutaneous toxicities are common and their management presents a novel challenge to physicians and patients. Ponatinib is a third-generation tyrosine kinase inhibitor increasingly reported to cause cutaneous eruption. A 50-year-old woman with a history of chronic myelogenous leukemia presented with a 4-month history of worsening atrophic and ichthyosiform pink plaques involving the axillae, thighs and abdomen; red patches were also observed on the cheeks and forehead. She was started on the third-generation, ponatinib, 5 months earlier because of disease refractory to previous therapies including interferon, imatinib, dasatinib and bosutinib. A skin biopsy revealed perifollicular fibrosis, alternating orthokeratosis and parakeratosis, and a sparse perivascular lymphocytic infiltrate consistent with a pityriasis rubra pilaris-like reaction. Topical tretinoin 0.025% cream was initiated, resulting in resolution within 3 weeks without discontinuation of ponatinib. A review of previous reports identified significant similarities among the ponatinib-induced drug reactions. Here, we highlight not only that cutaneous eruptions occur on ponatinib therapy, but that the dermatologic manifestations are characteristic and unique, and benefit from retinoid therapy, without requiring interruption of vital chemotherapy. PMID- 29138997 TI - Syncopedia: training a new generation of syncope specialists. PMID- 29138998 TI - Crafting socialist embryology: dialectics, aquaculture and the diverging discipline in Maoist China, 1950-1965. AB - In the 1950s, embryology in socialist China underwent a series of changes that adjusted the disciplinary apparatus to suit socialism and the national goal of self-reliance. As the Communist state called on scientists to learn from the Soviets, embryologists' comprehensive view on heredity, which did not contradict Trofim Lysenko (1898-1976)'s doctrines, provided a space for them to advance their discipline. Leading scientists, often trained abroad in the tradition of experimental embryology, rode on the tides of Maoist ideology and repositioned their research. Some of their creative realignment of previous research questions, materials, and traditions to Marxist philosophy and agricultural objectives generated productive programs. In particular, Tong Dizhou (1902-1979) translated Engels's dialectics of nature into a research question about cytoplasmic inheritance. His continuing investigation on it led to the first goldfish "clone" through a nuclear transplantation experiment; Zhu Xi and his associates transferred a goldfish model in embryology into studies on improving carp aquaculture, leading to a rare success in the Great Leap Forward of 1958. These directions for embryology continued well into the 1960s. At a time when global embryology was diversifying and began to be molecularized, eventually forming "developmental biology," socialist embryology took shape in China with a different set of epistemic and practical commitments. The history of its development challenges and enriches our understanding of the concrete process of change in one discipline under Mao, showing ways in which scientists creatively adapted state-sanctioned ideologies and visions to do productive work outside the framework of molecular biology during the Cold War. PMID- 29139000 TI - Effect of light polarization on the efficiency of photodynamic therapy of basal cell carcinomas: an in vitro cellular study. AB - In an in vitro study, the effect of light polarization on the efficiency of 5 aminolaevulinic acid (ALA) photodynamic therapy (PDT) of basal cell carcinoma (BCC) was investigated. Three states of light polarization (non-polarized, linearly polarized, and circularly polarized) were considered. Cells were exposed to green (532 pm 20 nm) irradiation from light emitting diodes. Cell survival was measured by the colorimetric assay (WST-1) and Trypan blue staining. The colorimetric assay showed a pronounced decrease in the cell viability (up to 30%) using polarized light compared to the non-polarized one in the wavelength region used. Similar results were obtained by the cell counting method (20-30% increase in cell death). The observed effect was dependent on the concentration of photosensitizer. The effect is more expressed in the case of linearly polarized light compared to the circularly polarized one. Results show that the use of polarized light increases the efficiency of in vitro ALA-PDT of BCC. Utilizing polarized light, it is possible to obtain the same effect from PDT by lower concentrations of photosensitizer. Additionally, the concentration dependency of PDT response and photo-bleaching is also reduced. PMID- 29139001 TI - The Assessment for Disinvestment of Intramuscular Interferon Beta for Relapsing Remitting Multiple Sclerosis in Brazil. AB - In Brazil, inclusion and exclusion of health technologies within the Unified Health System (SUS) is the responsibility of the National Committee for Health Technology Incorporation (CONITEC). A recent Cochrane systematic review demonstrated that intramuscular interferon beta 1a (IFN-beta-1a-IM) was inferior to the other beta interferons (IFN-betas) for multiple sclerosis (MS). As a result, CONITEC commissioned an analysis to review possible disinvestment within SUS. The objective of this paper is to describe the disinvestment process for IFN beta-1a-IM in Brazil. The first assessment comprised a literature review and mixed treatment comparison meta-analysis. The outcome of interest was the proportion of relapse-free patients in 2 years. This analysis confirmed the inferiority of IFN-beta-1a-IM. Following this, CONITEC recommended disinvestment, with the decision sent for public consultation. More than 3000 contributions were made on CONITEC's webpage, most of them against the preliminary decision. As a result, CONITEC commissioned a study to assess the effectiveness of IFN-beta-1a IM among Brazilian patients in routine clinical care. The second assessment involved an 11-year follow-up of a non-concurrent cohort of 12,154 MS patients developed by deterministic-probabilistic linkage of SUS administrative databases. The real-world assessment further demonstrated that IFN-beta-1a-IM users had a statistically higher risk of treatment failure, defined as treatment switching or relapse treatment or death, with the assessment showing that IFN-beta-1a-IM was inferior to the other IFN-betas and to glatiramer acetate in both direct and indirect analysis. In the drug ranking with 40,000 simulations, IFN-beta-1a-IM was the worst option, with a success rate of only 152/40,000. Following this, CONITEC decided to exclude the intramuscular presentation of IFN-beta from the current MS treatment guidelines, giving patients who are currently on this treatment the option of continuing until treatment failure. In conclusion, we believe this is the first example of this new disinvestment process in action, providing an exemplar for other treatments in Brazil as well as other countries. PMID- 29139002 TI - Deinococcus multiflagellatus sp. nov., isolated from a car air-conditioning system. AB - A gamma radiation-resistant and pink-to-red pigmented bacterial strain, designated ID1504T, was isolated from a car air-conditioning system sampled in Korea. The cells were observed to be Gram-stain negative, aerobic, motile with peritrichous flagella and short rod-shaped. Phylogenetically, the strain groups with the members of the genus Deinococcus and exhibits high 16S rRNA gene sequence similarities with Deinococcus arenae SA1T (94.0%), Deinococcus actinosclerus BM2T (93.9%) and Deinococcus soli N5T (93.5%). The predominant fatty acids were identified as C17:0, C16:0, summed feature 3 (C16:1 omega7c and/or C16:1 omega6c) and iso-C17:0. The major respiratory quinone was identified as MK-8. The polar lipids were found to be comprised of unidentified phospholipids, unidentified glycolipids, an unidentified aminophospholipid and an unidentified lipid. The DNA G+C content of the strain was determined to be 68.3 mol%. On the basis of the phenotypic, genotypic and chemotaxonomic characteristics, strain ID1504T should be classified in a novel species in the genus Deinococcus, for which the name Deinococcus multiflagellatus sp. nov. (= KACC 19287T = NBRC 112888T) is proposed. PMID- 29139003 TI - Differential roles for ArcA and ArcB homologues in swarming motility in Serratia marcescens FS14. AB - ArcAB is a two-component regulatory system that can help bacteria respond to and survive in a changing environment. To identify the function of ArcAB homologues in Serratia marcescens FS14, in-frame deletion mutants of the arcA, arcB and arcAB genes were constructed. Surprisingly, ArcB affects the motility of FS14, but ArcA does not. These results are the reverse of those found in Escherichia coli. Further studies demonstrated that ArcB could promote bacterial motility by activating the synthesis of flagella and particularly by activating the expression of the biosurfactant serrawettin W1. Our results suggest that ArcB may regulate FS14 motility by interacting with an unidentified response regulator other than ArcA. The regulation of ArcAB may be bacterial strain-specific, and the same regulatory system may participate in different mechanisms to adapt to different environments. PMID- 29139004 TI - Progressive multifocal leukoencephalopathy in the absence of immunosuppression. AB - A 69-year-old woman presented with a cortical hand syndrome progressing over several weeks. MRI brain showed characteristic appearances of progressive multifocal leukoencephalopathy (PML), confirmed by detection of the JC virus in CSF, despite the absence of any evidence of immunosuppression. Treatment with mirtazapine, mefloquine and cidofovir did not affect the progression of the disease, which was fatal within 7 months of presentation. This report adds to the small case literature that suggests that PML can occur in immunocompetent people, albeit extremely rarely. PMID- 29139006 TI - Correction to: Usefulness of abbreviated breast MRI screening for women with a history of breast cancer surgery. AB - In the original publication of the article, the acknowledgment section was missed out inadvertently. The acknowledgement section is below. PMID- 29139008 TI - Dactylogyrids (Monogenoidea) infecting the gill lamellae of some beloniform fishes from Moreton Bay, Queensland, Australia, with a redescription of Hareocephalus thaisae Young, 1969 and descriptions of six new species of Hemirhamphiculus Bychowsky & Nagibina, 1969. AB - Three species of beloniform fishes were found infected with species of Monogenoidea Bychowsky, 1937 during a survey of the diversity of parasites infecting the fishes of Moreton Bay, Queensland, Australia. The diagnoses of Hareocephalus Young, 1969 and Hemirhamphiculus Bychowsky & Nagibina, 1969 (both Polyonchoinea Bychowsky, 1937: Dactylogyridae Bychowsky, 1933) were emended. Hareocephalus thiasae Young, 1969, type-species of the genus, was recorded and redescribed from the gill lamellae of the stout longtom Tylosurus gavialoides (Castelnau) (Belonidae), and six new species of Hemirhamphiculus were described from the gill lamellae of three host species: Hemirhamphiculus exserocephalus n. sp. from T. gavialoides; Hemirhamphiculus choanophallus n. sp. and Hemirhamphiculus flagrum n. sp. from the river garfish Hyporhamphus regularis (Gunther) (Hemiramphidae); and Hemirhamphiculus perexiguus n. sp., Hemirhamphiculus krabsi n. sp., and Hemirhamphiculus imcomptus n. sp. from the southeastern snub-nose garfish Arrhamphus sclerolepis krefftii (Steindachner) (Hemiramphidae). An unidentified species of the Suborder Microcotylinea Lebedev, 1972 (Heteronchoinea Boeger & Kritsky, 2001) was found infecting single specimens of each of H. regularis and A. sclerolepis krefftii. Parahemirhamphiculus Bychowsky & Nagibina, 1969 is placed in junior subjective synonymy with Hemirhamphiculus, and its three species, Parahemirhamphiculus pinguis Bychowsky & Nagibina, 1969, Parahemirhamphiculus brevilamellatus Zhang, 2001, and Parahemirhamphiculus longilamellatus An & Zhang, 1988 are transferred to Hemirhamphiculus. PMID- 29139007 TI - Adding high-intensity interval training to conventional training modalities: optimizing health-related outcomes during chemotherapy for breast cancer: the OptiTrain randomized controlled trial. AB - PURPOSE: Exercise training is an effective and safe way to counteract cancer related fatigue (CRF) and to improve health-related quality of life (HRQoL). High intensity interval training has proven beneficial for the health of clinical populations. The aim of this randomized controlled trial was to compare the effects of resistance and high-intensity interval training (RT-HIIT), and moderate-intensity aerobic and high-intensity interval training (AT-HIIT) to usual care (UC) in women with breast cancer undergoing chemotherapy. The primary endpoint was CRF and the secondary endpoints were HRQoL and cancer treatment related symptoms. METHODS: Two hundred and forty women planned to undergo chemotherapy were randomized to supervised RT-HIIT, AT-HIIT, or UC. Measurements were performed at baseline and at 16 weeks. Questionnaires included Piper Fatigue Scale, EORTC-QLQ-C30, and Memorial Symptom Assessment Scale. RESULTS: The RT-HIIT group was superior to UC for CRF: total CRF (p = 0.02), behavior/daily life (p = 0.01), and sensory/physical (p = 0.03) CRF. Role functioning significantly improved while cognitive functioning was unchanged for RT-HIIT compared to declines shown in the UC group (p = 0.04). AT-HIIT significantly improved emotional functioning versus UC (p = 0.01) and was superior to UC for pain symptoms (p = 0.03). RT-HIIT reported a reduced symptom burden, while AT-HIIT remained stable compared to deteriorations shown by UC (p < 0.01). Only RT-HIIT was superior to UC for total symptoms (p < 0.01). CONCLUSIONS: 16 weeks of resistance and HIIT was effective in preventing increases in CRF and in reducing symptom burden for patients during chemotherapy for breast cancer. These findings add to a growing body of evidence supporting the inclusion of structured exercise prescriptions, including HIIT, as a vital component of cancer rehabilitation. TRIAL REGISTRATION: Clinicaltrials.gov Registration Number: NCT02522260. PMID- 29139009 TI - LFM-A13, a potent inhibitor of polo-like kinase, inhibits breast carcinogenesis by suppressing proliferation activity and inducing apoptosis in breast tumors of mice. AB - The goals of the present study were to define the anticancer activity of LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide), a potent inhibitor of Polo-like kinase (PLK), in a mouse mammary cancer model induced by 7,12-dimethylbenz(a)anthracene (DMBA) in vivo and explore its anticancer mechanism(s). We also examined whether the inhibition of PLK by LFM A13 would improve the efficiency of paclitaxel in breast cancer growth in vivo. To do this, female BALB/c mice received 1 mg of DMBA once a week for 6 weeks with oral gavage. LFM-A13 (50 mg/kg body weight) was administered intraperitoneally with DMBA administration and continued for 25 weeks. We found that LFM-A13, paclitaxel, and their combination have a significant effect on the DMBA-induced breast tumor incidence, mean tumor numbers, average tumor weight, and size. At the molecular level, the administration of LFM-A13 hindered mammary gland carcinoma development by regulating the expression of PLK1, cell cycle-regulating proteins cyclin D1, cyclin dependent kinase-4 (CDK-4), and the CDK inhibitor, p21. Moreover, LFM-A13 treatment upregulated the levels of IkappaB, the pro apoptotic proteins Bax, and caspase-3, and down-regulated p53 and the antiapoptotic protein Bcl-2 in mammary tumors. The combination of LFM-A13 with paclitaxel was found to be more effective compared with either agent alone. Collectively, these results suggest that LFM-A13 has an anti-proliferative activity against breast cancer in vivo and that LFM-A13 and paclitaxel combination could be a strategy for the treatment of breast cancer. PMID- 29139010 TI - Radiobiology and radiotherapy of brain metastases. AB - Brain metastases are the most common intracranial tumors in adults, accounting for more than 50% of all such cases. The approach to and management of brain metastases have evolved significantly in recent years due to several reasons. These include advances in neurosurgical and radiotherapeutic techniques, improved systemic therapy options offering better systemic and intracranial disease control and prolongation of survival as a result of these improvements, making side-effects of proposed therapies (e.g. neurocognitive decline from whole brain radiotherapy) an important consideration. In this article, we review the the primary therapeutic approaches to the management of brain metastases, namely, surgery, stereotactic radiosurgery, and whole brain radiation therapy and the primary factors dictating choice. PMID- 29139011 TI - Curing brain metastases. PMID- 29139012 TI - Psychometric performance of the Romanian version of the SarQoL(r), a health related quality of life questionnaire for sarcopenia. AB - : Our study assessed the psychometric properties of the Romanian SarQoL(r) questionnaire. Normal distribution and high internal consistency were found. Sarcopenic subjects reported a reduced global quality of life compared to non sarcopenics. The Romanian version of the SarQoL(r) questionnaire, conceptually and literally equivalent with the source instrument, is qualified in terms of psychometric properties. PURPOSE/INTRODUCTION: We have recently provided a translated and culturally tailored version of the first quality of life (QoL) questionnaire specific for sarcopenia, the SarQoL(r), in Romanian language. The aim of this study was to assess the psychometric performances of the translated questionnaire. METHODS: A total of 100 volunteers were enrolled in the study. Sarcopenia was diagnosed according to the algorithm proposed by the European Working Group on Sarcopenia in Older People (EWGSOP). To test the psychometric performance, discriminative power, internal consistency, floor and ceiling effects, and construct validity analyses were made. We assessed the correlation between SarQoL(r) and similar/different domains of other two QoL questionnaires. RESULTS: Sarcopenic subjects reported a reduced global QoL compared to non sarcopenic individuals. Significantly (p = 0.018) higher total scores for non sarcopenic subjects compared to those of sarcopenics indicate a good discriminative power of the Romanian questionnaire. Sarcopenic individuals had significantly lower scores in almost all domains. The Cronbach's alpha value of 0.946 indicates a high internal consistency. No floor or ceiling effects were found. A strong positive correlation was also found between similar domain scores from SF-36 and EQ-5D questionnaires with the Total SarQoL(r) score. Moreover, lower scores of quality of life have been shown to be significantly associated with lower muscle strength, in univariate analyses, and lower gait speed, both in univariate and multivariate analyses. CONCLUSIONS: Our results indicate that the Romanian version of the SarQoL(r) questionnaire, qualified in terms of psychometric properties, could be a useful tool to assess the sarcopenia-related QoL among frail Romanian individuals. PMID- 29139013 TI - Engineering Analysis of Tricuspid Annular Dynamics in the Beating Ovine Heart. AB - Functional tricuspid regurgitation is a significant source of morbidity and mortality in the US. Furthermore, treatment of functional tricuspid regurgitation is suboptimal with significant recurrence rates, which may, at least in part, be due to our limited knowledge of the relationship between valvular shape and function. Here we study the dynamics of the healthy in vivo ovine tricuspid annulus to improve our understanding of normal annular deformations throughout the cardiac cycle. To this end, we determine both clinical as well as engineering metrics of in vivo annular dynamics based on sonomicrometry crystals surgically attached to the annulus. We confirm that the tricuspid annulus undergoes large dynamic changes in area, perimeter, height, and eccentricity throughout the cardiac cycle. This deformation may be described as asymmetric in-plane motion of the annulus with minor out-of-plane motion. In addition, we employ strain and curvature to provide mechanistic insight into the origin of this deformation. Specifically, we find that strain and curvature vary considerable across the annulus with highly localized minima and maxima resulting in aforementioned configurational changes throughout the cardiac cycle. It is our hope that these data provide valuable information for clinicians and engineers alike and ultimately help us improve treatment of functional tricuspid regurgitation. PMID- 29139014 TI - The Ictal-Interictal Continuum: To Treat or Not to Treat (and How)? AB - Continuous electroencephalography (cEEG) monitoring is becoming increasingly used in neurologic and non-neurologic intensive care units (ICUs). Non-convulsive seizures (NCSz) and periodic discharges (PDs) are commonly seen in critically ill patients. Some of these PD patterns, also known as the ictal-interictal continuum (IIC), are associated with an increased risk of seizures and poor outcome. However, we do not fully understand the significance of these periodic patterns and the decision of how aggressively to treat remains controversial. IIC patterns are associated with pathophysiologic changes that closely resemble those of seizures. Here we make the argument that, rather than feature description on EEG, associated changes in brain physiology should dictate management choices. PMID- 29139015 TI - Defining the Optimal Midline Shift Threshold to Predict Poor Outcome in Patients with Supratentorial Spontaneous Intracerebral Hemorrhage. AB - BACKGROUND: Midline shift (MLS) has been associated with unfavorable outcome in patients with intracerebral hemorrhage (ICH). However, the optimal criteria to define the MLS measurements that indicate future outcome in ICH patients are absent, and the quantitative threshold of MLS that differentiates favorable and poor clinical outcome should be further explored. METHODS: We enrolled patients with ICH who underwent admission computed tomography (CT) within 6 h after onset of symptoms. We assessed MLS at several locations, including the pineal gland, septum pellucidum, and cerebral falx. MLS(max) was defined as the maximum midline shift among these locations. Functional outcomes were assessed with the Modified Rankin Scale (mRS) at 3 months. We performed multivariate logistic regression analysis to investigate the MLS locations for predicting poor outcome. ROC curve analysis was used to establish whether MLS values were predictive of 90-day poor outcome. RESULTS: In 199 patients with ICH, 78 (39.2%) patients had poor functional outcome at 3-month follow-up. Pineal gland shift, septum pellucidum shift, cerebral falx shift, and MLS(max) all showed a significant difference between poor outcome and favorable outcome (p < 0.001). After adjustment for age, baseline Glasgow Coma Scale score, ICH location, time to initial CT, baseline ICH volume, and intraventricular hemorrhage, the MLS(max) was independently associated with poor outcome (p = 0.032). MLS(max) > 4 mm (our proposed optimal threshold) was more likely to have poorer outcomes than those without (p < 0.001). CONCLUSIONS: MLS(max) can be a good independent predictor of clinical outcome, and MLS(max) > 4 mm is an optimal threshold associated with poor outcome in patients with ICH. PMID- 29139016 TI - Methodological strategies in using home sleep apnea testing in research and practice. AB - PURPOSE: Home sleep apnea testing (HSAT) has increased due to improvements in technology, accessibility, and changes in third party reimbursement requirements. Research studies using HSAT have not consistently reported procedures and methodological challenges. This paper had two objectives: (1) summarize the literature on use of HSAT in research of adults and (2) identify methodological strategies to use in research and practice to standardize HSAT procedures and information. METHODS: Search strategy included studies of participants undergoing sleep testing for OSA using HSAT. MEDLINE via PubMed, CINAHL, and Embase with the following search terms: "polysomnography," "home," "level III," "obstructive sleep apnea," and "out of center testing." RESULTS: Research articles that met inclusion criteria (n = 34) inconsistently reported methods and methodological challenges in terms of: (a) participant sampling; (b) instrumentation issues; (c) clinical variables; (d) data processing; and (e) patient acceptability. Ten methodological strategies were identified for adoption when using HSAT in research and practice. CONCLUSIONS: Future studies need to address the methodological challenges summarized in this paper as well as identify and report consistent HSAT procedures and information. PMID- 29139017 TI - Short-Term and Long-Term Outcomes of a Vocational Rehabilitation Program for Patients with Acquired Brain Injury in The Netherlands. AB - Purpose To describe short-term and long-term work status after a vocational rehabilitation (VR) program in patients with acquired brain injury (ABI) in the Netherlands. Methods Patients with ABI who participated in a VR program between 2007 and 2010 were included in this study. The 4-month VR program included a multidisciplinary assessment, three meetings with all stakeholders and reintegration with coaching on the job. Short-term results at the end of the VR program were based on data extracted from medical records. Long-term results were determined at 3-6 years (mean 4.4 years) after the program based on patient reported data. Outcome measures included return to work, hours at work and task adjustments. Results Fifty-eight patients were included [mean age 48 (SD 9.4) years; n = 33 male; all working before ABI]. After the intervention, 50 patients (86%) had returned to work, working on average 60% of their former hours. Working tasks were adjusted in 48 patients. At long-term follow-up 28 patients had paid work, working on average 5.3 h more than immediately after the VR program. Conclusions Directly after the intervention 86% of the patients had returned to work. After 3-6 years, 64% of these patients were still working in a paid job. PMID- 29139018 TI - Vaccination Against Hydatidosis: Molecular Cloning and Optimal Expression of the EG95NC- Recombinant Antigen in Escherichia coli. AB - Cystic echinococcosis (CE) is a widely distributed zoonosis that is highly endemic in the Mediterranean basin. The disease represents a serious public health threat and causes economic losses. The parasite life-cycle involves dogs and ruminants as definitive and intermediate hosts; humans are accidently infected, causing serious clinical issues. Vaccination of ruminants and dog treatments represent the most efficient measures to prevent parasite transmission. The recombinant protein vaccine, EG95, has been used successfully in sheep vaccine trials against CE in several countries. In this study, we expressed the modified antigen, EG95NC-GST, in Escherichia coli for use as a vaccine against Echinococcus granulosus in ruminants. We tested three different media formulations for E. coli culture and established for each culture conditions for optimal levels of soluble EG95 expression. The results demonstrate that SOC and TB media provided high yields in cell density and EG95 protein expression. Purification of the recombinant protein with affinity chromatography (using FPLC) was also performed to increase the purity of the EG95NC--GST antigen. PMID- 29139020 TI - Comment on: Open versus Minimally Invasive Resection of Gastric GIST: A Multi institutional Analysis of Short- and Long-Term Outcomes. PMID- 29139019 TI - Pharmacists' confidence when providing pharmaceutical care on anticoagulants, a multinational survey. AB - Background Guidelines on the management of orally anticoagulated patients are continuously evolving, leading to an increased need for pharmacists to be fully integrated in care provision. Objective To identify self-reported gaps in confidence among practicing pharmacists in the area of anticoagulation. Setting Pharmacists in different work settings in different countries. Method Cross sectional international survey from October 2015 till November 2016 among pharmacists working in different settings to assess their level of confidence when delivering anticoagulants as well as to identify possible educational needs regarding this medication class. Validation of the survey was ensured. Results Responses from 4212 pharmacists originating from 18 countries were obtained. Pharmacists' level of confidence was significantly higher (p < 0.001) when advising patients on vitamin K antagonists (VKAs) versus non-vitamin K antagonists (NOACs). In general, hospital pharmacists displayed higher confidence levels compared to community pharmacists when advising patients on anticoagulation (p < 0.001). Two distinct patterns of confidence levels emerged relating to basic and advanced pharmaceutical care. Confidence levels when providing advanced pharmaceutical care were significantly higher for Oceania and lower for South America (p < 0.005). Conclusions Pharmacists felt more confident in supporting patients receiving VKAs compared to the more recently introduced NOACs. With the increasing use of NOACs and the risks pertaining to anticoagulation therapy, it is essential to invest in education for pharmacists to address their knowledge gaps enabling them to confidently support patients receiving oral anticoagulants. PMID- 29139021 TI - Perioperative Complications and Mortality in Patients with Urothelial Carcinoma and End-Stage Renal Disease Undergoing One-Stage Complete Urinary Tract Extirpation. AB - BACKGROUND: Complete urinary tract extirpation (CUTE) is a complex procedure with substantial risk for perioperative complications. The association between clinical characteristics and the risk of major postoperative complications has not been systematically investigated. OBJECTIVE: The aim of this study was to analyze the incidence and risks for major perioperative complications after CUTE. METHODS: Respective chart review of 81 patients with urothelial carcinoma (UC) who were treated with one-stage CUTE between January 2004 and December 2015. Fisher's exact test with Chi square and two-tailed t test were used in categorical and continuous variables, respectively. Univariable and multivariable logistic regression models were used to evaluate the probability of major complications. RESULTS: In this population, 53 (65.4%) patients had Clavien grade 0-2 complications ('no major complications') and 28 (34.6%) patients had Clavien grade 3-5 complications ('major complications'). Compared with the major complications group, patients in the no major complications group were younger, had lower Charlson Comorbidity Index (CCI), higher preoperative serum albumin, and shorter duration of hospitalization (p < 0.05 for all). Major complications were more common in low-volume surgeons (p = 0.002). On multivariate logistic regression analyses, CCI >= 5 (odds ratio [OR] 6.25, 95% confidence interval [CI] 1.42-27.47; p = 0.015) and surgery by a provider who performed three or fewer cases during the study interval (OR 13.4, 95% CI 2.20-80.89; p = 0.005) were independent predictors for major complications. CONCLUSIONS: High CCI should alert providers to increased probability of major complications, and warrant vigilant management after CUTE. Surgeon volume was inversely related to major postoperative complications. PMID- 29139022 TI - Effect of Plasma-Activated Lactated Ringer's Solution on Pancreatic Cancer Cells In Vitro and In Vivo. AB - BACKGROUND: The medical applications of nonequilibrium atmospheric pressure plasma in cancer therapy have attracted attention. We previously reported on the antitumor effect of plasma-activated medium. However, this approach requires plasma-activated liquids that are administrable to the human body. In this study, we produced plasma-activated lactated Ringer's solution (PAL) and evaluated its antitumor effect and mechanism. Furthermore, we evaluated the effect of the intraperitoneal administration of PAL using a peritoneal dissemination mouse tumor model. METHODS: The antitumor effect of PAL on pancreatic cancer cell lines was evaluated using proliferation and apoptosis assays. In addition, cellular reactive oxygen species (ROS) generation was examined. The role of ROS was assessed using a proliferation assay with N-acetyl cysteine (NAC). An adhesion assay was performed to evaluate the effect of PAL on cell adhesion. Finally, pancreatic cancer cells stably expressing luciferase (AsPC-1/CMV-Luc) were injected intraperitoneally into mice, followed by intraperitoneal injection of PAL. Peritoneal dissemination was monitored using in vivo bioluminescent imaging. RESULTS: The antitumor effect of PAL was shown in all cell lines in vitro. The TUNEL assay showed that PAL induced apoptosis. ROS uptake was observed in PAL treated cells, and the antitumor effect was inhibited by NAC. Cell adhesion also was suppressed by PAL. The intraperitoneal administration of PAL suppressed the formation of peritoneal nodules in vivo. CONCLUSIONS: Our study demonstrated the antitumor effects of PAL in vitro and in vivo. Intraperitoneal administration of PAL may be a novel therapeutic option for peritoneal metastases. PMID- 29139023 TI - Reply: YAP is a Key Factor to Improve the Management of Cancer Treatments. PMID- 29139024 TI - Immigrant Trauma and Mental Health Outcomes Among Latino Youth. AB - While research has demonstrated an association between trauma and mental health, this study examined the association between trauma experienced premigration, during migration, and postmigration, and current mental health status among Latino youth aged 12-17 years old living in the US for < 3 years. Participants reported traumatic events experienced in their home country, during migration, and after settling in the US. Regression models examined trauma experienced at each stage of the migration process predicting current levels of depression, anxiety, and post-traumatic stress disorder. Two-thirds of youth experienced at least one traumatic event, 44% experienced an event once, and 23% experienced two or more traumatic events during migration. Trauma experienced at different migration stages was associated with distinctive mental health outcomes. It is essential that access to culturally sensitive assessment and treatment services be available to ensure transition to a healthy adulthood. PMID- 29139025 TI - Coagulopathy in Zellweger spectrum disorders: a role for vitamin K. AB - INTRODUCTION: Zellweger spectrum disorders (ZSDs) are caused by an impairment of peroxisome biogenesis, resulting in multiple metabolic abnormalities. This leads to a range of symptoms, including hepatic dysfunction and coagulopathy. This study evaluated the incidence and severity of coagulopathy and the effect of vitamin K supplementation orally and IV in ZSD. METHODS: Data were retrospectively retrieved from the medical records of 30 ZSD patients to study coagulopathy and the effect of vitamin K orally on proteins induced by vitamin K absence (PIVKA-II) levels. Five patients from the cohort with a prolonged prothrombin time, low factor VII, and elevated PIVKA-II levels received 10 mg of vitamin K IV. Laboratory results, including thrombin generation, at baseline and 72 h after vitamin K administration were examined. RESULTS: In the retrospective cohort, four patients (13.3%) experienced intracranial bleedings and 14 (46.7%) reported minor bleeding. No thrombotic events occurred. PIVKA-II levels decreased 38% after start of vitamin K therapy orally. In the five patients with a coagulopathy, despite treatment with oral administration of vitamin K, vitamin K IV caused an additional decrease (23%) of PIVKA-II levels and increased thrombin generation. CONCLUSION: Bleeding complications frequently occur in ZSD patients due to liver disease and vitamin K deficiency. Vitamin K deficiency is partly corrected by vitamin K supplementation orally, and vitamin K administered IV additionally improves vitamin K status, as shown by further decrease of PIVKA-II and improved thrombin generation. PMID- 29139026 TI - Structural elucidation of novel biomarkers of known metabolic disorders based on multistage fragmentation mass spectra. AB - Specific diagnostic markers are the key to effective diagnosis and treatment of inborn errors of metabolism (IEM). Untargeted metabolomics allows for the identification of potential novel diagnostic biomarkers. Current separation techniques coupled to high-resolution mass spectrometry provide a powerful tool for structural elucidation of unknown compounds in complex biological matrices. This is a proof-of-concept study testing this methodology to determine the molecular structure of as yet uncharacterized m/z signals that were significantly increased in plasma samples from patients with phenylketonuria and 3-hydroxy-3 methylglutaryl-CoA lyase deficiency. A hybrid linear ion trap-orbitrap high resolution mass spectrometer, capable of multistage fragmentation, was used to acquire accurate masses and product ion spectra of the uncharacterized m/z signals. In order to determine the molecular structures, spectral databases were searched and fragmentation prediction software was used. This approach enabled structural elucidation of novel compounds potentially useful as biomarkers in diagnostics and follow-up of IEM patients. Two new conjugates, glutamyl-glutamyl phenylalanine and phenylalanine-hexose, were identified in plasma of phenylketonuria patients. These novel markers showed high inter-patient variation and did not correlate to phenylalanine levels, illustrating their potential added value for follow-up. As novel biomarkers for 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, three positional isomers of 3-methylglutaconyl carnitine could be detected in patient plasma. Our results highlight the applicability of current accurate mass multistage fragmentation techniques for structural elucidation of unknown metabolites in human biofluids, offering an unprecedented opportunity to gain further biochemical insights in known inborn errors of metabolism by enabling high confidence identification of novel biomarkers. PMID- 29139027 TI - "Magic Bullets" at the center stage of immune therapy: a special issue on therapeutic antibodies. PMID- 29139028 TI - Histone chaperone Spt16p is required for heterochromatin mediated silencing in budding yeast. PMID- 29139029 TI - ASGE EndoVators Summit: Defining the Role and Value of Endoscopic Therapies in Obesity Management. PMID- 29139031 TI - In vivo Analysis of the Anti-atrial Fibrillatory, Proarrhythmic and Cardiodepressive Profiles of Dronedarone as a Guide for Safety Pharmacological Evaluation of Antiarrhythmic Drugs. AB - Anti-atrial fibrillatory, proarrhythmic and cardiodepressive profiles of dronedarone were analyzed using the halothane-anesthetized beagle dogs (n = 4) to create a standard protocol for clarifying both efficacy and adverse effects of anti-atrial fibrillatory drugs. Intravenous administration of dronedarone hydrochloride in doses of 0.3 and 3 mg/kg over 30 s attained the peak plasma concentrations of 61 and 1248 ng/mL, respectively, reflecting sub- to supra therapeutic ones. The low dose decreased the left ventricular contraction and mean blood pressure, which were enhanced at the high dose. The high dose also decreased the heart rate and cardiac output, but increased the total peripheral resistance and left ventricular end-diastolic pressure, showing its potent cardiodepressive profile. Moreover, the high dose delayed the atrioventricular nodal and intraventricular conductions in addition to the ventricular repolarization, suggesting its inhibitory action on the Ca2+, Na+ and K+ channels in the in situ heart, respectively. The high dose also prolonged the effective refractory period 1.9 times greater in the atrium than in the ventricle, explaining its clinically demonstrated efficacy against the atrial arrhythmias. Dronedarone significantly prolonged the Tpeak-Tend in a dose-related manner with a tendency to prolong the terminal repolarization period and J-Tpeakc, indicating considerable risk to induce torsade de pointes. No significant change was detected in the P-wave duration by either dose, indicating the lack of effect on the atrial Na+ channel in vivo. The current experimental protocol and the results of dronedarone can be used as a guide for safety pharmacological evaluation of new anti-atrial fibrillatory drugs. PMID- 29139030 TI - Potential risk factors for reactive arthritis and persistence of symptoms at 2 years: a case-control study with longitudinal follow-up. AB - The objective of the study is to determine the risk factors for the development of reactive arthritis (ReA) and examine the factors associated with the persistence of symptoms. Patients with a new diagnosis of ReA and controls with a gastrointestinal (GI), urogenital, or sexually transmitted infection in the 3-6 months prior to study entry were prospectively enrolled in Guatemala City. ReA patients fulfilled the Assessment in Spondyloarthritis International Society criteria for peripheral spondyloarthropathy (SpA). Patients underwent history, examination, Achilles tendon ultrasound, and blood draw. Human leukocyte antigen (HLA) type and serum biomarkers were measured. t tests and nonparametric equivalents were used to examine the association of clinical, laboratory, and imaging factors with ReA. Patients were contacted 2 years later to assess for persistence of symptoms. Study subjects included patients with ReA (N = 32) and controls (N = 32). ReA patients were most frequently infected in April whereas controls were most frequently infected in August. Two ReA patients and two controls were HLA-B27-positive. Serum cathepsin K and C-reactive protein were higher in ReA patients compared to controls (p = 0.03 for both), while total cholesterol and low-density lipoprotein were lower (p = 0.008 and 0.045, respectively). Among those with ReA, 15 (47%) patients had continued symptoms at 2 years. These patients had a lower matrix metalloproteinase-3 level at diagnosis than patients for whom ReA resolved (p = 0.004). HLA-B27 was not associated with development of ReA in Guatemala; however, the month of infection was associated with ReA. The most striking finding was the persistence of arthritis at 2 years in nearly half of the patients. PMID- 29139032 TI - Radium, biophysics, and radiobiology: tracing the history of radiobiology in twentieth-century China. AB - Radiobiology assesses the biological hazards of exposure to radioactive substances and nuclear radiation. This article explores the history of radiobiology in twentieth-century China by examining the overlapping of radium research and biophysics, from roughly the 1920s Nationalist period to the 1960s Communist period; from the foreign purchase of radium by the Rockefeller Foundation's China Medical Board during the Republican era, to the institutional establishment of radiobiology as a subset of biophysics in the People's Republic. Western historiography of radiobiology highlights the connection between the military development of nuclear weapons and the civilian use of radiation in biology, as well as the international export of radioisotopes and nuclear reactors. Considering the exclusion of China from Western atomic diplomacy, I argue that the study of the Chinese history of bomb-making and radiobiology is necessary not just to fill an existing knowledge gap, but more importantly to elucidate the influence of the Chinese nuclear weapons program and Cold War atomic politics on Chinese life-science enterprises. Through examining the formational history of the radiobiology program in China, I hope to shed light on the implications of the atomic age for Chinese biology in the twentieth century. PMID- 29139033 TI - Relationship between airflow obstruction and coronary atherosclerosis in asymptomatic individuals: evaluation by coronary CT angiography. AB - Airflow obstruction is associated with increased cardiovascular morbidity and mortality. However, the causal mechanisms linking airflow obstruction with higher incidence of cardiovascular events remain elusive. We evaluated the relationship between airflow obstruction, a key feature of chronic obstructive pulmonary disease (COPD), and prevalence, extent, and severity of coronary atherosclerosis in a large cohort of asymptomatic subjects. Participants were recruited from those undergoing spirometry and coronary computed tomography angiography (CCTA) as part of a general health evaluation from March 2009 to February 2011. Subjects were required to be over 40 years of age with no known CAD. Airflow obstruction was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 70%. Obstructive CAD, as measured by CCTA, was defined as maximum intra-luminal stenosis >= 50%. Participants with airflow obstruction or normal lung function were compared in terms of obstructive CAD prevalence, the extent and severity of coronary atherosclerosis; including coronary artery calcium score (CACS), atheroma burden score (ABS), atheroma burden obstructive score (ABOS), segment involvement score (SIS), and segment stenosis score (SSS). A total of 1888 subjects were eligible for study inclusion. Compared with participants with normal lung function, those exhibiting airflow obstruction were more likely to have obstructive CAD (p = 0.002). Airflow obstruction was associated with higher CACS (p = 0.043), ABS (p = 0.002), ABOS (p = 0.017), SIS (p = 0.003), and SSS (p = 0.002). Multivariable analyses adjusted for conventional cardiovascular risk factors revealed that airflow obstruction was independently associated with presence of CAD (odds ratio 1.673, confidence intervals [CI] 1.002-2.789, p = 0.048). In this asymptomatic population, the presence of airflow obstruction was associated with a greater prevalence, extent, and severity of coronary atherosclerosis and was seen to be an independent predictor of the presence of CAD. PMID- 29139034 TI - Vessel centerline reconstruction from non-isocentric and non-orthogonal paired monoplane angiographic images. AB - PURPOSE: Three-dimensional reconstruction of a vessel centerline from paired planar coronary angiographic images is critical to reconstruct the complex three dimensional structure of the coronary artery lumen and the relative positioning of implanted devices. In this study, a new vessel centerline reconstruction method that can utilize non-isocentric and non-orthogonal pairs of angiographic images was developed and tested. METHODS: Our new method was developed in in vitro phantom models of bifurcated coronary artery with and without stent, and then tested in in vivo swine models (twelve coronary arteries). This method was also validated using data from six patients. RESULTS: Our new method demonstrated high accuracy (root mean square error = 0.27 mm or 0.76 pixel), and high reproducibility across a broad imaging angle (20 degrees -130 degrees ) and between different cardiac cycles in vitro and in vivo. Use of this method demonstrated that the vessel centerline in the stented segment did not deform significantly over a cardiac cycle in vivo. In addition, the total movement of the isocenter in each image could be accurately estimated in vitro and in vivo. The performance of this new method for patient data was similar to that for in vitro phantom models and in vivo animal models. CONCLUSIONS: We developed a vessel centerline reconstruction method for non-isocentric and non-orthogonal angiographic images. It demonstrated high accuracy and good reproducibility in vitro, in vivo, and in clinical setting, suggesting that our new method is clinically applicable despite the small sample size of clinical data. PMID- 29139035 TI - Certolizumab Pegol in the Treatment of Psoriasis and Psoriatic Arthritis: Preliminary Real-Life Data. AB - INTRODUCTION: We present the results of real-life tests conducted in adults affected by psoriatic arthritis (PsA) with mild cutaneous involvement to evaluate the efficacy of certolizumab pegol (CZP), an anti-tumor necrosis factor-alpha agent approved in Europe for the treatment of rheumatoid arthritis and PsA. METHODS: Assessments included an evaluation of the Psoriasis Area and Severity Index (PASI) and the Disease Activity Score computed on 44 joints (DAS-44) correlated to the erythrocyte sedimentation rate (ESR) (DAS44-ESR). A total of 41 patients (16 men, 25 women; mean age 59.8 +/- 8 years) completed the study. Of these, 36 patients were affected by both PsA and psoriasis, and five patients were affected only by PsA. A total of 32 patients (group A) completed 3 months of treatment (W12), and 12 patients completed 6 months of treatment (W24) (group B). RESULTS: The clinical efficacy of CZP was consistent on both the cutaneous and rheumatic components of the treatment. The mean PASI score decreased from 4.4 +/- 4.7 at baseline (BL) to 2.3 +/- 3.7 at W12 (group A), and from 5.1 +/- 5.7 at BL to 0.8 +/- 1.2 at W24 (group B). The DAS44-ESR decreased from 4.4 +/- 0.6 at BL to a mean of 2.2 +/- 0.9 at W12 (group A) and from 4.1 +/- 0.6 at BL to a mean of 1.9 +/- 0.5 at W24 (group B). No adverse events were reported. CONCLUSION: Our results demonstrate that CZP can be used safely and effectively to treat both the cutaneous and joint components of PsA. However, long-term data are needed to confirm our preliminary observations. PMID- 29139036 TI - Myocardial stunning by gated SPECT: An old tool reinvented in a stunning turn. PMID- 29139037 TI - Prevalence of oral lichen planus in Iranian children and adolescents: a 12-year retrospective study. AB - AIM: To investigate the prevalence of oral lichen planus in patients younger than 18 years, referred to a dermatology centre in Iran during 2002-2014. Lichen planus is a chronic inflammatory, immune-mediated disease that could affect the oral mucosa and is a pre-cancerous condition. The disease usually develops in middle age with female predominance and is rare in children. METHODS: In this retrospective study, cases with definitive histopathologic diagnosis of lichen planus, over a 12-year period from 2002 to 2014 from a dermatologic hospital archive were evaluated. The prevalence of both cutaneous and oral lichen planus, the male:female ratio and site of involvement were calculated using SPSS version 21. RESULTS: Thirty-six of 564 patients younger than 18 years old diagnosed with lichen planus. Two females (0.4%) had oral lichen planus. One patient had erosive, and one had bullous, oral lichen planus. CONCLUSION: Oral lichen planus had a very low frequency in Iranian population younger than 18 years old, identifying these patients is recommended for long-term follow-up. PMID- 29139038 TI - The impact of donor and recipient weight incompatibility on renal transplant outcomes. AB - BACKGROUND: Donor/recipient size mismatching and correlation to allograft outcome remains poorly defined. This study assessed the impact of donor body weight (DBW) to recipient body weight (RBW) ratio on allograft function and survival. METHODS: A total of 898 deceased donor renal transplant recipients were included in the study. Patients were divided into quartiles depending on the ratio of DBW/RBW: Q1 (<= 0.88), Q2 (0.89-1.00), Q3 (1.01-1.22) and Q4 (> 1.22). Donor and recipient characteristics were obtained from the national kidney transplant service database. Serum creatinine and estimated glomerular filtration rate (eGFR) at 1 and 5 years after transplant were compared. RESULTS: Q4 patients had a higher eGFR 1 year post-transplant (median 59.5 ml/min, IQR 46.8-76.2) compared to Q1-Q3 which had median eGFRs of 54.3, 54.8 and 55.3 ml/min, respectively (p < 0.001). At 5 years post-transplant, there were modest differences in the eGFR across the four quartiles, Q1-4 with median eGFRs of 56.9, 61.1, 61.2 and 58.6 ml/min, respectively (p = 0.02). However, there were no significant differences in 1- and 5-year allograft survival between groups. CONCLUSIONS: In the setting of deceased donor renal transplantation, mismatching of donor to recipient weight had no impact on 5-year allograft survival, but a low DBW/RBW ratio is modestly associated with lower eGFR. PMID- 29139039 TI - Genetic screening and molecular characterization of MET alterations in non-small cell lung cancer. AB - PURPOSE: Aberrant activation of MET as a result of exon 14-skipping (METex14) mutations or gene amplification is an oncogenic mechanism in non-small cell lung carcinoma (NSCLC) and a potential therapeutic target. The purpose of this study was to characterize MET alterations in a cohort of NSCLC patients treated with surgery. METHODS AND PATIENTS: 157 NSCLCs of various histopathologies, including pulmonary sarcomatoid carcinomas (PSC), were tested for MET alterations. METex14 mutations, MET copy number alterations and the levels of MET protein were determined by Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry, respectively. Concurrent alterations of other important cancer genes and immunostaining of the downstream effector, phopho-S6, were also determined. RESULTS: METex14 mutations and MET amplification were detected in seven tumors. MET genetic alterations were found predominantly in the lung adenocarcinoma (ADC) and PSC histopathologies. High levels of MET protein were found in most MET-amplified tumors, but not in all METex14-mutated tumors. Strong phopho-S6 staining was observed in about half of the MET-activated tumors. One tumor with METex14 exhibited concurrent ERBB2 amplification. CONCLUSIONS: MET activation, by either METex14 mutations or amplification, is characteristic of a subset of early stage NSCLCs and may coexist with ERBB2 amplification. This may have potential therapeutic implications. The presence of METex14 mutations was associated with low levels of MET protein, which may limit the use of total MET immunostaining as a marker for preselecting patients for MET-targeted therapies. PMID- 29139040 TI - Recommendations for the follow-up care of female breast cancer survivors: a guideline of the Spanish Society of Medical Oncology (SEOM), Spanish Society of General Medicine (SEMERGEN), Spanish Society for Family and Community Medicine (SEMFYC), Spanish Society for General and Family Physicians (SEMG), Spanish Society of Obstetrics and Gynecology (SEGO), Spanish Society of Radiation Oncology (SEOR), Spanish Society of Senology and Breast Pathology (SESPM), and Spanish Society of Cardiology (SEC). AB - The increased incidence and decreased mortality of breast cancer have produced an increased number of breast cancer survivors. The type of sequelae and comorbidities that these patients present call for a collaborative follow-up by hospital-based specialized care and primary care. In this document, we present a guideline drafted and agreed among scientific societies whose members care for breast cancer survivors. The purpose of this guideline is to achieve the shared and coordinated follow-up of these patients by specialized care and primary care professionals. In it, we review the health issues derived from the treatments performed, with recommendations about the therapeutic approach to each of them, as well as a proposal for joint follow-up by primary and specialized care. PMID- 29139041 TI - Drug Safety Analysis in a Real-Life Cohort of Parkinson's Disease Patients with Polypharmacy. AB - BACKGROUND: Polypharmacy is common in geriatric Parkinson's disease (PD) patients in advanced disease stages with multiple comorbidities, bearing multiple risks for drug safety in theory. OBJECTIVE: The aim of this study was to empirically identify the most frequent and relevant contraindications and drug interactions actually occurring and compromising drug safety in PD in real life. METHODS: We conducted a prospective observational study in a multimorbid cohort of PD patients with polypharmacy admitted to a specialized hospital. Inclusion criteria were the presence of at least one comorbidity requiring pharmacotherapy and at least five different drugs in the discharge prescription. Hoehn and Yahr stage during the 'on' state, therapeutic problems related to motor and non-motor PD symptoms, comorbidities, and drug regimens on admission and discharge were analyzed for contraindications and interactions. RESULTS: Overall, 127 patients were included (medium Hoehn and Yahr stage = IV, range II-V). Interactions with the anti-PD medication were mainly caused by other central nervous system (CNS) active substances, cytochrome P450-metabolized substances, and QT-time prolonging substances. Contraindications against the anti-PD medication mainly occurred from internal, haematopoietic, neurologic and psychiatric diseases, and QT-time prolonging drugs. The highest frequency of interactions and contraindications were identified with levodopa (n = 119 at admission/n = 126 at discharge), entacapone (n = 46/42), pramipexole (n = 44/24), and amantadine (n = 32/30). CONCLUSIONS: Several medically relevant risk factors (interactions and contraindications) frequently occurred in advanced PD patients. These findings provide a basis for developing programmes for awareness, education, monitoring, and preventive interventions to avoid adverse incidents. Future studies will need to evaluate preventive efficacy of structured drug safety programmes. PMID- 29139043 TI - Early-onset baldness and the risk of aggressive prostate cancer: findings from a case-control study. AB - PURPOSE: We aimed to evaluate the associations between androgenetic alopecia at a young age and subsequent development of aggressive prostate cancer (PC). METHODS: Using a case-control design with self-administered questionnaire, we evaluated the association between aggressive PC and very early-onset balding at age 20, and early-onset balding at age 40 years in 1,941 men. Cases were men with high-grade and/or advanced stage cancer and controls were clinic based men who had undergone biopsy and were found to be histologically cancer negative. Additionally, for cases we assessed whether early-onset balding was associated with earlier onset of disease. RESULTS: Men with very early-onset balding at age 20 years were at increased risk for subsequent aggressive PC [odds ratio (OR) 1.51, 95% confidence interval (CI) 1.07-2.12] after adjustment for age at baseline, family history of PC, smoking status, alcohol intake, body shape, timing of growth spurt and ejaculatory frequency. Additionally, these men were diagnosed with PC approximately 16 months earlier than cases without the exposure. The effect was present particularly for men with advanced stage pT3+ disease (OR 1.68, 95% CI 1.14-2.47) while men with organ-confined high-grade (8-10) PC did not exhibit the same relationship. No significant associations were observed for men who were balding at age 40 years, given no balding at age 20. CONCLUSION: Men with androgenetic alopecia at age 20 years are at increased risk of advanced stage PC. This small subset of men are potentially candidates for earlier screening and urological follow-up. PMID- 29139042 TI - Obesity and Altered Aspirin Pharmacology. AB - Obesity is an independent risk factor for cardiovascular morbidity and mortality due to atherothrombotic events and represents a group of patients who are in need of optimized antithrombotic therapy. Central to the obesity-related risk of atherothrombosis is a pro-thrombotic state characterized by increased levels of coagulation factors, impaired fibrinolysis, and platelet hyper-reactivity, which results from the interaction among the features clustering in obesity: insulin resistance, inflammation, oxidative stress, and endothelial dysfunction. Aspirin is a cornerstone antiplatelet drug that has substantial interpatient variability in pharmacodynamic response and a number of reports have demonstrated that obesity is a risk factor for a reduced aspirin pharmacodynamic response. The inflammatory state associated with obesity, particularly a metabolic endotoxemia, may set in motion a number of mechanisms that increase platelet reactivity and platelet turnover and decrease aspirin bioavailability, all contributing to a poor aspirin response. A greater understanding of the mechanisms underlying obesity-related high on-aspirin platelet reactivity will help in optimization of antithrombotic therapy in this patient population. PMID- 29139046 TI - Insufflation stabilization bag (ISB): a cost-effective approach for stable pneumorectum using a modified CO2 insufflation reservoir for TAMIS and taTME. PMID- 29139045 TI - Electroretinography in idiopathic intracranial hypertension: comparison of the pattern ERG and the photopic negative response. AB - PURPOSE: To evaluate the relationship between electrophysiological measures of retinal ganglion cell (RGC) function in patients who have idiopathic intracranial hypertension (IIH). METHODS: The pattern electroretinogram (pERG) and photopic negative response (PhNR) were recorded from 11 IIH patients and 11 age-similar controls. The pERG was elicited by a contrast-reversing checkerboard. The PhNR, a slow negative component following the flash ERG b-wave, was recorded in response to a long-wavelength flash presented against a short-wavelength adapting field. The PhNR was elicited using full-field (ffPhNR) and focal macular (fPhNR) stimuli. Additionally, Humphrey visual field mean deviation (HVF MD) was measured and ganglion cell complex volume (GCCV) was obtained by optical coherence tomography. RESULTS: The ffPhNR, fPhNR, and pERG amplitudes were outside of the normal range in 45, 9, and 45% of IIH patients, respectively. However, only mean ffPhNR amplitude was reduced significantly in the patients compared to controls (p < 0.01). The pERG amplitude correlated significantly with HVF MD and GCCV (both r > 0.65, p < 0.05). There were associations between ffPhNR amplitude and HVF MD (r = 0.58, p = 0.06) and with GCCV (r = 0.52, p = 0.10), but these did not reach statistical significance. fPhNR amplitude was not correlated significantly with HVF MD or GCCV (both r < 0.40, p > 0.20). CONCLUSIONS: Although the fPhNR is generally normal in IIH, other electrophysiological measures of RGC function, the ffPhNR and pERG, are abnormal in some patients. These measures provide complementary information regarding RGC dysfunction in these individuals. PMID- 29139047 TI - Stereotactic navigation during laparoscopic surgery for locally recurrent rectal cancer. PMID- 29139049 TI - Feedforward architectures driven by inhibitory interactions. AB - Directed information transmission is paramount for many social, physical, and biological systems. For neural systems, scientists have studied this problem under the paradigm of feedforward networks for decades. In most models of feedforward networks, activity is exclusively driven by excitatory neurons and the wiring patterns between them, while inhibitory neurons play only a stabilizing role for the network dynamics. Motivated by recent experimental discoveries of hippocampal circuitry, cortical circuitry, and the diversity of inhibitory neurons throughout the brain, here we illustrate that one can construct such networks even if the connectivity between the excitatory units in the system remains random. This is achieved by endowing inhibitory nodes with a more active role in the network. Our findings demonstrate that apparent feedforward activity can be caused by a much broader network-architectural basis than often assumed. PMID- 29139048 TI - High adherence to the Western, Prudent, and Mediterranean dietary patterns and risk of gastric adenocarcinoma: MCC-Spain study. AB - BACKGROUND: The influence of dietary habits on the development of gastric adenocarcinoma is not clear. The objective of the present study was to explore the association of three previously identified dietary patterns with gastric adenocarcinoma by sex, age, cancer site, and morphology. METHODS: MCC-Spain is a multicase-control study that included 295 incident cases of gastric adenocarcinoma and 3040 controls. The association of the Western, Prudent, and Mediterranean dietary patterns-derived in another Spanish case-control study-with gastric adenocarcinoma was assessed using multivariable logistic regression models with random province-specific intercepts and considering a possible interaction with sex and age. Risk according to tumor site (cardia, non-cardia) and morphology (intestinal/diffuse) was evaluated using multinomial regression models. RESULTS: A high adherence to the Western pattern increased gastric adenocarcinoma risk [odds ratiofourth_vs._first_quartile (95% confidence interval), 2.09 (1.31; 3.33)] even at low levels [odds ratiosecond_vs._first_quartile (95% confidence interval), 1.63 (1.05; 2.52)]. High adherence to the Mediterranean dietary pattern could prevent gastric adenocarcinoma [odds ratiofourth_vs._first_quartile (95% confidence interval), 0.53 (0.34; 0.82)]. Although no significant heterogeneity of effects was observed, the harmful effect of the Western pattern was stronger among older participants and for non-cardia adenocarcinomas, whereas the protective effect of the Mediterranean pattern was only observed among younger participants and for non-cardia tumors. CONCLUSION: Decreasing the consumption of fatty and sugary products and of red and processed meat in favor of an increase in the intake of fruits, vegetables, legumes, olive oil, nuts, and fish might prevent gastric adenocarcinoma. PMID- 29139050 TI - Modeling mesoscopic cortical dynamics using a mean-field model of conductance based networks of adaptive exponential integrate-and-fire neurons. AB - Voltage-sensitive dye imaging (VSDi) has revealed fundamental properties of neocortical processing at macroscopic scales. Since for each pixel VSDi signals report the average membrane potential over hundreds of neurons, it seems natural to use a mean-field formalism to model such signals. Here, we present a mean field model of networks of Adaptive Exponential (AdEx) integrate-and-fire neurons, with conductance-based synaptic interactions. We study a network of regular-spiking (RS) excitatory neurons and fast-spiking (FS) inhibitory neurons. We use a Master Equation formalism, together with a semi-analytic approach to the transfer function of AdEx neurons to describe the average dynamics of the coupled populations. We compare the predictions of this mean-field model to simulated networks of RS-FS cells, first at the level of the spontaneous activity of the network, which is well predicted by the analytical description. Second, we investigate the response of the network to time-varying external input, and show that the mean-field model predicts the response time course of the population. Finally, to model VSDi signals, we consider a one-dimensional ring model made of interconnected RS-FS mean-field units. We found that this model can reproduce the spatio-temporal patterns seen in VSDi of awake monkey visual cortex as a response to local and transient visual stimuli. Conversely, we show that the model allows one to infer physiological parameters from the experimentally-recorded spatio temporal patterns. PMID- 29139051 TI - Subject-specific finite element modelling of the human foot complex during walking: sensitivity analysis of material properties, boundary and loading conditions. AB - The objective of this study was to develop and validate a subject-specific framework for modelling the human foot. This was achieved by integrating medical image-based finite element modelling, individualised multi-body musculoskeletal modelling and 3D gait measurements. A 3D ankle-foot finite element model comprising all major foot structures was constructed based on MRI of one individual. A multi-body musculoskeletal model and 3D gait measurements for the same subject were used to define loading and boundary conditions. Sensitivity analyses were used to investigate the effects of key modelling parameters on model predictions. Prediction errors of average and peak plantar pressures were below 10% in all ten plantar regions at five key gait events with only one exception (lateral heel, in early stance, error of 14.44%). The sensitivity analyses results suggest that predictions of peak plantar pressures are moderately sensitive to material properties, ground reaction forces and muscle forces, and significantly sensitive to foot orientation. The maximum region specific percentage change ratios (peak stress percentage change over parameter percentage change) were 1.935-2.258 for ground reaction forces, 1.528-2.727 for plantar flexor muscles and 4.84-11.37 for foot orientations. This strongly suggests that loading and boundary conditions need to be very carefully defined based on personalised measurement data. PMID- 29139052 TI - A validated patient-specific FSI model for vascular access in haemodialysis. AB - The flow rate inside arteriovenous fistulas is many times higher than physiological flow and is accompanied by high wall shear stress resulting in low patency rates. A fluid-structure interaction finite element model is developed to analyse the blood flow and vessel mechanics to elucidate the mechanisms that can lead to failure. The simulations are validated against flow measurements obtained from magnetic resonance imaging data. PMID- 29139053 TI - Incorporating tissue anisotropy and heterogeneity in finite element models of trabecular bone altered predicted local stress distributions. AB - Trabecular bone is composed of organized mineralized collagen fibrils, which results in heterogeneous and anisotropic mechanical properties at the tissue level. Recently, biomechanical models computing stresses and strains in trabecular bone have indicated a significant effect of tissue heterogeneity on predicted stresses and strains. However, the effect of the tissue-level mechanical anisotropy on the trabecular bone biomechanical response is unknown. Here, a computational method was established to automatically impose physiologically relevant orientation inherent in trabecular bone tissue on a trabecular bone microscale finite element model. Spatially varying tissue-level anisotropic elastic properties were then applied according to the bone mineral density and the local tissue orientation. The model was used to test the hypothesis that anisotropy in both homogeneous and heterogeneous models alters the predicted distribution of stress invariants. Linear elastic finite element computations were performed on a 3 mm cube model isolated from a microcomputed tomography scan of human trabecular bone from the distal femur. Hydrostatic stress and von Mises equivalent stress were recorded at every element, and the distributions of these values were analyzed. Anisotropy reduced the range of hydrostatic stress in both tension and compression more strongly than the associated increase in von Mises equivalent stress. The effect of anisotropy was independent of the spatial redistribution high compressive stresses due to tissue elastic heterogeneity. Tissue anisotropy and heterogeneity are likely important mechanisms to protect bone from failure and should be included for stress analyses in trabecular bone. PMID- 29139054 TI - Poland's Syndrome: Are Postzygotic Mutations in beta-Actin Associated with its Pathogenesis? PMID- 29139055 TI - Downstream Breast Imaging Following Screening Mammography in Medicare Patients with Advanced Cancer: A Population-Based Study. AB - BACKGROUND: Screening tests are generally not recommended in patients with advanced cancer and limited life expectancy. Nonetheless, screening mammography still occurs and may lead to follow-up testing. OBJECTIVE: We assessed the frequency of downstream breast imaging following screening mammography in patients with advanced colorectal or lung cancer. DESIGN: Population-based study. PARTICIPANTS: The study included continuously enrolled female fee-for-service Medicare beneficiaries >=65 years of age with advanced colorectal (stage IV) or lung (stage IIIB-IV) cancer reported to a Surveillance, Epidemiology, and End Results (SEER) registry between 2000 and 2011. MAIN MEASURES: We assessed the utilization of diagnostic mammography, breast ultrasound, and breast MRI following screening mammography. Logistic regression models were used to explore independent predictors of utilization of downstream tests while controlling for cancer type and patient sociodemographic and regional characteristics. KEY RESULTS: Among 34,127 women with advanced cancer (23% colorectal; 77% lung cancer; mean age at diagnosis 75 years), 9% (n = 3159) underwent a total of 5750 screening mammograms. Of these, 11% (n = 639) resulted in at least one subsequent diagnostic breast imaging examination within 9 months. Diagnostic mammography was most common (9%; n = 532), followed by ultrasound (6%; n = 334) and MRI (0.2%; n = 14). Diagnostic mammography rates were higher in whites than African Americans (OR, 1.6; p <0.05). Higher ultrasound utilization was associated with more favorable economic status (OR, 1.8; p <0.05). CONCLUSIONS: Among women with advanced colorectal and lung cancer, 9% continued screening mammography, and 11% of these screening studies led to at least one additional downstream test, resulting in costs with little likelihood of meaningful benefit. PMID- 29139056 TI - Ensuring Implementation Fidelity of a 10-Week Home Visiting Program in Two Randomized Clinical Trials. AB - Introduction Implementation fidelity is a challenge for the adoption of evidence based programs within social service broadly and child welfare specifically. However, implementation fidelity is critical for maintaining the integrity of clinical trials and for ensuring successful delivery of services in public health settings. Methods Promoting First Relationships (r) (PFR), a 10-week home visiting parenting intervention, was evaluated in two randomized clinical trials with populations of families in child welfare. Seven providers from community agencies participated in the trials and administered PFR. Fidelity data collected included observational measures of provider behavior, provider records, and input from clients to assess training uptake, adherence to content, quality of delivery, program dosage, and participant satisfaction. Results In mock cases to assess training uptake, providers demonstrated an increase in PFR verbalization strategies and a decrease non-PFR verbalizations from pre to post PFR training, and overall this was maintained a year later (Mann-Whitney U's = 0, p's < .01). Adherence to content in actual cases was high, with M = 97% of the program elements completed. Quality of delivery varied across providers, indicated by PFR consultation strategies (Wilks' Lambda F = 18.24, df = 15, p < .001) and global ratings (F = 13.35, df = 5, p < .001). Program dosage was high in both trials (71 and 86% receiving 10 sessions), and participant satisfaction was high (M = 3.9, SD = 0.2; 4 = greater satisfaction). Discussion This system of training and monitoring provides an example of procedures that can be used effectively to achieve implementation fidelity with evidence-based programs in social service practice. PMID- 29139057 TI - Cadaveric simulation: a review of reviews. AB - BACKGROUND: Traditional surgical training, largely based on the Halstedian model "see one, do one, teach one" is not as effective in the era of working time restrictions and elaborate shift-patterns. As a result, contemporary surgeons turned to educational methods outside the operating theatre such as simulation. Cadavers are high fidelity models but their use has ethical and cost implications and their availability may be limited. In this review, we explore the role of cadaveric simulation in modern surgical education. METHODS: All the Evidence Based Medicine databases were searched for relevant reviews. The resulting studies were assessed for inclusion to this review, according to pre-determined criteria. Data extraction was performed using a custom-made spreadsheet, and the quality of included reviews was assessed using a validated scoring system (AMSTAR). RESULTS: The literature review yielded 33 systematic reviews; five of which matched the inclusion criteria and were included in this review of reviews. Cadaveric simulation was found to have good face (subjective assessment of usefulness) and content validity (whether a specific element adds or retracts to the educational value) while trainees improved their surgical skills after practicing on cadavers. However, concerns have been raised about ethical issues, high cost and availability. CONCLUSION: Cadavers are an effective medium for surgical teaching, and it may be appropriate for them to be used whenever surrounding conditions such cost and availability allow. Further research is required to provide evidence on whether there is equivalence between cadavers and other educational media which may not bear the same shortcomings. PMID- 29139058 TI - Expression and Serum Levels of Mucin 5AC (MUC5AC) as a Biomarker for Cholangiocarcinoma: a Meta-analysis. AB - AIM: The potential of biomarkers in detecting early cholangiocarcinoma (CCA) is facilitated by examining CCA-associated proteins from primary studies. One such protein is mucin 5AC (MUC5AC) but inconsistency of reported associations between its expression/serum levels and CCA prompts a meta-analysis to obtain more precise estimates. METHODS: A literature search yielded 17 included articles where multiple data in some raised the number of studies to 22. We calculated pooled odds ratios (OR) and 95% confidence intervals from negative and positive readings of MUC5AC levels. Data were subgrouped by ethnicity, detection method, sample source, and cancer type. RESULTS: Outcome in the overall analysis was non significant but those in the subgroups were. Thus, significant associations (P < 0.001) indicating high MUC5AC levels were found in three subgroups: (i) Thai (OR 8.32) and (ii) serum (OR 4.52). Heterogeneity of these two outcomes (I 2 = 90 93%) was erased with outlier treatment (I 2 = 0%) which also modulated the pooled effects (OR 2.48-2.59). (iii) Immunoblot (OR 2.61) had low initial heterogeneity (I 2 = 2%). Robustness and significant tests for interaction (P interaction = 0.01-0.02) improved MUC5AC associations with CCA in the Thai population. CONCLUSIONS: Our pooled effect findings target the biomarker potential of MUC5AC to the Thai population. PMID- 29139059 TI - Evolution of Rubisco activase gene in plants. AB - KEY MESSAGE: Rubisco activase of plants evolved in a stepwise manner without losing its function to adapt to the major evolutionary events including endosymbiosis and land colonization. Rubisco activase is an essential enzyme for photosynthesis, which removes inhibitory sugar phosphates from the active sites of Rubisco, a process necessary for Rubisco activation and carbon fixation. The gene probably evolved in cyanobacteria as different species differ for its presence. However, the gene is present in all other plant species. At least a single gene copy was maintained throughout plant evolution; but various genome and gene duplication events, which occurred during plant evolution, increased its copy number in some species. The exons and exon-intron junctions of present day higher plant's Rca, which is conserved in most species seem to have evolved in charophytes. A unique tandem duplication of Rca gene occurred in a common grass ancestor, and the two genes evolved differently for gene structure, sequence, and expression pattern. At the protein level, starting with a primitive form in cyanobacteria, RCA of chlorophytes evolved by integrating chloroplast transit peptide (cTP), and N-terminal domains to the ATPase, Rubisco recognition and C terminal domains. The redox regulated C-terminal extension (CTE) and the associated alternate splicing mechanism, which splices the RCA-alpha and RCA-beta isoforms were probably gained from another gene in charophytes, conserved in most species except the members of Solanaceae family. PMID- 29139061 TI - Lupus Anticoagulant-Hypoprothrombinemia Syndrome. PMID- 29139060 TI - Iron metabolism in erythroid cells and patients with congenital sideroblastic anemia. AB - Sideroblastic anemias are anemic disorders characterized by the presence of ring sideroblasts in a patient's bone marrow. These disorders are typically divided into two types, congenital or acquired sideroblastic anemia. Recently, several genes were reported as responsible for congenital sideroblastic anemia; however, the relationship between the function of the gene products and ring sideroblasts is largely unclear. In this review article, we will focus on the iron metabolism in erythroid cells as well as in patients with congenital sideroblastic anemia. PMID- 29139063 TI - Spinal Muscular Atrophy with Preserved Deep Tendon Reflexes. PMID- 29139062 TI - Tools in Asthma Evaluation and Management: When and How to Use Them? AB - The goals of asthma management are accurate diagnosis, prompt initiation of treatment and monitoring of disease progression to limit potential morbidity and mortality. While the diagnosis and management is largely based on history taking and clinical examination, there are an increasing number of tools available that could be used to aid diagnosis, define phenotypes, monitor progress and assess response to treatment. Tools such as the Asthma Predictive Index could help in making predictions about the possibility of asthma in childhood based on certain clinical parameters in pre-schoolers. Lung function measurements such as peak expiratory flow, spirometry, bronchodilator responsiveness, and bronchial provocation tests help establish airway obstruction and variability over time. Tools such as asthma questionnaires, lung function measurements and markers of airway inflammation could be used in combination with clinical assessments to assess ongoing asthma control. Recent advances in digital technology, which open up new frontiers in asthma management, need to be evaluated and embraced if proven to be of value. This review summarises the role of currently available tools in asthma diagnosis and management. While many of the tools are readily available in resource rich settings, it becomes more challenging when working in resource poor settings. A rational approach to the use of these tools is recommended. PMID- 29139064 TI - TP53 Mutation, MYCN Amplification, and Large Cell/Anaplastic Histology in Medulloblastoma. PMID- 29139065 TI - Aggressive Behavior in Young Children Co-detained with Imprisoned Mothers. PMID- 29139066 TI - Improving Quality of Banked Milk: Utility of Dornic Acid Test. AB - OBJECTIVE: To identify, if Dornic acid test done on human milk bank sample is as effective as doing routine culture, both pre and post pasteurization. METHODS: The authors analyzed 477 samples, both pre and post pasteurization. Dornic acid measurement was performed by using N/9 NaOH and titrated to get dornicity of the sample. Senstivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) at different Dornic acid levels were calculated. To find diagnostic power of this study, ROC curve was prepared. Dornic acid for paired pre and post pasteurization were noted and analysed for statistical significance. RESULTS: A significant growth was seen in 21% (98/477) samples with coagulase negative staphylococci and gram negative organisms being the major contaminants seen prior to pasteurization. In the index study, Dornic acidity >=4 degrees D had a sensitivity of 98% but very low specificity of just over 10%. However, 8 degrees D had 92% specificity and acceptable sensitivity of 72% in comparison to gold standard microbiological criteria, making it a good test for analyzing the quality of milk before pasteurization. CONCLUSIONS: Dornic acid test at 8 degrees D has a very high specificity with acceptable sensitivity in comparison to dornicity at 4 degrees D. It can be used as a simple method to select better quality of milk sample prior to pasteurization. PMID- 29139067 TI - Thromboembolic and bleeding risk management in elderly patients: a case report. PMID- 29139068 TI - Minor corral changes and adoption of good handling practices can improve the behavior and reduce cortisol release in Nellore cows. AB - Inadequate corral facilities and improper handling are major causes of stress in beef cattle. The purpose of this study was to evaluate the effects of minor changes in the corral and adoption of good handling practices on the behavior, cortisol release, and time spent taking blood samples in Nellore cows. Minor corral changes included obstructing the cow's vision when the handler walked deep into the animal's flight zone and the elimination of bright objects, color contrasts, puddles, shadows, and darkness in the corral. Handling was improved by eliminating dogs, electric goads (prods), and yelling, as well as adopting a calm behavior. A total of 141 Nellore cows from two typical extensive livestock farms were studied. The cows were evaluated individually before and after the corral changes. Blood samples were collected in the restraint device for cortisol measurement. The minor corral changes and the adoption of good handling practices result in better results for all variables studied. The results showed differences in the interactions between treatment and ranch for chute score (P = 0.0091) and exit score (P < 0.0001). The cortisol release was lower (P < 0.001) and better for the improved methods, resulting in calmer cows compared to cortisol released before the minor changes (41.03 +/- 2.9 vs 60.40 +/- 3.8 ng/mL). Minor changes made in the corrals and the adoption of good handling practices were effective in improving cow behavior in the chute and in reducing exit velocity, cortisol released, and the time spent taking blood samples. PMID- 29139070 TI - Mobile Health Application and e-Health Literacy: Opportunities and Concerns for Cancer Patients and Caregivers. AB - Health literacy is critical for cancer patients as they must understand complex procedures or treatment options. Caregivers' health literacy also plays a crucial role in caring for cancer patients. Low health literacy is associated with low adherence to medications, poor health status, and increased health care costs. There is a growing interest in the use of mobile health applications (apps) to improve health literacy. Mobile health apps can empower underserved cancer patients and their caregivers by providing features or functionalities to enhance interactive patient-provider communication and to understand medical information more readily. Despite the potentiality of improving health literacy through mobile health apps, there exist several related concerns: no equal access to mobile technology, no familiarity or knowledge of using mobile health apps, and privacy and security concerns. These elements should be taken into account for health policy making and mobile apps design and development. Importantly, mobile apps should be developed with the goal of achieving a high range of user access by considering all health literacy level and various cultural and linguistic needs. PMID- 29139069 TI - Piloting the effectiveness of pig health education in combination with oxfendazole treatment on prevention and/or control of porcine cysticercosis, gastrointestinal parasites, African swine fever and ectoparasites in Angonia District, Mozambique. AB - A community-based intervention combining health education (HE) and treatment of pigs for control of porcine cysticercosis (PC), gastrointestinal (GI) helminths, African swine fever (ASF) and external parasites was tested involving six villages of resource-poor smallholder pig farmers. Farmers and pigs of six rural villages were randomly allocated into group 1 (HE), which served as controls, and group 2 (HE + OFZ) pigs received a single oral dose of 30 mg/kg OFZ. Farmers were trained in pig health, housing and feeding. The proportion of farmers with confined pigs, the adoption rate of the introduced pig pen, the sero-prevalence of PC and ASF, the prevalence and intensity of GI nematodes and the prevalence of ectoparasites were measured at 9, 15 and 24 months after initiation and compared to a baseline survey to seek the effectiveness of the interventions. There was no clear effect of the intervention on the sero-prevalence of PC, but analysis of the rate of change in prevalence between the two groups showed significant effect with the rate of change to lower prevalence in the HE + OFZ group compared to the HE group. Although HE managed to improve the farmer's knowledge in the control and prevention of ASF and ectoparasites, there was no significant reduction in the sero-prevalence of ASF and the prevalence of ectoparasites throughout the two year period. The reported ineffectiveness of the intervention in this study suggested that more research is needed to develop more effective methods for controlling PC, ASF and pig parasites. PMID- 29139071 TI - The Outcomes of an Educational Program Involving Men as Motivators to Encourage Women to Be Screened for Cervical Cancer. AB - Cervical cancer is a major health problem in South Africa. Despite having a national, population-based screening program, screening coverage is as low as 13%. Based on the role men could play in increasing cervical cancer screening and the low level of knowledge, men living in the study setting had about this health issue, we developed and pilot tested an educational program aimed at empowering men to teach their female partners and family members about cervical cancer and motivate them to be screened. The study setting was Ward 23 in Muldersdrift, a semi-urban, resource poor area situated northeast of Johannesburg. We used an intervention research design to assess the outcomes of our educational program. The primary outcome was screening uptake, with knowledge the secondary outcome. Statistics and face-to-face and telephone interviews, guided by questionnaires, were used to collect the data which were analyzed by means of descriptive statistics and content analysis. A total of 120 men (n = 120) participated in the educational program and 100 (n = 100) completed the post-test questionnaire. Only 30 women (n = 30) reported for screening. The men's knowledge improved after the education program but did not guarantee that they would educate women about cervical cancer as only 55% (n = 66) indicated they taught a female family member or their partner. Cultural restrictions were the most common reason presented for not teaching women about this health issue. Ways of supporting men to overcome cultural barriers prohibiting them from discussing matters related to sexuality should be explored, before refining and replicating the intervention. PMID- 29139073 TI - Correction to: Economic growth and CO2 emissions: an investigation with smooth transition autoregressive distributed lag models for the 1800-2014 period in the USA. AB - The original publication of this paper contains a mistake. PMID- 29139072 TI - Elimination and detoxification of 2,4-D by Umbelopsis isabellina with the involvement of cytochrome P450. AB - The chemical 2,4-dichlorophenoxyacetic acid (2,4-D) is used in agriculture as a herbicide. Its intensive use has an adverse effect on the environment. This study involved examining the degradation of 2,4-D compound by the filamentous fungus Umbelopsis isabellina. After 5 days of incubation, 98% of the herbicide (added at 25 mg L-1) was found to be removed. The elimination of 2,4-D by U. isabellina was connected with the formation of 2,4-dichlorophenol (2,4-DCP), which resulted in a 60% decrease in the sample toxicity toward Artemia franciscana larvae. The metabolism of 2,4-D was inhibited by the addition of metyrapone, a known cytochrome P450 inhibitor. It provides evidence that cytochrome P450 system is involved in 2,4-D metabolism in U. isabellina. PMID- 29139074 TI - Excessive use of nitrogenous fertilizers: an unawareness causing serious threats to environment and human health. AB - Farmers occasionally need to add nitrogen fertilizer to their farms and gardens to make available just the precise nutrients for their plants' growth. The applications of inorganic nitrogen fertilizers to various crops have been continuously increasing since last many decades globally. Although nitrogen fertilizer contributes substantially to yield enhancement, but excessive use of this manure has posed serious threats to environment and human health. Rate of nitrogen fertilizers application has a close relationship with nitrate accumulation in surrounding environment, groundwater, as well as leafy and root vegetables. Consumption of diets having high nitrate contents has contributed to endogenous nitrosation, which could lead to thyroid condition, various kinds of human cancers, neural tube defects (during fetus development), and diabetes. In this short review, the authors have tried to create awareness among general public, farming community, health practitioners, and agricultural scientists for the risk involved with excessive use of nitrogen fertilizers to human health. Carcinogenic activity and other adverse effects of N-nitroso compounds might be prevented by consuming vitamin C and antioxidants containing fruits and vegetables. PMID- 29139075 TI - Investigation of the effects of slow-release fertilizer and struvite in biodegradation in filter drains and potential application of treated water in irrigation of road verges. AB - Filter drains are usually laid along the margins of highways. Highway runoffs are polluted with hydrocarbons and high levels of total dissolved solids. Therefore, effective pollution removal mechanism is necessary in order to avoid contamination of surrounding soils and groundwater. Biodegradation is amongst pollution removal mechanisms in filter drains, but it is a relatively slow process which is dependent on wide range of factors including the type of pollutant and availability of nutrients. This paper reports on a study conducted to investigate the impact of slow-release fertilizer and struvite in enhancement of biodegradation of hydrocarbon in filter drains. Filter drain models incorporated with geotextile were challenged with cumulative oil loading of 178 mg/m2/week with a view to comparing the efficiency of these two nutrient sources under high oil pollution loading and realistic rainfall conditions of 13 mm/week. Nutrients and street dust were applied at one-off rate of 17 g/m2 and 1.55 g/rig to provide nutrient enhancement and simulate field conditions respectively. The impact of the nutrients was studied by monitoring bacterial and fungal growth using nutrient agar, Rose Bengal Agar media and CO2 evolution. EC, pH, heavy metals, TPH, elemental analysis and SAR were used to investigate water quality of effluent of filter drains for potential application as irrigation fluid for trees and flowers planted on road verges. The results show that nutrient application encouraged microbial activities and enhanced biodegradation rates with differences in type of nutrient applied. Also, it was observed that incorporation of geotextiles in filter drains improved pollution retention efficiency and there is a potential opportunity for utilization of struvite in SuDS systems as sustainable nutrient source. PMID- 29139076 TI - Extended Spectrum Beta-Lactamase (ESBL)-producing bacteria isolated from hospital wastewaters, rivers and aquaculture sources in Nigeria. AB - Untreated wastewater is a risk factor for the spread of antibiotic resistance in the environment. However, little is known about the contribution of untreated wastewater to the burden of antibiotic resistance in the Nigerian environment. In this study, a total of 143 ceftazidime-/cefpodoxime-resistant bacteria isolated from untreated wastewater and untreated wastewater-contaminated surface and groundwater in Nigeria were screened for extended-spectrum beta-lactamase (ESBL) genes, integrons and integron gene cassettes by PCR. The genetic environment of bla CTX-M-15 was mapped by PCR and potentially conjugative plasmids were detected among the isolates by degenerate primer MOB typing (DPMT). ESBL production was confirmed in 114 (79.7%) isolates and ESBL genes (bla SHV, bla CTX-M-15 and bla TEM) were detected in 85 (74.6%) ESBL-producing isolates. bla CTX-M-15 was associated with ISEcp1 and with orf477 in 12 isolates and with ISEcp1, IS26 and orf477 in six others. To the best of our knowledge, this is the first report of bla CTX-M-15 in hand-dug wells and borehole serving as sources of drinking water and a first report of the genetic environment of bla CTX-M-15 in environmental bacteria from Nigeria. The results of this study confirm untreated wastewater as an important medium for the spread of ESBL-producing bacteria within the Nigerian environment. Hence, the widespread practice of discharging untreated wastewater into the aquatic ecosystem in Nigeria is a serious risk to public health. PMID- 29139077 TI - Spatiotemporal patterns and source attribution of nitrogen pollution in a typical headwater agricultural watershed in Southeastern China. AB - Excessive nitrogen (N) discharge from agriculture causes widespread problems in aquatic ecosystems. Knowledge of spatiotemporal patterns and source attribution of N pollution is critical for nutrient management programs but is poorly studied in headwaters with various small water bodies and mini-point pollution sources. Taking a typical small watershed in the low mountains of Southeastern China as an example, N pollution and source attribution were studied for a multipond system around a village using the Hydrological Simulation Program-Fortran (HSPF) model. The results exhibited distinctive spatio-seasonal variations with an overall seriousness rank for the three indicators: total nitrogen (TN) > nitrate/nitrite nitrogen (NOx--N) > ammonia nitrogen (NH3-N), according to the Chinese Surface Water Quality Standard. TN pollution was severe for the entire watershed, while NOx--N pollution was significant for ponds and ditches far from the village, and the NH3-N concentrations were acceptable except for the ponds near the village in summer. Although food and cash crop production accounted for the largest source of N loads, we discovered that mini-point pollution sources, including animal feeding operations, rural residential sewage, and waste, together contributed as high as 47% of the TN and NH3-N loads in ponds and ditches. So, apart from eco fertilizer programs and concentrated animal feeding operations, the importance of environmental awareness building for resource management is highlighted for small farmers in headwater agricultural watersheds. As a first attempt to incorporate multipond systems into the process-based modeling of nonpoint source (NPS) pollution, this work can inform other hydro-environmental studies on scattered and small water bodies. The results are also useful to water quality improvement for entire river basins. PMID- 29139078 TI - Combination Strategy of Quantitative Proteomics Uncovers the Related Proteins of Colorectal Cancer in the Interstitial Fluid of Colonic Tissue from the AOM-DSS Mouse Model. AB - Quantitative proteome analysis using iTRAQ is an important technique to find disease-related proteins. As an important component of tumor microenvironment, tissue interstitial fluid (TIF) has drawn a great attention for its potential as a source for exploration of the solid tumor biomarkers. On the basis of a mouse model of colorectal cancer (CRC) that was induced by the carcinogenetic reagents, we adopted a quantitative proteome analysis with iTRAQ to discover the CRC related proteins in the TIFs and with MRM to evaluate the corresponding abundance changes in the individual mouse TIF and serum samples. PMID- 29139079 TI - Neuromodulatory procedures for gait disorders in Parkinson's disease. AB - The neurophysiology of gait is complex and involves numerous structures in the central nervous system. Gait disorders occur frequently in Parkinson's disease (PD), and their management may become cumbersome, especially in the more advanced stages. Neuromodulatory treatments, including deep brain stimulation, cortical stimulation and spinal cord stimulation, are reviewed with respect to their effectiveness to improve gait in PD patients. Although positive effects have been reported for all of these procedures, many issues remain in view of methodological heterogeneity, variability in outcome measures and sample size. Gait in PD remains a difficult issue with a tremendous impact on quality of life, for which future research is badly needed. PMID- 29139080 TI - A Review of Insulin Resistance in Type 1 Diabetes: Is There a Place for Adjunctive Metformin? AB - There is a rising trend of overweight and obesity among individuals with type 1 diabetes. This is often associated with insulin resistance, increased insulin dose requirements and poor glycemic control. Insulin resistance is also seen during puberty and is strongly related to increased risk of cardiovascular disease. The role of metformin as an adjunct to ongoing intensive insulin therapy in type 1 diabetics has been evaluated in several randomized trials, including the recently concluded T1D Exchange Network trial in adolescents and the REMOVAL trial in adults. Metformin reduces the insulin dose requirement, insulin-induced weight gain, and total and LDL cholesterol, but results in an increased risk of gastrointestinal adverse effects and a minor increase in the risk of hypoglycemia. In addition, metformin has been shown to reduce maximal carotid intima media thickness and therefore may extend cardioprotective benefits in type 1 diabetes. The role of metformin as adjunctive therapy in type 1 diabetes needs to be explored further in outcome trials. PMID- 29139081 TI - Liraglutide Improves Cardiovascular Risk as an Add-on to Metformin and Not to Insulin Secretagogues in Type 2 Diabetic Patients: A Real-life 48-Month Retrospective Study. AB - INTRODUCTION: Although liraglutide is widely recognized to have glycemic and extra-glycemic effects, few studies have compared these effects in relation to hypoglycemic treatment starting from the diagnosis of diabetes. We evaluated the effectiveness of liraglutide in reducing the Framingham risk score (FRS) and visceral adiposity index (VAI) in relation to first-line hypoglycemic treatment from diagnosis of type 2 diabetes, continued without any changes. METHODS: We selected 105 diabetic outpatients who were treated with liraglutide for at least 48 months as an add-on therapy to metformin alone (group A, n = 52) or insulin secretagogues (group B, n = 53) from diagnosis time. RESULTS: Although both groups showed a reduction in BMI, waist circumference, blood pressure, HbA1c and triglycerides, only group A showed a significant reduction in FRS (p < 0.001) and VAI (p = 0.012) after 48 months. No significant intergroup difference was found for any parameters at either baseline or 48 months, with the exception of FRS at 48 months, lower in group A (p = 0.002), regardless of duration of disease, improvement in glycemic control and VAI. CONCLUSION: Our data show that during a 48-month follow-up liraglutide was more efficacious in reducing cardiovascular risk than when it was used as add-on therapy to the first-line therapy from diagnosis with metformin and not with insulin secretagogues. PMID- 29139082 TI - ASGE EndoVators Summit: Defining the Role and Value of Endoscopic Therapies in Obesity Management. PMID- 29139083 TI - Comparison of Hepatectomy for Patients with Metabolic Syndrome-Related HCC and HBV-Related HCC. AB - BACKGROUND: Metabolic syndrome (MetS) is a group of clinicopathological manifestations. The outcome of liver surgery in metabolic syndrome-related hepatocellular carcinoma (MetS-HCC) still needs to be evaluated. We aim to clarify the outcomes following liver resection in patients with MetS-HCC compared those with hepatitis B virus-related HCC (HBV-HCC). METHODS: All the consecutive patients undergoing hepatectomy for HCC between January 2009 and December 2012 were retrospectively considered. Patients were divided into three groups: MetS HCC, MetS-HBV-HCC, and HBV-HCC. Data on clinical characteristics, postoperative complications, and long-term outcome were collected and analyzed. RESULTS: A total of 1352 patients were included in this study. In MetS-HCC group, the severe morbidity rate was 33.33%, which was higher than that of HBV-HCC group (15.68%). In subgroup analysis, patients with MetS-HCC in American Joint Committee on Cancer (AJCC) stage I had superior DFS and OS when compared with those of the other two groups. CONCLUSIONS: We should pay more attention to patients with MetS HCC perioperatively due to the high rate of surgical complications. Nevertheless, curative treatment should be provided to patients with MetS. PMID- 29139084 TI - Common Hepatic Artery Abutment or Encasement Is an Adverse Prognostic Factor in Patients with Borderline and Unresectable Pancreatic Cancer. AB - BACKGROUND: Localized and unresectable pancreatic ductal adenocarcinoma (PDA) comprises one third of new diagnoses and includes borderline resectable (BR) and locally advanced (LA) unresectable disease. In a cohort of patients who were treated and followed at a single institution, we assessed clinical and radiographic predictors of outcome. METHODS: The study included 69 consecutive patients with BR or LA PDA. Serial imaging studies were reviewed by both a pancreatic surgeon and a radiologist for vascular abutment or encasement by cancer, and they were recorded. RESULTS: The cohort included 25 patients with BR and 44 patients with LA PDA, with median overall survivals (OS) of 15 and 14 months, respectively (p = 0.802). Fifteen patients were resected (22%), with a median OS of 21 months from diagnosis (HR 2.50, p = 0.006) and 13 months from resection. Median OS from diagnosis was 33 months in patients without lymph node metastases at resection (n = 10), but just 17 months with lymph node metastases (n = 5, HR = 8.95, p = 0.011). There were 12 two-year survivors in the total cohort (17%), and seven of them never underwent resection. First-line treatments consisted of gemcitabine (n = 13), modern first-line combinations (FOLFIRNOX or gemcitabine/nab-paclitaxel, n = 24), or alternative multi-agent therapies (n = 32); there were no statistical differences between treatment subgroups (OS of 10, 13, and 16 months, respectively). Common hepatic artery (CHA) abutment or encasement at diagnosis was associated with poor survival (adjusted hazard ratio, CHA abutment = 2.47 (p = 0.015) and CHA encasement = 2.16 (p = 0.036)). CONCLUSION: In this cohort, common hepatic arterial abutment or encasement and residual lymph node disease at resection portended a particularly poor outcome in patients with localized, unresectable PDA. PMID- 29139085 TI - In Reply: Colonic-Type Adenocarcinoma of the Tongue and Oral Cavity (CATOC). PMID- 29139086 TI - Diagnostic Approaches for Salivary Gland Tumors with Secretory and Microcystic Features. AB - Secretory carcinoma (SC) of the salivary gland is a new entity that shares the unique morphologic features and cytogenetic characteristics of the ETV6-NTRK3 fusion gene with its breast counterpart. Before identification of SC of the salivary gland, it was most frequently diagnosed as acinic cell carcinoma (AciCC). We retrospectively reviewed our own database of salivary gland tumors harboring microcystic and papillary architecture and/or secretory features that were originally diagnosed as AciCC. We selected nine cases of AciCC showing diffuse S-100 expression on immunohistochemistry (IHC). A recently diagnosed case of SC was included in the study as a reference sample. We performed IHC of S-100 and mammaglobin and ETV6 gene fluorescence in situ hybridization (FISH) in all cases. Seven cases were positive for both S-100 and mammaglobin, while five of the seven (71.4%) demonstrated ETV6 gene translocation by FISH. In the cases which did not co-express either S-100 or mammaglobin on IHC, ETV6 gene rearrangement was not shown on FISH. In conclusion, if a salivary gland tumor has morphologic features of SC with co-expression of S-100 and mammaglobin, ETV6 FISH can be performed to confirm the diagnosis of SC of the salivary gland. PMID- 29139087 TI - The Role of Reactive Oxygen Species in Adipogenic Differentiation. AB - Interest in reactive oxygen species and adipocyte differentiation/adipose tissue function is steadily increasing. This is due in part to a search for alternative avenues for combating obesity, which results from the excess accumulation of adipose tissue. Obesity is a major risk factor for complex disorders such as cancer, type 2 diabetes, and cardiovascular diseases. The ability of mesenchymal stromal/stem cells (MSCs) to differentiate into adipocytes is often used as a model for studying adipogenesis in vitro. A key focus is the effect of both intra and extracellular reactive oxygen species (ROS) on adipogenesis. The consensus from the majority of studies is that ROS, irrespective of the source, promote adipogenesis.The effect of ROS on adipogenesis is suppressed by antioxidants or ROS scavengers. Reactive oxygen species are generated during the process of adipocyte differentiation as well as by other cell metabolic processes. Despite many studies in this field, it is still not possible to state with certainty whether ROS measured during adipocyte differentiation are a cause or consequence of this process. In addition, it is still unclear what the exact sources are of the ROS that initiate and/or drive adipogenic differentiation in MSCs in vivo. This review provides an overview of our understanding of the role of ROS in adipocyte differentiation as well as how certain ROS scavengers and antioxidants might affect this process. PMID- 29139088 TI - Contrasting Views on the Role of Mesenchymal Stromal/Stem Cells in Tumour Growth: A Systematic Review of Experimental Design. AB - The effect of mesenchymal stromal/stem cells (MSCs) on tumour growth remains controversial. Experimental evidence supports both an inhibitory and a stimulatory effect. We have assessed factors responsible for the contrasting effects of MSCs on tumour growth by doing a meta-analysis of existing literature between 2000 and May 2017. We assessed 183 original research articles comprising 338 experiments. We considered (a) in vivo and in vitro experiments, (b) whether in vivo studies were syngeneic or xenogeneic, and (c) if animals were immune competent or deficient. Furthermore, the sources and types of cancer cells and MSCs were considered together with modes of cancer induction and MSC administration. 56% of all 338 experiments reported that MSCs promote tumour growth. 78% and 79% of all experiments sourced human MSCs and cancer cells, respectively. MSCs were used in their naive and engineered form in 86% and 14% of experiments, respectively, the latter to produce factors that could alter either their activity or that of the tumour. 53% of all experiments were conducted in vitro with 60% exposing cancer cells to MSCs via coculture. Of all in vivo experiments, 79% were xenogeneic and 63% were conducted in immune-competent animals. Tumour growth was inhibited in 80% of experiments that used umbilical cord-derived MSCs, whereas tumour growth was promoted in 64% and 57% of experiments that used bone marrow- and adipose tissue-derived MSCs, respectively. This contrasting effect of MSCs on tumour growth observed under different experimental conditions may reflect differences in experimental design. This analysis calls for careful consideration of experimental design given the large number of MSC clinical trials currently underway. PMID- 29139089 TI - Cancer Stem Cells in Head and Neck Carcinomas: Identification and Possible Therapeutic Implications. AB - The recurrence and/or lack of response of certain tumors to radio- and chemotherapy has been attributed to a small subpopulation of cells termed cancer stem cells (CSCs). CSCs have been identified in many tumors (including solid and hematological tumors). CSCs are characterized by their capacity for self-renewal, their ability to introduce heterogeneity within a tumor mass and its metastases, genomic instability, and their insensitivity to both radiation and chemotherapy. The latter highlights the clinical importance of studying this subpopulation since their resistance to traditional treatments may lead to metastatic disease and/or tumor relapse. Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignancy worldwide with the highest incidence occurring in East Asia and eastern and southern Africa. Several cellular subpopulations believed to have CSC properties have been isolated from HNSCCs, but at present, identification and characterization of CSCs remains an experimental challenge with no established or standardized protocols in place to confirm their identity. In this review we discuss current approaches to the study of CSCs with a focus on HNSCCs, particularly in the context of what this might mean from a therapeutic perspective. PMID- 29139090 TI - Tofacitinib: A Review in Rheumatoid Arthritis. AB - Tofacitinib (Xeljanz(r)) is a potent, selective JAK inhibitor that preferentially inhibits Janus kinase (JAK) 1 and JAK3. In the EU, oral tofacitinib 5 mg twice daily is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant of, one or more DMARDs. Several clinical studies of <= 24 months' duration showed that tofacitinib monotherapy (as first- or second-line treatment) and combination therapy with a conventional synthetic DMARD (csDMARD; as second- or third-line treatment) was effective in reducing signs and symptoms of disease and improving health-related quality of life (HR-QOL), with benefits sustained during long-term therapy (<= 96 months). Tofacitinib monotherapy inhibited progression of structural damage in methotrexate-naive patients during <= 24 months' treatment, with beneficial effects also seen in patients receiving tofacitinib plus methotrexate as second-line therapy for 12 months. Tofacitinib was generally well tolerated during <= 114 months' treatment, with most adverse events of mild or moderate severity. The tolerability profile of tofacitinib was generally similar to that of biological DMARDs (bDMARDs), with infections and infestations the most common adverse events (AEs) in tofacitinib recipients. However, the incidence of herpes zoster (HZ) was higher with tofacitinib than in the general RA population, although infections were clinically manageable. When added to background methotrexate, tofacitinib was noninferior to adalimumab in terms of efficacy, and both combination therapies had generally similar tolerability profiles. Although additional comparative studies are needed to more definitively position tofacitinib relative to bDMARDs and other targeted synthetic DMARDs, current evidence indicates that oral tofacitinib is a useful option for the treatment of patients with RA. PMID- 29139092 TI - Effects of Allopurinol on Endothelial Function: A Systematic Review and Meta Analysis of Randomized Placebo-Controlled Trials. AB - INTRODUCTION: Uric acid (UA), the final product of purine catabolism, may be associated with an increased risk of cardiovascular disease. AIM: The aim of this meta-analysis of randomized placebo-controlled trials was to evaluate whether lowering serum UA (SUA) levels with allopurinol is associated with improved flow mediated dilation (FMD), a validated marker of early vascular damage. METHODS: A literature search was carried out from inception until 20 June 2017. Meta analysis was performed using an inverse variance-weighted, random-effects model with standardized mean difference (SMD) as the effect size estimate. RESULTS: Meta-analysis of data from the ten eligible randomized controlled trials (RCTs), with 670 subjects, suggested a significant increase in FMD following allopurinol treatment (weighted mean difference [WMD] 1.79%, 95% confidence interval [CI] 1.01-2.56, p < 0.001; I 2: 86.77%). The effect size was robust and remained significant after omission of each single study. Subgroup analyses of RCTs based on the administered dose or duration of treatment did not reveal any significant impact of these variables on FMD change. Nor was a significant association found between allopurinol-induced changes in SUA levels and FMD (slope 0.46, p = 0.253), whereas baseline FMD significantly influenced the degree of FMD improvement following allopurinol treatment (slope 0.52, p = 0.022). Nitroglycerin-mediated dilation was not altered by allopurinol treatment (WMD 0.88%, 95% CI - 1.15-2.91, p = 0.395; I 2: 80.88%). CONCLUSION: This meta analysis of available RCTs suggests a significant benefit from allopurinol intake in increasing FMD in humans, independent of its effect on SUA levels. PMID- 29139091 TI - Pharmacological Approach to the Management of Crohn's Disease Patients with Perianal Disease. AB - Perianal localization of Crohn's disease involves significant morbidity, affects quality of life and results in an increased use of healthcare resources. Medical and surgical therapies contribute to its management. The objective of this review is to address the current understanding in the management of perianal Crohn's disease, with the main focus in reviewing pharmacological therapies, including stem cells. In complex fistulas, once local sepsis has been controlled by surgical drainage and/or antibiotics, anti-TNF drugs (infliximab, adalimumab) are the first-line therapy, with or without associated immunomodulators. Combining surgery and anti-TNF therapy has additional benefits for healing. However, response is inadequate in up to half of cases. A possible role of new biological drugs in this context (vedolizumab, ustekinumab) is an area of ongoing investigation, as is the local application of autologous or allogeneic mesenchymal stem cells. These are non-hematopoietic multipotent cells with anti inflammatory and immunomodulatory properties, the use of which may successfully treat refractory patients, and seem to be a promising and safe alternative to achieving fistula healing in Crohn's disease, without known systemic effects. PMID- 29139094 TI - Investigating the therapeutic potential and mechanism of curcumin in breast cancer based on RNA sequencing and bioinformatics analysis. AB - BACKGROUND: Breast cancer is a prevalent cancer in female. This study aims to investigate the therapeutic potential and mechanism of curcumin in breast cancer. METHODS: After cultivation, human breast cancer cells (MCF-7 cells) were treated with 0.1% (v/v) 15 umol/ml curcumin-dimethylsulfoxide solution and 0.1% (v/v) dimethylsulfoxide, respectively, at 37 degrees C and 5% CO2 for 48 h. Total RNA was extracted, cDNA library was constructed, and cDNAs were amplified and sequenced. After data preprocessing, the Cufflinks software was utilized to identify differentially expressed genes (DEGs, |log2 fold change| > 0.5 and p value < 0.05). Then, functional and pathway enrichment analyses were performed through DAVID (p value < 0.05) and WebGestalt [false discovery rate (FDR) < 0.05], respectively. Furthermore, drug and disease association analyses (FDR < 0.05) were conducted through WebGestalt and DAVID, respectively. STRING was employed to construct protein-protein interaction (PPI) network (combined score > 0.4). RESULTS: After DEGs screening, 347 DEGs were identified. Up-regulated DEGs were enriched in 14 functions and 3 pathways, and associated with 12 drugs. Down regulated DEGs were enriched in 14 functions and 9 pathways, and associated with 14 drugs. Moreover, 5 DEGs were associated with breast cancer, including PGAP3, MAP3K1, SERPINE1, PON2, and GSTO2. PPI network was constructed, and the top DEGs were FOS, VIM, FGF2, MAPK1, SPARC, TOMM7, PSMB10, TCEB2, SOCS1, COL4A1, UQCR11, SERPINE1, and ISG15. CONCLUSION: Curcumin might have therapeutic potential in breast cancer through regulating breast cancer-related genes, including SERPINE1, PGAP3, MAP3K1, MAPK1, GSTO2, VIM, SPARC, and FGF2. However, validations are required. PMID- 29139095 TI - Local alkylating chemotherapy applied immediately after 5-ALA guided resection of glioblastoma does not provide additional benefit. AB - Grade IV glioma is the most common and aggressive primary brain tumour. Gross total resection with 5-aminolevulinic acid (5-ALA) guided surgery combined with local chemotherapy (carmustine wafers) is an attractive treatment strategy in these patients. No previous studies have examined the benefit carmustine wafers in a treatment programme of 5-ALA guided resection followed by a temozolomide based chemoradiotherapy protocol. The objective of this study was to examine the benefit of carmustine wafers on survival in patients undergoing 5-ALA guided resection. A retrospective cohort study of 260 patients who underwent 5-ALA resection of confirmed WHO 2007 Grade IV glioma between July 2009 and December 2014. Survival curves were calculated using the Kaplan-Meier method from surgery. The log-rank test was used to compare survival curves between groups. Cox regression was performed to identify variables predicting survival. A propensity score matched analysis was used to compare survival between patients who did and did not receive carmustine wafers while controlling for baseline characteristics. Propensity matched analysis showed no significant survival benefit of insertion of carmustine wafers over 5-ALA resection alone (HR 0.97 [0.68-1.26], p = 0.836). There was a trend to higher incidence of wound infection in those who received carmustine wafers (15.4 vs. 7.1%, p = 0.064). The Cox regression analysis showed that intraoperative residual fluorescent tumour and residual enhancing tumour on post-operative MRI were significantly predictive of reduced survival. Carmustine wafers have no added benefit following 5-ALA guided resection. Residual fluorescence and residual enhancing disease following resection have a negative impact on survival. PMID- 29139096 TI - The modified frailty index and 30-day adverse events in oncologic neurosurgery. AB - The modified frailty index (mFI) is emerging as a leading measure for preoperative risk assessment using routinely available medical record data. Our objective was to determine if mFI predicts morbidity and mortality in the diverse national cohort of patients undergoing neurosurgery for intracranial neoplasms. We identified patients in the National Surgical Quality Improvement Program who underwent oncologic neurosurgery procedures between 2008 and 2012. The mFI, ranging from 0 to 1, was calculated as the proportion of 11 possible risk factors present. We assessed the associations between mFI and 30-day mortality, neurologic and medical complications, prolonged length of stay, and unfavorable discharge in univariate and multivariable analyses and compare the index to established risk stratification techniques. A total of 9149 patients were identified. Mortality, severe medical complications, prolonged length of stay, and unfavorable discharge increased incrementally with increasing levels of frailty. Severe neurologic complications were highest in those with low frailty. In multivariable logistic regression analysis, increased frailty increased the odds of all adverse outcomes, including neurologic complications. The mFI increased the ability to predict all outcomes beyond available indices and was the most reliable predictor of neurologic complications. The mFI can be calculated from routinely collected medical record data and is predictive of 30 day adverse outcomes in a wide variety of neurosurgical oncology patients. The index may be a useful component of preoperative risk assessment with implications for shared decision-making, perioperative planning, and risk adjusted outcomes measurement in national quality registries. PMID- 29139098 TI - ? PMID- 29139097 TI - Correction to: Leukemia Inhibitory Factor Increases Survival of Pluripotent Stem Cell-Derived Cardiomyocytes. AB - Please note that Carolina Bluguermann's surname was misspelled (as Bluguermann) in this article as originally published. PMID- 29139099 TI - [Test Your Knowledge]. PMID- 29139101 TI - [Endobronchial Ultrasound (EBUS) - an Update 2017]. AB - Endobronchial Ultrasound (EBUS) with the two modalities curved and radial EBUS significantly improved the diagnostics in several pulmonary diseases. The examination and staging of mediastinal and hilar lymph nodes in patients with known or suspected lung malignancy as well as the evaluation of unknown pulmonary or mediastinal lesions can be achieved with minimal invasive means when using EBUS. More invasive surgical procedures for diagnostic purposes can be omitted. The diagnostic yield also increases when EBUS is applied in sarcoidosis or mediastinal lymph node tuberculosis but only to some extend in case of lymphoma. Samples obtained by EBUS-TBNA should be handled efficiently to allow molecular analysis in lung cancer. EBUS is a safe procedure, and complication rate is extremely low. Further advances of the EBUS technology focus on improving analysis of the information provided by the ultrasound image and a better tissue sampling by developing of new EBUS bronchoscopes and TBNA-needles. PMID- 29139100 TI - [Guidelines for Non-Invasive and Invasive Home Mechanical Ventilation for Treatment of Chronic Respiratory Failure - Update 2017]. AB - Today, invasive and non-invasive home mechanical ventilation have become a well established treatment option. Consequently, in 2010 the German Society of Pneumology and Mechanical Ventilation (DGP) has leadingly published the guidelines on "Non-Invasive and Invasive Mechanical Ventilation for Treatment of Chronic Respiratory Failure". However, continuing technical evolutions, new scientific insights, and health care developments require an extensive revision of the guidelines.For this reason, the updated guidelines are now published. Thereby, the existing chapters, namely technical issues, organizational structures in Germany, qualification criteria, disease specific recommendations including special features in pediatrics as well as ethical aspects and palliative care, have been updated according to the current literature and the health care developments in Germany. New chapters added to the guidelines include the topics of home mechanical ventilation in paraplegic patients and in those with failure of prolonged weaning.In the current guidelines different societies as well as professional and expert associations have been involved when compared to the 2010 guidelines. Importantly, disease-specific aspects are now covered by the German Interdisciplinary Society of Home Mechanical Ventilation (DIGAB). In addition, societies and associations directly involved in the care of patients receiving home mechanical ventilation have been included in the current process. Importantly, associations responsible for decisions on costs in the health care system and patient organizations have now been involved.The currently updated guidelines are valid for the next three years, following their first online publication on the home page of the Association of the Scientific Medical Societies in German (AWMF) in the beginning of July 2017. A subsequent revision of the guidelines remains the aim for the future. PMID- 29139103 TI - Differentiation potential of human adipose stem cells bioprinted with hyaluronic acid/gelatin-based bioink through microextrusion and visible light-initiated crosslinking. AB - Bioprinting has a great potential to fabricate three-dimensional (3D) functional tissues and organs. In particular, the technique enables fabrication of 3D constructs containing stem cells while maintaining cell proliferation and differentiation abilities, which is believed to be promising in the fields of tissue engineering and regenerative medicine. We aimed to demonstrate the utility of the bioprinting technique to create hydrogel constructs consisting of hyaluronic acid (HA) and gelatin derivatives through irradiation by visible light to fabricate 3D constructs containing human adipose stem cells (hADSCs). The hydrogel was obtained from a solution of HA and gelatin derivatives possessing phenolic hydroxyl moieties in the presence of ruthenium(II) tris-bipyridyl dication and sodium ammonium persulfate. hADSCs enclosed in the bioprinted hydrogel construct elongated and proliferated in the hydrogel. In addition, their differentiation potential was confirmed by examining the expression of pluripotency marker genes and cell surface marker proteins, and differentiation to adipocytes in adipogenic differentiation medium. Our results demonstrate the great potential of the bioprinting method and the resultant hADSC-laden HA/gelatin constructs for applications in tissue engineering and regenerative medicine. PMID- 29139104 TI - Ancestry and dental development: A geographic and genetic perspective. AB - OBJECTIVE: In this study, we investigated the influence of ancestry on dental development in the Generation R Study. METHODS: Information on geographic ancestry was available in 3,600 children (1,810 boys and 1,790 girls, mean age 9.81 +/- 0.35 years) and information about genetic ancestry was available in 2,786 children (1,387 boys and 1,399 girls, mean age 9.82 +/- 0.34 years). Dental development was assessed in all children using the Demirjian method. The associations of geographic ancestry (Cape Verdean, Moroccan, Turkish, Dutch Antillean, Surinamese Creole and Surinamese Hindustani vs Dutch as the reference group) and genetic content of ancestry (European, African or Asian) with dental development was analyzed using linear regression models. RESULTS: In a geographic perspective of ancestry, Moroccan (beta = 0.18; 95% CI: 0.07, 0.28), Turkish (beta = 0.22; 95% CI: 0.12, 0.32), Dutch Antillean (beta = 0.27; 95% CI: 0.12, 0.41), and Surinamese Creole (beta = 0.16; 95% CI: 0.03, 0.30) preceded Dutch children in dental development. Moreover, in a genetic perspective of ancestry, a higher proportion of European ancestry was associated with decelerated dental development (beta = -0.32; 95% CI: -.44, -.20). In contrast, a higher proportion of African ancestry (beta = 0.29; 95% CI: 0.16, 0.43) and a higher proportion of Asian ancestry (beta = 0.28; 95% CI: 0.09, 0.48) were associated with accelerated dental development. When investigating only European children, these effect estimates increased to twice as large in absolute value. CONCLUSION: Based on a geographic and genetic perspective, differences in dental development exist in a population of heterogeneous ancestry and should be considered when describing the physiological growth in children. PMID- 29139105 TI - Preoperative medical therapy before surgery for uterine fibroids. AB - BACKGROUND: Uterine fibroids occur in up to 40% of women aged over 35 years. Some are asymptomatic, but up to 50% cause symptoms that warrant therapy. Symptoms include anaemia caused by heavy menstrual bleeding, pelvic pain, dysmenorrhoea, infertility and low quality of life. Surgery is the first choice of treatment. In recent years, medical therapies have been used before surgery to improve intraoperative and postoperative outcomes. However, such therapies tend to be expensive.Fibroid growth is stimulated by oestrogen. Gonadotropin-hormone releasing analogues (GnRHa) induce a state of hypo-oestrogenism that shrinks fibroids , but has unacceptable side effects if used long-term. Other potential hormonal treatments, include progestins and selective progesterone-receptor modulators (SPRMs).This is an update of a Cochrane Review published in 2000 and 2001; the scope has been broadened to include all preoperative medical treatments. OBJECTIVES: To assess the effectiveness and safety of medical treatments prior to surgery for uterine fibroids. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL in June 2017. We also searched trials registers (ClinicalTrials.com; WHO ICTRP), theses and dissertations and the grey literature, handsearched reference lists of retrieved articles and contacted pharmaceutical companies for additional trials. SELECTION CRITERIA: We included randomised comparisons of medical therapy versus placebo, no treatment, or other medical therapy before surgery, myomectomy, hysterectomy or endometrial resection, for uterine fibroids. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included a total of 38 RCTs (3623 women); 19 studies compared GnRHa to no pretreatment (n = 19), placebo (n = 8), other medical pretreatments (progestin, SPRMs, selective oestrogen receptor modulators (SERMs), dopamine agonists, oestrogen receptor antagonists) (n = 7), and four compared SPRMs with placebo. Most results provided low-quality evidence due to limitations in study design (poor reporting of randomisation procedures, lack of blinding), imprecision and inconsistency. GnRHa versus no treatment or placebo GnRHa treatments were associated with reductions in both uterine (MD -175 mL, 95% CI -219.0 to -131.7; 13 studies; 858 participants; I2 = 67%; low-quality evidence) and fibroid volume (heterogeneous studies, MD 5.7 mL to 155.4 mL), and increased preoperative haemoglobin (MD 0.88 g/dL, 95% CI 0.7 to 1.1; 10 studies; 834 participants; I2 = 0%; moderate-quality evidence), at the expense of a greater likelihood of adverse events, particularly hot flushes (OR 7.68, 95% CI 4.6 to 13.0; 6 studies; 877 participants; I2 = 46%; moderate-quality evidence).Duration of hysterectomy surgery was reduced among women who received GnRHa treatment (-9.59 minutes, 95% CI 15.9 to -3.28; 6 studies; 617 participants; I2 = 57%; low-quality evidence) and there was less blood loss (heterogeneous studies, MD 25 mL to 148 mL), fewer blood transfusions (OR 0.54, 95% CI 0.3 to 1.0; 6 studies; 601 participants; I2 = 0%; moderate-quality evidence), and fewer postoperative complications (OR 0.54, 95% CI 0.3 to 0.9; 7 studies; 772 participants; I2 = 28%; low-quality evidence).GnRHa appeared to reduce intraoperative blood loss during myomectomy (MD 22 mL to 157 mL). There was no clear evidence of a difference among groups for other primary outcomes after myomectomy: duration of surgery (studies too heterogeneous for pooling), blood transfusions (OR 0.85, 95% CI 0.3 to 2.8; 4 studies; 121 participants; I2 = 0%; low-quality evidence) or postoperative complications (OR 1.07, 95% CI 0.43 to 2.64; I2 = 0%; 5 studies; 190 participants; low-quality evidence). No suitable data were available for analysis of preoperative bleeding. GnRHa versus other medical therapies GnRHa was associated with a greater reduction in uterine volume (-47% with GnRHa compared to -20% and -22% with 5 mg and 10 mg ulipristal acetate) but was more likely to cause hot flushes (OR 12.3, 95% CI 4.04 to 37.48; 5 studies; 183 participants; I2 = 61%; low-quality evidence) compared with ulipristal acetate. There was no clear evidence of a difference in bleeding reduction (ulipristal acetate 5 mg: OR 0.71, 95% CI 0.3 to 1.7; 1 study; 199 participants; moderate-quality evidence; ulipristal acetate 10 mg: OR 0.39, 95% CI 0.1 to 1.1; 1 study; 203 participants; moderate-quality evidence) or haemoglobin levels (MD -0.2, 95% CI -0.6 to 0.2; 188 participants; moderate-quality evidence).There was no clear evidence of a difference in fibroid volume between GnRHa and cabergoline (MD 12.71 mL, 95% CI 5.9 to 31.3; 2 studies; 110 participants; I2 = 0%; low-quality evidence).The included studies did not report usable data for any other primary outcomes. SPRMs versus placebo SPRMs (mifepristone, CDB-2914, ulipristal acetate and asoprisnil) were associated with greater reductions in uterine or fibroid volume than placebo (studies too heterogeneous to pool) and increased preoperative haemoglobin levels (MD 0.93 g/dL, 0.5 to 1.4; 2 studies; 173 participants; I2 = 0%; high-quality evidence). Ulipristal acetate and asoprisnil were also associated with greater reductions in bleeding before surgery (ulipristal acetate 5 mg: OR 41.41, 95% CI 15.3 to 112.4; 1 study; 143 participants; low-quality evidence; ulipristal acetate 10 mg: OR 78.83, 95% CI 24.0 to 258.7; 1 study; 146 participants; low quality evidence; asoprisnil: MD -166.9 mL; 95% CI -277.6 to -56.2; 1 study; 22 participants; low-quality evidence). There was no evidence of differences in preoperative complications. No other primary outcomes were measured. AUTHORS' CONCLUSIONS: A rationale for the use of preoperative medical therapy before surgery for fibroids is to make surgery easier. There is clear evidence that preoperative GnRHa reduces uterine and fibroid volume, and increases preoperative haemoglobin levels, although GnRHa increases the incidence of hot flushes. During hysterectomy, blood loss, operation time and complication rates were also reduced. Evidence suggests that ulipristal acetate may offer similar advantages (reduced fibroid volume and fibroid-related bleeding and increased haemoglobin levels) although replication of these studies is advised before firm conclusions can be made. Future research should focus on cost-effectiveness and distinguish between groups of women with fibroids who would most benefit. PMID- 29139106 TI - De-Stigmatizing Migraine - With Words. PMID- 29139107 TI - Antenatal influenza and pertussis vaccine uptake among Aboriginal mothers in Western Australia. AB - BACKGROUND: Antenatal influenza and pertussis vaccination prevent serious disease in mothers and infants. Aboriginal individuals are at increased risk of infection yet little is known about vaccine coverage among Aboriginal mothers. AIMS: To estimate the uptake of influenza and pertussis vaccination among pregnant Aboriginal women in Western Australia and identify barriers and enablers to vaccination. MATERIALS AND METHODS: Four hundred Aboriginal women, aged >=18 years, who gave birth to a live infant between April and October 2015, were randomly selected and invited to participate in telephone interviews. Of the 387 women who did not decline, 178 had a functioning phone number and 100 completed the survey. Analyses were weighted by maternal residence. RESULTS: During pregnancy the majority of Aboriginal mothers were recommended influenza (66%; unweighted, 65/96 = 68%) and pertussis (65%; unweighted, 62/94 = 66%) vaccines, with 62% (unweighted, 56/94 = 56%) and 63% (unweighted, 60/93 = 65%) receiving the vaccinations, respectively. Almost all vaccinated women (98%) reported wanting to protect their baby as the reason for immunisation. Rural mothers were more likely than metropolitan mothers to have been vaccinated against influenza (odds ratio (OR) 4.1, 95% CI 1.7-10.2) and pertussis (OR 3.1, 95% CI 1.2-7.6). Recommendation by a healthcare provider was strongly associated with vaccine uptake (influenza: OR 15.6, 95% CI 4.9-49.5; pertussis: OR 13.3, 95% CI 4.6 38.0). CONCLUSION: Vaccination uptake among Western Australian Aboriginal mothers is comparable with rates reported for non-Aboriginal populations worldwide. Provider recommendation is the single most important factor associated with vaccination uptake, underlining the importance of integrating vaccination into routine antenatal care. PMID- 29139108 TI - A 3' untranslated region polymorphism rs2304277 in the DNA repair pathway gene OGG1 is a novel risk modulator for urothelial bladder carcinoma. AB - Altered DNA repair capacity may affect an individual's susceptibility to cancers due to compromised genomic integrity. This study was designed to elucidate the association of selected polymorphisms in DNA repair genes with urothelial bladder carcinoma (UBC). OGG1 rs1052133 and rs2304277, XRCC1 rs1799782 and rs25487, XRCC3 rs861539, XPC rs2228001, and XPD rs13181 were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 200 UBC cases and 200 controls. We found association of OGG1 rs2304277 [odds ratio (OR)GG = 3.55, 95% confidence interval (CI) = 1.79-7.06] and XPC rs2228001 (ORAC = 2.38, 95% CI = 1.43-3.94) with UBC. In stratified analysis with respect to smoking status, OGG1 rs2304277 and XPC rs2228001 exhibited increased risk in smokers [(rs2304277 ORGG = 4.96, 95% CI = 1.51-16.30) (rs2228001 ORAC = 2.19, 95% CI = 1.02-4.72)] as well as nonsmokers [(rs2304277 ORGG = 2.95, 95% CI = 1.26-6.90) (rs2228001 ORAC = 2.57, 95% CI = 1.31-5.04)]. These polymorphisms were also associated with both low-grade [(rs2304277 ORGG = 3.73, 95% CI = 1.72-8.09) (rs2228001 ORAC = 2.18, 95% CI = 1.21-3.92)] and high-grade tumors [(rs2304277 ORGG = 3.45, 95% CI = 1.52 7.80) (rs2228001 ORAC = 2.81, 95% CI = 1.48-5.33)] as well as with non-muscle invasive bladder cancer [(rs2304277 ORGG = 4.03, 95% CI = 1.87-8.67) (rs2228001 ORAC = 2.14, 95% CI = 1.20-3.81)] and muscle-invasive bladder cancer [(rs2304277 ORGG = 3.06, 95%CI = 1.31-7.13) (rs2228001 ORAC = 2.95, 95%CI = 1.51-5.75)]. This is the first study on DNA repair gene polymorphisms and UBC in the Pakistani population. It identifies OGG1 rs2304277 and replicates XPC rs2228001 as significant modulators of UBC susceptibility. PMID- 29139109 TI - beta-cyclodextrin encapsulated polyphenols as effective antioxidants. AB - Formation of dityrosine (DT) cross-linkages in proteins is one of the most widely used markers of oxidative stress. Ribonuclease A (RNase A) has 6 Tyr residues and shows a characteristic DT fluorescence peak upon oxidation in addition to major changes in its secondary structure. DT formation can be prevented by using polyphenols (GA, ECG, and EGCG) which are known to have strong antioxidant activity. However, it has been observed that ECG and EGCG initiate protein oligomerization due to protein-polyphenol cross-linkages. To prevent the formation of such cross-linkages we have used beta-cyclodextrin (beta-CD) to encapsulate the polyphenols and studied its antioxidant properties along with that of free polyphenols. The polyphenol/beta-cyclodextrin (beta-CD) inclusion complexes not only prevent DT formation but also reduce protein oligomerization. This may be attributed to the fact that the quinone forming rings of ECG and EGCG become encapsulated in the cavity of beta-CD and are no longer available for protein cross-linking. PMID- 29139111 TI - A retrotransposon in an HKT1 family sodium transporter causes variation of leaf Na+ exclusion and salt tolerance in maize. AB - Soil salinity is one of several major abiotic stresses that constrain maize productivity worldwide. An improved understanding of salt-tolerance mechanisms will thus enhance the breeding of salt-tolerant maize and boost productivity. Previous studies have indicated that the maintenance of leaf Na+ concentration is essential for maize salt tolerance, and the difference in leaf Na+ exclusion has previously been associated with variation in salt tolerance between maize varieties. Here, we report the identification and functional characterization of a maize salt-tolerance quantitative trait locus (QTL), Zea mays Na+ Content1 (ZmNC1), which encodes an HKT-type transporter (designated as ZmHKT1). We show that a natural ZmHKT1 loss-of-function allele containing a retrotransposon insertion confers increased accumulation of Na+ in leaves, and salt hypersensitivity. We next show that ZmHKT1 encodes a plasma membrane-localized Na+ -selective transporter, and is preferentially expressed in root stele (including the parenchyma cells surrounding the xylem vessels). We also show that loss of ZmHKT1 function increases xylem sap Na+ concentration and causes increased root-to-shoot Na+ delivery, indicating that ZmHKT1 promotes leaf Na+ exclusion and salt tolerance by withdrawing Na+ from the xylem sap. We conclude that ZmHKT1 is a major salt-tolerance QTL and identifies an important new gene target in breeding for improved maize salt tolerance. PMID- 29139110 TI - Unconditional cash transfers for reducing poverty and vulnerabilities: effect on use of health services and health outcomes in low- and middle-income countries. AB - BACKGROUND: Unconditional cash transfers (UCTs; provided without obligation) for reducing poverty and vulnerabilities (e.g. orphanhood, old age or HIV infection) are a type of social protection intervention that addresses a key social determinant of health (income) in low- and middle-income countries (LMICs). The relative effectiveness of UCTs compared with conditional cash transfers (CCTs; provided so long as the recipient engages in prescribed behaviours such as using a health service or attending school) is unknown. OBJECTIVES: To assess the effects of UCTs for improving health services use and health outcomes in vulnerable children and adults in LMICs. Secondary objectives are to assess the effects of UCTs on social determinants of health and healthcare expenditure and to compare to effects of UCTs versus CCTs. SEARCH METHODS: We searched 17 electronic academic databases, including the Cochrane Public Health Group Specialised Register, the Cochrane Database of Systematic Reviews (the Cochrane Library 2017, Issue 5), MEDLINE and Embase, in May 2017. We also searched six electronic grey literature databases and websites of key organisations, handsearched key journals and included records, and sought expert advice. SELECTION CRITERIA: We included both parallel group and cluster-randomised controlled trials (RCTs), quasi-RCTs, cohort and controlled before-and-after (CBAs) studies, and interrupted time series studies of UCT interventions in children (0 to 17 years) and adults (18 years or older) in LMICs. Comparison groups received either no UCT or a smaller UCT. Our primary outcomes were any health services use or health outcome. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened potentially relevant records for inclusion criteria, extracted data and assessed the risk of bias. We tried to obtain missing data from study authors if feasible. For cluster-RCTs, we generally calculated risk ratios for dichotomous outcomes from crude frequency measures in approximately correct analyses. Meta-analyses applied the inverse variance or Mantel-Haenszel method with random effects. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included 21 studies (16 cluster-RCTs, 4 CBAs and 1 cohort study) involving 1,092,877 participants (36,068 children and 1,056,809 adults) and 31,865 households in Africa, the Americas and South-East Asia in our meta-analyses and narrative synthesis. The 17 types of UCTs we identified, including one basic universal income intervention, were pilot or established government programmes or research experiments. The cash value was equivalent to 1.3% to 53.9% of the annualised gross domestic product per capita. All studies compared a UCT with no UCT, and three studies also compared a UCT with a CCT. Most studies carried an overall high risk of bias (i.e. often selection and/or performance bias). Most studies were funded by national governments and/or international organisations.Throughout the review, we use the words 'probably' to indicate moderate-quality evidence, 'may/maybe' for low quality evidence, and 'uncertain' for very low-quality evidence. UCTs may not have impacted the likelihood of having used any health service in the previous 1 to 12 months, when participants were followed up between 12 and 24 months into the intervention (risk ratio (RR) 1.04, 95% confidence interval (CI) 1.00 to 1.09, P = 0.07, 5 cluster-RCTs, N = 4972, I2 = 2%, low-quality evidence). At one to two years, UCTs probably led to a clinically meaningful, very large reduction in the likelihood of having had any illness in the previous two weeks to three months (odds ratio (OR) 0.73, 95% CI 0.57 to 0.93, 5 cluster-RCTs, N = 8446, I2 = 57%, moderate-quality evidence). Evidence from five cluster-RCTs on food security was too inconsistent to be combined in a meta-analysis, but it suggested that at 13 to 24 months' follow-up, UCTs could increase the likelihood of having been food secure over the previous month (low-quality evidence). UCTs may have increased participants' level of dietary diversity over the previous week, when assessed with the Household Dietary Diversity Score and followed up 24 months into the intervention (mean difference (MD) 0.59 food categories, 95% CI 0.18 to 1.01, 4 cluster-RCTs, N = 9347, I2 = 79%, low-quality evidence). Despite several studies providing relevant evidence, the effects of UCTs on the likelihood of being moderately stunted and on the level of depression remain uncertain. No evidence was available on the effect of a UCT on the likelihood of having died. UCTs probably led to a clinically meaningful, moderate increase in the likelihood of currently attending school, when assessed at 12 to 24 months into the intervention (RR 1.06, 95% CI 1.03 to 1.09, 6 cluster-RCTs, N = 4800, I2 = 0%, moderate-quality evidence). The evidence was uncertain for whether UCTs impacted livestock ownership, extreme poverty, participation in child labour, adult employment or parenting quality. Evidence from six cluster-RCTs on healthcare expenditure was too inconsistent to be combined in a meta-analysis, but it suggested that UCTs may have increased the amount of money spent on health care at 7 to 24 months into the intervention (low-quality evidence). The effects of UCTs on health equity (or unfair and remedial health inequalities) were very uncertain. We did not identify any harms from UCTs. Three cluster-RCTs compared UCTs versus CCTs with regard to the likelihood of having used any health services, the likelihood of having had any illness or the level of dietary diversity, but evidence was limited to one study per outcome and was very uncertain for all three. AUTHORS' CONCLUSIONS: This body of evidence suggests that unconditional cash transfers (UCTs) may not impact a summary measure of health service use in children and adults in LMICs. However, UCTs probably or may improve some health outcomes (i.e. the likelihood of having had any illness, the likelihood of having been food secure, and the level of dietary diversity), one social determinant of health (i.e. the likelihood of attending school), and healthcare expenditure. The evidence on the relative effectiveness of UCTs and CCTs remains very uncertain. PMID- 29139112 TI - The effects of reinforcer magnitude in the preceding and upcoming ratios on between-ratio pausing in multiple, mixed, and single fixed-ratio schedules. AB - Hens responded under multiple fixed-ratio schedules with equal response requirements and either a 1-s or a 6-s reinforcer. Upcoming reinforcer size was indicated by key color. Components were presented in a quasirandom series so that all four component transitions occurred. Postreinforcement pauses were affected by the upcoming and preceding reinforcer size, with longer pauses after large reinforcers followed by small reinforcers than when followed by large ones, and longer pauses after small reinforcers that were followed by small reinforcers rather than large ones. Pauses increased with fixed-ratio size and the effects of reinforcer size were larger the larger the ratio. When reinforcer size was not signaled-mixed fixed-ratio schedules-pauses were shorter after small than after large reinforcers. Signalling the upcoming reinforcer attenuated the effect of the previous reinforcer size on pause duration when small was followed by small and when either small or large by large, but enhanced the effect when large was followed by small. There was no effect of reinforcer size on pause duration when single fixed-ratio schedules were arranged. The effects of reinforcer size on pauses depends on the size and range of the fixed ratios as well as the exact procedures used in the study. PMID- 29139113 TI - Prevalence of Headache in Patients With Mitochondrial Disease: A Cross-Sectional Study. AB - BACKGROUND: Mitochondrial diseases are a heterogeneous group of diseases with different phenotypes and genotypes. Headache and, particularly migraine, seems to occur often in patients with MELAS and in patients with CPEO phenotypes. The International Classification of Headache Disorders (ICHD-3 beta) has classified headache as a secondary entity only in MELAS patients. Other headache phenotypes in mitochondrial diseases are not considered in ICHD-3beta. In this study, we analyzed headache phenomenology in a large group of patients with mitochondrial disorders. METHODS: A cross-sectional questionnaire-based study on 85 patients with mitochondrial disease with different genotypes and phenotypes was conducted between 2010 and 2011. A structured headache questionnaire according to ICHD-2 was used followed by a telephone interview by a headache expert. Prevalence and characteristics of headache could be analyzed in 42 patients. Headache diagnosis was correlated with genotypes and phenotypes. In addition, the mtDNA haplotype H was analyzed. RESULTS: Headache was reported in 29/42 (70%; 95% CI, from 55.1 to 83.0%) of the patients. Tension-type headache (TTH) showed the highest prevalence in 16/42 (38%; 95% CI, from 23.4 to 52.8%) patients, followed by migraine and probable migraine in 12/42 (29%; 95% CI, from 14.9 to 42.2%) patients. Nine of the 42 (21%; 95% CI, from 9 to 33.8%) patients reported two different headache types. Patients with the mtDNA mutation m.3243A > G (n = 8) and MELAS (n = 7) showed the highest prevalence of headaches (88% and 85%, respectively). In patients with the CPEO phenotype (n = 32), headache occurred in 14/18 (78%; 95% CI, from 58.6 to 97%) of patients with single deletions, and in 7/13 (54%; 95% CI, from 26.7 to 80.9%) patients with multiple mtDNA deletions. There were no association between the mtDNA haplotype Hand the headache-diagnosis. CONCLUSIONS: The prevalence of headache was higher in patients with mitochondrial diseases than reported in the general population. In all phenotype and genotype groups, TTH was more frequent than migraine. The data also show that the current ICHD-3 beta exclusively focused on MELAS syndrome as vasculopathy does not consider the broader spectrum of headache phenotypes in mitochondrial disorders. PMID- 29139114 TI - Operation family caregiver: Problem-solving training for military caregivers in a community setting. AB - OBJECTIVE: This study, conducted over a 2-year period at 9 sites, describes the outcomes of an evidence-based support program, Operation Family Caregiver, to gain an understanding of how a tailored, problem-solving training could assist military caregivers, who provide care and assistance to those injured, ill, or disabled as a result of war. METHOD: A pre-post research design was employed to examine caregiver burden, depression, health complaints, satisfaction with life, children's anxiety, and problem solving among a convenience sample of caregivers of 128 military service members and veterans. RESULTS: Analysis revealed a decrease in depression, burden, and health complaints and an increase in satisfaction of life and positive problem-solving skills (p < .001). CONCLUSION: This program may be beneficial to caregiving families of military service and veterans living with posttraumatic stress, traumatic brain injury, and/or a physical disability. PMID- 29139115 TI - Risk of Stroke Associated With Use of Estrogen Containing Contraceptives in Women With Migraine: A Systematic Review. AB - OBJECTIVE: Migraine with aura has been associated with increased risk of ischemic and hemorrhagic stroke. Prior studies have shown a further increase in risk in women using combined hormonal contraceptives (CHCs). This has led to guidelines recommending against use of CHCs in this population. We sought to assess whether the risk of stroke is associated with the dose of estrogen and whether there is evidence of synergism between migraine and CHCs. We also sought to assess whether an interaction effect exists between migraine and CHCs. METHODS: We searched PubMed, the Cochrane Library, and EMBASE from inception through January 2016 for relevant English-language studies of adults, of any design. We included studies that examined exposure to CHCs and reported outcomes of ischemic or hemorrhagic stroke. Data extraction and assessment of study quality were conducted independently by reviewer pairs and quality was assessed with the GRADE and Newcastle Ottawa scales. RESULTS: Of 2480 records, 15 studies met inclusion criteria and six provided odds ratios for the relevant population. The point estimates for the odds ratios for ischemic stroke in women with migraine who used CHCs with any dose of estrogen ranged from 2.08 to 16.9. Studies were generally small and confidence intervals were wide. No studies reported odds ratios for stroke risk as a function of estrogen dose in women with migraine, largely due to insufficient sample sizes. No interaction effect between migraine and CHCs was seen in the seven studies that assessed this. One study differentiated risk by presence or absence of migraine aura and found an increased risk in the migraine with aura population (OR 6.1; CI 3.1 to 12.1 in migraine with aura vs 1.8; CI 1.1 to 2.9 in the migraine without aura group). Studies generally had high Newcastle Ottawa scores and low GRADE levels of evidence. No studies met all three supplementary quality criteria (assessed migraine subtype, used International Classification of Headache Disorders criteria for diagnosis of migraine, and stratified risk by estrogen dose). CONCLUSIONS: This systematic review shows a lack of good quality studies assessing risk of stroke associated with low dose estrogen use in women with migraine. Further study in this area is needed. The available evidence is consistent with an additive increase in stroke risk with CHC use in women with migraine with aura. Since the absolute risk of stroke is low even in the presence of these risk factors, use of CHCs in women who have migraine with aura should be based on an individualized assessment of harms and benefits. PMID- 29139116 TI - Correcting the Count: Improving Vital Statistics Data Regarding Deaths Related to Obesity. AB - Obesity can involve any organ system and compromise the overall health of an individual, including premature death. Despite the increased risk of death associated with being obese, obesity itself is infrequently indicated on the death certificate. We performed an audit of our records to identify how often "obesity" was listed on the death certificate to determine how our practices affected national mortality data collection regarding obesity-related mortality. During the span of nearly 25 years, 0.2% of deaths were attributed to or contributed by obesity. Over the course of 5 years, 96% of selected natural deaths were likely underreported as being associated with obesity. We present an algorithm for certifiers to use to determine whether obesity should be listed on the death certificate and guidelines for certifying cases in which this is appropriate. Use of this algorithm will improve vital statistics concerning the role of obesity in causing or contributing to death. PMID- 29139117 TI - Size-dependent social attraction and repulsion explains the decision of Atlantic cod Gadus morhua to enter baited pots. AB - The present study tested whether the presence of already retained fishes inside baited fish pots acted as a social attraction and affected the entrance probability of Atlantic cod Gadus morhua in a fjord in northern Norway. Video analysis revealed that the probability of an entrance initially increased with the presence of low numbers of fishes inside the pot, but subsequently decreased at a critical number of caught fishes. The critical number was dependent on the size of the G. morhua attempting to enter. This demonstrates that social attraction and repulsion play a role in G. morhua pot fishing and has important implications for the capture efficiency of fisheries executed with pots. PMID- 29139118 TI - Di-2-ethylhexyl phthalate (DEHP) exposure disturbs lipid metabolism in juvenile yellow catfish Tachysurus fulvidraco. AB - This study was conducted to determine the mechanism by which di-2-ethylhexyl phthalate (DEHP) exposure influences lipid metabolism of juvenile yellow catfish Tachysurus fulvidraco. Fish were exposed to three DEHP concentrations (0, 0.1 and 0.5 mg l-1 DEHP) for 8 weeks. Fatty acid synthase (FAS) activity significantly decreased with increasing DEHP concentrations, the highest value was in the Tween control group, whereas the lowest activities of carnitine palmitoyltransferase (CPT) and lipoprotein lipase (LPL) were in this group. The messenger (m)RNA levels of 6-phospho-gluconate dehydrogenase (6PGD), FAS and acetyl-CoA carboxylase a (ACCa) significantly increased with increasing DEHP concentration, the highest values were in the 0.5 mg l-1 DEHP group. The mRNA level of peroxisome proliferator-activated receptor gamma (PPARgamma) was lower in Tween control than in fish exposed to 0.1 and 0.5 mg l-1 DEHP. The highest mRNA level of ACCb was in the 0.1 mg l-1 DEHP group. These results indicate that DEHP exposure can disturb lipid metabolism at the enzymatic and mRNA levels in Pelteobagrus fulvidraco. PMID- 29139119 TI - Effect of Sterilants on Amplification and Detection of Target DNA from Bacillus cereus Spores. AB - To conceal criminal activity of a bioterrorist or agroterrorist, the site of pathogen generation is often treated with sterilants to kill the organisms and remove evidence. As dead organisms cannot be analyzed by culture, this study examined whether DNA from sterilant-treated Bacillus cereus spores was viable for amplification. The spores were exposed to five common sterilants: bleach, Sterilox(r), oxidizer foam (L-Gel), a peroxyacid (Actril(r)), and formaldehyde vapor. The spores were inoculated on typical surfaces found in offices and laboratories to test for environmental effects. It was found that the surface influenced the efficiency of recovery of the organisms. The DNA isolated from the recovered spores was successfully detected using RT-qPCR for all treatments except for formaldehyde, by amplifying the phosphatidylinositol phospholipase C and sphingomyelinase genes. The results demonstrated that evidence from sites treated with sterilants can still provide information on the uncultured organism, using DNA amplification. PMID- 29139120 TI - Increasing temperature decreases the predatory effect of the intertidal shanny Lipophrys pholis on an amphipod prey. AB - Interactions between Lipophrys pholis and its amphipod prey Echinogammarus marinus were used to investigate the effect of changing water temperatures, comparing current and predicted mean summer temperatures. Contrary to expectations, predator attack rates significantly decreased with increasing temperature. Handling times were significantly longer at 19 degrees C than at 17 and 15 degrees C and the maximum feeding estimate was significantly lower at 19 degrees C than at 17 degrees C. Functional-response type changed from a destabilizing type II to the more stabilizing type III with a temperature increase to 19 degrees C. This suggests that a temperature increase can mediate refuge for prey at low densities. Predatory pressure by teleosts may be dampened by a large increase in temperature (here from 15 to 19 degrees C), but a short term and smaller temperature increase (to 17 degrees C) may increase destabilizing resource consumption due to high maximum feeding rates; this has implications for the stability of important intertidal ecosystems during warming events. PMID- 29139121 TI - Xyloglucan is released by plants and promotes soil particle aggregation. AB - Soil is a crucial component of the biosphere and is a major sink for organic carbon. Plant roots are known to release a wide range of carbon-based compounds into soils, including polysaccharides, but the functions of these are not known in detail. Using a monoclonal antibody to plant cell wall xyloglucan, we show that this polysaccharide is secreted by a wide range of angiosperm roots, and relatively abundantly by grasses. It is also released from the rhizoids of liverworts, the earliest diverging lineage of land plants. Using analysis of water-stable aggregate size, dry dispersion particle analysis and scanning electron microscopy, we show that xyloglucan is effective in increasing soil particle aggregation, a key factor in the formation and function of healthy soils. To study the possible roles of xyloglucan in the formation of soils, we analysed the xyloglucan contents of mineral soils of known age exposed upon the retreat of glaciers. These glacial forefield soils had significantly higher xyloglucan contents than detected in a UK grassland soil. We propose that xyloglucan released from plant rhizoids/roots is an effective soil particle aggregator and may, in this role, have been important in the initial colonization of land. PMID- 29139122 TI - Vaccination with human amniotic epithelial cells confer effective protection in a murine model of Colon adenocarcinoma. AB - As a prophylactic cancer vaccine, human amniotic membrane epithelial cells (hAECs) conferred effective protection in a murine model of colon cancer. The immunized mice mounted strong cross-protective CTL and antibody responses. Tumor burden was significantly reduced in tumor-bearing mice after immunization with hAECs. Placental cancer immunotherapy could be a promising approach for primary prevention of cancer. In spite of being the star of therapeutic strategies for cancer treatment, the results of immunotherapeutic approaches are still far from expectations. In this regard, primary prevention of cancer using prophylactic cancer vaccines has gained considerable attention. The immunologic similarities between cancer development and placentation have helped researchers to unravel molecular mechanisms responsible for carcinogenesis and to take advantage of stem cells from reproductive organs to elicit robust anti-cancer immune responses. Here, we showed that vaccination of mice with human amniotic membrane epithelial cells (hAECs) conferred effective protection against colon cancer and led to expansion of systemic and splenic cytotoxic T cell population and induction of cross-protective cytotoxic responses against tumor cells. Vaccinated mice mounted tumor-specific Th1 responses and produced cross-reactive antibodies against cell surface markers of cancer cells. Tumor burden was also significantly reduced in tumor-bearing mice immunized with hAECs. Our findings pave the way for potential future application of hAECs as an effective prophylactic cancer vaccine. PMID- 29139123 TI - New insights into the mechanisms of phytochrome-cryptochrome coaction. AB - Contents Summary 547 I. Introduction 547 II. Phytochromes mediate light-induced transcription of BICs to inactivate cryptochromes 548 III. PPKs phosphorylate light-signaling proteins and histones to affect plant development 548 IV. Prospect 550 Acknowledgements 550 References 550 SUMMARY: Plants perceive and respond to light signals by multiple sensory photoreceptors, including phytochromes and cryptochromes, which absorb different wavelengths of light to regulate genome expression and plant development. Photophysiological analyses have long revealed the coordinated actions of different photoreceptors, a phenomenon referred to as the photoreceptor coaction. The mechanistic explanations of photoreceptor coactions are not fully understood. The function of direct protein-protein interaction of phytochromes and cryptochromes and common signaling molecules of these photoreceptors, such as SPA1/COP1 E3 ubiquitin ligase complex and bHLH transcription factors PIFs, would partially explain phytochrome-cryptochrome coactions. In addition, newly discovered proteins that block cryptochrome photodimerization or catalyze cryptochrome phosphorylation may also participate in the phytochrome and cryptochrome coaction. This Tansley insight, which is not intended to make a comprehensive review of the studies of photoreceptor coactions, attempts to highlight those recent findings and their possible roles in the photoreceptor coaction. PMID- 29139124 TI - Histochemical distribution of four types of enzymes and mucous cells in the gastrointestinal tract of reared half-smooth tongue sole Cynoglossus semilaevis. AB - The histochemical distribution of acid phosphatase (ACP), alkaline phosphatase (ALP), non-specific esterase (NSE), peroxidase (POD) and mucous-cell types was evaluated in the gastrointestinal tract of the half-smooth tongue sole Cynoglossus semilaevis. The enzymes were detected in the entire stretch of the gastrointestinal tract. ACP activity was found in the supranuclear region of enterocytes and the lamina propria of the intestine, as well as the cytoplasm of epithelial cells of the stomach. The staining intensity of ACP in the anterior and posterior intestines was stronger than in the stomach. ALP activity was detected in the striated border of enterocytes and muscularis of the whole intestine, lamina propria and supranuclear cytoplasm of the enterocytes in the anterior intestine, as well as in the blood vessels of the stomach. The staining intensity for ALP in the anterior intestine was stronger than in the posterior segment and the latter was stronger than in the stomach. NSE activity was detected in the cytoplasm of the epithelial cells in the entire gastrointestinal tract, with the anterior intestine showing stronger intensity than the stomach. POD activity was located in the blood cells of the lamina propria of the gastrointestinal tract and the levels in the stomach were similar to the anterior and posterior intestines. Alcian blue (pH 2.5) periodic acid Schiff (AB-PAS) histochemical results revealed three types of mucous cells in the gastrointestinal tract. Type I cells (PAS+AB-) were observed among the gastric mucosa columnar cells in the stomach and enterocytes in the basal region of the villi and in the middle and top regions of the intestinal villi. Type II cells (PAS-AB+) and type III cells (PAS+AB+) were not detected in the stomach but were distributed ubiquitously among enterocytes in the middle and top regions of the intestinal villi. PMID- 29139125 TI - Validation of the distress tolerance scale-short form in obsessive compulsive disorder. AB - OBJECTIVE: This study aimed to develop and validate the Distress Tolerance Scale Short Form (DTS-SF), a modification of the original Distress Tolerance Scale, in a severe/complex sample of individuals with obsessive compulsive disorder (OCD). Currently, there are multiple self-report measurements of distress tolerance (DT), highlighting the need for a more refined measure. METHOD: Participants included 222 individuals with a primary diagnosis of OCD (57% male, average age = 31) seeking intensive/residential treatment. Participants completed surveys at admission, discharge, and each week. RESULTS: An exploratory factor analysis revealed a one-factor solution representing overall DT ability. The DTS-SF was found to be sensitive to treatment effects. Appropriate associations between the DTS-SF and other measures were also found, with lower DT associated with greater OCD and depression severity and lower reported quality of life. CONCLUSION: The DTS-SF was found to be a valid and reliable measure with high clinical utility for quickly and accurately measuring DT. PMID- 29139126 TI - Understanding the association between discrimination and depression among sexual minority people of color: Evidence for diminishing returns of socioeconomic advantage. AB - OBJECTIVE: To examine the differential association of heterosexism and racism on depression as moderated by socioeconomic status (SES) among sexual minority people of color. METHOD: A cross-sectional sample of sexual minority people of color (n = 170) was surveyed on their experiences of heterosexism, racism, depression, and SES in a national online study based in the United States. RESULTS: Bivariately, SES was inversely associated with depression, racism, and heterosexism. Moderation analyses found that for individuals with less socioeconomic advantage, the associations between heterosexism and depression were not as strong. However, at higher socioeconomic advantage, heterosexism was more strongly positively associated with depression. CONCLUSION: These results suggest that the effects of discrimination on depression in sexual minority individuals of color may be accentuated at higher socioeconomic levels. Implications suggest helping sexual minority clients of color from higher SES backgrounds explore the effects of discrimination on their mental health. PMID- 29139127 TI - Combined transcriptome and translatome analyses reveal a role for tryptophan dependent auxin biosynthesis in the control of DOG1-dependent seed dormancy. AB - The importance of translational regulation during Arabidopsis seed germination has been shown previously. Here the role of transcriptional and translational regulation during seed imbibition of the very dormant DELAY OF GERMINATION 1 (DOG1) near-isogenic line was investigated. Polysome profiling was performed on dormant and after-ripened seeds imbibed for 6 and 24 h in water and in the transcription inhibitor cordycepin. Transcriptome and translatome changes were investigated. Ribosomal profiles of after-ripened seeds imbibed in cordycepin mimic those of dormant seeds. The polysome occupancy of mRNA species is not affected by germination inhibition, either as a result of seed dormancy or as a result of cordycepin treatment, indicating the importance of the regulation of transcript abundance. The expression of auxin metabolism genes is discriminative during the imbibition of after-ripened and dormant seeds, which is confirmed by altered concentrations of indole-3-acetic acid conjugates and precursors. PMID- 29139128 TI - Development of secondary sexual characters and their relationship to ontogeny and seasonal reproductive period in Hyphessobrycon igneus (Ostariophysi: Characiformes). AB - Sexual dimorphism in size, anal-fin shape and coloration of Hyphessobrycon igneus, Characidae, were examined. Males were more frequent at larger body sizes, confirming body size as a sexually dimorphic trait. Anal-fin shape and the colour of all fins were the same for females and juveniles, differing only in adult males. Likewise, only adult males had bony hooks on fin rays; larger and more sexually mature males had the most numerous and developed hooks and hooks were most developed in degree and number during peak reproductive periods. Fin hooks regressed in number and developmental degree after the reproductive period, but restarted development with the beginning of the new reproductive period without completely disappearing. Results show that bony hooks have a development and regression cycle related to reproductive seasonality. PMID- 29139129 TI - Reproductive biology of female striped marlin Kajikia audax in the western Pacific Ocean. AB - Length and mass data for 1260 (536 females, 683 males, 41 sex unknown) striped marlin Kajikia audax were collected at the fish markets of Tungkang, Singkang and Nanfangao from July 2004 to September 2010. Of these samples, 534 gonads (236 females and 298 males) ranging from 95 to 206 cm in eye-to-fork length (LEF ) and 8 to 88 kg in round mass (MR ), were collected. Chi-square tests indicated sex ratios were homogeneous among months in 2004 and 2006-2008, but not in 2005, 2009 and 2010; and there were significant differences in sex ratio by size. The overall sex ratio (RS ) differed significantly from the expected 0.5. Kajikia audax are sexually dimorphic and the proportions of females increased with size between 140 and 210 cm LEF . Reproductive activity was assessed using a gonado somatic index (IG ), external appearance of the gonads and histological examination and results indicated that the spawning season occurred from April to August with a peak in June to July. Based on histological observations and the distribution of oocyte diameters, K. audax are multiple spawners and their oocytes develop asynchronously. The estimated length-at-50% maturity (LEF50 ) was c. 181 cm (c. 4.8 years of age) for females. The proportion of reproductively active females in the spawning season with ovaries containing postovulatory follicles (0.27) indicated that they spawned every 3.7 days on average. The hydrated oocyte method estimated mean +/- S.D. batch fecundity (FB ) to be 4.4 +/ 2.02 million eggs; average relative fecundity was 53.6 +/- 13.9 oocytes g-1 MR ; and the average annual fecundity was 181.3 +/- 48.3 million eggs. The parameters estimated in this study are key information for stock assessments of K. audax in the north-western and central Pacific and will contribute to the conservation, management and sustainable yield of this species. PMID- 29139130 TI - Less Cortical Thickness in Patients With Persistent Post-Traumatic Headache Compared With Healthy Controls: An MRI Study. AB - OBJECTIVE: To investigate differences in cortical thickness in patients with persistent post-traumatic headache (PPTH) relative to healthy controls and to interrogate whether cortical morphology relates to headache burden (headache frequency, years with post-traumatic headache, PTH) in patients with PPTH. BACKGROUND: PTHs are one of the most common symptoms following concussion. In some patients, PTHs continue for longer than three months and are classified as PPTH. This study has two main goals: (1) To delineate the neuropathology of PPTH, by interrogating differences in cortical thickness in patients with PPTH relative to healthy controls. (2) To interrogate potential associations between brain morphology and headache burden in patients with PPTH by examining whether cortical thickness relates to frequency of headaches or years lived with PTH. METHODS: Adults with PPTH diagnosed according to ICHD 3 beta diagnostic criteria and healthy controls underwent brain MRI on a 3 Tesla scanner. Vertex-by-vertex whole brain estimates of cortical thickness were automatically calculated using FreeSurfer v5.3. Differences in cortical thickness in patients with PPTH relative to healthy controls were determined using a general linear model design. Associations were explored between regional clusters where patients with PPTH showed cortical thickness differences compared with healthy controls with headache frequency and years lived with PPTH. RESULTS: This study included 33 patients with PPTH and 33 healthy control subjects (healthy controls: median age = 33.0, IQR = 15.5; patients with PPTH: median age = 36.0, IQR = 20.5; P = .56). Patients with PPTH had less cortical thickness relative to healthy controls in the left and right superior frontal, caudal middle frontal, and precentral cortex as well as less cortical thickness in the right supramarginal, right superior and inferior parietal, and right precuneus region (P < .05, Monte Carlo corrected for multiple comparisons). There were no regions where patients with PPTH had more cortical thickness relative to healthy controls. A correlation analysis of regions that showed less cortical thickness in patients with PPTH demonstrated a negative correlation between left and right superior frontal thickness with headache frequency (P < .05). There was no association between regional cortical thickness and years lived with PPTH. CONCLUSION: Compared with healthy controls, patients with PPTH had less cortical thickness in bilateral frontal regions and right hemisphere parietal regions. For patients with PPTH, more frequent headaches were related to less thickness in the left and right superior frontal regions, potentially indicating that brain morphology changes in the superior frontal regions in patients with PPTH are modified by headache frequency. PMID- 29139132 TI - Light and temperature cues: multitasking receptors and transcriptional integrators. AB - Contents Summary 1029 I. Introduction 1029 II. Convergence at the receptor 1030 III. Convergence at transcriptional hubs 1031 IV. Convergence involving clock components 1033 V. Conclusions 1033 Acknowledgements 1033 References 1033 SUMMARY: The combined information provided by light and temperature cues helps to optimise plant body architecture and physiology. Plants possess elaborate systems to sense and respond to these stimuli. Simultaneous perception of light and temperature by dual receptors such as phytochrome B and phototropin leads to immediate signalling convergence. Conversely, cue asynchronies initiate separate pathways and the information of the earliest cue is stored, awaiting the arrival of the later cue to control transcription. Storage mechanisms can involve changes in the activity of selected clock components or epigenetic modifications, depending on the time delay between cues (hours, days or several months). We propose a conceptual framework in which the mechanisms of integration relate to the timing of cue sensing. PMID- 29139133 TI - Cranial shape variation in jacarean caimanines (Crocodylia, Alligatoroidea) and its implications in the taxonomic status of extinct species: The case of Melanosuchus fisheri. AB - Melanosuchus niger (Crocodylia, Alligatoroidea) is one of the six living caimanine species widely distributed throughout the Amazon River basin today. Although there is only one extant species of Melanosuchus, fossil material assigned to this genus, represented by M. fisheri, has been reported from the late Miocene in South America. However, the validity of this taxon has been questioned and a recent investigation indicates that the referred specimen of M. fisheri (MCZ 4336) actually belongs to Globidentosuchus brachyrostris, while those diagnostic characters present in the holotype (MCNC 243) fall into the spectrum of intraspecific variation of M. niger. Here, we compare the skull shape of the holotype of M. fisheri with the ontogenetic series of the four jacarean species (M. niger, Caiman yacare, Caiman crocodilus, and Caiman latirostris) using 2D-geometric morphometric analyses in two different views. The analyses indicate that MCNC 243 falls into the morphospace of M. niger and C. latirostris. Despite strong shape similarities between juveniles of C. latirostris and MCNC 243, further anatomical comparisons reveal notable differences between them. In contrast, no concrete anatomical differences can be found between MCNC 243 and M. niger, although shape analyses indicate that MCNC 243 is relatively robust for its size. Thus, this study is able to confirm that the genus Melanosuchus was present in the late Miocene, but it still remains unclear if MCNC 243 should be treated as a junior synonym or probably a sister species of M. niger. Its Miocene age favors the second option, but as the shape analyses were also not able to extract any diagnostic characters, it should be retained as Melanosuchus cf. niger. PMID- 29139134 TI - A global database for plants that hyperaccumulate metal and metalloid trace elements. PMID- 29139135 TI - Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. AB - Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML). Nineteen patients unselected for FLT3 mutational status received one of three quizartinib dihydrochloride dose levels (DL): 60 mg/d for 7 days (DL1; n = 6), 60 mg/d for 14 days (DL2; n = 7), and 40 mg/d for 14 days (DL-1; n = 6); administered orally starting on day 4 of chemotherapy. Median age was 43.8 years. Ten patients completed induction and consolidation. Three patients experienced dose-limiting toxicities (DLTs): 2 at DL2 (1 pericardial effusion; 1 febrile neutropenia, decreased platelet count, and QT prolongation); 1 at DL-1 (pericarditis). Maximum tolerated dose (MTD) was identified as DL-1. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade <=1 QT prolongation was observed at MTD. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia-free state. The phase 3 QuANTUM-First trial (NCT02668653) is further evaluating the effect of quizartinib plus SOC chemotherapy in ndAML FLT3-ITD mutated patients. PMID- 29139136 TI - Tilmicosin- and florfenicol-loaded hydrogenated castor oil-solid lipid nanoparticles to pigs: Combined antibacterial activities and pharmacokinetics. AB - The combined antibacterial effects of tilmicosin (TIL) and florfenicol (FF) against Actinobacillus pleuropneumoniae (APP) (n = 2), Streptococcus suis (S. suis) (n = 2), and Haemophilus parasuis (HPS) (n = 2) were evaluated by chekerboard test and time-kill assays. The pharmacokinetics (PKs) of TIL- and FF loaded hydrogenated castor oil (HCO)-solid lipid nanoparticles (SLN) were performed in healthy pigs. The results indicated that TIL and FF showed synergistic or additive antibacterial activities against APP, S. suis and HPS with the fractional inhibitory concentration (FIC) ranging from 0.375 to 0.75. The time-kill assays showed that 1/2 minimum inhibitory concentration (MIC) TIL combined with 1/2 MIC FF had a stronger ability to inhibit the growth of APP, S. suis, and HPS than 1 MIC TIL or 1 MIC FF, respectively. After oral administration, plasma TIL and FF concentrations could maintain about 0.1 MUg/ml for 192 and 176 hr. The SLN prolonged the last time point with detectable concentrations (Tlast ), area under the concentration-time curve (AUC0-t ), elimination half-life (T1/2ke ), and mean residence time (MRT) by 3.1, 5.6, 12.7, 3.4-fold of the active pharmaceutical ingredient (API) of TIL and 11.8, 16.5, 18.1, 12.1-fold of the API of FF, respectively. This study suggests that the TIL FF-SLN could be a useful oral formulation for the treatment of APP, S. suis, and HPS infection in pigs. PMID- 29139137 TI - Potential Exposure and Cancer Risk from Formaldehyde Emissions from Installed Chinese Manufactured Laminate Flooring. AB - Lumber Liquidators (LL) Chinese-manufactured laminate flooring (CLF) has been installed in >400,000 U.S. homes over the last decade. To characterize potential associated formaldehyde exposures and cancer risks, chamber emissions data were collected from 399 new LL CLF, and from LL CLF installed in 899 homes in which measured aggregate indoor formaldehyde concentrations exceeded 100 MUg/m3 from a total of 17,867 homes screened. Data from both sources were combined to characterize LL CLF flooring-associated formaldehyde emissions from new boards and installed boards. New flooring had an average (+/-SD) emission rate of 61.3 +/- 52.1 MUg/m2 -hour; >one-year installed boards had ~threefold lower emission rates. Estimated emission rates for the 899 homes and corresponding data from questionnaires were used as inputs to a single-compartment, steady-state mass balance model to estimate corresponding residence-specific TWA formaldehyde concentrations and potential resident exposures. Only ~0.7% of those homes had estimated acute formaldehyde concentrations >100 MUg/m3 immediately after LL CLF installation. The TWA daily formaldehyde inhalation exposure within the 899 homes was estimated to be 17 MUg/day using California Proposition 65 default methods to extrapolate cancer risk (below the regulation "no significant risk level" of 40 MUg/day). Using a U.S. Environmental Protection Agency linear cancer risk model, 50th and 95th percentile values of expected lifetime cancer risk for residents of these homes were estimated to be 0.33 and 1.2 per 100,000 exposed, respectively. Based on more recent data and verified nonlinear cancer risk assessment models, LL CLF formaldehyde emissions pose virtually no cancer risk to affected consumers. PMID- 29139138 TI - Folate status in women of reproductive age as basis of neural tube defect risk assessment. AB - Reliable folate status data for women of reproductive age (WRA) to assess global risk for neural tube defects (NTDs) are needed. We focus on a recent recommendation by the World Health Organization that a specific "optimal" red blood cell (RBC) folate concentration be used as the sole indicator of NTD risk within a population and discuss how to best apply this guidance to reach the goal of assessing NTD risk globally. We also emphasize the importance of using the microbiologic assay (MBA) as the most reliable assay for obtaining comparable results for RBC folate concentration across time and countries, the need for harmonization of the MBA through use of consistent key reagents and procedures within laboratories, and the requirement to apply assay-matched cutoffs for folate deficiency and insufficiency. To estimate NTD risk globally, the ideal scenario would be to have country-specific population-based surveys of RBC folate in WRA determined utilizing a harmonized MBA, as was done in recent studies in Guatemala and Belize. We conclude with guidance on next steps to best navigate the road map toward the goal of generating reliable folate status data on which to assess NTD risk in WRA in low- and middle-income countries. PMID- 29139139 TI - Epiphytic fungal community in Vitis vinifera of the Portuguese wine regions. AB - : In this work, fungi present in the grapevine's phyllosphere collected from the main demarcated wine regions of Portugal were identified, and their phylogenetic relationships were analysed. A total of 46 vine samples (leaves and berries) were collected from different parts of the country, being isolated a total of 117 fungal colonies that were identified to the genus level and sequenced in the following genetic regions: internal transcribed spacer region and 18S rRNA and beta-tubulin gene. Next, a phylogenetic tree reconstruction for each genetic region was built. The isolates retrieved from environmental samples belonged to the genera Alternaria (31%), Cladosporium (21%), Penicillium (19%), Aspergillus (7%) and Epicoccum (3%). No genetic signatures of exchange of genetic material were detected, and consequently, the reconstructed phylogenetic trees allowed to distinguish between these different species/genera. In the fungal composition of the Vitis vinifera phyllosphere, several potential pathogens were identified that can be associated with decreases in crop productivity. Knowledge of fungi identification and genetic diversity is pivotal for the development of more adequate crop management strategies. Furthermore, this information will provide guidelines for a more specific and wiser use of fungicides. SIGNIFICANCE AND IMPACT OF THE STUDY: The knowledge on the composition of the phyllosphere microbial community is still limited, especially when fungi are concerned. These micro-organisms not only play a crucial role in crop health and productivity but also interact with the winemaking process, determining the safety and quality of grape and grape-derived products. The elucidation of the micro-organisms present in the phyllosphere will have a notorious impact on plant breeding and protection programmes and disease management strategies, allowing a better control of pesticide applications. PMID- 29139140 TI - Two cases of infundibular squamous cell carcinoma on the nose with aggressive clinical behavior: Case report and review of the published work. AB - Case 1 was a 75-year-old Japanese man who presented with a poorly demarcated, dark-red nodule with a destructive defect in the center, measuring 3 cm * 2 cm on the right wing of his nose. The histological diagnosis was a common form of infundibular squamous cell carcinoma. Atypical neoplastic cells radiated from the wall of a follicular infundibulum. The majority of neoplastic cells were positive for AE1/AE3 and 34betaE12. Cytokeratin 17 expression was seen in the suprabasal cells of the deeply situated neoplastic components. Case 2 was a 73-year-old Japanese man who presented with a poorly demarcated, dark-red nodule with an irregularly shaped ulcer in the center, measuring 3 cm * 2 cm on the left wing of his nose. The histological diagnosis was a crater form of infundibular squamous cell carcinoma. Atypical neoplastic cells radiated from the broad base of the central keratin-filled crater, continuous with two infundibular canals. In both cases, some of the more deeply situated aggregations were composed of neoplastic keratinocytes with eosinophilic glassy or pale cytoplasm. In addition, no atypical keratinocytes could be seen in the interfollicular epidermis. In case 1, a hematogenous metastasis to the vocal cord and the forehead occurred in addition to a lymph node metastasis. In case 2, a local recurrence occurred with an intralymphatic dissemination. We describe two cases of infundibular squamous cell carcinoma on the nose with aggressive clinical behavior, one of which was accompanied by a hematogenous metastasis while another revealed a local recurrence. PMID- 29139141 TI - Developing novel species-specific DNA markers for PCR-based species identification of the Lactobacillus sakei group. AB - : Identification of members of the Lactobacillus sakei group (LSG) by common phenotypic and genotypic methods is generally inadequate and time-consuming. The objective of this study was to develop novel species-specific primers based on sequence-characterized amplified region (SCAR) markers using random amplified polymorphic DNA polymerase chain reaction (RAPD-PCR) analysis. Three species specific fragments were gel-purified, cloned and sequenced after preliminary screening of 80 random primers. Accordingly, three pairs of primers Lcur-F/R, Lgram-F/R and Lsakei-F/R were designed based on single species-specific bands (281, 278 and 472 bp) that were obtained from Lactobacillus curvatus, Lactobacillus graminis and L. sakei, respectively. The specificities of these primer pairs were confirmed in 21 LSG strains and 31 nontarget Lactobacillus strains. In addition, the detection limits for each primer pair were approx. 105 , 104 and 106 cells per gram of meat samples spiked with L. curvatus, L. graminis and L. sakei, respectively. In conclusion, we have successfully developed a rapid, accurate and effective PCR-based method for identification of species in the LSG. SIGNIFICANCE AND IMPACT OF THE STUDY: Neither phenotypic nor the most commonly used genotypic method (16S rRNA gene sequencing) provides sufficient resolution for accurate identification of the Lactobacillus sakei group. A sequence-characterized amplified region method developed in this study provides a rapid, cost-effective way to detect the member of the L. sakei group in meat sample. PMID- 29139142 TI - Safety of orally administered, USP-compliant levothyroxine sodium tablets in dogs. AB - The safety of synthetic levothyroxine sodium tablets (Thyro-Tabs(r) Canine; LLOYD, Inc.) in dogs was evaluated in a randomized, sham-dose controlled, parallel-group study. Young, healthy, euthyroid Beagle dogs were randomized into four groups (four females and four males per group) and received single daily doses of 0*, 2* (0.044 mg/kg), 6* (0.132 mg/kg), or 10* (0.22 mg/kg) the labeled starting dose of 0.022 mg kg-1 day-1 for 182 days. Every 2 weeks, physical examinations, electrocardiology examinations, and sample collections for thyroid panel, hematology, serum biochemistry, coagulation panel, and urinalysis were performed. At the end of the study, the dogs were euthanized and full necropsies performed. The most overt finding was the expected dose-dependent increase in serum concentrations of total and free thyroxine with dose-dependent suppression of the hypothalamic-pituitary-thyroid axis as evidenced by decreased serum thyroid-stimulating hormone concentrations, decreased thyroid+parathyroid/body weight ratios, and a trend for decreased pituitary weight/brain weight ratios. Clinical signs of thyrotoxicosis (excitation, tachypnea, tachycardia) in the treated dogs were sporadic with no dose-response relationship. Other findings statistically associated with levothyroxine treatment were generally mild and not clinically important. In summary, doses of levothyroxine sodium up to 10* the labeled starting dose were well tolerated in healthy dogs. PMID- 29139143 TI - Case of alopecia induced by sorafenib, possible mechanism similar to alopecia areata. PMID- 29139144 TI - Passages 2018. PMID- 29139145 TI - Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows. AB - Monepantel (MNP) is a novel anthelmintic compound launched into the veterinary pharmaceutical market. MNP is not licenced for use in dairy animals due to the prolonged elimination of its metabolite monepantel sulphone (MNPSO2 ) into milk. The goal of this study was to evaluate the presence of potential in vivo drug drug interactions affecting the pattern of milk excretion after the coadministration of the anthelmintics MNP and oxfendazole (OFZ) to lactating dairy cows. The concentrations of both parent drugs and their metabolites were measured in plasma and milk samples by HPLC. MNPSO2 was the main metabolite recovered from plasma and milk after oral administration of MNP. A high distribution of MNPSO2 into milk was observed. The milk-to-plasma ratio (M/P ratio) for this metabolite was equal to 6.75. Conversely, the M/P ratio of OFZ was 1.26. Plasma concentration profiles of MNP and MNPSO2 were not modified in the presence of OFZ. The pattern of MNPSO2 excretion into milk was also unchanged in animals receiving MNP plus OFZ. The percentage of the total administered dose recovered from milk was 0.09 +/- 0.04% (MNP) and 2.79 +/- 1.54% (MNPSO2 ) after the administration of MNP alone and 0.06 +/- 0.04% (MNP) and 2.34 +/- 1.38% (MNPSO2 ) after the combined treatment. The presence of MNP did not alter the plasma and milk disposition kinetics of OFZ. The concentrations of the metabolite fenbendazole sulphone tended to be slightly higher in the coadministered group. Although from a pharmacodynamic point of view the coadministration of MNP and OFZ may be a useful tool, the presence of OFZ did not modify the in vivo pharmacokinetic behaviour of MNP and therefore did not result in reduced milk concentrations of MNPSO2 . PMID- 29139147 TI - The development of lingual glands in the domestic duck (Anas platyrhynchos f. domestica): 3D-reconstruction, LM, and SEM study. AB - The major salivary glands of birds develop by branching or elongation of the epithelial cords. The development of the minor salivary glands in form of the lingual glands has never been described. Among birds, only Anatidae have three types of the lingual glands: rostral, caudo-lateral, and caudo-medial lingual glands. The study aims to characterize the manner and rate of the lingual glands development in the domestic duck and their topographical arrangement relative to the hyoid apparatus. The study reveals that all three types of the lingual glands develop by branching. We describe five stages of the lingual glands development in the domestic ducks: prebud, initial bud, pseudoglandular, canalicular, and terminal bud stage. The pattern of the lingual glands development in birds is similar to that described for mammals, with the exception, that the terminal buds are formed at the same time as the lumen of the glands. Generally, the rostral lingual gland starts to branch earlier than the caudal lingual glands. The 3D reconstruction shows the location and direction of lingual gland development relative to the entoglossal cartilage and basibranchial bone. Light microscopy and scanning electron microscopy allow to characterize the histogenesis of the embryonic epithelium into glandular epithelium. At a time of hatching only secretory units of caudal lingual glands resemble the secretory units of the adult domestic duck. The rostral and caudo-lateral lingual glands are arranged on the sides of the entoglossal cartilage and basibranchial bone and caudo-madial lingual glands are located over the basibranchial bone. We suggest that such an arrangement of the lingual glands in the domestic duck is important during food intake and responsible for reduction of friction and formation of food bites. PMID- 29139146 TI - Effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor velagliflozin, a new drug with therapeutic potential to treat diabetes in cats. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors are used in the treatment of human diabetics. They increase glucose excretion and correct hyperglycemia. We examined the investigational SGLT2 inhibitor velagliflozin in two groups of six neutered adult obese cats (equal gender distribution). Placebo (Pl) or drug (D; 1 mg/kg) was administered for 35 days. Routine blood examinations, fructosamine, beta-hydroxybutyrate (BHB), nonesterified fatty acids (NEFA), glucagon, adiponectin, and leptin were measured before and after treatment, also water intake, and urinary electrolytes, glucose, and volume. Indirect calorimetry, an intravenous glucose tolerance test (IVGTT; 0.8 g/kg) and insulin tolerance test (IVITT) were conducted. All cats tolerated treatment well. Significant changes with D included a decrease in the respiratory exchange ratio, an increase in cholesterol, a small increase in albumin, and a rise in BHB and NEFA. Glucose clearance was unaltered, although less insulin was secreted during the IVGTT (p = .056) suggesting improved insulin sensitivity. IVITT was unchanged. Treatment did not affect glucagon, leptin, or adiponectin. Water intake, urine output, urinary glucose excretion, and the glucose/creatinine ratio but not urinary electrolytes were significantly higher post-D. We conclude that velagliflozin is a promising drug, which increases urinary glucose excretion in cats and could thereby be beneficial for the treatment of hyperglycemia. PMID- 29139148 TI - Epstein-Barr virus-positive mucocutaneous ulcer in a patient with polycythemia vera treated with oral hydroxyurea. PMID- 29139149 TI - Underrecognized entity of the transient rise in the atrial capture threshold early after dual-chamber pacemaker implantation. AB - BACKGROUND: Steroid-eluting pacemaker leads suppress acute rises in pacing threshold by preventing inflammatory processes. However, we occasionally encounter not persistent but transient rise in the atrial capture threshold (TRACT) early after pacemaker implantation. We believe that this phenomenon is underrecognized in clinical practice and may potentially lead to unnecessary reintervention. We aimed to clarify the prevalence, predictors, and possible mechanisms of TRACT. METHODS AND RESULTS: We reviewed clinical records from 239 consecutive patients who underwent dual-chamber pacemaker implantation for sick sinus syndrome (SSS) (N = 102) or atrioventricular block (AVB) (N = 137). Atrial capture threshold was measured at implantation and 7 days, 2 months, and 8 months postimplantation. TRACT was defined as a rise in the threshold at day 7 to >=twice that at implantation, with an absolute value >=1.0 V/0.4 ms, and full recovery by 8 months into follow-up. TRACT was observed in 15 patients (6%), of whom13 (87%) suffered from SSS but not AVB. Patients with TRACT had greater body mass index (BMI) (25 +/- 5 kg/m2 vs 23 +/- 4 kg/m2 , P = 0.01), larger left atrium (42 +/- 5 mm vs 38 +/- 7 mm, P = 0.03), and were more likely to suffer from paroxysmal atrial fibrillation (60% vs 31%, P = 0.02) than those without TRACT. In multivariable logistic regression analysis, BMI and SSS were the independent predictors of TRACT (odds ratio [OR], 1.172; 95% confidence interval [CI], 1.019-1.349; P = 0.03 and OR, 11.53; 95% CI, 2.010-66.21; P = 0.006, respectively). CONCLUSIONS: The distinct phenomenon of TRACT was not rare in clinical practice early after dual-chamber pacemaker implantation, and its occurrence was strongly associated with SSS. PMID- 29139150 TI - Pigmented poroma on the temporal region dermoscopically mimicking basal cell carcinoma: A report of two cases. PMID- 29139151 TI - Digital pebbles without evidence of diabetes: A case report. PMID- 29139152 TI - Giant intracranial arteriovenous malformation as the focus of epileptic seizures. AB - A man in his late thirties was found in a supine position in the hallway of his house. He had been diagnosed with epilepsy at approximately 20 years old. Since stopping treatment, epileptic events occurred more frequently and his condition deteriorated in the past 2 years. Autopsy revealed that head injuries were found on the left side of his head. A fracture from the left parietal bone to the anterior cranial fossa was also detected. A subdural hemorrhage (hematoma) spanned a wide range. A subarachnoid hemorrhage was also identified in the left parietal region. His brain weighed 1603 g, was edematous, and showed right uncal herniation. In the right cerebral hemisphere, a thick, enlarged blood vessel ran from the sagittal sinus. An egg-sized tumorous lesion of blood vessels was found on the bottom of the frontal lobe. This vascular lesion had formed between the sagittal sinus and right anterior cerebral artery. Pathologically, veins and arteries were found together, and, thus, this case was diagnosed as an arteriovenous malformation (AVM). No other pathological and toxicological findings were observed. Subdural hematoma, the cause of death, occurred from the fall to the floor. An epileptic seizure may have been the cause of the fall. AVM on his brain was considered to be the focal lesion of epileptic seizures. PMID- 29139153 TI - A Four-Step Synthesis of Substituted 5,11-Dicyano-6,12-diaryltetracenes with Enhanced Stability and High Fluorescence Emission. AB - A four-step synthesis of substituted 5,11-dicyano-6,12-diaryltetracenes was developed, starting from readily available para-substituted benzophenones. The key step of this straightforward route is the complex cascade reaction between tetraaryl[3]cumulenes and tetracyanoethene (TCNE) resulting in 5,5,11,11 tetracyano-5,11-dihydrotetracenes. The mechanism of this transformation was reinvestigated by means of theoretical calculations. The target tetracenes were obtained by a newly developed decyanation/aromatization reaction catalyzed by CuI or CuII complexes in solution, conditions compatible with a broad range of functional groups. A computational mechanistic study sheds light on this transformation. Structures of all tetracene derivatives were confirmed by X-ray crystallography. The presented dicyanotetracene derivatives exhibit outstanding optoelectronic properties and enhanced photostability, significantly surpassing the reference rubrene (5,6,11,12-tetraphenyltetracene). PMID- 29139154 TI - Principal component analysis of three-dimensional face shape: Identifying shape features that change with age. AB - BACKGROUND: The types of shape feature that constitutes a face have not been comprehensively established, and most previous studies of age-related changes in facial shape have focused on individual characteristics, such as wrinkle, sagging skin, etc. In this study, we quantitatively measured differences in face shape between individuals and investigated how shape features changed with age. METHODS: We analyzed three-dimensionally the faces of 280 Japanese women aged 20 69 years and used principal component analysis to establish the shape features that characterized individual differences. We also evaluated the relationships between each feature and age, clarifying the shape features characteristic of different age groups. RESULTS: Changes in facial shape in middle age were a decreased volume of the upper face and increased volume of the whole cheeks and around the chin. Changes in older people were an increased volume of the lower cheeks and around the chin, sagging skin, and jaw distortion. CONCLUSION: Principal component analysis was effective for identifying facial shape features that represent individual and age-related differences. This method allowed straightforward measurements, such as the increase or decrease in cheeks caused by soft tissue changes or skeletal-based changes to the forehead or jaw, simply by acquiring three-dimensional facial images. PMID- 29139155 TI - Additive-Enhanced Crystallization of Solution Process for Planar Perovskite Solar Cells with Efficiency Exceeding 19 . AB - To reduce intrinsic defect density in perovskite films, various additives are often added into the precursor solution. In this paper, a novel solution, in which isopropanol (IPA) was added into the precursor solution, was developed for the preparation of normal planar perovskite solar cells (PSCs). A champion power conversion efficiency (PCE) of 19.70 % was achieved with this approach. By adding IPA into the precursor solution, CH3 NH3 PbI3 perovskite showed better crystallization and stability, indicating improved film quality. Because of the improved morphology of perovskite crystal, the PCE of PSCs increased. In addition, the unencapsulated PSCs retained high output for up to 40 days in air at room temperature, indicating the stability of PSCs. These results may provide a new avenue for manufacturing high efficiency and high stability PSCs. PMID- 29139156 TI - Characterization of cysteine thiol modifications based on protein microenvironments and local secondary structures. AB - We have demonstrated earlier that protein microenvironments were conserved around disulfide-bridged cystine motifs with similar functions, irrespective of diversity in protein sequences. Here, cysteine thiol modifications were characterized based on protein microenvironments, secondary structures and specific protein functions. Protein microenvironment around an amino acid was defined as the summation of hydrophobic contributions from the surrounding protein fragments and the solvent molecules present within its first contact shell. Cysteine functions (modifications) were grouped into enzymatic and non enzymatic classes. Modifications studied were-disulfide formation, thio-ether formation, metal-binding, nitrosylation, acylation, selenylation, glutathionylation, sulfenylation, and ribosylation. 1079 enzymatic proteins were reported from high-resolution crystal structures. Protein microenvironments around cysteine thiol, derived from above crystal structures, were clustered into 3 groups-buried-hydrophobic, intermediate and exposed-hydrophilic clusters. Characterization of cysteine functions were statistically meaningful for 4 modifications (disulfide formation, thioether formation, sulfenylation, and iron/zinc binding) those have sufficient amount of data in the current dataset. Results showed that protein microenvironment, secondary structure and protein functions were conserved for enzymatic cysteine functions, in contrast to the same function from non-enzymatic cysteines. Disulfide forming enzymatic cysteines were tightly packed within intermediate protein microenvironment cluster, have alpha-helical conformation and mostly belonged to CxxC motif of electron transport proteins. Disulfide forming non-enzymatic cysteines did not belong to conserved motif and have variable secondary structures. Similarly, enzymatic thioether forming cysteines have conserved microenvironment compared to non enzymatic cystienes. Based on the compatibility between protein microenvironment and cysteine modifications, more efficient drug molecules could be designed against cysteine-related diseases. PMID- 29139157 TI - Seronegative granulomatosis with polyangiitis presenting with multiple cranial nerve palsies. AB - Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis (WG), is a rare systemic disease characterized by necrotizing granulomas and vasculitis that usually presents in the respiratory tract and renal system. Here, we report a case of anti-neutrophil cytoplasmic antibody (ANCA)-negative GPA with diagnostic difficulties. Neurologic involvement in GPA is not uncommon, with up to 50% of patients manifesting with neurologic defects; however, it is usually a late event. This patient was a 50-year-old man whose first manifestation was multiple neurologic defects without respiratory or renal symptoms. Since multiple neurologic deficits were the first manifestation and there were no pulmonary or renal symptoms, our patient was treated for 1 year for suspected infectious or inflammatory diseases such as non-tuberculous mycobacterial infection or immunoglobulin G4 (IgG4)-related disease with brain involvement; however, his symptoms would wax and wane. Reanalysis of the laboratory findings including biopsies, finally revealed this case to be compatible with GPA. Here, we report a case of GPA, focusing on the diagnostic pitfalls. PMID- 29139158 TI - Macro-anatomical and morphometric studies of the hindlimb of grasscutter (Thryonomys swinderianus, Temminck-1827). AB - The hindlimb of the grasscutter (Thryonomys swinderianus, Temminck-1827) was studied using 12 adult (>=6 months) rats of either sex with the mean weights of 1.42 +/- 0.20 kg and 0.82 +/- 0.13 kg for buck (n = 6) and doe (n = 6), respectively (p < .05). Characteristics of the bones were studied by gross observation after their preparation. Measurements of different segments of the hindlimb were also taken, giving a total average length of 31.80 cm. Correlation coefficients between length of bone and weight of rats were positive (p < .05) in bucks for all bone segments, except the pes (p > .05), whereas those in does were all non-significant (p > .05), with significant sexual dimorphism in the relationships. The average total number of bones in the hindlimb was 92, with no apparent sexual dimorphism. The bones of the hindlimb revealed important differences and similarities in morphology with those of other rodents. The Os coxae presented a relatively large obturator foramen, formed by the ramus of the ischium and shaft of the pubis. The femur had a body and two extremities with a prominent head, well-defined neck and trochanter. The fibula, a slender bone with triangular-shaped proximal extremity, ran down the length of tibia with proximal attachment (via cartilage) and distal fusion, leaving an extensive interosseus space. The pes revealed eight tarsals and four metatarsals; each of the metatarsals showed three phalanges. PMID- 29139159 TI - Syntaxin 1B contributes to regulation of the dopaminergic system through GABA transmission in the CNS. AB - In neuronal plasma membrane, two syntaxin isoforms, HPC-1/syntaxin 1A (STX1A) and syntaxin 1B (STX1B), are predominantly expressed as soluble N-ethylmaleimide sensitive fusion attachment protein receptors, also known as t-SNAREs. We previously reported that glutamatergic and GABAergic synaptic transmissions are impaired in Stx1b null mutant (Stx1b-/- ) mice but are almost normal in Stx1a null mutant (Stx1a-/- ) mice. These observations suggested that STX1A and STX1B have distinct functions in fast synaptic transmission in the central nervous system (CNS). Interestingly, recent studies indicated that Stx1a-/- or Stx1a+/- mice exhibit disruption in the monoaminergic system in the CNS, causing unusual behaviour that is similar to neuropsychological alterations observed in psychiatric patients. Here, we studied whether STX1B contributes to the regulation of monoaminergic system and if STX1B is related to neuropsychological properties in human neuropsychological disorders similar to STX1A. We found that monoamine release in vitro was normal in Stx1b+/- mice unlike Stx1a-/- or Stx1a+/ mice, but the basal extracellular dopamine (DA) concentration in the ventral striatum was increased. DA secretion in the ventral striatum is regulated by GABAergic neurons, and Stx1b+/- mice exhibited reduced GABA release both in vitro and in vivo, disrupting the DAergic system in the CNS of these mice. We also found that Stx1b+/- mice exhibited reduced pre-pulse inhibition (PPI), which is believed to represent one of the prominent schizotypal behavioural profiles of human psychiatric patients. The reduction in PPI was rescued by DA receptor antagonists. These observations indicated that STX1B contributes to excess activity of the DAergic system through regulation of GABAergic transmission. PMID- 29139160 TI - Assessing the Ligand Properties of NHC-Stabilised Phosphorus(I) Cations. AB - The isolation and full characterisation of a series of cationic metal-carbonyl complexes bearing an N-heterocyclic carbene stabilised phosphorus(I) ligand are reported. Specifically, the mononuclear coordination complexes [LM(CO)5 ][BPh4 ] (M=Cr, Mo, W), [LFe(CO)4 ][BPh4 ] and the dinuclear complexes [LMn2 (CO)8 ][BPh4 ] and [LCo2 (CO)6 ][BPh4 ], in which L=[bis(1,3,4,5-tetramethylimidazol-2 ylidene)phosphanide]+ , have all been isolated in the solid state and structurally confirmed by single-crystal X-ray diffraction. The dicationic platinum complex trans-[L2 PtCl2 ][BPh4 ]2 is also reported and fully characterised. The donor ability of [L]+ has been assessed by IR spectroscopy of its metal-carbonyl complexes and by using DFT calculations. The results suggest that [L]+ is a weak pi-acceptor with moderate donor strength and thus it bridges the gap that exists between phosphines and amines in terms of ligand properties. Collectively, these molecules represent the first crystallographically characterised cationic metal-carbonyl derivatives of a PI -centred ligand and are a rare collection of cationic metal-carbonyl complexes. PMID- 29139161 TI - Cognitive abilities, brain white matter hyperintensity volume, and structural network connectivity in older age. AB - OBJECTIVE: To assess brain structural connectivity in relation to cognitive abilities in healthy ageing, and the mediating effects of white matter hyper intensity (WMH) volume. METHODS: MRI data were analysed in 558 members of the Lothian Birth Cohort 1936. Brains were segmented into 85 regions and combined with tractography to generate structural connectomes. WMH volume was quantified. Relationships between whole-brain connectivity, assessed using graph theory metrics, and four major domains of cognitive ability (visuospatial reasoning, verbal memory, information processing speed and crystallized ability) were investigated, as was the mediating effects of WMH volume on these relationships. RESULTS: Visuospatial reasoning was associated with network strength, mean shortest path length, and global efficiency. Memory was not associated with any network connectivity metric. Information processing speed and crystallized ability were associated with all network measures. Some relationships were lost when adjusted for mean network FA. WMH volume mediated 11%-15% of the relationships between most network measures and information processing speed, even after adjusting for mean network FA. CONCLUSION: Brain structural connectivity relates to visuospatial reasoning, information processing speed and crystallized ability, but not memory, in this relatively healthy age-homogeneous cohort of 73 year olds. When adjusted for mean FA across the network, most relationships are lost, except with information processing speed suggesting that the underlying topological network structure is related to this cognitive domain. Moreover, the connectome-processing speed relationship is partly mediated by WMH volume in this cohort. Hum Brain Mapp 39:622-632, 2018. (c) 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID- 29139162 TI - Epidemiology of therapeutic apheresis with a multidisciplinary approach at a high volume pediatric center. AB - INTRODUCTION: Therapeutic apheresis (TA) is used inconsistently in pediatric populations. We seek to define our multidisciplinary institutional practice. METHODS: We conducted a retrospective chart review of patients receiving TA from January 1, 2012 through October 31, 2015. Data collected included demographics, American Society of Apheresis (ASFA) indication, complications, and mortality. RESULTS: Over 46 months, 1198 TA procedures were conducted on 289 patients ranging in age from 5 months to 21 years with weights ranging from 4.76 to 170.3 kg (16 procedures in patients <10 kg). The procedures were 86% therapeutic plasma exchange, 10% red blood cell exchange, 4% extracorporeal photopheresis, and 5 leukocytapheresis procedures. TA was initiated in different clinical environments: 41% outpatient, 37% intensive care, 15% general inpatient, and 7% operating room. The ASFA category (6th edition) indications for the 1198 procedures included: 44% category I, 25% category II, 23% category III, a single category IV procedure, and the remainder (8%) uncategorized by ASFA. The rate of procedure failure and procedure-related mortality are 1 and 0%, respectively. Case mortality rate was 4%. CONCLUSION: At a large volume pediatric hospital, TA is commonly used and can be performed safely in a variety of settings by a multidisciplinary team. This demographic review catalogs the number and type of procedures performed as a second-line therapy or on the basis of limited evidence. Additional collaborative investigation is needed to evaluate unique implications of TA in pediatrics to maximize efficacy while preserving safety. PMID- 29139163 TI - Assessment of hard target modeling in CASP12 reveals an emerging role of alignment-based contact prediction methods. AB - We present our assessment of CASP12 modeling efforts for targets with no obvious templates of high sequence/structure similarity in the PDB, that is for evaluation units of the free modeling (FM) and free modeling/template-based modeling (FM/TBM) categories. Models were clustered and ranked using the Global Distance Test-Total Score and 5 additional metrics developed in previous CASP rounds, producing short lists of models that were subject to visual inspection in comparison to the target structures. The whole procedure was implemented as a web app that facilitates model selection and visual inspection, and could become useful to facilitate and standardize future assessments. We describe cases of (1) targets with remarkably good predictions, (2) targets whose models captured some global shape and topology features, and (3) targets for which models fail to capture even coarse features. We note that despite this CASP being among the most challenging ones, a measurable improvement of the top predictions is apparent, that we attribute to the emergence of accurate contact prediction methods and the increased number of available sequences. We also briefly discuss current limitations in tertiary structure prediction exemplified by CASP12 targets. Overall, the Baker, Zhang, and Lee manual groups and servers were identified as the top global performing groups. PMID- 29139164 TI - Enantioselective Hydrogenation of Imidazo[1,2-a]pyridines. AB - The enantioselective synthesis of tetrahydroimidazo[1,2-a]pyridines by direct hydrogenation was achieved using a ruthenium/N-heterocyclic carbene (NHC) catalyst. The reaction forgoes the need for protecting or activating groups, proceeds with complete regioselectivity, good to excellent yields, enantiomeric ratios of up to 98:2, and tolerates a broad range of functional groups. 5,6,7,8 Tetrahydroimidazo[1,2-a]pyridines, which are found in numerous bioactive molecules, were directly obtained by this method, and its applicability was demonstrated by the (formal) synthesis of several functional molecules. PMID- 29139165 TI - Secular change in adult stature of modern Greeks. AB - OBJECTIVES: In Greece, during the late 19th and early 20th century, the rural population adopted a more or less urban lifestyle. Furthermore, the first half of the 20th century finds Greece involved in five major wars, including a civil war, and consequent financial deprivation. This study investigates how the socioeconomic changes in Greece, during this period of time, have affected the stature of its population. METHODS: The Athens collection constitutes our sample with 189 adult individuals (104 males and 85 females). Stature was estimated with regression equations and secular change was evaluated by linear regression of stature with respect to the year of birth. Further analysis of our population sample was based on three time periods to explore the correlation between secular change and historical events. RESULTS: From 1879 to 1965, stature increased for both males and females. The subsequent analysis among different periods revealed that the male group exhibited a small although non-significant decline in stature during the years 1912 to 1950, which coincides with the long inter-war period. However, females appear less affected by the consequent deprivation. CONCLUSIONS: Our findings are consistent with earlier studies based on a much smaller time span. The negative effect of the economic and nutritional deprivation on stature as a result of warfare is apparent in our sample, at least for males. Furthermore, the positive effect of economic growth on stature is prominent for the entire population in the postwar period. PMID- 29139166 TI - Animal models of fibrodysplasia ossificans progressiva. AB - Fibrodysplasia Ossificans Progressiva is a rare human disease of heterotopic ossification. FOP patients experience progressive development of ectopic bone within fibrous tissues that contributes to a gradual loss of mobility and can lead to early mortality. Due to lack of understanding of the etiology and progression of human FOP, and the fact that surgical interventions often exacerbate FOP disease progression, alternative therapeutic methods are needed, including modeling in animals, to study and improve understanding of human FOP. In this review we provide an overview of the existing animal models of FOP and the key mechanistic findings from each. In addition, we highlight the specific advantages of a new adult zebrafish model, generated by our lab, to study human FOP. Developmental Dynamics 247:279-288, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29139167 TI - Zinc finger gene nolz1 regulates the formation of retinal progenitor cells and suppresses the Lim3/Lhx3 phenotype of retinal bipolar cells in chicken retina. AB - BACKGROUND: The zinc-finger transcription factor Nolz1 regulates spinal cord neuron development by interacting with the transcription factors Isl1, Lim1, and Lim3, which are also important for photoreceptors, horizontal and bipolar cells during retinal development. We, therefore, studied Nolz1 during retinal development. RESULTS: Nolz1 expression was seen in two waves during development: one early (peak at embryonic day 3-4.5) in retinal progenitors and one late (embryonic day 8) in newly differentiated cells in the inner nuclear layer. Overexpression and knockdown showed that Nolz1 decreases proliferation and stimulates cell cycle withdrawal in retinal progenitors with effects on the generation of retinal ganglion cells, photoreceptors, and horizontal cells without triggering apoptosis. Overexpression of Nolz1 gave more p27 positive cells. Sustained overexpression of Nolz1 in the retina gave fewer Lim3/Lhx3 bipolar cells. CONCLUSIONS: We conclude that Nolz1 has multiple functions during development and suggest a mechanism in which Nolz1 initially regulates the proliferation state of the retinal progenitor cells and then acts as a repressor that suppresses the Lim3/Lhx3 bipolar cell phenotype at the time of bipolar cell differentiation. Developmental Dynamics 247:630-641, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29139168 TI - Hunter-gatherer dental pathology: Do historic accounts of Aboriginal Australians correspond to the archeological record of dental disease? AB - OBJECTIVES: Studies of hunter-gatherer oral pathology, particularly in Australia, often focus upon dental wear and caries or assume that historic studies of Aboriginal people reflect the precontact past. Consequently the range of population variation has been underestimated. In this paper dental pathology from human remains from Roonka are compared with a model of dental pathology derived from historic studies. The aim is to identify aspects of dental pathology indicative of regional or intra-population diversity. METHODS: Adult dentitions (n = 115) dating from the mid to late Holocene were recorded for the following conditions: dental wear, caries, periapical voids, calculus, periodontal disease and antemortem tooth loss. Statistical analysis was used to identify patterns of dental pathology and to identify causal relationships between conditions. RESULTS: Dental wear is marked while dental caries rates are extremely low. Other indications of dental pathology are uncommon (<7% of teeth affected). Temporal heterogeneity is apparent: there are 3 young adults with caries who died in the postcontact period. There is also a small group of middle age to old adults with disproportionate abscessing and pulp exposure who may represent temporal variation or heterogeneity in individual frailty. CONCLUSIONS: The results confirm dental wear as the major cause of dental pathology in this group and that, at a general level, historic accounts do correspond with this archeological sample. However, intra-sample heterogeneity is apparent while 2 dental conditions, calculus and periodontal disease, along with the pattern of sex differences deviate from expectation, demonstrating that to identify regional variation attention needs to be paid to the dentoalveolar complex as a whole. PMID- 29139169 TI - Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid. AB - Sex differences in the incidence, clinical manifestation, disease course, and prognosis of neurological diseases, such as autism spectrum disorders or Alzheimer's disease, have been reported. Obesity has been postulated as a risk factor for cognitive decline and Alzheimer's disease and, during pregnancy, increases the risk of autism spectrum disorders in the offspring. Obesity is associated with increased serum and brain levels of free fatty acids, such as palmitic acid, which activate microglial cells triggering a potent inflammatory cascade. In this study, we have determined the effect of palmitic acid in the inflammatory profile, motility, and phagocytosis of primary male and female microglia, both in basal conditions and in the presence of a pro-inflammatory stimulus (interferon-gamma). Male microglia in vitro showed higher migration than female microglia under basal and stimulated conditions. In contrast, female microglia had higher basal and stimulated phagocytic activity than male microglia. Palmitic acid did not affect basal migration or phagocytosis, but abolished the migration and phagocytic activity of male and female microglia in response to interferon-gamma. These findings extend previous observations of sex differences in microglia and suggest that palmitic acid impairs the protective responses of these cells. PMID- 29139171 TI - Structural insights into a thermostable variant of human carbonic anhydrase II. AB - Carbonic anhydrase is an enzyme of interest for many biotechnological developments including carbon sequestration. These applications often require harsh conditions, so there is a need for the development of thermostable variants. One of the most thermostable human carbonic anhydrase II (HCAIIts) variants was patented in 2006. Here, we report the ultra-high resolution crystal structure of HCAIIts. The structural changes seen are consistent with each of the six mutations involved acting largely independently and variously resulting in increased H-bonding, improved packing, and reduced side chain entropy loss on folding to yield the increased stability. We further suggest that for four of the mutations, improvements in backbone conformational energetics is also a contributor and that considerations of such conformational propensities of individual amino acids are often overlooked. PMID- 29139170 TI - Single Cell Resolution of Human Hematoendothelial Cells Defines Transcriptional Signatures of Hemogenic Endothelium. AB - Endothelial-to-hematopoietic transition (EHT) is an important stage in definitive hematopoietic development. However, the genetic mechanisms underlying human EHT remain poorly characterized. We performed single cell RNA-seq using 55 hemogenic endothelial cells (HECs: CD31+ CD144+ CD41- CD43- CD45- CD73- RUNX1c+ ), 47 vascular endothelial cells without hematopoietic potential (non-HE: CD31+ CD144+ CD41- CD43- CD45- CD73- RUNX1c- ), and 35 hematopoietic progenitor cells (HPCs: CD34+ CD43+ RUNX1c+ ) derived from human embryonic stem cells (hESCs). HE and HP were enriched in genes implicated in hemogenic endothelial transcriptional networks, such as ERG, GATA2, and FLI. We found transcriptional overlap between individual HECs and HPCs; however, these populations were distinct from non-HE. Further analysis revealed novel biomarkers for human HEC/HPCs, including TIMP3, ESAM, RHOJ, and DLL4. Collectively, we demonstrate that hESC-derived HE and HP share a common developmental pathway, while non-HE are more heterogeneous and transcriptionally distinct. Our findings provide a novel strategy to test new genetic targets and optimize the production of definitive hematopoietic cells from human pluripotent stem cells. Stem Cells 2018;36:206-217. PMID- 29139172 TI - Association between structural brain network efficiency and intelligence increases during adolescence. AB - Adolescence represents an important period during which considerable changes in the brain take place, including increases in integrity of white matter bundles, and increasing efficiency of the structural brain network. A more efficient structural brain network has been associated with higher intelligence. Whether development of structural network efficiency is related to intelligence, and if so to which extent genetic and environmental influences are implicated in their association, is not known. In a longitudinal study, we mapped FA-weighted efficiency of the structural brain network in 310 twins and their older siblings at an average age of 10, 13, and 18 years. Age-trajectories of global and local FA-weighted efficiency were related to intelligence. Contributions of genes and environment were estimated using structural equation modeling. Efficiency of brain networks changed in a non-linear fashion from childhood to early adulthood, increasing between 10 and 13 years, and leveling off between 13 and 18 years. Adolescents with higher intelligence had higher global and local network efficiency. The dependency of FA-weighted global efficiency on IQ increased during adolescence (rph =0.007 at age 10; 0.23 at age 18). Global efficiency was significantly heritable during adolescence (47% at age 18). The genetic correlation between intelligence and global and local efficiency increased with age; genes explained up to 87% of the observed correlation at age 18. In conclusion, the brain's structural network differentiates depending on IQ during adolescence, and is under increasing influence of genes that are also associated with intelligence as it develops from late childhood to adulthood. PMID- 29139173 TI - Incidence of in-hospital and post-discharge diagnosed hospital-associated venous thromboembolism using linked administrative data. AB - BACKGROUND: Hospital-associated venous thromboembolism (HA-VTE) is a serious adverse event, preventable with appropriate care during and post-admission. Accurate measurement of in-hospital and post-discharge incidences is essential for implementation and evaluation of prevention strategies and monitoring. AIMS: To estimate in-hospital and post-discharge diagnosed VTE, trends and risk factors. METHODS: This was a population-based study in New South Wales, Australia, using linked hospital admission and emergency department data for 2010 2013 of adult patients with a minimum stay of 48 h. HA-VTE were diagnosed in hospital or post-discharge (within 90 days). Multi-level modelling schemes produced adjusted rates and ratios for patient, admission and hospital-related characteristics. RESULTS: From 1 865 059 admissions, the HA-VTE incidence rate was 9.7 per 1000 admissions; 71% were diagnosed post-discharge, and 4.3% died with a greater risk for VTE diagnosed in hospital compared to post-discharge (8.4% vs 2.6%, P < 0.001). Compared with surgical patients, medical patients developed fewer HA-VTE (IRR = 0.60, 95% CI: 0.58-0.63) but were more likely to be diagnosed post-discharge (OR = 2.19; 95% CI: 2.00-2.40). HA-VTE increased 6.5% over the period, driven by the 44% increase in in-hospital diagnoses and not by the 9% decrease in post-discharge diagnoses. CONCLUSIONS: HA-VTE is a continuing burden, and diagnosis after recent hospital discharge is notably high. Incidence varies across patients and facilities, highlighting the need for individual VTE risk assessment. Inclusive measures and routine monitoring of HA-VTE incidence and mortality are essential for implementing best practice and assessing effectiveness of prevention strategies. PMID- 29139174 TI - Neural mechanisms of interference control in working memory capacity. AB - The extent to which one can use cognitive resources to keep information in working memory is known to rely on (1) active maintenance of target representations and (2) downregulation of interference from irrelevant representations. Neurobiologically, the global capacity of working memory is thought to depend on the prefrontal and parietal cortices; however, the neural mechanisms involved in controlling interference specifically in working memory capacity tasks remain understudied. In this study, 22 healthy participants completed a modified complex working memory capacity task (Reading Span) with trials of varying levels of interference control demands while undergoing functional MRI. Neural activity associated with interference control demands was examined separately during encoding and recall phases of the task. Results suggested a widespread network of regions in the prefrontal, parietal, and occipital cortices, and the cingulate and cerebellum associated with encoding, and parietal and occipital regions associated with recall. Results align with prior findings emphasizing the importance of frontoparietal circuits for working memory performance, including the role of the inferior frontal gyrus, cingulate, occipital cortex, and cerebellum in regulation of interference demands. PMID- 29139175 TI - Hematopoietic Substrate-1-Associated Protein X-1 Regulates the Proliferation and Apoptosis of Endothelial Progenitor Cells Through Akt Pathway Modulation. AB - Endothelial precursor cells (EPCs) are involved in vasculogenesis of various physiological and pathological processes. The proliferation and survival mechanism of EPCs needs to be explored further for the purpose of developing an effective glioma treatment. Hematopoietic substrate-1-associated protein X-1 (HAX 1) has been reported as an anti-apoptotic protein that plays an important role in several malignant tumors. However, the effect and mechanism of HAX-1 on EPCs remains unknown. This study aims to investigate the effect of HAX-1 on the proliferation and apoptosis of EPCs and explore its mechanism. According to our results, HAX-1 was overexpressed in EPCs. The results of clone formation and 5 ethynyl-2'-deoxyuridine proliferation assay showed that HAX-1 promoted multiplication of EPCs. Flow cytometry showed HAX-1 knockout cell cycle arrest mainly in G0/G1 phase. Apoptosis analysis showed that HAX-1 could protect EPCs from apoptosis in oxidative stress. Western blot assay indicated that HAX-1 could inhibit the activation of caspase cascade and reduce the expression of p21, Bcl-2 associated X protein, and p53. HAX-1 also enhanced the degradation rate and ubiquitination of p53 through the promotion of phosphorylation of proteins MDM-2 and Akt1. Co-immunoprecipitation and immunofluorescent colocalization assays were performed to test the influence of HAX-1 on the interaction between Akt1 and heat shock protein 90 (Hsp90), which is crucial for the activity of Akt1. In conclusion, this novel study suggests that HAX-1 could facilitate the Akt1 pathway through Hsp90, which led to a decline in the levels of p53, and finally promoted the proliferation and inhibited the apoptosis of EPCs. Stem Cells 2018;36:406-419. PMID- 29139176 TI - Costs of an ostomy self-management training program for cancer survivors. AB - OBJECTIVE: To measure incremental expenses to an oncologic surgical practice for delivering a community-based, ostomy nurse-led, small-group, behavior skills training intervention to help bladder and colorectal cancer survivors understand and adjust to their ostomies and improve their health-related quality of life, as well as assist family caregivers to understand survivors' needs and provide appropriate supportive care. METHODS: The intervention was a 5-session group behavior skills training in ostomy self-management following the principles of the Chronic Care Model. Faculty included Wound, Ostomy, and Continence Nurses (WOCNs) using an ostomy care curriculum. A gender-matched peer-in-time buddy was assigned to each ostomy survivor. The 4-session survivor curriculum included the following: self-management practice and solving immediate ostomy concerns; social well-being; healthy lifestyle; and a booster session. The single family caregiver session was coled by a WOCN and an ostomy peer staff member and covered relevant caregiver and ostomate support issues. Each cohort required 8 weeks to complete the intervention. Nonlabor inputs included ostomy supplies, teaching materials, automobile mileage for WOCNs, mailing, and meeting space rental. Intervention personnel were employed by the University of Arizona. Labor expenses included salaries and fringe benefits. RESULTS: The total incremental expense per intervention cohort of 4 survivors was $7246 or $1812 per patient. CONCLUSIONS: A WOCN-led group self-help ostomy survivorship intervention provided affordable, effective, care to cancer survivors with ostomies. PMID- 29139178 TI - Notch1 and Notch2 Coordinately Regulate Stem Cell Function in the Quiescent and Activated States of Muscle Satellite Cells. AB - Satellite cells, the muscle tissue stem cells, express three Notch receptors (Notch1-3). The function of Notch1 and Notch2 in satellite cells has to date not been fully evaluated. We investigated the role of Notch1 and Notch2 in myogenic progression in adult skeletal muscle using tamoxifen-inducible satellite cell specific conditional knockout mice for Notch1 (N1-scKO), Notch2 (N2-scKO), and Notch1/Notch2 (scDKO). In the quiescent state, the number of satellite cells was slightly reduced in N2-scKO, but not significantly in N1-scKO, and almost completely depleted in scDKO mice. N1-scKO and N2-scKO mice both exhibited a defect in muscle regeneration induced by cardiotoxin injection, while muscle regeneration was severely compromised with marked fibrosis in scDKO mice. In the activated state, ablation of either Notch1 or Notch2 alone in satellite cells prevented population expansion and self-renewal but induced premature myogenesis. Therefore, our results indicate that Notch1 and Notch2 coordinately maintain the stem-cell pool in the quiescent state by preventing activation and regulate stem cell-fate decision in the activated state, governing adult muscle regeneration. Stem Cells 2018;36:278-285. PMID- 29139177 TI - A structural overview of mycobacterial adhesins: Key biomarkers for diagnostics and therapeutics. AB - Adherence, colonization, and survival of mycobacteria in host cells require surface adhesins, which are attractive pharmacotherapeutic targets. A large arsenal of pilus and non-pilus adhesins have been identified in mycobacteria. These adhesins are capable of interacting with host cells, including macrophages and epithelial cells and are essential to microbial pathogenesis. In the last decade, several structures of mycobacterial adhesins responsible for adhesion to either macrophages or extra cellular matrix proteins have been elucidated. In addition, key structural and functional information have emerged for the process of mycobacterial adhesion to epithelial cells, mediated by the Heparin-binding hemagglutinin (HBHA). In this review, we provide an overview of the structural and functional features of mycobacterial adhesins and discuss their role as important biomarkers for diagnostics and therapeutics. Based on the reported data, it appears clear that adhesins are endowed with a variety of different structures and functions. Most adhesins play important roles in the cell life of mycobacteria and are key virulence factors. However, they have adapted to an extracellular life to exert a role in host-pathogen interaction. The type of interactions they form with the host and the adhesin regions involved in binding is partly known and is described in this review. PMID- 29139179 TI - Involvement of LeMRP, an ATP-binding cassette transporter, in shikonin transport and biosynthesis in Lithospermum erythrorhizon. AB - Shikonin and its derivatives are important medicinal secondary metabolites accumulating in roots of Lithospermum erythrorhizon. Although some membrane proteins have been identified as transporters of secondary metabolites, the mechanisms underlying shikonin transport and accumulation in L. erythrorhizon cells still remain largely unknown. In this study, we isolated a cDNA encoding LeMRP, an ATP-binding cassette transporter from L. erythrorhizon, and further investigated its functions in the transport and biosynthesis of shikonin using the yeast transformation and transgenic hairy root methods, respectively. Real time PCR was applied for expression analyses of LeMRP and shikonin biosynthetic enzyme genes. Functional analysis of LeMRP using the heterologous yeast cell expression system showed that LeMRP could be involved in shikonin transport. Transgenic hairy roots of L. erythrorhizon demonstrated that LeMRP overexpressing hairy roots produced more shikonin than the empty vector (EV) control. Real-time PCR results revealed that the enhanced shikonin biosynthesis in the overexpression lines was mainly caused by highly up-regulated expression of genes coding key enzymes (LePAL, HMGR, Le4CL and LePGT) involved in shikonin biosynthesis. Conversely, LeMRP RNAi decreased the accumulation of shikonin and effectively down-regulated expression level of the above genes. Typical inhibitors of ABC proteins, such as azide and buthionine sulphoximine, dramatically inhibited accumulation of shikonin in hairy roots. Our findings provide evidence for the important direct or indirect role of LeMRP in transmembrane transport and biosynthesis of shikonin. PMID- 29139180 TI - Successful heart transplantation in patients with active Staphylococcus bloodstream infection and suspected mechanical circulatory support device infection. AB - BACKGROUND: An active bloodstream infection (BSI) is typically considered a contraindication to heart transplantation (HT). However, in some patients with Staphylococcus bacteremia and mechanical circulatory support device infection, positive blood cultures may persist until removal of the infected device, and eradicating the infection prior to HT may not be possible. We report the outcomes of six patients with active Staphylococcus BSI at the time of HT. METHODS: All cases of HT performed at The Mount Sinai Hospital from 2009 through 2015 were reviewed. All patients with a mechanical circulatory support device and an active Staphylococcus BSI at the time of HT were included. RESULTS: Six patients with active Staphylococcus bacteremia and suspected mechanical circulatory support device infection underwent HT. All patients were bacteremic with Staphylococcus species at the time of HT. All were managed with antimicrobial therapy, radical debridement at the time of HT, and limited use of immunosuppression, and all survived until hospital discharge with no evidence of relapsed Staphylococcus infection. CONCLUSION: These results suggest that some carefully selected patients with active Staphylococcus bacteremia and suspected mechanical circulatory support device infection may safely undergo HT, and that HT may effectively eliminate the underlying infection. PMID- 29139181 TI - Direct antiviral treatment of chronic hepatitis C in heart transplant recipients. AB - Direct-acting antiviral agents (DAAs) are a safe and effective treatment for chronic hepatitis C (CHC). This may be particularly valuable for patients with severe comorbidities or baseline conditions, including non-liver solid organ transplant. We report cases of two heart transplant recipients with CHC treated with DAAs (sofosbuvir and daclatasvir) achieving sustained virological response. Treatment was well tolerated and no relevant side effects were observed. The drug drug interactions and graft function were carefully monitored. PMID- 29139182 TI - Deep-Level Defect Enhanced Photothermal Performance of Bismuth Sulfide-Gold Heterojunction Nanorods for Photothermal Therapy of Cancer Guided by Computed Tomography Imaging. AB - Bismuth sulfide (Bi2 S3 ) nanomaterials are emerging as a promising theranostic platform for computed tomography imaging and photothermal therapy of cancer. Herein, the photothermal properties of Bi2 S3 nanorods (NRs) were unveiled to intensely correlate to their intrinsic deep-level defects (DLDs) that potentially could work as electron-hole nonradiative recombination centers to promote phonon production, ultimately leading to photothermal performance. Bi2 S3 -Au heterojunction NRs were designed to hold more significant DLD properties, exhibiting more potent photothermal performance than Bi2 S3 NRs. Under 808 nm laser irradiation, Bi2 S3 -Au NRs could trigger higher cellular heat shock protein 70 expression and more apoptotic cells than Bi2 S3 NRs, and caused severe cell death and tumor growth inhibition, showing great potential for photothermal therapy of cancer guided by computed tomography imaging. PMID- 29139184 TI - Achieving Strong Positive Cooperativity through Activating Weak Non-Covalent Interactions. AB - Positive cooperativity achieved through activating weak non-covalent interactions is common in biological assemblies but is rarely observed in synthetic complexes. Two new molecular tubes have been synthesized and the syn isomer binds DABCO based organic cations with high orientational selectivity. Surprisingly, the ternary complex with two hosts and one guest shows a high cooperativity factor (alpha=580), which is the highest reported for synthetic systems without involving ion-pairing interactions. The X-ray single-crystal structure revealed that the strong positive cooperativity likely originates from eight C-H???O hydrogen bonds between the two head-to-head-arranged syn tube molecules. These relatively weak hydrogen bonds were not observed in the free hosts and only emerged in the complex. Furthermore, this complex was used as a basic motif to construct a robust [2+2] cyclic assembly, thus demonstrating its potential in molecular self-assembly. PMID- 29139183 TI - Photoinduced Pedalo-Type Motion in an Azodicarboxamide-Based Molecular Switch. AB - Well-defined structural changes of molecular units that can be triggered by light are crucial for the development of photoactive functional materials. Herein, we report on a novel switch that has azodicarboxamide as its photo-triggerable element. Time-resolved UV-pump/IR probe spectroscopy in combination with quantum chemical calculations shows that the azodicarboxamide functionality, in contrast to other azo-based chromophores, does not undergo trans-cis photoisomerization. Instead, a photoinduced pedalo-type motion occurs, which because of its volume conserving properties enables the design of functional molecular systems with controllable motion in a confined space. PMID- 29139185 TI - Mental health literacy: A cross-cultural study of American and Chinese bachelor of nursing students. AB - : WHAT IS KNOWN ON THE SUBJECT?: Many nursing students have inadequate preparation for practice in mental health nursing in the United States and China. The concept of mental illness has different connotations in different cultures. Studies differ from country to country concerning the influence of nursing education on students' knowledge about and attitudes towards mental disorders. There is a lack of cross-cultural research that takes a broad perspective to explore how nursing students' knowledge and beliefs about mental disorders are influenced by the culture within education and healthcare systems. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Nursing students in the United States and China shared similar views on a broad range of intervention options including professional help, psychotropic medications and activity interventions for managing depression and schizophrenia. The major difference between the two nursing student groups was that the Chinese students showed more preference to occasional alcohol consumption and specialized therapies including cognitive behavioural therapy and electroconvulsive therapy and the US students held less skepticism towards traditional and religious practices as possible treatment options for depression and schizophrenia. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The Chinese nursing students need to be educated about safe alcohol consumption guidelines adopted by the National Health and Family Planning Commission. The US nursing students need to increase their awareness of national practice guidelines for managing mental disorders, particularly with respect to the use of specialized therapies such as cognitive-behavioural therapy and electroconvulsive therapy. We support professional and psychosocial interventions in caring for patients with mental disorders. ABSTRACT: INTRODUCTION Nursing students in the United States and China have reported inadequate preparedness for practice in mental health nursing. It is important to investigate nursing students' mental health literacy levels for a better understanding of their practice readiness in mental health field upon completion of their education. Aim This study was aimed at developing an understanding of American and Chinese nursing students' mental health literacy regarding the effectiveness of specific interventions for managing depression and schizophrenia. Method The "Australian National Mental Health Literacy Survey" was completed by a group of 310 nursing students including 152 Americans and 158 Chinese between April 2016 and April 2017 to compare students' rated intervention options on two provided vignettes. Results The two student groups reached consensus on many intervention options. However, the Chinese students showed more preference to occasional alcohol consumption and specialized therapies and the US students held less skepticism towards traditional practices as treatment options for depression and schizophrenia. Discussion and implications for practice The findings support professional and psychosocial interventions in caring for patients with mental disorders. There is a significant need for specific education on safe alcohol consumption guidelines for Chinese nursing students and clinical practice guidelines for managing mental disorders for American nursing students. PMID- 29139186 TI - Factors associated with home hazards: Findings from the Malaysian Elders Longitudinal Research study. AB - AIM: Previous studies have investigated home hazards as a risk factor for falls without considering factors associated with the presence of home hazards. The present study aimed to determine patterns of home hazards among urban community dwelling older Malaysians, and to identify factors contributing to home hazards. METHODS: Cross-sectional data from the initial wave of the Malaysian Elders Longitudinal Research study were used. Basic demographics were obtained from the Global Questionnaire. Basic and instrumental activities of daily living were measured using the Katz and Lawton-Brody scales, and home hazards were identified using the Home Falls and Accidents Screening Tool. Participants were also asked if they had fallen in the previous 12 months. RESULTS: Data were analyzed from 1489 participants. Hazards were frequently identified (>30%) in the toilet and bathroom areas (no grab rail, no non-slip mat, distant toilet), slippery floors, no bedside light access and inappropriate footwear. Lower educational attainment, traditional housing, Chinese ethnicity, greater number of home occupants, lower monthly expenditure, poor vision and younger age were the factors independently associated with home hazards. CONCLUSIONS: This study provides evidence that home hazards are a product of the interaction of the individual's function within their home environment. Hazards are also influenced by local sociocultural and environmental factors. The relationship between home hazards and falls appears complex and deserves further evaluation. Geriatr Gerontol Int 2018; 18: 387-395. PMID- 29139188 TI - Biomimetic Peptide-Gated Nanoporous Membrane for On-Demand Molecule Transport. AB - The controllable molecule transport is crucial to realize many highly valuable applications both in vivo and in vitro. Nanoporous membranes, with nanoscopic pores, high porosity, uniform pore dimensions, and controllable surface chemical properties, hold tremendous potential to achieve this function. Herein, we report a nano-gating system for on-demand molecule transport based on a peptide-gated nanoporous membrane. Acting as gatekeeper, the peptides introduced to the nanoporous membrane provide an opportunity to realize on-demand on-off states via reversible conformational switching of the peptides. This nano-gating system offers sustained release and can be used as a sophisticated molecule transport platform for localized drug delivery with a feedback function. PMID- 29139187 TI - Pharmacokinetics and safety of paclitaxel delivery into porcine airway walls by a new endobronchial drug delivery catheter. AB - BACKGROUND AND OBJECTIVE: Intratumoral administration of chemotherapeutic agents is a treatment modality that has proven efficacious in reducing the recurrence of tumours and increases specificity of treatment while minimizing systemic side effects. Direct intratumoral injection of malignant airway obstruction has potential therapeutic benefits but tissue drug concentrations and side-effect profiles are poorly understood. METHODS: Bronchial wall injection of generic paclitaxel (PTX) (102 injections of 0.05, 0.5, 1.5 or 2.5 mg/mL in 10 healthy pigs), saline (14 injections in 2 healthy pigs) or Abraxane (ABX) (24 injections of 0.5 mg/mL in 4 healthy pigs) was performed with a microneedle infusion catheter. Local histopathology, plasma and tissue PTX concentrations were evaluated at 7, 20 or 28 days post-injection. RESULTS: Injection of generic PTX directly into the bronchial wall at doses up to 1.5 mg/mL only caused minimal tissue injury. Dose-limiting tissue reaction was observed at 2.5 mg/mL. Plasma PTX was detectable for up to 5 days but not at 28 days, with area under the curve (AUC)(0-5d) 20- to 50-fold lower than the AUC(0-infinity) of 6300 ng h/mL for the approved intravenous dose. At 7 and 28 days post-injection, bronchial PTX tissue concentrations were above a 10-nmol/L cancer therapeutic level. PTX was not found in peripheral tissues. Similar results were observed between ABX and generic PTX. CONCLUSION: Results of these studies confirm the administration of PTX directly into the bronchial wall is safe and feasible. PTX was detectable in plasma for <7 days but tissue concentrations remained therapeutic throughout the follow-up period. PMID- 29139189 TI - Clostridium difficile infection in hospitalized octogenarian patients. AB - AIM: To evaluate the risk factors and outcome of Clostridium difficile infection in hospitalized octogenarian patients. METHODS: A retrospective analysis of risk factors and outcome of C. difficile infection in hospitalized octogenarians was carried out at two academic centers in Romania from January 2014 to September 2016. Demographic, clinical and laboratory characteristics; antibiotics and proton pump inhibitors use in-hospital and 2 months before admission; comorbidities; length of hospital stay; treatment; and outcome were carefully collected from the patients' medical charts and compared with those from octogenarians hospitalized during the same period. RESULTS: A total of 286 octogenarians were hospitalized during the study period and among them 79 (27.6%) were diagnosed with C. difficile infection. On multivariate logistic regression analyses, the previous 2 months' hospitalizations (OR 10.231, 95% CI 1.769 58.965, P = 0.009), antibiotic use 2 months before admission (OR 12.596, 95% CI 1.024-15.494, P = 0.048), antibiotic treatment during hospitalization (OR 6.302, 95% CI 3.510-11.316, P < 0.0001), arterial hypertension (OR 11.228, 95% CI 1.917 65.783, P = 0.007), chronic kidney disease (OR 4.474, 95% CI 1.037-19.299, P = 0.045) and chronic cardiac failure (OR 7.328, 95% CI 2.068-25.967, P = 0.002) were independently associated with infection. Patients with infection had longer length of hospital stay than those without (15.3 +/- 5.1 vs 11.1 +/- 4.3 days, P < 0.0001). None of the patients with infection had severe disease, none required surgery and none died during hospitalization. CONCLUSIONS: Hospitalized octogenarians with comorbidities, recently hospitalized or receiving antibiotic treatment are at risk for C. difficile infection. Clinicians evaluating such patients should have a high index of suspicion for this infection. Geriatr Gerontol Int 2018; 18: 315-320. PMID- 29139190 TI - A man before his time: Russell's insights into nicotine, smoking, treatment and curbing the smoking problem. AB - BACKGROUND AND AIMS: This narrative review aimed to provide a brief overview of five key research 'classics' produced by the innovative and radical thought leader, Professor Michael Anthony Hamilton Russell (1932-2009), drawing upon his other work wherever feasible. METHODS: Narrative review. From more than 250 publications, we selected papers we considered seminal texts, published in 1971, 1976, 1978, 1979 and 1991. RESULTS: Russell was among the first researchers to explain that smoking was a dependence disorder caused by the drug nicotine decades before this was recognized formally. He therefore saw quickly the importance of delivering nicotine in a less harmful format as a way of controlling nicotine withdrawal when stopping smoking, first studying nicotine gum. In addition to pharmacotherapies, Russell's research also explored the role of behavioural support, particularly the role of general practitioners (GPs), alone as well as supported by specialist clinics; this research underpinned initiatives in England to reimburse doctors for giving advice to smokers, and to provide a national network of smoking cessation services. Research on nicotine uptake from other delivery systems and routes led Russell to theorize that the speed and dose of delivery impacted upon the effectiveness of a product to act as a substitute for smoking. He commented on the addictiveness of the high nicotine boli delivered in quick succession when smoking cigarettes and argued that alternative recreational nicotine delivery systems would need to be promoted actively to smokers in order for them to compete with cigarettes, a forerunner for contemporary debates on electronic cigarettes. CONCLUSIONS: The legacy of Russell's landmark research is seen in present-day nicotine science, policy and discourse. PMID- 29139191 TI - Repurposing Statins for Renal Protection: Is It a Class Effect? PMID- 29139192 TI - Donepezil is associated with decreased in-hospital mortality as a result of pneumonia among older patients with dementia: A retrospective cohort study. AB - AIM: Pneumonia is one of the major causes of mortality in older adults. As the average lifespan has extended and new modalities to prevent or treat pneumonia are developed, the factors that affect the length of hospital stay (LHS) and in hospital mortality of older patients with pneumonia have changed. The object of the present study was to determine the factors associated with LHS and mortality as a result of pneumonia among older patients with dementia. METHODS: With a retrospective cohort study design, we used the data derived from the Japanese Administrative Database and diagnosis procedure combination/per diem payment system (DPC/PDPS) database. There were 39 336 admissions of older patients for pneumonia between August 2010 and March 2012. Patients with incomplete data were excluded, leaving 25 602 patients for analysis. RESULTS: Having dementia decreased mortality (OR 0.71, P < 0.001) and increased LHS. Multiple logistic regression analysis identified donepezil as an independent factor that decreased mortality in patients with dementia (OR 0.36, P < 0.001). Donepezil was prescribed for 28.7% of these patients, and their mortality rate was significantly lower than those of patients with dementia who were not treated with donepezil and of patients without dementia. The mortality rate was higher for patients with dementia who were not treated with donepezil compared with patients who did not have dementia. All other factors that influenced LHS and mortality were similar to those reported by others. CONCLUSIONS: Donepezil seems to decrease in-hospital mortality as a result of pneumonia among older patients with dementia. Geriatr Gerontol Int 2018; 18: 269-275. PMID- 29139193 TI - Higher doses of intraoperative analgesia are associated with lower levels of persistent pain and less analgesic consumption six months after total hip arthroplasty. AB - BACKGROUND: Persistent postoperative pain is a major health problem affecting nearly 30% of all patients undergoing total hip arthroplasty. Previous studies have demonstrated an association between the intensity of acute postoperative pain and persistent pain, but this association might be an epiphenomenon of insufficient intraoperative analgesia. In this study, we investigated the association between the intraoperative level of analgesia and the persistent postoperative pain 6 months after surgery. METHODS: We investigated 110 patients undergoing primary total hip arthroplasty under total intravenous general anaesthesia in a prospective cohort study. A highly standardized surgical and a standardized anaesthetic procedure were performed to reduce variability and psychosocial influences were investigated to adjust for confounders. Acute postoperative pain was controlled using patient-controlled analgesia pumps. Postoperative pain intensities and analgesic requirements were monitored for 6 months following surgery. RESULTS: Of 105 patients included in the analysis, 32% continued using daily pain medication 6 months after surgery and reported a median pain level of 4/10. Multivariate analyses confirmed that the amount of intraoperative analgesia is a significant predictor of regular analgesic use and pain intensity 6 months after surgery. CONCLUSIONS: Higher levels of intraoperative analgesia are associated with lower levels of persistent pain and less analgesic consumption 6 months after total hip arthroplasty. Persistent pain may be attributable to intraoperative nociception, which is likely not adequately assessed and suppressed using current clinical measures. SIGNIFICANCE: Our study suggests that lower doses of intraoperative analgesia are associated with higher levels of persistent postoperative pain. Persistent pain may be caused by intraoperative nociception, which is likely not adequately suppressed using current clinical standard analgesic measures. PMID- 29139194 TI - Advantages of care for patients with hip fractures in the acute geriatric unit: Hip study Anoia. AB - AIM: Hip fracture as a result of bone fragility is characterized by poor health outcomes in the medium and long term. Our goal was to compare a new orthogeriatric model with the old trauma model and evaluate improvements in clinical management. METHODS: We carried out a comparative unicentric study, a historical sample (trauma model) collected from 1 June 2007 to 31 May 2010, versus a prospective sample (orthogeriatric model) collected from 1 June 2010 until 31 May 2013. We included all patients aged >69 years with hip fracture as a result of bone fragility. RESULTS: A total of 792 patients were evaluated (mean age 84.3 years). The surgical waiting period went from 2.70 days in the trauma model to 1.86 days in the orthogeriatric model (P < 0.001); the average stay was 15.76 days in the trauma model, and for the orthogeriatric model was reduced to 5.90 days (P < 0.001); mortality went from 4.5% to 1.3% (P <= 0.010); 1 month readmission for hip dislocation was reduced from 2.3% to 0.5% (P = 0.032). After a 6-month follow up, we had 302 trauma model patients and 287 orthogeriatric model patients. After 1 year, we had 288 patients in the trauma model and 264 patients in the orthogeriatric model. The main cause of abandonment was death, 108 patients (27.3%) in the trauma model and 100 patients (27.5%) in the orthogeriatric model (P = 0.951). CONCLUSIONS: When we compared the two models, we found statistically significant better results in the preoperative waiting period, average stay, hospital mortality and 1 month readmission as a result of hip prosthesis luxation in favor of the orthogeriatric model. Geriatr Gerontol Int 2018; 18: 407-414. PMID- 29139195 TI - Phenotypic characteristics associated with slow gait speed in idiopathic pulmonary fibrosis. AB - BACKGROUND AND OBJECTIVE: Usual gait speed over 4 m (4MGS) is an established functional performance measure in older adults that consistently predicts adverse health outcomes, but few data exist in idiopathic pulmonary fibrosis (IPF). We assessed the reliability of 4MGS, its relationship with established outcome measures and its responsiveness to pulmonary rehabilitation. METHODS: In four prospective IPF cohorts, 4MGS inter-observer (n = 46) and test-retest (n = 46) reliability, concurrent validity (n = 65 and n = 62) and responsiveness (n = 60) were determined. The phenotypic characteristics of all patients stratified according to slow 4MGS (<0.8 m/s) were compared, including lung function parameters, HRCT of the chest, 6-min walking distance (6MWD), Medical Respiratory Council (MRC) dyspnoea score, King's Brief Interstitial Lung Disease (KBILD) questionnaire and Gender, Age and lung Physiology (GAP) prognostic index. RESULTS: Intra-class correlation coefficients for inter-observer and test-retest reliability were 0.996 and 0.983, respectively. There was a strong association between 4MGS and 6MWD (r = 0.76; P < 0.0001) and moderate correlations with MRC (r = -0.56), KBILD (r = 0.44) and GAP index (r = -0.41); all P < 0.005. 4MGS improved significantly with pulmonary rehabilitation (mean (95% CI) change: 0.16 (0.12-0.20) m/s), effect size 0.65. Patients with slow 4MGS had significantly worse exercise performance (6MWD: -167 (-220 to -133) m), dyspnoea, health status and prognosis index than those with preserved 4MGS, despite similar lung function and HRCT parameters. CONCLUSION: 4MGS is a simple, reliable, valid and responsive tool that may detect a patient phenotype with worse exercise performance, dyspnoea, health status and prognosis index in stable IPF. PMID- 29139196 TI - Education and employment outcomes of young adults with a history of developmental language disorder. AB - BACKGROUND: Developmental language disorder (DLD) presents a considerable barrier for young adults to engage in further education and training. Early studies with young adults with DLD revealed poor educational achievement and lack of opportunities to progress in education. More recent studies have provided more positive findings. Relatively sparse data exist, however, on current cohorts and the factors that predict outcomes. AIMS: To examine educational and employment outcomes in young adulthood in a sample of people with histories of DLD compared with an age-matched peer group without DLD. We ask: How do educational pathways and early jobs compare between those with and without DLD? Are young adults with DLD receiving similar levels of income as their peers? To what extent are language and literacy abilities associated with outcomes? METHODS & PROCEDURES: Participants included 84 individuals with DLD (67% males) and 88 age-matched peers without DLD (56% males). Participants were on average 24 years of age. They completed a battery of psycholinguistic, literacy and nonverbal skills assessments. Data were also collected on educational qualifications, current educational status, extent of educational support received, employment status, history and support, as well as current income. OUTCOMES & RESULTS: Those with DLD obtained lower academic and vocational qualifications. Higher educational/vocational qualifications were associated with better language, better reading and higher performance IQ (PIQ). There were few differences between the two groups in terms of engagement with education, but the mean age at leaving education was significantly earlier in the participants with DLD. Substantially more participants with DLD reported receiving support or dispensation from their educational institution. There was no significant difference between groups in the proportion of young people currently employed, though a higher proportion of the age-matched peers was in work full time. Participants with DLD were much more likely to be in non-professional occupations. However, when examining pay in relation to types of occupation, the groups' incomes were broadly comparable. CONCLUSIONS & IMPLICATIONS: At the group level, young people with a history of DLD more commonly have less skilled employment and more rarely achieve professional roles. At the individual level there is considerable variation with smaller but not trivial proportions of young adults with a history of DLD showing good educational and employment outcomes. There are positive aspects to early adult outcomes for some young people with a history of DLD. PMID- 29139197 TI - Survival prediction among nursing home residents: A longitudinal study. AB - AIM: To determine the survival time and predictors of survival of residents in a nursing home. METHODS: Nursing home residents admitted from June 2008 (when the nursing home started operating) to December 2012 (n = 230) to a new nursing home in Hong Kong were prospectively followed. The predictors of survival in the residents were assessed annually, with the exception of those who did not want to continue with the study, or were hospitalized, discharged from the nursing home or died, to compare changes occurring from 2008 to 2012. Cox's regression analysis was used to examine the predictors of survival. RESULTS: A total of 66 of the nursing home residents (28.7%) died during the study period. The median length of survival was 20.46 months. Sex, the number of diseases, depressive symptoms, cognitive status and nutritional status were found to be significant predictors of survival. CONCLUSIONS: It is crucial for healthcare providers to offer quality care to residents in long-term care to enhance their well-being in the final sojourn of their lives. Although there are no consistent reports of predictors in the international literature, it is important to address the modifiable predictors, as this might lead to improvements in the quality of life of the residents. Geriatr Gerontol Int 2018; 18: 428-433. PMID- 29139198 TI - Factors Affecting Drug-Development Strategies in Asian Global Clinical Trials for Drug Approval in Japan. AB - We assessed the current status of Asian global clinical trials (GCTs) and factors, such as therapeutic areas, main metabolic enzymes targeted, approval status in the United States or the European Union, development strategies, influencing drug-development strategies in Asian GCTs and in general GCTs for drug approval in Japan. The findings suggested that region-specific diseases in Asia, intrinsic and extrinsic ethnic differences between Japanese/Asian and Caucasian populations, and the status of the drugs' development in the United States or the European Union all affected Asian GCTs. These factors may influence the drug development process in Asian GCTs. Furthermore, we found that pharmacokinetics data in Asian GCTs comparing similarities between Japanese and other Asian populations were mainly obtained from late-phase trials, which may delay the identification of potential differences in ethnic factors. PMID- 29139199 TI - In silico ligand-based modeling of hBACE-1 inhibitors. AB - Alzheimer's disease is a chronic neurodegenerative disease affecting more than 30 million people worldwide. Development of small molecule inhibitors of human beta secretase 1 (hBACE-1) is being the focus of pharmaceutical industry for the past 15-20 years. Here, we successfully applied multiple ligand-based in silico modeling techniques to understand the inhibitory activities of a diverse set of small molecule hBACE-1 inhibitors reported in the scientific literature. Strikingly, the use of only a small subset of 230 (13%) molecules allowed us to develop quality models that performed reasonably well on the validation set of 1,476 (87%) inhibitors. Varying the descriptor sets and the complexity of the modeling techniques resulted in only minor improvements to the model's performance. The current results demonstrate that predictive models can be built by choosing appropriate modeling techniques in spite of using small datasets consisting of diverse chemical classes, a scenario typical in triaging of high throughput screening results to identify false negatives. We hope that these encouraging results will help the community to develop more predictive models that would support research efforts for the debilitating Alzheimer's disease. Additionally, the integrated diversity of the techniques employed will stimulate scientists in the field to use in silico statistical modeling techniques like these to derive better models to help advance the drug discovery projects faster. PMID- 29139200 TI - Allosteric mechanism of quinoline inhibitors for HIV RT-associated RNase with MD simulation and dynamics fluctuation network. AB - The human immunodeficiency virus (HIV) is a retrovirus which infects T lymphocyte of human body and causes immunodeficiency. Reverse transcriptase inhibitors (RTIs) can inhibit some functions of RT, preventing virus synthesis (double stranded DNA), so that HIV virus replication can be reduced. Experimental results indicate a series of benzimidazole-based inhibitors which target HIV RT associated RNase to inhibit the reverse transcription of HIV virus. However, the allosteric mechanism is still unclear. Here, molecular dynamics simulations and dynamics fluctuation network analysis were used to reveal the binding mode between the inhibitors and RT-associated RNase. The most active molecule has more hydrophobic and electrostatic interactions than the less active inhibitor. Dynamics correlation network analysis indicates that the most active inhibitor perturbs the network of RT-associated RNase and decreases the correlation of nodes. 3D-QSAR model suggests that two robust and reliable models were constructed and validated by independent test set. 3D-QSAR model also shows that bulky negatively charged or hydrophilic substituent is favorable to bioactivity. These results reveal the allosteric mechanism of quinoline inhibitors and help to improve the bioactivity. PMID- 29139201 TI - Defining the protein complexome of translation termination factor eRF1: Identification of four novel eRF1-containing complexes that range from 20S to 57S in size. AB - The eukaryotic eRF1 translation termination factor plays an important role in recognizing stop codons and initiating the end to translation. However, which exact complexes contain eRF1 and at what abundance is not clear. We have used analytical ultracentrifugation with fluorescent detection system to identify the protein complexome of eRF1 in the yeast Saccharomyces cerevisiae. In addition to eRF1 presence in translating polysomes, we found that eRF1 associated with five other macromolecular complexes: 77S, 57S, 39S, 28S, and 20S in size. Generally equal abundances of each of these complexes were found. The 77S complex primarily contained the free 80S ribosome consistent with in vitro studies and did not appear to contain significant levels of the monosomal translating complex that co migrates with the free 80S ribosome. The 57S and 39S complexes represented, respectively, free 60S and 40S ribosomal subunits bound to eRF1, associations not previously reported. The novel 28S and 20S complexes (containing minimal masses of 830 KDa and 500 KDa, respectively) lacked significant RNA components and appeared to be oligomeric, as eRF1 has a mass of 49 KDa. The majority of polysomal complexes containing eRF1 were both substantially deadenylated and lacking in closed-loop factors eIF4E and eIF4G. The thirteen percent of such translating polysomes that contained poly(A) tails had equivalent levels of eIF4E and eIF4G, suggesting these complexes were in a closed-loop structure. The identification of eRF1 in these unique and previously unrecognized complexes suggests a variety of new roles for eRF1 in the regulation of cellular processes. PMID- 29139202 TI - LEGO-Inspired Drug Design: Unveiling a Class of Benzo[d]thiazoles Containing a 3,4-Dihydroxyphenyl Moiety as Plasma Membrane H+ -ATPase Inhibitors. AB - The fungal plasma membrane H+ -ATPase (Pma1p) is a potential target for the discovery of new antifungal agents. Surprisingly, no structure-activity relationship studies for small molecules targeting Pma1p have been reported. Herein, we disclose a LEGO-inspired fragment assembly strategy for the design, synthesis, and discovery of benzo[d]thiazoles containing a 3,4-dihydroxyphenyl moiety as potential Pma1p inhibitors. A series of 2-(benzo[d]thiazol-2-ylthio)-1 (3,4-dihydroxyphenyl)ethanones was found to inhibit Pma1p, with the most potent IC50 value of 8 MUm in an in vitro plasma membrane H+ -ATPase assay. These compounds were also found to strongly inhibit the action of proton pumping when Pma1p was reconstituted into liposomes. 1-(3,4-Dihydroxyphenyl)-2-((6 (trifluoromethyl)benzo[d]thiazol-2-yl)thio)ethan-1-one (compound 38) showed inhibitory activities on the growth of Candida albicans and Saccharomyces cerevisiae, which could be correlated and substantiated with the ability to inhibit Pma1p in vitro. PMID- 29139203 TI - Jon Van Rood. PMID- 29139204 TI - Subporpholactone, Subporpholactam, Imidazolosubporphyrin, and Iridium Complexes of Imidazolosubporphyrin: Formation of Iridium Carbene Complexes. AB - Pyrrole-modified subporphyrins bearing a non-pyrrolic cyclic unit, subporpholactone, subporpholactam, and imidazolosubporphyrin were newly synthesized. They show subporphyrin-like absorption and fluorescence spectra that are red-shifted in the order of subporpholactam 0.05). The median percentage scores for anxiety and motion sickness immediately following the study were both 0. In general, anxiety and motion sickness scores were low throughout the study. All patients except one completed the study. CONCLUSIONS: Slow, single arc rotation in upright and lying orientations was well tolerated in this study. These results support the need for further studies into the clinical implementation of patient rotation, which could have a major impact on the practice and cost of radiotherapy. PMID- 29139208 TI - A knowledge-based approach to automated planning for hepatocellular carcinoma. AB - PURPOSE: To build a knowledge-based model of liver cancer for Auto-Planning, a function in Pinnacle, which is used as an automated inverse intensity modulated radiation therapy (IMRT) planning system. METHODS AND MATERIALS: Fifty Tomotherapy patients were enrolled to extract the dose-volume histograms (DVHs) information and construct the protocol for Auto-Planning model. Twenty more patients were chosen additionally to test the model. Manual planning and automatic planning were performed blindly for all twenty test patients with the same machine and treatment planning system. The dose distributions of target and organs at risks (OARs), along with the working time for planning, were evaluated. RESULTS: Statistically significant results showed that automated plans performed better in target conformity index (CI) while mean target dose was 0.5 Gy higher than manual plans. The differences between target homogeneity indexes (HI) of the two methods were not statistically significant. Additionally, the doses of normal liver, left kidney, and small bowel were significantly reduced with automated plan. Particularly, mean dose and V15 of normal liver were 1.4 Gy and 40.5 cc lower with automated plans respectively. Mean doses of left kidney and small bowel were reduced with automated plans by 1.2 Gy and 2.1 Gy respectively. In contrast, working time was also significantly reduced with automated planning. CONCLUSIONS: Auto-Planning shows availability and effectiveness in our knowledge based model for liver cancer. PMID- 29139209 TI - Protocol for a new concept of no-prep ultrathin ceramic veneers. AB - OBJECTIVES: No-prep veneers, although ideally considered the best option because of tooth structure maximum preservation, have been frequently criticized for some potential limitations including esthetic outcomes and periodontal complications. CLINICAL CONSIDERATIONS: A new protocol to optimize no-prep veneers restorations is presented. A key point of the proposed technique is to identify optimal margins' positions: margin is positioned in the point of maximum convexity of teeth, avoiding the over contouring of traditional no-prep veneers. CONCLUSION: The procedure can be appreciated for the marginal accuracy and the resulting aesthetic stability. The case reports show that properly managed no-prep veneers can have biologically healthy and aesthetically pleasant tooth-restoration transitions and emergence profiles. CLINICAL SIGNIFICANCE: High-quality no-prep veneers can be more challenging to realize than conventional veneers and the success seems to depend on a combination of good case selection, margins' position, sound adhesive principles, clinical, and laboratory experience. PMID- 29139211 TI - Protostane-Type Triterpenoids from Alisma orientale. AB - Twenty-eight protostane triterpenoids, including a new degraded one (1), nine new ones (2 - 10), and two new natural ones (11 and 12), have been isolated from the dried rhizomes of Alisma orientale. Alisol R (1) was the first 20,21,22,23,24,25,26,27-octanorprotostane triterpenoid. The absolute configurations of 25-methoxyalisol F (2) and 16beta-hydroperoxyalisol B 23 acetate (3) were determined by X-ray diffraction analysis. In addition, alismaketone-B 23-acetate (28) showed potent vasorelaxant activity on endothelium intact thoracic aorta rings precontracted with KCl. PMID- 29139213 TI - Heterogeneous neuronal activity in the lateral habenula after short- and long term cocaine self-administration in rats. AB - Cocaine addiction is thought to be the result of drug-induced functional changes in a neural network implicated in emotions, learning and cognitive control. Recent studies have implicated the lateral habenula (LHb) in drug-directed behavior, especially its aversive aspects. Limited cocaine exposure has been shown to alter neuronal activity in the LHb, but the impact of long-term drug exposure on habenula function has not been determined. Therefore, using c-fos as a marker, we here examined neuronal activity in LHb in rats that self administered cocaine for either 10 or 60 days. Both the density of labeled cells and the cellular labeling intensity were measured in the lateral (LHbL) and medial (LHbM) parts of LHb. After 10 days of cocaine self-administration, both the density and intensity of c-fos-positive cells were significantly increased in LHbL, but not LHbM, while after 60 days, an increased density (but not intensity) of labeled neurons in both LHbL and LHbM was observed. Most c-fos-labeled neurons were glutamatergic. In addition, we found increased GAD65 expression after 10 but not 60 days of cocaine self-administration in the rostral mesencephalic tegmental nucleus. These data shed light on the complex temporal dynamics by which cocaine self-administration alters activity in LHb circuitry, which may play an important role in the descent to compulsive drug use as a result of prolonged cocaine taking experience. PMID- 29139212 TI - Shape-Controlled Surface-Coating to Pd@Mesoporous Silica Core-Shell Nanocatalysts with High Catalytic Activity and Stability. AB - Cubic Pd nanocrystals with shape-controlled mesoporous silica shells have been theoretically designed and successfully synthesized for investigating the effect of a porous nanoshell on catalytic performance of the core. Cubic Pd@cubic mesoporous silica keeps activity of all facets and shows highest catalytic activity and enhanced reusability in the hydrogenation of nitrobenzene. PMID- 29139210 TI - Timing of neuronal plasticity in development and aging. AB - Molecular oscillators are well known for their roles in temporal control of some biological processes like cell proliferation, but molecular mechanisms that provide temporal control of differentiation and postdifferentiation events in cells are less understood. In the nervous system, establishment of neuronal connectivity during development and decline in neuronal plasticity during aging are regulated with temporal precision, but the timing mechanisms are largely unknown. Caenorhabditis elegans has been a preferred model for aging research and recently emerges as a new model for the study of developmental and postdevelopmental plasticity in neurons. In this review we discuss the emerging mechanisms in timing of developmental lineage progression, axon growth and pathfinding, synapse formation, and reorganization, and neuronal plasticity in development and aging. We also provide a current view on the conserved core axon regeneration molecules with the intention to point out potential regulatory points of temporal controls. We highlight recent progress in understanding timing mechanisms that regulate decline in regenerative capacity, including progressive changes of intrinsic timers and co-opting the aging pathway molecules. WIREs Dev Biol 2018, 7:e305. doi: 10.1002/wdev.305 This article is categorized under: Invertebrate Organogenesis > Worms Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Nervous System Development > Worms Gene Expression and Transcriptional Hierarchies > Regulatory RNA. PMID- 29139214 TI - A theoretical insight into selectivity of inhibitors toward two domains of bromodomain-containing protein 4 using molecular dynamics simulations. AB - Bromodomains (BRDs) have been an attractive candidate for development of efficient inhibitors toward gene transcription. Molecular dynamics (MD) simulations followed by principal component (PC) analysis were performed to investigate binding selectivity of inhibitors RVX297, BSP, JQ1, SF2523, and CPD2 toward two domains (BD1 and BD2) of bromodomain-containing protein 4 (BRD4). The results show that inhibitor bindings exert different effect on motions of the BC loops in BD1 and BD2. The rank of binding free energies calculated using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method agrees with the one determined by experiment. The results also suggest that the binding ability of RVX297, BSP, and JQ1 to BD2 is stronger than that of them to BD1, while the binding ability of SF2523 to BD2 is obviously weaker than that of SF2523 to BD1. Alanine mutation calculations and the calculated inhibitor-residue interaction spectrum prove that the current five inhibitors have obvious binding selectivity toward BD1 and BD2. This study is not only helpful for further understanding the differences in internal dynamics of BD1 and BD2 caused by inhibitor bindings, but also can theoretically contribute significant guidance to designs of effective and high selective anticancer drugs targeting BD1 and BD2 in BRD4. PMID- 29139217 TI - Corrigendum. PMID- 29139215 TI - Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: a review of the National Cancer Database. AB - For elderly patients with locally advanced esophageal cancer, therapeutic approaches and outcomes in a modern cohort are not well characterized. Patients >=70 years old with clinical stage II and III esophageal cancer diagnosed between 1998 and 2012 were identified from the National Cancer Database and stratified based on treatment type. Variables associated with treatment utilization were evaluated using logistic regression and survival evaluated using Cox proportional hazards analysis. Propensity matching (1:1) was performed to help account for selection bias. A total of 21,593 patients were identified. Median and maximum ages were 77 and 90, respectively. Treatment included palliative therapy (24.3%), chemoradiation (37.1%), trimodality therapy (10.0%), esophagectomy alone (5.6%), or no therapy (12.9%). Age >=80 (OR 0.73), female gender (OR 0.81), Charlson-Deyo comorbidity score >=2 (OR 0.82), and high-volume centers (OR 0.83) were associated with a decreased likelihood of palliative therapy versus no treatment. Age >=80 (OR 0.79) and Clinical Stage III (OR 0.33) were associated with a decreased likelihood, while adenocarcinoma histology (OR 1.33) and nonacademic cancer centers (OR 3.9), an increased likelihood of esophagectomy alone compared to definitive chemoradiation. Age >=80 (OR 0.15), female gender (OR 0.80), and non-Caucasian race (OR 0.63) were associated with a decreased likelihood, while adenocarcinoma histology (OR 2.10) and high-volume centers (OR 2.34), an increased likelihood of trimodality therapy compared to definitive chemoradiation. Each treatment type demonstrated improved survival compared to no therapy: palliative treatment (HR 0.49) to trimodality therapy (HR 0.25) with significance between all groups. Any therapy, including palliative care, was associated with improved survival; however, subsets of elderly patients with locally advanced esophageal cancer are less likely to receive aggressive therapy. Care should be taken to not unnecessarily deprive these individuals of treatment that may improve survival. PMID- 29139218 TI - Corrigendum. PMID- 29139216 TI - Patterns and drivers of fish extirpations in rivers of the American Southwest and Southeast. AB - Effective conservation of freshwater biodiversity requires spatially explicit investigations of how dams and hydroclimatic alterations among climate regions may interact to drive species to extinction. We investigated how dams and hydroclimatic alterations interact with species ecological and life history traits to influence past extirpation probabilities of native freshwater fishes in the Upper and Lower Colorado River (CR), Alabama-Coosa-Tallapoosa (ACT), and Apalachicola-Chattahoochee-Flint (ACF) basins. Using long-term discharge data for continuously gaged streams and rivers, we quantified streamflow anomalies (i.e., departure "expected" streamflow) at the sub-basin scale over the past half century. Next, we related extirpation probabilities of native fishes in both regions to streamflow anomalies, river basin characteristics, species traits, and non-native species richness using binomial logistic regression. Sub-basin extirpations in the Southwest (n = 95 Upper CR, n = 130 Lower CR) were highest in lowland mainstem rivers impacted by large dams and in desert springs. Dampened flow seasonality, increased longevity (i.e., delayed reproduction), and decreased fish egg sizes (i.e., lower parental care) were related to elevated fish extirpation probability in the Southwest. Sub-basin extirpations in the Southeast (ACT n = 46, ACF n = 22) were most prevalent in upland rivers, with flow dependency, greater age and length at maturity, isolation by dams, and greater distance upstream. Our results confirm that dams are an overriding driver of native fish species losses, irrespective of basin-wide differences in native or non-native species richness. Dams and hydrologic alterations interact with species traits to influence community disassembly, and very high extirpation risks in the Southeast are due to interactions between high dam density and species restricted ranges. Given global surges in dam building and retrofitting, increased extirpation risks should be expected unless management strategies that balance flow regulation with ecological outcomes are widely implemented. PMID- 29139219 TI - Illusory nature of achieving glycaemic control. PMID- 29139220 TI - Creating and facilitating change for Person-Centred Coordinated Care (P3C): The development of the Organisational Change Tool (P3C-OCT). AB - BACKGROUND: Person Centred Coordinated Care (P3C) is a UK priority for patients, carers, professionals, commissioners and policy makers. Services are developing a range of approaches to deliver this care with a lack of tools to guide implementation. METHODOLOGY: A scoping review and critical examination of current policy, key literature and NHS guidelines, together with stakeholder involvement led to the identification of domains, subdomains and component activities (processes and behaviours) required to deliver P3C. These were validated through codesign with stakeholders via a series of workshops and cognitive interviews. RESULTS: Six core domains of P3C were identified as follows: (i) my goals, (ii) care planning, (iii) transitions, (iv) decision making (v), information and communication and (vi) organizational support activities. These were populated by 29 core subdomains (question items). A number of response codes (components) to each question provide examples of the processes and activities that can be actioned to achieve each core subdomain of P3C. CONCLUSION: The P3C-OCT provides a coherent approach to monitoring progress and supporting practice development towards P3C. It can be used to generate a shared understanding of the core domains of P3C at a service delivery level, and support reorganization of care for those with complex needs. The tool can reliably detect change over time, as demonstrated in a sample of 40 UK general practices. It is currently being used in four UK evaluations of new models of care and being further developed as a training tool for the delivery of P3C. PMID- 29139221 TI - Evaluation of hypothalamus-pituitary-thyroid axis function by chronic perchlorate exposure in male rats. AB - Perchlorate is a widespread endocrine disruptor that was previously correlated with increased serum TSH levels and decreased thyroid hormones production both in animals and humans. Even so, the regulation of gene/protein expression in the hypothalamus, pituitary and thyroid by chronic perchlorate exposure was not completely elucidated. Therefore, this study aimed to investigate the underlying mechanisms involved in the disruption of hypothalamus-pituitary-thyroid axis by chronic perchlorate exposure. Male Wistar rats were treated or not with NaClO4 in the drinking water (35 mg/Kg/day) for 60 days. Thereafter, hormone/cytokines serum levels were measured through multiplex assays; genes/proteins expression were investigated by qPCR/Western Blotting and thyroid morphology was evaluated through histological analysis. Serum TSH levels were increased and serum T4 /T3 levels were decreased in perchlorate-treated animals. This treatment also altered the thyrotropin-releasing hormone mRNA/protein content in the hypothalamus. Additionally, the expression of both subunits of TSH were increased in the pituitary of perchlorate-treated rats, which also presented significant alterations in the thyroid morphology/gene expression. Furthermore, perchlorate exposure reduced liver Dio1 mRNA expression and increased the content of pro inflammatory cytokines in the thyroid and the serum. In conclusion, our study adds novel findings about the perchlorate-induced disruption of the hypothalamus pituitary-thyroid axis gene/protein expression in male rats. The data presented herein also suggest that perchlorate induces thyroid and systemic inflammation through the increased production of cytokines. Taken together, our results suggest that perchlorate contamination should be monitored, especially in the individuals most susceptible to the deleterious effects of reduced levels of thyroid hormones. PMID- 29139222 TI - Serological evidence for the co-circulation of two lineages of influenza D viruses in equine populations of the Midwest United States. AB - Influenza D virus (IDV) is a newly described influenza type of the Orthomyxoviridae virus family that was first isolated from diseased swine in 2011 and has subsequently been detected in cattle around the world in 2014. In addition, serological evidence for IDV infection in humans has been recently established. Despite all the progress, the full range of susceptible hosts for this novel virus has yet to be determined, but includes swine, bovine, small ruminants and human. This study was designed to determine if equine is a possible host to this newly emerging influenza virus. Three hundred and sixty-four equine serum samples were collected in 2015 from 141 farms within the Midwestern United States. Serum samples were examined using hemagglutination inhibition (HI) assay against two established IDV lineages (D/OK and D/660) and one IDV-related human ICV lineage (C/JHB). Results of this study showed 44 (44 of 364, 12%) samples positive for antibodies against D/OK, 39 (39 of 364, 11%) samples positive for antibodies against D/660, and 41 (41 of 364, 11%) samples positive for antibodies against C/JHB. A subset of these samples was further confirmed via microtitre neutralization (MN) assay. Our data demonstrated that horses are susceptible to two lineages of IDV, and that these viruses were present in equine populations throughout multiple Midwestern states of the United States. These findings continue to support the need for further surveillance of IDV viruses in agricultural species to work towards a better understanding of the full host range and natural reservoirs of influenza D virus. PMID- 29139223 TI - Dosimetric effects of intrafractional isocenter variation during deep inspiration breath-hold for breast cancer patients using surface-guided radiotherapy. AB - The aim of this study was to investigate potential dose reductions to the heart, left anterior descending coronary artery (LAD), and ipsilateral lung for left sided breast cancer using visually guided deep inspiration breath-hold (DIBH) with the optical surface scanning system CatalystTM, and how these potential dosimetric benefits are affected by intrafractional motion in between breath holds. For both DIBH and free breathing (FB), treatment plans were created for 20 tangential and 20 locoregional left-sided breast cancer patients. During DIBH treatment, beam-on was triggered by a region of interest on the xiphoid process using a 3 mm gating window. Using a novel nonrigid algorithm, the CatalystTM system allows for simultaneous real-time tracking of the isocenter position, which was used to calculate the intrafractional DIBH isocenter reproducibility. The 50% and 90% cumulative probabilities and maximum values of the intrafractional DIBH isocenter reproducibility were calculated and to obtain the dosimetric effect isocenter shifts corresponding to these values were performed in the treatment planning system. For both tangential and locoregional treatment, the dose to the heart, LAD and ipsilateral lung was significantly reduced for DIBH compared to FB. The intrafractional DIBH isocenter reproducibility was very good for the majority of the treatment sessions, with median values of approximately 1 mm in all three translational directions. However, for a few treatment sessions, intrafractional DIBH isocenter reproducibility of up to 5 mm was observed, which resulted in large dosimetric effects on the target volume and organs at risk. Hence, it is of importance to set tolerance levels on the intrafractional isocenter motion and not only perform DIBH based on the xiphoid process. PMID- 29139224 TI - A polyelectrolyte multilayer platform for investigating growth factor delivery modes in human liver cultures. AB - Polyelectrolyte multilayers (PEMs) of chitosan and heparin are useful for mimicking growth factor (GF) binding to extracellular matrix (ECM) as in vivo. Here, we developed a PEM platform for delivering bound/adsorbed GFs to monocultures of primary human hepatocytes (PHHs) and PHH/non-parenchymal cell (NPC) co-cultures, which are useful for drug development and regenerative medicine. The effects of ECM protein coating (collagen I, fibronectin, and Matrigel(r)) and terminal PEM layer on PHH attachment/functions were determined. Then, heparin-terminated/fibronectin-coated PEMs were used to deliver varying concentrations of an adsorbed model GF, transforming growth factor beta (TGFbeta), to PHH monocultures while using soluble TGFbeta delivery via culture medium as the conventional control. Soluble TGFbeta delivery caused a severe, monotonic, and sustained downregulation of all PHH functions measured (albumin and urea secretions, cytochrome-P450 2A6 and 3A4 enzyme activities), whereas adsorbed TGFbeta delivery caused transient upregulation of 3 out of 4 functions. Finally, functionally stable co-cultures of PHHs and 3T3-J2 murine embryonic fibroblasts were created on the heparin-terminated/fibronectin-coated PEMs modified with adsorbed TGFbeta to elucidate similarities and differences in functional response relative to the monocultures. In conclusion, chitosan-heparin PEMs constitute a robust platform for investigating the effects of GF delivery modes on PHH monocultures and PHH/NPC co-cultures. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 971-984, 2018. PMID- 29139226 TI - Cortical nociceptive processes are reduced by visual alpha-band entrainment in the human brain. AB - BACKGROUND: Acute noxious stimuli induce a suppression of cortical alpha activity, yet little is known about whether increasing alpha activity affects the processing of noxious stimuli. We have previously shown that visual alpha stimulation reduces experimental pain. Here, we demonstrate that increasing alpha power causes a reciprocal suppression of acute nociceptive processing. METHODS: We attempted to increase cortical alpha activity through visual entrainment at 8 Hz, 10 Hz and 12 Hz to investigate the influence on the electrophysiological pain response. Moderately painful laser-heat stimuli were delivered following 10 minutes of visual entrainment across the alpha range. RESULTS: Alpha power increased significantly relative to the 1 Hz control condition following 8 Hz and 10 Hz visual stimulation. Significant reductions in the P2 peak amplitude of the laser-evoked potential were found following visual entrainment at 10 Hz; the frequency stimulation resulting in the largest reduction in pain perception. Source analysis revealed that, following the 10 Hz stimulation, sources of increased alpha power and decreased nociceptive processing overlapped in precuneus and posterior cingulate cortex, with further reductions in nociceptive processing in insula cortex. CONCLUSIONS: As far as we are aware, this is the first study to provide direct evidence that experimental induction of increased alpha power suppresses the cortical processing of acute pain. SIGNIFICANCE: While it is known that visual stimulation can increase the brain's oscillatory alpha rhythms, here, we show that this increase in alpha power occurs alongside reduced cortical processing of nociception, as measured with EEG. This establishes an objective marker of alpha entrainment-based analgesia that may be useful in the development of neuromodulatory treatments for clinical pain. PMID- 29139225 TI - Oolong tea prevents cardiomyocyte loss against hypoxia by attenuating p-JNK mediated hypertrophy and enhancing P-IGF1R, p-akt, and p-Badser136 activity and by fortifying NRF2 antioxidation system. AB - Tea, the most widely consumed natural beverage has been associated with reduced mortality risk from cardiovascular disease. Oolong tea is a partially fermented tea containing high levels of catechins, their degree of oxidation varies between 20%-80% causing differences in their active metabolites. In this study we examined the effect of oolong tea extract (OTE) obtained by oxidation at low temperature for short-time against hypoxic injury and found that oolong tea provides cyto-protective effects by suppressing the JNK mediated hypertrophic effects and by enhancing the innate antioxidant mechanisms in neonatal cardiomyocytes and in H9c2 cells. OTE effectively attenuates 24 h hypoxia triggered cardiomyocyte loss by suppressing caspase-3-cleavage and apoptosis in a dose-dependent manner. OTE also enhances the IGFIR/p-Akt associated survival mechanism involving the elevation of p-Badser136 in a dose-dependent manner to aid cellular adaptations against hypoxic challenge. The results show the effects and mechanism of Oolong tea to provide cardio-protective benefits during hypoxic conditions. PMID- 29139227 TI - Corrigendum to "Molecular Phylogeny and Ontogeny of a New Ciliate Genus, Paracladotricha salina n. g., n. sp. (Ciliophora, Hypotrichia) by Shao et al. 2014". PMID- 29139228 TI - Corrigendum to "Morphological and Molecular Identification of the New Species, Trichodina pseudoheterodentata sp. n. (Ciliophora, Mobilida, Trichodinidae) from the Channel Catfish, Ictalurus punctatus, in Chongqing China by Tang et al". PMID- 29139229 TI - Corrigendum to "Description and Phylogeny of Urostyla grandis wiackowskii subsp. nov. (Ciliophora, Hypotricha) from an Estuarine Mangrove in Brazil by Paiva et al". PMID- 29139230 TI - Corrigendum to "Two New Brackish Ciliates, Amphileptus spiculatus sp. n. and A. bellus sp. n. from Mangrove Wetlands in Southern China, with Notes on the Molecular Phylogeny of the Family Amphileptidae (Protozoa, Ciliophora, Pleurostomatida) by Wu et al". PMID- 29139231 TI - Corrigendum to "Two Gonostomatid Ciliates from the Soil of Lombardia, Italy; including Note on the Soil Mapping Project by Bharti et al". PMID- 29139232 TI - Corrigendum to "The Morphology of Three Loxophyllum Species (Ciliophora, Pleurostomatida) from Southern China, L. lembum sp. n., L. vesiculosum sp. n. and L. perihoplophorum Buddenbrock, 1920, with Notes on the Molecular Phylogeny of Loxophyllum by Wu et al". PMID- 29139233 TI - Corrigendum to "Morphology and Phylogenetic Placement of Three New Zoothamnium species (Ciliophora: Peritrichia) from Coastal Waters of Southern China by Shen et al". PMID- 29139234 TI - Corrigendum to "Morphology, Morphogenesis, and Molecular Phylogeny of Paraparentocirrus sibillinensis n. gen., n. sp., a "Stylonychine Oxytrichidae" (Ciliophora, Hypotrichida) Without Transverse Cirri by Kumar et al". PMID- 29139235 TI - Corrigendum to "Description of Ganymedes yurii sp. n. (Ganymedidae), a New Gregarine Species from the Antarctic Amphipod Gondogeneia sp. (Crustacea) by Diakin et al. PMID- 29139236 TI - Corrigendum to "Morphology and Phylogeny of Three New Loxophyllum Species (Ciliophora, Pleurostomatida) from Mangrove Wetlands of Southern China by Wu et al". PMID- 29139237 TI - ZooBank Registration Requirement. PMID- 29139238 TI - Corrigendum to "The Green Tetrahymena utriculariae n. sp. (Ciliophora, Oligohymenophorea) with Its Endosymbiotic Algae (Micractinium sp.), Living in Traps of a Carnivorous Aquatic Plant by Pitsch et al". PMID- 29139239 TI - Corrigendum to "Mycamoeba gemmipara nov. gen., nov. sp., the First Cultured Member of the Environmental Dermamoebidae Clade LKM74 and its Unusual Life Cycle by Blandenier et al". PMID- 29139241 TI - Porcine respiratory disease complex after the introduction of H1N1/2009 influenza virus in Brazil. AB - From 2009 to 2015, 74 lungs from suckling (6.8%), nursing (70.3%), fattening (20.3%) pigs and pregnant sows (2.7%) with respiratory signs from pig farms in Southern Brazil were submitted to a diagnostic laboratory for necropsy and/or histologic examination and screening for respiratory agents by RT-qPCR, immunohistochemistry (IHC), virus isolation (VI) and subtyping for influenza A virus (IAV), IHC and nested PCR for Mycoplasma hyopneumoniae (Mhyo), PCR for porcine circovirus 2 (PCV2), RT-qPCR for porcine reproductive and respiratory syndrome virus (PRRSV) and bacterial culture. All lung samples were positive for IAV using RT-qPCR. Seventy-two lungs had histologic lesions associated with acute to subacute IAV infection characterized by necrotizing bronchiolitis/bronchitis or bronchointerstitial pneumonia with lymphocytic peribronchiolitis and bronchiolar/bronchial hyperplasia, respectively. Forty-nine lungs (66.2%) were positive by IHC for IAV nucleoprotein. The H1N1/2009 was the most common subtype and the only IAV detected in 58.1% of lungs, followed by H1N2 (9.5%) and H3N2 (6.8%). Coinfection of IAV and Mhyo was seen in 23 (31%) cases. Although 14.9% of the lungs were positive for PCV2 using PCR, no suggestive lesions of PCV2 disease were observed. Porcine reproductive and respiratory syndrome virus (PRRSV) was not detected, consistent with the PRRS-free status of Brazil. Secondary bacterial infections (8/38) were associated with suppurative bronchopneumonia and/or pleuritis. Primary IAV infection with Mhyo coinfection was the most common agents found in porcine respiratory disease complex (PRDC) in pigs in Southern Brazil. PMID- 29139242 TI - [The effiectiveness of extracorporeal shock wave lithotripsy in treating proxima ureteral stones]. AB - : Extracorporeal shock wave lithotripsy (ESWL) has proven efficacy in the treatment of proximal ureteral stones. The research to date has not been able to establish real time to spontaneous stone clearance after ESWL and the appropriateness and effectiveness of -blockers in stimulating residual stone clearance after ESWL. AIM: To conduct a comprehensive assessment of the effectiveness of ESWL in treating proximal ureteral stones and determine the appropriateness of using -blockers to stimulate residual stone clearance. MATERIALS AND METHODS: ESWL was performed in 40 patients with X-ray positive proximal ureteral stones. Before ESWL and at 3 months after the treatment all patients underwent multispiral computed tomography. ESWL was considered successful if there was a complete clearance of the stones with no residual fragments on the control MSCT. If a residual ureteral stone was found at 3 months after ESWL, a 2-week course of silodosin was administered. RESULTS: Complete stone clearance was achieved in 37.5% of patients. Silodosin therapy for residual stones resulted in stone clearance in 68.4% of cases. Taken together, ESWL monotherapy and additional 3 months of lithokinetic therapy resulted in stone clearance in 70.0% of patients. The remaining patients underwent contact ureteral lithotripsy. CONCLUSION: Spontaneous stone passage after ESWL for proximal ureteral stones occurs not in all patients. Most commonly it occurred during the first three weeks after ESWL, and thereafter stone passage was not observed. In half of the patients with residual stones they were asymptomatic. The effectiveness of ESWL as a monotherapy for ureteral stones greater than 15 mm is incomplete. Adding silodosin during the long-term post ESWL period improves the passage of asymptomatic residual stones in 2/3 of patients, which makes its use promising. PMID- 29139243 TI - Wide-field spectrally resolved quantitative fluorescence imaging system: toward neurosurgical guidance in glioma resection. AB - In high-grade glioma surgery, tumor resection is often guided by intraoperative fluorescence imaging. 5-aminolevulinic acid-induced protoporphyrin IX (PpIX) provides fluorescent contrast between normal brain tissue and glioma tissue, thus achieving improved tumor delineation and prolonged patient survival compared with conventional white-light-guided resection. However, commercially available fluorescence imaging systems rely solely on visual assessment of fluorescence patterns by the surgeon, which makes the resection more subjective than necessary. We developed a wide-field spectrally resolved fluorescence imaging system utilizing a Generation II scientific CMOS camera and an improved computational model for the precise reconstruction of the PpIX concentration map. In our model, the tissue's optical properties and illumination geometry, which distort the fluorescent emission spectra, are considered. We demonstrate that the CMOS-based system can detect low PpIX concentration at short camera exposure times, while providing high-pixel resolution wide-field images. We show that total variation regularization improves the contrast-to-noise ratio of the reconstructed quantitative concentration map by approximately twofold. Quantitative comparison between the estimated PpIX concentration and tumor histopathology was also investigated to further evaluate the system. PMID- 29139244 TI - Raman exfoliative cytology for oral precancer diagnosis. AB - Oral premalignant lesions (OPLs) such as leukoplakia, erythroplakia, and oral submucous fibrosis, often precede oral cancer. Screening and management of these premalignant conditions can improve prognosis. Raman spectroscopy has previously demonstrated potential in the diagnosis of oral premalignant conditions (in vivo), detected viral infection, and identified cancer in both oral and cervical exfoliated cells (ex vivo). The potential of Raman exfoliative cytology (REC) in identifying premalignant conditions was investigated. Oral exfoliated samples were collected from healthy volunteers (n=20), healthy volunteers with tobacco habits (n=20), and oral premalignant conditions (n=27, OPL) using Cytobrush. Spectra were acquired using Raman microprobe. Spectral acquisition parameters were: lambdaex: 785 nm, laser power: 40 mW, acquisition time: 15 s, and average: 3. Postspectral acquisition, cell pellet was subjected to Pap staining. Multivariate analysis was carried out using principal component analysis and principal component-linear discriminant analysis using both spectra- and patient wise approaches in three- and two-group models. OPLs could be identified with ~77% (spectra-wise) and ~70% (patient-wise) sensitivity in the three-group model while with 86% (spectra-wise) and 83% (patient-wise) in the two-group model. Use of histopathologically confirmed premalignant cases and better sampling devices may help in development of improved standard models and also enhance the sensitivity of the method. Future longitudinal studies can help validate potential of REC in screening and monitoring high-risk populations and prognosis prediction of premalignant lesions. PMID- 29139246 TI - [Systemic evaluation and Meta-analysis of Xianling Gubao capsule in treatment of primary osteoporosis in randomized controlled trials]. AB - To evaluate the efficacy and safety of Xianling Gubao capsule in the treatment of osteoporosis (OP). Eight Chinese and English databases were retrieved (from establishment to February 2017), and clinical trials were screened according to the preset inclusion criteria and exclusion criteria. Then risk assessment tools were used for quality evaluation of the studies, and data extraction and analysis were conducted by using RevMan 5.3 software for Meta-analysis. A total of 1 895 articles were retrieved, and finally 54 studies were included. The total sample number was 5 030, including 2 543 cases in experimental group and 2 487 cases in control group. As compared with CT (routine therapy) intervention, Xianling Gubao capsules showed higher SOP efficiency and improved bone mineral density in patients with OP [MD=0.08, 95%CI (0.06, 0.10)]. As compared with control group, Xianling Gubao capsule+CT showed higher efficiency in PMOP and SOP, increased bone mineral density in OP patients [MD=0.04, 95%CI (0.03, 0.05)], POP patients [MD=0.08, 95%CI (0.05, 0.10)], and SOP patients [MD=0.06, 95%CI (0.05, 0.07)], relieved osteoporotic pain in OP patients [MD=-0.93,95%CI(-1.16, -0.70), increased alkaline phosphatase level in OP patients [MD=7.53, 95%CI (5.91, 9.14), blood calcium in OP patients [MD=0.03, 95%CI (0.01, 0.06)], and osteocalcin level in OP patients [MD=4.09, 95%CI (3.20, 4.98)], and increased serum phosphorus level in SOP patients [MD=0.03, 95%CI (0.00, 0.05)]. The main adverse reactions reported were liver injury and gastrointestinal symptoms. Xianling Gubao capsule alone or combined use with other medicines had better efficacy than western medicine alone in the treatment of osteoporosis. However, because of potential bias in the included studies, more high-quality randomized controlled trials would be needed to improve the level of evidence. PMID- 29139245 TI - Evaluation of a pointwise microcirculation assessment method using liquid and multilayered tissue simulating phantoms. AB - A fiber-optic probe-based instrument, designed for assessment of parameters related to microcirculation, red blood cell tissue fraction (fRBC), oxygen saturation (SO2), and speed resolved perfusion, has been evaluated using state-of the-art tissue phantoms. The probe integrates diffuse reflectance spectroscopy (DRS) at two source-detector separations and laser Doppler flowmetry, using an inverse Monte Carlo method for identifying the parameters of a multilayered tissue model. Here, we characterize the accuracy of the DRS aspect of the instrument using (1) liquid blood phantoms containing yeast and (2) epidermis dermis mimicking solid-layered phantoms fabricated from polydimethylsiloxane, titanium oxide, hemoglobin, and coffee. The root-mean-square (RMS) deviations for fRBC for the two liquid phantoms were 11% and 5.3%, respectively, and 11% for the solid phantoms with highest hemoglobin signatures. The RMS deviation for SO2 was 5.2% and 2.9%, respectively, for the liquid phantoms, and 2.9% for the solid phantoms. RMS deviation for the reduced scattering coefficient (MUs'), for the solid phantoms was 15% (475 to 850 nm). For the liquid phantoms, the RMS deviation in average vessel diameter (D) was 1 MUm. In conclusion, the skin microcirculation parameters fRBC and SO2, as well as, MUs' and D are estimated with reasonable accuracy. PMID- 29139247 TI - [Systematic review on safety of Xianling Gubao capsule]. AB - To systemically evaluate the safety of Xianling Gubao capsule after launching. Computer retrieval of Medline, EMbase, the Web of Science, Clinical Trials. gov, the Cochrane Library, CNKI, VIP, WanFang Data and CBM was conducted to collect information on all the research types of Xianling Gubao capsule. The literature was screened according to inclusion and exclusion criteria, and the quality of the studies was assessed according to the internationally accepted quality evaluation standards for data extraction and analysis. A total of 156 papers were included in this study, including 117 randomized control trials, 11 quasi randomized control trials, 10 non-randomized control trials, 11 case report series, and 7 individual case reports; a total of 167 studies were analyzed. Xianling Gubao capsules were used in 7 496 patients, with an accumulative 377 cases of adverse reactions (ADR) and 4 cases of severe adverse reactions, including 1 death, 1 cerebrovascular accident, 1 case of skin allergy reaction, and 1 case of gastrointestinal discomfort; gastrointestinal system damage was most common in mild ADRs. In this study, we found that the overall safety of Xianling Gubao capsule was acceptable, but it lacked the mechanism study on the safety of the drug after marketing or the prospective long-term clinical observation study, so the further studies on the safety of drug use should be conducted. Meanwhile, the application scope of Xianling Gubao capsules was beyond the manual, in urgent needs of the relevant departments to formulate norms and provide better guidance for clinical medication. PMID- 29139248 TI - [Post-marketing safety surveillance of Diemailing Kudiezi injection: real world study in 30 233 cases]. AB - This study was aimed to obtain the incidence of adverse drug reaction (ADR) of Diemailing Kudiezi injection, explore its characteristics, related risk factors and application in real world. A prospective single cohort study was conducted from 25 hospitals (including Chinese medicine hospitals and Western medicine hospitals) for 4 years. 30 233 consecutive inpatients using Diemailing Kudiezi injection were observed. Their general information was analyzed by using statistic frequency description. Association rules were used to analyze the correlation between comorbidities or drug combinations; the influential factors for ADRs were initially screened by using cross contingency method and Chi-square test, and then Group LASSAO method was used for further analysis. 54 patients with adverse drug events and 30 patients with ADRs were reported among 30 233 patients, with a total ADR incidence of 0.099%[95%CI (0.06%, 0.13%)]. There were 27 patients identified as the "general" ADR, one patients with "severe" ADR (anaphylactic shock) and two patients with new ADRs. ADR occurred most in 30 min after using Diemailing Kudiezi injection, in a total of 16 patients. The most ADRs were palpitation, vomiting, chills, pruritus and rash, 6 times for each symptom. Diemailing Kudiezi injection was well tolerated in the general population. The overall incidence of adverse reactions was rare, with high safety. However, the real incidence of ADRs may be underestimated in this study, and the blood samples were not obtained for the patients, so further mechanism studies shall be conducted. PMID- 29139249 TI - [Clinical features analysis of Qingkailing injection for adolescent patients based on real world HIS]. AB - To explore the clinical application features of Qingkailing injection for adolescent patients. This study was based on the information from the hospitalized patients in 1998-2011 in HIS (hospital information system) of 16 tertiary hospitals in China. 615 adolescent patients with Qingkailing injection were used to investigate the clinical characteristics of Qingkailing injection. Apriori algorithm was adopted to establish the model, and Clementine 12.0 was used for correlation analysis. The results showed that male patients (355 cases) were more than female patients (243 cases); the age of the most patients was under 14 years old, with an average age of 9.40 years old; the hospital stay was most of 4-7 d; the patients were mostly concentrated in pediatrics, mainly including upper respiratory tract infection; outpatient admission to the majority (451 cases, accounting for 75.54%). The traditional Chinese medicine (TCM) syndrome mainly included phlegm-dampness internal resistance (38.46%), Qi and Yin Deficiency (11.54%), Liver qi stagnation (15.38%), and Yang deficiency syndrome (11.54%); the highest admission rate was during Slight Cold (13.01%). In combined application, the most common western medicine pair was Cephalosporin injection+vitamin C (with supporting rate of 24.6%) and the most common TCM pair was Shuanghuanglian+Ganmao Qingre granules (with supporting rate of 4.065%). The most common 3 western medicines in combined use were Potassium chloride injection+Cephalosporin injection+vitamin C (supporting rate of 15.93%); while the most common three Chinese medicines were Shuanghuanglian+Yunnan Baiyao+Ganmao Qingre granules (supporting rate of 1.138%). Qingkailing injection was also widely used in adolescent patients; the diagnosis and use were basically in line with the instructions; men were slightly more than women; age of onset, solar terms and TCM syndromes were highly consistent. Qingkailing injection was mainly combined with western medicines in combined drug use, and Chinese medicines were also available. Combined drug use was more reasonable. Based on the results of the real world HIS, Qingkailing injection could provide the idea and reference for regulating the medication in adolescent patients. PMID- 29139250 TI - [Clinical safety imtensive hospital monitoring on Shenfu injection with 30 106 cases]. AB - This paper is to report the implementation and results of safety monitoring of Shenfu injection. Prospective, multicenter, large sample, registry-type centralized hospital monitoring mode was used, and the three-level quality control and anti-omissive mechanisms were used strictly. In the monitoring was carried out in 28 hospitals and lasted for 4 years. 30 106 patients were registered; ADE occurred in 114 patients, and ADR was identified in 23 patients with an incidence rate of 0.076% for ADR [95% confidence interval (0.045%,0.108%), which was in a rare level. The main ADRs included rash, pruritus, discomfort at the site of the infusion, nausea, vomiting, abdominal pain, dizziness, chest tightness, heart palpitations, chills, fever and dyspnea. No severe ADRs were found in the monitoring. This paper also fund that history of allergy, methods of administration, dosage, solvent, concentration, and combined medication may affect the incidence of ADR in the use of Shenfu injection. PMID- 29139251 TI - [Clinical application features of Fufang Kushen injection in treating malignant esophageal tumor: real world study based on hospital information system]. AB - To analyze the clinical application features of Fufang Kushen injection in treating malignant esophageal tumors in the real world by using hospital information system database, and provide reference for clinical application of Fufang Kushen injection. The electronic medical data from 2 550 patients with malignant esophageal tumors using Fufang Kushen injection from 22 large-scale hospitals nationwide were extracted based on the hospital information system (HIS) established by Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences. Then the descriptive analysis based on frequency and rate was conducted for general characteristics, diagnostic characteristics, characteristics of dosage and medication information, characteristics of drug combination, and discharge outcome characteristics. The results showed that the average age of patients treated with Fufang Kushen injection for malignant esophageal tumors was 62.3 years old; more males than females; admitted to hospital mainly in department of cardiology, oncology and digestology first. The total efficiency was 47.15% based on the discharge outcome characteristics; the most common dosage was 10-20 mL for single use; the course of treatment was mainly 4-7 d; and the common drugs in drug combinations included dexamethasone, tropisetron injection, thymosin injection, compound amino acid injection, pantoprazole sodium injection, fluorouracil, et al. The characteristics of the crowd using Fufang Kushen injection to treat the malignant esophageal tumors were clear and in line with the general rule of malignant esophageal tumors; its clinical dosage and scope of treatment for malignant esophageal tumors in the real world were basically consistent with the specification; and the types of clinical drug use combinations were more extensive. PMID- 29139252 TI - [Intensive hospital monitoring of Shuxuening injection in 30 209 cases]. AB - In order to obtain the characteristics and incidence of adverse reactions of Shuxuening injection (Xingxue), the design method of a multi-center, large sample intensive monitoring in the hospitals was adopted. The hospitalized patients with use of Shuxuening injection from 27 medical institutions were enrolled as the research subjects to monitor their entire process of treatment cycle. The main content of monitoring included the patients' general information, diagnostic information, medication information, and adverse event information. A total of 30 209 patients with Shuxuening injection were enrolled; adverse reactions occurred in 34 cases, with an incidence of 0.113%, which belonged to the rare adverse reactions. Adverse reactions were characterized by headache, dizziness, pruritus, palpitations, nausea, et al. All the above results showed that Xingxue Shuxuening injection had high safety in clinical application. PMID- 29139253 TI - [Complex network analysis on Shenxiong glucose injection in combined use with Chinese and Western medicine for cerebral infarction in real world study]. AB - In order to analyze Shenxiong glucose injection in combined use with other medicines for cerebral infarction in real world, the basic information, Chinese and western medicine diagnosis information, doctors'advice information, and laboratory checking information for the patients with Shenxiong glucose injection in treatment of cerebral infarction were extracted from the hospital information system (HIS) of sixteen 3A hospitals. Apriori Algorithm was used to establish models, and Clementine 12.0 was used for correlation analysis. Then complex network was established to analyze the combined drug use and visualize the results. A total of 635 patients were included in the study, among which 599 patients (94.33%) showed superior effect. Shenxiong glucose injection was often used with platelet suppressant drug, neuroprotective agent, lipid regulating agents, free radical scavenger, vitamins and Chinese medicine blood activating and stasis eliminating agent in the treatment of cerebral infarction. In the patients with superior effect, neuroprotective agent and free radical scavengers were also used based on the combined use with Aspirin, hypolipidemic drugs and blood activating and stasis removing agents, highlighting the rain protection strategies. Shenxiong glucose injection in combined use with Chinese and western medicines for cerebral infarction complied with the latest clinical practice guideline on the treatment of cerebral infarction, and the application of neuroprotective agent was propitious to improve the therapeutic effect. PMID- 29139254 TI - [Clinical analysis of cervus and cucumis polypeptide injection for lumbar vertebrae diseases based on real world hospital information system]. AB - To analyze the clinical drug use characteristics and medication rules of cervus and cucumis polypeptide injection (CCP injection) for the patients with lumbar vertebra diseases. Based on the electronic medical data of 6 990 patients with CCP injection for lumbar vertebra diseases from 25 first-class hospitals over the whole country from 2004, statistical analysis was conducted for their general information, diagnostic information, orders information, laboratory test information and treatment results. The results showed that the age distribution was highest in patients aged 45 to 64 (3 883, 55.55%); protrusion of lumbar intervertebral disc was most common among lumbar vertebra diseases (5 519, 82.50%); and TCM syndrome mainly included hemostasis. The daily dose was most between 8-12 mL, with a usual treatment course of 1-3 d. Commonly used western medicines in combined drug use included hypertonic dehydrating agent, antibiotics and nutrition nerve medicines, and the commonly used traditional Chinese medicines in combined drug use included the drugs with promoting blood circulation to remove blood stasis, kidney-tonifying and bone-building agents, and formula for clearing heat and removing toxicity, etc. The most commonly used western medicines are methylamine, adenosine, lidocaine injection, mannitol, et al, and the most commonly used Chinese medicines included Jintiange capsules, Qianggu capsules, et al. It is suggested that CCP injection for lumbar vertebrae diseases is mainly used in middle-aged and elderly patients, and is frequently used in combination with kidney-tonifying and bone-building agents, drugs with promoting blood circulation to remove blood stasis, analgesic agents and antibiotics. PMID- 29139255 TI - [Association rules analysis for exploring combined medication characteristics of Fufang Kushen injection: real-world study based on 49 597 cases]. AB - The present study aimed to analyze the association rules of Fufang Kushen injection in combined medications in the real world based on electrical medical records in hospital information system, and provide reference for its reasonable clinical application. The electrical medical records of the hospitalized patients using Fufang Kushen injection were extracted to analyze the frequency distribution characteristics in combined application with Western medicine, and analyze the specific association rules between these combinations by using Apriori algorithm. A total of 49 597 patients were included in the study, and its common combined medications included 5-HT receptor blockers, hepatic protector, antibiotics, chemotherapeutic drugs, immunomodulatory drugs, glucocorticoids, analgetics and proton pump inhibitors. The results revealed that the distribution characteristics in combined application and association combinations of Fufang Kushen injection had specific rules, consistent with the clinical orientation of this drug in treatment of malignant tumor. Such results may provide reference for reasonable application of Fufang Kushen injection in clinical treatment. PMID- 29139256 TI - [Correlative analysis advance of chemical constituents of Polyporus umbellatus and Armillaria mellea]. AB - Medicinal Polyporus umbellatus is the dry sclerotia of P. umbellatus, with the effect of diuresis; Armillaria mellea is a parasitic fungus which can infect plants up to 300 genera, with sedative, anticonvulsant and some other biological activities. As the medicinal value of P. umbellatus and A. mellea is increasingly wide concerned, the market quantity demanded of them is gradually increased and the demand outstrips the supply. The symbiotic A. mellea and P. umbellatus are both the medicinal and edible fungi with diverse activities, including hypoglycemic action, improve immunity and antitumor and so on. The growth of the sclerotia forming from the mycelium of P. umbellatus is related to the infection of the symbiotic A. mellea and their secondary products. In this study, by comparing the chemical constituents of the mycelium and sclerotia of P. umbellatus and A. mellea, we found that they all produced steroids and nitrogen containing heterocycles. The sclerotia of P. umbellatus and A. mellea also produced triterpenes secondary metabolites. In addition, the mycelium and infected sclerotia of P. umbellatus mainly produced different steroids, and the sclerotia produced some other special secondary metabolites, such as long-chain fatty acids, ceramides, phenol and so on. By analyzing above all kinds of differences, speculated that these may be caused by the infection of the symbiotic A. mellea which mainly produced sesquiterpenes, diterpenes and other secondary metabolites. The contents and types of compounds of P. umbellatus and A. mellea are closely related to their symbiosis and reproduction, therefore, many symbiosis mechanisms should be found by utilizing more molecular biology technology to elucidate this complex symbiotic infection and provide scientific basis for improving the yield and quality of P. umbellatus and A. mellea. PMID- 29139257 TI - [Reviews on alpha-glucosidase inhibitor from plant secondary metabolites]. AB - alpha-Glucosidase inhibitor was a new type of antidiabetics which was developed in the late 1970s. By reducing the postprandial blood sugar concentration, it could effectively control the blood sugar levels, thereby reducing the occurrence of diabetic complications. Studies have shown that plant secondary metabolites have important biological functions such as hpyerglycemic, anti-hyperlipidemia, immunomodulatory, and antitumor effects. In this paper, the sources of plant secondary metabolites which are able to inhibit alpha-glucosidase and their inhibition mechanism would be reviewed to provide references for seeking more safe and efficient plant secondary metabolites of alpha-glucosidase inhibitors. PMID- 29139258 TI - [Regulatory effects of traditional Chinese medicine on autophagy in myocardial ischemia reperfusion injury]. AB - Autophagy is a basic process of eliminating unnecessary or damaged organelles by lysosome to maintain the internal environment homeostasis. Recent studies have revealed that autophagy plays an important role in pathology of myocardial ischemia reperfusion. In the phase of ischemia, moderate autophagy can protect the cells against various stress; but in the phase of reperfusion, excessive autophagy can increase the death of cells. Therefore, the dual role of autophagy in myocardial ischemia reperfusion provides a new therapeutic target for the treatment of heart disease. In recent years, more and more Chinese medicines have been proved to adjust the autophagy in myocardial cells, and protect the damaged myocardium by enhancing or inhibiting autophagy. This article would review the molecular mechanisms of autophagy and its role in myocardial ischemia reperfusion injury as well as the regulation effect of Chinese medicine on it. PMID- 29139259 TI - [Progress in molecular identification of snake drugs]. AB - Snake drugs have high values in clinical medication for anti-inflammatory, analgesia activities and dredging collaterals. However, owing to their deficient resource and substantial profit, many counterfeits for snake drugs have appeared on the market. Traditional methods for Chinese medicine authentication include identification of origin, morphology identification, microscopy and physiochemical identification. But these methods are restricted in application because of their high morphological requirement for specimens, complex process for assays and indeterminate results guided by subjective. With the development of molecular biology and molecular genetic techniques, new theories and technologies for molecular detection have been introduced to the authentication of Chinese medicine, such as RAPD, specific PCR amplification, DNA barcoding analysis and so on, improved the authentication system of Chinese medicine. Here, we will give a brief review of molecular detection methods for snake drugs authentication. PMID- 29139260 TI - [Study on distribution of five heavy metal elements in different parts of Cordyceps sinensis by microwave digestion ICP-MS]. AB - The contents of five heavy metals (Cu, Pb, As, Cd, Hg) in 17 batches of Cordyceps sinensis were determined by microwave digestion-ICP-MS, and their distribution in C. sinensis were analyzed. The results showed that the contents of Cu, Pb, Cd and Hg in all batches were in accordance with the international standards of Chinese Medicine-Chinese Herbal Medicine Heavy Metal Limit, with their contents in the stroma higher than that in the caterpillar body, and the excess rate of As, which mainly concentrated in the caterpillar body part of C. sinensis, was 88.24%, as the content of As in the caterpillar body was 7 to 12 fold of that in the stroma. In this study, the distribution of five heavy metals in C. sinensis was clarified, and the existing problems of arsenic limit of heavy metal in C. sinensis were analyzed, and some suggestions were put forward. It is hoped that the reference standard can be provided for the limited standard of arsenic in C. sinensis. PMID- 29139261 TI - [Study on suitable distribution areas of Sichuan safflower in Sichuan province based on 3S technologies]. AB - Sichuan safflower (Carthamus tinctorius) is a traditional Chinese medicine for promoting blood circulation and removing blood stasis. In this paper, taking Sichuan province as an example, based on TM image, digital elevation model (DEM), meteorology, soil and other data, and using remote sensing and GIS technology to extract grassland, elevation, temperature and precipitation, soil and other influencing factors, the spatial distribution of the suitability of safflower was studied, and the field investigation was carried out. The results indicate that Sichuan safflower resources are mainly concentrated in the eastern and northeastern parts of Sichuan, and the suitable distribution area is about 6 277.14 km2. The area of suitable area of Dazhou is 1 143.45 km2, which is suitable for the province area of 18.22%. From the county point of view, the suitable area of Dachuan is about 507.15 km2, and accounting for 17.9% of county. In addition, Naxi, Qingshen, Jiangan and other 12 counties of the suitable area of more than 100 km2, and accounted for more than 10% of the county. The results of remote sensing and GIS analysis are in accordance with the real area of Sichuan safflower resources. It is feasible to find out the area suitable for the growth of Sichuan safflower by 3S technologies. It can provide a scientific basis for the monitoring and development of Chinese herbal resources. PMID- 29139262 TI - [Effect of different fertilization treatments on yield and secondary metabolites of Codonopsis pilosula]. AB - The research studies the effect of different fertilization treatments on yield and accumulation of secondary metabolites of Codonopsis pilosula by using single factor randomized block design, in order to ensure reasonable harvesting time and fertilization ratio, and provide the basis for standardized cultivation of C. pilosula. According to the clustering results, the nitrogen fertilizer benefitted for the improvement of root diameter and biomass of C. pilosula. The phosphate fertilizer could promote the content of C. pilosula polysaccharide. The organic fertilizers could increase the content of lobetyolin. With the time going on, C. pilosula's yield, polysaccharide and ehanol-soluble extracts increased while the content of lobetyolin decreased. According to various factors, October is a more reasonable harvest period. Organic fertilizers are more helpful to the yield and accumulation of secondary metabolites of C. pilosula. PMID- 29139263 TI - [Next generation sequencing and transcriptome analysis of root bark from Paeonia suffruticosa cv. Feng Dan]. AB - Moutan Cortex is an important traditional Chinese medicine, "Fengdan Pi" was known as Dao-di herbs from the root bark of Paeonia suffruticosa cv. Feng Dan for its extracted various active components. However, the genetic basis for their activity is virtually unknown. The transcriptome of the root bark from "Fengdan" was sequenced using the Illumina HiSeq 4000 sequencing platform. The clean reads were then de novo assembled into 72 997 unigenes. Among them, the number of unigenes which could been annotated by dataset Nr and GO was 41 139 and 34 592. The 20 016 unigenes could been annotated by KEGG dataset, which were involved in 5 major categories, 34 middle categories, and 352 metabolism pathways. The number of unigenes which were mapped to the phenylpropanoid biosynthesis pathway, terpenoid backbone biosynthesis pathway, terpenoid biosynthesis pathway, alkaloid biosynthesis pathway, and flavonoid biosynthesis pathway was 214, 104, 152, 55 and 36 respectively, suggesting that they are involves in these pathways of pharmaceutically important. Furthermore, there also showed remarkable differences in groups which enrichment ratio of the different expressed gene compared. In addition, a total of 9 939 SSRs were identified from the sequence of 72 997 unigenes. This study not only provides many valuable basal data which was important gene in the synthesis pathway of secondary metabolites with gene searching, but also has important significance to find molecular marker in germplasm for breeding and improvement. PMID- 29139264 TI - [Construction of cell factories for high production of nerolidol in Saccharomyces cerevisiae]. AB - Nerolidol is an important constituent of terpenoid essential oil and has excellent anti-tumor, anti-bacterial, and anti-oxidative properties. For realizing heterogenous production of nerolidol, our research firstly integrated the codon-optimized Actinidia sinensis nerolidol synthase gene (NES) into the terpenoid chassis strain FPP-001, and obtained NES-001 that could produce 2.71 mg*L-1 nerolidol. Then, the N-terminal of the NES was fused with FPS by linker peptide GGGS. With this strategy, nerolidol production improved by 59.80-fold, reaching 162.07 mg*L-1. Finally, by introduction of auxotrophic marker TRP1 in NES-002, the resulting strain NES-003 could produce 1 711.53 mg*L-1 by high cell density fermentation method. This study provides the basis for the fermentative production of nerolidol and other sesquiterpenoids. PMID- 29139265 TI - [Stability optimization of puerarin nanocrystalline self-stabilizied Pickering emulsion by response surface methodology]. AB - A new Pickering emulsion, puerarin nanocrystalline self-stabilized Pickering emulsion (Pu-NSSPE) was developed. Box-Behnken design was used for optimizing the preparation formulation of Pu-NSSPE to improve its stability, and the effects of concentration of puerarin, volume ratio of water to oil, and pH value of water phase on the stratification index of emulsion, droplet size and drug concentration in emulsion were investigated. Results showed that the optimized Pu NSSPE could be prepared with the concentration of puerarin of 0.5%, the volume ratio of water to oil of 9?1 and the pH of water of 9. The size of emulsion droplet of optimized Pu-NSSPE was (12.70+/-1.17) MUm and the drug content was (4.49+/-0.21) g*L-1. The above indexes had no significant changes within the storage of 6 months at room temperature, indicating good stability. Microstructure characterizations by scanning electron micrograph, confocal laser scanning microscope and fluorescence microscope showed that the optimized Pu NSSPE had a stable core-shell structure of emulsion droplet formed by the adsorption of puerarin nanocrystallines at the surface of oil droplets, which may be the microstructure reason for the long stability of Pu-NSSPE. PMID- 29139266 TI - [Effect of fluidized bed technology on micromeritics properties of Leonurus Herba extract]. AB - Based on different binders, the Leonurus Herba extract powders were fluidized and modified. The physical properties such as hygroscopicity, flowability, filling property and compression property were studied by various micromeritics methods before and after modification. The results showed that the physical properties of Leonurus Herba extract were close to those of microcrystalline cellulose, and its comprehensive flow index was between 61-75. Fluidization process can improve hygroscopicity, so the moisture absorption indexes of the samples were significantly lower than those of the original Leonurus Herba extract samples. With the plastic constant, compression ratio and yield stress, Heckel equation and Kawakita equation as the the investigation indicators, results showed that fluidization process based on binder water was superior to other methods in increasing the compressibility of the extracts. In low and medium pressure, the fluidized and modified extract can form the tablets with a certain strength. Fluidized transformation had a greater influence on the properties of original Leonurus Herba extracts, which was instructive to guide significance for the surface modification of pharmaceutical powders and provide the basis for the development of extract tablet. PMID- 29139267 TI - [Preparation of nanosuspension of quercetin with a miniaturized milling method]. AB - The nanosuspension of quercetin (QT-NS) was prepared by a miniaturized milling method, and the process was optimized by Box-Behnken response surface method. Then the accumulative release rate of QT-NS in vitro was determined. The results showed that the optimal process parameters were as follows: ZrO2 4.5 mL, milling speed 690 r*min-1 and milling time 1.5 h; the particle size of QT-NS was (169+/ 5) nm, polydispersity index of 0.204+/-0.006 and stability index of 0.827+/ 0.014, respectively. There was a little deviation between the theoretically predicted value and the measured value, indicating that this model had a good prediction effect. The accumulative release rate in vitro of QT-NS in 120 min was significantly higher than that of the raw drug and physical mixture. This simple low-cost miniaturization approach could prepare QT-NS successfully, and could provide reference for the formulation of the nanosuspension. PMID- 29139268 TI - [Mineral composition analysis and hemostatic effect of limonitum with different mineral genesis]. AB - Models were established in mice with warfarin sodium method, and their bleeding time and hemostasis time were measured by tail cutting method and slide method respectively. Rats were administered for 15 consecutive days to measure their recalcification time, plasma viscosity, platelet adhesion rate, platelet aggregation rate and other blood indexes. As compared with the blank group, the bleeding time was prolonged in model groupn(P<0.05). As compared with the model group, the results showed that the positive vitamin K, the leaching type water decoction and the sediment type decoction could significantly shorten the bleeding time (P<0.01); positive vitamin K significantly (P<0.01) shortened clotting time, and the leaching type water decoction, the sediment type water decoction and the sediment type powder could also shorten the clotting time (P<0.05). As compared with blank group, low dose, medium dose of leaching type water decoction, medium dose of powder, high dose of sediment type decoction and low dose of drug residues could reduce plasma viscosity (P<0.05), and high dose of leaching powder and low dose of water decoction could significantly reduce (P<0.01) plasma viscosity. As compared with blank group, Limonitum leaching type decoction high dose group could significantly reduce the platelet adhesion rate (P<0.05), while sediment type water decoction could significantly increase the platelet adhesion rate (P<0.05); the high dose of leaching type water decoction, high dose of drug residues, low dose of leaching type powder and low dose of drug residues could decrease the platelet aggregation rate (P<0.05), while high dose of leaching type water decoction and high dose of the powder could increase the platelet aggregation rate (P<0.05). Analysis of mineral compositions was conducted by polarized light microscopy and X-ray diffraction (XRD). The results of the both methods showed that Limonitum mineral compositions contained goethite, quartz, and kaolinite, and sedimentary type also contained illite and albite. Sediment type of Limonitum showed better hemostatic effect, which may be related to the high content of goethite and illite. PMID- 29139269 TI - [Phenolic acid derivatives of Euphorbia ebracteolata]. AB - A variety of chromatographic methods were applied to research the chemical composition of the roots of Euphorbia ebracteolata. Meanwhile, the structures of these compounds were identified by spectroscopic data, such as 1D, 2D NMR and HR ESI-MS. In the present research, a new phenolic acid compound, 1,3,4,5 tetrahydroxy-2-O-beta-D-[(6'-Gallic acyl)-glucopyranyl] isopentane(1), was isolated from the roots of E. ebracteolata, as well as three known compounds, isopropyl-2-O-beta-D-(6'-gallic acyl)-glucopyranoside(2), ellagic acid(3) and 3,4'-di-O-methylellagic acid(4) respectively. Additionally, compounds 2 and 4 were isolated from the Euphorbia genus for the first time. PMID- 29139270 TI - [Chemical constituents from root of Angelica decursiva]. AB - The compounds were isolated and purified by HP20 macroporous adsorption resin, ODS, silica gel, and Sephadex LH-20 column chromatography, as well as semi preparative HPLC chromatography from the 80% ethanol extract of the root of Angelica decursiva, and their structures were identified based on their physiochemical properties and spectroscopic data. Twelve compounds were structures were identified as (9R,10R)-9-acetoxy-8,8-dimethyl-9,10-dihydro-2H,8H benzo[1,2-b:3,4-b']dipyran-2-one-10-yl ester (1), bakuchicin (2), (3', S,4'S) disenecioyloxy-3',4'-dihydroseselin (3), (3'R,4'R)-3'-angeloyloxy-4'-senecioyloxy 3',4'-dihydroseselincalipteryxin (4), (+)-8,9-dihydro-8-(2-hydroxypropan-2-yl)-2 oxo-2H-furo[2,3h]chromen-9-yl-3-methylbut-2-enoate (5), libanoridin (6), selinidin (7), suberosin (8), crocatone (9), peujaponisinol B (10), peujaponisinol A (11), and ostenol (12), respectively. Compounds 1-5 were isolated from the plants of Angelica genus for the first time. Compounds 7-12 were isolated from A. decursiva for the first time. PMID- 29139271 TI - [Studies on the chemical components of Nelumbinis Plumula and the inhibitory activity on protein disulfide isomerase]. AB - Increasing evidence suggested that protein disulfide isomerase supported the survival and progression of several cancers. Nelumbinis Plumula is a Chinese traditional herb which showed antitumor activity. To find if the Nelumbinis Plumula affect protein disulfide isomerase activity, we studied its chemical constituents, and 12 monomeric compounds were isolated by means of solvent extraction, silica gel column chromatography, preparative HPLC and recrystallization. Among them, N-methylcoclaurine, kaempferol, chrysoeriol-7-O neohesperidoside and mannitol were obtained for the first time. Following, we tested the compounds inhibitory activity on protein disulfide isomerase. The results showed that N-methylcoclaurine, neferine, liensinine and isoliensinine could inhibit the activity of protein disulfide isomerase in vitro, their IC50 values were 1.4, 2.9, 4.0 and 5.4 MUmol*L-1, respectively. PMID- 29139272 TI - [Comparative study on specific chromatograms and main active components of wild and cultivated rhizomes of Paris polyphylla var. yunnanensis]. AB - The present study is to compare specific chromatograms and main acitive components between wild and cultivated rhizomes of Paris polyphylla var. yunnanensis by HPLC. HPLC analysis was performed on a Waters XSelect HSS T3 C18 clumn (4.6 mm*250 mm, 5 MUm), with a mobile phase consisting of acetonitrile (A) water (B) at a flow rate of 1 mL*min-1 (0-50 min,30%-50%A;50-80 min,50% A,80-85 min,50%-30%A;85-100 min,30% A). The detection wavelength was 203 nm and the column temperature was controlled at 30 C, and the injection volume was 10 MUL. HPLC specific chromatograms of wild and cultivated rhizomes of P. polyphylla var. yunnanensis were established and nine steroidal saponins were simultaneously determined by the above method. The mean contents of paris saponin VII, paris saponin H and total average contents of four pennogenyl saponins in Rhizomes of wild samples were significantly higher than those of cultivated ones. However, this result is opposite from the average content of paris saponin I and total average contents of five dioscins in the wild and cultivated samples. Because the significant differences occurred for the specific chromatograms and main active components between the wild and cultivated P. polyphylla var. yunnanensis, much more pharmacological and clinical researches are therefore necessary. PMID- 29139273 TI - [Comparative study on promoting blood effects of Danshen-Honghua herb pair with different preparations based on chemometrics and multi-attribute comprehensive index methods]. AB - To evaluate the promoting blood circulation and removing blood stasis effects of Danshen-Honghua(DH) herb pair with different preparations (alcohol, 50% alcohol and water) on blood rheology and coagulation functions in acute blood stasis rats, and optimize the best preparation method of DH based on principal component analysis(PCA), hierarchical cluster heatmap analysis and multi-attribute comprehensive index methods. Ice water bath and subcutaneous injection of adrenaline were both used to establish the acute blood stasis rat model. Then the blood stasis rats were administrated intragastrically with DH (alcohol, 50% alcohol and water) extracts. The whole blood viscosity(WBV), plasma viscosity(PV), erythrocyte sedimentation rate(ESR) and haematocrit(HCT) were tested to observe the effects of DH herb pair with different preparations and doses on hemorheology of blood stasis rats; the activated partial thromboplastin time(APTT), thrombin time(TT), prothrombin time(PT), and plasma fibrinogen(FIB) were tested to observe the effects of DH herb pair with different preparations on blood coagulation function and platelet aggregation of blood stasis rats. Then PCA, hierarchical cluster heatmap analysis and multi-attribute comprehensive index methods were all used to comprehensively evaluate the total promoting blood circulation and removing blood stasis effects of DH herb pair with different preparations. The hemorheological indexes and coagulation parameters of model group had significant differences with normal blank group. As compared with the model group, the DH herb pair with different preparations at low, middle and high doses could improve the blood hemorheology indexes and coagulation parameters in acute blood stasis rats with dose-effect relation. Based on the PCA, hierarchical cluster heatmap analysis and multi-attribute comprehensive index methods, the high dose group of 50% alcohol extract had the best effect of promoting blood circulation and removing blood stasis. Under the same dose but different preparations, 50% alcohol DH could obviously improve the hemorheology and blood coagulation function in acute blood stasis rats. These results suggested that DH herb pair with different preparations could obviously ameliorate the abnormality of hemorheology and blood coagulation function in acute blood stasis rats, and the optimized preparation of DH herb pair on promoting blood effects was 50% alcohol extract, providing scientific basis for more effective application of the DH herb pair in modern clinic medicine. PMID- 29139274 TI - [Dihydroartemisinin inhibits proliferation of pancreatic cancer JF-305 cells by regulating expression of apoptosis related proteins and production of reactive oxygen species]. AB - To investigate the effect of dihydroartemisinin on apoptosis of human pancreatic cancer cell line JF-305 and the role of reactive oxygen species(ROS) in the apoptosis of JF-305 cells induced by dihydroartemisinin. MTT assays were used to detect effect of different concentrations of dihydroartemisinin on cells proliferation of JF-305 lines. Cell cycle was detected by flow cytometry, and the apoptotic morphology was observed by Hoechst 333258 fluorescence staining. Annexin V fluorescence staining was used to detect the apoptosis changes of JF 305 cells, while DCFH-DA was used to detect the changes of ROS during apoptosis process. Western blot was used to detect the protein expression changes of Bax, Bcl-2, Cleaved caspase-3, Cleaved caspase-9 and Cyto C. As compared with the control group, the JF-305 cells proliferation was inhibited significantly(P<0.05) after treatment with different concentrations of dihydroartemisimin for 48 h; cell cycle was blocked in the G2/M phase; apoptotic morphology of nuclear condensation, aggregation, and fragmentation was found, and the apoptosis ratio was increased(P<0.05). DCFH-DA detection showed that the cell ROS was increased significantly after dihydroartemisinin treatment(P<0.05). Western blot results showed that the expression of Bcl-2 protein was down-regulated; the expression of Bax protein was up-regulated; the ration of Bax/Bcl-2 was increased and the protein expression levels of Cleaved caspase-3, Cleaved caspase-9 and Cyto C were increased after dihydroartemisinin treatment. Therefore, dihydroartemisinin could induce apoptosis of JF-305 cells, and the possible mechanism may be related to the formation and increasing of ROS. PMID- 29139275 TI - Depression in adults linked to maltreatment in childhood. PMID- 29139276 TI - Preventing stroke and assessing risk in women. AB - Ischaemic stroke is rare in premenopausal women but risk increases with advancing age and doubles in the ten years following the menopause. Up to the age of 75 years men have a 25% higher risk of suffering a stroke compared with women. However, the increased life expectancy of women ultimately results in a higher overall incidence. Twice as many women die from stroke compare with breast cancer. Women with cerebrovascular disease are more likely to present with atypical symptoms than men. Altered mental status (including unresponsiveness, confusion and behavioural change) is the most common nonconventional symptom, and is reported by 23% of women compared with 15% of men. Other nonconventional symptoms reported more commonly by women include face or hemibody pain, lightheadedness and headache. Atrial fibrillation (AF) and hypertension, although less common than in men, are more potent risk factors for stroke in women. Compared with men with AF, women with AF are at increased risk of ischaemic stroke (6.2% versus 4.2% per year). This increased risk persists in anticoagulated patients with a relative risk ratio of 2.0. Pregnancy is a unique risk factor for stroke in women. The risk is highest in the third trimester and peripartum period. Women with hypertension in pregnancy, whether secondary to pre-existing disease, preeclampsia or eclampsia have a six-to nine-fold increased risk of stroke compared with normotensive women. Preeclampsia doubles the risk of stroke in later life. Gestational diabetes is also associated with higher risk of stroke extending beyond childbearing years. PMID- 29139277 TI - Tailor management to the patient with fibroids. AB - Fibroids are benign, hormone-dependent tumours of uterine smooth muscle and connective tissue. They are commonly asymptomatic, but can cause symptoms such as heavy menstrual bleeding and pelvic pressure symptoms. Between 20 to 30% of women with heavy menstrual bleeding have fibroids. Fibroids are most prevalent in women aged 30-50 years and there may be a genetic predisposition. They are more common in black women than white women. Other risk factors include obesity and nulliparity. Asymptomatic women should only be referred if their uterus is palpable abdominally, if fibroids distort the uterine cavity or the uterus is larger than 12 cm in length. Symptomatic women should be referred when heavy menstrual bleeding has not responded to medical treatment, if large fibroids are causing pressure symptoms or when fibroids are associated with fertility or obstetric problems. Malignant change (leiomyosarcoma) is rare in premenopausal women. Fast track referral is indicated for women with rapid onset and progressive symptoms or rapidly enlarging fibroids, as these symptoms are suspicious of leiomyosarcoma; postmenopausal women presenting with enlarging fibroids or vaginal bleeding; and women with fibroids with any other features of cancer e.g. abnormal bleeding or weight loss. PMID- 29139278 TI - Improving pain control in diabetic neuropathy. AB - Diabetic neuropathy is thought to affect 1.9% of the world's population and 50% of patients with a diagnosis of diabetes mellitus which would equate to 2.25 million people in the UK. The term diabetic neuropathy includes multiple distinct clinical entities that have been classified under the broad headings of focal and multifocal neuropathies and symmetrical neuropathies. Peripheral diabetic neuropathy, a chronic distal symmetrical predominantly sensory neuropathy, is the most common form of diabetic neuropathy. Most patients describe moderate to severe pain, using neuropathic descriptors such as burning, shooting or electric shocks. The common presentation is of painful symptoms originating in the feet, that then spread to the knees before involving the distal portion of the upper limbs in a 'glove and stocking' distribution. There are number of specific neuropathic pain assessment tools that can be readily used in a non-specialist setting in the community, such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) questionnaire. This combines five simple questions and two examination findings to give a dimensionless score for the pain out of 24, with a score >= 12 suggesting a neuropathic component is likely. PMID- 29139279 TI - Self-perception of Physical Appearance in Adolescents: Gender, Age and Ethnic Aspects. AB - The study used cross-sectional data of 462 girls and 372 boys of Russian ethnicity and 90 Kalmyk girls 12-17-year-olds. In both groups children were examined by the same researchers according to the same research protocol. All of the observations have been performed in agreement with bioethical procedures; protocols of consent were filled either by the subject (elder children) or by his/her parent(s). Standing height, weight, body circumferences and skinfolds thickness were taken on each individual according to the standard technique. Body mass index (BMI) was calculated. In Arkhangelsk city 114 boys and 172 girls among the total number of studied subjects filled in the questionnaires, and in Elista 34 girls among 90. Data sets were divided according to sex, age, somatotypes and ethnicity. The results of the present study showed significant correlations between somatotypes of the subjects, their BMI and self-estimation of their physical appearance. In self-perception of one's body, weight was the most important characteristics in girls, while in boys it was stature. No differences were found in most of self-evaluation scores between Russian girls of Arkhangelsk city and Kalmyk girls of Elista, apart from the fact that the latter had lower scores in the estimation of their body shape, possibly because they were fatter. The strategies chosen by the adolescents for modifications of their bodies in their quest for "ideal" figures were in favor of dieting versus physical activity, which puts the question of popularization of physical culture and sports on a nation-wide scale. PMID- 29139280 TI - Are Patients Ready for Lesbian, Gay and Bisexual Family Physicians - A Croatian Study. AB - Discrimination and harassment of lesbian, gay and bisexual (LGB) physicians from their colleagues and superiors are known. However there is little knowledge about the patients' attitudes and discrimination toward physicians. A cross sectional Internet survey was conducted in urban Croatian regions. The participants were asked to answer questions regarding their socio-demographic status, the Attitudes Towards Lesbians and Gay Men Scale (ATLG), and whether they would refuse to see a LGB physician and, if so, why. Of the 1004 participants, 8.8% said they would refuse a male GB physician while 7.9% would refuse a female LB physician, and 7.3% would refuse both. The two most common reasons for discriminating were: "disaccord with political or religious beliefs" and "fear of being sexually harassed". A logistical regression model showed that male sex, higher ATLG score and higher age were associated with more refusals of male GB physicians. Also higher age, higher ATLG score were associated with more refusals of female LB physicians, while personal contact with LGB people was associated with less refusals of both groups. The observed prevalence of discrimination is significant. The results suggest that discrimination is based on emotional reasons and stereotypical beliefs. Educational efforts should be directed towards changing misconceptions about LGB people. PMID- 29139281 TI - Czech contributions to searching for starting points of transculturality. AB - This study concerns with defining and classifying particular attempts to find outlines of transculturality in the Czech surroundings. It makes efforts especially to characterize the so called Hradec Kralove school of transculturality, which it reduces into two dominating different streams: the socio-cultural and the metaphysical stream. The study divides the socio-cultural ways of transculturality into three central models: the nihilistic, the symbolical and the humanitarian-psychological model. The metaphysical stream is then divided into the biblically anthropological and the historically contextual model. PMID- 29139282 TI - Genetic Structure of an Isolated Rural Population in North Albania Evaluated Through Isonymic Method. AB - The genetic structure of a rural isolated population living in Kukes District in northern part of Albania, was analyzed through the surnames distribution. The data suitable for this analysis were obtained from Electoral Register (2009) offered by Central Election Commission of Albania. In order to estimate the population diversity, the information from the populations of 10 administrative units (communes) for a total of 1768 surnames belonging to 39571 individuals was used. Indicators of genetic structure such as Fisher's alpha, an estimate of surname diversity and coefficient of consanguinity (F), were obtained. Different genetic distances between all possible pairs of 10 municipalities (populations) were calculated and the correlation with geographic distance was tested. Lasker's, Nei and Euclidean distances were positively correlated with geographic distance, indicating the presence of isolation by distance. In addition, the application of multivariate analysis such as Cluster and Principal Components to isonymic distance matrix revealed that the trend of genetic relationships among the investigated populations was according to their geographic locations. This is an important indication that geographic distance could be a determinant factor in the definition of the above population's genetic structure. PMID- 29139283 TI - Is sports choice and participation related to 2D:4D? A study among adult male students in Wroclaw, Poland. AB - Psychology and personality of individuals may have implications for choice of, and performance in sports disciplines. Individual- and group sports differ in psychological requirements, such as, competitiveness, sensation seeking and risk taking attitude, often required in sports. There is sex difference in human in these qualities, which also show association with prenatal testosterone exposures. Second-to-fourth digit lengths ratio (2D:4D) is an indicator of prenatal testosterone exposure. Lower 2D:4D indicates higher prenatal testosteron exposure and vice versa. Males generally have lower 2D:4D than females. This study cross-sectional study investigated the relationship of 2D:4D with team based- or individual sports. The participants were 421 Polish male students with a mean (+SD) age of 19.78 (+0.79) years. Among them, 139 were engaged in sports and 282 were not. Mean 2D:4D in each hand of individual sporting group was significantly lower than the team sports- and no sports groups. Participants not involved in any sports had the highest mean 2D:4D value. However, the team sportsmen's 2D:4D did not differ from the non sporting group. Prenatal testosterone exposure might have implication in sports choice and participation. PMID- 29139284 TI - Menstrual Changes in Body Composition of Female Athletes. AB - The aim of the study was to determine whether the tendencies and scope of changes in body mass, body composition and body girths across the menstrual cycle were similar or different in women of different body build. Anthropometric examinations were carried out in a group of 40 naturally regularly menstruated females practicing team sports (aged 19-21, B-v 169.3+/-6.4 cm, body mass 59.6+/ 7.0 kg), in the follicular, periovulatory and luteal phases of the menstrual cycle. The phases were determined on the basis of data from two consecutive menstrual cycles taking into account the cycle's length. To establish the type of body build, Body Mass Index, hydration status and skinfold thickness were measured. For a statistical analysis, a multiple comparisons with multiple confidence intervals were applied. The increase in body mass between the follicular and the luteal phases was observed in all groups of women, the biggest gain was recorded in slim women, who in the luteal phase weighted 0.8 kg more. The amount of fat mass increased significantly across the menstrual cycle only in more hydrated (by about 0.66 kg) and slim women (by about 0.54 kg). Significant changes between consecutive phases of the menstrual cycle in waist and hip girths, and suprailiac skinfold thickness in some groups of women also indicate influence of fatness and hydration status and slenderness. In view of the presented results, the body build seems important for an analysis of the pattern of each component's changes across the menstrual cycle, especially for female athletes. Certain changes can be seen only in some groups of women, therefore somatic features can be considered as a predictor of the intensity of changes. PMID- 29139286 TI - Highly Sensitive Flexible Pressure Sensors Based on Printed Organic Transistors with Centro-Apically Self-Organized Organic Semiconductor Microstructures. AB - A highly sensitive pressure sensor based on printed organic transistors with three-dimensionally self-organized organic semiconductor microstructures (3D OSCs) was demonstrated. A unique organic transistor with semiconductor channels positioned at the highest summit of printed cylindrical microstructures was achieved simply by printing an organic semiconductor and polymer blend on the plastic substrate without the use of additional etching or replication processes. A combination of the printed organic semiconductor microstructure and an elastomeric top-gate dielectric resulted in a highly sensitive organic field effect transistor (FET) pressure sensor with a high pressure sensitivity of 1.07 kPa-1 and a rapid response time of <20 ms with a high reliability over 1000 cycles. The flexibility and high performance of the 3D OSC FET pressure sensor were exploited in the successful application of our sensors to real-time monitoring of the radial artery pulse, which is useful for healthcare monitoring, and to touch sensing in the e-skin of a realistic prosthetic hand. PMID- 29139285 TI - Subradiant Dipolar Interactions in Plasmonic Nanoring Resonator Array for Integrated Label-Free Biosensing. AB - With the development of advanced nanofabrication technologies over the past decade, plasmonic nanostructures have attracted wide attention for their potential in label-free biosensing applications. However, the sensing performance of nanostructured plasmonic sensors is primarily limited by the broad-line-width features with low peak-to-dip signal ratio in the extinction spectra that result from strong radiative damping. Here, we propose and systematically investigate the in-plane and out-of-plane dipolar interactions in an array of plasmonic nanoring resonators that are from the spatial combination of classic nanohole and nanodisk structures. Originating from the strong coupling of the dipolar modes from parent nanohole and nanodisk structures, the subradiant lattice plasmon resonance in the nanoring resonator array exhibits narrow-line width spectral features with high peak-to-dip signal ratio and strong near-field electromagnetic enhancement, making it an ideal platform for high-sensitivity chemical and biomedical sensing. We experimentally demonstrate that the plasmonic nanoring resonator array can be used for high-sensitivity refractive index sensing and real-time monitoring of biomolecular specific binding interactions at nanomolar concentration. Moreover, due to its simple normal incident illumination scheme and polarization independent optical response, we further transfer the plasmonic nanoring resonator array onto the optical fiber tip to demonstrate an integrated and miniaturized platform for label-free remote biosensing, which implies that the plasmonic nanoring resonator array may be a potential candidate for developing high performance and highly integrated photonic biosensing systems. PMID- 29139287 TI - High-Performance, Self-Powered Photodetectors Based on Perovskite and Graphene. AB - An ideal photodetector must exhibit a fast and wide tunable spectral response, be highly responsive, have low power consumption, and have a facile fabrication process. In this work, a self-powered photodetector with a graphene electrode and a perovskite photoactive layer is assembled for the first time. The graphene electrode is prepared using a solution transfer process, and the perovskite layer is prepared using a solution coating process, which makes the device low cost. Graphene can form a Schottky junction with TiO2 to efficiently separate/transport photogenerated excitons at the graphene/perovskite interface. Unlike the conventional photovoltaic structure, in this photodetector, both photogenerated electrons and holes are transported along the same direction to graphene, and electrons tunneled into TiO2 are collected by the cathode and holes transported by graphene are collected by the anode; therefore, the photodetector is self powered. The photodetector has a broad range of detection, from 260 to 900 nm, an ultrahigh on-off ratio of 4 * 106, rapid response to light on-off (<5 ms), and a high level of detection of ~1011 Jones. The high performance is primarily due to the unique charge-transport property of graphene and strong light absorption properties of perovskite. This work suggests a new method for the production of self-powered photodetectors with high performance and low power consumption on a large scale. PMID- 29139288 TI - Dissolution of Pt during Oxygen Reduction Reaction Produces Pt Nanoparticles. AB - The loss of Pt during the oxygen reduction reaction (ORR) affects the performance and economic viability of fuel cells and sensors. Our group previously observed the dissolution of Pt nanoelectrodes at moderately negative potentials during the ORR. Here we report a more detailed study of this process and identify its product. The nanoporous Pt surface formed during the ORR was visualized by AFM and high-resolution SEM, which also showed ~5 nm sized Pt particles on the glass surface surrounding the electrode. The release of these nanoparticles into the solution was confirmed by monitoring their catalytically amplified collisions with a Hg-coated microelectrode used as the tip in the scanning electrochemical microscope (SECM). PMID- 29139289 TI - Tetraaza[14]- and Octaaza[18]paracyclophane: Synthesis and Characterization of Their Neutral and Cationic States. AB - Two kinds of aza[1n]paracyclophanes, tetraaza[14]paracyclophane (P4) and octaaza[18]paracyclophane (P8), were synthesized as the smallest and the largest monodisperse macrocyclic oligomers of polyaniline ever made. Herein we report the electronic nature of the cationic species of these two macrocycles with different ring size. By combining ESR spectroscopy and DFT calculations it was suggested that P4.+ was classified as delocalized class III or poised on the class II/III borderline while P8.+ was regarded as a localized class II mixed-valence system. We successfully isolated the dication of P4 as a stable dicationic salt P42+.2[SbF6]-, and the structure of P42+ was determined by X-ray crystal analysis. Variable-temperature NMR measurements for P42+.2[SbF6]- unequivocally showed that P42+ was a 22pi electron system with a singlet ground state. The supercharged hexacation of P8 was also isolated as P86+.6[SbCl6]-, and X-ray crystal analysis revealed that P86+ includes one SbCl6- anion in its macrocyclic cavity. PMID- 29139291 TI - An Integrative Approach to Decipher the Chemical Antagonism between the Competing Endophytes Paraconiothyrium variabile and Bacillus subtilis. AB - An integrative approach combining traditional natural products chemistry, molecular networking, and mass spectrometry imaging has been undertaken to decipher the molecular dialogue between the fungus Paraconiothyrium variabile and the bacterium Bacillus subtilis, which were isolated as endophytes from the conifer Cephalotaxus harringtonia and are characterized by a strong and mutual antibiosis. From this study, we highlight that bacterial surfactins and a fungal tetronic acid are involved in such competition and that the fungus is able to hydrolyze surfactins to fight against the bacterial partner. PMID- 29139290 TI - Decomposing Dynamical Couplings in Mutated scFv Antibody Fragments into Stabilizing and Destabilizing Effects. AB - Conformational fluctuations within scFv antibodies are characterized by a novel perturbation-response decomposition of molecular dynamics trajectories. Both perturbation and response profiles are stratified into stabilizing and destabilizing conditions. The linker between the VH and VL domains exhibits the dominant dynamical response by being coupled to nearly the entire protein, responding to both stabilizing and destabilizing perturbations. Perturbations within complementarity-determining regions (CDR) induce rich behavior in dynamic response. Among many effects, stabilizing any CDR loop in the VH domain triggers a destabilizing response in all CDR loops in the VL domain and vice versa. Destabilizing residues within the VL domain are likely to stabilize all CDR loops in the VH domain, and, when these residues are not buried, the CDR loops in the VL domain are also likely to be stabilized. These effects, described by shifts in normal mode characteristics, initiate a propensity for dynamic allostery with possible functional implications in bispecific antibodies. PMID- 29139292 TI - Enhanced Electrical Properties and Air Stability of Amorphous Organic Thin Films by Engineering Film Density. AB - The influences of film density and molecular orientation on the carrier conduction and air stability of vacuum-deposited amorphous organic films of N,N' di(1-naphthyl)-N,N'-diphenyl-(1,1'-biphenyl)-4,4'-diamine (alpha-NPD) were investigated. The substrate temperature (Tsub) during vacuum deposition had different effects on the film density and molecular orientation of alpha-NPD. Film density was a concave function of Tsub; maximum density was attained at Tsub = 270-300 K. alpha-NPD molecules were randomly oriented at Tsub = 342 K, and their horizontal orientation on the substrate became dominant as Tsub decreased. Hole current and air stability were clearly raised by increasing the film density by 1 to 2%; these effects were, respectively, attributed to enhanced carrier hopping between neighboring alpha-NPD molecules and suppressed penetration of oxygen and water. These results imply that increasing film density is more effective to enhance the electrical performance of organic thin-film devices with alpha-NPD films than control of molecular orientation. PMID- 29139293 TI - Ti-Doped GaOx Resistive Switching Memory with Self-Rectifying Behavior by Using NbOx/Pt Bilayers. AB - Crossbar arrays (CBAs) with resistive random access memory (ReRAM) constitute an established architecture for high-density memory. However, sneak paths via unselected cells increase the total power consumption of these devices and limit the array size. To eliminate such sneak-path problems, we propose a Ti/GaOx/NbOx/Pt structure with a self-rectifying resistive-switching (RS) behavior. In this structure, to reduce the operating voltage, we used a Ti/GaOx stack to increase the number of trap sites in the RS GaOx layer through interfacial reactions between the Ti and GaOx layers. This increase enables easier carrier transport with reduced electric fields. We then adopted a NbOx/Pt stack to add rectifying behavior to the RS GaOx layer. This behavior is a result of the large Schottky barrier height between the NbOx and Pt layers. Finally, both the Ti/GaOx and NbOx/Pt stacks were combined to realize a self-rectifying ReRAM device, which exhibited excellent performance. Characteristics of the device include a low operating voltage range (-2.8 to 2.5 V), high on/off ratios (~20), high selectivity (~104), high operating speeds (200-500 ns), a very low forming voltage (~3 V), stable operation, and excellent uniformity for high density CBA-based ReRAM applications. PMID- 29139294 TI - Improved Electrostatic Embedding for Fragment-Based Chemical Shift Calculations in Molecular Crystals. AB - Fragment-based methods predict nuclear magnetic resonance (NMR) chemical shielding tensors in molecular crystals with high accuracy and computational efficiency. Such methods typically employ electrostatic embedding to mimic the crystalline environment, and the quality of the results can be sensitive to the embedding treatment. To improve the quality of this embedding environment for fragment-based molecular crystal property calculations, we borrow ideas from the embedded ion method to incorporate self-consistently polarized Madelung field effects. The self-consistent reproduction of the Madelung potential (SCRMP) model developed here constructs an array of point charges that incorporates self consistent lattice polarization and which reproduces the Madelung potential at all atomic sites involved in the quantum mechanical region of the system. The performance of fragment- and cluster-based 1H, 13C, 14N, and 17O chemical shift predictions using SCRMP and density functionals like PBE and PBE0 are assessed. The improved embedding model results in substantial improvements in the predicted 17O chemical shifts and modest improvements in the 15N ones. Finally, the performance of the model is demonstrated by examining the assignment of the two oxygen chemical shifts in the challenging gamma-polymorph of glycine. Overall, the SCRMP-embedded NMR chemical shift predictions are on par with or more accurate than those obtained with the widely used gauge-including projector augmented wave (GIPAW) model. PMID- 29139295 TI - Synthesis of Aminobenzopyranoxanthenes with Nitrogen-Containing Fused Rings. AB - An efficient and practical method for the synthesis of a variety of aminobenzopyranoxanthenes (ABPXs) with different nitrogen-containing fused rings was developed. On the basis of the mechanistic studies of the formation of the xanthene framework, the presented methodology was developed to facilitate access to previously inaccessible asymmetric ABPXs. PMID- 29139297 TI - Direct Exosome Quantification via Bivalent-Cholesterol-Labeled DNA Anchor for Signal Amplification. AB - Exosomes, as an important subpopulation of extracellular vesicles (EVs), play an important role in intercellular communications in various important pathophysiological processes, especially cancer-related. However, reliable and convenient quantitative methods for their determination are still technically challenging. In this study, we developed an efficient and direct method by combining immunoaffinity and lipid membrane surface modification into a single platform for specific isolation and accurate quantification of exosomes. Exosomes are specifically captured by immunomagnetic beads, and then a bivalent cholesterol (B-Chol)-labeled DNA anchor with high affinity is spontaneously inserted into the exosome membrane. The rationally designed sticky end of the anchor acts as the initiator for the subsequent horseradish peroxidase (HRP) linked hybridization chain reaction (HCR) for signal amplification. Detection is based on the color change of HRP-catalyzed H2O2-mediated oxidation of 3,3',5,5'- tetramethyl benzidine (TMB), which can be conveniently observed by the naked eye and monitored by UV-vis spectrometry. This proposed method enables sensitive detection of 2.2 * 103 exosomes per microliter with a relative standard deviation of <5.6%, with 100-fold higher sensitivity compared to conventional ELISA. We believe that our assay has considerable potential as a routine bioassay (cost efficient, reliable, and easy to operate) for the accurate quantification of exosomes in clinical samples. PMID- 29139296 TI - Differential Content of Proteins, mRNAs, and miRNAs Suggests that MDSC and Their Exosomes May Mediate Distinct Immune Suppressive Functions. AB - Myeloid-derived suppressor cells (MDSC) are immature myeloid cells that accumulate in the circulation and the tumor microenvironment of most cancer patients. There, MDSC suppress both adaptive and innate immunity, hindering immunotherapies. The inflammatory milieu often present in cancers facilitates MDSC suppressive activity, causing aggressive tumor progression and metastasis. MDSC from tumor-bearing mice release exosomes, which carry biologically active proteins and mediate some of the immunosuppressive functions characteristic of MDSC. Studies on other cell types have shown that exosomes may also carry RNAs which can be transferred to local and distant cells, yet the mRNA and microRNA cargo of MDSC-derived exosomes has not been studied to date. Here, the cargo of MDSC and their exosomes was interrogated with the goal of identifying and characterizing molecules that may facilitate MDSC suppressive potency. Because inflammation is an established driving force for MDSC suppressive activity, we used the well-established 4T1 mouse mammary carcinoma system, which includes "conventional" as well as "inflammatory" MDSC. We provide evidence that MDSC derived exosomes carry proteins, mRNAs, and microRNAs with different quantitative profiles than those of their parental cells. Several of these molecules have known or predicted functions consistent with MDSC suppressive activity, suggesting a potential mechanistic redundancy. PMID- 29139298 TI - SiC Nanofiber Mat: A Broad-Band Microwave Absorber, and the Alignment Effect. AB - Fiber alignment is a key factor that determines the physical properties of nanofiber mats. In this work, SiC nanofiber mats with or without fiber alignment are fabricated via electrospinning and the microwave electromagnetic properties of their silicone resin composites (5 wt %) are investigated in 2-18 GHz. By comparing with the composite containing SiC whisker, it is found that the nanofiber mats show superior dielectric loss and a minimal reflection loss (RL) of around -49 dB at 8.6 GHz and 4.3 mm thickness, associated with a broad effective absorption (<-10 dB) bandwidth (EAB) of about 7.2 GHz at 2.8 mm thickness. Moreover, the performance can be further enhanced (RL = -53 dB at 17.6 GHz and 2.3 mm thickness) by aligning the nanofiber in the plane of mat, accompanied by the shift of absorption peak to higher-frequency direction and broader EAB up to 8.6 GHz at 3 mm. In addition, the stacking ways of aligned SiC nanofiber mats (either parallel or perpendicular) are proved to have a negligible effect on their microwave properties. Compared with parallel stacking of the aligned mats, cross-stacking (perpendicular) only leads to a slight drop of the attenuation ability. It confirms that alignment of nanofiber in the mats offers a more effective approach to improve the microwave absorption properties than changing the ways of stacking. Furthermore, it is worth mentioning that the low loading fraction (5 wt %) is a great advantage to reduce the weight as well as the cost for large-scale production. All of these facts indicate that the aligned SiC nanofiber mats can serve as a great lightweight and broad-band microwave absorber. PMID- 29139299 TI - Integrating Zeolite-Type Chalcogenide with Titanium Dioxide Nanowires for Enhanced Photoelectrochemical Activity. AB - Developing photoanodes with efficient visible-light harvesting and excellent charge separation still remains a key challenge in photoelectrochemical water splitting. Here zeolite-type chalcogenide CPM-121 is integrated with TiO2 nanowires to form a heterostructured photoanode, in which crystalline CPM-121 particles serve as a visible light absorber and TiO2 nanowires serve as an electron conductor. Owing to the small band gap of chalcogenides, the hybrid electrode demonstrates obvious absorption in visible-light range. Electrochemical impedance spectroscopy (EIS) shows that electron transport in the hybrid electrode has been significantly facilitated due to the heterojunction formation. A >3-fold increase in photocurrent is observed on the hybrid electrode under visible-light illumination when it is used as a photoanode in a neutral electrolyte without sacrificial agents. This study opens up a new avenue to explore the potential applications of crystalline porous chalcogenide materials for solar-energy conversion in photoelectrochemistry. PMID- 29139300 TI - Development and preliminary evidence of the psychometric properties of the GNE myopathy functional activity scale. AB - AIM: GNE myopathy, a rare, severe, progressive myopathy, presents with lower extremity distal muscle weakness. The GNE myopathy functional activity scale (GNEM-FAS) evaluates the impact of GNE myopathy on functioning in adults. This paper presents the psychometric validation of the GNEM-FAS. PATIENTS & METHODS: Validation of the GNEM-FAS was performed using data from a randomized, double blind, placebo-controlled Phase-II study (n = 46). RESULTS: Domain score distributions were acceptable. Moderate inter-item correlations (typical range, 0.40-0.70), strong item convergent and discriminant validity and high internal consistency reliability (alpha = 0.88-0.92) supported the instrument structure. Test-retest reliability was strong (ICC range: 0.87-0.95). Scale scores distinguished among subjects with differing disease severity (p < 0.05). CONCLUSION: This study provides preliminary evidence of the GNEM-FAS as a valid, reliable assessment. PMID- 29139301 TI - Design of a 24-week trial of empagliflozin once daily in hypertensive black/African American patients with type 2 diabetes mellitus. AB - OBJECTIVE: Black/African American individuals have a higher prevalence of type 2 diabetes mellitus (T2DM), diabetes-related complications and hypertension, but they are often underrepresented in clinical trials. The sodium-glucose co transporter 2 inhibitor, empagliflozin, was associated with significant improvements in glucose control (via hemoglobin [Hb] A1c) and reductions in blood pressure (BP; via office and ambulatory BP monitoring) in a primarily white population with T2DM and hypertension. The aim of this ongoing study is to assess the safety and efficacy of empagliflozin in terms of glucose- and BP-lowering in a self-identified black/African American population with T2DM and hypertension. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3b study carried out at 85 centers in the USA. It was designed to assess the safety and efficacy of empagliflozin (10 or 25 mg/day) versus placebo in black/African American patients with uncontrolled T2DM and hypertension. Patients receiving stable glucose-lowering therapy prestudy continued at the same dose during the trial; BP-lowering medication was also held stable. The primary endpoint was the change from baseline in HbA1c at Week 24. Key secondary endpoints were change from baseline in: mean 24-hour ambulatory systolic BP (SBP) at Week 12, mean trough ambulatory SBP at Week 12, body weight at Week 24 and trough seated SBP at Week 12. RESULTS: The study will report final data in 2018. CONCLUSIONS: Results of this study will add to our understanding of the efficacy and safety of empagliflozin in self-identified black/African American patients with T2DM and hypertension. (ClinicalTrials.gov identifier: NCT02182830.). PMID- 29139302 TI - Autism spectrum disorder and interoception: Abnormalities in global integration? AB - Research over the past three decades has seen a revived interest in the way the human body-and the way in which it is perceived-interacts with aspects of our experience. Consequently, interoception (i.e. the perception of physiological feedback from the body) has recently been shown to be associated with a wide range of cognitive, emotional, and affective functions, making it broadly relevant to the study of autism spectrum disorder. Although limited qualitative accounts and empirical studies suggest that individuals with autism spectrum disorder encounter abnormalities when perceiving and integrating physiological feedback from their bodies, other studies have suggested that people with/without autism spectrum disorder do not differ in interoceptive ability after accounting for alexithymia. In this article, we discuss the newly recognized importance of interoception in autism spectrum disorder with a focus on how deficits in the perception of bodily feedback might relate to the core features and co-occuring psychopathology of autism spectrum disorder. Finally, a new integrated theory is advanced which posits that people with autism spectrum disorder may experience a reduced capacity to integrate interoceptive information that may result in a narrow attentional bodily focus and reduced motivational and behavioral drives. PMID- 29139303 TI - Effects on the medical revenue of comprehensive pricing reform in Chinese urban public hospitals after removing drug markups: case of Nanjing. AB - AIMS: The State Council of China requires that all urban public hospitals must eliminate drug markups by September 2017, and that hospital drugs must be sold at the purchase price. Nanjing-one of the first provincial capital cities to implement the reform-is studied to evaluate the effects of the comprehensive reform on drug prices in public hospitals, and to explore differential compensation plans. METHODS: Sixteen hospitals were selected, and financial data were collected over the 48-month period before the reform and for 12 months after the reform. An analysis was carried out using a simple linear interrupted time series model. RESULTS: The average difference ratio of drug surplus fell 13.39% after the reform, and the drug markups were basically eliminated. Revenue from medical services showed a net growth of 28.25%. The overall compensation received from government financial budget and medical service revenue growth was 103.69% for the loss from policy-permitted 15% markup sales, and 116.48% for the net loss. However, there were large differences in compensation levels at different hospitals, ranging from -21.92% to 413.74% by medical services revenue growth, causing the combined rate of both financial and service compensation to vary from 28.87-413.74%, There was a significant positive correlation between the services compensation rate and the proportion of medical service revenue (p < .001), and the compensation rate increased by 8% for every 1% increase in the proportion of services revenue. DISCUSSION: Nanjing's pricing and compensation reform has basically achieved the policy targets of eliminating the drug markups, promoting the growth of medical services revenue, and adjusting the structure of medical revenue. However, the growth rate of service revenue of hospitals varied significantly from one another. CONCLUSIONS: Nanjing's reform represents successful pricing and compensation reform in Chinese urban public hospitals. It is recommended that a differentiated and dynamic compensation plan should be established in accordance with the revenue structure of different hospitals. PMID- 29139304 TI - Object-directed imitation in autism spectrum disorder is differentially influenced by motoric task complexity, but not social contextual cues. AB - We examined the role of social motivation and motor execution factors in object directed imitation difficulties in autism spectrum disorder. A series of to-be imitated actions was presented to 35 children with autism spectrum disorder and 20 typically developing children on an Apple(r) iPad(r) by a socially responsive or aloof model, under conditions of low and high motor demand. There were no differences in imitation performance (i.e. the number of actions reproduced within a fixed sequence), for either group, in response to a model who acted socially responsive or aloof. Children with autism spectrum disorder imitated the high motor demand task more poorly than the low motor demand task, while imitation performance for typically developing children was equivalent across the low and high motor demand conditions. Furthermore, imitative performance in the autism spectrum disorder group was unrelated to social reciprocity, though positively associated with fine motor coordination. These results suggest that difficulties in object-directed imitation in autism spectrum disorder are the result of motor execution difficulties, not reduced social motivation. PMID- 29139305 TI - Development of optimized self-nanoemulsifying lyophilized tablets (SNELTs) to improve finasteride clinical pharmacokinetic behavior. AB - OBJECTIVE: Preparation of an optimized finasteride (FSD) lyophilized tablets loaded with self-nanoemulsifying drug delivery system (SNEDDS). SIGNIFICANCE: Enhance FSD bioavailability in male pattern baldness and benign prostatic hyperplasia. METHODS: Two-step optimization was implemented to achieve the study goals. First; the mixture design was used to develop an optimized SNEDDS through which the effect of cosurfactant number of carbon atoms on SNEDDS particle size and thermodynamic stability has been tested. Second; the different tablet excipients have been used to develop an optimized self-nanoemulsifying lyophilized tablets (SNELTs). The prepared tablets have been fully characterized. Interaction among tablet components has been studied. Finally, FSD clinical pharmacokinetic has been investigated on human volunteers. RESULTS: Anise oil and tween 80 were selected as oily phase and surfactant, respectively while different aliphatic alcohols were studied as cosurfactants. Percentages of oil, surfactant, and cosurfactants were significantly affecting SNEDDS particle size. Increasing cosurfactant number of carbon atoms achieved smaller particle size and higher stability. The optimized SNEDDS was found to contain 10.3455, 45.8972, and 43.7573% of anise oil, tween 80, and butanol, respectively. Variations in FSD cumulative release and disintegration time, from the prepared tablets, were attributed to change in the percent of plasdone XL, Avicel and silica. No interaction among components was noticed. Clinical pharmacokinetics illustrated significant enhancement in the studied parameters from the optimized lyophilized tablets loaded with drug SNEDDS when compared to marketed FSD product. CONCLUSION: Lyophilized tablets could be considered as a good alternative for conventional solid dosage forms especially when loaded with drug nanosystems. PMID- 29139306 TI - Equilibria, kinetics and mechanism for the degradation of the cytotoxic compound L-NG-nitroarginine. AB - L-NG-nitroarginine (LNNA), an analog of L-arginine, is a competitive inhibitor of nitric oxide synthase which causes the selective reduction of blood flow to tumor cells. Despite the potential of LNNA to function as an adjuvant in cancer therapies, its poor solubility and stability have hindered the development of an injectable formulation of LNNA that is suitable for human administration. This work, for the first time, details a systematic study on the determination of equilibrium Ka constants and the rate law of LNNA degradation. The four Ka values of LNNA were determined to be 1.03, 1.10 * 10-2, 2.51 * 10-10, and 1.33 * 10-13 M. From the kinetic and equilibrium studies, we have shown that the deprotonated form of LNNA is the main form of LNNA that undergoes degradation in aqueous media at room temperature. The rate law of LNNA degradation was found to be first order with respect to OH- concentration and first order with respect to LNNA- concentration. The rate constant at 25 degrees C and 1 atm was determined to be 0.04453 M-1min-1. A base catalyzed mechanism of LNNA degradation was proposed based on the kinetic study. The mechanism was found to be very useful in explaining the discrepancies and changes of the rate law at different pH values. It is thus recommended that LNNA should be formulated as a concentrated solution in acidic conditions for maximum chemical stability during storage and be diluted with a basic solution to near physiological pH just before administration. PMID- 29139307 TI - Skin-to-Skin Contact as Quality Measurement. PMID- 29139308 TI - The impact of deployment and traumatic brain injury on the health and behavior of children of US military service members and veterans. AB - This study examined the impact of service member/veteran (SMV) combat deployment and traumatic brain injury (TBI) on the health and behavior of his or her children. Participants were 104 female spouse caregivers of US SMVs who had sustained a mild, severe, or penetrating TBI. Participants completed the Children's Health and Behavior Questionnaire (CHBQ; r = .758 to .881) that evaluates school grades, behavior, medical health, emotional health, and social participation: (a) prior to the first combat deployment, (b) in the month prior to the TBI, (c) within 2 years after the TBI, and (d) 2 or more years after the TBI. A substantial number of children experienced a decline in health and behavior following the TBI (41.7%-79.1%). Of those who declined (a) 68.8%-75.5% declined within the first 2 years post-injury, followed by improvement or stabilization; (b) 6.7%-15.6% declined only after 2 or more years post-injury; (c) 15.6%-25.0% declined within the first 2 years post-injury and then again 2 or more years post-injury; and (d) 16.9%-26.5% experienced a decline as a result of deployment, followed by an additional decline after the SMV's TBI. Services are required for children of SMVs following TBI and deployment, particularly children at risk for poor outcome. PMID- 29139309 TI - Polyphenolic characterisation of plant mixture (Lisosan(r) Reduction) and its hypocholesterolaemic effect in high fat diet-fed mice. AB - Lisosan(r) Reduction is a plant mixture produced from powder of fermented Triticum aestivum (Lisosan(r) G), Desmodium adscendens, Malus domestica, Picrorhiza kurroa and Hordeum vulgare. The aim of this study was to characterise the phenolic profile of Lisosan(r) Reduction and to evaluate the effects of aqueous extract on mice fed a high fat diet (HFD). Syringic acid, trans sinapic acid and neochlorogenic acid were identified by HPLC-DAD to be the dominant polyphenols of Lisosan(r) Reduction, followed by vitexin, trans p-coumeric acid and trans ferulic acid. Mice treated with aqueous extract of Lisosan(r) Reduction (60 mg/kg b.w.) showed a significant decrease of serum cholesterol, glucose and triglycerides level and a significant increase of CYP7A1 gene expression, compared to HFD group. PMID- 29139310 TI - Pudendal nerve injury impairs anorectal function and health related quality of life measures >=2 years after 3D conformal radiotherapy for prostate cancer. AB - PURPOSE: To compare GI symptoms, measures of generic and disease specific health related quality of life (HRQoL), anorectal and pudendal nerve function and anal sphincter morphology between (i) patients >=2 years after 3D conformal radiotherapy (3D-CRT)+/-high dose rate (HDR) brachytherapy for carcinoma of the prostate and aged matched patients before radiotherapy and (ii) symptomatic and asymptomatic patients >=2 years after 3D-CRT +/- HDR brachytherapy. MATERIAL AND METHODS: Methodology included: (i) modified LENT-SOMA scales for GI symptoms, (ii) EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires for generic and disease specific HRQoL, (iii) anorectal manometry and terminal motor latency for anorectal and pudendal nerve function and (iv) endorectal ultrasound for anal sphincter morphology. GI symptoms, parameters of HRQoL, anorectal and pudendal nerve function and anal sphincter morphology were compared using Mann-Whitney's U, unpaired t and chi2 tests. RESULTS: Impairment of HRQoL bowel symptoms in the patients >=2 years after 3D-CRT +/- HDR brachytherapy was associated with worse anorectal motor and sensory function, internal and external anal sphincter morphology and 5* greater prevalence of pudendal nerve dysfunction compared with age matched patients before radiotherapy. Symptomatic patients had worse (i) HRQoL measures including global quality of life and bowel and urinary symptom scores, (ii) rectal bleeding, fecal urgency and incontinence scores and (iii) a 2* higher prevalence of pudendal nerve dysfunction compared with asymptomatic patients. Rectal and anal (i) V 40 Gy >65%, (ii) Dmax >60 Gy, (iii) pudendal nerve Dmax >60 Gy and (iv) Anal V 60 Gy >40% were associated with a greater prevalence of pudendal nerve dysfunction. CONCLUSIONS: 3D-CRT +/- HDR brachytherapy for prostate carcinoma, impairs late functional measures including HRQoL, anorectal and pudendal nerve function. Rectal, anal and pudendal nerve radiation dose constraints are proposed for reducing the prevalence of pudendal nerve dysfunction. PMID- 29139311 TI - Baseline sleep quality is a significant predictor of quit-day smoking self efficacy among low-income treatment-seeking smokers. AB - Compared to non-smokers, smokers have an increased risk for poor sleep quality, which could undermine confidence to quit. This study examined whether baseline sleep quality was associated with quit-day smoking self-efficacy among smokers enrolled in a smoking cessation trial. Treatment-seeking low-income smokers were randomized to either a low-intensity physical activity integrated with standard smoking cessation intervention or standard care cessation only. Poor sleep quality was significantly associated with lower quit-day (week 4) smoking self efficacy ( beta = -0.61; standard error = 8.1; p = .03). Over half the samples (53%) reported poor sleep quality, thus addressing baseline sleep quality is an important consideration in smoking cessation programs. PMID- 29139312 TI - Burnout and depression: Causal attributions and construct overlap. AB - Burnout has been commonly regarded as a job-induced syndrome. In this 468 participant study (67% female; mean age: 46.48), we examined the extent to which individuals with burnout and depressive symptoms attribute these symptoms to their job. Fewer than half (44%) of the individuals with burnout symptoms viewed their job as the main cause of these symptoms. The proportion of participants ascribing their depressive symptoms to work was similar (39%). Results from correlation and cluster analyses were indicative of burnout-depression overlap. Our findings suggest that burnout may not be a specifically job-induced syndrome and further question the validity of the burnout construct. PMID- 29139313 TI - Body-image, quality of life and psychological distress: a comparison between kidney transplant patients and a matching healthy sample. AB - The purpose of the current study was to assess the uniqueness of the condition of kidney transplant recipients in comparison to a sample of matching healthy peers in relation to body-image dissatisfaction and identification, quality of life and psychological distress. Participants were 45 kidney transplant recipients who were under follow-up care at a Transplant Unit of a major Medical Center, and a sample of 45 matching healthy peers. Measures were taken using self-report questionnaires [Body-Image Ideals Questionnaire (BIIQ), Body Identification Questionnaire (BIQ), Brief Symptoms Inventory (BSI), and the SF-12]. The major findings were the following: (i) kidney transplant recipients reported lower levels of quality of life and higher levels of PsD when compared to their healthy peers; (ii) no difference in body-image dissatisfaction was found between the two studied groups; (iii) significant correlations between body-image dissatisfaction quality of life and PsD were found only in the kidney transplant recipients. The kidney transplantation condition has a moderating effect in the association between body-image dissatisfaction PsD but not in the association between body image dissatisfaction and quality of life; (iv) kidney transplant recipients experienced higher levels of body identification than did their healthy peers. Taken together, these findings highlight the unique condition of kidney transplant recipients, as well as the function that body-image plays within the self. PMID- 29139314 TI - Cost-utility analysis of life-long prophylaxis with recombinant factor VIIIFc vs recombinant factor VIII for the management of severe hemophilia A in Sweden. AB - AIMS: Prophylaxis with recombinant factor VIII (rFVIII) is the standard of care for severe hemophilia A in Sweden. The need for frequent injections with existing rFVIII products may, however, result in poor adherence to prophylaxis, leading to increased bleeding and long-term joint damage. Recombinant FVIIIFc (rFVIIIFc) is an extended half-life fusion protein which can offer prolonged protection and reduced dosing frequency. The objective of this study was to evaluate the cost utility of prophylaxis with rFVIIIFc in severe hemophilia A from the perspective of the Swedish health system. METHODS: A Markov model was built to estimate lifetime costs and benefits of prophylaxis with rFVIIIFc vs rFVIII products. Clinical outcomes were represented by annualized bleeding rate (ABR) and quality of life via disutility applied to bleeding events and injection frequency. Costs included the cost of FVIII for routine prophylaxis and bleed resolution. The pooled comparator was costed by weighting the cost of individual products by their market share. RESULTS: In the base case, rFVIIIFc was dominant vs the pooled comparator. Savings of SEK 9.0 million per patient resulted from lower factor consumption for prophylaxis and bleed resolution. Fewer bleeds and reduced injection frequency yielded an estimated 0.59 quality-adjusted life years (QALYs). Results were sensitive to drug dosage and robust to variation in other parameters. Probabilistic sensitivity analysis suggested a greater than 85% probability of rFVIIIFc being cost-effective at a willingness-to-pay threshold of 500,000 SEK/QALY. LIMITATIONS: Due to unavailibilty of patient-level data, treatment benefit was based on a non-adjusted indirect comparison. Dosing and treatment outcomes were assumed to persist over the model duration in the absence of long-term outcome data. CONCLUSION: The results suggest that rFVIIIFc may be a cost-effective option for hemophilia A prophylaxis, generating greater quality of life and reduced costs for the Swedish payer compared to more frequently administered rFVIII alternatives. PMID- 29139315 TI - Statin use and risk for type 2 diabetes: what clinicians should know. AB - Statins are the first line of pharmacologic treatment for the management of hypercholesterolemia in patients at risk for atherosclerotic cardiovascular (CV) disease. In recent years, several randomized, controlled trials (RCTs) and observational studies have reported increased risk for new-onset type 2 diabetes mellitus (T2D) with statin treatment, particularly with use of high-intensity statins that reduce low-density lipoprotein cholesterol (LDL-C) by 50% or more. This paper summarizes the data from RCTs and observational studies for statin associated T2D risk, and puts into perspective this evidence, weighed against the established benefits of statin therapy for CV risk reduction. In RCTs, the increase in T2D risk with statin therapy appears to be attributable mainly to those with major T2D risk factors. The increase in incidence of T2D in those with major risk is approximately 25% for statin use, compared to placebo, and for intensive statin therapy compared to moderate-intensity statin therapy. However, in those with major T2D risk factors, the number of CV disease events prevented for each excess case of T2D is close to or greater than one, indicating that the risk-benefit ratio still strongly favors use of statin therapy, or intensive statin therapy, for patients with sufficient CV disease risk to warrant cholesterol-lowering drug therapy. Recommendations are summarized for evaluation of the T2D risk factor profile before initiation of and during statin therapy. In addition, the importance of lifestyle management and other preventive measures is emphasized for management of risks for both T2D and CV disease events in patients receiving statin therapy. PMID- 29139316 TI - Association of Gastrocnemius Muscle Stiffness With Passive Ankle Joint Stiffness and Sex-Related Difference in the Joint Stiffness. AB - Passive ankle joint stiffness is affected by all structures located within and over the joint, and is greater in men than in women. Localized muscle stiffness can be assessed by ultrasound shear wave elastography, and muscle architecture such as fascicle length and pennation angle can be measured by B-mode ultrasonography. Thus, the authors assessed localized muscle stiffness of the medial gastrocnemius (MG) with consideration of individual variability in the muscle architecture, and examined the association of the muscle stiffness with passive ankle joint stiffness and the sex-related difference in the joint stiffness. Localized muscle stiffness of the MG in 16 men and 17 women was assessed at 10 degrees and 20 degrees plantar flexion, neutral anatomical position, and 10 degrees and 20 degrees dorsiflexion. Fascicle length and pennation angle of the MG were measured at these joint positions. Passive ankle joint stiffness was determined by the ankle joint angle-torque relationship. Localized MG muscle stiffness was not significantly correlated with passive ankle joint stiffness, and did not show significant sex-related difference, even when considering the muscle architecture. This finding suggests that muscle stiffness of the MG would not be a prominent factor in determining passive ankle joint stiffness and the sex-related difference in the joint stiffness. PMID- 29139317 TI - A gamma process modeling approach for the comparison of dissolution profiles. AB - In this paper, we propose a stochastic gamma process model for assessing the similarity of two dissolution profiles. Based on the proposed stochastic model, we utilize the difference factor and similarity factor to test the similarity of two dissolution profiles based on bootstrap confidence intervals. The performances of the proposed methods are compared with a multivariate test procedure via Monte Carlo simulation studies. The proposed testing methods are shown to be powerful and effectively controlling the error rate. The proposed model provides a simple yet useful alternative parametric statistical model for assessing the similarity of two dissolution profiles. All the methods are illustrated with a numerical example. PMID- 29139318 TI - Improved Newborn Care: Evidence-Based Protocol for the Evaluation and Management of Early-Onset Sepsis. PMID- 29139320 TI - Effects of Cable News Watching on Older Adults' Physiological and Self-Reported Stress and Cognitive Function. AB - Older adults are the largest consumer of cable news, which includes negative and politicized content and may constitute a daily stressor. As older adults are also vulnerable to the negative consequences of stress, we hypothesized that cable news watching could induce a stress reaction and impair cognitive function. We tested exposures to cable news (i.e., Fox News and MSNBC) in a within-subject randomized controlled design in 34 healthy older adults. We also included negative (Public Broadcasting Station) and positive (trier social stress test) controls. Cable news watching had no effect on psychological stress, physiological stress, or cognitive function. This remained true even if the news exposures were discordant with participants' political affiliation. We conclude that brief cable news watching does not induce a physiological or subjective stress response or cognitive impairment among healthy older adults. PMID- 29139321 TI - Effects of White Noise Achilles Tendon Vibration on Quiet Standing and Active Postural Positioning. AB - Applying white noise vibration to the ankle tendons has previously been used to improve passive movement detection and alter postural control, likely by enhancing proprioceptive feedback. The aim of the present study was to determine if similar methods focused on the ankle plantarflexors affect the performance of both quiet standing and an active postural positioning task, in which participants may be more reliant on proprioceptive feedback from actively contracting muscles. Twenty young, healthy participants performed quiet standing trials and active postural positioning trials designed to encourage reliance on plantarflexor proprioception. Performance under normal conditions with no vibration was compared to performance with 8 levels of vibration amplitude applied to the bilateral Achilles tendons. Vibration amplitude was set either as a percentage of sensory threshold (n = 10) or by root-mean-square (RMS) amplitude (n = 10). No vibration amplitude had a significant effect on quiet standing. In contrast, accuracy of the active postural positioning task was significantly (P = .001) improved by vibration with an RMS amplitude of 30 MUm. Setting vibration amplitude based on sensory threshold did not significantly affect postural positioning accuracy. The present results demonstrate that appropriate amplitude tendon vibration may hold promise for enhancing the use of proprioceptive feedback during functional active movement. PMID- 29139322 TI - How pupils on the autism spectrum make sense of themselves in the context of their experiences in a mainstream school setting: A qualitative metasynthesis. AB - Evidence that interpersonal interactions and self-appraisal in social context are crucial in developing self-understanding raises concerns about how pupils with autism spectrum disorder make sense of themselves in school settings where many experience social marginalisation. Metasynthesis was used to systematically extract and integrate findings from qualitative studies examining the mainstream school experiences of these students. Synthesised findings identified three, intermeshing, aspects of experience which contribute to many pupils with autism spectrum disorder making sense of themselves as 'different' to typical peers in a negative way: difficulties linked to autism spectrum disorder; interpersonal relationships, particularly with peers; and accessibility of the school environment. Typical pupils' attitudes and responses towards peers with autism spectrum disorder, unusual sensory reactions to the physical school environment and individual sense-making about the self are highlighted as key areas requiring further research and intervention to improve the experiences, self-esteem and well-being of pupils with autism spectrum disorder in inclusive settings and to inform educational policy and practice. PMID- 29139323 TI - Jaboticaba (Plinia peruviana) extract nanoemulsions: development, stability, and in vitro antioxidant activity. AB - OBJECTIVE: The aim of this work is to develop and characterize nanoemulsions containing jaboticaba extract (Plinia peruviana) aiming pharmaceutical and cosmetic applications. METHODS: Nanoemulsions were prepared by high-pressure homogenization method using different concentrations of components (oil, surfactant, and extract) and homogenization pressures, in order to optimize the preparation conditions. Both unloaded and extract-loaded nanoemulsions were characterized according to their size, polydispersity, zeta potential, pH, morphology, and physical stability. Total phenolic and flavonoid contents in free jaboticaba extract and jaboticaba-loaded nanoemulsions were determined spectrophotometrically, while ellagic acid content was determined by high performance liquid chromatography (HPLC) analysis. In vitro antioxidant activity was investigated by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) methods. RESULTS: Colloidal dispersions exhibited a mean particle size around 200 nm, with monodisperse size distribution (PdI <0.3), and spherical shape. Stability studies showed that nanoemulsions were stable over 120 d of storage at room temperature. Jaboticaba nanoemulsions showed significant concentrations of phenolics, flavonoids, and ellagic acid, with encapsulation efficiency values higher than 90%. Antioxidant properties of jaboticaba nanoemulsions were demonstrated by its remarkable ability to scavenge DPPH free radicals and to reduce ferric-tripyridyltriazine complex, which can be attributed to their phenolic and flavonoid contents. CONCLUSIONS: The results suggest that nanoemulsions containing jaboticaba extract can be considered a promising candidate as a new antioxidant agent. PMID- 29139324 TI - Molecular dynamics simulations and novel drug discovery. AB - INTRODUCTION: Molecular dynamics (MD) simulations can provide not only plentiful dynamical structural information on biomacromolecules but also a wealth of energetic information about protein and ligand interactions. Such information is very important to understanding the structure-function relationship of the target and the essence of protein-ligand interactions and to guiding the drug discovery and design process. Thus, MD simulations have been applied widely and successfully in each step of modern drug discovery. Areas covered: In this review, the authors review the applications of MD simulations in novel drug discovery, including the pathogenic mechanisms of amyloidosis diseases, virtual screening and the interaction mechanisms between drugs and targets. Expert opinion: MD simulations have been used widely in investigating the pathogenic mechanisms of diseases caused by protein misfolding, in virtual screening, and in investigating drug resistance mechanisms caused by mutations of the target. These issues are very difficult to solve by experimental methods alone. Thus, in the future, MD simulations will have wider application with the further improvement of computational capacity and the development of better sampling methods and more accurate force fields together with more efficient analysis methods. PMID- 29139325 TI - The Applicability of Resilience Training to the Mitigation of Trauma-Related Mental Illness in Military Personnel [Formula: see text]. AB - BACKGROUND: Ongoing participation by the United States in military operations around the world places military personnel at an increased potential for exposure to trauma, which may directly result in an increased risk for mental health issues. It is important to develop and test new approaches to prevent and mitigate the effects of trauma in military personnel. One such area of research is focused on psychological resilience to prevent the sequelae of trauma. OBJECTIVES: This article examines empirical research of resilience training in military personnel and discusses the potential applicability of such training in this population. DESIGN: In this literature review, four randomized control trials and one retrospective, parallel group study were reviewed. RESULTS: Each intervention had the goal of mitigating behavioral health issues after trauma exposure. The results of the various interventions were wide-ranging from no measurable difference in treatment groups to significant differences in outcomes. CONCLUSIONS: Despite the inconclusive results of our review, we have determined that resilience training for active duty service members to help prevent the deleterious effects of trauma on mental health is a compelling and necessary avenue for further research. PMID- 29139327 TI - Neuropsychology of cardiovascular disease. PMID- 29139326 TI - DNA polymerase eta mutational signatures are found in a variety of different types of cancer. AB - DNA polymerase (pol) eta is a specialized error-prone polymerase with at least two quite different and contrasting cellular roles: to mitigate the genetic consequences of solar UV irradiation, and promote somatic hypermutation in the variable regions of immunoglobulin genes. Misregulation and mistargeting of pol eta can compromise genome integrity. We explored whether the mutational signature of pol eta could be found in datasets of human somatic mutations derived from normal and cancer cells. A substantial excess of single and tandem somatic mutations within known pol eta mutable motifs was noted in skin cancer as well as in many other types of human cancer, suggesting that somatic mutations in A:T bases generated by DNA polymerase eta are a common feature of tumorigenesis. Another peculiarity of pol etamutational signatures, mutations in YCG motifs, led us to speculate that error-prone DNA synthesis opposite methylated CpG dinucleotides by misregulated pol eta in tumors might constitute an additional mechanism of cytosine demethylation in this hypermutable dinucleotide. PMID- 29139328 TI - Repression of oxidative phosphorylation sensitizes leukemia cell lines to cytarabine. AB - OBJECTIVES: Leukemia is a group of bone marrow cancers and drug resistance is one of the challenges in treatment. Caffeic acid phenethyl ester's (CAPE's) anti proliferative and apoptotic properties have been reported in leukemia cell lines. However, CAPE's effect on drug resistance and cellular metabolism is still unknown. Thus, in this study, we aimed to explore CAPE's effect on drug resistance and oxidative phosphorylation (oxphos). METHODS: Leukemia cell lines NB-4, HL-60, and K562 were treated with CAPE. ATP-based cell viability assay was used. For gene expression studies, RNAs were isolated and reverse transcribed. To investigate CAPE's effect on mitochondrial dysfunction in AML cell lines, we examined oxygen consumption rates (OCRs) in our cell lines. RESULTS: We found 5 MUM CAPE sensitized all cell lines to cytarabine. This similar effect was also observed in the Decitabine-resistant K562 cell line. However, no difference was seen in MDR1 expression upon CAPE treatment in all cell lines. OCR significantly decreased upon CAPE treatment in all cell lines, while the expression of key regulatory glycolytic enzymes increased in K562 and NB-4 cell lines. Expression of STAT3 also changed upon CAPE treatment. DISCUSSION: Our results suggested that CAPE alters cellular metabolism by decreasing oxphos and increasing glycolysis in K562 and NB-4 cells. Furthermore, CAPE treatment altered STAT3 expression regarding alterations in oxphos and aerobic glycolysis. CONCLUSION: Our results suggest a new property of CAPE, which is oxphos repression, and a presumptive link between altered metabolism and drug resistance. PMID- 29139329 TI - The first decade of advanced cell therapy clinical trials using perinatal cells (2005-2015). AB - AIM: The first review of advanced cell therapy trials with perinatal cells. MATERIALS & METHODS: We compiled 281 clinical trials of advanced cell therapy with perinatal cells that were registered in 2005-2015. RESULTS: The most common cell source in these trials is cord blood, but the cell type that provides the mechanism of action in the majority of trials is mesenchymal stem/stromal cells. We analyze trends among the 15 parameters we compiled for these trials. CONCLUSION: Advanced cell therapy with perinatal cells is a new field that covers a wide range of diagnoses but where most of the trials are early Phase. Researchers in different countries tend to work with a preferred cell source and cell type. PMID- 29139330 TI - Comparing Care for Dual-Eligibles Across Coverage Models: Empirical Evidence From Oregon. AB - Dual-eligible beneficiaries or "duals" are individuals enrolled in both the Medicare and Medicaid programs. For both Medicare and Medicaid, they may be enrolled in fee-for-service or managed care, creating a mix of possible coverage models. Understanding these different models is essential to improving care for duals. Using All-Payer All-Claims data, we empirically described health service use and quality of care for Oregon duals across five coverage models with different combinations of fee-for-service, managed care, and plan alignment status across Medicare and Medicaid. We found substantial heterogeneity in care across these five coverage models. We also found that duals in plans with aligned financial incentives for Medicare and Medicaid experienced more improvement in their care relative to those with nonaligned Medicare Advantage and Medicaid managed care plans. These results highlight the importance of developing policies that account for the heterogeneity of the dual population and their coverage options. PMID- 29139331 TI - Kinematic modeling of a 7-degree of freedom spatial hybrid manipulator for medical surgery. AB - The prime objective of this work is to deal with the kinematics of spatial hybrid manipulators. In this direction, in 1955, Denavit and Hartenberg proposed a consistent and concise method, known as D-H parameters method, to deal with kinematics of open serial chains. From literature review, it is found that D-H parameter method is widely used to model manipulators consisting of lower pairs. However, the method leads to ambiguities when applied to closed-loop, tree-like and hybrid manipulators. Furthermore, in the dearth of any direct method to model closed-loop, tree-like and hybrid manipulators, revisions of this method have been proposed from time-to-time by different researchers. One such kind of revision using the concept of dummy frames has successfully been proposed and implemented by the authors on spatial hybrid manipulators. In that work, authors have addressed the orientational inconsistency of the D-H parameter method, restricted to body-attached frames only. In the current work, the condition of body-attached frames is relaxed and spatial frame attachment is considered to derive the kinematic model of a 7-degree of freedom spatial hybrid robotic arm, along with the development of closed-loop constraints. The validation of the new kinematic model has been performed with the help of a prototype of this 7-degree of freedom arm, which is being developed at Council of Scientific & Industrial Research-Central Scientific Instruments Organisation Chandigarh to aid the surgeon during a medical surgical task. Furthermore, the developed kinematic model is used to develop the first column of the Jacobian matrix, which helps in providing the estimate of the tip velocity of the 7-degree of freedom manipulator when the first joint velocity is known. PMID- 29139332 TI - The views of adults with Huntington's disease on assisted dying: A qualitative exploration. AB - BACKGROUND: Assisted dying is frequently debated publicly and research often includes the views of health professionals on this issue. However, the views of people with life-limiting conditions, for whom this issue is likely to have a different resonance, are less well represented. AIM: The purpose of this study was to explore the views of people who live with the inevitability of developing Huntington's disease, a genetically transmitted disease which significantly limits life, on assisted dying. DESIGN: Using thematic analysis methodology, individual semi-structured interviews were conducted. SETTING/PARTICIPANTS: Seven participants (five women and two men) who were gene positive for Huntington's disease took part in the study. RESULTS: Four themes were extracted: (1) autonomy and kindness in assisted dying: the importance of moral principles; (2) Huntington's disease threatens life and emphasises issues relating to death; (3) dilemmas in decision-making on assisted dying: "There are no winners" and (4) the absence of explicit discussion on dying and Huntington's disease: "Elephants in the room". CONCLUSIONS: Our findings suggest that talking to patients about assisted death may not cause harm and may even be invited by many patients with Huntington's disease. The perspectives of those who live with Huntington's disease, especially given its extended effects within families, add significant clinical and theoretical insights. PMID- 29139333 TI - The Endurance of Interpersonal Confrontations as a Prejudice Reduction Strategy. AB - Previous work has found that individuals who have been confronted for discrimination demonstrate a reduction in explicit prejudice and use fewer stereotypes immediately after the confrontation. Although confronting prejudice has been touted as a tool for prejudice reduction, it is not known how these effects translate over time and what processes might account for their endurance. Across two studies, the present research finds that individuals used significantly fewer negative stereotypes 7 days after confrontation (Study 1) and engaged in behavioral inhibition to stereotypical cues on a probe task 1 week after confrontation. Moreover, guilt and prolonged rumination mediated these effects for confronted participants (Studies 1 and 2). Across two studies, the present studies reveal the lasting effects of interpersonal confrontations in prejudice reduction and the process by which these effects endure. PMID- 29139334 TI - Teaching evidence-based lifestyle management in family medicine training. PMID- 29139336 TI - Home Health Aides' Perceptions of Quality Care: Goals, Challenges, and Implications for a Rapidly Changing Industry. AB - Home care payment models, quality measures, and care plans are based on physical tasks workers perform, ignoring relational care that supports clients' cognitive, emotional, and social well-being. As states seek to rein in costs and improve the efficiency and quality of care, they will need to consider how to measure and support relational care. In four focus groups ( n = 27) of unionized, agency based New York City home health aides, workers reported aide-client relationships were a cornerstone of high-quality care, and building them required communication, respect, and going the extra mile. Since much of this care was invisible outside the worker-client relationship, aides received little supervisory support and felt excluded from the formal care team. Aligning payment models with quality requires understanding the full scope of services aides provide and a quality work environment that offers support and supervision, engages aides in patient care, and gives them a voice in policy decisions. PMID- 29139335 TI - SHPRH as a new player in ribosomal RNA transcription and its potential role in homeostasis of ribosomal DNA repeats. AB - There are hundreds of copies of rDNA repeats in mammalian chromosomes and the ratio of active, poised, or inactive rDNA is regulated in epigenetic manners. Recent studies demonstrated that a post-DNA replication repair enzyme, SHPRH affects rRNA transcription by recognizing epigenetic markers on rDNA promoters and unveiled potential links between DNA repair and ribosome biogenesis. This study suggests that SHPRH could be a link between mTOR-mediated epigenetic regulations and rRNA transcription, while concomitantly affecting genomic integrity. PMID- 29139337 TI - Do People With Severe Traumatic Brain Injury Benefit From Making Errors? A Randomized Controlled Trial of Error-Based and Errorless Learning. AB - BACKGROUND: Errorless learning (ELL) and error-based learning (EBL) are commonly used approaches to rehabilitation for people with traumatic brain injury (TBI). However, it is unknown whether making errors is beneficial in the learning process to promote skills generalization after severe TBI. OBJECTIVE: To compare the efficacy of ELL and EBL for improving skills generalization, self-awareness, behavioral competency, and psychosocial functioning after severe TBI. METHOD: A total of 54 adults (79% male; mean age = 38.0 years, SD = 13.4) with severe TBI were randomly allocated to ELL or EBL and received 8 * 1.5-hour therapy sessions that involved meal preparation and other goal-directed activities. The primary outcome was total errors on the Cooking Task (near-transfer). Secondary outcome measures included the Zoo Map Test (far-transfer), Awareness Questionnaire, Patient Competency Rating Scale, Sydney Psychosocial Reintegration Scale, and Care and Needs Scale. RESULTS: Controlling for baseline performance and years of education, participants in the EBL group made significantly fewer errors at postintervention (mean = 36.25; 95% CI = 32.5-40.0) than ELL participants (mean = 42.57; 95% CI = 38.8-46.3). EBL participants also demonstrated greater self awareness and behavioral competency at postintervention than ELL participants ( P < .05). There were no significant differences on other secondary outcomes ( P > .05), or at the 6-month follow-up assessment. CONCLUSION: EBL was found to be more effective than ELL for enhancing skills generalization on a task related to training and improving self-awareness and behavioral competency. PMID- 29139338 TI - Freeze-drying of silica nanoparticles: redispersibility toward nanomedicine applications. AB - AIM: To study freeze-drying of silica nanoparticles (SiO2NPs) in order to find suitable conditions to produce lyophilized powders with no aggregation after resuspension and storage. METHODS: SiO2NPs were synthesized using a Stober-based procedure, and characterized by scanning electron microscopy, dynamic light scattering and nitrogen adsorption/desorption isotherms. SiO2NPs hydrodynamic diameters were compared prior and after freeze-drying in the presence/absence of carbohydrate protectants. RESULTS: Glucose was found to be the most suitable protectant against the detrimental effects of lyophilization. The minimum concentration of carbohydrate required to effectively protect SiO2NPs from aggregation during freeze-drying is influenced by the nanoparticle's size and texture. Negligible aggregation was observed during storage. CONCLUSION: Carbohydrates can be used during SiO2NPs freeze-drying process to obtain redispersable solids that maintain original sizes without residual aggregation. PMID- 29139340 TI - Erratum. PMID- 29139339 TI - High prevalence of hypertension and its selected risk factors among adult tribal population in Central India. AB - A community based cross-sectional study was carried out to assess the prevalence of hypertension and associated risk factors like salt intake, 24-h urinary sodium excretion and body mass index (BMI) among tribal population of Mandla District, Central India. A total of 3090 individuals, from 1258 house hold drawn from 33 sampled villages and 12 urban wards were studied for blood pressure measurements and clinical examination, while 414 urine samples were collected for estimation of 24-h sodium excretion. Bivariate and multivariate logistic regression were used to assess the associations of BMI, urinary sodium output and other risk factors with hypertension. Across the sample, 28.2% of males and 23.6% of females had either stage-I or stage-II hypertension. More than 8% of subjects <30 years were hypertensive. The prevalence of hypertension shows a strong association with the increase in BMI and tribals with BMI > 25 were considerably more to have high blood pressure. Salt intake is directly related to the hypertension. The prevalence of hypertension was significantly greater among those whose salt intake was more than 10 g per day. A positive association between urine sodium excretion and blood pressure was observed. The results of the present study show that the tribal population is also affected by the life style diseases at par with the non-tribal population. PMID- 29139342 TI - Healthcare - a rising burden of cost to all. PMID- 29139343 TI - Mycobacterium abscessus, a taxonomic puzzle. PMID- 29139345 TI - Herbicide ingredients change Salmonella enterica sv. Typhimurium and Escherichia coli antibiotic responses. AB - Herbicides are frequently released into both rural and urban environments. Commercial herbicide formulations induce adaptive changes in the way bacteria respond to antibiotics. Salmonella enterica sv. Typhimurium and Escherichia coli were exposed to common co-formulants of formulations, and S. enterica sv. Typhimurium was exposed to active ingredients dicamba, 2,4-D and glyphosate to determine what ingredients of the commercial formulations caused this effect. Co formulants Tween80 and carboxymethyl cellulose induced changes in response, but the pattern of the responses differed from the active ingredients, and effect sizes were smaller. A commercial wetting agent did not affect antibiotic responses. Active ingredients induced changes in antibiotic responses similar to those caused by complete formulations. This occurred at or below recommended application concentrations. Targeted deletion of efflux pump genes largely neutralized the adaptive response in the cases of increased survival in antibiotics, indicating that the biochemistry of induced resistance was the same for formulations and specific ingredients. We found that glyphosate, dicamba, and 2,4-D, as well as co-formulants in commercial herbicides, induced a change in susceptibility of the potentially pathogenic bacteria E. coli and S. enterica to multiple antibiotics. This was measured using the efficiency of plating (EOP), the relative survival of the bacteria when exposed to herbicide and antibiotic, or just antibiotic, compared to survival on permissive media. This work will help to inform the use of non-medicinal chemical agents that induce changes in antibiotic responses. PMID- 29139344 TI - Aeropyrum pernix membrane topology of protein VKOR promotes protein disulfide bond formation in two subcellular compartments. AB - Disulfide bonds confer stability and activity to proteins. Bioinformatic approaches allow predictions of which organisms make protein disulfide bonds and in which subcellular compartments disulfide bond formation takes place. Such an analysis, along with biochemical and protein structural data, suggests that many of the extremophile Crenarachaea make protein disulfide bonds in both the cytoplasm and the cell envelope. We have sought to determine the oxidative folding pathways in the sequenced genomes of the Crenarchaea, by seeking homologues of the enzymes known to be involved in disulfide bond formation in bacteria. Some Crenarchaea have two homologues of the cytoplasmic membrane protein VKOR, a protein required in many bacteria for the oxidation of bacterial DsbAs. We show that the two VKORs of Aeropyrum pernix assume opposite orientations in the cytoplasmic membrane, when expressed in E. coli. One has its active cysteines oriented toward the E. coli periplasm (ApVKORo) and the other toward the cytoplasm (ApVKORi). Furthermore, the ApVKORo promotes disulfide bond formation in the E. coli cell envelope, while the ApVKORi promotes disulfide bond formation in the E. coli cytoplasm via a co-expressed archaeal protein ApPDO. Amongst the VKORs from different archaeal species, the pairs of VKORs in each species are much more closely related to each other than to the VKORs of the other species. The results suggest two independent occurrences of the evolution of the two topologically inverted VKORs in archaea. Our results suggest a mechanistic basis for the formation of disulfide bonds in the cytoplasm of Crenarchaea. PMID- 29139346 TI - In vivo mallard experiments indicate that zanamivir has less potential for environmental influenza A virus resistance development than oseltamivir. AB - Neuraminidase inhibitors are a cornerstone of influenza pandemic preparedness before vaccines can be mass-produced and thus a neuraminidase inhibitor-resistant pandemic is a serious threat to public health. Earlier work has demonstrated the potential for development and persistence of oseltamivir resistance in influenza A viruses exposed to environmentally relevant water concentrations of the drug when infecting mallards, the natural influenza reservoir that serves as the genetic base for human pandemics. As zanamivir is the major second-line neuraminidase inhibitor treatment, this study aimed to assess the potential for development and persistence of zanamivir resistance in an in vivo mallard model; especially important as zanamivir will probably be increasingly used. Our results indicate less potential for development and persistence of resistance due to zanamivir than oseltamivir in an environmental setting. This conclusion is based on: (1) the lower increase in zanamivir IC50 conferred by the mutations caused by zanamivir exposure (2-17-fold); (2) the higher zanamivir water concentration needed to induce resistance (at least 10 ug l-1); (3) the lack of zanamivir resistance persistence without drug pressure; and (4) the multiple resistance related substitutions seen during zanamivir exposure (V116A, A138V, R152K, T157I and D199G) suggesting lack of one straight-forward evolutionary path to resistance. Our study also adds further evidence regarding the stability of the oseltamivir-induced substitution H275Y without drug pressure, and demonstrates the ability of a H275Y-carrying virus to acquire secondary mutations, further boosting oseltamivir resistance when exposed to zanamivir. Similar studies using influenza A viruses of the N2-phylogenetic group of neuraminidases are recommended. PMID- 29139347 TI - Aestuariicoccus marinus gen. nov., sp. nov., isolated from sea-tidal flat sediment. AB - A Gram-stain-negative, strictly aerobic and halotolerant bacterial strain, designated strain NAP41T, was isolated from a sea tidal flat in the Yellow Sea of South Korea. Cells were non-motile cocci showing oxidase- and catalase-positive activities. Growth of strain NAP41T was observed at 15-40 degrees C (optimum, 37 degrees C), at pH 6.5-9.0 (optimum, pH 7.0-7.5) and in the presence of 0.5-12 % (w/v) NaCl (optimum, 2 %). Strain NAP41T contained summed feature 8 (comprising C18 : omega7c/C18 : 1omega6c) and C18 : 0 as the major fatty acids and ubiquinone 10 as the sole isoprenoid quinone. Phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, an unidentified aminolipid and three unidentified lipids were detected as the polar lipids. The G+C content of the genomic DNA was 56.0 mol%. Strain NAP41T was most closely related to Primorskyibacter insulae SSK3-2T, Thalassococcus lentus YCS-24T and Roseivivax lentus DSM 29430T with 96.67, 96.39 and 96.39 % 16S rRNA gene sequence similarities, respectively, and formed a phylogenetic lineage distinct from closely related taxa within the family Rhodobacteraceae with low bootstrap values. On the basis of phenotypic, chemotaxonomic and molecular properties, strain NAP41T represents a novel species of a novel genus of the family Rhodobacteraceae, for whichthe name Aestuariicoccus marinus gen. nov., sp. nov. is proposed. The type strain of the type species is NAP41T (KACC 18431T=JCM 30739T). PMID- 29139348 TI - Regulation of hepatitis C virus replication via threonine phosphorylation of the NS5A protein. AB - The hepatitis C virus non-structural 5A (NS5A) protein is highly phosphorylated and plays roles in both virus genome replication and assembly of infectious virus particles. NS5A comprises three domains separated by low complexity sequences (LCS). Mass spectrometry analysis of NS5A revealed the existence of a singly phosphorylated tryptic peptide corresponding to the end of LCS I and the beginning of domain II that contained a number of potential phosphorylatable residues (serines and threonines). Here we use a mutagenic approach to investigate the potential role of three of these threonine residues. Phosphomimetic mutations of two of these (T242E and T244E) resulted in significant reductions in virus genome replication and the production of infectious virus, suggesting that the phosphorylation of these residues negatively regulated virus RNA synthesis. Mutation of T245 had no effect, however when T245E was combined with the other two phosphomimetic mutations (TripleE) the inhibitory effect on replication was less pronounced. Effects of the mutations on the ratio of basally/hyperphosphorylated NS5A, together with the apparent molecular weight of the basally phosphorylated species were also observed. Lastly, two of the mutations (T245A and TripleE) resulted in a perinuclear restricted localization of NS5A. These data add further complexity to NS5A phosphorylation and suggest that this analysis be extended outwith the serine rich cluster within LCS I. PMID- 29139349 TI - Leucobacter triazinivorans sp. nov., a s-triazine herbicide prometryn-degrading bacterium isolated from sludge. AB - A Gram-stain-positive, rod-shaped, non-motile bacterial strain, designated JW-1T, was isolated from activated sludge collected from the outlet of an aeration tank in a prometryn-manufacturing plant, located in Binzhou City, Shandong province, PR China. Phylogenetic analysis, based on 16S rRNA gene sequences, indicated that strain JW-1T belongs to the genus Leucobacter and its closest neighbours are 'Leucobacter kyeonggiensis' F3-P9 (98.95 % similarity), Leucobacter celer subsp. astrifaciens CBX151T (98.62 %), Leucobacter celer subsp. celer NAL101T (98.53 %), Leucobacter chromiiresistens JG31T (97.86 %) and Leucobacter chironomi DSM 19883T (97.37 %). DNA-DNA hybridization values with the above strains were <55 %. The DNA G+C content of strain JW-1T was 72.6 mol%. The major fatty acids of strain JW 1T were iso-C16 : 0, anteiso-C15 : 0, anteiso-C17 : 0 and iso-C15 : 0. The predominant polar lipids were diphosphatidylglycerol, phosphatidylglycerol and glycolipid. The predominant menaquinone was MK-11. The cell wall amino acids were 2,4-diaminobutyric acid, alanine, glutamic acid, glycine and threonine. Based on the molecular and chemotaxonomic data, as well as the physiological and biochemical characteristics, strain JW-1T is considered to represent a novel species of the genus Leucobacter, for which the name Leucobacter triazinivorans is proposed. The type strain is JW-1T (=DSM 105188T=LMG 30083T). PMID- 29139351 TI - ? PMID- 29139350 TI - Nemorella caseinilytica gen. nov., sp. nov., isolated from forest soil. AB - Two novel strains, J116-2T and J116-1, were isolated from forest soil and were taxonomically characterized by a polyphasic approach. Both strains were yellow coloured, Gram-stain-negative, strictly aerobic, non-motile and rod-shaped bacteria. The strains were non-sporulating, catalase-positive and oxidase negative. Strains J116-2T and J116-1 were able to grow at 20-32 degrees C, pH 6.0-8.5, and 0-0.5 % (w/v) NaCl concentration. Based on 16S rRNA gene sequence analyses, strains J116-2T and J116-1 formed a distinct lineage within the family Chitinophagaceae of the phylum Bacteroidetes and were closely related to genera Taibaiella (89.86-89.30 % sequence similarity), Falvihumibacter (89.20-89.06 %), Filimonas (89.06 %) and Chitinophaga(89.01-88.77 %). The pairwise sequence similarity between strains J116-2T and J116-1 was found to be 99.86 %. Flexirubin type pigments were absent in both strains. The only respiratory quinone was menaquinone-7 (MK-7); the major polar lipid was phosphatidylethanolamine; the predominant polyamine was homospermidine; and the major fatty acids were C15 : 0iso, C15 : 1iso G and C17 : 0iso 3-OH. The genomic DNA G+C content values of strains J116-2T and J116-1 were 51.1 and 50.9 mol%, respectively. On the basis of phenotypic, genotypic and phylogenetic analysis, strain J116-2T represents a novel species of a new genus in the family Chitinophagaceae, for which the name Nemorella caseinilytica gen. nov., sp. nov. is proposed. The type strain of Nemorella caseinilytica is J116-2T (=KEMB 9005-550T=KACC 19168T=NBRC 112827T). PMID- 29139352 TI - [Contraception for young women with focus on long-acting, reversible contraceptives]. AB - Long-acting, reversible contraceptives are about 20 times more effective in terms of contraceptive efficacy than oral hormonal contraceptives, patch or vaginal ring are. Long-acting, reversible contraceptives are not associated with serious adverse events but induce changes in menstrual bleeding pattern in about 75% of the users. The progestogen intrauterine device is effective in the treatment of menor-rhagia and dysmenorrhoea. Increased use of long-acting reversible contraceptives is expected to reduce unplanned pregnancies and legal abortions in all ages. Concomitant use of barrier methods is important to prevent sexually transmitted diseases. PMID- 29139353 TI - [Non-surgical treatment of lumbar radiculopathy]. AB - The objective of this paper is to give insight into evidence-based recommendations on key clinical questions regarding treatment of lumbar disc herniation with radiculopathy. This paper is based on the recently published Danish national clinical guideline for non-operative treatment. Limited evidence is found regarding non-surgical treatment of patients with lumbar radiculopathy. Physiotherapy, in the form of group sessions, seems to have the best level of evidence. However, evidence is still very limited and of poor quality. No evidence has been found with regards to acupuncture or manipulation therapy. PMID- 29139354 TI - [Idiopathic pulmonary fibrosis is an overlooked disease]. AB - Idiopathic pulmonary fibrosis is a chronic, progressive and fatal disease which primarily occurs in male patients over 60 years with a smoking history. Cryobiopsy is a new promising method for obtaining lung tissue for histologic analysis with fewer complications than surgical lung biopsy. Cryobiopsy allows more patients to be diagnosed. Antifibrotic treatment has shown to decrease progression and prolong survival time in both early and later stages of the disease. Early diagnosis and treatment are therefore of great importance to prevent disease progression and reduce mortality. PMID- 29139355 TI - [Post-concussion syndrome is a neuro-cognitive condition]. AB - Post-concussion syndrome (PCS) is often caused by an uncomplicated mild head injury but followed by long-lasting somatic, cognitive and psychiatric symptoms. For many years PCS has been an area of controversy between clinicians. New diagnostic techniques and clinical researches has shed light to some neurobiological aspects behind PCS. In Diagnostic and Statistical Manual of Mental Disorders V PCS is redefined as a neuro-cognitive condition emphasizing the importance of neuropsychological deficits among these patients. New clinical recommendations do not support previous concept of long-term rest, but suggest gradual training back to a daily life. PMID- 29139356 TI - [Persistent trophoblast tissue after salpingectomy]. AB - We present a case of persistent trophoblast tissue (PT) five weeks after salpingectomy for tubal pregnancy. The fallopian tube-sparing method (salpingotomy) has a greater risk of PT than removal of the whole fallopian tube (salpingectomy) has. A 32-year-old woman was treated with salpingectomy on suspicion of a bleeding ectopic pregnancy and was readmitted due to PT. There is no evidence for measuring the human chorionic gonadotropin (hCG) level as routine follow-up after salpingectomy, but it is important to be aware of the risk of PT and if in doubt measure the levels of hCG. PMID- 29139357 TI - The Third-Party Payers/Withholders: They Have a License to Steal and They Use It. PMID- 29139358 TI - Management of Cutaneous Cancers in Patients Undergoing Organ Transplantation-Part I: Current Status: Reactive Approach. PMID- 29139359 TI - Oral Lichen Planus: A Cross-Sectional/Descriptive Study of 33 Patients. AB - Oral lichen planus (OLP), a well-known entity, is often neglected; however, its assessment is considered essential for evolving future strategies for treatment. Thirty-three patients with OLP from 200 consecutive patients with oral mucosal lesions were studied according to demography. Tobacco chewing, smoking, and alcohol intake were recorded. Examination of the oral cavity, using a head light and tongue depressor, was undertaken to define the morphology of the lesion(s). Colored photographs were an essential part of the process. OLP, a frequently encountered manifestation of oral mucosal lesions, was responsible for 16.50% of the total number of lesions. There was a preponderance of lesions in women aged 40 to 59 years, in contrast to men in the same age group. The duration of the lesions was variable, and tobacco chewing/smoking and amalgam fillings might have exacerbated them. Morphology ranged from a reticular, erythematous pattern to an erosive one. The diagnosis is largely clinical, but it can be confirmed by histopathology. PMID- 29139360 TI - Vitamin D Deficiency in an Alopecia Referral Clinic During a 3-Month Period: The Need to Pursue Systemic Screening. AB - Alopecia is typically viewed as a localized process, and comorbidities are not usually analyzed. The authors examine the prevalence of vitamin D deficiency among patients attending an alopecia clinic during a 3-month period. The data showed that 79% of patients had vitamin D deficiency, and the average value of low vitamin D was 19.1 mg/mL in patients. Vitamin D levels have not been examined extensively in skin disorders, and it is not clear whether vitamin D levels are correlative or causative in alopecia. The co-occurrence of both findings at such a dramatic level suggests the need for evaluation of this laboratory value in the alopecia population. PMID- 29139361 TI - Angiokeratoma of the Glans Penis. AB - Angiokeratomas are benign vascular lesions characterized by ectatic blood vessels in the papillary dermis with overlying acanthosis and hyperkeratosis, often occurring as idiopathic scrotal tumor and rarely as penile lesions. Twelve men, including our case of a 58-year-old white man, have been reported with angiokeratomas of the glans penis. The lesions typically present as asymptomatic dome-shaped papules ranging in size from 0.5 to 5 mm and present as red, purple, blue, or black lesions along the penile coronal rim. Histopathologic examination of the lesions reveals dilated, thin-walled vascular structures in the upper portion of the dermis with overlying acanthosis and/or hyperkeratosis. Such angiokeratomas may have a multifactorial etiology with elevations in local venous pressure, degeneration of elastic tissue, and/or capillary injury. Biopsy would exclude a melanocytic lesion, particularly melanoma. Laser surgery is an option for patients presenting with multiple lesions or lesions that coalesce to form a plaque. PMID- 29139362 TI - Efficacy and Tolerability of a Twice-Daily, Three-Step Men's Skincare Regimen in Improving Overall Skin Quality and Reducing Shave-Related Irritation. AB - More men are beginning to take advantage of opportunities to improve the health and appearance of their skin; however, the effectiveness of men's skincare regimens has not been well studied. The authors investigated the efficacy and tolerance of a twice-daily, three-step men's skincare regimen in improving skin appearance and reducing shave-related issues. Twenty-nine men who used a wet shaving method completed a specific, three-step, twice-daily facial regimen-a Shave Cleanser, a Post-Shave Treatment, and Day Protection-in place of their usual routine for 4 weeks. This skincare regimen produced significant improvements in tactile smoothness, clarity, radiance, and pore size at weeks 2 and 4 and in fine lines, razor burn, and photodamage at week 4 (P<.05). Significant improvements were seen in the appearance of nicks/cuts and folliculitis of the face and neck after weeks 2 and 4 (P<.05). Mean change in the moisture content of the stratum corneum was significant at week 4 (P<.05). The majority of men provided positive self-assessments and indicated an interest in continuing this regimen. PMID- 29139363 TI - Cryosurgery for Facial and Scalp Lesions of Basal Cell Carcinoma: A Study in 29 Elderly Patients. AB - Basal cell carcinoma (BCC) is one of the pre-eminent tumors of the epidermis, recognized by explicit clinical-pathologic characteristics. It is relatively uncommon in South Asia including India and is amenable to a variety of modalities, including cryosurgery. The outcome of cryosurgery was evaluated in 18 men and 11 women, aged 58 to 83 years, who were treated with two freeze-thaw cycles of liquid nitrogen under local anesthesia, after requisite preparations. Of the 29 patients, 27 had complete clearance of the lesions in the course of 3 years of follow-up, while only 2 had a recurrence, one at 17 months and one at 23 months. Recurrences were treated with a repeat cryosurgery, with a cure rate of 93%. Cryosurgery is a simple, inexpensive, and dermatologist-friendly office procedure with a high cure rates for well-defined facial BCC lesions. PMID- 29139364 TI - Advanced Management of Severe Keloids. AB - Keloids negatively impact the health and quality of life of many affected dermatologic patients. Treating keloids is often difficult, and suboptimal responses are frequent. Fortunately, there are many treatment options available to the clinician that may lead to improved clinical outcomes. We present a review of currently available therapeutic options. Intralesional steroid injection remains the first-line treatment for keloids. Imiquimod, direct interferon therapy, or intralesional 5-flurouracil may alleviate the need for excessive corticosteroid therapy. Radiation and laser therapy are emerging therapeutic options that have demonstrated efficacy in reviewed studies. Given the unsatisfactory outcomes associated with pressure dressings, vitamin E, ablative laser, and surgical excision, these options should be avoided in keloid management. Further research is needed to evaluate the efficacy and recurrence associated with the reviewed therapeutics. PMID- 29139366 TI - Compromising Patient Care: Gross Payment Disparities in Dermatopathology-Part I. PMID- 29139367 TI - Crisaborole 2% Ointment (EucrisaTM). PMID- 29139368 TI - Herpes Zoster, Immunosuppression, and Vaccination: Far from a Blistering Pace. PMID- 29139369 TI - Oral Mucocoele: The Magic of Sclerotherapy. PMID- 29139370 TI - Perianal Ulcer in an Asian Man. AB - A 79-year-old Chinese man presented with a 2-month history of pruritic, tender ulceration covering his perianal region. He was initially treated with oral amoxicillin/clavulanic acid and vancyclovir, with no improvement. His history included hypertension. On physical examination, there was a 1.5-cm solitary, pink shallow ulcer with a tender erythematous base on the right side of the buttock cleft (Figure 1). PMID- 29139371 TI - Hailey-Hailey Disease Presenting as Lichenoid Plaques on the Thigh. AB - A 40-year-old woman presented with multiple itchy violaceous papules and plaques on the medial aspects of both thighs. This was accompanied by a burning sensation on friction and increased itching that interfered with her daily activities, particularly in the summer. The family history was noncontributory. Cutaneous examination showed multiple flat-topped hyperkeratotic violaceous papules and plaques, appearing in linear fashion on the medial aspects of the thighs bilaterally (Figure 1). Histopathologic examination showed acanthosis, widespread suprabasal acantholysis resembling a "dilapidated brick wall," without any evidence of dyskeratosis. There was a mild dermal perivascular infiltrate (Figure 2). On the basis of the clinical and histologic findings, she was diagnosed as having localized Hailey-Hailey disease. She was treated conservatively with topical corticosteroids and antimicrobials. She was also advised to lose weight, to avoid friction, and to wear loose-fitting cotton garments. There was marked symptomatic relief, and the lesion showed mild improvement over the next 2 months. PMID- 29139372 TI - Two Cases of Lepromatous Leprosy from Exposure to Armadillos in Florida. AB - The first patient was a 41-year-old white man who was referred to the dermatology clinic with a 2-year history of numerous erythematous, hypoesthetic, poorly demarcated papules and plaques present on the trunk, buttocks, and bilateral upper and lower extremities (Figures 1 and 2). The lesions had initially begun as localized erythematous plaques on the right flank, and were diagnosed and treated as cellulitis and allergic contact dermatitis by primary care on separate occasions, with no resolution and continued gradual but persistent spread. PMID- 29139373 TI - Primary Malignant Melanoma of the Bladder. AB - A 81-year-old man was admitted to our university for a second opinion after diagnosis of bladder melanoma in December 2014. His medical history included arterial hypertension, hypothyroidism, peripheral arterial disease treated with a bypass, and corneal transplantation. His medical history was negative for malignant melanoma. He experienced gross hematuria in the absence of any other clinical manifestations, and urine cytology identified atypical cells. The patient underwent transurethral resection of the bladder with diagnosis of melanoma. PMID- 29139374 TI - A Helpful Addition to the Flap Literature. PMID- 29139375 TI - Kitty Litter Dermatitis from-Bromo-2-Nitropropane-1,3-Diol. AB - 70-year-old white man presented with a 6-week history of an acute pruritic eruption in the axillary vaults, inguinal folds, and central lumbar area. Due to the severity of the pruritus, the patient was evaluated in the emergency department. He was treated with intramuscular triamcinolone, oral fluconazole, clobetasol cream, and miconazole powder, which provided only minimal relief. The patient had presented with brightly erythematous patches in the axillary vaults and inguinal folds with numerous erythematous, scaly, coalescing papules and plaques agminated on the lumbar region (Figure). Due to persistence, despite topical corticosteroids, an allergic contact dermatitis was suspected so patch testing using the T.R.U.E. Test (SMARTPractice Denmark ApS, Hillerod, Denmark) epicutaneous system was conducted. Results were positive for 5-chloro-2-methyl-4 isothazolinone (panel 2.1, #17), budesonide (panel 3.1, #30), and 2-bromo-2 nitropropane-1,3-diol, also known as bronopol (panel 3.1, #36). The patient's topical medications were adjusted based on these results, and he was advised to avoid any products containing these contactants. PMID- 29139376 TI - The longitudinal effects of peritonitis on peritoneal membrane function?. AB - BACKGROUND: The longitudinal effects of peritoneal dialysis (PD) peritonitis on small solute clearance and ultrafiltration are controversial. MATERIALS AND METHODS: We identified 27 patients with PD peritonitis over a 4-year period at a tertiary hospital. Adequacy tests at an "early" (1 - 3 months), "intermediate" (6 +/- 2 months), and a "late" (12 +/- 2 months) time period after the episode were compared with a pre-peritonitis baseline. The effect of time on serum albumin, weekly creatinine clearance, Kt/V, and net fluid volume removal was assessed. RESULTS: At 12 months, 16/27 (59.3%) patients were no longer on PD. Ten were transferred to hemodialysis, predominantly due to peritonitis (60%). Five patients died, and 1 received a renal allograft. Total daily fluid volume removal significantly decreased over time with an aggregated mean reduction of 523 mL/day between the baseline and 12-month test (1,624 +/- 139 mL vs. 1,101 +/- 160 mL; p = 0.02). This was due to an equivalent loss of both ultrafiltration and residual urine output, although the separate decline in these individual parameters was not statistically significant. There was no significant change in Kt/V, creatinine clearance, or serum albumin indicating preserved solute transport in those patients with sustained technique survival post peritonitis. CONCLUSION: Peritonitis is a common cause for transfer to hemodialysis. Fluid volume removal is the most significantly affected parameter at 12 months post peritonitis, driven by the combination of both ultrafiltration reduction and loss of residual diuresis. Clinicians should be aware that peritonitis identifies patients at high risk for technique failure. These findings should prompt clinicians to closely surveil volume status and consider backup dialytic strategies as early as 12 months post peritonitis.?. PMID- 29139378 TI - [The right measurement for a better guidance]. PMID- 29139379 TI - [About the technique of muscle biopsy (IV). The advent of histochemistry and cytoenzymology in the analysis of muscle biopsies. A short and personal historical overview]. PMID- 29139377 TI - Laboratory colonization and mass rearing of phlebotomine sand flies (Diptera, Psychodidae). AB - Laboratory colonies of phlebotomine sand flies are necessary for experimental study of their biology, behaviour and mutual relations with disease agents and for testing new methods of vector control. They are indispensable in genetic studies and controlled observations on the physiology and behaviour of sand flies, neglected subjects of high priority. Colonies are of particular value for screening insecticides. Colonized sand flies are used as live vector models in a diverse array of research projects, including xenodiagnosis, that are directed toward control of leishmaniasis and other sand fly-associated diseases. Historically, labour-intensive maintenance and low productivity have limited their usefulness for research, especially for species that do not adapt well to laboratory conditions. However, with growing interest in leishmaniasis research, rearing techniques have been developed and refined, and sand fly colonies have become more common, enabling many significant breakthroughs. Today, there are at least 90 colonies representing 21 distinct phlebotomine sand fly species in 35 laboratories in 18 countries worldwide. The materials and methods used by various sand fly workers differ, dictated by the availability of resources, cost or manpower constraints rather than choice. This paper is not intended as a comprehensive review but rather a discussion of methods and techniques most commonly used by researchers to initiate, establish and maintain sand fly colonies, with emphasis on the methods proven to be most effective for the species the authors have colonized. Topics discussed include collecting sand flies for colony stock, colony initiation, maintenance and mass-rearing procedures, and control of sand fly pathogens in colonies. PMID- 29139380 TI - [Tracheotomy and myopathy: history of an encounter]. PMID- 29139381 TI - [Titin-related muscle disorders: an expanding spectrum]. AB - Titin-related diseases of the skeletal and cardiac muscles open a new, fruitful chapter of myology. Confined for a long time to a limited number of clinical entities, the phenotypic spectrum of titinopthies is nowadays expanding rapidly together with the discovery of many pathogenic mutations of the TTN gene. Like for many genes of large size, the fine tuning and use of high-throughput sequencing (NGS) constitutes a little revolution in the field. This powerful tool allows, although with real technical hurdles, the establishment of the definite diagnosis of titinopathy. A better knowledge of the natural history of each subtype of titinopathy enables as of now an optimized management of patients, notably when a cardiac or respiratory risk factor is identified. Research efforts in the titin-related conditions are gradually getting organized. Interactions between clinicians and geneticists are an absolute necessity. The still fragmentary knowledge of the pathogenesis of each titinopathy prevents to date to figure out any curative therapy in the very near future. PMID- 29139382 TI - [Episodes of recurrent pneumothorax in a patient with collagen VI-related congenital muscular dystrophy]. PMID- 29139383 TI - [Towards a national standardisation of NGS studies in the diagnosis of myopathies]. PMID- 29139384 TI - [Seronegative myasthenia gravis]. PMID- 29139385 TI - [The potential of artificial intelligence in myology: a viewpoint from a non robot]. PMID- 29139386 TI - [Diagnosis of inflammatory myopathies at the CHU Bordeaux from 2012 to 2014: implementation of novel classifications]. PMID- 29139387 TI - [Charcot Marie Tooth disease: principles of rehabilitation, physiotherapy and occupational therapy]. PMID- 29139388 TI - [GNE myopathy: proven failure of sialic acid supplementation... what's next?] PMID- 29139390 TI - ? PMID- 29139389 TI - [NGS to the rescue of an atypical case of alphadystroglycanopathy with a LGMD phenotype]. PMID- 29139391 TI - [Age-related cognitive decline in adults with DM1: a 9-year longitudinal study]. PMID- 29139392 TI - [Myonuclear domain and microtubule proteome during skeletal muscle maturation]. AB - In the normal course of muscle fiber development, myonuclei actively position and adapt a precise localization in mature fibers, shaping MyoNuclear Domains (MNDs). Myonuclei positioning in fibers appears to be essential for muscle function as defects in MNDs settings are always associated with dysfunction (i.e., centronuclear myopathy, sarcopenia). Previous studies have shown that myonuclei positioning in fibers is reversible, suggesting that in pathologies presenting MNDs impairment, myonuclei could be re-addressed to the "correct" position in fibers and this could benefit to muscle function. Cytoskeleton networks, and particularly microtubules, have been implicated in early nuclei localization in myotubes. As the microtubule network is completely redesigned during muscle maturation, we hypothesized that "microtubules associated proteomes" would change between immature and mature fibers and contribute to a microtubule-dependent process resulting in MNDs setting and maintenance in mature fibers. We performed an in vitro biochemical approach to isolate microtubules partners in immature (myotubes) and mature myofibers. Using mass-spectrometry identification, we selected 244 candidates, differentially associated/expressed with microtubules during myofiber maturation and potentially controlling MNDs settings. We are currently conducting a siRNA screen approach on these candidates to decipher their respective implication in early and late phases of MNDs establishment, using an unbiased assay developed by our team allowing statistical analysis of MNDs regarding myonuclei content. This approach will lead to the identification of new pathways related to nuclear positioning and MNDs setting in normal condition and in myopathies associated to MNDs impairment such as CNMs. PMID- 29139393 TI - ? PMID- 29139394 TI - Thickness-dependent surface plasmon resonance of ITO nanoparticles for ITO/In-Sn bilayer structure. AB - Tuning the localized surface plasmon resonance (LSPR) in doped semiconductor nanoparticles (NPs), which represents an important characteristic in LSPR sensor applications, still remains a challenge. Here, indium tin oxide/indium tin alloy (ITO/In-Sn) bilayer films were deposited by electron beam evaporation and the properties, such as the LSPR and surface morphology, were investigated by UV-VIS NIR double beam spectrophotometer and atomic force microscopy (AFM), respectively. By simply engineering the thickness of ITO/In-Sn NPs without any microstructure fabrications, the LSPR wavelength of ITO NPs can be tuned by a large amount from 858 to 1758 nm. AFM images show that the strong LSPR of ITO NPs is closely related to the enhanced coupling between ITO and In-Sn NPs. Blue shifts of ITO LSPR from 1256 to 1104 nm are also observed in the as-annealed samples due to the higher free carrier concentration. Meanwhile, we also demonstrated that the ITO LSPR in ITO/In-Sn NPs structures has good sensitivity to the surrounding media and stability after 30 d exposure in air, enabling its application prospects in many biosensing devices. PMID- 29139395 TI - Three-dimensional architecture hybrid perovskite solar cells using CdS nanorod arrays as an electron transport layer. AB - Three-dimensional (3D) architecture perovskite solar cells (PSCs) using CdS nanorod (NR) arrays as an electron transport layer were designed and prepared layer-by-layer via a physical-chemical vapor deposition (P-CVD) process. The CdS NRs not only provided a scaffold to the perovskite film, but also increased the interfacial contact between the perovskite film and electron transport layer. As an optimized result, a high power conversion efficiency of 12.46% with a short circuit current density of 19.88 mA cm-2, an open-circuit voltage of 1.01 V and a fill factor of 62.06% was obtained after 12 h growth of CdS NRs. It was four times the efficiency of contrast planar structure with a similar thickness. The P CVD method assisted in achieving flat and voidless CH3NH3PbI3-x Cl x perovskite film and binding the CdS NRs and perovskite film together. The different density of CdS NRs had obvious effects on light transmittance of 350-550 nm, the interfacial area and the difficulty of combining layers. Moreover, the efficient 1D transport paths for electrons and multiple absorption of light, which are generated in 3D architecture, were beneficial to realize a decent power conversion efficiency. PMID- 29139396 TI - Folic acid modified Pluronic F127 coating Ag2S quantum dot for photoacoustic imaging of tumor cell-targeting. AB - In this study, an oil-soluble Ag2S quantum dot (QD) was synthesized through thermal decomposition using the single-source precursor method, and Pluronic F127 (PF127), a triblock copolymer functionalized with folic acid (FA), was deposited on the surface of the QD, then a water-soluble PF127-FA@Ag2S nanoprobe with targeting ability was fabricated. The as-prepared PF127-FA@Ag2S exhibited spheroidal morphology and high dispersibility, with average diameters of 115 +/- 20.7 nm (as observed by transmission electron microscopy). No obvious toxicity of the PF127-FA@Ag2S nanoprobe was found in standard 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide assay and colony-formation assay, indicating good biocompatibility and safety. The resulting PF127-FA@Ag2S exhibited excellent stability between 4 degrees C-40 degrees C. Additionally, the capacity of the tumor cell-targeting high contrast enhanced photoacoustic imaging of PF127 FA@Ag2S was verified in comparison with A547 and HeLa cells. In other words, the excellent properties of PF127-FA@Ag2S show great potential in further research for targeting and photoacoustic imaging. PMID- 29139397 TI - Medical Journalism. PMID- 29139398 TI - Planning for the Control of Venereal Diseases in Tamil Nadu for the Next Ten Years. PMID- 29139399 TI - Epiloia (Case repors withreview of literature). PMID- 29139400 TI - Absorption and Excretion of Dapsone in Leprosy Patients. PMID- 29139401 TI - What is yor diagnosis? PMID- 29139402 TI - Multiple Cutaneous Horns with Absorption of Terminal Phalanges (A case report). PMID- 29139403 TI - Pemphigus Vulgaris Presenting As Dermatitis Herpetiformis. PMID- 29139404 TI - Subcutaneous Sporotrichosis in India. PMID- 29139405 TI - Perioral Dermatitis (a preliminary report). PMID- 29139406 TI - Marital Status and Venereal Disease. PMID- 29139407 TI - Association News and Notes. PMID- 29139408 TI - Chickenpox Causing Digital or Peripheral Gangrene (A case report). PMID- 29139409 TI - Tuberculosis of the Skin. PMID- 29139410 TI - Urinary Porphyrins - A Quantitative Assay in 25 Normal Persons by Spectrophotometric Method. PMID- 29139411 TI - Exfoliative Dermatitis-Dermatophytid (Case reports). PMID- 29139412 TI - Pityriasis Rotunda: (Discoid Ichthyosis). PMID- 29139413 TI - ABO Blood Groups and Sero-positivity For Syphilis in Blood Donors and Antenatal Cases. PMID- 29139414 TI - Leiomyoma Cutis (A clinico-pathological review with a case report). PMID- 29139415 TI - Pilomatrixoma (calcifying Epithelioma of Malherbe and Chenantais) (A case report). PMID- 29139416 TI - Ichtryosis Vulgaris Associated with Cataract and Nephrotic Syndrome. PMID- 29139418 TI - What is your diagnosis? PMID- 29139417 TI - Eosinophilic Granuloma of the Temporal Bone with Cutaneous Manifestations (Case report). PMID- 29139419 TI - Darier's Disease (Clinical Study of 8 cases). PMID- 29139420 TI - An Hypothesis Explaining Some Aspects of the Pathogenesis of Nerve Involment in Leprosy. PMID- 29139422 TI - Transgro?v Medium for Trichomonas Vaginalis (A preliminary study). PMID- 29139423 TI - Simultaneous Occurrence of Herpes Zoster and Varicella in a Patient of Tuderculous Lymphadenitis. PMID- 29139426 TI - Antiurticarial Studies with an Indigenous Drug. PMID- 29139425 TI - Rifampicin (rimactane) in Acute Gonorrhoea. PMID- 29139424 TI - Single Injection Treatment of Streptococcal Pyoderma with Benzathine Penicillin. PMID- 29139427 TI - What is your diagnosis? PMID- 29139428 TI - Clinical Trial of Jadit in Superficial Mycoses. PMID- 29139429 TI - Glomus Tumours with Disuse Atrophy. PMID- 29139430 TI - Beclomethasone Dipropionate - A New Topical Corticosteroid. PMID- 29139431 TI - Tuberculids - A Concept. PMID- 29139432 TI - An Appraisal of Some (STS) Serological Surveys (India). PMID- 29139433 TI - Letters to the Editor. PMID- 29139435 TI - Editorial. PMID- 29139436 TI - Histopathological Changes in Tracheal Mucosa Following Total Laryngectomy. AB - The aim of this study was to determine the long term histopathologic changes in tracheal mucosa after a total laryngectomy , and to find out the relationship between the progression of histopathologic changes in tracheal mucosa and the duration of breathing through the tracheostomy. Tracheal mucosal biopsies were taken from a total of 35 patients, of both sexes, who underwent a total laryngectomy for laryngeal carcinoma at least one year prior. Histologic specimens of tracheal mucosa were stained with hematoxylin and eosin and examined under light microscopy. Almost all of the patients demonstrated histopathologic changes or abnormalities. Based on the results, histological findings were grouped into seven categories: normal respiratory epithelium, mild, moderate and advanced basal cell hyperplasia, squamous metaplasia, and slight and moderate and dysplasia. The time elapsed since surgery was calculated for each histopathological change separately. In laryngeal carcinoma patients, after a total laryngectomy histopathologic changes occur in tracheal mucosa. The mildest histopathological changes are found in the patients who had a longer period between the operation and the examination. PMID- 29139437 TI - Epidemiology of Scabies. PMID- 29139438 TI - A Clinical Study of 85 Case of Pemphigus. PMID- 29139439 TI - Bed-sores in Prolonged Bed-rest. PMID- 29139440 TI - Maduromycosis of the Gluteal Region (A case report). PMID- 29139441 TI - Urticaria Pigmentosa and Diarrhoea (A case report). PMID- 29139443 TI - What is your diagnosis? PMID- 29139442 TI - Birth Order and Venereal Diseases in the Males. PMID- 29139444 TI - A Clinicopathological Study of Pemphigus. PMID- 29139445 TI - Syringoma-A Case Report with Review of Literature. PMID- 29139446 TI - Immunological Aspects of Herpes Virus Varicella. PMID- 29139447 TI - Clinical Study of Mycetoma. PMID- 29139449 TI - A Case Report of Generalised Morphea. PMID- 29139450 TI - Oil Dermatitis. PMID- 29139451 TI - Chromoblastomycosis. PMID- 29139452 TI - Dermatophytoses in Visakhapatnam. PMID- 29139453 TI - Familial Discoid Lupus Erythematosus. AB - A familial occurrence of discoid lupus erythematosus is reported in a brother and sister. PMID- 29139454 TI - Mycosis Fungoides - Tumour D'emblee. PMID- 29139455 TI - Topical Retinoic Acid in the Treatment of Acne Vulgaris. PMID- 29139456 TI - Mycosis Fungoides. PMID- 29139457 TI - What is your diagnosis? PMID- 29139458 TI - Evaluation of the Fluorescent Treponemal Antibody CSF Test (FTA - CSF Test). PMID- 29139459 TI - Clinical Trial of Framygen Gream E4 Various Pyodermas. PMID- 29139460 TI - Serum Proteins in Folliculitis Et Atrophicans. PMID- 29139461 TI - Pyoderma Gangrenosltm in Association with Ulcerative Colitis. PMID- 29139463 TI - Mycetoma Caused by Madurella Grisea in India. PMID- 29139464 TI - Nevus Sebaceous of Jadassohn (A case report with review of literature). PMID- 29139465 TI - Venereal Diseases Among Bengalis and Pakistanis - an Apraisal on Further Social Factors. PMID- 29139466 TI - Systemic Mastocytosis (A case report). PMID- 29139467 TI - Cutaneous Rhinosporidiosis. PMID- 29139468 TI - Epidermodysplasia Verruciformis (A case report). PMID- 29139469 TI - Scabies - A Retrospect. PMID- 29139470 TI - Acrodermatitis Enteropathica. PMID- 29139471 TI - Folliculitis Cruris Pustulosa Et Atrophicans. PMID- 29139472 TI - What is your diagnosis? PMID- 29139473 TI - Adrenal Cortical Functions in Pemphigus. PMID- 29139474 TI - Editorial. PMID- 29139475 TI - Intestinal epithelial cell-specific RARalpha depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system. AB - Retinoic acid (RA), a dietary vitamin A metabolite, is crucial in maintaining intestinal homeostasis. RA acts on intestinal leukocytes to modulate their lineage commitment and function. Although the role of RA has been characterized in immune cells, whether intestinal epithelial cells (IECs) rely on RA signaling to exert their immune-regulatory function has not been examined. Here we demonstrate that lack of RA receptor alpha (RARalpha) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack of RARalpha resulted in increased KLF4+ goblet cell precursors in the distal bowel, whereas RA treatment inhibited klf4 expression and goblet cell differentiation in zebrafish. These changes in secretory cells are associated with increased Reg3g, reduced luminal bacterial detection, and an underdeveloped intestinal immune system, as evidenced by an almost complete absence of lymphoid follicles and gut resident mononuclear phagocytes. This underdeveloped intestinal immune system shows a decreased ability to clear infection with Citrobacter rodentium. Collectively, our findings indicate that epithelial cell-intrinsic RARalpha signaling is critical to the global development of the intestinal immune system. PMID- 29139476 TI - Detection of HIV-1-specific gastrointestinal tissue resident CD8+ T-cells in chronic infection. AB - Tissue-resident memory (TRM) CD8+ T-cells are non-recirculating, long-lived cells housed in tissues that can confer protection against mucosal pathogens. Human immunodeficiency virus-1 (HIV-1) is a mucosal pathogen and the gastrointestinal tract is an important site of viral pathogenesis and transmission. Thus, CD8+ TRM cells may be an important effector subset for controlling HIV-1 in mucosal tissues. This study sought to determine the abundance, phenotype, and functionality of CD8+ TRM cells in the context of chronic HIV-1 infection. We found that the majority of rectosigmoid CD8+ T-cells were CD69+CD103+S1PR1- and T betLowEomesoderminNeg, indicative of a tissue-residency phenotype similar to that described in murine models. HIV-1-specific CD8+ TRM responses appeared strongest in individuals naturally controlling HIV-1 infection. Two CD8+ TRM subsets, distinguished by CD103 expression intensity, were identified. CD103Low CD8+ TRM primarily displayed a transitional memory phenotype and contained HIV-1-specific cells and cells expressing high levels of Eomesodermin, whereas CD103High CD8+ TRM primarily displayed an effector memory phenotype and were EomesoderminNeg. These findings suggest a large fraction of CD8+ T-cells housed in the human rectosigmoid mucosa are tissue-resident and that TRM contribute to the anti-HIV-1 immune response. Further exploration of CD8+ TRM will inform development of anti HIV-1 immune-based therapies and vaccines targeted to the mucosa. PMID- 29139477 TI - A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation. AB - Flavones represent a class of polyphenols that are found in many plant-derived food sources. Herein, we provide evidence that the anti-inflammatory and antiproliferative effect of the flavone apigenin relies on the regulation of the gut microbiota by the NOD-like receptor family pyrin domain containing 6 (Nlrp6). When challenged by dextran sulfate sodium (DSS) in drinking water, mice were protected against colitis upon cohousing with apigenin-treated animals. In contrast, the protective effect was lost in the absence of Nlrp6. Sequencing of the 16S ribosomal RNA gene revealed a shift in the composition of the gut microbiota in apigenin-treated mice that was not observed in the absence of Nlrp6. Equally important, we find that the antiproliferative effect of apigenin was dominantly transmitted after cohousing, while being compromised in Nlrp6 deficient mice. In contrast, the symptoms of colitis were alleviated upon apigenin administration even in the absence of either caspase-1/11 or Asc. Collectively, these data indicate that apigenin modulated an inflammasome independent mechanism by which Nlrp6 reprograms the gut microbiota for protecting mice against colitis. Our study highlights a modulation of the Nlrp6 signaling pathway by a prominent constituent of the human diet that may point toward improved ways to treat inflammatory bowel diseases. PMID- 29139479 TI - IBD: Inflammatory biomarkers improve management of Crohn's disease. PMID- 29139478 TI - Trigger-happy resident memory CD4+ T cells inhabit the human lungs. AB - Resident memory T cells (TRM) reside in the lung epithelium and mediate protective immunity against respiratory pathogens. Although lung CD8+ TRM have been extensively characterized, the properties of CD4+ TRM remain unclear. Here we determined the transcriptional signature of CD4+ TRM, identified by the expression of CD103, retrieved from human lung resection material. Various tissue homing molecules were specifically upregulated on CD4+ TRM, whereas expression of tissue egress and lymph node homing molecules were low. CD103+ TRM expressed low levels of T-bet, only a small portion expressed Eomesodermin (Eomes), and although the mRNA levels for Hobit were increased, protein expression was absent. On the other hand, the CD103+ TRM showed a Notch signature. CD4+CD103+ TRM constitutively expressed high transcript levels of numerous cytotoxic mediators that was functionally reflected by a fast recall response, magnitude of cytokine production, and a high degree of polyfunctionality. Interestingly, the superior cytokine production appears to be because of an accessible interferon-gamma (IFNgamma) locus and was partially because of rapid translation of preformed mRNA. Our studies provide a molecular understanding of the maintenance and potential function of CD4+ TRM in the human lung. Understanding the specific properties of CD4+ TRM is required to rationally improve vaccine design. PMID- 29139481 TI - Pancreatic cancer: Tailored therapy for pancreatic tumour subtype. PMID- 29139480 TI - Position paper: The potential role of optical biopsy in the study and diagnosis of environmental enteric dysfunction. AB - Environmental enteric dysfunction (EED) is a disease of the small intestine affecting children and adults in low and middle income countries. Arising as a consequence of repeated infections, gut inflammation results in impaired intestinal absorptive and barrier function, leading to poor nutrient uptake and ultimately to stunting and other developmental limitations. Progress towards new biomarkers and interventions for EED is hampered by the practical and ethical difficulties of cross-validation with the gold standard of biopsy and histology. Optical biopsy techniques - which can provide minimally invasive or noninvasive alternatives to biopsy - could offer other routes to validation and could potentially be used as point-of-care tests among the general population. This Consensus Statement identifies and reviews the most promising candidate optical biopsy technologies for applications in EED, critically assesses them against criteria identified for successful deployment in developing world settings, and proposes further lines of enquiry. Importantly, many of the techniques discussed could also be adapted to monitor the impaired intestinal barrier in other settings such as IBD, autoimmune enteropathies, coeliac disease, graft-versus host disease, small intestinal transplantation or critical care. PMID- 29139483 TI - Surface-enhanced Raman spectroscopy: bottlenecks and future directions. AB - In this feature article, we discuss in detail developmental bottleneck issues in Raman spectroscopy in its early stages and surface-enhanced Raman spectroscopy (SERS) in the past four decades. We divide SERS research into two different directions with different targets. Fundamental research is extending the limits of SERS to single-molecule, sub-nanometer resolution and femtosecond processes. In contrast, practical research is expanding the range of applications with the aim of providing versatile analytical tools for surface, materials, life, environmental, forensic and food sciences and also commercial instruments for use in daily life. In the second direction there have continually been many complex bottlenecks to be overcome. We attempt to enumerate the key issues in detail and also describe the achievements made to overcome the bottlenecks. In the last, but not least important part, we discuss the remaining bottlenecks and possible strategies for overcoming them to enable SERS to be an even more powerful and versatile technique. PMID- 29139484 TI - FTIR imaging detects diet and genotype-dependent chemical composition changes in wild type and mutant C. elegans strains. AB - This study focuses on the use of Fourier Transform Infrared (FTIR) microspectroscopy to determine chemical changes induced in the nematode Caenorhabditis elegans by supplementation of C. elegans maintenance media (CeMM) by Eicosapentaenoic acid (EPA). Wild-type C. elegans (N2) and mutant strains (tub 1 and fat-3) were grown in CeMM alone, and CeMM supplemented with EPA at 25 or 100 MUM. Feeding was performed for 72 h. FTIR imaging was performed in transmission mode on individual worms. The FTIR imaging analysis of wild-type animals revealed the presence of vibrations assigned to unsaturated fatty acids, specifically bands at 3008 cm-1 ([double bond, length as m-dash]C-H, olefinic stretch) and 1744 cm-1 (C[double bond, length as m-dash]O, unsaturated fatty acids). It confirmed previously reported synthesis of unsaturated fatty acids in wild-type C. elegans. For the FTIR spectra of mutant strains, these vibrations were absent or present only as very small shoulder, which indicates that tub-1 and fat-3 synthesize essentially saturated fatty acids as indicated by the presence of -CH2 and C[double bond, length as m-dash]O vibrations. These results are in agreement with previous studies which reported that these mutants have altered lipid compositions. Principal component analysis showed differences in chemical composition between wild-type and mutant strains as well as between mutant strains cultured in normal CeMM and those cultured in CeMM supplemented with EPA. This study demonstrated the usefulness of FTIR microspectroscopy to investigate fat metabolism in C. elegans. PMID- 29139485 TI - Visible-light-induced installation of oxyfluoroalkyl groups. AB - (Hetero)aryloxytetrafluoroethylation of heteroaromatics and alkenes has been achieved by visible-light photocatalysis utilizing readily synthesized oxyfluoroalkyl reagents. The mild reaction conditions and the high diversity on both substrates and oxyfluoroalkyl reagents make this a useful method for late stage modifications in the development of various functional molecules. PMID- 29139486 TI - Simple and rapid colorimetric detection of melanoma circulating tumor cells using bifunctional magnetic nanoparticles. AB - Circulating tumor cells (CTCs) are a promising biomarker for monitoring cancer metastasis and therapy response. However, the rarity and inherent fragility of CTCs pose great challenges for CTC detection. Currently, CTC detection requires advanced instruments that might be inaccessible in most hospitals or labs. To allow simple and rapid CTC detection, we propose a sensor platform that relies only on the intrinsic properties of magnetic nanoparticles (MNPs) including rapid separation as well as nanozyme activity. The detection of melanoma CTC, which causes most skin cancer-related deaths, is demonstrated based on bifunctional MNPs. The magnetic property of MNPs enables melanoma CTC isolation and enrichment within 5 min from blood. The nanozyme activity of MNPs allows naked-eye detection of melanoma CTC by catalyzing the oxidation of colourless 3,3',5,5' tetramethylbenzidine (TMB) into blue coloured products. Melanoma CTC enumeration can be further achieved by UV-vis measurement. Our platform has successfully detected 13 melanoma CTCs per mL within 50 min. We thus believe this platform could find broad applications both in the clinic and in research. PMID- 29139487 TI - Catalytic double hydroarylation of alkynes to 9,9-disubstituted 9,10 dihydroacridine derivatives by an electrophilic phenoxyphosphonium dication. AB - The electrophilic pyridinium-substituted phenoxy-phosphonium dicationic salt [(PhO)P(2-(N-Mepy))Ph2][B(C6F5)4]2, is shown to be an effective catalyst for the double hydroarylation of alkynes with diarylamines to afford a series of 9-methyl 9-aryl-9,10-dihydroacridine and 9,10-dimethyl-9-aryl-9,10-dihydroacridine derivatives. PMID- 29139482 TI - Opioid misuse in gastroenterology and non-opioid management of abdominal pain. AB - Opioids were one of the earliest classes of medications used for pain across a variety of conditions, but morbidity and mortality have been increasingly associated with their chronic use. Despite these negative consequences, chronic opioid use is increasing worldwide, with the USA and Canada having the highest rates. Chronic opioid use for noncancer pain can have particularly negative effects in the gastrointestinal and central nervous systems, including opioid induced constipation, narcotic bowel syndrome, worsening psychopathology and addiction. This Review summarizes the evidence of opioid misuse in gastroenterology, including the lack of evidence of a benefit from these drugs, as well as the risk of harm and negative consequences of opioid use relative to the brain-gut axis. Guidelines for opioid management and alternative pharmacological and nonpharmacological strategies for pain management in patients with gastrointestinal disorders are also discussed. As chronic pain is complex and involves emotional and social factors, a multimodal approach targeting both pain intensity and quality of life is best. PMID- 29139488 TI - Gold-catalyzed [2+2+2+2]-annulation of 1,3,5-hexahydro-1,3,5-triazines with alkoxyallenes. AB - An unprecedented gold-catalyzed [2+2+2+2]-annulation of 1,3,5-hexahydro-1,3,5 triazines with alkoxyallenes has been developed, providing eight-membered heterocycles in good to excellent yields. Deuterium labeling and control experiments reveal the possible reaction mechanism for this annulation. PMID- 29139489 TI - Online monitoring of a photocatalytic reaction by real-time high resolution FlowNMR spectroscopy. AB - We demonstrate how FlowNMR spectroscopy can readily be applied to investigate photochemical reactions that require sustained input of light and air to yield mechanistic insight under realistic conditions. The Eosin Y mediated photo oxidation of N-allylbenzylamine is shown to produce imines as primary reaction products from which undesired aldehydes form after longer reaction times. Facile variation of reaction conditions during the reaction in flow allows for probe experiments that give information about the mode of action of the photocatalyst. PMID- 29139490 TI - Synthesis and shift-reagent-assisted full NMR assignment of bacterial (Z8,E2,omega)-undecaprenol. AB - The repeating isoprene unit is a fundamental biosynthetic motif. The repetitive structure presents challenges both for synthesis and for structural characterization. In this synthesis of the (Z8,E2,omega)-undecaprenol of prokaryotic glycobiology, we exemplify solutions to these challenges. Allylation of sulfone-derived carbanions controlled the stereochemistry, and its proof-of structure was secured by Eu(hfc)3 complexation to disperse the overlaid resonances of its 1H NMR spectrum. PMID- 29139491 TI - Supramolecular block copolymers for gene delivery: enhancement of transfection efficiency by charge regulation. AB - A class of cationic supramolecular block copolymers with readily controlled charges has been exploited. Upon post-synthetic structural optimization, this copolymer exhibits comparable biocompatibility, greatly improved pDNA condensation capability and biostability, and further enhanced transfection efficiency in vitro. This work provides valuable insight into the creation of advanced nonviral vectors for gene delivery. PMID- 29139492 TI - Gram-scale synthesis of monodisperse sulfonated polystyrene nanospheres for rapid and efficient sequestration of heavy metal ions. AB - Herein, gram-scale monodisperse sulfonated polystyrene (SPS) nanospheres are synthesized and examined as a sorbent for the removal of heavy metal ions (Pb2+, Zn2+ and Cu2+). The resulting uniform SPS nanospheres exhibit remarkable adsorption capabilities and kinetics, facile regeneration and outstanding recyclability, affording promising applications in food engineering and water cleanup. PMID- 29139493 TI - Novel fullerene-based porous materials constructed by a solvent knitting strategy. AB - Here we choose a dihydronaphthyl-functionalized C60 fullerene as a building block and utilize a novel solvent knitting strategy based on Friedel-Crafts alkylation reaction to construct two kinds of novel porous materials by using dichloromethane (DCM) and 1,2-dichloroethane (DCE) as solvents and external crosslinkers. The resulting porous materials show relatively high apparent BET surface areas and gas uptake abilities. PMID- 29139495 TI - A simple fluorene core-based non-fullerene acceptor for high performance organic solar cells. AB - A small molecule non-fullerene acceptor based on a fluorene core having a furan pi-spacer and end capped with rhodanine (FRd2) is developed for solution processable bulk heterojunction organic solar cells (OSCs). The simplistic synthetic protocol reduces several reaction steps and hence production cost. Extended pi-conjugation via furan units and the presence of electronegative rhodanine groups result in a power conversion efficiency of 9.4% in OSCs, which is the highest so far among these categories of molecules. PMID- 29139496 TI - Exploring the science of thinking independently together: Faraday Discussion Volume 204 - Complex Molecular Surfaces and Interfaces, Sheffield, UK, July 2017. AB - The 2017 Faraday Discussion on Complex Molecular Surfaces and Interfaces brought together theoreticians and experimentalists from both physical and chemical backgrounds to discuss the relevant applied and fundamental research topics within the broader field of chemical surface analysis and characterization. Main discussion topics from the meeting included the importance of "disordered" two dimensional (2D) molecular structures and the utility of kinetically trapped states. An emerging need for new experimental tools to address dynamics and kinetic pathways involved in self-assembled systems, as well as the future prospects and current limitations of in silico studies were also discussed. The following article provides a brief overview of the work presented and the challenges discussed during the meeting. PMID- 29139494 TI - Discovery of nicoyamycin A, an inhibitor of uropathogenic Escherichia coli growth in low iron environments. AB - High-throughput screening and activity-guided purification identified nicoyamycin A, a natural product comprised of an uncommon 3-methyl-1,4-dioxane ring incorporated into a desferrioxamine-like backbone via a spiroaminal linkage. Nicoyamycin A potently inhibits uropathogenic Escherichia coli growth in low iron medium, a promising step toward developing novel antibiotics to treat recalcitrant bacterial infections. PMID- 29139497 TI - Weak ferromagnetic ordering in brownmillerite Ca2Fe2O5 and its effect on electric field gradients. AB - Brownmillerite Ca2Fe2O5 (CFO) exhibits a magnetic transition at TN ~ 730 K. Many studies have reported the magnetic properties of CFO. However, the magnetic structure of CFO is still debated, i.e., whether the magnetic ordering is purely antiferromagnetic or weakly ferromagnetic, which originated from canted magnetic moments. In addition, the reason for the CFO showing large magnetoresistance is still unclear. This study attempts to address the unresolved issues stated above by multiple investigations on the crystal structure, magnetization, and Mossbauer parameters. Based on the results of the investigation, we conclude that the CFO is not purely antiferromagnetic but weakly ferromagnetic. That is the reason for the disappearance of the spontaneous magnetization at the magnetic critical temperature TN. The Mossbauer spectroscopy shows that the magnetic moments slightly cant against the a-direction, resulting in the presence of a net magnetic moment along the c-direction under the space group of Pnma. A reason for the canted magnetic moments is due to the presence of the Dzyalosinskii-Moriya (DM) interaction. The electric field gradient (EFG) refined from the Mossbauer spectroscopy investigated at 287 K is larger than that at 750 K, which is higher than TN. This suggests that the EFG changes below TN. A local electric polarization induced by the DM interaction is a possible reason for the change in the EFG. As a result, strong correlations between the magnetic ordering and the electrical properties appear in the CFO. The Arrhenius plot of the total electrical conductivity showed a kink at TN, which is one of these strong correlations. PMID- 29139498 TI - Controllable engineering of asymmetric phosphatidylserine-containing lipid vesicles using calcium cations. AB - A novel method to produce controllable asymmetric lipid vesicles using Ca2+ is reported. The enrichment of negatively charged phosphatidylserine (PS) molecules in the inner leaflet is found not due to charge-charge attraction, but rather a modulation effect on the occupying size of the headgroups of PS molecules. PMID- 29139499 TI - The role of phase separation and related topography in the exceptional ice nucleating ability of alkali feldspars. AB - Our understanding of crystal nucleation is a limiting factor in many fields, not least in the atmospheric sciences. It was recently found that feldspar, a component of airborne desert dust, plays a dominant role in triggering ice formation in clouds, but the origin of this effect was unclear. By investigating the structure/property relationships of a wide range of feldspars, we demonstrate that alkali feldspars with certain microtextures, related to phase separation into Na and K-rich regions, show exceptional ice-nucleating abilities in supercooled water. We found no correlation between ice-nucleating efficiency and the crystal structures or the chemical compositions of these active feldspars, which suggests that specific topographical features associated with these microtextures are key in the activity of these feldspars. That topography likely acts to promote ice nucleation, improves our understanding of ice formation in clouds, and may also enable the design and manufacture of bespoke nucleating materials for uses such as cloud seeding and cryopreservation. PMID- 29139500 TI - Self-assembly of (WO3)3 clusters on a highly oriented pyrolytic graphite surface and nanowire formation: a combined experimental and theoretical study. AB - Tungsten oxide cluster anions (WO3)3- produced from a magnetron source were soft landed on highly oriented pyrolytic graphite (HOPG) surfaces at different temperatures, and the structures formed upon deposition were analyzed using ex situ atomic force microscopy. Under liquid nitrogen cooling conditions of 100 K, the clusters form small branched nanostructures extending over a few nanometers with a height not exceeding 1 nm. At 673 K, nanowires approximately 100 nm long and less than 10 nm in diameter are observed. Dedicated atomistic modeling of the early steps of the assembly process was carried out using a polarizable potential parametrized to reproduce electronic structure calculations on small clusters, and accounting for the corrugated interaction with the ideal HOPG surface. Molecular dynamics simulations reproduce the branched nanostructures formed at low temperature fairly well, and confirm the loss of ramification at higher temperatures. Additional simulations of coalescence processes between nanoislands containing a hundred (WO3)3 units produce elongated shapes as observed experimentally, providing a typical size of the individual building blocks. The preferred orientation of nanowires and additional in situ X-ray photoelectron spectra both further suggest that the nanostructures grow along terraces and could bind through chemical processes and possibly tungsten carbide formation. PMID- 29139501 TI - The reaction of fluorine atoms with methanol: yield of CH3O/CH2OH and rate constant of the reactions CH3O + CH3O and CH3O + HO2. AB - Xenondifluoride, XeF2, has been photolysed in the presence of methanol, CH3OH. Two reaction pathways are possible: F + CH3OH -> CH2OH + HF and F + CH3OH -> CH3O + HF. Both products, CH2OH and CH3O, will be converted to HO2 in the presence of O2. The rate constants for the reaction of both radicals with O2 differ by more than 3 orders of magnitude, which allows an unequivocal distinction between the two reactions when measuring HO2 concentrations in the presence of different O2 concentrations. The following yields have then been determined from time-resolved HO2 profiles: phiCH2OH = (0.497 +/- 0.013) and phiCH3O = (0.503 +/- 0.013). Experiments under low O2 concentrations lead to reaction mixtures containing nearly equal amounts of HO2 (converted from the first reaction) and CH3O (from the second reaction). The subsequent HO2 decays are very sensitive to the rate constants of the reaction between these two radicals and the following rate constants have been obtained: k(CH3O + CH3O) = (7.0 +/- 1.4) * 10-11 cm3 s-1 and k(CH3O + HO2) = (1.1 +/- 0.2) * 10-10 cm3 s-1. The latter reaction has also been theoretically investigated on the CCSD(T)//M06-2X/aug-cc-pVTZ level of theory and CH3OH + O2 have been identified as the main products. Using MUVTST, a virtually pressure independent rate constant of k(CH3O + HO2) = 4.7 * 10-11 cm3 s-1 has been obtained, in good agreement with the experiment. PMID- 29139502 TI - Development of the first model of a phosphorylated, ATP/Mg2+-containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design. AB - A model of phosphorylated and ATP-containing B-Raf protein kinase is needed as a tool for the structure-based design of new allosteric inhibitors, since no crystal structure of such a system has been resolved. Here, we present the development of such a model as well as a thorough analysis of its structural features. This model was prepared using a systematic molecular dynamics approach considering the presence or absence of both the phosphate group at the Thr599 site and the ATP molecule. Then, different structural features (i.e. DFG motif, Mg2+ binding loop, activation loop, phosphorylation site and alphaC-helix region) were analysed for each trajectory to validate the aimed 2pBRAF_ATP model. Moreover, the structure and activating interactions of this 2pBRAF_ATP model were found to be in agreement with previously reported information. Finally, the model was further validated by means of a molecular docking study with our previously developed lead compound I confirming that this ATP-containing, phosphorylated protein model is suitable for further structure-based design studies. PMID- 29139503 TI - Formation of a spiro compound via coupling of a cyclopentadienyl ligand with a diene moiety of titanacyclopentadiene. AB - The treatment of titanacyclopentadienes with bismuth(iii) chloride gave spiro compounds in moderate yields. Two carbon atoms of the diene moiety of the titanacyclopentadiene were connected to one carbon atom of the Cp ligand. This is in sharp contrast to the formation of dihydroindene derivatives, where two carbon carbon bonds were formed between the diene moiety and the adjacent two carbon atoms of the Cp ligand. PMID- 29139504 TI - Thionated naphthalene diimides: tuneable chromophores for applications in photoactive dyads. AB - Varying the degree of thionation of a series of naphthalene diimide (NDI) and naphthalic imide (NI) phenothiazine dyad systems affords a systematic approach for tuning the system's donor-acceptor energy gap. Each dyad was compared to model NDI/NI systems and fully characterised through single crystal X-ray diffraction, NMR, cyclic voltammetry, electron paramagnetic resonance (EPR), transient absorption spectroscopy (TA), time-resolved infra-red spectroscopy (TRIR) and DFT. The measurements reveal that thionation increases both electron affinity of the NDI/NI acceptor dyad component and accessibility of the singly or doubly reduced states. Furthermore, FTIR and TA measurements show that excited state behaviour is greatly affected by thionation of the NDI and induces a decrease in the lifetime of the excited states formed upon the creation of charge separated states. PMID- 29139509 TI - NEXAFS spectroscopy of ionic liquids: experiments versus calculations. AB - Experimental near edge X-ray absorption fine structure (NEXAFS) spectra are reported for 12 ionic liquids (ILs) encompassing a range of chemical structures for both the sulfur 1s and nitrogen 1s edges and compared with time-dependent density functional theory (TD-DFT) calculations. The energy scales for the experimental data were carefully calibrated against literature data. Gas phase calculations were performed on lone ions, ion pairs and ion pair dimers, with a wide range of ion pair conformers considered. For the first time, it is demonstrated that TD-DFT is a suitable method for simulating NEXAFS spectra of ILs, although the number of ions included in the calculations and their conformations are important considerations. For most of the ILs studied, calculations on lone ions in the gas phase were sufficient to successfully reproduce the experimental NEXAFS spectra. However, for certain ILs - for example, those containing a protic ammonium cation - calculations on ion pairs were required to obtain a good agreement with experimental spectra. Furthermore, significant conformational dependence was observed for the protic ammonium ILs, providing insight into the predominant liquid phase cation-anion interactions. Among the 12 investigated ILs, we find that four have an excited state that is delocalised across both the cation and the anion, which has implications for any process that depends on the excited state, for example, radiolysis. Considering the collective experimental and theoretical data, we recommend that ion pairs should be the minimum number of ions used for the calculation of NEXAFS spectra of ILs. PMID- 29139510 TI - Crystal structures and magnetic properties of two series of phenoxo-O bridged dinuclear Ln2 (Ln = Gd, Tb, Dy) complexes. AB - Six dinuclear lanthanide compounds of the formulae [Ln2(3m L4)2(L2)2(MeOH)2].6MeOH (Ln = Gd - 1a, Tb - 1b, and Dy - 1c) and [Ln2(3m L4)2(L2)2(DMF)2] (Ln = Gd - 2a, Tb - 2b, and Dy - 2c; DMF = N,N dimethylformamide, H23m-L4 = (2-[(E)-(3-metoxysalicylidene)amino]phenol), and HL2 = 1,3-diphenyl-1,3-diketopropane) were prepared and characterized by elemental analysis, FTIR spectroscopy, thermogravimetric measurements, single-crystal X-ray structural analysis, and magnetometry, and Gd2 and Dy2 compounds by ab initio methods as well. The structural analysis revealed the isostructurallity of the compounds within the series of 1a-c and 2a-c. The analysis of the variable temperature magnetic data showed the presence of a weak antiferromagnetic coupling in the Gd2 compounds (J/cm-1 = -0.13 for 1a and J/cm-1 = -0.17 for 2a). The magnetocaloric effect was studied on compound 2a with the maximum value of DeltaSM = 22.9 J kg-1 K-1 at T = 2.0 K and B = 9 T, which is the highest value among the Gd2 double phenoxo-bridged compounds observed up to now. Both the Dy2 compounds (1c and 2c) exhibit slow-relaxation of magnetization in zero external static magnetic field. Magnetic anisotropy, intradimer magnetic coupling and magnetization blocking barriers were also studied by ab initio methods for 1c and 2c. PMID- 29139511 TI - Radiation chemistry of solid acetone in the interstellar medium - a new dimension to an old problem. AB - A laboratory investigation of acetone, an interstellar and cometary molecule, has produced new results concerning its decomposition in a radiation environment. Mid infrared spectroscopy has been used to follow amorphous acetone's destruction by ionizing radiation (1 MeV protons) at 20 K. Radiation products identified are the CH4, CO, and CO2 usually made in such experiments, along with ketene, allene, and the acetonyl radical, all identified here for the first time in irradiated solid acetone. Evidence for the reduction product 2-propanol was suggestive, but a firm identification could not be made either for it or for the C2 hydrocarbons (i.e., C2H6, C2H4, C2H2). The acetyl radical was not observed as a radiation product. Isotopically labeled reagents were used to demonstrate ketene formation and to emphasize that multiple approaches are needed for robust assignments of infrared spectral features of irradiated icy solids. Results from a supporting radiation experiment with isotopically labeled acetic acid are described. Comparisons are made to a previous study of acetone's stability in extraterrestrial radiation environments, and caution is urged in measuring and interpreting CO abundances in irradiated icy solids. PMID- 29139512 TI - Bright type-II photoluminescence from Mn-doped CdS/ZnSe/ZnS quantum dots with Mn2+ ions as exciton couplers. AB - Mn2+ ions were introduced as exciton couplers to enhance the quantum yield (QY) of type-II photoluminescence (PL) from CdS/ZnSe/ZnS quantum dots (QDs) with slow hot-exciton cooling and low radiative rate. Transient absorption spectroscopy verifies the faster bleach recovery and faster peak red-shifting at the charge transfer state. And the transient PL peak of the QDs changes from blue-shifting to red-shifting due to Mn2+ doping. The QY of type-II PL can be enhanced from ~35% to ~60% by Mn2+ doping. As the energy-transfer-stations of hot excitons during rapid ET (~100 ps), Mn2+ ions transform more excitons from hot to cold for emission. As the couplers of cold excitons during long thermal equilibrium (~100 ns), Mn2+ ions further decrease exciton trapping by strong bidirectional coupling. This work provides a unique way of acquiring high QY of type-II PL, and highlights the general law of PL enhancement in Mn-doped QDs. PMID- 29139513 TI - Current knowledge of intestinal absorption of bioactive peptides. AB - Peptides have been demonstrated as potentially beneficial compounds against several life-style related diseases such as hypertension, hypercholesterolemia, and atherosclerosis, among others. However, limited research has been carried out on peptide absorption, resulting in a lack of understanding and control of this process. Therefore, this review discusses the recent insights gathered on in vitro and in vivo absorption of peptides across intestinal membranes, into blood circulation. Briefly, some di-/tripeptides permeate through intestinal membranes in their intact forms via peptide transporter systems, while others are vulnerable to protease degradation. Oligopeptides (>tetrapeptides) show a lower transport ability than di-/tripeptides, possibly due to the presence of paracellular tight junctions. The hydrophobicity of peptides (log P) does not seem to influence absorption, while peptide length and degradation of peptides (and peptide sequences) by intestinal proteases may be determinant factors of the absorption process. PMID- 29139514 TI - Differential array sensing for cancer cell classification and novelty detection. AB - A series of semi-specific peptides reported in the literature to bind various epitopes on cell surfaces were used in a differential sensing array to pattern cell line identity. The peptides were conjugated to thiazole orange to act as both a fluorescence reporter and a DNA intercalator. Fluorescence data for the peptides exposed to cells, with and without exogenous double stranded DNA (dsDNA), led to chemometric fingerprints for eight cancer cell lines. In contrast to the use of structures meant to act in completely non-specific ways, the use of a limited level of specificity generated linear discriminant score plots with high dimensionality, i.e. several principle components carrying significant variance. The arrays were found to correctly classify the cell lines from 60% to 100% depending upon the cell line. Due to the high dimensionality score plots, the identification of cell lines that were not part of the training set was examined. Support vector machines were used as a novelty detection routine and showed that a cancer line not part of the original training set could be correctly identified as being novel. PMID- 29139515 TI - A pseudopericyclic [3,5]-sigmatropic rearrangement of a coumarin trichloroacetimidate derivative. AB - Thermolysis of a coumarin trichloroacetimidate yields a single rearrangement product. The proposed mechanism is a pseudopericyclic allowed (Woodward-Hoffman forbidden) [3,5]-sigmatropic rearrangement to form the corresponding amide followed by a sigmatropic [1,5]-hydrogen migration. Transition state calculations at the B3LYP/6-31G(d,p) level support this mechanism and suggest the selectivity is influenced by the stability of the intermediates. PMID- 29139516 TI - Dissociative reactions of benzonorbornadienes with tetrazines: scope of leaving groups and mechanistic insights. AB - Bioorthogonal dissociative reactions boast diverse potential applications in chemical biology and drug delivery. The reaction of benzonorbornadienes with tetrazines to release amines from carbamate leaving groups was recently introduced as a bioorthogonal bond-cleavage reaction. The present study aimed at investigating the scope of leaving groups that are compatible with benzonorbornadienes. Synthesis of several benzonorbornadienes with different releasable groups is reported, and the reaction of these molecules with tetrazine was found to be rapid and afforded high release yields. The tetrazine-induced release of molecules proceeds in a cascade of steps including inverse-electron demand cycloaddition and cycloreversion reactions that form unstable isoindoles/isobenzofuran intermediates and spontaneously eliminate a leaving group of interest. In the case of oxygen-bridged BNBDs at room temperature, we observed the formation of an unproductive byproduct. PMID- 29139517 TI - Nanofibre preparation of non-processable polymers by solid-state polymerization of molecularly self-assembled monomers. AB - Polybisbenzimidazobenzophenanthroline-dione (BBB) is a high-performance polymer which is characterized by very high mechanical strength in combination with exceptional thermal stability, but it cannot be processed to electrospun fibres for any useful applications due to its insolubility and infusibility. We overcame all obstacles in the electrospinning of BBB by a new bottom-up, and facile approach for the solid-state polymerization of self-assembled monomer precursors. Key to this new strategy is the incorporation of a high molecular weight sacrificial polymer to aid in fibre formation. The resulting electrospun BBB fibres and belts prepared thereof according to this new approach are very strong and show excellent thermal stability. We envisage that this procedure could be applied to other classes of non-processable high-performance polymers for the preparation of electrospun fibres for applications such as filtration, sound insulation, battery separation, electrodes, fire protection, and reaction engineering under demanding conditions. PMID- 29139524 TI - Computational modelling of the redistribution of copper isotopes by proteins in the liver. AB - Changes in the stable isotope composition of copper in blood serum as a result of biological processes in the liver were quantified as coupled equilibrium fractionation processes. The model used calculated reduced partition function ratios corresponding to interactions involving individual proteins using Density Functional Theory. This quantified the effect that each process had on the redistribution of copper isotopes in the liver. It was not possible to calculate the reduced partition function of CTR1 as a high resolution crystal structure of its copper binding domains are unavailable at the time of writing, and an optimization process was used to estimate the reduced partition function of CTR1 and constrain the possible isotopic fractionation associated with interactions involving CTR1 independent of direct DFT calculations and assumptions of its structure. The exchange of copper between ceruloplasmin and ATP7B has the most significant impact on the copper isotopic composition of blood serum. The model calculation for the isotopic composition of ceruloplasmin and albumin are delta65Cu = (-0.54 +/- 0.10)0/00 and delta65Cu = (0.08 +/- 0.25)0/00 respectively, assuming that serum is 90% ceruloplasmin and 10% albumin using a measured delta65Cu of serum of (0.52 +/- 0.08)0/00. The model also predicts that the isotopic composition of the tri-nuclear binding motif of ceruloplasmin may be relatively depleted in the lighter isotope of Cu compared to the other copper binding sites by as much as -1.08 +/- 0.450/00. PMID- 29139525 TI - Electron spin fluctuation in intense laser fields. AB - The effects of the orientation, wavelength and carrier-envelope phase of laser pulses on the spin fluctuation in HeH2+ and LiH3+ molecular ions in their bound electronic states, during their interactions with linearly polarized intense laser pulses, were investigated by solving numerically the time-dependent Dirac equation with the Foldy-Wouthuysen transformation. The results of this study showed that an increase in the wavelength of the laser pulse at a fixed intensity reduces the lifetime of the coherent spin states and increases the sensitivity of the spin vector to the applied laser field in both HeH2+ and LiH3+ species. This sensitivity also depends on the carrier-envelope phase of the laser pulse due to the asymmetry of these systems. Furthermore, the influence of spin-orbit coupling on the dynamics of the spin in the interaction of the highly charged atomic species, N6+, with ultra-intense laser pulses was investigated by considering different initial orbitals and spin polarizations. The results show that significantly different spin-forces are induced when an interaction starts with two parallel and perpendicular polarized spin states with respect to the direction of the laser pulse propagation. Furthermore, spin-orbit coupling affects the quantization of the spin space and results in asymmetric spin fluctuation depending on the initial spin polarization state and the electron orbital momentum, which is induced by the electric field of the laser pulse. PMID- 29139528 TI - Assembly of small molecule surfactants at highly dynamic air-water interfaces. AB - Small-angle neutron scattering has been used to probe the interfacial structure of foams stabilised by small molecule surfactants at concentrations well below their critical micelle concentration. The data for wet foams showed a pronounced Q-4 dependence at low Q and noticeable inflexions over the mid Q range. These features were found to be dependent on the surfactant structure (mainly the alkyl chain length) with various inflexions across the measured Q range as a function of the chain length but independent of factors such as concentration and foam age/height. By contrast, foam stability (for C < CMC) was significantly different at this experimental range. Drained foams showed different yet equally characteristic features, including additional peaks attributed to the formation of classical micellar structures. Together, these features suggest the dynamic air-water interface is not as simple as often depicted, indeed the data have been successfully described by a model consisting paracrystalline stacks (multilayer) of adsorbed surfactant layers; a structure that we believe is induced by the dynamic nature of the air-water interface in a foam. PMID- 29139529 TI - Lab-on-capillary: a rapid, simple and quantitative genetic analysis platform integrating nucleic acid extraction, amplification and detection. AB - In this work, we describe for the first time a genetic diagnosis platform employing a polydiallyldimethylammonium chloride (PDDA)-modified capillary and a liquid-based thermalization system for rapid, simple and quantitative DNA analysis with minimal user interaction. Positively charged PDDA is modified on the inner surface of the silicon dioxide capillary by using an electrostatic self assembly approach that allows the negatively charged DNA to be separated from the lysate in less than 20 seconds. The capillary loaded with the PCR mix is incorporated in the thermalization system, which can achieve on-site real-time PCR. This system is based on the circulation of pre-heated liquids in the chamber, allowing for high-speed thermalization of the capillary and fast amplification. Multiple targets can be simultaneously analysed with multiplex spatial melting. Starting with live Escherichia coli (E. coli) cells in milk, as a realistic sample, the current method can achieve DNA extraction, amplification, and detection within 40 min. PMID- 29139530 TI - When droplets become stars: charged dielectric droplets beyond the Rayleigh limit. AB - When a nano-drop comprising a single spherical central ion and dielectric solvent is charged above a well-defined threshold, it acquires a stable star morphology. In contrast, conducting droplets, will undergo fission. Here we report combined atomistic molecular dynamics and continuum modelling study of star formation of droplets that contain a highly charged ion. We assume that in the continuum model the dielectric response is linear. In this linear continuum model, which is an extension of Rayleigh model, the energy of the drop is comprised of terms analogous to those in Rayleigh model, which are surface energy and electrostatic energy of dielectric droplet charged by a central point charge. We present the stability analysis of the continuum model to determine the threshold of instability. Indeed we find that the model accounts well for the onset of the instabilities. Molecular dynamics show that the number of points of the star shaped nano-drops depends only on the surface tension, dielectric constant and size of the droplet, and on the magnitude of the charge of the central ion, but not on its sign. Intuitively, it is expected that when a spherical dielectric drop becomes unstable it would transform into a non-spherical finite shape of the same volume as the initial spherical shape with the point charge located in the drop interior. To test whether the extended Rayleigh model can account for the observed droplet shapes, we performed numerical simulations of the linear continuum model. Contrary to the expectations, the simulations of the extended Rayleigh model does not reproduce the stable star shapes found in the atomistic simulations, not even when we account for the bending rigidity and spontaneous curvature of the surface. We argue that the assumption that the dielectric response is linear breaks down if the droplet surface approaches the central macro-ion, where the electric field strength is such that dielectric saturation sets in. We envisage that for certain solvents, these stars could be made permanent by cross-linking, opening the way to the production of a novel class of highly-non-convex colloids. PMID- 29139533 TI - At the very beginning of life on Earth: the thiol-rich peptide (TRP) world hypothesis. AB - Life developed on Earth probably about 3.8 billion years ago, on a planet that was already largely covered by oceans and where the atmosphere was very humid. The reactions, which may have led to the formation of the first polymers, particularly to the first peptides and nucleic acids, must have been compatible with these conditions. This is the case of the reaction of nitriles with aminothiols, such as cysteine and homocysteine. Since aminonitriles are the probable precursors of amino acids, this condensation reaction has been able to rapidly yield dipeptides, tripeptides, oligomers and even true polymers, each containing thiol functions. These thiol-rich peptides (TRP's) would then have assumed the various catalytic roles that the peptides containing cysteine residues play today. They allowed a rapid bloom of life in the primitive ocean. In this scenario, RNA's are not the first polymers, but have been synthesized, like DNA's, thanks to the catalytic properties of thiols in a mostly TRP world. In this world, due to its ability to form a thiolactone, homocysteine may have played the leading role in enabling the previously formed oligomers to be stappled together, thus accelerating the formation of long peptide chains. PMID- 29139534 TI - Beyond the sea: Crepidula atrasolea as a spiralian model system. AB - This paper introduces the black-footed slipper snail, Crepidula atrasolea, as a new model for biological studies in the Spiralia. C. atrasolea is a calyptraeid gastropod, and congener of the Atlantic slipper snail, C. fornicata. Like C. fornicata, C. atrasolea shares a sedentary, filter-feeding, protandrous lifestyle, but is preferable as a developmental model because of its short generation time, year-round reproduction, and direct development. In our lab, individuals go from egg to reproductive females in under six months, as compared to an estimated 1-2 years for C. fornicata. Here we provide details for collecting and transporting animals, setting up inland aquaria, and maintaining laboratory colonies of C. atrasolea. We also describe early development, which is similar to that in other calyptraeids. Females brood encapsulated embryos for three weeks, which hatch as "crawl-away" juveniles. We also present a developmental transcriptome for C. atrasolea, covering early cleavage through late organogenesis stages, as a useful tool for future studies of gene expression and function. We provide this information to the broader developmental community to facilitate widespread use of this system. PMID- 29139535 TI - Contribution of cranial neural crest cells to mouse skull development. AB - The mammalian skull vault is a highly regulated structure that evolutionally protects brain growth during vertebrate development. It consists of several membrane bones with different tissue origins (e.g. neural crest-derived frontal bone and mesoderm-derived parietal bone). Although membrane bones are formed through intramembranous ossification, the neural crest-derived frontal bone has superior capabilities for osteoblast activities and bone regeneration via TGF, BMP, Wnt, and FGF signaling pathways. Neural crest (NC) cells are multipotent, and once induced, will follow specific paths to migrate to different locations of the body where they give rise to a diverse array of cell types and tissues. Recent studies using genetic mouse models have greatly advanced our knowledge of NC cell induction, proliferation, migration and differentiation. Perturbations or disruptions of neural crest patterning lead to severe developmental defects or diseases. This review summarizes recent discoveries including novel functions of genes or signaling molecules that are capable of governing developmental processes of neural crest patterning, which may function as a gene regulatory network in controlling skull development. The proposed regulatory network will be important to understand how the signaling pathways and genes converge to regulate osteoblast activities and bone formation, which will be beneficial for the potential identification of molecular targets to prevent or alleviate human diseases or disorders involving defective neural crest development. PMID- 29139536 TI - Planar polarity of the extraembryonic epithelia in the preimplantation porcine conceptus. AB - The present review deals with the trophoblast structure during the free intrauterine life of the pig blastocyst. The term trophoblast is used here to describe the association of the first extraembryonic cell layers, the trophectoderm and the primitive endoderm that are polarized epithelia, a fact established by ultrastructural and immunocytochemical data. The aim of this synthesis is to gather the relative works dispersed in the litterature and to explain the implication of the planar polarity of these cell layers on their developmental fate and roles. These epithelia are intricately dependent on each other for the maintenance of their differentiated state and continuity. The modalities of their spectacular expansion can be explained in part by biomechanical concepts. PMID- 29139537 TI - Planaria: an animal model that integrates development, regeneration and pharmacology. AB - Although planarians are established model organisms in developmental biology and regeneration studies, in the last forty years or so, they have caught the attention of pharmacologists, especially to study the pharmacology of drugs of abuse. This review covers the following topics: some fundamentals of the history of animal models and planarians in biomedical research; an abbreviated story of systematic pharmacology research using planarians as a model organism; an example of how planarians are contributing to the search for compounds against acute cocaine toxicity; an analysis of the number of papers on planarians and pharmacological topics from 1900-2016; some perspectives on pharmacology in developmental and regeneration studies, arguing in favor of the planarian model as a leading subject for this interdisciplinary area of research, and finally some concluding thoughts. PMID- 29139538 TI - Limitations of the Pax7-creERT2 transgene for driving deletion of Nf1 in adult mouse muscle. AB - Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder that results in a variety of characteristic manifestations. Prior studies have shown reduced muscle size and global skeletal muscle weakness in children with NF1. This associated weakness can lead to significant challenges impacting on quality of life. Pre-clinical studies using a muscle-specific NF1 knockout mouse have linked this weakness to an underlying primary metabolic deficiency in the muscle. However, the neonatal lethality of this strain prevents analysis of the role of NF1 in adult muscle. In this study, we present the characterization of an inducible muscle-specific NF1 knockout strain (Nf1Pax7i f/f ) produced by cross breeding the Pax7-CreERT2 strain with the conditional Nf1flox/flox line. Tamoxifen dosing of 8-week old Nf1Pax7i f/f mice led to recombination of the floxed allele in muscle, as detected by PCR. Detailed phenotypic analysis of treated adult mice over 8 weeks revealed no changes in bodyweight or muscle weight, no histological signs of myopathy, and no functional evidence of distress or impairment. Subsequent analysis using the Ai9 Cre-dependent tdTomato reporter strain was used to analyse labelling in embryos and in adult mice. Cell tracking studies identified a lower than expected rate of integration of recombined satellite cells into adult muscle. In contrast, a high persistent contribution of embryonic cells that were Pax7+ were found in adult muscle. These findings indicate important caveats with the use of the Pax7-CreER T2 strain and highlight a need to develop new tools for investigating the function of NF1 in mature muscle. PMID- 29139539 TI - An empirical model of Onecut binding activity at the sea urchin SM50 C-element gene regulatory region. AB - Studying the formation of endoskeleton in many species is complex and difficult. The sea urchin embryo offers an unparalleled platform for understanding this process because of the ease with which its skeletogenic mesenchyme cells can be manipulated. In this study, preliminary evidence from biochemical studies towards understanding the role of the Onecut transcription factor during sea urchin skeletogenic mesenchyme cell specification is presented. Based on the evidence, an empirical model is proposed showing how Onecut, together with associated co factors, may be using the C-element of the SM50 gene regulatory region in advance of the sea urchin Strongylocentrotus purpuratus spicule development. In the model, Onecut recognizes and binds the DNA sequence CATCGATCTC in the C-element without temporal restriction. Onecut then utilizes different sets of co-factors to switch from its unknown function early in development (four cell stage to the mesenchyme blastula stage), to its known role in the oral-aboral boundary thereafter. At the writing of this report, definitive evidence as to whether the "early" factors are expressed in all cells except the micromere lineages, or whether the "late" factors are expressed in micromere descendants or ectodermal precursors only are lacking. The former would suggest a possible Onecut repression function for the early co-factors outside the micromere lineages; the latter scenario would suggest a Onecut activation function for the late co factors in the presumptive ciliary band. PMID- 29139540 TI - Neurosphere formation potential resides not in the caudal cell mass, but in the secondary neural tube. AB - The caudal cell mass (CCM) is known as the main player in secondary neurulation, forming the secondary neural tube (2NT). This suggests that the CCM may have the character of neural progenitor cells. The neural potential of the CCM and the 2NT (CCM + 2NT) was assessed by in vitro culture of neurospheres during Hamburger and Hamilton stages (HH) of secondary neurulation (HH16 to HH32). We also analyzed the neural potential of the developing central nervous system (CNS) by comparing the neurosphere culture from the brain, upper / lower spinal cord, and CCM + 2NT from various HH stages. The CCM + 2NT was capable of forming neurospheres. Of the various HH stages, the greatest number of neurospheres from CCM + 2NT were cultured at HH28. Because the 2NT is most prominent at HH28, we hypothesized that the 2NT, rather than the CCM, had the main potential to produce neurospheres. When the neurospheres were cultured separately from the CCM and the 2NT, 2NT made significantly more neurospheres. When comparing different parts of the CNS, at HH16, the greatest number of neurospheres was formed from the brain. At HH32, it was the CCM + 2NT. The region with the greatest number of neurospheres progressed in a cephalo-caudal direction during development. This study showed that neurospheres can be cultured from CCM + 2NT, and the main player in neurosphere formation was the 2NT. The present study has also revealed cephalo-caudal trend in the neural potential of developing CNS. PMID- 29139541 TI - Characterization of the Autophagy related gene-8a (Atg8a) promoter in Drosophila melanogaster. AB - Autophagy is an evolutionarily conserved process which is upregulated under various stress conditions, including nutrient stress and oxidative stress. Amongst autophagy related genes (Atgs), Atg8a (LC3 in mammals) is induced several fold during nutrient limitation in Drosophila. The minimal Atg8a cis-regulatory module (CRM) which mediates transcriptional upregulation under various stress conditions is not known. Here, we describe the generation and analyses of a series of Atg8a promoter deletions which drive the expression of an mCherry-Atg8a fusion cassette. Expression studies revealed that a 200 bp region of Atg8a is sufficient to drive expression of Atg8a in nutrient rich conditions in fat body and ovaries, as well as under nutrient deficient conditions in the fat body. Furthermore, this 200 bp region can mediate Atg8a upregulation during developmental histolysis of the larval fat body and under oxidative stress conditions induced by H2O2. Finally, the expression levels of Atg8a from this promoter are sufficient to rescue the lethality of the Atg8a mutant. The 200 bp promoter-fusion reporter provides a valuable tool which can be used in genetic screens to identify transcriptional and post-transcriptional regulators of Atg8a. PMID- 29139542 TI - Temporal and spatial expression patterns of Hedgehog receptors in the developing inner and middle ear. AB - The mammalian inner ear is a complex organ responsible for balance and hearing. Sonic hedgehog (Shh), a member of the Hedgehog (Hh) family of secreted proteins, has been shown to play important roles in several aspects of inner ear development, including dorsoventral axial specification, cochlear elongation, tonotopic patterning, and hair cell differentiation. Hh proteins initiate a downstream signaling cascade by binding to the Patched 1 (Ptch1) receptor. Recent studies have revealed that other types of co-receptors can also mediate Hh signaling, including growth arrest-specific 1 (Gas1), cell-adhesion molecules related/down-regulated by oncogenes (Cdon), and biregional Cdon binding protein (Boc). However, little is known about the role of these Hh co-receptors in inner ear development. In this study, we examined the expression patterns of Gas1, Cdon, and Boc, as well as that of Ptch1, in the developing mouse inner ear from otocyst (embryonic day (E) 9.5) until birth and in the developing middle ear at E15.5. Ptch1, a readout of Hh signaling, was expressed in a graded pattern in response to Shh signaling throughout development. Expression patterns of Gas1, Cdon, and Boc differed from that of Ptch1, and each Hh co-receptor was expressed in specific cells and domains in the developing inner and middle ear. These unique and differential expression patterns of Hh co-receptors suggest their roles in mediating various time- and space-specific functions of Shh during ear development. PMID- 29139543 TI - Molecular cloning and expression analysis of Sox3 during gonad and embryonic development in Misgurnus anguillicaudatus. AB - Sox3 is a single-exon gene located on the X chromosome in most vertebrates. It belongs to the SoxB1 subfamily, which is part of the larger Sox family. Previous studies have revealed that Sox3 is expressed in many fish species. However, how Sox3 influences the development of Misgurnus anguillicaudatus remains unknown. In this study, a Sox3 homologue, termed MaSox3, was cloned from the brain of M. anguillicaudatus using homology-based cloning and the rapid amplification of cDNA ends method. Sequence analysis reveals that MaSox3 encodes a hydrophilic protein, which contains a characteristic HMG-box DNA-binding domain of 79 amino acids, and shares high homology with Sox3 in other species. Additionally, quantitative real time reverse transcription PCR and in situ hybridization showed that MaSox3 is consistently expressed during embryogenesis, with peak expression during the neurula stage and broad expression in the central nervous system. Moreover, tissue distribution analyses have revealed that MaSox3 is abundant in the adult brain, the particle cell layer, and the gonad. Additionally, its expression is observed in primary spermatocyte cells, primary oocytes and previtellogenic oocyte cells. Taken together, all of these results suggest that the expression of the MaSox3 gene is highly conserved during vertebrate evolution and involved in a wide range of developmental processes including embryogenesis, neurogenesis and gonad development. PMID- 29139544 TI - Automatic detection of DNA double strand breaks after irradiation using an gammaH2AX assay. AB - Radiation therapy belongs to the most common approaches for cancer therapy leading amongst others to DNA damage like double strand breaks (DSB). DSB can be used as a marker for the effect of radiation on cells. For visualization and assessing the extent of DNA damage the gammaH2AX foci assay is frequently used. The analysis of the gammaH2AX foci assay remains complicated as the number of gammaH2AX foci has to be counted. The quantification is mostly done manually, being time consuming and leading to person-dependent variations. Therefore, we present a method to automatically analyze the number of foci inside nuclei, facilitating and quickening the analysis of DSBs with high reliability in fluorescent images. First nuclei were detected in fluorescent images. Afterwards, the nuclei were analyzed independently from each other with a local thresholding algorithm. This approach allowed accounting for different levels of noise and detection of the foci inside the respective nucleus, using Hough transformation searching for circles. The presented algorithm was able to correctly classify most foci in cases of "high" and "average" image quality (sensitivity>0.8) with a low rate of false positive detections (positive predictive value (PPV)>0.98). In cases of "low" image quality the approach had a decreased sensitivity (0.7-0.9), depending on the manual control counter. The PPV remained high (PPV>0.91). Compared to other automatic approaches the presented algorithm had a higher sensitivity and PPV. The used automatic foci detection algorithm was capable of detecting foci with high sensitivity and PPV. Thus it can be used for automatic analysis of images of varying quality. PMID- 29139545 TI - The effect of ice crystals formations on the flesh quality of frozen horse mackerel (Trachurus japonicus). AB - : It is known that the formation of ice crystals has a negative impact on the flesh quality of frozen meat. This study focuses on how the formation of ice crystals in the dorsal ordinary muscle affects the flesh quality of frozen horse mackerel (Trachurus japonicus). Freeze-thawed muscle specimens (F-TMS) of horse mackerel were first stored at -24C and then thawed. The K-value, expressible water, breaking strength of unfrozen muscle specimens (UMS) and F-TMS, and histological structure (light microscope [LM], scanning electron microscope [SEM] of UMS, frozen muscle specimens [FMS], and F-TMS) were investigated. K-values were higher in the F-TMS than in the UMS, and the increasing rate of K-value in F TMS was approximately 1.4-fold higher than UMS. Similarly, the percentage of expressible water was higher in the F-TMS than in the UMS. The breaking strength of the UMS decreased with storage period, but it remained at a higher level than that of F-TMS. Numerous ice crystal formations in muscle cells of FMS and small interstices between cells of F-TMS were observed under LM. Moreover, we observed a relatively collapsed honeycomb structure of the extracellular matrix (ECM) under SEM, and found that collagen fibril networks of endomysiums became looser after thawing. Therefore, ice crystals contribute to vulnerabilities in the ECM. These results suggest that a decrease of freshness and the degradation of physical properties caused by ECM destruction may be due to the formation of ice crystals in muscle structures during freezing, leading to the deterioration of flesh quality during storage. PRACTICAL APPLICATIONS: The flesh quality deteriorated after thawing on the basis of degradation of physical properties. Moreover, it could be presumed that the K-value increase was exacerbated by ice crystals, and the decreasing speed of chemical freshness was sped up accompanied by ice storage after thawing. Thus, the formation of ice crystals, which destroyed the muscle cells and structures, may be one of the dominant factors causing the deterioration in the flesh quality. PMID- 29139547 TI - Early intervention and environmental factors: optimizing the development of infants born preterm. PMID- 29139546 TI - Up-regulation of PYK2/PKCalpha-dependent haem oxygenase-1 by CO-releasing molecule-2 attenuates TNF-alpha-induced lung inflammation. AB - BACKGROUND AND PURPOSE: Haem oxygenase-1 (HO-1) could provide cytoprotection against various inflammatory diseases. However, the mechanisms underlying the protective effect of CO-releasing molecule-2 (CORM-2)-induced HO-1 expression against TNF-alpha-induced inflammatory responses in human pulmonary alveolar epithelial cells (HPAEpiCs) remain unknown. EXPERIMENTAL APPROACH: CORM-2-induced HO-1 protein and mRNA expression, and signalling pathways were determined by Western blot and real-time PCR, coupled with respective pharmacological inhibitors or transfection with siRNAs. The effect of CORM-2 on TNF-alpha-induced increase in leukocyte counts in BAL fluid and VCAM-1 expression in lung was determined by cell counting and Western blot analysis. KEY RESULTS: CORM-2 attenuated the TNF-alpha-induced pulmonary haematoma, VCAM-1 expression and increase in leukocytes through an up-regulation of HO-1 in mice; this effect of CORM-2 was reversed by the HO-1 inhibitor zinc protoporphyrin IX. Furthermore, CORM-2 increased HO-1 protein and mRNA expression as well as the phosphorylation of PYK2, PKCalpha and ERK1/2 (p44/p42 MAPK) in HPAEpiCs; these effects were attenuated by their respective pharmacological inhibitors or transfection with siRNAs. Inhibition of PKCalpha by Go6976 or Go6983 attenuated CORM-2-induced stimulation of PKCalpha and ERK1/2 phosphorylation but had no effect on PYK2 phosphorylation. Moreover, inhibition of PYK2 by PF431396 reduced the phosphorylation of all three protein kinases. Finally, PYK2/PKCalpha/ERK1/2 mediated stimulation of activator protein 1 was shown to play a key role in CORM 2-induced HO-1 expression via an up-regulation of c-Fos mRNA. CONCLUSIONS AND IMPLICATIONS: CORM-2 activates a PYK2/PKCalpha/ERK1/2/AP-1 pathway leading to HO 1 expression in HPAEpiCs. This HO-1/CO system might have potential as a therapeutic target in pulmonary inflammation. PMID- 29139549 TI - Elevated potassium outward currents in hyperoxia treated atrial cardiomyocytes. AB - Supplementation of 100% oxygen is a very common intervention in intensive care units (ICU) and critical care centers for patients with dysfunctional lung and lung disorders. Although there is advantage in delivering sufficient levels of oxygen, hyperoxia is reported to be directly associated with increasing in hospital deaths. Our previous studies reported ventricular and electrical remodeling in hyperoxia treated mouse hearts, and in this article, for the first time, we are investigating the effects of hyperoxia on atrial electrophysiology using whole-cell patch-clamp electrophysiology experiments along with assessment of Kv1.5, Kv4.2, and KChIP2 transcripts and protein profiles using real-time quantitative RT-PCR and Western blotting. Our data showed that induction of hyperoxia for 3 days in mice showed larger outward potassium currents with shorter action potential durations (APD). This increase in current densities is due to significant increase in ultrarapid delayed rectifier outward K+ currents (IKur ) and rapidly activating, rapidly inactivating transient outward K+ current (Ito ) densities. We also observed a significant increase in both transcripts and protein levels of Kv1.5 and KChIP2 in hyperoxia treated atrial cardiomyocytes, whereas no significant change was observed in Kv4.2 transcripts or protein. The data presented here further support our previous findings that hyperoxia induces not only ventricular remodeling, but also atrial electrical remodeling. PMID- 29139550 TI - Long-term clinical and echocardiographic outcomes of Mitraclip therapy in patients nonresponders to cardiac resynchronization. AB - OBJECTIVES: This study deals with clinical and echocardiographic outcomes in cardiac resynchronization therapy (CRT) nonresponders patients undergoing Mitraclip procedure. BACKGROUND: Functional mitral regurgitation (FMR) occurs in approximately one-third of heart failure (HF) patients. Resynchronization therapy may correct FMR in patients with HF; however, significant FMR persists in 20-25% of CRT patients. METHODS: All patients included were previously treated with CRT for at least 6 months and remained classified as New York Heart Association (NYHA) functional class III or IV despite optimal medical therapy; the echocardiographic assessment showed lack of decrease of the left ventricular end systolic volume (LVESV) of at least 10% and residual moderate-to-severe or severe FMR. Clinical and echocardiographic follow-up was scheduled at 1, 3, 6, and 12 months after Mitraclip implantation, and every 6 months thereafter. RESULTS: Thirty patients fulfilled inclusion criteria. Before Mitraclip implantation NYHA class was III in 83% and IV in 17% of patients; after CRT no patient experienced an improvement in FMR. There was a significant improvement in NYHA class from baseline to 6 months, which remained sustained at 12 and 24 months. The degree of FMR significantly improved from baseline to 6 months and from 6 to 12 months. There was left ventricle remodeling with significant reduction of LVESV and an increase of left ventricle ejection fraction at 6 and 12 months, while the opposite trend was noted between 12 and 24 months CONCLUSION: Treatment of moderate to severe FMR in CRT nonresponder is feasible, safe, and reasonably effective in reducing cardiac symptoms. PMID- 29139548 TI - Prospects from systems serology research. AB - Antibodies are highly functional glycoproteins capable of providing immune protection through multiple mechanisms, including direct pathogen neutralization and the engagement of their Fc portions with surrounding effector immune cells that induce anti-pathogenic responses. Small modifications to multiple antibody biophysical features induced by vaccines can significantly alter functional immune outcomes, though it is difficult to predict which combinations confer protective immunity. In order to give insight into the highly complex and dynamic processes that drive an effective humoral immune response, here we discuss recent applications of 'Systems Serology', a new approach that uses data-driven (also called 'machine learning') computational analysis and high-throughput experimental data to infer networks of important antibody features associated with protective humoral immunity and/or Fc functional activity. This approach offers the ability to understand humoral immunity beyond single correlates of protection, assessing the relative importance of multiple biophysical modifications to antibody features with multivariate computational approaches. Systems Serology has the exciting potential to help identify novel correlates of protection from infection and may generate a more comprehensive understanding of the mechanisms behind protection, including key relationships between specific Fc functions and antibody biophysical features (e.g. antigen recognition, isotype, subclass and/or glycosylation events). Reviewed here are some of the experimental and computational technologies available for Systems Serology research and evidence that the application has broad relevance to multiple different infectious diseases including viruses, bacteria, fungi and parasites. PMID- 29139551 TI - Members of the DEAL subfamily of the DUF1218 gene family are required for bilateral symmetry but not for dorsoventrality in Arabidopsis leaves. AB - Most plant leaves exhibit bilateral symmetry, which has been hypothesized as an inevitable consequence of the existence of the proximodistal and dorsoventral axes. No gene has been described that affects leaf bilateral symmetry but not dorsoventrality in Arabidopsis thaliana. We screened for viable insertional mutations that affect leaf morphology, and out of more than 700 mutants found only one, desigual1-1 (deal1-1), that exhibited bilateral symmetry breaking but no obvious defects in dorsoventrality. We found that deal1-1 is an allele of VASCULATURE COMPLEXITY AND CONNECTIVITY (VCC). Several overlapping regulatory pathways establish the interspersed lobes and indentations along the margin of Arabidopsis thaliana leaves. These pathways involve feedback loops of auxin, the PIN-FORMED1 (PIN1) auxin efflux carrier, and the CUP-SHAPED COTYLEDON2 (CUC2) transcriptional regulator. Early vcc (deal1) leaf primordia fail to acquire bilateral symmetry and instead form ectopic lobes and sinuses. The vcc leaves show aberrant recruitment of marginal cells expressing properly polarized PIN1, resulting in misplaced auxin maxima. Normal PIN1 polarization requires CUC2 expression and CUC2 genetically interacts with VCC; VCC also affects CUC2 expression. VCC has a domain of unknown function, DUF1218, and localizes to the endoplasmic reticulum membrane. VCC acts partially redundantly with its two closest paralogs, DEAL2 and DEAL3, in early leaf margin patterning and is required for bilateral symmetry, but its loss of function does not visibly affect dorsoventrality. PMID- 29139552 TI - Critical evaluation of the PALM-COEIN classification system among women with abnormal uterine bleeding in low-resource settings. AB - OBJECTIVE: To assess the feasibility of the PALM-COEIN system for the classification of abnormal uterine bleeding (AUB) in low-resource settings and to suggest modifications. METHODS: A prospective study was conducted among women with AUB who were admitted to the gynecology ward of a tertiary care hospital and research center in central India between November 2014 and October 2016. All patients were managed as per department protocols. The causes of AUB were classified before treatment using the PALM-COEIN system (classification I) and on the basis of the histopathology reports of the hysterectomy specimens (classification II); the results were compared using classification II as the gold standard. RESULTS: The study included 200 women with AUB; hysterectomy was performed in 174 women. Preoperative classification of AUB per the PALM-COEIN system was correct in 130 (65.0%) women. Adenomyosis (evaluated by transvaginal ultrasonography) and endometrial hyperplasia (evaluated by endometrial curettage) were underdiagnosed. CONCLUSION: The PALM-COEIN classification system helps in deciding the best treatment modality for women with AUB on a case-by-case basis. The incorporation of suggested modifications will further strengthen its utility as a pretreatment classification system in low-resource settings. PMID- 29139553 TI - Distinct B subunits of PP2A regulate the NF-kappaB signalling pathway through dephosphorylation of IKKbeta, IkappaBalpha and RelA. AB - PP2A is composed of a scaffolding subunit (A), a catalytic subunit (C) and a regulatory subunit (B) that is classified into four families including B, B', B'' and B'''/striatin. Here, we found that a distinct PP2A complex regulates NF kappaB signalling by dephosphorylation of IKKbeta, IkappaBalpha and RelA/p65. The PP2A core enzyme AC dimer and the holoenzyme AB'''C trimer dephosphorylate IKKbeta, IkappaBalpha and RelA, whereas the ABC trimer dephosphorylates IkappaBalpha but not IKKbeta and RelA in cells. In contrast, AB'C and AB''C trimers have little effect on dephosphorylation of these signalling proteins. These results suggest that different forms of PP2A regulate NF-kappaB pathway signalling through multiple steps each in a different manner, thereby finely tuning NF-kappaB- and IKKbeta-mediated cellular responses. PMID- 29139556 TI - Delivery outcomes of large-for-gestational-age newborns stratified by the presence or absence of gestational diabetes mellitus. AB - OBJECTIVE: To evaluate separate and combined contributions of gestational diabetes mellitus (GDM) and large-for-gestational age (LGA) on delivery outcomes. METHODS: In a retrospective cohort study of term singleton deliveries between 2007 and 2014 in Tel Aviv, Israel, outcomes were compared between non-GDM/AGA pregnancies (reference) and three study groups: non-GDM/LGA, GDM/appropriate for gestational age (AGA) and GDM/LGA. RESULTS: Overall, there were 62 102 deliveries, of which 53 201 (85.7%) were eligible for inclusion. Of these, 43 775 (82.3%) were non-GDM/AGA, 6441 (12.1%) non-GDM/LGA, 2351 (4.4%) GDM/AGA, and 634 (1.2%) GDM/LGA. Compared with the reference group, the study groups had higher mean maternal age and higher rates of previous cesarean delivery, polyhydramnios, induction of labor, and cesarean delivery. Considering only women attempting vaginal delivery, the three groups were independently associated with adverse outcomes including cesarean delivery (adjusted odds ratio [aOR], 1.5, 1.6, and 2.6 for non-GDM/LGA, GDM/AGA, and GDM/LGA, respectively), mainly for prolonged first stage of labor, and hypoglycemia (aOR, 1.9, 2.5, and 4.6, respectively). LGA with and without GDM was associated with shoulder dystocia (aOR, 14.5 and 6.9, respectively), prolonged second stage, and jaundice. CONCLUSION: GDM and LGA share similarities in pregnancy complications. The presence of both has a cumulative impact. PMID- 29139554 TI - Immune checkpoint inhibitors: new strategies to checkmate cancer. AB - Immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or programmed cell death protein 1 (PD-1) receptors have demonstrated remarkable efficacy in subsets of patients with malignant disease. This emerging treatment modality holds great promise for future cancer treatment and has engaged pharmaceutical research interests in tumour immunology. While ICIs can induce rapid and durable responses in some patients, identifying predictive factors for effective clinical responses has proved challenging. This review summarizes the mechanisms of action of ICIs and outlines important preclinical work that contributed to their development. We explore clinical data that has led to disease-specific drug licensing, and highlight key clinical trials that have revealed ICI efficacy across a range of malignancies. We describe how ICIs have been used as part of combination therapies, and explore their future prospects in this area. We conclude by discussing the incorporation of these new immunotherapeutics into precision approaches to cancer therapy. PMID- 29139557 TI - Using somatosensory mismatch responses as a window into somatotopic processing of tactile stimulation. AB - Brain responses to tactile stimulation have often been studied through the examination of ERPs elicited to touch on the body surface. Here, we examined two factors potentially modulating the amplitude of the somatosensory mismatch negativity (sMMN) and P300 responses elicited by touch to pairs of body parts: (a) the distance between the representation of these body parts in somatosensory cortex, and (b) the physical distances between the stimulated points on the body surface. The sMMN and the P300 response were elicited by tactile stimulation in two oddball protocols. One protocol leveraged a discontinuity in cortical somatotopic organization, and involved stimulation of either the neck or the hand in relation to stimulation of the lip. The other protocol involved stimulation to the third or fifth finger in relation to the second finger. The neck-lip pairing resulted in significantly larger sMMN responses (with shorter latencies) than the hand-lip pairing, whereas the reverse was true for the amplitude of the P300. Mean sMMN amplitude and latency did not differ between finger pairings. However, larger P300 responses were elicited to stimulation of the fifth finger than the third finger. These results suggest that, for certain combinations of body parts, early automatic somatosensory mismatch responses may be influenced by distance between the cortical representations of these body parts, whereas the later P300 response may be more influenced by the distance between stimulated body parts on the body surface. Future investigations can shed more light on this novel suggestion. PMID- 29139555 TI - Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non-alcoholic fatty liver disease. AB - BACKGROUND AND PURPOSE: The gut-liver axis is associated with the progression of non-alcoholic fatty liver disease (NAFLD). Targeting the gut-liver axis and bile acid-based pharmaceuticals are potential therapies for NAFLD. The effect of tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD, on intestinal barrier function, intestinal inflammation, gut lipid transport and microbiota composition was analysed in a murine model of NAFLD. EXPERIMENTAL APPROACH: The NAFLD mouse model was established by feeding mice a high-fat diet (HFD) for 16 weeks. TUDCA was administered p.o. during the last 4 weeks. The expression levels of intestinal tight junction genes, lipid metabolic and inflammatory genes were determined by quantitative PCR. Tissue inflammation was evaluated by haematoxylin and eosin staining. The gut microbiota was analysed by 16S rRNA gene sequencing. KEY RESULTS: TUDCA administration attenuated HFD-induced hepatic steatosis, inflammatory responses, obesity and insulin resistance in mice. Moreover, TUDCA attenuated gut inflammatory responses as manifested by decreased intestinal histopathology scores and inflammatory cytokine levels. In addition, TUDCA improved intestinal barrier function by increasing levels of tight junction molecules and the solid chemical barrier. The components involved in ileum lipid transport were also reduced by TUDCA administration in HFD-fed mice. Finally, the TUDCA-treated mice showed a different gut microbiota composition compared with that in HFD-fed mice but similar to that in normal chow diet-fed mice. CONCLUSIONS AND IMPLICATIONS: TUDCA attenuates the progression of HFD-induced NAFLD in mice by ameliorating gut inflammation, improving intestinal barrier function, decreasing intestinal fat transport and modulating intestinal microbiota composition. PMID- 29139558 TI - Peptide fragments of Hsp70 modulate its chaperone activity and sensitize tumor cells to anti-cancer drugs. AB - Most Hsp70 chaperone inhibitors exert anti-cancer effects; however, their high cytotoxicity proposed the use of peptide fragments of the chaperone as safer modulators of its activity and as complements to customary drugs. One such peptide, ICit-2, was found to inhibit substrate-binding and refolding activities of the chaperone. Using various approaches, we established that ICit-2 binds Hsp70, which may explain its inhibitory action. ICit-2 penetrates A-431 cancer cells and, in combination with doxorubicin (Dox), enhances the cytotoxicity and growth inhibitory effect of the drug. Similarly, using the B16 mouse melanoma model, we found that ICit-2 inhibits the rate of tumor growth by 48% compared to Dox alone, confirming that the peptide can be employed to sensitize resistant tumors to cytostatic medicines. PMID- 29139559 TI - Associations among tooth loss, systemic inflammation and antibody titers to periodontal pathogens in Japanese patients with cardiovascular disease. AB - BACKGROUND AND OBJECTIVE: It is well known that there is a strong relationship between periodontitis and cardiovascular disease (CVD). Tooth loss reflects an end-stage condition of oral diseases, such as periodontitis. Infection with specific periodontal pathogens is known as a possible factor that influences development of CVD. The aim of this study was to assess the relationship between the number of residual teeth and systemic inflammatory conditions in patients with CVD. MATERIAL AND METHODS: We divided 364 patients with CVD into four groups, according to the number of residual teeth: (i) >=20 teeth; (ii) 10-19 teeth; (iii) 1-9 teeth; and (iv) edentulous. We recorded medical history, blood data and periodontal conditions. Serum samples were obtained and their IgG titers against three major periodontal pathogens were measured. RESULTS: Smoking rate and the prevalence of diabetes mellitus were higher in edentulous patients and in subjects with a few teeth compared with patients with many teeth. The levels of C reactive protein were higher in patients with 1-9 teeth than in those with 10-19 teeth and with >=20 teeth. The level of Porphyromonas gingivalis IgG in the group with 10-19 teeth was statistically higher than that in the group with >=20 teeth. The level of P. gingivalis IgG in the edentulous group tended to be lower than that in the other groups. CONCLUSION: The patients with 1-9 teeth had the highest level of C-reactive protein among the four groups, and the patients with 10-19 teeth had the highest level of IgG to periodontal bacteria. We conclude that the number of remaining teeth may be used to estimate the severity of systemic inflammation in patients with CVD. PMID- 29139560 TI - The Mammalian Circadian Clock Exhibits Chronic Ethanol Tolerance and Withdrawal Induced Glutamate Hypersensitivity, Accompanied by Changes in Glutamate and TrkB Receptor Proteins. AB - BACKGROUND: Alcohol tolerance and withdrawal-induced effects are criteria for alcohol use disorders listed by the DSM-V. Although tolerance and withdrawal have been studied over many decades, there is still uncertainty regarding mechanistic distinctions that characterize these different forms of ethanol (EtOH)-induced plasticity. Previously, we demonstrated that the suprachiasmatic nucleus (SCN) circadian clock develops both acute and rapid tolerance to EtOH inhibition of glutamate-induced circadian phase shifts. Here, we demonstrate that chronic EtOH tolerance and withdrawal-induced glutamate hypersensitivity occur in vitro and that rapid tolerance, chronic tolerance, and glutamate hypersensitivity have distinct cellular changes. METHODS: We use single-unit extracellular electrophysiological recordings to determine whether chronic tolerance to EtOH inhibition of glutamatergic phase shifts and withdrawal-induced glutamate hypersensitivity develop in the SCN. We use Western blotting to compare phosphorylation state and total expression of N-methyl-D-aspartate (NMDA) receptor subunits and associated proteins in the SCN after mice were exposed to varying EtOH consumption paradigms. RESULTS: Chronic tolerance developed after a minimum of 8 days of 4 h/d EtOH access, as indicated by a decreased sensitivity to EtOH inhibition of glutamate-induced phase shifts. We also observed an increased sensitivity to glutamate-induced phase shifts in SCN tissue following withdrawal. We demonstrated an increase in the ratio of NR2B:NR2A NMDA receptor subunit expression after 21 days, but not after 10 days of EtOH drinking. This increase persisted during EtOH withdrawal, along with an increase in NR2B Y1472 phosphorylation, mature brain-derived neurotrophic factor, and phosphorylated TrkB. CONCLUSIONS: These results demonstrate that multiple tolerance forms and withdrawal-induced glutamate hypersensitivity occur in the SCN and that these different forms of EtOH-induced plasticity are accompanied by distinct changes in cellular physiology. Importantly, this study further demonstrates the power of using the SCN as a model system to investigate EtOH-induced plasticity. PMID- 29139562 TI - LncRNA GHET1 predicts poor prognosis in hepatocellular carcinoma and promotes cell proliferation by silencing KLF2. AB - Hepatocellular carcinoma (HCC) has been identified as one of the leading causes of cancer-related death worldwide. Recently, long non-coding RNAs (lncRNAs) attract much attention of researchers, and they are demonstrated to be dysregulated in a variety of cancers, including HCC. LncRNA gastric carcinoma high expressed transcript 1 lncRNA GHET1 is found to be dysregulated in gastric cancer (GC). However, its clinical value and potential biological function in HCC remains unclear. In this study, the expression level of GHET1 was analyzed in 72 HCC tissues and matched normal tissues by using Quantitative RT-PCR (qRT-PCR). GHET1 expression was significantly up-regulated in HCC tissues and the higher level of GHET1 was related to vascular invasion, cirrhosis, tumor size, edmindson grade, and poor prognosis. Moreover, knockdown of GHET1 inhibited cell proliferation of HCC, and also caused cell cycle arrest and induced apoptosis in HCC cell lines. We also found that GHET1 could epigenetically repress transcription of Kruppel-like factor 2 (KLF2) in HCC cells by recruiting PRC2 into KLF2 promoter region. Our results indicated that lncRNA GHET1, as a growth regulator, might serve as a novel prognostic biomarker and therapy target for HCC. PMID- 29139561 TI - The novel, potent and highly selective 5-HT4 receptor agonist YH12852 significantly improves both upper and lower gastrointestinal motility. AB - BACKGROUND AND PURPOSE: 5-HT4 receptor agonists have been shown to be effective at treating various gastrointestinal tract disorders. However, a lack of selectivity against off-targets has been a limiting factor for their clinical use. EXPERIMENTAL APPROACH: The binding affinity and selectivity of YH12852 for human 5-HT4(a) receptor in CHO-K1 cells were evaluated using radioligand binding assays, and agonistic activity was assessed using a beta-lactamase reporter system. Contractile activity and propulsive motility were measured in the guinea pig isolated distal colon. Its prokinetic effect on the gastrointestinal tract was evaluated in guinea pigs, dogs and monkeys. Its tissue distribution was evaluated in rats. KEY RESULTS: YH12852 exhibited high affinity and potency for human recombinant 5-HT4(a) receptor with high selectivity over other 5-HT and non 5-HT receptors, ion channels, enzymes and transporters. YH12852 induced contractions and increased propulsive motility in guinea pig isolated colon. These effects were abolished by the 5-HT4 receptor antagonist GR113808. YH12852 increased defecation more effectively than prucalopride in guinea pigs and dogs and improved gastric emptying more effectively than mosapride in guinea pigs, dogs and monkeys. YH12852 was highly distributed to the gastrointestinal tract as the target organ. CONCLUSION AND IMPLICATIONS: The high in vitro potency and selectivity of YH12852 for 5-HT4 receptor translated into potent in vivo efficacy with good tolerability. YH12852 significantly improved both upper and lower bowel motility in the animal models tested and has the potential to address considerable unmet needs in patients with functional constipation, gastroparesis or both. PMID- 29139563 TI - The interplay of gender and social background: A longitudinal study of interaction effects in reading attitudes and behaviour. AB - BACKGROUND: Researchers often report and discuss gender differences. However, recent research has drawn attention to interaction effects between gender and other social categories. AIMS: This study analysed the development of disparities in students' reading-related self-concept, intrinsic motivation, and behaviour, as they relate to differences in gender and socio-economic family background. Drawing on expectancy-value theory, we regarded reading-related self-concept, motivation, and behaviour as key to explaining the growing differences between boys and girls in adolescence. Specifically, we focused on the interaction between gender and socio-economic background in children, which has been discussed in the context of moderating gender differences but not in the context of reading-related attitudes and behaviour. SAMPLE: The investigation is based on a longitudinal sample of N = 717 German students between third and sixth grades. METHOD: We used questionnaire data from both students and parents. To compare students' development across time, we applied multigroup latent growth curve models. RESULTS: We found evidence of increasing gender differences, which were also moderated by the socio-economic status (SES) of parents: a gender gap either already existed (intrinsic motivation and reading behaviour) or intensified (reading self-concept and reading behaviour) between third and sixth grades. The interaction of gender and SES seemed particularly important for reading self concept, with the gender gap growing less substantially for higher-SES children. Moreover, this pattern persisted for reading self-concept, even when controlling for achievement differences. CONCLUSIONS: The results provide evidence that gender, social background, and the interaction of the two are relevant for development in the domain of reading, even in young children. PMID- 29139565 TI - Leukocyte adhesion defect-I: rare primary immune deficiency. AB - Leukocyte adhesion defect I is a rare disorder (1:1,000,000) caused by diminished expression of CD-18 beta2 integrins on leukocytes leading to abnormal adhesion, migration, and chemotaxis. Clinical manifestations include delayed separation of umbilical cord, omphalitis, recurrent severe infections, impaired wound healing, persistent oral ulcers, and severe periodontitis in primary and permanent dentition. A 5-year-old girl, second-born child to parents with consanguinity, presented with pain and mobility of lower teeth. There was history of recurrent infections and multiple hospital admissions with CD18 level-3% and frame shift mutation in ITGB2, on 21q22.3. There were scars on hands and feet. Oral examination revealed multiple missing teeth and periodontitis in primary dentition. Oral prophylaxis and palliative treatments were performed with periodic follow-ups. Interdisciplinary care is ubiquitous for patients with immune deficiencies. Early consultation with pediatric dentists and exploration of medical history is essential for diagnosis and treatment of rare diseases. PMID- 29139564 TI - Incident diuretic drug use and adverse respiratory events among older adults with chronic obstructive pulmonary disease. AB - AIMS: Diuretic drugs may theoretically improve respiratory health outcomes in chronic obstructive pulmonary disease (COPD) through several possible mechanisms, but they might also lead to respiratory harm. We evaluated the association of incident oral diuretic drug use with respiratory-related morbidity and mortality among older adults with COPD. METHODS: This was a population-based, retrospective cohort study using health administrative data from Ontario, Canada, for the period 2008-2013. We identified adults aged 66 years and older with nonpalliative COPD using a validated algorithm. Respiratory-related morbidity and mortality were evaluated within 30 days of incident oral diuretic drug use compared to nonuse using Cox proportional hazard regression and applying inverse probability of treatment weighting using the propensity score to minimize confounding. RESULTS: Out of 99 766 individuals aged 66 years and older with COPD identified, incident diuretic receipt occurred in 51.7%. Relative to controls, incident diuretic users had significantly increased rates for hospitalization for COPD or pneumonia [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.07-1.40], as well as more emergency room visits for COPD or pneumonia (HR 1.35, 95% CI 1.18 1.56), COPD or pneumonia-related mortality (HR 1.41; 95% CI 1.04-1.92) and all cause mortality (HR 1.20, 95% CI 1.06-1.35). The increased respiratory-related morbidity and mortality observed were specifically as a result of loop diuretic use. CONCLUSIONS: Incident diuretic drugs, and more specifically loop diuretics, were associated with increased rates of respiratory-related morbidity and mortality among older adults with nonpalliative COPD. Further studies are needed to determine if this association is causative or due to unresolved confounding. PMID- 29139566 TI - Patient-reported rates of chronic pain and recurrence after groin hernia repair. AB - BACKGROUND: The effectiveness of different procedures in routine surgical practice for hernia repair with respect to chronic postoperative pain and reoperation rates is not clear. METHODS: This was prospective cohort study based on a unique combination of patient-reported outcomes and national registry data. Virtually all patients with a groin hernia repair in Sweden between September 2012 and April 2015 were sent a questionnaire 1 year after surgery. Persistent pain, defined as at least 'pain present, cannot be ignored, and interferes with concentration on everyday activities' in the past week was the primary outcome. Reoperation for recurrence recorded in the register was the secondary outcome. RESULTS: In total, 22 917 patients (response rate 75.5 per cent) who had an elective unilateral groin hernia repair were analysed. Persistent pain present 1 year after hernia repair was reported by 15.2 per cent of patients. The risk was least for endoscopic total extraperitoneal (TEP) repair (adjusted odds ratio (OR) 0.84, 95 per cent c.i. 0.74 to 0.96), compared with open anterior mesh repair. TEP repair had an increased risk of reoperation for recurrence (adjusted OR 2.14, 1.52 to 2.98), as did open preperitoneal mesh repair (adjusted OR 2.34, 1.42 to 3.71) at 2.5-year follow-up. No other methods of repair differed significantly from open anterior mesh repair. CONCLUSION: The risk of significant pain 1 year after groin hernia repair in routine surgical practice was 15.2 per cent. This figure was lower in patients who had surgery by an endoscopic technique, but at the price of a significantly higher risk of reoperation for recurrence. PMID- 29139567 TI - Effectiveness of an oral health educational intervention for individuals with special health care needs from a southern Brazilian city. AB - AIM: To assess the effects of an oral health education strategy targeted at students with disabilities. METHODS: This quasi-experimental study included students aged 7 to 24 years. The intervention was conducted for 5 weeks and divided into 2 phases: (1) comprising supervised toothbrushing and educational activities to students; (2) verbal oral health instructions and oral hygiene demonstration targeted at the caregivers. A clinical examination was conducted to evaluate the dental debris and gingival bleeding before the intervention, and the Wilcoxon test was performed after phase 1 and 2 for comparisons between paired samples. RESULTS: A significant decrease in dental debris and gingival indices compared with baseline occurred after phase 1 (p < 0.05). After the meeting with caregivers (phase 2), there was significant decrease in the debris-index (p < 0.05). CONCLUSIONS: Providing a simple and short-term educational intervention to students with disabilities had a positive impact on their oral health. PMID- 29139568 TI - Biomimetic syntheses of racemic natural products. AB - Racemic natural products are rarely produced in plants and microorganisms and are thought to be the result of nonenzymatic, spontaneous reactions. These compounds are often highly complex with multiple contiguous chiral centers that present a challenge to organic synthesis. Formation of these racemates often occurs by cyclization reactions that can generate multiple stereocenters from achiral precursors. Biomimetic synthesis of these racemic natural products provides support for their proposed nonenzymatic spontaneous biosynthesis. These elegant syntheses also provide scalable and efficient routes to these complex natural products. Although the number of reported racemic natural products is relatively low, an isolated natural product that has a very small optical rotation has been shown to be a true racemate. Thus, the occurrence of racemic natural products could be more common than thought. PMID- 29139569 TI - Lipase-catalyzed enantioselective transesterification of prochiral 1-((1,3 dihydroxypropan-2-yloxy)methyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione in ionic liquids. AB - The application of ionic liquids as solvents for transesterification of prochiral pirymidine acyclonucleoside using lipase (EC 3.1.1.3) Amano PS from Burkholderia cepacia (BCL) is reported. The effect of using medium reaction, acyl group donor, and temperature on the activity and enantioselectivity of BCL was studied. From the investigated ionic solvents, the hydrophobic ionic liquid [BMIM]PF6 ] was the preferred medium for enzymatic reactions. However, the best result was obtained in the mixture [BMIM][PF6 ]:TBME (1:1 v/v) at 50 degrees C. Enzyme activity and selectivity in [BMIM][PF6 ]:TBME (1:1 v/v) was slightly higher in than in conventional organic solvents (for example, TBME), and in this condition, good activity and enantioselectivity were associated with unique properties of ionic liquid such as hydrophobicity and high polarity. Independently of solvents, monester of (R)-configuration was obtained in excess. Under optimal conditions, desymmetrization of the prochiral compound using different acyl donors was performed. If vinyl butyrate was used as the acylating agent, BCL completely selectively acylated enantiotopic hydroxyl groups. PMID- 29139570 TI - Distribution of segmental foot kinematics in patients with degenerative joint disease of the ankle. AB - Degenerative joint disease (DJD) of the ankle is a debilitating chronic disease associated with severe pain and dysfunction resulting in antalgic gait alteration. Little information is available about segmental foot and ankle motion distribution during gait in ankle osteoarthritis. The aim of the current study was to dynamically characterize segmental foot and ankle kinematics of patients with severe ankle arthrosis requiring total ankle replacement. This was a prospective study involving 36 (19 M, 17 F) adult patients with a clinical diagnosis of ankle arthrosis ("DJD" group) and 36 (23 M, 13 F) healthy subjects ("Control" group). Motion data were collected at 120 Hz using a 3-D motion camera system at self-selected speed along a 6-m walkway and processed using the Milwaukee Foot Model (MFM). The SF-36 Health Survey and Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale were administered to evaluate functional levels. Findings include decreases in walking speed, cadence, stride length and swing phase, and reduced outcomes scores (SF-36 and AOFAS). Multisegemental motion in patients with ankle DJD demonstrates significant changes in foot mechanics characterized by altered segment kinematics and significant reduction in dynamic ROM at the tibia, hindfoot, forefoot, and hallux when compared to controls. The results demonstrate decreased temporal-spatial parameters and low outcomes scores indicative of functional limitations. Statement of clinical significance: Altered segment kinematics and reduced overall range of motion demonstrate how a single joint pathology affects kinematic distribution in the other segments of the foot and ankle and alters patients' overall gait. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1739-1746, 2018. PMID- 29139572 TI - Exposing ecological and economic costs of the research-implementation gap and compromises in decision making. AB - The frequently discussed gap between conservation science and practice is manifest in the gap between spatial conservation prioritization plans and their implementation. We analyzed the research-implementation gap of one zoning case by comparing results of a spatial prioritization analysis aimed at avoiding ecological impact of peat mining in a regional zoning process with the final zoning plan. We examined the relatively complex planning process to determine the gaps among research, zoning, and decision making. We quantified the ecological costs of the differing trade-offs between ecological and socioeconomic factors included in the different zoning suggestions by comparing the landscape-level loss of ecological features (species occurrences, habitat area, etc.) between the different solutions for spatial allocation of peat mining. We also discussed with the scientists and planners the reasons for differing zoning suggestions. The implemented plan differed from the scientists suggestion in that its focus was individual ecological features rather than all the ecological features for which there were data; planners and decision makers considered effects of peat mining on areas not included in the prioritization analysis; zoning was not truly seen as a resource-allocation process and not emphasized in general minimizing ecological losses while satisfying economic needs (peat-mining potential); and decision makers based their prioritization of sites on site-level information showing high ecological value and on single legislative factors instead of finding a cost-effective landscape-level solution. We believe that if the zoning and decision-making processes are very complex, then the usefulness of science based prioritization tools is likely to be reduced. Nevertheless, we found that high-end tools were useful in clearly exposing trade-offs between conservation and resource utilization. PMID- 29139571 TI - Human prosthetic joint infections are associated with myeloid-derived suppressor cells (MDSCs): Implications for infection persistence. AB - : Prosthetic joint infection (PJI) is a devastating complication of joint arthroplasty surgery typified by biofilm formation. Currently, mechanisms whereby biofilms persist and evade immune-mediated clearance in immune competent patients remain largely ill-defined. Therefore, the current study characterized leukocyte infiltrates and inflammatory mediator expression in tissues from patients with PJI compared to aseptic loosening. CD33+ HLA-DR- CD66b+ CD14-/low granulocytic myeloid-derived suppressor cells (G-MDSCs) were the predominant leukocyte population at sites of human PJI compared to aseptic tissues. MDSCs inhibit T cell proliferation, which coincided with reduced T cells in PJIs compared to aseptic tissues. IL-10, IL-6, and CXCL1 were significantly elevated in PJI tissues and have been implicated in MDSC inhibitory activity, expansion, and recruitment, respectively, which may account for their preferential increase in PJIs. This bias towards G-MDSC accumulation during human PJI could account for the chronicity of these infections by preventing the pro-inflammatory, antimicrobial actions of immune effector cells. CLINICAL SIGNIFICANCE: Animal models of PJI have revealed a critical role for MDSCs and IL-10 in promoting infection persistence; however, whether this population is prevalent during human PJI and across distinct bacterial pathogens remains unknown. This study has identified that granulocytic-MDSC infiltrates are unique to human PJIs caused by distinct bacteria, which are not associated with aseptic loosening of prosthetic joints. Better defining the immune status of human PJIs could lead to novel immune-mediated approaches to facilitate PJI clearance in combination with conventional antibiotics. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1605-1613, 2018. PMID- 29139573 TI - Gait patterns, symptoms, and function in patients with isolated tibiofemoral osteoarthritis and combined tibiofemoral and patellofemoral osteoarthritis. AB - The purpose of this study was to compare hip and knee biomechanics during walking in individuals with isolated tibiofemoral osteoarthritis (TFOA), combined TFOA and patellofemoral osteoarthritis (PFOA), and those without knee osteoarthritis (OA), and to compare patient-reported symptoms and function in individuals with isolated TFOA and those with combined TFOA and PFOA. Participants with and without knee OA were assessed and categorized into (i) no OA, (ii) isolated TFOA, and (iii) combined TFOA and PFOA, based on Kellgren and Lawrence diagnostic criteria. Quantitative motion analyses were conducted during walking, and hip and knee kinematics, and external moments were calculated. Peak values in the sagittal and frontal planes during stance phase were computed. Patient-reported symptoms and function data were obtained using the Western Ontario McMaster Universities Arthritis Index. Multivariate analyses of variance were conducted to compare between-group differences in gait and patient-reported symptoms and function data. The results showed no statistically significant differences in hip and knee kinematics and external moments between the three groups. Relative to those with isolated TFOA, individuals with combined TFOA and PFOA had greater pain (mean difference [95%CI]: 1.5 [0.05-3.1]), stiffness (0.8 [0.02-1.5]), and poorer function (5.4 [0.2-10.7]). In conclusion, the combined TFOA and PFOA radiographic disease pattern is associated with worse pain and function compared to the isolated TFOA disease pattern. The results of the present study provide no indications that treatments designed to change walking biomechanics should differ between individuals with isolated TFOA and those with combined TFOA and PFOA. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1666-1672, 2018. PMID- 29139574 TI - An oxorhenium complex bearing a chiral cyclohexane-1-olato-2-thiolato ligand: Synthesis, stereochemistry, and theoretical study of parity violation vibrational frequency shifts. AB - In our effort towards measuring the parity violation energy difference between two enantiomers, a simple chiral oxorhenium complex 5 bearing enantiopure 2 mercaptocyclohexan-1-ol has been prepared as a potential candidate species. Vibrational circular dichroism revealed a chiral environment surrounding the rhenium atom, even though the rhenium is not a stereogenic center itself, and enabled to assign the (1S,2S)-(-) and (1R,2R)-(+) absolute configuration for 5. For both compound 5 and complex 4, previously studied by us and bearing a propane 2-olato-3-thiolato ligand, relativistic calculations predict parity violating vibrational frequency differences of a few hundreds of millihertz, above the expected sensitivity attainable by a molecular beam Ramsey interferometer that we are constructing. PMID- 29139575 TI - Developmental Links Between Gaming and Depressive Symptoms. AB - The current longitudinal study tested the reciprocal relationships between video game play and depressive symptoms among 9,421 adolescents from the Add Health (Mage = 16.15 years, SD = 1.64, 55% female), over 11 years (Waves 2, 3, and 4), ages 16 to 27. Based on structural equation modeling as well as latent growth models, findings indicated that (1) excessive gaming was largely transient over time, from adolescence to early adulthood; (2) excessive gaming predicted increases in depressive symptoms; and (3) in turn, depressive symptoms predicted decreases in gaming over time. Multigroup model tests by sex provided additional evidence that longitudinal relationships from excessive gaming to depressive symptoms were supported for male, but not for female youth. PMID- 29139576 TI - Effects of lateral-offset sole shoes on knee adduction moment in women with medial compartment knee osteoarthritis. AB - This study aimed to determine the impact of wearing a lateral-offset sole shoe (LOSS) on knee adduction moment (KAM) in patients with medial knee osteoarthritis (OA). From December 2012 to November 2016, patients with medial knee OA were recruited. Ninety-three knees (50 left, 43 right) of 93 female patients were analyzed. The first peak KAMs were measured with patients (i) walking barefoot; (ii) walking in conventional shoes; and (iii) walking in LOSSs. The patients had grade 1 (n = 19), grade 2 (n = 49), grade 3 (n = 20), and grade 4 (n = 5) knee OA. First peak KAMs differed significantly in all three conditions (p = 0.031). In the post hoc analysis, first peak KAMs were significantly lower during LOSS walking than during conventional shoe walking (p = 0.001), but there were no differences in peak KAMs between barefoot and LOSS walking (p = 0.784). In the subgroup analysis, patients with grades 2 and 3 OA showed significantly lower first peak KAMs during LOSS walking than during conventional shoe walking (p = 0.029 and p = 0.011, respectively). Both the peak eversion ankle angle and moment of barefoot walking showed a significant increase compared with LOSS and conventional shoe walking, while there was no significant difference between LOSS and conventional shoe walking (p = 0.612 and p = 0.197, respectively). Our results suggest that LOSS wearing caused significant KAM reductions compared with conventional shoe wearing. Since LOSS wearing does not cause changes in the peak eversion ankle angle and moment during the load response, it may be an effective method to reduce the KAM in women with knee OA. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1694-1700, 2018. PMID- 29139577 TI - Copper uptake, patterns of bioaccumulation, and effects in glochidia (larvae) of the freshwater mussel (Lampsilis cardium). AB - The early life stages of freshwater mussels are particularly sensitive to copper (Cu) contamination. We measured the acute toxicity, bioaccumulation, and sublethal effects of Cu in glochidia. In addition, we used radiolabeled Cu (64 Cu) to examine the time-dependent kinetics of uptake over 24 h. Uptake of 64 Cu by live and dead glochidia exposed to 0.11 MUmol/L exhibited similar hyperbolic patterns over the first 40 min, indicating an adsorptive phase independent of larval metabolism. Thereafter, uptake was linear with time, with a 10-fold lower bioaccumulation rate in live than in dead animals, representing a close to steady state of Cu regulation. In contrast, dead glochidia exhibited a progressively increasing uptake, possibly attributable to the fact that metal-binding sites become more accessible. Mortality was strongly correlated with bioaccumulation (48 h); live glochidia exposed to Cu concentrations >0.27 MUmol/L lost their regulatory ability and accumulated Cu to an even greater extent than dead animals. Exposure to Cu induced significant decreases in whole-body Na+ and Mg2+ concentrations; increases in reactive oxygen species concentration, lipid peroxidation, and protein carbonylation; and a decrease in antioxidant capacity against peroxyl radicals. Overall, these results clarify the patterns of Cu uptake and regulation, emphasize the importance of distinguishing between live and dead larvae, and indicate that toxicity is associated with Cu bioaccumulation, involving both ionoregulatory disturbance and oxidative stress. Environ Toxicol Chem 2018;37:1092-1103. (c) 2017 SETAC. PMID- 29139578 TI - Structure-Property Relationships in CuII -Binding Tetramolecular G-Quadruplex DNA. AB - A series of artificial metal-base tetrads composed of a CuII cation coordinating to four pyridines, covalently attached to the ends of tetramolecular G-quadruplex DNA strands [LA-D d(G4 )]4 (LA-D =ligand derivatives), was systematically studied. Structurally, the square-planar [Cu(pyridine)4 ] complex behaves analogously to the canonical guanine quartet. Copper coordination to all studied ligand derivatives was found to increase G-quadruplex thermodynamic stability, tolerating a great variety of ligand linker lengths (1-5 atoms) and thus demonstrating the robustness of the chosen ligand design. Only at long linker lengths, the stabilizing effect of copper binding is compensated by the loss of conformational freedom. A previously reported ligand LE with chiral backbone enables incorporation at any oligonucleotide position. We show that ligand chirality distinctly steers CuII -induced G-quadruplex stabilization. 5'-End formation of two metal-base tetrads by tetramolecular G-quadruplex [LE2 d(G)4 ]4 shows that stabilization in the presence of CuII is not additive. All results are based on UV/Vis thermal denaturation, thermal difference, circular dichroism experiments and molecular dynamics simulations. PMID- 29139580 TI - Novel carbohydrate binding modules in the surface anchored alpha-amylase of Eubacterium rectale provide a molecular rationale for the range of starches used by this organism in the human gut. AB - Gut bacteria recognize accessible glycan substrates within a complex environment. Carbohydrate binding modules (CBMs) of cell surface glycoside hydrolases often drive binding to the target substrate. Eubacterium rectale, an important butyrate producing organism in the gut, consumes a limited range of substrates, including starch. Host consumption of resistant starch increases the abundance of E. rectale in the intestine, likely because it successfully captures the products of resistant starch degradation by other bacteria. Here, we demonstrate that the cell wall anchored starch-degrading alpha-amylase, Amy13K of E. rectale harbors five CBMs that all target starch with differing specificities. Intriguingly these CBMs efficiently bind to both regular and high amylose corn starch (a type of resistant starch), but have almost no affinity for potato starch (another type of resistant starch). Removal of these CBMs from Amy13K reduces the activity level of the enzyme toward corn starches by ~40-fold, down to the level of activity toward potato starch, suggesting that the CBMs facilitate activity on corn starch and allow its utilization in vivo. The specificity of the Amy13K CBMs provides a molecular rationale for why E. rectale is able to only use certain starch types without the aid of other organisms. PMID- 29139579 TI - Topical adjuvants incompletely remove adherent Staphylococcus aureus from implant materials. AB - Adjuvant treatments including Betadine, Dakin's solution (sodium hypochlorite), or hydrogen peroxide (H2 O2 ) have been attempted to eradicate prosthetic joint infection caused by biofilm or intracellular bacteria. The purpose of this study was to evaluate the in vitro abilities of chemical adjuvants to decrease Staphylococcus aureus (S. aureus) biofilm presence on orthopaedic implant grade materials, including titanium, stainless steel, and cobalt chrome. S. aureus biofilms were grown for 48 h and evaluated for baseline colony forming units/centimeter squared (CFU/cm2 ) and compared to treatments with Betadine, Dakin's solution, H2 O2 , or 1% chlorine dioxide (ClO2 ). Control discs (n = 18) across all metals had an average of 4.2 * 107 CFU/cm2 . All treatments had statistically significant reductions in CFU/cm2 when compared to respective control discs (p < 0.05). For all metals combined, the most efficacious treatments were Betadine and H2 O2 , with an average 98% and 97% CFU/cm2 reduction, respectively. There were no significant differences between reductions seen with Betadine and H2 O2 , but both groups had statistically greater reductions than Dakin's solution and ClO2 . There was no change in antibiotic resistance patterns after treatment. Analysis of S. aureus biofilms demonstrated a statistically significant reduction in biofilm after a five-minute treatment with the modalities, with an average two log reduction in CFU/cm2 . Statement of clinical significance: While statistically significant reductions in CFU/cm2 were accomplished with chemical adjuvant treatments, the overall concentration of bacteria never fell below 105 CFU/cm2 , leading to questionable clinical significance. Further techniques to eradicate biofilm should be investigated. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1599-1604, 2018. PMID- 29139581 TI - Breast radiology malpractice suits: Characteristics of frequency and outcomes- national and statewide distinctions. AB - The purpose of this study was to determine the frequency and outcomes of breast malpractice suits among all enrollees in One Call Medical Inc.'s panel of interpreting radiologists nationally and to evaluate state-by-state variations. The 8401 radiologists enrolled had 4764 suits, of which 826 were related to breast disease. In New York and New Jersey, the ratio of breast suits to One Call Radiologists was 0.28 and 0.27, twice as much as in any other state. Breast suits in radiology have a wide variation in frequency across the country with New York and New Jersey far exceeding all others in relative frequency and number of radiologists with multiple breast suits. PMID- 29139582 TI - Bilateral synchronous breast malignant phyllodes in a pregnant woman. PMID- 29139583 TI - Total duct excision through a linear radial areola incision. PMID- 29139584 TI - Large pseudoangiomatous stromal hyperplasia of the breast in adolescent patient. PMID- 29139585 TI - Metaplastic spindle cell carcinoma of the breast in a patient with neurofibromatosis type 1. AB - We report a unique case of a 67-year-old woman with neurofibromatosis type 1, who was also diagnosed with metaplastic spindle cell carcinoma of the left breast. She had many neurofibromatosis lesions on her body, as well as the mass in the left breast. After the breast mass was diagnosed as a malignant mesenchymal tumor by core needle biopsy, the patient underwent left modified radical mastectomy. Subsequently, the pathological analysis of the tumor showed it to be a metaplastic spindle cell carcinoma. The co-occurrence of neurofibromatosis type 1 and breast cancer, in particular metaplastic spindle cell carcinoma, is very rare. PMID- 29139586 TI - Breast abscess after intravenous methamphetamine injection into the breast. AB - Intravenous drug use is a problem plaguing our society. We present a case of a young female who injected methamphetamine into her mammary vein, resulting in the formation of a breast abscess. This case demonstrates a rare but dangerous complication of intravenous drug use and a possible differential diagnosis in a patient presenting with a breast abscess. PMID- 29139587 TI - Metastatic giant malignant phyllodes tumor of the breast. PMID- 29139588 TI - Breast cancer in young women aged 35 and under: Patterns of care and outcome. PMID- 29139589 TI - Severe fasting hypoglycemia in a child after total pancreatectomy with islet autotransplantation. AB - TPIAT is an increasingly utilized treatment option for select children with CP. Post-TPIAT fasting hypoglycemia, unrelated to exogenous insulin, is a complication recently reported in adults. This phenomenon has not been described in children. We review a case of severe fasting hypoglycemia in an adolescent female occurring 10 months post-TPIAT. A 12-year-old girl underwent TPIAT for CP. Ten months postoperatively she developed recurrent hypoglycemia on a total daily insulin dose of 0.03 units/kg. Consequently, insulin therapy was discontinued. Approximately 20 hours after her last rapid-acting insulin exposure, she had an episode of fasting hypoglycemia (33 mg/dL on glucometer). Her CGM documented two separate, precipitous drops in glucose overnight. The family was instructed to revise her diet, and there were no subsequent episodes of severe, fasting hypoglycemia. This is the first report of fasting hypoglycemia occurring post TPIAT in a pediatric patient. Use of a CGM allowed for documentation of glucose trends and alarm notification of hypoglycemic events. Dietary changes appeared to help mitigate hypoglycemia recurrence. This report demonstrates that fasting hypoglycemia is a potential complication that should be recognized and safeguarded against in post-TPIAT pediatric patients. PMID- 29139590 TI - Breast density in screening mammography in Indian population - Is it different from western population? AB - Mammography is the only method presently considered appropriate for mass screening of breast cancer. However, higher breast density was strongly associated with lower mammographic sensitivity. Breast density is also identified as independent and strongest risk factors for breast cancer. Studies have shown women with high breast density have four to six times increased risk of breast cancer as compare to women with fatty breast. It varies between different age group it generally decreases with increasing age in postmenopausal women and it can be different in different ethnic groups and people from different geographical areas. This study evaluates the breast density in Indian population and its relationship with the age. We reviewed of all screening mammography examinations performed from May 2012 to January 2015 at our institute PGIMER, Chandigarh, INDIA. Descriptive analyses were used to examine the association between age and breast density. A total of 6132 screening mammograms were performed. Each subgroup categorized by decade of age. There was a significant inverse relationship between age and breast density (P < .001). Twenty-two percent of patients between 40 and 49 years old had dense breasts. This percentage decreased to 9% of women in their 50s. Only 7% of women in their 60s and 8% of women in their 70s had dense breasts. This data has been compared with the Western study done in New York University (NYU) shows there is significant difference (P value <.05) in the breast density in Indian and Western population with more Indians having ACR Grade 1 and 2 and Western population having 2 and 3. We found an inverse relationship between patient age and mammographic breast density. However, there were a large proportion of young women who had lower grades of mammographic density which could potentially benefit from the use of routine screening mammography in this subgroup of patients. Moreover, the breast density of Indian population is less when compared to the Western population. This might suggest that mammography is a good modality of choice for screening Indian population. PMID- 29139591 TI - MR imaging appearance of noncalcified and calcified DCIS. AB - To evaluate the MR appearance of noncalcified ductal carcinoma in situ (DCIS), with comparison to calcified DCIS. A retrospective, IRB-approved review of all DCIS diagnosed via MR biopsy between 2007 and 2011 was performed. DCIS was categorized as noncalcified based on the absence of calcifications on mammography and specimen radiography. MR morphology (focus, mass, nonmass enhancement [NME]) and enhancement kinetics (initial and delayed) for noncalcified DCIS were recorded and compared based on nuclear grade (1-3), size (<1.5 cm, 1.5-5 cm, >5 cm), and presence of necrosis. Imaging features of noncalcified and calcified DCIS were also compared. 115 cases of MR biopsy-proven DCIS were identified: 65 (56%) noncalcified and 50 (44%) calcified. For noncalcified DCIS, NME morphology was more common than mass or focus (60% vs 30.8% and 9.2%). There was a significant association between morphology and enhancement kinetics, with NME more likely demonstrating medium and persistent kinetics, and foci or masses demonstrating rapid and plateau or washout kinetics (P < .05). There was also a significant association between morphology and nuclear grade, with NME more likely seen with grade 3 DCIS (P = .024), and between size and initial enhancement, with lesions <1.5 cm more likely to have rapid initial enhancement (P = .0036). No significant difference was identified between calcified and noncalcified DCIS in terms of morphology, enhancement characteristics, nuclear grade, or presence of necrosis. The MR appearance of noncalcified DCIS closely mirrors that of calcified DCIS. Recognizing these imaging features may allow for improved identification of this MRI-detected abnormality, even in the absence of calcifications. PMID- 29139592 TI - Single dose systemic acetaminophen to improve patient reported quality of recovery after ambulatory segmental mastectomy: A prospective, randomized, double blinded, placebo controlled, clinical trial. AB - Few systemic drug interventions are efficacious to improve patient reported quality of recovery after ambulatory surgery. We aimed to evaluate whether a single dose systemic acetaminophen improve quality of recovery in female patients undergoing ambulatory breast surgery. We hypothesized that patients receiving a single dose systemic acetaminophen at the end of the surgical procedure would have a better global quality of postsurgical recovery compared to the ones receiving saline. The study was a prospective randomized double blinded, placebo controlled, clinical trial. Healthy female subjects were randomized to receive 1 g single dose systemic acetaminophen at the end of the surgery or the same volume of saline. The primary outcome was the Quality of Recovery 40 (QOR-40) questionnaire at 24 hours after surgery. Other data collected included opioid consumption and pain scores. Data were analyzed using group t tests and the Wilcoxon exact test. The association between opioid consumption and quality of recovery was evaluated using Spearman rho. P < .05 was used to reject the null hypothesis for the primary outcome. Seventy subjects were randomized and sixty five completed the study. Patients' baseline characteristics and surgical factors were similar between the study groups. There was a clinically significant difference in the global QoR-40 scores between the acetaminophen and the saline groups, median (IQR) of 189 (183 to 194) and 183 (175 to 190), respectively, P = .01. In addition, there was an inverse relationship (Spearman's rho= -0.33) between oral opioid consumption at home (oral morphine equivalents) and 24 hour postoperative quality of recovery, P = .007. A single dose of systemic acetaminophen improves patient reported quality of recovery after ambulatory breast surgery. The use of systemic acetaminophen is an efficacious strategy to improve patient perceived quality of postsurgical recovery and analgesic outcomes after hospital discharge for ambulatory breast surgery. PMID- 29139593 TI - Benefit finding trajectories in cancer patients receiving psychological care: Predictors and relations to depressive and anxiety symptoms. AB - OBJECTIVES: This study aimed to (1) identify benefit finding trajectories in cancer patients receiving psychological care; (2) examine associations of benefit finding trajectories with levels of and changes in psychological symptoms; and (3) examine whether socio-demographic and medical characteristics distinguished trajectories. DESIGN: Naturalistic longitudinal study design. METHODS: Participants were 241 cancer patients receiving psychological care at specialized psycho-oncological institutions in the Netherlands. Data were collected before starting psychological care, and three and 9 months thereafter. Latent class growth analysis was performed to identify benefit finding trajectories. RESULTS: Five benefit finding trajectories were identified: 'high level-stable' (8%), 'very low level-small increase' (16%), 'low level-small increase' (39%), 'low level-large increase' (9%), and 'moderate level-stable' (28%). People in distinct benefit finding trajectories reported significant differential courses of depression but not of anxiety symptoms. Compared with the other four trajectories, people in the 'low level-large increase' trajectory reported the largest decreases in depression over time. Perceptions of cancer prognosis distinguished these trajectories, such that people with a favourable prognosis were more likely to belong to the 'high level-stable' trajectory, while people perceiving an uncertain prognosis were more likely to belong to the 'low level large increase' trajectory of benefit finding. CONCLUSIONS: Cancer patients showed distinct benefit finding trajectories during psychological care. A small proportion reporting a large increase in benefit finding were also most likely to show decreases in depressive symptoms over time. These findings suggest a relation between perceiving benefits from cancer experience and improved psychological functioning in cancer patients receiving psychological care. Statement of contribution What is already known on this subject? People vary in course of benefit finding (BF) after trauma, with some experiencing enhanced BF and others decreased BF. Empirical studies have identified subgroups of cancer patients with distinct BF trajectories. What does this study add? This is the first study showing that cancer patients followed different BF trajectories during psychological care. Only a small proportion experienced clinically meaningful increases in BF over time. More attention is needed for cancer patients with decreased BF, as they are at a higher risk of remaining depressed. PMID- 29139594 TI - A Multiperspective Approach to Solvent Regulation of Enzymatic Activity: HMG-CoA Reductase. AB - 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase was investigated in different organic cosolvents by means of kinetic and calorimetric measurements, molecular dynamics simulations, and small-angle X-ray scattering. The combined experimental and theoretical techniques were essential to complement each other's limitations in the investigation of the complex interaction pattern between the enzyme, different solvent types, and concentrations. In this way, the underlying mechanisms for the loss of enzyme activity in different water-miscible solvents could be elucidated. These include direct inhibitory effects onto the active center and structural distortions. PMID- 29139596 TI - Real Sociedad Espanola de Quimica Prizes 2017. PMID- 29139595 TI - Structure and Electronic Properties of Unnatural Base Pairs: The Role of Dispersion Interactions. AB - Recent reports of the successful incorporation of unnatural base pairs (UBPs), such as d5SICS-dNaM, in the gene sequence and replication with DNA is an important milestone in synthetic biology. Followed by this, several other UBPs, such as dTPT3-dNaM, dTPT3-dFIMO, dTPT3-IMO, dTPT3-FEMO, FTPT3-NaM, FTPT3-FIMO, FTPT3-IMO, and FTPT3-FEMO, have demonstrated similar or better retention and fidelity inside cells. Of these base pairs, dNaM-dTPT3 has been optimized to be a better fit inside a pAIO plasmid. Based on both implicit and explicit dispersion corrected density functional theory (DFT) calculations, we show that although this set of UBPs is significantly diverse in elemental and structural configuration, the members do share a common trait of favoring a slipped parallel stacked dimer arrangement. Unlike the natural bases (A, T, G, C, and U), this set of UBPs has a negligible affinity for a Watson-Crick (WC)-type planar structure because they are invariably more stable within slipped parallel stacked orientations. We also observed that all the UBPs have either similar or higher binding energies with the natural bases in similar stacked orientations. When arranged between two natural base pairs, the UBPs exhibited a binding energy similar to that of three-base sequences of natural bases. Our computational data show that the most promising base pairs are 5SICS-NaM, TPT3-NaM, and TPT3-FEMO. These results are consistent with recent progress on experimental research into UBPs along with our previous calculations on the d5SICS-dNaM pair and, therefore, strengthen the hypothesis that hydrogen bonding might not be absolutely essential and that interbase stacking dispersion interactions play a key role in the stabilization of genetic materials. PMID- 29139597 TI - Time-Resolved Interception of Multiple-Charge Accumulation in a Sensitizer Acceptor Dyad. AB - Biomimetic models that contain elements of photosynthesis are fundamental in the development of synthetic systems that can use sunlight to produce fuel. The critical task consists of running several rounds of light-induced charge separation, which is required to accumulate enough redox equivalents at the catalytic sites for the target chemistry to occur. Long-lived first charge separated state and distinct electronic signatures for the sequential charge accumulated species are essential features to be able to track these events on a spectroscopic ground. Herein, we use a double-excitation nanosecond pump-pump probe experiment to interrogate two successive rounds of photo-induced electron transfer on a molecular dyad containing a naphthalene diimide (NDI) linked to a [Ru(bpy)3 ]2+ (bpy=bipyridine) chromophore by using a reversible electron donor. We report an unprecedented long-lived two-electron charge accumulation (t=200 MUs). PMID- 29139598 TI - Preparation and comparative evaluation of 99m Tc-HYNIC-cNGR and 99m Tc-HYNIC-PEG2 -cNGR as tumor-targeting molecular imaging probes. AB - The tripeptide sequence asparagine-glycine-arginine (NGR) specifically recognizes aminopeptidase N (APN or CD13) receptors highly expressed on tumor cells and vasculature. Thus, NGR peptides can precisely deliver therapeutic and diagnostic compounds to CD13 expressing cancer sites. In this regard, 2 NGR peptide ligands, HYNIC-c(NGR) and HYNIC-PEG2 -c(NGR), were synthesized, radiolabeled with 99m Tc, and evaluated in CD13-positive human fibrosarcoma HT-1080 tumor xenografts. The radiotracers, 99m Tc-HYNIC-c(NGR) and 99m Tc-HYNIC-PEG2 -c(NGR), could be prepared in approximately 95% radiochemical purity and exhibited excellent in vitro and in vivo stability. The radiotracers were hydrophilic in nature with log P values being -2.33 +/- 0.05 and -2.61 +/- 0.08. The uptake of 2 radiotracers 99m Tc-HYNIC-c(NGR) and 99m Tc-HYNIC-PEG2 -c(NGR) was similar in nude mice bearing human fibrosarcoma HT-1080 tumor xenografts, which was significantly reduced (P < .05) during blocking studies. The 2 radiotracers being hydrophilic cleared rapidly from blood, liver, and intestine and were excreted through renal pathway. The pharmacokinetics of 99m Tc-labeled HYNIC peptide could not be modulated through introduction of PEG2 unit, thus posing a challenge for studies with other linkers towards enhanced tumor uptake and retention. PMID- 29139599 TI - Adherence to a multifactorial fall prevention program following paramedic care: Predictors and impact on falls and health service use. Results from an RCT a priori subgroup analysis. AB - OBJECTIVE: To identify predictors and impact of adherence to a multifactorial fall-prevention program on falls and health service utilisation. METHODS: Randomised controlled trial with a priori subgroup analysis within intervention group according to adherence. Participants were community dwelling, (>=65 years), not transported to hospital following fall-related paramedic care. The Attitudes to Falls-Related Interventions Scale (AFRIS) was completed at baseline, adherence levels were measured (three-point scale) at six months, and falls and health service utilisation were recorded for 12 months. Multivariate logistic regression and area under the curve were calculated with 95% confidence interval (CI). RESULTS: Attitudes to Falls-Related Interventions Scale scores (n = 85) were independent of baseline characteristics. At six months, 39 (46%) participants reported full adherence. Independent predictors of adherence were positive AFRIS (OR 4.10, 95% CI 1.48-11.39) and receiving 3+ recommendations (OR 3.36, 95% CI 1.26-9.00). Adherers experienced fewer falls (IRR 0.53, 95% CI 0.45-0.80) and fall-related health service use (emergency department presentations IRR 0.37, 95% CI 0.17-0.82) compared to non-adherers. CONCLUSION: Older adults who adhere to recommendations benefit, regardless of fall-risk profile. PMID- 29139600 TI - ArcR modulates biofilm formation in the dental plaque colonizer Streptococcus gordonii. AB - Biofilm formation and cell-cell sensing by the pioneer dental plaque colonizer Streptococcus gordonii are dependent upon arginine. This study aimed to identify genetic factors linking arginine-dependent responses and biofilm formation in S. gordonii. Isogenic mutants disrupted in genes required for the biosynthesis or catabolism of arginine, or for arginine-dependent gene regulation, were screened for their ability to form biofilms in a static culture model. Biofilm formation by a knockout mutant of arcR, encoding an arginine-dependent regulator of transcription, was reduced to < 50% that of the wild-type whereas other strains were unaffected. Complementation of S. gordonii ?arcR with a plasmid-borne copy of arcR restored the ability to develop biofilms. By DNA microarray analysis, 25 genes were differentially regulated in S. gordonii ?arcR compared with wild-type under arginine-replete conditions including eight genes encoding components of phosphotransferase systems for sugar uptake. By contrast, disruption of argR or ahrC genes, which encode paralogous arginine-dependent regulators, each resulted in significant changes in the expression of more than 100 genes. Disruption of a gene encoding a putative extracellular protein that was strongly regulated in S. gordonii ?arcR had a minor impact on biofilm formation. We hypothesize that genes regulated by ArcR form a critical pathway linking arginine sensing to biofilm formation in S. gordonii. Further elucidation of this pathway may provide new targets for the control of dental plaque formation by inhibiting biofilm formation by a key pioneer colonizer of tooth surfaces. PMID- 29139601 TI - Utility of the ACC/AHA lesion classification as a predictor of procedural, 30-day and 12-month outcomes in the contemporary percutaneous coronary intervention era. AB - BACKGROUND: Correlations between the ACC/AHA coronary lesion classification and clinical outcomes in the contemporary percutaneous coronary intervention (PCI) era are not well established. METHODS: We analyzed clinical characteristics and outcomes according to ACC/AHA lesion classification (A, B1, B2, C) in 13,701 consecutive patients from the Melbourne Interventional Group (MIG) registry. Patients presenting with STEMI, cardiogenic shock and out-of-hospital cardiac arrest were excluded. The primary endpoints were 30-day and 12-month mortality. Secondary endpoints were procedural success as well as 30-day and 12-month major adverse cardiac events. RESULTS: Of the 13,701 patients treated, 1,246 (9.1%) had type A lesions, 5,519 (40.3%) had type B1 lesions, 4,449 (32.5%) had Type B2 lesions and 2,487 (18.2%) had Type C lesions. Patients with type C lesions were more likely to be older and have impaired renal function, diabetes, previous myocardial infarction, peripheral vascular disease and prior bypass graft surgery (all P < 0.01). They were also more likely to require rotational atherectomy, drug-eluting stents and longer stent lengths (all P < 0.01). Increasing lesion complexity was associated with lower procedural success (99.6% vs. 99.1% vs. 96.6% vs. 82.7%, P < 0.001) and worse 30-day (0.2% vs. 0.3% vs. 0.7% vs. 0.6%, P < 0.001) and 12-month mortality (2.2% vs. 2.0% vs. 3.2% vs. 2.9%, P <0.01). Kaplan Meier analysis showed complex lesions (type B2 and C) had lower survival at 12-months (P = 0.003). CONCLUSIONS: PCI to more complex lesions continues to be associated with lower procedural success rates as well as inferior medium-term clinical outcomes. Thus the ACC/AHA lesion classification should still be calculated preprocedure to predict acute PCI success and clinical outcomes. PMID- 29139603 TI - Catalytic Transfer Hydrogenation of Biomass-Derived Carbonyls over Hafnium-Based Metal-Organic Frameworks. AB - A series of highly crystalline, porous, hafnium-based metal-organic frameworks (Hf-MOFs) have been shown to catalyze the transfer hydrogenation reaction of levulinic ester to produce gamma-valerolactone by using isopropanol as a hydrogen donor. The results are compared with their zirconium-based counterparts. The role of the metal center in Hf-MOFs has been identified and reaction parameters optimized. NMR studies using isotopically labeled isopropanol provide evidence that the transfer hydrogenation occurs through a direct intermolecular hydrogen transfer route. The catalyst, Hf-MOF-808, can be recycled several times with only a minor decrease in catalytic activity. The generality of the procedure has been demonstrated by accomplishing the transformation with aldehydes, ketones, and alpha,beta-unsaturated carbonyl compounds. The combination of Hf-MOF-808 with the Bronsted-acidic Al-Beta zeolite gives the four-step one-pot transformation of furfural to gamma-valerolactone in good yield of 75 %. PMID- 29139602 TI - Cell yield, chondrogenic potential, and regenerated cartilage type of chondrocytes derived from ear, nasoseptal, and costal cartilage. AB - Functional reconstruction of large cartilage defects in subcutaneous sites remains clinically challenging because of limited donor cartilage. Tissue engineering is a promising and widely accepted strategy for cartilage regeneration. To date, however, this strategy has not achieved a significant breakthrough in clinical translation owing to a lack of detailed preclinical data on cell yield and functionality of clinically applicable chondrocytes. To address this issue, the current study investigated the initial cell yield, proliferative potential, chondrogenic capacity, and regenerated cartilage type of human chondrocytes derived from auricular, nasoseptal, and costal cartilage using a scaffold-free cartilage regeneration model (cartilage sheet). Chondrocytes from all sources exhibited high sensitivity to basic fibroblast growth factor within 8 passages. Nasoseptal chondrocytes presented the strongest proliferation rate, whereas auricular chondrocytes obtained the highest total cell amount using comparable cartilage sample weights. Importantly, all chondrocytes at fifth passage showed strong chondrogenic capacity both in vitro and in the subcutaneous environment of nude mice. Although some significant differences in histological structure, cartilage matrix content and cartilage type specific proteins were observed between the in vitro engineered cartilage and original tissue; the in vivo regenerated cartilage showed mature cartilage features with high similarity to their original native tissue, except for minor matrix changes influenced by the in vivo environment. The current study provides detailed preclinical data for choice of chondrocyte source and thus promotes the clinical translation of cartilage regeneration approach. PMID- 29139604 TI - Editorial "Joint modeling of longitudinal and time-to-event data and beyond". PMID- 29139605 TI - H-likelihood approach for joint modeling of longitudinal outcomes and time-to event data. AB - In longitudinal studies, a subject may have different types of outcomes that could be correlated. For example, a response variable of interest would be measured repeatedly over time on the same subject and at the same time, an event time representing a single event or competing-risks event is also observed. In this paper, we propose a joint modeling framework that accounts for the inherent association between such multiple outcomes via frailties (unobserved random effects). Among outcomes, at least one outcome is an event time that has a type of a single event or competing-risks event. For inference we use the hierarchical likelihood (h-likelihood) that provides an unified efficient fitting procedure for the joint models. Numerical studies are provided to show the performance of the proposed method and two data examples are shown. PMID- 29139606 TI - Two-stage model for multivariate longitudinal and survival data with application to nephrology research. AB - In many follow-up studies different types of outcomes are collected including longitudinal measurements and time-to-event outcomes. Commonly, it is of interest to study the association between them. Joint modeling approaches of a single longitudinal outcome and survival process have recently gained increasing attention from both frequentist and Bayesian perspective. However, in many studies several longitudinal biomarkers are of interest and instead of selecting one single biomarker, the relationships between all these outcomes and their association with survival needs to be investigated. Our motivating study comes from Peritoneal Dialysis Programme in Nephrology research from Nephrology Unit, CHP (Hospital de Santo Antonio), Porto, Portugal in which the interest relies on the possible association between various biomarkers (calcium, phosphate, parathormone, and creatinine) and the patients' survival. To this aim, we propose a two-stage model-based approach for multivariate longitudinal and survival data that allowed us to study such complex association structure. The multivariate model suggested in this paper provided new insights in the area of nephrology research showing valid results in comparison with those models studying each longitudinal biomarker with survival separately. PMID- 29139607 TI - Iatrogenic Arteriovenous Fistula of the breast following core-biopsy presenting in pregnancy. AB - Core-biopsy of the breast is the standard of care for assessment of breast lumps. It is rarely associated with a vascular injury resulting in the formation of an arteriovenous fistula. Though previously noted in the medical literature, it has never been reported in the context of pregnancy and lactation. PMID- 29139608 TI - Current state of screening high-ACE youth and emerging adults in primary care. AB - BACKGROUND AND PURPOSE: Trauma comes in many forms, including interpersonal, community, and institutional trauma. The adverse childhood event (ACE) studies demonstrated that adverse experiences in childhood can have a profound, cumulative impact on the course of health and development over a lifetime. It is critical for healthcare providers, such as nurse practitioners (NPs), working in primary care to screen adolescents and emerging adults for a history of ACEs and trauma. A review of current assessment tools used in assessing this population in health settings is needed to determine how screening for ACEs is being performed. CONCLUSIONS: Clinically efficient tools for screening and assessment of high-ACE youth in primary care settings are lacking. Developing a process to assess ACEs, risk behaviors, and physical and mental health status that is efficient to use during a time limited clinical visit is an important step in providing holistic care to a challenging population. IMPLICATIONS FOR PRACTICE: Primary care NPs are in the perfect position to implement assessments of ACEs through trauma-informed nursing care. ACE assessment in clinical practice will provide vital information to guide the development of tailored interventions for reducing risk behaviors and mitigate the long-term impacts of ACEs. PMID- 29139609 TI - Development of a high-throughput method based on thin-film microextraction using a 96-well plate system with a cork coating for the extraction of emerging contaminants in river water samples. AB - In this study, a new method was developed in which a biosorbent material is used as the extractor phase in conjunction with a recently described sample preparation technique called thin-film microextraction and a 96-well plate system. The method was applied for the determination of emerging contaminants, such as 3-(4-methylbenzylidene) camphor, ethylparaben, triclocarban, and bisphenol A in water samples. The separation and detection of the analytes were performed by high-performance liquid chromatography with diode array detection. These contaminants are considered hazardous to human health and other living beings. Thus, the development of an analytical method to determine these compounds is of great interest. The extraction parameters were evaluated using multivariate and univariate optimization techniques. The optimum conditions for the method were 3 h of extraction time, 20 min of desorption with 300 MUL of acetonitrile and methanol (50:50, v/v), and the addition of 5% w/v sodium chloride to the sample. The analytical figures of merit showed good results with linear correlation coefficients higher than 0.99, relative recoveries of 72-125%, interday precision (n = 3) of 4-18%, and intraday precision (n = 9) of 1-21%. The limit of detection was 0.3-5.5 MUg/L, and the limit of quantification was 0.8-15 MUg/L. PMID- 29139610 TI - Prevalence of epilepsy in Podgorica, Montenegro. AB - The purpose of this study was to assess for the first time the prevalence of epilepsy in the capital of Montenegro and to describe the clinical and epidemiological profile of the disorder. A door-to-door screening was performed on population of 6 randomly selected areas of Podgorica (capital of Montenegro) using validated screening questionnaire. In phase 1, the screening by questionnaire of 4007 individuals identified 307 suspected cases of epilepsy. Four of them dropped out of further investigation just before entering the phase 2. In phase 2, the remaining 303 suspected cases were first examined by general practioner and then by an epileptologist, on two follow-up visits. The confirmation of epilepsy was based on clinical examination. Electroencephalogram (EEG), computed tomography (CT) and/or magnetic resonance imaging (MRI) were also used. 29 persons were diagnosed with epilepsy. An overall prevalence of 7.2 cases per 1000 inhabitants was calculated (CI 95% 5.0-10.0). Majority of them had been previously diagnosed (86.20%), 27 had active epilepsy and over a half of them were on polymedication (65.51%). Referring to the 27 patients with active epilepsy, the predominant seizure type was partial (all types) in 14 (48.27%) and undetermined in 2 (6.89%). Cause of epilepsy was determined in 10 patients. EEG abnormalities were found in almost all patients (89.65%). CT anomaly was determined in 9 whereas only 1 patient had an abnormal MRI finding. The estimated prevalence of epilepsy indicated higher rates compared to neighboring counties and the rest of the Europe, but limitations of the study (high rejection rate and stigma) should be taken into consideration. PMID- 29139611 TI - Anti-inflammatory effects of tetracyclines. PMID- 29139612 TI - The changing faces of Langerhans cells. PMID- 29139613 TI - Nipple-sparing mastectomy as treatment for patients with ductal carcinoma in situ: A 10-year follow-up study. AB - The objective was to determine the 10-year oncological safety of nipple-sparing mastectomy (NSM) in patients diagnosed with ductal carcinoma in situ (DCIS). The use of NSM preserves the nipple-areola complex (NAC). As residual fibroglandular breast tissue can remain behind the spared NAC, its use for patient with breast cancer is controversial. The oncologic outcomes and complication rates after performing NSM compared to other techniques are still under debate and a concern when treating patients with breast cancer. We retrospectively reviewed 69 consecutive NSM patients diagnosed with DCIS during 1984-2016 at the Valencia Institute of Oncology, Valencia, Spain. 13 of 82 reviewed cases were excluded from the analysis owing to the presence of invasive tumor in the final pathologic report. All 69 patients who underwent NSM due to DCIS were included and analyzed. The indications were as follows: unfavorable correlation between tumor size and breast size in 53 patients, 10 patients with multifocal or multicentric tumors and breast cancer recurrence after breast-conserving surgery in six patients. The reconstruction was performed using a prosthetic implant: saline-filled implant 33 (47.8%) or tissue expander 36 (52.2%). No frozen section was performed in the patients included in our study. The presence of DCIS was confirmed in 60 patients and in the other nine patients we found no tumor in the mastectomy specimen (removed due to excisional biopsy procedure). High risk features were: tumor grade 3 in 27 (39.2%) cases and comedonecrosis in 32 (46.4%) cases. In 27 patients surgical axillary staging was performed and no residual disease in the axilla was observed. After a mean follow-up period of 142.6 +/- 70.7 months no nipple necrosis was observed. In 15 patients (21.7%) an additional surgical procedure was performed. 48 patients (69.6%) did not receive any adjuvant treatment. Adjuvant hormone therapy was given to 20 patients (29%) and one patients received radiation therapy (1.4%). Eight patients showed a local relapse (11.6%). One patient developed a recurrence within the nipple-areola region presented as Paget's disease (1.4%). One patient presented a thorax wall relapse after 42 months of disease-free survival and died because of metastatic dissemination of the tumor. The DFS rate was 88.4% and the overall survival rate was 98.6%. In patients with DCIS that are not candidates to breast-conserving therapy, NSM is a realistic option of treatment. No case of nipple necrosis was observed. A low rate of nipple relapse (1.4%) and a good survival rate (98.5%) were observed after a median follow-up of 142.6 months. PMID- 29139614 TI - Human dental stem cell derived transgene-free iPSCs generate functional neurons via embryoid body-mediated and direct induction methods. AB - Induced pluripotent stem cells (iPSCs) give rise to neural stem/progenitor cells, serving as a good source for neural regeneration. Here, we established transgene free (TF) iPSCs from dental stem cells (DSCs) and determined their capacity to differentiate into functional neurons in vitro. Generated TF iPSCs from stem cells of apical papilla and dental pulp stem cells underwent two methods-embryoid body-mediated and direct induction, to guide TF-DSC iPSCs along with H9 or H9 Syn GFP (human embryonic stem cells) into functional neurons in vitro. Using the embryoid body-mediated method, early stage neural markers PAX6, SOX1, and nestin were detected by immunocytofluorescence or reverse transcription-real time polymerase chain reaction (RT-qPCR). At late stage of neural induction measured at Weeks 7 and 9, the expression levels of neuron-specific markers Nav1.6, Kv1.4, Kv4.2, synapsin, SNAP25, PSD95, GAD67, GAP43, and NSE varied between stem cells of apical papilla iPSCs and H9. For direct induction method, iPSCs were directly induced into neural stem/progenitor cells and guided to become neuron-like cells. The direct method, while simpler, showed cell detachment and death during the differentiation process. At early stage, PAX6, SOX1 and nestin were detected. At late stage of differentiation, all five genes tested, nestin, betaIII-tubulin, neurofilament medium chain, GFAP, and Nav, were positive in many cells in cultures. Both differentiation methods led to neuron-like cells in cultures exhibiting sodium and potassium currents, action potential, or spontaneous excitatory postsynaptic potential. Thus, TF-DSC iPSCs are capable of undergoing guided neurogenic differentiation into functional neurons in vitro, thereby may serve as a cell source for neural regeneration. PMID- 29139615 TI - Breast education for schoolgirls; why, what, when, and how? AB - Schools are fundamental settings for health education and adolescent females are an important group for promoting positive breast habits. We surveyed 2089 schoolgirls (11-18 years) to provide evidence for, and guidance on, breast education for schoolgirls. 26% reported negative feelings about their breasts and 87% reported >= one breast concern. 72% wanted to know more about breast cancer (69% rating this extremely important). >50% wanted to know more about breast sag and breast pain. Preferred delivery format was age eleven (50%), girls only taught sessions (41%) with female teachers (43%). A need for breast education and delivery preferences was identified. PMID- 29139616 TI - RAFT Polymerization for the Synthesis of Tertiary Amine-Based Diblock Copolymer Nucleic Acid Delivery Vehicles. AB - The synthesis and characterization of a family of nine pH-responsive, diblock copolymers designed to effectively deliver nucleic acids are reported. The stabilizing A block is comprised of an oligo(ethylene glycol) methyl ether methacrylate to impart water solubility. The cationic blocks of varying degrees of polymerization (DPs) are derived from three pH responsive, tertiary amine containing methacrylates capable of complexing negatively charged nucleic acids. The cytotoxicity studies utilizing human embryonic kidney cells (HEK-293) and Michigan Cancer Foundation-7 (MCF-7) breast cancer cells indicate no decrease of cell viability with the diblock copolymers, with the exception of the two highest DPs of the cationic blocks with ethyl-substitutes tertiary amine. Gene knockdown experiments indicate high siRNA delivery and MYC gene knockdown in MCF-7 breast cancer cells for eight of the nine studied block copolymers. The results of the current study enable further development of the pH-responsive copolymer family for promising nucleic acid delivery vehicles applicable for clinical use. PMID- 29139617 TI - World's smallest combined en bloc liver-pancreas transplantation. AB - We present a case of a 2-year-old child who underwent a combined en bloc liver and pancreas transplant following complications of WRS. WRS is characterized clinically through infantile insulin-dependent diabetes mellitus, neutropenia, recurrent infections, propensity for liver failure following viral infections, bone dysplasia, and developmental delay. Usually, death occurs from fulminant liver and concomitant kidney failure. Few cases with WRS are reported in the literature, mostly from consanguineous parents. To the best of our knowledge, combined en bloc liver and pancreas transplant has not been performed in small children. PMID- 29139618 TI - Beyond sarcopenia: Characterization and integration of skeletal muscle quantity and radiodensity in a curable breast cancer population. AB - Skeletal muscle loss, commonly known as sarcopenia, is highly prevalent and prognostic of adverse outcomes in oncology. However, there is limited information on adults with early breast cancer and examination of other skeletal muscle indices, despite the potential prognostic importance. This study characterizes and examines age-related changes in body composition of adults with early breast cancer and describes the creation of a novel integrated muscle measure. Female patients diagnosed with stage I-III breast cancer with abdominal computerized tomography (CT) scans within 12 weeks from diagnosis were identified from local tumor registry (N = 241). Skeletal muscle index (muscle area per height [cm2 /m2 ]), skeletal muscle density, and subcutaneous and visceral adipose tissue areas, were determined from CT L3 lumbar segments. We calculated a novel integrated skeletal measure, skeletal muscle gauge, which combines skeletal muscle index and density (SMI * SMD). 241 patients were identified with available CT imaging. Median age 52 years and range of 23-87. Skeletal muscle index and density significantly decreased with age. Using literature based cut-points, older adults (>=65 years) had significantly higher proportions of sarcopenia (63 vs 28%) and myosteatosis (90 vs 11%) compared to younger adults (<50 years). Body mass index was positively correlated with skeletal muscle index and negatively correlated with muscle density. Skeletal muscle gauge correlated better with increasing age (rho = 0.52) than with either skeletal muscle index (rho = 0.20) or density (rho = 0.46). Wide variations and age-related changes in body composition metrics were found using routinely obtained abdominal CT imaging. Skeletal muscle index and density provide independent, complementary information, and the product of the two metrics, skeletal muscle gauge, requires further research to explore its impact on outcomes in women with curable breast cancer. PMID- 29139619 TI - Rare occurrence of EGFR exon 19 deletion in invasive lobular carcinoma of the breast. PMID- 29139620 TI - Changing patterns in water toxicity associated with current use pesticides in three California agriculture regions. AB - Regulation of agriculture irrigation water discharges in California, USA, is assessed and controlled by its 9 Regional Water Quality Control Boards under the jurisdiction of the California State Water Resources Control Board. Each Regional Water Board has developed programs to control pesticides in runoff as part of the waste discharge requirements implemented through each region's Irrigated Lands Regulatory Program. The present study assessed how pesticide use patterns differ in the Imperial (Imperial County) and the Salinas and Santa Maria (Monterey County) valleys, which host 3 of California's prime agriculture areas. Surface water toxicity associated with current use pesticides was monitored at several sites in these areas in 2014 and 2015, and results were linked to changes in pesticide use patterns in these areas. Pesticide use patterns appeared to coincide with differences in the way agriculture programs were implemented by the 2 respective Regional Water Quality Control Boards, and these programs differed in the 2 Water Board Regions. Different pesticide use patterns affected the occurrence of pesticides in agriculture runoff, and this influenced toxicity test results. Greater detection frequency and higher concentrations of the organophosphate pesticide chlorpyrifos were detected in agriculture runoff in Imperial County compared to Monterey County, likely due to more rigorous monitoring requirements for growers using this pesticide in Monterey County. Monterey County agriculture runoff contained toxic concentrations of pyrethroid and neonicotinoid pesticides, which impacted amphipods (Hyalella azteca) and midge larvae (Chironomus dilutus) in toxicity tests. Study results illustrate how monitoring strategies need to evolve as regulatory actions affect change in pesticide use and demonstrate the importance of using toxicity test indicator species appropriate for the suite of contaminants in runoff in order to accurately assess environmental risk. Integr Environ Assess Manag 2018;14:270 281. (c) 2017 SETAC. PMID- 29139621 TI - Paneth and intestinal stem cells preserve their functional integrity during worsening of acute cellular rejection in small bowel transplantation. AB - Graft survival after small bowel transplantation remains impaired due to acute cellular rejection (ACR), the leading cause of graft loss. Although it was shown that the number of enteroendocrine progenitor cells in intestinal crypts was reduced during mild ACR, no results of Paneth and intestinal stem cells localized at the crypt bottom have been shown so far. Therefore, we wanted to elucidate integrity and functionality of the Paneth and stem cells during different degrees of ACR, and to assess whether these cells are the primary targets of the rejection process. We compared biopsies from ITx patients with no, mild, or moderate ACR by immunohistochemistry and quantitative PCR. Our results show that numbers of Paneth and stem cells remain constant in all study groups, whereas the transit-amplifying zone is the most impaired zone during ACR. We detected an unchanged level of antimicrobial peptides in Paneth cells and similar numbers of Ki-67+ IL-22R+ stem cells revealing cell functionality in moderate ACR samples. We conclude that Paneth and stem cells are not primary target cells during ACR. IL-22R+ Ki-67+ stem cells might be an interesting target cell population for protection and regeneration of the epithelial monolayer during/after a severe ACR in ITx patients. PMID- 29139622 TI - Comments on "Impact of spontaneous donor hypothermia on graft outcomes after kidney transplantation". PMID- 29139624 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 47/2017. PMID- 29139623 TI - Extracellular proteinases of Candida species pathogenic yeasts. AB - The increased incidence of severe disseminated infections caused by the opportunistic yeast-like fungi Candida spp. highlights the urgent need for research into the major virulence factors of these pathogens-extracellular aspartic proteinases of the candidapepsin and yapsin families. Classically, these enzymes were considered to be generally destructive factors that damage host tissues and provide nutrients for pathogen propagation. However, in recent decades, novel and more specific functions have been suggested for extracellular candidal proteinases. These include contributions to cell wall maintenance and remodeling, the formation of polymicrobial biofilms, adhesion to external protective barriers of the host, the deregulation of host proteolytic cascades (such as the complement system, blood coagulation and the kallikrein-kinin system), a dysregulated host proteinase-inhibitor balance, the inactivation of host antimicrobial peptides, evasion of immune responses and the induction of inflammatory mediator release from host cells. Only a few of these activities recognized in Candida albicans candidapepsins have been also confirmed in other Candida species, and characterization of Candida glabrata yapsins remains limited. PMID- 29139625 TI - Late graft failure after kidney transplantation as the consequence of late versus early events. AB - Beyond the first posttransplant year, 3% of kidney transplants fail annually. In a prospective, multicenter cohort study, we tested the relative impact of early versus late events on risk of long-term death-censored graft failure (DCGF). In grafts surviving at least 90 days, early events (acute rejection [AR] and delayed graft function [DGF] before day 90) were recorded; serum creatinine (Cr) at day 90 was defined as baseline. Thereafter, a 25% rise in serum Cr or new-onset proteinuria triggered graft biopsy (index biopsy, IBx), allowing comparison of risk of DCGF associated with early events (AR, DGF, baseline serum Cr >2.0 mg/dL) to that associated with later events (IBx). Among 3678 patients followed for 4.7 +/- 1.9 years, 753 (20%) had IBx at a median of 15.3 months posttransplant. Early AR (HR = 1.77, P < .001) and elevated Cr at Day 90 (HR = 2.56, P < .0001) were associated with increased risk of DCGF; however, later-onset dysfunction requiring IBx had far greater impact (HR = 13.8, P < .0001). At 90 days, neither clinical characteristics nor early events distinguished those who subsequently did or did not undergo IBx or suffer DCGF. To improve long-term kidney allograft survival, management paradigms should promote prompt diagnosis and treatment of both early and later events. PMID- 29139626 TI - Errors in the nursing management of a deteriorating patient. AB - Effective management of the deteriorating patient requires early recognition of the signs of deterioration, timely review and appropriate interventions. However, this does not always occur. Errors in the recognition and management of a deteriorating patient are rarely related to a single factor; rather they are a complex interaction of system and human factors. This article presents a case study focusing on understanding the factors that led to errors resulting in the death of a patient. Understanding the complex interaction of system and human factors enables the identification of strategies that could be used to decrease the likelihood of a similar incident occurring. PMID- 29139627 TI - Understanding and meeting your legal responsibilities as a nurse. AB - Nurses, midwives and nursing students are legally responsible for their actions. This article discusses the legal standard of care required in relation to nursing and midwifery practice and nurses' professional standards and code of conduct. It examines how courts in the UK determine if nurses have met their duty of care and how nurses must ensure they maintain competence to provide safe care. It examines why organisational knowing - understanding the organisation in which one is employed; its people, values and how it works - is important for all nurses, regardless of their level in the organisation. It also discusses workplace incivility and its adverse effects on nurses, patient care and healthcare organisations. The article explains that if nurses are uncertain why they are doing something, they should investigate this further, because the law expects nurses to be able to justify their actions, or failure to act. PMID- 29139628 TI - First report on PVL-positive methicillin-resistant Staphylococcus aureus of SCCmec type V, spa type T441 in Croatia. AB - The aim of the study was to investigate the molecular epidemiology of community- associated MRSA in Primorsko-Goranska County of Croatia during a six-year period(2001-2007). In period from 2001 and 2007, 46 MRSA isolates were collected in Rijeka, strains were subjected to susceptibility testing according to CLSI guidelines, mecA gene detection and SCCmec typing as well as detection of PVL. Strains were typed by Pulse Field Gel Electrophoresis (PFGE) and spa typing. All isolates were susceptible to vancomycin, linezolid, mupirocin, nitrofurantoin, only one strain was resistant to fusidic acid and co-trimoxazole. Results of SCCmec typing showed the presence of SCCmec type IV in 26 MRSA strains, SCCmec type V in three strains, and 13 strains comprised SCCmec I. SCCmec type II and III were not observed. Four MRSA strains were non-typeable by applied SCCmec typing methods. PVL was detected in 4 strains, two SCCmec IV and two SCCmec V. PFGE analysis, grouped MRSA strains into six similarity groups and 18 singletons. Dominating spa types in this collection of strains were t015, with 15 strains, followed by t041(N=7), t051,(N=2 ), t2850(N=2), t008(N=2)and single isolates t441, t002, t448, t018, t019, t355, t390, t026, t449, t148. We also detected two new spa types, t3510 and t3509, respectively. This is the first report on SCCmec type V in Croatia, and, to our knowledge, first report of PVL-positive mehicillin resistant Staphylococcus aureus SCCmec type V and t441(ST59-MRSA-V) in this part of Europe. PMID- 29139630 TI - Treatment of Severe Acquired Haemophilia A with Immunosuppressive Agent: A Case Report of One Patient. AB - Acquired haemophilia A (AHA) is a rare hemorrhagic disease caused by an autoantibody against coagulation factorVIII. Nonhaemophiliac patients develop autoantibodies (inhibitors) directed against the factor VIII circulating coagulationprotein. Disease is associated with an increased morbidity and mortality. Inhibitors against FVIII induce acute andlife-threatening hemorrhagic diathesis because of abnormal blood clotting. FVIII inhibitors demonstrate bleeding disordersand prolonged activated partial thromboplastin time and a normal prothrombin time. AHA should be considered inthe differential diagnosis particularly in postpartum women and in the elderly patients with bleeding tendency. Treatmentof acute hemorrhage is focused in the control of the acute bleeding episode and the long term suppression of the autoantibody.In congenital hemophilia A with inhibitors, in which using repetitive infusions of high dose FVIII concentrates iseffective for inhibitor eradication. This report present one patient treated with immunosuppressive regimens. The mosteffective fi rst-line treatment for the eradication of factor VIII autoantibodies is the combination of steroides and cyclophosphamide. PMID- 29139631 TI - Historical Overview of the Human Population-Genetic Studies in Bosnia and Herzegovina: Small Country, Great Diversity. AB - Modern Bosnia and Herzegovina is a multinational and multi-religious country, situated in the western part of theBalkan Peninsula in South-eastern Europe. According to recent archaeological fi ndings, Bosnia and Herzegovina hasbeen occupied by modern humans since the Palaeolithic period. The structure of Bosnia Herzegovina's human populationsis very complex and specifi c, due to which it is interesting for various population-genetic surveys. The population of Bosniaand Herzegovina has been the focus of bio-anthropological and population genetics studies since the 19th century. Thefi rst known bio-anthropological analyses of Bosnia-Herzegovina population were primarily based on the observation ofsome phenotypic traits. Later examinations included cytogenetic and DNA based molecular markers. The results of allstudies which have been done up to date showed no accented genetic difference among the populations (based on geographicalregions) with quite high diversity within them. Human population of Bosnia and Herzegovina is closely relatedto other populations in the Balkans. However, there are still many interesting features hidden within the existing diversityof local human populations that are still waiting to be discovered and described. PMID- 29139632 TI - The Partnership of Public Health and Anthropology. AB - Public health focuses on health of the population and it is concerned with threats to health based on population healthanalysis. Anthropology covers most aspects that concern human beings. Both sciences converge on community and thisfact represents a foundation for the partnership between public health and anthropology. Biological/medical anthropologyis one of the highly developed fi elds of anthropology and the most important for public health. PMID- 29139633 TI - Intercultural Contact and Multilingualism in an Intimate Relationship in the Austro-Hungarian Littoral. AB - The paper presents a case study of multilingualism in private correspondence in turn-of-the-century Austro-HungarianIstria. Language attitudes and use of German, Italian and Slovenian are analyzed, with results indicating the compatibilityof national feelings with an appreciation of multilingualism, as well as the important role that intimate interculturalrelationships play in this regard in a culturally mixed region. PMID- 29139634 TI - Separated Children's Migration in the Mediterranean Sea. An Ethnohistorical Perspective. AB - In the imaginary of Italian people, the Island of Lampedusa (Italy) has always been considered a paradise destination for summer holidays. The beauty of this small island at the heart of the Mediterranean Sea, far from big harbors and cities, with its rich biodiversity and unspoilt nature, has made it a national and international tourist attraction. However, in recent years its name become associated with scenes of tragic, desperate journeys made by people of different origins trying to reach Europe from North African coasts. This shift exists not only in Italian people's perception, but also all over the world, as the news related to Lampedusa and other Italian areas affected by this phenomenon often finds a place in major foreign newspapers. Even if migrants have been reaching Italian (and, more generally, South European) coasts for the last 20 years, the date of 3 October 2013 constitutes a significant turning point, as the shipwreck that occurred on this day lead to numerous deaths and the Italian coast guard has been accused of an unsuccessful, belated rescue of the people on the vessel. In recent months the number of people, especially unaccompanied children, arriving by boat has increased. Most of them are fleeing from wars and persecution, and even if they are aware of the risk of crossing the Mediterranean Sea, they still decide to try. The paper presents the results of an ethnographic research conducted with unaccompanied and separated children in Sicily, in order to point out their oral memories. PMID- 29139635 TI - Roman Military Medicine and Croatian Archaeological Perspectives. AB - This article offers a general examination of the sources responsible for understanding Roman military medicine, starting with literal and epigraphical sources all the way to archaeological remains consisting of hospitals, the infrastructure of military garrisons and small medical tools. Given that not one of the literary sources does not directly mention the medical personnel within the various military units, epigraphical discoveries widely represent the main source of our knowledge on the subject. On the other hand, the archaeological exploration of military garrisons offers proof of the medical care of Roman soldiers. If at first it appears that Roman military medicine is perfectly obvious and clear, actually this is not the case as many questions remain to be answered and debated. In all this, Croatia has its own archaeological perspective, where notably, one site stands out, which could hold a key role according to the layout of buildings within the garrison including its hospital. PMID- 29139636 TI - Changes in Blood Pressure After Single Bout of Aerobic Exercise in Young Healthy People- Influence of Body Composition. AB - Amount of change in blood pressure after exercise is related to risk of hypertension and cardiovascular diseases. The aim of this study was to determine whether there is a difference in the amount of change of blood pressure after exercise among people with different morphological characteristics, especially with differences in percent of body fat. 30 healthy subjects (15 males and 15 females) aged 25-30 years were included in the study. They were measured for weight and height, and their body composition was assesed by bioelectrical impendance device GAYA 357. Blood pressure was measured at rest and immediately after performing Cooper's test. After classification of subjects according to BMI (body mass index) and according to percent of body fat (PBF) differences in the size of change in blood pressure among categories were compared. Results indicate that there is no difference between sexes in amount of change for DBP, but there is difference in change of SBP; in males this change was significantly higher than in females. We also found difference in SBP results at rest between different categories of BMI (p=0,023), that was not influenced by gender, while the difference between categories based on different PBF were under the influence of gender. Based on results conclusion can be made that percent of body fat is a factor that influence amount of change in blood pressure with exercise, and is potentially important, and could be predictive factor, like BMI or together with it, in determining the risk of hypertension in young healthy people. PMID- 29139637 TI - Effects of Trigeminal Nerve Dysfunction in Various Types of Headaches. AB - Headaches are one of the most common ailments in modern society, leading to severe diminishing of general activities and they result in significant impact on the patient's quality of life. Blink reflex is an objective neurophysiological method for determining the status of the trigeminal system, facial nerve and the lateral part of medulla oblongata. The aim of this study was to examine the connection between trigeminal nerve dysfunction and various types of headaches using functional electrophysiological assessment of blink reflex tests in patients and controls. The sample comprised 60 subjects with headache attacks, 44 females, and 16 males). The control group consisted of 30 healthy subjects (19 females, and 11 males) who did not suffer from headaches. The age of subjects ranged from 20 years to 76 years with the mean of 42.81 years. Trigeminal nerve function was assessed by using blink reflex tests in patients suffering from headaches and in controls, applying the standard procedure described by Kimura et al. Pathological findings of blink reflex were observed in 58.3 % of patients suffering from headaches and in only 20 % of cases in the control group. The application of Yates' chi2 test showed a significant correlation between pathological blink reflex and headache occurrence (chi2 = 10.354; P = 0.001). Normal blink reflex was found in 41.7 % of patients suffering from headaches and in 80 % of control group subjects. Females with pathological blink reflex have 4 times higher risk for headaches than controls (OR = 4.107; 95% CI = 1.036 - 17.565). Males with pathological blink reflex have a considerably higher risk for headaches, and it was 13 times higher than in controls (OR = 13.500; 95% CI = 1.555 - 153.646). There is a strong correlation between pathological blink reflex and the occurrence of headaches in both genders, indicating significant association of trigeminal nerve dysfunction with the occurrence of headaches. The use of blink reflex testing could be of help to detect patients with an increased risk for headaches. PMID- 29139638 TI - Differences in Movement of Temporomandibular Joints in Athletes With and Without Orofacial Injuries. AB - All sporting activities have an associated risk of orofacial injuries due to falls, collisions with players, devices, and hard surfaces. The purpose of this investigation was to determine is there alteration of condylar path and frontal guidance values in athletes with and without orofacial injuries. The sample consists of 34 athletes who were divided into two groups (Control and Examines group). "Control group" consists of 11 athletes without data of macrotrauma of the stomatognatic system (athletes who didn't get blow to the face). The second group is "Examines group" witch consists of 23 athletes with macrotrauma (athletes who get blow to the face), 11 of them were athletes with macrotrauma on the right side of jaw and 12 of them were athletes with macrotrauma on the left side of jaw. Athletes with anamnestic blow to the jaws, immediately after injury, have had stiffness/pain of masticatory muscles, pain in region of TMJ, and limitation of jaw movements. But all symptoms diminished and finally were gone after some days or weeks after injury. In time of investigation all of them were completely without any symptom of temporomandibular dysfunction according to RDC/TMD protocol, and were completely satisfied with function of their stomatognathic system. Athletes with macrotrauma have limitation of Bennett angle on the one side while on the opposite side Bennett angle is larger than the average values given in literature. As conclusion, if athletes with macrotrauma need prosthetic therapy, without individual articulator adjustment, prosthodontics work can cause iatrogenic interference. That interference during time may cause temporomandibular dysfunction. All patients need individual approach to their stomatognatic system, and only in that way damage to the system can be avoided. PMID- 29139639 TI - Diversity of Y-chromosomal and mtDNA Markers Included in Mediscope Chip within Two Albanian Subpopulations from Croatia and Kosovo: Preliminary Data. AB - The aim of this preliminary study is to analyze genetic specificity of Kosovo Albanians comparing with neighboring populations using new genetic tool - MEDISCOPE gene chip, to investigate the feasibility of this approach. We collected 37 DNA samples (9 Croats, 17 Albanians from Croatia and 11 Albanians from Kosovo) from unrelated males born in Croatia and Kosovo. Additionally, samples were expanded with female individuals and mtDNA analysis included a total of 61 samples (15 Croats, 23 Albanians from Croatia and 23 Albanians from Kosovo). This pilot study suggests that the usage of the MEDISCOPE chip could be recognized as an efficient tool within recognition of the population genetic specificity even within extremely small sample size. PMID- 29139640 TI - Transnational and Intercultural Practices in the Adriatic Littoral of the Late Habsburg Empire. AB - The paper describes the strategy of an interdisciplinary project on the patterns of transnational interactions and mobility that shaped intercultural dialogue in the south-eastern periphery of the late Austro-Hungarian Empire. Methodologically, it is structured around three interconnected analytic levels of institutions, associations and everyday life, that are mutually constitutive, and the exploration of three dimensions characterizing social spaces: social practices in different domains of life, symbolic system (focusing on language) and the use of artifacts, or material life. Based on secondary sources, the imperial naval port of Pula is analyzed within the methodological frame that goes beyond methodological nationalism. PMID- 29139641 TI - Sex Hormone Binding Globulin (SHBG) as a Marker of Clinical Disorders. AB - Sex hormone binding globulin (SHBG) is an important protein, not only for transporting sex steroids which is its primary role, but with the discovery of a specific receptor that binds SHBG, a novel approach regarding classic 'free hormone hypothesis' should be implemented. Research in SHBG gene and it expression has been done, as well as cellular signaling that controls it. It provides significant knowledge of the impact of certain well -defined cellular level signaling pathways and how they affect the level of SHBG production. Moreover, new insights have proven that SHBG isn't just a peripherally synthesized protein. Its origin has been proven to exist in the brain, namely in the hypothalamus and the pituitary, where it is spatially closely related to oxytocin-producing neurons. The main peripheral organ that produces SHBG is the liver. Since the liver is the central metabolic organ, certain metabolic diseases will result in changed SHBG serum levels. On the other hand, endocrine disorders that affect tissues involved in sex hormone regulation will also have an impact on SHBG levels. Thusly, SHBG stands as one of the mediators between various endocrine tissues and definitely contributes with its own pathophysiological role in diseases such as: obesity, metabolic syndrome, polycystic ovary syndrome, osteoporosis, breast and prostate cancer. Its value expands to the area of clinical medicine as a marker of certain pathological states. Some studies already established its reliability and the growing trend to implement it as a useful clinical marker is present. It still remains largely understudied, from physiological and clinical aspect, but recent findings give notions that SHBG plays an important role in health and disease and could be a useful assessment marker. PMID- 29139642 TI - Matrilineal Heritage in Southern Iberia Reveals Deep Genetic Links between Continents. AB - Within the Mediterranean Basin, the Iberian Peninsula has been a focus of attraction for several cultures and civilizationsfrom its prehistory and history, making it a target territory for studying human migration patterns and peoplingprocesses using a wide and heterogeneous spectrum of genomic markers. While its Cantabrian fringe represents the mostregularly analysed area in terms of its mitochondrial diversity, the absence of monographic surveys on the maternal geneticcomposition of southern Iberians (i.e., Andalusians) is striking. In this work, we present a comprehensive view ofvarious aspects of the human maternal heritage of the autochthonous Andalusian population regarding specific mitochondrialhaplogroups considered key candidates to determine the genetic relationship between Europe and Africa. Datareveal that southern Iberian populations do not have genetically homogeneous mitochondrial DNA profiles, and theirobserved genetic affinity with north-western African populations represents strong signals of old, sustained and bidirectionalhuman movements between the northern and southern shores of the western Mediterranean. Thorough analyses ofAfrican mtDNA haplogroups have shown that the most relevant African contribution within Iberian Peninsula could beexplained as a consequence of prehistoric events. The subsequent historic episodes helped to strengthen the ties betweenboth shores. In southern Iberia, mitochondrial and other genetic markers show that the Strait of Gibraltar together withits surrounding maritime areas should be considered a bridge between continents. More broadly, the Mediterranean Seahas acted as a transport surface, that is, as a permeable barrier to human migrations from prehistoric and historic times.In conclusion, this research contributes to our knowledge of processes that have shaped the recent human genetic historyin the Mediterranean and, more specifically, of the population dynamics that the inhabitants of southern Iberia haveexperienced with respect to other neighbouring North African populations. PMID- 29139643 TI - The remote isolate of the Croatian littoral - 50 years of research on the island of Susak with new insights into its genetic diversity. AB - This paper presents a review of the 50-year long anthropological and epidemiological research of the Susak population. Island of Susak is an example of extreme genetic isolate, with a very low level of heterozygosity and a significantly high level of inbreeding, due to the practice of endogamy. Its specific features have put the island in the focus of diverse research during the last five decades and in this study we additionally present new insights into the island's maternal genetic heritage. For this purpose, mitochondrial DNA (mtDNA) haplogroup diversity was defined based on SNPs of the control and coding region on the sample of 64 autochthonous individuals from the island. Only three main haplogroups were detected - H, T and one W sample, with a limited number of haplotypes, and certain typical European haplogroups (U, K, J, V, X,) were completely absent. Haplotype analysis revealed five possible founder lineages of altogether 16 different haplotypes. Island of Susak also has the second lowest reported GDV (gene diversity index) among Croatian isolates, which is in line with its reduced mtDNA diversity. Since such island communities are most likely to disappear in the near future, we see these results as a valuable contribution for further population genetics and epidemiological studies. PMID- 29139644 TI - Body Image Issues In Lithuanian Magazines Aimed For Children And Adolescents In Relation To Body Mass Index And Body Size Perception Of 16-19 Y. Old Girls During The Last 15 Years. AB - Mass media plays an important role in forming body image and makes the significant impact on body size perception in children and adolescents. The aim of present study was to reveal trends in depiction of body image cues in Lithuanian magazines aimed for children and adolescents in relation to changes of real body mass index (BMI) and body size perception of 16-19 y. old girls in the year 2000 and the 2015. Three popular journals published both in the year 2000 and the 2015, were chosen for in-depth analysis of their contents (the periodicity of different topics was counted and compared). Attention given to a healthy body image has increased and the promotion of especially skinny females' body has decreased during the last 15 years from the dominant type in the year 2000 to depiction of slightly thin or normal body build in the 2015. However, the real BMI of 16-19 y. old Lithuanian girls has significantly increased during the 2000-2015 period (from 20.09 till 21.32 kg/m2; p<0,001). Despite this fact, the older adolescent girls were more satisfied with their own body size and shape in the year 2015 than in the 2000. The present study showed that changing depictions of body image issues in mass media (magazines aimed for adolescent girls) were in parallel with the proper self-esteem of body size in adolescent girls. PMID- 29139645 TI - Finger Length Ratio and Body Composition In Chuvashians. AB - Very few studies that evaluated the association between fi nger length ratio and body composition in adult populationshowed very diverse results. We carried out a radiographic study on a large population sample who had participated ina Chuvashian skeletal aging study investigating different aspects of skeletal aging. The aims of this study were to evaluatethe association between 2D:4D ratio and various indices of body composition in Chuvashian males and females. Thestudy sample included 802 males (mean age 46.98+/-17.10 years) and 783 females (mean age 48.65+/-16.62 years). Singleplain radiographs of both hands were taken. Each hand was classifi ed according to whether the index fi nger was longer(Type 1), equal to (Type 2) or shorter than the ring fi nger (Type 3) by visual comparison of the soft tissue outline of thefi nger ends on the radiograph. Anthropometry, including body weight, stature, and six circumferences from the body trunkand extremities were taken from each participant. We found no evidence of substantial associations between visually assessedfi nger length ratio and adult BMI, WC, hip and chest circumferences, WHT and WCR for men and women. Theseresults suggest that associations between fi nger length ratio and hormone-related diseases and disorders can be interpreteddirectly, independent of any mediating effects of adult body composition parameters. PMID- 29139646 TI - Physical Fitness And Digit Ratio (2D:4D) In Male Students From Wroclaw, Poland. AB - There is sex-difference in humans as regards aerobic efficiency, physical strength and endurance and the sex difference is greatly dependent upon differential concentration of testosterone during different phases of growth and development including the intrauterine phase or prenatal growth. Second-to-fourth digit lengths ratio (2D:4D) is an putative indicator of prenatal testosterone exposure. Lower 2D:4D indicates higher prenatal testosterone exposure and vice versa. Males generally have lower 2D:4D than females. This cross-sectional study investigated the relationship between the fitness measures and 2D:4D in young adult Polish males. The study included 118 Polish male students first course in General Kosciuszko Military Academy of Land Forces in Wroclaw. Their mean (+SD) age was 20.4 (+1.60) years. Eurofit test set was employed to assess physical fitness. Apart from height, weight, second and fourth digit lengths, hand grip strength was also measured by a standard isometric dynamometer. The study showed a weak relationship between 2D:4D of right hand and results of physical fitness tests. The smaller was the 2D:4D, the better was the result of endurance and strength tests. This finding was in accord with reports by other studies, indicating that individuals with smaller 2D:4D tend to perform better in these aspects of physical ability. However, we also found an opposite relationship with the results to agility tests. Male students with higher 2D:4D scored better in 5x10 meters shuttle run. This finding did not match with results reported by other studies. This study indicated towards possibility that an association between low 2D:4D and sport and athletic achievement and also physical performances were due to, at least in part, the action of prenatal testosterone. Further studies are required to investigate the relationship of fitness parameters with digit ratio and ultimately with prenatal testosterone exposure. PMID- 29139647 TI - Is Increased Facial Asymmetry Associated With The Use Of Hormonal Contraceptive Among Polish Young Women In Wroclaw? AB - Fluctuating asymmetry (FA) is the small random deviations from a perfect bilateral symmetry in a morphologicaltrait. It is considered as an indicator of biological quality and developmental stability of individual. Adverse environmentalconditions and high levels of sex steroids may increase FA. Symmetry in women was found to be related with phasesof the menstrual cycles (MC). This cross sectional study aimed to compare facial symmetry between women using and notusing hormonal contraceptives with reference to the phases of their fertile and non-fertile phases of MC. Participants were150 young adult Polish female students in Wroclaw, Poland. Facial photograph of each woman was taken and informationon the use of hormonal contraception, date of menarche, number of days past since the last menstruation (beginningof bleeding) were collected. Measurements of facial asymmetry were taken digitally in pixels on facial photographs byusing ImageJ software. The results revealed that the women who used HC had a significantly higher total and centralfacial FA than those who did not use HC. However, the women in relatively non fertile phase did not demonstrate a differencein FA among the non-users of HC. PMID- 29139648 TI - Upper Palaeolithic and Mesolithic Ornamental Traditions in the Eastern Adriatic Coast and Hinterland. AB - Archaeological finds of personal ornaments reveal not only behavioural patterns of the society they belong to, but also their forms of manifestations indicate connections, contacts and communication paths, exchange networks and movements of prehistoric populations. This paper advances the current knowledge regarding ornamental traditions in Eastern Adriatic area during Late Upper Palaeolithic and Mesolithic periods. Thirteen prehistoric sites from this area have yielded more than thousand finds of ornamental assemblage, making Eastern Adriatic coast and hinterland fruitful area for the research of this type of archaeological assemblage. Results of the analysis have shown existence of diachronic changes in the selection of raw materials from Upper Palaeolithic to Mesolithic period. Personal ornaments are less abundant during Upper Palaeolithic, but are typologically diverse compared to Mesolithic period when the selectivity of the raw material with the large increase of the number of finds is present. PMID- 29139649 TI - Construction of the Questionnaire on Foreign Language Learning Strategies in Specific Croatian Context. AB - Learning strategies are special thoughts or behaviours that individuals use to understand, learn or retain new information,according to the point of view of O'Malley & Chamot. The other view, promoted by Oxford, believes learningstrategies are specific actions taken by the learner to make learning easier, faster, more enjoyable, and more transferrableto new situations of language learning and use. The use of appropriate strategies ensures greater success in languagelearning. The aim of the research was to establish metric characteristics of the Questionnaire on learning strategies createdby the author, in line with the template of the original SILL questionnaire (Strategy Inventory for Language Learning).The research was conducted at the Rochester Institute of Technology Croatia on a sample of 201 participants wholearned German, Spanish, French and Italian as a foreign language. The results have shown that one component latentdimensions which describe the space of foreign language learning strategies according to Oxford's classification, havemetric characteristics which are low, but still satisfactory (reliability and validity). All dimensions of learning strategiesappeared not to be adequately defined. Therefore, we excluded compensation strategies and merged social and affectivestrategies into social affective strategies into the unique dimension. Overall, this version of Oxford's original questionnaire,based on Oxford's theoretical construct, applied on Croatian students, clearly shows that current version of the questionnairehas poor metric characteristics. One of the explanations of the results obtained could be positioned in multiculturalcontext and intercultural dialogue. Namely, particular social, political and economic context in Croatia could shapeeven foreign language learning strategies. PMID- 29139650 TI - Metrically adjusted questionnaires can provide more information for scientists- an example from the tourism. AB - The article deals with the issue of research methodology, illustrating the use of known research methods for new purposes. Questionnaires that originally do not have metric characteristics can be called "handy questionnaires". In this article, the author is trying to consider the possibilities of their improved scientific usability, which can be primarily ensured by improving their metric characteristics, consequently using multivariate instead of univariate statistical methods. In order to establish the base for the application of multivariate statistical procedures, the main idea is to develop strategies to design measurement instruments from parts of the handy questionnaires. This can be accomplished in two ways: before deciding upon the methods for data collection (redesigning the handy questionnaires) and before the collection of the data (a priori) or after the data has been collected, without modifying the questionnaire (a posteriori). The basic principles of applying these two strategies of the metrical adaptation of handy questionnaires are described. PMID- 29139651 TI - The Risk for Fall and Functional Dependence in Polish Adults 60-87 Years Old. AB - The constantly rising percentage of the elderly (60+), who are particularly at risk of the dangerous consequence of falls,results not only in the loss of independence in daily life, but also in a serious threat to health and life. Therefore, manyauthors emphasize the necessity of conducting prophylaxis and prevention among senior citizens. The most importantaspect of fall prophylaxis is care about the optimum level of agility. Exercise should focus on increasing muscular strength,balance and dexterity. The aim of the present study is to determine the relationship between functional fitness and therisk for falls of older people in the light of maintaining physical independence. The research group consisted of 522 persons:142 males and 380 females aged 60-84 years from Wroclaw (a city in the south-west of Poland). All subjects providedwritten consent, and were measured and tested in 2009 through 2015, excluding the winter months. Body height andweight were measured. Body mass index was calculated. The Senior Fitness Test was used to assess functional capacityand efficiency. The results of the Senior Fitness Test were used to estimate Maintaining Physical Independence in OlderAdults. The differences in the means of the results of all the tests between the age and sex-specific groups were assessedby means of a two way analysis of variance, where sex and age were factors and results of appropriate test dependentvariables. Logistic regression was used to estimate the risk for fall, based on the incidence of fall in the last year, for eachtest comparing the individuals met referenced criteria to maintain functionally dependence and independent, controlledfor age and BMI. The risk for falls was more than twice greater in the case of the studied females, whose muscular strengthof the upper part of the body was lower. The females in whose cases no fewer than two tests failed to ascertain functionalindependence, had a greater risk for falls. In the case of the males, no statistically-significant connections between functionalindependence and the risk for falls was found. PMID- 29139653 TI - Medical and Philosophical News. PMID- 29139652 TI - Liposarcoma of the Spermatic Cord -A Rare Pathological Entity. AB - Liposarcoma of the spermatic cord is a very rare neoplasm with fewer than 200 cases recorded in world literature. Thisreport describes a case of liposarcoma of the spermatic cord which developed after radical prostatectomy and salvageradiotherapy for prostate cancer treatment. Four years following surgical treatment of the primary neoplasm and one yearfollowing radiotherapy, the 67 year -old patient was referred to the urology clinic for the emergence of a mass in the righthemiscrotum region. Ultrasonography revealed a homogenous isodense mass measuring 4.5 cm in diameter, while positronemission tomography (PET) with 2 deoxy-2(18F) fluoro-D-glucose (FDG) indicated the presence of viable tumors cells.Radical orchiectomy was performed to remove the neoplasm which appeared to be dedifferentiated liposarcoma of thespermatic cord. Lymph nodes were not affected, but the surgical margins were found positive and the patient was referredto further oncologic treatment. PMID- 29139654 TI - Medical and Philosophical News. PMID- 29139655 TI - A New Method of Treating the Fistula Lachrymalis. PMID- 29139656 TI - A New Method of Treating Uterine Haemorrhages after Delivery. PMID- 29139657 TI - Medical and Philosophical News. PMID- 29139659 TI - Medical and Philosophical News. PMID- 29139658 TI - Medical and Philosophical News. PMID- 29139661 TI - Medical and Philosophical News. PMID- 29139660 TI - Case of a Patient Who Voided Hydatides with His Urine; with an Account of the Appearances on Dissection. PMID- 29139662 TI - Medical and Philosophical News. PMID- 29139663 TI - A Table of the Greatest, Least, and Mean Heights of the Thermometer and Barometer, and of the Fall of Rain in London in 1779. PMID- 29139664 TI - A Case of Venereal Consumption Cured by Mercurial Frictions. PMID- 29139665 TI - Medical and Philosophical News. PMID- 29139666 TI - Medical and Philosophical News. PMID- 29139667 TI - Medical and Philosophical News. PMID- 29139669 TI - Medical and Philosophical News. PMID- 29139668 TI - Medical and Philosophical News. PMID- 29139670 TI - Medical and Philosophical News. PMID- 29139671 TI - A Case of Hydrophthalmia Successfully Treated. PMID- 29139672 TI - A Case of Obstinate Costiveness. PMID- 29139673 TI - Some Observations on the Gout, from an Unpublished Paper on That Subject, by a Celebrated Physician Lately Deceased. PMID- 29139674 TI - Medical and Philosophical News. PMID- 29139675 TI - Medical and Philosophical News. PMID- 29139676 TI - Medical and Philosophical News. PMID- 29139677 TI - Medical and Philosophical News. PMID- 29139679 TI - Medical and Philosophical News. PMID- 29139680 TI - An Account of a Dropsy Cured by Blue Vitriol. PMID- 29139678 TI - An Account of a White Swelling Successfully Treated. PMID- 29139681 TI - Medical and Philosophical News. PMID- 29139682 TI - Medical and Philosophical News. PMID- 29139683 TI - An Account of a Caries of the Spine, and of the Appearances on Dissection. PMID- 29139684 TI - Medical and Philosophical News. PMID- 29139685 TI - Medical and Philosophical News. PMID- 29139686 TI - Errata. AB - [This corrects the article on p. 409 in vol. 1.]. PMID- 29139687 TI - Medical and Philosophical News. PMID- 29139688 TI - Errata. AB - [This corrects the article on p. 246 in vol. 1.]. PMID- 29139690 TI - Errata. AB - [This corrects the article on p. 1 in vol. 1.]. PMID- 29139689 TI - Errata. AB - [This corrects the article on p. 73 in vol. 1.]. PMID- 29139692 TI - Errata. AB - [This corrects the article on p. 109 in vol. 1.]. PMID- 29139691 TI - Errata. AB - [This corrects the article on p. 284 in vol. 1.]. PMID- 29139693 TI - Errata. AB - [This corrects the article on p. 20 in vol. 1.]. PMID- 29139694 TI - Errata. AB - [This corrects the article on p. 320 in vol. 1.]. PMID- 29139695 TI - Errata. AB - [This corrects the article on p. 312 in vol. 1.]. PMID- 29139696 TI - A Case of Hydrocephalus Internus Cured by Mercury; with Some Remarks on That Disease. PMID- 29139698 TI - A Case of Epilepsy Successfully Treated. PMID- 29139697 TI - Errata. AB - [This corrects the article on p. 32 in vol. 1.]. PMID- 29139699 TI - Deaths. PMID- 29139700 TI - Medical and Philosophical News. PMID- 29139701 TI - Errata. AB - [This corrects the article on p. 231 in vol. 1.]. PMID- 29139702 TI - Medical and Philosophical News. PMID- 29139703 TI - An Account of an Experiment Lately Made at Florence in a Case of Hydrophobia. PMID- 29139705 TI - Some Account of Tipioca; and of the Species of Ipecacuanha Found near Rio Janeiro. PMID- 29139704 TI - An Experiment to Determine the Effect of Extirpating One Ovarium upon the Number of Young Produced. PMID- 29139706 TI - An Account of the Insect Found in the Itch. From a Work Lately Published, in German, on the Etiology of That Disease. PMID- 29139707 TI - Account of the Effects of a Large Dose of Emetic Tartar; with Remarks. PMID- 29139708 TI - Case of an Exfoliation of the Anterior Part of the Upper Jaw Bone. PMID- 29139709 TI - Botanical Description of the Benjamin Tree of Sumatra. PMID- 29139710 TI - Account of an Amputation Performed with Success in the Middle of the Foot. PMID- 29139711 TI - An Account of the Efficacy of Arsenic in Intermittents. PMID- 29139712 TI - An Account of Some Experiments with Opium in the Cure of the Venereal Disease. PMID- 29139713 TI - Remarks on Elastic Bandages. PMID- 29139714 TI - An Account of the Successful Termination of a Case Attended with Symptoms of Phthisis Pulmonalis; with Remarks on the Treatment of That Disease. PMID- 29139715 TI - A Case of Hydrophobia. PMID- 29139716 TI - A Singular Case of Diabetes, Consisting Entirely in the Quality of the Urine; with an Inquiry into the Different Theories of That Disease. PMID- 29139717 TI - Additional Observations on Amputation. PMID- 29139718 TI - Observations on Pemphigus. PMID- 29139719 TI - Experiments Made to Determine the Positive and Relative Quantities of Moisture Absorbed from the Atmosphere by Various Substances, under Similar Circumstances. PMID- 29139720 TI - An Account of Three Cases, Viz. 1. of the Extraction and Depression of the Cataract in the Same Patient; 2. of an Encysted Hydrocele of the Tunica Communis of the Spermatic Chord, Communicating with the Tunica Vaginalis Testis; and 3. of an Amputation below the Knee, the Event of Which Shows That the Advantages of the Union by the First Intention, after Such an Operation, Are as Easily Obtained in the Leg as in the Thigh. PMID- 29139721 TI - Observations on Some Causes of the Excess of the Mortality of Males above That of Females. PMID- 29139722 TI - Cases of the Spontaneous Cure of Aneurism, with Remarks. PMID- 29139723 TI - Observations on Sudden Deaths Occasioned by a Rupture of the Left Ventricle of the Heart. PMID- 29139724 TI - An Account of a Painful Swelling of the Perinaeum, Which Took Place Immediately after Delivery, and Terminated in Sphacelus. PMID- 29139725 TI - Hints Respecting the Hydrocephalus Internus. PMID- 29139727 TI - An Account of the Successful Employment of Catgut in a Case of Fistula in Perinaeo. PMID- 29139726 TI - Case of a Suppression of Urine, Which Terminated Fatally; with an Account of the Appearances on Dissection. PMID- 29139729 TI - Errata. AB - [This corrects the article on p. 256 in vol. 9.]. PMID- 29139728 TI - Of the Epidemic Catarrh of the Year 1788. PMID- 29139731 TI - Errata. AB - [This corrects the article on p. 28 in vol. 9.]. PMID- 29139730 TI - Of the Epidemic Catarrh of the Year 1788. PMID- 29139732 TI - An Account of a Case of Amaurosis Cured by Electricity. PMID- 29139734 TI - Errata. AB - [This corrects the article on p. 201 in vol. 9.]. PMID- 29139733 TI - An Account of the Effects of the Astragalus Exscapus Linn. In the Cure of the Venereal Disease. PMID- 29139736 TI - Case of a Man, Whose Body Was Covered with Encysted Tumours. PMID- 29139735 TI - An Account of the Preparation and Use of the Phosphorated Soda; Being an Abstract of a Paper on the Subject, Inserted in the Journal De Physique for August, 1788. PMID- 29139737 TI - Observations on the Use of Opium in Removing Symptoms Supposed to Be Owing to Morbid Irritability. PMID- 29139738 TI - Case of a Wound of the Throat Successfully Treated. PMID- 29139739 TI - An Account of the Efficacy of Vitriolic AEther, in Removing the Gout in the Stomach. PMID- 29139740 TI - Case of an Extra-Uterine Foetus. PMID- 29139742 TI - Case of a Young Lady Who Swallowed a Pin. PMID- 29139741 TI - An Account of the Effects of the Digitalis Purpurea in Dropsy. PMID- 29139743 TI - A Case of Strangulated Hernia. PMID- 29139744 TI - Account of a Species of Hydrocephalus, Which Sometimes Takes Place in Cases of Mania. PMID- 29139745 TI - History of a Case in Which Hydatids Were Voided by the Mouth, and Likewise from a Large Tumor on the Back. PMID- 29139746 TI - Account of the Effects of Camphor in a Case of Insanity. PMID- 29139747 TI - Farther Observations on the Use of Opium, in Removing Symptoms Supposed to Be Owing to Morbid Irritability. PMID- 29139748 TI - An Account of the Salutary Effect of Mercury in a Case Attended with Symptoms of Hydrocephalus Internus. PMID- 29139749 TI - Case of a Tumor of the Leg, Supposed to Have Been Occasioned by a Ruptured Vein. PMID- 29139750 TI - An Account of the Great Efficacy of the Digitalis Purpurea in Dropsies. PMID- 29139751 TI - Errata. AB - [This corrects the article on p. 329 in vol. 6.]. PMID- 29139752 TI - Errata. AB - [This corrects the article on p. 76 in vol. 6.]. PMID- 29139753 TI - Case of a Fractured Scull Successfully Treated. PMID- 29139754 TI - Errata. AB - [This corrects the article on p. 185 in vol. 6.]. PMID- 29139755 TI - Observations on the Putrid Ulcer. PMID- 29139756 TI - Errata. AB - [This corrects the article on p. 60 in vol. 6.]. PMID- 29139758 TI - A Case of Plumb Stones Retained in the Intestines. PMID- 29139757 TI - Errata. AB - [This corrects the article on p. 36 in vol. 6.]. PMID- 29139760 TI - A Case of Inverted Uterus Successfully Treated; Two Cases of the Spontaneous Evolution of the Foetus; and an Instance of the Caesarean Operaration Performed by a Woman on Herself. PMID- 29139759 TI - A Short History of Vitriolic AEther, with an Account of Its Peculiar Efficacy in Gouty Affections of the Stomach; and an Attempt to Investigate Hoffman's Genuine Method of Preparing His Anodyne Mineral Liquor. PMID- 29139761 TI - Errata. AB - [This corrects the article on p. 401 in vol. 6.]. PMID- 29139762 TI - Errata. AB - [This corrects the article on p. 99 in vol. 6.]. PMID- 29139763 TI - Errata. AB - [This corrects the article on p. 218 in vol. 6.]. PMID- 29139764 TI - A Case of Hydrophobia. PMID- 29139765 TI - Errata. AB - [This corrects the article on p. 118 in vol. 6.]. PMID- 29139766 TI - Case of a Curvature of the Spine Successfully Treated. PMID- 29139767 TI - Case of a Child Who Swallowed a Pin. PMID- 29139768 TI - Some Account of the Good Effects of the Gastric Juice in the Cure of Ulcers; and of Magistery of Bismuth in Painful Affections of the Stomach. PMID- 29139769 TI - The Case of Mr. Holder; with Some Cursory Remarks on the Existence of Polypose Concretions in the Heart. PMID- 29139770 TI - Case of Pyuria Successfully Treated. PMID- 29139771 TI - A Remarkable Instance of a Patient's Recovery after Taking a Very Large Dose of Corrosive Sublimate. PMID- 29139772 TI - A Case of Fragility of the Bones. PMID- 29139773 TI - An Account of a Remarkable Tumor on the Head Opened and Cured. PMID- 29139774 TI - A Case of a Strangulated Hernia Successfully Treated; to Which Are Added Some Remarks on the Use of Cold Applications in the Reduction of Herniae. PMID- 29139775 TI - Case of a Considerable Effusion of Bile into the Cavity of the Abdomen, in Consequence of a Fall; with the Appearances on Dissection, and Some Additional Remarks. PMID- 29139776 TI - Case of Hydatids Discharged by Coughing. PMID- 29139777 TI - Case of a Bronchial Polypus; with Remarks on the Formation of Polypose Concretions in the Lungs. PMID- 29139778 TI - Case of an Encysted Tumor of the Eyelid, Which Was Found to Contain Hair. PMID- 29139779 TI - Two Instances of the Good Effects of Blisters in Incontinence of Urine. PMID- 29139781 TI - Erratum. AB - [This corrects the article on p. 33 in vol. 7.]. PMID- 29139780 TI - An Account of the Good Effects of Calomel in a Case of Obstructed Menses. PMID- 29139782 TI - Some Remarks on the Supposed Effects of Lime and Magnesia in Promoting the Solubility of Peruvian Bark. PMID- 29139783 TI - An Account of a Remakable Disease of the Heart. PMID- 29139784 TI - Case of Worms Discharged through an Opening in the Navel. PMID- 29139785 TI - An Account of the Dysentery, as It Appeared among His Majesty's Troops in Jamaica during the Late War; with Dissections Explaining the Proximate Cause of That Disease; and a More Simple and Efficacious Method of Treatment Thence Resulting Described. PMID- 29139786 TI - Observations on the Cause and Cure of the Tetanus. PMID- 29139787 TI - An Account of Mr. Hunter's Method of Performing the Operation for the Popliteal Aneurism. PMID- 29139788 TI - Remarks on Mr. Lucas's Practical Observations on Amputation. PMID- 29139789 TI - Two Successful Cases of Delivery by the Crotchet, in Extreme Deformity of the Pelvis. PMID- 29139790 TI - Case of an Abcess of the Liver Occasioned by a Blow; with an Account of the Appearances on Dissection. PMID- 29139791 TI - An Account of a Remarkable Cure of a Dropsy of the Belly, after the Patient Had Been Tapped Sixteen Times. PMID- 29139792 TI - Case of a Lumbar Abscess, with an Account of the Appearances on Dissection. PMID- 29139793 TI - A Case of Hydrophobia. PMID- 29139794 TI - Two Instances of the Effects of Drinking Pure Spirits, in Repeated and Large Quantities. PMID- 29139796 TI - Farther Account of the Case of a Negro Woman Who Performed the Caesarean Operation on Herself. PMID- 29139795 TI - An Account of a Successful Method of Reducing the Funis, in Cases in Which It Comes down before the Head of the Foetus. PMID- 29139797 TI - Observations on the Use and Abuse of Mercury in the Cure of the Syphilis. PMID- 29139799 TI - Description of a Plant Yielding Asa Foetida. PMID- 29139798 TI - Some Experiments Made with a View to Ascertain the Duration of the Infectious Power of Variolous Matter. PMID- 29139800 TI - Result of Some Observations Made by Benjamin Rush, M. D. Professor of Chemistry in the University of Philadelphia, during His Attendance as Physician General of the Military Hospitals of the United States in the Late War. PMID- 29139801 TI - An Account of a Remarkable Fact Relative to the Small Pox. PMID- 29139802 TI - Observations on the Use of the Globe Pessary. PMID- 29139803 TI - Dissertation sur la Rage, qui a remporte le premier prix de la Societe Royale de Medecine de Paris, le 11 Mars, 1783. PMID- 29139804 TI - An Account of a Suppression of Stools and Urine, Occasioned by an Accumulation of Hardened Faeces in the Rectum. PMID- 29139805 TI - An Account of a Singular Fact, in the Practice of Inoculation of the Small Pox. PMID- 29139806 TI - A Case, Shewing the Efficacy of Flowers of Zinc, in the Epilepsy. PMID- 29139807 TI - An Account of a Fatal Vomiting, Apparently Brought on by a Disease of the Kidney's. PMID- 29139808 TI - Case of a Retention of Urine Removed by Electricity. PMID- 29139809 TI - An Account of a General Inoculation at Painswick. PMID- 29139811 TI - Of Diseases, Supposed to Be Venereal, Produced by Transplanted Teeth. PMID- 29139810 TI - Recommendation of Electricity for the Cure of the Cataract; Illustrated by a Case. PMID- 29139812 TI - Case of a Painful Affection of the Face Cured by Electricity. PMID- 29139813 TI - Observations and Facts Relative to the Practice of Inoculation of the Small-Pox. PMID- 29139814 TI - Experiments and Observations on the Contents of the Medullary Cells in Dropsy. PMID- 29139815 TI - An Account of a Disease Occasioned by Transplanting a Tooth. PMID- 29139816 TI - Singular Termination of Dropsy. PMID- 29139817 TI - Medical Reports of the Effects of Arsenic in the Cure of Agues, Remitting Fevers, and Periodic Head-Achs. PMID- 29139818 TI - An Account of the Horn Distemper in Cattle, with Observations on That Disease. PMID- 29139819 TI - Remarks on Malignant Fevers; and Their Cure by Cold Water and Fresh Air. PMID- 29139820 TI - An Account of an Extraordinary Conformation of the Heart. PMID- 29139821 TI - History of a Case in Which Symptoms of Pulmonary Consumption Were Suddenly Relieved by the Expectoration of a Piece of Carious Bone. PMID- 29139822 TI - Observations and Queries on Animal Heat. PMID- 29139823 TI - Miscellaneous Observations on the Medical and Surgical Uses of Cold Water. PMID- 29139824 TI - Account of a Case in Which the Colour of the Skin Was Changed. PMID- 29139826 TI - Case of a Fracture of the Scull Successfully Treated. PMID- 29139825 TI - Case of an Excrescence in the Urethra of a Female Patient Successfully Treated. PMID- 29139827 TI - Of the Effect of Magnesia in Promoting the Solubility of Peruvian Bark; with Some Account of What Is Called the Essential Salt of Bark. PMID- 29139829 TI - Case of Chorea Sancti Viti Cured by Cuprum Ammoniacum. PMID- 29139828 TI - An Account of a Case in Which the Head of the Os Femoris, Shattered by a Gun Shot, Is Supposed to Have Been Regenerated. PMID- 29139830 TI - Observations on the Effects of Magistery of Bismuth, Given Internally, as an Antispasmodic. PMID- 29139831 TI - Case of Worms Discharged through a Wound of the Groin. PMID- 29139832 TI - A History of a Large Tumour, in the Region of the Abdomen, Containing Hair. PMID- 29139833 TI - An Account of the Good Effects of Electricity in Four Cases of a Diseased Testicle. PMID- 29139834 TI - A Remarkable Case of a Gun-Shot Wound. PMID- 29139835 TI - Observations on Necrosis. PMID- 29139836 TI - Case of a Remarkably Large Tumour Found in the Cavity of the Abdomen. PMID- 29139837 TI - Observations on the Longevity of the Inhabitants of Ipswich and Hingham, and Proposals for Ascertaining the Value of Estates Held for Life, and the Reversion of Them. PMID- 29139838 TI - Practical Observations on Amputation. PMID- 29139839 TI - Observations on the Treatment of Convulsions during Parturition. PMID- 29139840 TI - Account of a Case in Which a Cherry-Stone Was Extracted from an Abscess in the Abdomen. PMID- 29139841 TI - Medical and Philosophical News. PMID- 29139842 TI - Medical and Philosophical News. PMID- 29139843 TI - Remarks on the Nature and Treatment of Intermittents, as They Occurred at Hampstead in the Spring of 1781. PMID- 29139844 TI - Some Remarks on the Remitting Fevers of the West Indies. PMID- 29139845 TI - An Account of a Remarkable Operation on a Broken Arm. PMID- 29139846 TI - Medical and Philosophical News. PMID- 29139847 TI - Case of a Boy Poisoned by the Root of Hemlock-Dropwort. PMID- 29139848 TI - A Case of Tussis Convulsiva Attended with Emphysema, That Terminated Fatally. PMID- 29139849 TI - Errata. AB - [This corrects the article on p. 233 in vol. 2.]. PMID- 29139851 TI - Medical and Philosophical News. PMID- 29139850 TI - An Account of an Abscess of the Mediastinum, Mistaken for an Aneurism. PMID- 29139853 TI - Medical and Philosophical News. PMID- 29139852 TI - Account of a Woman Who Had the Small Pox during Pregnancy, and Who Communicated the Same Disease to Her Foetus. PMID- 29139854 TI - A Case of Hemiplegia, Succeeded by Mania. PMID- 29139855 TI - Medical and Philosophical News. PMID- 29139856 TI - A Remarkable Case of Uterine Haemorrhage. PMID- 29139857 TI - Two Cases of Scurvy Attended with Some Uncommon Circumstances. PMID- 29139859 TI - An Account of the Late Captain M******'s Case. PMID- 29139858 TI - A Remarkable Case of a Diseased Testicle Successfully Treated. PMID- 29139860 TI - Medical and Philosophical News. PMID- 29139861 TI - Biographical Anecdotes. PMID- 29139862 TI - An Account of the Effects of a Large Dose of Saccharum Saturni. PMID- 29139863 TI - An Account of Some Symptoms of Fever, and of the Means of Removing Them. PMID- 29139864 TI - An Account of Two Cases of Haematuria. PMID- 29139865 TI - Medical and Philosophical News. PMID- 29139866 TI - An Account of Two Cases of Hydrocephalus Internus. PMID- 29139868 TI - Medical and Philosophical News. PMID- 29139867 TI - Miscellaneous Facts and Observations. PMID- 29139869 TI - An Account of a Remarkable Fracture of the Scull, by a Pistol-Ball, That Entered the Cranium at the Right Temple and Was Successfully Extracted. PMID- 29139870 TI - An Account of the Good Effects of Fixed Air in a Case of Putrid Fever; and of a Profuse Haemorrhage from the Ears Terminated by a Fit of Epilepsy. PMID- 29139871 TI - Case of a Student Who Swallowed a Golden Breast-Pin Four Inches in Length, and Voided It by Stool, without Any Ill Consequence. PMID- 29139873 TI - An Improved Method of Amputating a Cancerous Breast; with an Account of Two Cases in Which It Was Performed with Success. PMID- 29139872 TI - Errata. AB - [This corrects the article on p. 56 in vol. 4.]. PMID- 29139874 TI - Errata. AB - [This corrects the article on p. 176 in vol. 4.]. PMID- 29139875 TI - Errata. AB - [This corrects the article on p. 238 in vol. 4.]. PMID- 29139876 TI - Errata. AB - [This corrects the article on p. 104 in vol. 4.]. PMID- 29139877 TI - A Description of a Curious Lusus Naturae. PMID- 29139878 TI - Medical and Philosophical News. PMID- 29139879 TI - Errata. AB - [This corrects the article on p. 24 in vol. 4.]. PMID- 29139880 TI - Errata. AB - [This corrects the article on p. 299 in vol. 4.]. PMID- 29139881 TI - Errata. AB - [This corrects the article on p. 318 in vol. 4.]. PMID- 29139882 TI - An Account of a Contagious Disorder, Called the Venom, Which Has Prevailed Lately Amongst the Horned Cattle in Friesland. PMID- 29139883 TI - An Account of Some Extraordinary Symptoms Occasioned by Worms; with Farther Remarks on Hydrocephalus Internus. PMID- 29139884 TI - An Account of the Medicinal Plants Growing in Jamaica. PMID- 29139885 TI - Case of a Rupture of the Tendo Achillis. PMID- 29139886 TI - Account of a Case, in Which a Considerable Portion of the Lower Jaw Bone Was Removed; to Which Are Added Some Remarks on the Effects Produced by Matter Formed in the Socket of a Tooth, and Confined There. PMID- 29139887 TI - An Account of a Peculiarity of Vision in a Girl at East Dereham in Norfolk. PMID- 29139888 TI - Additional Remarks on the Supposed Influence of the Moon in Fevers. PMID- 29139889 TI - Extract of a Letter from Mr. Robert Chessher, Surgeon at Hinckley, in Leicestershire; Containing an Account of a Case of Luxation of the Os Humeri, in Which the Reduction of the Bone Was Facilitated by Inducing Sickness and Faintness by Means of Emetic Tartar. PMID- 29139890 TI - Case of an Extra-Uterine Foetus. PMID- 29139891 TI - Observations on the Use of Arsenic in Intermittent Fevers. PMID- 29139892 TI - An Account of the Means Employed on Board His Majesty's Sloop Weasel to Preserve the Health of the Crew during a Voyage to Africa and the West Indies. PMID- 29139893 TI - Supplement to the Account of Mr. Hunter's Method of Performing the Operation for the Popliteal Aneurism, Inserted in the Seventh Volume of This Work. PMID- 29139894 TI - A Case of Mortification of the Leg. PMID- 29139895 TI - Case of a Ganglion of the Tendons, Opened, and Successfully Treated. PMID- 29139896 TI - An Account of the Success with Which the Method of Uniting Parts by the First Intention Has Been Adopted in the Radical Cure of the Hydrocele. PMID- 29139897 TI - A Letter to Dr. Simmons, F. R. S. from Mr. James Lucas, One of the Surgeons of the General Infirmary at Leeds. PMID- 29139898 TI - An Account of Two Cases of Violent Constipation of the Bowels; the First Successfully Treated by the Internal and External Application of Cold Water; and the Second Terminating by a Discharge of Matter from the Vagina. PMID- 29139899 TI - A Case of Hydrophobia. PMID- 29139900 TI - An Account of the Good Effects of Mercury in a Disease Apparently of the Lymphatic System, Attended with Nervous Symptoms. PMID- 29139901 TI - Some Remarks on the Supposed Influence of the Moon on Fevers. PMID- 29139902 TI - On the Cause of the Death of Children When the Umbilical Cord Is Compressed during Labour. PMID- 29139903 TI - Experiments and Observations on the External Use of Emetic Tartar. PMID- 29139904 TI - An Account of the Efficacy of Mercury in the Cure of Inflammatory Diseases, and the Dysentery. PMID- 29139905 TI - Case of a Woman at the Hague, on Whom the Section of the Symphysis of the Ossa Pubis Has Twice Been Performed with Success. PMID- 29139906 TI - An Account of a Curious Fact Relative to the Effects of Crude Mercury. PMID- 29139907 TI - Case in Which the Substance of the Uterus Was in a Great Measure Destroyed during Pregnancy; with an Account of the Appearances on Dissection. PMID- 29139908 TI - An Account of the Late Dr. Hugh Martin's Cancer Powder; with Brief Observations on Cancers. PMID- 29139909 TI - Farther Account of a Case of Mollities Ossium. PMID- 29139910 TI - Observations on the Case of Mollities Ossium Described in the Preceding Article; with Some General Remarks on That Disease. PMID- 29139911 TI - Farther Observations on the Action of Lime Water and Magnesia on Common Peruvian Bark. PMID- 29139912 TI - Some Observations on the Connexion of the New and Full Moon with the Invasion and Relapse of Fevers. PMID- 29139913 TI - The Antiseptic Virtues of Vegetable Acid and Marine Salt Combined, in Various Disorders Accompanied with Putridity. PMID- 29139914 TI - An Account of the Successful Extirpation of a Remarkable Schirrus of the Scrotum. PMID- 29139915 TI - Farther Observations and Facts Relative to the Practice of Inoculation of the Small Pox. PMID- 29139916 TI - Errata. AB - [This corrects the article on p. 217 in vol. 8.]. PMID- 29139917 TI - Case of an Extra-Uterine Foetus. PMID- 29139918 TI - An Account of a Large Mass of Hydatids Discharged from the Uterus. PMID- 29139920 TI - Errata. AB - [This corrects the article on p. 123 in vol. 7.]. PMID- 29139919 TI - An Account of a Case, in Which a Part of the Femoral Artery Was Dilated in Consequence of Its Being Laid Bare by a Wound, and Which Was Successfully Treated by Obliterating the Cavity of the Artery, at That Part, by Compression. PMID- 29139921 TI - Case of a Fracture of the Sternum. PMID- 29139923 TI - Two Cases of Fracture of the Scull; with Remarks. To Which Is Added a Case of a Wound of the Head That Terminated Fatally; with an Account of the Appearances on Dissection. PMID- 29139922 TI - An Account of the Cultivation and Preparation of Aloes, in the Island of Barbadoes. PMID- 29139925 TI - Errata. AB - [This corrects the article on p. 3 in vol. 8.]. PMID- 29139924 TI - Observations on Extra-Uterine Cases, and on Ruptures of the Uterus. PMID- 29139926 TI - A Case of Emphysema. PMID- 29139928 TI - Case of a Luxation of the Thigh Bone. PMID- 29139927 TI - Case of Obstruction of the Bowels, with Remarks. PMID- 29139929 TI - A Short History of Three Cases of Women, Who Were Inoculated for the Small-pox during Pregnancy. PMID- 29139930 TI - An Account of a Remarkable Spasmodic Affection. PMID- 29139931 TI - Errata. AB - [This corrects the article on p. 318 in vol. 5.]. PMID- 29139932 TI - Medical and Philosophical News. PMID- 29139934 TI - Case of a Fistula in Ano, Cured by Means of a Caustic. PMID- 29139933 TI - Errata. AB - [This corrects the article on p. 248 in vol. 5.]. PMID- 29139935 TI - Case of an Extra Uterine Foetus. PMID- 29139937 TI - Case of a Stone of the Bladder. PMID- 29139936 TI - Errata. AB - [This corrects the article on p. 425 in vol. 4.]. PMID- 29139938 TI - Some Remarks on the Nature and Treatment of Cancers. PMID- 29139939 TI - Several Instances of the Good Effects of Opium in Mortifications. PMID- 29139940 TI - Medical and Philosophical News. PMID- 29139941 TI - Case of a Paralytic Affection, Occasioned by the Calx of Lead, and Cured by Electricity. PMID- 29139942 TI - Observations to Prove That in Cases Where the Upper Extremities Present, at the Time of Birth, the Delivery May Be Effected by the Spontaneous Evolution of the Child. PMID- 29139943 TI - Observations to Prove That the Hydrophobia Is Not, as Some Writers Have Asserted, Unknown in America. To Which Is Added, an Account of the Decussation of the Optic Nerves in Quadrupeds. PMID- 29139944 TI - A Case of Chronic Dysentery Successfully Treated by Large Doses of the Vitrum Antimonii Ceratum. PMID- 29139945 TI - Remarks on the Preceding Case. PMID- 29139946 TI - Of the Decussation of the Optic Nerves in Quadrupeds. PMID- 29139948 TI - Case of Injury of the Brain, Occasioned without Any Blow or External Violence upon the Head. PMID- 29139947 TI - Farther Remarks on the Spontaneous Evolution of Children, Presenting with the Arm at the Time of Birth. PMID- 29139949 TI - Medical and Philosophical News. PMID- 29139950 TI - Account of an Expeditious Cure of a Fractured Scull. PMID- 29139952 TI - Medical and Philosophical News. PMID- 29139951 TI - Some Remarks on Angina Pectoris. PMID- 29139954 TI - Supplement to the Account of the Good Effects of Opium in Mortifications. PMID- 29139953 TI - Case of an Enlargement of the Spleen; to Which Is Added an Account of Some Remarkable Appearances Observed on Opening the Body of a Gentleman Whose Death Was Occasioned by a Perforation in His Bladder. PMID- 29139955 TI - An Account of the Poisonous Effects of the Oenanthe Crocata, or Hemlock Dropwort. PMID- 29139956 TI - An Account of the Fatal Effects Produced by Attempting to Remove a Ganglion by Seton. PMID- 29139957 TI - A Case of Painful Menstruation, Attended with Vomiting. PMID- 29139958 TI - Medical and Philosophical News. PMID- 29139959 TI - Remarks on the Use of the Nux Vomica in Dysentery. PMID- 29139960 TI - A Case of Calculus, Attended with a Fungus of the Bladder. PMID- 29139961 TI - Medical and Philosophical News. PMID- 29139962 TI - Farther Remarks on the Method of Treating the Remittent Fevers of the West Indies; with Observations on the Best Means of Preserving Health in Jamaica. PMID- 29139963 TI - A Table of the Greatest, Least, and Mean Heights of the Thermometer and Barometer, and of the Fall of Rain in London in 1780. PMID- 29139964 TI - Case of a Fatal Ulceration of the Bladder, Occasioned by a Caries of the Os Pubis; with an Account of the Appearances on Dissection. PMID- 29139965 TI - Some Remarks on Hydrocephalus Internus. PMID- 29139966 TI - Case of a Schirrous Affection of the Stomach; with an Account of the Appearances on Dissection. PMID- 29139967 TI - Observations on the Use of Electricity in Deafness. PMID- 29139968 TI - A Botanical and Medical Account of the Quassia Simaruba, or Tree Which Produces the Cortex Simaruba. PMID- 29139970 TI - A Case of Suppression of Urine in Which Relief Was Obtained from Puncturing the Bladder above the Pubis, but Which Afterwards Terminated Fatally; with an Account of the Appearances on Dissection; and Some Remarks on the Paracentesis of the Bladder. PMID- 29139969 TI - Some Account of a New Extract of Bark Prepared in South America. PMID- 29139971 TI - Case of a Woman Who Underwent the Section of the Symphysis Pubis. PMID- 29139972 TI - Farther Account of a New Method of Treating Diseases of the Joints of the Knee and Elbow. PMID- 29139973 TI - Observations on the Properties Commonly Attributed by Medical Writers to Human Milk, on the Changes It Undergoes in Digestion, and the Diseases Supposed to Originate from This Source in Infancy. PMID- 29139974 TI - Observations on the Angustura Bark. PMID- 29139975 TI - An Account of an Improved Method of Treating the Puerperal Fever. PMID- 29139977 TI - Errata. AB - [This corrects the article on p. 104 in vol. 3.]. PMID- 29139976 TI - Errata. AB - [This corrects the article on p. 29 in vol. 3.]. PMID- 29139978 TI - Errata. AB - [This corrects the article on p. 213 in vol. 3.]. PMID- 29139979 TI - Errata. AB - [This corrects the article on p. 85 in vol. 3.]. PMID- 29139981 TI - A Remarkable Case of Paralysis of the Lower Extremities, Successfully Treated by an Issue. PMID- 29139980 TI - Errata. AB - [This corrects the article on p. 435 in vol. 3.]. PMID- 29139982 TI - Observations on the Medicinal Uses of the Oleum Fecoris Aselli, or Cod Liver Oil, in the Chronic Rheumatism, and Other Painful Disorders. PMID- 29139983 TI - Errata. AB - [This corrects the article on p. 418 in vol. 3.]. PMID- 29139985 TI - Medical and Philosophical News. PMID- 29139984 TI - Errata. AB - [This corrects the article on p. 385 in vol. 3.]. PMID- 29139987 TI - Medical and Philosophical News. PMID- 29139986 TI - An Account of the Salutary Effect of Blisters in a Case Attended with Symptoms of Hydrocephalus Internus. PMID- 29139988 TI - An Account of a Remarkable Nervous Affection. PMID- 29139989 TI - Instances of the Medicinal Effects of Magnetism. PMID- 29139990 TI - A Case of Retention of Urine, in Which a Puncture of the Bladder, in the Hypogastric Region, Proved, under Very Unpromising Circumstances, Successful; to Which Are Added Three Cases of Retention of Urine, and Some Remarks on Diseases of the Urinary Bladder. PMID- 29139992 TI - Extract of a Letter from Mr. Philip Werner, Surgeon of the Royal Navy, and of the British Factory at Algiers, to Dr. Simmons, Containing Some Account of the Inoculation of the Small Pox in Algiers; Together with Other Miscellaneous Observations. PMID- 29139991 TI - Pathological Observations on the Brain. PMID- 29139993 TI - An Account of the Singular Effects of Music on a Patient. PMID- 29139994 TI - Case of a Woman Who, after Having Been Gored in the Abdomen by an Ox in the Sixth Month of Pregnancy, Underwent the Caesarean Operation. PMID- 29139996 TI - A Case of Fractured Ribs Which Terminated Fatally; with the Appearances on Dissection, and Remarks. PMID- 29139995 TI - An Account of a Distemper, by the Common People in England Vulgarly Called the Mumps. PMID- 29139997 TI - Observations on Gangrenes and Mortifications, Accompanied with, or Occasioned by, Convulsive Spasms, or Arising from Local Injury, Producing Irritation. PMID- 29139998 TI - An Account of the Effects of Laurel Water as Observed in the Bodies of Two Persons Who Died at Turin, January 22, 1785. PMID- 29139999 TI - Case of an Abscess in the Lower Part of the Belly Which Communicated with the Intestine, and Terminated Successfully. PMID- 29140000 TI - An Account of Two Cases of Pemphigus; to Which Is Added a Fact Relative to the Early Practice of Inoculation of the Small Pox in Wales. PMID- 29140001 TI - A Case of Diabetes. PMID- 29140002 TI - An Account of Two Cases of Amenorrhoea, with Some Observations on the Use of the Root of Madder in That Disease. PMID- 29140003 TI - Observations on the Diseases and Medical Practice of Boutan and Thibet; Being Part of a Paper Entitled "Some Account of the Vegetable and Mineral Productions of Boutan and Thibet". PMID- 29140004 TI - Description of an Improved Instrument for the Fistula in Ano. PMID- 29140005 TI - Observations on the Luxation of the Bones of the Pelvis. PMID- 29140006 TI - A Physical Inquiry into the Powers and Operation of Medicines. PMID- 29140007 TI - Observations on Stone in the Urinary Bladder, and on Lithotomy. PMID- 29140008 TI - Farther Remarks on the Treatment of Phthisis Pulmonalis. PMID- 29140009 TI - A Case of Phthisis Pulmonalis; with Remarks. PMID- 29140011 TI - To the Reader. PMID- 29140010 TI - An Account of Uncommon Symptoms Succeeding the Measles; with Some Additional Remarks on the Infection of Measles and Small Pox. PMID- 29140012 TI - Case of a Scirrhous Affection of the Stomach; with an Account of the Appearances on Dissection. PMID- 29140014 TI - General Index. PMID- 29140013 TI - Case of Fracture of the Scull. PMID- 29140015 TI - An Account of the Successful Application of Electricity in a Case of Wry Neck. PMID- 29140016 TI - Some Account of a Disease Lately Observed in Infants. PMID- 29140017 TI - Observations on the Angustura Bark. PMID- 29140018 TI - A Case of Monstrous Birth. PMID- 29140019 TI - Some Reflections on the Paracentesis of the Urinary Bladder; with a Description of an Instrument Employed in Puncturing the Bladder through the Rectum. PMID- 29140020 TI - Account of a Wound of the Ulnar Artery, at the Wrist, Cured by Tying It up at Some Distance from the Wound. PMID- 29140022 TI - Observations on the Treatment of Gun-Shot Wounds. PMID- 29140021 TI - An Account of Two Cases of Retroverted Uterus. PMID- 29140023 TI - Of the Good Effects of a Decoction of the Outer Shell of the Walnut in the Cure of Ulcers. PMID- 29140024 TI - Observations on a Disease Consequent to Transplanting Teeth. PMID- 29140025 TI - Hints Towards the Investigation of the Nature, Cause, and Cure of the Rabies Canina: Addressed to Dr. Haygarth. PMID- 29140026 TI - Case of a Fractured Scull Unsuccessfully Treated. PMID- 29140028 TI - Some Account of the Tanjore Antidotes for the Bite of a Mad Dog; and Also for the Bite of Venomous Serpents. PMID- 29140027 TI - An Account of a Particular Change of Structure in the Human Ovarium. PMID- 29140029 TI - Some Observations on the Medicinal Effects of the Lichen Islandicus and Arnica Montana. PMID- 29140030 TI - Remarks on Febrile Contagion. PMID- 29140031 TI - A Remarkable Case of Numerous Births; with Observations. PMID- 29140033 TI - A Case of Hernia. PMID- 29140032 TI - A Case of Taeniae Hydatigenae, or Hydatids, Successfully Treated by the Use of Mercury. PMID- 29140034 TI - An Account of the Successful Application of the Trepan in a Disease of the Tibia. PMID- 29140035 TI - An Account of an Epidemic Sore Throat Which Appeared at Chesham, in Buckinghamshire, in the Year 1788. PMID- 29140037 TI - Errata. AB - [This corrects the article on p. 283 in vol. 10.]. PMID- 29140036 TI - A Case of Cancer of the Breast; with Remarks. PMID- 29140038 TI - An Account of a Monster of the Human Species, in Two Letters; One from Baron Reichel to Sir Joseph Banks, Bart., and the Other from Mr. James Anderson to Baron Reichel. PMID- 29140039 TI - Errata. AB - [This corrects the article on p. 243 in vol. 10.]. PMID- 29140040 TI - An Account of the Good Effects of Mercury in Two Cases of Impeded Deglutition; to Which Is Added an Instance of the Relief Obtained from the Same Remedy in a Spasmodic Affection of the Neck of the Bladder. PMID- 29140042 TI - Errata. AB - [This corrects the article on p. 162 in vol. 10.]. PMID- 29140041 TI - A Critical and Anatomical Examination of the Parts Immediately Interested in the Operation for a Cataract; with an Attempt to Render the Operation Itself, Whether by Depression or Extraction, More Certain and Successful. PMID- 29140043 TI - Errata. AB - [This corrects the article on p. 283 in vol. 10.]. PMID- 29140044 TI - Facts Relative to the Small Pox. PMID- 29140045 TI - Observations on Pemphigus. PMID- 29140046 TI - An Account of a Remarkable Disease of the Heart, Lungs, and One of the External Mammae; with the Morbid Appearances as They Presented on Dissection. PMID- 29140047 TI - An Account of the Method of Making a Wine, Called by the Tartars Koumiss; with Observations on Its Use in Medicine. PMID- 29140048 TI - Farther Remarks on the Efficacy of Blue Vitriol in the Cure of Dropsy. PMID- 29140050 TI - An Account of a Remarkable Transposition of the Viscera in the Human Body. PMID- 29140049 TI - Farther Account of the Bark Described in the Preceding Article. PMID- 29140051 TI - Some Account of the Medicinal Properties of a Bark Lately Procured from South America. PMID- 29140052 TI - A Case of Hepatitis; with Remarks. PMID- 29140053 TI - An Account of an Epidemic Fever That Prevailed in Cornwall in the Year 1788. PMID- 29140054 TI - An Account of a Method of Performing the Operation of Lithotomy at Two Different Times. PMID- 29140055 TI - Account of a Calculus Extracted from a Cyst in the Neck. PMID- 29140056 TI - Description of an Improved Instrument for the Fistula in Ano. PMID- 29140057 TI - The Scope of Preemption under the 2009 Family Smoking Prevention and Tobacco Control Act. PMID- 29140058 TI - Could State Regulations be the Next Frontier in Preemption Jurisprudence? Drug Compounding as a Case Study. PMID- 29140059 TI - Preemption of Non-Federal Restraints on Off-Label Product Communications. AB - Evolving First Amendment principles are forcing FDA and other federal regulators of medical products to rethink traditional regulatory approaches to off-label product communications. State regulators, which have actively sought injunctions restricting manufacturer communications to the four-corners of the FDA-approved product label, must additionally abide by federal preemption principles. This article reviews the application of preemption principles to off-label communications and concludes that most, if not all, state-law restraints on off label communications are preempted by federal law. This finding has important implications for state enforcement initiatives, and puts into question the validity of some elements of existing state-law injunctions. PMID- 29140060 TI - The Benefits of Regulatory Friction in Shaping Policy. AB - The regulation of food, drugs, and controlled substances in this country is exceedingly complex. Local, state, and federal regulation coexist, and common law remedies supplement positive law. Strata of regulation are necessary because patterns of production and consumption vary by region and demographic, while federal regulation provides regulatory uniformity across the United States. As localities struggle to sustain autonomy in response to local preference while working within a centralized system, and federal agencies struggle to maintain regulatory uniformity to foster a national marketplace, we see interaction and friction between regulatory spheres. While this friction usually becomes apparent through a lens of adversity, it is also a space of foment for policy change and democratic engagement. In this Paper I explore this productive space by looking at several recent instances of action by states in food, dietary supplements, and controlled substances regulation that highlight this friction. An analysis of these actions and the challenges to them provides an opportunity to view the interaction between different levels of regulatory authority and to discuss implications of the judicial review of these enactments. We see complex and shifting alliances working to change policy, and we see benefits in the push and pull caused by these actions. PMID- 29140061 TI - Tracing FTC's Line on Commercial Speech: What Makes an Ad an Ad and Why Does It Matter? PMID- 29140062 TI - Remarks of the FDA Commissioner: The Food and Drug Law Institute's 59th Annual Conference. PMID- 29140063 TI - The Law of 180-Day Exclusivity. PMID- 29140064 TI - Truth, Falsity, and Fraud: Off-Label Drug Settlements and the Future of the Civil False Claims Act. AB - The pharmaceutical industry may be losing the battle of public opinion, but it has won important victories in the war over First Amendment commercial speech. In December 2012, the Second Circuit held in United States v. Caronia that the misbranding provisions of the Food, Drug, and Cosmetic Act could not prohibit a sales representative's truthful statements promoting off-label uses of his company's products. At the same time, a parallel area of pharmaceutical litigation has curiously remained almost untouched: Civil False Claims Act (FCA) settlements based on allegations that manufacturers caused false claims to be submitted by promoting their drugs off-label. Yet logic suggests that if manufacturers have a First Amendment right to discuss off-label drug uses, claims submitted when drugs are prescribed for those uses should not be considered false. This inconsistency is problematic and likely unsustainable. If manufacturers are emboldened by Caronia to challenge off-label FCA suits, the focus likely will be on the truth of the company's statements. Despite its name, however, FCA is unsuited to addressing disputes over medical and scientific data. To maintain the integrity of this key anti-fraud enforcement tool, it is crucial to separate the truth of the claims for payment from the truth of the manufacturer's underlying scientific statements. Because Medicare and Medicaid coverage determinations rely heavily on FDA approval, however, those issues are inextricably intertwined. This article explores why off-label promotion has been treated inconsistently in these contexts, and how this trend highlights the limitations of the FCA as a panacea for health care fraud. PMID- 29140065 TI - A Spoonful of (Added) Sugar Helps the Constitution Go Down: Curing the Compelled Speech Commercial Speech Doctrine with FDA's Added Sugars Rule. AB - On May 27, 2016, the Food and Drug Administration (FDA) announced that it was adopting a new rule that requires food manufacturers to list-on the already mandated Nutrition Facts label-how many grams of sugar have been added to a food product. Many opponents have criticized this "added sugars" rule on First Amendment grounds, arguing that the rule violates the commercial speech rights of food manufacturers. Whether the rule would survive constitutional scrutiny or not is an open question because the compelled commercial speech doctrine is anything but clear. Courts are split over whether Zauderer's rational basis test, Central Hudson's intermediate scrutiny, or some combination of the two should apply to a mandated disclosure like FDA's added sugars rule. This Paper explains that the added sugars rule is unique in the history of mandated nutrition labeling in that the rule is motivated largely by public health concerns and backed by reports that assert that consumers should limit their intake of added sugars. In contrast, correcting and preventing consumer deception has been a major driving force behind the remainder of FDA's mandated nutrition labeling. Because of this distinct rationale, the added sugars rule does not fit neatly into any currently existing compelled commercial speech test. This Paper uses the added sugars rule to highlight the deficiencies in the existing tests. Finally, this Paper proposes a new compelled commercial speech test that would adequately balance the interest of all of the effected parties: the government, the public, and food manufacturers. PMID- 29140066 TI - You Want a Warning with That? Sugar-Sweetened Beverages, Safety Warnings, and the Constitution. PMID- 29140067 TI - First Amendment Limits on Compulsory Speech. AB - Government-mandated labeling requirements have a long history, and are used extensively by FDA in regulating the industries under its jurisdiction. All such requirements can be characterized as a form of "compelled speech," opening the door to First Amendment challenges. And some of these challenges, depending on the nature of the labeling requirement, have even been successful. Under Zauderer v. Office of Disciplinary Counsel of Supreme Court of Ohio, regulations that compel disclosure of information will, in many cases, merit only very limited First Amendment scrutiny-less, even, than most other regulations of commercial speech, which receive a type of "intermediate scrutiny." The labeling requirement that can best avoid or overcome a First Amendment challenge, therefore, will follow the example of the regulation described in Zauderer. For example, Zauderer applied its lower scrutiny by noting that the compelled speech at issue was a disclosure of "purely factual and uncontroversial information." Conversely, a successful First Amendment challenge to a labeling requirement will often involve an argument that the labeling requirement is outside the scope of what the Zauderer Court contemplated: so, for example, one may argue that a compelled disclosure is either "not factual" or else "controversial," putting it beyond Zauderer's reach. After briefly reviewing the major Supreme Court cases that establish the levels of scrutiny for commercial speech and compelled disclosures, the paper will discuss how the various elements of Zauderer have been analyzed by several lower courts, and how some courts have distinguished Zauderer in the context of labeling and other mandatory disclosure laws. In particular, the paper will focus on cases involving First Amendment challenges to food, tobacco, and drug labeling requirements-some successful, some not, and some ongoing-including cases challenging FDA, USDA, and state-level labeling requirements. The decided cases do not all agree on how to understand the elements of Zauderer-for example, must a disclosure be factually controversial to fall outside of Zauderer's limited review, or may it be factually unquestionable but relating to a controversial topic? What role, if any, should public acceptance, knowledge, and history play? What sorts of interests may the government invoke to justify a labeling requirement? Although some courts have taken (or at least hinted at) strict limits on the meaning of Zauderer, most courts have read Zauderer as applying somewhat more expansively to circumstances beyond its facts. The paper concludes that generally, courts have read Zauderer more expansively in part because such a reading is consistent with existing, familiar labeling requirements, and a narrow reading of Zauderer limited to its facts would rest on a slippery slope to abolishing many accepted and historically unquestioned labeling requirements. Any future attempts to expand judicial review of labeling requirements would do well to highlight limiting principles that address such concerns. PMID- 29140068 TI - Arginine-Rich Peptide-Induced Supramolecular Self-Assembly of Water-Soluble Anionic Alkynylplatinum(II) Complexes: A Continuous and Label-Free Luminescence Assay for Trypsin and Inhibitor Screening. AB - A water-soluble anionic alkynylplatinum(II) 2,6-bis(benzimidazol-2'-yl)pyridine (bzimpy) complex has been strategically designed and synthesized to show supramolecular self-assembly with cationic arginine-rich peptides through unique noncovalent Pt(II)...Pt(II) and pi-pi stacking interactions. Upon introduction of trypsin, the arginine-rich peptides can be hydrolyzed into small fragments and deaggregation of the platinum(II) complex molecules is observed. The aggregation deaggregation process has been probed by UV-vis absorption, emission, and resonance light scattering (RLS) studies. This platinum(II) complex has been employed for developing a new, continuous and label-free luminescence assay for trypsin as well as for inhibitor screening, and has been successfully applied to detect trypsin in diluted serum solutions. PMID- 29140069 TI - Dual Functions of Cyclometalated Iridium(III) Complexes: Anti-Metastasis and Lysosome-Damaged Photodynamic Therapy. AB - Four phosphorescent cyclometalated iridium(III) complexes containing benzimidazole moiety have been designed and synthesized. These Ir(III) complexes can effectively inhibit several cancerous processes, including cell migration, invasion, colony formation, and angiogenesis. Interestingly, they show a much higher singlet oxygen quantum yield in an acidic solution than in a neutral solution. Upon irradiation at 425 nm with low energy (1.2 J cm-2), they can induce apoptosis through lysosomal damage, evaluation of reactive oxygen species level, and activation of caspase-3/7. The highest phototoxicity index is >476, with almost no dark cytotoxicity observed for Ir4. Ir4 can also inhibit tumor growth effectively in nude mice in vivo after photodynamic therapy. An in vitro assay against 70 kinases indicates that maternal embryonic leucine zipper kinase (MELK), PIK3CA, and AMPK are the possible molecular targets. The half maximal inhibitory concentration of Ir4 toward MELK is 1.27 MUM. Our study demonstrates that these Ir(III) complexes are promising anticancer agents with dual functions, including metastasis inhibition and lysosome-damaged photodynamic therapy. PMID- 29140070 TI - Effect of Amidogen Functionalization on Quantum Spin Hall Effect in Bi/Sb(111) Films. AB - Knowledge about chemical functionalization is of fundamental importance to design novel two-dimensional topological insulators. Despite theoretical predictions of quantum spin Hall effect (QSH) insulator via chemical functionalization, it is quite challenging to obtain a high-quality sample, in which the toxicity is also an important factor that cannot be ignored. Herein, using first-principles calculations, we predict an intrinsic QSH effect in amidogen-functionalized Bi/Sb(111) films (SbNH2 and BiNH2), characterized by nontrivial Z2 invariant and helical edge states. The bulk gaps derived from px,y orbitals reaches up to 0.39 and 0.83 eV for SbNH2 and BiNH2 films, respectively. The topological properties are robust against strain engineering, electric field, and rotation angle of amidogen, accompanied with sizable bulk gaps. Besides, the topological phases are preserved with different arrangements of amidogen. The H-terminated SiC(111) is verified as a good candidate substrate for supporting the films without destroying their QSH effect. These results have substantial implications for theoretical and experimental studies of functionalized Bi/Sb films, which also provide a promising platform for realizing practical application in dissipationless transport devices at room temperature. PMID- 29140071 TI - Ion Implantation-Modified Fluorine-Doped Tin Oxide by Zirconium with Continuously Tunable Work Function and Its Application in Perovskite Solar Cells. AB - In recent years, perovskite solar cells have drawn a widespread attention. As an electrode material, fluorine-doped tin oxide (FTO) is widely used in various kinds of solar cells. However, the relatively low work function (WF) (~4.6 eV) limits its application. The potential barrier between the transparent conductive oxide electrode and the hole transport layer (HTL) in inverted perovskite solar cells results in a decrease in device performance. In this paper, we propose a method to adjust WF of FTO by implanting zirconium ions into the FTO surface. The WF of FTO can be precisely and continuously tuned between 4.59 and 5.55 eV through different dopant concentration of zirconium. In the meantime, the modified FTO, which had a WF of 5.1 eV to match well the highest occupied molecular orbital energy level of poly(3,4 ethylenedioxylenethiophene):polystyrene sulfonate, was used as the HTL in inverted planar perovskite solar cells. Compared with the pristine FTO electrode based device, the open circuit voltage increased from 0.82 to 0.91 V, and the power conversion efficiency increased from 11.6 to 14.0%. PMID- 29140072 TI - Aerosol-Phase Extraction Method for Determination of Ca, K, Mg, and Na in Biodiesel through Inductively Coupled Plasma Optical Emission Spectrometry. AB - A novel extraction method was developed, optimized, and validated for the elemental analysis of organic samples. The method, called aerosol-phase extraction (APE), is based on nebulization of the extracting aqueous solution (0.1 mol.L-1 nitric acid) on the sample. Extraction was performed at the interface of generated extractant droplets as they entered into contact with the samples. Afterward, the phases were allowed to separate and Ca, K, Na, and Mg were determined in aqueous phase by means of inductively coupled plasma optical emission spectroscopy (ICP-OES). Measurement of aerosol characteristics demonstrated that a water-in-oil emulsion was generated. Therefore, once the aqueous solution was dispersed into the sample, the phases spontaneously separated. Furthermore, the interfacial specific surface area exhibited values on the order of 1 m2.mL-1, hence enhancing the extraction kinetics over conventional extraction methods. Key variables affecting the extraction yield were the nebulization gas flow rate, liquid flow rate, extraction time, acid concentration, nebulizer tip to sample surface gap, and morg/maq ratio. Once the optimal conditions were selected, the method was applied and validated for the determination of Ca, K, Na, and Mg by ICP-OES in 0.5 mL biodiesel samples with an expanded uncertainty lower than 2%. With the APE method, the extraction time was around 1 min, whereas conventional methods employed to perform this kind of extraction required from 4 to 50 min. Additionally, the APE involved preconcentration of analytes, thus lowering the limit of detection (LOD) to the nanograms per milliliter level (i.e., LODs based on the 3sb criterion were 32, 20, 19, and 24 ng.mL-1 for Ca, K, Na, and Mg, respectively). Furthermore, accuracy of quantification of Ca, K, Na, and Mg concentration by APE was not significantly different as compared to that afforded by conventional liquid liquid extraction. Finally, Ca, K, Na, and Mg contents were determined in four real samples in the 0.5-13 mg.kg-1 range. The obtained results were not statistically different from those encountered with a microwave-based digestion method. PMID- 29140073 TI - Three-Dimensional, Enzyme Biohydrogel Electrode for Improved Bioelectrocatalysis. AB - Higher loading of enzymes on electrodes and efficient electron transfer from the enzyme to the electrode are urgently needed to enhance the current density of biofuel cells. The two-dimensional nature of the electrode surface limits the enzyme loading on the surface, and unfavorable interactions with electrode surfaces cause inactivation of the enzyme. Benign biohydrogels are designed here to address enzyme degradation, and the three-dimensional nature of the biohydrogel enhanced the enzyme density per unit area. A general strategy is demonstrated here using a redox active enzyme glucose oxidase embedded in a bovine serum albumin biohydrogel on flexible carbon cloth electrodes. In the presence of ferricyanide as a mediator, this bioelectrode generated a maximum current density (jmax) of 13.2 mA.cm-2 at 0.45 V in the presence of glucose with a sensitivity of 67 MUA.mol-1.cm-2 and a half-life of >2 weeks at room temperature. A strong correlation of current density with water uptake by the biohydrogel was observed. Moreover, a soluble mediator (sodium ferricyanide) in the biohydrogel enhanced the current density by ~1000-fold, and citrate-phosphate buffer has been found to be the best to achieve the maximum current density. A record 2.2% of the loaded enzyme was electroactive, which is greater than the highest value reported (2-fold). Stabilization of the enzyme in the biohydrogel resulted in retention of the enzymatic activity over a wide range of pH (4.0 8.0). We showed here that biohydrogels are excellent media for enzymatic electron transfer reactions required for bioelectronics and biofuel cell applications. PMID- 29140074 TI - Facile and Versatile Strategy for Construction of Anti-Inflammatory and Antibacterial Surfaces with Polydopamine-Mediated Liposomes Releasing Dexamethasone and Minocycline for Potential Implant Applications. AB - Reducing early nonbacterial inflammation induced by implanted materials and infection resulting from bacterial contamination around the implant-abutment interface could greatly decrease implant failure rates, which would be of clinical significance. In this work, we presented a facile and versatile strategy for the construction of anti-inflammatory and antibacterial surfaces. Briefly, the surfaces of polystyrene culture plates were first coated with polydopamine and then decorated with dexamethasone plus minocycline-loaded liposomes (Dex/Mino liposomes), which was validated by contact angle goniometry, quartz crystal microbalance, and fluorescence microscopy. Dex/Mino liposomes were dispersed on functional surfaces and the drug release kinetics exhibited the sustained release of dexamethasone and minocycline. Our results demonstrated that the Dex/Mino liposome-modified surfaces had good biocompatibility. Additionally, liposomal dexamethasone reduced proinflammatory mediator expression (particularly IL-6 and TNF-alpha) in lipopolysaccharide-stimulated human gingival fibroblasts and human mesenchymal stem cells. Moreover, liposomal minocycline prevented the adhesion and proliferation of Porphyromonas gingivalis (Gram-negative bacteria) and Streptococcus mutans (Gram-positive bacteria). These findings demonstrate that an anti-inflammatory and antibacterial surface was developed, using dopamine as a medium and combining a liposomal delivery device, which has potential for use to reduce implant failure rates. Accordingly, the surface modification strategy presented could be useful in biofunctionalization of implant materials. PMID- 29140075 TI - Strictosidine Synthase Triggered Enantioselective Synthesis of N-Substituted (S) 3,14,18,19-Tetrahydroangustines as Novel Topoisomerase I Inhibitors. AB - Monoterpenoid indole alkaloids (MIAs) comprise an important class of molecules for drug discovery, and they have variant carbon skeletons with prominent bioactivities. For instance, in spite of limitations to their use, camptothecins are the only clinically approved topoisomerase I (Top1) inhibitors. The enzyme strictosidine synthase, which is key for MIA biosynthesis, was applied to the enantioselective preparation of three N-substituted (S)-3,14,18,19 tetrahydroangustine (THA) derivatives. These non-camptothecin MIAs were shown to have moderate in vitro HepG2 cytotoxicity and Top1 inhibition activities. The (S) configured MIAs had stronger cytotoxicity and Top1 inhibition than their chemically synthesized (R)-enantiomers, which aligned with the results of molecular dynamics simulations. A series of N-substituted (S)-THAs were then chemoenzymatically synthesized to investigate structure-activity relationships. The most active analogue observed was the N-(2-Cl benzoyl)-substituted derivative (7i). Insight into the binding mode of 7i and a Top1-DNA covalent complex was investigated by molecular dynamics simulations, which will facilitate future efforts to optimize the Top1 inhibitory activities of non-camptothecin MIAs. PMID- 29140076 TI - Direct Analysis of Lignin Phenols in Freshwater Dissolved Organic Matter. AB - A novel approach for the analysis of dissolved lignin in freshwaters is presented. Lignin concentrations in natural water samples are low, and a lignin extraction is usually required to obtain sufficient material for analysis. In this study, the alkaline CuO oxidation, which liberates a set of lignin-derived phenols, is performed directly on 15 mL of water sample in a microwave digestion system, hence reducing the required sample amount and preparation time considerably. These features make the method particularly suitable to study diagenetic changes of dissolved lignin in small-scale laboratory or field experiments. Phenol separation and quantification by gas chromatography tandem mass spectrometry lead to method detection limits between 22.7 and 1260 ng/L for single phenols, which corresponds to minimum lignin concentrations in the range of 8.5 MUg/L (Sigma8), offering applications for wetland, river, and lake waters with high terrestrial dissolved organic matter inputs. As a general method improvement, we present the addition of EDTA during phenol workup. EDTA binds remaining copper, thereby speeding up sample flow through the solid phase sorbent during phenol extraction and, furthermore, prevents substantial phenol losses, which occur if a water sample contains nitrate. Three natural water samples, a fresh leaf leachate and two humic-rich lake waters, were analyzed by the direct method presented here and in comparison with the established C18 extraction approach. Results show a similar reproducibility of both methods but reveal lower absolute lignin phenol yields in the humic-rich lake water samples upon C18 extraction. PMID- 29140077 TI - Superior Robust Ultrathin Single-Crystalline Silicon Carbide Membrane as a Versatile Platform for Biological Applications. AB - Micromachined membranes are promising platforms for cell culture thanks to their miniaturization and integration capabilities. Possessing chemical inertness, biocompatibility, and integration, silicon carbide (SiC) membranes have attracted great interest toward biological applications. In this paper, we present the batch fabrication, mechanical characterizations, and cell culture demonstration of robust ultrathin epitaxial deposited SiC membranes. The as-fabricated ultrathin SiC membranes, with an ultrahigh aspect ratio (length/thickness) of up to 20 000, possess high a fracture strength up to 2.95 GPa and deformation up to 50 MUm. A high optical transmittance of above 80% at visible wavelengths was obtained for 50 nm membranes. The as-fabricated membranes were experimentally demonstrated as an excellent substrate platform for bio-MEMS/NEMS cell culture with the cell viability rate of more than 92% after 72 h. The ultrathin SiC membrane is promising for in vitro observations/imaging of bio-objects with an extremely short optical access. PMID- 29140078 TI - Molecular Recognition and Immobilization of Ligand-Conjugated Redox-Responsive Polymer Nanocontainers. AB - We present the preparation of ligand-conjugated redox-responsive polymer nanocontainers by the supramolecular decoration of cyclodextrin vesicles with a thin redox-cleavable polymer shell that displays molecular recognition units on its surface. Two widely different recognition motifs (mannose-Concanavalin A and biotin-streptavidin) are compared and the impact of ligand density on the nanocontainer surface as well as an additional functionalization with nonadhesive poly(ethylene glycol) is studied. Aggregation assays, dynamic light scattering, and a fluorometric quantification reveal that the molecular recognition of ligand conjugated polymer nanocontainers by receptor proteins is strongly affected by the multivalency of interactions and the association strength of the recognition motif. Finally, microcontact printing is used to prepare streptavidin-patterned surfaces, and the specific immobilization of biotin-conjugated nanocontainers is demonstrated. As a prototype of a nanosensor, these tethered nanocontainers can sense a reductive environment and react by releasing a payload. PMID- 29140079 TI - Progress and Trends in AIE-Based Bioprobes: A Brief Overview. AB - Luminescent bioprobes are powerful analytical means for biosensing and optical imaging. Luminogens featured with aggregation-induced emission (AIE) attributes have emerged as ideal building blocks for high-performance bioprobes. Bioprobes constructed with AIE luminogens have been identified to be a novel class of FL light-up probing tools. In contrast to conventional bioprobes based on the luminophores with aggregation-caused quenching (ACQ) effect, the AIE-based bioprobes enjoy diverse superiorities, such as lower background, higher signal-to noise ratio and sensitivity, better accuracy, and more outstanding resistance to photobleaching. AIE-based bioprobes have been tailored for a vast variety of purposes ranging from biospecies sensing to bioimaging to theranostics (i.e., image-guided therapies). In this review, recent five years' advances in AIE-based bioprobes are briefly overviewed in a perspective distinct from other reviews, focusing on the most appealing trends and progresses in this flourishing research field. There are altogether 11 trends outlined, which have been classified into four aspects: the probe composition and form (bioconjugtes, nanoprobes), the output signal of probe (far-red/near-infrared luminescence, two/three-photon excited fluorescence, phosphorescence), the modality and functionality of probing system (dual-modality, dual/multifunctionality), the probing object and application outlet (specific organelles, cancer cells, bacteria, real samples). Typical examples of each trend are presented and specifically demonstrated. Some important prospects and challenges are pointed out as well in the hope of intriguing more interests from researchers working in diverse areas into this exciting research field. PMID- 29140080 TI - Vapor-Assisted Solution Approach for High-Quality Perovskite CH3NH3PbBr3 Thin Films for High-Performance Green Light-Emitting Diode Applications. AB - The vapor-assisted solution method was developed to prepare high-quality organic inorganic halide perovskite CH3NH3PbBr3 (MAPbBr3) thin films. We detailedly investigated the effect of evaporation time and temperature of MABr powder on the microstructure, crystallinity, and optical characterizations of MAPbBr3 thin films, and a controllable morphology evolution with varying surface coverage was observed. Temperature-dependent and time-resolved photoluminescence measurements were carried out to investigate the optical transition mechanisms and carrier recombination dynamics of MAPbBr3 thin films. Our results revealed that no structural phase transition occurred within the heating process (10-300 K). In addition to the exciton-related emission, a trapped charge-carrier emission appeared at a critical temperature of 140 K. The corresponding temperature sensitivity coefficient of band gap, exciton binding energy, and optical phonon energy of the MAPbBr3 thin films were extracted from the experimental data. Furthermore, planar perovskite light-emitting diodes (PeLEDs) based on a Al/LiF/TPBi/MAPbBr3/NiO/ITO structure were fabricated, and a high-purity green emission at ~532 nm with a low line width (25 nm) was achieved. The devices demonstrated remarkable performances with high luminance (6530 cd/m2), current efficiency (8.16 cd/A), external quantum efficiency (4.36%), and power efficiency (4.49 lm/W). This research will provide valuable information for the preparation of high-quality perovskite thin films, facilitating their future applications in novel high-performance PeLEDs. PMID- 29140082 TI - Self-Assembly and Catalytic Reactivity of BINOL-Bridged Bis(phenanthroline) Metallocages. AB - Upon treatment with ZnII ions, a series of BINOL-bridged bis(phenanthroline) ligands was self-assembled into [M2L3] metallocages, which were carefully characterized by NMR spectroscopy and ESI-MS spectrometry. Among them, a racemic mixture of the BINOL-bridged bis(phenanthrolines) underwent chiral self-sorting to afford two homochiral metallocages. The narcissistic self-sorting process of the metallocages was observed in the complexation reaction of the constitutionally isomeric bis(phenanthrolines) with varying connection positions. Moreover, the endo hydroxyl-functionalized metallocage [Zn2{( S)-L2OH}3] exhibited catalytic activity and substrate selectivity for the Knoevenagel condensation reactions of aromatic tricarbaldehydes with malononitrile. PMID- 29140081 TI - The Human Milk Glycome as a Defense Against Infectious Diseases: Rationale, Challenges, and Opportunities. AB - Each year over 3 million people die from infectious diseases with most of these deaths being poor and young children who live in low- and middle-income countries. Infectious diseases emerge for a multitude of reasons. On the social front, reasons include a breakdown of public health standards, international travel, and immigration (for financial, civil, and social reasons). At the molecular level, the modern rise of infectious diseases is tied to the juxtaposition of drug-resistant pathogens and a lack of new antimicrobials. The consequence is the possibility that humankind will return to the preantibiotic era wherein millions of people will perish from what should be trivial illnesses. Given the stakes, it is imperative that the chemistry community take leadership in delivering new antibiotic leads for clinical development. We believe this can happen through innovation in two areas. First is the development of novel chemical scaffolds to treat infections caused by multidrug-resistant pathogens. The second area, which is not exclusive to the first, is the generation of antibiotics that do not cause collateral damage to the host or the host's microbiome. Both can be enabled through advances in chemical synthesis. It is with this general philosophy in mind that we hypothesized human milk oligosaccharides (HMOs) could serve as novel chemical scaffolds for antibacterial development. We provide herein a personal account of our laboratory's progress toward the goal of using HMOs as a defense against infectious diseases. PMID- 29140083 TI - A Critical Role of Ser26 Hydrogen Bonding in Abeta42 Assembly and Toxicity. AB - Amyloid beta-protein (Abeta) assembly is a seminal process in Alzheimer's disease. Elucidating the mechanistic features of this process is thought to be vital for the design and targeting of therapeutic agents. Computational studies of the most pathologic form of Abeta, the 42-residue Abeta42 peptide, have suggested that hydrogen bonding involving Ser26 may be particularly important in organizing a monomer folding nucleus and in subsequent peptide assembly. To study this question, we experimentally determined structure-activity relationships among Abeta42 peptides in which Ser26 was replaced with Gly, Ala, alpha aminobutryic acid (Abu), or Cys. We observed that aliphatic substitutions (Ala and Abu) produced substantially increased rates of formation of beta-sheet, hydrophobic surface, and fibrils, and higher levels of cellular toxicity. Replacement of the Ser hydroxyl group with a sulfhydryl moiety (Cys) did not have these effects. Instead, this peptide behaved like native Abeta42, even though the hydropathy of Cys was similar to that of Abu and very different from that of Ser. We conclude that H bonding of Ser26 is the factor most important in its contribution to Abeta42 conformation, assembly, and subsequent toxicity. PMID- 29140084 TI - Characterization of a UGT84 Family Glycosyltransferase Provides New Insights into Substrate Binding and Reactivity of Galloylglucose Ester-Forming UGTs. AB - Galloylated plant specialized metabolites play important roles in plant environment interactions and in the promotion of human and animal health. The galloylation reactions are mediated by the formation of galloylglucose esters from gallic acid and UDP-glucose, catalyzed by the plant UGT84 family glycosyltransferases. To explore and exploit the structural determinants of UGT84 activities, we performed homology modeling and substrate docking of PgUGT84A23, a galloylglucose ester-forming family 84 UGT, as well as sequence comparisons of PgUGT84A23 with other functionally characterized plant UGTs. By employing site directed mutagenesis of candidate amino acids, enzyme assays with analogous substrates, and kinetic analysis, we elucidated key amino acid sites for PgUGT84A23 substrate binding and reactivity. The galloylglucose ester-forming UGT84s have not been shown to glycosylate genistein (an isoflavonoid) in vivo. Unexpectedly, amino acids highly conserved among UGT84s that affect specifically the binding of genistein but not gallic acid or other tested sugar acceptors were identified. This result suggests that genistein may resemble the substrate profile for the enzyme ancestor of the galloylglucose ester-forming UGTs and recruited during transition from a general to a more specialized defense function. Overall, a better understanding of the structure-function relationship of UGT84s will facilitate enzyme engineering for the production of pharmaceutically and industrially valuable glycosylated compounds. PMID- 29140085 TI - Electronic Structure of Anilinopyridinate-Supported Ru25+ Paddlewheel Compounds. AB - The electronic structures of the diruthenium compounds Ru2(ap)4Cl (1, ap = 2 anilinopyridinate) and Ru2(ap)4OTf (2) were investigated with UV-vis, resonance Raman, and magnetic circular dichroism (MCD) spectroscopies; SQUID magnetometry; and density functional theory (DFT) calculations. Both compounds have quartet spin ground states with large axial zero-field splitting of ~60 cm-1 that is characteristic of Ru25+ compounds having a (pi*, delta*)3 electron configuration and a Ru-Ru bond order of ~2.5. Two major visible absorption features are observed at ~770 and 430 nm in the electronic spectra, the assignments of which have previously been ambiguous. Both bands have significant charge-transfer character with some contributions from d -> d transitions. MCD spectra were measured to enable the identification of d -> d transitions that are not easily observable by UV-vis spectroscopy. In this way, we are able to identify bands due to delta -> delta* and delta -> pi* transitions at ~16 100 and 11 200-12 300 cm 1, respectively, the latter band being sensitive to the pi-donating character of the axial ligand. The Ru-Ru stretches are coupled with pyridine rocking motions and give rise to observed resonance Raman peaks at ~350 and 420 cm-1, respectively. PMID- 29140086 TI - Applications of Oxygenases in the Chemoenzymatic Total Synthesis of Complex Natural Products. AB - Nature has produced a diverse range of oxygenases for the modification of secondary metabolites with selectivity profiles that are unmatched by conventional man-made catalysts. In the past two decades, organic chemists have begun to harness the synthetic potential of these biocatalysts to develop efficient chemoenzymatic synthesis of complex natural products. Judicious combination of synthetic and enzymatic transformations in multistep synthesis can often result in powerful disconnections that compare favorably with contemporary chemical strategies for accessing the target natural products, while at the same time presenting opportunities to innovate. This Perspective highlights strategic applications of enzymatic hydroxylation to simplify problems in natural product synthesis. Finally, newly discovered enzymes that would facilitate further developments in this field are discussed. PMID- 29140087 TI - Binuclear Cyclopentadienylmetal Methylene Sulfur Dioxide Complexes of Rhodium and Iridium Related to a Photochromic Metal Dithionite Complex. AB - The photochromic dithionite complex Cp*2Rh2(MU-CH2)2(MU-O2SSO2) (Cp* = eta5 Me5C5) is of interest because it undergoes an unusual fully reversible unimolecular photochemical rearrangement to the isodithionite complex Cp*2Rh2(MU CH2)2(MU-O2SOSO). In order to obtain more insight into these systems, a comprehensive density functional theory study has been carried out on isomeric Cp2M2(CH2)2(SO2)2 (M = Rh, Ir) derivatives. The experimentally observed rhodium complexes with coupled sulfur dioxide (SO2) units to give dithionite or isodithionite ligands are surprisingly high-energy kinetic isomers in our analysis, reflecting the need for dithionite rather than SO2 for their synthesis. Many isomeric structures containing two separate SO2 ligands are found to lie at lower energies than these dithionite and isodithionite complexes. In the lowest energy Cp2M2(CH2)2(SO2)2 isomers, the two methylene groups couple to form an ethylene ligand that can be either terminal or bridging. In slightly higher energy structures, a formal hydrogen shift is predicted to occur within the ethylene ligand to give a methylcarbene CH3CH ligand. Isomers with a bridging methylcarbene ligand are energetically preferred over isomers with a terminal methylcarbene ligand. Generation of the lower-energy Cp2Rh2(CH2)2(SO2)2 isomers containing separate SO2 ligands should be achievable through reactions of SO2 with more highly reduced cyclopentadienylrhodium methylene complexes such as Cp*2Rh2(MU-CH2)2. PMID- 29140089 TI - Effects of Variable Boron Concentration on the Properties of Superhard Tungsten Tetraboride. AB - Tungsten tetraboride is an inexpensive, superhard material easily prepared at ambient pressure. Unfortunately, there are relatively few compounds in existence that crystallize in the same structure as tungsten tetraboride. Furthermore, the lack of data in the tetraboride phase space limits the discovery of any new superhard compounds that also possess high incompressibility and a three dimensional boron network that withstands shear. Thus, the focus of the work here is to chemically probe the range of thermodynamically stable tetraboride compounds with respect to both the transition metal and the boron content. Tungsten tetraboride alloys with a variable concentration of boron were prepared by arc-melting and investigated for their mechanical properties and thermal stability. The purity and phase composition were confirmed by energy dispersive X ray spectroscopy and powder X-ray diffraction. For variable boron WBx, it was found that samples prepared with a metal to boron ratio of 1:11.6 to 1:9 have similar hardness values (~40 GPa at 0.49 N loading) as well as having a similar thermal oxidation temperature of ~455 degrees C. A nearly single phase compound was successfully stabilized with tantalum and prepared with a nearly stoichiometric amount of boron (4.5) as W0.668Ta0.332B4.5. Therefore, the cost of production of WB4 can be decreased while maintaining its remarkable properties. Insights from this work will help design future compounds stable in the adaptable tungsten tetraboride structure. PMID- 29140088 TI - Symmetrical and Nonsymmetrical Meso-Meso Directly Linked Hydroporphyrin Dyads: Synthesis and Photochemical Properties. AB - A series of a rigid meso-meso directly linked chlorin-chlorin, chlorin bacteriochlorin, and bacteriochlorin-bacteriochlorin dyads, including free bases as well as Zn(II), Pd(II), and Cu(II) complexes, has been synthesized, and their absorption, emission, singlet oxygen (1O2) photosensitization, and electronic properties have been examined. Marked bathochromic shifts of the long-wavelength Q y absorption band and increase in fluorescence quantum yields in dyads, in comparison to the corresponding monomers, are observed. Nonsymmetrical dyads (except bacteriochlorin-bacteriochlorin) show two distinctive Q y bands, corresponding to the absorption of each dyad component. A nearly quantitative S1 S1 energy transfer between hydroporphyrins in dyads, leading to an almost exclusive emission of hydroporphyrin with a lower S1 energy, has been determined. Several symmetrical and all nonsymmetrical dyads exhibit a significant reduction in fluorescence quantum yields in solvents of high dielectric constants; this is attributed to the photoinduced electron transfer. The complexation of one macrocycle by Cu(II) or Pd(II) enhances intersystem crossing in the adjacent, free base dyad component, which is manifested by a significant reduction in fluorescence and increase in quantum yield of 1O2 photosensitization. PMID- 29140090 TI - Quantum Mechanics/Molecular Mechanics Simulations Identify the Ring-Opening Mechanism of Creatininase. AB - Creatininase catalyzes the conversion of creatinine (a biosensor for kidney function) to creatine via a two-step mechanism: water addition followed by ring opening. Water addition is common to other known cyclic amidohydrolases, but the precise mechanism for ring opening is still under debate. The proton donor in this step is either His178 or a water molecule bound to one of the metal ions, and the roles of His178 and Glu122 are unclear. Here, the two possible reaction pathways have been fully examined by means of combined quantum mechanics/molecular mechanics simulations at the SCC-DFTB/CHARMM22 level of theory. The results indicate that His178 is the main catalytic residue for the whole reaction and explain its role as proton shuttle during the ring-opening step. In the first step, His178 provides electrostatic stabilization to the gem diolate tetrahedral intermediate. In the second step, His178 abstracts the hydroxyl proton of the intermediate and delivers it to the cyclic amide nitrogen, leading to ring opening. The latter is the rate-limiting step with a free energy barrier of 18.5 kcal/mol, in agreement with the experiment. We find that Glu122 must be protonated during the enzyme reaction, so that it can form a stable hydrogen bond with its neighboring water molecule. Simulations of the E122Q mutant showed that this replacement disrupts the H-bond network formed by three conserved residues (Glu34, Ser78, and Glu122) and water, increasing the energy barrier. Our computational studies provide a comprehensive explanation for previous structural and kinetic observations, including why the H178A mutation causes a complete loss of activity but the E122Q mutation does not. PMID- 29140091 TI - Evidence for Symmetry Reduction in Ti3(Al1-deltaCudelta)C2 MAX Phase Solid Solutions. AB - Ti3[Al1-deltaCudelta]C2 MAX phase solid solutions have been synthesized by sintering compacted Ti3AlC2-Cu composites produced by mechanical milling. Using X ray and neutron diffraction techniques, it is demonstrated that the Cu mixing into the Al site is accompanied by lattice distortion, which leads to symmetry reduction from a hexagonal to a monoclinic structure. Such symmetry reduction likely results from this mixing through deviation of the A-site position from the special (0, 0, 1/4) position within the P63/mmc space group of the original Ti3AlC2 structure. Moreover, it is demonstrated that the Cu admixture into the A site can be adjusted from the composition of the reactant mixture. The lattice parameter variation of the solid solution compounds, with 10-50 atom % Cu in the A site, is found to be consistent with Vegard's law. PMID- 29140092 TI - Determinants and Expansion of Specificity in a Trichothecene UDP Glucosyltransferase from Oryza sativa. AB - Family 1 UDP-glycosyltransferases (UGTs) in plants primarily form glucose conjugates of small molecules and, besides other functions, play a role in detoxification of xenobiotics. Indeed, overexpression of a barley UGT in wheat has been shown to control Fusarium head blight, which is a plant disease of global significance that leads to reduced crop yields and contamination with trichothecene mycotoxins such as deoxynivalenol (DON), T-2 toxin, and many other structural variants. The UGT Os79 from rice has emerged as a promising candidate for inactivation of mycotoxins because of its ability to glycosylate DON, nivalenol, and hydrolyzed T-2 toxin (HT-2). However, Os79 is unable to modify T-2 toxin (T-2), produced by pathogens such as Fusarium sporotrichioides and Fusarium langsethii. Activity toward T-2 is desirable because it would allow a single UGT to inactivate co-occurring mycotoxins. Here, the structure of Os79 in complex with the products UDP and deoxynivalenol 3-O-glucoside is reported together with a kinetic analysis of a broad range of trichothecene mycotoxins. Residues associated with the trichothecene binding pocket were examined by site-directed mutagenesis that revealed that trichothecenes substituted at the C4 position, which are not glycosylated by wild-type Os79, can be accommodated in the binding pocket by increasing its volume. The H122A/L123A/Q202L triple mutation, which increases the volume of the active site and attenuates polar contacts, led to strong and equivalent activity toward trichothecenes with C4 acetyl groups. This mutant enzyme provides the broad specificity required to control multiple toxins produced by different Fusarium species and chemotypes. PMID- 29140093 TI - Early Diagnosis and Treatment of Asymptomatic Vertical Enamel and Dentin Cracks. AB - Asymptomatic vertical enamel and dentin cracks can lead to multiple pathologic consequences ranging from caries to pulpal involvement, periodontal involvement, complete tooth fracture, and tooth loss if intervention is postponed. Early diagnosis, using magnification, tactile examination, transillumination, and dyes, and early restorative and occlusal treatments can be incorporated into daily practice to prevent further crack propagation before asymptomatic cracks become symptomatic and cause further damage to the dentition and surrounding tissues. This article reviews the rationales and presents a systematic approach for early diagnosis and treatment of asymptomatic vertical enamel and dentin cracks based on current evidence. PMID- 29140094 TI - The Principles of Functional and Mucostatic Impressions for Complete Denture Bases: A Review. AB - In addition to needing to be hygienic and biocompatible, the base of a complete denture (CD) should provide intimate adaptation to the mucosa of a ridge. The ridge form may differ under function than when at rest because of the compressibility of mucosa. This viscoelastic behavior of ridge mucosa has been a focus of research and a clinical challenge confronted by dentists when making impressions. This article discusses the basic principles of nonpressure mucostatic and selective-pressure functional impression concepts and provides a theoretical and scientific basis for the design of a CD base. PMID- 29140095 TI - A Customized Healing Abutment for Immediate and Delayed Implant Cases. AB - Anatomically contoured healing abutments have been shown to contain and protect slow-resorbing substitution grafts, resulting in bone and soft-tissue volume augmentation. Even in healed sites customized healing abutments have demonstrated favorable outcomes compared to standard healing abutments. Through two separate cases, this article describes a technique that enables simple chairside fabrication of precisely contoured customized healing abutments and exact 3 dimensional intraoral positioning. With this technique, the soft tissues upon maturation closely resemble the natural root contour, which allows for the generation of esthetic and functional implant-supported restorations. PMID- 29140096 TI - Redesigning Existing Provisional Restorations While Maintaining Established Transmucosal Anatomy in a Multi-Implant System/Natural Tooth, Full-Arch Case. AB - Redesigning existing provisional restorations when a combination of two different implant systems and natural teeth exist in the same arch can be challenging. Problems such as acrylic locking into undercuts and loss of spatial landmarks both subgingivally and supragingivally are common concerns for the practitioner. Two techniques, presented herein, offer treatment options to retain the previously developed transmucosal anatomies of implant-level provisional abutments while allowing for redesign of the clinical crown component of the same long-term provisional restorations. By modifying only the supragingival aspect of the provisional prosthesis, the previously developed transmucosal areas remain intact. Use of a segmented matrix from an approved wax-up offers greater control versus a single matrix of the entire arch. PMID- 29140097 TI - CAD/CAM Technologies Allowing Restorative Dentistry to "Push the Envelope". PMID- 29140098 TI - Surface Roughness of Methacrylate- and Silorane-Based Composites After Finishing and Polishing Procedures. AB - OBJECTIVE: To compare the effect of surface finishing and polishing protocols on the surface roughness (Ra) of methacrylate-based and silorane-based resin composites. METHODS AND MATERIALS: Fifty specimens (5 mm x 2 mm) of each composite material were prepared using a split mold: FiltekTM Supreme Ultra (3M ESPE), Tetric EvoCeram(r) (Ivoclar Vivadent), Tetric CeramTM HB (Ivoclar Vivadent), and FiltekTM LS Low Shrink (3M ESPE). Specimens were divided into five groups (n = 10) according to the following procedures: G1 - 15-um fine diamond bur (FDB); G2 - 15-um FDB followed by a 20-fluted tungsten carbide bur; G3 - 15 um FDB followed by diamond-impregnated micropolishing points (D-FINE Double Diamond Polishing System, Clinician's Choice); G4 - 15-um FDB followed by diamond impregnated micropolishing points (Flame Point Pre-polisher and Shine, Brassseler USA); and G5 - 15-um FDB followed by the application of a surface sealer (PermaSeal(r), Ultradent Products, Inc.). Ra was measured in three different regions using a surface profilometer (Mitutoyo Surfest SJ-210, Mitutoyo America). RESULTS: Multiple comparisons were obtained using a one-way ANOVA with Tukey's B rank order test ( = 0.05). No significant differences in Ra were observed among the resin composites tested in the same condition. The use of a FDB generated the highest roughness values, while the use of a surface sealer resulted in the lowest roughness values for all resin composites tested (P < .05). No significant difference in Ra was observed between the use of a multi-fluted carbide bur and the rubber point D-FINE Double Diamond Polishing System for all resin composites tested. PMID- 29140099 TI - Oral Healthcare for Persons With Intellectual or Developmental Disabilities: Why Is There a Disparity? AB - Despite some progress, a significant disparity still exists in oral healthcare between individuals with intellectual or developmental disabilities and the general population. Barriers generated by finances, a lack of appropriately trained dental providers, and the patients themselves combine to create significant challenges to providing dental care. However, strategies exist that can help to decrease the magnitude of these hurdles so this disparity can be minimized. PMID- 29140100 TI - Lip Repositioning Technique With Smile Elevator Muscle Containment - A Novel Cosmetic Approach for Gummy Smile: Case Report. AB - Excessive gingival display (EGD) is a challenge for dentists attempting to provide their patients a pleasant smile. EGD associated with hyperactivity of the smile elevator muscles can be treated with various surgical techniques; regardless of which technique is used, to achieve a predictable result with long term stability limiting upper lip movement when the patient smiles, a firm muscle containment is imperative. This report describes an innovative suture procedure associated with a lip repositioning technique aimed at maintaining the traction and containment of the smile elevator muscles. This case demonstrates a successful and stable result for excessive gingival exposure, addressing and satisfying a patient's esthetic concerns. PMID- 29140101 TI - Fabrication of a Surgical Guide for Lateral Sinus Augmentation. AB - Cone-beam computed tomography (CBCT) scans are used in planning implant treatment to help determine volume of available bone and identify anatomical structures. This enhances planning, particularly when inadequate bone is present in the posterior maxilla due to proximity of the inferior aspect of the maxillary sinus to the crestal bone. To place dental implants into this area, sinus augmentation is often needed to provide sufficient bone volume to support implants and allow prosthetic loading with predictable long-term results. Use of surgical guides for implant placement and sinus augmentation aids the practitioner in providing precision treatment. This article will discuss a method for fabrication of a surgical guide to transfer CBCT information intraorally to enable creation of a precisely placed lateral sinus window. PMID- 29140102 TI - Comparative genomics of type 1 IncC plasmids from China. AB - AIM: This study dealt with genomic characterization of type 1 IncC resistance plasmids, capable of spreading across taxonomic borders, from China. MATERIALS & METHODS: p112298-tetA was sequenced and compared with type 1 IncC reference plasmid pR148 and two available sequenced type 1 IncC plasmids pHS36-NDM and pVAS3-1 from China. RESULTS: These plasmids contained one or more exogenous resistance islands, which included the ARI-A islands, the ARI-B islands, the ISEcp1-blaCMY units and the bla KPC-2 region and were inserted at various sites in the IncC backbone and thus represented three distinct lineages. CONCLUSION: Complex rearrangement and homologous recombination events have occurred during evolution of p112298-tetA, making it significantly differ modularly from the other three plasmids with respect to both plasmid backbone and exogenous resistance regions. PMID- 29140103 TI - Salmonella Gallinarum field isolates and its relationship to vaccine strain SG9R. AB - 1. The aim of the present study was to determine if the 9R-strain of the Salmonella Gallinarum live vaccine was responsible for having fowl typhoid outbreaks in chicken flocks from both chicken and turkey breeders as well as to verify the antimicrobial resistance of the isolates from the outbreaks. 2. The triplex polymerase chain reaction, standard antimicrobial test, beta-lactamase genes identification and Ion Torrent PMG whole-genome sequence were used in the field isolates and in the vaccine strain of S. Gallinarum. 3. The 60 tested isolates were not from vaccine origin and manifested high resistance to drugs from macrolide and quinolone groups. Whole-genome sequencing (WGS) and single nucleotide polymorphism analysis on selected isolates for core genes from Salmonella enterica confirmed the wild origin of these isolates and showed two possible sources of S. Gallinarum in the studied outbreaks. 4. S. Gallinarum isolated from fowl typhoid outbreaks in the studied period were not caused by the use of the SG9R live vaccine. The source of strains sequenced was diverse. PMID- 29140104 TI - Corrective Statements from the Tobacco Industry: More Evidence for Why We Need Effective Tobacco Control. PMID- 29140105 TI - Durvalumab in non-small-cell lung cancer patients: current developments. AB - Immune checkpoint inhibitors (ICIs) are a key component of treating advanced cancer patients, principally antibodies against CTLA-4 and PD-1 or PD-L1. Durvalumab (MEDI4736) is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1, which binds to PD-1 and CD80, but not to PD-L2. Single-agent durvalumab showed clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, particularly the >=25% PD-L1+ population. Durvalumab is under evaluation in early, locally advanced and advanced disease as monotherapy and combined with ICIs, targeted therapies, chemotherapy and radiotherapy. Impressive activity has been recently reported after chemoradiation in locally advanced patients; promising activity was observed with other ICI combinations, and potentially with other drugs including platinum-based chemotherapy. In contrast, early data reveal lower response rates in EGFR and ALK positive patients. PMID- 29140106 TI - Lignans and secoiridoid glycosides from the stem barks of Jasminum tortuosum. AB - This paper reports on the first phytochemical analysis ever performed on Jasminum tortuosum Willd. This analysis, mainly carried out by means of column chromatography separation, NMR spectroscopy and mass spectrometry, led to the isolation and the identification of four compounds, namely the lignans ginkgool (1) and olivil-4'-O-beta-glucopyranoside (2) and the secoiridoids oleoside dimethyl ester (3) and oleoside 11-methyl ester (4). The presence of these compounds is significant from a chemotaxonomic point of view, confirming the correct botanical classification of the species and, from a phytochemical standpoint, may suggest its possible use in the ethno-medicinal field. PMID- 29140107 TI - A cross-sectional study of ethnicity-based differences in treatment seeking for symptoms of acute coronary syndrome. AB - BACKGROUND: Patient-related delays in acquiring medical care for symptoms of acute coronary syndrome remain unacceptably long. Many clinical and sociodemographic characteristics associated with treatment-seeking delay are known; however, ethnicity has not been extensively evaluated. OBJECTIVE: The purpose of this study was to examine ethnicity-based differences in the time-to treatment-seeking intervals of patients experiencing symptoms of acute coronary syndrome. METHOD: Data for this descriptive study were collected for the larger Acute Coronary Syndrome Care in Emergency Departments (ASCEND) study. The larger study is a prospective, observational study in which patients presenting to hospital emergency departments and triaged as having symptoms suggestive of acute coronary syndrome are identified. The primary outcome of this study, the time-to treatment-seeking interval, was defined as the time between symptom onset and treatment seeking. The predictor variable, ethnicity, was measured with self reported data and categorised as Chinese, South Asian, or 'Other' ethnic group. Participants in the 'Other' ethnic group were predominantly of European ancestry. Univariate and multivariate analyses were undertaken, along with nonparametric testing. RESULTS: The study sample consisted of 419 participants: 36 Chinese, 126 South Asian, and 257 'Other' participants. The median time-to-treatment-seeking interval, for the total sample, was 180 minutes. A Kruskal-Wallis test demonstrated no statistically significant differences in the time-to-treatment seeking intervals by ethnicity. CONCLUSION: No ethnicity-based differences in the time-to-treatment-seeking intervals for symptoms of acute coronary syndrome were found. It is possible that Chinese and South Asian patients living in western countries are more aware of the potential signs and symptoms of acute coronary syndrome or feel more confident to access healthcare services than they have been previously. PMID- 29140108 TI - Cytomegalovirus and HIV Persistence: Pouring Gas on the Fire. AB - The inherent stability of a small population of T cells that are latently infected with HIV despite antiretroviral therapy (ART) remains a stubborn obstacle to an HIV cure. By exploiting the memory compartment of our immune system, HIV maintains persistence in a small subset of quiescent cells with varying phenotypes, thus evading immune surveillance and clinical detection. Understanding the molecular and immunological mechanisms that maintain the latent reservoir will be critical to the success of HIV eradication strategies. Human cytomegalovirus (CMV), another chronic viral infection, frequently co-occurs with HIV and occupies an oversized proportion of memory T cell responses. CMV and HIV have both evolved complex strategies to manipulate our immune system for their own advantage. Given the increasingly clear links between CMV replication, chronic immune activation, and increased HIV reservoirs, we present a closer examination of the interplay between these two chronic coinfections. Here we review the effects of CMV on the immune system and show how they may affect persistence of the latent HIV reservoir during ART. The studies described herein suggest that hijacking of cytokine and chemokine signaling, manipulation of cell development pathways, and transactivation of HIV expression by CMV might be pouring gas on the fire of HIV persistence. Future interventional studies are required to formally determine the extent to which CMV is causally associated with inflammation and HIV reservoir expansion. PMID- 29140110 TI - IL-21 Therapy Controls Immune Activation and Maintains Antiviral CD8+ T Cell Responses in Acute Simian Immunodeficiency Virus Infection. AB - Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replicate during acute infection in lymphocytes of the gastrointestinal tract, before disseminating systemically. Localized replication and associated loss of gut-resident CD4+ T cells occur regardless of the portal of entry of the virus (e.g., intravenous vs. rectal). Thus, HIV and SIV are tropic for gut tissue, and their pathogenesis requires the special environment of the intestine. T helper 17 (Th17) cells are important contributors to microbial defense in the gut that are vulnerable to HIV infection and whose loss is associated with translocation of microbial products to the systemic circulation, leading to chronic immune activation and disease progression. Interleukin (IL)-21 promotes differentiation and survival of Th17 cells and stimulates CD8+ T cell function. By promoting Th17 cell survival, IL-21 could limit bacterial translocation and immune activation in the setting of acute or rebounding HIV/SIV disease. In this study, we tested the effect of recombinant IL-21-IgFc treatment, given at the time of infection, on SIVmac251 infection. We found that rIL-21-IgFc decreases immune activation and maintains effective antiviral responses by CD8+ T cells in blood, but this maintenance is not associated with lower viral loads. rIL-21-IgFc treatment also did not generally support Th17 cell populations, but Th17 cells remained strongly and independently associated with control of plasma viremia. For example, the single animal exhibiting greatest control over viremia in our study also manifested the highest levels of IL-21 in plasma, Th17 cell maintenance in blood, and Th17 cells in intestinal tissue. These findings provide rationale for further exploration of IL-21 treatment as a support for host CD8+ T cell responses in HIV cure strategies. PMID- 29140112 TI - A 2017 review of pharmacotherapy for treating focal epilepsy: where are we now and how will treatment develop? AB - INTRODUCTION: Focal epilepsy is the most common type of epilepsy with approximately 30 million patients affected worldwide. There is a major challenge to develop new antiepileptic treatments as currently approximately one third of patients remain uncontrolled under our best standards of care. Areas covered: An overview is given on first- and second generation antiepileptic drugs and their mechanisms of action, and on recent new strategies for antiepileptic targets, including drugs aiming at disease modification. Expert opinion: Newer antiepileptic drugs have enabled a better tolerated and individualized treatment for many patients. Despite the successful history of antiepileptic drug development programs, second and third generation antiepileptic drugs targeting synaptic transmission have, however, failed to solve the problem of pharmacoresistance. New directions in pharmacological development include chronic models of epilepsy in drug screening and address primary and secondary epileptogenesis rather than focusing on the suppression of the symptoms, acute seizures. There is hope that the new approaches will allow for patient stratification for targeted therapy and will prove efficacy particularly in the patient group so far drug resistant. PMID- 29140111 TI - Purging Exhausted Virus-Specific CD8 T Cell Phenotypes by Somatic Cell Reprogramming. AB - Cytotoxic T cells are critical in controlling virus infections. However, continuous antigen stimulation and negative regulatory factors cause CD8 T cells to enter a dysfunctional state (T cell exhaustion), resulting in viral persistence. We hypothesized that the exhausted T cell state could be molecularly rejuvenated using a somatic cell reprogramming technology, which is technically able to convert any types of cells to induced pluripotent stem cells (iPSCs), to regenerate functional T cells capable of purging chronic infection. We generated a new mouse line (B6/129OKSM) in which every somatic cell contains four doxycycline-inducible reprogramming genes (Oct4, Klf4, Sox2, and c-Myc: OKSM), and infected them with lymphocytic choriomeningitis virus (LCMV) clone 13 to establish chronic infection. Exhausted LCMV-specific T cells isolated by flow sorting were successfully reprogrammed ex vivo into iPSCs in the presence of doxycycline. Upon injection into blastocysts and subsequent transfer into foster females, the reprogrammed cells differentiated into functional naive T cells that maintained their original antigen specificity. These results provide proof of concept that somatic cell reprogramming of exhausted T cells into iPSCs can erase imprints of their previous exhausted state and in turn regenerate functional virus-specific T cells. PMID- 29140113 TI - Prediction of Pancreatic Neuroendocrine Tumor Grade Based on CT Features and Texture Analysis. AB - OBJECTIVE: The purposes of this study were to assess whether CT texture analysis and CT features are predictive of pancreatic neuroendocrine tumor (PNET) grade based on the World Health Organization (WHO) classification and to identify features related to disease progression after surgery. MATERIALS AND METHODS: Preoperative contrast-enhanced CT images of 101 patients with PNETs were assessed. The images were evaluated for tumor location, tumor size, tumor pattern, predominantly solid or cystic composition, presence of calcification, presence of heterogeneous enhancement on contrast-enhanced images, presence of pancreatic duct dilatation, presence of pancreatic atrophy, presence of vascular involvement by the tumor, and presence of lymphadenopathy. Texture features were also extracted from CT images. Surgically verified tumors were graded according to the WHO classification, and patients underwent CT or MRI follow-up after surgical resection. Data were analyzed with chi-square tests, kappa statistics, logistic regression analysis, and Kaplan-Meier curves. RESULTS: The CT features predictive of a more aggressive tumor (grades 2 and 3) were size larger than 2.0 cm (odds ratio [OR], 3.3; p = 0.014), presence of vascular involvement (OR, 25.2; p = 0.003), presence of pancreatic ductal dilatation (OR, 6.0; p = 0.002), and presence of lymphadenopathy (OR, 6.8; p = 0.002). The texture parameter entropy (OR, 3.7; p = 0.008) was also predictive of more aggressive tumors. Differences in progression-free survival distribution were found for grade 1 versus grades 2 and 3 tumors (chi2 [df, 1] = 21.6; p < 0.001); for PNETs with vascular involvement (chi2 [df, 1] = 20.8; p < 0.001); and for tumors with entropy (spatial scale filter 2) values greater than 4.65 (chi2 (df, 1) = 4.4; p = 0.037). CONCLUSION: CT texture analysis and CT features are predictive of PNET aggressiveness and can be used to identify patients at risk of early disease progression after surgical resection. PMID- 29140109 TI - Host Methyltransferases and Demethylases: Potential New Epigenetic Targets for HIV Cure Strategies and Beyond. AB - A successful HIV cure strategy may require reversing HIV latency to purge hidden viral reservoirs or enhancing HIV latency to permanently silence HIV transcription. Epigenetic modifying agents show promise as antilatency therapeutics in vitro and ex vivo, but also affect other steps in the viral life cycle. In this review, we summarize what we know about cellular DNA and protein methyltransferases (PMTs) as well as demethylases involved in HIV infection. We describe the biology and function of DNA methyltransferases, and their controversial role in HIV infection. We further explain the biology of PMTs and their effects on lysine and arginine methylation of histone and nonhistone proteins. We end with a focus on protein demethylases, their unique modes of action and their emerging influence on HIV infection. An outlook on the use of methylation-modifying agents in investigational HIV cure strategies is provided. PMID- 29140114 TI - Radiology Reporting: Current Practices and an Introduction to Patient-Centered Opportunities for Improvement. AB - OBJECTIVE: As health care evolves, the radiology report must also change to satisfy referring physician and patient expectations. Knowledge of the issues and controversies regarding a patient-centered approach to reporting practices is important. This article will aid the radiologist in this endeavor by summarizing key facets of radiology reporting, including current reporting standards and emerging patient-centered concepts in report language, formatting, and delivery. CONCLUSION: Future efforts to improve radiology reporting practices need to account for the needs of an increasingly heterogeneous audience that includes patients. Radiologists must exploit information technologies to craft and deliver meaningful patient-centered reports. A modern radiology report will be a powerful, flexible document that strengthens the connection between the radiologist and the patient. PMID- 29140115 TI - Ultrasound-Unenhanced CT Fusion for Detection and Localization of Ureteral Stones. AB - OBJECTIVE: The standard of care for the diagnosis and follow-up of urolithiasis is unenhanced CT. The hypothesis of this study was that that by using image fusion of subsequent ultrasound (US) with the initial unenhanced CT, ureteral stones can be precisely localized. CONCLUSION: Of the 25 stones founds on unenhanced CT studies, 22 (88%) were confidently identified using US-unenhanced CT fusion within 72 hours after the initial CT scan was obtained. US-unenhanced CT fusion might obviate the need for repeated CT scans for monitoring urolithiasis. PMID- 29140117 TI - Comparison of Radiation Dose and Image Quality of Abdominopelvic CT Using Iterative (AIDR 3D) and Conventional Reconstructions. AB - OBJECTIVE: The purpose of this study is to compare radiation dose and image quality of abdominopelvic CT studies reconstructed with iterative and conventional techniques. MATERIALS AND METHODS: This retrospective study enrolled 99 patients who underwent abdominopelvic CT examinations with the portal venous phase images reconstructed with both filtered back projection and Adaptive Iterative Dose Reduction 3D (AIDR 3D) at different time points. Subjective assessment of image quality was performed by two radiologists who scored axial images for overall quality, sharpness, noise, and acceptability in a blinded fashion. The SD of the mean attenuation of the liver, aorta, and paraspinal muscle (as a measurement of image noise) and contrast-to-noise and signal-to noise ratios for liver and aorta were used as objective parameters of image quality. Radiation dose parameters included CT dose index volume (CTDIvol), dose length product, effective dose (ED), and size-specific dose estimate (SSDE). Results were compared for different body mass index (BMI; weight in kilograms divided by the square of height in meters) categories. Paired t test and McNemar paired tests for noninferiority were used, with p < 0.05 considered statistically significant. RESULTS: We obtained a 62.5% mean reduction in CTDIvol, a 58% mean reduction in ED, and a 63% mean reduction in SSDE when AIDR 3D was used (p < 0.001). Subjective parameters of image quality were considered noninferior for AIDR 3D studies compared with filtered back projection (p < 0.001), except for the sharpness of images of patients with BMI 20-24.9. Variable results were found regarding objective assessment of image quality. CONCLUSION: AIDR 3D allowed a significant reduction in radiation dose of abdominopelvic CT examinations without a loss of image quality in general. PMID- 29140116 TI - A Randomized Study of Patient Risk Perception for Incidental Renal Findings on Diagnostic Imaging Tests. AB - OBJECTIVE: The purpose of this study is to assess differences in patient distress, risk perception, and treatment preferences for incidental renal findings with descriptive versus combined descriptive and numeric graphical risk information. MATERIALS AND METHODS: A randomized survey study was conducted for adult patients about to undergo outpatient imaging studies at a large urban academic institution. Two survey arms contained either descriptive or a combination of descriptive and numeric graphical risk information about three hypothetical incidental renal findings at CT: 2-cm (low risk) and 5-cm (high risk) renal tumors and a 2-cm (low risk) renal artery aneurysm. The main outcomes were patient distress, perceived risk (qualitative and quantitative), treatment preference, and valuation of lesion discovery. RESULTS: Of 374 patients, 299 participated (79.9% response rate). With inclusion of numeric and graphical, rather than only descriptive, risk information about disease progression for a 2 cm renal tumor, patients reported less worry (3.56 vs 4.12 on a 5-point scale; p < 0.001) and favored surgical consultation less often (29.3% vs 46.9%; p = 0.003). The proportion choosing surgical consultation for the 2-cm renal tumor decreased to a similar level as for the renal artery aneurysm with numeric risk information (29.3% [95% CI, 21.7-36.8%] and 27.9% [95% CI, 20.5-35.3%], respectively). Patients overestimated the absolute risk of adverse events regardless of risk information type, but significantly more so when given descriptive information only, and valued the discovery of lesions regardless of risk information type (range, 4.41-4.81 on a 5-point scale). CONCLUSION: Numeric graphical risk communication for patients about incidental renal lesions may facilitate accurate risk comprehension and support patients in informed decision making. PMID- 29140118 TI - 11C-Choline PET/CT for Detection and Localization of Parathyroid Adenomas. AB - OBJECTIVE: The purpose of this study is to determine the efficacy of 11C-choline PET/CT for the detection of parathyroid adenomas by retrospectively reviewing a large patient population. MATERIALS AND METHODS: In this single-institution retrospective study, 7088 11C-choline PET/CT scans performed of 2933 men with prostate cancer from January 2005 through February 2016 were evaluated. Patients with suspected parathyroid adenomas were identified through a review of the electronic medical record and relevant imaging. Patient demographics, laboratory results, and lesion characteristics were noted. Pathologically proven parathyroid adenomas and lesions in patients with imaging or laboratory findings consistent with the diagnosis were considered positive. RESULTS: Thirteen men (mean [+/- SD] age, 72 +/- 7 years) with pathologically or laboratory-proven parathyroid adenomas were identified. All had abnormally elevated serum calcium and parathyroid hormone levels. All adenomas were tracer avid on 11C-choline PET/CT (maximum standardized uptake value, 5.6 +/- 3.0), with activity averaging 4.2 times that of the blood pool and 2.1 times that of the adjacent thyroid. One case of an ectopic adenoma was identified. Of the six pathologically confirmed cases, none displayed high-grade features such as capsular, vascular, or adjacent tissue invasion. Three additional patients with possible parathyroid adenomas at 11C choline PET/CT were ultimately found to have thyroid lesions on the basis of tissue diagnosis; however, none of these patients had abnormal calcium or parathyroid hormone levels. CONCLUSION: In our patient population, 11C-choline PET/CT identified parathyroid adenomas with high specificity. Prospective investigation is warranted to validate this result and delineate the utility of 11C-choline PET/CT relative to other modalities. PMID- 29140119 TI - CT Features of the Usual Interstitial Pneumonia Pattern: Differentiating Connective Tissue Disease-Associated Interstitial Lung Disease From Idiopathic Pulmonary Fibrosis. AB - OBJECTIVE: A substantial proportion of cases of usual interstitial pneumonia (UIP) are due to connective tissue disease (CTD)-associated interstitial lung disease (ILD). The purpose of this study was to determine whether specific CT findings can help differentiate a UIP pattern of CTD-ILD from a UIP pattern of idiopathic pulmonary fibrosis (IPF) and whether these signs are associated with survival. MATERIALS AND METHODS: Adults visiting an ILD clinic from 2006 to 2015 enrolled in a research registry with a multidisciplinary diagnosis of CTD-ILD or IPF and a UIP pattern at high-resolution CT were included in the study. In these subjects with CT findings of UIP due to either IPF or CTD-ILD, three CT findings anecdotally associated with CTD-ILD were assessed for diagnostic accuracy: the "straight-edge" sign, the "exuberant honeycombing" sign, and the "anterior upper lobe" sign. Survival assessments were performed with univariate and multivariable techniques. RESULTS: The subjects included 63 patients who had CTD-ILD and 133 patients who had IPF with a UIP pattern at CT. All three CT signs were significantly more common in subjects with CTD-ILD than those with IPF (prevalence, 22.2-25.4% for CTD-ILD, 6.0-12.8% for IPF; p = 0.028 to < 0.001). The highest specificity (94.0%) and sensitivity (25.4%) were seen for the straight-edge sign. No CT sign was associated with survival in multivariable analysis. CONCLUSION: Although UIP is usually associated with IPF, the index of suspicion for CTD-ILD should be raised in the care of patients with any of the three CT signs. A thorough workup for CTD-ILD should be pursued, including referral to the rheumatology department. PMID- 29140120 TI - Imaging and imagination. PMID- 29140121 TI - Treating Bronchiectasis. PMID- 29140123 TI - Classifying Pulmonary Hypertension in Hereditary Hemorrhagic Telangiectasia. Hemodynamics Matter. PMID- 29140122 TI - Lymphangioleiomyomatosis Diagnosis and Management: High-Resolution Chest Computed Tomography, Transbronchial Lung Biopsy, and Pleural Disease Management. An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. AB - BACKGROUND: Recommendations regarding key aspects related to the diagnosis and pharmacological treatment of lymphangioleiomyomatosis (LAM) were recently published. We now provide additional recommendations regarding four specific questions related to the diagnosis of LAM and management of pneumothoraces in patients with LAM. METHODS: Systematic reviews were performed and then discussed by a multidisciplinary panel. For each intervention, the panel considered its confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences, patient values and preferences, cost, and feasibility. Evidence-based recommendations were then formulated, written, and graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. RESULTS: For women who have cystic changes on high-resolution computed tomography of the chest characteristic of LAM, but who have no additional confirmatory features of LAM (i.e., clinical, radiologic, or serologic), the guideline panel made conditional recommendations against making a clinical diagnosis of LAM on the basis of the high-resolution computed tomography findings alone and for considering transbronchial lung biopsy as a diagnostic tool. The guideline panel also made conditional recommendations for offering pleurodesis after an initial pneumothorax rather than postponing the procedure until the first recurrence and against pleurodesis being used as a reason to exclude patients from lung transplantation. CONCLUSIONS: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed. PMID- 29140124 TI - Apprenticeship-based training in neurogastroenterology and motility. AB - INTRODUCTION: Although neurogastroenterology and motility (NGM) disorders affect 50% of patients seen in clinics, many gastroenterologists receive limited NGM training. One-month apprenticeship-based NGM training has been provided at ten centers in the USA for a decade, however, outcomes of this training are unclear. Our goal was to describe the effectiveness of this program from a trainees perspective. Areas covered: We describe the training model, learning experiences, and outcomes of one-month apprenticeship-based training in NGM at a center of excellence, using a detailed individual observer account and data from 12 consecutive trainees that completed the program. During a one-month training period, 302 procedures including; breath tests (BT) n = 132, anorectal manometry (ARM) n = 29 and esophageal manometry (EM) n = 28, were performed. Post-training, all trainees (n = 12) knew indications for motility tests, and the majority achieved independence in basic interpretation of BT, EM and ARM. Additionally, in a multiple-choice NGM written-test paper, trainees achieved significant improvements in test scores post-training (P = 0.003). Expert commentary: One month training at a high-volume center can facilitate rapid learning of NGM and the indications, basic interpretation and utility of motility tests. Trainees demonstrate significant independence, and this training model provides an ideal platform for those interested in sub-specialty NGM. PMID- 29140125 TI - Diabetes area patent participation analysis - part II: years 2011-2016. AB - INTRODUCTION: Diabetes is a metabolic disease characterized by elevated levels of plasma glucose. When untreated, diabetes increases the risk of developing co morbidities such as cardiovascular disease. Several drugs, often used as part of combination therapies, have been approved to treat the disease, but these drugs will eventually fail to effectively control blood glucose levels, at which point insulin replacement therapy is required. A medical need exists for new antidiabetic drugs that exhibit good efficacy with improved safety/toleration profiles and can be added on top of existing therapies, or that can provide additional benefits beyond glucose lowering such as pancreatic beta (beta)-cell protection. Areas covered: This review analyzes drug targets and applicants of patents that published between 2011-2016 claiming novel small or large molecules for the treatment of diabetes, and compares the results to the 2008-2010 time period. Expert opinion: A majority of patent activity around the discovery of new antidiabetic drugs in 2011-2016 was directed against 15 targets, most of which were also the focus of drug discovery efforts in the 2008-2010 time period. The top targets by total patent counts were DPP4, GLP1R, INSR, GPR119, and SGLT2 (SLC5A2). With the exception of GPR119, these are the pharmacological targets of some of the best-selling antidiabetic drugs currently on the market. The top targets of patent families with the largest size counts, a metric useful in assessing patent value and applicant interest, were AMPK, CALCR, DPP4, and GLP1R. The patent analysis identified several emerging targets with greater patent activity in 2011-2016 compared to 2008-2010, including FFAR1, FFAR4, and FGFR1. Most of the patent activity in 2011-2016 was directed at established and precedented diabetes targets, the modulation of which may lead to improvements in glucose control and a delay in the progression of the disease. Few targets were identified that promote pancreatic beta-cell regeneration and beta-cell health, areas where future opportunities may exist for developing transformative drug therapies that may potentially lead to cures for diabetes. PMID- 29140126 TI - New insights into the role of vitamin D in hepatocellular carcinoma. AB - INTRODUCTION: In addition to being crucial for host immune defense, vitamin D is involved in cell proliferation, apoptosis, differentiation, inflammation, invasion and metastasis, angiogenesis and micro-RNA modulation. To date, clinical studies have demonstrated that vitamin D deficiency is common not only in patients with chronic liver diseases but also in those with hepatocellular carcinoma (HCC). Experimental studies have also demonstrated that vitamin D and its receptors are related to the occurrence of HCC and the prognoses of patients with HCC. Areas covered: In this review, we discuss the potential anti-tumor role of vitamin D in HCC based on current findings from epidemiological studies, basic science, and clinical studies and provide new insights into the pathogenesis and treatment of HCC. Expert commentary: Recent studies have revealed the anti-tumor effects of vitamin D to a certain degree. Vitamin D and its analogs may provide new treatment targets and prognostic factors for HCC that might be essential for the primary or secondary prevention of HCC and the monitoring of its progression. PMID- 29140127 TI - Proprioceptive Training for the Prevention of Ankle Sprains: An Evidence-Based Review. AB - : Reference: Schiftan GS, Ross LA, Hahne AJ. The effectiveness of proprioceptive training in preventing ankle sprains in sporting populations: a systematic review and meta-analysis. J Sci Med Sport. 2015;18(3):238-244. CLINICAL QUESTION: Does the use of proprioceptive training as a sole intervention decrease the incidence of initial or recurrent ankle sprains in the athletic population? DATA SOURCES: The authors completed a comprehensive literature search of MEDLINE, CINAHL, SPORTDiscus, and Physiotherapy Evidence Database (PEDro) from inception to October 2013. The reference lists of all identified articles were manually screened to obtain additional studies. The following key words were used. Phase 1 population terms were sport*, athlet*, and a combination of the two. Phase 2 intervention terms were propriocept*, balance, neuromusc* adj5 train*, and combinations thereof. Phase 3 condition terms were ankle adj5 sprain*, sprain* adj5 ankle, and combinations thereof. STUDY SELECTION: Studies were included according to the following criteria: (1) the design was a moderate- to high-level randomized controlled trial (>4/10 on the PEDro scale), (2) the participants were physically active (regardless of previous ankle injury), (3) the intervention group received proprioceptive training only, compared with a control group that received no proprioceptive training, and (4) the rate of ankle sprains was reported as a main outcome. Search results were limited to the English language. No restrictions were placed on publication dates. DATA EXTRACTION: Two authors independently reviewed the studies for eligibility. The quality of the pertinent articles was assessed using the PEDro scale, and data were extracted to calculate the relative risk. Data extracted were number of participants, intervention, frequency, duration, follow-up period, and injury rate. MAIN RESULTS: Of the initial 345 studies screened, 7 were included in this review for a total of 3726 participants. Three analyses were conducted for proprioceptive training used (1) to prevent ankle sprains regardless of history (n = 3654), (2) to prevent recurrent ankle sprains (n = 1542), or (3) as the primary preventive measure for those without a history of ankle sprain (n = 946). Regardless of a history of ankle sprain, participants had a reduction in ankle-sprain rates (relative risk [RR] = 0.65, 95% confidence interval [CI] = 0.55, 0.77; numbers needed to treat [NNT] = 17, 95% CI = 11, 33). For individuals with a history of ankle sprains, proprioceptive training demonstrated a reduction in repeat ankle sprains (RR = 0.64, 95% CI = 0.51, 0.81; NNT = 13, 95% CI = 7, 100). Proprioceptive training as a primary preventive measure demonstrated significant results (RR = 0.57, 95% CI = 0.34, 0.97; NNT = 33, 95% CI = 16, 1000). CONCLUSIONS: Proprioceptive training programs were effective in reducing the incidence rates of ankle sprains in the athletic population, including those with and those without a history of ankle sprains. PMID- 29140128 TI - Lower Extremity Musculoskeletal Injury Risk After Concussion Recovery in High School Athletes. AB - CONTEXT: Although an association between concussion and musculoskeletal injury has been described in collegiate and professional athletes, no researchers have investigated an association in younger athletes. OBJECTIVE: To determine if concussion in high school athletes increased the risk for lower extremity musculoskeletal injury after return to activity. DESIGN: Observational cohort study. SETTING: One hundred ninety-six high schools across 26 states. PATIENTS OR OTHER PARTICIPANTS: We used data from the National Athletic Treatment, Injury and Outcomes Network surveillance system. Athletic trainers provided information about sport-related concussions and musculoskeletal injuries in athletes in 27 sports, along with missed activity time due to these injuries. MAIN OUTCOME MEASURE(S): Three general estimating equations were modeled to predict the odds of sustaining (1) any lower extremity injury, (2) a time-loss lower extremity injury, or (3) a non-time-loss lower extremity injury after concussion. Predictors were the total number of previous injuries, number of previous concussions, number of previous lower extremity injuries, number of previous upper extremity injuries, and sport contact classification. RESULTS: The initial dataset contained data from 18 216 athletes (females = 39%, n = 6887) and 46 217 injuries. Lower extremity injuries accounted for most injuries (56.3%), and concussions for 4.3% of total injuries. For every previous concussion, the odds of sustaining a subsequent time-loss lower extremity injury increased 34% (odds ratio [OR] = 1.34; 95% confidence interval [CI] = 1.13, 1.60). The number of previous concussions had no effect on the odds of sustaining any subsequent lower extremity injury (OR = 0.97; 95% CI = 0.89, 1.05) or a non time-loss injury (OR = 1.01; 95% CI = 0.92, 1.10). CONCLUSIONS: Among high school athletes, concussion increased the odds of sustaining subsequent time-loss lower extremity injuries but not non-time-loss injuries. By definition, time-loss injuries may be considered more severe than non-time-loss injuries. The exact mechanism underlying the increased risk of lower extremity injury after concussion remains elusive and should be further explored in future research. PMID- 29140129 TI - Calling Injury Timeouts for the Medical Evaluation of Concussion: Determinants of Collegiate Football Officials' Behavior. AB - CONTEXT: Sports officials can play an important role in concussion safety by calling injury timeouts so that athletic trainers can evaluate athletes with possible concussions. Understanding the determinants of whether officials call an injury timeout when they suspect a concussion has important implications for the design of interventions to better support officials in this role. OBJECTIVE: To assess the knowledge of US collegiate football officials about concussion symptoms and to determine the associations between knowledge, perceived injunctive norms, and self-efficacy in calling injury timeouts for suspected concussions. DESIGN: Cross-sectional study. SETTING: Electronic survey. PATIENTS OR OTHER PARTICIPANTS: Of the 3074 US collegiate football officials contacted, 1324 (43% response rate) participated. MAIN OUTCOME MEASURE(S): Concussion knowledge, injunctive norms (belief about what others would want them to do), and behavioral self-efficacy (confidence in their ability to call injury timeouts for suspected concussions in athletes during challenging game-day conditions). RESULTS: Officials reported calling approximately 1 injury timeout for a suspected concussion every 4 games during the 2015 season. Structural equation modeling indicated that officials with more concussion-symptom knowledge had greater self-efficacy. Independent of an official's symptom knowledge, injunctive norms that were more supportive of calling an injury timeout were associated with greater self-efficacy. CONCLUSIONS: Concussion education for officials is important because when officials are aware of concussion symptoms, they are more confident in calling injury timeouts. Beyond increasing symptom knowledge, fostering sports environments that encourage concussion safety can support officials in calling injury timeouts. Athletic trainers can help by educating stakeholders, including officials, about the importance of concussion safety. When officials believe that other stakeholders support concussion safety, they are more likely to call injury timeouts if they suspect a concussion has occurred. PMID- 29140130 TI - The effects of hydrogen peroxide and lipopolysaccharide on rat alveolar L2 cells. AB - PURPOSE: This study aimed to investigate differential cell responses of alveolar epithelial cells (AECs) after treatments with lipopolysaccharide (LPS) and hydrogen peroxide (H2O2) to mimic the exposure to inflammation and oxidative stress and the mechanisms of a double-hit model of apoptosis. MATERIALS AND METHODS: AECs were cultured and treated with combinations of 1 MUg/mL of LPS and 500 MUM H2O2 as follows: LPS-only at 0 h, LPS at 0 h with H2O2 at 6 h (LPS + H2O2), H2O2-only at 0 h, H2O2 at 0 h with LPS at 6 h (H2O2 + LPS), and control. We investigated mRNA expression (TNF-alpha, Fas, Fas ligand, Bax, Bcl-2, Caspase 7), protein expression (Fas, Bax, Bcl-2, Caspase-7) and apoptosis (Caspase-3 activity, TUNEL assay) at 0, 3, 6, 9, 12, and 24 h. RESULTS: In the H2O2 + LPS group, the Caspase-7, and Fas mRNA levels were significantly higher than the other groups at 9 h and 12 h, and Bax was higher at 12 h. The Bax/Bcl-2 protein expression ratio was significantly higher in the H2O2 + LPS group than that of the other groups at 12h and 24h. Apoptotic index was highest in the H2O2 + LPS group at 24 h. CONCLUSIONS: The sequence of stimulation may modify the cell response in rat AECs. The results suggest that previous oxidative stress and subsequent LPS-induced inflammation primarily influence apoptosis of L2 cells by up-regulation of cell signaling. PMID- 29140131 TI - Effects of inhaled corticosteroids on the expression of TNF family molecules in murine model of allergic asthma. AB - BACKGROUND: The tumor necrosis factor superfamily member LIGHT (the official gene symbol approved by NCBI Gene Database), an inflammatory factor secreted by T cells after allergen exposure, recently discovered to play crucial roles in asthmatic airway remodeling. However, it is unclear whether LIGHT could be controlled by inhaled corticosteroids, a key component of asthma management. This study was to investigate the effects and potential mechanisms of inhaled budesonide on the expressions of LIGHT and its receptors (LTbetaR and HVEM) of lung tissues in ovalbumin-sensitized mice. MATERIALS AND METHODS: Thirty-three BALB/c mice were randomly divided into the control, asthma model, and budesonide treatment groups (11 in each group). Mice were sensitized and challenged by OVA to develop mouse model of chronic asthma, and treated with aerosolized budesonide before OVA challenge. Bronchoalveolar lavage fluid (BALF) and lungs were obtained after the final OVA challenge. Protein and mRNA Levels of LIGHT, LTbetaR, and HVEM in the lungs were investigated by immunohistochemistry, image analysis, and real-time PCR. Expressions of IL-6 and IFN-gamma in BALF were measured by ELISA. RESULTS: Inhaled budesonide significantly reduced protein and mRNA levels of lung LIGHT, LTbetaR, and HVEM in asthmatic mice. Correspondingly, the number of eosinophils and neutrophils and IL-6 levels in BALF after budesonide treatment were found to be decreased, whereas the IFN-gamma levels in BALF were increased. Moreover, the expressions of LIGHT and HVEM mRNA showed positive correlation with IL-6 levels in the treatment group. CONCLUSIONS: Inhaled budesonide can down regulate the expressions of LIGHT, LTbetaR, and HVEM in the lungs of asthmatic mice, and LIGHT/LTbetaR/HVEM interactions may be a potentially key target for asthma treatment. PMID- 29140132 TI - Mediation of the single-walled carbon nanotubes induced pulmonary fibrogenic response by osteopontin and TGF-beta1. AB - PURPOSE OF THE STUDY: A number of in vivo studies have shown that pulmonary exposure to carbon nanotubes (CNTs) may lead to an acute local inflammatory response, pulmonary fibrosis, and granulomatous lesions. Among the factors that play direct roles in initiation and progression of fibrotic processes are epithelial-mesenchymal transition and myofibroblasts recruitment/differentiation, both mediated by transforming growth factor-beta1 (TGF-beta1). Yet, other contributors to TGF-beta1 associated signaling, such as osteopontin (OPN) has not been fully investigated. MATERIALS AND METHODS: OPN-knockout female mice (OPN-KO) along with their wild-type (WT) counterparts were exposed to single-walled carbon nanotubes (SWCNT) (40 ug/mouse) via pharyngeal aspiration and fibrotic response was assessed 1, 7, and 28 days post-exposure. Simultaneously, RAW 264.7 and MLE 15 cells were treated with SWCNT (24 hours, 6 ug/cm2 to 48 ug/cm2) or bleomycin (0.1 ug/ml) in the presence of OPN-blocking antibody or isotype control, and TGF beta1 was measured in supernatants. RESULTS AND CONCLUSIONS: Diminished lactate dehydrogenase activity at all time points, along with less pronounced neutrophil influx 24 h post-exposure, were measured in broncho-alveolar lavage (BAL) of OPN KO mice compared to WT. Pro-inflammatory cytokine release (IL-6, TNF-alpha, MCP 1) was reduced. A significant two-fold increase of TGF-beta1 was found in BAL of WT mice at 7 days, while TGF-beta1 levels in OPN-KO animals remained unaltered. Histological examination revealed marked decrease in granuloma formation and less collagen deposition in the lungs of OPN-KO mice compared to WT. RAW 264.7 but not MLE-15 cells exposed to SWCNT and bleomycin had significantly less TGF-beta1 released in the presence of OPN-blocking antibody. We believe that OPN is important in initiating the cellular mechanisms that produce an overall pathological response to SWCNT and it may act upstream of TGF-beta1. Further investigation to understand the mechanistic details of such interactions is critical to predict outcomes of pulmonary exposure to CNT. PMID- 29140134 TI - A Nutrition Recovery Station Following Recreational Exercise Improves Fruit Consumption but Does Not Influence Fluid Recovery. AB - Immediate postexercise access to fruit/fluid via a recovery "station" is a common feature of mass participation sporting events. Yet little evidence exists examining their impact on subsequent dietary intake. The aim of this study was to determine if access to fruit/water/sports drinks within a recovery station significantly alters dietary and fluid intakes in the immediate postexercise period and influences hydration status the next morning. 127 (79 males) healthy participants (M +/- SD, age = 22.5 +/- 3.5y, body mass (BM) = 73 +/- 13kg) completed two self-paced morning 10km runs separated by 1 week. Immediately following the first run, participants were randomly assigned to enter (or not) the recovery station for 30min. All participants completed the alternate recovery option the following week. Participants recorded BM before and after exercise and measured Urine Specific Gravity (USG) before running and again the following morning. For both trial days, participants also completed 24h food and fluid records via a food diary that included photographs. Paired-sample t tests were used to assess differences in hydration and dietary outcome variables (Recovery vs. No Recovery). No difference in preexercise USG or BM change from exercise were observed between treatments (p's > .05). Attending the recovery zone resulted in a greater total daily fluid (Recovery = 3.37 +/- 1.46L, No Recovery = 3.16 +/- 1.32L, p = .009) and fruit intake (Recovery = 2.37 +/- 1.76 servings, No Recovery = 1.55 +/- 1.61 servings, p > .001), but had no influence on daily total energy (Recovery = 10.15 +/- 4.2MJ, No Recovery = 10.15 +/- 3.9MJ), or macronutrient intakes (p > .05). Next morning USG values were not different between treatments (Recovery = 1.018 +/- 0.007, No Recovery = 1.019 +/- 0.009, p > .05). Recovery stations provide an opportunity to modify dietary intake which promote positive lifestyle behaviors in recreational athletes. PMID- 29140133 TI - ITE inhibits growth of human pulmonary artery endothelial cells. AB - AIM: Pulmonary arterial hypertension (PAH), a deadly disorder is associated with excessive growth of human pulmonary artery endothelial (HPAECs) and smooth muscle (HPASMCs) cells. Current therapies primarily aim at promoting vasodilation, which only ameliorates clinical symptoms without a cure. 2-(1'H-indole-3'-carbonyl) thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous aryl hydrocarbon receptor (AhR) ligand, and mediates many cellular function including cell growth. However, the roles of ITE in human lung endothelial cells remain elusive. Herein, we tested a hypothesis that ITE inhibits growth of human pulmonary artery endothelial cells via AhR. MATERIALS AND METHODS: Immunohistochemistry was performed to localize AhR expression in human lung tissues. The crystal violet method and MTT assay were used to determine ITE's effects on growth of HPAECs. The AhR activation in HPAECs was confirmed using Western blotting and RT-qPCR. The role of AhR in ITE-affected proliferation of HPAECs was assessed using siRNA knockdown method followed by the crystal violet method. RESULTS: Immunohistochemistry revealed that AhR was present in human lung tissues, primarily in endothelial and smooth muscle cells of pulmonary veins and arteries, as well as in bronchial and alveolar sac epithelia. We also found that ITE dose- and time-dependently inhibited proliferation of HPAECs with a maximum inhibition of 83% at 20 uM after 6 days of treatment. ITE rapidly decreased AhR protein levels, while it increased mRNA levels of cytochrome P450 (CYP), family 1, member A1 (CYP1A1) and B1 (CYP1B1), indicating activation of the AhR/CYP1A1 and AhR/CYP1B1 pathways in HPAECs. The AhR siRNA significantly suppressed AhR protein expression, whereas it did not significantly alter ITE-inhibited growth of HPAECs. CONCLUSIONS: ITE suppresses growth of HPAECs independent of AhR, suggesting that ITE may play an important role in preventing excessive growth of lung endothelial cells. PMID- 29140135 TI - Pseudoprogression on bevacizumab treatment: tumor-dynamics in the modern era of systemic treatment for metastatic colorectal cancer. PMID- 29140136 TI - Salt + Glycerol-Induced Hyperhydration Enhances Fluid Retention More Than Salt- or Glycerol-Induced Hyperhydration. AB - Hyperhydration has been demonstrated to improve work capacity and cardiovascular and thermoregulatory functions, enhance orthostatic tolerance, slow or neutralize bone demineralization, and decrease postdive bubble formation. Adding sodium or glycerol to a hyperhydration solution optimizes fluid retention. Sodium and glycerol produce their effect through different physiological mechanisms. If combined into a hyperhydration solution, their impact on fluid retention could potentially be greater than their singular effect. We compared the effect of salt induced hyperhydration (SIH), glycerol-induced hyperhydration (GIH), and salt + glycerol-induced hyperhydration (SGIH) on fluid balance responses during a 3-hr passive experiment. Using a randomized, crossover, and counterbalanced experiment, 15 young men (22 +/- 4 years) underwent three, 3-hr hyperhydration experiments during which they ingested 30 ml/kg fat-free mass (FFM) of water with an artificial sweetener plus either (a) 7.5 g of table salt/L (SIH), (b) 1.4 g glycerol/kg FFM (GIH), or (c) 7.5 g of table salt/L + 1.4 g glycerol/kg FFM (SGIH). After 3 hr, there were no significant differences in plasma volume changes among experiments (SIH: 11.3% +/- 9.9%; GIH: 7.6% +/- 12.7%; SGIH: 11.3% +/- 13.7%). Total urine production was significantly lower (SIH: 775 +/- 329 ml; GIH: 1,248 +/- 270 ml; SGIH: 551 +/- 208 ml) and fluid retention higher (SIH: 1,127 +/- 212 ml; GIH: 729 +/- 115 ml; SGIH: 1,435 +/- 140 ml) with SGIH than either GIH or SIH. Abdominal discomfort was low and not significantly different among experiments. In conclusion, results show that SGIH reduces urine production and provides more fluid retention than either SIH or GIH. PMID- 29140137 TI - Oxygen Uptake and Muscle Deoxygenation Kinetics During Skating: Comparison Between Slide-Board and Treadmill Skating. AB - PURPOSE: To compare the oxygen-uptake ([Formula: see text]) kinetics during skating on a treadmill and skating on a slide board and to discuss potential mechanisms that might control the [Formula: see text] kinetics responses during skating. METHODS: Breath-by-breath pulmonary [Formula: see text] and near infrared spectroscopy-derived muscle deoxygenated hemoglobin and myoglobin ([HHbMb]) were monitored continuously in 12 well-trained, young, long-track speed skaters. On-transient [Formula: see text] and [HHbMb] responses to skating on a treadmill and skating on a slide board at 80% of the estimated gas exchange threshold were fitted as monoexponential function. The signals were time-aligned, and the individual [HHbMb]-to-[Formula: see text] ratio was calculated as the average value from 20 to 120 s after exercise starts. RESULTS: The time constants for the adjustment of phase II [Formula: see text] (tau [Formula: see text]) and [HHbMb] (tau [HHbMb]) were low and similar between slide board and treadmill skating (18.1 [3.4] vs 18.9 [3.6] for tau [Formula: see text] and 12.6 [4.0] vs 12.4 [4.0] s for tau [HHbMb]). The [Formula: see text] ratio was not different from 1.0 (P > .05) in both conditions. CONCLUSIONS: The fast [Formula: see text] kinetics during skating suggest that chronic adaptation to skating might overcome any possible restriction in leg blood flow during low-intensity exercise. The [Formula: see text] ratio values also suggest a good matching of O2 delivery to O2 utilization in trained speed skaters. The similar tau [Formula: see text] and tau [HHbMb] values between slide board and treadmill further reinforce the validity of using a slide board for skating testing and training purposes. PMID- 29140138 TI - COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer. AB - AIM: Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyze COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition. METHODS: In a multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells. For each compartment, COX-2 expression was graded as high or low, based on a product score of extension and intensity of positively stained cells. RESULTS: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95% CI 0.81-1.27 and HR 1.12; 95% CI 0.78-1.61, respectively). High COX-2 scores in tumor (n = 71) or stromal cells (n = 55) was not associated with a superior survival outcome with celecoxib vs. placebo (HR =0.96, 95% CI 0.60-1.54; and HR =1.51; 95% CI 0.86-2.66), and no significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p = .48 and .25, respectively). CONCLUSIONS: In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy. PMID- 29140139 TI - Health-related quality of life in different states of breast cancer - comparing different instruments. AB - BACKGROUND: The prognosis of breast cancer has improved significantly during the last few decades increasing the interest in health-related quality of life (HRQoL). The aim of this study was to compare the HRQoL scores produced by different instruments and to shed light on their validity in various states of breast cancer by studying the association of cancer-related symptoms with HRQoL. MATERIAL AND METHODS: An observational, cross-sectional study of breast cancer patients treated in the Helsinki and Uusimaa Hospital District from September 2009 to April 2011. A total of 840 patients completed three HRQoL questionnaires: the EQ-5D-3L (including VAS), 15D and EORTC QLQ-30 and a questionnaire concerning sociodemographic factors. Patients were divided into five mutually exclusive groups: primary treatment (n = 118), recovery (6-18 months from diagnosis) (n = 150), remission (>18 months) (n = 382), metastatic disease (n = 176) and palliative care (n = 14). The association of HRQoL with sociodemographic and clinical factors and cancer-related symptoms, screened by the EORTC QLQ-30, was studied by multivariate modeling using stepwise linear regression analysis. RESULTS: HRQoL scores were the best at the time closest to diagnosis and deteriorated with disease progression. The EQ-5D had a pronounced ceiling effect with 40.8% of the respondents scoring 1 (perfect health) compared to 6% for the 15D and 5.6% for VAS. In regression analyses, pain, fatigue and financial difficulties were the most important predictors of lower HRQoL. The 15D showed better discriminatory power and content validity. The EORTC QLQ-C30 functioning deteriorated in advanced states of the disease with physical, social and role functioning being the most affected. Insomnia, fatigue and pain were the most commonly reported symptoms in all groups. CONCLUSIONS: Different HRQoL instruments produce notably different HRQoL scores. The EQ-5D has a pronounced ceiling effect. Pain and fatigue are the most common symptoms associated with poor HRQoL in all disease states. PMID- 29140140 TI - The Physiological Mechanisms of Effect of Vitamins and Amino Acids on Tendon and Muscle Healing: A Systematic Review. AB - AIMS/OBJECTIVES: To evaluate the current literature via systematic review to ascertain whether amino acids/vitamins provide any influence on musculotendinous healing and if so, by which physiological mechanisms. METHODS: EBSCO, PubMed, ScienceDirect, Embase Classic/Embase, and MEDLINE were searched using terms including "vitamins," "amino acids," "healing," "muscle," and "tendon." The primary search had 479 citations, of which 466 were excluded predominantly due to nonrandomized design. Randomized human and animal studies investigating all supplement types/forms of administration were included. Critical appraisal of internal validity was assessed using the Cochrane risk of Bias Tool or the Systematic Review Centre for Laboratory Animal Experimentation Risk of Bias Tool for human and animal studies, respectively. Two reviewers performed duel data extraction. RESULTS: Twelve studies met criteria for inclusion: eight examined tendon healing and four examined muscle healing. All studies used animal models, except two human trials using a combined integrator. Narrative synthesis was performed via content analysis of demonstrated statistically significant effects and thematic analysis of proposed physiological mechanisms of intervention. Vitamin C/taurine demonstrated indirect effects on tendon healing through antioxidant activity. Vitamin A/glycine showed direct effects on extracellular matrix tissue synthesis. Vitamin E shows an antiproliferative influence on collagen deposition. Leucine directly influences signaling pathways to promote muscle protein synthesis. DISCUSSION: Preliminary evidence exists, demonstrating that vitamins and amino acids may facilitate multilevel changes in musculotendinous healing; however, recommendations on clinical utility should be made with caution. All animal studies and one human study showed high risk of bias with moderate interobserver agreement (k = 0.46). Currently, there is limited evidence to support the use of vitamins and amino acids for musculotendinous injury. Both high-quality animal experimentation of the proposed mechanisms confirming the physiological influence of supplementation and human studies evaluating effects on tissue morphology and biochemistry are required before practical application. PMID- 29140141 TI - Short clinical examination for temporomandibular symptoms in general practice. AB - OBJECTIVE: The aims of the study are to assess the reliability of the short clinical examination, and to compare the information gained with a well-known and validated examination, the diagnostic criteria for temporomandibular disorders (DC/TMD). MATERIALS AND METHODS: The study comprises 52 consecutive, newly referred patients at their first visit and examination to an Orofacial Pain and TMD Clinic, 15 years and older, mean age 44 years. The patients first answered three screening questions for reported symptoms. The clinical examination was performed using both the short examination and the DC/TMD and the result was compared. Another group of 40 newly referred patients, with similar inclusion criteria, was examined twice according to the short clinical examination by two examiners, and the inter-examiner variation was studied. The protocol of the short clinical examination is described. RESULT: The overall agreement between the two methods was fairly good to excellent, as was the degree of agreement between repeated examinations and two examiners using the short clinical examination method. The sensitivity and specificity of the short examination for diagnoses were acceptable to high (with DC/TMD as the golden standard). CONCLUSIONS: The short clinical examination has acceptable reliability and, together with three screening questions, provides enough information about the jaw function to decide whether there is a dysfunction. PMID- 29140142 TI - Coffee Ingestion Enhances 1-Mile Running Race Performance. AB - CONTEXT: Caffeine, often in the form of coffee, is frequently used as a supplement by athletes in an attempt to facilitate improved performance during exercise. PURPOSE: To investigate the effectiveness of coffee ingestion as an ergogenic aid prior to a 1-mile (1609 m) race. METHODS: In a double-blind, randomized, cross-over, and placebo-controlled design, 13 trained male runners completed a 1-mile race 60 minutes following the ingestion of 0.09 g.kg-1 coffee (COF), 0.09 g.kg-1 decaffeinated coffee (DEC), or a placebo (PLA). All trials were dissolved in 300 mL of hot water. RESULTS: The race completion time was 1.3% faster following the ingestion of COF (04:35.37 [00:10.51] min:s.ms) compared with DEC (04:39.14 [00:11.21] min:s.ms; P = .018; 95% confidence interval [CI], 0.11 to -0.01; d = 0.32) and 1.9% faster compared with PLA (04:41.00 [00:09.57] min:s.ms; P = .006; 95% CI, -0.15 to -0.03; d = 0.51). A large trial and time interaction for salivary caffeine concentration was observed (P < .001; [Formula: see text]), with a very large increase (6.40 [1.57] MUg.mL-1; 95% CI, 5.5-7.3; d = 3.86) following the ingestion of COF. However, only a trivial difference between DEC and PLA was observed (P = .602; 95% CI, -0.09 to 0.03; d = 0.17). Furthermore, only trivial differences were observed for blood glucose (P = .839; [Formula: see text]) and lactate (P = .096; [Formula: see text]) and maximal heart rate (P = .286; [Formula: see text]) between trials. CONCLUSIONS: The results of this study show that 60 minutes after ingesting 0.09 g.kg-1 of caffeinated coffee, 1-mile race performance was enhanced by 1.9% and 1.3% compared with placebo and decaffeinated coffee, respectively, in trained male runners. PMID- 29140143 TI - Sweat Sodium, Potassium, and Chloride Concentrations Analyzed Same Day as Collection Versus After 7 Days Storage in a Range of Temperatures. AB - The purpose of this study was to determine the effect of storage temperature on sodium ([Na+]), potassium ([K+]), and chloride ([Cl-]) concentrations of sweat samples analyzed 7 days after collection. Using the absorbent patch technique, 845 sweat samples were collected from 39 subjects (32 +/- 7 years, 72.9 +/- 10.5 kg) during exercise. On the same day as collection (PRESTORAGE), 609 samples were analyzed for [Na+], [Cl-], and [K+] by ion chromatography (IC) and 236 samples were analyzed for [Na+] using a compact ion-selective electrode (ISE). Samples were stored at one of the four conditions: -20 degrees C (IC, n = 138; ISE, n = 60), 8 degrees C (IC, n = 144; ISE, n = 59), 23 degrees C (IC, n = 159; ISE, n = 59), or alternating between 8 degrees C and 23 degrees C (IC, n = 168; ISE, n = 58). After 7 days in storage (POSTSTORAGE), samples were reanalyzed using the same technique as PRESTORAGE. PRESTORAGE sweat electrolyte concentrations were highly related to that of POSTSTORAGE (intraclass correlation coefficient: .945 .989, p < .001). Mean differences (95% confidence intervals) between PRESTORAGE and POSTSTORAGE were statistically, but not practically, significant for most comparisons: IC [Na+]: -0.5(0.9) to -2.1(0.9) mmol/L; IC [K+]: -0.1(0.1) to 0.2(0.1) mmol/L; IC [Cl-]: -0.4(1.4) to -1.3(1.3) mmol/L; ISE [Na+]: -2.0(1.1) to 1.3(1.1) mmol/L. Based on typical error of measurement results, 95% of the time PRESTORAGE and POSTSTORAGE sweat [Na+], [K+], and [Cl-] by IC analysis fell within +/-7-9, +/-0.6-0.7, and +/-9-13 mmol/L, respectively, while sweat [Na+] by ISE was +/-6 mmol/L. All conditions produced high reliability and acceptable levels of agreement in electrolyte concentrations of sweat samples analyzed on the day of collection versus after 7 days in storage. PMID- 29140144 TI - Joint Moment-Angle Properties of the Hip Extensors in Subjects With and Without Patellofemoral Pain. AB - Strength deficits of hip extension in individuals with patellofemoral syndrome are commonly reported in literature. No literature to date has examined these deficits with variable positions of the knee and hip; altering knee angle alters the length and therefore potentially the force produced by the biarticular muscles. Beyond strength, neuromuscular control can also be assessed through the analysis of isometric joint moment steadiness. Subjects consisted of a group of individuals with patellofemoral syndrome (n = 9), and a group of age- and size matched controls with no symptoms (n = 9). Maximum isometric joint moments for hip extension were measured at 4 points within the joint's range of motion, at 2 different knee positions (0 degrees and 90 degrees ) for each group. The joint moment signals were analyzed by computing signal Coefficient of Variation (CV). The results indicate that no significant differences were found between the groups of subjects for the hip extension moments when the knee was extended. However, there was a significant difference between the groups for the joint moments of hip extension with the knee flexed at all 4 hip positions. Results also showed hip extension CV values to be significantly higher in the patellofemoral group compared with the control group, indicating greater signal noise and therefore poorer neuromuscular control of the hip extensor musculature. This study demonstrated that individuals with patellofemoral syndrome have reduced hip extension strength and reduced neuromuscular control with the knee flexed compared with a control group. These results have implications for the etiology of patellofemoral syndrome and its rehabilitation. PMID- 29140145 TI - Monitoring Rugby Players for Fitness and Fatigue: What Do Coaches Want? AB - PURPOSE: The advantages of monitoring players in a team are well documented. However, barriers associated with lack of resources and time prevent teams from implementing systematic monitoring programs. This study aimed to identify (1) the methods rugby teams use to monitor the training load and associated response to the training load and (2) prerequisites of a monitoring protocol that are scientifically suitable and practically applicable for monitoring fitness and fatigue of rugby players. METHODS: Coaches and support staff working with varying levels of rugby union were invited to complete an online questionnaire. RESULTS: Of the 55 respondents, 96% indicated that although they regarded monitoring the training load and training-load response as important, there is no monitoring protocol that is cost-effective, time efficient, and nonaversive to the players. Respondents measured several variables when monitoring and incorporated more subjective than objective measures. Respondents (41%) indicated that they would like a protocol that is time efficient (5-10 min) and provides immediate feedback on players who identify as fatigued (50%). For coaches to have confidence in the information provided by the protocol, it needs to meet basic clinimetric principles of reliability and validity. The technical and biological error in the measurement needs to be known so that meaningful changes in fatigue and fitness can be distinguished from natural variations in the measurements. CONCLUSIONS: Prerequisites of an ideal monitoring protocol for rugby players were identified. It follows that a monitoring protocol that fulfills these prerequisites should satisfy both scientific principles and the coach's demands. PMID- 29140146 TI - Awareness and Attitude Toward Use of Dietary Supplements and the Perceived Outcomes Among Saudi Adult Male Members of Fitness Centers in Saudi Arabia. AB - Dietary supplements are believed to enhance athletic performance and/or prevent/reverse pathological states. Despite the increasing use of dietary supplements in Saudi Arabia, systematic studies in this field are lacking. This study aims to assess the relation between demographic and social characteristics and dietary supplement use among adult males in Saudi Arabia. Demographic and dietary supplements data from fitness club participants were collected through a questionnaire, and the Pearson chi-square test was used to determine associations. A total of 448 apparently healthy adult males above 20 years of age, who were registered at fitness centers located in Saudi Arabia, participated in the study. The majority (275 [62%]) of the study participants were younger (20 30 years), of normal weight (189 [43%]), without health problems (332 [79%]), and obtained an undergraduate degree or higher (336 [77%]). The majority (58%) took supplements under the supervision of a professional and the rest depended on Internet (22%), friends (12%), or books (4%) for choosing supplement types. The main motives of the participants for visiting the fitness center were: weight loss (N = 149 [35%]), keeping fit (N = 101 [24%]), and muscle building (N = 151 [35%]). One hundred and fifty-five participants (44%) were taking supplements on a daily basis with 34 (10%) having taken it for a prolonged duration (>1 year). The most commonly used supplements were proteins (29%) and multivitamins (21%). Supplement use was not associated with the participants' family income or level of education but was positively associated with younger age (<31 years), chi2(2, N = 443) = 4.96, p = .03. PMID- 29140147 TI - Sprint Running Performance and Technique Changes in Athletes During Periodized Training: An Elite Training Group Case Study. AB - PURPOSE: To understand how training periodization influences sprint performance and key step characteristics over an extended training period in an elite sprint training group. METHODS: Four sprinters were studied during 5 mo of training. Step velocities, step lengths, and step frequencies were measured from video of the maximum velocity phase of training sprints. Bootstrapped mean values were calculated for each athlete for each session, and 139 within-athlete, between sessions comparisons were made with a repeated-measures analysis of variance. RESULTS: As training progressed, a link in the changes in velocity and step frequency was maintained. There were 71 between-sessions comparisons with a change in step velocity yielding at least a large effect size (>1.2), of which 73% had a correspondingly large change in step frequency in the same direction. Within-athlete mean session step length remained relatively constant throughout. Reductions in step velocity and frequency occurred during training phases of high volume lifting and running, with subsequent increases in step velocity and frequency happening during phases of low-volume lifting and high-intensity sprint work. CONCLUSIONS: The importance of step frequency over step length to the changes in performance within a training year was clearly evident for the sprinters studied. Understanding the magnitudes and timings of these changes in relation to the training program is important for coaches and athletes. The underpinning neuromuscular mechanisms require further investigation but are likely explained by an increase in force-producing capability followed by an increase in the ability to produce that force rapidly. PMID- 29140148 TI - The Reliability of Individualized Load-Velocity Profiles. AB - PURPOSE: To examine the reliability of peak velocity (PV), mean propulsive velocity (MPV), and mean velocity (MV) in the development of load-velocity profiles (LVP) in the full-depth free-weight back squat performed with maximal concentric effort. METHODS: Eighteen resistance-trained men performed a baseline 1-repetition maximum (1-RM) back-squat trial and 3 subsequent 1-RM trials used for reliability analyses, with 48-h intervals between trials. 1-RM trials comprised lifts from 6 relative loads including 20%, 40%, 60%, 80%, 90%, and 100% 1-RM. Individualized LVPs for PV, MPV, or MV were derived from loads that were highly reliable based on the following criteria: intraclass correlation coefficient (ICC) >.70, coefficient of variation (CV) <=10%, and Cohen d effect size (ES) <0.60. RESULTS: PV was highly reliable at all 6 loads. MPV and MV were highly reliable at 20%, 40%, 60%, 80%, and 90% but not 100% 1-RM (MPV: ICC = .66, CV = 18.0%, ES = 0.10, SEM = 0.04 m.s-1; MV: ICC = .55, CV = 19.4%, ES = 0.08, SEM = 0.04 m.s-1). When considering the reliable ranges, almost perfect correlations were observed for LVPs derived from PV20-100% (r = .91-.93), MPV20 90% (r = .92-.94), and MV20-90% (r = .94-.95). Furthermore, the LVPs were not significantly different (P > .05) between trials or movement velocities or between linear regression versus 2nd-order polynomial fits. CONCLUSIONS: PV20 100%, MPV20-90%, and MV20-90% are reliable and can be utilized to develop LVPs using linear regression. Conceptually, LVPs can be used to monitor changes in movement velocity and employed as a method for adjusting sessional training loads according to daily readiness. PMID- 29140149 TI - Correction to: Irani et al., Unilateral pleural effusion as the sole clinical presentation of severe ovarian hyperstimulation syndrome: a systematic review. PMID- 29140150 TI - Radiotherapy for cervical cancer - impact on the vaginal epithelium and sexual function. AB - BACKGROUND: Women who have been treated for cervical cancer have persistent changes in their sexual function, which result in considerable distress. The aim of this study was to investigate the morphology of the vaginal epithelium in cervical cancer survivors treated with radiotherapy and its correlation to serum levels of sex steroid hormones and sexual function. MATERIAL AND METHODS: We included 34 patients treated for cervical cancer with radiotherapy and 37 healthy age-matched control women scheduled for benign gynecological surgery. After inspection and grading of vaginal atrophy, vaginal biopsies were taken. Epithelial structures were analyzed by measuring epithelial thickness as well as the number, height and width of the dermal papillae and the dermal papillae distance. Sex steroid hormone levels were analyzed and a questionnaire designed to assess sexual function was filled out. RESULTS: In the cervical cancer survivors treated with radiotherapy, the vaginal epithelium volume was reduced compared to control women. Longer distance between the dermal papillae (p < .001) and a shorter distance from basal layer to epithelial surface (p < .05) were measured. Mucosal atrophy was observed in 91% of the survivors. There was no difference in serum estradiol between cancer survivors and control women, implying that the cancer survivors were sufficiently substituted. The epithelial thickness correlated to serum levels of estradiol. The cervical cancer survivors reported more physical sexual symptoms. The highest relative risk (RR) was found for insufficient vaginal lubrication (RR 12.6), vaginal inelasticity (RR 6.5), reduced genital swelling when sexually aroused (RR 5.9), and for reduction of vaginal length during intercourse (RR 3.9). CONCLUSION: We found that cervical cancer treatment including radiotherapy is associated with vaginal epithelial atrophy and sexual dysfunction. To hamper the atrophic process affecting the sexual function, an early start of local estrogen after therapy might be of importance. PMID- 29140151 TI - A Comparison of the Nutrient Intakes of Macronutrient-Based Dieting and Strict Dieting Bodybuilders. AB - The purpose of this study was to provide a descriptive assessment of the nutritional habits of competitive bodybuilders and compare the nutrient intakes of macronutrient-based dieting and strict dieting individuals. Data from 41 subjects (30 males and 11 females) were used in analyses. Participants completed a comprehensive food frequency questionnaire, and diets were analyzed using a computer system. Males consumed an average of 2,577.2 kcal (SD = 955.1), with an average fat intake of 83.6 g (SD = 41.3), an average carbohydrate intake of 323.3 g (SD = 105.2), and an average protein intake of 163.4 g (SD = 70.4). There were no significant differences between male macronutrient-based dieting and strict dieting bodybuilders when mean intakes were compared for all nutrients, including the macronutrients, selected vitamins and minerals, dietary fiber, added sugars, and saturated fat. Females in this study consumed an average of 1,794 kcal (SD = 453.1), with an average fat intake of 58.3 g (SD = 23.1), a mean carbohydrate intake of 217.8 g (SD = 85.9), and an average protein intake of 103.8 g (SD = 35.7). For females, macronutrient-based dieters consumed significantly greater amounts of several nutrients, including protein, vitamin E, vitamin K, and vitamin C. Over half of individuals from all groups consumed less than the recommended amounts of several of the micronutrients. Based on this information, it is recommended that competitive bodybuilders should be advised to take their micronutrition into greater consideration. PMID- 29140152 TI - Trend Analysis of 20 Years of FIM Road Racing Grand Prix Motorcycle World Championship. AB - PURPOSE: The technological advancements in motorcycle road racing have ensured the evolution of motorcycle performance; however, it is unknown whether these advancements have resulted in increased speed and therefore risk. To better understand the top level of this sport and inform future regulations, performance related strategies, and safety procedures, this study aimed to (1) analyze and describe how the performance characteristics of the top class of the Federation Internationale de Motocyclisme Grand Prix motorcycle world championship (GPWC) have changed with time and (2) quantify potential interactions between performance data (ie, crashes, speed, and environmental conditions). METHODS: Variables such as top 10 riders' speed of racing, crashes, starting position of winner, participants, and environmental conditions were collected from official race reports from 1997 to 2016. Data standardization was also ensured by including only dry competitions in the analysis. RESULTS: The mean racing speed ranged from a minimum of 155 (7.27) km.h-1 (year 2000) to a maximum of 165 (6.48) km.h-1 (year 2015). Linear mixed-model analysis revealed that the variables year and class significantly influenced changes in mean speed (faster racing). Per race, 12-14% of starters (95% confidence interval) suffered a crash. No significant associations were found between crashes and mean speed, ground temperature, air temperature, or air humidity. CONCLUSIONS: The speed of dry racing of the top class of the GPWC has increased over a 20-y span. Motorcycle circuit racing riders should consider the importance of being prepared to cope with crashing events to minimize chances of injury. PMID- 29140153 TI - Conflating Time and Energy: Views From Older Adults in Lower Socioeconomic Status Areas on Physical Activity. AB - Perceptions of time and energy and their role in physical activity engagement were examined in older adults living in lower socioeconomic status areas. Semistructured interviews were conducted with 19 participants aged 67-94 years. A thematic framework analysis identified four themes: Time is Energy (older adults conflate time and energy in relation to physical activity), Reduced Day (engaging in activities outside a certain time frame is deemed unacceptable), Being Given Enough Time (need for time to socialize and go at own pace), and Seasonal Impact (seasonal differences affecting access). Enjoyment appears to mitigate the perceived energy drain and increase the capacity for physical activities for many. Conflation of time and energy may explain observed discrepancies between older adults' actual and perceived available time. Having locally based physical activities means less time/energy is required to attend, leaving more resources for physical activity itself. A limited availability of resources in lower socioeconomic status areas is therefore problematic. PMID- 29140154 TI - No Difference in Young Adult Athletes' Resting Energy Expenditure When Measured Under Inpatient or Outpatient Conditions. AB - Low energy availability can place athletes at increased risk of injury and illness and can be detected by a lower metabolic rate. The lowest metabolic rate is captured at the bedside, after an overnight fast and termed inpatient resting energy expenditure (REE). Measurements done in a laboratory with a shorter overnight fast are termed outpatient REE. Although important to know what the lowest energy expenditure, a bedside measure and/or 12-hr fast is not always practical or logistically possible particularly when you take into account an athlete's training schedule. The aim of this investigation was to compare a bedside measure of resting metabolism with a laboratory measure in athletes following an 8-hr fast. Thirty-two athletes (24 females and eight males) underwent measures of resting metabolism using indirect calorimetry once at their bedside (inpatient) and once in a simulated laboratory setting (outpatient). Paired t test was used to compare the mean +/- SD differences between the two protocols. Inpatient REE was 7,302 +/- 1,272 kJ/day and outpatient REE was 7,216 +/- 1,116 kJ/day (p = .448). Thirteen participants repeated the outpatient protocol and 17 repeated the inpatient protocol to assess the day-to-day variation. Reliability was assessed using the intraclass correlation coefficient and typical error. The inpatient-protocol variability was 96% with a typical error of 336.2 kJ/day. For the outpatient protocol, the intraclass correlation coefficient and typical error were 87% and 477.6 kJ/day, respectively. Results indicate no difference in REE when measured under inpatient and outpatient conditions; however, the inpatient protocol has greater reliability. PMID- 29140155 TI - Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx(r)): a placebo-controlled randomised phase II study (PLIANT). AB - PURPOSE: Oxaliplatin causes disabling acute and chronic peripheral neuropathy. We explored the preventive effects of calmangafodipir, mimicking the mitochondrial enzyme manganese superoxide dismutase, thereby protecting cells from oxidative stress, in a placebo-controlled, double-blinded randomised phase II study (ClinicalTrials.gov.NCT01619423) in patients with metastatic colorectal cancer (mCRC). PATIENT AND METHODS: mCRC patients treated with modified FOLFOX-6 (folinic acid 200 mg/m2, 5-fluorouracil bolus 400 mg/m2, oxaliplatin 85 mg/m2 and 5-fluorouracil 2400 mg/m2 continuous infusion for 46 h) every fortnight for 8 cycles in first or second line were eligible. Calmangafodipir was given in a phase I dose-finding and in a phase II placebo-controlled study, as a 5-min infusion 10 min prior to oxaliplatin. Neurotoxicity was evaluated by the physician using the Oxaliplatin Sanofi Specific Scale and by the patient using the cold allodynia test and the Leonard scale. RESULTS: Eleven patients were included in phase I without any detectable toxicity to calmangafodipir. In the phase II study, 173 patients were randomised to placebo (n = 60), calmangafodipir 2 umol/kg (n = 57) and calmangafodipir 5 umol/kg (n = 45, initially 10 umol/kg, n = 11). Calmangafodipir-treated patients (all three doses pooled) had less physician graded neurotoxicity (odds ratio (90% confidence interval one-sided upper level) 0.62(1.15), p = .16), significantly less problems with cold allodynia (mean 1.6 versus 2.3, p < .05) and significantly fewer sensory symptoms in the Leonard scale (cycle 1-8 mean 1.9 versus 3.0, p < .05 and during follow-up after 3 and 6 months, mean 3.5 versus 7.3, p < .01). Response rate, progression free and overall survival did not differ among groups. CONCLUSIONS: Calmangafodipir at a dose of 5 umol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes. PMID- 29140157 TI - Case Study: Body Composition Periodization in an Olympic-Level Female Middle Distance Runner Over a 9-Year Career. AB - This case study features an Olympic-level female middle-distance runner implementing a science-based approach to body composition periodization. Data are emerging to suggest that it is not sustainable from a health and/or performance perspective to be at peak body composition year-round, so body composition needs to be strategically periodized. Anthropometric (n = 44), hematological, other health measures, and 1,500-m race performances (n = 83) were periodically assessed throughout a 9-year career. General preparation phase (September to April) featured the athlete at ~2-4% over ideal competition phase body weight (BW) and body fat (%), with optimal energy availability being prioritized. The competition body composition optimization phase (May to August) included creating an individualized time frame and caloric deficit with various feedback metrics (BW, performance, and hunger) to guide the process. There were significant seasonal fluctuations in anthropometric outcomes between phases (47.3 +/- 0.8 vs. 48.3 +/- 0.9 kg BW; 53.6 +/- 7.8 vs. 61.6 +/- 9.7 mm International Society for the Advancement of Kinanthropometry sum of 8 [So8] skinfolds; p < .01), and a significant correlation of decreasing So8 during the peak competition period over her career (r = -.838; p = .018). The range of body composition during the competition period was 46.0-48.0 kg BW and a So8 range was 42.0-55.9 mm. There were also significant positive correlations between slower 1,500-m race times and increasing So8 (r = .437; p < .01), estimated fat mass (r = .445; p < .01), and BW (r = .511; p < .0001). The athlete only had two career injuries. This case study demonstrates a body composition periodization approach that allowed for targeted peak yearly performances, which improved throughout her career, while maximizing training adaptation and long-term athlete health through optimal energy availability. PMID- 29140156 TI - Conditioned medium from human gingival mesenchymal stem cells protects motor neuron-like NSC-34 cells against scratch-injury-induced cell death. AB - Neuronal cell death is a normal process during central nervous system (CNS) development and is also involved in the death of motor neurons in diverse spinal motor neuron degenerative diseases. Here, we investigated the neuroprotective effect of secretory factors released from human gingival mesenchymal stem cells (hGMSCs) in mechanically injured murine motor-neuron-like NSC-34 cells. The cells were exposed to scratch injury and the markers for apoptosis and oxidative stress were examined. Immunocytochemistry results showed that proapoptotic markers cleaved caspase-3 and Bax were elevated while anti-apoptotic protein Bcl-2 was suppressed in scratch-injured NSC-34 cells. Oxidative stress markers SOD-1, inducible nitric oxide synthase (iNOS), Cox-2, and proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) were activated. Conditioned medium (CM) derived from hGMSCs (hGMSC-CM) significantly blocked the cell death by suppressing SOD-1, iNOS, TNF-alpha, cleaved caspase-3, and Bax. Bcl-2 and anti-inflammatory cytokine anti-interleukin 10 (IL-10) were increased in hGMSC-CM-treated injured cells. Moreover, hGMSC-CM treatment upregulated neurotrophins anti-brain-derived neurotrophic factor (BDNF) and NT3. Western blot data of hGMSC-CM revealed the presence of neurotrophins nerve growth factor (NGF), NT3, anti-inflammatory cytokines IL-10, and transforming growth factor beta (TGF-beta), suggesting their positive role to elicit neuroprotection. Our results propose that hGMSC-CM may serve as a simple and potential autologous therapeutic tool to treat motor neuron injury. PMID- 29140158 TI - Endosomal trafficking regulates receptor-mediated transcytosis of antibodies across the blood brain barrier. AB - Current methods for examining antibody trafficking are either non-quantitative such as immunocytochemistry or require antibody labeling with tracers. We have developed a multiplexed quantitative method for antibody 'tracking' in endosomal compartments of brain endothelial cells. Rat brain endothelial cells were co incubated with blood-brain barrier (BBB)-crossing FC5, monovalent FC5Fc or bivalent FC5Fc fusion antibodies and control antibodies. Endosomes were separated using sucrose-density gradient ultracentrifugation and analyzed using multiplexed mass spectrometry to simultaneously quantify endosomal markers, receptor-mediated transcytosis (RMT) receptors and the co-incubated antibodies in each fraction. The quantitation showed that markers of early endosomes were enriched in high density fractions (HDF), whereas markers of late endosomes and lysosomes were enriched in low-density fractions (LDF). RMT receptors, including transferrin receptor, showed a profile similar to that of early endosome markers. The in vitro BBB transcytosis rates of antibodies were directly proportional to their partition into early endosome fractions of brain endothelial cells. Addition of the Fc domain resulted in facilitated antibody 'redistribution' from LDF into HDF and additionally into multivesicular bodies (MVB). Sorting of various FC5 antibody formats away from late endosomes and lysosomes and into early endosomes and a subset of MVB results in increased antibody transcytosis at the abluminal side of the BBB. PMID- 29140159 TI - Athletes Rated as Poor Single-Leg Squat Performers Display Measurable Differences in Single-Leg Squat Biomechanics Compared With Good Performers. AB - CONTEXT: It is important to validate single-leg squat visual rating criteria used in clinical practice and research. Foot orthoses may improve single-leg squat performance in those who demonstrate biomechanics associated with increased risk of lower limb injury. OBJECTIVE: Validate visual rating criteria proposed by Crossley et al, by determining whether athletes rated as poor single-leg squat performers display different single-leg squat biomechanics than good performers; and evaluate immediate effects of foot orthoses on single-leg squat biomechanics in poor performers. DESIGN: Comparative cross-sectional study. SETTING: University laboratory. PARTICIPANTS: 79 asymptomatic athletes underwent video classification of single-leg squat performance based on established visual rating criteria (overall impression, trunk posture, pelvis "in space," hip movement, and knee movement), and were rated as good (n = 23), fair (n = 41), or poor (n = 15) performers. INTERVENTION: A subset of good (n = 16) and poor (n = 12) performers underwent biomechanical assessment, completing 5 continuous single-leg squats on their dominant limb while 3-dimensional motion analysis and ground reaction force data were recorded. Poor performers repeated the task standing on prefabricated foot orthoses. MAIN OUTCOME MEASURES: Peak external knee adduction moment (KAM) and peak angles for the trunk, hip, knee, and ankle. RESULTS: Compared with good performers, poor performers had a significantly lower peak KAM (mean difference = 0.11 Nm/kg, 95% confidence interval = 0.02 to 0.2 Nm/kg), higher peak hip adduction angle (-4.3 degrees , -7.6 degrees to -0.9 degrees ), and higher peak trunk axial rotation toward their stance limb (3.8 degrees , 0.4 degrees to 7.2 degrees ). Foot orthoses significantly increased the peak KAM in poor performers (-0.06 Nm/kg, -0.1 to -0.01 Nm/kg), with values approximating those observed in good performers. CONCLUSIONS: Findings validate Crossley et al's visual rating criteria for single-leg squat performance in asymptomatic athletes, and suggest that "off-the-shelf" foot orthoses may be a simple intervention for poor performers to normalize the magnitude of the external KAM during single-leg squat. PMID- 29140160 TI - Clinical Measures and Their Contribution to Dysfunction in Individuals With Patellar Tendinopathy. AB - CONTEXT: Patellar tendinopathy is prevalent in physically active populations and it affects their quality of living, performance of activity, and may contribute to the early cessation of their athletic careers. A number of previous studies have identified contributing factors for patellar tendinopathy however their contributions to self-reported dysfunction remain unclear. OBJECTIVE: The purpose of this investigation was to determine if strength, flexibility, and various lower extremity static alignments contributed to self-reported function and influence the severity of patellar tendinopathy. DESIGN: Cross sectional research design. SETTING: University Laboratory. PARTICIPANTS: 30 participants with patellar tendinopathy volunteered for this study (age: 23.4+/-3.6 years, height: 1.8+/-0.1m, mass: 80.0+/-20.3kg, BMI: 25.7+/-4.3). MAIN OUTCOME MEASURES: Participants completed seven different patient-reported outcomes. Isometric knee extension and flexion strength, hamstring flexibility and alignment measures of rearfoot angle, navicular drop, tibial torsion, q angle, genu recurvatum, pelvic tilt, and leg length differences were assessed. Pearson's correlation coefficients were assessed to determine significantly correlated outcome variables with each of the patient-reported outcomes. The factors with the highest correlations were used to identify factors that contribute the most to pain and dysfunction using backward selection, linear regression models. RESULTS: Correlation analysis found significant relationships between questionnaires and BMI (r=-0.35-0.46), normalized knee extension (r=0.38-0.50) and flexion strength (r=-0.34-0.50), flexibility (r=0.32- -0.38, q angle (r=0.38-0.56) and pelvic tilt (r=-0.40). Regression models (R2= 0.22-0.54) identified thigh musculature strength and supine q angle to have greatest predictability for severity in patient-reported outcomes. CONCLUSIONS: These findings put an emphasis of bodyweight management, improving knee extensor and flexor strength, posterior flexibility in patellar tendinopathy patients. PMID- 29140161 TI - Relationship Between Physical Activity and Clinical Outcomes After ACL Reconstruction. AB - CONTEXT: Reductions in objectively measured moderate to vigorous physical activity (MVPA) have been reported among individuals with anterior cruciate ligament reconstruction (ACLR). Self-reported measures of physical activity are commonly used to assess participation in physical activity after ACLR despite the lack of evidence to support the validity of such measures within this population. OBJECTIVE: The objective of this research was to determine the relationships between objectively measured MVPA, self-reported physical activity, and knee function among individuals with ACLR. SETTING: University laboratory. Patients (or Other Participants): Thirty-one participants with a history of ACLR (sex: 23 females and 8 males; age = 19.8 [1.4] y) and 31 matched controls (sex: 23 females and 8 males; age = 20.6 [1.7] y) enrolled in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURES: Participants completed self-reported physical activity using the Tegner Activity Scale and the Marx Activity Rating Scale. Participant MVPA was objectively measured using an ActiGraph wGT3X-BT accelerometer for a 7 day period during which the monitor was worn for not less than 10 hours per day. Primary outcome measures were the amount of time spent in MVPA (minutes per week) and time spent in MVPA performed in bouts of >=10 minutes (minutes per week). Relationships between the Tegner Activity Score, Marx Activity Rating Scale, and objectively measured MVPA variables were assessed using partial Spearman's rank correlation coefficients after controlling for activity monitor wear time. RESULTS: There were no significant relationships between objectively measured MVPA and self-reported physical activity (rho <= 0.31, P >= .05) or self-reported knee-related function (rho <= .41, P >= .05) among ACLR participants. CONCLUSIONS: Objectively measured physical activity is not significantly related to self-reported physical activity or self-reported knee function among individuals with a history of ACLR. Consideration of objective and self-reported physical activity within this population may provide key insights into disconnects between perception and the reality of physical activity engagement following ACLR. PMID- 29140162 TI - Eight-Week Return to Play Following Latarjet Shoulder Reconstruction in an Australian Football Player: A Case Report. AB - INTRODUCTION: Anterior shoulder dislocation is a common injury in many sports, resulting in extended time lost from play with an extremely high recurrence rate in young athletes playing a high-risk sport. Latarjet shoulder reconstruction is a common surgical procedure used to prevent subsequent dislocation with an expected rehabilitation time frame of between 4 and 6 months before return to play. CASE DESCRIPTION: A 21-year-old male Australian football player experienced 2 left-sided shoulder dislocations before undergoing a left Latarjet shoulder reconstruction. He was assessed clinically and with magnetic resonance imaging, which revealed significant tearing of the anterior labrum. The authors theorized that maximal glenohumeral stability occurs after bony healing of the coracoid onto the glenoid at 6 weeks. The patient then underwent an 8-week structured and graduated rehabilitation program aimed at preventing loss of shoulder range of motion, muscle, and functional capacity and returned to play at 8 weeks postinjury with no complications or recurrence at 12-month follow-up. DISCUSSION: This is the first time an 8-week rehabilitation following Latarjet shoulder reconstruction has been reported. In athletes with anterior glenohumeral dislocation who require accelerated return to play, a Latarjet reconstruction with an 8-week rehabilitation protocol may be considered. PMID- 29140163 TI - HSP70s Enhance a Phytophthora infestans Effector-Induced Cell Death via an MAPK Cascade in Nicotiana benthamiana. AB - A destructive pathogen, Phytophthora infestans, secretes hundreds of effectors for successful survival in its host plants. The effectors modulate the plant defense system at diverse cellular compartments to take an advantage of pathogen survivals. A few research studies have shown the mode of action of each effector and their interacting proteins in plant cells. Here, we investigated the mode of action of a P. infestans effector, Pi23226, which induces cell death in Nicotiana benthamiana. To identify its host factors, we performed coimmunoprecipitation and liquid chromatography-mass spectrometry, and selected members of heat shock protein 70 (HSP70s) as candidates. These HSP70s, known to function as chaperones, were associated with Pi23226 in planta and accelerated Pi23226-induced cell death. Additionally, they were found to be involved in plant basal defense by suppressing the growth of P. infestans. We also found that specific components of a mitogen-activated protein kinase cascade were involved in Pi23226-induced cell death. Our findings show that HSP70s functions in defense systems by regulating effector-triggered cell death and by suppressing the growth of the pathogen. This suggests that host plants manipulate the ubiquitous proteins to detect pathogen effectors for functioning in the defense system. PMID- 29140164 TI - Second-order Kinetics of DTPA and Plutonium in Rat Plasma. AB - In 2008, Serandour et al. reported on their in vitro experiment involving rat plasma samples obtained after an intravenous intake of plutonium citrate. Different amounts of DTPA were added to the plasma samples and the percentage of low-molecular-weight plutonium measured. Only when the DTPA dosage was three orders of magnitude greater than the recommended 30 MUmol/kg was 100% of the plutonium apparently in the form of chelate. These data were modeled assuming three competing chemical reactions with other molecules that bind with plutonium. Here, time-dependent second-order kinetics of these reactions are calculated, intended eventually to become part of a complete biokinetic model of DTPA action on actinides in laboratory animals or humans. The probability distribution of the ratio of stability constants for the reactants was calculated using Markov Chain Monte Carlo. These calculations substantiate that the inclusion of more reactions is needed in order to be in agreement with known stability constants. PMID- 29140166 TI - Inactivation of a Single Eucaryotic Gene Irradiated in Vitro in Transcriptionally Active Chromatin Form. AB - The transcriptional activity of endogenous RNA polymerases has been used to study the inactivation of a single eucaryotic gene irradiated in chromatin form in aqueous solution. The gene codes for the ribosomal RNA precursor in Tetrahymena where it exists in multiple copies as free extrachromosomal molecules. The gene chromatin is isolated with intact RNA polymerases on the coding strand. Irradiation with 10-MeV electrons reduces the in vitro RNA synthesis on the isolated chromatin in a dose-dependent manner which allows the amount of DNA damage to be determined. Irradiation of the gene chromatin in dilute solution under various gas atmospheres demonstrates that OH radicals account for most of the inactivation. Under these conditions, $e_{{?rm aq}}^{-}$ is unimportant, while the results suggest that H may contribute to inactivation of gene transcription. PMID- 29140165 TI - Improved Total-Body Irradiation Survival by Delivery of Two Radiation Mitigators that Target Distinct Cell Death Pathways. AB - The acute lethality of total-body irradiation (TBI) involves damage to multiple organs, including bone marrow and intestine. Ionizing radiation mitigators that are effective when delivered 24 h or later after TBI include the anti-apoptotic drug, JP4-039 and the anti-necroptotic drug, necrostatin-1. In contrast to effective delivery of JP4-039 at 24 h after TBI, necrostatin-1 is most effective when delivery is delayed until 48 h, a time that correlates with the elevation of necroptosis-inducing inflammatory cytokines and necroptosis-induced serine phosphorylation of receptor-interacting serine/threonine-protein kinase-3 (RIP3) in tissues. The goal of this work was to determine whether administration of JP4 039 influenced the optimal delivery time for necrostatin-1. We measured daily levels of 33 proteins in plasma compared to intestine and bone marrow of C57BL/6NTac female mice over a 7-day time period after 9.25 Gy TBI (LD50/30). Protein responses to TBI in plasma were different from those measured in intestine or bone marrow. In mice that were given JP4-039 at 24 h after TBI, we delayed necrostatin-1 delivery for 72 h after TBI based on measured delay in RIP 3 kinase elevation in marrow and intestine. Sequential delivery of these two radiation mitigator drugs significantly increased survival compared to single drug administration. PMID- 29140167 TI - Intratester Reliability and Construct Validity of a Hip Abductor Eccentric Strength Test. AB - CONTEXT: Side-lying hip abductor strength tests are commonly used to evaluate muscle strength. In a "break" test, the tester applies sufficient force to lower the limb to the table while the patient resists. The peak force is postulated to occur while the leg is lowering, thus representing the participant's eccentric muscle strength. However, it is unclear whether peak force occurs before or after the leg begins to lower. OBJECTIVES: To determine intrarater reliability and construct validity of a hip abductor eccentric strength test. DESIGN: Intrarater reliability and construct validity study. PARTICIPANTS: Twenty healthy adults (26 [6] y; 1.66 [0.06] m; 62.2 [8.0] kg) made 2 visits to the laboratory at least 1 week apart. MAIN OUTCOME MEASURES: During the hip abductor eccentric strength test, a handheld dynamometer recorded peak force and time to peak force, and limb position was recorded via a motion capture system. Intrarater reliability was determined using intraclass correlation, SEM, and minimal detectable difference. Construct validity was assessed by determining if peak force occurred after the start of the lowering phase using a 1-sample t test. RESULTS: The hip abductor eccentric strength test had substantial intrarater reliability (intraclass correlation(3,3) = .88; 95% confidence interval, .65-.95), SEM of 0.9 %BWh, and a minimal detectable difference of 2.5 %BWh. Construct validity was established as peak force occurred 2.1 (0.6) seconds (range: 0.7-3.7 s) after the start of the lowering phase of the test (P <= .001). CONCLUSION: The hip abductor eccentric strength test is a valid and reliable measure of eccentric muscle strength. This test may be used clinically to assess changes in eccentric muscle strength over time. PMID- 29140168 TI - Revisiting the Roles of Tobamovirus Replicase Complex Proteins in Viral Replication and Silencing Suppression. AB - Tobamoviral replicase possesses an RNA-dependent RNA polymerase (RDR) domain and is translated from genomic (g)RNA via a stop codon readthrough mechanism at a one to-ten ratio relative to a shorter protein lacking the RDR domain. The two proteins share methyltransferase and helicase domains and form a heterodimer implicated in gRNA replication. The shorter protein is also implicated in suppressing RNA silencing-based antiviral defenses. Using a stop codon mutant of Oilseed rape mosaic tobamovirus (ORMV), we demonstrate that the readthrough replicase (p182) is sufficient for gRNA replication and for subgenomic RNA transcription during systemic infection in Nicotiana benthamiana and Arabidopsis thaliana. However, the mutant virus displays milder symptoms and does not interfere with HEN1-mediated methylation of viral short interfering (si)RNAs or plant small (s)RNAs. The mutant virus tends to revert the stop codon, thereby restoring expression of the shorter protein (p125), even in the absence of plant Dicer-like activities that generate viral siRNAs. Plant RDR activities that generate endogenous siRNA precursors do not prevent replication or movement of the mutant virus, and double-stranded precursors of viral siRNAs representing the entire virus genome are likely synthesized by p182. Transgenic expression of p125 partially recapitulates the ORMV disease symptoms associated with overaccumulation of plant sRNAs. Taken together, the readthrough replicase p182 is sufficient for viral replication and transcription but not for silencing suppression. By contrast, the shorter p125 protein suppresses silencing, provokes severe disease symptoms, causes overaccumulation of unmethylated viral and plant sRNAs but it is not an essential component of the viral replicase complex. PMID- 29140169 TI - Relationship Between Physical Therapy Characteristics, Surgical Procedure, and Clinical Outcomes in Patients After ACL Reconstruction. AB - CONTEXT: Postoperative rehabilitation is critical to optimize outcomes after anterior cruciate ligament reconstruction (ACLR). However, the relationship between physical therapy (PT) and clinical outcomes is unclear. OBJECTIVE: To describe PT characteristics following ACLR and to assess the relationships between PT characteristics, surgical procedure, and clinical outcomes. DESIGN: Cross-sectional. SETTING: Laboratory. Patients (or Other Participants): A total of 60 patients (31 females/29 males, age = 22.4 [9.2] y, height = 171.7 [9.9] cm, and mass = 70.2 [14.7] kg) with a history of primary unilateral ACLR (53.6% patellar tendon and 46.4% hamstring) participated. INTERVENTION(S): Patients completed a performance assessment and rated subjective knee function prior to physician clearance (mean = 6.3 [1.3] mo postoperatively) and were contacted within 6 months of clearance to complete a PT questionnaire. MAIN OUTCOME MEASURES: PT questionnaire item response, knee extension maximum voluntary isometric contraction (MVIC) torque, peak isokinetic knee extension torque, single leg hop distance, and International Knee Documentation Committee were measured. Correlations assessed relationships between PT quantity and clinical outcomes. Independent t tests compared PT quantity and clinical outcomes based on return-to-sport status, readiness to return to sport, and surgical procedure. RESULTS: Patients completed regular PT (2 d/wk, 25 wk, 58 visits) and were most likely to conclude when discharged by the therapist (68.3%). More than half (56.7%) returned to sport, yet most (73.3%) felt unready at discharge. Isokinetic torque was correlated with days of PT/week (r = .29, P = .03). Isokinetic torque and hop symmetry were reduced in patients who returned to sport (P < .05). Patients who felt ready to return completed fewer weeks of PT (P < .05). Patients with a patellar tendon graft completed more days of PT/week and total visits, but demonstrated lower MVIC torque, MVIC symmetry, and isokinetic symmetry (P < .05). CONCLUSIONS: Many patients felt unready to return to sport at PT discharge. PT frequency was associated with isokinetic torque, yet this relationship was small. Outcomes were reduced in patients who returned to sport, suggesting premature resumption of preinjury activity. PMID- 29140171 TI - Exemplars. PMID- 29140170 TI - Clinical Diagnostic Tests Versus MRI Diagnosis of ACL Tears. AB - Clinical Scenario: The anterior cruciate ligament (ACL) injury is a common knee injury within varying athletic levels. Clinical diagnostic tests and magnetic resonance imaging (MRI) are two methods of evaluating ACL injuries. Clinical Question: Are clinical diagnostic tests as accurate as MRI when diagnosing ACL tears? Summary of Key Findings: Three cross-sectional design studies were included. One study found that clinical diagnostic tests were superior to MRI when diagnosing an ACL tear. Another study found that clinical diagnostic tests were equal to MRI when measuring sensitivity, but scored higher in specificity, positive predictive value, negative predictive value, and diagnostic accuracy. The last study found that clinical diagnostic tests scored higher than MRI on specificity and positive predictive value, were equal when measuring accuracy, and scored lower when measuring sensitivity and negative predictive value. Clinical Bottom Line: The evidence supports the use of clinical diagnostic tests when diagnosing an ACL tear. Strength of Recommendation: Level 2-3. PMID- 29140172 TI - Soapbox. PMID- 29140173 TI - Guest Editorial. PMID- 29140174 TI - Eminent Editor. PMID- 29140175 TI - Response. PMID- 29140177 TI - Student Corner. AB - The application of the Total Quality Management (TQM) philosophy within the health care sector would enhance the development of nursing power, leadership and knowledge. TQM challenges conventional management techniques as it requires a participative management style in order to be effective. There are many potential benefits for nurses, when quality assurance monitoring within a hierarchical management structure, is replaced with a focus on continuous quality improvement by every member of staff. These benefits are described within the context of both organisational and personal commitment to Total Quality Management. PMID- 29140178 TI - Infraspinatus Cross Sectional Area and Shoulder Range of Motion Change Following Live-Game Baseball Pitching. AB - CONTEXT: Following a baseball pitching bout, changes can occur to glenohumeral range of motion that could be linked to injury. These effects are in part due to the posterior shoulder's eccentric muscle activity, which can disrupt muscle contractile elements and lead to changes in muscle cross sectional area (CSA), as measured by ultrasound. OBJECTIVE: To assess changes in muscle CSA, and range of motion immediately before and after pitching, and days 1-5 following pitching. DESIGN: Repeated measures. SETTING: Satellite athletic training room. PATIENTS: Ten elite college baseball pitchers participating in the fall season (age: 18.8+/ 1.2 years, height: 189.2+/-7.3 cm, mass: 93.1+/-15.3 kg, 8 starters, 2 long relievers). INTERVENTION: A pitching bout of at least 25 pitches (63.82+/-17.42 pitches). MAIN OUTCOME MEASURES: Dominant and non-dominant infraspinatus CSA, as measured by ultrasound, and glenohumeral range of motion including internal rotation (IRROM), external rotation (ERROM), and total range of motion (TROM) before pitching, after pitching, and days 1-5 following the pitching bout. RESULTS: Dominant limb CSA significantly increased day 1 after pitching, and returned to baseline on day 2(p=0.0008). Dominant and non-dominant TROM did not change until day 5(4.4 degrees, p=0.0061) and day 3(4.5 degrees, p=0.0024), respectively, where they increased. Dominant IRROM was significantly decreased for 3 days (day 1: 1.9 degrees, p=0.0039, day 2: 3.1 degrees, p=0.0047, day 3: 0.3 degrees, p=0.0055) following pitching and returned to baseline on day 4, with no such changes in the non-dominant limb. Dominant ERROM significantly increased immediately post pitching (4.4 degrees, p=0.0011) but returned to baseline by day 1. CONCLUSIONS: The results of the study demonstrate infraspinatus CSA does not recover until 2 days following pitching, and IRROM does not recover until 4 days following pitching. Baseball pitching elicits damage to the posterior shoulder muscle architecture, resulting in changes to physical characteristics that last up to 4 days following pitching. PMID- 29140179 TI - Relationship Between 2 Standardized Tackling Proficiency Tests and Rugby League Match-Play Tackle Performance. AB - This study investigated the relationship between 2 different assessments of tackling ability, physical qualities, and match-play performance in semiprofessional rugby league players. A total of 18 semiprofessional rugby league players (mean [SD]: age = 23.1 [2.0] y and body mass = 98.8 [11.8] kg) underwent tests of upper- and lower-body strength and power. Tackling ability was assessed using video analysis of under- and over-the-ball tackle drills. A total of 2360 tackles were analyzed from match play. Over-the-ball tackle ability was positively related to the proportion of dominant tackles (Spearman rank-order correlation coefficients [rs] = .52; 95% confidence interval [CI] .07-.79, P = .03) and average play-the-ball speeds (rs = .50; 95% CI .04-.78, P = .03) and negatively related to tackles that conceded offloads (rs = -.55; 95% CI -.78 to .04, P = .04). Under-the-ball tackle ability was significantly related to the proportion of dominant tackles (rs = .57; 95% CI .14-.82, P = .01) and missed tackles (rs = -.48; 95% CI -.77 to .02, P = .05). Good over-the-ball tacklers performed proportionally more dominant tackles, allowed significantly fewer offloads, and had longer average play-the-ball speeds. Good under-the-ball tacklers missed proportionately fewer tackles. This study suggests that both the under-the-ball and over-the-ball standardized tackle assessments are associated with varying indicators of match-play tackle performance and justifies the practical utility of these tests to assess and develop both types of tackles. PMID- 29140180 TI - The Role of Lumbopelvic-Hip Complex Stability in Softball Throwing Mechanics. AB - CONTEXT: Studies have found that a 20% reduction in energy generation from the lumbopelvic-hip complex during overhead throws leads to a 34% increase in load on the shoulder. OBJECTIVE: The purpose of this study was to assess the effects of lumbopelvic-hip complex stability, via the single leg squat assessment, on throwing mechanics of softball athletes. DESIGN: Prospective cohort study. SETTING: Laboratory setting. PARTICIPANTS: A total of 50 softball athletes (164.0 [104.0] cm, 65.6 [11.3] kg, 16.3 [3.8] y, 8.61 [3.62] y of experience) performed 3 overhead throws and a single leg squat on each leg. INTERVENTION: Four stability groups were derived: (1) stable on both legs (bilateral stability), (2) unstable on the throwing side leg (TS instability) and stable on the nonthrowing side leg, (3) unstable on the nonthrowing side leg (NTS instability) and stable on the throwing side leg, and (4) unstable on both legs (bilateral instability). All throws were analyzed across 4 throwing events: foot contact (FC), maximum external shoulder rotation (MER), ball release (BR), and maximum internal shoulder rotation (MIR). MAIN OUTCOME MEASURES: Mann-Whitney U tests revealed significant differences between the bilateral stability and the TS instability groups in trunk flexion at BR; the bilateral stability and the NTS instability groups in trunk flexion at BR, shoulder horizontal abduction at FC, shoulder rotation at FC, and pelvis flexion at MIR; the TS instability and the bilateral instability groups in trunk rotation at FC; and the NTS instability and the bilateral instability groups in trunk flexion at MER and shoulder rotation at FC. CONCLUSION: These findings demonstrate the different mechanisms in which energy can be lost through lumbopelvic-hip complex instability as evident in throwing mechanics. The findings from this study suggest that the current methods used for classification could act as a tool for coaches, physicians, and athletic trainers when assessing their athletes' injury susceptibility. PMID- 29140181 TI - Rational design of a high-strength bone scaffold platform based on in situ hybridization of bacterial cellulose/nano-hydroxyapatite framework and silk fibroin reinforcing phase. AB - Bacterial cellulose/hydroxyapatite (BC/HAp) composite had favourable bioaffinity but its poor mechanical strength limited its widespread applications in bone tissue engineering (BTE). Silk fibroin, which possesses special crystalline structure, has been widely used as organic reinforcing material, and different SFs have different amino acid sequences, which exhibit different bioaffinity and mechanical properties. In this regard, bacterial cellulose-Antheraea yamamai silk fibroin/hydroxyapatite (BC-AYSF/HAp), bacterial cellulose-Bombyx mori silk fibroin/hydroxyapatite (BC-BMSF/HAp), and BC/HAp nano-composites were synthesized via a novel in situ hybridization method. Compared with BC/HAp and BC-BMSF/HAp, the BC-AYSF/HAp exhibited better interpenetration, which may benefit for the transportation of nutrients and wastes, the adhesion of cells as well. Additionally, the BC-AYSF/HAp also presented superior thermal stability than the other two composites revealed by differential thermal analysis (DTA) and thermogravimetric analysis (TGA). Compression testing indicated that the mechanical strength of BC-BMSF/HAp was greatly reinforced compared with BC/HAp and was even a little higher than that of BC-AYSF/HAp. Tensile testing showed that BC-AYSF/HAp possesses extraordinary mechanical properties with a higher elastic modulus at low strain and higher fracture strength simultaneously than the other two composites. In vitro cell culture exhibited that MC3T3-E1 cells on the BC-AYSF/HAp membrane took on higher proliferative potential than those on the BC-BMSF/HAp membrane. These results suggested that compared with BC-BMSF/HAp, the BC-AYSF/HAp composite was more appropriate as an ideal bone scaffold platform or biomedical membrane to be used in BTE. PMID- 29140182 TI - TGF-beta1 and CXCL12 modulate proliferation and chemotherapy sensitivity of acute myeloid leukemia cells co-cultured with multipotent mesenchymal stromal cells. AB - OBJECTIVES: Multipotent mesenchymal stromal cells (MSCs) play a central role within the bone marrow (BM) niche, supporting hematopoiesis via soluble factors like cytokines and chemokines. In our study, we sought to investigate the effect of blocking transforming growth factor beta 1 (TGF-beta1) and C-X-C motif chemokine 12 (CXCL12) receptor CXCR4 on acute myeloid leukemia (AML) cells in an MSC co-culture system. METHODS: Human MSCs were obtained by BM aspirates and their phenotype and functional properties were confirmed in vitro. Co-cultures of AML cells on MSCs were initiated and compared to those on mouse fibroblasts (MS 5) and liquid cultures. Additionally, the effect of blocking CXCR4 and TGF-beta1 on AML cells was tested with and without the addition of cytarabine. RESULTS: MSCs from BM showed a typical phenotype and differentiation pattern. Co-culture of AML cells on MSCs resulted in a significantly higher proliferation capacity than on MS-5 or liquid culture. Blockade of TGF-beta1 increased AML cell proliferation and chemosensibility, while the CXCR4 antagonist plerixafor showed anti-proliferative effects and did not change cytarabine-induced cell death compared to control. DISCUSSION: Human MSCs are potent feeder cells, able to maintain AML cells in long-term culture. This favorable co-existence seems to be due in part to molecules important for communication within the niche. Blockade of TGF-beta1 and CXCL12 was associated with different effects on AML cell proliferation and chemotherapy resistance. CONCLUSION: These findings suggest a strong supporting affinity between MSCs and AML cells within the leukemic niche, where TGF-beta1 and CXCL12 pathways play an important role. PMID- 29140183 TI - Examining the Presence of Back Pain in Competitive Athletes: A Focus on Stress and Recovery. AB - CONTEXT: Explanatory approaches for back pain (BP) in athletes focus on biomechanical factors while neglecting psychological perspectives. Psychological factors have gained importance in the prediction of injuries in athletes and BP in the general population, with stress and recovery emerging as central risk factors. However, scarce evidence exists regarding the role of these aspects for the prevalent burden of BP. OBJECTIVE: To investigate the association between stress and recovery parameters and the presence of BP. DESIGN: Cross-sectional design. SETTING: The questionnaires were distributed after the training sessions. PARTICIPANTS: A total of 345 competitive athletes (mean age = 18.31 y [SD = 5.40]) were investigated. The classification of the athletes' competitive status was based on performance level. INTERVENTIONS: Data were collected using questionnaires for the assessment of stress, recovery, and BP. MAIN OUTCOME MEASURES: The authors performed a multiple logistic regression to obtain odds ratios for stress and recovery parameters with regard to the outcome variable BP status. RESULTS: For stress, the dimension "overall stress" (odds ratio = 1.83; 95% confidence interval, 1.30-2.59; P = .001) and the scale "physical complaints" (odds ratio = 1.68; 95% confidence interval, 1.25-2.25; P = .001) of the general version of the Recovery-Stress Questionnaire resulted to be significantly associated with BP. None of the recovery-related scales displayed a statistically significant relationship with BP. CONCLUSION: The outcomes of this study imply a modest association between stress and the presence of BP in competitive athletes. Practitioners may take these findings into account regarding the conception of training and for monitoring purposes. PMID- 29140184 TI - Refining the ischemic penumbra with topography. AB - It has been 40 years since the ischemic penumbra was first conceptualized through work on animal models. The topography of penumbra has been portrayed as an infarcted core surrounded by penumbral tissue and an extreme rim of oligemic tissue. This picture has been used in many review articles and textbooks before the advent of modern imaging. In this paper, we review our understanding of the topography of the ischemic penumbra from the initial experimental animal models to current developments with neuroimaging which have helped to further define the temporal and spatial evolution of the penumbra and refine our knowledge. The concept of the penumbra has been successfully applied in clinical trials of endovascular therapies with a time window as long as 24 h from onset. Further, there are reports of "good" outcome even in patients with a large ischemic core. This latter observation of good outcome despite having a large core requires an understanding of the topography of the penumbra and the function of the infarcted regions. It is proposed that future research in this area takes departure from a time-dependent approach to a more individualized tissue and location-based approach. PMID- 29140185 TI - Thrombolysis: Improving door-to-needle times for ischemic stroke treatment - A narrative review. AB - Background The effectiveness of thrombolysis is highly time dependent. For this reason, short target times have been set to reduce time to treatment from hospital arrival, which is called door-to-needle time. Summary of review There has been considerable work done at single centers and across multiple hospitals to improve door-to-needle time. There have been reductions of 8 to 47 min when applying one or more improvement strategies at single centers, and there have been many multi-hospital initiatives. The delays to treatment have been attributed to both patient and hospital factors, and strategies to address these delays have been proven to reduce door-to-needle time. The most effective strategies include pre-notification of arrival by Emergency Medical Services (EMS), single-call activation of stroke team, rapid registration process, moving the patient to computed tomography on EMS stretcher, and administration of alteplase in the scanner. There are many exciting areas of future direction including reduction of door-to-needle time in developing countries, improving pre hospital response times, and improving the efficiency of endovascular treatment. Conclusions There is now a broad understanding of the causes of delays to fast treatment and the strategies that can be employed to improve door-to-needle time such that most centers could achieve median door-to-needle time of 30 min. PMID- 29140186 TI - Acute Effect of 2 Self-Myofascial Release Protocols on Hip and Ankle Range of Motion. AB - CONTEXT: Self-myofascial release (SMR) is an intervention popularly used by rehabilitation, fitness, and sports professionals to improve recovery and performance. In SMR, the athlete/patient applies pressure to the muscle and fascia using various tools, such as balls, rods, foam rolls, and massagers. OBJECTIVE: This study aimed to evaluate the acute effect of 2 SMR protocols (short term and long term) of the posterior thigh and calf muscles on hip and ankle range of motion (ROM) in physically active men. PARTICIPANTS: A total of 14 adult males (24.9 [3.2] y, 77.2 [13.2] kg, and 1.75 [0.06] m) who exercise regularly (at least twice a week, 45 min per session) participated in this study. INTERVENTIONS: Participants performed a short-term SMR protocol (2 * 10 repetitions, SSMR) and a long-term SMR protocol (2 * 20 repetitions, LSMR) of the posterior thigh (using a foam roller) and calf (using a massage stick) muscles in counterbalanced order, on 2 different days with a 48-hour interval. MAIN OUTCOME MEASURES: Ankle dorsiflexion and hip-flexion ROM, evaluated at 5 moments: pre- and post-SSMR, pre- and post-LSMR, and in the control condition, which was always performed at the first visit. RESULTS: The SMR promoted significant gains for both dorsiflexion (F1,13 = 202.67, P < .001, [Formula: see text]) and hip flexion (F1,13 = 66.46, P < .001, [Formula: see text]), regardless of the protocol and limb analyzed. The average increase for both limbs corresponded, approximately, to 11% for ankle dorsiflexion and to 6% for and in hip flexion. CONCLUSIONS: The results suggest that SMR of the posterior thigh and calf muscles acutely increases the ROM of both hip flexion and ankle dorsiflexion and that duplicating the SMR volume from 10 to 20 repetitions per set seems not to promote additional gains. PMID- 29140189 TI - Predicting the sources of impaired wh-question comprehension in non-fluent aphasia: A cross-linguistic machine learning study on Turkish and German. AB - This study investigates the comprehension of wh-questions in individuals with aphasia (IWA) speaking Turkish, a non-wh-movement language, and German, a wh movement language. We examined six German-speaking and 11 Turkish-speaking IWA using picture-pointing tasks. Findings from our experiments show that the Turkish IWA responded more accurately to both object who and object which questions than to subject questions, while the German IWA performed better for subject which questions than in all other conditions. Using random forest models, a machine learning technique used in tree-structured classification, on the individual data revealed that both the Turkish and German IWA's response accuracy is largely predicted by the presence of overt and unambiguous case marking. We discuss our results with regard to different theoretical approaches to the comprehension of wh-questions in aphasia. PMID- 29140191 TI - Editorial. PMID- 29140190 TI - Evaluation of a Shoulder Injury Prevention Program in Wheelchair Basketball. AB - CONTEXT: Previous literature has theorized that alterations in shoulder physical characteristics are present in wheelchair athletes and contribute to shoulder pain and injury. Limited empirical evidence is present that evaluates the effectiveness of a shoulder injury prevention program focusing on improving these altered characteristics. OBJECTIVE: To evaluate the effectiveness of a 6-week intervention program at improving characteristics that increases the risk of developing pain or shoulder injury. DESIGN: Pretest and posttest. SETTING: Home based and controlled laboratory. PARTICIPANTS: Seven college wheelchair athletes. INTERVENTIONS: Shoulder range of motion (ROM) and scapular muscle strength were assessed, and a 5-minute injury prevention program was taught to participants. Participants completed the intervention 3 times per week for 6 weeks. Following completion of the program, a postintervention screening was performed. MAIN OUTCOME MEASURES: Internal rotation (IR)/external rotation (ER) ROM, retraction strength, and IR/ER strength. RESULTS: Participants experienced a significant improvement in dominant limb shoulder IR ROM (t6 = 3.56, P = .01) with an average increase of 11.4 degrees of IR ROM and a significant improvement in dominant limb shoulder ER ROM (t6 = 2.79, P = .03) with an average increase of 8.0 degrees of ER ROM. There were no significant increases in shoulder IR or ER strength and scapular retraction strength (P > .05). CONCLUSIONS: Improvements in ROM have previously been linked to decreases in shoulder pain and injury in other upper extremity dominant sports by improving scapular kinematics. These results provide evidence that a 6-week strengthening and stretching intervention program may decrease risk factors for shoulder injury in wheelchair basketball athletes. PMID- 29140192 TI - A study of female nurses combining partner and parent roles with working a continuous threeshift roster: The impact on sleep, fatigue and stress. AB - This study of female nurses working a continuous 3-shift roster found that the average sleep duration per 24-hours across the roster is almost one hour less for nurses who combine shiftwork, partner and parent roles. In particular, they are not free to use the later starting afternoon shift as an opportunity to repay the sleep debt incurred on night shift.The results show an interaction between work and family roles resulting in chronic fatigue that is a risk factor especially when combined with the acute fatigue associated with night work.The sleep record data is supported by interview data which highlight shiftwork as a stressor that reduces the opportunity for participation in social and leisure activities by all three of the groups studied: single, partnered and partnered with children.The strain of shiftwork on personal and social relationships reduces the resources available for coping with the emotional and physical stressors encountered by nurses in their work and family roles. PMID- 29140199 TI - Exemplar. PMID- 29140194 TI - Validity of a Smartphone Application for Measuring Ankle Plantar Flexion. AB - CONTEXT: Range of motion is a component of a physical examination used in the diagnostic and rehabilitative processes. Following ankle injury and/or during research, it is common to measure plantar flexion with a universal goniometer. The ease and availability of digital inclinometers created as applications for smartphones have led to an increase in using this method of range of motion assessment. Smartphone applications have been validated as alternatives to inclinometer measurements in the knee; however, this application has not been validated for plantar flexion in the ankle. OBJECTIVES: The purpose of this study was (1) to assess the validity of the Clinometer Smartphone ApplicationTM produced by Plaincode App Development for use in the ankle (ie, plantar flexion) and (2) to assess the validity of the inclinometer procedures used to measure ankle dorsiflexion for measuring ankle plantar flexion. DESIGN: Blinded repeated measures correlational design. SETTING: University-based outpatient rehabilitative clinic. PARTICIPANTS: A convenience sample (N = 50) of participants (27 females and 23 males) who reported to the clinic (mean age = 30.48 y). INTERVENTION: Patients were long seated on a plinth, with the knee in terminal extension. Three plantar flexion measurements were taken with a goniometer on each foot by the primary researcher. The primary researcher then conducted 3 blinded measurements with The Clinometer Smartphone ApplicationTM following the same procedure. A second researcher, who was blinded to the goniometer measurements, recorded the inclinometer measurements. After data were collected, a Pearson's correlation was calculated to determine the validity of the clinometer app compared with goniometry. MAIN OUTCOME MEASURE: Degrees of motion for ankle plantar flexion. RESULTS: Measurements produced using the Clinometer Smartphone ApplicationTM were highly correlated for right foot (r = .92, P < .001), left foot (r = .92, P < .001), and combined (r = .92, P < .001) with goniometer measurements using a plastic universal goniometer. CONCLUSION: The Clinometer Smartphone ApplicationTM is a valid instrument for measuring plantar flexion of the ankle. PMID- 29140201 TI - Editorial. PMID- 29140200 TI - Exemplar. AB - Reflection identifies one' s professional capabilities, increases knowledge of self and improves understanding and management of patients. Conducting reflective practice is conducive to professional development and growth. A complex medical and nursing management of a psychiatric emergency is illustrated through this critical incident. Psychiatric nurses play a key role in de-escalating the aggressive behaviour of psychotic patients. Through reflection, the basic tools of psychiatric nurses are reviewed and the prime components of psychiatric therapy are discussed. PMID- 29140203 TI - Soap Box. PMID- 29140202 TI - Exemplar. AB - Nursing care is affected by the culture we live in and even when nursing care is given the same way in different societies, it can be given that way for different reasons. This was found when doing a comparison between how certain aspects of nursing care were performed and viewed in Australia and Papua New Guinea. The framework for comparison was derived from part of Lawler' s book (1991) Behind the Screens: Nursing, Somology, and the Problem of the Body. The feelings and accounts of staff and students working in Papua New Guinea (in 1997) are compared with those expressed by Australian nurses interviewed by Lawler in the mid 1980s. Interviews and observations in Papua New Guinea are summarised and then analysed looking at similarities and differences between the two cultures especially in giving body care and care after death. PMID- 29140206 TI - Publisher' s note. PMID- 29140205 TI - Students' Corner. AB - This somewhat colloquial reflection on personal experience reveals some commonly perceived images and metaphors pertaining to nursing that have been birthed in history, perpetuated by the media, and entrenched in the minds of both onlookers and, unfortunately, of those not quite so detached. The reader might identify with some, and be amazed at others, or be provoked on a similar journey of reminiscence and reconsideration of the images that have shaped and informed their practice. The literature presents the not always positive portrayal of nursing, and the resultant adverse effect this exerts not only upon the profession, but upon its practitioners as well. Thus is set forth the challenge of how to respond. PMID- 29140207 TI - Soap Box. AB - Like all professionals, nurses live with the inevitability of change. The extent to which change is experienced as a crisis rather than as an opportunity is determined by the degree of control that nurses have over the change process. This paper outlines the determinants of change, examines the impact of change on nursing practice, explores professional ways of knowing and proposes critical thinking as a means by which nurses can interpret and manipulate change and illustrates a curriculum approach that facilitates the acquisition of the capacity to think critically. PMID- 29140208 TI - Exemplars. PMID- 29140209 TI - Soapbox. PMID- 29140211 TI - Guest Editorial. PMID- 29140210 TI - Student Corner. AB - In this overview of paediatric pain management the physiological and psychological effects of untreated pain are described. Reasons for the undertreatment of pain are identified as incorrect assumptions about children and pain; personal attitudes of families, nurses and physicians; inadequate research and training; and assessment difficulties. The problems of paediatric pain assessment are considered and an assessment strategy known as QUESTT is presented. Pharmacological and nonpharmacological interventions are discussed and the conclusion reached that despite the difficulties, infant and child pain can be controlled by using adequate nursing knowledge and treatment. PMID- 29140212 TI - Eminent Editor. PMID- 29140213 TI - Response. PMID- 29140217 TI - Soapbox. PMID- 29140218 TI - Response. PMID- 29140219 TI - Guest Editorial. PMID- 29140220 TI - Student Corner. AB - Controversy about induced abortion is caused by issues such as the moral, medical and legal definitions of viability; the intrinsic value of human life; and the rights of the foetus versus the rights of the mother. These issues pose ethical dilemmas for nurses seeking to enhance and support the autonomy of women who wish to have an abortion. Nurses are also obligated to adhere to their professional Code of Ethics and Code of Conduct, which are founded on preserving life and not destroying it. PMID- 29140222 TI - Eminent Editor. AB - This final editorial of the 1996 Eminent Editor series continues the debates surrounding the processes of writing qualitative research for publication. Trudy Rudge RN RPN BA(Hons) is Senior Lecturer in the Faculty of Nursing, University of South Australia with a background in acute care, psychiatric nursing and community areas of nursing. She is completing her doctoral studies on an exploration of wound care procedures in nursing using poststructural theories to illuminate this taken-for-granted nursing practice. Trudy has been a contributor and reviewer for Contemporary Nurse so I asked her to discuss how nurses can represent their clinical research speaking from the political platforms of feminism, praxis-oriented research and poststructuralism. Her use of the imagery of unpacking a library as a representation of unpacking clinical practice is a telling example of the stylistic discursive possibilities of writing these research genres. PMID- 29140223 TI - Exemplars. PMID- 29140225 TI - Key patterns and predictors of response to treatment for military veterans with post-traumatic stress disorder: a growth mixture modelling approach. AB - BACKGROUND: To determine the patterns and predictors of treatment response trajectories for veterans with post-traumatic stress disorder (PTSD). METHODS: Conditional latent growth mixture modelling was used to identify classes and predictors of class membership. In total, 2686 veterans treated for PTSD between 2002 and 2015 across 14 hospitals in Australia completed the PTSD Checklist at intake, discharge, and 3 and 9 months follow-up. Predictor variables included co morbid mental health problems, relationship functioning, employment and compensation status. RESULTS: Five distinct classes were found: those with the most severe PTSD at intake separated into a relatively large class (32.5%) with small change, and a small class (3%) with a large change. Those with slightly less severe PTSD separated into one class comprising 49.9% of the total sample with large change effects, and a second class comprising 7.9% with extremely large treatment effects. The final class (6.7%) with least severe PTSD at intake also showed a large treatment effect. Of the multiple predictor variables, depression and guilt were the only two found to predict differences in response trajectories. CONCLUSIONS: These findings highlight the importance of assessing guilt and depression prior to treatment for PTSD, and for severe cases with co morbid guilt and depression, considering an approach to trauma-focused therapy that specifically targets guilt and depression-related cognitions. PMID- 29140227 TI - Categorical improvement in functional impairment in depressed patients treated with desvenlafaxine. AB - OBJECTIVE: This post-hoc pooled analysis evaluated categorical change in functional impairment in patients with major depressive disorder (MDD) treated with desvenlafaxine versus placebo and examined whether early improvement in functioning predicted functional outcomes at study endpoint. METHODS: Data were pooled from eight randomized, double-blind, placebo-controlled studies of desvenlafaxine for the treatment of MDD, including adults who were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo (N=3,384). Shift tables were generated for categorical changes in functional impairment from baseline based on Sheehan Disability Scale (SDS) subscale scores. The categories were none/mild (0-3), moderate (4-6), and marked/extreme (7-10). Treatment comparisons for prespecified shifts of interest and predictive value of week 2 or 4 improvement in SDS subscale scores for functional outcome at week 8 were assessed using logistic regression. RESULTS: Greater proportions of patients receiving desvenlafaxine 50 and 100 mg achieved improvement from baseline to week 8 for each prespecified shift endpoint versus placebo (all p <= 0.02). Early improvement in SDS subscale scores was a statistically significant predictor of functional outcome at week 8, both overall and for each treatment group (all p<0.0001). CONCLUSIONS: Treatment with desvenlafaxine 50 or 100 mg/d led to significantly greater categorical improvement in functional impairment versus placebo, and improvement in SDS subscale scores significantly predicted functional outcome. Monitoring patient progress early in the course of antidepressant treatment using a functional assessment such as the SDS may help clinicians determine whether or not treatment adjustments are needed. PMID- 29140226 TI - Childhood inflammatory markers and intelligence as predictors of subsequent persistent depressive symptoms: a longitudinal cohort study. AB - BACKGROUND: To identify developmental sub-groups of depressive symptoms during the second decade of life, a critical period of brain development, using data from a prospective birth cohort. To test whether childhood intelligence and inflammatory markers are associated with subsequent persistent depressive symptoms. METHODS: IQ, a proxy for neurodevelopment, was measured at age 8 years. Interleukin 6 (IL-6) and C-reactive protein, typical inflammatory markers, were measured at age 9 years. Depressive symptoms were measured six times between 10 and 19 years using the short mood and feelings questionnaire (SMFQ), which were coded as binary variable and then used in latent class analysis to identify developmental sub-groups of depressive symptoms. RESULTS: Longitudinal SMFQ data from 9156 participants yielded three distinct population sub-groups of depressive symptoms: no symptoms (81.2%); adolescent-onset symptoms (13.2%); persistent symptoms (5.6%). Lower IQ and higher IL-6 levels in childhood were independently associated with subsequent persistent depressive symptoms in a linear, dose response fashion, but not with adolescent-onset symptoms. Compared with the group with no symptoms the adjusted odds ratio for persistent depressive symptoms per s.d. increase in IQ was 0.80 (95% CI, 0.68-0.95); that for IL-6 was 1.20 (95% CI, 1.03-1.39). Evidence for an association with IL-6 remained after controlling for initial severity of depressive symptoms at 10 years. There was no evidence that IL-6 moderated or mediated the IQ-persistent depressive symptom relationship. CONCLUSIONS: The results indicate potentially important roles for two distinct biological processes, neurodevelopment and inflammation, in the aetiology of persistent depressive symptoms in young people. PMID- 29140228 TI - Co-factor-independent phosphoglycerate mutase of Leishmania donovani modulates macrophage signalling and promotes T-cell repertoires bearing epitopes for both MHC-I and MHC-II. AB - Immunoactivation depends upon the antigen potential to modulate T-cell repertoires. The present study has enumerated the effect of 61 kDa recombinant Leishmania donovani co-factor-independent phosphoglycerate mutase (rLd-iPGAM) on mononuclear cells of healthy and treated visceral leishmaniasis subjects as well as on THP-1 cell line. rLd-iPGAM stimulation induced higher expression of interleukin-1beta (IL-1beta) in the phagocytic cell, its receptor and CD69 on T cell subsets. These cellular activations resulted in upregulation of host protective cytokines IL-2, IL-12, IL-17, tumour necrosis factor-alpha and interferon-gamma, and downregulation of IL-4, IL-10 and tumour growth factor beta. This immune polarization was also evidenced by upregulation of nuclear factor-kappa light-chain enhancer of activated B cells p50 and regulated expression of suppressor of mother against decapentaplegic protein-4. rLd-iPGAM stimulation also promoted lymphocyte proliferation and boosted the leishmaniacidal activity of macrophages by upregulating reactive oxygen species. It also induced 1.8-fold higher release of nitric oxide (NO) by promoting the transcription of inducible nitric oxide synthase gene. Besides, in silico analysis suggested the presence of major histocompatibility complex class I and II restricted epitopes, which can proficiently trigger CD8+ and CD4+ cells, respectively. This study reports rLd-iPGAM as an effective immunoprophylactic agent, which can be used in future vaccine design. PMID- 29140229 TI - Epidemiology of Imported Malaria Cases in Japan, 2006-2014: A Sentinel Traveler Surveillance Approach. AB - Malaria continues to be imported into Japan. To better assess the risk of imported malaria, we describe malaria species, suspected country/area of infection (accounting for the number of travelers), demographic characteristics, clinical manifestation, and healthcare access, based on the national surveillance data from 2006 to 2014. Among 557 cases, the median age was 33 years (range: 1-83 years), and 76% were male; 306 (55%) were classified as Japanese based on the reported name. The majority were Plasmodium falciparum infections (58%), followed by Plasmodium vivax infections (30%). Most P. falciparum cases were acquired in Africa and P. vivax in Asia/Oceania. Notification rates per 10,000 Japanese travelers for P. falciparum were highest for Africa, P. vivax were highest for Asia/Oceania, and high for both species for Papua New Guinea. Ten percent of the cases were clinically severe at the time of notification. Nearly 80% of severe cases were P. falciparum infections, and among P. falciparum cases, Japanese ethnicity was associated with severe case status (P = 0.03). Plasmodium falciparum cases among Japanese cases showed that older age (>= 50 years) was associated with severe case status (odds ratio = 5.4; 95% confidence interval = 1.9-15.2), adjusted for sex and healthcare access. More informative assessments are possible by accounting for the number of travelers. Older Japanese represent an important demographic to target prevention and early treatment efforts for malaria. PMID- 29140231 TI - Nodular Lymphangitis Syndrome. PMID- 29140230 TI - Effect of Tenofovor Diproxil Fumarate on Renal Function and Urinalysis Abnormalities in HIV-Infected Cameroonian Adults. AB - In Sub-Saharan Africa, the prevalence of HIV-associated kidney diseases is as high as 53.3%. Combined antiretroviral treatment (cART), especially tenofovir disoproxil fumarate (TDF), is known to be nephrotoxic. We undertook this cross sectional study conducted in 2015 at the Regional Hospital Limbe in the Southwest Region of Cameroon to determine the prevalence of renal dysfunction and its correlates among treatment-experienced HIV-infected patients on TDF and treatment naive patients. In April 2016, a follow-up was performed on those who had been treatment-naive and were started on cART after enrolment in the study. We compared 119 patients on TDF-containing regimens with 47 treatment-naive patients. Proteinuria was significantly more prevalent, and creatinine was significantly higher among treatment-naive patients than among those on treatment (52.2% versus 26.1%; P = 0.003 and P = 0.009, respectively). The proportion of patients with an estimated glomerular filtration rate (eGFR) < 60 mL/minute was significantly higher among treatment-naive patients than among those on TDF treatment (40.4% versus 24.4%; P = 0.041). Treatment-naive patients displayed an improvement in creatinine levels and eGFR after 6 months of treatment. To the best of our knowledge, this is the first study to investigate the impact of TDF on renal parameters in Cameroon. TDF appears to be safe and does not appear to be a significant cause of renal impairment. However, renal parameters should be monitored regularly, as recommended by the guidelines. PMID- 29140232 TI - Country-Wide Surveillance of Molecular Markers of Antimalarial Drug Resistance in Senegal by Use of Positive Malaria Rapid Diagnostic Tests. AB - In Senegal, antimalarial drugs used in treatment and prevention of malaria are one of the main reasons for the current success in controlling malaria. However, the successful control of malaria is highly dependent on continued effectiveness of these drugs which may be compromised by the spread of drug resistance. Therefore, surveillance of drug resistance in the malaria parasites is essential. The objective of this pilot study was to test the feasibility of routinely sampled malaria rapid diagnostic tests (RDTs) at a national scale to assess the temporal changes in the molecular profiles of antimalarial drug resistance markers of Plasmodium falciparum parasites. Overall, 9,549 positive malaria RDTs were collected from 14 health facilities across the country. A limited random set of RDTs were analyzed regarding Pfcrt gene polymorphisms at codon 72-76. Overall, a high but varied prevalence (> 50%) of the wild-type CVMNK haplotype was observed including a higher CVMNK prevalence in the northern part (75%) compared with the southern part of the country (59%). With caution, the study provides a proof of concept that reuse of discarded P. falciparum positive RDTs can be applied in large-scale surveillance of antimalarial drug resistance. PMID- 29140233 TI - Case Report: A Case of Recurrent Strongyloides stercoralis Colitis in a Patient with Multiple Myeloma. AB - Strongyloides stercoralis chronic infection is frequently subclinical and thus under-recognized, although its increasing prevalence in nonendemic regions has implications for immunocompromised hosts. We present a 75-year-old male with stage II multiple myeloma who presented with relapse of Strongyloides infection after initial treatment, negative surveillance testing, and subsequent resumption of chemotherapy for his multiple myeloma. The optimal regimen for secondary prophylaxis against recurrent infections is unknown. Secondary prophylaxis should be considered for patients who recur and/or remain at high risk of recurrence because of ongoing immunosuppression. We implemented a prophylactic regimen of ivermectin 200 mcg/kg once monthly. In addition, improved laboratory assays for strongyloidiasis are needed to aid with diagnosis, monitoring of treatment response, and early detection of relapse. PMID- 29140235 TI - The Hookworm Blues: We Still Got 'em. PMID- 29140234 TI - Prevalence of Trypanosoma cruzi and Other Trypanosomatids in Frequently-Hunted Wild Mammals from the Peruvian Amazon. AB - To better understand the ecology of Trypanosoma cruzi in the northeastern Peruvian Amazon, we evaluated the prevalence of T. cruzi and other trypanosomatids in four orders of wild mammals hunted and consumed by inhabitants of three remote indigenous communities in the Peruvian Amazon. Of 300 wild mammals sampled, 115 (38.3%) were infected with trypanosomatids and 15 (5.0%) with T. cruzi. The prevalence of T. cruzi within each species was as follows: large rodents (Cuniculus paca, 5.5%; Dasyprocta spp., 2.6%), edentates (Dasypus novemcinctus, 4.2%), and carnivores with higher prevalence (Nasua nasua, 18.8%). The high prevalence of T. cruzi and other trypanosomatids in frequently hunted wild mammals suggests a sizeable T. cruzi sylvatic reservoir in remote Amazonian locations. PMID- 29140237 TI - Rickettsia typhi and Haemophagocytic Syndrome. PMID- 29140236 TI - Impact of Childhood Nutritional Status on Pathogen Prevalence and Severity of Acute Diarrhea. AB - Children with acute and chronic malnutrition are at increased risk of morbidity and mortality following a diarrheal episode. To compare diarrheal disease severity and pathogen prevalence among children with and without acute and chronic malnutrition, we conducted a cross-sectional study of human immunodeficiency virus-uninfected Kenyan children aged 6-59 months, who presented with acute diarrhea. Children underwent clinical and anthropometric assessments and provided stool for bacterial and protozoal pathogen detection. Clinical and microbiological features were compared using log binomial regression among children with and without wasting (mid-upper arm circumference <= 125 mm) or stunting (height-for-age z score <= -2). Among 1,363 children, 7.0% were wasted and 16.9% were stunted. After adjustment for potential confounders, children with wasting were more likely than nonwasted children to present with at least one Integrated Management of Childhood Illness danger sign (adjusted prevalence ratio [aPR]: 1.3, 95% confidence interval [CI]: 1.0 to 1.5, P = 0.05), severe dehydration (aPR: 2.4, 95% CI: 1.5 to 3.8, P < 0.01), and enteroaggregative Escherichia coli recovered from their stool (aPR: 1.8, 1.1-2.8, P = 0.02). There were no differences in the prevalence of other pathogens by wasting status after confounder adjustment. Stunting was not associated with clinical severity or the presence of specific pathogens. Wasted children with diarrhea presented with more severe disease than children without malnutrition which may be explained by a delay in care-seeking or diminished immune response to infection. Combating social determinants and host risk factors associated with severe disease, rather than specific pathogens, may reduce the disparities in poor diarrhea-associated outcomes experienced by malnourished children. PMID- 29140238 TI - The Effects of Malnutrition and Diarrhea Type on the Accuracy of Clinical Signs of Dehydration in Children under Five: A Prospective Cohort Study in Bangladesh. PMID- 29140239 TI - A Challenging Case of Disseminated Subcutaneous Mycosis from Inner Rio de Janeiro State, Brazil. PMID- 29140240 TI - Case Report: Strongyloides stercoralis Hyperinfection in a Patient with Chronic Lymphocytic Leukemia. AB - Strongyloides stercoralis is an intestinal nematode that can cause disseminated infection in an immunocompromised host. It is most commonly acquired in developing countries. It was previously a common infection in many parts of the United States, particularly in the Appalachian region, but is rarely identified currently. Here, we describe a patient born and raised in Appalachia, with no history of travel outside the United States, who presented with chronic lymphocytic leukemia and S. stercoralis hyperinfection characterized by acute respiratory failure, altered mental status, and extended-spectrum-beta-lactamase Klebsiella pneumoniae bacteremia. Despite prompt identification of the parasite on sputum microscopy and initiation of therapy with oral ivermectin and meropenem, the patient subsequently died. This case highlights the continued possibility of S. stercoralis infection in patients from Appalachia. PMID- 29140241 TI - Direct Biomarkers of Microbial Translocation Correlate with Immune Activation in Adult Zambians with Environmental Enteropathy and Hepatosplenic Schistosomiasis. AB - Microbial translocation is a poorly understood consequence of several disorders such as environmental enteropathy (EE) and hepatosplenic schistosomiasis (HSS). Herein, we compared biomarkers of microbial origin and immune activation in adults with these disorders and in healthy controls. A cross-sectional study was conducted in participants with EE recruited from Misisi compound, Lusaka, Zambia; HSS patients and healthy controls from the University Teaching Hospital, Lusaka. Plasma lipopolysaccharides (LPSs) was measured by limulus amoebocyte lysate assay, plasma 16S ribosomal RNA (16S rRNA) gene copy number was quantified by quantitative real-time polymerase chain reaction, Toll-like receptor ligand (TLRL) activity by QUANTI-Blue detection medium, and cytokines from cell culture supernatant by Cytometric Bead Array. In univariate analysis LPS, 16S rRNA gene copy number, and TLR activity were all high and correlated with each other and with cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL 10, and IL-4 secreted by the RAW-Blue cells. After controlling for baseline characteristic, biomarkers of microbial translocation in blood were predictors of TNF-alpha, IL-6, and IL-10 activation in cell culture supernatant from EE participants and HSS patients but not in healthy controls. TLR activity showed the strongest correlation with TNF-alpha. These data provide correlative evidence that microbial translocation contributes to systemic cytokine activation in two disorders common in the tropics, with total TLR ligand estimation showing the strongest correlation with TNF-alpha (r = 0.66, P < 0.001). PMID- 29140242 TI - Guillain-Barre Syndrome, Acute Disseminated Encephalomyelitis and Encephalitis Associated with Zika Virus Infection in Brazil: Detection of Viral RNA and Isolation of Virus during Late Infection. AB - Zika virus (ZIKV) emerged in Brazil in 2015, which was followed by an increase of Guillain-Barre Syndrome (GBS) cases. We report the epidemiological, clinical, and laboratory findings of the first six neurological cases associated with ZIKV in Brazil seen in a reference neurology hospital in Pernambuco, Brazil. In all cases, ZIKV was detected in serum and/or cerebrospinal fluid (CSF) samples. In this case series, four cases were defined as GBS, one as acute disseminated encephalomyelitis (ADEM) and the other as encephalitis. ZIKV was detected in all cases by RT-PCR and virus isolation was successful in two patients. The time between ZIKV acute symptoms and the development of neurological manifestations varied from 3 to 13 days and ZIKV was detected between 15 and 34 days after the initial symptoms. Our results highlight the need to include ZIKV as a differential diagnosis for neurological syndromes in countries with circulation of this arbovirus. Because the viremia in these patients appears to persist longer, direct diagnostic techniques such as RT-PCR and viral isolation should be considered even if it is after the acute phase of viral infection. PMID- 29140243 TI - A versatile genetic tool for post-translational control of gene expression in Drosophila melanogaster. AB - Several techniques have been developed to manipulate gene expression temporally in intact neural circuits. However, the applicability of current tools developed for in vivo studies in Drosophila is limited by their incompatibility with existing GAL4 lines and side effects on physiology and behavior. To circumvent these limitations, we adopted a strategy to reversibly regulate protein degradation with a small molecule by using a destabilizing domain (DD). We show that this system is effective across different tissues and developmental stages. We further show that this system can be used to control in vivo gene expression levels with low background, large dynamic range, and in a reversible manner without detectable side effects on the lifespan or behavior of the animal. Additionally, we engineered tools for chemically controlling gene expression (GAL80-DD) and recombination (FLP-DD). We demonstrate the applicability of this technology in manipulating neuronal activity and for high-efficiency sparse labeling of neuronal populations. PMID- 29140244 TI - Subcellular analysis of pigeon hair cells implicates vesicular trafficking in cuticulosome formation and maintenance. AB - Hair cells are specialized sensors located in the inner ear that enable the transduction of sound, motion, and gravity into neuronal impulses. In birds some hair cells contain an iron-rich organelle, the cuticulosome, that has been implicated in the magnetic sense. Here, we exploit histological, transcriptomic, and tomographic methods to investigate the development of cuticulosomes, as well as the molecular and subcellular architecture of cuticulosome positive hair cells. We show that this organelle forms rapidly after hatching in a process that involves vesicle fusion and nucleation of ferritin nanoparticles. We further report that transcripts involved in endocytosis, extracellular exosomes, and metal ion binding are differentially expressed in cuticulosome positive hair cells. These data suggest that the cuticulosome and the associated molecular machinery regulate the concentration of iron within the labyrinth of the inner ear, which might indirectly tune a magnetic sensor that relies on electromagnetic induction. PMID- 29140245 TI - Bacterial fumarase and L-malic acid are evolutionary ancient components of the DNA damage response. AB - Fumarase is distributed between two compartments of the eukaryotic cell. The enzyme catalyses the reversible conversion of fumaric to L-malic acid in mitochondria as part of the tricarboxylic acid (TCA) cycle, and in the cytosol/nucleus as part of the DNA damage response (DDR). Here, we show that fumarase of the model prokaryote Bacillus subtilis (Fum-bc) is induced upon DNA damage, co-localized with the bacterial DNA and is required for the DDR. Fum-bc can substitute for both eukaryotic functions in yeast. Furthermore, we found that the fumarase-dependent intracellular signaling of the B. subtilis DDR is achieved via production of L-malic acid, which affects the translation of RecN, the first protein recruited to DNA damage sites. This study provides a different evolutionary scenario in which the dual function of the ancient prokaryotic fumarase, led to its subsequent distribution into different cellular compartments in eukaryotes. PMID- 29140246 TI - An Eya1-Notch axis specifies bipotential epibranchial differentiation in mammalian craniofacial morphogenesis. AB - Craniofacial morphogenesis requires proper development of pharyngeal arches and epibranchial placodes. We show that the epibranchial placodes, in addition to giving rise to cranial sensory neurons, generate a novel lineage-related non neuronal cell population for mouse pharyngeal arch development. Eya1 is essential for the development of epibranchial placodes and proximal pharyngeal arches. We identify an Eya1-Notch regulatory axis that specifies both the neuronal and non neuronal commitment of the epibranchial placode, where Notch acts downstream of Eya1 and promotes the non-neuronal cell fate. Notch is regulated by the threonine phosphatase activity of Eya1. Eya1 dephosphorylates p-threonine-2122 of the Notch1 intracellular domain (Notch1 ICD), which increases the stability of Notch1 ICD and maintains Notch signaling activity in the non-neuronal epibranchial placodal cells. Our data unveil a more complex differentiation program in epibranchial placodes and an important role for the Eya1-Notch axis in craniofacial morphogenesis. PMID- 29140247 TI - DDM1 and Lsh remodelers allow methylation of DNA wrapped in nucleosomes. AB - Cytosine methylation regulates essential genome functions across eukaryotes, but the fundamental question of whether nucleosomal or naked DNA is the preferred substrate of plant and animal methyltransferases remains unresolved. Here, we show that genetic inactivation of a single DDM1/Lsh family nucleosome remodeler biases methylation toward inter-nucleosomal linker DNA in Arabidopsis thaliana and mouse. We find that DDM1 enables methylation of DNA bound to the nucleosome, suggesting that nucleosome-free DNA is the preferred substrate of eukaryotic methyltransferases in vivo. Furthermore, we show that simultaneous mutation of DDM1 and linker histone H1 in Arabidopsis reproduces the strong linker-specific methylation patterns of species that diverged from flowering plants and animals over a billion years ago. Our results indicate that in the absence of remodeling, nucleosomes are strong barriers to DNA methyltransferases. Linker-specific methylation can evolve simply by breaking the connection between nucleosome remodeling and DNA methylation. PMID- 29140248 TI - Glutamate is required for depression but not potentiation of long-term presynaptic function. AB - Hebbian plasticity is thought to require glutamate signalling. We show this is not the case for hippocampal presynaptic long-term potentiation (LTPpre), which is expressed as an increase in transmitter release probability (Pr). We find that LTPpre can be induced by pairing pre- and postsynaptic spiking in the absence of glutamate signalling. LTPpre induction involves a non-canonical mechanism of retrograde nitric oxide signalling, which is triggered by Ca2+ influx from L-type voltage-gated Ca2+ channels, not postsynaptic NMDA receptors (NMDARs), and does not require glutamate release. When glutamate release occurs, it decreases Pr by activating presynaptic NMDARs, and promotes presynaptic long-term depression. Net changes in Pr, therefore, depend on two opposing factors: (1) Hebbian activity, which increases Pr, and (2) glutamate release, which decreases Pr. Accordingly, release failures during Hebbian activity promote LTPpre induction. Our findings reveal a novel framework of presynaptic plasticity that radically differs from traditional models of postsynaptic plasticity. PMID- 29140249 TI - Maternal Gdf3 is an obligatory cofactor in Nodal signaling for embryonic axis formation in zebrafish. AB - Zebrafish Gdf3 (Dvr1) is a member of the TGFbeta superfamily of cell signaling ligands that includes Xenopus Vg1 and mammalian Gdf1/3. Surprisingly, engineered homozygous mutants in zebrafish have no apparent phenotype. Elimination of Gdf3 in oocytes of maternal-zygotic mutants results in embryonic lethality that can be fully rescued with gdf3 RNA, demonstrating that Gdf3 is required only early in development, beyond which mutants are viable and fertile. Gdf3 mutants are refractory to Nodal ligands and Nodal repressor Lefty1. Signaling driven by TGFbeta ligand Activin and constitutively active receptors Alk4 and Alk2 remain intact in gdf3 mutants, indicating that Gdf3 functions at the same pathway step as Nodal. Targeting gdf3 and ndr2 RNA to specific lineages indicates that exogenous gdf3 is able to fully rescue mutants only when co-expressed with endogenous Nodal. Together, these findings demonstrate that Gdf3 is an essential cofactor of Nodal signaling during establishment of the embryonic axis. PMID- 29140250 TI - Gdf3 is required for robust Nodal signaling during germ layer formation and left right patterning. AB - Vertebrate embryonic patterning depends on signaling from Nodal, a TGFbeta superfamily member. There are three Nodal orthologs in zebrafish; southpaw directs left-right asymmetries, while squint and cyclops function earlier to pattern mesendoderm. TGFbeta member Vg1 is implicated in mesoderm formation but the role of the zebrafish ortholog, Growth differentiation factor 3 (Gdf3), has not been fully explored. We show that zygotic expression of gdf3 is dispensable for embryonic development, while maternally deposited gdf3 is required for mesendoderm formation and dorsal-ventral patterning. We further show that Gdf3 can affect left-right patterning at multiple stages, including proper development of regional cell morphology in Kupffer's vesicle and the establishment of southpaw expression in the lateral plate mesoderm. Collectively, our data indicate that gdf3 is critical for robust Nodal signaling at multiple stages in zebrafish embryonic development. PMID- 29140252 TI - Generation of genipin cross-linked fibrin-agarose hydrogels tissue-like models for tissue engineering applications. AB - Generation of biomimetic and biocompatible artificial tissues is the basic research objective for tissue engineering (TE). In this sense, the biofabrication of scaffolds that resemble the tissues' extracellular matrix (ECM) is an essential aim in this field. Uncompressed and nanostructured fibrin-agarose hydrogels (FAH and NFAH respectively) emerged as promising scaffold in TE, but its structure and biomechanical properties must be improved in order to broad their TE applications. Here we generated and characterized novel membrane-like models with increased structural and biomechanical properties based on the chemical cross-linking of FAH and NFAH with genipin (GP at 0.1, 0.25, 0.5 and 0.75%). Furthermore, scaffolds were subjected to rheological (G, G', G" modulus), ultrastructural and ex vivo biocompatibility analyses. Results showed that all GP concentrations increased the stiffness (G) and especially the elasticity (G') of FAH and NFAH. Ultrastructural analyses demonstrated that GP and nanostructuration of FAH allowed controlling the porosity of FAH. In addition, biological studies revealed that higher concentration of GP (0.75%) started to compromise the cell function and viability. Finally, this study demonstrated the possibility to generate natural and biocompatible FAH and NFAH with improved structural and biomechanical properties by using 0.1% to 0.5% of GP. However, further in vivo studies are needed in order to demonstrate the biocompatibility, biodegradability and regeneration capability of these cross-linked scaffolds. PMID- 29140253 TI - Electrical resistivity and wave character of free electrons in amorphous and nanoglass Sc75Fe25. AB - The residual electrical resistivity of metallic amorphous alloys, rho0, is typically in the range 50 MUOmega cm < rho0 < 310 MUOmega cm corresponding to a mean free path of conduction electrons of order a few interatomic distances. In crystalline metals with low defect levels such as Cu however, the residual electrical resistivity is about rho0 ~ 1.54 x 10-2 MUOmega cm, leading to extensive progression of free electrons through the crystalline material, of typically up to 4 x 106 nm. The relatively "high" values for the electrical resistivity of distorted Sc75Fe25 alloys are discussed here within the framework of the wave character of electrons. The present investigation of amorphous and nanoglass Sc75Fe25 over the temperature range 1.9 - 320 K, focuses on clarification of the temperature dependence of the resistivity, rho(T). These alloys systems, which show a range of behaviours for temperature dependent resistivity - including temperature independent residual resistivity, as well as positive and negative polarities for the slope drho(T)/dT - are examined in detail. PMID- 29140254 TI - Semiconductor of spinons: from Ising band insulator to orthogonal band insulator. AB - We use the ionic Hubbard model to study the effects of strong correlations on a two-dimensional semiconductor. The spectral gap in the limit where on-site interactions are zero is set by the staggered ionic potential, while in the strong interaction limit it is set by the Hubbard U. Combining mean field solutions of the slave spin and slave rotor methods, we propose two interesting gapped phases in between: (i) the insulating phase before the Mott phase can be viewed as gapping a non-Fermi liquid state of spinons by the staggered ionic potential. The quasi-particles of underlying spinons are orthogonal to physical electrons, giving rise to the 'ARPES-dark' state where the ARPES gap will be larger than the optical and thermal gap. (ii) The Ising insulator corresponding to ordered phase of the Ising variable is characterized by single-particle excitations whose dispersion is controlled by Ising-like temperature and field dependences. The temperature can be conveniently employed to drive a phase transition between these two insulating phases where Ising exponents become measurable by ARPES and cyclotron resonance. The rare earth monochalcogenide semiconductors where the magneto-resistance is anomalously large can be a candidate system for the Ising band insulator. We argue that the Ising and orthogonal insulating phases require strong enough ionic potential to survive the downward renormalization of the ionic potential caused by Hubbard U. PMID- 29140251 TI - Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm. AB - Nodal is considered the key inducer of mesendoderm in vertebrate embryos and embryonic stem cells. Other TGF-beta-related signals, such as Vg1/Dvr1/Gdf3, have also been implicated in this process but their roles have been unclear or controversial. Here we report that zebrafish embryos without maternally provided vg1 fail to form endoderm and head and trunk mesoderm, and closely resemble nodal loss-of-function mutants. Although Nodal is processed and secreted without Vg1, it requires Vg1 for its endogenous activity. Conversely, Vg1 is unprocessed and resides in the endoplasmic reticulum without Nodal, and is only secreted, processed and active in the presence of Nodal. Co-expression of Nodal and Vg1 results in heterodimer formation and mesendoderm induction. Thus, mesendoderm induction relies on the combination of two TGF-beta-related signals: maternal and ubiquitous Vg1, and zygotic and localized Nodal. Modeling reveals that the pool of maternal Vg1 enables rapid signaling at low concentrations of zygotic Nodal. PMID- 29140255 TI - Letter From the Editor. PMID- 29140256 TI - XXX. Robert E. Scully, M.D. PMID- 29140257 TI - Synthesis, Spectroscopic Characterization and Antimicrobial Potential of Certain New Isatin-Indole Molecular Hybrids. AB - Molecular hybridization has a wide application in medicinal chemistry to obtain new biologically active compounds. New isatin-indole molecular hybrids 5a-n have been synthesized and characterized by various spectroscopic tools. The in vitro antimicrobial potential of the prepared compounds 5a-n was assessed using diameter of the inhibition zone (DIZ) and minimum inhibitory concentration (MIC) assays against a panel of Gram-negative bacteria, Gram-positive bacteria and fungi. Most of the synthesized compounds 5a-n showed weak activities against Gram negative bacteria while compounds 5b and 5c exhibited good activities against Gram-positive bacteria. On the other hand, compound 5j emerged as the most active compound towards Candida albicans (C. albicans), with an MIC value of 3.9 ug/mL, and compound 5g as the most active congener towards Asperagillus niger (A. niger), with an MIC value of 15.6 ug/mL. Moreover, compound 5h manifested the best anti-P. notatum effect, with an MIC value of 7.8 ug/mL, making it equipotent with compound 5g. PMID- 29140258 TI - Do Effort and Reward at Work Predict Changes in Cognitive Function? First Longitudinal Results from the Representative German Socio-Economic Panel. AB - It has been suggested that work characteristics, such as mental demands, job control, and occupational complexity, are prospectively related to cognitive function. However, current evidence on links between psychosocial working conditions and cognitive change over time is inconsistent. In this study, we applied the effort-reward imbalance model that allows to build on previous research on mental demands and to introduce reward-based learning as a principle with beneficial effect on cognitive function. We aimed to investigate whether high effort, high reward, and low over-commitment in 2006 were associated with positive changes in cognitive function in terms of perceptual speed and word fluency (2006-2012), and whether the co-manifestation of high effort and high reward would yield the strongest association. To this end, we used data on 1031 employees who participated in a large and representative study. Multivariate linear regression analyses supported our main hypotheses (separate and combined effects of effort and reward), particularly on changes in perceptual speed, whereas the effects of over-commitment did not reach the level of statistical significance. Our findings extend available knowledge by examining the course of cognitive function over time. If corroborated by further evidence, organization based measures in the workplace can enrich efforts towards preventing cognitive decline in ageing workforces. PMID- 29140259 TI - Ramanomics: New Omics Disciplines Using Micro Raman Spectrometry with Biomolecular Component Analysis for Molecular Profiling of Biological Structures. AB - Modern instrumentation for Raman microspectroscopy and current techniques in analysis of spectral data provide new opportunities to study molecular interactions and dynamics at subcellular levels in biological systems. Implementation of biomolecular component analysis (BCA) to microRaman spectrometry provides basis for the emergence of Ramanomics, a new biosensing discipline with unprecedented capabilities to measure concentrations of distinct biomolecular groups in live cells and organelles. Here we review the combined use of microRaman-BCA techniques to probe absolute concentrations of proteins, DNA, RNA and lipids in single organelles of live cells. Assessing biomolecular concentration profiles of organelles at the single cell level provides a physiologically relevant set of biomarkers for cellular heterogeneity. In addition, changes to an organelle's biomolecular concentration profile during a cellular transformation, whether natural, drug induced or disease manifested, can provide molecular insight into the nature of the cellular process. PMID- 29140261 TI - Proximate Composition and Nutritional Value of Three Macroalgae: Ascophyllum nodosum, Fucus vesiculosus and Bifurcaria bifurcata. AB - Proximate composition (moisture, protein, lipid and ash content) and nutritional value (fatty acid, amino acid and mineral profile) of three macroalgae (Ascophyllum nodosum, Fucus vesiculosus and Bifurcaria bifurcate) were studied. Chemical composition was significantly (p < 0.001) different among the three seaweeds. In this regard, the B. bifurcata presented the highest fat content (6.54% of dry matter); whereas, F. vesiculosus showed the highest protein level (12.99% dry matter). Regarding fatty acid content, the polyunsaturated fatty acids (PUFAs) were the most abundant followed by saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). On the other hand, the three seaweeds are a rich source of K (from 3781.35 to 9316.28 mg/100 g), Mn (from 8.28 to 1.96 mg/100 g), Na (from 1836.82 to 4575.71 mg/100 g) and Ca (from 984.73 to 1160.27 mg/100 g). Finally, the most abundant amino acid was glutamic acid (1874.47-1504.53 mg/100 dry matter), followed by aspartic acid (1677.01-800.84 mg/100 g dry matter) and alanine (985.40-655.73 mg/100 g dry matter). PMID- 29140260 TI - Vaccinia Virus Natural Infections in Brazil: The Good, the Bad, and the Ugly. AB - The orthopoxviruses (OPV) comprise several emerging viruses with great importance to human and veterinary medicine, including vaccinia virus (VACV), which causes outbreaks of bovine vaccinia (BV) in South America. Historically, VACV is the most comprehensively studied virus, however, its origin and natural hosts remain unknown. VACV was the primary component of the smallpox vaccine, largely used during the smallpox eradication campaign. After smallpox was declared eradicated, the vaccination that conferred immunity to OPV was discontinued, favoring a new contingent of susceptible individuals to OPV. VACV infections occur naturally after direct contact with infected dairy cattle, in recently vaccinated individuals, or through alternative routes of exposure. In Brazil, VACV outbreaks are frequently reported in rural areas, affecting mainly farm animals and humans. Recent studies have shown the role of wildlife in the VACV transmission chain, exploring the role of wild rodents as reservoirs that facilitate VACV spread throughout rural areas. Furthermore, VACV circulation in urban environments and the significance of this with respect to public health, have also been explored. In this review, we discuss the history, epidemiological, ecological and clinical aspects of natural VACV infections in Brazil, also highlighting alternative routes of VACV transmission, the factors involved in susceptibility to infection, and the natural history of the disease in humans and animals, and the potential for dissemination to urban environments. PMID- 29140262 TI - Influence of Professional Affiliation on Expert's View on Welfare Measures. AB - The present study seeks to investigate the influence of expert affiliation in the weighing procedures within animal welfare assessments. Experts are often gathered with different backgrounds with differing approaches to animal welfare posing a potential pitfall if affiliation groups are not balanced in numbers of experts. At two time points (2012 and 2016), dairy cattle and swine experts from four different stakeholder groups, namely researchers (RES), production advisors (CONS), practicing veterinarians (VET) and animal welfare control officers (AWC) were asked to weigh eight different welfare criteria: Hunger, Thirst, Resting comfort, Ease of movement, Injuries, Disease, Human-animal bond and Emotional state. A total of 54 dairy cattle experts (RES = 15%, CONS = 22%, VET = 35%, AWC = 28%) and 34 swine experts (RES = 24%, CONS = 35%, AWC = 41%) participated. Between-and within-group differences in the prioritization of criteria were assessed. AWC cattle experts differed consistently from the other cattle expert groups but only significantly for the criteria Hunger (p = 0.04), and tendencies towards significance within the criteria Thirst (p = 0.06). No significant differences were found between expert groups among swine experts. Inter-expert differences were more pronounced for both species. The results highlight the challenges of using expert weightings in aggregated welfare assessment models, as the choice of expert affiliation may play a confounding role in the final aggregation due to different prioritization of criteria. PMID- 29140263 TI - Access to Guideline-Recommended Pharmacogenomic Tests for Cancer Treatments: Experience of Providers and Patients. AB - Genomic tests are the fastest growing sector in medicine and medical science, yet there remains a dearth of research on access to pharmacogenomic tests and medications. The objective of this study is to explore providers' and patients' experiences and views on test access as well as strategies used for gaining access. We interviewed clinicians who prescribed medications that should be guided by pharmacogenomic testing and patients who received those prescriptions. We organized the themes into the four dimensions suggested by the World Health Organization framework on access to medications and health technologies. Guideline-recommended pharmacogenomic tests for cancer care are generally available, although the timeliness of return of test results is sometimes suboptimal. Accessibility of pharmacogenomic tests is made challenging by the process of ordering pharmacogenomic tests, which is time-consuming. Affordability is a barrier to some patients as expressed by both providers and patients, who noted that the cost of pharmacogenomic tests and medications is high. Acceptability of the tests is high as both providers and patients view the tests positively. Understanding challenges to accessing pharmacogenomic tests will allow policymakers to develop policies that streamline access to genomics-based technologies to improve population health. PMID- 29140264 TI - What If Healthy Aging Is the 'New Normal'? AB - We dedicate this special issue to our colleague, Dr. Lucinda Bryant (1941 2016).[...]. PMID- 29140266 TI - Forecasting the Water Demand in Chongqing, China Using a Grey Prediction Model and Recommendations for the Sustainable Development of Urban Water Consumption. AB - High accuracy in water demand predictions is an important basis for the rational allocation of city water resources and forms the basis for sustainable urban development. The shortage of water resources in Chongqing, the youngest central municipality in Southwest China, has significantly increased with the population growth and rapid economic development. In this paper, a new grey water forecasting model (GWFM) was built based on the data characteristics of water consumption. The parameter estimation and error checking methods of the GWFM model were investigated. Then, the GWFM model was employed to simulate the water demands of Chongqing from 2009 to 2015 and forecast it in 2016. The simulation and prediction errors of the GWFM model was checked, and the results show the GWFM model exhibits better simulation and prediction precisions than those of the classical Grey Model with one variable and single order equation GM(1,1) for short and the frequently-used Discrete Grey Model with one variable and single order equation, DGM(1,1) for short. Finally, the water demand in Chongqing from 2017 to 2022 was forecasted, and some corresponding control measures and recommendations were provided based on the prediction results to ensure a viable water supply and promote the sustainable development of the Chongqing economy. PMID- 29140265 TI - Anti-Inflammatory Potential of 1-Nitro-2-Phenylethylene. AB - Inflammation is a reaction of the host to infectious or sterile stimuli and has the physiological purpose of restoring tissue homeostasis. However, uncontrolled or unresolved inflammation can lead to tissue damage, giving rise to a plethora of chronic inflammatory diseases, including metabolic syndrome and autoimmunity pathologies with eventual loss of organ function. Beta-nitrostyrene and its derivatives are known to have several biological activities, including anti edema, vasorelaxant, antiplatelet, anti-inflammatory, and anticancer. However, few studies have been carried out regarding the anti-inflammatory effects of this class of compounds. Thereby, the aim of this study was to evaluate the anti inflammatory activity of 1-nitro-2-phenylethene (NPe) using in vitro and in vivo assays. Firstly, the potential anti-inflammatory activity of NPe was evaluated by measuring TNF-alpha produced by human macrophages stimulated with lipopolysaccharide (LPS). NPe at non-toxic doses opposed the inflammatory effects induced by LPS stimulation, namely production of the inflammatory cytokine TNF alpha and activation of NF-kappaB and ERK pathways (evaluated by phosphorylation of inhibitor of kappa B-alpha [IkappaB-alpha] and extracellular signal-regulated kinase 1/2 [ERK1/2], respectively). In a well-established model of acute pleurisy, pretreatment of LPS-challenged mice with NPe reduced neutrophil accumulation in the pleural cavity. This anti-inflammatory effect was associated with reduced activation of NF-kappaB and ERK1/2 pathways in NPe treated mice as compared to untreated animals. Notably, NPe was as effective as dexamethasone in both, reducing neutrophil accumulation and inhibiting ERK1/2 and IkappaB-alpha phosphorylation. Taken together, the results suggest a potential anti inflammatory activity for NPe via inhibition of ERK1/2 and NF-kappaB pathways on leukocytes. PMID- 29140267 TI - Detection of Partial Discharge Sources Using UHF Sensors and Blind Signal Separation. AB - The measurement of the emitted electromagnetic energy in the UHF region of the spectrum allows the detection of partial discharges and, thus, the on-line monitoring of the condition of the insulation of electrical equipment. Unfortunately, determining the affected asset is difficult when there are several simultaneous insulation defects. This paper proposes the use of an independent component analysis (ICA) algorithm to separate the signals coming from different partial discharge (PD) sources. The performance of the algorithm has been tested using UHF signals generated by test objects. The results are validated by two automatic classification techniques: support vector machines and similarity with class mean. Both methods corroborate the suitability of the algorithm to separate the signals emitted by each PD source even when they are generated by the same type of insulation defect. PMID- 29140268 TI - Electrochemical and Infrared Absorption Spectroscopy Detection of SF6 Decomposition Products. AB - Sulfur hexafluoride (SF6) gas-insulated electrical equipment is widely used in high-voltage (HV) and extra-high-voltage (EHV) power systems. Partial discharge (PD) and local heating can occur in the electrical equipment because of insulation faults, which results in SF6 decomposition and ultimately generates several types of decomposition products. These SF6 decomposition products can be qualitatively and quantitatively detected with relevant detection methods, and such detection contributes to diagnosing the internal faults and evaluating the security risks of the equipment. At present, multiple detection methods exist for analyzing the SF6 decomposition products, and electrochemical sensing (ES) and infrared (IR) spectroscopy are well suited for application in online detection. In this study, the combination of ES with IR spectroscopy is used to detect SF6 gas decomposition. First, the characteristics of these two detection methods are studied, and the data analysis matrix is established. Then, a qualitative and quantitative analysis ES-IR model is established by adopting a two-step approach. A SF6 decomposition detector is designed and manufactured by combining an electrochemical sensor and IR spectroscopy technology. The detector is used to detect SF6 gas decomposition and is verified to reliably and accurately detect the gas components and concentrations. PMID- 29140269 TI - The Prevalence of Dietary Supplement Use among College Students: A Nationwide Survey in Japan. AB - To clarify the prevalence of dietary supplement use among college students, we conducted Internet-based nationwide questionnaire surveys with 157,595 Japanese college students aged between 18 to 24 years old who were registrants of Macromill Inc. (Tokyo, Japan). Among the 9066 respondents (response rate 5.8%), 16.8% were currently using dietary supplements. The prevalence of dietary supplement use did not differ significantly between males (17.1%) and females (16.7%). However, it increased according to their grade (13.1% to 20.5%), and it was higher in medical and pharmaceutical college students (22.0%) compared to others (16.7%). The main purpose of dietary supplement use was for the health benefits in both males and females. Other reasons were to build muscle in males, and as a beauty supplement and for weight loss in females. According to the purpose of dietary supplement use, the most commonly-used dietary supplements were vitamin/mineral supplements in both males and females, then protein and weight loss supplements in males and females, respectively. Although most students obtained information about dietary supplements via the Internet, they typically purchased the supplements from drug stores. Of the students surveyed, 7.5% who were currently using or used to use dietary supplements experienced adverse effects, with no significant difference between genders (8.8% in male, 7.0% in female). In conclusion, the prevalence of dietary supplement use increased with grade among college students in Japan. Some of them experienced adverse effects. Education may be important to prevent adverse effects resulting from supplement use in college. PMID- 29140270 TI - The Oxepane Motif in Marine Drugs. AB - Oceans have shown to be a remarkable source of natural products. The biological properties of many of these compounds have helped to produce great advances in medicinal chemistry. Within them, marine natural products containing an oxepanyl ring are present in a great variety of algae, sponges, fungus and corals and show very important biological activities, many of them possessing remarkable cytotoxic properties against a wide range of cancer cell lines. Their rich chemical structures have attracted the attention of many researchers who have reported interesting synthetic approaches to these targets. This review covers the most prominent examples of these types of compounds, focusing the discussion on the isolation, structure determination, medicinal properties and total synthesis of these products. PMID- 29140272 TI - An Investigation of Polyoxometalate Hybrid Materials as Patternable Dielectrics and Lithographic Resists. AB - Polyoxometalate (POM) hybrid materials have shown potential as spin-coatable, patternable dielectric thin-films and components for lithographic resists. In particular, the octamolybdate cluster has been shown to possess good spin-coating properties and the patterning capabilities of hybrid octamolybdate thin-films were explored using a combination of broadband UV and electron beam lithography (EBL) techiniques. Dielectric properties of these films were determined by ellipsometry, and octamolybdate clusters were subsequently investigated as negative resists in various blends for potential uses in next-generation photolithography, where contrast, sensitivity, and line edge roughness characteristics were determined. Preliminary evidence for the suppression of the diffusion of photo-generated acids is presented. PMID- 29140273 TI - Larix decidua Bark as a Source of Phytoconstituents: An LC-MS Study. AB - Larix decidua bark is a waste of the timber industry and is widely diffused in Northern Italy. This material can be considered a good source of antioxidants and phytoconstituents with possible use in cosmetic or nutraceutical products. In this study, simple extraction of larch bark was performed using mixtures of ethanol/water. Furthermore, the phytochemical composition of larch bark extract was studied using LC-MSn methods and the main constituents were identified as flavonoids, spiro-polyphenols, and procyanidins. To confirm the identification by LC-MS semi-preparative HPLC was performed in order to isolate the main constituents and verify the structures by 1H-NMR. Antioxidant properties were studied using an in vitro approach combining DPPH assay and LC-MS in order to establish different roles of the various classes of phytochemicasl of the extract. DPPH activity of some of the isolated compounds was also assessed. The overall results indicate this waste material as a good source of antioxidant compounds, mainly procyanidins, whichresulted the most active constituents in the DPPH assay. PMID- 29140271 TI - Molecular-Targeted Therapies for Epidermal Growth Factor Receptor and Its Resistance Mechanisms. AB - Cancer therapies targeting epidermal growth factor receptor (EGFR), such as small molecule kinase inhibitors and monoclonal antibodies, have been developed as standard therapies for several cancers, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, breast cancer, and squamous cell carcinoma of the head and neck. Although these therapies can significantly prolong progression-free survival, curative effects are not often achieved because of intrinsic and/or acquired resistance. The resistance mechanisms to EGFR-targeted therapies can be categorized as resistant gene mutations, activation of alternative pathways, phenotypic transformation, and resistance to apoptotic cell death. Analysis of the processes that modulate EGFR signal transduction by EGFR targeted inhibitors, such as tyrosine kinase inhibitors and monoclonal antibodies, has revealed new therapeutic opportunities and has elucidated novel mechanisms contributing to the discovery of more effective anticancer treatments. In this review, we discuss the roles of EGFR in cancer development, therapeutic strategies for targeting EGFR, and resistance mechanisms to EGFR-targeted therapies, with a focus on cancer therapies for individual patients. PMID- 29140274 TI - An Efficient Approach for Lipase-Catalyzed Synthesis of Retinyl Laurate Nutraceutical by Combining Ultrasound Assistance and Artificial Neural Network Optimization. AB - Although retinol is an important nutrient, retinol is highly sensitive to oxidation. At present, some ester forms of retinol are generally used in nutritional supplements because of its stability and bioavailability. However, such esters are commonly synthesized by chemical procedures which are harmful to the environment. Thus, this study utilized a green method using lipase as a catalyst with sonication assistance to produce a retinol derivative named retinyl laurate. Moreover, the process was optimized by an artificial neural network (ANN). First, a three-level-four-factor central composite design (CCD) was employed to design 27 experiments, which the highest relative conversion was 82.64%. Further, the optimal architecture of the CCD-employing ANN was developed, including the learning Levenberg-Marquardt algorithm, the transfer function (hyperbolic tangent), iterations (10,000), and the nodes of the hidden layer (6). The best performance of the ANN was evaluated by the root mean squared error (RMSE) and the coefficient of determination (R2) from predicting and observed data, which displayed a good data-fitting property. Finally, the process performed with optimal parameters actually obtained a relative conversion of 88.31% without long-term reactions, and the lipase showed great reusability for biosynthesis. Thus, this study utilizes green technology to efficiently produce retinyl laurate, and the bioprocess is well established by ANN-mediated modeling and optimization. PMID- 29140275 TI - Old Fashioned vs. Ultra-Processed-Based Current Diets: Possible Implication in the Increased Susceptibility to Type 1 Diabetes and Celiac Disease in Childhood. AB - Ultra-processed foods are ready-to-heat and ready-to-eat products created to replace traditional homemade meals and dishes due to convenience and accessibility. Because of their low-fiber and high-fat and sugar composition, these foodstuffs could induce a negative impact on health. They are partially responsible for obesity and chronic non-transmissible diseases; additionally, they could impact in the prevalence of autoimmune diseases such as type 1 diabetes and celiac disease. The rationale is that the nutritional composition of ultra-processed foodstuffs can induce gut dysbiosis, promoting a pro-inflammatory response and consequently, a "leaky gut". These factors have been associated with increased risk of autoimmunity in genetically predisposed children. In addition, food emulsifiers, commonly used in ultra-processed products could modify the gut microbiota and intestinal permeability, which could increase the risk of autoimmunity. In contrast, unprocessed and minimally processed food-based diets have shown the capacity to promote gut microbiota eubiosis, anti-inflammatory response, and epithelial integrity, through bacterial butyrate production. Thus, to decrease the susceptibility to autoimmunity, genetically predisposed children should avoid ultra-processed food products and encourage the consumption of fresh and minimally processed foods. PMID- 29140276 TI - Clinical Profile Associated with Adverse Childhood Experiences: The Advent of Nervous System Dysregulation. AB - BACKGROUND: We report the prevalence of children with multiple medical symptoms in a pediatric neurology clinic, describe their symptom profiles, and explore their association with adverse childhood experiences (ACEs). METHODS: We retrospectively reviewed 100 consecutive patients from an outpatient pediatric neurology clinic. Patients were included if they were >=5 years old and reported >=4 symptoms that were unexplained for >=3-months. Symptom profiles across six functional domains were recorded: (1) executive dysfunction, (2) sleep disturbances, (3) autonomic dysregulation, (4) somatization, (5) digestive symptoms, and (6) emotional dysregulation. ACEs were scored for all patients. RESULTS: Seventeen patients reported >=4 medical symptoms. Somatization, sleep disturbances, and emotional dysregulation occurred in 100% patients, with executive dysfunction (94%), autonomic dysregulation (76%), and digestive problems (71%) in the majority. Forty-two children reported >=1 ACE, but children with >=4 symptoms were more likely to report ACEs compared to other children (88% vs. 33%; p < 0.0001) and had a higher median total ACE score (3 vs. 1; p < 0.001). CONCLUSIONS: Children with multiple medical symptoms should be screened for potential exposure to ACEs. A clinical profile of symptoms across multiple functional domains suggests putative neurobiological mechanisms involving stress and nervous system dysregulation that require further study. PMID- 29140277 TI - Enantioselective Biosynthesis of l-Phenyllactic Acid by Whole Cells of Recombinant Escherichia coli. AB - BACKGROUND: l-Phenyllactic acid (l-PLA)-a valuable building block in the pharmaceutical and chemical industry-has recently emerged as an important monomer in the composition of the novel degradable biocompatible material of polyphenyllactic acid. However, both normally chemically synthesized and naturally occurring phenyllactic acid are racemic, and the product yields of reported l-PLA synthesis processes remain unsatisfactory. METHODS: We developed a novel recombinant Escherichia coli strain, co-expressing l-lactate dehydrogenase (l-LDH) from Lactobacillus plantarum subsp. plantarum and glucose dehydrogenase (GDH) from Bacillus megaterium, to construct a recombinant oxidation/reduction cycle for whole-cell biotransformation of phenylpyruvic acid (PPA) into chiral l PLA in an enantioselective and continuous manner. RESULTS: During fed-batch bioconversion with intermittent PPA feeding, l-PLA yield reached 103.8 mM, with an excellent enantiomeric excess of 99.7%. The productivity of l-PLA was as high as 5.2 mM.h-1 per OD600 (optical density at 600 nm) of whole cells. These results demonstrate the efficient production of l-PLA by the one-pot biotransformation system. Therefore, this stereoselective biocatalytic process might be a promising alternative for l-PLA production. PMID- 29140278 TI - Development of Gallic Acid-Modified Hydrogels Using Interpenetrating Chitosan Network and Evaluation of Their Antioxidant Activity. AB - In this work, antioxidant hydrogels were prepared by the construction of an interpenetrating chitosan network and functionalization with gallic acid. The poly(2-hydroxyethyl methacrylate) p(HEMA)-based hydrogels were first synthesized and subsequently surface-modified with an interpenetrating polymer network (IPN) structure prepared with methacrylamide chitosan via free radical polymerization. The resulting chitosan-IPN hydrogels were surface-functionalized with gallic acid through an amide coupling reaction, which afforded the antioxidant hydrogels. Notably, gallic-acid-modified hydrogels based on a longer chitosan backbone exhibited superior antioxidant activity than their counterpart with a shorter chitosan moiety; this correlated to the amount of gallic acid attached to the chitosan backbone. Moreover, the surface contact angles of the chitosan-modified hydrogels decreased, indicating that surface functionalization of the hydrogels with chitosan-IPN increased the wettability because of the presence of the hydrophilic chitosan network chain. Our study indicates that chitosan-IPN hydrogels may facilitate the development of applications in biomedical devices and ophthalmic materials. PMID- 29140279 TI - Free-Standing and Self-Crosslinkable Hybrid Films by Core-Shell Particle Design and Processing. AB - The utilization and preparation of functional hybrid films for optical sensing applications and membranes is of utmost importance. In this work, we report the convenient and scalable preparation of self-crosslinking particle-based films derived by directed self-assembly of alkoxysilane-based cross-linkers as part of a core-shell particle architecture. The synthesis of well-designed monodisperse core-shell particles by emulsion polymerization is the basic prerequisite for subsequent particle processing via the melt-shear organization technique. In more detail, the core particles consist of polystyrene (PS) or poly(methyl methacrylate) (PMMA), while the comparably soft particle shell consists of poly(ethyl acrylate) (PEA) and different alkoxysilane-based poly(methacrylate)s. For hybrid film formation and convenient self-cross-linking, different alkyl groups at the siloxane moieties were investigated in detail by solid-state Magic Angle Spinning Nuclear Magnetic Resonance (MAS, NMR) spectroscopy revealing different crosslinking capabilities, which strongly influence the properties of the core or shell particle films with respect to transparency and iridescent reflection colors. Furthermore, solid-state NMR spectroscopy and investigation of the thermal properties by differential scanning calorimetry (DSC) measurements allow for insights into the cross-linking capabilities prior to and after synthesis, as well as after the thermally and pressure-induced processing steps. Subsequently, free-standing and self-crosslinked particle-based films featuring excellent particle order are obtained by application of the melt-shear organization technique, as shown by microscopy (TEM, SEM). PMID- 29140281 TI - Non-Contact Sensor for Long-Term Continuous Vital Signs Monitoring: A Review on Intelligent Phased-Array Doppler Sensor Design. AB - It has been the dream of many scientists and engineers to realize a non-contact remote sensing system that can perform continuous, accurate and long-term monitoring of human vital signs as we have seen in many Sci-Fi movies. Having an intelligible sensor system that can measure and record key vital signs (such as heart rates and respiration rates) remotely and continuously without touching the patients, for example, can be an invaluable tool for physicians who need to make rapid life-and-death decisions. Such a sensor system can also effectively help physicians and patients making better informed decisions when patients' long-term vital signs data is available. Therefore, there has been a lot of research activities on developing a non-contact sensor system that can monitor a patient's vital signs and quickly transmit the information to healthcare professionals. Doppler-based radio-frequency (RF) non-contact vital signs (NCVS) monitoring system are particularly attractive for long term vital signs monitoring because there are no wires, electrodes, wearable devices, nor any contact-based sensors involved so the subjects may not be even aware of the ubiquitous monitoring. In this paper, we will provide a brief review on some latest development on NCVS sensors and compare them against a few novel and intelligent phased-array Doppler based RF NCVS biosensors we have built in our labs. Some of our NCVS sensor tests were performed within a clutter-free anechoic chamber to mitigate the environmental clutters, while most tests were conducted within the typical Herman Miller type office cubicle setting to mimic a more practical monitoring environment. Additionally, we will show the measurement data to demonstrate the feasibility of long-term NCVS monitoring. The measured data strongly suggests that our latest phased array NCVS system should be able to perform long-term vital signs monitoring intelligently and robustly, especially for situations where the subject is sleeping without hectic movements nearby. PMID- 29140280 TI - TRPV3 Channel in Keratinocytes in Scars with Post-Burn Pruritus. AB - Post-burn pruritus is a common and distressing sequela of burn scars. Empirical antipruritic treatments usually fail to have a satisfactory outcome because of their limited selectivity and possible side effects. Therefore, novel drug targets need to be identified. Here, we aimed to investigate the possible role of protease-activated receptor 2 (PAR2) and transient receptor potential vanniloid 3 (TRPV3), along with the relation of TRPV3 to thymic stromal lymphopoietin (TSLP). Specimens from normal (unscarred) or burn-scarred (with or without pruritus) tissue were obtained from burn patients for this study. In each sample, the keratinocytes were isolated and cultured, and the intracellular Ca2+ level at the time of stimulation of each factor was quantified and the interaction was screened. PAR2 function was reduced by antagonism of TRPV3. Inhibiting protein kinase A (PKA) and protein kinase C (PKC) reduced TRPV3 function. TSLP mRNA and protein, and TSLPR protein expressions, increased in scars with post-burn pruritus, compared to scars without it or to normal tissues. In addition, TRPV1 or TRPV3 activation induced increased TSLP expression. Conclusively, TRPV3 may contribute to pruritus in burn scars through TSLP, and can be considered a potential therapeutic target for post-burn pruritus. PMID- 29140282 TI - Magnetic Material Assessment of a Novel Ultra-High Step-Up Converter with Single Semiconductor Switch and Galvanic Isolation for Fuel-Cell Power System. AB - In this paper, a novel step-up converter is proposed, which has the particular features of single semiconductor switch, ultra-high conversion ratio, galvanic isolation, and easy control. Therefore, the proposed converter is suitable for the applications of fuel-cell power system. Coupled inductors and switched capacitors are incorporated in the converter to obtain an ultra-high voltage ratio that is much higher than that of a conventional high step-up converter. Even if the turns ratio of coupled inductor and duty ratio are only to be 1 and 0.5, respectively, the converter can readily achieve a voltage gain of up to 18. Owing to this outstanding performance, it can also be applied to any other low voltage source for voltage boosting. In the power stage, only one active switch is used to handle the converter operation. In addition, the leakage energy of the two couple inductors can be totally recycled without any snubber, which simplifies the control mechanism and improves the conversion efficiency. Magnetic material dominates the conversion performance of the converter. Different types of iron cores are discussed for the possibility to serve as a coupled inductor. A 200 W prototype with 400 V output voltage is built to validate the proposed converter. In measurement, it indicates that the highest efficiency can be up to 94%. PMID- 29140283 TI - Templated Sphere Phase Liquid Crystals for Tunable Random Lasing. AB - A sphere phase liquid crystal (SPLC) composed of three-dimensional twist structures with disclinations among them exists between isotropic phase and blue phase in a very narrow temperature range, about several degrees centigrade. A low concentration polymer template is applied to improve the thermal stability of SPLCs and broadens the temperature range to more than 448 K. By template processing, a wavelength tunable random lasing is demonstrated with dye doped SPLC. With different polymer concentrations, the reconstructed SPLC random lasing may achieve more than 40 nm wavelength continuous shifting by electric field modulation. PMID- 29140284 TI - Crack Propagation Calculations for Optical Fibers under Static Bending and Tensile Loads Using Continuum Damage Mechanics. AB - Static fatigue behavior is the main failure mode of optical fibers applied in sensors. In this paper, a computational framework based on continuum damage mechanics (CDM) is presented to calculate the crack propagation process and failure time of optical fibers subjected to static bending and tensile loads. For this purpose, the static fatigue crack propagation in the glass core of the optical fiber is studied. Combining a finite element method (FEM), we use the continuum damage mechanics for the glass core to calculate the crack propagation path and corresponding failure time. In addition, three factors including bending radius, tensile force and optical fiber diameter are investigated to find their impacts on the crack propagation process and failure time of the optical fiber under concerned situations. Finally, experiments are conducted and the results verify the correctness of the simulation calculation. It is believed that the proposed method could give a straightforward description of the crack propagation path in the inner glass core. Additionally, the predicted crack propagation time of the optical fiber with different factors can provide effective suggestions for improving the long-term usage of optical fibers. PMID- 29140286 TI - Evidence to Use Botulinum Toxin Injections in Tension-Type Headache Management: A Systematic Review. AB - Tension-type headache (TTH) is the most common type of chronic recurring head pain. It can occur twice as often in women as in men. It is the most common type of headache. Its lifetime prevalence is 30% to 78% in the general population. TTH treatment should be multilevel. It often consists of taking pain medication, muscle relaxants, antidepressants, using biofeedback therapy, acupuncture, and attending behavioral therapy. Several clinical trials also suggest that botulinum toxin (BTX) may be an effective treatment option for such patients. The aim of this study was to evaluate if BTX can be used as a treatment method in TTH in the light of current medical literature. The authors searched the PubMed, EBSCOhost, OVID, Web of Knowledge, Cochrane Library and CINAHL databases to identify relevant publications. The authors finally included 11 papers-prospective and retrospective cohort studies. Among most of the selected studies, there was a significant correlation between using BTX and reduction of TTH pain intensity and severity. By analyzing qualified studies, it can be concluded that botulinum toxin seems to be effective in TTH management. PMID- 29140285 TI - Chitosan/Cyclodextrin/TPP Nanoparticles Loaded with Quercetin as Novel Bacterial Quorum Sensing Inhibitors. AB - The widespread emergence of antibiotic-resistant bacteria has highlighted the urgent need of alternative therapeutic approaches for human and animal health. Targeting virulence factors that are controlled by bacterial quorum sensing (QS), seems a promising approach. The aims of this study were to generate novel nanoparticles (NPs) composed of chitosan (CS), sulfo-butyl-ether-beta cyclodextrin (Captisol(r)) and/or pentasodium tripolyphosphate using ionotropic gelation technique, and to evaluate their potential capacity to arrest QS in bacteria. The resulting NPs were in the size range of 250-400 nm with CS70/5 and 330-600 nm with CS70/20, had low polydispersity index (<0.25) and highly positive zeta potential ranging from zeta ~+31 to +40 mV. Quercetin, a hydrophobic model flavonoid, could be incorporated proportionally with increasing amounts of Captisol(r) in the NPs formualtion, without altering significantly its physicochemical properties. Elemental analysis and FTIR studies revealed that Captisol(r) and quercetin were effectively integrated into the NPs. These NPs were stable in M9 bacterial medium for 7 h at 37 degrees C. Further, NPs containing Captisol(r) seem to prolong the release of associated drug. Bioassays against an E. coli Top 10 QS biosensor revealed that CS70/5 NPs could inhibit QS up to 61.12%, while CS70/20 NPs exhibited high antibacterial effects up to 88.32%. These results suggested that the interaction between NPs and the bacterial membrane could enhance either anti-QS or anti-bacterial activities. PMID- 29140287 TI - Interaction between Diethyldithiocarbamate and Cu(II) on Gold in Non-Cyanide Wastewater. AB - A surface-enhanced Raman scattering (SERS) detection method for environmental copper ions (Cu2+) was developed according to the vibrational spectral change of diethyldithiocarbamate (DDTC) on gold nanoparticles (AuNPs). The ultraviolet visible (UV-Vis) absorption spectra indicated that DDTC formed a complex with Cu2+, showing a prominent peak at ~450 nm. We found Raman spectral changes in DDTC from ~1490 cm-1 to ~1504 cm-1 on AuNPs at a high concentration of Cu2+ above 1 MUM. The other ions of Zn2+, Pb2+, Ni2+, NH4+, Mn2+, Mg2+, K+, Hg2+, Fe2+, Fe3+, Cr3+, Co2+, Cd2+, and Ca2+ did not produce such spectral changes, even after they reacted with DDTC. The electroplating industrial wastewater samples were tested under the interference of highly concentrated ions of Fe3+, Ni2+, and Zn2+. The Raman spectroscopy-based quantification of Cu2+ ions was able to be achieved for the wastewater after treatment with alkaline chlorination, whereas the cyanide-containing water did not show any spectral changes, due to the complexation of the cyanide with the Cu2+ ions. A micromolar range detection limit of Cu2+ ions could be achieved by analyzing the Raman spectra of DDTC in the cyanide-removed water. PMID- 29140288 TI - Capillary Electrophoresis Hyphenated with Mass Spectrometry for Determination of Inflammatory Bowel Disease Drugs in Clinical Urine Samples. AB - Azathioprine is the main thiopurine drug used in the treatment of immune-based inflammations of gastrointestinal tract. For the purpose of therapy control and optimization, effective and reliable analytical methods for a rapid drug monitoring in biological fluids are essential. Here, we developed a separation method based on the capillary electrophoresis (CE) hyphenated with tandem mass spectrometry (MS/MS) for the simultaneous determination of azathioprine and its selected metabolites (6-thioguanine, 6-mercaptopurine, and 6 methylmercaptopurine) as well as other co-medicated drugs (mesalazine, prednisone, and allopurinol). The optimized CE-MS/MS conditions provided a very efficient and stable system for the separation and sensitive detection of these drugs in human urine matrices. The developed method was successfully applied for the assay of the targeted drugs and their selected metabolites in urine samples collected from patients suffering from inflammatory bowel disease (IBD) and receiving azathioprine therapy. The developed CE-MS/MS method, due to its reliability, short analysis time, production of complex clinical profiles, and favorable performance parameters, evaluated according to FDA guidelines for bioanalytical method validation, is proposed for routine clinical laboratories to optimize thiopurine therapy, estimate enzymatic activity, and control patient compliance with medication and co-medication. PMID- 29140291 TI - I-DWRL: Improved Dual Wireless Radio Localization Using Magnetometer. AB - In the dual wireless radio localization (DWRL) technique each sensor node is equipped with two ultra-wide band (UWB) radios; the distance between the two radios is a few tens of centimeters. For localization, the DWRL technique must use at least two pre-localized nodes to fully localize an unlocalized node. Moreover, in the DWRL technique it is also not possible for two sensor nodes to properly communicate location information unless each of the four UWB radios of two communicating sensor nodes cannot approach the remaining three radios. In this paper, we propose an improved DWRL (I-DWRL) algorithm along with mounting a magnetometer sensor on one of the UWB radios of all sensor nodes. This addition of a magnetometer helps to improve DWRL algorithm such that only one localized sensor node is required for the localization of an unlocalized sensor node, and localization can also be achieved even when some of the four radios of two nodes are unable to communicate with the remaining three radios. The results show that with the use of a magnetometer a greater number of nodes can be localized with a smaller transmission range, less energy and a shorter period of time. In comparison with the conventional DWRL algorithm, our I-DWRL not only maintains the localization error but also requires around half of semi-localizations, 60% of the time, 70% of the energy and a shorter communication range to fully localize an entire network. Moreover, I-DWRL can even localize more nodes while transmission range is not sufficient for DWRL algorithm. PMID- 29140289 TI - Cats and Carbohydrates: The Carnivore Fantasy? AB - The domestic cat's wild ancestors are obligate carnivores that consume prey containing only minimal amounts of carbohydrates. Evolutionary events adapted the cat's metabolism and physiology to this diet strictly composed of animal tissues and led to unique digestive and metabolic peculiarities of carbohydrate metabolism. The domestic cat still closely resembles its wild ancestor. Although the carnivore connection of domestic cats is well recognised, little is known about the precise nutrient profile to which the digestive physiology and metabolism of the cat have adapted throughout evolution. Moreover, studies show that domestic cats balance macronutrient intake by selecting low-carbohydrate foods. The fact that cats evolved consuming low-carbohydrate prey has led to speculations that high-carbohydrate diets could be detrimental for a cat's health. More specifically, it has been suggested that excess carbohydrates could lead to feline obesity and diabetes mellitus. Additionally, the chances for remission of diabetes mellitus are higher in cats that consume a low-carbohydrate diet. This literature review will summarise current carbohydrate knowledge pertaining to digestion, absorption and metabolism of carbohydrates, food selection and macronutrient balancing in healthy, obese and diabetic cats, as well as the role of carbohydrates in prevention and treatment of obesity and diabetes mellitus. PMID- 29140290 TI - Ameliorative Effects of Grape Seed Proanthocyanidin Extract on Growth Performance, Immune Function, Antioxidant Capacity, Biochemical Constituents, Liver Histopathology and Aflatoxin Residues in Broilers Exposed to Aflatoxin B1. AB - Aflatoxicosis is a grave threat to the poultry industry. Dietary supplementation with antioxidants showed a great potential in enhancing the immune system; hence, protecting animals against aflatoxin B1-induced toxicity. Grape seed proanthocyanidin extract (GSPE) one of the most well-known and powerful antioxidants. Therefore, the purpose of this research was to investigate the effectiveness of GSPE in the detoxification of AFB1 in broilers. A total of 300 one-day-old Cobb chicks were randomly allocated into five treatments of six replicates (10 birds per replicate), fed ad libitum for four weeks with the following dietary treatments: 1. Basal diet (control); 2. Basal diet + 1 mg/kg AFB1 contaminated corn (AFB1); 3. Basal diet + GSPE 250 mg/kg; (GSPE 250 mg/kg) 4. Basal diet + AFB1 (1 mg/kg) + GSPE 250 mg/kg; (AFB1 + GSPE 250 mg/kg) 5. Basal diet + AFB1 (1mg/kg) + GSPE 500 mg/kg, (AFB1 + GSPE 500 mg/kg). When compared with the control group, feeding broilers with AFB1 alone significantly reduced growth performance, serum immunoglobulin contents, negatively altered serum biochemical contents, and enzyme activities, and induced histopathological lesion in the liver. In addition, AFB1 significantly increased malondialdehyde content and decreased total superoxide dismutase, catalase, glutathione peroxide, glutathione-S transferase, glutathione reductase activities, and glutathione concentration within the liver and serum. The supplementation of GSPE (250 and 500 mg/kg) to AFB1 contaminated diet reduced AFB1 residue in the liver and significantly mitigated AFB1 negative effects. From these results, it can be concluded that dietary supplementation of GSPE has protective effects against aflatoxicosis caused by AFB1 in broiler chickens. PMID- 29140292 TI - Anisotropic Failure Strength of Shale with Increasing Confinement: Behaviors, Factors and Mechanism. AB - Some studies reported that the anisotropic failure strength of shale will be weakened by increasing confinement. In this paper, it is found that there are various types of anisotropic strength behaviors. Four types of anisotropic strength ratio ( S A 1 ) behaviors and three types of anisotropic strength difference ( S A 2 ) behaviors have been classified based on laboratory experiments on nine groups of different shale samples. The cohesion c w and friction angle phi w of the weak planes are proven to be two dominant factors according to a series of bonded-particle discrete element modelling analyses. It is observed that shale is more prone to a slight increase of S A 1 and significant increase of S A 2 with increasing confinement for higher cohesion c w and lower to medium friction angle phi w . This study also investigated the mechanism of the anisotropic strength behaviors with increasing confinement. Owing to different contributions of c w and phi w under different confinements, different combinations of c w and phi w may have various types of influences on the minimum failure strength with the increasing confinement; therefore, different types of anisotropic behaviors occur for different shale specimens as the confinement increases. These findings are very important to understand the stability of wellbore and underground tunneling in the shale rock mass, and should be helpful for further studies on hydraulic fracture propagations in the shale reservoir. PMID- 29140294 TI - A Human Body Pressure Distribution Imaging System Based on Wavelet Analysis and Resistance Tomography. AB - In this paper, a pressure distribution sensing system based on wavelet analysis and resistance tomography is proposed to overcome the shortcomings of a traditional electrode type pressure distribution sensor, which needs to be arranged with many electrodes and has a high production cost. The system uses ADS1256, a constant current source module, a serial communication module, a Raspberry host, a touch screen, and other components. The wavelet transform is used to preprocess the collected signal to improve the anti-jamming performance of the system. The method of resistance tomography is used to realize the real time imaging of pressure distribution. Finally, the reliability of the system is verified using conductive silica gel as a sensitive material. The experimental results show that wavelet analysis preprocessing can significantly improve the quality of pressure distribution imaging. PMID- 29140293 TI - The Trends in Cardiovascular Diseases and Respiratory Diseases Mortality in Urban and Rural China, 1990-2015. AB - With the rapid development of the economy over the past 20 years, the mortality rates from cardiovascular diseases (CVDs) and respiratory diseases (RDs) have changed in China. This study aimed to analyze the trends of mortality rates and years of life lost (YLLs) from CVDs and RDs in the rural and urban population from 1990 to 2015. Using data from Chinese yearbooks, joinpoint regression analysis was employed to estimate the annual percent change (APC) of mortality rates from CVDs and RDs. YLLs due to CVDs and RDs were calculated by a standard method, adopting recommended standard life expectancy at birth values of 80 years for men and 82.5 years for women. Age-standardized mortality rates and YLL rates were calculated by using the direct method based on the Chinese population from the sixth population census of 2010. Age-standardized mortality rates from CVDs for urban residents and from RDs for both urban and rural residents showed decreasing trends in China from 1990 to 2015. Age-standardized mortality rates from CVDs among rural residents remained constant during above period and outstripped those among urban residents gradually. The age-standardized YLL rates of CVDs for urban and rural residents decreased 35.2% and 8.3% respectively. Additionally, the age-standardized YLL rates of RDs for urban and rural residents decreased 64.2% and 79.0% respectively. The age-standardized mortality and YLL rates from CVDs and RDs gradually decreased in China from 1990 to 2015. We observed more substantial declines of the mortality rates from CVDs in urban areas and from RDs in rural areas. PMID- 29140295 TI - Quantification of Cardiovascular Disease Biomarkers in Human Platelets by Targeted Mass Spectrometry. AB - Platelets are known to be key players in thrombosis and hemostasis, contributing to the genesis and progression of cardiovascular diseases. Due to their pivotal role in human physiology and pathology, platelet function is regulated tightly by numerous factors which have either stimulatory or inhibitory effects. A variety of factors, e.g., collagen, fibrinogen, ADP, vWF, thrombin, and thromboxane promote platelet adhesion and aggregation by utilizing multiple intracellular signal cascades. To quantify platelet proteins for this work, a targeted proteomics workflow was applied. In detail, platelets are isolated and lyzed, followed by a tryptic protein digest. Subsequently, a mix of stable isotope labeled peptides of interesting biomarker proteins in concentrations ranging from 0.1 to 100 fmol is added to 3 MUg digest. These peptides are used as an internal calibration curve to accurately quantify endogenous peptides and corresponding proteins in a pooled platelet reference sample by nanoLC-MS/MS with parallel reaction monitoring. In order to assure a valid quantification, limit of detection (LOD) and limit of quantification (LOQ), as well as linear range, were determined. This quantification of platelet activation and proteins by targeted mass spectrometry may enable novel diagnostic strategies in the detection and prevention of cardiovascular diseases. PMID- 29140296 TI - Microstructure, Mechanical and Tribological Properties of Oxide Dispersion Strengthened High-Entropy Alloys. AB - A novel metal matrix composite CrMnFeCoNi with Y2O3 as reinforcement phase was designed and manufactured by mechanical alloying and spark plasma sintering. After sintering at 900 degrees C for 5 min, the microstructure consisted of a FCC matrix and Y2O3 nanoparticles. The addition of 0.25 wt % Y2O3 increased the room temperature tensile strength of the CrMnFeCoNi base from 868 MPa to 1001 MPa, while the mechanical properties of the addition of 0.5 wt % Y2O3 composite decreased. In the meantime, the addition of Y2O3 had no significant influence on the coefficient of friction, while the addition of 0.25 wt % Y2O3 composite shows excellent wear-resistance. PMID- 29140297 TI - A Proteomic Approach to Investigate the Drought Response in the Orphan Crop Eragrostis tef. AB - The orphan crop, Eragrostis tef, was subjected to controlled drought conditions to observe the physiological parameters and proteins changing in response to dehydration stress. Physiological measurements involving electrolyte leakage, chlorophyll fluorescence and ultra-structural analysis showed tef plants tolerated water loss to 50% relative water content (RWC) before adverse effects in leaf tissues were observed. Proteomic analysis using isobaric tag for relative and absolute quantification (iTRAQ) mass spectrometry and appropriate database searching enabled the detection of 5727 proteins, of which 211 proteins, including a number of spliced variants, were found to be differentially regulated with the imposed stress conditions. Validation of the iTRAQ dataset was done with selected stress-related proteins, fructose-bisphosphate aldolase (FBA) and the protective antioxidant proteins, monodehydroascorbate reductase (MDHAR) and peroxidase (POX). Western blot analyses confirmed protein presence and showed increased protein abundance levels during water deficit while enzymatic activity for FBA, MDHAR and POX increased at selected RWC points. Gene ontology (GO)-term enrichment and analysis revealed terms involved in biotic and abiotic stress response, signaling, transport, cellular homeostasis and pentose metabolic processes, to be enriched in tef upregulated proteins, while terms linked to reactive oxygen species (ROS)-producing processes under water-deficit, such as photosynthesis and associated light harvesting reactions, manganese transport and homeostasis, the synthesis of sugars and cell wall catabolism and modification, to be enriched in tef downregulated proteins. PMID- 29140298 TI - Enhancement of Bone Marrow-Derived Mesenchymal Stem Cell Osteogenesis and New Bone Formation in Rats by Obtusilactone A. AB - The natural pure compound obtusilactone A (OA) was identified in Cinnamomum kotoense Kanehira & Sasaki, and shows effective anti-cancer activity. We studied the effect of OA on osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). OA possesses biocompatibility, stimulates Alkaline Phosphatase (ALP) activity and facilitates mineralization of BMSCs. Expression of osteogenesis markers BMP2, Runx2, Collagen I, and Osteocalcin was enhanced in OA-treated BMSCs. An in vivo rat model with local administration of OA via needle implantation to bone marrow-residing BMSCs revealed that OA increased the new bone formation and trabecular bone volume in tibias. Micro-CT images and H&E staining showed more trabecular bone at the needle-implanted site in the OA group than the normal saline group. Thus, OA confers an osteoinductive effect on BMSCs via induction of osteogenic marker gene expression, such as BMP2 and Runx2 expression and subsequently elevates ALP activity and mineralization, followed by enhanced trabecular bone formation in rat tibias. Therefore, OA is a potential osteoinductive drug to stimulate new bone formation by BMSCs. PMID- 29140299 TI - PDGFRalpha Regulated by miR-34a and FoxO1 Promotes Adipogenesis in Porcine Intramuscular Preadipocytes through Erk Signaling Pathway. AB - Suitable intramuscular fat (IMF) content improves porcine meat quality. The vital genes regulating IMF deposition are necessary for the selection and breeding of an IMF trait. However, the effect and mechanism of PDGFRalpha on IMF deposition are still unclear. Here, PDGFRalpha is moderately expressed in porcine longissimus dorsi muscle (LD), whereas it highly expressed in white adipose tissue (WAT). Moreover, PDGFRalpha-positive cells were located in the gaps of LD fibers which there were IMF adipocytes. Compared with 180-day-old and lean-type pigs, the levels of PDGFRalpha were much higher in one-day-old and fat-type pigs. Meanwhile the levels of PDGFRalpha gradually decreased during IMF preadipocyte differentiation. Furthermore, PDGFRalpha promoted adipogenic differentiation through activating Erk signaling pathway. Based on PDGFRalpha upstream regulation analysis, we found that the knockdown of FoxO1 repressed lipogenesis by downregulating PDGFRalpha, and miR-34a inhibited adipogenesis through targeting PDGFRalpha. Collectively, PDGFRalpha is a positive regulator of IMF deposition. Therefore, we suggest that PDGFRalpha is a possible target to improve meat quality. PMID- 29140301 TI - Catalytic Oxidation of Lignins into the Aromatic Aldehydes: General Process Trends and Development Prospects. AB - This review discusses principal patterns that govern the processes of lignins' catalytic oxidation into vanillin (3-methoxy-4-hydroxybenzaldehyde) and syringaldehyde (3,5-dimethoxy-4-hydroxybenzaldehyde). It examines the influence of lignin and oxidant nature, temperature, mass transfer, and of other factors on the yield of the aldehydes and the process selectivity. The review reveals that properly organized processes of catalytic oxidation of various lignins are only insignificantly (10-15%) inferior to oxidation by nitrobenzene in terms of yield and selectivity in vanillin and syringaldehyde. Very high consumption of oxygen (and consequentially, of alkali) in the process-over 10 mol per mol of obtained vanillin-is highlighted as an unresolved and unexplored problem: scientific literature reveals almost no studies devoted to the possibilities of decreasing the consumption of oxygen and alkali. Different hypotheses about the mechanism of lignin oxidation into the aromatic aldehydes are discussed, and the mechanism comprising the steps of single-electron oxidation of phenolate anions, and ending with retroaldol reaction of a substituted coniferyl aldehyde was pointed out as the most convincing one. The possibility and development prospects of single stage oxidative processing of wood into the aromatic aldehydes and cellulose are analyzed. PMID- 29140300 TI - Novel Strategies on Personalized Medicine for Breast Cancer Treatment: An Update. AB - Breast cancer is the most common cancer type among women worldwide. With breast cancer patients and survivors being reported to experience a repertoire of symptoms that are detrimental to their quality of life, the development of breast cancer treatment strategies that are effective with minimal side effects is therefore required. Personalized medicine, the treatment process that is tailored to the individual needs of each patient, is recently gaining increasing attention for its prospect in the development of effective cancer treatment regimens. Indeed, recent studies have identified a number of genes and molecules that may be used as biomarkers for predicting drug response and severity of common cancer associated symptoms. These would provide useful clues not only for the determination of the optimal drug choice/dosage to be used in personalized treatment, but also for the identification of gene or molecular targets for the development of novel symptom management strategies, which ultimately would lead to the development of more personalized therapies for effective cancer treatment. In this article, recent studies that would provide potential new options for personalized therapies for breast cancer patients and survivors are reviewed. We suggest novel strategies, including the optimization of drug choice/dosage and the identification of genetic changes that are associated with cancer symptom occurrence and severity, which may help in enhancing the effectiveness and acceptability of the currently available cancer therapies. PMID- 29140302 TI - Danger: High Voltage-The Role of Voltage-Gated Calcium Channels in Central Nervous System Pathology. AB - Voltage-gated calcium channels (VGCCs) are widely distributed within the central nervous system (CNS) and presumed to play an important role in the pathophysiology of a broad spectrum of CNS disorders including Alzheimer's and Parkinson's disease as well as multiple sclerosis. Several calcium channel blockers have been in clinical practice for many years so that their toxicity and side effects are well studied. However, these drugs are primarily used for the treatment of cardiovascular diseases and most if not all effects on brain functions are secondary to peripheral effects on blood pressure and circulation. While the use of calcium channel antagonists for the treatment of CNS diseases therefore still heavily depends on the development of novel strategies to specifically target different channels and channel subunits, this review is meant to provide an impulse to further emphasize the importance of future research towards this goal. PMID- 29140303 TI - Two Cycloartenol Synthases for Phytosterol Biosynthesis in Polygala tenuifolia Willd. AB - Oxidosqualene cyclases (OSCs) are enzymes that play a key role in control of the biosynthesis of phytosterols and triterpene saponins. In order to uncover OSC genes from Polygala tenuifolia seedlings induced by methyl jasmonate (MeJA), RNA sequencing analysis was performed using the Illumina sequencing platform. A total of 148,488,632 high-quality reads from two samples (control and the MeJA treated) were generated. We screened genes related to phytosterol and triterpene saponin biosynthesis and analyzed the transcriptional changes of differentially expressed unigene (DEUG) values calculated by fragments per kilobase million (FPKM). In our datasets, two full-length cDNAs of putative OSC genes, PtCAS1, and PtCAS2, were found, in addition to the PtBS (beta-amyrin synthase) gene reported in our previous studies and the two cycloartenol synthase genes of P. tenuifolia. All genes were isolated and characterized in yeast cells. The functional expression of the two PtCAS genes in yeast cells showed that the genes all produce a cycloartenol as the sole product. When qRT-PCR analysis from different tissues was performed, the expressions of PtCAS1 and PtCAS2 were highest in flowers and roots, respectively. After MeJA treatment, the transcripts of PtCAS1 and PtCAS2 genes increased by 1.5- and 2-fold, respectively. Given these results, we discuss the potential roles of the two PtCAS genes in relation to triterpenoid biosynthesis. PMID- 29140304 TI - Ultra-Fast Microwave Synthesis of ZnO Nanorods on Cellulose Substrates for UV Sensor Applications. AB - In the present work, tracing and Whatman papers were used as substrates to grow zinc oxide (ZnO) nanostructures. Cellulose-based substrates are cost-efficient, highly sensitive and environmentally friendly. ZnO nanostructures with hexagonal structure were synthesized by hydrothermal under microwave irradiation using an ultrafast approach, that is, a fixed synthesis time of 10 min. The effect of synthesis temperature on ZnO nanostructures was investigated from 70 to 130 degrees C. An Ultra Violet (UV)/Ozone treatment directly to the ZnO seed layer prior to microwave assisted synthesis revealed expressive differences regarding formation of the ZnO nanostructures. Structural characterization of the microwave synthesized materials was carried out by scanning electron microscopy (SEM) and X ray diffraction (XRD). The optical characterization has also been performed. The time resolved photocurrent of the devices in response to the UV turn on/off was investigated and it has been observed that the ZnO nanorod arrays grown on Whatman paper substrate present a responsivity 3 times superior than the ones grown on tracing paper. By using ZnO nanorods, the surface area-to-volume ratio will increase and will improve the sensor sensibility, making these types of materials good candidates for low cost and disposable UV sensors. The sensors were exposed to bending tests, proving their high stability, flexibility and adaptability to different surfaces. PMID- 29140305 TI - Probabilistic Prognosis of Environmental Radioactivity Concentrations due to Radioisotopes Discharged to Water Bodies from Nuclear Power Plants. AB - Due to their very low values, the complexity of comparing the contribution of nuclear power plants (NPPs) to environmental radioactivity with modeled values is recognized. In order to compare probabilistic prognosis of radioactivity concentrations with environmental measurement values, an exercise was performed using public data of radioactive routine discharges from three representative Spanish nuclear power plants. Specifically, data on liquid discharges from three Spanish NPPs: Almaraz, Vandellos II, and Asco to three different aquatic bodies (river, lake, and coast) were used. Results modelled using generic conservative models together with Monte Carlo techniques used for uncertainties propagation were compared with values of radioactivity concentrations in the environment measured in the surroundings of these NPPs. Probability distribution functions were inferred for the source term, used as an input to the model to estimate the radioactivity concentrations in the environment due to discharges to the water bodies. Radioactivity concentrations measured in bottom sediments were used in the exercise due to their accumulation properties. Of all the radioisotopes measured in the environmental monitoring programs around the NPPs, only Cs-137, Sr-90, and Co-60 had positive values greater than their respective detection limits. Of those, Sr-90 and Cs-137 are easily measured in the environment, but significant contribution from the radioactive fall-out due to nuclear explosions in the atmosphere exists, and therefore their values cannot be attributed to the NPPs. On the contrary, Co-60 is especially useful as an indicator of the radioactive discharges from NPPs because its presence in the environment can solely be attributed to the impact of the closer nuclear facilities. All the modelled values for Co-60 showed a reasonable correspondence with measured environmental data in all cases, being conservative in two of them. The more conservative predictions obtained with the models were the activity concentrations in the sediments of a lake (Almaraz) where, on average, values two times higher were obtained. For the case of rivers (Asco), calculated results were adequately conservative-up to 3.4 times on average. However, the results for coasts (Vandellos II) were in the same range as the environmental measurements, obtaining predictions that are only-at maximum-1.1 times higher than measured values. Only for this specific case of coasts could it be established that the models are not conservative enough, although the results, on average, are relatively close to the real values. PMID- 29140306 TI - Chitosan Spray-Dried Microparticles for Controlled Delivery of Venlafaxine Hydrochloride. AB - Venlafaxine controlled drug delivery systems using different matrixes have been tested to reduce undesirable side effects in the treatment of depression. The legal status of chitosan (Cs) in Pharmacy has dramatically improved after its acceptance as excipient in several Pharmacopeias and, therefore, there is great interest in pharmaceutical formulations based on this polymer. In this paper, chitosan microcapsules cross-linked with sodium tripolyphosphate (TPP) for oral delivery of venlafaxine were formulated using the spray drying technique. The effect of chitosan physico-chemical properties, TPP concentration and TPP/Cs ratio on drug release was evaluated. The microcapsules were characterized in terms of size, zeta potential and morphology. The physical state of the drug was determined by X-ray diffraction (XRD) and the drug release from the microcapsules was studied in simulated gastric and intestinal fluids. The release pattern fitted well to the Peppas-Koersmeyer model with n exponents indicating anomalous transport. PMID- 29140307 TI - Practical and Sustainable Synthesis of Optically Pure Levocabastine, a H1 Receptor Antagonist. AB - A practical and sustainable method for the synthesis of levocabastine hydrochloride (1), a H1 receptor antagonist for the treatment of allergic conjunctivitis, that can be applied to the industrial production of the compound has been developed. Substantial improvements over the previously reported procedure are achieved via efficient preparation of an optically active key intermediate (5) without chiral resolution and with a more effective detosylation, which complements the previous procedure. Notably, our process requires no chromatographic purification and provides levocabastine hydrochloride in greater than 99.5% purity in a 14.2% overall yield. PMID- 29140308 TI - Synergistic Effect of Fluorinated and N Doped TiO2 Nanoparticles Leading to Different Microstructure and Enhanced Photocatalytic Bacterial Inactivation. AB - This work focuses on the development of a facile and scalable wet milling method followed by heat treatment to prepare fluorinated and/or N-doped TiO2 nanopowders with improved photocatalytic properties under visible light. The structural and electronic properties of doped particles were investigated by various techniques. The successful doping of TiO2 was confirmed by X-ray photoelectron spectroscopy (XPS), and the atoms appeared to be mainly located in interstitial positions for N whereas the fluorination is located at the TiO2 surface. The formation of intragap states was found to be responsible for the band gap narrowing leading to the faster bacterial inactivation dynamics observed for the fluorinated and N doped TiO2 particles compared to N-doped TiO2. This was attributed to a synergistic effect. The results presented in this study confirmed the suitability of the preparation approach for the large-scale production of cost-efficient doped TiO2 for effective bacterial inactivation. PMID- 29140309 TI - Biosensors to Diagnose Chagas Disease: A Brief Review. AB - Chagas disease (CD), which mostly affects those living in deprived areas, has become one of Latin America's main public health problems. Effective prevention of the disease requires early diagnosis, initiation of therapy, and regular blood monitoring of the infected individual. However, the majority of the Trypanosoma cruzi infections go undiagnosed because of mild symptoms, limited access to medical attention and to a high variability in the sensitivity and specificity of diagnostic tests. Consequently, more affordable and accessible detection technologies capable of providing early diagnosis and T. cruzi load measurements in settings where CD is most prevalent are needed to enable enhanced intervention strategies. This work analyzes the potential contribution of biosensing technologies, reviewing examples that have been tested and contrasted with traditional methods, both serological and parasitological (i.e., molecular detection by PCR), and discusses some emerging biosensing technologies that have been applied for this public health issue. Even if biosensing technologies still require further research efforts to develop portable systems, we arrive at the conclusion that biosensors could improve the accuracy of CD diagnosis and the follow-up of patients' treatments in terms of the rapidity of results, small sample volume, high integration, ease of use, real-time and low cost detection when compared with current conventional technologies. PMID- 29140310 TI - Effect of Abscisic Acid on Accumulation of Five Active Components in Root of Glycyrrhiza uralensis. AB - Licorice is one of the most generally used herbal medicines in the world; however, wild licorice resources have decreased drastically. Cultivated Glycyrrhiza uralensis Fischer are the main source of licorice at present, but the content of main active components in cultivated G. uralensis are lower than in wild G. uralensis. Therefore, the production of high-quality cultivated G. uralensis is an urgent issue for the research and production fields. In this study, the content of five active components and seven endogenous phytohormones in cultivated G. uralensis (two-year-old) were determined by high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA), respectively. Furthermore, different concentrations (25-200 mg/L) of exogenous abscisic acid (ABA) were sprayed on the leaves of G. uralensis in the fast growing period. Results showed that ABA, zeatin riboside (ZR), and dihydrozeatin riboside (DHZR) had strong correlation with active components. In addition, the content of five active components increased remarkably after ABA treatment. Our results indicate that ABA is significantly related to the accumulation of active components in G. uralensis, and the application of exogenous ABA at the proper concentration is able to promote the accumulation of main components in G. uralensis. PMID- 29140311 TI - Scene-Aware Adaptive Updating for Visual Tracking via Correlation Filters. AB - In recent years, visual object tracking has been widely used in military guidance, human-computer interaction, road traffic, scene monitoring and many other fields. The tracking algorithms based on correlation filters have shown good performance in terms of accuracy and tracking speed. However, their performance is not satisfactory in scenes with scale variation, deformation, and occlusion. In this paper, we propose a scene-aware adaptive updating mechanism for visual tracking via a kernel correlation filter (KCF). First, a low complexity scale estimation method is presented, in which the corresponding weight in five scales is employed to determine the final target scale. Then, the adaptive updating mechanism is presented based on the scene-classification. We classify the video scenes as four categories by video content analysis. According to the target scene, we exploit the adaptive updating mechanism to update the kernel correlation filter to improve the robustness of the tracker, especially in scenes with scale variation, deformation, and occlusion. We evaluate our tracker on the CVPR2013 benchmark. The experimental results obtained with the proposed algorithm are improved by 33.3%, 15%, 6%, 21.9% and 19.8% compared to those of the KCF tracker on the scene with scale variation, partial or long-time large area occlusion, deformation, fast motion and out-of-view. PMID- 29140312 TI - Plasma Amino Acid Abnormalities in Chronic Heart Failure. Mechanisms, Potential Risks and Targets in Human Myocardium Metabolism. AB - The goal of this study was to measure arterial amino acid levels in patients with chronic heart failure (CHF), and relate them to left ventricular function and disease severity. Amino acids (AAs) play a crucial role for heart protein-energy metabolism. In heart failure, arterial AAs, which are the major determinant of AA uptake by the myocardium, are rarely measured. Forty-one subjects with clinically stable CHF (New York Heart Association (NYHA) class II to IV) were analyzed. After overnight fasting, blood samples from the radial artery were taken to measure AA concentrations. Calorie (KcalI), protein-, fat-, carbohydrate-intake, resting energy expenditure (REE), total daily energy expenditure (REE * 1.3), and cardiac right catheterization variables were all measured. Eight matched controls were compared for all measurements, with the exception of cardiac catheterization. Compared with controls, CHF patients had reduced arterial AA levels, of which both their number and reduced rates are related to Heart Failure (HF) severity. Arterial aspartic acid correlated with stroke volume index (r = 0.6263; p < 0.0001) and cardiac index (r = 0.4243; p = 0.0028). The value of arterial aspartic acid (umol/L) multiplied by the cardiac index was associated with left ventricular ejection fraction (r = 0.3765; p = 0.0076). All NYHA groups had adequate protein intake (>=1.1 g/kg/day) and inadequate calorie intake (KcalI < REE * 1.3) was found only in class IV patients. This study showed that CHF patients had reduced arterial AA levels directly related to clinical disease severity and left ventricular dysfunction. PMID- 29140313 TI - A New Low Complexity Angle of Arrival Algorithm for 1D and 2D Direction Estimation in MIMO Smart Antenna Systems. AB - This paper proposes a new low complexity angle of arrival (AOA) method for signal direction estimation in multi-element smart wireless communication systems. The new method estimates the AOAs of the received signals directly from the received signals with significantly reduced complexity since it does not need to construct the correlation matrix, invert the matrix or apply eigen-decomposition, which are computationally expensive. A mathematical model of the proposed method is illustrated and then verified using extensive computer simulations. Both linear and circular sensors arrays are studied using various numerical examples. The method is systematically compared with other common and recently introduced AOA methods over a wide range of scenarios. The simulated results show that the new method has several advantages in terms of reduced complexity and improved accuracy under the assumptions of correlated signals and limited numbers of snapshots. PMID- 29140314 TI - Self-perceived fatigue in adolescents in relation to body composition and physical outcomes. AB - BackgroundIncreased self-perceived fatigue (SpF) has already been identified in chronic conditions such as obesity, but it is also a growing problem in school attending adolescents (+/-25%). This study tried to link body composition to SpF and physical activity/performance. Additionally, indicators for fatigue were determined.MethodsA total of 452 adolescents were recruited. Body composition was measured and physical activity, physical performance, and SpF were assessed. Based on the total SpF (Multidimensional Fatigue Inventory) outcomes, three groups were created: low fatigue (LF) medium fatigue (MF) and high fatigue (HF).ResultsFat was significantly lower in the LF group compared with MF (P<0,05) and HF (P<0.01). Grip endurance was increased in LF (P<0.05) and MF (P<0.01) compared with HF; similar results were found with the Cooper test. Sport Index was increased in LF compared with MF and HF (P<0.01). Fat and physical activity were related to fatigue (P<0.01). Decreased fatigue resistance, Sport Index and higher fat percentage increased the chance of being extremely fatigued.ConclusionThis study emphasizes the importance of using fat mass and fat percentage instead of body mass index when screening adolescents. To prevent increased SpF, it is necessary to stimulate youngsters to be physically active and to promote healthy behaviors. PMID- 29140315 TI - Accelerating two-dimensional infrared spectroscopy while preserving lineshapes using GIRAF. AB - We introduce a computationally efficient structured low-rank algorithm for the reconstruction of two-dimensional infrared (2D IR) spectroscopic data from few measurements. The signal is modeled as a combination of exponential lineshapes that are annihilated by appropriately chosen filters. The annihilation relations result in a low-rank constraint on a Toeplitz matrix constructed from signal samples, which is exploited to recover the unknown signal samples. Quantitative and qualitative studies on simulated and experimental data demonstrate that the algorithm outperforms the discrete compressed sensing algorithm, both in uniform and non-uniform sampling settings. PMID- 29140316 TI - Hybrid system for in vivo epifluorescence and 4D optoacoustic imaging. AB - Epifluorescence imaging is widely used in cell and molecular biology due to its excellent sensitivity, contrast, and ease of implementation. Optoacoustic imaging has been shown to deliver a highly complementary and unique set of capabilities for biological discovery, such as high spatial resolution in noninvasive deep tissue observations, fast volumetric imaging capacity, and spectrally enriched contrast. In this Letter, we report on a hybrid system combining planar fluorescence and real-time volumetric four-dimensional optoacoustic imaging by means of a fiberscope integrated within a handheld hemispherical ultrasound detection array. The in vivo imaging performance is demonstrated by non-invasive visualization of fast contrast agent perfusion through the mouse brain. The proposed synergistic combination of fluorescence and optoacoustic imaging can benefit numerous studies looking at multi-scale in vivo dynamics, such as functional neuroimaging, visualization of organ perfusion and contrast agent uptake, cell tracking, and pharmacokinetic and bio-distribution analysis. PMID- 29140317 TI - Scanning system for angle-resolved low-coherence interferometry. AB - Angle-resolved low-coherence interferometry (a/LCI) detects precancer by enabling depth-resolved measurements of nuclear morphology in vivo. A significant limitation of a/LCI is the point-probe nature of the method, sampling <0.5 mm2 before probe relocation is necessary. In this work, we demonstrate a scanning method capable of assessing an area >100 mm2 without repositioning. By utilizing a reflection-only three-optic rotator prism and a two-axis scanning mirror, we demonstrate radial scans of a sample with a linear range of 12 mm and a full rotational range of 180 degrees . Use of this design will improve the diagnostic utility of a/LCI for wide-area screening of tissue health. PMID- 29140318 TI - Electron-induced photon emission above the quantum cutoff due to time-energy uncertainty. AB - The light emission from a tunneling junction induced by tunneling electrons has been studied around the cutoff at hnu=eVt. The emitted photons are found to exceed the excitation energy provided by the energy of the tunneling electrons. The experiments have been performed by a low- temperature scanning tunneling microscope at 80 K for an Ag(111) surface and an Ag-covered PtIr tip. A detailed analysis of the emission spectra reveals that the findings cannot be explained by the thermal broadening of the electron Fermi distribution alone. However, a correct description is found if a finite lifetime of the excited states in the range of 30-80 fs is included. PMID- 29140319 TI - 3D-point-cloud-based apparent magnitude model of space objects. AB - A new 3D-point-cloud-based model is presented for calculating the apparent magnitude of space objects. This model does not consider topological relations of space objects, but it can accurately describe the shape of a space object and calculate its apparent magnitude. Once a 3D point cloud of a space object and its material parameters under a certain wavelength are obtained, the apparent magnitude can be solved. Through this model, the apparent magnitude of space objects with different shapes and the wrinkled surface can be calculated easily. Simulation results show that the increase in the number of points can improve the accuracy of this model. PMID- 29140320 TI - Filtering characteristics of a three-lens slit spatial filter for high-power lasers. AB - Aiming for a three-lens slit spatial filtering system with excellent performances in inhibition of pinhole closure, improvement of beam quality, compactness of the system, and lowering the requirement of vacuum, the filtering characteristics and image relay of the slit spatial filter are demonstrated. The results show that the beam quality is greatly improved, and the system has a good property in image relay, which has potential applications in high-power lasers. PMID- 29140321 TI - Single-silicon CCD-CMOS platform for multi-spectral detection from terahertz to x rays. AB - Charge-coupled devices (CCDs) are a well-established imaging technology in the visible and x-ray frequency ranges. However, the small quantum photon energies of terahertz radiation have hindered the use of this mature semiconductor technological platform in this frequency range, leaving terahertz imaging totally dependent on low-resolution bolometer technologies. Recently, it has been shown that silicon CCDs can detect terahertz photons at a high field, but the detection sensitivity is limited. Here we show that silicon, complementary metal-oxide semiconductor (CMOS) technology offers enhanced detection sensitivity of almost two orders of magnitude, compared to CCDs. Our findings allow us to extend the low-frequency terahertz cutoff to less than 2 THz, nearly closing the technological gap with electronic imagers operating up to 1 THz. Furthermore, with the silicon CCD/CMOS technology being sensitive to mid-infrared (mid-IR) and the x-ray ranges, we introduce silicon as a single detector platform from 1 EHz to 2 THz. This overcomes the present challenge in spatially overlapping a terahertz/mid-IR pump and x-ray probe radiation at facilities such as free electron lasers, synchrotron, and laser-based x-ray sources. PMID- 29140322 TI - Fourier processing with partially coherent fields. AB - We describe how Fourier signal processing techniques can be generalized to partially coherent fields. Using standard coherence theory, we first show that focusing of a partially coherent beam by a lens modifies its coherence properties. We then consider a 4f imaging system composed of two lenses and discuss how spatial filtering in the Fourier plane allows one to tune the coherence properties of the beam. This, in turn, provides control over the beam's directionality, spectrum, and degree of polarization. PMID- 29140323 TI - Point-spread function engineering enhances digital Fourier microscopy. AB - While numerous optical methods exist to probe the dynamics of biological or complex fluid samples, in recent years digital Fourier microscopy techniques such as differential dynamic microscopy have emerged as ways to efficiently combine elements of imaging and scattering methods. Here, we demonstrate, through experiments and simulations, how point-spread function engineering can be used to extend the reach of differential dynamic microscopy. PMID- 29140324 TI - Method to retrieve the nocturnal aerosol optical depth with a CCD laser aerosol detective system. AB - Aerosol optical depth (AOD) is a crucial parameter in describing the atmospheric pollution and analyzing the influences of aerosol on the radiative equilibrium. Currently, no method can precisely and continuously measure the nocturnal AOD. In this study, a novel method was developed to retrieve the nocturnal AOD based on a remote sensing instrument called the charge-coupled device-laser aerosol detective system (CCD-LADS). CCD-LADS consists of a CCD camera, a continuous laser, a fisheye lens, and related filters. The AOD can be calculated by integrating the aerosol extinction coefficient profile retrieved from CCD-LADS measurements. The retrieved AOD was validated with AERONET and MODIS data sets. The comparison shows good agreement. PMID- 29140325 TI - Six-pack off-axis holography. AB - We present a new holographic concept, named six-pack holography (6PH), in which we compress six off-axis holograms into a single multiplexed off-axis hologram without loss of magnification or resolution. The multiplexed hologram contains straight off-axis fringes with six different orientations, and can be generated optically or digitally. We show that since the six different complex wavefronts do not overlap in the spatial frequency domain, they can be fully reconstructed. 6PH allows more than 50% improvement in the spatial bandwidth consumption when compared to the best multiplexing method proposed so far. We expect the 6PH concept to be useful for a variety of applications, such as field-of-view multiplexing, wavelength multiplexing, temporal multiplexing, multiplexing for super-resolution imaging, and others. PMID- 29140326 TI - Photoacoustic endomicroscopy based on a MEMS scanning mirror. AB - In this Letter, we present a high-resolution photoacoustic endomicroscopy probe based on a microelectromechanical systems (MEMS) scanning mirror. The built-in optical assembly consists of a 0.7 mm graded-index (GRIN) lens for light focusing and a phi1 mm MEMS mirror to reflect and scan the beam. A miniaturized unfocused ultrasound transducer with a center frequency of 10 MHz is used for photoacoustic detection. Sharp blades, carbon fibers, and black tapes were utilized to evaluate the performance of the system. In vivo mouse ears and resected rectums were imaged to further demonstrate the feasibility of this probe for potential biological and clinical applications. PMID- 29140327 TI - Optical voice encryption based on digital holography. AB - We propose an optical voice encryption scheme based on digital holography (DH). An off-axis DH is employed to acquire voice information by obtaining phase retardation occurring in the object wave due to sound wave propagation. The acquired hologram, including voice information, is encrypted using optical image encryption. The DH reconstruction and decryption with all the correct parameters can retrieve an original voice. The scheme has the capability to record the human voice in holograms and encrypt it directly. These aspects make the scheme suitable for other security applications and help to use the voice as a potential security tool. We present experimental and some part of simulation results. PMID- 29140328 TI - Retina-simulating phantom produced by photolithography. AB - Cone photoreceptors have a narrow acceptance angle that is well matched to the size of the eye pupil and dampens the visual impact of aberrations and scattering. However, the structure of the human retina is not replicated in existing eye models used to test refractive designs or retinal implants that restore partial vision to the blind. Here, we report on an artificial waveguide based retinal phantom manufactured by photolithography in photoresist film with dimensions and refractive index contrast similar to the retinal receptor layer. The optical performance of the waveguide array is analyzed in terms of angular coupling efficiency, and it is experimentally verified that the structure leads to improved resolution and contrast of optical images transmitted through the layer when defocus is present. PMID- 29140329 TI - Demonstration of a CW diode-pumped Ar metastable laser operating at 4 W. AB - Optically pumped rare gas lasers are being investigated as potential high-energy, high beam quality systems. The lasing medium consists of rare gas atoms (Rg=Ne, Ar, Kr, or Xe) that have been electric discharge excited to the metastable np5(n+1)s P32 state. Following optical excitation, helium (He) at pressures of 200-1000 Torr is used as the energy transfer agent to create a population inversion. The primary technical difficulty for this scheme is the discharge production of sufficient Rg* metastables in the presence of >200 Torr of He. In this Letter, we describe a pulsed discharge that yields >1013 cm-3Ar* in the presence of He at total pressures up to 750 Torr. Using this discharge, a diode pumped Ar* laser providing 4.1 W has been demonstrated. PMID- 29140330 TI - All-optimized integrated RF photonic notch filter. AB - We report a silicon nitride chip-based radio-frequency photonic notch filter with an unprecedented performance including an RF gain of 8 dB, a record-low noise figure of 15.6 dB, and a spurious-free dynamic range of 116 dB.Hz2/3, with a stop band rejection of 50 dB. This level of performance is achieved by using on chip resonators' unique phase responses, and thorough optimizations of the photonic link. These record results will potentially stimulate future implementations of integrated microwave photonic subsystems for real-world applications. PMID- 29140331 TI - Multi-wavelength filtering with a waveguide integrated phase-modulated Bragg grating. AB - We present a multi-wavelength band-rejection filter on a titanium dioxide-coated silicon-on-insulator platform. The concept rests on the use of a finely tuned waveguide-based Bragg grating for which the periods are slightly varied from one to another. This phase-modulated Bragg grating enables precise customization of integrated waveguide filters. The number of rejection bands and the center-to center separation between them are tailored by dividing the grating into several super-periods and coding an optimal phase function onto each super-period. The optimal phase function is obtained by employing an iterative Fourier transform algorithm. The design is supported by an experimental demonstration. PMID- 29140332 TI - Physical significance of backscattering phase measurements. AB - Quantitative phase imaging of transparent objects in transmission allows for a direct interpretation of the results: the phase shift measured is linear in the refractive index contrast and object thickness. However, the same measurement in a backscattering geometry yields fundamentally different results, because the incident field component is absent from the detected field. As a result, the relationship between the measured phase and object properties is obscure. We derived analytical expressions for the propagating fields under the first-order Born approximation and studied the interpretation of the measured phase shifts in backscattering versus transmission geometries. Our analysis shows that the backscattering phase shift is the result of the plane wave superposition originating at various depths in the object, which makes it impossible to infer quantitative morphology or topography information of 3D transparent samples from a reflection phase image alone. PMID- 29140333 TI - Second-order moments of Schell-model beams with various correlation functions in atmospheric turbulence. AB - The general formulae for second-order moments of Schell-model beams with various correlation functions in atmospheric turbulence are derived and validated by the Bessel-Gaussian Schell-model beams and cosine-Gaussian-correlated Schell-model beams. Our finding shows that the second-order moments of partially coherent Schell-model beams are related to the second-order partial derivatives of source spectral degree of coherence at the origin. The formulae we provide are much more convenient to analyze and research propagation problems in turbulence. PMID- 29140334 TI - Carrier-envelope offset stabilization of a GHz repetition rate femtosecond laser using opto-optical modulation of a SESAM. AB - We demonstrate, to the best of our knowledge, the first carrier-envelope offset (CEO) frequency stabilization of a GHz femtosecond laser based on opto-optical modulation (OOM) of a semiconductor saturable absorber mirror (SESAM). The 1.05 GHz laser is based on a Yb:CALGO gain crystal and emits sub-100-fs pulses with 2.1-W average power at a center wavelength of 1055 nm. The SESAM plays two key roles: it starts and stabilizes the mode-locking operation and is simultaneously used as an actuator to control the CEO frequency. This second functionality is implemented by pumping the SESAM with a continuous-wave 980-nm laser diode in order to slightly modify its nonlinear reflectivity. We use the standard f-to-2f method for detection of the CEO frequency, which is stabilized by applying a feedback signal to the current of the SESAM pump diode. We compare the SESAM-OOM stabilization with the traditional method of gain modulation via control of the pump power of the Yb:CALGO gain crystal. While the bandwidth for gain modulation is intrinsically limited to ~250 kHz by the laser cavity dynamics, we show that the OOM provides a feedback bandwidth above 500 kHz. Hence, we were able to obtain a residual integrated phase noise of 430 mrad for the stabilized CEO beat, which represents an improvement of more than 30% compared to gain modulation stabilization. PMID- 29140335 TI - Improving the sensitivity of velocity measurements in laser speckle contrast imaging using a noise correction method. AB - We demonstrate that noise is an important factor contributing to the decline of sensitivity and linear response range of velocity measurements for laser speckle contrast imaging. We propose to use a noise correction method to improve the sensitivity of velocity measurements. For a kind of camera in which the mean values of the dark noise have been subtracted and negative counts have been set to zero, we propose a method to estimate the true dark noise based on the maximum likelihood estimation, which expands the application scope of the noise correction method. PMID- 29140336 TI - Whispering gallery modes in a liquid-filled hollow glass microsphere. AB - We develop a hydrofluoric (HF) etching process to open a microhole on the hollow glass microsphere (HGM). The typical whispering gallery mode (WGM) resonance was observed by coupling the HGM with a tapered fiber. Dioctyl phthalate was filled into the HGM, and the resonance wavelength decreased at elevated temperatures. We analyzed the WGM resonance properties inside the liquid-filled HGM with a higher or lower refractive index in comparison to the HGM wall. Four different liquids were also injected into the HGM to investigate the influence of the thermo-optic coefficient on the temperature sensitivity. Size-dependent experiments further showed that HGMs with varying sizes have varying temperature sensitivity. The maximum temperature sensitivity observed was 334.3 pm/ degrees C. PMID- 29140337 TI - Direct imaging of tunable photonic nanojets from a self-assembled liquid crystal microdroplet. AB - We report the direct experimental observation of electrically tunable photonic nanojets (PNJs) generated from self-assembled liquid crystal (LC) microdroplets formed by dispersing nematic LCs in polymer matrix. Optical measurements were performed with a home-built laser-scanning confocal microscope system. PNJs with subwavelength beam waists were successfully obtained from LC microdroplets of 5 MUm diameter, similar to those from SiO2 microspheres of the same size. By applying external voltage of a few volts, some of major properties of PNJs, such as beam length and brightness, are tuned. Electro-tunable PNJs from self assembled LC microdroplets may open the way for the development of novel micro optical devices. PMID- 29140338 TI - Scattering of waves by a half-space of periodic scatterers using broadband Green's function. AB - An efficient scatterer-free full-wave solution for plane wave scattering from a half-space of two-dimensional (2D) periodic scatterers is derived using broadband Green's function. The Green's function is constructed using band solutions of the infinite periodic structure, and it satisfies boundary conditions on all the scatterers. A low wavenumber extraction technique is applied to the Green's function to accelerate the convergence of the modal expansion. This facilitates the Green's function with low wavenumber extraction (BBGFL) to be evaluated over a broadband as the modal solutions are independent of wavenumber. Coupled surface integral equations (SIE) are constructed using the BBGFL and the free-space Green's function respectively for the two half-spaces with unknowns only on the interface. The method is distinct from the effective medium approach which represents the periodic scatters with an effective medium. This new approach provides accurate near-field solutions around the interface with localized field patterns useful for surface plasmon polaritons and topological edge states examinations. PMID- 29140339 TI - All-fiber sixth-harmonic generation of deep UV. AB - We simulate and experimentally demonstrate deep ultraviolet generation from a 1550 nm laser source in a fully fiberized system by cascading second- and third harmonic generation using a periodically poled silica fiber and an optical sub micron diameter fiber. Harmonic generation is achieved by harnessing intermodal phase matching in optical microfibers and a permanent chi(2) induced via thermal poling. As a result, efficient nonlinear processes can be observed, despite the low third-order nonlinear susceptibility of silica glass. PMID- 29140341 TI - Gaussian beams diffracting in time. AB - We show how to transform the mathematical expression of any monochromatic paraxial light beam into the expression of a pulsed beam whose diffraction is switched from the axial direction to its temporal structure. We exemplify this transformation with time-diffracting Gaussian beams. The conditions for the obtained diffraction-free wave to be physically meaningful are discussed. PMID- 29140340 TI - Response of an erbium-doped dual-polarization fiber laser to a perpendicular gradient magnetic field. AB - Direct interaction between fiber lasers and a magnetic field is useful but seldom explored because fiber is known as magnetic field insensitive. In this Letter, the response of an erbium-doped dual-polarization fiber laser to a perpendicular gradient magnetic field is investigated. Measured as beat note frequency change, significant response greater than 500 MHz has been observed that is within theoretical expectation, and translates to a birefringence change of about 4*10-6 and a potentially very high response to a magnetic field of about 12.8 pT/Hz. The response can be further enhanced by increasing the gradient of the gradient magnetic field. PMID- 29140342 TI - Fiber-format dual-comb coherent Raman spectrometer. AB - We demonstrate a fiber-format system for dual-comb coherent anti-Stokes Raman scattering spectroscopy. The system is based on two ytterbium fiber (Yb) femtosecond lasers at repetition frequencies of 94 MHz, a Yb amplifier, and a photonic crystal fiber for spectral broadening and generation of pulses with a central wavelength of 1040 nm and durations in the sub-20-fs regime. We observed Raman spectra of acetonitrile and ethyl acetate with spectral coverage from 100 to 1300 cm-1, resolution of 8 cm-1, and a signal-to-noise ratio of around 100, when averaging over 10 acquisitions. The design is suitable for implementing portable dual-comb coherent Raman spectrometers. PMID- 29140343 TI - Passively Q-switched Pr:YLF laser with a Co2+:MgAl2O4 saturable absorber. AB - We report on a 2omega-OPSL-pumped passively Q-switched Pr3+:LiYF4 laser operating at the wavelengths of 523, 607, and 640 nm. For this, we utilized a Co2+-doped MgAl2O4 (MALO) crystal as a saturable absorber in the visible range for the first time, to the best of our knowledge. In the green spectral region, the pulse duration was 210 ns with a pulse energy of 3.6 MUJ and a repetition rate of 125 kHz. The minimum pulse duration of 87 ns at the highest pulse energy of 8.6 MUJ was obtained at a repetition rate of 110 kHz at 607 nm. The highest Q-switched average laser power of 1.4 W was obtained at an absorbed continuous-wave pump power of 3.3 W with a slope efficiency of 47% at 640 nm. Absorption saturation measurements with Co:MALO were performed, and ground and excited state absorption cross sections in the visible spectral range were determined. PMID- 29140344 TI - Experimental realization of narrowband four-photon Greenberger-Horne-Zeilinger state in a single cold atomic ensemble. AB - Multi-photon entangled states not only play a crucial role in research on quantum physics but also have many applications in quantum information fields such as quantum computation, quantum communication, and quantum metrology. To fully exploit the multi-photon entangled states, it is important to establish the interaction between entangled photons and matter, which requires that photons have narrow bandwidth. Here, we report on the experimental generation of a narrowband four-photon Greenberger-Horne-Zeilinger state with a fidelity of 64.9% through multiplexing two spontaneous four-wave mixings in a cold Rb85 atomic ensemble. The full bandwidth of the generated GHZ state is about 19.5 MHz. Thus, the generated photons can effectively match the atoms, which are very suitable for building a quantum computation and quantum communication network based on atomic ensembles. PMID- 29140345 TI - Optimized optical coupling to silica-clad photonic crystal waveguides. AB - Silica-clad silicon photonic crystal waveguides (PCWs) are promising components for various applications because of their simple fabrication and generation of slow light. However, an optical loss higher than 4 dB occurs when they are simply coupled to input/output silicon wire waveguides. To reduce the optical loss, we proposed a junction structure in which light in the waveguide is first coupled to a high-group-velocity radiation mode at an expanded core and subsequently converted to the slow-light mode in a tapered core of the PCW. The coupling loss at a junction is calculated to be 0.28 dB at its minimum and less than 0.5 dB for the wavelength range of 12 nm. We measured a coupling loss of 0.46 dB for the device fabricated by the silicon photonics process. This low-loss junction well supports the practical use of PCWs. PMID- 29140346 TI - Performance evaluation of underwater optical communications using spatial modes subjected to bubbles and obstructions. AB - Spatial modes have attracted increasing interest in free-space and fiber-based optical communications. Underwater wireless optical communication is becoming a promising technique in marine exploration. Here we investigate the underwater wireless optical communications using different spatial modes, i.e., traditional Gaussian modes, orbital angular momentum modes having helical phase fronts, and diffraction-free and obstruction-tolerant Bessel modes. We evaluate the underwater transmission performance of three spatial modes subjected to dynamic bubbles, which cause similar power fluctuations, regardless of spatial modes. We also demonstrate an underwater transmission link subjected to static obstructions using three spatial modes carrying 1.4 Gbaud orthogonal frequency division multiplexing 16-ary quadrature amplitude modulation (16-QAM) signals. The Bessel mode shows the best performance against obstructions. PMID- 29140347 TI - Origin of the temperature-induced redshift of the charge transfer band of GdVO4. AB - The charge transfer band (CTB) of the VO43- groups in vanadates shifts to longer wavelengths with increasing temperature. The origin of this temperature-induced redshift was explored by studying the temperature-dependent excitation and emission spectra of GdVO4 ranging from 300 to 480 K. The influences of the thermal population and the decline of the charge transfer gap on the spectral shift were analyzed using the configurational coordinate diagram. We conclude that the thermal population of vibrational sublevels of the ground electronic energy level dominates the temperature-induced redshift of the CTB. Taking advantage of the redshift and the thermal quenching, a novel ratiometric temperature-sensing strategy was proposed. Drastic temperature dependence was achieved, indicating a promising candidate for an optical thermometer with high sensing performance. PMID- 29140348 TI - Photonically assisted microwave waveform generation by gain-transparent SBS induced carrier processing: erratum. AB - In our previous work [Opt. Lett.42, 3852 (2017)OPLEDP0146 959210.1364/OL.42.003852], there is an error in Fig. 1. That error is addressed here. PMID- 29140349 TI - All-fiber mode converter based on long-period fiber gratings written in few-mode fiber. AB - We investigated an all-fiber mode converter based on long-period fiber gratings (LPFGs) written in the few-mode fiber. Mode conversion between the fundamental core mode and different higher-order core modes (LP11, LP21, and LP02 modes) can be realized via a single LPFG with an efficiency of 99% at the resonance wavelength. Moreover, optimized mode conversion between the LP01 and LP21 modes can be realized by cascading two LPFGs with different grating pitches. The maximum conversion efficiency is estimated to be ~99.5% at 1553 nm. The orbital angular momentum states with different topological charges (+/-1,+/-2) are demonstrated experimentally. The all-fiber LPFG mode converters could have promising applications in the mode-division multiplexing optical communications. PMID- 29140350 TI - Performance optimization of hollow-core fiber photothermal gas sensors. AB - We report performance optimization of hollow-core photonic bandgap fiber (HC-PBF) photothermal (PT) gas sensors. The PT phase modulation efficiency of a C2H2 filled HC-PBF (HC-1550-02) is found independent of the pump modulation frequency for up to ~330 kHz, but starts to drop quickly to 10% of the maximum value at a couple of megahertz. With a 1.1 m long HC-PBF gas cell with angle-cleaved single mode fiber/HC-PBF joints to reduce reflection and a modified 3*3 Sagnac interferometer with balanced detection for phase demodulation, a noise equivalent concentration of ~67 ppbC2H2 is achieved with a 1 s time constant, and it goes down to ~18 ppb with 145 s integration time. The system has good long-term stability and exhibits signal fluctuations of <1% over a ~5 h period. PMID- 29140351 TI - Design of optical wavelength demultiplexer based on off-axis meta-lens. AB - We propose an off-axis meta-lens-based optical wavelength demultiplexer. The performance of the device initially proposed with four output channels (1527-1596 nm, channel spacing 23 nm) composed of an optical fiber array is analyzed by both scalar diffraction theory and ray tracing method. The results show that the fiber energy coupling efficiency of the demultiplexer could be larger than 89% and the channel bandwidth is about 9 nm. Influences of the two key parameters, focal length f and off-axis angle alpha, are also investigated. We find that the minimum spectral linewidth of the channel is inversely proportional to the sine of alpha and nearly independent of f for a meta-lens with large F-number (F>5), while the effective spectral range is negatively (positively) dependent on alpha (f). These results are significant in guiding us to build small and compact demultiplexing devices for optical telecommunication. PMID- 29140352 TI - Extended ellipticity control for attosecond pulses by high harmonic generation. AB - Attosecond (1 as=10-18 s) pulses produced through high harmonic generation (HHG) are a basis for studies of electron dynamics during light-matter interaction on an electron's natural time scale. Extensively exploited HHG technology has, however, a few unsolved problems, where producing of circularly polarized or chiral attosecond pulses belongs to them. We have demonstrated experimentally a way to control the ellipticity of attosecond pulse trains produced via HHG in two-color, bi-circular laser fields. We show that the combination of a nonlinear medium position and the intensities of the two-color driving laser fields create an effective helicity-dependent filter. Based on this approach, we report generation of chiral spectra providing potential to produce attosecond pulses with polarization tuned from the rotating, but linear to highly elliptic, with ellipticity as much as epsilon=0.75. This new way to create a chiral-sensitive element offers a simple and practical knob to control polarization for a combined harmonics field in a smooth and predictable manner. PMID- 29140353 TI - Atom-mediated spontaneous parametric down-conversion in periodic waveguides. AB - We propose the concept of atom-mediated spontaneous parametric down-conversion, in which photon-pair generation can take place only in the presence of a single two-level emitter, relying on the bandgap evanescent modes of a nonlinear periodic waveguide. Using a guided signal mode, an evanescent idler mode, and an atom-like emitter with the idler's transition frequency embedded in the structure, we find a heralded excitation mechanism, in which the detection of a signal photon outside the structure heralds the excitation of the embedded emitter. We use a rigorous Green's function quantization method to model this heralding mechanism in a 1D periodic waveguide and determine its robustness against losses. PMID- 29140354 TI - Enhancement of Raman scattering of a gaseous medium near the surface of a silver holographic grating. AB - The Letter demonstrates a possibility to enhance the Raman scattering of a gaseous medium due to an enhanced electromagnetic field caused by the excitation of propagating surface plasmon polaritons (PSPPs) on a silver holographic grating. Efficiency of collinear and noncollinear schemes of PSPP excitation on a metal-gaseous medium interface was studied. When using a collinear scheme, we registered an eightfold enhancement of the Raman scattering of atmospheric nitrogen and oxygen, where the average gain near the PSPP-active surface was ~4*103. PMID- 29140355 TI - Enhancing the resolution of a near-eye display with a Pancharatnam-Berry phase deflector. AB - We report an electro-optic image shifter to enhance the resolution of display devices with a Pancharatnam-Berry phase deflector (PBD). The switching time of our PBD is less than 1 ms. Through synchronizing and computational factorization, we are able to double the display resolution for reducing the screen door effect. Such a thin and lightweight PBD image shifter can be easily integrated into wearable display devices. Its potential application for virtual reality and augmented reality is emphasized. PMID- 29140356 TI - On Sagnac frequency splitting in a solid-state ring Raman laser. AB - We report on an accurate measurement of the frequency splitting of an optical rotating ring microcavity made out of calcium fluoride. By measuring the frequencies of the clockwise and counter-clockwise coherent Raman emissions confined in the cavity modes, we show that the frequency splitting is inversely proportional to the refractive index of the cavity host material. The measurement has an accuracy of 1% and unambiguously confirms the classical theoretical prediction based on special theory of relativity. This Letter also demonstrates the usefulness of the ring Raman microlaser for rotation measurements. PMID- 29140357 TI - Experimental evidence for partial spatial coherence in imaging Mueller polarimetry. AB - We demonstrate experimentally the validity of the partial spatial coherence formalism in Mueller polarimetry and show that, in a finite spatial resolution experiment, the measured response is obtained through convolving the theoretical one with the instrument function. The reported results are of primary importance for Mueller imaging systems. PMID- 29140358 TI - Q-switch-pumped supercontinuum for ultra-high resolution optical coherence tomography. AB - In this Letter, we investigate the possibility of using a commercially available Q-switch-pumped supercontinuum (QS-SC) source, operating in the kilohertz regime, for ultra-high resolution optical coherence tomography (UHR-OCT) in the 1300 nm region. The QS-SC source proves to be more intrinsically stable from pulse to pulse than a mode-locked-based SC (ML-SC) source while, at the same time, is less expensive. However, its pumping rate is lower than that used in ML-SC sources. Therefore, we investigate here specific conditions to make such a source usable for OCT. We compare images acquired with the QS-SC source and with a current state-of-the-art SC source used for imaging. We show that comparable visual contrast obtained with the two technologies is achievable by increasing the readout time of the camera to include a sufficient number of QS-SC pulses. PMID- 29140359 TI - Ns-duration transient Bragg gratings in silica fibers. AB - We demonstrate, for the first time to our knowledge, fast all-optical switching in standard silica fibers, based on a transient Bragg grating. The grating is implemented in the fiber using an immunization photo-pretreatment process, followed by side illumination with femtosecond laser pulses through a suitable phase mask. Each pulse is nonlinearly absorbed, creating a thermal grating that is washed out by thermal diffusion. Reflections measured from such gratings are characterized by a very fast rise time, nanoseconds duration, and a high extinction ratio. PMID- 29140360 TI - Ultracompact, high extinction ratio polarization beam splitter-rotator based on hybrid plasmonic-dielectric directional coupling. AB - A polarization beam splitter-rotator based on asymmetric directional coupling is proposed. An ultrashort cross-polarization coupling length of 7.7 MUm is achieved by manipulating the optical field distribution via the plasmonic effect, which is the shortest one reported so far, to the best of our knowledge. At the wavelength of 1.55 MUm, the extinction ratios are as high as 50.9 dB and 28.2 dB for fundamental transverse magnetic (TM0) and transverse electric (TE0) polarizations, respectively, and the corresponding insertion losses are 1.545 dB and 0.037 dB. In addition, the TM0-to-TE0 polarization conversion efficiency is higher than 95% within a bandwidth of 70 nm. PMID- 29140361 TI - Self-referenced octave-wide subharmonic GaP optical parametric oscillator centered at 3 MUm and pumped by an Er-fiber laser. AB - We report an octave-wide mid-IR spectrum (2.3-4.8 MUm) obtained from a subharmonic optical parametric oscillator (OPO) based on a newly developed nonlinear crystal, orientation-patterned gallium phosphide (OP-GaP), which was synchronously pumped by a femtosecond 1560 nm fiber laser. We proved that the octave-wide output is in the form of a single frequency comb. The observed f-to 2f frequency beats, originating directly from the OPO, can be used for self referencing and phase locking of the pump laser comb with no need for supercontinuum generation. With an average output power of ~30 mW, this setup might be beneficial for a variety of spectroscopic applications in the mid-IR. PMID- 29140362 TI - Coupling in a dual metallo-dielectric nanolaser system. AB - To achieve high packing density in on-chip photonic integrated circuits, subwavelength scale nanolasers that can operate without crosstalk are essential components. Metallo-dielectric nanolasers are especially suited for this type of dense integration due to their lower Joule loss and nanoscale dimensions. Although coupling between optical cavities when placed in proximity to one another has been widely reported, whether the phenomenon is induced for metal clad cavities has not been investigated thus far. We demonstrate coupling between two metallo-dielectric nanolasers by reducing the separation between the two cavities. A split in the resonant wavelength and quality factor is observed, caused by the creation of bonding and anti-bonding supermodes. To preserve the independence of the two closely spaced cavities, the resonance of one of the cavities is detuned relative to the other, thereby preventing coupling. PMID- 29140363 TI - Snapshot second-harmonic generation polarimeter based on spectral analysis. AB - A new high-speed second-harmonic generation (SHG) polarimetric method is reported. It is based on the spectral analysis of the SHG radiation emitted by a nonlinear medium excited with circularly polarized femtosecond laser pulses. The setup uses only passive components for polarization encoding and a fast spectrometer for spectral analysis. The method is validated on a z-cut quartz plate, then on a collagen-rich biological tissue with a view to single image polarization-resolved SHG microscopy. PMID- 29140364 TI - Bose-Hubbard hopping due to resonant Rayleigh scattering. AB - We show theoretically that dynamic behavior of light confined in the modes of a nonlinear optical ring cavity characterized by resonant Rayleigh scattering can be described using the Bose-Hubbard model. Nonlinear interaction between clockwise and counterclockwise optical modes results in instability and intermode hopping occurring at a rate defined by the frequency separation of the Rayleigh doublet harmonics. Hopping may lead to an instability and breathing behavior of a Kerr frequency comb observed in the cavity. PMID- 29140365 TI - Narrowband silicon waveguide Bragg reflector achieved by highly ordered graphene oxide gratings. AB - Graphene oxide (GO) ultrathin film can be wafer-scale deposited by spin coating, can be patterned by laser interference lithography and oxygen plasma etching, can be thinned atomically (0.26 nm/min) and oxidized by ozone treatment, and is a relatively transparent and low-refractive-index material compared to pristine graphene. All those unique properties prompt us to realize a low-loss (~5 dB/cm), high-extinction-ratio (19 dB), and narrowband (0.425 nm) GO/silicon hybrid waveguide Bragg reflector by transferring 7-nm-thick GO gratings (n=1.58) atop a silicon strip waveguide. Unlike a sidewall-corrugated strip waveguide Bragg reflector that generally exhibits distorted corrugation profiles and is sensitive to fabrication errors, the as-realized GO-grating-covered strip waveguide Bragg reflector exhibits a stable reflecting wavelength and controllable reflection bandwidth that can be well predicted by numerical simulations. PMID- 29140366 TI - Rotational control of computer generated holograms. AB - We develop a basis for three-dimensional rotation of arbitrary light fields created by computer generated holograms. By adding an extra phase function into the kinoform, any light field or holographic image can be tilted in the focal plane with minimized distortion. We present two different approaches to rotate an arbitrary hologram: the Scheimpflug method and a novel coordinate transformation method. Experimental results are presented to demonstrate the validity of both proposed methods. PMID- 29140367 TI - Compact bolometric radiometer for free-electron lasers in a wavelength range from extreme-ultraviolet to x-rays. AB - A reliable diagnostic device for free-electron lasers (FELs) is essential for both users and the evaluation of FEL sources and beamline optics. Here, we propose a compact bolometric radiometer (CBR) that can operate at room temperature. The CBR is mainly designed for FELs in the wavelength range from the extreme-ultraviolet (EUV) to x-rays; moreover, we confirmed that the proposed device can also be applied to synchrotron radiation. As an application of the CBR, we evaluated an FEL beamline transmission by means of bolometric technique in the EUV range for the first time, to the best of our knowledge. This indicates that the CBR is an effective diagnostic device for FELs. PMID- 29140368 TI - In Vitro Bioactivity Test of Real Dental Implants According to ISO 23317. AB - PURPOSE: The goal of this study was to compare the in vitro bioactivity in simulated body fluid (SBF) of commercially available dental implants. MATERIALS AND METHODS: Bioactivity, according to ISO 23317, of commercially available dental implants with various surface modifications (BIO-surface, SLA, SLActive, TiUnite, and OsseoSpeed) was tested in SBF for 1 and 3 weeks. Surface characterizations, especially calcium and phosphorus surface content before and after the immersion in SBF, were performed. The effect of surface treatment on bioactivity was studied. RESULTS: Differences between surfaces before immersion in SBF were confirmed by Raman spectroscopy, x-ray photoelectron spectroscopy (XPS), energy-dispersive x-ray spectroscopy (EDX), and scanning electron microscope (SEM) analysis. Calcium and phosphorus surface content was increasing within the tested period in the case of two (BIO-surface and SLActive) of the five tested dental implants. Calcium-phosphate precipitation was observed by SEM, XPS, EDX, and x-ray micro-diffraction (MU-XRD) analysis. CONCLUSION: Two (BIO surface from LASAK and SLActive from Straumann) of the five tested dental implants were found to be bioactive, according to ISO 23317. Although it is difficult to unambiguously determine the properties that have influence on the hydroxyapatite precipitation rate, multiple properties that the two surfaces have in common were found. PMID- 29140369 TI - Wear at the Implant-Abutment Interface of Zirconia Abutments Manufactured by Three CAD/CAM Systems. AB - PURPOSE: To evaluate the changes in the external-hexagon surface of the titanium (Ti) implant before and after mechanical cycling, when coupled with zirconia (Zr) abutments (A) manufactured by three computer-aided design/computer-aided manufacturing (CAD/CAM) systems (Neodent Digital, Zirkonzahn, and AmannGirrbach) and the ZrTi abutment manufactured by Neodent. MATERIALS AND METHODS: Four groups were formed (n = 6): titanium implant with Zr AmannGirrbach abutment (AZrAG), with Zr Zirkonzahn abutment (AZrZ), with Zr Neodent abutment (AZrN), and with Zr abutment with infrastructure in Ti Neodent (AZrTiN). Standardized abutments were made from three identical abutments milled in wax. Images of the surface of each side of the hexagons of the implant were obtained by scanning electron microscopy, before and after mechanical cycling, to evaluate the parameters: (1) scratches in the hexagon face; (2) hexagon superior shoulder kneading; (3) hexagon shoulder wear; (4) alterations on the hexagon base; and (5) scratches on the hexagon top. The abutments were coupled with the implants, and Cr-Co crowns were cemented. The implant/abutment/crown assemblies were submitted to mechanical cycling (400 N, 8.0 Hz) for 1 million cycles. The observed changes were classified as follows: absence (0), mild (1), moderate (2), and severe (3). The results were analyzed using the Mann-Whitney, Kruskal-Wallis, and Dunn tests (P < .05). RESULTS: For parameter 1, a significant difference (P = .008) was observed between AZrZ and AZrAG, with more scratches in AZrZ; and between AZrN and AZrTiN (P = .006), with more scratches in AZrN. For parameter 2, a significant difference (P < .05) was observed between AZrZ and AZrAG and between AZrZ and AZrN, with greater kneading in AZrZ; among AZrN and AZrTiN, there was no significant difference (P = .103). For parameter 3, a significant difference (P < .05) was observed between AZrZ and the other groups of Zr, with more wear in AZrZ; between AZrN and AZrTiN, there was no significant difference (P = .107). For parameter 4, a significant difference (P < .05) was observed between AZrZ and AZrN, with more scratches in AZrZ; a significant difference (P = .002) was also observed between AZrN and AZrTiN, with more scratches in AZrN. For parameter 5, a significant difference (P < .05) was observed between AZrZ and AZrAG and between AZrZ and AZrN, with the fewest scratches in AZrZ; a significant difference (P = .006) was also observed between AZrN and AZrTiN, with more alterations in AZrN. Considering all the alterations, the AZrZ group showed more surface alteration, 1.74 (0.99); followed by AZrN, 1.43 (0.92); AZrAG, 1.32 (0.96); and AZrTiN, 0.88 (0.94). CONCLUSION: Among the Neodent abutments, the AZrN group had shown more surface alterations. Among the Zr groups, AZrZ samples had shown the most altered surfaces, suggesting that alterations on the implant/Zr abutment hexagon surfaces are related to the abutment milled hexagon shape. PMID- 29140370 TI - Mandibular Bone Structure Analysis Using Cone Beam Computed Tomography vs Primary Implant Stability: An Ex Vivo Study. AB - PURPOSE: To evaluate the relationship between mandibular bone structure parameters measured on preimplant cone beam computed tomography (CBCT) images and primary implant stability. MATERIALS AND METHODS: Twenty-one hemimandibles were scanned on the 3D Accuitomo 170 CBCT. Next, an implant was placed in each hemimandible, after which insertion torque and implant stability quotient (ISQ) measurements were acquired. The following measurements were performed on the preimplant CBCT scans: bone surface, bone volume, fractal dimension, connectivity, trabecular thickness and spacing, and skeleton analysis. Measurements were performed using various regions of interest in the vicinity of the implant site. In addition, cortical thickness was measured. The correlation between bone structure parameters, insertion torque, and ISQ was calculated. RESULTS: The overall correlation was low to medium (|R| = 0.002-0.723). For the bone around the entire implant site, the highest correlation with ISQ was found for skeleton analysis and trabecular thickness. The highest overall correlation between bone structure and ISQ was found in the coronal region. For insertion torque, no significant correlation was found for the bone around the entire implant; the highest overall correlation was found in the apical region. The highest number of significant correlations between bone structure and primary implant stability were found for trabecular thickness and fractal dimension. CONCLUSION: While each of the investigated bone structure parameters can have a predictive value in terms of primary implant stability, they should be measured at specific regions surrounding a planned implant site, and can provide complementary information regarding the local bone quality. PMID- 29140371 TI - Biofunctionalization of Titanium Granules with Simvastatin for Improving Osteogenic Activity and Antibacterial Properties (Ex Vivo Study). AB - PURPOSE: Titanium-based biomaterials present good biocompatibility, while their osseointegration and antibacterial properties need to be improved. This study aimed to enhance the bone-bonding ability of titanium-based granules, which are intended to be used as bone graft. MATERIALS AND METHODS: The titanium granules were anodized in ethylene glycol-based electrolyte and subsequently annealed to be loaded separately with simvastatin. The samples were then inspected with attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) for drug loading. The release of simvastatin from titanium granule samples was measured after soaking samples in phosphate-buffered saline (PBS) for 30 days using ultraviolet-visible (UV/Vis) spectroscopy. The alkaline phosphatase (ALP) activity of MG63 osteosarcoma-loaded samples was measured, and microbroth dilution assay was performed to evaluate the antibacterial potential of drug loaded and nonloaded titanium granule samples for bacterial growth. RESULTS: The results expressed the gradual and constant release of simvastatin within the duration of the examination. ALP of the samples showed improved activity of anodized and annealed granules, while the antibacterial test illustrated no significant improvement in their bactericidal effects. However, the simvastatin loaded samples showed an improved antibacterial effect compared with nonloaded samples. CONCLUSION: It is assumed that anodizing, annealing, and subsequent simvastatin loading of titanium granules could be used as surface modification to improve osseointegration and restrain bacterial growth and adhesion. It is fair to believe that the results of this study could be used to treat titanium granules as bone graft substitute materials for dental and orthopedic applications. PMID- 29140372 TI - Cytotoxicity of Dental Implants: The Effects of Ultrastructural Elements. AB - PURPOSE: In this in vitro study, the purpose was to assess the cytotoxicity profiles of seven commercial dental implant materials by using cell culture methods on an osteoblastic cell line. MATERIALS AND METHODS: The microstructure of seven commercial dental implants (each given a letter code) was investigated via scanning electron microscopy and energy-dispersive x-ray analysis. Medium extracts were collected on the first and fifth days for each group and tested using MC3T3-E1 cell line. Cytotoxicity was evaluated with Xcelligance System and XTT reagent, and apoptosis was determined by Annexin-V staining. One-way analysis of variance (ANOVA) and Tukey's multiple range tests were used for statistical analyses. In all tests, P was set as .05. RESULTS: ANOVA results disclosed that Ti (P = .001), Na (P = .001), Ca (P = .019), Al (P = .024), and P (P = .020) amounts were significantly different between test materials. Cytotoxicity and apoptosis analyses revealed that implant materials (C) and (E) were the materials with the lowest cell vitality and the highest apoptosis rates among the test materials. Phosphorus was the only element that presented the highest amount in C and E (14.23% and 12.29%, respectively) compared with the other implant materials tested. (F) and (G) had favorable results for all experiments. CONCLUSION: The results suggest that pure dental implant materials with a lower number of additional elements may possess fewer cytotoxic effects than the other implant materials tested in this study. PMID- 29140373 TI - Clinical Considerations of Adapted Drilling Protocol by Bone Quality Perception. AB - PURPOSE: To evaluate insertion torque value (ITV) and marginal bone loss (MBL) of an implant system after a clinically perceived bone quality-adapted drilling. MATERIALS AND METHODS: This multicenter retrospective study included patients treated with implants, conventionally loaded, in completely healed sites. Operators customized the osteotomy preparation according to radiographic assessment and their perception of bone quality. Drilling sequence, bone quality, and ITV were recorded at the time of surgery. Radiographs were taken at the time of implant placement and permanent restoration. MBL between implant placement and permanent restoration was calculated. The implant was used as the statistical unit. Demographic and implant characteristics were shown by means of descriptive statistics. Outcome values were compared using analysis of variance (ANOVA) and Kruskal-Wallis tests. Multiple regression models were used to test the effect of independent variables on ITV and MBL. RESULTS: One hundred eighty-eight implants placed in 87 patients were included in the analysis. The mean observation period was 144 +/- 59 days. The mean ITV was 30.8 +/- 15.1 Ncm. ITV differed significantly based on arches (mandible/maxilla) (P = .001), bone quality (P < .001), implant diameter (P = .032), and drilling protocol (P = .019). Median MBL was 0.05 mm (0.00; 0.24). A significant difference was found between the mandible and maxilla (P = .008) and between drilling protocols (P = .011). In particular, significantly higher MBL was found in the undersized drilling protocol. Multiple regression analysis showed that ITV was influenced by bone quality and implant diameter. MBL was influenced by bone quality, implant diameter, ITV, and the interaction between bone quality and ITV. It was estimated that MBL was greater with increased bone density and ITV. CONCLUSION: Excessive ITV in dense bone can cause negative marginal bone responses. A presurgical radiographic assessment and the perception of bone quality are necessary to select an optimal drilling protocol and to minimize surgical trauma. PMID- 29140374 TI - Implant-Abutment Connections: A Review of Biologic Consequences and Peri implantitis Implications. AB - Clinicians very often have seen marginal bone loss around dental implants at the crest level early on after implant placement and uncovering. Early clinical publications had suggested that this bone loss occurred during the first year of loading. Thus, numerous attempts have been made to minimize or eliminate such bone loss. However, the timing and reason for this bone loss are not always apparent. The objective of this study was to review the evidence regarding marginal bone loss around dental implants from the standpoint of biologic consequences to help understand marginal bone changes around dental implants. One hypothesis for the bone loss around these implants was related to the presence of bacteria in the interfaces between the implant and abutment connections. The literature was reviewed regarding the three major types of implant-abutment crestal connections, including butt-joint, platform-switched, and no interface (tissue-level or one-body). This review article revealed that 1.5 to 2.0 mm of bone loss occurred around bone-level, butt-joint connections when the interface was created because the microgap was wide enough for penetration and colonization of bacteria, and that this bone loss was not observed around implants with no interface because they did not have a contaminated interface at the bone crest. Many studies have shown an advantage in the amount of marginal bone resorption for implants with a platform-switched connection, and there appears to be a significantly different biologic reaction. Recent publications indicate that such contaminated implant-abutment connections might have an effect on peri implantitis and failure over time. PMID- 29140375 TI - Plasma of Argon Increases Cell Attachment and Bacterial Decontamination on Different Implant Surfaces. AB - PURPOSE: This in vitro study tested the effects of argon atmospheric pressure dielectric barrier discharge (APDBD) on different implant surfaces with regard to physical changes, bacterial decontamination, and osteoblast adhesion. MATERIALS AND METHODS: Seven hundred twenty disks with three different surface topographies machined (MAC), titanium plasma-sprayed (TPS), and zirconia-blasted and acid etched (ZRT)-were tested in this experiment. Bacterial adhesion tests were performed repeatedly on a simplified biofilm of Streptococcus mitis. Bacteria were incubated in the presence of the samples, which were subsequently either left untreated as controls or treated with APDBD for 30, 60, and 120 seconds. Samples were then metalized, prior to the recurring acquisition of images using a scanning electronic microscope (SEM). Protein adsorption, surface wettability, and early biologic response were determined for both treated (120 seconds) and untreated implant surfaces. For depicting the eukaryotic cell behavior, preosteoblastic murine cells were used. Cells were conveniently stained, and nuclei were counted. Cell viability was assessed by a chemiluminescent assay at 1, 2, and 3 days. RESULTS: On all treated samples, values of the contact angle measurements were lower than 10 degrees. The untreated samples showed values of contact angle of 80, 100, and 110 degrees, respectively, for MAC, TPS, and ZRT. The protein adsorption on TPS and ZRT was significantly increased after the plasma of argon treatment. However, no significant effect was noted on the MAC disks. The number and the cell spreading area of adherent osteoblasts significantly increased in all treated surfaces. Nonetheless, argon treatment did not influence the osteoblast proliferation and viability at different time points. Bacteria adhesion was significantly reduced, even after 60 seconds of argon treatment. CONCLUSION: Preliminary data showed that argon atmospheric pressure dielectric barrier discharge disinfected the implant surface, with potential to promote osteoblast attachment and spreading, suggesting this may be a possible approach to clean a peri-implantitis-contaminated implant surface. PMID- 29140376 TI - Evaluating Maxillary Sinus Septa Using Cone Beam Computed Tomography: Is There a Difference in Frequency and Type Between the Dentate and Edentulous Posterior Maxilla? AB - PURPOSE: To analyze and compare the frequency, type, and location of maxillary sinus septa in patients with a dentate and an edentulous posterior maxilla using cone beam computed tomography (CBCT) imaging. MATERIALS AND METHODS: The study consisted of 100 maxillary sinuses: 50 from patients with a dentate and 50 from patients with an edentulous posterior maxilla. The aim was to assess the frequency, morphology, and location of maxillary sinus septa in axial, sagittal, and coronal CBCT images. Images were only included in this study provided that patients were older than 30 years of age, at least one maxillary sinus was completely visible in the field of view (FOV), and the sinus membrane exhibited a mucosal thickening of a maximum 4 mm. Differences regarding age, sex, side, septa location, and type of dentition (dentate/edentulous posterior maxilla) were analyzed. RESULTS: The mean age of the 100 patients (66 women, 34 men) was 58.3 years. A total of 60 sinus septa were found in exactly half of the evaluated sinuses. The major part of the septa was found on the floor of the maxillary sinus (n = 34/56.7%). Of these, the majority was located in the posterior maxilla in the region of the second molars (n = 27/79.4%). The most common orientation of the septa was coronal (63.3%), followed by septa in relation to the infraorbital canal (23.3%). Regarding the status of the dentition in the posterior maxilla in relation to the distribution of sinus septa, septa were present in 26 (52%) dentate and in 24 (48%) edentulous regions. Thus, for a potential influence of the status of the dentition in the posterior maxilla on the frequency of sinus septa, no significant impact was found (P = .69). CONCLUSION: Sinus septa are frequent anatomical structures, and are found equally often in patients with a dentate and an edentulous posterior maxilla. This is of clinical relevance, as patients with missing teeth in the posterior area of the maxilla are often in need of a sinus floor elevation (SFE) procedure when dental implant placement is intended. As sinus septa are reported to be an important reason for surgical complications during SFE, a three-dimensional radiographic examination using CBCT prior to surgery might be helpful for diagnostic evaluation and treatment planning. PMID- 29140377 TI - Influence of the Prosthetic Index on Fracture Resistance of Morse Taper Dental Implants. AB - PURPOSE: Manufacturers have inserted a prosthetic index, an internal hexagon to guide prosthetic components inside Morse taper implants. However, it is still unclear if this mechanism could decrease the mechanical strength of Morse taper implants. The aim of this study was to evaluate the influence of the prosthetic index inside Morse taper implants on fracture resistance compared with nonindexed implants. MATERIALS AND METHODS: Fifty-seven Morse taper implants, with 11.5 degree angulation of the internal conical portion, were divided into three groups: implants without the prosthetic index and solid Morse taper universal post (group 1), implants with the prosthetic index and solid Morse taper universal post (group 2), and implants and abutments with the prosthetic index (group 3). All groups were modeled for finite element stress analysis (FEA), simulating force application of a perpendicular load to the abutments. Fracture resistance (n = 10) was determined under the same condition. Dynamic loading (n = 9) was also performed. The statistical analysis was performed using one-way analysis of variance (ANOVA), and the Tukey test was applied (alpha = .05). The metallographic analysis was used to identify the fracture distribution and the microstructure of the titanium alloy. RESULTS: There was no statistically significant difference between the values of all tested groups. According to the FEA, the prosthetic index region was out of stress. The mean fracture resistances and loading test were 353.7 N and 200 N for group 1, 397.3 N and 170 N for group 2, and 372.0 N and 160 N for group 3, respectively. Metallographic analysis showed a macroscopic failure pattern just as demonstrated by FEA. CONCLUSION: The presence of the prosthetic index on Morse taper implants did not decrease its resistance to fracture for the tested implants. PMID- 29140378 TI - Perception by Osseointegrated Dental Implants Supporting a Fixed Prosthesis: A Prospective Study. AB - PURPOSE: Osseointegrated implants have been shown to transmit a certain sensibility termed as osseoperception. The purpose of this study was to determine the perception by implants over a period of 6 months after loading in comparison to the natural dentition. MATERIALS AND METHODS: Twenty subjects (ages 40 to 50 years) were included in this split-mouth clinical trial. The subjects were divided into two groups (n = 10) as follows: group 1-subjects with recently cemented implant-supported fixed prosthesis opposing natural teeth; group 2 subjects with recently cemented implant-supported fixed prosthesis in both arches. The implant-supported prostheses were considered as the test sites, whereas natural teeth on the contralateral side were considered as the control. Articulating papers of varied thickness were placed interocclusally in the posterior region in a predetermined random order of true and false insertions. The subjects' ability to perceive the presence/absence of the test papers was recorded for every insertion. The evaluation was performed immediately after cementation and at 1 week, 3 months, and 6 months after cementation. The minimum interocclusal thickness detected by the subjects at the test and control sites at different time intervals was used for further analysis. RESULTS: All subjects with implant-supported prostheses perceived a certain thickness of articulating paper. The minimum interocclusal thickness detected by the implant-supported prosthesis decreased postloading; however, the difference was not statistically significant (P > .008). At the end of the follow-up period, the minimum interocclusal thickness detected by the implants in group 1 was similar to the controls, whereas it was significantly higher than the controls in group 2 (P < .05). CONCLUSION: There was progressive improvement in the perception by implant supported prostheses during the follow-up period, and it was nearing the perception by natural teeth in subjects with implants opposing natural teeth. PMID- 29140379 TI - Seven-Year Follow-up of Full-Arch Prostheses Supported by Four Implants: A Prospective Study. AB - PURPOSE: To evaluate biologic and prosthetic outcomes of implant-supported mandibular full-arch fixed prostheses treated with the All-on-4 treatment concept after 7 years. MATERIALS AND METHODS: Patients were selected to receive full-arch fixed immediate prostheses supported by four implants up to 72 hours after surgery. The following biologic aspects were evaluated: Plaque Index (PI) and Bleeding Index (BI), implant stability by resonance frequency, and marginal bone loss (MBL) measured with the aid of periapical radiographs. The prosthetic complications evaluated were related to screw loosening, framework or acrylic teeth fractures, or fractures of implants. The means of implant stability and MBL were subjected to analysis of variance and the Tukey test (P < .05). For PI and BI, the Friedmann test was used (P < .05). RESULTS: Sixteen patients (12 women and 4 men; mean age: 59.1 years) received 64 implants, and in all patients, two implants were positioned axially at the incisor region and two distally tilted implants at the region of the second premolars or molars. Patients were evaluated immediately after surgery and at 1, 2, and 7 years. Fifteen patients attended the recall after 2 years; one patient could not attend the scheduled follow-up visit and was excluded from the sample. In the 7-year evaluation, the sample size decreased to 12 patients; one could not attend because of a severe disease, and two were deceased. The cumulative implant survival rate was 100%. There was a significant (P < .0162) decrease in PI at the 1- and 7-year evaluations (71.87% and 47.92%, respectively), while the BI was the same at 1 and 7 years (43.75%). There was no statistical difference in MBL (P = .12) and implant stability (P = .48) between axial and tilted implants (P = .48). The survival rate of prostheses was 100%. The following technical complications were observed: tooth fracture occurred in one patient (6.25%); loosening of prosthetic screws and abutments were observed in three patients (18.75%); after 5 years, three patients (18.75%) had changed the denture acrylic teeth because of the replacement of the removable total maxillary prostheses with fixed implant prostheses. CONCLUSION: For the 12 patients who attended the recall after 7 years, implant loss was not found, the implant stability was high, MBL was low, and prosthetic complications were easily solved. Thus, it can be concluded that rehabilitation with implant-supported mandibular full-arch fixed prostheses with four implants has proved to be a treatment with a high survival rate. PMID- 29140380 TI - Success and Failure Rates of 1,344 6- to 9-mm-Length Rough-Surface Implants Placed at the Time of Transalveolar Sinus Elevations, Restored with Single Crowns, and Followed for 60 to 229 Months in Function. AB - PURPOSE: To assess the success and stability of 6-, 7-, 8-, and 9-mm-long, 6.5-mm wide-neck tissue-level implants placed at the time of transalveolar sinus augmentation therapy, utilizing a trephine and osteotome approach, which were restored with single crowns. MATERIALS AND METHODS: In total, 1,344 implants were placed by the author, varying in length from 6 to 9 mm, with parallel-wall 4.8-mm diameter implant bodies and 6.5-mm-diameter implant necks. The implants were restored with single abutments and crowns by a variety of practitioners. They were followed for 60 to 229 months in function, with a mean time of 121.1 months in function. Implant success was evaluated by the author utilizing a combination of the Albrektsson et al criteria, and buccal and palatal/lingual bone sounding under anesthesia. RESULTS: The overall cumulative success rate was 98.8%. One hundred ninety 6-mm-long implants demonstrated a cumulative success rate of 97.5% at a mean time of 109.2 months in function. Eleven 7-mm-long implants demonstrated a cumulative success rate of 100% at a mean time of 218.5 months in function. One thousand ninety-four 8-mm-long implants demonstrated a cumulative success rate of 98.9% at a mean time of 112.3 months in function. Forty-nine 9-mm long implants demonstrated a cumulative success rate of 100% at a mean time of 212.1 months in function. CONCLUSION: Implants of 6 to 9 mm in length, placed at the time of trephine and osteotome transalveolar sinus elevation procedures and restored with abutments and single crowns, demonstrate a high level of long-term clinical success, assuming specific comprehensive treatment criteria are met. PMID- 29140381 TI - Consistency of Dental Hygiene Therapy Utilizing Various Dental Hygiene Instrumentation and Its Effect on Peri-implant Health and Survival of Dental Implants: A Retrospective Study. AB - PURPOSE: The purpose of this retrospective study was to provide practice-based evidence to determine if the consistency of dental hygiene therapy, despite utilizing instrumentation literature that has proven to cause alterations to implant surfaces, affects peri-implant health or survival. MATERIALS AND METHODS: The study sample comprised patients with implant-supported full-arch fixed dental prostheses who were distributed into two groups. The consistent hygiene group patients had dental hygiene therapy at a minimum biannually and were exposed to at least three dental hygiene instrument materials. The inconsistent hygiene group patients had dental hygiene therapy at a minimum once every 3 to 10 years and were exposed to at least three dental hygiene instrument materials. Years of survival free of soft tissue pathology and/or implant failure were estimated. Continuous features were summarized with medians, interquartile ranges (IQRs), and ranges; categorical features were summarized with frequency counts and percentages. RESULTS: Among 48 patients in the consistent hygiene group, 11 patients experienced soft tissue pathology or implant failure at a median of 11.3 years; among 99 patients in the inconsistent hygiene group, 17 patients experienced soft tissue pathology or implant failure at a median of 4.8 years. The survival free of soft tissue pathology or implant failure rate at 5 years was 94% for the consistent hygiene group and 91% for the inconsistent hygiene group. The survival free of soft tissue pathology or implant failure rate at 20 years was 70% for the consistent hygiene group and 79% for the inconsistent hygiene group (P = .91). CONCLUSION: Although no statistical differences were found between the groups, this practice-based evidence suggests more consistent dental hygiene therapy increases the median in years in which soft tissue pathology or implant failure is present. PMID- 29140382 TI - Implant Mandibular Overdentures Retained by Immediately Loaded Implants: A 1-Year Randomized Trial Comparing the Clinical and Radiographic Outcomes Between Mini Dental Implants and Standard-Sized Implants. AB - PURPOSE: The aim of this 1-year randomized trial was to evaluate and compare the clinical and radiographic performance of four immediately loaded mini dental implants (MDIs) and two immediately loaded standard-sized tissue-level (STL) implants, placed in the interforaminal region of the mandible and used to retain mandibular overdentures (IODs) in completely edentulous patients. MATERIALS AND METHODS: A total of 50 completely edentulous patients wearing conventional maxillary dentures and complaining about insufficient retention of their mandibular dentures were divided into two groups; 25 patients received four MDIs and 25 patients received two STL implants. The marginal bone loss (MBL) at the mesial and distal sides of each implant was assessed by means of standardized intraoral radiographs after a period of 1 year. Implant success and survival rates were also calculated. RESULTS: Immediate loading was possible for all patients in the first group. In the second group, an immediate loading protocol could not be applied for 10 patients. These patients were treated with a delayed loading protocol. A mean MBL of 0.42 +/- 0.56 mm for the MDIs and 0.54 +/- 0.49 mm for the immediately loaded STL implants was recorded at the end of the evaluation period. There was no statistically significant difference between the MDIs and the immediately loaded STL implants. Two MDIs failed, resulting in a survival rate of 98%. The success rate was 91%. For the immediately loaded conventional implants, the survival rate was 100% and the success rate 96.7% after 1 year of function. However, in 10 patients, the immediate loading protocol could not be followed. CONCLUSION: Considering the limitations of this short-term clinical study, immediate loading of four unsplinted MDIs or two splinted STL implants to retain mandibular overdentures seems to be a feasible treatment option. The marginal bone level changes around the MDIs were well within the clinically acceptable range. PMID- 29140383 TI - A Randomized Split-Mouth Clinical Trial on Effectiveness of Amnion-Chorion Membranes in Alveolar Ridge Preservation: A Clinical, Radiologic, and Morphometric Study. AB - PURPOSE: Recent case reports suggest that amnion-chorion membranes (ACM) and dense polytetrafluoroethylene membranes (dPTFE) can be left exposed during ridge preservation. The aim of this study was to compare the effectiveness of these membranes in ridge preservation, particularly when they are intentionally left exposed. MATERIALS AND METHODS: A split-mouth, single-blind, randomized trial design was used to compare treatments with the two membranes in 22 nonmolar sites on the same arch. Ridge dimensions were recorded clinically and with cone beam computed tomography prior to and 3 months after ridge preservation. Postoperative discomfort was recorded with Visual Analog Scale (VAS) forms. Mixed-model analysis of variance was used to test significance. RESULTS: Clinical and radiographic ridge dimensions were not significantly different between the two treatments. ACM sites had significantly more osteoid and higher bone volume density but significantly less graft particles and bone surface density compared with dPTFE. Mineralized bone area and soft tissue area were not significantly different between the two treatments. ACM sites had significantly lower postoperative VAS scores compared with dPTFE. CONCLUSION: Intentionally exposed ACM is equally effective in ridge preservation compared with dPTFE. Additionally, ACM use may aid in reducing postoperative VAS scores, and potentially result in better quality of bone available for implant placement, as evidenced by improved histomorphometric measures. PMID- 29140384 TI - Two Bilateral Zygomatic Implants Placed and Immediately Loaded: A Retrospective Chart Review with Up-to-54-Month Follow-up. AB - PURPOSE: To report on the outcome of placement of two bilateral zygomatic implants with an immediately loaded prosthesis. MATERIALS AND METHODS: A retrospective chart review was conducted of all patients treated with zygomatic implants between August 1, 2011 and June 6, 2016. All patients had at least two zygomatic implants placed bilaterally and immediately loaded with a provisional prosthesis the same day of implant placement. The implants were Nobel Biocare TiUnite or machined surface with lengths of 30 to 52.5 mm. All patients were treated by a team consisting of one surgeon, a restorative dentist or prosthodontist, an anesthesiologist, and a laboratory technician. Implant success was defined as successful integration of the implant; prosthetic success was defined as retention of the prosthesis under normal function. RESULTS: One hundred five zygomatic implants were placed and immediately loaded in 28 patients over a period of 1 to 60 months. Ages ranged from 46 to 81 years, with 26 female and 2 male patients. All the implants were placed by one surgeon. The immediate load on the day of implant placement was completed by either one of 2 prosthodontists or 11 restorative dentists. Implant success was 96% (101/105). All four failed implants were in one patient and were TiUnite surface coated. CONCLUSION: This study demonstrated that two zygomatic implants bilaterally placed and immediately loaded with a full-arch splinted prosthesis will provide a predictable outcome. PMID- 29140385 TI - Virtual Treatment Planning for Implant-Retained Nasal Prosthesis: A Clinical Report. AB - Osseointegrated craniofacial implants have improved retention and patients' perceptions of implant-retained nasal prostheses; however, the determination of the available bone sites for implant placement post-rhinectomy is difficult. This case report describes the use of cone beam computed tomography scanning and computer-assisted virtual planning in conjunction with digital photographs for rehabilitation of a facial defect with an implant-retained silicon nasal prosthesis. Two implants were planned in the anatomical area with adequate bone volume to achieve favorable cosmetic outcomes and accessibility for hygiene maintenance. The implant-retained nasal prosthesis resulted in a meaningful improvement in the esthetics without the need for plastic surgery. In such cases, the post-rhinectomy reconstruction surgery should be limited to preparation of the surgical defect area for an implant-retained prosthesis. Silicone prostheses are reliable alternatives to surgery and should be considered in selected cases. PMID- 29140386 TI - Retrospective Study of Survival of Extraoral Endosseous Craniofacial Implants in Head and Neck Surgery Patients. AB - PURPOSE: To determine the survival rate of implants placed in different craniofacial locations and factors affecting survival. MATERIALS AND METHODS: This study retrospectively reviewed a consecutive series of patients treated at the Royal Melbourne Hospital who received craniofacial implants for an array of benign and malignant conditions. Implant survival per site and cumulative survival were determined. Surgical and implant variables were assessed using the Kaplan-Meier and Cox Proportional Hazards Models. RESULTS: Fifty-two patients had 156 implants placed to reconstruct the nose, orbit, and ears. A total of 43 implants failed (overall survival: 72.4%) in the orbital (29/63, failure rate: 46%) and auricular sites (14/70, failure rate: 17%). No implants failed in the nasal site (0/9). Three-, 5-, and 10-year cumulative survival was also determined. Independent risk factors for decreased survival included postoperative radiation therapy (P = .005, RR: 3.2, 95% CI: 1.4 to 7.0), implants placed in the orbit (P = .004, RR: 5.0, 95% CI: 1.6 to 15.2), and implants that were not loaded with a prosthesis (P = .007, RR: 2.7, 95% CI: 1.3 to 5.4). CONCLUSION: Failure rates varied according to site in this cohort of patients. A number of independent risk factors affecting implant survival in extraoral sites were identified. PMID- 29140387 TI - Full-Mouth Rehabilitation with Calvarium Bone Grafts and Dental Implants for a Papillon-Lefevre Syndrome Patient: Case Report. AB - Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder of keratinization associated with palmoplantar keratoderma and severe periodontitis resulting in complete edentulism in late adolescence. The pathognomonic dental features of PLS are pathologic migration, hypermobility, and exfoliation of the teeth without any signs of root resorption. It has been suggested that an effective way to treat PLS patients presenting early in the disease progression is extraction of the erupted primary dentition or hopeless permanent teeth followed by antibiotic coverage with periodontal therapy for the remaining teeth. Unfortunately, studies have shown that this regimen only temporarily delays the progression of periodontal disease and does not prevent further tooth loss and bone destruction in the long term. Post-tooth loss, atrophic ridges make conventional prosthodontic rehabilitation quite challenging, and more recently, implant-supported prostheses have been considered as a viable alternative. In a PLS patient, implant placement is complicated by inadequate bone volume; thus, bone augmentation techniques or the use of short implants is often considered. When large volumes of bone are required, parietal calvarium bone can be used to predictably reconstruct severe defects. A PLS patient aged 21 years presented a chief complaint of ill-fitting conventional complete dentures. The patient had severely atrophic ridges, requiring significant bone augmentation for an implant supported prosthesis. The present case is the first example of bone augmentation using autogenous calvarium parietal graft followed by endosseous implant placement and prosthetic restoration in a PLS patient. PMID- 29140388 TI - Titanium Activates the DNA Damage Response Pathway in Oral Epithelial Cells: A Pilot Study. AB - PURPOSE: To evaluate the effect of titanium (Ti) particles on oral epithelial cell homeostasis and the potential of dental implants to release Ti debris upon insertion. MATERIALS AND METHODS: Dental implants with varying surface treatments were employed to determine the feasibility of particle release during implant placement as well as the impact of free Ti debris on oral epithelial cells. Ti particles derived from implant surfaces were isolated and cultured in direct contact with normal oral epithelial cells for 48 hours. Further, cells were fixed and processed for immunofluorescence assay to detect the activation of the DNA damage response (DDR) using CHK2 and BRCA1 molecular markers. Positive cells demonstrating DNA damage were quantified and statistically analyzed. RESULTS: Ti particles derived from implants containing phosphate-enriched titanium oxide (PETO), fluoride-modified (FM), and grit-blasted (GB) surface treatments were able to activate CHK2 and trigger the recruitment of BRCA1 in oral epithelial cells. Also, implants with GB surfaces were able to release Ti particles upon implant placement. CONCLUSION: The results indicate that Ti debris may be detached from the implant surface upon placement. Also, free Ti particles can trigger DDR signaling in oral epithelial cells. These findings suggest that Ti particles/debris released into a surgical wound may contribute to the disruption of epithelial homeostasis, and potentially compromise the oral epithelial barrier. PMID- 29140389 TI - Influence of rhBMP-2 on Guided Bone Regeneration for Placement and Functional Loading of Dental Implants: A Radiographic and Histologic Study in Dogs. AB - PURPOSE: Evidence on the outcomes of functional loading placed in recombinant human bone morphogenetic protein 2 (rhBMP-2)/acellular collagen sponge (ACS) induced bone is lacking. The aim of this study was to verify whether guided bone regeneration (GBR) with rhBMP-2/ACS enhances regeneration of missing bone and osseointegration of dental implants subject to functional loading. MATERIALS AND METHODS: Two bilateral standardized large saddle-type defects (~10 * 10 * 6 mm) were surgically created in each mandible of seven beagle dogs 2 months after tooth extraction. Defects were immediately reconstructed randomly using rhBMP-2 (O-BMP or InFuse) soaked in ACS, deproteinized bovine bone mineral (DBBM) granules, or ACS alone as surgical control and subsequently covered with collagen membrane. Screw-type sand-blasted, acid-etched dental implants were placed 3 months later into the reconstructed defects and into adjacent bone. Osseointegration was allowed to progress for 3 months before functional loading of 3 months until sacrifice. RESULTS: Significantly more bone fill was radiographically observed for GBR with rhBMP-2/ACS (O-BMP: 92.5%, InFuse: 79%) in comparison to the DBBM (52%) and ACS alone groups (56.6%). Osseointegration was achieved and maintained in all experimental defects challenged by prostheses driven functional load. The bone density ranged from 37.49% in the ACS group to 64.9% in the rhBMP-2/ACS (InFuse) group with no significance. The highest mean percentage of BIC was found in rhBMP-2/ACS (InFuse: 52.98%) with no statistical difference. Crestal bone resorption was observed around implants placed in reconstructed areas without any significant difference. CONCLUSION: GBR with rhBMP-2/ACS provided the greatest bone fill among the three treatment procedures. GBR with rhBMP-2/ACS showed efficacy for placement, osseointegration, and functional loading of titanium implants in alveolar ridge defects. PMID- 29140390 TI - A carboxylated graphene nanodisks/glucose oxidase nanotags and Mn:CdS/TiO2 matrix based dual signal amplification strategy for ultrasensitive photoelectrochemical detection of tumor markers. AB - Graphene nanodisks with good conductivity and plenty of edge sites were synthesized to load glucose oxidase (GRD-GOD) and coupled with a Mn2+ doped CdS quantum dot (QD) modified TiO2 electrode (CdS:Mn/TiO2) for a highly sensitive photoelectrochemical (PEC) immunoassay. The specific immune-recognition behaviour can bring the GRD-GOD labelled antigen into the antibody immobilized CdS:Mn/TiO2 interface and dramatically enhance the photocurrent response via a dual signal amplification strategy. First, graphene nanodisks with a strong electron transfer capacity can improve the conductivity of both the insulating protein layers and the CdS:Mn/TiO2 matrix, thus facilitating the regeneration of trapped carriers and hot electrons in the CdS:Mn QD films and enhancing the PEC performance. Second, graphene nanodisks introduce a great number of GOD molecules into a PEC detection process, which catalyze glucose to produce numerous molecules of H2O2. The latter act as sacrificial electron donors to scavenge photogenerated holes, retard the electron-hole recombination, and significantly improve the photo-to electron conversion efficiency. Based on the dual signal amplification strategy and using a carcinoembryonic antigen as a model target, a highly sensitive PEC immunoassay was therefore developed with an extremely low limit of detection of 5.65 fg mL-1 and a rather wide linear range from 10 fg mL-1 to 1 ng mL-1. The immunoassay showed good reproducibility and stability, as well as good selectivity and high accuracy in serum sample analysis. In this regard, PEC immunosensors may have great application potential for the screening of tumor markers and the prevention and monitoring of serious diseases. PMID- 29140392 TI - Improving the relevance and efficiency of human exposure assessments within the process of regulatory risk assessment. AB - The process for undertaking exposure assessments varies dependent on its purpose. But for exposure assessments to be relevant and accurate, they are reliant on access to reliable information on key exposure determinants. Acquiring such information is seldom straightforward and can take significant time and resources. This articles examines how the application of tiered and targeted approaches to information acquisition, within the context of European human health risk assessments, can not only lead to improvements in the efficiency and effectiveness of the process but also in the confidence of stakeholders in its outputs. The article explores how the benefits might be further improved through the coordination of such activities, as well as those areas that represent barriers to wider international harmonisation. PMID- 29140393 TI - Magneto-structural correlation of hexakis-dmso cobalt(ii) complex. AB - The magnetostructural correlation of the hexakis-dmso cobalt(ii) complex, [Co(dmso)6](BPh4)2 (dmso: dimethylsulfoxide), was investigated by single-crystal X-ray diffraction study and magnetic measurements. The magnetic analysis concluded the negative Delta value (H = Delta(L - 2/3) + E(L - L) - (3/2)kappalambdaL.S + beta[-(3/2)kappaLu + geSu].Hu (u = x, y, z)), and this was explained by the tetragonal elongation of the octahedral geometry. The magnetostructural correlation was ascertained by both the angular overlap model calculation and the density functional theory calculation. PMID- 29140396 TI - A 2D self-assembled MoS2/ZnIn2S4 heterostructure for efficient photocatalytic hydrogen evolution. AB - Semiconductor photocatalysis for hydrogen production is a promising route to address current energy demands. It is still a great challenge to spatially separate photogenerated electrons and holes in bulk photocatalysts because of the long carrier transport pathway from the bulk to the surface. 2D heterostructured photocatalysts with the type II band alignment can not only shorten the carrier transport pathway, but also create an electric field at the interface to suppress the carrier recombination. However, ultrathin and intimate-contact 2D heterostructured photocatalysts have rarely been achieved so far. Herein, we reported that ZnIn2S4 nanosheets were self-assembled on few-layer MoS2 nanosheets to fabricate ultrathin and intimate-contact 2D heterostructured photocatalysts. This 2D heterostructure was formed thanks to the strong electrostatic adsorption between MoS2 and ZnIn2S4. Under visible light irradiation, the H2 evolution rate of 2D MoS2/ZnIn2S4 heterostructured photocatalysts can reach 8898 MUmol g-1 h-1, which is almost 16 times higher than that of the pure ZnIn2S4 photocatalysts. The dramatically enhanced photocatalytic performance was ascribed to the better charge separation and the accelerated surface reaction due to the heterostructure and more active sites provided by MoS2. These results provided a new insight for the design and development of 2D heterostructured photocatalysts. PMID- 29140397 TI - Progress in the understanding of the pathology of allergic asthma and the potential of fruit proanthocyanidins as modulators of airway inflammation. AB - Allergic asthma is a chronic inflammatory lung disease characterized by sensitization of the airways, and the development of immunoglobulin E antibodies, to benign antigens. The established pathophysiology of asthma includes recurrent lung epithelial inflammation, excessive mucus production, bronchial smooth muscle hyperreactivity, and chronic lung tissue remodeling, resulting in reversible airflow restriction. Immune cells, including eosinophils and the recently characterized type 2 innate lymphoid cells, infiltrate into the lung tissue as part of the inflammatory response in allergic asthma. It is well established that a diet high in fruits and vegetables results in a reduction of the risk of developing inflammatory diseases. Secondary plant metabolites, such as proanthocyanidins which are found in apples, blackcurrants, boysenberries, cranberries, and grapes, have shown promising results in reducing or preventing allergic asthma airway inflammation. Recent evidence has also highlighted the importance of microbiome-mediated metabolism of plant polyphenols in modulating the immune system. In this review, we will discuss advances in our understanding of the pathophysiology of allergic asthma, including the role of the microbiome in lung immune function, and how proanthocyanidins modulate the airway inflammation. We will highlight the potential of dietary proanthocyanidins to impact on allergic asthma and the immune system. PMID- 29140398 TI - Legacy organochlorine pollutants in glacial watersheds: a review. AB - Northern Hemisphere alpine glaciers have been identified as a point of concentration and reemergence of legacy organochlorine pollutants (OCPs). In this review, we compile a selection of published literature combining long-range, global atmospheric transport and distribution-based compartmental environmental flux models, as well as data from glacial meltwater, ice core, crevasse and proglacial lake sediment studies. Regional studies of ice and meltwater in alpine glaciers of the northern latitudes show similarities in sample deposition profiles and concentration due to chemical atmospheric residence time, precipitation type and glacier flow rates. In glaciated locations near areas of extensive OCPs use, such as the Swiss and Italian Alps, glacier sample concentrations are higher, while in areas more distant from use, including Arctic nations, OCPs concentrations in glaciers are significantly lower. Our review identifies alpine glaciers co-located with regions characterized by OCPs use as a significant organochlorine pollutant distribution source, secondary in timing and location to direct deposition, with subsequent bioaccumulation and potential human risk impacts. PMID- 29140404 TI - Evaluation of Opportunities to Improve Hematopathology Diagnosis for Vietnam Pathologists. AB - Objectives: We evaluate the need for, feasibility of, and impediments to improving hematopathology diagnoses for cancer hospitals in Vietnam. Methods: Two hematopathologists from the United States visited three major cancer treatment hospitals in Vietnam to workshop a sampling of difficult hematopathology cases. With Vietnamese pathologists, they toured histopathology, immunohistochemistry, and ancillary laboratory facilities. Results: Automated tissue processors and slide staining equipment were documented for each of the three hospitals. Between seven and 11 hematopathology cases were reviewed for each hospital. Exact/complete diagnostic concordance was 50% or less for all three laboratories. The major impediments to accurate specific diagnoses were limitations of immunohistochemical stains, limited stains available in house, and, for one of the hospitals, difficulty with interpretation of the immunohistochemistry. Conclusions: Vietnamese pathologists would benefit from hematopathology training or opportunities to consult with hematopathologists in the United States. Expert hematopathology consultation services are currently unavailable within Vietnam, as postgraduate training for laboratory physicians consists of residency training in anatomic pathology only. Limitations in the quality of histopathology and immunohistochemistry could impose a barrier to success of efforts to improve hematopathology diagnosis. Implementation of a histopathology and immunohistochemistry quality improvement program might overcome this limitation. PMID- 29140403 TI - KLHL6 Is Preferentially Expressed in Germinal Center-Derived B-Cell Lymphomas. AB - Objectives: KLHL6 is a recently described BTB-Kelch protein with selective expression in lymphoid tissues and is most strongly expressed in germinal center B cells. Methods: Using gene expression profiling as well as immunohistochemistry with an anti-KLHL6 monoclonal antibody, we have characterized the expression of this molecule in normal and neoplastic tissues. Protein expression was evaluated in 1,058 hematopoietic neoplasms. Results: Consistent with its discovery as a germinal center marker, KLHL6 was positive mainly in B-cell neoplasms of germinal center derivation, including 95% of follicular lymphomas (106/112). B-cell lymphomas of non-germinal center derivation were generally negative (0/33 chronic lymphocytic leukemias/small lymphocytic lymphomas, 3/49 marginal zone lymphomas, and 2/66 mantle cell lymphomas). Conclusions: In addition to other germinal center markers, including BCL6, CD10, HGAL, and LMO2, KLHL6 immunohistochemistry may prove a useful adjunct in the diagnosis and future classification of B-cell lymphomas. PMID- 29140405 TI - The Apoptotic Crypt Abscess: An Underappreciated Histologic Finding in Gastrointestinal Pathology. AB - Objectives: To differentiate apoptotic crypt abscesses (ACAs) from neutrophilic crypt abscesses (NCAs). Methods: Cases with crypt abscesses were classified as containing ACAs, NCAs, or mixed crypt abscesses (MCAs) by H&E staining. Sections were stained with cleaved caspase 3 and myeloperoxidase and recategorized. Results: Fifty-nine cases were reviewed: inflammatory bowel disease (IBD; n = 33), acute cellular rejection (n = 5), graft vs host disease (GVHD; n = 14), cytomegalovirus (n = 5), and drug reaction (n = 2). Concordance was seen in 59%, with most reclassifications resulting from a change of ACAs to MCAs. When cases were classified as having NCA vs those with apoptosis (ACA and MCA), there was 85% agreement (P < .01). NCAs were present in IBD (96%) and not in GVHD or drug injury. Crypt abscesses with apoptosis were seen in 18% of IBD and 96% of non-IBD cases. Conclusions: ACAs and MCAs can be distinguished from NCAs and may be a diagnostically useful finding. PMID- 29140406 TI - Smad3-STAT3 crosstalk in pathophysiological contexts. AB - Smad3 and STAT3 are intracellular molecules that transmit signals from plasma membrane receptors to the nucleus. Smad3 operates downstream of growth/differentiation factors that utilize activin receptor-like kinase (ALK)-4, 5, or 7, such as transforming growth factor-beta (TGF-beta), activin, and myostatin. STAT3 principally functions downstream of cytokines that exert their effects via gp130 and Janus family kinases, including interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and oncostatin M. Accumulating evidence indicates that Smad3 and STAT3 engage in crosstalk in a highly context-dependent fashion, cooperating in some conditions while acting antagonistically each other in others. Here, we review the crosstalk between Smad3 and STAT3 in various biological contexts, including early tumorigenesis, epithelial-mesenchymal transition, fibrosis, and T cell differentiation. PMID- 29140407 TI - Targeted Treatment of Yaws With Household Contact Tracing: How Much Do We Miss? AB - Yaws is a disabling bacterial infection found primarily in warm and humid tropical areas. The World Health Organization strategy mandates an initial round of total community treatment (TCT) with single-dose azithromycin followed either by further TCT or active case-finding and treatment of cases and their contacts (the Morges strategy). We sought to investigate the effectiveness of the Morges strategy. We employed a stochastic household model to study the transmission of infection using data collected from a pre-TCT survey conducted in the Solomon Islands. We used this model to assess the proportion of asymptomatic infections that occurred in households without active cases. This analysis indicated that targeted treatment of cases and their household contacts would miss a large fraction of asymptomatic infections (65%-100%). This fraction was actually higher at lower prevalences. Even assuming that all active cases and their households were successfully treated, our analysis demonstrated that at all prevalences present in the data set, up to 90% of (active and asymptomatic) infections would not be treated under household-based contact tracing. Mapping was undertaken as part of the study "Epidemiology of Yaws in the Solomon Islands and the Impact of a Trachoma Control Programme," in September-October 2013. PMID- 29140408 TI - Philadelphia Chromosome-like Mixed-Phenotype Acute Leukemia Demonstrating P2RY8 CRLF2 Fusion and JAK1 Mutation. AB - Objectives: Philadelphia chromosome-like (Ph-like) genetic alterations define a subset of B lymphoblastic leukemia/lymphoma (B-ALL), which represents a separate provisional entity in the World Health Organization 2016 updated classification. However, these alterations have not been described outside the context of B-ALL. Methods: Cytogenomic array and molecular analysis identified a Ph-like signature in a mixed-phenotype acute leukemia (MPAL), B/myeloid, confirmed using conventional immunophenotypic and cytochemical analysis. Results: Flow cytometry identified a blast population demonstrating a B-cell lineage and myeloperoxidase positivity. A P2RY8-CRLF2 fusion and JAK1 mutation were detected, both of which are associated with Ph-like features. Conclusions: To our knowledge, this is the first report of Ph-like MPAL, which may represent a new diagnostic entity. We emphasize the need for refinement of diagnostic criteria for MPALs and highlight an opportunity for expansion of inclusion criteria in ongoing clinical trials studying the use of tyrosine kinase inhibitor therapy to include cases of Ph-like MPAL. PMID- 29140409 TI - Ebolavirus interferon antagonists-protein interaction perspectives to combat pathogenesis. AB - Zaire ebolavirus, one of the most pathogenic species of Ebolavirus, is a significant threat to the human community being both highly infectious and lethal. The viral proteins (VPs), specifically VP24 and VP35, antagonize the interferon (IFN) proteins accountable for human immune response. Several efforts have been made to design vaccines and therapeutics drugs. However, the success is not encouraging because of limited knowledge about the binding site information of the VPs. Such limitations stem largely from the highly infectious nature of the virus that requires specialized personnel and biosafety laboratories. As an alternative, computational techniques have also been adopted to improve the success rate of drug discovery. This article elaborates on the interactions between viral and human IFN proteins that lead to IFN antagonism. A computational framework is proposed after evaluating existing computational studies. This protein interaction and protein design-based computational framework identified critical interacting residues of the VP (VP24) responsible for the formation of a stable complex with the human KPNA5 (karyopherin alpha proteins 5). The mutations of those critical residues, as demonstrated in this article, affected the overall stability of the complex because of a sharp decrease in both the number of hydrogen bonds and possible charge-charge interactions. Therefore, we proposed that the framework could be an effective alternative to experimental work for destabilizing interactions between the VPs and human proteins responsible for IFN induction and response. PMID- 29140410 TI - Rare coronary anomaly with hemodynamic consequence: squeezing of the right coronary artery. PMID- 29140412 TI - Alcohol consumption and lung cancer risk in never smokers: a pooled analysis of case-control studies. AB - Background: Lung cancer is the deadliest cancer in developed countries but the etiology of lung cancer risk in never smokers (LCRINS) is largely unknown. We aim to assess the effects of alcohol consumption, in its different forms, on LCRINS. Methods: We pooled six multi-center case-control studies developed in the northwest of Spain. Cases and controls groups were composed of never smokers. We selected incident cases with anatomopathologically confirmed lung cancer diagnoses. All participants were personally interviewed. We performed two groups of statistical models, applying unconditional logistic regression with generalized additive models. One considered the effect of alcohol type consumption and the other considered the quantity of each alcoholic beverage consumed. Results: A total of 438 cases and 863 controls were included. Median age was 71 and 66, years, respectively. Adenocarcinoma was the predominant histological type, comprising 66% of all cases. We found that any type of wine consumption posed an OR of 2.20 OR 95%CI 1.12-4.35), and spirits consumption had an OR of 1.90 (95%CI 1.13-3.23). Beer consumption had an OR of 1.33 (95%CI 0.82 2.14). These results were similar when women were analyzed separately, but for men there was no apparent risk for any alcoholic beverage. The dose-response analysis for each alcoholic beverage revealed no clear pattern. Conclusions: Wine and spirits consumption might increase the risk of LCRINSs, particularly in females. These results have to be taken with caution given the limitations of the present study. PMID- 29140411 TI - Effect of Angiotensin II and ACTH on Adrenal Blood Flow in the Male Rat Adrenal Gland In Vivo. AB - Angiotensin II (Ang II) and adrenocorticotropic hormone (ACTH) regulate adrenal vascular tone in vitro through endothelial and zona glomerulosa cell-derived mediators. The role of these mediators in regulating adrenal blood flow (ABF) and mean arterial pressure (MAP) was examined in anesthetized rats. Ang II (0.01 to 100 ng/kg) increased ABF [maximal increase of 97.2 +/- 6.9 perfusion units (PUs) at 100 ng/kg] and MAP (basal, 115 +/- 7 mm Hg; Ang II, 163 +/- 5 mm Hg). ACTH (0.1 to 1000 ng/kg) also increased ABF (maximum increase of 91.4 +/- 10.7 PU) without changing MAP. ABF increase by Ang II was partially inhibited by the nitric oxide (NO) synthase inhibitor N-nitro-l-arginine methyl ester (L-NAME) (maximum increase of 72.9 +/- 4.2 PU), the cytochrome P450 inhibitor miconazole (maximum increase of 39.1 +/- 6.8 PU) and the epoxyeicosatrienoic acid (EET) antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) (maximum increase of 56.0 +/- 13.7 PU) alone, whereas combined administration of miconazole and L-NAME (maximum increase of 16.40 +/- 8.98 PU) ablated it. These treatments had no effect on MAP. Indomethacin did not affect the increase in ABF or MAP induced by Ang II. The ABF increase by ACTH was partially ablated by miconazole and 14,15 EEZE but not by L-NAME. Steroidogenic stimuli such as Ang II and ACTH increase ABF to promote oxygen and cholesterol delivery for steroidogenesis and aldosterone transport to its target tissues. The increases in ABF induced by Ang II are mediated by release of NO and EETs, whereas ABF increases with ACTH are mediated by EETs only. PMID- 29140413 TI - Comparison of Chemical Constituents in Scrophulariae Radix Processed by Different Methods based on UFLC-MS Combined with Multivariate Statistical Analysis. AB - Scrophulariae Radix is one of the most popular traditional Chinese medicines (TCMs). Primary processing of Scrophulariae Radix is an important link which closely related to the quality of products in this TCM. The aim of this study is to explore the influence of different processing methods on chemical constituents in Scrophulariae Radix. The difference of chemical constituents in Scrophulariae Radix processed by different methods was analyzed by using ultra fast liquid chromatography-triple quadrupole-time of flight mass spectrometry coupled with principal component analysis and orthogonal partial least squares discriminant analysis. Furthermore, the contents of 12 index differential constituents in Scrophulariae Radix processed by different methods were simultaneously determined by using ultra fast liquid chromatography coupled with triple quadrupole-linear ion trap mass spectrometry. Gray relational analysis was performed to evaluate the different processed samples according to the contents of 12 constituents. All of the results demonstrated that the quality of Scrophulariae Radix processed by "sweating" method was better. This study will provide the basic information for revealing the change law of chemical constituents in Scrophulariae Radix processed by different methods and facilitating selection of the suitable processing method of this TCM. PMID- 29140414 TI - Dose-finding designs for cumulative toxicities using multiple constraints. AB - This article addresses the concern regarding late-onset dose-limiting toxicities (DLT), moderate toxicities below the threshold of a DLT and cumulative toxicities that may lead to a DLT, which are mostly disregarded or handled in an ad hoc manner when determining the maximum tolerated dose (MTD) in dose-finding cancer clinical trials. An extension of the Time-to-Event Continual Reassessment Method (TITE-CRM) which allows for the specification of toxicity constraints on both DLT and moderate toxicities, and can account for partial information is proposed. The method is illustrated in the context of an Erlotinib dose-finding trial with low DLT rates, but a significant number of moderate toxicities leading to treatment discontinuation in later cycles. Based on simulations, our method performs well at selecting the dose level that satisfies both the DLT and moderate-toxicity constraints. Moreover, it has similar probability of correct selection compared to the TITE-CRM when the true MTD based on DLT only and the true MTD based on grade 2 or higher toxicities alone coincide, but reduces the probability of recommending a dose above the MTD. PMID- 29140415 TI - APOBEC3A/B deletion polymorphism and cancer risk. AB - Activity of the apolipoprotein B mRNA editing enzyme, catalytic-polypeptide-like (APOBEC) enzymes has been linked to specific mutational processes in human cancer genomes. A germline APOBEC3A/B deletion polymorphism is associated with APOBEC dependent mutational signatures, and the deletion allele has been reported to confer an elevated risk of some cancers in Asian populations, while the results in European populations, so far, have been conflicting. We genotyped the APOBEC3A/B deletion polymorphism in a large population-based sample consisting of 11 106 Caucasian (Norwegian) individuals, including 7279 incident cancer cases (1769 breast, 1360 lung, 1585 colon, and 2565 prostate cancer) and a control group of 3827 matched individuals without cancer (1918 females and 1909 males) from the same population. Overall, the APOBEC3A/B deletion polymorphism was not associated with risk of any of the four cancer types. However, in subgroup analyses stratified by age, we found that the deletion allele was associated with increased risk for lung cancer among individuals <50 years of age (OR 2.17, CI 1.19-3.97), and that the association was gradually reduced with increasing age (P = 0.01). A similar but weaker pattern was observed for prostate cancer. In support of these findings, the APOBEC3A/B deletion was associated with young age at diagnosis among the cancer cases for both cancer forms (lung cancer: P = 0.02; dominant model and prostate cancer: P = 0.03; recessive model). No such associations were observed for breast or colon cancer. PMID- 29140417 TI - Fasting plasma glucose in young adults free of diabetes is associated with cognitive function in midlife. AB - Background: Evidence for an association of fasting plasma glucose (FPG) with cognitive function in adults free of diabetes is scarce and based on middle-aged and older adults. We examined the association of FPG, measured at age 30, and of change in FPG from age 30 to 43, with cognitive function at age 50. Methods: 505 nondiabetic participants of the population-based Jerusalem Lipid Research Clinic (LRC) cohort study had baseline FPG, 2-h post-oral challenge plasma glucose (OGTT) and insulin determined at ages 28-32, and FPG and OGTT again at ages 41 46. Subsequently at ages 48-52, global cognitive function and its five specific component domains were assessed with a NeuroTrax computerized test battery, using multiple linear regression and multivariable logistic models. Results: Hyperglycemia (FPG >= 5.6 mmol/l vs. <5.6 mmol/l) at baseline was associated with poorer global cognitive function in midlife (predominantly in the visual spatial and attention domains), independent of socio-demographic characteristics, life style variables, body mass index (BMI), and inflammatory and biochemical variables (standardized Beta = -0.121, P = 0.002, plinear trend(FPG continuous) =0.016). Similarly, increased odds for low-ranked (lowest fifth) global cognition was evident (ORper mmol/l FPG=2.31, 95% CI = 1.30-4.13, P = 0.005). Baseline OGTT, insulin resistance (HOMA-IR) and change in FPG and OGTT over 13 years were not associated with cognition. Conclusion: A higher FPG in young adults was associated with lower cognitive performance in midlife. Although we cannot dismiss the possibility of reverse causation, hyperglycemia at a young age may be a modifiable risk factor for low-ranked cognitive function in midlife. PMID- 29140419 TI - Dietary glutamine, glutamate and mortality: two large prospective studies in US men and women. AB - Background: Emerging studies have related circulating glutamine metabolites to various chronic diseases such as cardiovascular disease and cancer; diet is the major source of nutrients involved in glutamine metabolism. However, it remains unknown whether dietary intakes of glutamine, glutamate,and their ratio are related to total and cause-specific mortality. Methods: We followed 74 082 women from the Nurses' Health Study (1984-2012) and 42 303 men from the Health Professionals Follow-up Study (1986-2012), who were free of cardiovascular disease and cancer at baseline. Diet was updated every 2 to 4 years by using validated food frequency questionnaires. The content of glutamine and glutamate in foods was calculated based on protein fractions generated from gene sequencing methods and adjusted for total energy intake. Results: We documented 30 424 deaths during 2 878 344 person-years of follow-up. After adjustment for potential confounders including lifestyle and dietary factors, higher intakes of glutamine and glutamine-to-glutamate ratio were associated with significantly lower risk of total and cause-specific mortality. Compared with people in the lowest quintile of dietary glutamine-to-glutamate ratio, the pooled hazard ratio (HR) in the highest quintile was 0.87 [95% confidence interval (CI): 0.84, 0.91; P for trend < 0.001) for total mortality, 0.81 (95% CI: 0.75, 0.88; P for trend < 0.001) for cardiovascular mortality, and 0.93 (95% CI: 0.87, 0.99; P for trend = 0.01) for cancer mortality. Conclusions: We found dietary glutamine and glutamine-to glutamate ratio were inversely related to risk of mortality, particularly cardiovascular mortality, independent of other dietary and lifestyle factors, in US men and women. PMID- 29140421 TI - Decomposition of the Total Effect in the Presence of Multiple Mediators and Interactions. AB - Mediation analysis allows decomposing a total effect into a direct effect of the exposure on the outcome and an indirect effect operating through a number of possible hypothesized pathways. Recent studies have provided formal definitions of direct and indirect effects when multiple mediators are of interest and have described parametric and semiparametric methods for their estimation. Investigating direct and indirect effects with multiple mediators, however, can be challenging in the presence of multiple exposure-mediator and mediator mediator interactions. In this paper we derive a decomposition of the total effect that unifies mediation and interaction when multiple mediators are present. We illustrate the properties of the proposed framework in a secondary analysis of a pragmatic trial for the treatment of schizophrenia. The decomposition is employed to investigate the interplay of side effects and psychiatric symptoms in explaining the effect of antipsychotic medication on quality of life in schizophrenia patients. Our result offers a valuable tool to identify the proportions of total effect due to mediation and interaction when more than one mediator is present, providing the finest decomposition of the total effect that unifies multiple mediators and interactions. PMID- 29140420 TI - Growth Trajectories, Breast Size, and Breast-Tissue Composition in a British Prebirth Cohort of Young Women. AB - Mammographic percent density, the proportion of fibroglandular tissue in the breast, is a strong risk factor for breast cancer, but its determinants in young women are unknown. We examined associations of magnetic resonance imaging (MRI) breast-tissue composition at age 21 years with prospectively collected measurements of body size and composition from birth to early adulthood and markers of puberty (all standardized) in a sample of 500 nulliparous women from a prebirth cohort of children born in Avon, United Kingdom, in 1991-1992 and followed up to 2011-2014. Linear models were fitted to estimate relative change in MRI percent water, which is equivalent to mammographic percent density, associated with a 1-standard-deviation increase in the exposure of interest. In mutually adjusted analyses, MRI percent water was positively associated with birth weight (relative change (RC) = 1.03, 95% confidence interval (CI): 1.00, 1.06) and pubertal height growth (RC = 1.07, 95% CI: 1.02, 1.13) but inversely associated with pubertal weight growth (RC = 0.86, 95% CI: 0.84, 0.89) and changes in dual-energy x-ray absorptiometry percent body fat mass (e.g., for change between ages 11 years and 13.5 years, RC = 0.96, 95% CI: 0.93, 0.99). Ages at thelarche and menarche were positively associated with MRI percent water, but these associations did not persist upon adjustment for height and weight growth. These findings support the hypothesis that growth trajectories influence breast tissue composition in young women, whereas puberty plays no independent role. PMID- 29140418 TI - Perioperative management of the obese surgical patient. AB - Introduction: The escalation in the prevalence of obesity throughout the world has led to an upsurge in the number of obese surgical patients to whom perioperative care needs to be delivered. Sources of data: After determining the scope of the review, the authors used PubMed with select phrases encompassing the words in the scope. Both preclinical and clinical reports were considered. Areas of agreement: There were no controversies regarding preoperative management and the intraoperative care of the obese surgical patient. Areas of controversy: Is there a healthy obese state that gives rise to the obesity paradox regarding postoperative complications? Growing points: This review considers how to prepare for and manage the obese surgical patient through the entire spectrum, from preoperative assessment to possible postoperative intensive care. Areas timely for developing research: What results in an obese patient developing 'unhealthy' obesity? PMID- 29140423 TI - Ventricular assist device implantation in a young patient with non-compaction cardiomyopathy and hereditary spherocytosis. AB - A case of a 15-year-old female patient with acute heart failure due to non compaction cardiomyopathy and hereditary anaemia (hereditary spherocytic elliptocytosis) requiring ventricular assist device implantation as a bridge to transplantation is presented. The possible effects of mechanical stress on erythrocytes potentially induced by mechanical circulatory support remains unclear, but it may lead to haemolytic crisis in patients suffering from hereditary anaemia. In our case, ventricular assist device therapy was feasible, and haematological complications did not occur within 6 weeks of bridging our patient to heart transplantation. PMID- 29140422 TI - Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors. AB - Background: To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods: We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin-etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with 'distant' disease. The Kaplan-Meier method was used to estimate PFS and OS. Results: With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER 'distant' cohort between 2000 and 2014, P-value <0.0001. Conclusion: The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER 'distant' cohort. PMID- 29140424 TI - Cholesterol variability: a marker for increased risk or a risk factor? PMID- 29140425 TI - Annular rupture during transcatheter aortic valve replacement: novel treatment with amplatzer vascular plugs. PMID- 29140426 TI - Development and Validation of Stereo Selective Method for the Separation of Razoxane Enantiomers in Hydrophilic Interaction Chromatography. AB - A novel sensitive and high throughput chiral hydrophilic interaction chromatographic (HILIC) method was developed to separate razoxane enantiomers namely levrazoxane (R-isomer) and dexrazoxane (DEX) in pharmaceutical active ingredient samples. A systematic chiral chromatographic screening system was employed in using multiple HPLC chromatographic modes on various polysaccharide based chiral columns to obtain a potential separation between enantiomers. HPLC separation was achieved using a mobile phase of aqueous 10 mM ammonium bicarbonate and mixture of organic modifiers (70/30, v/v) in the ratio of (5/95, v/v) on an immobilized polysaccharide based chiral stationary phase namely CHIRALPAK IE-3. The chromatographic resolution between the enantiomers was found to be not <8 in the developed method. The values of the limit of detection and limit of quantification of DEX and levrazoxane were found to be 0.0037, 0.011 and 0.0043, 0.013 MUgmL-1, respectively. The validated method yielded good results regarding precision, linearity, selectivity and found to be superior in sensitivity when compared to reported method for the accurate quantification of undesired enantiomer. PMID- 29140427 TI - Sudden Unexpected Cardiac Death on Monday in Younger and Older Men: The Manitoba Follow-up Study. PMID- 29140428 TI - HPV-negative, but not HPV-positive, oropharyngeal carcinomas induce fibroblasts to support tumour invasion through micro-environmental release of HGF and IL-6. AB - Human papillomavirus (HPV) infection is causally related to a subset of oropharyngeal carcinomas (OPC) and is linked to a more favourable prognosis compared to HPV-negative OPC. The mechanisms underlying this effect on prognosis are not fully understood, but interactions with the tumour microenvironment may be pivotal. Here, we investigated the role of the tumour microenvironment in HPV positive compared to HPV-negative cancer using 2D and 3D modelling of OPC interactions with stromal fibroblasts. HPV-negative, but not HPV-positive, OPC derived cell lines induced a rapid fibroblast secretory response that supported 2D cancer cell migration and invasion in vitro. Array profiling of this HPV negative induced fibroblast secretome identified hepatocyte growth factor (HGF) as the principal secreted factor that promoted cancer cell migration. The interaction between HPV-negative cell lines and fibroblasts in 2D was prevented using c-Met (HGF receptor) inhibitors, which further restricted both HPV-negative and positive cell invasion in 3D co-culture models. Furthermore, we discovered a synergistic relationship between HGF and IL-6 in the support of migration that relates JAK activation to HGF responsiveness in HPV-negative lines. In summary, our data show significant differences in the interactions between HPV-positive and HPV-negative OPC cells and stromal fibroblasts. In addition, we, provide in vitro evidence to support the clinical application of c-MET inhibitors in the control of early HPV-negative OPC. PMID- 29140429 TI - Factors Associated With 30-Day Mortality Rate in Respiratory Infections Caused by Streptococcus pneumoniae. AB - In multivariable analysis of associations between initial antibiotic therapy and clinical outcomes in 5005 patients with microbiologically confirmed Streptococcus pneumoniae infections, "discordant" empiric antibiotic therapy was not associated with 30-day mortality rate (hazard ratio, 0.94; 95% confidence interval, .67 1.32). PMID- 29140430 TI - The European Society for Medical Oncology (ESMO) Precision Medicine Glossary. AB - Background: Precision medicine is rapidly evolving within the field of oncology and has brought many new concepts and terminologies that are often poorly defined when first introduced, which may subsequently lead to miscommunication within the oncology community. The European Society for Medical Oncology (ESMO) recognises these challenges and is committed to support the adoption of precision medicine in oncology. To add clarity to the language used by oncologists and basic scientists within the context of precision medicine, the ESMO Translational Research and Personalised Medicine Working Group has developed a standardised glossary of relevant terms. Materials and methods: Relevant terms for inclusion in the glossary were identified via an ESMO member survey conducted in Autumn 2016, and by the ESMO Translational Research and Personalised Medicine Working Group members. Each term was defined by experts in the field, discussed and, if necessary, modified by the Working Group before reaching consensus approval. A literature search was carried out to determine which of the terms, 'precision medicine' and 'personalised medicine', is most appropriate to describe this field. Results: A total of 43 terms are included in the glossary, grouped into five main themes-(i) mechanisms of decision, (ii) characteristics of molecular alterations, (iii) tumour characteristics, (iv) clinical trials and statistics and (v) new research tools. The glossary classes 'precision medicine' or 'personalised medicine' as technically interchangeable but the term 'precision medicine' is favoured as it more accurately reflects the highly precise nature of new technologies that permit base pair resolution dissection of cancer genomes and is less likely to be misinterpreted. Conclusions: The ESMO Precision Medicine Glossary provides a resource to facilitate consistent communication in this field by clarifying and raising awareness of the language employed in cancer research and oncology practice. The glossary will be a dynamic entity, undergoing expansion and refinement over the coming years. PMID- 29140431 TI - Microvascular Adaptations to Exercise: Protective Effect of PGC-1 Alpha. AB - BACKGROUND: Sedentary behavior and obesity are major risk factors for cardiovascular disease. Regular physical activity has independent protective effects on the cardiovascular system, but the mechanisms responsible remain elusive. Recent studies suggest that the protein peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1alpha) participates in the response to exercise training. We hypothesized that the arterioles of athletes maintain dilation to flow despite combined inhibition of multiple vasodilators, but loss of PGC-1alpha renders these vessels susceptible to inhibition of a single vasodilator pathway. In addition, arterioles from overweight and obese individuals will display an an exercise-like phenotype when PGC-1alpha is activated. METHODS: Isolated arterioles from exercise-trained (ET) and from mildly overweight or obese subjects (body mass index >25) were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the absence and presence of compounds that inhibit various endothelium dependent vasodilators. RESULTS: Microvessels of ET subjects displayed robust dilation that could not be inhibited through targeting the combination of nitric oxide, prostaglandins, and hydrogen peroxide, but were inhibited via interference with membrane hyperpolarization. Loss of PGC-1alpha (siRNA) in the microcirculation of ET subjects eliminates this vasodilatory robustness rendering vessels susceptible to blockade of H2O2 alone. Pharmacological activation of PGC 1alpha with alpha-lipoic acid in isolated microvessels from sedentary, overweight, and obese subjects increases arteriolar resistance to vasodilator blockade and protects against acute increases in intraluminal pressure. CONCLUSIONS: These findings suggest that the microvascular adaptations to exercise training, and the exercise-induced protection against acute vascular stress in overweight/obese subjects, are mediated by PGC-1alpha. PMID- 29140433 TI - IL-27/IL-27 Receptor Signaling Provides Protection in Clostridium difficile Induced Colitis. AB - Background: Clostridium difficile is a leading cause of nosocomial infection. The role of cytokine interleukin-27 (IL-27) in the immunopathology of C. difficile infection (CDI) remains unknown. Methods: The production of IL-27 was determined in human and murine CDI. Furthermore, wild-type (WT) and IL-27 receptor-deficient (WSX-1-/-) mice were treated with an antibiotic mixture and infected with C. difficile to investigate the effects of IL-27 on host response to CDI. Results: IL-27 production was elevated during CDI in humans and mice. Infected WSX-1-/- mice experienced increased weight loss, enhanced colonic histology damage, less C. difficile clearance, and decreased survival compared to WT controls during CDI. IL-27 administration reduced CDI-associated mortality and tissue pathology with improved C. difficile clearance in WT mice after C. difficile challenge. Mechanistically, IL-27-mediated host defense against CDI was associated with downregulation of IL-17A and IL-23, but upregulation of IL-10 and interferon gamma during CDI. Conclusions: Our data suggest a previously unrecognized role for IL-27 in the pathogenesis of CDI, potentially providing new insight for IL-27 mediated protection against C. difficile-induced pathology. PMID- 29140432 TI - Long-term Immune Response to Yellow Fever Vaccination in Human Immunodeficiency Virus (HIV)-Infected Individuals Depends on HIV RNA Suppression Status: Implications for Vaccination Schedule. AB - Background: In human immunodeficiency virus (HIV)-infected individuals, the immune response over time to yellow fever vaccination (YFV) and the necessity for booster vaccination are not well understood. Methods: We studied 247 participants of the Swiss HIV Cohort Study (SHCS) with a first YFV after HIV diagnosis and determined their immune responses at 1 year, 5 years, and 10 years postvaccination by yellow fever plaque reduction neutralization titers (PRNTs) in stored blood samples. A PRNT of 1:>=10 was regarded as reactive and protective. Predictors of vaccination response were analyzed with Poisson regression. Results: At vaccination, 82% of the vaccinees were taking combination antiretroviral therapy (cART), 83% had suppressed HIV RNA levels (<400 copies/mL), and their median CD4 T-cell count was 536 cells/MUL. PRNT was reactive in 46% (95% confidence interval [CI], 38%-53%) before, 95% (95% CI, 91% 98%) within 1 year, 86% (95% CI, 79%-92%) at 5 years, and 75% (95% CI, 62%-85%) at 10 years postvaccination. In those with suppressed plasma HIV RNA at YFV, the proportion with reactive PRNTs remained high: 99% (95% CI, 95%-99.8%) within 1 year, 99% (95% CI, 92%-100%) at 5 years, and 100% (95% CI, 86%-100%) at 10 years. Conclusions: HIV-infected patients' long-term immune response up to 10 years to YFV is primarily dependent on the control of HIV replication at the time of vaccination. For those on successful cART, immune response up to 10 years is comparable to that of non-HIV-infected adults. We recommend a single YFV booster after 10 years for patients vaccinated on successful cART, whereas those vaccinated with uncontrolled HIV RNA may need an early booster. PMID- 29140434 TI - Managing public health data: mobile applications and mass vaccination campaigns. AB - In response to data collection challenges during mass immunization events, Denver Public Health developed a mobile application to support efficient public health immunization and prophylaxis activities. The Handheld Automated Notification for Drugs and Immunizations (HANDI) system has been used since 2012 to capture influenza vaccination data during Denver Health's annual employee influenza campaign. HANDI has supported timely and efficient administration and reporting of influenza vaccinations through standardized data capture and database entry. HANDI's mobility allows employee work locations and schedules to be accommodated without the need for a paper-based data collection system and subsequent manual data entry after vaccination. HANDI offers a readily extensible model for mobile data collection to streamline vaccination documentation and reporting, while improving data quality and completeness. PMID- 29140436 TI - '...What God and the Angels Know of us?' Character, Autonomy, and best Interests in Minimally Conscious State. AB - Determining the best interests of incapacitated patients has been observed to be an opaque area of the law, and this is no less so in decisions about the (non )treatment of patients in the minimally conscious state. A systematic examination of the way best interests are used in judgments relating to this population suggests that narratives involving the character of the patient frequently form an important plank of judicial reasoning. Since insights into the concept of best interests may be gained by an engagement with the philosophy of well-being, I identify the court's character-based approach with perfectionist theories of well being. These use human nature to furnish an objective list of abilities needed for human flourishing. Guided by the Mental Capacity Act (MCA), this list becomes focused primarily on autonomy. Incapacitated patients are assumed to have wishes, but to lack agency. Judges search for these wishes in narratives about the patient and supply the means to exercise these wishes. This analysis suggests three concerns about the court's approach: first, by placing so great a weight on autonomy, the law offers an impoverished account of human nature; secondly, adversarial law encourages partial determinations of character, and this raises concerns about whether the courts are equipped to explore the complexities of character narratives; and, thirdly, experimental psychology indicates character is not as predictable as an assessment under MCA requires. While character narratives may unburden decision-makers, this analysis suggests the limits of autonomy may have been exceeded in this area of the law. PMID- 29140435 TI - HMDB 4.0: the human metabolome database for 2018. AB - The Human Metabolome Database or HMDB (www.hmdb.ca) is a web-enabled metabolomic database containing comprehensive information about human metabolites along with their biological roles, physiological concentrations, disease associations, chemical reactions, metabolic pathways, and reference spectra. First described in 2007, the HMDB is now considered the standard metabolomic resource for human metabolic studies. Over the past decade the HMDB has continued to grow and evolve in response to emerging needs for metabolomics researchers and continuing changes in web standards. This year's update, HMDB 4.0, represents the most significant upgrade to the database in its history. For instance, the number of fully annotated metabolites has increased by nearly threefold, the number of experimental spectra has grown by almost fourfold and the number of illustrated metabolic pathways has grown by a factor of almost 60. Significant improvements have also been made to the HMDB's chemical taxonomy, chemical ontology, spectral viewing, and spectral/text searching tools. A great deal of brand new data has also been added to HMDB 4.0. This includes large quantities of predicted MS/MS and GC-MS reference spectral data as well as predicted (physiologically feasible) metabolite structures to facilitate novel metabolite identification. Additional information on metabolite-SNP interactions and the influence of drugs on metabolite levels (pharmacometabolomics) has also been added. Many other important improvements in the content, the interface, and the performance of the HMDB website have been made and these should greatly enhance its ease of use and its potential applications in nutrition, biochemistry, clinical chemistry, clinical genetics, medicine, and metabolomics science. PMID- 29140438 TI - Corrigendum: SnRK1 phosphorylation of FUSCA3 positively regulates embryogenesis, seed yield, and plant growth at high temperature in Arabidopsis. PMID- 29140437 TI - Metabolite profiling at the cellular and subcellular level reveals metabolites associated with salinity tolerance in sugar beet. AB - Sugar beet is among the most salt-tolerant crops. This study aimed to investigate the metabolic adaptation of sugar beet to salt stress at the cellular and subcellular levels. Seedlings were grown hydroponically and subjected to stepwise increases in salt stress up to 300 mM NaCl. Highly enriched fractions of chloroplasts were obtained by non-aqueous fractionation using organic solvents. Total leaf metabolites and metabolites in chloroplasts were profiled at 3 h and 14 d after reaching the maximum salinity stress of 300 mM NaCl. Metabolite profiling by gas chromatography-mass spectrometry (GC-MS) resulted in the identification of a total of 83 metabolites in leaves and chloroplasts under control and stress conditions. There was a lower abundance of Calvin cycle metabolites under salinity whereas there was a higher abundance of oxidative pentose phosphate cycle metabolites such as 6-phosphogluconate. Accumulation of ribose-5-phosphate and ribulose-5-phosphate coincided with limitation of carbon fixation by ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). Increases in glycolate and serine levels indicated that photorespiratory metabolism was stimulated in salt-stressed sugar beet. Compatible solutes such as proline, mannitol, and putrescine accumulated mostly outside the chloroplasts. Within the chloroplast, putrescine had the highest relative level and probably assisted in the acclimation of sugar beet to high salinity stress. The results provide new information on the contribution of chloroplasts and the extra-chloroplast space to salinity tolerance via metabolic adjustment in sugar beet. PMID- 29140441 TI - The Complete Phylogeny of Pangolins: Scaling Up Resources for the Molecular Tracing of the Most Trafficked Mammals on Earth. AB - Pangolins, considered the most-trafficked mammals on Earth, are rapidly heading to extinction. Eight extant species of these African and Asian scale-bodied anteaters are commonly recognized, but their evolutionary relationships remain largely unexplored. Here, we present the most comprehensive phylogenetic assessment of pangolins, based on genetic variation of complete mitogenomes and 9 nuclear genes. We confirm deep divergence among Asian and African pangolins occurring not later than the Oligocene-Miocene boundary ca. 23 million years ago (Ma) (95% HPD = 18.7-27.2), limited fossil evidence suggesting dispersals from Europe. We recognize 3 genera including Manis (Asian pangolins), Smutsia (large African pangolins), and Phataginus (small African pangolins), which first diversified in the Middle-Upper Miocene (9.8-13.3 Ma) through a period of gradual cooling coinciding with a worldwide taxonomic diversification among mammals. Based on large mitogenomic distances among the 3 genera (18.3-22.8%) and numerous (18) morphological traits unique to Phataginus, we propose the subfamily Phatagininae subfam. nov. to designate small African pangolins. In contrast with the morphological-based literature, our results establish that the thick-tailed pangolin (Manis crassicaudata) is sister-species of the Sunda (Manis javanica) and Palawan (Manis culionensis) pangolins. Mitogenomic phylogenetic delineations supported additional pangolin species subdivisions (n = 13), including 6 African common pangolin (Phataginus tricuspis) lineages, but these patterns were not fully supported by our multi-locus approach. Finally, we identified more than 5000 informative mitogenomic sites and diagnostic variation from 5 nuclear genes among all species and lineages of pangolins, providing an important resource for further research and for effectively tracing the worldwide pangolin trade. PMID- 29140440 TI - Cord Metabolic Profiles in Obese Pregnant Women: Insights Into Offspring Growth and Body Composition. AB - Context: Offspring exposed in utero to maternal obesity have an increased risk of later obesity; however, the underlying mechanisms remain unknown. Objective: To assess the effect of an antenatal lifestyle intervention in obese women on the offspring's cord blood metabolic profile and to examine associations of the cord blood metabolic profile with maternal clinical characteristics and offspring anthropometry at birth and age 6 months. Design: Randomized controlled trial and cohort study. Setting: The UK Pregnancies Better Eating and Activity Trial. Participants: Three hundred forty-four mother-offspring pairs. Intervention: Antenatal behavioral lifestyle (diet and physical activity) intervention. Main Outcome Measures: Targeted cord blood metabolic profile, including candidate hormone and metabolomic analyses. Results: The lifestyle intervention was not associated with change in the cord blood metabolic profile. Higher maternal glycemia, specifically fasting glucose at 28 weeks gestation, had a linear association with higher cord blood concentrations of lysophosphatidylcholines (LPCs) 16.1 (beta = 0.65; 95% confidence interval: 0.03 to 0.10) and 18.1 (0.52; 0.02 to 0.80), independent of the lifestyle intervention. A principal component of cord blood phosphatidylcholines and LPCs was associated with infant z scores of birth weight (0.04; 0.02 to 0.07) and weight at age 6 months (0.05; 0.00 to 0.10). Cord blood insulin growth factor (IGF)-1 and adiponectin concentrations were positively associated with infant weight z score at birth and at 6 months. Conclusions: Concentrations of LPCs and IGF-1 in cord blood are related to infant weight. These findings support the hypothesis that susceptibility to childhood obesity may be programmed in utero, but further investigation is required to establish whether these associations are causally related. PMID- 29140439 TI - Bivalent Vaccine Effectiveness Against Type-Specific HPV Positivity: Evidence for Cross-Protection Against Oncogenic Types Among Dutch STI Clinic Visitors. AB - Background: Observational postmarketing studies are important to assess vaccine effectiveness (VE). We estimated VE from the bivalent human papillomavirus (HPV) vaccine against HPV positivity of vaccine and nonvaccine types in a high-risk population. Methods: We included all vaccine-eligible women from the PASSYON study, a biennial cross-sectional survey in Dutch sexually transmitted infection clinics. Vaginal swabs were analyzed using a polymerase chain reaction-based assay (SPF10-LiPA25) able to detect the 12 high-risk HPV (hrHPV) types 16/18/31/33/35/39/45/51/52/56/58/59. We compared hrHPV positivity between self reported vaccinated (>=1 dose) and unvaccinated women, and estimated VE by a logistic mixed model. Results: We included 1087 women of which 53% were hrHPV positive and 60% reported to be vaccinated. The adjusted pooled VE against HPV 16/18 was 89.9% (81.7%-94.4%). Moreover, we calculated significant VE against nonvaccine types HPV-45 (91%), HPV-35 (57%), HPV-31 (50%), and HPV-52 (37%). Among women who were offered vaccination 5/6 years ago, we estimated similar VE against HPV-16/18 (92%) and all hrHPV types (35%) compared to women who were offered vaccination <5 years ago (83% and 33%, respectively). Conclusion: We demonstrated high VE of the bivalent vaccine against HPV-16/18 and cross protection against HPV-45/35/31/52. Protection against HPV-16/18 was sustained up to 6 years postvaccination. PMID- 29140442 TI - Variability in Intrahousehold Transmission of Ebola Virus, and Estimation of the Household Secondary Attack Rate. AB - Transmission between family members accounts for most Ebola virus transmission, but little is known about determinants of intrahousehold spread. From detailed exposure histories, intrahousehold transmission chains were created for 94 households of Ebola survivors in Sierra Leone: 109 (co-)primary cases gave rise to 317 subsequent cases (0-100% of those exposed). Larger households were more likely to have subsequent cases, and the proportion of household members affected depended on individual and household-level factors. More transmissions occurred from older than from younger cases, and from those with more severe disease. The estimated household secondary attack rate was 18%. PMID- 29140443 TI - DC-SIGN Polymorphisms Associate with Risk of Hepatitis C Virus Infection Among Men who Have Sex with Men but not Among Injecting Drug Users. AB - We aimed to identify whether genetic polymorphisms within L-SIGN or DC-SIGN correlate with hepatitis C virus (HCV) susceptibility. A men who have sex with men (MSM) and an injecting drug users (IDU) cohort of HCV cases and multiple exposed uninfected controls were genotyped for numerous L-SIGN and DC-SIGN polymorphisms. DC-SIGN single nucleotide polymorphisms (SNPs) -139, -871, and 939 correlated with HCV acquisition in the MSM cohort only. When the same SNPs were introduced into a transcription activity assay they demonstrated a reduction in expression with predicted alteration in binding of transcription factors. DC SIGN promoter SNPs correlated with risk of HCV acquisition via sexual but not IDU exposure, likely through modulation of mRNA expression levels. PMID- 29140445 TI - Precise method for measuring spatial coherence in TEM beams using Airy diffraction patterns. AB - We have developed a method to precisely measure spatial coherence in electron beams. The method does not require an electron biprism and can be implemented in existing analytical transmission electron microscopes equipped with a post-column energy filter. By fitting the Airy diffraction pattern of the selector aperture, various parameters such as geometric aberrations of the lens system and the point spread function of the diffraction blurring are precisely determined. From the measurements of various beam diameters, components that are attributed to the partial spatial coherence are successfully separated from the point-spread functions. A linear relationship between the spatial coherence length and beam diameter is revealed, thus indicating that a wide range of coherence lengths can be determined by our proposed method as long as the coherence length remains >80% of the aperture diameter. A remarkable feature of this method is its ability to simultaneously determine diffraction blurring and lens aberrations. Possible applications of this method are also discussed. PMID- 29140444 TI - Safety and Immunogenicity of Different Formulations of Norovirus Vaccine Candidate in Healthy Adults: A Randomized, Controlled, Double-Blind Clinical Trial. AB - Background: We investigated safety and immunogenicity of 1-2 doses of different bivalent virus-like particle (VLP) norovirus vaccine candidate (NoV) formulations in healthy 18- to 64-year-olds. Methods: On days 1 and 28, participants (n = 420) randomized to 14 equal groups received intramuscular control vaccine (hepatitis A) or 1 of 11 NoV formulations containing varying dosages of GI.1 and GII.4c genotype VLP antigens with aluminum hydroxide [Al(OH)3], and 0 MUg, 15 MUg, or 50 MUg monophosphoryl lipid A (MPL). Immunogenicity was assessed on days 1, 28, 56, 208 and 393. Solicited local and systemic reactions were recorded for 7 days, unsolicited adverse events (AEs) until day 56, and serious AEs throughout the trial. Results: All NoV formulations induced similar increases in pan immunoglobulin, immunoglobulin A, and histo-blood group binding antigen-blocking antibodies by day 56, mostly after 1 dose, that persisted above baseline to day 393. Higher GI.1 content interfered with GII.4c responses, and responses did not benefit from MPL. Overall reactogenicity consisted of mainly mild injection site pain, headache, and fatigue. No vaccine-related serious AEs were reported. Conclusions: All candidate NoV formulations were well tolerated. Overall, 15 MUg GI.1/50 MUg GII.4c elicited the best balance of immunogenicity with no clear benefit of MPL, and is the candidate formulation being taken forward in clinical development. Clinical Trials Registration: NCT02038907. PMID- 29140446 TI - Up-regulation of MPK4 increases the feeding efficiency of the green peach aphid under elevated CO2 in Nicotiana attenuata. AB - Previous research has shown that elevated CO2 reduces plant resistance against insects and enhances the water use efficiency of C3 plants, which improves the feeding efficiency of aphids. Although plant mitogen-activated protein kinases (MAPKs) are known to regulate water relations and phytohormone-mediated resistance, little is known about the effect of elevated CO2 on MAPKs and the cascading effects on aphids. By using stably transformed Nicotiana attenuata plants silenced in MPK4, wound-induced protein kinase (WIPK), or salicylic acid induced protein kinase (SIPK), we determined the functions of MAPKs in plant aphid interactions and their responses to elevated CO2. The results showed that among all plant genotypes, inverted repeat MPK4 plants had the largest stomatal apertures, the lowest water content, the strongest jasmonic acid (JA)-dependent resistance, and the lowest aphid numbers, suggesting that MPK4 affects plant responses to aphids by regulating stomatal aperture and JA-dependent resistance. Regardless of aphid infestation, elevated CO2 up-regulated MPK4, but not WIPK or SIPK, in wild-type plants. Elevated CO2 increased the number, mean relative growth rate, and feeding efficiency of aphids on all plant genotypes except inverted repeat MPK4. We conclude that MPK4 is a CO2-responsive plant determinant that regulates the molecular interaction between plants and aphids. PMID- 29140447 TI - Octulose: a forgotten metabolite? PMID- 29140448 TI - Internal locus of control, health literacy and health, an Israeli cultural perspective. AB - The association between health literacy (HL) and health outcomes, including self perceived health (SPH) has been well documented. Yet the complexity of this association is not yet completely clear. Drawing on the Health Literacy Scale (HLS) study in Israel, we examined the association between HL, Internal Health Locus of Control (IHLOC) and SPH among Jews and Arabs. A face-to-face survey was conducted among 242 Arabs and 358 Jews. The questionnaire measured SPH, IHLOC and two measures of HL: a European HLScale (HLS-EU-16) and the Hebrew/Arabic Health Literacy Test (H/AHLT), based on the Short Test Of Functional Health Literacy in Adults. Analysis included multivariable logistic regressions and bootstrapping to identify mediation effects. Among Jews, IHLOC seems to be a significant mediator between HL and SPH. IHLOC was strongly associated with SPH (OR = 6.13; CI = 3.2, 11.8), while HL was not significantly associated directly with SPH. Similar results were observed when using the H/AHLT as a measure of HL. Among Arabs a different pattern emerges; IHLOC was neither associated with SPH nor was it a mediator of the association between HL and SPH. The two measures of HL seem to have different associations with SPH among Arabs, as only H/AHLT was associated significantly with SPH, and not HLS-EU-16. Thus, those with higher levels of IHLOC assess their health as better than those with low IHLOC only among Jews, and not among Arabs. IHLOC seems to be a significant mediator between HL and SPH among some cultures. Among Arabs, only functional HL seems to be positively associated with SPH. PMID- 29140449 TI - A quantum mechanical exploration of phonon energy-loss spectroscopy using electrons in the aloof beam geometry. AB - Phonon energy-loss spectroscopy using electrons has both high resolution and low resolution components, associated with short- and long-range interactions, respectively. In this paper, we discuss how these two contributions arise from a fundamental quantum mechanical perspective. Starting from a correlated model for the atomic motion we show how short range 'impact' scattering and long range 'dipole' scattering arises. The latter dominates in aloof beam imaging, an imaging geometry in which radiation damage can be avoided. PMID- 29140450 TI - Smoking cessation delivery by general practitioners in Crete, Greece. AB - Background: Tobacco dependence treatment in clinical settings is of prime public health importance, especially in Greece, a country experiencing one of the highest rates of tobacco use in Europe. Methods: Our study aimed to examine the characteristics of tobacco users and document rates of tobacco treatment delivery in general practice settings in Crete, Greece. A cross-sectional sample of patients (n = 2, 261) was screened for current tobacco use in 25 general practices in Crete, Greece in 2015/16. Current tobacco users completed a survey following their clinic appointment that collected information on patient characteristics and rates at which the primary care physician delivered tobacco treatment using the evidence-based 4 A's (Ask, Advise, Assist, Arrange) model during their medical appointment and over the previous 12-month period. Multi level modeling was used to analyze data and examine predictors of 4 A's delivery. Results: Tobacco use prevalence was 38% among all patients screened. A total of 840 tobacco users completed the study survey [mean age 48.0 (SD 14.5) years, 57.6% male]. Approximately, half of the tobacco users reported their general practitioner 'asked' about their tobacco use and 'advised' them to quit smoking. Receiving 'assistance' with quitting (15.7%) and 'arranging' follow-up support (<3%) was infrequent. Patient education, presence of smoking-related illness, a positive screen for anxiety or depression and the type of medical appointment were associated with 4 A's delivery. Conclusion: Given the fundamental importance of addressing tobacco treatment, increasing the rates of 4 A's treatment in primary care settings in Greece is an important target for improving patient care. PMID- 29140451 TI - Lipids in membrane dynamics during autophagy in plants. AB - Autophagy is a critical pathway for plant adaptation to stress. Macroautophagy relies on the biogenesis of a specialized membrane named the phagophore that maturates into a double membrane vesicle. Proteins and lipids act synergistically to promote membrane structure and functions, yet research on autophagy has mostly focused on autophagy-related proteins while knowledge of supporting lipids in the formation of autophagic membranes remains scarce. This review expands on studies in plants with examples from other organisms to present and discuss our current understanding of lipids in membrane dynamics associated with the autophagy pathway in plants. PMID- 29140452 TI - Mechanical Ventilation Induces Interleukin 4 Secretion in Lungs and Reduces the Phagocytic Capacity of Lung Macrophages. AB - Patients receiving mechanical ventilation are at risk of developing ventilator associated pneumonia. Here, we show that clinically utilized ventilation protocols in rats with 5 mL/kg or 8 mL/kg tidal volumes cause increased interleukin 4 (IL-4) expression, lowered ratio of TH1:TH2 transcriptional factors (Tbet:Gata3), and increased arginase 1-positive (Arg1+) macrophages and eosinophils in lungs. Macrophages from ventilated lungs had reduced ex vivo capacity toward phagocytosing bacteria. Ventilated animals, when further challenged with bacterial pneumonia, continued to show persistence of Arg1+ M2 macrophages as well as an increased bacterial burden compared with spontaneously breathing animals receiving the same bacterial dose. Increased IL-4 expression also occurred in a mouse ventilation model, and abrogation of IL-4 signaling restored lung bacterial burden in an IL-4Ralpha-/- ventilator-associated pneumonia model. Our data suggest that mechanical ventilation induces an immunosuppressive state in lungs, providing new insight in the development of ventilator-associated pneumonia. PMID- 29140453 TI - Faecal transplantation for IBD management-pitfalls and promises. AB - Background: Faecal microbiota transplantation (FMT) as a potential treatment for inflammatory bowel disease (IBD) is an area of active current research, having been stimulated by the remarkable efficacy of FMT in treatment of Clostridium difficile-associated colitis. Sources of data: This review is based on data from numerous case series on FMT in IBD since 1989 and results of four RCTs in ulcerative colitis (UC); three fully published. Areas of agreement: Early signals of short to medium-term efficacy of FMT for UC are promising. Areas of controversy: Methodology, underlying mechanisms and questions regarding safety of FMT remain controversial. Growing points: Many trials of FMT in adults and children are currently recruiting. Areas timely for developing research: Future trials of FMT will likely revisit Crohn's disease and patients undergoing pouch surgery. Advances in microbial culture complementing genetic sequencing and investigations into the virome and mycobiome in IBD will be of great future interest. PMID- 29140454 TI - Gestational age-specific perinatal mortality rates for assisted reproductive technology (ART) and other births. AB - STUDY QUESTION: Is perinatal mortality rate higher among births born following assisted reproductive technology (ART) compared to non-ART births? SUMMARY ANSWER: Overall perinatal mortality rates in ART births was higher compared to non-ART births, but gestational age-specific perinatal mortality rate of ART births was lower for very preterm and moderate to late preterm births. WHAT IS KNOWN ALREADY: Births born following ART are reported to have higher risk of adverse perinatal outcomes compared to non-ART births. STUDY DESIGN, SIZE, DURATION: This population-based retrospective cohort study included 407 368 babies (391 952 non-ART and 15 416 ART)-393 491 singletons and 10 877 twins or high order multiples. PARTICIPANTS/MATERIALS, SETTING, METHODS: All births (>=20 weeks of gestation and/or >=400 g of birthweight) in five states and territories in Australia during the period 2007-2009 were included in the study, using National Perinatal Data Collection (NPDC). Primary outcome measures were rates of stillbirth, neonatal and perinatal deaths. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were used to estimate the likelihood of perinatal death. MAIN RESULTS AND THE ROLE OF CHANCE: Rates of multiple birth and low birthweight were significantly higher in ART group compared to the non-ART group (P < 0.01). Overall perinatal mortality rate was significantly higher for ART births (16.5 per 1000 births, 95% CI 14.5-18.6), compared to non-ART births (11.3 per 1000 births, 95% CI 11.0-11.6) (AOR 1.45, 95% CI 1.26-1.68). However, gestational age specific perinatal mortality rate of ART births (including both singletons and multiples) was lower for very preterm (<32 weeks' gestation) and moderate to late preterm births (32-36 weeks' gestation) (AOR 0.61, 95% CI 0.53-0.70 and AOR 0.61, 95% CI 0.53-0.70, respectively) compared to non-ART births. Congenital abnormality and spontaneous preterm were the most common causes of neonatal deaths in both ART and non-ART group. LIMITATIONS, REASONS FOR CAUTION: Due to different cut-off limit for perinatal period in Australia, the results of this study should be interpreted with cautions for other countries. Australian definition of perinatal period commences at 20 completed weeks (140 days) of gestation and ends 27 completed days after birth which is different from the definition by World Health Organisation (commences at 22 completed weeks (154 days) of gestation and ends seven completed days after birth) and by Centers for Disease Control and Prevention (includes infant deaths under age 7 days and fetal deaths at 28 weeks of gestation or more). WIDER IMPLICATIONS OF THE FINDINGS: Preterm birth is the single most important contributing factor to increased risk of perinatal mortality among ART singletons compared to non-ART singletons. Further research on reducing early preterm delivery, with the aim of reducing the perinatal mortality among ART births is needed. Couples who access ART treatment should be fully informed regarding the risk of preterm birth and subsequent risk of perinatal death. STUDY FUNDING/COMPETING INTEREST(S): There was no funding associated with this study. No conflict of interest was declared. PMID- 29140455 TI - A sparse differential clustering algorithm for tracing cell type changes via single-cell RNA-sequencing data. AB - Cell types in cell populations change as the condition changes: some cell types die out, new cell types may emerge and surviving cell types evolve to adapt to the new condition. Using single-cell RNA-sequencing data that measure the gene expression of cells before and after the condition change, we propose an algorithm, SparseDC, which identifies cell types, traces their changes across conditions and identifies genes which are marker genes for these changes. By solving a unified optimization problem, SparseDC completes all three tasks simultaneously. SparseDC is highly computationally efficient and demonstrates its accuracy on both simulated and real data. PMID- 29140456 TI - Minimotif Miner 4: a million peptide minimotifs and counting. AB - Minimotif Miner (MnM) is a database and web system for analyzing short functional peptide motifs, termed minimotifs. We present an update to MnM growing the database from ~300 000 to >1 000 000 minimotif consensus sequences and instances. This growth comes largely from updating data from existing databases and annotation of articles with high-throughput approaches analyzing different types of post-translational modifications. Another update is mapping human proteins and their minimotifs to know human variants from the dbSNP, build 150. Now MnM 4 can be used to generate mechanistic hypotheses about how human genetic variation affect minimotifs and outcomes. One example of the utility of the combined minimotif/SNP tool identifies a loss of function missense SNP in a ubiquitylation minimotif encoded in the excision repair cross-complementing 2 (ERCC2) nucleotide excision repair gene. This SNP reaches genome wide significance for many types of cancer and the variant identified with MnM 4 reveals a more detailed mechanistic hypothesis concerning the role of ERCC2 in cancer. Other updates to the web system include a new architecture with migration of the web system and database to Docker containers for better performance and management. Weblinks:minimotifminer.org and mnm.engr.uconn.edu. PMID- 29140457 TI - Genistein-Specific G6DT Gene for the Inducible Production of Wighteone in Lotus japonicus. AB - Prenylated isoflavonoids have been found in several legume plants, and they possess various biological activities that play important roles in both plant defense and human health. However, it is still unknown whether prenylated isoflavonoids are present in the model legume plant Lotus japonicus. In the present study, we found that the prenylated isoflavonoid wighteone was produced in L. japonicus when leaf was supplemented with genistein. Furthermore, a novel prenyltransferase gene, LjG6DT, was identified, which shared high similarity with and was closely related to several known prenyltransferase genes involved in isoflavonoid biosynthesis. The recombinant LjG6DT protein expressed in yeast exhibited prenylation activity toward genistein as an exclusive substrate, which produced wighteone, a prenylated genistein at the C-6 position that occurs normally in legume plants. The LjG6DT-green fluorescent protein (GFP) fusion protein is targeted to plastids. The transcript level of LjG6DT is induced by glutathione, methyl jasmonate and salicylic acid, implying that LjG6DT is involved in stress response. Overexpression of LjG6DT in L. japonicus hairy roots led to increased accumulation of wighteone when genistein was supplied, indicating that LjG6DT is functional in vivo. Feeding assays with the upstream intermediate naringenin revealed that accumulation of wighteone in L. japonicus was dependent on genistein supplementation, and accumulation of wighteone is competed by genistein methylation. This study demonstrated that phytoalexin wighteone is inducibly produced in L. japonicus, and it provides new insight into the biosynthesis and accumulation of prenylated isoflavonoids in legume plants. PMID- 29140458 TI - DIRECT MEASUREMENTS OF SKIN, EYE LENS AND THYROID DOSE DURING PEDIATRIC BRAIN CT EXAMINATIONS. AB - Pediatric brain computed tomography (CT) is identified as the most frequent CT examination in children. The aim of the study is the direct measurement of skin, eye lens and thyroid dose in pediatric patients during brain CT examinations. The study included 35 pediatric patients who underwent brain CT examinations. The patients were categorized in three age groups: Group A (age range: 0.8-1 years), Group B (age range: 2.0-4.9 years) and Group C (age range: 5.5-15.5 years). thermoluminescent dosimeters (TLDs) were placed on the eyes, the frontal region of the head, the mastoid apophysis and the thyroid gland. The skin dose was found 16.6 +/- 1.5, 38.8 +/- 5.1 and 41.7 +/- 9.4 mGy for Groups A, B and C, respectively. The mean dose for the eye lens was 10.5 +/- 3.3, 29.9 +/- 8.6 and 34.2 +/- 14.9 mGy and for the thyroid 1.7 +/- 0.4, 2.4 +/- 0.5 and 1.9 +/- 0.4 mGy for Groups A, B and C, respectively. In vivo dosimetry using TLDs proved to be an efficient method. Gantry tilting and patient's set-up seem to significantly affect eye lens dose. PMID- 29140459 TI - RBM45 competes with HDAC1 for binding to FUS in response to DNA damage. AB - DNA damage response (DDR) is essential for genome stability and human health. Recently, several RNA binding proteins (RBPs), including fused-in-sarcoma (FUS), have been found unexpectedly to modulate this process. The role of FUS in DDR is closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Given that RBM45 is also an ALS-associated RBP, we wondered whether RBM45 plays any function during this process. Here, we report that RBM45 can be recruited to laser microirradiation-induced DNA damage sites in a PAR- and FUS-dependent manner, but in a RNA-independent fashion. Depletion of RBM45 leads to abnormal DDR signaling and decreased efficiency in DNA double-stranded break repair. Interestingly, RBM45 is found to compete with histone deacetylase 1 (HDAC1) for binding to FUS, thereby regulating the recruitment of HDAC1 to DNA damage sites. A common familial ALS-associated FUS mutation (FUS-R521C) is revealed to prefer to cooperate with RBM45 than HDAC1. Our findings suggest that RBM45 is a key regulator in FUS-related DDR signaling whose dysfunction may contribute to the pathogenesis of ALS. PMID- 29140460 TI - A Meta-Analysis of Social Skills Training and Related Interventions for Psychosis. AB - Objective: Evidence suggests that social skills training (SST) is an efficacious intervention for negative symptoms in psychosis, whereas evidence of efficacy in other psychosis symptom domains is limited. The current article reports a comprehensive meta-analytic review of the evidence for SST across relevant outcome measures, control comparisons, and follow-up assessments. The secondary aim of this study was to identify and investigate the efficacy of SST subtypes. Methods: A systematic literature search identified 27 randomized controlled trials including N = 1437 participants. Trials assessing SST against active controls, treatment-as-usual (TAU), and waiting list control were included. Risk of bias was assessed using the Cochrane risk of bias assessment tool. A series of 70 meta-analytic comparisons provided effect sizes in Hedges' g. Heterogeneity and publication bias were assessed. Results: SST demonstrated superiority over TAU (g = 0.3), active controls (g = 0.2-0.3), and comparators pooled (g = 0.2 0.3) for negative symptoms, and over TAU (g = 0.4) and comparators pooled (g = 0.3) for general psychopathology. Superiority was indicated in a proportion of comparisons for all symptoms pooled and social outcome measures. SST subtype comparisons were underpowered, although social-cognitive approaches demonstrated superiority vs comparators pooled. SST treatment effects were maintained at proportion of follow-up comparisons. Conclusions: SST demonstrates a magnitude of effect for negative symptoms similar to those commonly reported for cognitive behavioral therapy (CBT) for positive symptoms, although unlike CBT, SST is not routinely recommended in treatment guidelines for psychological intervention. SST may have potential for wider implementation. Further stringent effectiveness research alongside wider pilot implementation of SST in community mental health teams is warranted. PMID- 29140461 TI - A bacterial three-hybrid assay detects Escherichia coli Hfq-sRNA interactions in vivo. AB - The interaction of RNA molecules with proteins is a critical aspect of gene regulation across all domains of life. Here, we report the development of a bacterial three-hybrid (B3H) assay to genetically detect RNA-protein interactions. The basis for this three-hybrid assay is a transcription-based bacterial two-hybrid assay that has been used widely to detect and dissect protein-protein interactions. In the three-hybrid assay, a DNA-bound protein with a fused RNA-binding moiety (the coat protein of bacteriophage MS2 (MS2CP)) is used to recruit a hybrid RNA upstream of a test promoter. The hybrid RNA consists of a constant region that binds the tethered MS2CP and a variable region. Interaction between the variable region of the hybrid RNA and a target RNA binding protein that is fused to a subunit of Escherichia coli RNA polymerase (RNAP) stabilizes the binding of RNAP to the test promoter, thereby activating transcription of a reporter gene. We demonstrate that this three-hybrid assay detects interaction between non-coding small RNAs (sRNAs) and the hexameric RNA chaperone Hfq from E. coli and enables the identification of Hfq mutants with sRNA-binding defects. Our findings suggest that this B3H assay will be broadly applicable for the study of RNA-protein interactions. PMID- 29140463 TI - Anatomic Investigation of the Trajectory for Stereotactic Laser Amygdalohippocampectomy. AB - BACKGROUND: Magnetic resonance imaging-guided laser interstitial thermal therapy (LITT) has emerged as a promising treatment for mesial temporal lobe epilepsy. Surgeons must understand the relevant anatomy that is traversed by the catheter and affected by ablation. OBJECTIVE: To study the anatomic structures crossed by the LITT catheter until it reaches the amygdala. METHODS: Three human cadaveric heads were implanted with catheters using a frameless stereotactic technique. The Visualase(r) system (Medtronic, Dublin, Ireland) was utilized to ablate along the trajectory. Coronal and oblique axial slices were created. Fiber tract dissections were performed in a lateral-medial and inferior-superior scheme. Magnetic resonance tractography was acquired to illustrate the tracts dissected. RESULTS: Entry points occurred within 4 cm of the transverse and sagittal sinus, inferior to the lambdoid suture. The cortex of the inferior occipital gyrus was crossed in the region of the transverse occipital sulcus. The vertical occipital fasciculus was crossed en route to passing through the optic radiations. The catheter crossed through or inferior to the optic radiations before piercing the parahippocampal gyrus at about 4 cm from the skull. The catheter entered the hippocampus as it pierced the superior margin of the parahippocampus at 6 cm. The catheter entered the head of the hippocampus to lie inferolateral to the amygdala in the last centimeter of the trajectory. CONCLUSION: Understanding the anatomic principles of LITT catheter trajectories will improve the ability to perform this procedure. The current study is the first to examine the anatomy of this trajectory and will serve as the basis for future studies. PMID- 29140462 TI - Data Portal for the Library of Integrated Network-based Cellular Signatures (LINCS) program: integrated access to diverse large-scale cellular perturbation response data. AB - The Library of Integrated Network-based Cellular Signatures (LINCS) program is a national consortium funded by the NIH to generate a diverse and extensive reference library of cell-based perturbation-response signatures, along with novel data analytics tools to improve our understanding of human diseases at the systems level. In contrast to other large-scale data generation efforts, LINCS Data and Signature Generation Centers (DSGCs) employ a wide range of assay technologies cataloging diverse cellular responses. Integration of, and unified access to LINCS data has therefore been particularly challenging. The Big Data to Knowledge (BD2K) LINCS Data Coordination and Integration Center (DCIC) has developed data standards specifications, data processing pipelines, and a suite of end-user software tools to integrate and annotate LINCS-generated data, to make LINCS signatures searchable and usable for different types of users. Here, we describe the LINCS Data Portal (LDP) (http://lincsportal.ccs.miami.edu/), a unified web interface to access datasets generated by the LINCS DSGCs, and its underlying database, LINCS Data Registry (LDR). LINCS data served on the LDP contains extensive metadata and curated annotations. We highlight the features of the LDP user interface that is designed to enable search, browsing, exploration, download and analysis of LINCS data and related curated content. PMID- 29140464 TI - HOCOMOCO: towards a complete collection of transcription factor binding models for human and mouse via large-scale ChIP-Seq analysis. AB - We present a major update of the HOCOMOCO collection that consists of patterns describing DNA binding specificities for human and mouse transcription factors. In this release, we profited from a nearly doubled volume of published in vivo experiments on transcription factor (TF) binding to expand the repertoire of binding models, replace low-quality models previously based on in vitro data only and cover more than a hundred TFs with previously unknown binding specificities. This was achieved by systematic motif discovery from more than five thousand ChIP Seq experiments uniformly processed within the BioUML framework with several ChIP Seq peak calling tools and aggregated in the GTRD database. HOCOMOCO v11 contains binding models for 453 mouse and 680 human transcription factors and includes 1302 mononucleotide and 576 dinucleotide position weight matrices, which describe primary binding preferences of each transcription factor and reliable alternative binding specificities. An interactive interface and bulk downloads are available on the web: http://hocomoco.autosome.ru and http://www.cbrc.kaust.edu.sa/hocomoco11. In this release, we complement HOCOMOCO by MoLoTool (Motif Location Toolbox, http://molotool.autosome.ru) that applies HOCOMOCO models for visualization of binding sites in short DNA sequences. PMID- 29140465 TI - Short-chain arabinoxylans prepared from enzymatically treated wheat grain exert prebiotic effects during the broiler starter period. AB - Carbohydrate-degrading multi-enzyme preparations (MEP) are used to improve broiler performances. Their mode of action is complex and not fully understood. In this study, we compared the effect of water-soluble fractions isolated at the pilot scale from wheat grain incubated with (WE) and without (WC) MEP. The fractions were incorporated in a wheat-based diet (0.1% w/w) to feed Ross PM3 broilers and compared with a non-supplemented control group (NC). The body weight gain (BWG), feed intake (FI), and feed conversion ratio (FCR) until d 14 were determined. At d 14, ileal and cecal contents and tissue samples were collected from euthanized animals. The intestinal contents were used to measure the short chain fatty acids (SCFA) concentration using gas chromatography and to determine the abundance and composition of microbiota using 16S sequencing. Villi length of ileal samples was measured, while L-cell and T-cell densities were determined using immuno-histochemistry. The MEP treatment increased the amount of water soluble arabinoxylans (AX) and reduced their molecular weight while retaining their polymer behavior. The WE fraction significantly (P < 0.05) increased FI by 13.8% and BWG by 14.7% during the first wk post hatch when compared to NC. No significant effect on FCR was recorded during the trial. The WE increased the abundance of Enterococcus durans and Candidatus arthromitus in the ileum and of bacteria within the Lachnospiraceae and Ruminococcaceae families, containing abundant butyrate-producing bacteria, in the ceca. It also increased the concentration of SCFA in the ceca, decreased the T-lymphocyte infiltration in the intestinal mucosa, and increased the glucagon-like-peptide-2 (GLP-2)-producing L cell density in the ileal epithelium compared with WC and NC. No significant effects were observed on villi length. These results showed that AX present in the WE fraction altered the microbiota composition towards butyrate producers in the ceca. Butyrate may be responsible for the reduction of inflammation, as suggested by the decrease in T-lymphocyte infiltration, which may explain the higher feed intake leading to improved animal growth. PMID- 29140466 TI - Transcription-induced supercoiling as the driving force of chromatin loop extrusion during formation of TADs in interphase chromosomes. AB - Using molecular dynamics simulations, we show here that growing plectonemes resulting from transcription-induced supercoiling have the ability to actively push cohesin rings along chromatin fibres. The pushing direction is such that within each topologically associating domain (TAD) cohesin rings forming handcuffs move from the source of supercoiling, constituted by RNA polymerase with associated DNA topoisomerase TOP1, towards borders of TADs, where supercoiling is released by topoisomerase TOPIIB. Cohesin handcuffs are pushed by continuous flux of supercoiling that is generated by transcription and is then progressively released by action of TOPIIB located at TADs borders. Our model explains what can be the driving force of chromatin loop extrusion and how it can be ensured that loops grow quickly and in a good direction. In addition, the supercoiling-driven loop extrusion mechanism is consistent with earlier explanations proposing why TADs flanked by convergent CTCF binding sites form more stable chromatin loops than TADs flanked by divergent CTCF binding sites. We discuss the role of supercoiling in stimulating enhancer promoter contacts and propose that transcription of eRNA sends the first wave of supercoiling that can activate mRNA transcription in a given TAD. PMID- 29140467 TI - Genomic prediction in a nuclear population of layers using single-step models. AB - Single-step genomic prediction method has been proposed to improve the accuracy of genomic prediction by incorporating information of both genotyped and ungenotyped animals. The objective of this study is to compare the prediction performance of single-step model with a 2-step models and the pedigree-based models in a nuclear population of layers. A total of 1,344 chickens across 4 generations were genotyped by a 600 K SNP chip. Four traits were analyzed, i.e., body weight at 28 wk (BW28), egg weight at 28 wk (EW28), laying rate at 38 wk (LR38), and Haugh unit at 36 wk (HU36). In predicting offsprings, individuals from generation 1 to 3 were used as training data and females from generation 4 were used as validation set. The accuracies of predicted breeding values by pedigree BLUP (PBLUP), genomic BLUP (GBLUP), SSGBLUP and single-step blending (SSBlending) were compared for both genotyped and ungenotyped individuals. For genotyped females, GBLUP performed no better than PBLUP because of the small size of training data, while the 2 single-step models predicted more accurately than the PBLUP model. The average predictive ability of SSGBLUP and SSBlending were 16.0% and 10.8% higher than the PBLUP model across traits, respectively. Furthermore, the predictive abilities for ungenotyped individuals were also enhanced. The average improvements of prediction abilities were 5.9% and 1.5% for SSGBLUP and SSBlending model, respectively. It was concluded that single-step models, especially the SSGBLUP model, can yield more accurate prediction of genetic merits and are preferable for practical implementation of genomic selection in layers. PMID- 29140468 TI - GenBank. AB - GenBank(r) (www.ncbi.nlm.nih.gov/genbank/) is a comprehensive database that contains publicly available nucleotide sequences for 400 000 formally described species. These sequences are obtained primarily through submissions from individual laboratories and batch submissions from large-scale sequencing projects, including whole genome shotgun and environmental sampling projects. Most submissions are made using BankIt, the National Center for Biotechnology Information (NCBI) Submission Portal, or the tool tbl2asn. GenBank staff assign accession numbers upon data receipt. Daily data exchange with the European Nucleotide Archive and the DNA Data Bank of Japan ensures worldwide coverage. GenBank is accessible through the NCBI Nucleotide database, which links to related information such as taxonomy, genomes, protein sequences and structures, and biomedical journal literature in PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of the GenBank database are available by FTP. Recent updates include changes to sequence identifiers, submission wizards for 16S and Influenza sequences, and an Identical Protein Groups resource. PMID- 29140469 TI - SuperDRUG2: a one stop resource for approved/marketed drugs. AB - Regular monitoring of drug regulatory agency web sites and similar resources for information on new drug approvals and changes to legal status of marketed drugs is impractical. It requires navigation through several resources to find complete information about a drug as none of the publicly accessible drug databases provide all features essential to complement in silico drug discovery. Here, we propose SuperDRUG2 (http://cheminfo.charite.de/superdrug2) as a comprehensive knowledge-base of approved and marketed drugs. We provide the largest collection of drugs (containing 4587 active pharmaceutical ingredients) which include small molecules, biological products and other drugs. The database is intended to serve as a one-stop resource providing data on: chemical structures, regulatory details, indications, drug targets, side-effects, physicochemical properties, pharmacokinetics and drug-drug interactions. We provide a 3D-superposition feature that facilitates estimation of the fit of a drug in the active site of a target with a known ligand bound to it. Apart from multiple other search options, we introduced pharmacokinetics simulation as a unique feature that allows users to visualise the 'plasma concentration versus time' profile for a given dose of drug with few other adjustable parameters to simulate the kinetics in a healthy individual and poor or extensive metabolisers. PMID- 29140471 TI - Optimizing the electrical conductivity of marinade solution for water-holding capacity of broiler breast meat. AB - This study explored the possibility of forecasting the performance of marinade solutions in improving the water-holding capacity (WHC; weight gain, drip loss, cooking loss, and total yield) of marinated broiler breast meat based upon the electrical conductivity (EC) of the marinade solution. Normal- (50 <= L* <= 56) and light-colored samples (L* > 56), obtained from a production line, were marinated with 1 to 6% sodium bicarbonate (NaHCO3), 0.5 to 3% sodium tripolyphosphate (STPP), 1 to 6% sodium chloride (NaCl), and 0.05 to 0.5% acetic acid (CH3COOH) solutions. EC of all solutions increased with increasing solute concentration, and high EC of any salt solution correlated with increased weight gain and decreased drip loss and cooking loss, leading to increased total yield. CH3COOH had the least effect on the WHC of marinated breast meat. The effect of increasing EC of marinade solutions on drip loss was similar in the light- and normal-colored samples, but light-colored samples consistently had higher cooking losses and lower total yields compared with the normal-colored samples. At the same EC, NaHCO3 and STPP solutions had greater abilities to improve the total yield of marinated breast meat than the NaCl solution. Therefore, the WHC of the sample did not depend on the EC of the solution alone. However, increasing EC had a high correlation with gains in WHC of marinated breast meat for all marinade solutions (r > 0.96 for total yield). The total yield of both normal- and light colored samples of broiler breast meat could be improved to a value higher than 75% when samples were marinated in salt solutions with EC >= 8.79 mS/cm for NaHCO3 or >= 9.91 mS/cm for STPP. NaCl solutions with EC >=70.08 and >=44.58 mS/cm could be used to improve total yield to values higher than 75% for light- and normal-colored samples, respectively. Our results revealed that EC could be used to forecast the performance of marinade solution in improving the WHC of marinated breast meat. PMID- 29140472 TI - Uric acid predicts adverse outcomes in chronic kidney disease: a novel insight from trajectory analyses. AB - Background: Very little is known about longitudinal trajectories of serum uric acid (SUA) over the course of chronic kidney disease (CKD). We aimed to determine whether longitudinal SUA trajectories are associated with the risk of end-stage renal disease (ESRD) and all-cause mortality among CKD patients. Methods: We conducted a prospective cohort study from a 13-year multidisciplinary pre-ESRD care registry. The final study population consisted of 5090 CKD patients aged 20 90 years between 2003 and 2015. An individual's SUA trajectory was defined by group-based trajectory modeling in four distinct patterns: high, moderate-high, moderate and low. Time to ESRD and death was analyzed by multiple Cox regression. Results: A total of 948 ESRD events and 472 deaths occurred with incidence rates of 57.9 and 28.7 per 1000 person-years, respectively. Compared with those with a low SUA trajectory, the adjusted hazard ratio of patients for incident ESRD was in a dose-response manner as follows: moderate, 1.89 [95% confidence interval (CI), 1.37-2.60]; moderate-high, 2.49 (1.75-3.55); and high, 2.84 (1.81-4.47); after considering the competing risk of death. For all-cause mortality, the corresponding risk estimate of the same SUA trajectory was 1.38 (95% CI, 0.89 2.12), 1.95 (1.22-3.10) and 4.52 (2.48-8.26), respectively. The unfavorable effect of elevated SUA trajectories on progression to ESRD was differentially higher among CKD patients without using urate-lowering agents at baseline (P for interaction = 0.018). Conclusions: Elevated SUA trajectories are associated with accelerated kidney failure and all-cause mortality in CKD patients. Adequate experimental evidence is urgently needed to inform when and how to optimize SUA in this population. PMID- 29140470 TI - Database resources of the National Center for Biotechnology Information. AB - The National Center for Biotechnology Information (NCBI) provides a large suite of online resources for biological information and data, including the GenBank(r) nucleic acid sequence database and the PubMed database of citations and abstracts for published life science journals. The Entrez system provides search and retrieval operations for most of these data from 39 distinct databases. The E utilities serve as the programming interface for the Entrez system. Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized data sets. New resources released in the past year include PubMed Data Management, RefSeq Functional Elements, genome data download, variation services API, Magic-BLAST, QuickBLASTp, and Identical Protein Groups. Resources that were updated in the past year include the genome data viewer, a human genome resources page, Gene, virus variation, OSIRIS, and PubChem. All of these resources can be accessed through the NCBI home page at www.ncbi.nlm.nih.gov. PMID- 29140473 TI - JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework. AB - JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) and TF flexible models (TFFMs) for TFs across multiple species in six taxonomic groups. In the 2018 release of JASPAR, the CORE collection has been expanded with 322 new PFMs (60 for vertebrates and 262 for plants) and 33 PFMs were updated (24 for vertebrates, 8 for plants and 1 for insects). These new profiles represent a 30% expansion compared to the 2016 release. In addition, we have introduced 316 TFFMs (95 for vertebrates, 218 for plants and 3 for insects). This release incorporates clusters of similar PFMs in each taxon and each TF class per taxon. The JASPAR 2018 CORE vertebrate collection of PFMs was used to predict TF-binding sites in the human genome. The predictions are made available to the scientific community through a UCSC Genome Browser track data hub. Finally, this update comes with a new web framework with an interactive and responsive user-interface, along with new features. All the underlying data can be retrieved programmatically using a RESTful API and through the JASPAR 2018 R/Bioconductor package. PMID- 29140474 TI - Identification of novel systemic sclerosis biomarkers employing aptamer proteomic analysis. AB - There is an important unmet need for clinically validated non-invasive biomarkers for SSc diagnosis, assessment of disease activity, extent of internal organ involvement, therapeutic response and prognosis. There is also an unmet need for biomarkers to accurately differentiate primary RP from recent onset RP evolving into SSc. The lack of sensitive and specific biomarkers for SSc and SSc associated RP is a limitation for the optimal clinical management of these patients. The development of highly sensitive and specific proteomic analysis employing aptamers and the expansion in the number of proteins that can be specifically identified by aptamer proteomics have opened new horizons for biomarker discovery. Here, we review the background and rationale for aptamer proteomic analysis for the identification of novel non-invasive biomarkers for SSc and recent onset RP evolving into SSc. Large scale application of aptamer proteomic platforms for this purpose will be of substantial value for the precision and personalized medical care of SSc patients. These studies will be placed in context by comparison with proteomic biomarker studies performed for other rheumatological inflammatory and autoimmune diseases. PMID- 29140476 TI - Identification of multiple genomic DNA sequences which form i-motif structures at neutral pH. PMID- 29140475 TI - The European Nucleotide Archive in 2017. AB - For 35 years the European Nucleotide Archive (ENA; https://www.ebi.ac.uk/ena) has been responsible for making the world's public sequencing data available to the scientific community. Advances in sequencing technology have driven exponential growth in the volume of data to be processed and stored and a substantial broadening of the user community. Here, we outline ENA services and content in 2017 and provide insight into a selection of current key areas of development in ENA driven by challenges arising from the above growth. PMID- 29140477 TI - When can the Child Speak for Herself? The Limits of Parental Consent in Data Protection Law for Health Research. AB - Draft regulatory guidance suggests that if the processing of a child's personal data begins with the consent of a parent, then there is a need to find and defend an enduring consent through the child's growing capacity and on to their maturity. We consider the implications for health research of the UK Information Commissioner's Office's (ICO) suggestion that the relevant test for maturity is the Gillick test, originally developed in the context of medical treatment. Noting the significance of the welfare principle to this test, we examine the implications for the responsibilities of a parent to act as proxy for their child. We argue, contrary to draft ICO guidance, that a data controller might legitimately continue to rely upon parental consent as a legal basis for processing after a child is old enough to provide her own consent. Nevertheless, we conclude that data controllers should develop strategies to seek fresh consent from children as soon as practicable after the data controller has reason to believe they are mature enough to consent independently. Techniques for effective communication, recommended to address challenges associated with Big Data analytics, might have a role here in addressing the dynamic relationship between data subject and processing. Ultimately, we suggest that fair and lawful processing of a child's data will be dependent upon data controllers taking seriously the truism that consent is ongoing, rather than a one-time event: the core associated responsibility is to continue to communicate with a data subject regarding the processing of personal data. PMID- 29140478 TI - Comparison of Cocaine/Crack Biomarkers Concentrations in Oral Fluid, Urine and Plasma Simultaneously Collected From Drug Users. AB - The use of oral fluid (OF) as an alternative specimen for drug analysis has become very popular in forensic toxicology. Many clinical studies have evaluated the correlations between concentrations of cocaine and its metabolites in OF and other matrices, but results have shown high variability. In addition, there are no data available regarding the correlations between biomarkers of crack-cocaine use in different matrices. This study evaluated the relationship between concentrations of cocaine/crack-cocaine biomarkers in OF, urine and plasma samples collected from cocaine users. All samples were analyzed for the presence of cocaine (COC), benzoylecgonine (BZE) and anhydroecgonine (AEC) by a validated liquid chromatography-mass spectrometry method. Median COC, BZE and AEC concentrations ranged from 4.20 to 33.26 ng/mL, from 13.03 to 3,615.86 ng/mL and from 7.40 to 1,892.5 ng/mL across matrices, respectively. The relationship between drug concentrations in OF versus plasma (OF/P) and OF versus urine (OF/U) was evaluated by their coefficients of determination (R2). Least-squares regression analyses demonstrated significant correlations between OF/P and OF/U for cocaine and BE (P < 0.05), with R2 = 0.17, 0.07 for cocaine and R2 = 0.73, 0.45 for BE, respectively. The correlation coefficients (r) found for BZE, COC and AEC in OF/P and OF/U were 0.85 and 0.67 (P < 0.05); 0.41 and 0.26 (P < 0.05); and 0.30 and -0.37 (P > 0.05), respectively. Many factors contribute to the variability of drug correlation ratios in studies involving random samples, including uncertainty about the time of last administration and dosage. Overall, we found significant R2 values for COC and BZE in OF/P and OF/U, but not for AEC. Despite the good correlations found in some cases, especially for BZE, the large variation in drug concentrations seen in this work suggests that OF concentrations should not be used to estimate concentrations of COC, BZE or AEC in plasma and/or urine. PMID- 29140479 TI - Editorial. PMID- 29140480 TI - The intrinsically disordered N-terminal arm of the brome mosaic virus coat protein specifically recognizes the RNA motif that directs the initiation of viral RNA replication. AB - In the brome mosaic virus (BMV) virion, the coat protein (CP) selectively contacts the RNA motifs that regulate translation and RNA replication (Hoover et al., 2016. J. Virol. 90, 7748). We hypothesize that the unstructured N-terminal arm (NTA) of the BMV CP can specifically recognize RNA motifs. Using ion mobility spectrometry-mass spectrometry, we demonstrate that peptides containing the NTA of the CP were found to preferentially bind to an RNA hairpin motif that directs the initiation of BMV RNA synthesis. RNA binding causes the peptide to change from heterogeneous structures to a single family of structures. Fluorescence anisotropy, fluorescence quenching and size exclusion chromatography experiments all confirm that the NTA can specific recognize the RNA motif. The peptide introduced into plants along with BMV virion increased accumulation of the BMV CP and accelerated the rate of minus-strand RNA synthesis. The intrinsically disordered BMV NTA could thus specifically recognize BMV RNAs to affect viral infection. PMID- 29140482 TI - Estimating autoantibody signatures to detect autoimmune disease patient subsets. AB - Autoimmune diseases are characterized by highly specific immune responses against molecules in self-tissues. Different autoimmune diseases are characterized by distinct immune responses, making autoantibodies useful for diagnosis and prediction. In many diseases, the targets of autoantibodies are incompletely defined. Although the technologies for autoantibody discovery have advanced dramatically over the past decade, each of these techniques generates hundreds of possibilities, which are onerous and expensive to validate. We set out to establish a method to greatly simplify autoantibody discovery, using a pre filtering step to define subgroups with similar specificities based on migration of radiolabeled, immunoprecipitated proteins on sodium dodecyl sulfate (SDS) gels and autoradiography [Gel Electrophoresis and band detection on Autoradiograms (GEA)]. Human recognition of patterns is not optimal when the patterns are complex or scattered across many samples. Multiple sources of errors-including irrelevant intensity differences and warping of gels-have challenged automation of pattern discovery from autoradiograms.In this article, we address these limitations using a Bayesian hierarchical model with shrinkage priors for pattern alignment and spatial dewarping. The Bayesian model combines information from multiple gel sets and corrects spatial warping for coherent estimation of autoantibody signatures defined by presence or absence of a grid of landmark proteins. We show the pre-processing creates more clearly separated clusters and improves the accuracy of autoantibody subset detection via hierarchical clustering. Finally, we demonstrate the utility of the proposed methods with GEA data from scleroderma patients. PMID- 29140483 TI - Integrative Whole-Person Oncology Care in the UK. AB - The term "whole-person cancer care"-an approach that addresses the needs of the person as well as treating the disease-is more widely understood in the United Kingdom than its synonym "integrative oncology." The National Health Service (NHS) provides free access to care for all, which makes it harder to prioritize NHS funding of whole-person medicine, where interventions may be multimodal and lacking in cost-effectiveness data. Despite this, around 30% of cancer patients are known to use some form of complementary or alternative medicine (CAM). This is virtually never medically led, and usually without the support or even the knowledge of their oncology teams, with the exception of one or two large cancer centers. UK oncology services are, however, starting to be influenced from three sides; first, by well-developed and more holistic palliative care services; second, by directives from central government via the sustainable health care agenda; and third, by increasing pressure from patient-led groups and cancer charities. CAM remains unlikely to be provided through the NHS, but nutrition, physical activity, mindfulness, and stress management are already becoming a core part of the NHS "Living With and Beyond Cancer" agenda. This supports cancer survivors into stratified pathways of care, based on individual, self-reported holistic needs and risk assessments, which are shared between health care professionals and patients. Health and well-being events are being built into cancer care pathways, designed to activate patients into self-management and support positive lifestyle change. Those with greater needs can be directed toward appropriate external providers, where many examples of innovative practice exist. These changes in policy and vision for the NHS present an opportunity for integrative oncology to develop further and to reach populations who would, in many other countries, remain underserved or hard to reach by whole-person approaches. PMID- 29140481 TI - Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. AB - Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility. PMID- 29140484 TI - State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research-NCI Strategic Workshop Highlights of Discussion Report. AB - In May 2016, the Office of Cancer Complementary and Alternative Medicine, Division of Cancer Diagnosis and Treatment, of the National Cancer Institute convened a special workshop focused on the State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research. The current state of the science, gaps, and future opportunities were reviewed and discussed by a distinguished panel of experts in this field of research, and the highlights of this meeting are reported herein. PMID- 29140485 TI - Growth of Integrative Medicine at Leading Cancer Centers Between 2009 and 2016: A Systematic Analysis of NCI-Designated Comprehensive Cancer Center Websites. AB - Background: Cancer centers have increasingly offered integrative medicine therapies in response to their patients' unmet needs. We evaluated the growth of integrative medicine in leading academic cancer centers in the United States as reflected by their public-facing websites. Methods: We performed a systematic review of 45 National Cancer Institute (NCI)-designated comprehensive cancer center websites. Two researchers independently evaluated whether the websites provided information regarding integrative medicine modalities and, if so, whether the services were provided in the same health system. They compared the proportion of cancer centers providing the information on each modality in 2016 with the data from the prior study in 2009. Results: The most common integrative medicine therapies mentioned on the 45 NCI-designated comprehensive cancer center websites were exercise (97.8%) and acupuncture and meditation (88.9% each), followed by yoga (86.7%), massage (84.4%), and music therapy (82.2%). The majority of the websites also provided information on nutrition (95.6%), dietary supplements (93.3%), and herbs (88.9%). The most common therapies offered in the health systems were acupuncture/massage (73.3% each), meditation/yoga (68.9% each), and consultations about nutrition (91.1%), dietary supplements (84.4%), and herbs (66.7%). Compared with 2009, there was a statistically significant increase in the number of websites mentioning acupuncture, dance therapy, healing touch, hypnosis, massage, meditation, Qigong, and yoga (all P < .05). Conclusions: Leading US cancer centers increasingly present integrative medicine content on their websites, and the majority of them provide these services to patients in the same health systems. PMID- 29140487 TI - Comprehensive Lifestyle Change: Harnessing Synergy to Improve Cancer Outcomes. PMID- 29140486 TI - The National Cancer Institute's Conference on Acupuncture for Symptom Management in Oncology: State of the Science, Evidence, and Research Gaps. AB - The Division of Cancer Treatment and Diagnosis, Office of Cancer Complementary and Alternative Medicine, at the National Cancer Institute (NCI) held a symposium on "Acupuncture for Cancer Symptom Management" on June 16 and 17, 2016. Invited speakers included 19 scientists and scholars with expertise in acupuncture and cancer research from the United States, Europe, and China. The conference reviewed the NCI's grant funding on acupuncture, analyzed the needs of cancer patients, reviewed safety issues, and assessed both the current scientific evidence and research gaps of acupuncture in oncology care. Researchers and stakeholders presented and discussed basic mechanisms of acupuncture; clinical evidence for specific symptoms; and methodological challenges such as placebo effects, novel biostatistical methods, patient-reported outcomes, and comparative effectiveness research. This paper, resulting from the conference, summarizes both the current state of the science and clinical evidence of oncology acupuncture, identifies key scientific gaps, and makes recommendations for future research to increase understanding of both the mechanisms and effects of acupuncture for cancer symptom management. PMID- 29140488 TI - US National Cancer Institute-China Collaborative Studies on Chinese Medicine and Cancer. AB - Since 2007, the US National Cancer Institute (NCI) Office of Cancer Complementary and Alternative Medicine (OCCAM), together with the Cancer Institute of the China Academy of Chinese Medical Sciences (CICACMS), institutes at China Academy of Sciences and Chinese Academy of Medical Sciences, have engaged in collaborations on Chinese medicine (CM) and cancer research. Through these collaborations, CM drugs and compounds have been studied at NCI labs. This paper summarizes the discoveries and progress on these research projects, exploring the aspects of cancer prevention, botanical drug mechanisms of action and component analysis/quality control (QC), and anticancer activity screening. These and other related projects have been presented in various jointly convened workshops and have provided the backdrop for establishing a new organization, the International Consortium for CM and Cancer, to promote international collaborations in this field. PMID- 29140489 TI - Including the Patient Voice in Patient-Centered Outcomes Research in Integrative Oncology. AB - The objective of this paper is to describe our experience as patient advisors as we work on a Patient-Centered Outcomes Research Institute-funded project, CHoosing Options for Insomnia in Cancer Effectively (CHOICE). The CHOICE Study is a comparative effectiveness trial comparing acupuncture with cognitive behavioral therapy for insomnia in cancer survivors. We describe the composition of the patient advisory panel, the patient engagement process, and our contributions throughout the study, and we highlight some of our successes so far. Our motivation to contribute to the research process and our hopes for the future of patient-centered outcomes research are discussed. PMID- 29140490 TI - Distress Management Through Mind-Body Therapies in Oncology. AB - Distress is highly prevalent in cancer survivors, from the point of diagnosis through treatment and recovery, with rates higher than 45% reported worldwide. One approach for helping people cope with the inherent stress of cancer is through the use of mind-body therapies (MBTs) such as mediation, yoga, hypnosis, relaxation, and imagery, which harness the power of the mind to affect physical and psychological symptoms. One group of MBTs with a growing body of research evidence to support their efficacy focus on training in mindfulness meditation; these are collectively known as mindfulness-based interventions (MBIs). Research supports the role of MBIs for dealing with common experiences that cause distress around cancer diagnosis, treatment, and survivorship including loss of control, uncertainty about the future, fears of recurrence, and a range of physical and psychological symptoms including depression, anxiety, insomnia, and fatigue. Growing research also supports their cost-effectiveness, and online and mobile adaptations currently being developed and evaluated increase promise for use in a global context. PMID- 29140491 TI - Validation and Application of the MD Anderson Symptom Inventory for Traditional Chinese Medicine (MDASI-TCM). AB - Background: The MD Anderson Symptom Inventory (MDASI) is a brief, yet thorough, patient-reported outcomes measure for assessing the severity of common cancer related symptoms and their interference with daily functioning. We report the development of an MDASI version tailored for use with Traditional Chinese Medicine in China (the MDASI-TCM). Methods: Chinese-speaking patients with mixed cancer types (n = 317) participated in the study. The development and validation process included four steps: 1) identify candidate TCM-specific items, with input from patients, oncologists, and TCM specialists; 2) eliminate candidate TCM items lacking relevance, based on patient report; 3) psychometrically examine the MDASI TCM's validity and reliability in cancer patients receiving TCM-based care; and 4) cognitively debrief patients to assess the MDASI-TCM's relevance, understandability, and acceptability. Results: Seven TCM-specific symptom items (sweating, feeling cold, constipation, bitter taste, coughing, palpitations, and heat in palms/soles) were clinically and psychometrically meaningful to add to the core MDASI. Approximately 61% of patients had moderate to severe symptoms (rated >=5 on the MDASI-TCM's 0-10 scale). Cronbach alpha coefficients were .90 for symptom-severity items and .93 for interference items, indicating internal consistency reliability. Known-group validity was substantiated by the MDASI TCM's detection of differences in symptom severity according to performance status (P < .001) and interference levels by cancer stage (P < .05). Cognitive debriefing indicated that patients found the MDASI-TCM to be an understandable, easy-to-use tool. Conclusions: The Chinese MDASI-TCM is a valid, reliable, and concise measure of symptom severity and interference that can be used to assess Chinese cancer patients and survivors receiving TCM-based care. PMID- 29140492 TI - Integrating Traditional and Allopathic Medicine: An Opportunity to Improve Global Health in Cancer. PMID- 29140493 TI - A Comprehensive Definition for Integrative Oncology. AB - Background: Integrative oncology, which is generally understood to refer to the use of a combination of complementary medicine therapies in conjunction with conventional cancer treatments, has been defined in different ways, but there is no widely accepted definition. We sought to develop and establish a consensus for a comprehensive definition of the field of integrative oncology. Methods: We used a mixed-methods approach that included a literature analysis and a consensus procedure, including an interdisciplinary expert panel and surveys, to develop a comprehensive and acceptable definition for the term "integrative oncology." Results: The themes identified in the literature and from the expert discussion were condensed into a two-sentence definition. Survey respondents had very positive views on the draft definition, and their comments helped to shape the final version. The final definition for integrative oncology is: "Integrative oncology is a patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, quality of life, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before,during, and beyond cancer treatment." Conclusions: This short and comprehensive definition for the term integrative oncology will facilitate a better understanding and communication of this emerging field. This definition will also drive focused and cohesive effort to advance the field of integrative oncology. PMID- 29140494 TI - Comparative Effectiveness Research in Integrative Oncology. PMID- 29140495 TI - Traditional and Complementary Medicine in Pediatric Oncology and Low-Middle Income Countries: Recommendations from the International Society of Pediatric Oncology (SIOP), T&CM Collaborative. AB - Significant strides have been made in the treatment of childhood cancer. Improvements in survival have led to increased attention toward supportive care indications; including the use of traditional and complementary medicine (T&CM). The use of T&CM among children and adolescents with cancer is well documented in both high-income countries (HICs) and low-middle income countries (LMICs). A higher incidence of the use of T&CM has been reported among children undergoing treatment in LMICs, which has elevated concerns related to drug interactions, adherence to therapy, and treatment-related toxicities. These observations have underscored the need for effective models of integrative care that are culturally sensitive yet sustainable in an LMIC setting. We present considerations inclusive of the clinical care, educational opportunities, governmental policy, and research priorities necessary for the development of models of integrative care for pediatric cancer units in an LMIC setting. PMID- 29140497 TI - Integrating Complementary and Traditional Practices in Middle-Eastern Supportive Cancer Care. AB - The Middle East is a promising arena in which researchers can explore the interchange between cross-cultural traditional medicine and supportive cancer care, as provided within an integrative oncology setting. Integrative oncology research and clinical practice in this part of the world have been focusing, for the most part, on the use of herbal medicine and mind-body-spiritual modalities, both of which are deeply rooted in traditional medical care. A regional, multinational, and interdisciplinary collaboration is currently being undertaken as part of the academic activities of the Middle-East Research Group in Integrative Oncology (MERGIO). This group is part of the Middle-East Cancer Consortium, a body supported by the National Cancer Institute. MERGIO currently facilitates a number of innovative educational, basic science, and clinical research projects that are investigating the effectiveness and safety of traditional herbal remedies. In order to create a structured, pragmatic "bedside to-bench" and subsequent "back-to-bedside" approach, MERGIO has designed a patient-tailored integrative oncology model of supportive-palliative care. This approach addresses both patients' individual health belief models and the larger social-cultural-religious context, as defined by the health-related values of the patient's community. PMID- 29140496 TI - Association Between Use of Traditional Chinese Medicine Herbal Therapy and Survival Outcomes in Patients With Stage II and III Colorectal Cancer: A Multicenter Prospective Cohort Study. AB - Background: Chinese cancer patients often use Traditional Chinese Medicine (TCM) herbal medicine during or after active cancer treatments. However, little is known about how TCM herbal medicine impacts cancer outcomes. This study aimed to evaluate the association between TCM herbal therapy and survival outcomes in patients with stage II or III colorectal cancer. Methods: We conducted an eight center prospective cohort study in China among patients who had undergone radical resection for stage II and III colorectal cancer. All patients received comprehensive conventional treatments according to National Comprehensive Cancer Network (NCCN) guidelines, and follow-up visits were conducted over five years. We defined high exposure as a patient's use of TCM individualized herbs for more than one year, ascertained via clinical interviews. The primary outcome was disease-free survival (DFS), with overall survival (OS) as a secondary outcome. Results: Between April 2007 and February 2009, we enrolled 312 patients into the cohort; 166 (53.2%) met the definition of high exposure to TCM herbs. Adjusting for covariates, high exposure to TCM was associated with both better DFS (hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.39 to 0.98) and OS (HR = 0.31, 95% CI = 0.14 to 0.68). In subgroup exploratory analysis, the effects demonstrated that the differences in outcomes were statistically significant in patients who had received chemotherapy. Conclusion: Longer duration of TCM herbal use is associated with improved survival outcomes in stage II and III colorectal cancer patients in China. More research is needed to evaluate the effects and underlying mechanisms of herbal medicine on colorectal cancer outcomes. PMID- 29140498 TI - The Role of Physical Activity in Oncology Care. PMID- 29140499 TI - Simple arithmetic: not so simple for highly math anxious individuals. AB - Fluency with simple arithmetic, typically achieved in early elementary school, is thought to be one of the building blocks of mathematical competence. Behavioral studies with adults indicate that math anxiety (feelings of tension or apprehension about math) is associated with poor performance on cognitively demanding math problems. However, it remains unclear whether there are fundamental differences in how high and low math anxious individuals approach overlearned simple arithmetic problems that are less reliant on cognitive control. The current study used functional magnetic resonance imaging to examine the neural correlates of simple arithmetic performance across high and low math anxious individuals. We implemented a partial least squares analysis, a data driven, multivariate analysis method to measure distributed patterns of whole brain activity associated with performance. Despite overall high simple arithmetic performance across high and low math anxious individuals, performance was differentially dependent on the fronto-parietal attentional network as a function of math anxiety. Specifically, low-compared to high-math anxious individuals perform better when they activate this network less-a potential indication of more automatic problem-solving. These findings suggest that low and high math anxious individuals approach even the most fundamental math problems differently. PMID- 29140500 TI - The persuasion network is modulated by drug-use risk and predicts anti-drug message effectiveness. AB - While a persuasion network has been proposed, little is known about how network connections between brain regions contribute to attitude change. Two possible mechanisms have been advanced. One hypothesis predicts that attitude change results from increased connectivity between structures implicated in affective and executive processing in response to increases in argument strength. A second functional perspective suggests that highly arousing messages reduce connectivity between structures implicated in the encoding of sensory information, which disrupts message processing and thereby inhibits attitude change. However, persuasion is a multi-determined construct that results from both message features and audience characteristics. Therefore, persuasive messages should lead to specific functional connectivity patterns among a priori defined structures within the persuasion network. The present study exposed 28 subjects to anti-drug public service announcements where arousal, argument strength, and subject drug use risk were systematically varied. Psychophysiological interaction analyses provide support for the affective-executive hypothesis but not for the encoding disruption hypothesis. Secondary analyses show that video-level connectivity patterns among structures within the persuasion network predict audience responses in independent samples (one college-aged, one nationally representative). We propose that persuasion neuroscience research is best advanced by considering network-level effects while accounting for interactions between message features and target audience characteristics. PMID- 29140502 TI - Social Worker Identity: A Profession in Context. AB - Social work is a broad field encompassing micro, mezzo, and macro areas of practice. Consequently, the field lacks a unifying professional identity due to the expansiveness of the profession. Professional identity is conceptualized as an extension of social identity, vis-a-vis the embodiment of three qualities: connectedness, expansiveness, and effectiveness. This study used 12 in-depth, individual interviews with practicing social workers to explore these qualities. Findings from interviews reveal six primary themes and 21 subthemes pertaining to social worker identity. Themes and subthemes are organized according to three broad families (social work in context, professional trajectories, and external influences). Implications for policy, practice, and future research are presented. PMID- 29140501 TI - Understanding the Association Between Negative Symptoms and Performance on Effort Based Decision-Making Tasks: The Importance of Defeatist Performance Beliefs. AB - Effort-based decision-making paradigms are increasingly utilized to gain insight into the nature of motivation deficits. Research has shown associations between effort-based decision making and experiential negative symptoms; however, the associations are not consistent. The current study had two primary goals. First, we aimed to replicate previous findings of a deficit in effort-based decision making among individuals with schizophrenia on a test of cognitive effort. Second, in a large sample combined from the current and a previous study, we sought to examine the association between negative symptoms and effort by including the related construct of defeatist beliefs. The results replicated previous findings of impaired cognitive effort-based decision making in schizophrenia. Defeatist beliefs significantly moderated the association between negative symptoms and effort-based decision making such that there was a strong association between high negative symptoms and deficits in effort-based decision making, but only among participants with high levels of defeatist beliefs. Thus, our findings suggest the relationship between negative symptoms and effort performance may be understood by taking into account the role of defeatist beliefs, and finding that might explain discrepancies in previous studies. PMID- 29140503 TI - Social Action among Social Work Practitioners: Examining the Micro-Macro Divide. AB - Social work is a profession that seeks to enhance the well-being of all people and promote social justice and social change through a range of activities, such as direct practice, community organizing, social and political action, and policy development. However, the current literature suggests that the profession's focus on social justice and social action are weakening, replaced by individualism and therapeutic interventions. This article examines data derived from a survey of 188 National Association of Social Workers members from Maryland; Virginia; and Washington, DC, to explore levels of social action participation among social workers and determine whether identifying as a macro-level practitioner would predict higher levels of social action activity compared with being a micro-level practitioner. Findings indicate that social workers in this sample engage in only a moderate level of social action behavior. In addition, identifying oneself as a mezzo- or macro-level practitioner predicts increased frequency of social action behavior. Implications include emphasizing the importance of social action in schools of social work and practice settings and adequately preparing social work professionals to engage in social action. PMID- 29140504 TI - Selective Attention, Working Memory, and Executive Function as Potential Independent Sources of Cognitive Dysfunction in Schizophrenia. AB - People with schizophrenia demonstrate impairments in selective attention, working memory, and executive function. Given the overlap in these constructs, it is unclear if these represent distinct impairments or different manifestations of one higher-order impairment. To examine this question, we administered tasks from the basic cognitive neuroscience literature to measure visual selective attention, working memory capacity, and executive function in 126 people with schizophrenia and 122 healthy volunteers. Patients demonstrated deficits on all tasks with the exception of selective attention guided by strong bottom-up inputs. Although the measures of top-down control of selective attention, working memory, and executive function were all intercorrelated, several sources of evidence indicate that working memory and executive function are separate sources of variance. Specifically, both working memory and executive function independently contributed to the discrimination of group status and independently accounted for variance in overall general cognitive ability as assessed by the MATRICS battery. These two cognitive functions appear to be separable features of the cognitive impairments observed in schizophrenia. PMID- 29140505 TI - THE NRPI MULTI-PURPOSE ON-LINE MONITORING STATION FOR MEASUREMENT OF NATURAL RADIOACTIVITY IN THE AMBIENT ATMOSPHERE AND IN THE SOIL. AB - During years 2010-12 an automated, on-line and wireless outdoor measurement station of atmospheric radon, gamma dose rate and meteorological parameters was realised at the National Radiation Protection Institute (NRPI) in Prague. At the turn of the year 2013 an expansion of the existing station was completed. Under the project funded by the Czech Technological Agency a new updated station was established, additionally equipped with modules for measurement of atmospheric radon/thoron short-lived decay products, radon in water and soil and radon exhalation rate from soil. After the introduction of the station updated key detection parameters and benefits, its use for atmospheric modelling and monitoring is demonstrated. There are summarised results from the 3-year measurement period in the NRPI outdoor area in Prague and from simultaneous annual measurement performed by another similar station located near uranium mud fields in DIAMO, state enterprise, Straz pod Ralskem. Observed seasonal and diurnal variations of atmospheric radon concentrations and variability of the equilibrium factor, F, are illustrated and compared. PMID- 29140506 TI - Quantification of the Effect of Toxicants on the Intracellular Kinetic Energy and Cross-Sectional Area of Mammary Epithelial Organoids by OCT Fluctuation Spectroscopy. AB - The ability to assess toxicant exposures of 3D in vitro mammary models that recapitulate the tissue microenvironment can aid in our understanding of environmental exposure risk over time. Longitudinal studies of 3D model systems, however, are cumbersome and suffer from a lack of high-throughput toxicological assays. In this study, we establish a noninvasive and label-free optical coherence tomography (OCT)-based imaging platform for tracking exposure-response relationships in 3D human mammary epithelial organoid models. The OCT-based assay includes metrics that quantify organoid intracellular kinetic energy and cross sectional area (CSA). We compare the results to those obtained using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) mitochondrial dye conversion assay. Both estrogen receptor (ER)-positive (MCF7) and ER-negative (MCF10DCIS.com) breast cell lines were studied, beginning one hour after exposure and continuing for several days. Six days of exposure to 17beta-estradiol or the selective ER modulator 4-hydroxytamoxifen respectively increased or decreased MCF7 organoid CSA (p < .01), consistent with the role of estrogen signaling in ER positive mammary epithelial cell proliferation. We also observed a significant decrease in the intracellular kinetic energy of MCF10DCIS.com organoids after 24 h of exposure to doxorubicin, a cytotoxic intercalating agent that causes DNA double-strand breaks (p < .01). MTT-based metabolic activity of MCF10DCIS.com organoids after 48 h of doxorubicin exposure decreased with dose in a similar manner as OCT-based energy metrics. These results demonstrate the feasibility of an OCT-based assay to quantify mammary epithelial cell toxicant response in vitro, noninvasively, longitudinally, and in the context of tissue microenvironments, providing a new high-throughput screening tool for toxicological studies. PMID- 29140507 TI - Commentary: Who was Leonard Darwin? Commentary on Darwin L: 'Heredity and environment: a warning to eugenists' in the Eugenics Review 1916. PMID- 29140509 TI - Administrative Discharges in Addiction Treatment: Bringing Practice in Line with Ethics and Evidence. PMID- 29140508 TI - Interactions with the healthcare system influence advance care planning activities: results from a representative survey in 11 developed countries. AB - Aim: To identify factors associated with completion of Advance Care Planning (ACP) by patients seen in primary care in developed countries. We hypothesized that the quality of primary care is associated. Method: We analysed respondent reported individual and healthcare utilization factors associated with the completion of ACP activities from the 2014 Commonwealth Fund International Health Policy Survey of Older Adults in 11 Countries. The primary outcome is the combined number of ACP activities completed. ACP activities included discussion of treatment preferences, documentation of healthcare wishes, or documentation of a surrogate decision maker. A quality of primary care index was calculated. Results: Respondents averaged 69 years old. Most were women, graduated high school, rated their income as average or higher, and rated their health as good or better. A minority reported multimorbidity, accessed the emergency department or hospital, or were informal caregivers. Out of 25530 survey respondents, 13409 (53%) reported completion of any ACP activity; 11579 (45%) had discussed treatment preferences. Generalized linear mixed model results suggest that hospitalization (rate ratio [RR] 1.18), multimorbidity (RR 1.16), informal caregiving (RR 1.13), higher education level (RR 1.14), income (RR 1.05), access to higher quality primary care (RR 1.04) and ED visits (RR 1.04) were associated with higher rates of ACP activities. Male gender (RR 0.85) and higher perceived health status (RR 0.96) were associated with lower rates. Conclusions: In this international study, individuals with greater interaction with the healthcare system through hospitalization, multimorbidity, access to quality primary care and informal caregiving reported more ACP activities. PMID- 29140510 TI - Saccharomyces genome database informs human biology. AB - The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is an expertly curated database of literature-derived functional information for the model organism budding yeast, Saccharomyces cerevisiae. SGD constantly strives to synergize new types of experimental data and bioinformatics predictions with existing data, and to organize them into a comprehensive and up-to-date information resource. The primary mission of SGD is to facilitate research into the biology of yeast and to provide this wealth of information to advance, in many ways, research on other organisms, even those as evolutionarily distant as humans. To build such a bridge between biological kingdoms, SGD is curating data regarding yeast-human complementation, in which a human gene can successfully replace the function of a yeast gene, and/or vice versa. These data are manually curated from published literature, made available for download, and incorporated into a variety of analysis tools provided by SGD. PMID- 29140511 TI - Two Fatal Cases Involving Cardiovascular Drugs Diltiazem and Amlodipine. AB - A liquid chromatographic tandem mass spectrometric method for the identification and quantification of 18 cardiovascular drugs was developed in order to evaluate two cases of fatal intoxication involving diltiazem and amlodipine respectively. Samples were simply diluted and centrifuged using a three-steps procedure with methanol, acetonitrile and mobile phase. The method proved to be selective and all the validation parameters fulfilled the acceptance criteria. In particular, linearity was studied in the range limits of quantitation (LOQ)-1,000 ng/mL (LOQ ranging from 0.8 to 33.3 ng/mL for urine and from 0.7 to 41.3 ng/mL for whole blood). The method was successfully applied to two real cases involving diltiazem and amlodipine fatal intoxications, respectively. Though the subject intoxicated by diltiazem did survive several hours after drug intake, central and peripheral blood levels at autopsy were extremely high (23.4 and 13.4 mg/L, respectively); the cause could be due to the formation of a pharmacobezoar that was found in the duodenum and that could have delayed the drug absorption. Moreover, diltiazem showed postmortem redistribution. On the contrary, the amlodipine peripheral blood level in the second case was relatively low (0.17 mg/L), thus confirming that even the uncontrolled intake of a less toxic calcium channel blocker can lead to death. Furthermore, blood samples were analyzed after 2 years of storage at -20 degrees C: both diltiazem and amlodipine showed a significant degradation (70 and 99%, respectively). PMID- 29140514 TI - IDH mutation testing in gliomas-where do we draw the line? PMID- 29140513 TI - Amino Acid and Fatty Acid Levels Affect Hepatic Phosphorus Metabolite Content in Metabolically Healthy Humans. AB - Objective: Hepatic energy metabolism negatively relates to insulin resistance and liver fat content in patients with type 2 diabetes, but its role in metabolically healthy humans is unclear. We hypothesized that intrahepatocellular gamma adenosine triphosphate (gammaATP) and inorganic phosphate (Pi) concentrations exhibit similar associations with insulin sensitivity in nondiabetic, nonobese volunteers. Design: A total of 76 participants underwent a four-point sampling, 75-g oral glucose tolerance test (OGTT), as well as in vivo31P/1H magnetic resonance spectroscopy. In 62 of them, targeted plasma metabolomic profiling was performed. Pearson correlation analyses were performed for the dependent variables gammaATP and Pi. Results: Adjusted for age, sex, and body mass index (BMI), hepatic gammaATP and Pi related to 2-hour OGTT glucose (r = 0.25 and r = 0.27, both P < 0.05), and Pi further associated with nonesterified fatty acids (NEFAs; r = 0.28, P < 0.05). However, neither gammaATP nor Pi correlated with several measures of insulin sensitivity. Hepatic gammaATP correlated with circulating leucine (r = 0.42, P < 0.001) and Pi with C16:1 fatty acids palmitoleic acid and C16:1w5 (r = 0.28 and 0.30, respectively, P < 0.01), as well as with delta-9-desaturase index (r = 0.33, P < 0.05). Only the association of gammaATP with leucine remained important after correction for multiple testing. Leucine and palmitoleic acid, together with age, sex, and BMI, accounted for 26% and for 15% of the variabilities in gammaATP and Pi, respectively. Conclusions: Specific circulating amino acids and NEFAs, but not measures of insulin sensitivity, partly affect hepatic phosphorus metabolites, suggesting mutual interaction between hepatic energy metabolism and circulating metabolites in nondiabetic humans. PMID- 29140512 TI - A novel tetratricopeptide repeat protein, WHITE TO GREEN1, is required for early chloroplast development and affects RNA editing in chloroplasts. AB - The chloroplast is essential for plant photosynthesis and production, but the regulatory mechanism of chloroplast development is still elusive. Here, a novel gene, WHITE TO GREEN1 (WTG1), was identified to have a function in chloroplast development and plastid gene expression by screening Arabidopsis leaf coloration mutants. WTG1 encodes a chloroplast-localized tetratricopeptide repeat protein that is expressed widely in Arabidopsis cells. Disruption of WTG1 suppresses plant growth, retards leaf greening and chloroplast development, and represses photosynthetic gene expression, but complemented expression of WTG1 restored a normal phenotype. Moreover, WTG1 protein is associated with the organelle RNA editing factors MORF8 and MORF9, and RNA editing of the plastid petL-5 and ndhG 50 transcripts was affected in wtg1 mutants. These results indicate that WTG1 affects both transcriptional and posttranscriptional regulation of plastid gene expression, and provide evidence for the involvement of a tetratricopeptide repeat protein in chloroplast RNA editing in Arabidopsis. PMID- 29140515 TI - Surveillance for Q Fever Endocarditis in the United States, 1999-2015. AB - Background: Q fever is a worldwide zoonosis caused by Coxiella burnetii. In some persons, particularly those with cardiac valve disease, infection with C. burnetii can cause a life-threatening infective endocarditis. There are few descriptive analyses of Q fever endocarditis in the United States. Methods: Q fever case report forms submitted during 1999-2015 were reviewed to identify reports describing endocarditis. Cases were categorized as confirmed or probable using criteria defined by the Council for State and Territorial Epidemiologists (CSTE). Demographic, laboratory, and clinical data were analyzed. Results: Of 140 case report forms reporting endocarditis, 49 met the confirmed definition and 36 met the probable definition. Eighty-two percent were male and the median age was 57 years (range, 16-87 years). Sixty-seven patients (78.8%) were hospitalized, and 5 deaths (5.9%) were reported. Forty-five patients (52.9%) had a preexisting valvulopathy. Eight patients with endocarditis had phase I immunoglobulin G antibody titers >800 but did not meet the CSTE case definition for Q fever endocarditis. Conclusions: These data summarize a limited set of clinical and epidemiological features of Q fever endocarditis collected through passive surveillance in the United States. Some cases of apparent Q fever endocarditis could not be classified by CSTE laboratory criteria, suggesting that comparison of phase I and phase II titers could be reexamined as a surveillance criterion. Prospective analyses of culture-negative endocarditis are needed to better assess the clinical spectrum and magnitude of Q fever endocarditis in the United States. PMID- 29140518 TI - Erratum. PMID- 29140516 TI - Effectiveness of Masks and Respirators Against Respiratory Infections in Healthcare Workers: A Systematic Review and Meta-Analysis. AB - This systematic review and meta-analysis quantified the protective effect of facemasks and respirators against respiratory infections among healthcare workers. Relevant articles were retrieved from Pubmed, EMBASE, and Web of Science. Meta-analyses were conducted to calculate pooled estimates. Meta analysis of randomized controlled trials (RCTs) indicated a protective effect of masks and respirators against clinical respiratory illness (CRI) (risk ratio [RR] = 0.59; 95% confidence interval [CI]:0.46-0.77) and influenza-like illness (ILI) (RR = 0.34; 95% CI:0.14-0.82). Compared to masks, N95 respirators conferred superior protection against CRI (RR = 0.47; 95% CI: 0.36-0.62) and laboratory confirmed bacterial (RR = 0.46; 95% CI: 0.34-0.62), but not viral infections or ILI. Meta-analysis of observational studies provided evidence of a protective effect of masks (OR = 0.13; 95% CI: 0.03-0.62) and respirators (OR = 0.12; 95% CI: 0.06-0.26) against severe acute respiratory syndrome (SARS). This systematic review and meta-analysis supports the use of respiratory protection. However, the existing evidence is sparse and findings are inconsistent within and across studies. Multicentre RCTs with standardized protocols conducted outside epidemic periods would help to clarify the circumstances under which the use of masks or respirators is most warranted. PMID- 29140520 TI - Therapeutic target database update 2018: enriched resource for facilitating bench to-clinic research of targeted therapeutics. AB - Extensive efforts have been directed at the discovery, investigation and clinical monitoring of targeted therapeutics. These efforts may be facilitated by the convenient access of the genetic, proteomic, interactive and other aspects of the therapeutic targets. Here, we describe an update of the Therapeutic target database (TTD) previously featured in NAR. This update includes: (i) 2000 drug resistance mutations in 83 targets and 104 target/drug regulatory genes, which are resistant to 228 drugs targeting 63 diseases (49 targets of 61 drugs with patient prevalence data); (ii) differential expression profiles of 758 targets in the disease-relevant drug-targeted tissue of 12 615 patients of 70 diseases; (iii) expression profiles of 629 targets in the non-targeted tissues of 2565 healthy individuals; (iv) 1008 target combinations of 1764 drugs and the 1604 target combination of 664 multi-target drugs; (v) additional 48 successful, 398 clinical trial and 21 research targets, 473 approved, 812 clinical trial and 1120 experimental drugs, and (vi) ICD-10-CM and ICD-9-CM codes for additional 482 targets and 262 drugs against 98 disease conditions. This update makes TTD more useful for facilitating the patient focused research, discovery and clinical investigations of the targeted therapeutics. TTD is accessible at http://bidd.nus.edu.sg/group/ttd/ttd.asp. PMID- 29140522 TI - ECOdrug: a database connecting drugs and conservation of their targets across species. AB - Pharmaceuticals are designed to interact with specific molecular targets in humans and these targets generally have orthologs in other species. This provides opportunities for the drug discovery community to use alternative model species for drug development. It also means, however, there is potential for mode of action related effects in non-target wildlife species as many pharmaceuticals reach the environment through patient use and manufacturing wastes. Acquiring insight in drug target ortholog predictions across species and taxonomic groups has proven difficult because of the lack of an optimal strategy and because necessary information is spread across multiple and diverse sources and platforms. We introduce a new research platform tool, ECOdrug, that reliably connects drugs to their protein targets across divergent species. It harmonizes ortholog predictions from multiple sources via a simple user interface underpinning critical applications for a wide range of studies in pharmacology, ecotoxicology and comparative evolutionary biology. ECOdrug can be used to identify species with drug targets and identify drugs that interact with those targets. As such, it can be applied to support intelligent targeted drug safety testing by ensuring appropriate and relevant species are selected in ecological risk assessments. ECOdrug is freely accessible and available at: http://www.ecodrug.org. PMID- 29140521 TI - Prevalence of Catatonia and Its Moderators in Clinical Samples: Results from a Meta-analysis and Meta-regression Analysis. AB - Catatonia is an independent syndrome that co-occurs with several mental and medical conditions. We performed a systematic literature review in PubMed/Scopus until February 2017 and meta-analyzed studies reporting catatonia prevalence. Across 74 studies (cross-sectional = 32, longitudinal = 26, retrospective = 16) providing data collected from 1935 to 2017 across all continents, mean catatonia prevalence was 9.0% (k = 80, n = 110764; 95% CI = 6.9-11.7, I2 = 98%, publication bias P < .01), decreasing to 7.8% (k = 19, n = 7612, 95% CI = 7-8.7, I2 = 38.9%) in a subgroup with low heterogeneity. Catatonia prevalence was 23.9% (k = 8, n = 1168, 95% CI = 10-46.9, I2 = 96%) in patients undergoing ECT/having elevated creatinine phosphokinase. Excluding ECT samples, the catatonia prevalence was 8.1% (k = 72, n = 109606, 95% CI = 6.1-10.5, I2 = 98%, publication bias P < .01), with sensitivity analyses demonstrating that country of study origin (P < .001), treatment setting (P = .003), main underlying condition (P < .001), and sample size (P < .001)moderated catatonia prevalence, being highest in Uganda (48.5%, k = 1) and lowest in Mexico (1.9%, 95% CI = 0.4-8.8, I2 = 67%, k = 2), highest in nonpsychiatric out- or inpatient services (15.8%, 95% CI = 8.1-28.4, I2 = 97%, k = 15)and lowest in psychiatric outpatients services (3.2%, 95% CI = 1.7-6.1, I2 = 50%, k = 3), highest in presence of medical or neurological illness with no comorbid psychiatric condition (20.6%, 95% CI = 11.5-34.2, I2 = 95%, k = 10)and lowest in mixed psychiatric samples (5.7%, 95% CI = 4.2-7.7, I2 =98%, k = 43), highest in studies with sample sizes <100 (20.7%, 95% CI = 12.8-31.6, I2 = 90%, k = 17) and lowest in studies with sample sizes >1000 (2.3%, 95% CI = 1.3-3.9, I2 = 99%, k = 16). Meta-regression showed that smaller sample size (P < .01) and less major depressive disorder (P = .02) moderated higher catatonia prevalence. Year of data collection did not significantly moderate the results. Results from this first meta-analysis of catatonia frequencies across time and disorders suggest that catatonia is an epidemiologically and clinically relevant condition that occurs throughout several mental and medical conditions, whose prevalence has not decreased over time and does not seem to depend on different rating scales/criteria. However, results were highly heterogeneous, calling for a cautious interpretation. PMID- 29140523 TI - Sequential Coiling-Assisted Deployment of Flow Diverter for Treatment of Fusiform Middle Cerebral Artery Aneurysms. AB - BACKGROUND AND IMPORTANCE: Fusiform intracranial aneurysms remain challenging lesions to treat. These aneurysms have historically required bypass procedures or clip remodeling constructs for cure. Recently, endovascular specialists have reported experience with flow diversion for complex fusiform aneurysms of the vertebrobasilar system, with mixed results. Vascular anatomy for anterior circulation fusiform aneurysms may make these lesions more amenable to flow diversion and embolization procedures; however, published experience with these techniques is lacking. In this report, we describe a sequential coiling-assisted deployment of flow diverter for the treatment of fusiform middle cerebral artery (MCA-M1) aneurysms in 2 cases, 1 presenting acutely with subarachnoid hemorrhage and another with progressive aneurysm enlargement. CLINICAL PRESENTATION: Two patients, a 36-yr-old male presenting with subarachnoid hemorrhage and a 60-yr old female presenting with aneurysm enlargement were treated for fusiform aneurysms of the M1 segment of the MCA using a sequential, partial deployment of coils and flow diverter through 2 microcatheters to facilitate mutual mechanical support for both coil and flow diverter (Pipeline Embolization Device; Medtronic Inc, Dublin, Ireland). Both patients achieved favorable outcomes and follow-up angiography demonstrated complete vessel reconstruction in both cases. CONCLUSION: The treatment of complex, fusiform, large vessel aneurysms remains challenging. As experience with new endovascular technologies and techniques grows, these lesions may be treated safely with interventional methods. The technique of partial flow diverter deployment and stabilization with coils with sequential delivery of both devices using dual microcatheter was both safe and effective. PMID- 29140524 TI - NONCODEV5: a comprehensive annotation database for long non-coding RNAs. AB - NONCODE (http://www.bioinfo.org/noncode/) is a systematic database that is dedicated to presenting the most complete collection and annotation of non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs). Since NONCODE 2016 was released two years ago, the amount of novel identified ncRNAs has been enlarged by the reduced cost of next-generation sequencing, which has produced an explosion of newly identified data. The third-generation sequencing revolution has also offered longer and more accurate annotations. Moreover, accumulating evidence confirmed by biological experiments has provided more comprehensive knowledge of lncRNA functions. The ncRNA data set was expanded by collecting newly identified ncRNAs from literature published over the past two years and integration of the latest versions of RefSeq and Ensembl. Additionally, pig was included in the database for the first time, bringing the total number of species to 17. The number of lncRNAs in NONCODEv5 increased from 527 336 to 548 640. NONCODEv5 also introduced three important new features: (i) human lncRNA-disease relationships and single nucleotide polymorphism-lncRNA-disease relationships were constructed; (ii) human exosome lncRNA expression profiles were displayed; (iii) the RNA secondary structures of NONCODE human transcripts were predicted. NONCODEv5 is also accessible through http://www.noncode.org/. PMID- 29140525 TI - rSNPBase 3.0: an updated database of SNP-related regulatory elements, element gene pairs and SNP-based gene regulatory networks. AB - Here, we present the updated rSNPBase 3.0 database (http://rsnp3.psych.ac.cn), which provides human SNP-related regulatory elements, element-gene pairs and SNP based regulatory networks. This database is the updated version of the SNP regulatory annotation database rSNPBase and rVarBase. In comparison to the last two versions, there are both structural and data adjustments in rSNPBase 3.0: (i) The most significant new feature is the expansion of analysis scope from SNP related regulatory elements to include regulatory element-target gene pairs (E-G pairs), therefore it can provide SNP-based gene regulatory networks. (ii) Web function was modified according to data content and a new network search module is provided in the rSNPBase 3.0 in addition to the previous regulatory SNP (rSNP) search module. The two search modules support data query for detailed information (related-elements, element-gene pairs, and other extended annotations) on specific SNPs and SNP-related graphic networks constructed by interacting transcription factors (TFs), miRNAs and genes. (3) The type of regulatory elements was modified and enriched. To our best knowledge, the updated rSNPBase 3.0 is the first data tool supports SNP functional analysis from a regulatory network prospective, it will provide both a comprehensive understanding and concrete guidance for SNP-related regulatory studies. PMID- 29140526 TI - Risk and Protective Factors for Family Violence among Low-Income Fathers: Implications for Violence Prevention and Fatherhood Programs. AB - Over the last decade there has been an increased focus on improving father engagement to improve child and family outcomes. Recent research suggests that child and family outcomes improve with increased fatherhood engagement. This exploratory study examined risk and protective factors associated with approval of family violence among a sample of low-income fathers (N = 686) enrolled in a responsible fatherhood program. The program goals include increasing father involvement and economic stability and encouraging healthy relationships-with a focus on preventing intimate partner violence. Toward these aims, this study explored factors associated with fathers' self-reported approval of family violence. Understanding the prevalence of risk and protective factors in this population and factors associated with fathers' potential for family violence is important in developing programs to address responsible fatherhood and healthy relationships. PMID- 29140527 TI - Functional organization of face processing in the human superior temporal sulcus: a 7T high-resolution fMRI study. AB - The superior temporal sulcus (STS) is a major component of the human face perception network, implicated in processing dynamic changeable aspects of faces. However, it remains unknown whether STS holds functionally segregated subdivisions for different categories of facial movements. We used high resolution functional magnetic resonance imaging (fMRI) at 7T in 16 volunteers to compare STS activation with faces displaying angry or happy expressions, eye-gaze shifts and lip-speech movements. Combining univariate and multivariate analyses, we show a systematic topological organization within STS, with gaze-related activity predominating in the most posterior and superior sector, speech-related activity in the anterior sector and emotional expressions represented in the intermediate middle STS. Right STS appeared to hold a finer functional segregation between all four types of facial movements, and best discriminative abilities within the face-selective posterior STS (pSTS). Conversely, left STS showed greater overlap between conditions, with a lack of distinction between mouth movements associated to speech or happy expression and better discriminative abilities (for gaze and speech vs emotion conditions) outside pSTS. Differential sensitivity to upper (eye) or lower (mouth) facial features may contribute to, but does not appear to fully account for, these response patterns. PMID- 29140529 TI - Editorial Board Changes for 2018. PMID- 29140528 TI - Evaluation of renal function change during first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma. AB - Background: The change in renal function induced by first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma remains unclear. Methods: One hundred and thirty-four patients were evaluated. Sunitinib (SU) and sorafenib (SO) were administered to 91 (67.9%) and 43 (32.1%) patients, respectively. The change in estimated glomerular filtration rate (DeltaeGFR) was calculated as [(eGFR at each time point - pre-treatment eGFR)/pre-treatment eGFR] * 100. DeltaeGFR was compared between SU- and SO users using a mixed-effects model for repeated measures data with two or greater. Additionally, predictors for DeltaeGFR <= -10% at 6 months after therapy initiation were evaluated using multivariate logistic regression analysis. Results: Throughout the 24 months after therapy initiation, DeltaeGFR was negatively greater in SU users, compared with that in SO users (P < 0.0001). In SU users, renal dysfunction was observed regardless of pre-treatment chronic kidney disease (CKD) status, whereas the magnitude of renal dysfunction was milder in SO users. In SO users without pre treatment CKD, renal function did not significantly deteriorate. Moreover, DeltaeGFR <= -10% was more frequently observed in SU users after 3 months (P = 0.0121) and 6 months (P = 0.0009). Finally, SU usage was an independent predictor for DeltaeGFR <= -10% at 6 months (odds ratio 8.87, P = 0.0053), along with pre treatment hypertension (odds ratio 4.69, P = 00072). Conclusions: Deterioration of renal function was stronger with SU than SO. During SU therapy, renal function should be monitored and pre-treatment kidney function should be taken into consideration for therapy selection. PMID- 29140530 TI - Antipsychotic Combinations for Schizophrenia. PMID- 29140531 TI - An update on sORFs.org: a repository of small ORFs identified by ribosome profiling. AB - sORFs.org (http://www.sorfs.org) is a public repository of small open reading frames (sORFs) identified by ribosome profiling (RIBO-seq). This update elaborates on the major improvements implemented since its initial release. sORFs.org now additionally supports three more species (zebrafish, rat and Caenorhabditis elegans) and currently includes 78 RIBO-seq datasets, a vast increase compared to the three that were processed in the initial release. Therefore, a novel pipeline was constructed that also enables sORF detection in RIBO-seq datasets comprising solely elongating RIBO-seq data while previously, matching initiating RIBO-seq data was necessary to delineate the sORFs. Furthermore, a novel noise filtering algorithm was designed, able to distinguish sORFs with true ribosomal activity from simulated noise, consequently reducing the false positive identification rate. The inclusion of other species also led to the development of an inner BLAST pipeline, assessing sequence similarity between sORFs in the repository. Building on the proof of concept model in the initial release of sORFs.org, a full PRIDE-ReSpin pipeline was now released, reprocessing publicly available MS-based proteomics PRIDE datasets, reporting on true translation events. Next to reporting those identified peptides, sORFs.org allows visual inspection of the annotated spectra within the Lorikeet MS/MS viewer, thus enabling detailed manual inspection and interpretation. PMID- 29140532 TI - Right posterior parietal cortex is involved in disengaging from threat: a 1-Hz rTMS study. AB - The right posterior parietal cortex (PPC) is implicated in spatial attention, but its specific role in emotional spatial attention remains unclear. In this study, we combined inhibitory transcranial magnetic stimulation (TMS) with a fear conditioning paradigm to test the role of the right PPC in attentional control of task-irrelevant threatening distractors. In a sham-controlled within-subject design, 1-Hz repetitive TMS was applied to the left and right PPC after which participants performed a visual search task with a distractor that was either associated with a loud noise burst (threat) or not (non-threat). Results demonstrated attentional capture across all conditions as evidenced by the typical reaction time costs of the distractor. However, only after inhibitory rTMS to the right PPC reaction time cost in the threatening distractor condition was increased relative to the non-threatening distractor condition, suggesting that attention lingered longer on the threatening distractor. We propose that the right PPC is involved in disengagement of attention from emotionally salient stimuli in order to re-orient attention to task relevant stimuli and may have implications for anxiety disorders associated with difficulties to disengage from threatening stimuli. PMID- 29140534 TI - Divergent effects of oxytocin on (para-)limbic reactivity to emotional and neutral scenes in females with and without borderline personality disorder. PMID- 29140533 TI - Come together: human-avatar on-line interactions boost joint-action performance in apraxic patients. AB - Limb apraxia (LA) is a high-order motor disorder linked to left-hemisphere damage. It is characterized by defective execution of purposeful actions upon delayed imitation, or verbal command when the actions are performed in isolated, non-naturalistic, conditions. Whether interpersonal interactions provide social affordances that activate neural resources different from those requested by individual action execution, which may improve LA performance, is unknown. To fill this gap, we measured interaction performance, behavioral and kinematic indexes of left-brain damaged patients with/without LA in a social reach-to-grasp task involving two different degrees of spatio-temporal interactivity with an avatar. We found that LA patients' impairment in coordinating with the virtual partner was abolished in highly interactive conditions (where patients selected their actions on-line based on the behavior of the virtual partner) with respect to low interactive conditions (where actions were selected beforehand based on abstract instructions). Voxel-based-Lesion-Symptom-Mapping indicated that impairments in low-interactive conditions were underpinned by lesions of premotor, motor and insular areas, and of the basal ganglia. Our approach expands current understanding of the behavioral and neural correlates of interactive motor performance by highlighting the important role of social affordances, and provides novel, potentially important, views on rehabilitation of higher-order motor cognition disorders. PMID- 29140535 TI - Socioeconomic disparities in small-for-gestational-age birth and preterm birth. AB - BACKGROUND: Maternal socioeconomic disadvantage has been associated with increased risk of small-for-gestational-age birth and preterm birth. Few studies, however, have considered maternal education and income simultaneously to better understand the mechanisms underlying perinatal health disparities. This analysis examines both maternal education and income and their association with the risk of small-for-gestational-age birth and preterm birth. DATA AND METHODS: The study is based on 127,694 singleton live births from the 2006 Canadian Birth-Census Cohort, a national cohort of births registered from May 2004 to May 2006 that were linked to the 2006 long-form Census. Unadjusted rates of small-for gestational-age birth (sex-specific birth weight below the 10th percentile for gestational age) and preterm birth (before 37 completed weeks of gestation) were estimated across selected maternal characteristics. Logistic regression was used to estimate crude and covariate-adjusted risk ratios of both outcomes according to maternal education and income adequacy quintiles. RESULTS: Small-for gestational-age birth was associated with both maternal education and income adequacy, while preterm birth was associated with maternal education only. These findings persisted after taking factors including maternal age, ethnicity, and marital status into account. The results suggest that the mechanism by which maternal education is associated with these outcomes is likely not through income, nor does income replace education as a potentially meaningful measure of socioeconomic position. INTERPRETATION: The mechanisms underlying associations between socioeconomic position and perinatal health disparities are complex. The results of this study indicate that more than one socioeconomic factor may play a role. PMID- 29140536 TI - Birth outcomes among First Nations, Inuit and Metis populations. AB - BACKGROUND: First Nations, Inuit, and Metis are at higher risk of adverse birth outcomes than are non-Indigenous people. However, relatively little perinatal information is available at the national level for Indigenous people overall or for specific identity groups. DATA AND METHODS: This analysis describes and compares rates of preterm birth, small-for-gestational-age birth, large-for gestational-age birth, stillbirth, and infant mortality (neonatal, postneonatal, and cause-specific) in a nationally representative sample of First Nations, Inuit, Metis, and non-Indigenous births. The study cohort consisted of 17,547 births to Indigenous mothers and 112,112 births to non-Indigenous mothers from 2004 through 2006. The cohort was created by linking the Canadian Live Birth, Infant Death and Stillbirth Database to the long form of the 2006 Census, which contains a self-reported Indigenous identifier. RESULTS: With the exception of small-for-gestational-age birth, adverse birth outcomes occurred more frequently among First Nations, Inuit, and Metis women than among non-Indigenous women. Inuit had the highest preterm birth rate (11.4 per 100 births; 95% CI: 9.7 to 13.1) among the three Indigenous groups. The large-for-gestational-age rate was highest for First Nations births (20.9 per 100 births; 95% CI: 19.9 to 21.8). Infant mortality rates were more than twice as high for each Indigenous group compared with the non-Indigenous population, and rates of sudden infant death syndrome were more than seven times higher among First Nations and Inuit. DISCUSSION: The results confirm disparities in birth outcomes between Indigenous and non-Indigenous populations, and demonstrate differences among First Nations, Metis and Inuit. PMID- 29140537 TI - Using normal and high pulse coverage with picosecond laser treatment of wrinkles and acne scarring: Long term clinical observations. AB - OBJECTIVE: The picosecond 755 nm alexandrite laser using a diffractive lens array has demonstrated consistent clinical efficacy for improving the appearance of acne scarring and wrinkles amongst other benefits. This small pilot study is to assess the difference, if any, in clinical benefit if a higher than the standard protocol for number of pulses delivered to a tissue area is used compared to the standard protocol guidelines. METHOD: Seven subjects received treatment to one side of the face with a standard protocol number of laser pulses with the other side of the face receiving higher than standard number of pulses from the same 755 nm picosecond laser using an additional diffractive lens array. Photographs at final follow up were compared to baseline by two blinded Board Certified Dermatologists and assessed for improvements to acne scarring using a 6-point grading score, for wrinkles using the Fitzpatrick Wrinkle & Elastosis 3-point grading scale and a Global Aesthetic Improvement Scale assessment. Subjects also completed a satisfaction questionnaire. RESULTS: For the acne scarring subjects, the average improvement from baseline to final follow up was 4.0 +/- 1.0 for the standard treated side and 4.5 +/- 0.5 for the high pulse side. There was no statistically significant difference between the two treated sides (P > 0.05, n = 3 paired t-test). For the wrinkle subjects, the average grading of the standard pulse side improved from 2.0 +/- 0.82 to 1.75 +/- 1.0 from baseline to final follow-up. The high pulse side improved from 1.5 +/- 1.0 to 1.125 +/- 0.25 from baseline to final follow-up. There was no statistically significant difference between the improvement of the standard and high pulse treatment sides (P > 0.05, n = 4 paired t-test). The comparison of baseline to final follow-up images of each subject found both sides to be Much or Very Much improved with no statistically significant difference between the standard and high pulse sides (P > 0.05, n = 7 paired t-test). Six of the seven subjects did not note any difference between the effect on different sides of the face and four of the seven rated their overall improvement after treatment as Good, three subjects as Reasonable and one subject with Slight Improvement. All subjects found the treatment comfortable and easy to tolerate and there was no increased incidence of side effects other than the mild occurrences typically observed for this type of treatment. CONCLUSION: This is a small pilot study with limited subject numbers and further data is needed to be able to make firm conclusions of observed trends, which suggest that the use of higher than standard suggested protocol number of pulses with the diffractive lens array and the 755 nm picosecond laser does not appear to offer any additional benefit over that that can already be achieved with the standard number of pulses, but also does not increase risk of detrimental post treatment effects either. Lasers Surg. Med. 50:51-55, 2018. (c) 2017 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc. PMID- 29140538 TI - Is liver transplantation for intractable attacks of porphyria a viable treatment in a developing country? PMID- 29140539 TI - Cross-regulation among arabinose, xylose and rhamnose utilization systems in E. coli. AB - : Bacteria frequently encounter multiple sugars in their natural surroundings. While the dynamics of utilization of glucose-containing sugar mixtures have been well investigated, there are few reports addressing regulation of utilization of glucose-free mixtures particularly pentoses. These sugars comprise a considerable fraction in hemicellulose which can be converted by suitable biocatalysts to biofuels and other value-added products. Hence, understanding of transcriptional cross-regulation among different pentose sugar utilization systems is essential for successful development of industrial strains. In this work, we study mixed sugar utilization with respect to three secondary carbon sources - arabinose, xylose and rhamnose at single-cell resolution in Escherichia coli. Our results reveal that hierarchical utilization among these systems is not strict but rather can be eliminated or reversed by altering the relative ratios of the preferred and nonpreferred sugars. Since transcriptional cross-regulation among pentose sugar systems operates through competitive binding of noncognate sugar-regulator complex, altering sugar concentrations is thought to eliminate nonspecific binding by affecting concentration of the regulator - sugar complexes. SIGNIFICANCE AND IMPACT OF THE STUDY: Plant biomass comprises of hexose and pentose sugar mixtures. These sugars are processed by micro-organisms to form products like biofuels, polymers etc. One of the major challenges with mixed sugar processing by micro-organisms is hierarchical utilization of sugars due to cross-regulation among sugar systems. In this work, we discuss cross-regulation among three secondary carbon sources - arabinose, xylose and rhamnose. Our results show that cross-regulation between pentose sugars is complex with multiple layers of regulation. These aspects need to be addressed for effective design of processes to extract energy from biomass. PMID- 29140540 TI - MicroRevolution in understanding primary biliary cholangitis pathophysiology. PMID- 29140541 TI - Regulatory T-cells in acute dengue viral infection. AB - Although regulatory T-cells (Tregs ) have been shown to be expanded in acute dengue, their role in pathogenesis and their relationship to clinical disease severity and extent of viraemia have not been fully evaluated. The frequency of Tregs was assessed in 56 adult patients with acute dengue by determining the proportion of forkhead box protein 3 (FoxP3) expressing CD4+ CD25+ T-cells (FoxP3+ cells). Dengue virus (DENV) viral loads were measured by quantitative real-time polymerase chain reaction (PCR) and DENV-specific T-cell responses were measured by ex-vivo interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) assays to overlapping peptide pools of DENV-NS3, NS1 and NS5. CD45RA and CCR4 were used to phenotype different subsets of T-cells and their suppressive potential was assessed by their expression of cytotoxic T lymphocyte-antigen 4 (CTLA-4) and Fas. While the frequency of FoxP3+ cells in patients was significantly higher (P < 0.0001) when compared to healthy individuals, they did not show any relationship with clinical disease severity or the degree of viraemia. The frequency of FoxP3+ cells did not correlate with either ex-vivo IFN-gamma DENV-NS3-, NS5- or NS1-specific T-cell responses. FoxP3+ cells of patients with acute dengue were predominantly CD45RA+ FoxP3low , followed by CD45RA-FoxP3low , with only a small proportion of FoxP3+ cells being of the highly suppressive effector Treg subtype. Expression of CCR4 was also low in the majority of T-cells, with only CCR4 only being expressed at high levels in the effector Treg population. Therefore, although FoxP3+ cells are expanded in acute dengue, they predominantly consist of naive Tregs , with poor suppressive capacity. PMID- 29140542 TI - Perioperative von Willebrand factor dynamics are associated with liver regeneration and predict outcome after liver resection. AB - : von Willebrand Factor (vWF) was found to mediate platelet influx during the early phase of liver regeneration in mice. Furthermore, increased vWF-antigen (vWF-Ag) levels were shown to be predictive for outcome of patients with chronic liver disease. Accordingly, we aimed to assess the relevance of perioperative vWF Ag dynamics in terms of liver regeneration and clinical outcome in patients undergoing liver resection (LR). Accordingly, we observed that vWF-Ag and its activity-estimated by ristocetin cofactor measurement-increased immediately after induction of liver regeneration and was associated with platelet accumulation within the liver. However, a significant vWF-Ag burst was only observed in patients with unaffected postoperative liver regeneration. E-selectin, as an established marker for endothelial cell activation, was found to correlate with vWF-Ag in the liver vein after induction of liver regeneration (R = 0.535, P = 0.022). Preoperative vWF-Ag levels significantly predicted postoperative liver dysfunction (LD; N = 95; area under the curve, 0.725; P = 0.009). Furthermore, a cutoff of vWF-Ag >=182% was defined to identify patients with a higher risk for postoperative LD or morbidity. This was confirmed within an independent mulitcenter validation cohort (N = 133). Ultimately, multivariable analysis revealed that vWF-Ag was an independent predictor of postoperative LD and morbidity. CONCLUSION: Within this study, we were able to provide evidence that an initial vWF burst is required to allow for adequate platelet accumulation and concomitant liver regeneration post-LR and might be abolished as a consequence of intrahepatic endothelial cell dysfunction. We were further able to reveal and validate the potential of preoperative vWF-antigen levels to predict poor postoperative outcome in patients undergoing LR. Despite the pathophysiological relevance of our findings, vWF-Ag seems to be a valuable tool for preoperative risk assessment in patients undergoing LR. (Hepatology 2018;67:1516-1530). PMID- 29140543 TI - Infant mortality in white-faced capuchins: The impact of alpha male replacements. AB - Infanticide is common in the context of alpha male replacements (AMR), particularly in groups where alpha males experience high reproductive skew and the infants are unlikely to be related to a new alpha male. We examined the relationship between the rate of infant mortality, infant age, and the occurrence and type of AMR in white-faced capuchin monkeys (Cebus capucinus imitator) of the Santa Rosa population in Sector Santa Rosa, Area de Conservacion Guanacaste. Specifically, we investigated how the source of the new alpha male (coresident or extragroup) and relative aggression level during AMRs influenced infant mortality in this species. Between 1986 and 2015, we recorded 221 births in five study groups. Infants present at the time of an AMR, or born within 5.5 months following an AMR (i.e., conceived prior to AMR), experienced significantly higher mortality than those born during periods of group stability. Infant age was a significant predictor of infant survival, with the probability of surviving increasing by 0.4% for each additional day older an infant was at the time of the AMR. Infant mortality rates did not differ between AMRs by coresident males and extragroup males, possibly because the degree of relatedness between infants and new alphas did not significantly differ between coresident and extragroup AMRs. Infant mortality rates did not differ significantly between aggressive AMRs and more peaceful AMRs. Our results are consistent with predictions derived from the sexual selection hypothesis (SSH) of infanticide and suggest that future studies examine the role of testosterone as an underlying proximate mechanism for the aggression leading to this behavior. We argue that the sexual selection and generalized aggression hypotheses (GAH) of infanticide are best considered as different levels of analysis rather than competing hypotheses. PMID- 29140544 TI - Case Report: A Cryptosporidium infection in a patient with relapsed T lymphoblastic lymphoma undergoing allogeneic stem cell transplantation. AB - Cryptosporidium infection is a rare cause of enterocolitis. In immunocompromised patients, cryptosporidiosis may lead to debilitating and life-threatening diarrhea and malabsorption, occasionally with multi-organ involvement. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) requires long-term immunosuppressive therapy, while cellular immunity is usually compromised due to intensive conditioning chemotherapy. Diarrhea in patients who underwent allo-HSCT may be a sign of an infection, but can also be the result of intestinal graft versus-host disease (GvHD). Here, we describe the case of a patient who developed severe diarrhea following allo-HSCT for relapsed T-lymphoblastic lymphoma. Initially, GvHD was suspected and treatment was initiated accordingly. However, a colon biopsy showed signs of cryptosporide oocysts alongside only low-grade GvHD. Following molecular confirmation of the diagnosis of cryptosporidiosis, an intensive treatment regimen was started. Despite the severe clinical course, the patient recovered and was discharged with only residual symptoms. PMID- 29140545 TI - Neobladder-Vaginal fistula: The University of Southern California experience. AB - AIMS: The use of orthotropic neobladder (ONB) construction in women has increased in popularity. With increasing numbers so have complications distinct to this procedure. Neobladder vaginal fistula (NVF) is a rare but challenging complication. We present our experience correcting this problem. METHODS: An IRB approved database of female patients with an ONB was retrospectively reviewed. Patients with a history of NVF were identified and charts reviewed. Our standard technique of radical cystectomy and orthotopic diversion in female patients includes interposition of omentum between the neobladder and anterior vaginal wall and sacrocolpopexy. RESULTS: Two hundred and forty-nine female patients underwent cystectomy and ONB construction between 1995 and 2015. Fourteen patients were diagnosed with a NVF (5.6% incidence). The average age and follow up was 67 years and 33.7 months, respectively. Surgery for fistula closure was attempted in 13 patients. One repair was combined abdominal and transvaginal; the remaining 12 were performed transvaginally. Location of NVF was categorized as at the urethra-neobladder anastomosis (UNA, nine patients) and anterior vaginal wall (AVW, four patients). Eight patients had a successful fistula repair (61.5%) but only five patients ultimately retained their ONB (39%). CONCLUSIONS: Patients with a NVF pose a surgical challenge. Successful fistula repair does not necessarily result in adequate continence due to an incompetent outlet. NVF location at the UNA is the more common location and is more challenging in regard to successful resolution of the NVF as well as possible urinary incontinence post NVF repair. PMID- 29140546 TI - A synthesis of [14 C]sodium ferrocyanide decahydrate. AB - The 2-step synthesis of [14 C]sodium ferrocyanide decahydrate is described. Ferrous hydroxide was prepared from iron powder and then reacted with [14 C]sodium cyanide to afford the product. The [14 C]sodium ferrocyanide decahydrate was characterized by HPLC and 13 C NMR. PMID- 29140547 TI - Islet transplantation as safe and efficacious method to restore glycemic control and to avoid severe hypoglycemia after donor organ failure in pancreas transplantation. AB - The aim of this study was to assess safety and efficacy of islet transplantation after initial pancreas transplantation with subsequent organ failure. Patients undergoing islet transplantation at our institution after pancreas organ failure were compared to a control group of patients with pancreas graft failure, but without islet transplantation and to a group receiving pancreas retransplantation. Ten patients underwent islet transplantation after initial pancreas transplantation failed and were followed for a median of 51 months. The primary end point of HbA1c <7.0% and freedom of severe hypoglycemia was met by nine of 10 patients after follow-up after islet transplantation and in all three patients in the pancreas retransplantation group, but by none of the patients in the group without retransplantation (n = 7). Insulin requirement was reduced by 50% after islet transplantation. Kidney function (eGFR) declined with a rate of 1.0 mL +/- 1.2 mL/min/1.73 m2 per year during follow-up after islet transplantation, which tended to be slower than in the group without retransplantation (P = .07). Islet transplantation after deceased donor pancreas transplant failure is a method that can safely improve glycemic control and reduce the incidence of severe hypoglycemia and thus establish similar glycemic control as after initial pancreas transplantation, despite the need of additional exogenous insulin. PMID- 29140548 TI - A phase Ib, open-label, single arm study to assess the safety, pharmacokinetics, and impact on humoral sensitization of SANGUINATE infusion in patients with end stage renal disease. AB - The endeavor to study desensitization in kidney transplantation has not been matched by an effort to investigate strategies to prevent sensitization. In this study (NCT02437422), we investigated the safety, impact on sensitization, and pharmacokinetics of SANGUINATE (SG), a hemoglobin-based oxygen carrier, as a potential alternative to packed red blood cells (PRBC) in transplant candidates with end-stage renal disease (ESRD). Ten ESRD subjects meeting inclusion/exclusion (I/E) criteria were planned to receive three weekly infusions of SG (320 mg/kg). The study was stopped after five subjects were enrolled, and their data were analyzed after completing a follow-up period of 90 days. Two subjects had elevated troponin I levels in setting of SG infusion, one of which was interpreted as a non-ST elevation myocardial infarction. All other adverse events were transient. SG pharmacokinetic analysis showed mean (SD) Cmax , Tmax , AUC, and half-life of 4.39 (0.69) mg/mL, 2.42 (0.91) hours, 171.86 (52.35) mg h/mL, and 40.60 (11.96) hours, respectively. None of the subjects developed new anti-HLA antibodies following SG infusion and throughout the study period. In conclusion, SG is a potential alternative to PRBCs in ESRD patients considered for kidney transplantation as it was not associated with humoral sensitization. Larger studies in highly sensitized patients are required to further evaluate for potential safety signals. PMID- 29140549 TI - Improving pancreas graft utilization through importation. AB - BACKGROUND: We analyze our outcomes utilizing imported allografts as a strategy to shorten wait list time for pancreas transplantation. METHODS: This is an observational retrospective cohort of 26 recipients who received either a locally procured (n = 16) or an imported pancreas graft (n = 10) at our center between January 2014 and May 2017. Wait list times of this cohort were compared to UNOS Region 9 (New York State and Western Vermont). Hospital financial data were also reviewed to analyze the cost-effectiveness of this strategy. RESULTS: Imported pancreas grafts had significantly increased cold ischemia times (CIT) and peak lipase (PL) levels compared to locally procured grafts (CIT 827 vs 497 minutes; P = .001, PL 563 vs 157 u/L; P = .023, respectively). There were no differences in graft or patient survival. The median wait time was significantly lower for simultaneous kidney-pancreas transplants at our center (518 days, n = 21) compared to Region 9 (1001 days, n = 65) P = .038. Despite financial concerns, the cost of transport for imported grafts was offset by lower standard acquisition costs. CONCLUSIONS: Imported pancreas grafts may be a cost-effective strategy to increase organ utilization and shorten wait times in regions with longer waiting times. PMID- 29140550 TI - Long noncoding RNA H19 interacts with polypyrimidine tract-binding protein 1 to reprogram hepatic lipid homeostasis. AB - : H19 is an imprinted long noncoding RNA abundantly expressed in embryonic liver and repressed after birth. We show that H19 serves as a lipid sensor by synergizing with the RNA-binding polypyrimidine tract-binding protein 1 (PTBP1) to modulate hepatic metabolic homeostasis. H19 RNA interacts with PTBP1 to facilitate its association with sterol regulatory element-binding protein 1c mRNA and protein, leading to increased stability and nuclear transcriptional activity. H19 and PTBP1 are up-regulated by fatty acids in hepatocytes and in diet-induced fatty liver, which further augments lipid accumulation. Ectopic expression of H19 induces steatosis and pushes the liver into a "pseudo-fed" state in response to fasting by promoting sterol regulatory element-binding protein 1c protein cleavage and nuclear translocation. Deletion of H19 or knockdown of PTBP1 abolishes high-fat and high-sucrose diet-induced steatosis. CONCLUSION: Our study unveils an H19/PTBP1/sterol regulatory element-binding protein 1 feedforward amplifying signaling pathway to exacerbate the development of fatty liver. (Hepatology 2018;67:1768-1783). PMID- 29140552 TI - The influence of phylogeny, social style, and sociodemographic factors on macaque social network structure. AB - Among nonhuman primates, the evolutionary underpinnings of variation in social structure remain debated, with both ancestral relationships and adaptation to current conditions hypothesized to play determining roles. Here we assess whether interspecific variation in higher-order aspects of female macaque (genus: Macaca) dominance and grooming social structure show phylogenetic signals, that is, greater similarity among more closely-related species. We use a social network approach to describe higher-order characteristics of social structure, based on both direct interactions and secondary pathways that connect group members. We also ask whether network traits covary with each other, with species-typical social style grades, and/or with sociodemographic characteristics, specifically group size, sex-ratio, and current living condition (captive vs. free-living). We assembled 34-38 datasets of female-female dyadic aggression and allogrooming among captive and free-living macaques representing 10 species. We calculated dominance (transitivity, certainty), and grooming (centrality coefficient, Newman's modularity, clustering coefficient) network traits as aspects of social structure. Computations of K statistics and randomization tests on multiple phylogenies revealed moderate-strong phylogenetic signals in dominance traits, but moderate-weak signals in grooming traits. GLMMs showed that grooming traits did not covary with dominance traits and/or social style grade. Rather, modularity and clustering coefficient, but not centrality coefficient, were strongly predicted by group size and current living condition. Specifically, larger groups showed more modular networks with sparsely-connected clusters than smaller groups. Further, this effect was independent of variation in living condition, and/or sampling effort. In summary, our results reveal that female dominance networks were more phylogenetically conserved across macaque species than grooming networks, which were more labile to sociodemographic factors. Such findings narrow down the processes that influence interspecific variation in two core aspects of macaque social structure. Future directions should include using phylogeographic approaches, and addressing challenges in examining the effects of socioecological factors on primate social structure. PMID- 29140551 TI - B-cell receptor repertoire sequencing in patients with primary immunodeficiency: a review. AB - The advent of next-generation sequencing (NGS) now allows a detailed assessment of the adaptive immune system in health and disease. In particular, high throughput B-cell receptor (BCR) repertoire sequencing provides detailed information about the functionality and abnormalities of the B-cell system. However, it is mostly unknown how the BCR repertoire is altered in the context of primary immunodeficiencies (PID) and whether findings are consistent throughout phenotypes and genotypes. We have performed an extensive literature search of the published work on BCR repertoire sequencing in PID patients, including several forms of predominantly antibody disorders and combined immunodeficiencies. It is somewhat surprising that BCR repertoires, even from severe clinical phenotypes, often show only mild abnormalities and that diversity or immunoglobulin gene segment usage is generally preserved to some extent. Despite the great variety of wet laboratory and analytical methods that were used in the different studies, several findings are common to most investigated PIDs, such as the increased usage of gene segments that are associated with self-reactivity. These findings suggest that BCR repertoire characteristics may be used to assess the functionality of the B-cell compartment irrespective of the underlying defect. With the use of NGS approaches, there is now the opportunity to apply BCR repertoire sequencing to multiple patients and explore the PID BCR repertoire in more detail. Ultimately, using BCR repertoire sequencing in translational research could aid the management of PID patients by improving diagnosis, estimating functionality of the immune system and improving assessment of prognosis. PMID- 29140553 TI - Outcomes of pneumatic dilation in achalasia: Extended follow-up of more than 25 years with a focus on manometric subtypes. AB - BACKGROUND AND AIM: Pneumatic dilation (PD) is the most popular nonsurgical treatment for achalasia. This study investigated predicting factors, including manometric subtypes for symptom recurrence in the long term, in patients with achalasia treated with a single PD. METHODS: Between 1983 and 2013, a total of 107 patients were treated initially with a single PD and included in this longitudinal cohort study. Outcomes were correlated with demographics, symptoms (Eckardt score), and esophagographic and manometric features. Manometric tracings were retrospectively classified according to the three subtypes of the Chicago classification. RESULTS: Ninety-one (85%) patients were successfully treated after the first PD. The median follow-up was 13.8 years (interquartile range 7 20). During follow-up, 54% of the patients experienced a clinical relapse. The overall cumulative success rates at 2, 5, 10, 15, 20, and 25 years were 64%, 53%, 49%, 42%, 36%, and 36%, respectively. Age < 40 years, lower esophageal sphincter pressure > 15 mmHg, a cardia width < 5 mm, and an esophageal barium column height > 1 cm 4 to 12 weeks post-dilation significantly correlated with symptom recurrence, whereas achalasia subtypes did not significantly correlate with the treatment results. CONCLUSION: Pneumatic dilation in achalasia is an effective therapy in the short term, but its effect wanes in the very long term. Young age at presentation, a high lower esophageal sphincter pressure, a narrow cardia, and an esophageal barium column of > 1 cm after PD are predictive factors for the need of repeated treatment. PMID- 29140554 TI - Factors associated with oral health-related quality of life in patients with diabetes. AB - BACKGROUND: Oral pathologies are prevalent in diabetes, and they may affect the quality of life and patient's perception of their oral health. The aim of this study was to investigate the factors associated with oral health-related quality of life of patients with diabetes. METHODS: A cross sectional study was conducted involving 316 patients visiting a hospital diabetic unit. Sociodemographic, oral and medical care data were recorded, and a General Oral Health Assessment Index (GOHAI) questionnaire was completed. A multivariable analysis was performed. RESULTS: Of the 316 study participants, 61.7% had type 2 diabetes (T2DM) and 20.5% had poorly controlled diabetes. Forty-five percent had at least one oral complication, 55% had visited a dentist within the past year and 67% reported having poor oral health and 281 answered the GOHAI questionnaire. A low GOHAI score (<=50) was obtained for 24.6% of the patients and was associated with T2DM, poorer oral health, dry mouth sensation and use of a removable prosthesis. CONCLUSIONS: Oral health status was poorer and had a negative effect on the quality of life among patients with T2DM, possibly contributing to poorly balanced nutrition. PMID- 29140555 TI - WITHDRAWN: Electrical cardioversion for atrial fibrillation and flutter. AB - BACKGROUND: Atrial fibrillation increases stroke risk and adversely affects cardiovascular haemodynamics. Electrical cardioversion may, by restoring sinus rhythm, improve cardiovascular haemodynamics, reduce the risk of stroke, and obviate the need for long-term anticoagulation. OBJECTIVES: To assess the effects of electrical cardioversion of atrial fibrillation or flutter on the risk of thromboembolic events, strokes and mortality (primary outcomes), the rate of cognitive decline, quality of life, the use of anticoagulants and the risk of re hospitalisation (secondary outcomes) in adults (>18 years). SEARCH METHODS: We searched the Cochrane CENTRAL Register of Controlled Trials (1967 to May 2004), MEDLINE (1966 to May 2004), Embase (1980 to May 2004), CINAHL (1982 to May 2004), proceedings of the American College of Cardiology (published in Journal of the American College of Cardiology 1983 to 2003), www.trialscentral.org, www.controlled-trials.com and reference lists of articles. We hand-searched the indexes of the Proceedings of the British Cardiac Society published in British Heart Journal (1980 to 1995) and in Heart (1995 to 2002); proceedings of the European Congress of Cardiology and meetings of the Joint Working Groups of the European Society of Cardiology (published in European Heart Journal 1983-2003); scientific sessions of the American Heart Association (published in Circulation 1990-2003). Personal contact was made with experts. SELECTION CRITERIA: Randomised controlled trial or controlled clinical trials of electrical cardioversion plus 'usual care' versus 'usual care' only, where 'usual care' included any combination of anticoagulants, antiplatelet drugs and drugs for 'rate control'. We excluded trials which used pharmacological cardioversion as the first intervention, and trials of new onset atrial fibrillation after cardiac surgery. There were no language restrictions. DATA COLLECTION AND ANALYSIS: For dichotomous data, odds ratios were calculated; and for continuous data, the weighted mean difference was calculated. MAIN RESULTS: We found three completed trials of electrical cardioversion (rhythm control) versus rate control, recruiting a total of 927 participants (Hot Cafe; RACE; STAF) and one ongoing trial (J-RHYTHM). There was no difference in mortality between the two strategies (OR 0.83; CI 0.48 to 1.43). There was a trend towards more strokes in the rhythm control group (OR 1.9; 95% CI 0.99 to 3.64). At follow up, three domains of quality of life (physical functioning, physical role function and vitality) were significantly better in the rhythm control group (RACE 2002; STAF 2003). AUTHORS' CONCLUSIONS: Electrical cardioversion (rhythm control) led to a non-significant increase in stroke risk but improved three domains of quality of life. PMID- 29140556 TI - WITHDRAWN: Transcendental meditation for the primary prevention of cardiovascular disease. AB - BACKGROUND: A major determinant in cardiovascular disease (CVD) is stress. As transcendental meditation (TM) is thought to help in lowering negative stress indicators, it may be a beneficial strategy for the primary prevention of CVD. OBJECTIVES: To determine the effectiveness of TM for the primary prevention of CVD. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 10); MEDLINE (Ovid) (1946 to week three November 2013); EMBASE Classic and EMBASE (Ovid) (1947 to week 48 2013); ISI Web of Science (1970 to 28 November 2013); and Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment Database and Health Economics Evaluations Database (November 2013). We also searched the Allied and complementary Medicine Database (AMED) (inception to January 2014) and IndMed (inception to January 2014). We handsearched trial registers and reference lists of reviews and articles and contacted experts in the field. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of at least three months' duration involving healthy adults or adults at high risk of CVD. Trials examined TM only and the comparison group was no intervention or minimal intervention. We excluded trials that involved multi factorial interventions. Outcomes of interest were clinical CVD events (cardiovascular mortality, all-cause mortality and non-fatal events) and major CVD risk factors (e.g. blood pressure and blood lipids, occurrence of type 2 diabetes, quality of life, adverse events and costs). DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion, extracted data and assessed the risk of bias. MAIN RESULTS: We identified four trials (four papers) (430 participants) for inclusion in this review. We identified no ongoing studies. The included trials were small, short term (three months) and at risk of bias. In all studies, TM was practised for 15 to 20 minutes twice a day.None of the included studies reported all-cause mortality, cardiovascular mortality or non-fatal endpoints as trials were short term, but one study reported survival rate three years after the trial was completed. In view of the considerable statistical heterogeneity between the results of the studies for the only outcomes reported, systolic blood pressure (I2 = 72%) and diastolic blood pressure (I2 = 66%), we decided not to undertake a meta-analysis. None of the four trials reported blood lipids, occurrence of type 2 diabetes, adverse events, costs or quality of life. AUTHORS' CONCLUSIONS: Currently, there are few trials with limited outcomes examining the effectiveness of TM for the primary prevention of CVD. Due to the limited evidence to date, we could draw no conclusions as to the effectiveness of TM for the primary prevention of CVD. There was considerable heterogeneity between trials and the included studies were small, short term and at overall serious risk of bias. More and larger long-term, high-quality trials are needed. PMID- 29140557 TI - WITHDRAWN: Pharmacological cardioversion for atrial fibrillation and flutter. AB - BACKGROUND: Atrial fibrillation is the commonest cardiac dysrhythmia. It is associated with significant morbidity and mortality. There are two approaches to the management of atrial fibrillation: controlling the ventricular rate or converting to sinus rhythm in the expectation that this would abolish its adverse effects. OBJECTIVES: To assess the effects of pharmacological cardioversion of atrial fibrillation in adults on the annual risk of stroke, peripheral embolism, and mortality. SEARCH METHODS: We searched the Cochrane Controlled Trials Register (Issue 3, 2002), MEDLINE (2000 to 2002), EMBASE (1998 to 2002), CINAHL (1982 to 2002), Web of Science (1981 to 2002). We hand searched the following journals: Circulation (1997 to 2002), Heart (1997 to 2002), European Heart Journal (1997-2002), Journal of the American College of Cardiology (1997-2002) and selected abstracts published on the web site of the North American Society of Pacing and Electrophysiology (2001, 2002). SELECTION CRITERIA: Randomised controlled trials or controlled clinical trials of pharmacological cardioversion versus rate control in adults (>18 years) with acute, paroxysmal or sustained atrial fibrillation or atrial flutter, of any duration and of any aetiology. DATA COLLECTION AND ANALYSIS: One reviewer applied the inclusion criteria and extracted the data. Trial quality was assessed and the data were entered into RevMan. MAIN RESULTS: We identified two completed studies AFFIRM (n=4060) and PIAF (n=252). We found no difference in mortality between rhythm control and rate control relative risk 1.14 (95% confidence interval 1.00 to 1.31).Both studies show significantly higher rates of hospitalisation and adverse events in the rhythm control group and no difference in quality of life between the two treatment groups.In AFFIRM there was a similar incidence of ischaemic stroke, bleeding and systemic embolism in the two groups. Certain malignant dysrhythmias were significantly more likely to occur in the rhythm control group. There were similar scores of cognitive assessment.In PIAF, cardioverted patients enjoyed an improved exercise tolerance but there was no overall benefit in terms of symptom control or quality of life. AUTHORS' CONCLUSIONS: There is no evidence that pharmacological cardioversion of atrial fibrillation to sinus rhythm is superior to rate control. Rhythm control is associated with more adverse effects and increased hospitalisation. It does not reduce the risk of stroke. The conclusions cannot be generalised to all people with atrial fibrillation. Most of the patients included in these studies were relatively older (>60 years) with significant cardiovascular risk factors. PMID- 29140558 TI - Adherence to treatment guidelines and survival for older patients with stage II or III colon cancer in Texas from 2001 through 2011. AB - BACKGROUND: Treatment guidelines for colon cancer recommend colectomy with lymphadenectomy of at least 12 lymph nodes for patients with stage I to stage III disease as surgery adherence (SA) and adjuvant chemotherapy for individuals with stage III disease. Herein, the authors evaluated adherence to these guidelines among older patients in Texas with colon cancer and the associated survival outcomes. METHODS: Using Texas Cancer Registry data linked with Medicare data, the authors included patients with AJCC stage II and III colon cancer who were aged >=66 years and diagnosed between 2001 and 2011. SA and adjuvant chemotherapy adherence rates to treatment guidelines were estimated. The chi-square test, general linear regression, survival probability, and Cox regression were used to identify factors associated with adherence and survival. RESULTS: The rate of SA increased from 47.2% to 84% among 6029 patients with stage II or stage III disease from 2001 to 2011, and the rate of adjuvant chemotherapy increased from 48.9% to 53.1% for patients with stage III disease during the same time period. SA was associated with marital status, tumor size, surgeon specialty, and year of diagnosis. Patient age, sex, marital status, Medicare state buy-in status, comorbidity status, and year of diagnosis were found to be associated with adjuvant chemotherapy. The 5-year survival probability for patients receiving guideline-concordant treatment was the highest at 87% for patients with stage II disease and was 73% for those with stage III disease. After adjusting for demographic and tumor characteristics, improved cancer cause-specific survival was associated with the receipt of stage-specific, guideline-concordant treatment for patients with stage II or stage III disease. CONCLUSIONS: The adherence to guideline-concordant treatment among older patients with colon cancer residing in Texas improved over time, and was associated with better survival outcomes. Future studies should be focused on identifying interventions to improve guideline-concordant treatment adherence. Cancer 2018;124:679-87. (c) 2017 American Cancer Society. PMID- 29140559 TI - Comparative efficacy and tolerability of solifenacin 5 mg/day versus other oral antimuscarinic agents in overactive bladder: A systematic literature review and network meta-analysis. AB - AIMS: To compare efficacy and tolerability of solifenacin 5 mg/day versus other oral antimuscarinic agents for the treatment of overactive bladder (OAB). METHODS: Literature searches of MEDLINE, Embase, and the Cochrane Library were undertaken to identify randomized controlled trials in OAB (2000-2015) for antimuscarinic agents. A network meta-analysis (NMA) was performed to estimate efficacy and tolerability outcomes for solifenacin 5 mg/day relative to other antimuscarinics. RESULTS: The NMA included 53 eligible trials (published, n = 48; unpublished on search date, n = 5). Solifenacin 5 mg/day was significantly more effective than tolterodine 4 mg/day for reducing incontinence and urgency urinary incontinence (UUI) episodes, but significantly less effective than solifenacin 10 mg/day for micturition; no other statistically significant differences were noted for efficacy. Solifenacin 5 mg/day had a statistically significant lower risk of dry mouth compared with darifenacin 15 mg/day, fesoterodine 8 mg/day, oxybutynin extended-release 10 mg/day, oxybutynin immediate-release (IR) 9-15 mg/day, tolterodine IR 4 mg/day, propiverine 20 mg/day, and solifenacin 10 mg/day. There were no significant differences between solifenacin 5 mg/day and other antimuscarinics for risk of blurred vision, or for 11 of 17 active comparators for risk of constipation. CONCLUSIONS: This NMA suggests that the efficacy of solifenacin 5 mg/day is at least similar to other common antimuscarinics across the spectrum of OAB symptoms analyzed, and is more effective than tolterodine 4 mg/day in reducing incontinence and UUI episodes. Solifenacin 5 mg/day has a lower risk of dry mouth compared with several agents. PMID- 29140560 TI - Negative Posttrauma Cognitions Mediate the Association Between Morally Injurious Events and Trauma-Related Psychopathology in Treatment-Seeking Veterans. AB - Exposure to potentially morally injurious events has been shown to be associated with posttraumatic stress disorder (PTSD) and depression symptoms in military personnel. Few studies have examined factors that help to explain how potentially morally injurious events may contribute to the development of trauma-related psychopathology. Negative posttrauma cognitions are thought to play a role in the etiology of PTSD and depression following trauma; however, it is unclear whether more global beliefs about the self, others, and world play a role in the development of PTSD and depression due to morally injurious events. Using structural equation modeling, we tested whether morally injurious experiences were indirectly related to trauma-related psychopathology (PTSD and depression) through negative posttrauma cognitions in a sample of veterans seeking treatment for PTSD. An indirect effects only model best fit the data and showed that morally injurious experiences, specifically perceived transgressions by oneself and perceived betrayal, were indirectly associated with trauma-related psychopathology through negative posttrauma cognitions, beta = .17; 95% CI [.04, .31] and beta = .25; 95% CI [.11, .41], respectively. Our findings suggest that negative posttrauma cognitions may be an important mechanism linking exposure to morally injurious events and trauma-related psychopathology. PMID- 29140562 TI - Urodynamic measurements reflect physiological bladder function in rats. AB - AIMS: Our objective was to investigate and compare bladder function in rats assessed by metabolic cage and by urodynamic measurements in fully awake animals. METHODS: Bladder function of female Lewis rats was investigated in naive animals by metabolic cage at baseline, 14-16 days after bladder catheter and external urethral sphincter electromyography electrode implantation in fully awake animals by urodynamics, and again by metabolic cage. RESULTS: Investigating the same animals (n = 8), voided volume, average flow, and duration of voiding were similar (P > 0.05) in naive animals measured by metabolic cage and after catheter implantation by urodynamic measurements and by metabolic cage. In naive animals measured by metabolic cage, voided volumes were significantly different in the light (resting phase) versus the dark (active phase) part of the 24 h cycle (mean difference 0.14 mL, 21%, P = 0.004, n = 27). CONCLUSIONS: Lower urinary tract function assessed by metabolic cage or by urodynamic meaurements in fully awake rats was indistinguishable. Thus, catheter implantation did not significantly change physiological bladder function. This shows that urodynamic measurements in awake animals are an appropriate approach to study lower urinary tract function in health and disease in animal models, directly paralleling the human diagnostic procedures. PMID- 29140561 TI - Interaction among smoking status, single nucleotide polymorphisms and markers of systemic inflammation in healthy individuals. AB - Cigarette smoke contains toxic and carcinogenic substances that contribute to the development of cancer and various diseases. Genetic variation might be important, because not all smokers develop smoking-related disease. The current study addressed the possible interactions among selected single nucleotide polymorphisms (SNPs) in genes related to systemic inflammation, smoking status, the levels of circulating immune response cells and plasma biomarkers of systemic inflammation. Sixty-four healthy blood donors were recruited, 31 of whom were current smokers and 33 were never-users of tobacco products, references. Compared to references, the smokers showed significantly increased levels of circulating total white blood cells, lymphocytes, monocytes, neutrophils, basophils and C reactive protein (CRP). Smokers also more frequently exhibited circulating cell phenotypes that are associated with an immunocompromised state: CD8dim cells in the lymphocyte group, CD13+ CD11+ , CD13+ CD14+ , CD13+ CD56+ cells in the monocyte group and CD13+ CD11+ , CD13+ CD56+ cells in the neutrophil group. We observed an interaction among SNPs, smoking status and some of the studied biomarkers. The average plasma CRP level was significantly higher among the smokers, with the highest level found among those with the CRP rs1800947 CC genotype. Additionally, an increased CD8+ GZB+ cells in the CD8dim group were found among smokers with the GZB rs8192917 AA genotype. Thus, smoking appears to be associated with systemic inflammation and increased levels of circulating immunosuppressive cells. The extent of these effects was associated with SNPs among the smokers. This observation may contribute to a better understanding of the genetic susceptibility of smoking-related disease and the variations observed in clinical outcomes. PMID- 29140563 TI - "Stink flirting" in ring-tailed lemurs (Lemur catta): Male olfactory displays to females as honest, costly signals. AB - Sexual selection for honest behavioral displays of quality has driven the development of remarkably complex courtship behavior in many animal species. Olfactory displays are often overlooked as an area of inquiry compared to auditory and visual displays. Ring-tailed lemur (Lemur catta) scent marking of substrates has been studied extensively, although the male olfactory displays of anointing and wafting tails to females has received relatively little attention. We studied the role of male olfactory displays to females, evaluating whether such signals function as honest, costly signals of male dominance status in two groups of wild L. catta at Berenty Reserve, Madagascar. Our results suggest that male tail anointing and tail wafting displays to pre-estrous and estrous females are correlated with male dominance rank, and moreover appear to operate as costly signals, as such displays increase aggression received from males and females while other types of scent marking do not. Furthermore, females showed greater mating preference (as measured by sexual presents) for resident males who performed the "anoint tail" and "waft tail" displays towards them. When males perform the "anoint tail" and "waft tail" displays to females, they receive higher levels of aggression than if they were to perform other types of scent marking. Interestingly, immigrating (peripheral) males performed the "anoint tail" and "waft tail" displays at higher rates than resident males, which could honestly indicate their quality or may simply be associated with the alternative mating strategy of transferring between groups to gain mating opportunities. Our finding that tail anointing and tail wafting displays function as honest signals of dominance for resident males-and that these costly displays appear to positively affect female mate choice-is the first evidence of this function for this particular olfactory signal in L. catta. PMID- 29140565 TI - Visualization and Modeling of the In Vivo Distribution of Mesenchymal Stem Cells. AB - This unit describes a protocol for elucidating the in vivo disposition of administered mesenchymal stem cells (MSCs). Specifically, direct visualization of donor cell spatiotemporal distribution and assessment of donor cell quantity in recipient organs are described. Protocols for data analysis are suggested, with the goal of developing a model to characterize and predict the physiological kinetics of administered MSCs. The use of this model is described, suggesting that it can be applied to abnormal conditions and has potential interspecies and inter-route predictive capability. These universal methods can be employed, regardless of the type of stem cell or disease, to guide future experiments and design treatment protocols. (c) 2017 by John Wiley & Sons, Inc. PMID- 29140564 TI - beta-Catenin and interleukin-1beta-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis. AB - : Congenital hepatic fibrosis (CHF), a genetic disease caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, encoding for the protein fibrocystin/polyductin complex, is characterized by biliary dysgenesis, progressive portal fibrosis, and a protein kinase A-mediated activating phosphorylation of beta-catenin at Ser675. Biliary structures of Pkhd1del4/del4 mice, a mouse model of CHF, secrete chemokine (C-X-C motif) ligand 10 (CXCL10), a chemokine able to recruit macrophages. The aim of this study was to clarify whether CXCL10 plays a pathogenetic role in disease progression in CHF/Caroli disease and to understand the mechanisms leading to increased CXCL10 secretion. We demonstrate that treatment of Pkhd1del4/del4 mice for 3 months with AMG-487, an inhibitor of CXC chemokine receptor family 3, the cognate receptor of CXCL10, reduces the peribiliary recruitment of alternative activated macrophages (cluster of differentiation 45+ F4/80+ cells), spleen size, liver fibrosis (sirius red), and cyst growth (cytokeratin 19-positive area), consistent with a pathogenetic role of CXCL10. Furthermore, we show that in fibrocystin/polyductin complex defective cholangiocytes, isolated from Pkhd1del4/del4 mice, CXCL10 production is mediated by Janus kinase/signal transducer and activator of transcription 3 in response to interleukin 1beta (IL-1beta) and beta-catenin. Specifically, IL-1beta promotes signal transducer and activator of transcription 3 phosphorylation, whereas beta-catenin promotes its nuclear translocation. Increased pro-IL-1beta was regulated by nuclear factor kappa-light-chain-enhancer of activated B cells, and increased secretion of active IL-1beta was mediated by the activation of Nod like receptors, pyrin domain containing 3 inflammasome (increased expression of caspase 1 and Nod-like receptors, pyrin domain containing 3). CONCLUSION: In fibrocystin/polyductin complex-defective cholangiocytes, beta-catenin and IL 1beta are responsible for signal transducer and activator of transcription 3 dependent secretion of CXCL10; in vivo experiments show that the CXCL10/CXC chemokine receptor family 3 axis prevents the recruitment of macrophages, reduces inflammation, and halts the progression of the disease; the increased production of IL-1beta highlights the autoinflammatory nature of CHF and may open novel therapeutic avenues. (Hepatology 2018;67:1903-1919). PMID- 29140566 TI - Mesenchymal Stem Cell Preparation and Transfection-free Ferumoxytol Labeling for MRI Cell Tracking. AB - Mesenchymal stem cells (MSCs) are multipotent cells and are the most widely studied cell type for stem cell therapies. In vivo cell tracking of MSCs labeled with an FDA-approved superparamagnetic iron-oxide (SPIO) particle by magnetic resonance imaging (MRI) provides essential information, e.g., MSC engraftment, survival, and fate, thus improving cell therapy accuracy. However, current methodology for labeling MSCs with Ferumoxytol (Feraheme(r) ), the only FDA approved SPIO particle, needs transfection agents. This unit describes a new "bio mimicry" protocol to prepare more native MSCs by using more "in vivo environment" of MSCs, so that the phagocytic activity of cultured MSCs is restored and expanded MSCs can be labeled with Ferumoxytol, without the need for transfection agents and/or electroporation. Moreover, MSCs re-size to a more native size, reducing from 32.0 to 19.5 MUm. The MSCs prepared from this protocol retain more native properties and would be useful for biomedical applications and MSC tracking studies by MRI. (c) 2017 by John Wiley & Sons, Inc. PMID- 29140567 TI - Human Adipose-Derived Stromal Cell Isolation Methods and Use in Osteogenic and Adipogenic In Vivo Applications. AB - Adipose tissue represents an abundant and easily accessible source of multipotent cells, which may serve as excellent building blocks for tissue engineering. This article presents a newly described protocol for isolating adipose-derived stromal cells (ASCs) from human lipoaspirate, compared to the standard protocol for harvesting ASCs established in 2001. Human ASC isolation is performed using two methods, and resultant cells are compared through cell yield, cell viability, cell proliferation and regenerative potential. The osteogenic and adipogenic potential of ASCs isolated using both protocols are assessed in vitro and gene expression analysis is performed. The focus of this series of protocols is the regenerative potential of both cell populations in vivo. As such, the two in vivo animal models described are fat graft retention (soft tissue reconstruction) and calvarial defect healing (bone regeneration). The techniques described comprise fat grafting with cell assisted lipotransfer, and calvarial defect creation healed with cell-seeded scaffolds. (c) 2017 by John Wiley & Sons, Inc. PMID- 29140568 TI - CRISPR/Cas9-Based Safe-Harbor Gene Editing in Rhesus iPSCs. AB - NHP iPSCs provide a unique opportunity to test safety and efficacy of iPSC derived therapies in clinically relevant NHP models. To monitor these cells in vivo, there is a need for safe and efficient labeling methods. Gene insertion into genomic safe harbors (GSHs) supports reliable transgene expression while minimizing the risk the modification poses to the host genome or target cell. Specifically, this protocol demonstrates targeting of the adeno-associated virus site 1 (AAVS1), one of the most widely used GSH loci in the human genome, with CRISPR/Cas9, allowing targeted marker or therapeutic gene insertion in rhesus macaque induced pluripotent stem cells (RhiPSCs). Furthermore, detailed instructions for screening targeted clones and a tool for assessing potential off target nuclease activity are provided. (c) 2017 by John Wiley & Sons, Inc. PMID- 29140570 TI - Rapid Screening of the Endodermal Differentiation Potential of Human Pluripotent Stem Cells. AB - Human pluripotent stem cells (hPSCs) hold tremendous promise for regenerative medicine, disease modeling, toxicology screening, and developmental biology. These applications are hindered due to inherent differences in differentiation potential observed among different hPSC lines. This is particularly true for the differentiation of hPSCs toward the endodermal lineage. Several groups have developed methods to screen hPSCs for their endodermal differentiation potential (EP). Particularly notable studies include (i) the use of WNT3A expression as a predictive biomarker, (ii) an embryoid body-based screen, and (iii) a transcriptomics-based approach. We recently developed a rapid screen to access the EP of hPSCs solely based on morphological analysis. The screen takes 4 days to perform and yields results that are easy to interpret. As the screen is based on our recently developed small molecule protocol for hepatocyte like cell (HLC) differentiation of hPSCs, this method is extremely cost-effective compared to the aforementioned approaches. (c) 2017 by John Wiley & Sons, Inc. PMID- 29140569 TI - Single-Cell Functional Analysis of Stem-Cell Derived Cardiomyocytes on Micropatterned Flexible Substrates. AB - Human pluripotent stem-cell derived cardiomyocytes (hPSC-CMs) hold great promise for applications in human disease modeling, drug discovery, cardiotoxicity screening, and, ultimately, regenerative medicine. The ability to study multiple parameters of hPSC-CM function, such as contractile and electrical activity, calcium cycling, and force generation, is therefore of paramount importance. hPSC CMs cultured on stiff substrates like glass or polystyrene do not have the ability to shorten during contraction, making them less suitable for the study of hPSC-CM contractile function. Other approaches require highly specialized hardware and are difficult to reproduce. Here we describe a protocol for the preparation of hPSC-CMs on soft substrates that enable shortening, and subsequently the simultaneous quantitative analysis of their contractile and electrical activity, calcium cycling, and force generation at single-cell resolution. This protocol requires only affordable and readily available materials and works with standard imaging hardware. (c) 2017 by John Wiley & Sons, Inc. PMID- 29140571 TI - Is overactive bladder microvasculature disease a component of systemic atheroscleorosis? AB - AIMS: To evaluate the relationship between overactive bladder (OAB) and systemic atherosclerosis in a cohort of women. METHODS: In this case-control study, we assessed atherosclerosis indicators, such as Framingham risk scores and carotid and femoral artery intima-media thickness, and evaluated possible bladder wall responses to atherosclerosis using endovaginal color Doppler ultrasound and the detection of urinary cytokines in women with OAB and in controls. Quantitative assessment of blood perfusion at the bladder neck was performed using a method that allows for the dynamic monitoring of flow in a predefined region of interest at every point of the cardiac cycle. The independent samples t-test was used to evaluate the relationship between OAB and the atherosclerotic findings when parametric conditions were met, and the Mann-Whitney U test was used when parametric conditions were not met. Kendall's Tau was used to assess the correlation between OAB severity and the atherosclerotic variables. P < 0.05 was considered statistically significant. RESULTS: There were 74 OAB patients and 73 controls; in total, 147 women were evaluated. We found that all atherosclerosis indicators were significantly associated with OAB and that there was a significant relationship between OAB and decreased bladder neck perfusion. Additionally, there were correlations of OAB severity with systemic atherosclerosis and impaired vascular perfusion of the bladder. CONCLUSIONS: Decreased perfusion at the bladder neck, the Framingham scores in severe OAB, and the correlation between them suggest that OAB microvascular disease may be a component of systemic atherosclerosis rather than a separate process. PMID- 29140573 TI - 99m Tc-labeled rHuEpo for imaging of the erythropoietin receptor in tumors. AB - To analyze erythropoietin receptor (EpoR) status in tumors, recombinant human erythropoietin (rHuEpo) was labeled with 99m Tc by 99m Tc-centered 1-pot synthesis, resulting in high radiochemical purity, stability, and biological activity. Both in vitro cell culture experiments and biodistribution studies of normal rats demonstrated successful EpoR targeting. The biodistribution of labeled rHuEpo in a NCI-H1975 xenograft model showed tumor accumulation (tumor-to muscle ratio, 4.27 +/- 1.77), confirming the expression of active EpoR in tumors. Thus, as a novel single positron emission computerized tomography tracer for the imaging of EpoR expression in vivo, 99m Tc-rHuEpo is effective for exploring the role of EpoR in cancer growth, metastasis and angiogenesis. PMID- 29140574 TI - Letter to the Editor-1 regarding "Extracapsular dissection versus superficial parotidectomy in benign parotid gland tumors: The Vienna Medical School experience". PMID- 29140572 TI - Dissecting human ILC heterogeneity: more than just three subsets. AB - Innate lymphoid cells (ILCs) have been divided into three distinct groups based on functional capacities, cytokine profiles and transcription factor expression. Studies performed mainly in mice have demonstrated the importance of ILCs in chronic inflammation, infection, allergy and cancer. In this review, we discuss the heterogeneity of human ILC and focus primarily on the taxonomy of human ILC cell subsets and their phenotypical and functional diversity. We summarize recent findings concerning the diversity of ILCs between and within the major subsets [natural killer (NK), ILC1, intra-epithelial ILC1 (ieILC1), ILC2, ILC3, lymphoid tissues inducer (LTi) and ILC progenitor (ILCP)], as well as the abundance of each in human tissues. We also discuss the similarities observed between groups of cells in term of receptors expressed and cytokines produced, and how these relate to the pleiotropic properties of each subset. PMID- 29140575 TI - Complications of double free flap and free flap combined with locoregional flap in head and neck reconstruction: A systematic review. AB - BACKGROUND: The purpose of this clinical review was to assess the feasibility of reconstructing complex head and neck defects with 2 or more free flaps simultaneously. METHODS: A total of 38 articles were reviewed. The patient population included those who received 2 or more free flaps or a single free flap plus a locoregional flap. The primary outcome assessed was rate of complications. RESULTS: Among double flaps, the minor complication rate was 6.96% and the major complication rate was 20.0%. In comparison, the free flap plus locoregional flap group had higher rates of minor and major complications of 30.4% and 29.5%, respectively. The median operating time was 660 minutes for double flaps and 602 minutes for free flap plus locoregional flap (P = .828). CONCLUSION: Compared to the single free flap plus locoregional flap, double free flaps are relatively reliable without increasing surgical complications or decreasing flap survival, while only modestly increasing operating times. PMID- 29140576 TI - Comparison between qualitative and quantitative assessment of background parenchymal enhancement on breast MRI. AB - BACKGROUND: Potential clinical implications of the level of background parenchymal enhancement (BPE) on breast MRI are increasing. Currently, BPE is typically evaluated subjectively. Tests of concordance between subjective BPE assessment and computer-assisted quantified BPE have not been reported. PURPOSE OR HYPOTHESIS: To compare subjective radiologist assessment of BPE with objective quantified parenchymal enhancement (QPE). STUDY TYPE: Cross-sectional observational study. POPULATION: Between 7/24/2015 and 11/27/2015, 104 sequential patients (ages 23 - 81 years, mean 49 years) without breast cancer underwent breast MRI and were included in this study. FIELD STRENGTH/SEQUENCE: 3T; fat suppressed axial T2, axial T1, and axial fat suppressed T1 before and after intravenous contrast. ASSESSMENT: Four breast imagers graded BPE at 90 and 180 s after contrast injection on a 4-point scale (a-d). Fibroglandular tissue masks were generated using a phantom-validated segmentation algorithm, and were co registered to pre- and postcontrast fat suppressed images to define the region of interest. QPE was calculated. STATISTICAL TESTS: Receiver operating characteristic (ROC) analyses and kappa coefficients (k) were used to compare subjective BPE with QPE. RESULTS: ROC analyses indicated that subjective BPE at 90 s was best predicted by quantified QPE <=20.2 = a, 20.3-25.2 = b, 25.3-50.0 = c, >50.0 = d, and at 180 s by quantified QPE <= 32.2 = a, 32.3-38.3 = b, 38.4 74.5 = c, >74.5 = d. Agreement between subjective BPE and QPE was slight to fair at 90 s (k = 0.20-0.36) and 180 s (k = 0.19-0.28). At higher levels of QPE, agreement between subjective BPE and QPE significantly decreased for all four radiologists at 90 s (P <= 0.004) and for three of four radiologists at 180 s (P <= 0.004). DATA CONCLUSION: Radiologists were less consistent with QPE as QPE increased. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1685-1691. PMID- 29140577 TI - Herbivory and drought generate short-term stochasticity and long-term stability in a savanna understory community. AB - Rainfall and herbivory are fundamental drivers of grassland plant dynamics, yet few studies have examined long-term interactions between these factors in an experimental setting. Understanding such interactions is important, as rainfall is becoming increasingly erratic and native wild herbivores are being replaced by livestock. Livestock grazing and episodic low rainfall are thought to interact, leading to greater community change than either factor alone. We examined patterns of change and stability in herbaceous community composition through four dry periods, or droughts, over 15 years of the Kenya Long-term Exclosure Experiment (KLEE), which consists of six different combinations of cattle, native wild herbivores (e.g., zebras, gazelles), and mega-herbivores (giraffes, elephants). We used principal response curves to analyze the trajectory of change in each herbivore treatment relative to a common initial community and asked how droughts contributed to community change in these treatments. We examined three measures of stability (resistance, variability, and turnover) that correspond to different temporal scales and found that each had a different response to grazing. Treatments that included both cattle and wild herbivores had higher resistance (less net change over 15 years) but were more variable on shorter time scales; in contrast, the more lightly grazed treatments (no herbivores or wild herbivores only) showed lower resistance due to the accumulation of consistent, linear, short-term change. Community change was greatest during and immediately after droughts in all herbivore treatments. But, while drought contributed to directional change in the less grazed treatments, it contributed to both higher variability and resistance in the more heavily grazed treatments. Much of the community change in lightly grazed treatments (especially after droughts) was due to substantial increases in cover of the palatable grass Brachiaria lachnantha. These results illustrate how herbivory and drought can act together to cause change in grassland communities at the moderate to low end of a grazing intensity continuum. Livestock grazing at a moderate intensity in a system with a long evolutionary history of grazing contributed to long-term stability. This runs counter to often-held assumptions that livestock grazing leads to directional, destabilizing shifts in grassland systems. PMID- 29140578 TI - Alleviation of cadmium-induced oxidative stress by trehalose via inhibiting the Nrf2-Keap1 signaling pathway in primary rat proximal tubular cells. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates a cluster of oxidative stress-inducible genes in cells. Here, we aimed to investigate whether trehalose (Tre) protects primary rat proximal tubular (rPT) cells against cadmium (Cd)-induced oxidative stress via Nrf2 antioxidant pathway. Data showed that Tre treatment inhibited Nrf2 nuclear translocation and restored the decline in Kelch-like ECH-associated protein 1 (Keap1) protein level in Cd-exposed rPT cells. Moreover, Cd-activated Nrf2 target genes, including phase II detoxifying enzymes, that is, NAD(P)H quinone oxidoreductase 1 and heme oxygenase-1, direct antioxidant proteins, that is, glutathione peroxidase, superoxide dismutase, catalase, and glutathione biosynthesis-related proteins, that is, glutamatecysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione reductase, were all downregulated by co treatment with Tre. Collectively, these findings demonstrate that Tre treatment alleviates Cd-induced oxidative stress in rPT cells by inhibiting the Nrf2-Keap1 signaling pathway. PMID- 29140579 TI - Attitudes and barriers to the use of donation after cardiac death livers: Comparison of a United States transplant center survey to the United Network for Organ Sharing data. PMID- 29140580 TI - Enhanced biological fixation of ligaments to bone tissues utilizing chitin fabrics. AB - In ligament reconstruction involving anterior cruciate ligament surgery, biological fixation between the transferred ligament and bone tissue is critical for achieving successful outcomes. Here, we administered chitin fabrics into the bone tunnels and evaluated their efficacy in promoting biological fixation. An animal model on the rat's patellar ligament was employed. First, bone tunnels were created in the lateral condyle of the femur. The ligament was then separated from the tibial tuberosity, and half was inserted into the tunnel and fixed with the use of end button. Animals in the experimental group were treated with microfiber nonwoven chitin fabric, whereas control animals received no treatment. Specimens were collected at 2, 4, and 6 weeks after surgery, and the fixation strength was measured by mechanical tests. Histological sections were prepared from samples prepared 4 weeks after surgery, and the diameter of bone tunnel and the width ratio of collagenous tissue in the bone tunnel were measured. Administration of chitin significantly increased the mean fixation strength at 4 and 6 weeks after surgery. Furthermore, chitin also promoted bone formation in the bone tunnel and increased the density of collagen fibers. Thus, microfiber nonwoven chitin fabric enhanced the biological fixation of the ligament to the bone tissue. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2355-2360, 2018. PMID- 29140581 TI - Comparison of long-term outcomes between pull-through resection and mandibular lip-split surgery for T4a tongue/floor of mouth cancers. AB - BACKGROUND: The purpose of this study was to determine whether the pull-through resection is better than the mandibular lip-split for advanced tongue/floor of mouth (FOM) cancers, which remains inconclusive. METHODS: A retrospective cohort study was performed on 91 patients with T4a tongue/FOM cancers from 2009 to 2014. Cases with mandibular resection were excluded. The pull-through resection was used when the mouth opening was >=15 mm; otherwise the mandibular lip-split was used. RESULTS: Fifty-eight patients received pull-through resections and 33 underwent mandibular-lip splits and the mean follow-up periods were 42 and 45 months, respectively. Surgical margin, locoregional recurrence, and 5-year survival were similar between the 2 groups. The pull-through approach had a significantly shorter operation time, lower rates of flap infection, osteoradionecrosis, metal plate exposure, loss of tooth vitality, and better aesthetics. CONCLUSION: Our data suggest that the pull-through resection does not compromise disease control for advanced tongue/FOM cancers and is superior to the mandibular lip-split in terms of operation time, postoperative complications, and aesthetics. PMID- 29140582 TI - Abortion Knowledge and Experiences Among U.S. Servicewomen: A Qualitative Study. AB - CONTEXT: U.S. servicewomen have a higher rate of unintended pregnancy than civilian women, yet the military does not provide or cover abortion, except in limited circumstances. Servicewomen's experiences with abortion care have received little research attention. METHODS: Twenty-one in-depth interviews with servicewomen who had had an abortion during active-duty service in the prior two years were conducted between January 2015 and July 2016. Women reported on their experiences accessing abortion, as well as their knowledge and opinions of the military's abortion policy. Data were analyzed thematically using inductive and deductive codes. RESULTS: In regard to their pregnancy and abortion experiences, servicewomen cited concerns about confidentiality, stigma and negative effects on their career, which prevented half of participants from seeking care from the military. Of those who visited a military treatment facility during pregnancy, some reported feeling upset or abandoned by the lack of options counseling and referral. Women reported that the military's abortion policy had negative health and emotional consequences for servicewomen, and negative financial and logistical consequences for both servicewomen and the military. Most did not have accurate knowledge of the abortion policy. Upon learning the law, the majority believed that the military should provide and cover abortion; yet, servicewomen also expressed apprehension about the military's involvement in abortion care, because of concerns about privacy and negative effects on women's careers. CONCLUSIONS: Policy recommendations to better meet the needs of servicewomen include wider dissemination of the military's abortion policy, establishing abortion referral and support guidelines, and improving confidentiality in military health services. PMID- 29140583 TI - Association study of NDST3 gene for schizophrenia, bipolar disorder, major depressive disorder in the Han Chinese population. AB - The NDST3 gene at 4q26 was a functional candidate gene for mental disorders. Recently, a novel genome-wide significant risk locus at chromosome 4q26 was identified and the top single nucleotide polymorphism rs11098403 in the vicinity of NDST3 gene was reported to confer risk of schizophrenia in Caucasian. Nevertheless, association between NDST3 gene polymorphisms and schizophrenia, bipolar disorder, or major depressive disorders has not been well studied in the Han Chinese population. To further investigate whether NDST3 is a risk gene for these mental disorders, we genotyped and analyzed eight tag SNPs (rs11098403, rs10857057, rs2389521, rs4833564, rs6837896, rs7689157, rs3817274, rs609512) covering NDST3 gene in 1,248 schizophrenia cases, 1,056 major depression cases, 1,344 bipolar disorder cases, and 1,248 controls of Chinese origin. However, there was no significant difference in allelic or genotypic frequency observed between each case group and healthy controls. Accordingly, our study does not support that the NDST3 gene plays a major role in schizophrenia, bipolar disorder, and major depressive disorder in the Han Chinese population. PMID- 29140584 TI - The association between female genital fistula symptoms and gender-based violence: A multicountry secondary analysis of household survey data. AB - OBJECTIVE: The Demographic and Health Surveys (DHS), which include standardised questions on female genital fistula symptoms, provide a unique opportunity to evaluate the epidemiology of fistula. This study sought to examine associations between self-reported fistula symptoms and experience of gender-based violence (GBV) among women interviewed in DHS surveys. METHODS: This study used data from thirteen DHS surveys with standardised fistula and domestic violence modules. Data from the most recent survey in each country were pooled, weighting each survey equally. Multivariable logistic regressions controlled for maternal and demographic factors. RESULTS: Prevalence of fistula symptoms in this sample of 95 625 women ranges from 0.3% to 1.8% by country. The majority of women reporting fistula symptoms (56%) have ever experienced physical violence, and more than one quarter have ever experienced sexual violence (27%), compared with 38% and 13% among women with no symptoms, respectively. Similarly, 16% of women with fistula symptoms report recently experiencing sexual violence-twice the percentage among women not reporting symptoms (8%). Women whose first experience of sexual violence was from a non-partner have almost four times the odds of reporting fistula symptoms compared with women who never experienced sexual violence. These associations indicate a need to investigate temporal and causal relationships between violence and fistula. CONCLUSIONS: The increased risk of physical and sexual violence among women with fistula symptoms suggests that fistula programmes should incorporate GBV into provider training and services. PMID- 29140585 TI - TIMAP, the versatile protein phosphatase 1 regulator in endothelial cells. AB - Transforming growth factor (TGF)-beta inhibited membrane associated protein, TIMAP, is the member of the myosin phosphatase targeting protein (MYPT) family of protein phosphatase 1 (PP1) regulatory subunits. The N-terminal part of TIMAP has a typical MYPT family structure with a sequence element called MyPhone (myosin phosphatase N-terminal element), a putative bipartite nuclear localization signal, a PP1 catalytic subunit binding motif, and five ankyrin repeats. The C terminal half of TIMAP is intrinsically disordered, but ends with a functional CAAX box for lipid modification which allows localization of TIMAP at the plasma membrane. TIMAP is prenylated by farnesyl transferase with the contribution of the anchoring protein, RACK1 in the cytoplasm. The controlling effect of TIMAP on PP1 is moderated by PKA/GSK3beta and PKC mediated phosphorylation of TIMAP, the sites are located in the disordered region of the protein. TIMAP is abundant in endothelial cells. A growing body of evidence attained through characterization of newly identified protein partners calls attention to its critical role in normal and pathological activities of the endothelium via regulation of PP1. TIMAP binds the non-integrin laminin receptor 1 and the endothelin converting enzyme 1, which may connect TIMAP to angiogenesis, tumor invasion and metastasis. Barrier protecting role of TIMAP was shown for pulmonary artery endothelial cells. ERM (ezrin-radixin-moesin) proteins, as potential in vivo PP1-TIMAP substrates, are critical targets in the barrier maintenance. TIMAP affects phosphorylation level and subcellular localization of merlin and eukaryotic elongation factor-1A1. Merlin is a key component of signaling pathways regulating cell proliferation, membrane domain formation and cell-cell junction organization. Noncanonical functions of the elongation factor include a role in organization of cytoskeleton dynamics and in apoptosis. The interacting/binding partners identified so far demonstrate a rather complex role of TIMAP in key functions of the endothelium offering TIMAP as a plausible target in pathological issues. (c) 2017 IUBMB Life, 69(12):918-928, 2017. PMID- 29140586 TI - Annual global mean temperature explains reproductive success in a marine vertebrate from 1955 to 2010. AB - The salient feature of anthropogenic climate change over the last century has been the rise in global mean temperature. However, global mean temperature is not used as an explanatory variable in studies of population-level response to climate change, perhaps because the signal-to-noise ratio of this gross measure makes its effect difficult to detect in any but the longest of datasets. Using a population of Leach's storm-petrels breeding in the Bay of Fundy, we tested whether local, regional, or global temperature measures are the best index of reproductive success in the face of climate change in species that travel widely between and within seasons. With a 56-year dataset, we found that annual global mean temperature (AGMT) was the single most important predictor of hatching success, more so than regional sea surface temperatures (breeding season or winter) and local air temperatures at the nesting colony. Storm-petrel reproductive success showed a quadratic response to rising temperatures, in that hatching success increased up to some critical temperature, and then declined when AGMT exceeded that temperature. The year at which AGMT began to consistently exceed that critical temperature was 1988. Importantly, in this population of known-age individuals, the impact of changing climate was greatest on inexperienced breeders: reproductive success of inexperienced birds increased more rapidly as temperatures rose and declined more rapidly after the tipping point than did reproductive success of experienced individuals. The generality of our finding that AGMT is the best predictor of reproductive success in this system may hinge on two things. First, an integrative global measure may be best for species in which individuals move across an enormous spatial range, especially within seasons. Second, the length of our dataset and our capacity to account for individual- and age-based variation in reproductive success increase our ability to detect a noisy signal. PMID- 29140587 TI - Comparison of haematology and biochemistry parameters in healthy South African infants with laboratory reference intervals. AB - OBJECTIVE: Paediatric laboratory reference intervals used in Africa and Asia may be derived from historical intervals of predominantly Caucasian infants in Europe or North America. These intervals may therefore not be compatible with the range of normality for developing country populations. We aimed to compare haematology and biochemistry parameters in healthy South African infants with local laboratory reference intervals. METHODS: We compared the baseline haematology and biochemistry results of 634 (316 male and 318 female) HIV-unexposed infants, aged 3-6 months, living in a rural area of the Western Cape Province, South Africa, against laboratory reference intervals supplied by the South African National Health Laboratory Services (NHLS). We calculated the percentage of observed values out of bound (in terms of lower and upper limits) compared to laboratory reference intervals. RESULTS: Of the 634 healthy infants screened, 316 (49.84%) were male and 318 (50.16%) female. A majority (91.05%) had platelet counts above the laboratory reference interval upper limit (350 * 109 cells/l), while over half, 54.85% and 56.98% had mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) values below the lower limits of 77.0-105.0 fl and 26.0-34.0 pg, respectively. A small proportion were outside the reference limits for haematocrit, namely 15.71% below and 7.14% above the normal limits of 0.31-0.38 l/l. For male and female infants, 33.65% and 18.04% of alkaline phosphatase (ALP) values and 7.01% and 14.56% of alanine transaminase (ALT) values were above the upper limits, respectively. For male infants, 10.83% of gamma-glutamyl transferase (GGT) values, and for female infants, 31.11% of GGT values were below the lower limits of 12 U/l for males and 15 U/l for females. We observed no significant deviations (>10% out of bound) from NHLS reference intervals in the remaining haematology and biochemistry parameters measured. CONCLUSIONS: Haematology and biochemistry parameters in apparently healthy South African infants deviate frequently from national laboratory reference intervals, including abnormalities consistent with subclinical hypochromic microcytic anaemia. It is important that clinical laboratory reference intervals for children are derived locally, rather than being adopted from Caucasian norms in developed countries, because clinical trials of vaccines, drugs and diagnostics are increasingly conducted in sub-Saharan Africa. PMID- 29140588 TI - Family management of childhood chronic conditions: Does it make a difference if the child has an intellectual disability? AB - The purpose of this analysis was to assess the applicability of the Family Management Measure (FaMM) to families in which there was a child with an intellectual disability versus a chronic condition. Drawing on data from 571 parents of children with a chronic physical condition and 539 parents of children with Down syndrome, we compared the two groups across the six FaMM scales. After accounting for the covariate effects of race, ethnicity, family income, and child age, we found significant differences in four of the six FaMM scales, with parents of children with Down syndrome reporting a significantly more positive view on the Condition Management Effort and View of Condition Impact scales and a significantly less positive view on the Child's Daily Life and Condition Management Ability scales than parents of children with a chronic physical condition. There were no significant differences between groups on the Family Life Difficulty and the Parental Mutuality scales. The analysis provided evidence of the applicability of the FaMM for studying families in which there is a child with Down syndrome and its utility in identifying the common and unique challenges of family management between the groups. PMID- 29140589 TI - Simple Access to the Heaviest Alkaline Earth Metal Hydride: A Strongly Reducing Hydrocarbon-Soluble Barium Hydride Cluster. AB - Reaction of Ba[N(SiMe3 )2 ]2 with PhSiH3 in toluene gave simple access to the unique Ba hydride cluster Ba7 H7 [N(SiMe3 )2 ]7 that can be described as a square pyramid spanned by five Ba2+ ions with two flanking BaH[N(SiMe3 )2 ] units. This heptanuclear cluster is well soluble in aromatic solvents, and the hydride 1 H NMR signals and coupling pattern suggests that the structure is stable in solution. At 95 degrees C, no coalescence of hydride signals is observed but the cluster slowly decomposes to undefined barium hydride species. The complex Ba7 H7 [N(SiMe3 )2 ]7 is a very strong reducing agent that already at room temperature reacts with Me3 SiCH=CH2 , norbornadiene, and ethylene. The highly reactive alkyl barium intermediates cannot be observed and deprotonate the (Me3 Si)2 N- ion, as confirmed by the crystal structure of Ba14 H12 [N(SiMe3 )2 ]12 [(Me3 Si)(Me2 SiCH2 )N]4 . PMID- 29140590 TI - Reply to the Letter to the Editor-1 regarding "Extracapsular dissection versus superficial parotidectomy in benign parotid gland tumors: The Vienna Medical School experience". PMID- 29140591 TI - Preventive effects of tonsil-derived mesenchymal stem cells on osteoradionecrosis in a rat model. AB - BACKGROUND: The purpose of this study was to investigate the effects of tonsil derived mesenchymal stem cells (MSCs) on osteoradionecrosis (ORN). METHOD: We generated a mandibular ORN rat model using a combination of 20-Gy single-dose irradiation and tooth extraction. Study groups were negative control (tooth extraction only), ORN group (irradiation, tooth extraction), Matrigel-1 group (Matrigel; BD Biosciences, San Jose, CA; irradiation, Matrigel application immediately after tooth extraction), tonsil-derived MSC-1 group (irradiation, tonsil-derived MSC application immediately after tooth extraction), Matrigel-4 group (irradiation, Matrigel application 4 weeks after tooth extraction), and tonsil-derived MSC-4 group (irradiation, tonsil-derived MSC application 4 weeks after tooth extraction). RESULT: Bone mineral density was significantly lower in the ORN group than in the negative control group. The tonsil-derived MSC-1 group showed significantly higher bone mineral density than did the ORN and tonsil derived MSC-4 groups. CONCLUSION: A single 20-Gy dose of irradiation combined with tooth extraction successfully generated ORN in the rat model. The tonsil derived MSCs can be effective for bone regeneration in ORN, particularly when applied immediately after dentoalveolar trauma or surgery. PMID- 29140592 TI - A Versatile Strategy to Main Chain Sulfur/Selenium-Functionalized Polycarbonates by Macro-Ring Closure of Diols and Subsequent Ring-Opening Polymerization. AB - Herein, a new class of main chain functionalized aliphatic polycarbonates with sulfur/selenium functional groups on the backbone is reported. Sulfur/selenium containing cyclic carbonate monomers (MR ) are designed and synthesized by enzyme catalyzed intermolecular macro-ring closure of related diols. The proposed synthetic strategy is tolerant of other functionalities such as N-substituted groups. The ring opening polymerization (ROP) of MR occurs readily as a versatile route to generate a new family of main chain sulfur/selenium substituted aliphatic polycarbonates (PR) with predictable molecular weights (MW), narrow molecular-weight distribution and controlled copolymer composition. The resultant polymers can be oxidized and/or reduced by treatment with hydrogen peroxide (H2 O2 ) or dithiothreitol (DTT), highlighting their potential for applications in the stimuli-responsive field and inflammation/cancer targeting. With these desirable results, it is revealed that this versatile technique can provide a broad-reaching method to the next generation of innovative materials, especially, well-defined biodegradable chalcogen-based main chain functional biomaterials. PMID- 29140593 TI - Nursing perception of risk in common nursing practice situations. AB - As health care organizations seek to be highly reliable, systems that include layers of redundancy have been created to protect patients from harm. Many of these layers of protection are dependent on nurses making a decision to follow or adhere to the human aspects of the process. Because these decisions begin with a perception and identification of risk, understanding what nurses perceive to be a risk to patients is an essential part of designing safer health care systems. The purposes of this qualitative study were to (1) describe what nurses perceive as risky to patients in common nursing practice situations, (2) describe the effects of the perceptions of risk on clinical decision making and behavior, and (3) identify what factors nurses perceive as increasing or decreasing risk. PMID- 29140594 TI - Cord blood platelet gel alone or in combination with photobiomodulation therapy for the treatment of oral ulcerations in patients with epidermolysis bullosa: A pilot clinical comparative study. PMID- 29140595 TI - Modulation of Quorum Sensing in a Gram-Positive Pathogen by Linear Molecularly Imprinted Polymers with Anti-infective Properties. AB - We describe the development, characterization, and biological testing of a new type of linear molecularly imprinted polymer (LMIP) designed to act as an anti infective by blocking the quorum sensing (QS) mechanism and so abrogating the virulence of the pathogen Streptococcus pneumoniae. The LMIP is prepared (polymerized) in presence of a template molecule, but unlike in traditional molecular imprinting approaches, no cross-linker is used. This results in soluble low-molecular-weight oligomers that can act as a therapeutic agent in vitro and in vivo. The LMIP was characterized by mass spectrometry to determine its monomer composition. Fragments identified were then aligned along the peptide template by computer modeling to predict the possible monomer sequence of the LMIP. These findings provide a proof of principle that LMIPs can be used to block QS, thus setting the stage for the development of LMIPs a novel drug-discovery platform and class of materials to target Gram-positive pathogens. PMID- 29140596 TI - Florence robotic intracorporeal neobladder (FloRIN): a new reconfiguration strategy developed following the IDEAL guidelines. AB - OBJECTIVE: To describe our step-by-step technique for robotic intracorporeal neobladder configuration, including the stages of conception, development and exploration of this surgical innovation, according to the Idea, Development, Exploration, Assessment, Long-term follow-up (IDEAL) Collaboration guidelines. PATIENTS AND METHODS: The Florence robotic intracorporeal neobladder (FloRIN) was performed employing the following main surgical steps: isolation of 50 cm of ileum; bowel anastomosis; urethro-ileal anastomosis creating an asymmetrical 'U' shape (30 cm distally and 20 cm proximally to anastomosis), ileum detubularisation; posterior wall reconfiguration as an 'L'; bladder neck reconstruction; anterior folding of the posterior plate to reach the 12 o'clock position; uretero-enteral 'orthotopic' bilateral anastomosis. The conception and development of the FloRIN followed the IDEAL guidelines recommended stages: Phase 1 (simulation) involved the neobladder robotic configuration using silicone models. Phase 2a (development) aimed to reproduce the configuration in an open fashion in one patient, and then in the first three robotic procedures. Phase 2b (exploration) consisted of the technique standardisation in 15 consecutive robotic approaches. Phase 2a and 2b included urodynamics and imaging assessment of the patients treated. RESULTS: From February 2016 to September 2017 FloRIN was performed in 18 patients. Comparing the first three (Phase 2a) with the subsequent 15 patients (Phase 2b), the median (interquartile range [IQR]) reconstruction operating time was 260 (220-340) vs 160 (150-210) min, respectively. Postoperative surgical complications occurred in four of the 18 patients (22.1%), including one surgical Clavien-Dindo Grade III and three Grade I, postoperative medical Clavien-Dindo Grade II complications occurred in three (16.7%) patients. On urodynamic examination (available in nine [50%] patients) the median (IQR) reservoir cystometric capacity, compliance, and post-void residual were 240 (220-267) mL, 18 (12.5-19.8) mL/cmH2 O, and 0 (0-50) mL, respectively. Ultrasonography showed no Grade >=2 vesico-ureteric reflux. CONCLUSION: We describe the FloRIN configuration, showing its technical feasibility with acceptable time efficiency. The first cases studied had good reservoir capacity, low pressure with no reflux, and complete voiding. PMID- 29140597 TI - Improving -Omics-Based Research and Precision Health in Minority Populations: Recommendations for Nurse Scientists. AB - PURPOSE: The purpose of this article is to provide an overview of the role of nurse scientists in -omics-based research and to promote discussion around the conduct of -omics-based nursing research in minority communities. Nurses are advocates, educators, practitioners, scientists, and researchers, and are crucial to the design and successful implementation of -omics studies, particularly including minority communities. The contribution of nursing in this area of research is crucial to reducing health disparities. METHODS: In this article, challenges in the conduct of -omics-based research in minority communities are discussed, and recommendations for improving diversity among nurse scientists, study participants, and utilization of training and continuing education programs in -omics are provided. FINDINGS AND CONCLUSIONS: Many opportunities exist for nurses to increase their knowledge in -omics and to continue to build the ranks of nurse scientists as leaders in -omics-based research. In order to work successfully with communities of color, nurse scientists must advocate for participation in the Precision Medicine Initiative, improve representation of nurse faculty of color, and increase utilization of training programs in -omics and lead such initiatives. CLINICAL RELEVANCE: All nursing care has the potential to be affected by the era of -omics and precision health. By taking an inclusive approach to diversity in nursing and -omics research, nurses will be well placed to be leaders in reducing health disparities through research, practice, and education. PMID- 29140598 TI - Disinfection of chicken fillets in packages with atmospheric cold plasma: effects of treatment voltage and time. AB - AIMS: To study effects of treatment voltage and time of in-package atmospheric cold plasmas (ACP) on quality of raw chicken meat. METHODS AND RESULTS: Meat was packed in trays in air, treated with ACP and stored at 4 degrees C for 24 h or 3 days. Increasing voltage from 55 to 80 kV caused increasing O3 inside packages, but had no effects on microbes, colour and pH after 24 h of storage at 4 degrees C. There were no differences in O3 , microbes, colour lightness and pH between treatment times 3, 6 and 9 min at 80 kV after 3-day storage. However, microbial populations on ACP-treated meat were lower than untreated control. Treatments at 80 kV for >3 min reduced meat redness and yellowness. CONCLUSIONS: ACP voltage does not affect microbes, colour and pH of meat after 24 h of storage. ACP treatments for >=3 min at 80 kV reduce microbes and affect colour of raw meat. SIGNIFICANCE AND IMPACT OF THE STUDY: Our data demonstrate that increasing ACP voltage from 55 to 80 kV or time from 3 to 9 min may not affect meat microbial growth and pH. Increasing treatment time longer than 3 min may affect meat appearance. PMID- 29140599 TI - From Mental Illness to Mental Health: Improving Access to Care. PMID- 29140600 TI - Vegetation cover-another dominant factor in determining global water resources in forested regions. AB - Forested catchments provide critically important water resources. Due to dramatic global forest change over the past decades, the importance of including forest or vegetation change in the assessment of water resources under climate change has been highly recognized by Intergovernmental Panel on Climate Change (IPCC); however, this importance has not yet been examined quantitatively across the globe. Here, we used four remote sensing-based indices to represent changes in vegetation cover in forest-dominated regions, and then applied them to widely used models: the Fuh model and the Choudhury-Yang model to assess relative contributions of vegetation and climate change to annual runoff variations from 2000 to 2011 in forested landscape (forest coverage >30%) across the globe. Our simulations show that the global average variation in annual runoff due to change in vegetation cover is 30.7% +/- 22.5% with the rest attributed to climate change. Large annual runoff variation in response to vegetation change is found in tropical and boreal forests due to greater forest losses. Our simulations also demonstrate both offsetting and additive effects of vegetation cover and climate in determining water resource change. We conclude that vegetation cover change must be included in any global models for assessing global water resource change under climate change in forest-dominant areas. PMID- 29140601 TI - Pilot study of living donor liver transplantation for patients with hepatocellular carcinoma exceeding Milan Criteria (Barcelona Clinic Liver Cancer extended criteria). AB - A subset of patients with hepatocellular carcinoma (HCC) beyond Milan criteria might obtain acceptable survival outcomes after liver transplantation. Living donor liver transplantation (LDLT) has emerged as a feasible alternative to overcome the paucity of donors. In 2001, we started a protocol for LDLT in Child A-B patients with HCC fulfilling a set of criteria-the Barcelona Clinic Liver Cancer (BCLC) expanded criteria-that expanded the conventional indications of transplantation: 1 tumor <= 7 cm, 5 tumors <= 3 cm, and 3 tumors <= 5 cm without macrovascular invasion or downstaging to Milan after locoregional therapies. We present a prospective cohort of 22 patients with BCLC extended indications based on size/number (n = 17) or downstaging (n = 5) treated with LDLT between 2001 and 2014. Characteristics of the patients were as follows: median age, 57 years old; males/female, n = 20/2; Child-Pugh A/B, n = 16/6; and alpha fetoprotein < 100 ng/mL, n = 21. Twelve patients received neoadjuvant locoregional therapies. At the time of transplantation, 12 patients had HCC staging beyond Milan criteria and 10 within. Pathological reports showed that 50% exceeded BCLC expanded criteria. Perioperative mortality was 0%. After a median follow-up of 81 months, the 1-, 3-, 5-, and 10-year survival was 95.5%, 86.4%, 80.2%, and 66.8%, respectively. Overall, 7 patients recurred (range, 9-108 months), and the 5-year and 10-year actuarial recurrence rates were 23.8% and 44.4%, respectively. In conclusion, a proper selection of candidates for extended indications of LDLT for HCC patients provide survival outcomes comparable to those obtained within the Milan criteria, but these results need confirmation. Liver Transplantation 24 369 379 2018 AASLD. PMID- 29140602 TI - Cardiovascular safety of long-acting insulin analogs in type 2 diabetes patients: Is there a better basal insulin? PMID- 29140603 TI - Protic NNN and NCN Pincer-Type Ruthenium Complexes Featuring (Trifluoromethyl)pyrazole Arms: Synthesis and Application to Catalytic Hydrogen Evolution from Formic Acid. AB - NNN and NCN pincer-type ruthenium(II) complexes featuring two protic pyrazol-3-yl arms with a trifluoromethyl (CF3 ) group at the 5-position were synthesized and structurally characterized to evaluate the impact of the substitution on the properties and catalysis. The increased Bronsted acidity by the highly electron withdrawing CF3 pendants was demonstrated by protonation-deprotonation experiments. By contrast, the IR spectra of the carbonyl derivatives as well as the cyclic voltammogram indicated that the electron density of the ruthenium atom is negligibly influenced by the CF3 group. Catalysis of these complexes in the decomposition of formic acid to dihydrogen and carbon dioxide was also examined. The NNN pincer-type complex 1 a with the CF3 group exhibited a higher catalytic activity than the tBu-substituted analogue 1 b. In addition, the bis(CF3 pyrazolato) ammine derivative 4 catalyzed the reaction even in the absence of base additives. PMID- 29140604 TI - Simultaneous Measurements of Geometric and Viscoelastic Properties of Hydrogel Microbeads Using Continuous-Flow Microfluidics with Embedded Electrodes. AB - Geometric and mechanical characterizations of hydrogel materials at the microscale are attracting increasing attention due to their importance in tissue engineering, regenerative medicine, and drug delivery applications. Contemporary approaches for measuring the these properties of hydrogel microbeads suffer from low-throughput, complex system configuration, and measurement inaccuracy. In this work, a continuous-flow device is developed to measure geometric and viscoelastic properties of hydrogel microbeads by flowing the microbeads through a tapered microchannel with an array of interdigitated microelectrodes patterned underneath the channel. The viscoelastic properties are derived from the trajectories of microbeads using a quasi-linear viscoelastic model. The measurement is independent of the applied volumetric flow rate. The results show that the geometric and viscoelastic properties of Ca-alginate hydrogel microbeads can be determined independently and simultaneously. The bulky high-speed optical systems are eliminated, simplifying the system configuration and making it a truly miniaturized device. A throughput of up to 394 microbeads min-1 is achieved. This study may provide a powerful tool for mechanical profiling of hydrogel microbeads to support their wide applications. PMID- 29140605 TI - Highly Transparent and Integrable Surface Texture Change Device for Localized Tactile Feedback. AB - Human-machine haptic interaction is typically detected by variations in friction, roughness, hardness, and temperature, which combines to create sensation of surface texture change. Most of the current technologies work to simulate changes in tactile perception (via electrostatic, lateral force fields, vibration motors, etc.) without creating actual topographical transformations. This makes it challenging to provide localized feedback. Here, a new concept for on-demand surface texture augmentation that is capable of physically forming local topographic features in any predesigned pattern is demonstrated. The transparent, flexible, integrable device comprises of a hybrid electrode system with conductive hydrogel, silver nanowires, and conductive polymers with acrylic elastomer as the dielectric layer. Desired surface textures can be controlled by a predesigned pattern of electrodes, which operates as independent or interconnected actuators. Surface features with up to a height of 0.155 mm can be achieved with a transformation time of less than a second for a device area of 18 cm2 . High transparency levels of 76% are achieved due to the judicious choice of the electrode and the active elastomer layer. The capability of localized and controlled deformations makes this system highly useful for applications such as display touchscreens, touchpads, braille displays, on-demand buttons, and microfluidic devices. PMID- 29140607 TI - ? PMID- 29140606 TI - MR textural analysis on T2 FLAIR images for the prediction of true oligodendroglioma by the 2016 WHO genetic classification. AB - BACKGROUND: The genetic status of 1p/19q is important for differentiating oligodendroglioma, isocitrate-dehydrogenase (IDH)-mutant, and 1p/19q-codeleted from diffuse astrocytoma, IDH-mutant according to the 2016 World Health Organization (WHO) criteria. PURPOSE: To assess the value of magnetic resonance textural analysis (MRTA) on T2 fluid-attenuated inversion recovery (FLAIR) images for making a genetically integrated diagnosis of true oligodendroglioma by WHO guidelines. STUDY TYPE: Retrospective case control. SUBJECTS: In all, there were 54 patients with a histopathological diagnosis of diffuse glioma (grade II). All were tested for IDH and 1p/19q. FIELD STRENGTH/SEQUENCE: 3.0T, including T2 FLAIR sequence, axial T1 -weighted, and T2 -weighted sequence. ASSESSMENT: MRTA on a representative tumor region of interest (ROI) was made on preoperative T2 FLAIR images around the area that had the largest diameter of solid tumor using Omni Kinetics software. STATISTICAL TESTS: Differences between IDH-mutant and 1p/19q codeleted and IDH-mutant and 1p/19q-intact gliomas were analyzed by the Mann Whitney rank sum test. Receiver operating characteristic curves (ROC) were created to assess MRTA diagnostic performance. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with a cutoff value according to the Youden Index. RESULTS: Comparisons demonstrated significant differences in kurtosis (P = 0.007), energy (0.008), entropy (0.008), mean deviation (MD) (<0.001), and high gray-level run emphasis (HGLRE) (0.002), cluster shade (0.025), and sum average (0.002). First-order features comprising entropy (area under the curve [AUC] = 0.718, sensitivity = 97.1%) and energy (0.719, 94.1%) had the highest sensitivity but lower specificity (both 45%). Second-order features such as HGLRE (AUC = 0.750, sensitivity = 73.5%, specificity = 80.0%) and sum average (0.751, 70.6%, 80.0%) had relatively higher specificity, and all had AUC >0.7. MD had the highest diagnostic performance, with AUC = 0.878, sensitivity = 94.1%, specificity = 75.0%, PPV = 86.5%, and NPV = 88.2%. DATA CONCLUSION: MRTA on T2 FLAIR images may be helpful in identifying oligodendroglioma, IDH-mutant, and 1p/19q-codeleted. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017. PMID- 29140608 TI - ? PMID- 29140609 TI - ? PMID- 29140610 TI - ? PMID- 29140612 TI - ? PMID- 29140611 TI - ? PMID- 29140613 TI - ? PMID- 29140614 TI - ? PMID- 29140615 TI - Operator Exposure to Hydrogen Sulfide from Dairy Manure Storages Containing Gypsum Bedding. AB - Dairy manure storages containing gypsum-based bedding have been linked anecdotally with injury and death due to presumed dangerous levels of gases released. Recycled gypsum products are used as a cost-effective bedding alternative to improve animal welfare and provide agronomic benefits to manure recycled back to the land. Sulfur contained in gypsum (calcium sulfate) can contribute to hydrogen sulfide (H2S) gas formation under the anaerobic storage conditions typical of dairy manure slurry. Disturbance of stored manure during agitation releases a burst of volatile gases. On-farm monitoring was conducted to document conditions during manure storage agitation relative to gas concentration and operator safety. One objective was to document operator exposure to H2S levels; therefore, each operator wore a personal gas monitor while performing tasks associated with manure storage agitation. Data from three dairy bedding management categories on ten farms were compared: (1) traditional organic bedding, (2) gypsum bedding, and (3) gypsum bedding plus a manure additive thought to reduce H2S formation and/or release. Portable meters placed around the perimeter of dairy manure storages recorded H2S concentrations prior to and during 19 agitation events. Results show that farms using gypsum bedding produced higher H2S concentrations during manure storage agitation than farms using traditional bedding. In most cases, gypsum-containing manure storages produced H2S levels above recognized safe thresholds for both livestock and humans. Farm operators were most at risk during activities in close proximity to the manure storage during agitation, and conditions 10 m away from the storage were above the 20 ppm H2S threshold on some farms using gypsum bedding. Although H2S concentrations rose to dangerous levels, only two of 18 operators were exposed to >50 ppm H2S during the first 60 min of manure storage agitation. Operators who are aware of the risk of high H2S concentrations near gypsum-laden manure storages can reduce their exposure risk by working upwind and away from the H2S plume within a closed tractor cab. PMID- 29140616 TI - Comparisons of Agricultural Seating for Paraplegia. AB - People with spinal cord injury/paraplegia are operating agricultural machinery despite the lack of research evidence to support seating interventions. These operators represent a vulnerable population in the agricultural workforce, and information to support their health in the workplace is urgently warranted. This research compared a group of subjects with paraplegia on different intervention cushion conditions during a simulated tractor driving task. Numerical data acquired from a pressure-mapping instrument were explored for statistical relationships within a small cohort of people with paraplegia participating in a feasibility study that was previously reported for clinical results. Relationships reaching statistical significance were found to support the primary hypothesis, while other hypotheses did not reach the threshold of significance. The primary hypothesis, that a contour tractor seat intervention condition would be inferior to other intervention conditions, was supported. For this cohort of heterogeneous users with paraplegia, a contour tractor seat of foam and cloth fabric manufacture was not an appropriate intervention selection versus other aftermarket wheelchair cushions. PMID- 29140617 TI - Methods of Collecting and Analyzing Rearward Visibility Data for Agricultural Machinery: Hazard and/or Object Detectability. AB - Recent interest in rearward visibility for private, construction, and commercial vehicles and documentation of rearward runovers involving bystanders outside the field of vision of the vehicle operator led to an investigation into the need for enhanced methods of rearward visibility for large, off-highway, agricultural equipment. A review of the literature found limited relevant research and minimal data on incidents involving rearward runovers of bystanders and co-workers. This article reviews the findings regarding the methods identified and tested to collect and analyze rearward visibility data, from the operator's perspective, for large self-propelled agricultural equipment, including the four-wheel drive tractors, combines, agricultural sprayers, and skid-steer loaders that are increasingly found on agricultural production sites. The methods identified, largely drawn from research conducted on private and commercial vehicles, were tested to determine their application in identifying rearward blind spots. These methods are described, and the findings from field-testing of specific machines are provided. Recommendations include establishing an appropriate engineering standard regarding rearward visibility of agricultural equipment with limited rearward vision and the use of rearward alarm systems for warning bystanders of rearward movement. PMID- 29140618 TI - Utah Regional Differences in Respirator Use and Fit Testing among Pesticide Applicators. AB - The purpose of this study was to determine regional differences within Utah in response to piloting a mobile respirator training and fit assessment program for pesticide applicators. The objectives were to describe worker perceptions of respirator use and training experiences. Pilot trainings were offered in two southern counties and two northern counties of Utah. A total of 141 individuals completed the post-training questionnaire regarding use and fit testing experience with respirators as well as perceptions of the benefits to protecting respiratory health. The majority of respondents were male (95.7%, f = 112). The proportion of participants in the southern counties who had respirator training experience (61.0%, f = 25) was not significantly higher (?2 = 3.763, df = 1, p = 0.05) than the proportion of participants in the northern counties (43.0%, f = 43). Three-fourths (73.5%, f = 72) of participants in the northern counties agreed that they expect to wear a respirator in dusty conditions, while two thirds (61.0%, f = 25) of participants in the southern counties agreed that they expect to wear a respirator in dusty conditions. The results indicated that more training should be done to improve perceptions and beliefs about using respirators. A high priority for this population will be identification of comfortable respirator options as well as communicating the importance of proper fit testing. PMID- 29140619 TI - "I Would Go if My Arm Were Hanging off": A Qualitative Study of Healthcare Seeking Behaviors of Small Farm Owners in Central New York State. AB - Compared to their rural non-farming peers, farmers are less likely to access preventive healthcare services; however, the reasons for this disparity are poorly understood. We conducted semi-structured interviews with a total of 30 farm household members in central New York. Interview topics included farming identity, perceptions of one's health, past experiences with acute and preventive healthcare, and attitudes toward seeking healthcare services. Grounded Theory analysis of the interview transcripts revealed that (1) utilizing healthcare services is felt to be in conflict with the farming identity, (2) the need to conserve time and money for farm applications poses a barrier to healthcare utilization, (3) farmers decide to seek healthcare when they believe it is necessary to ensure survival of the farm, and (4) the decision to seek healthcare is most strongly driven by the presence of intolerable symptoms, prompting from others, and the perception that treatment will yield clear benefits. Efforts to increase farmers' utilization of healthcare services must address these considerations. PMID- 29140620 TI - How Agricultural Media Cover Safety Compared with Periodicals in Two Other Hazardous Industries. AB - This analysis featured a uniquely broad look at challenges and potentials for engaging agricultural and other industrial media more effectively in covering safety. It involved a content analysis of selected industry periodicals serving agriculture, mining, and transportation, which are three of the nation's most hazardous industries, in terms of human safety. Use of the social amplification of risk framework (SARF) provided insight on safety coverage. In particular, it tested previous research indicating that media coverage tends to amplify (increase) more than attenuate (decrease) a sense of risk. Analysis involved 18 periodicals (9 agriculture, 7 transportation, and 2 mining) spanning a five-year period from 2008 to 2012. Full-text digital analysis identified terms found in safety articles across all three industries. A manual review of articles revealed the quantity and nature of safety coverage within and among these industries. Results identified 528 safety-related articles published during the period. Transportation and mining periodicals averaged more than twice as many safety articles as the agricultural periodicals. The amount of coverage within the three industries also varied greatly. Findings on the nature of coverage supported previous media research within the SARF. Coverage across all three industries was clearly oriented more to amplifying than to attenuating risk. This study adds to the understanding of variations, commonalities, challenges, and potentials for enhancing safety coverage by media serving these three industries. It also provides direction for engaging industry media more effectively in the public safety mission. The authors recommend seven areas of opportunity for further research. PMID- 29140621 TI - Australian Leadership: Saving Lives with Crush Prevention Devices. AB - The burden of injury and death due to quad bike [all-terrain vehicle, or ATV] use cannot be allowed to continue unchecked, and ongoing delay in action may permit to further avoidable tragedies." -Royal Australasian College of Surgeons (2016, p. 13). PMID- 29140622 TI - Evaluation of a Commercial Tractor Safety Monitoring System Using a Reverse Engineering Procedure. AB - There is a high rate of work-related deaths in agriculture. In Italy, despite the obligato-ry installation of ROPS, fatal accidents involving tractors represent more than 40% of work-related deaths in agriculture. As death is often due to an overturn that the driver is incapable of predicting, driver assistance devices that can signal critical stability conditions have been studied and marketed to prevent accidents. These devices measure the working parameters of the tractor through sensors and elaborate the values using an algorithm that, taking into account the geometric characteristics of the tractor, pro-vides a risk index based on models elaborated on a theoretical basis. This research aimed to verify one of these stability indexes in the field, using a commercial driver as sistance device to monitor five tractors on the University of Bologna experimental farm. The setup of the device involved determining the coordinates of the center of gravity of the tractor and the implement mounted on the tractor. The analysis of the stability in-dex, limited to events with a significant risk level, revealed a clear separation into two groups: events with high values of roll or pitch and low speeds, typical of a tractor when working, and events with low values of roll and pitch and high steering angle and forward speed, typical of travel on the road. The equation for calculating the critical speed when turning provided a significant contribution only for events that were typi-cal of travel rather than field work, suggesting a diversified calculation approach ac cording to the work phase. PMID- 29140623 TI - Effects of Rubber Tracks on Narrow-Track Tractors on the Non-Continuous Rolling Prediction Model. AB - Tractor rollover is one of the most hazardous events for the driver. The rollover protective structure (ROPS) was introduced to passively protect the driver. In the specific case of two-post protective structures fitted in front of the driver on narrow-track wheeled agricultural tractors, the ROPS has to avoid non continuous rolling in the event of a lateral rollover. In order to check non continuous rolling behavior in narrow-track wheeled agricultural tractors, a mathematical model is included in the preliminary ROPS tests of the standardized testing procedures issued by the Organization for Economic Co-operation and Development (OECD). A recent approach in the design of narrow-track tractors is the fitting of rubber tracks. A safety issue consequent to this new arrangement is that the standardized calculation does not cover narrow rubber-tracked tractors because it was originally developed assuming only the behavior of the tire in a lateral rollover. The aim of this study was to extend the field of application of the standardized calculation for non-continuous rolling behavior, allowing rubber-tracked tractors to be fitted with a front ROPS suitable for operation in narrow orchards and vineyards. The effect of track-ground interaction compared to tire-ground interaction was evaluated. The track shape and non-deformed behavior of the rubber track at a state of unstable equilibrium under full load caused the tractor to rotate around the outer edge of the track; therefore, the tipping axes and wheel characteristics in the original mathematical model were revised. The tracked tractor checked with the revised model required a higher ROPS with respect to the equivalent wheeled tractor to obtain non-rolling behavior. The ROPS needed to be increased by 0.28 m to meet the safety requirement. PMID- 29140624 TI - Narrow-Track Agricultural Tractors: A Survey on the Load of the Hand-Operated Foldable Rollbar. AB - To protect the driver in case of a tractor overturn, narrow-track tractors (used in vineyards and orchards) can be equipped with a rollover protective structure (ROPS) consisting of a two-pillar front-mounted foldable rollbar. The transition from the horizontal (rest) to the vertical (protection) position of this ROPS is performed manually by the driver. In addition to the time spent performing this task many times each day, a moderate physical load is required, given that these rollbars often have a mass of some tens of kilograms. In practice, neglect and poor attention to safety lead to the foldable rollbar remaining continuously in the rest position rather than being moved to the vertical (protection) position. Several rollover accidents have been fatal for the driver because the tractor, although equipped with a two-pillar front-mounted ROPS, had the rollbar in the horizontal position at the time of the event, thus assuring no protection to the driver. This issue is quite serious. To remove at least one of the problems for the proper management of this type of ROPS, the OECD has recently updated its Code 6 by introducing an optional test addressing the manual handling of front mounted rollbars, providing a maximum load of 100 N. Several tests were conducted on new rollbars to ascertain the accuracy of this limit. The 100 N value was generally exceeded, which is cause for criticism. Indeed, a more appropriate reference for manual handling in this case would be the higher loads (up to 250 N) already provided by other standards for non-continuous tasks. PMID- 29140625 TI - Development and Evaluation of a Computer-Based ROPS Design Program. AB - Tractor overturn is the leading cause of agricultural fatalities in the U.S. Most of these fatalities can be eliminated using a rollover protective structure (ROPS) and a seatbelt. Unfortunately, not all agricultural tractors designed to support ROPS have ROPS designs. A computer-based ROPS design program (CRDP) was developed and successfully tested to provide quick and simple two-post, rear axle mounted ROPS designs based on SAE Standard J2194. The program uses the tractor dimensions and mass to calculate the dimensions needed for ROPS components. Excel was used as the framework to provide the input, calculation, and ROPS drawing worksheets. Three ROPS (for Massey Ferguson 265, Long 460, and Allis Chalmers 5040 tractors) were designed and constructed using the CRDP. Static rear, side, and vertical tests were conducted based on SAE J2194 on two of the ROPS. All ROPS performance deflection (RPD) tests were less than the ROPS allowable deflection (RAD), indicating that the ROPS passed the static tests. The third ROPS was successfully mounted on the tractor axle housing within one hour, demonstrating the ease of installation using a bolted corner bracket design. Although the CRDP provided quick and simple ROPS designs, this program does not eliminate the requirement to conduct and pass the performance tests for ROPS designs specified in OSHA and SAE standards. PMID- 29140626 TI - The Effect of Speed on Foldable ROPS Actuation Forces. AB - The number of fatalities caused by tractor rollovers has decreased in recent years, but the number of fatal tractor rollover accidents with a folded-down rollover protective structure (ROPS) has increased. Operating a ROPS-equipped tractor in low overhead clearance zones is difficult and sometimes impossible. The foldable ROPS (FROPS) was designed to solve the rigid ROPS problem, but lowering and raising a conventional FROPS is a time-consuming and strenuous process. After operators fold down a FROPS to pass a low overhead clearance zone, some prefer to leave it in the folded or inoperative position, increasing the risk of a rollover fatality. The actuation forces for raising and lowering a FROPS are not well known and may be influenced by actuation speed. A completely randomized block design with two blocks, five levels of speed, and multiple replications was conducted to investigate the effect of speed on actuation torque. The blocks were two sizes of tractor FROPS. The test included five levels of speed, including two levels of static measurement and three levels of dynamic measurement. A variable-speed motor system was used to control the speed for raising and lowering the FROPS. The actuation torque is a function of the FROPS upper part shape, dimensions, material density, turning acceleration, and friction. A theoretical model was developed to predict the actuation torque based on the FROPS shape, dimensions, and material density. For one ROPS, due to friction, the dynamic actuation torque was greater for raising and less for lowering than the theoretical torque. Indicator variable regression was used to analyze the effect of speed on actuation torque. Results showed that speed had a significant (p > 0.05) effect on actuation torque. Although there were statistically significant differences between the dynamic actuation torques, these differences were relatively small and negligible compared to the differences between the static torques. PMID- 29140627 TI - Development of an Open-Source Tractor Driving Simulator for Tractor Stability Tests. AB - Developing devices for stability monitoring and rollover alerts is a promising possibility to prevent overturn events, which pose a severe risk to tractor operators. However, performing relevant tests with operators in the field is dangerous and impractical. As an alternative, this work identifies the challenges of simulating a tractor driving environment in a laboratory and details the solutions put in place to develop a tractor driving simulator at Penn State University. The simulator includes an instrumented tractor cab mounted on a custom motion base, a 2.43 m tall, 360 degrees high-definition screen, a sound system, and a nine-computer network running open-source software that can be used to conduct experiments and simulate driving scenarios relevant to tractor instabilities. The system is used for an experiment that evaluates the driver's ability to perceive tilt angles at various tilt and roll combinations. Pilot-test results show that roll and pitch are systematically overestimated, producing perceptual errors that are unbiased, independent for roll and pitch, and typically have magnitudes of 4 degrees . These results can aid the development of instability monitoring systems by considering human tilt perception to set alert thresholds. Future projects and applications of the tractor driving simulator are also discussed. PMID- 29140628 TI - Tractor ROPS and Stability Research: Introduction to this Special Issue. AB - Agricultural production has clearly benefited from the development of the tractor. The tractor provides a traction device and mobile power source. However, operating large equipment with high clearance on uneven ground leads to stability and overturn issues. Around the world, tractor overturns are still a leading cause of agricultural production fatalities. This special issue of the Journal of Agricultural Safety and Health focuses on recent research on tractor ROPS (rollover protective structures) and stability. Engineers and scientists in both Italy and the U.S. have been working on these topics, attempting to solve old problems and address rising issues. Understanding the factors leading to tractor instability, investigating the structures protecting the operator, and examining the continuous roll potential will all lead to increased operator protection and reduced fatalities. PMID- 29140629 TI - Development and Evaluation of a Basic First Aid Curriculum for Spanish-Speaking Dairy Workers. AB - . Over the past decade, the New York State dairy industry has grown substantially, resulting in an increase in immigrant workers who speak languages other than English. Estimates suggest that over 50% of workers on large New York dairies are Spanish-speaking individuals who immigrated to the U.S. from Guatemala, Mexico, and other Latin American countries. With a growing population of Spanish-speaking workers, safety concerns on farms have become a prominent issue. This article reviews the development and evaluation of a basic dairy first aid curriculum, which is intended to educate Spanish-speaking immigrant dairy workers on emergency response and first aid. The materials developed are culturally relevant and can be easily understood by low-literacy, non-English speaking workers. In evaluation of the materials using pre- and post-testing, a significant knowledge gain was identified in workers who participated in the training. PMID- 29140630 TI - Analysis of the Effect of Prevailing Weather Conditions on the Occurrence of Grain Dust Explosions. AB - Grain dust explosions have been occurring in the U.S. for the past twenty years. In the past ten years, there have been an average of ten explosions a year, resulting in nine fatalities and 93 injuries. In more than half of these cases, the ignition source remains unidentified. The effect of ambient humidity on the likelihood of a dust explosion has been discussed for many years. However, no investigation into a possible link between the two has been carried out. In this study, we analyzed local weather data and grain dust explosions during the period 2006 to 2014 to measure potential relationships between the two events. The 84 analyzed explosions do not show any trend with regard to prevailing temperatures, or relative or absolute humidity. In addition, the ignition source could not be identified in 54 of the incidents. The majority of grain dust explosion incidents occurred at grain elevator facilities, where the dust generation potential was high compared with grain processing industries. PMID- 29140631 TI - Airborne Formaldehyde Levels During Simulated Formalin Egg Treatments in Vertical Flow Tray Incubators at a Production Fish Hatchery. AB - Formalin, an aqueous solution of formaldehyde and methanol, is widely used in aquaculture facilities to treat water molds during egg incubation. Given the carcinogenic properties of formaldehyde, an understanding of the occupational exposure of aquaculture workers is essential. This study evaluated formaldehyde levels in a production fish hatchery incubation room under six different formalin treatment scenarios: one, three, or five vertical flow incubation stacks received 1,667 mg L-1 formalin treatments for 15 min with the incubation room door either open or closed. The results indicate that the level of formaldehyde being aerosolized increased as the number of stacks treated increased, with maximum levels ranging from approximately 0.5 ppm when only one stack was treated to over 2.0 ppm when five stacks were treated and the door was closed. Having the door open during formalin treatment resulted in significantly lower aerosolized formalin levels when three or five stacks were treated and a reduction in the time required for a return to basal levels when five stacks were treated. Based on these results, it is imperative that hatchery workers are able to leave confined incubation locations or use appropriate safety equipment during formalin treatments. PMID- 29140632 TI - Grain Entrapment Pressure on the Torso: Can You Breathe while Buried in Grain? AB - The pressure applied to the chest and back of a simulated grain entrapment victim was measured. Pressure sensors were attached to the chest and back of a manikin that was buried in grain in the vertical position. Measurements were made in four grain types at four grain depths ranging from the top of the manikin's shoulders to 0.61 m (24 in.) over the head. The pressure ranged from 1.6 to 4.0 kPa (0.23 to 0.57 psi). Based on available physiological information, this amount of pressure is unlikely to limit the respiration of an otherwise healthy adult male victim. However, other factors, such as the victim's age, gender, and body position in the grain, may influence respiration. The aspiration of grain appears to be the most likely asphyxiation risk during grain bin entrapment. Entering a grain storage bin is inherently dangerous, and Occupational Safety and Health Administration (OSHA) guidelines for permit-required confined spaces and grain handling facilities must be followed. Due to the risk of grain aspiration during engulfment, the development of safety equipment that could help protect the airway of a victim should be investigated. PMID- 29140634 TI - Combustibility Determination for Cotton Gin Dust and Almond Huller Dust. AB - It has been documented that some dusts generated while processing agricultural products, such as grain and sugar, can constitute combustible dust hazards. After a catastrophic dust explosion in a sugar refinery in 2008, the Occupational Safety and Health Administration (OSHA) initiated action to develop a mandatory standard to comprehensively address the fire and explosion hazards of combustible dusts. Cotton fiber and related materials from cotton ginning, in loose form, can support smoldering combustion if ignited by an outside source. However, dust fires and other more hazardous events, such as dust explosions, are unknown in the cotton ginning industry. Dust material that accumulates inside cotton gins and almond huller plants during normal processing was collected for testing to determine combustibility. Cotton gin dust is composed of greater than 50% inert inorganic mineral dust (ash content), while almond huller dust is composed of at least 7% inert inorganic material. Inorganic mineral dust is not a combustible dust. The collected samples of cotton gin dust and almond huller dust were sieved to a known particle size range for testing to determine combustibility potential. Combustibility testing was conducted on the cotton gin dust and almond huller dust samples using the UN test for combustibility suggested in NFPA 652.. This testing indicated that neither the cotton gin dust nor the almond huller dust should be considered combustible dusts (i.e., not a Division 4.1 flammable hazard per 49 CFR 173.124). PMID- 29140635 TI - Emergency Department Visits for Hand and Finger Injuries Associated with the Use of Log Splitters. AB - The purpose of this study was to examine patients treated in an emergency department (ED) for injuries related to the use of log splitters. Data were obtained from the National Electronic Injury Surveillance System for the years 2011-2014. National estimates of ED visits for injuries associated with the use of log splitters were obtained, and descriptive epidemiological characteristics are presented. An estimated 37,000 ED visits for injuries related to the use of log splitters occurred during the study period. The majority of injuries occurred to the hand, with lacerations, fractures/avulsions, and amputations being the most common. The findings indicate that injuries from log splitters constitute a serious public health problem. Efforts to reduce injuries are discussed in accordance with the inherent challenges of detailing the circumstances surrounding these injuries. PMID- 29140633 TI - The Impact of Work Demand and Gender on Occupational and Psychosocial Stress in Hispanic Farmworkers. AB - Hispanic farmworkers experience hazardous work conditions, language barriers, poverty, and limited healthcare access that increase their risk for health problems. We sought to characterize occupational and lifestyle stressors in farmworker couples and to examine the impact of seasonal work demand and gender on health outcomes. We administered surveys to 31 couples (N = 62) in May (low work demand) and September (high work demand) of 2012. Measures included acculturation, perceived stress, depressive symptoms, quality of life, decision latitude, support (supervisor, co-worker), and work-family conflict. This population did not report significant differences in stress in low and high work demand times. Women reported more work-family conflict (F = 19.06, p 0.0001; F = 11.28, p = 0.0015) and less supervisor support (F = 6.56, p = 0.0135). Women experienced more conflict between work and family and less support at work. This group reported low depressive symptomology and moderate levels of stress; a subset reported elevated levels. PMID- 29140636 TI - Trends and Patterns in Unintentional Injury Fatalities in Australian Agriculture. AB - Agriculture is recognized internationally as a hazardous industry. This article describes the trends and patterns of unintentional farm fatalities in Australia. Data from the National Coronial Information System were analyzed to assess all unintentional farm fatalities for the 2001-2015 period. A secondary comparison with earlier coronial system data from 1989-1992 was also completed to ascertain historical changes. There was no statistically significant change in the rate of work-related fatalities per 100,000 workers in the 2001-2015 period. However, there was a significant curvilinear reduction in all cases of fatality (work and non-work related) per 10,000 agricultural establishments, which decreased from 2001 to 2009-2011 and then increased to 2015. The longer-term data from 1989-2015 revealed a reduction of 30% in work-related cases per 100,000 workers and a reduction of 35% in all cases (work and non-work) per 10,000 agricultural establishments. For both work-related and all cases, there was a statistically significant reduction from 1989 to 2005 and then no change thereafter. The longer term reduction in farm fatalities ceased in the mid-2000s, and the rate has remained stable since. Fatal injuries continue to impose a significant burden on Australian farming communities, with the rate remaining relatively static for the past ten years. New evidence-based interventions targeting priority areas are required to reduce the incidence of fatalities in Australia agriculture. PMID- 29140637 TI - Hazard Identification and Risk Assessment for Improving Farm Safety on Canadian Farms. AB - Agriculture is one of the most hazardous industries worldwide. The number of serious accidents on farms, despite sophisticated technology, development of effective prevention methods, and high-quality training and improved skill levels of farmers, is still very high. The purpose of this study was to develop and apply a generic farm safety protocol to hazards that have been identified in previously published literature and demonstrate the potential benefits of such a protocol with a view to raising awareness of farm safety. Hazards in agriculture were categorized, and literature highlighting the risks associated with hazards was collated. A protocol was developed and applied to establish the likelihood of a hazard causing injury and the consequence of that injury should adverse effects of hazards be realized. The results indicated farm ownership, farm being used as a primary residence, and missing rollover protective structures as the greatest farm risks with expected likelihood and extreme consequence such as death or permanent disablement. Other hazards that require immediate attention while developing mitigation strategies include accident history and existing medical conditions of the farmer, working environment (i.e., alone and isolated), water bodies in the proximity of the farm, lack of periodic machine maintenance, uncovered power take-off and other rotating parts of the tractor, missing safety decals, auger entanglements, and unprotected use of pesticides. Intervention strategies may be guided by considering the results presented in this study. Moreover, farm safety specialists should increase their efforts to promote effective injury prevention methods and enforce safe work environments. The developed protocol addresses almost all common aspects of farming hazards and can be used to mitigate risks associated with hazards in any farm setting. PMID- 29140638 TI - Apparent Coefficient of Friction of Wheat on Denim. AB - Calculation of the extraction force for a grain entrapment victim requires a coefficient of friction between the grain and the surface of the victim. Because denim is a common fabric for the work clothes that cover entrapment victims, the coefficient of friction between grain and denim becomes necessary. The purpose of this research was to calculate the apparent coefficient of friction of wheat on denim fabric using a proven procedure. The expectation is to improve the current understanding of conditions that influence extraction forces for victims buried in wheat. The apparent coefficient of friction of wheat on denim fabric was calculated to be 0.167 with a standard deviation of +/-0.013. The wheat had a moisture content of 10.7% (w.b.) and bulk density of 778.5 kg m-3. The apparent coefficient of friction of wheat on denim was not significantly affected by pull speeds of 0.004, 0.008, and 0.021 mm s-1 nor normal grain pressures of 3.2, 4.8, 6.3, 7.9, and 11.1 kPa. This is a beginning of understanding the conditions that influence the extraction forces for grain entrapment victims. PMID- 29140639 TI - Determining the Effectiveness of Mirrors and Camera Systems in Monitoring the Rearward Visibility of Self-Propelled Agricultural Machinery. AB - This study concerned the ability of operators of tractors and other self propelled agricultural machinery to visually recognize objects and/or hazards within close proximity to the rear of those machines and/or any implements in tow, especially when backing up. It was hypothesized that the data collected would identify the factors affecting rearward visibility and help determine the effectiveness of two backup-assisting devices (i.e., mirrors and camera systems) in enhancing the operator's ability to observe objects or hazards. The study's experimental design involved the following: (1) selecting nine self-propelled machines for testing (five tractors of varying sizes, a combine, a sprayer, a skid steer loader, and a UTV); (2) laying out a five cell by five cell test grid behind each machine, with an indicator pole centered in each cell; (3) positioning the mirrors (exterior/interior) and camera system (camera and display monitor) for maximum visibility; and (4) collecting images from a 50th percentile male operator's eye midpoint position. The findings were recorded graphically onto a master grid for the backup-assisting devices (both individually and in combination) on each machine. Analysis of the results confirmed that various issues related to the machines impact the effectiveness of mirrors and camera systems in enhancing rearward visibility. Among them are the operator station's design and configuration, seat adjustability, optional accessories, exterior lighting, type of implement in tow, hitching method, and highway transport mode. These findings led to recommendations relative to each of the mirrors and camera systems, as well as observations of operator interactions with accessories and perceived effects on the operator's ability to view obstructed areas in close proximity to the machinery. PMID- 29140640 TI - Using Workers' Compensation Claims Data to Characterize Occupational Injuries in the Commercial Grain Elevator Industry. AB - Workplace injuries in the grain handling industry are common, yet little research has characterized worker injuries in grain elevators across all hazard types. Learning from past injuries is essential for preventing future occurrences, but the lack of injury information for the grain handling industry hinders this effort. The present study addresses this knowledge gap by using data from over 7000 workers' compensation claims reported from 2008 to 2016 by commercial grain handling facilities in the U.S. to characterize injury costs and severity. The total amount paid for each claim was used as a measure of injury severity. The effects of employee age and tenure, cause of injury, and body part injured on the cost of work-related injuries were investigated. Contingency tables were used to classify the variable pairs. The chi-square test and chi-square residuals were employed to evaluate the relationship between the variable pairs and identify the at-risk groups. Results showed that the employee age and tenure, cause of injury, and body part injured have a significant influence on the cost paid for the claim. Several at-risk groups were identified as a result of the analyses. Findings from the study will assist commercial grain elevators in the development of targeted safety interventions and assist grain elevator safety managers in mitigating financial and social losses from occupational injuries. PMID- 29140641 TI - Agricultural Worker Injury Comparative Risk Assessment Methodology: Assessing Corn and Biofuel Switchgrass Production Systems. AB - Keeping workers safe is a continuing challenge in agricultural production. Risk assessment methodologies have been used widely in other industries to better understand systems and enhance decision making, yet their use in production agriculture has been limited. This article describes the considerations and the approach taken to measure the difference in worker injury risks between two agricultural production systems. A model was developed specifically for the comparison of worker injury risk between corn and biofuel switchgrass production systems. The model is composed of injury and exposure values that were used in a Monte Carlo simulation. The output of this risk assessment shows that approximately 99% of the values from the Monte Carlo simulation rank corn production as a greater worker injury risk than biofuel switchgrass production. Furthermore, the greatest contributing factors for each production system were identified as harvest, and that finding aligns with current literature. PMID- 29140642 TI - Raising Awareness of Farm Equipment on Public Roadways in Tennessee. AB - A program was developed to educate young drivers about laws and guidelines governing farm equipment on public roadways in Tennessee. The goal of the program was to make young drivers aware of their responsibilities and the responsibilities of farm equipment drivers when sharing public roadways. A presentation was developed outlining the topics and was accompanied by identical pre- and post-surveys. The material was presented to drivers' education classes and agriculture science classes at several high schools in west and middle Tennessee. A total of 365 students between the ages of 13 and 19 participated in the program. The pre- and post-survey scores were used to determine the effectiveness of the program. The average score of the pre-survey for all participants was 66.0%. This score significantly improved to 89.3% for the post survey (p 0.0001 for paired t-test). Based on these scores, the students were able to gain a better understanding of the laws and guidelines in Tennessee concerning farm equipment on public roadways. PMID- 29140643 TI - Assessment of Interventions to Improve Air Quality in a Livestock Building. AB - This study examined the effectiveness of engineering controls to reduce contaminant concentrations in a swine farrowing room during winter in the U.S. Midwest. Over two winters, changes in air quality were evaluated following installation of a 1700 m3 h-1 (1000 cfm) recirculating ventilation system to provide 5.4 air exchanges per hour. This system incorporated one of two readily available dust control systems, one based on filtration and the other on cyclonic treatment. A second treatment evaluated reductions in carbon dioxide (CO2) associated with replacement of standard, unvented gas-fired heaters with new vented heaters, installed between the two winter test periods. The concentrations of carbon monoxide and hydrogen sulfide were negligible in the test room. Although concentrations of ammonia increased over each winter test period, the increase was unrelated to increased air movement from the new recirculating ventilation system. The dust concentrations were significantly reduced by the ventilation system for both inhalable dust (23% to 44% with filtration, 33% with cyclone) and respirable dust (32% with filtration, 20% with cyclone), significant (p 0.024) for all except respirable dust using the cyclone (p = 0.141). The filtration unit is recommended to improve livestock building air quality because it was more effective than the cyclone unit at reducing respirable dust. Carbon dioxide concentrations were significantly lower with vented heaters (mean = 1400 ppm, SD = 330 ppm) compared to unvented heaters (mean = 2480 ppm, SD = 160 ppm). A 940 ppm reduction in CO2 was attributed to the use of the vented heater, after accounting for differences in outdoor temperatures and animal housing over both test periods. The benefits of readily available technology to significantly reduce concentrations of dust and CO2 demonstrates useful control options to improve air quality in swine buildings. PMID- 29140644 TI - Evaluation of Low-Cost Hydrogen Sulfide Monitors for Use in Livestock Production. AB - Direct-reading gas monitors warn workers of the risk of potentially fatal hydrogen sulfide (H2S) exposures that may arise during manure handling. Low-cost, low-maintenance H2S monitors are available from many manufacturers, but differences in their features and performance make selection challenging for farmers. Moreover, little information is available on the practical maintenance and performance of these devices in agricultural environments. The objective of this study was to provide information to agricultural workers to aid in the selection, maintenance, and use of low-cost H2S monitors. This laboratory study evaluated the performance of several low-cost monitors over a simulated period of use of one year in a swine barn. Four models were exposed to H2S concentrations of 1 to 10 ppm over 18 weeks to examine the drift in reported concentration and changes in the alarm reaction time. Over the simulated barn year, the performance of alarm-only monitors declined faster than that of monitors displaying the H2S concentration. Of concern was the high-level (20 ppm) alarm failures after an equivalent of 139 days (Altair) and 289 days (BW Clip) in a swine barn, well within the monitor's reported shelf-life. Models displaying concentration exhibited fewer failures but were inaccurate in the displayed concentration when challenged with 20 ppm of H2S. The T40 Rattler provided consistently higher readings (+2.3 ppm), and the Pac 3500 showed consistently lower readings (-3.4 ppm) when challenged with 20 ppm. This study confirms the need for routine bump tests for these low-cost monitors to ensure that the monitor reacts to the presence of H2S, even if the manufacturer does not recommend this procedure. Most importantly, agricultural workers should inspect and bump test these monitors prior to any potentially high-risk activity, such as manure agitation, pumping, or pressure washing, to ensure that the monitor appropriately detects and warns users. PMID- 29140645 TI - Likelihood of Entanglement when Materials are Dropped Vertically onto a Rotating PTO Knuckle. AB - Power take-off (PTO) is a common method of transferring power from a tractor to a towed piece of machinery. The PTO is also a well-documented cause of severe and often permanent disabling injuries to farm operators. The physical conditions that cause entanglements are not well established. Several studies have explored the parameters of PTO entanglements as materials have been drawn across a rotating PTO knuckle to test for entanglement probability. The objective of this study was to determine probability of entanglement when materials are dropped vertically onto a PTO knuckle spinning at 540 rpm. A total of 360 randomized trials were conducted with ten replications for each of the six positions (center of yoke, edge of yoke rotating downward, edge of yoke rotating upward, center of cross, edge of cross rotating downward, and edge of cross rotating upward) and six different materials (woven cotton athletic shoe lace, cotton workboot lace, leather workboot lace, cotton twine, denim strip, and Tyvek strip). Not a single entanglement was recorded. Dramatic high-speed video imagery authenticated the material's motion and path as it interacted with the rotating PTO knuckle. PMID- 29140646 TI - Early Developments in the Regulation of Biologics. AB - This article is a history of the policy positions and legal interpretations adopted by the Public Health Service (PHS) under the 1902 Biologics Control Act. PHS generally interpreted the scope of the Act narrowly because it lacked authority to deny marketing licenses for ineffective biologics and wanted to minimize the number of worthless drugs with the imprimatur of a governmental license. In addition, PHS implemented important regulatory strategies not expressly authorized by the Act. PMID- 29140647 TI - FDA Regulation of Clinical Applications of CRISPR-CAS Gene-Editing Technology. AB - Scientists have repurposed an adaptive immune system of single cell organisms to create a new type of gene-editing tool: CRISPR (clustered regularly interspaced short palindromic repeats)-Cas technology. Scientists in China have reported its use in the genome modification of non-viable human embryos. This has ignited a spirited debate about the moral, ethical, scientific, and social implications of human germline genome engineering. There have also been calls for regulations; however, FDA has yet to formally announce its oversight of clinical applications of CRISPR-Cas systems. This paper reviews FDA regulation of previously controversial biotechnology breakthroughs, recombinant DNA and human cloning. It then shows that FDA is well positioned to regulate CRISPR-Cas clinical applications, due to its legislative mandates, its existing regulatory frameworks for gene therapies and assisted reproductive technologies, and other considerations. PMID- 29140648 TI - E-cigarette Regulation and Harm Reduction: The Case of Hong Kong. AB - Harm reduction is an internationally recognized tobacco control strategy. E cigarettes, being a less harmful alternative to smoking, have the potential to achieve harm reduction. Within this context, this article critiques Hong Kong's legal regime governing e-cigarettes and the proposed prohibition of the product. It is argued that the current law is uncertain and inadequate. Although a reform of laws relating to e-cigarettes is needed, it is argued that banning the product altogether as a means to reducing the harm of tobacco use is unsupported by evidence. PMID- 29140649 TI - The Extent of Harm to the Victim as an Alternative Aggravating Factor for the Conviction of Felony Fraud in the Context of Food-Safety Violations. AB - Finding the intent to defraud or mislead for the conviction of felony fraud could be very tricky in the context of food regulation. As compared to the split among the US federal circuit courts on the interpretation of intent, Taiwan courts looked into the extent of harm to the victim to determine whether the defendant should be convicted of felony fraud. In order to limit the scope of felony liability, Taiwanese law requires an additional showing of the extent of harm to the victim. Recently, courts in Taiwan further expanded the scope of the statutory language, "harmful to human health," to include potential harm as demonstrated by animal studies. This approach provides courts in other jurisdiction with an alternative aggravating factor to assess criminal liability in nondisclosure cases arising out of non-compliance with food law. PMID- 29140650 TI - Knowledge Sharing as a Social Dilemma in Pharmaceutical Innovation. AB - This article addresses the problem of restricted access to industry-sponsored clinical trial data. In particular, it analyzes the intersection of the competing claims that mandatory disclosure of pharmaceutical test data impedes drug sponsors' innovation incentives and that access facilitates new drug development. These claims are characterized in terms of public-good and common-resource dilemmas. The analysis finds confidentiality protection of primary research data plays an ambiguous role. While secrecy, as such, does not solve the public-good problem in pharmaceutical innovation (in the presence of regulatory instruments that protect the originator drug against generic competition), it is likely to exacerbate the common-resource problem, in view of data as a source of scientific knowledge. It is argued that the claim by the research-based industry that disclosure of clinical data impedes innovation incentives is misplaced and should not be leveraged against pro-access policies. While much attention has been paid to the problem of appropriability of drug R&D investment, this analysis highlights another consequence resulting from the private provision of clinical trials, i.e., factual confidentiality and possession of data by drug sponsors. The associated social costs are qualified in terms of internalized knowledge externalities. Since, in a competitive environment, companies are unlikely to change the strategy of non-sharing of primary data, the resulting economic inefficiencies at the sector level call for regulatory intervention. To reconcile the competing policy objectives, it is proposed that the rules of access should be designed in such a way that third-party use of primary data does not interfere with protection against generic competition. At the same time, the long-term collective benefit can be maximized when the "cooperative choice" (i.e., when everyone shares data) becomes the "dominant strategy." This can be achieved only when access is not subject to the authorization of the initial trial sponsors, and when primary data is aggregated, refined, and managed on the collective basis. PMID- 29140651 TI - FDA-Required Tobacco Product Inserts & Onserts-and the First Amendment. AB - In 2012, a federal court of appeals struck down an FDA rule requiring graphic health warnings on cigarettes as violating First Amendment commercial speech protections. Tobacco product inserts and onserts can more readily avoid First Amendment constraints while delivering more extensive information to tobacco users, and can work effectively to support and encourage smoking cessation. This paper examines FDA's authority to require effective inserts and onserts and shows how FDA could design and support them to avoid First Amendment problems. Through this process, the paper offers helpful insights regarding how key Tobacco Control Act provisions can and should be interpreted and applied to follow and promote the statute's purposes and objectives. The paper's rigorous analysis of existing First Amendment case law relating to compelled commercial speech also provides useful guidance for any government efforts either to compel product disclosures or to require government messaging in or on commercial products or their advertising, whether done for remedial, purely informational, or behavior modification purposes. PMID- 29140652 TI - Commemorating the 40th Anniversary of the 1976 Medical Device Amendments. PMID- 29140653 TI - Outsource Power, Import Safety? Challenges and Opportunities of the U.S.-China Food Safety Regulatory Cooperation. AB - The United States has a high stake in China's serious food safety problem, as food products of Chinese origin have dominated the U.S. food market in numerous areas and continue to grow. The conclusion of the U.S.-China Food Safety Agreement ("the Agreement") has allowed FDA to strengthen regulatory cooperation with its Chinese counterpart in various aspects. The Agreement also paves the way for the implementation of the new regulatory tools incorporated in FSMA, especially in the cross-border context. However, both the Agreement and FSMA have certain crucial limitations that may create future hurdles to effective implementation in the U.S.-China cooperation. This paper therefore endeavors to first examine China's governance challenges over food safety, with a focus on the 2009 Food Safety Law, the 2015 Amendment, and the fundamental problem of "thin" rule of law. This paper moves to analyze the U.S.-China Food Safety Agreement, reviewing the agreement's strengths and weaknesses. It further assesses FSMA's innovative institutional design to regulate imported food products and its limitations. However, both the U.S.-China Food Safety Agreement and FSMA arguably create a regulatory dilemma for FDA when addressing imported food safety, due to structural mismatch between the broad scope of power granted to FDA and the long chain of power outsourcing to governments or private companies as primary "regulators." Neither the Agreement nor FSMA give FDA adequate capacity to closely oversee such "agents" along the chain of power outsourcing. Framing the U.S.-China food safety cooperation as a multilayer structure that "outsources power" to "import safety," this paper concludes by stressing the need for a robust accountability and effective mechanism for U.S.-China food safety cooperation. PMID- 29140654 TI - Proposed Industry Best Practices in Development and Marketing of Medical Foods for the Management of Chronic Conditions and Diseases while Awaiting Regulation. AB - Ideal therapeutics have low toxicity and can effectively manage condition(s) or disease(s). The Food & Drug Administration (FDA) marketing category of therapeutics called "medical foods" (MFs) meets such a definition. Medical foods have existed in Federal law since passage the Orphan Drug Act in 1988, which created a category of nutritional therapeutics separate from drugs. Unfortunately, MFs are not widely understood by the medical community or utilized in all patients who need them due to lack of a FDA-approval process, unclear and contradictory guidance especially with regard for need for an investigational new drug (IND) application, and no clear regulations regarding their development and marketing. The goals of this article are to propose "Best Practices" to guide the medical food industry in the development and marketing of products as well as to serve as a starting point for suggestions regarding further FDA regulation so that therapeutics which are shown to be generally recognized as safe (GRAS), provide food ingredients to meet a distinctive nutritional requirement for a specific condition/disease and are proven effective for the management for that condition/disease can be used to benefit patients who need them. PMID- 29140655 TI - The "Natural" vs. "Natural Flavors" Conflict in Food Labeling: A Regulatory Viewpoint. AB - Food branded with a Natural label can be found in any grocery store across the United States. Consumers consider this label to be an important attribute when making a purchasing decision and billions of dollars are spent annually on these products. While many consumers believe Natural foods are healthier, heavy reliance on that assumption is misguided as "Natural" has no formal legal definition-it's merely defined pursuant to an FDA approved informal policy. Another important health attribute in a consumer's purchasing decision is the presence of natural flavors in food. However, unlike the term Natural, FDA has promulgated legally binding regulations for natural flavors. These flavors are currently the fourth most common food ingredient listed on food labels. In reality, "natural flavors" are a far cry from what consumers might expect, as they can contain both artificial and synthetic chemicals (often used as processing aids). Nonetheless, without a legally binding Natural regulation, there has been little opportunity to contest the naturalness of natural flavors in the past. Recently, FDA has initiated a notification of request for comments on use of the term Natural, so an attempt to promulgate regulations may be underway. Thus, it is appropriate to consider where natural flavors will fall if binding regulations are set forth. This article looks at the Natural debate, its history, and model regulatory standards worth considering. Within that context, it also provides a critical discussion concerning a misunderstood, yet federally regulated, ingredient that our society so heavily consumes: natural flavors. PMID- 29140656 TI - An Analysis of "Natural" Food Litigation to Build a Sesame Allergy Consumer Class Action. AB - In a world where food allergy is still an incurable disease, law and regulation stand as necessary mechanisms to provide food-allergic consumers with the information they need to protect their health. The Food Allergen Labeling and Consumer Protection Act of 2004 provided specific labeling requirements for the "Top Eight" allergens in the U.S.: milk, soy, gluten, egg, tree nut, peanut, fish, and Crustacean shellfish. Since then, sesame has become more prevalent as an allergen and remains just as dangerous, inducing anaphylactic shock in some sesame-allergic individuals. Yet sesame remains unregulated, despite advocates and congressional members arguing for its inclusion. This note entertains one solution to this problem by exploring the most strategic way to bring a sesame allergy class action against a private food company under California's consumer protection statutes. Because this kind of class action does not have much, if any, precedent, this note analyzes the basic, preliminary issues that any litigant would have to navigate around to certify a class, including preemption, standing, and the claim itself, by focusing on how courts have examined these issues in the recent "natural" class action litigation. It also analyzes the legal, moral, and practical aspects of choosing a type of relief, as well as whom to include in the class. Finally, this note briefly considers how FDA itself can ensure sesame is regulated on the labels of food products, given that some of the legal issues may well be insurmountable for this particular class action. This note explores the potential solutions to difficult legal hurdles in constructing a sesame allergy class action, arguing that litigating a sesame allergy class action-even if it is not ultimately successful-could start a productive conversation that might lead Congress or FDA to provide greater public health and consumer protection for those with sesame allergy. PMID- 29140657 TI - Sunlight and Other Disinfectants: Disclosure Obligations under the Federal Securities and Drug Regulatory Regimes. AB - Drug development requires patience. Beyond the inherent uncertainty of the development process itself, U.S. drug developers must comply with the regulatory approval process overseen by the U.S. Food and Drug Administration (FDA). Because this process takes time, drug development also costs money. Drug companies seeking to raise funds in U.S. capital markets must navigate the securities regime governed by the Securities & Exchange Commission (SEC). Despite their similar roles as protectors of consumers and public markets, SEC and FDA send conflicting signals about the information drug companies need to disclose to the public. While SEC primarily regulates by mandating public disclosure, FDA has historically regulated drugs through its pre-approval process and has only recently begun to add disclosure mechanisms to its regulatory regime. Moreover, a trio of federal statutes requires FDA to keep sensitive information submitted by drug companies confidential. The regimes' distinct priorities and approaches create tensions that surface when publicly traded drug companies must decide whether and how to publicly disclose information related to drug development. This paper surveys the two agencies' conflicting priorities and regulations and explores the resulting problems that can arise for drug companies. It recommends that Congress liberalize statutory restraints on FDA's ability to disclose sponsor-submitted confidential information in order to help alleviate the tensions between these regimes and provide the public with more accurate information about drug companies and their products. PMID- 29140658 TI - Killing U.S. Slowly: Curing the Epidemic Rise of Cancer Drug Prices. AB - In August 2015, more than 110 U.S. oncologists published an article detailing the deleterious effects of rising cancer drugs prices and calling for numerous reforms to our prescription drug system. These prices are the result of decades of political maneuvering; they reflect the way our country has chosen to pay for healthcare, to foster and reward innovation, and to promote a national free market system. While these choices have resulted in immense profits for pharmaceutical companies-and subsidized the development of prescription drugs globally-they have also left many cancer patients unable to afford their medications. And, without providing significant improvements in life expectancy, the rising prices of cancer drugs seem like an unreasonable burden on U.S. healthcare spending. A multitude of reforms have been proposed. At the federal level, many of the reforms seek to amend existing regulatory regimes, such as allowing Medicare to negotiate drug prices, reforming the patent system, and allowing patients to import drugs from other countries. The pharmaceutical and biotechnology industries have pushed back against almost all of them. Some of these proposals are more ambitious than others; some more likely to succeed. With costs rising every day, policy makers, legislators, and industry professionals need to focus their attention on those reforms that are attainable and will result in sustainable, reduced prescription drug prices. This paper discusses various U.S. regulatory frameworks that impact prescription drug prices and evaluates proposed reforms to these frameworks in terms of which ones are most likely to succeed. PMID- 29140659 TI - Making the Case for a National Food Strategy in the United States. PMID- 29140660 TI - Assessing the Relative Influence and Efficacy of Public and Private Food Safety Regulation Regimes: Comparing Codex and Global G.A.P. Standards. AB - An extensive global system of private food regulation is under construction, one that exceeds conventional regulation thought of as being driven by public authorities like FDA and USDA in the U.S. or the Food Standards Agency in the UK. Agrifood and grocer organizations, in concert with some farming groups, have been the primary designers of this new food regulatory regime. These groups have established alliances that compete with national regulators in complex ways. This article analyzes the relationship between public and private sources of food safety regulation by examining standards adopted by the Codex Alimentarius Commission, a food safety organization jointly run by the Food and Agricultural Organization and the World Health Organization and GlobalG.A.P., a farm assurance program created in the late 1990s by supermarket chains and their major suppliers which has now expanded into a global certifying coalition. While Codex standards are adopted, often as written, by national food safety regulators who are principal drivers of the standard setting process, customers for agricultural products in many countries now demand evidence of GlobalG.A.P. certification as a prerequisite for doing business This article tests not only the durability and strength of private sector standard setting in the food safety system, but also the desirability of that system as an alternative to formal, governmental processes embodied, for our purposes, in the standards adopted by Codex. In many cases, official standards and GlobalG.A.P. standards clash in ways that implicate not only food safety but the flow of agricultural products in the global trading system. The article analyzes current weaknesses in both regimes and possibilities for change that will better reconcile the two competing systems. PMID- 29140661 TI - An International Model for Antibiotics Regulation. AB - We face a global antibiotics resistance crisis. Antibiotic drugs are rapidly losing their effectiveness, potentially propelling us toward a post-antibiotic world. The largest use of antibiotics in the world is in food-producing animals. Food producers administer these drugs in routine, low doses-the types of doses that are incidentally the most conducive to breeding antibiotic resistance. In general, individual countries have been too slow to act in regulating misuse and overuse of antibiotics in foodproducing animals. This problem will only worsen with the significant projected growth in meat consumption and production expected in emerging economies in the near future. Although individual countries regulating antibiotics can have important effects, one country alone cannot insulate itself entirely from the effects of antibiotic resistance, nor can one country solve the crisis for itself or for the world. The global nature of the food system and the urgency of the problem require immediate global solutions. Adapting a democratic experimentalist approach at the international level can help achieve this goal. Using an international democratic experimentalist framework in conjunction with the World Organization for Animal Health (OIE) would provide for increased systematized data collection and lead to heightened, scientifically informed OIE standards, enforceable by the World Trade Organization (WTO), which could have a significant impact on the reduction of subtherapeutic use of antibiotics internationally. International democratic experimentalism addresses the global intricacy, time sensitivity, context- and culture-specificity, and knowledgeintensiveness of this problem. By encouraging more countries to experiment to solve this problem, the democratic experimentalist model would help develop a larger database of solutions to enable more meaningful cross-country comparisons across a wider range of contexts. This approach maintains democratic governance and legitimacy while maximizing data collection, efficiency, translatability, transparency, and information-sharing. Adapting democratic experimentalism internationally can enable the kind of concerted international effort required to address the pressing problem of antibiotic resistance. PMID- 29140662 TI - Re-Framing Biotechnology Regulation. AB - Biotechnology is about to spill the banks of federal regulation. New genetic engineering techniques like CRISPR-Cas9 promise revolutionary breakthroughs in medicine, agriculture, and public health-but those techniques would not be regulated under the terms of the Coordinated Framework for Regulation of Biotechnology. This revolutionary moment in biotechnology offers an opportunity to correct the flaws in the framework, which was hastily patched together at the advent of the technology. The framework has never captured all relevant technologies, has never satisfied the public that risk is being effectively managed, and has never been accessible to small companies and publicly-funded labs that increasingly are positioned to make radical, life-saving innovations. This Article offers a proposal for new legislation that would reshape biotechnology regulation to better meet these goals. Key reforms include tying regulation to risk rather than technology category; consolidating agency review; capturing distinct regulatory expertise through inter-agency consultations; creating a clearinghouse to help guide applicants and disseminate information; setting up more comprehensive monitoring of environmental effects; and providing federal leadership to fill key data gaps and address socio-economic impacts. PMID- 29140663 TI - A Recipe for Justice: Support for a Federal Food Justice Interagency Working Group. AB - Systemic social justice issues are characterized as having complex and far reaching causes. Food justice is one such an issue. Food justice is defined as "justice for all [people] in the food system," from agricultural production to consumer products. Policies seeking to remedy systemic social justice issues often need to include the attention of many levels of government and coordination across multiple agencies to move issues forward. That is why finding a model for interagency collaboration that has evidenced success, especially over the long term, is inspiring and worth mirroring.This Comment compares food justice to the environmental justice movement, and proposes modeling a federal, interagency program to address food justice based on the Environmental Protection Agency's Environmental Justice Interagency Working Group (EJ IWG). This Comment includes an overview of the food justice movement, and argues that the U.S. Department of Agriculture (USDA), despite its history of civil rights violations, would be the best federal agency to lead an interagency working group because it administers essential rural development and consumer programs. It also explores whether the model employed by the Environmental Protection Agency's EJ IWG is a viable model for a food justice program at the USDA, and what features of the EJ IWG would suit such a food justice interagency working group. PMID- 29140674 TI - Triptycene-Based Microporous Cyanate Resins for Adsorption/Separations of Benzene/Cyclohexane and Carbon Dioxide Gas. AB - Triptycene-based cyanate monomers 2,6,14-tricyanatotriptycene (TPC) and 2,6,14 tris(4-cyanatophenyl)triptycene (TPPC) that contain different numbers of benzene rings per molecule were synthesized, from which two microporous cyanate resins PCN-TPC and PCN-TPPC were prepared. Of interest is the observation that the two polymers have very similar porosity parameters, but PCN-TPPC uptakes considerably higher benzene (77.8 wt %) than PCN-TPC (17.6 wt %) at room temperature since the higher concentration of phenyl groups in PCN-TPPC enhances the pi-pi interaction with benzene molecules. Besides, the adsorption capacity of benzene in PCN-TPPC is dramatically 7 times as high as that of cyclohexane. Contrary to the adsorption of organic vapors, at 273 K and 1.0 bar, PCN-TPC with more heteroatoms in the network skeleton displays larger uptake of CO2 and higher CO2/N2 selectivity (16.4 wt %, 60) than those of PCN-TPPC (14.0 wt %, 39). The excellent and unique adsorption properties exhibit potential applications in the purification of small molecular organic hydrocarbons, e.g., separation of benzene from benzene/cyclohexane mixture as well as CO2 capture from flue gas. Moreover, the results are helpful for deeply understanding the effect of porous and chemical structures on the adsorption properties of organic hydrocarbons and CO2 gas. PMID- 29140675 TI - Identification of Novel Allosteric Modulators of Glutamate Transporter EAAT2. AB - Dysfunction of excitatory amino acid transporters (EAATs) has been implicated in the pathogenesis of various neurological disorders, such as stroke, brain trauma, epilepsy, and neurodegenerative diseases, among others. EAAT2 is the main subtype responsible for glutamate clearance in the brain, having a key role in regulating transmission and preventing excitotoxicity. Therefore, compounds that increase the expression or activity of EAAT2 have therapeutic potential for neuroprotection. Previous studies identified molecular determinants for EAAT2 transport stimulation in a structural domain that lies at the interface of the rigid trimerization domain and the central substrate binding transport domain. In this work, a hybrid structure based approach was applied, based on this molecular domain, to create a high-resolution pharmacophore. Subsequently, virtual screening of a library of small molecules was performed, identifying 10 hit molecules that interact at the proposed domain. Among these, three compounds were determined to be activators, four were inhibitors, and three had no effect on EAAT2-mediated transport in vitro. Further characterization of the two best ranking EAAT2 activators for efficacy, potency, and selectivity for glutamate over monoamine transporters subtypes and NMDA receptors and for efficacy in cultured astrocytes is demonstrated. Mutagenesis studies suggest that the EAAT2 activators interact with residues forming the interface between the trimerization and transport domains. These compounds enhance the glutamate translocation rate, with no effect on substrate interaction, suggesting an allosteric mechanism. The identification of these novel positive allosteric modulators of EAAT2 offers an innovative approach for the development of therapies based on glutamate transport enhancement. PMID- 29140676 TI - Synthesis of Large-Area Tungsten Disulfide Films on Pre-Reduced Tungsten Suboxide Substrates. AB - We report a facile method for the synthesis of large-area tungsten disulfide (WS2) films by means of chemical vapor deposition (CVD). To promote WS2 film growth, the precursor solution, which includes pre-reduced tungsten suboxides, is prepared by using hydrazine as the strong reducing agent and spin-coated onto the growth substrate. Growth is then carried out in a CVD chamber vaporized with dimethyl disulfide as the sulfur precursor. Although only WS2 flakes are grown with unreduced tungsten precursors under a hydrogen atmosphere, WS2 films are readily attained on pre-reduced tungsten suboxide substrates without the need for further reduction by hydrogen, which is noted to induce discontinuity of the grown film. The result presents the coverage of WS2 to be proportional to the amount of reduced tungsten suboxides, which is revealed by X-ray photoelectron spectroscopy. Furthermore, it is found that the multilayer WS2 flakes grow along the grain boundary, which allows the analysis of the grain size of WS2 films by optical microscopy images only. WS2 field effect transistors are fabricated by conventional photolithography and show an average electron mobility of 0.4 cm2 V 1 s-1 and a high on/off ratio of 106 at room temperature. PMID- 29140677 TI - Synthesis of Multi-Au-Nanoparticle-Embedded Mesoporous Silica Microspheres as Self-Filtering and Reusable Substrates for SERS Detection. AB - Surface-enhanced Raman-scattering-based (SERS-based) biosensing in biological fluids is constrained by nonspecific macromolecule adsorptions and disposable property of the SERS substrate. Here, novel multi-Au-nanoparticle-embedded mesoporous silica microspheres (AuNPs/mSiO2) were prepared using a one-pot method, which served as reliable substrates for SERS enhancement associated with salient features of self-filtering ability and reusability. The fabrication and physical characterization of AuNPs/mSiO2 microspheres were discussed, and SERS activity of this novel substrate was investigated by using 4-mercaptobenzoic acid (4-MBA) as Raman probe. The responses of our substrates to Raman intensities exhibited a SERS enhancement factor of 2.01 * 107 and high reproducibility (relative standard deviation of 6.13%). Proof-of-concept experiments were designed to evaluate the self-filtering ability of the substrates in bovine serum albumin (BSA) and human serum solution, separately. The results clearly demonstrate that mesoporous SiO2 can serve as a molecular sieve via size exclusion and avoid Raman signal interference of biomacromolecules in biological fluids. Subsequently, feasibility of practical application of AuNPs/mSiO2 microspheres was assessed by quantitative detection of methotrexate (MTA) in serum. The method exhibited good linearity between 1 and 110 nM with the correlation coefficients of 0.996, which proved that the obtained AuNPs/mSiO2 microspheres were good SERS substrates for determination of small biomolecules directly in biological fluids without need of manipulating samples. In addition, the substrate maintained its SERS response during multiple cycles, which was evaluated by recording Raman signals for 4-MBA before and after thermal annealing, thereby demonstrating the high thermostability and satisfactory reusability. These results offered the AuNPs/mSiO2 microspheres attractive advantages in their SERS biosensing. PMID- 29140678 TI - Robust Superhydrophobic Carbon Nanotube Film with Lotus Leaf Mimetic Multiscale Hierarchical Structures. AB - Superhydrophobic carbon nanotube (CNT) films have demonstrated many fascinating performances in versatile applications, especially for those involving solid/liquid interfacial processes, because of their ability to affect the material/energy transfer at interfaces. Thus, developing superhydrophobic CNTs has attracted extensive research interests in the past decades, and it could be achieved either by surface coating of low-free energy materials or by constructing micro/nanohierarchical structures via various complicated processes. So far, developing a simple approach to fabricate stable superhydrophobic CNTs remains a challenge because the capillary force induced coalescence frequently happens when interacting with liquid. Herein, drawing inspirations from the lotus leaf, we proposed a simple one-step chemical vapor deposition approach with programmable controlled gas flow to directly fabricate a CNT film with rather stable superhydrophobicity, which can effectively prevent even small water droplets from permeating into the film. The robust superhydrophobicity was attributable to typical lotus-leaf-like micro/nanoscale hierarchical surface structures of the CNT film, where many microscale clusters composed of entangled nanotubes randomly protrude out of the under-layer aligned nanotubes. Consequently, dual-scale air pockets were trapped within each microscale CNT cluster and between, which could largely reduce the liquid/solid interface, leading to a Cassie state. Moreover, the superhydrophobicity of the CNT film showed excellent durability after long time exposure to air and even to corrosive liquids with a wide range of pH values. We envision that the approach developed is advantageous for versatile physicochemical interfacial processes, such as drag reduction, electrochemical catalysis, anti-icing, and biosensors. PMID- 29140679 TI - Green Approach to Improving the Strength and Flame Retardancy of Poly(vinyl alcohol)/Clay Aerogels: Incorporating Biobased Gelatin. AB - Biobased gelatins were used to improve the compressive properties and flammability of poly(vinyl alcohol)/montmorillonite (PVA/MMT) aerogels, fabricated using a simple and environmentally friendly freeze-drying method. Because of the excellent compatibility and strong interfacial adhesion between PVA and gelatin, the compressive moduli of aerogels were enhanced dramatically with the incorporation of gelatin. PVA/MMT/porcine-gelatin aerogels exhibit compressive modulus values as much as 12.4 MPa, nearly 300% that of the control PVA/MMT aerogel. The microstructure of the PVA/MMT/gelatin aerogels shows a three dimensional co-continuous network. Combustion testing demonstrated that with the addition of gelatin, the self-extinguishing time of the aerogel was cut by half and the limiting-oxygen-index values increased to 28.5%. The peak heat-release rate, obtained from cone calorimetry, also decreased with the incorporation of gelatin. Thermogravimetric analysis demonstrated that the gelatins slowed the sharp decomposition of the PVA matrix polymer and increased the thermal stability of the aerogels at the major decomposition stage of the composite aerogels. These results indicate that as a green, biobased material, gelatin could simultaneously improve the mechanical properties and the properties of flame retardancy. PMID- 29140680 TI - Helicity Inversion of Supramolecular Hydrogels Induced by Achiral Substituents. AB - Probing the supramolecular chirality of assemblies and controlling their handedness are closely related to the origin of chirality at the supramolecular level and the development of smart materials with desired handedness. However, it remains unclear how achiral residues covalently bonded to chiral amino acids can function in the chirality inversion of supramolecular assemblies. Herein, we report macroscopic chirality and dynamic manipulation of chiroptical activity of hydrogels self-assembled from phenylalanine derivatives, together with the inversion of their handedness achieved solely by exchanging achiral substituents between oligo(ethylene glycol) and carboxylic acid groups. This helicity inversion is mainly induced by distinct stacking mode of the self-assembled building blocks, as collectively confirmed by scanning electron microscopy, circular dichroism, crystallography, and molecular dynamics calculations. Through this straightforward approach, we were able to invert the handedness of helical assemblies by merely exchanging achiral substituents at the terminal of chiral gelators. This work not only presents a feasible strategy to achieve the handedness inversion of helical nanostructures for better understanding of chiral self-assembly process in supramolecular chemistry but also facilities the development of smart materials with controllable handedness in materials science. PMID- 29140681 TI - Orthogonal Operation of Constitutional Dynamic Networks Consisting of DNA-Tweezer Machines. AB - Overexpression or down-regulation of cellular processes are often controlled by dynamic chemical networks. Bioinspired by nature, we introduce constitutional dynamic networks (CDNs) as systems that emulate the principle of the nature processes. The CDNs comprise dynamically interconvertible equilibrated constituents that respond to external triggers by adapting the composition of the dynamic mixture to the energetic stabilization of the constituents. We introduce a nucleic acid-based CDN that includes four interconvertible and mechanically triggered tweezers, AA', BB', AB' and BA', existing in closed, closed, open, and open configurations, respectively. By subjecting the CDN to auxiliary triggers, the guided stabilization of one of the network constituents dictates the dynamic reconfiguration of the structures of the tweezers constituents. The orthogonal and reversible operations of the CDN DNA tweezers are demonstrated, using T-A.T triplex or K+-stabilized G-quadruplex as structural motifs that control the stabilities of the constituents. The implications of the study rest on the possible applications of input-guided CDN assemblies for sensing, logic gate operations, and programmed activation of molecular machines. PMID- 29140682 TI - Molecular Patterning and Directed Self-Assembly of Gold Nanoparticles on GaAs. AB - The ability to create micro-/nanopatterns of organic self-assembled monolayers (SAMs) on semiconductor surfaces is crucial for fundamental studies and applications in a number of emerging fields in nanoscience. Here, we demonstrate the direct patterning of thiolate SAMs on oxide-free GaAs surface by dip-pen nanolithography (DPN) and microcontact printing (MUCP), facilitated by a process of surface etching and passivation of the GaAs. A quantitative analysis on the molecular diffusion on GaAs was conducted by examining the writing of nanoscale dot and line patterns by DPN, which agrees well with surface diffusion models. The functionality of the patterned thiol molecules was demonstrated by directed self-assembly of gold nanoparticles (Au NPs) onto a template of 4-aminothiophenol (ATP) SAM on GaAs. The highly selective assembly of the Au NPs was made evident with atomic force microscopy (AFM) and scanning electron microscopy (SEM). The ability to precisely control the assembly of Au NPs on oxide-free semiconductor surfaces using molecular templates may lead to an efficient bottom-up method for the fabrication of nanoplasmonic structures. PMID- 29140683 TI - Nanocomposite Phosphor Consisting of CaI2:Eu2+ Single Nanocrystals Embedded in Crystalline SiO2. AB - High luminescence efficiency is obtained in halide- and chalcogenide-based phosphors, but they are impractical because of their poor chemical durability. Here we report a halide-based nanocomposite phosphor with excellent luminescence efficiency and sufficient durability for practical use. Our approach was to disperse luminescent single nanocrystals of CaI2:Eu2+ in a chemically stable, translucent crystalline SiO2 matrix. Using this approach, we successfully prepared a nanocomposite phosphor by means of self-organization through a simple solid-state reaction. Single nanocrystals of 6H polytype (thr notation) CaI2:Eu2+ with diameters of about 50 nm could be generated not only in a SiO2 amorphous powder but also in a SiO2 glass plate. The nanocomposite phosphor formed upon solidification of molten CaI2 left behind in the crystalline SiO2 that formed from the amorphous SiO2 under the influence of a CaI2 flux effect. The resulting nanocomposite phosphor emitted brilliant blue luminescence with an internal quantum efficiency up to 98% upon 407 nm violet excitation. We used cathodoluminescence microscopy, scanning transmission electron microscopy, and Rietveld refinement of the X-ray diffraction patterns to confirm that the blue luminescence was generated only by the CaI2:Eu2+ single nanocrystals. The phosphor was chemically durable because the luminescence sites were embedded in the crystalline SiO2 matrix. The phosphor is suitable for use in near-ultraviolet light-emitting diodes. The concept for this nanocomposite phosphor can be expected to be effective for improvements in the practicality of poorly durable materials such as halides and chalcogenides. PMID- 29140684 TI - Janus Gold Nanoplatform for Synergetic Chemoradiotherapy and Computed Tomography Imaging of Hepatocellular Carcinoma. AB - There is a pressing need to develop nanoplatforms that integrate multimodal therapeutics to improve treatment responses and prolong the survival of patients with unresectable hepatocellular carcinoma (HCC). Mesoporous silica-coated gold nanomaterials have emerged as a novel multifunctional platform combining tunable surface plasmon resonance and mesoporous properties that exhibit multimodality properties in cancer theranostics. However, their reduced radiation-absorption efficiency and limited surface area hinder their further radiochemotherapeutic applications. To address these issues, we designed Janus-structured gold mesoporous silica nanoparticles using a modified sol-gel method. This multifunctional theranostic nanoplatform was subsequently modified via the conjugation of folic acid for enhanced HCC targeting and internalization. The loaded anticancer agent doxorubicin can be released from the mesopores in a pH responsive manner, facilitating selective and safe chemotherapy. Additionally, the combination of chemotherapy and radiotherapy induced synergistic anticancer effects in vitro and exhibited remarkable inhibition of tumor growth in vivo along with significantly reduced systematic toxicity. Additionally, the Janus NPs acted as targeted computed tomography (CT)-imaging agents for HCC diagnosis. Given their better performance in chemoradiotherapy and CT imaging as compared with that of their core-shell counterparts, this new nanoplatform designed with dual functionalities provides a promising strategy for unresectable HCC theranostics. PMID- 29140685 TI - Heterogeneous Ti3SiC2@C-Containing Na2Ti7O15 Architecture for High-Performance Sodium Storage at Elevated Temperatures. AB - Rational design of heterogeneous electrode materials with hierarchical architecture is a potential approach to significantly improve their energy densities. Herein, we report a tailored microwave-assisted synthetic strategy to create heterogeneous hierarchical Ti3SiC2@C-containing Na2Ti7O15 (MAX@C-NTO) composites as potential anode materials for high-performance sodium storage in a wide temperature range from 25 to 80 degrees C. This composite delivers first reversible capacities of 230 mAh g-1 at 200 mA g-1 and 149 mAh g-1 at 3000 mA g-1 at 25 degrees C. A high capacity of ~93 mAh g-1 without any apparent decay even after more than 10 000 cycles is obtained at an ultrahigh current density of 10 000 mA g-1. Moreover, both a high reversible capacity and an ultralong durable stability are achieved below 60 degrees C for the same composites, wherein a 75.2% capacity retention (~120 mAh g-1 at 10 000 mA g-1) is achieved after 3000 cycles at 60 degrees C. To the best of our knowledge, both the sodium storage performances and the temperature tolerances outperform those of all the Ti-based sodium storage materials reported so far. The superior sodium storage performances of the as-synthesized composites are attributed to the heterogeneous core-shell architecture, which not only provides fast kinetics by high pseudocapacitance but also prolongs cycling life by preventing particle agglomeration and facilitates the transportation of electrons and sodium ions by large micro/mesopore structure. PMID- 29140686 TI - Regulatory Mechanism of Mycobacterium tuberculosis Phosphoserine Phosphatase SerB2. AB - Almost all organisms contain the same biosynthetic pathway for the synthesis of l serine from the glycolytic intermediate, d-3-phosphoglycerate. However, regulation of this pathway varies from organism to organism. Many organisms control the activity of the first enzyme in the pathway, d-3-phosphoglycerate dehydrogenase (PGDH), by feedback inhibition through the interaction of l-serine with the ACT domains within the enzyme. The last enzyme in the pathway, phosphoserine phosphatase (PSP), has also been reported to be inhibited by l serine. The high degree of sequence homology between Mycobacterium tuberculosis PSP (mtPSP) and Mycobacterium avium PSP (maPSP), which has recently been shown to contain ACT domains, suggested that the mtPSP also contained ACT domains. This raised the question of whether the ACT domains in mtPSP played a functional role similar to that of the ACT domains in PGDH. This investigation reveals that l serine allosterically inhibits mtPSP by a mechanism of partial competitive inhibition by binding to the ACT domains. Therefore, in mtPSP, l-serine is an allosteric feedback inhibitor that acts by decreasing the affinity of the substrate for the enzyme. mtPGDH is also feedback inhibited by l-serine, but only in the presence of millimolar concentrations of phosphate. Therefore, the inhibition of mtPSP by l-serine would act as a secondary control point for the regulation of the l-serine biosynthetic pathway under physiological conditions where the level of phosphate would be below that needed for l-serine feedback inhibition of mtPGDH. PMID- 29140687 TI - Experimental and Theoretical Approach to Variable Chlorination-Promoted Skeletal Transformations in Fullerenes: The Case of C102. AB - The first example of three alternative chlorination-promoted skeletal transformation pathways in the same fullerene cage is presented. Isolated pentagon-rule (IPR) C102(19) undergoes both Stone-Wales rotations to give non-IPR #283794C102Cl20 and C2 losses to form nonclassical C98 and non-IPR C96. X-ray structural characterization of the transformation products and a theoretical study of their formation pathways are reported. PMID- 29140688 TI - RNA Chemical Proteomics Reveals the N6-Methyladenosine (m6A)-Regulated Protein RNA Interactome. AB - Epitranscriptomic RNA modifications can regulate mRNA function; however, there is a major gap in our understanding of the biochemical mechanisms mediating their effects. Here, we develop a chemical proteomics approach relying upon photo-cross linking with synthetic diazirine-containing RNA probes and quantitative proteomics to profile RNA-protein interactions regulated by N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic RNA. In addition to identifying YTH domain-containing proteins and ALKBH5, known interactors of this modification, we find that FMR1 and LRPPRC, two proteins associated with human disease, "read" this modification. Surprisingly, we also find that m6A disrupts RNA binding by the stress granule proteins G3BP1/2, USP10, CAPRIN1, and RBM42. Our work provides a general strategy for interrogating the interactome of RNA modifications and reveals the biochemical mechanisms underlying m6A function in the cell. PMID- 29140689 TI - Tissue Inhibitor of Metalloprotease-2 (TIMP-2): Bioprocess Development, Physicochemical, Biochemical, and Biological Characterization of Highly Expressed Recombinant Protein. AB - Tissue inhibitor of metalloprotease-2 (TIMP-2) is a secreted 21 kDa multifunctional protein first described as an endogenous inhibitor of matrix metalloproteinases (MMPs) that prevents breakdown of the extracellular matrix often observed in chronic diseases. TIMP-2 diminishes the level of growth factor mediated cell proliferation in vitro, as well as neoangiogenesis and tumor growth in vivo independent of its MMP inhibitory activity. These physiological properties make TIMP-2 an excellent candidate for further preclinical development as a biologic therapy of cancer. Here we present a straightforward bioprocessing methodology that yields >35 mg/L recombinant human TIMP-2 6XHis-tagged protein (rhTIMP-2) from suspension cultures of HEK-293-F cells. Enhanced rhTIMP-2-6XHis yields were achieved by optimization of both TIMP-2 cDNA codon sequence and cell culture conditions. Using a two-step chromatographic process, we achieved >95% purity with minimal processing losses. Purified rhTIMP-2-6XHis was free of mouse antigen contamination. Circular dichroism spectroscopy indicated a well-folded rhTIMP-2-6XHis that is highly stable and refractory to pH changes. Two dimensional heteronuclear single-quantum coherence nuclear magnetic resonance of full length rhTIMP-2-6XHis also indicated a monodisperse, well-folded protein preparation. Purified rhTIMP-2-6XHis inhibited MMP-2 enzymatic activity in a dose dependent fashion with an IC50 of ~1.4 nM. Pretreatment of A549 lung cancer and JygMC(A) triple-negative breast cancer cells with rhTIMP-2-6XHis in low-nanomolar amounts inhibited EGF-induced proliferation to basal (unstimulated) levels. This study therefore not only offers a robust bioprocess methodology for rhTIMP-2 production but also characterizes critical physicochemical and biological attributes that are useful for monitoring quality control of the production process. PMID- 29140690 TI - New Sesquiterpenoids from Eugenia jambolana Seeds and Their Anti-microbial Activities. AB - Twenty four sesquiterpenoids, 1-24, including 11 new sesquiterpenoids, jambolanins A-K, and two new norsesquiterpenoids, jambolanes A and B, along with six known triterpenoids, were isolated from the seeds of Eugenia jambolana fruit. Their structures were elucidated on the basis of NMR and MS spectrometry data analysis. Among the isolates, compound 13 possessed a rare 6,7-seco-guaiene skeleton, and compounds 14 and 15 were norsesquiterpenoids containing a spiro[4.4]nonane skeleton. Antimicrobial assay evaluation revealed that sesquiterpenoids, 4, 5/6, 17, 19, 21, 23, and 24 inhibited the growth of the Gram positive bacterium, Staphylococcus aureus. The current study advances scientific knowledge of E. jambolana phytochemicals and suggests that its sesquiterpenoids may contribute, in part, to the anti-infective effects attributed to the edible fruit of this plant. PMID- 29140691 TI - Importance of Rigidity in Designing Small Molecule Drugs To Tackle Protein Protein Interactions (PPIs) through Stabilization of Desired Conformers. AB - Tackling PPIs, particularly by stabilizing clinically favored conformations of target proteins, with orally available, bona fide small molecules remains a significant but immensely worthwhile challenge for the pharmaceutical industry. Success may be more likely through the application of nature's learnings to build intrinsic rigidity into the design of clinical candidates. PMID- 29140692 TI - Synthesis of Surface-Analogue Square-Planar Tetranuclear Nickel Hydride Clusters and Bonding to MU4-NR, -O and -BH Ligands. AB - Tetranuclear Ni complexes were synthesized with bonding to BH, NR, and O in atypical surface-like geometries. The previously reported electron-deficient cluster [( iPr3P)Ni]5H6 (1) reacts with N-methylmorpholine oxide to give [( iPr3P)Ni]4H4(MU4-O) (2), which contains O coordinated in the center of a square plane arrangement of Ni atoms. Reaction of 1 with benzonitrile gave the square planar tetranuclear Ni cluster [( iPr3P)Ni]4H4(MU4-NCH2Ph) (3), which contains an imido donor in a square-based-pyramidal geometry. This reaction also gives [( iPr3P)Ni(N=CPh)]3 (4), with bridging benzonitrile ligands. Trimer 4 was independently synthesized from the reaction of Ni(COD)2, iPr3P, and PhC=N. The addition of dihydrogen to a 1:1 mixture of [( iPr3P)2Ni]2(N2) and ( iPr3P)2NiCl2 yielded [( iPr3P)Ni]4(MU3-H)4(MU2-Cl)2 (5), with a tetrahedral Ni core, in contrast to the square-planar geometries of 2 and 3. The solid-state structure of 5 was determined using both X-ray and neutron diffraction. Reaction of 5 with LiBH4 gave [( iPr3P)Ni]4H4(MU4-BH)2] (6) via loss of LiCl and H2. PMID- 29140693 TI - Nonadiabatic Dynamics of Cycloparaphenylenes with TD-DFTB Surface Hopping. AB - We implemented a version of the decoherence-corrected fewest switches surface hopping based on linear-response time-dependent density functional tight binding (TD-DFTB), enhanced by transition density analysis. The method has been tested for the gas-phase relaxation dynamics of two cycloparaphenylene molecules, [8]CPP and [10]CPP, explaining some important features of their nonadiabatic dynamics, such as the origin of their long fluorescence lifetimes (related to the slow radiative emission from the S1 state) and the trend of increasing the fluorescence rate with the molecular size (related to an increase in the S1-S0 energy gaps and oscillator strengths in the larger molecule). The quality of the TD-DFTB electronic structure information was assessed through four quantities: excitation energies; charge-transfer (CT) numbers, which estimate the charge transfer character of states; participation ratio (PR), which describes delocalization of electronic density; and participation ratio of natural transition orbitals (PRNTO), which describes the multiconfigurational character of states. These quantities were computed during dynamics and recomputed for the same geometries with the higher-level long-range-corrected TD-LC-DFTB and a lower level single-determinant approximation for the excited states, SD-(LC)-DFTB. Taking TD-LC-DFTB as the standard, TD-DFTB underestimates the excitation energies by ~0.5 eV and overestimates CT and PR. SD-DFTB underestimates excitation energies and overestimates CT to the same extent that TD-DFTB does, but it predicts reasonable PR distributions. SD-LC-DFTB leads to an extreme overestimation of the excitation energies by ~3 eV, overestimates the charge transfer character of the state, but predicts the PR values very close to those obtained with TD-LC-DFTB. PMID- 29140694 TI - Tyrocidine A Analogues Bearing the Planar d-Phe-2-Abz Turn Motif: How Conformation Impacts Bioactivity. AB - The d-Phe-Pro beta-turn of the cyclic beta-hairpin antimicrobial decapeptide tyrocidine A, (Tyrc A) was substituted with the d-Phe-2-aminobenzoic acid (2-Abz) motif in a synthetic analogue (1). The NMR structure of 1 demonstrated that compound 1 retained the beta-hairpin structure of Tyrc A with additional planarity, resulting in approximately 30-fold reduced hemolysis than Tyrc A. Although antibacterial activity was partially compromised, a single Gln to Lys substitution (2) restored activity equivalent to Tyrc A against S. aureus, enhanced activity against two Gram negative strains and maintained the reduced hemeloysis of 1. Analysis by transmission electron microscopy (TEM) suggested a membrane lytic mechanism of action for these peptides. Compound 2 also exhibits nanomolar antifungal activity in synergy with amphotericin B. The d-Phe-2-Abz turn may serve as a tool for the synthesis of structurally predictable beta hairpin libraries. Unlike traditional beta-turn motifs such as d-Pro-Gly, both the 2-Abz and d-Phe rings may be further functionalized. PMID- 29140695 TI - RNA G-Quadruplexes in Kirsten Ras (KRAS) Oncogene as Targets for Small Molecules Inhibiting Translation. AB - The human KRAS transcript contains a G-rich 5'-UTR sequence (77% GC) harboring several G4 motifs capable to form stable RNA G-quadruplex (RG4) structures that can serve as targets for small molecules. A biotin-streptavidin pull-down assay showed that 4,11-bis(2-aminoethylamino)anthra[2,3-b]furan-5,10-dione (2a) binds to RG4s in the KRAS transcript under low-abundance cellular conditions. Dual luciferase assays demonstrated that 2a and its analogue 4,11-bis(2 aminoethylamino)anthra[2,3-b]thiophene-5,10-dione (2b) repress translation in a dose-dependent manner. The effect of the G4-ligands on Panc-1 cancer cells has also been examined. Both 2a and 2b efficiently penetrate the cells, suppressing protein p21KRAS to <10% of the control. The KRAS down-regulation induces apoptosis together with a dramatic reduction of cell growth and colony formation. In summary, we report a strategy to suppress the KRAS oncogene in pancreatic cancer cells by means of small molecules binding to RG4s in the 5'-UTR of mRNA. PMID- 29140696 TI - Attosecond X-ray Diffraction Triggered by Core or Valence Ionization of a Dipeptide. AB - With the advancement of intense ultrafast X-ray sources, it is now possible to create a molecular movie by following the electronic dynamics in real time and real space through time-resolved X-ray diffraction. Here we employ real-time time dependent density functional theory (RT-TDDFT) to simulate the electronic dynamics after an impulse core or valence ionization in the glycine-phenylalanine (GF) dipeptide. The time-evolving dipole moment, the charge density, and the time resolved X-ray diffraction signals are calculated. The charge oscillation is calculated for 7 fs for valence ionization and 500 as for core ionization. The charge oscillation time scale is comparable to that found in a phenylalanine monomer (4 fs) [ Science 2014 , 346 , 336 ] and is slightly longer because of the elongated glycine chain. Following valence ionization, the charge migration across the GF is mediated by the delocalized lone-pair orbitals of oxygen and nitrogen of the electron-rich amide group. The temporal Fourier transform of the dipole moment provides detailed information on the charge migration dynamics and the molecular orbitals involved. Heterodyne-detected attosecond X-ray diffraction signals provide the magnitude and phase of the scattering amplitude in momentum space and can thus be inverted to yield the charge density in real space. PMID- 29140697 TI - Accurate Excited-State Geometries: A CASPT2 and Coupled-Cluster Reference Database for Small Molecules. AB - We present an investigation of the excited-state structural parameters determined for a large set of small compounds with the dual goals of defining reference values for further works and assessing the quality of the geometries obtained with relatively cheap computational approaches. In the first stage, we compare the excited-state geometries obtained with ADC(2), CC2, CCSD, CCSDR(3), CC3, and CASPT2 and large atomic basis sets. It is found that CASPT2 and CC3 results are generally in very good agreement with one another (typical differences of ca. 3 * 10-3 A) when all electrons are correlated and when the aug-cc-pVTZ atomic basis set is employed with both methods. In a second stage, a statistical analysis reveals that, on the one hand, the excited-state (ES) bond lengths are much more sensitive to the selected level of theory than their ground-state (GS) counterparts and, on the other hand, that CCSDR(3) is probably the most cost effective method delivering accurate structures. Indeed, CCSD tends to provide too compact multiple bond lengths on an almost systematic basis, whereas both CC2 and ADC(2) tend to exaggerate these bond distances, with more erratic error patterns, especially for the latter method. The deviations are particularly marked for the polarized CO and CN bonds, as well as for the puckering angle in formaldehyde homologues. In the last part of this contribution, we provide a series of CCSDR(3) GS and ES geometries of medium-sized molecules to be used as references in further investigations. PMID- 29140698 TI - Mutation-Induced Deamidation of Corneal Dystrophy-Related Transforming Growth Factor beta-Induced Protein. AB - Mutations in the transforming growth factor beta-induced protein (TGFBIp) cause phenotypically diverse corneal dystrophies, where protein aggregation in the cornea leads to severe visual impairment. Previous studies have shown a relationship between mutant-specific corneal dystrophy phenotypes and the thermodynamic stability of TGFBIp. Using liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance (NMR), we investigated correlations between the structural integrity of disease-related mutants of the fourth FAS1 domain (FAS1-4) and deamidation of TGFBIp residue Asn622. We observed a high rate of Asn622 deamidation in the A546D and A546D/P551Q FAS1-4 mutants that were both largely unstructured as determined by NMR. Conversely, the more structurally organized A546T and V624M FAS1-4 mutants had reduced deamidation rates, suggesting that a folded and stable FAS1-4 domain precludes Asn622 deamidation. Wild-type, R555Q, and R555W FAS1-4 mutants displayed very slow deamidation, which agrees with their similar and ordered NMR structures, where Asn622 is in a locked conformation. We confirmed the FAS1-4 mutational effect on deamidation rates in full-length TGFBIp mutants and found a similar ranking compared to that of the FAS1-4 domain alone. Consequently, the deamidation rate of Asn622 can be used to predict the structural effect of the many destabilizing and/or stabilizing mutations reported for TGFBIp. In addition, the deamidation of Asn622 may influence the pathophysiology of TGFBIp-induced corneal dystrophies. PMID- 29140699 TI - Size Consistent Excited States via Algorithmic Transformations between Variational Principles. AB - We demonstrate that a broad class of excited state variational principles is not size consistent. In light of this difficulty, we develop and test an approach to excited state optimization that transforms between variational principles to achieve state selectivity, size consistency, and compatibility with quantum Monte Carlo. To complement our formal analysis, we provide numerical examples that confirm these properties and demonstrate how they contribute to a more black box approach to excited states in quantum Monte Carlo. PMID- 29140700 TI - High-Pressure Behavior of Silver Fluorides up to 40 GPa. AB - A combined experimental-theoretical study of silver(I) and silver(II) fluorides under high pressure is reported. For AgI, the CsCl-type structure is stable to at least 39 GPa; the overtone of the IR-active mode is seen in the Raman spectrum. Its AgIIF2 sibling is a unique compound in many ways: it is more covalent than other known difluorides, crystallizes in a layered structure, and is enormously reactive. Using X-ray diffraction and guided by theoretical calculations (density functional theory), we have been able to elucidate crystal structures of high pressure polymorphs of AgF2. The transition from ambient pressure to an unprecedented nanotubular structure takes place via an intermediate orthorhombic layered structure, which lacks an inversion center. The observed phase transitions are discussed within the broader framework of the fluorite -> cotunnite -> Ni2In series, which has been seen for other metal difluorides. PMID- 29140702 TI - Influence of the Carotenoid Composition on the Conformational Dynamics of Photosynthetic Light-Harvesting Complexes. AB - Nonphotochemical quenching (NPQ) is the major self-regulatory mechanism of green plants, performed on a molecular level to protect them from an overexcitation during the direct sunlight. It is believed that NPQ becomes available due to conformational dynamics of the light-harvesting photosynthetic complexes and involves a direct participation of carotenoids. In this work, we perform a single molecule microscopy on major light-harvesting complexes (LHCII) from different Arabidopsis thaliana mutants exhibiting various carotenoid composition. We show how the distinct carotenoids affect the dynamics of the conformational switching between multiple coexisting light-emitting states of LHCII and demonstrate that properties of the quenched conformation are not influenced by the particular carotenoids available in LHCII. We also discuss the possible origin of different conformational states and relate them to the fluorescence decay kinetics observed during the bulk measurements. PMID- 29140703 TI - Synthesis of (2S)-2-Chloro-2-fluororibolactone via Stereoselective Electrophilic Fluorination. AB - A novel and efficient route for the preparation of (2S)-2-chloro-2-fluorolactone 29 is described. This approach takes advantage of a highly efficient diastereoselective electrophilic fluorination reaction (94% yield; >50:1 dr). PMID- 29140704 TI - Direct Observation of Splitting in Oil-In-Water-In-Oil Emulsion Droplets via a Microchannel Mimicking Membrane Pores. AB - Direct observation of double emulsion droplet permeation through a microchannel that mimicked 100 MUm membrane pores with a porosity of 66.7% provided insights regarding splitting mechanisms in porous membranes. The microchannel was fabricated by standard soft lithography, and the oil-in-water-in-oil double emulsion droplets were prepared with a glass capillary device. By changing the flow rate from 0.5 to 5.0 * 10-2 m s-1, three characteristic behaviors were observed: (a) passage into one channel without splitting; (b) division into two smaller components; and (c) stripping of the middle water phase of the double emulsion droplets into a smaller double emulsion droplet and a smaller water-in oil single emulsion droplet. The mechanisms are discussed with respect to the balance of viscous forces and interfacial tension, the contact point with the tip of the channel, and the relative position of the innermost droplet within the middle droplet. PMID- 29140701 TI - HYDROPHOBE Challenge: A Joint Experimental and Computational Study on the Host Guest Binding of Hydrocarbons to Cucurbiturils, Allowing Explicit Evaluation of Guest Hydration Free-Energy Contributions. AB - The host-guest complexation of hydrocarbons (22 guest molecules) with cucurbit[7]uril was investigated in aqueous solution using the indicator displacement strategy. The binding constants (103-109 M-1) increased with guest size, pointing to the hydrophobic effect and dispersion interactions as driving forces. The measured affinities provide unique benchmark data for the binding of neutral guest molecules. Consequently, a computational blind challenge, the HYDROPHOBE challenge, was conducted to allow a comparison with state-of-the-art computational methods for predicting host-guest affinity constants. In total, three quantum-chemical (QM) data sets and two explicit-solvent molecular dynamics (MD) submissions were received. When searching for sources of uncertainty in predicting the host-guest affinities, the experimentally known hydration energies of the investigated hydrocarbons were used to test the employed solvation models (explicit solvent for MD and COSMO-RS for QM). Good correlations were obtained for both solvation models, but a rather constant offset was observed for the COSMO data, by ca. +2 kcal mol-1, which was traced back to a required reference state correction in the QM submissions (2.38 kcal mol-1). Introduction of the reference-state correction improved the predictive power of the QM methods, particularly for small hydrocarbons up to C5. PMID- 29140705 TI - Cornusides A-O, Bioactive Iridoid Glucoside Dimers from the Fruit of Cornus officinalis. AB - Fifteen new and rare iridoid glucoside dimers, cornusides A-O (1-15), and 10 known iridoid glucosides (16-25) were isolated from the fruit of Cornus officinalis. These new chemical structures were established through spectroscopic analysis (UV, IR, HRESIMS, 1D and 2D NMR). Compounds 1-25 were tested for their inhibitory activities by measuring IL-6-induced STAT3 promoter activity in HepG2 cells, and 3, 12, 17, 22, and 23 showed inhibitory effects, with IC50 values of 11.9, 12.2, 14.0, 7.0, and 6.9 MUM, respectively. PMID- 29140706 TI - Galactosylated Pro-Drug of Ursodeoxycholic Acid: Design, Synthesis, Characterization, and Pharmacological Effects in a Rat Model of Estrogen-Induced Cholestasis. AB - Ursodeoxycholic acid (UDCA) is considered the first-choice therapy for cholestatic disorders. To enhance solubility and exploit specific transporters in liver, we synthesized a new galactosyl pro-drug of UDCA (UDCAgal). Ethinylestradiol (EE)-induced cholestasis was used to study and compare the effects of UDCAgal with UDCA on bile flow, hepatic canalicular efflux transporter expression, and inflammation. UDCAgal resulted quite stable both at pH 7.4 and 1.2 and regenerated the parent drug after incubation in human plasma. Its solubility, higher than UDCA, was pH- and temperature-independent. UDCAgal displayed a higher cell permeation compared to UDCA in liver HepG2 cells. Moreover, in cholestatic rats, UDCAgal showed a higher potency compared to UDCA in reducing serum biomarkers (AST, ALT, and ALP) and cytokines (TNF-alpha and IL 1beta). The higher effect of UDCAgal on the increase in bile salt export pump and multidrug resistance-associated protein 2 transcription indicated an improved spillover of bile acids from the liver. UDCAgal showed a reduction in CCL2, as well as TNF-alpha, IL-1beta, and cyclooxygeanse-2 mRNAs, indicating a reduction in hepatic neutrophil accumulation and inflammation. Moreover, UDCAgal, similarly to UDCA, heightens bile flow and modulates biliary acids secretion. These results indicate that UDCAgal has a potential in the treatment of cholestatic disease. PMID- 29140707 TI - Grapefruit Flavonoid Naringenin Regulates the Expression of LXRalpha in THP-1 Macrophages by Modulating AMP-Activated Protein Kinase. AB - The present work investigates the modulation of grapefruit flavonoid naringenin over liver X receptor alpha (LXRalpha) and its target genes in THP-1 macrophages, focusing on AMP-activated protein kinase (AMPK) implication. Naringenin induced LXRalpha at mRNA and protein levels besides influencing the expression of LXRalpha target genes ABCA1, ABCG1 (ATP-binding cassette A1 and G1), and SREBP1c (sterol response element binding protein 1c) in THP-1 macrophages. The increased LXRalpha mRNA and protein expression was reverted when AMPK was inhibited by its chemical inhibitor, compound C or by transfection with AMPK alpha1 and alpha2 siRNA. Naringenin treatments were also able to promote reverse cholesterol transport in THP-1 cells, which is in line with the increase in the ABCA1 and ABCG1 expression found. Treatments with this flavonoid also inhibited cell migration in THP-1 cells. In conclusion, LXRalpha and its target genes are up regulated by naringenin in an AMPK dependent manner in human macrophages. The enhancement in the expression of genes involved in cholesterol efflux may reveal a new mechanism by which this polyphenol can prevent atherosclerosis and foam cell progression. PMID- 29140708 TI - Role of Vapor Mass Transfer in Flow Coating of Colloidal Dispersions in the Evaporative Regime. AB - In flow-coating processes at low substrate velocity, solvent evaporation occurs during the film withdrawal and the coating process directly yields a dry deposit. In this regime, often referred to as the evaporative regime, several works performed on blade-coating-like configurations have reported a deposit thickness hd proportional to the inverse of the substrate velocity V. Such a scaling can be easily derived from simple mass conservation laws, assuming that evaporation occurs on a constant distance, referred to as the evaporation length, noted Lev in the present paper and of the order of the meniscus size. However, the case of colloidal dispersions deserves further attention. Indeed, the coating flow leads to a wet film of densely packed colloids before the formation of the dry deposit. This specific feature is related to the porous nature of the dry deposit, which can thus remain wet when capillary forces are strong enough to prevent the receding of the solvent through the pores of the film (the so-called pore emptying). The length of this wet film may possibly be much larger than the meniscus size, therefore modifying the solvent evaporation rate, as well as the scaling hd ~ 1/V. This result was suggested recently by different groups using basic modeling and assuming for simplicity a uniform evaporation rate over the wet film. In this article, we go a step further and investigate the effect of multidimensional vapor mass transfer in the gas phase on Lev and hd in the specific case of colloidal dispersions. Using simplified models, we first provide analytical expressions in asymptotic cases corresponding to 1D or 2D diffusive vapor transport. These theoretical investigations then led us to show that Lev is independent of the evaporation rate amplitude, and roughly independent of its spatial distribution. Conversely, hd strongly depends on the characteristics of vapor mass transfer in the gas phase, and different scaling laws are obtained for the 1D or the 2D case. These theoretical findings are finally tested by comparison with experimental results supporting our theoretical simplified approach. PMID- 29140709 TI - Tuning Anatase Surface Reactivity toward Carboxylic Acid Anchor Groups. AB - The effect of different post-treatments on TiO2 anatase surface reactivity was investigated in order to obtain the best techniques for enhancing anatase performance in diverse applications, e.g., in photocatalysis and especially as photoelectrodes for dye-sensitized solar cells (DSSCs). Different post-treatments of compact anodic anatase TiO2 were compared, including O2 plasma, UV irradiation, immersion in H2O2, vapor thermal treatment, and post-anodization, evaluating the increase of the amount of OH reactive groups on the surface and removal of surface contamination. In XPS spectra, the increase of OH groups is evident by the O 1s peak at higher binding energy. ToF-SIMS principal component analysis demonstrated that treatments performed in aqueous media led to a cleaner surface, with substantial removal of electrolyte residues. Stearic acid and the organic dye N719 were adsorbed to the differently post-treated anatase, and adsorption was evaluated by contact angle and dye desorption measurements. A higher loading with molecules containing carboxylic acid functionalities was confirmed by both techniques on the treated samples. The post-treatments that presented the highest amounts of dye were used to prepare photoelectrodes, and these were tested in DSSCs where the efficiency values doubled in comparison with the non-post-treated electrode. PMID- 29140710 TI - Transition-Metal-Free Intermolecular alpha-Arylation of Ketones via Enolonium Species. AB - Herein it is shown, for the first time, that enolonium species are powerful electrophiles capable of reacting with aromatic compounds in an intermolecular manner to afford alpha-arylated ketones. The reaction is compatible with a variety of functional groups, is of wide scope with respect to aromatic compounds and ketone, and even works for polymerization-prone substrates such as substituted pyrroles, thiophenes, and furans. Only 1.6 to 5 equiv of the commodity aromatic substrates is needed. PMID- 29140711 TI - Probing the Surface Charge on the Basal Planes of Kaolinite Particles with High Resolution Atomic Force Microscopy. AB - High-resolution atomic force microscopy is used to map the surface charge on the basal planes of kaolinite nanoparticles in an ambient solution of variable pH and NaCl or CaCl2 concentration. Using DLVO theory with charge regulation, we determine from the measured force-distance curves the surface charge distribution on both the silica-like and the gibbsite-like basal plane of the kaolinite particles. We observe that both basal planes do carry charge that varies with pH and salt concentration. The silica facet was found to be negatively charged at pH 4 and above, whereas the gibbsite facet is positively charged at pH below 7 and negatively charged at pH above 7. Investigations in CaCl2 at pH 6 show that the surface charge on the gibbsite facet increases for concentration up to 10 mM CaCl2 and starts to decrease upon further increasing the salt concentration to 50 mM. The increase of surface charge at low concentration is explained by Ca2+ ion adsorption, while Cl- adsorption at higher CaCl2 concentrations partially neutralizes the surface charge. Atomic resolution imaging and density functional theory calculations corroborate these observations. They show that hydrated Ca2+ ions can spontaneously adsorb on the gibbsite facet of the kaolinite particle and form ordered surface structures, while at higher concentrations Cl- ions will co adsorb, thereby changing the observed ordered surface structure. PMID- 29140712 TI - High Expression of UGT1A1/1A6 in Monkey Small Intestine: Comparison of Protein Expression Levels of Cytochromes P450, UDP-Glucuronosyltransferases, and Transporters in Small Intestine of Cynomolgus Monkey and Human. AB - Cynomolgus monkeys have been widely used for the prediction of drug absorption in humans. The purpose of this study was to clarify the regional protein expression levels of cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UGTs), and transporters in small intestine of cynomolgus monkey using liquid chromatography tandem mass spectrometry, and to compare them with the corresponding levels in human. UGT1A1 in jejunum and ileum were >4.57- and >3.11-fold and UGT1A6 in jejunum and ileum were >16.1- and >8.57-fold, respectively, more highly expressed in monkey than in human. Also, jejunal expression of monkey CYP3A8 (homologue of human CYP3A4) was >3.34-fold higher than that of human CYP3A4. Among apical drug efflux transporters, BCRP showed the most abundant expression in monkey and human, and the expression levels of BCRP in monkey and human were >1.74- and >1.25-fold greater than those of P-gp and >2.76- and >4.50-fold greater than those of MRP2, respectively. These findings should be helpful to understand species differences of the functions of CYPs, UGTs, and transporters between monkey and human. The UGT1A1/1A6 data would be especially important because it is difficult to identify isoforms responsible for species differences of intestinal glucuronidation by means of functional studies due to overlapping substrate specificity. PMID- 29140713 TI - Direct Observation of Plasmon-Induced Interfacial Charge Separation in Metal/Semiconductor Hybrid Nanostructures by Measuring Surface Potentials. AB - Plasmon-induced interfacial charge separation (PICS) is one of the key processes responsible for the improved conversion efficiencies of energy-harvesting devices that incorporate metal nanostructures. In this Letter, we reveal a mechanism of PICS by visualizing (with nanometer-scale resolution) and characterizing plasmon exciton coupling between p-type poly(pyrrole) (PPy) nanowires (NWs) and Ag nanoparticles (NPs) using light-irradiated Kelvin probe force microscopy (KPFM). Under blue-light irradiation, the Ag NPs are expected to donate electrons to the PPy NWs via a hot electron injection process. However, in this Letter, we observe that under blue-light irradiation the plasmonically and excitonically excited electrons in the semiconductor back-transfer to the metal. The PICS in this system can be explained by comparing it with a similar one where Au NPs are attached to n-type ZnO NWs; we observed a net electron transfer from the Au NPs to the ZnO NWs (an upward band bending is formed at the interface of the two materials, presumably obstructing electron back-transfer). Indeed, energy band matching between the metal and the semiconductor components of hybrid nanostructures influences PICS pathways. These experimental findings and our proposed mechanism consistently explain the PICS occurring in the PPy NW-Ag NP system with important implications on explaining their cooperative optoelectronic activities. PMID- 29140714 TI - Copper-Catalyzed Dehydrogenative Formal [4 + 2] and [3 + 2] Cycloadditions of Methylnaphthalenes and Electron-Deficient Alkenes. AB - Higher pi-extended naphthalene, contained in methylnaphthalenes, which could capture alkyl radicals via SOMO-LUMO interactions, enabled the development of Cu catalyzed formal [4 + 2] and [3 + 2] cycloadditions between methylnaphthalenes and electron-deficient alkenes. Under copper catalysis, a series of electron deficient alkenes and methylnaphthalenes with different substituents were successfully incorporated with di-tert-butyl peroxide (TBP) as an oxidant and radical initiator, providing a wide range of cycloadducts. PMID- 29140715 TI - Measurement of Charge Transfer to Aqueous Droplets in High Voltage Electric Fields. AB - The electric charge acquired by aqueous droplets when they contact an electrode is a crucial parameter in experimental and industrial applications where electric fields are used to manipulate droplet motion and coalescence. For unclear reasons, many investigators have found that aqueous droplets acquire significantly more positive than negative charge. Extant techniques for determining the droplet charge typically rely on a hydrodynamic force balance that depends on accurate characterization of the drag forces acting on the droplet. Here we present an alternative methodology for measuring the droplet charge via direct measurement of the electric current. As the droplet approaches the electrode the current is observed to gradually increase, followed by a large pulse when the droplet makes apparent contact. We interpret the transient current signals as the superposition of the natural response of an RLC circuit and an induced current described by the Shockley-Ramo theory. Nonlinear regression of the observed current to the theoretical model allows for the droplet charge to be extracted, independent of any assumptions about the force balance on the droplet. We demonstrate that regression of the current signal yields charge values that are on average within 4% of charges measured via a force balance. We use the chronocoulometric methodology to investigate how the charge varies with the applied potential, and we demonstrate that deionized water droplets contacting planar electrodes acquire on average 69% more positive charge than negative charge. PMID- 29140716 TI - Transversely Divergent Second Harmonic Generation by Surface Plasmon Polaritons on Single Metallic Nanowires. AB - Coherently adding up signal wave from different locations are a prerequisite for realizing efficient nonlinear optical processes in traditional optical configurations. While nonlinear optical processes in plasmonic waveguides with subwavelength light confinement are in principle desirable for enhancing nonlinear effects, so far it has been difficult to improve the efficiency due to the large momentum mismatch. Here we demonstrate, using remotely excited surface plasmon polaritons (SPPs), axial collimated but transversely divergent second harmonic (SH) generation in a single silver nanowire-monolayer molybdenum disulfide hybrid system. Fourier imaging of the generated SH signal confirms the momentum conservation conditions between the incident and reflected SPPs and reveals distinct features inherent to the 1D plasmonic waveguides: (i) the SH photons are collimated perpendicular to the nanowire axis but are divergent within the perpendicular plane; (ii) the collimation (divergence) is inversely proportional to the length of the active region (lateral confinement of the SPPs); and (iii) the SH emission pattern resembles that of an aligned dipole chain on top of the substrate with an emission peak at the critical angle. Our results pave the way to generate and manipulate SH emission around subwavelength waveguides and open up new possibilities for realizing high efficiency on-chip nonlinear optics. PMID- 29140718 TI - PEM-fitter: A Coarse-Grained Method to Validate Protein Candidate Models. AB - The volumetric images produced by Cryo-Electron Microscopy (cryo-EM) technique are used to model macromolecular assemblies and machines. De novo protein modeling uses these images to computationally model the structure of the molecules. Many candidate conformations are usually generated during the intermediate step. Conventionally, each of these candidates is evaluated by time consuming approaches such as potential energy. We introduce an initial version of a geometrical screening method that uses the skeleton of the cryo-EM images to evaluate candidate structures. The aim of this method is to reduce the number of native-like candidate conformations and, therefore, reduce the time required for structural evaluation by energy calculations. A test of two datasets was performed. The first dataset contains 10 proteins and shows that our method can successfully detect the correct native structure for the given skeleton among a set of different protein structures. The second dataset contains 12 proteins and shows that our method can filter slightly modified decoy conformations of the same protein. The efficiency of the method is also reported. PMID- 29140719 TI - Effects of different etching methods and bonding procedures on shear bond strength of orthodontic metal brackets applied to different CAD/CAM ceramic materials. AB - OBJECTIVE: To investigate the shear bond strength (SBS) of orthodontic metal brackets applied to different types of ceramic surfaces treated with different etching procedures and bonding agents. MATERIALS AND METHODS: Monolithic CAD/CAM ceramic specimens (N = 120; n = 40 each group) of feldspathic ceramic Vita Mark II, resin nanoceramic Lava Ultimate, and hybrid ceramic Vita Enamic were fabricated (14 * 12 * 3 mm). Ceramic specimens were separated into four subgroups (n = 10) according to type of surface treatment and bonding onto the ceramic surface. Within each group, four subgroups were prepared by phosphoric acid, hydrofluoric acid, Transbond XT primer, and Clearfill Ceramic primer. Mandibular central incisor metal brackets were bonded with light-cure composite. The SBS data were analyzed using three-way analysis of variance (ANOVA) and Tukey HSD tests. RESULTS: The highest SBS was found in the Vita Enamic group, which is a hybrid ceramic, etched with hydrofluoric acid and applied Transbond XT Adhesive primer (7.28 +/- 2.49 MPa). The lowest SBS was found in the Lava Ultimate group, which is a resin nano-ceramic etched with hydrofluoric acid and applied Clearfill ceramic primer (2.20 +/- 1.21 MPa). CONCLUSIONS: CAD/CAM material types and bonding procedures affected bond strength ( P < .05), but the etching procedure did not ( P > .05). The use of Transbond XT as a primer bonding agent resulted in higher SBS. PMID- 29140720 TI - Relationship between voice function and skeletal effects of rapid maxillary expansion. AB - OBJECTIVE: To evaluate the effects of rapid maxillary expansion (RME) on the vocal quality, maxillary central incisors, midpalatal suture, and nasal cavity in patients with maxillary crossbite. MATERIALS AND METHODS: Coronal CT scans of 30 subjects (14 boys, 16 girls; mean age, 12.01 +/- 0.75) were taken before RME (T0), and at the end of the expansion phase (T1). Voice samples of all patients were recorded with a high-quality condenser microphone (RODE NT2-A) on a desktop computer at T0 and T1. Statistical analyses were performed using a paired-sample t-test. The degree of association between the changes in the voice parameters and nasal width was assessed with Pearson's correlation. RESULTS: RME treatment produced a significant increase in the transverse dimensions of the midpalatal suture and nasal cavity between T0 and T1 ( P < .05). The maximum F0 and jitter (%) results were shown to decrease statistically significantly from T0 to T1 ( P < .001 and P = .042, respectively). Between T0 and T1, shimmer (%) and shimmer (dB) exhibited statistically significant increases ( P = .037 and P = .019, respectively). CONCLUSIONS: After RME therapy, voice quality differences were found to be associated with increases in nasal width. PMID- 29140721 TI - Long-term stability of soft tissue changes in anterior open bite adults treated with zygomatic miniplate-anchored maxillary posterior intrusion. AB - OBJECTIVES: To evaluate soft tissue changes and their long-term stability in skeletal anterior open bite adults treated by maxillary posterior teeth intrusion using zygomatic miniplates and premolar extractions. MATERIALS AND METHODS: Lateral cephalograms of 26 patients were taken at pretreatment (T1), posttreatment (T2), 1 year posttreatment (T3), and 4 years posttreatment (T4). RESULTS: At the end of treatment, the soft tissue facial height and profile convexity were reduced. The lips increased in length and thickness, with backward movement of the upper lip and forward movement of the lower lip. The total relapse rate ranged from 20.2% to 31.1%. At 4 years posttreatment, 68.9% to 79.8% of the soft tissue treatment effects were stable. The changes in the first year posttreatment accounted for approximately 70% of the total relapse. CONCLUSIONS: Soft tissue changes following maxillary posterior teeth intrusion with zygomatic miniplates and premolar extractions appear to be stable 4 years after treatment. PMID- 29140723 TI - Abstracts of the HIV Research for Prevention Meeting, HIVR4P, 17-20 October, 2016, Chicago, USA. PMID- 29140722 TI - Reproductive Impacts of Endocrine-Disrupting Chemicals on Wildlife Species: Implications for Conservation of Endangered Species. AB - Wildlife have proven valuable to our understanding of the potential effects of endocrine-disrupting chemicals (EDCs) on human health by contributing considerably to our understanding of the mechanisms and consequences of EDC exposure. But the threats EDCs present to populations of wildlife species themselves are significant, particularly for endangered species whose existence is vulnerable to any reproductive perturbation. However, few studies address the threats EDCs pose to endangered species owing to challenges associated with their study. Here, we highlight those barriers and review the available literature concerning EDC effects on endangered species. Drawing from other investigations into nonthreatened wildlife species, we highlight opportunities for new approaches to advance our understanding and potentially mitigate the effects of EDCs on endangered species to enhance their fertility. PMID- 29140724 TI - The Significance of Eosinophilic Inflammation in Chronic Obstructive Pulmonary Disease. PMID- 29140725 TI - Reply to Cooper et al.: The Significance of Eosinophilic Inflammation in Chronic Obstructive Pulmonary Disease. PMID- 29140726 TI - Treatment Setting and Outcomes of Cystic Fibrosis Pulmonary Exacerbations. AB - RATIONALE: There are important gaps in knowledge of the optimal treatment of cystic fibrosis pulmonary exacerbations. Previous observational studies comparing inpatient with outpatient treatment have suffered from methodologic weaknesses, especially indication bias. OBJECTIVES: We analyzed data from the Epidemiologic Study of Cystic Fibrosis using techniques to control for indication bias to determine whether there is an advantage to inpatient treatment of cystic fibrosis pulmonary exacerbations. METHODS: We identified typical pulmonary exacerbations in patients ages 6 years and older during the 3-year observation period ending in 2005. In our primary analysis, we used the instrumental variables method, implemented using two-stage least squares regression, to evaluate the effect of the proportion of total time that intravenous treatment was administered on an inpatient (versus outpatient) basis on the likelihood of return of percent predicted forced expiratory volume in 1 second to greater than or equal to 90% of baseline post-treatment. We also evaluated two other indicators of treatment setting, three other measures of treatment response, and two alternative modeling techniques, and we also looked for differences between children and adults. RESULTS: Our final analysis included 4,497 pulmonary exacerbations in 2,773 individual patients at 75 sites. We calculated the mean proportion of intravenous treatment time that was provided in the hospital setting at each site. The median across sites was 0.581 (interquartile range, 0.396-0.753). The median treatment success rate across sites was 74.2% (interquartile range, 67.9 to 79.2%). Univariate analysis and two-stage least squares models showed a positive relationship between treatment success and proportion of inpatient treatment days. Our primary model revealed an absolute increase of 9.08% (95% confidence interval, 2.55-15.61; P = 0.006) in the achievement of a return of percent predicted forced expiratory volume in 1 second to greater than or equal to 90% of baseline comparing complete inpatient treatment with no inpatient treatment. Treatment response was not related to duration of intravenous therapy. Similar results were found for all our modeling techniques and outcomes. CONCLUSIONS: Patients with cystic fibrosis treated at sites with more reliance on inpatient treatment were more likely to achieve successful forced expiratory volume in 1 second recovery. There was no relationship between treatment duration and recovery of forced expiratory volume in 1 second. PMID- 29140727 TI - Population Genomics of Herbicide Resistance: Adaptation via Evolutionary Rescue. AB - The evolution of herbicide resistance in weed populations is a highly replicated example of adaptation surmounting the race against extinction, but the factors determining its rate and nature remain poorly understood. Here, we explore theory and empirical evidence for the importance of population genetic parameters including effective population size, dominance, mutational target size, and gene flow-in influencing the probability and mode of herbicide resistance adaptation and its variation across species. We compiled data on the number of resistance mutations across populations for 79 herbicide-resistant species. Our findings are consistent with theoretical predictions that self-fertilization reduces resistance adaptation from standing variation within populations, but increases independent adaptation across populations. Furthermore, we provide evidence for a ploidy-mating system interaction that may reflect trade-offs in polyploids between increased effective population size and greater masking of beneficial mutations. We highlight the power of population genomic approaches to provide insights into the evolutionary dynamics of herbicide resistance with important implications for understanding the limits of adaptation. PMID- 29140728 TI - Sample-Based Models of Protein Energy Landscapes and Slow Structural Rearrangements. AB - Proteins often undergo slow structural rearrangements that involve several angstroms and surpass the nanosecond timescale. These spatiotemporal scales challenge physics-based simulations and open the way to sample-based models of structural dynamics. This article improves an understanding of current capabilities and limitations of sample-based models of dynamics. Borrowing from widely used concepts in evolutionary computation, this article introduces two conflicting aspects of sampling capability and quantifies them via statistical (and graphical) analysis tools. This allows not only conducting a principled comparison of different sample-based algorithms but also understanding which algorithmic ingredients to use as knobs via which to control sampling and, in turn, the accuracy and detail of modeled structural rearrangements. We demonstrate the latter by proposing two powerful variants of a recently published sample-based algorithm. We believe that this work will advance the adoption of sample-based models as reliable tools for modeling slow protein structural rearrangements. PMID- 29140729 TI - Gene expression and gene associations during the development of heart failure with preserved ejection fraction in the Dahl salt sensitive model of hypertension. AB - Gene expression and associations were examined in a model of heart failure with preserved ejection fraction (HFpEF), a condition with minimal effective treatment. Genes with at least two studies showing significant changes in Dahl rat with heart failure were examined by meta-analysis. Significantly increased in expression were iNOS, p47phox, ADM, ANP, OPN, ACE, MCP-1, GP91PHOX, ICAM-1, TGF beta1, CTGF, ET-1, p22phox, ETB, BNP, ETA, MMP13, Col1a1, MMP2, TIMP1, Col3a1, Il 1beta, beta-MHC, ECE1, MMP14, AGT, and MMP9. In contrast, GLUT4, VEGF, eNOS, HIF 1alpha, and PGC1-alpha were significantly decreased in expression. The top biological process clusters identified in Database for Annotation, Visualization and Integrated Discovery, ToppGene, and PANTHER were collagen metabolic process, cellular ion homeostasis, regulation of cell migration, and response to decreased oxygen levels. These data suggest refocusing understanding of the pathophysiology of HFpEF to pathways involved in collagen metabolism, cell migration likely for inflammatory cells, and responses to decreased oxygen levels. Abbreviations Inducible nitric oxide synthase (INOS), neutrophil cytosolic factor 1 (p47phox), adrenomedullin (ADM), atrial natriuretic peptide (ANP), osteopontin (OPN/SPP1), angiotensin converting enzyme (ACE), monocyte chemotactic protein 1 (MCP-1), cytochrome b-245 beta polypeptide (gp91phox), intercellular adhesion molecule 1 (ICAM-1), transforming growth factor beta 1 (TGF-beta1), connective tissue growth factor (CTGF), endothelin-1 (ET-1), cytochrome B-245, alpha polypeptide (p22phox), endothelin receptor type B (ETB/EDNRB), brain natriuretic peptide (BNP), endothelin receptor type A (ETA/EDNRA), matrix metallopeptidase 13 (MMP13), type I collagen (Col1a1), matrix metallopeptidase 2 (MMP2), TIMP metallopeptidase inhibitor 1 (TIMP1), Type III collagen (Col3a1), interleukin 1 beta (IL-1beta), beta myocin heavy chain (beta-MHC), endothelin converting enzyme 1 (ECE1) matrix metallopeptidase 14 (MMP14), angiotensinogen (AGT), angiotensin II receptor Type 1 (AT1R), cytochrome C oxidase I (COX1), fms-like tyrosine kinase 1 (FLT1), TIMP metallopeptidase inhibitor 2 (TIMP2), phospholamban (PLN), vascular cell adhesion molecule 1 (VCAM1), extracellular matrix (ECM). PMID- 29140730 TI - Clarifying the concept of the "Social" in risk assessments for human subjects research. AB - International guidelines for the conduct of research with human participants, such as those put forth by the Council for International Organizations of Medical Sciences (CIOMS, 2002), recommend that research review committees account for social risk and benefits to society in their review of proposed research. What do the concepts of the "social" and "society" mean in the context of the review of human participants research? Here we analyze concepts of social and society to define the terms: social harm, social risk, social benefit, and benefits to society. We argue that use of these terms invite more questions than answers and beg for difficult empirical research to determine the nature, likelihood, and magnitude of this category of risk and benefit. Until more research is done and these questions are answered, we advise reviewers to adopt an attitude of provisionalism and caution in their review of specifically "social" risks and benefits and "benefits to society." PMID- 29140731 TI - Recovery of an injured cingulum concurrent with improvement of short-term memory in a patient with mild traumatic brain injury. AB - OBJECTIVES: We reported on a patient with mild traumatic brain injury (TBI) who showed recovery of an injured cingulum concurrent with improvement of short-term memory, which was demonstrated on follow-up diffusion tensor tractography (DTT). METHODS: A 55-year-old male patient suffered head trauma resulting from falling from approximately 2 m while working at a construction site. The patient showed mild memory impairment (especially short-term memory impairment) at 3 months after onset: Memory Assessment Scale (global memory: 95 (37%ile), short-term memory: 75 (5%ile), verbal memory: 80 (9%ile) and visual memory: 112 (79%ile)). By contrast, at 2 years after onset, his mild memory impairment had improved to a normal state: Memory Assessment Scale (global memory: 104 (61%ile), short-term memory: 95 (37%ile), verbal memory: 101 (53%ile) and visual memory: 106 (66%ile)). RESULTS: On 3-month DTT, discontinuation of the right anterior cingulum was observed over the genu of the corpus callosum, while on 2-year DTT, the discontinued right anterior cingulum was elongated to the right basal forebrain. CONCLUSION: In conclusion, recovery of an injured cingulum concurrent with improvement of short-term memory was demonstrated in a patient with mild TBI. PMID- 29140732 TI - A rare form of ankyloblepharon filiforme adnatum associated with the Hay-Wells syndrome and a c.1709T>C mutation on the TP63 gene. AB - INTRODUCTION: Ankyloblepharon filiforme adnatum associated with Hay-Wells syndrome is a rare congenital disease caused by mutations in TP63 gene on the 3q27 chromosome. Here, we report a case of a new-born suffering from this syndrome in whom we detected a mutation c.1709T>C not previously included in the Ensemble database. CASE DESCRIPTION: A girl delivered in the 34th week of gestation from a physiological pregnancy was born with extensive burn-like skin defects, ankyloblepharon filiforme adnatum, palate cleft, onychodystrophy of all limbs and syndactyly of toes. Hay-Wells syndrome was suspected and confirmed by genetic examination. A heterozygous missense change c.1709T>C was found in the TP63 gene. This variant leads to a 570th codon exchange of leucine for proline (p.Leu570Pro) on the protein level. The eyelid separation was performed surgically, burns were treated locally and cosmetic surgeries correcting other defects are planned for the near future. The girl is still monitored by a multidisciplinary team. CONCLUSIONS: The mutation was not previously described in the literature or databases and should be included into these as probably pathogenic. A multidisciplinary approach is necessary to care for a patient with Hay-Wells syndrome, such care however can provide good results. PMID- 29140733 TI - Proinflammatory Dietary Intake is Associated with Increased Risk of Colorectal Cancer: Results of a Case-Control Study in Argentina Using a Multilevel Modeling Approach. AB - Little evidence regarding the inflammatory potential of diet and its effect on colorectal cancer exists in Latin American countries. The aim of the present study was to evaluate the association between the Dietary Inflammatory Index (DII(r)) and colorectal cancer (CRC) risk in Cordoba, Argentina. A frequency matched case-control study (N = 446, including 144 (32.3%) CRC cases and 302 (67.7%) controls was conducted in Cordoba (Argentina) from 2008 through 2015. DII(r) scores were computed based on dietary intake assessed by a validated food frequency questionnaire (FFQ). Multilevel logistic regression models were fit to evaluate the association between DII scores and CRC, following adjustment for age, body mass index, sex, energy intake, smoking habits, socio-economic status, physical activity, and use of nonsteroidal anti-inflammatory drugs as first-level covariates and level of urbanization as the contextual variable. Odds of colorectal cancer increased linearly with increasing DII scores (ORcontinuous 1.34; 95%CI 1.07 to 1.69 and ORtertile3 vs. tertile1 1.21; 95%CI 1.01 to 1.44). The association was stronger among men than women (ORcontinuous 1.29; 95%CI 1.21 to 1.37 vs. ORcontinuous 1.05; 95%CI 0.83 to 1.33, respectively). A proinflammatory diet, reflected by higher DII scores, was positively associated with colorectal cancer occurrence, mainly in men. PMID- 29140734 TI - Preeclampsia knowledge among women in Utah. AB - BACKGROUND: Despite the benefits of preeclampsia (PE) education in improving health outcomes, little is known about how often healthcare providers in Utah include PE in prenatal education or how much information women retain. As such, the purpose of this study was to explore PE awareness among mothers in Utah and inquire how often PE is included in prenatal education. Factors associated with PE knowledge were also investigated. METHODS: A cross-sectional survey was conducted. Questions were created from two Preeclampsia Awareness Surveys developed by the Preeclampsia Foundation. PE knowledge was measured with 29 items from the 2014 Preeclampsia Awareness Survey, and a knowledge score was calculated. RESULTS: A total of 340 women completed the survey. Over half (56.7%) of women reported their healthcare provider described the signs and symptoms of PE to them. The mean PE knowledge score was 17.07. Hearing of PE from a healthcare provider, having the signs and symptoms of PE described by a healthcare provider and having a history of PE were significantly associated with a higher PE knowledge score. CONCLUSIONS: Patient awareness is essential to the successful management of PE. The need for improved PE education in Utah was evident in this survey. As not all healthcare providers are diligent in instructing patients regarding PE, more research is needed to fully assess the knowledge of mothers and examine the practices of providers. An explanation of PE signs and symptoms should be given to all women at prenatal care visits to improve health outcomes. PMID- 29140735 TI - Factors associated with visual acuity in patients with cystoid macular oedema and Retinitis Pigmentosa. AB - PURPOSE: Retinitis pigmentosa is the most common inherited retinal dystrophy. The factors associated with visual acuity in patients with other retinal diseases are well known, but are poorly understood in patients with retinitis pigmentosa. This knowledge is useful for prognosis and to support secondary endpoints in clinical trials. METHODS: We conducted a cross-sectional study of consecutive patients recruited from the inherited retinal disease service from January 2012 to December 2012. Central macular thickness (CMT) was measured using spectral domain optical coherence tomography. RESULTS: Data were available for 81 patients and 162 eyes. After multivariable analyses, older age, earlier age of onset of symptoms, and thicker CMT were associated with lower visual acuity. Gender and inheritance pattern were not associated with visual acuity. Each decade older age, younger age of onset, and thicker CMT was associated with 0.12, 0.10, and 0.11 worse logarithm of the minimal angle of resolution units of visual acuity, respectively (p < 0.05 for all). CONCLUSIONS: Age, age of onset, and CMT are associated with visual acuity and important factors to measure in studies of retinitis pigmentosa. PMID- 29140736 TI - Extremely low frequency magnetic field protects injured spinal cord from the microglia- and iron-induced tissue damage. AB - Spinal cord injury (SCI) is insult to the spinal cord, which results in loss of sensory and motor function below the level of injury. SCI results in both immediate mechanical damage and secondary tissue degeneration. Following traumatic insult, activated microglia release proinflammatory cytokines and excess iron due to hemorrhage, initiating oxidative stress that contributes to secondary degeneration. Literature suggests that benefits are visible with the reduction in concentration of iron and activated microglia in SCI. Magnetic field attenuates oxidative stress and promotes axonal regeneration in vitro and in vivo. The present study demonstrates the potential of extremely low frequency magnetic field to attenuate microglia- and iron-induced secondary injury in SCI rats. Complete transection of the spinal cord (T13 level) was performed in male Wistar rats and subsequently exposed to magnetic field (50 Hz,17.96 uT) for 2 h daily for 8 weeks. At the end of the study period, spinal cords were dissected to quantify microglia, macrophage, iron content and study the architecture of lesion site. A significant improvement in locomotion was observed in rats of the SCI + MF group as compared to those in the SCI group. Histology, immunohistochemistry and flow cytometry revealed significant reduction in lesion volume, microglia, macrophage, collagen tissue and iron content, whereas, a significantly higher vascular endothelial growth factor expression around the epicenter of the lesion in SCI + MF group as compared to SCI group. These novel findings suggest that exposure to ELF-MF reduces lesion volume, inflammation and iron content in addition to facilitation of angiogenesis following SCI. PMID- 29140737 TI - Older Americans Were Sicker And Faced More Financial Barriers To Health Care Than Counterparts In Other Countries. AB - High-income countries are grappling with the challenge of caring for aging populations, many of whose members have chronic illnesses and declining capacity to manage activities of daily living. The 2017 Commonwealth Fund International Health Policy Survey of Older Adults in eleven countries showed that US seniors were sicker than their counterparts in other countries and, despite universal coverage under Medicare, faced more financial barriers to health care. The survey's findings also highlight economic hardship and mental health problems that may affect older adults' health, use of care, and outcomes. They show that in some countries, one in five elderly people have unmet needs for social care services-a gap that can undermine health. New to the survey is a focus on the "high-need" elderly (those with multiple chronic conditions or functional limitations), who reported high rates of emergency department use and care coordination failures. Across all eleven countries, many high-need elderly people expressed dissatisfaction with the quality of health care they had received. PMID- 29140738 TI - Do Outcomes of Osteochondral Allograft Transplantation Differ Based on Age and Sex? A Comparative Matched Group Analysis. AB - BACKGROUND: The effect of patient age or sex on outcomes after osteochondral allograft transplantation (OCA) has not been assessed. PURPOSE: To determine clinical outcomes for male and female patients aged >=40 years undergoing OCA compared with a group of patients aged <40 years. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A review of prospectively collected data of consecutive patients who underwent OCA by a single surgeon with a minimum follow up of 2 years was conducted. The reoperation rate, failure rate, and patient reported outcome scores were reviewed. All outcomes were compared between patients aged <40 or >=40 years, with subgroup analyses conducted based on patient sex. Failure was defined as revision OCA, conversion to knee arthroplasty, or gross appearance of graft failure at second-look arthroscopic surgery. Descriptive statistics, Fisher exact or chi-square testing, and Mann Whitney U testing were performed, with P < .05 set as significant. RESULTS: A total of 170 patients (of 212 eligible patients; 80.2% follow-up) who underwent OCA with a mean follow-up of 5.0 +/- 2.7 years (range, 2.0-15.1 years) were included, with 115 patients aged <40 years (mean age, 27.6 +/- 7.3 years; 58 male, 57 female) and 55 patients aged >=40 years (mean age, 44.9 +/- 4.0 years; 33 male, 22 female). There were no differences in the number of pre-OCA procedures between the groups ( P = .085). There were no differences in the reoperation rate (<40 years: 38%; >=40 years: 36%; P = .867), time to reoperation (<40 years: 2.12 +/- 1.90 years; >=40 years: 3.43 +/- 3.43 years; P = .126), or failure rate (<40 years: 13%; >=40 years: 16%; P = .639) between the older and younger groups. Patients in both groups demonstrated significant improvement in Lysholm (both: P < .001), International Knee Documentation Committee (IKDC) (both: P < .001), Knee Injury and Osteoarthritis Outcome Score (KOOS) (both: P < .001), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (both: P < .001), and Short Form-12 (SF-12) physical (both: P < .001) scores compared with preoperative values. Patients aged >=40 years demonstrated significantly higher KOOS symptom ( P = .015) subscores compared with patients aged <40 years. There were no significant differences in the number of complications, outcome scores, or time to failure between the sexes. In patients aged <40 years, female patients experienced failure significantly more quickly than male patients ( P = .039). In contrast, in patients aged >=40 years, male patients experienced failure significantly more quickly than female patients ( P = .046). CONCLUSION: This study provides evidence that OCA is a safe and reliable treatment option for osteochondral defects in patients aged >=40 years. Male and female patients had similar outcomes. Patients aged <40 years demonstrated lower KOOS symptom subscores postoperatively compared with older patients, potentially attributable to higher expectations of return to function postoperatively as compared with older patients. PMID- 29140739 TI - CFTR Genotype and Maximal Exercise Capacity in Cystic Fibrosis: A Cross-sectional Study. AB - RATIONALE: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human skeletal muscle cells. Variations of CFTR dysfunction among patients with cystic fibrosis may be an important determinant of maximal exercise capacity in cystic fibrosis. Previous studies on the relationship between CFTR genotype and maximal exercise capacity are scarce and contradictory. OBJECTIVES: This study was designed to explore factors influencing maximal exercise capacity, expressed as peak oxygen uptake (V.O2peak), with a specific focus on CFTR genotype in children and adults with cystic fibrosis. METHODS: In an international, multicenter, cross-sectional study, we collected data on CFTR genotype and cardiopulmonary exercise tests in patients with cystic fibrosis who were ages 8 years and older. CFTR mutations were classified into functional classes I-V. RESULTS: The final analysis included 726 patients (45% females; age range, 8-61 yr; forced expiratory volume in 1 s, 16 to 123% predicted) from 17 cystic fibrosis centers in North America, Europe, Australia, and Asia, all of whom had both valid maximal cardiopulmonary exercise tests and complete CFTR genotype data. Overall, patients exhibited exercise intolerance (V.O2peak, 77.3 +/- 19.1% predicted), but values were comparable among different CFTR classes. We did not detect an association between CFTR genotype functional classes I-III and either V.O2peak (percent predicted) (adjusted beta = -0.95; 95% CI, -4.18 to 2.29; P = 0.57) or maximum work rate (Wattmax) (adjusted beta = -1.38; 95% CI, 5.04 to 2.27; P = 0.46) compared with classes IV-V. Those with at least one copy of a F508del-CFTR mutation and one copy of a class V mutation had a significantly lower V.O2peak (beta = -8.24%; 95% CI, -14.53 to -2.99; P = 0.003) and lower Wattmax (adjusted beta = -7.59%; 95% CI, -14.21 to -0.95; P = 0.025) than those with two copies of a class II mutation. On the basis of linear regression analysis adjusted for relevant confounders, lung function and body mass index were associated with V.O2peak. CONCLUSIONS: CFTR functional genotype class was not associated with maximal exercise capacity in patients with cystic fibrosis overall, but those with at least one copy of a F508del-CFTR mutation and a single class V mutation had lower maximal exercise capacity. PMID- 29140740 TI - Upregulation of Tyrosine Kinase FYN in Human Thyroid Carcinoma: Role in Modulating Tumor Cell Proliferation, Invasion, and Migration. AB - Tyrosine kinase FYN-a member of the SRC family of kinases-is associated with mediating mitogenic signals and regulating cell cycle entry, growth, and proliferation. It was hypothesized that FYN is upregulated in thyroid carcinoma, which plays a critical role in tumorigenesis. FYN expression level in thyroid carcinoma tissue and tumor cell lines was determined. Also, the effects of FYN on thyroid cancer (TC) growth, signaling, cell cycle, and apoptosis were evaluated in vitro. FYN was knocked down in thyroid cancer cells (TPC-1) by siRNA to investigate the effects on cell proliferation, invasion, and migration. First, FYN was upregulated both in thyroid carcinoma tissue and in tumor cell lines. Loss of FYN by siRNA weakened proliferation, invasion, and migration of PTC-1 cells. Furthermore, it was demonstrated that knockdown of FYN can inhibit the G0/G1 phase of cell cycle. It was also observed that reduced expression of FYN could increase the level of NF-kappaB/P65 and IkappaBalpha. This study was the first to demonstrate critical positive regulation of thyroid tumorigenesis by FYN, which could be a potential target gene for thyroid carcinoma treatment. In addition, findings from this study highlighted the potential role of FYN inhibitors in TC therapy. PMID- 29140741 TI - Comparative In Vitro Study of 11C-Methionine and 11C-Deuterodeprenyl Uptake in Three Human Glioma Cell Lines. AB - AIM: To compare the uptake of 11C-deuterodeprenyl (11C-DED) and 11C-methionine (11C-MET) in three human glioma cell lines and study the relationship with glial fibrillary acid protein (GFAP) and monoamine oxidase B (MAO B) expression. 11C DED is used in positron emission tomography imaging as a marker of astrocytosis in various central nervous system pathologies. It binds irreversibly to MAO B, a glial dimeric enzyme with increased activity in some neurological pathologies. MATERIALS AND METHODS: Binding and internalization studies of 11C-MET and 11C-DED were performed in astrocytoma grade III, glioblastoma grade IV, and radio resistant glioblastoma grade IV cells. Immunofluorescence was used. RESULTS: 11C MET specific activity bound to membrane was 9.0%-11.1% and that internalized was 88.9%-91.0%. 11C-DED specific activity bound to membrane was 34.8%-58.0% and that internalized was 38.7%-65.2%. Immunocytochemistry revealed GFAP and MAO B expression. CONCLUSIONS: The expression of MAO B measured by 11C-DED uptake or immunocytochemistry was not significantly different in grade III or IV cells. The GFAP signal was higher for grade IV compared to grade III. 11C-MET uptake was high in all the tumor cells. 11C-DED is a dopamine analogue and the transport across cell membranes is expected to be mediated by DAT receptors present in astrocytes. Reactive astrocytes surround tumor lesions; so the authors suggest that the 11C-DED uptake might be caused by the reactive astrocytosis and not by MAO B expression in tumor cells. PMID- 29140742 TI - The poor availability of syntaxes of structural equation modeling. AB - The syntax or codes used to fit Structural Equation Models (SEMs) convey valuable information on model specifications and the manner in which SEMs are estimated. We requested SEM syntaxes from a random sample of 229 articles (published in 1998 2013) that ran SEMs using LISREL, AMOS, or Mplus. After exchanging over 500 emails, we ended up obtaining a meagre 57 syntaxes used in these articles (24.9% of syntaxes we requested). Results considering the 129 (corresponding) authors who replied to our request showed that the odds of the syntax being lost increased by 21% per year passed since publication of the article, while the odds of actually obtaining a syntax dropped by 13% per year. So SEM syntaxes that are crucial for reproducibility and for correcting errors in the running and reporting of SEMs are often unavailable and get lost rapidly. The preferred solution is mandatory sharing of SEM syntaxes alongside articles or in data repositories. PMID- 29140743 TI - Research ethics review for the use of anonymized samples and data: A systematic review of normative documents. AB - While the anonymization of biological samples and data may help protect participant privacy, there is still debate over whether this alone is a sufficient safeguard to ensure the ethical conduct of research. The purpose of this systematic review is to examine whether the review of an ethics committee is necessary in the context of anonymized research, and what the considerations in said ethics review would be. The review of normative documents issued by both national and international level organizations reveals a growing concern over the ability of anonymization procedures to prevent against reidentification. This is particularly true in the context of genomic research where genetic material's uniquely identifying nature along with advances in technology have complicated previous standards of identifiability. Even where individual identities may not be identifiable, there is the risk of group harm that may not be protected by anonymization alone. We conclude that the majority of normative documents support that the review of an ethics committee is necessary to address the concerns associated with the use of anonymized samples and data for research. PMID- 29140744 TI - Evaluation of Two Surface Sampling Methods for Microbiological and Chemical Analyses To Assess the Presence of Biofilms in Food Companies. AB - Biofilms are an important source of contamination in food companies, yet the composition of biofilms in practice is still mostly unknown. The chemical and microbiological characterization of surface samples taken after cleaning and disinfection is very important to distinguish free-living bacteria from the attached bacteria in biofilms. In this study, sampling methods that are potentially useful for both chemical and microbiological analyses of surface samples were evaluated. In the manufacturing facilities of eight Belgian food companies, surfaces were sampled after cleaning and disinfection using two sampling methods: the scraper-flocked swab method and the sponge stick method. Microbiological and chemical analyses were performed on these samples to evaluate the suitability of the sampling methods for the quantification of extracellular polymeric substance components and microorganisms originating from biofilms in these facilities. The scraper-flocked swab method was most suitable for chemical analyses of the samples because the material in these swabs did not interfere with determination of the chemical components. For microbiological enumerations, the sponge stick method was slightly but not significantly more effective than the scraper-flocked swab method. In all but one of the facilities, at least 20% of the sampled surfaces had more than 102 CFU/100 cm2. Proteins were found in 20% of the chemically analyzed surface samples, and carbohydrates and uronic acids were found in 15 and 8% of the samples, respectively. When chemical and microbiological results were combined, 17% of the sampled surfaces were contaminated with both microorganisms and at least one of the analyzed chemical components; thus, these surfaces were characterized as carrying biofilm. Overall, microbiological contamination in the food industry is highly variable by food sector and even within a facility at various sampling points and sampling times. PMID- 29140745 TI - Passage of Campylobacter jejuni and Campylobacter coli Subtypes through 0.45- and 0.65-Micrometer-Pore-Size Nitrocellulose Filters. AB - Campylobacter can be difficult to recover from complex samples due to overgrowth by background bacteria. A 0.45- or 0.65-MUm-pore-size filter overlaid on agar plates can be used as a means to separate Campylobacter from confounding non Campylobacter cells, facilitating detection on solid plating media. It is unclear what percentage of cells in a Campylobacter suspension passes through a filter and results in visible colonies. The objective of this study was to compare the number of Campylobacter cells detected by the filter method with those detected by direct plating and determine if the filter method can be used to estimate cellular density of an unknown Campylobacter in suspension. Overnight liquid cultures of six subtypes of Campylobacter jejuni and six of Campylobacter coli, all originally detected in chicken samples, were used for this study. Motility of isolates was tested by using a stab into soft agar, incubating plates, and measuring colony size. Each subtype was applied to Campy-Cefex agar directly and through a 0.45- or 0.65-MUm-pore-size filter. Filters were removed, plates were incubated, and colonies were counted; three replications were conducted. Mean recovery by direct plating was 8.3 log CFU/mL. Regardless of pore size, the overall mean number of Campylobacter detected by using the filter method was significantly less than that using direct plating (P < 0.05). The mean difference between direct plating and plating though a 0.65-MUm-pore-size filter for motile Campylobacter was log 2.4 CFU/mL, with a 95% confidence interval of +/-0.2 log CFU/mL. PMID- 29140746 TI - Inactivation Kinetics of Pathogens during Thermal Processing in Acidified Broth and Tomato Puree (pH 4.5). AB - Thermal inactivation kinetics for single strains of Shiga toxin-producing Escherichia coli (STEC), Listeria monocytogenes, and Salmonella enterica were measured in acidified tryptic soy broth (TSB; pH 4.5) heated at 54 degrees C. Inactivation curves also were measured for single-pathogen five-strain cocktails of E. coli O157:H7, L. monocytogenes, and S. enterica heated in tomato puree (pH 4.5) at 52, 54, 56, and 58 degrees C. Inactivation curves were fit using log linear and nonlinear (Weibull) models. The Weibull model yields the time for a 5 log reduction (t*) and a curve shape parameter (beta). Decimal reduction times (D values) and thermal resistance constants (z-values) from the two models were compared by defining t* = 5D* for the Weibull model. When the log-linear and Weibull models match at the 5-log reduction time, then t* = 5D* = 5D and D = D*. In 18 of 20 strains heated in acidified TSB, D and D* for the two models were not significantly different, although nonlinearity was observed in 35 of 60 trials. Similarly, in 51 of 52 trials for pathogen cocktails heated in tomato puree, D and D* were not significantly different, although nonlinearity was observed in 31% of trials. At a given temperature, D-values for S. enterica << L. monocytogenes < E. coli O157:H7 in tomato puree (pH 4.5). When using the two models, z-values calculated from the D-values were not significantly different for a given pathogen. Across all pathogens, z-values for E. coli O157:H7 and S. enterica were not different but were significantly lower than the z-values for L. monocytogenes. These results are useful for supporting process filings for tomato based acidified food products with pH 4.5 and below and are relevant to small processors of tomato-based acidified canned foods who do not have the resources to conduct research on and validate pathogen lethality. PMID- 29140747 TI - Association of Social Service Spending, Environmental Quality, and Health Behaviors on Health Outcomes. AB - Recent studies on state-level spending on social services have shown that states with higher ratios of social to health care spending were associated with better health outcomes. This study extends this work by examining the association of specific elements of social service spending and other determinants of health, such as health behaviors, education, and environmental factors at the metropolitan/city level, on several measures of health outcomes between 2005 and 2014. This study found that several potential determinants of health including exercise, air pollution, smoking, per pupil educational spending, and several types of social service spending were associated with improvements in health outcomes. These health outcomes included age-adjusted mortality, chronic disease prevalence, days of poor health, and obesity rates. The results suggest that a broader strategy beyond health care that includes investments in social services, improved environmental quality, and health behaviors could improve the health of communities. PMID- 29140748 TI - Paramedic-Initiated Home Care Referrals and Use of Home Care and Emergency Medical Services. AB - OBJECTIVE: We examined the association between paramedic-initiated home care referrals and utilization of home care, 9-1-1, and Emergency Department (ED) services. METHODS: This was a retrospective cohort study of individuals who received a paramedic-initiated home care referral after a 9-1-1 call between January 1, 2011 and December 31, 2012 in Toronto, Ontario, Canada. Home care, 9-1 1, and ED utilization were compared in the 6 months before and after home care referral. Nonparametric longitudinal regression was performed to assess changes in hours of home care service use and zero-inflated Poisson regression was performed to assess changes in the number of 9-1-1 calls and ambulance transports to ED. RESULTS: During the 24-month study period, 2,382 individuals received a paramedic-initiated home care referral. After excluding individuals who died, were hospitalized, or were admitted to a nursing home, the final study cohort was 1,851. The proportion of the study population receiving home care services increased from 18.2% to 42.5% after referral, representing 450 additional people receiving services. In longitudinal regression analysis, there was an increase of 17.4 hours in total services per person in the six months after referral (95% CI: 1.7-33.1, p = 0.03). The mean number of 9-1-1 calls per person was 1.44 (SD 9.58) before home care referral and 1.20 (SD 7.04) after home care referral in the overall study cohort. This represented a 10% reduction in 9-1-1 calls (95% CI: 7 13%, p < 0.001) in Poisson regression analysis. The mean number of ambulance transports to ED per person was 0.91 (SD 8.90) before home care referral and 0.79 (SD 6.27) after home care referral, representing a 7% reduction (95% CI: 3-11%, p < 0.001) in Poisson regression analysis. When only the participants with complete paramedic and home care records were included in the analysis, the reductions in 9-1-1 calls and ambulance transports to ED were attenuated but remained statistically significant. CONCLUSIONS: Paramedic-initiated home care referrals in Toronto were associated with improved access to and use of home care services and may have been associated with reduced 9-1-1 calls and ambulance transports to ED. PMID- 29140749 TI - Pharmacists as vaccinators: An analysis of their experiences and perceptions of their new role. AB - OBJECTIVES: In 2012, Ontario pharmacists were granted immunization privileges to administer influenza vaccines to the public. This study explored the experiences and practices of pharmacist vaccinators and the impact of vaccination pain on their practice. METHODS: Semi-structured interviews were conducted with 12 pharmacists in the Greater Toronto Area. Transcribed interview data were coded and analyzed via thematic analysis. KEY FINDINGS: Data analysis revealed 4 main themes: 1) expanded scope of practice as an enhancement and challenge to relationships; 2) professional satisfaction and workload demands; 3) knowledge and attitudes regarding pain and fear; 4) practices regarding pain and fear management. Pharmacists reported satisfaction in their new role, despite the associated increased workload. Pharmacists felt that vaccination pain was not a key consideration when administering vaccines and that pain management was generally not necessary. Fear was identified as more important than pain and vaccinating children was challenging and time intensive. Pharmacists' main focus was on injection techniques in managing pain. CONCLUSION: These findings suggest that pharmacists are accepting of their role as vaccinators but more research is needed to examine impact on workload and pharmacist knowledge and perceptions of injection-related pain and fear. PMID- 29140750 TI - Postlicensure safety surveillance of congenital anomaly and miscarriage among pregnancies exposed to quadrivalent human papillomavirus vaccine. AB - Limited safety data are available on inadvertent exposure to quadrivalent human papillomavirus vaccine (4vHPV) during pregnancy. We conducted a descriptive observational postlicensure safety surveillance study in Kaiser Permanente Southern California and Northern California to assess congenital anomaly and miscarriage among pregnancies exposed to 4vHPV. Using electronic medical records, we identified women who received a dose of 4vHPV between August 2006 and March 2008 within 30 days preconception or any time during a possible pregnancy. A broad algorithm was developed using diagnostic and procedure codes and laboratory tests to identify pregnancy, congenital anomalies, and miscarriages. Medical records of all potential congenital anomaly cases and a random sample of 100 potential miscarriage cases were reviewed to confirm pregnancy exposure and diagnosis. Results were reviewed by an independent Safety Review Committee (SRC). Among the population of 189,629 females who received at least one dose of 4vHPV during the study period, 2,678 females were identified as possibly having a 4vHPV exposed pregnancy. Among 170 potential congenital anomalies identified, 44 (26%) were found to be both 4vHPV-exposed and confirmed congenital anomaly cases. Among the 633 potential miscarriages identified, the records of a random sample of 100 cases were reviewed, and 9 cases (9%) were confirmed as 4vHPV-exposed miscarriages. The SRC noted no safety signal for congenital anomaly or miscarriage associated with 4vHPV exposure during pregnancy. The rate of major congenital anomaly (3.6%) was in the range of background estimates from the literature. There was no apparent pattern of timing of 4vHPV exposure among 4vHPV exposed miscarriages. PMID- 29140751 TI - Further delineation of the oculoauricular syndrome phenotype: A new family with a novel truncating HMX1 mutation. AB - Biallelic HMX1 mutations cause a very rare autosomal recessive genetic disorder termed as oculoauricular syndrome (OAS) because it is characterized only by the combination of eye and ear anomalies. We identified a new family bringing to three the total families reported with this disorder. Our proband presented with anteriorly protruded ears and malformed ear pinnae in association with microphthalmia, congenital cataract, microcornea, and iris and optic disc colobomata. Additionally, he had high and broad forehead with asymmetry giving a recognizable facial gestalt. Further, short left mandibular ramus and bifid cingulum in the boy and short right mandibular ramus in his father were observed. Mutation analysis revealed a novel homozygous nonsense mutation c.487G>T in the second exon of the HMX1 that predicted to introduce a premature stop codon at position 163 (p.E163*). Parents showed the heterozygous state of the detected mutation. Investigations in a process as complex as craniofacial development suggest that there are still additional, as yet unidentified, genes that play in orchestrate to determine the final phenotype. PMID- 29140752 TI - The Quiet Room. PMID- 29140753 TI - A mutated recombinant subunit vaccine protects mice and guinea pigs against botulinum type A intoxication. AB - Botulinum neurotoxins (BoNTs) are the most potent toxins to mammals. A toxoid vaccine was previously used for prevention of botulinum intoxication; however, this vaccine is no longer available. Currently, no approved botulinum vaccines are available from the Food and Drug Administration (FDA). Recently, a recombinant host cell receptor-binding subunit created for use as a potential vaccine completed phase 2 clinical trials. The current study designed a vaccine candidate against BoNT type A (BoNT/A) using a structural design. Our vaccine candidate was the BoNT/A heavy chain C-terminal region (HCR) that contained the point mutation BA15 (R1269A) within the ganglioside-binding site. A Biacore affinity test showed that the affinity of BA15 for ganglioside GT1b was 100 times lower than that of the HCR. A SNAP25 cleavage assay revealed that immunized sera blocked SNAP25 cleavage of the BoNT/A toxin via BA15. In an in vivo experiment, mice and guinea pigs immunized with BA15 produced neutralizing antibodies that protected against 3,000 LD50 of BoNT/A. In conclusion, the results of both in vitro and in vivo assays showed that our BA15 vaccine candidate was similar to the recombinant host cell receptor-binding subunit vaccine. The inability of BA15to bind ganglioside shows that BA15 is a potential safe vaccine candidate. PMID- 29140755 TI - Expression of Concern. AB - The Journal Editors hereby issue this note of an expression of concern for the following publication: Benjamin, A. J., Jr., Kepes, S., & Bushman, B. J. (2017). Effects of weapons on aggressive thoughts, angry feelings, hostile appraisals, and aggressive behavior: A meta-analytic review of the weapons effect literature. Personality and Social Psychology Review. Advance online publication. doi:10.1177/1088868317725419 The authors of this manuscript contacted the editors indicating they had discovered some errors in the computation of effect sizes in their meta-analysis. Initial reanalysis suggested that at least one of the substantive conclusions of the manuscript was affected by the error; the authors now urge greater caution in interpreting the effect size of weapons on aggressive behavioral outcomes. The authors will undertake a thorough reanalysis and will modify the results and interpretations accordingly, and this notice will be updated upon their completion of the modifications. The editorial staff appreciates the proactive efforts of the authors in this matter. The Editors and SAGE strive to uphold the very highest standards of publication ethics and are committed to supporting the high standards of integrity of Personality and Social Psychology Review. Authors, reviewers, editors, and interested readers should consult the ethics section of SAGE and the Committee on Publication Ethics (COPE) website for guidelines on publication ethics. PMID- 29140754 TI - Comparing diversity of fungi from living leaves using culturing and high throughput environmental sequencing. AB - High-throughput sequencing technologies using amplicon approaches have changed the way that studies investigating fungal distribution are undertaken. These powerful and time-efficient technologies have the potential for the first time to accurately map fungal distributions across landscapes or changes in diversity across ecological or biological gradients of interest. There is no requirement for a fungus to form a fruiting body to be detected, and both culturable and nonculturable organisms can be detected. Here we use high-throughput amplicon sequencing from bulk DNA extracts to test the impact that biases associated with culture-based methods had on an earlier study that compared the influence of site and host on fungal diversity in Nothofagaceae forests in New Zealand. Both detection methods sampled tissue from the same set of symptomless, living leaves. We found that both the culturing and high-throughput approaches show that host is a stronger driver of fungal community structure than site, but that both methods have some taxonomic biases. We also found that the individual trees selected for high-throughput sampling can impact the alpha-diversity detected and through this could potentially affect subsequent analyses based on a comparison of this diversity. PMID- 29140756 TI - Cellular and Molecular Mechanisms of Autoimmune Hepatitis. AB - Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication. PMID- 29140757 TI - New Insights into Lymphoma Pathogenesis. AB - Lymphomas represent clonal proliferations of lymphocytes that are broadly classified based upon their maturity (peripheral or mature versus precursor) and lineage (B cell, T cell, and natural killer cell). Insights into the pathogenetic mechanisms involved in lymphoma impact the classification of lymphoma and have significant implications for the diagnosis and clinical management of patients. Serial scientific and technologic advances over the last 30 years in immunology, cytogenetics, molecular biology, gene expression profiling, mass spectrometry based proteomics, and, more recently, next-generation sequencing have contributed to greatly enhance our understanding of the pathogenetic mechanisms in lymphoma. Novel and emerging concepts that challenge our previously accepted paradigms about lymphoma biology and how these impact diagnosis, molecular testing, disease monitoring, drug development, and personalized and precision medicine for lymphoma are discussed. PMID- 29140758 TI - Personal Accounts of Poverty: A Thematic Analysis of Social Media. AB - The field of social work seeks to enhance human well-being by addressing the needs of people living in poverty. Three billion people around the world use the internet daily, and 65% of them use social media. This article qualitatively identifies emergent themes about the lived experiences of poverty from people who reported either being poor or having have been poor, using selected social media posts (N = 1,495) on the website Reddit. We found that the experiences of poverty bring arduousness and hardship, which necessitates an arsenal of survival strategies and skills. It was also found that some people who were poor experienced the saving grace of unexpected charitable acts, which eased their burden. Moreover, these experiences manifest in vestigial feelings and behaviors even when one is no longer poor. An understanding of the lived experiences by poor people themselves is a foundational task for social work educators, practitioners, and researchers. PMID- 29140759 TI - Adult Profiles of Child Sexual Abuse Survivors: Attachment Insecurity, Sexual Compulsivity, and Sexual Avoidance. AB - The present study examined the possibility of different groups of child sexual abuse (CSA) survivors based on their different patterns of attachment and sexual problems. A sample of 324 CSA survivors and 484 participants who did not report any child maltreatment experiences completed online questionnaires. A cluster analysis on attachment and sexual outcomes revealed that CSA survivors formed two distinct profiles. The first profile included CSA survivors with elevated attachment anxiety and low to moderate scores on attachment avoidance, sexual compulsion, and sexual avoidance. The second profile comprised CSA survivors with high scores on attachment anxiety, attachment avoidance, sexual compulsion, and sexual avoidance. These groups were then compared on CSA severity, gender differences, and other child maltreatment experiences. As compared to CSA survivors of the first profile, survivors from the second profile reported more intrusive and extrafamilial CSA, higher rates of psychological maltreatment and witnessed parental violence, and experienced more personal and couple distress. These results suggest that CSA survivors form a heterogeneous population and that sexual abuse is differentially associated with the complex unfolding of the attachment and sexual systems within two distinct subgroups. PMID- 29140760 TI - Emergency Legal Authority and the Opioid Crisis. PMID- 29140761 TI - Limb Segment Load Inhibits the Recovery of Soleus H-Reflex After Segmental Vibration in Humans. AB - We investigated the effects of vertical vibration and compressive load on soleus H-reflex amplitude and postactivation depression. We hypothesized that, in the presence of a compressive load, limb vibration induces a longer suppression of soleus H-reflex. Eleven healthy adults received vibratory stimulation at a fixed frequency (30 Hz) over two loading conditions (0% and 50% of individual's body weight). H-reflex amplitude was depressed ~88% in both conditions during vibration. Cyclic application of compression after cessation of the vibration caused a persistent reduction in H-reflex excitability and postactivation depression for > 2.5 min. A combination of limb segment vibration and compression may offer a nonpharmacologic method to modulate spinal reflex excitability in people after CNS injury. PMID- 29140762 TI - The genus Parasola: phylogeny and the description of three new species. AB - Parasola represents an enigmatic lineage of veil-less, coprinoid fungi in Psathyrellaceae (Agaricales). The species-level taxonomy of the genus has been in a flux recently, resulting in the elimination of some long-established names and the description of new taxa. Here, we reconstruct the phylogeny of Parasola using two nuc rDNA loci, the internal transcribed spacer region (ITS1-5.8S-ITS2) and 28S and identify several putatively undescribed species, of which three are formally described here (Parasola crataegi, P. ochracea, and P. plicatilis similis) based on molecular and morphological data. Morphological descriptions for the new species and an identification key to accepted Parasola species are given. We revise and discuss our current understanding of the phylogeny of Parasola. PMID- 29140764 TI - Framework for a Population-Based Surveillance Program for Hepatocellular Cancer. PMID- 29140765 TI - Quantitative weight of evidence assessment of higher-tier studies on the toxicity and risks of neonicotinoids in honeybees. 2. Imidacloprid. AB - A quantitative weight of evidence (QWoE) methodology was used to assess higher tier studies on the effects of imidacloprid (IMI) on honeybees. Assessment endpoints were population size and viability of commercially managed bees and quantity of hive products. A colony-level no-observed-adverse effect concentration (NOAEC) of 25 ug IMI/kg syrup, equivalent to an oral no-observed adverse-effect-dose of 7.3 ng/bee/d for all responses, was measured. The overall weight of evidence indicates that there is minimal risk to honeybees from exposure to IMI from its use as a seed treatment. Exposures via dusts from currently used seed coatings present a de minimis risk to honeybees when the route of exposure is via uptake in plants that are a source of pollen or nectar for honeybees. There were few higher-tier observational (ecoepidemiological) studies conducted with IMI. Considering all lines of evidence, the quality of the studies included in this analysis was variable, but the results of the studies were consistent and point to the same conclusion - that IMI had no adverse effects on viability of the honeybee colony. Thus, the overall conclusion is that IMI, as currently used as a seed treatment and with good agricultural practices, does not present a significant risk to honeybees at the level of the colony. PMID- 29140766 TI - The rise of alternative bread leavening technologies in the nineteenth century. AB - This article reveals how nineteenth-century chemists and health reformers tried to eradicate the use of yeast in bread, claiming they had devised healthier and more sanitary ways to raise bread. It describes the alternative technological solutions to baking bread, investigating factors that influenced their development and adaptation in the marketplace. A lack of scientific and cultural consensus surrounding yeast, what it was and what it did, fermented during this period. The conflict over yeast helped create a heterogeneous industrialization of the baking industry, changing processes and ingredients and creating new forms of bakery products. By examining the claims of promoters of rival scientific beliefs and technologies, as well as those of users and social commentators, we can see that technology's eventual adaptation and impact on society is not predictable at its outset. Exploring the relationship between differing scientific beliefs, cultural understandings and alternative technologies also shows how science and industry cannot be isolated from their social and cultural context. The examination of the nineteenth-century technological development of commonplace commodities such as bread, baking powder and yeast, also reveals and explores a story that has not been told before in the history of science and technology. Why it has not been told is as enlightening as the story itself, revealing as it does our own privileging of what is important in science and history. PMID- 29140767 TI - Genomic Medicine Without Borders: Which Strategies Should Developing Countries Employ to Invest in Precision Medicine? A New "Fast-Second Winner" Strategy. AB - Genomic medicine has greatly matured in terms of its technical capabilities, but the diffusion of genomic innovations worldwide faces significant barriers beyond mere access to technology. New global development strategies are sorely needed for biotechnologies such as genomics and their applications toward precision medicine without borders. Moreover, diffusion of genomic medicine globally cannot adhere to a "one-size-fits-all-countries" development strategy, in the same way that drug treatments should be customized. This begs a timely, difficult but crucial question: How should developing countries, and the resource-limited regions of developed countries, invest in genomic medicine? Although a full-scale investment in infrastructure from discovery to the translational implementation of genomic science is ideal, this may not always be feasible in all countries at all times. A simple "transplantation of genomics" from developed to developing countries is unlikely to be feasible. Nor should developing countries be seen as simple recipients and beneficiaries of genomic medicine developed elsewhere because important advances in genomic medicine have materialized in developing countries as well. There are several noteworthy examples of genomic medicine success stories involving resource-limited settings that are contextualized and described in this global genomic medicine innovation analysis. In addition, we outline here a new long-term development strategy for global genomic medicine in a way that recognizes the individual country's pressing public health priorities and disease burdens. We term this approach the "Fast-Second Winner" model of innovation that supports innovation commencing not only "upstream" of discovery science but also "mid-stream," building on emerging highly promising biomarker and diagnostic candidates from the global science discovery pipeline, based on the unique needs of each country. A mid-stream entry into innovation can enhance collective learning from other innovators' mistakes upstream in discovery science and boost the probability of success for translation and implementation when resources are limited. This a la carte model of global innovation and development strategy offers multiple entry points into the global genomics innovation ecosystem for developing countries, whether or not extensive and expensive discovery infrastructures are already in place. Ultimately, broadening our thinking beyond the linear model of innovation will help us to enable the vision and practice of genomics without borders in both developed and resource-limited settings. PMID- 29140768 TI - Public Health Burden of Hearing Impairment and the Promise of Genomics and Environmental Research: A Case Study in Ghana, Africa. AB - Hearing impairment (HI) is one of the most disabling conditions of major global health burden that contributes adversely to the social and economic development of a country, if not managed properly. A proper assessment of the nationwide burden and etiology of HI is instrumental in the prevention, treatment, and management of the condition. This article sought to perform an expert review of HI in Ghana to determine the present knowledge of its burden and possible causes of the condition. A literature search was conducted in PubMed using the following keywords: "hearing loss" OR "hearing impairment" OR "deafness" AND "Ghana." The literature was scanned until July 20, 2017, with specific inclusion of targeted landmark and background articles on HI. From the search, 18 of out 5869 articles were selected and considered for the review. The results of the search indicated that there were no extensive studies to determine the national burden of HI in Ghana. However, the few studies assessed suggested that the disease is either acquired or inherited. The burden of acquired HI was higher in adults than children, women than men, and people working in a noisy environment. Regarding the genetic cause, specific founder mutations in GJB2 gene (R143W, L79P, V178A, R184Q, A197S, I203K, and L214P) was the only identified genetic cause of HI in Ghana, but the other HI genes were not investigated. There has been some modest effort to study HI in Ghana, but comprehensive studies on the genetic and environmental etiologies (using the "multi-OMICS" approaches), classification, and burden of HI on Ghana are needed. PMID- 29140769 TI - Addressing Maternal Health During CDC's Ebola Response in the United States. AB - Previous outbreaks suggest that pregnant women with Ebola virus disease (EVD) are at increased risk for severe disease and death. Healthcare workers who treat pregnant women with EVD are at increased risk of body fluid exposure. Despite the absence of pregnant women with EVD in the United States, CDC activated the Maternal Health Team (MHT), a functional unit dedicated to emergency preparedness and response issues, on October 18, 2014. We describe major activities of the MHT. A high-priority MHT activity was to publish guiding principles early in the response. The MHT also prepared guidance documents, provided guidance and technical support for hospital preparedness, and addressed inquiries. We analyzed maternal health inquiries received through CDC-INFO, MHT, and CDC's Medical Investigations Team from August 2014 to December 2015. Internal call logs used to capture, monitor, and track inquiries for the three data sources were merged. Inquiries not related to maternal health issues and duplicates were removed. Each inquiry was categorized by route (email/phone), inquirer type, and topic. In total, 201 inquiries were received from clinicians, public health professionals, and the public. The predominant topic was related to infection control for high risk situations such as labor and delivery. During the Ebola response, most inquiries were received via email rather than telephone, a notable shift compared to the H1N1 emergency response. Lessons learned during the H1N1 and Ebola responses are currently informing CDC's Zika Response, an unprecedented emergency response primarily focused on reproductive health issues. PMID- 29140770 TI - Specificity and genetic diversity of xylose-fermenting Scheffersomyces yeasts associated with small blue stag beetles of the genus Platycerus in East Asia. AB - Among insect-fungus relationships, xylose-fermenting Scheffersomyces yeasts are well known for their potential in utilizing wood hemicelluloses and their association with various wood-feeding insects. However, their specificity to host insects or strain-level diversity within host species has not been clearly elucidated. In the insect family Lucanidae, larvae usually feed on decaying wood, and adult females consistently possess a fungus-storage organ, called the mycangium, near the abdominal tip. Here the authors investigated host-symbiont relationships between Scheffersomyces yeast symbionts and small blue stag beetles of the genus Platycerus (Coleoptera: Lucanidae) in East Asia by using intergenic spacer (IGS) region as a genetic marker. All yeast strains isolated from the female mycangium of three Platycerus species, P. hongwonpyoi from Korea and P. acuticollis and P. delicatulus from Japan, were allied to Scheffersomyces segobiensis based on the sequences of the nrDNA 26S and internal transcribed spacer (ITS), in which no sequence difference was observed among those strains. However, IGS regions showed clear genetic differentiation within the yeast symbionts of P. hongwonpyoi, as well as between those of Korean and Japanese Platycerus species. In the IGS sequences, nucleotide substitutions were mainly distributed in the whole stretch of IGS1 and the anterior half of IGS2, whereas nucleotide gaps were localized at IGS1 and the middle of IGS2. Despite the conserved association between the Platycerus beetles and the specific strains of S. segobiensis in East Asia, geophylogenetic divergence patterns of the yeast symbionts were not concordant with those of the insect hosts. PMID- 29140771 TI - BRAF V600E Status Alone Is Not Sufficient as a Prognostic Biomarker in Pediatric Low-Grade Glioma. PMID- 29140773 TI - Reply to D.T.W. Jones et al. PMID- 29140772 TI - Role of Patient Coping Strategies in Understanding the Effects of Early Palliative Care on Quality of Life and Mood. AB - Purpose The early integration of oncology and palliative care (EIPC) improves quality of life (QOL) and mood for patients with advanced cancer. However, the mechanisms by which EIPC benefits these outcomes remain unclear. We therefore examined whether EIPC improved patients' coping strategies and if changes in coping accounted for intervention effects on QOL and depressive symptoms. Patients and Methods For this secondary analysis of an EIPC trial, we examined data from 350 patients with newly diagnosed incurable lung or GI cancer. Participants completed assessments of QOL (Functional Assessment of Cancer Therapy-General), depressive symptoms (Patient Health Questionnaire-9), and coping (Brief COPE) at baseline and 24 weeks. We used linear regression to test intervention effects on use of coping strategies and mediation regression models with bias-corrected bootstrapping to examine whether improvements in coping mediated the effects of early palliative care on patient-reported outcomes. Results Compared with usual oncology care, EIPC significantly increased patient use of approach-oriented coping strategies ( B = 1.09; SE = 0.44; P = .01) and slightly reduced use of avoidant strategies ( B = -0.44; SE = 0.23; P = .06) from baseline to 24 weeks. Also, the increased use of approach-oriented coping and reduction in avoidant coping were associated with higher QOL and lower depressive symptoms at 24 weeks. The positive changes in approach-oriented coping, but not avoidant coping, significantly mediated the effects of EIPC on QOL (indirect effect, 1.27; 95% CI, 0.33 to 2.86) and depressive symptoms (indirect effect, 0.39; 95% CI, -0.87 to -0.08). Conclusion Patients with incurable cancer who received EIPC showed increased use of approach-oriented coping, which was associated with higher QOL and reduced depressive symptoms. Palliative care may improve these outcomes by providing patients with the skills to cope effectively with life-threatening illness. PMID- 29140775 TI - Editor's Note. PMID- 29140774 TI - Anal Cancer Risk Among People With HIV Infection in the United States. AB - Purpose People with HIV infection have an elevated risk of anal cancer. However, recent calendar trends are incompletely described, and which population subgroups might benefit from cancer screening is unknown. Methods We used linked data from HIV and cancer registries in nine US areas (1996 to 2012). We calculated standardized incidence ratios to compare anal cancer incidence in people with HIV infection with the general population, used Poisson regression to evaluate anal cancer incidence among subgroups of people with HIV and to assess temporal trends, and estimated the cumulative incidence of anal cancer to measure absolute risk. Results Among 447,953 people with HIV infection, anal cancer incidence was much higher than in the general population (standardized incidence ratio, 19.1; 95% CI, 18.1 to 20.0). Anal cancer incidence was highest among men who have sex with men (MSM), increased with age, and was higher in people with AIDS than in those without AIDS (ie, HIV only; adjusted incidence rate ratio, 3.82; 95% CI, 3.27 to 4.46). Incidence among people with HIV increased steeply during 1996 to 2000 (annual percentage change, 32.8%; 95% CI, -1.0% to 78.2%), reached a plateau during 2001 to 2008, and declined during 2008 to 2012 (annual percentage change, 7.2%; 95% CI, -14.4% to 0.6%). Cumulative incidence after a 5-year period was high for MSM with HIV only age 45 to 59 or >= 60 years (0.32% to 0.33%) and MSM with AIDS age 30 to 44, 45 to 59, or >= 60 years (0.29% to 0.65%). Conclusion Anal cancer incidence is markedly elevated among people with HIV infection, especially in MSM, older individuals, and people with AIDS. Recent declines may reflect delayed benefits of HIV treatment. Groups with high cumulative incidence of anal cancer may benefit from screening. PMID- 29140776 TI - Control and Release in Complex Relationships. AB - Artist James Alan Smith is driven to involve himself in the creative process, whether through coding or visual art. The effect of his abstract and representation pieces is extraordinary and mysterious, and each encourages viewers to see the complex relationships between the various layers. PMID- 29140777 TI - Computer Graphics Animation for Objective Self-Evaluation. AB - The increased number of students enrolling in dance classes in Japan has resulted in a shortage of qualified instructors, leaving classes to be taught by instructors who are not trained in dance. The authors developed a system specifically designed to help nonqualified dance instructors teach dance using motion capture and animation. The goal is to allow dancers to easily self evaluate their own performances by comparing it to a standard example. PMID- 29140778 TI - Visual Communication and Cognition in Everyday Decision-Making. AB - Understanding cognition and the context of decision-making should be prioritized in the design process in order to accurately anticipate the outcome for intended audiences. A thorough understanding of cognition has been excluded from being a part of foundational design principals in visual communication. By defining leisure, direct, urgent, and emergency scenarios and providing examples of work that deeply considers the viewer's relationship to the design solution in context of these scenarios allows us to affirm the relevancy of cognition as a design variable and the importance of projects that advocate public utility. PMID- 29140779 TI - Experiencing the Sights, Smells, Sounds, and Climate of Southern Italy in VR. AB - This article explores what it takes to make interactive computer graphics and VR attractive as a promotional vehicle, from the points of view of tourism agencies and the tourists themselves. The authors exploited current VR and human-machine interface (HMI) technologies to develop an interactive, innovative, and attractive user experience called the Multisensory Apulia Touristic Experience (MATE). The MATE system implements a natural gesture-based interface and multisensory stimuli, including visuals, audio, smells, and climate effects. PMID- 29140780 TI - Full-Body Animation of Human Locomotion in Reduced Gravity Using Physics-Based Control. AB - The proposed physics-based approach can generate stable and robust full-body animation of various gaits under different gravitational conditions. As input, this method takes motion-captured human motions in the Earth's gravity and builds an inverted-pendulum on cart (IPC) control model, which is analyzed using the motion-captured data. The authors use a pre-estimation model based on the Froude number to predict the desired velocity and stride frequency of a character model in hypogravity and then generate full-body animation using a pendulum trajectory generator, motion planner, and tracking. PMID- 29140781 TI - A Generative Audio-Visual Prosodic Model for Virtual Actors. AB - An important problem in computer animation of virtual characters is the expression of complex mental states during conversation using the coordinated prosody of voice, rhythm, facial expressions, and head and gaze motion. In this work, the authors propose an expressive conversion method for generating natural speech and facial animation in a variety of recognizable attitudes, using neutral speech and animation as input. Their method works by automatically learning prototypical prosodic contours at the sentence level from an original dataset of dramatic attitudes. PMID- 29140782 TI - Cloth Animation Retrieval Using a Motion-Shape Signature. AB - In cloth simulation, the behavior of textiles largely depends on initial conditions, parameters, and simulation techniques. Usually, several combinations of those aspects are altered until a simulation setting is found to create a satisfying animation. However, if an initial condition, such as a collision object, is changed afterward or the cloth behavior is transferred to a different scene, the existing set of simulation parameters could no longer be suitable for the desired look. In this case, it is difficult to find a new configuration by changing parameters manually and to determine if it conforms the desired properties. This article introduces a feature vector that is used as a motion shape signature to capture the spatiotemporal shape characteristics of cloth and can be applied as a similarity measure for physics-based cloth animations. PMID- 29140783 TI - Blending Face Details: Synthesizing a Face Using Multiscale Face Models. AB - Creating realistic 3D face models is a challenging problem in computer graphics because humans are so sensitive to facial abnormalities. The authors propose a method to synthesize a 3D face model using weighted blending of multiscale details from different face models. Using multiscale continuous displacement maps (CDMs), they achieve full correspondences across multiple scales in the parameter space. Their results demonstrate detail transfer across faces with highly different proportions, such as between humans and nonhuman creatures. An artist evaluation also indicated the proposed approach is intuitive and easy to use. PMID- 29140784 TI - Sketch-Based Articulated 3D Shape Retrieval. AB - Sketch-based queries are a suitable and superior alternative to traditional text- and example-based queries for 3D shape retrieval. The authors developed an articulated 3D shape retrieval method that uses easy-to-obtain 2D sketches. In contrast to existing sketch-based retrieval systems that lower the 3D database models to 2D, their algorithm implicitly lifts the 2D query to 2.5D by inferring depth information from possibly self-intersecting sketches using a good continuation rule. It does not require 3D example models to initiate queries, but results show that it achieves accuracy comparable to a state-of-the-art example based 3D shape retrieval method. PMID- 29140785 TI - CI Thermometer: Visualizing Confidence Intervals in Correlation Analysis. AB - Correlation analysis is one of the most popular statistical methods. Despite that, the way research reports correlation is often misleading. The difficulty increases with the amount of information that must be read and interpreted. The proposed CI thermometer makes correlation matrices much easier to read and provides information that would be difficult to interpret when presented in another way. PMID- 29140786 TI - Selection of an Anticalin(r) against the membrane form of Hsp70 via bacterial surface display and its theranostic application in tumour models. AB - We describe the selection of Anticalins against a common tumour surface antigen, human Hsp70, using functional display on live Escherichia coli cells as fusion with a truncated EspP autotransporter. While found intracellularly in normal cells, Hsp70 is frequently exposed in a membrane-bound state on the surface of tumour cells and, even more pronounced, in metastases or after radiochemotherapy. Employing a recombinant Hsp70 fragment comprising residues 383-548 as the target, Anticalins were selected from a naive bacterial library. The Anticalin with the highest affinity (KD=13 nm), as determined towards recombinant full-length Hsp70 by real-time surface plasmon resonance analysis, was improved to KD=510 pm by doped random mutagenesis and another cycle of E. coli surface display, followed by rational combination of mutations. This Anticalin, which recognises a linear peptide epitope located in the interdomain linker of Hsp70, was demonstrated to specifically bind Hsp70 in its membrane-associated form in immunofluorescence microscopy and via flow cytometry using the FaDu cell line, which is positive for surface Hsp70. The radiolabelled and PASylated Anticalin revealed specific tumour accumulation in xenograft mice using positron emission tomography (PET) imaging. Furthermore, after enzymatic coupling to the protein toxin gelonin, the Anticalin showed potent cytotoxicity on FaDu cells in vitro. PMID- 29140787 TI - TGF-beta requires the activation of canonical and non-canonical signalling pathways to induce skeletal muscle atrophy. AB - The transforming growth factor type-beta (TGF-beta) induces skeletal muscle atrophy characterised by a decrease in the fibre's diameter and levels of myosin heavy chain (MHC), also as an increase of MuRF-1 expression. In addition, TGF beta induces muscle atrophy by a mechanism dependent on reactive oxygen species (ROS). TGF-beta signals by activating both canonical Smad-dependent, and non canonical signalling pathways such as ERK1/2, JNK1/2, and p38 MAPKs. However, the participation of canonical and non-canonical signalling pathways in the TGF-beta atrophic effect on skeletal muscle is unknown. We evaluate the impact of Smad and MAPK signalling pathways on the TGF-beta-induced atrophic effect in C2C12 myotubes. The results indicate that TGF-beta activates Smad2/3, ERK1/2 and JNK1/2, but not p38 in myotubes. The pharmacological inhibition of Smad3, ERK1/2 and JNK1/2 activation completely abolished the atrophic effect of TGF-beta. Finally, the inhibition of these canonical and non-canonical pathways did not decrease the ROS increment, while the inhibition of ROS production entirely abolished the phosphorylation of Smad3, ERK1/2 and JNK1/2. These results suggest that TGF-beta requires Smad3, ERK1/2 and JNK1/2 activation to produce skeletal muscle atrophy. Moreover, the induction of ROS by TGF-beta is an upstream event to canonical and non-canonical pathways. PMID- 29140788 TI - Impact of protamine I on colon cancer proliferation, invasion, migration, diagnosis and prognosis. AB - This paper investigates protamine I (PRM1) expression and its effects on proliferation, invasion and migration of colon cancer cells as well as its function in clinical diagnosis and prognosis. Gene chips were used to screen differentially expressed genes. PRM1 expression was detected by Western blotting and quantitative real time-polymerase chain reaction (qRT-PCR). Hematoxylin and eosin (HE) staining and immunohistochemistry were utilized to compare the expression of PRM1 from multiple differentiation levels of colon cancer tissues. Cell viability, cell apoptosis and cell cycle were tested using the MTT assay and flow cytometry. Cell invasion and migration capability were tested using the Transwell assay and wound healing. In vivo effects of PRM1 on colon cancer were explored using a xenograft model. PRM1 expression in serum was detected by enzyme linked immunosorbent assay (ELISA). The expression level of PRM1 was significantly higher in colon cancer tissues and the staining degree of PRM1 in poorly-differentiated was stronger. pcDNA3.1-PRM1 decreased cell apoptosis while it increased the proliferation, cell invasion and migration. The si-PRM1 group displayed an opposite tendency. The serum PRM1 level was significantly higher and could serve as a diagnostic biomarker for colon cancer. PMID- 29140789 TI - Mechanism and dynamics of INPP5E transport into and inside the ciliary compartment. AB - The inositol polyphosphate 5'-phosphatase E (INPP5E) localizes to cilia. We showed that the carrier protein phosphodiesterase 6 delta subunit (PDE6delta) mediates the sorting of farnesylated INPP5E into cilia due to high affinity binding and release by the ADP-ribosylation factor (Arf)-like protein Arl3.GTP. However, the dynamics of INPP5E transport into and inside the ciliary compartment are not fully understood. Here, we investigate the movement of INPP5E using live cell fluorescence microscopy and fluorescence recovery after photobleaching (FRAP) analysis. We show that PDE6delta and the dynein transport system are essential for ciliary sorting and entry of INPP5E. However, its innerciliary transport is regulated solely by the intraflagellar transport (IFT) system, independent from PDE6delta activity and INPP5E farnesylation. By contrast, movement of Arl3 into and within cilia occurs freely by diffusion and IFT independently. The farnesylation defective INPP5E CaaX box mutant loses the exclusive ciliary localization. The accumulation of this mutant at centrioles after photobleaching suggests an affinity trap mechanism for ciliary entry, that in case of the wild type is overcome by the interaction with PDE6delta. Collectively, we postulate a three-step mechanism regulating ciliary localization of INPP5E, consisting of farnesylation- and PDE6delta-mediated targeting, INPP5E PDE6delta complex diffusion into the cilium with transfer to the IFT system, and retention inside cilia. PMID- 29140790 TI - Antioxidant capacity in patients with type 2 diabetes: a preliminary investigation on gender-specific differences in an Italian population. PMID- 29140791 TI - Reply to: Hyperuricemia does not seem to be an independent risk factor for coronary heart disease. PMID- 29140792 TI - A Bayesian hierarchical model for identifying significant polygenic effects while controlling for confounding and repeated measures. AB - Genomic studies of plants often seek to identify genetic factors associated with desirable traits. The process of evaluating genetic markers one by one (i.e. a marginal analysis) may not identify important polygenic and environmental effects. Further, confounding due to growing conditions/factors and genetic similarities among plant varieties may influence conclusions. When developing new plant varieties to optimize yield or thrive in future adverse conditions (e.g. flood, drought), scientists seek a complete understanding of how the factors influence desirable traits. Motivated by a study design that measures rice yield across different seasons, fields, and plant varieties in Indonesia, we develop a regression method that identifies significant genomic factors, while simultaneously controlling for field factors and genetic similarities in the plant varieties. Our approach develops a Bayesian maximum a posteriori probability (MAP) estimator under a generalized double Pareto shrinkage prior. Through a hierarchical representation of the proposed model, a novel and computationally efficient expectation-maximization (EM) algorithm is developed for variable selection and estimation. The performance of the proposed approach is demonstrated through simulation and is used to analyze rice yields from a pilot study conducted by the Indonesian Center for Rice Research. PMID- 29140793 TI - Medical specialty preferences in early medical school training in Canada. AB - Objectives: To understand what medical students consider when choosing their specialty, prior to significant clinical exposure to develop strategies to provide adequate career counseling. Methods: A cross-sectional study was performed by distributing optional questionnaires to 165 first-year medical students at the University of Ottawa in their first month of training with a sample yield of 54.5% (n=90). Descriptive statistics, analysis of variance, Spearman's rank correlation, Cronbach's alpha coefficient, Kaiser-Meyer-Olkin Measure, and exploratory factor analyses were used to analyze the anonymized results. Results: "Job satisfaction", "lifestyle following training" and, "impact on the patient" were the three highest rated considerations when choosing a specialty. Fifty-two and seventeen percent (n=24) and 57.89% (n=22) of males and females ranked non-surgical specialties as their top choice. Student confidence in their specialty preferences was moderate, meaning their preference could likely change (mean=2.40/5.00, SD=1.23). ANOVA showed no significant differences between confidence and population size (F(2,86)=0.290, p=0.75) or marital status (F(2,85)=0.354, p=0.70) in both genders combined. Five underlying factors that explained 44.32% of the total variance were identified. Five themes were identified to enhance career counseling. Conclusions: Medical students in their first month of training have already considered their specialty preferences, despite limited exposure. However, students are not fixed in their specialty preference. Our findings further support previous results but expand what students consider when choosing their specialty early in their training. Medical educators and administrators who recognize and understand the importance of these considerations may further enhance career counseling and medical education curricula. PMID- 29140795 TI - It's the holes that matter. PMID- 29140796 TI - Temperature and impurity effect on parallel field magnetoconductance of bulk insulating topological insulator (Bi1-x Sb x )2Te3. AB - We have performed a systematic parallel field magnetotransport studies of (Bi1-x Sb x )2Te3 to understand the temperature and impurity effect on the interference of bulk conductance on the surface states of highly insulating topologically insulating compound Bi2Te3. The compound exhibits a weak antilocalization effect (WAL) at low temperature and low magnetic field. WAL weakens and a weak localization effect is observed to be developed in the compound with the increase in temperature due to the creation of topologically trivial 2D electron gas states. Strong interlayer interference and coupling of bulk carriers with surface states are observed at low temperature. A similar temperature effect is observed for all concentrations of Sb. Topologically protected surface states enhance with the increase in Sb contents up to x = 0.3; however, a further increase in Sb concentration leads to a decrease in surface states. The data has been analysed via the generalised Altshuler and Aronov model for parallel field transport anticipating weak antilocalization and interlayer interference. PMID- 29140797 TI - Characterising endourologist learning curve during percutaneous nephrolithotomy: implications on occupational dose and patients. AB - In this study we have characterised the learning curve for percutaneous nephrolithotomy procedures over 301 cases for six years. Different surrogate parameters of clinical expertise have been used, such as dose area product, total procedure time, fluoroscopy time and personal equivalent doses. In addition, two different endourologists have been monitored; one of whom had specific Radiation Protection training (ICRP 85). Eye lens dose was estimated from thermoluminescent dosimeters. Significant differences were observed between both endourologists, especially in the fluoroscopy time. Finally, both entrance skin dose and effective doses of patients have been determined. PMID- 29140794 TI - Targeted elimination of senescent Ras-transformed cells by suppression of MEK/ERK pathway. AB - The Ras-Raf-MEK-ERK pathway plays a central role in tumorigenesis and is a target for anticancer therapy. The successful strategy based on the activation of cell death in Ras-expressing cells is associated with the suppression of kinases involved in Ras pathway. However, activation of cytoprotective autophagy overcomes antiproliferative effect of the inhibitors and develops drug resistance. We studied whether cellular senescence induced by HDAC inhibitor sodium butyrate in E1a+cHa-Ras-transformed rat embryo fibroblasts (ERas) and A549 human Ki-Ras mutated lung adenocarcinoma cells would enhance the tumor suppressor effect of MEK/ERK inhibition. Treatment of control ERas cells with PD0325901 for 24 h results in mitochondria damage and apoptotic death of a part of cellular population. However, the activation of AMPK-dependent autophagy overcomes pro apoptotic effects of MEK/ERK inhibitor and results in restoration of the mitochondria and rescue of viability. Senescent ERas cells do not develop cytoprotective autophagy upon inhibition of MEK/ERK pathway due to spatial dissociation of lysosomes and autophagosomes in the senescent cells. Senescent cells are unable to form the autophagolysosomes and to remove the damaged mitochondria resulting in apoptotic death. Our data show that suppression of MEK/ERK pathway in senescent cells provides a new strategy for elimination of Ras expressing cells. PMID- 29140798 TI - Response to Dr Baverstock's letter to the editor. PMID- 29140799 TI - Letter in response to Pfinder et al on the efficacy of the WHO guidelines on iodine prophylaxis. PMID- 29140800 TI - Glassy magnetic ground state and Kondo-like behaviour in Mn10FeGe8 alloy. AB - We report a detailed investigation of the ground-state magnetic properties of newly synthesized [Formula: see text] [Formula: see text] alloy. The sample can be thought of being derived by substituting one Mn atom by Fe of the parent compound [Formula: see text] [Formula: see text]. Fe-substitution leads to a drastic change in the magnetic ground state as well as to the magneto-transport properties of the parent alloy. On cooling below 250 K, [Formula: see text] [Formula: see text] undergoes a transition from paramagnetic phase to a state having significant ferromagnetic correlations. The ground state is found to be canonical spin glass (CSG) type in nature as evident from the dc magnetization and ac susceptibility measurements. Interestingly, the resistivity data shows an upturn at low temperature below about 30 K, mimicking Kondo-like behaviour. [Formula: see text] [Formula: see text] turns out to be a rare example among 3d transition metal alloys, where a Kondo-like state coexists within a CSG phase. PMID- 29140801 TI - Validation of the Microlife BP A3 PC upper arm blood pressure monitor in patients with diabetes mellitus according to the ANSI/AAMI/ISO 81060-2: 2013 protocol. AB - OBJECTIVE: The aim of the present study was to validate the blood pressure (BP) measurement device, Microlife BP A3 PC, in patients with diabetes mellitus, according to the ANSI/AAMI/ISO 81060-2:2013 protocol. PATIENTS AND METHODS: In 85 individuals aged 56-88 years, with predefined criteria for diabetes mellitus, BP measurements on the upper arm were performed alternately using the Microlife BP A3 PC and a standard mercury reference sphygmomanometer. A total of 333 comparisons were included for analysis. RESULTS: The mean difference between the Microlife BP A3 PC and the reference was -1.5+/-6.3 mmHg for systolic BP (SBP) and -1.3+/-5.2 mmHg for diastolic BP (DBP) according to criterion 1 of the protocol. For SBP, a total of 209 of the 333 measurements were within the range of 5 mmHg (62.8%), whereas the corresponding numbers for DBP were 232 of 333 (69.7%). For criterion 2, the intraindividual differences for the test device and the reference were -1.50+/-4.73 mmHg for SBP and -1.30+/-4.55 mmHg for DBP, thus being within the defined ranges provided by the protocol. CONCLUSION: The Microlife BP A3 PC fulfilled the requirements of criteria 1 and 2 of the ANSI/AAMI/ISO 81060-2:2013 protocol and can also be recommended for BP measurement in diabetic patients. PMID- 29140802 TI - Characterization With Scanning Electron Microscopy/Energy-Dispersive X-ray Spectrometry of Microtraces From the Ligature Mean in Hanging Mechanical Asphyxia: A Series of Forensic Cases. AB - The authors applied scanning electron microscopy with energy-dispersive x-ray spectrometry to the furrow derived from hanging means. The study was conducted with the purpose to detect possible extraneous microtraces, deriving from the ligature, that could have had an interaction with the cutaneous biological matrix, thanks to a transfert mechanism, in the proximities of the lesion.Fifteen cutaneous samples of the furrow and an equal number of fragments of graphite tape, directly positioned on the lesion produced by the ligature mean and used as a "conductor" of possible traces, were analyzed using scanning electron microscopy with energy-dispersive x-ray spectrometry.The research of microscopic traces on the furrow using this technique highlights extraneous traces leading to 3 main categories: natural fabrics, and synthetic and metallic materials, excluding possible environmental pollutants. The analysis, run on 7 hanging deaths, made available by the judicial authority, found a morphological and compositional compatibility with the traces found on the cutaneous furrow produced during hanging.The technique used in this study is innovative in the pathological-forensic field, and can be considered useful in clarifying and studying this typology of asphyxia leading to a specific ligature material, when missing, or attributing the cause of death to hanging when the furrow is not macroscopically obvious. PMID- 29140803 TI - Use of Postmortem Computed Tomography to Detect Bowel Obstruction and its Relationship to the Cause of Death. AB - Bowel distension frequently indicates bowel obstruction, which is a common diagnosis in clinical radiology. Typically, symptoms and complaints lead to radiological examinations and the detection of the etiology. Untreated intestinal obstructions can lead to a fatal outcome through cardiac failure due to septic shock. Certain of these cases undergo medicolegal investigations depending on the case history, the condition of the decedent, the location of the finding, or recent visits to medical professionals. Computed tomography (CT) is a recommended method in clinical radiology for the detection of bowel obstruction, which is indicated by bowel distension and further radiological signs (eg, the whirl sign, which indicates a volvulus). Postmortem CT (PMCT) has increased worldwide, but PMCT differs from clinical CT; thus, the question of whether PMCT is also reliable for the detection of bowel obstruction in decedents or is negatively affected by postmortem modifications should be discussed. This study consists of 10 cases displaying radiological signs of bowel obstruction. Apart from bowel distension, the most common radiological signs (whirl sign, coffee bean sign, bird beak sign, and u-shape sign) are described and depicted. All decedents underwent autopsy and had a postmortem interval of less than 72 hours. Based on these cases, we assess the reliability of PMCT for detecting bowel obstruction and determining its relationship to the cause of death. PMID- 29140804 TI - Exploration of Predictive Biomarkers for Sudden Unexplained Cardiac Death in Nonelderly People: A Case-Control Study With Biochemical Parameters Related to Heart Failure. AB - Sudden unexplained cardiac death (SUCD) can occasionally occur in nonelderly patients with epilepsy, psychiatric disorders, or no medical history. This study was conducted to aim to analyze whether values of the biomarkers for heart failure are associated with the SUCD. Serum concentrations of N-terminal probrain natriuretic peptide, high-sensitivity C-reactive protein (hs-CRP), and tumor necrosis factor alpha were analyzed in 57 nonelderly patients with SUCD who was diagnosed at medicolegal autopsy. The subjects were divided into 3 subgroups according to the medical history: (1) epilepsy, (2) psychiatric disorders, and (3) no specific medical history. The results showed that serum hs-CRP levels were significantly high in patients with epilepsy (P = 0.01) or psychiatric disorders (P = 0.01) as compared with the controls. Also, significantly high concentrations of hs-CRP were observed in psychiatric patients with schizophrenia, compared with the controls (P = 0.003) or the other psychiatric diseases (P = 0.01). The level of N-terminal probrain natriuretic peptide and tumor necrosis factor alpha did not show a significant difference between the SUCD and the controls. These results might suggest the association between high serum hs-CRP levels and the potential impairment of the cardiac function before the fatal event. PMID- 29140805 TI - Health-Related Decisions for Serious Illness Among Ethnically Diverse Older Adults. AB - We investigated the influence of sociodemographic factors, acculturation, ethnicity, health status, and spirituality on older adults' health-related decisions when confronted with a choice between competing options. The sample included 451 participants: African Americans (15.74%), Afro-Caribbeans (25.5%), European Americans (36.36%), and Hispanic Americans (22.4%). Compared with others, European Americans and Hispanic Americans favored quality of life over a lengthy life. Sociodemographic factors, acculturation, ethnicity, health status, and spirituality accounted for variations of decisions. The variability of decisions calls for multiple care options to explore the value of different trade offs in order to avoid predetermined clinical practice guidelines, especially in nursing. PMID- 29140806 TI - Florid Granuloma Annulare-Like Reaction in Regional Lymph Nodes After "Regression" of Red Pigment in Tattoos. AB - A healthy 50-year-old woman had a tattoo performed on the posterior aspect of her neck and another on the dorsum of her left foot. Several weeks later, she noted redness, tenderness, and intense pruritis at both tattoo sites. Treatment with cephalexin and hydrocortisone cream was instituted, without success. Within a few months, the red, but not black, pigment had disappeared from both tattoos and was replaced by pale areas of scarring. Persistently enlarged left supraclavicular and suboccipital lymph nodes were excised 7 and 10 months after receipt of the tattoos, respectively. The nodes were pigmented on gross examination, and on microscopy, a granuloma annulare-like reaction was observed. Normal lymphoid tissue was seen to be replaced by large palisading granulomas with central degenerative change, abundant stromal mucin, and scattered deposits of tattoo pigment. Histochemical stains, tissue culture, and serological studies revealed no evidence of infection. There are rare reports of granuloma annulare-like reactions in tattoos, and these are believed to represent delayed-type hypersensitivity reactions. Our case is unique in the observation of this reaction pattern in regional lymph nodes, and it expands the spectrum of complications known to be associated with tattoos. PMID- 29140807 TI - Persistent Upper Lip Swelling in a Young Woman. PMID- 29140808 TI - Randomized trial evaluating the effect of aged garlic extract with supplements versus placebo on adipose tissue surrogates for coronary atherosclerosis progression. AB - AIMS: Increased epicardial adipose tissue (EAT), pericardial adipose tissue (PAT), periaortic adipose tissue (PaAT), and subcutaneous adipose tissue (SAT) are mediators of metabolic risk, and are associated with the severity of coronary artery calcium (CAC). Aged garlic extract (AGE) has been shown to reduce the progression of coronary atherosclerosis. This study evaluates the effect of AGE with supplements (AGE+S) on EAT, PAT, SAT, and PaAT. METHODS: Sixty asymptomatic participants participated in a randomized trial evaluating the effect of AGE+S versus placebo on coronary atherosclerosis progression, and underwent CAC at baseline and after 12 months of treatment. EAT, PAT, PaAT, and SAT volumes were measured on CAC scans. PAT was calculated as: intrathoracic adipose tissue-EAT. SAT was defined as the volume of fat depot anterior to the sternum and posterior to the vertebra. PaAT was defined as fat depot around the descending aorta. RESULTS: At 1 year, the increase in EAT, PAT, PaAT, and SAT was significantly lower in the AGE+S as compared with the placebo group (P<0.05). The odds ratios of increase in EAT, PAT, PaAT, and SAT were 0.63 [95% confidence interval (CI): 0.43-0.90], 0.72 (95% CI: 0.45-0.93), 0.81 (95% CI: 0.65-0.98), and 0.87 (CI: 0.52-0.98), respectively, compared with the placebo group, which even remained significant (all P<0.05) after adjustment for cardiovascular risk factors and statin therapy and BMI. CONCLUSION: This study shows that AGE+S is associated with favorable effects on reducing the progression rate of adipose tissue volumes. PMID- 29140810 TI - Are We Scoring a Goal by Banning Headers From Soccer? PMID- 29140809 TI - Stem cell therapy for acute myocardial infarction: on the horizon or still a dream? PMID- 29140811 TI - Prevalence of Spondylolysis in Symptomatic Adolescent Athletes: An Assessment of Sport Risk in Nonelite Athletes. AB - OBJECTIVE: To assess the risk of spondylolysis by sport in nonelite adolescent athletes with low back pain (LBP). DESIGN: Retrospective case series. SETTING: Hospital-based sports medicine clinic. PATIENTS: The medical charts of 1025 adolescent athletes with LBP (age 15 +/- 1.8 years) were examined; 308 (30%) were diagnosed with a spondylolysis. ASSESSMENT OF RISK: Risk of spondylolysis was assessed in 11 sports for males and 14 sports for females. MAIN OUTCOME MEASURE: Relative risk of diagnosis of spondylolysis injury. RESULTS: The risk of spondylolysis differed by sex with baseball (54%), soccer (48%), and hockey (44%) having the highest prevalence in males and gymnastics (34%), marching band (31%), and softball (30%) for female athletes. Baseball was the only sport to demonstrate a significant increased risk of spondylolysis. CONCLUSIONS: The sports with the greatest risk of spondylolysis in adolescent athletes in this study were not consistent with published literature. Clinicians should be cautious generalizing high-risk sports to their practice, as geographic region and level of the athlete may significantly influence the incidence of spondylolysis in the population they are treating. PMID- 29140813 TI - Chad Brummett, M.D., Recipient of the 2017 James C. Cottrell, M.D., Presidential Scholar Award: Erratum. PMID- 29140814 TI - Visual snow syndrome: what we know so far. AB - PURPOSE OF REVIEW: We provide an overview of the neurological condition known as visual snow syndrome. Patients affected by this chronic disorder suffer with a pan-field visual disturbance described as tiny flickering dots, which resemble the static noise of an untuned television. RECENT FINDINGS: The term 'visual snow' has only appeared in the medical literature very recently. The clinical features of the syndrome have now been reasonably described and the pathophysiology has begun to be explored. This review focuses on what is currently known about visual snow. SUMMARY: Recent evidence suggests visual snow is a complex neurological syndrome characterized by debilitating visual symptoms. It is becoming better understood as it is systematically studied. Perhaps the most important unmet need for the condition is a sufficient understanding of it to generate and test hypotheses about treatment. PMID- 29140815 TI - Neuroimaging diagnostic and monitoring approaches in ophthalmology. AB - PURPOSE OF REVIEW: We review new applications of optical coherence tomography (OCT) technology in neuro-ophthalmology. We also describe new technologies for visualizing the extracranial vessels in the diagnosis of giant cell arteritis (GCA). RECENT FINDINGS: Newer OCT modalities are expanding the evaluation of the optic disc, and are being applied to a number of neurologic conditions such as demyelinating and neurodegenerative disease. Swept-source OCT and enhanced-depth imaging OCT are refining the fine-grained analysis of the optic nerve head in the diagnosis of papilledema and optic nerve drusen. OCT-angiography is opening up new avenues to the study of the vasculature of the optic nerve head and its disorders, including ischemic optic neuropathy. Newer technologies in the diagnosis of GCA include vascular ultrasound, magnetic resonance imaging (MRI) of the extracranial vasculature and PET imaging of the large vessels. SUMMARY: OCT and several of its derivations are advancing diagnosis, and in some cases prognostication, in a variety of inflammatory, ischemic and compressive optic neuropathies. These technologies hold potential in the laboratory as well, yielding insights into the mechanisms of a variety of neurological conditions. In addition, further developments in MRI and ultrasonography techniques are shaping the approach to the diagnosis of GCA. PMID- 29140816 TI - The role of small incision suture-less cataract surgery in the developed world. AB - PURPOSE OF REVIEW: Manual small incision cataract surgery (MSICS) has recently gone through much refinement and fine tuning. It is often taken as an alternate option for phacoemulsification, especially in developing country. This review will present some insight on its applications especially for developed nations. The role of MSCIS in tackling complex cataracts with stony hard nucleus is fairly established. The role of training residents with MSCIS has certain advantages though debatable. RECENT FINDINGS: MSCIS is much faster and cost-effective surgical technique often possible in suboptimal condition and avoids the capital and maintenance cost of phacoemulsification. The visual outcome and postoperative complications in both phacoemulsification and MSCIS are comparable. Slightly greater astigmatism in MSICS can be lessened with a slight modification of surgical technique. The successful application of MSCIS in large public health programmes has successfully helped to increase the cataract surgical rate and quality. It is the technique of choice for blindness control programme in developing country. SUMMARY: MSICS is established as safe and cost-effective procedure in developing country with results as good as phaoemulsification. Although it may not be the best option for developed nations, it is a valuable skill especially for surgical conversion and to deal with complex and advance cataract cases. Hence, it should be a part of resident training programme in developed world and it should be in the armamentarium of every cataract surgeon. PMID- 29140817 TI - New developments in optical coherence tomography imaging for glaucoma. AB - PURPOSE OF REVIEW: Since its introduction in ophthalmology, optical coherence tomography (OCT) has undergone significant advances in imaging protocols, algorithms, and addition of new parameters which have maximized its potential for diagnosing, evaluating the response to treatment, and assessing the progression of various ocular diseases, including glaucoma. This review provides an update on recent developments in OCT with respect to the management of glaucoma. RECENT FINDINGS: Most recent notable developments include the introduction of the minimum distance band, which is a three-dimensional optic nerve head parameter, and Swept-Source OCT with its single wide-field scanning capability. The introduction of OCT angiography provides additional structural and functional measures for glaucoma management. Adaptive optics helps visualize individual RNFL bundles and measure their widths. SUMMARY: Continued improvements in OCT technology is both enhancing our understanding of glaucoma and improving our ability to manage the disease. PMID- 29140818 TI - Drop instillation and glaucoma. AB - PURPOSE OF REVIEW: To describe the current state of knowledge regarding glaucoma patients' eye drop technique, interventions attempting to improve eye drop technique, and methods for assessing eye drop technique. RECENT FINDINGS: In observational studies, between 18.2 and 80% of patients contaminate their eye drop bottle by touching their eye or face, 11.3-60.6% do not instill exactly one drop, and 6.8-37.3% miss the eye with the drop. Factors significantly associated with poorer technique include older age, lack of instruction on eye drop technique, female sex, arthritis, more severe visual field defect, lack of positive reinforcement to take eye drops, lower educational level, low self efficacy, and being seen at a clinic rather than a private practice. Among intervention studies, four of five studies using a mechanical device and three of four studies using educational interventions to improve technique showed positive results, but none of the studies were randomized controlled trials. SUMMARY: Poor eye drop technique is a significant impediment to achieving good control of intraocular pressure in glaucoma. Both mechanical device interventions and educational interventions offer promise to improve patients' technique, but studies with stronger designs need to be done followed by introduction into clinical practice. PMID- 29140819 TI - Positive and Negative Impacts of a Continuing Professional Development Intervention on Pharmacist Practice: A Balanced Measure Evaluation. AB - INTRODUCTION: Evaluations of behavior change interventions aimed at improving professional practice are increasingly focused on impacts at the practice and patient outcome levels. Many of these evaluations assume that if the intended changes occur, the result represents an improvement. However, given the systemic nature of clinical practice, a change in one area can produce changes in other areas as well, some of which may adversely affect the patient. Balancing measures are used to determine whether unintended consequences of an intervention have been introduced into other areas of the system. The aims of this study were to evaluate the impact of behavior change intervention-based continuing professional development (CPD) on pharmacist interventions (resolution of drug therapy problems-DTPs) and resolution of quality indicator DTPs and knowledge change for urinary tract infections (UTI) and pneumonia. As a balancing measure, we aimed to determine whether delivery of behavior change interventions targeting pneumonia and UTI practice results in a negative impact on other important pharmacist interventions, specifically the resolution of heart failure DTPs. METHODS: A quasiexperimental study was conducted at a Canadian health authority that evaluated the impacts of an 8-week multifaceted behavior change intervention delivered to 58 ward-based pharmacists. The primary outcome was change in proportion of UTI and pneumonia DTPs resolved from the 6-month preintervention to 6-month postintervention phase. Secondary outcomes were changes in proportion of UTI and pneumonia quality indicator DTPs resolved, knowledge quiz scores, and proportion of quality indicator DTPs resolved for heart failure as a balancing measure. RESULTS: A total of 58 pharmacists were targets of the intervention. The proportion of resolved UTI and pneumonia DTPs increased from 17.8 to 27.2% (relative risk increase 52.8%, 95% confidence interval [CI] 42.8-63.6%; P < 0.05). The proportion of resolved UTI and pneumonia quality indicator DTPs increased from 12.2% to 18.2% (relative risk increase 49.9%, 95% CI 34.5-67.0%; P < 0.05). Resolved heart failure DTPs decreased from 14.3 to 8.5% (RRR 40.4%, 95% CI 33.9-46.2%; P < 0.05). Thirty-six pharmacists completed the pre- and post quiz. Scores increased from 11.3/20 +/- 3.2/20 to 14.8/20 +/- 2.9/20 (P < 0.05). DISCUSSION: CPD using a multifaceted behavior change intervention improved pharmacist behavior and knowledge for UTI and pneumonia. However, these improvements may be offset by reduced interventions for other disease states, such as heart failure. Strategies to mitigate the unintended effects on other professional behaviors should be implemented when delivering CPD focused on changing one aspect of professional behavior. PMID- 29140821 TI - Retarding progression of chronic kidney disease: use of modalities that counter acid retention. AB - PURPOSE OF REVIEW: Acid retention because of chronic kidney disease (CKD) increases tissue acidity and accelerates progression of CKD, whereas reduction in acid retention slows progression of CKD. Herein, we describe the mechanisms through which increased tissue acidity worsens CKD, modalities for countering acid retention and their impact on progression of CKD, and current recommendations for therapy. RECENT FINDINGS: Studies in animals and humans show that increased tissue acidity raises the renal levels of endothelin, angiotensin II, aldosterone, and ammoniagenesis, thereby worsening renal fibrosis and causing progression of CKD. Measures that counter acid retention, such as providing alkali or modifying the quantity or type of dietary protein, reduce the levels of endothelin, angiotensin II, aldosterone, and ammoniagenesis, slowing progression of CKD. Alkali can be provided as NaHCO3, sodium citrate, or base in fruits and vegetables. A serum [HCO3] of 24-26 mEq/l is targeted, because higher values can be associated with adverse consequences. SUMMARY: Insights into the mechanisms through which increased tissue acidity mediates progression of CKD and the beneficial impact of ameliorating positive acid balance underlie our recommendation for modalities that counter acid retention in CKD. PMID- 29140820 TI - Renal effects of cytokines in hypertension. AB - PURPOSE OF REVIEW: Inflammatory cytokines contribute to the pathogenesis of hypertension through effects on renal blood flow and sodium handling. This review will update recent advances that explore the renal actions of immune cells and cytokines in the pathogenesis of hypertension. RECENT FINDINGS: Populations of cells from both the innate and adaptive immune systems contribute to hypertension by modulating functions of the vasculature and epithelial cells in the kidney. Macrophages and T lymphocytes can directly regulate the hypertensive response and consequent target organ damage. Dendritic cells and B lymphocytes can alter blood pressure (BP) indirectly by facilitating T-cell activation. Proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin 17, interleukin 1, and interferon-gamma augment BP and/or renal injury when produced by T helper 1 cells, T helper 17 cells, and macrophages. In contrast, interleukin 10 improves vascular and renal functions in preclinical hypertension studies. The effects of transforming growth factor-beta are complex because of its profibrotic and immunosuppressive functions that also depend on the localization and concentration of this pleiotropic cytokine. SUMMARY: Preclinical studies point to a key role for cytokines in hypertension via their actions in the kidney. Consistent with this notion, anti-inflammatory therapies can attenuate BP elevation in human patients with rheumatologic disease. Conversely, impaired natriuresis may further polarize both T lymphocytes and macrophages toward a proinflammatory state, in a pathogenic, feed-forward loop of immune activation and BP elevation. Understanding the precise renal actions of cytokines in hypertension will be necessary to inhibit cytokine-dependent hypertensive responses while preserving systemic immunity and tumor surveillance. PMID- 29140823 TI - Single-Center Retrospective Study on Meibomian Gland Loss in Patients With Ocular Chronic Graft-Versus-Host Disease. AB - OBJECTIVES: This study aimed to analyze the influencing factors of meibomian gland loss in patients with ocular chronic graft-versus-host disease (GVHD) and its correlation with other clinical ocular surface assessment indexes. METHODS: The clinical data of patients with ocular chronic GVHD from the ocular surface and corneal outpatient clinic of the First Affiliated Hospital of Soochow University were reviewed from June 2012 to June 2016. The relationship between the percentage of meibomian gland acinar area and the influencing factors, such as patient's sex, age, transplantation method, human leukocyte antigen (HLA) matching, the time when eye discomfort appeared after transplantation (month), and the severity of ocular chronic GVHD, was investigated. Moreover, the correlation between the percentage of meibomian gland acinar area and other ocular surface assessment indexes, such as subjective ocular symptom score, eyelid margin score, tear film break-up time, corneal and conjunctival staining score, and the Schirmer test, was analyzed. RESULTS: A linear relationship was found between the percentage of meibomian gland acinar area and the severity of ocular chronic GVHD, but no linear relationship existed between the percentage of meibomian gland acinar area and the factors such as sex, age, transplantation method, HLA matching, and the time when eye discomfort appeared after transplantation. A negative correlation was observed between the percentage of meibomian gland acinar area and eyelid margin score. CONCLUSIONS: The percentage of meibomian gland acinar area can reflect the severity of ocular chronic GVHD. The clinical significance of the percentage of meibomian gland acinar area needs further investigation. PMID- 29140822 TI - Optimizing Pregnancy Treatment Interventions for Moms (OPTI-Mom): A Pilot Study. AB - OBJECTIVES: The public health burden of opioid use disorder (OUD) among pregnant women has significantly increased in recent years. The Optimizing Pregnancy Treatment Interventions for Moms study was a pilot project that examined the feasibility of a patient navigation (PN) intervention model to reduce substance use and improve mental health, quality of life, and to increase engagement with treatment services among pregnant women with OUD. METHODS: A 1-group repeated measures pilot study was conducted with treatment-seeking pregnant women with opioid dependence initiating buprenorphine maintenance treatment. Participants received the PN intervention delivered as 10 sessions before delivery and 4 sessions postpartum. Participants completed assessments at baseline and after the prenatal and postnatal portions of the intervention. Demographics were assessed using descriptive statistics, and general estimating equation analyses were employed to examine changes in health and service engagement across time. RESULTS: in all, 21 women were enrolled and completed the PN intervention and follow-up assessments. Participants reported improvements in abstinence from illicit opioids (B = 0.15, 95% confidence interval [CI] 0.1-0.2), drug use (odds ratio [OR] 5.25, 95% CI 2.1-13.0), and depression (OR 7.70, 95% CI 2.4-25.1). Results also showed nonsignificant trends suggesting enhancements in general health (B = 0.17, 95% CI 0.0-0.3, P = 0.06) and increases in substance use treatment attendance (B = 2.15, 95% CI -0.2 to 4.5, P = 0.07). Most study participants achieved adequate or better prenatal care. CONCLUSIONS: These findings provide support that PN is a feasible adjunctive intervention that shows promise for health improvements and service engagement among treatment-seeking pregnant women with opioid dependence initiating buprenorphine. PMID- 29140824 TI - Beginnings of Astigmatism Understanding and Management in the 19th Century. AB - Within the last 200 years, the perception of astigmatism has evolved from that of an infrequent and peculiar defect of the eye to a distortion almost as common as spherical refractive errors. Most of the significant findings on this condition were made in the 19th century, including the first description by Thomas Young (1773-1829) and the introduction of the treatment methods used today. The purpose of this study was to investigate the milestones in the understanding and management of astigmatism that occurred up to the year 1900. This fascinating history illustrates how knowledge evolves across time, geographical areas, and interdisciplinary boundaries. The first article looking at the use of a cylindrical lens to correct astigmatism was written by George Airy (1801-1892) in 1825. The term "astigmatism" was introduced in by William Whewell (1794-1866) in 1846. Methods for subjective and objective evaluation were subsequently established, including the introduction of a cross cylinder, keratoscope, astigmatic dial, and the development of retinoscopy and ophthalmoscopy. In the last two decades of the 19th century, the first attempt to alter the refraction in astigmatic patients by changing the shape of the cornea was made. It must be noted that diverse challenges were encountered in this field on the way to the development of a treatment, including the technical manufacture of a lens, the precise measurement of the refractive error, and understanding the optical properties of the eye. The importance of the 19th century was that interdisciplinary cooperation, such as that seen in this study, between physicists and astronomers, and mathematicians and physicians, led to the development of comprehensive knowledge on astigmatism. PMID- 29140825 TI - Recurrent Corneal Erosions Secondary to Use of Sleep Mask. AB - A 31-year-old woman with a history of unusual appearing recurrent linear corneal epithelial defects and subepithelial scaring in both eyes underwent 2 years of evaluation and treatment. It was eventually discovered that the patient was using a sleep mask with excessive fabric pilling, which was found to be the source of her chronic epitheliopathy. After discontinuation of the sleep mask, the patient experienced complete resolution of symptoms. When evaluating recurrent corneal epithelial defects, external sources of repeated trauma, including sleepwear, should be investigated. PMID- 29140826 TI - Effects of integrating rhythmic arm swing into robot-assisted walking in patients with subacute stroke: a randomized controlled pilot study. AB - This study aimed to identify the effects of rhythmic arm swing during robot assisted walking training on balance, gait, motor function, and activities of daily living among patients with subacute stroke. Twenty patients with subacute stroke were recruited, and thereafter randomly allocated to either the experimental group that performed the robot-assisted walking training with rhythmic arm swing, or the control group that performed the training in arm fixation. In total, 30 training sessions were carried out. The outcome measures included the 10-m walk test, Berg balance scale, timed up-and-go test, fall index that was measured using the Tetrax system, motor function test of Fugl-Meyer assessment, and modified Barthel index. The patients of both groups showed significant improvement in all parameters after the intervention (P<0.05). The Berg balance scale, Fugl-Meyer assessment, and modified Barthel index scores at post-test appeared to be significantly higher for the experimental group than for the control group (P<0.05). These findings indicate that more favorable effects from robot-assisted walking training in patients with subacute stroke may be obtained by the use of rhythmic arm swing. PMID- 29140827 TI - Reliability of translation of the RAND 36-item health survey in a post rehabilitation population. AB - The aim of this study is to evaluate the reliability of the RAND 36-item Health survey as a measure of health-related quality of life in a general Dutch post rehabilitation population. A total of 752 ex-rehabilitation patients were invited to complete the Dutch RAND 36-item health survey. After 2 weeks, the people who responded to the first questionnaire were asked to complete the same questionnaire again. Internal consistency of the questionnaire was expressed as Cronbach's alpha. Test-retest reliability was expressed as intraclass correlation coefficient (ICC) and presented in Bland-Altman plots. Internal consistency was found acceptable for all subscales (n=276; Cronbach's alpha ranged from 0.81 to 0.95). Test-retest reliability was found acceptable for research and group comparisons for all subscales (n=184; ICC ranged from 0.71 to 0.88). Overall, test-retest reliability of the physical functioning (ICC=0.86), pain (ICC=0.87), and general health (ICC=0.88) subscale was relatively high, and that of health change (ICC=0.71) was relatively low. Reliability of the questionnaire did not notably differ between participants who indicated stable health and participants who indicated health change during the past weeks. In conclusion, the Dutch translation of the RAND 36-item health survey is reliable for research and group comparisons in a general post-rehabilitation population. However, the RAND 36 item health survey is not sufficiently reliable for individual comparisons within this population. PMID- 29140828 TI - Biomimetic nanoparticles for transplantation tolerance. AB - PURPOSE OF REVIEW: The current review aims to provide a current landscape and future trends of biomimetic nanoparticles which have the potential to revolutionize the field of transplantation in the next decade. RECENT FINDINGS: Currently, the inability to safely induce robust donor-specific immunological tolerance makes it difficult to achieve immunosuppression-free graft survival. Despite progresses in the development of nanotherapeutics for antigen-specific immunomodulation in autoimmune diseases and in cancer treatments, few have been proposed and tested in transplantation with success. The complexity of parallel rejection mechanisms, multitude of antigen epitopes, and potential epitope spreading have challenged conventional nanodelivery systems in transplant models. Overcoming such challenges, biomimetic nanotherapeutics represent a promising alternative, as they allow better recapitulation of the complexity of the main biological players involved in tolerance. Within biomimetic nanodelivery systems, we envision that hybrid systems mimicking extracellular vesicles have the potential to bridging the gap between cell-based therapies, which are effective but costly and difficult to translate in clinical practice, and fully synthetic systems which are relatively easy to manufacture but lack the capacity to recapitulate the complexity of transplant antigens and tolerance mechanisms. SUMMARY: Next-generation nanotherapeutics for tolerance delivery is evolving toward biomimetic systems capable of capturing an increasing level of antigen complexity and exploiting multiple tolerance pathways. PMID- 29140829 TI - Guiding regulatory T cells to the allograft. AB - PURPOSE OF REVIEW: The application of regulatory T cell (Treg) therapy in organ transplantation is actively being pursued using unmodified, typically polyclonal cells. As the results of these ongoing clinical trials emerge, it is time to plan the next wave of clinical trials of Tregs. Here we will review a key strategy to improve Treg effectiveness and reduce side effects, namely increasing Treg specificity - both in terms of antigen recognition and localization to the allograft. RECENT FINDINGS: Study of chemokine signatures accompanying acute rejection has revealed several chemokines that could be targeted to increase Treg homing. For example, Tregs possessing a Th1-like phenotype and expressing CXCR3 are better able to migrate towards local inflammation. Allografts themselves can be modified to increase Treg-attracting chemokines and Tregs themselves can produce chemokines, facilitating local proximity to their targets of suppression. Finally, tailoring Treg antigen specificity by T-cell or chimeric antigen receptor engineering is another approach to increase the specificity of suppression and optimize localization. SUMMARY: Treg localization to the graft is important, but the important role of lymph node and germinal center homing cannot be overlooked. There is an opportunity to learn from advances made in cancer immunotherapy to optimize Treg therapy for transplantation. PMID- 29140830 TI - Aspects of growth and development: endocrine and nonendocrine paradigms. PMID- 29140831 TI - Relative Efficacies of HBOC-201 and Polyheme to Increase Oxygen Transport Compared to Blood and Crystalloids. "2017 Military Supplement". AB - BACKGROUND: Because total hemoglobin in circulation ([THb]) is an established predictor of clinical outcomes in anemic individuals, the relative efficacies of resuscitation fluids to increase [THb] can be used to design better hemoglobin based oxygen carrier (HBOC) clinical trials. METHODS: Expected efficacies of HBOC 201 (13 g Hb/dL) and packed RBCs (pRBCs, 24 g Hb/dL) to increase [THb] were calculated and interpreted in the context of SAEs in the HEM-0115 phase III clinical trial.The PolyHeme phase III clinical trial compared the HBOC, PolyHeme (10 g Hb/dL), to crystalloid control prehospital and packed RBCs in hospital. The comparative abilities of these resuscitation fluids to maintain [THb] were interpreted in the context of mortality. RESULTS: In HEM-0115, infusion of HBOC 201 increased [THb] by 0.18 +/- 0.03 g/dL (N=121) compared to 0.87 +/- 0.07 g/dL (N = 115) following one unit of pRBCs. These observed increases in [THb] were similar to expected increases for these fluids. Use of HBOC-201 was associated with 0.34 SAEs per patient compared to 0.25 SAEs per patient in the pRBC arm (p = 0.016).Hemoglobin (Hb) Deficit was greater in HBOC-201-treated patients than in pRBC controls and emerged as a predictor of SAEs in a logistics model. Randomization to HBOC-201 had no power to predict SAEs.PolyHeme more effectively maintained [THb] than did crystalloid prior to arrival at hospital, associated with initially higher survival in the PolyHeme arm. Thereafter, PolyHeme subjects sustained lower [THb] and higher mortality than controls. CONCLUSION: Greater anemia in subjects randomized to HBOC-201 was consistent with the relative efficacies of HBOC-201 and pRBCs to increase [THb] and may have contributed to more SAEs in the HBOC arm of HEM-0115 and greater long-term mortality in the PolyHeme trial. PMID- 29140832 TI - Platelet Function Changes in a Time-Dependent Manner Following Traumatic Brain Injury in a Murine Model. AB - Traumatic brain injury (TBI) results in systemic changes in coagulation and inflammation that contribute to post-traumatic morbidity and mortality. The potential interaction of platelets and pro-inflammatory cytokines in the modulation of coagulation, microthrombosis, and venous thromboembolic events after moderate TBI has not been determined. Using a murine model, we hypothesized that the degree of platelet-induced coagulation varies depending on the platelet aggregation agonist platelet-induced coagulation changes in a time-dependent manner following TBI, and changes in platelet-induced coagulation are mirrored by changes in the levels of circulating pro-inflammatory cytokines. An established weight-drop model was used to induce TBI in anesthetized mice. Blood samples were collected at intervals after injury for measurements of platelet count, serum fibrinogen, pro-inflammatory cytokines, and determination of soluble P-selectin levels. Thromboelastometry was used to evaluate changes in hemostasis. Platelet function was determined using whole blood impedance aggregometry. Ten minutes following TBI, adenosine diphosphate-induced platelet aggregation decreased as measured by platelet aggregometry. Despite no changes in platelet counts and serum fibrinogen, platelet aggregation, pro-inflammatory cytokines, and soluble P selectin were increased at 6 h after TBI. Rotation thromboelastometry demonstrated increased maximal clot firmness at 6 h. Platelet function and coagulability returned to baseline levels 24 h following head injury. Our data demonstrate that after TBI, acute platelet dysfunction occurs followed by rebound platelet hyperaggregation. Alterations in post-TBI platelet aggregation are reflected in whole blood thromboelastometry and are temporally associated with the systemic pro-inflammatory response. PMID- 29140833 TI - Immune checkpoint inhibitor therapy in a liver transplant recipient with a rare subtype of melanoma: a case report and literature review. AB - Immunotherapy with immune checkpoint inhibitors (ICIs) may be considered as a treatment option for various types of tumors, but the transplant recipient population as well as patients requiring long-term systemic immunosuppression for other reasons have been systematically excluded from clinical trials involving ICIs. We report a case of successful treatment with ICI in a liver transplant recipient diagnosed with a rare subtype of melanoma. This patient had not required any modification to her antirejection immunosuppression before or during immunotherapy, had not experienced any serious immune-related adverse event, and had a durable objective response for nearly 1.5 year now. A summary of a literature review on other case reports is included to show that ICIs can be safe and provide clinically meaningful benefit in transplant patients, although acute rejection and graft loss remain a significant risk. Given the serious complication of graft failure, a detailed discussion of risks and benefits with immunotherapy needs to be made for an informed consent. Nevertheless, transplant recipients with cancer should not be deprived of this potentially life-saving or life-prolonging treatment, and inclusion of this population in future clinical trials should be considered. PMID- 29140834 TI - Prognostic factors in patients with metastatic spinal cord compression secondary to melanoma: a systematic review. AB - Melanoma is one of the most common primary tumours associated with metastatic spinal cord compression (MSCC). The aim of this review is to identify prognostic factors specifically for MSCC secondary to melanoma. A systematic search of literature was performed in MEDLINE, Embase and the Cochrane Library to identify studies reporting prognostic factors for patients with MSCC secondary to melanoma. Two studies, involving a total of 39 patients, fulfilled the inclusion criteria. The variables associated with increased survival were receiving postoperative radiotherapy, receiving chemotherapy, perioperative lactate dehydrogenase level less than or equal to 8.0 ukat/l, preoperative haemoglobin level more than 11.5 mg/dl, an interval of 4 or more years between melanoma diagnosis and skeletal metastasis, absence of further skeletal metastases, absence of visceral metastases, Eastern Cooperative Oncology Group Performance Status of 2 or less, two or fewer involved vertebrae, being ambulatory preradiotherapy and an interval of more than 7 days between developing motor deficits and radiotherapy. The variables associated with good functional outcome were slow development of motor dysfunction, good performance status and being ambulatory before radiotherapy. The most important prognostic factors for survival are Eastern Cooperative Oncology Group Performance Status of 2 or less and absence of visceral metastases. There is a lack of studies looking specifically at prognostic factors for patients with MSCC secondary to melanoma, and the number of patients involved in the existing studies is small. PMID- 29140835 TI - Pyoderma Gangrenosum: The Great Impostor. PMID- 29140836 TI - Pyoderma Gangrenosum: A Critical Appraisal. AB - GENERAL PURPOSE: To provide information about pyoderma gangrenosum (PG), including pathophysiology, diagnostic criteria, and treatment. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to: ABSTRACT: Pyoderma gangrenosum (PG) is an uncommon cutaneous disease, presenting with recurrent painful ulcerations most commonly on the lower extremities. The diagnosis is made according to a typical presentation, skin lesion morphology, skin biopsy, histopathology, and the exclusion of other etiologies. Classically, PG presents with painful ulcers with well-defined violaceous borders; other variants including bullous, pustular, and vegetative/granulomatous can also occur. Treatment of PG involves a combination of topical and systemic anti-inflammatory and immunosuppressive medications, wound care, antimicrobial agents for secondary infections, and treatment of the underlying etiology. This article is a continuing education review of the literature with a focus on the clinical application of the pathophysiology, diagnosis, and treatment of this challenging disease. PMID- 29140837 TI - Disruption of Biofilms and Neutralization of Bacteria Using Hypochlorous Acid Solution: An In Vivo and In Vitro Evaluation. AB - OBJECTIVES: The aims of this study were to assess the effectiveness of a hypochlorous acid-based wound cleanser (Vashe Wound Solution [VWS], SteadMed Medical, Fort Worth, Texas) in disrupting methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa biofilms relative to other cleansers using an in vitro collagen biofilm model and to evaluate cleansers' cytotoxicity. The bioburden reduction of venous stasis wounds by VWS and another cleanser was evaluated. METHODS: Plates coated with collagen films incubated with active bacteria cultures to yield biofilm mimics were treated with VWS, 1% and 10% povidone-iodine (PI), 0.05% chlorhexidine wound solution (CWS), or normal saline for 3 or 10 minutes. Biofilms were then analyzed for biomass density using a crystal violet assay, quantitative cultures, and fluorescent microscopy. Cytotoxicity was measured using neutral red uptake by primary human dermal fibroblasts. Pre- and postcleansing exudates and swab samples obtained from venous stasis wounds of patients were processed and plated on a series of selective agar plates for bacteria typing and quantification. RESULTS: All agents tested significantly neutralized methicillin-resistant S aureus and P aeruginosa biofilms compared with saline control as assessed by crystal violet assay and fluorescent microscopy assays. Undiluted VWS was significantly less cytotoxic compared with 1% PI, CWS, and 10% PI (in increasing order of cytotoxicity). There was no significant difference in bacterial reduction in wounds after treatment with VWS or CWS for any type of bacteria examined using selective media. In wounds that were treated with VWS or CWS, there was a similar percentage reduction in bacterial colony-forming units from precleansing levels when plated on tryptic soy agar, MacConkey, streptococcal, and mannitol salt agar plates. Plates treated with CWS trended toward higher bacterial reduction on nonselective and gram-negative agars, whereas VWS trended toward higher bacterial reduction in Streptococcus-selective agars. CONCLUSIONS: These findings support the use of VWS in the treatment of wounds with biofilms and to reduce the bioburden of venous stasis ulcers. While VWS-treated biofilms had higher biomass than CWS- and saline treated biofilms, most of the cellular component was not viable. Ultimately, VWS had a similar effectiveness to CWS in eliminating bacteria but with lower cytotoxicity. PMID- 29140838 TI - Assessing Specimens of Devitalized Tissue in Chronic Sacral Pressure Ulcers: A Pilot Study. AB - Pressure ulcers (PrUs)* are chronic wounds caused by a combination of factors, such as repetitive ischemia perfusion injury, bacterial colonization of the wound bed, local tissue hypoxia, or an altered cellular and systemic stress response. The objectives of this study were to analyze fragments of devitalized tissue of Stages III and IV PrUs and compare them with healthy tissue to evaluate the expression of the genes involved in wound inflammation. Samples of healthy skin from patients undergoing plastic surgery (n = 3) were collected, as well as from patients with devitalized tissue from Stages III and IV PrUs (n = 3) by means of sharp debridement. Gene expression analysis identified 5 up-regulated genes and 6 down-regulated genes in the devitalized tissue. Fibroblast cultures treated with devitalized tissue extract showed less attraction and cellular growth compared with the control group. Western blotting analysis showed a tendency of 3 particular genes to decrease in cell cultures treated with devitalized tissue extract. This study demonstrates that all of these mediators stimulate and promote inflammation in the wound bed and that a better understanding of the mechanisms of chronic wound development could lead to novel therapeutic strategies. PMID- 29140839 TI - Effectiveness and Safety of a Thermosensitive Hydrogel Cultured Epidermal Allograft for Burns. AB - OBJECTIVE: To retest the safety and effectiveness of a thermosensitive hydrogel type cultured epithelial allograft (KeraHeal-Allo; MCTT, Seoul, South Korea) and identify the subjective experience of patients and doctors with this product. DESIGN AND SETTING: Prospective interventional phase 3 study in 3 burn centers near Seoul, South Korea. PATIENTS: Thirty-three patients with deep second-degree burns larger than 200 cm (for intervention and control sites of 100 cm each) were enrolled. INTERVENTION: A cultured epithelial allograft containing 2 * 10/1.5 mL keratinocytes was applied to each patient's intervention site. Three principal investigators (1 in each institution) evaluated the effectiveness of the allograft at their institution and the others'. Researchers administered a subjective satisfaction survey during each patient's last visit. MAIN OUTCOME MEASURE: The primary end point of the study was the re-epithelialization period. MAIN RESULTS: The re-epithelialization period for the intervention was 2.8 +/- 2.2 days faster than that of control sites at other institutions (P < .001) and 2.5 +/- 3.4 days faster than that of control sites in the same institution (P < .001). There were no reported adverse events. Satisfaction scores provided by patients and doctors showed significantly high scores on all items. CONCLUSUIONS: This type of cultured epithelial allograft is safe and well received by patients and providers and promotes re-epithelialization. PMID- 29140840 TI - High-Voltage Electrical Stimulation Versus Ultrasound in the Treatment of Pressure Ulcers. AB - OBJECTIVE: The aim of this study was to assess and compare the efficacy of high voltage electrical stimulation (HVES) with ultrasound (US) in treating Stage II through Stage IV pressure ulcers (PrUs)* of hospitalized patients. DESIGN: This study was designed as a prospective, controlled trial in which patients were randomly assigned to 2 groups. PARTICIPANTS AND SETTINGS: A total of 27 patients (22 male, 5 female) hospitalized for neurologic rehabilitation in the Clinic of Physical Medicine and Rehabilitation with Stage II through Stage IV PrUs were included in this study. The patients were randomly assigned to either HVES or US treatment group, and all patients underwent standard wound care. Over 4 to 12 weeks, HVES was applied for 60 minutes 3 times per week, and US was applied 3 times per week. MAIN OUTCOME MEASURES: Properties of the PrUs were noted during pre- and posttreatment. RESULTS: The PrUs of patients in the HVES and US groups healed at a mean rate of 43% and 63%, respectively. There was no statistically significant intergroup difference in healing found after treatment. Regression analysis was performed for the factors that could influence the wound surface areas, and significant effects were detected among the level of ambulation, pretreatment stage, and smoking. CONCLUSIONS: Both HVES and US are promising methods for wound healing, and both electrotherapy modalities have been demonstrated to support the healing of PrUs. PMID- 29140841 TI - 3 Medicare Announcements You May Have Missed. PMID- 29140844 TI - 2017 in Review: Looking Back and Leaning Forward. PMID- 29140845 TI - Pyoderma Gangrenosum: A Critical Appraisal. PMID- 29140846 TI - Punishment eliminates directed forgetting: an event-related potential study. AB - This study investigated motivational effect of reward and punishment on directed forgetting using the event-related potential technique. Participants were instructed to encode two-character words in Chinese, followed by the indicator of 'remember' or 'forget'. Then, participants were required accomplishing the judgment task of old and new words. The results suggest that (i) directed forgetting effect is significant in the punishment condition but not in the reward condition, and (ii) a positive amplitude is induced in the punishment condition but not in the reward condition. Furthermore, directed forgetting can be effectively influenced by reward motivation, whereas punishment motivation is antagonistic to active forgetting because a substantial cognitive resource attracts considerable attention. Therefore, this study supports encoding inhibition theory. PMID- 29140847 TI - Overexpressed wild-type superoxide dismutase 1 exhibits amyotrophic lateral sclerosis-related misfolded conformation in induced pluripotent stem cell-derived spinal motor neurons. AB - Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which motor neurons selectively degenerate. Superoxide dismutase 1 (SOD1) was found to be a causative gene of familial ALS, and mutant SOD1 transgenic mice recapitulated ALS phenotypes. Analysis of these mice showed accumulation of misfolded SOD1 protein in motor neurons. Misfolded SOD1 accumulation was found in spinal motor neurons of both familial ALS patients with the SOD1 mutation and sporadic ALS patients. However, it is unclear what condition causes wild-type SOD1 misfolding in patients without the SOD1 mutation. Here, we generated induced pluripotent stem cells from mutant SOD1 transgenic mice, wild-type SOD1 transgenic mice, and control mice, and differentiated them into spinal motor neurons to analyze misfolded SOD1 accumulation. We found that misfolded SOD1 protein was accumulated in spinal motor neurons of both mutant and wild-type SOD1 transgenic mice as detected by a specific antibody against the misfolded conformation of SOD1. These results suggest that an increased expression level of wild-type SOD1 may accelerate the ALS pathology and that our in vitro model would be a useful tool for misfolded SOD1 research. PMID- 29140848 TI - Mortality Trends After a Voluntary Checklist-based Surgical Safety Collaborative. AB - OBJECTIVE: To determine whether completion of a voluntary, checklist-based surgical quality improvement program is associated with reduced 30-day postoperative mortality. BACKGROUND: Despite evidence of efficacy of team-based surgical safety checklists in improving perioperative outcomes in research trials, effective methods of population-based implementation have been lacking. The Safe Surgery 2015 South Carolina program was designed to foster state-wide engagement of hospitals in a voluntary, collaborative implementation of a checklist program. METHODS: We compared postoperative mortality rates after inpatient surgery in South Carolina utilizing state-wide all-payer discharge claims from 2008 to 2013, linked with state vital statistics, stratifying hospitals on the basis of completion of the checklist program. Changes in risk adjusted 30-day mortality were compared between hospitals, using propensity score adjusted difference-in-differences analysis. RESULTS: Fourteen hospitals completed the program by December 2013. Before program launch, there was no difference in mortality trends between the completion cohort and all others (P = 0.33), but postoperative mortality diverged thereafter (P = 0.021). Risk-adjusted 30-day mortality among completers was 3.38% in 2010 and 2.84% in 2013 (P < 0.00001), whereas mortality among other hospitals (n = 44) was 3.50% in 2010 and 3.71% in 2013 (P = 0.3281), reflecting a 22% difference between the groups on difference-in-differences analysis (P = 0.0021). CONCLUSIONS: Despite similar pre existing rates and trends of postoperative mortality, hospitals in South Carolina completing a voluntary checklist-based surgical quality improvement program had a reduction in deaths after inpatient surgery over the first 3 years of the collaborative compared with other hospitals in the state. This may indicate that effective large-scale implementation of a team-based surgical safety checklist is feasible. PMID- 29140849 TI - Endoscopic Submucosal Dissection for Superficial Proximal Esophageal Neoplasia is Highly Successful. AB - OBJECTIVE: The aim of this study was to evaluate the outcomes of endoscopic submucosal dissection (ESD) for superficial proximal esophageal neoplasia. SUMMARY OF BACKGROUND DATA: The surgery for a tumor located in proximal esophagus is relatively difficult and leads to a high morbidity and mortality. ESD is a minimally invasive endoscopic treatment of superficial neoplasia of the gastrointestinal tract allowing en block resection with low recurrence rates; however, ESD for superficial proximal esophageal neoplasia is little known. METHODS: We retrospectively analyzed 102 consecutive patients who fit the inclusion criteria with 106 lesions who underwent ESD from February 2009 to July 2015 at the Zhongshan Hospital, Fudan University in Shanghai, China. During the study, the en bloc and pathologically complete resection rates, complication rate, incidence of esophageal stricture after ESD, disease-specific, and overall survival rates were evaluated. RESULTS: The mean age was 62 (45-84) years with 100% en bloc resection rate. The mean operation time was 48 (10-144) minutes. The mean diameter of the resected tumors was 2.9 (1.2-6.5) cm. The pathological diagnoses were high-grade intraepithelial dysplasia in 45 (42.5%) lesions, and the rest were squamous cell carcinoma with staging of intraepithelial in 18 (17.0%), lamina propria in 13 (12.3%), muscularis mucosa in 16 (15.1%), SM1 in 10 (9.4%), and SM2 or deeper in 4 (3.8%) of the lesions. The R0 resection rates were 94.3% (100/106). There was no delayed bleeding. Two small perforations observed were closed successfully with clips. Symptomatic esophageal strictures in 17 (16.7%) patients were treated by endoscopic balloon dilation with a mean of 4 (1 14) times and 88.2% (15/17) success. Additional treatments of esophagectomy or chemoradiotherapy were recommended to patients with SM1 or deeper neoplasia or incomplete resection. Local recurrence was observed in 3 (2.9%) cases. Fifteen patients were lost to follow-up. Five-year overall survival rate was 98% and disease-specific survival rate was 100%. The mean follow-up time was 33.6 months. CONCLUSIONS: ESD for the superficial proximal esophageal neoplasia is a safe and a very effective treatment method with a 100% 5-year disease-specific survival rate. PMID- 29140850 TI - Hepatocellular Carcinoma With Bile Duct Tumor Thrombus: Extrahepatic Bile Duct Preserving or Not? Reply. PMID- 29140851 TI - A Giant With Clay Feet. PMID- 29140852 TI - Comment on: Improving Escalation of Care: Development and Validation of the Quality of Information Transfer Tool. PMID- 29140854 TI - Predictors of In-hospital Postoperative Opioid Overdose After Major Elective Operations: A Nationally Representative Cohort Study: Erratum. PMID- 29140853 TI - Reply to Letter: "Improving Escalation of Care: Development and Validation of the Quality of Information Transfer Tool". PMID- 29140855 TI - Impact of Enhanced Recovery After Surgery and Fast Track Surgery Pathways on Healthcare-associated Infections. Results From a Systematic Review and Meta analysis: Erratum. PMID- 29140856 TI - Beyond "Measure Twice": New Performance Standards in Surgery: Erratum. PMID- 29140857 TI - That's Inappropriate! Social Norms in an Older Population-based Cohort. AB - BACKGROUND: Social cognition is not routinely assessed in older adults. We report population-based normative data on the Social Norms Questionnaire (SNQ22) which asks individuals about the appropriateness of specific behaviors in hypothetical scenarios, errors being related either to breaking with norms or to over-adhering to perceived norms. Total SNQ scores represent the number of correct responses while subscale scores are error totals. METHODS: We administered the SNQ22 to 744 adults aged 65+ within a population-based study, and examined the distribution of scores by demographics, other cognitive measures, and Clinical Dementia Rating (CDR). RESULTS: Most participants performed well with few errors. Women and young old individuals performed significantly better than men and older individuals on total score and over-adherence; women had fewer break-norms errors than men. No race or education effects were observed. Worse (higher) total scores and (lower) over-adherence errors were inversely associated with literacy, CDR, Mini-Mental State Examination, attention, memory, language, executive, and visuospatial domains. Break-norms errors were rare and not associated with any of the above. CONCLUSIONS: In population-based normative data on the SNQ22. age and sex influenced total score and over-adherence errors, which showed the expected associations with CDR and other cognitive domains. Social norms screening may be useful in the cognitive assessment of older adults. PMID- 29140858 TI - Computerized Cognitive Testing in Primary Care: A Qualitative Study. AB - Computerized cognitive assessment tools may facilitate early identification of dementia in the primary care setting. We investigated primary care physicians' (PCPs') views on advantages and disadvantages of computerized testing based on their experience with the Computer Assessment of Mild Cognitive Impairment (CAMCI). Over a 2-month period, 259 patients, 65 years and older, from the family practice of 13 PCPs completed the CAMCI. Twelve PCPs participated in an individual interview. Generally, PCPs felt that the relationship between them and their patients helped facilitate cognitive testing; however, they thought available paper tests were time consuming and not sufficiently informative. Despite concerns regarding elderly patients' computer literacy, PCPs noticed high completion rates and that their patients had generally positive experiences completing the CAMCI. PCPs appreciated the time-saving advantage of the CAMCI and the immediately generated report, but thought the report should be shortened to 1 page and that PCPs should receive training in its interpretation. Our results suggest that computerized cognitive tools such as the CAMCI can address PCPs' concerns with cognitive testing in their offices. Recommendations to improve the practicality of computerized testing in primary care were suggested. PMID- 29140860 TI - Central Serous Chorioretinopathy Associated With Fingolimod Treatment. PMID- 29140859 TI - Patient and Caregiver Assessment of the Benefits From the Clinical Use of Amyloid PET Imaging. AB - INTRODUCTION: Few studies to date have explored patient and caregiver views on the clinical use of amyloid positron emission tomography (PET). METHODS: A 7-item questionnaire assessing patient and caregiver views (510 total respondents) toward amyloid PET imaging was advertised broadly through alz.org/trialmatch. RESULTS: We received 510 unique responses from 48 US states, 2 Canadian provinces, the Dominican Republic, and Greece. Both patients and caregivers indicated that they would want to receive amyloid imaging if offered the opportunity. Over 88% of respondents had a positive response (~10% with neutral and 2% with negative responses) to whether amyloid PET should be offered routinely and be reimbursed. Such information was felt to be useful for long-term legal, financial, and health care planning. Respondents identifying with early age cognitive decline (younger than 65 y) were more likely to explore options for disability insurance (P=0.03). Responders from the Midwest were more likely to utilize information from amyloid imaging for legal planning (P=0.02), disability insurance (P=0.02), and life insurance (P=0.04) than other US regions. DISCUSSION: Patients and caregivers supported the use of amyloid PET imaging in clinical practice and felt that the information would provide significant benefits particularly in terms of future planning. PMID- 29140861 TI - Sealing of Corneal Lacerations Using Photoactivated Rose Bengal Dye and Amniotic Membrane. AB - PURPOSE: Watertight closure of perforating corneoscleral lacerations is necessary to prevent epithelial ingrowth, infection, and potential loss of the eye. Complex lacerations can be difficult to treat, and repair with sutures alone is often inadequate. In this study, we evaluated a potentially sutureless technology for sealing complex corneal and scleral lacerations that bonds the amniotic membrane (AM) to the wound using only green light and rose bengal dye. METHODS: The AM was impregnated with rose bengal and then sealed over lacerations using green light to bond the AM to the deepithelialized corneal surface. This process was compared with suture repair of 3 laceration configurations in New Zealand White rabbits in 3 arms of the study. A fourth study arm assessed the side effect profile including viability of cells in the iris, damage to the blood-retinal barrier, retinal photoreceptors, retinal pigment epithelium, and choriocapillaris in Dutch Belted rabbits. RESULTS: Analyses of the first 3 arms revealed a clinically insignificant increase in polymorphonuclear inflammation. In the fourth arm, iris cells appeared unaffected and no evidence of breakdown of the blood-retinal barrier was detected. The retina from green light laser-treated eyes showed normal retinal pigment epithelium, intact outer segments, and normal outer nuclear layer thickness. CONCLUSIONS: The results of these studies established that a light-activated method to cross-link AM to the cornea can be used for sealing complex penetrating wounds in the cornea and sclera with minimal inflammation or secondary effects. PMID- 29140862 TI - Retroprosthetic Membrane Formation in Boston Keratoprosthesis: A Case-Control Matched Comparison of Titanium Versus PMMA Backplate. AB - PURPOSE: Retroprosthetic membrane (RPM) formation is the most common complication after Boston type 1 keratoprosthesis (KPro) implantation. It affects visual acuity and can predispose to corneal melt. Two KPro backplate materials are available: titanium and polymethyl methacrylate (PMMA). This study investigates the influence of the KPro backplate material on visually significant RPM formation. METHODS: A retrospective case-control-matched study involving 40 patients; 20 eyes implanted with a titanium backplate KPro were case-matched with 20 eyes implanted with a PMMA backplate KPro between 2007 and 2015 with 1-year minimum follow-up. RESULTS: The mean follow-up duration was 28.1 +/- 8.9 and 53.6 +/- 24.3 months in the titanium and PMMA groups, respectively. At 12 months postoperatively, 7 eyes with titanium and 6 eyes with PMMA backplates developed a visually significant RPM. By the end of the study, a total of 11 eyes with titanium and 9 eyes with PMMA KPros developed a visually significant RPM. There was no statistically significant difference between both groups. Three of 11 eyes with titanium KPros that had a visually significant RPM required surgical membranectomy, whereas all eyes with PMMA KPros were successfully treated with the yttrium-aluminum-garnet laser. Recurrence of RPMs was found in 7/11 eyes in the titanium group and 2/9 eyes in the PMMA group with no statistical significance. CONCLUSIONS: Titanium backplate KPros do not significantly reduce RPM formation compared with PMMA backplate KPros in a case-control-matched setting. A larger prospective study is warranted to evaluate comparative long term performance and guide newer designs. PMID- 29140863 TI - Practice Patterns and Job Satisfaction of Mohs Surgeons. AB - BACKGROUND: There is a paucity of data on Mohs surgery workforce patterns. OBJECTIVE: To identify if gender differences exist in practice patterns of Mohs surgeons, factors that influence these differences, and factors influencing job satisfaction among Mohs surgeons. MATERIALS AND METHODS: An electronic survey was distributed to dermatology organizations targeting members of the American College of Mohs Surgery (ACMS), from October 2015 to April 2016. RESULTS: Two hundred twenty-seven ACMS members responded; 37% were women. Twenty-five percent of women and 19% of men work part time. Thirty-seven percent of women practice in academia versus 22% of men. Forty-three percent of women and 23% of men identified children as a factor affecting their ability to work full time. Gender comparisons for current job satisfaction show 57% of men and 35% of women being very satisfied. Supervision/feedback/recognition adds to satisfaction at a higher rate for women (53%) than for men (29%). For both genders combined, work content, patient base, and autonomy had the highest average job satisfaction ratings. CONCLUSION: Gender differences exist in practice patterns and job satisfaction of Mohs surgeons. This study demonstrates factors that could influence job satisfaction among female Mohs surgeons-knowledge that is important to individuals who lead, mentor, or supervise female Mohs surgeons. PMID- 29140864 TI - Bupivacaine as an Adjunct to Lidocaine in Mohs Micrographic Surgery: A Prospective Randomized Controlled Trial. AB - BACKGROUND: In Mohs micrographic surgery (MMS), the standard local anesthetic agent used is lignocaine with adrenaline. However, MMS can be prolonged; thus reinjections of local anesthetics are often required. OBJECTIVE: Is 0.5% bupivacaine with 1:200,000 epinephrine a useful adjunctive treatment when compared with the use of 1% lidocaine with 1:100,000 epinephrine in MMS for the nose? METHODS: Participants undergoing MMS received 2.5 mL of 1% lidocaine with 1:100,000 epinephrine before commencement of Stage 1. At the end of Stage 1, participants were randomized sequentially to either 2.5 mL 0.5% bupivacaine with 1:200,000 epinephrine (Group A) or 2.5 mL of 1% lidocaine with 1:100,000 epinephrine (Group B). Effectiveness of anesthesia was assessed using 30 G needle to 5 points of the wound before further stage or repair. RESULTS: Fifty-one patients were randomized, 26 to Group A, and 25 to Group B. No differences between the 2 groups in size of defect and time lapse between time of injection and time of testing were observed. Seven of 25 were tested positive in Group B. Zero of 26 tested positive in Group A (p = .003, 95% confidence interval: 10% 46%). CONCLUSION: Adjunctive use of 0.5% bupivacaine with 1:200,000 epinephrine is effective in prolonging anesthesia in MMS. PMID- 29140865 TI - Influence of Syringe Volume on Foam Stability in Sclerotherapy for Varicose Vein Treatment. AB - BACKGROUND: Despite the popularity of sclerotherapy for treating varicose veins, it still exhibits various problems, such as pulmonary embolism, deep-vein thrombosis, phlebitis, and visual disorders. OBJECTIVE: To investigate syringe volume influence on foam stability, obtain the foam decay rule, and provide a reference for clinics. MATERIALS AND METHODS: Five types of syringes are used to prepare foam at room temperature with various liquid-gas ratios. Foam decay process experiments were performed 5 times and recorded by video. The stability indices used include drainage time, half-life, bubble diameter, bubble surface density, and drainage rate. RESULTS: The 30 and 2-mL syringes, respectively, recorded the highest and lowest drainage speeds. Foam drainage time and half life, differences varied between 15 and 70 seconds, and 20 and 100 seconds, respectively. Foam bubble diameters were distributed over 0.1 to 2.0 mm with roughly 200 to 700 bubbles per square centimeter. CONCLUSION: Increased syringe volume causes the bubble diameter to increase. Thus, foam dispersion increases and foam half-life decreases; hence, foam becomes unstable. It is, thus, better to use a small syringe several times to prepare foam in clinics using segmented injections. PMID- 29140866 TI - One Thousand Five Hundred Fifty Nanometer Erbium-Doped Nonablative Fractional Laser for the Treatment of Striae Distensae in Patients of Skin of Color (Fitzpatrick Skin Types IV-VI). PMID- 29140867 TI - Role of Hyaluronidase in the Treatment of Hypertrophic Scars. PMID- 29140868 TI - Dog Ear Regression in Function of Skin Elasticity. PMID- 29140869 TI - Rhinophyma: A Treatment Review. AB - BACKGROUND: Rhinophyma is the overgrowth of sebaceous glands in nasal tissue and its etiology unclear. Without treatment, rhinophyma can be progressive and cause concern both with respect to function and cosmesis. OBJECTIVE: The objective of this work is to describe treatment options for rhinophyma and their respective risks and benefits. MATERIALS AND METHODS: A PubMed search was performed to include the terms "rhinophyma" and "treatment." RESULTS: Numerous physically destructive modalities exist for treatment of rhinophyma, falling primarily into 3 categories: mechanical destruction, directed electrical energy/radiofrequency, and directed laser energy. CONCLUSION: There are multiple treatment modalities available to dermatologists for the treatment of rhinophyma. To the best of our knowledge, there are no randomized, prospective, control studies for any treatment, which makes it difficult to recommend a single treatment over another. Nonetheless, it is important to recognize that scarring and hypopigmentation most often occur on or near the nasal ala. Moreover, risks may increase if tissue destruction extends to the papillary dermis or pilosebaceous units are ablated. PMID- 29140870 TI - A Retrospective Assessment of Postoperative Bleeding Complications in Anticoagulated Patients Following Mohs Micrographic Surgery. AB - BACKGROUND: A significant number of patients undergoing Mohs micrographic surgery (MMS) for skin cancer are treated with oral anticoagulants. The incidence of postoperative complications associated with new classes of oral anticoagulants remains largely unknown. OBJECTIVE: To determine the incidence of postoperative complications in patients undergoing MMS on both traditional oral anticoagulants and new novel oral anticoagulants. MATERIALS AND METHODS: A single-center retrospective chart review was performed for all patients treated with oral anticoagulants who underwent MMS between July 1, 2012 and June 30, 2015 at University of California, San Diego. RESULTS: The data from this study demonstrated that patients treated with a novel oral anticoagulant at the time of MMS had a statistically significant greater risk for developing postoperative hemorrhagic complications compared to patients treated with traditional oral anticoagulants. CONCLUSION: Dermatologic surgeons should manage both traditional oral anticoagulants and novel oral anticoagulants in a similar manner. Future studies are warranted. PMID- 29140871 TI - HIV Prevalence and Associated Risk Factors Among Men Who Have Sex With Men in Dar es Salaam, Tanzania. AB - INTRODUCTION: Limited studies and differential risk behaviors among men who have sex with men (MSM) in Africa calls for population-specific studies. We present results from the largest integrated biobehavioral survey among MSM in Africa to inform programming. METHODS: This was a cross-sectional study using respondent driven sampling to recruit MSM aged 18 and above. Data on sociodemographic characteristics and HIV-related risks were collected and all participants were tested for HIV, herpes simplex virus type-2 (HSV-2), hepatitis-B virus (HBV), and syphilis RESULTS:: A total of 753 MSM with a mean age of 26.5 years participated in the study and 646 (85.7%) provided blood for biological testing. The prevalence of HIV was 22.3%, HSV-2 40.9%, syphilis 1.1%, and HBV 3.25%. Significant risk factors for HIV were age above 25, having no children [adjusted odds ratio (aOR), 2.4, 95% confidence interval (CI): 1.4 to 4.2], low HIV-risk perception (aOR, 2.6, 95% CI: 1.2 to 5.3), receptive position (aOR, 8.7, 95% CI: 1.2 to 5.3), and not using water-based lubricants (aOR, 2.6, 95% CI: 1.0 to 4.5) during the last anal sex. Also associated with HIV infection was, having sexual relationships with women (aOR, 8.0, 95% CI: 4.1 to 15.6), engaging in group sex (aOR, 3.8, 95% CI: 1.6 to 8.4), HSV-2 seropositivity (aOR, 4.1, 95% CI: 2.6 to 6.5), and history of genital ulcers (aOR, 4.1, 95% CI: 1.1 to 7.2). CONCLUSIONS: HIV infection and HSV-2 were highly prevalent among MSM. Low perceived HIV risk, practice of risk behaviors, and infection with HSV-2 were significant predictors of HIV infection. Behavioral interventions, HSV-2 suppressive therapies, and pre exposure prophylaxis are highly needed. PMID- 29140872 TI - Experimental Investigation of Implicit HIV and Preexposure Prophylaxis Stigma: Evidence for Ancillary Benefits of Preexposure Prophylaxis Use. AB - BACKGROUND: Preexposure prophylaxis (PrEP) stigma (ie, negative attitudes toward PrEP users) has been widely documented and is considered a significant barrier to implementation. However, few studies have examined PrEP stigma using implicit measures designed to reduce demand characteristics in responding. This study examined implicit PrEP- and HIV-related stigma among gay and bisexual men using geospatial social networking applications (ie, "hookup apps"). METHODS: Participants were presented with 4 simulated online profiles (pretested for comparability) paired with each of the following characteristics: HIV negative, HIV positive, on PrEP, or substance user. Participants rated the profiles on attractiveness, desirability, trustworthiness, likelihood of condom use, and riskiness of sex. RESULTS: There was no evidence of PrEP-related stigma, ie, participants did not rate profiles of PrEP users more negatively than profiles of HIV-negative individuals not disclosing PrEP use. However, profiles of HIV positive individuals were rated significantly less attractive and desirable than HIV-negative or PrEP profiles. When the sample was split by history of PrEP use, negative ratings of HIV-positive profiles remained only among participants who had never taken PrEP. Participants with any history of PrEP use demonstrated no difference in ratings by HIV status. CONCLUSION: These data provide the first empirical evidence for lower HIV stigma among PrEP users. Individuals who have used PrEP may "see" HIV-positive individuals differently than those without a history of PrEP use. The lack of evidence for PrEP-related stigma is encouraging and suggests that negative stereotypes about PrEP users may not extend to negative implicit judgments about them on social networking sites. PMID- 29140873 TI - Experienced HIV-Related Stigma in Health Care and Community Settings: Mediated Associations With Psychosocial and Health Outcomes. AB - INTRODUCTION: There are multiple dimensions of HIV-related stigma that can compromise the mental and physical health of people living with HIV. We focused on the dimension of experienced stigma, defined as exposure to acts of discrimination, devaluation, and prejudice, and investigated its relationship with HIV health and psychosocial outcomes. METHODS: We examined associations between experienced stigma in the community and health care settings and psychosocial and health outcomes for people living with HIV (N = 203) receiving care at an urban HIV clinic in the Southeastern United States. We also investigated whether those effects are unique to experienced stigma or are mediated by other dimensions of HIV-related stigma. RESULTS: Experienced stigma was associated with suboptimal clinical outcomes such as viral nonsuppression, as well as poor affective, cognitive, and mental health outcomes (self-esteem, depressive symptoms, avoidance coping, and blame coping) and interpersonal outcomes such as social support and physician trust. Furthermore, serial mediation models suggested significant indirect effects of experienced stigma through internalized stigma and anticipated stigma from various theoretically expected sources of stigma (eg, community members, friends and family, and health care workers), with varying effects depending on the source. CONCLUSIONS: These findings suggest nuanced mechanisms for the effects of experienced HIV-related stigma, especially in health care settings, and may be used to inform stigma reduction interventions. Interventions designed to address experienced stigma in health care settings might be more tailored to specific outcomes, such as depression and physician trust, than interventions designed to address experienced stigma in the community. PMID- 29140874 TI - HIV and Age Do Not Synergistically Affect Age-Related T-Cell Markers. AB - INTRODUCTION: Despite major progress in controlling HIV disease through antiretroviral therapy, changes in immune phenotype and function persist in individuals with chronic HIV, raising questions about accelerated aging of the immune system. METHODS: We conducted a cross-sectional study (2005-2007) of HIV infected (n = 111) and uninfected (n = 114) men from the Veterans Aging Cohort Study. All HIV-infected subjects were on antiretroviral therapy with VL <400 copies/mL for at least 3 years. T-cell markers were examined using flow cytometry. We evaluated the impact of HIV serostatus and age on T-cell phenotypes (expressed as percentages of the total CD4 and CD8 T-cell population) using multivariate linear regression, adjusted for smoking, alcohol, and race/ethnicity. We tested for interactions between HIV and age by including interaction terms. RESULTS: Among both HIV-infected and uninfected subjects, increasing age was associated with a decreased proportion of naive CD4 T cells (P = 0.014) and CD8 T cells (P < 0.0001). Both HIV infection and increasing age were associated with higher proportions of effector memory CD4 T cells (P < 0.0001 for HIV; P = 0.04 for age) and CD8 T cells (P = 0.0001 for HIV; P = 0.0004 for age). HIV infection, but not age, was associated with a higher proportion of activated CD8 T cells (P < 0.0001). For all T-cell subsets tested, there were no significant interactions between HIV infection and age. CONCLUSIONS: Age and HIV status independently altered the immune system, but we found no conclusive evidence that HIV infection and advancing age synergistically result in accelerated changes in age-associated T-cell markers among virally suppressed individuals. PMID- 29140875 TI - Bone Mineral Density Declines Twice as Quickly Among HIV-Infected Women Compared With Men. AB - BACKGROUND: Initial declines in bone mineral density (BMD) after antiretroviral therapy initiation in HIV are well described, but data on long-term changes and risk factors for decline, particularly among women, are limited. METHODS: HIV infected men and women in the Modena Metabolic Clinic underwent dual-energy X-ray absorptiometry (DXA) scans every 6-12 months for up to 10 years (median 4.6 years). Mixed effect regression models in combined and sex-stratified models determined annual rates of decline and clinical factors associated with BMD. Models included demographics, HIV-specific factors, and bone-specific factors; a final model added a sex * time interaction term. RESULTS: A total of 839 women and 1759 men contributed >=2 DXA scans. The majority (82%) were 50 years and younger; 76% had HIV-1 RNA <50 copies per milliliter at baseline; 15% of women were postmenopausal and 7% of men had hypogonadism; and 30% and 27%, respectively, had hepatitis C virus (HCV) coinfection. The adjusted slopes in BMD among women and men were significantly different at both the femoral neck (women 0.00897 versus men -0.00422 g/cm per year; P < 0.001) and L-spine (women -0.0127 versus men -0.00763 g/cm per year; P < 0.001). Modifiable risks associated with BMD decline included antiretroviral therapy exposure (greater decline with tenofovir disoproxil fumarate and less decline with integrase strand transfer inhibitor therapy), HCV, physical activity, and vitamin D insufficiency. CONCLUSIONS: Among HIV-infected individuals, bone density at the femoral neck, a significant predictor of fracture risk, declined twice as quickly among women compared with men. Female sex was independently associated with both lower femoral neck and lumbar BMD over time in adjusted models. PMID- 29140876 TI - Evidence-based guidance to assist volunteers working with at-risk children in a school context. AB - AIM: One of the activities of the Belgian Red Cross is the 'Bridging the Gap' project, in collaboration with local schools. In this project, volunteers join the teaching staff to improve personal development goals in at-risk children with poor performance. The aim of this study was to develop evidence-based guidance for the volunteers to help them choose the right didactical approach for supporting these children. METHOD: Systematic literature searches were performed in three bibliographic databases (the Campbell Library, MEDLINE and ERIC) to find the effectiveness of 16 different didactical activities. In addition, during a consensus meeting with relevant stakeholders, we discussed the applicability and meaningfulness of these activities for volunteers in the school context. RESULTS: We identified 38 relevant studies out of 12 056 references. Evidence of effectiveness was available for the following activities: book reading, road safety education, number games, puzzle making, singing, block-building activities, reading poetry, computer-assisted instruction, storyboards, role play and a library visit. Based on the discussion with stakeholders, we developed evidence-based guidance with recommendations and suggestions to assist volunteers in their task. CONCLUSION: This evidence-based guidance was developed to help volunteers working in a school context to choose which didactical activities to carry out with at-risk children, with the aim of improving the children's personal development. The list of didactical approaches we promote is not exhaustive and will most likely continue to grow, as many activities are currently not (well) described in scientific studies. In addition, contextual factors that may play a role in the success or failure of certain didactical activities are also subject to change. PMID- 29140877 TI - Atypical Placental Site Nodule Arising in a Postcesarean Section Scar: Case Report and Review of the Literature. AB - The distinction between benign and malignant trophoblastic lesions often presents a diagnostic challenge, even in entities with defined morphologic and immunohistochemical criteria. Lesions arising from chorionic-type intermediate trophoblast, namely placental site nodule (PSN) and epithelioid trophoblastic tumor (ETT), can be distinguished by existing criteria. However, a putative intermediate lesion termed "atypical placental site nodule" (APSN) has been described in the literature but is not well-classified. We present a case of APSN, along with a brief literature review, and we propose more definitive morphologic and immunohistochemical criteria for this entity, in order to facilitate easier diagnosis and gather more information regarding outcomes. PMID- 29140878 TI - Clear Cell Renal Cell Carcinoma Metastatic to the Gynecologic Tract: A Clinicopathologic Analysis of 17 Cases. AB - Clear cell renal cell carcinomas (CCRCC) rarely metastasizes to the gynecologic tract. In this study, we analyzed a multi-institutional data set to provide insights into the clinical, morphologic, and immunophenotypic features of this phenomenon. Seventeen metastatic CCRCC involving the gynecologic tract [ovary/fallopian tube (n=9), vulva (n=2), uterine corpus (n=3), cervix (n=2), uterine serosa (n=1)] were analyzed. Mean patient age was 62 yr (range: 45-79 yr). Most cases (15/17) presented as a recurrence 6 to 72 mo postnephrectomy, 1 case was concurrently diagnosed, and 1 case (a cervical metastasis) was diagnosed prenephrectomy. In 10 cases, metastases to other locations were identified within 6 wk of the gynecologic tract lesion. The adnexa were the most common site of metastases and the mean tumor size of adnexal metastases was 3.7 cm; in only 2 of 9 cases were metastases bilateral and only 1 had external surface nodules. The morphologic and immunohistochemical features of metastatic CCRCC were compared with those of 102 mullerian clear cell carcinomas (mullerian CCC: 49 endometrial, 53 ovarian). Although CCRCC and mullerian CCC displayed extensive morphologic overlap, a higher mitotic index and a higher frequency of an alveolar pattern were seen in CCRCC, whereas diffuse hobnail cells, hyaline globules, tubulocystic pattern, or any papillary pattern were more frequently seen in mullerian CCC. CA IX, CD10, and renal cell carcinoma antigen were more frequently expressed in CCRCC than mullerian CCC, whereas Napsin-A, CK7, and p504S showed the reverse. PAX8 and HNF1beta did not significantly distinguish between the 2 groups. In summary, gynecologic tract metastases most often occur as a relapse of a previously resected CCRCC, and these relapses may occur many years postnephrectomy. Gynecologic tract metastases are often accompanied by concurrent metastases to other organs. The gross pathology of metastatic CCRCC in the ovary may potentially overlap with primary neoplasia. However, the expected morphology and immunophenotype of CCRCC are maintained in most gynecologic tract metastases. As such, although metastatic CCRCC and mullerian CCC may display significant overlap in pathologic features, several morphologic and immunophenotypic features are useful in their distinction. PMID- 29140879 TI - Metastatic Endocervical Adenocarcinoma in a Mature Cystic Teratoma: A Case of a Tumor-to-Tumor Metastasis. AB - Tumor-to-tumor metastasis is a rare phenomenon defined as a metastasis in a histologically distinct tumor. We report an unusual case of a 51-yr-old woman who presented with a cervical, bleeding lesion diagnosed as a poorly differentiated adenocarcinoma, HPV18+. Imaging studies revealed an unresectable cervical carcinoma with an associated left ovarian multicystic teratoma. A suspicious solid nodule within the teratoma was also reported. Bilateral salpingo oophorectomy was performed before the cervical tumor was treated. Pathologic findings showed a multicystic tumor measuring 110*40*30 mm with an area of adenocarcinoma, morphologically similar to the cervical neoplasm. The immunoprofile obtained in the malignant ovarian component (p16+, carcinogenic embryonic antigen+, vimentin-, estrogen receptor-) was similar to the one in the cervix. Moreover, both lesions harbored HPV18. These findings confirmed the presence of a metastatic cervical adenocarcinoma in a mature cystic teratoma. In the differential diagnosis, both somatic malignant transformation of the mature cystic teratomas and the presence of a "collision tumor" were considered and are discussed in this case report. PMID- 29140880 TI - High-risk Human Papillomavirus Determination in Formalin-fixed, Paraffin-embedded Cervical Tissue Using the Roche Cobas 4800 System: A Comparative Study With Liquid-based Cytology. AB - Roche cobas 4800 human papillomavirus (HPV) test is an automated real-time polymerase chain reaction-based system that allows the simultaneous detection of 14 human papillomavirus high-risk (HR-HPV) genotypes. This test is Food and Drug Administration approved since 2011 for HPV determination in liquid-based cytologic samples, but a clinically validated technique for formalin-fixed, paraffin-embedded (FFPE) tissue specimens is presently not commercially available. In our laboratory, we have developed an HPV detection procedure in FFPE tissue by cobas 4800 HPV test. In order to validate our method, we retrospectively studied 165 FFPE cervical biopsy and conization specimens with varied diagnoses from our files. In 50 of them, we contrasted the results with those obtained from simultaneous liquid-based cytologies from the same patients. Finally, seeking the possible complementary clinical usefulness of the procedure, we compared the HPV genotypes detected in cervical intraepithelial neoplasia grade 1 (CIN1)-diagnosed biopsies from 20 patients with a subsequent high-grade CIN (CIN2+) diagnosis with those from another group of 20 patients without a posterior CIN2+ diagnosis. Eighty-seven percent of the assays provided informative results. HR-HPV was detected in 28 of 32 (88%) invasive cervical squamous carcinomas. Coincidental HR-HPV genotypes were obtained in 32 of 50 (64%) cases with simultaneous cervical biopsy and liquid-based cytologic samples. A significant higher risk of progression to CIN2+ was found when HPV16 (P=0.022) or any HR-HPV genotype (P=0.037) was detected in CIN1 biopsies. The reported procedure provides an automated, technically time-saving, easy to integrate into laboratory routine, and reliable method of HR-HPV determination in FFPE specimens. PMID- 29140882 TI - Extravascular Migratory Metastasis (Pericytic Mimicry) in Sarcomatoid Squamous Cell Carcinoma of the Vulva: A Report of 2 Cases. AB - Extravascular migratory metastasis (EVMM), also known as pericytic mimicry or angiotropism, is a mechanism of angiocentric tumor spread that has been investigated mainly in cutaneous malignant melanoma where it has been associated with an increased risk of metastasis. In EVMM, the tumor cells spread along the external (ablumenal) aspect of vessels without breaching the endothelium, a process that is therefore distinct from the more widely recognized intraluminal invasion. Although EVMM has also been reported in a limited range of other tumor types, to our knowledge it has not been described in squamous cell carcinoma (SCC). Herein we report EVMM in 2 cases of sarcomatoid SCC of the vulva. The tumors arose in patients aged 78 and 61 yr both of whom had previous histories of histologically conventional vulval SCCs occurring in a background of lichen sclerosus and differentiated-type vulval intraepithelial neoplasia. Both tumors recurred leading to fatal metastasis in 1 patient and a requirement for pelvic exenteration in the second. Intravascular tumor involvement was not identified in either case. These cases support the view that sarcomatoid SCCs of the vulva are clinically aggressive neoplasms, and EVMM may contribute toward the risk of local and distant spread in these tumors. PMID- 29140881 TI - PDGFB Rearrangements in Dermatofibrosarcoma Protuberans of the Vulva: A Study of 11 Cases Including Myxoid and Fibrosarcomatous Variants. AB - Dermatofibrosarcoma protuberans (DFSP) is a low-grade fibroblastic sarcoma that tends to arise in young to middle age adults and involve the trunk and proximal extremities. Rare examples of vulvar DFSP have been reported, including myxoid, myoid, and fibrosarcomatous variants, but detection of the characteristic t(17;22)(q22;q13) that produces COL1A1-PDGFB gene fusion has not been evaluated in a large series of primary vulvar tumors. The clinical, morphologic, immunohistochemical, and molecular cytogenetic features of 11 cases were examined. Patient age ranged from 29 to 75 yr (mean, 46 yr; median, 43 yr). Seven tumors were purely classic DFSP, 1 was purely myxoid DFSP and the remaining 3 had varying quantities of fibrosarcomatous DFSP. All cases of classic DFSP had diffuse expression of CD34 and low-level p53 immunoreactivity. Myxoid variants had strong, but reduced expression of CD34. Fibrosarcomatous DFSP showed focal CD34 expression and increased p53 reactivity. Nine of 11 tumors (82%) had rearrangement of PDGFB by fluorescence in situ hybridization. The 2 nonrearranged tumors were a classic DFSP and a myxoid DFSP with fibrosarcomatous transformation. Follow-up was available for 9 patients (82%) and ranged from 1 to 108 mo (mean, 30 mo; median, 21 mo). Eight patients had tumors with positive margins, one of which developed local recurrence after no further therapy. No patient developed metastasis. The high frequency of PDGFB rearrangement in vulvar DFSP provides a useful exploit in diagnostically challenging cases and genetic evidence of probable clinical response to targeted therapeutics in cases of locally advanced or metastatic tumors. PMID- 29140883 TI - MAGE-A4 and MAGE-A1 Immunohistochemical Expression in High-grade Endometrial Cancer. AB - The aim was to investigate MAGE-A4 and MAGE-A1 protein expression in high-grade endometrial cancer and determine its correlation with histologic subtype, FIGO stage, presence of vascular invasion, disease free, and overall survival. Immunohistochemical staining was performed by using 77B (MAGE-A1) and 57B (MAGE A4) monoclonal antibodies on paraffin-embedded sections from high-grade endometrial cancers diagnosed in University Hospital Split between 1998 and 2011 (n=77). Median follow-up time for survivors was 48 mo. MAGE-A4 was found to be expressed in 33% of endometrioid type endometrial cancers grade 3 and in 27% of serous and clear cell carcinomas. MAGE-A1 was found to be expressed in 93% endometrioid endometrial cancer grade 3 and 86% of serous and clear cell carcinomas. Univariate analysis showed that positive immunohistochemical staining for MAGE-A4 was associated with decreased disease free and overall survival in patients with high-grade endometrial cancer. Multivariate analysis showed an association between MAGE-A4 overexpression and decreased disease free but not overall survival in high-grade endometrial cancer. No correlation was found between MAGE-A1 immunohistochemical expression and patient survival. There was no significant correlation between MAGE-A4 and MAGE-A1 expression and histologic subtype, FIGO stage, lymph node metastasis, muscular infiltration, and lymphovascular invasion. MAGE-A4 immunohistochemical expression is associated with decreased disease free and overall survival in patients with high-grade endometrial cancer. Our findings suggest that MAGE-A1 may be expressed in the epithelial cells of the normal endometrium. MAGE-A1 is highly expressed in high grade endometrial cancer, with no impact on survival. PMID- 29140884 TI - Ovarian Sex Cord-stromal Tumors With Melanin Pigment: Report of a Previously Undescribed Phenomenon. AB - We report 2 ovarian sex cord-stromal tumors, a luteinized adult granulosa cell tumor and a cellular fibroma, with melanin pigment. These occurred in 44 and 61 yr-old patients, respectively. As far as we are aware, melanin pigment has not been described previously in an ovarian sex cord-stromal tumor, although it has been reported in a testicular Sertoli cell tumor. We review ovarian neoplasms containing melanin pigment. PMID- 29140885 TI - John Henryism Coping and Metabolic Syndrome Among Young Black Adults. AB - OBJECTIVE: The aim of the study was to test the novel hypothesis that, among black Americans who used John Henryism coping, those from low socioeconomic status backgrounds would be more likely to develop metabolic syndrome than those from higher socioeconomic backgrounds. METHODS: This is an ancillary analysis of Strong African American Families Healthy Adult Program, a longitudinal cohort of 391 black youths and their caregivers. From ages 11 to 18 years, family socioeconomic status was assessed. At age 25 years, John Henryism was assessed, blood samples were drawn, and measurements were taken of blood pressure and waist circumference. Metabolic syndrome status was based on International Diabetes Federation guidelines. RESULTS: A significant interaction emerged between family socioeconomic disadvantage and John Henryism coping in predicting metabolic syndrome diagnosis (odds ratio = 1.047, 95% confidence interval = 1.004-1.091). Participants who were high in John Henryism coping were more likely to display metabolic syndrome if they were from disadvantaged backgrounds (predicted prevalence of 26.7%) than if they were from more privileged backgrounds (predicted prevalence of 9.6%). CONCLUSIONS: These patterns illustrate for the first time that John Henryism coping can undermine cardiometabolic health among black youths from disadvantaged backgrounds. PMID- 29140886 TI - Safety of Venipuncture Sites at the Cubital Fossa as Assessed by Ultrasonography. AB - OBJECTIVE: The aim of the present observational study was to identify safe and suitable venipuncture sites for nursing in the clinical setting using ultrasonography to measure the depth and cross-sectional area of each superficial vein before and after tourniquet application as well as the distance between each superficial vein and the median nerve or brachial artery. METHODS AND RESULTS: Twenty healthy volunteers (21.8 [0.6] y) were recruited. The visible rate of each superficial vein before and after tourniquet application was 65% for the basilic vein, 90% to 95% for the median cubital vein, and 65% to 80% for the cephalic vein. The cross-sectional area of the median cubital vein after tourniquet application was significantly larger than that of the basilic vein and cephalic vein. The distance between the basilic vein or median cubital vein and median nerve was significantly smaller than that between the cephalic vein and median nerve. The distance between the basilic vein or median cubital vein and brachial artery was significantly smaller than that between the cephalic vein and brachial artery. CONCLUSIONS: These results demonstrated that the cephalic vein at the cubital fossa is a relatively safe venipuncture site because of its distance from the median nerve and brachial artery. When puncturing the cephalic vein is difficult because it is not visible, the median cubital vein at the cubital fossa may be selected for venipuncture due to its cross-sectional area and visibility; however, care is needed to avoid penetrating the vein because the median nerve and brachial artery are located underneath.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29140887 TI - Inconsistencies Between Two Cross-Cultural Adaptations of the Hospital Survey on Patient Safety Culture Into French. AB - OBJECTIVES: Two cross-cultural adaptations of the 12-dimension Hospital Survey on Patient Safety Culture (HSOPSC) into French coexist: the Occelli and Vlayen versions. The objective of this study was to assess the psychometric properties of the Occelli version in comparison with those reported for the Vlayen and the original US versions of this instrument. METHODS: Using the original data from a cross-sectional study of 5,064 employees at a single university hospital in France, we examined the acceptability, internal consistency, factorial structure, and construct validity of the Occelli version of the HSOPSC. RESULTS: The response rate was 76.8% (n = 3888). Our study yielded lower missing value rates (median, 0.4% [range, 0.0%-2.4%] versus 0.8% [range, 0.2%-11.4%]) and lower dimension scores (median, 3.19 [range, 2.67-3.54] versus 3.42 [range, 2.92-3.96]) than those reported for the Vlayen version. Cronbach alphas (median, 0.64; range, 0.56-0.84) compared unfavorably with those reported for the Vlayen (median, 0.73; range, 0.57-0.86) and original US (median, 0.78; range, 0.63-0.84) versions. The results of the confirmatory factor analysis were consistent between the Vlayen and Occelli versions, making it possible to conduct surveys from the 12 dimensional structure with both versions. CONCLUSIONS: The inconsistencies observed between the Occelli and Vlayen versions of the HSOPSC may reflect either differences between the translations or heterogeneity in the study population and context. Current evidence does not clearly support the use of one version over the other. The two cross-cultural adaptations of the HSOPSC can be used interchangeably in French-speaking countries. PMID- 29140888 TI - Intrathoracic Pressure Regulation Improves Cerebral Perfusion and Cerebral Blood Flow in a Porcine Model of Brain Injury: Erratum. PMID- 29140889 TI - Can Chlamydia Serology Be Used to Help Inform a Potential Future Chlamydia Vaccination Strategy? PMID- 29140890 TI - Selecting an HIV Test: A Narrative Review for Clinicians and Researchers. AB - Given the many options available, selecting an HIV test for a particular clinical or research setting can be daunting. Making an informed decision requires an assessment of the likelihood of acute infection in the test population and an understanding of key aspects of the tests themselves. The ability of individual tests to reliably detect HIV infection depends on the target(s) being detected, when they can be expected to be present after infection, and the concentration of stable target in test specimens, all of which are explained by the virologic and serologic events after infection. The purpose of this article is to review the timeline of HIV infection, nomenclature, and characteristics of different tests; compare point-of-care and laboratory-based tests; discuss the impact of different specimens on test performance; and provide practical advice to help clinicians and researchers new to the field select a test that best suits their needs. PMID- 29140891 TI - The Evolution of HIV Testing Continues. PMID- 29140892 TI - Proficiency Testing for Meropenem and Piperacillin Therapeutic Drug Monitoring: Preliminary Results From the Belgian Society on Infectiology and Clinical Microbiology Pharmacokinetic-Pharmacodynamic Working Group. PMID- 29140893 TI - Effect of N-Desalkylquetiapine/Quetiapine Plasma Level Ratio on Anxiety and Depression in Bipolar Disoder: A Prospective Observational Study: Erratum. PMID- 29140894 TI - Incontinence-Associated Dermatitis and Immobility as Pressure Injury Risk Factors: A Multisite Epidemiologic Analysis. AB - PURPOSE: The purpose of this study was to measure the prevalence of incontinence associated dermatitis (IAD) among incontinent persons in the acute care setting, characteristics of IAD in this group, and associations among IAD, urinary, fecal, and dual incontinence, immobility, and pressure injury in the sacral area. DESIGN: Descriptive and correlational analysis of data from a large database of IAD, and pressure injuries of sacral area and heels. SUBJECTS AND SETTING: The sample comprised 5342 adult patients in acute care facilities in 36 states representing all regions of the United States. Facilities used a variety of products for prevention of IAD and sacral area pressure injuries. METHODS: Data were collected for use in a national quality improvement study evaluating current practices related to the prevention of IAD and pressure injuries affecting the sacral area and heels. Data were exported to a spreadsheet, and triple checked for accuracy before being imported to a statistical analysis software program. Descriptive statistics were used to describe prevalence rates for incontinence, types of incontinence, IAD, characteristics of IAD, and pressure injuries. Multivariate logistic regression analysis was conducted on the end point of facility-acquired sacral/buttock pressure injury and the risk factors of immobility and type of incontinence. RESULTS: More than one-third of patients (n = 2492 of 5342 patients; 46.6%) were incontinent of urine, stool, or both. The overall prevalence rate of IAD was 21.3% (1140/5342); the prevalence of IAD among patients with incontinence was 45.7% (1140/2492). Slightly more than half of the IAD was categorized as mild (596/1140, 52.3%), 27.9% (318/1140) was categorized as moderate, and 9.2% (105/1140) was deemed severe. In addition, 14.8% (169/1140) of patients with IAD also had a fungal rash. The prevalence of pressure injury in the sacral area among individuals with incontinence was 17.1% (427/2492), and the prevalence of full-thickness pressure injury in this population was 3.8% (95/2492). Multivariate analysis revealed that both presence of IAD (odds ratio [OR], 4.56; 95% confidence interval [CI], 3.68-5.65) and immobility (OR, 3.56; 95% CI, 2.73-4.63) was associated with a significantly increased likelihood of developing a sacral pressure injury. Multivariate analysis also revealed that presence of IAD (OR, 2.65; 95% CI, 1.74-4.03) and immobility (OR, 6.05; 95% CI, 3.14-11.64) was associated with a significantly increased likelihood of developing full-thickness sacral pressure injury. CONCLUSION: Our study findings are consistent with prior research, supporting a clinically relevant association between IAD and pressure injury of the sacral area. This risk persists even after controlling for presence of immobility, suggesting that IAD functions as an independent risk factor for pressure injury occurrence.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29140895 TI - An Ex Vivo Comparison of 2 Cyanoacrylate Skin Protectants. AB - PURPOSE: The purpose of these experiments was to compare 2 commercially available skin protectants with different chemical compositions. DESIGN: Two materially different skin protectants were applied to ex vivo pig skin, subjected to stresses, and the resulting skin was observed and analyzed. METHODS: Using ex vivo pig skin, we sought to better understand the physical differences between a cyanoacrylate-based and a mixed cyanoacrylate/acrylic polymer-based skin protectant. A combination of imaging techniques and microscopic analyses was used to observe and quantify differences in layer thickness and the degree of steadfastness of the layers to liquid stresses. RESULTS: The experiments revealed that the solely cyanoacrylate-based protectant created a layer that was, on average, 5.1 times thicker than the mixed polymer product (p= 1.8 * 10). Observation via electron microscopy also revealed that the extent of coverage varied between the 2 products. In a final experiment, we observed that the mixed polymer product maintained a high degree of adhesiveness, which led to the removal of sheets of epithelium upon gentle blotting. CONCLUSIONS: The experiments revealed that while the 2 skin protectants share a common ingredient, both the quantity of that ingredient and the inclusion of other materials in one of them lead to substantially different properties when tested in the research setting. PMID- 29140896 TI - Cold Water Ingestion Improves Exercise Tolerance of Heat-Sensitive People with MS. AB - PURPOSE: Heat intolerance commonly affects the exercise capacity of people with multiple sclerosis (MS) during bouts of hot weather. Cold water ingestion is a simple cooling strategy, but its efficacy for prolonging exercise capacity with MS remains undetermined. We sought to identify whether cold water ingestion blunts exercise-induced rises in body temperature and improves exercise tolerance in heat-sensitive individuals with MS. METHODS: On two separate occasions, 20 participants (10 relapsing-remitting MS (expanded disability status scale, 2 4.5); 10 age-matched healthy controls) cycled at ~40% VO2max at 30 degrees C and 30% relative humidity until volitional exhaustion (or a maximum of 60 min). Every 15 min, participants ingested 3.2 mL.kg of either 1.5 degrees C (CLD) or 37 degrees C (NEU) water. Rectal (Tre) temperature, mean skin (Tsk) temperature, and heart rate (HR) were measured throughout. RESULTS: All 10 controls but only 3 of 10 MS participants completed 60 min of exercise in NEU trial. The remaining 7 MS participants all cycled longer (P = 0.006) in CLD (46.4 +/- 14.2 min) compared with NEU (32.7 +/- 11.5 min), despite a similar absolute Tre (NEU: 37.32 degrees C +/- 0.34 degrees C; CLD: 37.28 degrees C +/- 0.26 degrees C; P = 0.44), change in Tre (NEU: 0.38 degrees C +/- 0.21 degrees C; CLD: 0.34 degrees C +/- 0.24 degrees C), absolute Tsk (NEU: 34.48 degrees C +/- 0.47 degrees C; CLD: 34.44 degrees C +/- 0.54 degrees C; P = 0.82), and HR (NEU: 114 +/- 20 bpm; CLD: 113 +/ 18 bpm; P = 0.38) for the same exercise volume. CONCLUSIONS: Cold water ingestion enhanced exercise tolerance of MS participants in the heat by ~30% despite no differences in Tre, Tsk or HR. These findings support the use of a simple cooling strategy for mitigating heat intolerance with MS and lend insight into the potential role of cold-afferent thermoreceptors that reside in the abdomen and oral cavity in the modulation of exercise tolerance with MS in the heat. PMID- 29140897 TI - Psychological and Psychophysiological Effects of Recuperative Music Postexercise. AB - PURPOSE: Few studies have examined the psychological and psychophysiological effects of recuperative music after exhaustive exercise. The main purpose of the present study was to examine the effects of two music conditions compared with a no-music control on psychological and psychophysiological recovery processes after exercise. METHODS: A randomized, fully counterbalanced, crossover design was used. Core affect, salivary cortisol, heart rate, and blood pressure were measured before exhaustive exercise, immediately after, and in 10-, 20-, and 30 min intervals during passive recovery (21 women and 21 men; 20.9 +/- 1.7 yr) over three separate trials (slow, sedative music; fast, stimulative music; no-music control). The exercise task entailed incremental cycle ergometry performed at 75 rpm with an increase in intensity of 22.5 W.min at the end of each minute until exhaustion. Data were analyzed using mixed-model 3 (condition) * 4 (time) * 2 (gender) MANOVA/ANCOVA. RESULTS: The largest decline in affective arousal between active and passive recovery phases was evident in the slow, sedative condition (etap = 0.50). Women had a more pronounced reduction in arousal than did men in the slow, sedative music condition. Heart rate measures showed that fast, stimulative music inhibited the return of heart rate toward resting levels (etap = 0.06). Similarly, salivary cortisol levels tended to be lower in response to slow, sedative music (etap = 0.11). There was a main effect of condition for affective valence indicating that the slow, sedative condition elicited more positive affective responses compared with the control and fast, stimulative conditions (etap = 0.12). CONCLUSIONS: The present findings support the notion that slow, sedative music can expedite the recovery process immediately after strenuous exercise. PMID- 29140898 TI - A Construct Validation Study of PLAYfun. AB - INTRODUCTION: Physical Literacy Assessment for Youth (PLAYfun) is a measure of motor competence, comprehension, and confidence which is part of a suite of scales used to assess physical literacy in children and youth; however, its measurement properties have not been reported in the published literature. The purpose of this study is to examine the factor structure of PLAYfun, in addition to variations in PLAYfun subscale results by age and sex. METHOD: In this study, we use a sample of children and youth 7 to 14 yr of age (n = 215) to test a proposed factor structure for the motor competence component of PLAYfun and to examine age and sex differences in subscale and total scores. The initial (n = 128) and secondary (n = 98) samples were drawn from a stratified (by geographic region), random sample of 27 after-school programs from a larger pool of 400 programs across the province of Ontario. Seven research assistants were initially trained on the administration of PLAYfun and rated a small pilot sample of 10 children. These trained assessors then assessed the full sample. RESULTS: Interrater agreement was very good (intraclass correlation, 0.87). The hypothesized five-factor structure of the scale was found to have an acceptable fit to the data (root mean square error of approximation, 0.055; 90% confidence interval, 0.03-0.075; comparative fit index, 0.95; Tucker-Lewis Index, 0.94). In general, PLAYfun scores increased with age as developmentally expected. There were few sex differences across skills, but girls did not perform as well as boys on upper and lower body object control skills. CONCLUSIONS: The factor structure and patterns of results by age and sex support PLAYfun as a measure of motor competence. Continued evaluation of the tool and other subscales of PLAY is required. PMID- 29140899 TI - Isotemporal Substitution of Sedentary Behavior and Physical Activity on Function. AB - : The amount of time spent in sedentary behaviors (SB) progressively increases with age, while reducing time spent in light-intensity physical activity (LPA) and moderate- to vigorous-intensity physical activity (MVPA). These trajectories in PA and SB are linked to accelerated reductions in physical functioning. PURPOSE: This study aimed to examine the association of substituting SB time with LPA and MVPA on physical function in older adults. METHODS: Ninety-one older adults (mean age, 70.7 +/- 10.2 yr) wore a hip-mounted accelerometer to measure SB, LPA, and MVPA time. Measures of physical function included a 400-m walk test (400W), the usual gait speed (UGS), the five times sit-to-stand (5xSTS) test, and the short physical performance battery (SPPB). Isotemporal substitution regression modeling was performed to assess the relationship of replacing the amount of time spent in one activity for another. RESULTS: Replacing 30 min.d of SB with LPA was associated with a significant improvement in 400W (P = 0.0497), whereas MVPA resulted in a significant improvement (P < 0.01) in 400W, UGS, 5xSTS, and SPPB. Replacing 60 min.d of SB with 10 min.d of MVPA and 50 min.d of LPA was associated with significant improvements in the 400W, UGS, and 5xSTS (P < 0.05). Meanwhile, as little as 5 min.d of MVPA and 55 min.d of LPA were linked to a 78% increased odds of scoring with good function in the SPPB (P = 0.0247). CONCLUSION: Replacing SB with LPA was linked to a significant improvement in the 400W, but not the other brief functional measures. Mixed doses of LPA and MVPA may add flexibility to interventions targeting reductions of SB in older adults for clinically relevant improvements in physical function. PMID- 29140900 TI - Associations between BMI Change and Cardiometabolic Risk in Retired Football Players. AB - PURPOSE: Elevated rates of cardiometabolic diseases have been observed in former American football players. The current study sought to determine whether change in body mass index (DeltaBMI) after retirement influences the prevalence of CHD, diabetes, or high blood pressure (HBP) in former professional football players. METHODS: Retired professional football players (n = 3729) were sent a survey with questions regarding health status, playing history, and demographic information. Self-reported BMI at the time of retirement was subtracted from current self reported BMI to calculate DeltaBMI. Prevalence of CHD, diabetes, and HBP were determined by asking participants if they had ever been diagnosed by a health care professional. Binomial regression with a Poisson residual and robust variance estimation was used to compute crude prevalence ratios (PR) and 95% confidence intervals (CI) for each outcome. Adjusted PR values were calculated by adjusting for BMI at the time of retirement, age, years of football experience, race, exercise habits, alcohol use, steroid history, smoking history, and playing position. RESULTS: Complete data were available for 2062 respondents. Prevalence of CHD increased 25%-31% for each five-point increase in DeltaBMI after retirement (crude PR = 1.25, 95% CI = 1.03-1.52, P = 0.026; adjusted PR = 1.31, 95% CI = 1.11-1.55, P = 0.001). Diabetes prevalence increased 69%-88% for each five-point DeltaBMI increase (crude = 1.88, 95% CI = 1.45-2.44, P < 0.001; adjusted = 1.69, 95% CI = 1.32-2.15, P < 0.001). A five-point increase in DeltaBMI was associated with a 35%-40% increase in HBP prevalence (crude = 1.40, 95% CI = 1.27-1.53, P < 0.001; adjusted = 1.35, 95% CI = 1.24-1.47, P < 0.001). CONCLUSIONS: After controlling for relevant covariates, postretirement DeltaBMI was positively and independently associated with prevalence of CHD, diabetes, and HBP. Postretirement interventions using diet and/or exercise to influence body composition may improve long-term health in retired football players. PMID- 29140901 TI - State-of-the-Art Techniques in Treating Peripheral Nerve Injury. AB - BACKGROUND: Peripheral nerve injuries remain a major clinical concern, as they often lead to chronic disability and significant health care expenditures. Despite advancements in microsurgical techniques to enhance nerve repair, biological approaches are needed to augment nerve regeneration and improve functional outcomes after injury. METHODS: Presented herein is a review of the current literature on state-of-the-art techniques to enhance functional recovery for patients with nerve injury. Four categories are considered: (1) electroceuticals, (2) nerve guidance conduits, (3) fat grafting, and (4) optogenetics. Significant study results are highlighted, focusing on histologic and functional outcome measures. RESULTS: This review documents the current state of the literature. Advancements in neuronal stimulation, tissue engineering, and cell-based therapies demonstrate promise with regard to augmenting nerve regeneration and appropriate rehabilitation. CONCLUSIONS: The future of treating peripheral nerve injury will include multimodality use of electroconductive conduits, fat grafting, neuronal stimulation, and optogenetics. Further clinical investigation is needed to confirm the efficacy of these technologies on peripheral nerve recovery in humans, and how best to implement this treatment for a diverse population of nerve-injured patients. PMID- 29140902 TI - Endoscopic Carpal Tunnel Release with and without Sedation. AB - BACKGROUND: This study evaluated outcomes and complications with endoscopic carpal tunnel release performed with local anesthesia only versus local anesthesia with sedation. The authors hypothesized that patient outcomes and satisfaction would be equivalent in both groups irrespective of anesthesia type. METHODS: One hundred fifty-four consecutive patients undergoing endoscopic carpal tunnel release with local anesthesia either with or without sedation were prospectively enrolled in a study of satisfaction and outcomes. Patients were surveyed preoperatively and at 2 weeks and 3 months postoperatively to evaluate satisfaction, symptoms, complications, and disability using the 11-question Disabilities of the Arm, Shoulder, and Hand questionnaire survey; the Levine-Katz carpal tunnel survey; and a customized Likert scale. RESULTS: The hypothesis was upheld. Patients reported high levels of satisfaction (96 percent in the local anesthesia group and 93 percent in the local anesthesia with sedation group at 3 weeks). Disability, pain, and symptom scores did not differ significantly between groups at either postoperative time point. After surgery, patients in the sedation group recalled more mean preoperative anxiety (four of 10 versus 2.03 of 10 at 3 months). If they were to undergo surgery again, patients in the sedation group were likely to desire either sedation (68 percent) or general anesthesia (29 percent), whereas patients in the local anesthesia-only group were likely to wish for similar local-only anesthesia (78 percent). There were no reoperations or epinephrine-related complications in either group. CONCLUSIONS: Patients undergoing endoscopic carpal tunnel release with the local anesthesia or local anesthesia plus sedation experience similar levels of satisfaction and outcomes. Both methods of anesthesia provide excellent results and allow surgeons and patients to choose freely between the two anesthetic techniques. PMID- 29140903 TI - Cleft-Related Orthognathic Surgery Based on Maxillary Vertical Lengthening of the Anterior Facial Height. AB - BACKGROUND: The conventional approach during orthognathic surgery for cleft related deformities has focused largely on restoration of maxilla retrusion, using the maxillary advancement as a standard treatment objective. However, the authors thought that maxillary vertical shortening and deficient incisor show could be additional key elements of cleft-related deformities. Although slight vertical lengthening can be obtained with only maxillary advancement, it would not be enough to obtain satisfactory aesthetic results in terms of the anterior facial height. The authors hypothesized that vertical deficiency and anteroposterior maxillary retrusion exists in cleft-related deformities. Therefore, orthognathic surgery including intentional vertical lengthening and advancement would be better than the conventional simple advancement. METHODS: A new approach was used to treat consecutive patients with dentofacial deformities between December of 2007 and December of 2016. Patients with cleft-related dentofacial deformities were included in the study. RESULTS: Forty-one patients with cleft-related dentofacial deformities were included. The distance from the nasion to the incisor tip was 76.70 mm; the angle of the lines connecting the sella, nasion, and point A was 74.03 degrees; and the incisor show was 1.02 mm. Corresponding measurements in 40 patients without clefts were 81.57 mm, 80.08 degrees, and 3.38 mm, respectively. Postoperatively, the average vertical lengthening achieved was 0.88 mm in the simple maxillary advancement group and 7.65 mm in the intentional vertical lengthening accompanied by maxillary advancement group. CONCLUSION: The authors' results suggest that simultaneous maxillary vertical lengthening with horizontal advancement is a viable approach to orthognathic surgery for cleft-related deformities, given the long-term stability of outcomes demonstrated in this study. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29140904 TI - Reconstruction of Microtias with Constricted Ear Features: A 22-Year Experience. AB - BACKGROUND: The surgical correction of microtias with constricted ear features has remained a challenge because of the variable shape and large volume of the remnant cartilage and skin involved. To clarify how this remnant cartilage and skin should be treated, the authors have reviewed and analyzed cases operated on at their center. METHODS: A total of 167 cases of microtia with constricted ear features, operated on from 1992 to 2014, were included in the study. They were reviewed through medical records and photographs, analysis of surgical methods, and postoperative outcomes. RESULTS: A total of 141 cases (84 percent) were followed for 2 months to 13 years (average, 28 months). The average score given for the aesthetic outcomes, rated on a four-point Likert scale (i.e., 1 = poor, 2 = fair, 3 = good, and 4 = excellent), was 3.1. For framework construction, the authors used remnant cartilage-saving methods (n = 37) or remnant cartilage replacement methods (n = 104). The average scores for the aesthetic outcome for these methods were 2.56 (median, 3) and 3.36 (median, 4), respectively. The difference in these scores was statistically significant (p < 0.001). For the coverage of new frameworks, various flap techniques were used. CONCLUSION: To correct microtias with constricted ear features with consistent postoperative results, the deformed cartilage remnant should be completely replaced with a costal cartilage framework, and the remnant skin should be maximally saved. PMID- 29140905 TI - Gender-Confirmation Surgery Using the Pedicle Transverse Colon Flap for Vaginal Reconstruction: A Clinical Outcome and Sexual Function Evaluation Study. AB - : Vaginal reconstruction and vaginoplasty are indicated in vaginal agenesis, following pelvic tumor resection, trauma, and for gender-confirmation surgery. In this article, the authors present the clinical outcomes and sexual function evaluation when using the pedicle transverse colon flap for gender-confirmation surgery in transgender women. This is a retrospective chart review of all transgender women who underwent gender-confirmation surgery using the pedicle transverse colon flap. Demographics, procedure specifics, and surgical outcomes were recorded and analyzed. Sexual function was measured using the Female Sexual Function Index and the Female Genital Self-Image Scale 1 year after surgery. Fifteen patients underwent gender-confirmation surgery using the aforementioned technique. The average age of the patients was 20 years (range, 18 to 32 years), and the average operating room time was 10.1 hours (range, 8 to 12.5 hours). The average length and width of the flaps were 15 and 2.8 cm, respectively. During a 12-year follow-up, two complications were reported: one patient had pain caused by narrowing at the introitus, which required intervention, and one patient had an excessive amount of secretions in the first month, which subsided 3 months after surgery. The mean Female Sexual Function Index score was 28.6 (range, 24 to 31). All patients achieved normal sexual function as indicated by a Female Sexual Function Index score of 25 or more. For the Female Genital Self-Image Scale, the mean total score was 20.0 +/- 4.5 (range, 7 to 28). The pedicle transverse colon flap is another valuable alternative method for vaginoplasty with promising results and minor complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29140906 TI - Nose and Lip Graft Variants: A Subunit Anatomical Study. AB - BACKGROUND: In the field of vascularized composite tissue allotransplantation, the surgical design of facial subunit grafts is an evolving concept. The purpose of the present article is to study the possibility of dividing the historical nose and lip face transplant into several morphologic and functional subunit grafts, depending on their respective supply. METHODS: This study was conducted in 20 adult cadavers. The facial artery and its branches were dissected bilaterally in 16 fresh and four embalmed heads. Nasolabial perfusion was assessed by selective injection of methylene blue and eosin (n = 2) or India ink (n = 2) in the superior labial and distal facial arteries. Dynamic perfusion through the distal facial artery was illustrated by fluoroscopy (n = 3). Three nose-upper lip grafts were harvested and injected with barium sulfate for microangiography computed tomographic analysis. Finally, three isolated nasal and bilabial grafts were procured and their vascular patency assessed by fluoroscopy. RESULTS: The distal facial artery can perfuse the entire nose, septum, and upper lip, without any contribution of the superior labial artery. A dense anastomotic network indeed exists between the respective distal rami of both vessels. Furthermore, the exclusion of the superior labial artery from the harvested nasal subunit allowed safe bilabial subunit procurement, from the same specimen. CONCLUSIONS: The authors' results demonstrate the feasibility of harvesting nasal and labial subunits, in an isolated or a combined manner. These results can find applications in subunit autologous replantation, allotransplantation, allogenic face partial retransplantation, and the emerging field of vascularized composite tissue engineering. PMID- 29140907 TI - The Singapore Sling: F1 Race Team Cognitive Function and Mood Responses During the Singapore Grand Prix. AB - The current investigation measured cognitive performance, subjective ratings of mood and sleep in Formula 1(r) (F1) race team members during the 2013 Singapore Grand Prix. Two weeks prior to the Singapore Grand Prix participants (n = 16; mean age 33.5 years, range 22-48 years) underwent baseline cognitive assessments as well as a questionnaire on mood and sleep quality/duration. These assessments were repeated on the race weekend prior to practice (S1) and post qualifying (S2). A significant increase in simple reaction time (SRT), that is slowing of total response time was observed from baseline to S1 (33.69 +/- 6.52 ms; p<.001) and from baseline to S2 (34.63+/- 8.19ms; p=.002). Mood related effects were observed with subjective stress levels increased from baseline to S1 (18.06 +/- 6.18; p=.032) and a decrease in how refreshed the race team members felt between S1 and S2 (18.56 +/- 6.14; p=.029). In addition a negative association between change in SRT and change in quality of sleep (R=0.47; p=.016) as well as negative association in how refreshed individuals reported feeling and SRT between S1 and S2 (R=0.37; p=.017). The findings suggest that the demands presented by an F1 race environment have significant effects on cognitive function and mood, however, the exact cause of any decrements would most likely be a combination and interaction of multiple factors. Future research should endeavour to adopt a holistic approach and investigate physiological and cognitive endpoints to fully explore the demands of this challenging motorsport. PMID- 29140908 TI - Heart Rate Monitoring in Basketball: Applications, Player Responses, and Practical Recommendations. AB - Berkelmans, DM, Dalbo, VJ, Kean, CO, Milanovic, Z, Stojanovic, E, Stojiljkovic, N, and Scanlan, AT. Heart rate monitoring in basketball: applications, player responses, and practical recommendations. J Strength Cond Res 32(8): 2383-2399, 2018-The aims of this review were to collate the existing literature encompassing heart rate (HR) monitoring in basketball to (a) identify the applications of HR measurement; (b) report HR responses in male and female players during training and game-play; (c) evaluate use of current HR-based training load models; and (d) provide recommendations for future research and best practice approaches for basketball practitioners. Heart rate monitoring in basketball carries 3 primary applications: (a) monitoring exercise intensity; (b) assessing player fatigue status; and (c) quantifying internal training load. When interpreting the available training and game-play HR data in basketball players, key differences have been observed between playing positions and playing levels. Sex- and age based differences in HR responses during basketball training and game-play are apparent across separate studies; however, further research exploring HR responses in wider player groups is needed, especially in female and junior players. There is also a lack of research directly comparing player HR responses during training and game-play to ascertain the effectiveness of different drills in preparing players for competition. Heart rate-based models have been frequently used to quantify the internal training load in basketball players, including Banister's Training Impulse (TRIMP), Lucia's TRIMP, and Edwards' Summated-Heart-Rate-Zones (SHRZ). The SHRZ model seems to hold practical advantages and better detect changes in player responses across training cycles compared with other approaches. Practical outcomes of this review center on recommendations for position-specific training plans, drills to promote desired cardiovascular stress, analysis of HR outcome measures, and ideal training load monitoring approaches. PMID- 29140909 TI - The Effects of Load on Peak Power Output Fatigue During the Bench Throw. AB - The ability to create power is an important variable for athletic success. No study to date has compared peak power output (PPO) fatigue across multiple sets and with different loads with the bench throw. This study aimed to begin the process of establishing empirical upper body power training guidelines for moderately strong athletes by determining how load (30%, 45%, 60% 1RM) affects PPO (Watts) dropoff during 3 sets of 10 repetitions of the bench throw. 10 resistance-trained male volunteers ((mean +/- SD): age 20.58 +/- 1.36 years, height 176.05 +/- 9.09 cm., weight 78.65 +/- 9.93 kg, bench press 1RM 99.79 +/ 18.52 kg) performed 3 sets of 10 repetitions of the bench throw with one of the three loads during 3 weekly sessions. A Humac 360 device collected concentric phase PPO data during each repetition. The data were analyzed using one-way (Treatment) and two-way (Treatment * Time) repeated measures ANOVA. A significant decrease in PPO was observed during repetitions 5-7 at 30%, 3-4 at 45%, and 2-3 at 60% 1RM. Based on the results of this study, coaches who want to maximize power should potentially keep sets of upper body plyometrics within these repetition ranges. The authors recommend that moderately strong athletes perform the bench throw on a Smith machine at 45% or 60% 1RM to produce high PPO over multiple sets. PMID- 29140910 TI - Polygenic Profile and Exercise-Induced Muscle Damage by a Competitive Half Ironman. AB - Del Coso, J, Salinero, JJ, Lara, B, Gallo-Salazar, C, Areces, F, Herrero, D, and Puente, C. Polygenic profile and exercise-induced muscle damage by a competitive half-ironman. J Strength Cond Res XX(X): 000-000, 2017-To date, it is still unknown why some individuals develop higher levels of muscle damage than other individuals, despite participating in exercise with comparable levels of physical intensity. The aim of this investigation was to analyze 7 single-nucleotide polymorphisms (SNPs) that are candidates to explain individual variations in the level of muscle damage attained during a half-ironman competition. Using the model of Williams and Folland (2, 1, and 0 points for optimal, intermediate, and suboptimal genotype), we determined the total genotype score from the accumulated combination of 7 SNPs (ACE = 287bp Ins/Del; ACTN3 = p.R577X; creatine kinase, muscle type = NcoI; insulin-like growth factor 2 = C13790G; interleukin-6 = 174G>C; myosin light chain kinase = C37885A; and tumor necrosis factor-alpha = 308G>A) in 22 experienced triathletes. Before and after the race, a sample of venous blood was obtained to measure serum markers of muscle damage. Two groups of triathletes were established according to their postcompetition serum CK concentration: low CK responders (n = 10; 377 +/- 86 U.L) vs. high CK responders (n = 12; 709 +/- 136 U.L). At the end of the race, low CK responders had lower serum myoglobin concentrations (384 +/- 243 vs. 597 +/- 293 ng.ml, p = 0.04). Although the groups were similar in age, anthropometric characteristics, and training habits, total genotype score was higher in low CK responders than in high CK responders (7.7 +/- 1.1 vs. 5.5 +/- 1.1 point, p < 0.01). A favorable polygenic profile can contribute to reducing the level of muscle damage developed during endurance exercise. PMID- 29140911 TI - Effect of Bench Press Load Knowledge on Repetitions, Rating of Perceived Exertion, and Attentional Focus. AB - Beaudoin, CM, Cox, Z, Dundore, T, Thomas, T, Kim, J, and Pillivant, D. Effect of bench press load knowledge on repetitions, rating of perceived exertion, and attentional focus. J Strength Cond Res 32(2): 514-519, 2018-Few studies have examined the role of the teleoanticipation during resistance training. The purpose of this study was to examine the effect of bench press (BP) load knowledge on repetitions completed, ratings of perceived exertion (RPEs), and attentional focus (% associative). Thirty-six recreationally active resistance trained men (n = 25) and women (n = 11) participated in this study (age = 20.97 +/- 1.87 years; ht = 174.12 +/- 9.41 cm; and mass = 80.14 +/- 14.03 kg). All subjects completed 3 testing sessions: (a) 1 repetition maximum (1RM) BP determination; (b) submaximal BP repetitions to fatigue known load (KL); and (c) submaximal BP repetitions to fatigue unknown load (UL). Known load and UL sessions were randomized and counterbalanced and both completed at 70% 1RM. An estimated weight ratio was computed using the subject's estimate of the UL weight relative to the KL weight. An independent samples t-test revealed no significant testing order difference for the estimated weight ratio. Two-way repeated measures analysis of variances revealed no significant differences in the number of repetitions (p = 0.63), RPE (p = 0.18), or attentional focus (% associative) (p = 0.93) between the KL and UL conditions. Pearson correlations found a moderate positive association between KL repetitions completed and % associative focus when the UL was completed before the KL. Load knowledge did not influence the number of repetitions, RPE, or attentional focus while completing the BP. Further research examining the use of pacing strategies, RPE, and attentional focus during KL and UL conditions are warranted. PMID- 29140912 TI - Reliable Testing Battery for Assessing Physical Qualities of Elite Academy Rugby League Players. AB - Dobbin, N, Hunwicks, R, Highton, J, and Twist, C. Reliable testing battery for assessing physical qualities of elite academy rugby league players. J Strength Cond Res XX(X): 000-000, 2017-This study assessed the interday reliability of a testing battery for the assessment of physical qualities of rugby league players. Fifty players (age 17.1 +/- 1.1 years; stature 181.3 +/- 6.3 cm; and body mass 89.0 +/- 11.6 kg) from 3 Super League academies participated in this study. Tests of countermovement jump performance, 10- and 20-m sprint performance, change of direction, medicine ball throw, and a modified Yo-Yo Intermittent Recovery Test Level 1 (prone Yo-Yo IR1) were completed on 3 separate occasions. Between-day intraclass correlation coefficient, typical error (TE), coefficient of variation, and the smallest worthwhile change (SWC) were calculated to determine the reliability and sensitivity of each measure. Individual tests (except medicine ball throw) were not systematically different between trials (p > 0.05), with an interday variability that was <10%. In all instances, the TE was larger than the calculated SWC change, although variability was less than that typically observed after a training intervention or specific training period (i.e., preseason). Using a magnitude-based inference approach, we present the required change for all performance tests to be 75% confident and the change is beneficial. This simple and time efficient testing battery is sufficiently reliable to detect previously observed changes in a range of physical qualities of rugby league players. PMID- 29140913 TI - Sex Differences in Aerobic Fitness in Top-Class Soccer Referees. AB - Castagna, C, Bizzini, M, D'Ottavio, S, and Araujo Povoas, SC. Gender differences in aerobic fitness in top-class soccer referees. J Strength Cond Res XX(X): 000 000, 2017-The aim of this study was to assess the aerobic-fitness differences between male and female top-class soccer field referees (FRs). This with the purpose to provide cutoff values useful for training prescription in female FRs. Forty female top-class FRs (age 34.18 +/- 3.50 years and 5 +/- 3.9 years international refereeing experience) and 52 male FRs (age 38.4 +/- 3.3 years and 5 +/- 3.5 years international refereeing experience) candidates in the preliminary open list developed by the FIFA Refereeing Department for the 2014 and 2015 World Cup Tournaments, participated in the study. The FRs were tested for aerobic fitness under laboratory conditions with a progressive speed treadmill test until exhaustion. Female FRs showed to possess, on average, lower (large effect) levels of aerobic fitness and performance compared with their male counterparts. The female FRs' V[Combining Dot Above]O2max (48.1 +/- 4.4 ml.kg.min) was 7% (large effect) lower than the male FRs (51.9 ml.kg.min). Peak treadmill speed was 11% lower (large effect) in female FRs (16.27 +/- 0.94 vs. 14.64 +/- 0.96 km.h). The receiver operating characteristic curve analysis enabled cutoff values (47.8 ml.kg.min for V[Combining Dot Above]O2max) that may be used as preliminary cues to guide physiological selection and training prescription in female FRs aiming to officiate male-soccer matches. Only 2.5% of the female FRs showed V[Combining Dot Above]O2max higher than the mean values of male FRs when using the scaled notation (0.68). Female FRs aiming to officiate male competitions should consider training intensities at anaerobic threshold speed (13 km.h, 95% heart rate max) when developing aerobic fitness. Given the very large sex differences in aerobic performance, strength/power training should be proposed to perspective female top-class FRs. PMID- 29140914 TI - Sequencing Effects of Neuromuscular Training on Physical Fitness in Youth Elite Tennis Players. AB - Fernandez-Fernandez, J, Granacher, U, Sanz-Rivas, D, Sarabia Marin, JM, Hernandez Davo, JL, and Moya, M. Sequencing effects of neuromuscular training on physical fitness in youth elite tennis players. J Strength Cond Res 32(3): 849-856, 2018 The aim of this study was to analyze the effects of a 5-week neuromuscular training (NMT) implemented before or after a tennis session in prepubertal players on selected components of physical fitness. Sixteen high-level tennis players with a mean age of 12.9 +/- 0.4 years participated in this study, and were assigned to either a training group performing NMT before tennis-specific training (BT; n = 8) or a group that conducted NMT after tennis-specific training (AT; n = 8). Pretest and posttest included: speed (5, 10, and 20 m); modified 5-0 5 agility test; countermovement jump (CMJ); overhead medicine ball throw (MBT); and serve velocity (SV). Results showed that the BT group achieved positive effects from pretest to posttest measures in speed (d = 0.52, 0.32, and 1.08 for 5, 10, and 20 m respectively), 5-0-5 (d = 0.22), CMJ (d = 0.29), MBT (d = 0.51), and SV (d = 0.32), whereas trivial (10 m, 20 m, CMJ, SV, and MBT) or negative effects (d = -0.19 and -0.24 for 5 m and 5-0-5, respectively) were reported for the AT group. The inclusion of an NMT session before the regular tennis training led to positive effects from pretest to posttest measures in performance-related variables (i.e., jump, sprint, change of direction capacity, as well as upper body power), whereas conducting the same exercise sessions after the regular tennis training was not accompanied by the same improvements. PMID- 29140915 TI - The Actual Versus Idealized Self: Exploring Responses to Feedback About Implicit Bias in Health Professionals. AB - PURPOSE: Implicit bias can adversely affect health disparities. The implicit association test (IAT) is a prompt to stimulate reflection; however, feedback about bias may trigger emotions that reduce the effectiveness of feedback interventions. Exploring how individuals process feedback about implicit bias may inform bias recognition and management curricula. The authors sought to explore how health professionals perceive the influence of the experience of taking the IAT and receiving their results. METHOD: Using constructivist grounded theory methodology, the authors conducted semistructured interviews with 21 pediatric physicians and nurses at the Schulich School of Medicine and Dentistry, Western University, Ontario, Canada, from September 2015 to November 2016 after they completed the mental illness IAT and received their result. Data were analyzed using constant comparative procedures to work toward axial coding and development of an explanatory theory. RESULTS: When provided feedback about their implicit attitudes, participants described tensions between acceptance and justification, and between how IAT results relate to idealized and actual personal and professional identity. Participants acknowledged desire for change while accepting that change is difficult. Most participants described the experience of taking the IAT and receiving their result as positive, neutral, or interesting. CONCLUSIONS: These findings contribute to emerging understandings of the relationship between emotions and feedback and may offer potential mediators to reconcile feedback that reveals discrepancies between an individual's actual and idealized identities. These results suggest that reflection informed by tensions between actual and aspirational aspects of professional identity may hold potential for implicit bias recognition and management curricula. PMID- 29140916 TI - Gender Disparities in Medical Student Research Awards: A 13-Year Study From the Yale School of Medicine. AB - PURPOSE: The Liaison Committee on Medical Education mandates instruction in research conduct, and many U.S. medical schools require students to complete a research project. All Yale School of Medicine (YSM) graduating students submit a research thesis, and ~5% are awarded highest honors. Gender disparities exist in areas related to physician research productivity, including academic rank, research funding, and publications. The authors asked whether gender disparities exist for medical student research. METHOD: The authors conducted a retrospective review of 1,120 theses submitted by graduating medical students from 2003 to 2015 at YSM and collected data on gender, mentoring, research type, sponsoring department, and other characteristics. Multivariate logistic regression modeling examined gender differences in medical student research awards. RESULTS: Women authored 50.9% of theses, but earned only 30.9% of highest honors awards (OR 0.41; 95% CI: 0.23, 0.74). Among factors associated with increased receipt of highest honors that differed by gender, men were more likely than women to work with a mentor with a history of three or more thesis honorees, take a fifth year of study, secure competitive research funding, undertake an MD-master of health science degree, and conduct laboratory research (all P < .001). After adjustment for these factors, and for underrepresented in medicine status and sponsoring department, women remained less likely to receive highest honors (OR 0.51; 95% CI: 0.27, 0.98). CONCLUSIONS: Women YSM students were less likely to receive highest honors for medical research. Gender disparities in postgraduate biomedical research success may start during undergraduate medical education. PMID- 29140917 TI - Medical Trainees' Experiences of Treating People With Chronic Pain: A Lost Opportunity for Medical Education. AB - PURPOSE: Evidence suggests that physicians' opinions about patients with chronic pain become progressively negative over the course of medical training, leading to decline in empathy for these patients. Few qualitative studies have focused on this issue, and thus the experiences shaping this process remain unexplored. This study addressed how medical trainees learn about chronic pain management through informal and formal curricula. METHOD: This study adopted a constructive qualitative approach informed by the theoretical lens of the hidden curriculum. Thirteen open-ended interviews were conducted with medical students and residents at various training stages; interviewees had experience treating patients with chronic pain, shadowing the care of these patients, or both. Interviews elicited information about stage of medical training, general descriptions of work, and concrete experiences of managing patients with chronic pain. All interviews were collected in Toronto between June and August 2015. RESULTS: Most interviewees described the management of chronic pain as challenging and unrewarding and attributed this at least in part to their perception that pain was subjective. Trainees also recounted that their inability to cure chronic pain left them confused about how to provide care, and voiced a perception that preceptors seemed to view these patients as having little educational value. CONCLUSIONS: Specifically because chronic pain is subjective and incurable, listening and communication become crucial for patient care. Instead of sheltering trainees, medical educators should be offered the opportunity to reflect on the skills that are required to provide patient-centered care for this population. This approach has the potential to greatly benefit both trainees and patients. PMID- 29140918 TI - Integrating Social Determinants of Health Into Graduate Medical Education: A Call for Action. AB - Social determinants of health (SDH) are the major drivers of health and disparate health outcomes across communities and populations. Given this, the authors assert that competency in recognizing and mitigating SDH should become a vital component of graduate medical education in all specialties. Although the most effective approaches to educating trainees about SDH are uncertain, in this Invited Commentary, the authors offer several key principles for implementing curricula focusing on SDH. These include universalization of the material, integration into clinical education, identification of space for trainee introspection, clarification of specific competencies in identification and mitigation of SDH, and creation of robust faculty development programming. The authors highlight several examples of curricular approaches to SDH, touching on orientation, experiential learning, community-based and service-learning opportunities, interprofessional activities, and the hidden curriculum. The authors argue that all clinical trainees must learn to recognize and mitigate SDH and that doing so will allow them to achieve meaning and mastery in medicine and to better meet society's pressing health needs. PMID- 29140919 TI - Collaboration and Teamwork in the Health Professions: Rethinking the Role of Conflict. AB - Whereas the business professions have long recognized that conflict can be a source of learning and innovation, the health professions still tend to view conflict negatively as being disruptive, inefficient, and unprofessional. As a consequence, the health professions tend to avoid conflict or resolve it quickly. This neglect to appreciate conflict's positive attributes appears to be driven in part by (1) individuals' fears about being negatively perceived and the potential negative consequences in an organization of being implicated in conflict, (2) constrained views and approaches to professionalism and to evaluation and assessment, and (3) lingering autocracies and hierarchies of power that view conflict as a disruptive threat.The author describes changing perspectives on collaboration and teamwork in the health professions, discusses how the health professions have neglected to appreciate the positive attributes of conflict, and presents three alternative approaches to more effectively integrating conflict into collaboration and teamwork in the health professions. These three approaches are (1) cultivating psychological safety on teams to make space for safe interpersonal risk taking, (2) viewing conflict as a source of expansive learning and innovation (via models such as activity theory), and (3) democratizing hierarchies of power through health humanities education ideally by advancing the health humanities to the core of the curriculum.The author suggests that understanding conflict's inevitability and its innovative potential, and integrating it into collaboration and teamwork, may have a reassuring and emancipating impact on individuals and teams. This may ultimately improve performance in health care organizations. PMID- 29140920 TI - Oral lithium as an adjunctive therapy during radioiodine treatment for hyperthyroidism. PMID- 29140921 TI - Response to: Oral lithium as an adjunctive therapy during radioiodine treatment for hyperthyroidism. PMID- 29140922 TI - Fingolimod reduces neuropathic pain behaviors in a mouse model of multiple sclerosis by a sphingosine-1 phosphate receptor 1-dependent inhibition of central sensitization in the dorsal horn. AB - Multiple sclerosis (MS) is an autoimmune-inflammatory neurodegenerative disease that is often accompanied by a debilitating neuropathic pain. Disease-modifying agents slow down the progression of multiple sclerosis and prevent relapses, yet it remains unclear if they yield analgesia. We explored the analgesic potential of fingolimod (FTY720), an agonist and/or functional antagonist at the sphingosine-1-phosphate receptor 1 (S1PR1), because it reduces hyperalgesia in models of peripheral inflammatory and neuropathic pain. We used a myelin oligodendrocyte glycoprotein 35 to 55 (MOG35-55) mouse model of experimental autoimmune encephalomyelitis, modified to avoid frank paralysis, and thus, allow for assessment of withdrawal behaviors to somatosensory stimuli. Daily intraperitoneal fingolimod reduced behavioral signs of central neuropathic pain (mechanical and cold hypersensitivity) in a dose-dependent and reversible manner. Both autoimmune encephalomyelitis and fingolimod changed hyperalgesia before modifying motor function, suggesting that pain-related effects and clinical neurological deficits were modulated independently. Fingolimod also reduced cellular markers of central sensitization of neurons in the dorsal horn of the spinal cord: glutamate-evoked Ca signaling and stimulus-evoked phospho extracellular signal-related kinase ERK (pERK) expression, as well as upregulation of astrocytes (GFAP) and macrophage/microglia (Iba1) immunoreactivity. The antihyperalgesic effects of fingolimod were prevented or reversed by the S1PR1 antagonist W146 (1 mg/kg daily, i.p.) and could be mimicked by either repeated or single injection of the S1PR1-selective agonist SEW2871. Fingolimod did not change spinal membrane S1PR1 content, arguing against a functional antagonist mechanism. We conclude that fingolimod behaves as an S1PR1 agonist to reduce pain in multiple sclerosis by reversing central sensitization of spinal nociceptive neurons. PMID- 29140924 TI - Association between pain and frailty among Chinese community-dwelling older adults: depression as a mediator and its interaction with pain. AB - Pain and frailty are both prevalent and have severe health impacts among older adults. We conducted a cross-sectional observational study to examine the association between pain and frailty, and depression as a mediator and its interaction with pain on frailty among 1788 Chinese community-dwelling older adults. Physical frailty, pain intensity, and depressive symptoms were assessed using the Frailty Phenotype, the Faces Pain Scale-revised, and the 5-item Geriatric Depression Scale, respectively. We found that both pain (odds ratio [OR] = 1.61; 95% confidence interval [CI]: 1.32-1.97) and depressive symptoms (OR = 4.67; 95% CI: 3.36-6.50) were positively associated with physical frailty (OR = 1.61; 95% CI: 1.32-1.97), and depressive symptoms were associated with pain (OR = 1.94; 95% CI: 1.15-3.39), attenuating the association between pain and physical frailty by 56.1%. Furthermore, older adults with both pain and depressive symptoms (OR = 8.13; 95% CI: 5.27-12.53) had a higher risk of physical frailty than those with pain (OR = 1.41; 95% CI: 1.14-1.76) or depressive symptoms (OR = 3.63; 95% CI: 2.25-5.85) alone. The relative excess risk of interaction, the attributable proportion due to interaction, and the synergy index (S) were 4.08, 0.50, and 2.34, respectively. These findings suggest that the positive association of pain with frailty is persistent and partially mediated by depression, and comorbid depression and pain have an additive interaction on physical frailty. It has an implication of multidisciplinary care for frail older adults with pain. PMID- 29140923 TI - Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain. AB - Peripheral nerve injury (PNI) activates the immune system, resulting in increased proinflammatory cytokines at the site of injury and in the spinal cord dorsal horn. Exercise modulates the immune system promoting an anti-inflammatory phenotype of macrophages in uninjured muscle, and increases in anti-inflammatory cytokines can promote healing and analgesia. We proposed that PNI will decrease, and treadmill exercise will increase, release of anti-inflammatory cytokines at the site of injury and in the spinal cord. We show that 2 weeks of treadmill exercise improves neuropathic pain behaviors in mice: mechanical hyperalgesia, escape and avoidance behavior, and spontaneous locomotor activity. Peripheral nerve injury reduced anti-inflammatory cytokines (interleukin-4 [IL-4], IL-1ra, and IL-5) at the site of nerve injury and in the spinal dorsal horn, whereas exercise restored IL-4, IL-1ra, and IL-5 concentrations to preinjury levels. IL4 mice and mice treated with IL-4 antibody did not develop analgesia to treadmill exercise. Using immunohistochemical staining of the sciatic nerve, treadmill exercise increased the percentage of M2 macrophages (secretes anti-inflammatory cytokines) and decreased M1 macrophages (secretes proinflammatory cytokines) when compared with sedentary mice. The increased M2 and decreased M1 macrophages in exercised mice did not occur in IL-4 mice. In the spinal cord, PNI increased glial cell activation, brain-derived neurotrophic factor and beta-nerve growth factor levels, and decreased IL-4 and IL-1ra levels, whereas treadmill exercise suppressed glial cells activation (Glial Fibrillary Acidic Protein and Iba1 immunoreactivity), reduced brain-derived neurotrophic factor and beta-nerve growth factor, and increased IL-4, IL-1ra, and IL-5 concentrations. Our results suggest that IL-4 mediates the analgesia produced by low-intensity exercise by modulating peripheral and central neuroimmune responses in mice with neuropathic pain. PMID- 29140925 TI - Mobilization of CD4+ T lymphocytes in inflamed mucosa reduces pain in colitis mice: toward a vaccinal strategy to alleviate inflammatory visceral pain. AB - T lymphocytes play a pivotal role in endogenous regulation of inflammatory visceral pain. The analgesic activity of T lymphocytes is dependent on their production of opioids, a property acquired on antigen activation. Accordingly, we investigated whether an active recruitment of T lymphocytes within inflamed colon mucosa via a local vaccinal strategy may counteract inflammation-induced visceral pain in mice. Mice were immunized against ovalbumin (OVA). One month after immunization, colitis was induced by adding 3% (wt/vol) dextran sulfate sodium into drinking water containing either cognate antigen OVA or control antigen bovine serum albumin for 5 days. Noncolitis OVA-primed mice were used as controls. Visceral sensitivity was then determined by colorectal distension. Oral administration of OVA but not bovine serum albumin significantly reduced dextran sulfate sodium-induced abdominal pain without increasing colitis severity in OVA primed mice. Analgesia was dependent on local release of enkephalins by effector anti-OVA T lymphocytes infiltrating the inflamed mucosa. The experiments were reproduced with the bacillus Calmette-Guerin vaccine as antigen. Similarly, inflammatory visceral pain was dramatically alleviated in mice vaccinated against bacillus Calmette-Guerin and then locally administered with live Mycobacterium bovis. Together, these results show that the induction of a secondary adaptive immune response against vaccine antigens in inflamed mucosa may constitute a safe noninvasive strategy to relieve from visceral inflammatory pain. PMID- 29140926 TI - Variability in negative emotions among individuals with chronic low back pain: relationships with pain and function. AB - Chronic pain is associated with elevated negative emotions, and resources needed to adaptively regulate these emotions can be depleted during prolonged pain. Studies of links between pain, function, and negative emotions in people with chronic pain, however, have focused almost exclusively on relationships among mean levels of these factors. Indexes that may reflect aspects of emotion regulation have typically not been analyzed. We propose that 1 index of emotion regulation is variability in emotion over time as opposed to average emotion over time. The sample was 105 people with chronic low back pain and 105 of their pain free spouses. They completed electronic diary measures 5x/d for 14 consecutive days, producing 70 observations per person from which we derived estimates of within-subject variance in negative emotions. Location-scale models were used to simultaneously model predictors of both mean level and variance in patient negative emotions over time. Patients reported significantly more variability in negative emotions compared to their spouses. Patients who reported higher average levels of pain, pain interference, and downtime reported significantly higher levels of variability in negative emotions. Spouse-observed pain and pain behaviors were also associated with greater variability in patients' negative emotions. Test of the inverse associations between negative emotion level and variability in pain and function were significant but weaker in magnitude. These findings support the notion that chronic pain may erode negative emotion regulation resources, to the potential detriment of intra- and inter-personal function. PMID- 29140928 TI - Nerve growth factor locally sensitizes nociceptors in human skin. AB - Nerve growth factor (NGF) injected into the human skin causes local hyperalgesia to mechanical and electrical stimuli lasting for weeks. Pig data suggested axonal sensitization of C-nociceptors as a contributing mechanism. Here, we recorded single C-nociceptors in 11 human subjects 3 weeks after intracutaneous injection of 1 MUg NGF into the foot dorsum. For each identified unit, the receptive field was mapped and, whenever possible, we recorded 2 terminal branches of the same unit, 1 from the hyperalgesic NGF-site ("inside") and the other from the nonsensitized skin ("outside"). In the saline-treated control feet, mechano insensitive nociceptors (CMi) were more abundant than at the NGF sites (36% vs 19%). Units with axonal properties of CMi fibres but displaying positive mechanical responses ("CMi-like") dominated at the NGF site (27% vs 6%). Moreover, axonal branches innervating the hyperalgesic skin displayed significantly lower electrical thresholds and less activity-dependent conduction velocity slowing when compared with "outside" or control skin. The "inside" branches also showed long-lasting after-discharges and less adaptation to repeated mechanical stimuli. NGF-induced long-term nociceptor hyperexcitability was maximum at the terminal branches directly treated with NGF. The sensitization included sensory and axonal components affecting both activation thresholds and supra-threshold responses. Our data suggest that a combination of sensory sensitization and axonal hyperexcitability is underlying the localized hyperalgesia by facilitating action potential generation and conduction. Axonal changes were also found in the asymptomatic skin surrounding the NGF-treatment sites, thereby possibly reflecting "nociceptive priming." PMID- 29140929 TI - Tactile acuity (dys)function in acute nociceptive low back pain: a double-blind experiment. AB - Research shows that chronic pain is related to cortical alterations that can be reflected in reduced tactile acuity, but whether acute pain perception influences tactile acuity has not been tested. Considering the biological role of nociception, it was hypothesized that nociceptive pain will lead to a rapid improvement in tactile acuity and that this effect is correlated with pain intensity and pain distribution. In this randomised double-blind controlled experiment (trial no. NCT03021278), healthy participants were exposed to 1 of 3 experimental conditions: acute, nociceptive low back pain induced by saline injection, a sham injection (without piercing the skin) potentially inducing nocebo pain, or no intervention. Tactile acuity was measured by a battery of tests, including two-point discrimination threshold (TPD), before, during the pain experience, and after it subsided. We found that TPD did not improve but deteriorated during pain induction in the experimental group compared with the control group (P < 0.001; eta = 0.20) and changed from 56.94 mm (95% confidence interval: 53.43-60.44) at baseline to 64.22 mm (95% confidence interval: 60.42 68.02) during the pain experience. Maximum reported pain was a significant predictor (beta = 0.55, P = 0.01) and accounted for 26% of the variance in TPD (P < 0.05). Other tests, point-to-point test and two-point estimation task, changed with a similar trend but did not reach significance. We concluded that acute, nociceptive pain does not improve but deteriorates tactile acuity linearly. The biological role of the observed phenomenon is unknown, and therefore, future studies should address this question. PMID- 29140930 TI - Attention bias modification for children: what should we make of a null finding? PMID- 29140927 TI - Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations. AB - Clinical trials to test the safety and efficacy of analgesics across all pediatric age cohorts are needed to avoid inappropriate extrapolation of adult data to children. However, the selection of acute pain models and trial design attributes to maximize assay sensitivity, by pediatric age cohort, remains problematic. Acute pain models used for drug treatment trials in adults are not directly applicable to the pediatric age cohorts-neonates, infants, toddlers, children, and adolescents. Developmental maturation of metabolic enzymes in infants and children must be taken into consideration when designing trials to test analgesic treatments for acute pain. Assessment tools based on the levels of cognitive maturation and behavioral repertoire must be selected as outcome measures. Models and designs of clinical trials of analgesic medications used in the treatment of acute pain in neonates, infants, toddlers, children, and adolescents were reviewed and discussed at an Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) Pediatric Pain Research Consortium consensus meeting. Based on extensive reviews and continuing discussions, the authors recommend a number of acute pain clinical trial models and design attributes that have the potential to improve the study of analgesic medications in pediatric populations. Recommendations are also provided regarding additional research needed to support the use of other acute pain models across pediatric age cohorts. PMID- 29140931 TI - Hemispheric Cerebral Oximetry Monitoring During Pediatric Seizure Activity in a Pediatric Emergency Department. AB - BACKGROUND: Sustained neuronal activity during seizures causes cellular perturbations, alterations in cerebral physiology, and potentially neurological injury, a neurological emergency. With variable clinical manifestations of seizures, frequent failure of seizure recognition by providers in pediatric and developmentally challenged patients can increase seizure complications. Neuroresuscitation should include rapid cerebral physiology assessment for increased seizure recognition and optimal neurological outcomes. In neurological emergencies, cerebral oximetry has demonstrated its utility in altered cerebral physiology and a standard combat neurological assessment tool. During adult seizures, cerebral oximetry (regional cerebral oxygen saturation [rcSO2]) has been shown as a useful neurological assessment tool, but research is lacking in pediatric emergency department (PED) seizure patients. OBJECTIVE: The aim of this study was to identify trends in rcSO2 readings for patients presenting to the PED with seizure activity and in the postseizure state in order to evaluate usefulness of rcSO2 as a neurological assessment tool in pediatric seizure patients. METHODS: This was a PED observational case series comparing hemispheric rcSO2 readings in first-time clinically evident generalized and focal seizure patients to first-time postseizure patients with no PED seizures. RESULTS: Generalized or focal seizure (n = 185) hemispheric rcSO2 revealed significant differences compared with nonseizure and controls' rcSO2 readings (n = 115) (P < 0.0001). Generalized and focal seizure rcSO2's were either less than 60% or greater than 80% compared with nonseizure rcSO2 (P < 0.0001). Ipsilateral focal seizure rcSO2 correlated to seizure side (P < 0.0001) and was less than the contralateral rcSO2 (P < 0.0001), with interhemispheric rcSO2 discordance greater than 16 (P < 0.0001). Seizure to preseizure rcSO2 discordance was as follows: generalized 15.2, focal: left 19.8, right 20.3 (P < 0.0001). CONCLUSIONS: Hemispheric during-seizure rcSO2 readings significantly correlated with generalized and focal seizures and reflected altered cerebral physiology. Ipsilateral focal seizure rcSO2 readings correlated to the focal side with wide interhemispheric rcSO2 discordance. All postseizure rcSO2 readings returned to preseizure readings, showing altered cerebral physiology resolution. Overall, in generalized or focal seizure, rcSO2 readings were less than 60% or greater than 80%, and in focal seizure, interhemispheric rcSO2 discordance was greater than 10. During seizures, hemispheric rcSO2 readings demonstrated its potential pediatric seizure utility. Utilizing rcSO2 readings related to seizure activity could expedite pediatric and developmentally challenged patients' seizure recognition, cerebral assessment, and interventions especially in pharmacoresistant seizures.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29140932 TI - Characteristics of Treatment-experienced HIV-infected African Children and Adolescents Initiating Darunavir and/or Etravirine-based Antiretroviral Treatment. AB - BACKGROUND: Data are limited on the selection and sequencing of second-line and third-line pediatric antiretroviral treatment (ART) in resource-limited settings. This study aimed to evaluate characteristics of African pediatric patients initiated on darunavir (DRV) and/or etravirine (ETR) through a specific drug donation program. METHODS: This was a cross-sectional study of baseline immunologic, virologic and demographic characteristics of children and adolescents initiating DRV-based and/or ETR-based ART. Descriptive statistics were used. RESULTS: Study enrolled 48 patients (45.8% women; median age = 15 years [interquartile range 17.7-10.3]) at 9 clinical sites in Zambia, Swaziland, Kenya and Lesotho. The majority (87.5%; n = 42) had received >=2 prior ART regimens; most (81.2%) had received lopinavir/ritonavir-based ART before switch. All patients had detectable HIV RNA (median = 56,653 copies/mL). Forty seven patients (98.9%) had HIV genotype results: 41 (87.2%) had >=1 nucleos(t)ide reverse transcriptase inhibitor (NRTI)-resistance mutation (RM), predominantly M184V (76.6%; n = 36); 31 (65.9%) had >=1 non-NRTI-RM, including 27 (57.4%) with >=1 ETR-RM; 30 (63.8%) had >=3 protease inhibitor RM, including 20 (42.6%) with >=1 DRV-RM. For new ART regimens, DRV and raltegravir were most frequently prescribed (83.3%; n = 40 on DRV and raltegravir, each). Eighteen patients (37.5%) were initiated on the NRTI-sparing ART. CONCLUSIONS: In our study, a significant proportion of treatment-experienced African children and adolescents had one or more DRV-RM and ETR-RM. For the new regimen, more than a third of pediatric patients failing second-line ART were prescribed NRTI-sparing regimens. Better understanding of the current approaches to pediatric ART sequencing in resource-limited settings is needed. PMID- 29140933 TI - T-SPOT.TB Performance in Routine Pediatric Practice in a Low TB Burden Setting. AB - BACKGROUND: The T-SPOT.TB, an interferon-gamma release assay, is an indirect test of Mycobacterium tuberculosis infection. Due to sparse and conflicting evidence, the use of interferon-gamma release assay is limited in young and HIV-infected children. We determined the prevalence of invalid, borderline, positive and negative results and associations with key demographic variables during routine pediatric use in a low tuberculosis burden setting. METHODS: For pediatric samples received at Oxford Diagnostic Laboratories between 2010 and 2015, the associations between initial test outcome and demographics were estimated by bivariate analysis and logistic regression. RESULTS: A total of 44,289 samples (median age 12.5 years; interquartile range 7.7-15.5), including 5057 samples (11.6%) from children under 5 years old, were received from 46 U.S. states, Washington, DC and Puerto Rico. A total of 592 samples (1.3%) could not be tested. T-SPOT.TB positivity was strongly correlated (r = 0.60; P < 0.0001) with state TB incidence. Compared with negative results, positive results were more likely in samples from older children (P < 0.0001), public health clinics (P < 0.0001) and rural locations (P = 0.005). Although infrequent (0.6%), invalid results were more common in samples collected at HIV clinics (odds ratio = 2.5, 95% confidence interval: 1.3-4.9) and from younger children (P = 0.03). These invalid results were more likely due to a robust nil (negative) control response rather than a weak mitogen (positive) control response. CONCLUSIONS: The T SPOT.TB test correlated strongly with well-recognized risk factors for tuberculosis infection and provided evaluable results in 98% of children. To optimize the impact of testing on clinical decision making and patient outcomes, local epidemiology and individual patient risk should be considered when incorporating IGRAs into pediatric guidelines. PMID- 29140934 TI - Response of Symptomatic Persistent Chronic Disseminated Candidiasis to Corticosteroid Therapy in Immunosuppressed Pediatric Patients: Case Study and Review of the Literature. AB - BACKGROUND: Chronic disseminated candidiasis (CDC) is a severe invasive fungal infection principally observed during neutrophil recovery in patients with acute leukemia treated with intensive chemotherapy. Its pathophysiology remains unclear. We describe the management of 6 children with symptomatic CDC who did not respond to antifungal therapy. METHODS: The databases of the hematology oncology departments of 2 tertiary pediatric medical centers were searched for all patients diagnosed with CDC from 2003 to 2015, who responded to corticosteroids after failing antifungal therapy. Clinical, laboratory and radiologic data were collected. RESULTS: Six patients (3 women, 3 men; 9-18 years of age) met the study criteria. Underlying diseases were acute lymphoblastic leukemia (n = 3) and large B-cell lymphoma, acute myeloid leukemia and severe aplastic anemia (n = 1 each). Presenting symptoms/signs of CDC were fever in all cases, with abdominal or chest pain, and/or mucositis. Candida infection was identified in blood cultures in 4 patients and in bronchoalveolar lavage fluid in one. In the absence of response to antifungal agents (4-50 days from CDC diagnosis), prednisone 2 mg/kg/day or equivalent was administered. CDC attributable clinical symptoms resolved in 4 patients within 6-19 days; one patient required an additional nonsteroidal anti-inflammatory agent. Abnormalities on imaging decreased or disappeared within 5 months to 2 years in 4 patients. CONCLUSIONS: In children with persistent symptomatic CDC, despite adequate antifungal therapy, administration of corticosteroids may yield rapid resolution of symptoms and decreased inflammatory markers. In patients who do not respond to steroids, the addition of a nonsteroidal anti-inflammatory drug should be considered. PMID- 29140935 TI - Cerebral Infarction and Refractory Seizures in a Neonate with Suspected Zika Virus Infection. AB - Congenital Zika syndrome is a set of congenital anomalies associated with Zika virus infection during pregnancy. We present the unique case of a neonate born to a suspected Zika virus-positive mother that developed an embolic stroke and medication-resistant seizures. This report may impact the evolving definition of congenital Zika syndrome. PMID- 29140936 TI - Increased Kawasaki Disease Incidence Associated With Higher Precipitation and Lower Temperatures, Japan, 1991-2004. AB - BACKGROUND: Kawasaki disease (KD) is an acute febrile vasculitis, which primarily affects children. The etiology of KD is unknown; while certain characteristics of the disease suggest an infectious origin, genetic or environmental factors may also be important. Seasonal patterns of KD incidence are well documented, but it is unclear whether these patterns are caused by changes in climate or by other unknown seasonal effects. METHODS: The relationship between KD incidence and deviations from expected temperature and precipitation were analyzed using KD incidence data from Japanese nationwide epidemiologic surveys (1991-2004) and climate data from 136 weather stations of the Japan Meteorological Agency. Seven separate Poisson-distributed generalized linear regression models were run to examine the effects of temperature and precipitation on KD incidence in the same month as KD onset and the previous 1, 2, 3, 4, 5 and 6 months, controlling for geography as well as seasonal and long-term trends in KD incidence. RESULTS: KD incidence was negatively associated with temperature in the previous 2, 3, 4 and 5 months and positively associated with precipitation in the previous 1 and 2 months. The model that best predicted variations in KD incidence used climate data from the previous 2 months. An increase in total monthly precipitation by 100 mm was associated with increased KD incidence (rate ratio [RR] 1.012, 95% confidence interval [CI]: 1.005-1.019), and an increase of monthly mean temperature by 1 degrees C was associated with decreased KD incidence (RR 0.984, 95% CI: 0.978-0.990). CONCLUSIONS: KD incidence was significantly affected by temperature and precipitation in previous months independent of other unknown seasonal factors. Climate data from the previous 2 months best predicted the variations in KD incidence. Although fairly minor, the effect of temperature and precipitation independent of season may provide additional clues to the etiology of KD. PMID- 29140937 TI - Sapovirus in Rectal and Nasopharyngeal Swab Samples of Children with Symptoms of Acute Gastroenteritis. AB - The study included 102 hospitalized children 0-72 months of age, with symptoms of acute gastroenteritis. One fecal and one nasopharyngeal swab sample were obtained from each child. Samples were screened for sapovirus and viral loads were determined. Sapovirus was detected in 18.6% of fecal samples and in 36.3% of nasopharyngeal swab samples. High viral loads were detected. PMID- 29140938 TI - Immunity After Childhood Vaccinations in Perinatally HIV-exposed Children With and Without HIV Infection in Latin America. AB - BACKGROUND: Perinatally HIV-infected (PHIV) children are at risk for under vaccination and poor vaccine response at 4 years of age. Childhood vaccine coverage and immune response were compared between PHIV and HIV-exposed uninfected (HEU) children in Latin America and the Caribbean. METHODS: PHIV and HEU children were enrolled prospectively at 15 sites from 2002 to 2009. Full vaccination by age 4 years was defined as: 3 hepatitis B virus vaccine doses; 4 tetanus toxoid-containing vaccine doses; 3 doses of Haemophilus influenzae type b vaccine by age 12 months or >=1 dose given after age 12 months; one measles containing vaccine dose; one rubella-containing vaccine dose. Immunity was defined by serum antibody titer. Fisher exact test (for categorical measures) and t test (for continuous measures) were used for comparisons. RESULTS: Among 519 children seen at age 4 years, 191 had serum specimens available (137 PHIV, 54 HEU). Among those with specimens available, 29.3% initiated combination antiretroviral therapy (cART) <12 months of age, 30.9% initiated at >=12 months of age, and 39.8% had not received cART by the time they were seen at 4 years of age. At 4 years of age, 59.9% were on PI-containing cART (cART/PI), and 20.4% were on no ART. PHIV children were less likely than HEU children to be fully vaccinated for tetanus (55.5% vs. 77.8%, P = 0.005) and measles and rubella (both 70.1% vs. 94.4%, P < 0.001). Among those fully vaccinated, immunity was significantly lower among PHIV than HEU for all vaccines examined: 20.9% versus 37.8% for hepatitis B virus (P = 0.04), 72.0% versus 90.5% for tetanus (P = 0.02), 51.4% versus 68.8% for H. influenzae type b (P = 0.05), 80.2% versus 100% for measles (P < 0.001) and 72.9% versus 98.0% for rubella (P < 0.001) vaccine, respectively. CONCLUSIONS: Compared with HEU, PHIV children were significantly less likely to be immune to vaccine-preventable diseases when fully vaccinated. Strategies to increase immunity against vaccine-preventable diseases among PHIV require further study. PMID- 29140939 TI - Infliximab Therapeutic Drug Monitoring Changes Clinical Decisions in a Virtual Biologics Clinic for Inflammatory Bowel Disease. AB - BACKGROUND: Virtual biologics clinics are often used to review patients with inflammatory bowel disease receiving biological therapy, with decisions whether to continue, switch, or stop therapy made based on review of symptoms, disease history, and investigations. We aimed to investigate whether therapeutic drug monitoring of infliximab (IFX) trough levels and anti-drug antibodies influences decision making within a virtual biologics clinic. METHODS: For all patients with inflammatory bowel disease receiving IFX maintenance therapy, 2 decisions were recorded in a preset format. The first decision was based on assessment of clinical details, with clinicians blinded to IFX trough levels and anti-drug antibodies. The second decision was made after unblinding of these data. RESULTS: Among 191 patients (mean age 40 years; 106 (55.5%) male), IFX trough levels were sub-therapeutic in 53 (27.7%) (<2 mg/L), therapeutic in 100 (52.4%), and supra therapeutic in 38 (19.9%) (>6 mg/L). Anti-drug antibodies were detected in 58 (30.4%), and were >50 AU/mL in 26 (13.6%). Blinded treatment decisions were changed on unblinding these data in 56 cases (29.3%; P < 0.0001). Knowledge of these data led to 7 (3.7%) patients receiving intensified IFX, whereas 33 (17.3%) patients were able to either dose de-escalate or stop IFX. CONCLUSIONS: Basing decisions on therapeutic drug monitoring, rather than clinical acumen alone, led to a change in almost one-third of decisions made, offering considerable cost savings and reducing exposure to potentially toxic therapies. Routine therapeutic drug monitoring should be considered an integral part of annual biologics assessment (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B629). PMID- 29140940 TI - Rapid Infliximab Infusion in Children with Inflammatory Bowel Disease: A Multicenter North American Experience. AB - BACKGROUND: Infliximab (IFX) infusion may lead to development of anti-IFX antibodies, and subsequent infusion reactions (IRs). The safety of rapid IFX infusion administered over 60 minutes has been under-investigated in children with inflammatory bowel disease. In a multicenter study, the frequency and nature of rapid infusion-associated IRs were examined. METHODS: The medical records of all consecutive children with inflammatory bowel disease receiving rapid IFX infusions between January 2014 and December 2016 were reviewed. Poisson regression analysis was used to identify possible associated factors with IRs. RESULTS: A total of 4120 rapid infusions for 453 children (median age 16 yrs [interquartile range 13.8-17.8], 289 males, 374 with Crohn's disease) were included. One hundred thirty-five participants (29.8%) received rapid IFX infusion for induction and maintenance while the rest received rapid IFX infusion after a median of 5 (interquartile range 4-9) standard infusions. The median dose of IFX using rapid protocol was 8 mg/kg/infusion (interquartile range 6-10). Two hundred sixty-seven (59%) patients received 1 or more premedications and 161 (35.5%) participants received concomitant immunosuppression. Twenty-one participants (4.6%) had IRs with rapid infusions and 2 participants discontinued IFX because of IRs (0.4%). Antihistamine premedications were associated with less frequent IR (adjusted relative risk = 0.30; 95% confidence interval, 0.14-0.64; P = 0.002). CONCLUSIONS: In children with inflammatory bowel disease, rapid IFX infusion administered over 60 minutes is safe and well-tolerated. Antihistamine premedications may reduce frequency of IRs (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B632). PMID- 29140941 TI - Phenotype and Management of Infantile-onset Inflammatory Bowel Disease: Experience from a Tertiary Care Center in China. AB - BACKGROUND: Infantile-onset inflammatory bowel disease (IBD) comprises rare and clinically severe disorders. We examined the phenotypes and genetic causes of patients with infantile-onset IBD from a tertiary medical center. METHODS: We enrolled 38 patients with infantile-onset IBD and applied standardized treatment with medical, surgical, and supportive care. Targeted sequencing and whole-exome sequencing were performed. Clinical data were retrieved from medical records. RESULTS: Median age of onset of disease was 12.5 (interquartile range: 7.0-30.0) days. All patients had diarrhea, whereas 18 (47.4%) patients reported hematochezia. Thirteen (34.2%) patients had oral ulcers, 15 (39.5%) patients had perianal abscess, and 9 (52.9%) female patients had rectovaginal fistula. Six (18.8%) patients had intestinal strictures and 4 (12.1%) patients had perforation. Twelve (31.6%) patients underwent surgical procedures. Median age of surgery was 272.5 days, and cumulative probability for surgery during first year was 32.1%. One-year mortality of patients was 25.9%. Sequencing showed 24 (63.2%) patients had causative IL10RA mutations, 1 patient had EPCAM mutation, 1 patient had TNFAIP3 mutation, and 1 patient had LRBA mutation, whereas causative mutations cannot be identified in the other 11 (28.9%) patients. Umbilical cord blood stem cell transplantation has been applied to 8 cases with IL10RA mutations, of whom 5 (71.4%) patients have achieved clinical remission. CONCLUSIONS: Patients with infantile-onset IBD had severe phenotype and early onset. Medical, surgical interventions with supportive care are essential. High throughput sequencing ensures appropriate treatment. Hematopoietic stem cell transplantation can be performed in selected patients with IL10RA mutations (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B657). PMID- 29140942 TI - Minority Pediatric Patients with Inflammatory Bowel Disease Demonstrate an Increased Length of Stay. AB - BACKGROUND: Genetic and other biological factors may lead to differences in disease behavior among children with inflammatory bowel disease of different races, which may be further modified by disparities in care delivery. Using the Kids' Inpatient Database, we aimed to evaluate differences in the management of pediatric patients with inflammatory bowel disease by race, focusing on length of stay (LOS). METHODS: We performed a cross-sectional analysis using 2000 to 2012 data from the Kids' Inpatient Database, a nationally representative database. We identified pediatric patients (<=18 years of age) with discharge diagnoses of Crohn's disease (CD) or ulcerative colitis (UC). We used multivariable logistic regression to evaluate the relationship between race and LOS, controlling for age, payer status need for surgery, and year of admission. RESULTS: We identified 27,295 hospitalizations for children with inflammatory bowel disease (62% CD and 38% UC), Compared with white patients with CD, black (adjusted odds ratio 1.37; 95% confidence interval, 1.22-1.53; P < 0.001) and Hispanic patients (adjusted odds ratio: 1.37; 95% confidence interval: 1.19-1.59; P < 0.001) with CD demonstrated increased odds of a LOS greater than the 75th percentile. When compared with white patients with UC, Hispanic patients also demonstrated increased odds of a LOS greater than the 75th percentile (adjusted odds ratio: 1.20; 95% confidence interval, 1.02-1.42, P = 0.015). CONCLUSIONS: After controlling for age, year of admission, and clinical phenotypes, black and Hispanic patients with CD and Hispanic patients with UC had longer LOS than white patients. These may be due to differences in provider/hospital characteristics, socioeconomic differences, and/or differences in genetics and other biological factors (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B656). PMID- 29140943 TI - Antibodies Toward Vedolizumab Appear from the First Infusion Onward and Disappear Over Time. AB - BACKGROUND: Vedolizumab (VDZ) has been approved for the treatment of patients with moderate-to-severe Crohn's disease and ulcerative colitis. The GEMINI trials reported a low prevalence of anti-VDZ antibodies (AVA). However, the AVA assays used in GEMINI were drug sensitive, resulting in a possible underestimation of the rate of AVA formation. This study aimed to monitor immunogenicity of VDZ in a real-life cohort using a drug-resistant AVA assay. METHODS: Using a combination of VDZ/AVA complex precipitation and acid dissociation, a drug-resistant assay for AVA detection in the presence of high VDZ concentrations has been developed and analytically validated. The assay was applied on serum samples of 179 VDZ treated patients with inflammatory bowel disease to evaluate the prevalence and time course of AVA. RESULTS: A dose-response curve ranging from 25 to 1600 ng/mL using 1/125 diluted serum was obtained, allowing the detection of AVA concentrations up to 200 MUg/mL of MA-VDZ19C11 equivalents, a calibrator antibody to VDZ. This assay was highly AVA specific and drug resistant. Four of 179 VDZ treated patients (2.2%) were AVA positive and AVA were detected already after the first VDZ infusion. AVA were all transient in these patients without need for any dosage optimization. There was no correlation between VDZ and AVA concentrations in the AVA-positive samples. CONCLUSIONS: AVA appear from the first VDZ infusion onward and disappear over time. The low prevalence of AVA suggests that immunogenicity does not influence response to treatment. PMID- 29140944 TI - Subcutaneous Golimumab in Pediatric Ulcerative Colitis: Pharmacokinetics and Clinical Benefit. AB - BACKGROUND: Current treatments for pediatric ulcerative colitis (UC) are limited. We evaluated the pharmacokinetics and clinical benefits of subcutaneous golimumab, an anti-tumor necrosis factor agent, in moderately-to-severely active pediatric patients with UC refractory to conventional therapy. METHODS: We report a multicenter, open-label study of golimumab with a pharmacokinetics phase (week 0-14). Patients had moderately-to-severely active UC and were naive to anti-tumor necrosis factor treatment. At weeks 0 and 2, patients received golimumab induction dosed by weight (<45 kg [90/45 mg/m]; >=45 kg [200/100 mg]). Week 6 clinical responders continued golimumab q4w. Serum golimumab concentrations, clinical outcomes (Mayo score, PUCAI score), and adverse events are reported. RESULTS: Thirty-five patients (71.4% pancolitis) aged 6 to 17 years had baseline median (interquartile range), age, weight, and disease duration of 15.0 (11.0 16.0) years, 50.6 (35.2-59.0) kg, and 1.2 (0.6-3.1) years, respectively. Baseline Mayo and PUCAI scores were 8.0 (6.0-9.0) and 45 (35.0-65.0), respectively. Median (interquartile range) serum golimumab concentrations were comparable to a historical reference adult UC population at weeks 2 (5.72 [3.80-9.17] MUg/mL), 4 (7.61 [3.22-9.51] MUg/mL), and 6 (2.64 [0.92-3.83] MUg/mL). Serum golimumab concentrations were generally lower in the <45 kg than >=45 kg weight subgroup. At week 6, 60%, 34%, and 54%, of patients achieved Mayo clinical response, PUCAI clinical remission, and mucosal healing (Mayo subscore 0/1). No clinically important safety concerns were reported. CONCLUSIONS: This open-label study demonstrates that pediatric and adult golimumab pharmacokinetics are similar. Clinical benefit and safety shows promise in biologically naive pediatric patients with UC. PMID- 29140945 TI - A Retrospective Cohort Study of the Incidence, Health Care Resource Utilization and Costs of International Classification of Diseases, Clinical Modification, 9th Revision Diagnosed Influenza and Related Complications in US Children. AB - BACKGROUND: There is a paucity of data on the clinical and economic impact of seasonal influenza in children. This study estimated the incidence of diagnosed influenza and related complications and associated health care resource utilization and costs in US children. METHODS: Children >=6 months and <18 years old diagnosed with influenza using International Classification of Diseases, Clinical Modification, 9th revision codes and enrolled in a health plan during at least one influenza season between 2010 and 2014 were matched to similar patients without diagnosed influenza (GSK study identifier: HO-15-15728). Outcomes included incidence of influenza and complications, health care resource utilization frequency and health care costs during 21 days of follow-up. Adjusted costs were estimated using generalized linear models. RESULTS: Incidence (per 1000) of influenza was 20.3 (commercially insured) and 32.6 (Medicaid), with the highest incidence among 6-35 months old (Commercial: 26.8; Medicaid: 47.9). Approximately 12%-17% of influenza patients experienced complications, with the 6 35 months group having the highest percentage (25%-30%). The 6-35-month-old influenza patients with complications had the highest proportion with hospitalizations (5%-6%) and emergency room visits (Commercial: 19%; Medicaid: 36%). Influenza patients with (vs. without) complications had greater adjusted mean influenza-specific costs (Commercial: $1161 vs. $337; Medicaid: $1199 vs. $354; P<0.05), and influenza cases (vs. controls) had greater adjusted mean all cause costs (Commercial: $688 vs. $470; Medicaid: $818 vs. $453; P < 0.05). CONCLUSIONS: Pediatric patients with influenza incurred higher health care costs compared with matched controls, and influenza-specific costs were greater among those with complications. PMID- 29140946 TI - Comparison of the QuantiFERON TB Gold In-tube Assay With Tuberculin Skin Test for the Diagnosis of Latent Tuberculosis Infection Among HIV-infected and Uninfected Children. AB - BACKGROUND: Diagnosis of latent tuberculosis infection (LTBI) is facilitated by tuberculin skin testing (TST) or interferon-gamma release assays such as the QuantiFERON TB Gold In-Tube (QTF-GIT) assays. Limited data exist on the utility of interferon-gamma release assays in HIV-infected children, which may be falsely negative due to immunosuppression. METHODS: A cross-sectional study comparing TST to QTF-GIT for the diagnosis of suspected LTBI was performed in children in Tijuana, Mexico, and in San Diego, California. Concordance between TST (>=5 mm for HIV infected and >=10 mm for HIV uninfected) and QTF-GIT was evaluated utilizing kappa coefficients. Multivariate logistic regression assessed factors influencing the results. RESULTS: One hundred sixty-five children (70 HIV infected and 95 HIV uninfected) were evaluated (median age, 8.0 years). Among HIV infected children, the median CD4 cell count was 913 cells/MUL, with 92.9% of subjects on antiretroviral treatment and 80.0% with an HIV RNA load <400 copies/mL (76% <50 copies/mL). Among HIV-infected children with no history of tuberculosis, 12 HIV had either a positive QTF-GIT or TST >= 5 mm or both, giving a suspected LTBI prevalence of 20.3% (compared with 61.3% among HIV-uninfected children). Moderate concordance was demonstrated in HIV-infected children (both tests positive, kappa = 0.42; 95% confidence interval: 8.9%-75.4%) and HIV uninfected children (both tests positive, kappa = 0.59; 95% confidence interval: 43.0%-76.5%). CONCLUSIONS: A moderate correlation exists between TST and QTF-GIT among HIV-infected and uninfected children with preserved immune function in an area of moderate tuberculosis endemicity. PMID- 29140947 TI - Congenital Cytomegalovirus: A European Expert Consensus Statement on Diagnosis and Management. PMID- 29140949 TI - Predictive ability and interobserver reliability of computed tomography findings for angioembolization in patients with pelvic fracture. AB - BACKGROUND: The purpose of this study was to identify computed tomography (CT) findings that predict the need for angioembolization in patients with pelvic fracture. METHODS: This retrospective cross-sectional study was performed between April 2006 and October 2015 at two urban emergency medical centers in Japan. The study included patients who underwent CT within 3 hours of arrival and were diagnosed with a pelvic fracture. The study outcome was undergoing angioembolization within 24 hours of arrival. Four independent readers blinded to all clinical information interpreted the CT scans for blush, thickness of retroperitoneal hematoma, and diameter and laterality of muscle swelling around the pelvis. Receiver operating characteristics analyses provided area under the receiver-operating characteristic curves (AUROC) and diagnostic indicators at the estimated thresholds including sensitivity, specificity, positive and negative predictive values and diagnostic odds ratio (DOR). The interobserver reliability of all radiographic findings was also evaluated. RESULTS: Fifty-two of 244 eligible patients underwent angioembolization. The predictive ability in terms of DOR was relatively better with blush on CT scan (sensitivity, 0.57; specificity, 0.86; DOR, 8.05) than with laterality of muscle swelling of 12.9 mm or greater (sensitivity, 0.79; specificity, 0.55; DOR, 4.60; AUROC, 0.75) and thickness of retroperitoneal hematoma of 22.7 mm or greater (sensitivity, 0.65; specificity, 0.74; DOR, 5.39; AUROC, 0.73). The interobserver reliability of blush, laterality of muscle swelling, and thickness of retroperitoneal hematoma was 0.43, 0.54, and 0.70, respectively. CONCLUSION: All of the tested CT findings failed to show both sufficient predictive ability and sufficient interobserver agreement. Further diagnostic accuracy studies to validate these findings or establish a prediction model incorporating these findings are expected. LEVEL OF EVIDENCE: Diagnostic, level V. PMID- 29140948 TI - Hypertonic saline resuscitation after emergent laparotomy and temporary abdominal closure. AB - BACKGROUND: Our objective was to establish the safety of 3% hypertonic saline (HTS) resuscitation for trauma and acute care surgery patients undergoing emergent laparotomy and temporary abdominal closure (TAC) with the hypothesis that HTS administration would be associated with hyperosmolar hypercholoremic acidosis, lower resuscitation volumes, and higher fascial closure rates, without adversely affecting renal function. METHODS: We performed a retrospective cohort analysis of 189 trauma and acute care surgery patients who underwent emergent laparotomy and TAC, comparing patients with normal baseline renal function who received 3% HTS at 30 mL/h (n = 36) to patients with standard resuscitation (n = 153) by baseline characteristics, resuscitation parameters, and outcomes including primary fascial closure and Kidney Disease: Improving Global Outcomes stages of acute kidney injury. RESULTS: The HTS and standard resuscitation groups had similar baseline illness severity and organ dysfunction, though HTS patients had lower serum creatinine at initial laparotomy (1.2 mg/dL vs. 1.4 mg/dL; p = 0.078). Forty-eight hours after TAC, HTS patients had significantly higher serum sodium (145.8 mEq/L vs. 142.2 mEq/L, p < 0.001), chloride (111.8 mEq/L vs. 106.6 mEq/L, p < 0.001), and osmolarity (305.8 mOsm/kg vs. 299.4 mOsm/kg; p = 0.006), and significantly lower arterial pH (7.34 vs. 7.38; p = 0.011). The HTS patients had lower intravenous fluid (IVF) volumes within 48 hours of TAC (8.5 L vs. 11.8 L; p = 0.004). Serum creatinine, urine output, and kidney injury were similar between groups. Fascial closure was achieved for 92% of all HTS patients and 77% of all standard resuscitation patients (p = 0.063). Considering all 189 patients, higher IVF resuscitation volumes within 48 hours of TAC were associated with decreased odds of fascial closure (odds ratio, 0.90; 95% confidence interval, 0.83-0.97; p = 0.003). CONCLUSION: Hypertonic saline resuscitation was associated with the development of a hypernatremic, hyperchloremic, hyperosmolar acidosis, and lower total IVF resuscitation volumes, without adversely affecting renal function. These findings may not be generalizable to patients with baseline renal dysfunction and susceptibility to hyperchloremic acidosis-induced kidney injury. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 29140950 TI - Development of clinical process measures for pediatric burn care: Understanding variation in practice patterns. AB - BACKGROUND: There has been little systematic examination of variation in pediatric burn care clinical practices and its effect on outcomes. As a first step, current clinical care processes need to be operationally defined. The highly specialized burn care units of the Shriners Hospitals for Children system present an opportunity to describe the processes of care. The aim of this study was to develop a set of process-based measures for pediatric burn care and examine adherence to them by providers in a cohort of pediatric burn patients. METHODS: We conducted a systematic literature review to compile a set of process based indicators. These measures were refined by an expert panel of burn care providers, yielding 36 process-based indicators in four clinical areas: initial evaluation and resuscitation, acute excisional surgery and critical care, psychosocial and pain control, and reconstruction and aftercare. We assessed variability in adherence to the indicators in a cohort of 1,076 children with burns at four regional pediatric burn programs in the Shriners Hospital system. The percentages of the cohort at each of the four sites were as follows: Boston, 20.8%; Cincinnati, 21.1%; Galveston, 36.0%; and Sacramento, 22.1%. The cohort included children who received care between 2006 and 2010. RESULTS: Adherence to the process indicators varied both across sites and by clinical area. Adherence was lowest for the clinical areas of acute excisional surgery and critical care, with a range of 35% to 48% across sites, followed by initial evaluation and resuscitation (range, 34%-60%). In contrast, the clinical areas of psychosocial and pain control and reconstruction and aftercare had relatively high adherence across sites, with ranges of 62% to 93% and 71% to 87%, respectively. Of the 36 process indicators, 89% differed significantly in adherence between clinical sites (p < 0.05). Acute excisional surgery and critical care exhibited the most variability. CONCLUSION: The development of this set of process-based measures represents an important step in the assessment of clinical practice in pediatric burn care. Substantial variation was observed in practices of pediatric burn care. However, further research is needed to link these process-based measures to clinical outcomes. LEVEL OF EVIDENCE: Therapeutic/care management, level IV. PMID- 29140951 TI - Platelet aggregation after blunt trauma is associated with the acute respiratory distress syndrome and altered by cigarette smoke exposure. AB - BACKGROUND: The risk of the acute respiratory distress syndrome (ARDS) is increased in passive and active smokers after blunt trauma. However, the mechanisms responsible, including the role of platelet aggregation, for this association are unknown. METHODS: We analyzed 215 patients with severe blunt trauma from a prospective observational cohort at a Level I trauma center between 2010 and 2015. Subjects underwent impedance-based platelet aggregometry in response to platelet agonists arachidonic acid, adenosine diphosphate, collagen, and thrombin receptor activating peptide-6. Acute respiratory distress syndrome within the first 8 days of admission was adjudicated using Berlin criteria. Plasma cotinine was measured to assess cigarette smoke exposure. Regression analyses were used to assess the relationship between (1) platelet aggregation and ARDS and (2) cigarette smoke exposure and platelet aggregation. RESULTS: At both 0 hour and 24 hours, impaired platelet aggregation was associated with increased odds of developing ARDS. Cigarette smoke exposure was associated with increased platelet aggregation upon arrival to the emergency department. However, at 24 hours, cigarette smoke exposure was associated with increased impairment in platelet aggregation, reflecting a statistically significant decline in platelet aggregation over the initial 24 hours after trauma. The relationship between this decline in platelet aggregation and ARDS differed by cigarette smoke exposure status, suggesting that impaired platelet activation differentially affects the risk of ARDS in those with cigarette smoke exposure (arachidonic acid, p for interaction: 0.005, collagen p for interaction: 0.02, adenosine diphosphate, p for interaction: 0.05). CONCLUSION: Impaired platelet aggregation at 0 hour and 24 hours is associated with an increased risk of developing ARDS after severe blunt trauma. Cigarette smoke-exposed patients are more likely to develop impaired platelet aggregation over the first 24 hours of admission, which may contribute to their increased risk of ARDS. LEVEL OF EVIDENCE: Prognostic/Epidemiological, level III. PMID- 29140952 TI - "Don't lose hope early": Hemorrhagic diffuse axonal injury on head computed tomography is not associated with poor outcome in moderate to severe traumatic brain injury patients. AB - BACKGROUND: Diffuse axonal injury (DAI) on magnetic resonance imaging has been associated with poor functional outcome after moderate-severe traumatic brain injury (msTBI). Yet, DAI assessment with highly sensitive magnetic resonance imaging techniques is unfeasible in the acute trauma setting, and computed tomography (CT) remains the key diagnostic modality despite its lower sensitivity. We sought to determine whether CT-defined hemorrhagic DAI (hDAI) is associated with discharge and favorable 3- and 12-month functional outcome (Glasgow Coma Scale score >=4) after msTBI. METHODS: We analyzed 361 msTBI patients from the single-center longitudinal Outcome Prognostication in Traumatic Brain Injury study collected over 6 years (November 2009 to November 2015) with prospective outcome assessments at 3 months and 12 months. Patients with microhemorrhages on CT were designated "CT-hDAI-positive" and those without as "CT-hDAI-negative." For secondary analyses "CT-hDAI-positive" was stratified into two phenotypes according to presence ("associated") versus absence ("predominant") of concomitant large acute traumatic lesions to determine whether presence versus absence of additional focal mass lesions portends a different prognosis. RESULTS: Seventy (19%) patients were CT-hDAI-positive (n = 36 predominant; n = 34 associated hDAI). In univariate analyses, CT-hDAI-positive status was associated with discharge survival (p = 0.004) and favorable outcome at 3 months (p = 0.003) and 12 months (p = 0.005). After multivariable adjustment, CT-hDAI positivity was no longer associated with discharge survival and functional outcome (all ps > 0.05). Stratified by hDAI phenotype, predominant hDAI patients had worse trauma severity, longer intensive care unit stays, and more systemic medical complications. Predominant hDAI, but not associated hDAI, was an independent predictor of discharge survival (adjusted odds ratio, 24.7; 95% confidence interval [CI], 3.2-192.6; p = 0.002) and favorable 12-month outcome (adjusted odds ratio, 4.7; 95% CI, 1.5-15.2; p = 0.01). Sensitivity analyses using Cox regression confirmed this finding for 1-year survival (adjusted hazard ratio, 5.6; 95% CI, 1.3-23; p = 0.048). CONCLUSION: The CT defined hDAI was not an independent predictor of unfavorable short- and long-term outcomes and should not be used for acute prognostication in msTBI patients. Predominant hDAI patients had good clinical outcomes when supported to intensive care unit discharge and beyond. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 29140953 TI - Contemporary management of rectal injuries at Level I trauma centers: The results of an American Association for the Surgery of Trauma multi-institutional study. AB - INTRODUCTION: Rectal injuries have been historically treated with a combination of modalities including direct repair, resection, proximal diversion, presacral drainage, and distal rectal washout. We hypothesized that intraperitoneal rectal injuries may be selectively managed without diversion and the addition of distal rectal washout and presacral drainage in the management of extraperitoneal injuries are not beneficial. METHODS: This is an American Association for the Surgery of Trauma multi-institutional retrospective study from 2004 to 2015 of all patients who sustained a traumatic rectal injury and were admitted to one of the 22 participating centers. Demographics, mechanism, location and grade of injury, and management of rectal injury were collected. The primary outcome was abdominal complications (abdominal abscess, pelvic abscess, and fascial dehiscence). RESULTS: After exclusions, there were 785 patients in the cohort. Rectal injuries were intraperitoneal in 32%, extraperitoneal in 58%, both in 9%, and not documented in 1%. Rectal injury severity included the following grades I, 28%; II, 41%; III, 13%; IV, 12%; and V, 5%. Patients with intraperitoneal injury managed with a proximal diversion developed more abdominal complications (22% vs 10%, p = 0.003). Among patients with extraperitoneal injuries, there were more abdominal complications in patients who received proximal diversion (p = 0.0002), presacral drain (p = 0.004), or distal rectal washout (p = 0.002). After multivariate analysis, distal rectal washout [3.4 (1.4-8.5), p = 0.008] and presacral drain [2.6 (1.1-6.1), p = 0.02] were independent risk factors to develop abdominal complications. CONCLUSION: Most patients with intraperitoneal injuries undergo direct repair or resection as well as diversion, although diversion is not associated with improved outcomes. While 20% of patients with extraperitoneal injuries still receive a presacral drain and/or distal rectal washout, these additional maneuvers are independently associated with a three fold increase in abdominal complications and should not be included in the treatment of extraperitoneal rectal injuries. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 29140954 TI - Development of a Claims-based Frailty Indicator Anchored to a Well-established Frailty Phenotype: Erratum. PMID- 29140955 TI - On-line Ratings of Spine Surgeons: Analysis of 208 surgeons. AB - STUDY DESIGN: Observational study OBJECTIVE.: To evaluate the online ratings of spine surgeons and variables that may affect online ratings. SUMMARY OF BACKGROUND DATA: Physician review websites (PRW) are rapidly growing for-profit businesses. Most Orthopaedic surgeons are rated on at least one PRW as are other surgical specialists. To date the online ratings of spine surgeons have not been evaluated. METHODS: Cervical Spine Research Society (CSRS) surgeon ratings on 5 physician rating websites were performed in April 2016: 'healthgrade.com', 'vitals.com', 'ratemd.com', 'webmd.com' and 'yelp.com'. Numeric ratings from the PRWs were standardized on a scale of 0 to 100 with a higher score indicating positive ratings. Sex, practice sector (academic or private), specialty (orthopaedics or neurosurgery), geographic location, and years of practice were also collected. RESULTS: 209 spine surgeons were included in our study. 208 of the 209 (99.52%) were rated at least once in one of the five PRWs. Average number of ratings per surgeon was 2.96. Average rating was 80 (40 to 100). There were 4 female (1.92%) and 204 male surgeons (98.1%). There were 121 (58.2%) in academic practice and 87 (41.8%) in private practice. There were 175 (84.1%) orthopaedic surgeons and 33 (15.9%) neurosurgeons. Most of the surgeons were Caucasian 163 (78.4%) and worked in the South and Northeast 135 (64.9%). Those in academic practice had significantly higher ratings (81.6 versus 77.65; p = 0.026). Number of years in practice was significantly associated with ratings (p = 0.0003) with those in practice for 21 or more years having significantly lower ratings. CONCLUSIONS: In this first study evaluating the online ratings of spine surgeons, we found that 99.5% of spine surgeon had at least one rating on a PRW. The average score, 80, indicated mostly positive ratings. Being in practice for twenty years or less and being in academic practice significantly associated with higher ratings. LEVEL OF EVIDENCE: 4. PMID- 29140956 TI - Comments on Legal Implications Incidental Surgical Durotomy. PMID- 29140957 TI - Beneficial Effects of Angiotensin-(1-7) on CD34+ Cells From Patients With Heart Failure. AB - The dysfunctional nature of CD34 cells from patients with heart failure (HF) may make them unsuitable for autologous stem-cell therapy. In view of evidence that the vasoprotective axis of the renin-angiotensin system (RAS) improves CD34 cell functions, we hypothesized that CD34 cells from patients with HF will be dysfunctional and that angiotensin-(1-7) [Ang-(1-7)] would improve their function. Peripheral blood was collected from New York Heart Association class II IV patients with HF (n = 31) and reference subjects (n = 16). CD34 cell numbers from patients with HF were reduced by 47% (P < 0.05) and also displayed 76% reduction in migratory capacity and 56% (P < 0.05) lower production of nitric oxide. These alterations were associated with increases in RAS genes angiotensin converting enzyme and AT2R (595%, P < 0.05) mRNA levels and 80% and 85% decreases in angiotensin-converting enzyme 2 and Mas mRNA levels, respectively. Treatment with Ang-(1-7) enhanced CD34 cell function through increased migratory potential and nitric oxide production, and reduced reactive oxygen species generation. These data show that HF CD34 cells are dysfunctional, and Ang-(1-7) improves their functions. This suggests that activation of the vasoprotective axis of the RAS may hold therapeutic potential for autologous stem-cell therapy in patients with HF. PMID- 29140958 TI - Should Hospitals Market Opioid-Sparing Analgesia to Patients? PMID- 29140959 TI - Comparison of Continuous Proximal Versus Distal Adductor Canal Blocks for Total Knee Arthroplasty: A Randomized, Double-Blind, Noninferiority Trial. AB - BACKGROUND AND OBJECTIVES: Adductor canal blocks (ACBs) are associated with improved analgesia, preserved quadriceps strength, and decreased length of hospitalization after total knee arthroplasty (TKA). However, controversy remains regarding the ideal location of a continuous block within the adductor canal, and it remains unclear whether similar clinical benefits are obtained irrespective of block location. In this randomized, double-blind, noninferiority study, we hypothesized that a continuous proximal ACB provides postoperative analgesia that is no worse than a continuous distal ACB. METHODS: Subjects presenting for unilateral TKA were randomized in a 1:1 ratio to either a continuous proximal or distal ACB group. The primary outcome of this noninferiority study was opioid consumption within the first 24 hours following surgery. Secondary outcomes included quadriceps strength, pain scores, distance ambulated, and patient satisfaction. RESULTS: Seventy-three subjects, 36 from the proximal group and 37 from the distal group, completed the study per protocol. The intention-to-treat analysis demonstrated a cumulative mean intravenous morphine equivalent consumption difference between the proximal and distal groups of -7.2 mg (95% confidence interval, -14.8 to 0.4; P < 0.001), demonstrating noninferiority of the proximal approach. The per-protocol analysis yielded similar results: -6.2 mg (95% confidence interval, -14.1 to 1.6; P < 0.001). No secondary outcomes showed statistically significant differences between the proximal and distal groups. CONCLUSIONS: This study demonstrates that a continuous proximal ACB offers noninferior postoperative analgesia compared with a distal continuous ACB in the first 24 hours after TKA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT02701114). PMID- 29140960 TI - Radiofrequency Procedures to Relieve Chronic Hip Pain: An Evidence-Based Narrative Review. AB - BACKGROUND AND OBJECTIVES: Chronic hip pain from osteoarthritis and other degenerative conditions is a common problem. A few publications have recently reported analgesic success of radiofrequency (RF) procedures on nerves innervating the hip, but interpretation is hampered by lack of clarity regarding indications, clinical protocols, anatomic targets, and longevity of benefit from RF procedures. METHODS: We reviewed the following medical literature databases for publications on RF procedures on the hip joint for chronic pain: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Google Scholar through February 28, 2017. Existing knowledge on innervation of the hip joint was synthesized. Data on analgesic and functional outcomes and adverse effects measured at any time points following the interventions were also collected, analyzed, and reported in this narrative review. RESULTS: Fourteen publications on ablative RF treatments of innervation of the hip joint were identified. A high success rate of these procedures in relieving chronic pain of the hip joint was reported at 8 days to 36 months after the procedures, but none of the publications were randomized controlled trials. There was evidence for improvement in function and a lack of serious adverse events of RF treatments. CONCLUSIONS: Radiofrequency treatments for the sensory innervation of the hip joint have the potential to reduce pain secondary to degenerative conditions. Ongoing concerns remain regarding the anatomic targets, as well as quality, procedural aspects, and monitoring of outcomes in publications on this topic. Randomized controlled trials of high methodological quality are required to further elaborate the role of these interventions in this population. PMID- 29140961 TI - Cervical Foraminal Epidural Blood Patch for the Targeted Treatment of Refractory Cerebrospinal Fluid Leakage From a Dural Sleeve. AB - Epidural blood patches (EBPs) are routinely used to treat symptoms (eg, headaches) associated with spontaneous intracranial hypotension. Although cerebrospinal fluid leakage commonly involves the periforaminal areas of the cervical or thoracic spine, EBPs have been historically performed at the lumbar level. Recent evidence suggests that targeting the causative spinal segment may provide greater clinical benefits. While previous reports have targeted foraminal leaks with segmental thoracic or cervical injections, we present a case report detailing the novel use of a navigable epidural catheter to perform a selective EBP at the C7/T1 foramen. PMID- 29140962 TI - Anatomic Study of Innervation of the Anterior Hip Capsule: Implication for Image Guided Intervention. AB - BACKGROUND AND OBJECTIVES: The purpose of this cadaveric study was to determine the pattern of anterior hip capsule innervation and the associated bony landmarks for image-guided radiofrequency denervation. METHODS: Thirteen hemipelvises were dissected to identify innervation of the anterior hip capsule. The femoral (FN), obturator (ON), and accessory obturator (AON) nerves were traced distally, and branches supplying the anterior capsule documented. The relationships of the branches to bony landmarks potentially visible with ultrasound were identified. RESULTS: The anterior hip capsule received innervation from the FNs and ONs in all specimens and the AON in 7 of 13 specimens. High branches of the FN (originating above the inguinal ligament) were found exclusively in 12 specimens and passed between the anterior inferior iliac spine and the iliopubic eminence. The ONs were innervated exclusively by high branches (proximal to the division), by low branches (from the posterior branch), and by both in 4, 5, and 4 specimens, respectively. The most consistent landmark was the inferomedial acetabulum (radiographic "teardrop"). When present, the AON coursed over the iliopubic eminence before innervating the anterior hip capsule. CONCLUSIONS: Branches of the FNs and ONs consistently provided innervation to the anterior hip capsule. The AON also contributed innervation in many specimens. The relationship of the articular branches from these 3 nerves to the inferomedial acetabulum and the space between the anterior inferior iliac spine and iliopubic eminence may suggest potential sites for radiofrequency ablation. PMID- 29140963 TI - When the momentum has gone: what will be the role of extracorporeal lung support in the future? AB - PURPOSE OF REVIEW: There has been expanding interest in and use of extracorporeal support in respiratory failure concurrent with technological advances and predominantly observational data demonstrating improved outcomes. However, until there is more available data from rigorous, high-quality randomized studies, the future of extracorporeal support remains uncertain. RECENT FINDINGS: Outcomes for patients supported with extracorporeal devices continue to show favorable trends. There are several large randomized controlled trials that are in various stages of planning or completion for extracorporeal membrane oxygenation (ECMO) and extracorporeal carbon dioxide removal (ECCO2R) in the acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD), which may help clarify the role of this technology for these disease processes, and which stand to have a significant impact on a large proportion of patients with acute respiratory failure. Novel applications of extracorporeal lung support include optimization of donor organ quality through ex-vivo perfusion and extracorporeal cross-circulation, allowing for multimodal therapeutic interventions. SUMMARY: Despite the ongoing rise in ECMO use for acute respiratory failure, its true value will not be known until more information is gleaned from prospective randomized controlled trials. Additionally, there are modalities beyond the current considerations for extracorporeal support that have the potential to revolutionize respiratory failure, particularly in the realm of chronic lung disease and lung transplantation. PMID- 29140964 TI - Whole-body computed tomography in severely injured patients. AB - PURPOSE OF REVIEW: To provide an update on the relevant and recent studies on whole-body computed tomography (WBCT) imaging of severely injured patients. RECENT FINDINGS: The advantages of WBCT in time saving, diagnostic accuracy and even in survival have been proven in numerous studies. WBCT can also be beneficial in haemodynamically unstable major trauma patients. The CT scanner should be located close to the emergency department or even in the trauma room. The issue of radiation is still quite important, however, iterative as well as split-bolus protocols can nowadays reduce radiation significantly. The question: which trauma patient should receive WBCT and which not is not yet solved sufficiently. Postmortem WBCT has a promising potential to promptly define the definitive cause of death of trauma victims comparably to traditional autopsy. SUMMARY: On account of the recent advances, whole-body CT has become a crucial part of the initial in-hospital assessment of severely injured patients. It is recommended as the standard radiological tool for the emergency diagnostic work up in major trauma patients. PMID- 29140965 TI - Long-term Hearing Preservation After Resection of Vestibular Schwannoma: A Systematic Review and Meta-analysis. AB - OBJECTIVE: The objective is to perform a systematic review and meta-analysis of the literature on the long-term results of hearing preservation after vestibular schwannoma resection. DATA SOURCES: Ovid/Medline, PubMed, Embase, and the Cochrane library from January 1980 to January 2015. STUDY SELECTION: Inclusion criteria: age >=18 years, minimum 10 patients in the treatment group, hearing preserving microsurgery, no previous radiation treatment, serviceable hearing at immediate postop follow-up, hearing outcomes reported using Gardner Robinson or the American Academy of Otolaryngology-Head and Neck Surgeons hearing grading scales, and average follow-up of 5 years. Preoperative, immediate postoperative, and last follow-up audiograms were required. Exclusion criteria included neurofibromatosis type 2 patients and surgery for salvage therapy or decompression. DATA EXTRACTION: Quality evaluated using Methodological Index for Non-Randomized Studies. DATA SYNTHESIS: Meta-analysis was performed using R v3.2.2, Metafor package v 1.9-7. Cohen's D was used to determine effect size. Ten reports had at least 5-year follow-up and used standardized hearing grading scales. The systematic review found that if hearing was preserved at Class A or B at early postop visit, the chance of preserving hearing at 5 years was excellent. Those who maintained speech discrimination score >= 89% at the early postoperative follow-up had better long-term hearing preservation. The meta analysis reveals that only preoperative and postoperative pure-tone average was associated with long-term hearing preservation. CONCLUSION: Long-term (>5 yr) hearing durability rates are generally very good. Most studies do not report patient and tumor characteristics, therefore precluding combining studies for meta-analysis. Only preoperative and postoperative postoperative pure-tone average was associated with long-term hearing durability. PMID- 29140966 TI - How Was Your Otology Training? A Survey of Recent Otolaryngology Residents. AB - OBJECTIVE: To survey graduating residents or recent graduates of otolaryngology residency programs to evaluate their Otology/Neurotology (ON) experience in residency and discern if they had received adequate training in time to decide whether to pursue a fellowship in Otology or Neurotology. STUDY DESIGN: Internet based survey. METHODS: A survey was distributed to all US otolaryngology residency programs to distribute to 5th year residents and recent graduates in last 4 years. The survey assessed satisfaction in ON experience, presence of ON fellows, adequacy of experience to decide on ON fellowship, post-graduate year (PGY) year at which residents observed, performed, and proficiently performed five procedures (tympanoplasty, mastoidectomy, ossiculoplasty, stapedectomy, and cochlear implant), and plan for performing these surgeries in practice. RESULTS: 89/106 (84%) of respondents felt they had adequate training in Otology in time to decide whether or not to pursue a fellowship and were found to observe and perform surgeries significantly earlier in training by PGY including: mastoidectomy (observed PGY 1.9 versus PGY 2.3, performed PGY 2.9 versus PGY 3.5), ossiculoplasty (observed 2.1 versus 3.0, performed 3.6 versus 4.3), stapedectomy (observed 2.3 versus 3.0, performed 3.9 versus 4.5), and cochlear implant (observed 2.1 versus 2.8, performed 3.4 versus 4.1) all p < 0.05. There were 19/106 (17.9%) respondents who came from programs with fellowships and 78.9% thought fellows were beneficial to their ON experience. CONCLUSIONS: Early exposure to ON surgeries may aid in residents' decision to pursue a fellowship in ON. The presence of fellows appears to facilitate residents' ON experience. PMID- 29140967 TI - Near-Infrared Spectroscopy and Vascular Occlusion Test for Predicting Clinical Outcome in Pediatric Cardiac Patients: A Prospective Observational Study. AB - OBJECTIVES: This study is designed to determine the feasibility and utility of vascular occlusion test variables as measured by INVOS Medtronic, Dublin, Ireland) in pediatric cardiac patients. DESIGN: A prospective observational study. SETTING: A tertiary children's hospital. PATIENTS: Children less than or equal to 8 years old who were scheduled for elective cardiac surgery under cardiopulmonary bypass. INTERVENTIONS: A vascular occlusion test (3 min of ischemia and reperfusion) was performed on the calf at three time points: after induction of anesthesia (T0), during cardiopulmonary bypass (T1), and after sternal closure (T2). MEASUREMENTS AND MAIN RESULTS: Baseline regional tissue hemoglobin oxygen saturation, deoxygenation rate, minimum regional tissue hemoglobin oxygen saturation, and reoxygenation rate were measured using INVOS. Influence of age on variables at each measurement point was also checked using linear regression analysis. Receiver operating characteristics curve analysis was performed to determine the ability of vascular occlusion test variables at T2 to predict the occurrence of major adverse events. Both the deoxygenation and reoxygenation rates were lowest in T1. There was a tendency to decreased regional tissue hemoglobin oxygen saturation in younger patients at T0 (r = 0.37; p < 0.001), T1 (r = 0.33; p < 0.001), and T2 (r = 0.42; p < 0.001) during vascular occlusion. Minimum regional tissue hemoglobin oxygen saturation was correlated with age at T0 (r = 0.51; p < 0.001) and T2 (r = 0.35; p = 0.001). Patients with major adverse events had similar baseline regional tissue hemoglobin oxygen saturation but lower minimum regional tissue hemoglobin oxygen saturation (48.8% +/- 19.3% vs 63.3% +/- 13.9%; p < 0.001) and higher reoxygenation rate (4.30 +/- 3.20 vs 2.57 +/- 2.39 %/s; p = 0.008) at T2 compared with those without. The minimum regional tissue hemoglobin oxygen saturation less than 51% after sternal closure could predict the occurrence of major adverse events with a sensitivity of 61.1% and a specificity of 85.4%. CONCLUSIONS: Vascular occlusion test using INVOS can be applied in children undergoing cardiac surgery. Vascular occlusion test variables are influenced by age and cardiopulmonary bypass. The minimum regional tissue hemoglobin oxygen saturation less than 51% after sternal closure is associated with worse clinical outcomes in pediatric cardiac patients. PMID- 29140969 TI - Risk Factors for Ventilator-Associated Events in a PICU. AB - OBJECTIVE: The term ventilator-associated events includes ventilator-associated condition, infection-related ventilator-associated complication, and ventilator associated pneumonia. We sought to identify potential new risk factors for ventilator-associated condition and infection-related ventilator-associated complication in the PICU population. DESIGN: Matched case control study. SETTING: Children's hospital at a tertiary care academic medical center. PATIENTS: During the study period, 606 patients were admitted to PICU and ventilated more than 48 hours; 70 children met ventilator-associated condition criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied the definition for ventilator associated condition (i.e., a sustained increase in ventilator settings after a period of stable or decreasing support) to our database. Within ventilator associated condition cases, 40 cases were infection-related ventilator-associated complication and 30 cases were noninfectious-related ventilator-associated condition. We identified 140 controls and matched to ventilator-associated condition cases with regard to age, immunocompromised status, and ventilator days to event. Patients with ventilator-associated condition had longer ICU stay versus controls; 24 days median (12-43 interquartile range) versus 7 days (4-14); (p < 0.01), respectively, and longer duration of ventilatory support 17 days (10 32) versus 6 days (3-10); p < 0.01, respectively. Mortality was 22.8% in the ventilator-associated condition versus 9% in the control group (p < 0.01). A multivariate regression analysis adjusted for Pediatric Index of Mortality 2 identified mean peak inspiratory pressure and acute kidney injury to be associated with ventilator-associated condition (odds ratio, 1.12 [95% CI, 1.02 1.22] and odds ratio, 2.85 [1.43-5.66], respectively). Acute kidney injury and neuromuscular blockade in a multivariate regression analysis adjusted for Pediatric Index of Mortality 2 were associated with infection-related ventilator associated complication (odds ratio, 2.36 [1.03-5.40] and 3.19 [1.17-8.68], respectively). CONCLUSIONS: There is an association between ventilator-associated condition and infection-related ventilator-associated complication in critically ill children with acute kidney injury, ventilatory support, and neuromuscular blockade. Attention should be given by clinical practitioners to recognize these modifiable risk factors and to implement strategies to decrease the prevalence of ventilator-associated events. PMID- 29140968 TI - End-Tidal Carbon Dioxide Use for Tracheal Intubation: Analysis From the National Emergency Airway Registry for Children (NEAR4KIDS) Registry. AB - OBJECTIVE: Waveform capnography use has been incorporated into guidelines for the confirmation of tracheal intubation. We aim to describe the trend in waveform capnography use in emergency departments and PICUs and assess the association between waveform capnography use and adverse tracheal intubation-associated events. DESIGN: A multicenter retrospective cohort study. SETTING: Thirty-four hospitals (34 ICUs and nine emergency departments) in the National Emergency Airway Registry for Children quality improvement initiative. PATIENTS: Primary tracheal intubation in children younger than 18 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient, provider, and practice data for tracheal intubation procedure including a type of end-tidal carbon dioxide measurement, as well as the procedural safety outcomes, were prospectively collected. The use of waveform capnography versus colorimetry was evaluated in association with esophageal intubation with delayed recognition, cardiac arrest, and oxygen desaturation less than 80%. During January 2011 and December 2015, 9,639 tracheal intubations were reported. Waveform capnography use increased over time (39% in 2010 to 53% in 2015; p < 0.001), whereas colorimetry use decreased (< 0.001). There was significant variability in waveform capnography use across institutions (median 49%; interquartile range, 25-85%; p < 0.001). Capnography was used more often in emergency departments as compared with ICUs (66% vs. 49%; p < 0.001). The rate of esophageal intubation with delayed recognition was similar with waveform capnography versus colorimetry (0.39% vs. 0.46%; p = 0.62). The rate of cardiac arrest was also similar (p = 0.49). Oxygen desaturation occurred less frequently when capnography was used (17% vs. 19%; p = 0.03); however, this was not significant after adjusting for patient and provider characteristics. CONCLUSIONS: Significant variations existed in capnography use across institutions, with the use increasing over time in both emergency departments and ICUs. The use of capnography during intubation was not associated with esophageal intubation with delayed recognition or the occurrence of cardiac arrest. PMID- 29140970 TI - Clinical Impact of External Laryngeal Manipulation During Laryngoscopy on Tracheal Intubation Success in Critically Ill Children. AB - OBJECTIVES: External laryngeal manipulation is a commonly used maneuver to improve visualization of the glottis during tracheal intubation in children. However, the effectiveness to improve tracheal intubation attempt success rate in the nonanesthesia setting is not clear. The study objective was to evaluate the association between external laryngeal manipulation use and initial tracheal intubation attempt success in PICUs. DESIGN: A retrospective observational study using a multicenter emergency airway quality improvement registry. SETTING: Thirty-five PICUs within general and children's hospitals (29 in the United States, three in Canada, one in Japan, one in Singapore, and one in New Zealand). PATIENTS: Critically ill children (< 18 years) undergoing initial tracheal intubation with direct laryngoscopy in PICUs between July 1, 2010, and December 31, 2015. MEASUREMENTS AND MAIN RESULTS: Propensity score-matched analysis was performed to evaluate the association between external laryngeal manipulation and initial attempt success while adjusting for underlying differences in patient and clinical care factors: age, obesity, tracheal intubation indications, difficult airway features, provider training level, and neuromuscular blockade use. External laryngeal manipulation was defined as any external force to the neck during laryngoscopy. Of the 7,825 tracheal intubations, the initial tracheal intubation attempt was successful in 1,935/3,274 intubations (59%) with external laryngeal manipulation and 3,086/4,551 (68%) without external laryngeal manipulation (unadjusted odds ratio, 0.69; 95% CI, 0.62-0.75; p < 0.001). In propensity score-matched analysis, external laryngeal manipulation remained associated with lower initial tracheal intubation attempt success (adjusted odds ratio, 0.93; 95% CI, 0.90-0.95; p < 0.001). CONCLUSIONS: External laryngeal manipulation during direct laryngoscopy was associated with lower initial tracheal intubation attempt success in critically ill children, even after adjusting for underlying differences in patient factors and provider levels. The indiscriminate use of external laryngeal manipulation cannot be recommended. PMID- 29140971 TI - Effect of S. Mutans and S. Sanguinis on Growth and Adhesion of P. Gingivalis and Their Ability to Adhere to Different Dental Materials. AB - BACKGROUND Caries and periodontal diseases are caused by the biofilm formed by caries- and periodontal disease-related bacteria. Specific biofilms could be formed on different filling materials in oral cavity. Thus, to explore the inhibition effect of restorative filling materials on biofilm formation is of great significance in the treatment of caries and periodontal disease. MATERIAL AND METHODS The supernatants of S. mutans, S. sanguinis, and P. gingivalis suspension were combined with BHI broth. After 24 h, the live P. gingivalis number was calculated by colony counting and the biofilm was monitored by fluorescence microscopy. To test the adhesive ability of S. mutans and S. sanguinis on different dental materials, the biofilm was formed on different dental materials and then the bacterial number was calculated by using a Spectramax 250 microplate reader at OD 550, and the adhesive ability of S. mutans and S. sanguinis on different dental materials was analyzed by scanning electron microscopy. RESULTS The growth and biofilm formation of P. gingivalis was significantly inhibited by S. mutans and S. sanguinis supernatants (P<0.05). All groups except the zinc phosphate cement group (B) exerted a strong inhibitory effect on the biofilm formation of S. mutans and S. sanguinis (P<0.05). CONCLUSIONS The supernatants of S. mutans and S. sanguinis significantly inhibited the growth and biofilm formation of P. gingivalis, and the adhesive ability of S. mutans and S. sanguinis are different on different dental materials. These results provide useful information on dental caries, periodontal disease, and dental materials. PMID- 29140972 TI - Long noncoding RNA profiling revealed differentially expressed lncRNAs associated with disease activity in PBMCs from patients with rheumatoid arthritis. AB - Long noncoding RNAs (lncRNAs) have recently emerged as important biological regulators, and the aberrant expression of lncRNAs has been reported in numerous diseases. However, the expression of lncRNAs in peripheral blood mononuclear cells (PBMCs) in rheumatoid arthritis (RA) has not been well documented. We applied a microarray analysis to profile the lncRNA and mRNA expression in 3 pairs of samples. Each sample was mixed with equivalent PBMCs from 9 female RA patients and 9 corresponding healthy controls, and the data were validated via qPCR using another cohort that comprised 36 RA patients and 24 healthy controls. A bioinformatic analysis was performed to investigate the potential functions of differentially expressed genes. Overall, 2,099 lncRNAs and 2,307 mRNAs were differentially expressed between the RA patients and healthy controls. The bioinformatic analysis indicated that the differentially expressed lncRNAs regulated the abnormally expressed mRNAs, which were involved in the pathogenesis of RA through several different pathways. The qPCR results showed that the expression levels of ENST00000456270 and NR_002838 were significantly increased in the RA patients, whereas the expression levels of NR_026812 and uc001zwf.1 were significantly decreased. Furthermore, the expression level of ENST00000456270 was strongly associated with the serum levels of IL-6 and TNF-a and the Simplified Disease Activity Index (SDAI) of the RA patients. Our data provided comprehensive evidence regarding the differential expression of lncRNAs in PBMCs of RA patients, which shed light on the understanding of the molecular mechanisms of lncRNAs in the pathogenesis of RA. PMID- 29140974 TI - Physician-patient communication about overactive bladder: Results of an observational sociolinguistic study. AB - INTRODUCTION: Overactive bladder (OAB) and urinary incontinence are common problems that have significant impact on quality of life (QOL). Less than half of sufferers seek help from their physicians; many who do are dissatisfied with treatment and their physicians' understanding of their problems. Little is known about the sociolinguistic characteristics of physician-patient communication about OAB in community practice. METHODS: An IRB-approved observational sociolinguistic study of dialogues between patients with OAB and treating physicians was conducted. Study design included semi-structured post-visit interviews, post-visit questionnaires, and follow-up phone calls. Conversations were analyzed using techniques from interactional sociolinguistics. RESULTS: Communication was physician- rather than patient-centered. Physicians spoke the majority of words and 83% of questions were closed-ended. The impact of OAB on QOL and concerns about and adherence to treatment were infrequently addressed by physicians, who were poorly aligned with patients in their understanding. These topics were addressed more frequently when open-ended questions successfully eliciting elaborated responses were used in ask-tell-ask or ask-tell sequences. DISCUSSION: Clinical dialogue around OAB is physician-centered; topics critical to managing OAB are infrequently and inadequately addressed. The use of patient centered communication is correlated with more discussion of critical topics, and thus, more effective management of OAB. PMID- 29140973 TI - A coupled-oscillator model of olfactory bulb gamma oscillations. AB - The olfactory bulb transforms not only the information content of the primary sensory representation, but also its underlying coding metric. High-variance, slow-timescale primary odor representations are transformed by bulbar circuitry into secondary representations based on principal neuron spike patterns that are tightly regulated in time. This emergent fast timescale for signaling is reflected in gamma-band local field potentials, presumably serving to efficiently integrate olfactory sensory information into the temporally regulated information networks of the central nervous system. To understand this transformation and its integration with interareal coordination mechanisms requires that we understand its fundamental dynamical principles. Using a biophysically explicit, multiscale model of olfactory bulb circuitry, we here demonstrate that an inhibition-coupled intrinsic oscillator framework, pyramidal resonance interneuron network gamma (PRING), best captures the diversity of physiological properties exhibited by the olfactory bulb. Most importantly, these properties include global zero-phase synchronization in the gamma band, the phase-restriction of informative spikes in principal neurons with respect to this common clock, and the robustness of this synchronous oscillatory regime to multiple challenging conditions observed in the biological system. These conditions include substantial heterogeneities in afferent activation levels and excitatory synaptic weights, high levels of uncorrelated background activity among principal neurons, and spike frequencies in both principal neurons and interneurons that are irregular in time and much lower than the gamma frequency. This coupled cellular oscillator architecture permits stable and replicable ensemble responses to diverse sensory stimuli under various external conditions as well as to changes in network parameters arising from learning-dependent synaptic plasticity. PMID- 29140975 TI - Natural variation of a sensor kinase controlling a conserved stress response pathway in Escherichia coli. AB - Previous studies have shown that exponentially growing Escherichia coli can detect mild acidity (~pH 5.5) and, in response, synthesize enzymes that protect against severe acid shock. This adaptation is controlled by the EvgS/EvgA phosphorelay, a signal transduction system present in virtually every E. coli isolate whose genome has been sequenced. Here we show that, despite this high level of conservation, the EvgS/EvgA system displays a surprising natural variation in pH-sensing capacity, with some strains entirely non-responsive to low pH stimulus. In most cases that we have tested, however, activation of the EvgA regulon still confers acid resistance. From analyzing selected E. coli isolates, we find that the natural variation results from polymorphisms in the sensor kinase EvgS. We further show that this variation affects the pH response of a second kinase, PhoQ, which senses pH differently from the closely related PhoQ in Salmonella enterica. The within-species diversification described here suggests EvgS likely responds to additional input signals that may be correlated with acid stress. In addition, this work highlights the fact that even for highly conserved sensor kinases, the activities identified from a subset of isolates may not necessarily generalize to other members of the same bacterial species. PMID- 29140976 TI - Independent degradation in genes of the plastid ndh gene family in species of the orchid genus Cymbidium (Orchidaceae; Epidendroideae). AB - In this paper, we compare ndh genes in the plastid genome of many Cymbidium species and three closely related taxa in Orchidaceae looking for evidence of ndh gene degradation. Among the 11 ndh genes, there were frequently large deletions in directly repeated or AT-rich regions. Variation in these degraded ndh genes occurs between individual plants, apparently at population levels in these Cymbidium species. It is likely that ndh gene transfers from the plastome to mitochondrial genome (chondriome) occurred independently in Orchidaceae and that ndh genes in the chondriome were also relatively recently transferred between distantly related species in Orchidaceae. Four variants of the ycf1-rpl32 region, which normally includes the ndhF genes in the plastome, were identified, and some Cymbidium species contained at least two copies of that region in their organellar genomes. The four ycf1-rpl32 variants seem to have a clear pattern of close relationships. Patterns of ndh degradation between closely related taxa and translocation of ndh genes to the chondriome in Cymbidium suggest that there have been multiple bidirectional intracellular gene transfers between two organellar genomes, which have produced different levels of ndh gene degradation among even closely related species. PMID- 29140977 TI - Low cost and open source multi-fluorescence imaging system for teaching and research in biology and bioengineering. AB - The advent of easy-to-use open source microcontrollers, off-the-shelf electronics and customizable manufacturing technologies has facilitated the development of inexpensive scientific devices and laboratory equipment. In this study, we describe an imaging system that integrates low-cost and open-source hardware, software and genetic resources. The multi-fluorescence imaging system consists of readily available 470 nm LEDs, a Raspberry Pi camera and a set of filters made with low cost acrylics. This device allows imaging in scales ranging from single colonies to entire plates. We developed a set of genetic components (e.g. promoters, coding sequences, terminators) and vectors following the standard framework of Golden Gate, which allowed the fabrication of genetic constructs in a combinatorial, low cost and robust manner. In order to provide simultaneous imaging of multiple wavelength signals, we screened a series of long stokes shift fluorescent proteins that could be combined with cyan/green fluorescent proteins. We found CyOFP1, mBeRFP and sfGFP to be the most compatible set for 3-channel fluorescent imaging. We developed open source Python code to operate the hardware to run time-lapse experiments with automated control of illumination and camera and a Python module to analyze data and extract meaningful biological information. To demonstrate the potential application of this integral system, we tested its performance on a diverse range of imaging assays often used in disciplines such as microbial ecology, microbiology and synthetic biology. We also assessed its potential use in a high school environment to teach biology, hardware design, optics, and programming. Together, these results demonstrate the successful integration of open source hardware, software, genetic resources and customizable manufacturing to obtain a powerful, low cost and robust system for education, scientific research and bioengineering. All the resources developed here are available under open source licenses. PMID- 29140978 TI - Adherence to inhaled therapies of COPD patients from seven Latin American countries: The LASSYC study. AB - BACKGROUND: This study assessed the adherence profiles to inhaled therapies and the agreement between two patient self-report adherence methods in stable COPD lpatients from seven Latin American countries. METHODS: This observational, cross sectional, multinational, multicenter study involved 795 COPD patients (post bronchodilator forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC] <0.70). Adherence to inhaled therapy was assessed using the specific Test of Adherence to Inhalers (10-item TAI) and the generic 8-item Morisky Medication Adherence Scale (MMAS-8) questionnaires. The percentage agreement and the kappa index were used to compare findings. RESULTS: 59.6% of patients were male (69.5+/-8.7 years); post-bronchodilator FEV1 percent predicted was 50.0+/ 18.6%. Mean values for 10-item TAI and MMAS-8 questionnaires were 47.4+/-4.9 and 6.8+/-1.6, respectively. Based on the TAI questionnaire, 54.1% of patients had good, 26.5% intermediate, and 19.4% poor adherence. Using the MMAS-8 questionnaire, 51% had high, 29.1% medium, and 19.9% low adherence. According to both questionnaires, patients with poor adherence had lower smoking history, schooling but higher COPD Assessment Test score, exacerbations in the past-year and post-bronchodilator FEV1. The agreement between 10-item TAI and MMAS-8 questionnaires was moderate (Kappa index: 0.42; agreement: 64.7%). CONCLUSION: Suboptimal adherence to medication was frequent in COPD patients from Latin America. Low adherence was associated with worse health status impairment and more exacerbations. There was inadequate agreement between the two questionnaires. Greater effort should be made to improve COPD patients' adherence to treatment, and assessment of adherence with more specific instruments, such as the TAI questionnaire, would be more convenient in these patients. CLINICAL TRIAL REGISTRATION: NCT02789540. PMID- 29140979 TI - Ginsenoside Rg3 inhibits angiogenesis in a rat model of endometriosis through the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway. AB - OBJECTIVE: This study aimed to investigate the link between the inhibitory effect of ginsenoside Rg3 on the ectopic endometrium growth and the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway, a mechanism known to inhibit angiogenesis and induce ectopic endometrial cell apoptosis. MATERIALS AND METHODS: A model of endometriosis was established by allotransplantation in rats. The rats were randomly divided into 5 groups: the ginsenoside Rg3 low-dose group (group A,5mg/kgBW/d of ginsenoside Rg3), the ginsenoside Rg3 high-dose group (group B, 10mg/kgBW/d of ginsenoside Rg3), the gestrinone group (group C, 0.5mg/kgBW/d of gestrinone), the control group (groupD, 10ml/kg BW/d of 0.5%CMC-Na) and the ovariectomized group (group E, 10ml/kgBW/d of 0.5%CMC-Na). Rats were executed after 21 days of continuous administration. The ectopic endometrium volume was measured and the inhibitory rate was calculated. The levels of serum estradiol (E2) and progesterone (P) were detected by Electro-Chemiluminescence Immunoassay (ECLI). The protein expressionof VEGF, VEGFR-2, p-Akt, and p-mTOR inthe ectopic endometrium wastested by immunohistochemistry(IHC) and Western Blotting. The mRNA expression levels of VEGF, VEGFR-2, Akt, and mTOR were tested by Real-Time Polymerase Chain Reaction (PCR). The apoptosis rate of the ectopic endometrial cells was detected by Terminal Deoxynucleotidyl Transferase-mediated Digoxigenin dUTP Nick-End Labeling Assay(TUNEL). MAIN RESULTS: Tissue measurements revealed a dose-dependent inhibition effect of ginsenoside Rg3 on the growth of the ectopic endometrium in treated rats compared to controls. Immunohistochemical and Western Blotting assays confirmed that the expression of VEGF, p-Akt, and p-mTOR was down regulated in ginsenoside Rg3 -treated lesions. Real-time PCR results also showed that the mRNA expression levels of VEGF, Akt, and mTOR in the ectopic endometrium were reduced. CONCLUSIONS: The present study demonstrates, for the first time, that ginsenoside Rg3 suppresses angiogenesis in developing endometrial lesions. The ginsenoside Rg3 inhibitory effect on the growth of the ectopic endometrium in EMs rats might occur through the blocking of the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway, thus halting angiogenesis and promoting the apoptosis of ectopic endometrial cells. PMID- 29140981 TI - Wavelet brain angiography suggests arteriovenous pulse wave phase locking. AB - When a stroke volume of arterial blood arrives to the brain, the total blood volume in the bony cranium must remain constant as the proportions of arterial and venous blood vary, and by the end of the cardiac cycle an equivalent volume of venous blood must have been ejected. I hypothesize the brain to support this process by an extraluminally mediated exchange of information between its arterial and venous circulations. To test this I introduce wavelet angiography methods to resolve single moving vascular pulse waves (PWs) in the brain while simultaneously measuring brain pulse motion. The wavelet methods require angiographic data acquired at significantly faster rate than cardiac frequency. I obtained these data in humans from brain surface optical angiograms at craniotomy and in piglets from ultrasound angiograms via cranial window. I exploit angiographic time of flight to resolve arterial from venous circulation. Initial wavelet reconstruction proved unsatisfactory because of angiographic motion alias from brain pulse motion. Testing with numerically simulated cerebral angiograms enabled the development of a vascular PW cine imaging method based on cross correlated wavelets of mixed high frequency and high temporal resolution respectively to attenuate frequency and motion alias. Applied to the human and piglet data, the method resolves individual arterial and venous PWs and finds them to be phase locked each with separate phase relations to brain pulse motion. This is consistent with arterial and venous PW coordination mediated by pulse motion and points to a testable hypothesis of a function of cerebrospinal fluid in the ventricles of the brain. PMID- 29140980 TI - Prokaryotic diversity and biogeochemical characteristics of benthic microbial ecosystems at La Brava, a hypersaline lake at Salar de Atacama, Chile. AB - Benthic microbial ecosystems of Laguna La Brava, Salar de Atacama, a high altitude hypersaline lake, were characterized in terms of bacterial and archaeal diversity, biogeochemistry, (including O2 and sulfide depth profiles and mineralogy), and physicochemical characteristics. La Brava is one of several lakes in the Salar de Atacama where microbial communities are growing in extreme conditions, including high salinity, high solar insolation, and high levels of metals such as lithium, arsenic, magnesium, and calcium. Evaporation creates hypersaline conditions in these lakes and mineral precipitation is a characteristic geomicrobiological feature of these benthic ecosystems. In this study, the La Brava non-lithifying microbial mats, microbialites, and rhizome associated concretions were compared to each other and their diversity was related to their environmental conditions. All the ecosystems revealed an unusual community where Euryarchaeota, Crenarchaeota, Acetothermia, Firmicutes and Planctomycetes were the most abundant groups, and cyanobacteria, typically an important primary producer in microbial mats, were relatively insignificant or absent. This suggests that other microorganisms, and possibly novel pathways unique to this system, are responsible for carbon fixation. Depth profiles of O2 and sulfide showed active production and respiration. The mineralogy composition was calcium carbonate (as aragonite) and increased from mats to microbialites and rhizome-associated concretions. Halite was also present. Further analyses were performed on representative microbial mats and microbialites by layer. Different taxonomic compositions were observed in the upper layers, with Archaea dominating the non-lithifying mat, and Planctomycetes the microbialite. The bottom layers were similar, with Euryarchaeota, Crenarchaeota and Planctomycetes as dominant phyla. Sequences related to Cyanobacteria were very scarce. These systems may contain previously uncharacterized community metabolisms, some of which may be contributing to net mineral precipitation. Further work on these sites might reveal novel organisms and metabolisms of biotechnological interest. PMID- 29140982 TI - Development, standardization and testing of a bacterial wound infection model based on ex vivo human skin. AB - Current research on wound infections is primarily conducted on animal models, which limits direct transferability of these studies to humans. Some of these limitations can be overcome by using-otherwise discarded-skin from cosmetic surgeries. Superficial wounds are induced in fresh ex vivo skin, followed by intradermal injection of Pseudomonas aeruginosa under the wound. Subsequently, the infected skin is incubated for 20 hours at 37 degrees C and the CFU/wound are determined. Within 20 hours, the bacteria count increased from 107 to 109 bacteria per wound, while microscopy revealed a dense bacterial community in the collagen network of the upper wound layers as well as numerous bacteria scattered in the dermis. At the same time, IL-1alpha and IL-1beta amounts increased in all infected wounds, while-due to bacteria-induced cell lysis-the IL-6 and IL-8 concentrations rose only in the uninfected samples. High-dosage ciprofloxacin treatment resulted in a decisive decrease in bacteria, but consistently failed to eradicate all bacteria. The main benefits of the ex vivo wound model are the use of healthy human skin, a quantifiable bacterial infection, a measureable donor dependent immune response and a good repeatability of the results. These properties turn the ex vivo wound model into a valuable tool to examine the mechanisms of host-pathogen interactions and to test antimicrobial agents. PMID- 29140983 TI - Ecosystem services in European protected areas: Ambiguity in the views of scientists and managers? AB - Protected Areas are a key component of nature conservation. They can play an important role in counterbalancing the impacts of ecosystem degradation. For an optimal protection of a Protected Area it is essential to account for the variables underlying the major Ecosystem Services an area delivers, and the threats upon them. Here we show that the perception of these important variables differs markedly between scientists and managers of Protected Areas in mountains and transitional waters. Scientists emphasise variables of abiotic and biotic nature, whereas managers highlight socio-economic, cultural and anthropogenic variables. This indicates fundamental differences in perception. To be able to better protect an area it would be advisable to bring the perception of scientists and managers closer together. Intensified and harmonised communication across disciplinary and professional boundaries will be needed to implement and improve Ecosystem Service oriented management strategies in current and future Protected Areas. PMID- 29140984 TI - An observational study on sport-induced modulation of negative attitude towards disability. AB - The present study investigates whether sport activities involving children with a disability can reduce negative attitudes towards disability in children without disability. We compared the effect of being schoolmate or member of the same football team whereby a child with disability was member of the class/team or not. This lead to four groups that were assessed both at the beginning and at the end of the school year. Two measures were collected: an ad-hoc questionnaire and an Implicit Association Test. The two assessments were designed to measure explicit and implicit attitudes towards children with disabilities. Results suggested that sport activities over one school year reduced more (p < .001) the implicit negative attitude towards disability (Mean = -.17, sd = .10) than the contact with the classmate in the school context (Mean = -.03, sd = .14), possibly due to their team building characteristic. PMID- 29140986 TI - Correction: Kinesin-1 promotes chondrocyte maintenance during skeletal morphogenesis. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006918.]. PMID- 29140985 TI - Notch signaling and progenitor/ductular reaction in steatohepatitis. AB - BACKGROUND AND OBJECTIVE: Persistent hepatic progenitor cells (HPC) activation resulting in ductular reaction (DR) is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries. Therefore, we aimed to investigate the role of Notch during HPC/DR activation in a mouse model of steatohepatitis. METHODS: Steatohepatitis was generated using methionine-choline deficient (MCD) diet. For hepatocyte lineage tracing, R26R-YFP mice were infected with AAV8-TBG-Cre. RESULTS: MCD diet promoted a strong HPC/DR response that progressively diffused in the lobule, and correlated with increased fibrosis and TGF-beta1 expression. Notch signaling was unchanged in laser-capture microdissected HPC/DR, whereas Notch receptors were down regulated in hepatocytes. However, in-vivo lineage tracing experiments identified discrete hepatocytes showing Notch-1 activation and expressing (the Notch-dependent) Sox9. Stimulation of AML-12 hepatocyte-cell line with immobilized Jag1 induced Sox9 and down-regulated albumin and BSEP expression. TGF-beta1 treatment in primary hepatic stellate cells (HSC) induced Jag1 expression. In MCD diet-fed mice, alphaSMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-beta1 stimulated HSC. In-vivo Notch inhibition reduced HPC response and fibrosis progression. CONCLUSION: Our data suggest that Notch signaling is an important regulator of DR and that in steatohepatitis, hepatocytes exposed to Jag1-positive HSC, contribute to pathologic DR by undergoing Notch-mediated differentiation towards an HPC-like phenotype. Given the roles of Notch in fibrosis and liver cancer, these data suggest mesenchymal expression of Jag1 as an alternative therapeutic target. PMID- 29140987 TI - Dating the beginning of the Roman viticultural model in the Western Mediterranean: The case study of Chianti (Central Italy). AB - Although domestication of the grapevine (Vitis vinifera L.) has been extensively documented, the history of genotype selection and evolution of vineyard management remain relatively neglected fields of study. The find of 454 waterlogged grapevine pips from a well-dated Etrusco-Roman site in the Chianti district (Tuscany, Central Italy) is an extraordinary chance to gain insights into the progress of viticulture occurring in a key historical period in one of the world's most famous wine regions. The molecular and geometrical analyses of grape seeds showed (a) the presence in the site of different grapevine individuals and (b) a sudden increase in pip size, occurring at around 200 BC, whic explainable by the selection and introduction of new varieties. In this period, the Etruscans settlers in Chianti were stimulated by northward-expanding Roman culture to use novel vineyard management practices. We hypothesize that one of the most important innovations may have been the introduction of pruning, inducing vine physiological conditions more favorable to pip growth. Such changes were the consequence of specific entrepreneurial choices made by the Romans in a period of economic investment in grape cultivation and wine making to satisfy the increased trade demand after the conquest of the Central-Western Mediterranean basin. PMID- 29140988 TI - Sex difference in the interaction of alcohol intake, hepatitis B virus, and hepatitis C virus on the risk of cirrhosis. AB - BACKGROUND: The joint effect of the interaction of alcohol intake, hepatitis B virus (HBV) and hepatitis C virus (HCV) on the risk of cirrhosis is still unexplored because a large sample size is required for this investigation. OBJECTIVE: Evaluation of interaction of HBV, HCV and alcohol abuse on the risk of cirrhosis. DESIGN: We analysed 12,262 consecutive patients with chronic liver disease of various aetiologies referring to 95 Italian liver units in 2001 or 2014. To evaluate the interaction between alcohol abuse, HBV infection, and HCV infection, patients unexposed to either factors were used as reference category. Adjustment for BMI and age was done by multiple logistic regression analysis. RESULTS: Females were older than males (p<0.01) and less frequently showed HBV and alcoholic aetiology (p<0.01). In both sexes, an overtime increasing age and an increasing proportion of subjects with liver cirrhosis was observed, reflecting a better survival (0.01). An additive interaction is observed in females: the O.R. generated by the simultaneous presence of HBV, HCV, and alcohol (5.09; 95% C.I. 1.06-24.56) exceeds the sum (4.14) of the O.R. generated by a single exposure (O.R. = 0.72 for HBsAg positivity, OR = 1.34 for anti-HCV positivity, and O.R. = 2.08 for alcohol intake). No interaction is observed in male sex. CONCLUSIONS: The observed gender difference suggests that the simultaneous presence of HBV/HCV coinfection and risky alcohol intake enhances the mechanism of liver damage to a greater extent in females than in males. PMID- 29140989 TI - Joint approach based on clinical and imaging features to distinguish non neoplastic from neoplastic pituitary stalk lesions. AB - PURPOSE: Distinguishing non-neoplastic pituitary stalk lesions (non-NPSLs) from neoplastic pituitary stalk lesions (NPSLs) is a major concern in guiding treatment for a thickened pituitary stalk. Our study aimed to aid provide preoperative diagnostic assistance by combining clinical and magnetic resonance imaging (MRI) findings to distinguish non-NPSLs from NPSLs. MATERIALS AND METHODS: We recruited 158 patients with thickened pituitary stalk lesions visible on MRI. Laboratory findings included hypopituitarism, diabetes insipidus (DI), and hyperprolactinemia. MR images were assessed for anterior-posterior thickness (mm), diffuse pituitary stalk thickening, cystic changes, a high T1 signal, and glandular or extrasellar involvement. A diagnostic model was developed using a recursive partitioning logistic regression analysis. The model was validated in an independent dataset comprising 63 patients, and its diagnostic performance was compared with that of the original radiological reports. RESULTS: A univariate analysis found significant associations of DI (P = 0.006), absence of extrasellar involvement (P = 0.002), and lower stalk thickness (P = 0.031) with non-NPSLs. A diagnostic model was created using the following parameters (in order of priority): 1) lack of extrasellar involvement, 2) stalk thickness < 5.3 mm, and 3) presence of DI. The diagnostic performance (area under the curve; AUC) of this model in the independent set was 0.813, representing a significant improvement over the original radiological reports (AUC: 0.713, P = 0.029). CONCLUSION: The joint diagnostic approach based on clinical and imaging-based factors robustly distinguished non-NPSLs from NPSLs. This approach could guide treatment strategies and prevent unnecessary surgery in patients with non-NPSL. PMID- 29140990 TI - Cultivar architecture modulates spore dispersal by rain splash: A new perspective to reduce disease progression in cultivar mixtures. AB - Cultivar mixtures can be used to improve the sustainability of disease management within farming systems by growing cultivars that differ in their disease resistance level in the same field. The impact of canopy aerial architecture on rain-splash dispersal could amplify disease reduction within mixtures. We designed a controlled conditions experiment to study single splash-dispersal events and their consequences for disease. We quantified this impact through the spore interception capacities of the component cultivars of a mixture. Two wheat cultivars, differing in their aerial architecture (mainly leaf area density) and resistance to Septoria tritici blotch, were used to constitute pure stands and mixtures with 75% of resistant plants that accounted for 80% of the canopy leaf area. Canopies composed of 3 rows of plants were exposed to standardized spore fluxes produced by splashing calibrated rain drops on a linear source of inoculum. Disease propagation was measured through spore fluxes and several disease indicators. Leaf susceptibility was higher for upper than for lower leaves. Dense canopies intercepted more spores and mainly limited horizontal spore transfer to the first two rows. The presence of the resistant and dense cultivar made the mixed canopy denser than the susceptible pure stand. No disease symptoms were observed on susceptible plants of the second and third rows in the cultivar mixture, suggesting that the number of spores intercepted by these plants was too low to cause disease symptoms. Both lesion area and disease conditional severity were significantly reduced on susceptible plants within mixtures on the first row beside the inoculum source. Those reductions on one single-splash dispersal event, should be amplified after several cycle over the full epidemic season. Control of splash-dispersed diseases within mixtures could therefore be improved by a careful choice of cultivars taking into consideration both resistance and architecture. PMID- 29140991 TI - A Bayesian method for detecting pairwise associations in compositional data. AB - Compositional data consist of vectors of proportions normalized to a constant sum from a basis of unobserved counts. The sum constraint makes inference on correlations between unconstrained features challenging due to the information loss from normalization. However, such correlations are of long-standing interest in fields including ecology. We propose a novel Bayesian framework (BAnOCC: Bayesian Analysis of Compositional Covariance) to estimate a sparse precision matrix through a LASSO prior. The resulting posterior, generated by MCMC sampling, allows uncertainty quantification of any function of the precision matrix, including the correlation matrix. We also use a first-order Taylor expansion to approximate the transformation from the unobserved counts to the composition in order to investigate what characteristics of the unobserved counts can make the correlations more or less difficult to infer. On simulated datasets, we show that BAnOCC infers the true network as well as previous methods while offering the advantage of posterior inference. Larger and more realistic simulated datasets further showed that BAnOCC performs well as measured by type I and type II error rates. Finally, we apply BAnOCC to a microbial ecology dataset from the Human Microbiome Project, which in addition to reproducing established ecological results revealed unique, competition-based roles for Proteobacteria in multiple distinct habitats. PMID- 29140992 TI - Transcriptome profile of lung dendritic cells after in vitro porcine reproductive and respiratory syndrome virus (PRRSV) infection. AB - The porcine reproductive and respiratory syndrome (PRRS) is an infectious disease that leads to high financial and production losses in the global swine industry. The pathogenesis of this disease is dependent on a multitude of factors, and its control remains problematic. The immune system generally defends against infectious diseases, especially dendritic cells (DCs), which play a crucial role in the activation of the immune response after viral infections. However, the understanding of the immune response and the genetic impact on the immune response to PRRS virus (PRRSV) remains incomplete. In light of this, we investigated the regulation of the host immune response to PRRSV in porcine lung DCs using RNA-sequencing (RNA-Seq). Lung DCs from two different pig breeds (Pietrain and Duroc) were collected before (0 hours) and during various periods of infection (3, 6, 9, 12, and 24 hours post infection (hpi)). RNA-Seq analysis revealed a total of 20,396 predicted porcine genes, which included breed-specific differentially expressed immune genes. Pietrain and Duroc infected lung DCs showed opposite gene expression courses during the first time points post infection. Duroc lung DCs reacted more strongly and distinctly than Pietrain lung DCs during these periods (3, 6, 9, 12 hpi). Additionally, cluster analysis revealed time-dependent co-expressed groups of genes that were involved in immune relevant pathways. Key clusters and pathways were identified, which help to explain the biological and functional background of lung DCs post PRRSV infection and suggest IL-1beta1 as an important candidate gene. RNA-Seq was also used to characterize the viral replication of PRRSV for each breed. PRRSV was able to infect and to replicate differently in lung DCs between the two mentioned breeds. These results could be useful in investigations on immunity traits in pig breeding and enhancing the health of pigs. PMID- 29140993 TI - Prognostic significance of cyclin D1 protein expression and gene amplification in invasive breast carcinoma. AB - The oncogenic capacity of cyclin D1 has long been established in breast cancer. CCND1 amplification has been identified in a subset of patients with poor prognosis, but there are conflicting data regarding the predictive value of cyclin D1 protein overexpression. This study was designed to analyze the expression of cyclin D1 and its correlation with CCND1 amplification and their prognostic implications in invasive breast cancer. By using the tissue microarray technique, we performed an immunohistochemical study of ER, PR, HER2, p53, cyclin D1, Ki67 and p16 in 179 invasive breast carcinoma cases. The FISH method was performed to detect HER2/Neu and CCND1 amplification. High cyclin D1 expression was identified in 94/179 (52%) of invasive breast cancers. Cyclin D1 overexpression and CCND1 amplification were significantly associated (p = 0.010). Overexpression of cyclin D1 correlated with ER expression, PR expression and Luminal subtypes (p<0.001), with a favorable impact on overall survival in the whole series. However, in the Luminal A group, high expression of cyclin D1 correlated with shorter disease-free survival, suggesting that the prognostic role of cyclin D1 depends on the molecular subtype. CCND1 gene amplification was detected in 17 cases (9%) and correlated significantly with high tumor grade (p = 0.038), high Ki-67 protein expression (p = 0.002), and the Luminal B subtype (p = 0.002). Patients with tumors with high amplification of CCND1 had an increased risk of recurrence (HR = 2.5; 95% CI, 1.2-4.9, p = 0.01). These findings suggest that CCND1 amplification could be useful for predicting recurrence in invasive breast cancer. PMID- 29140994 TI - Copy number gains at chr3p25 and chr11p11 are associated with lymph node involvement and survival in muscle-invasive bladder tumors. AB - Patients with muscle-invasive bladder cancer (MIBC) have poorer prognoses if cancer has metastasized to the lymph nodes. Genomic markers of lymph node involvement (LNI) would be useful for treatment planning, especially if measured at the biopsy stage, but large-scale studies of tumor tissue at any stage are needed to discover robust markers of LNI. We performed a genome-wide query of copy number alterations (CNA) in 237 MIBC surgical tumor specimens from patients in The Cancer Genome Atlas who had radical cystectomy and lymphadenectomy without neoadjuvant treatment. Pathology reports were independently reviewed to confirm LNI, and copy number data was analyzed to confirm gene-level gains and losses while adjusting for tumor purity and ploidy. Using logistic regression and elastic net models, we identified the CNA most significantly associated with LNI. Multivariable logistic regression was used to describe these CNA associations while adjusting for clinical variables. Kaplan-Meier and Cox regression were used to describe their association with overall survival. Gains in 26 genes were identified as having strong associations with LNI. After adjusting for age, gender, race, pathological tumor stage, histology, and number of nodes examined, gains in 22 genes on chr3p25 or chr11p11 remained significantly associated with LNI (p<0.01) and improved model discrimination over clinical variables alone (p = 0.04). They were also associated with shorter overall survival (adjusted p = 0.02). These results suggest that a simple genomic test for gains in chr3p25 and chr11p11 could inform adjuvant treatment or clinical trial decisions if validated in external cohorts. Additional studies will also be needed to determine if these CNA are detectible in biopsy tissue and can inform clinical decisions at the preoperative stage. PMID- 29140995 TI - Process strengths determine the forms of the relationship between plant species richness and primary productivity. AB - The current rates of biodiversity loss have exceeded the rates observed during the earth's major extinction events, which spurs the studies of the ecological relationships between biodiversity and ecosystem functions, stability, and services to determine the consequences of biodiversity loss. Plant species richness-productivity relationship (SRPR) is crucial to the understanding of these relationships in plants. Most ecologists have reached a widespread consensus that the loss of plant diversity undoubtedly impairs ecosystem functions, and have proposed many processes to explain the SRPR. However, none of the available studies has satisfactorily described the forms and mechanisms clarifying the SRPR. Observed results of the SRPR forms are inconsistent, and studies have long debated the ecological processes explaining the SRPR. Here, I have developed a simple model that combines the positive and/or negative effects of sixteen ecological processes on the SRPR and models that describe the dynamics of complementary-selection effect, density effect, and the interspecific competitive stress influenced by other ecological processes. I can regulate the strengths of the effects of these ecological processes to derive the asymptotic, positive, humped, negative, and irregular forms of the SRPR, and verify these forms using the observed data. The results demonstrated that the different strengths of the ecological processes determine the forms of the SRPR. The forms of the SRPR can change with variations in the strengths of the ecological processes. The dynamic characteristics of the complementary-selection effect, density effect, and the interspecific competitive stress on the SRPR are diverse, and are dependent on the strengths and variation of the ecological processes. This report explains the diverse forms of the SRPR, clarifies the integrative effects of the different ecological processes on the SRPR, and deepens our understanding of the interactions that occur among these ecological processes. PMID- 29140997 TI - Topical anaesthesia reduces sensitivity of castration wounds in neonatal piglets. AB - The aim of this study was to do determine the efficacy of the topical anaesthetic Tri-Solfen(r) in the amelioration of the pain of castration in piglets. The trial was conducted over a three day period, and blocked across six litters with 12 piglets treated on days one and two, and 16 on day three. The piglets were randomly allocated by weight and litter to 1 of 4 treatment groups: (i) sham castration (SHAM; n = 10); (ii) surgical castration with no anaesthetic intervention (CAST; n = 10); (iii) surgical castration with post-operative topical anaesthesia (TRI; n = 10); (iv) surgical castration with a pre-operative intra-testicular lignocaine hydrochloride injection (LIG; n = 10). Wound sensitivity testing involved von Frey monofilaments of weights 4g and 300g, and an 18 gauge needle, used to stimulate the wound and surrounding skin respectively, at various pre-determined sites. Neonatal piglets receiving topical anaesthesia (Tri-Solfen(r)) spray into castration wounds had significantly lower wound sensitivity responses for up to 4h, compared to those castrated following intra-testicular lignocaine injection or those with no treatment. The use of topical anaesthetic is suggested as a practical and affordable method of improving piglet welfare during castration. PMID- 29140996 TI - Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function. AB - The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies. PMID- 29140998 TI - Using whole genome sequencing to study American foulbrood epidemiology in honeybees. AB - American foulbrood (AFB), caused by Paenibacillus larvae, is a devastating disease in honeybees. In most countries, the disease is controlled through compulsory burning of symptomatic colonies causing major economic losses in apiculture. The pathogen is endemic to honeybees world-wide and is readily transmitted via the movement of hive equipment or bees. Molecular epidemiology of AFB currently largely relies on placing isolates in one of four ERIC-genotypes. However, a more powerful alternative is multi-locus sequence typing (MLST) using whole-genome sequencing (WGS), which allows for high-resolution studies of disease outbreaks. To evaluate WGS as a tool for AFB-epidemiology, we applied core genome MLST (cgMLST) on isolates from a recent outbreak of AFB in Sweden. The high resolution of the cgMLST allowed different bacterial clones involved in the disease outbreak to be identified and to trace the source of infection. The source was found to be a beekeeper who had sold bees to two other beekeepers, proving the epidemiological link between them. No such conclusion could have been made using conventional MLST or ERIC-typing. This is the first time that WGS has been used to study the epidemiology of AFB. The results show that the technique is very powerful for high-resolution tracing of AFB-outbreaks. PMID- 29140999 TI - Variation in the diversity-productivity relationship in young forests of the eastern United States. AB - The diversity-productivity relationship has not been studied as extensively in forests as in other ecosystems. We address this gap in our knowledge by examining the relationship of productivity (primarily the periodic annual increment in aboveground biomass, but also the mean annual increment) with five species diversity indices, stand, and environmental factors. We used 967 naturally regenerated Forest Inventory and Analysis plots with stand age <=30 years, located in the conterminous thirty-one eastern states, and satisfying strict selection requirements. Generally, mixed-species (heterospecific) stands were as productive as or even somewhat more productive than pure (monospecific) stands. The periodic and mean annual increments were both positively correlated with species richness (R2 = 0.04 and 0.20, p<0.001). Similarly, the zero-order and partial correlations with productivity were positive for four of the diversity indices (species richness, functional diversity, phylogenetic diversity, and phylogenetic species richness) and not significant for the fifth (functional dispersion). Greater diversity was more important on low-productivity sites and in stands with low stocking. As forests generally get more diverse and productive away from the poles, we tested if the nature of the productivity-diversity relationship changed latitudinally. Productivity was weakly positively correlated with four of the diversity indices north of 40 degrees latitude, but weakly negatively with three of the indices to the south. Our examination of the productivity-diversity relationship in stands containing either of the two most dominant species, quaking aspen or loblolly pine, revealed that pure loblolly pine stands were somewhat more productive than only three of the eight mixtures with loblolly in the composition, while pure aspen stands were no more productive than any of the aspen mixtures. Overall, monospecific stands did not seem to have a clear productivity advantage over mixtures. The findings of this study have implications for woody biomass production, carbon sequestration by forests, and biodiversity conservation. PMID- 29141000 TI - Soluble glycoprotein VI, a specific marker of platelet activation is increased in the plasma of subjects with seropositive rheumatoid arthritis. AB - OBJECTIVES: Anti-citrullinated protein antibodies (ACPA) have been shown to cause platelet activation in vitro, through the low-affinity immunoglobulin G (IgG) receptor (FcgammaRIIa) on platelets. Platelet activation via engagement of FcgammaRIIa results in proteolytic cleavage and shedding of platelet specific glycoprotein VI (GPVI) which can be detected in the plasma as soluble GPVI (sGPVI). We hypothesized that plasma levels of sGPVI would be increased among patients with seropositive RA as a consequence of antibody-induced platelet activation and GPVI shedding. METHODS: Samples from 84 patients with RA (65 seropositive and 19 seronegative) and 67 healthy controls were collected prospectively and analysed for sGPVI using a standardised ELISA. RESULTS: Patients with seropositive RA had significantly higher levels of sGPVI compared to seronegative RA and controls. Median (IQR) sGPVI levels were 4.2 ng/ml (3.2, 8.0) in seropositve RA, 2.2 ng/ml (1.5, 3.5) in seronegative RA and 2.2 ng/ml (1.6, 3.4) in controls (p<0.0001). sGPVI levels correlated with ACPA titres (r = 0.32, p = 0.0026) and with RF titres (r = 0.48, p<0.0001). CONCLUSION: Plasma sGPVI, a specific marker of platelet activation is increased among patients with seropositive RA. PMID- 29141001 TI - The associations between magnetic resonance imaging findings and low back pain: A 10-year longitudinal analysis. AB - PURPOSE: To conduct a 10-year longitudinal analysis of the relationship between magnetic resonance imaging (MRI) findings and low back pain (LBP). MATERIALS AND METHODS: Ninety-one volunteers with a history of LBP, but without current LBP were recruited between 2005 and 2006. Participants' baseline demographics and MRI findings were recorded. All volunteers were invited for a follow-up MRI in 2016; of these, 49 volunteers (53.8%) participated in the follow-up. We enquired whether they had LBP history during the 10 years between the baseline and follow up examinations. Sagittal T1 and T2-weighted MRI were used to assess the intervertebral space from T12/L1 to L5/S1. We evaluated the presence of disc degeneration by Pfirrmann's grading system, disc bulging, high intensity zone (HIZ), spondylolisthesis, and any type of Modic changes in the follow-up MRIs. We compared the follow-up MRI findings with the baseline findings; the progress of each finding over the 10 years were also compared between the groups with (n = 36) and without (n = 13) LBP. RESULTS: Average age of the study participants at follow-up was 44.8 years; 25 were female and 24 were male. Average age, sex, body mass index, and smoking habits of those who did and did not participate in the follow-up study, as well as the demographic characteristics of those who did and did not have LBP history during the 10 years, were not significantly different. Compared with the group without LBP history, the group that had LBP history during the 10 years did not have a significantly increased prevalence of disc degeneration, disc bulging, and HIZ in the follow-up and baseline MRIs. Spondylolisthesis and any type of Modic changes were also not associated with LBP history during the 10 years. CONCLUSIONS: Follow-up MRI findings consistent with Pfirrmann grading >=4, disc bulging, HIZ, spondylolisthesis, and any type of Modic changes were not associated with LBP history during the 10 years between the baseline and follow-up study. The progresses of these findings were also not associated with the LBP history. In addition, baseline MRI findings were not associated with LBP history during the 10 years; therefore, our data suggest that baseline MRI findings cannot predict future LBP. PMID- 29141002 TI - Correlates of decisional dynamics in the dorsal anterior cingulate cortex. AB - We hypothesized that during binary economic choice, decision makers use the first option they attend as a default to which they compare the second. To test this idea, we recorded activity of neurons in the dorsal anterior cingulate cortex (dACC) of macaques choosing between gambles presented asynchronously. We find that ensemble encoding of the value of the first offer includes both choice dependent and choice-independent aspects, as if reflecting a partial decision. That is, its responses are neither entirely pre- nor post-decisional. In contrast, coding of the value of the second offer is entirely decision dependent (i.e., post-decisional). This result holds even when offer-value encodings are compared within the same time period. Additionally, we see no evidence for 2 pools of neurons linked to the 2 offers; instead, all comparison appears to occur within a single functionally homogenous pool of task-selective neurons. These observations suggest that economic choices reflect a context-dependent evaluation of attended options. Moreover, they raise the possibility that value representations reflect, to some extent, a tentative commitment to a choice. PMID- 29141003 TI - TRPA1 and TRPV1 are required for lidocaine-evoked calcium influx and neuropeptide release but not cytotoxicity in mouse sensory neurons. AB - BACKGROUND: Local anaesthetics (LA) reduce neuronal excitability by inhibiting voltage-gated Na+ channels. When applied at high concentrations in the direct vicinity of nerves, LAs can also induce relevant irritation and neurotoxicity via mechanisms involving an increase of intracellular Ca2+. In the present study we explored the role of the Ca2+-permeable ion channels TRPA1 and TRPV1 for lidocaine-induced Ca2+-influx, neuropeptide release and neurotoxicity in mouse sensory neurons. METHODS: Cultured dorsal root ganglion (DRG) neurons from wildtype and mutant mice lacking TRPV1, TRPA1 or both channels were explored by means of calcium imaging, whole-cell patch clamp recordings and trypan blue staining for cell death. Release of calcitonin gene-related peptide (CGRP) from isolated mouse peripheral nerves was determined with ELISA. RESULTS: Lidocaine up to 10 mM induced a concentration-dependent reversible increase in intracellular Ca2+ in DRG neurons from wildtype and mutant mice lacking one of the two receptors, but not in neurons lacking both TRPA1 and TRPV1. 30 mM lidocaine also released Ca2+ from intracellular stores, presumably from the endoplasmic reticulum. While 10 mM lidocaine evoked an axonal CGRP release requiring expression of either TRPA1 or TRPV1, CGRP release induced by 30 mM lidocaine again mobilized internal Ca2+ stores. Lidocaine-evoked cell death required neither TRPV1 nor TRPA1. SUMMARY: Depending on the concentration, lidocaine employs TRPV1, TRPA1 and intracellular Ca2+ stores to induce a Ca2+-dependent release of the neuropeptide CGRP. Lidocaine-evoked cell death does not seem to require Ca2+ influx through TRPV1 or TRPV1. PMID- 29141005 TI - Fast, axis-agnostic, dynamically summarized storage and retrieval for mass spectrometry data. AB - Mass spectrometry, a popular technique for elucidating the molecular contents of experimental samples, creates data sets comprised of millions of three dimensional (m/z, retention time, intensity) data points that correspond to the types and quantities of analyzed molecules. Open and commercial MS data formats are arranged by retention time, creating latency when accessing data across multiple m/z. Existing MS storage and retrieval methods have been developed to overcome the limitations of retention time-based data formats, but do not provide certain features such as dynamic summarization and storage and retrieval of point meta-data (such as signal cluster membership), precluding efficient viewing applications and certain data-processing approaches. This manuscript describes MzTree, a spatial database designed to provide real-time storage and retrieval of dynamically summarized standard and augmented MS data with fast performance in both m/z and RT directions. Performance is reported on real data with comparisons against related published retrieval systems. PMID- 29141004 TI - Lack of mitochondrial MutS homolog 1 in Toxoplasma gondii disrupts maintenance and fidelity of mitochondrial DNA and reveals metabolic plasticity. AB - The importance of maintaining the fidelity of the mitochondrial genome is underscored by the presence of various repair pathways within this organelle. Presumably, the repair of mitochondrial DNA would be of particular importance in organisms that possess only a single mitochondrion, like the human pathogens Plasmodium falciparum and Toxoplasma gondii. Understanding the machinery that maintains mitochondrial DNA in these parasites is of particular relevance, as mitochondrial function is a validated and effective target for anti-parasitic drugs. We previously determined that the Toxoplasma MutS homolog TgMSH1 localizes to the mitochondrion. MutS homologs are key components of the nuclear mismatch repair system in mammalian cells, and both yeast and plants possess MutS homologs that localize to the mitochondria where they regulate DNA stability. Here we show that the lack of TgMSH1 results in accumulation of single nucleotide variations in mitochondrial DNA and a reduction in mitochondrial DNA content. Additionally, parasites lacking TgMSH1 function can survive treatment with the cytochrome b inhibitor atovaquone. While the Tgmsh1 knockout strain has several missense mutations in cytochrome b, none affect amino acids known to be determinants of atovaquone sensitivity and atovaquone is still able to inhibit electron transport in the Tgmsh1 mutants. Furthermore, culture of Tgmsh1 mutant in the presence atovaquone leads to parasites with enhanced atovaquone resistance and complete shutdown of respiration. Thus, parasites lacking TgMSH1 overcome the disruption of mitochondrial DNA by adapting their physiology allowing them to forgo the need for oxidative phosphorylation. Consistent with this idea, the Tgmsh1 mutant is resistant to mitochondrial inhibitors with diverse targets and exhibits reduced ability to grow in the absence of glucose. This work shows TgMSH1 as critical for the maintenance and fidelity of the mitochondrial DNA in Toxoplasma, reveals a novel mechanism for atovaquone resistance, and exposes the physiological plasticity of this important human pathogen. PMID- 29141006 TI - The mitochondrial genome of Muga silkworm (Antheraea assamensis) and its comparative analysis with other lepidopteran insects. AB - Muga (Antheraea assamensis) is an economically important silkmoth endemic to the states of Assam and Meghalaya in India and is the producer of the strongest known commercial silk. However, there is a scarcity of genomic and proteomic data for understanding the organism at a molecular level. Our present study is on decoding the complete mitochondrial genome (mitogenome) of A. assamensis using next generation sequencing technology and comparing it with other available lepidopteran mitogenomes. Mitogenome of A. assamensis is an AT rich circular molecule of 15,272 bp (A+T content ~80.2%). It contains 37 genes comprising of 13 protein coding genes (PCGs), 22 tRNA and 2 rRNA genes along with a 328 bp long control region. Its typical tRNAMet-tRNAIle-tRNAGln arrangement differed from ancestral insects (tRNAIle-tRNAGln-tRNAMet). Two PCGs cox1 and cox2 were found to have CGA and GTG as start codons, respectively as reported in some lepidopterans. Interestingly, nad4l gene showed higher transversion mutations at intra-species than inter-species level. All PCGs evolved under strong purifying selection with highest evolutionary rates observed for atp8 gene while lowest for cox1 gene. We observed the typical clover-leaf shaped secondary structures of tRNAs with a few exceptions in case of tRNASer1 and tRNATyr where stable DHU and TPsiC loop were absent. A significant number of mismatches (35) were found to spread over 19 tRNA structures. The control region of mitogenome contained a six bp (CTTAGA/G) deletion atypical of other Antheraea species and lacked tandem repeats. Phylogenetic position of A. assamensis was consistent with the traditional taxonomic classification of Saturniidae. The complete annotated mitogenome is available in GenBank (Accession No. KU379695). To the best of our knowledge, this is the first report on complete mitogenome of A. assamensis. PMID- 29141008 TI - Smartphone-based quantitative measurements on holographic sensors. AB - The research reported herein integrates a generic holographic sensor platform and a smartphone-based colour quantification algorithm in order to standardise and improve the determination of the concentration of analytes of interest. The utility of this approach has been exemplified by analysing the replay colour of the captured image of a holographic pH sensor in near real-time. Personalised image encryption followed by a wavelet-based image compression method were applied to secure the image transfer across a bandwidth-limited network to the cloud. The decrypted and decompressed image was processed through four principal steps: Recognition of the hologram in the image with a complex background using a template-based approach, conversion of device-dependent RGB values to device independent CIEXYZ values using a polynomial model of the camera and computation of the CIEL*a*b* values, use of the colour coordinates of the captured image to segment the image, select the appropriate colour descriptors and, ultimately, locate the region of interest (ROI), i.e. the hologram in this case, and finally, application of a machine learning-based algorithm to correlate the colour coordinates of the ROI to the analyte concentration. Integrating holographic sensors and the colour image processing algorithm potentially offers a cost effective platform for the remote monitoring of analytes in real time in readily accessible body fluids by minimally trained individuals. PMID- 29141007 TI - Escitalopram and NHT normalized stress-induced anhedonia and molecular neuroadaptations in a mouse model of depression. AB - Anhedonia is defined as a diminished ability to obtain pleasure from otherwise positive stimuli. Anxiety and mood disorders have been previously associated with dysregulation of the reward system, with anhedonia as a core element of major depressive disorder (MDD). The aim of the present study was to investigate whether stress-induced anhedonia could be prevented by treatments with escitalopram or novel herbal treatment (NHT) in an animal model of depression. Unpredictable chronic mild stress (UCMS) was administered for 4 weeks on ICR outbred mice. Following stress exposure, animals were randomly assigned to pharmacological treatment groups (i.e., saline, escitalopram or NHT). Treatments were delivered for 3 weeks. Hedonic tone was examined via ethanol and sucrose preferences. Biological indices pertinent to MDD and anhedonia were assessed: namely, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine receptor D2 (Drd2) mRNA expression levels. The results indicate that the UCMS-induced reductions in ethanol or sucrose preferences were normalized by escitalopram or NHT. This implies a resemblance between sucrose and ethanol in their hedonic-eliciting property. On a neurobiological aspect, UCMS-induced reduction in hippocampal BDNF levels was normalized by escitalopram or NHT, while UCMS-induced reduction in striatal Drd2 mRNA levels was normalized solely by NHT. The results accentuate the association of stress and anhedonia, and pinpoint a distinct effect for NHT on striatal Drd2 expression. PMID- 29141009 TI - Evidence for proactive and reactive helping in two- to five-year-olds from a small-scale society. AB - Humans are unique in their propensity for helping. Not only do we help others in need by reacting to their requests, we also help proactively by assisting in the absence of a request. Proactive helping requires the actor to detect the need for help, recognize the intention of the other, and remedy the situation. Very little is known about the development of this social phenomenon beyond an urban, industrialized setting. We examined helping in nineteen two- to five-year old children in small-scale rural villages of Vanuatu. In the experimental condition, the intentions of the experimenter were made salient, whereas in the control condition they were ambiguous. Children helped more often in the experimental compared to the control condition, suggesting that the propensity to monitor others' goals and act accordingly can be detected in different cultural contexts. PMID- 29141010 TI - Multiple effects of toxins isolated from Crotalus durissus terrificus on the hepatitis C virus life cycle. AB - Hepatitis C virus (HCV) is one of the main causes of liver disease and transplantation worldwide. Current therapy is expensive, presents additional side effects and viral resistance has been described. Therefore, studies for developing more efficient antivirals against HCV are needed. Compounds isolated from animal venoms have shown antiviral activity against some viruses such as Dengue virus, Yellow fever virus and Measles virus. In this study, we evaluated the effect of the complex crotoxin (CX) and its subunits crotapotin (CP) and phospholipase A2 (PLA2-CB) isolated from the venom of Crotalus durissus terrificus on HCV life cycle. Huh 7.5 cells were infected with HCVcc JFH-1 strain in the presence or absence of these toxins and virus was titrated by focus formation units assay or by qPCR. Toxins were added to the cells at different time points depending on the stage of virus life cycle to be evaluated. The results showed that treatment with PLA2-CB inhibited HCV entry and replication but no effect on HCV release was observed. CX reduced virus entry and release but not replication. By treating cells with CP, an antiviral effect was observed on HCV release, the only stage inhibited by this compound. Our data demonstrated the multiple antiviral effects of toxins from animal venoms on HCV life cycle. PMID- 29141012 TI - Effects of music therapy and music-based interventions in the treatment of substance use disorders: A systematic review. AB - Music therapy (MT) and music-based interventions (MBIs) are increasingly used for the treatment of substance use disorders (SUD). Previous reviews on the efficacy of MT emphasized the dearth of research evidence for this topic, although various positive effects were identified. Therefore, we conducted a systematic search on published articles examining effects of music, MT and MBIs and found 34 quantitative and six qualitative studies. There was a clear increase in the number of randomized controlled trials (RCTs) during the past few years. We had planned for a meta-analysis, but due to the diversity of the quantitative studies, effect sizes were not computed. Beneficial effects of MT/ MBI on emotional and motivational outcomes, participation, locus of control, and perceived helpfulness were reported, but results were inconsistent across studies. Furthermore, many RCTs focused on effects of single sessions. No published longitudinal trials could be found. The analysis of the qualitative studies revealed four themes: emotional expression, group interaction, development of skills, and improvement of quality of life. Considering these issues for quantitative research, there is a need to examine social and health variables in future studies. In conclusion, due to the heterogeneity of the studies, the efficacy of MT/ MBI in SUD treatment still remains unclear. PMID- 29141011 TI - Nucleotide patterns aiding in prediction of eukaryotic promoters. AB - Computational analysis of promoters is hindered by the complexity of their architecture. In less studied genomes with complex organization, false positive promoter predictions are common. Accurate identification of transcription start sites and core promoter regions remains an unsolved problem. In this paper, we present a comprehensive analysis of genomic features associated with promoters and show that probabilistic integrative algorithms-driven models allow accurate classification of DNA sequence into "promoters" and "non-promoters" even in absence of the full-length cDNA sequences. These models may be built upon the maps of the distributions of sequence polymorphisms, RNA sequencing reads on genomic DNA, methylated nucleotides, transcription factor binding sites, as well as relative frequencies of nucleotides and their combinations. Positional clustering of binding sites shows that the cells of Oryza sativa utilize three distinct classes of transcription factors: those that bind preferentially to the [-500,0] region (188 "promoter-specific" transcription factors), those that bind preferentially to the [0,500] region (282 "5' UTR-specific" TFs), and 207 of the "promiscuous" transcription factors with little or no location preference with respect to TSS. For the most informative motifs, their positional preferences are conserved between dicots and monocots. PMID- 29141013 TI - indCAPS: A tool for designing screening primers for CRISPR/Cas9 mutagenesis events. AB - Genetic manipulation of organisms using CRISPR/Cas9 technology generally produces small insertions/deletions (indels) that can be difficult to detect. Here, we describe a technique to easily and rapidly identify such indels. Sequence identified mutations that alter a restriction enzyme recognition site can be readily distinguished from wild-type alleles using a cleaved amplified polymorphic sequence (CAPS) technique. If a restriction site is created or altered by the mutation such that only one allele contains the restriction site, a polymerase chain reaction (PCR) followed by a restriction digest can be used to distinguish the two alleles. However, in the case of most CRISPR-induced alleles, no such restriction sites are present in the target sequences. In this case, a derived CAPS (dCAPS) approach can be used in which mismatches are purposefully introduced in the oligonucleotide primers to create a restriction site in one, but not both, of the amplified templates. Web-based tools exist to aid dCAPS primer design, but when supplied sequences that include indels, the current tools often fail to suggest appropriate primers. Here, we report the development of a Python-based, species-agnostic web tool, called indCAPS, suitable for the design of PCR primers used in dCAPS assays that is compatible with indels. This tool should have wide utility for screening editing events following CRISPR/Cas9 mutagenesis as well as for identifying specific editing events in a pool of CRISPR-mediated mutagenesis events. This tool was field-tested in a CRISPR mutagenesis experiment targeting a cytokinin receptor (AHK3) in Arabidopsis thaliana. The tool suggested primers that successfully distinguished between wild type and edited alleles of a target locus and facilitated the isolation of two novel ahk3 null alleles. Users can access indCAPS and design PCR primers to employ dCAPS to identify CRISPR/Cas9 alleles at http://indcaps.kieber.cloudapps.unc.edu/. PMID- 29141014 TI - Prevalence and risk factors of anal human papillomavirus infection among HIV negative men who have sex with men in Urumqi city of Xinjiang Uyghur Autonomous Region, China. AB - BACKGROUND: Infection with human papillomavirus (HPV) is the most common sexually transmitted infection among men who have sex with men (MSM). Study on prevalence and risk factors of anal HPV infection among HIV-negative MSM in Northwestern China was rare. METHODS: We performed a cross-sectional study of HPV prevalence using anal swab specimens among HIV-negative MSM in Urumqi city of Xinjiang Uyghur Autonomous Region, China between April 1st and October 30th in 2016. Prevalence of any anal HPV infection, high-risk and low-risk HPV infection was estimated. Risk factors associated with any anal HPV infection was analyzed using univariate and multivariate logistic regression models. RESULTS: Among 538 potential participants, 500(92.9%) were recruited in this study. The genotyping results of anal HPV infection were available for all. Of them, 259 (51.8%), 190 (38.0%) and 141(28.2%) were positive for at least one of the targeted 37 HPV genotypes, high-risk HPV genotypes, and any low-risk HPV genotypes. The most prevalent anal HPV genotype was HPV 6(11.8%), followed by HPV 16(11.2%), HPV 11(10.8%), HPV 51(7.0%) and HPV 18(5.4%).Among those infected with at least one of the targeted 37 anal HPV genotypes, 75(29.0%), 155(59.8%) and 191(73.7%) were infected with 2-valent, quadrivalent and 9-valent HPV vaccine-covered genotypes. Receptive anal intercourse in the past year was the only predictor of any anal HPV infection in multivariate logistic regression model. CONCLUSION: Prevalence of any anal HPV infection and high-risk HPV infection among HIV-negative MSM in Urumqi city of Xinjiang is high. The majority of genotypes detected in our study were covered by quadrivalent and 9-valent HPV vaccines. Regular anal exams and early HPV vaccination among MSM may be considered in future HPV prevention programs in Xinjiang, China. PMID- 29141015 TI - Nematocytes: Discovery and characterization of a novel anculeate hemocyte in Drosophila falleni and Drosophila phalerata. AB - Immune challenges, such as parasitism, can be so pervasive and deleterious that they constitute an existential threat to a species' survival. In response to these ecological pressures, organisms have developed a wide array of novel behavioral, cellular, and molecular adaptations. Research into these immune defenses in model systems has resulted in a revolutionary understanding of evolution and functional biology. As the field has expanded beyond the limited number of model organisms our appreciation of evolutionary innovation and unique biology has widened as well. With this in mind, we have surveyed the hemolymph of several non-model species of Drosophila. Here we identify and describe a novel hemocyte, type-II nematocytes, found in larval stages of numerous Drosophila species. Examined in detail in Drosophila falleni and Drosophila phalerata, we find that these remarkable cells are distinct from previously described hemocytes due to their anucleate state (lacking a nucleus) and unusual morphology. Type-II nematocytes are long, narrow cells with spindle-like projections extending from a cell body with high densities of mitochondria and microtubules, and exhibit the ability to synthesize proteins. These properties are unexpected for enucleated cells, and together with our additional characterization, we demonstrate that these type-II nematocytes represent a biological novelty. Surprisingly, despite the absence of a nucleus, we observe through live cell imaging that these cells remain motile with a highly dynamic cellular shape. Furthermore, these cells demonstrate the ability to form multicellular structures, which we suggest may be a component of the innate immune response to macro-parasites. In addition, live cell imaging points to a large nucleated hemocyte, type-I nematocyte, as the progenitor cell, leading to enucleation through a budding or asymmetrical division process rather than nuclear ejection: This study is the first to report such a process of enucleation. Here we describe these cells in detail for the first time and examine their evolutionary history in Drosophila. PMID- 29141016 TI - Intestinal microbiota profiles associated with low and high residual feed intake in chickens across two geographical locations. AB - Intestinal microbe-host interactions can affect the feed efficiency (FE) of chickens. As inconsistent findings for FE-associated bacterial taxa were reported across studies, the present objective was to identify whether bacterial profiles and predicted metabolic functions that were associated with residual feed intake (RFI) and performance traits in female and male chickens were consistent across two different geographical locations. At six weeks of life, the microbiota in ileal, cecal and fecal samples of low (n = 34) and high (n = 35) RFI chickens were investigated by sequencing the V3-5 region of the 16S rRNA gene. Location associated differences in alpha-diversity and relative abundances of several phyla and genera were detected. RFI-associated bacterial abundances were found at the phylum and genus level, but differed among the three intestinal sites and between males and females. Correlation analysis confirmed that, of the taxonomically classifiable bacteria, Lactobacillus (5% relative abundance) and two Lactobacillus crispatus-OTUs in feces were indicative for high RFI in females (P < 0.05). In males, Ruminococcus in cecal digesta (3.1% relative abundance) and Dorea in feces (<0.1% relative abundance) were best indicative for low RFI, whereas Acinetobacter in feces (<1.5% relative abundance) related to high RFI (P < 0.05). Predicted metabolic functions in feces of males confirmed compositional relationships as functions related to amino acid, fatty acid and vitamin metabolism correlated with low RFI, whereas an increasing abundance of bacterial signaling and interaction (i.e. cellular antigens) genes correlated with high RFI (P < 0.05). In conclusion, RFI-associated bacterial profiles could be identified across different geographical locations. Results indicated that consortia of low abundance taxa in the ileum, ceca and feces may play a role for FE in chickens, whereby only bacterial FE-associations found in ileal and cecal digesta may serve as useful targets for dietary strategies. PMID- 29141017 TI - Temozolomide post pazopanib treatment failure in patients with advanced sarcoma: A case series. AB - BACKGROUND: Sarcomas are rare, heterogeneous tumors for which prognosis remains dismal in patients with advanced disease. Pazopanib, a vascular endothelial growth factor receptor inhibitor, has shown modest efficacy in patients with soft tissue sarcoma who fail cytotoxic chemotherapy. The cytotoxic agent temozolomide has also demonstrated activity in patients with advanced sarcoma. OBJECTIVE: We performed a retrospective case series to evaluate the feasibility of adding temozolomide to pazopanib in advanced sarcoma patients following single-agent pazopanib failure. PATIENTS AND METHODS: Patients with recurrent, metastatic sarcomas who had progressed on single-agent pazopanib and continued on pazopanib with the addition of temozolomide were included in this retrospective analysis to examine the tolerability and responses associated with the treatment combination. RESULTS: Nine patients with a range of sarcoma subtypes were identified (55% female; median age, 48 years; median number of therapies prior to pazopanib, 3). All patients received combination therapy. One patient was recently started on therapy and was excluded from the analysis (n = 8 evaluable patients). Median PFS for single-agent pazopanib was 7.5 months (range 2-19). For the eight evaluable patients (63% female), best response at 4 months with pazopanib plus temozolomide was partial response (n = 1), stable disease (n = 3) and progressive disease (n = 4), with a median PFS of 3.5 months (range 0-15). Median PFS with combination treatment in patients with stable disease or response was 8 months (range 5-15). All four patients who achieved clinical benefit remain on therapy and are tolerating the combination therapy with expected but manageable side effects. CONCLUSIONS: In heavily pretreated patients with advanced sarcoma, the addition of temozolomide to pazopanib was found to be tolerable. Future prospective trials are required to deduce whether temozolomide extends the clinical benefit of pazopanib. PMID- 29141018 TI - Evaluation of the proliferation marker Ki-67 in a large prostatectomy cohort. AB - The tumor proliferation index marker Ki-67 is strongly associated with tumor cell proliferation, growth and progression, and is widely used in routine clinicopathological investigation. Prostate cancer is a complex multifaceted and biologically heterogeneous disease, and overtreatment of localized, low volume indolent tumors, is evident. Here, we aimed to assess Ki-67 expression and related outcomes of 535 patients treated with radical prostatectomy. The percentage of tumor epithelial cells expressing Ki-67 was determined by immunohistochemical assay, both digital image analysis and visual scoring by light microscope were used for quantification. The association of Ki-67 and prostate cancer was evaluated, as well as its prognostic value. There was a positive correlation between high expression of Ki-67 and Gleason score > 7 (p < 0.001) as well as tumor size (>= 20 mm, p = 0.03). In univariate analyses, a high expression of Ki-67 in tumor epithelium was significantly associated with biochemical failure (BF) (digital scoring, p = 0.014) and (visual scoring, p = 0.004). In the multivariate analyses, a high level of Ki-67 was an independent poor prognostic factor for biochemical failure-free survival (BFFS) (Visual scoring, Ki67, p = 0.012, HR:1.50, CI95% 1.10-2.06). In conclusion, high Ki-67 expression is an independent negative prognostic marker for biochemical failure. Our findings support the role of Ki-67 as a significant, poor prognostic factor for in prostate cancer outcome. PMID- 29141019 TI - Exploring the relationship between video game expertise and fluid intelligence. AB - Hundreds of millions of people play intellectually-demanding video games every day. What does individual performance on these games tell us about cognition? Here, we describe two studies that examine the potential link between intelligence and performance in one of the most popular video games genres in the world (Multiplayer Online Battle Arenas: MOBAs). In the first study, we show that performance in the popular MOBA League of Legends' correlates with fluid intelligence as measured under controlled laboratory conditions. In the second study, we also show that the age profile of performance in the two most widely played MOBAs (League of Legends and DOTA II) matches that of raw fluid intelligence. We discuss and extend previous videogame literature on intelligence and videogames and suggest that commercial video games can be useful as 'proxy' tests of cognitive performance at a global population level. PMID- 29141021 TI - Correction: Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006054.]. PMID- 29141020 TI - Genomic analysis of atypical fibroxanthoma. AB - Atypical fibroxanthoma (AFX), is a rare type of skin cancer affecting older individuals with sun damaged skin. Since there is limited genomic information about AFX, our study seeks to improve the understanding of AFX through whole exome and RNA sequencing of 8 matched tumor-normal samples. AFX is a highly mutated malignancy with recurrent mutations in a number of genes, including COL11A1, ERBB4, CSMD3, and FAT1. The majority of mutations identified were UV signature (C>T in dipyrimidines). We observed deletion of chromosomal segments on chr9p and chr13q, including tumor suppressor genes such as KANK1 and CDKN2A, but no gene fusions were found. Gene expression profiling revealed several biological pathways that are upregulated in AFX, including tumor associated macrophage response, GPCR signaling, and epithelial to mesenchymal transition (EMT). To further investigate the presence of EMT in AFX, we conducted a gene expression meta-analysis that incorporated RNA-seq data from dermal fibroblasts and keratinocytes. Ours is the first study to employ high throughput sequencing for molecular profiling of AFX. These data provide valuable insights to inform models of carcinogenesis and additional research towards tumor-directed therapy. PMID- 29141022 TI - Trabecular bone in the calcaneus of runners. AB - Trabecular bone of the human calcaneus is subjected to extreme repetitive forces during endurance running and should adapt in response to this strain. To assess possible bone functional adaptation in the posterior region of the calcaneus, we recruited forefoot-striking runners (n = 6), rearfoot-striking runners (n = 6), and non-runners (n = 6), all males aged 20-41 for this institutionally approved study. Foot strike pattern was confirmed for each runner using a motion capture system. We obtained high resolution peripheral computed tomography scans of the posterior calcaneus for both runners and non-runners. No statistically significant differences were found between runners and nonrunners or forefoot strikers and rearfoot strikers. Mean trabecular thickness and mineral density were greatest in forefoot runners with strong effect sizes (<0.80). Trabecular thickness was positively correlated with weekly running distance (r2 = 0.417, p<0.05) and years running (r2 = 0.339, p<0.05) and negatively correlated with age at onset of running (r2 = 0.515, p<0.01) Trabecular thickness, mineral density and bone volume ratio of nonrunners were highly correlated with body mass (r2 = 0.824, p<0.05) and nonrunners were significantly heavier than runners (p<0.05). Adjusting for body mass revealed significantly thicker trabeculae in the posterior calcaneus of forefoot strikers, likely an artifact of greater running volume and earlier onset of running in this subgroup; thus, individuals with the greatest summative loading stimulus had, after body mass adjustment, the thickest trabeculae. Further study with larger sample sizes is necessary to elucidate the role of footstrike on calcaneal trabecular structure. To our knowledge, intraspecific body mass correlations with measures of trabecular robusticity have not been reported elsewhere. We hypothesize that early adoption of running and years of sustained moderate volume running stimulate bone modeling in trabeculae of the posterior calcaneus. PMID- 29141023 TI - Domestic sheep show average Coxiella burnetii seropositivity generations after a sheep-associated human Q fever outbreak and lack detectable shedding by placental, vaginal, and fecal routes. AB - Coxiella burnetii is a globally distributed zoonotic bacterial pathogen that causes abortions in ruminant livestock. In humans, an influenza-like illness results with the potential for hospitalization, chronic infection, abortion, and fatal endocarditis. Ruminant livestock, particularly small ruminants, are hypothesized to be the primary transmission source to humans. A recent Netherlands outbreak from 2007-2010 traced to dairy goats resulted in over 4,100 human cases with estimated costs of more than 300 million euros. Smaller human Q fever outbreaks of small ruminant origin have occurred in the United States, and characterizing shedding is important to understand the risk of future outbreaks. In this study, we assessed bacterial shedding and seroprevalence in 100 sheep from an Idaho location associated with a 1984 human Q fever outbreak. We observed 5% seropositivity, which was not significantly different from the national average of 2.7% for the U.S. (P>0.05). Furthermore, C. burnetii was not detected by quantitative PCR from placentas, vaginal swabs, or fecal samples. Specifically, a three-target quantitative PCR of placenta identified 0.0% shedding (exact 95% confidence interval: 0.0%-2.9%). While presence of seropositive individuals demonstrates some historical C. burnetii exposure, the placental sample confidence interval suggests 2016 shedding events were rare or absent. The location maintained the flock with little or no depopulation in 1984 and without C. burnetii vaccination during or since 1984. It is not clear how a zero-shedding rate was achieved in these sheep beyond natural immunity, and more work is required to discover and assess possible factors that may contribute towards achieving zero-shedding status. We provide the first U.S. sheep placental C. burnetii shedding update in over 60 years and demonstrate potential for C. burnetii shedding to reach undetectable levels after an outbreak event even in the absence of targeted interventions, such as vaccination. PMID- 29141024 TI - Quantifying indices of short- and long-range white matter connectivity at each cortical vertex. AB - Several neurodevelopmental diseases are characterized by impairments in cortical morphology along with altered white matter connectivity. However, the relationship between these two measures is not yet clear. In this study, we propose a novel methodology to compute and display metrics of white matter connectivity at each cortical point. After co-registering the extremities of the tractography streamlines with the cortical surface, we computed two measures of connectivity at each cortical vertex: the mean tracts' length, and the proportion of short- and long-range connections. The proposed measures were tested in a clinical sample of 62 patients with 22q11.2 deletion syndrome (22q11DS) and 57 typically developing individuals. Using these novel measures, we achieved a fine grained visualization of the white matter connectivity patterns at each vertex of the cortical surface. We observed an intriguing pattern of both increased and decreased short- and long-range connectivity in 22q11DS, that provides novel information about the nature and topology of white matter alterations in the syndrome. We argue that the method presented in this study opens avenues for additional analyses of the relationship between cortical properties and patterns of underlying structural connectivity, which will help clarifying the intrinsic mechanisms that lead to altered brain structure in neurodevelopmental disorders. PMID- 29141025 TI - Suppression of inflammatory and infection responses in lung macrophages by eucalyptus oil and its constituent 1,8-cineole: Role of pattern recognition receptors TREM-1 and NLRP3, the MAP kinase regulator MKP-1, and NFkappaB. AB - Eucalyptus oil (EO) used in traditional medicine continues to prove useful for aroma therapy in respiratory ailments; however, there is a paucity of information on its mechanism of action and active components. In this direction, we investigated EO and its dominant constituent 1,8-cineole (eucalyptol) using the murine lung alveolar macrophage (AM) cell line MH-S. In an LPS-induced AM inflammation model, pre-treatment with EO significantly reduced (P <=0.01or 0.05) the pro-inflammatory mediators TNF-alpha, IL-1 (alpha and beta), and NO, albeit at a variable rate and extent; 1,8-cineole diminished IL-1 and IL-6. In a mycobacterial-infection AM model, EO pre-treatment or post-treatment significantly enhanced (P <=0.01) the phagocytic activity and pathogen clearance. 1,8-cineole also significantly enhanced the pathogen clearance though the phagocytic activity was not significantly altered. EO or 1,8-cineole pre treatment attenuated LPS-induced inflammatory signaling pathways at various levels accompanied by diminished inflammatory response. Among the pattern recognition receptors (PRRs) involved in LPS signaling, the TREM pathway surface receptor (TREM-1) was significantly downregulated. Importantly, the pre treatments significantly downregulated (P <=0.01) the intracellular PRR receptor NLRP3 of the inflammasome, which is consistent with the decrease in IL-1beta secretion. Of the shared downstream signaling cascade for these PRR pathways, there was significant attenuation of phosphorylation of the transcription factor NF-kappaB and p38 (but increased phosphorylation of the other two MAP kinases, ERK1/2 and JNK1/2). 1,8-cineole showed a similar general trend except for an opposite effect on NF-kappaB and JNK1/2. In this context, either pre-treatment caused a significant downregulation of MKP-1 phosphatase, a negative regulator of MAPKs. Collectively, our results demonstrate that the anti-inflammatory activity of EO and 1,8-cineole is modulated via selective downregulation of the PRR pathways, including PRR receptors (TREM-1 and NLRP3) and common downstream signaling cascade partners (NF-kappaB, MAPKs, MKP-1). To our knowledge, this is the first report on the modulatory role of TREM-1 and NLRP3 inflammasome pathways and the MAPK negative regulator MKP-1 in context of the anti-inflammatory potential of EO and its constituent 1,8-cineole. PMID- 29141026 TI - In-depth phenotypic characterization of multicellular tumor spheroids: Effects of 5-Fluorouracil. AB - MultiCellular Tumor Spheroids (MCTS), which mimic the 3-Dimensional (3D) organization of a tumor, are considered as better models than conventional cultures in 2-Dimensions (2D) to study cancer cell biology and to evaluate the response to chemotherapeutic drugs. A real time and quantitative follow-up of MCTS with simple and robust readouts to evaluate drug efficacy is still missing. Here, we evaluate the chemotherapeutic drug 5-Fluorouracil (5-FU) response on the growth and integrity of MCTS two days after treatment of MCTS and for three colorectal carcinoma cell lines with different cohesive properties (HT29, HCT116 and SW480). We found different sensitivity to 5-FU for the three CRC cell lines, ranging from high (SW480), intermediate (HCT116) and low (HT29) and the same hierarchy of CRC cell lines sensitivity is conserved in 2D. We also evidence that 5-FU has a strong impact on spheroid cohesion, with the apparition of a number of single detaching cells from the spheroid in a 5-FU dose- and cell line-dependent manner. We propose an innovative methodology for the chemosensitivity evaluation in 3D MCTS that recapitulates and regionalizes the 5-FU-induced changes within MCTS over time. These robust phenotypic read-outs could be easily scalable for high-throughput drug screening that may include different types of cancer cells to take into account tumor heterogeneity and resistance to treatment. PMID- 29141027 TI - The efficacy of chimeric antigen receptor (CAR) immunotherapy in animal models for solid tumors: A systematic review and meta-analysis. AB - BACKGROUND: Most recently, an emerging theme in the field of tumor immunology predominates: chimeric antigen receptor (CAR) therapy in treating solid tumors. The number of related preclinical trials was surging. However, an evaluation of the effects of preclinical studies remained absent. Hence, a meta-analysis was conducted on the efficacy of CAR in animal models for solid tumors. METHODS: The authors searched PubMed/Medline, Embase, and Google scholar up to April 2017. HR for survival was extracted based on the survival curve. The authors used fixed effect models to combine the results of all the trials. Heterogeneity was assessed by I-square statistic. Quality assessment was conducted following the Stroke Therapy Academic Industry Roundtable standard. Publication bias was assessed using Egger's test. RESULTS: Eleven trials were included, including 54 experiments with a total of 362 animals involved. CAR immunotherapy significantly improved the survival of animals (HR: 0.25, 95% CI: 0.13-0.37, P < 0.001). The quality assessment revealed that no study reported whether allocation concealment and blinded outcome assessment were conducted, and only five studies implemented randomization. CONCLUSIONS: This meta-analysis indicated that CAR therapy may be a potential clinical strategy in treating solid tumors. PMID- 29141028 TI - Developing methods for assessing abundance and distribution of European oysters (Ostrea edulis) using towed video. AB - Due to large-scale habitat losses and increasing pressures, benthic habitats in general, and perhaps oyster beds in particular, are commonly in decline and severely threatened on regional and global scales. Appropriate and cost-efficient methods for mapping and monitoring of the distribution, abundance and quality of remaining oyster populations are fundamental for sustainable management and conservation of these habitats and their associated values. Towed video has emerged as a promising method for surveying benthic communities in a both non destructive and cost-efficient way. Here we examine its use as a tool for quantification and monitoring of oyster populations by (i) analysing how well abundances can be estimated and how living Ostrea edulis individuals can be distinguished from dead ones, (ii) estimating the variability within and among observers as well as the spatial variability at a number of scales, and finally (iii) evaluating the precision of estimated abundances under different scenarios for monitoring. Overall, the results show that the can be used to quantify abundance and occurrence of Ostrea edulis in heterogeneous environments. There was a strong correlation between abundances determined in the field and abundances estimated by video-analyses (r2 = 0.93), even though video analyses underestimated the total abundance of living oysters by 20%. Additionally, the method was largely repeatable within and among observers and revealed no evident bias in identification of living and dead oysters. We also concluded that the spatial variability was an order of magnitude larger than that due to observer errors. Subsequent modelling of precision showed that the total area sampled was the main determinant of precision and provided general method for determining precision. This study provides a thorough validation of the application of towed video on quantitative estimations of live oysters. The results suggest that the method can indeed be very useful for this purpose and we therefor recommend it for future monitoring of oysters and other threatened habitats and species. PMID- 29141029 TI - Correction: The microbiome in urogenital schistosomiasis and induced bladder pathologies. AB - [This corrects the article DOI: 10.1371/journal.pntd.0005826.]. PMID- 29141030 TI - Brain response to luminance-based and motion-based stimulation using inter modulation frequencies. AB - Steady state visual evoked potential (SSVEP)-based brain computer interface (BCI) has advantages of high information transfer rate (ITR), less electrodes and little training. So it has been widely investigated. However, the available stimulus frequencies are limited by brain responses. Simultaneous modulation of stimulus luminance is a novel method to resolve this problem. In this study, three experiments were devised to gain a deeper understanding of the brain response to the stimulation using inter-modulation frequencies. First, luminance based stimulation using one to five inter-modulation frequencies was analyzed for the first time. The characteristics of the brain responses to the proposed stimulation were reported. Second, the motion-based stimulation with equal luminance using inter-modulation frequencies was also proposed for the first time. The response of the brain under these conditions were similar to that of luminance-based stimulation which can induce combination frequencies. And an elementary analysis was conducted to explain the reason of the occurrence of combination frequencies. Finally, the online test demonstrated the efficacy of our proposed two stimulation methods for BCI. The average ITRs reached 34.7836 bits/min and 39.2856 bits/min for luminance-based and motion-based stimulation respectively. This study demonstrated that the simultaneous modulation of stimulus luminance could extend to at least five frequencies to induce SSVEP and the brain response to the stimulus still maintained a certain positive correlation with luminance. And not only luminance-based stimulation, but also motion-based stimulation with equal luminance can elicit inter-modulation frequencies to effectively increase the number of targets for multi-class SSVEP. PMID- 29141031 TI - Developmental patterning of sub-epidermal cells in the outer integument of Arabidopsis seeds. AB - The seed, the reproductive unit of angiosperms, is generally protected by the seed coat. The seed coat is made of one or two integuments, each comprising two epidermal cells layers and, in some cases, extra sub-epidermal cell layers. The thickness of the seed-coat affects several aspects of seed biology such as dormancy, germination and mortality. In Arabidopsis, the inner integument displays one or two sub-epidermal cell layers that originate from periclinal cell divisions of the innermost epidermal cell layer. By contrast, the outer integument was considered to be two-cell layered. Here, we show that sub epidermal chalazal cells grow in between the epidermal outer integument cell layers to create an incomplete three-cell layered outer integument. We found that the MADS box transcription factor TRANSPARENT TESTA 16 represses growth of the chalaza and formation of sub-epidermal outer integument cells. Finally, we demonstrate that sub-epidermal cells of the outer and inner integument respond differently to the repressive mechanism mediated by FERTILIZATION INDEPENDENT SEED Polycomb group proteins and to fertilization signals. Our data suggest that integument cell origin rather than sub-epidermal cell position underlies different responses to fertilization. PMID- 29141032 TI - A qualitative exploration of malaria operational research situation in Nigeria. AB - BACKGROUND: Malaria, remains one of the leading causes of high morbidity and mortality in Nigeria despite implementation of several public health interventions for its control. Operational limitations and methodological gaps have been associated with malaria control interventions and research, and these have necessitated the need for a well-tailored Malaria Operational Research (MOR) agenda. However, there is paucity of evidence-based information on relevant stakeholders' experience, awareness, perceptions and use of MOR and suggestions on setting MOR agenda. As part of a larger study to provide data for national MOR agenda setting, we assessed the MOR research situation from the perspectives of key stakeholders in Nigeria and contribution of MOR to the malaria elimination agenda. METHODS: We conducted key informant interviews among 40 purposively selected stakeholders from the six geo-political zones in Nigeria. Data was collected using a pre-tested key informant interview guide which comprised issues related to experience, awareness, use of MOR and MOR needs, and suggestions for MOR. We conducted a detailed content analysis. RESULTS: Half of the participants had participated in MOR. Participants perceived MOR as important. Only few were aware of existing framework for MOR in Nigeria while above half expressed that MOR is yet to be used to inform policy in Nigeria. Participants identified several MOR needs such as development of improved diagnostic techniques, and interventions for promoting early diagnosis, prompt treatment and quality programmatic data. Participants opined the need for country-specific prioritised MOR agenda that cut across malaria thematic areas including malaria prevention and case management. Participants suggested the involvement of various stakeholders and multi-disciplinary approach in setting MOR. CONCLUSION: Although some stakeholders have been involved in MOR, it is still rarely used to inform policy and several needs exist across thematic areas. A broad-based stakeholder involvement, multi-disciplinary approach to agenda setting and its wide dissemination have been suggested. PMID- 29141033 TI - Transcriptome profiling of claw muscle of the mud crab (Scylla paramamosain) at different fattening stages. AB - In crustaceans, muscle growth and development is complicated, and to date substantial knowledge gaps exist. In this study, the claw muscle, hepatopancreas and nervous tissue of the mud crab (Scylla paramamosain) were collected at three fattening stages for sequence by the Illumina sequencing. A total of 127.87 Gb clean data with no less than 3.94 Gb generated for each sample and the cycleQ30 percentages were more than 86.13% for all samples. De Bruijn assembly of these clean data produced 94,853 unigenes, thereinto, 50,059 unigenes were found in claw muscle. A total of 121 differentially expressed genes (DEGs) were revealed in claw muscle from the three fattening stages with a Padj value < 0.01, including 63 genes with annotation. Functional annotation and enrichment analysis showed that the DEGs clusters represented the predominant gene catalog with roles in biochemical processes (glycolysis, phosphorylation and regulation of transcription), molecular function (ATP binding, 6-phosphofructokinase activity, and sequence-specific DNA binding) and cellular component (6-phosphofructokinase complex, plasma membrane, and integral component of membrane). qRT-PCR was employed to further validate certain DEGs. Single nucleotide polymorphism (SNP) analysis obtained 159,322, 125,963 and 166,279 potential SNPs from the muscle transcriptome at stage B, stage C and stage D, respectively. In addition, there were sixteen neuropeptide transcripts being predicted in the claw muscle. The present study provides a comprehensive transcriptome of claw muscle of S. paramamosain during fattening, providing a basis for screening the functional genes that may affect muscle growth of S. paramamosain. PMID- 29141034 TI - Structure of the human chromosome interaction network. AB - New Hi-C technologies have revealed that chromosomes have a complex network of spatial contacts in the cell nucleus of higher organisms, whose organisation is only partially understood. Here, we investigate the structure of such a network in human GM12878 cells, to derive a large scale picture of nuclear architecture. We find that the intensity of intra-chromosomal interactions is power-law distributed. Inter-chromosomal interactions are two orders of magnitude weaker and exponentially distributed, yet they are not randomly arranged along the genomic sequence. Intra-chromosomal contacts broadly occur between epigenomically homologous regions, whereas inter-chromosomal contacts are especially associated with regions rich in highly expressed genes. Overall, genomic contacts in the nucleus appear to be structured as a network of networks where a set of strongly individual chromosomal units, as envisaged in the 'chromosomal territory' scenario derived from microscopy, interact with each other via on average weaker, yet far from random and functionally important interactions. PMID- 29141035 TI - Influence of boron supplementation on performance, immunity and antioxidant status of lambs fed diets with or without adequate level of calcium. AB - Little is known about biological significance of effects of dietary Boron (B) and Calcium (Ca) interaction on health and production of farm animals. This is a preliminary investigation to evaluate the effects of B supplementation in lambs fed diets with (normal) or without adequate (low) levels of Ca. Twenty-four crossbred ram lambs were randomly distributed into four groups with six animals each in a 2x2 factorial design namely, normal-Ca diet (NCa) and low-Ca diet (LCa) fed without or with 40 ppm B (NCaB-40 and LCaB-40). The lambs were fed paddy straw and hybrid napier hay-based total mixed ration (60 roughage: 40 concentrate) during 180 days experimental period. Compared to control, the LCa diet lowered (P<0.01) average daily gain of lambs, but B-supplementation (LCaB 40) of the same nullified the effect. The lowered (P<0.05) total antioxidant activity and humoral immune response in lambs fed LCa diet were restored (P>0.05) to become at par with the control (NCa) upon supplementation of B (LCaB-40). The mRNA expression of SOD1 was lowered (P<0.05) due to LCa diet feeding which too was normalized on B-supplementation to become at par (P>0.05) with the control (NCa). Further, B-supplementation restored lowered (P<0.05) SOD1 gene expression on LCa diet, but enhanced (P<0.05) that in NCaB-40 group, when compared to the control (NCa) diet fed animals. However, these variations were not reflected in the SOD activity in the erythrocytes. The cell-mediated immune response was higher (P<0.05) in lambs fed LCa and LCaB-40 groups and there was no significant interaction between the levels of either Ca or B in diets with the period of immune response measurement. B- supplementation of LCa diet ameliorated tissue degenerative changes in liver and kidney. It was concluded that feeding LCa diet to lambs resulted in reduced growth rate, total antioxidant activity, humoral immune response along with degenerative changes in liver and kidney tissues, but B-supplementation of such diet restored most of these changes and ameliorated histopathological alterations. PMID- 29141036 TI - The disjunct pattern of the Neotropical harvestman Discocyrtus dilatatus (Gonyleptidae) explained by climate-driven range shifts in the Quaternary: Paleodistributional and molecular evidence. AB - The disjunct distribution of the harvestman Discocyrtus dilatatus (Opiliones, Gonyleptidae) is used as a case study to test the hypothesis of a trans-Chaco Pleistocene paleobridge during range expansion stages. This would have temporarily connected humid regions ('Mesopotamia' in northeastern Argentina, and the 'Yungas' in the northwest, NWA) in the subtropical and temperate South American lowlands. The present study combines two independent approaches: paleodistributional reconstruction, using the Species Distribution Modeling method MaxEnt and projection onto Quaternary paleoclimates (6 kya, 21 kya, 130 kya), and phylogeographic analyses based on the cytochrome oxidase subunit I molecular marker. Models predict a maximal shrinkage during the warm Last Interglacial (130 kya), and the rise of the hypothesized paleobridge in the Last Glacial Maximum (21 kya), revealing that cold-dry stages (not warm-humid ones, as supposed) enabled the range expansion of this species. The disjunction was formed in the mid-Holocene (6 kya) and is intensified under current conditions. The median-joining network shows that NWA haplotypes are peripherally related to different Mesopotamian lineages; haplotypes from Santa Fe and Cordoba Provinces consistently occupy central positions in the network. According to the dated phylogeny, Mesopotamia-NWA expansion events would have occurred in the last glacial period, in many cases closely associated to the Last Glacial Maximum, with most divergence events occurring shortly thereafter. Only two (out of nine) NWA haplotypes are shared with Mesopotamian localities. A single, presumably relictual NWA haplotype was found to have diverged much earlier, suggesting an ancient expansion event not recoverable by the paleodistributional models. Different measures of sequence statistics, genetic diversity, population structure and history of demographic changes are provided. This research offers the first available evidence for the historical origin of NWA disjunct populations of a Mesopotamian harvestman. PMID- 29141037 TI - eDNA for detection of five highly invasive molluscs. A case study in urban rivers from the Iberian Peninsula. AB - Biological invasions are an important threat to biodiversity especially in aquatic ecosystems, and their frequency is generally higher near urban areas. Potentially invasive non-indigenous molluscs were deliberately introduced into European waters for food (Corbicula fluminea) and biocontrol (Melanoides tuberculata), and unintentionally introduced by ballast water (Mytilopsis leucophaeata, Corbicula fluminea), stock contamination (Sinanodonta woodiana), accidental escapes from aquaculture (Sinanodonta woodiana), aquarium trade releases (Melanoides tuberculata) and even attached to aquatic birds (Corbicula fluminea). Three rivers from the Iberian Peninsula were monitored near the three most populated inland cities to evaluate the presence of these invasive molluscs through PCR amplification using taxon-specific primers from eDNA. New primers were designed within 16S rRNA and cytochrome oxidase subunit I genes, tested in silico from BLAST methodology and experimentally in vitro before application in the field. C. fluminea was found in Ebro River (near Zaragoza); M. leucophaeata in Guadalquivir River (near Sevilla). M. tuberculata and S. woodiana were found from enclosed areas (lake and reservoir respectively) upstream, respectively, Zaragoza and Madrid. The new tools are ready to be used in other regions where these species are also invasive. PMID- 29141039 TI - Identification of isolates of the plant pathogen Leptosphaeria maculans with resistance to the triazole fungicide fluquinconazole using a novel In Planta assay. AB - Leptosphaeria maculans is the major pathogen of canola (oilseed rape, Brassica napus) worldwide. In Australia, the use of azole fungicides has contributed to the 50-fold increase in canola production in the last 25 years. However, extensive application of fungicides sets the stage for the selection of fungal populations with resistance. A high-throughput in planta assay was developed to allow screening of thousands of isolates from multiple populations. Using this screen, isolates were identified with decreased sensitivity to the fungicide fluquinconazole when applied at field rates as a protective seed dressing: these isolates cause significantly larger lesions on cotyledons and true leaves and increased disease severity at plant maturity. This increased in planta resistance was specific to fluquinconazole, with no cross resistance to flutriafol or tebuconazole/prothioconazole. In a limited set of 22 progeny from a cross between resistant and susceptible parents, resistance segregated in a 1:1 ratio, suggesting a single gene is responsible. A survey of 200 populations from across canola growing regions of Australia revealed fungicide resistance was present in 15% of the populations. Although in vitro analysis of the fungicide resistant isolates showed a significant shift in the average EC50 compared to the sensitive isolates, this was not as evident as the in planta assays. The development of this novel, high-throughput in planta assay has led to the identification of the first fungicide resistant L. maculans isolates, which may pose a threat to the productivity of the Australian canola industry. PMID- 29141038 TI - Depot-specific inflammation with decreased expression of ATM2 in white adipose tissues induced by high-margarine/lard intake. AB - A high-fat diet has been recognized as an important risk factor of obesity, with variable impacts of different fatty acid compositions on the physiological process. To understand the effects of a high-margarine/lard diet, which is a major source of trans fatty acids (TFAs)/ saturated fatty acids (SFAs), elaidic acid as a biomarker of margarine intake was used to screen affected adipokines on mature human adipocytes in vitro. Weaned male Wistar rats were fed a high-fat diet enriched with margarine/lard to generate obesity-prone (OP) and obesity resistant (OR) models, which were then used to explore the inflammatory responses of depot-specific white adipose tissue. Adiposity, glucose and lipid metabolism parameters and macrophage cell markers were also compared in vivo. In the subcutaneous depot, a high-margarine diet induced elevated IL-6, MCP-1 and XCL1 expression levels in both M-OP and M-OR groups. High-lard diet-fed rats displayed higher protein expression levels of MCP-1 and XCL1 compared with the control group. In the epididymal depot, significantly elevated IL-6 production was observed in M-OP rats, and high-lard diet-fed rats displayed elevated IL-6 and decreased XCL1 expression. In the retroperitoneal depot, a high-margarine diet caused higher IL-6 and MCP-1 expression levels, a high-lard diet caused elevated IL-6 expression in L-OP/L-OR rats, and elevated XCL1 expression was observed only in L-OP rats. In general, CD206 mRNA levels were notably down-regulated by high fat diet feeding in the above-mentioned depots. CD11c mRNA levels were slightly upregulated in the subcutaneous depot of OP rats fed a high-margarine/lard diet. In the epidydimal depot, higher expression levels of F4/80 and CD206 mRNA were observed only in high-margarine diet-fed OP rats. These results suggest that depot-specific inflammation with decreased expression of adipose tissue anti inflammatory M2-type (ATM2) macrophages could be induced by high-margarine/lard intake. PMID- 29141040 TI - Medical therapy versus radiofrequency endometrial ablation in the initial treatment of heavy menstrual bleeding (iTOM Trial): A clinical and economic analysis. AB - BACKGROUND: Radiofrequency endometrial ablation (REA) is currently a second line treatment in women with heavy menstrual bleeding (MHB) if medical therapy (MTP) is contraindicated or unsatisfactory. Our objective is to compare the effectiveness and cost burden of MTP and REA in the initial treatment of HMB. METHODS: We performed a randomized trial at Mayo Clinic Rochester, Minnesota. The planned sample size was 60 patients per arm. A total of 67 women with HMB were randomly allocated to receive oral contraceptive pills (Nordette (r)) or Naproxen (Naprosyn(r)) (n = 33) or REA (n = 34). Primary 12-month outcome measures included menstrual blood loss using pictorial blood loss assessment chart (PBLAC), patients' satisfaction, and Menorrhagia Multi-Attribute Scale (MMAS). Secondary outcomes were total costs including direct medical and indirect costs associated with healthcare use, patient out-of-pocket costs, and lost work days and activity limitations over 12 months. RESULTS: Compared to MTP arm, women who received REA had a significantly lower PBLAC score (median [Interquartile range, IQR]: 0 [0-4] vs. 15 [0-131], p = 0.003), higher satisfaction rates (96.8%vs.63.2%, p = 0.003) and higher MMAS (median [IQR]: 100 [100-100] vs. 100 [87-100], p = 0.12) at 12 months. Direct medical costs were higher for REA ($5,331vs.$2,901, 95% confidence interval (CI) of mean difference:$727,$4,852), however, when indirect costs are included, the difference did not reach statistical significance ($5,469 vs. $3,869, 95% CI of mean difference:-$339, $4,089). CONCLUSION: For women with heavy menstrual bleeding, initial radiofrequency endometrial ablation compared to medical therapy offered superior reduction in menstrual blood loss and improvement in quality of life without significant differences in total costs of care. CLINICAL TRIAL REGISTRATION: NCT01165307. PMID- 29141041 TI - Effects of a mixed berry beverage on cognitive functions and cardiometabolic risk markers; A randomized cross-over study in healthy older adults. AB - BACKGROUND: Berries and associated bioactive compounds, e.g. polyphenols and dietary fibre (DF), may have beneficial implications with respect to the metabolic syndrome, including also cognitive functions. The aim of this study was to evaluate effects on cognitive functions and cardiometabolic risk markers of 5 wk intervention with a mixture of berries, in healthy humans. METHODS: Forty healthy subjects between 50-70 years old were provided a berry beverage based on a mixture of berries (150g blueberries, 50g blackcurrant, 50g elderberry, 50g lingonberries, 50g strawberry, and 100g tomatoes) or a control beverage, daily during 5 weeks in a randomized crossover design. The control beverage (water based) was matched with respect to monosaccharides, pH, and volume. Cognitive tests included tests of working memory capacity, selective attention, and psychomotor reaction time. Cardiometabolic test variables investigated were blood pressure, fasting blood concentrations of glucose, insulin, blood lipids, inflammatory markers, and markers of oxidative stress. RESULTS: The daily amounts of total polyphenols and DF from the berry beverage were 795 mg and 11g, respectively. There were no polyphenols or DF in the control beverage. The berry intervention reduced total- and LDL cholesterol compared to baseline (both P<0.05), and in comparison to the control beverage (P<0.005 and P<0.01, respectively). The control beverage increased glucose concentrations (P<0.01) and tended to increase insulin concentrations (P = 0.064) from base line, and increased insulin concentrations in comparison to the berry beverage (P<0.05). Subjects performed better in the working memory test after the berry beverage compared to after the control beverage (P<0.05). No significant effects on the other test variables were observed. CONCLUSIONS: The improvements in cardiometabolic risk markers and cognitive performance after the berry beverage suggest preventive potential of berries with respect to type 2 diabetes, cardiovascular disease, and associated cognitive decline. Possibly the polyphenols and DF contributed to the beneficial effects. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01562392. PMID- 29141042 TI - A tissue microRNA signature that predicts the prognosis of breast cancer in young women. AB - Since breast cancers in young women are generally aggressive, young patients tend to be intensively treated with anti-cancer drugs. To optimize the strategy for treatment, particularly in young women, prognostic biomarkers are urgently required. The objective of this study was to identify a tissue microRNA (miRNA) signature that predicts prognosis in young breast cancer patients. Total RNA from 45 breast cancer patients aged <35 years was extracted from formalin-fixed paraffin-embedded (FFPE) tissues and analyzed using miRNA microarrays. Patients were categorized into two groups according to recurrence status within the 5 year period after surgery: recurrence (n = 11) and non-recurrent (n = 34). Histological parameters of hormone receptors and Ki-67 were statistically compared between the two groups. Differentially expressed miRNAs were identified, and their associations with overall survival (OS) were evaluated by log-rank test. The median observation period was 5.8 years for the recurrent group, and 9.1 years for the non-recurrent group. Nine miRNAs were significantly differentially expressed between the recurrent and non-recurrent groups. Receiver Operating Characteristic curve analysis was performed to evaluate the prediction accuracy of the identified miRNAs, and the resultant area under the curve was >0.7. Five of the miRNAs were validated by qRT-PCR, and the expression levels of three of those five (miR-183-5p, miR-194-5p, and miR-1285-5p), both alone and in combination, were associated with OS. In conclusion, we identified three candidate miRNAs that could be used separately or in combination as prognostic biomarkers in young breast cancer patients. This miRNA signature may enable selection of better treatment choices for young women with this disease. PMID- 29141043 TI - Lateral migration of electrospun hydrogel nanofilaments in an oscillatory flow. AB - The recent progress in bioengineering has created great interest in the dynamics and manipulation of long, deformable macromolecules interacting with fluid flow. We report experimental data on the cross-flow migration, bending, and buckling of extremely deformable hydrogel nanofilaments conveyed by an oscillatory flow into a microchannel. The changes in migration velocity and filament orientation are related to the flow velocity and the filament's initial position, deformation, and length. The observed migration dynamics of hydrogel filaments qualitatively confirms the validity of the previously developed worm-like bead-chain hydrodynamic model. The experimental data collected may help to verify the role of hydrodynamic interactions in molecular simulations of long molecular chains dynamics. PMID- 29141044 TI - High-dimensional linear state space models for dynamic microbial interaction networks. AB - Medical researchers are increasingly interested in knowing how the complex community of micro-organisms living on human body impacts human health. Key to this is to understand how the microbes interact with each other. Time-course studies on human microbiome indicate that the composition of microbiome changes over short time periods, primarily as a consequence of synergistic and antagonistic interactions of the members of the microbiome with each other and with the environment. Knowledge of the abundance of bacteria-which are the predominant members of the human microbiome-in such time-course studies along with appropriate mathematical models will allow us to identify key dynamic interaction networks within the microbiome. However, the high-dimensional nature of these data poses significant challenges to the development of such mathematical models. We propose a high-dimensional linear State Space Model (SSM) with a new Expectation-Regularization-Maximization (ERM) algorithm to construct a dynamic Microbial Interaction Network (MIN). System noise and measurement noise can be separately specified through SSMs. In order to deal with the problem of high-dimensional parameter space in the SSMs, the proposed new ERM algorithm employs the idea of the adaptive LASSO-based variable selection method so that the sparsity property of MINs can be preserved. We performed simulation studies to evaluate the proposed ERM algorithm for variable selection. The proposed method is applied to identify the dynamic MIN from a time-course vaginal microbiome study of women. This method is amenable to future developments, which may include interactions between microbes and the environment. PMID- 29141045 TI - CSF in the ventricles of the brain behaves as a relay medium for arteriovenous pulse wave phase coupling. AB - The ventricles of the brain remain perhaps the largest anatomic structure in the human body without established primary purpose, even though their existence has been known at least since described by Aristotle. We hypothesize that the ventricles help match a stroke volume of arterial blood that arrives into the rigid cranium with an equivalent volume of ejected venous blood by spatially configuring cerebrospinal fluid (CSF) to act as a low viscosity relay medium for arteriovenous pulse wave (PW) phase coupling. We probe the hypothesis by comparing the spatiotemporal behavior of vascular PW about the ventricular surfaces in piglets to internal observations of ventricle wall motions and adjacent CSF pressure variations in humans. With wavelet brain angiography data obtained from piglets, we map the travel relative to brain pulse motion of arterial and venous PWs over the ventricle surfaces. We find that arterial PWs differ in CF phase from venous PWs over the surfaces of the ventricles consistent with arteriovenous PW phase coupling. We find a spatiotemporal difference in vascular PW phase between the ventral and dorsal ventricular surfaces, with the PWs arriving slightly sooner to the ventral surfaces. In humans undergoing neuroendoscopic surgery for hydrocephalus, we measure directly ventricle wall motions and the adjacent internal CSF pressure variations. We find that CSF pressure peaks slightly earlier in the ventral Third Ventricle than the dorsal Lateral Ventricle. When matched anatomically, the peri-ventricular vascular PW phase distribution in piglets complements the endo-ventricular CSF PW phase distribution in humans. This is consistent with a role for the ventricles in arteriovenous PW coupling and may add a framework for understanding hydrocephalus and other disturbances of intracranial pressure. PMID- 29141046 TI - The effect of observing novice and expert performance on acquisition of surgical skills on a robotic platform. AB - BACKGROUND: Observational learning plays an important role in surgical skills training, following the traditional model of learning from expertise. Recent findings have, however, highlighted the benefit of observing not only expert performance but also error-strewn performance. The aim of this study was to determine which model (novice vs. expert) would lead to the greatest benefits when learning robotically assisted surgical skills. METHODS: 120 medical students with no prior experience of robotically-assisted surgery completed a ring carrying training task on three occasions; baseline, post-intervention and at one week follow-up. The observation intervention consisted of a video model performing the ring-carrying task, with participants randomly assigned to view an expert model, a novice model, a mixed expert/novice model or no observation (control group). Participants were assessed for task performance and surgical instrument control. RESULTS: There were significant group differences post intervention, with expert and novice observation groups outperforming the control group, but there were no clear group differences at a retention test one week later. There was no difference in performance between the expert-observing and error-observing groups. CONCLUSIONS: Similar benefits were found when observing the traditional expert model or the error-strewn model, suggesting that viewing poor performance may be as beneficial as viewing expertise in the early acquisition of robotic surgical skills. Further work is required to understand, then inform, the optimal curriculum design when utilising observational learning in surgical training. PMID- 29141047 TI - Is species richness driving intra- and interspecific interactions and temporal activity overlap of a hantavirus host? An experimental test. AB - High species diversity of the potential animal host community for a zoonotic pathogen may reduce pathogen transmission among the most competent host, a phenomenon called the "dilution effect", but the mechanisms driving this effect have been little studied. One proposed mechanism is "encounter reduction" where host species of low-competency decrease contact rates between infected and susceptible competent hosts, especially in directly transmitted diseases. We conducted an experiment in outdoor enclosures in northwestern Mexico where we manipulated rodent assemblages to assess the effect of species richness on the frequency of intra- and interspecific interactions and activity patterns of a hantavirus reservoir host (North American deermouse; Peromyscus maniculatus). Trials consisted of three treatments of rodent assemblages that differed in species richness, but had equal abundance of deermice; treatment 1 consisted of only deermice, treatment 2 included deermice and one non-competent host species, and treatment 3 included two non-competent host species in addition to deermice. To measure interactions and temporal activity, we strategically deployed foraging stations and infrared cameras. We did not find differences in the frequency of intraspecific interactions of deermice among treatments, but there were significantly more interspecific interactions between deermouse and non-competent hosts in treatment 2 than treatment 3, which is explained by the identity of the non-competent host species. In addition, there were differences in activity patterns between rodent species, and also between deermice from treatment 1 and treatment 2. These results indicate that at least at a small-scale analysis, the co-occurrence with other species in the study area does not influence the frequency of intraspecific interactions of deermice, and that deermice may be changing their activity patterns to avoid a particular non-competent host species (Dipodomys merriami). In conclusion, in this deermouse-hantavirus system a potential dilution effect would not be through intraspecific encounter reduction in the most competent hantavirus host. To identify variables of host assemblages that can influence pathogen transmission, we highlight the need to address the identity of species and the composition of assemblages, not only host species richness or diversity. PMID- 29141048 TI - Microcirculation in open vs. minimally invasive dorsal stabilization of thoracolumbar fractures. AB - Standard open and percutaneous minimally invasive surgical procedures co-exist in the treatment of fractures of the thoracolumbar spine. Shorter skin incisions just above the pedicles are used in minimally invasive procedures. Full-length skin incisions and invasive preparations are applied in the standard open approach. While both methods show equivalent rates of intraoperative surgical complications and comparable clinical and radiological outcomes, blood loss and operation time have shown to be decreased in minimally invasive treatment. However, no study so far has investigated differences in microcirculation. This study hypothesized less impairment of microcirculation in the minimally invasive approach compared to the open approach and an improvement of microcirculation over time. A prospective cohort study was conducted using non-invasive laser Doppler spectrophotometry (an O2C "oxygen to see" device) for measurement of cutaneous and subcutaneous blood oxygenation (SO2), haemoglobin concentration (Hb), and blood flow at depths of 2, 8, and 15 mm at six locations on the skin. Measurements were performed before surgery, 8 and 24 h after surgery, and 2, 4, 7, 12 and 20 days after surgery, however the number of patients measured decreased towards the later time points. Forty patients were included in the study, 20 with each approach (18 females and 22 males). Pair-wise comparison of the types of surgical procedure for each measurement point revealed a significantly higher flow value in the minimally invasive group at one of the measurement points located between the incisions (P = .041). The point-wise analyses of SO2 and Hb did not show significant differences between the approaches. In conclusion, significantly albeit moderately higher flow values could be found in minimally invasive procedures compared to open operations of thoracolumbar fractures in the area of skin that is spared by the incisions. PMID- 29141049 TI - Prognostic value of pretreatment serum carbohydrate antigen 19-9 level in patients with colorectal cancer: A meta-analysis. AB - BACKGROUND: Carbohydrate antigen 19-9 (CA 19-9) is one of the most frequently used tumor markers for gastrointestinal cancer, particularly for diagnostic purposes. However, its value in predicting prognosis remains controversial. In this study, we sought to clarify this by conducting a meta-analysis of relevant studies. METHODS: We systematically searched several databases, including PubMed, EMBASE and Web of Science for articles pertaining to the relationship between pretreatment serum CA 19-9 levels and prognosis in patients with colorectal cancer (CRC). The reported hazard ratios (HR) of overall survival (OS), disease free survival (DFS), pooled progression-free survival (PFS) and recurrence-free survival (RFS) in the analyzed studies were compared by fixed effects/random effects models. RESULTS: Seventeen studies involving 6434 patients with CRC were included in our meta-analysis. A comprehensive analysis of the collected data revealed that high serum CA 19-9 levels before treatment were significantly associated with poor OS (HR: 1.58, 95% CI: 1.36-1.83, P<0.001), DFS (HR: 1.71, 95% CI: 1.38-2.13, P<0.001), PFS (HR: 1.30,95%CI:0.93-1.82, P = 0.121) and RFS (HR: 1.43, 95% CI: 1.11-1.83, P = 0.006). This association between high pretreatment serum CA 19-9 levels and poor survival held true across different geographical regions, analysis types, methods used for HR determination, sample size, and treatment methods. CONCLUSIONS: The results of this study indicate that pretreatment serum CA 19-9 level can be used as a prognostic indicator for patients with CRC. PMID- 29141050 TI - Differential immunomodulation in human monocytes versus macrophages by filarial cystatin. AB - Parasitic nematodes have evolved powerful immunomodulatory molecules to enable their survival in immunocompetent hosts by subverting immune responses and minimizing pathological processes. One filarial molecule known to counteract host immune responses by inducing IL-10 and regulatory macrophages in mice is filarial cystatin. During a patent filarial infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive. The microfilarial larval stage was formerly shown to induce human regulatory monocytes and macrophages. Thus, here we aim was to determine how filarial cystatin of the human pathogenic filaria Brugia malayi (BmCPI-2) contributes to immune hyporesponsiveness in human monocytes and macrophages elicited by microfilaria. For this purpose, filarial cystatin was depleted from microfilarial lysate (Mf). Detecting the immunomodulatory potential of cystatin-depleted Mf revealed that IL-10, but not IL-8 and IL-6 induction in monocytes and macrophages is dependent on the presence of cystatin. In addition, the Mf-induced expression of the regulatory surface markers PD-L1 and PD-L2 in human monocytes, but not in macrophages, is dependent on cystatin. While Mf-treated monocytes result in decreased CD4+ T-cell proliferation in a co-culture assay, stimulation of T-cells with human monocytes treated with cystatin-depleted Mf lead to a restoration of CD4+ T-cell proliferation. Moreover, IL-10 induction by cystatin within Mf was dependent on p38 and ERK in macrophages, but independent of the ERK pathway in monocytes. These findings indicate that filarial nematodes differentially trigger and exploit various signaling pathways to induce immunomodulation in different myeloid cell subsets. PMID- 29141052 TI - Association between urinary manganese and blood pressure: Results from National Health and Nutrition Examination Survey (NHANES), 2011-2014. AB - Manganese is a trace mineral required for metabolism, growth and tissue formation, and reproduction. It is mainly obtained through food and water, as well as through occupational exposure. This study used data from National Health and Nutrition Examination Survey, combining the 2011-12 and 2013-14 cycles. We conducted linear regression analyses on urinary manganese and blood pressure. Significant negative associations (p<0.01) between urinary manganese and both systolic and diastolic blood pressure existed after adjusting for age, sex, body mass index, race/ethnicity, and status of taking antihypertensive medication. These results indicate that urinary manganese may play some role in blood pressure and protecting against hypertension, a major risk factor for cardiovascular disease. PMID- 29141051 TI - Molecular and epidemiological characterization of carbapenemase-producing Enterobacteriaceae in Norway, 2007 to 2014. AB - The prevalence of carbapenemase-producing Enterobacteriaceae (CPE) is increasing worldwide. Here we present associated patient data and molecular, epidemiological and phenotypic characteristics of all CPE isolates in Norway from 2007 to 2014 confirmed at the Norwegian National Advisory Unit on Detection of Antimicrobial Resistance. All confirmed CPE isolates were characterized pheno- and genotypically, including by whole genome sequencing (WGS). Patient data were reviewed retrospectively. In total 59 CPE isolates were identified from 53 patients. Urine was the dominant clinical sample source (37%) and only 15% of the isolates were obtained from faecal screening. The majority of cases (62%) were directly associated with travel or hospitalization abroad, but both intra hospital transmission and one inter-hospital outbreak were observed. The number of CPE cases/year was low (2-14 cases/year), but an increasing trend was observed. Klebsiella spp. (n = 38) and E. coli (n = 14) were the dominant species and blaKPC (n = 20), blaNDM (n = 19), blaOXA-48-like (n = 12) and blaVIM (n = 7) were the dominant carbapenemase gene families. The CPE isolates were genetically diverse except for K. pneumoniae where clonal group 258 associated with blaKPC dominated. All isolates were multidrug-resistant and a significant proportion (21%) were resistant to colistin. Interestingly, all blaOXA-48-like, and a large proportion of blaNDM-positive Klebsiella spp. (89%) and E. coli (83%) isolates were susceptible in vitro to mecillinam. Thus, mecillinam could have a role in the treatment of uncomplicated urinary tract infections caused by OXA-48- or NDM producing E. coli or K. pneumoniae. In conclusion, the impact of CPE in Norway is still limited and mainly associated with travel abroad, reflected in the diversity of clones and carbapenemase genes. PMID- 29141053 TI - Clinical and prognostic value of hTERT mRNA expression in patients with non-small cell lung cancer. AB - Telomerase, undetectable in normal somatic cells, plays a critical role in carcinogenesis of the majority of human tumors including lung carcinoma. The aim of our study was to determine human telomerase reverse transcriptase (hTERT) mRNA expression in patients with non-small cell lung cancer (NSCLC) in order to estimate its usefulness as diagnostic and/or prognostic factor. hTERT expression was analyzed in a group of 12 females and 28 males with NSCLC using Quantitative Real-Time Polymerase Chain Reaction (QRT-PCR method) in cancerous and non cancerous lung tissues. Results were analyzed according to clinical data and one , two-, and five-year survival rates. hTERT expression in the cancerous tissue was significantly higher than in the lung parenchyma free from neoplasm infiltration (p<0.05). There was no significant association between hTERT expression in the tumor tissue and age, gender, grading or clinical stage. A significant difference in hTERT expression between two types of histopathological patterns (adenocarcinoma and squamous cell carcinoma) was detected (p=0.01). No association between hTERT expression in NSCLC specimens and survival rates was found. hTERT mRNA detection by QRT-PCR in tumor and corresponding cancer-free tissues can be used as a diagnostic marker in patients with NSCLC, but seems not to be a prognostic factor. PMID- 29141054 TI - Managing Seborrheic Keratoses: Evolving Strategies for Optimizing Patient Outcomes. AB -

The seborrheic keratosis is the most common benign skin tumor of middle-aged and elderly adults, affecting nearly 83 million individuals in the US alone. Although these are benign lesions, many patients still undergo some form of treatment. Clinicians are frequently presented with a challenge when determining whether to remove a seborrheic keratosis, and which treatment modality to use when doing so. The most commonly used method of removal is cryotherapy, however there are numerous other options that can be employed with varying degrees of efficacy. In this article, we highlight the use of topical keratolytics, vitamin D analogues, and lasers, to name a few. We also address potential side effects associated with these treatment options, as well as discuss patients' preferences and concerns. We conclude with the most recent advances in topical treatments currently under clinical investigation, and offer treatment strategies aimed at maximizing patient satisfaction.

J Drugs Dermatol. 2017;16(11):1064 1068.

. PMID- 29141055 TI - Treatment of Photoaging With a Dual-Wavelength, 532 nm and 1,064 nm Picosecond Domain Laser Producing a Fractionated Treatment Beam Using a Holographic Optic. AB - :

BACKGROUND: A dual-wavelength, picosecond-domain, fractionated laser delivering 1,064nm and 532nm laser energy through a holographic optic was investigated for safety and effectiveness at improving the appearance of chronic photoaging. MATERIALS AND METHODS: A total of 27 subjects were enrolled with 24 completing the study, and 14 subjects were treated with 1,064 nm and 10 with 532 nm. The 1,064 nm-treated subjects received 5 monthly treatments while the 532 nm treated subjects received 4 monthly treatments. Improvement was measured by blinded evaluation of pre- and post-treatment images 12 weeks following the final treatment. Subjects also evaluated treatment effect and side-effects. RESULTS: Blinded reviewers correctly identified the baseline image in 52 of 72 paired images, or 72% of the time, with a mean improvement score of 1.4 using an 11 point rating scale (P less than 0.0001). Post-treatment erythema, mild edema, and petechiae were the only side effects noted. CONCLUSION: The fractionated, picosecond-domain, 532 nm and 1,064 nm laser is safe and effective for improvement of facial photodamage. The laser was well tolerated with mild erythema, edema, and petechiae as the most common side-effects.

J Drugs Dermatol. 2017;16(11):1077-1082.

. PMID- 29141056 TI - In-Vivo Histological Analysis of a Fractional CO2 Laser System Intended for Treatment of Soft Tissue. AB - :

BACKGROUND: Fractional ablative lasers have been shown to be safe and effective for improving wrinkles, scars, skin texture, and dyspigmentation. However, the exact effects of this technology in vivo on epidermal and dermal skin constituents have not been delineated. This study evaluated the in vivo histological effects over time of treatment with a fractional ablative CO2 system, using different treatment parameters. MATERIALS AND METHODS: Healthy adult volunteers were enrolled in this multicenter clinical study. Study participants, previously scheduled for abdominoplasty, received fractional CO2 laser treatment on the abdomen at a predetermined time prior to surgery. Biopsies were taken at baseline and after CO2 treatment. Morphological and morphometric analyses were performed in the ablated and coagulated tissue areas. RESULTS: Nine healthy adult volunteers were treated. Histologic evaluation showed 800-900 micron diameter zones of ablation and coagulation confined to the upper most layer of the skin in the mode with the greatest fractional skin coverage using Light Mode 30 - 50% (spot diameter of 150 microns, 30-60 millijoules fluence), while ablation to levels of up to 900 microns in depth using the Deep Mode (spot diameter 150 microns, 50-80 millijoules). Healing times of treated tissue varied from 1-day post-treatment with the Light Mode, and up to 10 days post-treatment with the Deep Mode. No remnants of ablation or coagulation were seen after 30 days post CO2 treatment with either mode. There were no adverse events associated with treatments. CONCLUSION: Treatment of the skin using the fractional CO2 device leads to skin resurfacing via ablation and coagulation of the treated area at a depth proportional to the delivered energy. The higher the energy used, the greater the degree of ablation and coagulation in tissue, which can lead to a greater tissue response in terms of fibroblast activity, collagen remodeling, and new collagen formation.

J Drugs Dermatol. 2017;16(11):1085 1090.

. PMID- 29141057 TI - Lasers, Light, and the Treatment of Acne: A Comprehensive Review of the Literature. AB - INTRODUCTION: Acne vulgaris is common dermatologic condition with an estimated prevalence of 70 to 87%. Acne has been shown to have a significant impact on patient quality of life and mental health, especially as inflammatory lesions typically occur on cosmetically sensitive areas with the potential for permanent scarring. There have been numerous advances in the treatment of inflammatory acne with light-based and laser devices. OBJECTIVE: To review the current evidence for light-based and laser treatments in the management of inflammatory acne. METHODS: An analysis was conducted of PubMed indexed English language literature regarding management of inflammatory acne using light-based and laser treatments. RESULTS: Evidence for the utilization of laser and light-based therapy for acne was summarized in a comprehensive review. Laser and light-based treatment holds the advantages of improved patient compliance and safety profiles in comparison to pharmacologic therapy. Efficacy of device based treatment varied in comparison to standard topical treatment regimens, often more effective when used in combination therapy. Adverse effects reported were generally self-limited. DISCUSSION: These treatments do and will continue to play an important and enlarging role in the management of acne. Larger scale studies with standardization of treatment protocols are warranted.

J Drugs Dermatol. 2017;16(11):1095-1102.

. PMID- 29141058 TI - Disparity in Cutaneous Pigmentary Response to LED vs Halogen Incandescent Visible Light: Results from a Single Center, Investigational Clinical Trial Determining a Minimal Pigmentary Visible Light Dose. AB - :

Background: While most of the attention regarding skin pigmentation has focused on the effects of ultraviolet radiation, the cutaneous effects of visible light (400 to 700nm) are rarely reported. OBJECTIVE: The purpose of this study was to investigate the cutaneous pigmentary response to pure visible light irradiation, examine the difference in response to different sources of visible light irradiation, and determine a minimal pigmentary dose of visible light irradiation in melanocompetent subjects with Fitzpatrick skin type III - VI. METHODS: The study was designed as a single arm, non-blinded, split-side dual intervention study in which subjects underwent visible light irradiation using LED and halogen incandescent light sources delivered at a fluence of 0.14 Watts/cm2 with incremental dose progression from 20 J/cm2 to 320 J/cm2. Pigmentation was assessed by clinical examination, cross-polarized digital photography, and analytic colorimetry. RESULTS: Immediate, dose-responsive pigment darkening was seen with LED light exposure in 80% of subjects, beginning at 60 Joules. No pigmentary changes were seen with halogen incandescent light exposure at any dose in any subject. CONCLUSION: This study is the first to report a distinct difference in cutaneous pigmentary response to different sources of visible light, and the first to demonstrate cutaneous pigment darkening from visible LED light exposure. Our findings raise the concern that our increasing daily artificial light surroundings may have clandestine effects on skin biology.

J Drugs Dermatol. 2017;16(11):1105-1110.

. PMID- 29141059 TI - A Retrospective Study on Efficacy of Pulsed Dye Laser and Intense Pulsed Light for the Treatment of Facial Telangiectasia. AB -

Both pulsed dye laser (PDL) and intense pulsed light (IPL) systems have been demonstrated to be effective for treatment of facial telangiectasia, however there have been very few comparative studies between both treatments involving purely Asian patient populations. In this study, we performed a retrospective analysis to compare the efficacy of PDL and IPL systems for the treatment of facial telangiectasia. A total of 416 patients with facial telangiectasia who were treated by PDL or IPLs in our department from August 2012 to March 2015 were included in this study. The subjects received one of the following five treatments: PDL 595 nm (9-12 J/cm2), MaxG (500-670 nm & 870-1200 nm, 30-46 J/cm2), IPL (560-1200 nm, 18-24 J/cm2), M22 560 (560-1200 nm, 15-18 J/cm2), and M22 590 (590-1200 nm, 15-20 J/cm2). Each treatment had two sessions with 6-week intervals. The improvement percentage score in facial telangiectasia after the final treatment was evaluated by two non-treating physicians. We found almost all patients (less than 95.00%) had marked improvements or nearly complete clearance of the lesions after PDL 595 nm or MaxG treatment, as compared to 41.38%-56.58% patients in the other three groups that showed similar degrees of improvements. Both PDL 595 nm (9-12 J/cm2) and MaxG (500-670 nm & 870-1200 nm, 30-46 J/cm2) treatments resulted in significantly superior vessel clearance than the IPL systems with other wavelength bands (560-1200 nm or 590-1200 nm) and relatively lower fluence (15-24 J/cm2). Our results also suggested fluence levels account for the significant differences in the effectiveness delivered by different IPL systems. We concluded that PDL 595 nm and MaxG showed comparable clinical efficacy and both treatments resulted in most beneficial outcomes.

J Drugs Dermatol. 2017;16(11):1112-1116.

. PMID- 29141060 TI - Efficacy of Low-Fluence Nd:YAG 1064 nm Laser for the Treatment of Post Inflammatory Hyperpigmentation in the Axillary Area. AB - :

OBJECTIVE: Post-inflammatory hyperpigmentation results in aesthetically unpleasant discoloration of the skin in the affected area. The efficacy of low fluence Q-switched 1064-nm Nd:YAG laser has so far not been evaluated for the treatment of the axilla. This observational study was designed to evaluate whether the application of the laser treatment can satisfactorily reduce axillary hyperpigmentation. MATERIAL AND METHODS: 17 females (mean age, 34.27 +/- 9.24; range, 19-48) were treated in a single center between 2014 and 2016 for post inflammatory hyperpigmentation of the axillary area. One treatment session was done every 2 weeks. Pairwise pre- / post-treatment assessment was graded by the practitioner, the patient, and an independent non-medical observer for consistency using a standardized grading scale. RESULTS: Post-treatment evaluation revealed an improvement score of 4 +/- 0.44; range, 4-5 (good improvement) with a variance of 0.19 after the treatment. The scoring of the practitioner rs= 0.31 correlated higher with the patient-related outcome than with the scoring of the independent non-medical observer rs= 0.17. The minimum number of sessions needed for an excellent patient-evaluated improvement was 3, but an increased number of sessions was not significantly correlated with the outcome. The results of the treatment lasted for at least 6 months after the last session. CONCLUSION: A low-fluence Q-switched 1064-nm Nd:YAG laser provided safe and effective treatment for post-inflammatory hyperpigmentation in the axillary area, with good-to-excellent improvement after a minimum of 3 sessions.

J Drugs Dermatol. 2017;16(11):1118-1123.

. PMID- 29141061 TI - A Randomized, Investigator-Blinded Comparison of Two Topical Regimens in Fitzpatrick Skin Types III-VI With Moderate to Severe Facial Hyperpigmentation. AB - :

Purpose: Though hydroquinone (HQ) remains the gold standard for treatment of hyperpigmentation, concerns about its safety have prompted the development of HQ free topical skin lightening systems. OBJECTIVE: To compare the efficacy and tolerability of a new HQ-free system and a popular HQ-based system for the improvement of facial hyperpigmentation and photoaging in darker skin types. METHODS: This investigator-blinded trial randomized 30 subjects of Fitzpatrick skin types III to VI with moderate to severe hyperpigmentation to a new 7-product HQ-free system or a 7-product HQ-based system for 12 weeks. At 4, 8, and 12 week follow-up visits, a blinded investigator assessed efficacy and tolerability using standardized scales. Subjects also performed a self-assessment at each visit. SUMMARY: Both the HQ-free and HQ-based systems produced significant improvements in Overall Hyperpigmentation that were sustained through week 12 (P=0.008, 0.0003). The HQ-based system demonstrated better improvement in overall hyperpigmentation at weeks 4, 8, 12 (P=0.01, 0.001, 0.003, respectively). Mottled Pigmentation Area Severity Index (MoPASI) scores improved with both systems (P=0.02, 0.01), with no statistically significant differences between the two treatment groups. Subject-rated hyperpigmentation was not different between groups. Subjects reported significantly more discomfort with the HQ-free system at week 8 (P=0.02); otherwise, measures of irritation were the same between groups. All irritation was described as mild to moderate. At week 12, 100% of subjects in the HQ-free group and 92.3% of subjects in the HQ-based group were satisfied with their outcome. CONCLUSION: Both a new HQ-free skincare system and a widely-available HQ-based system improved hyperpigmentation in Fitzpatrick skin types III to VI. Though the HQ-based system produced greater improvement in hyperpigmentation when compared to the HQ-free system, there was no difference in MoPASI scores between the treatment groups. Subjects were satisfied with both treatments and reported only mild to moderate irritation using either system.

J Drugs Dermatol. 2017;16(11):1127-1132.

. PMID- 29141062 TI - Management of Severe Acne Vulgaris With Topical Therapy. AB -

Acne vulgaris (acne) is the most common skin disease we see in dermatology practice. Although rare in childhood, severe acne can affect up to 12% of the adolescent population. A chronic disease, it requires both aggressive management and effective maintenance strategies. Oral antibiotics, in combination with topical agents are recommended for treatment, with topical agents being continued as maintenance therapy to minimize resistance and recurrence. However, concerns with systemic side effects have recently resulted in a greater focus on the potential of fixed combination topical therapies to treat severe acne. Here we review the available clinical evidence. There are no studies investigating the use of fixed combination topical therapy exclusively in severe acne. However, studies assessing the treatment of moderate-to-severe acne include subpopulation data in severe patients. Adapalene 0.3%-benzoyl peroxide (BP) 2.5% was found to be effective in patients with severe acne, whereas the fixed combination with a lower concentration of adapalene (0.1%) was no more effective than vehicle. Clindamycin-BP 1.2%/3.75% gel and clindamycin-BP 1.2%/2.5% gel were both found to be effective in severe acne with an apparent BP-dose response. Clindamycin phosphate 1.2%-tretinoin 0.025% demonstrated similar efficacy in severe acne, but with little benefit over individual monads. Realistic topical treatment options now exist for the management of severe acne where patient and physician preference can impact positive outcomes.

J Drugs Dermatol. 2017;16(11):1134-1138.

. PMID- 29141063 TI - Novel Treatment Using Low-Dose Naltrexone for Lichen Planopilaris. AB -

Lichen planopilaris (LPP) is a variant of lichen planus that affects the scalp causing scarring hair loss. Patients also frequently experience symptoms of scalp itch, pain, and burning. To date, there are no long-term remittive nor curative therapies available. Low-dose naltrexone has anti-inflammatory properties and has recently been described in the context of treating autoimmune conditions. This retrospective medical record review describes four LPP patients treated with low dose (3 milligrams per day) naltrexone. This medication provided benefit in these four patients including reduction in symptoms of pruritus, clinical evidence of inflammation of the scalp, and disease progression. All patients tolerated naltrexone without adverse effects. This is the first case series demonstrating the beneficial effects of low-dose naltrexone for patients with LPP. This medication was well-tolerated by the patients and is cost-effective.

J Drugs Dermatol. 2017;16(11):1140-1142.

. PMID- 29141064 TI - Port-Wine Stains: A Focused Review on Their Management. AB -

Port-wine stain (PWS) is the second most common congenital vascular malformation characterized as ectatic capillaries and venules in the dermis that clinically appears as a deep red to purple patch on the skin. Typically, PWS progressively darken and may become hypertrophic or nodular without treatment. There are several treatment options available for PWS from topical antiangiogenic agents to laser therapies. Vascular-specific lasers are the gold standard in treating PWS and classically pulsed dye lasers are usually the treatment of choice. However, some patients with PWS are recalcitrant to PDL and may require a combination of treatment methods. Nonetheless, even with the advancements in laser therapies utilized today, it is can be difficult to achieve complete clearance of the PWS. Thus, new innovations for treating recalcitrant PWS are underway in order to improve overall patient treatment outcomes.

J Drugs Dermatol. 2017;16(11):1145-1151.

. PMID- 29141065 TI - Use of Isoquercetin in the Treatment of Prurigo Nodularis. AB -

Atopic dermatitis and prurigo nodularis result from complex interactions between the skin, the immune system, and the external environment. The pruritus associated with these conditions greatly impacts patients' quality of life and lacks uniformly effective treatment. A 57-year-old patient presented with severe atopic dermatitis and subsequent prurigo nodularis refractory to numerous standard therapies. The supplement isoquercetin was initiated and he noted significant, sustained reduction in his pruritus after only four weeks. Isoquercetin is a glycoside derivative with antihistamine properties of quercetin, a natural polyphenol flavonoid found in many plants. It may offer itch relief in patients who have failed more conventional therapies.

J Drugs Dermatol. 2017;16(11):1156-1158.

. PMID- 29141066 TI - Vancomycin Infiltrate-Induced Dermatitis Mimicking Bullous Cellulitis. AB -

Extravasation of medications can manifest as tenderness, pain, tissue necrosis, and thrombophlebitis and lead to infection and severe long-term complications. Risk factors for leakage of medications include mechanical and pharmacologic mechanisms such as cannulation technique, vasoconstriction, and cytotoxicity. Well-known vesicants like anthracyclines, vinca alkaloids, and vasopressors are usually administered with proper caution. Often overlooked are many antimicrobial agents, which typically act via differences in osmolality and pH. Vancomycin harms the vascular wall by the latter (pH 2.5-4.5). Although similar in appearance to vancomycin hypersensitivity reactions (eg, linear immunoglobulin A bullous dermatosis), we present a patient whose dermatitis and subsequent cellulitis likely originated due to extravasation of the drug from the peripheral intravenous catheter. The visible dermatitis mimicked bullous cellulitis from toxin-producing Staphylococcus aureus, Group A Streptococcus, and gram-negative rods or anaerobes in the setting of neutropenia. Our case illustrates the importance of getting an appropriate history and recognizing non infectious causes of rashes that mimic chronic infections.

. PMID- 29141067 TI - An Elusive Amelanotic Melanoma and Review of Dermoscopic Findings. AB -

Amelanotic melanoma (AM) is one of the great masqueraders in dermatology. It is a very difficult clinical diagnosis to make because these tumors are devoid of pigment and other clues of melanoma. They are commonly misdiagnosed clinically as other benign and malignant conditions. We present a new case of AM in an 84-year old woman with a history of non-melanoma skin cancer. She had a thin pink plaque that was initially misdiagnosed as a basal cell carcinoma. We also discuss dermoscopy and its valuable role to improve diagnostic accuracy. A review of dermoscopic features that favor and oppose the clinical diagnosis of AM is discussed. Even with dermoscopy, it is still important to have a high index of suspicion and a low threshold to biopsy when the clinical diagnosis is unclear.

J Drugs Dermatol. 2017;16(11):1164-1165.

. PMID- 29141068 TI - New Insight Into the Pathophysiology of Hair Loss Trigger a Paradigm Shift in the Treatment Approach. AB -

Hair loss affects millions of men and women of all ages and ethnicities, impacting appearance, social interactions, and psycho-emotional well-being. Although a number of options are available, they are limited, carry a potential risk of side effects, and none have proven to be comprehensive for treatment of hair loss. Across the spectrum of hair loss disorders, there has long been a segmentation into distinct mechanisms, driving the main trend in current therapeutics to focus on targeting single molecules or pathways. However, research points to similar dysregulation of intrinsic signaling pathways within follicle physiology that span the hair loss disorder spectrum - with a common inflammatory component identified in most hair loss pathogenesis, including that of androgenetic alopecia (AGA).

J Drugs Dermatol. 2017;16(11 Suppl):s135-140.

. PMID- 29141069 TI - A Novel Multi-Targeting Approach to Treating Hair Loss, Using Standardized Nutraceuticals. AB -

Hair loss is a complicated problem that causes significant concern for those who are affected. Patients seeking medical treatment have limited options that include topical minoxidil and oral finasteride. While these treatments are backed by long term clinical use and research outcomes, many patients find topical minoxidil difficult to incorporate into their daily routine and some are concerned with the side effects associated with finasteride. In the office setting, patients may be treated with more invasive procedures such as platelet rich plasma injections (PRP) and hair transplantation, treatments that often must be repeated and can lead to a costly investment. Consumers are increasingly interested in natural treatments for hair loss. Many turn to basic supplements only to be disappointed when they fail to deliver due to lack of standardization and efficacy. In this paper we review the benefits of a nutraceutical containing a specific blend of highly purified, standardized, bio-optimized, and bioavailable botanical extracts to treat hair loss. These phytoactives were selected because of their diverse multi-modal biologic activity against inflammation, DHT, stress mediators, oxidative damage, and intermediary signaling cascades. This supplement represents a paradigm shift as it addresses not only the factors that trigger hair loss but the downstream mediators of inflammation as well. Multi-center clinical studies are currently underway to confirm the efficacy and benefits of this unique nutraceutical.

J Drugs Dermatol. 2017;16(11 Suppl):s141-148.

. PMID- 29141070 TI - Comparison of Neurologic Trauma and Motorcycle Helmet Use in Drivers vs Passengers. PMID- 29141071 TI - Usefulness of Total 12-Lead QRS Voltage as a Clue to Diagnosis of Patients With Cardiac Sarcoidosis Severe Enough to Warrant Orthotopic Heart Transplant. AB - Importance: Severe heart failure caused by cardiac sarcoidosis is difficult to diagnosis without biopsy. Objective: To assess whether total electrocardiographic 12-lead QRS voltage may be a clue to diagnosis. Design, Setting, Participants: Case-series study with cases collected at Baylor University Medical Center at Dallas, Dallas, Texas, from January 13, 2005, to January 24, 2017. The clinical records of 16 patients with severe heart failure caused by cardiac sarcoidosis were studied. Examination of total 12-lead electrocardiographic QRS voltage (peak of the R wave to the nadir of either the Q or S wave, whichever was deeper) was performed prior to orthotopic heart transplant (OHT). Gross and microscopic pathologic specimens of the native hearts were studied. Main Outcomes and Measures: The primary outcome was to correlate the total 12-lead QRS voltage measurement with various morphologic features in the native diseased heart. Results: The 16-patient study group consisted of 8 men and 8 women; 12 (75%) were white and 4 (25%) were black. At the time of OHT, patient age ranged from 50 to 67 years (mean, 57 years). Cardiac sarcoidosis was diagnosed by pre-OHT biopsy results in 2 (13%) patients and by examination of the native heart after OHT in 14 (87%) patients. Total nonpaced 12-lead QRS voltage mean was 117 mm (range, 52 155 mm) for 8 patients and total paced 12-lead QRS voltage was 90 mm (range, 67 161 mm) for 12 patients. These low mean values were similar to those of patients with carcinoid heart disease (mean [SD], 105 [40] mm), cardiac amyloidosis (104 [35] mm), and severe cardiac adiposity (120 [31] mm) studied at necropsy or after OHT. In contrast, mean (SD) values were 323 (109) mm in patients with massive cardiomegaly, 257 mm in patients with severe aortic stenosis, 272 (86) mm in patients with severe pure aortic regurgitation, 220 (67) mm in patients with severe pure mitral regurgitation, 197 (64) mm in patients with hypertrophic cardiomyopathy, and 153 (40) mm in patients with idiopathic dilated cardiomyopathy. Conclusions and Relevance: Most patients diagnosed with cardiac sarcoidosis causing severe heart failure and warranting OHT had low total 12-lead QRS voltage measurements despite having native hearts of increased weight. This finding may provide a clue to the diagnosis of this disease. PMID- 29141073 TI - Forces of Tool-Tissue Interaction to Assess Surgical Skill Level. PMID- 29141074 TI - Underuse of the Sentinel Lymph Node Biopsy for High-Risk Squamous Cell Carcinoma of the Skin. PMID- 29141072 TI - Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults. AB - Importance: Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). Objective: To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. Design, Setting, and Participants: This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Exposures: Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Main Outcomes and Measures: Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Results: Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 * 10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003). Conclusions and Relevance: CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD. PMID- 29141075 TI - Treatment for Livedoid Vasculopathy: A Systematic Review. AB - Importance: Livedoid vasculopathy is a painful, ulcerative condition of the lower extremities for which no established treatment exists. Current treatment paradigms rely on low levels of evidence, primarily case reports and case series. Objective: To systematically review the treatment for livedoid vasculopathy and synthesize the available clinical data. Evidence Review: A systematic review of the literature using Ovid MEDLINE (covering the period January 1, 1946, through June 9, 2017) and Ovid EMBASE (covering January 1, 1947, through June 9, 2017) databases was performed with a broad and inclusive search strategy along with a subsequent search of the references of retrieved articles. All case series reports published in the English language and in a peer-reviewed journal discussing the treatment for livedoid vasculopathy diagnosis were included. Findings: A total of 29 case series reports published in the English language and in a peer-reviewed journal discussed the treatment for livedoid vasculopathy. These reports represented a total of 339 patients, of whom 230 (68%) were female and 69 (20%) were male; sex was not stated for 40 patients. Treatment with anticoagulants, antiplatelets, anabolic steroids, thrombolytics, hyperbaric oxygen, intravenous immunoglobulins, vitamin supplementation, UV light, and a combination of 1 or more of these among other therapies had a favorable outcome. Anticoagulants were the most commonly used monotherapy, achieving a favorable response in 62 of 63 patients (98%). Anabolic steroids, intravenous immunoglobulins, and antiplatelets were the second, third, and fourth most commonly used treatments, respectively. All of these therapies were associated with good clinical outcomes. Adverse events were observed in 44 patients (13%). Conclusions and Relevance: A variety of treatments with varying degrees of success have been used to treat livedoid vasculopathy. Randomized clinical trials should be performed in the future to better establish these treatments in clinical practice. PMID- 29141076 TI - Errors in Introduction, Methods, and Discussion Sections. PMID- 29141077 TI - Pediatric Use of Antipsychotic Medications Before and After Medicaid Peer Review Implementation. PMID- 29141078 TI - 75-Year-Old Woman With Multiple Systemic Emboli. PMID- 29141079 TI - Visual Function Response to Ocriplasmin for the Treatment of Vitreomacular Traction and Macular Hole: The OASIS Study. AB - Purpose: To assess the effect of ocriplasmin on visual function response (VFR) measured using visual acuity (VA) and vision-related quality of life, and to quantify the association between release of vitreomacular adhesion (VMA) at day 28 and VFR. Methods: Prespecified analysis of secondary endpoints from a randomized controlled trial. Of 220 participants with symptomatic VMA/vitreomacular traction (VMT), including VMT associated with a macular hole up to 400 MUm, 146 received a single intravitreal injection of 125 MUg ocriplasmin and 74 a sham injection. Based on principal components analysis results, a VFR was defined as either a VA improvement of >=2 lines or an improvement exceeding the minimal clinically important difference (MCID) in the composite or the mental health subscale scores of the Visual Function Questionnaire (VFQ-25). The MCID was estimated using the standard error of measurement approach. The main outcome measure was the VFR at month 6, with further assessments at months 12 and 24. Results: The MCID was estimated at 3.71 points for the VFQ-25 composite score and 10.71 for the VFQ-25 mental health subscale score. A VFR occurred in 51.0% of ocriplasmin versus 23.3% of sham participants (P = 0.0001). The VFR was maintained through months 12 and 24: 53.1% and 50.3% in ocriplasmin versus 21.9% and 20.5% in sham participants, respectively (P < 0.0001). Resolution of VMA at day 28 significantly increased the odds of a VFR at each assessment period. Conclusions: Treatment with ocriplasmin compared with sham resulted in a significant improvement in VFR. The 6-month treatment effect was sustained at months 12 and 24. PMID- 29141080 TI - The Associations of Lens Power With Age and Axial Length in Healthy Chinese Children and Adolescents Aged 6 to 18 Years. AB - Purpose: To investigate the relationship between lens power and age as well as the relationship between lens power and axial length (AL) in Chinese children and adolescents. Methods: The participants underwent a comprehensive ophthalmic examination that included AL, cycloplegic refraction, and Pentacam measurements. The crystalline lens power was calculated using Bennett's formula and then compared among the children of different age groups, refractive statuses, and AL categories. The association of lens power and AL was analyzed using multiple regression. Results: A total of 1992 children and adolescents aged 6- to 18-years old were included. The difference in lens power was greater before 10-years old, followed by a relatively smaller difference in children aged 10 to 14 years and the difference in lens power came to a near plateau in adolescents after 14-years old. The negative association between lens power and AL was found to be more evident in nonmyopes than in myopes irrespective of age (younger than 10 years: nonmyopes: beta = -1.499, myopes: beta = -0.872; older than 10 years: nonmyopes: beta = -1.288, myopes: beta = -0.390, all P < 0.001). Conclusions: The lens power in children and adolescents aged 6 to 18 years exhibited three stages. The association between lens power and AL differed between the nonmyopes and myopes. These findings suggested that less reduction in lens power might be associated with both growing age and increasing AL in myopes. PMID- 29141081 TI - Imminent Death Liver Donation for Children: Potential to Meet an Unmet Need. PMID- 29141083 TI - Vegetating Darier Disease Treated With Botulinum Toxin. PMID- 29141082 TI - Diagnostic Accuracy of Pediatric Teledermatology Using Parent-Submitted Photographs: A Randomized Clinical Trial. AB - Importance: Advances in smartphone photography (both quality and image transmission) may improve access to care via direct parent-to-clinician telemedicine. However, the accuracy of diagnoses that are reliant on parent provided photographs has not been formally compared with diagnoses made in person. Objective: To assess whether smartphone photographs of pediatric skin conditions taken by parents are of sufficient quality to permit accurate diagnosis. Design, Setting, and Participants: A prospective study was conducted among 40 patient-parent dyads at a pediatric dermatology clinic at the Children's Hospital of Philadelphia from March 1 to September 30, 2016, to assess concordance between diagnoses made by an independent pediatric dermatologist based on in-person examination and those based on parental photographs. Half of the patient-parent dyads were randomized for a secondary analysis to receive instructions on how best to take photographs with smartphones. Clinicians were blinded to whether parents had received photography instructions. Exposures: Half of the patient-parent dyads received a simple, 3-step instruction sheet on how best to take photographs using a smartphone (intervention group); the other half did not (control group). Main Outcomes and Measures: Concordance between photograph-based vs in-person diagnosis in the intervention vs control groups, as quantified using Cohen kappa, a measure of interrater agreement that takes into account the possibility of agreement occurring by chance. Results: Among the 40 patient-parent dyads (22 female children and 18 male children; mean [SD] age, 6.96 [5.23] years), overall concordance between photograph-based vs in-person diagnosis was 83% (95% CI, 71%-94%; kappa = 0.81). Diagnostic concordance was 89% (95% CI, 75%-97%; kappa = 0.88) in a subgroup of 37 participants with photographs considered of high enough quality to make a diagnosis. No statistically significant effect of photography instructions on concordance was detected (group that received instructions, 85%; group that did not receive instructions, 80%; P = .68). In cases of diagnostic disagreement, appropriate follow-up was suggested. Conclusions and Relevance: Parent-operated smartphone photography can accurately be used as a method to provide pediatric dermatologic care. Trial Registration: clinicaltrials.gov Identifier: NCT03246945. PMID- 29141084 TI - Association of Obsessive-Compulsive Disorder With Objective Indicators of Educational Attainment: A Nationwide Register-Based Sibling Control Study. AB - Importance: To our knowledge, the association of obsessive-compulsive disorder (OCD) and academic performance has not been objectively quantified. Objective: To investigate the association of OCD with objectively measured educational outcomes in a nationwide cohort, adjusting for covariates and unmeasured factors shared between siblings. Design, Setting, And Participants: This population-based birth cohort study included 2 115 554 individuals who were born in Sweden between January 1, 1976, and December 31, 1998, and followed up through December 31, 2013. Using the Swedish National Patient Register and previously validated International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, we identified persons with OCD; within the cohort, we identified 726 198 families with 2 or more full siblings, and identified 11 482 families with full siblings discordant for OCD. Data analyses were conducted from October 1, 2016, to September 25, 2017. Main Outcomes and Measures: The study evaluates the following educational milestones: eligibility to access upper secondary school after compulsory education, finishing upper secondary school, starting a university degree, finishing a university degree, and finishing postgraduate education. Results: Of the 2 115 554 individuals in the cohort, 15 120 were diagnosed with OCD (59% females). Compared with unexposed individuals, those with OCD were significantly less likely to pass all core and additional courses at the end of compulsory school (adjusted odds ratio [aOR] range, 0.35 0.60) and to access a vocational or academic program in upper secondary education (aOR, 0.47; 95% CI, 0.45-0.50 and aOR, 0.61; 95% CI, 0.58-0.63, for vocational and academic programs, respectively). People with OCD were also less likely to finish upper secondary education (aOR, 0.43; 95% CI, 0.41-0.44), start a university degree (aOR, 0.72; 95% CI, 0.69-0.75), finish a university degree (aOR, 0.59; 95% CI, 0.56-0.62), and finish postgraduate education (aOR, 0.52; 95% CI, 0.36-0.77). The results were similar in the sibling comparison models. Individuals diagnosed with OCD before age 18 years showed worse educational attainment across all educational levels compared with those diagnosed at or after age 18 years. Exclusion of patients with comorbid neuropsychiatric disorders, psychotic, anxiety, mood, substance use, and other psychiatric disorders resulted in attenuated estimates, but patients with OCD were still impaired across all educational outcomes. Conclusions and Relevance: Obsessive compulsive disorder, particularly when it has an early onset, is associated with a pervasive and profound decrease in educational attainment, spanning from compulsory school to postgraduate education. PMID- 29141085 TI - The contribution of foveal and peripheral visual information to ensemble representation of face race. AB - The brain can only attend to a fraction of all the information that is entering the visual system at any given moment. One way of overcoming the so-called bottleneck of selective attention (e.g., J. M. Wolfe, Vo, Evans, & Greene, 2011) is to make use of redundant visual information and extract summarized statistical information of the whole visual scene. Such ensemble representation occurs for low-level features of textures or simple objects, but it has also been reported for complex high-level properties. While the visual system has, for example, been shown to compute summary representations of facial expression, gender, or identity, it is less clear whether perceptual input from all parts of the visual field contributes equally to the ensemble percept. Here we extend the line of ensemble-representation research into the realm of race and look at the possibility that ensemble perception relies on weighting visual information differently depending on its origin from either the fovea or the visual periphery. We find that observers can judge the mean race of a set of faces, similar to judgments of mean emotion from faces and ensemble representations in low-level domains of visual processing. We also find that while peripheral faces seem to be taken into account for the ensemble percept, far more weight is given to stimuli presented foveally than peripherally. Whether this precision weighting of information stems from differences in the accuracy with which the visual system processes information across the visual field or from statistical inferences about the world needs to be determined by further research. PMID- 29141086 TI - Use of Entrustable Professional Activities in the Assessment of Surgical Resident Competency. AB - Importance: Competency-based assessments of surgical resident performance require metrics of entrustable autonomy. Objectives: To designate entrustable professional activities (EPAs) in global performance and in specific operations, and to identify differences in perceived capability, autonomy, and expectations between surgical faculty and residents. Design, Setting, and Participants: This survey study was conducted from August 9, 2016, through August 24, 2016, in the Department of Surgery at the UCLA David Geffen School of Medicine. The survey instrument consisted of 5-point Likert scales for assessing perceptions of entrustability for 5 global and 5 operative EPAs. Faculty members were surveyed regarding resident capabilities and expected capabilities by postgraduate year. Residents were surveyed regarding their own capabilities, actual autonomy entrusted in the last EPA performed, and expected capabilities. Main Outcomes and Measures: Differences in mean ratings were assessed across 7 comparison domains. Results: Among 78 total faculty members, 31 (40%) participated in the survey. Among 49 residents, 39 (80%) participated in the survey. Residents generally rated their global EPA performance higher than the faculty did (mean, 3.7 vs 2.8; P < .01), but operative EPA performance ratings were equivalent (mean, 2.7 vs 2.4; P < .12). Faculty members perceived senior residents as underperforming expectations in operative EPAs. Most faculty members (80%) expected residents not to be independently capable of performing complex operations by graduation. Faculty members perceived residents in postgraduate years 4 and 5 to have greater operative capability than the level of autonomy entrusted to those residents (95% CI, 3.3-3.5 vs 1.9-2.2). Conclusions and Relevance: Global and operative EPAs are practical for developing competency-based curricula. Graduated autonomy should be granted to improve the operative experience for residents. PMID- 29141088 TI - Hyperpigmented Cutaneous Plaques With Ulceration on the Legs. PMID- 29141087 TI - Effect of Granulocyte-Macrophage Colony-Stimulating Factor With or Without Supervised Exercise on Walking Performance in Patients With Peripheral Artery Disease: The PROPEL Randomized Clinical Trial. AB - Importance: Benefits of granulocyte-macrophage colony-stimulating factor (GM-CSF) for improving walking ability in people with lower extremity peripheral artery disease (PAD) are unclear. Walking exercise may augment the effects of GM-CSF in PAD, since exercise-induced ischemia enhances progenitor cell release and may promote progenitor cell homing to ischemic calf muscle. Objectives: To determine whether GM-CSF combined with supervised treadmill exercise improves 6-minute walk distance, compared with exercise alone and compared with GM-CSF alone; to determine whether GM-CSF alone improves 6-minute walk more than placebo and whether exercise improves 6-minute walk more than an attention control intervention. Design, Setting, and Participants: Randomized clinical trial with 2 * 2 factorial design. Participants were identified from the Chicago metropolitan area and randomized between January 6, 2012, and December 22, 2016, to 1 of 4 groups: supervised exercise + GM-CSF (exercise + GM-CSF) (n = 53), supervised exercise + placebo (exercise alone) (n = 53), attention control + GM-CSF (GM-CSF alone) (n = 53), attention control + placebo (n = 51). The final follow-up visit was on August 15, 2017. Interventions: Supervised exercise consisted of treadmill exercise 3 times weekly for 6 months. The attention control consisted of weekly educational lectures by clinicians for 6 months. GM-CSF (250 MUg/m2/d) or placebo were administered subcutaneously (double-blinded) 3 times/wk for the first 2 weeks of the intervention. Main Outcomes and Measures: The primary outcome was change in 6-minute walk distance at 12-week follow-up (minimum clinically important difference, 20 m). P values were adjusted based on the Hochberg step-up method. Results: Of 827 persons evaluated, 210 participants with PAD were randomized (mean age, 67.0 [SD, 8.6] years; 141 [67%] black, 82 [39%] women). One hundred ninety-five (93%) completed 12-week follow-up. At 12-week follow-up, exercise + GM-CSF did not significantly improve 6-minute walk distance more than exercise alone (mean difference, -6.3 m [95% CI, -30.2 to +17.6]; P = .61) or more than GM-CSF alone (mean difference, +28.7 m [95% CI, +5.1 to +52.3]; Hochberg-adjusted P = .052). GM-CSF alone did not improve 6-minute walk more than attention control + placebo (mean difference, -1.4 m [95% CI, -25.2 to +22.4]; P = .91). Exercise alone improved 6-minute walk compared with attention control + placebo (mean difference, +33.6 m [95% CI, +9.4 to +57.7]; Hochberg-adjusted P = .02). Conclusions and Relevance: Among patients with PAD, supervised treadmill exercise significantly improved 6-minute walk distance compared with attention control + placebo, whereas GM-CSF did not significantly improve walking performance, either when used alone or when combined with supervised treadmill exercise. These results confirm the benefits of exercise but do not support using GM-CSF to treat walking impairment in patients with PAD. Trial Registration: clinicaltrials.gov Identifier: NCT01408901. PMID- 29141091 TI - Erratum. PMID- 29141092 TI - Erratum. PMID- 29141093 TI - Erratum. PMID- 29141096 TI - Quantifying publication bias in meta-analysis. AB - Publication bias is a serious problem in systematic reviews and meta-analyses, which can affect the validity and generalization of conclusions. Currently, approaches to dealing with publication bias can be distinguished into two classes: selection models and funnel-plot-based methods. Selection models use weight functions to adjust the overall effect size estimate and are usually employed as sensitivity analyses to assess the potential impact of publication bias. Funnel-plot-based methods include visual examination of a funnel plot, regression and rank tests, and the nonparametric trim and fill method. Although these approaches have been widely used in applications, measures for quantifying publication bias are seldom studied in the literature. Such measures can be used as a characteristic of a meta-analysis; also, they permit comparisons of publication biases between different meta-analyses. Egger's regression intercept may be considered as a candidate measure, but it lacks an intuitive interpretation. This article introduces a new measure, the skewness of the standardized deviates, to quantify publication bias. This measure describes the asymmetry of the collected studies' distribution. In addition, a new test for publication bias is derived based on the skewness. Large sample properties of the new measure are studied, and its performance is illustrated using simulations and three case studies. PMID- 29141097 TI - Fighting an uphill battle: the recovery of frogs in Australia's Wet Tropics. PMID- 29141098 TI - Discussion of "quantifying publication bias in meta-analysis" by Lin et al. AB - Inspection and analysis of funnel plots cannot reliably identify publication and reporting bias, the non-publication of results that are not statistically significant. Instead, researchers should thoroughly and systematically search available information sources such as databases, registries and unpublished reports. Even then, it is not possible to ever know whether a systematic review has uncovered all available studies, but the search can inform attempts to construct plausible statistical models of the missing data mechanism. PMID- 29141099 TI - Discussion on Quantifying publication bias in meta-analysis. AB - In this discussion, I will describe some issues that are related to the article presented by Lin and Chu. In particular, I discuss three concerns that should be addressed before their methodology may be accepted for general use. PMID- 29141100 TI - Religiosity and psychological resilience in patients with schizophrenia and bipolar disorder: an international cross-sectional study. AB - OBJECTIVE: The impact of religious/spiritual activities on clinical outcomes in patients with serious mental illnesses remains controversial, which was addressed in this international cross-sectional study. METHOD: Three-hundred sixty-nine subjects were recruited from Austria (n = 189) and Japan (n = 180), consisting of 112 outpatients with paranoid schizophrenia, 120 with bipolar I disorder (DSM IV), and 137 healthy controls. Religiosity was assessed in terms of attendance and importance of religious/spiritual activities, while resilience was assessed using the 25-item Resilience Scale. General linear models were used to test whether higher religiosity will be associated with higher resilience, higher social functioning, and lower psychopathology. The association between levels of spiritual well-being and resilience was also examined. RESULTS: Attendance of religious services (F[4,365] = 0.827, P = 0.509) and importance of religion/spirituality (F[3,365] = 1.513, P = 0.211) did not show significant associations with resilience. Regarding clinical measures, a modest association between higher importance of religion/spirituality and residual manic symptoms was observed in bipolar patients (F[3,118] = 3.120, P = 0.029). In contrast to the findings regarding religiosity, spiritual well-being showed a strong positive correlation with resilience (r = 0.584, P < 0.001). CONCLUSION: The protective effect of religiosity in terms of resilience, social functioning, and psychopathology was not evident in our sample. Spiritual well-being appears more relevant to resilience than religiosity. PMID- 29141101 TI - The outcomes of adolescent mental disorders. PMID- 29141102 TI - Statistically optimized ceftriaxone sodium biotransformation through Achromobacter xylosoxidans strain Cef6: an unusual insight for bioremediation. AB - The present study underlines a unique promising approach toward efficient biotransformation of ceftriaxone sodium (Ceftx), a highly frequent prescribed cephalosporin antibiotic, by a newly bacterium namely Achromobacter xylosoxidans strain Cef6 isolated from Ceftx contaminated raw materials in pharmaceutical industries. A three step sequential statistical-mathematical approach (Plackett Burman design [PBD], Central Composite Design [CCD], and ridge-canonical analyses) was anticipated to optimize the biotransformation process. Ceftx concentration and medium volume: bottle volume ratio, two key determinants, significantly (p < 0.05) affected the process outcome deduced by regression analysis of PBD' data. CCD and ridge-canonical analyses localized the optimal levels of Ceftx concentration and medium volume: 250 ml bottle volume ratio to be 0.39 and 7.973 g Ceftx/L modified tryptic soy broth achieving Ceftx biotransformation (100%) after 39 h under aerobic static conditions at 30 degrees C, irrespectively deduced via HPLC analysis. Impressively, only one of five Ceftx byproducts was detected by the end of the biotransformation process. To the best of authors' knowledge, this is the first report addressing a detailed study regarding efficient biotransformation of Ceftx by single bacterium not bacterial consortium under aerobic conditions. Present data would greatly encourage applying this approach for decontamination of some Ceftx contaminated environmental sites. PMID- 29141103 TI - Risk profiles of personality traits for suicidality among mood disorder patients and community controls. AB - OBJECTIVE: To examine the associations between personality traits and suicidal ideation (SI) and attempt (SA) in mood disorder patients and community controls. METHOD: We recruited 365 bipolar, 296 major depressive disorder patients, and 315 community controls to assess their lifetime suicidality. Participants filled out self-reported personality questionnaires to collect data of personality traits, including novelty seeking (NS), harm avoidance (HA), extraversion (E), and neuroticism (N). We used logistic regression models adjusted for diagnoses to analyze combinational effects of personality traits on the risk of suicide. Additionally, radar charts display personality profiles for suicidal behaviours by groups. RESULTS: All personality traits were associated with the risk of suicidality with various effect size, except for E that showed protective effect. High N or HA had prominent and independent risk effects on SI and SA. Combinations of high N and low E, or high HA and NS were the risk personality profiles for suicidality. Higher N scores further distinguished SA from SI in mood disorder patients. CONCLUSION: Introvert personality traits showed independent risk effects on suicidality regardless of diagnosis status. Among high-risk individuals with suicidal thoughts, higher neuroticism tendency is further associated with increased risk of suicide attempt. PMID- 29141104 TI - Thaw circles around tree trunks provide spring ephemeral plants with a big head start on the growing season. PMID- 29141106 TI - NGWA News. PMID- 29141105 TI - Feasibility of intraperitoneal placental-derived mesenchymal stem cell injection in stomachs of diabetic mice. AB - BACKGROUND AND AIM: Diabetic gastropathy is associated with loss of interstitial cells of Cajal and autonomic neuropathy. Effective management for diabetic gastropathy is still unavailable. This study was aimed to confirm the pathogenetic changes in diabetic gastropathy and to examine the effect of treatment with placental-derived mesenchymal stem cells (PDMSCs) in stomachs of animal models. METHODS: Fourteen non-obese diabetic/ShiLtJ mice of 8 weeks were bled until week 30. Diabetes mellitus developed in 10 out of 14 mice, which all survived with insulin. The mice were grouped into three groups: nondiabetic group (n = 4), diabetic sham group (n = 5), and diabetic PDMSC group (n = 5) all of which were treated with intraperitoneal PDMSCs injection at week 30. All mice were killed at week 34, and the stomachs were examined by immunohistochemical stain with c-kit and neuronal nitric oxide synthase antibodies. RESULTS: The number of c-kit positive cells in stomach decreased significantly in the diabetic sham group compared with that in the nondiabetic group (21.2 +/- 6.7 vs 88.0 +/- 29.3, P = 0.006) but increased with PDMSC treatment (21.2 +/- 6.7 vs 64.0 +/- 15.1, P = 0.02). The positive rate of neuronal nitric oxide synthase in neural plexus was also significantly lower in the diabetic sham group than in the nondiabetic group (22.3% +/- 18.5% vs 48.0% +/- 22.7%, P = 0.003) but increased with PDMSC treatment (22.3% +/- 18.5% vs 43.3% +/- 20.5%, P = 0.03). CONCLUSIONS: Interstitial cells of Cajal and neural plexus decreased in stomachs of mice with diabetes mellitus but were significantly repaired with intraperitoneal injection of PDMSC. PMID- 29141107 TI - Metal transformation as a strategy for bacterial detoxification of heavy metals. AB - Microorganisms can modify the chemical and physical characters of metals leading to an alteration in their speciation, mobility, and toxicity. Aqueous heavy metals solutions (Hg, Cd, Pb, Ag, Cu, and Zn) were treated with the volatile metabolic products (VMPs) of Escherichia coli Z3 for 24 h using aerobic bioreactor. The effect of the metals treated with VMPs in comparison to the untreated metals on the growth of E. coli S1 and Staphylococcus aureus S2 (local isolates) was examined. Moreover, the toxic properties of the treated and untreated metals were monitored using minimum inhibitory concentration assay. A marked reduction of the treated metals toxicity was recorded in comparison to the untreated metals. Scanning electron microscopy and energy dispersive X-ray analysis revealed the formation of metal particles in the treated metal solutions. In addition to heavy metals at variable ratios, these particles consisted of carbon, oxygen, sulfur, nitrogen elements. The inhibition of metal toxicity was attributed to the existence of ammonia, hydrogen sulfide, and carbon dioxide in the VMPs of E. coli Z3 culture that might responsible for the transformation of soluble metal ions into metal complexes. This study clarified the capability of E. coli Z3 for indirect detoxification of heavy metals via the immobilization of metal ions into biologically unavailable species. PMID- 29141108 TI - Rejoinder to "quantifying publication bias in meta-analysis". PMID- 29141109 TI - Hepatic peroxisome proliferator-activated receptor alpha mediates the major metabolic effects of Wy-14643. AB - BACKGROUND AND AIM: Peroxisome proliferator-activated receptor alpha (PPARalpha) is a molecular target of various fibrate drugs clinically used to lower serum lipids. However, the tissue-specific functions of PPARalpha remain to be elucidated. This study aimed to explore the tissue-specific functions of PPARalpha in response to Wy-14643. METHODS: A hepatocyte-specific Ppara knockout mouse line was used to explore the impact of hepatic PPARalpha activity on the systemic response to treatment with the potent PPARalpha agonist Wy-14643. RESULTS: Wy-14643 mainly activated hepatic PPARalpha and regulated the expression of PPARalpha target genes in liver. Hepatic Ppara disruption abolished the triglyceride lowering effects of Wy-14643, prevented agonist-induced hypophagia, and ablated PPARalpha target gene response in the liver. CONCLUSIONS: These findings indicate that Wy-14643 treatment mainly activates hepatic PPARalpha, and the hypolipidemic and hypophagic effects of Wy-14643 are dependent on PPARalpha activation within hepatocytes. PMID- 29141110 TI - Discussion on "Quantifying Publication Bias in Meta-Analysis" by Lin and Chu. PMID- 29141111 TI - Three-Component Synthesis and Photophysical Properties of Novel Coumarin-Based Merocyanines. AB - Novel E-configured coumarin-based merocyanines were efficiently synthesized by a one-pot, three-component Sonogashira coupling-Michael addition starting from triflyl coumarins, terminal alkynes and secondary amines. The photophysical properties of the synthesized yellow to orange merocyanines were studied by UV/Vis and fluorescence spectroscopy and rationalized by Hammett-Taft correlations and DFT and TD-DFT calculations. Most compounds were only weakly fluorescent in solution; however, two compounds were investigated in more detail with respect to their aggregation behavior. The system for R2 =H and NR23 =pyrrolidinyl shows aggregation induced emission at a water content of 40-60 % in methanol, while the chromophore with R2 =p-Me2 NC6 H4 and NR23 =morpholinyl displays considerable aggregation induced emission enhancement with a concomitant redshift at increasing water contents in THF. PMID- 29141112 TI - Multiscale Geometric Design Principles Applied to 3D Printed Schwarzites. AB - Schwartzites are 3D porous solids with periodic minimal surfaces having negative Gaussian curvatures and can possess unusual mechanical and electronic properties. The mechanical behavior of primitive and gyroid schwartzite structures across different length scales is investigated after these geometries are 3D printed at centimeter length scales based on molecular models. Molecular dynamics and finite elements simulations are used to gain further understanding on responses of these complex solids under compressive loads and kinetic impact experiments. The results show that these structures hold great promise as high load bearing and impact-resistant materials due to a unique layered deformation mechanism that emerges in these architectures during loading. Easily scalable techniques such as 3D printing can be used for exploring mechanical behavior of various predicted complex geometrical shapes to build innovative engineered materials with tunable properties. PMID- 29141113 TI - Highly Selective Manganese(I)/Lewis Acid Cocatalyzed Direct C-H Propargylation Using Bromoallenes. AB - A manganese(I)/Lewis acid cocatalyzed direct C-H propargylation with high selectivity has been developed. BPh3 was discovered to not only promote the reactivity, but also enhance the selectivity. Secondary, tertiary, and even quaternary carbon centers at the propargylic position could be directly constructed. Both internal and terminal alkynes are easily accessible. The chirality was successfully transferred from an axially chiral allene to central chirality. The reactivity of the manganese catalyst in this reaction was found to be unique among transition metal catalysts. PMID- 29141114 TI - pH/Ultrasound Dual-Responsive Gas Generator for Ultrasound Imaging-Guided Therapeutic Inertial Cavitation and Sonodynamic Therapy. AB - Herein, a pH/ultrasound dual-responsive gas generator is reported, which is based on mesoporous calcium carbonate (MCC) nanoparticles by loading sonosensitizer (hematoporphyrin monomethyl ether (HMME)) and modifying surface hyaluronic acid (HA). After pinpointing tumor regions with prominent targeting efficiency, HMME/MCC-HA decomposes instantaneously under the cotriggering of tumoral inherent acidic condition and ultrasound (US) irradiation, concurrently accompanying with CO2 generation and HMME release with spatial/temporal resolution. Afterward, the CO2 bubbling and bursting effect under US stimulus results in cavitation-mediated irreversible cell necrosis, as well as the blood vessel destruction to further occlude the blood supply, providing a "bystander effect." Meanwhile, reactive oxygen species generated from HMME can target the apoptotic pathways for effective sonodynamic therapy. Thus, the combination of apoptosis/necrosis with multimechanisms consequently results in a remarkable antitumor therapeutic efficacy, simultaneously minimizing the side effects on major organs. Moreover, the echogenic property of CO2 make the nanoplatform as a powerful ultrasound contrast agent to identify cancerous lesions. Based on the above findings, such all-in-one drug delivery platform of HMME/MCC-HA is utilized to provide the US imaging guidance for therapeutic inertial cavitation and sonodynamic therapy simultaneously, which highlights possibilities of advancing cancer theranostics in biomedical fields. PMID- 29141115 TI - Activation of Dinitrogen with a Superalkali Species, Li3 F2. AB - The capability of the superalkali Li3 F2 to activate dinitrogen (N2 ) is presented. The (Li3 F2 )nN2 clusters (n=1-6) were investigated first at the MP2/6 311+G(3d2f,2df,2p)//B3LYP/6-311G(2d,d,p) level of theory. Clusters up to n=4 were also optimized through the CBS-QB3 composite model. The complete dissociation of N2 was confirmed through visualized molecular orbitals and bond order calculation. The N-N bond is weakened by the addition of Li3 F2 superalkali units. The enthalpy of atomization DeltaatH0? and formation (DeltafH0? ), charge flows (Deltaq), binding energies, and the energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital are calculated to help explain the N2 activation. PMID- 29141116 TI - Fluorine in a C-F Bond as the Key to Cage Formation. AB - Cage molecules have long been employed to trap reactive or transient species, as their rigid nature allows them to enforce situations that otherwise would not persist. In this Minireview, we discuss our use of rigid cage structures to investigate the close noncovalent interactions of fluorine with other functional groups and determine how mutual proximity affects both physical properties and reactivity. Unusual covalent interactions of fluorine are also explored: the cage can close to form the first solution-phase C-F-C fluoronium ion. PMID- 29141117 TI - Tunable Energy Landscapes to Control Pathway Complexity in Self-Assembled N Heterotriangulenes: Living and Seeded Supramolecular Polymerization. AB - Herein, the synthesis and self-assembling features of N-heterotriangulenes 1-3 decorated in their periphery with 3,4,5-trialkoxy-N-(alkoxy)benzamide moieties that enable kinetic control of the supramolecular polymerization process are described. The selection of an appropriate solvent results in a tunable energy landscape in which the relative energy of the different monomeric or aggregated species can be regulated. Thus, in a methylcyclohexane/toluene (MCH/Tol) mixture, intramolecular hydrogen-bonding interactions in the peripheral side units favor the formation of metastable inactivated monomers that evolve with time at precise conditions of concentration and temperature. A pathway complexity in the supramolecular polymerization of 1-3 cannot be determined in MCH/Tol mixtures but, importantly, this situation changes by using CCl4 . In this solvent, the off pathway product is a face-to-face H-type aggregate and the on-pathway product is the slipped face-to-face J-type aggregate. The autocatalytic transformation of the metastable monomeric units, as well as the two competing off- and on-pathway aggregates allow the realization of seeded and living supramolecular polymerizations. Interestingly, the presence of chiral, branched side chains in chiral (S)-2 noticeably retards the kinetics of the investigated transformations. This work brings to light the relevance of controlling the pathway complexity in self-assembling units and opens new avenues for the investigation of complex and functional supramolecular structures. PMID- 29141118 TI - PbS/CdS Core-Shell Quantum Dots Suppress Charge Transfer and Enhance Triplet Transfer. AB - A sub-monolayer CdS shell on PbS quantum dots (QDs) enhances triplet energy transfer (TET) by suppressing competitive charge transfer from QDs to molecules. The CdS shell increases the linear photon upconversion quantum yield (QY) from 3.5 % for PbS QDs to 5.0 % for PbS/CdS QDs when functionalized with a tetracene acceptor, 5-CT. While transient absorption spectroscopy reveals that both PbS and PbS/CdS QDs show the formation of the 5-CT triplet (with rates of 5.91+/-0.60 ns 1 and 1.03+/-0.09 ns-1 respectively), ultrafast hole transfer occurs only from PbS QDs to 5-CT. Although the CdS shell decreases the TET rate, it enhances TET efficiency from 60.3+/-6.1 % to 71.8+/-6.2 % by suppressing hole transfer. Furthermore, the CdS shell prolongs the lifetime of the 5-CT triplet and thus enhances TET from 5-CT to the rubrene emitter, further bolstering the upconverison QY. PMID- 29141119 TI - Distal Weak Coordination of Acetamides in Ruthenium(II)-Catalyzed C-H Activation Processes. AB - C-H activations with challenging arylacetamides were accomplished by versatile ruthenium(II) biscarboxylate catalysis. The distal C-H functionalization offers ample scope-including twofold oxidative C-H functionalizations and alkyne hydroarylations-through facile base-assisted internal electrophilic-type substitution (BIES) C-H ruthenation by weak O-coordination. PMID- 29141120 TI - Biotinylated Photopolymers for 3D-Printed Unibody Lab-on-a-Chip Optical Platforms. AB - The present work reports the first demonstration of straightforward fabrication of monolithic unibody lab-on-a-chip (ULOCs) integrating bioactive micrometric 3D scaffolds by means of multimaterial stereolithography (SL). To this end, a novel biotin-conjugated photopolymer is successfully synthesized and optimally formulated to achieve high-performance SL-printing resolution, as demonstrated by the SL-fabrication of biotinylated structures smaller than 100 um. By optimizing a multimaterial single-run SL-based 3D-printing process, such biotinylated microstructures are incorporated within perfusion microchambers whose excellent optical transparency enables real-time optical microscopy analyses. Standard biotin-binding assays confirm the existence of biotin-heads on the surfaces of the embedded 3D microstructures and allow to demonstrate that the biofunctionality of biotin is not altered during the SL-printing, thus making it exploitable for further conjugation with other biomolecules. As a step forward, an in-line optical detection system is designed, prototyped via SL-printing and serially connected to the perfusion microchambers through customized world-to chip connectors. Such detection system is successfully employed to optically analyze the solution flowing out of the microchambers, thus enabling indirect quantification of the concentration of target interacting biomolecules. The successful application of this novel biofunctional photopolymer as SL-material enables to greatly extend the versatility of SL to directly fabricate ULOCs with intrinsic biofunctionality. PMID- 29141121 TI - Pseudocyesis: Birth of a Phantom. PMID- 29141122 TI - Willingness to Engage in Health Behavior Change Interventions Among Primary Care Patients Positive For Tobacco Use and At-Risk Drinking. AB - Objective: To examine intervention preferences of primary care patients who recently screened positive for tobacco use and at-risk drinking. Methods: Primary care patients who screened positive for recent tobacco use and at-risk drinking were eligible to participate in a one-time telephone-based survey conducted from August 2015 to December 2015. The survey asked questions about how willingness to engage in an intervention in integrated primary care was influenced by the described format and focus of the intervention. Data from patients who smoked cigarettes and met criteria for at-risk drinking in the last 30 days (N = 53) were included in the analyses. Results: Participants reported that they would be more willing to engage in an intervention focused on helping them reduce their risk of medical problems than in services focused specifically on discussing cigarette or alcohol use (P = .00). Participants did not indicate a preference related to whether the intervention was delivered during a primary care appointment, immediately following a primary care appointment, or as a scheduled follow-up (P = .693). Conclusions: Patients may be more willing to engage in a behavior intervention when general health is emphasized over a focus specifically on tobacco or alcohol use. Patients were equally receptive to receiving brief interventions in several different formats available within an integrated primary care setting. PMID- 29141123 TI - Improving Mental Health Training for Primary Care Residents: A Resident-Led Educational Intervention. AB - Objective: Psychiatric training in family medicine residency programs is necessary but not always sufficient. A brief educational intervention was designed to help improve family medicine residents' knowledge, comfort, and attitudes in delivering mental health care. Methods: A 6-hour didactic curriculum was taught by 2 psychiatry residents to family medicine residents between February and April 2015. Preintervention and postintervention surveys assessed participant demographics, knowledge, comfort levels, and attitudes regarding treating patients with psychiatric illness. Descriptive statistics were used to summarize results. Relationships between the sessions attended and preintervention and postintervention knowledge, comfort, and attitudes were investigated. Results: Of 24 eligible residents, 15 completed each of the surveys preintervention and postintervention. Psychiatric knowledge scores were similar in the preintervention (mean score = 70%, SD = 15%) and postintervention (mean score = 69%, SD = 16%) groups. A significant positive correlation emerged between the number of didactic sessions attended and postintervention comfort levels (Spearman rank correlation coefficient: rho = 0.61, P = .02). The number of sessions attended was also positively associated with postintervention knowledge scores, although this did not reach statistical significance (rho = 0.40, P = .16). No relationship emerged between the number of sessions attended and participant attitudes (F2,12 = 1.88, P = .19). Conclusions: A brief, resident-led educational intervention positively impacted family medicine residents' comfort in managing patients with psychiatric comorbidities. Further research is needed to establish the sustainability of gains and the impact of such educational interventions on patient care outcomes. PMID- 29141124 TI - The Effects of Valbenazine in Participants with Tardive Dyskinesia: Results of the 1-Year KINECT 3 Extension Study. AB - BACKGROUND: Valbenazine, a highly selective vesicular monoamine transporter 2 inhibitor, is approved for the treatment of tardive dyskinesia. This is the first report of long-term effects in adults with tardive dyskinesia. METHODS: Participants with a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or a mood disorder who completed the 6-week, double-blind, placebo-controlled period of KINECT 3 were eligible to enter the 42-week valbenazine extension (VE) period and subsequent 4-week washout period. The extension phase was conducted from December 16, 2014, to August 3, 2016. Participants who received placebo and entered the VE period were re-randomized 1:1 to valbenazine 80 or 40 mg while others continued valbenazine at the KINECT 3 dose. Safety assessments included treatment-emergent adverse events (TEAEs) and scales for suicidal ideation/behavior, treatment-emergent akathisia or parkinsonism, and psychiatric symptoms. Efficacy assessments included the Abnormal Involuntary Movement Scale (AIMS) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD). RESULTS: 198 participants entered the VE period, 124 (62.6%) completed treatment (week 48), and 121 (61.1%) completed the follow-up visit after washout (week 52). During the VE period, 69.2% of participants had >= 1 TEAE, 14.6% had a serious TEAE, and 15.7% discontinued due to a TEAE. During washout, 13.1% of participants experienced a TEAE. No apparent risk for suicidal ideation or behavior was found. Long-term valbenazine treatment did not appear to induce or worsen akathisia or parkinsonism. Participants generally remained psychiatrically stable during the study. AIMS and CGI-TD measures indicated sustained tardive dyskinesia improvement, with scores returning toward baseline after 4 weeks of valbenazine washout. CONCLUSIONS: The long-term safety and tolerability of valbenazine were generally favorable, and maintenance of treatment effect was apparent with both doses during this long-term study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02274558. PMID- 29141125 TI - Elevated Proinflammatory Markers in 22q11.2 Deletion Syndrome Are Associated With Psychosis and Cognitive Deficits. AB - OBJECTIVE: 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder whose phenotype includes high rates of a schizophrenia-like psychotic disorder and immune system abnormalities. Thus, 22q11.2DS is an ideal model for studying the relationship between psychosis and inflammation. The aim of the present study was to identify inflammatory markers that may play a role in the pathophysiologic pathways associated with psychosis and cognitive deficits in 22q11.2DS. METHODS: Forty-nine individuals with 22q11.2DS (13 with psychotic disorders according to DSM-IV criteria and 36 without psychotic disorders) and 30 age- and sex-matched healthy controls underwent psychiatric and cognitive assessments at an outpatient clinic. Blood samples from all participants were analyzed for C-reactive protein (CRP), interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNFalpha), and IL 1 receptor antagonist levels. The study was conducted between August 2014 and September 2015. RESULTS: The 22q11.2DS participants had elevated levels of CRP (P = .004), IL-6 (P = .001), TNFalpha (P < .001), and IL-10 (P = .028) compared with controls. Furthermore, the psychotic 22q11.2DS participants had higher levels of IL-6 (P < .001) and IL-6/IL-10 ratio (used as an indicator for proinflammatory activation, P < .001) compared with the nonpsychotic 22q11.2DS individuals and controls. IL-6 levels and the IL-6/IL-10 ratio correlated with the severity of the cognitive deficits in the 22q11.2DS participants. CONCLUSIONS: Our preliminary findings indicate an involvement of inflammatory processes in the pathophysiology of psychosis and cognitive deficits in 22q11.2DS and are in line with the accumulating evidence for the role of neuroinflammation in nonsyndromic schizophrenia. PMID- 29141126 TI - Exacerbation of Depression Symptoms in the Presence of Dermatitis Herpetiformis Rash, Celiac Disease, and Low Cholesterol. PMID- 29141127 TI - In Vivo Disease Control Efficacy of Isoquinoline Alkaloids Isolated from Corydalis ternata against Wheat Leaf Rust and Pepper Anthracnose. AB - Phytochemicals have been considered as alternatives for synthetic fungicides because of their biodegradability and low toxicity. In this study, we found that the methanolic extract of Corydalis ternata suppressed the development of plant diseases caused by Puccinia triticina and Colletotrichum coccodes. As the antifungal substance, three isoquinoline alkaloids (dehydrocorydaline, stylopine, and corydaline) were isolated from C. ternata. These active compounds also exhibited in vivo antifungal activity against P. triticina and C. coccodes. Taken together, our results suggest that C. ternata and its active compounds can be used to control plant diseases. PMID- 29141129 TI - Recent Trends in Salmonella Outbreaks and Emerging Technology for Biocontrol of Salmonella Using Phages in Foods: A Review. AB - Salmonella is one of the principal causes of foodborne outbreaks. As traditional control methods have shown less efficacy against emerging Salmonella serotypes or antimicrobialresistant Salmonella, new approaches have been attempted. The use of lytic phages for the biocontrol of Salmonella in the food industry has become an attractive method owing to the many advantages offered by the use of phages as biocontrol agents. Phages are natural alternatives to traditional antimicrobial agents; they have proven effective in the control of bacterial pathogens in the food industry, which has led to the development of different phage products. The treatment with specific phages in the food industry can prevent the decay of products and the spread of bacterial diseases, and ultimately promotes safe environments for animal and plant food production, processing, and handling. After an extensive investigation of the current literature, this review focuses predominantly on the efficacy of phages for the successful control of Salmonella spp. in foods. This review also addresses the current knowledge on the pathogenic characteristics of Salmonella, the prevalence of emerging Salmonella outbreaks, the isolation and characterization of Salmonella-specific phages, the effectiveness of Salmonella-specific phages as biocontrol agents, and the prospective use of Salmonella-specific phages in the food industry. PMID- 29141128 TI - Immune-Enhancing Effect of Nanometric Lactobacillus plantarum nF1 (nLp-nF1) in a Mouse Model of Cyclophosphamide-Induced Immunosuppression. AB - Nanometric Lactobacillus plantarum nF1 (nLp-nF1) is a biogenics consisting of dead L. plantarum cells pretreated with heat and a nanodispersion process. In this study, we investigated the immune-enhancing effects of nLp-nF1 in vivo and in vitro. To evaluate the immunostimulatory effects of nLp-nF1, mice immunosuppressed by cyclophosphamide (CPP) treatment were administered with nLp nF1. As expected, CPP restricted the immune response of mice, whereas oral administration of nLp-nF1 significantly increased the total IgG in the serum, and cytokine production (interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF alpha)) in bone marrow cells. Furthermore, nLp-nF1 enhanced the production of splenic cytokines such as IL-12, TNF-alpha, and interferon gamma (IFN-gamma). In vitro, nLp-nF1 stimulated the immune response by enhancing the production of cytokines such as IL-12, TNF-alpha, and IFN-gamma. Moreover, nLp-nF1 given a food additive enhanced the immune responses when combined with various food materials in vitro. These results suggest that nLp-nF1 could be used to strengthen the immune system and recover normal immunity in people with a weak immune system, such as children, the elderly, and patients. PMID- 29141130 TI - Enhancement of L-Threonine Production by Controlling Sequential Carbon-Nitrogen Ratios during Fermentation. AB - Controlling the residual glucose concentration is important for improving productivity in L-threonine fermentation. In this study, we developed a procedure to automatically control the feeding quantity of glucose solution as a function of ammonia-water consumption rate. The feeding ratio (RC/N) of glucose and ammonia water was predetermined via a stoichiometric approach, on the basis of glucose-ammonia water consumption rates. In a 5-L fermenter, 102 g/l L-threonine was obtained using our glucose-ammonia water combined feeding strategy, which was then successfully applied in a 500-L fermenter (89 g/l). Therefore, we conclude that an automatic combination feeding strategy is suitable for improving L threonine production. PMID- 29141131 TI - Simultaneous Detection of Four Foodborne Viruses in Food Samples Using a One-Step Multiplex Reverse Transcription PCR. AB - A one-step multiplex reverse transcription PCR (RT-PCR) method comprising six primer sets (for the detection of norovirus GI and GII, hepatitis A virus, rotavirus, and astrovirus) was developed to simultaneously detect four kinds of pathogenic viruses. The size of the PCR products for norovirus GI and GII, hepatitis A virus (VP3/VP1 and P2A regions), rotavirus, and astrovirus were 330, 164, 244, 198, 629, and 449 bp, respectively. The RT-PCR with the six primer sets showed specificity for the pathogenic viruses. The detection limit of the developed multiplex RT-PCR, as evaluated using serially diluted viral RNAs, was comparable to that of one-step single RT-PCR. Moreover, this multiplex RT-PCR was evaluated using food samples such as water, oysters, lettuce, and vegetable product. These food samples were artificially spiked with the four kinds of viruses in diverse combinations, and the spiked viruses in all food samples were detected successfully. PMID- 29141132 TI - Intraspecies Volatile Interactions Affect Growth Rates and Exometabolomes in Aspergillus oryzae KCCM 60345. AB - Volatile organic compounds (VOCs) are increasingly been recognized as the chemical mediators of mold interactions, shaping their community dynamics, growth, and metabolism. Herein, we selectively examined the time-correlated (0 D 11 D, where D = incubation days) effects of intraspecies VOC-mediated interactions (VMI) on Aspergillus oryzae KCCM 60345 (S1), following co cultivation with partner strain A. oryzae KACC 44967 (S2), in a specially designed twin plate assembly. The comparative evaluation of S1VMI (S1 subjected to VMI with S2) and its control (S1Con) showed a notable disparity in their radial growth (S1VMI < S1Con) at 5 D, protease activity (S1VMI > S1Con) at 3-5 D, amylase activity (S1VMI < S1Con) at 3-5 D, and antioxidant levels (S1VMI > S1Con) at 3 D. Furthermore, we observed a distinct clustering pattern for gas chromatography-time of flight-mass spectrometry datasets from 5 D extracts of S1VMI and S1Con in principle component analysis (PC1: 30.85%; PC2: 10.31%) and partial least squares discriminant analysis (PLS-DA) (PLS1: 30.77; PLS2: 10.15%). Overall, 43 significantly discriminant metabolites were determined for engendering the metabolic variance based on the PLS-DA model (VIP > 0.7, p < 0.05). In general, a marked disparity in the relative abundance of amino acids (S1VMI > S1Con) at 5 D, organic acids (S1VMI > S1Con) at 5 D, and kojic acid (S1VMI < S1Con) at 5-7 D were observed. Examining the headspace VOCs shared between S1 and S2 in the twin plate for 5 D incubated samples, we observed the relatively higher abundance of C-8 VOCs (1-octen-3-ol, (5Z)-octa-1,5-dien-3-ol, 3 octanone, 1-octen-3-ol acetate) having known semiochemical functions. The present study potentially illuminates the effects of VMI on commercially important A. oryzae's growth and biochemical phenotypes with subtle details of altered metabolomes. PMID- 29141133 TI - Hierarchical Assembly of DNA Filaments with Designer Elastic Properties. AB - The elastic features of protein filaments are encoded in their component units and in the way they are connected, thus defining a biunivocal relationship between the monomer and the result of its self-assembly. Using DNA origami approaches, we constructed a reconfigurable module, composed of two quasi independent domains and four possible interfaces, capable of facial and lateral growing through specific recognition patterns. Whereas the flexibility of the intra-domains region can be regulated by switchable DNA motifs, the inter-domain interfaces feature mutually and self-complementary shapes, whose pairwise association leads to filaments of programmable periodicity and variable persistence length. Thus, we show here that the assembly pathway leading to oligomeric chains can be finely tuned and fully controlled, enabling the emulation of protein-like filaments using a single construction principle. Our approach results in artificial materials with a large variety of ultrastructures and bending strengths comparable, or even superior, to their natural counterparts. PMID- 29141134 TI - Cellular Analysis Using Microfluidics. PMID- 29141135 TI - Fatty Acid Composition of Lamb Liver, Muscle, And Adipose Tissues in Response to Rumen-Protected Conjugated Linoleic Acid (CLA) Supplementation Is Tissue Dependent. AB - The tissue-specific response to rumen-protected conjugated linoleic acid supply (rpCLA) of liver, two muscles, and three adipose tissues of heavy lambs was studied. Twenty-four lambs, 8 months old, divided into 4 groups of 6, were fed at libitum on a ration supplemented without or with a mixture of rpCLA. Silica and hydrogenated soybean oil was the rpCLA coating matrix. The lambs were slaughtered at 11 months of age. Tissues were collected and analyzed for their FA profiles. The dietary rpCLA supplement had no influence on carcass fatness nor on the fat content of the liver and tissues and had little influence on the FA profiles of these tissues. In the adipose tissues, rpCLA increased the proportions of saturated FAs, 18:0 and 18:2t10c12, and decreased the proportions of monounsaturated FAs in the adipose tissues. In muscles, the effects were the opposite. The results suggest that Delta9 desaturase activity is inhibited by the rpCLA mixture in adipose tissues to a greater extent than in the other tissues. PMID- 29141136 TI - Systemic mRNA Delivery to the Lungs by Functional Polyester-based Carriers. AB - Messenger RNA (mRNA) has recently come into focus as an emerging therapeutic class with great potential for protein replacement therapy, cancer immunotherapy, regenerative medicine, vaccines, and gene editing. However, the lack of effective and safe delivery methods impedes the broad application of mRNA-based therapeutics. We report a robust approach to develop efficient polymeric delivery carriers for mRNA. Lead polyesters were identified by in vitro screening of a 480 member combinatorially modified poly(trimethylolpropane allyl ether-co-suberoyl chloride) library for the delivery of luciferase encoding mRNA (Luc mRNA) to IGROV1 cells. The formulation of mRNA polyplex nanoparticles (NPs) with Pluronic F127 decreased the surface charge. Although this improved the stability of mRNA nanoparticles, the delivery potency decreased with increased F127 content. Thus, we determined that NP stabilization with 5% F127 could balance the protective effects and delivery potency. 5% F127 formulated PE4K-A17-0.33C12 mRNA NPs enabled luciferase expression predominantly in the lungs after intravenous injection into mice. The efficient mRNA delivery specifically to lungs by degradable carriers suggests the potential for the treatment of pulmonary diseases. PMID- 29141137 TI - Wafer-Scale Growth and Transfer of Highly-Oriented Monolayer MoS2 Continuous Films. AB - Large scale epitaxial growth and transfer of monolayer MoS2 has attracted great attention in recent years. Here, we report the wafer-scale epitaxial growth of highly oriented continuous and uniform monolayer MoS2 films on single-crystalline sapphire wafers by chemical vapor deposition (CVD) method. The epitaxial film is of high quality and stitched by many 0 degrees , 60 degrees domains and 60 degrees -domain boundaries. Moreover, such wafer-scale monolayer MoS2 films can be transferred and stacked by a simple stamp-transfer process, and the substrate is reusable for subsequent growth. Our progress would facilitate the scalable fabrication of various electronic, valleytronic, and optoelectronic devices for practical applications. PMID- 29141138 TI - Differential Effects of Strand Asymmetry on the Energetics and Structural Flexibility of DNA Internal Loops. AB - Internal loops within structured nucleic acids disrupt local base stacking and destabilize neighboring helical domains; however, these structural motifs also expand the conformational and functional capabilities of structured nucleic acids. Variations in the size, distribution of loop nucleotides on opposing strands (strand asymmetry), and sequence alter their biophysical properties. Here, the thermodynamics and structural flexibility of oligo-T-rich DNA internal loops were systematically investigated in terms of loop size and strand asymmetry. From optical melting experiments, a thermodynamic prediction model is proposed for the energetic penalty of internal loops that accounts for diminishing enthalpic and increasing entropic contributions due to loop size and strand asymmetry for bulges, asymmetric loops, and symmetric loops. These single stranded domains become less sequence-dependent and more polymeric as the loop size increases. Single-molecule fluorescence resonance energy transfer studies reveal a gradual transition in conformation and structural flexibility from an elongated domain to an increasingly flexible bend that results from increasing strand asymmetry. The findings provide a framework for understanding the thermodynamic and conformational effects of internal loops for the rational design of functional DNA nanostructures. PMID- 29141139 TI - Effect of Synthetic High Density Lipoproteins Modification with Polyethylene Glycol on Pharmacokinetics and Pharmacodynamics. AB - Synthetic high density lipoprotein nanoparticles (sHDLs) capable of mobilizing excess cholesterol from atherosclerotic arteries and delivering it to the liver for elimination have been shown to reduce plaque burden in patients. Unfortunately, sHDLs have a narrow therapeutic index and relative to the endogenous HDL shorter circulation half-life. Surface modification with polyethylene glycol (PEG) was investigated for its potential to extend sHDL circulation in vivo. Various amounts (2.5, 5, and 10%) and different chain lengths (2 and 5 kDa) of PEG-modified lipids were incorporated in sHDL's lipid membrane. Incorporating PEG did not reduce the ability of sHDL to facilitate cholesterol efflux, nor did it inhibit cholesterol uptake by the liver cells. By either adding more PEG or using PEG of longer chain lengths, the circulation half life was extended. Addition of PEG also increased the area under the curve for the phospholipid component of sHDL (p < 0.05), but not for the apolipoprotein A-I peptide component of sHDL, suggesting sHDL is remodeled by endogenous lipoproteins in vivo. The extended phospholipid circulation led to a higher mobilization of plasma free cholesterol, a biomarker for facilitation of reverse cholesterol transport. The area under the cholesterol mobilization increased about 2-4-fold (p < 0.05), with greater increases observed for longer PEG chains and higher molar percentages of incorporated PEGylated lipids. Mobilized cholesterol was associated primarily with the HDL fraction, led to a transient increase in VLDL cholesterol, and returned to baseline 24 h postdose. Overall, PEGylation of sHDL led to beneficial changes in sHDL particle pharmacokinetic and pharmacodynamic behaviors. PMID- 29141140 TI - N-Heterocyclic Carbene Self-Assembled Monolayers on Gold as Surface Plasmon Resonance Biosensors. AB - Surface plasmon resonance (SPR)-based biosensing is a powerful tool to study the recognition processes between biomolecules in real-time without need for labels. The use of thiol chemistry is a critical component in surface functionalization of various SPR biosensor surfaces on gold. However, its use is hampered by the high propensity for oxidation of the gold-thiol linkage even in ambient atmosphere, resulting in a short lifetime of SPR sensor chips unless strict precautions are taken. Herein, we describe an approach to overcome this limitation by employing highly robust self-assembled monolayers (SAMs) of alkylated N-heterocyclic carbenes (NHCs) on gold. An alkylated NHC sensor surface was developed and its biosensing capabilities were compared to a commercial thiol based analogue-a hydrophobic association (HPA) chip-in terms of its ability to act as a reliable platform for biospecific interaction analysis under a wide range of conditions. The NHC-based SPR sensor outperforms related thiol-based sesnsors in several aspects, including lower nonspecific binding capacity, better chemical stability, higher reproducibility, shorter equilibration time, and longer life span. We also demonstrate that the NHC-based sensor can be used for rapid and efficient formation of a hybrid lipid bilayer for use in membrane interaction studies. Overall, this work identifies the great promise in designing NHC-based surfaces as a new technology platform for SPR-based biosensing. PMID- 29141141 TI - Electronic and Torsional Effects on Hydrogen Atom Transfer from Aliphatic C-H Bonds: A Kinetic Evaluation via Reaction with the Cumyloxyl Radical. AB - A kinetic study on the hydrogen atom transfer (HAT) reactions from the aliphatic C-H bonds of a series of 1-Z-pentyl, 1-Z-propyl, and Z-cyclohexyl derivatives and of a series of N-alkylamides and N-alkylphthalimides to the electrophilic cumyloxyl radical (CumO*) has been carried out. With 1-pentyl and 1-propyl derivatives, alpha-CH2 activation toward CumO* is observed for Z = Ph, OH, NH2, and NHAc, as evidenced by an increase in kH as compared to the unsubstituted alkane substrate. A decrease in kH has been instead measured for Z = OAc, NPhth, CO2Me, Cl, Br, and CN, indicative of alpha-CH2 deactivation with HAT that predominantly occurs from the most remote methylenic site. With cyclohexyl derivatives, alpha-CH activation is only observed for Z = OH and NH2, indicative of torsional effects as an important contributor in governing the functionalization selectivity of monosubstituted cyclohexanes. In the reactions of N-alkylamides and N-alkylphthalimides with CumO*, the reactivity and selectivity patterns parallel those observed in the oxidation of the same substrates with H2O2 catalyzed by manganese complexes, supporting the hypothesis that both reactions proceed through a common HAT mechanism. The implications of these findings and the potential of electronic, stereoelectronic, and torsional effects as tools to implement selectivity in C-H oxidation reactions are briefly discussed. PMID- 29141142 TI - Closing the Loop on Transition-Metal-Mediated Nitrogen Fixation: Chemoselective Production of HN(SiMe3)2 from N2, Me3SiCl, and X-OH (X = R, R3Si, or Silica Gel). AB - Treatment of the Mo(IV) terminal imido complex, (eta5 C5Me5)[N(Et)C(Ph)N(Et)]Mo(NSiMe3) (3), with a 1:2 mixture of iPrOH and Me3SiCl resulted in the rapid formation of the Mo(IV) dichloride, (eta5 C5Me5)[N(Et)C(Ph)N(Et)]MoCl2 (1), and the generation of 1 equiv each of HN(SiMe3)2 and iPrOSiMe3. Similarly, a 1:2 mixture of Me3SiOH and Me3SiCl provided 1, HN(SiMe3)2, and O(SiMe3)2. Finally, silica gel, when coupled with excess equivalents of Me3SiCl, was also effectively used as the X-OH reagent for the generation of 1 and HN(SiMe3)2. A proposed mechanism for the 3 -> 1 transformation involves formal addition of HCl across the Mo?N imido bond through initial hydrogen-bonding between X-OH and the N-atom of 3 to form the adduct IIIb, followed by chloride delivery from Me3SiCl to the metal center via a six membered transition state (IV) that leads to the intermediate, (eta5 C5Me5)[N(Et)C(Ph)N(Et)]Mo(Cl)(NHSiMe3) (V), and XOSiMe3 as a co-product. Metathetical exchange of the new Mo-N amido bond of V by a second equivalent of Me3SiCl then generates 1 and HN(SiMe3). These results serve to complete a highly efficient chemical cycle for nitrogen fixation that is mediated by a set of well characterized transition-metal complexes. PMID- 29141143 TI - Michael-Michael Addition Reactions Promoted by Secondary Amine-Thiourea: Stereocontrolled Construction of Barbiturate-Fused Tetrahydropyrano Scaffolds and Pyranocoumarins. AB - Bifunctional secondary amine-thiourea organocatalysts were successfully applied in the stereocontrolled synthesis of barbiturate-fused tetrahydropyrano scaffolds. Compared with typically used tertiary amine-thiourea organocatalysts, the developed catalysts exhibited excellent catalytic performance in the domino Michael-Michael reaction between N, N'-dimethylbarbituric acid and Morita-Baylis Hillman acetates of nitroalkenes to yield pharmaceutically important heterocycles in good yields with excellent enantioselectivities. Moreover, this catalytic protocol can also be applied to synthesize biologically active pyranocoumarin compounds. PMID- 29141144 TI - Engineering Interface with One-Dimensional Co3O4 Nanostructure in Catalytic Membrane Electrode: Toward an Advanced Electrocatalyst for Alcohol Oxidation. AB - Electrochemical oxidation has attracted vast interest as a promising alternative to traditional chemical processes in fine chemical synthesis owing to its fast and sustainable features. An electrocatalytic membrane reactor (ECMR) with a three-dimensional (3D) electrode has been successfully designed for the selective oxidation of alcohols with high current efficiency to the corresponding acids or ketones. The anode electrode was fabricated by the in situ loading of one dimensional (1D) Co3O4 nanowires (NWs) on the conductive porous Ti membrane (Co3O4 NWs/Ti) via the combination of a facile hydrothermal synthesis and subsequent thermal treatment. The electrocatalytic oxidation (ECO) results of alcohols exhibited superior catalytic performance with a higher current efficiency on the Co3O4 NWs/Ti membrane compared with those of Co3O4 nanoparticles on the Ti membrane (Co3O4 NPs/Ti). Even under low reaction temperatures such as 0 degrees C, it still displayed a very high ECO activity for alcohol oxidation in the ECMR. For example, >99% conversion and 92% selectivity toward benzoic acid were obtained for the benzyl alcohol electrooxidation. The electrode is particularly effective for the cyclohexanol oxidation, and a selectivity of >99% to cyclohexanone was achieved at 0 degrees C, higher than most reported noble-metal catalysts under the aerobic reaction conditions. The extraordinary electrocatalytic performance of the 3D Co3O4 NWs/Ti membrane electrode demonstrates the significant influence of morphology effect and engineering interfaces in membrane electrodes on the electrocatalytic activity and charge transfer process of nanocatalysts. Our results propose that similar membrane electrodes serve as versatile platforms for the applications of 1D nanomaterials, porous electrodes, and ECMRs. PMID- 29141145 TI - Homochiral versus Heterochiral Trifluoromethylated Pseudoproline Containing Dipeptides: A Powerful Tool to Switch the Prolyl-Amide Bond Conformation. AB - The design of constrained peptides is of prime importance in the development of bioactive compounds and for applications in supramolecular chemistry. Due to its nature, the peptide bond undergoes a spontaneous cis-trans isomerism, and the cis isomers are much more difficult to stabilize than the trans forms. By using oxazolidine-based pseudoprolines (PsiPro) substituted by a trifluoromethyl group, we show that the cis peptide bond can be readily switched from 0% to 100% in Xaa PsiPro dipeptides. Our results prove that changing the configuration of the Calpha in Xaa or in PsiPro is sufficient to invert the cis:trans populations while changing the nature of the Xaa side chain finely tuned the conformers ratio. Moreover, a strong correlation is found between the puckering of the oxazolidine ring and the peptide bond conformation. This finding highlights the role of the trifluoromethyl group in the stabilization of the peptide bond geometry. We anticipate that such templates will be very useful to constrain the backbone geometry of longer peptides. PMID- 29141146 TI - The Effect of Pressure and Temperature on Mid-Infrared Sensing of Dissolved Hydrocarbons in Water. AB - Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy using a polymer coated internal reflection element/waveguide is an established sensor platform for the detection of a range of organic and hydrocarbon molecules dissolved in water. The polymer coating serves two purposes: to concentrate hydrocarbons from the aqueous phase and to exclude water along with other interfering molecules from the surface of the internal reflection element. Crucial to reliable quantification and analytical performance is the calibration of the ATR-FTIR sensor which is commonly performed in water under mild ambient conditions (i.e., 25 degrees C and 1 atm). However, there is a pressing need to monitor environmental and industrial processes/events that may occur at high pressures and temperatures where this calibration approach is unsuitable. Using a ruggedized optical fiber probe with a diamond-based ATR, we have conducted mid infrared sensor experiments to understand the influence of high pressure (up to 207 bar) and temperature (up to 80 degrees C) on the detection of toluene and naphthalene dissolved in water. Using a poly(isobutylene) film, we have shown that the IR spectroscopic response is relatively unaffected by changes in pressure; however, a diminished response was observed with increasing temperature. We reveal that changes in the refractive index of the polymer film with temperature have only a minor effect on sensitivity. A more plausible explanation for the observed significant change in sensor response with temperature is that the partitioning process is exothermic and becomes less favorable with increasing temperature. This Article shows that the sensitivity is relatively invariant to pressure; however, the thermal variations are significant and need to be considered when quantifying the concentration of hydrocarbons in water. PMID- 29141147 TI - A Water-Soluble Galactose-Decorated Cationic Photodynamic Therapy Agent Based on BODIPY to Selectively Eliminate Biofilm. AB - A multitude of serious chronic infections are involved in bacterial biofilms that are difficult to eradicate. Here, a water-soluble galactose-functionalized cationic 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based photodynamic therapy agent was synthesized for selectively eliminating the bacterial biofilm. These conjugates can capture bacteria to form aggregations through electrostatic interaction and then generate a large number of reactive oxygen species (ROS) under visible light irradiation to kill the bacteria without the emergence of bacterial resistance. Simultaneously, this agent could effectively inhibit and eradicate both Gram-positive and Gram-negative bacterial biofilms. The in-depth analysis of the antimicrobial mechanism confirmed that the conjugates can quickly bind on the bacterial surface, irreversibly disrupt the bacterial membrane, and distinctly inhibit intracellular enzyme activity, ultimately leading to the bacterial death. Importantly, these conjugates are highly selective toward bacterial cells over mammalian cells as well as no cytotoxicity to A549 cells and no discernible hemolytic activity. Collectively, this water-soluble galactose decorated cationic BODIPY-based photodynamic therapy agent design provides promising insights for the development of therapy for antibiotic-resistant bacteria. PMID- 29141148 TI - Plasmonically Enhanced Galactoxyloglucan Endowed Gold Nanoparticles Exposed Tumor Targeting Biodistribution Envisaged in a Surface-Enhanced Raman Scattering Platform. AB - Biopolymer-capped gold nanoparticles (AuNPs) were perceived for tracing biodistribution in a solid tumor mice through surface-enhanced Raman scattering (SERS) fingerprinting. In this strategy, a robust and ecofriendly green chemistry approach was adopted to construct galactoxyloglucan (PST001) endowed AuNPs (PST GNPs) with cancer-cell-selective toxic nature and excellent biocompatibility. Plasmonically enhanced light-scattering properties facilitated PST-GNPs to be a superior SERS substrate with high Raman signal enhancement. In this context, PST GNPs were scrutinized for the noninvasive label-free SERS live-cell spectral imaging to evaluate the fingerprint molecular details of cellular processes. Consequently, the inherent SERS feature of PST-GNPs enabled us to investigate the dynamic and complex nature with NP biodistrubution in tumor-bearing mice on a SERS platform that illustrated the tumor targeting nature. Henceforth, the present findings emphasized a futuristic clinically relevant scenario for tracing the in vivo NP dissemination in a label-free fashion for providing vital biochemical details on a molecular level. PMID- 29141150 TI - All-Dielectric Dual-Color Pixel with Subwavelength Resolution. AB - An all-dielectric optical antenna supporting Mie resonances enables light confinement below the free-space diffraction limit. The Mie scattering wavelengths of the antenna depend on the structural geometry, which allows the antennas to be used for colored imprint images. However, there is still room for improving the spatial resolution, and new polarization-dependent color functionalities are highly desirable for realizing a wider color-tuning range. Here, we show all-dielectric color printing by means of dual-color pixels with a subwavelength-scale resolution. The simple nanostructures fabricated with monocrystalline silicon exhibit various brilliant reflection color by tuning the physical dimensions of each antenna. The designed nanostructures possess polarization-dependent properties that make it possible to create overlaid color images. The pixels will generate individual color even if operating as a single element, resulting in the achievement of subwavelength-resolution encoding without color mixing. This printing strategy could be used to further extend the degree of freedom in structural color design. PMID- 29141149 TI - Surface Modification of Cisplatin-Complexed Gold Nanoparticles and Its Influence on Colloidal Stability, Drug Loading, and Drug Release. AB - Cisplatin-complexed gold nanoparticles (PtII-AuNP) provide a promising strategy for chemo-radiation-based anticancer drugs. Effective design of such platforms necessitates reliable assessment of surface engineering on a quantitative basis and its influence on drug payload, stability, and release. In this paper, poly(ethylene glycol) (PEG)-stabilized PtII-AuNP was synthesized as a model antitumor drug platform, where PtII is attached via a carboxyl-terminated dendron ligand. Surface modification by PEG and its influence on drug loading, colloidal stability, and drug release were assessed. Complexation with PtII significantly degrades colloidal stability of the conjugate; however, PEGylation provides substantial improvement of stability in conjunction with an insignificant trade off in drug loading capacity compared with the non-PEGylated control (<20% decrease in loading capacity). In this context, the effect of varying PEG concentration and molar mass was investigated. On a quantitative basis, the extent of PEGylation was characterized and its influence on dispersion stability and drug load was examined using electrospray differential mobility analysis (ES DMA) hyphenated with inductively coupled plasma mass spectrometry (ICP-MS) and compared with attenuated total reflectance-FTIR. Using ES-DMA-ICP-MS, AuNP conjugates were size-classified based on their electrical mobility, while PtII loading was simultaneously quantified by determination of Pt mass. Colloidal stability was quantitatively evaluated in biologically relevant media. Finally, the pH-dependent PtII release performance was evaluated. We observed 9% and 16% PtII release at drug loadings of 0.5 and 1.9 PtII/nm2, respectively. The relative molar mass of PEG had no significant influence on PtII uptake or release performance, while PEGylation substantially improved the colloidal stability of the conjugate. Notably, the PtII release over 10 days (examined at 0.5 PtII/nm2 drug loading) remained constant for non-PEGylated, 1K-PEGylated, and 5K-PEGylated conjugates. PMID- 29141151 TI - Light-Responsive Nanoparticles for Highly Efficient Cytoplasmic Delivery of Anticancer Agents. AB - Stimuli-responsive nanostructures have shown great promise for intracellular delivery of anticancer compounds. A critical challenge remains in the exploration of stimuli-responsive nanoparticles for fast cytoplasmic delivery. Herein, near infrared (NIR) light-responsive nanoparticles were rationally designed to generate highly efficient cytoplasmic delivery of anticancer agents for synergistic thermo-chemotherapy. The drug-loaded polymeric nanoparticles of selenium-inserted copolymer (I/D-Se-NPs) were rapidly dissociated in several minutes through reactive oxygen species (ROS)-mediated selenium oxidation upon NIR light exposure, and this irreversible dissociation of I/D-Se-NPs upon such a short irradiation promoted continuous drug release. Moreover, I/D-Se-NPs facilitated cytoplasmic drug translocation through ROS-triggered lysosomal disruption and thus resulted in highly preferable distribution to the nucleus even in 5 min postirradiation, which was further integrated with light-triggered hyperthermia for achieving synergistic tumor ablation without tumor regrowth. PMID- 29141152 TI - Tm-Values and Unfolded Fraction Can Predict Aggregation Rates for Granulocyte Colony Stimulating Factor Variant Formulations but Not under Predominantly Native Conditions. AB - Protein engineering and formulation optimization strategies can be taken to minimize protein aggregation in the biopharmaceutical industry. Short-term stability measures such as the midpoint transition temperature (Tm) for global unfolding provide convenient surrogates for longer-term (e.g., 2-year) degradation kinetics, with which to optimize formulations on practical time scales. While successful in some cases, their limitations have not been fully evaluated or understood. Tm values are known to correlate with chemical degradation kinetics for wild-type granulocyte colony stimulating factor (GCSF) at pH 4-5.5. However, we found previously that the Tm of an antibody Fab fragment only correlated with its rate of monomer loss at temperatures close to the Tm. Here we evaluated Tm, the fraction of unfolded protein (fT) at temperature T, and two additional short-term stability measures, for their ability to predict the kinetics of monomer and bioactivity loss of wild-type GCSF and four variants, at 37 degrees C, and in a wide range of formulations. The GCSF variants introduced one to three mutations, giving a range of conformational stabilities spanning 7.8 kcal mol-1. We determined the extent to which the formulation rank order differs across the variants when evaluated by each of the four short-term stability measures. All correlations decreased as the difference in average Tm between each pair of GCSF variants increased. The rank order of formulations determined by Tm was the best preserved, with R2-values >0.7. Tm-values also provided a good predictor (R2 = 0.73) of the aggregation rates, extending previous findings to include GCSF variant-formulation combinations. Further analysis revealed that GCSF aggregation rates at 37 degrees C were dependent on the fraction unfolded at 37 degrees C (fT37), but transitioned smoothly to a constant baseline rate of aggregation at fT37 < 10-3. A similar function was observed previously for A33 Fab formulated by pH, ionic strength, and temperature, without excipients. For GCSF, all combinations of variants and formulations fit onto a single curve, suggesting that even single mutations destabilized by up to 4.8 kcal mol-1, are insufficient to change significantly the baseline rate of aggregation under native conditions. The baseline rate of aggregation for GCSF under native conditions was 66-fold higher than that for A33 Fab, highlighting that they are a specific feature of each native protein structure, likely to be dependent on local surface properties and dynamics. PMID- 29141154 TI - Obstructive Sleep Apnea and Cardiovascular Disease. REM Sleep Matters! PMID- 29141153 TI - Using Observational Data to Calibrate Simulation Models. AB - BACKGROUND: Individual-level simulation models are valuable tools for comparing the impact of clinical or public health interventions on population health and cost outcomes over time. However, a key challenge is ensuring that outcome estimates correctly reflect real-world impacts. Calibration to targets obtained from randomized trials may be insufficient if trials do not exist for populations, time periods, or interventions of interest. Observational data can provide a wider range of calibration targets but requires methods to adjust for treatment-confounder feedback. We propose the use of the parametric g-formula to estimate calibration targets and present a case-study to demonstrate its application. METHODS: We used the parametric g-formula applied to data from the HIV-CAUSAL Collaboration to estimate calibration targets for 7-y risks of AIDS and/or death (AIDS/death), as defined by the Center for Disease Control and Prevention under 3 treatment initiation strategies. We compared these targets to projections from the Cost-effectiveness of Preventing AIDS Complications (CEPAC) model for treatment-naive individuals presenting to care in the following year ranges: 1996 to 1999, 2000 to 2002, or 2003 onwards. RESULTS: The parametric g formula estimated a decreased risk of AIDS/death over time and with earlier treatment. The uncalibrated CEPAC model successfully reproduced targets obtained via the g-formula for baseline 1996 to 1999, but over-estimated calibration targets in contemporary populations and failed to reproduce time trends in AIDS/death risk. Calibration to g-formula targets improved CEPAC model fit for contemporary populations. CONCLUSION: Individual-level simulation models are developed based on best available information about disease processes in one or more populations of interest, but these processes can change over time or between populations. The parametric g-formula provides a method for using observational data to obtain valid calibration targets and enables updating of simulation model inputs when randomized trials are not available. PMID- 29141155 TI - Neutrophil-mediated Suppression of Influenza-induced Pathology Requires CD11b/CD18 (MAC-1). AB - Severe influenza virus infection can lead to life-threatening pathology through immune-mediated tissue damage. In various experimental models, this damage is dependent on T cells. There is conflicting evidence regarding the role of neutrophils in influenza-mediated pathology. Neutrophils are often regarded as cells causing tissue damage, but, in recent years, it has become clear that a subset of human neutrophils is capable of suppressing T cells, which is dependent on macrophage-1 antigen (CD11b/CD18). Therefore, we tested the hypothesis that immune suppression by neutrophils can reduce T cell-mediated pathology after influenza infection. Wild-type (WT) and CD11b-/- mice were infected with A/HK/2/68 (H3N2) influenza virus. Disease severity was monitored by weight loss, leukocyte infiltration, and immunohistochemistry. We demonstrated that CD11b-/- mice suffered increased weight loss compared with WT animals upon infection with influenza virus. This was accompanied by increased pulmonary leukocyte infiltration and lung damage. The exaggerated pathology in CD11b-/- mice was dependent on T cells, as it was reduced by T cell depletion. In addition, pathology in CD11b-/- mice was accompanied by higher numbers of T cells in the lungs early during infection compared with WT mice. Importantly, these differences in pathology were not associated with an increased viral load, suggesting that pathology was immune-mediated rather than caused by virus-induced damage. In contrast to adoptive transfer of CD11b-/- neutrophils, a single adoptive transfer of WT neutrophils partly restored protection against influenza induced pathology, demonstrating the importance of neutrophil CD11b/CD18. Our data show that neutrophil CD11b/CD18 limits pathology in influenza-induced, T cell-mediated disease. PMID- 29141156 TI - Plasmid AZOBR_p1-borne fabG gene for putative 3-oxoacyl-[acyl-carrier protein] reductase is essential for proper assembly and work of the dual flagellar system in the alphaproteobacterium Azospirillum brasilense Sp245. AB - Azospirillum brasilense can swim and swarm owing to the activity of a constitutive polar flagellum (Fla) and inducible lateral flagella (Laf), respectively. Experimental data on the regulation of the Fla and Laf assembly in azospirilla are scarce. Here, the coding sequence (CDS) AZOBR_p1160043 (fabG1) for a putative 3-oxoacyl-[acyl-carrier protein (ACP)] reductase was found essential for the construction of both types of flagella. In an immotile leaky Fla- Laf- fabG1::Omegon-Km mutant, Sp245.1610, defects in flagellation and motility were fully complemented by expressing the CDS AZOBR_p1160043 from plasmid pRK415. When pRK415 with the cloned CDS AZOBR_p1160045 (fliC) for a putative 65.2 kDa Sp245 Fla flagellin was transferred into the Sp245.1610 cells, the bacteria also became able to assemble a motile single flagellum. Some cells, however, had unusual swimming behavior, probably because of the side location of the organelle. Although the assembly of Laf was not restored in Sp245.1610 (pRK415-p1160045), this strain was somewhat capable of swarming motility. We propose that the putative 3-oxoacyl-[ACP] reductase encoded by the CDS AZOBR_p1160043 plays a role in correct flagellar location in the cell envelope and (or) in flagellar modification(s), which are also required for the inducible construction of Laf and for proper swimming and swarming motility of A. brasilense Sp245. PMID- 29141157 TI - The devastating effect of exposure to high irradiation dose on liver and the performance of synthesized nano-Hap in relieve the associated symptoms in rats. AB - Ionizing radiation is one of the environmental factors that may contribute to liver dysfunction through a mechanism involving oxidative stress. This investigation studied the possible therapeutic effects of nano-HAp on hepatotoxicity in rats induced with gamma (gamma) radiation. The study was carried out using 3 groups with 10 rats in each. Group 1 comprised the non irradiated control rats, whereas the rats in groups 2 and 3 received a single dose of 10 Gy gamma-radiation. The rats in group 3 were treated with nano-HAp [100 mg.(kg body mass)-1] once a week for 2 weeks starting the day after irradiation. The results showed that the rats exposed to gamma-radiation had fragmented DNA, and significantly decreased levels of liver tissue enzymes such as paraoxonase 1, gamma glutamyl, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Pro-inflammatory factors such as interleukin (IL)-2, IL 6, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) in tissue were significantly increased compared with the controls. Also, exposure to gamma-radiation significantly decreased the activity of superoxide dismutase and glutathione oxidase and increased lipid peroxidation in liver tissue. These effects were accompanied by severe histopathological changes to the hepatocytes. Intravenous injection of nano-HAp after irradiation has significant therapeutic potential against irradiation-induced liver damage because the treatment with nano-HAp restored antioxidant activity in the liver, antagonized the significant changes in the levels of IL-2, IL-6, TNF-alpha, IFN-gamma, and restored the tissue level of paraoxonase 1, gamma glutamyl, ALT, and AST. Administering nano HAp seemed to relieve the pathological changes induced by gamma-radiation. Based on these results, it could be concluded that nano-HAp may have a therapeutic effect against liver dysfunction induced by gamma-radiation through antagonizing the generation of free radicals and enhancing the antioxidant defense mechanisms. PMID- 29141158 TI - The Combined Effect of Cold and Moisture on Manual Performance. AB - : Objective The aim of this study was to investigate the combined effect of cold and moisture on manual performance and tactile sensitivity. Background People working in the ocean environment often perform manual work in cold and wet conditions. Although the independent effects of cold and moisture on hand function are known, their combined effect has not been investigated. Method Participants completed sensory (Touch-Test, two-point discrimination) and motor (Purdue Pegboard, Grooved Pegboard, reef knot untying) tests in the following conditions: dry hand, wet hand, cold hand, and cold and wet hand. Results For the Purdue Pegboard and knot untying tasks, the greatest decrement in performance was observed in the cold-and-wet-hand condition, whereas the decrements seen in the cold-hand and wet-hand conditions were similar. In the Grooved Pegboard task, the performance decrements exhibited in the cold-and-wet-hand condition and the cold hand condition were similar, whereas no decrement was observed in the wet-hand condition. Tactile sensitivity was reduced in the cold conditions for the Touch Test but not the two-point discrimination test. CONCLUSION: The combined effect of cold and moisture led to the largest performance decrements except when intrinsic object properties helped with grasp maintenance. The independent effects of cold and moisture on manual performance were comparable. Application Tools and equipment for use in the cold ocean environment should be designed to minimize the effects of cold and moisture on manual performance by including object properties that enhance grasp maintenance and minimize the fine-dexterity requirements. PMID- 29141159 TI - Compelling Reasons for Repairing Human Germlines. PMID- 29141160 TI - Advanced Non-Small-Cell Lung Cancer. PMID- 29141161 TI - Cognitive Function in a Randomized Trial of Evolocumab. PMID- 29141162 TI - Safety of Degludec versus Glargine in Type 2 Diabetes. PMID- 29141163 TI - Case 35-2017. A 57-Year-Old Woman with Hypoesthesia and Weakness in the Legs and Arms. PMID- 29141165 TI - Immunotherapy for Unresectable Stage III Non-Small-Cell Lung Cancer. PMID- 29141166 TI - Designing Ethical Trials of Germline Gene Editing. PMID- 29141164 TI - Lomustine and Bevacizumab in Progressive Glioblastoma. AB - BACKGROUND: Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than lomustine alone among patients at first progression of glioblastoma. METHODS: We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive lomustine plus bevacizumab (combination group, 288 patients) or lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O6 methylguanine-DNA methyltransferase (MGMT) was assessed. Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival. RESULTS: A total of 437 patients underwent randomization. The median number of 6-week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval [CI], 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression-free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P<0.001). Grade 3 to 5 adverse events occurred in 63.6% of the patients in the combination group and 38.1% of the patients in the monotherapy group. The addition of bevacizumab to lomustine affected neither health-related quality of life nor neurocognitive function. The MGMT status was prognostic. CONCLUSIONS: Despite somewhat prolonged progression-free survival, treatment with lomustine plus bevacizumab did not confer a survival advantage over treatment with lomustine alone in patients with progressive glioblastoma. (Funded by an unrestricted educational grant from F. Hoffmann-La Roche and by the EORTC Cancer Research Fund; EORTC 26101 ClinicalTrials.gov number, NCT01290939 ; Eudra-CT number, 2010-023218-30 .). PMID- 29141167 TI - "Popeye" Sign. PMID- 29141168 TI - Methemoglobinemia Due to Antifreeze Ingestion. PMID- 29141169 TI - Health Insurance Coverage and Health. PMID- 29141170 TI - Data Sharing from Clinical Trials - A Research Funder's Perspective. PMID- 29141171 TI - The Code, the Cloud, and the Doppler. PMID- 29141172 TI - An Unusual Cause of Leg Pain. PMID- 29141173 TI - Falciform Ligament Sign. PMID- 29141174 TI - Diuretic Treatment in Heart Failure. PMID- 29141176 TI - Letter From the Editor: Guest Editorials. PMID- 29141175 TI - Sudden Cardiac Arrest during Participation in Competitive Sports. AB - BACKGROUND: The incidence of sudden cardiac arrest during participation in sports activities remains unknown. Preparticipation screening programs aimed at preventing sudden cardiac arrest during sports activities are thought to be able to identify at-risk athletes; however, the efficacy of these programs remains controversial. We sought to identify all sudden cardiac arrests that occurred during participation in sports activities within a specific region of Canada and to determine their causes. METHODS: In this retrospective study, we used the Rescu Epistry cardiac arrest database (which contains records of every cardiac arrest attended by paramedics in the network region) to identify all out-of hospital cardiac arrests that occurred from 2009 through 2014 in persons 12 to 45 years of age during participation in a sport. Cases were adjudicated as sudden cardiac arrest (i.e., having a cardiac cause) or as an event resulting from a noncardiac cause, on the basis of records from multiple sources, including ambulance call reports, autopsy reports, in-hospital data, and records of direct interviews with patients or family members. RESULTS: Over the course of 18.5 million person-years of observation, 74 sudden cardiac arrests occurred during participation in a sport; of these, 16 occurred during competitive sports and 58 occurred during noncompetitive sports. The incidence of sudden cardiac arrest during competitive sports was 0.76 cases per 100,000 athlete-years, with 43.8% of the athletes surviving until they were discharged from the hospital. Among the competitive athletes, two deaths were attributed to hypertrophic cardiomyopathy and none to arrhythmogenic right ventricular cardiomyopathy. Three cases of sudden cardiac arrest that occurred during participation in competitive sports were determined to have been potentially identifiable if the athletes had undergone preparticipation screening. CONCLUSIONS: In our study involving persons who had out-of-hospital cardiac arrest, the incidence of sudden cardiac arrest during participation in competitive sports was 0.76 cases per 100,000 athlete years. The occurrence of sudden cardiac arrest due to structural heart disease was uncommon during participation in competitive sports. (Funded by the National Heart, Lung, and Blood Institute and others.). PMID- 29141177 TI - Health-Care Reform U.S. Style. PMID- 29141178 TI - Peri-conception and first trimester diet modifies reproductive development in bulls. AB - Nutritional perturbation during gestation alters male reproductive development in rodents and sheep. In cattle both the developmental trajectory of the feto placental unit and its response to dietary perturbations is dissimilar to that of these species. This study examined the effects of dietary protein perturbation during the peri-conception and first trimester periods upon reproductive development in bulls. Nulliparous heifers (n=360) were individually fed a high- or low-protein diet (HPeri and LPeri) from 60 days before conception. From 24 until 98 days post conception, half of each treatment group changed to the alternative post-conception high- or low-protein diet (HPost and LPost) yielding four treatment groups in a 2*2 factorial design. A subset of male fetuses (n=25) was excised at 98 days post conception and fetal testis development was assessed. Reproductive development of singleton male progeny (n=40) was assessed until slaughter at 598 days of age, when adult testicular cytology was evaluated. Low peri-conception diet delayed reproductive development: sperm quality was lowered during pubertal development with a concomitant delay in reaching puberty. These effects were subsequent to lower FSH concentrations at 330 and 438 days of age. In the fetus, the low peri-conception diet increased the proportion of seminiferous tubules and decreased blood vessel area in the testis, whereas low first trimester diet increased blood vessel number in the adult testis. We conclude that maternal dietary protein perturbation during conception and early gestation may alter male testis development and delay puberty in bulls. PMID- 29141179 TI - Formation of longitudinal axon pathways in Caenorhabditis elegans. AB - The small number of neurons and the simple architecture of the Caenorhabditis elegans (C. elegans) nervous system enables researchers to study axonal pathfinding at the level of individually identified axons. Axons in C. elegans extend predominantly along one of the two major body axes, the anterior-posterior axis and the dorso-ventral axis. This review will focus on axon navigation along the anterior-posterior axis, leading to the establishment of the longitudinal axon tracts, with a focus on the largest longitudinal axon tract, the ventral nerve cord (VNC). In the VNC, axons grow out in a stereotypic order, with early outgrowing axons (pioneers) playing an important role in guiding later outgrowing (follower) axons. Genetic screens have identified a number of genes specifically affecting the formation of longitudinal axon tracts. These genes include secreted proteins, putative receptors and adhesion molecules, as well as intracellular proteins regulating the cell's response to guidance cues. In contrast to dorso ventral navigation, no major general guidance cues required for the establishment of longitudinal pathways have been identified so far. The limited penetrance of defects found in many mutants affecting longitudinal navigation suggests that guidance cues act redundantly in this process. The majority of the axon guidance genes identified in C. elegans are evolutionary conserved, i.e. have homologs in other animals, including vertebrates. For a number of these genes, a role in axon guidance has not been described outside C. elegans. Taken together, studies in C. elegans contribute to a fundamental understanding of the molecular basis of axonal navigation that can be extended to other animals, including vertebrates and probably humans as well. PMID- 29141180 TI - Motor neuron migration and positioning mechanisms: New roles for guidance cues. AB - Motor neurons differentiate from progenitor cells and cluster as motor nuclei, settling next to the floor plate in the brain stem and spinal cord. Although precise positioning of motor neurons is critical for their functional input and output, the molecular mechanisms that guide motor neurons to their proper positions remain poorly understood. Here, we review recent evidence of motor neuron positioning mechanisms, highlighting situations in which motor neuron cell bodies can migrate, and experiments that show that their migration is regulated by axon guidance cues. The view that emerges is that motor neurons are actively trapped or restricted in static positions, as the cells balance a push in the dorsal direction by repulsive Slit/Robo cues and a pull in the ventral direction by attractive Netrin-1/DCC cues. These new functions of guidance cues are necessary fine-tuning to set up patterns of motor neurons at their proper positions in the neural tube during embryogenesis. PMID- 29141181 TI - Axon pathfinding for locomotion. AB - Motor neurons of the spinal cord are responsible for the assembly of neuromuscular connections indispensable for basic locomotion and skilled movements. A precise spatial relationship exists between the position of motor neuron cell bodies in the spinal cord and the course of their axonal projections to peripheral muscle targets. Motor neuron innervation of the vertebrate limb is a prime example of this topographic organization and by virtue of its accessibility and predictability has provided access to fundamental principles of motor system development and neuronal guidance. The seemingly basic binary map established by genetically defined motor neuron subtypes that target muscles in the limb is directed by a surprisingly large number of directional cues. Rather than being simply redundant, these converging signaling pathways are hierarchically linked and cooperate to increase the fidelity of axon pathfinding decisions. A current priority is to determine how multiple guidance signals are integrated by individual growth cones and how they synergize to delineate class specific axonal trajectories. PMID- 29141183 TI - Functional Outcomes of Acute Inpatient Rehabilitation in Patients With Chronic Graft-Versus-Host Disease. AB - BACKGROUND: Growing numbers of allogeneic stem cell transplants and improved posttransplant care have led to an increase of individuals with chronic graft versus-host disease (cGVHD). Although cGVHD leads to functional impairment for many, there is limited literature regarding the benefits of acute inpatient rehabilitation for patients with cGVHD. OBJECTIVE: To assess Functional Independence Measure (FIM) outcomes of patients with cGVHD during acute inpatient rehabilitation and to compare inpatient rehabilitation outcomes with patients with burn injuries, a rehabilitation patient population with similar comorbidities. DESIGN: Retrospective chart review. SETTING: Acute rehabilitation center at a large academic medical center. PATIENTS (OR PARTICIPANTS): A total of 37 adult patients with cGVHD and 30 with burn injuries admitted to inpatient rehabilitation from 2010 to 2015. METHODS OR INTERVENTIONS: Linear regression analysis to evaluate group (cGVHD versus burn) differences in functional gains. Effect size and minimal detectable change at the 90% confidence level (MDC90) were used to evaluate change in FIM outcomes. MAIN OUTCOME MEASUREMENTS: Total FIM gain, motor FIM gain, and FIM efficiency. RESULTS: Patients with cGVHD had statistically significant lower functional gains than patients with burn injuries, with an average of 11.66 fewer total FIM points (P <= .001), 10.54 fewer motor FIM points (P = .01), and 2.45 units less of FIM efficiency (P = .01). At the time of discharge, 7 (18%) patients with cGVHD exceeded the MDC90 values for total FIM gain versus 9 (30%) patients with burn injuries (P = .26). Eight (21%) patients with cGVHD exceeded the MDC90 for motor FIM gain versus 13 (43%) patients with burn injuries (P = .048). Effect sizes for patients with cGVHD and with burn injury were moderate to large, respectively, with patients with burn injuries having nearly twice the magnitude of gains as patients with cGVHD. CONCLUSIONS: Despite achieving more modest functional gains than patients with burn injuries, patients with cGVHD improved in function after acute inpatient rehabilitation. If replicated in larger studies, patients with functional impairment from cGVHD can be considered for inpatient rehabilitation. Future work should also determine minimal clinically important differences in function gain from inpatient rehabilitation for patients with cGVHD. LEVEL OF EVIDENCE: II. PMID- 29141182 TI - Optogenetic activation of 5-HT neurons in the dorsal raphe suppresses seizure induced respiratory arrest and produces anticonvulsant effect in the DBA/1 mouse SUDEP model. AB - Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication. Seizure-induced respiratory arrest (S-IRA) occurs in many witnessed SUDEP patients and animal models as an initiating event leading to death. Thus, understanding the mechanisms underlying S-IRA will advance the development of preventive strategies against SUDEP. Serotonin (5-HT) is an important modulator for many vital functions, including respiration and arousal, and a deficiency of 5-HT signaling is strongly implicated in S-IRA in animal models, including the DBA/1 mouse. However, the brain structures that contribute to S-IRA remain elusive. We hypothesized that the dorsal raphe (DR), which sends 5-HT projections to the forebrain, is implicated in S-IRA. The present study used optogenetics in the DBA/1 mouse model of SUDEP to selectively activate 5-HT neurons in the DR. Photostimulation of DR 5-HT neurons significantly and reversibly reduced the incidence of S-IRA evoked by acoustic stimulation. Activation of 5-HT neurons in the DR suppressed tonic seizures in most DBA/1 mice without altering the seizure latency and duration of wild running and clonic seizures evoked by acoustic stimulation. This suppressant effect of photostimulation on S-IRA is independent of seizure models, as optogenetic stimulation of DR also reduced S-IRA induced by pentylenetetrazole, a proconvulsant widely used to model human generalized seizures. The S-IRA-suppressing effect of photostimulation was increased by 5 hydroxytryptophan, a chemical precursor for 5-HT synthesis, and was reversed by ondansetron, a specific 5-HT3 receptor antagonist, indicating that reduction of S IRA by photostimulation of the DR is specifically mediated by enhanced 5-HT neurotransmission. Our findings suggest that deficits in 5-HT neurotransmission in the DR are implicated in S-IRA in DBA/1 mice, and that targeted intervention in the DR is potentially useful for prevention of SUDEP. PMID- 29141184 TI - Unrecognized venous injuries after cardiac implantable electronic device transvenous lead extraction. AB - BACKGROUND: The major complication rate of transvenous lead extraction (TLE) is estimated to be 1%-2%. Laceration of the central veins can be fatal. OBJECTIVES: To define the incidence and extent of venous injuries on a microscopic level after TLE and compare these data with those of clinically documented events of venous laceration. METHODS: We studied all patients who underwent TLE at our tertiary center within 30 months via a variety of techniques. Extracted leads and tissue around them were fixed in formalin. Pathologic examination was standardized to examine the leads identifying the areas covered by tissue cuffs along the length of the lead. The cuffs were removed and sectioned transversely to their longitudinal axis. Microscopic examination was performed using hematoxylin and eosin stains and Movat stains to identify the presence of vein tissue. RESULTS: In all, 861 leads (585 pacemaker and 272 defibrillator leads) were extracted from 461 patients (median age 63 years, standard deviation 15 years), with an average of 1.9 leads per patient and a median lead age of 2546 days. On microscopic review, 80 leads (9.3%) in 72 of 461 patients (15.6%) showed segments of vein, most of which were transmural (venous tissue including adventitia). Despite this finding, only 5 catastrophic complications (1.1%) occurred that required emergent surgical intervention. Risk factors for venous injury included implantable cardioverter defibrillator lead, age of lead, and the use of laser sheath. CONCLUSIONS: Microscopic venous injuries during lead extraction are common but often not recognized clinically. PMID- 29141185 TI - Increased cross-bridge recruitment contributes to transient increase in force generation beyond maximal capacity in human myocardium. AB - : Cross-bridge attachment allows force generation to occur, and rate of tension redevelopment (ktr) is a commonly used index of cross-bridge cycling rate. Tension overshoots have been observed briefly after a slack-restretch ktr maneuver in various species of animal models and humans. In this study, we set out to determine the properties of these overshoots and their possible underlying mechanism. Utilizing human cardiac trabeculae, we have found that tension overshoots are temperature-dependent and that they do not occur at resting states. In addition, we have found that myosin cross-bridge cycle is vital to these overshoots as inhibition of the cycle results in the blunting of the overshoots and the magnitude of the overshoots are dependent on the level of myofilament activation. Lastly, we show that the number of cross-bridges transiently increase during tension overshoots. These findings lead us to conclude that tension overshoots are likely due to a transient enhancement of the recruitment of myosin heads into the cross-bridge cycling, regulated by the myocardium, and with potential physiological significance in determining cardiac output. NEWS AND NOTEWORTHY: We show that isolated human myocardium is capable of transiently increasing its maximal force generation capability by increasing cross-bridge recruitment following slack-restretch maneuver. This process can potentially have important implications and significance in cardiac contraction in vivo. PMID- 29141186 TI - Hyperbaric oxygen therapy ameliorates pathophysiology of 3xTg-AD mouse model by attenuating neuroinflammation. AB - There is a real need for new interventions for Alzheimer's disease (AD). Hyperbaric oxygen therapy (HBOT), the medical administration of 100% oxygen at conditions greater than 1 atmosphere absolute, has been used successfully to treat several neurological conditions, but its effects on AD pathology have never been thoroughly examined. Therefore, we exposed old triple-transgenic (3xTg) and non-transgenic mice to HBOT followed by behavioral, histological, and biochemical analyses. HBOT attenuated neuroinflammatory processes by reducing astrogliosis, microgliosis, and the secretion of proinflammatory cytokines (IL-1beta and TNFalpha) and increasing expression of scavenger receptor A, arginase1, and antiinflammatory cytokines (IL-4 and IL-10). Moreover, HBOT reduced hypoxia, amyloid burden, and tau phosphorylation in 3xTg mice and ameliorated their behavioral deficits. Therefore, we suggest that HBOT has multifaceted effects that reduce AD pathologies, even in old mice. Given that HBOT is used in the clinic to treat various indications, including neurological conditions, these results suggest HBOT as a novel therapeutic intervention for AD. PMID- 29141187 TI - Factors associated with final year nursing students' desire to work in the primary health care setting: Findings from a national cross-sectional survey. AB - BACKGROUND: Registered nurses are under-represented in the primary health care setting both internationally and in Australia, and this shortage is predicted to worsen. To address the increasingly complex healthcare needs of an ageing population, it is vital to develop and sustain a primary health care nursing workforce, yet attracting nurses is challenging. In Australia, registered nurses graduating from university typically commence their careers in hospital-based transition to professional practice programs. Similar programs in primary health care settings may be a valuable strategy for developing the primary health care nursing workforce, yet little is known about nursing students desire to work in this setting, factors that influence this, or their expectations of primary health care-focused transition to professional practice programs. OBJECTIVES: This study sought to identify factors associated with final year nursing students' desire to work in primary health care setting including demographic factors, expectations of future employment conditions, and job content. It also explored expectations of graduate transition programs based in primary health care. DESIGN: A cross-sectional survey design comprising a quantitative online survey. SETTING: 14 Australian universities from all states/territories, both rural and urban. PARTICIPANTS: 530 final-year nursing students. METHODS: Binary logistic regression identifying factors contributing to desire to work in primary health care. RESULTS: The desire of nursing students to work in primary health care is associated with older age, greater perceived value of employment conditions including flexibility, and less perceived importance of workplace support. CONCLUSIONS: Collaborative efforts from primary health care nurses, health professionals, academics and policy makers are needed to attract new graduate nurses to primary health care. PMID- 29141188 TI - Autistic traits modulate the activity of the ventromedial prefrontal cortex in response to female faces. AB - Previous findings have revealed abnormal visual attention or processing of faces among individuals with autism spectrum condition (ASC). However, little attention has been paid to the relationship between autistic traits and neural mechanisms associated with representing facial values. Using fMRI, we investigated the patterns of brain activity in the vmPFC and VS in response to faces of elderly males, elderly females, young males, and young females. During fMRI, subjects with a relatively high autism quotient (high group) and those with a relatively low autism quotient (low group) were presented with a face and asked to rate its pleasantness. After fMRI, the subjects were presented with pairs of faces and asked to select the face that they preferred. Our results indicate a dissociable modulatory effect of autistic traits on the vmPFC and VS: The vmPFC activity in the low group was more sensitive to age differences in female faces compared to that in the high group, whereas VS activity did not show differences between groups. These results suggest that, in the BVS, autistic traits selectively modulate the vmPFC activity associated with facial value representation. PMID- 29141189 TI - Role of Cyclooxygenase Inhibitors in Diminution of Dissimilar Stress-induced Depressive Behavior and Memory Impairment in Rats. AB - Memory functions can be considerably affected by various life events and stress has shown to be a chief regulator. Different stress patterns have distinct effects on the overall functioning of the brain. Stress provokes inflammation not only in the periphery but also in the brain. Neuroinflammation causes alterations in neuronal structure and function, which eventually progress to the development of neurodegenerative diseases. Inflammatory reactions are modulated through communication between the nervous, endocrine and immune systems. An excessive release of stress hormones and changes in the neurotransmission system may cause cognitive impairments. The present study investigated dissimilar stress-related memory deficits and their diminution by non-steroidal anti-inflammatory drugs (NSAIDs). Treatment with cyclooxygenase inhibitors, which inhibit prostaglandin synthesis, has enhanced memory functions in a number of neuroinflammatory states. In this study, rats were exposed to a series of dissimilar stressors and behavioral parameters for depression and memory functions were examined. Corticosterone, serotonin (5-HT) and dopamine (DA) levels were also estimated. Results from the forced swim test, elevated plus maze test and Morris water maze test showed significant effects of NSAIDs. A significant decrease in plasma corticosterone and increased DA and 5-HT levels were observed in NSAID-treated dissimilar-stressed rats. This study demonstrates the therapeutic potential of NSAIDs for dissimilar stress-induced depressive behaviors and impaired memory functions and related hormonal and neurochemical changes in the rat brain. PMID- 29141190 TI - Relationship between rTMS effects and MEP features before rTMS. AB - Repetitive transcranial magnetic stimulation (rTMS) is a promising method for use in the clinical field, as it can induce modulation of cortical excitability. Generally, rTMS inhibits the motor cortex when delivered at less than 1 Hz. However, it has been indicated that a facilitative effect is induced by 1 Hz rTMS, depending on the stimulation parameters and the individual. Therefore, the aim of this study was to investigate the features of the subject that could affect the 1 Hz rTMS effect when rTMS stimulus conditions change. First, motor evoked potentials (MEP) were measured under rTMS conditions with a variety of stimulus intensities and numbers of pulses. The MEP features before rTMS and the MEP modulation by the rTMS were then analyzed. Furthermore, correlations between the MEP features and the rTMS effect were investigated. It was found that the MEP amplitude and MEP onset before rTMS can influence the rTMS effect. Furthermore, negative correlations were found between these MEP features and the rTMS effect. MEPs with a small amplitude and early latency were little influenced by the inhibitive effect of 1 Hz rTMS, while MEPs with a large amplitude and late latency were readily affected by the inhibitive effect of 1 Hz rTMS. In this study, we focused on the MEP features before rTMS and identified the features of the subject that could influence the rTMS effect when the rTMS stimulus condition was changed. PMID- 29141191 TI - Microbial lipids and added value metabolites production by Yarrowia lipolytica from pork lard. AB - Yarrowia lipolytica is a suitable microbial platform to convert low-value hydrophobic substrates into microbial oils and other important metabolites. In this work, this yeast species was used to simultaneously synthetize ex novo lipids and produce citric acid and lipase from animal fat (pork lard) adding higher value to the low-cost fatty substrate. The effect of pH, lard concentration, arabic gum concentration and oxygen mass transfer rate (OTR) on lipids accumulation on Y. lipolytica batch cultures was assessed by an experimental design based on Taguchi method. OTR was by far the most influential parameter in the range of 96mgL-1h-1-480mgL-1h-1. A bio-modification of initial lipidic substrate was observed and, depending on the nutritional and operational conditions, specialty lipids with specific composition and high added-value were obtained. The unsaturated-to-saturated fatty acids ratio of these microbial lipids is higher than in initial substrate, which indicates that they are more suitable than animal fat for food additives. Moreover, the simultaneous induction of lipase and citric acid by Y. lipolytica growing in animal fat demonstrates that a biorefinery approach may be designed based on animal fat raw material. PMID- 29141192 TI - Impact of the cultivation strategy on resveratrol production from glucose in engineered Corynebacterium glutamicum. AB - The health benefits of polyphenols such as stilbenes and flavonoids for humans are increasingly attracting attention. Resveratrol is a well-characterized naturally-occurring stilbene and potent anti-oxidant, which is used as food supplement and cosmetic ingredient. Several microorganisms including Corynebacterium glutamicum were engineered for resveratrol production from glucose. Based on the cultivation of a resveratrol-producing C. glutamicum strain in shake flasks, different strategies for improving production under controlled conditions at bioreactor scale were tested. To this end, different cultivation parameters including substrate concentration and operation modes (batch and fed batch) were evaluated. Whereas the highest biomass concentration was observed during fed-batch fermentation, the maximum resveratrol production was achieved in batch mode. The maximal titer obtained was 12mgL-1 of resveratrol without the addition of the fatty acid synthase inhibitor cerulenin, which was previously shown to be crucial for production with C. glutamicum. The specific growth rate during production seems to have a significant effect in resveratrol production and apparently low specific growth rates may redirect the metabolic bottleneck from p-coumaric acid formation to malonyl-CoA or ATP availability. We also show that high oxygen concentrations in the bioreactor negatively affected the obtained resveratrol titers with C. glutamicum, which is most likely due to the strong tendency of resveratrol to oxidize or oligomerize. Thus, up-scaling of the resveratrol production process is technically challenging and individual process parameters have to be optimized cautiously. PMID- 29141193 TI - Evolution of the CLOCK and BMAL1 genes in a subterranean rodent species (Lasiopodomys mandarinus). AB - Lasiopodomys mandarinus, a subterranean rodent, spends its entire life underground. To test whether the CLOCK and BMAL1 genes of L. mandarinus have undergone adaptive evolution to underground darkness, we cloned and analyzed their complete cDNA sequences, using Lasiopodomys brandtii as a control. The phylogenetic trees of the CLOCK and BMAL1 genes were similar to the trees of the conserved Cyt b gene,further, L. mandarinus clustered with L. brandtii and Microtus ochrogaster in the phylogenetic tree. The Q-rich region of the CLOCK gene in L. mandarinus was different from that of other subterranean rodents. Using phylogenetic analysis maximum likelihood (PAML), the omega value (omega<1) in different lineages showed that both genes have undergone purifying selection. The M8 model identified some positive selection sites in the CLOCK gene, most of which were located in the trans-transcription activation domain (TAD). In conclusion, CLOCK and BMAL1 genes did not exhibit convergent molecular evolution in subterranean rodents. Moreover, our study highlights the important functionality of the TAD, which is putatively of functional relevance to CLOCK protein activity. The present findings provide novel insights into adaptation to underground darkness, at the gene level, in subterranean rodents. PMID- 29141194 TI - Marginal stability drives irreversible unfolding of large multi-domain family 3 glycosylhydrolases from thermo-tolerant yeast. AB - Protein folding is an extremely complex and fast, yet perfectly defined process, involving interplay of many intra and inter-molecular forces. In vitro, these molecular interactions are reversible for many proteins e.g., smaller and monomeric, organized into single domains. However, refolding of larger multi domain/multimeric proteins is much more complicated, proceeds in a hierarchal way and is often irreversible. In a comparative study on two large, multi-domain and multimeric isozymes, beta-glucosidase I (BGLI) and beta-glucosidase II (BGLII) from Pichia etchellsii, we studied spontaneous and assisted refolding under three denaturing conditions viz. GdnHCl, alkaline pH and heat. During refolding, higher refolding yields were obtained for BGLII in case of pH induced unfolding (13.89%+/-0.25) than BGLI (6%+/-0.85) while for GdnHCl induced unfolding, refolding was marginal (BGLI=5%+/-0.5; BGLII=6%+/-0.69). Thermal unfolding was irreversible while assisted refolding also showed little structural gain for both proteins. When the apparent free energies of unfolding (DeltaGUapp) were calculated from GdnHCl unfolding data, their values were strikingly found to be lower (BGLI DeltaGUapp=3.02kcal/mol; BGLII DeltaGUapp=2.99kcal/mol) than reported for globular (DeltaGU=5-15kcal/mol)/multimeric proteins (DeltaGU=23-29kcal/mol) indicating marginal stability results in low refolding. PMID- 29141195 TI - Determination of the effect of Pinellia ternata (Thunb.) Breit. on nervous system development by proteomics. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Banxia (BX) is the dried tuber of Pinellia ternata (Thunb.) Breit., a commonly prescribed Chinese medicinal herb for the treatment of cough, phlegm, and vomiting in pregnant women. However, raw BX has been demonstrated to exert toxic effects on reproduction and the precise and comprehensive mechanisms remain elusive. AIM OF THE STUDY: We applied an iTRAQ (isobaric tags for relative and absolute quantitation, iTRAQ)-based proteomic method to explore the mechanisms of raw BX-induced fetal toxicity in mice. MATERIALS AND METHODS: The mice were separated into two groups, control mice and BX-treated mice. From gestation days 6-8, the control group was treated with normal saline and the BX group was exposed to BX suspension (2.275g/kg/day). Gastrulae were obtained and analyzed using the quantitative proteomic approach of iTRAQ coupled to liquid chromatography-tandem mass spectrometry (LC-MS/MS). A multi-omics data analysis tool, OmicsBean (http://www.omicsbean.cn), was employed to conduct bioinformatic analysis of differentially abundant proteins (DAPs). Quantitative real-time PCR (qRT-PCR) and western blotting methods were applied to detect the protein expression levels and validate the quality of the proteomics. RESULTS: A total of 1245 proteins were identified with < 1% false discovery rate (FDR) and 583 protein abundance changes were confidently assessed. Moreover, 153 proteins identified in BX-treated samples showed significant differences in abundance. Bioinformatics analysis showed that the functions of 37 DAPs were predominantly related to nervous system development. The expression levels of the selected proteins for quantification by qRT-PCR or western blotting were consistent with the results in iTRAQ-labeled proteomics data. CONCLUSION: The results suggested that oral administration of BX in mice may cause fetal abnormality of the nervous system. The findings may be helpful to elucidate the underlying mechanisms of BX-induced embryotoxicity. PMID- 29141196 TI - ASIC2a overexpression enhances the protective effect of PcTx1 and APETx2 against acidosis-induced articular chondrocyte apoptosis and cytotoxicity. AB - Acid hydrarthrosis is another important pathological character in rheumatoid arthritis (RA), and acid-sensing ion channel 1a (ASIC1a) plays a destructive role in acidosis-induced articular chondrocyte cytotoxicity. Recently, ASIC2a has been reported to possess neuroprotective effect on acidosis-induced injury of neuronal cells. However, whether ASIC2a has an enhanced effect on the protective effect of blocking ASIC1a and ASIC3 against acid-induced chondrocyte apoptosis is still unclear. The aim of present study was to investigate the chondroprotective effect of ASIC2a with PcTx1 (ASIC1a specific blocker) and APETx2 (ASIC3 specific blocker) on acidosis-induced chondrocyte apoptosis. Our results revealed that acid (pH 6.0) decreased the cell viability and induced apoptosis of articular chondrocytes. PcTx1 and APETx2 combination significantly attenuated acidosis induced chondrocyte cytotoxicity due to inhibit apoptosis, and this role could be enhanced by ASIC2a overexpression compared with the PcTx1 and APETx2 combination alone group. Moreover, both the [Ca2+]i levels and the levels of phosphorylated ERK1/2 as well as p38 were further reduced in acidosis-induced chondrocytes after ASIC2a overexpression in the presence of PcTx1 and APETx2. Furthermore, ASIC2a overexpression also reduced acid-induced the expression of ASIC1a. In addition, ASIC2a overexpression further promoted the PcTx1 and APETx2-increased levels of type II collagen in acidosis-induced chondrocytes. Taken together, the current data suggested that ASIC2a overexpression might enhance the anti-apoptotic and protective role of PcTx1 and APETx2 against acid-induced rat articular chondrocyte apoptosis by regulating ASIC1a expression and the [Ca2+]i levels and at least in part, suppressing p38 and ERK1/2 MAPK signaling pathways. PMID- 29141197 TI - Medical abortion reversal: science and politics meet. AB - Medical abortion is a safe, effective, and acceptable option for patients seeking an early nonsurgical abortion. In 2014, medical abortion accounted for nearly one third (31%) of all abortions performed in the United States. State-level attempts to restrict reproductive and sexual health have recently included bills that require physicians to inform women that a medical abortion is reversible. In this commentary, we will review the history, current evidence-based regimen, and regulation of medical abortion. We will then examine current proposed and existing abortion reversal legislation. The objective of this commentary is to ensure physicians are armed with rigorous evidence to inform patients, communities, and policy makers about the safety of medical abortion. Furthermore, given the current paucity of evidence for medical abortion reversal, physicians and policy makers can dispel bad science and misinformation and advocate against medical abortion reversal legislation. PMID- 29141198 TI - Longitudinal Change in Central Corneal Thickness in the Tema Eye Survey. AB - PURPOSE: To determine the change and rate of change in central corneal thickness (CCT) and their determinants. DESIGN: Longitudinal observational population-based study. METHODS: A total of 758 normal and 58 glaucomatous subjects underwent complete eye examination, with CCT measurements at 2 separate visits. Change and rate of change in CCT were determined. Univariate and multivariate linear regression analyses were performed to determine the factors associated with change and rate of change. RESULTS: The mean follow-up duration was 8.4 +/- 0.7 years. The overall change was -8.9 +/- 16.7 MUm in OD and -9.8 +/- 16.2 MUm in OS, both P < .0001. Changes in glaucomatous and normal subjects were -14.1 +/- 2.2 MUm vs -8.6 +/- 0.6 MUm in OD (P = .02) and -14.5 +/- 2.2 MUm vs -9.5 +/- 0.6 MUm in OS (P = .03), respectively. The overall rate of thinning was -1.1 MUm/year (OD) and -1.2 MUm/year (OS). Rates in glaucomatous and normal eyes were -1.7 +/- 0.3 MUm/year vs -1.0 +/- 0.1 MUm/year in OD (P = .02) and -1.7 +/- 0.3 MUm/year vs -1.1 +/- 0.1 MUm/year in OS (P = .03), respectively. Change and rate of change were associated with baseline CCT (beta = -0.1 to -0.09 and -0.011, respectively, all P < .001) and glaucoma (beta = -6.8 to -5.6, P <= .009, and -0.75 to -0.69, P <= .007, respectively). CONCLUSION: CCT decreased significantly over time. The change and rate of change were greater in glaucomatous than normal eyes, and were greater than described in cross-sectional studies. PMID- 29141199 TI - Disruption of mitochondrial function as mechanism for anti-cancer activity of a novel mitochondriotropic menadione derivative. AB - Menadione, also known as vitamin K3, is a 2-methyl-1,4 naphthoquinone with a potent cytotoxic activity mainly resulting from its quinone redox-cycling with production of reactive oxygen species (ROS). Although increased ROS generation is considered a relevant mechanism in cancer cell death, it may not be sufficiently effective to kill cancer cells due to phenotypic adaptations. Therefore, combining ROS-generating agents with other molecules targeting important cancer cell phenotypes can be an effective therapeutic strategy. As mitochondrial dysfunction has been implicated in many human diseases, including cancer, we describe here the discovery of a mitochondrial-directed agent (MitoK3), which was developed by conjugating a TPP cation to the C3 position of the menadione's naphthoquinone ring, increasing its selective accumulation in mitochondria, as well as led to alterations of its redox properties and consequent biological outcome. MitoK3 disturbed the mitochondrial bioenergetic apparatus, with subsequent loss of mitochondrial ATP production. The combinatory strategy of MitoK3 with anticancer agent doxorubicin (DOX) resulted in a degree of cytotoxicity higher than those of the individual molecules, as the combination triggered tumour apoptotic cell death evident by caspase 3/9 activities, probably through mitochondrial destabilization or by interference with mitochondrial redox processes. The results of this investigation support the importance of drug discovery process in developing molecules that can be use as adjuvant therapy in patients with specific cancer subtypes. PMID- 29141200 TI - Phosgene oxime: Injury and associated mechanisms compared to vesicating agents sulfur mustard and lewisite. AB - Phosgene Oxime (CX, Cl2CNOH), a halogenated oxime, is a potent chemical weapon that causes immediate acute injury and systemic effects. CX, grouped together with vesicating agents, is an urticant or nettle agent with highly volatile, reactive, corrosive, and irritating vapor, and has considerably different chemical properties and toxicity compared to other vesicants. CX is absorbed quickly through clothing with faster cutaneous penetration compared to other vesicating agents causing instantaneous and severe damage. For this reason, it could be produced as a weaponized mixture with other chemical warfare agents to enhance their deleterious effects. The immediate devastating effects of CX and easy synthesis makes it a dangerous chemical with both military and terrorist potentials. Although CX is the most potent vesicating agent, it is one of the least studied chemical warfare agents and the pathophysiology as well as long term effects are largely unknown. CX exposure results in immediate pain and inflammation, and it mainly affects skin, eye and respiratory system. There are no antidotes available against CX-induced injury and the treatment is only supportive. This review summarizes existing knowledge regarding exposure, toxicity and the probable underlying mechanisms of CX compared to other important vesicants' exposure. PMID- 29141201 TI - Cardiovascular Risk and Statin Eligibility of Young Adults After an MI: Partners YOUNG-MI Registry. AB - BACKGROUND: Despite significant progress in primary prevention, the rate of MI has not declined in young adults. OBJECTIVES: The purpose of this study was to evaluate statin eligibility based on the 2013 American College of Cardiology/American Heart Association guidelines for treatment of blood cholesterol and 2016 U.S. Preventive Services Task Force recommendations for statin use in primary prevention in a cohort of adults who experienced a first time myocardial infarction (MI) at a young age. METHODS: The YOUNG-MI registry is a retrospective cohort from 2 large academic centers, which includes patients who experienced an MI at age <=50 years. Diagnosis of type 1 MI was adjudicated by study physicians. Pooled cohort risk equations were used to estimate atherosclerotic cardiovascular disease risk score based on data available prior to MI or at the time of presentation. RESULTS: Of 1,685 patients meeting inclusion criteria, 210 (12.5%) were on statin therapy prior to MI and were excluded. Among the remaining 1,475 individuals, the median age was 45 years, there were 294 (20%) women, and 846 (57%) had ST-segment elevation MI. At least 1 cardiovascular risk factor was present in 1,225 (83%) patients. The median 10 year atherosclerotic cardiovascular disease risk score of the cohort was 4.8% (interquartile range: 2.8% to 8.0%). Only 724 (49%) and 430 (29%) would have met criteria for statin eligibility per the 2013 American College of Cardiology/American Heart Association guidelines and 2016 U.S. Preventive Services Task Force recommendations, respectively. This finding was even more pronounced in women, in whom 184 (63%) were not eligible for statins by either guideline, compared with 549 (46%) men (p < 0.001). CONCLUSIONS: The vast majority of adults who present with an MI at a young age would not have met current guideline-based treatment thresholds for statin therapy prior to their MI. These findings highlight the need for better risk assessment tools among young adults. PMID- 29141202 TI - Cooperativity and flexibility in enzyme evolution. AB - Enzymes are flexible catalysts, and there has been substantial discussion about the extent to which this flexibility contributes to their catalytic efficiency. What has been significantly less discussed is the extent to which this flexibility contributes to their evolvability. Despite this, recent years have seen an increasing number of both experimental and computational studies that demonstrate that cooperativity and flexibility play significant roles in enzyme innovation. This review covers key developments in the field that emphasize the importance of enzyme dynamics not just to the evolution of new enzyme function(s), but also as a property that can be harnessed in the design of new artificial enzymes. PMID- 29141203 TI - Mouse adenovirus type 1 infection of adipose tissue. AB - Human adenovirus (HAdV) type 36 seropositivity has been linked to obesity in humans. That link is supported by a small number of studies using HAdV-36 infection of animals that are not natural hosts for HAdVs. In this study, we infected mice with mouse adenovirus type 1 (MAV-1), a mouse pathogen, to determine whether MAV-1 infected adipose tissue and was associated with adipose tissue inflammation and obesity. We detected MAV-1 in adipose tissue during acute MAV-1 infection, but we did not detect virus-induced increases in adipose tissue cytokine expression or histological evidence of adipose tissue inflammation during acute infection. MAV-1 did not persist in adipose tissue at later times, and we did not detect long-term adipose inflammation, increased adipose tissue mass, or body weight in infected mice. Our data indicate that MAV-1 is not associated with obesity in infected mice. PMID- 29141204 TI - Characterization of the complete genome, antigenicity, pathogenicity, tissue tropism, and shedding of a recombinant avian infectious bronchitis virus with a ck/CH/LJL/140901-like backbone and an S2 fragment from a 4/91-like virus. AB - In this study, we isolated an infectious bronchitis virus, designated I1101/16, from broiler breeders in China. Analysis of the S1 gene showed that isolate I1101/16 was genetically close to strain ck/CH/LJL/140901, which belongs to the TW I genotype (also known as lineage GI-7 based on the recent IBV classification), however the S2 gene showed genetic diversity comparing to that of S1 gene. Comparison of the genomic sequences showed that the genome of isolate I1101/16 was similar to that of strain ck/CH/LJL/140901 from the 5' end of the genome to the 5' end of the S2 gene and from the 5' end of the 3a gene to the end of the genome, whereas the remaining parts of the genome sequences were more closely related to those of strain 4/91 than those of ck/CH/LJL/140901, thereby suggesting that recombination might have occurred during the origin of the virus. SimPlot and Bootscan analysis of the complete genomic sequence confirmed this hypothesis, where it showed that isolate I1101/16 arose through recombination events between ck/CH/LJL/140901- and 4/91-like viruses. Isolate I1101/16 and strain ck/CH/LJL/140901 shared identical amino acids in almost all five of their B cell epitopes, but the two viruses had a serotype relatedness value of 65, which is well below 80, i.e., the lower cutoff value for viruses of the same serotype. In addition, pathogenicity tests demonstrated that isolate I1101/16 was more pathogenic to 1-day-old specific-pathogen-free chickens than strain ck/CH/LJL/140901, according to analysis of the clinical signs, whereas strain ck/CH/LJL/140901 exhibited prolonged replication and shedding after challenge compared with isolate I1101/16. This study did not provide evidence that recombination can directly alter the antigenicity, virulence, replication, shedding, and tissue tropism of a virus, but it did show that recombination events are likely to be major determinants of viral evolution. PMID- 29141205 TI - Investigation of alimentary canal ultrastructure following knockdown of the Dicer 2 gene in planthoppers reveals the potential pathogenicity of southern rice black streaked dwarf virus to its insect vector. AB - An increasing number of studies are suggesting that plant viruses, including southern rice black-streaked dwarf virus (SRBSDV), can adversely affect biological characteristics of insect vectors by unknown mechanisms. To study the adverse effect of SRBSDV at cellular level on the insect vector, we promoted viral infection by the disruption of the small interfering RNA (siRNA) pathway. The transmission electron microscopy was utilized to describe the ultrastructural changes that occurred in insects when the core component of the siRNA pathway, Dicer-2, was knocked down. The increasing accumulation of SRBSDV in virus infected vector, the white-backed planthoppers, caused severe cytopathology in the alimentary canal. Similar cytopathology changes in the midgut ultrastructure were characterized in the virus-infected incompetent vector, the small brown planthopper. These results not only add support to the existing evidence suggesting that the siRNA pathway has an antiviral effect, but also reveal the universal and potential ability of SRBSDV to cause damage to the insect tissues of both the vector and non-vector. PMID- 29141206 TI - Role of the Pif1-PCNA Complex in Pol delta-Dependent Strand Displacement DNA Synthesis and Break-Induced Replication. AB - The S. cerevisiae Pif1 helicase functions with DNA polymerase (Pol) delta in DNA synthesis during break-induced replication (BIR), a conserved pathway responsible for replication fork repair and telomere recombination. Pif1 interacts with the DNA polymerase processivity clamp PCNA, but the functional significance of the Pif1-PCNA complex remains to be elucidated. Here, we solve the crystal structure of PCNA in complex with a non-canonical PCNA-interacting motif in Pif1. The structure guides the construction of a Pif1 mutant that is deficient in PCNA interaction. This mutation impairs the ability of Pif1 to enhance DNA strand displacement synthesis by Pol delta in vitro and also the efficiency of BIR in cells. These results provide insights into the role of the Pif1-PCNA-Pol delta ensemble during DNA break repair by homologous recombination. PMID- 29141207 TI - Distinct TERB1 Domains Regulate Different Protein Interactions in Meiotic Telomere Movement. AB - Meiotic telomeres attach to the nuclear envelope (NE) and drive the chromosome movement required for the pairing of homologous chromosomes. The meiosis-specific telomere proteins TERB1, TERB2, and MAJIN are required to regulate these events, but their assembly processes are largely unknown. Here, we developed a germ-cell specific knockout mouse of the canonical telomere-binding protein TRF1 and revealed an essential role for TRF1 in directing the assembly of TERB1-TERB2 MAJIN. Further, we identified a TERB2 binding (T2B) domain in TERB1 that is dispensable for the TRF1-TERB1 interaction but is essential for the subsequent TERB1-TERB2 interaction and therefore for telomere attachment to the NE. Meanwhile, cohesin recruitment at telomeres, which is required for efficient telomere movement, is mediated by the MYB-like domain of TERB1, but not by TERB2 MAJIN. Our results reveal distinct protein interactions through various domains of TERB1, which enable the sequential assembly of the meiotic telomere complex for their movements. PMID- 29141208 TI - CRISPR Transcriptional Activation Analysis Unmasks an Occult gamma-Secretase Processivity Defect in Familial Alzheimer's Disease Skin Fibroblasts. AB - Mutations in presenilin (PSEN) 1 and 2, which encode components of the gamma secretase (GS) complex, cause familial Alzheimer's disease (FAD). It is hypothesized that altered GS-mediated processing of the amyloid precursor protein (APP) to the Abeta42 fragment, which is accumulated in diseased brain, may be pathogenic. Here, we describe an in vitro model system that enables the facile analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes. In FAD patient derived fibroblast cultures, CRISPR activation of APP or BACE unmasked an occult processivity defect in downstream GS-mediated carboxypeptidase cleavage of APP, ultimately leading to higher Abeta42 levels. These data suggest that, selectively in neurons, relatively high levels of BACE1 activity lead to substrate pressure on FAD-mutant GS complexes, promoting CNS Abeta42 accumulation. Our results introduce an additional platform for analysis of neurological disease. PMID- 29141209 TI - High-Throughput Drug Screening Identifies Pazopanib and Clofilium Tosylate as Promising Treatments for Malignant Rhabdoid Tumors. AB - Rhabdoid tumors (RTs) are aggressive tumors of early childhood characterized by SMARCB1 inactivation. Their poor prognosis highlights an urgent need to develop new therapies. Here, we performed a high-throughput screening of approved drugs and identified broad inhibitors of tyrosine kinase receptors (RTKs), including pazopanib, and the potassium channel inhibitor clofilium tosylate (CfT), as SMARCB1-dependent candidates. Pazopanib targets were identified as PDGFRalpha/beta and FGFR2, which were the most highly expressed RTKs in a set of primary tumors. Combined genetic inhibition of both these RTKs only partially recapitulated the effect of pazopanib, emphasizing the requirement for broad inhibition. CfT perturbed protein metabolism and endoplasmic reticulum stress and, in combination with pazopanib, induced apoptosis of RT cells in vitro. In vivo, reduction of tumor growth by pazopanib was enhanced in combination with CfT, matching the efficiency of conventional chemotherapy. These results strongly support testing pazopanib/CfT combination therapy in future clinical trials for RTs. PMID- 29141210 TI - PfClpC Is an Essential Clp Chaperone Required for Plastid Integrity and Clp Protease Stability in Plasmodium falciparum. AB - The deadly malaria parasite Plasmodium falciparum contains a nonphotosynthetic plastid, known as the apicoplast, that functions to produce essential metabolites, and drugs that target the apicoplast are clinically effective. Several prokaryotic caseinolytic protease (Clp) genes have been identified in the Plasmodium genome. Using phylogenetic analysis, we focused on the Clp members that may form a regulated proteolytic complex in the apicoplast. We genetically targeted members of this complex and generated conditional mutants of the apicoplast-localized PfClpC chaperone and PfClpP protease. Conditional inhibition of the PfClpC chaperone resulted in growth arrest and apicoplast loss and was rescued by addition of the essential apicoplast-derived metabolite IPP. Using a double-conditional mutant parasite line, we discovered that the chaperone activity is required to stabilize the mature protease, revealing functional interactions. These data demonstrate the essential function of PfClpC in maintaining apicoplast integrity and its role in regulating the proteolytic activity of the Clp complex. PMID- 29141211 TI - Lateral Preoptic Control of the Lateral Habenula through Convergent Glutamate and GABA Transmission. AB - The lateral habenula (LHb) is a brain structure that participates in cognitive and emotional processing and has been implicated in several mental disorders. Although one of the largest inputs to the LHb originates in the lateral preoptic area (LPO), little is known about how the LPO participates in the regulation of LHb function. Here, we provide evidence that the LPO exerts bivalent control over the LHb through the convergent transmission of LPO glutamate and gamma aminobutyric acid (GABA) onto single LHb neurons. In vivo, both LPO-glutamatergic and LPO-GABAergic inputs to the LHb are activated by aversive stimuli, and their predictive cues yet produce opposing behaviors when stimulated independently. These results support a model wherein the balanced response of converging LPO glutamate and LPO-GABA are necessary for a normal response to noxious stimuli, and an imbalance in LPO->LHb glutamate or GABA results in the type of aberrant processing that may underlie mental disorders. PMID- 29141212 TI - A Central Amygdala-Substantia Innominata Neural Circuitry Encodes Aversive Reinforcement Signals. AB - Aversive stimuli can impact motivation and support associative learning as reinforcers. However, the neural circuitry underlying the processing of aversive reinforcers has not been elucidated. Here, we report that a subpopulation of central amygdala (CeA) GABAergic neurons expressing protein kinase C-delta (PKC delta+) displays robust responses to aversive stimuli during negative reinforcement learning. Importantly, projections from PKC-delta+ neurons of the CeA to the substantia innominata (SI) could bi-directionally modulate negative reinforcement learning. Moreover, consistent with the idea that SI-projecting PKC delta+ neurons of the CeA encode aversive information, optogenetic activation of this pathway produces conditioned place aversion, a behavior prevented by simultaneous ablating of SI glutamatergic neurons. Taken together, our data define a cell-type-specific neural circuitry modulating associative learning by encoding aversive reinforcement signals. PMID- 29141213 TI - CPEB2 Activates GRASP1 mRNA Translation and Promotes AMPA Receptor Surface Expression, Long-Term Potentiation, and Memory. AB - Activity-dependent synthesis of plasticity-related proteins is necessary to sustain long-lasting synaptic modifications and consolidate memory. We investigated the role of the translational regulator cytoplasmic polyadenylation element binding protein 2 (CPEB2) in learning and memory because regulated mRNA translation contributes to synaptic plasticity. Forebrain-restricted CPEB2 conditional knockout (cKO) mice exhibited impaired hippocampus-dependent memory in contextual fear conditioning and Morris water maze tests. CPEB2 cKO hippocampi showed impaired long-term potentiation in the Schaffer collateral-CA1 pathway. Reduced surface, but not total, expression of AMPA receptors (AMPARs) in CPEB2 KO neurons led us to identify that CPEB2 enhanced the translation of GRASP1 mRNA to facilitate recycling and maintain the surface level of AMPARs. Ectopic expression of CPEB2 or GRASP1 in CA1 areas of CPEB2 cKO mouse hippocampi rescued long-term potentiation and spatial memory in a water maze test. Thus, CPEB2-regulated GRASP1 mRNA translation is pivotal for AMPAR recycling, long-term plasticity, and memory. PMID- 29141214 TI - Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure. AB - Abnormal folate one-carbon metabolism (FOCM) is implicated in neural tube defects (NTDs), severe malformations of the nervous system. MTHFR mediates unidirectional transfer of methyl groups from the folate cycle to the methionine cycle and, therefore, represents a key nexus in partitioning one-carbon units between FOCM functional outputs. Methionine cycle inhibitors prevent neural tube closure in mouse embryos. Similarly, the inability to use glycine as a one-carbon donor to the folate cycle causes NTDs in glycine decarboxylase (Gldc)-deficient embryos. However, analysis of Mthfr-null mouse embryos shows that neither S adenosylmethionine abundance nor neural tube closure depend on one-carbon units derived from embryonic or maternal folate cycles. Mthfr deletion or methionine treatment prevents NTDs in Gldc-null embryos by retention of one-carbon units within the folate cycle. Overall, neural tube closure depends on the activity of both the methionine and folate cycles, but transfer of one-carbon units between the cycles is not necessary. PMID- 29141215 TI - Octopamine Drives Endurance Exercise Adaptations in Drosophila. AB - Endurance exercise is an effective therapeutic intervention with substantial pro healthspan effects. Male Drosophila respond to a ramped daily program of exercise by inducing conserved physiological responses similar to those seen in mice and humans. Female flies respond to an exercise stimulus but do not experience the adaptive training response seen in males. Here, we use female flies as a model to demonstrate that differences in exercise response are mediated by differences in neuronal activity. The activity of octopaminergic neurons is specifically required to induce the conserved cellular and physiological changes seen following endurance training. Furthermore, either intermittent, scheduled activation of octopaminergic neurons or octopamine feeding is able to fully substitute for exercise, conferring a suite of pro-healthspan benefits to sedentary Drosophila. These experiments indicate that octopamine is a critical mediator of adaptation to endurance exercise in Drosophila. PMID- 29141216 TI - Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells. AB - Foxp3+ regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp3+ Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp3+ Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2 dependent metabolic regulation. PMID- 29141218 TI - Reciprocal Expression of IL-35 and IL-10 Defines Two Distinct Effector Treg Subsets that Are Required for Maintenance of Immune Tolerance. AB - Regulatory T cells (Tregs) can exert their functions through multiple suppressive mechanisms; however, it is unclear how Tregs exactly employ these mechanisms. In this study, we found that interleukin-35 (IL-35)-producing Tregs were a distinct effector population from the IL-10-producing subset. We also revealed that these two subsets of effector Tregs have different transcription factor dependency. Terminal differentiation regulator Blimp1 was only critical for IL-10 production, but not for IL-35; Foxp3 was essential for IL-35 but dispensable for IL-10 production. Furthermore, we demonstrated that IL-35-producing and IL-10-producing Tregs have a different activation status, do not share the same geographic locations in secondary lymphoid organs, and work in a complementary way to prevent autoimmunity. Thus, our study highlights the importance of effector Treg generation. We also provide evidence of Treg activation status tuning the generation of distinct effector Treg subsets, which work cooperatively to maintain immune tolerance. PMID- 29141217 TI - Th1-like Plasmodium-Specific Memory CD4+ T Cells Support Humoral Immunity. AB - Effector T cells exhibiting features of either T helper 1 (Th1) or T follicular helper (Tfh) populations are essential to control experimental Plasmodium infection and are believed to be critical for resistance to clinical malaria. To determine whether Plasmodium-specific Th1- and Tfh-like effector cells generate memory populations that contribute to protection, we developed transgenic parasites that enable high-resolution study of anti-malarial memory CD4 T cells in experimental models. We found that populations of both Th1- and Tfh-like Plasmodium-specific memory CD4 T cells persist. Unexpectedly, Th1-like memory cells exhibit phenotypic and functional features of Tfh cells during recall and provide potent B cell help and protection following transfer, characteristics that are enhanced following ligation of the T cell co-stimulatory receptor OX40. Our findings delineate critical functional attributes of Plasmodium-specific memory CD4 T cells and identify a host-specific factor that can be targeted to improve resolution of acute malaria and provide durable, long-term protection against Plasmodium parasite re-exposure. PMID- 29141219 TI - Preventive Inhibition of Liver Tumorigenesis by Systemic Activation of Innate Immune Functions. AB - Liver cancer has become the second most deadly malignant disease, with no efficient targeted or immune therapeutic agents available yet. While dissecting the roles of cytoplasmic signaling molecules in hepatocarcinogenesis using an inducible mouse gene targeting system, Mx1-cre, we identified a potent liver tumor-inhibitory effect of synthetic double-stranded RNA (dsRNA), polyinosinic polycytidylic acid (pIC), an inducer of the Mx1-cre system. Injection of pIC at the pre-cancer stage robustly suppressed liver tumorigenesis either induced by chemical carcinogens or by Pten loss and associated hepatosteatosis. The immunostimulatory dsRNA inhibited liver cancer initiation, apparently by boosting multiple anti-tumor activities of innate immunity, including induction of immunoregulatory cytokines, activation of NK cells and dendritic cells, and reprogramming of macrophage polarization. This study paves the way for the development of preventive and early interfering strategies for liver cancer to reduce the rapidly increasing incidences of liver cancer in an ever-growing population with chronic liver disorders. PMID- 29141220 TI - Phosphorylation and Ubiquitination Regulate Protein Phosphatase 5 Activity and Its Prosurvival Role in Kidney Cancer. AB - The serine/threonine protein phosphatase 5 (PP5) regulates multiple cellular signaling networks. A number of cellular factors, including heat shock protein 90 (Hsp90), promote the activation of PP5. However, it is unclear whether post translational modifications also influence PP5 phosphatase activity. Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1delta (CK1delta) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90. Overexpression of the phosphomimetic T362E-PP5 mutant hyper-dephosphorylates substrates such as the co chaperone Cdc37 and glucocorticoid receptor in cells. Our proteomic approach revealed that the tumor suppressor von Hippel-Lindau protein (VHL) interacts with and ubiquitinates K185/K199-PP5 for proteasomal degradation in a hypoxia- and prolyl-hydroxylation-independent manner. Finally, VHL-deficient clear cell renal cell carcinoma (ccRCC) cell lines and patient tumors exhibit elevated PP5 levels. Downregulation of PP5 causes ccRCC cells to undergo apoptosis, suggesting a prosurvival role for PP5 in kidney cancer. PMID- 29141221 TI - Chemotherapy-Induced Depletion of OCT4-Positive Cancer Stem Cells in a Mouse Model of Malignant Testicular Cancer. AB - Testicular germ cell tumors (TGCTs) are among the most responsive solid cancers to conventional chemotherapy. To elucidate the underlying mechanisms, we developed a mouse TGCT model featuring germ cell-specific Kras activation and Pten inactivation. The resulting mice developed malignant, metastatic TGCTs composed of teratoma and embryonal carcinoma, the latter of which exhibited stem cell characteristics, including expression of the pluripotency factor OCT4. Consistent with epidemiological data linking human testicular cancer risk to in utero exposures, embryonic germ cells were susceptible to malignant transformation, whereas adult germ cells underwent apoptosis in response to the same oncogenic events. Treatment of tumor-bearing mice with genotoxic chemotherapy not only prolonged survival and reduced tumor size but also selectively eliminated the OCT4-positive cancer stem cells. We conclude that the chemosensitivity of TGCTs derives from the sensitivity of their cancer stem cells to DNA-damaging chemotherapy. PMID- 29141222 TI - JNK Promotes Epithelial Cell Anoikis by Transcriptional and Post-translational Regulation of BH3-Only Proteins. AB - Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here, we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo. Moreover, JNK-promoted anoikis required pro apoptotic members of the BCL2 family of proteins. We show that JNK acts through a BAK/BAX-dependent apoptotic pathway by increasing BIM expression and phosphorylating BMF, leading to death of detached epithelial cells. PMID- 29141223 TI - Gradients of Rac1 Nanoclusters Support Spatial Patterns of Rac1 Signaling. AB - Rac1 is a small RhoGTPase switch that orchestrates actin branching in space and time and protrusion/retraction cycles of the lamellipodia at the cell front during mesenchymal migration. Biosensor imaging has revealed a graded concentration of active GTP-loaded Rac1 in protruding regions of the cell. Here, using single-molecule imaging and super-resolution microscopy, we show an additional supramolecular organization of Rac1. We find that Rac1 partitions and is immobilized into nanoclusters of 50-100 molecules each. These nanoclusters assemble because of the interaction of the polybasic tail of Rac1 with the phosphoinositide lipids PIP2 and PIP3. The additional interactions with GEFs and possibly GAPs, downstream effectors, and other partners are responsible for an enrichment of Rac1 nanoclusters in protruding regions of the cell. Our results show that subcellular patterns of Rac1 activity are supported by gradients of signaling nanodomains of heterogeneous molecular composition, which presumably act as discrete signaling platforms. PMID- 29141224 TI - Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines. AB - Tumor-sequencing studies have revealed the widespread genetic diversity of melanoma. Sequencing of 108 genes previously implicated in melanomagenesis was performed on 462 patient-derived xenografts (PDXs), cell lines, and tumors to identify mutational and copy number aberrations. Samples came from 371 unique individuals: 263 were naive to treatment, and 108 were previously treated with targeted therapy (34), immunotherapy (54), or both (20). Models of all previously reported major melanoma subtypes (BRAF, NRAS, NF1, KIT, and WT/WT/WT) were identified. Multiple minor melanoma subtypes were also recapitulated, including melanomas with multiple activating mutations in the MAPK-signaling pathway and chromatin-remodeling gene mutations. These well-characterized melanoma PDXs and cell lines can be used not only as reagents for a large array of biological studies but also as pre-clinical models to facilitate drug development. PMID- 29141226 TI - A Pan-cancer Analysis of the Expression and Clinical Relevance of Small Nucleolar RNAs in Human Cancer. AB - Increasing evidence has demonstrated that small nucleolar RNAs (snoRNAs) play important roles in tumorigenesis. We systematically investigated the expression landscape and clinical relevance of snoRNAs in >10,000 samples across 31 cancer types from The Cancer Genome Atlas. We observed overall elevated expression of snoRNAs and their ribonucleoproteins in multiple cancer types. We showed complex regulation of snoRNA expression by their host genes, copy number variation, and DNA methylation. Unsupervised clustering revealed that the snoRNA expression subtype is highly concordant with other molecular/clinical subtypes. We further identified 46 clinically relevant snoRNAs and experimentally demonstrated functional roles of SNORD46 in promoting cell proliferation, migration, and invasion. We developed a user-friendly data portal, SNORic, to benefit the research community. Our study highlights the significant roles of snoRNAs in the development and implementation of biomarkers or therapeutic targets for cancer and provides a valuable resource for cancer research. PMID- 29141227 TI - In Situ Fixation Redefines Quiescence and Early Activation of Skeletal Muscle Stem Cells. AB - State of the art techniques have been developed to isolate and analyze cells from various tissues, aiming to capture their in vivo state. However, the majority of cell isolation protocols involve lengthy mechanical and enzymatic dissociation steps followed by flow cytometry, exposing cells to stress and disrupting their physiological niche. Focusing on adult skeletal muscle stem cells, we have developed a protocol that circumvents the impact of isolation procedures and captures cells in their native quiescent state. We show that current isolation protocols induce major transcriptional changes accompanied by specific histone modifications while having negligible effects on DNA methylation. In addition to proposing a protocol to avoid isolation-induced artifacts, our study reveals previously undetected quiescence and early activation genes of potential biological interest. PMID- 29141225 TI - A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma. AB - Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups. PMID- 29141228 TI - Transcriptional Profiling of Quiescent Muscle Stem Cells In Vivo. AB - Muscle stem cells (MuSCs) persist in a quiescent state and activate in response to specific stimuli. The quiescent state is both actively maintained and dynamically regulated. However, analyses of quiescence have come primarily from cells removed from their niche. Although these cells are still quiescent, biochemical changes certainly occur during the isolation process. Here, we analyze the transcriptome of MuSCs in vivo utilizing MuSC-specific labeling of RNA. Notably, labeling transcripts during the isolation procedure revealed very active transcription of specific subsets of genes. However, using the transcription inhibitor alpha-amanitin, we show that the ex vivo transcriptome remains largely reflective of the in vivo transcriptome. Together, these data provide perspective on the molecular regulation of the quiescent state at the transcriptional level, demonstrate the utility of these tools for probing transcriptional dynamics in vivo, and provide an invaluable resource for understanding stem cell state transitions. PMID- 29141229 TI - Widespread Translational Remodeling during Human Neuronal Differentiation. AB - Faithful cellular differentiation requires temporally precise activation of gene expression programs, which are coordinated at the transcriptional and translational levels. Neurons express the most complex set of mRNAs of any human tissue, but translational changes during neuronal differentiation remain incompletely understood. Here, we induced forebrain neuronal differentiation of human embryonic stem cells (hESCs) and measured genome-wide RNA and translation levels with transcript-isoform resolution. We found that thousands of genes change translation status during differentiation without a corresponding change in RNA level. Specifically, we identified mTOR signaling as a key driver for elevated translation of translation-related genes in hESCs. In contrast, translational repression in active neurons is mediated by regulatory sequences in 3' UTRs. Together, our findings identify extensive translational control changes during human neuronal differentiation and a crucial role of 3' UTRs in driving cell-type-specific translation. PMID- 29141231 TI - Molecular Mechanism by which Prominent Human Gut Bacteroidetes Utilize Mixed Linkage Beta-Glucans, Major Health-Promoting Cereal Polysaccharides. PMID- 29141230 TI - Sub-minute Phosphoregulation of Cell Cycle Systems during Plasmodium Gamete Formation. AB - The transmission of malaria parasites to mosquitoes relies on the rapid induction of sexual reproduction upon their ingestion into a blood meal. Haploid female and male gametocytes become activated and emerge from their host cells, and the males enter the cell cycle to produce eight microgametes. The synchronized nature of gametogenesis allowed us to investigate phosphorylation signaling during its first minute in Plasmodium berghei via a high-resolution time course of the phosphoproteome. This revealed an unexpectedly broad response, with proteins related to distinct cell cycle events undergoing simultaneous phosphoregulation. We implicate several protein kinases in the process, and we validate our analyses on the plant-like calcium-dependent protein kinase 4 (CDPK4) and a homolog of serine/arginine-rich protein kinases (SRPK1). Mutants in these kinases displayed distinct phosphoproteomic disruptions, consistent with differences in their phenotypes. The results reveal the central role of protein phosphorylation in the atypical cell cycle regulation of a divergent eukaryote. PMID- 29141232 TI - FOXP1 Promotes Embryonic Neural Stem Cell Differentiation by Repressing Jagged1 Expression. AB - Mutations in FOXP1 have been linked to neurodevelopmental disorders including intellectual disability and autism; however, the underlying molecular mechanisms remain ill-defined. Here, we demonstrate with RNA and chromatin immunoprecipitation sequencing that FOXP1 directly regulates genes controlling neurogenesis. We show that FOXP1 is expressed in embryonic neural stem cells (NSCs), and modulation of FOXP1 expression affects both neuron and astrocyte differentiation. Using a murine model of cortical development, FOXP1-knockdown in utero was found to reduce NSC differentiation and migration during corticogenesis. Furthermore, transplantation of FOXP1-knockdown NSCs in neonatal mice after hypoxia-ischemia challenge demonstrated that FOXP1 is also required for neuronal differentiation and functionality in vivo. FOXP1 was found to repress the expression of Notch pathway genes including the Notch-ligand Jagged1, resulting in inhibition of Notch signaling. Finally, blockade of Jagged1 in FOXP1 knockdown NSCs rescued neuronal differentiation in vitro. Together, these data support a role for FOXP1 in regulating embryonic NSC differentiation by modulating Notch signaling. PMID- 29141233 TI - miRNome Profiling of Purified Endoderm and Mesoderm Differentiated from hESCs Reveals Functions of miR-483-3p and miR-1263 for Cell-Fate Decisions. AB - Pluripotent stem cells hold great promise for regenerative medicine since they can differentiate into all somatic cells. MicroRNAs (miRNAs) could be important for the regulation of these cell-fate decisions. Profiling of miRNAs revealed 19 differentially expressed miRNAs in the endoderm and 29 in the mesoderm when analyzing FACS-purified cells derived from human embryonic stem cells. The mesodermal-enriched miR-483-3p was identified as an important regulator for the generation of mesodermal PDGFRA+ paraxial cells. Repression of its target PGAM1 significantly increased the number of PDGFRA+ cells. Furthermore, miR-483-3p, miR 199a-3p, and miR-214-3p might also have functions for the mesodermal progenitors. The endoderm-specific miR-489-3p and miR-1263 accelerated and increased endoderm differentiation upon overexpression. KLF4 was identified as a target of miR-1263. RNAi-mediated downregulation of KLF4 partially mimicked miR-1263 overexpression. Thus, the effects of this miRNA were mediated by facilitating differentiation through destabilization of pluripotency along with other not yet defined targets. PMID- 29141235 TI - Bioremediation of PCB-contaminated shallow river sediments: The efficacy of biodegradation using individual bacterial strains and their consortia. AB - Elimination of dangerous toxic and hydrophobic chlorinated aromatic compounds, mainly PCBs from the environment, is one of the most important aims of the environmental biotechnologies. In this work, biodegradation of an industrial mixture of PCBs (Delor 103, equivalent to Aroclor 1242) was performed using bacterial consortia composed of four bacterial strains isolated from the historically PCB-contaminated sediments and characterized as Achromobacter xylosoxidans, Stenotrophomonas maltophilia, Ochrobactrum anthropi and Rhodococcus ruber. The objective of this research was to determine the biodegradation ability of the individual strains and artificially prepared consortia composed of two or three bacterial strains mentioned above. Based on the growth parameters, six consortia were constructed and inoculated into the historically contaminated sediment samples collected in the efflux canal of Chemko Strazske plant - the former producer of the industrial mixtures of PCBs. The efficacy of the biotreatment, namely bioaugmentation, was evaluated by determination of ecotoxicity of treated and non-treated sediments. The most effective consortia were those containing the strain R. ruber. In the combination with A. xylosoxidans, the biodegradation of the sum of the indicator congeners was 85% and in the combination with S. maltophilia nearly 80%, with inocula applied in the ratio 1:1 in both cases. Consortium containing the strain R. ruber and S. maltophilia showed pronounced degradation of the highly chlorinated PCB congeners. Among the consortia composed of three bacterial strains, only that consisting of O. anthropi, R. ruber and A. xylosoxidans showed higher biodegradation (73%). All created consortia significally reduced the toxicity of the contaminated sediment. PMID- 29141234 TI - Elevated p53 Activities Restrict Differentiation Potential of MicroRNA-Deficient Pluripotent Stem Cells. AB - Pluripotent stem cells (PSCs) deficient for microRNAs (miRNAs), such as Dgcr8-/- or Dicer-/- embryonic stem cells (ESCs), contain no mature miRNA and cannot differentiate into somatic cells. How miRNA deficiency causes differentiation defects remains poorly understood. Here, we report that miR-302 is sufficient to enable neural differentiation of differentiation-incompetent Dgcr8-/- ESCs. Our data showed that miR-302 directly suppresses the tumor suppressor p53, which is modestly upregulated in Dgcr8-/- ESCs and serves as a barrier restricting neural differentiation. We demonstrated that direct inactivation of p53 by SV40 large T antigen, a short hairpin RNA against Trp53, or genetic ablation of Trp53 in Dgcr8 /- PSCs enables neural differentiation, while activation of p53 by the MDM2 inhibitor nutlin-3a in wild-type ESCs inhibits neural differentiation. Together, we demonstrate that a major function of miRNAs in neural differentiation is suppression of p53 and that modest activation of p53 blocks neural differentiation of miRNA-deficient PSCs. PMID- 29141236 TI - Concentrations of a PGF2alpha metabolite during pregnancy on the days that luteolysis occurs in nonbred heifers. AB - Concentrations of a metabolite of PGF2alpha (PGFM) were compared between nonbred (n = 6) and pregnant (n = 8) heifers on days 16, 17, and 18 postovulation. On each day, an 8-h session of hourly blood sampling was done. Averaged over the 8-h sessions, mean concentration of PGFM was less (P < 0.0009) in the pregnant group (45.2 +/- 3.2 pg/mL) than that in the nonbred group (65.6 +/- 7.9 pg/mL), but the minimal concentration per session was not significantly different between groups. Pulses of PGFM (identified by coefficient of variance) were similar in frequency between groups but were less (P < 0.03) prominent at the peak in the pregnant group (60.0 +/- 5.3 pg/mL) than that in the nonbred group (92.8 +/- 10.7 pg/mL). These results indicated similarity between groups in frequency and initial development of a PGFM pulse but without later development and a reduction in prominence in the pregnant group. The progesterone response to a PGFM pulse of similar prominence was made before the beginning of luteolysis in individuals in the nonbred group and during the hourly sessions on days 16 to 18 in the pregnant group. Progesterone concentration in the nonbred group decreased (P < 0.05) during 2 h before the PGFM peak (8.8 +/- 1.6 to 5.6 +/- 1.0 ng/mL) and rebounded (P < 0.05) completely during the 2 h after the peak (5.6 +/- 1.0 to 9.6 +/- 2.2 ng/mL). A transient progesterone decrease during a similar PGFM pulse and similar initial progesterone concentration did not occur in the pregnant group. Results supported the hypotheses that (1) pregnant heifers have identifiable but less prominent PGFM pulses during the days that luteolysis occurs in nonbred heifers and (2) the corpus luteum locally resists the luteolytic effect of PGF2alpha in pregnant heifers before the days of onset of luteolysis in nonbred heifers. PMID- 29141237 TI - Influence of sewage treatment plant effluent discharge into multipurpose river on its water quality: A quantitative health risk assessment of Cryptosporidium and Giardia. AB - Sewage treatment plants (STPs) are one of the sources of pathogens discharged into surface water. An investigation was carried out over the duration of 12 months in Henan Province, China, to evaluate the health influence of municipal wastewater effluent discharge on water quality of the receiving water. A discharge-based quantitative microbial risk assessment (QMRA) was employed, taking into account the vegetables consumption habits of the Chinese, population subgroups with different immune statuses and ages, to evaluate the incremental disease burden from agricultural irrigation and swimming exposure scenarios associated with increased concentration of the protozoan Cryptosporidium and/or Giardia in the receiving river. The results shown that all the STP influent samples contained Cryptosporidium and Giardia with average density of 142.31 oocysts/L and 1187.06 cysts/L, respectively. The QMRA results demonstrated that the estimated additional health burdens due to discharged effluent for both parasites were slightly violated the threshold of 10-6 DALYs per person per year set by WHO. Mitigation measures should be planned and executed by season since more disease burdens were borne during hot season than other seasons. The sensitivity analysis highlighted the great importance of stability of STP treatment process. This study provides useful information to improve the safety of surface water and deduce the disease burden of the protozoa in Henan Province and other region inside and outside China. PMID- 29141238 TI - Rationale redesign of type III secretion systems: toward the development of non pathogenic E. coli for in vivo delivery of therapeutic payloads. AB - Transkingdom secretion systems that bacteria use to inject proteins directly into the cytosol of mammalian host cells play an essential role in the virulence of many Gram-negative bacterial pathogens. Current efforts are underway to repurpose these machines as novel therapeutics; type III secretion systems as vectors for the delivery of proteins of therapeutic value including heterologous antigens for vaccine development and type IV secretion systems as vectors for DNA. While initial studies focused on the use of attenuated or replication incompetent pathogens, the recent development of non-pathogenic Escherichia coli that encode programmable type III secretion systems expands possibilities for the in vivo directed delivery of therapeutic payloads. PMID- 29141239 TI - Exposing Toxoplasma gondii hiding inside the vacuole: a role for GBPs, autophagy and host cell death. AB - The intracellular parasite Toxoplasma gondii resides inside a vacuole, which shields it from the host's intracellular defense mechanisms. The cytokine interferon gamma (IFNgamma) upregulates host cell effector pathways that are able to destroy the vacuole, restrict parasite growth and induce host cell death. Interferon-inducible GTPases such as the Guanylate Binding Proteins (GBPs), autophagy proteins and ubiquitin-driven mechanisms play important roles in Toxoplasma control in mice and partly also in humans. The host inflammasome is regulated by GBPs in response to bacterial infection in murine cells and may also respond to Toxoplasma infection. Elucidation of murine Toxoplasma defense mechanisms are guiding studies on human cells, while inevitably leading to the discovery of human-specific pathways that often function in a cell type-dependent manner. PMID- 29141240 TI - Host-microbe interactions: Malassezia and human skin. AB - The skin is our first line of defense, protecting us from invasion and evaporation. Its variable structure, changing geography, and complex immune repertoire provide a vast interface for our cutaneous microbial community. Skin is inhabited by many thousands of microbes, but this review focuses on the dominant eukaryote, Malassezia, and its host interaction. Malassezia compromises 17 species with variable niche specificities and differing pathogenic potential. It has been known as a skin inhabitant for over 100 years, and is now accepted to be on all warm-blooded animals. Malassezia occupy healthy and diseased skin, so their role as commensal or pathogenic organisms is complex. Malassezia interact with their host indirectly through immune interplay and directly via chemical mediators. While some interactions are known, many remain to be fully understood. PMID- 29141241 TI - MMP-9 and Its Regulators TIMP-1 and EMMPRIN in Patients with Acute ST-Elevation Myocardial Infarction: A NORDISTEMI Substudy. AB - OBJECTIVES: The extracellular matrix is involved in wound repair after acute myocardial infarction (AMI). We investigated whether matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and the MMP inducer (EMMPRIN) are associated with infarct size, left ventricular function, and clinical outcome in ST-elevation-MI (STEMI). METHODS: In 243 STEMI patients, circulating EMMPRIN, MMP-9, and TIMP-1 were analyzed 3 days and 3 months post AMI. Infarct size and left ventricular ejection fraction were assessed by single photon emission computed tomography (SPECT) (n = 230/226) and MRI (n = 111/167) at 3 months. RESULTS: EMMPRIN, MMP-9, and TIMP-1 levels and the MMP-9/TIMP-1 ratio declined from day 3 to 3 months (p < 0.001, all). TIMP-1 levels at day 3 correlated significantly with SPECT- and MRI-based infarct size, troponin T (p < 0.04, all), and amino-terminal pro-B-type natriuretic peptide (NT-proBNP; p < 0.001). The upper quartile of day 3 TIMP-1 levels showed an adjusted odds ratio of 5.0 (95% confidence interval 1.2-20.6) for having a large infarct size. An insignificant relationship between MMP-9 and clinical events within 1 year (death, AMI, or stroke) (n = 15) was observed, probably due to the lack of statistical power. CONCLUSION: The decline in EMMPRIN, MMP-9, and TIMP-1 3 months after acute STEMI is probably due to initial acute-phase processes. The associations between TIMP-1, infarct size, and NT-proBNP indicate a role for TIMP 1 in cardiac remodeling. PMID- 29141242 TI - Chloroquine Autophagic Inhibition Rebalances Th17/Treg-Mediated Immunity and Ameliorates Systemic Lupus Erythematosus. AB - BACKGROUND: Imbalanced cellular immunity is critical to the pathogenesis of systemic lupus erythematosus (SLE). Recently, autophagy has emerged as a key homeostatic mechanism in T lymphocytes. This study was conducted to explore the impact of autophagy on the Th17/ regulatory T (Treg) immune imbalance in SLE. METHODS: Peripheral Th17 and Treg cells from newly diagnosed patients with SLE and healthy controls were detected by flow cytometry. Additionally, the effects of chloroquine (CQ) autophagic inhibition on the Th17/Treg immune response were investigated in vitro. In addition, hydroxychloroquine (HCQ) treatment of the Th17/Treg immune response and the disease progression of lupus MRL/lpr mice were studied in vivo. RESULTS: Compared with healthy controls, both peripheral Th17 and Treg cells of patients with SLE exhibited activated autophagy, resulting in a heightened Th17 proinflammatory response and diminished Treg immunosuppression. Furthermore, in vitro experiments indicated that CQ autophagic inhibition effectively rebalanced the Th17/Treg immune responses in patients with SLE. In vivo studies of MRL/lpr mice similarly confirmed that HCQ treatment decisively inhibited the autophagy of Th17/Treg cellular subsets, restoring the immune balance, lowering the serum levels of inflammatory cytokines and autoantibodies, and improving renal histopathology. CONCLUSION: Activated autophagy contributed to the Th17/Treg immune imbalance in SLE, and chloroquine autophagic inhibition rebalanced Th17/ Treg-mediated immunity and ameliorated SLE. PMID- 29141243 TI - Trolline Ameliorates Liver Fibrosis by Inhibiting the NF-kappaB Pathway, Promoting HSC Apoptosis and Suppressing Autophagy. AB - BACKGROUND/AIMS: Previous studies have shown that trolline possesses various forms of pharmacological activity, including antibacterial and antiviral potency. The present paper addressed the putative hepatoprotective effects of trolline. METHODS: Rats received 2 ml/kg CCl4 (mixed 1: 1 in peanut oil) intragastrically twice a week for 8 weeks to induce hepatic fibrosis. The animals were then treated with trolline for additional 4 weeks. Liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively. Serum transaminase activity and collagen-related indicator level were determined by commercially available kits. NF-kappaB pathway activation was also examined. Moreover, the effects of trolline on hepatic stellate cell (HSC T6) apoptosis, mitochondrial membrane potential (MMP), and autophagy were assessed. RESULTS: Trolline significantly alleviated CCl4-induced liver injury and notably reduced the accumulation of collagen in liver tissues. Trolline treatment also markedly decreased inflammatory cytokines levels by inhibiting the NF-kappaB pathway. Trolline strongly inhibited HSC-T6 activation and notably induced cell apoptosis by modulating the Bax/Bcl-2 ratio, caspase activity, and MMP. Moreover, trolline significantly inhibited HSC-T6 autophagy, as evidenced by the decrease in the formation of autophagic vacuoles and the number of autophagosomes, by regulating the expression levles of LC3, Beclin-1, P62, Atg 5 and 7. CONCLUSION: Our study demonstrates that trolline ameliorates liver fibrosis, possibly by inhibiting the NF-kappaB pathway, promoting HSCs apoptosis and suppressing autophagy. PMID- 29141244 TI - Exploring Parental Expectations and Experiences Around "Gentle" and "Standard" Caesarean Section. AB - BACKGROUND/AIMS: "Gentle" or "natural" cesarean sections are implemented to improve parental satisfaction. The objective of this study was to investigate whether there is a need for adopting such a gentle approach. METHODS: We recruited those with low-risk pregnancies scheduled for elective cesarean delivery at term. Three questionnaires were administered to both partners: prior to delivery, 2-5 days after delivery, and 6 weeks postpartum. Questionnaires assessed the couple's expectations, fears, and satisfaction prior to and after cesarean section. Additionally, participants attended 2 structured interviews: one prior to delivery and one 6 weeks after delivery. RESULTS: Fifteen couples underwent a "standard" cesarean section (group 1) and 6 underwent a "gentle" section (group 2). Overall, parental satisfaction with cesarean section was high. However, women in the standard group felt less involved in childbirth and both groups still preferred vaginal delivery in light of eventual future pregnancies. Participants in group 2 showed less fear of childbirth after delivery than prior to delivery. There were no differences in total questionnaire scores between groups or between mothers and partners. CONCLUSION: This study shows that there is room for improvement in satisfaction levels around cesarean section, even though satisfaction is generally high. A "gentle" cesarean section may help to achieve this. PMID- 29141245 TI - Roscovitine, a CDK5 Inhibitor, Alleviates Sevoflurane-Induced Cognitive Dysfunction via Regulation Tau/GSK3beta and ERK/PPARgamma/CREB Signaling. AB - BACKGROUND/AIMS: Multiple exposures to anesthesia in children may increase the risk of developing cognitive impairment. Sevoflurane is an anesthetic that is commonly used in children during surgery. Cyclin-dependent kinase (CDK) 5 is involved in the regulation of sevoflurane-induced cognitive dysfunction, but the mechanistic details remain unclear. The present study evaluated the mechanism by which CDK5 mediates sevoflurane-induced cognitive dysfunction in mice. METHODS: Hippocampal neurons were isolated from postnatal day 0 C57BL/6 mouse pups. Six day-old wild-type mice were exposed to sevoflurane and then treated with the CDK5 inhibitor roscovitine. The effects on cognitive function were evaluated with the Morris water maze and neuronal damage in the hippocampus was assessed by immunohistochemical analysis. RESULTS: CDK5 activation increased neuronal damage by inducing Tau/glycogen synthase kinase (GSK) 3beta and suppressing extracellular signal-regulated kinase (ERK)/peroxisome proliferator-activated receptor (PPAR)gamma/cyclic AMP response element-binding protein (CREB) signaling following exposure to sevoflurane. CDK5 inhibition by roscovitine administration alleviated sevoflurane-induced neuronal damage and cognitive impairment. CONCLUSIONS: Inhibiting CDK5 with roscovitine has neuroprotective effects against neuronal injury and cognitive dysfunction caused by sevoflurane anesthesia that are exerted via modulation of Tau/GSK3beta and ERK/PPARgamma/CREB signaling. PMID- 29141246 TI - Evaluation of Temporal Virological Responses to Interferon-alpha-2b plus Ribavirin among Genotype 3a Hepatitis C Virus-Infected Patients. AB - OBJECTIVES: The present study aimed to examine the impact of rapid virological response (RVR) and early virological response (EVR) on sustained virological response (SVR) in chronic hepatitis C genotype 3a individuals. METHODS: The patients were given antiviral therapy with IFN-alpha-2b, 3 million units 3 times a week and 800-1,200 mg of ribavirin daily adjusted to the patient's body weight (<60 kg 800 mg day-1, and >60 kg 1,200 day-1). The patients received this combination therapy for 24 weeks. The patients were evaluated for their viral load at week 4, 12, and 24 using RT-PCR. RESULTS: Out of 1,471 patients, 43.3% showed a negative viral load in week 4, demonstrating RVR, whereas 56.6% maintained a high viral load. These were further separated based on viral reduction in their plasma: either negative for HCV-RNA at week 12 (n = 575), manifesting EVR, or showing a 2-log reduction in HCV viral load classified as partial EVR (PEVR; n = 259). The PEVR response was less (29.7%) compared with RVR (85.9%) and EVR (69.0%), although nonresponders were found in both groups. CONCLUSIONS: Individuals incompliant with their treatment who have a higher RVR significantly influence their SVR towards a better remission that can be treated within a short duration with standard treatment. PMID- 29141247 TI - Connections of Anterior Thalamic Visual Centers in the Leopard Frog, Rana pipiens. AB - The amphibian retina projects to two discrete regions of neuropil in the anterior thalamus: the neuropil of Bellonci and the corpus geniculatum. These retinorecipient areas are encompassed within a larger zone of surrounding neuropil we call the NCZ (for neuropil of Bellonci/corpus geniculatum zone). The NCZ is characterized electrophysiologically by a distinctive tonic oscillatory response to blue light; it appears to be a visual module involved in processing the stationary visual environment. Using horseradish peroxidase (HRP), we mapped the connections of the NCZ. Retrogradely labeled cell bodies are found in: (1) the contralateral anterior thalamus; (2) both retinas; and (3) the posterior medial dorsal thalamus (PMDT). Anterogradely labeled fibers are found in: (1) the contralateral anterior thalamus; (2) the ipsilateral PMDT; (3) the ipsilateral neuropil lateral to the posterior tuberculum in the ventrolateral posterior thalamus; and (4) the ipsilateral anterior medulla. There are no direct connections between the NCZ and the telencephalon, the tectum, or the suprachiasmatic nucleus. Applying HRP to the PMDT, we found that its inputs are limited to the contralateral and ipsilateral NCZ and the contralateral PMDT. Thus, PMDT appears to be a satellite of the NCZ. Blue light elicits tonic oscillatory electrical responses in the PMDT quite similar to the responses to blue light in the NCZ. We discuss how the leopard frog NCZ and the mammalian ventral lateral geniculate nucleus share anatomical and physiological properties. PMID- 29141248 TI - Association of Functional Genetic Variants of HOTAIR with Hepatocellular Carcinoma (HCC) Susceptibility in a Chinese Population. AB - BACKGROUND/AIMS: The HOX transcript antisense intergenic RNA (HOTAIR), a long non coding RNA (lncRNA), plays an important role in the pathogenesis and progression of multiple tumors. The aim of the present study was to evaluate whether common single nucleotide polymorphisms (SNPs) in HOTAIR are related to hepatocellular carcinoma (HCC) susceptibility in a Chinese population. METHODS: We genotyped three SNPs of HOTAIR in a hepatocellular carcinoma (HCC) case-control study, including 482 cases and 520 control subjects. SNPs were genotyped using real-time polymerase chain reaction (RT-PCR). Associations between gene polymorphisms and HCC were evaluated using multiple logistic regression analysis. The allele specific effects on HOTAIR expression in HCC were confirmed by real time quantitative PCR and luciferase activity assays. The influence of HOTAIR SNPs on the proliferation of HCC cells was evaluated using a CCK-8 assay. RESULTS: Significant associations were observed between the HOTAIR rs920778 C>T polymorphism and HCC risk (TT versus CC: OR = 1.634, 95% CI =1.028-2.598, P = 0.046) and the allelic model (allele T versus allele C: OR =1.293, 95% CI = 1.060 1.577, P = 0.011). However, no statistically significant differences of rs4759314 and rs1899663 genotypes were observed between patients and controls (both P > 0.05). The increased risk for rs920778 TT genotype carriers was more evident in a sub-group of drinkers (OR = 3.103, 95% CI = 1.151-8.368, p=0.025) and in people positive for HBV infection (OR = 2.885, 95% CI = 1.086-7.663, p=0.034). RT-PCR and luciferase activity assay confirmed that the rs920778 TT genotype induced significantly higher HOTAIR levels than did the CC genotype (P < 0.05). CCK-8 assays and colony formation assays demonstrated that the rs920778 TT genotype had a higher proliferation rate of HCC cells than did the CC genotype (P < 0.05). CONCLUSION: These results suggest that SNP rs920778 of HOTAIR acts as a potential biomarker for predicting hepatocellular carcinoma, and further studies are warranted to confirm these findings. PMID- 29141249 TI - beta-Catenin Cooperates with CREB Binding Protein to Promote the Growth of Tumor Cells. AB - BACKGROUND/AIMS: beta-catenin is an integral component of the canonical Wnt signaling pathway, and its mutations are an autosomal recessive cause of colorectal cancer (CRC), medulloblastoma (MDB), and ovarian cancer. Nevertheless, little is known about its function in lung cancers. METHODS: We first knocked down beta-catenin by siRNA to investigate its effects on lung cancer cell proliferation, migration and apoptosis. Then we verified the interaction between beta-catenin and CREB binding protein (CBP) by immunofluoresence and co immunoprecipition assays. Finally, the expression of beta-catenin and CBP in human lung adenocarcinoma specimens were analyzed by immunohistochemistry assay. RESULTS: beta-catenin knockdown inhibited cell proliferation, promoted apoptosis and suppressed cell migration in A549 and H460 cells accompanied by the decreased expression of Myc, PCNA, VEGF, CD44, MMP-9, MMP-13 and activated bax/caspase-3 pathway. Furthermore, co-immunoprecipition and immunofluoresence analyses revealed that CBP interacted with beta-catenin and contributed to beta-catenin mediated lung cancer cell growth. Abolishment of their interaction by the Wnt/beta-catenin inhibitor ICG-001 remarkably suppressed cell proliferation. Immunohistochemistry assay of tissue microarrays from patients with lung cancer indicated that both CBP and beta-catenin were highly expressed in tumor tissues and predicted poor prognosis in lung adenocarcinoma patients. CONCLUSIONS: Our study has provided new evidence for the role of beta-catenin in promoting the growth of lung cancer cells through cooperation with CBP, and suggested that dual targeting of beta-catenin and CBP could be a potential therapeutic strategy in lung cancer treatment. PMID- 29141250 TI - A Small Supernumerary Marker Derived from the Pericentromeric Region of Chromosome 5: Case Report and Delineation of Partial Trisomy 5p Phenotype. AB - A 17-year-old girl presented with a distinct phenotype mainly featuring craniofacial dysmorphism, including a disproportioned large, round, elongated face; hypertelorism; deep-set eyes with short palpebral fissures; obesity (BMI 37), and a neuropsychiatric disorder with high-functioning autism. Postnatal conventional cytogenetic analyses from peripheral blood revealed a mosaic small supernumerary marker chromosome (sSMC) with a mos 47,XX,+mar[7]/46,XX[43] karyotype. By cenM-FISH technique, the sSMC was identified as a ring derivative of chromosome 5. Metaphase FISH analysis with a set of dedicated probes defined its origin from the pericentromeric region of chromosome 5, including the NIPBL gene at 5p13.2. Such sSMCs, exceedingly rare in the literature, underlie proximal trisomy 5p. In order to delineate a core phenotype of proximal trisomy 5p, we compared our patient's features with those of 6 patients found in the literature with similar der(5) chromosomes. Furthermore, a dozen individuals with 5p13 (micro)duplication syndrome was compared and discussed. We identified highly distinctive craniofacial dysmorphism, obesity, and intellectual disability and/or autism spectrum disorder as typical features of proximal 5p trisomy. In the critical region (band 5p13), the NIPBL gene is likely to be a major determinant of the neurobehavioral phenotype, and its presence at the sSMC level may be relevant to predict clinical outcome. PMID- 29141251 TI - Opioid Receptors Contribute to Antinociceptive Effect of Tianeptine on Colorectal Distension-Induced Visceral Pain in Rats. AB - Tianeptine is a clinically effective atypical antidepressant with distinct neurochemical properties. In this study, we aimed to investigate the contribution of opioid receptors in the antinociceptive effect of tianeptine on visceral pain in awake rats and to differentiate the subtype and the localization (central and/or peripheral) of these opioid receptors involved in this antinociception. Visceromotor response to noxious colorectal distension (CRD) was quantified with electromyographic recordings, obtained from previously implanted electrodes into the external oblique musculature of rats under anesthesia, before and after tianeptine administration. The opioid receptor antagonist naloxone hydrochloride (NLX) and peripherally restricted opioid receptor antagonist naloxone methiodide (NLXM) were administered intravenously 10 min before tianeptine (10 mg/kg, i.v.). The antinociceptive effect of tianeptine was abolished by NLX (1 and 2 mg/kg, i.v.), but was partially reduced by NLXM (1 and 2 mg/kg, i.v.). A u-opioid receptor-selective dose (0.03 mg/kg, i.v.) of NLX, but not NLXM, significantly inhibited the antinociceptive effect of tianeptine. Our results suggest that antinociceptive effect of tianeptine on CRD-induced visceral nociception in rats involves the activation of both central and peripheral opioid receptors. PMID- 29141253 TI - Errata. PMID- 29141254 TI - Role of Glutamatergic System in Obsessive-Compulsive Disorder with Possible Therapeutic Implications. PMID- 29141252 TI - Musashi1 Promotes Non-Small Cell Lung Carcinoma Malignancy and Chemoresistance via Activating the Akt Signaling Pathway. AB - BACKGROUND/AIMS: Lung cancer is one of the leading causes for cancer mortality. The poor therapeutic outcome of non-small cell lung carcinoma (NSCLC) is mainly due to late diagnosis and chemoresistance. In this study, we investigated the role of Musashi1 (MSI1) in NSCLC malignancy and chemoresistance. METHODS: Colony formation, MTT, glucose uptake and lactate production assays were employed to study lung cancer cell malignancy and chemoresistance. RT-PCR and Western blotting were performed to detect mRNA and protein expressions of genes. We used immunohistochemistry and Pearson correlation analysis to study the relationship of gene expression. RESULTS: We demonstrated that MSI1 was able to promote the proliferation and glucose metabolism of NSCLC cells, and to mediate the sensitivity to chemotherapy drugs in NSCLC cells. Importantly, we found that MSI1 could regulate the activity of Akt signaling. The regulation of NSCLC proliferation, glucose metabolism and chemoresistance by MSI1 was dependent on the modulation of the activity of the Akt signaling pathway. We also found that MSI1 was a target of miR-181a-5p, a microRNA involved in the regulation of cancer development. The expression levels of MSI1 and miR-181a-5p were negatively correlated in NSCLC. CONCLUSION: MSI1 promotes non-small cell lung carcinoma malignancy and chemoresistance via activating the Akt signaling pathway, which provides a new strategy for the therapy of NSCLC. PMID- 29141255 TI - Is Venlafaxine More Effective than Escitalopram and Nortriptyline in the Management of Painful Symptoms in Patients with Major Depression? AB - BACKGROUND: Conflicting data regarding the efficacy of antidepressants of different mechanism of action on unexplained painful physical symptoms (UPPS) in depression have been published so far. OBJECTIVE: The aim of this study was to compare the impact of escitalopram (ESC), nortriptyline (NOR), and venlafaxine (VEN) on UPPS in patients with major depression. MATERIALS AND METHODS: Sixty patients, participants in the GENDEP study, with a diagnosis of depression according to the ICD-10 criteria were randomly assigned to treatment with ESC (10 30 mg, mean dose 15.2, standard deviation [SD]+/-9.2) or NOR (50-150 mg, mean dose 106.2, SD+/-8.2). Additionally, 30 patients who were treated with VEN (75 225 mg, mean dose 181.3, SD+/-8.8) were included. Before inclusion (day 0) and throughout the study (days 14, 28, 42, 56), the severity of pain was monitored using the visual analog scale. RESULTS: The patients treated with ESC, NOR, and VEN did not differ in the intensity of pain at days 0, 14, 28, 42, and 56. CONCLUSION: Our results do not support the hypothesis suggesting the superiority of VEN over ESC and NOR in the management of UPPS in major depression. PMID- 29141256 TI - Thrombosis Prevention with Botulinum Toxin A after Traumatic Crush Injury in a Rat Model. AB - BACKGROUND: Revascularized digits may fail because of vessel thrombosis. The current study aimed to develop a standard model for crush injury in the rat femoral artery to evaluate the antithrombotic effect of perivascular botulinum toxin A (BTX-A) injection. METHODS: We explored bilateral femoral arteries of 10 rats using a microscopic technique. The crush injury was reproduced using a bulldog clamp. One randomly chosen leg of each rat was injected with BTX-A. The other side received normal saline as its own control. After 24 hours, the femoral arteries were ligated distal to the trauma site and were divided between the traumatized and ligated sites. RESULTS: All arteries injected with BTX-A had pulsatile bleeding without thrombosis. Arteries injected with normal saline had thrombosis without bleeding, except for one with oozing. The results showed the efficacy of BTX-A and its potential use in microvascular trauma (p < 0.001). CONCLUSION: The use of BTX-A preoperatively in the emergency department may help reduce traumatic stress and subsequent thrombosis and improve trauma management results. Complementary studies are needed to assess the ability of BTX-A to reduce thrombosis and vasospasm and improve survival of traumatized digits. PMID- 29141257 TI - Phalloplasty in Female-to-Male Transsexuals by Gottlieb and Levine's Free Radial Forearm Flap Technique-A Long-Term Single-Center Experience Over More than Two Decades. AB - BACKGROUND: The free radial forearm flap phalloplasty is the most utilized method for penile reconstruction. Among the techniques described in the literature, evidence for the flap design after Gottlieb and Levine is poor. METHODS: From January 1993 until December 2015, 402 phalloplasties were performed in our clinic. Among the 247 free radial forearm flap phalloplasties, 232 free radial forearm flap phalloplasties were performed after Gottlieb and Levine in 229 patients. Operation and patient-specific characteristics were evaluated. RESULTS: This study presents the highest number of free radial forearm flap phalloplasties after Gottlieb and Levine. The rate of total flap failure was 3%; 46% of the patients were heavy smokers. Urinary fistulae and strictures are common. The revision rate for urinary fistulae and/or strictures was 1.3 per patient. The number of postoperative complications, such as bleeding (14.2%), thrombosis of the flap requiring revision (11.2%), or delayed wound healing (16.8%) was considering the high rate of nicotine abuse (45.9%) reasonable. CONCLUSION: The free radial forearm phalloplasty in the design by Gottlieb and Levine is well established at our institution and has proven safe and reliable since 1993. The operative results are satisfactory for both patients and surgeons even in the presence of relevant comorbidities and heavy smoking. We acknowledge the long ordeal and psychological pressure that our patients suffer from, before presenting in our outpatient clinic. PMID- 29141258 TI - The Omental Free Flap-A Review of Usage and Physiology. AB - BACKGROUND: The omental flap has a rich history of use over the last century, and specifically as a free flap in the last four decades. It has a wide variety of applications in reconstructive surgery and has shown itself to be a reliable donor tissue. We seek to review the properties that make the omental free flap a valuable tool in reconstruction, as well as its many surgical applications in all anatomic regions of the body. METHODS: We conducted a narrative review of the literature on Medline and Google Scholar. We reviewed basic science articles discussing the intrinsic properties of omental tissue, along with clinical papers describing its applications. RESULTS: The omental free flap is anatomically suitable for harvest and wound coverage and has molecular properties that promote healing and improve function at recipient sites. It has demonstrated utility in a wide variety of reconstructive procedures spanning the head and neck, extremities, and viscera and for several purposes, including wound coverage, lymphedema treatment, and vascularization. It is also occasionally employed in the thoracic cavity and chest wall, though more often as a pedicled flap. More novel uses include its use for cerebrospinal fluid leaks. CONCLUSIONS: The omental free flap is a valuable option for reconstructive efforts in nearly all anatomic regions. This is a result of its inherent anatomy and vascularity, and its angiogenic, immunogenic, and lymphatic properties. PMID- 29141259 TI - Femoral, Direct, and Rare Inguinal Hernias in Children-An Update. PMID- 29141260 TI - Timing and Management of Inguinal Hernia in the Premature Baby. PMID- 29141261 TI - [Virtual Planning of Prosthetic Treatment of the Orbit]. PMID- 29141262 TI - Impact of Pregnancy History and 17-Hydroxyprogesterone Caproate on Cervical Cytokines and Matrix Metalloproteinases. AB - OBJECTIVE: The objective of this study was to evaluate the impact of pregnancy history and 17-hydroxyprogesterone caproate (17-OHPC) treatment on cervical fluid cytokines and matrix metalloproteinases (MMPs). STUDY DESIGN: Cervical fluid was obtained between 160/7 and 246/7 weeks from women with only prior term births (controls, n = 26), women with one or more prior spontaneous preterm births (SPTBs) choosing to receive 17-OHPC (17-OHPC, n = 24), or to not receive 17-OHPC (refusers, n = 12). Cervical fluid collections were repeated 2, 4, and 8 weeks after the first sample and concentrations of MMPs and cytokines were measured by multiplex immune assay. RESULTS: Among women whose earliest prior delivery occurred between 16 and 23 weeks, cervical fluid concentration of interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha at baseline were significantly elevated when compared with cervical cytokines of women whose earliest delivery occurred between 32 and 36 weeks (relative risk ratio was 3.37 for IL-6 [95% confidence interval, CI, 1.08-10.53, p < 0.05], 2.81 for IL-10 [95% CI, 1.39-5.70, p < 0.05], and 6.34 for TNF-alpha [95% CI, 2.19-18.68, p < 0.001]). Treatment with 17-OHPC had no significant impact on these cytokines. CONCLUSION: The cervical fluid of women with a history of an early prior SPTB is characterized by inflammation that is unaffected by 17-OHPC. PMID- 29141264 TI - Comparison of Azithromycin versus Erythromycin for Prolongation of Latency in Pregnancies Complicated by Preterm Premature Rupture of Membranes (Podcast). PMID- 29141263 TI - Cross-Correlation of Heart Rate and Oxygen Saturation in Very Low Birthweight Infants: Association with Apnea and Adverse Events. AB - BACKGROUND: Analysis of subtle vital sign changes could facilitate earlier treatment of acute inflammatory illnesses. We previously showed that high cross correlation of heart rate and oxygen saturation (XCorr-HR-SpO2) occurs in some very low birthweight (VLBW) infants with sepsis, and hypothesized that this corresponds to apnea. METHODS: In 629 VLBW infants, we analyzed XCorr-HR-SpO2 in relation to central apnea with bradycardia and desaturation (ABD), BD with or without central apnea (BD), and percent time in periodic breathing (PB) throughout the neonatal intensive care unit (NICU) stay (75 infant-years). We reviewed 100 days with extremely high XCorr-HR-SpO2 (>0.7) and control days for clinical associations. Next, we identified all cases of late-onset septicemia (LOS) and necrotizing enterocolitis (NEC) and analyzed change in XCorr-HR-SpO2 before diagnosis. RESULTS: Mean XCorr-HR-SpO2 was ~0.10, and increasing XCorr-HR SpO2 was associated with increasing ABD, BD, and PB (correlation coefficients >0.93). Days with maximum XCorr-HR-SpO2 >0.7 were more likely to have an adverse event than control days (49% versus 13%). In 93 cases of LOS or NEC, there was a 67% increase in XCorr-HR-SpO2 in the 24-hour period prior to diagnosis compared with the previous day (p < 0.01). CONCLUSION: High XCorr-HR-SpO2 is associated with apnea and adverse events including LOS and NEC. PMID- 29141265 TI - [HBV-infections in Germany - health care costs in a real-life-setting]. AB - Background An estimated 500 000 people are infected with hepatitis B in Germany, inducing an enormous burden on infected patients and the health care system. The aim of our study was to estimate the real-life costs of treating hepatitis B and to analyze sociodemographic factors. Methods We conducted a retrospective, non interventional, single-center study from 07/2009 to 12/2012. Information on health care delivery was extracted from patient records. Besides that, a questionnaire survey regarding sociodemographic parameters and quality of life of HBV-infected patients was performed. Results A total of 117 patients were included in our study and grouped in six different disease stages. The response rate of our survey was 80 %. We determined annual total costs of ? 3509. The different groups altered between ? 221 and ? 5618. The main costs (80 %) were caused by the antiviral therapy. Costs of co-medication and hospitalizations were of minor importance. Laboratory costs were primarily caused by determination of virological parameters. Route of transmission of HBV-infection was unknown in 2/3 of all cases. Restrictions in quality of life due to the HBV-infection were reported by 60 % of the patients. Patients receiving interferon treatment reported highest restrictions. In an extrapolation, we estimated total annual hepatitis B treatment costs of 430 million ? in Germany. Conclusion This is the first study estimating real-life treatment costs of hepatitis B infections in Germany. Further research should follow in the context of newly introduced generic antivirals. PMID- 29141266 TI - [Impact of abdominal ultrasound on the identification of the site of infection in the emergency department - Analysis whether it makes sense to perform abdominal ultrasound examination for the identfication of the site of infection if medical history and clinical examination do not indicate an abdominal focus.] AB - Introduction A very high number of patients presenting in emergency departments suffer from an unknown infection or rather fever. If diagnostic imaging is necessary ultrasound can be performed. Whether ultrasound is superior to medical history and clinical examination considering the significantly enhanced technology in recent years and hence has to be performed in patients without abdominal symptoms with non-obvious focus cannot be answered by review of the literature. The objective of this study was to evaluate the relevance of abdominal ultrasound in the determination of the site of infection and to analyse whether an abdominal ultrasound for the identification of the source of infection is dispensable in patients in whom history and clinical examination do not indicate an abdominal focus. Methods All patients undergoing an ultrasound between 2013/04 and 2013/07 in the emergency department of the university hospital of Regensburg were retrospectively analysed. 500 abdominal ultrasound examinations were performed for identifying an abdominal site of infection. These cases were analysed whether medical history and clinical examination were indicating an abdominal focus. Furthermore, on the basis of patient record and medical report the result of the performed ultrasound, final diagnosis, clinical parameters (lab results, fever) were retrospectively analysed. Results Based on the medical report in 208 (41.6 %) of the 500 reviewed cases there has been an abdominal focus. In 122 of these patients (59.0 %) abdominal ultrasound identified the abdominal focus correctly. In 206 patients (99.0 %) medical history and in 152 patients (73.1 %) clinical examination indicated an abdominal focus. A subgroup analysis regarding immunocompromised patients revealed that in 25 of 38 patients (65.8 %) an abdominal focus was determined via abdominal ultrasound. In patients with unremarkable medical history and clinical examination (23 examinations) no abdominal focus could be found via abdominal ultrasound. Discussion An urgent examination of the abdomen via ultrasound is dispensable in patients in whom history (provided complete history) and clinical examination (i.e. particularly no immunosuppression) do not indicate an abdominal focus. PMID- 29141267 TI - [The revised version of standard terminology in gastroenterological endoscopy - result of a consensus project of the german society for gastroenterology, digestive and metabolic diseases]. AB - A uniform and comprehensive terminology is essential in the correct documentation of diagnostic or therapeutic endoscopic procedure. In the German-speaking world, the standard terminology available so far is based on a previous version published in 1999. Therefore, the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) has undergone a comprehensive revision and re structuring of the terminology. This appeared mandatory due to various changes, new diagnoses and new endoscopic procedures. The suggestions drawn up by individual working groups were approved by consensus and are now available as an online document (https://doi.org/10.1055/s-0043-121167) for modifying current software systems. In order to ensure an up-to-date documentation in the future, it was decided that annual updates will be performed by the DGVS to check respective software packages for modifications and new contents. PMID- 29141268 TI - Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) - a rare recently described gastric polyposis syndrome - report of a case. AB - In rare cases with multiple gastric polyps in the corpus and fundus, a recently described gastric polyposis syndrome called gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) has to be considered. We report on the findings in a patient fulfilling the criteria of this disease.A female patient born in 1977 underwent gastroscopy in 2005 due to recurrent abdominal pain. Endoscopy revealed more than 100 fundic gland polyps in the corpus and fundus. An ileocolonoscopy was inconspicuous. The patient did not take proton pump inhibitors. In follow-up biopsies, fundic gland polyps with low-grade dysplasia were observed. In 2015 gastroscopy with biopsy revealed for the first time high grade dysplasia in a polyp, and the patient underwent prophylactic gastrectomy.Macroscopic examination of the gastrectomy specimen revealed hundreds of polyps predominantly measuring 3 mm in diameter covering the fundus and corpus. Histology showed fundic gland polyps, mainly covered by normal appearing foveolae. However, several of them were covered by lesions reminiscent of gastric foveolar adenomas with low- and focally high-grade dysplasia. Molecular pathology revealed a point mutation in the adenomatous polyposis coli promotor 1B. These findings in conjunction with the knowledge that the patient's father had died of gastric carcinoma in his 50 s led to the diagnosis of the autosomal dominant syndrome GAPPS, which has hitherto been described in 9 families. PMID- 29141270 TI - ? PMID- 29141269 TI - [Practice guideline autoimmune liver diseases - AWMF-Reg. No. 021-27]. AB - The guideline was created under the leadership of the DGVS and with participation of neighbouring scientific societies and is intended as a practical aid for the diagnosis and therapy of autoimmune liver diseases. The aim is to represent the current state of science, promote the recognition of the disease and improve the treatment of patients. PMID- 29141271 TI - [Diversion]. PMID- 29141272 TI - Peripheral airway dysfunction and relationship with symptoms in smokers with preserved spirometry. AB - BACKGROUND AND OBJECTIVE: Smokers develop respiratory symptoms and peripheral airway dysfunction even when spirometry is preserved. Multiple breath nitrogen washout (MBNW) and impulse oscillometry system (IOS) are potentially useful measures of peripheral airway function but they have not been compared in such subjects. We hypothesized that MBNW and IOS are jointly abnormal in smokers with normal spirometry and that these abnormalities relate to respiratory symptoms. METHODS: Eighty smokers with normal spirometry completed a symptom questionnaire, had ventilation heterogeneity in diffusion (Sacin) and convection-dependent (Scond) airways and trapped gas volume at functional residual capacity as a percentage of vital capacity (%VtrFRC/VC) measured by MBNW. Respiratory resistance and reactance at 5 and 20 Hz were measured using IOS. RESULTS: Respiratory symptoms were reported in 55 (68%) subjects. Forty (50%) subjects had at least one abnormal MBNW parameter, predominantly in Sacin. Forty-one (51%) subjects had at least one abnormal IOS parameter, predominantly in resistance. Sixty-one (76%) subjects had an abnormality in either MBNW or IOS. Chronic bronchitis symptoms were associated with an increased Scond, while wheeze was associated with lower spirometry and an increased resistance. Abnormalities in MBNW and IOS parameters were unrelated to each other. CONCLUSIONS: Respiratory symptoms and peripheral airway dysfunction are common in smokers with normal spirometry. Symptoms of chronic bronchitis related to conductive airway abnormalities, while wheeze was related to spirometry and IOS. The clinical significance of abnormalities in peripheral airway function in smokers remains undetermined. PMID- 29141273 TI - Antidepressant use during pregnancy and childhood cancer in the offspring. AB - PURPOSE: Antidepressant use during pregnancy has been increasing in recent years. We evaluated whether in utero exposure to antidepressants increased the risk of childhood cancer. METHODS: This population-based cohort study using national registers in Denmark comprised 915 128 liveborn singletons during 1998-2012. We categorised children into three mutually exclusive exposure groups according to maternal redemption of an antidepressant prescription from 2 years before pregnancy until delivery of the index child: Unexposed (N = 863 033), prior user (use before but not during pregnancy) (N = 30 607), and use during pregnancy (N = 21 488). The children were followed from birth until first diagnosis of cancer, death, emigration, or December 31, 2012, whichever came first. The children were followed maximum 14.9 years and contributed to 6.9 * 106 person-years at risk. We estimated hazard ratios (HRs) of cancer using Cox regression with 95% confidence intervals (CIs). RESULTS: In total, 1298 (0.1%) children were diagnosed with cancer. Antidepressant use during pregnancy was not associated with a significantly increased risk of childhood cancer in general; the HR was 1.03 (95% CI, 0.63-1.68), compared to children born by mothers who discontinued antidepressant use prior to pregnancy. The association between in utero exposure to antidepressants and childhood cancer did not depend on type or duration of antidepressant use. There was no strong evidence indicating a higher risk of leukaemia or nervous system tumours among children exposed to antidepressants in utero. CONCLUSION: Antidepressant use during pregnancy was not significantly associated with childhood cancer in general nor with leukaemia or nervous system tumours in specific. PMID- 29141274 TI - Use of direct oral anticoagulants in the first year after market entry of edoxaban: A Danish nationwide drug utilization study. AB - OBJECTIVES: To describe the early uptake of edoxaban; the fourth direct oral anticoagulant (DOAC) to enter the market. METHODS: Using the Danish nationwide health registries, we identified new users of edoxaban (n = 609) from June 6 (day of marketing) through June 2017. For comparison, we also identified new users of dabigatran (n = 2211), rivaroxaban (n = 19 227), and apixaban (n = 14 736). Users were described regarding indication of use, previous anticoagulant experience, comorbidity, and co-medication. RESULTS: The rate of edoxaban initiation increased to 2.0 per 100 000 person months in June 2017, compared with 6.3, 37.5, and 27.0 for dabigatran, rivaroxaban, and apixaban. Atrial fibrillation was the most common registered indication for edoxaban (67%) as well as the other DOACs (41-55%). Overall, users of edoxaban were comparable to users of other DOACs (median age 75 vs 72-76 years and 57% vs 53-59% males), except for a generally lower concomitant use of other drugs. Noticeably, 95% of edoxaban users had previously received anticoagulant treatment compared with 31% to 43% for new users of other DOACs, with 77% switching directly from another anticoagulant treatment to edoxaban (45% directly from VKA and 32% directly from DOACs). CONCLUSIONS: While the use of edoxaban is still limited compared with other DOACs, it is increasing. The majority of edoxaban users switch to edoxaban from other anticoagulant treatments. Continued monitoring of the utilization of DOACs, including effectiveness and safety, is considered essential to the safe and rational use of these drugs. PMID- 29141276 TI - Myoclonic Status Epilepticus of Unknown Etiology in an Elderly Patient. PMID- 29141277 TI - Subcutaneous Immunoglobulins are a Valuable Treatment Option in Myasthenia Gravis. PMID- 29141275 TI - Roles of the Declive, Folium, and Tuber Cerebellar Vermian Lobules in Sportspeople. AB - The cerebellum plays vital roles in balance control and motor learning, including in saccadic adaptation and coordination. It consists of the vermis and two hemispheres and is anatomically separated into ten lobules that are designated as I-X. Although neuroimaging and clinical studies suggest that functions are compartmentalized within the cerebellum, the function of each cerebellar lobule is not fully understood. Electrophysiological and lesion studies in animals as well as neuroimaging and lesion studies in humans have revealed that vermian lobules VI and VII (declive, folium, and tuber) are critical for controlling postural balance, saccadic eye movements, and coordination. In addition, recent structural magnetic resonance imaging studies have revealed that these lobules are larger in elite basketball and short-track speed skaters. Furthermore, in female short-track speed skaters, the volume of this region is significantly correlated with static balance. This article reviews the function of vermian lobules VI and VII, focusing on the control of balance, eye movements, and coordination including coordination between the eyes and hands and bimanual coordination. PMID- 29141278 TI - A Survey of the Neuro-Oncology Landscape. AB - The field of neuro-oncology is evolving rapidly. Many important advances have recently been reported, and other promising investigations have the potential to soon make substantial impacts in the field, especially in the areas of high-grade gliomas and brain metastases. We present an overview of the current status of this field, highlighting the key recent advances as well as representative work of key clinical investigations, since these concepts have the potential to influence clinical management if they are demonstrated to be safe and efficacious. This overview includes some work that has only appeared in abstract form in order to provide a timely understanding of how the field is actively changing and what may lie on the horizon. We focus on both medical and surgical neuro-oncology advances in this highly multidisciplinary subspecialty. PMID- 29141279 TI - Efficacy of Stiripentol in Dravet Syndrome with or without SCN1A Mutations. AB - BACKGROUND AND PURPOSE: The aim of this study was to determine the effectiveness of stiripentol (STP) add-on therapy to valproate and clobazam in patients with Dravet syndrome (DS) according to the presence of mutations in the sodium channel alpha-1 subunit gene (SCN1A). METHODS: We performed direct sequencing to analyze SCN1A mutations in 32 patients with clinically confirmed with DS, and classified them into mutation (pathogenic or likely pathogenic) and nonmutation groups based on American College of Medical Genetics and Genomics guidelines. We compared the efficacy of STP in reducing the seizure frequency between the two groups. RESULTS: The 32 patients comprised 15 patients in the mutation group (with definite SCN1A mutations) and 17 patients in the nonmutation group with variants of unknown significance or benign variants. The clinical profile did not differ significantly between the mutation and nonmutation groups. The seizure frequency relative to baseline reduced by 72.53+/-23.00% (mean+/-SD) in the mutation group versus 50.58+/-40.14% in the nonmutation group (p=0.004). The efficacy of STP was better in DS patients with missense mutations that in those with truncation mutations, and was not favorable in patients with mutations at linkers between domains (DII-DIII), linkers between segments of domain I (DI S1-S2), or splice sites, although the small number of patients prevented statistical analyses. CONCLUSIONS: The efficacy of STP was significantly better in DS patients with definite SCN1A mutations than in those without mutations. PMID- 29141280 TI - Subjective Cognitive Complaints and Objective Cognitive Impairment in Parkinson's Disease. AB - BACKGROUND AND PURPOSE: Subjective cognitive complaints (SCCs) are very common in patients with Parkinson's disease (PD). However, the relationship between SCCs and objective cognitive impairment is still unclear. This study aimed to determine whether SCCs are correlated with objective cognitive performance in patients with PD. METHODS: Totals of 148 cognitively normal patients, 71 patients with mild cognitive impairment (MCI), and 31 demented patients were recruited consecutively from a movement-disorders clinic. Their SCCs and cognitive performances were evaluated using the Cognitive Complaints Interview (CCI) and a comprehensive neuropsychological battery. RESULTS: The CCI score increased with age, duration of PD, and depression score, and was inversely correlated with cognitive performance. The association between CCI score and performance remained significant after adjustment for the depression score, age, and duration of PD. The CCI score could be used to discriminate patients with dementia from cognitively normal and MCI patients [area under the receiver operating characteristics curve (AUC) of 0.80], but not patients with MCI or dementia from cognitively normal patients (AUC of 0.67). CONCLUSIONS: SCCs as measured by the CCI are strongly correlated with objective cognitive performance in patients with PD. The CCI can also be used to screen for dementia in patients with PD. PMID- 29141281 TI - Rapid Progression of Bilateral Vestibulopathy Due to Metastatic Lung Cancer. PMID- 29141282 TI - Neuromyelitis Optica Spectrum Disorder in a Patient with Ankylosing Spondylitis. PMID- 29141283 TI - Group B Streptococcus Meningitis Presenting as the Initial Symptom of a Recurrent Pituitary Adenoma. PMID- 29141284 TI - Henoch-Schonlein Purpura Presenting as Mononeuritis Multiplex. PMID- 29141285 TI - Repetitive Transcranial Magnetic Stimulation for Limb-Kinetic Apraxia in Parkinson's Disease. PMID- 29141286 TI - Ultrasound features of secondary appendicitis in pediatric patients. AB - PURPOSE: The purpose of this study was to evaluate the ultrasonographic findings of secondary appendicitis (SA) and to discuss the differential findings compared with primary appendicitis. METHODS: In this study, we analyzed the ultrasonographic findings of 94 patients under 15 years old of age treated at our institution from May 2005 to May 2014 who had bowel inflammation and an inflamed appendix with a maximal outer diameter >6 mm that improved with nonsurgical treatment (the SA group). Ninety-nine patients with pathologically proven acute appendicitis (the primary appendicitis [PA] group) from June 2013 to May 2014 and 44 patients with pathologically negative appendectomy results from May 2005 to May 2014 were also included to compare the ultrasonographic features of these conditions. A retrospective review of the ultrasonographic findings was performed by two radiologists. The clinical and laboratory findings were also reviewed. The results were statically analyzed using analysis of variance, the Pearson chi square test, and the two-tailed Fisher exact test. RESULTS: Compared with PA, cases of SA had a smaller diameter (9.8 mm vs. 6.6 mm, P<0.001), and were less likely to show periappendiceal fat inflammation (98% vs. 6%, P<0.001) or an appendicolith (34% vs. 11%, P<0.001). SA showed mural hyperemia on color Doppler ultrasonography as frequently as PA (P=0.887). CONCLUSION: The ultrasonographic features of SA included an increased diameter compared to a healthy appendix and the same level of hyperemia as in PA. However, the diameter was commonly in the equivocal range (mean diameter, 6.6 mm), and periappendiceal fat inflammation was rarely present in SA. PMID- 29141287 TI - [Observation of systemic adverse reactions by specific immunotherapy and analysis of risk factors in allergic rhinitis]. AB - Objective: To investigate the systemic adverse effects of specific subcutaneous immunotherapy (SCIT) in patients with allergic rhinitis (AR) and explore the possible risk factors. Methods: A retrospective study was conducted on AR patients who underwent SCIT from January 2014 to January 2017 in Department of Otorhinolaryngology, the First Affiliated Hospital of Chongqing Medical University. For patients with adverse reactions, the detailed medical history during treatment was reviewed. Results: A total of 1608 injections were performed on 102 patients, there were 12 cases / 21 times systemic adverse events, including systemic urticaria, angioedema and Grade I systemic adverse reactions. There were 3 cases of grade IV adverse reactions. Systemic adverse reaction was prone to an initial treatment phase where the dose and concentration of the injection were increasing. Meanwhile, it was more common in young patients aged 20-40 years old and easy to occur in May and June. About the possible risk factors, the most common one was obvious local adverse reactions (17/21), followed by prolonged injection interval (9/21), the recent exposure to a large number of allergens (7/21) and strong positive skin prick results (7/21). Conclusions: The systemic adverse effects, which were induced by SCIT, mainly included systemic urticaria, angioedema and Grade I systemic adverse reactions. Systemic adverse reaction was prone to an initial treatment phase where the dose and concentration of the injection were increasing. PMID- 29141288 TI - [Application of stroboscopy and narrow band imaging endoscopy in the diagnosis of vocal cord leukoplakia]. AB - Objective: To investigate the value of stroboscopy and narrow band imaging (NBI)endoscopy in the diagnosis of vocal cord leukoplakia. Methods: Two hundred and forty-six patients with vocal cord leukoplakia who underwent laryngeal microsurgery and diagnosed by histopathology were recruited between August 2014 and July 2016 in this retrospective study. The diagnostic accuracy of stroboscopy and narrow band imaging endoscopy in the diagnosis of vocal cord leukoplakia was compared. SPSS21.0 software was used to analyze the data. Results: A significantly positive correlation was found between the decrease grade of mucosal wave and the histopathological diagnosis(Spearman r=0.526, P<0.01). A significantly positive correlation was found between the lesion classified by detailed morphologic findings of epithelial microvessel and the histopathological diagnosis(Spearman r=0.480, P<0.01). The sensitivity of stroboscopy for detecting severe dysplasia, carcinoma and invasive carcinoma was 92.73%, higher than NBI endoscopy. The specificity of NBI endoscopy was 90.55%, higher than stroboscopy. The results of logistic regression analysis showed: the positive pathological type risk in the group with mucosal waves severely reduced and absent was 3.906 and 19.737 times higher than the group with mucosal waves slightly reduced. In the group with mucosal waves severely reduced and absent, significant difference was observed when combined use of NBI endoscopy(P<0.001, P=0.047). Conclusions: In the diagnosis of vocal cord leukoplakia, stroboscopy is useful for detecting severe dysplasia, carcinoma and invasive carcinoma with high sensitivity. In the group with mucosal waves severely reduced and absent, combined use of NBI endoscopy was able to improve the diagnostic accuracy. PMID- 29141289 TI - [A retrospective study on the assessment of dysphagia after partial laryngectomy]. AB - Objective: To retrospectively investigate the long-term swallowing function of patients with laryngeal carcinoma, who underwent partial laryngectomy, discuss the effectiveness and reliability of Kubota drinking test in the assessment of patients with dysphagia, who underwent partial laryngectomy, and analyze the influence of different ways of operation on swallowing function. Methods: Clinical data were retrospectively analyzed on 83 patients with laryngeal carcinoma, who underwent partial laryngectomy between September 2012 and August 2015. Questionnaire survey, Kubota drinking test and video fluoroscopic swallowing study (VFSS) were conducted for patients during a scheduled interview. Patients were grouped by two ways: the one was whether epiglottis was retained, and the other was whether either arytenoids or both were reserved. The influence of different surgical techniques on swallowing function was analyzed according to the results of Kubota drinking test. The agreement and reliability of Kubota drinking test were statistically analyzed with respect to VFSS treated as the gold standard. SPSS23.0 software was used to analyze the data. Results: Questionnaire results revealed that among 83 patients underwent partial laryngectomy 32.53% suffered from eating disorder, and 43.37% experienced painful swallowing. The incidence of dysphagia was 40.96% according to the results of Kubota drinking test. There was statistical difference between the group with epiglottis remained and that having epiglottis removed in terms of the absence of dysphagia and severity. The statistical values of normal, moderate and severe dysphagia were in the order of 18.160, 7.229, 12.344(P<0.05). Also, statistical difference existed between the groups with either and both arytenoids reserved in terms of the absence of dysphagia as well as that of intermediate severity, and their statistical values were 4.790 and 9.110(P<0.05). A certain degree of agreement and reliability was present between the results of Kubota drinking test and VFSS(Kappa=0.551, r=0.810). Conclusions: It was of considerable significance to reserve epiglottis and arytenoids for the retention of swallowing function for patients post partial laryngectomy. There are certain degree of agreement and reliability between the results of Kubota drinking test and VFSS. The test, therefore, could be used as a tool for screening patients suffering from dysphagia post partial laryngectomy. PMID- 29141290 TI - [The significance of preservation of the supraclavicular nerve in endoscopic thyroidectomy via gasless anterior chest approach]. AB - Objective: To evaluate the significance for the preservation of the supraclavicular nerve in endoscopic thyroidectomy via gasless anterior chest approach. Methods: We retrospectively evaluated 168 patients who underwent unilateral endoscopic thyroidectomy via gasless anterior chest approach, with preservation of the medial branch of the supraclavicular nerve in 110 patients and not in other 58 patients. Semmes-Weinstein monofilament (SWM) test and a visual analogue scale (VAS) were used to assess the recovery of sensation in anterior chest within 1-12 months postoperatively. Difference in the scores of SWM or VAS between groups was tested with Mann-Whitney U test, and the rates of SWM and VAS scores returning to normal levels in individual periods after surgery was compared with Chi-square test. Results: The preserved group showed more favorable results than the non-preserved group in both SMW and VAS scores. Compared to control group, SWM score in preserved group possessed a higher rate recovery to normal level at any period after operation, which was close to complete normality in 7-9 months postoperatively, and SWM score in non-preserved group was still partially normal in 10-12 months from surgery. Preferable results for VAS were also found in the preserved group, except no significant difference in VAS between groups in1-3 months or 10-12 months after operation. Conclusion: Preservation of the medial branch of the supraclavicular nerve in endoscopic thyroidectomy via gasless anterior chest approach can improve sensation recovery in anterior chest, thus improving postoperative quality of life of patients. PMID- 29141291 TI - [Peripheral blood circulating tumor cells in local advanced head and neck squamous cell carcinoma]. AB - Objective: To investigate the value of detecting circulating tumor cells (CTCs) in patients with local advanced head and neck squamous cell carcinoma (LAHNSCC). Methods: Twenty cases of LAHNSCC and eight healthy cases as the negative control were collected. The clinicopathological factors were evaluated. The LAHNSCC CTCs were enriched by specific antibody nanofluidic chip immunoassay using CytoSorter CTCs sorting system. LAHNSCC CTCs were identified by immunofluorescence staining. The relationships between CTCs and the clinicopathological features of LAHNSCC were analyzed. The numbers of CTCs were monitored and compared two weeks after inductive chemotherapy and at the end of the treatment. Results: CTCs were detect in 15 (75%) 20 patients with LASHNCC, with an average number of 22.4 CTCs. There was a correlation between the numbers of CTCs and age or N staging (P<0.05). Among the 15 cases with CTCs, 13 cases received inductive chemotherapy, for whom CTCs were detected again after inductive chemotherapy in all of these 13 patients, with an average number of 9.5 CTCs. Ten of the fourteen cases (71.4%) were still CTCs detected After whole treatments CTCs were detected in 14 patients, of them, 10 (71.4%) patients showed positive CTCs, with an average 1.6 CTCs. The numbers of CTCs decreased after either inductive chemotherapy or the whole treatment. The number of detected CTCs after whole treatment decreased nearly to background levels. Conclusions: CTCs have a high detection rate in the peripheral blood of patients with LAHNSCC, especially in patients >=60 years old and with >= N2 stage before treatment. Real-time detection of dynamic change of CTCs may assist to evaluate therapeutic effect. PMID- 29141293 TI - [Postoperative effects of balloon sinuplasty on chronic rhinosinusitis: a Meta analysis]. AB - Objective: To evaluate the postoperative clinical effects of balloon sinuplasty on chronic rhinosinusitis. Methods: PubMed, OVID, Embase, Cochrane Library, Proquest, Web of Science, Sinomed, Wan Fang and CNKI database (from established time to March of 2017) were searched for trials about the chronic rhinosinusitis treated by balloon sinuplasty. The relavent literatures were screened, and the prospective control studies were chosen. Lund-Mackay and SNOT-20 scores were used as the outcome idicators, and the methodological quality of the literatures were evaluated strictly. The extracted data were analyzed by Revman 5.3 software. Results: A total of 7 prospective before-after self-controlled studies were included, and the overall quality of which was relatively high. Meta-analysis showed that the Lund-Mackay scores at 6 months post-operation, the SNOT-20 scores at 6 months and more than 1 year post-operation were significant lower than baseline when balloon sinuplasty used in the surgery; the SNOT-20 scores at more than 1 year post-operation was lower than baseline when a standalone ballon sinuplasty was performed. All the results was statistically significant (P<0.05), and all the SMD were more than 0.8. Conclusions: The postoperative effect of balloon sinuplasty on chronic rhinosinusitis is obvious, and the subjective symptoms in patients is relieved effectively. PMID- 29141292 TI - [The difference expression and diagnostic value of RPL5 in papillary thyroid carcinoma of children and adults]. AB - Objective: To study the difference expression and diagnostic value of ribosomal protein L5 (RPL5) in papillary thyroid carcinoma (PTC) of children and adults. Methods: Realtime-PCR was performed to detect the expression of RPL5 in 22 PTC tissues and 13 pericarcinous tissues. Receiver operating characteristic (ROC) curve and Youden's index were used to evaluate the diagnostic value of RPL5 in PTC of children and adults. Results: The expression of RPL5 in PTC tissues was higher than in pericarcinous tissues. The area under curve (AUC) was 0.820 (P=0.001), and Youden's index was 0.568. The expression of RPL5 in PTC of adults was higher than children (P<0.05). The AUC and Youden's index were respectively 0.721 (P=0.069) and 0.414 in children, whereas being respectively 0.896 (P=0.0005) and 0.709 in adults. RPL5 in diagnosis of PTC of adults was better than CK19, Galectin-3 and TPO, which are commonly used for the pathologic diagnosis of PTC. Conclusion: The expression of RPL5 in PTC is higher than pericarcinous tissues, and its expression in PTC of adults is higher than children. Furthermore, PTC is a potential indicator for diagnosis of PTC. PMID- 29141295 TI - [Endonasal endoscopic approach in the extraction of intracranial and intraorbital foreign body: one case report]. PMID- 29141294 TI - [Positions of the implanted stimulating electrodes for artificial facial nerve for inducing contraction of the orbicularis oris muscle in rabbit with peripheral facial paralysis]. AB - Objective: To explore the optimal positions of the implanted stimulating eletrodes for artificial facial nerve (AFN) for inducing contraction of the orbicularis oris muscle (OOM) in rabbit with peripheral facial paralysis. Methods: According to the four microelectrodes of the AFN stimulating side, four modes of the implanted positions were divided. In line with different modes, the electrodes were implanted into the affected OOM of the rabbits with unilateral peripheral facial paralysis. AFN output electric stimulation to induce contraction of the affected OOM with uniform stimulating frequency and pulse length in vitro. Then compared the stimulus threshold amplitude and the peak amplitude separately among different modes by SAS 9.3 version statistical software. Results: The differences of the stimulus threshold amplitude and the peak amplitude had no statistically significant separately between the first mode and the second mode (P>0.05), but there were statistically significant differences between the third mode and the fourth mode (P<0.05). Both kinds of the amplitudes were approximated between the first mode and the second mode respectively, and higher than those in the third mode or the fourth mode. Furthermore, both kinds of the amplitudes in the fourth mode were higher than those in the third mode. Conclusions: The microelectrodes of the AFN stimulating lateral are implanted into the upper lip with a public microelectrode and an output microelectrode, into the lower lip with an output microelectrode, and into the way, which is located to the angle 40 degrees to 45 degrees about the line joining between the midpoint of the ipsilateral auricle root and the corner of the mouth with an output microelectrode. This is the third positional mode which requires lowest effective stimulus current intensity. Thus the mode is suitable as the optimal placement programme. PMID- 29141296 TI - [Acute infective rhinosinusitis leads to blindness: one case report]. PMID- 29141297 TI - [The repair and evaluation of benign cervical tracheoesophageal fistula from external of the neck route]. PMID- 29141298 TI - [Thyroid-like low-grade papillary adenocarcinoma of the posterior nasal septum: one case report]. PMID- 29141299 TI - [Clear cell carcinoma of the head and face: a study of four cases]. PMID- 29141300 TI - [PET-CT suggested laryngeal cancer with bone metastasis but diagnosed with multiple myeloma]. PMID- 29141301 TI - [Obstructive sleep apnea-hypopnea syndrome complicated with obesity hypoventilation syndrome: a case report]. PMID- 29141302 TI - [A case of rare spontaneous hematoma in the neck]. PMID- 29141303 TI - [Minutes of the 2017 China Rhinology Annual Meeting]. PMID- 29141304 TI - [The role of temporal fine structure in tone recognition and music perception]. AB - The sound signal can be decomposed into temporal envelope and temporal fine structure information. The temporal envelope information is crucial for speech perception in quiet environment, and the temporal fine structure information plays an important role in speech perception in noise, Mandarin tone recognition and music perception, especially the pitch and melody perception. PMID- 29141305 TI - [Research progress on rhinitis medicamentosa]. AB - Rhinitis medicamentosa (RM) refers to nonallergic inflammation in the nasal mucosa which is caused by the abuse of nasal decongestant and it often occurs in patients with allergic/nonallergic rhinitis along with nasal congestion. RM is characterized by nasal congestion based on long-term use of nasal decongestant, without rhinorrhoea or sneezing. The signs of RM include nasal swelling, thickening, loss of elasticity, and loss of sensitivity to the decongestant. The histological changes of RM are loss of nasal mucosa cilia, squamous epithelium metaplasia, edema of epithelium cell, hyperplasia of goblet cell, increased expression of epidermal growth factor receptor and infiltration of inflammatory cells, etc. There is no precise diagnosis standard for RM, making it even harder for its objective diagnosis. Patients with RM should immediately stop using nasal decongestant, in stead of using nasal glucocorticoid spray for the recovery of the nasal mucosa's function. PMID- 29141307 TI - [The changing horizon of encephalitis in the era of precision medicine]. PMID- 29141306 TI - [Methods and advances in the research of lymphatics in the head and neck]. AB - The lymphatic system plays an important role in human health and disease. In addition to a role in the immune response, the lymphatics can also serve as a pathway for cancer metastasis.Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers.In the case where the primary focus has been controlled, cervical lymph node metastasis is one of the most important factors affecting the prognosis of head and neck cancer.Thus, understanding the anatomy of the lymphatic system is of paramount importance in predicting cancer metastasis and to perform proper lymph node dissection in cancer patients.The objective of this review is to summarize current imaging approaches that facilitate both basic science and clinical investigations of lymphatic vasculature.Mutation analysis of the laryngeal lymphatic system may provide a theoretical basis for the diagnosis and treatment of HNSCC. PMID- 29141308 TI - [Guidelines for the diagnosis and treatment of steroid-resistant nephrotic syndrome]. PMID- 29141309 TI - [Interpretation of guidelines for the diagnosis and treatment of steroid resistant nephrotic syndrome]. PMID- 29141310 TI - [Analysis of gene mutation of early onset epileptic spasm with unknown reason]. AB - Objective: To summarize the gene mutation of early onset epileptic spasm with unknown reason. Method: In this prospective study, data of patients with early onset epileptic spasm with unknown reason were collected from neurological department of Children's Hospital of Fudan University between March 2016 and December 2016. Patients with known disorders such as infection, metabolic, structural, immunological problems and known genetic mutations were excluded. Patients with genetic disease that can be diagnosed by clinical manifestations and phenotypic characteristics were also excluded. Genetic research methods included nervous system panel containing 1 427 epilepsy genes, whole exome sequencing (WES), analysis of copy number variation (CNV) and karyotype analysis of chromosome. The basic information, phenotypes, genetic results and the antiepileptic treatment of patients were analyzed. Result: Nine of the 17 cases with early onset epileptic spasm were boys and eight were girls. Patients' age at first seizure onset ranged from 1 day after birth to 8 months (median age of 3 months). The first hospital visit age ranged from 1 month to 2 years (median age of 4.5 months). The time of following-up ranged from 8 months to 3 years and 10 months. All the 17 patients had early onset epileptic spasm. Video electroencephalogram was used to monitor the spasm seizure. Five patients had Ohtahara syndrome, 10 had West syndrome, two had unclear classification. In 17 cases, 10 of them had detected pathogenic genes. Nine cases had point mutations, involving SCN2A, ARX, UNC80, KCNQ2, and GABRB3. Except one case of mutations in GABRB3 gene have been reported, all the other cases had new mutations. One patient had deletion mutation in CDKL5 gene. One CNV case had 6q 22.31 5.5MB repeats. Ten cases out of 17 were using 2-3 antiepileptic drugs (AEDs) and the drugs had no effect. Seven cases used adrenocorticotropic hormone (ACTH) and prednisone besides AEDs (a total course for 8 weeks). Among them, five cases had no effect and two cases were seizure free recently. A case with GABRB3 (C.905A>G) had seizure controlled for 3 mouths. A case with ARX (C.700G>A) had seizure controlled for 6 mouths. Conclusion: The early onset epileptic spasm with unknown reason is highly related to genetic disorders. A variety of genetic mutations, especially new mutations were found. Genetic heterogeneity of epileptic spasm is obvious. PMID- 29141311 TI - [Study on mosaicism of SCN1A gene mutation in parents of children with Dravet syndrome]. AB - Objective: To investigate the clinical phenotypes and the mutant allele proportion of parents with SCN1A gene mutation mosaicism of Dravet syndrome (DS) children, thus to provide guidance for family reproduction and prenatal diagnosis. Method: The clinical data and peripheral blood DNA samples of DS patients with a SCN1A gene mutation proved by Sanger sequencing were collected prospectively from February 2005 to November 2016 in Department of Pediatrics, Peking University First Hospital. The same mutation was searched in parents and other available relatives. Parental somatic mosaicism was confirmed and quantified by Ion Torrent Personal Genome Machine (PGM) and Raindrop droplet digital PCR (ddPCR). The families were followed up and prenatal diagnosis was provided. Result: Mosaicisms of SCN1A gene mutation in parents were identified in 5.2% (30 out of 575) DS families. Seventeen were fathers and thirteen were mothers. The mutant allele proportion ranged from 1.7% to 32.9% by PGM and from 0.82% to 34.51% by ddPCR, respectively. In 30 parents with somatic mosaicism, thirteen were asymptomatic, ten had a history of febrile seizures (FS), five with epilepsy, one with febrile seizure plus and one had a history of afebrile seizure. Four families had two children with DS. Three siblings of the probands were confirmed genetically with the same pathogenic mutation. One deceased sister of the proband was assumed to have the same pathogenic mutation because she matched DS diagnosis after medical history review despite no blood sample. Two families received prenatal diagnosis. One second pregnancy was terminated because the fetus inherited the mutation as the mother's wish. Conclusion: Sanger sequencing detects parents of some children with DS are SCN1A mutation mosaics. PGM and ddPCR can be used for accurate quantification of mutant mosaics, which can provide accurate guidance for family genetic counseling. PMID- 29141312 TI - [Clinical manifestation and gene analyses of 15 patients with intellectual disability or developmental delay complicated with congenital nystagmus]. AB - Objective: To analyze the clinical and genetic features of 15 cases with intellectual disability or developmental delay (ID/DD) complicated with congenital nystagmus. Method: The clinical characteristics and the results of laboratory tests, images and genetics of 15 patients with ID/DD complicated with congenital nystagmus, confirmed by gene diagnosis in the Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics from March 2015 to October 2016, were retrospectively analyzed. The physiological function of 13 disease genes and the molecular signaling pathways were also comparatively studied. Result: The patients included 11 males and four females, with an age of 2 months-15 years (median age 27 months). The result of multiplex ligation dependent probe amplification was positive in two patients only with hypomyelination on head MRI. Positive results were found in 13 patients with or without abnormal head MRI or other deformities using targeted capture technology and next generation sequencing. Two patients were diagnosed with Pelizaeus Merzbacher disease, two had hypomyelination with an atrophy of the basal ganglia and cerebellum and two had oculocutaneous albinism. Pelizaeus-Merzbacher-like disease was found in one case, cerebro-oculo-facio-skeletal syndrome in one case, Rubinstein-Taybi syndrome in one case, mental retardation type 5 in one case, methylmalonic aciduria combined with hyperhomocysteinemia in 1 case, ataxia telangiectasia in one case, hypomyelinating leukodystrophy type 8 in one case, Marinesco-Sjogren syndrome in one case and CHARGE syndrome in one case. A total of 12 novo mutations were reported in this study. Conclusion: The causes of children with ID/DD complicated with congenital nystagmusis are complex. Comprehensive clinical and auxiliary examinations should be performed to improve the accuracy of the diagnosis. Reasonable application of different genetic testing methods can significantly improve the diagnostic accuracy of molecular genetic etiology in children with ID/DD. PMID- 29141313 TI - [Tocilizumab for refractory systemic juvenile idiopathic arthritis]. AB - Objective: To evaluate the efficacy and side effects of tocilizumab for the treatment of systemic juvenile idiopathic arthritis. Method: In this prospective self case-control study, the children diagnosed with refractory systemic juvenile idiopathic arthritis admitted to Department of Rheumatism and Immunology of Children's Hospital Affiliated to Capital Institute of Pediatrics from December 2013 to June 2016 were enrolled and information before and after treatment of tocilizumab was analyzed. The tocilizumab was introvenously guttae in a dose of 8 12 mg/kg every 2 weeks. Complete blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were tested before and after the application of tocilizumab. Detailed clinical manifestations were recorded. All results were analyzed by chi(2) test and t test. Result: Forty patients with a median age of (6.6+/-3.7) years were enrolled, including 15 males and 25 females. All of the patients presented with fever and 38 patients got normal temperature 24-48 hours after treatment with tocilizumab. Symptoms disappeared in 13 and improved in 4 patients after treatment among the 17 patients who presented with arthritis. Within the 10 patients who manifested with rashes, 9 patients' rashes disappeared without relapse accompanied by the normalization of temperature after the treatment of tocilizumab. One patient got normal temperature but intermittently emerged rashes after symptoms of arthritis improved. In the 40 patients, 38 well tolerated tocilizumab while 2 showed rashes and chill which disappeared shortly after antianaphylaxis treatment. No severe treatment-related infection was found in any patients. According to the study, the white blood cell counts(*10(9)/L), CRP(mg/L) and ESR(mm/1h) tested 2 weeks after the treatment with tocilizumab were significantly lower than that before treatment(12.1+/-1.2 vs. 16.5+/-1.8, 47+/-8 vs. 67+/-9, 21+/-5 vs. 57+/-6, t=2.75, 3.98, 5.22, P=0.009, 0, 0, respectively). No significant changes were found in concentration of IL-6 and TNF-alpha (65(207) vs. 45(137) ng/L, and 14(6) vs. 17(19)ng/L, Z=-1.247 and-1.285, P=0.212 and 0.199 respectively). Conclusion: Tocilizumab is a treatment with good efficacy and safety for refractory systemic juvenile idiopathic arthritis. Adverse effects would be found in some patients. PMID- 29141314 TI - [A novel compound heterozygous mutation in ABCA3 gene in a child with diffuse parenchymal lung disease]. AB - Objective: To summarize the clinical characteristics of the diffuse parenchymal lung diseases in a child caused by a novel compound heterozygous ABCA3 mutation and explore the association between the phenotype and ABCA3 mutation. Method: The clinical material of a patient diagnosed with diffuse parenchymal lung disease with ABCA3 mutation in December 2016 in Shenzhen Children's Hospital was analyzed. The information about ABCA3 gene mutation updated before April, 2017 was searched and collected from the gene databases (including 1000Genomes, HGMD, EXAC) and the literatures (including Wanfang Chinese database and Pubmed). Result: The girl was one year and nine months old. She presented with chronic cough, tachypnea, cyanosis and failure to thrive since she was one year and three months old. Her condition gradually deteriorated after she was empirically treated. Physical examination showed malnutrition, tachypnea and clubbed-fingers. Her high resolution computed tomography (HRCT) revealed diffused ground-glass opacities, thickened interlobular septum, and multiple subpleural small air filled lung cysts. The second generation sequencing study identified a novel compound heterozygous mutation (c.1755delC+c.2890G>A) in her ABCA3 gene, which derived respectively from her parents and has not been reported in the database and the literatures mentioned above. Conclusion: c.1755delC+c.2890G>A is a new kind of compound heterozygous mutation in ABCA3, which can cause children's diffuse parenchymal lung disease. Its phenotype is related to its genotype. PMID- 29141315 TI - [Clinical efficacy of one-lung ventilation in treatment of children postoperatively intractable atelectasis]. AB - Objective: To investigate the effect of fiberoptic bronchoscope-guided one-lung ventilation (OLV) on treatment of intractable atelectasis in children. Method: This retrospective cohort study was conducted in Pediatric Intensive Care Unit, Children's Hospital of Chongqing Medical University from December 2014 to May 2017. Six patients with intractable atelectasis of left lung were included. Three cases were male and three female with the age from 1.5 to 11.0 years. The endotracheal tube was intubated to the left main bronchus for OLV by the guidance of fiberoptic bronchoscopy. The effect of treatment by monitoring the chest imaging after treatment was evaluated. Result: Six pediatric patients were successfully cured by OLV. The duration of OLV ranged from 1.5 to 30.0 hours, and the intervals of OLV were usually 3 to 5 days. Each patient received 6 to 20 OLV treatments. Chest images showed the left lung reexpanded obviously after OLV treatments. Five patients successfully weaned from invasive ventilation and were discharged. Another patient turned better, discharged from hospital with noninvasive ventilation and weaned from noninvasive ventilation one month later after discharge. During the procedure of OLV, the vital signs of all patients were stable and no complication occurred. Conclusion: OLV with selective bronchial intubation guided by fiber bronchoscope is a safe and effective treatment for intractable atelectasis in children. PMID- 29141316 TI - [A clinical analysis of micafungin treatment of pulmonary invasive fungal infection in pediatric patients with acute leukemia or post hematopoietic stem cells transplantation]. AB - Objective: To investigate the efficacy and safety of micafungin (MCF) for pulmonary invasive fungal disease (PIFD) in pediatric patients with acute leukemia or post hematopoietic stem cells transplantation. Method: Twenty-five neutropenic PIFD children with acute leukemia or post hematopoietic stem cells transplantation in Sun Yat-sen Memorial Hospital of Sun Yat-sen University were selected from January 2012 to June 2015, including 12 males and 13 females, age range 2-15 (average 6.2+/-2.0) years. There were 12 cases of acute leukemia (AL) after chemotherapy, 4 cases of acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 9 cases of beta-thalassemia major after allo-HSCT. All children received MCM for the treatment of PIFD, the dosage of MCM was 3-4 mg/ (kg.d) , once a day. The children received 2 to 6 courses of treatment, individually with a course of 7 days. 1, 3-beta-D glucan assay (G test), galactomannan antigen test (GM test), high-resolution CT and the biochemical indexes for organ functions were closely monitored. Result: Twenty five cases were diagnosed as PIFD, including 2 patients diagnosed as proven, 6 as probable and 17 as possible. Of the 25 cases, 1 was confirmed aspergillus by biopsy pathology and 1 was candida albicans by blood culture. The G and GM test with positive results was 5 and 2 respectively. Chest CT scans of the 25 cases had obvious lesions: air crescent sign and cavitation in 4 cases, diffuse ground glass change in 9 cases, double lung scattered patchy, small nodules and cord like high density shadow in 7 cases, unilateral or bilateral chest wall wedge shaped consolidation edge in 5 cases and pleural effusion in 5 patients. The effective rate of MCF in treatment of PIFD was 68% (17/25), including 13 cases cured, 4 cases improved, 4 cases were improved clinically and in 4 cases the treatment was ineffective. Eight cases were effective in MCF monotherapy group (12 cases) and nine were effective in MCF combined therapy group(13 cases), respectively. Side-effects including allergies, gastrointestinal side effects, electrolyte disturbances, impairment of liver and kidney function, and myelosuppression were not found in those children treated with MCF. Conclusion: Micafungin is effective and safe in the treatment of pulmonary invasive fungal disease in pediatric patients with acute leukemia or post hematopoietic stem cell transplantation. PMID- 29141317 TI - [Study of gene mutation in 62 hemophilia A children]. AB - Objective: To analyze the mutation type of FVIII gene in children with hemophilia A and to explore the relationship among hemophilia gene mutation spectrum, gene mutation and clinical phenotype. Method: Sixty-two children with hemophilia A from Department of Pediatric Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology between January 2015 and March 2017 were enrolled. All patients were male, aged from 4 months to 7 years and F VIII activity ranged 0.2%-11.0%. Fifty cases had severe, 10 cases had moderate and 2 cases had mild hemophilia A. DNA was isolated from peripheral blood in hemophilia A children and the target gene fragment was amplified by PCR, in combination with the second generation sequencing, 22 and 1 introns were detected. Negative cases were detected by the second generation sequencing and results were compared with those of the international FVIII gene mutation database. Result: There were 20 cases (32%) of intron 22 inversion, 2 cases (3%) of intron 1 inversion, 18 cases (29%) of missense mutation, 5 cases (8%) of nonsense mutation, 7 cases (11%) of deletion mutation, 1 case(2%)of splice site mutation, 2 cases (3%) of large fragment deletion and 1 case of insertion mutation (2%). No mutation was detected in 2 cases (3%), and 4 cases (7%) failed to amplify. The correlation between phenotype and genotype showed that the most common gene mutation in severe hemophilia A was intron 22 inversion (20 cases), accounting for 40% of severe patients, followed by 11 cases of missense mutation (22%). The most common mutation in moderate hemophilia A was missense mutation (6 cases), accounting for 60% of moderate patients. Conclusion: The most frequent mutation type in hemophilia A was intron 22 inversion, followed by missense mutation, again for missing mutation. The relationship between phenotype and genotype: the most frequent gene mutation in severe hemophilia A is intron 22 inversion, followed by missense mutation; the most frequent gene mutation in medium hemophilia A is missense mutation. PMID- 29141318 TI - [Ras-associated autoimmune leukoproliferative disorder: a report of 2 cases and literature review]. AB - Objective: To investigate the clinical features and genetic characteristics of cases with Ras-associated autoimmune leukoproliferative disorder(RALD). Method: Characteristics of clinical data and gene mutation of the first two cases in China with RALD were retrospectively analyzed. The related literature was searched by using search terms "NRAS" , "KRAS" or "RALD" . Result: Case1, a seven year-seven-month old girl, was admitted due to "thrombocytopenia and splenomegaly for three years" . Palpation showed enlargement of submandibular lymph nodes and hepatosplenomegaly.The platelet count fluctuated between 15*10(9)/L and 60*10(9)/L. Hemoglobin was as 57 g/L and Coomb's test was positive.Lung computed tomography revealed interstitial lung disease, bilateral pleural effusion, pericardial effusion, myocardial injury and ascites. Case2, a seven-year-five month old girl, was admitted due to "recurrent thrombocytopenia for seven years, intermittent eyelid and abdominal swelling for three years" . Palpation showed enlargement of cervical and right inguinal lymph nodes, and hepatosplenomegaly.The number of platelet and monocyte were 9*10(9)/L and 5.46*10(9)/L, respectively. Bone marrow smear revealed an increase in the proportion of primitive immature cells (0.09 to 0.11). Lung computed tomography revealed interstitial lung disease, pericardial effusion, cardiac enlargement and pulmonary hypertension. The gene sequencing results showed KRAS gene c.38G> A somatic mutation in case1, and p.G12D and NRAS gene c.38G> A, p.G13D somatic mutation in case2. A total of 8 reports were retrieved including 23 cases caused by NRAS(10 cases) or KRAS(13 cases) gene somatic mutation. All the 23 cases showed hypergammaglobulinemia, splenomegaly, B cells hyperplasia or mononucleosis. Conclusion: RALD often manifests as hepatosplenomegaly,lymphoproliferation, autoimmune hematocytopenia, B cells hyperplasia or mononucleosis, hypergammaglobulinemia. Gene sequencing analysis can help diagnose the disease. PMID- 29141320 TI - [Diagnosis of one child herpes simplex virus type 1 encephalitis with next generation sequencing]. PMID- 29141321 TI - [Generalized disseminated tuberculosis in a infant which of the first symptom in the spine]. PMID- 29141319 TI - [Homozygous ectonucleotide pyrophosphatase/phosphodiesterase 1 variants in a girl with hypophosphatemic rickets and literature review]. AB - Objective: To investigate the clinical features and genetic characteristics of patients with ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene variants. Method: The clinical data of a patient with ENPP1 homozygous variants from Capital Institute of Pediatrics was collected, the related literature was searched from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, National Center from Biotechnology Information and PubMed by using search term "ENPP1" , "hypophosphatemic rickets" . The literature retrieval was confined from 1980 to February 2017. The clinical manifestations, bone metabolism examinations, X-RAY and genotypes were reviewed. Result: Our patient was an 11 years old girl, with 7 years history of lower limb malformation. She showed significant valgus deformity of the knee (genu valgum). Metabolic examination revealed reduced level of plasma phosphate (0.86 mmol/L), a normal level of plasma calcium (2.30 mmol/L) and an elevated alkaline phosphatase level of 688 IU/L. The calcium-phosphorus product was 25.9. A homozygous nonsense variants of ENPP1 gene, c.783C>G (p.Tyr261X) in exon 7 was identified in the patient. Both parents were heterozygous carriers. Literature review identified 3 Chinese patients from one publication and 17 cases from twenty one publications around the world. None of the patients was found PHEX variants which is the most common variants among hypophosphatemic rickets patients. The disease onset age was 11 months to 10 years. Eight patients had short stature, five patients had the history of generalized arterial calcification of infancy. Four suffered from deafness, three showed localized calcifications of arteries, three patients manifested pseudoxanthoma elasticum and two suffered from ossification of posterior longitudinal ligament. Nine missense variants, six splicing variants and 4 nonsense variants were reported among these twenty patients. c.783C>G was found in two Chinese patients. Conclusion: ENPP1 gene mutation was a cause of patient with hypophosphatemic rickets. Comorbid features included generalized arterial calcification of infancy, early onset hearing loss, pseudoxanthoma and ossification of posterior longitudinal ligament. ENPP1 gene testing should be performed on hypophosphatemic rickets patients without PHEX gene variants. Long term follow up is recommended. The most common types of ENPP1 gene variants were nonsense/splicing variants. The gene c.783C>G was the most common variants in Chinese patients. PMID- 29141322 TI - [Advances in clinical and imaging studies of acute necrotizing encephalopathy]. PMID- 29141323 TI - [A systematic review of seizure risk and efficacy of methylphenida tetreatment on epilepsy combined with attention deficit hyperactivity disorder]. PMID- 29141324 TI - [Significance of procalcitonin in children's non-bacterial infectious diseases]. PMID- 29141325 TI - [Genetic characteristics of acute promyelocytic leukemia and the application of next-generation sequencing technology in APL]. PMID- 29141326 TI - [The relationships between researchers and subjects in epidemiological studies]. AB - The relationship between the researchers and the subjects would influence the data collection process in epidemiological studies. It would be conducive to obtain more in-depth and effective research data and find the problems or related influencing factors if we reflect on the relationship between the researchers and the subjects. PMID- 29141327 TI - [Gender differences in stressful life events and depression in Chinese adults aged 30-79 years]. AB - Objective: To investigate gender specific differences in the association between stressful life events (SLEs) and depression in Chinese adults aged 30-79 years. Methods: In the baseline survey during 2004-2008, the China Kadoorie Biobank (CKB) recruited 512 891 men and women aged 30-79 years from 10 areas of China. Detailed information on SLEs, including demographic and socio-economic status, smoking, alcohol drinking and history of chronic disease, as well as depression symptoms and major depressive episodes (MDEs) in preceding 12 months, was collected by using standardized questionnaire. Multinomial logistic regression model was employed to estimate the relative risk ratio (RRR) and 95%CI of SLEs (3 categories, 10 items) on depression and the dose-response relationship between the number of SLEs experienced and depression. The interactions between gender and SLEs on depression were examined with likelihood ratio test. Results: Among the 512 891 participants, 35 085 (6.8%) reported family-related events, 5 972 (1.2%) reported finance-related events, and 4 453 (0.9%) reported other stressful life events. Females had a higher occurrence of family-related events, while males had a higher occurrence of finance-related and other events (all P-value <0.001). After adjusted for potential confounders, SLEs were significantly associated with MDEs (RRR=11.99, 95%CI: 10.49-13.71 for males; RRR=14.15, 95%CI: 12.97-15.43 for females), and with depressive symptoms (RRR=7.43, 95%CI: 6.94 7.95 for males; RRR=8.30, 95%CI: 7.91-8.72 for females). And the associations were stronger in females than in males (P for interaction=0.049). In the three categories of SLEs, family-related events showed stronger association in female (P for interaction <0.001), while no gender specific differences were observed for the other two categories (all P-value>0.05). Furthermore, the effect of the number of SLEs experienced increased in a dose-response manner on depressive symptoms and MDEs for both genders, but no gender specific differences were found. Conclusions: The gender modifies the association between stressful life events and depression in Chinese adults, and women experienced family-related events have a greater risk of depression. The more the stressful events experienced, the more likely to have depression. PMID- 29141328 TI - [Association between smoking/smoking cessation and glycemic control in male patients with type 2 diabetes]. AB - Objective: To explore the association of smoking and smoking cessation with glycemic control in male patients with type 2 diabetes. Methods: From December 2013 to January 2014, a total of 7 763 male patients with type 2 diabetes, who received national basic public health service in Changshu county of Suzhou city, Huai'an and Qinghe districts of Huai'an city, Jiangsu province, were recruited by cluster sampling. Questionnaire survey and anthropometric measurements were conducted, and fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels were measured. Multiple linear regression model was used to evaluate the association of smoking and smoking cessation with glycemic control. Results: The prevalence of current smoking was 45.5% in male patients with type 2 diabetes. The levels of FPG and HbA1c increased with number of cigarettes smoked per day compared with non-smokers (P<0.001). Among patients with drug treatment, the average increase of HbA1c level in current smokers with smoking duration >=30 years and smoking index >=40 pack-years were 0.27% (95%CI: 0.05%-0.49%) and 0.38% (95%CI: 0.23%-0.53%), respectively. FPG and HbA1c level decreased obviously with smoking cessation years among former smokers (P<0.05). Among the patients receiving no drug treatment, no dose-response relationships were observed between smoking duration, smoking cessation years and levels of FPG and HbA1c. Conclusion: Cigarette smoking was negatively related with glycemic control in male type 2 diabetes patients, especially in patients with drug treatment. Smoking cessation may be beneficial for glycemic control. Smoking cessation should be encouraged for diabetes patients as early as possible. PMID- 29141329 TI - [Association between illness and mental status in pregnant women and birth defects]. AB - Objective: To understand the prevalence of birth defects, related diseases and mental status of women during pregnancy in Shaanxi province and to analyse the major risk factors on birth defects and congenital heart disease. Possible association between maternal diseases or mental status and the risk of birth defects, was also explored. Methods: A cross-sectional design was used in this study and stratified multistage random sampling method was used. The whole survey was from Jury 2013 to November 2013. Logistic regression method was used to analyze the association between maternal diseases, mental status during pregnancy and birth defects. Results: The overall prevalence of birth defects was 195.04 per 10 000 in Shaanxi. Among the 29 121 mothers participating in this study, 51.1% developed illness and 6.8% "changed their mental status during pregnancy. After adjusting all the confounding factors, results showed that, histories of cold" , fever, and intrahepatic cholestasis were (OR=1.33, 95%CI: 1.10-1.61, OR=1.54, 95%CI: 1.09-2.16, and OR=32.77, 95%CI:4.08-263.04) respectively, during pregnancy that related to birth defects. Self-reported unstable mental status (OR=1.60, 95%CI: 1.19-2.15) and family friction (OR=2.07, 95%CI: 1.12-3.79) were both related to the birth rates. Histories of cold and fever (OR=1.59, 95%CI: 1.28-1.98; OR=1.43, 95%CI: 1.48-4.00), during early pregnancy, unstable mental status during mid-pregnant period (OR=1.52, 95%CI: 1.05-2.19), unstable mental status during late-pregnant period (OR=1.63, 95%CI: 1.05-2.19) and family friction during late-pregnant period (OR=2.89, 95%CI: 1.16-7.20) were found to be related to birth defects. Compared with those without history of cold, those with the history of cold during first (OR=1.24, 95%CI: 1.02-1.52) and second stages (OR=2.06, 95%CI: 1.30-3.26) of pregnancy were more likely to bear fetus with birth defects. Compared with those without these histories, those with histories of fever (OR=1.49, 95%CI: 1.04-2.13), emotional problem (OR=1.71, 95%CI: 1.19 2.45) and related diseases (OR=2.67, 95%CI: 1.32-5.39) during the first period of pregnancy were more likely to bear fetus with birth defects. Conclusion: The incidence of birth defects in Shaanxi was high. Histories of cold, fever, unstable mental status and family friction during pregnancy, seemed to have increased the risks of bearing child with birth defects. PMID- 29141330 TI - [Prenatal supplementations of iron, iron-containing multimicronutrients and antianemic Chinese patent medicines in women in Shaanxi province, 2010-2013]. AB - Objective: To understand the prevalence of prenatal supplementations of iron, iron-containing multi-micronutrients (IMMN) and antianemic Chinese patent medicines (ACPM) and associated factors in women in Shaanxi province. Methods: A sample of 28 367 childbearing-age women who gave birth during 2010-2013 and had specific information of the prenatal nutrients supplementation were recruited using stratified multistage cluster random sampling in Shaanxi province. The information about their basic characteristics and prenatal supplementation of nutrients were collected by a questionnaire survey. Descriptive analysis method was used to analyze the intake rate of iron, IMMN and ACPM during each period of pregnancy, and logistic regression model was used to identify associated factors. Results: The overall prevalence of prenatal iron, IMMN and ACPM supplementation was low (28.99%), and the intake rate of iron was the lowest (5.33%). The prevalence of prenatal supplementation of iron, IMMN and ACPM were lower before pregnancy and in the first trimester than in the second and third trimester. The intake rates for consecutive 2 periods were very low (all were lower than 2.00%). The intake rates of iron, IMMN and ACPM significantly increased year by year. Women living in central Shaanxi had relatively high intake rates of iron (7.22%) and IMMN (16.55%), and women in southern Shaanxi had relatively high intake rate of ACPM (18.50%). The results of logistic regression analysis showed that higher educational level (OR=1.920, 95%CI: 1.617-2.279), antenatal care times>=6 (OR=1.832, 95%CI: 1.604-2.091), etc. were the positive factors for iron intake, and these positive factors were similar to those for IMMN intake. Additionally, rural residence was the negative factor for IMMN intake (compared with urban residence, OR=0.872, 95%CI: 0.788-0.966). Conversely, higher educational level (OR=0.855, 95%CI: 0.746-0.979), higher household income (OR=0.864, 95%CI: 0.796 0.938) were negative factors for ACPM intake, and rural residence was its positive factor (OR=1.285, 95%CI: 1.141-1.447). Conclusions: The prevalence of prenatal supplementation of iron, IMMN and ACPM were low in women in Shaanxi, especially the intake rate of iron was the lowest. The prophylactic iron supplementation before pregnancy or in the first trimester was rare. Measures should be taken to improve the prenatal supplementation of iron in Shaanxi and to standardize the clinical use of ACPM. PMID- 29141331 TI - [Correlation between percentage of body fat and simple anthropometric parameters in children aged 6-9 years in Guangzhou]. AB - Objective: To evaluate the accuracy of simple anthropometric parameters in diagnosing obesity in children in Guangzhou. Methods: A cross-sectional study, including 465 children aged 6-9 years, was carried out in Guangzhou. Their body height and weight, waist circumference (WC) and hip circumference were measured according to standard procedure. Body mass index (BMI), waist to hip ratio (WHR) and waist-to-height ratio (WHtR) were calculated. Body fat percentage (BF%) was determined by dual-energy X-ray absorptiometry. Multiple regression analysis was applied to evaluate the correlations between age-adjusted physical indicators and BF%, after the adjustment for age. Obesity was defined by BF%. Receiver operating characteristic (ROC) curve analyses were performed to assess the diagnostic accuracy of the indicators for childhood obesity. Area under-ROC curves (AUCs) were calculated and the best cut-off point that maximizing 'sensitivity + specificity-1' was determined. Results: BMI showed the strongest association with BF% through multiple regression analysis. For 'per-standard deviation increase' of BMI, BF% increased by 5.3% (t=23.1, P<0.01) in boys and 4.6% (t=17.5, P<0.01) in girls, respectively. The ROC curve analysis indicated that BMI exhibited the largest AUC in both boys (AUC=0.908) and girls (AUC=0.895). The sensitivity was 80.8% in boys and 81.8% in girls, and the specificity was 88.2% in boys and 87.1% in girls. Both the AUCs for WHtR and WC were less than 0.8 in boys and girls. WHR had the smallest AUCs (<0.8) in both boys and girls. Conclusion: BMI appeared to be a good predicator for BF% in children aged 6-9 years in Guangzhou. PMID- 29141332 TI - [Reliability and validity of Driving Anger Scale in professional drivers in China]. AB - Objective: To assess the reliability and validity of the Chinese version of Driving Anger Scale (DAS) in professional drivers in China and provide a scientific basis for the application of the scale in drivers in China. Methods: Professional drivers, including taxi drivers, bus drivers, truck drivers and school bus drivers, were selected to complete the questionnaire. Cronbach's alpha and split-half reliability were calculated to evaluate the reliability of DAS, and content, contract, discriminant and convergent validity were performed to measure the validity of the scale. Results: The overall Cronbach's alpha of DAS was 0.934 and the split-half reliability was 0.874. The correlation coefficient of each subscale with the total scale was 0.639-0.922. The simplified version of DAS supported a presupposed six-factor structure, explaining 56.371% of the total variance revealed by exploratory factor analysis. The DAS had good convergent and discriminant validity, with the success rate of calibration experiment of 100%. Conclusion: DAS has a good reliability and validity in professional drivers in China, and the use of DAS is worth promoting in divers. PMID- 29141333 TI - [Investigation of human brucellosis diagnosis and report quality in medical institutions in key areas of Shanxi province]. AB - Objective: To evaluate the accuracy of human brucellosis diagnosis and reporting in medical institutions in Shanxi province, and understand the performance of clinical doctors to diagnose human brucellosis according to diagnostic criteria. Methods: Field investigation was conducted in 6 medical institutions in the key areas of human brucellosis in Shanxi province. The diagnosis data of the reported brucellosis cases in 2015 were collected and reviewed retrospectively for the evaluation of the diagnosis accuracy with systematic sampling method. The database was established with Excel 2010 and the descriptive analysis and statistical test were conducted with software R 3.3.2. Results: The diagnosis consistent rate of the 377 brucellosis cases reviewed was 70.8% (267/377), the diagnosis consistent rates in medical institutions at city-level and country level were 77.0% (127/165) and 66.0% (140/212) respectively, the differences had significance (chi(2)=5.4, P=0.02). Among the reviewed cases, the diagnosis consistent rate of laboratory diagnosis and clinical diagnosis were 87.1% (256/294) and 13.3% (11/83) respectively, and the differences had significance (chi(2)=170.7, P<0.001). Among the 21 investigated clinical doctors, the numbers of the doctors who correctly diagnosed the suspected cases, probable cases and lab-confirmed cases were only 3, 0 and 8 respectively. All of the clinical doctors knew that it is necessary to report the brucellosis cases within 24 hours after diagnosis. Conclusion: The accuracy of human brucellosis diagnosis in key areas of human brucellosis in Shanxi was low, and the performance of the clinical doctors to diagnose human brucellosis according to diagnostic and case classification criteria was unsatisfied. PMID- 29141334 TI - [Human exposure to live poultry among residents during the second wave of avian influenza A (H7N9) epidemic in Beijing, 2013-2014]. AB - Objective: To investigate human exposure to live poultry (poultry feeding and purchasing) in the residents in Beijing and related factors during the second wave of avian influenza A(H7N9) epidemic during 2013-2014, and provide scientific evidence for avian influenza prevention and control. Methods: A total of 7 366 adults aged >=18 years were selected through multi-stage stratified sampling in Beijing for a questionnaire survey. Logistic regression model was used to analyze the influence factors of human exposure to live poultry. Results: The live poultry feeding rate and live poultry purchasing rate in residents in Beijing in the past year were 5.3% (95%CI: 4.8%-5.8%) and 6.0% (95%CI: 5.5%-6.5%) respectively. Logistic regression analysis indicated that lower educational level of primary school and below, (OR=1.82, 95%CI: 1.22-2.72); being farmer (OR=2.49, 95%CI:1.89-3.29) or being unemployed (OR=1.65, 95%CI: 1.08-2.52); being non local resident (OR=1.54, 95%CI: 1.10-2.16); living in suburban area (OR=2.36, 95%CI: 1.77-3.16); having one child (OR=1.76, 95%CI: 1.42-2.17) or >=2 children (OR=2.15, 95%CI: 1.43-3.22) in the family were the risk factors associated with feeding poultry compared with higher educational level of college and above, being employed, being local resident, living in urban area and having no child. And being farmer (OR=1.61, 95%CI: 1.27-2.02); being non local resident (OR=1.76, 95%CI: 1.31-2.35); living in suburban area (OR=2.05, 95%CI: 1.61-2.61); having one child (OR=1.24, 95%CI: 1.02-1.52) or >=2 children (OR=1.78, 95%CI: 1.21-2.63) were the risk factors for purchasing live poultry. Conclusion: Some residents living in Beijing still have exposure to live poultry, and targeted measures should be taken to reduce the exposure to poultry. PMID- 29141335 TI - [Previous HIV testing behavior and related factors in men who have sex with men in gay bathroom in Hangzhou, Zhejiang province]. AB - Objective: To understand the related factors on previous HIV testing behavior among MSM who visit gay bathroom in Hangzhou, Zhejiang province. Methods: Through time-location sampling (TLS) survey, men who had oral sex or anal sex with men in past 6 months were interviewed in the gay bathroom in Hangzhou from October 2015 to January 2016. Software SPSS 22.0 was used to analyze the HIV testing acceptance, sexual behaviors and condom usage of MSM during past 6 months, and chi(2) test and logistic regression model were used for univariate and multivariate analyses. Results: Our study planned to recruit 480 gay bathroom MSM, due to the unwilling or other factors, 465 MSM were surveyed. A total of 47.3% (220/465) gay bathroom MSM received HIV testing during past 6 months. Multivariate analysis indicated that being married (OR=0.35, 95%CI: 0.18-0.69), peer education (OR=4.31, 95%CI: 1.32-14.09), homosexual behavior during past 6 months (OR=1.85, 95%CI: 1.08-3.14), extramarital heterosexual behavior during past 6 months (OR=4.12, 95%CI: 2.45-6.91) might be positive factors related with HIV testing acceptation in MSM. Conclusion: Being married, homosexual behavior during past 6 months, extramarital heterosexual behavior, partner education might be the positive factors related with acceptance of HIV testing among gay bathroom MSM. Therefore, peer education needs to be strengthened. HIV testing after high risk sexual behavior needs to be promoted in MSM. PMID- 29141336 TI - [Data distribution and transformation in population based sampling survey of viral load in HIV positive men who have sex with men in China]. AB - Objective: To understand the distribution of population viral load (PVL) data in HIV infected men who have sex with men (MSM), fit distribution function and explore the appropriate estimating parameter of PVL. Methods: The detection limit of viral load (VL) was <= 50 copies/ml. Box-Cox transformation and normal distribution tests were used to describe the general distribution characteristics of the original and transformed data of PVL, then the stable distribution function was fitted with test of goodness of fit. Results: The original PVL data fitted a skewed distribution with the variation coefficient of 622.24%, and had a multimodal distribution after Box-Cox transformation with optimal parameter (lambda) of-0.11. The distribution of PVL data over the detection limit was skewed and heavy tailed when transformed by Box-Cox with optimal lambda=0. By fitting the distribution function of the transformed data over the detection limit, it matched the stable distribution (SD) function (alpha=1.70, beta=-1.00, gamma=0.78, delta=4.03). Conclusions: The original PVL data had some censored data below the detection limit, and the data over the detection limit had abnormal distribution with large degree of variation. When proportion of the censored data was large, it was inappropriate to use half-value of detection limit to replace the censored ones. The log-transformed data over the detection limit fitted the SD. The median (M) and inter-quartile ranger (IQR) of log transformed data can be used to describe the centralized tendency and dispersion tendency of the data over the detection limit. PMID- 29141337 TI - [Epidemiology of imported infectious diseases in China, 2013-2016]. AB - Objective: To describe the epidemic of imported infectious diseases in China between 2013 and 2016, including the kinds of infectious diseases, affected provinces, source countries and the epidemiological characteristics, and provide scientific information for the prevention and control of imported infectious diseases. Methods: Data of cases of imported infectious diseases in China from 2013 to 2016 were collected from national information reporting system of infectious diseases, Microsoft Excel 2010 and SPSS 18.0 were used to conduct data cleaning and analysis. Results: From 2013 to 2016, a total of 16 206 imported cases of infectious diseases were reported in China. Of all the cases, 83.12% (13 471 cases) were malaria cases, followed by dengue fever (2 628 cases, 16.22%). The majority of the imported cases were males (14 522 cases, 89.61%). Most cases were aged 20-50 years. Except Zika virus disease and yellow fever, which were mainly reported before and after spring festival, other imported infectious diseases mainly occurred in summer and autumn. The epidemic in affected provinces varied with the types of infectious diseases, and Yunnan reported the largest case number of imported infectious diseases, followed by Jiangsu, Guangxi and Guangdong. The imported cases were mainly from Asian countries, such as Burma, and African countries, such as Angola, Equatorial Guinea and Ghana, which also varied with the types of infectious diseases. Conclusions: We should pay more attention to imported infectious diseases and strengthen the prevention and control measures in our country. In order to reduce the incidence of imported infectious diseases, the health education should be enforced for persons who plan to travel abroad and the active surveillance should be strengthened for returned travelers. PMID- 29141338 TI - [Spatial and temporal clustering characteristics of typhoid and paratyphoid fever and its change pattern in 3 provinces in southwestern China, 2001-2012]. AB - Objective: To analyze the spatial and temporal clustering characteristics of typhoid and paratyphoid fever and its change pattern in Yunnan, Guizhou and Guangxi provinces in southwestern China in recent years. Methods: The incidence data of typhoid and paratyphoid fever cases at county level in 3 provinces during 2001-2012 were collected from China Information System for Diseases Control and Prevention and analyzed by the methods of descriptive epidemiology and geographic informatics. And the map showing the spatial and temporal clustering characters of typhoid and paratyphoid fever cases in three provinces was drawn. SaTScan statistics was used to identify the typhoid and paratyphoid fever clustering areas of three provinces in each year from 2001 to 2012. Results: During the study period, the reported cases of typhoid and paratyphoid fever declined with year. The reported incidence decreased from 30.15 per 100 000 in 2001 to 10.83 per 100 000 in 2006(annual incidence 21.12 per 100 000); while during 2007-2012, the incidence became stable, ranging from 4.75 per 100 000 to 6.83 per 100 000 (annual incidence 5.73 per 100 000). The seasonal variation of the incidence was consistent in three provinces, with majority of cases occurred in summer and autumn. The spatial and temporal clustering of typhoid and paratyphoid fever was demonstrated by the incidence map. Most high-incidence counties were located in a zonal area extending from Yuxi of Yunnan to Guiyang of Guizhou, but were concentrated in Guilin in Guangxi. Temporal and spatial scan statistics identified the positional shifting of class I clustering area from Guizhou to Yunnan. Class I clustering area was located around the central and western areas (Zunyi and Anshun) of Guizhou during 2001-2003, and moved to the central area of Yunnan during 2004-2012. Conclusion: Spatial and temporal clustering of typhoid and paratyphoid fever existed in the endemic areas of southwestern China, and the clustering area covered a zone connecting the central areas of Guizhou and Yunnan. From 2004 to 2012, the most important clustering area shifted from Guizhou to Yunnan. Findings from this study provided evidence for the identifying key areas for typhoid and paratyphoid fever control and prevention and allocate health resources. PMID- 29141339 TI - [Survival time of HIV/AIDS cases and related factors in Beijing, 1995-2015]. AB - Objective: To analyze the survival time of HIV/AIDS cases and related factors in Beijing from 1995 to 2015. Methods: A retrospective cohort study was conducted to analyze the data of 12 874 HIV/AIDS cases. The data were collected from Chinese HIV/AIDS Comprehensive Information Management System. Life table method was applied to calculate the survival proportion, and Cox proportion hazard regression model were used to identify the factors related with survival time. Results: Among 12 874 HIV/AIDS cases, 303 (2.4%) died of AIDS related diseases; 9 346 (72.6%) received antiretroviral therapy. The average survival time was 226.5 months (95%CI: 223.0-230.1), and the survival rates of 1, 5, 10, and 15 years were 98.2%, 96.4%, 93.2%, and 91.9% respectively. Multivariate Cox proportion hazard regression model showed that AIDS phase (HR=1.439, 95%CI: 1.041-1.989), heterosexual transmission (HR=1.646, 95%CI: 1.184-2.289), being married (HR=2.186, 95%CI: 1.510-3.164); older age (>=60 years) at diagnosis (HR=6.608, 95%CI: 3.546-12.316); lower CD(4)(+)T cell counts at diagnosis (<350 cells/MUl) (HR=8.711, 95%CI: 5.757-13.181); receiving no antiretroviral therapy (ART) (HR=18.223, 95%CI: 13.317-24.937) were the high risk factors influencing the survival of AIDS patients compared with HIV phase, homosexual transmission, being unmarried, younger age (<=30 years), higher CD(4)(+)T cell count (>=350 cell/MUl) and receiving ART. Conclusion: The average survival time of HIV/AIDS cases was 226.5 months after diagnoses. Receiving ART, higher CD(4)(+)T cell counts at the first test, HIV phase, younger age, being unmarried and the homosexual transmission were related to the longer survival time of HIV/AIDS cases. Receiving no ART, the lower CD(4)(+)T cell counts at the first test, AIDS phase, older age, being married and heterosexual transmission indicated higher risk of death due to AIDS. PMID- 29141340 TI - [Survival time of HIV/AIDS death cases after antiretroviral therapy and related factors in Henan province, 2003-2015]. AB - Objective: To analyze and investigate the survival time of dead HIV/AIDS patients after antiretroviral therapy (ART) and related factors in Henan province. Methods: The database of national integrated management system of HIV/AIDS was used to collect the information of dead patients who received ART between January 2003 and December 2015. Software SPSS 23.0 was used to analyze the survival time of dead patients and related factors. Result: A total of 6 267 AIDS patients died after ART and the average survival time was 23.85 months (Q(R): 6.87-50.46 months). Within 6 months, 7-12 months and 13-24 months after ART, the numbers of dead patients were 1 441 (23.00%), 652 (10.40%) and 1 052 (16.79%), respectively. The number of dead cases decreased after 24 months of ART. The number of AIDS related deaths was 5 085 (81.1%); and 799 (12.7%) deaths were due to other causes, in which 179 (2.9%) were caused by accidents and 109 (1.7%) were caused by suicides. The differences in annual composition ratio of death causes during 2003-2015 had significance (chi(2)=864.27, P<0.01). Twelve months, 36 months, 60 months and 120 months after ART, the survival ratios were 66.59%, 36.62%, 19.24% and 0.64% respectively. Compared with patients infected through blood donation, the HR of the patients infected through sexual transmission was 1.602 (95%CI: 1.483-1.732). Compared with patients with initial level of CD(4)(+)T lymphocyte >=350 unit/MUl, the HR of patients with initial level of CD(4)(+)T lymphocyte<50 unit/MUl was 2.320 (95%CI: 2.119-2.539). Compared with patients receiving second line ART, the HR of patients receiving no second line ART was 3.312 (95%CI: 3.083 3.558). Conclusion: The AIDS related deaths mainly occurred in the first six months after ART. As the increase of duration of ART, the death rate decreased. Sexual transmission, low initial level of CD(4)(+)T lymphocyte and receiving no second line ART were the risk factors for the deaths of HIV/AIDS patients. PMID- 29141341 TI - [Spatial-temporal distribution of smear positive pulmonary tuberculosis in Liangshan Yi autonomous prefecture, Sichuan province, 2011-2016]. AB - Objective: To analyze the spatial and temporal distribution of smear positive pulmonary tuberculosis (PTB) in Liangshan Yi autonomous prefecture in Sichuan province from 2011 to 2016. Methods: The registration data of PTB in 618 townships of Liangshan from 2011 to 2016 were collected from "Tuberculosis Management Information System of National Disease Prevention and Control Information System" . Software ArcGIS 10.2 was used to establish the geographic information database and realize the visualization of the analysis results. Software OpenGeoda 1.2.0 was used to conduct the analyses on global indication of spatial autocorrelation (GISA) and local indication of spatial autocorrelation (LISA). Software SaTScan 9.4.1 was used for spatio-temporal scanning analysis. Results: From 2011 to 2016, the registration rate of smear positive PTB in Liangshan declined from 56.97/100 000 (2 666 cases) to 21.11/100 000 (1 038 cases). The global spatial autocorrelation coefficient Moran's I ranged from 0.25 to 0.45 and the difference was significant (all P=0.000). Local autocorrelation analysis showed that "high-high" area covered 43, 34, 37, 34, 42 and 61 townships from 2011 to 2016, respectively, mainly in Leibo county. Spatial temporal clustering analysis found one class I clustering in the area around Bagu township of Meigu county and two class II clustering in the areas around Liumin and Hekou township of Huili county, respectively (all P=0.000). Conclusion: Obvious spatial temporal clustering of smear positive PTB distribution was found in Liangshan from 2011-2016. Hot spot areas with serious smear positive PTB epidemic and high spread risk were mainly found in northeastern Liangshan, including townships in Leibo and Meigu counties. Targeted TB prevention and control should be conducted in these areas. PMID- 29141342 TI - [Influence of humidex on incidence of bacillary dysentery in Hefei: a time-series study]. AB - Objective: To investigate the effect of humidex combined with mean temperature and relative humidity on the incidence of bacillary dysentery in Hefei. Methods: Daily counts of bacillary dysentery cases and weather data in Hefei were collected from January 1, 2006 to December 31, 2013. Then, the humidex was calculated from temperature and relative humidity. A Poisson generalized linear regression combined with distributed lag non-linear model was applied to analyze the relationship between humidex and the incidence of bacillary dysentery, after adjusting for long-term and seasonal trends, day of week and other weather confounders. Stratified analyses by gender, age and address were also conducted. Results: The risk of bacillary dysentery increased with the rise of humidex. The adverse effect of high humidex (90 percentile of humidex) appeared in 2-days lag and it was the largest at 4-days lag (RR=1.063, 95%CI: 1.037-1.090). Subgroup analyses indicated that all groups were affected by high humidex at lag 2-5 days. Conclusion: High humidex could significantly increase the risk of bacillary dysentery, and the lagged effects were observed. PMID- 29141343 TI - [Study on influence of air temperature on daily chronic obstructive pulmonary disease mortality in Ningbo]. AB - Objective: To study the influence of daily air temperature on daily chronic obstructive pulmonary disease (COPD) mortality in residents in Ningbo. Methods: A time-series analysis using distributional lag non-linear model (DLNM) was conducted to estimate the attributable numbers and fraction of average air temperature on the daily COPD mortality in Ningbo from 2011 to 2016, by controlling the long-term time trend, day of week, air pollutants and other weather variables. Results: A reverse J-shape relationship was found between the average air temperature and COPD mortality, and the minimum-mortality temperature (MMT) was 25.5 C. The relative risks of extreme low and extreme high air temperature over lag 0-14 d were 2.767 (95%CI: 1.950-3.928) and 1.197 (95%CI: 1.021-1.404). In total, 31.62% (95%CI: 23.05%-38.89%) of COPD mortality (4 963 cases, 95%CI: 3 469-6 027) was attributable to non-MMT exposure, More attributable deaths were due to low air temperature, with a fraction of 30.41% corresponding to 4 772 deaths, compared with 1.22% and 192 deaths due to high air temperature. Low air temperature and high temperature were more likely to influence the mortality in females and those aged >=65 years, but the influence was not significant in people aged <65 years. Conclusion: Both high and low air temperature were associated with an increased risk of COPD mortality in residents in Ningbo, especially during cold season, related measures on disease prevention should be taken to protect vulnerable population to reduce the risk of COPD mortality. PMID- 29141344 TI - [Study on smoking attributed death and effects of smoking cessation in residents aged 35-79 years in Tianjin, 2016]. AB - Objective: To analyze the influence of smoking on deaths in residents aged 35-79 years and the effects of smoking cessation in Tianjin. Methods: The data of 39 499 death cases aged 35-79 years in 2016 in Tianjin were collected, the risks for deaths caused by smoking related diseases and excess deaths as well as effects of smoking cessation were analyzed after adjusting 5 year old age group, education level and marital status. Results: Among the 39 499 deaths cases, 1 589 (13.56%) were caused by smoking, the percentage of the excess mortality of lung cancer caused by smoking was highest (47.60%); the risk of death due to lung cancer in smokers was 2.75 times higher than that in non-smokers (95%CI: 2.47-3.06). Among the female deaths, 183 (7.29%) were caused by smoking, the percentage of the excess mortality of lung cancer was highest (28.90%); and the risk of death of lung cancer in smokers was 4.04 times higher than that in non-smokers (95%CI: 3.49-4.68). The OR for disease in ex-smokers was 0.80 compared with 1.00 in smokers (95%CI: 0.72-0.90). The OR in males who had quitted smoking for >=10 years was lower (0.74, 95%CI: 0.63-0.86) than that in those who had quitted smoking for 1-9 years (0.85, 95%CI: 0.74-0.98), but the difference was not significant. Conclusion: Smoking is one of the most important risk factors for deaths in residents in Tianjin. Smoking cessation can benefit people's health. PMID- 29141345 TI - [Comparison of results of two immunoassays for detection of hepatitis B surface antigen in pregnant women]. AB - Objective: To evaluate and compare the detection consistency of hepatitis B surface antigen (HBsAg) by two immunoassays: enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescent immunoassay (ECLIA). Methods: A prospective study was conducted among 2 296 pregnant women recruited consecutively from January 1, 2014 to January 31, 2015 in a hospital. Blood samples were collected from them for the detection of HBsAg by using ELISA and ECLIA, Kappa test was performed on the results. Nested polymerase chain reaction and sequencing of HBV S gene were also performed in all samples. Phylogenetic analysis was performed using Mega 6.0 software. Results: The two methods had high detection consistence of HBsAg (Kappa=0.71). There were significant differences in detection result of B genotype and adw2 serotype HBV strains between two methods. Among 123 identified HBV strains, 113 belonged to genotype B and available for further analysis. The difference in detection of substitution rates between two methods or different positive groups were not significant. Compared with ELISA single positive group, the ECLIA single positive group had completely different substitution sites. Conclusion: The two methods had high detection consistence of HBsAg, but there were still 32.4% HBV DNA positive cases in ELISA/ECLIA single positive group, and complete complementary substitution sites between ELISA single positive group and ECLIA single positive group. Our results suggested that more effective detection procedure should be considered for the possible impact of the HBV silent transmission and infection. PMID- 29141346 TI - [Etiologic characteristics of Shigella sonnei strains isolated from some areas of Guangdong province and Guangxi Zhuang Autonomous Region of China, 2014-2016]. AB - Objective: To investigated the etiologic characteristics of Shigella (S.) sonnei strains causing outbreaks and sporadic cases in some areas of Guangdong province and Guangxi Zhuang Autonomous Region during 2014-2016. Methods: Fourteen S. sonnei strains isolated from outbreaks and 6 S. sonnei strains from sporadic cases from Guangdong and Liuzhou of Guangxi Zhuang Autonomous Region were tested for antimicrobial resistance and analyzed by pulsed-field gel electrophoresis (PFGE). Six typical strains were selected for whole genome sequencing typing and compared with 51 strains isolated both at home and abroad from NCBI genome database. Results: The antibiotic resistance test indicated the isolates had high resistance rate to ampicillin, tetracycline, gentamicin, trimethoprim/sulfamethoxazole and nalidixic acid, while sensitive to azithromycin, chloromycetin and imipenem. PFGE showed high similarity (93.2%) among the strains isolated from different areas. The whole genome sequencing analysis also revealed that all the typical strains were clustered into a same evolution branch, close to some strains from Korea. Conclusions: The S. sonnei strains isolated from some areas of Guangdong and Guangxi Zhuang Autonomous Region showed high resistance to commonly used antibiotics, but they were sensitive to azithromycin, chloramphenicol and imipenem. The isolates in this study also showed similar PFGE patterns and close phylogenic evolution. PMID- 29141347 TI - [Antimicrobial resistance and molecular subtypes of Salmonella typhi and Salmonella paratyphoid isolates from Jiangsu province, 2012-2015]. AB - Objective: To retrospectively analyze the antimicrobial resistance phenotype and molecular typing characteristics of Salmonella (S.) typhi and S. paratyphi in Jiangsu province from 2012 to 2015. Methods: The samples were collected from typhoid and paratyphoid patients in Jiangsu province. The biochemical identification and serotyping were carried out after isolation and culture. Kirby Bauer (K-B) testing was used to detect the drug susceptibility of the strains. The molecular typing characteristics of S. typhi and S. paratyphi were analyzed by pulsed field gel electrophoresis (PFGE). Results: The resistant rates of 134 S. typhi and S. paratyphi A strains to nalidixic acid were highest (61.2% and 86.7%), while the resistant rates to remaining antibiotics were less than 15.0%. Most of S. typhi and S. paratyphi A strains were resistant to only one antibiotic. Multidrug-resistant (MDR) strains of S. typhi and S. paratyphi A accounted for 2.6% and 13.3% respectively. The composition of the all-sensitive strains of S. typhi increased by 44.3% in 2015, at the same time, there were also MDR S. paratyphi A strains, which were resistant to 5 and 6 antibiotics. S. paratyphi A could be divided into eight molecular patterns by PFGE, showing that the similarity between the MDR strains and other strains was relatively low. The S. paratyphi A strains with same pattern were resistant to same antibiotics. S. typhi could be divided into 68 molecular patterns by PFGE, with large variability between different patterns. There was no corresponding relationship between the patterns and the drug resistance characteristics. Conclusions: The overall antibiotic resistance of S. typhi and S. paratyphi A strains showed a decreasing trend, but the number of antibiotics to which they were resistant increased. PFGE patterns of S. typhi showed diversity without correspondence to antibiotic characteristics. PFGE patterns of S. paratyphi A were less with correspondence to antibiotic characteristics. We should pay more attention to key patterns in key areas. PMID- 29141348 TI - [Molecular epidemiology and transmission of HIV-1 infection in Zhejiang province, 2015]. AB - Objective: To understand the distribution of HIV-1 subtype diversity and its transmission characteristics in Zhejiang province. Methods: A total of 302 newly diagnosed HIV-1 positive patients were selected through stratified random sampling in Zhejiang in 2015. HIV-1 pol genes were sequenced successfully with reverse transcription PCR/nested PCR and phylogenetic analysis was conducted for 276 patients. Then a molecular epidemiologic study was performed combined with field epidemiological investigation. Results: Of 276 sequence samples analyzed, 122 CRF07_BC strains (44.2%), 103 CRF01_AE strains (37.3%), 17 CRF08_BC strains (6.1%), 9 B strains (3.2%), 6 CRF55_01B strains (2.2%), 5 C strains (1.8%), 1 CRF59_01B strain (0.4%), 1 CRF67_01B strain (0.4%), 1 A1 strain (0.4%), and 11 URFs strains (4.0%) were identified. Phylogenetic analysis revealed 16 clusters with only 15.1% (34/225) sequences involved among CRF07_BC and CRF01_AE strains. The clustered cases in MSM were higher than that in populations with other transmission routes. And clusters existed between the populations with different transmission routes. Conclusion: The major strains of HIV-1 in Zhejiang are CRF07_BC and CRF01_AE. The HIV subtypes showed more complexity in Zhejiang. It is necessary to strengthen the surveillance for HIV subtypes, carry out classified management and conduct effective prevention and control in the population at high risk. PMID- 29141349 TI - [Evaluation and application of estimation of glomerular filtration rate based on serum creatinine and cystatin C in renal function staging]. AB - Objective: To evaluate the accordance of chronic kidney disease (CKD) staging between the CKD-EPI2009 equation, the CKD-EPI2012 equation and the modification of diet in renal disease (MDRD) equation and compare the predictive value of common cardiovascular disease. Methods: A total of 11 151 adults from Jurong area, Jiangsu province, were surveyed from September to November in 2015 and their serum creatinine and cystatin C were detected. The glomerular filtration rate (GFR) was estimated by three equations. Results: In the individuals with history of chronic renal insufficiency, the results of CKD staging of CKD-EPI2009 equation and CKD-EPI2012 equation were all consistent with that of MDRD equation (P<0.001), and the consistence between CKD-EPI2012 equation and CKD-EPI2009 equation was even higher. In the people without history of CKD, the results of CKD staging of CKD-EPI2009 equation and CKD-EPI2012 equation were also highly consistent with the results of MDRD equation (P<0.001) and Kappa values were 0.662 and 0.654 respectively whilst the results of CKD staging estimated by CKD EPI2012 equation and MDRD equation were only moderately consistent (Kappa=0.436, P<0.001). In the whole observational population, the CKD staging results of MDRD equation, CKD-EPI2009 equation and CKD-EPI2012 equation had a good consistency evaluated by Band-Altman method. The consistency of CKD staging between CKD-EPI (2009, 2012) equation and MDRD equation was higher in >=70 years old group than that in <70 years old group as well as in males than in females. For predicting hypertension, the AUCs of CKD-EPI equations calculated GFRs were significantly higher than that of MDRD equation; the AUCs of CKD-EPI2012 equation calculated GFR for predicting stroke and coronary heart disease were higher than that of MDRD equations whereas no significant difference in GFR prediction result was found between CKD-EPI2009 equation and MDRD equation. Conclusion: MDRD equation and CKD-EPI equation for GFR estimation have high consistency in CKD staging whilst the predictive value of chronic cardiovascular disease by CKD-EPI equation estimated GFR was higher than that of MDRD equation. PMID- 29141350 TI - [Comparison of different methods in dealing with HIV viral load data with diversified missing value mechanism on HIV positive MSM]. AB - Objective: To compare results of different methods: in organizing HIV viral load (VL) data with missing values mechanism. Methods We used software SPSS 17.0 to simulate complete and missing data with different missing value mechanism from HIV viral loading data collected from MSM in 16 cities in China in 2013. Maximum Likelihood Methods Using the Expectation and Maximization Algorithm (EM), regressive method, mean imputation, delete method, and Markov Chain Monte Carlo (MCMC) were used to supplement missing data respectively. The results: of different methods were compared according to distribution characteristics, accuracy and precision. Results HIV VL data could not be transferred into a normal distribution. All the methods showed good results in iterating data which is Missing Completely at Random Mechanism (MCAR). For the other types of missing data, regressive and MCMC methods were used to keep the main characteristic of the original data. The means of iterating database with different methods were all close to the original one. The EM, regressive method, mean imputation, and delete method under-estimate VL while MCMC overestimates it. Conclusion: MCMC can be used as the main imputation method for HIV virus loading missing data. The iterated data can be used as a reference for mean HIV VL estimation among the investigated population. PMID- 29141351 TI - [Qidong Chronic Hepatitis B Cohort: participants enrollment and comparison of baseline characteristics by gender stratification]. AB - Objective: To establish a study cohort of chronic hepatitis B (CHB) in Qidong and evaluate its baseline characteristics. Methods: CHB outpatients of the Third People's Hospital of Qidong were invited to participate in baseline survey from January 1, 2016, including questionnaire survey, liver function detection, serum detection of HBV infection and upper abdomen ultrasound detection. Anticipated sample size was at least one thousand. Baseline data were inputted by EpiData 3.1 software and then cleaned and analyzed by SAS 9.3 software. Results: As of 18 July, 2016, a total of 1 006 participants had been enrolled into the current study, including 615 males with an average age of (44.26+/-9.97) years and 391 females with an average age of (46.66+/-11.17) years. The difference in family history of liver disease was not significant between males and females (P>0.05), while the differences in other key information, such as age, education level, tobacco consumption, alcohol drinking, tea consumption, and antiviral intervention, were significant between males and females (P<0.05). Among the key clinical parameters, such as ALT, HBeAg, HBsAg, HBV DNA, albumin, and width of splenic vein and portal vein, only the abnormal rates of ALT and total bilirubin levels were higher in males than in females, the difference was significant (P<0.05). Conclusion: Outpatient department-based CHB cohort was established successfully in Qidong, and sub-cohort could be divided according to the differences on baseline characteristics. PMID- 29141352 TI - [Overdiagnosis in mammography screening for breast cancer]. AB - Screening has been always considered as a double-edged sword. Cancer screening could save lives in some cases, however, in other cases, it might also turn people into overdiagnosis. Overdiagnosis is the diagnosis of cancer that will never cause symptoms or death during a patient's lifetime. Therefore, overdiagnosis might lead to unnecessary treatments and lifetime surveillance, and then increase economic burden and psychological burden. In this review, we focus on how to correctly evaluate the overdiagnosis rate, and how to avoid or reduce the harms caused by overdiagnosis in the future according to the reasons associated with overdiagnosis. After systematically reviewing the previous studies, we will try to identify the potential reasons associated with overdiagnosis in breast cancer screening with mammography, address how to correctly evaluate the overdiagnosis rate, and finally provide some suggestions to reduce the overdiagnosis. PMID- 29141353 TI - [Progress in research of thyroid carcinoma related gene mutation and epigenetics]. AB - Thyroid cancer is one of the most common endocrine malignant tumors, and its molecular pathogenesis is also a process of multiple genes involved in many steps of carcinogenesis. With the development of molecular biology technology, a variety of related gene mutations and epigenetic phenomena have been found in thyroid cancer tissues. It is helpful to understand the latest progress in the research of the gene mutation and epigenetics of thyroid cancer for its early diagnosis, prevention and the development of targeted drugs. PMID- 29141354 TI - [Research progress on unprotected anal intercourse and its influencing factors in men who have sex with men]. AB - The prevalence of HIV infections continues to rise among Chinese MSM. This population is prone to has high-risk behaviors including having multiple sexual partners, unprotected anal intercourse (UAI), etc. This paper summarizes the situation of UAI and related influencing factors, including age, educational level, number of sexual partners, recreational drug abusing and related status of discrimination, etc. The purpose of this article is to provide reference for targeted intervention and prevention of HIV among MSM population. PMID- 29141356 TI - [Attention to the importance of dietary factors in the pathogenesis and treatment of rheumatism]. PMID- 29141355 TI - [The new concept of prevention and treatment for Glucocorticoid-induced osteonecrosis of femoral head]. PMID- 29141357 TI - [Prevention for glucocorticoid-induced osteonecrosis of femoral head: a long-term clinical follow-up trail]. AB - Objective: To evaluated the outcome of prevention and treatment for glucocorticoid-induced osteonecrosis of femoral head with anticoagulant and vasodilator drugs. Methods: A prospective, randomized, double-blind study was performed. From August 2003 to August 2006, 58 patients with large amounts of hormone therapy in the Zhongshan Hospital Affiliated Dalian University were enrolled and randomly assigned to the control group (placebo) or preventive group (anticoagulant and vasodilator drugs). And we prospectively analyzed the clinical outcomes of 24 patients with glucocorticoid-induced osteonecrosis of femoral head early stage (treatment group)treated by anticoagulant and vasodilator drugsat the same time. Disease incidence rate and progression were evaluated by radiography and magnetic resonance imaging (MRI), Follow-up of patients with femoral head survival curve was drawn. The Harris Hip Score and the Short Form 36 health survey were used to rate hip function and quality of life, respectively. Results: Thus, a total of 80 patients were assessed in this study, 24 cases in control group[follow up from 7.5 to 13.0(10.7+/-1.6)years], 22 cases in preventive group and 24 cases in treatment group. There was significant difference in theincidence rate of Osteonecrosis of femoral head, survive rate of femoral head and HHS score between the control groupand preventive group(41.7% vs 13.6%, 66.7% vs 70.8% , P<0.01). Conclusion: Anticoagulant and vasodilator drugs could effect on preventing theglucocorticoid-induced osteonecrosis of femoral head, reducing disease progression, or improving life quality. PMID- 29141358 TI - [Effect of different tourniquet releasing strategy on blood loss in total knee arthroplasty]. AB - Objective: To explore the influences on peri-operative blood loss and postoperative blood transfusion in primary total knee arthroplasty when using different methods to release the pneumatic tourniquet. Methods: From January 2015 to December 2016, 484 patients with osteoarthritis were enrolled, undergoing primary unilateral total knee arthroplasty in the Orthopedics Department of Peking University Third Hospital. Retrospective data was used, and all the patients had been operated on by three independent working groups. Group A was the strategic tourniquet release group. After the completion of all osteotomy and soft tissue balance, the tourniquet was released for five minutes for coagulation of bleeding tissue and was then inflated again before component cementation untill the end of the operation. In Group B, full-time tourniquet usage was applied to patients, and was just released post wound closure and pressure dressing. In Group C, the tourniquet was inflated from the beginning of incision to the end of cementation. It was then released after the prosthesis was cemented. A series of data in these three groups were observed and recorded, including output of drain, decrease of hemoglobin level in the first and third day after operation, the total measured blood loss, the hidden blood loss, the number of transfused patients, and the rates of allogenic blood transfusion. Results: The decrease of hemoglobin level in the first day after operation, the output of drain and the total level of measured blood loss were slightly higher in Group A. The decrease of hemoglobin level in the third day after operation and the hidden blood loss was slightly higher in Group B. Group C had the lowest total measured blood loss and hidden blood loss among the three groups. However, no significant differences of outcomes were observed among these groups. A total of 29 patients received blood transfusion(Group A 10/165, 6.1%; Group B 11/177, 6.2%; Group C 8/142, 5.6%). There was no significant differences among the three groups in output of drain(P=0.496), decrease of hemoglobin level(P=0.242), total measured blood loss(P=0.390), hidden blood loss(P=0.204), or postoperative blood transfusion rate(P=0.976). Conclusions: Under the routine application of the multimodal blood-loss prevention approach, including tranexamic acid, drain under atmospheric pressure, compression and cryotherapy after operation, the different choices of tourniquet releasing strategies have no significant effect on peri operative blood loss or postoperative blood transfusion rate in total knee arthroplasty. PMID- 29141359 TI - [Analysis of the tibial baseplate coverage and symmetrical tibial prosthesis in primary total knee arthroplasty]. AB - Objective: To investigate the tibial baseplate coverage with symmnetrical tibial prosthesis in primary total knee arthroplasty (TKA). Methods: From August 2014 to February 2015, 39 patients (39 knees) with varus knee osteoarthritis were retrospective reviewed in Department of Orthopaedics, Tianjin Xiqing Hospital. Nine males and 30 females; aged 50 to 78 years (67+/-6 year). 3D tibia models of the knee were built with Mimics 10.01 software, simulated TKA surgeries were performed. The morphology of the proximal tibia was measured, including the mediolateral (ML), anteroposterior (AP) and medial and lateral tibial plateau AP dimensions. 3D models of PFC Sigma tibial prosthesis were imported and the tibial coverage characters were analyzed. Results: The AP and ML dimensions of the tibial resection surface were (45.7+/- 3.4) mm, (71.7+/- 4.2) mm respectively, the plateau aspect ration ratio (AP/ML) was 63.8%+/-3.0%. The medial tibial plateau AP[(46.9+/- 3.3) mm]was significantly greater than the lateral side[(41.8+/-3.3) mm, P=0.000], the asymmetric ratio averaged 112.4%+/-6.9%. The medial tibial plateau, anteromedial, posteromedial, posterolateral unsatisfied coverage ratio were 33.3%, 76.9%, 20.5%, 33.3% respectively. There are 5 cases underhang and 3 cases overhang in the posteromedial side, whereas 1 case underhang and 12 cases overhang posterolateral, the overhang ratio was 30.8%. Posteromedial, posterolateral prosthesis coverage had linear positive correlation to the ipsilateral tibial plateau AP diameter. Conclusions: The medial AP diameter of tibial plateau is significantly lager than the lateral side in varus knee osteoarthritis patients. With symmetrical tibial baseplate placement in TKA, the prosthesis usually lead to medial tibial plateau anterior and posterior underhang and posterolateral overhang. PMID- 29141360 TI - [Total hip arthroplasty in patients with Psoriatic arthritis]. AB - Objective: To evaluate the clinical efficacy of Total hip arthroplasty (THA) in treating the hip joint involvement of Psoriatic arthritis (PsA). Methods: From January 2005 to December 2016, a total of 15 PsA patients (20 hip joints) underwent THA in Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. All the patients had obvious restriction in daily life before operation. The mean Harris score was 25.2 averagely and the mean total range of the hip joint movement was 39.6 degrees before surgery. All the prosthesis were biotype and ceramic to ceramic. Results: All patients were followed up with an average of 35.7 months and could take care of themselves. The Harris score of hip joint was 83.2 averagely, including 15 hips excellent, 3 good, and 2 passable, with an excellent and good rate of 90%. The mean total range of the hip joint movement was 175 degrees after surgery. There was no infection, nerve injury or loosening of the prosthesis. 1 hip appeared avulsion fracture of greater trochanter of femur, and the joint function was satisfying at the last time of follow-up. Conclusion: THA is an effective method in treating affected hip joint of PsA. It can restore the hip function and improve the life quality of the PsA patients. PMID- 29141361 TI - [Effect of probucol on preventing contrast-induced nephropathy in patients undergoing percutaneous coronary intervention]. AB - Objective: To investigate the preventive effect, possible mechanism and safety of probucol on contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) in patients with coronary heart disease (CHD). Methods: A total of 641 patients with coronary heart disease were consecutively enrolled from Department of Cardiology, in Tianjin Chest Hospital, Tianjin TEDA International Cardiovascular Hospital, Tianjin First Central Hospital, Tianjin Fourth Central Hospital. They were randomly divided into probucol group (n=321) and control group (n=320). The probucol group was given oral probucol 500 mg twice daily for day 0 to day 3 after PCI; the control group was given only conventional therapy. All patients were given intravenous drip 0.9% sodium chloride solution before 12 to 24 hours of operation. The levels of serum creatinine (Scr), blood urea nitrogen (BUN), evaluate glomerular filtration rate (eGFR), cystatin C (Cys-C), and high-sensitivity C-reactive protein (hs-CRP), neutrophil gelatinase associated lipocalin (NGAL), superoxide dismutase (SOD) and glutathione (GSH) were measured before and 72 h after the PCI operation in both groups. The incidence rates of CIN, the adverse events during hospitalization and postoperative 14-day follow-up were recorded in two groups. Results: There was no statistically significantly difference in the levels of Scr, BUN, eGFR, Cys-C, hs CRP, NGAL, SOD and GSH between the two groups before PCI (P>0.05). The levels of serum Scr, BUN, Cys-C, hs-CRP, NGAL, SOD and GSH after operation in the two groups were higher than those before the operation (P<0.05). The levels of hs-CRP and NGAL in the probucol group were lower than those in the control group [(10+/ 4) vs (11+/-4)mg/L, (25+/-8)vs (34+/-7)U/ml, P<0.05]. The levels of eGFR, SOD and GSH in probucol group were higher than those in control group [(80+/-27) vs (72+/ 26) ml.min(-1).1.73 m(-2,) (67+/-9) vs (58+/-8)U/ml, (4.6+/-0.9) vs (3.9+/ 0.8)U/ml, P<0.05]. The incidence of CIN was 4.0% in the probucol group and 10.9% in the control group, and the difference was statistically significant (P<0.05, chi(2)=-3.31). Multivariate Logistic regression analysis showed that probucol was an independent protective factor for CIN (OR=0.334, 95%CI 0.172-0.648, P=0.001). There were no adverse events such as myasthenia gravis, abnormal liver function and cardiovascular events during the hospitalization and 14-day follow-up. Conclusions: Probucol can reduce the incidence of contrast-induced nephropathy after PCI. The protection mechanism is related with its anti-inflammatory and anti-oxidative stress effects, and it has good safety. PMID- 29141362 TI - [Evaluation of the psychological feature and quality of life in outpatients with somatic symptoms disorder in a general hospital]. AB - Objective: To explore the psychological features and quality of life in outpatients with somatic symptoms disorder in a general hospital. Methods: This cross-sectional study was conducted from 2014-05 to 2015-06. Patients diagnosed with major depressive disorder (MDD) and somatic symptoms disorder (SSD) were recruited from psychological outpatient department, and patients with peptic ulcer (PU) / reflux esophagitis (RE) were recruited from Gastroenterology. Depression scale of the patient health questionnaire (PHQ-9), Generalized Anxiety Disorder 7-item scale (GAD-7), Toronto Alexithymia scale (TAS), 12-item Short Form Health Survey (SF-12), items from Somatoform Disorder Screening Questionnaire were employed to evaluate the severity of depression, anxiety, alexithymia, quality of life, health care use and subjective feelings. Results: Scores of PHQ-9 (10+/-6), GAD-7 (8+/-5), TAS (74+/-7) in patients with SSD were significantly higher than PU/RE patients (5+/-4, 5+/-4, 71+/-8, respectively), and the physical component summary (PCS) (40+/-8) and mental component summary (MCS) (37+/-10) of SSD patients were much lower than PU/RE (PCS 45+/-6, MCS 47+/ 9) (P<0.01). No significant difference was found in the scores of PHQ-9, GAD-7, MCS-12, TAS between SSD and MDD group, but PCS-12 score of SSD group was much lower than that of MDD (P=0.017). Patients of SSD had more visits, more impact on life and longer duration of disorder. Multiple linear regression found that PHQ-9 score, subject feeling that life quality was affected were significant influential factors of PCS (F=14.600, P=0.001), and PHQ-9 score, occupation and ability to distinct emotion and physical feelings were significant influential factors of MCS (F=28.022, P=0.001). Conclusions: The SSD patients in a general hospital suffer from somatic symptoms and emotional distress, and quality of life is affected significantly. Clinicians should thoroughly evaluate patients according to bio-psycho-social aspects and give intervention individually. PMID- 29141363 TI - [Characteristics of high resolution diffusion weighted imaging apparent diffusion coefficient histogram and its correlations with cancer stages in patients with nasopharyngeal carcinoma]. AB - Objective: To investigate the features of apparent diffusion coefficient (ADC) histogram parameters based on entire tumor volume data in high resolution diffusion weighted imaging of nasopharyngeal carcinoma (NPC) and to evaluate its correlations with cancer stages. Methods: This retrospective study included 154 cases of NPC patients[102 males and 52 females, mean age (48+/-11) years]who had received readout segmentation of long variable echo trains of MRI scan before radiation therapy. The area of tumor was delineated on each section of axial ADC maps to generate ADC histogram by using Image J. ADC histogram of entire tumor along with the histogram parameters-the tumor voxels, ADC(mean), ADC(25%), ADC(50%), ADC(75%), skewness and kurtosis were obtained by merging all sections with SPSS 22.0 software. Intra-observer repeatability was assessed by using intra class correlation coefficients (ICC). The patients were subdivided into two groups according to cancer volume: small cancer group (<305 voxels, about 2 cm(3)) and large cancer group (>=2 cm(3)). The correlation between ADC histogram parameters and cancer stages was evaluated with Spearman test. Results: The ICC of measuring ADC histogram parameters of tumor voxels, ADC(mean), ADC(25%), ADC(50%), ADC(75%), skewness, kurtosis was 0.938, 0.861, 0.885, 0.838, 0.836, 0.358 and 0.456, respectively. The tumor voxels was positively correlated with T staging (r=0.368, P<0.05). There were significant differences in tumor voxels among patients with different T stages (K=22.306, P<0.05). There were significant differences in the ADC(mean), ADC(25%), ADC(50%) among patients with different T stages in the small cancer group(K=8.409, 8.187, 8.699, all P<0.05), and the up mentioned three indices were positively correlated with T staging (r=0.221, 0.209, 0.235, all P<0.05). Skewness and kurtosis differed significantly between the groups with different cancer volume(t=-2.987, Z=-3.770, both P<0.05). Conclusion: The tumor volume, tissue uniformity of NPC are important factors affecting ADC and cancer stages, parameters of ADC histogram (ADC(mean), ADC(25%), ADC(50%)) increases with T staging in NPC smaller than 2 cm(3). PMID- 29141364 TI - [Effects of combination therapy with aspirin, prednisone, and Elevit in patients with unexplained recurrent early pregnancy loss]. AB - Objective: To investigate the effect of triple therapy with aspirin, prednisone and Elevit in patients with unexplained recurrent early pregnancy loss. Methods: From January 1, 2013 to December 31, 2016, a total of 353 women of childbearing age were enrolled in Peking Union Medical College Hospital, including blood, urine and vaginal swabs. One hundred and fifty-five patients were observed normal results of blood test, urine test and vaginal swabs. According to the treatment regimen, 155 patients were divided into two groups, 89 patients (57.42%) treated with (aspirin, prednisone, and Elevit) as experimental group, and the other 66 cases (42.58%) taking folic acid as control group. The fetal bud, fetal heart and neck hyaline layer thickness were examined by ultrasonography at 12 weeks. Visible fetal bud, fetal heart, and nuchal translucency thickness <0.3 cm were used as indicators of successful treatment. t test and chi(2) test were used to analyze and compare the statistical significance of the differences between the two groups of patients, and the Logistic method was used to analyze the data and observe the effect of medication. Results: There were 67 patients successfully treated in the experimental group, the successful rate was 83.75% (67/80), and 33 patients in the control group were successfully treated, the successful rate was 54.10% (33/61). There were significant statistical differences in two groups (P<0.05). Conclusion: The effect of triple therapy with aspirin, prednisone and Elevit in patients with unexplained recurrent early pregnancy loss is significant. PMID- 29141365 TI - [Effect of short-acting combined oral contraceptives on bleeding after induced abortion]. AB - Objective: To explore the effect of short-acting combined oral contraceptives on vaginal bleeding after induced abortion. Methods: A total of 726 patients, who had took induced abortion from July 2016 to September 2016 in obstetrics and gynecology outpatient department of Nanfang Hospital, Southern Medical University, were included and divided into the observation group and the control group according to whether they took short-acting combined oral contraceptives after induced abortion, with 312 cases, 414 cases respectively.The vaginal bleeding days, amounts of bleeding, the endometrial thickness 3 weeks later, and whether the patient had menstrual recovery on time were observed and analyzed. Results: The observation group had less bleeding days and amount of bleeding, compared with the control group.69.87% (218/312) patients of the observation group had more than 8mm of endometrial thickness on postoperative day 21, while 61.11% (253/414) of the observation group did, the difference was statistically significant (P=0.034).90.06% (281/312) patients of the observation group had menstrual recovery on time, while 82.61% (342/414) of the observation group did, the difference was statistically significant (P=0.004). Conclusion: Short-acting combined oral contraceptives after induced abortion can significantly shorten the vaginal bleeding days, reduce the amount of bleeding, promote endometrial repair and menstrual recovery.There fore, it has important clinical significance and application value. PMID- 29141366 TI - [In vitro early detection of amyloid plaques in Alzheimer's disease by Pittsburgh compound B-modified magnetic nanoparticles]. AB - Objective: To construct magnetic nanoparticles targeting beta-amyloid (Abeta) plaques, the pathological biomarker of Alzheimer's disease (AD) and to study their binding capability in vitro. Methods: Superparamagnetic nanoparticles Mn(0.6)Zn(0.4)Fe(2)O(4) (MZF) were coated with amphiphilic star-block copolymeric micelles and modified with Abeta-specific probe Pittsburgh compound B (PiB) to construct a novel magnetic nanoparticle MZF-PiB, which specifically targeted amyloid plaques. Transmission electron microscope was used to study the morphological features of MZF-PiB. Superparamagnetism of MZF-PiB was assessed by its r(2) relaxation rate by using 3.0 T MRI scanner. Cytotoxic test was applied to determine biosafety of MZF-PiB nanoparticles in differentiated human neuroblastoma cells (SH-SY5Y) and Madin-Darby canine kidney (MDCK). In vitro binding tests were conducted via immunohistochemistry on 6-month old AD mice brain sections. Differences of cell viability between groups were compared with one-way analysis of variance. Results: MZF-PiB nanoparticles were successfully constructed. Transmission electron microscope images showed that the nanoparticles were about 100 nm in size. The r(2) relaxation rate was 163.11 mMS( 1). No differences were found in cell viability of SH-SY5Y and MDCK incubated with MZF-PiB suspension for 24 h or 48 h when compared with those of untreated cells (F=2.336, 2.539, 0.293, 1.493, all P>0.05). In vitro binding tests indicated that the MZF-PiB were specifically bound to amyloid plaques. The smallest size of detected plaques was 27 MUm. Conclusion: PiB-modified nanoparticles targeting Abeta are biologically safe and highly superparamagnetic, possessing the capability to detect amyloid plaques early in vitro and the potential for early diagnosis of AD. PMID- 29141367 TI - [Differentiation of induced pluripotent stem cells into neural stem cells induced by brain-derived neurotrophic factor via Wnt/beta-catenin and extracellular signal-regulated kinase/mitogen-activated protein kinases signal pathway]. AB - Objective: To investigate the mechanism of brain-derived neurotrophic factor (BDNF) promoting induced pluripotent stem cells (iPSCs) to differentiate into neural stem cells (NSCs) via Wnt/beta-catenin and extracellular signal-regulated kinase/mitogen-activated protein kinases (ERK/MAPK) signal pathways. Methods: iPSCs were cultured and identified. The iPSCs were induced to differentiate into NSCs by BDNF and retinoic acid (RA). Nestin was detected by immunofluorescence and flow cytometry after iPSCs differentiated. The technique of small interfering RNA (siRNA) was used to silence the gene expression of beta-catenin and ERK, and iPSCs were divided into control group, BDNF group (adding 10 MUg/L BDNF), siRNA ERK/BDNF group (transfected with siRNA-ERK and adding 10 MUg/L BDNF) and siRNA beta-catenin/BDNF group (transfected with siRNA-beta-catenin and adding 10 MUg/L BDNF). Real-time polymerase chain reaction (RT-PCR) and Western blotting were used to detect the mRNA and protein expression of key elements of Wnt/beta catenin and ERK/MAPK signaling pathways, included beta-catenin, ERK1/2, c-fos, c jun, and c-myc. The least significant difference test was used when data were compared between groups. Results: The immunofluorescence showed that iPSCs expressed octamer-binding transcription factor-4 (Oct4), SRY-related HMG box protein-2 (Sox2) and Nanog genes. The flow cytometry showed that Nestin-positive cells were 78.7% for BDNF and 43.5% for RA, and it was only 7.8% for routine medium. Compared with those in the control group, the mRNA expression of beta catenin, ERK1/2, c-fos, c-jun, and c-myc in the BDNF group were upregulated significantly (t=2.80, 2.318, 2.255, 1.799, 1.582, 1.663, all P<0.05), and the same results were acquired with the protein expression (t=2.805, 2.318, 2.255, 1.799, 1.582, 1.663, all P<0.050). Compared with those in BDNF group, the mRNA and protein expression of ERK1/2 in siRNA-ERK/BDNF group down-regulated obviously (t=1.917, 2.042, 1.673, 1.540, all P<0.05), and the mRNA and protein expression of c-fos and c-jun were down-regulated (t=1.022, 0.907, 0.848, 0.801, all P<0.05). However, the mRNA and protein expression of beta-catenin and c-myc were not suppressed by siRNA-ERK (t=0.216, 0.185, 0.097, 0.112, all P>0.05). In siRNA beta-catenin/BDNF group, the mRNA and protein expression of beta-catenin and c myc was obviously down-regulated when compared with those in BDNF group (t=3.104, 2.774, 2.235, 1.911, all P<0.05), and expression of ERK1/2, c-fos and c-jun were down-regulated too (t=0.776-1.192, all P<0.05). Conclusion: BDNF promotes the differentiation of iPSCs by activating Wnt/beta-catenin and ERK/MAPK signal pathway, there should be cross-talk between the two signal pathways, and c-fos and c-jun may be common nuclear transcription factors. PMID- 29141368 TI - [Long-term efficacy of open reduction and internal fixation versus external fixation for unstable distal radius fractures: a meta-analysis]. AB - Objective: To make a systematic assessment of the Long-term efficacy of open reduction and internal fixation versus external fixation for unstable distal radius fractures. Methods: A computer-based online search of PubMed, ScienceDirect, EMBASE, BIOSIS, Springer and Cochrane Library were performed. The randomized and controlled trials of open reduction and internal fixation versus external fixation for unstable distal radius fractures were collected. The included trials were screened out strictly based on the criterion of inclusion and exclusion. The quality of included trials was evaluated. RevMan 5.0 was used for data analysis. Results: Sixteen studies involving 1 268 patients were included. There were 618 patients with open reduction and internal fixation and 650 with external fixation. The results of meta-analysis indicated that there were statistically significant differences with regard to the complications postoperatively (infection(I(2)=0%, RR=0.27, 95% CI 0.16-0.45, Z=4.92, P<0.000 01) and total complications(I(2)=0%, RR=0.71, 95% CI 0.59-0.85, Z=3.65, P=0.000 3) ), DASH scores(I(2)=37%, MD=-5.67, 95% CI -8.31--3.04, Z=4.22, P<0.000 1) and volar tilt(I(2)=78%, MD=2.29, 95% CI 0.33-4.24, Z=2.30, P=0.02)(P<0.05) at the end of follow-up period were noted. There were no statistically significant differences observed between two approaches with respect to the clinical outcomes (grip strength, flexion, extension, pronation, supination, radial deviation and ulnar deviation) and radiographic outcome(radial length) at the end of follow-up period(P<0.05). Conclusion: Both open reduction and internal fixation and external fixation are effective treatment for unstable distal radius fractures. Compared with external fixation, open reduction and internal fixation provides reduced complications postoperatively, lower DASH scores and better restoration of volar tilt for treatment of distal radius fractures. PMID- 29141369 TI - [Discuss the unity of opposites between precision medicine and Traditional Chinese Medicine]. PMID- 29141370 TI - [A noteworthy disease: non-alcoholic fatty pancreatic disease]. PMID- 29141371 TI - [Effect of recombinant human growth hormone therapy on metabolic parameters in patients with craniopharyngioma]. AB - Objective: To investigate the effects of recombinant human growth hormone (rhGH) on metabolic parameters in patients with craniopharyngioma surgeries. Methods: Totallys 30 patients with craniopharyngioma were included in this retrospective study. They were divided into growth hormone (GH) group and control group according to whether they received rhGH therapy or not. The following parameters, including body mass index (BMI), weight, waist circumstance, transaminase, fasting blood glucose, lipid profile and high-sensitivity C-reactive protein (hsCRP) were compared after rhGH therapy for 4-6 months. Results: In GH group, patients were 18-46 (30.0+/-8.8) years old. The duration after craniopharyngioma surgery was (12.9+/-5.4) years. Before rhGH therapy, they had got sufficient thyroid and glucocorticoid hormone replacement. After rhGH therapy, the body weight decreased from (92.3+/-20.1) to (87.6 +/-14.6) kg (P=0.190), with a reduction of BMI from (30.1+/-5.9) to (28.2+/-3.7) kg/m(2) (P=0.120). The waist circumference decreased from (104.4+/-9.4) cm to (98.8+/-10.6) cm (P=0.002). Alanine aminotransferase (ALT) decreased from (52+/-34) to (28+/-19) U/L (P=0.029), with a reduction of aspartate transaminase (AST) from (46+/-21) to (33+/-18) U/L (P=0.035) and gamma-glutamyl transpeptadase (GGT) from (59+/-42) to (29+/-15) U/L (P=0.02). hsCRP decreased from (5.3+/-4.9) to (2.3+/-2.8) mg/L (P=0.006) and triglyceride (TG) decreased from (1.8+/-0.7) to (1.5+/-0.6) mmol/L (P=0.028). Fasting blood glucose, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and free fat acid (FFA) were not significantly changed(all P>0.05). In the control group, the above mentioned parameters did not changed significantly during 4-6 months of observational period(all P>0.05). Conclusion: rhGH therapy improves metabolic parameters in patients after craniopharyngioma surgery by decreasing body weight, waist circumstance and fat deposit in liver, as well as lowering TG and hsCRP levels. PMID- 29141372 TI - [Role of adrenal vein sampling in differential diagnosis of primary aldosteronism subtypes]. AB - Objective: To investigate the role of adrenal vein sampling (AVS) in identifying the subtype of primary aldosteronism (PA). Methods: AVS was performed in 50 patients who were confirmed as PA between September 2010 and September 2016 in Nanjing Drum Tower Hospital. Clinical, biochemical and follow-up data were reviewed retrospectively. Bilaterally simultaneous catheterization without cosyntropin stimulation and contemporaneous cortisol measurement during AVS were used. Selectivity index (SI)>=1.5 suggested that the sample was from the adrenal vein.Lateralization index (LI) >=2 suggested unilateral disease.Clinical data was further compared and the AVS findings were analyzed. Results: AVS was successful performed in 41 cases of 50 patients, and the success rate was 82%. According to the results of AVS and postoperative pathology, 41 cases were divided into aldosterone-producing adenoma (APA)/unilateral adrenal hyperplasia (UAH) group (24 cases) and idiopathic hyperaldosteronism (IHA) group (17 cases). Compared with IHA group, patients with APA/UAH showed longer duration of hypertension[10.0 (5.0, 13.0) y vs 4.0 (2.0, 8.0) y, P=0.046], higher proportion of hypokalemia (95.8% vs 64.7%, P=0.009). Furthermore, patients with APA/UAH demonstrated lower plasma renin activity (P=0.089), higher plasma aldosterone concentration and aldosterone to renin ratio (ARR) (both P<0.05). The diagnostic concordance between CT and adrenal vein sampling was only 48.8%(20/41). Conclusions: The application of bilaterally simultaneous catheterization and contemporaneous cortisol measurement improves success rate and diagnostic accuracy of AVS. AVS is useful in subtype diagnosis of PA with equivocal imaging findings. PMID- 29141373 TI - [A concentration-response observation of hydromorphone combined with ropivacaine in labor analgesia]. AB - Objective: To investigate the median effective dose (ED(50)) of hydromorphone and the appropriate concentration of ropivacaine combined with hydromorphone in epidural labor analgesia. Methods: One hundred and forty nulliparous women undergoing labor selected for delivery with epidural analgesia were enrolled in our hospital from January to June 2016. The first of top 50 women received 0.12% ropivacaine plus 20 MUg/ml hydromorphone complex solution, then sequential women were used the modified sequential method to determine the ED(50) and ED(95) of hydromorphone. The other 90 women were randomly divided and receieved 0.08% ropivacaine and 15 MUg/ml hydromorphone(H1 group), 0.10% ropivacaine and 15 MUg/ml hydromorphone (H2 group), 0.12% ropivacaine and 15 MUg/ml hydromorphone (group H3) respectively for epidural labor analgesia. In the course of labor, block levels of epidural analgesia, the Bromage scores, analgesia scores and fetal heart rate-uterine concraction were monitored. In addition, onset time of anesthesia, labor time, mode of delivery, cases of increased oxytocin using, neonatal Apgar score, incidence of nausea and vomiting, itching and fetal heart reduction were recorded. Results: The ED(50) and ED(95) values of hydromorphone were 10.49 (95% CI: 8.89-11.79) and 15.15 (95% CI: 13.25-22.25) MUg/ml respectively. The onset time in group H1 was significantly longer than those in group H2 and H3((14.23+/-3.82) , ( 11.32+/-2.16), (10.83+/-2.56)min, respectively), the difference was statistically significant (t=5.854, 6.212, all P<0.05). Analgesic VAS score at 30, 60 and 90 min time points in H1 group was significantly higher than that in H2 group and H3 group (all P<0.05). VAS score at withdrawal in H1 group was significantly higher than that in group H3 ( (3.25+/-0.75) vs (0.27+/-0.12) ), the difference was statistically significant ( t=9.314, P<0.05). VAS scores at the fourth, fifth, sixth contractions after analgesia in H1 group were significantly higher than those in H2 and H3 groups (all P<0.05). The incidence of motor nerve block in group H3 was higher than that in group H1 and group H2 (26.67%, 6.66%, 3.33%, respectively), the difference was statistically significant (chi(2)=6.413, 4.320, all P<0.05). Conclusions: 0.10% ropivacaine combined with 15 MUg/ml hydromorphone has a good analgesic effect, slight motor block, high safety and worthy clinical application for labor analgesia. PMID- 29141374 TI - [Association of PD-1, TIM-3 and TREM-1 single nucleotide polymorphisms with pulmonary tuberculosis susceptibility]. AB - Objective: To investigate the association of programmed cell death 1(PD-1), T cell immunoglobulin mucin 3 (TIM-3) and triggering receptor expressed on myeloid cells-1 (TREM-1) genes polymorphisms with pulmonary tuberculosis susceptibility. Methods: In this case-control study, peripheral venous blood of 100 pulmonary tuberculosis patients (pulmonary tuberculosis group) in the Jintan People's Hospital of Changzhou and of community physical examination volunteers (health control group) was collected from Mar 2015 to Sep 2016. A total of 66 single nucleotide polymorphisms (SNP) in PD-1, TIM-3 and TREM1 sequences were selected and SNP genotype and allele frequency were analyzed using the next-generation sequencing technology. Association of these SNP with pulmonary tuberculosis susceptibility was investigated using linkage disequilibrium (LD) analysis and genetic models. Results: Among these 66 SNP, 24 SNP with Hardy-Weinberg equilibrium P (HWE-P) value <0.001 or minimum allele frequency (MAF) <0.05 were kicked out. The remaining 42 SNP were analyzed with LD analysis and genetic models. There was no significant difference in genotype frequencies between pulmonary tuberculosis group and health control group (all P>0.05). Five SNP (rs41435650, rs28539662, rs13023138, rs75565781, rs36084323) in PD-1 were identified in a significant haplotype (TACGC) between pulmonary tuberculosis group and health control group (P=0.014). Among these haplotypes, strong LD was observed between rs28539662 and rs75565781 (r(2)=0.871), as well as rs36084323 (r(2)=0.864). Rs75565781 showed highest correlation with rs36084323 (r(2)=0.966). Conclusion: These SNP in PD-1, TIM-3 and TREM-1 genes are not associated with the susceptibility of pulmonary tuberculosis. PMID- 29141375 TI - [Relationship between the severity of reflux esophagitis and the esophageal motility features on high resolution manometry]. AB - Objective: To analyze esophageal motility dysfunction in gastroesophageal reflux disease (GERD) with different severity of esophagitis, and the relationship between the esophageal motility dysfunction and the severity of esophagitis. Methods: GERD patients simultaneously undergone endoscopy and high-resolution manometry were divided into four groups: Non-esophagitis (Non-erosive gastroesophageal reflux disease, NERD) group, mild esophagitis group, moderate esophagitis group and severe esophagitis group. The gender and age were matched for each group, and every group consisted of 80 cases. Nonparametric test was used to analyze the differences in HRM parameters, such as upper esophageal sphincter (UES) pressure, lower esophageal sphincter (LES) pressure, LES length, LES-CD (crural diaphragm) separation distance, and the percentage of failed peristalsis of the four groups, and the differences between each two of the groups were also analyzed. Results: Nonparametric test showed that the LES pressure and length decreased with the severity of esophagitis, and there were statistical differences (P<0.001, P=0.030). The failed peristalsis percentage increased with the severity of esophagitis and the difference was statistically significant (P<0.001). The LES-CD separation distance was increased with the severity of esophagitis and had statistically significance (P<0.001). When comparing the differences between each two of the groups, there were significant differences (P<0.001, P=0.012, P<0.001, P<0.001) between NERD group and severe esophagitis group in the HRM parameters of the lower esophageal sphincter pressure, the LES length, the LES-CD separation distance, and the percentage of ineffective swallowing in the NERD and severe esophagitis group. The detection rate of HH was significantly increased from NERD to severe esophagitis, the detection rate of HH was 6.3% to 82.5% in gastoracopy and 16.3% to 45.0% in HRM, and the diagnostic consistency was fair (Kappa Value: 0.31). Conclusions: Hypo dynamic state of esophageal and HH are the main motility characteristics of erosive gastroesophageal reflux disease, Esophageal motility abnormalities increase in parallel with the severity of GERD from NERD to severe esophagitis, these motility disorders may also play important roles in causing esophagitis. PMID- 29141376 TI - [Clinical significance of acute gastrointestinal injury grades in inflammatory response of critically ill patients]. AB - Objective: To explore the value of acute gastrointestinal injury (AGI) grades in inflammatory response of critically ill patients. Methods: Ptients with AGI severity from I to IV were randomly selected(20 for each)from July 2014 to June 2015 in ICU of Yantai Yuhuangding Hospital. The expression of NF-kappaB were detected by immunofluorescence. The expression of TNF-alpha and IL-6 were detected by enzyme linked immunosorbent assay (ELISA). Procalcitonin (PCT) and C reactive protein (CRP) were measured. Statistical analysis was carried out. Results: For AGI grade I and AGI grade II patients, NF- kappaB p65 were located mainly in cytoplasm. For AGI grade III and AGI grade IV patients, NF-kappaB p65 were mainly located in the nucleus, indicating that inflammatory stimulation induces nuclear translocation of NF-kappaB. With the higher grade of AGI, TNF alpha and IL-6 secretion increased significantly.For AGI grade I to grade IV patients, TNF-alpha were expressed as (89.76+/-19.78)ng/L, (130.54+/-23.18)ng/L, (224.65+/-39.02)ng/L, (293.17+/-36.79)ng/L, and the difference was statistically significant (P<0.05) respectively. IL-6 were expressed as (45.96+/-9.62)ng/L, (89.26+/-12.77)ng/L, (203.71+/-58.26)ng/L, (331.18+/-64.28) ng/L, the difference was statistically significant (P<0.05). With the higher grade of AGI, PCT and CRP levels were significantly increased.For AGI grade I to grade IV patients, PCT levels were (2.65+/-1.78) MUg/L, (3.92+/-2.14) MUg/L, (9.92+/-3.89) MUg/L, (27.34+/-8.45) MUg/L, and the difference was statistically significant (P<0.05). CRP levels were (13.82+/-4.93) mg/L, (32.14+/-8.97) mg/L, (93.49+/-25.72) mg/L, (183.05+/-51.36) mg/L, and the difference between each group was statistically significant (P<0.05). Conclusions: There is a certain correlation between AGI classification and inflammatory markers in critically ill patients, which shows that gastrointestinal dysfunction may be the promoter and stimulating factor in systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). This provides a clinical basis for judging the severity of inflammatory response in critically ill patients according to AGI grades. PMID- 29141377 TI - [The clinical significance of anti- ubiquitin C-terminal hydrolase L1 autoantibodies in the diagnosis of neuropsychiatric systemic lupus erythematosus]. AB - Objective: To analyze the clinical significance of anti- ubiquitin C-terminal hydrolase L1(UCHL-1)autoantibodies in neuropsychiatric systemic lupus erythematosus (NPSLE). Methods: Autoantibodies in cerebrospinal fluid specimen of 56 inpatients were detected by using indirect enzyme-linked immunosorbent assay (ELISA) and the fullmedical history and clinical manifestations were analyzed retrospectively. Results: The levels of anti-UCHL-1 autoantibodies in NPSLE group were significant higher than that in other controls (P<0.05). The positive rate of anti-UCHL-1 autoantibodies in NPSLE group was 23.7% (9/38), which was higher than that in the control groups (0%). A significant difference of anti-UCHL-1 autoantibodies was observed in the patients with blood system involvement (P=0.012). The positive rates of anti-UCHL autoantibodies in the patients with negative SLE related autoantibodies including AnuA, anti-dsDNA, Acl, anti-nRNP, anti-rRNP and anti-Smantibody negative were 41.7%, 29.4%, 29.2%, 25.9%, 25.0%, 25.0%, respectively.The levels of anti-UCHL-1 autoantibodies had a positive correlation with 24-hours proteinuria (r=0.361, P=0.039). Conclusion: Anti-UCHL-1 autoantibodies had promising value in the diagnosis of neuropsychiatric systemic lupus erythematosus. PMID- 29141378 TI - [The expression and significance of microtubule - driven protein KIF2A in epithelial ovarian cancer]. AB - Objective: To investigate the protein and mRNA expression of KIF2A in ovarian cancer, and to investigate the migration and invasion ability changes in ovarian cancer cell line HO-8910 transfected by KIF2A-siRNA. Methods: Immunohistochemical method was used to detect the expression of KIF2A in 30 cases of ovarian cancer and 20 cases of ovarian normal tissues. The expression of KIF2A mRNA was detected by RT-PCR. The mRNA and protein expression of KIF2A in cell line HO-8910 was detected by RT-PCR and Western blot after transfected by KIF2A-siRNA in vitro. After the transfection, the cell migration and invasion ability were observed by scratch test and transwell experiments. Result: The expression of KIF2A mRNA and protein in HO-8910 was significantly lower than that in normal ovarian tissue (P<0.05). The capacities of migration and invasion of HO-8910 was suppressed notably after the knockdown of KIF2A (P<0.05). Conclusion: KIF2A gene expression was increased in ovarian cancer, and knockdown of KIF2A gene can inhibit the migration and invasion of ovarian cancer cells. It suggested that KIF2A gene may be a new target for the development of ovarian cancer. PMID- 29141379 TI - [Clinical value of tumor size in the evaluation of adrenal incidentalomas]. AB - Objective: To investigate the clinical value of tumor size in the evaluation of endocrinological and histological natures regarding adrenal incidentaloma (AI) patients. Methods: A total of 1 941 AI patients who were hospitalized in Department of Endocrinology, Chinese PLA General Hospital between January 1997 and December 2016 were retrospectively reviewed. The demographics of patients, imaging features, functional status and histological results were analyzed. Results: Of 1 941 patients, 984 (50.70%) were males, and 957 (49.30%) were females. The median age was 52 years old. Endocrine evaluation according to the mass size showed that the proportion of non-functional AI and primary aldosteronism (PA) was declined from 84.55% (558/660) to 27.95% (45/161) and from 6.82% (45/660) to 0, respectively. The highest frequency of subclinical Cushing's syndrome (SCS), PA and pheochromocytomas were observed in 2.1-4.0, <=2.0 and 4.0 6.0 cm group, respectively. Histological results showed that in>6 cm group, the frequency of malignancy were sharply increased. Multivariate logistical regression analysis indicated tumor size had a significant association with the presence of malignancy (OR=1.043, 95% CI: 1.033-1.054, P<0.001). A mass size of 4.0 cm was of great value in distinguishing malignant tumors from the benign ones, with a sensitivity of 89.19%, and a specificity of 69.91%. Conclusion: Mass size was of great value in the endocrinological evaluation, as well as distinguishing malignant tumors from the benign ones in AI patients. PMID- 29141380 TI - [The analysis of anesthetic management for renal cell carcinoma with associated inferior vena cava tumor thrombus]. AB - Objective: To explore the key points of anesthetic management for renal cell carcinoma combined with inferior vena cava (IVC) tumor thrombus. Methods: Twenty seven cases of renal cell carcinoma with inferior vena cava (IVC) tumor thrombus underwent radical nephrectomy and inferior caval venous thrombectomy were reviewed retrospectively during January 2014 to January 2017 in our hospital.Analyzed data includs demographics, classification of tumor, perioperative anesthetic management and monitoring approaches, IVC clamping time , vital signs during cardiopulmonary bypass(CPB), estimated blood loss (EBL), usage of blood products, hospitalization time and ICU time , as well as postoperative outcomes. Results: Clinical staging revealed 5 patients(18.5%) with classItumor thrombus, 11 patients(40.7%) with levelIItumor thrombus, 6 patients (22.2%) with level III tumor thrombus and 5 patients (18.5%) with level IV tumor thrombus. All patients had underwent a balanced general anesthesia technique with volatile agents, opioids and muscle relaxants. In addition to standard ASA monitors, all patients had direct arterial pressure and central venous pressure monitoring, and blood warming and infusing system. TEE was utilized in 9(33.3%)patients and in which contains all 5 patients(100%)with level IV tumor thrombus. Intraoperative TEE guidance resulted in a significant surgical plan modification in 1 patient(11.1%). Compared to patients with class I(313 (136, 346) min), classII(302(245, 393)min)and classIIIthrombus tumor(391(272, 505)min), patients with Class IV had longer operating time (525(481, 647)min, P<0.05). Compared to patients with Class I(600(500, 850)ml), Class II(1 700(750, 3 000)ml), and Class III(1 775(1 500, 3 000)ml), patients with Class IV had more blood loss(4 000(2 000, 7 000)ml, P<0.05). The clamping time of Class I, Class II and Class III was 8(8, 9)min, 20(13, 26)min and 10(6, 25)min, respectively, and there is no significant difference (P>0.05) within theses group. The probability of pumping norepinephrine of Class I(8(8, 9)min), Class II(20(13, 26)min), and Class III(10(6, 25)min)had no significant difference (chi(2)=5.147, P>0.05). Perioperative mortality was 7.4%. Conclusions: The anesthetic management of Inferior vena cava (IVC) tumor thrombus is rather challenging.The preoperative evaluation with accurate classification of the tumor and the intraoperative intense monitoring of vital signs with appropriate reaction are the key points of anesthetic management for this kind of surgery. PMID- 29141381 TI - [Inflammatory myofibroblastic tumor of the hepatobiliary pancreatic system: report of three cases and literature review]. AB - Objective: To improve the understanding, diagnosis and treatment of inflammatory myofibroblastic tumor (IMT) of the hepatobiliary pancreatic system through the cases review. Methods: The clinical data of three cases of pathologically-proved IMT of the hepatobiliary pancreatic system was reported and relevant literatures were reviewed. Results: Among three cases of IMT discussed, there consisted of a case of liver, a case of gallbladder and a case of pancreas. The clinical manifestations were nonspecific, and the preoperative diagnosis was difficult. All the patients with suspected malignant tumors underwent surgical treatment. The prognosis was good, with no recurrence. Conclusion: IMT is a benign tumor and is rare in hepatobiliary pancreatic system. The clinical manifestations are not typical and the imaging examinations are not specific. Its diagnosis depends on pathology. Surgery is an effective treatment. IMT has a tendency of recurrence, and its postoperative follow-up is of great significance. PMID- 29141382 TI - [Characterization and uncertainty evaluation of aqueous reference materials for cholesterol]. AB - Objective: Characterization and evaluation of the uncertainty of the reference materials of cholesterol in aqueous solution. Methods: The certified reference material GBW09203b was weighed accurately and dissolved into methyl cyclodextrin aqueous solution to prepare six kinds of candidate reference materials of cholesterol according to the concentration. The materials were tested for homogeneity and stability using routine methods and were evaluated the uncertainty derived from the inhomogeneity and instability. The uncertainty due to measurement was derived from the purity of the raw material, the weighing and the density measurement. The certified values and expanded uncertainties were calculated according to the ISO Guide. The expanded uncertainty of the certified value was the combination of standard uncertainty of measurement, inhomogeneity and instability. The coverage factor, k, was determined from the Student's t distribution corresponding to the calculated effective degrees of freedom and 95% level of confidence. Results: It showed that the six candidate reference materials were homogeneous and were tested to be stable for at least 1 year at 70 C and -20 C using the isochronous stability study. The relative uncertainties due to the inhomogeneity were 0.14%, 0.11%, 0.13%, 0.47%, 0.39% and 0.11%. The relative uncertainty due to the instability was 0.25% at -70 C. The uncertainties of measurement were 0.06%, 0.05%, 0.05%, 0.05%, 0.05% and 0.05%.The certified values (reference value +/- expanded uncertainty, mmol/L) were as follows: (0.651+/-0.004), (1.310 +/-0.007), (2.574+/-0.015), (5.210+/-0.055), (7.710+/ 0.072), (10.242+/-0.056) mmol/L. Conclusions: Six kinds of certified reference materials for cholesterol in aqueous solution have been prepared, which were homogeneity, stable and reliable. It showed that the uncertainty of measurement was very small compared with the uncertainty due to inhomogeneity and instability. PMID- 29141383 TI - [Critical elements of cataract prevention work in China]. AB - Surgical treatment of cataract is the emphasis of prevention of blindness in China. In the past ten years, cataract prevention work has made great strides. However, the cataract surgery rate (CSR) in one million people is still far away from the developed countries, and not enough to eliminate the blindness of cataract in our country. The CSR is related to many factors. In this article, the issue of the CSR increase is commented from four aspects, including improving the quantity and quality of cataract surgery, increasing the allocation of ophthalmic resources to primary hospitals, strengthening the cooperation between the urban and backward areas in ophthalmology, and the economic factors. It is hoped that our ophthalmic practitioners pay more attention to the prevention of blindness, and the quantity and quality of cataract surgery could be increased. (Chin J Ophthalmol, 2017, 53: 801-804). PMID- 29141384 TI - [Problems deserving attention in preventing infection in cataract surgery]. AB - Endophthalmitis is one of the most serious complications of cataract surgery. The surgeons try to reduce the incidence of endophthalmitis. In order to prevent postoperative infection, irrigation of the conjunctival sac with povidone iodine and injection of antibiotics into the anterior chamber before the end of the surgery are used. Although there are a lot of reports about the concentration, mode and duration of povidone iodine application, there is no consensus. There are many options for antibiotics, including cefuroxime, vancomycin and moxifloxacin. Side effects of using povidone iodine and antibiotics have also been reported. An aseptic surgical mask plays an important role in isolating bacteria for prevention of infection. However, whether it could completely isolate bacteria can not be determined. In this article, several issues concerning the prevention of infection after cataract surgery are discussed. We hope that there will be a multi-center and large-sample research to assist in drawing up operating specifications. (Chin J Ophthalmol, 2017, 53: 805-809). PMID- 29141385 TI - [Clinical observation of visual quality after the individual implantation of intraocular lens guided by corneal Q value]. AB - Objective: To describe the feasibility of individual IOL implantation guided by corneal Q value and observe patients postoperative visual quality under different residual spherical aberration. Methods: Prospective study. One hundred and twenty cases (171 eyes)cataract patients in our hospital were selected for the individual implantation of intraocular lens guided by corneal Q value which obtained by Oberscan before operation. Based on spherical aberration calculated by corneal Q value, choose appropriate IOL personalitily to make postoperative whole eye surface aberration +0.1 MUm (group of positive spherical aberration) or 0 MUm (group of zero spherical aberration). To observe spherical aberration, the uncorrected visual acuity, best corrected visual acuity and contrast sensitivity (including no glare and glare) 1 month and 3 months after surgery. Dates were analyzed with one-way ANOVA and LSD method for multiple comparisons between groups. Results: Spherical aberration after operation: group of positive spherical aberration: (0.111+/-0.023)MUm, group of zero spherical aberration: (0.020+/-0.019)MUm, control group: (0.299+/-0.073)MUm. At 1 months and 3 months, uncorrected visual acuity, and corrected visual acuity were not statistically different between groups (t=0.474, 1.607, P>0.05). Contrast sensitivity (including no glare and glare) 3 months after surgery display: at whole space frequency, the group of positive spherical aberration(reserved +0.1 MUm spherical aberration) contrast sensitivity is better than that of the group of zero spherical aberration(reserved 0.0 MUm spherical aberration) and the control group(F=32.885, 35.493, 19.969, 20.572,P<0.05). The group of zero spherical aberration is better than control group at space frequency of 3 and 6 c/d(F=6.506, 7.521, P<0.05). Conclusions: The individual implantation of introcular lens guided by corneal Q value is feasible. + 0.1 MUm spherical aberration after surgery can achieve the best contrast sensitivity and stereo vision, and 0 spherical aberration after surgery can improve the postoperative contrast sensitivity and stereo vision than a traditional method, but its advantage mainly embodies in the middle and lower spatial frequency. (Chin J Ophthalmol, 2017, 53: 814-820). PMID- 29141386 TI - [Clinical characteristics and surgical effect observation of congenital aniridia combined with cataract]. AB - Objective: To analyze the clinical manifestations, surgical approaches and postoperative prognosis for the cases of congenital aniridia combined with cataract. Methods: In this retrospective case series, 26 patients diagnosed with congenital aniridia combined with cataract were collected from Zhongshan Ophthalmic Center from February 2002 to August 2016. The Clinical data were collected to analyze the clinical features, surgical approaches and postoperative prognosis. T-test was used for statistical analysis. Results: Twenty-six bilateral congenital aniridia patients were included in the case series, with 50% male cases. The average age for the first visit was (8.72+/-8.06) years old. Hereditary patients constitutes 30.8% (8/26) of the total number. The proportions for bilateral and unilateral cataracts were 88.5% (23/26) and 11.5% (3/26) respectively, and 49 eyes suffering from both congenital aniridia and cataract were therefore included in the final analysis. The most common morphology cataract subtypes were lamellar cataract (24.5%, 12/49), posterior subcapsular cataract (22.4%, 11/49), and total cataract (18.4%,9/49). The observed ocular comorbidities included nystagmus (36.7%, 18/49), vitreous opacity (28.6%, 14/49), foveal hypoplasia (20.4%, 10/49), ametropia (12.2%, 6/49), exotropia (12.2%, 6/49), congenital glaucoma (12.2%, 6/49), esotropia (4.1%, 2/49), congenital ptosis (4.1%, 2/49), lens ectopia (4.1%, 2/49), scleral staphyloma (2.0%, 1/49) and pigmentary degeneration of retina (2.0%, 1/49). 30.6% (15/49) eyes were performed the cataract extraction surgery. The percentage of postoperative best corrected visual acuity (BCVA) for >=0.1 and >=0.3 were 93.3% (14/15) and 20.0% (3/15) respectively. Evaluated ocular pressure (33.3%, 5/15), severe posterior capsular opacification (PCO) (13.3%, 2/15) and choroidal hemorrhage combined with choroidal detachment (6.7%, 1/15) were detected as the postoperative complications. Followed by cataract extraction, 80.0% (12/15) eyes were sequentially performed the intraocular lens implantation, while, 20.0% (3/12) eyes remained aphakia due to ocular comorbidities. Conclusions: Congenital aniridia combined with cataract are rare diseases, calling for the precious retrospective researches. This disorder tended to affect both eyes and occurred hereditary. The clinical courses of the cases presented progressive features. Ocular comorbidities were the crucial factors to influence the surgical approaches and postoperative prognosis. (Chin J Ophthalmol, 2017, 53: 821-827). PMID- 29141387 TI - [Anterior corneal high-order aberrations in eyes with senile cataract in a Chinese population]. AB - Objective: To investigate the distribution of anterior corneal high-order aberrations (HOAs) in Chinese eyes with cataract and their correlations with age and axial length for the choice of aspheric intraocular lens. Methods: Retrospective study. Six hundred twenty-five Chinese patients with cataract[male: 260, female: 365, age: (71.2+/-8.0) years] were categorized into 4 groups in accordance with their axial lengths. Anterior corneal HOAs in the central 6- mm zone was measured with an iTrace wavefront analyzer. The correlations between axial length, age and total HOAs, spherical aberration, trefoil aberration, and coma aberration were analyzed using Spearman analysis. The differences in total HOAs, spherical aberration, trefoil aberration, and coma aberration among 4 groups were assessed using the Krusal-Wallis H test. Results: Anterior corneal HOAs showed the nonnormal distribution. The median of corneal total HOAs was 0.666 MUm (range 0.246 to 4.115 MUm). Medians of coma aberration, spherical aberration and trefoil aberration were 0.313 MUm (range 0.015 to 1.879 MUm), 0.275 MUm (range 0.005 to 1.797 MUm) and 0.341 MUm (range 0.019 to 2.319 MUm), respectively. A significant negative correlation was found between axial length and total HOAs, coma aberration, spherical aberration, trefoil aberration (r= 0.230, -0.235, -0.143, -0.153, P<0.05). But no correlation was found between age and them (r=0.056, 0.045, 0.065, 0.022, P>0.05). Differences in total HOAs, coma aberration, spherical aberration, trefoil aberration were found among various axial groups (H=21.953, 20.665, 15.368, 16.881, P<0.05). Conclusions: Anterior corneal HOAs varied greatly among the majority of the patients. A significant negative correlation was found between axial length and anterior corneal HOAs, but no correlation was found between age and them. (Chin J Ophthalmol, 2017, 53: 828-834). PMID- 29141388 TI - [Effects of SMP-30 overexpression on apoptosis of human lens epithelial cells induced by ultraviolet B irradiation]. AB - Objective: This study was to observe the effect of SMP-30 on ultraviolet B (UVB) induced apoptosis of human lens epithelial cells(HLE-B3) in vitro. Methods: Experimental study. The SMP-30 cDNA was amplified by PCR and inserted into the pRFP-N1 expressing vector which had been double digested by XhoI/HindIII. HLE-B3 cells were cultured and divided into three groups: normal group, pRFP-N1 vector plasmid group and pRFP-N1-SMP-30 plasmid group (SMP-30). Then cells were exposed to UVB and the survival rate of cells was detected by MTT assay. The effects of SMP-30 on UVB-induced HLE-B3 apoptosis were measured by the Cell Death Detection ELISA kit. Meanwhile, the influence of SMP-30 on UVB-induced apoptosis-relative protein expression in HLE-B3 cells was tested by Western blots. Moreover, 2', 7' Dichlorofluorescin diacetate staining was performed to monitor the protective effects of SMP-30 on UVB-induced HLE-B3 reactive oxygen species(ROS). One-way analysis of variance combined with Dunnett's statistical method were performed to analyze the data. Results: The full length of PSF cDNA fragment was correctly inserted into the pRFP-N1 vector, which was confirmed by DNA sequencing. The SMP 30 fragment was inserted to the plasmid pRFP-N1 correctly, which was also confirmed by DNA sequencing. The PRFP-N1-SMP-30 plasmid was transfected into HLE B3 successfully. SMP-30 expression was up-regulated in the transfection group, compared with the control group. Data showed that the survival rate of HLE-B3 after the pRFP-N1-SMP-30 plasmid transfection was 0.90+/-0.14, while the apoptosis rate was 0.43+/-0.06 and the ROS production was 0.52+/-0.02, showing significant difference in comparison with the vector plasmid group and the normal group(t=5.830, 9.934, 12.19, P<0.05). In the meantime, SMP-30 overexpression down regulated the levels of Bax and cleav-caspase-3, but up-regulated the Bcl-2 and Pro-caspase-3 expression levels under UVB irradiation. Conclusion: SMP-30 overexpression plays a protective role in UVB-induced apoptosis via regulating the expression of apoptosis-related proteins and inhibiting the production of ROS in HLE-B3 cells. (Chin J Ophthalmol, 2017, 53: 835-841). PMID- 29141389 TI - [Ultrasonic diagnosis of retinal detachment in eyes with silicone oil tamponade]. AB - Objective: To examine the features and values of ultrasonic diagnosis for retinal detachment in eyes with silicone oil tamponade (SOT). Methods: A prospective study. A total of 257 eyes (257 patients) were filled with silicone oil between December 1, 2015 and August 1, 2016 in the Department of Ophthalmology at a hospital in Beijing. All of the patients underwent a color Doppler ultrasound examination in the supine and sitting positions a week prior to surgery. The pre surgery conditions were compared with the subsequent observations during the surgery to analyze the features and values of ultrasonic diagnosis for retinal detachment in eyes with SOT. Results: Ultrasound manifestations of eyes with SOT included pseudo extension of the ocular axis and an arc-shaped echo between the eye wall and silicone oil. Diagnostic accuracy was 85.6% in the supine position and 93.8% in the sitting position. Conclusion: Ultrasound diagnosis for retinal detachment in eyes with SOT manifests itself in certain patterns. Compared with the traditional ultrasound examination in the supine position, the sitting position examination can be used to further increase the diagnostic accuracy in the ultrasound diagnosis for retinal detachment in eyes with SOT, providing reliable evidence for clinical and differential diagnosis. (Chin J Ophthalmol, 2017, 53: 842-846). PMID- 29141390 TI - [The clinical analysis of corneal interface fluid syndrome after Laser lamellar corneal refractive surgery]. AB - Objective: To analysis, the clinical characteristics, refractive changes, and clinical treatment of interface fluid syndrome after laser lamellar corneal refractive surgery. Methods: During Dec. 2010 to Apr. 2016. In total 6 cases(9 eyes), 3 cases were bilateral, 3 cases were unilateral. Five patients were male and 1 was female. The age of the patients ranged from 20 to 29 years was (24.83+/ 4.02) years. Six cases(9 eyes)of IFS were diagnosed at our hospital. The history and complete ophthalmic examination that include Slit-lamp examination, Slit-lamp photography, refraction, corneal thickness measurement, corneal endothelial cell counting, IOP, anterior segment OCT(AS-OCT), exams were recorded. Results: Post lasik Primary open angle glaucoma was 2 eyes in 1 patient. 1 patient(1 eye)was Posner-Schlossmann Syndrome and 1 patient(1 eye)was iritis after femtosecond laser. Post-small incision lenticule extraction by steroid drops induced elevated IOP were 5 eyes in 3 patients. Slit-lamp exam indicated edematous corneal flap or cap, lamellar haze, interface fluids accumulation. AS-OCT showed obvious interface dark area. The corneal flap or cap thickening and wrinkles, IOP change, diopter myopic shift, Corneal thickening. Conclusions: IFS is a rare but serious complication after Laser lamellar corneal refractive surgery. The main causes are high intraocular pressure and/or dysfunction of corneal endothelium. For patients with high IOP after laser lamellar corneal refractive surgery, follow up should be observed closely. accurate diagnosis by OCT and corneal endothelial cell counting. Early diagnosis, accurate treatment, its prognosis is good. (Chin J Ophthalmol, 2017, 53: 847-854). PMID- 29141391 TI - [Research updates on glaucoma after congenital cataract surgery]. AB - Postoperative glaucoma is one of the most common complications after congenital cataract surgery and an important cause of unsatisfactory long-term visual acuity rehabilitation. Recently, the diagnostic criteria of glaucoma after congenital cataract surgery have been gradually complemented; the measurement of intraocular pressure is improved and the follow-up is standardized. The risk factors of glaucoma after congenital cataract surgery include age at surgery, ocular abnormalities and central corneal thickness, some of which still remain controversial. The main treatment of postoperative glaucoma is surgery, while some patients need adjuvant medications in addition to surgery. (Chin J Ophthalmol, 2017, 53: 863-867). PMID- 29141392 TI - [The progress of studies on aqueous humor dynamics abnormality induced by trabecular meshwork and Schlemm canal endothelial cell senescence and its relation with glaucoma]. AB - Glaucoma is the second leading cause of blindness in the world next to cataract. Aging is a strong risk factor leading to elevated intraocular pressure (IOP). IOP is associated with aqueous humor circulation. Trabecular meshwork cells and Schlemm canal endothelial cells, which form the conventional outflow pathway, play an important role in maintaining the IOP. Cell senescence induces abnormalities of the aqueous humor dynamics, leading to elevated IOP. Trabecular meshwork cells cause increased intrinsic stiffness, autophagy dysfunction, abnormal expression of microRNA and mitochondrial dysfunction with senescence. The senescence of Schlemm canal endothelial cells decreases cell permeability and mechanotransduction and disrupts the endothelial nitric oxide synthase signaling pathway. The changes will increase aqueous humor outflow resistance and elevate IOP. This review discusses how cell senescence induces aqueous humor dynamics abnormalities and the relation with glaucoma. (Chin J Ophthalmol, 2017, 53: 868 873). PMID- 29141393 TI - [The role of myelin oligodendrocyte glycoprotein antibodies for detection of demyelinating optic neuritis]. AB - The incidence of neuromyelitis optica spectrum disorders (NMOSD) in the Asian population is much higher than in Europe and North America. Optic neuritis is the first sign of NMOSD for some people. Identification of aquaporin 4 antibody is a milestone in the research of NMOSD and has been included in the diagnosis standard of NMOSD, but about 20% to 30% of NMOSD patients is aquaporin 4 antibody negative. With the cell-based assays, oligodendrocyte glycoprotein antibodies in demyelinating diseases of the central nervous system have aroused the attention of researchers. This article reviews the research history of oligodendrocyte glycoprotein antibodies in optic neuritis. (Chin J Ophthalmol, 2017, 53: 874 877). PMID- 29141394 TI - Proximal Resection Margins: More Prognostic than Distal Resection Margins in Patients Undergoing Hilar Cholangiocarcinoma Resection. AB - PURPOSE: Even though the therapeutic gold standard of hilar cholangiocarcinoma (HCCA) resection is cancer-free resection margin (RM), surgical treatment still remains challenging. This study evaluated the prognostic significance of RM status in resected HCCA patients and identified survival prognostic factors. Materials and Methods: We reviewed records of 96 HCCA patients who underwent surgery from 2001 to 2012 and analyzed the RM status and prognostic factors that affecting survival. RESULTS: Negative RM (n=31, 33%) was significantly associated with better survival vs. positive RM (n=65, 67%) (mean survival time [MST], 33 months vs. 21 months; p=0.011). Margins with histological findings of non dysplastic epithelium, low-grade dysplasia, and carcinoma in situ were not associated with survival differences (MST, 33 months vs. 33 months vs. 30 months; p=0.452), whereas positive margins were associated with poorer survival relative to carcinoma in situ (MST, 30 months vs. 21 months; p=0.050). Among patients with R0 resection, narrow (<= 5 mm) and wide (> 5 mm) margins were not associated with survival differences (MST, 33 months vs. 30 months; p=0.234). Although positive proximal RM was associated with poorer survival compared to negative RM (MST, 19 vs. 33; p=0.002), no survival difference was observed between positive and negative distal RMs (MST, 30 vs. 33; p=0.628). Proximal RM positivity (hazard ratio [HR], 2.688; p=0.007) and nodal involvement (HR, 3.293; p < 0.001) were independent survival prognostic factors. CONCLUSION: A clear RM, especially proximal RM status, was significant prognosticator, and proximal bile duct resection to the greatest technically feasible extent may be necessary, with careful consideration of the potential morbidity and oncologic outcomes after resection. However, an aggressive approach to obtain a negative distal RM might be controversial and should be considered carefully, depending on the patient's status. PMID- 29141395 TI - Beliefs and Intentions to Undergo Lung Cancer Screening among Korean Males. AB - PURPOSE: Low-dose computed tomography (LDCT) has been reported as an effective screening method for lung cancer in high-risk populations. We aimed to examine willingness to be screened among Korean males using LDCT and to determine factors associated with lung cancer screening intentions (LCS) based on the Health Belief Model (HBM). Materials and Methods: Data were obtained from the 2015 Korean National Cancer Screening Survey, a cross-sectional survey that utilized nationally representative random sampling. The survey included 1,730 male participants 40-74-year-old. Respondents were questioned regarding their willingness to undergo LCS and components of HBM. Factors associated with intentions to undergo screening were explored using logistic regression. RESULTS: Among participants, 65.2% were current smokers. Among high-risk subjects, 60.6% of men reported intentions to undergo LCS, compared to 49.9% of average-risk males. Men with higher perceived susceptibility in the average- and high-risk groups were, respectively, 1.63 (95% confidence interval [CI], 1.39 to 1.91) and 2.30 (95% CI, 1.14 to 4.63) times more likely to intend to undergo LCS compared to those with lower perceived barriers. Also, men in the average- and high-risk groups with higher perceived barriers to screening were, respectively, 0.79 (95% CI, 0.68 to 0.91) and 0.52 (95% CI, 0.29 to 0.92) times less likely to intend to undergo LCS compared to those with lower perceived barriers. CONCLUSION: Tailored interventions designed to promote accurate perceptions of susceptibility and risk, as well as to reduce perceived barriers to screening, may effectively increase adherence to recommendations for LCS among high-risk Korean men. PMID- 29141396 TI - Proposal of a Pretreatment Nomogram for Predicting Local Recurrence after Intensity-Modulated Radiation Therapy in T4 Nasopharyngeal Carcinoma: A Retrospective Review of 415 Chinese Patients. AB - PURPOSE: Local relapse-free survival (LRFS) differs widely among patients with T4 category nasopharyngeal carcinoma (NPC). We aimed to build a nomogram incorporating clinicopathological information to predict LRFS in T4 NPC after definitive intensity-modulated radiation therapy (IMRT). Materials and Methods: Retrospective study of 415 Chinese patients with non-metastatic T4 NPC treated with definitive IMRT with or without chemotherapy at our cancer center between October 2009 and September 2013. The nomogram for LRFS at 3 and 5 years was generated based on multivariate Cox proportional hazards regression, and validated using bootstrap resampling, assessing discriminative performance using the concordance index (C-index) and determining calibration ability via calibration curves. RESULTS: Five-year LRFS was 88.8%. We identified and incorporated four independent prognostic factors for LRFS: ethmoid sinus invasion, primary gross tumor volume, age, and pretreatment body mass index. The C-index of the nomogram for local recurrence was 0.732 (95% confidence interval, 0.726 to 0.738), indicating excellent predictive accuracy. The calibration curve revealed excellent agreement between nomogram-predicted and observed LRFS probabilities. Risk subgroups based on total point score cutoff values enabled effective discrimination of LRFS. CONCLUSION: This pretreatment nomogram enables clinicians to accurately predict LRFS in T4 NPC after definitive IMRT, and could help to facilitate personalized patient counselling and treatment strategies. PMID- 29141397 TI - Supporting Low-income Cancer Patients: Recommendations for the Public Financial Aid Program in the Republic of Korea. AB - PURPOSE: As the recent term of "financial toxicity" implies, cancer causes a treatment-related financial harm. Financial Aid Program for Cancer Patient (FAPCP) is a government's financial support for low-income patients in the Republic of Korea. This study aimed to describe FAPCP applicants' condition and to investigate factors influencing financial burden, which would provide the basis for implementing a strategy for FAPCP administration. Materials and Methods: The telephone survey results from 2,700 FAPCP participants were analyzed, including demographic, socioeconomic, and disease characteristics and experiences associated with financial burden and the actions or measures to cope with them. RESULTS: Overall, 87.6% experienced financial burden more than moderate degree, 39.2% got financial help/a loan, 17.8% disposed of their property, and 10.2% changed or stopped treatment owing to medical costs. Monthly household income was connected to financial burden, and the highest income group was associated with the lowest financial burden (odds ratio [OR], 0.21; 95% confidence interval [CI], 0.11 to 0.38) and the lowest rate of changing/stopping care (OR, 0.23; 95% CI, 0.05 to 1.00). Parents of childhood cancer patients got financial help/a loan (OR, 2.24; 95% CI, 1.03 to 4.88) and disposed of their property (OR, 3.18; 95% CI, 1.40 to 7.22) more frequently, and Medical Aids applicants showed the highest rate of changing/stopping care (OR, 3.01; 95% CI, 1.89 to 4.78). CONCLUSION: FAPCP targets low income groups; however, financial burden and the consequent actions taken still exist disproportionately, depending on the income of the applicants. FAPCP should focus on more vulnerable groups including Medical Aid applicants and parents of childhood cancer patients, by increasing funds and expanding their support coverage. PMID- 29141398 TI - The Prognostic Significance of Notch1 and Fatty Acid Binding Protein 7 (FABP7) Expression in Resected Tracheobronchial Adenoid Cystic Carcinoma: A Multicenter Retrospective Study. AB - PURPOSE: Adenoid cystic carcinoma (ACC) of the trachea and bronchus is a rare tumor. Although MYB-NFIB oncogene fusion and Notch1 mutation have been identified in ACC, little is known about the expression and clinical significance of Notch1 and its target gene fatty acid binding protein 7 (FABP7) in tracheobronchial ACC. Materials and Methods: Primary tracheobronchial ACC that were resected between 1998 and 2014 were identified through the pathology and oncology database from five thoracic oncology centers in China. A tissue array was constructed from the patients' samples and the expressions of Notch1 and FABP7 were evaluated by immunohistochemistry. The association between the expression of both markers and survival was determined. RESULTS: Overexpression of Notch1 and FABP7, detected in 37.8% and 38.3% of 368 patients with tracheobronchial ACC, respectively, was an independent prognostic indicator for recurrencefree survival (RFS) by multivariable Cox proportional hazard model (p=0.032 and p=0.048, respectively). Overexpression of Notch1, but not of FABP7, predicted overall survival (OS) (p=0.018). When categorized into four groups according to coexpression of Notch1 and FABP7, patients with overexpression of both Notch1 and FABP7 belonged to the group with the shortest RFS and OS (p=0.01 and p=0.048, respectively). CONCLUSION: Expression of Notch1 and FABP7, and coexpression of Notch1 and FABP7, is strongly associated with poor survival in resected tracheobronchial ACC. These data are consistent with the hypothesis that poor differentiation of tracheobronchial ACC correlates with the activation of Notch signaling. PMID- 29141399 TI - Factors affecting cognitive function according to gender in community-dwelling elderly individuals. AB - OBJECTIVES: This study aimed to identify the factors affecting the cognitive function of elderly people in a community by gender. METHODS: We obtained 4,878 secondary data of people aged >=65 years in 2016 at a dementia prevention center in Gyeyang-gu, Incheon. Data were obtained through Mini-Mental Status Examination optimized for screening dementia and a questionnaire. The data were statistically analyzed using analysis of variance, analysis of covariance, and hierarchical regression. RESULTS: There were significant differences in cognitive function according to gender, and the differences were significant even when age was controlled, but gender differences disappeared when education was controlled. Age, education, social activities, number of comorbid diseases, and alcohol drinking affected cognitive function through interaction with gender, but interaction with gender disappeared when education was controlled. Regression analysis showed that depression, cohabitant, social activities etc., had a significant impact on both men and women under controlled education and age. In men, the effect of social activities was greater than that of women, and hyperlipidemia had the effect only in women. CONCLUSIONS: The differences in gender-related cognitive functions were due to differences in gender education period. The period of education is considered to have a great influence on cognitive function in relation to the economic level, occupation, and social activity. PMID- 29141400 TI - Antifungal treatment with echinocandins: a 10-year clinical experience. AB - OBJECTIVE: The number of studies evaluating the use of echinocandins, whether or not its indication meets international guidelines, in clinical practice is limited. The objective of the present study was to determine the use of echinocandins in a tertiary Spanish hospital in 10 years of clinical practice, and to evaluate its impact on prognosis. METHODS: This retrospective study involved adult nonneutropenic ill patients with suspicion of fungal invasion who started treatment with echinocandins between 2006 and 2015. RESULTS: The number of patients treated with echinocandins was 153, and candidemia was detected thereafter in 25.5%. Factors associated with in-hospital mortality in patients receiving echinocandins were: sex male, septic shock, Charlson comorbidity index, and total stay at the hospital. In-hospital mortality after 7, 30 and 90 days was 13.7%, 24.8%, and 56.8%, respectively. From patients receiving echinocandins, 98 did no show multifocal colonization, 50 had Candida score <2.5, and 49 did not meet Ostrosky-Zeichner prediction rule. A total of 19 patients did not show any of these 3 potential risk factors for candidemia. CONCLUSIONS: The use of echinocandins in 10 years of clinical practice in our tertiary hospital has been performed according to international guidelines; however, candidemia was only diagnosed thereafter in only 25.5% of cases. Furthermore, according to our results, the adequate use of echinocandins seems not to be associated with reduced mortality rates. Further studies, involving a large cohort of patients and more hospitals, are required to corroborate these results. PMID- 29141401 TI - [Simulation of an outbreak of Acinetobacter baumannii in hospitals]. AB - OBJECTIVE: Acinetobacter baumannii infections have increased over time becoming a significant issue. Consequently, those applications that allow to predict the evolution of an outbreak and the relevance of the different control methods, are very important. The design of mathematical models plays a central role in this topic. METHODS: Development of a deterministic mathematical model based on ordinary differential equations whose variables and parameters are defined upon the basis of knowledge of the epidemiology and characteristics of A. baumannii. This model is analyzed from a qualitative point of view and, also, its computational implementation is derived. RESULTS: Several simulations were obtained developed from different initial conditions. The qualitative analysis of these simulations provides formal evidence of most effective control measures. CONCLUSIONS: The implementation of the computational model is an extremely useful tool in terms of managing A. baumannii outbreaks. There is mathematical proof of the fact that the observance of efficient hygiene and screening rules reduces the number of infected patients. PMID- 29141402 TI - [Epidemiology of the carbapenemase-producing Enterobacteriaceae spread in a community acute hospital and a non-acute rehabilitation hospital in Madrid]. AB - OBJECTIVE: In Spain, the overall prevalence of carbapenem-resistant Enterobacteriaceae (CRE) is increasing. We describe the epidemiological, clinical and microbiological characteristics features of patients with colonization or infection due to CRE in two hospitals in the north-west of Madrid during two years. One hospital was a community acute hospital and the second one was a non acute rehabilitation hospital. METHODS: A total of 197 CPE isolates were detected during 2013-2014. Microbiological, epidemiological and clinical data were collected, since the first isolate was found in March 2013. RESULTS: A 33.5% of patients with CRE had symptomatic infection and the remaining 66.5% were colonizations. Klebsiella pneumoniae (87.8%) was the most prevalent species and OXA-48 the most frequent carbapenemase (91.9%). We found intra-interhospital spread and some differences in the epidemiology of CRE depending on the hospital, such as more genetic variability in the non-acute rehabilitation hospital. CONCLUSIONS: Studying the CRE transmission we founded an increased incidence in a short period of time and a rapid dissemination of strains between both hospitals. This highlights the need to standardize screening measures for potential carriers and infection control programs in our hospitals. PMID- 29141403 TI - Lipogels for Encapsulation of Hydrophilic Proteins and Hydrophobic Small Molecules. AB - Lipid-polymer hybrid materials have the potential to exhibit enhanced stability and loading capabilities in comparison to parent liposome or polymer materials. However, complexities lie in formulating and characterizing such complex nanomaterials. Here we describe a lipid-coated polymer gel (lipogel) formulated using a single-pot methodology, where self-assembling liposomes template a UV curable polymer gel core. Using fluorescently labeled lipids, protein, and hydrophobic molecules, we characterized their formation, purification, stability, and encapsulation efficiency via common instrumentation methods such as dynamic light scattering (DLS), matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS), UV-vis spectroscopy, fluorescence spectroscopy, and single-particle total internal reflection fluorescence (TIRF) microscopy. In addition, we confirmed that these dual-guest-loaded lipogels are stable in solution for several months. The simplicity of this complete aqueous formation and noncovalent dual-guest encapsulation holds potential as a tunable nanomaterial scaffold. PMID- 29141404 TI - Photoinduced Inverse Spin Hall Effect of Surface States in the Topological Insulator Bi2Se3. AB - The three-dimensional (3D) topological insulator (TI) Bi2Se3 exhibits topologically protected, linearly dispersing Dirac surface states (SSs). To access the intriguing properties of these SSs, it is important to distinguish them from the coexisting two-dimensional electron gas (2DEG) on the surface. Here, we use circularly polarized light to induce the inverse spin Hall effect in a Bi2Se3 thin film at different temperatures (i.e., from 77 to 300 K). It is demonstrated that the photoinduced inverse spin Hall effect (PISHE) of the top SSs and the 2DEG can be separated based on their opposite signs. The temperature and power dependence of the PISHE also confirms our method. Furthermore, it is found that the PISHE in the 2DEG is dominated by the extrinsic mechanism, as revealed by the temperature dependence of the PISHE. PMID- 29141405 TI - Injectable Thermosensitive Polypeptide-Based CDDP-Complexed Hydrogel for Improving Localized Antitumor Efficacy. AB - In this study, a type of novel thermosensitive polypeptide-based hydrogel with tunable gelation behavior through changing the content of carboxyl groups was developed for the purpose of improving the cisplatin (CDDP) release behavior and enhancing the localized antitumor efficiency. The introduction of carboxyl groups in methoxy-poly(ethylene glycol)-b-(poly(gamma-ethyl-l-glutamate-co-l-glutamic acid) (mPEG-b-P(ELG-co-LG)) not only led to adjustable mechanical properties of the hydrogel but also significantly reduced the burst release of the drug through the complexation between the carboxyl groups of polypeptide and CDDP. Furthermore, both the good biocompatibility and the biodegradable properties of mPEG-b-P(ELG-co-LG) hydrogel were observed in vivo. Interestingly, the CDDP complexed mPEG-b-P(ELG-co-LG) hydrogel exhibited significantly enhanced antitumor efficacy in vivo compared to the mPEG-b-PELG hydrogel loaded with CDDP without complexation, although a lower cytotoxicity and IC50 of the CDDP-complexed hydrogel was observed in vitro. Overall, the new type of injectable CDDP complexed hydrogel may serve as an efficient platform for sustained CDDP delivery in localized tumor therapy. PMID- 29141406 TI - Rutinosylated Ferulic Acid Attenuates Food Allergic Response and Colitis by Upregulating Regulatory T Cells in Mouse Models. AB - The purpose of this study was to screen phytochemicals capable of inducing immune tolerance via enhanced transforming growth factor-beta1 (TGF-beta1) secretion and investigate their effects in a mouse model of food allergy and colitis. In a screening test using THP-1-derived dendritic cells, a significant increase in TGF beta1 levels was observed upon treatment with ferulic acid and its glycosides, among which ferulic acid rutinoside (FAR) induced the highest level of TGF-beta1 secretion. Oral administration of FAR suppressed serum levels of immunoglobulin E and histamine in ovalbumin-sensitized mice and triggered the differentiation of regulatory T (Treg) cells. In comparison to the control, FAR treatment also induced stronger TGF-beta1 secretion from splenic dendritic cells. FAR treatment attenuated dextran-sulfate-sodium-induced colitis in the model mice and induced Treg differentiation. These results suggest that FAR exerts potent immunomodulatory effects against allergic and intestinal inflammatory responses by inducing Treg differentiation. PMID- 29141407 TI - Partial Solar Radiation Exclusion with Color Shade Nets Reduces the Degradation of Organic Acids and Flavonoids of Grape Berry (Vitis vinifera L.). AB - The incidence of solar radiation on red-skinned grapes can promote the synthesis of flavonoids desirable for wine production, but elevated temperature may impair their accumulation. We performed a shade cloth trial covering the fruit zone (from pepper-corn size to maturity) with four polyethylene 1 m curtains with different optical properties (20% shading factor Pearl colored and 40% shading factor Aluminet, Blue, and Black colored) and a Control with no cover. Cluster temperature was 3.7 degrees C lower on the Southwest side in Black-40% clusters during the warmest part of the day compared to Control. Results indicated a lower berry weight under the Aluminet-40%. Berries under the nets often had significantly lower pH and higher TA than Control, but only the Black-40% were significant at harvest. Black-40% had higher values of anthocyanins than Control toward the last weeks of development. Berry skin flavonol and anthocyanin composition and concentration were measured by C18 reversed-phased HPLC; and proanthocyanidin isolates were characterized by acid catalysis in the presence of excess phloroglucinol followed by reversed-phase HPLC. Proanthocyanidins and flavonol contents were lower in Black-40% before veraison and the first part of ripening, respectively. However, their contents in Control decreased toward the end of ripening to a point where any net was different from Control. Anthocyanin and flavonol profiles were richer in 3', 4', 5' hydroxylated forms. Proanthocyanidin chain length was not affected while small changes were observed in the proportion of terminal catechin/epicatechin and in seed galloylation in response to treatments. Results show that shade cloths may efficiently palliate temperature spikes, especially the last weeks before harvest, while transmitting enough radiation into the fruit zone to achieve a better grape composition compared to uncovered grapes. PMID- 29141408 TI - Accurate Quantification of Nucleic Acids Using Hypochromicity Measurements in Conjunction with UV Spectrophotometry. AB - UV absorbance spectrophotometry is widely used for the quantification of nucleic acids. For accurate quantification, it is important to determine the hypochromicity of the oligonucleotide or complex nucleic acid structure. The use of thermal denaturation studies in conjunction with UV spectrophotometry to determine hypochromicity requires prolonged, elevated temperatures, which may cause partial hydrolysis of RNA. In addition, dsRNA is difficult to denature even at elevated temperature, and the extinction coefficients of nucleic acids are also affected by temperature, which makes it difficult to accurately determine the nucleic acid concentration. To overcome these caveats, we have utilized the chemical denaturant dimethyl sulfoxide which, in conjunction with a short thermal denaturation, prevents renaturation of the duplex nucleic acids (dsDNA/RNA). Using this approach, we have measured the absorbance of both the unstructured and structured nucleic acids to accurately measure their hypochromicity and determine their extinction coefficients. For a range of different dsRNA, we have for the first time determined values of 46.18-47.29 MUg/mL/A260 for the quantification of dsRNA using UV spectrophotometry. Moreover, this approach enables the accurate determination of the relative proportion of duplex nucleic acids in mixed ds/ss nucleic acid solutions, demonstrating significant advantages over current methods. PMID- 29141409 TI - A Versatile Probe for Caffeine Detection in Real-Life Samples via Excitation Triggered Alteration in the Sensing Behavior of Fluorescent Organic Nanoaggregates. AB - Excitation triggered alteration in the sensing behavior of fluorescent nanoaggregates was explored in water, considering caffeine as the "target analyte". Merely by changing the excitation wavelength, we could specifically excite either the monomeric species or the fluorescent nanoaggregates. The monomer showed highly sensitive interaction with caffeine despite poor selectivity, while the "strongly associated" fluorescent nanoaggregates displayed relatively high selectivity with low sensitivity. In addition, the extent of self aggregation was also found to be influenced by the micropolarity of the local surroundings and the electronics of the core carbazole unit. Furthermore, the present protocol was utilized for the estimation of caffeine in different beverages and biological fluids with reasonably high accuracy. Inexpensive, portable paper strips were designed for a rapid, on-site detection of caffeine without involving sophisticated instruments or trained technicians. PMID- 29141410 TI - Spotlights: Volume 8, Issue 22. PMID- 29141411 TI - In the Limelight: Perspective Collections on Perovskites. PMID- 29141412 TI - Formation of supramolecular protein structures on gold surfaces. AB - Recent research has highlighted the exciting possibilities enabled by the use of protein structures as nanocomponents to form functional nanodevices. To this end, control over protein-protein and protein-surface interactions is essential. In this study, the authors probe the interaction of human peroxiredoxin 3 with gold surfaces, a protein that has been previously identified as having potential use in nanotechnology. Analytical ultracentrifugation and transmission electron microscopy revealed the pH mediated assembly of protein toroids into tubular structures across a small pH range. Quartz crystal microbalance with dissipation measurements showed differences in absorbed protein mass when pH is switched from pH 8.0 to 7.2, in line with the formation of supramolecular structures observed in solution studies. Scanning tunneling microscopy under ambient conditions showed that these protein tubes form on surfaces in a concentration dependent manner, with a tendency for protein adsorption and supramolecular assembly at the edges of Au(111) terraces. Finally, self-assembled monolayer modification of Au surfaces was explored as a means to control the adsorption and orientation of pH triggered protein structures. PMID- 29141413 TI - Single-reference coupled cluster theory for multi-reference problems. AB - Coupled cluster (CC) theory is widely accepted as the most accurate and generally applicable approach in quantum chemistry. CC calculations are usually performed with single Slater-determinant references, e.g., canonical Hartree-Fock (HF) wavefunctions, though any single determinant can be used. This is an attractive feature because typical CC calculations are straightforward to apply, as there is no potentially ambiguous user input required. On the other hand, there can be concern that CC approximations give unreliable results when the reference determinant provides a poor description of the system of interest, i.e., when the HF or any other single determinant ground state has a relatively low weight in the full CI expansion. However, in many cases, the reported "failures" of CC can be attributed to an unfortunate choice of reference determinant, rather than intrinsic shortcomings of CC itself. This is connected to well-known effects like spin-contamination, wavefunction instability, and symmetry-breaking. In this contribution, a particularly difficult singlet/triplet splitting problem in two phenyldinitrene molecules is investigated, where CC with singles, doubles and perturbative triples [CCSD(T)] was reported to give poor results. This is analyzed by using different reference determinants for CCSD(T), as well as performing higher level CCSDT-3 and CCSDT calculations. We show that doubly electron attached and doubly ionized equation-of-motion (DEA/DIP-EOM) approaches are powerful alternatives for treating such systems. These are operationally single-determinant methods that adequately take the multi-reference nature of these molecules into account. Our results indicate that CC remains a powerful tool for describing systems with both static correlation and dynamic correlation, when pitfalls associated with the choice of the reference determinant are avoided. PMID- 29141414 TI - Orientational cross correlations between entangled branch polymers in primitive chain network simulations. AB - Although it has not been frequently discussed, contributions of the orientational cross-correlation (OCC) between entangled polymers are not negligible in the relaxation modulus. In the present study, OCC contributions were investigated for 4- and 6-arm star-branched and H-branched polymers by means of multi-chain slip link simulations. Owing to the molecular-level description of the simulation, the segment orientation was traced separately for each molecule as well as each subchain composing the molecules. Then, the OCC was calculated between different molecules and different subchains. The results revealed that the amount of OCC between different molecules is virtually identical to that of linear polymers regardless of the branching structure. The OCC between constituent subchains of the same molecule is significantly smaller than the OCC between different molecules, although its intensity and time-dependent behavior depend on the branching structure as well as the molecular weight. These results lend support to the single-chain models given that the OCC effects are embedded into the stress-optical coefficient, which is independent of the branching structure. PMID- 29141415 TI - Contribution to viscosity from the structural relaxation via the atomic scale Green-Kubo stress correlation function. AB - We studied the connection between the structural relaxation and viscosity for a binary model of repulsive particles in the supercooled liquid regime. The used approach is based on the decomposition of the macroscopic Green-Kubo stress correlation function into the correlation functions between the atomic level stresses. Previously we used the approach to study an iron-like single component system of particles. The role of vibrational motion has been addressed through the demonstration of the relationship between viscosity and the shear waves propagating over large distances. In our previous considerations, however, we did not discuss the role of the structural relaxation. Here we suggest that the contribution to viscosity from the structural relaxation can be taken into account through the consideration of the contribution from the atomic stress auto correlation term only. This conclusion, however, does not mean that only the auto correlation term represents the contribution to viscosity from the structural relaxation. Previously the role of the structural relaxation for viscosity has been addressed through the considerations of the transitions between inherent structures and within the mode-coupling theory by other authors. In the present work, we study the structural relaxation through the considerations of the parent liquid and the atomic level stress correlations in it. The comparison with the results obtained on the inherent structures also is made. Our current results suggest, as our previous observations, that in the supercooled liquid regime, the vibrational contribution to viscosity extends over the times that are much larger than the Einstein's vibrational period and much larger than the times that it takes for the shear waves to propagate over the model systems. Besides addressing the atomic level shear stress correlations, we also studied correlations between the atomic level pressure elements. PMID- 29141416 TI - Perturbation expansions of stochastic wavefunctions for open quantum systems. AB - Based on the stochastic unravelling of the reduced density operator in the Feynman path integral formalism for an open quantum system in touch with harmonic environments, a new non-Markovian stochastic Schrodinger equation (NMSSE) has been established that allows for the systematic perturbation expansion in the system-bath coupling to arbitrary order. This NMSSE can be transformed in a facile manner into the other two NMSSEs, i.e., non-Markovian quantum state diffusion and time-dependent wavepacket diffusion method. Benchmarked by numerically exact results, we have conducted a comparative study of the proposed method in its lowest order approximation, with perturbative quantum master equations in the symmetric spin-boson model and the realistic Fenna-Matthews Olson complex. It is found that our method outperforms the second-order time convolutionless quantum master equation in the whole parameter regime and even far better than the fourth-order in the slow bath and high temperature cases. Besides, the method is applicable on an equal footing for any kind of spectral density function and is expected to be a powerful tool to explore the quantum dynamics of large-scale systems, benefiting from the wavefunction framework and the time-local appearance within a single stochastic trajectory. PMID- 29141417 TI - Simulations of Coulomb systems confined by polarizable surfaces using periodic Green functions. AB - We present an efficient approach for simulating Coulomb systems confined by planar polarizable surfaces. The method is based on the solution of the Poisson equation using periodic Green functions. It is shown that the electrostatic energy arising from the surface polarization can be decoupled from the energy due to the direct Coulomb interaction between the ions. This allows us to combine an efficient Ewald summation method, or any other fast method for summing over the replicas, with the polarization contribution calculated using Green function techniques. We apply the method to calculate density profiles of ions confined between the charged dielectric and metal surfaces. PMID- 29141418 TI - Solvent quality influences surface structure of glassy polymer thin films after evaporation. AB - Molecular dynamic simulations are used to investigate the structural effects of treating a glassy polymer thin film with solvents of varying quality and subsequently evaporating the solvent. Both a monodisperse film and a polydisperse film are studied for poor to good solvent conditions, including the limit in which the polymer film is fully dissolved. In agreement with previous studies, the dissolved polymer-solvent mixtures form a polymer-rich skin on top of the forming film during evaporation. In the case of the polydisperse films, a segregation of the lower molecular weight polymer to the film interface is observed. We provide a detailed, systematic analysis of the interface structure and properties during and after evaporation. We find that for non-dissolved films, the surface width of the film after solvent evaporation is enhanced compared to the case without solvent. Our results show that due to the kinetic arrest of the surface structure, the increased surface width is preserved after solvent evaporation for both mono- and polydisperse films. We conclude that it is important to take poor solvent effects into account for the surface morphology of already formed thin glassy films, an effect which is often neglected. PMID- 29141419 TI - Development and application of a 2-electron reduced density matrix approach to electron transport via molecular junctions. AB - Can an electronic device be constructed using only a single molecule? Since this question was first asked by Aviram and Ratner in the 1970s [Chem. Phys. Lett. 29, 277 (1974)], the field of molecular electronics has exploded with significant experimental advancements in the understanding of the charge transport properties of single molecule devices. Efforts to explain the results of these experiments and identify promising new candidate molecules for molecular devices have led to the development of numerous new theoretical methods including the current standard theoretical approach for studying single molecule charge transport, i.e., the non-equilibrium Green's function formalism (NEGF). By pairing this formalism with density functional theory (DFT), a wide variety of transport problems in molecular junctions have been successfully treated. For some systems though, the conductance and current-voltage curves predicted by common DFT functionals can be several orders of magnitude above experimental results. In addition, since density functional theory relies on approximations to the exact exchange-correlation functional, the predicted transport properties can show significant variation depending on the functional chosen. As a first step to addressing this issue, the authors have replaced density functional theory in the NEGF formalism with a 2-electron reduced density matrix (2-RDM) method, creating a new approach known as the NEGF-RDM method. 2-RDM methods provide a more accurate description of electron correlation compared to density functional theory, and they have lower computational scaling compared to wavefunction based methods of similar accuracy. Additionally, 2-RDM methods are capable of capturing static electron correlation which is untreatable by existing NEGF-DFT methods. When studying dithiol alkane chains and dithiol benzene in model junctions, the authors found that the NEGF-RDM predicts conductances and currents that are 1-2 orders of magnitude below those of B3LYP and M06 DFT functionals. This suggests that the NEGF-RDM method could be a viable alternative to NEGF-DFT for molecular junction calculations. PMID- 29141420 TI - Spectroscopic characterization of the complex of vinyl radical and carbon dioxide: Matrix isolation and ab initio study. AB - We report on the preparation and vibrational characterization of the C2H3?CO2 complex, the first example of a stable intermolecular complex involving vinyl radicals. This complex was prepared in Ar and Kr matrices using UV photolysis of propiolic acid (HC3OOH) and subsequent thermal mobilization of H atoms. This preparation procedure provides vinyl radicals formed exclusively as a complex with CO2, without the presence of either CO2 or C2H3 monomers. The absorption bands corresponding to the nu5(C2H3), nu7(C2H3), nu8(C2H3), nu2(CO2), and nu3(CO2) modes of the C2H3?CO2 complex were detected experimentally. The calculations at the UCCSD(T)/L2a level of theory predict two structures of the C2H3?CO2 complex with Cs and C1 symmetries and interaction energies of -1.92 and 5.19 kJ mol-1. The harmonic vibrational frequencies of these structures were calculated at the same level of theory. The structural assignment of the experimental species is not straightforward because of rather small complexation induced shifts and matrix-site splitting of the bands (for both complex and monomers). We conclude that the C1 structure is the most probable candidate for the experimental C2H3?CO2 complex based on the significant splitting of the bending vibration of CO2 and on the energetic and structural considerations. PMID- 29141421 TI - Accuracy of trajectory surface-hopping methods: Test for a two-dimensional model of the photodissociation of phenol. AB - Trajectory surface hopping (TSH) methods have been widely used for the study of nonadiabatic molecular dynamics. In the present work, the accuracy of two TSH algorithms, Tully's fewest switching algorithm and an algorithm based on the Landau-Zener formula, has been critically evaluated in comparison with exact nonadiabatic quantum dynamics calculations for a model of the photoinduced hydrogen-atom dissociation reaction in phenol. The model consists of three electronic states (S0, 1pipi*, 1pisigma*) and two nuclear degrees of freedom (the OH stretching coordinate and CCOH dihedral angle) and displays two successive conical intersections (1pipi*/1pisigma* and 1pisigma*/S0). Considering instantaneous photoexcitation from different vibrational levels of the S0 state to the 1pipi* state, we examined the time-dependent electronic population dynamics as well as the branching ratio of the two dissociation channels. The results of fully converged trajectory calculations are compared with the results of exact quantum wave-packet calculations. It is found that both TSH algorithms describe the dynamics at the 1pisigma*/S0 conical intersection, which is accessed with high excess energy, with good accuracy. The 1pipi*/1pisigma* conical intersection, on the other hand, is accessed with little excess energy so tunneling effects as well as wave-packet interference effects which cannot be reproduced with classical trajectory calculations become relevant. Overall, the performance of the fewest-switching and Landau-Zener surface-hopping algorithms for the photodissociation of phenol is very similar. The populations of the adiabatic S1 and S2 states are found to exhibit fast oscillations which reflect nonadiabatic electronic transitions driven by coherent dynamics in the OH stretching mode. These electronic population oscillations are qualitatively reproduced by both TSH algorithms. PMID- 29141422 TI - Coverage dependent molecular assembly of anthraquinone on Au(111). AB - A scanning tunneling microscopy study of anthraquinone (AQ) on the Au(111) surface shows that the molecules self-assemble into several structures depending on the local surface coverage. At high coverages, a close-packed saturated monolayer is observed, while at low coverages, mobile surface molecules coexist with stable chiral hexamer clusters. At intermediate coverages, a disordered 2D porous network interlinking close-packed islands is observed in contrast to the giant honeycomb networks observed for the same molecule on Cu(111). This difference verifies the predicted extreme sensitivity [J. Wyrick et al., Nano Lett. 11, 2944 (2011)] of the pore network to small changes in the surface electronic structure. Quantitative analysis of the 2D pore network reveals that the areas of the vacancy islands are distributed log-normally. Log-normal distributions are typically associated with the product of random variables (multiplicative noise), and we propose that the distribution of pore sizes for AQ on Au(111) originates from random linear rate constants for molecules to either desorb from the surface or detach from the region of a nucleated pore. PMID- 29141423 TI - Probing cluster surface morphology by cryo kinetics of N2 on cationic nickel clusters. AB - We present the stepwise N2 adsorption kinetics of size selected Nin+ (n = 5-20) clusters at 26 K as obtained by a hybrid tandem ion trap instrument. Pseudo-first order kinetic fits confirm consecutive adsorption steps without evidence of cluster isomers and up to adsorption limits, which scale with the cluster size. The reaction rates for the initial N2 adsorption increase smoothly with the cluster size and similar to hard sphere cluster modeling. The isothermal kinetics allow for the tentative elucidation of cluster surface morphologies and for their classification into highly symmetrical clusters with all smooth surfaces, small clusters with rough surfaces, and large clusters with partially rough and smooth surface areas. The parallel characterization of the vibrational spectroscopy of some cluster adsorbate complexes supports and refines the achieved conclusions and is published back to back with this contribution [S. Dillinger, J. Mohrbach, and G. Niedner-Schatteburg, J. Chem. Phys. 147, 184305 (2017)]. These two studies elucidate the adsorbate to cluster interaction, and they confirm and specify the sometimes considerable structural fluxionality of finite and curved metal surfaces in high detail. This work precedes further studies along the present lines of thought. PMID- 29141424 TI - Stationary state distribution and efficiency analysis of the Langevin equation via real or virtual dynamics. AB - Langevin dynamics has become a popular tool to simulate the Boltzmann equilibrium distribution. When the repartition of the Langevin equation involves the exact realization of the Ornstein-Uhlenbeck noise, in addition to the conventional density evolution, there exists another type of discrete evolution that may not correspond to a continuous, real dynamical counterpart. This virtual dynamics case is also able to produce the desired stationary distribution. Different types of repartition lead to different numerical schemes, of which the accuracy and efficiency are investigated through studying the harmonic oscillator potential, an analytical solvable model. By analyzing the asymptotic distribution and characteristic correlation time that are derived by either directly solving the discrete equations of motion or using the related phase space propagators, it is shown that the optimal friction coefficient resulting in the minimum characteristic correlation time depends on the time interval chosen in the numerical implementation. When the recommended "middle" scheme is employed, both analytical and numerical results demonstrate that, for good numerical performance in efficiency as well as accuracy, one may choose a friction coefficient in a wide range from around the optimal value to the high friction limit. PMID- 29141425 TI - Macromolecules with amphiphilic monomer units at interface of two immiscible liquids. AB - The adsorption of macromolecules with amphiphilic monomer units at the liquid liquid interface was studied. The amphiphilic structure of monomer units with groups selectively interacting with alpha and beta liquids was described by the A graft-B dumbbell model. The calculations were performed for the symmetrical interaction of A and B groups with liquids, different selectivity parameters xi and degree of polymerization N. The simulations indicate a three-step adsorption scenario, including non-adsorbed, weak and strong localization states. It was shown that the adsorption of (A-graft-B)N macromolecules obeys scaling laws developed to describe the adsorption of the alternating (AB)N copolymer at the liquid-liquid interface with critical selectivity parameter xic of transition into the weak localization state depending on the degree of polymerization as N 1/5; critical selectivity parameter xiinfinity of transition to the strong localization regime non-depending on the degree of polymerization; and relative change of perpendicular Rz radius of gyration varying as a power function of xiN1/5: Rz(xi)/Rz(0) ~ (xiN1/5)rho and rho = -2nu/(1 - v). Meanwhile, (A-graft B)N macromolecules have much lower xic and xiinfinity values and thus are more prospective for practical applications. PMID- 29141426 TI - The magnitude of the intrinsic rate constant: How deep can association reactions be in the diffusion limited regime? AB - Intrinsic and effective rate constants have an important role in the theory of diffusion-limited reactions. In a previous paper, we provide detailed microscopic expressions for these intrinsic rates [A. Vijaykumar, P. G. Bolhuis, and P. R. ten Wolde, Faraday Discuss. 195, 421 (2016)], which are usually considered as abstract quantities and assumed to be implicitly known. Using these microscopic expressions, we investigate how the rate of association depends on the strength and the range of the isotropic potential and the strength of the non-specific attraction in case of the anisotropic potential. In addition, we determine the location of the interface where these expressions become valid for anisotropic potentials. In particular, by investigating the particles' orientational distributions, we verify whether the interface at which these distributions become isotropic agrees with the interface predicted by the effective association rate constant. Finally, we discuss how large the intrinsic association rate can become, and what are the consequences for the existence of the diffusion limited regime. PMID- 29141427 TI - Tensor-structured coupled cluster theory. AB - We derive and implement a new way of solving coupled cluster equations with lower computational scaling. Our method is based on the decomposition of both amplitudes and two electron integrals, using a combination of tensor hypercontraction and canonical polyadic decomposition. While the original theory scales as O(N6) with respect to the number of basis functions, we demonstrate numerically that we achieve sub-millihartree difference from the original theory with O(N4) scaling. This is accomplished by solving directly for the factors that decompose the cluster operator. The proposed scheme is quite general and can be easily extended to other many-body methods. PMID- 29141428 TI - Effect of surface curvature on diffusion-limited reactions on a curved surface. AB - To investigate how the curvature of a reactive surface can affect reaction kinetics, we use a simple model in which a diffusion-limited bimolecular reaction occurs on a curved surface that is hollowed inward, flat, or extended outward while keeping the reactive area on the surface constant. By numerically solving the diffusion equation for this model using the finite element method, we find that the rate constant is a non-linear function of the surface curvature and that there is an optimal curvature providing the maximum value of the rate constant, which indicates that a spherical reactant whose entire surface is reactive (a uniformly reactive sphere) is not the most reactive species for a given reactive surface area. We discuss how this result arises from the interplay between two opposing effects: the exposedness of the reactive area to its partner reactants, which causes the rate constant to increase as the curvature increases, and the competition occurring on the reactive surface, which decreases the rate constant. This study helps us to understand the role of curvature in surface reactions and allows us to rationally design reactants that provide a high reaction rate. PMID- 29141429 TI - An efficient multi-scale Green's function reaction dynamics scheme. AB - Molecular Dynamics-Green's Function Reaction Dynamics (MD-GFRD) is a multiscale simulation method for particle dynamics or particle-based reaction-diffusion dynamics that is suited for systems involving low particle densities. Particles in a low-density region are just diffusing and not interacting. In this case, one can avoid the costly integration of microscopic equations of motion, such as molecular dynamics (MD), and instead turn to an event-based scheme in which the times to the next particle interaction and the new particle positions at that time can be sampled. At high (local) concentrations, however, e.g., when particles are interacting in a nontrivial way, particle positions must still be updated with small time steps of the microscopic dynamical equations. The efficiency of a multi-scale simulation that uses these two schemes largely depends on the coupling between them and the decisions when to switch between the two scales. Here we present an efficient scheme for multi-scale MD-GFRD simulations. It has been shown that MD-GFRD schemes are more efficient than brute force molecular dynamics simulations up to a molar concentration of 102 MUM. In this paper, we show that the choice of the propagation domains has a relevant impact on the computational performance. Domains are constructed using a local optimization of their sizes and a minimal domain size is proposed. The algorithm is shown to be more efficient than brute-force Brownian dynamics simulations up to a molar concentration of 103 MUM and is up to an order of magnitude more efficient compared with previous MD-GFRD schemes. PMID- 29141430 TI - Lithium atoms on helium nanodroplets: Rydberg series and ionization dynamics. AB - The electronic excitation spectrum of lithium atoms residing on the surface of helium nanodroplets is presented and analyzed employing a Rydberg-Ritz approach. Utilizing resonant two-photon ionization spectroscopy, two different Rydberg series have been identified: one assigned to the nS(Sigma) series and the other with predominantly nP(Pi) character. For high Rydberg states, which have been resolved up to n = 13, the surrounding helium effectively screens the valence electron from the Li ion core, as indicated by the apparent red-shift of Li transitions and lowered quantum defects on the droplet with respect to their free atom counterparts. For low n states, the screening effect is weakened and the prevailing repulsive interaction gives rise to strongly broadened and blue shifted transitions. The red-shifts originate from the polarization of nearby He atoms by the positive Li ion core. As a consequence of this effect, the ionization threshold is lowered by 116 +/- 10 cm-1 for Li on helium droplets with a radius of about 40 A. Upon single-photon ionization, heavy complexes corresponding to Li ions attached to intact helium droplets are detected. We conclude that ionization close to the on-droplet ionization threshold triggers a dynamic process in which the Li ion core undergoes a transition from a surface site into the droplet. PMID- 29141431 TI - Development of isothermal-isobaric replica-permutation method for molecular dynamics and Monte Carlo simulations and its application to reveal temperature and pressure dependence of folded, misfolded, and unfolded states of chignolin. AB - We developed a two-dimensional replica-permutation molecular dynamics method in the isothermal-isobaric ensemble. The replica-permutation method is a better alternative to the replica-exchange method. It was originally developed in the canonical ensemble. This method employs the Suwa-Todo algorithm, instead of the Metropolis algorithm, to perform permutations of temperatures and pressures among more than two replicas so that the rejection ratio can be minimized. We showed that the isothermal-isobaric replica-permutation method performs better sampling efficiency than the isothermal-isobaric replica-exchange method and infinite swapping method. We applied this method to a beta-hairpin mini protein, chignolin. In this simulation, we observed not only the folded state but also the misfolded state. We calculated the temperature and pressure dependence of the fractions on the folded, misfolded, and unfolded states. Differences in partial molar enthalpy, internal energy, entropy, partial molar volume, and heat capacity were also determined and agreed well with experimental data. We observed a new phenomenon that misfolded chignolin becomes more stable under high-pressure conditions. We also revealed this mechanism of the stability as follows: TYR2 and TRP9 side chains cover the hydrogen bonds that form a beta-hairpin structure. The hydrogen bonds are protected from the water molecules that approach the protein as the pressure increases. PMID- 29141432 TI - Probing cluster surface morphology by cryo spectroscopy of N2 on cationic nickel clusters. AB - We present the cryogenic (26 K) IR spectra of selected [Nin(N2)m]+ (n = 5-20, m = 1 - mmax), which strongly reveal n- and m-dependent features in the N2 stretching region, in conjunction with density functional theory modeling of some of these findings. The observed spectral features allow us to refine the kinetic classification [cf. J. Mohrbach, S. Dillinger, and G. Niedner-Schatteburg, J. Chem. Phys. 147, 184304 (2017)] and to define four classes of structure related surface adsorption behavior: Class (1) of Ni6+, Ni13+, and Ni19+ are highly symmetrical clusters with all smooth surfaces of equally coordinated Ni atoms that entertain stepwise N2 adsorption up to stoichiometric N2:Nisurface saturation. Class (2) of Ni12+ and Ni18+ are highly symmetrical clusters minus one. Their relaxed smooth surfaces reorganize by enhanced N2 uptake toward some low coordinated Ni surface atoms with double N2 occupation. Class (3) of Ni5+ and Ni7+ through Ni11+ are small clusters of rough surfaces with low coordinated Ni surface atoms, and some reveal semi-internal Ni atoms of high next-neighbor coordination. Surface reorganization upon N2 uptake turns rough into rough surface by Ni atom migration and turns octahedral based structures into pentagonal bipyramidal structures. Class (4) of Ni14+ through Ni17+ and Ni20+ are large clusters with rough and smooth surface areas. They possess smooth icosahedral surfaces with some proximate capping atom(s) on one hemisphere of the icosahedron with the other one largely unaffected. PMID- 29141433 TI - Communication: Symmetry-adapted perturbation theory with intermolecular induction and dispersion energies from the Bethe-Salpeter equation. AB - A method for calculating intermolecular induction and dispersion energies based on a GW description of the monomers and employing response functions from the Bethe-Salpeter equation is proposed. Calculations on a test set of 10 weakly bound complexes with GW-based symmetry-adapted perturbation theory (GW-SAPT) show an improved performance in comparison with symmetry-adapted perturbation theory based on density-functional theory (DFT-SAPT). PMID- 29141434 TI - Dynamic heterogeneity in an orientational glass. AB - The family of compounds CBrnCl4-n has been proven helpful in unraveling microscopic mechanisms responsible for glassy behavior. Some of the family members show translational ordered phases with minimal disorder which appears to reveal glassy features, thus deserving special attention in the search for universal glass anomalies. In this work, we studied CBrCl3 dynamics by performing extensive molecular dynamics simulations. Molecules of this compound perform reorientational discrete jumps, where the atoms exchange equivalent positions among each other revealing a cage-orientational jump motion fully comparable to the cage-rototranslational jump motion in supercooled liquids. Correlation times were calculated from rotational autocorrelation functions showing good agreement with previous reported dielectric results. From mean waiting and persistence times calculated directly from trajectory results, we are able to explain which microscopic mechanisms lead to characteristic times associated with alpha- and beta-relaxation times measured experimentally. We found that two nonequivalent groups of molecules have a longer characteristic time than the other two nonequivalent groups, both of them belonging to the asymmetric unit of the monoclinic (C2/c) lattice. PMID- 29141435 TI - Extension of the source-sink potential approach to Hartree-Fock and density functional theory: A new tool to visualize the ballistic current through molecules. AB - The recent source and sink potential approach by Pickup et al. [J. Chem. Phys. 143, 194105 (2015)] is extended to Hartree-Fock and density functional theory, allowing the calculation of the transmission and the visualization of ballistic currents through molecules at these levels of theory. This visualization allows the study of the transmission process in real-space, providing an important tool to better understand the conduction process. PMID- 29141436 TI - Surface hopping dynamics including intersystem crossing using the algebraic diagrammatic construction method. AB - We report an implementation for employing the algebraic diagrammatic construction to second order [ADC(2)] ab initio electronic structure level of theory in nonadiabatic dynamics simulations in the framework of the SHARC (surface hopping including arbitrary couplings) dynamics method. The implementation is intended to enable computationally efficient, reliable, and easy-to-use nonadiabatic dynamics simulations of intersystem crossing in organic molecules. The methodology is evaluated for the 2-thiouracil molecule. It is shown that ADC(2) yields reliable excited-state energies, wave functions, and spin-orbit coupling terms for this molecule. Dynamics simulations are compared to previously reported results using high-level multi-state complete active space perturbation theory, showing favorable agreement. PMID- 29141437 TI - Pushing configuration-interaction to the limit: Towards massively parallel MCSCF calculations. AB - A new large-scale parallel multiconfigurational self-consistent field (MCSCF) implementation in the open-source NWChem computational chemistry code is presented. The generalized active space approach is used to partition large configuration interaction (CI) vectors and generate a sufficient number of batches that can be distributed to the available cores. Massively parallel CI calculations with large active spaces can be performed. The new parallel MCSCF implementation is tested for the chromium trimer and for an active space of 20 electrons in 20 orbitals, which can now routinely be performed. Unprecedented CI calculations with an active space of 22 electrons in 22 orbitals for the pentacene systems were performed and a single CI iteration calculation with an active space of 24 electrons in 24 orbitals for the chromium tetramer was possible. The chromium tetramer corresponds to a CI expansion of one trillion Slater determinants (914 058 513 424) and is the largest conventional CI calculation attempted up to date. PMID- 29141438 TI - Synthesis and stability of hydrogen selenide compounds at high pressure. AB - The observation of high-temperature superconductivity in hydride sulfide (H2S) at high pressures has generated considerable interest in compressed hydrogen-rich compounds. High-pressure hydrogen selenide (H2Se) has also been predicted to be superconducting at high temperatures; however, its behaviour and stability upon compression remains unknown. In this study, we synthesize H2Se in situ from elemental Se and molecular H2 at pressures of 0.4 GPa and temperatures of 473 K. On compression at 300 K, we observe the high-pressure solid phase sequence (I-I' IV) of H2Se through Raman spectroscopy and x-ray diffraction measurements, before dissociation into its constituent elements. Through the compression of H2Se in H2 media, we also observe the formation of a host-guest structure, (H2Se)2H2, which is stable at the same conditions as H2Se, with respect to decomposition. These measurements show that the behaviour of H2Se is remarkably similar to that of H2S and provides further understanding of the hydrogen chalcogenides under pressure. PMID- 29141439 TI - Double cross polarization for the indirect detection of nitrogen-14 nuclei in magic angle spinning NMR spectroscopy. AB - Nitrogen-14 NMR spectra at fast magic-angle spinning rates can be acquired indirectly by means of two-dimensional techniques based on double cross polarization transfer 1H -> 14N ->1H. Experimental evidence is given for polycrystalline samples of glycine, l-histidine, and the dipeptide Ala-Gly. Either one-bond or long-range correlations can be favored by choosing the length of the cross polarization contact pulses. Longer contact pulses allow the detection of unprotonated nitrogen sites. In contrast to earlier methods that exploited second-order quadrupolar/dipolar cross-terms, cross polarization operates in the manner of the method of Hartmann and Hahn, even for 14N quadrupolar couplings up to 4 MHz. Simulations explain why amorphous samples tend to give rise to featureless spectra because the 14N quadrupolar interactions may vary dramatically with the lattice environment. The experiments are straightforward to set up and are shown to be effective for different nitrogen environments and robust with respect to the rf-field strengths and to the 14N carrier frequency during cross polarization. The efficiency of indirect detection of 14N nuclei by double cross polarization is shown to be similar to that of isotopically enriched 13C nuclei. PMID- 29141440 TI - Explaining the T,V-dependent dynamics of glass forming liquids: The cooperative free volume model tested against new simulation results. AB - In this article, we derive a rate model, the "cooperative free volume" (CFV) model, to explain relaxation dynamics in terms of a system's free volume, Vfree, and its temperature, T, over widely varied pressure dependent conditions. In the CFV model, the rate a molecule moves a distance on the order of its own size is dependent on the cooperation of surrounding molecules to open up enough free space. To test CFV, we have generated extensive T,V dependent simulation data for structural relaxation times, tau, on a Kob and Andersen type Lennard-Jones (KA LJ) fluid. The Vfree = V - Vhc values are obtained by estimating the limiting hard core volume, Vhc, through analysis of the KA-LJ PVT data. We provide the first simulation evidence that shows ln tau to be linearly proportional to 1/Vfree on isotherms, with T-dependent slopes, thus confirming our recent analysis of experimental systems. The linear relationship exhibited by the simulation data is further shown to occur at temperatures both above and below the transition to Arrhenius behavior. We also show that the gas kinetic T dependent contribution is important in simulation results and that there can be a significant entropic contribution from lingering molecular hard-cores at high T. A key result is that non-Arrhenius relaxation behavior is always exhibited on isobars of the KA-LJ fluid, even at high T. The CFV model predicts all of this behavior over a surprisingly wide range of the KA-LJ T,V space, fitting it with just a single set of three parameters. The CFV approach leads to a framework wherein the number of cooperating particles, and thus, the process free energy of activation, is inversely proportional to Vfree, and this is the foundation for the form of the model's volume contribution, a form that we find to hold for all systems and at all temperatures. PMID- 29141441 TI - Correlation between heart size and emphysema in patients with chronic obstructive pulmonary disease: CT-based analysis using inspiratory and expiratory scans. AB - The objective of this study was to investigate the relationship between the extent of emphysema and heart size in patients with chronic obstructive pulmonary disease (COPD) using inspiratory and expiratory chest computed tomography (CT). This retrospective study was approved by the institutional review board and informed consent was waived. We measured lung volume (LV), low attenuation area percent (%LAA; less than or equal to -950 HU), maximum cardiac area, and maximum transverse cardiac diameter on inspiratory/expiratory chest CT in 60 patients with COPD. Spearman rank correlation analysis was used to determine the correlations between the heart and lung CT measurements, and the correlations between these measurements and spirometric values. On inspiratory CT, the maximum transverse cardiac diameter was negatively correlated with LV ( rho = -0.42; p < 0.01) and %LAA ( rho = -0.43; p < 0.001). Furthermore, on expiratory CT, the maximum cardiac area was negatively correlated with LV ( rho = -0.35; p < 0.01) and %LAA ( rho = -0.37; p < 0.01), and there was a negative correlation between transverse cardiac diameter and %LAA ( rho = -0.34; p < 0.01). Although inspiratory cardiac size was not correlated with any of the spirometric values, the maximum cardiac area and transverse diameter on expiratory scans were significantly correlated with the reduced airflow values on spirometry ( p < 0.01). In patients with COPD, the transverse cardiac diameter decreased as the emphysema progressed. A smaller cardiac area on expiratory CT suggested the presence of large LVs, emphysema, and airflow limitation in COPD. PMID- 29141442 TI - Editorial Comment on: Percuflex Helical Ureteral Stents Significantly Reduce Patient Analgesic Requirements Compared to Control Stents by Chew et al. PMID- 29141443 TI - Effects of wavelength, fluence, and dose on fragmentation pathways and photoproduct ion yield in 213 nm and 266 nm ultraviolet photodissociation experiments. AB - Ultraviolet photodissociation tandem mass spectrometry is a powerful tool to investigate the structure of biomolecules, due to its ability to generate rich fragmentation patterns or bond selective cleavage, as a function of used laser wavelength, laser fluence, dose (number of accumulated laser pulses), and available chromophores. Herein, we report first results obtained with a newly developed two-wavelength (266 nm and 213 nm) ultraviolet photodissociation setup coupled to a Fourier-transform ion cyclotron resonance mass spectrometer. Photoproduct yields for protonated 3-iodo-l-tyrosine were up to ~75%. Dose and fluence dependent measurements for protonated 3-iodo-l-tyrosine, doubly charged protonated bradykinin and Fe(II) attached to 1,2-dioleoyl-sn-glycero-3 phosphocholine reveal that the ultraviolet photodissociation mechanism for photoproduct formation qualitatively differs between these model systems. Three derived photodissociation models were used to interpret the experimental results and show that while protonated 3-iodo-l-tyrosine and Fe(II) attached to 1,2 dioleoyl-sn-glycero-3-phosphocholine most likely dissociates via a single-photon process, fragmentation of doubly charged bradykinin ions was found to be most consistent with sequential two-photon dissociation (213 nm). The introduced dissociation models present an easy means to study the mechanism of ultraviolet photodissociation processes for a variety of analytes without prior knowledge of their photochemistry or to optimize experimental conditions by adjusting laser fluence or number of laser pulses. PMID- 29141444 TI - Associations Among Obesity, Inflammation, and Tryptophan Catabolism in Pregnancy. AB - OBJECTIVE: To evaluate relationships among obesity in pregnancy and plasma levels of tryptophan (TRP) and kynurenine (KYN), inflammatory markers, and depressed mood. METHODS: Pregnant women ( N = 374) were enrolled, and data were collected at a mean gestation of 20 weeks in this cross-sectional study. Plasma was analyzed for TRP, KYN, neopterin, and nitrite levels. Women completed demographic and mood scales. RESULTS: There was a statistically significant inverse correlation between body mass index (BMI) and TRP and positive correlations between BMI and KYN and the kynurenine/tryptophan (KYN/TRP) ratio. Neopterin was correlated with KYN/TRP, suggesting that the indoleamine 2,3-dioxygenase-1 (IDO 1) enzyme was activated. The correlations of neopterin and nitrite with BMI were too small to be clinically meaningful but may provide mechanistic insight. There was a correlation between depressed mood and nitrite levels. Depressed mood was also associated with lower TRP levels. When the sample was divided into pregnant women with or without obesity, TRP was significantly lower and the KYN/TRP ratio was significantly higher in the women with obesity. CONCLUSION: The pro inflammatory state of obesity in pregnancy may drive activation of IDO-1, resulting in diversion of TRP away from serotonin and melatonin production and toward KYN metabolites. This alteration could contribute to depression, impaired sleep, increased production of excitotoxic neurotransmitters, and reinforcement of a pro-inflammatory state in pregnancy. PMID- 29141445 TI - Measurement of dabigatran: previously demonstrated Hemoclot(r) Thrombin Inhibitor assay reagent instability on Sysmex CS-2100i is no longer an issue. AB - The Hemoclot(r) Thrombin Inhibitor (HTI) assay has been recommended for measurement of dabigatran concentrations in specific clinical situations. Traditionally, reagents for biochemical assays are prepared from instructions found in the package insert. For the HTI reagents the manufacturer recommends incubating the reagents much longer than indicated in the package insert. These recommendations are added to the application sheets designed for different analyzers. Many clinicians and laboratory personnel may be unaware of the discrepancy between the two instructions, resulting in incorrect handling of the reagents. The aim of this study was to investigate the effect of the two different preparation methods on reagent stability and test results. For the standard concentration range, reagent stability on Sysmex CS-2100i was only two hours instead of the eight hours indicated by the producer when following package insert instructions (incubation time: 15 min). Stability was increased to five hours when following the application sheet (incubation time: 60 min). Two years later, the study was repeated using samples of patients treated with dabigatran etexilate. This time, reagent stability was at least six hours. Since the reagent composition was unchanged, the increased stability could be due to changed logistics by the supplier, with stock and transfer closer by. Previously demonstrated HTI reagent instability is no longer an issue at our laboratory. The reliability of results of clinical studies in which the assay has been used is potentially compromised. PMID- 29141447 TI - What Is Offered on Mobile Applications in Spanish About Diabetes Mellitus? PMID- 29141446 TI - Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. AB - Hypoxia treatment enhances paracrine effect of mesenchymal stem cells (MSCs). The aim of this study was to investigate whether exosomes from hypoxia-treated MSCs (ExoH) are superior to those from normoxia-treated MSCs (ExoN) for myocardial repair. Mouse bone marrow-derived MSCs were cultured under hypoxia or normoxia for 24 h, and exosomes from conditioned media were intramyocardially injected into infarcted heart of C57BL/6 mouse. ExoH resulted in significantly higher survival, smaller scar size and better cardiac functions recovery. ExoH conferred increased vascular density, lower cardiomyocytes (CMs) apoptosis, reduced fibrosis and increased recruitment of cardiac progenitor cells in the infarcted heart relative to ExoN. MicroRNA analysis revealed significantly higher levels of microRNA-210 (miR-210) in ExoH compared with ExoN. Transfection of a miR-210 mimic into endothelial cells (ECs) and CMs conferred similar biological effects as ExoH. Hypoxia treatment of MSCs increased the expression of neutral sphingomyelinase 2 (nSMase2) which is crucial for exosome secretion. Blocking the activity of nSMase2 resulted in reduced miR-210 secretion and abrogated the beneficial effects of ExoH. In conclusion, hypoxic culture augments miR-210 and nSMase2 activities in MSCs and their secreted exosomes, and this is responsible at least in part for the enhanced cardioprotective actions of exosomes derived from hypoxia-treated cells. PMID- 29141448 TI - Utilizing evidence-based assessment instruments to detect well-being and distress in English- and Spanish-speaking caregivers of individuals affected by dementia. AB - Objective The purpose of this study was to examine the most effective and available English and Spanish language caregiver assessments for providers and caregivers. Methods Assessments were included if they screened for caregiving related concerns, including stress, depression, and caregiving burden and could be administered directly to caregivers in person or online. Results Eighteen assessments are designed to assess caregiver burden, distress, depression, and grief. Six did not have psychometric data to support efficacy but are widely used in clinical and research settings. Six were validated in Spanish, and one other is available in Spanish but not validated. Conclusion As many as 80% of care recipients are cared for in the home by family members who act as informal caregivers. Caregivers of persons with dementia may experience depression symptoms, high caregiver burden, and feelings of being constrained. Due to the lack of psychometric evidence available, the validity of some assessments is questionable. PMID- 29141449 TI - Decisions and attitudes regarding participation and proxy in clinical trials among patients with impaired cognitive function. AB - Background Medical decision-making capacity is impaired in Alzheimer's disease and mild cognitive impairment. Medical decision-making capacity depends on many different cognitive functions and varies due to situation and cognitive, social, and emotional status of the patient. Our aim was to analyze dementia patients' capacity to estimate risks and benefits in different clinical trials and determine how cognitive decline affects their attitude toward possible participation and proxy consent. Methods Groups: Alzheimer's disease (n = 20), mild cognitive impairment (n = 21) and healthy controls (n = 33). Two hypothetical clinical trials, a standardized interview and three visual analogue scales were used to investigate decisions, estimations, reasoning, and attitudes. Results A general positive attitude toward participation in clinical trials was shown among all groups. Both patients and controls motivated possible participation as "own-benefit" in the low-risk trial and to "help-others" in the high-risk trial. Individuals who accepted to participate in the high-risk trial scored lower in medical decision-making capacity in comparison to participants who would not have participated (p < .01). Patients in the Alzheimer's disease but not mild cognitive impairment and healthy control groups underestimated risks and overestimated benefits in the high-risk/low-benefit trial (p < .05). A family member was most frequently chosen as possible proxy (91%). Conclusions Medical decisions and research consent should be interpreted with caution in patients who are already in early stages of dementia, as the patients' acceptance to participate in high-risk trials may be due an insufficient decisional capacity and risk analysis, accelerated by a general desire to make good to society. We emphasize the use of a standardized tool to evaluate medical decisional capacity in clinical research. PMID- 29141450 TI - Investigation of cerebrospinal fluid flow in the cerebral aqueduct using high resolution phase contrast measurements at 7T MRI. AB - Background The cerebral aqueduct is a central conduit for cerebrospinal fluid (CSF), and non-invasive quantification of CSF flow in the aqueduct may be an important tool for diagnosis and follow-up of treatment. Magnetic resonance (MR) methods at clinical field strengths are limited by low spatial resolution. Purpose To investigate the feasibility of high-resolution through-plane MR flow measurements (2D-PC) in the cerebral aqueduct at high field strength (7T). Material and Methods 2D-PC measurements in the aqueduct were performed in nine healthy individuals at 7T. Measurement accuracy was determined using a phantom. Aqueduct area, mean velocity, maximum velocity, minimum velocity, net flow, and mean flow were determined using in-plane resolutions 0.8 * 0.8, 0.5 * 0.5, 0.3 * 0.3, and 0.2 * 0.2 mm2. Feasibility criteria were defined based on scan time and spatial and temporal resolution. Results Phantom validation of 2D-PC MR showed good accuracy. In vivo, stroke volume was -8.2 +/- 4.4, -4.7 +/- 2.8, -6.0 +/- 3.8, and -3.7 +/- 2.1 uL for 0.8 * 0.8, 0.5 * 0.5, 0.3 * 0.3, and 0.2 * 0.2 mm2, respectively. The scan with 0.3 * 0.3 mm2 resolution fulfilled the feasibility criteria for a wide range of heart rates and aqueduct diameters. Conclusion 7T MR enables non-invasive quantification of CSF flow and velocity in the cerebral aqueduct with high spatial resolution. PMID- 29141451 TI - Editorial Comment on: Next Generation Single-Use Ureteroscopes: An In Vitro Comparison by Wollin et al. PMID- 29141452 TI - Quality characteristics of sauerkraut fermented by using a Lactobacillus paracasei starter culture grown in tofu whey. AB - The quality parameters of sauerkraut fermented using Lactobacillus paracasei in terms of its lactic acid bacteria count, texture, colour and biochemical properties were studied. As a starter culture L. paracasei grown in tofu whey was used for sauerkraut fermentation. The experiments were planned using central composite rotatable design of response surface methodology for input variables - culture volume (ml), fermentation time (days) and salt concentration (g/100 g). The linear and interactive effect of variables on responses was understood by statistically significant (p < 0.01) second-order models. Amongst all the input variables culture volume was found to have an overwhelming effect over all the responses. There was a significant (p < 0.01) increase in the lactic acid bacteria count of finished product; it was less hard but there was a departure in colour from the traditional product. The optimized condition for sauerkraut fermentation in terms of culture volume (ml), fermentation time (day) and salt concentration (g/100 g) was 30 ml, 28 days and 1 g/100 g, respectively. It was also observed that phenolics content was better in starter culture sauerkraut over the one traditionally prepared. PMID- 29141453 TI - Relationship between metabolic syndrome and nodular thyroid diseases. AB - Nodular thyroid diseases are common in Turkey. Insulin resistance (IR) is considered as the most important component of metabolic syndrome (MetS), and it is thought to directly affect thyroid diseases, together with other components of MetS. The aim of this study was to evaluate potential factors associated with thyroid nodularity. This study was part of the prospective MELEN study. In total, randomly selected 2233 subjects were evaluated. A euthyroid subgroup of participants (n = 1432) was selected and 421 of them had MetS. Both goitres and multinodular goitres (MNGs) were significantly more common in the MetS (+) group (p < .001). Older age was the only factor that significantly affected the presence of a nodular goitre (NG) (p < .001). The presence of a MNG was associated with older age (p < .001), systolic blood pressure level (p < .008) and MetS (p < .001). There was no difference in the thyroid volume or presence of nodular thyroid diseases between the IR (+) and (-) groups. Both the thyroid volume and the presence of MNGs were significantly associated with MetS, independent of thyroid-stimulating hormone (TSH) and IR. We suggest that the individual components of MetS may influence thyroid nodularity to some degree and that together they exert a cumulative effect on the thyroid gland. As a result, in the absence of MetS, we further suggest that IR alone does not explain the increase in thyroid volume and thyroid nodule formation. PMID- 29141454 TI - Editorial Comment on: Thermal Response to High-Power Holmium Laser Lithotripsy by Aldoukhi et al. PMID- 29141456 TI - Increased serum levels of mBDNF in women with minimal and mild endometriosis have no predictive power for the disease. AB - The objective of our pilot clinical, prospective study was to determine the serum levels of mature brain-derived neurotrophic factor, in of women with endometriosis and controls and explore whether mature brain-derived neurotrophic factor is a potential biomarker for the disease. The patients were selected from the Endometriosis Marker Austria prospective cohort study conducted at the tertiary referral certified Endometriosis Center of the Medical University of Vienna. All women underwent laparoscopic surgery because there was a suspicion of endometriosis, or the women had pelvic pain, adnexal cysts, unexplained infertility, or uterine fibroids. Our main outcome parameter was total levels of mature brain-derived neurotrophic factor in serum, measured using ELISA. Our results show that serum levels of mature brain-derived neurotrophic factor are significantly higher in women with endometriosis compared to women without endometriosis. The mean serum protein levels are significantly higher in women with rAFS stage I and II endometriosis, whereas no difference was found in women with stage III and IV endometriosis and controls. Postoperative follow-up at 6-10 weeks revealed that surgical intervention leads to equilibration of the levels of secreted mature brain-derived neurotrophic factor between women with and without endometriosis. The difference between serum mature brain-derived neurotrophic factor levels of women with endometriosis compared to women without endometriosis is independent of menstrual cycle phase and overall self-reported pelvic pain. ROC-curve analysis showed that, the mature brain-derived neurotrophic factor is not a useful biomarker for endometriosis. In conclusion, although women with stage I and II endometriosis have increased levels of mature brain-derived neurotrophic factor in serum compared to controls, the difference is not predictive for the disease. Impact statement Endometriosis is a disease that can have a significant impact on the quality of life of affected women. The gold standard for diagnosis to this day remains visualization through laparoscopic surgery with histological verification. Current studies are attempting to find a biomarker with high sensitivity and specificity, which would bypass the surgery associated risks and would significantly reduce costs. In an attempt to elucidate whether mature serum BDNF can serve as diagnostic marker for the disease, we compared the levels of the protein in women with endometriosis to endometriosis free controls. While our results showed that serum concentrations of the mature protein were significantly higher in women with endometriosis, we did not find this marker to have the sensitivity or specificity needed in order to allow a reliable diagnosis. PMID- 29141455 TI - Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy. AB - Methionine adenosyltransferase genes encode enzymes responsible for the biosynthesis of S-adenosylmethionine, the principal biological methyl donor and precursor of polyamines and glutathione. Mammalian cells express three genes - MAT1A, MAT2A, and MAT2B - with distinct expression and functions. MAT1A is mainly expressed in the liver and maintains the differentiated states of both hepatocytes and bile duct epithelial cells. Conversely, MAT2A and MAT2B are widely distributed in non-parenchymal cells of the liver and extrahepatic tissues. Increasing evidence suggests that methionine adenosyltransferases play significant roles in the development of cancers. Liver cancers, namely hepatocellular carcinoma and cholangiocarcinoma, involve dysregulation of all three methionine adenosyltransferase genes. MAT1A reduction is associated with increased oxidative stress, progenitor cell expansion, genomic instability, and other mechanisms implicated in tumorigenesis. MAT2A/MAT2B induction confers growth and survival advantage to cancerous cells, enhancing tumor migration. Highlighted examples from colon, gastric, breast, pancreas and prostate cancer studies further underscore methionine adenosyltransferase genes' role beyond the liver in cancer development. In this subset of extra-hepatic cancers, MAT2A and MAT2B are induced via different regulatory mechanisms. Understanding the role of methionine adenosyltransferase genes in tumorigenesis helps identify attributes of these genes that may serve as valuable targets for therapy. While S adenosylmethionine, and its metabolite, methylthioadenosine, have been largely explored as therapeutic interventions, targets aimed at regulation of MAT gene expression and methionine adenosyltransferase protein-protein interactions are now surfacing as potential effective strategies for treatment and chemoprevention of cancers. Impact statement This review examines the role of methionine adenosyltransferases (MATs) in human cancer development, with a particular focus on liver cancers in which all three MAT genes are implicated in tumorigenesis. An overview of MAT genes, isoenzymes and their regulation provide context for understanding consequences of dysregulation. Highlighting examples from liver, colon, gastric, breast, pancreas and prostate cancers underscore the importance of understanding MAT's tumorigenic role in identifying future targets for cancer therapy. PMID- 29141457 TI - Disparities Associated With Inpatient Palliative Care Utilization by Patients With Metastatic Gynecologic Cancers: A Study of 3337 Women. AB - OBJECTIVE: To determine the factors associated with inpatient palliative care (PC) use in patients with metastatic gynecologic cancer. METHODS: Data were obtained from the Nationwide Inpatient Sample (NIS) for patients with metastatic cervical, uterine, and ovarian cancers. Chi-square and multivariate models were used for statistical analyses. RESULTS: Of 67 947 inpatients with metastatic gynecologic cancer, 3337 (5%) utilized PC (median age: 63 years, range: 18-102 years). For the entire cohort, the majority was white (59%) and the remainder was black (10%), Hispanic (8%), and Asian (3%). Sixty-one percent had ovarian, 25% uterine, and 14% cervical cancers. Forty-four percent had Medicare, 37% private insurance, 12% Medicaid, and 3% were uninsured. Fifty-three percent of patients were treated at teaching hospitals, while 33% were treated at nonteaching hospitals. In multivariate analysis, the use of PC was associated with older age (>=63, median; odds ratio [OR] = 1.52, 95% confidence interval [CI]: 1.36-1.70; P < .0001) and black race (OR = 1.22, CI: 1.08-1.39; P < .01). Compared to patients with ovarian cancer, patients with uterine (OR = 1.63, CI: 1.46-1.83; P < .0001) and cervical (OR = 1.14, CI: 1.104-1.25; P < .01) cancer had higher rates of PC utilization. The proportion of patients receiving PC increased from 2% in 2005 to 10% in 2011. In a subset analysis of the 4517 patients who died during hospitalization, only 1056 (23%) patients received PC. CONCLUSION: Patients who were older, black, or had uterine and cervical cancers were more likely to use PC. Although the overall use of PC has increased, less than one-quarter of patients who died in the hospital used PC services during their final hospital admission. PMID- 29141458 TI - The Selection of Death Place Among Patients Receiving Hospital-Based Palliative Care Service in Taiwan. AB - INTRODUCTION: To analyze the selection of a place to die and its related factors in patients who received hospice shared care service in Taiwan. METHODS: This study included patients who received hospice shared care service in a metropolitan hospital as the research participants. A total of 172 questionnaires were collected, and 146 of them were used as valid samples for analysis. This study applied the multivariate logistic regression analysis to assess the significance of independent variables associated with the selection of place of death. RESULTS: The results revealed that 52.6% of the patients select hospital as the place to end their life, while 43.8% of them select their home as the place of death. Furthermore, younger adult patients (<65), those who with a higher educational level (>=10 years), and those with a clear cognizance of the disease progression tended to select hospital as the place to spend their last days. CONCLUSIONS: The research disclosed that more patients with the hospice shared care service prefer hospital to their home as the place to die. In order to provide end-of-life care for patients with low cost and appropriate treatment, it is important to understand the related sociodemographic factors and the need of the patients to provide well-designed hospice/specialist palliative care regimen. PMID- 29141459 TI - Factors Associated With Caregivers' Resilience in a Terminal Cancer Care Setting. AB - BACKGROUND: Resilience implies characteristics such as self-efficacy, adaptability to change, optimism, and the ability to recover from traumatic stress. Studies on resilience in family caregivers (FCs) of patients with terminal cancer are rare. This study aims to examine the factors associated with FCs' resilience in a terminal cancer care setting. METHODS: This is a cross sectional study of 273 FCs from 7 hospice and palliative care units in Korea. Resilience was categorized as high and low, and factors associated with resilience were grouped or categorized into subscales. A multivariate logistic regression analysis was used to examine relevant factors. RESULTS: High FCs' resilience was significantly associated with FCs' health status, depression, and social support. In a multivariate regression model, FCs' perception of good health (adjusted odds ratio [aOR] = 2.26, 95% confidence interval [CI] = 1.16 4.40), positive social support (aOR = 3.70, 95% CI = 1.07-12.87), and absence of depression (aOR = 3.12, 95% CI = 1.59-6.13) remained significantly associated with high FCs' resilience. CONCLUSION: Lack of family support is associated with and may be a cause of diminished resilience. And more concern should be paid to FCs to improve FCs' health and emotional status. Education programs might be effective for improving caregivers' resilience. Further research with supportive interventions is indicated. PMID- 29141461 TI - Development of magnetic anionic liposome/atelocollagen complexes for efficient magnetic drug targeting. AB - Magnetic nanoparticle-incorporated liposomes (magnetic liposomes) are considered a promising site-specific drug delivery carrier vehicle. With regard to their surface charge, magnetic anionic liposomes (Mag-AL) demonstrate little toxicity in comparison with magnetic cationic liposomes (Mag-CL), whereas their cellular association and uptake efficiency are low. In the current study, we constructed complexes of Mag-AL and atelocollagen (ATCOL), which is a biocompatible and minimally immunogenic biomaterial, to improve the cellular uptake properties of Mag-AL in vitro and in vivo. The cellular association and/or uptake of Mag-AL in RAW264 cells, a murine macrophage-like cell line, under a magnetic field was significantly increased when Mag-AL was complexed with ATCOL, and the highest cellular association was observed with complexes constructed using 5 ug/mL of ATCOL. The complexes showed liposome concentration-dependent and time-dependent cellular association under a magnetic field, and their cellular uptake efficiency was comparable with that of Mag-CL. In addition, Mag-CL showed significant cytotoxicity in a liposome concentration-dependent manner, whereas Mag-AL/ATCOL complexes produced no cytotoxic effect against RAW264 cells. Furthermore, the efficient cellular association of Mag-AL/ATCOL complexes in RAW264 cells was observed even in the presence of serum, and their liver accumulation was significantly increased at a magnetic field-exposed region after intravenous injection in rats. These results indicate that Mag-AL/ATCOL complexes could be a safe and efficient magnetic responsive drug carrier. PMID- 29141460 TI - Safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin and low-dose metformin. AB - BACKGROUND: This study investigated the safety and efficacy of metformin up titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin (100 mg/day) and low-dose metformin (500 or 750 mg/day). RESEARCH DESIGN AND METHODS: Fifty patients were randomly allocated to the control group (maintaining the initial low-dose of metformin) and the dose increase group (up titrating of metformin to 1,500-2,250 mg/day) for 24 weeks. The primary outcome was change in HbA1c from baseline to 24 weeks. RESULTS: Among the 25 patients allocated to the dose increase group, four patients were not able to complete the study protocol because of gastrointestinal symptoms. HbA1c in the dose increase group was significantly but modestly lower than in the control group (change in HbA1c: 0.22 +/- 0.57 vs. -0.15 +/- 0.58%, group comparison, P < 0.05). The dose increase group did not gain weight during the study period, and no hypoglycemic events were reported in both groups. The rate of gastrointestinal symptoms in the dose increase group was profoundly higher than in the control group (32 vs. 0%, P < 0.01). CONCLUSIONS: In Japanese patients with type 2 diabetes treated with vildagliptin and low-dose metformin, metformin up-titration significantly but modestly improved glycemic control without hypoglycemia and weight gain. PMID- 29141462 TI - A safety review of medications used for labour induction. AB - INTRODUCTION: Induction of labour is a commonly performed procedure around the world. There are various medications used for induction including those commonly used for cervical ripening (prostaglandins) and oxytocin. The ideal agent is one that decreases the time to achieving delivery without compromising maternal or neonatal safety. The 'optimal safe agent' remains undetermined. Areas covered: This article reviews the safety of currently used induction agents. Prostaglandins and oxytocin have proven to be effective in labour induction, and their profiles will be reviewed in this article. We discuss the data that supports combining some of the agents. We also cover the safety of medications used for labour induction in setting of a scarred uterus. Expert Opinion: There is continuous debate about the ideal induction agent: one that balances safety with efficacy. We recommend the practice that there is not one perfect agent for all, and that the clinical scenario and previous obstetric history should be considered before choosing an agent. In the future, pharmacogenomics may show that genetics may affect the individual response and adverse reactions to the various agents. PMID- 29141463 TI - Once-monthly injection of paliperidone palmitate in patients with recently diagnosed and chronic schizophrenia: a post-hoc comparison of efficacy and safety. AB - BACKGROUND: The use of long-acting injectable antipsychotics in recently diagnosed schizophrenia remains less explored. We evaluated the efficacy and safety of paliperidone palmitate once-monthly (PP1M) treatment in adult patients with recently diagnosed vs. chronic schizophrenia. RESEARCH DESIGN AND METHODS: These post-hoc analyses included two multicenter studies. Study 1 (NCT01527305) enrolled recently diagnosed (<=5 years) and chronic (>5 years) patients; Study 2 (NCT01051531) enrolled recently diagnosed patients only. Recently diagnosed patients were further sub-grouped into <=2 years or 2-5 years. The primary efficacy endpoint was the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. RESULTS: In Study 1, 41.5% patients had recent diagnosis (<=2 years: 56.8%; 2-5 years: 43.2%); 58.5% had chronic schizophrenia. In Study 2, 52.8% and 47.2% patients were grouped into <=2 years and 2-5 years, respectively. PANSS total score showed significantly greater improvement in patients with recently diagnosed vs. chronic schizophrenia. Similar results were obtained for PANSS responder rate, improvements in PANSS, and CGI-S scores. CONCLUSION: PP1M was efficacious in both recently diagnosed and chronic schizophrenia, with the benefits being more pronounced in patients with recently diagnosed schizophrenia. This adds to growing evidence recommending long-acting antipsychotic interventions at early stages of schizophrenia. PMID- 29141464 TI - Understanding posttraumatic growth of paratriathletes with acquired disability. AB - PURPOSE: To examine the relevance of key components of Organismic Valuing Theory of Growth through Adversity in understanding posttraumatic growth amongst paratriathletes with acquired disability. METHODS: Semi-structured interviews informed by organismic valuing theory of growth through adversity were conducted with 14 elite paratriathletes (eight male, six female). To increase the likelihood that participants had experienced posttraumatic growth, a short form of the Posttraumatic Growth Inventory was completed prior to interview participation. Interview data were analyzed using directed content analysis. RESULTS: Although the initial response to disability was largely negative, paratriathlon experiences were reported to be a mechanism through which growth was facilitated. In particular, participants suggested that social, competence, empowerment, and identity development processes were instrumental in facilitating posttraumatic growth. CONCLUSIONS: Analysis identified themes largely consistent with the main tenets of organismic valuing theory of growth through adversity, supporting its utility in understanding response to a traumatic event and subsequent growth. These findings also suggest that para sport may be an efficacious means for promoting posttraumatic growth, especially for individuals with severe initial reactions to their disability. Lastly, findings suggest that fostering perceptions of competence, autonomy, and social connection may promote posttraumatic growth. Implications for Rehabilitation Acquiring a physical disability may have a detrimental impact on the satisfaction of an individual's fundamental psychological needs. In order to foster posttraumatic growth, the para sport environment should allow for participants to feel competent, autonomous, and to have meaningful interactions with fellow athletes and coaches. Para sport may be particularly beneficial for individuals with previous sporting backgrounds and for those with severe initial reactions to their disability. PMID- 29141465 TI - Reliability of rapid urease test for screening gastric cancer in high-risk populations. PMID- 29141466 TI - Retrospective Cohort Analysis of Pedal Procedures in the Thrombocytopenic Patient. AB - Thrombocytopenia is an important medical condition to understand prior to performing procedures in the foot and ankle. We have set forth to highlight factors a physician should take into consideration before performing procedures in the thrombocytopenic patient. A retrospective cohort analysis at a large academic institution was undertaken utilizing a cohort discovery tool to discover incidence and management strategies for patients with foot-related conditions that require in-office procedures. We demonstrate that a full history and physical are important to guide treatment along with complete blood count testing prior to intervention. We included all patients at the institution that underwent a foot and ankle procedure in-office with podiatric surgery over 10 years where thrombocytopenia was demonstrable via complete blood count within 3 months of the procedure. Patients' charts were reviewed for 1 year following podiatric intervention and outcomes were recorded. The cohort reveals that patients with thrombocytopenia have many advanced comorbidities but performing procedures in this cohort is safe. Complications from procedures included erythrocyte transfusion, ulcer recurrence, need for formal surgical intervention, infection, falls, and death. We then provide a brief discussion about the etiology and management options available for thrombocytopenia. PMID- 29141467 TI - Oxidative stress biomarkers in amniotic fluid of pregnant women with hypothyroidism. AB - PURPOSE: Hypothyroidism in pregnancy is the serious state that may lead to fetal morbidity and mortality. Oxidative stress biomarkers in the amniotic fluid can provide important information on the health, development and maturation of the fetus during pregnancy. In this study, we examined whether maternal hypothyroidism contributes to increased oxidative stress biomarkers in the amniotic fluid during the first trimester of pregnancy. MATERIALS AND METHODS: The study was conducted on healthy pregnant women and pregnant women with hypothyroidism (gestational age: 16-18 weeks). Oxidative stress biomarkers, such as superoxide anion (O2*-), hydrogen peroxide (H2O2), nitric oxide (NO), peroxynitrite (ONOO-), lipid peroxide (LPO), reduced glutathione (GSH) and oxidized glutathione (GSSG) were assayed in the amniotic fluid. RESULTS: The results of this study indicated that concentrations of O2*- and NO are significantly higher, while the concentration of H2O2 is significantly lower in the amniotic fluid of pregnant women with hypothyroidism in comparison to healthy pregnant women. There were no differences in concentrations of LPO, GSH and GSSG among tested groups. Also, we found that amniotic fluid concentration of O2*- is negatively correlated with the body weight and Apgar score values of the newborns. CONCLUSION: These results suggest that pregnancy hypothyroidism is characterized by the amniotic fluid oxidative stress. Incorporation of the oxidative stress biomarkers measurement in the amniotic fluid may be of clinical importance in the management of pregnancy hypothyroidism. PMID- 29141468 TI - Predictive Laboratory Findings of Lower Extremity Amputation in Diabetic Patients: Meta-analysis. AB - Lower extremity amputation is a source of morbidity and mortality among diabetic patients. This meta-analysis aimed to identify significant laboratory data in patients with diabetic foot ulcer with high rates of lower extremity amputation. We performed a systematic literature review and meta-analysis using MEDLINE, EMBASE, and Cochrane databases. We extracted and evaluated 11 variables from the included studies based on amputation rates. This study used the Newcastle-Ottawa Scale to assess the quality of the studies. The search strategy identified 101 publications from which we selected 16 articles for review. We identified HbA1c, fasting blood glucose, white blood cells, C-reactive protein, and erythrocyte sedimentation rate as predictive variables of higher major amputation rate. Although further investigation of long-term and prospective studies is needed, we identified 5 variables as predisposing factors for higher major amputation in diabetic patients through meta-analysis. PMID- 29141469 TI - Maternal mortality ratio in Iran compared to other regions (1990-2015): progress and challenges. PMID- 29141470 TI - Wide-reaching effects of and concerns regarding geographic localization of hospitalist units. PMID- 29141471 TI - Dietary chlorogenic acid regulates gut microbiota, serum-free amino acids and colonic serotonin levels in growing pigs. AB - Chlorogenic acid (CGA) has many biological properties, including antibacterial, antioxidant and anti-inflammatory properties, and is one of the most abundant phenolic acids available in the human diet. The aim of this study was to investigate the effects of CGA on regulation of the gut microbiota, and on the levels of free amino acids and 5-hydroxytryptamine (5-HT, serotonin). Ninety-six healthy growing pigs were randomly assigned to two treatment groups: the Ctrl group (control group, standard feed) and the CGA group [standard feed plus 0.05% 3-caffeoylquinic acid (3-CQA)] for 60 days. The diversity of the gut microbiota was increased after CGA supplementation. Changes in these microbes were significantly associated with the serum free amino acid levels and colonic 5-HT level. Compared with the Ctrl group, the levels of serum aspartic acid, threonine, alanine, arginine, and colonic 5-HT were significantly increased (p < .05). These data suggest important roles for CGA in regulating the gut microbiota and increasing the serum free amino acid levels. PMID- 29141472 TI - The quality of life and associated factors in patients on maintenance hemodialysis - a multicenter study in Shanxi province. AB - OBJECTIVES: To assess the quality of life (QOL) and factors affecting QOL in hemodialysis patients so as to improve QOL of dialysis patients and provide the basis for better clinical care. METHODS: A retrospective study was performed to assess the QOL and factors affecting QOL in hemodialysis patients. We recruited 125 patients who had been receiving hemodialysis for at least 2 years in the dialysis units of nine hospitals in Shanxi Province, China, and conducted a multi center questionnaire survey between 1 May 2015 and 1 July 2016. We investigated the patients' general condition and clinical data and used the Short Form-36 (SF 36) scale to measure QOL in these patients. RESULTS: The overall SF-36 score was 107.55 +/- 14.50 in patients who had received hemodialysis for more than 2 years. Age (p < .05, F = 4.972) and gender (p < .01, t = 3.993) significantly affected the overall QOL score in these patients. Education level was also an influencing factor (p < .05, Z= -0.838), especially on the mental health of these patients. In addition, residual urine volume (p < .05, Z= -2.465) and diabetic nephropathy (p < .05, Z= -2.062) were important factors that affected the physical strength and QOL score in these patients. However, sources of medical expenses, marital status and different methods of dialysis, had no effect on the QOL score. CONCLUSION: The overall score of QOL in patients who have received maintenance hemodialysis for more than 2 years is higher in Shanxi Province than that in other provinces of China. Only a few factors influenced the QOL of these patients. PMID- 29141473 TI - Development of a nomogram for prediction of successful membrane sweeping. AB - OBJECTIVE: To evaluate the association of obstetric, maternal, and fetal variables with successful membrane sweeping and to develop a calculator that can predict spontaneous delivery within 24 hours of membrane sweeping. METHODS: This secondary analysis of the STRIP-G Study included all singleton term parturients who underwent membrane sweeping in a tertiary center in October 2011 to July 2013. Primary end point was a 24-hour time interval from sweeping to delivery. Women who delivered without formal induction within the 24-hour interval were included in the "successful sweeping group". Stepwise logistic regression was used to calculate the adjusted odds ratio (aOR) for successful membrane sweeping and to create the calculator. The predictive power of the calculator was evaluated by area under the curve (AUC) of the receiver operating characteristic (ROC) curve and by Nagelkerke R-square. The model was validated by the Hosmer Lemeshow test and by these validation measures: sensitivity, specificity, and positive and negative predictive value. RESULTS: We analyzed data from 542 women. Parity (aOR = 1.66, 95% confidence interval [CI] 1.1-2.54), cervical dilation (aOR = 3.33, 95%CI 2.04-5.44), and gestational age (aOR = 1.44, 95%CI 1.21-1.72) were independent predictors of spontaneous delivery during the first 24 hours. A cross validation procedure showed that the calculator had a good accuracy (68%). CONCLUSIONS: A simple calculator based on maternal age, parity, gestational age, cervical dilatation, effacement and station, can accurately predict the chances of delivery within 24 hours of membrane sweeping. This may assist physicians better counseling of women regarding the likelihood of successful membrane sweeping. PMID- 29141475 TI - Addressing needs of diverse stakeholders: Twelve tips for leaders of health professions education programs. AB - Designing and evaluating health professions educational programs require a range of skills in a rapidly changing educational and healthcare environment. Not all program directors possess all the required leadership skills. In this twelve tips article, we describe a systematic approach to effectively address the complexity facing program leadership, implement robust programs and meaningfully evaluate their impact. They also offer a roadmap for managing diverse stakeholders with often competing demands. The tips are categorized under three domains: Planning, Initial Implementation, and Monitoring. Specific recommendations are provided on addressing context, organizational culture, and key relationships along with practical techniques adapted from continuous quality improvement programs. An outcomes-based approach ensures that program leaders balance competing demands. The tips provide a structure for educational leaders worldwide to reflect on what is feasible in their own context, understand and address complexities in program design and evaluation, regardless of the resources at their disposal. PMID- 29141474 TI - Assessment of immunotoxicity in female Fischer 344/N and Sprague Dawley rats and female B6C3F1 mice exposed to hexavalent chromium via the drinking water. AB - Sodium dichromate dihydrate (SDD), an inorganic compound containing hexavalent chromium (Cr(VI)), is a common environmental contaminant of groundwater sources due to widespread industrial use. There are indications in the literature that Cr(VI) may induce immunotoxic effects following dermal exposure, including acting as both an irritant and a sensitizer; however, the potential immunomodulatory effects of Cr(VI) following oral exposure are relatively unknown. Following the detection of Cr(VI) in drinking water sources, the National Toxicology Program (NTP) conducted extensive evaluations of the toxicity and carcinogenicity of SDD following drinking water exposure, including studies to assess the potential for Cr(VI) to modulate immune function. For the immunotoxicity assessments, female Fischer 344/N (F344/N) and Sprague Dawley (SD) rats and female B6C3F1 mice were exposed to SDD in drinking water for 28 consecutive days and evaluated for alterations in cellular and humoral immune function as well as innate immunity. Rats were exposed to concentrations of 0, 14.3, 57.3, 172, or 516 ppm SDD while mice were exposed to concentrations of 0, 15.6, 31.3, 62.5, 125, or 250 ppm SDD. Final mean body weight and body weight gain were decreased relative to controls in 250 ppm B6C3F1 mice and 516 ppm SD rats. Water consumption was significantly decreased in F344/N and SD rats exposed to 172 and 516 ppm SDD; this was attributed to poor palatability of the SDD drinking water solutions. Several red blood cell-specific parameters were significantly (5-7%) decreased in 250 ppm mice; however, these parameters were unaffected in rats. Sporadic increases in the spleen IgM antibody response to sheep red blood cells (SRBC) were observed, however, these increases were not dose-dependent and were not reproducible. No significant effects were observed in the other immunological parameters evaluated. Overall, exposure to Cr(VI) in drinking water had limited effects on the immune system in both rats and mice. PMID- 29141476 TI - Comparison of sun exposure versus vitamin D supplementation for pregnant women with vitamin D deficiency. AB - INTRODUCTION: Maternal vitamin D deficiency is widespread health problem that is more important in pregnant women, which affects fetus growth and bone development. The aim of this study was to evaluate the effect of sun exposure versus vitamin D supplementation for pregnant women with vitamin D deficiency. MATERIALS AND METHODS: This prospective clinical trial was performed on 87 pregnant women with vitamin D deficiency. Group A was treated with vitamin D 4000 IU per day for 10 weeks, while group B was recommended for sun exposure for 30 minutes daily (30% body surface area) for 10 weeks in summer and between 10 am-4 pm in direct sunlight. After the delivery, 25-hydroxyvitamin D3 levels were measured in the same previous center. Moreover, weight, height, and head circumference of fetus were measured at delivery in both groups and compared with each other. RESULTS: After 10-week intervention, 25-hydroxyvitamin D3 levels was significantly higher in group treated with vitamin D as compared to sun expose group (31.27 versus 19.79 ng/ml). (p < .001). However, height (p = .118), weight (p = .245), and head circumference (p = .681) of infants in both groups did not show significant differences. CONCLUSIONS: Vitamin D supplementation is more effective than sun exposure in increasing 25-hydroxyvitamin D3 in pregnant women with vitamin D deficiency. PMID- 29141477 TI - Priority and prejudice: does low socioeconomic status bias waiting time for endoscopy? A blinded, randomized survey. AB - INTRODUCTION: An unwanted socioeconomic health gap is observed in Western countries with easily accessible, government-financed health care systems. Survival rates from several malignancies differ between socioeconomic clusters and the disparities remain after adjusting for major co-morbidities and health related behavior. The possibility of biased conduct among health care workers has been proposed as a contributing factor, but evidence is sparse. METHODS: A blinded, randomized online questionnaire survey was conducted among specialists in gastroenterology in Norway. Each respondent was asked to give priority for colonoscopy to three different referrals. By randomized sequence, half the referrals contained a discreet piece of information indicating low socioeconomic status (SES). The SES information given was focused on known low-status clusters in Norway, namely the morbidly obese and receivers of disability pensions. RESULTS: There were 107 respondents giving a response rate of 67%. A lower priority was consistently given to the referrals containing information on low SES, but the difference only reached statistical significance (p = .018) for one of the referrals. CONCLUSION: Information on low SES may influence how referrals for endoscopy are prioritized. PMID- 29141478 TI - Utility of quick oculomotor tests for screening the vestibular system in the subacute and chronic populations. AB - OBJECTIVE: The goal of this study was to determine the sensitivity and specificity of some widely used, easily administered clinical tests. BACKGROUND: Simple tests of oculomotor function have become widely used for clinical screening of patients suspected of having vestibular disorders despite a paucity of evidence showing good statistical support for their use in this highly variable population. METHODS: Healthy controls with no history of otologic or neurologic disorders (n = 291) were compared to patients with known vestibular disorders (n = 62). All subjects performed passive and active head shaking, un instrumented head impulse tests (HT), and video head impulse tests (vHIT) recorded with infrared video-oculography. RESULTS: For both passive and active head shaking, using presence/absence of vertigo and of nystagmus, sensitivity was low (<0.40). Sensitivity of presence/absence of saccades on HT was even lower (<0.15). On vHIT, gains were all approximately = 1.0, so sensitivity was very low (approximately 0.15-0.35). Sensitivity and specificity for presence/absence of saccades were moderately poor (less than 0.70). CONCLUSION: None of these tests are adequate for screening patients in the out-patient clinic for vestibular disorders or for screening people in epidemiologic studies to determine the prevalence of vestibular disorders. PMID- 29141479 TI - Development of a carboxymethyl chitosan functionalized nanoemulsion formulation for increasing aqueous solubility, stability and skin permeability of astaxanthin using low-energy method. AB - In this research, firstly astaxanthin (ASX)-loaded nanoemulsions (NEs) were produced using a convenient low-energy emulsion phase inversion method. The optimised ASX-NEs were prepared in the presence of Cremophor(r) EL and Labrafil(r) M 1944 CS, with a surfactant-to-oil ratio of 4:6. The ASX-NE droplets were spherical with a mean droplet diameter below 100 nm and a small negative surface charge. The system was stable without alteration of mean droplet diameter for three months. Then, the ASX-NE was functionalised with carboxymethyl chitosan (CMCS) through direct CMCS (0.02%) incorporation during the preparation process. The ASX chemical stability and skin permeability increased in the following order: ASX solution control < ASX-NE < CMCS-ASX-NE. Cell viability assays on L929 cells revealed low cytotoxicity of blank NE, ASX-NE and CMCS-ASX-NE in the range from 5 to 500 MUg mL-1. In conclusion, the CMCS-ASX-NE might be a promising delivery vehicle in dermal and transdermal products. PMID- 29141480 TI - Benchmarking for research-related competencies - a curricular mapping approach at medical faculties in Germany. AB - OBJECTIVES: Internationally, scientific and research-related competencies need to be sufficiently targeted as core outcomes in many undergraduate medical curricula. Since 2015, standards have been recommended for Germany in the National Competency-based Learning Objective Catalogue in Medicine (NKLM). The aim of this study is to develop a multi-center mapping approach for curricular benchmarking against national standards and against other medical faculties. METHOD: A total of 277 faculty members from four German medical faculties have mapped the local curriculum against the scientific and research-related NKLM objectives, using consented procedures, metrics, and tools. The amount of mapping citations of each objective is used as indicator for its weighting in the local curriculum. Achieved competency levels after five-year education are compared. RESULTS: All four programs fulfill the NKLM standards, with each emphasizing different sub-competencies explicitly in writing (Scholar: 17-41% of all courses; Medical Scientific Skills: 14-37% of all courses). Faculties show major or full agreement in objective weighting: Scholar 44%, scientific skills 79%. The given NKLM competency level is met or even outperformed in 78-100% of the courses. CONCLUSIONS: The multi-center mapping approach provides an informative dataset allowing curricular diagnosis by external benchmarking and guidance for optimization of local curricula. PMID- 29141481 TI - Liposome supported peritoneal dialysis in rat amitriptyline exposure with and without intravenous lipid emulsion. AB - Liposome supported peritoneal dialysis is a recently described technique which may eventually be applicable in the clinical scenario of the intoxicated patient. We evaluated the hypothesis that intravenous injection of lipid emulsion (ILE) would augment acidic pH gradient liposome supported peritoneal dialysis (LSPD). Orogastrically amitriptyline dosed rats were treated with either Sodium bicarbonate (NaHCO3) intravenously and standard intraperitoneal dialysate (Group A); NaHCO3 intravenously and LSPD (Group B); or ILE and LSPD (Group C). The primary endpoint was dialysate amitriptyline concentration after a 60 min dwell. Secondary analysis included an estimate of extraction ratio for peritoneal blood flow (ERs). There were significantly higher intraperitoneal concentrations of amitriptyline and ERs in the two groups treated with LSPD (Group B, p = 0.02, Group C, p < 0.01 vs. Group A). There was no observed effect for ILE on intraperitoneal amitriptyline concentration or ERs (p > 0.20). LSPD increased the amitriptyline concentration in peritoneal dialysate. No further increase was demonstrated with ILE. This may be either because such an effect is absent, or type II error. Exploratory analysis suggests LSPD may be driven by total rather than free drug concentrations. PMID- 29141482 TI - Obstetric practice guidelines: labor's love lost? AB - Implementation of clinical practice guidelines may moderate health care costs, improve care, reduce medicolegal liability, and provide a uniformity in care allowing meaningful investigation of treatments and outcomes. However, new guidelines are often uncritically embraced by clinicians, risk management organizations, insurance companies, and the courts as the standard of care. Adoption of incompletely vetted recommendations can lead to patient harm. Recent recommendations made by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine for assessment and management of labor provide an example of well-intended guidelines adopted uncritically. Ideally, but unattainably, each step in a practice guideline would be supported by results of prospective randomized trials. Usually, data from lower on the hierarchy of proof are included, and the personal or institutional preferences of the guideline developers influence the final product. These multiple resources help illuminate critical issues and balance competing perspectives, but can introduce biases that become embedded in our practice. The new labor management guidelines, which were never shown to be superior (or even equivalent) to current standards, have achieved widespread acceptance. Although they provide a formula for reducing the cesarean rate, they do so without concern for their potentially adverse effects on maternal or neonatal outcome. New guidelines should be outcome based and address how to practice obstetrics to yield the best possible results for mother and baby. PMID- 29141483 TI - Red blood cell distribution width as a marker of cerebral infarction in hemodialysis patients. AB - BACKGROUND: Red blood cell distribution width (RDW) is a cardiovascular biomarker. We evaluated the association between RDW and cerebral stroke risk in hemodialysis patients. METHODS: A cohort of 442 adult patients on hemodialysis was studied. Strokes were defined according to ICD-10 diagnosis codes. Routine complete blood counts, evaluated every 3-6 months, were used for RDW values. RESULTS: Among 442 hemodialysis patients, during the 50-month follow-up, there were 62 cases (14.0%) of cerebral stroke: 41 (9.3%) with cerebral infarction and 21 (4.8%) with cerebral hemorrhage. Compared with nonstroke patients, a significantly higher RDW was measured in patients with cerebral stroke and cerebral infarction. However, no significant difference was seen in RDW between patients with cerebral hemorrhage and nonstroke patients. After adjustment by age, hypertension, albumin, Charlson Comorbidity Score, and C-reactive protein in different multivariable Cox regression models, patients with the highest mean RDW quartile had a 2.55-fold (hazard ratio = 3.55; 95% confidence interval: 1.33 9.51) higher risk of developing cerebral infarction relative to those with the lowest mean RDW quartile. RDW was not an independent risk factor for cerebral hemorrhage. CONCLUSIONS: Increased RDW is an independent risk factor of cerebral infarction in hemodialysis patients. PMID- 29141484 TI - Cereal fibre intake in Australia: a cross-sectional analysis of the 2011-12 National Nutrition and Physical Activity Survey. AB - Extensive evidence supports health benefits of cereal fibre, however globally no national intake data exists. This study aimed to determine estimates of intake and food sources of cereal fibre, and relationships to dietary fibre intake in an Australian sample population. A cereal fibre database was applied to dietary intake data from the 2011-12 National Nutrition and Physical Activity Survey (n = 12,153). Usual intake based on 2-day intake data was weighted to infer population results. Median daily cereal fibre intake was 6.4 g/d (9.7 g/10 MJ/d) for adults (19-85 years) and 6.2 g/d (10.2 g/10 MJ/d) for children/adolescents (2-18 years). Individuals with the highest cereal fibre intake were more likely to meet dietary fibre recommendations than those with the lowest intake (males Q4: 17.1% Q1: 3.9%; females Q4: 20.3% Q1: 6.6%). Breakfast cereals, bread and bread rolls provided the most cereal fibre. This study provides first quantification of cereal fibre from all sources in an Australian national sample. PMID- 29141485 TI - Flexible competency based medical education: More time efficient, higher costs. AB - The financing of postgraduate medical education (PGME) becomes an important topic. PGME is costly, and in most western countries is partly paid by public funding. One of the models that can help to reduce costs is time-variable PGME. Moving to true outcome-based education can lead to more efficient training programs while maintaining educational quality. We analyzed the financial effects of time-variable PGME by identifying the educational activities of PGME programs and comparing the costs and revenues of these activities in gynecology training as an example. This resulted in a revenue-cost balance of PGME activities in gynecology. As gynecology consists of both surgical and non-surgical parts, this specialty is a good starting point for a training cost analysis that can be used for a more general discussion. Shortening PGME programs without losing educational quality appears to be possible with time-variable structures. However, shortening is only safely possible on those areas in which residents have already obtained the desired level of competence. This means that time can be gained at the expense of those educational activities in which residents generate the highest revenues. We therefore conclude that shorter education with the help of time-variable training schemes leads to overall higher costs at the hospital level. PMID- 29141486 TI - Recurrent pleomorphic adenoma: is treatment considerably delayed thus affecting surgical morbidity? AB - OBJECTIVE: To examine the incidence of late presentation of patients with recurrent pleomorphic adenoma (RPA) of the parotid gland. METHODS: This is a retrospective analysis of patients treated in our center. We examined patients demographics, disease characteristics, treatment, and outcome and as well as the time period length from the first discovery of a recurrent mass until seeking treatment at our clinic and its effect on morbidity. RESULTS: A total of 30 patients were included. 26% underwent initial enucleation in other institutions. In eight patients (26%), the recurrence of the mass was second or higher. The patients average time period length until seeking treatment was 2.48 years, with 33% of patients showing a time period length of over three years. Multifocal tumor, tumor diameter larger than 2 cm and facial nerve involvement were found in 15 (50%),16 (53.3%) and seven (25%) patients respectively. Patient's delay of presentation by >=3 years was associated with a tumor size of >=2 cm (Relative Risk [RR] = 2, p = .02). Patient's delay of presentation by >=2 years was also associated with a trend towards a higher rate of post-operative facial nerve palsy (RR = 3.37, p = .07, CI = 0.88-12.85). CONCLUSION: Most patients with RPA were presented late, thus affecting disease extent and surgical morbidity. PMID- 29141487 TI - Immunomodulatory activities of isolated compounds from the root-bark of Cussonia arborea. AB - CONTEXT: Cussonia arborea Hochst. ex A. Rich (Araliaceae) is a folk medicine used to treat various diseases. However, there is no report of the root phytochemistry. OBJECTIVE: This study isolates and identifies the immunomodulatory compounds from root-bark of C. arborea. MATERIALS AND METHODS: The methanol extract (18 g) was subjected to repeated column chromatography resulting in isolation of five compounds (1-5). Structure determination was achieved by analysis of their 1 D and 2 D NMR, and mass spectroscopy. The compounds (100-1.0 MUg/mL) were examined immunomodulatory for effect on production of reactive oxygen species (ROS) from whole blood phagocytes and on proliferation of T-cells. The compounds cytotoxicity (100-1.0 MUg/mL) was evaluated on NIH-3T3 normal fibroblast cells. RESULTS: Three pentacyclic triterpenoids [3, 23-dihydroxy-12-oleanen-28-oic acid (1), 3beta-hydroxylolean-12 en-28-oic (2) and 23-hydoxy-oxo-urs-12-en-28-oic acid (5)], two phytosterols: [stigmasterol (3)] and [3-O-beta-d-glucopyranosyl stigmasterol (4)] were all isolated from the methanol soluble extract. All the tested compounds (1-4) were found to be nontoxic on NIH-3T3 cells. Compound 1 and 2 moderately inhibited the production of ROS (IC50 = 24.4 +/- 4.3 and 37.5 +/- 0.1 MUg/mL, respectively) whereas compound 2 exhibited the highest inhibitory effect (IC50 = 12.6 +/- 0.4 MUg/mL) on proliferation of phytoheamagglutinin (PHA) activated T-cells. CONCLUSIONS: The isolated compounds (1-5) are reported for the first time from this species. In addition, compound 2 with suppressive potential on production of intracellular ROS and proliferation of T-cells could be of immense value in control of autoimmune diseases as well as in immune compromised patients. PMID- 29141488 TI - EUS-guided lauromacrogol ablation of insulinomas: a novel treatment. AB - BACKGROUND AND AIMS: EUS-guided ablation with ethanol has been used to treat insulinoma since 2006 as a minimally invasive alternative for those who are unwilling or unsuitable for surgeries. However, pancreatic fistula, pancreatitis and other adverse effects were found after the procedure in these patients. Herein, we aimed to find a novel feasible injection. METHODS: Seven patients with different chief complaints were diagnosed with insulinoma by symptoms, lab results and pathology results from EUS fine needle aspiration. All the patients refused to have surgeries and were treated by EUS-guided ablation with lauromacrogol. The injection volume was calculated by tumor size. All the patients were followed up by at least 1 month to see if there is any adverse effect. Blood glucose (BG), insulin and C-peptide levels were monitored before and after the procedure. RESULTS: Insulinoma size ranged from 0.76 cm *0.84 cm to 3.39 cm *1.84 cm. With a mean injection volume of 1.9 ml (range from 0.9 to 3.9 ml), all the patients showed relief in symptoms after the procedure. During the follow up, their BG, insulin and C-peptide levels went back to normal. None of the patients had any adverse effect. CONCLUSIONS: EUS-guided ablation with lauromacrogol showed good treatment results and received no adverse effect after the procedure. Hence, we consider it as an effective and safe method to treat insulinoma. PMID- 29141489 TI - Non-linear conversion of HX4 uptake for automatic segmentation of hypoxic volumes and dose prescription. AB - BACKGROUND: Tumour hypoxia is associated with increased radioresistance and poor response to radiotherapy. Pre-treatment assessment of tumour oxygenation could therefore give the possibility to tailor the treatment by calculating the required boost dose needed to overcome the increased radioresistance in hypoxic tumours. This study concerned the derivation of a non-linear conversion function between the uptake of the hypoxia-PET tracer 18F-HX4 and oxygen partial pressure (pO2). MATERIAL AND METHODS: Building on previous experience with FMISO including experimental data on tracer uptake and pO2, tracer-specific model parameters were derived for converting the normalised HX4-uptake at the optimal imaging time point to pO2. The conversion function was implemented in a Python-based computational platform utilising the scripting and the registration modules of the treatment planning system RayStation. Subsequently, the conversion function was applied to determine the pO2 in eight non-small-cell lung cancer (NSCLC) patients imaged with HX4-PET before the start of radiotherapy. Automatic segmentation of hypoxic target volumes (HTVs) was then performed using thresholds around 10 mmHg. The HTVs were compared to sub-volumes segmented based on a tumour to-blood ratio (TBR) of 1.4 using the aortic arch as the reference oxygenated region. The boost dose required to achieve 95% local control was then calculated based on the calibrated levels of hypoxia, assuming inter-fraction reoxygenation due to changes in acute hypoxia but no overall improvement of the oxygenation status. RESULTS: Using the developed conversion tool, HTVs could be obtained using pO2 a threshold of 10 mmHg which were in agreement with the TBR segmentation. The dose levels required to the HTVs to achieve local control were feasible, being around 70-80 Gy in 24 fractions. CONCLUSIONS: Non-linear conversion of tracer uptake to pO2 in NSCLC imaged with HX4-PET allows a quantitative determination of the dose-boost needed to achieve a high probability of local control. PMID- 29141490 TI - Study on enhanced lymphatic tracing of isosulfan blue injection by influence of osmotic pressure on lymphatic exposure. AB - Isosulfan blue (IB) is being used as a lymphatic tracer has been approved by the FDA in 1981. This study aimed at improving lymphatic exposure of IB injection by osmotic pressure regulation to achieve step-by step lymphatic tracing. First, IB injection with appropriate osmotic pressure, stability, and suitable pH was prepared. Next, the lymphatic tracing ability of different osmotic pressure was studied to determine the blue-stained state of IB in three-level lymph nodes after subcutaneous administration. Furthermore, pharmacokinetics of lymphatic drainage, lymph node uptake, and plasma concentration was investigate to explore the improving law of the lymphatic tracing by osmotic pressure, and combined with tissue irritation to determine the optimal osmotic pressure. At last, the tissue distribution in mice of IB injection which had the property of optimal osmotic pressure was investigated. The results showed that increasing osmotic pressure could significantly reduce injection site retention and increase IB concentration of lymph node. The lymph nodes could be obviously blue-stained by IB injection which had 938 mmol/kg osmotic pressure and would not cause inflammatory reaction and blood exposure. The tissue distribution study suggested that IB injection which had 938 mmol/kg osmotic pressure was mainly distributed into gallbladder and duodenum that verified the reports that 90% IB was excreted through the feces through biliary excretion. In conclusion, this study provides the basic study to improve lymphatic exposure of IB injection by regulate the osmotic pressure and have the potential to be the helpful guidance for the elective lymph node dissection. PMID- 29141491 TI - Association of psychosis, affective disorders and diseases affecting the immune system. AB - : Purpose of the article: There are indications of altered immune activity in depressed and psychotic patients compared to healthy controls in several studies. To explore the clinical importance of this phenomenon we examined the relation between different disorders affecting the immune system and psychoses and depression, respectively. MATERIALS AND METHODS: A total of 276 patients consecutively admitted to a psychiatric acute ward were included in the study. Of these 41 patients fulfilled the criteria for ICD-10 F20-29 (psychotic) diagnosis and 157 patients a F30-39 (affective) diagnosis. Information on diseases affecting the immune system in patients themselves and family members of the patients were obtained by a self-report questionnaire. RESULTS: Comparing the two groups showed a significant correlation between the F20-29 group and eczema (r = 0.116, p = .037). Comparing what patients reported for family members showed a significantly higher frequency of epilepsy (p = .033) in the F20-29 group. Summarizing all immunological diseases for family members showed a significantly higher frequency in the F30-39 group compared to the F20-29 group (chi2 = 4, 82, df = 1, p = .028). CONCLUSIONS: There may be differences between the F20-29 and F30-39 groups and their family members regarding risk for diseases affecting the immune system. This is in line with different activity of the immune system measured in blood for the disorders and may add information regarding etiology and pathology of these psychiatric diseases. Further studies including a greater number of subjects, as well as confirmation of the immunological diseases through blood samples are needed. PMID- 29141493 TI - The effect of unimodal affective priming on dichotic emotion recognition. AB - The present report concerns two experiments extending to unimodal priming the cross-modal priming effects observed with auditory emotions by Harding and Voyer [(2016). Laterality effects in cross-modal affective priming. Laterality: Asymmetries of Body, Brain and Cognition, 21, 585-605]. Experiment 1 used binaural targets to establish the presence of the priming effect and Experiment 2 used dichotically presented targets to examine auditory asymmetries. In Experiment 1, 82 university students completed a task in which binaural targets consisting of one of 4 English words inflected in one of 4 emotional tones were preceded by binaural primes consisting of one of 4 Mandarin words pronounced in the same (congruent) or different (incongruent) emotional tones. Trials where the prime emotion was congruent with the target emotion showed faster responses and higher accuracy in identifying the target emotion. In Experiment 2, 60 undergraduate students participated and the target was presented dichotically instead of binaurally. Primes congruent with the left ear produced a large left ear advantage, whereas right congruent primes produced a right ear advantage. These results indicate that unimodal priming produces stronger effects than those observed under cross-modal priming. The findings suggest that priming should likely be considered a strong top-down influence on laterality effects. PMID- 29141492 TI - A case report of hyponatremia after surgery for Conn's adenoma. AB - Primary aldosteronism (PA), also known as Conn's syndrome, is a frequent cause of secondary hypertension. If PA is due to a documented unilateral adrenal adenoma, adrenalectomy is the treatment of choice. Endocrine Society guidelines suggest monitoring potassium after adrenalectomy, while there is no mention of sodium disorders after surgery. Here we report the case of a patient with Conn's syndrome who developed hyponatremia after surgery. This was an unexpected event in the course of the treatment, which sheds light on the fact that low levels of aldosterone strongly influence sodium concentration, and advises clinicians to monitor sodium after adrenalectomy. PMID- 29141494 TI - Influence of script direction on word processing modes in left and right visual fields. AB - Word processing in left (LVF) and right (RVF) visual fields may be affected by left hemisphere activation during reading and by script direction. We evaluated the effect of script direction by presenting words in left-to-right (French) and right-to-left (Hebrew) scripts to bilingual French participants. Words of different lengths were presented in the LVF and the RVF in a naming task. Results showed (1) a stronger word length effect in the LVF than in the RVF in French, and no difference of word length effect between LVF and RVF in Hebrew; (2) a first-letter advantage only in the LVF in French and in the RVF in Hebrew, showing an effect of script direction on letter processing; and (3) a stronger advantage of external over internal letters in words presented in the LVF than in the RVF for both languages, showing a left hemisphere influence on letter activation. Thus, script direction and left hemisphere activation may affect different processes when reading words in LVF and RVF. Selective attention may orient and redistribute a processing "window" over the letter string according to script direction, and the modulation of attentional resources is influenced by left hemisphere activation. PMID- 29141495 TI - Late osteomyelitis and abscess formation of the ulna after high-voltage electrical injuries: review of literature and case report. PMID- 29141496 TI - Power and pacing calculations based on real-time locating data from a cross country skiing sprint race. AB - Pacing strategies in cross-country skiing have been investigated in several studies. However, none of the previous studies have been verified by collected skiing data giving the skiing velocities along a measured track. These can be used to calculate the propulsive power output. Collected real-time positioning data from a cross-country sprint skiing race were used to estimate the propulsive power by applying a power balance model. Analyses were made for the time-trial and the final for one female and one male skier. The average propulsive power over the whole race times were 311 and 296 W during the time trial and 400 and 386 W during the final, for the female and male skier, respectively. Compared to the average propulsive power over the whole race, the average active propulsive phases were calculated as 33 and 44% higher in the time trials and 36 and 37% higher in the finals for the female and male, respectively. The current study presents a novel approach to use real-time positioning data to estimate continuous propulsive power during cross-country sprint skiing, enabling in-depth analyses of power output and pacing strategies. PMID- 29141497 TI - Soft poly(2-chloroaniline)/pectin hydrogel and its electromechanical properties. AB - Pectin hydrogels were successfully fabricated with various physical crosslinkers and concentrations for soft actuator applications. A small amount of synthesized P2ClAn was added as a dispersed phase into the pectin matrix. The electromechanical properties of the pectin hydrogels and blends were investigated under the effects of electric field strength, ionic crosslinker type and concentration, and P2ClAn concentration. The electromechanical properties of the pectin hydrogel as crosslinked by Fe2+ were superior to other pectin hydrogels. The pristine pectin hydrogel and the P2ClAn/Pectin hydrogel blended with 0.10%v/v P2ClAn provided the high storage modulus sensitivity values of 8.61 and 14.01, respectively, under the electric field strength of 800 V/mm. The P2ClAn/Pectin hydrogel blend responded to the electric field with higher dielectrophoretic forces, but lower deflections relative to the pristine pectin hydrogel due to the additional P2ClAn polarization and the latter lower rigidity. PMID- 29141498 TI - Incidence and Natural Progression of Neurogenic Shock after Traumatic Spinal Cord Injury. AB - Neurogenic shock, a distributive type of circulatory shock after spinal cord injury (SCI), results in profound hypotension. The consequent hemodynamic instability complicates clinical management, delays surgical intervention, and impacts neurological outcome. Moreover, the reported incidence of this condition varies significantly. We establish the true incidence of neurogenic shock by comparing the most common clinical definitions used to diagnose the condition. Further, we characterize the acute progression and recovery of neurogenic shock. Daily blood pressure, heart rate, and fluid management as well as vasopressor therapy and neurologic status were collected over 30 days from 84 adults admitted to our tertiary trauma center after cervical (n = 56) and thoracic (n = 28) SCI. We found that the reported incidence of neurogenic shock varied greatly depending on which clinical definition was applied. By using a novel combination of hemodynamic and laboratory criteria to define neurogenic shock, the calculated incidence (29% cervical SCI) in our sample most appropriately reflects the true incidence, finding that hypovolemia was the primary factor responsible for the inconsistency in incidence reports between studies. In addition, we found a characteristic decline in blood pressure after the first week post-injury and that fluid management is not currently an integral aspect of clinical management (all persons were treated at a net fluid intake <= zero). The results demonstrate the need for accurate identification of neurogenic shock through consistent and appropriate criteria, which is not only important from a clinical point of view, but also in establishing accurate epidemiology to responsibly allocate resources to its management. PMID- 29141499 TI - Gastrointestinal causes of sudden unexpected death: A review. AB - Gastrointestinal conditions are a less common cause of sudden unexpected death when compared to other conditions such as cardiovascular conditions, but they are equally important. Various congenital and acquired gastrointestinal conditions that have resulted in sudden unexpected death are discussed. The possible lethal mechanisms behind each condition, along with any associated risk factors or secondary diseases, have been described. Through this article, we aim to highlight the need for physicians to prevent death in such conditions by ensuring that subclinical cases are diagnosed correctly before it is too late and by providing timely and efficacious treatment to the patient concerned. In addition, this review would certainly benefit the forensic pathologist while dealing with cases of sudden unexpected death due to gastrointestinal causes. This article is a review of the major gastrointestinal causes of sudden unexpected death. In addition, related fatal cases encountered occasionally in forensic autopsy practice are also included. There are several unusual and rare causes of life threatening gastrointestinal bleeding that may lead to sudden unexpected death to cover all the entities in detail. Nevertheless, this article is a general guide to the topic of gastrointestinal causes of sudden unexpected death. PMID- 29141500 TI - Considerations for the use of functional principal components analysis in sports biomechanics: examples from on-water rowing. AB - The proliferation of new biomechanical technology in laboratory and field settings facilitates the capture of data-sets consisting of complex time-series. An understanding of the appropriate statistical approaches for analysing and interpreting these data-sets is required and the functional data analysis (FDA) family of statistical techniques has emerged in the biomechanical literature. Given the use of FDA is currently in its infancy with biomechanical data, this paper will form the first of a two part series aiming to address practical issues surrounding the application of FDA techniques in biomechanics. This work focuses on functional principal components analysis (fPCA), which is explored using existing literature and sample data from an on-water rowing database. In particular methodological considerations for the implementation of fPCA such as temporal normalisation of data, removal of unwanted forms of variation in a data set and documented methods for preserving the original temporal properties within a set of curves are explored in detail as a part of this review. Limitations and strengths of the technique are outlined and recommendations are provided to encourage the appropriate use of fPCA within the field of applied sports biomechanics. PMID- 29141501 TI - Transient Hypertension after Spinal Cord Injury Leads to Cerebrovascular Endothelial Dysfunction and Fibrosis. AB - We aimed to create a clinically relevant pre-clinical model of transient hypertension, and then evaluate the pathophysiological cerebrovascular processes resulting from this novel stimulus, which has recently been epidemiologically linked to cerebrovascular disease. We first developed a clinically relevant model of transient hypertension, secondary to induced autonomic dysreflexia after spinal cord injury and demonstrated that in both patients and rats, this stimulus leads to drastic acute cerebral hyperperfusion. For this, iatrogenic urodynamic filling/penile vibrostimulation was completed while measuring beat-by-beat blood pressure and cerebral blood flow (CBF) in patients. We then developed a rodent model mimicking the clinical reality by performing colorectal distention (to induce autonomic dysreflexia) using pre-clinical beat-by-beat blood pressure and CBF assessments. We then performed colorectal distension in rats for four weeks (6x/day) to evaluate the long-term cerebrovascular consequences of transient hypertension. Outcome measures included middle cerebral artery endothelial function, remodeling, profibrosis and perivascular innervation; measured via pressure myography, immunohistochemistry, molecular biology, and magnetic resonance imaging. Our model demonstrates that chronic repetitive cerebral hyperperfusion secondary to transient hypertension because of autonomic dysreflexia: (1) impairs cerebrovascular endothelial function; (2) leads to profibrotic cerebrovascular stiffening characterized by reduced distensibility and increased collagen deposition; and (3) reduces perivascular sympathetic cerebrovascular innervation. These changes did not occur concurrent to hallmark cerebrovascular changes from chronic steady-state hypertension, such as hypertrophic inward remodeling, or reduced CBF. Chronic exposure to repetitive transient hypertension after spinal cord injury leads to diverse cerebrovascular impairment that appears to be unique pathophysiology compared with steady-state hypertension in non-spinal cord injured models. PMID- 29141502 TI - CO2 utilization via a novel anaerobic bioprocess configuration with simulated gas mixture and real stack gas samples. AB - : CO2, which is considered to be one of the major causes of climate change, has reached to critical levels in the atmosphere due to tremendous consumption of fossil fuels all over the world. In this study, anaerobic bioconversion of CO2 into bio-methane using a novel bioprocess configuration (HYBRID bioreactor) was studied under mesophilic conditions. Varying ratios of H2/CO2 gas mixture and volumetric feeding rates were investigated and no additional organic matter and trace element were needed throughout the study. The maximum methane production of 19 m3 CH4/m3reactor/d was achieved at a H2/CO2 ratio of 4:1 and feeding rate of 24 m3 gas/m3reactor/d. It was determined that H2 conversion rate is about 96%. For demonstration purpose, real stack gas sample from a petrochemical industry was also tested under optimized operational conditions. No inhibitory effect from stack gas mixture was observed. This study provided an environmentally friendly and sustainable solution for industries such as petrochemical industry in order to produce extra energy while capturing their waste CO2. Thereby, a sustainable and environmentally friendly model solution was presented for industries with high CO2 emissions. ABBREVIATIONS: COV: coefficient of variation; Gt: gigatone; IEA: International Energy Agency; IPCC: International Panel on Climate Change; MBBR: moving bed biofilm reactor; MJ: Megajoule; UASB: upflow anaerobic sludge blanket; VFR: volumetric feeding rate. PMID- 29141504 TI - To treat or not to treat: Microfilaria detected in Pap smear. PMID- 29141503 TI - Association of the genetic and traditional risk factors of ischaemic heart disease with STEMI and NSTEMI development. AB - INTRODUCTION: To evaluate the influence of traditional risk factors of ischaemic heart disease and genetic factors to predict different types of acute coronary syndromes. MATERIALS AND METHODS: Five hundred and twenty-three patients with acute coronary syndromes (393 with ST elevation myocardial infarction (STEMI) and 130 with non-ST elevation myocardial infarction (NSTEMI)) comprised the study group. The control group consisted of 645 subjects free from symptoms of ischaemic heart disease and stroke. Genetic polymorphisms of MMP-2 (-735) C/T, MMP-2 (-1306) C/T, MMP-3 (-1171) 5A/6A, MMP-9 (-1562) C/T and ACE I/D were evaluated using polymerase chain reaction. RESULTS: Patients with acute coronary syndromes more often had ID or II genotype than DD genotype of ACE ( P = 0.04) and 5A5A or 5A6A genotype than 6A6A genotype of MMP-3 ( P = 0.02) in comparison to the control group. The genotypes of other matrix metalloproteinase genes did not differ between the groups. 5A5A and 5A6A genotypes of MMP-3 (odds ratio (OR) 1.5; P = 0.021), II and ID genotypes of ACE (OR 1.7; P = 0.006) along with traditional ischaemic heart disease risk factors such as smoking (OR 4.9; P = 0.001), hypertension (OR 2.0; P = 0.001), diabetes mellitus (OR 2.9; P = 0.001) and dyslipidaemia (OR 2.1; P = 0.001) increased the risk of STEMI. However, the polymorphism of MMP-3 5A/6A and ACE I/D was not associated with the occurrence of NSTEMI. CONCLUSIONS: Genetic polymorphisms of MMP-3 5A/6A and ACE I/D along with conventional ischaemic heart disease risk factors increase the risk of the occurrence of STEMI, while having no influence on the pathogenesis of NSTEMI. PMID- 29141505 TI - Serum zinc, copper and iron status of children with coeliac disease on three months of gluten-free diet with or without four weeks of zinc supplements: a randomised controlled trial. AB - Data about the effect of zinc supplementation with gluten-free diet on normalisation of plasma zinc, copper and iron in patients with coeliac disease are scanty. We evaluated the effect of zinc supplementation on serum zinc, copper and iron levels in patients with coeliac disease, by randomising 71 children newly diagnosed with coeliac disease into two groups: Group A = gluten-free diet (GFD); and Group B = gluten-free diet with zinc supplements (GFD +Zn). The rise in iron and zinc was significantly higher in the latter, but the mean rise of copper levels was slightly higher in the former, but the difference was not significant. PMID- 29141506 TI - Triathlon transition study: quantifying differences in running movement pattern and precision after bike-run transition. AB - Various publications discuss the discrepancies of running in triathlons and stand alone runs. However, those methods, such as analysing step-characteristics or ground-contact time, lack the ability to quantitatively discriminate between subtle running differences. The attractor method can be applied to overcome those shortcomings. The purpose was to detect differences in athletes' running patterns (deltaM) and movement precision (deltaD) by comparing a 5,000 m run after a prior cycling session (TRun) with an isolated run over the same distance (IRun). Participants completed the conditions on a track and a stationary trainer, allowing the use of their personal bike to simulate an Olympic triathlon. During each run, three-dimensional acceleration data, using sensors attached to the ankles, were collected. Results showed that both conditions lead to elevated attractor parameters (deltaM and deltaD) over the initial five minutes before the athletes found their rhythm. This generates a new perspective because independent of running after a bike session or without preload, an athlete needs certain time to adjust to the running movement. Coaches must consider this factor as another tool to fine-tune pacing and performance. Moreover, the attractor method is a novel approach to gain deeper insight into human cyclic motions in athletic contexts. PMID- 29141507 TI - Sandwiched White Adipose Tissue: A Microphysiological System of Primary Human Adipose Tissue. AB - White adipose tissue (WAT) is a critical organ in both health and disease. However, physiologically faithful tissue culture models of primary human WAT remain limited, at best. In this study we describe a novel WAT culture system in which primary human WAT is sandwiched between tissue-engineered sheets of adipose derived stromal cells. This construct, called "sandwiched white adipose tissue" (SWAT), can be defined as a microphysiological system (MPS) since it is a tissue engineered, multicellular, three-dimensional organ construct produced using human cells. We validated SWAT against the National Institutes of Health MPS standards and found that SWAT is viable in culture for 8 weeks, retains physiologic responses to exogenous signaling, secretes adipokines, and engrafts into animal models. These attributes position SWAT as a powerful tool for the study of WAT physiology, pathophysiology, personalized medicine, and pharmaceutical development. PMID- 29141508 TI - Anti-Mullerian Hormone (AMH) May Stall Ovarian Cortex Function Through Modulation of Hormone Receptors Other Than the AMH Receptor. AB - OBJECTIVE: To test whether recombinant anti-Mullerian hormone (AMH) can inhibit ovarian cortex function by modulating the expression of other hormone receptors. MATERIALS AND METHODS: Pilot experimental study with ovarian cortex obtained from 5 patients. Immediately after explant, the ovarian cortex specimens were divided into 5 equal fragments. One fragment was flash-frozen (uncultured) and 4 were incubated for 48 hours at 37 degrees C in a pH-adjusted gamete buffer medium with increasing AMH concentrations of 0, 5, 25, and 50 ng/mL. After incubation, all specimens were rinsed and flash-frozen for polymerase chain reaction (PCR) executed in triplicates. We utilized real-time reverse transcription-polymerase chain reaction (RT-PCR) to determine messenger RNA (mRNA) levels of AMH and its receptor Anti-Mullerian Hormone-Receptor 2 (AMH-R2), follicle stimulating hormone receptor (FSH-R), luteinizing hormone receptor (LH-R), inhibin B, and insulin like growth factor 1 receptor 1 (IGF1-R1) in ovarian cortex tissue. In addition, we performed Ki-67 immunostaining to evaluate cell proliferation in the treatment groups. RESULTS: Absence of recombinant human AMH (rAMH) caused upregulation of all markers. Exposure to increasing rAMH concentrations caused tissue AMH expression downregulation ( P = .024), while AMH-R2 ( P = .005), FSH-R ( P = .009), LH-R ( P = .003), and inhibin B ( P = .001) mRNA expression followed a bell-shaped response with an increased expression at low dose, followed by a decreased expression at higher doses. Expression of IGF1-R1 was independent ( P = .039) of rAMH exposure. The Ki-67 immunostaining showed an increased cell proliferation in the media control compared to the uncultured and the tissue cultured with rAMH. CONCLUSIONS: Culture with increasing rAMH concentrations caused downregulation of its own, as well as other hormone receptors, and a decreased ovarian cortex cell proliferation. These results help understanding the inhibitory effects of AMH on follicular development. PMID- 29141509 TI - Relative Morphokinetics Assessed by Time-Lapse Imaging Are Altered in Embryos From Patients With Endometriosis. AB - INTRODUCTION: Time-lapse technology allows almost continuous noninvasive assessment of embryonic development. It was shown previously that relative kinetics defining cleavage synchronicity are better predictors of blastocyst quality than absolute time points. This study aims to compare relative kinetics in embryos from patients with and without endometriosis. METHODS: Time-lapse data were collected retrospectively from 596 patients undergoing infertility treatment for in vitro fertilization from January 2011 to July 2016. Four hundred twenty eight patients with confounding comorbidities (ie, polycystic ovary syndrome, pathological spermiogram in the included cycle, numerical/structural genetic abnormalities, preimplantation genetic screening performed) or incomplete data sets were excluded. Of the 168 included patients, 72 (42.9%) had endometriosis. Indications for in vitro fertilization of controls were tubal factor, unexplained infertility, or prolonged infertility. Relative kinetics were calculated as defined previously: cleavage synchronicity (CS)2-8=((t3-t2) + (t5-t4))/(t8-t2), CS4-8=(t8-t5)/(t8-t4), CS2-4=(t4-t3)/(t4-t2), DNA replication time ratio (DR)=(t3 t2)/(t5-t3). In women with more than one embryo, the median time was analyzed. RESULTS: Median age, body mass index, smoking status, and AMH levels were similar in both groups. Embryos from patients with endometriosis showed poorer relative kinetics. The relative time CS2-8 was decreased in embryos from patients with endometriosis (0.7 [0.0-0.93] vs 0.8 [0.0-0.94], P < .05) and CS4-8 was increased (0.4 [0.0-1.0] vs 0.3 [0.0-1.0], P < .05). The less powerful diagnostic relative kinetic parameters (CS2-4 and DR) were not significantly different. CONCLUSIONS: Embryos from patients with endometriosis presented with altered relative kinetics suggesting poorer embryo quality. These findings support recently published data demonstrating reduced oocyte quality in patients with endometriosis which is one possible explanation for their poor response to fertility treatment. PMID- 29141510 TI - Gasification of algal biomass (Cladophora glomerata L.) with CO2/H2O/O2 in a circulating fluidized bed. AB - Gasification is one of the most important thermochemical routes to produce both synthesis gas (syngas) and chars. The quality of produced syngas wieldy depends on the operating conditions (temperature, residence time, heating rate, and gasifying agent), hydrodynamic properties of gasifier (particle size, minimum fluidization velocity, and gasifier size), and type of feedstock (coal, biomass, oil, and municipal solid wastes). In the present study, simulation of syngas production via circulating fluidized bed (CFB) gasification of algal biomass (Cladophora glomerata L.) at different gasifying agents and particle sizes was carried out, using Aspen Plus simulator. The model which has been validated by using experimental data of the technical literature was used to evaluate the influence of operating conditions on gas composition and performance parameters. The results show that biomass gasification using pure oxygen as the gasification agent has great potential to improve the caloric value of produced gas and performance indicators. It was also found that the produced gas caloric value, syngas yield, and performance parameters (CCE and CGE) increase with reaction temperature but are inversely proportional to the biomass particle size. PMID- 29141511 TI - A Multimodal Magnetic Resonance Imaging Study of Recovery of Consciousness in Severe Traumatic Brain Injury: Preliminary Results. AB - Accurate and reliable assessment of the conscious state of patients with severe traumatic brain injury (TBI) is vital for their future management. The purpose of the present study is to find an effective and accurate magnetic resonance imaging (MRI) method for predicting recovery of consciousness in patients with severe TBI. Multimodal MR techniques, including structural MRI, MR spectroscopy (MRS), diffusion tensor imaging (DTI), were used to evaluate brain damage in 58 patients with severe TBI. Statistical analysis compared imaging results and recovery over a relatively long period to find the most potent prognostic indicators and predictive method. A total 33 patients gained recovery of consciousness (RC), and 25 did not (NRC). Compared with the RC group, those in the NRC group had a significantly lower N-acetylaspartate to creatine (NAA/Cr) ratio of pons (1.43 +/ 0.54 vs. 1.70 +/- 0.42), more fiber lines (1046.3 +/- 100.8 vs. 975.6 +/- 128.1), less peripheral grey matter (pgrey) (579.23 +/- 78.85 vs. 638.23 +/- 61.16), lower fractional anisotropy (FA) of fibers (0.42 +/- 0.04 vs. 0.45 +/- 0.03), older age (43.08 +/- 14.61 vs. 30.57 +/- 12.89), and higher apparent diffusion coefficient (ADC) of fibers (0.99 +/- 0.14 vs. 0.89 +/- 0.06); all p < 0.05. Age, pgrey, ADC of fibers, NAA/Cr of pons were selected by logistic regression analysis to predict RC, with p values of 0.033 and 0.031, 0.035, 0.030, respectively. Age, pgrey, ADC of fibers, NAA/Cr of pons are effective indicators in the predictive model of RC. PMID- 29141512 TI - The impact of own and others' alcohol consumption on social contagion following a collaborative memory task. AB - When one person alters his or her recollection of an event to be consistent with another person's erroneous account of the same event, social contagion has occurred. In two studies, we examined whether alcohol consumption influences the degree to which people engage in social contagion. In Study 1, participants consumed alcohol, an alcohol placebo, or a soft drink and then completed a collaborative recall test with a confederate who consumed a soft drink. In Study 2, participants consumed a soft drink and then completed a collaborative recall test with a confederate they believed had consumed a soft drink or alcohol (but no alcohol was ever consumed). In both studies, the confederate made scripted errors during the collaborative recall test. On post-collaborative individual recall and recognition tests, participants in both studies engaged in social contagion by including the confederate's errors in their own recollection. In Study 1, the drink participants consumed had no influence on social contagion. In Study 2, participants were less likely to engage in social contagion after collaborating with a confederate who had seemingly consumed alcohol. That same confederate was viewed as less accurate, trustworthy, and credible, which likely made participants less inclined to engage in social contagion. PMID- 29141513 TI - Alternative Scapular Stabilization Exercises to target strength, endurance and function of shoulders in tetraplegia: a prospective non-controlled intervention study. AB - OBJECTIVE: Scapular stabilization exercises (SSE) are well-established for the able-bodies. The aim of the current study is to access the potential benefits of SSE on isometric internal and external rotator strength, endurance and function of the shoulder in persons with tetraplegia, throughout a 12-week exercise program consisting of five resisted movements with elastic bands. DESIGN: Prospective non-controlled intervention study. Setting/Participants/Interventions: A convenience sample of 17 subjects (age, 40.0+/-10.0 years old) with SCI was recruited from the University Hospital at the State University of Campinas (UNICAMP) from March 2015 to February 2016. They performed 5-resisted-SSE for 12 weeks, using Thera-band(r) elastic bands. Four evaluations were required: Baseline1, Baseline2, 6W and 12W. OUTCOME MEASURES: The dependent variables were isometric internal and external rotation strength, flexion and abduction endurance and the Disabilities of the Arm, Shoulder and Hand (DASH) score. RESULTS: Isometric external rotation strength and flexion endurance increased after SSE and were classified as "clinically relevant" using minimal importance difference (MID). Abduction endurance increased but it was classified as "not clinically relevant". DASH score reported no significant differences but it was classified as "potentially clinically relevant". Correlations were observed among time since injury and endurance improvements. CONCLUSION: This study demonstrated that specific training of the scapula muscles shows a benefit for shoulder strength, endurance and function of the shoulder in subjects with tetraplegia and should be part of the rehabilitation program. Besides, the SSE can be performed by subjects with tetraplegia themselves on a regular basis. PMID- 29141514 TI - Regulatory effect of neuroglobin in the recovery of spinal cord injury. AB - OBJECTIVE: The present study was aimed to investigate the therapeutic potential of neuroglobin in the recovery of spinal cord injury. METHODS: The male albino Wistar strain rats were used as an experimental model, and adeno associated virus (AAV) was administered in the T12 section of spinal cord ten days prior to the injury. Basso Beattie Bresnahan (BBB) locomotor rating scale was used to determine the recovery of the hind limb during four weeks post-operation. Malondialdehyde (MDA), catalase and superoxide dismutase (SOD) were determined in the spinal cord tissues. Terminal deoxynucleotidyl transferase (TdT) dUTP Nick End Labeling (TUNEL) assay was carried out to determine the presence of apoptotic cells. Immunofluorescence analysis was carried out to determine the neuroglobin expression. Western blot analysis was carried out to determine the protein expressions of caspase-3, cytochrome c, bax and bcl-2 in the spinal cord tissues. RESULTS: Experimental results showed that rats were recovered from the spinal cord injury due to increased neuroglobin expression. Lipid peroxidation was reduced, whereas catalase and SOD activity were increased in the spinal cord tissues. Apoptosis and lesions were significantly reduced in the spinal cord tissues. Caspase-3, cytochrome c and bax levels were significantly reduced, whereas bcl-2 expression was reduced in the spinal cord tissues. CONCLUSION: Taking all these data together, it is suggested that the increased neuroglobin expression could improve the locomotor function. PMID- 29141515 TI - MRI-powered biomedical devices. AB - Magnetic resonance imaging (MRI) is beneficial for imaging-guided procedures because it provides higher resolution images and better soft tissue contrast than computed tomography (CT), ultrasound, and X-ray. MRI can be used to streamline diagnostics and treatment because it does not require patients to be repositioned between scans of different areas of the body. It is even possible to use MRI to visualize, power, and control medical devices inside the human body to access remote locations and perform minimally invasive procedures. Therefore, MR conditional medical devices have the potential to improve a wide variety of medical procedures; this potential is explored in terms of practical considerations pertaining to clinical applications and the MRI environment. Recent advancements in this field are introduced with a review of clinically relevant research in the areas of interventional tools, endovascular microbots, and closed-loop controlled MRI robots. Challenges related to technology and clinical feasibility are discussed, including MRI based propulsion and control, navigation of medical devices through the human body, clinical adoptability, and regulatory issues. The development of MRI-powered medical devices is an emerging field, but the potential clinical impact of these devices is promising. PMID- 29141516 TI - How to assess communication skills? Development of the rating scale ComOn Check. AB - BACKGROUND: Good communication is a core competency for all physicians. Thus, medical students require adequate preparation in communication skills. For research purposes, as well as for evaluation in teaching, there is a clear need for reliable assessment tools. We analyzed the shortcomings of existing instruments and saw a need for a new rating scale. The aim of this publication is to describe the development process for, and evaluation of, a new rating scale. METHODS: First, we developed the rating scale in 10 steps. Then, two raters evaluated the newly developed rating scale by rating 135 videotaped consultations of medical students with standardized patients. Additionally, standardized patients evaluated students' performance, which was used as an outside criterion to validate ratings. RESULTS: Our rating scale comprises six domains with 13 specific items evaluated on a five-point Likert scale: initiating conversation, patient's perception, structure of conversation, patient's emotions, end of conversation, and general communication skills. Item-total correlation coefficients between the checklist items ranged from 0.15 to 0.78. Subscale consistency was calculated for domains comprised of more than one item and Cronbach's alpha >= 0.77, indicating acceptable consistency. Standardized patients' global evaluation correlated moderately with overall expert ratings (Spearman's rho = .40, p < .001). CONCLUSION: Our rating scale is a reliable and applicable assessment tool. The rating scale focuses on the evaluation of general communication skills and can be applied in research as well as in evaluations, such as objective structured clinical examinations (OSCE). ABBREVIATIONS: CST: Communication skills training; ICC: Intra-class correlation coefficient; OSCE: Objective structured clinical examination; SP: Standardized patients; SD: Standard deviation; M: Mean. PMID- 29141517 TI - Protective effects of dietary omega-3 fatty acid supplementation on organophosphate poisoning. AB - In this study, we aimed to study the possible preventive effect of docosahexaenoic acid (DHA), a dietary omega-3 fatty acid, on toxicity caused by chlorpyrifos (CPF). Six groups of Sprague Dawley rats (200-250 g) consisting of equal numbers of males and females (n = 8) were assigned to study. The rats were orally given for 5 days. The control group was administered pure olive oil, which was the vehicle for CPF. The CPF challenge groups were administered oral physiological saline, pure olive oil, or DHA (50, 100 and 400 mg/kg dosages) for 5 days. The animals were weighed on the sixth day and then administered CPF (279 mg/kg, subcutaneously). The rats were weighed again 24 h following CPF administration. The body temperatures and locomotor activities of the rats were also measured. Blood samples, brain and liver tissues were collected for biochemical, histopathological and immunohistochemical examinations. A comparison with the control group demonstrated that CPF administration increased malondialdehyde (MDA) levels in blood, brain and liver, while it reduced catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) concentrations ( p < 0.05-0.001). Advanced oxidation protein products (AOPPs) increased only in the brain ( p < 0.001). DHA reduced these changes in MDA and AOPP values ( p < 0.05-0.001), while it increased CAT, SOD and GPx concentrations ( p < 0.05 0.001). Similarly, DHA prevented the decreases in body weight, body temperature and locomotor activities caused by CPF at 100 mg/kg and 400 mg/kg dosages ( p < 0.05-0.001). Similar to the physiological and biochemical changes, the histopathological damage scores, which increased with CPF ( p < 0.05-0.01), decreased at all three dosages of DHA ( p < 0.05-0.01). Our findings suggest that DHA, by supporting the antioxidant mechanism, reduces toxicity caused by CPF. PMID- 29141519 TI - Abstracts From the PRIM&R 2017 Advancing Ethical Research Conference. PMID- 29141518 TI - Surgical Management of Renal Cell Carcinoma Extending Into Venous System: A 20 Year Experience. AB - BACKGROUND AND AIMS: The purpose of this study is to report our 20-year experience with the surgical management of renal cell carcinoma extending into the inferior vena cava using a novel classification system. MATERIALS AND METHODS: We retrospectively reviewed the data of 103 patients (69 males, 34 females, mean age: 52.9 +/- 12.6 years) with renal cell carcinoma involving the venous system treated between 1993 and 2014. The inferior vena cava tumor thrombus was classified into five levels: 0 (renal vein, n = 12), 1 (infrahepatic, n = 33), 2a (low retrohepatic, n = 26), 2b (high retrohepatic, n = 19), and 3 (supradiaphragmatic, n = 13). Clinical data were summarized, and overall survival, cancer-specific survival, and disease-free survival were examined by Cox regression analysis. RESULTS: All patients underwent radical surgery. Complete resections of the renal tumor and thrombus were achieved in 101 patients (98.1%). Two intraoperative and one postoperative in-hospital deaths (2.9%) occurred. In total, 19 patients (18.8%) had a total of 29 postoperative complications. Mean follow-up time was 46 months (range, 1-239 months). The 5- and 10-year overall survival rates were 62.9% and 56.0%, respectively. Metastasis, rather than thrombus level, was a significant risk factor associated with overall survival (hazard ratio = 4.89, 95% confidence interval: 2.24-10.67, p < 0.001). CONCLUSION: Our novel classification system can be used to select the optimal surgical approach and method for patients with renal cell carcinoma and venous thrombus. Its use is associated with prolonged survival and relatively few complications. Metastasis is an independent risk factor of overall survival. PMID- 29141520 TI - A simple suture-guiding device for minimally invasive Achilles tendon repair. AB - BACKGROUND: Our hypothesis is to utilize a simple suture-guiding device for minimally invasive repair of Achilles tendon without any extra cost with a minimal risk of rerupture. The purpose of this study is to investigate the results of our minimally invasive technique for Achilles tendon repair using a simple ovarian clamp for suture guiding. MATERIALS AND METHODS: Twenty patients with acute Achilles tendon rupture were treated with minimally invasive repair by an expert orthopaedic surgeon. Instead of an Achillon device, an ovarian clamp was directed to the proximal and distal parts of the Achilles tendon. All data relating to daily activities, walking, climbing stairs, sports activity, American Orthopaedic Foot and Ankle Society (AOFAS) and Thermannscores were recorded. Sural nerve was evaluated with physical examination for paraesthesia, hyperaesthesia, lateralis cruris and foot pain in all patient controls. RESULTS: The average AOFAS score was 97.06 (76-100). All patients had intact Achilles tendon at last control. No rerupture was observed. Average time taken to return to work was 30.8 days (28-60 days). After 6 months, all patients returned to their previous sports activities. CONCLUSION: For Achilles tendon ruptures, minimally invasive repair techniques have shown successful results with low complication rates. Besides their success, some suture-guiding devices bring extra costs for patients or health insurance. Minimally invasive techniques may be performed with devices without any extra cost. Our new suture-guiding device provides knot placement under paratenon like Achillon device to improve outcomes, provides early return to work and minimizes the complications. Finally, our suture-guiding device has no extra cost. PMID- 29141521 TI - Incremental temperature cement delivery technique may prevent cement leakage in metastatic vertebral lesions. AB - OBJECTIVES: To analyze the clinical efficacy and cement leakage rate of percutaneous kyphoplasty (PKP) for the treatment of metastatic vertebral lesions between the two groups using different cement infusion techniques. METHODS: One hundred twenty-nine patients (160 metastatic vertebral fractures) who chose "the incremental temperature cement delivery technique" (ITCDT group) and 105 patients (128 metastatic vertebral fractures) who chose "traditional infusion technique" (TI group) were finally enrolled (nine patients were lost to the follow-up). The visual analog scale (VAS), Oswestry Disability Index (ODI), the local Cobb's angle, the relative height of the vertebral anterior border, and cement leakage were analyzed to evaluate the clinical efficacy of the two cement infusion techniques within postoperative 12 months. RESULTS: There was no significant difference in the VAS scores, ODI scores, the relative height of the vertebral anterior border, and local Cobb's angle between the ITCDT group and TI group preoperatively and postoperatively ( p > 0.05). The cement leakage occurred in three patients of ITCDT group (2.3%), which was significantly less than TI group (12 patients, 11.4%; p < 0.05). CONCLUSIONS: The ITCDT and TI technique in kyphoplasty are effective at relieving pain and improving functional disability, vertebral height, and kyphosis angle; However, kyphoplasty using the ITCDT causes less cement leakage significantly. PMID- 29141522 TI - Perceived comfort during minor hand surgeries with wide awake local anaesthesia no tourniquet (WALANT) versus local anaesthesia (LA)/tourniquet. AB - PURPOSE: Minor hand surgeries can be done under field sterility in procedure rooms. Surgeons are still sceptical about the usage of wide awake local anaesthesia no tourniquet (WALANT) technique. They perceive that patients can tolerate tourniquet for a brief period while they perform minor surgeries under local anaesthesia (LA). We compared the perceived comfort experienced by patients during minor hand surgeries with WALANT and LA/tourniquet. We investigated the difference in preoperative preparation time, operating time and blood loss between the two groups. METHODS: Between July and October 2016, a total of 72 patients were diagnosed with carpal tunnel syndrome, trigger finger or ganglion, at the University Malaya Medical Centre. Forty patients consented to participate in this study and were randomized into WALANT and LA/tourniquet groups. Anaesthesia was administered accordingly and tourniquet was applied. The time taken for preoperative preparation and surgery was recorded. Each surgeon estimated the blood loss. The perceived comfort level of each patient was quantified using a visual analogue score (VAS). Data were analysed using SPSS. RESULTS: The mean VAS for the WALANT group was 2.33 +/- 1.94, whereas it was 4.72 +/- 3.05 for the LA/tourniquet group, and the difference was statistically significant ( p < 0.05). The mean time for preoperative preparation in WALANT group was 19.17 +/- 12.61 min and LA/tourniquet group was 7.05 +/- 3.44 min. The difference between these groups was statistically significant ( p < 0.01). There was no significant difference in operating time and blood loss. CONCLUSION: WALANT technique was associated with better patient comfort. Tourniquet was the main reason for discomfort during surgeries. WALANT is an alternative in minor hand surgeries for a bloodless surgical field without the discomfort of tourniquet application. PMID- 29141523 TI - Introduction to the special section on child and adolescent psychotherapy research. PMID- 29141524 TI - Development of a Simple Sequential Organ Failure Assessment Score for Risk Assessment of Emergency Department Patients With Sepsis. AB - OBJECTIVES: Sepsis-3 recommends using the quick Sequential Organ Failure Assessment (qSOFA) score followed by SOFA score for sepsis evaluation. The SOFA is complex and unfamiliar to most emergency physicians, while qSOFA is insensitive for sepsis screening and may result in missed cases of sepsis. The objective of this study was to devise an easy-to-use simple SOFA score for use in the emergency department (ED). METHODS: Retrospective study of ED patients with sepsis with in-hospital mortality as the primary outcome. A simple SOFA score was derived and validated and compared with SOFA and qSOFA. RESULTS: A total of 3297 patients with sepsis were included, and in-hospital mortality was 10.1%. Simple SOFA had a sensitivity and specificity of 88% and 44% in the derivation set and 93% and 44% in the validation set for in-hospital mortality, respectively. The sensitivity and specificity of qSOFA was 38% and 86% and for SOFA was 90% and 50%, respectively. There were 2760 (84%) of 3297 qSOFA-negative (<2) patients. In this group, simple SOFA had a sensitivity and specificity of 86% and 48% in the derivation set and 91% and 48% in the validation set, respectively. Sequential Organ Failure Assessment was 86% sensitive and 57% specific in qSOFA-negative patients. For all encounters, the areas under the receiver-operator characteristic curves (AUROC) were 0.82 for SOFA, 0.78 (derivation) and 0.82 (validation) for simple SOFA, and 0.68 for qSOFA. In qSOFA-negative patients, the AUROCs were 0.80 for SOFA and 0.76 (derivation) and 0.82 (validation) for simple SOFA. CONCLUSIONS: Simple SOFA demonstrates similar predictive ability for in hospital mortality from sepsis compared to SOFA. External validation of these findings is indicated. PMID- 29141525 TI - Hyperacute Hemodynamic Effects of BiPAP Noninvasive Ventilation in Patients With Acute Heart Failure and Left Ventricular Systolic Dysfunction in Emergency Department. AB - BACKGROUND: Acute heart failure (AHF) is one of the leading causes of admission to emergency department (ED); severe hypoxemic AHF may be treated with noninvasive ventilation (NIV). Despite the demonstrated clinical efficacy of NIV in relieving symptoms of AHF, less is known about the hyperacute effects of bilevel positive airway pressure (BiPAP) ventilation on hemodynamics of patients admitted to ED for AHF. We therefore aimed to assess the effect of BiPAP ventilation on principal hemodynamic, respiratory, pulse oximetry, and microcirculation indexes in patients admitted to ED for AHF, needing NIV. METHODS: Twenty consecutive patients admitted to ED for AHF and left ventricular systolic dysfunction, needing NIV, were enrolled in the study; all patients were treated with NIV in BiPAP mode. The following parameters were measured at admission to ED (T0, baseline before treatment), 3 hours after admission and initiation of BiPAP NIV (T1), and after 6 hours (T2): arterial blood oxygenation (pH, partial pressure of oxygen in the alveoli/fraction of inspired oxygen ratio, Paco2, lactate concentration, HCO3-), hemodynamics (tricuspid annular plane systolic excursion, transpulmonary gradient, transaortic gradient, inferior vena cava diameter, brain natriuretic peptide [BNP] levels), microcirculation perfusion (end-tidal CO2 [etco2], peripheral venous oxygen saturation [SpvO2]). RESULTS: All evaluated indexes significantly improved over time (analysis of variance, P < .001 in quite all cases.). CONCLUSIONS: The BiPAP NIV may rapidly ameliorate several hemodynamic, arterial blood gas, and microcirculation indexes in patients with AHF and left ventricular systolic dysfunction. PMID- 29141526 TI - The IN-PANCIA Study: Clinical Evaluation of Gastrointestinal Dysfunction and Failure, Multiple Organ Failure, and Levels of Citrulline in Critically Ill Patients. AB - PURPOSE: Gastrointestinal dysfunction and failure (GID and GIF) in critically ill patients are a common, relevant, and underestimated complications in ICU patients. The aims of this study were (1) to determine plasmatic levels of citrulline, glutamine, and arginine as markers of GID/GIF in critically ill patients with or without GID/GIF with or without multiple organ failure (MOF) and (2) to assess the role of intra-abdominal hypertension in these patient groups. MATERIALS AND METHODS: This is a 1-year, monocentric (Italian hospital), prospective observational study. Inclusion criteria were adult patients with GID/GIF, with or without MOF. The GIF score was daily evaluated in 39 critically ill patients. Amino acids were measured at the time of GID or GIF. RESULTS: We enrolled 39 patients. Nine patients developed GID and 7 GIF; 6 of patients with GID/GIF developed MOF. Citrulline was lower ( P < .001) in patients with GID/GIF (11.3 [4.4] umol/L), compared to patients without GID/GIF (22.4 [6.8] umol/L); likewise, glutamine was lower in patients with GID/GIF, whereas arginine was nonstatistically different between the 2 groups. Intra-abdominal pressure was higher in patients affected by MOF (13.0 [2.2] mm Hg) than in patients with GIF/GID without MOF (9.6 [2.6] mm Hg) and compared to patients without GID/GIF (7.2 [2.1] mm Hg). CONCLUSIONS: Both GID and GIF in critically ill patients are associated with low levels of citrulline and glutamine, which could be considered as markers of small bowel dysfunction. The higher the GIF score, the lower the citrulline levels. Patients affected by MOF had higher levels of intra-abdominal pressure. PMID- 29141527 TI - Decreases in Mixed Venous Blood O2 Saturation in Cardiac Surgery Patients Following Extubation. AB - BACKGROUND: Decreases in mixed venous O2 saturation (SvO2) have been reported to occur in postcardiac surgery patients during weaning from mechanical ventilation. Our aim was to establish whether the physiological mechanism responsible for this phenomenon was a decrease in systemic O2 delivery (DO2) or an increase in global O2 consumption ([Formula: see text]O2). METHODS: We studied 21 mechanically ventilated, postoperative cardiac patients for 30 minutes before and 60 minutes after extubation. We monitored continuously arterial O2 saturation by pulse oximetry (SaO2) and central venous O2 saturation (ScvO2) with an oximetry catheter. Mixed venous O2 saturation (SvO2) and cardiac output were also measured continuously with an oximetry pulmonary artery catheter. Systemic O2 delivery and [Formula: see text]O2 were calculated according to accepted formulae. RESULTS: Immediately following extubation, ScvO2 and SvO2 decreased rapidly ( P < .01). Systemic O2 consumption increased from 65 (57) mL.min-1 to 194 (66) mL.min-1 ( P < .05) with no changes in DO2. Consequently, systemic O2 extraction rose from 38% (8%) to 45% (9%; P < .01). Preoperative left ventricular ejection fraction correlated with the decline in SvO2 postextubation. All patients weaned successfully. CONCLUSIONS: Decreases in SvO2 after discontinuation of ventilatory support in postcardiac surgery patients occur as [Formula: see text]O2 increases in response to greater energy requirements by muscles of ventilation that are not initially matched by increases in DO2. PMID- 29141528 TI - Engineering Clostridium absonum 7alpha-hydroxysteroid Dehydrogenase for Enhancing Thermostability Based on Flexible Site and DeltaDeltaG Prediction. AB - BACKGROUND: Enhancing thermostability of the 7alpha-Hydroxysteroid dehydrogenases (7alpha-HSDHs) is beneficial to its industrial application broadly. For protein engineering to enhance thermostability the nonrational strategy, directed evolution, has been applied in obtaining more stable proteins through error-prone PCR or DNA rearrangement generating random mutations. However, the successful application of directed evolution needs to build a large mutant library. Site directed mutations of CA 7alpha-HSDH had been performed to probe the relationship between the compactness increasing and thermostability enhancing. Although most of the mutations in beta-sheet core predicted by MAESTRO became more stable than wild type, unfortunately, all the mutations suffered dramatic activity loss. OBJECTIVE: The main objective of this study was to verify effects of the mutations in helices selected from the predicting results through MAESTRO on thermostability improving of CA 7alpha-HSDH. METHODS: Seven mutants, S22L, P124L, A125L, N171L, A195Q, L197E and Y259E were synthesized and verified through DNA sequencing in Sangon Biotech (Sangon, Shanghai, China). The two mutants, A104P and G105P were prepared by over-lapping PCR. The GST-fusion expression vector, pGEX-6p-1 (GE Healthcare), was used for protein expression with restriction sites BamH I and Not I. Thermostability was measured by circular dichroism (CD) spectrometer (MOS-450, BioLogic Inc). All the enzymes were diluted in PBS (pH 7.3, 10 mM) to OD222 value between 0.8 and 1, and temperature varied from 20 degrees C to 95 degrees C. Activity of enzyme was assayed by measuring the production of NADPH by UV-visible spectrophotometer at 340 nm. The activity assay was performed in 2 mL reaction mixture which contained PBS (pH 7.3, 10 mM), NADP+ (0.5 mM) and taurocholic acid (TCA) at 25 degrees C. RESULTS: Based on unfolding free energy changes (DeltaDeltaG) prediction seven mutations of Clostridium absonum (CA) 7alpha-HSDH were selected and experimentally verified, and these mutants fitted three-state denaturation model well, among which S22L located in the alphaA possessed the greatest Tm N->I increase (> 8 degrees C). Mutants P124L, L197E, N171L and Y259E also became more stable than wild type CA 7alpha HSDH with different ranges. Meanwhile, thermostability of the two mutants, A104P and G105P (in the coil between betaD and alphaD) resulting from the proline substitution method decreased significantly. Enzyme activity assays indicated that mutant L197E located in alphaF maximally maintained 28.7% of catalytic efficiency, and activity of the five mutants, P124L, A125L, N171L, A104P and G105P cannot be detected. CONCLUSION: Although all the mutants' activities decreased, the mutant L197E with the maximum activity retain suggested that the loop structure (residues 194 to 211) may be the favored candidate sites to enhance thermostability. In addition, CA 7alpha-HSDH may suffer structural destruction resulting from the proline substitution in A104 and G105. PMID- 29141529 TI - Experimental Autoimmune Encephalomyelitis (EAE) Model of Cynomolgus Macaques Induced by Recombinant Human MOG1-125 (rhMOG1-125) Protein and MOG34-56 Peptide. AB - BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) induced by self myelin antigen is a widely used in multiple sclerosis (MS) model for preclinical studies of new therapeutics and potential pathogenesis. By comparison with rodent EAE models, EAE models in primates are more similar to MS. Some groups have developed EAE models in primates by using common marmoset (Callithrix jacchus). However, this model has some limitations. EAE in cynomolgus monkey (Macaque fasciculrais) could overcome these limitations. OBJECTIVES: The main objective of this study was to establish an ideal EAE cynomolgus monkey model resembling human MS by immunizing human myelin oligodendrocyte glycoprotein (MOG) protein. METHODS: In this study, six female cynomolgus monkeys were divided into two separate experiment groups and one monkey as the control. EAE was induced in cynomolgus monkey by immunizing with the recombinant human myelin oligodendrocyte glycoprotein extracellular domain (1-125) (rhMOG1-125) and a synthetic peptide, representing peptide 34-56 of human myelin oligodendrocyte glycoprotein (MOG34 56) in complete Freund's adjuvant (CFA) by subcutaneous multipoint immunization in the armpit and inguinal region and in combination with intravenous injection of pertussis toxin, and subsequent booster immunizations with the same dose of antigen in incomplete Freund's adjuvant (IFA) until the animals developed clinically significant EAE (score>=2). The body weight, clinical scores, magnetic resonance imaging (MRI), histopathology, antibody, cytokine profiling and antigen specific lymphocyte proliferation were evaluated. RESULTS: The results showed that despite the different time intervals between onset and significant neurological deficits, all the cynomolgus monkeys immunized with rhMOG1-125 or MOG34-56 developed clinically significant acute fulminant or mild forms of EAE, with a success rate of 100%. The clinical courses were obvious heterogeneity which closely resembles MS. MOG34-56 immunization was much milder compared with rhMOG1-125 immunized individuals, at least in cynomolgus monkeys. Inflammation and demyelinated lesions were present in the brains and spinal cords. Immune profiling revealed high IgG levels associated with early onset of EAE but not the course of the disease. Significant antigen-specific T lymphocyte responses against immunodominant epitopes of MOG were also detected. CONCLUSION: Our results indicated rhMOG1-125 and MOG34-56 could induce successfully EAE models resembling MS in cynomolgus monkeys. The synergistic action of anti-myelin T cells and Abs during the pathogenesis of EAE could establish a more ideal EAE model. PMID- 29141530 TI - Recent Advances and Challenges in Steroid Metabolomics for Biomarker Discovery. AB - Steroid hormones belong to a group of low-molecular-weight compounds which are responsible for maintenance of various body functions, thus, their accurate assessment is crucial for evaluation of biosynthetic defects. The development of reliable methods allowing disease diagnosis is essential to improve early detection of various disorders connected with altered steroidogenesis. Currently, the field of metabolomics offers several improvements in terms of sensitivity and specificity of the diagnostic methods when opposed to classical diagnostic approaches. The combination of hyphenated techniques and pattern recognition methods allows to carry out a comprehensive assessment of the slightest alterations in steroid metabolic pathways. Moreover, metabolomics can also provide insights concerning personalized treatment of endocrine disorders in terms of supplying information about the response of the patient to treatment. In spite of several advantages, steroid metabolomics still faces some challenges which affect its availability and potential as a more widespread tool for biomarker discovery. This review will present the strengths, challenges and recent developments in steroid based metabolomics taking into consideration its potential in the area of clinical biomarkers discovery. PMID- 29141531 TI - Statins in aortic disease. AB - BACKGROUND: Numerous studies indicate that statins have also multiple beneficial actions (known as 'pleiotropic actions') on cardiovascular system through the improvement of endothelial dysfunction, inflammation, oxidative stress, increased arterial thrombosis, and the stabilization of the atherosclerotic plaque. Aortic disease primarily consists of aortic valve stenosis, aortic valve regurgitation, aneurysm disease, and genetic disorders such as Marfan syndrome, bicuspid aortic valve and aortic coarctation. Many studies have revealed the cardio-protective actions of statins in aortic disease. OBJECTIVE: Our aim was to present current data concerning present status of treatment with statins in aortic diseases. METHODS: A thorough search of PubMed and the Cochrane Database was conducted in order to identify the majority of studies and novel articles related to their use in aortic disease. RESULTS: Numerous studies in animals and humans indicate a beneficial effect of treatment with statins in the previous conditions apart from a few conflicting data. CONCLUSION: There is a need of further investigation in this field, especially for the estimation of the optimal type and dose of statins required in each clinical condition of aortic disease. PMID- 29141532 TI - Seizures and Antiepileptic Drugs: From Pathophysiology to Clinical Practice. AB - Recurrent, spontaneous seizure activity caused by abnormal neuronal firing in the brain is a hallmark of epilepsy, a common chronic neurological disorder. Recent research that has expanded the knowledge of the cellular and molecular mechanisms that modulate neuronal excitability and network activity in the brain provides the development and discovery of antiepileptic drugs (AEDs). AED therapy starts with the selection of the most appropriate drug for individual patient according to a strategic decision based on the risk-benefit ratio. Beyond three generations of AEDs developed over the last 40 years, more effective, better tolerated, disease-modifying pharmacological therapies are still needed to improve seizure outcome and reduce the safety burden. In this review, we aim to provide a special focus on epilepsy with an overview of underlying pathophysiological mechanisms that may contribute to seizure generation and propagation. Besides, knowledge of principle pharmacological properties of current AEDs which are essential for rational drug therapy is considered. Limited safety data are available especially for recent AEDs, we also discussed their safety profiles concerning major adverse effects, teratogenicity and their use in pregnancy and lactation. Epilepsy is a chronic disorder which needs special knowledge and experience during AED treatment with meticulous follow-up of patients to avoid short and long-term adverse effects with the best possible seizure controlled outcome and high quality of life. PMID- 29141533 TI - Targeting cancer stem cells and non-stem cancer cells: the potential of lipid based nanoparticles. AB - : Background Cancer stem cells (CSCs) have been described as a relevant contributor to tumorigenicity, metastasis, tumor recurrence and drug resistance, making this cell population a relevant target in solid tumors. METHODS: This has stimulated the development of different therapeutic strategies often targeting surface markers (CD44, epithelial cell adhesion molecule (EpCAM), aldehyde dehydrogenase (ALDH) and nucleolin) and/or signaling pathways that are aberrantly activated and contribute to CSCs proliferation and survival. RESULTS: There are a variety of signaling pathways often involved in physiological processes of cell function that aberrantly regulate CSCs, including Notch, Hedgehog, Wnt, PI3K/Akt, JAK/STAT and Ras/ERK signaling pathways. The inhibition of these pathways usually depletes CSC population and increases tumor sensitivity to chemotherapy. However, the recognition of the potential of cells to interconvert in response to environmental stimulus, turned both CSCs and non-stem cancer cells into two relevant therapeutic targets. Therefore, the use of drug combinations is increasingly needed. These drugs with different mechanisms of action often characterized by distinct pharmacokinetics profiles and, as such, will present distinct biodistribution patterns, following systemic administration. To synchronize pharmacokinetics, one can encapsulate synergistic drug combinations into lipid-based nanoparticles, assuring tumor delivery of the selected drug ratio. CONCLUSION: This review will focus on the multiple strategies to target CSCs, as well as on the potential of lipid-based nanoparticles to target both CSCs and non-stem cancer cells. PMID- 29141534 TI - Characterization Methods for Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC). AB - BACKGROUND: Solid lipid nanoparticles (SLN) and the next generation of nanostructured lipid carriers (NLC) seem to be a very promising alternative to other colloidal carriers such as liposomes, microemulsions, and polymeric nanoparticles. These combine the advantages of the cited nanocarriers and can improve the dissolution rate in biological fluids, increase the drug absorption, improve the tissue distribution in the target organ, enhance the drug bioavailability and ensure controlled drug release. SLN and NLC can ensure higher drug stability in the harsh environment, cover the bitter taste of the drug, and reduce the first-pass-effect after oral administration. However, these carriers suffer from some disadvantages such as low drug loading capacity, drug expulsion, and unpredictable gelation tendency. METHODS: This article aims to provide detail information about the process of complex characterization of SLN and NLC to produce an effective, quality and safe colloidal DDS with desired properties, based on the literature published in the period from 2000 to 2017. RESULTS: Characterization techniques in terms of size and particle size distribution; surface morphology, functionalization, and zeta potential; structure, depending on the degree of crystallinity, lipid modification, drug incorporation and loading capacity; drug release; co-existence of other nano- and microstructures; and toxicity assessment according to the process of production, lipids and surfactants used and route of administration are discussed in the article. CONCLUSION: The precise characterization of lipid nanocarriers as drug delivery systems ensures guarantees for the quality of the product as an effective and safe form. The typical composition of SLN and NLC requires a comprehensive approach of characterization and in-depth analysis of the results to perform a drug delivery system with desired properties. PMID- 29141535 TI - SLN- and NLC-encapsulating antifungal agents: skin drug delivery and their unexplored potential for treating onychomycosis. AB - BACKGROUND: Lipid nanoparticles have been extensively studied for drug delivery of antifungal drugs, especially for dermatophytosis treatments. They can accumulate in skin appendages and release drugs in a controlled manner and also increase skin moisture, due to the formation of an occlusive film. Since moisture heavily influences nail and skin permeability, these systems seem to pose great potential for antifungal drug delivery. METHODS: We therefore compare skin and nail physiopathological structure and discuss the potential use of lipid nanoparticles in managing skin and nail mycoses, highlighting their unexplored use in onychomycosis. RESULTS: Structural features become particularly relevant when treating local skin/nail disorders. Nail plate represents the most resistant barrier to the penetration of molecules. In recent years, at least 55 researches have been reported about lipid nanoparticles and, antifungal drugs. They have focused on production methods and nanoparticle ingredients influence on entrapment efficiency, fungal activity in vitro, stability, and drug release. Lipid nanoparticles such as SLN and NLC have shown great results in permeating the skin. Currently, however, there is just one study published using NLC applied directly to the nail plate. NLC containing voriconazole had a noteworthy impact on the penetration depth of a nanoencapsulated drug, which allowed its deeper penetration into porcine hooves than the unloaded drug. CONCLUSION: Evidence of the success of SLN and NLC in achieving high encapsulation efficiencies of antifungals and promoting cutaneous delivery indicates the potential of the systems in enhancing nail hydration and drug penetration into the nail plate. PMID- 29141536 TI - Development and tailoring of hybrid lipid nanocarriers. AB - BACKGROUND: Lipid nanoparticles are considered one of the most promising systems for controlled release of therapeutic molecules highly hydrophobic and with low biodisponibility. Solid lipid nanoparticles and nanostructured lipids carriers are widely seen as the workhorses of drug delivery systems because of low toxicity, enhanced encapsulation capacity, controlled drug kinetic release, easy tailoring and targeting and practicable scale up. CONCLUSIONS: A new generation of hybrid lipid nanoparticles has emerged by combining the lipidic properties with polymers, proteins and metallic structures. The main features of hybrid lipid nanoparticles including popular methods for synthesis and characterization, biological and toxicological properties, administration routes, drug encapsulation strategies, tailoring and targeting, and potential systems for use in biomedicine are described in the present review. PMID- 29141537 TI - OPHTHALMIC APPLICATIONS of SLN and NLC. AB - BACKGROUND: The eyes are among the most readily accessible organs in terms of location in the body, yet drug delivery to eye tissues is particularly problematic. The anatomy, physiology and biochemistry of the eye limit the ophthalmic delivery of drugs. Numerous strategies in ophthalmic drug delivery have been made to expand the bioavailability and to prolong the remaining time of drugs treated topically to eye. METHODS: Designing a novel delivery vehicles that can proficiently target the diseased eye tissue, generate high drug levels, and keep sustained and effective concentrations with no or minimum side effects is the main concentration of present examination. One of the encouraging approaches currently is the use of lipidic nanoparticle vehicles categorized by a submicron meter dimension. Due to their properties and numerous advantages, solid lipid nanoparticles and nanostructure lipid carriers are promising systems for ocular drug delivery. CONCLUSION: The focus of this review is on the recent developments in ophthalmic lipid nanoparticles, the rationale for their use, drug loaded SLNs and NLCs, and the characteristic advantages, limitations of this system and recent studies. PMID- 29141538 TI - Curcumin: A Natural Pan-HDAC Inhibitor in Cancer. AB - BACKGROUND: Histone deacetylases (HDACs) are a group of histone modification enzymes with pivotal role in disease pathogenesis especially in cancer development. Increased activity of certain types of HDACs and positive effects of HDAC inhibition has been shown in several types of cancers. Furthermore, few HDAC inhibitors have been approved by the FDA for cancer treatment, and this has generated interest in finding new HDAC inhibitors as potential anti-cancer agents. Curcumin, a natural polyphenol extracted from turmeric, is a safe and bioactive phytochemical with a wide range of molecular targets and pharmacological activities including promising anti-cancer properties. METHODS: A systematic literature search using appropriate keywords was made to identify articles reporting the modulatory effect of curcumin on HDACs in different types of cancer in vitro and in vivo. RESULTS: HDACs have emerged as novel targets of curcumin that their modulation may contribute to the putative anti-cancer effects of curcumin. Curcumin inhibits HDAC activity, and down-regulates the expression of HDAC types 1, 2, 3, 4, 5, 6, 8 and 11 in different cancer cell lines and mice, while the activity and expression of HDAC2 have been reported to be up-regulated by curcumin in COPD and heart failure models. CONCLUSION: Available in vitro and in vivo data are encouraging and in favor of the HDAC inhibitory activity of curcumin but clinical evidence on the efficacy of curcumin as an adjunct treatment in cancer patients is lacking. PMID- 29141539 TI - Selectively Targeted Anti-Neoplastic Cytotoxicity of Three Immunopharmaceuticals with Covalently Bound Fludarabine, Gemcitabine and Dexamethasone Moieties Synthesized Utilizing Organic Chemistry Reactions in a Multi-Stage Regimen. AB - BACKGROUND: Unintentional passive diffusion of conventional small molecular weight pharmaceuticals across intact membranes of normal healthy cells in tissues and organ systems induces sequelae that limit therapeutic dosage and duration of administration. Selective "targeted" delivery of pharmaceuticals is a molecular strategy that can potentially provide heightened margins-of-safety with greater potency and improved efficacy. MATERIALS AND METHODS: Monophosphate analogs of fludarabine, gemcitabine, and dexamethasone were combined with a carbodiimide reagent in the presence of imidazole to produce reactive intermediates that were subsequently covalently bound to monoclonal anti-IGF-1R or anti-EGFR IgG immunoglobulin. The resulting covalent immunopharmaceutical end-products, fludarabine-(5'-phosphoramidate)-[anti-IGF-1R], gemcitabine-(5'- phosphoramidate) [anti-IGF-1R], and dexamethasone-(C21-phosphoramidate)-[anti-EGFR] were evaluated by SDS-PAGE/chemiluminescent autoradiography (fragmentation/polymerization detection), UV spectrophotometric absorbance (purity; molar-incorporation-index), cell-ELISA (retained selective binding-avidity), and cell vitality-viability (selectively "targeted" anti-neoplastic cytotoxicity). RESULTS: Maximum selectively "targeted" anti-neoplastic cytotoxicity of fludarabine-(5' phosphoramidate)-[anti- IGF-1R], gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R], and dexamethasone-(C21-phosphoramidate)-[anti- EGFR] was detected at the pharmaceutical-equivalent concentrations of 10-5 M (94.7%), 10-7 M (93.1%), and 10-7 M (64.9%) respectively. DISCUSSION: Organic chemistry reactions were optimized in a template multi-stage synthesis regimen for fludarabine-( 5' phosphoramidate)-[anti-IGF-1R], gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R], and dexamethasone-( C21-phosphoramidate)-[anti-EGFR]. Attributes of the synthesis regimen include; [-i-] covalent bonding of pharmaceutical moeities at high molar incorporation indexes, [-ii-] implementation of organic chemistry reactions in a non-dedicated synthesis regimen allowing component substitution and [-iii-] optional preservation of presynthesized amine-reactive pharmaceutical intermediates for on-demand immunopharmaceutical synthesis. Attributes of the covalent immunopharmaceuticals are; absence of any synthetically introduced chemical groups, retained IgG-immunoglobulin binding-avidity and potent selective "targeted" anti-neoplastic cytotoxic potency. Under in-vivo conditions, supplemental anti-neoplastic cytotoxicity is realized through trophic receptor inhibition and activation of multiple cytotoxic host immune responses. PMID- 29141540 TI - Polyphenols, Antioxidants and the Sympathetic Nervous System. AB - BACKGROUND: A high dietary intake of polyphenols has been associated with a reduced cardiovascular mortality, due to their antioxidant properties. However, growing evidence suggests that counteracting oxidative stress in cardiovascular disease might also reduce sympathetic nervous system overactivity. METHODS: This article reviews the most commonly used techniques to measure sympathetic activity in humans; the role of sympathetic activation in the pathophysiology of cardiovascular diseases; current evidence demonstrating that oxidative stress is involved in the regulation of sympathetic activity and how antioxidants and polyphenols might counteract sympathetic overactivity, particularly focusing on preliminary data from human studies. RESULTS: The main mechanisms by which polyphenols are cardioprotective are related to the improvement of vascular function and their anti-atherogenic effect. Furthermore, a blood pressure lowering effect was consistently demonstrated in randomized controlled trials in humans, when the effect of flavonoid-rich foods, such as tea and chocolate, was tested. More recent studies suggest that inhibition of sympathetic overactivity might be one of the mechanisms by which these substances exert their cardioprotective effects. Indeed, an increased adrenergic traffic to the vasculature is a major mechanism of disease in a number of cardiovascular and extra-cardiac diseases, including hypertension, obesity, metabolic syndrome and heart failure. A considerable body of evidence, mostly from experimental studies, support the hypothesis that reactive oxygen species might exert sympathoexcitatory effects both at the central and at the peripheral level. Accordingly, supplementation with antioxidants might reduce adrenergic overdrive to the vasculature and blunt cardiovascular reactivity to stress. CONCLUSIONS: While supplementation with "classical" antioxidants such as ROS-scavengers has many limitations, increasing the intake of polyphenol-rich foods seems to be a promising novel therapeutic strategy to reduce the deleterious effects of increased adrenergic tone, particularly in essential hypertension. PMID- 29141541 TI - Ellagic Acid: A Logical Lead for Drug Development? AB - BACKGROUND: Naturally occurring polyphenols are the subject of increasing attention due to their potent antioxidant activity and their marked effects on the prevention of various oxidative stress-associated diseases such as cancer. Ellagic acid (EA) is an herbal polyphenol that is structurally a condensed dimer of gallic acid. METHODS: This review aims to provide a comprehensive and updated overview on the biological activities of EA and potential therapeutic applications. RESULTS: EA is found in fruits and nuts, either in the combined form with hexahydroxydiphenic acid or in the bound form (ellagitannins). EA exhibits many biological properties such as antioxidant, anti-diabetic, anticancer and apoptosis-inducing activities. These biological and pharmacological properties are relevant to the treatment of several human diseases. CONCLUSION: Owing to its multiple mechanisms of action, EA represents a potential therapeutic agent against human diseases particularly cancer. PMID- 29141542 TI - Cocoa Polyphenols: Evidence from Epidemiological Studies. AB - BACKGROUND: Accumulating evidence suggests potential preventive effects of chocolate/cocoa on the risk of cardio vascular disease (CVD). However, cocoa products also contain high levels of sugar and fat, which increase CVD risk factors. Even, the identity of the substance in chocolate/cocoa that has a favorable effect on CVD and CVD risk factors remains unclear, growing evidence from experimental studies suggests that cocoa polyphenols might be a major contributor to cardiovascular-protective effects. However, epidemiological studies, which are necessary to evaluate an association between the risk of CVD and cocoa polyphenol, remain sparse. METHODS: We will discuss recent evidence regarding the association between cocoa polyphenol consumption and the risks of CVD and its risk factors by reviewing recent epidemiological studies. We shall also provide some guidance for patient counseling and will discuss the public health implications for recommending cocoa polyphenol consumption to prevent CVD. RESULTS: Epidemiological studies evaluating the association between cocoa polyphenol itself and the risk of CVD are sparse. However, evidence from limited epidemiological studies suggests that cocoa polyphenol consumption may lower the risk of CVD. CONCLUSION: Given the potential adverse effects of the consumption of cocoa products with high fat and sugar and the fact that the most appropriate dose of cocoa polyphenol for cardio-protective effects has not yet been established, health care providers should remain cautious about recommending cocoa/cocoa polyphenol consumption to their patients to reduce the risk of CVD, taking the characteristics of individual patients into careful consideration. PMID- 29141543 TI - Effects of Fucoidan and Chemotherapeutic Agent Combinations on Malignant and Non malignant Breast Cell Lines. AB - OBJECTIVES: Breast cancer is a leading cause of death among women in both developed and Third World countries. Fucoidan is a natural plant metabolite produced by brown seaweeds with proven anticancer potential. This study determined the cytotoxic, apoptotic and cell cycle effects of fucoidan alone and in combination with first-line anticancer drugs (cisplatin, doxorubicin and taxol) in MCF-7 breast cancer cells and non-malignant MCF-12A breast epithelial cells as control. METHODS: Cytotoxicity was evaluated using the MTT reduction assay. Cell cycle distribution and apoptosis were assessed by flow cytometry using Annexin VFITC/PI and Hoechst 33342 staining, and caspases-3, -7 and -9 activation. RESULTS: Fucoidan alone was significantly more cytotoxic to MCF-7 breast cancer cells compared to the MCF-12A non-cancerous breast epithelial cell line. In MCF-7 cells, the presence of fucoidan caused cell cycle arrest at G1 with accumulation of cells in the sub-G1 phase with the activation of caspases-3, 7 and -9. Furthermore, combination of fucoidan with the standard chemotherapeutic agents-cisplatin, doxorubicin and taxol-significantly enhanced the cytotoxicity of these drugs and accumulation of cells in the G2/M and sub-G1 phases, and induction of apoptosis. No significant differences were observed between fucoidan treated and untreated MCF-12A cells with respect to cytotoxicity and cell cycle distribution profiles. By contrast, in non-cancerous MCF-12A cells, fucoidan attenuated the toxicity of doxorubicin and cisplatin in combination by increasing their IC50 values. This effect was not demonstrated with the taxol combination. CONCLUSIONS: Fucoidan is an effective antitumor agent, either alone or in combination with cisplatin, doxorubicin and taxol in MCF-7 breast cancer cells. Drug combinations that discriminate between cancerous and non-cancerous cells afford a plausible and viable strategy of attaining therapeutic efficacy and avoiding possible toxicity and side effects. These findings suggest that fucoidan is a promising candidate for cancer combination therapies. PMID- 29141544 TI - Recent Updates on the Phytochemistry, Pharmacological, and Toxicological Activities of Zingiber zerumbet (L.) Roscoe ex Sm. AB - BACKGROUND: Zingiber zerumbet (L.) Roscoe ex Sm. (family, Zingiberaceae) is a potent medicinal herb widely known as shampoo ginger and its rhizome is used in numerous ethnomedicinal applications including antipyretic, anti-inflammatory, antibacterial, anti-diarrheal, antidiabetics, carminative, and diuretic. The aim of this review was to bring together all the scientific updates on the phytochemistry and pharmacological activities of this herb, including their toxicological studies, and critically analyzed the outcomes to provide directions for future research on the herb as potential source of bioactive metabolites for pharmaceutical and nutraceutical applications. METHODS: A structured electronic search on worldwide accepted scientific databases (Web of Science, PubMed, Google Scholar, Science Direct, SciFinder, Wiley Online Library) was carried out to compile the relevant information. Some information was obtained from books and database on medicinal plants used in various countries. RESULTS: About 60 metabolites, mainly polyphenols, and terpenoids have been isolated and identified. However, most of the reported pharmacological studies were based on crude extracts, and only a few of those isolated metabolites, particularly zerumbone have been investigated for biological and pharmacological activities. Many of the mechanistic studies to understand the pharmacological effects of the plant are limited by many considerations with regard to design, experimentation and interpretation. CONCLUSION: The bioactive metabolites should be further investigated on their safety and more elaborate preclinical studies before clinical trials can be undertaken. PMID- 29141545 TI - Main Isoflavones Found in Dietary Sources as Natural Anti-inflammatory Agents. AB - BACKGROUND: Isoflavones are natural compounds belonging to the class of isoflavonoids, molecules with a chemical structure based on the 3-phenyl chromen 4-one backbone. As a particular element, the isoflavones are also called phytoestrogens, due to the structural similarity with 17-beta estradiol, the primary female sex hormone, presenting both estrogen-agonist and estrogen antagonist properties. This class of secondary plant metabolites has been extensively reported in the literature for a wide range of therapeutic activities including antioxidant, chemopreventive, anti-inflammatory, antiallergic, antibacterial, and cardio preventive effects. OBJECTIVE: To sum up the latest information regarding the main isoflavones found in dietary sources as natural anti-inflammatory agents. RESULTS: The review updates with the recent research about genistein, daidzein, glycitein, biochanin A, formononetin and equol as anti inflammatory phytocompounds. As a particular element, the implications of these isoflavones in the link between inflammation and angiogenesis are also discussed. CONCLUSION: The review concludes that the main isoflavones in dietary sources display in vitro and/or in vivo anti inflammatory potential by activating various biochemical and molecular mechanisms. The depicted findings translated into practical aspects strengthen the idea that the isoflavones genistein, daidzein, glycitein, biochanin A, formononetin and equol can be used in various inflammation based diseases as an alternative source for classical medication and that consummation of foods rich in isoflavones may represent prerequisite use in order to prevent the evolution of inflammation based diseases. PMID- 29141546 TI - Current Theories and Clinical Trial Evidence for Limiting Human Abdominal Aortic Aneurysm Growth. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) refers to localized dilation of abdominal aorta. AAA is largely asymptomatic, but aneurysmal rupture results in a high mortality rate. AAA with a diameter greater than 55 mm carries a high risk of rupture. There are currently no known medical treatments effective in limiting the growth of small AAA. OBJECTIVE: To review the current status of and challenges faced in limiting AAA growth. METHODS: Data from human investigations and animal model studies were summarized. In particular, the ClinicalTrials.gov website was searched for details of ongoing or completed studies related to AAA growth. We searched the key words 'abdominal aortic aneurysm' and 'drugs' to identify potential target drugs for slowing or stopping AAA growth. RESULTS: These clinical trials involve a number of challenges, including demonstrating the design of the trial, minimizing the participant dropout rate, and developing accurate outcome assessments during the trials. A number of clinical trials have concentrated on pharmaceutical intervention (such as angiotensin- converting enzyme inhibitors, beta-blockers, statins, and antibiotics) that could be effective for AAA patients in delaying or reversing aneurysm expansion and postponing the endpoint for elective surgical repair. CONCLUSIONS: Further randomized, controlled, clinical trials are required to develop effective nonsurgical therapies for AAA. PMID- 29141547 TI - Cardioprotective Effects of Serca2a Overexpression Against Ischemiareperfusion- induced Injuries in Rats. AB - AIMS: The aim of the present study was to assess how genetically increased Sarcoplasmic reticulum Ca2+-ATPase (Serca2a) expression affects cardiac injury after Ischemia/Reperfusion (I/R) exposure and the related mechanisms involved. METHODS AND RESULTS: Rats were subjected to Left Anterior Descending coronary artery (LAD) occlusion for 30 min followed by a 24-hour reperfusion. Cardiac function analysis revealed that cardiac function dramatically improved in Serca2a transgenic rats, (Serca2aTG) rats, compared to Wild Type (WT) rats. Serca2aTG rats developed a significantly smaller myocardial infarction size compared to those in WT group. The expression of the Bcl-2 was lower in Serca2aTG rats compared with WT rats; but, Bcl-2 expression was markedly increased in Serca2aTG rats compared with WT after I/R. In addition, Bax was markedly downregulated in Serca2aTG rats compared to WT group after I/R. Meanwhile, autophagy marker LC-3B was increased in Serca2aTG group, and p62 was only increased in WT group but not in Serca2aTG group in response to I/R. Electron microscope observation confirmed that there were more autophagosomes in Serca2aTG group than in WT rats after I/R. CONCLUSION: our findings demonstrated that the overexpression of Serca2a plays an important role in myocardial protection from I/R injury and postischemic functional recovery, which may be via antinecrotic, anti-apoptotic and pro autophagy signal pathways. Our research provides solid basic data and new perspective on clinical treatment in heart failure patients with long-term over expression of Serca2a. PMID- 29141548 TI - Cognitive Training in Patients with Alzheimer's Disease: Findings of a 12-month Randomized Controlled Trial. AB - BACKGROUND: Cognitive training (CT) is a non-pharmacological intervention based on a set of tasks that reflect specific cognitive functions. CT is aimed at improving cognition in patients with cognitive impairment, though no definitive conclusions have yet been drawn on its efficacy in Alzheimer's disease (AD). OBJECTIVE: To assess the effectiveness of a CT program designed to improve cognition in AD patients. METHOD: This is a randomized, controlled, single-blind, longitudinal trial with a no-treatment control condition in mild-to-moderate AD. Treated patients received in-group CT twice a week for six months, whereas controls did not. CT consisted of tasks ranging from paper-and-pencil to verbal learning exercises. Participants' cognitive levels were assessed at baseline, post-intervention and 6 months later by means of a complete neuropsychological test battery. Repeated measures ANOVA was used to analyze the effect of time on the outcome measures, as well as to compare treated and untreated patients over time, with demographic data considered as covariates. RESULTS: Of the 140 patients enrolled, 45 in the treated group and 85 controls concluded the study. The CT significantly improved treated subjects' cognitive functions immediately after the CT. Six months later, some test scores remained stable when compared with those obtained at baseline. The control group performed significantly worse than the treated group at each time-point, displaying a progressive cognitive decline over time. CONCLUSION: Our results suggest that CT may improve cognitive functions in patients with AD and may help to temporarily slow their cognitive decline. PMID- 29141549 TI - A High-throughput Quantitative Expression Analysis of Cancer-related Genes in Human HepG2 Cells in Response to Limonene, a Potential Anticancer Agent. AB - BACKGROUND: Citrus bioactive compounds, as active anticancer agents, have been under focus by several studies worldwide. However, the underlying genes responsible for the anticancer potential have not been sufficiently highlighted. OBJECTIVES: The current study investigated the gene expression profile of hepatocellular carcinoma, HepG2, cells after treatment with Limonene. METHODS: The concentration that killed 50% of HepG2 cells was used to elucidate the genetic mechanisms of limonene anticancer activity. The apoptotic induction was detected by flow cytometry and confocal fluorescence microscope. Two of the pro apoptotic events, caspase-3 activation and phosphatidylserine translocation were manifested by confocal fluorescence microscopy. Highthroughput real-time PCR was used to profile 1023 cancer-related genes in 16 different gene families related to the cancer development. RESULTS: In comparison to untreated cells, limonene increased the percentage of apoptotic cells up to 89.61%, by flow cytometry, and 48.2% by fluorescence microscopy. There was a significant limonene- driven differential gene expression of HepG2 cells in 15 different gene families. Limonene was shown to significantly (>2log) up-regulate and down-regulate 14 and 59 genes, respectively. The affected gene families, from the most to the least affected, were apoptosis induction, signal transduction, cancer genes augmentation, alteration in kinases expression, inflammation, DNA damage repair, and cell cycle proteins. CONCLUSION: The current study reveals that limonene could be a promising, cheap, and effective anticancer compound. The broad spectrum of limonene anticancer activity is interesting for anticancer drug development. Further research is needed to confirm the current findings and to examine the anticancer potential of limonene along with underlying mechanisms on different cell lines. PMID- 29141550 TI - Autophagy as a Potential Therapeutic Target in Breast Cancer Treatment. AB - One of the crucial reasons of breast cancer therapy failure is an impairment of mechanisms responsible for metabolism and cellular homeostasis, which makes it difficult to foresee the response to the treatment. Targeted therapy in breast cancer is dictated by the expression of specific molecules such as growth factor or hormone receptors. Many types of breast cancer exhibit different abnormalities in the apoptotic pathway, which confer the resistance to many forms of chemotherapy. Because of the fundamental importance of autophagy in the development and progression of cancer and its ability to affect treatment response, there has been an immense research on molecular regulation and signal transduction mechanisms that control this process. Here, we summarize the present knowledge concerning different breast cancer treatment strategies using drugs approved for the treatment of different breast cancer molecular subtypes with targeting pathways and factors associated with autophagy modulation/ regulation. PMID- 29141551 TI - Noninvasive cerebellar stimulation as a complement tool to pharmacotherapy. AB - Cerebellar ataxias represent a wide and heterogeneous group of diseases characterized by balance and coordination disturbance, dysarthria, dyssynergia and adyadococinesia, caused by a dysfunction in the cerebellum. In recent years there has been growing interest in discovering therapeutical strategy for specific forms of cerebellar ataxia. Together with pharmacological studies, there has been growing interest in non-invasive cerebellar stimulation techniques to improve ataxia and limb coordination. Both transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are non-invasive techniques to modulate cerebro and cerebellar cortex excitability using magnetic or electric fields. Here we aim to review the most relevant studies regarding the application of TMS and tDCS for the treatment of cerebellar ataxia. As pharmacological strategies were shown to be effective in specific forms of cerebellar ataxia and are not devoid of collateral effects, non-invasive stimulation may represent a promising strategy to improve residual cerebellar circuits functioning and a complement tool to pharmacotherapy. PMID- 29141552 TI - Para-prosthetic Leaks Following Mitral Valve Replacement: Case Analysis on a 20 year Period. AB - BACKGROUND: Mitral para-prosthetic leaks are rare but major complications of mitral heart valve replacements. When they must be re-operated, they are burdened with high mortality rates. We proposed to review our surgical experience in terms of approach and type of operation carried out. METHODS: Demographic, preoperative, intraoperative and postoperative characteristics of 34 patients benefited from a surgical treatment of mitral paravalvular leak, at the Brugmann University Hospital between 1996 and 2016, have been analysed retrospectively. We analysed the data to identify the risk factors of postoperative mortality. We then compared the data depending on the approach and the type of surgical treatment in order to compare the morbidity-mortality. RESULTS: The postoperative mortality rate was 11.7%. The presence of endocarditis and increase in lactate dehydrogenase were predictive factors of mortality. Cardiac complications and acute kidney failure were significantly more common in the decease population. Direct mitral paravalvular leak suturing was more frequently performed on early apparition, anterior and isolated leaks, whereas a mitral heart valve replacement was most often performed to cure active primary endocarditis. The incidence of complications and mortality rates were identical according to the approach and the type of operation performed. A mitral para-prosthetic leak recurrence was observed in 33% of the cases. CONCLUSION: Surgical treatment of mitral para prosthetic leaks is accompanied by a high mortality rate. The operative strategy plays a major role and can influence the morbidity-mortality encountered in those patients. PMID- 29141553 TI - Epigenetic Regulation of Gene Expression in Epithelial Stem Cells Fate. AB - BACKGROUND: Epithelial tissues have the ability to self-renew throughout animal's life due to the presence of the epithelial stem cells. Except for complicated genes regulation, the fate of epithelial stem cells is also regulated by the epigenetics, including DNA methylation, histone modification and microRNAs, which are emerging as vital elements of epigenetic regulation for epithelial stem cells self-renewal and differentiation. However, the mechanisms underlying these are still poorly understood. OBJECTIVE: In this review, we focus on the epigenetic regulation of gene expression in epithelial stem cells fate, using intestinal and epidermal stem cells as models. Meanwhile, a brief description of recent research about the possible impact of network regulation in epithelial stem cell-based amelogenesis by epigenetic regulation is therefore, being discussed. CONCLUSION: Epigenetic modification plays a vital role in the epithelial stem cells fate choice through the gene expression. The interaction between epigenetic modification and molecular signaling in epithelial stem cells fate choice still needs further exploration. PMID- 29141554 TI - Insight into the Role of Long Non-coding RNAs During Osteogenesis in Mesenchymal Stem Cells. AB - BACKGROUND: Long non-coding RNAs (LncRNAs) are non-protein coding transcripts longer than 200 nucleotides in length. Instead of being "transcriptional noise", lncRNAs are emerging as a key modulator in various biological processes and disease development. Mesenchymal stem cells can be isolated from various adult tissues, such as bone marrow and dental tissues. The differentiation processes into multiple lineages, such as osteogenic differentiation, are precisely orchestrated by molecular signals in both genetic and epigenetic ways. Recently, several lines of evidence suggested the role of lncRNAs participating in cell differentiation through the regulation of gene transcriptions. And the involvement of lncRNAs may be associated with initiation and progression of mesenchymal stem cell-related diseases. OBJECTIVE: We aimed at addressing the role of lncRNAs in the regulation of osteogenesis of mesenchymal stem cells derived from bone marrow and dental tissues, and discussing the potential utility of lncRNAs as biomarkers and therapeutic targets for mesenchymal stem cell related diseases. RESULTS: Numerous lncRNAs were differentially expressed during osteogenesis or odontogenesis of mesenchymal stem cells, and some of them were confirmed to be able to regulate the differentiation processes through the modifications of chromatin, transcriptional and post-transcriptional processes. LncRNAs were also associated with some diseases related with pathologic differentiation of mesenchymal stem cells. CONCLUSION: LncRNAs involve in the osteogenic differentiation of bone marrow and dental tissuederived mesenchymal stem cells, and they could become promising therapeutic targets and prognosis parameters. However, the mechanisms of the role of lncRNAs are still enigmatic and require further investigation. PMID- 29141555 TI - Antineoplastic Effects of NF-kappaB Inhibition by DHMEQ (Dehydroxymethylepoxyquinomicin) Alone and in Co-treatment with Radio-and Chemotherapy in Medulloblastoma Cell Lines. AB - BACKGROUND: NF-kappaB is a transcription factor involved in the transcriptional regulation of a large number of genes related to tumorigenesis in several cancer cell types, and its inhibition has been related to anticancer effect. DHMEQ (Dehydroxymethylepoxyquinomicin) is a compound that blocks the translocation of NF-kappaB from the cytoplasm to the nucleus, thus inhibiting its activity as a transcriptional activator. Several studies have shown the antineoplastic effects of DHMEQ in numerous tumor types, however, there are no surveys that tested their effects in MB. OBJECTIVES: The aim of the present study was to evaluate the effects of DHMEQ as NF-kappaB inhibitor in pediatric MB cell lines. METHOD: We used the UW402, UW473 and ONS-76 medulloblastoma (MB) cell lines to verify the effect of DHMEQ on proliferation, clonogenic capacity, apoptosis, cell invasion and migration, and evaluated the effect of the combination with other drugs and the potential as a radiosensitizator. RESULTS: A significant decrease in the cell growth, a strong inhibition of the clonogenic capacity, migration and cell invasion was observed after NF-kappaB inhibition in the three MB cell lines. Conversely, increased level of apoptosis rates were demonstrated. Additionally, treatments with DHMEQ combined with other chemotherapeutic agents were synergic in most points, and a strong radiosensitization by this compound was observed in the three MB cell lines. CONCLUSION: DHMEQ has potential antitumor effect on MB cells, and it may be considered a new therapeutic agent to improve treatment approaches in MB. PMID- 29141556 TI - Selecting Patients With Small Renal Masses For Active Surveillance. AB - The incidentally discovered, clinically-localized, small renal mass (clinical stage T1aN0M0, <=4cm) is the most commonly diagnosed entity in renal cell carcinoma (RCC) - now accounting for at least 40% of newly diagnosed renal tumors. Given the above argument, active surveillance (AS) has emerged as a viable management strategy for SRM. This review will examine and discuss the existing literature regarding selection criteria for AS. AS of clinical T1a renal masses is emerging as a safe and effective management strategy in selected patients, yet appropriate patient selection and counseling remains an area of great interest. Long-term clinical outcomes are just beginning to be reported, thus much of the supporting evidence on AS and patient selection is based on retrospective data of heterogeneous quality. Nevertheless, there are certain conclusions that can be a made, despite these current limitations. First, appropriate selection of candidates should include a comprehensive evaluation of competing health risks, tumor characteristics, and patient preferences. PMID- 29141557 TI - Halilectin-3, a Lectin from the Marine Sponge Haliclona caerulea, Induces Apoptosis and Autophagy in Human Breast Cancer MCF7 Cells Through Caspase-9 Pathway and LC3-II Protein Expression. AB - BACKGROUND: An ideal strategy for cancer treatment is the specific induction of tumor cell death, sparing normal cells. Marine sponges are rich biological reservoirs of biomolecules, especially lectins, which have attracted considerable attention due to potential biological effect on human cells. Lectins are proteins that bind specific carbohydrate signatures and some gained further interest for their capacity to bind tumor associated carbohydrates antigens and induce tumor cell apoptosis. OBJECTIVE: This study aimed to evaluate the antitumor potential of H3, a lectin, recently reported from marine sponge Haliclona caerulea on the human breast cancer cell line MCF7. RESULTS: H3 reduced MCF7 cell viability with an IC50 of 100 ug/ml, without a significant effect on normal cells. At 24 h, H3 induced a significant arrest in the G1 cell cycle phase. Consistently, almost 50% of the cells were in early apoptosis and showed remarkable increased expression of caspase-9 (CASP 9). H3 impaired dramatically the adhesiveness of MCF7 cells in culture. Assays conducted with Lysotracker Red probe showed increased organelle acidity, suggesting autophagic cell death, which was further supported by increased expression of microtubuleassociated protein light chain 3 (LC3) and observable conversion of LC3-I in LC3-II by western blot. CONCLUSION: The apoptotic effect of H3 may be related to a balance between apoptotic and autophagic cell death, mediated by increased expression of CASP 9 and LC3-II. To the best of our knowledge this is the first report about a sponge lectin triggering both apoptosis and autophagy in MCF7 cell. PMID- 29141558 TI - Modulation of Cancer Metabolism by Phytochemicals - A Brief Overview. AB - Despite tremendous research efforts for effective therapies, cancer remains the plague of the century and its burden is expected to increase worldwide in the near future. Metabolic reprogramming is a firmly established hallmark of all cancers, regardless of their cellular or tissue origin, being a prerequisite for both tumor growth and invasion. Functional dependence of tumors on glycolysis and glutaminolysis and the crucial contribution of mitochondria to the tumor bioenergetic versatility are well recognized features and established therapeutic targets. The complex landscape of tumor metabolism in the context of the dynamic, bidirectional crosstalk with its stromal environment is a rapidly evolving field that increasingly supports the view of cancer both as metabolic disease and a disease of impaired cellular 'communication'. Many of the approved anticancer drugs are derived from natural sources and the search of novel drug candidates is still a priority view the rapid development of chemoresistance. Phytochemicals are biologically active plant compounds with preventive and/or curative anticancer properties able to potentiate the effects of standard therapies while decreasing their toxicity via multitarget modulatory effects. The present mini review will briefly summarize the hallmarks of metabolic reprogramming in tumor cells and the phytochemicals that have been reported to modulate the dysregulated metabolism of tumor and its environment, with special emphasis on triterpenes. PMID- 29141559 TI - New Histopathological & Genetic Features to Improve Active Surveillance Selection for Low-Risk Prostate Cancer. AB - BACKGROUND: A recent surge in biomarkers to aid management of men with prostate cancer has occurred. Their applications are varied and not all tests are applicable to the active surveillance setting. OBJECTIVE: To review primary evidence on genetic and immunohistochemical biomarkers, and their role on patient selection and risk stratification for men on active surveillance for prostate cancer. EVIDENCE ACQUISITION: A PubMed electronic search using the terms (biomarker or genetic or histopathological) AND ("prostate cancer" AND "active surveillance") was performed from inception to April 2015. EVIDENCE SYNTHESIS: Of the biomarkers reviewed, Prostate Health Index (PHI) and Oncotype DX Genomic Prostate Score (GPS), were identified to currently hold greatest potential benefit to aid risk stratification of men for AS. Higher PHI, at baseline and during follow-up, was shown to predict pathological upgrading at rebiopsy at two single institutions, but with small cohorts (n<200). The Oncotype DX GPS test has been validated on men suitable for AS but having upfront radical prostatectomy. Increase in GPS was shown to predict upgrading and upstaging at radical prostatectomy and biochemical recurrence post radical prostatectomy. Prospective validation in AS cohorts is yet to be performed. CONCLUSIONS: PHI and Oncotype DX GPS show promise in aiding risk stratification for men on AS. However, larger prospective studies in AS cohorts are needed. Integration of biomarkers with existing clinical and imaging models remains a challenge. PMID- 29141560 TI - Growth kinetics and oncologic outcomes for small renal masses managed with active surveillance: a review of the literature. AB - An increasing number of enhancing renal masses are being discovered incidentally on cross-sectional imaging. Many can be characterized as small renal masses (SRMs), the natural history of which is heterogeneous and poorly understood. Active surveillance has been proposed as an initial management strategy for these tumors, particularly in the old and infirmed patient population. Herein, a rigorous review of the literature is provided to explore the incidence and epidemiology of SRMs as well as the growth kinetics and oncologic outcomes of SRMs under observation. Special consideration is given to competing risks to mortality and cost-analyses for the management of the SRM. Finally, the role of percutaneous biopsy and current prospective clinical trials of active surveillance for SRMs are reviewed. PMID- 29141561 TI - Steroidal Anticancer Agents: An Overview of Estradiol-related Compounds. AB - Research of steroidal compounds as anticancer agents started almost 50 years ago. During the past decades, several innovative new steroids, like cyproterone, finasteride, estramustin, exemestane and fulvestrant have successfully become a part of routine clinical practice. Meanwhile, a vast amount of new information have accumulated about the functions of the endogenous steroid system (including the characterization of enzymes, receptors, transcription pathways, etc.) and about the role of steroids in carcinogenesis. Therefore, it is regularly required to review the latest published results, focusing on a well-defined part within this research field that has definitely developed into a highly diversified speciality by now. Herein, we make an attempt to summarize the most recent results reported about anticancer agents of estrane backbone, focusing on their mechanisms of action and their structure-activity relationships. Due to the vast number and various accessibilities of scientific publications, neither other reviews nor this one can be considered as absolutely exhaustive. In spite of these restrictive factors, the current review makes a good opportunity to define the recent scientific trends in the field of estradiol-related anticancer agents. PMID- 29141562 TI - A Review of Electroporation-based Antitumor Skin Therapies and Investigation of Betulinic Acid-loaded Ointment. AB - BACKGROUND: Electrochemotherapy is a novel treatment for cutaneous and subcutaneous tumors utilizing the combination of electroporation and chemotherapeutic agents. Since tumors have an increasing incidence nowadays as a result of environmental and genetic factors, electrochemotherapy could be a promising treatment for cancer patients. OBJECTIVE: The aim of this article is to summarize the novel knowledge about the use of electroporation for antitumor treatments and to present a new application of electrochemotherapy with a well known plant derived antitumor drug betulinic acid. For the review we have searched the databases of scientific and medical research to collect the available publications about the use of electrochemotherapy in the treatment of various types of cancer. METHOD: By the utilization of the available knowledge, we investigated the effect of electroporation on the penetration of a topically applied betulinic acid formulation into the skin by ex vivo Raman spectroscopy on hairless mouse skin. RESULTS: Raman measurements have demonstrated that the penetration depth of betulinic acid can be remarkably ameliorated by the use of electroporation, so this protocol can be a possibility for the treatment of deeper localized cancer nodules. Furthermore, it proved the influence of various treatment times, since they caused different spatial distributions of the drug in the skin. CONCLUSION: The review demonstrates that electrochemotherapy is a promising tool to treat different kinds of tumors with high efficiency and with only a few moderate adverse effects. Moreover, it presents a non-invasive method to enhance the penetration of antitumor agents, which can offer novel prospects for antitumor therapies. PMID- 29141563 TI - Ganoderma lucidum Polysaccharides as An Anti-cancer Agent. AB - The mushroom Ganoderma lucidum (G. lucidum) has been used for centuries in Asian countries to treat various diseases and to promote health and longevity. Clinical studies have shown beneficial effects of G. lucidum as an alternative adjuvant therapy in cancer patients without obvious toxicity. G. lucidum polysaccharides (GLP) is the main bioactive component in the water soluble extracts of this mushroom. Evidence from in vitro and in vivo studies has demonstrated that GLP possesses potential anticancer activity through immunomodulatory, anti proliferative, pro-apoptotic, anti-metastatic and anti-angiogenic effects. Here, we briefly summarize these anticancer effects of GLP and the underlying mechanisms. PMID- 29141564 TI - A review on the management of small renal masses: active surveillance versus surgery. AB - Despite the rise of small renal tumour (SRMs) diagnosis and related surgeries, death rate of kidney cancer is increasing, suggesting a non-optimal management of SRMs. Active Surveillance (AS) for kidney cancer was introduced to face this paradox. However, incertitude remains on whether and when AS can replace surgery in selected patients. We performed a literature search, reviewed and discussed the evidence in favour of AS or surgery for SRMs. Histopathology and natural history of SRMs, including the percentage of benign tumours amongst SRMs, tumour growth rate, life expectancy of SRMs patients being generally older, and current results of AS series seem to support its use in selected groups. However, kidney cancer is a heterogeneous entity, metastasis and >=T3a status can be found also for SRMs and no biomarkers or other parameters are available to identify lethal SRMs. Despite the recent improvement in the diagnostic and prognostic work up through imaging modalities, renal biopsies and nomograms, the interpretation of a survival plot subjectively is still not possible. The majority of AS studies are retrospective and large level 1 evidence cohorts with long term follow up are lacking. No unanimity is present regarding inclusion and exclusion criteria to undergo AS, follow up timings and AS exit criteria. Surgery is the only definitive treatment and remains the current standard. A better understanding of kidney cancer biology and SRMs behaviour is needed to clarify the role of AS and its indications. PMID- 29141565 TI - Radio-Modulatory Potential of Caffeic Acid Phenethyl Ester: A Therapeutic Perspective. AB - BACKGROUND: Use of natural agents is an upcoming area of research in cancer biology. Caffeic acid phenethyl ester (CAPE) has received great attention because of its therapeutic potential in various conditions including cancer. It is an active/abundant component of propolis, a honey bee hive product produced by bees using their enzyme-rich digestive secretions on resinous mix, bee wax and pollen from plants. It is used to protect the beehive against bacteria and other infections. Therefore a literature survey was done to understand the therapeutic potential of this compound. Although a lot of work has been done on chemotherapeutic aspects of CAPE and many reviews were available, yet its role as a radiomodulator was not clear. OBJECTIVE: The objective of the review was to collect data on role of Caffeic acid phenethyl ester as radioprotector and /or sensitizer to evaluate its potential as modulator of radiation effects during cancer therapy. METHODS: For literature survey, Pubmed and Google search engines were used. Data were collected up to August 2017. PubMed advanced search builder showed 845 papers on CAPE. This search was further narrowed down to synthesis, bioavailability, CAPE derivatives, radioprotective and radiosensitizing effects of CAPE. RESULTS: This review focused on the differential radiomodulatory effects of CAPE in normal and cancer cells. Besides chemistry and bioavailability, it's potential as a therapeutic agent against radiation induced damage was also evaluated. CONCLUSION: CAPE was found to act both as radioprotector and radiosensitizer. Depending on the tissue type it can modulate the radiation response by following different mechanisms. PMID- 29141566 TI - Perioperative Levels of Adiponectin and Oxidative Stress in Patients Undergoing Laparoscopic Abdominal Surgery for Cancer. AB - BACKGROUND: Low circulating levels of adiponectin are associated with the occurrence of infection after surgery in patients with cancer. Data are lacking on whether surgical stress is associated with a reduction in circulating levels of adiponectin. Furthermore, the relationship between oxidative stress and postoperative complications has not been investigated. OBJECTIVE: The aim of this study was to evaluate the pre-, intra-, and postoperative levels of adiponectin in patients who underwent major abdominal surgery for malignancy and their association with postoperative complications. METHODS: An observational, prospective, single-center study was conducted in patients undergoing abdominal surgery for cancer. Circulating levels of adiponectin and of two biomarkers of oxidative stress were measured preoperatively, at the end of surgery, 24 and 48 hours after surgery. Patients were divided into two groups: complicated (CL+) and uncomplicated (CL-), according to the Clavien-Dindo classification. Temporal patterns of adiponectin and markers of oxidative stress were followed at different time points. RESULTS: Twelve patients were enrolled, seven with postoperative complications (CL+) and five without (CL-). The preoperative median levels of adiponectin were statistically different between CL+ and CL- groups (3.2 ug/ml vs 10.9 ug/ml; p=0.03). Levels of preoperative adiponectin were inversely related to the severity of postoperative complications (Rho= -0.68; p= 0.02). Pre-, intra- and postoperative levels of oxidative stress products were not statistically different between the two groups. Adiponectin levels decreased during surgery in both groups, while those of oxidative stress tended to increase. CONCLUSIONS: Preoperative adiponectin levels correlate with postoperative complications after cancer surgery. PMID- 29141567 TI - Discovery of Thiazole Based Bis Heterocyclic System for Anti- Inflammatory Potential. AB - BACKGROUND: We have developed a new series of 36 substituted thiazole derivatives prepared via reaction of substituted benzothiazole-2-amine with substituted phenacyl bromide. OBJECTIVE: This study was aimed to develop and successfully evaluate anti-inflammatory activity of substituted thiazole derivatives. METHOD: A new series of 36 substituted thiazole derivatives was synthesized and derivatives were characterized by analytical and spectrometric methods like IR, MS, and 1H NMR. The molecular docking was performed for all the synthesized thiazole derivatives to assess their binding affinities to COX-2 isozyme. The best compounds from docking study were subjected for their anti-inflammatory activity by using rat hind paw edema method. RESULTS: Results from carrageenan induced hind paw edema showed that compounds 3h, 5a, 5e, 9d, and 9h possess significant anti-inflammatory activity. The result from vascular permeability indicating inhibition of vascular permeability with compounds 3h and 9h is significant and results from cotton pellet granuloma formation models show greater degree of inhibition with compounds 3h and 5a to contribute to their significant anti-inflammatory activity. CONCLUSION: This study provides successful development of novel thiazole derivatives. Their binding affinities to COX-2 enzyme were also confirmed, indicating that developed molecules are comparable to diclofenac and hence could be promising anti-inflammatory agents. PMID- 29141568 TI - Novel 2-(nitrooxy)ethyl 2-(4-(substituted phenyl)-2-((substituted phenyl)amino)thiazol-5-yl)acetate as Anti-inflammatory, Analgesic and Nitric Oxide Releasing Agents: Synthesis and Molecular Docking Studies. AB - BACKGROUND: Due to the need and adverse effects associated with the available anti-inflammatory agents, an attempt was made to develop the new anti inflammatory agents with better activity and lesser adverse effects. OBJECTIVE: Synthetic approaches based on chemical modification of NSAIDs have been undertaken with the aim of improving NSAIDs safety profile. METHOD: In the present study, a series of thiazole derivatives (3a-3x) was synthesized and tested for its anti-inflammatory with analgesic and nitric oxide releasing properties. In this work, synthesis of molecules containing substituted diaryl ring on 5-membered thiazole ring with nitric oxide releasing moiety is described. RESULTS: Out of the twenty four synthesized compounds, five compounds showed considerable anti-inflammatory and analgesic activity in comparison with the standard. Most of the synthesized compounds showed considerable nitric oxide releasing property. The molecular docking study was used to rationalize binding interaction at the active site and the result showed good binding interaction. CONCLUSION: From the results of pharmacological studies, we conclude that the synthesized compounds have not only retained, but showed enhanced anti inflammatory and analgesic profile. PMID- 29141569 TI - ISATIN: New Hope Against Convulsion. AB - BACKGROUND: Epilepsy is one in every of the foremost important chronic neurological disorders with high incidence worldwide. Several epileptic patients don't seem to be fully treated with currently available marketed medicines likewise so many drugs have shown unfavorable side effect and drug interaction. Therefore, there are continuing interests to seek out new anticonvulsant drugs. METHODS: Literature search was carried out to indentify isatin containing derivatives as anticonvulsant drugs. RESULTS: Common synthetic schemes were studied to design and develop isatin derives anticonvulsant agents. Various structural features essential for the design of isatin compounds were reported. Anticonvulsant activity is evaluated by different tests were identified and their results can be considered for the design of novel isatin derivatives as anticonvulsants. CONCLUSION: In outline, isatin has been proved to be an excellent hybrid building the molecule with interesting biological activities. Among the prospect of derivatizing the N1, C2 and C3 positions, along with substitution on the aromatic ring, the synthetic modification for isatin is almost endless. Despite the fact that isatin derivatives are well-studied compounds, new derivatives are continually being discovered on the basis of known AEDs, isatin has been fused with other bioactive drug fragments and subsequently investigated as hybrid/dual action drugs and selectively targeted against convulsion. PMID- 29141570 TI - Effect of Extra Virgin Olive Oil and Table Olives on the ImmuneInflammatory Responses: Potential Clinical Applications. AB - BACKGROUND AND OBJECTIVE: Extra virgin olive oil (EVOO) is the common element among the Mediterranean countries. It can be considered a nutraceutical and functional food, thanks to its bioactive compounds. It can act and modulate different processes linked to ageing and age-related diseases related to a common chronic low grade inflammation. Depending on the cultivar, the growth conditions, the period of harvesting, the productive process and time of product storage, EVOO could contain different amount of vegetal components. Of course, the same is for table olives. METHODS: The aim of our review is to summarize the effects of EVOO and table olives on the immunemediated inflammatory response, focusing our attention on human studies. RESULTS: Our report highlights the effect of specific molecules obtained from EVOO on the modulation of specific cytokines and anti oxidants suggesting the importance of the daily consumption of both EVOO and table olives in the context of a Mediterranean dietary pattern. In addition, the different action on immune-inflammatory biomarkers, are depending on the olive tree cultivar. CONCLUSION: Thanks to their bioactive compounds, EVOO and table olive can be considered as nutraceutical and functional foods. The beneficial effects analysed in this review will help to understand the potential application of specific olive components as therapeutic adjuvant, supplements or drugs. PMID- 29141571 TI - Extra Virgin Olive Oil and Cardiovascular Diseases: Benefits for Human Health. AB - BACKGROUND AND OBJECTIVE: The cardioprotective properties of Mediterranean Diet were demonstrated for the first time from the Seven Country Study. In the last few decades, numerous epidemiological studies, as well as intervention trial, confirmed this observation, pointing out the close relationship between the Mediterranean diet and cardiovascular diseases. In this context, extra virgin olive oil (EVOO), the most representative component of this diet, seems to be relevant in lowering the incidence of cardiovascular events, including myocardial infarction and stroke. From a chemical point of view, 98-99% of the total weight of EVOO is represented by fatty acids, especially monounsaturated fatty acids such as oleic acid. Tocopherols, polyphenols and other minor constituents represent the remaining 1-2%. All these components may potentially contribute to "health maintenance" with their beneficial effects by EVOOO. METHODS: Studies that examined the effect of EVOO supplementation in healthy subjects and in individuals at cardiovascular risk were included. CONCLUSION: The studies analyzed demonstrated the role of EVOO as anti-inflammatory, antioxidant and vasodilatory nutrient that may contribute to lower the atherosclerotic burden. PMID- 29141572 TI - A Clinical Update and Global Economic Burden of Rheumatoid Arthritis. AB - BACKGROUND AND OBJECTIVE: Rheumatoid arthritis (RA) is a predominant inflammatory autoimmune disorder. The incidence and prevalence of RA is increasing with considerable morbidity and mortality worldwide. The pathophysiology of RA has become clearer due to many significant research outputs during the last two decades. Many inflammatory cytokines involved in RA pathophysiology and the presence of autoantibodies are being used as potential biomarkers via the use of effective diagnostic techniques for the early diagnosis of RA. Currently, several disease-modifying anti-rheumatic drugs are being prescribed targeting RA pathophysiology, which have shown significant contributions in improving the disease outcomes. DISCUSSION: Even though innovations in treatment strategies and monitoring are helping the patients to achieve early and sustained clinical and radiographic remission, the high cost of drugs and limited health care budgets are restricting the easy access of RA treatment. Both direct and indirect high cost of treatment are creating economic burden for the patients and affecting their quality of life. CONCLUSION: The aim of this review is to describe the updated concept of RA pathophysiology and highlight current diagnostic tools used for the early detection as well as prognosis - targeting several biomarkers of RA. Additionally, we explored the updated treatment options with side effects besides discussing the global economic burden. PMID- 29141573 TI - Liver Protective Effects of Extra Virgin Olive Oil: Interaction between Its Chemical Composition and the Cell-signaling Pathways Involved in Protection. AB - BACKGROUND AND OBJECTIVE: The liver is an organ susceptible to a multitude of injuries that causes liver damage, like steatosis, non-alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and ischemia-reperfusion injury. Extra virgin olive oil (EVOO), presents several protective effects on the liver, reducing hepatic steatosis, hepatocyte ballooning, fibrogenesis, preventing lipid peroxidation, among other effects. Due to its high levels of monounsaturated fatty acids, mainly oleic acid and phenolic compounds, such as hydroxytyrosol and oleuropein, EVOO is able to participate in the activation of different signaling pathways in the hepatocytes involved in the prevention of inflammation, oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and insulin resistance, allowing the prevention or resolution of liver damage. The aim of this work is to offer an update of the molecular effects of EVOO in the liver and its protective properties to prevent the establishment of liver damage through the regulation of different cell-signaling pathways. METHODS: Searches that considered the effects of EVOO in in vivo and in vitro models, whith emphasis in the molecular mechanism of liver tissue damage and prevention and/or treatment of steatosis, steatohepatitis, cirrhosis, hepatocellular carcinoma, and ischemia reperfusion injury. CONCLUSION: The most relevant molecular effects of EVOO involved in the prevention or resolution of liver damage are: (i) Activation of the nuclear transcription factor erythroid-derived 2-like 2 (Nfr2), inducing the cellular antioxidant response; (ii) Inactivation of the nuclear transcription factor-kappaB (NF- kappaB), preventing the cellular inflammatory response; and (iii) Inhibition of the PERK pathway, preventing endoplasmic reticulum stress, autophagy, and lipogenic response. PMID- 29141574 TI - Anti-inflammatory Activity of Extra Virgin Olive Oil Polyphenols: Which Role in the Prevention and Treatment of Immune-Mediated Inflammatory Diseases? AB - BACKGROUND AND OBJECTIVE: Altered inflammatory response characterizes chronic immunemediated inflammatory diseases (IMID) such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, and psoriasis. Accumulating evidence indicates that regular consumption of extra virgin olive oil (EVOO), the main source of fat in the Mediterranean diet, is associated with a reduced risk of developing chronic degenerative disorders such as cardiovascular diseases, type 2 diabetes and cancer. The beneficial effects on health of EVOO have been attributed, besides to the monounsaturated fats content, to the presence of phenolic compounds that have antioxidant, anti-inflammatory and immunomodulatory properties. The purpose of this review is to provide an overview of the effects of EVOO polyphenols on IMID highlighting the potential mechanisms of action. METHODS: Scientific papers were found by searching in PubMed up to May 2017 using the following key words: rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, and psoriasis also in combination with EVOO, phenolic compounds, oleuropein, oleocantal, hydroxytyrosol,tyrosol and oleochantal. RESULTS: In vitro and in vivo studies indicate that EVOO and its polyphenols can improve diseases symptoms in IMID, by acting both at local and systemic levels and by modulating several molecular pathways. Nevertheless, there are not sufficient data to achieve specific nutritional guidelines. CONCLUSION: Further research is needed to evaluate the real contribution of EVOO and its phenolic compounds in modulating the IMID-associated inflammatory perturbations, in order to develop appropriate nutritional recommendations. PMID- 29141575 TI - The Protective Effects of Extra Virgin Olive Oil on Immune-mediated Inflammatory Responses. AB - BACKGROUND AND OBJECTIVE: The increasing interest in the Mediterranean diet (MeDiet) hinges on the relevant role it plays in inflammatory diseases. Several clinical, epidemiological and experimental evidences suggest that consumption of the MeDiet reduces the incidence of certain pathologies related to oxidative stress, chronic inflammation and immune system diseases such as cancer, atherosclerosis and cardiovascular disease (CVD). These reductions can be partially attributed to extra virgin olive oil (EVOO) consumption which has been described as a key bioactive food because of its high nutritional quality and its particular composition of fatty acids, vitamins and polyphenols. Indeed, the beneficial effects of EVOO have been linked to its fatty acid composition, which is very rich in monounsaturated fatty acids (MUFA), and has moderate saturated and polyunsaturated fatty acids (PUFA). The current knowledge available on the beneficial effects of EVOO and its phenolic compounds, specifically its biological properties and antioxidant capacity against immune-mediated inflammatory responses (atherosclerosis, rheumatoid arthritis, diabetes, obesity, cancer, inflammatory bowel disease or neurodegenerative disease, among others) in addition to its potential clinical applications. CONCLUSION: The increasing body of studies carried out provides compelling evidence that olive polyphenols are potential candidates to combat chronic inflammatory states. PMID- 29141576 TI - Analysis of Elevated Levels of Nandrolone Decanoate Induced Cytochrome- P450 Alterations in Mice. AB - BACKGROUND: Frequent recreational use of Anabolic Androgenic Steroids (AAS) is an instance of substance abuse which mimics the status of a natural hormone and upon prolonged exposure may lead to adverse drug reactions. These adverse drug reactions proceed in a manner so as to alter the normal metabolism of an enzyme mediated pathway such as the Cytochrome P450 (CYP) family of enzymes. OBJECTIVE: The present study was conducted to investigate the impact of overuse of Nandrolone Decanoate (ND), an AAS, upon CYP enzyme activity and a CYP gene, belonging to CYP1 family. METHODS: The study was carried out using normal and ND treated male albino mice. Genetic analysis was conducted using normalized and treated cDNA and reverse transcriptase polymerase chain reaction based assays. For enzyme assay, 0.1ml of 25 mg ND was administered to the animals twice a week for a period of 90 days. Genetic analysis was carried out with the same dose but administered for a period of 360 days. RESULTS: CYP enzyme activity increased significantly (p<0.01) in the ND treated group of animals compared to that in the normal group. However, no noticeable alteration was observed at the molecular level. CONCLUSION: From the present study it could be inferred that, at elevated doses, ND has the potential to alter hepatic CYP enzyme activity without any modification in the CYP gene. This could be due to a possible adaptive response of the living system to such drugs. PMID- 29141577 TI - Extracellular Synthesis of Selenium Nanoparticles from an Actinomycetes Streptomyces griseoruber and Evaluation of its Cytotoxicity on HT-29 Cell Line. AB - BACKGROUND: Selenium nanoparticles (SeNPs) have gained significant importance because of its bioavailability, least toxicity, its interaction with proteins and its biocompatibility. OBJECTIVE: In the present study, the extracellular synthesis of SeNPs was carried out by using culture supernatant of Streptomyces griseoruber, an Actinomycetes member isolated from the soil and cytotoxicity was tested on HT-29 cell line. METHODS: Culture supernatant was mixed with 1mM sodium selenite for the biosynthesis of SeNPs. Characterisation of the synthesised SeNPs was done by UV-Visible spectrophotometer, FTIR, XRD, DLS and HR-TEM. The cytotoxicity of nanoparticles on HT-29 cell line was studied by MTT assay and with different staining procedure. RESULTS: Bioreduction of SeNPs was confirmed by UV-Visible spectrophotometer that showed the peak at 575 nm. Size and distribution of the biosynthesised SeNPs were analysed by HR-TEM that showed the formation of particle size in the range of 100-250nm. The synthesised SeNPs showed good cytotoxic activity against HT-29 cell line with 40.5%, 33% and 23.7% of cell viability at 2MUg/ ml, 4MUg/ml and 30MUg/ml concentration respectively. CONCLUSION: The present study reports the simple and eco-friendly synthesis of SeNPs that showed good cytotoxic activity against HT-29 cell line suggesting that biogenic SeNPs could be a potential chemotherapeutic agent. PMID- 29141578 TI - A Comprehensive Review on Role of Nanoparticles in Therapeutic Delivery of Medicine. AB - BACKGROUND: The effective targeted drug delivery system is significant for future development of medicinal product and healthcare. There are also different types of nanostructures which include solid lipid nanoparticles, liposomes, dendrimers, nanostructured lipid carriers, lipid drug conjugate, liquid crystalline particles, polymeric nanocrystals, polymeric nanoparticles and superparamagnetic nanoparticles which have been considered as advanced carriers in drug delivery system. Method & Discussion: In this regard, nano carriers are bringing revolution in therapeutic delivery of drug as compared to conventional delivery systems by overcoming the limitations of usual methods. CONCLUSION: The objective of this review is to cover the drug delivery system of various therapeutic drugs and biomolecules by means of polymeric nanoparticles, dendrimers, liposomal nanoparticles and magnetic nanoparticles by describing the methods of formulation development. PMID- 29141579 TI - A missense variant in the coil1A domain of the keratin 25 gene is associated with the dominant curly hair coat trait (Crd) in horse. AB - BACKGROUND: Curly horses present a variety of curl phenotypes that are associated with various degrees of curliness of coat, mane, tail and ear hairs. Their origin is still a matter of debate and several genetic hypotheses have been formulated to explain the diversity in phenotype, including the combination of autosomal dominant and recessive alleles. Our purpose was to map the autosomal dominant curly hair locus and identify the causal variant using genome-wide association study (GWAS) and whole-genome sequencing approaches. RESULTS: A GWAS was performed using a Bayesian sparse linear mixed model, based on 51 curly and 19 straight-haired French and North American horses from 13 paternal families genotyped on the Illumina EquineSNP50 BeadChip. A single strong signal was observed on equine chromosome 11, in a region that encompasses the type I keratin gene cluster. This region was refined by haplotype analysis to a segment including 36 genes, among which are 10 keratin genes (KRT-10, -12, -20, -23, -24, -25, -26, -27, -28, -222). To comprehensively identify candidate causal variants within all these genes, whole-genome sequences were obtained for one heterozygous curly stallion and its straight-haired son. Among the four non-synonymous candidate variants identified and validated in the curly region, only variant g.21891160G>A in the KRT25 gene (KRT25:p.R89H) was in perfect agreement with haplotype status in the whole pedigree. Genetic association was then confirmed by genotyping a larger population consisting of 353 horses. However, five discordant curly horses were observed, which carried neither the variant nor the main haplotype associated with curliness. Sequencing of KRT25 for two discordant horses did not identify any other deleterious variant, which suggests locus rather than allelic heterogeneity for the curly phenotype. CONCLUSIONS: We identified the KRT25:p.R89H variant as responsible for the dominant curly trait, but a second dominant locus may also be involved in the shape of hairs within North American Curly horses. PMID- 29141580 TI - Usability of human Infinium MethylationEPIC BeadChip for mouse DNA methylation studies. AB - BACKGROUND: The advent of array-based genome-wide DNA methylation methods has enabled quantitative measurement of single CpG methylation status at relatively low cost and sample input. Whereas the use of Infinium Human Methylation BeadChips has shown great utility in clinical studies, no equivalent tool is available for rodent animal samples. We examined the feasibility of using the new Infinium MethylationEPIC BeadChip for studying DNA methylation in mouse. RESULTS: In silico, we identified 19,420 EPIC probes (referred as mEPIC probes), which align with a unique best alignment score to the bisulfite converted reference mouse genome mm10. Further annotation revealed that 85% of mEPIC probes overlapped with mm10.refSeq genes at different genomic features including promoters (TSS1500 and TSS200), 1st exons, 5'UTRs, 3'UTRs, CpG islands, shores, shelves, open seas and FANTOM5 enhancers. Hybridization of mouse samples to Infinium Human MethylationEPIC BeadChips showed successful measurement of mEPIC probes and reproducibility between inter-array biological replicates. Finally, we demonstrated the utility of mEPIC probes for data exploration such as hierarchical clustering. CONCLUSIONS: Given the absence of cost and labor convenient genome-wide technologies in the murine system, our findings show that the Infinium MethylationEPIC BeadChip platform is suitable for investigation of the mouse methylome. Furthermore, we provide the "mEPICmanifest" with genomic features, available to users of Infinium Human MethylationEPIC arrays for mouse samples. PMID- 29141581 TI - Sanger sequencing in exonic regions of STK11 gene uncovers a novel de-novo germline mutation (c.962_963delCC) associated with Peutz-Jeghers syndrome and elevated cancer risk: case report of a Chinese patient. AB - BACKGROUND: Peutz-Jeghers syndrome (PJS) is caused by mutations in the tumor suppressor gene, STK11, and is characterized by gastrointestinal hamartomas, melanin spots on the lips and the extremities, and an increased risk of developing cancer. CASE PRESENTATION: We reported an isolated PJS patient who died of colon cancer, whose blood sample was collected together with all the available family members'. The entire coding region of the STK11 gene was amplified by PCR and analyzed by Sanger sequencing, through which, a novel mutation, c.962_963delCC in exon 8 was identified in this patient. This mutation causes a frameshift mutation and a premature termination at codon 358. Protein structure prediction by Swiss-Model indicated a dramatic change and partial loss of the C-terminal domain. We did not observe this mutation in both parents of the proband. Therefore, it is considered a novel de-novo mutation. Furthermore, the mutation was not found in 50 unrelated healthy people. CONCLUSIONS: The novel mutation we reported here had not been recorded in databases or literature, and the patient who possessed it suffered from PJS and colon cancer. So our results enlarge the spectrum of STK11 variants in PJS patients. This mutation is most likely responsible for development of the PJS phenotype, especially the cancer occurrence. PMID- 29141582 TI - A novel interaction between kinase activities in regulation of cilia formation. AB - BACKGROUND: The primary cilium is an extension of the cell membrane that encloses a microtubule-based axoneme. Primary cilia are essential for transmission of environmental cues that determine cell fate. Disruption of primary cilia function is the molecular basis of numerous developmental disorders. Despite their biological importance, the mechanisms governing their assembly and disassembly are just beginning to be understood. Cilia growth and disassembly are essential events when cells exit and reenter into the cell cycle. The kinases never in mitosis-kinase 2 (Nek2) and Aurora A (AurA) act to depolymerize cilia when cells reenter the cell cycle from G0. RESULTS: Coexpression of either kinase with its kinase dead companion [AurA with kinase dead Nek2 (Nek2 KD) or Nek2 with kinase dead AurA (AurA KD)] had different effects on cilia depending on whether cilia are growing or shortening. AurA and Nek2 are individually able to shorten cilia when cilia are growing but both are required when cilia are being absorbed. The depolymerizing activity of each kinase is increased when coexpressed with the kinase dead version of the other kinase but only when cilia are assembling. Additionally, the two kinases act additively when cilia are assembling but not disassembling. Inhibition of AurA increases cilia number while inhibition of Nek2 significantly stimulates cilia length. The complex functional relationship between the two kinases reflects their physical interaction. Further, we identify a role for a PP1 binding protein, PPP1R42, in inhibiting Nek2 and increasing ciliation of ARPE-19 cells. CONCLUSION: We have uncovered a novel functional interaction between Nek2 and AurA that is dependent on the growth state of cilia. This differential interdependence reflects opposing regulation when cilia are growing or shortening. In addition to interaction between the kinases to regulate ciliation, the PP1 binding protein PPP1R42 directly inhibits Nek2 independent of PP1 indicating another level of regulation of this kinase. In summary, we demonstrate a complex interplay between Nek2 and AurA kinases in regulation of ciliation in ARPE-19 cells. PMID- 29141583 TI - Clinical and molecular genetic characterization of familial MECP2 duplication syndrome in a Chinese family. AB - BACKGROUND: Chromosomal duplication at the Xq28 region including the MECP2 gene, share consistent clinical phenotypes and a distinct facial phenotype known as MECP2 duplication syndrome. The typical clinical features include infantile hypotonia , mild dysmorphic features, a broad range of neurodevelopmental disorders, recurrent infections, and progressive spasticity. METHODS: This Chinese MECP2 duplication syndrome family includes six patients (five males and one female), and four asymptomatic female carriers. Two kinds of chips including 4x180K CNV + SNP chip and custom 8x60K CNV chip were used to detect MECP2 duplication, and then fluorescent in situ hybridization (FISH) analysis was performed to identify the exact copy number of MECP2. X-chromosome inactivation (XCI) analysis on AR gene was detected for all female family members, and the m icrosatellite analysis on MECP2 was used to validate the recombination event on MECP2 region. RESULTS: The affected male subjects presented with a broad range of neurodevelopmental symptoms (severe intellectual disability, developmental delay, seizure, language deficit, and autism spectrum disorder) as well as facial dysmorphism and other symptoms which were consistent with that of Western patients previous reported. Seizure is reported in Chinese patients for the first time. In addition, we validated three recombination events for the MECP2 duplication allele during maternal transmission due to X homologous recombination. CONCLUSIONS: We provided the largest known Chinese pedigree with MECP2 duplication syndrome. The detailed clinical description and molecular genetic characterization in all affected family members further delineate the typical phenotype of this genomic disorder in Chinese population. PMID- 29141584 TI - SPRINT: ultrafast protein-protein interaction prediction of the entire human interactome. AB - BACKGROUND: Proteins perform their functions usually by interacting with other proteins. Predicting which proteins interact is a fundamental problem. Experimental methods are slow, expensive, and have a high rate of error. Many computational methods have been proposed among which sequence-based ones are very promising. However, so far no such method is able to predict effectively the entire human interactome: they require too much time or memory. RESULTS: We present SPRINT (Scoring PRotein INTeractions), a new sequence-based algorithm and tool for predicting protein-protein interactions. We comprehensively compare SPRINT with state-of-the-art programs on seven most reliable human PPI datasets and show that it is more accurate while running orders of magnitude faster and using very little memory. CONCLUSION: SPRINT is the only sequence-based program that can effectively predict the entire human interactome: it requires between 15 and 100 min, depending on the dataset. Our goal is to transform the very challenging problem of predicting the entire human interactome into a routine task. AVAILABILITY: The source code of SPRINT is freely available from https://github.com/lucian-ilie/SPRINT/ and the datasets and predicted PPIs from www.csd.uwo.ca/faculty/ilie/SPRINT/ . PMID- 29141585 TI - Transcriptome analysis in petals and leaves of chrysanthemums with different chlorophyll levels. AB - BACKGROUND: Chlorophylls (Chls) are magnesium-containing tetrapyrrole macromolecules responsible for the green color in plants. The Chl metabolic pathway has been intensively studied and nearly all the enzymes involved in the pathway have been identified and characterized. Synthesis and activity of these enzymes are tightly regulated in tissue- and developmental stage-specific manners. Leaves contain substantial amounts of Chls because Chls are indispensable for photosynthesis. In contrast, petals generally contain only trace amounts of Chls, which if present would mask the bright petal color. Limited information is available about the mechanisms that control such tissue specific accumulation of Chls. RESULTS: To identify the regulatory steps that control Chl accumulation, we compared gene expression in petals and leaves of chrysanthemum cultivars with different Chl levels. Microarray and quantitative real-time PCR analyses showed that the expression levels of Chl biosynthesis genes encoding glutamyl-tRNA reductase, Mg-protoporphyrin IX chelatase, Mg protoporphyrin IX monomethylester cyclase, and protochlorophyllide oxidoreductase were well associated with Chl content: their expression levels were lower in white petals than in green petals, and were highest in leaves. Among Chl catabolic genes, expression of STAY-GREEN, encoding Mg-dechelatase, which is a key enzyme controlling Chl degradation, was considerably higher in white and green petals than in leaves. We searched for transcription factor genes whose expression was well related to Chl level in petals and leaves and found three such genes encoding MYB113, CONSTANS-like 16, and DREB and EAR motif protein. CONCLUSIONS: From our transcriptome analysis, we assume that a low rate of Chl biosynthesis and a high rate of Chl degradation lead to the absence of Chls in white chrysanthemum petals. We identified several candidate transcription factors that might affect Chl accumulation in chrysanthemum petals. Functional analysis of these transcription factors will provide a basis for future molecular studies of tissue-specific Chl accumulation. PMID- 29141586 TI - Profiling membrane glycerolipids during gamma-ray-induced membrane injury. AB - BACKGROUND: gamma-rays are high-energy radiation that cause a range of random injuries to plant cells. Most studies on this issue have focused on gamma-ray induced nucleotide damage and the production of reactive oxygen species in cells, so little is known about the glycerolipid metabolism during gamma-rays induced membrane injury. Using an ESI-MS/MS-based lipidomic method, we analysed the lipidome changes in wild-type and phospholipase D (PLD)delta- and alpha1 deficient Arabidopsis after gamma-ray treatment. The aim of this study was to investigate the role of PLD-mediated glycerolipid metabolism in gamma-ray-induced membrane injury. RESULTS: The ion leakage of Arabidopsis leaves after 2885-Gy gamma-ray treatment was less than 10%. High does gamma-ray treatment could induce the accumulation of intracellular reactive oxygen species (ROS). Inhibition of PLDalpha1 caused severe lipid degradation under gamma-ray treatment. gamma-ray induced glycerolipid degradation mostly happened in chloroplastidic lipids, rather than extraplastidic ones. The levels of lysophosphatidylcholine (lysoPC) and lysophosphatidylethanolamine (lysoPE) were maintained in the WS ecotypes during gamma-ray treatments, while increased significantly in the Col ecotype treated with 1100 Gy. After 210- and 1100-Gy gamma-ray treatments, the level of lysophosphatidylglycerol (lysoPG) decreased significantly in the four genotypes of Arabidopsis. CONCLUSIONS: gamma-ray-induced membrane injury may occur via an indirect mechanism. The degradation of distinct lipids is not synchronous, and that interconversions among lipids can occur. During gamma-ray-induced membrane injury, the degradation of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) may be mediated by PLDzeta1 or phospholipase A1. The degradation of phosphatidylglycerol was not mediated by PLA, PLDdelta or PLDalpha1, but by phospholipase C or other PLDs. gamma-rays can decrease the double-bond index and increase the acyl chain length in membrane lipids, which may make membranes more rigid and further cause injury in membranes. PMID- 29141587 TI - Video feedback promotes relations between infants and vulnerable first-time mothers: a quasi-experimental study. AB - BACKGROUND: Supporting early mother-infant relationships to ensure infants' future health has been recommended. The aim of this study was to investigate whether video feedback using the Marte Meo method promotes a healthy early relationship between infants and vulnerable first-time mothers. Video feedback or usual care was delivered by health visitors during home visits in Danish municipalities. METHODS: This quasi-experimental study included pre- and post tests of 278 vulnerable families. Mothers were allocated to an intervention group (n = 69), a comparison group (n = 209) and an exactly matched video subsample from the comparison group (n = 63). Data consisted of self-reported questionnaires and video recordings of mother-infant interactions. Outcomes were mother-infant dyadic synchrony (CARE-Index), maternal confidence (KPCS), parental stress (PSS), maternal mood (EPDS) and infant socialemotional behaviours (ASQ:SE). The data were analysed using descriptive and linear multiple regression analysis. RESULTS: The levels of dyadic synchrony in the intervention group had significantly improved (p < 0.001) at follow-up with a mean score of 9.51 (95%CI;8.93-10.09) compared with 7.62 (95%CI;7.03-8.21). The intervention group also showed a higher level of maternal sensitivity with a mean score of 9.55 (95%CI;8.96-10.14) compared with 7.83 (95%CI;7.19-8.46) in the matched video subsample (p < 0.001). With respect to infant cooperation, similar improvements were found with a mean score of 9.43 (95% CI;8.88-9.99) in the intervention group compared with 7.73 (95%CI;7.13-8.33) in the matched video subsample from the comparison group (p < 0.001). Furthermore, mothers in the intervention group reported significantly lower levels of parental stress with a mean score of 32.04 (95%CI;30.13-33.94) compared with 35.29 (95%CI;34.07-36.52) in the comparison group (p = 0.03), as well as higher levels of maternal confidence with a mean score of 41.10 (95%CI;40.22-41.98) compared with 40.10 (95%CI;39.65-40.56) in the comparison group (p = 0.04). No significant differences were found in EPDS and ASQ:SE. CONCLUSION: The findings support the assumption that video feedback using the Marte Meo method early after birth may strengthen the relationship between infants and vulnerable firsttime mothers as well as improve maternal psychosocial functioning. Further research applying random assignment is needed to strengthen these conclusions; further research is also needed to assess any long term effects of the video feedback intervention using the Marte Meo method. TRIAL REGISTRATION: This study was registered on 24 January 2013 in ClinicalTrials.gov with the identifier: NCT01799447 . PMID- 29141588 TI - Parkinson disease polygenic risk score is associated with Parkinson disease status and age at onset but not with alpha-synuclein cerebrospinal fluid levels. AB - BACKGROUND: The genetic architecture of Parkinson's Disease (PD) is complex and not completely understood. Multiple genetic studies to date have identified multiple causal genes and risk loci. Nevertheless, most of the expected genetic heritability remains unexplained. Polygenic risk scores (PRS) may provide greater statistical power and inform about the genetic architecture of multiple phenotypes. The aim of this study was to test the association between PRS and PD risk, age at onset and cerebrospinal fluid (CSF) biomarkers (alpha-synuclein, Abeta1-42, t-tau and p-tau). METHODS: The weighted PRS was created using the genome-wide loci from Nalls et al., 2014 PD GWAs meta-analysis. The PRS was tested for association with PD status, age at onset and CSF biomarker levels in 829 cases and 432 controls of European ancestry. RESULTS: The PRS was associated with PD status (p = 5.83*10-08) and age at onset (p = 5.70*10-07). The CSF t-tau levels showed a nominal association with the PRS (p = 0.02). However, CSF alpha synuclein, amyloid beta and phosphorylated tau were not found to be associated with the PRS. CONCLUSION: Our study suggests that there is an overlap in the genetic architecture of PD risk and onset, although the different loci present different weights for those phenotypes. In our dataset we found a marginal association of the PRS with CSF t-tau but not with alpha-synuclein CSF levels, suggesting that the genetic architecture for the CSF biomarker levels is different from that of PD risk. PMID- 29141589 TI - Reconstructing cancer karyotypes from short read data: the half empty and half full glass. AB - BACKGROUND: During cancer progression genomes undergo point mutations as well as larger segmental changes. The latter include, among others, segmental deletions duplications, translocations and inversions.The result is a highly complex, patient-specific cancer karyotype. Using high-throughput technologies of deep sequencing and microarrays it is possible to interrogate a cancer genome and produce chromosomal copy number profiles and a list of breakpoints ("jumps") relative to the normal genome. This information is very detailed but local, and does not give the overall picture of the cancer genome. One of the basic challenges in cancer genome research is to use such information to infer the cancer karyotype. We present here an algorithmic approach, based on graph theory and integer linear programming, that receives segmental copy number and breakpoint data as input and produces a cancer karyotype that is most concordant with them. We used simulations to evaluate the utility of our approach, and applied it to real data. RESULTS: By using a simulation model, we were able to estimate the correctness and robustness of the algorithm in a spectrum of scenarios. Under our base scenario, designed according to observations in real data, the algorithm correctly inferred 69% of the karyotypes. However, when using less stringent correctness metrics that account for incomplete and noisy data, 87% of the reconstructed karyotypes were correct. Furthermore, in scenarios where the data were very clean and complete, accuracy rose to 90%-100%. Some examples of analysis of real data, and the reconstructed karyotypes suggested by our algorithm, are also presented. CONCLUSION: While reconstruction of complete, perfect karyotype based on short read data is very hard, a large fraction of the reconstruction will still be correct and can provide useful information. PMID- 29141590 TI - Health, nutrition, and development of children born preterm and low birth weight in rural Rwanda: a cross-sectional study. AB - BACKGROUND: As care for preterm and low birth weight (LBW) infants improves in resource-limited settings, more infants are surviving the neonatal period. Preterm and (LBW) infants are at high-risk of nutritional and medical comorbidities, yet little is known about their developmental outcomes in low income countries. This study evaluated the health, nutritional, and developmental status of preterm/LBW children at ages 1-3 years in Rwanda. METHODS: Cross sectional study of preterm/LBW infants discharged between October 2011 and October 2013 from a hospital neonatal unit in rural Rwanda. Gestational age and birth weight were gathered from hospital records to classify small for gestational age (SGA) at birth and prematurity. Children were located in the community for household assessments in November-December 2014. Caregivers reported demographics, health status, and child development using locally-adapted Ages and Stages Questionnaires (ASQ-3). Anthropometrics were measured. Bivariate associations with continuous ASQ-3 scores were conducted using Wilcoxon Rank Sum and Kruskal Wallis tests. RESULTS: Of 158 eligible preterm/LBW children discharged from the neonatal unit, 86 (54.4%) were alive and located for follow up. Median birth weight was 1650 grams, median gestational age was 33 weeks, and 50.5% were SGA at birth. At the time of household interviews, median age was 22.5 months, 46.5% of children had feeding difficulties and 39.5% reported signs of anemia. 78.3% of children were stunted and 8.8% wasted. 67.4% had abnormal developmental screening. Feeding difficulties (p = 0.008), anemia symptoms (p = 0.040), microcephaly (p = 0.004), stunting (p = 0.034), SGA (p = 0.023), very LBW (p = 0.043), lower caregiver education (p = 0.001), and more children in the household (p = 0.016) were associated with lower ASQ-3 scores. CONCLUSIONS: High levels of health, growth, and developmental abnormalities were seen in preterm/LBW children at age 1-3 years. As we achieve necessary gains in newborn survival in resource-limited settings, follow-up and early intervention services are critical for ensuring high-risk children reach their developmental potential. PMID- 29141591 TI - The impact of pregnancy loss on men's health and wellbeing: a systematic review. AB - BACKGROUND: Research indicates that men's psychological and physical health outcomes after pregnancy loss differ from those of women. Our goal was to identify all literature with a focus on men's experiences of pregnancy loss in order to outline current evidence concerning men's wellbeing. METHODS: A systematic review of literature on men and pregnancy loss was undertaken following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Joanna Briggs Institute (JBI) and Social Care Institute for Excellence (SCIE) guidelines. Literature was sourced from PsycINFO, PubMed, Scopus, CINAHL, and Google Scholar. Inclusion criteria were 1) studies that focused on pregnancy loss (including miscarriage, stillbirth, and ectopic pregnancy, 2) that men's voices were specifically represented, and 3) that studies were of primary data. RESULTS: A final sample of 29 articles was identified, of which 16 were quantitative, 10 qualitative, and 3 mixed methods. Quantitative and mixed methods studies indicated that while men tended to have less intense and less enduring levels of negative psychological outcomes than women, they are more likely to engage in compensatory behaviours, such as increased alcohol consumption. Qualitative studies indicated that men often feel that their role is primarily as a 'supporter' to their female partner, and that this precludes recognition of their own loss. These studies also reported that men may feel overlooked and marginalised in comparison to their female partners, whose pain is typically more visible. CONCLUSIONS: Further research is needed on men's experiences of pregnancy loss, focusing on cultural differences. The experience of gay and/or transgender men who face pregnancy loss is overlooked in the literature to date. PMID- 29141592 TI - Case report: electrical storm during induced hypothermia in a patient with early repolarization. AB - BACKGROUND: Population based studies showed an association of early repolarization in the electrocardiogram (ECG) and a higher rate of sudden cardiac death presumably due to ventricular fibrillation. The triggers for ventricular fibrillation in patients with early repolarization are not fully understood. CASE PRESENTATION: We describe the case of a young patient with a survived ventricular fibrillation arrest while asleep followed by multiple episodes of recurrent ventricular fibrillation. The admission ECG showed an early repolarization pattern with substantial J-point elevation in most of the ECG-leads. After initiation of a hypothermia protocol, the patient developed an electrical storm with multiple ventricular fibrillation episodes requiring multiple cardioversions. Intravenous isoproterenol infusion successfully suppressed the malignant arrhythmia. CONCLUSION: Hypothermia appears proarrhythmic in patients with early repolarization and may trigger ventricular fibrillation. This knowledge is particularly important when initiating temperature management protocols in patients after a survived cardiac arrest. During the acute phase of an early repolarization associated electrical storm, isoproterenol is the most effective treatment suppressing the ventricular fibrillation-inducing premature ventricular complexes at higher heart rates. PMID- 29141593 TI - Bidirectional alteration of Cav-1 expression is associated with mitogenic conversion of its function in gastric tumor progression. AB - BACKGROUND: Expression of caveolin-1 (Cav-1) is frequently altered in many human cancers and both tumor suppression and promotion functions of Cav-1 have been suggested based on its expression status. However, it remains unanswered how Cav 1 provokes opposite effects in different cancers or different phases of tumor progression. METHODS: To explore the implication of Cav-1 alteration in gastric tumorigenesis, the expression and mutational status of Cav-1 and its effects on tumor cell growth were characterized. RESULTS: A substantial fraction of primary tumors and cell lines displayed abnormally low or high Cav-1 mRNA expression, indicating the bidirectional alteration of Cav-1 in gastric cancers. While allelic imbalance and mutational alterations of the Cav-1 gene were rarely detected, aberrant promoter hyper- or hypo-methylation showed a tight correlation with bidirectional alteration of its expression. Abnormally low and high Cav-1 expression was more frequently observed in early and advanced cancers, respectively, suggesting the oncogenic switch of its function in tumor progression. Cell cycle progression, DNA synthesis, and colony forming ability were markedly decreased by Cav-1 transfection in low-expressing tumor cells but by its depletion in high-expressing cells. Interestingly, Cav-1 exerted opposite effects on MEK-ERK signaling in these two cell types through the reciprocal regulation of the RAF-ERK negative feedback loop. A feedback inhibition of RAF by ERK was stimulated by restoration of Cav-1 expression in low-expressing cells but by it depletion in high-expressing cells. As predicted, the opposite effects of Cav-1 on both tumor cell growth and inhibitory RAF phosphorylation were abolished if ERK is depleted. CONCLUSION: Bidirectional alteration of Cav-1 is linked to its opposite effects on gastric tumor cell growth, which stem from the reciprocal control on the RAF-ERK negative feedback loop. PMID- 29141594 TI - Hepatic paragonimiasis in a 15-month-old girl: a case report. AB - BACKGROUND: Paragonimiasis, particularly hepatic paragonimiasis (HP), is a type of zoonotic parasitic disease rarely encountered in infants. There have been only a few reports of HP, and no case of HP has been reported in an infant. CASE PRESENTATION: A 15-month-old girl presented with persistent mild fever with a duration of 1 month, hepatomegaly, and low-density lesions in the right hepatic lobe on abdominal ultrasound and computer tomography. Pathological examination and serum antibody detection were performed to verify HP. The diagnosis of HP was established based on findings of Charcot-Leyden crystals on liver lesion biopsy and antibodies against paragonimus westermani detected by enzyme-linked immunosorbent assay. After initiation of praziquantel (75 mg/kg/day for 3 days), all clinical findings promptly improved and the patient was discharged. CONCLUSION: It is very important to consider paragonimiasis in the clinical examination of infants from an area with paragonimiasis epidemic presenting with fever, hepatomegaly, low-density lesions in the liver. PMID- 29141595 TI - EEG dynamical correlates of focal and diffuse causes of coma. AB - BACKGROUND: Rapidly determining the causes of a depressed level of consciousness (DLOC) including coma is a common clinical challenge. Quantitative analysis of the electroencephalogram (EEG) has the potential to improve DLOC assessment by providing readily deployable, temporally detailed characterization of brain activity in such patients. While used commonly for seizure detection, EEG-based assessment of DLOC etiology is less well-established. As a first step towards etiological diagnosis, we sought to distinguish focal and diffuse causes of DLOC through assessment of temporal dynamics within EEG signals. METHODS: We retrospectively analyzed EEG recordings from 40 patients with DLOC with consensus focal or diffuse culprit pathology. For each recording, we performed a suite of time-series analyses, then used a statistical framework to identify which analyses (features) could be used to distinguish between focal and diffuse cases. RESULTS: Using cross-validation approaches, we identified several spectral and non-spectral EEG features that were significantly different between DLOC patients with focal vs. diffuse etiologies, enabling EEG-based classification with an accuracy of 76%. CONCLUSIONS: Our findings suggest that DLOC due to focal vs. diffuse injuries differ along several electrophysiological parameters. These results may form the basis of future classification strategies for DLOC and coma that are more etiologically-specific and therefore therapeutically-relevant. PMID- 29141596 TI - Effects of angiotensin receptor blockers on neointimal characteristics in angina patients requiring stent implantation: optical coherence tomography analysis. AB - BACKGROUND: Angiotensin receptor blockers (ARBs) are known for its anti inflammatory and anti-proliferative effects. The aim of the study was to evaluate long-term effects of ARBs on morphologic characteristics of stent restenosis in patients with coronary artery disease requiring stent implantation by optical coherence tomography (OCT). METHODS: Patients with coronary artery disease having history of drug-eluting stent implantation (n = 407) were analyzed on the basis of ARB therapy as the ARB group (n = 162) and the non-ARB group (n = 245). Neointimal characterizations were performed at lesions with diameter stenosis >30% with OCT in each group. Major adverse cardiovascular events (MACEs), lumen area, stent area, neointimal area, neointimal thickness, nonapposed struts, uncovered struts, and intraluminal mass between two groups were also observed. RESULTS: More patients in the ARB group revealed homogeneous and layered neointimal pattern (44.9% vs. 35.6%, P < 0.001, and 16.8% vs. 10.6%, P < 0.001, respectively), and whereas patients in the non-ARB group revealed heterogeneous neointimal pattern (1.1% vs. 7.6%, P < 0.001). Mean neointimal area (1.09 +/- 1.00 mm2 vs. 1.38 +/- 1.24 mm2) and mean neointimal thickness (140.6 +/- 112.0 MUm vs. 189.6 +/- 423.1 MUm) with OCT were smaller in the ARB group when compared to the non-ARB group. Percentage of covered stents was significantly higher in the ARB group when compared to the Non-ARB group (97.3% vs. 92.6%, P = 0.015). Other factors such as follow-up % diameter stenosis, late lumen loss, binary restenosis, MACEs, various neointimal characteristics analyzed by image analyzing software did not show significant differences. CONCLUSION: The use of ARBs after drug-eluting stent implantation demonstrated difference in neointimal characteristics, less amount of neointimal area and fewer number of uncovered stent struts during the follow-up OCT, indicating the anti-proliferative and anti inflammatory effects of ARBs. PMID- 29141597 TI - In response to Fogarty et al. and why adjuvant whole brain radiotherapy is not recommended routinely. AB - The routine use of adjuvant whole brain radiotherapy (AWBRT) after surgery or stereotactic radiosurgery is now discouraged by a number of international expert panels. Three decades of randomised studies have shown that, although AWBRT improves radiological measures of intracranial disease control, the clinical benefit is unclear and it is also associated with inferior quality of life and neurocognitive function. The number of patients with melanoma in these trials was low, but data suggesting that treatment-related side effects should vary according to histology of the primary malignancy are lacking. For metastatic melanoma, the role of AWBRT to control microscopic disease in the brain is also a less relevant concern because systemic therapies with intracranial activity are now available. Whether AWBRT is useful in select patients deemed at high risk of neurologic death remains undefined. PMID- 29141598 TI - Worklife expectancy in a cohort of Danish employees aged 55-65 years - comparing a multi-state Cox proportional hazard approach with conventional multi-state life tables. AB - BACKGROUND: Work life expectancy (WLE) expresses the expected time a person will remain in the labor market until he or she retires. This paper compares a life table approach to estimating WLE to an approach based on multi-state proportional hazards models. The two methods are used to estimate WLE in Danish members and non-members of an early retirement pensioning (ERP) scheme according to levels of health. METHODS: In 2008, data on self-rated health (SRH) was collected from 5212 employees 55-65 years of age. Data on previous and subsequent long-term sickness absence, unemployment, returning to work, and disability pension was collected from national registers. WLE was estimated from multi-state life tables and through multi-state models. RESULTS: Results from the multi-state model approach agreed with the life table approach but provided narrower confidence intervals for small groups. The shortest WLE was seen for employees with poor SRH and ERP membership while the longest WLE was seen for those with good SRH and no ERP membership. Employees aged 55-56 years with poor SRH but no ERP membership had shorter WLE than employees with good SRH and ERP membership. Relative WLE reversed for the two groups after age 57. At age 55, employees with poor SRH could be expected to spend approximately 12 months on long-term sick leave and 9 10 months unemployed before they retired - regardless of ERP membership. ERP members with poor SRH could be expected to spend 4.6 years working, while non members could be expected to spend 7.1 years working. CONCLUSION: WLE estimated through multi-state models provided an effective way to summarize complex data on labor market affiliation. WLE differed noticeably between members and non-members of the ERP scheme. It has been hypothesized that while ERP membership would prompt some employees to retire earlier than they would have done otherwise, this effect would be partly offset by reduced time spent on long-term sick leave or unemployment. Our data showed no indication of such an effect, but this could be due to residual confounding and self-selection of people with poor health into the ERP scheme. PMID- 29141599 TI - The effect of seasonal changes and climatic factors on suicide attempts of young people. AB - BACKGROUND: Seasonal changes and climatic factors like ambient temperature, sunlight duration and rainfall can influence suicidal behavior. METHODS: This study analyses the relationship between seasonal changes and climatic variations and suicide attempts in 2131 young patients in Istanbul, Turkey. RESULTS: In our study sample, there was an association between suicide attempts in youths and seasonal changes, as suicide attempts occurred most frequently during summer in females as well as in males. Furthermore, there was a positive correlation between the mean temperature over the past 10 days and temperature at the index day and suicide attempts in females. After seasonality effects were mathematically removed, the mean temperature 10 days before a suicide attempt remained significant in males only, indicating a possible short-term influence of temperature on suicide attempts. CONCLUSIONS: This study shows an association between suicide attempts of young people and climatic changes, in particular temperature changes as well as seasonal changes. Therefore, the influence of seasonal changes and climatic factors on young suicide attempters should get more attention in research to understand the biopsychosocial mechanisms playing a role in suicide attempts of young people. As suicide attempts most frequently occur in young people, further research is of considerable clinical importance. PMID- 29141600 TI - Quantifying the need for enhanced case management for TB patients as part of TB cohort audit in the North West of England: a descriptive study. AB - BACKGROUND: Patients with TB have diverse and often challenging clinical and social needs that may hamper successful treatment outcomes. Understanding the need for additional support during treatment (enhanced case management, or ECM) is important for workforce capacity planning. North West England TB Cohort Audit (TBCA) has introduced a 4-level ECM classification system (ECM 0-3) to quantify the need for ECM in the region. This study describes the data from the first 2 years of ECM classification. METHODS: Data collected between April 2013 and July 2015 were used to analyse the proportions of patients allocated to each ECM level and the prevalence of social and clinical factors indicating need for ECM. Single variable and multivariable logistic regression models were constructed to examine the association between ECM level and treatment outcome. RESULTS: Of 1714 notified cases 99.8% were assigned an ECM level: 31% ECM1, 19% ECM2 and 14% ECM3. The most common factors indicating need for ECM were language barriers (20.3%) and clinical complexity (16.9%). 1342/1493 (89.9%) of drug-sensitive, non-CNS cases completed treatment within 12 months. Patients in ECM2 and 3 were less likely to complete treatment at 12 months than patients in ECM0 (adjusted OR 0.47 [95% CI 0.27-0.84] and 0.23 [0.13-0.41] respectively). CONCLUSIONS: Use of TBCA to quantify different levels of need for ECM is feasible and has demonstrated that social and clinical complexity is common in the region. Results will inform regional workforce planning and assist development of innovative methods to improve treatment outcomes in these vulnerable groups. PMID- 29141601 TI - Associations between occupational stress, burnout and well-being among manufacturing workers: mediating roles of psychological capital and self-esteem. AB - BACKGROUND: Occupational stress is an important risk factor for mental health among occupational population. Exploring related mediators of workers' mental health are important to improve their health and performance. Our study aims to explore the relationships between work stress, positive psychological resources, burnout and well-being. METHODS: The study was performed during the period of June and July in 2015. A questionnaire that consisted of the Effort-reward Imbalance Scale, the Maslach Burnout Inventory-General Survey, the Psychological Capital Questionnaire, the Rosenberg Self-esteem Scale, the Flourishing Scale, as well as demographic and working factors. RESULTS: Psychological capital mediated the associations of effort-reward imbalance and emotional exhaustion, cynicism, professional efficacy and well-being. Self-esteem mediated the associations of effort-reward imbalance ratio with cynicism, professional efficacy and well being, and mediated the associations of overcommitment and cynicism, professional efficacy and well-being. CONCLUSIONS: The findings indicated that enhancing positive psychological resources could be considered in developing intervention strategies for psychological health among manufacturing employees. PMID- 29141602 TI - Association between sarcopenia and low back pain in local residents prospective cohort study from the GAINA study. AB - BACKGROUND: Low back pain (LBP) is one of the most common ailments that people experience in their lifetime. On the other hands, Sarcopenia also leads to several physical symptoms and contributes to reducing the quality of life of elderly people.The purpose of this study is to investigate the association between sarcopenia and low back pain among the general population. METHODS: The subjects included 216 adults (79 men and 137 women; mean age, 73.5 years) undergoing a general medical examination in Hino, Japan. Skeletal muscle index (SMI), The percentage of young adults' mean (%YAM) of the calcaneal bone mass using with quantitative ultrasound (QUS) method and walking speed were measured, and subjects who met the criteria of the Asian Working Group for Sarcopenia were assigned to the sarcopenia group. Subjects with decreased muscle mass only were assigned to the pre-sarcopenia group, and all other subjects were assigned to the normal group. Then, we compared the correlations with low back pain physical finding. The Oswestry Disability Index (ODI) and the low back pain visual analogue scale (VAS) were used as indices of low back pain. Statistical analysis was performed among three groups with respect their characteristic, demographics, data of sarcopenia determining factor, VAS and ODI. We also analysed prevalence of LBP and sarcopenia. We investigated the correlations between ODI and the sarcopenia-determining factors of walking speed, muscle mass and grip strength. RESULTS: Sarcopenia was noted in 12 subjects (5.5%). The pre-sarcopenia group included 38 subjects (17.6%), and the normal group included 166 subjects (76.9%). The mean ODI score was significantly higher in the sarcopenia group (25.2% +/- 12.3%; P < 0.05) than in the pre-sarcopenia group (11.2% +/- 10.0%) and the normal group (11.9% +/- 12.3%). %YAM and BMI were significantly lower in the sarcopenia group than in other groups (P < 0.05). A negative correlation existed between walking speed and ODI (r = -0.32, P < 0.001). CONCLUSIONS: The results of this study suggested that decreased physical ability due to quality of life in residents with LBP may be related to sarcopenia. PMID- 29141603 TI - DETECT I & DETECT II: a study protocol for a prospective multicentre observational study to validate the UroMark assay for the detection of bladder cancer from urinary cells. AB - BACKGROUND: Haematuria is a common finding in general practice which requires visual inspection of the bladder by cystoscopy as well as upper tract imaging. In addition, patients with non-muscle invasive bladder cancer (NMIBC) often require surveillance cystoscopy as often as three monthly depending on disease risk. However, cystoscopy is an invasive procedure which is uncomfortable, requires hospital attendance and is associated with a risk of urinary tract infection. We have developed the UroMark assay, which can detect 150 methylation specific alteration specific to bladder cancer using DNA from urinary sediment cells. METHODS: DETECT I and DETECT II are two multi-centre prospective observational studies designed to conduct a robust validation of the UroMark assay. DETECT I will recruit patients having diagnostic investigations for haematuria to determine the negative predictive value of the UroMark to rule out the presence of bladder cancer. DETECT II will recruit patients with new or recurrent bladder cancer to determine the sensitivity of the UroMark in detecting low, intermediate and high grade bladder cancer. NMIBC patients in DETECT II will be followed up with three monthly urine sample collection for 24 months while having surveillance cystoscopy. DETECT II will include a qualitative analysis of semi structured interviews to explore patients' experience of being diagnosed with bladder cancer and having cystoscopy and a urinary test for bladder cancer surveillance. Results of the UroMark will be compared to cystoscopy findings and histopathological results in patients with bladder cancer. DISCUSSION: A sensitive and specific urinary biomarker will revolutionise the haematuria diagnostic pathway and surveillance strategies for NMIBC patients. None of the six approved US Food and Drug Administration urinary test are recommended as a standalone test. The UroMark assay is based on next generation sequencing technology which interrogates 150 loci and represents a step change compared to other biomarker panels. This enhances the sensitivity of the test and by using a random forest classifier approach, where the UroMark results are derived from a cut off generated from known outcomes of previous samples, addresses many shortcomings of previous assays. TRIAL REGISTRATION: Both trails are registered on clinicaltrials.gov. DETECT I: NCT02676180 (18th December 2015). DETECT II: NCT02781428 (11th May 2016). PMID- 29141604 TI - Genome-wide identification of miRNAs and lncRNAs in Cajanus cajan. AB - BACKGROUND: Non-coding RNAs (ncRNAs) are important players in the post transcriptional regulation of gene expression (PTGR). On one hand, microRNAs (miRNAs) are an abundant class of small ncRNAs (~22nt long) that negatively regulate gene expression at the levels of messenger RNAs stability and translation inhibition, on the other hand, long ncRNAs (lncRNAs) are a large and diverse class of transcribed non-protein coding RNA molecules (> 200nt) that play both up-regulatory as well as down-regulatory roles at the transcriptional level. Cajanus cajan, a leguminosae pulse crop grown in tropical and subtropical areas of the world, is a source of high value protein to vegetarians or very poor populations globally. Hence, genome-wide identification of miRNAs and lncRNAs in C. cajan is extremely important to understand their role in PTGR with a possible implication to generate improve variety of crops. RESULTS: We have identified 616 mature miRNAs in C. cajan belonging to 118 families, of which 578 are novel and not reported in MirBase21. A total of 1373 target sequences were identified for 180 miRNAs. Of these, 298 targets were characterized at the protein level. Besides, we have also predicted 3919 lncRNAs. Additionally, we have identified 87 of the predicted lncRNAs to be targeted by 66 miRNAs. CONCLUSIONS: miRNA and lncRNAs in plants are known to control a variety of traits including yield, quality and stress tolerance. Owing to its agricultural importance and medicinal value, the identified miRNA, lncRNA and their targets in C. cajan may be useful for genome editing to improve better quality crop. A thorough understanding of ncRNA-based cellular regulatory networks will aid in the improvement of C. cajan agricultural traits. PMID- 29141605 TI - An intronic single-nucleotide polymorphism (rs13217795) in FOXO3 is associated with asthma and allergic rhinitis: a case-case-control study. AB - BACKGROUND: Asthma and allergic rhinitis are respiratory diseases with a significant global burden. Forkhead box O3 (FOXO3) is a gene involved in the etiology of a number of respiratory diseases. The objective of this study is to assess the association of rs13217795, an intronic FOXO3 single-nucleotide polymorphism, with asthma and allergic rhinitis. METHODS: In this case-case control genetic association study, genotyping was conducted using the PCR-RFLP method. Genotype-based associations were investigated under the general, recessive, and dominant models of disease penetrance using binomial logistic regression; and, allele-based associations were tested using Pearson's chi squared test. RESULTS: The final study population consisted of 94 controls, 124 asthmatics, and 110 allergic rhinitis patients. The general and recessive models of disease penetrance were statistically significant for both case-control comparisons. Under the general model, the odds of the asthma phenotype were 1.46 (0.64 to 3.34) and 3.42 (1.37 to 8.57) times higher in heterozygotes and derived allele homozygotes, respectively, compared to ancestral allele homozygotes. The corresponding odds ratios for the allergic rhinitis phenotype were 1.05 (0.46 to 2.40) and 2.35 (0.96 to 5.73), respectively. The dominant model of disease penetrance was not statistically significant. The minor allele in all study groups was the ancestral allele, with a frequency of 0.49 in controls. There was no deviation from Hardy-Weinberg equilibrium in controls. Both case-control allele-based associations were statistically significant. CONCLUSIONS: Herein we present the first report of the association between rs13217795 and allergic rhinitis, and the first independent verification of the association between rs13217795 and asthma. Marker selection in future genetic association studies of asthma and allergic rhinitis should include functional polymorphisms in linkage disequilibrium with rs13217795. PMID- 29141607 TI - Users' experiences of wearable activity trackers: a cross-sectional study. AB - BACKGROUND: Wearable activity trackers offer considerable promise for helping users to adopt healthier lifestyles. This study aimed to explore users' experience of activity trackers, including usage patterns, sharing of data to social media, perceived behaviour change (physical activity, diet and sleep), and technical issues/barriers to use. METHODS: A cross-sectional online survey was developed and administered to Australian adults who were current or former activity tracker users. Results were analysed descriptively, with differences between current and former users and wearable brands explored using independent samples t-tests, Mann-Whitney, and chi square tests. RESULTS: Participants included 200 current and 37 former activity tracker users (total N = 237) with a mean age of 33.1 years (SD 12.4, range 18-74 years). Fitbit (67.5%) and Garmin devices (16.5%) were most commonly reported. Participants typically used their trackers for sustained periods (5-7 months) and most intended to continue usage. Participants reported they had improved their physical activity (51-81%) more commonly than they had their diet (14-40%) or sleep (11-24%), and slightly more participants reported to value the real time feedback (89%) compared to the long term monitoring (78%). Most users (70%) reported they had experienced functionality issues with their devices, most commonly related to battery life and technical difficulties. CONCLUSIONS: Results suggest users find activity trackers appealing and useful tools for increasing perceived physical activity levels over a sustained period. PMID- 29141606 TI - Trends in bednet ownership and usage, and the effect of bednets on malaria hospitalization in the Kilifi Health and Demographic Surveillance System (KHDSS): 2008-2015. AB - BACKGROUND: Use of bednets reduces malaria morbidity and mortality. In Kilifi, Kenya, there was a mass distribution of free nets to children < 5 years in 2006. In 2009, a new policy was implemented to offer bednets to pregnant women and children < 5 years free of charge. Nets were again distributed to children and adults through national mass campaigns in 2012 and 2015. We aimed to evaluate trends in bednet ownership and usage, and the effect of bednets on the incidence of malaria hospitalization in children < 5 years within the Kilifi Health and Demographic Surveillance System (KHDSS). METHODS: Bednet ownership and usage were assessed during eight routine enumeration rounds of the KHDSS between 2008 and 2015. Malaria admissions (i.e. admissions to hospital with P. falciparum > 2500 parasitemia per MUl) among children < 5 years were captured using a system of continuous vital registration that links admissions at Kilifi County Hospital to the KHDSS population register. Survival analysis was used to assess relative risk of hospitalization with malaria among children that reported using a bednet compared to those who did not. RESULTS: We observed 63% and 62% mean bednet ownership and usage, respectively, over the eight-survey period. Among children < 5 years, reported bednet ownership in October-December 2008 was 69% and in March August 2009 was 73% (p < 0.001). An increase was also observed following the mass distribution campaigns in 2012 (62% in May-July 2012 vs 90% in May-October 2013, p < 0.001) and 2015 (68% in June-September 2015 vs 93% in October-November 2015, p < 0.001). Among children <5 years who reported using a net the night prior to the survey, the incidence of malaria hospitalization per 1000 child-years was 2.91 compared to 4.37 among those who did not (HR = 0.67, 95% CI: 0.52, 0.85 [p = 0.001]). CONCLUSION: On longitudinal surveillance, increasing bednet ownership and usage corresponded to mass distribution campaigns; however, this method of delivering bednets did not result in sustained improvements in coverage. Among children < 5 years old bednet use was associated with a 33% decreased incidence of malaria hospitalization. PMID- 29141608 TI - TRAVeLer: a tool for template-based RNA secondary structure visualization. AB - BACKGROUND: Visualization of RNA secondary structures is a complex task, and, especially in the case of large RNA structures where the expected layout is largely habitual, the existing visualization tools often fail to produce suitable visualizations. This led us to the idea to use existing layouts as templates for the visualization of new RNAs similarly to how templates are used in homology based structure prediction. RESULTS: This article introduces Traveler, a software tool enabling visualization of a target RNA secondary structure using an existing layout of a sufficiently similar RNA structure as a template. Traveler is based on an algorithm which converts the target and template structures into corresponding tree representations and utilizes tree edit distance coupled with layout modification operations to transform the template layout into the target one. Traveler thus accepts a pair of secondary structures and a template layout and outputs a layout for the target structure. CONCLUSIONS: Traveler is a command line open source tool able to quickly generate layouts for even the largest RNA structures in the presence of a sufficiently similar layout. It is available at http://github.com/davidhoksza/traveler . PMID- 29141609 TI - Assessment of success of the Ponseti method of clubfoot management in sub-Saharan Africa: a systematic review. AB - BACKGROUND: Clubfoot is one of the most common congenital deformities affecting mobility. It leads to pain and disability if untreated. The Ponseti method is widely used for the correction of clubfoot. There is variation in how the result of clubfoot management is measured and reported. This review aims to determine and evaluate how success with the Ponseti method is reported in sub-Saharan Africa. METHODS: Five databases were examined in August 2017 for studies that met the inclusion criteria of: (1) evaluation of the effect of clubfoot management; (2) use of the Ponseti method; (3) original study undertaken in sub-Saharan Africa; (4) published between 2000 and 2017. We used the PRISMA statement to report the scope of studies. The included studies were categorised according to a hierarchy of study methodologies and a 27-item quality measure identified methodological strengths and weaknesses. The definition of success was based on the primary outcome reported. RESULTS: Seventy-seven articles were identified by the search. Twenty-two articles met the inclusion criteria, of which 14 (64%) reported a primary outcome. Outcomes were predominantly reported though case series and the quality of evidence was low. Clinical assessment was the most commonly reported outcome measure and few studies reported long-term outcome. The literature available to assess success of clubfoot management is characterised by a lack of standardisation of outcomes, with different measures reporting success in 68% to 98% of cases. CONCLUSION: We found variation in the criteria used to define success resulting in a wide range of results. There is need for an agreed definition of good outcome (successful management) following both the correction and the bracing phases of the Ponseti method to establish standards to monitor and evaluate service delivery. PMID- 29141610 TI - Social relations and healthcare utilisation among middle-aged and older people: study protocol for an implementation and register-based study in Denmark. AB - BACKGROUND: While previous research establishes an association between social relations, health and use of healthcare services among older people, how to implement this knowledge in real-life settings has received much less attention. This study will explore the relationship between social relations, health and use of healthcare services in a Danish mid-life population sample. In addition, the study will explore individual and contextual factors affecting the implementation of a group-based life story intervention aimed at establishing and strengthening social relations among older people at nursing homes in Denmark. METHODS/DESIGN: A combined quantitative register-based approach and a qualitative implementation approach will be applied in this study. First, we will quantitatively analyse the relationship between social relations, health status and use of healthcare services among middle-aged people in Denmark by linking survey data on social relations, loneliness, self-perceived health and disease status from the Copenhagen Aging and Midlife Biobank (CAMB) (n = 7191) with national registries through the Public Health Database on use of healthcare services and demographic and socioeconomic factors. Second, we will qualitatively analyse individual and contextual factors affecting the implementation process of the group-based life story intervention based on semi-structured interviews (n = 16), observations and field notes with and among intervention stakeholders, i.e., participants and group leaders facilitating the intervention. DISCUSSION: The results of this study are expected to improve knowledge about mechanisms through which social relations are associated with health status and use of healthcare services and to inform the implementation of future interventions targeting social relations among older people at nursing homes. TRIAL REGISTRATION: The study has been registered and approved by the Danish Data Protection Agency. Seperate approvals have been attained for the qualitative data (Approval No. SUND-2016-08), and for the quantitative data in the CAMB database which has also received approval from the local ethical committee (approval No.H-A-2008-126 and No. 2013-41-1814, respectively). PMID- 29141611 TI - Are paraspinous intramuscular injections of botulinum toxin a (BoNT-A) efficient in the treatment of chronic low-back pain? A randomised, double-blinded crossover trial. AB - BACKGROUND: Treatment for patients with chronic low-back pain (LBP) is a public health issue. Intramuscular injections of botulinum toxin A (BoNT-A) have shown an analgesic effect on LBP in two previous randomized controlled studies. The objective of the study was to verify the efficacy of paravertebral injections of BoNT-A in patients with LBP. METHODS: Patients were included in this phase 3 randomized double-blinded trial comparing the efficacy of BoNT-A versus placebo in a crossover study on LBP. Both groups received 200 units of BoNT-A in paravertebral muscles or a placebo, and vice versa at Day 120. The main judgment criterion was LBP intensity 1 month after the injections, evaluated by using a visual pain scale (VAS). Secondary assessment criteria included: LBP intensity 90 and 120 days after injection day; number of days when an allowed antalgic oral treatment was needed in between each evaluation; functional disability measured by the Quebec Back Pain Disability Scale; quality of life; inability to work; patient satisfaction in relation to the treatment's effect; spinal mobility; and strength of spinal muscles, measured by isokinetic technique. RESULTS: Nineteen patients completed the study. There was no significant difference between the groups' average LBP during the last 8 days at Day30 (p = 0.97). There was no significant difference between the two groups regarding the secondary assessment criteria (p > 0.05). CONCLUSIONS: Injections of BoNT-A in the paravertebral muscles were not found to be effective to relieve chronic LBP. The limits of the study are that the dose of BoNT-A used was lower than in other studies, and that the limited number of patients included may explain the negative results. TRIAL REGISTRATIONS: Identifiers: NCT03181802 . Unique Protocol ID: CHUBX2003. PMID- 29141612 TI - Individual-level and community-level determinants of cervical cancer screening among Kenyan women: a multilevel analysis of a Nationwide survey. AB - BACKGROUND: Studies on the determinants of cervical cancer screening in sub Saharan Africa have focused mostly on individual-level characteristics of cervical cancer screening. Therefore, in this study, we included both individual- and community-level indicators to examine the determinants of cervical cancer screening among Kenyan women. METHODS: We analyzed data from the 2014 Kenya Demographic and Health Surveys. Our analysis focused on 9016 married women of reproductive age (15-49 years). We conducted multilevel analyses using generalized linear mixed models with the log-binomial function to simultaneously analyze the association of individual- and community-level factors with cervical cancer screening. RESULTS: About 72.1% of women (n = 6498) knew about cervical cancer. Of these women, only 19.4% had undergone cervical cancer screening [58.24% Papanicolaou (Pap) test and 41.76% visual inspection]. Our multivariate analysis results indicated that the prevalence of cervical cancer screening was higher among women aged 35-49 years than women aged 15-24 years. The prevalence was also higher among women residing in the Central, Nyanza, and Nairobi regions than women residing in the Coastal region. Cervical cancer screening was more prevalent among women who had media exposure, had higher household wealth index, were employed, were insured, and had visit a health facility in 12 months than did their counterparts. The prevalence of Pap test history was 19% higher among women who had sexual autonomy than women who did not have sexual autonomy. The prevalence of Pap test history was also higher among communities comprised of higher proportions of women with sexual autonomy and higher education. CONCLUSIONS: Policies should emphasize increasing gender equality, improving education at the community level, providing employment opportunities for women, and increasing universal health insurance coverage. These focal points can ensure equity in access to health care services and further increase the prevalence of cervical cancer screening in Kenya. PMID- 29141613 TI - Determinants of patient satisfaction following reconstructive shoulder surgery. AB - BACKGROUND: Obtaining patient satisfaction is a key goal of surgical treatment. It was the purpose of this study to identify pre-, peri- and postoperative factors determining patient satisfaction after shoulder surgery, quantify their relative importance and thereby allow the surgeon to focus on parameters, which will influence patient satisfaction. METHODS: We retrospectively reviewed 505 patients, who underwent either rotator cuff repair (n = 216) or total shoulder arthroplasty (n = 289). We examined 21 patient-specific and socio-demographic parameters as well as 31 values of the Constant-Score with regard to their impact on patient satisfaction. RESULTS: In the univariable analysis higher patient satisfaction was correlated with higher age, private health insurance, light physical work, retirement, primary surgery, non-smoking, absence of chronic alcohol abuse, absence of peri- or postoperative complications, operation performed by the medical director as well as various Constant Score sub-values (p < 0.05). In the multivariable analysis absence of peri- or postoperative complications (p = 0.008), little postoperative pain (p = 0.0001), a large range of postoperative active abduction (p = 0.05) and a high postoperative subjective shoulder value (p = 0.0001) were identified as independent prognostic factors for high satisfaction. CONCLUSION: After reconstructive shoulder surgery particular attention should be paid to prevention of complications, excellent perioperative pain control and restoration of abduction during rehabilitation. This study is first step towards a preoperative prediction model of a subjectively successful surgery as well as a tool to exclude irrelevant parameters in clinical routine. PMID- 29141614 TI - Differences in the prevalence of hospitalizations and utilization of emergency outpatient services for ambulatory care sensitive conditions between asylum seeking children and children of the general population: a cross-sectional medical records study (2015). AB - BACKGROUND: Hospitalizations for ambulatory care sensitive (ACS) conditions are established indicators for the availability and quality of ambulatory care. We aimed to assess the differences between asylum-seeking children and children of the general population in a German city with respect to (i) the prevalence of ACS hospitalizations, and (ii) the utilization of emergency outpatient services for ACS conditions. METHODS: Using anonymous account data, all children admitted to the University Hospital Heidelberg in 2015 were included in our study. A unique cost unit distinguished asylum seekers residing in a nearby reception center (exposed) from the children of the general population. We adapted international lists of ACS conditions and calculated the prevalence of ACS hospitalizations and the utilization of emergency outpatient services for ACS conditions, attributable fractions among the exposed (Afe) and the population attributable fraction among total admissions (PAF) for each outcome. Differences in the prevalence of each outcome between exposed and controls were analyzed in logistic regression models adjusted for sex, age group and quarterly admission. RESULTS: Of the 32,015 admissions in 2015, 19.9% (6287) were from inpatient and 80.1% (25,638) from outpatient care. In inpatient care, 9.8% (622) of all admissions were hospitalizations for ACS conditions. The Afe of ACS hospitalizations was 46.57%, the PAF was 1.12%. Emergency service use for ACS conditions could be identified in 8.3% (3088) of all admissions (Afe: 79.57%, PAF: 5.08%). The odds ratio (OR) of asylum-seeking children being hospitalized for ACS conditions in comparison to the control group was 1.81 [95% confidence interval, CI: 1.02; 3.2]. The OR of the asylumseeking population compared to the general population for the utilization of emergency service use for ACS conditions was 4.93 [95% CI: 4.11; 5.91]. CONCLUSIONS: Asylum-seeking children had significantly higher odds of ACS hospitalization and of utilization of emergency outpatient services for ACS conditions. Using the concept of ACS conditions allowed measuring the strength of primary care provided to this local asylum-seeking population. This approach could help to compare the strength of primary care provision in different locations, and allow an objective. PMID- 29141615 TI - Kinematic characterization of clinically observed aberrant movement patterns in patients with non-specific low back pain: a cross-sectional study. AB - BACKGROUND: Clinical observation of aberrant movement patterns during active forward bending is one criterion used to identify patients with non-specific low back pain suspected to have movement coordination impairment. The purpose of this study was to describe and quantify kinematic patterns of the pelvis and trunk using a dynamics systems approach, and determine agreement between clinical observation and kinematic classification. METHOD: Ninety-eight subjects performed repeated forward bending with clinical observation and kinematic data simultaneously collected. Kinematic data were plotted using angle-angle, coupling angle, and phase-plane diagrams. Accuracy statistics in conjunction with receiver operating characteristic curves were used to determine agreement between clinical observation and kinematic patterns. RESULTS: Kinematic patterns were consistent with clinical observation and definitions of typical and aberrant movement patterns with moderate agreement (kappa = 0.46-0.50; PABAK = 0.49-0.73). Early pelvic motion dominance in lumbopelvic coupling-angle diagram >=59 degrees within the first 38% of the movement represent observed altered lumbopelvic rhythm. Frequent disruptions in lumbar spine velocity represented by phase-plane diagrams with local minimum occurrences >=6 and sudden decoupling in lumbopelvic coupling-angle diagrams with sum of local minimum and maximum occurrences >=15 represent observed judder. CONCLUSION: These findings further define observations of movement coordination between the pelvis and lumbar spine for the presence of altered lumbopelvic rhythm and judder. Movement quality of the lumbar spine segment is key to identifying judder. This information will help clinicians better understand and identify aberrant movement patterns in patients with non specific low back pain. PMID- 29141616 TI - Contextual factors and clinical reasoning: differences in diagnostic and therapeutic reasoning in board certified versus resident physicians. AB - BACKGROUND: The impact of context on the complex process of clinical reasoning is not well understood. Using situated cognition as the theoretical framework and videos to provide the same contextual "stimulus" to all participants, we examined the relationship between specific contextual factors on diagnostic and therapeutic reasoning accuracy in board certified internists versus resident physicians. METHODS: Each participant viewed three videotaped clinical encounters portraying common diagnoses in internal medicine. We explicitly modified the context to assess its impact on performance (patient and physician contextual factors). Patient contextual factors, including English as a second language and emotional volatility, were portrayed in the videos. Physician participant contextual factors were self-rated sleepiness and burnout.. The accuracy of diagnostic and therapeutic reasoning was compared with covariates using Fisher Exact, Mann-Whitney U tests and Spearman Rho's correlations as appropriate. RESULTS: Fifteen board certified internists and 10 resident physicians participated from 2013 to 2014. Accuracy of diagnostic and therapeutic reasoning did not differ between groups despite residents reporting significantly higher rates of sleepiness (mean rank 20.45 vs 8.03, U = 0.5, p < .001) and burnout (mean rank 20.50 vs 8.00, U = 0.0, p < .001). Accuracy of diagnosis and treatment were uncorrelated (r = 0.17, p = .65). In both groups, the proportion scoring correct responses for treatment was higher than the proportion scoring correct responses for diagnosis. CONCLUSIONS: This study underscores that specific contextual factors appear to impact clinical reasoning performance. Further, the processes of diagnostic and therapeutic reasoning, although related, may not be interchangeable. This raises important questions about the impact that contextual factors have on clinical reasoning and provides insight into how clinical reasoning processes in more authentic settings may be explained by situated cognition theory. PMID- 29141617 TI - Comparison of [HSO4]-, [Cl]- and [MeCO2]- as anions in pretreatment of aspen and spruce with imidazolium-based ionic liquids. AB - BACKGROUND: Ionic liquids (ILs) draw attention as green solvents for pretreatment of lignocellulose before enzymatic saccharification. Imidazolium-based ILs with different anionic constituents ([HSO4]-, [Cl]-, [MeCO2]-) were compared with regard to pretreatment of wood from aspen and spruce. The objective was to elucidate how the choice of anionic constituent affected the suitability of using the IL for pretreatment of hardwood, such as aspen, and softwood, such as spruce. The investigation covered a thorough analysis of the mass balance of the IL pretreatments, the effects of pretreatment on the cell wall structure as assessed by fluorescence microscopy, and the effects of pretreatment on the susceptibility to enzymatic saccharification. Torrefied aspen and spruce were included in the comparison for assessing how shifting contents of hemicelluloses and Klason lignin affected the susceptibility of the wood to IL pretreatment and enzymatic saccharification. RESULTS: The glucose yield after IL pretreatment increased in the order [Cl]- < [HSO4]- < [MeCO2]- for aspen, but in the order [HSO4]- < [Cl]- < [MeCO2]- for spruce. For both aspen and spruce, removal of hemicelluloses and lignin increased in the order [Cl]- < [MeCO2]- < [HSO4]-. Fluorescence microscopy indicated increasingly disordered cell wall structure following the order [HSO4]- < [Cl]- < [MeCO2]-. Torrefaction of aspen converted xylan to pseudo-lignin and changed the glucose yield order to [HSO4]- < [Cl]- < [MeCO2]-. CONCLUSIONS: The acidity of [HSO4]- caused extensive hydrolysis of xylan, which facilitated pretreatment of xylan-rich hardwood. Apart from that, the degree of removal of hemicelluloses and lignin did not correspond well with the improvement of the enzymatic saccharification. Taken together, the saccharification results were found to mainly reflect (i) the different capacities of the ILs to disorder the cell wall structure, (ii) the recalcitrance caused by high xylan content, and (iii) the capacity of the [HSO4]--based IL to hydrolyze xylan. PMID- 29141618 TI - What do Australian consumers, pharmacists and prescribers think about documenting indications on prescriptions and dispensed medicines labels?: A qualitative study. AB - BACKGROUND: Documenting the indication on prescriptions and dispensed medicines labels is not standard practice in Australia. However, previous studies that have focused on the content and design of dispensed medicines labels, have suggested including the indication as a safety measure. The aim of this study was to investigate the perspectives of Australian consumers, pharmacists and prescribers on documenting the indication on prescriptions and dispensed medicines labels. METHODS: Semi-structured interviews were conducted and mock-up of dispensed medicines labels were designed for participants. Consumers (n = 19) and pharmacists (n = 7) were recruited by convenience sample at community pharmacies in Sydney (Australia) and prescribers (n = 8), including two medical students, were recruited through snowballing. RESULTS: Thirty-four participants were interviewed. Most participants agreed that documenting the indication would be beneficial especially for patients who are forgetful or take multiple medications. Participants also believed it would improve consumers' medication understanding and adherence. Prescribers and pharmacists believed it could help reduce prescribing and dispensing errors by matching the drug/dosage to the correct indication. Prescribers refrained from documenting the indication to protect patients' privacy; however, most patients did not consider documenting the indication as a breach of privacy. Prescribers raised concerns about the extra time to include indications on prescriptions and best language to document indications, using plain language as opposed to medical terminology. CONCLUSIONS: All interviewed stakeholders identified numerous benefits of documenting the indication on prescriptions and dispensed medicines labels. Whether these potential benefits can be realized remains unknown and addressing prescribers' concern regarding the time involved in documenting the indication on prescriptions remains a challenge for vendors of electronic medication management systems. PMID- 29141619 TI - Seasonal influenza vaccination of healthcare workers: systematic review of qualitative evidence. AB - BACKGROUND: Most countries recommend that healthcare workers (HCWs) are vaccinated seasonally against influenza in order to protect themselves and patients. However, in many cases coverage remains low. A range of strategies have been implemented to increase uptake. Qualitative evidence can help in understanding the context of interventions, including why interventions may fail to achieve the desired effect. This study aimed to synthesise evidence on HCWs' perceptions and experiences of vaccination for seasonal influenza. METHODS: Systematic review of qualitative evidence. We searched MEDLINE, EMBASE and CINAHL and included English-language studies which reported substantive qualitative data on the vaccination of HCWs for seasonal influenza. Findings were synthesised thematically. RESULTS: Twenty-five studies were included in the review. HCWs may be motivated to accept vaccination to protect themselves and their patients against infection. However, a range of beliefs may act as barriers to vaccine uptake, including concerns about side-effects, scepticism about vaccine effectiveness, and the belief that influenza is not a serious illness. HCWs value their autonomy and professional responsibility in making decisions about vaccination. The implementation of interventions to promote vaccination uptake may face barriers both from HCWs' personal beliefs and from the relationships between management and employees within the targeted organisations. CONCLUSIONS: HCWs' vaccination behaviour needs to be understood in the context of HCWs' relationships with each other, with management and with patients. Interventions to promote vaccination should take into account both the individual beliefs of targeted HCWs and the organisational context within which they are implemented. PMID- 29141620 TI - Treatment of genu valgum in children by means of temporary hemiepiphysiodesis using eight-plates: short-term findings. AB - BACKGROUND: Idiopathic genu valgum is a frequently diagnosed growth disorder in adolescence. Whenever the possibilities of conservative therapy have been exhausted, leg straightening by means of hemiepiphysiodesis has become the standard form of treatment. Because of their flexible screw-plate connection, eight-Plates have been reported in the literature to lead to lower complications regarding implant loosening and fracture compared to other implants. The aim of this retrospective survey was to analyse our own patient population who were treated for genu valgum by means of temporary hemiepiphysiodesis near the knee using eight-Plates to modulate growth. METHODS: Between July 2007 and July 2015, 198 eight-Plates were implanted near the knee in 132 children suffering from genu valgum to modulate growth. Depending on the deformity analysis, an eight-Plate was implanted on the distal medial femur and/or the proximal medial tibia. By December 2015, they had been removed from 105 patients. The etiology of genu valgum was mainly idiopathic or associated withobesity. Evaluation was carried out clinically and radiologically (whole-leg X-ray in standing) including determination of the joint angles. RESULTS: The median follow-up period was about 46 months (12-102 months). The median age at implantation was 12.7 +/-6.76 years. Of the 105 patients, 45.7% (n = 48) were girls. The eight-Plates remained in place for a median period of 13 +/-1.76 months. Irrespective of the location of hemiepiphysiodesis, the intermalleolar distance was corrected to a median of 0 +/ 2.1 cm while the anatomical femorotibial angle was corrected by on average 9 +/ 2.7 degrees Mechanical lateral distal femoral angle changed an average 7 +/- 7.72 degrees. Medial proximal tibial angle changed an average 4 +/- 6.02 degrees. Complications necessitating surgery occurred in 2.8% of cases (1 wound infection, 3 corrective osteotomies following overcorrection). CONCLUSION: Temporary hemiepiphysiodesis using eight-Plates is a gentle, simple and effective procedure used to treat genu valgum by modulating growth. Slight overcorrection is desirable due to the rebound phenomenon, especially in young patients with high growth potential and risk groups such as obese children. In adolescents with only low growth potential (older than 14 years), owing to the low correction potential, the indication should be strictly reviewed and the possible failure of therapy should be discussed with the patient. No differences were observed regarding the location of the implanted eight-Plates (femoral or tibial). PMID- 29141621 TI - Expectations and perceptions of primary healthcare professionals regarding their own continuous education in Catalonia (Spain): a qualitative study. AB - BACKGROUND: The planning and execution of continuous education in an organization that provides health services is a complex process. The objectives, learning sequences, and implementation strategies should all be oriented to improving the health of the population. The aim of this study was to analyse the expectations and perceptions of continuous educations by primary healthcare professionals (physicians and nurses) and identify aspects that hinder or encourage the process. METHODS: A qualitative study with 5 focus groups made up of 25 primary healthcare professionals from the Catalan Health Institute, Barcelona (Catalonia, Spain). The focus groups were audio-recorded and the results transcribed. The analysis involved: a) Reading of the data looking for meanings b) Coding of the data by themes and extracting categories c) Reviewing and refining codes and categories d) Reconstruction of the data providing an explanatory framework for the meanings e) Discussion about the interpretations of the findings and f) Discussed with relevant professionals from PHC (physicians and nurses)"Data regarding thematic content were analyzed with the support of Atlasti 5.1 software. RESULTS: The health needs of the population were often at the core of the learning processes but the participants' views did not always spontaneously refer to improvements in these issues. Common themes that could hinder learning and where identified, including contextual aspects such as work constraints (timetables, places being covered during training) and funding policies. New learning strategies to improve the effectiveness of continuous education were proposed such as the exchange of knowledge, the activation of personal commitment to change, and the improvement of organizational aspects. CONCLUSIONS: The primary healthcare professionals in our study viewed continuous education as a professional necessity and would like to translate the knowledge acquired to improving the health of the population. Nevertheless, professional, structural, and organizational issues impede the process. PMID- 29141622 TI - Am I getting an accurate picture: a tool to assess clinical handover in remote settings? AB - BACKGROUND: Good clinical handover is critical to safe medical care. Little research has investigated handover in rural settings. In a remote setting where nurses and medical students give telephone handover to an aeromedical retrieval service, we developed a tool by which the receiving clinician might assess the handover; and investigated factors impacting on the reliability and validity of that assessment. METHODS: Researchers consulted with clinicians to develop an assessment tool, based on the ISBAR handover framework, combining validity evidence and the existing literature. The tool was applied 'live' by receiving clinicians and from recorded handovers by academic assessors. The tool's performance was analysed using generalisability theory. Receiving clinicians and assessors provided feedback. RESULTS: Reliability for assessing a call was good (G = 0.73 with 4 assessments). The scale had a single factor structure with good internal consistency (Cronbach's alpha = 0.8). The group mean for the global score for nurses and students was 2.30 (SD 0.85) out of a maximum 3.0, with no difference between these sub-groups. CONCLUSIONS: We have developed and evaluated a tool to assess high-stakes handover in a remote setting. It showed good reliability and was easy for working clinicians to use. Further investigation and use is warranted beyond this setting. PMID- 29141623 TI - Low uptake of Aboriginal interpreters in healthcare: exploration of current use in Australia's Northern Territory. AB - BACKGROUND: In Australia's Northern Territory, most Aboriginal people primarily speak an Aboriginal language. Poor communication between healthcare providers and Aboriginal people results in adverse outcomes including death. This study aimed to identify remediable barriers to utilisation of Aboriginal Interpreter services at the Northern Territory's tertiary hospital, which currently manages over 25,000 Aboriginal inpatients annually. METHODS: This is a multi-method study using key stakeholder discussions, medical file audit, bookings data from the Aboriginal Interpreter Service 2000-2015 and an online cross-sectional staff survey. The Donabedian framework was used to categorise findings into structure, process and outcome. RESULTS: Six key stakeholder meetings each with approximately 15 participants were conducted. A key structural barrier identified was lack of onsite interpreters. Interpreter bookings data revealed that only 7603 requests were made during the 15-year period, with completion of requests decreasing from 337/362 (93.1%) in 2003-4 to 649/831 (78.1%) in 2014-15 (p < 0.001). Non-completion was more common for minority languages (p < 0.001). Medical files of 103 Aboriginal inpatients were audited. Language was documented for 13/103 (12.6%). Up to 60/103 (58.3%) spoke an Aboriginal language primarily. Of 422 staff who participated in the survey, 18.0% had not received 'cultural competency' training; of those who did, 58/222 (26.2%) indicated it was insufficient. The Aboriginal Interpreter Service effectiveness was reported to be good by 209/368 (56.8%), but only 101/367 (27.5%) found it timely. Key process barriers identified by staff included booking complexities, time constraints, inadequate delivery of tools and training, and greater convenience of unofficial interpreters. CONCLUSION: We identified multiple structural and process barriers resulting in the outcomes of poor language documentation and low rates of interpreter bookings. Findings are now informing interventions to improve communication. PMID- 29141624 TI - Incorporating patient partner scores into high stakes assessment: an observational study into opinions and attitudes. AB - BACKGROUND: Volunteer patients (also known as patient partners (PPs)) play a vital role in undergraduate healthcare curricula. They frequently take part in objective structured clinical examinations (OSCE) and rate aspects of students' performance. However, the inclusion and weighting of PP marks varies, while attitudes and opinions regarding how (and if) they should contribute towards the pass/fail outcome are uncertain. METHODS: A prospective observational study was conducted to explore beliefs of PPs regarding inclusion of their scores in a high stakes undergraduate OSCE in a single UK medical school. All PPs delivering components of the local MBChB curriculum were asked to participate in the questionnaire study. Quantitative and qualitative data were analysed using descriptive statistics and framework analysis respectively. RESULTS: Fifty out of 160 (31% response rate) PPs completed the questionnaire; 70% had participated in a final year OSCE. Thirty (60%) felt their marks should be incorporated into a student's overall score, while 28% were uncertain. The main reasons for inclusion were recognition of the patient perspective (31%) and their ability to assess attitudes and professionalism (27%), while reasons against inclusion included lack of PP qualification/training (18%) and concerns relating to consistency (14%). The majority of PPs were uncertain what proportion of the total mark they should contribute, although many felt that 5-10% of the total score was reasonable. Most respondents (70%) felt that globally low PP scores should not result in an automatic fail and many (62%) acknowledged that prior to mark inclusion, further training was required. CONCLUSION: These data show that most respondents considered it reasonable to "formalise their expertise" by contributing marks in the overall assessment of students in a high stakes OSCE, although what proportion they believe this should represent was variable. Some expressed concerns that using marks towards progress decisions may alter PP response patterns. It would therefore seem reasonable to compare outcomes (i.e. pass/fail status) using historical data both incorporating and not incorporating PP marks to evaluate the effects of doing so. Further attention to existing PP training programmes is also required in order to provide clear instruction on how to globally rate students to ensure validity and consistency. PMID- 29141626 TI - Health related quality of life of HIV/AIDS patients on highly active anti retroviral therapy at a university referral hospital in Ethiopia. AB - BACKGROUND: Highly active antiretroviral therapy improves the longevity of patients living with HIV/AIDS. We conducted the study in order to assess health related quality of life of HIV/AIDS patients and the association of socio demographic and disease related variables with health related quality of life. METHODS: Health facility based cross-sectional study among 400 HIV/AIDS patients taking highly active anti-retroviral therapy from Gondar University referral hospital was conducted. A pre-tested semi-structured questionnaire, which was adopted from World Health Organization Quality of life brief instrument, was used. The data were then analyzed using SPSS version 20 software for Windows. RESULTS: The majority of the respondents reported to to have a good physical health (15.55). The World Health Organization clinical stage was found to be significantly associated with all the domains of health related quality of life. The current acute illness condition of the respondents, however, did not show significant association with any of the domains of health related quality of life. CONCLUSIONS: The six domains of health related quality of life were found to be moderate. The physical health and spirituality of the patients were relatively higher than their social relationship. Sex, age, educational status, residence and marital status showed significant association with at least one domain of health related quality of life. PMID- 29141625 TI - MicroRNA profiling of dogs with transitional cell carcinoma of the bladder using blood and urine samples. AB - BACKGROUND: Early signs of canine transitional cell carcinoma (TCC) are frequently assumed to be caused by other lower urinary tract diseases (LUTD) such as urinary tract infections, resulting in late diagnosis of TCC which could be fatal. The development of a non-invasive clinical test for TCC could dramatically reduce mortality. To determine whether microRNAs (miRNAs) can be used as non invasive diagnostic biomarkers, we assessed miRNA expression in blood and/or urine from dogs with clinically normal bladders (n = 28), LUTD (n = 25), and TCC (n = 17). Expression levels of 5 miRNA associated with TCC pathophysiology (miR 34a, let-7c, miR-16, miR-103b, and miR-106b) were assessed by quantitative real time PCR. RESULTS: Statistical analyses using ranked ANOVA identified significant differences in miR-103b and miR-16 levels between urine samples from LUTD and TCC patients (miR-103b, p = 0.002; and miR-16, p = 0.016). No statistically significant differences in miRNA levels were observed between blood samples from LUTD versus TCC patients. Expression levels of miR-34a trended with miR-16, let 7c, and miR-103b levels in individual normal urine samples, however, this coordination was completely lost in TCC urine samples. In contrast, co-ordination of miR-34a, miR-16, let-7c, and miR-103b expression levels was maintained in blood samples from TCC patients. CONCLUSIONS: Our combined data indicate a potential role for miR-103b and miR-16 as diagnostic urine biomarkers for TCC, and that further investigation of miR-103b and miR-16 in the dysregulation of coordinated miRNA expression in bladder carcinogenesis is warranted. PMID- 29141627 TI - In vitro properties of concentrated canine platelets stored in two additive solutions: a comparative study. AB - BACKGROUND: Platelet transfusion therapy poses many challenges in veterinary clinical practice. Lack of readily available blood donors, short shelf-life, and inability to administer a sufficient number of platelets to meet a dog's transfusion need are the major difficulties encountered. Platelet additive solutions are already in use at American and European human blood banks, showing to be a realistic alternative. This study compares the in vitro platelet function in plasma, Composol, or SSP+ during storage for 13 days. Platelet rich plasma platelet concentrate with 35% plasma and 65% platelet additive solutions (Composol or SSP+) and a control group (100% plasma) were prepared. Swirling, platelet count, blood gases, metabolic variables, platelet activation markers, and apoptosis markers were analyzed on days 1, 5, 9 and 13. RESULTS: Swirling was well preserved and pH was acceptable (> 6.2) during storage for all platelet additive solutions units until day 9. SSP + units showed more stable pH and metabolic variables until day 13. Platelets in plasma showed higher glucose consumption than in Composol or in SSP+. The platelet additive solutions units showed better platelet metabolism maintenance, reduced glucose consumption and lactate production. The apoptotic markers were still low for 9 days in platelet concentrates with platelet additive solutions, suggesting the possibility to extend the shelf life with the use of SSP+ or Composol. CONCLUSIONS: Our findings suggest that the uses of Composol and SSP+ in canine platelet concentrates are potential alternatives in veterinary blood banks. PMID- 29141628 TI - Gene expression analyses of the small intestine of pigs in the ex-evacuation zone of the Fukushima Daiichi Nuclear Power Plant. AB - BACKGROUND: After the accident at the Fukushima Daiichi Nuclear Power Plant, radioactive contaminants were released over a widespread area. Monitoring the biological effects of radiation exposure in animals in the ex-evacuation zone should be continued to understand the health effects of radiation exposure in humans. The present study aimed to clarify the effects of radiation by investigating whether there is any alteration in the morphology and gene expressions of immune molecules in the intestine of pigs and inobuta (wild boar and domestic pig hybrid) in the ex-evacuation zone in 2012. Gene expression analysis was performed in small intestine samples from pigs, which were collected from January to February 2012, in the ex-evacuation zone. Pigs lived freely in this zone, and their small intestine was considered to be affected by the dietary intake of radioactive contaminants. RESULTS: Several genes were selected by microarray analysis for further investigation using real-time polymerase chain reaction. IFN-gamma, which is an important inflammatory cytokine, and TLR3, which is a pattern recognize receptor for innate immune system genes, were highly elevated in these pigs. The expressions of the genes of these proteins were associated with the radiation level in the muscles. We also examined the alteration of gene expressions in wild boars 5 years after the disaster. The expression of IFN-gamma and TLR3 remained high, and that of Cyclin G1, which is important in the cell cycle, was elevated. CONCLUSIONS: We demonstrated that some changes in gene expression occurred in the small intestine of animals in the ex evacuation zone after radiation. It is difficult to conclude that these alterations are caused by only artificial radionuclides from the Fukushima Daiichi Nuclear Power Plant. However, the animals in the ex-evacuation zone might have experienced some changes owing to radioactive materials, including contaminated soil, small animals, and insects. We need to continue monitoring the effects of long-term radiation exposure in living things. PMID- 29141629 TI - The potential impact of Brexit and immigration policies on the GP workforce in England: a cross-sectional observational study of GP qualification region and the characteristics of the areas and population they served in September 2016. AB - BACKGROUND: The UK is dependent on international doctors, with a greater proportion of non-UK qualified doctors working in its universal health care system than in any other European country, except Ireland and Norway. The terms of the UK exit from the European Union can reduce the ability of European Economic Area (EEA) qualified doctors to work in the UK, while new visa requirements will significantly restrict the influx of non-EEA doctors. We aimed to explore the implications of policy restrictions on immigration, by regionally and spatially describing the characteristics of general practitioners (GPs) by region of medical qualification and the characteristics of the populations they serve. METHODS: This is a cross-sectional study on 37,792 of 41,865 GPs in England, as of 30 September 2016. The study involved age, sex, full-time equivalent (FTE), country and region of qualification and geography (organisational regions) of individual GPs. Additionally at the practice and geography levels, we studied patient list size by age groups, average patient location deprivation, the overall morbidity as measured by the Quality and Outcomes Framework (QOF) and the average payment made to primary care per patient. RESULTS: Non-UK qualified GPs comprised 21.1% of the total numbers of GPs, with the largest percentage observed in East England (29.8%). Compared to UK qualified GPs, EEA and elsewhere qualified GPs had higher FTE (medians were 0.80, 0.89 and 0.93, respectively) and worked in practices with higher median patient location deprivation (18.3, 22.5 and 25.2, respectively). Practices with high percentages of EEA and elsewhere qualified GPs served patients who resided in more deprived areas, had lower GP-to-patient ratios and lower GP-to-cumulative QOF register ratios. A decrease in pay as the percentage of elsewhere qualified GPs increased was observed; a 10% increase in elsewhere qualified GPs was linked to a L1 decrease (95% confidence interval 0.5-1.4) in average pay per patient. CONCLUSIONS: A large percentage of the UK general practice workforce consists of non-UK qualified GPs who work longer hours, are older and serve a larger number of patients in more deprived areas. Following Brexit, difficulties in replacing this valuable workforce will primarily threaten the care delivery in deprived areas. PMID- 29141630 TI - CT-based analysis of muscle volume and degeneration of gluteus medius in patients with unilateral hip osteoarthritis. AB - BACKGROUND: The gluteus medius (GMED) affects hip function as an abductor. We evaluated muscle volume and degeneration of the GMED by using CT-based analysis and assessed factors that affect hip abductor strength in patients with unilateral hip osteoarthritis (OA). METHODS: We examined clinical and imaging findings associated with hip abductor strength in consecutive 50 patients with unilateral hip OA. Hip abductor muscle strength and Harris hip score (HHS) were assessed. Leg length discrepancy (LLD) and femoral offset were assessed using X ray; CT assessment was employed for volumetric and qualitative GMED analysis. Volumetric analysis involved measurement of cross sectional area (CSA) and three dimensional (3D) muscle volume. CT density was measured for the qualitative assessment of GMED degeneration with or without adjustment using a bone mineral reference phantom. RESULTS: Hip abductor muscle strength on the affected side was significantly lower than that on the contralateral healthy side and positively correlated with overall score and score for limping of gait of HHS, demonstrating the importance of hip abductor strength for normal hip function. A significant correlation was found between CSA and 3D muscle volume, unadjusted CT density and adjusted CT density, and hip abductor strength and these CT measurements. Multiple linear regression analysis demonstrated that 3D muscle volume, adjusted CT density, and LLD are independent factors affecting hip abduction. CONCLUSIONS: 3D measurement of muscle volume and adjusted CT density more accurately reflect quantity and the GMED quality than do conventional assessments. Increase in muscle volume, recovery of muscle degeneration, and correction of LLD are important for improving limping in patients with hip OA. PMID- 29141631 TI - Detection of rabbit Haemorrhagic disease virus 2 during the wild rabbit (Oryctolagus cuniculus) eradication from the Berlengas archipelago, Portugal. AB - BACKGROUND: In the regular wildlife monitoring action carried out in the summer of the past few years at the Berlenga Island, wild rabbits (Oryctolagus cuniculus) have been repeatedly found dead. However, the origin of those deaths was never investigated. Our aim was to investigate the cause of death of 11 rabbits collected between April and May 2016. RESULTS: While screening samples from rabbit carcasses for the major viral rabbit pathogens, five tested positive to RHDV2 but all were negative for RHDV and myxoma virus (MYXV). For six RHDV2 negative specimens, emaciation and parasitism were considered the most probable cause of death. Lesions identified in the RHDV2-positive rabbits included non suppurative diffuse hepatic necrosis and pulmonary lesions varying from congestion and oedema of the lungs to interstitial pneumonia. Sequencing analysis of the vp60 gene obtained from two specimens showed identical vp60 sequences. Comparison with other known RHDV2 strains from public databases through BLAST analysis revealed a closer similarity with strains from Alentejo collected during 2013. Maximum Likelihood and Bayesian phylogenetic analysis showed that the 2016 strains from the archipelago have a higher resemblance with a group of strains mostly collected in the South of Portugal between 2013 and 2014. CONCLUSION: The results suggest that RHDV2 may have been introduced on the Berlenga Island a few years ago, having evolved separately from mainland strains due to insularity. PMID- 29141632 TI - Declining amenable mortality: a reflection of health care systems? AB - BACKGROUND: Some studies have analyzed the association of health care systems variables, such as health service resources or expenditures, with amenable mortality, but the association of types of health care systems with the decline of amenable mortality has yet to be studied. The present study examines whether specific health care system types are associated with different time trend declines in amenable mortality from 2000 to 2014 in 22 European OECD countries. METHODS: A time trend analysis was performed. Using Nolte and McKee's list, age standardized amenable mortality rates (SDRs) were calculated as the annual number of deaths over the population aged 0-74 years per 100,000 inhabitants. We classified health care systems according to a deductively generated classification by Bohm. This classification identifies three dimensions that are not entirely independent of each other but follow a clear order: the regulation dimension is first, followed by the financing dimension and finally service provision. We performed a hierarchical semi-log polynomial regression analysis on the annual SDRs to determine whether specific health care systems were associated with different SDR trajectories over time. RESULTS: The results showed a clear decline in SDRs in all 22 health care systems between 2000 and 2014 although at different annual changes (slopes). Regression analysis showed that there was a significant difference among the slopes according to provision dimension. Health care systems with a private provision exhibited a slowdown in the decline of amenable mortality over time. It therefore seems that ownership is the most relevant dimension in determining a different pattern of decline in mortality. CONCLUSIONS: All countries experienced decreases in amenable mortality between 2000 and 2014; this decline seems to be partially a reflection of health care systems, especially when affected by the provision dimension. If the private ownership is maintained or promoted by health systems, these findings might be considered when thinking about regulation policies to control factors that might influence health care performance. PMID- 29141633 TI - Genome modification of CXCR4 by Staphylococcus aureus Cas9 renders cells resistance to HIV-1 infection. AB - BACKGROUND: The CRISPR/Cas9 system has been widely used for genome editing in mammalian cells. CXCR4 is a co-receptor for human immunodeficiency virus type 1 (HIV-1) entry, and loss of CXCR4 function can protect cells from CXCR4 (X4) tropic HIV-1 infection, making CXCR4 an important target for HIV-1 gene therapy. However, the large size of the CRISPR/SpCas9 system presents an obstacle to its efficient delivery into primary CD4+ T cells. Recently, a small Staphylococcus aureus Cas9 (SaCas9) has been developed as a genome editing tool can address this question. Therefore, it provides a promising strategy for HIV-1 gene therapy if it is used to target CXCR4. RESULTS: Here, we employed a short version of Cas9 from Staphylococcus aureus (SaCas9) for targeting CXCR4. We demonstrated that transduction of lenti-virus expressing SaCas9 and selected single-guided RNAs of CXCR4 in human CD4+ T cell lines efficiently induced the editing of the CXCR4 gene, making these cell lines resistant to X4-tropic HIV-1 infection. Moreover, we efficiently transduced primary human CD4+ T cells using adeno-associated virus delivered CRISPR/SaCas9 and disrupted CXCR4 expression. We also showed that CXCR4 edited primary CD4+ T cells proliferated normally and were resistant to HIV-1 infection. CONCLUSIONS: Our study provides a basis for possible application of CXCR4-targeted genome editing by CRISPR/SaCas9 in HIV-1 gene therapy. PMID- 29141634 TI - The effects of neoliberal policies on access to healthcare for people with disabilities. AB - Neoliberal reforms lead to deep changes in healthcare systems around the world, on account of their emphasis on free market rather than the right to health. People with disabilities can be particularly disadvantaged by such reforms, due to their increased healthcare needs and lower socioeconomic status. In this article, we analyse the impacts of neoliberal reforms on access to healthcare for disabled people. This article is based on a critical analytical review of the literature and on two case studies, Chile and Greece. Chile was among the first countries to introduce neoliberal reforms in the health sector, which led to health inequalities and stratification of healthcare services. Greece is one of the most recent examples of countries that have carried out extensive changes in healthcare, which have resulted in a deterioration of the quality of healthcare services. Through a review of the policies performed in these two countries, we propose that the pathways that affect access to healthcare for disabled people include: a) Policies directly or indirectly targeting healthcare, affecting the entire population, including disabled people; and b) Policies affecting socioeconomic determinants, directly or indirectly targeting disabled people, and indirectly impacting access to healthcare. The power differentials produced through neoliberal policies that focus on economic rather than human rights indicators, can lead to a category of disempowered people, whose health needs are subordinated to the markets. The effects of this range from catastrophic out-of pocket payments to compromised access to healthcare. Neoliberal reforms can be seen as a form of structural violence, disproportionately affecting the most vulnerable parts of the population - such as people with disabilities - and curtailing access to basic rights, such as healthcare. PMID- 29141635 TI - Repeat testing for chlamydia trachomatis, a "safe approach" to unsafe sex? a qualitative exploration among youth in Stockholm. AB - BACKGROUND: Chlamydia trachomatis testing is offered to youth in Sweden, through a network of Youth Health Clinics, free at the point of care, in an attempt to bring down the prevalence and incidence of the infection. Nevertheless, infections rates have continued to rise during the past two decades and re testing rates among youth for Chlamydia trachomatis has been reported to be high in Stockholm County. A few literature reports suggest that testing for sexually transmitted infections and the test result itself can have an undesirable impact on the sexual behaviour for the individual, i.e. increase sexual risk-taking. METHODS: This qualitative study aimed to explore the motives for repeated testing for Chlamydia trachomatis among youth using the services of the Youth Health Clinics in Stockholm, and how testing affects their subsequent risk-taking. We interviewed 15 repeat testers aging 18-22 years. RESULTS: Our main findings were that the fear of social stigma related to infecting a peer was a major driver of the re-testing process. The repetitive testing process, the test result, and the encounter with personnel did not decrease sexual risk-taking among this group. CONCLUSIONS: While testing and treatment services are an important part of Chlamydia trachomatis prevention it must not take the focus away from primary prevention strategies. Testing should be encouraged, but not to the exclusion of risk reduction measures. The testing services must be complemented with stronger emphasis on safe sex, especially for those who attend the clinics repeatedly, otherwise the easy accessible testing services risk counteracting its own purpose. Future research should focus on developing and evaluating youth appropriate interventions to increase condom use, taking into consideration factors which youth perceive as important to drive this behaviour change. PMID- 29141636 TI - Correction to: Updates on cardiovascular outcome trials in diabetes. AB - Following publication of the original article [1], the authors submitted a corrected version of Table 4 (see below). PMID- 29141637 TI - Molecules produced by probiotics prevent enteric colibacillosis in pigs. AB - BACKGROUND: With the advent of antimicrobial resistance in animal pathogens, novel methods to combat infectious diseases are being sought. Among these, probiotics have been proposed as a means of promoting animal health but problems with their use has been reported. Research has demonstrated that bioactive molecules produced during the growth of certain probiotics interfere with bacterial cell-to-cell communication, which consequently results in an attenuation of virulence in a number of pathogens, including E. coli. The objective of this study was to determine the efficacy of the bioactive molecules, termed proteobiotics, produced by Lactobacillus acidophilus in preventing enterotoxigenic E, coli (ETEC) infection in pigs, which is the etiological agent for enteric colibacillosis, a common disease of nursing and young pigs. RESULTS: To achieve this, piglets were fed a preparation of the bioactive at four levels: 0, 0.5*, 1.0* and 2.0* for 7 days prior to challenge with E. coli K88. There were 36 pigs (18 gilts and 18 barrows) per treatment, resulting in 144 piglets in total for the study. Each pen had 6 piglets (3 gilts and 3 barrows). Only piglets with no physical abnormality or conditions were used in the trial and intact male piglets and ridglings were excluded. The bioactive continued to be fed to the pigs post-challenge. Based of fecal and demeanour scores, pigs fed the low and high dose of the proteobiotic were significanlty less likely to show symptoms of illness than pigs fed no bioactive. While not being significant, the weight gain of pigs given the proteobiotics was improved. At day 4 following challenge, almost 50% of piglets that did not receive the proteobiotic were shedding ETEC in their feces, compared with about 15% of animals receiving the supplement. There was also an indication that the proteobiotics reduced colonization of the ileum by E. coli K88 and improved gut health. CONCLUSION: This study indicates that the bioactive molecules produced by L. acidophilus reduces incidence of enteric colibacillosis in pigs and their use on farms would help to reduce antibiotic use. PMID- 29141638 TI - Diffusion-weighted imaging of the brains of dogs with idiopathic epilepsy. AB - BACKGROUND: Idiopathic epilepsy is one of the most common neurological disorders in dogs. Unfortunately, up to 30% of dogs with idiopathic epilepsy show no improvement under antiepileptic drug treatment. Diffusion-weighted imaging is used in human medicine to identify epileptogenic foci in the brain to allow for more invasive treatments such as deep brain stimulation or surgical removal. The aim of this study was to ass the feasibility of interictal diffusion-weighted MRI in dogs and to evaluate the distribution of diffusion in the brains of dogs with idiopathic epilepsy (IE) and to compare these values to previously published values from healthy beagle dogs. Client-owned dogs with the final diagnosis of IE were included in this study. MRI examination was carried out using a 1.0Tesla superconductive magnet. Diffusion-weighted images using a single shot echo planar imaging sequence (SSh-EPI) with a b value of b = 0 s/mm2 and b = 800 s/mm2 were acquired in a dorsal and transverse plane with diffusion gradients in all three planes (x-, y- and z-plane). An ADC (apparent diffusion coefficient) map of the isometric image of each acquired slice was generated. Regions of interest (ROIs) were manually drawn around the caudate nucleus, the thalamus, the piriform lobe including the amygdala, the hippocampus, the semioval center and the temporal cerebral cortex by one of the authors. ROI drawings were repeated 5 times at different time points to assess intra-obersver variability. A multi-way mixed model analysis of variance (ANOVA) and two-way ANOVA were used during statistical analysis. A p value of p < 0.05 was considered significant. RESULTS: Dogs with IE showed a significantly increased ADC in the amygdala within the piriform lobe and in the semioval center (p < 0.05) compared with the healthy control group. CONCLUSION: Changes in the piriform lobe in cases of epilepsy are reported infrequently in human and veterinary medicine. Similar to our results, ADC changes in the interictal phase usually include an increase in ADC due to cell loss and increased intercellular spaces. Diffusion MRI might be a promising technique for the examination of canine epileptic patients lacking other gross neuromorphological abnormalities. PMID- 29141639 TI - Tobacco use and health insurance literacy among vulnerable populations: implications for health reform. AB - BACKGROUND: Under the Affordable Care Act (ACA), millions of Americans have been enrolling in the health insurance marketplaces. Nearly 20% of them are tobacco users. As part of the ACA, tobacco users may face up to 50% higher premiums that are not eligible for tax credits. Tobacco users, along with the uninsured and racial/ethnic minorities targeted by ACA coverage expansions, are among those most likely to suffer from low health literacy - a key ingredient in the ability to understand, compare, choose, and use coverage, referred to as health insurance literacy. Whether tobacco users choose enough coverage in the marketplaces given their expected health care needs and are able to access health care services effectively is fundamentally related to understanding health insurance. However, no studies to date have examined this important relationship. METHODS: Data were collected from 631 lower-income, minority, rural residents of Virginia. Health insurance literacy was assessed by asking four factual questions about the coverage options presented to them. Adjusted associations between tobacco use and health insurance literacy were tested using multivariate linear regression, controlling for numeracy, risk-taking, discount rates, health status, experiences with the health care system, and demographics. RESULTS: Nearly one third (31%) of participants were current tobacco users, 80% were African American and 27% were uninsured. Average health insurance literacy across all participants was 2.0 (SD 1.1) out of a total possible score of 4. Current tobacco users had significantly lower HIL compared to non-users (-0.22, p < 0.05) after adjustment. Participants who were less educated, African American, and less numerate reported more difficulty understanding health insurance (p < 0.05 each.) CONCLUSIONS: Tobacco users face higher premiums for health coverage than non-users in the individual insurance marketplace. Our results suggest they may be less equipped to shop for plans that provide them with adequate out-of-pocket risk protection, thus placing greater financial burdens on them and potentially limiting access to tobacco cessation and treatment programs and other needed health services. PMID- 29141640 TI - Discordance in self-report and observation data on mistreatment of women by providers during childbirth in Uttar Pradesh, India. AB - BACKGROUND: The study aims to assess the discordance between self-reported and observed measures of mistreatment of women during childbirth in public health facilities in Uttar Pradesh, India, as well as correlates of these measures and their discordance. METHODS: Cross sectional data were collected through direct observation of deliveries and follow-up interviews with women (n = 875) delivering in 81 public health facilities in Uttar Pradesh. Participants were surveyed on demographics, mistreatment during childbirth, and maternal and newborn complications. Provider characteristics (training, age) were obtained through interviews with providers, and observation data were obtained from checklists completed by trained nurse investigators to document quality of care at delivery. Mistreatment was assessed via self-report and observed measures which included 17 and 6 items respectively. Cohen's kappas assessed concordance between the 6 items common in the self-report and observed measures. Regression models assessed associations between characteristics of women and providers for each outcome. RESULTS: Most participants (77.3%) self-reported mistreatment in at least 1 of the 17-item measure. For the 6 items included in both self-report and observations, 9.1% of women self-reported mistreatment, whereas observers reported 22.4% of women being mistreated. Cohen's kappas indicated mostly fair to moderate concordance. Regression analyses found that multiparous birth (AOR = 1.50, 95% CI = 1.06-2.13), post-partum maternal complications (AOR = 2.0, 95% CI = 1.34-3.06); new-born complications (AOR = 2.6, 95% CI = 1. 96-4.03) and not having an Skilled Birth Attendant (SBA) trained provider (AOR = 1.47, 95% CI = 1.05-2.04) were associated with increased risk for mistreatment as measured by self-report. In contrast, only provider characteristics like older provider (AOR = 1.03, 95% CI = 1.02-1.05) and provider not trained in SBA (AOR = 1.44, 95% CI = 1.02-2.02) were associated with mistreatment as measured through observations. Younger age at marriage (AOR = 0.86, 95% CI = 0.78-0.95) and provider characteristics (older provider AOR = 1.05, 95% CI = 1.01-1.09; provider not trained in SBA AOR = 0.96, 95% CI = 0.92-0.99) were associated with discordance (based on mistreatment reported by observer but not by women). CONCLUSION: Provider mistreatment during childbirth is prevalent in Uttar Pradesh and may be under-reported by women, particularly when they are younger or when providers are older or less trained. The findings warrant programmatic action as well as more research to better understand the context and drivers of both behavior and reporting. TRIAL REGISTRATION: CTRI/2015/09/006219. Registered 28 September 2015. PMID- 29141641 TI - Gender and age disparity in the initiation of life-supporting treatments: a population-based cohort study. AB - BACKGROUND: The relationships between age and the life-supporting treatments use, and between gender and the life-supporting treatments use are still controversial. Using extracorporeal membrane oxygenation as an example of life supporting treatments, the objectives of this study were: (1) to examine the relationship between age and the extracorporeal membrane oxygenation use; (2) to examine the relationship between age and the extracorporeal membrane oxygenation use; and (3) to deliberate the ethical and societal implications of age and gender disparities in the initiation of extracorporeal membrane oxygenation. METHODS: This is a population-based, retrospective cohort study. Taiwan's extracorporeal membrane oxygenation cases from 2000 to 2010 were collected. The annual incidence rate of extracorporeal membrane oxygenation use adjusting for both age and gender distribution for each year from 2000 to 2010 was derived using the population of 2000 as the reference population. The trend of extracorporeal membrane oxygenation use was examined using time-series linear regression analysis. We conducted joinpoint regression for estimating the trend change of extracorporeal membrane oxygenation use. RESULTS: The trends of extracorporeal membrane oxygenation use both for different gender groups, and for different age groups have been significantly increasing over time. Men were more likely to be supported by extracorporeal membrane oxygenation than women. Women's perspectives toward life and death, and women's perception of well-being may be associated with the phenomenon. In addition, the patients at the age of 65 or older were more likely to be supported by extracorporeal membrane oxygenation than those younger than 65. Family autonomy/family-determination, and the Confucian tradition of filial piety and respecting elders may account for this phenomenon. CONCLUSIONS: This study showed gender and age disparities in the initiation of extracorporeal membrane oxygenation use in Taiwan, which may be accounted for by the cultural and societal values in Taiwan. For a healthcare professional who deals with patients'/family members' medical decision-making to initiate life-supporting treatments, he/she should be sensitive not only to the legality, but also the societal and ethical issues involved. PMID- 29141642 TI - Doing implementation research on health governance: a frontline researcher's reflexive account of field-level challenges and their management. AB - BACKGROUND: Implementation Research (IR) in and around health systems comes with unique challenges for researchers including implementation, multi-layer governance, and ethical issues. Partnerships between researchers, implementers, policy makers and community members are central to IR and come with additional challenges. In this paper, we elaborate on the challenges faced by frontline field researchers, drawing from experience with an IR study on Village Health Sanitation and Nutrition Committees (VHSNCs). METHODS: The IR on VHSNC took place in one state/province in India over an 18-month research period. The IR study had twin components; intervention and in-depth research. The intervention sought to strengthen the VHSNC functioning, and concurrently the research arm sought to understand the contextual factors, pathways and mechanism affecting VHSNC functions. Frontline researchers were employed for data collection and a research assistant was living in the study sites. The frontline research assistant experienced a range of challenges, while collecting data from the study sites, which were documented as field memos and analysed using inductive content analysis approach. RESULTS: Due to the relational nature of IR, the challenges coalesced around two sets of relationships (a) between the community and frontline researchers and (b) between implementers and frontline researchers. In the community, the frontline researcher was viewed as the supervisor of the intervention and was perceived by the community to have power to bring about beneficial changes with public services and facilities. Implementers expected help from the frontline researcher in problem-solving in VHSNCs, and feedback on community mobilization to improve their approaches. A concerted effort was undertaken by the whole research team to clarify and dispel concerns among the community and implementers through careful and constant communication. The strategies employed were both managerial, relational and reflexive in nature. CONCLUSION: Frontline researchers through their experiences shape the research process and its outcome and they play a central role in the research. It demonstrates that frontline researcher resilience is very crucial when conducting health policy and systems research. PMID- 29141643 TI - Integrative medicine primary care: assessing the practice model through patients' experiences. AB - BACKGROUND: The University of Arizona Integrative Health Center (UAIHC) was an innovative integrative medicine (IM) adult primary care clinic in Phoenix, Arizona. UAIHC used a hybrid payment model to deliver comprehensive healthcare that includes conventional and complementary medical treatments. METHODS: Fidelity measures were collected to evaluate how well the IM care delivery process matched ideals for IM. Patient experiences are presented here. Patients visiting UAIHC on 1 of 10 randomly selected days between September 2013 and February 2015 were surveyed. Patients were asked about their experience with: holistic care; promotion of health, self-care, and well-being; relationship and communication with practitioners; and overall satisfaction. RESULTS: Eighty-three patients completed surveys. Based on patient-reported experiences, UAIHC delivered IM care as defined by the practice model. CONCLUSIONS: Patients received holistic care, established positive caring relationships with providers who promoted their self-care and well-being, and reported high overall satisfaction with UAIHC. PMID- 29141644 TI - Lipopolysaccharide pretreatment increases protease-activated receptor-2 expression and monocyte chemoattractant protein-1 secretion in vascular endothelial cells. AB - BACKGROUND: This study investigated whether lipopolysaccharide (LPS) increase protease-activated receptor-2 (PAR-2) expression and enhance the association between PAR-2 expression and chemokine production in human vascular endothelial cells (ECs). METHODS: The morphology of ECs was observed through microphotography in cultured human umbilical vein ECs (EA. hy926 cells) treated with various LPS concentrations (0, 0.25, 0.5, 1, and 2 MUg/mL) for 24 h, and cell viability was assessed using the MTT assay. Intracellular calcium imaging was performed to assess agonist (trypsin)-induced PAR-2 activity. Western blotting was used to explore the LPS-mediated signal transduction pathway and the expression of PAR-2 and adhesion molecule monocyte chemoattractant protein-1 (MCP-1) in ECs. RESULTS: Trypsin stimulation increased intracellular calcium release in ECs. The calcium influx was augmented in cells pretreated with a high LPS concentration (1 MUg/mL). After 24 h treatment of LPS, no changes in ECs viability or morphology were observed. Western blotting revealed that LPS increased PAR-2 expression and enhanced trypsin-induced extracellular signal-regulated kinase (ERK)/p38 phosphorylation and MCP-1 secretion. However, pretreatment with selective ERK (PD98059), p38 mitogen-activated protein kinase (MAPK) (SB203580) inhibitors, and the selective PAR-2 antagonist (FSLLRY-NH2) blocked the effects of LPS-activated PAR-2 on MCP-1 secretion. CONCLUSIONS: Our findings provide the first evidence that the bacterial endotoxin LPS potentiates calcium mobilization and ERK/p38 MAPK pathway activation and leads to the secretion of the pro-inflammatory chemokine MCP-1 by inducing PAR-2 expression and its associated activity in vascular ECs. Therefore, PAR-2 exerts vascular inflammatory effects and plays an important role in bacterial infection-induced pathological responses. PMID- 29141645 TI - Measuring quality of life among people living with HIV: a systematic review of reviews. AB - AIM: A systematic review of reviews was conducted to identify and appraise brief measures of health-related quality of life (HRQoL) that have been used in peer reviewed research with people living with HIV. METHODS: The review was conducted in two stages: 1) search of electronic databases to identify systematic reviews of tools used to measure HRQoL in adults living with HIV, published since the year 2000; 2) selection of HRQol scales from those identified in the reviews. Inclusion criteria included scales that could be self-administered in 10 min or less, covering at least 3 domains of quality of life (physical function, social/role function and mental/emotional function). For generic scales, inclusion criteria included the availability of normative data while for HIV specific scales, patient input into the development of the scale was required. RESULTS: Ten reviews met the inclusion criteria. Nine generic scales met the inclusion criteria: the EuroQol five dimensions questionnaire (EQ-5D); Health Utilities Index; McGill Quality of Life questionnaire; Medical Outcomes Study (MOS) Short Form (SF)-12; SF-36; World Health Organisation Quality of Life (WHOQOL- BREF), Questions of Life Satisfaction (FLZM) and SF-20. Available psychometric data supported the EQ-5D and SF-36. Seven HIV-specific scales met the inclusion criteria: the AIDS Clinical Trials Group (ACTG)-21; HIV-QL-31; MOS HIV; Multidimensional Quality of Life Questionnaire for Persons with HIV/AIDS (MQOL-HIV), PROQOL-HIV, Symptom Quality of Life Adherence (HIV-SQUAD) and the WHOQOL-HIV BREF. Of the HIV -specific measures, the MOS-HIV was considered to have the most well-established psychometric properties, however limitations identified in the reviews included insufficient input from people living with HIV in the development of the scale, cross-cultural relevance and continued applicability. Two relatively new measures, the WHOQOL-HIV BREF and PROQOL-HIV, were considered to have promising psychometric properties and may have more relevance to people living with HIV. CONCLUSION: The findings highlight the need for further validation of HRQoL measures in people living with HIV. The choice of one measure over another is likely to be influenced by the purpose of the quality of life assessment and the domains of HRQoL that are most relevant to the specific research or clinical question. PMID- 29141646 TI - Physical activity and the environment: conceptual review and framework for intervention research. AB - BACKGROUND: Changing the physical environment is one way to promote physical activity and improve health, but evidence on intervention effectiveness is mixed. The theoretical perspectives and conceptual issues discussed or used in evaluative studies and related literature may contribute to these inconsistencies. We aimed to advance the intervention research agenda by systematically searching for and synthesising the literature pertaining to these wider conceptual issues. METHODS: We searched for editorials, commentaries, reviews, or primary qualitative or quantitative studies in multiple disciplines by electronic searches of key databases (MEDLINE and MEDLINE In-Process, Web of Science, Cochrane Reviews, ProQuest for dissertations, Health Evidence, EPPI Centre, TRID and NICE) and snowballing. We extracted theoretical and conceptual material and used thematic analysis in an in-depth, configurative narrative approach to synthesis. RESULTS: Our initial searches identified 2760 potential sources from fields including public health, sociology, behavioural science and transport, of which 104 were included. By first separating out and then drawing together this material, we produced a synthesis that identified five high-level conceptual themes: one concerning outcomes (physical activity as a behaviour and a socially embedded practice), one concerning exposures (environmental interventions as structural changes) and three concerning how interventions bring about their effects (the importance of social and physical context; (un) observable mechanisms linking interventions and changes in physical activity; and interventions as events in complex systems). These themes are inter-related but have rarely been considered together in the disparate literatures. Drawing on these insights, we present a more generalisable way of thinking about how environmental interventions work which could be used in future evaluation studies. CONCLUSIONS: Environmental and policy interventions are socially embedded and operate within a system. Evaluators should acknowledge this, and the philosophical perspective taken in their evaluation. Across disciplinary fields, future studies should seek to understand how interventions work through considering these systems, the context in which interventions take place, and the (un) observable mechanisms that may operate. This will help ensure that findings can be more easily interpreted and widely applied by policymakers. We hope that highlighting these conceptual issues will help others to interpret and improve upon a somewhat contested evidence base. PMID- 29141647 TI - Regulation of antimicrobial activity and xenocoumacins biosynthesis by pH in Xenorhabdus nematophila. AB - BACKGROUND: Xenocoumacin 1 (Xcn1) and Xenocoumacin 2 (Xcn2) are the main antimicrobial compounds produced by Xenorhabdus nematophila. Culture conditions, including pH, had remarkably distinct effects on the antimicrobial activity of X. nematophila. However, the regulatory mechanism of pH on the antimicrobial activity and antibiotic production of this bacterium is still lacking. RESULTS: With the increase of initial pH, the antimicrobial activity of X. nematophila YL001 was improved. The levels of Xcn1 and nematophin at pH 8.5 were significantly (P < 0.05) higher than that at pH 5.5 and 7.0. In addition, the expression of xcnA-L, which are responsible for the production of Xcn1 was increased and the expression of xcnMN, which are required for the conversion of Xcn1 to Xcn2 was reduced at pH 8.5. Also, the expression of ompR and cpxR were decreased at pH 8.5. CONCLUSION: The alkaline pH environment was found to be beneficial for the production of Xcn1 and nematophin, which in turn led to high antimicrobial activity of X. nematophila at pH 8.5. PMID- 29141648 TI - Polymorphisms at microRNA binding sites of Ara-C and anthracyclines-metabolic pathway genes are associated with outcome of acute myeloid leukemia patients. AB - BACKGROUND: Gene polymorphisms at microRNA-binding sites (poly-miRTS) may affect gene transcription and expression through miRNA regulation, which is associated with cancer susceptibility, sensitivity to chemotherapy and prognosis. This study investigated the association between poly-miRTS of Ara-C/anthracycline metabolic pathways genes and the outcome of acute myeloid leukemia (AML) in Chinese patients after Ara-C-based chemotherapy. METHODS: A total of 17 poly-miRTS were selected from the SNPinfo Web Server and genotyped in 206 Chinese Han non-FAB-M3 AML patients using the SEQUENOM Mass-ARRAY system. RESULTS: Among these 17 poly miRTS, five Ara-C metabolic gene single nucleotide polymorphisms (SNPs, NT5C2 rs10786736 and rs8139, SLC29A1 rs3734703, DCTD rs7278, and RRM1 rs1042919) were identified to significantly associate with complete AML remission and/or overall and relapse-free survival (OS and RFS, respectively), and four anthracycline metabolic gene SNPs (ABCC1 rs3743527, rs212091, and rs212090 and CBR1 rs9024) were significantly associated with chemotherapy-related toxicities. Moreover, SLC29A1 rs3734703 was shown to associate with both chemotherapy response and survival (adjusted OR 2.561 in the overdominant model; adjusted HR 2.876 for OS and 2.357 for RFS in the dominant model). CONCLUSIONS: The data from the current study demonstrated that the poly-miRTS of Ara-C/anthracyclines metabolic genes predicted the sensitivity and side effects of AML to Ara-C-based chemotherapy and patient survival. Further study will confirm them as biomarkers for AML patients after Ara-C-based chemotherapy. PMID- 29141649 TI - Number and type of guideline implementation tools varies by guideline, clinical condition, country of origin, and type of developer organization: content analysis of guidelines. AB - BACKGROUND: Guideline implementation tools (GI tools) can improve clinician behavior and patient outcomes. Analyses of guidelines published before 2010 found that many did not offer GI tools. Since 2010 standards, frameworks and instructions for GI tools have emerged. This study analyzed the number and types of GI tools offered by guidelines published in 2010 or later. METHODS: Content analysis and a published GI tool framework were used to categorize GI tools by condition, country, and type of organization. English-language guidelines on arthritis, asthma, colorectal cancer, depression, diabetes, heart failure, and stroke management were identified in the National Guideline Clearinghouse. Screening and data extraction were in triplicate. Findings were reported with summary statistics. RESULTS: Eighty-five (67.5%) of 126 eligible guidelines published between 2010 and 2017 offered one or more of a total of 464 GI tools. The mean number of GI tools per guideline was 5.5 (median 4.0, range 1 to 28) and increased over time. The majority of GI tools were for clinicians (239, 51.5%), few were for patients (113, 24.4%), and fewer still were to support implementation (66, 14.3%) or evaluation (46, 9.9%). Most clinician GI tools were guideline summaries (116, 48.5%), and most patient GI tools were condition specific information (92, 81.4%). Government agencies (patient 23.5%, clinician 28.9%, implementation 24.1%, evaluation 23.5%) and developers in the UK (patient 18.5%, clinician 25.2%, implementation 27.2%, evaluation 29.1%) were more likely to generate guidelines that offered all four types of GI tools. Professional societies were more likely to generate guidelines that included clinician GI tools. CONCLUSIONS: Many guidelines do not include any GI tools, or a variety of GI tools for different stakeholders that may be more likely to prompt guideline uptake (point-of-care forms or checklists for clinicians, decision-making or self management tools for patients, implementation and evaluation tools for managers and policy-makers). While this may vary by country and type of organization, and suggests that developers could improve the range of GI tools they develop, further research is needed to identify determinants and potential solutions. Research is also needed to examine the cost-effectiveness of various types of GI tools so that developers know where to direct their efforts and scarce resources. PMID- 29141650 TI - Neuropsychological function is improved among opioid dependent adults who adhere to opiate agonist treatment with buprenorphine-naloxone: a preliminary study. AB - BACKGROUND: Among persons with opioid use disorder (OUD), neuropsychological dysfunction is associated with depression, and better neuropsychological function is associated with opioid abstinence. However, it is unknown whether depressive symptomatology or adherence to opiate agonist treatment are associated with neuropsychological change over time. METHODS: We recruited 20 buprenorphine/naloxone-treated adults with OUD (M Age = 45.2 years [SD = 8.1]; 25% female) to complete baseline and 6 month visits containing a neuropsychological test battery and self-reported measures of depressive symptomatology and medication adherence. RESULTS: Depressive symptomatology was not significantly related to neuropsychological change (p's > .05). Greater adherence to buprenorphine/naloxone was associated with improvements in learning, memory, and global functioning (r's = .52-60; p's < .05). CONCLUSIONS: Among OUD patients, greater adherence to buprenorphine/naloxone is associated with improved neuropsychological functioning over time. In contrast, depressive symptomatology is not associated with neuropsychological functioning over time. Supporting adherence to buprenorphine/naloxone may improve and/or preserve learning and memory functioning in individuals treated for OUD. TRIAL REGISTRATION: NCT01108679 . Registered 21 April 2010. PMID- 29141651 TI - The dose of behavioral interventions to prevent and treat childhood obesity: a systematic review and meta-regression. AB - BACKGROUND: A better understanding of the optimal "dose" of behavioral interventions to affect change in weight-related outcomes is a critical topic for childhood obesity intervention research. The objective of this review was to quantify the relationship between dose and outcome in behavioral trials targeting childhood obesity to guide future intervention development. METHODS: A systematic review and meta-regression included randomized controlled trials published between 1990 and June 2017 that tested a behavioral intervention for obesity among children 2-18 years old. Searches were conducted among PubMed (Web-based), Cumulative Index to Nursing and Allied Health Literature (EBSCO platform), PsycINFO (Ovid platform) and EMBASE (Ovid Platform). Two coders independently reviewed and abstracted each included study. Dose was extracted as intended intervention duration, number of sessions, and length of sessions. Standardized effect sizes were calculated from change in weight-related outcome (e.g., BMI-Z score). RESULTS: Of the 258 studies identified, 133 had sufficient data to be included in the meta-regression. Average intended total contact (# sessions x length of sessions) was 27.7 (SD 32.2) hours and average duration was 26.0 (SD 23.4) weeks. When controlling for study covariates, a random-effects meta regression revealed no significant association between contact hours, intended duration or their interaction and effect size. CONCLUSIONS: This systematic review identified wide variation in the dose of behavioral interventions to prevent and treat pediatric obesity, but was unable to detect a clear relationship between dose and weight-related outcomes. There is insufficient evidence to provide quantitative guidance for future intervention development. One limitation of this review was the ability to uniformly quantify dose due to a wide range of reporting strategies. Future trials should report dose intended, delivered, and received to facilitate quantitative evaluation of optimal dose. TRIAL REGISTRATIONS: The protocol was registered on PROSPERO (Registration # CRD42016036124 ). PMID- 29141653 TI - Test of a workforce development intervention to expand opioid use disorder treatment pharmacotherapy prescribers: protocol for a cluster randomized trial. AB - BACKGROUND: Overdoses due to non-medical use of prescription opioids and other opiates have become the leading cause of accidental deaths in the USA. Buprenorphine and extended-release naltrexone are key evidence-based pharmacotherapies available to addiction treatment providers to address opioid use disorder (OUD) and prevent overdose deaths. Treatment organizations' efforts to provide these pharmacotherapies have, however, been stymied by limited success in recruiting providers (physicians, nurse practitioners, and physician assistants) to prescribe these medications. Historically, the addiction treatment field has not attracted physicians, and many barriers to implementing OUD pharmacotherapy exist, ranging from lack of confidence in treating OUD patients to concerns regarding reimbursement. Throughout the USA, the prevalence of OUD far exceeds the capacity of the OUD pharmacotherapy treatment system. Poor access to OUD pharmacotherapy prescribers has become a workforce development need for the addiction treatment field and a significant health issue. METHODS: This cluster randomized controlled trial (RCT) is designed to increase buprenorphine and extended-release naltrexone treatment capacity for OUD. The implementation intervention to be tested is a bundle of OUD pharmacotherapy capacity building practices called the Prescriber Recruitment Bundle (PRB), which was developed and piloted in a previous statewide buprenorphine implementation study. For this cluster RCT, organizational sites will be recruited and then randomized into one of two arms: (1) control, with treatment as usual and access to a website with PRB resources, or (2) intervention, with organizations implementing the PRB using the Network for the Improvement of Addiction Treatment organizational change model over a 24-month intervention period and a 10-month sustainability period. The primary treatment outcomes for each organizational site are self-reported monthly counts of buprenorphine slots, extended-release naltrexone capacity, number of buprenorphine patients, and number of extended-release naltrexone patients. This trial will be conducted in Florida, Ohio, and Wisconsin, resulting in 35 sites in each arm, for a total sample size of 70 organizations. DISCUSSION: This study addresses three issues of substantial public health significance: (1) the pressing opioid misuse epidemic, (2) the low uptake of OUD treatment pharmacotherapies, and (3) the need to increase prescriber participation in the addiction treatment workforce. TRIAL REGISTRATION: ClinicalTrials.gov NCT02926482. PMID- 29141654 TI - Early career researchers want Open Science. AB - Open Science is encouraged by the European Union and many other political and scientific institutions. However, scientific practice is proving slow to change. We propose, as early career researchers, that it is our task to change scientific research into open scientific research and commit to Open Science principles. PMID- 29141652 TI - Congenital myopathies: clinical phenotypes and new diagnostic tools. AB - Congenital myopathies are a group of genetic muscle disorders characterized clinically by hypotonia and weakness, usually from birth, and a static or slowly progressive clinical course. Historically, congenital myopathies have been classified on the basis of major morphological features seen on muscle biopsy. However, different genes have now been identified as associated with the various phenotypic and histological expressions of these disorders, and in recent years, because of their unexpectedly wide genetic and clinical heterogeneity, next generation sequencing has increasingly been used for their diagnosis. We reviewed clinical and genetic forms of congenital myopathy and defined possible strategies to improve cost-effectiveness in histological and imaging diagnosis. PMID- 29141656 TI - Measles lessons in an anti-vaccination era: public health is a social duty, not a political option. AB - BACKGROUND: Measles virus, member of the genus Morbillivirus in the family Paramyxoviridae, is a highly contagious human pathogen. An effective live attenuated vaccine is available and its use has the potential to eradicate the disease from the human population. Although the vaccine was introduced in national vaccination schedules, several measles outbreaks have occurred because of insufficient vaccination coverage. Since early January 2017, a new outbreak of measles in Italy has been observed. METHODS: We analyzed all the patients admitted to the Emergency Department of Bambino Gesu Children Hospital of Rome from the 1st of January 2017 to the end of May 2017 and discharged with diagnosis of suspected or confirmed measles or admitted to the Pediatric and Infectious Disease Unit. For each confirmed case, demographic data, vaccination history, exposure to source case, clinical presentation, date of onset of symptoms, hospitalization, laboratory test results, complications and therapy were collected. RESULTS: From the 1st of January 2017 to the 31st of May 2017, we enrolled 139 patients who were conducted to the Emergency Department of Bambino Gesu Children's Hospital because of measles: 33 patients were discharged with the diagnosis of suspected measles by clinical manifestations; 33 discharged with the diagnosis of confirmed measles by laboratory tests and 73 were admitted to the Pediatric and Infectious Disease Unit. Seven patients, who were exposed to mothers with measles, were admitted to receive treatment with Measles Immune Globulin intravenously. Among the 66 patients admitted to the hospital with measles, 31 cases (47%) occurred in unvaccinated individuals who were age eligible for measles vaccination; 29 (44%) were infants too young to be vaccinated; only five patients (8%) received one dose of measles-containing vaccine. Out of the 66 patients, 35 (53%) developed complications. Acute respiratory failure was the most reported complications (20%). Death, due to multiorgan failure by measles, occurred in one 9-girl-year-age patient with genetic disorders who was unvaccinated. CONCLUSIONS: Measles still represents a serious public health problem worldwide. Vaccination against measles is safe, effective, and cost-effective. High vaccination coverage (>95%) with two doses of measles vaccine is crucial to elimination. Health care professionals play an important role in vaccination uptake and prevention of measles spread during an outbreak. PMID- 29141655 TI - Long-term balancing selection contributes to adaptation in Arabidopsis and its relatives. AB - BACKGROUND: In contrast to positive selection, which reduces genetic variation by fixing beneficial alleles, balancing selection maintains genetic variation within a population or species and plays crucial roles in adaptation in diverse organisms. However, which genes, genome-wide, are under balancing selection and the extent to which these genes are involved in adaptation are largely unknown. RESULTS: We performed a genome-wide scan for genes under balancing selection across two plant species, Arabidopsis thaliana and its relative Capsella rubella, which diverged about 8 million generations ago. Among hundreds of genes with shared coding-region polymorphisms, we find evidence for long-term balancing selection in five genes: AT1G35220, AT2G16570, AT4G29360, AT5G38460, and AT5G44000. These genes are involved in the response to biotic and abiotic stress and other fundamental biochemical processes. More intriguingly, for these genes, we detected significant ecological diversification between the two haplotype groups, suggesting that balancing selection has been very important for adaptation. CONCLUSIONS: Our results indicate that beyond the well-known S-locus genes and resistance genes, many loci are under balancing selection. These genes are mostly correlated with resistance to stress or other fundamental functions and likely play a more important role in adaptation to diverse habitats than previously thought. PMID- 29141657 TI - Local estrogen axis in the human bone microenvironment regulates estrogen receptor-positive breast cancer cells. AB - BACKGROUND: Approximately 70% of all breast cancers express the estrogen receptor, and are regulated by estrogen. While the ovaries are the primary source of estrogen in premenopausal women, most breast cancer is diagnosed following menopause, when systemic levels of this hormone decline. Estrogen production from androgen precursors is catalyzed by the aromatase enzyme. Although aromatase expression and local estrogen production in breast adipose tissue have been implicated in the development of primary breast cancer, the source of estrogen involved in the regulation of estrogen receptor-positive (ER+) metastatic breast cancer progression is less clear. METHODS: Bone is the most common distant site of breast cancer metastasis, particularly for ER+ breast cancers. We employed a co-culture model using trabecular bone tissues obtained from total hip replacement (THR) surgery specimens to study ER+ and estrogen receptor-negative (ER-) breast cancer cells within the human bone microenvironment. Luciferase expressing ER+ (MCF-7, T-47D, ZR-75) and ER- (SK-BR-3, MDA-MB-231, MCF-10A) breast cancer cells were cultured directly on bone tissue fragments or in bone tissue-conditioned media, and monitored over time with bioluminescence imaging (BLI). Bone tissue-conditioned media were generated in the presence vs. absence of aromatase inhibitors, and testosterone. Bone tissue fragments were analyzed for aromatase expression by immunohistochemistry. RESULTS: ER+ breast cancer cells were preferentially sustained in co-cultures with bone tissues and bone tissue-conditioned media relative to ER- cells. Bone fragments analyzed by immunohistochemistry revealed expression of the aromatase enzyme. Bone tissue conditioned media generated in the presence of testosterone had increased estrogen levels and heightened capacity to stimulate ER+ breast cancer cell proliferation. Pretreatment of cultured bone tissues with aromatase inhibitors, which inhibited estrogen production, reduced the capacity of conditioned media to stimulate ER+ cell proliferation. CONCLUSIONS: These results suggest that a local estrogen signaling axis regulates ER+ breast cancer cell viability and proliferation within the bone metastatic niche, and that aromatase inhibitors modulate this axis. Although endocrine therapies are highly effective in the treatment of ER+ breast cancer, resistance to these treatments reduces their efficacy. Characterization of estrogen signaling networks within the bone microenvironment will identify new strategies for combating metastatic progression and endocrine resistance. PMID- 29141659 TI - Rescue of high-specificity Cas9 variants using sgRNAs with matched 5' nucleotides. AB - We report that engineered Cas9 variants with improved specificity-eCas9-1.1 and Cas9-HF1-are often poorly active in human cells, when complexed with single guide RNAs (sgRNAs) with a mismatch at the 5' terminus, relative to target DNA sequences. Because the nucleotide at the 5' end of sgRNAs, expressed under the control of the commonly-used U6 promoter, is fixed to a guanine, these attenuated Cas9 variants are not useful at many target sites. By using sgRNAs with matched 5' nucleotides, produced by linking them to a self-cleaving ribozyme, the editing activity of Cas9 variants can be rescued without sacrificing high specificity. PMID- 29141658 TI - Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice. AB - BACKGROUND: Radiation exposure poses a significant threat to public health. Hematopoietic injury is one of the major manifestations of acute radiation sickness. Protection and/or mitigation of hematopoietic stem cells (HSCs) from radiation injury is an important goal in the development of medical countermeasure agents (MCM). We recently identified thioredoxin (TXN) as a novel molecule that has marked protective and proliferative effects on HSCs. In the current study, we investigated the effectiveness of TXN in rescuing mice from a lethal dose of total body radiation (TBI) and in enhancing hematopoietic reconstitution following a lethal dose of irradiation. METHODS: We used in-vivo and in-vitro methods to understand the biological and molecular mechanisms of TXN on radiation mitigation. BABL/c mice were used for the survival study and a flow cytometer was used to quantify the HSC population and cell senescence. A hematology analyzer was used for the peripheral blood cell count, including white blood cells (WBCs), red blood cells (RBCs), hemoglobin, and platelets. Colony forming unit (CFU) assay was used to study the colongenic function of HSCs. Hematoxylin and eosin staining was used to determine the bone marrow cellularity. Senescence-associated beta-galactosidase assay was used for cell senescence. Western blot analysis was used to evaluate the DNA damage and senescence protein expression. Immunofluorescence staining was used to measure the expression of gamma-H2AX foci for DNA damage. RESULTS: We found that administration of TXN 24 h following irradiation significantly mitigates BALB/c mice from TBI-induced death: 70% of TXN-treated mice survived, whereas only 25% of saline-treated mice survived. TXN administration led to enhanced recovery of peripheral blood cell counts, bone marrow cellularity, and HSC population as measured by c-Kit+Sca 1+Lin- (KSL) cells, SLAM + KSL cells and CFUs. TXN treatment reduced cell senescence and radiation-induced double-strand DNA breaks in both murine bone marrow lineage-negative (Lin-) cells and primary fibroblasts. Furthermore, TXN decreased the expression of p16 and phosphorylated p38. Our data suggest that TXN modulates diverse cellular processes of HSCs. CONCLUSIONS: Administration of TXN 24 h following irradiation mitigates radiation-induced lethality. To the best of our knowledge, this is the first report demonstrating that TXN reduces radiation induced lethality. TXN shows potential utility in the mitigation of radiation induced hematopoietic injury. PMID- 29141660 TI - xCell: digitally portraying the tissue cellular heterogeneity landscape. AB - Tissues are complex milieus consisting of numerous cell types. Several recent methods have attempted to enumerate cell subsets from transcriptomes. However, the available methods have used limited sources for training and give only a partial portrayal of the full cellular landscape. Here we present xCell, a novel gene signature-based method, and use it to infer 64 immune and stromal cell types. We harmonized 1822 pure human cell type transcriptomes from various sources and employed a curve fitting approach for linear comparison of cell types and introduced a novel spillover compensation technique for separating them. Using extensive in silico analyses and comparison to cytometry immunophenotyping, we show that xCell outperforms other methods. xCell is available at http://xCell.ucsf.edu/ . PMID- 29141661 TI - Preventing enduring behavioural problems in young children through early psychological intervention (Healthy Start, Happy Start): study protocol for a randomized controlled trial. AB - BACKGROUND: Behavioural problems are common in early childhood, and can result in enduring costs to the individual and society, including an increased risk of mental and physical illness, criminality, educational failure and drug and alcohol misuse. Most previous research has examined the impact of interventions targeting older children when difficulties are more established and harder to change, and have rarely included fathers. We are conducting a trial of a psychological intervention delivered to families with very young children, engaging both parents where possible. METHODS: This study is a two-arm, parallel group, researcher-blind, randomized controlled trial, to test the clinical effectiveness and cost-effectiveness of a parenting intervention, Video Feedback Intervention to Promote Positive Parenting and Sensitive Discipline (VIPP-SD) for parents of young children (12-36 months) at risk of behavioural difficulties. VIPP-SD is an evidence-based parenting intervention developed at Leiden University in the Netherlands which uses a video-feedback approach to support parents, particularly by enhancing parental sensitivity and sensitive discipline in caring for children. The trial will involve 300 families, who will be randomly allocated into either an intervention group, who will receive the video-feedback intervention (n = 150), or a control group, who will receive treatment as usual (n = 150). The trial will evaluate whether VIPP-SD, compared to treatment as usual, leads to lower levels of behavioural problems in young children who are at high risk of developing these difficulties. Assessments will be conducted at baseline, and 5 and 24 months post-randomization. The primary outcome measure is a modified version of the Preschool Parental Account of Child Symptoms (Pre PACS), a structured clinical interview of behavioural symptoms. Secondary outcomes include caregiver-reported behavioural difficulties, parenting behaviours, parental sensitivity, parental mood and anxiety and parental relationship adjustment. An economic evaluation will also be carried out to assess the cost-effectiveness of the intervention compared to treatment as usual. DISCUSSION: If shown to be effective, the intervention could be delivered widely to parents and caregivers of young children at risk of behavioural problems as part of community based services. TRIAL REGISTRATION: ISRCTN Registry: ISRCTN58327365 . Registered 19 March 2015. PMID- 29141662 TI - Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. AB - BACKGROUND: Adipose tissue-derived mesenchymal stem cells (AT-MSCs) offer potential as a therapeutic option for chronic discogenic low back pain (LBP) because of their immunomodulatory functions and capacity for cartilage differentiation. The goal of this study was to assess the safety and tolerability of a single intradiscal implantation of combined AT-MSCs and hyaluronic acid (HA) derivative in patients with chronic discogenic LBP. METHODS: We performed a single-arm phase I clinical trial with a 12-month follow-up and enrolled 10 eligible chronic LBP patients. Chronic LBP had lasted for more than 3 months with a minimum intensity of 4/10 on a visual analogue scale (VAS) and disability level >= 30% on the Oswestry Disability Index (ODI). The 10 patients underwent a single intradiscal injection of combined HA derivative and AT-MSCs at a dose of 2 * 107 cells/disc (n = 5) or 4 * 107 cells/disc (n = 5). Safety and treatment outcomes were evaluated by assessing VAS, ODI, Short Form-36 (SF-36), and imaging (lumbar spine X-ray imaging and MRI) at regular intervals over 1 year. RESULTS: No patients were lost at any point during the 1-year clinical study. We observed no procedure or stem cell-related adverse events or serious adverse events during the 1-year follow-up period. VAS, ODI, and SF-36 scores significantly improved in both groups receiving both low (cases 2, 4, and 5) and high (cases 7, 8, and 9) cell doses, and did not differ significantly between the two groups. Among six patients who achieved significant improvement in VAS, ODI, and SF-36, three patients (cases 4, 8, and 9) were determined to have increased water content based on an increased apparent diffusion coefficient on diffusion MRI. CONCLUSIONS: Combined implantation of AT-MSCs and HA derivative in chronic discogenic LBP is safe and tolerable. However, the efficacy of combined AT-MSCs and HA should be investigated in a randomized controlled trial in a larger population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02338271 . Registered 7 January 2015. PMID- 29141663 TI - Quality assurance of the SCOPE 1 trial in oesophageal radiotherapy. AB - BACKGROUND: SCOPE 1 was the first UK based multi-centre trial involving radiotherapy of the oesophagus. A comprehensive radiotherapy trials quality assurance programme was launched with two main aims: 1. To assist centres, where needed, to adapt their radiotherapy techniques in order to achieve protocol compliance and thereby enable their participation in the trial. 2. To support the trial's clinical outcomes by ensuring the consistent planning and delivery of radiotherapy across all participating centres. METHODS: A detailed information package was provided and centres were required to complete a benchmark case in which the delineated target volumes and organs at risk, dose distribution and completion of a plan assessment form were assessed prior to recruiting patients into the trial. Upon recruiting, the quality assurance (QA) programme continued to monitor the outlining and planning of radiotherapy treatments. Completion of a questionnaire was requested in order to gather information about each centre's equipment and techniques relating to their trial participation and to assess the impact of the trial nationally on standard practice for radiotherapy of the oesophagus. During the trial, advice was available for individual planning issues, and was circulated amongst the SCOPE 1 community in response to common areas of concern using bulletins. RESULTS: 36 centres were supported through QA processes to enable their participation in SCOPE1. We discuss the issues which have arisen throughout this process and present details of the benchmark case solutions, centre questionnaires and on-trial protocol compliance. The range of submitted benchmark case GTV volumes was 29.8-67.8cm3; and PTV volumes 221.9 513.3 cm3. For the dose distributions associated with these volumes, the percentage volume of the lungs receiving 20Gy (V20Gy) ranged from 20.4 to 33.5%. Similarly, heart V40Gy ranged from 16.1 to 33.0%. Incidence of incorrect outlining of OAR volumes increased from 50% of centres at benchmark case, to 64% on trial. Sixty-five percent of centres, who returned the trial questionnaire, stated that their standard practice had changed as a result of their participation in the SCOPE1 trial. CONCLUSIONS: The SCOPE 1 QA programme outcomes lend support to the trial's clinical conclusions. The range of patient planning outcomes for the benchmark case indicated, at the outset of the trial, the significant degree of variation present in UK oesophageal radiotherapy planning outcomes, despite the presence of a protocol. This supports the case for increasingly detailed definition of practice by means of consensus protocols, training and peer review. The incidence of minor inconsistencies of technique highlights the potential for improved QA systems and the need for sufficient resource for this to be addressed within future trials. As indicated in questionnaire responses, the QA exercise as a whole has contributed to greater consistency of oesophageal radiotherapy in the UK via the adoption into standard practice of elements of the protocol. TRIAL REGISTRATION: The SCOPE1 trial is an International Standard Randomized Controlled Trial, ISRCTN47718479 . PMID- 29141664 TI - Prevalence and prognosis of acutely ill patients with organ failure at arrival to hospital: protocol for a systematic review. AB - BACKGROUND: Acutely ill patients are a heterogeneous group, and some of these suffer from organ failure. As the prognosis of organ failure improves with early treatment, it is important to identify these patients as early as possible. Most studies on organ failure have been performed in intensive care settings, or on selected groups of patients, where a high prevalence and mortality have been reported. Before patients arrive to the intensive care unit, or the general ward, most of them have passed through the emergency department (ED), where diagnosis and treatment has been initiated. The prevalence and prognosis of acutely ill patients, with organ failure, at arrival have been studied in some selected groups, but methods and results differ. This systematic review aims to identify, summarize, and analyze studies of prevalence and prognosis of new onset organ failure in acutely ill undifferentiated patients, at arrival to hospital. The result of the review will assist physicians working in an ED, when assessing patients' risk of organ failure and their associated prognosis. METHODS: The information sources used are electronic databases, PubMed, Cochrane Library, EMBASE, and CINAHL; references in included studies and review articles; and authors' personal files. One author will perform the title and abstract screening and exclude obviously ineligible studies. By an independent full-text screening, two authors will decide on the eligibility for the remaining studies. Eligible studies will include an unselected group of acutely ill adult patients at arrival to hospital, with one or more organ failures (respiratory, renal, cerebral, circulatory, hepatic, or coagulation failure). Included studies will have assessed the prevalence or prognosis, defined as mortality or ICU transfer, of new onset organ failure. From included studies, bibliographical and study description data, patient characteristics, and data related to prevalence of organ failure and prognosis will be extracted. We will assess risk of bias in included studies using the Quality in Prognosis Studies tool for prognostic studies and the Newcastle-Ottawa Scale for observational studies. We expect heterogeneity and to conduct a qualitative synthesis of the results. If, however, heterogeneity is low, we will conduct a random effects meta-analysis stratified by basic study design. DISCUSSION: This review will summarize and analyze studies of prevalence and prognosis of acutely ill patients, with organ failure at arrival to hospital, assist ED physicians assessing the risk of organ failure in unselected patients, and guide recommendations for further research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017060871. PMID- 29141665 TI - Matrix metalloproteinase-3 and the 7-joint ultrasound score in the assessment of disease activity and therapeutic efficacy in patients with moderate to severe rheumatoid arthritis. AB - BACKGROUND: This study aimed to investigate the reliability and validity of serum matrix metalloproteinase-3 (MMP-3) levels and articular ultrasound (US) scores in assessing disease activity and therapeutic response in rheumatoid arthritis (RA) patients. METHODS: A total of 151 RA patients were enrolled, of whom 22 were treated with certolizumab pegol (Cimzia, CZP). The RA patients were divided into the following four subgroups according to their disease activity score in 28 joints (DAS28): stable, mild activity, moderate activity, and high activity. Forty-three healthy controls were simultaneously studied. The serum MMP-3 levels and 7-joint US (US7) scores of all subjects were determined. The patients who were treated with CZP were subsequently followed for 6 months. RESULTS: The serum MMP-3 levels of all the RA patients were significantly higher than those of healthy controls, and those of patients with moderate and severe RA were significantly higher than those of patients with stable RA. The US7 scores of patients with severe RA were significantly higher than those of patients in other groups. Using the DAS28 as a reference standard, the corresponding cutoff value of MMP-3 was 70.5 ng/ml. After CZP treatment, the MMP-3 levels and US7 scores were significantly decreased at week 2, and the mean changes in US7 scores at weeks 12 and 24 were significantly higher in both groups with American College of Rheumatology 50% positive response (ACR50) and ACR 70% positive response (ACR70) than in the negative groups. CONCLUSION: Serum MMP-3 and the US7 scores could both effectively reflect disease activity and therapeutic responses in patients with moderate to severe RA. TRIAL REGISTRATION: CTR20140405 (RA0044), CTR20140405: A phase 3, Multicenter, Double-blind, Placebo Controlled, Parallel Group, Randomized, 24-Week Study to Evaluate the Safety and Efficacy of Certolizumab Pegol as Additional Medication to Methotrexate in Chinese Subjects With Active Rheumatoid Arthritis Who Have an Incomplete Response to Methotrexate, Registered on 13 June 2014. CTR20140412 (RA0078), CTR20140412: A phase 3, Multicenter, Open-label Extension Study to Assess the Safety and Efficacy of Certolizumab Pegol as Additional Medication to Methotrexate in Chinese Subjects With Active Rheumatoid Arthritis Who Participated in RA0044, Registered on 02 July 2014. PMID- 29141667 TI - More beds are not the answer: transforming detoxification units into medication induction centers to address the opioid epidemic. PMID- 29141666 TI - Intron retention enhances gene regulatory complexity in vertebrates. AB - BACKGROUND: While intron retention (IR) is now widely accepted as an important mechanism of mammalian gene expression control, it remains the least studied form of alternative splicing. To delineate conserved features of IR, we performed an exhaustive phylogenetic analysis in a highly purified and functionally defined cell type comprising neutrophilic granulocytes from five vertebrate species spanning 430 million years of evolution. RESULTS: Our RNA-sequencing-based analysis suggests that IR increases gene regulatory complexity, which is indicated by a strong anti-correlation between the number of genes affected by IR and the number of protein-coding genes in the genome of individual species. Our results confirm that IR affects many orthologous or functionally related genes in granulocytes. Further analysis uncovers new and unanticipated conserved characteristics of intron-retaining transcripts. We find that intron-retaining genes are transcriptionally co-regulated from bidirectional promoters. Intron retaining genes have significantly longer 3' UTR sequences, with a corresponding increase in microRNA binding sites, some of which include highly conserved sequence motifs. This suggests that intron-retaining genes are highly regulated post-transcriptionally. CONCLUSIONS: Our study provides unique insights concerning the role of IR as a robust and evolutionarily conserved mechanism of gene expression regulation. Our findings enhance our understanding of gene regulatory complexity by adding another contributor to evolutionary adaptation. PMID- 29141668 TI - Association of dietary patterns with diabetes complications among type 2 diabetes patients in Gaza Strip, Palestine: a cross sectional study. AB - BACKGROUND: The prevalence of diabetes mellitus is rising worldwide. When diabetes is uncontrolled, it has dire consequences for health and well-being. However, the role of diet in the origin of diabetes complications is not understood well. This study identifies major dietary patterns among type 2 diabetes patients and its association with diabetes complications in Gaza Strip, Palestine. METHODS: This cross sectional study was conducted among 1200 previously diagnosed type 2 diabetes mellitus (both genders, aged 20-64 years), patients receiving care in primary healthcare centers in Gaza Strip, Palestine. Dietary patterns were evaluated using a validated semi-quantitative food frequency questionnaire. Additional information regarding demographic and medical history variables was obtained with an interview-based questionnaire. Statistical analysis was performed using SPSS version 20. RESULTS: Two major dietary patterns were identified by factor analysis: Asian-like pattern and sweet-soft drinks snacks pattern. After adjustment for confounding variables, patients in the lowest tertile of the Asian-like pattern characterized by a high intake of whole grains, potatoes, beans, legumes, vegetables, tomatoes and fruit had a lower odds for (High BP, kidney problems, heart problems, extremities problems and neurological problems), (OR 0.710 CI 95% (.506-.997)), (OR 0.834 CI 95% (.700 .994)), (OR 0.730 CI 95% (.596-.895)), (OR 0.763 CI 95% (.667-.871)) and (OR 0.773 CI 95% (.602-.991)) respectively, (P value <0.05 for all). No significant association was found between the sweet-soft drinks snacks pattern with diabetes complications. CONCLUSION: The Asian-like pattern may be associated with a lower prevalence of diabetes complications among type 2 diabetes patients. PMID- 29141669 TI - Metastasis in the mandibular condyle: a case report. AB - BACKGROUND: Most bone metastases are observed in the trunk of the body. Metastasis in the mandibular condyle is rare. In many case reports, temporary common temporomandibular joint disorder-like symptoms can be a sign of relapse and metastasis. CASE PRESENTATION: We report a rare case of breast carcinoma metastatic to the left mandibular condyle in a 55-year-old Japanese woman, who visited our department for a dental check-up prior to chemotherapy. She had almost no symptoms, but radiographs suggested the existence of metastasis. CONCLUSIONS: In many case reports, patients had some symptoms. In this case report, our patient had slight symptoms, but we were able to confirm the metastasis from the symptoms and panoramic dental radiograph. When patients complain about discomfort of the temporomandibular joint, we need to consider the possibility of metastasis and notice changes on the panoramic dental radiograph. PMID- 29141670 TI - Correction to: Lung cancer mortality of residents living near petrochemical industrial complexes: a meta-analysis. AB - After publication of the article [1], it has been brought to our attention that the original version of this Article contained a typo in the 3rd paragraph of the section 'Review process and data extraction'. It concerns the equation published as "Var(lnRR) = Var(lnR1 + lnR0)". On the right part, the "+" within the parenthesis should be "-", as defined and derived from the left part. As a result, Var(lnRR) = Var(lnR1 + lnR0) should be revised to Var(lnRR) = Var(lnR1 - lnR0). PMID- 29141671 TI - Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation. AB - BACKGROUND: Sleep deprivation (SD) leads to cognitive impairment. Neuroinflammation could be a significant contributing factor in the same. An increase in regional brain pro-inflammatory cytokines induces cognitive deficits, however, the magnitude of the effect under SD is not apparent. It is plausible that microglia activation could be involved in the SD-induced cognitive impairment by modulation of neuronal cell proliferation, differentiation, and brain-derived neuronal factor (BDNF) level. The present study aimed to evaluate the possible beneficial effect of minocycline in amelioration of spatial memory decline during SD by its anti-inflammatory and neuroprotective actions. We scrutinized the effect of minocycline on the inflammatory cytokine levels associated with glial cells (microglia and astrocytes) activity and neurogenesis markers crucial for behavioral functions during SD. METHODS: Male Sprague-Dawley rats weighing 230-250 g were sleep deprived for 48 h using automated cage shaking apparatus. The spatial memory was tested using MWM apparatus immediately after completion of SD with and without minocycline. The animals were euthanized, blood was collected, and brain was extracted for neuroinflammation and neurogenesis studies. The set of experiments were also conducted with use of temozolomide, a neurogenesis blocker. RESULTS: Minocycline treatment increased the body weight, food intake, and spatial memory performance which declined during SD. It reduced the pro-inflammatory and increased the anti-inflammatory cytokine levels in hippocampus and plasma and inhibited the reactive gliosis in the hippocampus evidenced by improved cell count, morphology, and immunoreactivity. Additionally, minocycline administration promoted neurogenesis at different stages: proliferation (BrdU, Ki-67), differentiation (DCX) cells and growth factor (BDNF). However, no significant change was observed in maturation (NeuN) during SD. In addition, molecules related to behavior, inflammation, and neurogenesis were shown to be more affected after temozolomide administration during SD, and changes were restored with minocycline treatment. We observed a significant correlation of neurogenesis with microglial activation, cytokine levels, and spatial memory during SD. CONCLUSION: The present study demonstrated that the SD induced decline in spatial memory, neuronal cells proliferation, differentiation, and BDNF level could be attributed to upregulation of neuroinflammatory molecules, and minocycline may be an effective intervention to counteract these changes. Microglial activation is involved in SD-induced changes in inflammatory molecules, neurogenesis, and spatial memory. PMID- 29141672 TI - A novel GIT2-BRAF fusion in pilocytic astrocytoma. AB - BACKGROUND: KIAA1549-BRAF fusion is the most common genetic event in pilocytic astrocytoma (PA), and leads to activation of the mitogen activated protein kinase (MAPK) signaling pathway. Fusions of BRAF with other partner genes, as well as other genetic alterations not involving BRAF but also leading to MAPK pathway activation have been described rarely. CASE PRESENTATION: We present a new fusion partner in the low-grade glioma of a 10-year-old male, who presented with headaches and recent episodes of seizures. Magnetic resonance imaging (MRI) demonstrated a right temporal lobe tumor. Histological and immunohistochemical evaluation, and a next generation sequencing assay (Oncopanel, Illumina, 500 genes) including breaKmer analysis for chromosomal rearrangements were performed. Histology was remarkable for a low-grade glioma composed of mildly atypical astrocytes with piloid processes, in a focally microcystic background. Mitoses were not seen; unequivocal Rosenthal fibers or eosinophilic granular bodies were absent. The tumor was positive for OLIG2 and GFAP and negative for BRAF V600E and IDH1 R132H mutant protein immunostains. Oncopanel showed low SOX2 (3q26.33) copy number gain, and no gains at 7q34. There were no significant single nucleotide variants. BreaKmer detected a GIT2-BRAF fusion with loss of BRAF exons 1-8. The integrated diagnosis was low-grade glioma with piloid features, most consistent with pilocytic astrocytoma, WHO grade I. CONCLUSION: GIT2-BRAF fusion has not been reported in the literature in any tumor. Given that the BRAF sequence deleted is identical to that seen in other fusion events in PA, it most likely acts as tumor driver by activation of the MAPK pathway. PMID- 29141673 TI - A customized fixation plate with novel structure designed by topological optimization for mandibular angle fracture based on finite element analysis. AB - BACKGROUND: The purpose of this study was to design a customized fixation plate for mandibular angle fracture using topological optimization based on the biomechanical properties of the two conventional fixation systems, and compare the results of stress, strain and displacement distributions calculated by finite element analysis (FEA). METHODS: A three-dimensional (3D) virtual mandible was reconstructed from CT images with a mimic angle fracture and a 1 mm gap between two bone segments, and then a FEA model, including volume mesh with inhomogeneous bone material properties, three loading conditions and constraints (muscles and condyles), was created to design a customized plate using topological optimization method, then the shape of the plate was referenced from the stress concentrated area on an initial part created from thickened bone surface for optimal calculation, and then the plate was formulated as "V" pattern according to dimensions of standard mini-plate finally. To compare the biomechanical behavior of the "V" plate and other conventional mini-plates for angle fracture fixation, two conventional fixation systems were used: type A, one standard mini plate, and type B, two standard mini-plates, and the stress, strain and displacement distributions within the three fixation systems were compared and discussed. RESULTS: The stress, strain and displacement distributions to the angle fractured mandible with three different fixation modalities were collected, respectively, and the maximum stress for each model emerged at the mandibular ramus or screw holes. Under the same loading conditions, the maximum stress on the customized fixation system decreased 74.3, 75.6 and 70.6% compared to type A, and 34.9, 34.1, and 39.6% compared to type B. All maximum von Mises stresses of mandible were well below the allowable stress of human bone, as well as maximum principal strain. And the displacement diagram of bony segments indicated the effect of treatment with different fixation systems. CONCLUSIONS: The customized fixation system with topological optimized structure has good biomechanical behavior for mandibular angle fracture because the stress, strain and displacement within the plate could be reduced significantly comparing to conventional "one mini-plate" or "two mini-plates" systems. The design methodology for customized fixation system could be used for other fractures in mandible or other bones to acquire better mechanical behavior of the system and improve stable environment for bone healing. And together with SLM, the customized plate with optimal structure could be designed and fabricated rapidly to satisfy the urgent time requirements for treatment. PMID- 29141674 TI - Repair of articular cartilage and subchondral defects in rabbit knee joints with a polyvinyl alcohol/nano-hydroxyapatite/polyamide 66 biological composite material. AB - BACKGROUND: This study sought to prepare a new PVA/n-HA/PA66 composite to investigate the repair of articular cartilage and subchondral defects in rabbit knee joints. METHODS: A 5 * 5 * 5 mm-sized defect was created in the patellofemoral joints of 72 healthy adult New Zealand rabbits. The rabbits were then randomly divided into three groups (n = 24): PVA/n-HA+PA66 group, polyvinyl alcohol (PVA) group, and control (untreated) group. Cylindrical PVA/n-HA+PA66, 5 * 5 mm, comprised an upper PVA layer and a lower n-HA+PA66 layer. Macroscopic and histological evaluations were performed at 4, 8, 12, and 24 weeks, postoperatively. Type II collagen was measured by immunohistochemical staining. The implant/cartilage and bone interfaces were observed by scanning electron microscopy. RESULTS: At 24 weeks postoperatively, the lower PVA/n-HA+PA66 layer became surrounded by cartilage, with no obvious degeneration. In the PVA group, an enlarged space was observed between the implant and the host tissue that had undergone degeneration. In the control group, the articular cartilage had become calcified. In the PVA/n-HA+PA66 group, positive type II collagen staining was observed between the composite and the surrounding cartilage and on the implant surface. In the PVA group, positive staining was slightly increased between the PVA and the surrounding cartilage, but reduced on the PVA surface. In the control group, reduced staining was observed throughout. Scanning electron microscopy showed increased bone tissue in the lower n-HA+PA66 layer that was in close approximation with the upper PVA layer of the composite. In the PVA group, the bone tissue around the material had receded, and in the control group, the defect was filled with bone tissue, while the superior aspect of the defect was filled with disordered, fibrous tissue. CONCLUSION: The diphase biological composite material PVA/n-HA+PA66 exhibits good histocompatibility and offers a satisfactory substitute for articular cartilage and subchondral bone. PMID- 29141675 TI - Delayed initiation of antenatal care and associated factors in Ethiopia: a systematic review and meta-analysis. AB - BACKGROUND: Antenatal care uptake is among the key indicators for monitoring the progress of maternal outcomes. Early initiation of antenatal care facilitates the timely management and treatment of pregnancy complications to reduce maternal deaths. In Ethiopia, antenatal care utilization is generally low, and delayed initiation of care is very common. We aimed to systematically identify and synthesize available evidence on delayed initiation of antenatal care and the associated factors in Ethiopia. METHODS: Studies published in English from 1 January 2002 to 30 April 2017 were systematically searched from PubMed, Medline, EMBASE, CINAHL and other relevant sources. Two authors independently reviewed the identified studies against the eligibility criteria. The included studies were critically appraised using the Joanna Briggs-MAStARI instrument for observational studies. Meta-analysis was conducted in RevMan v5.3 for Windows using a Mantel Haenszel random effects model. The presence of statistical heterogeneity was checked using the Cochran Q test, and its level was quantified using the I2 statistics. Pooled estimate of the proportion of the outcome variable was calculated. Pooled Odd Ratios with 95% CI were calculated to measure the effect sizes. RESULT: The pooled magnitude of delayed antenatal care in Ethiopia was 64% (95% CI: 57%, 70%). Maternal age (OR = 0.70; 95% CI: 0.53, 0.93), place of residence (OR = 0.29, 95% CI: 0.16, 0.50), maternal education (OR = 0.49; 95% CI: 0.38, 0.63), husband's education (OR = 0.44; 95% CI: 0.23, 0.85), maternal occupation (OR = 0.75; 95% CI: 0.61, 0.93), monthly income (OR = 2.06; 95% CI: 1.23, 3.45), pregnancy intention (OR = 0.49; 95% CI: 0.40, 0.60), parity (OR = 0.46; 95% CI: 0.36, 0.58), knowledge of antenatal care (OR = 0.40; 95% CI: 0.32, 0.51), women's autonomy (OR = 0.38; 95% CI: 0.15, 0.94), partner involvement (OR = 0.24; 95% CI: 0.07, 0.75), pregnancy complications (OR = 0.23; 95% CI: 0.06, 0.95), and means of identifying pregnancy (OR = 0.50; 95% CI: 0.36, 0.69) were significantly associated with delayed antenatal care. CONCLUSION: Improving female education and women's empowerment through economic reforms, strengthening family planning programs to reduce unintended pregnancy and promoting partner involvement in pregnancy care could reduce the very high magnitude of delayed antenatal care in Ethiopia. TRIAL REGISTRATION: CRD42017064585 . PMID- 29141676 TI - Platelets are activated in ANCA-associated vasculitis via thrombin-PARs pathway and can activate the alternative complement pathway. AB - BACKGROUND: In this study, we investigated the mechanism of platelet activation in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), as well as the activation of the alternative complement pathway by platelets in AAV. METHODS: CD62P and platelet-leukocyte aggregates in AAV patients were tested by flow cytometry. Platelets were stimulated by plasma from active AAV patients. The effect of the thrombin-protease-activated receptors (PARs) pathway was evaluated by blocking thrombin or PAR1 antagonists. After platelets were activated by plasma from AAV patients, Ca/Mg-Tyrode's buffer and Mg-EGTA buffer were used to measure complement activation in liquid phase and on the surface of platelets. RESULTS: The levels of CD62P-expressing platelets and platelet-leukocyte aggregates were significantly higher in active AAV patients than those in remission and normal controls. Platelets were activated by plasma from active AAV patients (percentage of CD62P-expressing platelets, 97.7 +/- 3% vs. 1 +/- 0.2%, p < 0.0001, compared with those incubated with healthy donor plasma), and this was inhibited by thrombin or PAR1 antagonists (percentage of CD62P-expressing platelets, 97.7 +/- 3% vs. 2.7 +/- 1%, p < 0.0001, 97.7 +/- 3% vs. 5 +/- 1.4%, p < 0.0001, respectively). Platelets activated by plasma from AAV patients could trigger complement activation via the alternative pathway, as demonstrated by significant elevation of C3a, C5a, and sC5b-9 and significantly more C3c and C5b-9 deposition on the surface of platelets. CONCLUSIONS: Platelets were activated in AAV patients, and such activation was at least partially attributed to the thrombin-PARs pathway. Activated platelets triggered the alternative complement pathway in AAV. PMID- 29141677 TI - Factors associated with oral glucocorticoid use in patients with rheumatoid arthritis: a drug use study from a prospective national biologics registry. AB - BACKGROUND: Glucocorticoids (GCs) are used in ~ 60% of patients with rheumatoid arthritis (RA). Although disease-modifying, they also have significant adverse effects. Understanding factors associated with GC use may help minimise exposure. The aims of the present study were to describe oral GC use in RA; determine any change in use over time; and determine factors associated with oral GC use, commencement or cessation. METHODS: Adult patients with RA were identified in the Australian Rheumatology Association Database (ARAD), a national Australian registry that collects long-term outcome data from patients with inflammatory arthritis. Patients were categorised by their ARAD date of entry (DOE), with population-averaged logistic regression and transition state analysis used to determine any change in GC use over time. Fixed-effects panel regression was used to examine whether GC current use was associated with pain/arthritis activity/Health Assessment Questionnaire (HAQ) scores or medication use. Transition state analysis was used to assess whether these factors influenced the commencement or cessation of GCs. RESULTS: A total of 3699 patients with RA completed a baseline ARAD questionnaire (73% female, mean age 57 years). The probability of GC use decreased over time according to ARAD DOE: September 2001 to March 2005, 55% (95% CI 52-58%); March 2005 to September 2008, 47% (45-49%); September 2008 to March 2012, 42% (39-45%); and March 2012 to October 2015, 39% (34-43%) (p < 0.001). Conventional synthetic disease-modifying anti-rheumatic drugs (OR 10.13; 95% CI 8.22-12.47), non-steroidal anti-inflammatory drugs (1.18; 1.02-1.37) and opioids (2.14; 1.84-2.48) were associated with GC current use, as were lower pain scores (0.94; 0.90-0.98), higher arthritis activity scores (1.09; 1.05-1.14) and poorer HAQ scores (1.52; 1.30-1.79). Use of biologic disease modifying anti-rheumatic drugs (bDMARDs) was not associated with GC current use (0.98; 0.83-1.15) or GC cessation (HR 0.87; 95% CI 0.75-1.01), but it was associated with GC commencement (0.54; 0.47-0.62). CONCLUSIONS: The probability of oral GC use decreased over time, with reduced commencement and increased cessation of GCs. The modest effect of bDMARDs on GC cessation was not statistically significant. PMID- 29141678 TI - Novel functions of LHX2 and PAX6 in the developing telencephalon revealed upon combined loss of both genes. AB - Patterning of the telencephalic neuroepithelium is a tightly regulated process controlled by transcription factors and signalling molecules. The cortical primordium is flanked by two signalling centres, the hem medially, and the antihem laterally. The hem induces the formation of the hippocampus in adjacent neuroepithelium. Therefore, the position of the hem defines the position of the hippocampus in the brain. The antihem is positioned at the boundary between the dorsal and ventral telencephalon and proposed to provide patterning cues during development. LIM-homeodomain (LIM-HD) transcription factor LHX2 suppresses both hem and antihem fate in the cortical neuroepithelium. Upon loss of Lhx2, medial cortical neuroepithelium is transformed into hem, whereas lateral cortical neuroepithelium is transformed into antihem. Here, we show that transcription factor PAX6, known to regulate patterning of the lateral telencephalon, restricts this tissue from transforming into hem upon loss of Lhx2. When Lhx2 and Pax6 are both deleted, the cortical hem expands to occupy almost the complete extent of the cortical primordium, indicating that both factors act to suppress hem fate in the lateral telencephalon. Furthermore, the shift in the pallial-subpallial boundary and absence of the antihem, observed in the Pax6 mutant, are both restored in the Lhx2; Pax6 double mutant. Together, these results not only reveal a novel function for LHX2 in regulating dorsoventral patterning in the telencephalon, but also identify PAX6 as a fundamental regulator of where the hem can form, and therefore implicate this molecule as a determinant of hippocampal positioning. PMID- 29141679 TI - Intramuscular oxytocin versus intravenous oxytocin to prevent postpartum haemorrhage at vaginal delivery (LabOR trial): study protocol for a randomised controlled trial. AB - BACKGROUND: Primary postpartum haemorrhage (PPH) is one of the leading causes of maternal morbidity and mortality worldwide. The most common cause of primary PPH is uterine atony. Atonic PPH rates are increasing in developed countries despite routine active management of the third stage of labour. In less-developed countries, primary PPH remains the leading cause of maternal death. Although the value of routine oxytocics in the third stage of labour has been well established, there is inconsistent practice in the choice of agent and route of administration. Oxytocin is the preferred agent because it has fewer side effects than other uterotonics with similar efficacy. It can be given intravenously or intramuscularly; however, to date, the most effective route of administering oxytocin has not been established. METHODS/DESIGN: A double-blind randomised controlled trial is planned. The aim of the study is to compare the effects of an intramuscular bolus of oxytocin (10 IU in 1 mL) and placebo intravenous injection (1 mL 0.9% saline given slowly) with an intravenous bolus of oxytocin (10 IU in 1 mL given slowly over 1 min) and placebo intramuscular injection (1 mL 0.9% saline) at vaginal delivery. The study will recruit 1000 women at term (>36 weeks) with singleton pregnancies who are aiming for a vaginal delivery. The primary outcome will be PPH (measured blood loss >= 500 mL). A study involving 1000 women will have 80% power at the 5% two-sided alpha level, to detect differences in the proportion of patients with measured blood loss > 500 ml of 10% vs 5%. DISCUSSION: Given the increasing trends of atonic PPH it is both important and timely that we evaluate the most effective route of oxytocin administration for the management of the third stage of labour. To date, there has been limited research comparing the efficacy of intramuscular oxytocin vs intravenous oxytocin for the third stage of labour. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN14718882 . Registered on 4 January 2016. Pilot commenced 12.12.2015; trial commenced 04.01.2016. The protocol (Ref 012012) was approved by the National Maternity Hospital Research Ethics Committee on 10.06.2015 and the Research Ethics Committee of the Coombe Women & Infants University Hospital (Ref 26-2015) on 09.12.2015. PMID- 29141680 TI - Applying a community-based participatory research approach to improve access to healthcare for Eritrean asylum-seekers in Israel: a pilot study. AB - BACKGROUND: Israel hosts approximately 50,000 asylum seekers, most of them from Eritrea. Exclusive policies restrict their access to healthcare. In 2013, local activists partnered with Eritrean asylum seekers to assess health needs as well as willingness to pay for health insurance among the Eritrean communities. This initiative was meant as a step towards jointly advocating access to Israel's public healthcare system and towards strengthening collective efficacy among the asylum-seeking communities, as well as a first attempt to apply a community-based participatory research (CBPR) approach to migrant health research in Israel. METHODS: Applying a CBPR approach, a 22-item survey was developed by a team of activists, academics and community members. It was administered by community members in four different cities. Cell weighting was applied to align sample estimates with the population distribution. The results were analyzed by means of a Generalized Linear Model. Six follow-up interviews and two focus group discussions helped interpret the quantitative findings and provided additional information. RESULTS: The results from 445 questionnaires show that most (95%) asylum seekers are interested in purchasing health insurance. To this end, more than half of the respondents are willing to invest up to 300 NIS monthly, which represents a significant part (5-7.5%) of their median monthly income. Willingness to pay for health coverage was independent from employment and income; it was significantly associated with city of residence - which translates into current healthcare options - understanding of health insurance, and health seeking motives. The study further highlights the role of labor policies in shaping not only asylum seekers' access to care but also psychosocial wellbeing. CONCLUSIONS: The study provides initial evidence for asylum seekers' willingness to pay monthly contributions into a public health insurance scheme, in spite of economic hardship, and it points to understanding of and trust in the healthcare system as a central factor influencing willingness to pay. The outcomes of this initiative further offer some support for the potential of CBPR to enhance research into the health of marginalized populations and, moreover, to counter their social exclusion through capacity building and strengthening of collective efficacy. PMID- 29141682 TI - Correction to: Differences of muscle co-contraction of the ankle joint between young and elderly adults during dynamic postural control at different speeds. AB - CORRECTION: After the publication of this work [1] an error was noticed in Table 3. In the column 'Elderly', in the last row it states 98 +/- 11.87** however the correct value should be: 34.98 +/- 11.87**. The original article has been corrected. PMID- 29141681 TI - Patient influence in home-based reablement for older persons: qualitative research. AB - BACKGROUND: Reablement services are rehabilitation for older people living at home, being person-centered in information, mapping and the goal-setting conversation. The purpose of this study was to gain knowledge about conversation processes and patient influence in formulating the patients' goals. There are two research questions: How do conversation theme, structure and processes appear in interactions aiming to decide goals of home-based reablement rehabilitation for the elderly? How professionals' communication skills do influence on patients' participation in conversation about everyday life and goals of home-based reablement? METHODS: A qualitative field study explored eight cases of naturally occurring conversations between patients and healthcare professionals in a rehabilitation team. Patients were aged 67-90 years old. The reablement team consisted of an occupational therapist, physiotherapist, nurse and care workers. Data was collected by audio recording the conversations. Transcribed text was analyzed for conversational theme and communication patterns as they emerged within main themes. RESULTS: Patient participation differed with various professional leadership and communication in the information, mapping and goalsetting process. In the data material in its entirety, conversations consisted mainly of three parts where each part dealt with one of the three main topics. The first part was "Introduction to the program." The main part of the talk was about mapping ("Varying patient participation when discussing everyday life"), while the last part was about goal setting ("Goals of rehabilitation"). CONCLUSIONS: Home-based reablement requires communication skills to encourage user participation, and mapping of resources and needs, leading to the formulation of objectives. Professional health workers must master integrating two intentions: goal-oriented and person-centered communication that requires communication skills and leadership ability in communication, promoting patient influence and goal-setting. Quality of such conversations is complex, and requires the ability to apply integrated knowledge, skills and attitudes appropriate to communication situations. PMID- 29141683 TI - Pellet coculture of osteoarthritic chondrocytes and infrapatellar fat pad-derived mesenchymal stem cells with chitosan/hyaluronic acid nanoparticles promotes chondrogenic differentiation. AB - BACKGROUND: Cell source plays a key role in cell-based cartilage repair and regeneration. Recent efforts in cell coculture have attempted to combine the advantages and negate the drawbacks of the constituent cell types. The aim of this study was to evaluate the chondrogenic outcome of articular chondrocytes (ACs) and infrapatellar fat pad (IPFP)-derived mesenchymal stem cells (MSCs) in direct coculture. METHODS: ACs and IPFP MSCs from the same patients with knee osteoarthritis (OA) were cocultured in monolayer and in pellets. The monocultures of each cell type were also used as controls. Morphological and histologic analysis, immunofluorescence staining, reverse transcription-polymerase chain reaction, and enzyme-linked immunosorbent assay were performed to characterize the chondrogenic differentiation of cocultures. Furthermore, the effects of chitosan/hyaluronic acid (CS/HA) nanoparticle exposure on the chondrogenesis of cocultures were examined. RESULTS: In both monolayer and pellet coculture, the hypertrophy of MSCs and the inflammatory activities of ACs were inhibited, although the chondrogenic production in coculture was not promoted compared with that in monoculture. In addition, the exposure of CS/HA nanoparticles to pellet coculture improved the production of type II collagen and aggrecan. CONCLUSIONS: We demonstrate for the first time that pellet coculture of ACs and IPFP MSCs with CS/HA nanoparticles could promote chondrogenic outcome while preventing the inflammatory status of ACs and the hypertrophic differentiation of MSCs. These findings suggest that the combination of ACs, IPFP MSCs, and CS/HA might be useful in cartilage repair in knee OA. PMID- 29141684 TI - Bioinformatics prediction of miR-30a targets and its inhibition of cell proliferation of osteosarcoma by up-regulating the expression of PTEN. AB - BACKGROUND: MiRNAs are frequently abnormally expressed in the progression of human osteosarcoma. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is one of the tumor suppressors in various types of human cancer. In the present study, we detected how hsa-miR-30a-3p regulated PTEN and further tested the role of hsa-miR-30a-3p in the cell proliferation of osteosarcoma cells. METHODS: The levels of miR-30a were determined by real time PCR. The expression of PTEN was tested by western blotting analysis. Cell distribution of PTEN was observed with confocal laser scanning microscope. Cell viability was determined by MTT assay. RESULTS: The expression of miR-30a and PTEN was obviously decreased in MG-63, 143B and Saos-2 cells compared with primary osteoblasts. TargetScan analysis data showed miR-30a might bind with position 30-57 of 3'UTR of PTEN. Transfection with miR-30a-3p increased the level of PTEN in MG-63 cells, while transfection with miR-30a-3p inhibitor significantly decreased the expression of PTEN in osteosarcoma cells. Transfection with miR-30a-3p significantly inhibited cell proliferation of osteosarcoma cells, while miR-30a inhibitor obviously promoted cell viability of MG63 cells and Saos-2 cells. Inhibition of PTEN eliminated the proliferation inhibitory effect of miR-30a-3p. CONCLUSION: Thus, all these findings revealed the anti-tumor effects of miR-30a in human osteosarcoma cells, which could be mediated by regulating the level of PTEN. PMID- 29141685 TI - Correction to: Towards a balanced view of the bacterial tree of life. AB - CORRECTION: Following publication of the original article [1], the authors pointed out that the figure shown as figure S1 is actually figure S2 and vice versa. Figure S1 should show the barcharts, and figure S2 should shows the heatmaps. Figures captions are in the correct order. 1) "...SILVA-only OTUs (37,066 97% OTUs and 1266 85% clusters) (Additional file 3: Figure S2 )..." - > ...SILVA-only OTUs (37,066 97% OTUs and 1266 85% clusters) (Additional file 3: Figure S1 )..." 2) "...in groundwater and soil (Fig. 2, Additional file 2: Figure S1 )." - > "in groundwater and soil (Fig. 2, Additional file 2: Figure S2 )." 3) "...from genomes as training data (Additional file 3: Figure S2 , ..." - > "...from genomes as training data (Additional file 3: Figure S1 , ..." 4) "...were predicted to be chimeric (Additional file 3: Figure S2 )" - > "...were predicted to be chimeric (Additional file 3: Figure S1 )". PMID- 29141686 TI - Anisotropic Muller glial scaffolding supports a multiplex lattice mosaic of photoreceptors in zebrafish retina. AB - BACKGROUND: The multiplex, lattice mosaic of cone photoreceptors in the adult fish retina is a compelling example of a highly ordered epithelial cell pattern, with single cell width rows and columns of cones and precisely defined neighbor relationships among different cone types. Cellular mechanisms patterning this multiplex mosaic are not understood. Physical models can provide new insights into fundamental mechanisms of biological patterning. In earlier work, we developed a mathematical model of photoreceptor cell packing in the zebrafish retina, which predicted that anisotropic mechanical tension in the retinal epithelium orients planar polarized adhesive interfaces to align the columns as cone photoreceptors are generated at the retinal margin during post-embryonic growth. METHODS: With cell-specific fluorescent reporters and in vivo imaging of the growing retinal margin in transparent juvenile zebrafish we provide the first view of how cell packing, spatial arrangement, and cell identity are coordinated to build the lattice mosaic. With targeted laser ablation we probed the tissue mechanics of the retinal epithelium. RESULTS: Within the lattice mosaic, planar polarized Crumbs adhesion proteins pack cones into a single cell width column; between columns, N-cadherin-mediated adherens junctions stabilize Muller glial apical processes. The concentration of activated pMyosin II at these punctate adherens junctions suggests that these glial bands are under tension, forming a physical barrier between cone columns and contributing to mechanical stress anisotropies in the epithelial sheet. Unexpectedly, we discovered that the appearance of such parallel bands of Muller glial apical processes precedes the packing of cones into single cell width columns, hinting at a possible role for glia in the initial organization of the lattice mosaic. Targeted laser ablation of Muller glia directly demonstrates that these glial processes support anisotropic mechanical tension in the planar dimension of the retinal epithelium. CONCLUSIONS: These findings uncovered a novel structural feature of Muller glia associated with alignment of photoreceptors into a lattice mosaic in the zebrafish retina. This is the first demonstration, to our knowledge, of planar, anisotropic mechanical forces mediated by glial cells. PMID- 29141687 TI - Autologous adipose-derived regenerative cell therapy modulates development of hypertrophic scarring in a red Duroc porcine model. AB - BACKGROUND: Effective prevention and treatment of hypertrophic scars (HTSs), a common consequence of deep-partial thickness injury, remain a significant clinical challenge. Previous studies from our group have shown that autologous adipose-derived regenerative cells (ADRCs) represent a promising approach to improve wound healing and, thereby, impact HTS development. The purpose of this study was to assess the influence of local delivery of ADRCs immediately following deep-partial thickness cutaneous injury on HTS development in the red Duroc (RD) porcine model. METHODS: Bilateral pairs of deep-partial thickness excisional wounds (2 mm depth; 58 cm2 area) were created using an electric dermatome on RD pigs (n = 12). Autologous ADRCs were isolated from the inguinal fat pad and then sprayed directly onto the wound at a dose of 0.25 * 106 viable cells/cm2. The paired contralateral wound received vehicle control. Wound healing and development of HTS were assessed over 6 months using digital imaging, quantitative measurement of skin hardness and pigmentation, and histology. RESULTS: Data showed that ADRC treatment led to reduced scar hyperpigmentation compared to control (p < 0.05). Using the Durometer, at 2 and 6 months post injury, skin hardness was 10-20% lower in ADRCs-treated wounds compared to control vehicle (p < 0.05). A similar trend was observed with the skin fibrometer. ADRC treatment promoted more normal collagen organization, improvement in the number of rete ridges (p < 0.01), longer elastic fiber length (p < 0.01), and reduced hypervascularity (blood vessel density; p < 0.05). ADRC treatment was associated with modulation of IL-6 expression within the wound/scar with upregulation 2 weeks after injury (wound healing phase) and downregulation at 2 months (early scarring phase) post-treatment compared to control CONCLUSIONS: These findings support the potential therapeutic value of autologous ADRC administration for reduction of HTS development following deep-partial cutaneous injury. PMID- 29141688 TI - Chinese Registry of rheumatoid arthritis (CREDIT): II. prevalence and risk factors of major comorbidities in Chinese patients with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis patients are at higher risk of developing comorbidities. The main objective of this study was to evaluate the prevalence of major comorbidities in Chinese rheumatoid arthritis patients. We also aimed to identify factors associated with these comorbidities. METHODS: Baseline demographic, clinical characteristics and comorbidity data from RA patients enrolled in the Chinese Registry of rhEumatoiD arthrITis (CREDIT) from Nov 2016 to August 2017 were presented and compared with those from five other registries across the world. Possible factors related to three major comorbidities (cardiovascular disease, fragility fracture and malignancy) were identified using multivariate logistic regression analyses. RESULTS: A total of 13,210 RA patients were included (80.6% female, mean age 52.9 years and median RA duration 4.0 years). Baseline prevalence rates of major comorbidities were calculated: CVD, 2.2% (95% CI 2.0-2.5%); fragility fracture, 1.7% (95% CI 1.5-1.9%); malignancy, 0.6% (95% CI 0.5-0.7%); overall major comorbidities, 4.2% (95% CI 3.9-4.6%). Advanced age was associated with all comorbidities. Male gender and disease duration were positively related to CVD. Female sex and longer disease duration were potential risk factors for fragility fractures. Ever use of methotrexate (MTX) was negatively related to baseline comorbidities. CONCLUSIONS: Patients with rheumatoid arthritis in China have similar prevalence of comorbidities with other Asian countries. Advanced age and long disease duration are possible risk factors for comorbidities. On the contrary, MTX may protect RA patients from several major comorbidities, supporting its central role in the management of rheumatoid arthritis. PMID- 29141689 TI - Patient-derived xenograft in zebrafish embryos: a new platform for translational research in gastric cancer. AB - BACKGROUND: Gastric cancer (GC) is among the most commonly cancer occurred in Asian, especially in China. With its high heterogeneity and few of validated drug targets, GC remains to be one of the most under explored areas of precision medicine. In this study, we aimed to establish an in vivo patient-derived xenograft (PDX) model based on zebrafish (Danio rerio) embryos, allowing for a rapid analysis of the angiogenic and invasive potentials, as well as a fast drug sensitivity testing. METHODS: Two human gastric cancer cell lines (AGS and SGC 7901) were xenografted into zebrafish embryos, their sensitivity to 5-FU were tested both in vitro and in vivo. Fourteen human primary cells from gastric cancer tissue were xenografted into zebrafish embryos, their proliferating, angiogenic and metastatic activities were evaluated in vivo. Sensitivity to 5-FU, docetaxel, and apatinib were also tested on primary samples from four patients. RESULTS: SGC-7901 showed higher sensitivity to 5-FU than AGS both in vitro (6.3 +/- 0.9 MUM vs.10.5 +/- 1.8 MUM) and in vivo. Nine out of fourteen patient samples were successfully transplanted in zebrafish embryos and all showed proliferating, angiogenic and metastatic potentials in the living embryos. Four cases showed varied sensitivity to the selected three chemotherapeutic drugs. CONCLUSIONS: Our zebrafish PDX (zPDX) model is a preclinically reliable in vivo model for GC. The zPDX model is also a promising platform for the translational research and personalized treatment on GC. PMID- 29141690 TI - Resternotomy does not adversely affect outcome after left ventricular assist device implantation. AB - BACKGROUND: Resternotomy in cardiac surgery is considered a risk factor for postoperative complications. Previous studies have demonstrated an ambiguous relationship between resternotomy and clinical outcomes. Registry data from a mixed population of durable circulatory support devices suggest that history of cardiac surgery is a risk factor for mortality. Our study investigates the prognostic significance of resternotomy in a homogenous cohort of left ventricular assist device (LVAD) recipients. METHODS: The study included adult patients receiving a continuous-flow LVAD at our institution during the period 2010-2016. Postoperative adverse events and length of stay were analyzed. Survival was assessed at 6 months and by the end of the study. Multivariate risk factor analysis was conducted for independent predictors of death. RESULTS: One hundred twelve patients, who received an intrapericardial LVAD (HVAD, HeartWare), were included in our analysis. Twenty-four patients (21.4%) had a history of previous sternotomy. These patients were older and non-eligible for bridging, and had more frequently coronary heart disease. Univariate analysis demonstrated no differences in the observed complications postoperatively. Survival was similar among groups. Destination therapy was the only predictor of mortality in our analysis (p = 0.02). CONCLUSIONS: Resternotomy was not associated with worse outcomes after LVAD implantation in our cohort. PMID- 29141691 TI - Involvement of aberrantly activated HOTAIR/EZH2/miR-193a feedback loop in progression of prostate cancer. AB - BACKGROUND: Though androgen deprivation therapy is the standard treatment for prostate cancer (PCa), most patients would inevitably progress to castration resistant prostate cancer (CRPC) which is the main cause of PCa death. Therefore, the identification of novel molecular mechanism regulating cancer progression and achievement of new insight into target therapy would be necessary for improving the benefits of PCa patients. This study aims to study the function and regulatory mechanism of HOTAIR/EZH2/miR-193a feedback loop in PCa progression. METHODS: MSKCC and TCGA datasets were used to identify miR-193a expression profile in PCa. Cell Counting Kit-8 (CCK-8) assays, colony formation, invasion, migration, flow cytometry, a xenograft model and Gene Set Enrichment Analysis were used to detect and analyze the biological function of miR-193a. Then, we assessed the role of HOTAIR and EZH2 in regulation of miR-193a expression by using plasmid, lentivirus and small interfering RNA (siRNA). Luciferase reporter assays and chromatin immunoprecipitation assays were performed to detect the transcriptional activation of miR-193a by EZH2 and HOTAIR. Further, qRT-PCR and luciferase reporter assays were conducted to examine the regulatory role of miR 193a controlling the HOTAIR expression in PCa. Finally, the correlation between HOTAIR, EZH2 and miR-193a expression were analyzed using In situ hybridization and immunohistochemistry. RESULTS: We found that miR-193a was significantly downregulated in metastatic PCa through mining MSKCC and TCGA datasets. In vitro studies revealed that miR-193a inhibited PCa cell growth, suppressed migration and invasion, and promoted apoptosis; in vivo results demonstrated that overexpression of miR-193a mediated by lentivirus dramatically reduced PCa xenograft tumor growth. Importantly, we found EZH2 coupled with HOTAIR to repress miR-193a expression through trimethylation of H3K27 at miR-193a promoter in PC3 and DU145 cells. Interestingly, further evidence illustrated that miR-193a directly targets HOTAIR showing as significantly reduced HOTAIR level in miR-193a overexpressed cells and tissues. The expression level of miR-193a was inversely associated with that of HOTAIR and EZH2 in PCa. CONCLUSION: This study firstly demonstrated that miR-193a acted as tumor suppressor in CRPC and the autoregulatory feedback loop of HOTAIR/EZH2/miR-193a served an important mechanism in PCa development. Targeting this aberrantly activated feedback loop may provide a potential therapeutic strategy. PMID- 29141693 TI - Glycemic control and associated factors among type 2 diabetic patients at Shanan Gibe Hospital, Southwest Ethiopia. AB - OBJECTIVE: The aim of this study was to assess the rate of glycemic control and factors affecting glycemic control in type 2 diabetic patients. RESULTS: A total of 174 type 2 diabetic patients were interviewed and were studied. Mean age of the patients was 48.98 +/- 14.96 years (range 18-80 years). More than half (51.7%) of the patients were males. About a third of patients, 53 (30.5%), were on antidiabetic medications for less than 5 years. The most common prescribed antidiabetic medications were insulin, 48 (27.6%), and metformin 15 (8.6%). One hundred seven (61.5%) patients were on combination therapy (two drug treatment) and the remaining patients were on monotherapy. The majority, 103 (59.2%), of patients had uncontrolled blood glucose. A larger proportion of female patients, 54 (52.4%), had uncontrolled blood glucose than males. Level of education (p < 0.001) and duration of diabetes treatment (p < 0.001) were significantly associated with glycemic control. Adherence of patients to regular follow up (Adjusted Odds Ratio (AOR) = 2.42, 95% CI 1.08-5.44, p = 0.03) and diabetes treatment for 5-10 years (AOR = 4.64, 95% CI 1.79-12.06, p = 0.002) are found to be independent predictors of glycemic control among type 2 diabetes patients. PMID- 29141692 TI - The marketing plan and outcome indicators for recruiting and retaining parents in the HomeStyles randomized controlled trial. AB - BACKGROUND: Despite the critical importance of successful recruitment and retention to study integrity, reporting of recruitment and retention strategies along with factors associated with successful recruitment and retention of participants in health-related interventions remain rare, especially for health and obesity prevention programs. Thus, the purpose of this article is to retrospectively examine the recruitment and retention marketing plan used in the online HomeStyles randomized controlled trial (RCT) and discuss outcomes associated with completion of the intervention. METHODS: The HomeStyles RCT is an online intervention developed to motivate parents of young children to gain the skills and self-confidence needed to shape home environments and lifestyles to be protective against childhood obesity. Using the seven Ps of services marketing (i.e., people, place, product, physical evidence, price, promotion, and process), a comprehensive and systematic plan for recruitment and retention was implemented and outcomes assessed. RESULTS: A total of 489 parents with a young child aged 2 to < 6 years were eligible to participate, a final capture rate of 33%. Only 23% of Hispanic participants chose to use the Spanish-language version of HomeStyles intervention materials, below the demand anticipated. However, Hispanic enrollment overall was substantially higher than the U.S. population proportion (i.e., 17%). The number of participants prematurely leaving the study was similar in both treatment groups, indicating attrition was not differential. Completers reported high satisfaction of HomeStyles, using a 1-5 scale (strongly disagree to strongly agree) on guide attractiveness, interestingness, and usefulness. Despite all the retention efforts, the average monthly recruitment accrual rate of ~ 33 eligible enrolled participants at baseline (i.e., 489 participants/15-month recruitment period), declined to ~ 18, 11, 9, and 8 remaining recruited participants/month at midpoint, post, follow-up, and long-term follow-up surveys, respectively. In general, survey completers were significantly more likely to be female and perceived their child's health status to be better, and they were significantly less likely to be restrictive of their child's food intake. CONCLUSIONS: The findings of the present study highlight the need for far reaching, concentrated, and varied recruitment strategies; sufficient time in the research plan for recruitment and retention activities; and creative, tireless, flexible, persistent project staff for health-related interventions. PMID- 29141695 TI - Methylxanthines induce structural and functional alterations of the cardiac system in zebrafish embryos. AB - BACKGROUND: Zebrafish embryos are emerging as a model for pharmacological and toxicological studies. We used zebrafish embryos to study the general toxicity and cardiovascular effects of eight methylxanthines: aminophylline, caffeine, diprophylline, doxofylline, etophylline, 3-isobutyl-1-methylxanthine (IBMX), pentoxifylline and theophylline. METHODS: Microinjections of the eight methylxanthines were performed in 1-2 cell stage zebrafish embryos and the general toxicity and cardiovascular effects were analyzed at different time points. Embryotoxicity and teratogenicity were evaluated to understand the general toxicity of these compounds. Structural and functional alterations of the heart were evaluated to assess the cardiovascular effects. RESULTS: Our results showed different activity patterns of the methylxanthines drugs. Caffeine, IBMX, pentoxifylline and theophylline were highly embryotoxic and teratogenic; aminophylline, doxofylline and etophylline were embryotoxic and teratogenic only at higher doses, and diprophylline showed a minimal (<10%) embryotoxicity and teratogenicity. Most of these drugs induced structural alteration of the heart in 20-40% of the injected embryos with the maximum dose. This structural alteration was fatal with the embryos ultimately dying within 120 hpf. All the drugs induced a transient increase in heart rate at 48 hpf which returned to baseline within 96 hpf. This functional effect of methylxanthines showed similarity to the studies done in humans and other vertebrates. CONCLUSION: Our results indicate the potential toxicity and teratogenicity of different methylxanthines in the embryos during embryonic development, the most sensitive period of life. Although interspecies differences need to be considered before drawing any conclusion, our study elucidated that a single exposure of methylxanthines at therapeutic range could induce cardiac dysfunction besides causing embryotoxicity and teratogenicity. Of all the drugs, diprophylline appeared to be safer, with lower degree of embryotoxicity, teratogenicity and cardiac toxicity as compared to other methylxanthines. PMID- 29141697 TI - Microarray expression profile of lncRNAs and mRNAs in the placenta of non diabetic macrosomia. AB - Macrosomia, not only is closely associated with short-term, birth-related problems, but also has long-term consequences for the offspring. We investigated the expression of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in the placenta of macrosomia births using a microarray profile. The data showed that 2929 lncRNAs and 4574 mRNAs were upregulated in the placenta of macrosomia births compared with the normal birth weight group (fold change ?2.0, P<0.05), and 2127 lncRNAs and 2511 mRNAs were downregulated (fold change ?2.0, P<0.05). To detect the function of the differentially expressed lncRNAs and their possible relationship with the differentially expressed mRNAs, we also performed gene ontology analysis and pathway analysis. The results demonstrated that the PI3K AKT signalling pathway, the mitogen-activated protein kinase (MAPK) signalling pathway, the focal adhesion pathway, the B cell receptor signalling pathway, and the protein processing in endoplasmic reticulum and lysosome pathway were significantly differentially expressed in the macrosomia placenta. Four lncRNAs were randomly chosen from the differentially expressed lncRNAs to validate the microarray data by quantitative polymerase chain reaction (qPCR). The qPCR results were consistent with the microarray data. In conclusion, lncRNAs were significantly differentially expressed in the placenta of macrosomia patients, and may contribute to the pathogenesis of macrosomia. PMID- 29141696 TI - Use of a trigger tool to detect adverse drug reactions in an emergency department. AB - BACKGROUND: Although there are systems for reporting adverse drug reactions (ADR), these safety events remain under reported. The low-cost, low-tech trigger tool method is based on the detection of events through clues, and it seems to increase the detection of adverse events compared to traditional methodologies. This study seeks to estimate the prevalence of adverse reactions to drugs in patients seeking care in the emergency department. METHODS: Retrospective study from January to December, 2014, applying the Institute for Healthcare Improvement (IHI) trigger tool methodology for patients treated at the emergency room of a tertiary care hospital. RESULTS: The estimated prevalence of adverse reactions in patients presenting to the emergency department was 2.3% [CI95 1.3% to 3.3%]; 28.6% of cases required hospitalization at an average cost of US$ 5698.44. The most common triggers were hydrocortisone (57% of the cases), diphenhydramine (14%) and fexofenadine (14%). Anti-infectives (19%), cardiovascular agents (14%), and musculoskeletal drugs (14%) were the most common causes of adverse reactions. According to the Naranjo Scale, 71% were classified as possible and 29% as probable. There was no association between adverse reactions and age and sex in the present study. CONCLUSIONS: The use of the trigger tool to identify adverse reactions in the emergency department was possible to identify a prevalence of 2.3%. It showed to be a viable method that can provide a better understanding of adverse drug reactions in this patient population. PMID- 29141698 TI - Disfluencies signal reference to novel objects for adults but not children. AB - Speech disfluencies can guide the ways in which listeners interpret spoken language. Here, we examined whether three-year-olds, five-year-olds, and adults use filled pauses to anticipate that a speaker is likely to refer to a novel object. Across three experiments, participants were presented with pairs of novel and familiar objects and heard a speaker refer to one of the objects using a fluent ("Look at the ball/lep!") or disfluent ("Look at thee uh ball/lep!") expression. The salience of the speaker's unfamiliarity with the novel referents, and the way in which the speaker referred to the novel referents (i.e., a noun vs. a description) varied across experiments. Three- and five-year-olds successfully identified familiar and novel targets, but only adults' looking patterns reflected increased looks to novel objects in the presence of a disfluency. Together, these findings demonstrate that adults, but not young children, use filled pauses to anticipate reference to novel objects. PMID- 29141694 TI - The ICU-Diary study: prospective, multicenter comparative study of the impact of an ICU diary on the wellbeing of patients and families in French ICUs. AB - BACKGROUND: Post-intensive care syndrome includes the multiple consequences of an intensive care unit (ICU) stay for patients and families. It has become a new challenge for intensivists. Prevention programs have been disappointing, except for ICU diaries, which report the patient's story in the ICU. However, the effectiveness of ICU diaries for patients and families is still controversial, as the interpretation of the results of previous studies was open to criticism hampering an expanded use of the diary. The primary objective of the study is to evaluate the post-traumatic stress syndrome in patients. The secondary objectives are to evaluate the post-traumatic stress syndrome in families, anxiety and depression symptoms in patients and families, and the recollected memories of patients. Endpoints will be evaluated 3 months after ICU discharge or death. METHODS: A prospective, multicenter, randomized, assessor-blind comparative study of the effect of an ICU diary on patients and families. We will compare two groups: one group with an ICU diary written by staff and family and given to the patient at ICU discharge or to the family in case of death, and a control group without any ICU diary. Each of the 35 participating centers will include 20 patients having at least one family member who will likely visit the patient during their ICU stay. Patients must be ventilated within 48 h after ICU admission and not have any previous chronic neurologic or acute condition responsible for cognitive impairments that would hamper their participation in a phone interview. Three months after ICU discharge or death of the patient, a psychologist will contact the patient and family by phone. Post-traumatic stress syndrome will be evaluated using the Impact of Events Scale-Revised questionnaire, anxiety and depression symptoms using the Hospital Anxiety and Depression Scale questionnaire, both in patients and families, and memory recollection using the ICU Memory Tool Questionnaire in patients. The content of a randomized sample of diaries of each center will be analyzed using a grid. An interview of the patients in the intervention arm will be conducted 6 months after ICU discharge to analyze in depth how they use the diary. DISCUSSION: This study will provide new insights on the impact of ICU diaries on post-traumatic stress disorders in patients and families after an ICU stay. TRIAL REGISTRATION: ClinicalTrial.gov, ID: NCT02519725 . Registered on 13 July 2015. PMID- 29141699 TI - The Chimes of Freedom: Bob Dylan, Epigrammatic Validity, and Alternative Facts. AB - This essay brings together work I have done over the past 10 years: on the nature of ethics, on the purpose of ethics, and on its foundations in a way that, I hope, as E.M. Forster put it, connects "the prose and the passion." I deploy lessons learned in this process to identify and face what I believe to be crucial challenges to science and to freedom (as defended by, among others, Cicero, Pete Seeger, Bob Dylan, Thomas Hobbes, John Stuart Mill, and Bertrand Russell). Finally I consider threats to freedom of a different sort, posed by the creation and dissemination of "alternative facts" and by what is sometimes called "super" or "full" artificial intelligence (AI). PMID- 29141700 TI - Can a customer relationship management program improve recruitment for primary care research studies? AB - BACKGROUND: Recruiting family physicians into primary care research studies requires researchers to continually manage information coming in, going out, and coming in again. In many research groups, Microsoft Excel and Access are the usual data management tools, but they are very basic and do not support any automation, linking, or reminder systems to manage and integrate recruitment information and processes. OBJECTIVE: We explored whether a commercial customer relationship management (CRM) software program - designed for sales people in businesses to improve customer relations and communications - could be used to make the research recruitment system faster, more effective, and more efficient. FINDINGS: We found that while there was potential for long-term studies, it simply did not adapt effectively enough for our shorter study and recruitment budget. The amount of training required to master the software and our need for ongoing flexible and timely support were greater than the benefit of using CRM software for our study. PMID- 29141701 TI - The roles of word-form frequency and phonological neighbourhood density in the acquisition of Lithuanian noun morphology. AB - Four- and five-year-old children took part in an elicited familiar and novel Lithuanian noun production task to test predictions of input-based accounts of the acquisition of inflectional morphology. Two major findings emerged. First, as predicted by input-based accounts, correct production rates were correlated with the input frequency of the target form, and with the phonological neighbourhood density of the noun. Second, the error patterns were not compatible with the systematic substitution of target forms by either (a) the most frequent form of that noun or (b) a single morphosyntactic default form, as might be predicted by naive versions of a constructivist and generativist account, respectively. Rather, most errors reflected near-miss substitutions of singular for plural, masculine for feminine, or nominative/accusative for a less frequent case. Together, these findings provide support for an input-based approach to morphological acquisition, but are not adequately explained by any single account in its current form. PMID- 29141702 TI - Antibiotic Awareness Week and Hospital Antimicrobial Use Point Prevalence Study. PMID- 29141703 TI - Pilot of an Elementary School Cough Etiquette Intervention: Acceptability, Feasibility, and Potential for Sustainability. AB - Schools convene many people together for a prolonged time, facilitating spread of respiratory pathogens and amplifying epidemics. Crowded Bangladeshi schools lack the infrastructure to support optimal cough etiquette behaviors. We collected formative data on current practices from four elementary schools, and developed and piloted a low-cost cough etiquette intervention, promoting coughing and sneezing into upper sleeves at four additional schools. We trained teachers to lead behavior change sessions during regular hygiene classes for 4 weeks. We evaluated intervention acceptability, feasibility, and potential for sustainability at 1 month and at 14 months after the intervention commenced. At baseline, among 63 observed students, 58 (92%) coughed/sneezed into open air, five (8%) covered coughs/sneezes with their hands, which were not subsequently washed with soap and water as they judged this infeasible. After 4 weeks, among 70 observed students, 27 (39%) coughed/sneezed into upper sleeves, 33 (47%) into open air, and 10 (12%) covered with hands. After 14 months, among 230 observed students, 13 (6%) used upper sleeves, 154 (67%) coughed/sneezed into open air, and 59 (26%) covered with hands. Students reported that coughing/sneezing into upper sleeves was simple and protected them and their classmates from germs. This school-based intervention was acceptable and feasible, and resulted in short-term reductions in coughing/sneezing into open air, but these habits of comparatively new behavior were not sustained as teachers ceased behavior change session delivery. Strategies to support longer-term adoption of habits should be considered. PMID- 29141704 TI - Human Competence to Transmit Leishmania infantum to Lutzomyia longipalpis and the Influence of Human Immunodeficiency Virus Infection. AB - Visceral leishmaniasis (VL) caused by Leishmania infantum is a lethal disease transmitted by sand flies. Although, considered a zoonosis with dogs held as the main reservoirs, humans are also sources of infection. Therefore, control policies currently focused on dog culling may need to consider that VL and human immunodeficiency virus (HIV)/VL patients may also be infectious, contributing to transmission. Reservoir competence of patients with VL without and with HIV infection and of persons asymptomatically infected with Leishmania was assessed by xenodiagnosis with the vector Lutzomyia longipalpis. Parasites in sand fly's guts were identified by using optical microscopy and by conventional polymerase chain reaction (PCR). Leishmania infantum blood parasite burden was determined by quantitative PCR. Among the 61 participants, 27 (44%) infected sand flies as seen by microscopy or PCR. When infectiousness was assessed by microscopy, xenodiagnosis was positive in five (25%) patients not infected with HIV, whereas nine (45%) of those harboring HIV were positive. Among the 19 asymptomatic patients four (21%) infected sand flies only demonstrated by PCR. One (50%) asymptomatic patient with HIV had a positive xenodiagnosis by microscopy. 9/372 (2.4%) and 37/398 (9.2%) sand flies were infected when feeding in patients without and with HIV, respectively. Infectiousness was poorly correlated with quantitative PCR. The study shows that asymptomatic humans are capable of transmitting L. infantum, that ill persons with HIV infection are more infectious to sand flies, and that humans are more important reservoirs than previously thought. This fact may be considered when designing control policies for zoonotic VL. PMID- 29141705 TI - Phenotypic and Molecular Genetic Characteristics of Yersinia pestis at an Emerging Natural Plague Focus, Junggar Basin, China. AB - The 15th natural plague focus in China, the Junggar Basin plague focus, is located near an important communication route connecting China and Central Asia and was discovered after 2005. To characterize the phenotypic and genetic diversity of the Yersinia pestis population in this newly established focus, we collected 25 Y. pestis strains from six counties across Junggar Basin in 2005 2006, and determined their biochemical features and genotypes based on multiple locus variable number of tandem repeats analysis and clustered regularly interspaced short palindromic repeats analysis. We inferred the phylogenetic positions and possible sources of the Junggar strains by comparing their genotypes with the genetic diversity for known representative Y. pestis strains. Our results indicate that the major genotype of Junggar strains belongs to 2.MED1, a lineage of biovar Medievalis with identical biochemical characters and high virulence in mice. Although share a similar ecology, the 2.MED1 in Junggar Basin are not descended from known strains in the neighboring Central Asian Desert plague foci. Therefore, the emergence of the Junggar Basin plague focus is not attributable to the recent clonal spread of Y. pestis from Central Asia. We also identified two distinct minor genotypes in Junggar Basin, one of which clusters genetically with the 0.ANT1 strains of the Tianshan Mountain natural plague focus and another belongs to a 1.IN lineage not previously reported. Our study clarifies the phenotypic and genetic characters of Junggar Y. pestis strains. These findings extend our knowledge of the population diversity of Y. pestis and will facilitate future plague surveillance and prevention in Junggar Basin and adjacent regions. PMID- 29141706 TI - Application of Orbitrap Mass Spectrometry in Food Analysis. PMID- 29141708 TI - Sensitive Detection of Neonicotinoid Insecticides and Other Selected Pesticides in Pollen and Nectar Using Nanoflow Liquid Chromatography Orbitrap Tandem Mass Spectrometry. AB - In this work, a new method based on nanoflow LC with high-resolution MS was developed for the determination of eight pesticides in pollen and nectar samples, including neonicotinoid insecticides and other selected pesticides commonly found in bees and beeswax. Detection was undertaken with a hybrid quadrupole-Orbitrap mass spectrometer (Q ExactiveTM) equipped with a commercial nanospray ion source. The extraction of pesticides from pollen samples was performed by a modified micro-QuEChERS method scaled down to Eppendorf tubes, whereas nectar samples were simply diluted with a water-methanol (95 + 5, v/v) solution. Good linearity (>0.999 in all cases) was obtained between 0.05 and 500 ug/kg and between 0.04 and 400 ug/kg for pollen and nectar, respectively. Recovery rates in pollen ranged from 85 to 97%, with RSDs <12%. Matrix effect was evaluated and showed negligible effects for all studied pesticides. The lowest concentration levels tested and validated were 0.5 and 0.4 ug/kg for pollen and nectar matrixes, respectively. In addition, selected incurred samples were studied, obtaining several positive findings in pollen and nectar samples, demonstrating the sensitivity and applicability of the proposed method. PMID- 29141707 TI - Importance and Contribution of Community, Social, and Healthcare Risk Factors for Hepatitis C Infection in Pakistan. AB - Pakistan has a high prevalence of hepatitis C virus (HCV) infection, estimated at 4.9% (2,290/46,843) in the 2007 national HCV seroprevalence survey. We used data from this survey to assess the importance of risk factor associations with HCV prevalence in Pakistan. Exposures were grouped as community (going to the barbers, sharing smoking equipment, having an ear/nose piercing, tattoo, or acupuncture), healthcare (ever having hemodialysis, blood transfusion, or >= 5 injections in the last year), demographic (marital status and age), and socio economic (illiterate or laborer). We used mutually adjusted multivariable regression analysis, stratified by sex, to determine associations with HCV infection, their population attributable fraction, and how risk of infection accumulates with multiple exposures. Strength of associations was assessed using adjusted odds ratios (aOR). Community [aOR females 1.5 (95% confidence interval [CI]: 1.2, 1.8); males 1.2 (1.1, 1.4)] and healthcare [females 1.4 (1.2, 1.6); males 1.2 (1.1, 1.4)] exposures, low socio-economic status [females 1.6 (1.3, 1.80); males 1.3 (1.2, 1.5)], and marriage [females 1.5 (1.2, 1.9); males 1.4 (1.1, 1.8)] were associated with increased HCV infection. Among married women, the number of children was associated with an increase in HCV infection; linear trend aOR per child 1.06 (1.01, 1.11). Fewer infections could be attributed to healthcare exposures (females 13%; males 6%) than to community exposures (females 25%; males 9%). Prevalence increased from 3% to 10% when cumulative exposures increased from 1 to >= 4 [aOR per additional exposure for females 1.5 (1.4, 1.6); males 1.2 (1.2, 1.3)]. A combination of community, healthcare, and other factors appear to drive the Pakistan HCV epidemic, highlighting the need for a comprehensive array of prevention strategies. PMID- 29141710 TI - Pesticide Residue Analysis in Fruit- and Vegetable-Based Baby Foods Using GC Orbitrap MS. AB - This paper presents an efficiency evaluation of GC coupled with quadrupole Orbitrap MS for identification and quantitation in the multiresidue pesticide analysis of baby foods in full-scan mode. The identification criteria were studied following SANTE guidelines (retention time, mass accuracy, and ion ratio), comfortably complying with the values established, even at 0.003 mg/kg. Method validation was carried out on 15 selected GC-amenable pesticides covered by Commission Directive No. 2006/125/EC in three different baby food matrixes. Recovery studies were performed at 0.003 and 0.006 mg/kg, with 96% of the cases falling within the 70-120% range and with RSDs <15% for all the pesticides assayed. Linearity over 3 orders of magnitude was verified, with residuals <16% and correlation coefficient values >0.995. In general, matrix effect values were >100%. The LOQ was 0.003 mg/kg for 97% of the cases. The validated method was applied to 20 real baby food samples from Spain and to the European Union Proficiency Test FV-BF01 sample, in which the z-scores obtained were <1, thus demonstrating that this instrumentation has good quantitation capabilities. PMID- 29141709 TI - Rapid Diagnostic Testing of Hospitalized Malawian Children Reveals Opportunities for Improved HIV Diagnosis and Treatment. AB - Recent World Health Organization (WHO) guidelines recommend antiretroviral therapy (ART) for all HIV-infected people; previously CD4+ T lymphocyte quantification (CD4 count) or clinical staging determined eligibility for children >= 5 years old in low- and middle-income countries. We examined positive predictive value (PPV) of a rapid diagnostic test (RDT) algorithm and ART eligibility for hospitalized children with newly diagnosed HIV infection. We enrolled 363 hospitalized Malawian children age 2 months to 16 years with two serial positive HIV RDT from 2013 to 2015. Children aged <= 18 months whose nucleic acid testing was negative or unavailable were later excluded from the analysis (N = 16). If RNA PCR was undetectable, human immunodeficiency virus (HIV) enzyme immunoassay (EIA) and western blot (WB) were performed. Those with negative or discordant EIA and WB were considered HIV negative and excluded from further analysis (N = 6). ART eligibility was assessed using age, CD4 count, and clinical HIV stage. Among 150 patients with HIV RNA PCR results, 15 had undetectable HIV RNA. Of those, EIA and WB were positive in nine patients and negative or discordant in six patients. PPV of serial RDT was 90% versus RNA PCR alone and 96% versus combined RNA PCR, EIA, and WB. Of all patients aged >= 5 years, 8.9% were ineligible for ART under previous WHO guidelines. Improved HIV testing algorithms are needed for accurate diagnosis of HIV infection in children as prevalence of pediatric HIV declines. Universal treatment will significantly increase the numbers of older children who qualify for ART. PMID- 29141711 TI - Application of Gas Chromatography Coupled to Quadrupole-Orbitrap Mass Spectrometry for Pesticide Residue Analysis in Cereals and Feed Ingredients. AB - A method for residue analysis of pesticides and polychlorinated biphenyls in cereals and feed ingredients based on QuEChERS extraction, programmed temperature vaporizer large-volume injection, and GC with electron ionization (EI) quadrupole Orbitrap full-scan high-resolution MS (60 000 full width at half-maximum at m/z 200) has been developed. In addition to full-scan acquisition, simultaneous full scan and selected-ion monitoring acquisition was used to improve detectability in incidental cases in which analytes coeluted with intense signals from coextractants. The method was successfully validated down to 10 ug/kg for a single commodity (wheat) using matrix-matched calibration, and for multiple-feed matrixes using standard addition. Identification according to European Union requirements was achieved in >90% of the analyte/matrix combinations, and suggestions for further increasing identification rates have been made. Performance characteristics were compared to an existing method for residue analysis based on GC with EI tandem MS (triple quadrupole). PMID- 29141712 TI - Clinical Outcomes during Treatment Interruptions in Human Immunodeficiency Virus Hepatitis B Virus Co-infected Patients from Sub-Saharan Africa. AB - Antiretroviral treatment (ART) interruptions increase the risk of severe morbidity/mortality in human immunodeficiency virus (HIV)-infected individuals from subSaharan Africa. We aimed to determine whether the risk is further increased among HIV-hepatitis B virus (HBV) co-infected patients in this setting. In this sub-analysis of a randomized-control trial, 632 participants from Cote d'Ivoire randomized to receive continuous-ART (C-ART), structured ART interruptions of 2-months off, 4-months on (2/4-ART), and CD4-guided ART interruptions (CD4GT, interruption at 350/mm3 and reintroduction at 250/mm3) were analyzed. Incidence rates (IR) of serious HIV- and non-HIV-related morbidity were compared between patients stratified on hepatitis B surface antigen (HBsAg) status. Overall, 65 (10.3%) were HBsAg-positive, 29 (44.6%) of whom had HBV-DNA levels > 10,000 copies/mL. After a median 2.0 year (range = 0.2-3.1) follow-up, >= 1 serious HIV-related events occurred in 101 HIV mono-infected and 15 HIV-HBV co-infected patients (IR = 10.0 versus 13.2/100 person/years, respectively, P = 0.3), whereas the highest incidence was observed in co-infected patients with baseline HBV-replication > 10,000 copies/mL (IR = 24.0/100 person/years, P versus HIV mono-infected = 0.002). Incidence of bacterial infections was also highest in the co-infected group with HBV-replication > 10,000 copies/mL (IR = 12.9 versus 3.3/100 person/years in HIV mono-infected patients, P = 0.001). The relative effect of CD4GT or 2/4-ART versus C-ART was not different between infection groups (P for interaction = 0.4). No increase in the incidence of non-HIV-related morbidity was observed for co-infected patients (P = 0.5), even at HBV replication levels > 10,000 copies/mL (P = 0.7). In conclusion, co-infected patients with elevated HBV-replication at ART-initiation are more susceptible to HIV-related morbidity, especially invasive bacterial diseases, during treatment interruption. PMID- 29141713 TI - Resource Use and Costs of Dengue: Analysis of Data from Phase III Efficacy Studies of a Tetravalent Dengue Vaccine. AB - A tetravalent dengue vaccine (CYD-TDV) has recently been approved in 12 countries in southeast Asia and Latin America for individuals aged 9-45 years or 9-60 years (age indication approvals vary by country) living in endemic areas. Data on utilization of medical and nonmedical resources as well as time lost from school and work were collected during the active phase of two phase III efficacy studies performed in 10 countries in the Asia-Pacific region and Latin America (NCT01373281; NCT01374516). We compared dengue-related resource utilization and costs among vaccinated and nonvaccinated participants. Country-specific unit costs were derived from available literature. There were 901 virologically confirmed dengue episodes among participants aged >= 9 years (N = 25,826): corresponding to 373 episodes in the CYD-TDV group (N = 17,230) and 528 episodes in the control group (N = 8,596). Fewer episodes in the CYD-TDV group resulted in hospitalization than in the control group (7.0% versus 13.3%; P = 0.002), but both had a similar average length of stay of 4 days. Overall, a two-thirds reduction in resource consumption and missed school/work days was observed in the CYD-TDV group relative to the control group. The estimated direct and indirect cost (2014 I$) associated with dengue episodes per participant in the CYD-TDV group was 73% lower than in the control group (I$6.72 versus I$25.08); representing a saving of I$I8.36 (95% confidence interval [CI]:17.05-19.78) per participant with vaccination. This is the first study providing information on dengue costs among vaccinated individuals and direct confirmation that vaccination has the potential to reduce dengue illness costs. PMID- 29141714 TI - Falciparum Malaria Outbreak in Sabah Linked to an Immigrant Rubber Tapper. AB - Sabah is a Malaysian state situated in the northern part of Borneo, and it is endemic for malaria. The incidence of malaria is the lowest (0.05/1,000 population) in Penampang districts of Sabah. In June 26, 2012, two Plasmodium falciparum malaria cases were notified to public health department from a village in Penampang. Immediate investigation was initiated to identify the risk factors and to institute control measures. We performed active case finding by asking household members of all houses in the village regarding malaria symptoms and by examining blood smears. Environmental investigation was performed by collecting samples to detect mosquito breeding sites and to identify malaria transmitting vector mosquitoes. A case-control study with a ratio of 1:4 (11 cases and 44 controls) was conducted using self-administered questionnaire. The microscopic examination of blood smear for malarial parasite and entomology sampling was carried out. The malarial attack rate was 2.3%, 6/11 smears have gametocyte, and the case fatality rate was 9.1%. One case was a migrant rubber tapper from Indonesia which happened to be the first case with gametocyte positive. Overall, the incidence of malaria was higher (6/11) among rubber tappers. The odds of cases for those living nearby stagnant water were 7.3 [95% confidence interval: 1.2-43.5] times higher. In conclusion, an outbreak of P. falciparum malaria was introduced into a malaria-free village by a migrant rubber tapper, by whom the imported parasite was introduced to the community via vector Anopheles balabacensis. Living near stagnant water bodies was the risk factor in this outbreak. PMID- 29141715 TI - Clinical Isolation of Anaplasma phagocytophilum in South Korea. AB - We report the first isolation of Anaplasma phagocytophilum in South Korea. A 61 year-old woman presented with a 6-day history of fever, headache, and myalgia. Initial investigation showed neutropenia and thrombocytopenia. We diagnosed human granulocytic anaplasmosis by microscopic examination and serologic testing. The patient recovered fully without antibiotic therapy. The isolate was obtained from the patient's blood by cell culture and mouse inoculation. Its identity was confirmed by an immunofluorescence assay, sequencing of the 16S rRNA gene, msp2 (p44), and ankA genes, and staining and electron microscopy of morulae of A. phagocytophilum in cultured human promyelocytic leukemia HL-60 cells. PMID- 29141716 TI - Hansen's Disease and Rheumatoid Arthritis Crossover of Clinical Symptoms: A Case Series of 18 Patients in the United States. AB - Hansen's Disease (HD) is a rare, chronic granulomatous infection of the skin and peripheral nerves caused by the noncultivable organism Mycobacterium leprae. Arthritis is the third most common symptom of HD. Subjects with both confirmed HD on skin biopsy and chronic arthritis were identified at the National Hansen's Disease Program (NHDP). We conducted a series of medical chart reviews and extracted and logged personally deidentified data into a database and carried out descriptive analyses. Eighteen of 261 subjects presented to the NDHP with both HD and chronic arthritis between 2001 and 2015. Among these, 16 were male, 16 were white, and 15 were residents of Louisiana. The median age at diagnosis of HD was 67 years. Ten of these subjects were diagnosed with borderline lepromatous leprosy, seven were diagnosed with lepromatous, and one was diagnosed with borderline tuberculoid leprosy. Patients were symptomatic with arthritis for a median of 5.3 years before HD diagnosis. Sixty-two percent of patients (11) were diagnosed with rheumatoid arthritis (RA) before HD diagnosis, and 10 of which were seronegative RA. Hands, feet, wrists, and elbows were most commonly reported as affected joints. Over half of the patients (61%) had completed HD multidrug therapy at the time of review, and 73% of these subjects had persistent joint pain requiring steroids or methotrexate for symptomatic control. Chronic arthritis in HD patients is present in a series of US-acquired cases of HD. Arthritis did not resolve with successful treatment of HD in most cases. PMID- 29141717 TI - Diagnostic Accuracy of Global Pharma Health Fund MinilabTM in Assessing Pharmacopoeial Quality of Antimicrobials. AB - Global Pharma Health Fund (GPHF) MinilabTM, a semi-quantitative thin-layer chromatography (TLC)-based commercially available test kit, is widely used in drug quality surveillance globally, but its diagnostic accuracy is unclear. We investigated the diagnostic accuracy of Minilab system for antimicrobials, using high-performance liquid chromatography (HPLC) as reference standard. Following the Minilab protocols and the Pharmacopoeia of the People's Republic of China protocols, Minilab-TLC and HPLC were used to test five common antimicrobials (506 batches) for relative concentration of active pharmaceutical ingredients. The prevalence of poor-quality antimicrobials determined, respectively, by Minilab TLC and HPLC was amoxicillin (0% versus 14.9%), azithromycin (0% versus 17.4%), cefuroxime axetil (14.3% versus 0%), levofloxacin (0% versus 3.0%), and metronidazole (0% versus 38.0%). The Minilab TLC had false-positive and false negative detection rates of 2.6% (13/506) and 15.2% (77/506) accordingly, resulting in the following test characteristics: sensitivity 0%, specificity 97.0%, positive predictive value 0, negative predictive value 0.8, positive likelihood ratio 0, negative likelihood ratio 1.0, diagnostic odds ratio 0, and adjusted diagnostic odds ratio 0.2. This study demonstrates unsatisfying diagnostic accuracy of Minilab system in screening poor-quality antimicrobials of common use. Using Minilab as a stand-alone system for monitoring drug quality should be reconsidered. PMID- 29141718 TI - Dengue Fever Surveillance in India Using Text Mining in Public Media. AB - Despite the improvement in health conditions across the world, communicable diseases remain among the leading mortality causes in many countries. Combating communicable diseases depends on surveillance, preventive measures, outbreak investigation, and the establishment of control mechanisms. Delays in obtaining country-level data of confirmed communicable disease cases, such as dengue fever, are prompting new efforts for short- to medium-term data. News articles highlight dengue infections, and they can reveal how public health messages, expert findings, and uncertainties are communicated to the public. In this article, we analyze dengue news articles in Asian countries, with a focus in India, for each month in 2014. We investigate how the reports cluster together, and uncover how dengue cases, public health messages, and research findings are communicated in the press. Our main contributions are to 1) uncover underlying topics from news articles that discuss dengue in Asian countries in 2014; 2) construct topic evolution graphs through the year; and 3) analyze the life cycle of dengue news articles in India, then relate them to rainfall, monthly reported dengue cases, and the Breteau Index. We show that the five main topics discussed in the newspapers in Asia in 2014 correspond to 1) prevention; 2) reported dengue cases; 3) politics; 4) prevention relative to other diseases; and 5) emergency plans. We identify that rainfall has 0.92 correlation with the reported dengue cases extracted from news articles. Based on our findings, we conclude that the proposed method facilitates the effective discovery of evolutionary dengue themes and patterns. PMID- 29141720 TI - Prevalence of Chlamydia trachomatis-Specific Antibodies before and after Mass Drug Administration for Trachoma in Community-Wide Surveys of Four Communities in Nepal. AB - The target end date for the global elimination of trachoma as a public health problem is 2020. As countries begin the process for submitting their dossier for the validation of elimination of trachoma as a public health problem, strategies for post-validation surveillance must be considered. Seroprevalence of antibodies against antigens from the causative bacteria Chlamydia trachomatis (Ct) in young children has been shown to reflect trachomatous inflammation-follicular (TF) rates in both endemic and previously endemic settings. However, none of these studies has directly compared age seroprevalence in the same communities before and after mass drug administration (MDA) for trachoma. Here we report a marked shift in age seroprevalence curves in four villages in Kapilvastu District, Nepal, before and after MDA. Clinical examinations were performed and blood was taken before (N = 659) and 5 years after (N = 646) MDA. Rates of TF decreased from 17.6% in <= 9-year-olds before MDA (N = 52) to 0% in <= 9-year-olds (N = 73) after MDA. Positive antibody responses to Ct in the entire population decreased from 82.1% pre-MDA to 35.8% post-MDA, whereas those among <= 9-year-olds decreased from 59.6% to 4.1%. These data show that the postintervention decrease in TF was reflected in a drop in anti-Ct antibody responses, suggesting that antibody responses could be useful indicators for post-validation surveillance. PMID- 29141719 TI - Chloroquine-Primaquine versus Chloroquine Alone to Treat Vivax Malaria in Afghanistan: An Open Randomized Superiority Trial. AB - Afghanistan's national guidelines recommend primaquine (PQ) for radical treatment of Plasmodium vivax malaria, but this is rarely implemented because of concerns over potential hemolysis in patients who have G6PD deficiency. Between August 2009 and February 2014, we conducted an open-label, randomized controlled trial of chloroquine (CQ) alone versus chloroquine plus primaquine (0.25 mg base/kg/day for 14 days) (CQ+PQ) in patients aged 6 months and older with microscopy confirmed P. vivax infection. In the CQ+PQ group, G6PD deficiency was excluded by fluorescent spot testing. The primary outcome was P. vivax recurrence assessed by survival analysis over one year follow-up. Of 593 patients enrolled, 570 attended at or after 14 days of follow-up. Plasmodium vivax recurrences occurred in 37 (13.1%) of 282 patients in the CQ+PQ arm versus 86 (29.9%) of 288 in the CQ arm (Cox proportional hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.25-0.54) (intention-to-treat analysis). Protection against recurrence was greater in the first 6 months of follow-up (HR 0.082; 95% CI 0.029-0.23) than later (HR 0.65, 95% CI 0.41-1.03). Five of seven patients requiring hospital admission were considered possible cases of PQ-related hemolysis, and PQ was stopped in a further six; however, in none of these cases did hemoglobin fall by >= 2 g/dL or to below 7 g/dL, and genotyping did not detect any cases of Mediterranean variant G6PD deficiency. PQ 0.25 mg/kg/day for 14 days prevents relapse of P. vivax in Afghanistan. Patient visits during the first week may improve adherence. Implementation will require deployment of point-of-care phenotypic tests for G6PD deficiency. PMID- 29141721 TI - Coupling Ion Chromatography to Q-Orbitrap for the Fast and Robust Analysis of Anionic Pesticides in Fruits and Vegetables. AB - Ion chromatography coupled to a quadrupole Orbitrap mass analyzer was used to develop a multiresidue method for the determination of highly polar pesticides and their metabolites (chlorate, perchlorate, fosetyl-aluminum, glyphosate, aminomethylphosphonic acid (AMPA), phosphonic acid, N-acetyl AMPA, and N-acetyl glyphosate) in fruits and vegetables. After extraction with methanol, samples were diluted 5* with water. No derivatization was applied. Pesticides were separated in an anion-exchange column. Water was used as the ion chromatography mobile phase. A gradient was created by increasing the concentration of KOH in the mobile phase. Ion chromatography provided good and stable retention and separation for all studied compounds. All investigated pesticides had an LOQ of 0.01 mg/kg and a linear range of 0.01-0.50 mg/kg. The ion ratio of the m/z ions produced was stable and adequate (deviation <30%) in all cases. The obtained mass errors (always in full-scan MS and MS2 mode) were <0.2 mDa. The high resolution (>100 000) provided by the Orbitrap analyzer with the low m/z ions obtained (e.g., m/z 80) was effective in obtaining low background matrix signals. The influence of postcolumn infusion of organic solvent on sensitivity was investigated. Acetonitrile was found to be more effective than methanol, increasing the sensitivity 3* with respect to water. The method was validated for five vegetable-based matrixes. Both the sample processing and the analytical measurement were very fast. Hence, the methodology is ideal for high-throughput work. PMID- 29141722 TI - Spatio-Temporal Dynamics of Asymptomatic Malaria: Bridging the Gap Between Annual Malaria Resurgences in a Sahelian Environment. AB - In areas of seasonal malaria transmission, the incidence rate of malaria infection is presumed to be near zero at the end of the dry season. Asymptomatic individuals may constitute a major parasite reservoir during this time. We conducted a longitudinal analysis of the spatio-temporal distribution of clinical malaria and asymptomatic parasitemia over time in a Malian town to highlight these malaria transmission dynamics. For a cohort of 300 rural children followed over 2009-2014, periodicity and phase shift between malaria and rainfall were determined by spectral analysis. Spatial risk clusters of clinical episodes or carriage were identified. A nested-case-control study was conducted to assess the parasite carriage factors. Malaria infection persisted over the entire year with seasonal peaks. High transmission periods began 2-3 months after the rains began. A cluster with a low risk of clinical malaria in the town center persisted in high and low transmission periods. Throughout 2009-2014, cluster locations did not vary from year to year. Asymptomatic and gametocyte carriage were persistent, even during low transmission periods. For high transmission periods, the ratio of asymptomatic to clinical cases was approximately 0.5, but was five times higher during low transmission periods. Clinical episodes at previous high transmission periods were a protective factor for asymptomatic carriage, but carrying parasites without symptoms at a previous high transmission period was a risk factor for asymptomatic carriage. Stable malaria transmission was associated with sustained asymptomatic carriage during dry seasons. Control strategies should target persistent low-level parasitemia clusters to interrupt transmission. PMID- 29141723 TI - Emergence, Epidemiology, and Transmission Dynamics of 2009 Pandemic A/H1N1 Influenza in Kampala, Uganda, 2009-2015. AB - In sub-Saharan Africa, little is known about the epidemiology of pandemic-prone influenza viruses in urban settings. Using data from a prospective sentinel surveillance network, we characterized the emergence, epidemiology, and transmission dynamics of 2009 pandemic A/H1N1 influenza (H1N1pdm09) in Kampala, Uganda. After virus introduction via international air travel from England in June 2009, we estimated the basic reproductive number in Kampala to be 1.06-1.13, corresponding to attack rates of 12-22%. We subsequently identified 613 cases of influenza in Kampala from 2009 to 2015, of which 191 (31.2%) were infected with H1N1pdm09. Patients infected with H1N1pdm09 were more likely to be older adult (ages 35-64) males with illness onset during rainy season months. Urban settings in sub-Saharan Africa are vulnerable to importation and intense transmission of pandemic-prone influenza viruses. Enhanced surveillance and influenza pandemic preparedness in these settings is needed. PMID- 29141724 TI - Prostatic Abscess due to Burkholderia pseudomallei: Facilitating Diagnosis to Optimize Management. AB - Prostatic involvement is common in men with melioidosis. Indeed, some clinicians recommend radiological screening of all male patients as an undrained prostatic abscess may result in relapse of this potentially fatal disease. However, sophisticated medical imaging is frequently unavailable in the remote and resource-poor locations where patients are managed. In this retrospective study from Queensland, Australia, 22/144 (15%) men with melioidosis had a radiologically confirmed prostatic abscess. The absence of urinary symptoms had a negative predictive value (NPV) (95% confidence interval [CI]) for prostatic abscess of 96% (90-99%), whereas a urinary leukocyte count of < 50 * 106/L had an NPV (95% CI) of 100% (94-100%). A simple clinical history and basic laboratory investigations appear to exclude significant prostatic involvement relatively reliably and might be used to identify patients in whom radiological evaluation of the prostate is unnecessary. This may be particularly helpful in locations where radiological support is limited. PMID- 29141725 TI - Comparison of Enzyme-Linked Immunosorbent Assay Using Either Natural Octyl Disaccharide-Leprosy IDRI Diagnostic or Phenolic Glycolipid-I Antigens for the Detection of Leprosy Patients in Colombia. AB - Leprosy is a chronic infectious disease with a broad spectrum of manifestations. Delays in attaining correct diagnosis permit progressive peripheral nerve damage that can produce irreversible disabilities. Tests detecting antigen-specific antibodies can aid the diagnostic process and potentially detect patients earlier. Reported tests have lacked optimal sensitivity and specificity; however, the need to develop new tests to aid early diagnosis still remains. In this study, we determined the sensitivity, specificity, positive predictive value, and negative predictive value of enzyme-linked immunosorbent assay (ELISA) using natural octyl disaccharide-leprosy IDRI diagnostic (NDO-LID). Serum samples from confirmed multibacillary patients (N = 338) and paucibacillary patients (N = 58) were evaluated and contrasted against samples from individuals without leprosy (100 healthy persons, 36 leishmaniasis or tuberculosis patients). ELISA detecting either antigen-specific IgM, IgG, or the combination of IgG and IgM (with protein A) were conducted. At a sensitivity of 78% among all patients, serum IgM antibodies against the NDO-LID conjugate were detected at a greater level than those recognizing phenolic glycolipid-I antigen (64% overall sensitivity), while providing similar specificity (97% versus 100%, respectively). Given the inclusion of the LID-1 protein within NDO-LID, we also detected conjugate specific IgG within patient sera at a sensitivity of 81.6%. The use of protein A to simultaneously detect both antigen-specific IgG and IgM isotypes yielded the highest overall sensitivity of 86.3%. Taken together, our data indicate that the detection of both IgG and IgM antibodies against NDO-LID with protein A provided the best overall ability to detect Colombian leprosy patients. PMID- 29141726 TI - Status of Insecticide Resistance in Papua New Guinea: An Update from Nation-Wide Monitoring of Anopheles Mosquitoes. AB - Insecticide resistance (IR) monitoring is an important component of vector-borne disease control. The last assessment of IR in Papua New Guinea (PNG) was conducted in 2010. Since then, vector populations have been exposed to higher levels of pyrethroids with the continued nation-wide distribution of insecticide treated nets. Here, we provide an update on phenotypic IR in four highly malaria endemic areas of PNG. IR against deltamethrin, lambda-cyhalothrin, and dichlorodiphenyltrichloroethane was assessed using World Health Organization bioassays. A total of 108 bioassays for each insecticide were conducted screening 2,290 adult female anopheline mosquitoes. No phenotypic resistance was observed. Bioassay parameters agreed well with those observed in other studies that used the same assays and insecticides. These results indicate that the three tested insecticides are still universally effective in PNG. Continued IR monitoring (every 1-2 years) in PNG is recommended to detect reduced susceptibility early and adjust guidelines to prevent widespread resistance. PMID- 29141728 TI - Challenging Assumptions, Demanding Justification. PMID- 29141729 TI - Finding Patterns of Meaning: Margaret Newman's Theory of Health as Expanding Consciousness. AB - This article presents an evaluation of Margaret Newman's theory of health as expanding consciousness, through a literature review, to determine its usefulness for nursing practice and research. The evaluation illustrates that Newman's theory is valuable for guiding various aspects of nursing practice, education, and research. However, its use had been limited to spiritual, psychological, and social aspects of nursing care and needs to be further evaluated for its significance in acute care settings. Most of the studies that use Newman's theory are from the past, with limited studies conducted in recent years, indicating the need for further research. PMID- 29141727 TI - Point-of-Care Ultrasound for Extrapulmonary Tuberculosis in India: A Prospective Cohort Study in HIV-Positive and HIV-Negative Presumptive Tuberculosis Patients. AB - Diagnosing extrapulmonary tuberculosis (EPTB) is challenging. Point-of-care ultrasound (POCUS) for human immunodeficiency virus (HIV)-associated EPTB is applied in sub-Saharan Africa. This study aimed at evaluating the applicability of POCUS for diagnosing EPTB in HIV-positive and HIV-negative presumptive tuberculosis (TB) patients in India, a country of moderate relative TB and HIV burden. Presumptive TB patients at Kasturba Hospital, Manipal, India, prospectively underwent POCUS evaluating for pericardial, pleural and ascitic effusion, abdominal lymphadenopathy, and hepatic and splenic microabscesses. Findings were correlated with TB category (confirmed TB, clinical TB, unlikely TB), HIV status, and discharge diagnoses. A total of 425 patients underwent POCUS; 81 (20%) were HIV-positive. POCUS findings were more common in HIV/TB coinfected patients than in HIV-positive patients with unlikely TB (24/40 (60%) versus 9/41 (22%), P < 0.001). Abdominal lymphadenopathy and splenic microabscesses were strongly associated with TB in HIV-positive patients (P = 0.002 and P = 0.001). POCUS findings did not correlate with TB in HIV-negative patients; a third of HIV-negative patients with unlikely TB and POCUS findings had cancer, another third other infectious diseases. Sonographic findings were common in HIV-positive and HIV-negative presumptive TB patients. POCUS was a useful bedside test for the detection of HIV-associated EPTB. In HIV-negative patients, POCUS detected features associated with EPTB but also of malignancy and other infectious diseases. PMID- 29141730 TI - Keeping Abreast of Developments in the Cancer Wars: A View From the Front. AB - Cancer somehow lends itself to military analogies, perhaps because of its status as a threat to life itself. We've declared war on cancer over several decades, viewing cancer as a cell going rogue, dividing uncontrollably, and ultimately breaking through local boundaries to spread. Less well known, but critically relevant to the health care impact of questioning authority, is the war within the breast cancer management community, among those studying molecular and cellular targets in breast cancer biology and those managing the human targets that represent cancer's toll. This article outlines current concepts and controversies about breast cancer, presenting a bio/sociological basis and a mental toolkit for thinking about and coping with this conflict. PMID- 29141731 TI - Challenging Authority: The Impact of Practicing Nursing in the Legislature. AB - How does challenging authority look? This article describes two steps taken to prepare for and engage in challenges to existing laws. The first step is use of the nursing process to help structure deliberations about when to pursue, justify, and target a challenge to existing law to create desired outcomes. The second step is the important process of building the case for change and the broad base of support needed to push against resistance to change. The article details two examples of specific legislative successes the author accomplished using these two steps. PMID- 29141732 TI - Education as an Intervention Toward Recognizing and Eliminating Incivility. AB - Incivility in nursing is a pervasive and evasive problem that many nurses do not easily recognize or may simply shrug off as "normal." However, incivility produces a hostile work environment and can jeopardize safety. A study was conducted to (a) determine nurses' ability to recognize incivility in nursing after an online educational intervention on incivility, (b) ascertain the effectiveness of online education toward assisting nurses with understanding how to ward off this behavior, and (c) determine the types and effects of incivility participants experienced. Findings suggest that education on incivility may assist nurses with identifying uncivil behaviors exhibited by nurse peers and help them understand strategies to combat it. The types of incivility reported by participants were similar to findings of other studies; effects included unsafe behaviors and somatic consequences. PMID- 29141733 TI - Interprofessional Collaboration Between Mental Health Counselors and Nurses. AB - The continuous and rapid evolution of medical technology and the complexity of delivering person-centered care in the 21st century calls for collaboration among health care professionals. Global health now "involves many disciplines within and beyond the health sciences and promotes interdisciplinary collaboration; and is a synthesis of population-based prevention with individual-clinical care" (Koplan et al., 2009, p. 1995). The need for mental health practitioners to work in interprofessional contexts requires graduate and postgraduate programs to incorporate interprofessional education into their student training. This article focuses on an approach to interprofessional education for students in mental health nursing and counseling. PMID- 29141734 TI - Transition From Education to Practice for New Nursing Graduates: A Literature Review. AB - New nurse turnover costs organizations in the United States an estimated $1.4 billion to $2.9 billion per year (Meyer, Shatto, Delicath, & von der Lancken, 2017; Ulrich et al., 2010). Retention of graduate nurses can decrease costs, combat nursing shortages, and improve patient outcomes. Despite the increase in prevalence of nurse residency programs, new nurses are leaving their first positions at alarming rates. The purpose of this literature review is to examine the factors that affect graduate nurse transition to practice. Findings indicate that a supportive environment free from bullying, a positive preceptor experience, and self-confidence were keys to retaining new graduate nurses. PMID- 29141735 TI - Simulation Performance and National Council Licensure Examination for Registered Nurses Outcomes: Field Research Perspectives. AB - PURPOSE: This descriptive field study examines processes used to evaluate simulation for senior-level Bachelor of Science in Nursing (BSN) students in a capstone course, discusses challenges related to simulation evaluation, and reports the relationship between faculty evaluation of student performance and National Council Licensure Examination for Registered Nurses (NCLEX-RN) first time passing rates. METHODS: Researchers applied seven terms used to rank BSN student performance (n = 41, female, ages 22-24 years) in a senior-level capstone simulation. Faculty evaluation was correlated with students' NCLEX-RN outcomes. RESULTS: Students evaluated as "lacking confidence" and "flawed" were less likely to pass the NCLEX-RN on the first attempt. CONCLUSIONS: Faculty evaluation of capstone simulation performance provided additional evidence of student preparedness for practice in the RN role, as evidenced by the relationship between the faculty assessment and NCLEX-RN success. IMPLICATIONS: Simulation has been broadly accepted as a powerful educational tool that may also contribute to verification of student achievement of program outcomes and readiness for the RN role. PMID- 29141736 TI - A Research Experience Collecting Data Online: Advantages and Barriers. AB - This article details the use of an online survey tool to obtain information from nurse faculty, including the data collection process, the survey responses by nurse faculty, and the advantages and barriers of online data collection. The survey response rate indicates that online data collection is a valuable tool for nurse researchers. PMID- 29141737 TI - Nursing Students and Medication Errors: Why Don't They Question? AB - In health care, efforts have been aimed at reducing medication errors rates; yet, medication errors continue to affect approximately 5% of hospitalized patients. In health care education, simulation provides nursing students a safe opportunity for hands-on medication administration, often including dosage calculation. However, the safety checks associated with medication administration-including the Five Rights-are frequently overlooked. Although the efforts aimed toward increasing medication safety include external factors (such as environmental measures and electronic resources), recent observations in simulation suggest a different problem. When medication orders are incorrect, many students do not know whom, how, or what to question to correct the mistake. This article describes two semesters with senior undergraduate nursing students in simulation and provides explanations, in their own words, for why they did not correct the mistake but caused a medication error instead. By recognizing and overcoming the barriers that inhibit questioning, educators can teach students how to form questions, whom to question, and when to ask questions. PMID- 29141738 TI - Dynamic Clinical Algorithms: Digital Technology Can Transform Health Care Decision-Making. AB - Most health care in low-income countries is delivered at a primary care level by health workers who lack quality training and supervision, often distant from more experienced support. Lack of knowledge and poor communication result in a poor quality of care and inefficient delivery of health services. Although bringing great benefits in sectors such as finance and telecommunication in recent years, the Digital Revolution has lightly and inconsistently affected the health sector. These advances offer an opportunity to dramatically transform health care by increasing the availability and timeliness of information to augment clinical decision-making, based on improved access to patient histories, current information on disease epidemiology, and improved incorporation of data from point-of-care and centralized diagnostic testing. A comprehensive approach is needed to more effectively incorporate current digital technologies into health systems, bringing external and patient-derived data into the clinical decision making process in real time, irrespective of health worker training or location. Such dynamic clinical algorithms could provide a more effective framework within which to design and integrate new digital health technologies and deliver improved patient care by primary care health workers. PMID- 29141740 TI - A Lateral Flow Rapid Test for Human Toxocariasis Developed Using Three Toxocara canis Recombinant Antigens. AB - Laboratory diagnosis of toxocariasis is still a challenge especially in developing endemic countries with polyparasitism. In this study, three Toxocara canis recombinant antigens, rTES-26, rTES-30, and rTES-120, were expressed and used to prepare lateral flow immunoglobulin G4 (IgG4) dipsticks. The concordance of the results of the rapid test (comprising three dipsticks) with a commercial IgG-enzyme-linked immunosorbent assay (ELISA) (Cypress Diagnostics, Belgium) was compared against the concordance of two other commercial IgG-ELISA kits (Bordier, Switzerland and NovaTec, Germany) with the Cypress kit. Using Toxocara-positive samples, the concordance of the dipstick dotted with rTES-26, rTES-30, and rTES 120 was 41.4% (12/29), 51.7% (15/29), and 72.4% (21/29), respectively. When positivity with any dipstick was considered as an overall positive rapid test result, the concordance with the Cypress kit was 93% (27/29). Meanwhile, when compared with the results of the Cypress kit, the concordance of IgG-ELISA from NovaTec and Bordier was 100% (29/29) and 89.7% (26/29), respectively. Specific IgG4 has been recognized as a marker of active infection for several helminthic diseases; therefore, the two non-concordant results of the rapid test when compared with the NovaTec IgG-ELISA kit may be from samples of people with non active infection. All the three dipsticks showed 100% (50/50) concordance with the Cypress kit when tested with serum from individuals who were healthy and with other infections. In conclusion, the lateral flow rapid test is potentially a good, fast, and easy test for toxocariasis. Next, further validation studies and development of a test with the three antigens in one dipstick will be performed. PMID- 29141739 TI - Advancing Global Health through Development and Clinical Trials Partnerships: A Randomized, Placebo-Controlled, Double-Blind Assessment of Safety, Tolerability, and Immunogenicity of PfSPZ Vaccine for Malaria in Healthy Equatoguinean Men. AB - Equatorial Guinea (EG) has implemented a successful malaria control program on Bioko Island. A highly effective vaccine would be an ideal complement to this effort and could lead to halting transmission and eliminating malaria. Sanaria(r) PfSPZ Vaccine (Plasmodium falciparum sporozoite Vaccine) is being developed for this purpose. To begin the process of establishing the efficacy of and implementing a PfSPZ Vaccine mass vaccination program in EG, we decided to conduct a series of clinical trials of PfSPZ Vaccine on Bioko Island. Because no clinical trial had ever been conducted in EG, we first successfully established the ethical, regulatory, quality, and clinical foundation for conducting trials. We now report the safety, tolerability, and immunogenicity results of the first clinical trial in the history of the country. Thirty adult males were randomized in the ratio 2:1 to receive three doses of 2.7 * 105 PfSPZ of PfSPZ Vaccine (N = 20) or normal saline placebo (N = 10) by direct venous inoculation at 8-week intervals. The vaccine was safe and well tolerated. Seventy percent, 65%, and 45% of vaccinees developed antibodies to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) by enzyme-linked immunosorbent assay, PfSPZ by automated immunofluorescence assay, and PfSPZ by inhibition of sporozoite invasion assay, respectively. Antibody responses were significantly lower than responses in U.S. adults who received the same dosage regimen, but not significantly different than responses in young adult Malians. Based on these results, a clinical trial enrolling 135 subjects aged 6 months to 65 years has been initiated in EG; it includes PfSPZ Vaccine and first assessment in Africa of PfSPZ-CVac. ClinicalTrials.gov identifier: NCT02418962. PMID- 29141741 TI - A Hospital-Based Study of Intestinal Capillariasis in Thailand: Clinical Features, Potential Clues for Diagnosis, and Epidemiological Characteristics of 85 Patients. AB - Intestinal capillariasis caused by Capillaria philippinensis, a fish-borne nematode, is an important, emerging zoonotic helminthiasis. Cases may be fatal if suitable treatment is not administered in time. We reported a hospital-based study of 85 cases in Thailand, most of which were in the northeast. All patients had a history of eating raw or insufficiently cooked fresh water fish or prawns. The clinical manifestations are characterized by chronic diarrhea, borborygmi, abdominal pain, marked weight loss, muscle weakness, fatigue, dizziness, anorexia, and edema, as well as protein and electrolyte loss. Fecal examination revealed C. philippinensis in all patients. Although 16 of the total of 85 (18.8%) cases were initially found to be negative for C. philippinensis using fecal examination, further examination using an immunoblotting technique found them to be positive for the IgG antibody against Trichinella spiralis larval antigen. One day after administration of 400 mg of albendazole, eggs and/or larvae and/or adult C. philippinensis were found in 16 fecal samples. After treatment with mebendazole (200 mg twice a day for 30 days) or albendazole (200 mg twice a day for 10 days), all 85 patients recovered. The potential clues for diagnosis are clinical manifestations, history of eating raw contaminated food, and positive serological test, and fecal examinations under professional. Administration of anthelminthic drugs stimulates the excretion of larvae, eggs, and/or adult worms and can be used as a supportive method for the diagnosis of intestinal capillariasis in areas where serological test is not available. PMID- 29141742 TI - Characterizing the Last Latrine Nonowners in Rural Malawi. AB - Open defecation is a public health problem worldwide. Non-governmental organizations in developing countries use various approaches to increase latrine coverage, but for little-understood reasons, some of the population does not adopt latrine construction. The objective of our research was to uncover which of the factors predicting latrine construction are relevant to the last nonowners of latrines, termed laggards in the diffusion of innovations theory. In a cross sectional study, quantitative face-to-face interviews were conducted in households in rural Malawi (N = 824) to assess the behavioral determinants of latrine construction, mental health, and leadership. Around 14% of the households interviewed did not own a latrine. Study results suggest that nonowners have limited economic resources and perceive that latrine construction is expensive, that it is difficult to find money for latrine construction, and that it needs a lot of time and effort. The last nonowners of latrines live in smaller groups than latrine owners, communicate less with others about latrine construction, and are less influenced by the opinion of their leaders. They consist, in particular, of socially vulnerable households, are younger, are less educated, often have more impaired mental health, feel more vulnerable to contracting diseases, are less aware of the latrine construction of others in the village, feel less personally obliged to construct their own latrines, and are less confident in their ability to rebuild latrines damaged by flooding. The study confirmed that the assumptions of the diffusion of innovation theory are useful in combination with the risks, attitudes, norms, abilities, and self-regulation behavior change approach for developing evidence-based behavior change strategies in developing countries. PMID- 29141743 TI - Prognostic and Predictive Factors of Ebola Virus Disease Outcome in Elderly People during the 2014 Outbreak in Guinea. AB - Elderly people occupy a prominent position in African societies; however, their potential linkage to high case fatality rate (CFR) in Ebola virus disease (EVD) was often overlooked. We describe the predictive factors for EVD lethality in the elderly. A total of 2,004 adults and 309 elderly patients with confirmed EVD were included in the analysis. The median age (interquartile range) was 35 years (23 44) in adults and 65 years (60-70) in the elderly. The proportion of funeral participation was significantly higher in the elderly group than in the adult group. Duration (in days) between the onset of symptoms and admission was significantly longer in elderly. CFR in the elderly people was also significantly higher (80.6%) than in the adult group (66.2%). Funeral participation constituted a risk factor for the transmission of EVD in elderly people. PMID- 29141744 TI - Nonadherence to Antituberculosis Medications: The Impact of Stigma and Depressive Symptoms. AB - Medication nonadherence is common among tuberculosis (TB) patients in China and is of great concern. Herein, we determined the incidence of nonadherence in TB patients in central China and the impact of stigma and depressive symptoms on adherence; these issues are relatively unexplored. A cross-sectional survey was performed, and 1,342 TB patients were recruited from TB dispensaries in three counties in Hubei province using a multistage sampling method. The patients completed structured questionnaires that addressed medication adherence, TB related stigma, and depressive symptoms. The independent effects of stigma and depressive symptoms on adherence were determined via multinomial logistic regression analysis. The mean medication adherence score was 6.03 +/- 1.99. The percentage of TB patients with high, medium, and low medication adherence was 32.12%, 34.58%, and 33.31%, respectively. The impact of stigma and depressive symptoms on medication adherence was significant. TB patients with medium (odds ratios [OR]: 1.54, 95% confidence interval [CI]: 1.08-2.21) or high (OR: 5.32, 95% CI: 3.34-8.46) stigma or patients with mild (OR: 1.92, 95% CI: 1.34-2.75) or severe (OR: 3.67, 95% CI: 2.04-6.61) depressive symptoms showed a higher likelihood of having low adherence than those with low stigma or without depressive symptoms. TB-related stigma and depressive symptoms were common among TB patients in China, as was nonadherence, and independently associated with their adherence behavior. Social and psychological interventions that combat stigmatization and depression in TB patients should be adopted and optimized to improve medication adherence. PMID- 29141745 TI - Histology and Serum Cytokine Responses in an Imported Rickettsia slovaca Infection, Germany. AB - Rickettsia slovaca, a spotted fever group rickettsial pathogen, causes a syndrome consisting of scalp eschar and neck lymphadenopathy following tick bite. We analyzed the histologic skin reaction in the eschar, showing a prominent eosinophilic infiltration, as well as the presence of B lymphocytes and CD4- and CD8-positive T cells. Examination of the serum cytokine responses over time demonstrated an initial proinflammatory cytokine elevation followed by normalization. PMID- 29141746 TI - Monitoring and Control of Aedes albopictus, a Vector of Zika Virus, Near Residences of Imported Zika Virus Patients during 2016 in South Korea. AB - Zika virus (ZIKV) is an arthropod-borne virus mainly transmitted by Aedes species. A total of nine of the 16 imported ZIKV reported cases during the mosquito season in the Republic of Korea (ROK), following the return of local nationals from foreign ZIKV endemic countries, were surveyed for Aedes albopictus. Surveillance and vector control of Ae. albopictus, a potential vector of ZIKV, and related species are critical for reducing the potential for autochthonous transmission in the ROK. Surveillance and vector control were coordinated by Korean Centers for Disease Control & Prevention (KCDC) and conducted by local health authorities within 200 m of imported ZIKV patients' residences. After diagnosis, thermal fogging (3 * week * 3 weeks), residual spray for homes and nearby structures (1 * week * 3 weeks), and larval control (3 * week * 3 weeks) were conducted in accordance with national guidelines developed by KCDC in early 2016. Of the nine residences surveyed using BG Sentinel traps, Ae. albopictus trap indices (TIs) for the three (3) patients' residences located near/in forested areas were significantly higher than the six patients' residences located inside villages/urban areas or low-lying farmland without trees. Overall, Ae. albopictus TIs in forested areas decreased by 90.4% after adult and larval control, whereas TIs decreased by 75.8% for residences in nonforested areas. A total of 3,216 Aedes and Ochlerotatus spp. were assayed by real-time polymerase chain reaction for ZIKV, dengue, and chikungunya virus. Both species collected before and after vector control were negative for all viruses. Vector control within 200 m of residences of imported ZIKV patients, conducted in accordance with established guidelines, may have effectively reduced human mosquito-human transmission cycle by competent vectors in South Korea. PMID- 29141747 TI - Prevention Practices among United States Pregnant Women Who Travel to Zika Outbreak Areas. AB - We surveyed pregnant women from the United States to assess the prevention practices they used when traveling to countries with ongoing Zika virus (ZIKV) outbreaks. Of the 749 who agreed to participate, 710 completed the survey's travel questions and 59 of those had traveled to a ZIKV outbreak area in the past 12 months. Only 43% of the women who had traveled to ZIKV outbreak areas reported frequently using mosquito repellant with 32% stating they did not use it at all. They also did not frequently use other recommended methods to prevent mosquito bites. With the established risks to babies born to women who contract the ZIKV during pregnancy, it is a great concern that a large number of women who travel to outbreak areas during pregnancy are not protecting themselves against mosquito bites. Pregnant women need to be educated on the importance of taking precautions. PMID- 29141748 TI - Trypanosoma cruzi Infection Induces Pannexin-1 Channel Opening in Cardiac Myocytes. AB - Trypanosoma cruzi, the etiological agent of Chagas diseases, invades the cardiac tissue causing acute myocarditis and heart electrical disturbances. In T. cruzi invasion, the parasite induces [Ca2+]i transients in the host cells, an essential phenomenon for invasion. To date, knowledge on the mechanism that elicits transients of [Ca2+]i during the infection of cardiac myocytes has not been fully characterized. Pannexin1 (Panx1) channel are poorly selective channels found in all vertebrates that serve as a pathway for ATP release. In this article, we demonstrate that T. cruzi infection results in the opening of Panx1 channels in cardiac myocytes. We show that pharmacological blockade of Panx1 channels inhibits T. cruzi-induced [Ca2+]i transients and invasion in cardiac myocytes. Our results indicate that opening of Panx1 channels are required for T. cruzi invasion in cardiac myocytes, and we propose that targeting Panx1 channel could provide new potential therapeutic approaches to treat Chagas disease. PMID- 29141749 TI - Visualization of West Nile Virus in Urine Sediment using Electron Microscopy and Immunogold up to Nine Years Postinfection. AB - West Nile virus (WNV) is an important emerging flavivirus in North America. Experimental studies in animals infer the development of persistent infection in the kidneys. In humans, recent studies suggest the possibility of persistent renal infection and chronic kidney disease. Considering the discrepancies between published studies on viral RNA detection in urine of convalescing WNV-positive patients, we explored the use of electron microscopy (EM) with anti-WNV E protein antibody immunogold labeling to detect virus in the urine sediment from a subset of study participants in the Houston WNV cohort. In 42% of evaluated study participants had visible sediment present in urine after centrifugation; viral particles consistent with the size and morphology of WNV were successfully detected using EM in the urine sediment up to 9 years postinfection. The anti-WNV immunogold labeling bound to virus envelope in the sediment allowed for enhanced detection when compared with PCR and provide a new technique for understanding kidney disease in WNV patients. These results provide further evidence of persistent infection in at least a subset of individuals infected with WNV. These findings present a novel tool to diagnose persistent WNV infection and its possible link with progressive renal pathology. PMID- 29141750 TI - Use of a Novel Portable Three-Dimensional Imaging System to Measure Limb Volume and Circumference in Patients with Filarial Lymphedema. AB - The World Health Organization's Global Program to Eliminate Lymphatic Filariasis (LF) has reduced LF transmission worldwide, but millions remain affected by filarial lymphedema. Tools for clinically monitoring lymphedema in developing nations are limited. We tested a novel, portable, infrared three-dimensional imaging system (3DIS) against water displacement (WD) and tape measurement of limb circumference (TMLC) among patients with filarial leg lymphedema in Galle, Sri Lanka. Outcomes were accuracy and reproducibility of imaging system measurements. In parallel, we also tested the reproducibility of skin thickness ultrasound (STU) measurements. We examined 52 patients (104 limbs) with lymphedema of stages 0-6 (N = 28, 19, 20, 21, 2, 4, and 10, respectively). 3DIS measurements correlated nearly perfectly with WD (r2 = 0.9945) and TMLC values (r2 > 0.9801). The median time required to acquire imaging system measurements for both legs was 2.1 minutes, compared with 17, 7, and 29 minutes, respectively, for WD, TMLC, and STU. Median interexaminer coefficients of variation (CVs) for volume measurements were 1.1% (interquartile range [IQR] 0.5-2.1%) for WD and 1.7% (IQR 1.2-2.4%) for the 3DIS. CVs for circumference measurements were 1.4% (IQR 0.8-2.4%) by TMLC and 1.3% (0.8-1.9%) by 3DIS. Median interexaminer CV for STU was 13.7% (IQR 8.5-21.3%). The portable imaging system noninvasively provided accurate and reproducible limb volume and circumference measurements in approximately 2 minutes per patient. This portable technology has the potential to greatly improve assessment and monitoring of lymphedema in the clinic and in the field. PMID- 29141751 TI - Assessment of a Leishmaniasis Reporting System in Tropical Bolivia Using the Capture-Recapture Method. AB - This study evaluates the level of underreporting of the National Program of Leishmaniasis Control (NPLC) in two communities of Cochabamba, Bolivia during the period 2013-2014. Montenegro skin test-confirmed cases of cutaneous leishmaniasis (CL) were identified through active surveillance during medical campaigns. These cases were compared with those registered in the NPLC by passive surveillance. After matching and cleaning data from the two sources, the total number of cases and the level of underreporting of the National Program were calculated using the capture-recapture analysis. This estimated that 86 cases of CL (95% confidence interval [CI]: 62.1-110.8) occurred in the study period in both communities. The level of underreporting of the NPLC in these communities was very high: 73.4% (95% CI: 63.1-81.5%). These results can be explained by the inaccessibility of health services and centralization of the NPLC activities. This information is important to establish priorities among policy-makers and funding organizations as well as implementing adequate intervention plans. PMID- 29141752 TI - Differences in Nutritional and Health Status in School Children from the Highlands and Lowlands of Bolivia. AB - Children in the Bolivian Andes are exposed to endemic infections and meager nourishment, and live under poor hygienic conditions. The prevention of children malnutrition is a priority in many countries including Bolivia. In this study, the health status of schoolchildren in Taraco, a Puna district, at 4,000 meters above sea level (masl) and in Caranavi, at 650 masl in the wealthier subtropical valleys, was compared. The weight, height, and hematological and biochemical parameters in blood, parasites in stool, and clinical information in 120 children from rural Taraco and in 96 from semi-urban Caranavi, both predominantly of Aymara ethnicity, were registered. Eleven percent of Taraco children were undernourished compared with 3% in Caranavi. Instead, 41% of the children in Caranavi were obese or overweight, compared with 8% in Taraco. Anemia was found in 74% of the children in Taraco compared with 7% in Caranavi. Albumin levels were normal in all samples, albeit lower in Taraco. Similar and normal serum zinc levels were measured in both groups. Approximately 60% of the children in both locations showed insufficient vitamin D levels, with lower levels in Taraco children. Hymenolepis nana and Entamoeba coli, parasites determinant of poor hygienic conditions, were respectively detected in 78% and 21% of fecal samples from Taraco, and in 29% and 8% of samples from Caranavi. We show increased anemia, nutritional deficiencies, and indications of poor hygienic conditions in highlands compared with lowlands. The prevalence of obesity in the lowlands demands addressing diverse nutritional deficiencies in the regions of Bolivia. PMID- 29141753 TI - Serological Evaluation of Cutaneous Leishmania tropica Infection in Northern Israel. AB - Leishmania spp. are medically important unicellular parasites transmitted by phlebotomine sand flies. The World Health Organization recently highlighted the importance of reliable diagnostic tools for leishmaniasis. Our study of human infection was conducted in two endemic foci of Leishmania tropica in the Galilee region, northern Israel. Elevated anti-Leishmania antibodies were present in the majority (78.6%) of L. tropica-PCR positive individuals. Moreover, the enzyme linked immunosorbent assay showed high sensitivity, specificity, and negative and positive predictive values (ranging between 73% and 79%), thus fulfilling the basic requirement for future development of a serodiagnostic and screening tool. The anti-sand fly saliva antibodies used as biomarkers of exposure reflected the composition of the local sand fly fauna as well as the abundance of individual species. High levels of antibodies against vector salivary proteins may further indicate frequent exposure to sand flies and consequently a higher probability of Leishmania transmission. PMID- 29141754 TI - Effectiveness of the Hydrogen Sulfide Test as a Water Quality Indicator for Diarrhea Risk in Rural Bangladesh. AB - Microbiological water quality is usually assessed by the identification of Escherichia coli (E. coli), a fecal indicator. The hydrogen sulfide (H2S) test is an inexpensive, easy-to-use, and portable alternative field-based water quality test. Our study evaluated the H2S test's effectiveness as a water quality indicator for diarrhea risk. Field workers collected stored drinking water samples for H2S analysis and detection of E. coli by membrane filtration and measured caregiver-reported diarrhea among children < 5 years in the same households 1 month later. We assessed the association between the H2S test (incubated for 24 hours and 48 hours) and diarrhea prevalence, with 2-day and 7 day symptom recall periods (N = 1,348). We determined the sensitivity, specificity, and positive and negative predictive value (PPV, NPV) of the H2S test compared with E. coli (N = 525). Controlling for potentially confounding covariates, H2S-positive water (at 24 or 48 hours) was not associated with 2-day diarrhea prevalence (24-hour prevalence ratio [PR] = 1.03, 95% confidence interval [CI]: 0.63-1.69; 48-hour PR = 0.89, 95% CI: 0.58-1.38) or 7-day diarrhea prevalence (24-hour PR = 1.17, 95% CI: 0.76-1.78; 48-hour PR = 1.21, 95% CI: 0.81 1.80). The sensitivity, PPV, and NPV of the H2S test was significantly higher when the H2S test was incubated for 48 versus 24 hours whereas specificity showed the opposite trend. H2S test sensitivity, PPV, and NPV increased with increasing E. coli levels, consistent with previous evidence that the H2S test is a useful water quality tool in high-contamination settings. However, our results suggest that the H2S test is not an effective indicator for waterborne diarrhea. PMID- 29141755 TI - Case Report: Failure of Therapeutic Coma in Rabies Encephalitis. AB - Rabies encephalitis is a fulminant, almost universally fatal infection involving the central nervous system. A unique treatment protocol, including anti exicitotoxic therapy and induced coma was credited with the survival of a vaccinated teenager with bat rabies encephalitis in 2005. However, multiple efforts to replicate this expensive and intense protocol have not been successful. In this article, we report the failure of the protocol in Indian patients with canine-acquired rabies and elucidate the potential explanations for the failure of the protocol in our patients. PMID- 29141756 TI - Incidence of Acute Diarrhea-Associated Death among Children < 5 Years of Age in Bangladesh, 2010-12. AB - Although acute diarrheal deaths have declined globally among children < 5 years, it may still contribute to childhood mortality as an underlying or contributing cause. The aim of this project was to estimate the incidence of acute diarrhea associated deaths, regardless of primary cause, among children < 5 years in Bangladesh during 2010-12. We conducted a survey in 20 unions (administrative units) within the catchment areas of 10 tertiary hospitals in Bangladesh. Through social networks, our field team identified households where children < 5 years were reported to have died during 2010-12. Trained data collectors interviewed caregivers of the deceased children and recorded illness symptoms, health care seeking, and other information using an abbreviated international verbal autopsy questionnaire. We classified the deceased based upon the presence of diarrhea before death. We identified 880 deaths, of which 36 (4%) died after the development of acute diarrhea, 17 (2%) had diarrhea-only in the illness preceding death, and 19 (53%) had cough or difficulty breathing in addition to diarrhea. The estimated annual incidence of all-cause mortality in the unions < 13.6 km of the tertiary hospitals was 26 (95% confidence interval [CI] 16-37) per 1,000 live births compared with the mortality rate of 37 (95% CI 26-49) per 1,000 live births in the unions located >= 13.6 km. Diarrhea contributes to childhood death at a higher proportion than when considering it only as the sole underlying cause of death. These data support the use of interventions aimed at preventing acute diarrhea, especially available vaccinations for common etiologies, such as rotavirus. PMID- 29141757 TI - Protein-Specific Features Associated with Variability in Human Antibody Responses to Plasmodium falciparum Malaria Antigens. AB - The magnitude of antibody responses varies across the individual proteins that constitute any given microorganism, both in the context of natural infection and vaccination with attenuated or inactivated pathogens. The protein-specific factors underlying this variability are poorly understood. In 267 individuals exposed to intense seasonal malaria, we examined the relationship between immunoglobulin G (IgG) responses to 861 Plasmodium falciparum proteins and specific features of these proteins, including their subcellular location, relative abundance, degree of polymorphism, and whether they are predicted to have human orthologs. We found that IgG reactivity was significantly higher to extracellular and plasma membrane proteins and also correlated positively with both protein abundance and degree of protein polymorphism. Conversely, IgG reactivity was significantly lower to proteins predicted to have human orthologs. These findings provide insight into protein-specific factors that are associated with variability in the magnitude of antibody responses to natural P. falciparum infection-data that could inform vaccine strategies to optimize antibody-mediated immunity as well as the selection of antigens for sero-diagnostic purposes. PMID- 29141758 TI - In Vitro Sensitivity of Pyronaridine in Thai Isolates of Plasmodium falciparum. AB - Pyronaridine, a Mannich base antimalarial agent with a high activity against chloroquine-resistant Plasmodium falciparum, has been combined with artesunate as a new artemisinin based combination therapy (ACT). Pyronaridine-artesunate combination could be one of the choices for the treatment of uncomplicated falciparum malaria in multidrug-resistant areas including Thailand. The aim of this study was to determine in vitro sensitivity and cross-resistance pattern of pyronaridine in Thai isolates of P. falciparum. In addition, the influence of resistant genes concerning in vitro pyronaridine sensitivity was determined. The mean pyronaridine 50% inhibitory concentration (IC50) of 118 parasite isolates was 5.6 +/- 3.1 nM (range = 0.2-15.4 nM) with a significant positive correlation with artesunate IC50 (r = 0.246, P = 0.008) and amodiaquine IC50 (r = 0.220, P = 0.042) and a significant negative correlation with quinine IC50 (r = -0.185, P = 0.047). Parasites containing the pfmdr1 86Y allele exhibited significantly reduced pyronaridine sensitivity compared with those with the pfmdr1 N86 allele (7.6 +/- 3.3 nM and 5.4 +/- 3.0 nM, respectively, P = 0.032, independent t test); however, the difference may not be clinically relevant. Pyronaridine-artesunate could be the candidate ACT to treat multidrug-resistant falciparum malaria in Thailand with careful monitoring. PMID- 29141760 TI - Glucose-6-Phosphate Dehydrogenase Deficiency Genetic Variants in Malaria Patients in Southwestern Ethiopia. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked erythrocyte enzyme disorder with relevance to malaria treatment policy. Treatment with the antimalarial primaquine can result in hemolytic anemia in G6PD-deficient patients. With increased interest in primaquine use, it is important to identify G6PD variants in Ethiopia to inform malaria treatment policy. In the present study, mutations in the G6PD gene are identified in a sample of patients with malaria in Jimma town in southwest Ethiopia. Plasmodium species of infection were confirmed using polymerase chain reaction (PCR) and gel electrophoresis. PCR and Sanger sequencing were performed to observe a portion of the G6PD gene where the common G6PD mutations (A376G, G202A, and C563T) are found. Molecular analysis revealed that most of the samples were single Plasmodium vivax infections (83.7%). For G6PD genotyping, A376G was detected in 23.26% of individuals, whereas G202A and C563T were absent. Three other uncommon mutations were identified: rs782669677 (535G->A), rs370658483, (485 + 37 G->T), and a new mutation at chrX:154535443(C->T). Bioinformatic analysis of these mutations' potential functional impact suggests minimal effect on protein function. The discovery of both common and uncommon G6PD mutations contributes to the discussion on G6PD deficiency and appropriate primaquine treatment in Ethiopia. PMID- 29141761 TI - Leptospirosis Cases Infected with Uncommon Serogroups, Puerto Rico, 2013-2015. AB - Leptospirosis is an emerging bacterial zoonosis that is endemic but underrecognized throughout the tropics. Through prospective surveillance for acute febrile illness (AFI) among patients who presented to the emergency department of a hospital located in an urban region of Puerto Rico, four patients with laboratory-confirmed leptospirosis were identified. All patients had signs and symptoms of AFI, including fever, headache, and dehydration. Three patients had leukocytosis with thrombocytopenia and were admitted to the hospital. One hospitalized patient presented with jaundice, icteric sclera, and hematuria and developed rhabdomyolysis, whereas another patient with pulmonary edema was admitted to the intensive care unit. Microscopic agglutination titers among the four patients were highest against serogroups Icterohaemorrhagiae (serovar Mankarso), Australis (serovar Bratislava), Bataviae (serovar Bataviae), and Canicola (serovar Canicola). These case reports demonstrate that infection with these apparently uncommon serogroups can result in illness ranging from mild to life-threatening. PMID- 29141759 TI - Cell Type-Specific Immunomodulation Induced by Helminthes: Effect on Metainflammation, Insulin Resistance and Type-2 Diabetes. AB - Recent epidemiological studies have documented an inverse relationship between the decreasing prevalence of helminth infections and the increasing prevalence of metabolic diseases ("metabolic hygiene hypothesis"). Chronic inflammation leading to insulin resistance (IR) has now been identified as a major etiological factor for a variety of metabolic diseases other than obesity and Type-2 diabetes (metainflammation). One way by which helminth infections such as filariasis can modulate IR is by inducing a chronic, nonspecific, low-grade, immune suppression mediated by modified T-helper 2 (Th2) response (induction of both Th2 and regulatory T cells) which can in turn suppress the proinflammatory responses and promote insulin sensitivity (IS). This article provides evidence on how the cross talk between the innate and adaptive arms of the immune responses can modulate IR/sensitivity. The cross talk between innate (macrophages, dendritic cells, natural killer cells, natural killer T cells, myeloid derived suppressor cells, innate lymphoid cells, basophils, eosinophils, and neutrophils) and adaptive (helper T [CD4+] cells, cytotoxic T [CD8+] cells and B cells) immune cells forms two opposing circuits, one associated with IR and the other associated with IS under the conditions of metabolic syndrome and helminth-mediated immunomodulation, respectively. PMID- 29141762 TI - Efficacy of Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria in Cruzeiro do Sul, Brazil, 2016. AB - We evaluated the therapeutic efficacy of artemether-lumefantrine (AL) fixed-dose combination to treat uncomplicated Plasmodium falciparum malaria in Cruzeiro do Sul, Acre State, in the Amazon region of Brazil. Between December 2015 and May 2016, we enrolled 79 patients, 5-79 years old with fever or history of fever in the previous 48 hours and P. falciparum monoinfection confirmed by microscopy. Attempts were made to provide direct observation or phone reminders for all six doses of AL, and patients were followed-up for 28 days. AL was well tolerated, with no adverse events causing treatment interruption. All but one of the 74 patients who completed the 28-day follow-up had an adequate clinical and parasitologic response = 98.6% (95% CI: 93.2-100%). We could not amplify the one isolate of the case with recurrent infection to differentiate between recrudescence and reinfection. Five (6.3%) patients demonstrated persistent asexual parasitemia on Day 3, but none met definition for early treatment failure. We found no mutations in selected kelch13 gene domains, known to be associated with artemisinin resistance in P. falciparum isolates from Day 0. These results strongly support the continued use of AL as a first-line therapy for uncomplicated P. falciparum malaria in Acre. Routine monitoring of in vivo drug efficacy coupled with molecular surveillance of drug resistance markers remains critical. PMID- 29141763 TI - Pilot Study of the Addition of Mass Treatment for Malaria to Existing School Based Programs to Treat Neglected Tropical Diseases. AB - Malaria and neglected tropical diseases (NTDs), including schistosomiasis and soil transmitted helminths, threaten the health of school aged in sub-Saharan Africa. Established school-based mass drug administration (MDA) programs are used to control NTDs. Recent clinical trials have shown benefit of mass treatment of malaria in schools. The potential of adding malaria treatment to existing NTD programs has not been thoroughly evaluated. We offered malaria treatment with artemether-lumefantrine during routine NTD MDA and developed peer education programs in two primary schools in southern Malawi. We assessed participation, safety, and tolerability of coadministration of artemether-lumefantrine with praziquantel and albendazole. Results were compared with two schools conducting standard NTD MDA with additional monitoring by study staff. A total of 3,387 students (68%) received the standard NTD MDA. Among parents who came to schools on the day of the MDA, malaria treatment was well accepted; 87% of students who received the standard NTD MDA in intervention schools also consented for treatment with artemether-lumefantrine. The most frequent treatment emergent adverse events (AEs) were headache and vomiting. However, AEs were rare and were not more frequent in students who received artemether-lumefantrine in addition to praziquantel and albendazole. In this study, we found that the addition of malaria treatment to NTD MDA is well-received and safe. Such integrated programs may leverage existing infrastructures to reduce intervention costs and could become the framework for further integrated school-based health programs. PMID- 29141764 TI - Potential Role for Flubendazole in Limiting Filariasis Transmission: Observations of Microfilarial Sensitivity. AB - Flubendazole (FLBZ) is a potent and efficacious macrofilaricide after parenteral administration. Studies in animal models and one trial in patients infected with Onchocerca volvulus revealed that FLBZ elicits minimal effects on microfilariae (mf). Severe complications after ivermectin (IVM) treatment of patients with high Loa loa microfilaraemia are of great concern. We examined the potential of FLBZ to rapidly kill L. loa mf, the phenomenon proposed to underlie the complications. Mf of L. loa were exposed to FLBZ, its reduced metabolite, albendazole, or IVM in vitro. Viability of L. loa mf was unaffected by FLBZ (10 MUM, 72 hours); similar results were obtained with mf of Brugia malayi. We also measured the effects of FLBZ on transmission of mf. Aedes aegypti were fed FLBZ-exposed B. malayi mf and dissected 24 hours or 14 days postfeeding to count mf that crossed the midgut and developed to infective L3. FLBZ impaired the ability of mf to cross the midgut, regardless of duration of exposure (>= 2 hours). FLBZ also prevented the development of mf to L3s, irrespective of duration of exposure or concentration. FLBZ is not microfilaricidal under these conditions; however, it blocks transmission. These results support the possibility that FLBZ may be a useful macrofilaricide in loiasis regions and may limit transmission from treated individuals. PMID- 29141765 TI - Bionomics and Spatial Distribution of Triatomine Vectors of Trypanosoma cruzi in Texas and Other Southern States, USA. AB - Defining spatial and temporal occurrences of triatomine vectors of Trypanosoma cruzi, the agent of Chagas disease, in the US is critical for public health protection. Through a citizen science program and field collections from 2012 to 2016, we collected 3,215 triatomines, mainly from Texas. Using morphological and molecular approaches, we identified seven Triatoma species and report sex, length, and blood engorgement status. Many citizen-collected triatomines (92.9%) were encountered indoors, in peridomestic settings, or in dog kennels and represent spillover transmission risk of T. cruzi to humans and domestic animals. The most commonly collected species were Triatoma gerstaeckeri and Triatoma sanguisuga. Adult T. gerstaeckeri were collected from May to September, peaking from June to July, whereas adult T. sanguisuga were active later, from June to October, peaking from July to September. Based on cross correlation analyses, peaks of captures varied by species and across years. Point pattern analyses revealed unique occurrences of T. sanguisuga in north and east Texas, T. gerstaeckeri in south and west Texas, Triatoma indictiva and Triatoma lecticularia in central Texas, and Triatoma rubida in west Texas. These relatively unique spatial occurrences suggest associations with different suitable habitats and serve as a basis for future models evaluating the ecological niches of different vector species. Understanding the temporal and spatial heterogeneity of triatomines in the southern United States will improve targeted interventions of vector control and will guide public outreach and education to reduce human and animal contact with vectors and reduce the risk of exposure to T. cruzi. PMID- 29141766 TI - Molecular Detection and Characterization of Wolbachia pipientis from Culex quinquefasciatus Collected from Lahore, Pakistan. AB - The gram-negative, pleomorphic endosymbiont Wolbachia is known to infect a large number of insects and other arthropods naturally. This bacterium modifies the host biology, mainly causing reproductive alterations including feminization, death of male, parthenogenesis, and importantly cytoplasmic incompatibility. Wolbachia-induced cytoplasmic incompatibility results in nonviable offspring and vector population suppression. In addition, this bacterium rapidly spreads and propagates within the host population. This study is the first report on Wolbachia detection and characterization from Culex quinquefasciatus collected from Lahore, Pakistan. For this purpose, mosquito adults were collected from different localities of Lahore and identified at the species level. A total of 145 pairs of ovaries were individually subjected to DNA isolation, and polymerase chain reaction amplification of three (wsp, 16S rRNA, and ftsZ) genes were investigated. In all, 128 females were found positive, representing 82.3% infection rate. The phylogenetic analysis indicated that the detected endosymbiont had 100% homology with Wolbachia pipientis wPip strain and supergroup B. The detection of the local strain of Wolbachia (wPip) will be useful in investigating its potential for the control of dengue vector (Aedes aegypti) and reducing dengue transmission in Pakistan. PMID- 29141767 TI - Acute Q Fever Case Detection among Acute Febrile Illness Patients, Thailand, 2002 2005. AB - Acute Q fever cases were identified from a hospital-based acute febrile illness study conducted in six community hospitals in rural north and northeast Thailand from 2002 to 2005. Of 1,784 participants that underwent Coxiella burnetii testing, nine (0.5%) participants were identified in this case-series as acute Q fever cases. Eight case-patients were located in one province. Four case-patients were hospitalized. Median age was 13 years (range: 7-69); five were male. The proportion of children with acute Q fever infection was similar to adults (P = 0.17). This previously unrecognized at-risk group, school-age children, indicates that future studies and prevention interventions should target this population. The heterogeneity of disease burden across Thailand and milder clinical presentations found in this case-series should be considered in future studies. As diagnosis based on serology is limited during the acute phase of the disease, other diagnostic options, such as polymerase chain reaction, should be explored to improve acute case detection. PMID- 29141769 TI - Turning attention to clinician engagement in Victoria. AB - The engagement of clinicians with employing organisations and with the broader health system results in better safer care for patients. Concerns about the adequacy of clinician engagement in the state of Victoria led the Victorian Department of Health and Human Services to commission a scoping study. During this investigation more than 100 clinicians were spoken with and 1800 responded to surveys. The result was creation of a clear picture of what engagement and disengagement looked like at all levels - from the clinical microsystem to state health policy making. Multiple interventions are possible to enhance clinician engagement and thus the care of future patients. A framework was developed to guide future Victorian work with four elements: setting the agenda, informing, involving and empowering clinicians. Concepts of work or employee engagement that are used in other industries don't directly translate to healthcare and thus the definition of engagement chosen for use centred on involvement. This was designed to encourage system managers to ensure clinicians are full participants in design, planning and evaluation and in all decisions that affect them and their patients. PMID- 29141768 TI - Rat Fall Surveillance Coupled with Vector Control and Community Education as a Plague Prevention Strategy in the West Nile Region, Uganda. AB - Plague, primarily a disease of rodents, is most frequently transmitted by fleas and causes potentially fatal infections in humans. In Uganda, plague is endemic to the West Nile region. Primary prevention for plague includes control of rodent hosts or flea vectors, but targeting these efforts is difficult given the sporadic nature of plague epizootics in the region and limited resource availability. Here, we present a community-based strategy to detect and report rodent deaths (rat fall), an early sign of epizootics. Laboratory testing of rodent carcasses is used to trigger primary and secondary prevention measures: indoor residual spraying (IRS) and community-based plague education, respectively. During the first 3 years of the program, individuals from 142 villages reported 580 small mammal deaths; 24 of these tested presumptive positive for Yersinia pestis by fluorescence microscopy. In response, for each of the 17 affected communities, village-wide IRS was conducted to control rodent associated fleas within homes, and community sensitization was conducted to raise awareness of plague signs and prevention strategies. No additional presumptive Y. pestis-positive carcasses were detected in these villages within the 2-month expected duration of residual activity for the insecticide used in IRS. Despite comparatively high historic case counts, no human plague cases were reported from villages participating in the surveillance program; five cases were reported from elsewhere in the districts. We evaluate community participation and timeliness of response, report the frequency of human plague cases in participating and surrounding villages, and evaluate whether a program such as this could provide a sustainable model for plague prevention in endemic areas. PMID- 29141770 TI - Outcomes following changing from a two-tiered to a three-tiered hospital rapid response system. AB - Objectives The aim of the present study was to determine whether changing a hospital rapid response system (RRS) from a two-tiered to a three-tiered model can reduce disruption to normal hospital routines while maintaining the same overall patient outcomes.Methods Staff at an Australian teaching hospital attending medical emergency team and cardiac arrest (MET/CA) calls were interviewed after the RRS was changed from a two-tiered to three-tiered model, and the results were compared with a study using the same methods conducted before the change. The main outcome measures were changes in: (1) the incident rate resulting from staff leaving normal duties to attend MET/CA calls; (2) the cardiac arrest rate, (3) unplanned intensive care unit (ICU) admission rates; and (4) hospital mortality.Results We completed 1337 structured interviews (overall response rate 65.2%). The rate of incidents occurring as a result of staff leaving normal duties to attend MET/CA calls fell from 213.7 to 161.3 incidents per 1000 MET/CA call participant attendances (P<0.001), but the rate of cardiac arrest and unplanned ICU admissions did not change significantly. Hospital mortality was confounded by the opening of a new palliative care ward.Conclusion A three-tiered RRS may reduce disruption to normal hospital routines while maintaining the same overall patient outcomes.What is known about the topic? RRS calls result in significant disruption to normal hospital routines because staff can be called away from normal duties to attend. The best staffing model for an RRS is currently unknown.What does this paper add? The present study demonstrates, for the first time, that changing a hospital RRS from a two-tiered to a three-tiered model can reduce the rate of incidents reported by staff caused by leaving normal duties to attend RRS calls while maintaining the same overall patient outcomes.What are the implications for practitioners? Hospitals could potentially reduce disruption to normal hospital routines, without compromising patient care, by changing to a three-tiered RRS. PMID- 29141771 TI - Use of a rapid reverse-transcription recombinase aided amplification assay for respiratory syncytial virus detection. AB - In this study, a rapid reverse-transcription recombinase aided amplification (RT RAA) assay was developed to detect respiratory syncytial virus (RSV) subgroups A and B, respectively. The reaction was performed at 39 degrees C in less than 30min. The analytical sensitivities of RSVA and RSVB at 95% probability by probit regression analysis were 38copies per reaction and 35 copies per reaction, respectively, and no cross reactions with other related respiratory viruses were observed. The RT-RAA assay was further utilized to detect and subgroup 306 clinical specimens and the results showed that 79(25.82%, 79/306) samples were positive for RSV, of those 16(20.25%, 16/79) were identified as RSVA and 63(79.75%, 63/79) were RSVB, which is completely consistent with the results obtained by RSV RT-qPCR assay. In conclusion, the developed RAA assay will be of benefit as a faster, sensitive and specific alternative tool for detection of RSV. PMID- 29141772 TI - Acoustic Analysis of Soccer Fans in Acute Phonotrauma After the Match. AB - OBJECTIVES: Acute phonotrauma is the result of sound production by shouting or straining one's voice. In this study, we aimed to investigate the acute changes in the vocal folds and voices of soccer fans who voluntarily applied to our clinic after the soccer match where they engaged in acute phonotrauma. There are no other studies in the literature conducted on a similar sample group. STUDY DESIGN: This is a case-control study. METHODS: Videolaryngostroboscopic (VLS) examination, acoustic voice analysis, and Voice Handicap Index (VHI) questionnaire were performed on 29 voluntary soccer fans included to the study before the match and at the first hour after the match. The values obtained were compared statistically with each other and with 29 control groups without voice pathology. RESULTS: The jitter, shimmer, and normalized noise energy values measured after the match increased significantly statistically compared with the pre-match level, but harmonic noise ratio value decreased significantly (P < 0.05). VHI scores increased significantly after the match according to the pre match scores (P < 0.05). In the VLS examinations, there was no difference in the images before and after the match. CONCLUSIONS: It has been concluded that people who are using their voices loudly and intensely by shouting during the match are exposed to sound changes after the match, and if this situation becomes persistent, it may cause permanent voice pathologies. It is thought that VHI and acoustic voice analysis should be done together with VLS for diagnosis and follow up of voice changes for which the VLS examination alone is not sufficient. PMID- 29141773 TI - 47-Year-Old Woman With Anemia and Thrombocytopenia. PMID- 29141774 TI - 47-Year-Old Man With Abdominal Pain and Diarrhea. PMID- 29141775 TI - Impact of interventions by an antimicrobial stewardship program team on appropriate antimicrobial therapy in patients with bacteremic urinary tract infection. AB - BACKGROUND: Inappropriate antimicrobial therapy often leads to poor outcomes. This study aimed to evaluate the impact of an antimicrobial stewardship program (ASP) team on appropriate therapy, in patients with bacteremic urinary tract infection (UTI). PATIENTS AND METHODS: We retrospectively reviewed the interventions by the ASP team in 807 patients with bacteremic UTI. Interventions were divided into 3 groups: group A (conventional report), group B (conventional report and written alert on the chart), and group C (conventional report and oral recommendation with/without written alert). The appropriateness of antimicrobial therapy was assessed at 2 time points, based on blood culture results. RESULTS: The ASP team estimated that 166 and 576 patients received inappropriate antimicrobial therapy based on the results of Gram staining, and final report, respectively. Appropriate therapy after intervention was administered to 53.2% of group A, 63.5% of group B, and 89.3% of group C patients, respectively. Mortality was significantly lower in patients of de-escalation than in those with no antimicrobial changes, without prolonged hospital stay. CONCLUSION: This study provides one plausible benchmark for appropriate antimicrobial therapy by ASP, while observer bias and survivor treatment selection bias exist, and further studies including evaluation for severity are needed. PMID- 29141776 TI - Evaluation of a New Ensemble Learning Framework for Mass Classification in Mammograms. AB - BACKGROUND: Mammography is the most common screening method for diagnosis of breast cancer. MATERIALS AND METHODS: In this study, a computer-aided system for diagnosis of benignity and malignity of the masses was implemented in mammogram images. In the computer aided diagnosis system, we first reduce the noise in the mammograms using an effective noise removal technique. After the noise removal, the mass in the region of interest must be segmented and this segmentation is done using a deformable model. After the mass segmentation, a number of features are extracted from it. These features include: features of the mass shape and border, tissue properties, and the fractal dimension. After extracting a large number of features, a proper subset must be chosen from among them. In this study, we make use of a new method on the basis of a genetic algorithm for selection of a proper set of features. After determining the proper features, a classifier is trained. RESULTS: To classify the samples, a new architecture for combination of the classifiers is proposed. In this architecture, easy and difficult samples are identified and trained using different classifiers. Finally, the proposed mass diagnosis system was also tested on mini-Mammographic Image Analysis Society and digital database for screening mammography databases. CONCLUSION: The obtained results indicate that the proposed system can compete with the state-of-the-art methods in terms of accuracy. PMID- 29141777 TI - Design, synthesis and biological evaluation of novel oseltamivir derivatives as potent neuraminidase inhibitors. AB - Neuraminidase (NA) is one of the particular potential targets for novel antiviral therapy. In this work, a series of neuraminidase inhibitors with the cyclohexene scaffold were studied based upon the combination of 3D-QSAR, molecular docking, and molecular dynamics techniques. The results indicate that the built 3D-QSAR models yield reliable statistical information: the correlation coefficient (r2) and cross-validation coefficient (q2) of CoMFA (comparative molecular field analysis) are 0.992 and 0.819; the r2 and q2 of CoMSIA (comparative molecular similarity analysis) are 0.992 and 0.863, respectively. Molecular docking and MD simulations were conducted to confirm the detailed binding mode of enzyme inhibitor system. The new NA inhibitors had been designed, synthesized, and their inhibitory activities against group-1 neuraminidase were determined. One agent displayed excellent neuraminidase inhibition, with IC50 value of 39.6 MUM against NA, while IC50 value for oseltamivir is 61.1 MUM. This compound may be further investigated for the treatment of infection by the new type influenza virus. PMID- 29141779 TI - Five-field IMRT class solutions and dosimetric planning guidelines for implementing accelerated partial breast irradiation. AB - PURPOSE: A comprehensive set of planning guidelines was developed to aid in achieving reproducible dosimetric results for external beam accelerated partial breast irradiation (APBI). The methodology for the development of class solutions for dosimetric planning of the APBI technique, including dose constraint recommendations, is presented for target coverage and conformity as well as normal tissues. METHODS AND MATERIALS: A conservative patient setup was simulated on a linear accelerator, and a comprehensive arrangement of gantry and couch angles was measured for clearance. This provided the foundation for available beam arrangements to develop reproducible and conformal 5-field intensity modulated radiation therapy partial breast plans. Forty patients were planned. Patient plans were assessed according to anatomy specific features, such as laterality and seroma location within the breast. RESULTS: Clearance tables are presented to give permissible gantry and couch orientations according to measurements facilitated by patient simulation. Beam arrangement class solutions are presented for left- and right-sided APBI patients. Dosimetric recommendations are made based on the results of 40 patient plans. The median and range, describing target coverage and target conformity, are reported, as are normal tissue constraints for ipsilateral lung, ipsilateral breast, heart, liver, and contralateral breast. In all cases, the dose recommendations were at least as strict as multi-institutional APBI trials. In the case of ipsilateral lung and ipsilateral breast, the planning recommendations are more stringent. CONCLUSIONS: APBI using a 5-field intensity modulated radiation therapy technique was comprehensively developed and evaluated to provide recommendations yielding highly conformal and reproducible treatment plans. This provides a clear method to implement external beam APBI planning and delivery. PMID- 29141778 TI - Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE): A Translational, Integrated, and Transdisciplinary Approach. AB - BACKGROUND: It has been hypothesized that ischemic stroke can cause atrial fibrillation. By elucidating the mechanisms of neurogenically mediated paroxysmal atrial fibrillation, novel therapeutic strategies could be developed to prevent atrial fibrillation occurrence and perpetuation after stroke. This could result in fewer recurrent strokes and deaths, a reduction or delay in dementia onset, and in the lessening of the functional, structural, and metabolic consequences of atrial fibrillation on the heart. METHODS: The Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE) study is an investigator driven, translational, integrated, and transdisciplinary initiative. It comprises 3 complementary research streams that focus on atrial fibrillation detected after stroke: experimental, clinical, and epidemiological. The experimental stream will assess pre- and poststroke electrocardiographic, autonomic, anatomic (brain and heart pathology), and inflammatory trajectories in an animal model of selective insular cortex ischemic stroke. The clinical stream will prospectively investigate autonomic, inflammatory, and neurocognitive changes among patients diagnosed with atrial fibrillation detected after stroke by employing comprehensive and validated instruments. The epidemiological stream will focus on the demographics, clinical characteristics, and outcomes of atrial fibrillation detected after stroke at the population level by means of the Ontario Stroke Registry, a prospective clinical database that comprises over 23,000 patients with ischemic stroke. CONCLUSIONS: PARADISE is a translational research initiative comprising experimental, clinical, and epidemiological research aimed at characterizing clinical features, the pathophysiology, and outcomes of neurogenic atrial fibrillation detected after stroke. PMID- 29141780 TI - Guidelines for Screening Mammography. PMID- 29141781 TI - Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes. AB - BACKGROUND: Patients with heart failure (HF) have a poor prognosis and are categorized by ejection fraction (EF). OBJECTIVES: This study sought to characterize differences in outcomes in patients hospitalized with heart failure with preserved ejection fraction (HFpEF) (EF >=50%), heart failure with borderline ejection fraction (HFbEF) (EF 41% to 49%), and heart failure with reduced ejection fraction (HFrEF) (EF <=40%). METHODS: Data from GWTG-HF (Get With The Guidelines-Heart Failure) were linked to Medicare data for longitudinal follow-up. Multivariable models were constructed to examine 5-year outcomes and to compare survival to median survival of the U.S. POPULATION: RESULTS: A total of 39,982 patients from 254 hospitals who were admitted for HF between 2005 and 2009 were included: 18,299 (46%) had HFpEF, 3,285 (8.2%) had HFbEF, and 18,398 (46%) had HFrEF. Overall, median survival was 2.1 years. In risk-adjusted survival analysis, all 3 groups had similar 5-year mortality (HFrEF 75.3% vs. HFpEF 75.7%; hazard ratio: 0.99 [95% confidence interval: 0.958 to 1.022]; HFbEF 75.7% vs. HFpEF 75.7%; hazard ratio: 0.99 [95% confidence interval: 0.947 to 1.046]). In risk-adjusted analyses, the composite of mortality and rehospitalization was similar for all subgroups. Cardiovascular and HF readmission rates were higher in those with HFrEF and HFbEF compared with those with HFpEF. When compared with the U.S. population, HF patients across all age and EF groups had markedly lower median survival. CONCLUSIONS: Among patients hospitalized with HF, patients across the EF spectrum have a similarly poor 5 year survival with an elevated risk for cardiovascular and HF admission. These findings underscore the need to improve treatment of patients with HF. PMID- 29141782 TI - Long-Term Outcomes of Acute Heart Failure: Where Are We Now? PMID- 29141783 TI - Sexual Activity as a Trigger for Sudden Cardiac Arrest. PMID- 29141784 TI - Effects of Sodium Reduction and the DASH Diet in Relation to Baseline Blood Pressure. AB - BACKGROUND: Both sodium reduction and the DASH (Dietary Approaches to Stop Hypertension) diet, a diet rich in fruits, vegetables, and low-fat dairy products, and reduced in saturated fat and cholesterol, lower blood pressure. The separate and combined effects of these dietary interventions by baseline blood pressure (BP) has not been reported. OBJECTIVES: The authors compared the effects of low versus high sodium, DASH versus control, and both (low sodium-DASH vs. high sodium-control diets) on systolic blood pressure (SBP) by baseline BP. METHODS: In the DASH-Sodium (Dietary Patterns, Sodium Intake and Blood Pressure) trial, adults with pre- or stage 1 hypertension and not using antihypertensive medications, were randomized to either DASH or a control diet. On either diet, participants were fed each of 3 sodium levels (50, 100, and 150 mmol/day at 2,100 kcal) in random order over 4 weeks separated by 5-day breaks. Strata of baseline SBP were <130, 130 to 139, 140 to 149, and >=150 mm Hg. RESULTS: Of 412 participants, 57% were women, and 57% were black; mean age was 48 years, and mean SBP/diastolic BP was 135/86 mm Hg. In the context of the control diet, reducing sodium (from high to low) was associated with mean SBP differences of -3.20, 8.56, -8.99, and -7.04 mm Hg across the respective baseline SBP strata listed (p for trend = 0.004). In the context of high sodium, consuming the DASH compared with the control diet was associated with mean SBP differences of -4.5, -4.3, 4.7, and -10.6 mm Hg, respectively (p for trend = 0.66). The combined effects of the low sodium-DASH diet versus the high sodium-control diet on SBP were -5.3, 7.5, -9.7, and -20.8 mm Hg, respectively (p for trend <0.001). CONCLUSIONS: The combination of reduced sodium intake and the DASH diet lowered SBP throughout the range of pre- and stage 1 hypertension, with progressively greater reductions at higher levels of baseline SBP. SBP reductions in adults with the highest levels of SBP (>=150 mm Hg) were striking and reinforce the importance of both sodium reduction and the DASH diet in this high-risk group. Further research is needed to determine the effects of these interventions among adults with SBP >=160 mm Hg. (Dietary Patterns, Sodium Intake and Blood Pressure [DASH-Sodium]; NCT00000608). PMID- 29141785 TI - Environmental adversities and psychotic symptoms: The impact of timing of trauma, abuse, and neglect. AB - BACKGROUND: Trauma and adverse childhood experiences (ACE) occur more often in mental illness, including psychosis, than in the general population. Individuals with psychosis (cases) report a higher number and severity (dose) of adversities than healthy controls. While a dose-dependent increase of adversities has been related to more severe psychopathology, the role of type and timing is still insufficiently understood on the exacerbation of positive and negative psychotic symptoms. Moreover, dissociative symptoms were examined as potential mediator between adversities and severity of psychotic symptoms. METHODS: Exposure to adversities were assessed by interviews in n=180 cases and n=70 controls. In cases, symptom severities were obtained for psychotic symptoms and dissociation. Conditioned random forest regression determined the importance of type and timing of ACE for positive and negative symptom severity, and mediator analyses evaluated the role of dissociative symptoms in the relationship between adversities and psychotic symptoms. RESULTS: Cases experienced substantially more abuse and neglect than controls. Adversities were related in a dose-dependent manner to psychotic disorder. An array of adversities was associated with more severe positive symptoms, while the conditioned random forest regression depicted neglect at age 10 as the most important predictor. Dissociative symptoms mediated the small relation of trauma load in childhood and positive symptoms. CONCLUSION: The role of trauma and ACE on psychotic symptoms can be specified by neglect during frontocortical development in the exacerbation of positive symptoms. The mediating role of dissociation is restricted to the relation of childhood trauma and positive symptoms. PMID- 29141786 TI - Intraluminal thrombus is associated with early rupture of abdominal aortic aneurysm. AB - BACKGROUND: The implications of intraluminal thrombus (ILT) in abdominal aortic aneurysm (AAA) are currently unclear. Previous studies have demonstrated that ILT provides a biomechanical advantage by decreasing wall stress, whereas other studies have associated ILT with aortic wall weakening. It is further unclear why some aneurysms rupture at much smaller diameters than others. In this study, we sought to explore the association between ILT and risk of AAA rupture, particularly in small aneurysms. METHODS: Patients were retrospectively identified and categorized by maximum aneurysm diameter and rupture status: small (<60 mm) or large (>=60 mm) and ruptured (rAAA) or nonruptured (non-rAAA). Three dimensional AAA anatomy was digitally reconstructed from computed tomography angiograms for each patient. Finite element analysis was then performed to calculate peak wall stress (PWS) and mean wall stress (MWS) using the patient's systolic blood pressure. AAA geometric properties, including normalized ILT thickness (mean ILT thickness/maximum diameter) and % volume (100 * ILT volume/total AAA volume), were also quantified. RESULTS: Patients with small rAAAs had PWS of 123 +/- 51 kPa, which was significantly lower than that of patients with large rAAAs (242 +/- 130 kPa; P = .04), small non-rAAAs (204 +/- 60 kPa; P < .01), and large non-rAAAs (270 +/- 106 kPa; P < .01). Patients with small rAAAs also had lower MWS (44 +/- 14 kPa vs 82 +/- 20 kPa; P < .02) compared with patients with large non-rAAAs. ILT % volume and normalized ILT thickness were greater in small rAAAs (68% +/- 11%; 0.16 +/- 0.04 mm) compared with small non-rAAAs (53% +/- 16% [P = .02]; 0.11 +/- 0.04 mm [P < .01]) and large non-rAAAs (57% +/- 12% [P = .02]; 0.12 +/- 0.03 mm [P < .01]). Increased ILT % volume was associated with both decreased MWS and decreased PWS. CONCLUSIONS: This study found that although increased ILT is associated with lower MWS and PWS, it is also associated with aneurysm rupture at smaller diameters and lower stress. Therefore, the protective biomechanical advantage that ILT provides by lowering wall stress seems to be outweighed by weakening of the AAA wall, particularly in patients with small rAAAs. This study suggests that high ILT burden may be a surrogate marker of decreased aortic wall strength and a characteristic of high risk small aneurysms. PMID- 29141787 TI - The five things we all need to know about MACRA and alternative payment systems to compete and flourish. AB - Changes in how patient care will be reimbursed in the future are being determined right now. The law has changed to eliminate the past method of fee for service funded by the sustainable growth rate formula to payment based on quality. You need to know how the system functions to prevent a 4% reduction in Medicare reimbursement in 2019. You need to know this now because data collected today in 2017 will determine your rate for 2019. This review provides you knowledge of how the system has changed, what is required of you right now to be successful, and how you can succeed in the future. Pertinent references are provided to allow you to query the Centers for Medicare and Medicaid Services for the most up-to-date information. PMID- 29141788 TI - Interleukin 1 receptor antagonist and 2'-5'-oligoadenylate synthetase-like molecules as novel biomarkers for multiple sclerosis patients in Bahrain. AB - BACKGROUND: Multiple sclerosis (MS) is a multi-factorial disease of the Central Nervous System (CNS) affecting young adults leading to significant disabilities over time. MS is now believed to be prevalent in Arabian Gulf area with high incidence due to environmental factors and unknown genetic variations. The objectives of this study was to detect up-regulated potential genes that might be involved in neuroinflammatory process in MS patients in Bahrain and to measure the protein levels of the expressed genes. METHODS: A microarray was used to investigate mRNA expression from 12 MS patients and 12 control subjects in Bahrain where the mRNA came from peripheral blood leukocytes. Also, 80 MS patients and 80 control subjects were analyzed to measure serum protein levels of the expressed genes by ELISA. RESULTS: The data showed 15,480 genes expressed from over 47,000 transcripts and variants. Only 5 genes were significantly up regulated in MS patients vs control subjects; namely TNF-AIP6, IL-1RA, OASL, CLC and DOCK4 (p < 0.05). Conversely, KIAA0125 gene was significantly down-regulated (p < 0.0003). Analysis of the effector molecules of the up-regulated genes revealed that 83 MS patients had positive serum level of OASL, 87 MS patients had positive serum levels of IL-1RA, and none of the 88 MS patients showed detectable serum levels of TNF-AIP6, CLC or DOCK4. CONCLUSIONS: OASL and IL-1RA genes were strongly expressed in MS patients and that their effector molecules may be considered as biomarkers associated with the inflammatory process of the disease and possibly treatment response. PMID- 29141789 TI - A case of seropositive Neuromyelitis Optica in a paediatric patient with co existing acute nephrotic syndrome. AB - Neuromyelitis optica (NMO) and NMO spectrum disorder (NMOSD) is a rare relapsing autoimmune disease of the central nervous system constituting less than 1% of demyelinating diseases (Jeffery and Buncic, 1996). It preferentially affects the optic nerves and spinal cord, with the brain parenchyma generally spared. Demyelinating lesions are characterised by longitudinally extensive transverse myelitis (LETM) and often longitudinally extensive optic neuritis. Following the discovery of a novel pathogenic antibody, Aquaporin 4 in 2004 (Lennon et al., 2004) this disease has been seen as a separate entity from Multiple Sclerosis (MS). We report the case of a severe AQP4 IgG case of NMO in a 10 year old child. This case unusually had a coexisting diagnosis of acute nephrotic syndrome which has only been reported once previously in the literature2. This article will examine some of the treatment challenges and the spectrum of co-existing autoimmune disease in NMOSD. PMID- 29141790 TI - Cerebral toxoplasmosis in an MS patient receiving Fingolimod. AB - Multiple Sclerosis (MS) is an autoimmune disease in which lymphocytes target putative myelin antigens in the CNS, causing inflammation and neurodegeneration. Fingolimod (FTY720) is an immunosuppressive drug used as a second line therapy for relapsing forms of MS due to its safety profile and good response to treatment. Despite its safety, there are still concerns about the possibility of Fingolimod being linked to the development of opportunistic infections like disseminated varicella zoster infections and herpes simplex encephalitis. In this case report, we describe one patient with past medical history of MS in current treatment with Fingolimod for the last year which presents herself with hemiparesis, fever and fatigue. The initial MRI showed multiple demyelinating like lesions that could have corresponded to the tumefactive form of MS relapse. The blood work up revealed leukopenia with lymphopenia and a CD4+ count of 200 cell/mm3. Treatment for acute relapse was initiated with little to no response. Further examination was carried by the clinicians, a lumbar puncture was performed and it showed pleocytosis with increased protein levels. Later, several serologic studies were performed and both IgM and IgG antibodies for Toxoplasma were positive. Diagnosis of cerebral toxoplasmosis was made and there was no evidence of HIV infection or other causes of secondary immunodeficiency in this patient, except the use of fingolimod. Evidence of decreased levels of CD4+ due to Fingolimod use is concerning. The risk of opportunistic infections in these patients must be considered in order to start or continue therapy with these agents. Further studies are needed to determine the percentage of the population at risk of immunosuppression and its long-term consequences as well as new actions to prevent infections. PMID- 29141791 TI - Comparing the efficacy of disease-modifying therapies in multiple sclerosis. AB - Establishing the relative efficacy and safety of the different disease modifying therapies (DMTs) in multiple sclerosis (MS) is critical to the choice of agent that clinicians recommend for individual MS patients. The best evidence for the relative efficacy of the different DMTs comes from head-to-head randomized clinical trials (RCTs). Understanding that outcome-measures with the best established validity are the relapse rate and the actual (not the "confirmed") change in the extended disability status scale (EDSS), we conclude from these head-to-head RCTs that interferon-beta (IFNbeta) given subcutaneously multiple times per week (either IFNbeta-1b or IFNbeta-1a) and glatiramer acetate (GA) are about equivalent in terms of efficacy and that both of these agents, as well as many of the other DMTs, are superior to weekly intramuscular IFNbeta-1a. Nevertheless, as ever-newer agents with novel mechanisms of action are brought to the marketplace, such direct head-to-head trials are becoming increasingly impractical, raising the need for alternative methods to draw reasonable inferences from less rigorous clinical data. One possible approach to judging comparative efficacy is to make comparisons across clinical trials using the complimentary analytic methods of calculating both the relative risk/rate and the absolute risk/rate reductions. A consideration and application of this analytic approach is undertaken here. It is only with an understanding of the safety and efficacy of the different agents that we can select, together with the patient, the right agent for the right person. PMID- 29141792 TI - CD25 gene polymorphism and multiple sclerosis. PMID- 29141793 TI - Information processing deficits as a driving force for memory impairment in MS: A cross--sectional study of memory functions and MRI in early and late stage MS. AB - BACKGROUND: Memory impairment (MI) is a common symptom of MS. Previous studies were conflicting in respect to the possible existence of early MI and the role of hippocampal atrophy. The objective of this study was to investigate MI and structural MRI correlates in homogenous groups of early and late MS, controlling for a potential information-processing speed (IPS) deficit, and utilizing multiple memory test paradigms. METHODS: 152 individually matched subjects were recruited: early MS (EMS, N = 25, disease duration 1.0 +/- 0.8 years), late MS (LMS, N = 52, 16.5 +/- 5.2 years), and corresponding controls. Five memory tests were utilized to account for differences in learning material (verbal, visual), encoding (incidental, intentional), and retrieval (free recall, recognition, recurring recognition). Performance was related to IPS, memory-specific (hippocampal volumes), and unspecific MRI measures (T1/T2LL, brain volume, cortical thickness). RESULTS: Memory was impaired across all tests in LMS, but not in EMS. LMS-patients were also significantly impaired in IPS which was correlated with several memory scores. Regression analyses revealed IPS and cortical thickness as predictors for visual MI, and IPS, sex, and left hippocampal volume as predictors for verbal MI. CONCLUSION: Additionally to direct destructions in memory specific tracts such as the hippocampus, memory decline in MS may also be related to a general factor comprising slowed information-processing and global tissue loss. PMID- 29141794 TI - Short term outcome of ADEM: Results from a retrospective cohort study from South India. AB - INTRODUCTION: Acute disseminated encephalomyelitis (ADEM), an immune mediated inflammatory disease is common in children. The profile and immediate outcome of children hospitalized with ADEM is scarce in the available literature. OBJECTIVES: We aimed to study the clinical profile of children with ADEM and to look for prognostic factors for outcome at discharge from hospital METHODS: We chose a retrospective cohort study of all children diagnosed with ADEM at our institution between January 2006 and December 2015, and they were evaluated, after excluding other diagnoses when they were summoned for a follow up visit. The major outcome variables were the modified Rankin Scale (mRS), the Kurtzke Expanded Disability Status Scale (EDSS) and the Glasgow outcome score (GOS) RESULTS: There were 102 children (with a mean follow up of 4.81 +/- 2.78 years) and mean age at presentation, 6.16 +/- 3.1 years. Pyramidal signs, ataxia, fever at onset, brain stem signs, seizures, myelitis and headache were the commoner clinical manifestations. Movement disorders particularly disabling tremor was seen in 12%. Only 52% had MRI lesions confined to supratentorial region, with 20% having thalamic lesions, 14% with corpus callosal lesions and 28% with brain stem hyperintensities. Three patients expired during the acute stage of the disease, the rest recovering with a mean mRS score of 1.92 +/- 1.7 and EDSS score of 2.96 +/- 3.05. On multivariable regression analysis, using mRS, presence of fever at admission, myelopathy with a definite sensory level and ventilator associated pneumonia were associated with a bad outcome. Using EDSS score (multivariable regression), presence of myelopathy with a definite sensory level and coma were associated with a bad outcome. Using GOS score (multivariable regression), presence of myelitis with a definite sensory level, signs of meningeal irritation and encephalomyeloradiculoneuropathy type of ADEM were associated with a bad outcome and headache with a good prognosis. The mean of the number of hours of altered sensorium and the mean duration of hospital stay in days had a significant association using the mRS, EDSS score and GOS. CONCLUSION: This study shows a profile of ADEM in South Indian children at admission and at discharge from hospital. ADEM has a good immediate outcome though death during the nadir of disease has been recorded in this study and in the literature and effort should be taken for optimal life support for these children who would have a good outcome if life support is successful. We have been able to show that, presence of myelopathy, the mean number of hours of altered sensorium and the mean duration of hospital stay were associated with a bad prognosis using three different outcome scales. Fever at admission, ventilator associated pneumonia, more profound altered sensorium at nadir of disease, signs of meningeal irritation at presentation and lower motor neuron involvement also, during the course of disease were associated with an immediate bad outcome using one of the outcome scores used in our study. Future studies should also address the question of why children with myelopathy, signs of lower motor involvement and fever at onset have a bad immediate outcome. PMID- 29141795 TI - Validity and reliability of the International Cooperative Ataxia Rating Scale (ICARS) and the Scale for the Assessment and Rating of Ataxia (SARA) in multiple sclerosis patients with ataxia. AB - BACKGROUND: Ataxia is an extremely common problem in multiple sclerosis (MS) patients. Thus, appropriate scales are required for detailed assessment of this issue. The aim of our study was to investigate the reliability and validity of the Turkish version of the International Cooperative Ataxia Rating Scale (ICARS) and Scale for the Assessment and Rating of Ataxia (SARA), which are widely used in ataxia evaluation in the context of other cerebellar diseases. METHOD: This cross-sectional study included 80 MS patients with Kurtzke cerebellar functional system score (C-FSS) greater than zero and slight pyramidal involvement. The Expanded Disability Status Scale (EDSS), C-FSS, and Berg Balance Scale (BBS) were administered. SARA and ICARS were assessed on first admission by two physical therapists. Seven days later, second assessments were repeated in same way for reliability. RESULTS: Intra-rater and inter-rater reliability were found to be high for both ICARS and SARA (p< 0.001) The Cronbach's alpha coefficients were 0.922 and 0.921 for SARA (reviewer 1 and reviewer 2 respectively) and 0.952 and 0.952 for ICARS (reviewer 1 and reviewer 2, respectively). There were no floor or ceiling effects determined for either scale except for item 17 of ICARS (p= 0.055). The EDSS total score had significant correlations with both SARA and ICARS (rho: 0.557 and 0.707, respectively). C-FSS had moderate correlation with SARA and high correlation with ICARS (rho: 0.469 and 0.653, respectively). BBS had no significant correlation with SARA and ICARS. (rho: -0.048 and -0.008 respectively). According to the area under the curve (AUC) value, ICARS is the best scale to discriminate mild and moderate ataxia. (AUC: 0.875). Factor analyses of ICARS showed that the rating results were determined by five different factors that did not coincide with the ICARS sub-scales. CONCLUSION: Our study demonstrated that ICARS and SARA are both reliable in MS patients with ataxia. Although ICARS has some structural problems, it seems to be more valid given its high correlations with EDSS and C-FSS. SARA also can be preferred as a brief assessment. PMID- 29141796 TI - High dose biotin as treatment for progressive multiple sclerosis. AB - BACKGROUND: Published data suggested high dose biotin improved patients with progressive MS. We wished to determine benefits and side effects of administering daily high dose biotin to patients with progressive multiple sclerosis in a large MS specialty clinic. METHODS: Forty-three patients with progressive multiple scleroses were prescribed pharmaceutical grade biotin as a single daily dose of 300mg/day. Brain MRIs were performed at baseline and after one year on biotin. Quantitative neurologic exams (EDSS) and blood work monitoring for biotin toxicity were performed at baseline and every three months thereafter. RESULTS: High dose biotin was safe, and well tolerated, with no evidence of toxicity on blood work and no new lesions on brain MRIs. None of the patients' EDSS scores improved. One-third of patients (38-43%) worsened, most often with increased lower extremity weakness, worsened balance, and more falling, with two patients worsening sufficiently to increase their EDSS scores by 0.5. Several worsened patients improved after stopping biotin. CONCLUSION: High dose biotin was safe and well tolerated, but of no demonstrable long-term benefit. More than one-third of patients worsened while on biotin, most likely due to their disease, but in some patients also possibly due to the inability of their injured central nervous systems to respond to the increased metabolic demands induced by biotin. PMID- 29141797 TI - Diagnosis and management of Neuromyelitis Optica Spectrum Disorder (NMOSD) in Iran: A consensus guideline and recommendations. AB - Neuromyelitis Optica Spectrum Disorder (NMOSD) is a relapsing neuro inflammatory disease of the central nervous system that typically presents with optic neuritis or myelitis and may cause severe disability. The diagnostic criteria have been updated and several immunosuppressive agents have been demonstrated to prevent acute exacerbations. As the disease rarely develops in a progressive course, management of acute attacks and proper prevention of exacerbations may change the long term out-come and prevent future disability. Consensus recommendations and guidelines will help the physicians to improve their practice and unify the treatment approaches in different communities. In order to develop a national consensus and recommendations for the diagnosis and management of NMOSD in Iran, a group of neurologists with long term experience in management of NMOSD were gathered to develop this consensus based on available national and international data. The primary draft was prepared and discussed to suggest the most appropriate treatment for these patients. We propose strategies for early diagnosis and treatment for prevention of relapses and minimizing consequences of attacks as a primary therapeutic goal. Attacks are currently treated with intravenous corticosteroids and, in refractory cases, with plasma exchange. All participants agreed on preventive treatment with currently available immunosuppressive agents such as azothioprin, rituximab and mycofenolate mofetil based on previous positive data in NMOSD in order to reduce attack frequency. The current consensus reviews the previous data and provides the clinicians with practical recommendations and advices for the diagnosis and management of NMOSD based on scientific data and clinical experience. PMID- 29141798 TI - Ecotropic Viral Integration Site 5 (EVI5) variants are associated with multiple sclerosis in Iranian population. AB - BACKGROUND: Multiple sclerosis (MS) is a multifactorial disorder with immunological basis. Numerous genetic and environmental factors contribute in its pathogenesis. Several genetic loci have been shown to be associated with MS risk. Among genes whose participation in MS has been evaluated is Ecotropic Viral Integration Site 5 (EVI5). EVI5 is a common site of retroviral integration with a possible role in T-cell lymphomagenesis. METHODS: In the current study, we aimed to confirm association of the single nucleotide polymorphisms (SNPs) within EVI5 gene with MS in 410 relapsing-remitting MS patients and 410 controls from Iranian population. The rs6680578, rs10537781 and rs11810217 genotypes were defined by amplification-refractory mutation system (ARMS)-PCR method. RESULTS: The allele and genotype frequencies of rs6680578 and rs11810217 were not significantly different between cases and controls. However, in the rs10735781 the GG genotype was significantly associated with MS risk in recessive (P = 0.03, OR (95%CI) = 1.84 (1.05-3.19)) and co-dominant models (P = 0.02, OR 95%CI) = 1.90 (1.08 3.35)). In addition, T G T haplotype (rs6680578, rs10735781 and rs11810217 respectively) was associated with MS risk while T C C, A G T and A C T had a protective effect against MS. CONCLUSION: The results of the current study provide further evidences for participation of EVI5 in MS pathogenesis. PMID- 29141799 TI - The +4259A>C polymorphism of TIM-3 but not -1637C>T polymorphism of TIM-1 is associated with Multiple sclerosis in Isfahan population. AB - BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) which initiated and mediated by autoreactive T helper1 cells directed against myelin antigens. One of T cell surface receptors is T cell immunoglobulin and mucin domain (TIM) family which its importance in immunology is recently discovered. These molecules have important immunological function by regulation of T effector cells. METHODS: In the present study, we analyzed the frequency of +4259A>C polymorphism in TIM-3 and -1637C>T polymorphism in TIM-1 gene in MS patients and healthy controls using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) method. RESULTS: We found that the polymorphism +4259A>C in exon 3 of the TIM-3 gene is associated with susceptibility to the MS (P = 0.029, OR (95%CI) = 1.841) but the other polymorphism, -1637T>C, in the promoter region of TIM-1 is not (p= 0.064). CONCLUSION: Our findings suggest that +4259A>C polymorphism in TIM-3 gene may be one of the important genetic factors associated with the MS susceptibility among Iranian populations. PMID- 29141800 TI - Elevated plasma fibrinogen levels in multiple sclerosis patients during relapse. AB - : Fibrinogen is a protein that plays a key role in blood coagulation and thrombosis and it is involved in several inflammatory processes; in multiple sclerosis (MS) may be related with blood-brain barrier (BBB) disruption. We analysed the relationship between plasma fibrinogen levels and the presence of active lesions on magnetic resonance imaging (MRI) during relapses of multiple sclerosis (MS) and clinically isolated syndrome (CIS) patients. METHODS: We collected data of patients admitted to a tertiary-care hospital with relapse of MS and CIS from 2008 to 2013 and we analysed the relation between plasma fibrinogen levels (normal: 200mg/dl-417mg/dl) and the presence of active lesions on brain or spinal MRI. RESULTS: A total of 58 patients were included, 45 (77%) CIS patients, 12 (21%) relapsing-remitting MS (RR-MS) and 1 (2%) active progressive MS (P-MS). 17 patients had high plasma fibrinogen levels (> 417mg/dl). Among total of patients with elevated plasma fibrinogen, 15 (88%) had active lesions on MRI and only 2 (12%) did not have active lesion on MRI (p = 0,013) with a specificity of 95%. All patients with fibrinogen > 417mg/dl were CIS (p = < 0.05). DISCUSSION: We observed that high plasma fibrinogen levels had a high specificity high specificity, but low sensitivity (only 40%) for detection of active lesions on MRI during relapses of MS. These findings support the hypothesis that fibrinogen could play an important role on the development of MS lesions, however, additional studies are needed to confirm these results. PMID- 29141801 TI - Treating asymptomatic bacteriuria before immunosuppressive therapy during multiple sclerosis: Should we do it? PMID- 29141802 TI - Examining the contributions of environmental quality to pediatric multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a presumed autoimmune disease caused by genetic and environmental factors. It is hypothesized that environmental exposures (such as air and water quality) trigger the innate immune response thereby activating a pro-inflammatory cascade. OBJECTIVE: To examine potential environmental factors in pediatric MS using geographic information systems (GIS). METHODS: Pediatric MS cases and healthy controls were identified as part of an ongoing multicenter case-control study. Subjects' geographic locations were mapped by county centroid to compare to an Environmental Quality Index (EQI). The EQI examines 5 individual environmental components (air, land, water, social, built factors). A composite EQI score and individual scores were compared between cases and controls, stratified by median proximity to enrollment centers (residence <20 or >=20 miles from the recruiting center), using logistic regression. RESULTS: Of the 287 MS cases and 445 controls, 46% and 49% respectively live in areas where the total EQI is the highest (worst environmental quality). Total EQI was not significantly associated with the odds for MS (p = 0.90 < 20 miles from center; p = 0.43 >= 20 miles); however, worsening air quality significantly impacted the odds for MS in those living near a referral center (OR = 2.83; 95%CI 1.5, 5.4) and those who reside >= 20 miles from a referral center (OR = 1.61; 95%CI 1.2, 2.3). CONCLUSION: Among environmental factors, air quality may contribute to the odds of developing MS in a pediatric population. Future studies will examine specific air constituents and other location-based air exposures and explore potential mechanisms for immune activation by these exposures. PMID- 29141803 TI - "Nail loss after teriflunomide treatment: A new potential adverse event". AB - Nail loss might represent a new, reversible, adverse event associated with teriflunomide treatment. It shares close analogies with hair loss and thinning, known adverse events of teriflunomide. MS specialists should be aware of this possibility and evaluate treatment discontinuation. PMID- 29141804 TI - Validity and reproducibility of the Italian version of the patient determined disease steps scale in people with multiple sclerosis. PMID- 29141805 TI - Treating depression in multiple sclerosis with antidepressants: A brief review of clinical trials and exploration of clinical symptoms to guide treatment decisions. AB - Depression is a common comorbidity in patients with multiple sclerosis (MS). Those with MS and concurrent depression have poorer quality of life and are also less likely to be compliant with disease-modifying treatment, which may ultimately affect their MS disease course. Treating depression in MS with pharmacological agents can improve not only depression, but may also impact the MS disease course. However, no guidelines exist around treating depression in MS. Few randomized-controlled trials using antidepressants in MS exist. Here, we briefly review trials using antidepressant medications to treat depression in MS. We also propose individualizing treatment of depression in MS, as the depressive symptoms and MS symptoms and disease course differ significantly between patients. We explore the heterogeneity in presentation of depression through different comorbid symptoms in MS, and discuss which antidepressant options would be appropriate in each situation. We propose that future clinical trials should incorporate differences in issues between those with depression (e.g. sexual dysfunction, urinary incontinence) into analysis. As MS is incredibly heterogeneous, treating concurrent depression on a case-by-case basis may enable for improving quality of life and the MS disease course. PMID- 29141806 TI - Marked neutropenia: Significant but rare in people with multiple sclerosis after alemtuzumab treatment. AB - BACKGROUND: Alemtuzumab is a CD52-specific monoclonal antibody that markedly depletes T and B lymphocytes and inhibits relapsing multiple sclerosis (MS). However, polymorphonuclear neutrophils also express CD52 and can be depleted by alemtuzumab, thereby potentially contributing to the infections that develop post alemtuzumab treatment. Surprisingly, however, the degree of neutrophil depletion in MS was not included in the pivotal trial reports. METHODS: The regulatory submission of the Comparison of Alemtuzumab and Rebif(r) Efficacy in MS 1 and 2 trials was obtained from the European Medicines Agency through Freedom of Information. The data relating to neutrophils was extracted. RESULTS: Data extraction from the submission was straightforward. In year one 72/811 (8.9%) and in year two 116/808 (14.4%) people with MS (pwMS) developed neutropenia. The degree of neutropenia was generally mild, and only 5/811 (0.6%) in year 1 and 12/808 (1.5%) in year 2 developed grade 3-4 toxicity (< 1.0 * 109/L). Two pwMS developed severe neutropenia-related adverse events. CONCLUSIONS: Treatment with alemtuzumab induces neutropenia, which is mild in the large majority of pwMS treated. Leucocyte levels following alemtuzumab should be monitored as a marker of efficacy and safety; persistent neutropenia may require treatment. PMID- 29141807 TI - A possible role of impaired cell-mediated immunity in the pathogenesis of tumefactive demyelinating lesions. PMID- 29141808 TI - What should a person with relapsing-remitting multiple sclerosis know? - Focus group and survey data of a risk knowledge questionnaire (RIKNO 2.0). AB - BACKGROUND: Risk knowledge is relevant to make informed decisions in multiple sclerosis (MS). The risk knowledge questionnaire for relapsing-remitting MS (RIKNO 1.0) was developed and piloted in Germany. OBJECTIVE: To produce a revised RIKNO 2.0 questionnaire using mixed methodology in a European setting. METHODS: The questionnaire was translated in seven languages. MS patient and health professional (HP) expert feedback was obtained from Germany, Italy, Estonia, Serbia, and the UK. A German web-based survey of RIKNO 2.0 compared the tool with the MS Knowledge Questionnaire (MSKQ), each one used with two versions (with/without a "don't know" DN option). RESULTS: While RIKNO 2.0 was considered difficult, it was rated as highly educational. One item was reframed, and two new items were added. The web-based German survey (n = 708 completers) showed that the DN version did not increase participation rate and did not produce significantly higher scores. Internal consistency (Cronbach alpha) without SN response was 0.73. RIKNO 2.0 scores showed normality distribution irrespective of the answering format. Item difficulty was high ranging from 0.07 to 0.79. Less than 50% of questions were answered correctly (mean 8.9) compared to 80.4% in the MSKQ (mean 20.1). Higher numeracy competency and education were significantly, albeit weakly, associated to higher scores for both RIKNO 2.0 and MSKQ. CONCLUSION: Including "don't know" options in knowledge questionnaires does not increase percentage of correct replies. RIKNO 2.0 is a complex questionnaire to be used in an educational context and studies on patient information. The tool is now available in seven languages. PMID- 29141809 TI - Treatment satisfaction across injectable, infusion, and oral disease-modifying therapies for multiple sclerosis. AB - BACKGROUND: The recent approval of oral disease-modifying therapies (DMTs) for multiple sclerosis (MS) has provided patients with a new route of therapy administration. Little research has compared patients' experiences with and perceptions of injectable, infusion and oral MS therapies. METHODS: Three hundred fifty-seven treated MS patients enrolled in the CLIMB study completed the Treatment Satisfaction Questionnaire for Medication (TSQM). The TSQM provides information regarding perceived effectiveness, side effects, convenience and overall satisfaction. The patients were treated with either interferon beta-1a intramuscular (IFNbeta-1a IM) (n = 40), interferon beta-1a subcutaneous (IFNbeta 1a SC) (n = 45), glatiramer acetate (GA) (n = 118), natalizumab (NTZ) (n = 44), fingolimod (n = 66), or dimethyl fumarate (BG-12) (n = 44). Multivariable linear regression models were used to compare treatment satisfaction across all DMTs and between patients treated with injectable (n = 203), infusion (n = 44), and oral (n = 110) DMTs. All models were adjusted for sex, age, EDSS, and time on treatment. RESULTS: Patients taking oral DMTs reported significantly higher convenience scores compared to patients taking either injectable or infusion DMTs. The adjusted difference in the mean overall convenience score was 26.87 (95% CI: 21.4, 32.34) for the comparison of orals and injectables and 17.53 (95% CI: 11.15, 23.9) for the comparison of orals and infusion. In addition, the proportion of patients reporting a side effect was significantly lower for orals compared to injectables (adjusted OR= 0.35; 95% CI: 0.18, 0.68) and infusion compared to injectables (adjusted OR= 0.14; 95% CI: 0.05, 0.35). CONCLUSION: Patients reported treatment with the oral medications as more convenient than the injectable and infusion DMTs. PMID- 29141810 TI - Levels of peripheral Th17 cells and serum Th17-related cytokines in patients with multiple sclerosis: A meta-analysis. AB - BACKGROUND: Multiple reports have described the proportion of Th17 cells in peripheral blood and serum levels of Th17-related cytokines in patients with multiple sclerosis (MS). To clarify the status of Th17 cells and Th17-related cytokines in MS patients, we did a meta-analysis of the results published previously to assess the levels of peripheral Th17 cells and serum Th17-related cytokines in patients with MS. METHODS: We searched Embase, PubMed, Cochrane, Web of Knowledge, FDA.gov, and Clinical Trials.gov systematically for studies reporting the proportion of Th17 cells and the serum levels of Th17-related cytokines (IL-17, IL23) in MS patients. Our main endpoints were the proportion of Th17 cells among CD4+ T cells in peripheral blood (PB), serum IL-17 levels, and serum IL-23 levels. We assessed pooled data by using a random-effects model. It has been registered at International Prospective Register of Systematic Reviews (PROSPERO) (number CRD42017059113). RESULTS: Of 560 identified studies, a total of 12 studies were selected in our analysis. Compared with control subjects, MS patients had a higher proportion of Th17 cells [1.37, (0.53, 2.21)] in PB, an elevated levels of serum IL-17 [2.48, (1.25, 3.71)] and an increased IL-23 levels in serum [2.29, (0.58, 4.00)]. CONCLUSION: Under random effect model of meta analysis, the data showed that the proportion of Th17 cells in PB and levels of serum IL-17 and IL-23 increased among MS patients compared to control subjects. This result demonstrated that Th17 cells and Th17-related cytokines may be involved in the pathogenic mechanisms of MS. PMID- 29141811 TI - Do gait patterns differ in men and women with multiple sclerosis? AB - BACKGROUND: Multiple Sclerosis (MS) affects men and women differently from several points of view: prevalence, severity of cognitive impairments and disability accumulation. However, it is unknown whether ambulatory dysfunctions are sex-related. This study investigated the existence of differences in spatio temporal and kinematic parameters of gait in men and women with MS using 3D gait analysis. METHODS: Gait patterns of 60 people with MS (pwMS, 32F, 28M) with low to moderate disability (average Expanded Disability Status Scale score 3, range 1 5.5) who underwent a gait analysis in the period 2014-2017 were retrospectively analyzed to calculate spatio-temporal parameters of gait and kinematics in the sagittal plane at hip, knee and ankle joints. RESULTS: Significant differences between the groups were found in kinematics of gait. In particular, men exhibited reduced ankle plantar-flexion, increased knee flexion and hip flexion. In contrast, no differences were found in spatio-temporal parameters normalized by considering individuals' anthropometry. CONCLUSIONS: The findings of the present study highlight the need to investigate gait dysfunctions in pwMS taking sex into consideration. Such an approach might be useful not only in better understanding the pathophysiology of gait disturbances originated by MS, but also in supporting a better orientation of rehabilitative treatments. PMID- 29141812 TI - Neuromyelitis optica spectrum disorders in Iran. AB - BACKGROUND: Neuromyelitys optica spectrum disorder (NMOSD) is a rare demyelinating disease; as a result, the epidemiological data on this disorder is scarce. In this regard, the aim of this study was to estimate the prevalence, serology, and clinical features of NMOSD in Caucasian population in Tehran, Iran. METHOD: A cross sectional study was performed in Tehran from 2015 to 2016 among patients registered with NMOSD diagnosis, based on consensus criteria published in 2015. The researchers designed a questionnaire to cover the important epidemiological and clinical data of NMOSD in Tehran. Structured face to face interviews were conducted with 103 patients by trained interviewers to collect the data. The logistic regression was applied in analysis via SPSS software package. RESULT: The prevalence of NMOSD in Tehran was 0.86 per 100,000 in 2016. Female to male ratio was 5:1 with mean age at the disease onset of 31.54. NMO-IgG were positive in 44 (46.8%) patients, and the primary presenting symptoms of TM were observed in 29 (28.2%) patients. The adjusted odds ratio for sex was estimated for depression (OR = 6.83; 95% CI: 1.47, 31.71), migraine (OR = 1.27; 95% CI: 1.13, 1.42), and hypothyroidism (OR = 1.25; 95% CI: 1.12, 1.39). CONCLUSION: The researchers indicated that the rate of NMOSD is significantly higher among females and younger age group. In addition, the history of depression, migraine, and hypothyroidism has been observed more among female patients in comparison to male patients. PMID- 29141813 TI - The neutrophil-to-lymphocyte ratio as disease actvity marker in multiple sclerosis and optic neuritis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). The neutrophil-to-lymphocyte ratio (NLR) has been identified as a disease activity marker in several diseases. We aim to evaluate the significance of the NLR in the different subtypes of MS, optic neuritis (ON) and in relation to disease activity and Expanded Disability Status Scale (EDSS). METHODS: We included 378 patients and 813 healthy controls (HC) from The Nordic Reference Interval Project 2000 (NORIP). Complete blood count, demographic and clinical data from patients were evaluated retrospectively. The NLRs were compared for all participants by Student's t-test. The comparison of NLR between relapse and remission, SPMS and PPMS, and RRMS and progressive MS were all adjusted for age, gender, EDSS and disease duration by using the linear regression model. Pearson correlation analysis was made between NLR and time of blood sampling. Logistic regression models were constructed for EDSS >= 4.0 as outcome. RESULTS: The NLR was significantly higher (p < 0.001) in MS and ON compared to HC. Patients in relapse had a higher NLR (p < 0.01) than patients in remission. No difference in NLR was found between RRMS and progressive MS patients and neither between SPMS and PPMS patients. No association was found between NLR and an EDSS score >= 4.0. CONCLUSION: NLR was higher in MS and ON patients compared to HC, indicating the occurrence of chronic inflammation. NLR may be an inexpensive and easily accessible supplemental marker of disease activity in RRMS. This needs confirmation in future trials. PMID- 29141814 TI - The impact of treatment adherence on clinical and economic outcomes in multiple sclerosis: Real world evidence from Alberta, Canada. AB - BACKGROUND: Approximately 1 in 400 Albertans has multiple sclerosis (MS). The current study objective was to determine the real-world impact of adherence to disease-modifying therapies (DMTs) on healthcare utilization and costs among MS patients utilizing administrative data from the Alberta health system in Canada. METHODS: MS patients were identified using a validated case definition (>= 1 inpatient record or >= 5 practitioner claims within 2 years) and the study index DMT was defined as the first claim for a DMT between 1 April 2011 and 31 March 2014. Treatment adherence was calculated using medication possession ratio (MPR), and patients with MPR >= 80% were considered adherent; healthcare utilization and costs were explored using multivariable negative binominal regression and logistic regression models. RESULTS: The majority of the 2864 MS patients identified were females, aged 35-55 years old. Overall, 66% of patients were adherent. Compared to non-adherent patients, adherent patients had fewer ambulatory care visits (all-cause: 8.8 vs 10.9, p = 0.0012; MS-related: 4.3 vs 5.3; p = 0.001), physician visits (all-cause: 15.1 vs 18.2, p = 0.0001; MS related: 3.6 vs 4.4; p = 0.0001), and hospitalizations (all-cause: 5.2% vs 10.2%, p < 0.0001; MS-related: 1.2% vs 2.5%, p = 0.0088). After adjusting for potential confounding factors adherent patients had approximately 20% less physician visits (MS-related: IRR 0.82 (0.79,0.86), p < 0.0001; all-cause: IRR 0.83 (0.81,0.85), p < 0.0001) and ambulatory care visits (MS-related IRR 0.80 (0.77,0.84), p < 0.0001; all-cause: IRR 0.82 (0.80,0.84), p < 0.0001) and approximately 50% fewer hospitalizations (MS-related: OR 0.50 (0.28-0.89), p < 0.0001; all-cause: OR 0.48 (0.35-0.64), p < 0.0001) than non-adherent patients. CONCLUSIONS: The current study found a significant impact of non-adherence to MS therapy on increased health system utilization. These findings demonstrate the importance of treatment adherence on clinical decision-making for patients with MS. PMID- 29141815 TI - Cognitive impairment in neuromyelitis optica spectrum disorders: What do we know? AB - The aim of this study is to make a descriptive review of the bibliography available on cognitive dysfunction in patients with neuromyelitis optica spectrum disorders (NMOSD). We selected fifteen studies that quantitatively assess the relationship between NMOSD and one or more cognitive variables. Results showed that patients with NMOSD had a decrease in cognitive functions. Cognitive dysfunctions were found in 35-67% of patients with NMOSD, specifically in the attention, memory and information processing speed. Cognitive dysfunctions were found to relate to injuries in white matter as well as clinical variables and depression. PMID- 29141816 TI - Optic neuritis with radiological longitudinal spinal cord involvement and seronegative anti-aquaporin antibody: Evidence from a case study. AB - In recent years, not only the incidence of brain demyelinating disease has increased, but also it seems that the world is facing new forms of autoimmune diseases of the brain. Distinguishing these diseases from each other is very important, since each requires a different treatment. The new criteria that were put forward in 2015 were meant to pave the way for better diagnosis of these diseases called neuromyelitis optica spectrum disease (NMOSD). However, too much emphasis on the criteria based on the convergence and association of radiological findings with the clinical symptoms actually causes confusion in the diagnosis. Here, the case of a 16-year-old child suffering from optic neuritis has been discussed. Her cervical magnetic resonance imaging (MRI) revealed longitudinal extensive transverse myelitis (LETM); however, the patient had no symptoms of the spinal cord's involvement. According to the 2015 criterion, the diagnosis of NMOSD cannot be accepted for this patient. Therefore, this case report emphasizes on the modification of the existing criterion. PMID- 29141817 TI - Lymphocytes in the treatment with interferon beta-1 b. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease affecting the central nervous system. One of the basic medications for the treatment of a clinically isolated syndrome (CIS) or relapsing-remitting MS is interferon beta (INFbeta). Although the exact mechanism of its effects is unknown, the medication has an anti-inflammatory and immunomodulatory effect. The goal of this study was to determine the characters which are affected in patients treated with INFbeta. METHODS: A total of 97 patients (25 males and 72 females) were included into the study. Patients were treated by INFbeta 1-b (subcutaneous injection, 250ug, each other day). Clinical evaluations were performed by an attending neurologist. Peripheral blood samples were obtained just prior to treatment and 5 years after INFbeta 1-b. Statistical analysis and processing of the obtained data were performed by using a comprehensive statistical software package MATLAB(r). RESULTS: A significant decrease of the observed parameters after 5 years' of treatment (significant at the 1% significance level) was found in the absolute and relative CD69 count, absolute cytotoxic/suppressor T lymphocyte count, absolute total leukocyte count, absolute natural killer cells count. A significant decrease of the observed parameters after 5 years' of treatment (significant at the 5% significance level) was found in the absolute lymphocyte count, relative cytotoxic/suppressor T lymphocyte count, relative CD3+CD69+ count and absolute CD8+CD38+ count. CONCLUSION: The treatment with interferon beta reduces clinical exacerbations in multiple sclerosis (MS) through several known immunomodulatory mechanisms. However, the exact mechanism of effect of this medication is not known. This study presents some parameters that were affected by the long-term INFbeta treatment. PMID- 29141818 TI - Does including the full CVLT-II and BVMT-R improve BICAMS? Evidence from a Belgian (Dutch) validation study. AB - BACKGROUND: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is a fast, easy-to-administer and already widely validated neuropsychological battery for cognition in multiple sclerosis. OBJECTIVE: The goals of our study were to validate the BICAMS in a Belgian Dutch-speaking population and to investigate to what extent including extensive versions of two of the three BICAMS subtests improved its psychometric qualities. METHODS: Ninety seven persons with MS and ninety-seven healthy controls were included and group matched on age, education level and gender. All participants performed the BICAMS with an extensive version of the CVLT-II and BVMT-R. RESULTS: The SDMT and BVMT-R were able to dissociate between the MS and healthy control group, while the CVLT II was not. Distributions of CVLT-II scores suggest learning effects in the MS group, indicating the need for alternative word lists or the construction of an adapted version fitted for repeated administration. Including the full CVLT-II and BVMT-R did not markedly improve the psychometric qualities of the BICAMS. CONCLUSION: This study validates the BICAMS in a Belgian Dutch-speaking population and facilitates the use of it in clinical practice, while providing evidence that including full versions of the CVLT-II and BVMT-R does not increase its psychometric qualities markedly. PMID- 29141819 TI - Autoimmune aquaporin-4 induced damage beyond the central nervous system. AB - Initially, it was believed that Aquaporin-4 (AQP4)- immunoglobulin G (IgG) only affected the central nervous system (CNS), and peripheral AQP4-expressing organs were usually spared. However, in recent years, increasing evidence has demonstrated that AQP4-IgG causes damage to peripheral organs beyond the CNS such as skeletal muscle, vestibulocochlear nerves, gastrointestinal tract, blood system, kidney, lung and placenta. Recently, the term "autoimmune aquaporin-4 channelopathy" has been proposed to incorporate a wide range of diseases associated with AQP4-IgG, including neuromyelitis optica spectrum disorders and AQP4-IgG-induced peripheral nerves system damage. Herein, we provide an overview of the clinical evidence of AQP4-IgG-associated peripheral organ damages and discuss the pathogenesis. PMID- 29141820 TI - Fulminant intramedullary spinal cord sarcoidosis. AB - Neurosarcoidosis is a rare disease with various clinical phenotypes. Thus, case reports and series broaden the understanding of this entity (Ibitoye et al., 2017). We present a case of isolated intramedullary spinal cord sarcoidosis, an exceedingly rare phenotype, which needs to be distinguished especially from neuromyelitis optica spectrum disorders (NMOSD). This report exemplifies the need for a systematic approach to diagnosis and management of spinal cord sarcoidosis. PMID- 29141821 TI - Development and validation of the coping with multiple sclerosis questionnaire. AB - BACKGROUND: Development of a self-report measure of coping with multiple sclerosis is required based on cultural factors, which can advance our understanding of the level of coping for care planning and improvement of coping and quality of life. The current study aimed to develop and validate the scale of coping with Multiple Sclerosis. METHODS: This methodological study was conducted in three phases. In the first phase, the concept of coping with MS was defined by the hybrid model. In the second phase, the item pool was generated from findings of the first phase. In the third phase, psychometric properties of the scale were evaluated including face, content and construct validity as well as reliability. RESULTS: 192 items in primary item pool were finally reduced to 35 items after evaluating the validity (face, content and construct validity) and reliability. Factor analyses revealed five factors: self-efficacy, self-regulation, accepting the current situation, treatment seeking and adherence to it, and emotional balance. Internal consistency and stability of the developed questionnaire confirmed with 0.93 and 0.96 respectively that indicated excellent reliability. CONCLUSION: The 35-item developed questionnaire is valid and reliable for assessment of levels of coping in Iranian people with MS. PMID- 29141822 TI - Epidemiological and clinical characteristics of multiple sclerosis in paediatric population in Slovenia: A descriptive nation-wide study. AB - BACKGROUND: Although multiple sclerosis usually affects young adults, paediatric onset multiple sclerosis (pMS) is increasingly recognized in the past ten years. The aim of the present study was to evaluate the incidence of pMS in Slovenia and to characterize the clinical, laboratory and neuroradiological characteristics of pMS at the disease onset. METHODS: We performed a national retrospective descriptive study including all patients diagnosed with pMS between January 1992 and June 2017. We reviewed data of all patients younger than 18 years at the first demyelinating event. RESULTS: The estimated incidence of pMS was 0.66/100,000 children per year. We included 61 patients (77% were female) with a median age at diagnosis of 16.3 years. In 4 patients, onset of pMS was before the age of 12 years old (childhood-onset pMS). Relapsing-remitting multiple sclerosis was most prevalent, with only 2 patients presenting a primary progressive pMS. Polysymptomatic pMS was found at onset in 59% of patients and monosymptomatic in 41%. In the cerebrospinal fluid study, 88% of patients had positive oligoclonal bands. Brain magnetic resonance imaging studies showed a predominant supratentorial involvement (100% of patients). CONCLUSION: The clinical pattern of pMS in our cohort of patients was characterized by polysymptomatic presentation and predominantly sensory symptoms at onset, developing a relapsing remitting pMS pattern. It is important to gather more information about the incidence of pMS and its initial presentation and clinical course to improve early recognition and appropriate initiation of immunomodulatory treatment. PMID- 29141823 TI - Delayed lymphocyte re-population following discontinuation of dimethyl fumarate and after switching to other disease modifying drug therapies. AB - BACKGROUND: Dimethyl fumarate (DMF) reduces absolute lymphocyte counts, CD4, and CD8 counts, without significantly affecting total white blood cell counts. However, the recovery rate of these cells after discontinuation of DMF is unknown. The effect of subsequent disease modifying therapies (DMTs) on re population rate is also unknown. OBJECTIVES: 1. To study the re-population rate of absolute lymphocytes, CD4, and CD8 counts back to baseline after discontinuation of DMF. 2. To measure the effect of subsequent DMTs on the re population rate of these cells after DMF therapy. 3. To study the effect of the duration of exposure to DMF on repopulation of these cells. METHODS: A retrospective chart review of subjects who had discontinued DMF and in whom, CBC with differential, CD4 and CD8 counts were available at baseline, discontinuation and at follow-up (n = 113). Linear mixed models were used to analyze and assess linear trends in lymphocyte counts after DMF had been discontinued. RESULTS: DMF causes a significant drop in absolute lymphocyte, CD4, and CD8 counts. Re population of these cells after discontinuation of DMF is significantly delayed, irrespective of whether or not a subsequent DMT is used, although there is a difference in re-population rate among DMTs. The re-population rate is also dependent on the duration of time patients have been exposed to DMF; longer exposure was associated with more delayed recovery. CONCLUSION: During this 30 month study period, re-population rates were significantly delayed post-DMF, irrespective of what subsequent DMT the patients received. Furthermore, no recovery of lymphocyte counts occurred in patients who were started on fingolimod or alemtuzumab after DMF was discontinued; in fact there was a continued decline in all of the cell populations studied. PMID- 29141824 TI - Inhibition of neurogenesis in a case of Marburg variant multiple sclerosis. AB - INTRODUCTION: Neural stem cells (NSC) are located essentially in the subventricular zone (SVZ), subgranular zone (SGZ), and along the central canal of the spinal cord. These cells can proliferate in vitro and differentiate into neurons, oligodendrocytes, and astroglia, thus contributing to repair in multiple sclerosis (MS). We conducted a pathological study to analyse neurogenic response in a patient with Marburg variant MS. METHODS: We present the case of a 27-year old immunocompetent patient with Marburg variant MS, a fulminant form of the disease. The condition lasted 20 days. Diagnosis was based on clinical symptoms and MRI showed demyelinating lesions located in subependymal areas and histopathological findings. Neurogenic niches (SVZ and dentate gyrus) were analysed by confocal microscopy using markers of proliferation (Ki-67, PCNA), neuroblasts (PSA-NCAM, DCX, Tuj1), stem cells (Nestin, GFAPdelta, SOX2, PAX6, Musashi), astrocytes (GFAP, AQ4), oligodendrocytes (NG2, Olig), microglia and cell infiltrates (IBA-1, CD68, MHCII), and cell death (TUNEL). RESULTS: Expression of the markers GFAPdelta, SOX2, and PAX6 in NSC was found to be very low. Likewise, markers of proliferation (Ki-67) and intermediate precursors (NG2) were also reduced. This lack of markers of the first stages of cell differentiation means that neurogenesis is inhibited even in very early stages of the disease. CONCLUSION: Inhibition of neurogenesis in our patient, which cannot be explained by the fulminant nature of his symptoms, may be related to inflammation and immune response. This finding may further our knowledge of repair mechanisms in MS. PMID- 29141825 TI - Radiculopathy in neuromyelitis optica. How does anti-AQP4 Ab involve PNS? AB - BACKGROUND: Until recently, the peripheral nervous system (PNS) had been known to be spared in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). However, some studies of late have reported PNS damage in demyelination diseases of the central nervous system (CNS) such as MS and NMOSD. Although multiple studies have reported characteristics reminiscent of peripheral neuropathy in MS, there have been limited reports in NMOSD. To investigate the incidence and pathology of peripheral neuropathy in NMOSD, we reviewed articles describing such cases including our own case. METHODS: We performed a search of all clinical studies of peripheral neuropathy in NMOSD published up to December 17, 2016. We put no restrictions on language or year of publication in our search. The following keywords were searched: radiculopathy, peripheral nervous system diseases, neuromyelitis optica, neuromyelitis optica septrum disorder, aquaporin 4, electrodiagnosis, neural conduction and electromyography. RESULT: We review ten cases (nine published reports and our own case study) of peripheral neuropathy in NMOSD. Each case could be confirmed as radiculopathy by electrodiagnostic (EDX) testing. Presently, there are two disparate viewpoints on peripheral neuropathy in NMOSD. In the first, aquaporin 4, which exists in the transitional zone of the CNS-PNS at the root level, may be the target of radiculitis in NMOSD. In the second, there may be some other unknown antibody to an axoglial antigen or something else that may play an active role in PNS damage. In our survey of ten case studies, the EDX results confirmed mixed axonal loss as well as demyelination type radiculopathy, which lends support to the first viewpoint. CONCLUSION: Pathophysiology of PNS damage in NMOSD might be due to radiculopathy. Although it seems to be rare, radiculopathy may actually be underestimated, and correspondingly underreported, due to its overlap with symptoms of myelitis. Therefore, further evaluation is needed to establish the incidence and pathophysiology of radiculopathy in NMOSD. PMID- 29141826 TI - Effects of cognitive versus motor dual-task on spatiotemporal gait parameters in healthy controls and multiple sclerosis patients with and without fall history. AB - BACKGROUND: The purpose of the current study was to compare the effects of cognitive or motor tasks on gait performance between healthy controls and multiple sclerosis (MS) patients with and without fall history. METHODS: The investigation included MS patients with fall history (n = 25) and without fall history (n = 25) and matched healthy controls (n = 25). Participants walked at their preferred speed on a motorized treadmill under three walking conditions in a randomized order: walking only, walking while performing a concurrent cognitive task (counting backward aloud by 3s), and walking while performing a concurrent motor task (carrying a tray with glasses). RESULTS: The findings showed that in patients with MS, regardless of fall history, spatiotemporal gait parameters were different compared to healthy controls. In contrast to average gait parameters, variability in stride length and stride time could discriminate between MS fallers and non-fallers. Simultaneous performance of cognitive task and walking resulted in higher dual-task costs (DTC) in gait performance compared to the motor dual-task. However, the pattern of change was not different among the three groups. All participants responded to the cognitive task challenges by increasing stride length and decreasing cadence and stride length variability while maintaining cognitive task performance. CONCLUSIONS: The findings may reflect successful adaptation of locomotor system to preserve cognitive task performance under cognitive dual-task condition. Future studies should examine more complex concurrent cognitive and motor tasks to better understand the dual-task-related gait changes and their contribution to falls in patients with MS. PMID- 29141828 TI - Alternative diagnoses in patients referred to specialized centers for suspected MS. AB - OBJECTIVES: The aim of this study is to explore the frequency, type, and predictors of alternative diagnoses among patients referred with a recent diagnosis of multiple sclerosis (MS) to two specialized MS centers in the Middle East. METHODS: This is a retrospective review of a prospectively followed cohort of MS patients at 2 University specialized MS centers. All patients referred for MS were included. The final diagnosis was recorded and demographic, clinical, laboratory, electrophysiological and radiological variables were collected. RESULTS: A total of 554 patients were included in this study of which 431 were referred for diagnostic confirmation. The final diagnosis of MS was confirmed in 300 (70%), while 114 (26%) turned out to have an alternative diagnosis and 15 (3.5%) fulfilled criteria for radiologically isolated syndrome (RIS). The most common alternative diagnoses were psychogenic (16.3%), non-specific MRI white matter lesions (14.7%), NMO (9.5%), migraine (8.6%) and systemic autoimmune disorders (8.6%). The strongest predictors of a final diagnosis of MS were: younger age, presence of oligoclonal bands in the CSF, periventricular, corpus callosum, spinal (P<0.0001), or enhancing lesions (P<0.005) on MRI. CONCLUSIONS: Our study shows that 30% of patients referred for a suspicion of MS end up with a different diagnosis. The most common alternative diagnoses of MS in the Middle East are not different from what has been described in Western countries. Age, MRI and CSF findings can help with the differential diagnosis. PMID- 29141827 TI - A NMOSD case with multifocal nervous system involvement in a single attack. PMID- 29141829 TI - Cerebral cortical encephalitis followed by recurrent CNS demyelination in a patient with concomitant anti-MOG and anti-NMDA receptor antibodies. AB - We report the case of a patient who initially presented with fever, headache and seizure. MRI revealed a fluid attenuation inversion recovery (FLAIR) high intensity lesion involving the right temporal, parietal and occipital cortex. Afterwards, the patient developed three recurrent episodes, manifested as brainstem encephalitis, optic neuritis and ADEM-like illness successively, indicating demyelination. Both of his serum anti-MOG and CSF anti-NMDAR antibodies were proved positive by transfected cell based assays. We consider our case to have cortical encephalitis due to certain autoimmune mechanism initially, and then developed MOG-antibody mediated recurrent demyelination in the following episodes. PMID- 29141830 TI - Post herpes zoster infection neuromyelitis optica spectrum disorder. AB - Neuromyelitis optica is a severe autoimmune demyelinating disease; however, the trigger for autoimmunity in an individual patient is unclear. Here, we report the case of a 48 year old female presenting with longitudinally extensive transverse myelitis in the cervical region of the spinal cord two weeks post herpes zoster infection in right C6 dermatome. Though post herpetic myelitis was provisionally diagnosed, serological evaluation revealed aquaporin-4 antibody positivity, confirming the diagnosis of neuromyelitis optica spectrum disorder. Herpes zoster infection appears to have triggered the onset of autoimmunity, leading to the development of neuromyelitis optica spectrum disorder in this patient. PMID- 29141832 TI - Editors' Welcome. PMID- 29141833 TI - Comparative study of the clinical, histological, and biological characteristics of squamous cell carcinomas in areas previously treated with photodynamic therapy. AB - Although photodynamic therapy (PDT) is an effective treatment option for non melanoma skin cancer, the development of aggressive tumours in PDT-treated areas has been described. To evaluate the clinical, histological, and biological characteristics of squamous cell carcinomas (SCCs) in areas previously treated with PDT vs those arising in areas never treated with this therapeutic modality. A retrospective observational study was designed. We collected all cases of invasive SCCs in areas previously treated with PDT. The control group consisted of an equivalent number of SCCs randomly selected from the database of our pathology department. Expression of specific markers implicated in SCC progression, including p53, Ki67, COX-2, cyclin D1, E-cadherin, EGFR, survivin, and pERK, was analysed. A total of 699 patients were treated with PDT for non melanoma skin cancer during the course of the study. Ten invasive SCCs arising in areas previously treated with methylaminolevulinate-PDT were diagnosed in six patients. The control group consisted of 10 invasive SCCs from 10 patients never treated with PDT. In the PDT group, the mean tumour size was significantly lower and the absence of ulceration was more frequent than in the control group (p<0.024 and p = 0.035, respectively). A diffuse survivin staining pattern was observed in 90% of tumours in the PDT group versus 50% in the comparative group (p = 0.141). The number of SCCs arising in areas previously treated with PDT was very low and did not differ significantly from that of SCCs developing in non-PDT treated areas. PMID- 29141834 TI - Successful treatment of hereditary haemorrhagic telangiectasia using 595-nm pulsed dye laser. PMID- 29141831 TI - Long-term follow-up of a randomized study of combination interferon and glatiramer acetate in multiple sclerosis: Efficacy and safety results up to 7 years. AB - BACKGROUND: To report the long-term results of the blinded extension phase of the randomized, controlled study of the combined use of interferon beta-1a (IFN) 30MUg IM weekly and glatiramer acetate (GA) 20mg daily compared to each agent alone in relapsing-remitting multiple sclerosis (RRMS). METHODS: 1008 RRMS patients were followed on protocol until the last participant enrolled completed 3 years, allowing some subjects to be followed for up to 7 years. The primary endpoint was reduction in annualized relapse rate. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score and MRI metrics. RESULTS: Similar to the core study, combination IFN + GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed EDSS worsening or change in MSFC. Also similar to the core result, the combination was superior to either agent alone in reducing new lesion activity, but the 3 year MRI result did not presage a clinical benefit over the extended observation interval. CONCLUSION: Combining GA & IFN did not produce a significant clinical benefit over the entire study duration. The earlier effect on reducing MRI activity did not result in a later clinical advantage. The combination showed a sustained advantage in reducing disease activity free status. PMID- 29141835 TI - Angiolymphoid hyperplasia with eosinophilia on the abdomen with dendritic cell infiltration. PMID- 29141836 TI - B-cell lymphomatoid contact dermatitis caused by methylisothiazolinone and methylchloroisothiazolinone. PMID- 29141837 TI - User Acceptance of Wrist-Worn Activity Trackers Among Community-Dwelling Older Adults: Mixed Method Study. AB - BACKGROUND: Wearable activity trackers are newly emerging technologies with the anticipation for successfully supporting aging-in-place. Consumer-grade wearable activity trackers are increasingly ubiquitous in the market, but the attitudes toward, as well as acceptance and voluntary use of, these trackers in older population are poorly understood. OBJECTIVE: The aim of this study was to assess acceptance and usage of wearable activity trackers in Canadian community-dwelling older adults, using the potentially influential factors as identified in literature and technology acceptance model. METHODS: A mixed methods design was used. A total of 20 older adults aged 55 years and older were recruited from Southwestern Ontario. Participants used 2 different wearable activity trackers (Xiaomi Mi Band and Microsoft Band) separately for each segment in the crossover design study for 21 days (ie, 42 days total). A questionnaire was developed to capture acceptance and experience at the end of each segment, representing 2 different devices. Semistructured interviews were conducted with 4 participants, and a content analysis was performed. RESULTS: Participants ranged in age from 55 years to 84 years (mean age: 64 years). The Mi Band gained higher levels of acceptance (16/20, 80%) compared with the Microsoft Band (10/20, 50%). The equipment characteristics dimension scored significantly higher for the Mi Band (P<.05). The amount a participant was willing to pay for the device was highly associated with technology acceptance (P<.05). Multivariate logistic regression with 3 covariates resulted in an area under the curve of 0.79. Content analysis resulted in the formation of the following main themes: (1) smartphones as facilitators of wearable activity trackers; (2) privacy is less of a concern for wearable activity trackers, (3) value proposition: self-awareness and motivation; (4) subjective norm, social support, and sense of independence; and (5) equipment characteristics matter: display, battery, comfort, and aesthetics. CONCLUSIONS: Older adults were mostly accepting of wearable activity trackers, and they had a clear understanding of its value for their lives. Wearable activity trackers were uniquely considered more personal than other types of technologies, thereby the equipment characteristics including comfort, aesthetics, and price had a significant impact on the acceptance. Results indicated that privacy was less of concern for older adults, but it may have stemmed from a lack of understanding of the privacy risks and implications. These findings add to emerging research that investigates acceptance and factors that may influence acceptance of wearable activity trackers among older adults. PMID- 29141838 TI - Online Perceptions of Mothers About Breastfeeding and Introducing Formula: Qualitative Study. AB - BACKGROUND: Although the benefits of breastfeeding are well established for babies and their mothers, many women give formula to their infants. Whether to breastfeed or to give infant formula is a complex decision to make. Many parents use the Internet to find information and support that relate to infant feeding decisions. OBJECTIVE: The aim of this study was to analyze the perceptions of mothers, who are discussing the topic on Web forums, about introducing infant formula. METHODS: This is a qualitative, descriptive, and cross-sectional study on online data from parenting Web forums. The text was analyzed using qualitative content analysis. RESULTS: The analysis resulted in 1 main theme, "balancing between social expectations and confidence in your parental ability," which is further divided into 3 themes: "striving to be a good mother," "striving for your own well-being," and "striving to discover your own path." CONCLUSIONS: Breastfeeding is complex, and health care personnel can, with a more open approach toward formula, create better support for mothers by helping them to be more confident in their parental ability. PMID- 29141840 TI - Cerebral Oxygenation Measurements by Magnetic Resonance Imaging in Fetuses With and Without Heart Defects. AB - BACKGROUND: Children with major congenital heart defects are risking impaired cerebral growth, delayed cerebral maturation, and neurodevelopmental disorders. We aimed to compare the cerebral tissue oxygenation of fetuses with major heart defects to that of fetuses without heart defects as estimated by the magnetic resonance imaging modality T2*. T2* is low in areas with high concentrations of deoxyhemoglobin. METHODS AND RESULTS: At gestational age mean 32 weeks (early) and mean 37 weeks (late), we compared the fetal cerebral T2* in 28 fetuses without heart defects to that of 15 fetuses with major heart defects: transposition of the great arteries (n=7), coarctation of the aorta/hypoplastic aortic arch (n=5), tetralogy of Fallot (n=1), hypoplastic right heart (n=1), and common arterial trunk (n=1). The women were scanned with a 1.5 T Philips scanner using a breath-hold multiecho gradient echo sequence. Among fetuses without heart defects, the mean T2* value was 157 ms (95% confidence interval [CI], 152-163) early and 125 ms (95% CI, 120-130) late. These figures were significantly lower (mean 14 ms; 95% CI, 6-22; P<0.001) among fetuses with heart defects 143 ms (95% CI, 136-150) early and 111 ms (95% CI, 104-118) late. CONCLUSIONS: Our findings indicate that fetal cerebral T2* is measurable and that fetal cerebral tissue oxygenation measured by T2* is lower in fetuses with heart defects compared with fetuses without heart defects. This corroborates the hypothesis that tissue hypoxia may be a potential pathogenic factor that possibly affects brain development in fetuses with heart defects. PMID- 29141841 TI - In Utero Brain Development in Fetuses With Congenital Heart Disease: Another Piece of the Jigsaw Provided by Blood Oxygen Level-Dependent Magnetic Resonance Imaging. PMID- 29141839 TI - Patient Health Record Systems Scope and Functionalities: Literature Review and Future Directions. AB - BACKGROUND: A new generation of user-centric information systems is emerging in health care as patient health record (PHR) systems. These systems create a platform supporting the new vision of health services that empowers patients and enables patient-provider communication, with the goal of improving health outcomes and reducing costs. This evolution has generated new sets of data and capabilities, providing opportunities and challenges at the user, system, and industry levels. OBJECTIVE: The objective of our study was to assess PHR data types and functionalities through a review of the literature to inform the health care informatics community, and to provide recommendations for PHR design, research, and practice. METHODS: We conducted a review of the literature to assess PHR data types and functionalities. We searched PubMed, Embase, and MEDLINE databases from 1966 to 2015 for studies of PHRs, resulting in 1822 articles, from which we selected a total of 106 articles for a detailed review of PHR data content. RESULTS: We present several key findings related to the scope and functionalities in PHR systems. We also present a functional taxonomy and chronological analysis of PHR data types and functionalities, to improve understanding and provide insights for future directions. Functional taxonomy analysis of the extracted data revealed the presence of new PHR data sources such as tracking devices and data types such as time-series data. Chronological data analysis showed an evolution of PHR system functionalities over time, from simple data access to data modification and, more recently, automated assessment, prediction, and recommendation. CONCLUSIONS: Efforts are needed to improve (1) PHR data quality through patient-centered user interface design and standardized patient-generated data guidelines, (2) data integrity through consolidation of various types and sources, (3) PHR functionality through application of new data analytics methods, and (4) metrics to evaluate clinical outcomes associated with automated PHR system use, and costs associated with PHR data storage and analytics. PMID- 29141842 TI - Treatment of Atrial Fibrillation and Concordance With the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines: Findings From ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation). AB - BACKGROUND: It is unclear how frequently patients with atrial fibrillation receive guideline-concordant (GC) care and whether guideline concordance is associated with improved outcomes. METHODS AND RESULTS: Using data from ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), we determined how frequently patients received care that was concordant with 11 recommendations from the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society atrial fibrillation guidelines pertaining to antithrombotic therapy, rate control, and antiarrhythmic medications. We also analyzed the association between GC care and clinical outcomes at both the patient level and center level. A total of 9570 patients were included. The median age was 75 years (interquartile range, 67-82), and the median CHA2DS2-VASc score was 4 (interquartile range, 3-5). A total of 5977 patients (62.5%) received care that was concordant with all guideline recommendations for which they were eligible. Rates of GC care were higher in patients treated by providers with greater specialization in arrhythmias (60.0%, 62.4%, and 67.0% for primary care physicians, cardiologists, and electrophysiologists, respectively; P<0.001). During a median of 30 months of follow-up, patients treated with GC care had a higher risk of bleeding hospitalization (hazard ratio=1.21; P=0.021) but a similar risk of death, stroke, major bleeding, and all-cause hospitalization. CONCLUSIONS: Over a third of patients with atrial fibrillation in this large outpatient registry received care that differed in some respect from guideline recommendations. There was no apparent association between GC care and improved risk-adjusted outcomes. PMID- 29141843 TI - STABLE-SR (Electrophysiological Substrate Ablation in the Left Atrium During Sinus Rhythm) for the Treatment of Nonparoxysmal Atrial Fibrillation: A Prospective, Multicenter Randomized Clinical Trial. AB - BACKGROUND: Circumferential pulmonary vein isolation (CPVI) alone or combined with adjuvant substrate modifications is unsatisfactory for atrial fibrillation (AF) control in nonparoxysmal AF patients. Ablation targeting the fibrotic areas after CPVI (STABLE-SR [Electrophysiological Substrate Ablation in the Left Atrium During Sinus Rhythm]) is a newly evolved substrate modification strategy. METHODS AND RESULTS: In this multicenter, randomized clinical trial, 229 symptomatic nonparoxysmal AF patients were 1:1 randomized to STABLE-SR group (n=114) or conventional STEPWISE group (n=115). In the STABLE-SR group, after CPVI, cavotricuspid isthmus ablation and cardioversion to sinus rhythm, left atrial high-density mapping was performed. Areas with low-voltage and complex electrogram were further homogenized and eliminated, respectively. Dechanneling would be done if necessary. In the STEPWISE group, additional linear lesions and defragmentation were performed.The primary end point was freedom from documented atrial tachyarrhythmias for >=30 s after a single ablation procedure without antiarrhythmic medications at 18 months. At 18 months, 74.0% of the patients in the STABLE-SR group and 71.5% in the STEPWISE group (hazard ratio, 0.78; 95% confidence interval, 0.47-1.29; P=0.325) achieved success according to intention to-treat analysis. However, less procedure time (186.8+/-52.7 versus 210.5+/-48.0 minutes, P<0.001), reduced post-CPVI fluoroscopic time (11.0+/-7.8 versus 13.7+/ 8.9 minutes, P=0.006), and shorter energy delivery time (60.1+/-25.1 versus 75.0+/-24.3 minutes, P<0.001) were observed in the STABLE-SR group compared with the STEPWISE group. CONCLUSIONS: STABLE-SR is a simplified, personalized, and effective ablation strategy in nonparoxysmal AF patients. More importantly, over 50% nonparoxysmal AF patients do not need further ablation beyond CPVI and therefore can avoid excessive ablation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01761188. PMID- 29141845 TI - Measuring the Impact of Guideline Concordance: The More Things Change, the More They Stay the Same. PMID- 29141844 TI - Architectural T-Wave Analysis and Identification of On-Therapy Breakthrough Arrhythmic Risk in Type 1 and Type 2 Long-QT Syndrome. AB - BACKGROUND: Although the hallmark of long-QT syndrome (LQTS) is abnormal cardiac repolarization, there are varying degrees of phenotypic expression and arrhythmic risk. Our aim was to evaluate the performance of a morphological T-wave analysis program in defining breakthrough LQTS arrhythmic risk beyond the QTc value. METHODS AND RESULTS: We analyzed 407 genetically confirmed patients with LQT1 (n=246; 43% men) and LQT2 (n=161; 41% men) over the mean follow-up period of 6.4+/-3.9 years. ECG analysis was conducted using a novel, proprietary T-wave analysis program. Time to a LQTS-associated cardiac event was analyzed using Cox proportional hazards regression methods. Twenty-three patients experienced >=1 defined breakthrough cardiac arrhythmic events with 5- and 10-year event rates of 4% and 7%. Two independent predictors of future LQTS-associated cardiac events from the surface ECG were identified: left slope of T wave in lead V6 (hazard ratio=0.40 [0.24-0.69]; P<0.001) and T-wave center of gravity x axis (last 25% of wave) in lead I (hazard ratio=1.90 [1.21-2.99]; P=0.005), C statistic of 0.77 (0.65-0.89). When added to the QTc (C statistic 0.68 for QTc alone), discrimination improved to 0.78. Genotype analysis showed weaker association between these T-wave variables and LQT1-triggered events while these features were stronger in patients with LQT2 and significantly outperformed the QTc (C statistic, 0.82 [0.71-0.93]). CONCLUSION: Detailed morphological analysis of the T wave provides novel insights into risk of breakthrough arrhythmic events in LQTS, particularly LQT2. This observation has the potential to guide clinical decision making and further refine risk stratification. PMID- 29141846 TI - Atrial Substrate Modification for Atrial Fibrillation: Striving to Get Smarter. PMID- 29141847 TI - T-Wave Morphology Analysis to Detect High Risk in Long-QT Syndrome. PMID- 29141848 TI - MYC Overexpression at the Protein and mRNA Level and Cancer Outcomes among Men Treated with Radical Prostatectomy for Prostate Cancer. AB - Background: The proto-oncogene MYC is implicated in prostate cancer progression. Whether MYC tumor expression at the protein or mRNA level is associated with poorer prognosis has not been well studied.Methods: We conducted a cohort study including 634 men from the Physicians' Health Study and Health Professionals Follow-up Study treated with radical prostatectomy for prostate cancer in 1983 2004 and followed up for a median of 13.7 years. MYC protein expression was evaluated using IHC, and we used Cox regression to calculate HRs and 95% confidence intervals (CIs) of its association with lethal prostate cancer (distant metastases/prostate cancer-related death). We assessed the association between MYC mRNA expression and lethal prostate cancer in a case-control study, including 113 lethal cases and 291 indolent controls.Results: MYC nuclear protein expression was present in 97% of tumors. MYC protein expression was positively correlated with tumor proliferation rate (r = 0.37; P < 0.001) and negatively correlated with apoptotic count (r = -0.17; P < 0.001). There were no significant associations between MYC protein expression and stage, grade, or PSA level at diagnosis. The multivariable HR for lethal prostate cancer among men in the top versus bottom quartile of MYC protein expression was 1.09 (95% CI, 0.50-2.35). There was no significant association between MYC mRNA expression and lethal prostate cancer.Conclusions: Neither MYC protein overexpression nor MYC mRNA overexpression are strong prognostic markers in men treated with radical prostatectomy for prostate cancer.Impact: This is the largest study to examine the prognostic role of MYC protein and mRNA expression in prostate cancer. Cancer Epidemiol Biomarkers Prev; 27(2); 201-7. (c)2017 AACR. PMID- 29141850 TI - Autoantibodies against HSF1 and CCDC155 as Biomarkers of Early-Stage, High-Grade Serous Ovarian Cancer. AB - Background: Tumor-directed circulating autoantibodies (AAb) are a well established feature of many solid tumor types, and are often observed prior to clinical disease manifestation. As such, they may provide a good indicator of early disease development. We have conducted a pilot study to identify novel AAbs as markers of early-stage HGSOCs.Methods: A rare cohort of patients with early (FIGO stage Ia-c) HGSOCs for IgG, IgA, and IgM-mediated AAb reactivity using high content protein arrays (containing 9,184 individual proteins). AAb reactivity against selected antigens was validated by ELISA in a second, independent cohort of individual patients.Results: A total of 184 antigens were differentially detected in early-stage HGSOC patients compared with all other patient groups assessed. Among the six most highly detected "early-stage" antigens, anti-IgA AAbs against HSF1 and anti-IgG AAbs CCDC155 (KASH5; nesprin 5) were significantly elevated in patients with early-stage malignancy. Receiver operating characteristic (ROC) analysis suggested that AAbs against HSF1 provided better detection of early-stage malignancy than CA125 alone. Combined measurement of anti-HSF1, anti-CCDC155, and CA125 also improved efficacy at higher sensitivity.Conclusions: The combined measurement of anti-HSF1, anti-CCDC155, and CA125 may be useful for early-stage HGSOC detection.Impact: This is the first study to specifically identify AAbs associated with early-stage HGSOC. The presence and high frequency of specific AAbs in early-stage cancer patients warrants a larger scale examination to define their value for early disease detection at primary diagnosis and/or recurrence. Cancer Epidemiol Biomarkers Prev; 27(2); 183-92. (c)2017 AACR. PMID- 29141851 TI - A Review of Physical Activity and Circulating miRNA Expression: Implications in Cancer Risk and Progression. AB - The role of circulating miRNAs (c-miRNAs) in carcinogenesis has garnered considerable scientific interest. miRNAs may contribute actively to cancer development and progression, making them potential targets for cancer prevention and therapy. Lifestyle factors such as physical activity (PA) have been shown to alter c-miRNA expression, but the subsequent impact on cancer risk and prognosis is unknown. To provide a better understanding of how PA reduces the risk of cancer incidence and improves patient outcomes, we conducted a review of the impact of PA on c-miRNA expression, which includes a comprehensive synthesis of studies examining the impacts of acute and chronic exercise on expression of c miRNAs. While the variability in methods used to assess miRNA expression creates challenges in comparing and/or synthesizing the literature, results to date suggest that the circulating form of several miRNAs known for playing a role in cancer (c-miR-133, c-miR-221/222, c-miR-126, and c-let-7) are altered by both acute and chronic PA. Additional research should develop standardized procedures for assessing both c-miRNA and PA measurement to improve the comparability of research results regarding the direction and amplitude of changes in c-miRNAs in response to PA. Cancer Epidemiol Biomarkers Prev; 27(1); 11-24. (c)2017 AACR. PMID- 29141849 TI - Polycystic Ovary Syndrome, Oligomenorrhea, and Risk of Ovarian Cancer Histotypes: Evidence from the Ovarian Cancer Association Consortium. AB - Background: Polycystic ovary syndrome (PCOS), and one of its distinguishing characteristics, oligomenorrhea, have both been associated with ovarian cancer risk in some but not all studies. However, these associations have been rarely examined by ovarian cancer histotypes, which may explain the lack of clear associations reported in previous studies.Methods: We analyzed data from 14 case control studies including 16,594 women with invasive ovarian cancer (n = 13,719) or borderline ovarian disease (n = 2,875) and 17,718 controls. Adjusted study specific ORs were calculated using logistic regression and combined using random effects meta-analysis. Pooled histotype-specific ORs were calculated using polytomous logistic regression.Results: Women reporting menstrual cycle length >35 days had decreased risk of invasive ovarian cancer compared with women reporting cycle length <=35 days [OR = 0.70; 95% confidence interval (CI) = 0.58 0.84]. Decreased risk of invasive ovarian cancer was also observed among women who reported irregular menstrual cycles compared with women with regular cycles (OR = 0.83; 95% CI = 0.76-0.89). No significant association was observed between self-reported PCOS and invasive ovarian cancer risk (OR = 0.87; 95% CI = 0.65 1.15). There was a decreased risk of all individual invasive histotypes for women with menstrual cycle length >35 days, but no association with serous borderline tumors (Pheterogeneity = 0.006). Similarly, we observed decreased risks of most invasive histotypes among women with irregular cycles, but an increased risk of borderline serous and mucinous tumors (Pheterogeneity < 0.0001).Conclusions: Our results suggest that menstrual cycle characteristics influence ovarian cancer risk differentially based on histotype.Impact: These results highlight the importance of examining ovarian cancer risk factors associations by histologic subtype. Cancer Epidemiol Biomarkers Prev; 27(2); 174-82. (c)2017 AACR. PMID- 29141852 TI - Collagen Alignment as a Predictor of Recurrence after Ductal Carcinoma In Situ. AB - Background: Collagen fibers surrounding breast ducts may influence breast cancer progression. Syndecan-1 interacts with constituents in the extracellular matrix, including collagen fibers, and may contribute to cancer cell migration. Thus, the orientation of collagen fibers surrounding ductal carcinoma in situ (DCIS) lesions and stromal syndecan-1 expression may predict recurrence.Methods: We evaluated collagen fiber alignment and syndecan-1 expression in 227 women diagnosed with DCIS in 1995 to 2006 followed through 2014 (median, 14.5 years; range, 0.7-17.6). Stromal collagen alignment was evaluated from diagnostic tissue slides using second harmonic generation microscopy and fiber analysis software. Univariate analysis was conducted using chi2 tests and ANOVA. The association between collagen alignment z-scores, syndecan-1 staining intensity, and time to recurrence was evaluated using HRs and 95% confidence intervals (CIs).Results: Greater fiber angles surrounding DCIS lesions, but not syndecan-1 staining intensity, were related to positive HER2 (P = 0.002) status, comedo necrosis (P = 0.03), and negative estrogen receptor (P = 0.002) and progesterone receptor (P = 0.02) status. Fiber angle distributions surrounding lesions included more angles closer to 90 degrees than normal ducts (P = 0.06). Collagen alignment z-scores for DCIS lesions were positively related to recurrence (HR = 1.25; 95% CI, 0.84 1.87 for an interquartile range increase in average fiber angles).Conclusions: Although collagen alignment and stromal syndecan-1 expression did not predict recurrence, collagen fibers perpendicular to the duct perimeter were more frequent in DCIS lesions with features typical of poor prognosis.Impact: Follow up studies are warranted to examine whether additional features of the collagen matrix may more strongly predict patient outcomes. Cancer Epidemiol Biomarkers Prev; 27(2); 138-45. (c)2017 AACR. PMID- 29141853 TI - The Effects of Resistance Exercise on Biomarkers of Breast Cancer Prognosis: A Pooled Analysis of Three Randomized Trials. AB - Background: Using a secondary data analysis from randomized controlled trials comparing one year of resistance exercise (n = 109) to a placebo control condition (n = 106) in postmenopausal, posttreatment breast cancer survivors, we investigated the influence of resistance training and changes in body composition on markers associated with cancer progression.Methods: Measures included serum levels of insulin, IGF-1, IGFBP1-3, leptin, serum amyloid A (SAA), adiponectin, C reactive protein (CRP), IL1beta, TNFalpha, IL6, and IL8, and body composition (total, lean and fat mass in kg) by DXA at baseline, 6, and 12 months. Linear mixed effects models were used to examine the association between group, biomarkers, and body composition and whether or not changes in muscle strength or body composition influenced the effect of exercise on biomarkers.Results: CRP decreased over time among women participating in resistance training compared with increases in controls (P = 0.045). In stratified analyses and compared with increases in controls, women who gained strength reduced CRP (P = 0.003) and maintained levels of IL1beta and IL6. Among exercisers who lost weight (>=2 kg), CRP (P = 0.045), leptin (P < 0.01), and SAA (P = 0.029) decreased, whereas IGF BP1 (P = 0.036) increased compared with controls.Conclusions: Resistance training may lower inflammation and improve insulin pathway profiles, but the magnitude and degree of benefit from exercise may depend upon whether or not women gained strength, a possible marker of compliance with training, and/or lost weight during exercise.Impact: Future resistance training trials should consider these potential influencing factors as they may determine how well exercise can slow cancer progression and prevent disease recurrence. Cancer Epidemiol Biomarkers Prev; 27(2); 146-53. (c)2017 AACR. PMID- 29141855 TI - Notice of Retraction. PMID- 29141854 TI - A P53-Deficiency Gene Signature Predicts Recurrence Risk of Patients with Early Stage Lung Adenocarcinoma. AB - Background: Lung cancer is associated with the highest mortality rate of all cancer types, and the most common histologic subtype of lung cancer is adenocarcinoma. To apply more effective therapeutic treatment, molecular markers that are able to predict the recurrence risk of patients with adenocarcinoma are critically needed. Mutations in TP53 tumor suppressor gene have been found in approximately 50% of lung adenocarcinoma cases, but the presence of a TP53 mutation does not always associate with increased mortality.Methods: The Cancer Genome Atlas RNA sequencing data of lung adenocarcinoma were used to define a novel gene signature for P53 deficiency. This signature was then used to calculate a sample-specific P53 deficiency score based on a patient's transcriptomic profile and tested in four independent lung adenocarcinoma microarray datasets.Results: In all datasets, P53 deficiency score was a significant predictor for recurrence-free survival where high P53 deficiency score was associated with poor survival. The score was prognostic even after adjusting for several key clinical variables including age, tumor stage, smoking status, and P53 mutation status. Furthermore, the score was able to predict recurrence-free survival in patients with stage I adenocarcinoma and was also associated with smoking status.Conclusions: The P53 deficiency score was a better predictor of recurrence-free survival compared with P53 mutation status and provided additional prognostic values to established clinical factors.Impact: The P53 deficiency score can be used to stratify early-stage patients into subgroups based on their risk of recurrence for aiding physicians to decide personalized therapeutic treatment. Cancer Epidemiol Biomarkers Prev; 27(1); 86-95. (c)2017 AACR. PMID- 29141856 TI - Impact of Diabetes Mellitus on Outcomes in Patients Supported With Left Ventricular Assist Devices: A Single Institutional 9-Year Experience. AB - BACKGROUND: Diabetes mellitus (DM) is a risk factor for morbidity and mortality in patients with heart failure. The effect of DM on post-left ventricular assist device (LVAD) implantation outcomes is unclear. This study sought to investigate whether patients with DM had worse outcomes than patients without DM after LVAD implantation and whether LVAD support resulted in a better control of DM. METHODS AND RESULTS: We retrospectively reviewed 341 consecutive adults who underwent implantation of LVAD from 2007 to 2016. Patient characteristics and adverse events were studied and compared between patients with and without DM. One hundred thirty-one patients (38%) had DM. Compared with patients without DM, those with DM had higher rates of ischemic cardiomyopathy, LVAD implantation as destination therapy, and increased baseline body mass index. In a proportional hazards (Cox) model with adjustment for relevant covariates and median follow-up of 16.1 months, DM was associated with increased risk of all-cause mortality (hazard ratio, 1.73; 95% confidence interval: 1.18-2.53; P=0.005) and increased risk of nonfatal LVAD-related complications, including a composite of stroke, pump thrombosis, and device infection (hazard ratio, 2.1; 95% confidence interval: 1.35-3.18; P=0.001). Preoperative hemoglobin A1c was not significantly associated with mortality or adverse events among patients with DM. LVAD implantation resulted in a remarkable decrease in hemoglobin A1c levels (7.4+/ 1.9 pre-LVAD versus 6.0+/-1.5 and 6.3+/-1.4 after 3 and 12 months post-LVAD, respectively; P<0.0001) and a significant reduction in requirements of DM medications. CONCLUSIONS: DM is associated with increased rates of all-cause mortality and major adverse events despite favorable glycemic control after LVAD implantation. PMID- 29141857 TI - Contemporary Characteristics and Outcomes in Chagasic Heart Failure Compared With Other Nonischemic and Ischemic Cardiomyopathy. AB - BACKGROUND: Chagas' disease is an important cause of cardiomyopathy in Latin America. We aimed to compare clinical characteristics and outcomes in patients with heart failure (HF) with reduced ejection fraction caused by Chagas' disease, with other etiologies, in the era of modern HF therapies. METHODS AND RESULTS: This study included 2552 Latin American patients randomized in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure) trials. The investigator-reported etiology was categorized as Chagasic, other nonischemic, or ischemic cardiomyopathy. The outcomes of interest included the composite of cardiovascular death or HF hospitalization and its components and death from any cause. Unadjusted and adjusted Cox proportional hazards models were performed to compare outcomes by pathogenesis. There were 195 patients with Chagasic HF with reduced ejection fraction, 1300 with other nonischemic cardiomyopathy, and 1057 with ischemic cardiomyopathy. Compared with other etiologies, Chagasic patients were more often female, younger, and had lower prevalence of hypertension, diabetes mellitus, and renal impairment (but had higher prevalence of stroke and pacemaker implantation) and had worse health-related quality of life. The rates of the composite outcome were 17.2, 12.5, and 11.4 per 100 person-years for Chagasic, other nonischemic, and ischemic patients, respectively-adjusted hazard ratio for Chagasic versus other nonischemic: 1.49 (95% confidence interval, 1.15-1.94; P=0.003) and Chagasic versus ischemic: 1.55 (1.18-2.04; P=0.002). The rates of all-cause mortality were also higher. CONCLUSIONS: Despite younger age, less comorbidity, and comprehensive use of conventional HF therapies, patients with Chagasic HF with reduced ejection fraction continue to have worse quality of life and higher hospitalization and mortality rates compared with other etiologies. CLINICAL TRIAL REGISTRATION: PARADIGM-HF: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255; ATMOSPHERE: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658. PMID- 29141859 TI - Unique Pattern of Aortic Regurgitation Caused by Rupture Into the Left Ventricular Interleaflet Triangle of a Sinus Valsalva Aneurysm Involving the Left Coronary Cusp. PMID- 29141858 TI - Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). AB - BACKGROUND: An enhanced inflammatory response predicts worse outcomes in heart failure (HF). We hypothesized that administration of IL-1 (interleukin-1) receptor antagonist (anakinra) could inhibit the inflammatory response and improve peak aerobic exercise capacity in patients with recently decompensated systolic HF. METHODS AND RESULTS: We randomly assigned 60 patients with reduced left ventricular ejection fraction (<50%) and elevated C-reactive protein levels (>2 mg/L), within 14 days of hospital discharge, to daily subcutaneous injections with anakinra 100 mg for 2 weeks, 12 weeks, or placebo. Patients underwent measurement of peak oxygen consumption (Vo2 [mL/kg per minute]) and ventilatory efficiency (the VE/Vco2 slope). Treatment with anakinra did not affect peak Vo2 or VE/Vco2 slope at 2 weeks. At 12 weeks, patients continued on anakinra showed an improvement in peak Vo2 from 14.5 (10.5-16.6) mL/kg per minute to 16.1 (13.2 18.6) mL/kg per minute (P=0.009 for within-group changes), whereas no significant changes occurred within the anakinra 2-week or placebo groups. The between-groups differences, however, were not statistically significant. The incidence of death or rehospitalization for HF at 24 weeks was 6%, 31%, and 30%, in the anakinra 12 week, anakinra 2-week, and placebo groups, respectively (log-rank test P=0.10). CONCLUSIONS: No change in peak Vo2 occurred at 2 weeks in patients with recently decompensated systolic HF treated with anakinra, whereas an improvement was seen in those patients in whom anakinra was continued for 12 weeks. Additional larger studies are needed to validate the effects of prolonged anakinra on peak Vo2 and rehospitalization for HF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936909. PMID- 29141860 TI - Multicenter Evaluation of Octreotide as Secondary Prophylaxis in Patients With Left Ventricular Assist Devices and Gastrointestinal Bleeding. AB - BACKGROUND: Gastrointestinal (GI) bleeding is one of the most common complications after continuous-flow left ventricular assist device implantation. More than one third of patients with incident bleed go on to develop recurrent GI bleeding. Octreotide, a somatostatin analog, is proposed to reduce the risk of recurrent GI bleeding in this population. METHODS AND RESULTS: This multicenter, retrospective analysis evaluated 51 continuous-flow left ventricular assist device patients who received secondary prophylaxis with octreotide after their index GI bleed from 2009 to 2015. All patients had a hospitalization for GI bleed and received octreotide after discharge. Patient demographics, medical and medication history, and clinical characteristics of patients who rebled after receiving octreotide were compared with non-rebleeders. These data were also compared with matched historical control patients previously enrolled in the HMII (HeartMate II) clinical trials, none of whom received octreotide, to provide a context for the bleeding rates. Twelve patients (24%) who received secondary octreotide prophylaxis developed another GI bleed, whereas 39 (76%) did not. There were similar intergroup demographics; however, significantly more bleeders had a previous GI bleeding history before left ventricular assist device placement (33% versus 5%; P=0.02) and greater frequency of angiodysplasia confirmed during endoscopy (58% versus 23%; P=0.03). Fewer patients in this study experienced a recurrent GI bleed compared with a matched historical control group that did not receive octreotide (24% versus 43%; P=0.04). CONCLUSIONS: Patients with continuous-flow left ventricular assist device receiving secondary prophylaxis with octreotide had a significantly lower GI bleed recurrence compared with historical controls not treated with octreotide. Additional prospective studies are needed to confirm these data. PMID- 29141861 TI - Is There a Sweet Spot for Left Ventricular Assist Devices and Diabetes Mellitus? PMID- 29141863 TI - Eight-Color Multiplex Immunohistochemistry for Simultaneous Detection of Multiple Immune Checkpoint Molecules within the Tumor Microenvironment. AB - Therapies targeting immune checkpoint molecules CTLA-4 and PD-1/PD-L1 have advanced the field of cancer immunotherapy. New mAbs targeting different immune checkpoint molecules, such as TIM3, CD27, and OX40, are being developed and tested in clinical trials. To make educated decisions and design new combination treatment strategies, it is vital to learn more about coexpression of both inhibitory and stimulatory immune checkpoints on individual cells within the tumor microenvironment. Recent advances in multiple immunolabeling and multispectral imaging have enabled simultaneous analysis of more than three markers within a single formalin-fixed paraffin-embedded tissue section, with accurate cell discrimination and spatial information. However, multiplex immunohistochemistry with a maximized number of markers presents multiple difficulties. These include the primary Ab concentrations and order within the multiplex panel, which are of major importance for the staining result. In this article, we report on the development, optimization, and application of an eight color multiplex immunohistochemistry panel, consisting of PD-1, PD-L1, OX40, CD27, TIM3, CD3, a tumor marker, and DAPI. This multiplex panel allows for simultaneous quantification of five different immune checkpoint molecules on individual cells within different tumor types. This analysis revealed major differences in the immune checkpoint expression patterns across tumor types and individual tumor samples. This method could ultimately, by characterizing the tumor microenvironment of patients who have been treated with different immune checkpoint modulators, form the rationale for the design of immune checkpoint based immunotherapy in the future. PMID- 29141862 TI - The Activation of Human Dermal Microvascular Cells by Poly(I:C), Lipopolysaccharide, Imiquimod, and ODN2395 Is Mediated by the Fli1/FOXO3A Pathway. AB - Endothelial cell (EC) dysfunction has been associated with inflammatory and autoimmune diseases; however, the factors contributing to this dysfunction have not been fully explored. Because activation of TLRs has been implicated in autoimmune diseases, the goal of this study was to determine the effects of TLR ligands on EC function. Human dermal microvascular ECs (HDMECs) treated with TLR3 [Poly(I:C)], TLR4 (LPS), and TLR7 (imiquimod) agonists showed decreased proliferation and a reduced total number of branching tubules in three dimensional human dermal organoid ex vivo culture. In contrast, the TLR9 ligand class C, ODN2395, increased angiogenesis. The antiproliferative effects of TLR3, TLR4, and TLR7 ligands correlated with significant downregulation of a key regulator of vascular homeostasis, Fli1, whereas TLR9 increased Fli1 levels. Furthermore, Poly(I:C) and LPS induced endothelial to mesenchymal transition that was reversed by the pretreatment with TGF-beta neutralizing Ab or re-expression of Fli1. We showed that Fli1 was required for the HDMEC proliferation by transcriptionally repressing FOXO3A. In contrast to TLR9, which suppressed activation of the FOXO3A pathway, TLR3, TLR4, and TLR7 ligands activated FOXO3A as indicated by decreased phosphorylation and increased nuclear accumulation. The inverse correlation between Fli1 and FOXO3A was also observed in the vasculature of scleroderma patients. This work revealed opposing effects of TLR9 and TLR3, TLR4, and TLR7 on the key angiogenic pathways, Fli1 and FOXO3A. Our results provide a mechanistic insight into the regulation of angiogenesis by TLRs and confirm a central role of Fli1 in regulating vascular homeostasis. PMID- 29141864 TI - IL-1beta Induces Pathologically Activated Osteoclasts Bearing Extremely High Levels of Resorbing Activity: A Possible Pathological Subpopulation of Osteoclasts, Accompanied by Suppressed Expression of Kindlin-3 and Talin-1. AB - As osteoclasts have the central roles in normal bone remodeling, it is ideal to regulate only the osteoclasts performing pathological bone destruction without affecting normal osteoclasts. Based on a hypothesis that pathological osteoclasts form under the pathological microenvironment of the bone tissues, we here set up optimum culture conditions to examine the entity of pathologically activated osteoclasts (PAOCs). Through searching various inflammatory cytokines and their combinations, we found the highest resorbing activity of osteoclasts when osteoclasts were formed in the presence of M-CSF, receptor activator of NF-kappaB ligand, and IL-1beta. We have postulated that these osteoclasts are PAOCs. Analysis using confocal laser microscopy revealed that PAOCs showed extremely high proton secretion detected by the acid-sensitive fluorescence probe Rh-PM and bone resorption activity compared with normal osteoclasts. PAOCs showed unique morphology bearing high thickness and high motility with motile cellular processes in comparison with normal osteoclasts. We further examined the expression of Kindlin-3 and Talin-1, essential molecules for activating integrin beta-chains. Although normal osteoclasts express high levels of Kindlin-3 and Talin-1, expression of these molecules was markedly suppressed in PAOCs, suggesting the abnormality in the adhesion property. When whole membrane surface of mature osteoclasts was biotinylated and analyzed, the IL-1beta-induced cell surface protein was detected. PAOCs could form a subpopulation of osteoclasts possibly different from normal osteoclasts. PAOC-specific molecules could be an ideal target for regulating pathological bone destruction. PMID- 29141866 TI - Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors. AB - Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer. Its expression correlates inversely with survival and increases with tumor grade. However, the biological role of PSMA has not been explored, and its role in prostate cancer remained elusive. Filling this gap, we demonstrate that in prostate cancer, PSMA initiates signaling upstream of PI3K through G protein-coupled receptors, specifically via the metabotropic glutamate receptor (mGluR). PSMA's carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate mGluR I. Activated mGluR I subsequently induces activation of phosphoinositide 3-kinase (PI3K) through phosphorylation of p110beta independent of PTEN loss. The p110beta isoform of PI3K plays a particularly important role in the pathogenesis of prostate cancer, but the origin of its activation was so far unknown. PSMA expression correlated with PI3K-Akt signaling in cells, animal models, and patients. We interrogated the activity of the PSMA-PI3K axis through positron emission tomography and magnetic resonance imaging. Inhibition of PSMA in preclinical models inhibited PI3K signaling and promoted tumor regression. Our data present a novel oncogenic signaling role of PSMA that can be exploited for therapy and interrogated with imaging. PMID- 29141865 TI - Development and plasticity of meningeal lymphatic vessels. AB - The recent discovery of meningeal lymphatic vessels (LVs) has raised interest in their possible involvement in neuropathological processes, yet little is known about their development or maintenance. We show here that meningeal LVs develop postnatally, appearing first around the foramina in the basal parts of the skull and spinal canal, sprouting along the blood vessels and cranial and spinal nerves to various parts of the meninges surrounding the central nervous system (CNS). VEGF-C, expressed mainly in vascular smooth muscle cells, and VEGFR3 in lymphatic endothelial cells were essential for their development, whereas VEGF-D deletion had no effect. Surprisingly, in adult mice, the LVs showed regression after VEGF C or VEGFR3 deletion, administration of the tyrosine kinase inhibitor sunitinib, or expression of VEGF-C/D trap, which also compromised the lymphatic drainage function. Conversely, an excess of VEGF-C induced meningeal lymphangiogenesis. The plasticity and regenerative potential of meningeal LVs should allow manipulation of cerebrospinal fluid drainage and neuropathological processes in the CNS. PMID- 29141867 TI - Host resistance to endotoxic shock requires the neuroendocrine regulation of group 1 innate lymphoid cells. AB - Upon infection, the immune system produces inflammatory mediators important for pathogen clearance. However, inflammation can also have deleterious effect on the host and is tightly regulated. Immune system-derived cytokines stimulate the hypothalamic-pituitary-adrenal (HPA) axis, triggering endogenous glucocorticoid production. Through interaction with ubiquitously expressed glucocorticoid receptors (GRs), this steroid hormone has pleiotropic effects on many cell types. Using a genetic mouse model in which the gene encoding the GR is selectively deleted in NKp46+ innate lymphoid cells (ILCs), we demonstrated a major role for the HPA pathway in host resistance to endotoxin-induced septic shock. GR expression in group 1 ILCs is required to limit their IFN-gamma production, thereby allowing the development of IL-10-dependent tolerance to endotoxin. These findings suggest that neuroendocrine axes are crucial for tolerization of the innate immune system to microbial endotoxin exposure through direct corticosterone-mediated effects on NKp46-expressing innate cells, revealing a novel strategy of host protection from immunopathology. PMID- 29141868 TI - Geographic clonal tracking in macaques provides insights into HSPC migration and differentiation. AB - The geographic distribution of hematopoiesis at a clonal level is of interest in understanding how hematopoietic stem and progenitor cells (HSPCs) and their progeny interact with bone marrow (BM) niches during regeneration. We tagged rhesus macaque autologous HSPCs with genetic barcodes, allowing clonal tracking over time and space after transplantation. We found marked geographic segregation of CD34+ HSPCs for at least 6 mo posttransplantation, followed by very gradual clonal mixing at different BM sites over subsequent months to years. Clonal mapping was used to document local production of granulocytes, monocytes, B cells, and CD56+ natural killer (NK) cells. In contrast, CD16+CD56- NK cells were not produced in the BM, and in fact were clonally distinct from multipotent progenitors producing all other lineages. Most surprisingly, we documented local BM production of CD3+ T cells early after transplantation, using both clonal mapping and intravascular versus tissue-resident T cell staining, suggesting a thymus-independent T cell developmental pathway operating during BM regeneration, perhaps before thymic recovery. PMID- 29141869 TI - Human stem cell-derived astrocytes replicate human prions in a PRNP genotype dependent manner. AB - Prions are infectious agents that cause neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD). The absence of a human cell culture model that replicates human prions has hampered prion disease research for decades. In this paper, we show that astrocytes derived from human induced pluripotent stem cells (iPSCs) support the replication of prions from brain samples of CJD patients. For experimental exposure of astrocytes to variant CJD (vCJD), the kinetics of prion replication occur in a prion protein codon 129 genotype-dependent manner, reflecting the genotype-dependent susceptibility to clinical vCJD found in patients. Furthermore, iPSC-derived astrocytes can replicate prions associated with the major sporadic CJD strains found in human patients. Lastly, we demonstrate the subpassage of prions from infected to naive astrocyte cultures, indicating the generation of prion infectivity in vitro. Our study addresses a long-standing gap in the repertoire of human prion disease research, providing a new in vitro system for accelerated mechanistic studies and drug discovery. PMID- 29141871 TI - Potential approaches to prevent hypoglycemia-associated autonomic failure. AB - Clear health benefits are associated with intensive glucose control in type 1 diabetes mellitus (T1DM). However, maintaining near-normal glycemia remains an elusive goal for many patients, in large part owing to the risk of severe hypoglycemia. In fact, recurrent episodes of hypoglycemia lead to 'hypoglycemia associated autonomic failure' (HAAF), characterized by defective counter regulatory responses to hypoglycemia. Extensive studies to understand the mechanisms underlying HAAF have revealed multiple potential etiologies, suggesting various approaches to prevent the development of HAAF. In this review, we present an overview of the literature focused on pharmacological approaches that may prevent the development of HAAF. The purported underlying mechanisms of HAAF include: 1) central mechanisms (opioid receptors, ATP-sensitive K+(KATP) channels, adrenergic receptors, serotonin selective receptor inhibitors, gamma aminobuyric acid receptors, N-methyl D-aspartate receptors); 2) hormones (cortisol, estrogen, dehydroepiandrosterone (DHEA) or DHEA sulfate, glucagon-like peptide-1) and 3) nutrients (fructose, free fatty acids, ketones), all of which have been studied vis-a-vis their ability to impact the development of HAAF. A careful review of the current literature reveals many promising therapeutic approaches to treat or reduce this important limitation to optimal glycemic control. PMID- 29141870 TI - Igbeta ubiquitination activates PI3K signals required for endosomal sorting. AB - A wealth of in vitro data has demonstrated a central role for receptor ubiquitination in endocytic sorting. However, how receptor ubiquitination functions in vivo is poorly understood. Herein, we report that ablation of B cell antigen receptor ubiquitination in vivo uncouples the receptor from CD19 phosphorylation and phosphatidylinositol 3-kinase (PI3K) signals. These signals are necessary and sufficient for accumulating phosphatidylinositol (3,4,5) trisphosphate (PIP3) on B cell receptor-containing early endosomes and proper sorting into the MHC class II antigen-presenting compartment (MIIC). Surprisingly, MIIC targeting is dispensable for T cell-dependent immunity. Rather, it is critical for activating endosomal toll-like receptors and antiviral humoral immunity. These findings demonstrate a novel mechanism of receptor endosomal signaling required for specific peripheral immune responses. PMID- 29141872 TI - miR-23a acts as an oncogene in pancreatic carcinoma by targeting FOXP2. AB - MicroRNAs have been reported to play an important role in tumor development and progression by targeting oncogenes and tumor suppressors. miR-23a has been described as significantly upregulated in multiple cancers and involved in tumorigenesis. The aim of this study was to evaluate the potential roles of miR 23a in pancreatic ductal adenocarcinoma (PDAC). We found that miR-23a level was significantly increased in tissues of PDAC compared with that in the control by real-time PCR. FOXP2 expression was downregulated and inversely correlated with miR-23a. miR-23a directly targeted the 3'-untranslated region of FOXP2 mRNA and repressed its expression. Mechanistically, enhancement of miR-23a by transfection with mimics in Aspc-1 cells significantly promoted cell proliferation and invasion, while miR-23a inhibitors transfection in SW1990 cells induced an inhibitory effect. Moreover, restoration of FOXP2 impaired the pro-proliferation and proinvasion effects of miR-23a, indicating FOXP2 is a direct mediator of miR 23a functions. In conclusion, our findings suggest a novel miR-23a/FOXP2 link contributing to PDAC development and invasion. It may be a potential diagnostic and therapeutic target for PDAC. PMID- 29141873 TI - A new predictor of atrial fibrillation after coronary artery bypass graft surgery: HATCH score. AB - The aim of this study was to investigate the association between HATCH score and atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery. 369 patients (103 patients with AF and 266 patients without AF) undergoing isolated CABG surgery were analyzed. Complete medical records were retrospectively collected to investigate HATCH score. The median age of patients with AF was significantly higher than the median age of non-AF group (60.8+/-10.0 years vs 67.8+/-9.5 years, P<0.001). HATCH score was significantly higher in patients who developed AF after CABG surgery than the non-AF group (P=0.017). Multivariate logistic regression analysis showed that HATCH score (OR 1.334; 95% CI 1.022 to 1.741, P=0.034) was an independent predictor of AF after CABG surgery. Receiver operating characteristic curve analysis showed that the cut-off point of HATCH score related to predict AF was >1 (two or more), with a sensitivity of 42% and specificity of 70%. Patients with elevated preoperative HATCH score may have higher risk for AF after CABG surgery. PMID- 29141874 TI - S100A4 amplifies TGF-beta-induced epithelial-mesenchymal transition in a pleural mesothelial cell line. AB - Pleural fibrosis can dramatically lower the quality of life. Numerous studies have reported that epithelial-mesenchymal transition (EMT) regulated by transforming growth factor-beta (TGF-beta) is involved in fibrosis. However, the molecular mechanism is inadequately understood. Fibroblast-specific protein-1 (S100A4) is a target of TGF-beta signaling. In our previous study, we have reported that S100A4 is highly expressed in pleural fibrosis. Thus, we suggest that S100A4 took part in the TGF-beta-induced EMT in pleural fibrosis. In this study, we determined the expression of S100A4 and EMT-related markers in Met-5A cells (pleural mesothelial cells) treated with TGF-beta or TGF-beta inhibitor by real-time PCR and western blot. In order to explore the role of S100A4, we used siRNA to knock down the expression of S100A4 in cell model. We found that the expression of epithelial cell marker was decreased and the mesenchymal cell marker increased with S100A4 upregulation after treatment with TGF-beta. Moreover, the changes of EMT-related event were restricted when the expression of S100A4 was knocked down. Conversely, S100A4 can partially rescue the EMT-related expression changes induced by TGF-beta inhibitor. These findings suggest that S100A4 expression is induced by the TGF-beta pathway, and silencing S100A4 expression can inhibit the process of TGF-beta-induced EMT. PMID- 29141876 TI - Xenopus and the art of oxygen maintenance. PMID- 29141875 TI - Cognitive enhancers associated with decreased risk of injury in patients with dementia: a nationwide cohort study in Taiwan. AB - This study aimed to investigate the associations among dementia, psychotropic medications and the risk of overall injuries. In this nationwide matched cohort study, a total of 144 008 enrolled patients >=age of 50, with 36 002 study subjects who suffered from dementia and 108 006 controls matched for sex and age, from the Inpatient Dataset, for the period 2000-2010 in Taiwan were selected from the National Health Insurance Research Database, according to International Classification of Diseases, 9th Revision, Clinical Modification. When adjusting for the confounding factors, a Cox proportional hazards analysis was used to compare the risk of developing psychiatric disorders during the 10 years of follow-up. Of the study subjects, 6701 (18.61%) suffered injury when compared with 20 919 (19.37%) in the control group. The Cox regression analysis revealed that the study subjects were more likely to develop an injury (HR: 2.294, 95% CI=2.229 to 2.361, P<0.001) after adjusting for sex, age, monthly income, urbanization level, geographic region, and comorbidities. Psychotropic medications in the subjects with dementia were associated with the risk of injury (adjusted HR=0.217, 95% CI: 0.206 to 0.228, P<0.001). Cognitive enhancers, including acetylcholinesterase inhibitors and memantine, were associated with the risk of injury in the study subjects after being adjusted for all comorbidities and medications (adjusted HR=0.712(95% CI=0.512 to 0.925, P<0.01)). In conclusion, patients who suffered dementia had a higher risk of developing injury, and the cognitive enhancers were associated with the decreased risk of injury. PMID- 29141877 TI - Giving invertebrates an eye exam: an ophthalmoscope that utilizes the autofluorescence of photoreceptors. AB - One of the most important functional features of eyes is focusing light, as both nearsightedness and farsightedness have major functional implications. Accordingly, refractive errors are frequently assessed in vertebrates, but not in the very small invertebrate eyes. We describe a micro-ophthalmoscope that takes advantage of autofluorescent properties of invertebrate photoreceptors and test the device on the relatively well-understood eyes of jumping spiders and flies. In each case, our measurements confirmed previous findings with a greater degree of accuracy. For example, we could precisely resolve the layering of the anterior median eyes and could map out the extensive retina of the anterior lateral eyes of the spider. Measurements also confirmed that fly ommatidia are focused into infinity, but showed that their focal plane is situated slightly below the receptor surface. In contrast to other approaches, this device does not rely on reflective tapeta and allows for precise optical assessment of diverse invertebrate eyes. PMID- 29141878 TI - Lack of behavioural responses of humpback whales (Megaptera novaeangliae) indicate limited effectiveness of sonar mitigation. AB - Exposure to underwater sound can cause permanent hearing loss and other physiological effects in marine animals. To reduce this risk, naval sonars are sometimes gradually increased in intensity at the start of transmission ('ramp up'). Here, we conducted experiments in which tagged humpback whales were approached with a ship to test whether a sonar operation preceded by ramp-up reduced three risk indicators - maximum sound pressure level (SPLmax), cumulative sound exposure level (SELcum) and minimum source-whale range (Rmin) - compared with a sonar operation not preceded by ramp-up. Whales were subject to one no sonar control session and either two successive ramp-up sessions (RampUp1, RampUp2) or a ramp-up session (RampUp1) and a full-power session (FullPower). Full-power sessions were conducted only twice; for other whales we used acoustic modelling that assumed transmission of the full-power sequence during their no sonar control. Averaged over all whales, risk indicators in RampUp1 (n=11) differed significantly from those in FullPower (n=12) by -3.0 dB (SPLmax), -2.0 dB (SELcum) and +168 m (Rmin), but not significantly from those in RampUp2 (n=9). Only five whales in RampUp1, four whales in RampUp2 and none in FullPower or control sessions avoided the sound source. For RampUp1, we found statistically significant differences in risk indicators between whales that avoided the sonar and whales that did not: -4.7 dB (SPLmax), -3.4 dB (SELcum) and +291 m (Rmin). In contrast, for RampUp2, these differences were smaller and not significant. This study suggests that sonar ramp-up has a positive but limited mitigative effect for humpback whales overall, but that ramp-up can reduce the risk of harm more effectively in situations when animals are more responsive and likely to avoid the sonar, e.g. owing to novelty of the stimulus, when they are in the path of an approaching sonar ship. PMID- 29141879 TI - Lower limb biomechanical analysis during an unanticipated step on a bump reveals specific adaptations of walking on uneven terrains. AB - Although it is clear that walking over different irregular terrain is associated with altered biomechanics, there is little understanding of how we quickly adapt to unexpected variations in terrain. This study aims to investigate which adaptive strategies humans adopt when performing an unanticipated step on an irregular surface, specifically a small bump. Nine healthy male participants walked at their preferred walking speed along a straight walkway during five conditions: four involving unanticipated bumps of two different heights, and one level walking condition. Muscle activation of eight lower limb muscles and three dimensional gait analysis were evaluated during these testing conditions. Two distinct adaptive strategies were found, which involved no significant change in total lower limb mechanical work or walking speed. An ankle-based strategy was adopted when stepping on a bump with the forefoot, whereas a hip-based strategy was preferred when stepping with the rearfoot. These strategies were driven by a higher activation of the plantarflexor muscles (6-51%), which generated a higher ankle joint moment during the forefoot conditions and by a higher activation of the quadriceps muscles (36-93%), which produced a higher knee joint moment and hip joint power during the rearfoot conditions. These findings provide insights into how humans quickly react to unexpected events and could be used to inform the design of adaptive controllers for wearable robots intended for use in unstructured environments that can provide optimal assistance to the different lower limb joints. PMID- 29141880 TI - Divergent respiratory and cardiovascular responses to hypoxia in bar-headed geese and Andean birds. AB - Many high-altitude vertebrates have evolved increased capacities in their oxygen transport cascade (ventilation, pulmonary diffusion, circulation and tissue diffusion), enhancing oxygen transfer from the atmosphere to mitochondria. However, the extent of interspecies variation in the control processes that dictate hypoxia responses remains largely unknown. We compared the metabolic, cardiovascular and respiratory responses to progressive decreases in inspired oxygen levels of bar-headed geese (Anser indicus), birds that biannually migrate across the Himalayan mountains, with those of Andean geese (Chloephaga melanoptera) and crested ducks (Lophonetta specularioides), lifelong residents of the high Andes. We show that Andean geese and crested ducks have evolved fundamentally different mechanisms for maintaining oxygen supply during low oxygen (hypoxia) from those of bar-headed geese. Bar-headed geese respond to hypoxia with robust increases in ventilation and heart rate, whereas Andean species increase lung oxygen extraction and cardiac stroke volume. We propose that transient high-altitude performance has favoured the evolution of robust convective oxygen transport recruitment in hypoxia, whereas life-long high altitude residency has favoured the evolution of structural enhancements to the lungs and heart that increase lung diffusion and stroke volume. PMID- 29141881 TI - It's not all black and white: visual scene parameters influence optokinetic reflex performance in Xenopus laevis tadpoles. AB - The maintenance of visual acuity during active and passive body motion is ensured by gaze-stabilizing reflexes that aim at minimizing retinal image slip. For the optokinetic reflex (OKR), large-field visual motion of the surround forms the essential stimulus that activates eye movements. Properties of the moving visual world influence cognitive motion perception and the estimation of visual image velocity. Therefore, the performance of brainstem-mediated visuo-motor behaviors might also depend on image scene characteristics. Employing semi-intact preparations of mid-larval stages of Xenopus laevis tadpoles, we studied the influence of contrast polarity, intensity, contour shape and different motion stimulus patterns on the performance of the OKR and multi-unit optic nerve discharge during motion of a large-field visual scene. At high contrast intensities, the OKR amplitude was significantly larger for visual scenes with a positive contrast (bright dots on a dark background) compared with those with a negative contrast. This effect persisted for luminance-matched pairs of stimuli, and was independent of contour shape. The relative biases of OKR performance along with the independence of the responses from contour shape were closely matched by the optic nerve discharge evoked by the same visual stimuli. However, the multi-unit activity of retinal ganglion cells in response to a small single moving vertical edge was strongly influenced by the light intensity in the vertical neighborhood. This suggests that the underlying mechanism of OKR biases related to contrast polarity directly derives from visual motion-processing properties of the retinal circuitry. PMID- 29141882 TI - Transparent anemone shrimp (Ancylomenes pedersoni) become opaque after exercise and physiological stress in correlation with increased hemolymph perfusion. AB - Whole-body transparency, an effective camouflage strategy in many aquatic species, can be disrupted by environmental and/or physiological stressors. We found that tail-flip escape responses temporarily disrupt the transparency of the anemone shrimp Ancylomenes pedersoni After as few as three tail flips, the previously transparent abdominal muscle became cloudy. Eliciting additional tail flips to the point of exhaustion (16+/-1 s.e.m.; n=23) resulted in complete opacity, though the original transparency returned after 20-60 min of inactivity. We hypothesized that an exercise-induced increase in blood volume between muscle fibers creates regions of low refractive index fluid between high refractive index muscles, thereby increasing light scattering. We documented pre- and post contraction perfusion by injecting Alexa Fluor 594 wheat germ agglutinin that labeled sarcolemmal surfaces and endothelial cells in contact with hemolymph and found more hemolymph perfused through the abdominal tissue post-exercise, presumably owing to more capillaries opening. In addition, we altered salinity (to 550/00 and 80/00), perforated the abdomen and injected a vasodilator. All three treatments increased both perfusion and opacity, lending further support to our hypothesis that increased hemolymph perfusion to the abdomen is one mechanism that can disrupt a shrimp's transparency. The fact that transparent shrimp at rest have little to no evidence of perfusion to their abdominal musculature (unlike the opaque shrimp Lysmata pederseni, which had more perfusion even at rest) indicates that they may experience significant physiological trade-offs in order to maintain their transparency; specifically, limiting blood flow and thereby reducing oxygen delivery may result in reduced performance. PMID- 29141883 TI - Thermal history and gape of individual Mytilus californianus correlate with oxidative damage and thermoprotective osmolytes. AB - The ability of animals to cope with environmental stress depends - in part - on past experience, yet knowledge of the factors influencing an individual's physiology in nature remains underdeveloped. We used an individual monitoring system to record body temperature and valve gaping behavior of rocky intertidal zone mussels (Mytilus californianus). Thirty individuals were selected from two mussel beds (wave-exposed and wave-protected) that differ in thermal regime. Instrumented mussels were deployed at two intertidal heights (near the lower and upper edges of the mussel zone) and in a continuously submerged tidepool. Following a 23-day monitoring period, measures of oxidative damage to DNA and lipids, antioxidant capacities (catalase activity and peroxyl radical scavenging) and tissue contents of organic osmolytes were obtained from gill tissue of each individual. Univariate and multivariate analyses indicated that inter-individual variation in cumulative thermal stress is a predominant driver of physiological variation. Thermal history over the outplant period was positively correlated with oxidative DNA damage. Thermal history was also positively correlated with tissue contents of taurine, a thermoprotectant osmolyte, and with activity of the antioxidant enzyme catalase. Origin site differences, possibly indicative of developmental plasticity, were only significant for catalase activity. Gaping behavior was positively correlated with tissue contents of two osmolytes. Overall, these results are some of the first to clearly demonstrate relationships between inter-individual variation in recent experience in the field and inter individual physiological variation, in this case within mussel beds. Such micro scale, environmentally mediated physiological differences should be considered in attempts to forecast biological responses to a changing environment. PMID- 29141884 TI - A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer. AB - Numerous variants of unknown significance (VUS) have been identified through large-scale cancer genome projects, although their functional relevance remains uninvestigated. We developed a mixed-all-nominated-mutants-in-one (MANO) method to evaluate the transforming potential and drug sensitivity of oncogene VUS in a high-throughput manner and applied this method to 101 nonsynonymous epidermal growth factor receptor (EGFR) mutants. We discovered a number of mutations conferring resistance to EGFR tyrosine kinase inhibitors (TKIs), including gefitinib- and erlotinib-insensitive missense mutations within exon 19 and other gefitinib-resistant mutations, such as L833V, A839T, V851I, A871T, and G873E. L858R-positive tumors (12.8%) harbored compound mutations primarily in the cis allele, which decreased the gefitinib sensitivity of these tumors. The MANO method further revealed that some EGFR mutants that are highly resistant to all types of TKIs are sensitive to cetuximab. Thus, these data support the importance of examining the clinical relevance of uncommon mutations within EGFR and of evaluating the functions of such mutations in combination. This method may become a foundation for the in vitro and in vivo assessment of variants of cancer related genes and help customize cancer therapy for individual patients. PMID- 29141885 TI - A role for bacterial urease in gut dysbiosis and Crohn's disease. AB - Gut dysbiosis during inflammatory bowel disease involves alterations in the gut microbiota associated with inflammation of the host gut. We used a combination of shotgun metagenomic sequencing and metabolomics to analyze fecal samples from pediatric patients with Crohn's disease and found an association between disease severity, gut dysbiosis, and bacterial production of free amino acids. Nitrogen flux studies using 15N in mice showed that activity of bacterial urease, an enzyme that releases ammonia by hydrolysis of host urea, led to the transfer of murine host-derived nitrogen to the gut microbiota where it was used for amino acid synthesis. Inoculation of a conventional murine host (pretreated with antibiotics and polyethylene glycol) with commensal Escherichia coli engineered to express urease led to dysbiosis of the gut microbiota, resulting in a predominance of Proteobacteria species. This was associated with a worsening of immune-mediated colitis in these animals. A potential role for altered urease expression and nitrogen flux in the development of gut dysbiosis suggests that bacterial urease may be a potential therapeutic target for inflammatory bowel diseases. PMID- 29141886 TI - PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes. AB - Immunologically based clinical trials performed thus far have failed to cure type 1 diabetes (T1D), in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4 T cells, which destroy beta cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in programmed death ligand 1 (PD-L1), an important immune checkpoint, in the T1D nonobese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. We therefore sought to determine whether restoration of this defect would cure T1D as an alternative to immunosuppression. Genetically engineered or pharmacologically modulated HSPCs overexpressing PD-L1 inhibited the autoimmune response in vitro, reverted diabetes in newly hyperglycemic NOD mice in vivo, and homed to the pancreas of hyperglycemic NOD mice. The PD-L1 expression defect was confirmed in human HSPCs in T1D patients as well, and pharmacologically modulated human HSPCs also inhibited the autoimmune response in vitro. Targeting a specific immune checkpoint defect in HSPCs thus may contribute to establishing a cure for T1D. PMID- 29141887 TI - Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. AB - The immunosuppressive activity of mesenchymal stromal cells (MSCs) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSCs are undetectable after administration. Therefore, understanding the fate of infused MSCs could help predict clinical responses. Using a murine model of graft-versus-host disease (GvHD), we demonstrate that MSCs are actively induced to undergo perforin dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSCs, we found a striking parallel, whereby only those with high cytotoxic activity against MSCs responded to MSC infusion, whereas those with low activity did not. The need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSCs generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSCs and produce indoleamine 2,3 dioxygenase, which is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSCs or that all patients could be treated with ex vivo apoptotic MSCs. PMID- 29141888 TI - Lung cancer-associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell-immune cell cross-talk. AB - Dyspnea is a frequent, devastating, and poorly understood symptom of advanced lung cancer. In our cohort, among 519 patients who underwent a computed tomography scan for the diagnosis of lung cancer, 250 had a mean pulmonary artery diameter of >28 mm, indicating pulmonary hypertension (PH). In human lung cancer tissue, we consistently observed increased vascular remodeling and perivascular inflammatory cell accumulation (macrophages/lymphocytes). Vascular remodeling, PH, and perivascular inflammatory cell accumulation were mimicked in three mouse models of lung cancer (LLC1, KRasLA2 , and cRaf-BxB). In contrast, NOD.Cg PrkdcscidIl2rgtm1Wjl/SzJ immunodeficient xenograft and dominant-negative IKK2 mutant triple transgenic (Sftpc-rtTA/Tet-O-Ikk2DN) mice did not develop PH. Coculturing human lung cancer cells with macrophages and lymphocytes strongly up regulated cytokine release, provoking enhanced migration, apoptosis resistance, and phosphodiesterase 5 (PDE5)-mediated up-regulation of human lung vascular cells, which are typical features of PH. The PDE5 inhibitor sildenafil largely suppressed PH in the LLC1 model. We conclude that lung cancer-associated PH represents a distinct PH category; targeting inflammation in the microenvironment and PDE5 offers a potential therapeutic option. PMID- 29141889 TI - Pulmonary arteriovenous malformations emerge from the shadows. PMID- 29141892 TI - Making mindset matter. PMID- 29141893 TI - Lawyers for Guantanamo Bay detainees on hunger strike will fight US government in court. PMID- 29141890 TI - British Thoracic Society Clinical Statement on Pulmonary Arteriovenous Malformations. AB - Pulmonary arteriovenous malformations (PAVMs) are structurally abnormal vascular communications that provide a continuous right-to-left shunt between pulmonary arteries and veins. Their importance stems from the risks they pose (>1 in 4 patients will have a paradoxical embolic stroke, abscess or myocardial infarction while life-threatening haemorrhage affects 1 in 100 women in pregnancy), opportunities for risk prevention, surprisingly high prevalence and under appreciation, thus representing a challenging condition for practising healthcare professionals. The driver for the current Clinical Statement was the plethora of new data since previous hereditary haemorrhagic telangiectasia (HHT) guidelines generated in 2006 and a systematic Cochrane Review for PAVM embolisation in 2011. The British Thoracic Society (BTS) identified key areas in which there is now evidence to drive a change in practice. Due to the paucity of data in children, this Statement focused on adults over 16 years. The Statement spans the management of PAVMs already known to be present (interventional and medical), screening and diagnosis (for PAVMs and HHT) and follow-up of patients following a first diagnosis, intervention or negative screen for PAVMs. The Good Practice Points (in bold) were generated for a target audience of general respiratory, medical and specialist clinicians and were approved by the BTS Standards of Care Committee, before formal peer review and public consultation. The Statement spans embolisation treatment, accessory medical management and issues related to the likelihood of underlying HHT. PMID- 29141894 TI - NICE recommends routine NHS funding for new breast cancer drugs. PMID- 29141895 TI - Has the Mental Health Act had its day? PMID- 29141896 TI - Sixty seconds on . . . the circadian rhythm. PMID- 29141898 TI - John Launer: How to be a writer/doctor. PMID- 29141897 TI - Effects of health and social care spending constraints on mortality in England: a time trend analysis. AB - OBJECTIVE: Since 2010, England has experienced relative constraints in public expenditure on healthcare (PEH) and social care (PES). We sought to determine whether these constraints have affected mortality rates. METHODS: We collected data on health and social care resources and finances for England from 2001 to 2014. Time trend analyses were conducted to compare the actual mortality rates in 2011-2014 with the counterfactual rates expected based on trends before spending constraints. Fixed-effects regression analyses were conducted using annual data on PES and PEH with mortality as the outcome, with further adjustments for macroeconomic factors and resources. Analyses were stratified by age group, place of death and lower-tier local authority (n=325). Mortality rates to 2020 were projected based on recent trends. RESULTS: Spending constraints between 2010 and 2014 were associated with an estimated 45 368 (95% CI 34 530 to 56 206) higher than expected number of deaths compared with pre-2010 trends. Deaths in those aged >=60 and in care homes accounted for the majority. PES was more strongly linked with care home and home mortality than PEH, with each L10 per capita decline in real PES associated with an increase of 5.10 (3.65-6.54) (p<0.001) care home deaths per 100 000. These associations persisted in lag analyses and after adjustment for macroeconomic factors. Furthermore, we found that changes in real PES per capita may be linked to mortality mostly via changes in nurse numbers. Projections to 2020 based on 2009-2014 trend was cumulatively linked to an estimated 152 141 (95% CI 134 597 and 169 685) additional deaths. CONCLUSIONS: Spending constraints, especially PES, are associated with a substantial mortality gap. We suggest that spending should be targeted on improving care delivered in care homes and at home; and maintaining or increasing nurse numbers. PMID- 29141900 TI - Imminent health crises among the Rohingya people of Myanmar. PMID- 29141899 TI - Atypical G Protein beta5 Promotes Cardiac Oxidative Stress, Apoptosis, and Fibrotic Remodeling in Response to Multiple Cancer Chemotherapeutics. AB - The clinical use of multiple classes of cancer chemotherapeutics is limited by irreversible, dose-dependent, and sometimes life-threatening cardiotoxicity. Though distinct in their mechanisms of action, doxorubicin, paclitaxel, and 5-FU all induce rapid and robust upregulation of atypical G protein Gbeta5 in the myocardium correlating with oxidative stress, myocyte apoptosis, and the accumulation of proinflammatory and profibrotic cytokines. In ventricular cardiac myocytes (VCM), Gbeta5 deficiency provided substantial protection against the cytotoxic actions of chemotherapeutics, including reductions in oxidative stress and simultaneous attenuation of ROS-dependent activation of the ATM and CaMKII proapoptotic signaling cascades. In addition, Gbeta5 loss allowed for maintenance of Deltapsim, basal mitochondrial calcium uniporter expression, and mitochondrial Ca2+ levels, effects likely to preserve functional myocyte excitation-contraction coupling. The deleterious effects of Gbeta5 are not restricted to VCM, however, as Gbeta5 knockdown also reduces chemotherapy-induced release of proinflammatory cytokines (e.g., TNFalpha), hypertrophic factors (e.g., ANP), and profibrotic factors (e.g., TGFbeta1) from both VCM and ventricular cardiac fibroblasts, with the most dramatic reduction occurring in cocultured cells. Our experiments suggest that Gbeta5 facilitates the myofibroblast transition, the persistence of which contributes to pathologic remodeling and heart failure. The convergence of Gbeta5-mediated, ROS-dependent signaling pathways in both cell types represents a critical etiological factor in the pathogenesis of chemotherapy-induced cardiotoxicity. Indeed, intracardiac injection of Gbeta5-targeted shRNA allowed for heart-specific protection against the damaging impact of chronic chemotherapy. Together, our results suggest that inhibition of Gbeta5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.Significance: These findings suggest that inhibiting an atypical G-protein might provide a strategy to limit the cardiotoxicity in cancer patients treated with anthracyclines, taxanes, or fluoropyrimidines. Cancer Res; 78(2); 528-41. (c)2017 AACR. PMID- 29141901 TI - Minimum alcohol pricing goes ahead in Scotland after drinks industry loses legal battle. PMID- 29141902 TI - An intercollegiate call for children and young people's mental health. PMID- 29141903 TI - Mumps epidemic in North America proves unusually stubborn. PMID- 29141904 TI - Aid for earthquake survivors. PMID- 29141906 TI - Keratolimbal allograft for limbal stem cell deficiency after severe corneal chemical injury: a systematic review. AB - PURPOSE: To review the published literature on outcomes of keratolimbal allograft (KLAL) for the surgical treatment of limbal stem cell deficiency (LSCD) and corneal blindness after severe corneal chemical injury. METHODS: Literature searches were conducted in the following electronic databases: MEDLINE, EMBASE, Science Citation Index, CINAHL, LILACS and the Cochrane Library. Standard systematic review methodology was applied. The main outcome measure was the proportion of eyes with best-corrected visual acuity (BCVA) >=20/200 at last follow-up. Other measures of allograft success were also collected. RESULTS: We identified six reports in which KLAL outcomes in the eyes after chemical injury could be distinguished. There were no randomised controlled studies. The outcomes of KLAL in 36 eyes of 33 patients were analysed. One study with seven eyes did not specify KLAL follow-up specific to chemical injury. Median postoperative follow-up for the other 29 eyes in 26 patients was 42 months (range 6.2-114 months). In the same 29 eyes, 69% (20/29) had BCVA >=20/200 at the last follow-up examination. Eighty-nine per cent of all eyes (32/36) underwent penetrating keratoplasty simultaneous or subsequent to KLAL. CONCLUSIONS: The number of studies where outcomes of KLAL in eyes with severe corneal chemical injury could be discerned was limited, and variability was observed in outcome reporting. The quality of evidence to support the use of KLAL in LSCD in severe chemical corneal burns was low. Standardisation and longer follow-up are needed to better define evidence-based best practice when contemplating surgical intervention for blindness after corneal chemical injury. PROSPERO REGISTRATION NUMBER: CRD42017054733. PMID- 29141905 TI - Adaptive optics imaging of inherited retinal diseases. AB - Adaptive optics (AO) ophthalmoscopy allows for non-invasive retinal phenotyping on a microscopic scale, thereby helping to improve our understanding of retinal diseases. An increasing number of natural history studies and ongoing/planned interventional clinical trials exploit AO ophthalmoscopy both for participant selection, stratification and monitoring treatment safety and efficacy. In this review, we briefly discuss the evolution of AO ophthalmoscopy, recent developments and its application to a broad range of inherited retinal diseases, including Stargardt disease, retinitis pigmentosa and achromatopsia. Finally, we describe the impact of this in vivo microscopic imaging on our understanding of disease pathogenesis, clinical trial design and outcome metrics, while recognising the limitation of the small cohorts reported to date. PMID- 29141907 TI - Emergency versus standard response: time efficacy of London's Air Ambulance rapid response vehicle. AB - OBJECTIVE: The potential increased risk of an emergency response using a rapid response vehicle (RRV) should only be accepted when it allows a clinically significant time saving for management of patients who are critically injured or sick. Air ambulance services often use an RRV to maintain operational resilience. We compared the RRV response time on emergency versus standard driving to inform emergency services of time efficacy of emergency response in an urban environment. METHODS: Prospective observational controlled study of response data of emergency and standard driving. An identical RRV shadowed the medical team until the team was dispatched to a job (emergency driving). The shadow RRV then drove to the same given location from the same origin location in equal traffic conditions being compliant with all traffic signals, road signs and speed limits (standard driving). RESULTS: The emergency response resulted in an estimated reduction in median response time of 14 min (95% CI 9 to 19) which represented a time saving of 54.9%. The estimated difference in distance travelled (0.6 km) was not statistically significant. Median speed was significantly higher when using an emergency response (46.1 IQR 39-53.4 km/hour) versus standard response (20.1 IQR 16.3-24.7 km/hour), with an estimated difference of -24.5 km/hour (95% CI 28.8 to -20.5). CONCLUSIONS: The current study found RRVs to be significantly quicker when responding with lights, sirens and traffic rule exemptions compared with a response being compliant with all traffic signals, road signs and speed limits. PMID- 29141908 TI - Two Distinct Regulatory Mechanisms of Transcriptional Initiation in Response to Nutrient Signaling. AB - SAGA (Spt-Ada-Gcn5-Acetyltransferase) and TFIID (transcription factor IID) have been previously shown to facilitate the formation of the PIC (pre-initiation complex) at the promoters of two distinct sets of genes. Here, we demonstrate that TFIID and SAGA differentially participate in the stimulation of PIC formation (and hence transcriptional initiation) at the promoter of PHO84, a gene for the high-affinity inorganic phosphate (Pi) transporter for crucial cellular functions, in response to nutrient signaling. We show that transcriptional initiation of PHO84 occurs predominantly in a TFIID-dependent manner in the absence of Pi in the growth medium. Such TFIID dependency is mediated via the NuA4 (nucleosome acetyltransferase of H4) histone acetyltransferase (HAT). Intriguingly, transcriptional initiation of PHO84 also occurs in the presence of Pi in the growth medium, predominantly via the SAGA complex, but independently of NuA4 HAT. Thus, Pi in the growth medium switches transcriptional initiation of PHO84 from NuA4-TFIID to SAGA dependency. Further, we find that both NuA4-TFIID- and SAGA-dependent transcriptional initiations of PHO84 are facilitated by the 19S proteasome subcomplex or regulatory particle (RP) via enhanced recruitment of the coactivators SAGA and NuA4 HAT, which promote TFIID-independent and dependent PIC formation for transcriptional initiation, respectively. NuA4 HAT does not regulate activator binding to PHO84, but rather facilitates PIC formation for transcriptional initiation in the absence of Pi in the growth medium. On the other hand, SAGA promotes activator recruitment to PHO84 for transcriptional initiation in the growth medium containing Pi. Collectively, our results demonstrate two distinct stimulatory pathways for PIC formation (and hence transcriptional initiation) at PHO84 by TFIID, SAGA, NuA4, and 19S RP in the presence and absence of an essential nutrient, Pi, in the growth media, thus providing new regulatory mechanisms of transcriptional initiation in response to nutrient signaling. PMID- 29141909 TI - Local Fitness Landscapes Predict Yeast Evolutionary Dynamics in Directionally Changing Environments. AB - The fitness landscape is a concept that is widely used for understanding and predicting evolutionary adaptation. The topography of the fitness landscape depends critically on the environment, with potentially far-reaching consequences for evolution under changing conditions. However, few studies have assessed directly how empirical fitness landscapes change across conditions, or validated the predicted consequences of such change. We previously evolved replicate yeast populations in the presence of either gradually increasing, or constant high, concentrations of the heavy metals cadmium (Cd), nickel (Ni), and zinc (Zn), and analyzed their phenotypic and genomic changes. Here, we reconstructed the local fitness landscapes underlying adaptation to each metal by deleting all repeatedly mutated genes both by themselves and in combination. Fitness assays revealed that the height, and/or shape, of each local fitness landscape changed considerably across metal concentrations, with distinct qualitative differences between unconditionally (Cd) and conditionally toxic metals (Ni and Zn). This change in topography had particularly crucial consequences in the case of Ni, where a substantial part of the individual mutational fitness effects changed in sign across concentrations. Based on the Ni landscape analyses, we made several predictions about which mutations had been selected when during the evolution experiment. Deep sequencing of population samples from different time points generally confirmed these predictions, demonstrating the power of landscape reconstruction analyses for understanding and ultimately predicting evolutionary dynamics, even under complex scenarios of environmental change. PMID- 29141911 TI - Transcriptional integration of mitogenic and mechanical signals by Myc and YAP. AB - Mammalian cells must integrate environmental cues to determine coherent physiological responses. The transcription factors Myc and YAP-TEAD act downstream from mitogenic signals, with the latter responding also to mechanical cues. Here, we show that these factors coordinately regulate genes required for cell proliferation. Activation of Myc led to extensive association with its genomic targets, most of which were prebound by TEAD. At these loci, recruitment of YAP was Myc-dependent and led to full transcriptional activation. This cooperation was critical for cell cycle entry, organ growth, and tumorigenesis. Thus, Myc and YAP-TEAD integrate mitogenic and mechanical cues at the transcriptional level to provide multifactorial control of cell proliferation. PMID- 29141910 TI - Munc13 proteins control regulated exocytosis in mast cells. AB - Mast cells (MCs) are involved in host defenses against pathogens and inflammation. Stimulated MCs release substances stored in their granules via regulated exocytosis. In other cell types, Munc13 (mammalian homolog of Caenorhabditis elegans uncoordinated gene 13) proteins play essential roles in regulated exocytosis. Here, we found that MCs express Munc13-2 and -4, and we studied their roles using global and conditional knock-out (KO) mice. In a model of systemic anaphylaxis, we found no difference between WT and Munc13-2 KO mice, but global and MC-specific Munc13-4 KO mice developed less hypothermia. This protection correlated with lower plasma histamine levels and with histological evidence of defective MC degranulation but not with changes in MC development, distribution, numbers, or morphology. In vitro assays revealed that the defective response in Munc13-4-deficient MCs was limited to regulated exocytosis, leaving other MC secretory effector responses intact. Single cell capacitance measurements in MCs from mouse mutants differing in Munc13-4 expression levels in their MCs revealed that as levels of Munc13-4 decrease, the rate of exocytosis declines first, and then the total amount of exocytosis decreases. A requirement for Munc13-2 in MC exocytosis was revealed only in the absence of Munc13-4. Electrophysiology and EM studies uncovered that the number of multigranular compound events (i.e. granule-to-granule homotypic fusion) was severely reduced in the absence of Munc13-4. We conclude that although Munc13-2 plays a minor role, Munc13-4 is essential for regulated exocytosis in MCs, and that this MC effector response is required for a full anaphylactic response. PMID- 29141913 TI - Multiplexed Biomarker Panels Discriminate Zika and Dengue Virus Infection in Humans. AB - Zika virus (ZIKV) and dengue virus (DENV) are closely related flaviviruses that cause widespread, acute febrile illnesses, notably microcephaly for fetuses of infected pregnant women. Detecting the viral cause of these illnesses is paramount to determine risks to patients, counsel pregnant women, and help fight outbreaks. A combined diagnostic algorithm for ZIKV and DENV requires Reverse transcription polymerase chain reaction (RT-PCR) and IgM antibody detection. RT PCR differentiates between DENV and ZIKV infections during the acute phases of infection, but differentiation based on IgM antibodies is currently nearly impossible in endemic areas. We have developed a ZIKV/DENV protein array and tested it with serum samples collected from ZIKV- and DENV-infected patients and healthy subjects in Puerto Rico. Our analyses reveal a biomarker panel that are capable of discriminating ZIKV and DENV infections with high accuracy, including Capsid protein from African ZIKV strain MR766, and other 5 pair of proteins (NS1, NS2A, NS3, NS4B and NS5) from ZIKV and DENV respectively. Both sensitivity and specificity of the test for ZIKV from DENV are around 90%. We propose that the ZIKV/DENV protein array will be used in future studies to discriminate patients infected with ZIKV from DENV. PMID- 29141912 TI - WH2 and proline-rich domains of WASP-family proteins collaborate to accelerate actin filament elongation. AB - WASP-family proteins are known to promote assembly of branched actin networks by stimulating the filament-nucleating activity of the Arp2/3 complex. Here, we show that WASP-family proteins also function as polymerases that accelerate elongation of uncapped actin filaments. When clustered on a surface, WASP-family proteins can drive branched actin networks to grow much faster than they could by direct incorporation of soluble monomers. This polymerase activity arises from the coordinated action of two regulatory sequences: (i) a WASP homology 2 (WH2) domain that binds actin, and (ii) a proline-rich sequence that binds profilin actin complexes. In the absence of profilin, WH2 domains are sufficient to accelerate filament elongation, but in the presence of profilin, proline-rich sequences are required to support polymerase activity by (i) bringing polymerization-competent actin monomers in proximity to growing filament ends, and (ii) promoting shuttling of actin monomers from profilin-actin complexes onto nearby WH2 domains. Unoccupied WH2 domains transiently associate with free filament ends, preventing their growth and dynamically tethering the branched actin network to the WASP-family proteins that create it. Collaboration between WH2 and proline-rich sequences thus strikes a balance between filament growth and tethering. Our work expands the number of critical roles that WASP-family proteins play in the assembly of branched actin networks to at least three: (i) promoting dendritic nucleation; (ii) linking actin networks to membranes; and (iii) accelerating filament elongation. PMID- 29141915 TI - Laboratory Screening for Children Entering Foster Care. AB - OBJECTIVES: To determine the prevalence of medical illness detected by laboratory screening in children entering foster care in a single, urban county. METHODS: All children entering foster care in a single county in Ohio were seen at a consultation foster care clinic and had laboratory screening, including testing for infectious diseases such as HIV, hepatitis B, hepatitis C, syphilis, and tuberculosis as well as for hemoglobin and lead levels. RESULTS: Over a 3-year period (2012-2015), laboratory screening was performed on 1977 subjects entering foster care in a consultative foster care clinic. The prevalence of hepatitis B, hepatitis C, syphilis, and tuberculosis were all found to be <1%. There were no cases of HIV. Seven percent of teenagers entering foster care tested positive for Chlamydia. A secondary finding was that 54% of subjects were hepatitis B surface antibody-negative, indicating an absence of detected immunity to the hepatitis B virus. CONCLUSIONS: Routine laboratory screening for children entering foster care resulted in a low yield. Targeted, rather than routine, laboratory screening may be a more clinically meaningful approach for children entering foster care. PMID- 29141916 TI - Bone Age: A Handy Tool for Pediatric Providers. AB - Pediatricians have relied on methods for determining skeletal maturation for >75 years. Bone age continues to be a valuable tool in assessing children's health. New technology for bone age determination includes computer-automated readings and assessments obtained from alternative imaging modalities. In addition, new nonclinical bone age applications are evolving, particularly pertaining to immigration and children's rights to asylum. Given the significant implications when bone ages are used in high-stake decisions, it is necessary to recognize recently described limitations in predicting accurate age in various ethnicities and diseases. Current methods of assessing skeletal maturation are derived from primarily white populations. In modern studies, researchers have explored the accuracy of bone age across various ethnicities in the United States. Researchers suggest there is evidence that indicates the bone ages obtained from current methods are less generalizable to children of other ethnicities, particularly children with African and certain Asian backgrounds. Many of the contemporary methods of bone age determination may be calibrated to individual populations and hold promise to perform better in a wider range of ethnicities, but more data are needed. PMID- 29141914 TI - Proteotranscriptomics Reveal Signaling Networks in the Ovarian Cancer Microenvironment. AB - Ovarian cancer is characterized by early transcoelomic metastatic spread via the peritoneal fluid, where tumor cell spheroids (TU), tumor-associated T cells (TAT), and macrophages (TAM) create a unique microenvironment promoting cancer progression, chemoresistance, and immunosuppression. However, the underlying signaling mechanisms remain largely obscure. To chart these signaling networks, we performed comprehensive proteomic and transcriptomic analyses of TU, TAT, and TAM from ascites of ovarian cancer patients. We identify multiple intercellular signaling pathways driven by protein or lipid mediators that are associated with clinical outcome. Beyond cytokines, chemokines and growth factors, these include proteins of the extracellular matrix, immune checkpoint regulators, complement factors, and a prominent network of axon guidance molecules of the ephrin, semaphorin, and slit families. Intriguingly, both TU and TAM from patients with a predicted short survival selectively produce mediators supporting prometastatic events, including matrix remodeling, stemness, invasion, angiogenesis, and immunosuppression, whereas TAM associated with a longer survival express cytokines linked to effector T-cell chemoattraction and activation. In summary, our study uncovers previously unrecognized signaling networks in the ovarian cancer microenvironment that are of potential clinical relevance. PMID- 29141917 TI - Issues Related to Laboratory Screening for Children and Adolescents Entering Foster Care. PMID- 29141918 TI - Wild Microbiome Stems Tumorigenesis in Lab Mice. AB - Replacing laboratory mice's gut microbiomes with the microbial communities of their wild counterparts alters the lab animals' immune systems and boosts their resistance to colorectal cancer development and influenza. PMID- 29141919 TI - Rare Tumors in Kids May Respond to Tazemetostat. AB - In a phase I trial of the EZH2 inhibitor tazemetostat, children with INI1 deficient tumors-including relapsed or refractory malignant rhabdoid tumors, atypical teratoid rhabdoid tumors, epithelioid sarcomas, and poorly differentiated chordomas-responded well to treatment, with some experiencing durable responses. PMID- 29141920 TI - Parathyroid hormone-related protein modulates inflammation in mouse mesangial cells and blunts apoptosis by enhancing COX-2 expression. AB - Injury of mesangial cells (MC) is a prominent feature of glomerulonephritis. Activated MC secrete inflammatory mediators that induce cell apoptosis. Parathyroid hormone-related peptide (PTHrP) is a locally active cytokine that enhances cell survival and is upregulated by proinflammatory factors in many cell types. The aim of this study was to analyze the regulation of PTHrP expression by inflammatory cytokines and to evaluate whether PTHrP itself acts as a proinflammatory and/or survival factor on male murine MC in primary culture. Our results showed that IL-1beta (10 ng/ml) and TNF-alpha (10 ng/ml) rapidly and transiently upregulated PTHrP expression in MC. The effects of IL-1beta were both transcriptional and posttranscriptional, with stabilization of the PTHrP mRNA by human antigen R (HuR). Proteome profiler arrays showed that PTHrP itself enhanced cytokines within 2 h in cell lysates, mainly IL-17, IL-16, IL-1alpha, and IL-6. PTHrP also stimulated sustained expression (2-4 h) of chemokines, mainly regulated upon activation normal T cell expressed and secreted (RANTES)/C-C motif chemokine 5 (CCL5) and macrophage inflammatory protein-2 (MIP-2)/C-X-C motif chemokine 2 (CXCL2), thymus and activation-regulated chemokine (TARC)/CCL17, and interferon-inducible T cell alpha-chemoattractant (I-TAC)/CXCL11. Moreover, PTHrP markedly enhanced cyclooxygenase-2 (COX-2) expression and elicited its autoinduction through the activation of the NF-kappaB pathway. PTHrP induced MC survival via the COX-2 products, and PTHrP overexpression in MC blunted the apoptotic effects of IL-1beta and TNF-alpha. Altogether, these findings suggest that PTHrP functions as a booster of glomerular inflammatory processes and may be a negative feedback loop preserving MC survival. PMID- 29141921 TI - MicroRNA-574 suppresses oocyte maturation via targeting hyaluronan synthase 2 in porcine cumulus cells. AB - MicroRNAs (miRNAs) have been established as important regulators of gene expression in the mammalian ovary. A previous screen of small RNA in the porcine ovary identified the downregulation of miR-574 during oocyte maturation, although its role during this process was not established. Here, we found that miR-574 directly targets the transcript for hyaluronan synthase 2 protein (HAS2), a key enzyme in the production of extracellular matrix by the surrounding cumulus cells. Inhibiting this miRNA during in vitro maturation (IVM) increased HAS2 levels along with several markers of oocyte quality. Furthermore, inhibiting miR 574 increased oocyte meiotic progression. We then stably overexpressed miR-574 using a lentiviral vector to transduce cumulus cells during IVM. This gain-of function approach resulted in a 50% decrease in HAS2 expression and nearly 20% reduction in oocyte progression through meiosis. To confirm the specific targeting of HAS2 by miR-574, we constructed several luciferase vectors harboring the HAS2 3'-untranslated region. Cotransfection of the reporter and miR-574 attenuated luciferase activity. After mutating the putative miR-574 binding site, however, this effect was abolished and luciferase activity remained high. Our results show that the direct targeting of HAS2 by miR-574 negatively impacts oocyte quality during IVM and that inhibiting miR-574 derepresses HAS2 expression and subsequently improves oocyte maturation. Taken together, we help to elucidate a mechanism of posttranscriptional regulation by miRNA in the mammalian ovary. PMID- 29141922 TI - TRPC6 contributes to LPS-induced inflammation through ERK1/2 and p38 pathways in bronchial epithelial cells. AB - receptor potential canonical (TRPC) channels are presently an emerging target for airway disorders. Recent evidence has indicated that TRPC6 as a member of the TRPC family plays an important role in airway inflammation, but its precise function in bronchial epithelial cells remains unclear. The aim of this study was to investigate the role of TRPC6 in Toll-like receptor 4 (TLR4)-mediated inflammation in human bronchial epithelial cells stimulated by endotoxin [lipopolysaccharide (LPS)]. Hyp9 is a simplified phloroglucinol derivative of hyperforin that highly selectively activates TRPC6 channels. The results show that the activation of TRPC6 by Hyp9 induced the production of interleukin (IL)-8 and IL-6. LPS was also able to induce the release of IL-8 and IL-6, which was significantly aggravated by Hyp9 and reduced by knockdown of TRPC6. Treatment with LPS not only chronically induced the expression of TRPC6 mRNA and protein in a TLR4-dependent manner but also acutely increased Ca2+ influx through TRPC6 channels. In addition, LPS-induced overexpression of TRPC6 and Ca2+ influx were associated with the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt. Importantly, TRPC6 was required for the activation of ERK1/2, p38, and NF kappaB. In conclusion, these data reveal that LPS induced the overexpression of TRPC6 and TRPC6-dependent Ca2+ influx via the TLR4/PI3K/Akt pathway resulting in Ca2+ mobilization, which subsequently promoted the activation of ERK1/2, p38, and NF-kappaB and the inflammatory response in bronchial epithelial cells. PMID- 29141923 TI - Src family kinase inhibitors blunt PACAP-induced PAC1 receptor endocytosis, phosphorylation of ERK, and the increase in cardiac neuron excitability. AB - Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) activation of PAC1 receptors ( Adcyap1r1) significantly increases excitability of guinea pig cardiac neurons. This modulation of excitability is mediated in part by plasma membrane G protein-dependent activation of adenylyl cyclase and downstream signaling cascades. However, additional mechanisms responsible for the enhanced excitability are activated following internalization of the PAC1 receptor and endosomal signaling. Src family kinases play critical roles mediating endocytosis of many trophic factor and G protein-coupled receptors. The present study investigated whether Src family kinases also support the PACAP-induced PAC1 receptor internalization, phosphorylation of ERK, and enhanced neuronal excitability. Using human embryonic kidney cells stably expressing a green fluorescent protein-tagged PAC1 receptor, treatment with the Src family kinase inhibitor PP2 (10 uM) markedly reduced the PACAP-induced PAC1 receptor internalization, and in parallel, both PP2 and Src inhibitor 1 (Src-1, 2 uM) reduced ERK activation determined by Western blot analysis. In contrast, Src family kinase inhibitors did not eliminate a PACAP-induced rise in global calcium generated by inositol (1,4,5)-trisphosphate-induced release of calcium from endoplasmic reticulum stores. From confocal analysis of phosphorylated ERK immunostaining, PP2 treatment significantly attenuated PACAP activation of ERK in neurons within cardiac ganglia whole mount preparations. Intracellular recordings demonstrated that PP2 also significantly blunted a PACAP-induced increase in cardiac neuron excitability. These studies demonstrate Src-related kinase activity in PAC1 receptor internalization, activation of MEK/ERK signaling, and regulation of neuronal excitability. The present results provide further support for the importance of PAC1 receptor endosomal signaling as a key mechanism regulating cellular function. PMID- 29141924 TI - Antenatal Bartter syndrome presenting with vomiting and constipation mimicking subacute intestinal obstruction in a 20-day-old neonate. AB - Antenatal Bartter syndrome is a rare condition that can present with different clinical features. These features include early onset maternal polyhydramnios, failure to thrive, prematurity and nephrocalcinosis.We are presenting this 20-day old girl who had an antenatal history of polyhydramnios. She developed persistent non-bilious vomiting that was associated with constipation soon after birth. She presented with failure to thrive and features suggestive of intestinal obstruction. On the initial evaluation, she was noted to have hypokalaemic, hyponatraemic metabolic alkalosis. The initial work-up was done to exclude surgical and renal causes of her presentation, and the diagnosis was confirmed by gene analysis to be type III-classic Bartter syndrome. She was closely monitored for her growth and development with the appropriate salt replacement therapy. PMID- 29141925 TI - Unusual Salmonella typhi periprosthetic joint infection involving bilateral knees: management options and literature review. AB - A 70-year-old Indian woman, who had undergone primary bilateral total knee arthroplasty (TKA) for rheumatoid arthritis 10 months prior, presented with 10 days history of pain, swelling and erythema over both knees with pus discharging from the right knee. She had type 2 diabetes mellitus and was on long-term steroid, leflunomide and antitumour necrosis factor therapy for rheumatoid arthritis. Her clinical and laboratory features were suggestive of a haematogenous periprosthetic joint infection (PJI). The final diagnosis of bilateral Salmonella typhi PJI was made based on culture reports. Considering her underlying immunosuppression, a bilateral two-stage revision TKA was done with complete remission of symptoms and good functional recovery at last follow-up after 18 months. S. typhi infection of prosthetic joint has not been reported in the literature. Patients presenting with gastrointestinal complaints and PJI should alert the clinician to the possibility of infection with such atypical organisms endemic to the region. PMID- 29141926 TI - Ectopic ACTH syndrome complicated by multiple opportunistic infections treated with percutaneous ablation of the adrenal glands. AB - Ectopic adrenocorticotropic hormone (ACTH)-related Cushing's syndrome can lead to multiple complications including severe immunosuppression. If the ACTH-secreting tumour cannot be found, definitive treatment is surgical adrenalectomy, typically followed by glucocorticoid replacement. Here, we present a case of fulminant respiratory failure secondary to coinfection with Pneumocystis jirovecii and cytomegalovirus in a patient with ectopic ACTH-dependent Cushing's syndrome with occult primary. Due to significant deconditioning, she was unable to undergo definitive adrenalectomy and instead underwent percutaneous microwave ablation of the adrenal glands. PMID- 29141927 TI - Peripheral arterial disease as seen on X-ray and arteriography. PMID- 29141928 TI - Reversible brain lesion following growth hormone replacement therapy in an adolescent. AB - A 12.6-year-old girl presented with a 2-month history of headache, recurrent vomiting and 5 kg weight loss. She had been receiving recombinant human growth hormone (rhGH) replacement therapy at a dose of 0.035 mg/kg for the past 10 months, due to short stature. Investigations before initiating rhGH, including brain MRI, had been normal. Physical examination revealed a nystagmus and a mildly elevated arterial blood pressure. Brain MRI revealed a lesion in the posterior aspect of the medulla oblongata, adjacent to the foramen of Magendie. rhGH therapy was discontinued, followed by a gradual resolution of the symptoms. At follow-up 3 months later, she was asymptomatic and physical examination was unremarkable. A subsequent repeat brain MRI showed complete resolution of the lesion, supporting the diagnosis of a variant of reversible posterior leucoencephalopathy syndrome. This is the first case report of a reversible brain lesion linked to rhGH replacement therapy. PMID- 29141929 TI - Septic arthritis of knee joint due to Parvimonas micra. AB - Parvimonas species are anaerobic, Gram-positive cocci that are a constituent of normal oral and gastrointestinal flora. We present a case of right knee joint septic arthritis due to Parvimonas micra in an immunocompromised patient. A 61 year-old male renal and pancreatic transplant recipient on immunosuppressive therapy was admitted to our hospital due to intense pain, joint swelling and inability to move his right knee over the past 9 months. After synovial fluid was drawn, cultures were positive for P. micra, an anaerobic pathogen that is part of the flora of the oral cavity. We report a rare causative pathogen for septic arthritis in an immunocompromised patient. PMID- 29141930 TI - Carcinoma en cuirasse in a young female. PMID- 29141932 TI - Umbilical artery perforation: a potentially life-threatening complication of umbilical artery catheterisation. AB - Umbilical artery catheterisation is frequently performed in preterm or critically ill newborn infants for invasive monitoring of blood pressure and blood sampling for laboratory tests. It is associated with well-known complications like catheter-related infections, thromboembolic events and aneurysmal formation of the aorta. In this report, we present another major complication of umbilical artery catheterisation: umbilical artery perforation. This complication occurred in a prematurely born infant and resulted in severe haemorrhagic shock, subsequent renal failure and severe periventricular leukomalacia. Ultimately, the patient deceased 3 weeks after birth. Review of the literature identified only a few case reports and retrospective postmortem studies describing this complication. Neonatologists and paediatricians performing umbilical artery catheterisation should be aware of this rare, but potentially life-threatening complication. PMID- 29141931 TI - Norethisterone enanthate-induced cerebral venous sinus thrombosis (CVST). AB - A 23-year-old East Indian woman with no significant medical history, except a depot-norethisterone enanthate injection taken 3 weeks prior to admission, presented with a gradually worsening headache for the past 5 days. She had no fever, vomiting, neck stiffness, focal weakness or rash, and examination was unremarkable with no focal neurological deficits. Vasculitic, thrombophilia and sepsis screens were normal. A brain CT scan showed a left parietal lobe venous infarct, secondary to a venous dural sinus thrombosis, with MRI and Magnetic Resonance Venogram (MRV) confirming a signal void. She was diagnosed to have multiple cerebral venous sinus thrombosis due to norethisterone enanthate. She made a complete recovery following treatment with mannitol, dexamethasone and anticoagulants. A follow-up brain MRI done at 6 months was normal. PMID- 29141933 TI - Isolated azygos vein thrombosis: a rare phenomenon. PMID- 29141934 TI - Neonatal airway anomaly: vallecular cyst. PMID- 29141935 TI - Pyoderma gangrenosum: combination therapy with excellent results in a patient with underlying hepatitis C. PMID- 29141936 TI - Orbitonasal metallic foreign body. PMID- 29141937 TI - Novel differences in renal gene expression in a diet-induced obesity model. AB - Obesity is a significant risk factor for both chronic kidney disease and end stage renal disease. To better understand disease development, we sought to identify novel genes differentially expressed early in disease progression. We first confirmed that mice fed a high-fat (HF) diet exhibit early signs of renal injury including hyperfiltration. We then performed RNA-Seq using renal cortex RNA from C57BL6/J male mice fed either HF or control (Ctrl) diet. We identified 1,134 genes differentially expressed in the cortex on HF vs. Ctrl, of which 31 genes were selected for follow-up analysis. This included the 9 most upregulated, the 11 most downregulated, and 11 genes of interest (primarily sensory receptors and G proteins). Quantitative (q)RT-PCR for these 31 genes was performed on additional male renal cortex and medulla samples, and 11 genes (including all 9 upregulated genes) were selected for further study based on qRT-PCR. We then examined expression of these 11 genes in Ctrl and HF male heart and liver samples, which demonstrated that these changes are relatively specific to the renal cortex. These 11 genes were also examined in female renal cortex, where we found that the expression changes seen in males on a HF diet are not replicated in females, even when the females are started on the diet sooner to match weight gain of the males. In sum, these data demonstrate that in a HF-diet model of early disease, novel transcriptional changes occur that are both sex specific and specific to the renal cortex. PMID- 29141938 TI - Stimulation of the sensory pudendal nerve increases bladder capacity in the rat. AB - Pudendal nerve stimulation is a promising treatment approach for lower urinary tract dysfunction, including symptoms of overactive bladder. Despite some promising clinical studies, there remain many unknowns as to how best to stimulate the pudendal nerve to maximize therapeutic efficacy. We quantified changes in bladder capacity and voiding efficiency during single-fill cystometry in response to electrical stimulation of the sensory branch of the pudendal nerve in urethane-anesthetized female Wistar rats. Increases in bladder capacity were dependent on both stimulation amplitude and rate. Stimulation that produced increases in bladder capacity also led to reductions in voiding efficiency. Also, there was a stimulation carryover effect, and increases in bladder capacity persisted during several nonstimulated trials following stimulated trials. Intravesically administered PGE2 reduced bladder capacity, producing a model of overactive bladder (OAB), and sensory pudendal nerve stimulation again increased bladder capacity but also reduced voiding efficiency. This study serves as a basis for future studies that seek to maximize the therapeutic efficacy of sensory pudendal nerve stimulation for the symptoms of OAB. PMID- 29141939 TI - Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study. AB - Focal segmental glomerulosclerosis (FSGS) is an important cause of nondiabetic chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibition (SGLT2i) therapy attenuates the progression of diabetic nephropathy, but it remains unclear whether SGLT2i provides renoprotection in nondiabetic CKD such as FSGS. The primary aim of this pilot study was to determine the effect of 8 wk of dapagliflozin on glomerular filtration rate (GFR) in humans and in experimental FSGS. Secondary end points were related to changes in renal hemodynamic function, proteinuria, and blood pressure (BP). GFR (inulin) and renal plasma flow (para aminohippurate), proteinuria, and BP were measured in patients with FSGS ( n = 10), and similar parameters were measured in subtotally nephrectomized (SNx) rats. In response to dapagliflozin, changes in GFR, renal plasma flow, and 24-h urine protein excretion were not statistically significant in humans or rats. Systolic BP (SBP) decreased in SNx rats (196 +/- 26 vs. 165 +/- 33 mmHg; P < 0.001), whereas changes were not statistically significant in humans (SBP 112.7 +/- 8.5 to 112.8 +/- 11.2 mmHg, diastolic BP 71.8 +/- 6.5 to 69.6 +/- 8.4 mmHg; P = not significant), although hematocrit increased (0.40 +/- 0.05 to 0.42 +/- 0.05%; P = 0.03). In archival kidney tissue from a separate patient cohort, renal parenchymal SGLT2 mRNA expression was decreased in individuals with FSGS compared with controls. Short-term treatment with the SGLT2i dapagliflozin did not modify renal hemodynamic function or attenuate proteinuria in humans or in experimental FSGS. This may be related to downregulation of renal SGLT2 expression. Studies examining the impact of SGLT2i on markers of kidney disease in patients with other causes of nondiabetic CKD are needed. PMID- 29141941 TI - Insights from direct renal insulin infusion: a new hammer for an age-old nail. PMID- 29141940 TI - Effects of different storage solutions on renal ischemia tolerance after kidney transplantation in mice. AB - storage is the most prevalent method for graft preservation in kidney transplantation (KTX). The protective effects of various preservation solutions have been studied extensively in both clinical trials and experimental animal models. However, a paucity of studies have examined the effect of different preservation solutions on graft function in mouse KTX; in addition, the tolerance of the transplanted grafts to further insult has not been evaluated, which was the objective of the present study. We performed mouse KTX in three groups, with the donor kidneys preserved in different solutions for 60 min: saline, mouse serum, and University of Wisconsin (UW) solution. The graft functions were assessed by kidney injury markers and glomerular filtration rate (GFR). The grafts that were preserved in UW solution exhibited better functions, reflected by 50 and 70% lower plasma creatinine levels as well as 30 and 55% higher plasma creatinine levels in GFR than serum and saline groups, respectively, during the first week after transplants. To examine the graft function in response to additional insult, we induced ischemia-reperfusion injury (IRI) by clamping the renal pedicle for 18 min at 4 wk after KTX. We found that the grafts preserved in UW solution exhibited ~30 and 20% less injury assessed by kidney injury markers and histology than in other two preservation solutions. Taken together, our results demonstrated that UW solution exhibited a better protective effect in transplanted renal grafts in mice. UW solution is recommended for use in mouse KTX for reducing confounding factors such as IRI during surgery. PMID- 29141942 TI - Frailty and the management of hematologic malignancies. AB - The majority of blood cancers occur in the elderly. This fact conspires with an aging population in many countries to make rigorous assessment for frailty increasingly important for hematologic oncologists. In this review, we first define frailty and its relevance for patients with hematologic malignancy. Next, we review current data regarding the effect of domains of frailty on outcomes for blood cancers including myelodysplastic syndromes, acute leukemia, non-Hodgkin lymphomas such as chronic lymphocytic leukemia, and multiple myeloma. Finally, after presenting assessment and treatment options for the practicing hematologist, we propose elements of a new research agenda for geriatric hematology: the exchange of age limits for rigorous frailty screening, development of disease-specific measures, and inclusion of functional and patient reported outcomes alongside survival. PMID- 29141943 TI - Anemia at older age: etiologies, clinical implications, and management. AB - Anemia is quite frequently diagnosed in older individuals and is a key indicator of various reactive and clonal conditions. Many underlying diseases, like myelodysplastic syndrome (MDS), develop preferentially in elderly individuals. The prevalence of anemia at older age is increasing, and this is mainly attributable to more frequently applied diagnostics and demographic changes in our societies. The etiology of anemia at older age is complex and ranges from bone marrow failure syndromes to chronic kidney disease, and from nutritional deficiencies to inflammatory processes including inflammaging in immunosenescence. In a smaller number of cases, no clear-cut etiology is identified. These patients are referred to as unexplained anemia or idiopathic cytopenia of unknown significance. In others, somatic mutations in leukocytes are found, but diagnostic criteria for MDS or other hematologic diseases are not fulfilled, a condition termed clonal cytopenia of undetermined significance. Management of anemias at older age depends on (1) the severity of the anemia, (2) underlying condition(s), and (3) patient-related factors, including comorbidities. Even a mild anemia may substantially affect physical and cognitive capacities and quality of life. An underestimated aspect is that because of age related changes, organ function such as erythropoietin production in the kidney may become suboptimal. Management and treatment of anemia in older patients often require a multidisciplinary approach and detailed investigations of organ function. In this article, we review current concepts around anemias at older age, with special emphasis on etiologies, clinical implications, and innovative concepts in the management of these patients. PMID- 29141944 TI - DNA damage responses and p53 in the aging process. AB - The genome is constantly attacked by genotoxic insults. DNA damage has long been established as a cause of cancer development through its mutagenic consequences. Conversely, radiation therapy and chemotherapy induce DNA damage to drive cells into apoptosis or senescence as outcomes of the DNA damage response (DDR). More recently, DNA damage has been recognized as a causal factor for the aging process. The role of DNA damage in aging and age-related diseases is illustrated by numerous congenital progeroid syndromes that are caused by mutations in genome maintenance pathways. During the past 2 decades, understanding how DDR drives cancer development and contributes to the aging process has progressed rapidly. It turns out that the DDR factor p53 takes center stage during tumor development and also plays an important role in the aging process. Studies in metazoan models ranging from Caenorhabditis elegans to mammals have revealed cell-autonomous and systemic DDR mechanisms that orchestrate adaptive responses that augment maintenance of the aging organism amid gradually accumulating DNA damage. PMID- 29141945 TI - Introduction to a review series on hematologic disease at older age. PMID- 29141946 TI - Age-related clonal hematopoiesis. AB - Age-related alterations in the human blood system occur in B cells, T cells, cells of the innate system, as well as hematopoietic stem and progenitor cells (HSPCs). Interestingly, age-related, reduced genetic diversity can be identified at the stem cell level and also independently in B cells and T cells. This reduced diversity is most probably related to somatic mutations or to changes in the microenvironmental niche. Either process can select for specific clones or cause repeated evolutionary bottlenecks. This review discusses the age-related clonal expansions in the human HSPC pool, which was termed in the past age related clonal hematopoiesis (ARCH). ARCH is defined as the gradual, clonal expansion of HSPCs carrying specific, disruptive, and recurrent genetic variants, in individuals without clear diagnosis of hematological malignancies. ARCH is associated not just with chronological aging but also with several other, age related pathological conditions, including inflammation, vascular diseases, cancer mortality, and high risk for hematological malignancies. Although it remains unclear whether ARCH is a marker of aging or plays an active role in these various pathophysiologies, it is suggested here that treating or even preventing ARCH may prove to be beneficial for human health. This review also describes a decision tree for the diagnosis and follow-up for ARCH in a research setting. PMID- 29141947 TI - Aging of hematopoietic stem cells. AB - Hematopoietic stem cells (HSCs) ensure a balanced production of all blood cells throughout life. As they age, HSCs gradually lose their self-renewal and regenerative potential, whereas the occurrence of cellular derailment strongly increases. Here we review our current understanding of the molecular mechanisms that contribute to HSC aging. We argue that most of the causes that underlie HSC aging result from cell-intrinsic pathways, and reflect on which aspects of the aging process may be reversible. Because many hematological pathologies are strongly age-associated, strategies to intervene in aspects of the stem cell aging process may have significant clinical relevance. PMID- 29141948 TI - A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma. AB - Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were approved by the US Food and Drug Administration for patients with relapsed/refractory PTCL, exhibiting response rates of 25% and 29% respectively. Based on synergy in preclinical models of PTCL, we initiated a phase 1 study of pralatrexate plus romidepsin in patients with relapsed/refractory lymphoma. This was a single institution dose-escalation study of pralatrexate plus romidepsin designed to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetic profile, and response rates. Patients were treated with pralatrexate (10 to 25 mg/m2) and romidepsin (12 to 14 mg/m2) on 1 of 3 schedules: every week * 3 every 28 days, every week * 2 every 21 days, and every other week every 28 days. Treatment continued until progression, withdrawal of consent, or medical necessity. Twenty-nine patients were enrolled and evaluable for toxicity. Coadministration of pralatrexate and romidepsin was safe, well tolerated, with 3 DLTs across all schedules (grade 3 oral mucositis * 2; grade 4 sepsis * 1). The recommended phase 2 dose was defined as pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every other week. Twenty-three patients were evaluable for response. The overall response rate was 57% (13/23) across all patients and 71% (10/14) in PTCL. The phase 1 study of pralatrexate plus romidepsin resulted in a high response rate in patients with previously treated PTCL. A phase 2 study in PTCL will determine the efficacy of the combination. This trial was registered at www.clinicaltrials.gov as #NCT01947140. PMID- 29141950 TI - Maternal circadian rhythms and the programming of adult health and disease. AB - The in utero environment is inherently rhythmic, with the fetus subjected to circadian changes in temperature, substrates, and various maternal hormones. Meanwhile, the fetus is developing an endogenous circadian timing system, preparing for life in an external environment where light, food availability, and other environmental factors change predictably and repeatedly every 24 h. In humans, there are many situations that can disrupt circadian rhythms, including shift work, international travel, insomnias, and circadian rhythm disorders (e.g., advanced/delayed sleep phase disorder), with a growing consensus that this chronodisruption can have deleterious consequences for an individual's health and well-being. However, the impact of chronodisruption during pregnancy on the health of both the mother and fetus is not well understood. In this review, we outline circadian timing system ontogeny in mammals and examine emerging research from animal models demonstrating long-term negative implications for progeny health following maternal chronodisruption during pregnancy. PMID- 29141949 TI - Microvascular insulin resistance in skeletal muscle and brain occurs early in the development of juvenile obesity in pigs. AB - Impaired microvascular insulin signaling may develop before overt indices of microvascular endothelial dysfunction and represent an early pathological feature of adolescent obesity. Using a translational porcine model of juvenile obesity, we tested the hypotheses that in the early stages of obesity development, impaired insulin signaling manifests in skeletal muscle (triceps), brain (prefrontal cortex), and corresponding vasculatures, and that depressed insulin induced vasodilation is reversible with acute inhibition of protein kinase Cbeta (PKCbeta). Juvenile Ossabaw miniature swine (3.5 mo of age) were divided into two groups: lean control ( n = 6) and obese ( n = 6). Obesity was induced by feeding the animals a high-fat/high-fructose corn syrup/high-cholesterol diet for 10 wk. Juvenile obesity was characterized by excess body mass, hyperglycemia, physical inactivity (accelerometer), and marked lipid accumulation in the skeletal muscle, with no evidence of overt atherosclerotic lesions in athero-prone regions, such as the abdominal aorta. Endothelium-dependent (bradykinin) and -independent (sodium nitroprusside) vasomotor responses in the brachial and carotid arteries (wire myography), as well as in the skeletal muscle resistance and 2A pial arterioles (pressure myography) were unaltered, but insulin-induced microvascular vasodilation was impaired in the obese group. Blunted insulin-stimulated vasodilation, which was reversed with acute PKCbeta inhibition (LY333-531), occurred alongside decreased tissue perfusion, as well as reduced insulin stimulated Akt signaling in the prefrontal cortex, but not the triceps. In the early stages of juvenile obesity development, the microvasculature and prefrontal cortex exhibit impaired insulin signaling. Such adaptations may underscore vascular and neurological derangements associated with juvenile obesity. PMID- 29141951 TI - Selector genes display tumor cooperation and inhibition in Drosophila epithelium in a developmental context-dependent manner. AB - During animal development, selector genes determine identities of body segments and those of individual organs. Selector genes are also misexpressed in cancers, although their contributions to tumor progression per se remain poorly understood. Using a model of cooperative tumorigenesis, we show that gain of selector genes results in tumor cooperation, but in only select developmental domains of the wing, haltere and eye-antennal imaginal discs of Drosophila larva. Thus, the field selector, Eyeless (Ey), and the segment selector, Ultrabithorax (Ubx), readily cooperate to bring about neoplastic transformation of cells displaying somatic loss of the tumor suppressor, Lgl, but in only those developmental domains that express the homeo-box protein, Homothorax (Hth), and/or the Zinc-finger protein, Teashirt (Tsh). In non-Hth/Tsh-expressing domains of these imaginal discs, however, gain of Ey in lgl- somatic clones induces neoplastic transformation in the distal wing disc and haltere, but not in the eye imaginal disc. Likewise, gain of Ubx in lgl- somatic clones induces transformation in the eye imaginal disc but not in its endogenous domain, namely, the haltere imaginal disc. Our results reveal that selector genes could behave as tumor drivers or inhibitors depending on the tissue contexts of their gains. PMID- 29141952 TI - Characterization and analysis of CCR and CAD gene families at the whole-genome level for lignin synthesis of stone cells in pear (Pyrus bretschneideri) fruit. AB - The content of stone cells has significant effects on the flavour and quality of pear fruit. Previous research suggested that lignin deposition is closely related to stone cell formation. In the lignin biosynthetic pathway, cinnamoyl-CoA reductase (CCR) and cinnamyl alcohol dehydrogenase (CAD), dehydrogenase/reductase family members, catalyse the last two steps in monolignol synthesis. However, there is little knowledge of the characteristics of the CCR and CAD families in pear and their involvement in lignin synthesis of stone cells. In this study, 31 CCRs and 26 CADs were identified in the pear genome. Phylogenetic trees for CCRs and CADs were constructed; key amino acid residues were analysed, and three dimensional structures were predicted. Using quantitative real-time polymerase chain reaction (qRT-PCR), PbCAD2, PbCCR1, -2 and -3 were identified as participating in lignin synthesis of stone cells in pear fruit. Subcellular localization analysis showed that the expressed proteins (PbCAD2, PbCCR1, -2 and 3) are found in the cytoplasm or at the cell membrane. These results reveal the evolutionary features of the CCR and CAD families in pear as well as the genes responsible for regulation of lignin synthesis and stone cell development in pear fruit. PMID- 29141953 TI - Amyloid beta42 peptide is toxic to non-neural cells in Drosophila yielding a characteristic metabolite profile and the effect can be suppressed by PI3K. AB - The human Abeta42 peptide is associated with Alzheimer's disease through its deleterious effects in neurons. Expressing the human peptide in adult Drosophila in a tissue- and time-controlled manner, we show that Abeta42 is also toxic in non-neural cells, neurosecretory and epithelial cell types in particular. This form of toxicity includes the aberrant signaling by Wingless morphogen leading to the eventual activation of Caspase 3. Preventing Caspase 3 activation by means of p53 keeps epithelial cells from elimination but maintains the Abeta42 toxicity yielding more severe deleterious effects to the organism. Metabolic profiling by nuclear magnetic resonance (NMR) of adult flies at selected ages post Abeta42 expression onset reveals characteristic changes in metabolites as early markers of the pathological process. All morphological and most metabolic features of Abeta42 toxicity can be suppressed by the joint overexpression of PI3K. PMID- 29141954 TI - Tropical Drosophila ananassae of wet-dry seasons show cross resistance to heat, drought and starvation. AB - Plastic responses to multiple environmental stressors in wet or dry seasonal populations of tropical Drosophila species have received less attention. We tested plastic effects of heat hardening, acclimation to drought or starvation, and changes in trehalose, proline and body lipids in Drosophila ananassae flies reared under wet or dry season-specific conditions. Wet season flies revealed significant increase in heat knockdown, starvation resistance and body lipids after heat hardening. However, accumulation of proline was observed only after desiccation acclimation of dry season flies while wet season flies elicited no proline but trehalose only. Therefore, drought-induced proline can be a marker metabolite for dry-season flies. Further, partial utilization of proline and trehalose under heat hardening reflects their possible thermoprotective effects. Heat hardening elicited cross-protection to starvation stress. Stressor-specific accumulation or utilization as well as rates of metabolic change for each energy metabolite were significantly higher in wet-season flies than dry-season flies. Energy metabolite changes due to inter-related stressors (heat versus desiccation or starvation) resulted in possible maintenance of energetic homeostasis in wet- or dry-season flies. Thus, low or high humidity-induced plastic changes in energy metabolites can provide cross-protection to seasonally varying climatic stressors. PMID- 29141955 TI - The constant threat from a non-native predator increases tail muscle and fast start swimming performance in Xenopus tadpoles. AB - Predator-induced phenotypic plasticity is the ability of prey to adapt to their native predator. However, owing to environmental changes, encounters with unknown predators are inevitable. Therefore, study of prey and non-native predator interaction will reveal the primary stages of adaptive strategies in prey predator interactions in the context of evolutionary processes. Here, Xenopus tadpoles exposed to a non-native predator, a larval salamander, showed a significant increase in body weight and tail length to body length ratio. The Tmax2 test indicated a significant enhancement of the tail muscle and decrease in the relative ventral fin height in tadpoles exposed to predation risk, leading to significantly higher average swimming speeds. The analysis of muscle-related metabolites revealed that sarcosine increased significantly in tadpoles exposed to non-native predators. Multiple linear regression analysis of the fast-start swimming pattern showed that the fast-start swimming speed was determined by the time required for a tadpole to bend its body away from the threat (C-start) and the angle at which it was bent. In conclusion, morphological changes in tadpoles were functionally adaptive and induced by survival behaviors of Xenopus tadpoles against non-native predators. PMID- 29141956 TI - Rapid isolation and expansion of skin-derived precursor cells from human primary fibroblast cultures. AB - Skin-derived precursor (SKP) cells have self-renewal and multipotent abilities and are found in the dermis. SKP cells have been isolated previously from pre established dermal fibroblast cultures. In these procedures, long-term culture and low yield remain the crucial aspects requiring improvement. In this study, we exposed pre-established dermal fibroblasts to 30-min acid stress prior to isolating SKP cells (termed pH-SKP) and compared the yield to the previously published trypsin- and no-stress methods. Spheroid formation was confirmed and analyzed at days 3, 5 and 7. Stemness was investigated by immunohistochemistry for the stem cell markers Nestin, CD9, vimentin and NG2. Multipotency was investigated by differentiation into adipocytes, smooth muscle cells and fibroblasts. The pH-SKP spheroid yield at day 5 was four- and threefold higher than those obtained using trypsin- and no-stress methods, respectively. The expression of stem cell markers Nestin, CD9, vimentin and NG2 were significantly expressed in pH-SKPs compared to the fibroblast origin. Successful pH-SKP spheroid formation and differentiation were achieved and validated in 11 distinct human primary fibroblast lines. These results demonstrate that acute acidic stress treatment of dermal fibroblast cultures greatly improves SKP isolation, growth, yield and multipotency compared to previous methods. PMID- 29141957 TI - Adherent-invasive Escherichia coli in inflammatory bowel disease. AB - Intestinal microbiome dysbiosis has been consistently described in patients with IBD. In the last decades, Escherichia coli, and the adherent-invasive E coli (AIEC) pathotype in particular, has been implicated in the pathogenesis of IBD. Since the discovery of AIEC, two decades ago, progress has been made in unravelling these bacteria characteristics and its interaction with the gut immune system. The mechanisms of adhesion of AIEC to intestinal epithelial cells (via FimH and cell adhesion molecule 6) and its ability to escape autophagy when inside macrophages are reviewed here. We also explore the existing data on the prevalence of AIEC in patients with Crohn's disease and UC, and the association between the presence of AIEC and disease location, activity and postoperative recurrence. Finally, we highlight potential therapeutic strategies targeting AIEC colonisation of gut mucosa, including the use of phage therapy, bacteriocins and antiadhesive molecules. These strategies may open new avenues for the prevention and treatment of IBD in the future. PMID- 29141958 TI - DNA methylation defines regional identity of human intestinal epithelial organoids and undergoes dynamic changes during development. AB - OBJECTIVE: Human intestinal epithelial organoids (IEOs) are increasingly being recognised as a highly promising translational research tool. However, our understanding of their epigenetic molecular characteristics and behaviour in culture remains limited. DESIGN: We performed genome-wide DNA methylation and transcriptomic profiling of human IEOs derived from paediatric/adult and fetal small and large bowel as well as matching purified human gut epithelium. Furthermore, organoids were subjected to in vitro differentiation and genome editing using CRISPR/Cas9 technology. RESULTS: We discovered stable epigenetic signatures which define regional differences in gut epithelial function, including induction of segment-specific genes during cellular differentiation. Established DNA methylation profiles were independent of cellular environment since organoids retained their regional DNA methylation over prolonged culture periods. In contrast to paediatric and adult organoids, fetal gut-derived organoids showed distinct dynamic changes of DNA methylation and gene expression in culture, indicative of an in vitro maturation. By applying CRISPR/Cas9 genome editing to fetal organoids, we demonstrate that this process is partly regulated by TET1, an enzyme involved in the DNA demethylation process. Lastly, generating IEOs from a child diagnosed with gastric heterotopia revealed persistent and distinct disease-associated DNA methylation differences, highlighting the use of organoids as disease-specific research models. CONCLUSIONS: Our study demonstrates striking similarities of epigenetic signatures in mucosa-derived IEOs with matching primary epithelium. Moreover, these results suggest that intestinal stem cell-intrinsic DNA methylation patterns establish and maintain regional gut specification and are involved in early epithelial development and disease. PMID- 29141959 TI - An integrative strategy to identify the entire protein coding potential of prokaryotic genomes by proteogenomics. AB - Accurate annotation of all protein-coding sequences (CDSs) is an essential prerequisite to fully exploit the rapidly growing repertoire of completely sequenced prokaryotic genomes. However, large discrepancies among the number of CDSs annotated by different resources, missed functional short open reading frames (sORFs), and overprediction of spurious ORFs represent serious limitations. Our strategy toward accurate and complete genome annotation consolidates CDSs from multiple reference annotation resources, ab initio gene prediction algorithms and in silico ORFs (a modified six-frame translation considering alternative start codons) in an integrated proteogenomics database (iPtgxDB) that covers the entire protein-coding potential of a prokaryotic genome. By extending the PeptideClassifier concept of unambiguous peptides for prokaryotes, close to 95% of the identifiable peptides imply one distinct protein, largely simplifying downstream analysis. Searching a comprehensive Bartonella henselae proteomics data set against such an iPtgxDB allowed us to unambiguously identify novel ORFs uniquely predicted by each resource, including lipoproteins, differentially expressed and membrane-localized proteins, novel start sites and wrongly annotated pseudogenes. Most novelties were confirmed by targeted, parallel reaction monitoring mass spectrometry, including unique ORFs and single amino acid variations (SAAVs) identified in a re-sequenced laboratory strain that are not present in its reference genome. We demonstrate the general applicability of our strategy for genomes with varying GC content and distinct taxonomic origin. We release iPtgxDBs for B. henselae, Bradyrhizobium diazoefficiens and Escherichia coli and the software to generate both proteogenomics search databases and integrated annotation files that can be viewed in a genome browser for any prokaryote. PMID- 29141960 TI - Rapid molecular assays to study human centromere genomics. AB - The centromere is the structural unit responsible for the faithful segregation of chromosomes. Although regulation of centromeric function by epigenetic factors has been well-studied, the contributions of the underlying DNA sequences have been much less well defined, and existing methodologies for studying centromere genomics in biology are laborious. We have identified specific markers in the centromere of 23 of the 24 human chromosomes that allow for rapid PCR assays capable of capturing the genomic landscape of human centromeres at a given time. Use of this genetic strategy can also delineate which specific centromere arrays in each chromosome drive the recruitment of epigenetic modulators. We further show that, surprisingly, loss and rearrangement of DNA in centromere 21 is associated with trisomy 21. This new approach can thus be used to rapidly take a snapshot of the genetics and epigenetics of each specific human centromere in nondisjunction disorders and other biological settings. PMID- 29141962 TI - Personalised medicine for nonsmall cell lung cancer. AB - After years of standard care prescribed to cancer patients without any selection except the primary site and histology of the tumour, the era of precision medicine has revolutionised cancer care. Personalised medicine refers to the selection of patients for specific treatment based on the presence of specific biomarkers which indicate sensitivity to corresponding targeted therapies and/or lower toxicity risk, such that patients will have the greatest chance of deriving benefit from the treatments. Here, we review personalised medicine for nonsmall cell lung cancer. PMID- 29141961 TI - Chromatin accessibility dynamics reveal novel functional enhancers in C. elegans. AB - Chromatin accessibility, a crucial component of genome regulation, has primarily been studied in homogeneous and simple systems, such as isolated cell populations or early-development models. Whether chromatin accessibility can be assessed in complex, dynamic systems in vivo with high sensitivity remains largely unexplored. In this study, we use ATAC-seq to identify chromatin accessibility changes in a whole animal, the model organism Caenorhabditis elegans, from embryogenesis to adulthood. Chromatin accessibility changes between developmental stages are highly reproducible, recapitulate histone modification changes, and reveal key regulatory aspects of the epigenomic landscape throughout organismal development. We find that over 5000 distal noncoding regions exhibit dynamic changes in chromatin accessibility between developmental stages and could thereby represent putative enhancers. When tested in vivo, several of these putative enhancers indeed drive novel cell-type- and temporal-specific patterns of expression. Finally, by integrating transcription factor binding motifs in a machine learning framework, we identify EOR-1 as a unique transcription factor that may regulate chromatin dynamics during development. Our study provides a unique resource for C. elegans, a system in which the prevalence and importance of enhancers remains poorly characterized, and demonstrates the power of using whole organism chromatin accessibility to identify novel regulatory regions in complex systems. PMID- 29141964 TI - Acute decompensated pulmonary hypertension. AB - Acute right heart failure in chronic precapillary pulmonary hypertension is characterised by a rapidly progressive syndrome with systemic congestion resulting from impaired right ventricular filling and/or reduced right ventricular flow output. This clinical picture results from an imbalance between the afterload imposed on the right ventricle and its adaptation capacity. Acute decompensated pulmonary hypertension is associated with a very poor prognosis in the short term. Despite its major impact on survival, its optimal management remains very challenging for specialised centres, without specific recommendations. Identification of trigger factors, optimisation of fluid volume and pharmacological support to improve right ventricular function and perfusion pressure are the main therapeutic areas to consider in order to improve clinical condition. At the same time, specific management of pulmonary hypertension according to the aetiology is mandatory to reduce right ventricular afterload. Over the past decade, the development of extracorporeal life support in refractory right heart failure combined with urgent transplantation has probably contributed to a significant improvement in survival for selected patients. However, there remains a considerable need for further research in this field. PMID- 29141963 TI - Current and new challenges in occupational lung diseases. AB - Occupational lung diseases are an important public health issue and are avoidable through preventive interventions in the workplace. Up-to-date knowledge about changes in exposure to occupational hazards as a result of technological and industrial developments is essential to the design and implementation of efficient and effective workplace preventive measures. New occupational agents with unknown respiratory health effects are constantly introduced to the market and require periodic health surveillance among exposed workers to detect early signs of adverse respiratory effects. In addition, the ageing workforce, many of whom have pre-existing respiratory conditions, poses new challenges in terms of the diagnosis and management of occupational lung diseases. Primary preventive interventions aimed to reduce exposure levels in the workplace remain pivotal for elimination of the occupational lung disease burden. To achieve this goal there is still a clear need for setting standard occupational exposure limits based on transparent evidence-based methodology, in particular for carcinogens and sensitising agents that expose large working populations to risk. The present overview, focused on the occupational lung disease burden in Europe, proposes directions for all parties involved in the prevention of occupational lung disease, from researchers and occupational and respiratory health professionals to workers and employers. PMID- 29141965 TI - Food Groups and Risk of Hypertension: A Systematic Review and Dose-Response Meta Analysis of Prospective Studies. AB - The aim of this systematic review and meta-analysis was to summarize the evidence on the relation of the intakes of 12 major food groups, including whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages (SSBs) with the risk of hypertension. PubMed, Scopus, and Web of Science were searched systematically until June 2017 for prospective studies having quantitatively investigated the above-mentioned foods. We conducted meta-analysis on the highest compared with the lowest intake categories and linear and nonlinear dose-response meta-analyses to analyze the association. Summary RRs and 95% CIs were estimated by using a random-effects model. Overall, 28 reports were included in the meta-analysis. An inverse association for the risk of hypertension was observed for 30 g whole grains/d (RR: 0.92; 95% CI: 0.87, 0.98), 100 g fruits/d (RR: 0.97; 95% CI: 0.96, 0.99), 28 g nuts/d (RR: 0.70; 95% CI: 0.45, 1.08), and 200 g dairy/d (RR: 0.95; 95% CI: 0.94, 0.97), whereas a positive association for 100 g red meat/d (RR: 1.14; 95% CI: 1.02, 1.28), 50 g processed meat/d (RR: 1.12; 95% CI: 1.00, 1.26), and 250 mL SSB/d (RR: 1.07; 95% CI: 1.04, 1.10) was seen in the linear dose response meta-analysis. Indication for nonlinear relations of the intakes of whole grains, fruits, fish, and processed meats with the risk of hypertension was detected. In summary, this comprehensive dose-response meta-analysis of 28 reports identified optimal intakes of whole grains, fruits, nuts, legumes, dairy, red and processed meats, and SSBs related to the risk of hypertension. These findings need to be seen under the light of very-low to low quality of meta evidence. However, the findings support the current dietary guidelines in the prevention of hypertension. PMID- 29141966 TI - Nutritional Factors Affecting Adult Neurogenesis and Cognitive Function. AB - Adult neurogenesis, a complex process by which stem cells in the hippocampal brain region differentiate and proliferate into new neurons and other resident brain cells, is known to be affected by many intrinsic and extrinsic factors, including diet. Neurogenesis plays a critical role in neural plasticity, brain homeostasis, and maintenance in the central nervous system and is a crucial factor in preserving the cognitive function and repair of damaged brain cells affected by aging and brain disorders. Intrinsic factors such as aging, neuroinflammation, oxidative stress, and brain injury, as well as lifestyle factors such as high-fat and high-sugar diets and alcohol and opioid addiction, negatively affect adult neurogenesis. Conversely, many dietary components such as curcumin, resveratrol, blueberry polyphenols, sulforaphane, salvionic acid, polyunsaturated fatty acids (PUFAs), and diets enriched with polyphenols and PUFAs, as well as caloric restriction, physical exercise, and learning, have been shown to induce neurogenesis in adult brains. Although many of the underlying mechanisms by which nutrients and dietary factors affect adult neurogenesis have yet to be determined, nutritional approaches provide promising prospects to stimulate adult neurogenesis and combat neurodegenerative diseases and cognitive decline. In this review, we summarize the evidence supporting the role of nutritional factors in modifying adult neurogenesis and their potential to preserve cognitive function during aging. PMID- 29141968 TI - The Nitrate-Independent Blood Pressure-Lowering Effect of Beetroot Juice: A Systematic Review and Meta-Analysis. AB - Beetroot is considered a complementary treatment for hypertension because of its high content of inorganic NO3 This systematic review and meta-analysis aimed to clarify several aspects of beetroot juice supplementation on systolic blood pressure (SBP) and diastolic blood pressure (DBP). We searched PubMed, Scopus, and Embase databases, and the reference lists of previous reviews. Randomized clinical trials that investigated the effects of beetroot juice on resting blood pressure in humans were recruited for quality assessment, meta-analyses, subgroup analyses, and meta-regressions; of these, 22 were conducted between 2009 and 2017 and included a total of 47 intervention (n = 650) and 43 control (n = 598) groups. Overall, SBP (-3.55 mm Hg; 95% CI: -4.55, -2.54 mm Hg) and DBP (-1.32 mm Hg; 95% CI: -1.97, -0.68 mm Hg) were significantly lower in the beetroot juice supplemented groups than in the control groups. The mean difference of SBP was larger between beetroot juice-supplemented and control groups in the longer than in the shorter (>=14 compared with <14 d) study durations (-5.11 compared with 2.67 mm Hg) and the highest compared with the lowest (500 compared with 70 and 140 mL/d) doses of beetroot juice (-4.78 compared with -2.37 mm Hg). A positive correlation was observed between beetroot juice doses and the mean differences of blood pressures. In contrast, a smaller effect size of blood pressures was observed after supplementation with higher NO3 (milligrams per 100 mL beetroot juice). A weak effect size was observed in a meta-analysis of trials that used NO3-depleted beetroot juice as a placebo compared with other interventions (-3.09 compared with -4.51 mm Hg for SBP and -0.81 compared with -2.01 mm Hg for DBP). Our results demonstrate the blood pressure-lowering effects of beetroot juice and highlight its potential NO3-independent effects. PMID- 29141967 TI - Yogurt and Cardiometabolic Diseases: A Critical Review of Potential Mechanisms. AB - Associations between yogurt intake and risk of diet-related cardiometabolic diseases (CMDs) have been the subject of recent research in epidemiologic nutrition. A healthy dietary pattern has been identified as a pillar for the prevention of weight gain and CMDs. Epidemiologic studies suggest that yogurt consumption is linked to healthy dietary patterns, lifestyles, and reduced risk of CMDs, particularly type 2 diabetes. However, to our knowledge, few to no randomized controlled trials have investigated yogurt intake in relation to cardiometabolic clinical outcomes. Furthermore, there has been little attempt to clarify the mechanisms that underlie the potential beneficial effects of yogurt consumption on CMDs. Yogurt is a nutrient-dense dairy food and has been suggested to reduce weight gain and prevent CMDs by contributing to intakes of protein, calcium, bioactive lipids, and several other micronutrients. In addition, fermentation with bacterial strains generates bioactive peptides, resulting in a potentially greater beneficial effect of yogurt on metabolic health than nonfermented dairy products such as milk. To date, there is little concrete evidence that the mechanisms proposed in observational studies to explain positive results of yogurt on CMDs or parameters are valid. Many proposed mechanisms are based on assumptions that commercial yogurts contain strain specific probiotics, that viable yogurt cultures are present in adequate quantities, and that yogurt provides a minimum threshold dose of nutrients or bioactive components capable of exerting a physiologic effect. Therefore, the primary objective of this review is to investigate the plausibility of potential mechanisms commonly cited in the literature in order to shed light on the inverse associations reported between yogurt intake and various cardiometabolic health parameters that are related to its nutrient profile, bacterial constituents, and food matrix. This article reviews current gaps and challenges in identifying such mechanisms and provides a perspective on the research agenda to validate the proposed role of yogurt in protecting against CMDs. PMID- 29141969 TI - Cardiovascular and Antiobesity Effects of Resveratrol Mediated through the Gut Microbiota. AB - Encouraging scientific research into the health effects of dietary bioactive resveratrol has been confounded by its rapid first-pass metabolism, which leads to low in vivo bioavailability. Preliminary studies have shown that resveratrol can modulate gut microbiota composition, undergo biotransformation to active metabolites via the intestinal microbiota, or affect gut barrier function. In rodents, resveratrol can modify the relative Bacteroidetes:Firmicutes ratio and reverse the gut microbial dysbiosis caused by a high-fat diet. By upregulating the expression of genes involved in maintaining tight junctions between intestinal cells, resveratrol contributes to gut barrier integrity. The composition of the gut microbiome and rapid metabolism of resveratrol determines the production of resveratrol metabolites, which are found at greater concentrations in humans after ingestion than their parent molecule and can have similar biological effects. Resveratrol may affect cardiovascular risk factors such as elevated blood cholesterol or trimethylamine N-oxide concentrations. Modulating the composition of the gut microbiota by resveratrol may affect central energy metabolism and modify concentrations of satiety hormones to produce antiobesity effects. Encouraging research from animal models could be tested in humans. PMID- 29141970 TI - Natural Forms of Vitamin E as Effective Agents for Cancer Prevention and Therapy. AB - Initial research on vitamin E and cancer has focused on alpha-tocopherol (alphaT), but recent clinical studies on cancer-preventive effects of alphaT supplementation have shown disappointing results, which has led to doubts about the role of vitamin E, including different vitamin E forms, in cancer prevention. However, accumulating mechanistic and preclinical animal studies show that other forms of vitamin E, such as gamma-tocopherol (gammaT), delta-tocopherol (deltaT), gamma-tocotrienol (gammaTE), and delta-tocotrienol (deltaTE), have far superior cancer-preventive activities than does alphaT. These vitamin E forms are much stronger than alphaT in inhibiting multiple cancer-promoting pathways, including cyclo-oxygenase (COX)- and 5-lipoxygenase (5-LOX)-catalyzed eicosanoids, and transcription factors such as nuclear transcription factor kappaB (NF-kappaB) and signal transducer and activator of transcription factor 3 (STAT3). These vitamin E forms, but not alphaT, cause pro-death or antiproliferation effects in cancer cells via modulating various signaling pathways, including sphingolipid metabolism. Unlike alphaT, these vitamin E forms are quickly metabolized to various carboxychromanols including 13'-carboxychromanols, which have even stronger anti-inflammatory and anticancer effects than some vitamin precursors. Consistent with mechanistic findings, gammaT, deltaT, gammaTE, and deltaTE, but not alphaT, have been shown to be effective for preventing the progression of various types of cancer in preclinical animal models. This review focuses on cancer-preventive effects and mechanisms of gammaT, deltaT, gammaTE, and deltaTE in cells and preclinical models and discusses current progress in clinical trials. The existing evidence strongly indicates that these lesser-known vitamin E forms are effective agents for cancer prevention or as adjuvants for improving prevention, therapy, and control of cancer. PMID- 29141973 TI - Energy Metabolism Profile in Individuals with Prader-Willi Syndrome and Implications for Clinical Management: A Systematic Review. AB - Prader-Willi syndrome (PWS) is a rare genetic disorder associated with excessive weight gain. Hyperphagia associated with PWS may result in higher energy intake, but alterations in energy expenditure may also contribute to energy imbalance. The purpose of this critical literature review is to determine the presence of alterations in energy expenditure in individuals with PWS. Ten studies that measured total energy expenditure (TEE), resting energy expenditure (REE), sleep energy expenditure (SEE), activity energy expenditure (AEE), and diet induced thermogenesis (DIT) were included in this review. The studies provided evidence that absolute TEE, REE, SEE, and AEE are lower in individuals with PWS than in age-, sex-, and body mass index-matched individuals without the syndrome. Alterations in lean body mass and lower physical activity amounts appear to be responsible for the lower energy expenditure in PWS rather than metabolic differences. Regardless of the underlying mechanism for lower TEE, the estimation of energy requirements with the use of equations derived for the general population would result in weight gain in individuals with PWS. The determination of energy requirements for weight management in individuals with PWS requires a more comprehensive understanding of energy metabolism. Future studies should aim to comprehensively profile all specific components of energy expenditure in individuals with PWS with the use of appropriately matched controls and gold standard methods to measure energy metabolism and body composition. One component of energy expenditure that is yet to be explored in detail in PWS is DIT. A reduced DIT (despite differences in fat free mass), secondary to hormonal dysregulation, may be present in PWS individuals, leading to a reduced overall energy expenditure. Further research exploring DIT in PWS needs to be conducted. Dietary energy recommendations for weight management in PWS have not yet been clearly established. PMID- 29141972 TI - Epigenetic Regulation of Centromere Chromatin Stability by Dietary and Environmental Factors. AB - The centromere is a genomic locus required for the segregation of the chromosomes during cell division. This chromosomal region together with pericentromeres has been found to be susceptible to damage, and thus the perturbation of the centromere could lead to the development of aneuploidic events. Metabolic abnormalities that underlie the generation of cancer include inflammation, oxidative stress, cell cycle deregulation, and numerous others. The micronucleus assay, an early clinical marker of cancer, has been shown to provide a reliable measure of genotoxic damage that may signal cancer initiation. In the current review, we will discuss the events that lead to micronucleus formation and centromeric and pericentromeric chromatin instability, as well transcripts emanating from these regions, which were previously thought to be inactive. Studies were selected in PubMed if they reported the effects of nutritional status (macro- and micronutrients) or environmental toxicant exposure on micronucleus frequency or any other chromosomal abnormality in humans, animals, or cell models. Mounting evidence from epidemiologic, environmental, and nutritional studies provides a novel perspective on the origination of aneuploidic events. Although substantial evidence exists describing the role that nutritional status and environmental toxicants have on the generation of micronuclei and other nuclear aberrations, limited information is available to describe the importance of macro- and micronutrients on centromeric and pericentromeric chromatin stability. Moving forward, studies that specifically address the direct link between nutritional status, excess, or deficiency and the epigenetic regulation of the centromere will provide much needed insight into the nutritional and environmental regulation of this chromosomal region and the initiation of aneuploidy. PMID- 29141971 TI - Role of MicroRNA Regulation in Obesity-Associated Breast Cancer: Nutritional Perspectives. AB - Breast cancer is the most common malignancy diagnosed in women, and the incidence of breast cancer is increasing every year. Obesity has been identified as one of the major risk factors for breast cancer progression. The mechanisms by which obesity contributes to breast cancer development is not yet understood; however, there are a few mechanisms counted as potential producers of breast cancer in obesity, including insulin resistance, chronic inflammation and inflammatory cytokines, adipokines, and sex hormones. Recent emerging evidence suggests that alterations in microRNA (miRNA) expressions are found in several diseases, including breast cancer and obesity; however, miRNA roles in obesity-linked breast cancer are beginning to unravel. miRNAs are thought to be potential noninvasive biomarkers for diagnosis and prognosis of cancer patients with comorbid conditions of obesity as well as therapeutic targets. Recent studies have evidenced that nutrients and other dietary factors protect against cancer and obesity through modulation of miRNA expressions. Herein, we summarize a comprehensive overview of up-to-date information related to miRNAs and their molecular targets involved in obesity-associated breast cancer. We also address the mechanisms by which dietary factors modulate miRNA expression and its protective roles in obesity-associated breast cancer. It is hoped that this review would provide new therapeutic strategies for the treatment of obesity associated breast cancer to reduce the burden of breast cancer. PMID- 29141974 TI - Scaling up Dietary Data for Decision-Making in Low-Income Countries: New Technological Frontiers. AB - Dietary surveys in low-income countries (LICs) are hindered by low investment in the necessary research infrastructure, including a lack of basic technology for data collection, links to food composition information, and data processing. The result has been a dearth of dietary data in many LICs because of the high cost and time burden associated with dietary surveys, which are typically carried out by interviewers using pencil and paper. This study reviewed innovative dietary assessment technologies and gauged their suitability to improve the quality and time required to collect dietary data in LICs. Predefined search terms were used to identify technologies from peer-reviewed and gray literature. A total of 78 technologies were identified and grouped into 6 categories: 1) computer- and tablet-based, 2) mobile-based, 3) camera-enabled, 4) scale-based, 5) wearable, and 6) handheld spectrometers. For each technology, information was extracted on a number of overarching factors, including the primary purpose, mode of administration, and data processing capabilities. Each technology was then assessed against predetermined criteria, including requirements for respondent literacy, battery life, requirements for connectivity, ability to measure macro- and micronutrients, and overall appropriateness for use in LICs. Few technologies reviewed met all the criteria, exhibiting both practical constraints and a lack of demonstrated feasibility for use in LICs, particularly for large-scale, population-based surveys. To increase collection of dietary data in LICs, development of a contextually adaptable, interviewer-administered dietary assessment platform is recommended. Additional investments in the research infrastructure are equally important to ensure time and cost savings for the user. PMID- 29141975 TI - Dietary Strategies to Reduce Environmental Impact: A Critical Review of the Evidence Base. AB - The food system is a major source of environmental impact, and dietary change has been recommended as an important and necessary strategy to reduce this impact. However, assessing the environmental performance of diets is complex due to the many types of foods eaten and the diversity of agricultural production systems and local environmental settings. To assess the state of science and identify knowledge gaps, an integrative review of the broad topic of environment and diet was undertaken, with particular focus on the completeness of coverage of environmental concerns and the metrics used. Compared with the 14 discrete environmental areas of concern identified in the United Nations Sustainable Development Goals, the located journal literature mainly addressed greenhouse gas (GHG) emissions and, to a lesser extent, land and water use. Some relevant concerns were rarely addressed or not addressed at all. In the case of GHG emissions, changes in land use and soil carbon stocks were seldom considered. This represents a disconnect between the science informing strategic climate action in the agricultural sector and the science informing public health nutrition. In the case of land and water use, few studies used metrics that are appropriate in a life-cycle context. Some metrics produce inherently biased results, which misinform about environmental impact. The limited evidence generally points to recommended diets having lower environmental impacts than typical diets, although not in every case. This is largely explained by the overconsumption of food energy associated with average diets, which is also a major driver of obesity. A shared-knowledge framework is identified as being needed to guide future research on this topic. Until the evidence base becomes more complete, commentators on sustainable diets should not be quick to assume that a dietary strategy to reduce overall environmental impact can be readily defined or recommended. PMID- 29141976 TI - 25-Hydroxyvitamin D as a Biomarker of Vitamin D Status and Its Modeling to Inform Strategies for Prevention of Vitamin D Deficiency within the Population. AB - There is substantial evidence that the prevalence of vitamin D deficiency is unacceptably high in the population, and this requires action from a public health perspective. Circulating 25-hydroxyvitamin D [25(OH)D] is a robust and reliable marker of vitamin D status and has been used by numerous agencies in the establishment of vitamin D dietary requirements and for population surveillance of vitamin D deficiency or inadequacy. In a wider context, modeling of serum 25(OH)D data and its contributory sources, namely dietary vitamin D supply and UVB availability, can inform our understanding of population vitamin D status. The aim of this review is to provide the current status of knowledge in relation to modeling of such vitamin D-relevant data. We begin by highlighting the importance of the measurement of 25(OH)D and its standardization, both of which have led to new key data on the prevalence of vitamin D deficiency and inadequacy in North America and Europe. We then overview how state-of-the-art modeling can be used to inform our understanding of the potential effect of ergocalciferol and 25(OH)D on vitamin D intake estimates and how meteorological data on UVB availability, when coupled with other key data, can help predict population serum 25(OH)D concentration, even accounting for seasonal fluctuations, and lastly, how these in silico approaches can help inform policymakers on strategic options on addressing low vitamin D status through food-based approaches and supplementation. The potential of exemplar food-based solutions will be highlighted, as will the possibility of synergies between vitamin D and other dairy food-based micronutrients, in relation to vitamin D status and bone health. Lastly, we will briefly consider the interactions between season and vitamin D supplements on vitamin D status and health. PMID- 29141977 TI - Vitamins Associated with Brain Aging, Mild Cognitive Impairment, and Alzheimer Disease: Biomarkers, Epidemiological and Experimental Evidence, Plausible Mechanisms, and Knowledge Gaps. AB - The key to preventing brain aging, mild cognitive impairment (MCI), and Alzheimer disease (AD) via vitamin intake is first to understand molecular mechanisms, then to deduce relevant biomarkers, and subsequently to test the level of evidence for the impact of vitamins in the relevant pathways and their modulation of dementia risk. This narrative review infers information on mechanisms from gene and metabolic defects associated with MCI and AD, and assesses the role of vitamins using recent results from animal and human studies. Current evidence suggests that all known vitamins and some "quasi-vitamins" are involved as cofactors or influence >=1 of the 6 key sets of pathways or pathologies associated with MCI or AD, relating to 1) 1-carbon metabolism, 2) DNA damage and repair, 3) mitochondrial function and glucose metabolism, 4) lipid and phospholipid metabolism and myelination, 5) neurotransmitter synthesis and synaptogenesis, and 6) amyloidosis and Tau protein phosphorylation. The contemporary level of evidence for each of the vitamins varies considerably, but it is notable that B vitamins are involved as cofactors in all of the core pathways or pathologies and, together with vitamins C and E, are consistently associated with a protective role against dementia. Outcomes from recent studies indicate that the efficacy and safety of supplementation with vitamins to prevent MCI and the early stages of AD will most likely depend on 1) which pathways are defective, 2) which vitamins are deficient and could correct the relevant metabolic defects, and 3) the modulating impact of nutrient-nutrient and nutrient-genotype interaction. More focus on a precision nutrition approach is required to realize the full potential of vitamin therapy in preventing dementia and to avoid causing harm. PMID- 29141980 TI - Vitamin A. PMID- 29141978 TI - Cobalamin Status from Pregnancy to Early Childhood: Lessons from Global Experience. AB - Low cobalamin intake and status during pregnancy or lactation have been linked to adverse maternal and perinatal health outcomes, whereas low cobalamin status during early childhood is associated with impaired development in children. Women who begin pregnancy with depleted stores (low or very low plasma cobalamin) will give birth to depleted infants who are likely to develop deficiency symptoms during the first few weeks or months postpartum. Newly ingested cobalamin during pregnancy and lactation (from diet or supplements) is transferred to the child and is not likely to correct cobalamin status in depleted women. The prevalence of low cobalamin status is high especially in low-income settings or in populations with a low intake of animal products. Folate and cobalamin play interdependent roles in one-carbon metabolism. Although folic acid supplementation during early pregnancy is widely recommended and practiced, cobalamin supplementation during pregnancy and lactation has received little attention. Furthermore, the intake recommendations for pregnant and lactating women and in early life need reevaluation in the light of newly available evidence in the field. PMID- 29141979 TI - Measurement Errors in Dietary Assessment Using Self-Reported 24-Hour Recalls in Low-Income Countries and Strategies for Their Prevention. AB - Securing accurate measurements of dietary intake across populations is challenging. Of the methods, self-reported 24-h recalls are often used in low income countries (LICs) because they are quick, culturally sensitive, do not require high cognitive ability, and provide quantitative data on both foods and nutrients. Measuring intakes via 24-h recalls involves 1) collecting data on food intakes, 2) the appropriate use of relevant food-composition data for calculating nutrient intakes, and 3) statistically converting observed intakes to "usual intakes" for evaluating nutrient adequacy or relations between foods and nutrients and health outcomes. Like all dietary methods, 24-h recalls are subject to random errors that lower the precision and systematic errors that can reduce accuracy at each stage of the measurement protocol. Research has identified the potential sources of measurement errors in 24-h recall protocols and emphasized that sources of random error can be reduced by incorporating standardized quality control procedures and collecting more than one 24-h recall per person, with the number depending on the study objective. Careful design of the initial 24-h recall protocol can take into account potential sources of systematic error, such as day of the week, season, age, etc. Other sources of systematic error (e.g., energy underreporting) can best be detected by including a reference measure (e.g., doubly labeled water to measure energy expenditure). Alternatively, 24-h recall intakes of energy can be compared with same-day weighed intakes. Nevertheless, very few studies in LICs have assessed the validity of 24-h recalls in their study settings or adopted recommended standardized protocols to mitigate random errors. Hence, efforts should be made to improve the assessment, analysis, and interpretation of self-reported 24-h recall data for population studies in LICs. Accurate and precise dietary intake data at the national level can play an essential role in informing food, nutrition, and agricultural policies; food fortification planning; and compliance to food-based dietary guidelines. PMID- 29141981 TI - Impact of Tumor Purity on Immune Gene Expression and Clustering Analyses across Multiple Cancer Types. AB - Surgical archives of tumor specimens are often impure. The presence of RNA transcripts from nontumor cells, such as immune and stromal cells, can impede analyses of cancer expression profiles. To systematically analyze the impact of tumor purity, the gene expression profiles and tumor purities were obtained for 7,794 tumor specimens across 21 tumor types (available in The Cancer Genome Atlas consortium). First, we observed that genes with roles in immunity and oxidative phosphorylation were significantly inversely correlated and correlated with the tumor purity, respectively. The expression of genes implicated in immunotherapy and specific immune cell genes, along with the abundance of immune cell infiltrates, was substantially inversely correlated with tumor purity. This relationship may explain the correlation between immune gene expression and mutation burden, highlighting the need to account for tumor purity in the evaluation of expression markers obtained from bulk tumor transcriptome data. Second, examination of cluster membership of gene pairs, with or without controlling for tumor purity, revealed that tumor purity may have a substantial impact on gene clustering across tumor types. Third, feature genes for molecular taxonomy were analyzed for correlation with tumor purity, and for some tumor types, feature genes representing the mesenchymal and classical subtypes were inversely correlated and correlated with tumor purity, respectively. Our findings indicate that tumor purity is an important confounder in evaluating the correlation between gene expression and clinicopathologic features such as mutation burden, as well as gene clustering and molecular taxonomy. Cancer Immunol Res; 6(1); 87-97. (c)2017 AACR. PMID- 29141983 TI - Are Parents Who Feel the Need to Watch Over Their Children's Care Better Patient Safety Partners? AB - OBJECTIVES: Many parents report needing to watch over their child's hospital care to prevent mistakes. In this study, we assessed whether needing to watch over care predicts parent performance of recommended safety behaviors to reduce medication errors and health care-associated infections. METHODS: At admission, we surveyed 170 parents about their need to watch over care, demographics, and hospitalization factors. At discharge, parents were surveyed about medication awareness and hand hygiene behaviors. Logistic regression was used to examine how parents' need to watch over care predicted each behavior, adjusting for demographics and hospitalization factors. RESULTS: Thirty-eight percent of parents reported needing to watch over care. Most parents (77%) reported frequently or very frequently asking providers for drug names or doses. Fewer parents asked to check drug or infusion accuracy (29%) or to show or read aloud medication labels (21%). Few parents reminded providers to clean hands (4%), but most stated they would be comfortable asking (82%) and likely to speak up if a provider did not (78%). After adjustment, parents needing to watch over care were significantly more likely to ask providers to check drug or infusion accuracy (adjusted odds ratio = 4.59, 95% confidence interval 2.14-9.94) and for drug name or dose (adjusted odds ratio = 3.04, 95% confidence interval 1.25-7.39). CONCLUSIONS: Parents who report the need to watch over care are more likely to perform behaviors specific to safe medication use (but not hand hygiene) compared with those not reporting this need. Opportunities exist to engage parents as safety partners by leveraging their need to watch over care toward system-level safety initiatives. PMID- 29141982 TI - A Partial Loss-of-Function Variant in AKT2 Is Associated With Reduced Insulin Mediated Glucose Uptake in Multiple Insulin-Sensitive Tissues: A Genotype-Based Callback Positron Emission Tomography Study. AB - Rare fully penetrant mutations in AKT2 are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function AKT2 coding variant (p.Pro50Thr) was identified that is nearly specific to Finns (frequency 1.1%), with the low-frequency allele associated with an increase in fasting plasma insulin level and risk of type 2 diabetes. The effects of the p.Pro50Thr AKT2 variant (p.P50T/AKT2) on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated. We identified carriers (N = 20) and matched noncarriers (N = 25) for this allele in the population-based Metabolic Syndrome in Men (METSIM)study and invited these individuals back for positron emission tomography study with [18F] fluorodeoxyglucose during euglycemic hyperinsulinemia. When we compared p.P50T/AKT2 carriers to noncarriers, we found a 39.4% reduction in whole-body GU (P = 0.006) and a 55.6% increase in the rate of endogenous glucose production (P = 0.038). We found significant reductions in GU in multiple tissues-skeletal muscle (36.4%), liver (16.1%), brown adipose (29.7%), and bone marrow (32.9%)-and increases of 16.8-19.1% in seven tested brain regions. These data demonstrate that the p.P50T substitution of AKT2 influences insulin-mediated GU in multiple insulin-sensitive tissues and may explain, at least in part, the increased risk of type 2 diabetes in p.P50T/AKT2 carriers. PMID- 29141984 TI - The Council of Europe and the prohibition on human germline genome editing. PMID- 29141985 TI - Germline gene therapy is compatible with human dignity. PMID- 29141986 TI - ArfGAP1 restricts Mycobacterium tuberculosis entry by controlling the actin cytoskeleton. AB - The interaction of Mycobacterium tuberculosis (Mtb) with pulmonary epithelial cells is critical for early stages of bacillus colonization and during the progression of tuberculosis. Entry of Mtb into epithelial cells has been shown to depend on F-actin polymerization, though the molecular mechanisms are still unclear. Here, we demonstrate that mycobacterial uptake into epithelial cells requires rearrangements of the actin cytoskeleton, which are regulated by ADP ribosylation factor 1 (Arf1) and phospholipase D1 (PLD1), and is dependent on the M3 muscarinic receptor (M3R). We show that this pathway is controlled by Arf GTPase-activating protein 1 (ArfGAP1), as its silencing has an impact on actin cytoskeleton reorganization leading to uncontrolled uptake and replication of Mtb. Furthermore, we provide evidence that this pathway is critical for mycobacterial entry, while the cellular infection with other pathogens, such as Shigella flexneri and Yersinia pseudotuberculosis, is not affected. Altogether, these results reveal how cortical actin plays the role of a barrier to prevent mycobacterial entry into epithelial cells and indicate a novel role for ArfGAP1 as a restriction factor of host-pathogen interactions. PMID- 29141987 TI - BRACHYURY directs histone acetylation to target loci during mesoderm development. AB - T-box transcription factors play essential roles in multiple aspects of vertebrate development. Here, we show that cooperative function of BRACHYURY (T) with histone-modifying enzymes is essential for mouse embryogenesis. A single point mutation (TY88A) results in decreased histone 3 lysine 27 acetylation (H3K27ac) at T target sites, including the T locus, suggesting that T autoregulates the maintenance of its expression and functions by recruiting permissive chromatin modifications to putative enhancers during mesoderm specification. Our data indicate that T mediates H3K27ac recruitment through a physical interaction with p300. In addition, we determine that T plays a prominent role in the specification of hematopoietic and endothelial cell types. Hematopoietic and endothelial gene expression programs are disrupted in TY88A mutant embryos, leading to a defect in the differentiation of hematopoietic progenitors. We show that this role of T is mediated, at least in part, through activation of a distal Lmo2 enhancer. PMID- 29141988 TI - Genotyping by Sequencing in Almond: SNP Discovery, Linkage Mapping, and Marker Design. AB - In crop plant genetics, linkage maps provide the basis for the mapping of loci that affect important traits and for the selection of markers to be applied in crop improvement. In outcrossing species such as almond (Prunus dulcis Mill. D. A. Webb), application of a double pseudotestcross mapping approach to the F1 progeny of a biparental cross leads to the construction of a linkage map for each parent. Here, we report on the application of genotyping by sequencing to discover and map single nucleotide polymorphisms in the almond cultivars "Nonpareil" and "Lauranne." Allele-specific marker assays were developed for 309 tag pairs. Application of these assays to 231 Nonpareil * Lauranne F1 progeny provided robust linkage maps for each parent. Analysis of phenotypic data for shell hardness demonstrated the utility of these maps for quantitative trait locus mapping. Comparison of these maps to the peach genome assembly confirmed high synteny and collinearity between the peach and almond genomes. The marker assays were applied to progeny from several other Nonpareil crosses, providing the basis for a composite linkage map of Nonpareil. Applications of the assays to a panel of almond clones and a panel of rootstocks used for almond production demonstrated the broad applicability of the markers and provide subsets of markers that could be used to discriminate among accessions. The sequence-based linkage maps and single nucleotide polymorphism assays presented here could be useful resources for the genetic analysis and genetic improvement of almond. PMID- 29141989 TI - Analysis of Copy Number Variants on Chromosome 21 in Down Syndrome-Associated Congenital Heart Defects. AB - One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: (1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and (2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold. We tested 198 case individuals with DS+AVSD, and 211 control individuals with DS and a normal heart, using a custom microarray with dense probes tiled on chromosome 21 for array CGH (aCGH). We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. We also showed that previously DS+AVSD (DS and a complete AVSD)-associated common CNVs on chromosome 21 failed to replicate. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population. PMID- 29141990 TI - RNA-Sequencing of Drosophila melanogaster Head Tissue on High-Sugar and High-Fat Diets. AB - Obesity has been shown to increase risk for cardiovascular disease and type-2 diabetes. In addition, it has been implicated in aggravation of neurological conditions such as Alzheimer's. In the model organism Drosophila melanogaster, a physiological state mimicking diet-induced obesity can be induced by subjecting fruit flies to a solid medium disproportionately higher in sugar than protein, or that has been supplemented with a rich source of saturated fat. These flies can exhibit increased circulating glucose levels, increased triglyceride content, insulin-like peptide resistance, and behavior indicative of neurological decline. We subjected flies to variants of the high-sugar diet, high-fat diet, or normal (control) diet, followed by a total RNA extraction from fly heads of each diet group for the purpose of Poly-A selected RNA-Sequencing. Our objective was to identify the effects of obesogenic diets on transcriptome patterns, how they differed between obesogenic diets, and identify genes that may relate to pathogenesis accompanying an obesity-like state. Gene ontology analysis indicated an overrepresentation of affected genes associated with immunity, metabolism, and hemocyanin in the high-fat diet group, and CHK, cell cycle activity, and DNA binding and transcription in the high-sugar diet group. Our results also indicate differences in the effects of the high-fat diet and high-sugar diet on expression profiles in head tissue of flies, despite the reportedly similar phenotypic impacts of the diets. The impacted genes, and how they may relate to pathogenesis in the Drosophila obesity-like state, warrant further experimental investigation. PMID- 29141991 TI - Human sex hormone-binding globulin does not provide metabolic protection against diet-induced obesity and dysglycemia in mice. AB - BACKGROUND: Sex hormone-binding globulin (SHBG) is the main transporter of sex hormones in most vertebrates. Low SHBG levels have been linked to increased risk for diabetes and metabolic syndrome. Polymorphisms of the SHBG gene linked to low SHBG protein levels also strongly predicted increased risk of type 2 diabetes, thus raising the possibility that SHBG may play a role in the pathogenesis of insulin resistance and diabetes. AIM: To examine whether expression of human SHBG in mice may ameliorate the development of diabetes and metabolic syndrome in response to a high-fat diet (HFD). METHODS: Transgene mice expressing a human SHBG transgene (SHBG+) (N = 10/11; males/females) and their wild type littermates (N = 12/8; males/females) were fed HFD for 4.5 months. RESULTS: HFD induced comparable obesity in control and SHBG+ mice. Male transgenes had higher muscle mass after 2-3.5 months HFD (0.43 +/- 0.028 (n = 4) vs 0.38 +/- 0.053 g (n = 7), P = 0.05). Fasting blood glucose, as well as insulin or HOMA-IR, was not different in transgenic vs wild-type males after 4-5 months HFD. Female transgenes had higher fasting glucose (152 +/- 29 (n = 7) vs 115 +/- 27 mg/dL, P = 0.01 (n = 8)), but mean insulin and HOMA-IR were not different. Likewise, insulin tolerance test and intra-peritoneal glucose tolerance test (GTT) were not different. Finally, SHBG+ mice were not different from controls in terms of liver enzymes, serum triglyceride levels and blood pressure. CONCLUSION: In mice with diet-induced obesity, human SHBG did not protect against development of obesity or dysglycemia. PMID- 29141992 TI - Diabetes insipidus is an unfavorable prognostic factor for response to glucocorticoids in patients with autoimmune hypophysitis. PMID- 29141995 TI - Correction: Breast Tumor Kinase Phosphorylates p190RhoGAP to Regulate Rho and Ras and Promote Breast Carcinoma Growth, Migration, and Invasion. PMID- 29141996 TI - The distinct transcriptomes of slow and fast adult muscles are delineated by noncoding RNAs. AB - Adult muscles have a vast adaptation capacity, enabling function switches in response to altered conditions. During intensive physical activity, disease, or aging, adult skeletal muscles change and adjust their functions. The competence to adjust varies among muscles. Muscle-specific molecular mechanisms in healthy and normal conditions could designate changes in physiologic and pathologic conditions. We generated deep mRNA-sequencing data in adult fast and slow mouse muscles, and applying paired analysis, we identified that the muscle-specific signatures are composed of half of the muscle transcriptome. The fast muscles showed a more compact gene network that is concordant with homogenous myofiber typing, compared with the pattern in the slow muscle. The muscle-specific mRNA landscape did not correlate with alternative spicing, alternative polyadenylation, or the expression of muscle transcription factor gene networks. However, we found significant correlation between the differentially expressed noncoding RNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) and their target genes. More than 25% of the genes expressed in a muscle-specific fashion were found to be targets of muscle-specific miRNAs and lncRNAs. We suggest that muscle-specific miRNAs and lncRNAs contribute to the establishment of muscle specific transcriptomes in adult muscles.-Raz, V., Riaz, M., Tatum, Z., Kielbasa, S. M., 't Hoen, P. A. C. The distinct transcriptomes of slow and fast adult muscles are delineated by noncoding RNAs. PMID- 29141994 TI - Type II Diabetes and Incidence of Estrogen Receptor Negative Breast Cancer in African American Women. AB - White women with type II diabetes (T2D) have an estimated 20% increased risk of developing breast cancer. Little is known about associations by breast cancer subtype or among African American (AA) women, who are disproportionately affected by T2D and estrogen receptor negative (ER-) breast cancer. We assessed the relation of T2D to incidence of ER- and ER+ breast cancer in data from the Black Women's Health Study, a prospective cohort of AA women enrolled in 1995 and followed biennially. During 847,934 person-years of follow-up, there were 1,851 incident invasive breast cancers, including 914 ER+ and 468 ER- cases. Multivariable Cox proportional hazards models were used to compute HRs for breast cancer incidence associated with T2D relative to no T2D, controlling for body mass index (BMI) and other potential confounders. The HR for T2D relative to no T2D was 1.18 [95% confidence interval (CI) 1.00-1.40] for overall breast cancer incidence, with the increase accounted for by ER- cancer: HRs were 1.02 (95% CI, 0.80-1.31) for ER+ and 1.43 (95% CI, 1.03-2.00) for ER- cancer. The HR for T2D and ER- breast cancer was highest among nonobese women (1.92; 95% CI, 1.22-3.04). The findings suggest that AA women with T2D are at increased risk of developing ER- breast cancer and that poor metabolic health may be more important than obesity for this subtype. Given the high prevalence of T2D in AA women, the observed association could, in part, explain racial disparities in incidence of ER- breast cancer. Cancer Res; 77(22); 6462-9. (c)2017 AACR. PMID- 29141997 TI - CRISPR/Cas9-mediated genome editing reveals the synergistic effects of beta defensin family members on sperm maturation in rat epididymis. AB - The epididymis is a male reproductive organ involved in posttesticular sperm maturation and storage, but the mechanism underlying sperm maturation remains unclear. beta-Defensins (Defbs) belong to a family of small, cysteine-rich, cationic peptides that are antimicrobial and modulate the immune response. A large number of Defb genes are expressed abundantly in the male reproductive tract, especially in the epididymis. We and other groups have shown the involvement of several Defb genes in regulation of sperm function. In this study, we found that Defb23, Defb26, and Defb42 were highly expressed in specific regions of the epididymis. Rats with CRISPR/Cas9-mediated single-gene disruption of Defb23, Defb26, or Defb42 had no obvious fertility phenotypes. Those with the deletion of Defb23/ 26 or Defb23/ 26/ 42 became subfertile, and sperm isolated from the epididymal cauda of multiple-mutant rats were demonstrated decreased motility. Meanwhile, the sperm showed precocious capacitation and increased spontaneous acrosome reaction. Consistent with premature capacitation and acrosome reaction, sperm from multiple-gene-knockout rats had significantly increased intracellular calcium. These results suggest that Defb family members affect sperm maturation by a synergistic pattern in the epididymis.-Zhang, C., Zhou, Y., Xie, S., Yin, Q., Tang, C., Ni, Z., Fei, J., Zhang, Y. CRISPR/Cas9 mediated genome editing reveals the synergistic effects of beta-defensin family members on sperm maturation in rat epididymis. PMID- 29141999 TI - Celebrating 35 Years of the AJNR: November 1982 edition. PMID- 29141998 TI - Vanillic acid attenuates obesity via activation of the AMPK pathway and thermogenic factors in vivo and in vitro. AB - Energy expenditure is a target gaining recent interest for obesity treatment. The antiobesity effect of vanillic acid (VA), a well-known flavoring agent, was investigated in vivo and in vitro. High-fat diet (HFD)-induced obese mice and genetically obese db/db mice showed significantly decreased body weights after VA administration. Two major adipogenic markers, peroxisome proliferator activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha), were reduced while the key factor of energy metabolism, AMPKalpha, was increased in the white adipose tissue and liver tissue of VA-treated mice. Furthermore, VA inhibited lipid accumulation and reduced hepatotoxic/inflammatory markers in liver tissues of mice and HepG2 hepatocytes. VA treatment also decreased differentiation of 3T3-L1 adipocytes by regulating adipogenic factors including PPARgamma and C/EBPalpha. AMPKalpha small interfering RNA was used to examine whether AMPK was associated with the actions of VA. In AMPKalpha-nulled 3T3-L1 cells, the inhibitory action of VA on PPARgamma and C/EBPalpha was attenuated. Furthermore, in brown adipose tissues of mice and primary cultured brown adipocytes, VA increased mitochondria- and thermogenesis-related factors such as uncoupling protein 1 and PPARgamma-coactivator 1-alpha. Taken together, our results suggest that VA has potential as an AMPKalpha- and thermogenesis activating antiobesity agent.-Jung, Y., Park, J., Kim, H.-L., Sim, J.-E., Youn, D.-H., Kang, J., Lim, S., Jeong, M.-Y., Yang, W. M., Lee, S.-G., Ahn, K. S., Um, J.-Y. Vanillic acid attenuates obesity via activation of the AMPK pathway and thermogenic factors in vivo and in vitro. PMID- 29142000 TI - Heartbeat: Implementation gaps in cardiovascular care in middle-low income countries. PMID- 29142001 TI - Response: Risk score for cardiac surgery in active left-sided infective endocarditis. PMID- 29142002 TI - Toll-like receptor 2 has a prominent but nonessential role in innate immunity to Staphylococcus aureus pneumonia. AB - Staphylococcus aureus is an important cause of acute bacterial pneumonia. Toll like receptor 2 (TLR2) recognizes multiple components of the bacterial cell wall and activates innate immune responses to gram-positive bacteria. We hypothesized that TLR2 would have an important role in pulmonary host defense against S. aureus TLR null (TLR2-/-) mice and wild type (WT) C57BL/6 controls were challenged with aerosolized S. aureus at a range of inocula for kinetic studies of cytokine and antimicrobial peptide expression, lung inflammation, bacterial killing by alveolar macrophages, and bacterial clearance. Survival was measured after intranasal infection. Pulmonary induction of most pro-inflammatory cytokines was significantly blunted in TLR2-/- mice 4 and 24 h after infection in comparison with WT controls. Bronchoalveolar concentrations of cathelicidin related antimicrobial peptide also were reduced in TLR2-/- mice. Lung inflammation, measured by enumeration of bronchoalveolar neutrophils and scoring of histological sections, was significantly blunted in TLR2-/- mice. Phagocytosis of S. aureus by alveolar macrophages in vivo after low-dose infection was unimpaired, but viability of ingested bacteria was significantly greater in TLR2 /- mice. Bacterial clearance from the lungs was slightly impaired in TLR2-/- mice after low-dose infection only; bacterial elimination from the lungs was slightly accelerated in the TLR2-/- mice after high-dose infection. Survival after high dose intranasal challenge was 50-60% in both groups. TLR2 has a significant role in early innate immune responses to S. aureus in the lungs but is not required for bacterial clearance and survival from S. aureus pneumonia. PMID- 29142005 TI - The next step: mechanisms driving adrenocortical carcinoma metastasis. AB - Endocrine tumors have the peculiarity to become clinically evident not only due to symptoms related to space occupation by the growing lesion, similarly to most other tumors, but also, and most often, because of their specific hormonal secretion, which significantly contributes to their pathological burden. Malignant endocrine tumors, in addition, have the ability to produce distant metastases. Here, we critically review the current knowledge about mechanisms and biomarkers characterizing the metastatic process in adrenocortical carcinoma (ACC), a rare endocrine malignancy with a high risk of relapse and metastatization even when the primary tumor is diagnosed and surgically removed at an early stage. We highlight perspectives of future research in the domain and possible new therapeutic avenues based on targeting factors having an important role in the metastatic process of ACC. PMID- 29142003 TI - Disparities in Environmental Exposures to Endocrine-Disrupting Chemicals and Diabetes Risk in Vulnerable Populations. AB - Burgeoning epidemiological, animal, and cellular data link environmental endocrine-disrupting chemicals (EDCs) to metabolic dysfunction. Disproportionate exposure to diabetes-associated EDCs may be an underappreciated contributor to disparities in metabolic disease risk. The burden of diabetes is not uniformly borne by American society; rather, this disease disproportionately affects certain populations, including African Americans, Latinos, and low-income individuals. The purpose of this study was to review the evidence linking unequal exposures to EDCs with racial, ethnic, and socioeconomic diabetes disparities in the U.S.; discuss social forces promoting these disparities; and explore potential interventions. Articles examining the links between chemical exposures and metabolic disease were extracted from the U.S. National Library of Medicine for the period of 1966 to 3 December 2016. EDCs associated with diabetes in the literature were then searched for evidence of racial, ethnic, and socioeconomic exposure disparities. Among Latinos, African Americans, and low-income individuals, numerous studies have reported significantly higher exposures to diabetogenic EDCs, including polychlorinated biphenyls, organochlorine pesticides, multiple chemical constituents of air pollution, bisphenol A, and phthalates. This review reveals that unequal exposure to EDCs may be a novel contributor to diabetes disparities. Efforts to reduce the individual and societal burden of diabetes should include educating clinicians on environmental exposures that may increase disease risk, strategies to reduce those exposures, and social policies to address environmental inequality as a novel source of diabetes disparities. PMID- 29142004 TI - Advances in the management of MEN2: from improved surgical and medical treatment to novel kinase inhibitors. AB - Medullary thyroid carcinoma (MTC), a tumor derived from the neural crest, occurs either sporadically or as the dominant component of the type 2 multiple endocrine neoplasia (MEN) syndromes, MEN2A and MEN2B. The discovery that mutations in the RET protooncogene cause hereditary MTC was of great importance, since it led to the development of novel methods of diagnosis and treatment. For example, the detection of a mutated RET allele in family members at risk for inheriting MEN2A or MEN2B signaled that they would develop MTC, and possibly other components of the syndromes. Furthermore, the detection of a mutated allele created the opportunity, especially in young children, to remove the thyroid before MTC developed, or while it was confined to the gland. The discovery also led to the development of molecular targeted therapeutics (MTTs), mainly tyrosine kinase inhibitors, which were effective in the treatment of patients with locally advanced or metastatic MTC. While responses to MTTs are often dramatic, they are highly variable, and almost always transient, because the tumor cells become resistant to the drugs. Clinical investigators and the pharmaceutical industry are focusing on the development of the next generation of MTTs, which have minimal toxicity and greater specificity for mutated RET. PMID- 29142006 TI - Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma. AB - Rats affected by the MENX syndrome spontaneously develop multiple neuroendocrine tumors (NETs) including adrenal, pituitary and thyroid gland neoplasms. MENX was initially reported to be inherited as a recessive trait and affected rats were found to be homozygous for the predisposing Cdkn1b mutation encoding p27. We here report that heterozygous MENX-mutant rats (p27+/mut) develop the same spectrum of NETs seen in the homozygous (p27mut/mut) animals but with slower progression. Consequently, p27+/mut rats have a significantly shorter lifespan compared with their wild-type (p27+/+) littermates. In the tumors of p27+/mut rats, the wild type Cdkn1b allele is neither lost nor silenced, implying that p27 is haploinsufficient for tumor suppression in this model. Transcriptome profiling of rat adrenal (pheochromocytoma) and pituitary tumors having different p27 dosages revealed a tissue-specific, dose-dependent effect of p27 on gene expression. In p27+/mut rats, thyroid neoplasms progress to invasive and metastatic medullary thyroid carcinomas (MTCs) accompanied by increased calcitonin levels, as in humans. Comparison of expression signatures of late-stage vs early-stage MTCs from p27+/mut rats identified genes potentially involved in tumor aggressiveness. The expression of a subset of these genes was evaluated in human MTCs and found to be associated with aggressive RET-M918T-positive tumors. Altogether, p27 haploinsufficiency in MENX rats uncovered a novel, representative model of invasive and metastatic MTC exploitable for translational studies of this often aggressive and incurable cancer. PMID- 29142007 TI - Quest for adequate biodiversity surrogates in a time of urgency. PMID- 29142008 TI - Converging evidence for the role of transmodal cortex in cognition. PMID- 29142009 TI - Dominant negative mechanism of Presenilin-1 mutations in FAD. PMID- 29142010 TI - Value of Progression of Coronary Artery Calcification for Risk Prediction of Coronary and Cardiovascular Events: Result of the HNR Study (Heinz Nixdorf Recall). AB - BACKGROUND: Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular events. METHODS: In 3281 participants (45-74 years of age), free from cardiovascular disease until the second visit, risk factors, and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events, and total cardiovascular events including revascularization, as well, were recorded during a follow-up time of 7.8+/-2.2 years after the second CT. The added predictive value of 10 CAC progression algorithms on top of risk factors including baseline CAC was evaluated by using survival analysis, C-statistics, net reclassification improvement, and integrated discrimination index. A subgroup analysis of risk in CAC categories was performed. RESULTS: We observed 85 (2.6%) hard coronary, 161 (4.9%) hard cardiovascular, and 241 (7.3%) total cardiovascular events. Absolute CAC progression was higher with versus without subsequent coronary events (median, 115 [Q1-Q3, 23-360] versus 8 [0-83], P<0.0001; similar for hard/total cardiovascular events). Some progression algorithms added to the predictive value of baseline CT and risk assessment in terms of C-statistic or integrated discrimination index, especially for total cardiovascular events. However, CAC progression did not improve models including CAC5y and 5-year risk factors. An excellent prognosis was found for 921 participants with double-zero CACb=CAC5y=0 (10-year coronary and hard/total cardiovascular risk: 1.4%, 2.0%, and 2.8%), which was for participants with incident CAC 1.8%, 3.8%, and 6.6%, respectively. When CACb progressed from 1 to 399 to CAC5y>=400, coronary and total cardiovascular risk were nearly 2-fold in comparison with subjects who remained below CAC5y=400. Participants with CACb>=400 had high rates of hard coronary and hard/total cardiovascular events (10-year risk: 12.0%, 13.5%, and 30.9%, respectively). CONCLUSIONS: CAC progression is associated with coronary and cardiovascular event rates, but adds only weakly to risk prediction. What counts is the most recent CAC value and risk factor assessment. Therefore, a repeat scan >5 years after the first scan may be of additional value, except when a double zero CT scan is present or when the subjects are already at high risk. PMID- 29142011 TI - Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools: CENTRAL Magnetic Resonance Imaging Randomized Controlled Trial. AB - BACKGROUND: We aimed to assess whether distinct lifestyle strategies can differentially affect specific body adipose depots. METHODS: We performed an 18 month randomized controlled trial among 278 sedentary adults with abdominal obesity (75%) or dyslipidemia in an isolated workplace with a monitored provided lunch. Participants were randomized to isocaloric low-fat or Mediterranean/low carbohydrate (MED/LC) diet+28 g walnuts/day with/without added moderate physical activity (PA; 80% aerobic; supervised/free gym membership). Overall primary outcome was body fat redistribution, and the main specific end point was visceral adipose tissue (VAT). We further followed the dynamics of different fat depots (deep and superficial subcutaneous, liver, pericardial, muscle, pancreas, and renal sinus) by magnetic resonance imaging. RESULTS: Of 278 participants (age, 48 years, 89% men, body mass index, 30.8 kg/m2), 86% completed the trial with good adherence. The low-fat group preferentially decreased reported fat intake (-21.0% versus -11.5% for the MED/LC; P<0.001), and the MED/LC group decreased reported carbohydrates intake (-39.5% versus -21.3% for the low-fat group; P<0.001). The PA+ groups significantly increased the metabolic equivalents per week versus the PA- groups (19.0 versus 2.1; P=0.009). Whereas final moderate weight loss was indifferent, exercise attenuated the waist circumference rebound with the greatest effect in the MED/LCPA+ group (P<0.05). VAT (-22%), intrahepatic (-29%), and intrapericardial (-11%) fats declines were higher than pancreatic and femur intermuscular fats (1% to 2%) loss. Independent of weight loss, PA+ with either diet had a significantly greater effect on decreasing VAT (mean of difference, 6.67cm2; 95% confidence interval, -14.8 to -0.45) compared with PA-. The MED/LC diet was superior to the low-fat diet in decreasing intrahepatic, intrapericardial, and pancreatic fats (P<0.05 for all). In contrast, renal sinus and femoral intermuscular fats were not differentially altered by lifestyle interventions but by weight loss per se. In multivariate models further adjusted for weight loss, losing VAT or intrahepatic fat was independently associated with improved lipid profile, losing deep subcutaneous adipose tissue with improved insulin sensitivity, and losing superficial subcutaneous adipose tissue remained neutral except for an association with decreased leptin. CONCLUSIONS: Moderate weight loss alone inadequately reflects the significant lifestyle effects on atherogenic and diabetogenic fat depots. The MED/LC diet mobilizes specific ectopic fat depots, and exercise has an independent contribution to VAT loss. Fat depots exhibit diverse responsiveness and are differentially related to cardiometabolic markers. Distinct lifestyle protocols may uniquely induce fat mobilization from specific anatomic sites. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01530724. PMID- 29142012 TI - Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): A Phase 2, Randomized, Sham-Controlled Trial. AB - BACKGROUND: In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF >=40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF >=40%. METHODS: REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF >=40%, exercise PCWP >=25 mm Hg, and PCWP-right atrial pressure gradient >=5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise. RESULTS: A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70+/-9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5+/-6.4 mm Hg in the treatment group versus 0.5+/-5.0 mm Hg in the control group (P=0.14). There were no peri-procedural or 1 month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group (P=1.0). CONCLUSIONS: In patients with HF and EF >=40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02600234. PMID- 29142013 TI - Urbanism and the division of labour in the Roman Empire. AB - One of the hallmarks of human agglomeration is an increase in the division of labour, but the exact nature of this relationship has been debated among anthropologists, sociologists, economists, and historians and archaeologists. Over the last decade, researchers investigating contemporary urban systems have suggested a novel explanation for the links between the numbers of inhabitants in settlements and many of their most important characteristics, which is grounded in a view of settlements as social networks embedded in built environments. One of the remarkable aspects of this approach is that it is not based on the specific conditions of the modern world (such as capitalism or industrialization), which raises the issue of whether the relationships observed in contemporary urban systems can also be detected in pre-modern urban or even non-urban systems. Here, we present a general model for the relationship between the population and functional diversity of settlements, where the latter is viewed as an indicator of the division of labour. We then explore the applicability of this model to pre-modern contexts, focusing on cities in the Roman Empire, using estimates of their numbers of inhabitants, numbers of documented professional associations, and numbers of recorded inscriptions to develop an index of functional diversity. Our results are consistent with theoretical expectations, adding further support to the view that urban systems in both contemporary and pre-modern contexts reflect a common set of generative processes. PMID- 29142014 TI - Model predictions of deformation, embolization and permeability of partially obstructive blood clots under variable shear flow. AB - Thromboembolism, one of the leading causes of morbidity and mortality worldwide, is characterized by formation of obstructive intravascular clots (thrombi) and their mechanical breakage (embolization). A novel two-dimensional multi-phase computational model is introduced that describes active interactions between the main components of the clot, including platelets and fibrin, to study the impact of various physiologically relevant blood shear flow conditions on deformation and embolization of a partially obstructive clot with variable permeability. Simulations provide new insights into mechanisms underlying clot stability and embolization that cannot be studied experimentally at this time. In particular, model simulations, calibrated using experimental intravital imaging of an established arteriolar clot, show that flow-induced changes in size, shape and internal structure of the clot are largely determined by two shear-dependent mechanisms: reversible attachment of platelets to the exterior of the clot and removal of large clot pieces. Model simulations predict that blood clots with higher permeability are more prone to embolization with enhanced disintegration under increasing shear rate. In contrast, less permeable clots are more resistant to rupture due to shear rate-dependent clot stiffening originating from enhanced platelet adhesion and aggregation. These results can be used in future to predict risk of thromboembolism based on the data about composition, permeability and deformability of a clot under specific local haemodynamic conditions. PMID- 29142015 TI - Aqueous ball milling of nacre constituents facilitates directional self-assembly of aragonite nanoparticles of the gastropod Haliotis glabra. AB - A ball-milling approach was developed to investigate the constituents of isolated nacre tablets of the gastropod Haliotis glabra in aqueous suspension without additional chemical additives. The obtained particle mixtures were characterized using X-ray crystallography as well as scanning and transmission electron microscopy. Aragonite nanoparticles retained their crystal structure even after 14 h of ball milling. The long-term stability of the particle mixtures varied as a function of the ball-milling duration. An increased milling time led to rod like stable assemblies of aragonite nanoparticles. Selected area electron diffraction investigations revealed that the longitudinal axes in about one-third of these nanoparticle rods were oriented along the crystallographic c-axis of aragonite, indicating oriented attachment of the aragonite nanoparticles. These in vitro observations support the idea that a two-stage process, separated into crystallization of nanoparticles and oriented assembly of nanocrystals, could also occur in vivo. PMID- 29142016 TI - Multi-scale tarsal adhesion kinematics of freely-walking dock beetles. AB - In this experimental study, living dock beetles are observed during their free upside-down walk on a smooth horizontal substrate. Their weight is balanced by the adhesion of hairy structures present on their tarsomeres. The motions involved in the attachment and detachment of these structures were characterized by simultaneously imaging the beetle from the side at the body scale, and from the top at the scale of a single tarsal chain. The observed multi-scale three dimensional kinematics of the tarsi is qualitatively described, then quantified by image processing and physically modelled. A strong asymmetry is systematically observed between attachment and detachment kinematics, in terms of both timing and directionality. PMID- 29142017 TI - Modelling the effects of phylogeny and body size on within-host pathogen replication and immune response. AB - Understanding how quickly pathogens replicate and how quickly the immune system responds is important for predicting the epidemic spread of emerging pathogens. Host body size, through its correlation with metabolic rates, is theoretically predicted to impact pathogen replication rates and immune system response rates. Here, we use mathematical models of viral time courses from multiple species of birds infected by a generalist pathogen (West Nile Virus; WNV) to test more thoroughly how disease progression and immune response depend on mass and host phylogeny. We use hierarchical Bayesian models coupled with nonlinear dynamical models of disease dynamics to incorporate the hierarchical nature of host phylogeny. Our analysis suggests an important role for both host phylogeny and species mass in determining factors important for viral spread such as the basic reproductive number, WNV production rate, peak viraemia in blood and competency of a host to infect mosquitoes. Our model is based on a principled analysis and gives a quantitative prediction for key epidemiological determinants and how they vary with species mass and phylogeny. This leads to new hypotheses about the mechanisms that cause certain taxonomic groups to have higher viraemia. For example, our models suggest that higher viral burst sizes cause corvids to have higher levels of viraemia and that the cellular rate of virus production is lower in larger species. We derive a metric of competency of a host to infect disease vectors and thereby sustain the disease between hosts. This suggests that smaller passerine species are highly competent at spreading the disease compared with larger non-passerine species. Our models lend mechanistic insight into why some species (smaller passerine species) are pathogen reservoirs and some (larger non passerine species) are potentially dead-end hosts for WNV. Our techniques give insights into the role of body mass and host phylogeny in the spread of WNV and potentially other zoonotic diseases. The major contribution of this work is a computational framework for infectious disease modelling at the within-host level that leverages data from multiple species. This is likely to be of interest to modellers of infectious diseases that jump species barriers and infect multiple species. Our method can be used to computationally determine the competency of a host to infect mosquitoes that will sustain WNV and other zoonotic diseases. We find that smaller passerine species are more competent in spreading the disease than larger non-passerine species. This suggests the role of host phylogeny as an important determinant of within-host pathogen replication. Ultimately, we view our work as an important step in linking within-host viral dynamics models to between-host models that determine spread of infectious disease between different hosts. PMID- 29142018 TI - Terahertz: dictating the frequency of life. Do macromolecular vibrational modes impose thermal limitations on terrestrial life? AB - Conditions on exoplanets include elevated temperatures and pressures. The response of carbon-based biological macromolecules to such conditions is then relevant to the viability of life. The capacity of proteins and ribozymes to catalyse reactions or bind receptors, and nucleic acids to convey information, depends on them sampling different conformational states. These are determined by macromolecular vibrational states, or phonon modes, accessible using terahertz (THz: 1012Hz) absorption spectroscopy. THz spectra of biological macromolecules exhibit broad absorption at approximately 6 THz (equating to approx. 280 K) corresponding to dense transitions between phonon modes. There are also troughs at approximately 10 THz (approx. 500 K) implying diminishing numbers of available conformational states at higher temperatures; hence, fewer routes by which biochemical processes can be realized, as equilibrium is approached. Could this conformational bottleneck hinder the operation of biological macromolecules at higher temperatures? We suggest that the troughs at approximately 10 THz in absorbance spectra indicate that the hydrogen bonds, charge interactions and geometry of biological macromolecules associated with terrestrial life impose fundamental vibrational properties that could limit the upper temperature at which they may function. PMID- 29142019 TI - Molecular Imaging of GLUT1 and GLUT5 in Breast Cancer: A Multitracer Positron Emission Tomography Imaging Study in Mice. AB - Use of [18F]FDG-positron emission tomography (PET) in clinical breast cancer (BC) imaging is limited mainly by insufficient expression levels of facilitative glucose transporter (GLUT)1 in up to 50% of all patients. Fructose-specific facilitative hexose transporter GLUT5 represents an alternative biomarker for PET imaging of hexose metabolism in BC. The goal of the present study was to compare the uptake characteristics of selected hexose-based PET radiotracers in murine BC model EMT6. Uptake of 1-deoxy-1-[18F]fluoro-d-fructose (1-[18F]FDF), 6-deoxy-6 [18F]fluoro-d-fructose (6-[18F]FDF), 1-deoxy-1-[18F]fluoro-2,5-anhydro-mannitol (1-[18F]FDAM), 2-deoxy-2-[18F]fluoro-d-glucose (2-[18F]FDG), and 6-deoxy-6 [18F]fluoro-d-glucose (6-[18F]FDG) was studied in EMT6 cells, tumors, and muscle and correlated to GLUT1 and GLUT5 expression levels. Fructose-derivative 6 [18F]FDF revealed greater tumor uptake than did structural analog 1-[18F]FDF, whereas 1-[18F]FDAM with locked anomeric configuration showed similar low tumor uptake to that of 1-[18F]FDF. Glucose-derivative 6-[18F]FDG reached maximum tumor uptake at 20 minutes, with no further accumulation over time. Uptake of 2 [18F]FDG was greatest and continuously increasing owing to metabolic trapping through phosphorylation by hexokinase II. In EMT6 tumors, GLUT5 mRNA expression was 20,000-fold lower compared with GLUT1. Whereas the latter was much greater in tumor than in muscle tissue (GLUT1 50:1), the opposite was found for GLUT5 mRNA expression (GLUT5 1:6). GLUT5 protein levels were higher in tumor versus muscle tissue as determined by Western blot and immunohistochemistry. Our data suggest that tumor uptake of fructose metabolism-targeting radiotracers 1-[18F]FDF, 6 [18F]FDF, and 1-[18F]FDAM does not correlate with GLUT5 mRNA levels but is linked to GLUT5 protein levels. In conclusion, our results highlight the importance of detailed biochemical studies on GLUT protein expression levels in combination with PET imaging studies for functional characterization of GLUTs in BC. PMID- 29142020 TI - Time out: NFL conflicts of interest with public health efforts to prevent TBI. PMID- 29142021 TI - INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division. AB - Mitochondrial division requires division of both the inner and outer mitochondrial membranes (IMM and OMM, respectively). Interaction with endoplasmic reticulum (ER) promotes OMM division by recruitment of the dynamin Drp1, but effects on IMM division are not well characterized. We previously showed that actin polymerization through ER-bound inverted formin 2 (INF2) stimulates Drp1 recruitment in mammalian cells. Here, we show that INF2-mediated actin polymerization stimulates a second mitochondrial response independent of Drp1: a rise in mitochondrial matrix calcium through the mitochondrial calcium uniporter. ER stores supply the increased mitochondrial calcium, and the role of actin is to increase ER-mitochondria contact. Myosin IIA is also required for this mitochondrial calcium increase. Elevated mitochondrial calcium in turn activates IMM constriction in a Drp1-independent manner. IMM constriction requires electron transport chain activity. IMM division precedes OMM division. These results demonstrate that actin polymerization independently stimulates the dynamics of both membranes during mitochondrial division: IMM through increased matrix calcium, and OMM through Drp1 recruitment. PMID- 29142022 TI - Balance between Cytosolic and Chloroplast Translation Affects Leaf Variegation. AB - The development of functional chloroplasts relies on the fine coordination of expressions of both nuclear and chloroplast genomes. We have been using the Arabidopsis (Arabidopsis thaliana) yellow variegated (var2) leaf variegation mutant as a tool to dissect the regulation of chloroplast development. In this work, we screened for var2 genetic enhancer modifiers termed enhancer of variegation (evr) mutants and report the characterization of the first EVR locus, EVR1 We showed that EVR1 encodes the cytosolic 80S ribosome 40S small subunit protein RPS21B and the loss of EVR1 causes the enhancement of var2 leaf variegation. We further demonstrated that combined S21 activities from EVR1 and its close homolog, EVR1L1, are essential for Arabidopsis, and they act redundantly in regulating leaf development and var2 leaf variegation. Moreover, using additional cytosolic ribosomal protein mutants, we showed that although mutations in cytosolic ribosomal proteins all enhance var2 leaf variegation to varying degrees, the 40S subunit appears to have a more profound role over the 60S subunit in regulating VAR2-mediated chloroplast development. Comprehensive genetic analyses with var2 suppressors that are defective in chloroplast translation established that the enhancement of var2 leaf variegation by cytosolic ribosomal protein mutants is dependent on chloroplast translation. Based on our data, we propose a model that incorporates the suppression and enhancement of var2 leaf variegation, and hypothesize that VAR2/AtFtsH2 may be intimately involved in the balancing of cytosolic and chloroplast translation programs during chloroplast biogenesis. PMID- 29142023 TI - Emerging Roles of the Nuclear Cap-Binding Complex in Abiotic Stress Responses. PMID- 29142024 TI - A Model of Leaf Coordination to Scale-Up Leaf Expansion from the Organ to the Canopy. AB - Process-based crop growth models are popular tools with which to analyze and understand the impact of crop management, genotype-by-environment interactions, or climate change. The ability to predict leaf area development is critical to predict crop growth, particularly under conditions of limited resources. Here, we aimed at deciphering growth coordination rules between wheat (Triticum aestivum) plant organs (i.e. between leaves within a stem, between laminae and sheaths, and between the mainstem and axillary tillers) to model the dynamics of canopy development. We found a unique relationship between laminae area and leaf rank for the mainstem and its tillers, which was robust across a range of sowing dates and plant densities. Robust relationships between laminae and sheath areas also were found, highlighting the tight control of organ growth within and between phytomers. These relationships identified at the phytomer scale were used to develop a simulation model of leaf area dynamics at the canopy level that was integrated in the wheat model SiriusQuality. The model was then evaluated using several independent experiments. The model accurately predicts leaf area dynamics under different scenarios of nitrogen and water limitations. It accounted for 85%, 64%, and 73% of the variability of the surface area of leaf cohorts, total leaf area index, and total green area index, respectively. The process-based model of the dynamics of leaf area described here is a key element to quantify the value of candidate traits for use in plant breeding and to project the impact of climate change on wheat growth. PMID- 29142025 TI - Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia reperfusion injury. AB - Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) effects on cardiac ischemia/reperfusion (I/R) injury are unclear. Unlike SGLT2-i, dipeptidyl peptidase 4 inhibitors (DPP4-i) have shown effective cardioprotection in cardiac I/R injury. We aimed to investigate whether SGLT2-i reduces myocardial dysfunction and myocardial injury to a greater extent than DPP4-i in obese insulin-resistant rats with/without cardiac I/R injury. The high-fat (HF) diet induced obese insulin-resistant rats were divided into 4 groups and received the following treatments for 28 days: vehicle (HFV); vildagliptin at a dosage of 3 mg/kg/day (HFVil); dapagliflozin at a dosage of 1 mg/kg/day (HFDa) and combination drugs (HFDaVil). At the end, I/R injury was induced by a 30-min left anterior descending coronary occlusion and 120-min reperfusion. Dapagliflozin showed a greater efficacy than vildagliptin in improving the metabolic impairments, low frequency/high frequency (LF/HF) ratio, systolic blood pressure and left ventricular (LV) function in comparison to HFV rats. In cardiac I/R injury, dapagliflozin had a greater efficacy than vildagiptin in decreasing mitochondrial DRP1, cleaved caspase 3, LV dysfunction and infarct size in comparison to HFV rats. However, the combined therapy showed the greatest efficacy in attenuating LV dysfunction, mitochondrial DRP1 and infarct size in comparison to HFV rats. In conclusion, dapagliflozin has a more pronounced effect than vildagliptin in obese insulin-resistant rats for the improvement of LV function. In rats with cardiac I/R injury, although dapagliflozin had a greater efficacy on cardioprotection than vildagliptin, the combined therapy exerted the highest cardioprotective effects potentially by reducing mitochondrial fission. PMID- 29142026 TI - A Systematic Review of Quality Measures for Inflammatory Arthritis. AB - OBJECTIVE: To conduct a systematic review and quality appraisal of quality measures for inflammatory arthritis, including rheumatoid arthritis (RA), spondyloarthritis, psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA). METHODS: Embase, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from January 1, 2000, to October 23, 2016, using Medical Subject Headings terms for inflammatory arthritis and quality measures. A "grey literature" search of international arthritis organizations and quality measure libraries was also conducted. Two reviewers independently considered the papers for inclusion, with disagreements resolved by consensus. A modified guideline appraisal tool (AGREE II) was used to appraise the measure development process, which determined final inclusion. Measures were abstracted in duplicate and categorized into themes, measure type, and domains of quality. RESULTS: Thirteen measurement sets were included from 4 countries (United States, Canada, United Kingdom, Netherlands) and 1 European consortium. They included 10 sets on RA and 1 each for PsA, inflammatory arthritis, and JIA. There were 161 unique individual measures (136 process, 20 structure, and 5 outcome). Major themes included assessment, medications, and comorbidities. Measure development methods were varied, including RAND/University of California, Los Angeles appropriateness methodology, prioritization exercises, or other modified-Delphi methods. Inclusion of patients occurred in 77% of development groups. Discussion of barriers to measurement was infrequent. CONCLUSION: Inflammatory arthritis quality measures cover a diversity of themes encompassing process, structure, and outcomes of care across the 6 domains of quality. However, between organizations, measure development is not standardized. Local assessment of measurement feasibility before use outside the original development context is recommended. PMID- 29142027 TI - Underestimation of Risk of Carotid Subclinical Atherosclerosis by Cardiovascular Risk Scores in Patients with Psoriatic Arthritis. AB - OBJECTIVE: To test the performances of established cardiovascular (CV) risk scores in discriminating subclinical atherosclerosis (SCA) in patients with psoriatic arthritis. METHODS: These scores were calculated: Framingham risk score (FRS), QRISK2, Systematic COronary Risk Evaluation (SCORE), 10-year atherosclerotic cardiovascular disease risk algorithm (ASCVD) from the American College of Cardiology and the American Heart Association, and the European League Against Rheumatism (EULAR)-recommended modified versions (by 1.5 multiplication factor, m-). Carotid intima-media thickness > 0.9 mm and/or the presence of plaque determined by ultrasound were classified as SCA+. RESULTS: We recruited 146 patients [49.4 +/- 10.2 yrs, male: 90 (61.6%)], of whom 142/137/128/118 patients were eligible to calculate FRS/QRISK2/SCORE/ASCVD. Further, 62 (42.5%) patients were SCA+ and were significantly older, with higher systolic blood pressure and higher low-density lipoprotein cholesterol (all p < 0.05). All CV risk scores were significantly higher in patients with SCA+ [FRS: 7.8 (3.9-16.5) vs 2.7 (1.1-7.8), p < 0.001; QRISK2: 5.5 (3.1-10.2) vs 2.9 (1.2-6.3), p < 0.001; SCORE: 1 (0-2) vs 0 (0-1), p < 0.001; ASCVD: 5.6 (2.6-12.4) vs 3.4 (1.4-6.1), p = 0.001]. The Hosmer-Lemeshow test revealed moderate goodness of fit for the 4 CV scores (p ranged from 0.087 to 0.686). However, of the patients with SCA+, those identified as high risk were only 44.1% (by FRS > 10%), 1.8% (QRISK2 > 20%), 10.9% (SCORE > 5%), and 43.6% (ASCVD > 7.5%). By applying the EULAR multiplication factor, 50.8%/14.3%/14.5%/54.5% of the patients with SCA+ were identified as high risk by m-FRS/m-QRISK2/m-SCORE/m-ASCVD, respectively. EULAR modification increased the sensitivity of FRS and ASCVD in discriminating SCA+ from 44% to 51%, and 44% to 55%, respectively. CONCLUSION: All CV risk scores underestimated the SCA+ risk. EULAR-recommended modification improved the sensitivity of FRS and ASCVD only to a moderate level. PMID- 29142028 TI - High Baseline Serum Clara Cell 16 kDa Predicts Subsequent Lung Disease Worsening in Systemic Sclerosis. AB - OBJECTIVE: Clara cell secretory protein (CC16) is a sensitive marker of bronchial epithelial cell damage. The CC16 serum level is elevated in patients with pulmonary fibrosis, but its predictive value on lung disease progression has not yet been studied. We aimed to assess the value of serum CC16 concentration in predicting lung disease deterioration in patients with systemic sclerosis (SSc). METHODS: We prospectively analyzed and followed 106 patients with SSc during a 4 year period for the risk of developing combined deleterious event, defined as a 10% decrease in total lung capacity or forced vital capacity from baseline, or death, according to serum CC16 at inclusion. Receiver-operating characteristic (ROC) curve analysis was performed for prediction of events during the first 2 years after inclusion. Cumulative risks of combined events were computed by Kaplan-Meier analysis. RESULTS: The best cutoff level of serum CC16 for prediction of a combined event was 33 ng/ml, with 76% sensitivity and 65% specificity (area under the ROC curve: 0.71, 95% CI 0.61-0.81, p < 0.0001). Progression of lung disease evaluated by a mean time-to-event differed between patients with high baseline serum CC16 (42.8 mos, 36.3-49.3) and those with low serum CC16 (56.3 mos, 50.9-61.7; log-rank test, p < 0.001). After adjustment for age, duration of disease, clinical and lung function measures, the risk of combined event occurrence in patients with high serum CC16 was significantly higher than in those with low CC16 (HR 2.9, 1.2-6.75, p < 0.05). CONCLUSION: High baseline serum CC16 predicts lung disease worsening in patients with SSc. PMID- 29142029 TI - Routine Use of Quantitative Disease Activity Measurements among US Rheumatologists: Implications for Treat-to-target Management Strategies in Rheumatoid Arthritis. AB - OBJECTIVE: The aim of our study was to examine why real-world practices and attitudes regarding quantitative measurements of rheumatoid arthritis (RA) have received limited attention. METHODS: An e-mail survey asked US rheumatologists to self-report on their use of quantitative measurements (metric). RESULTS: Among 439 respondents, metric rheumatologists (58%) were more likely to be in group practice and to use tumor necrosis factor inhibitors. The quantitative tools most commonly used were the Health Assessment Questionnaire (35.5%) and the Routine Assessment of Patient Index Data 3 (27.1%). Reasons for not measuring included time needed and electronic availability. Based on simulated case scenarios, providing more quantitative information increased the likelihood that a patient would change to a different disease-modifying antirheumatic drug or biologic. CONCLUSION: Routine use of quantitative measurement for patients in the United States with RA is increasing over time but remains low. PMID- 29142030 TI - Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimumab plus Methotrexate vs Methotrexate Alone: A Placebo-controlled Clinical Trial. AB - OBJECTIVE: The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study, NCT00660647). METHODS: We included 180 disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves. RESULTS: In the ADA group, a higher pretreatment level of miR-27a 3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively. CONCLUSION: We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts. PMID- 29142031 TI - Activity Limitations in Patients with Axial Spondyloarthritis: A Role for Fear of Movement and (Re)injury Beliefs. AB - OBJECTIVE: To determine whether fear of movement and (re)injury [FOM/(R)I] beliefs, measured with the Tampa Scale for Kinesiophobia 11-item version (TSK 11), influence activity limitations and mediate the relationship between pain severity and activity limitations in axial spondyloarthritis (axSpA). METHODS: In 173 patients with axSpA, these data were collected: sex, body mass index, disease duration, medication, activity limitations (BASFI; Bath Ankylosing Spondylitis Functional Index), disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); BASDAIinf, items 5 and 6; BASDAIpain, items 2 and 3; C-reactive protein and physician's global assessment], spinal mobility (BASMI; Bath Ankylosing Spondylitis Metrology Index), and FOM/(R)I (TSK-11). Scaling assumptions and reliability of TSK-11 were tested with item-to-total correlations, item variances, and Cronbach's alpha coefficient. Hypothesis testing determined TSK-11's construct validity. Multiple linear regression showed the contribution of TSK-11 to BASFI (enter and backward modeling). Mediation by TSK-11 was analyzed (bias-corrected bootstrapping and Sobel test). RESULTS: Adequate scale (Cronbach's alpha = 0.80) and item internal consistency (range item-scale correlations 0.41-0.58, except for item 5, r = 0.23), equal item-scale correlations, and item variances were found for TSK-11. Construct validity was confirmed, except for the hypothesized positive relationship between TSK-11 and BASMI. Regression models (enter method, adjusted R2 range 53-74%) consistently identified TSK-11 as a determinant of BASFI (beta range 0.155 to 0.321, p < 0.05), although BASMI (beta range 0.441 to 0.537) and disease activity (beta range 0.243 to 0.571, p < 0.05) were the largest determinants. TSK-11 partially mediated the BASDAIpain/BASFI relationship (B = 0.107; Sobel test, p = 0.004; bias-corrected CI 0.046-0.197). CONCLUSION: TSK-11 is a promising and valid tool to assess fearful beliefs in relation to activity limitations in axSpA. Future research applying TSK-11 may reveal FOM/(R)I as a novel treatment target in axSpA. PMID- 29142032 TI - Minimal Disease Activity as a Treatment Target in Psoriatic Arthritis: A Review of the Literature. AB - As in other inflammatory rheumatic diseases, the objective of psoriatic arthritis (PsA) treatment is the achievement of a defined target. Recent recommendations propose aiming for remission or low disease activity; however, a consensual definition of remission is lacking. A state of minimal disease activity (MDA) has been established and is defined by low activity assessed by tender/swollen joint counts, tender entheseal points, Psoriasis Area and Severity Index or body surface area, patient pain and global activity visual analog scale, and functional evaluation by Health Assessment Questionnaire. Since its development, MDA has been used increasingly in studies and clinical trials. In this article, the potential use of MDA as a treatment target in PsA is reviewed. The frequencies of MDA achievement with biologic disease-modifying antirheumatic drugs are summarized based on data from registries, observational studies, and clinical trials. Predictors and the prognostic effect of attaining MDA are also evaluated. PMID- 29142033 TI - All-cause Healthcare Costs and Mortality in Patients with Systemic Sclerosis with Lung Involvement. AB - OBJECTIVE: Patients with systemic sclerosis (SSc) often develop interstitial lung disease (ILD) and/or pulmonary arterial hypertension (PAH). The effect of ILD and PAH on healthcare costs among patients with SSc is not well described. The objective of this analysis was to describe healthcare costs in patients with newly diagnosed SSc and SSc patients newly diagnosed with ILD and/or PAH in the United States. METHODS: This retrospective cohort analysis was conducted in the Truven Health MarketScan Commercial and Medicare Supplemental healthcare claims databases from 2003 to 2014. Based on International Classification of Diseases-9 Clinical Modification diagnosis codes on medical claims, patients were classified into 3 groups: incident SSc, SSc with incident ILD (SSc-ILD), and SSc with incident PAH (SSc-PAH). Patients were required to have continuous enrollment for 5 years to measure all-cause healthcare costs. Costs (adjusted to US$) were reported overall and by service type and year following diagnosis. Because of the overlap between groups, statistical comparisons were not conducted. RESULTS: There were 1957 patients with incident SSc, 219 with incident SSc-ILD, and 108 patients with incident SSc-PAH. Average (mean +/- SD) all-cause healthcare costs over followup were higher for patients with incident SSc-ILD ($191,107 +/- $322,193) or patients with incident SSc-PAH ($254,425 +/- $240,497), compared to patients with incident SSc ($101,839 +/- $167,155). Average annual costs over the 5-year period ranged from $18,513 to $23,268 for patients with incident SSc, from $31,285 to $55,446 for patients with incident SSc-ILD, and from $44,454 to $63,320 for patients with incident SSc-PAH. Costs tended to be the highest in the fifth year of followup. CONCLUSION: Among patients with SSc, ILD and PAH can result in substantial increases in healthcare costs. PMID- 29142034 TI - Cumulative Burden of Glucocorticoid-related Adverse Events in Patients with Systemic Lupus Erythematosus: Findings from a 12-year Longitudinal Study. AB - OBJECTIVE: The aim of this population-based study is to examine the adverse events (AE) associated with longitudinal systemic glucocorticoid (GC) use among an ethnic Chinese systemic lupus erythematosus (SLE) cohort. METHODS: Our study subjects were patients with newly diagnosed SLE aged 18 and older who received at least 1 prescription of systemic GC between 2001 and 2012 from Taiwan's National Health Insurance Research Database (NHIRD). The earliest prescription date of systemic GC for each subject was defined as the index date. For each subject, we calculated the average prednisolone-equivalent dose and the medication possession ratio (MPR) of GC use every 90 days for each patient after the index date. Patients with a diagnosis of AE (defined by the International Classification of Diseases-9-Clinical Modification diagnosis code) during the followup were also identified from the NHIRD. Generalized estimating equations adjusted for propensity score were applied to examine the association between longitudinal GC use and risks of prespecified AE (musculoskeletal, gastrointestinal, ophthalmologic, infectious, cardiovascular, neuropsychiatric, metabolic, and dermatologic diseases). RESULTS: We identified 11,288 patients with SLE (mean followup: 6.28 yrs). Higher doses and higher MPR of GC were associated with increased risk of osteonecrosis [adjusted OR (aOR) 2.87-9.09]. Similar results were found regarding the risk of osteoporosis (aOR 1.71-3.67), bacterial infection (aOR 2.12-3.89), Cushingoid syndrome (aOR 6.51-62.03), and sleep disorder (aOR 1.42-3.59). CONCLUSION: To our knowledge, this is the first study to show that the dose and intensity of longitudinal use of GC were both associated with risk of AE among a nationwide Asian SLE cohort. PMID- 29142035 TI - The Sex Influence on Response to Tumor Necrosis Factor-alpha Inhibitors and Remission in Axial Spondyloarthritis. AB - OBJECTIVE: The aim of this study was to evaluate the influence of sex on response to treatment and disease remission in patients with axial spondyloarthritis (axSpA). METHODS: In this retrospective multicenter study, patients with axSpA, according to the Assessment of Spondyloarthritis international Society (ASAS) criteria for axSpA, and treated with adalimumab, etanercept, golimumab, or infliximab, were studied. We compared clinical characteristics, patient-reported outcomes, disease activity, function, and response to treatment in male and female patients with this disease. RESULTS: Three hundred forty patients with axSpA (270 with ankylosing spondylitis, 19 with psoriatic arthritis with axial involvement, and 51 with nonradiographic axSpA) were studied. Male subjects had a significantly higher prevalence of grade IV sacroiliitis, higher levels of serum C-reactive protein, lower Maastricht Ankylosing Spondylitis Enthesitis Score, and fatigue when compared with females. Further, Kaplan-Meier survival curves showed that the rate of partial remission, ASAS40 response, and Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement, but not ASDAS inactive disease, were significantly lower in female patients. CONCLUSION: Our data suggest that female sex was associated with a lower rate of response to treatment and of disease remission in patients with axSpA treated with antitumor necrosis factor alpha drugs. PMID- 29142036 TI - Effect of Glucocorticoids on the Clinical and Radiographic Efficacy of Tofacitinib in Patients with Rheumatoid Arthritis: A Posthoc Analysis of Data from 6 Phase III Studies. AB - OBJECTIVE: Tofacitinib has been investigated for the treatment of rheumatoid arthritis (RA) in phase III studies in which concomitant glucocorticoids (GC) were allowed. We analyzed the effect of GC use on efficacy outcomes in patients with RA receiving tofacitinib and/or methotrexate (MTX) or conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in these studies. METHODS: Our posthoc analysis included data from 6 phase III studies (NCT01039688; NCT00814307; NCT00847613; NCT00853385; NCT00856544; NCT00960440). MTX-naive patients or patients with inadequate response to csDMARD or biological DMARD received tofacitinib 5 or 10 mg twice daily alone or with csDMARD, with or without concomitant GC. Patients receiving GC (<= 10 mg/day prednisone or equivalent) before enrollment maintained a stable dose throughout. Endpoints included the American College of Rheumatology (ACR) 20/50/70 response rates, rates of Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA; CDAI <= 10) and remission (CDAI <= 2.8), and changes from baseline in CDAI, 28-joint count Disease Activity Score (DAS28-4)-erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire-Disability Index (HAQ-DI), pain visual analog scale (VAS), and modified total Sharp score. RESULTS: Of 3200 tofacitinib treated patients, 1258 (39.3%) received tofacitinib monotherapy and 1942 (60.7%) received tofacitinib plus csDMARD; 1767 (55.2%) received concomitant GC. ACR20/50/70 response rates, rates of CDAI LDA and remission, and improvements in CDAI, DAS28-4-ESR, HAQ-DI, and pain VAS with tofacitinib were generally similar with or without GC in monotherapy and combination therapy studies. GC use did not appear to affect radiographic progression in tofacitinib-treated MTX-naive patients. MTX plus GC appeared to inhibit radiographic progression to a numerically greater degree than MTX alone. CONCLUSION: Concomitant use of GC with tofacitinib did not appear to affect clinical or radiographic efficacy. MTX plus GC showed a trend to inhibit radiographic progression to a greater degree than MTX alone. PMID- 29142037 TI - Elevated Psychosocial Stress at Work in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis. AB - OBJECTIVE: Psychosocial stress at work not only affects the healthy working population, but also workers with chronic diseases. We aimed to investigate the psychosocial work stress levels in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: A cross-sectional study applied the Effort-Reward Imbalance (ERI) questionnaire - an internationally established instrument that measures work stress - to patients with SLE and RA who were capable of work and to a group of controls without these diseases. Participants were recruited through rheumatologists in private practices, hospitals, and from self-help groups by personal communication, paper-based flyers, and online advertisements. Because very few studies tested the ERI's applicability in patient groups, with a lack of evidence in patients with inflammatory rheumatic diseases, internal consistency and construct validity of the ERI measure were evaluated. RESULTS: Data came from 270 patients with RA and 247 with SLE, and 178 controls. Patients showed elevated psychosocial stress at work compared to controls. Across the total sample and all groups, satisfactory internal consistencies of the scales effort, reward, and overcommitment were obtained (Cronbach's alpha coefficients > 0.70), and confirmatory factor analysis replicated the theoretical structure of the ERI model (goodness-of-fit index > 0.80). CONCLUSION: We found elevated psychosocial stress at work in patients with SLE and RA compared to controls by applying the ERI model. Despite some heterogeneity in the sample, we achieved satisfactory psychometric properties of the ERI questionnaire. Our results suggest that the ERI questionnaire is a psychometrically useful tool to be implemented in epidemiological studies of employed patients with SLE and RA. PMID- 29142038 TI - More Consistent Antimalarial Intake in First 5 Years of Disease Is Associated with Better Prognosis in Patients with Systemic Lupus Erythematosus. AB - OBJECTIVE: To examine whether more consistent use of antimalarial agents (AM) leads to better results in systemic lupus erythematosus (SLE). METHODS: From a longitudinal cohort study, we identified inception patients with a minimum of 5 years of followup. They were divided into 3 groups: patients who took AM > 60% of the time (group A), those who took AM < 60% of the time (group B), and those who did not receive AM (group C) during the first 5 years of followup. Outcomes included increase in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), flare, achieving low disease activity (LDA), adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000, cumulative doses of steroids (CMS), and AM-related retinal toxicity. Regression analysis models were constructed to identify predictors of the outcomes. RESULTS: There were 459 patients identified: 236 (51.4%) in group A, 88 (19.2%) in group B, and 135 (29.4%) in group C. The changes in SDI, flare event, and CMS were significantly lower in group A, which more often achieved LDA. Multivariable analysis revealed that the patients in group A had a lower risk of increasing SDI and were more likely to achieve LDA at Year 5 compared to the patients in group C. Patients taking AM had lower CMS over the 5 years of followup. There was only 1 patient with AM-related retinal toxicity in each group. CONCLUSION: More consistent use of an AM over the first 5 years of SLE is associated with better outcomes. PMID- 29142039 TI - Risk Factors Associated with Juvenile Idiopathic Arthritis: Exposure to Cigarette Smoke and Air Pollution from Pregnancy to Disease Diagnosis. AB - OBJECTIVE: To evaluate exposure to environmental factors inhaled during pregnancy and after birth until juvenile idiopathic arthritis (JIA) diagnosis among residents of a large city. METHODS: This is an exploratory case-control study that consists of 66 patients with JIA and 124 healthy controls matched by age and sex, living in the Sao Paulo, Brazil, metropolitan area until JIA diagnosis, and whose mothers had resided in this region during pregnancy. A structured and reliable questionnaire (kappa index for test-retest was 0.80) assessed demographic data, gestational and perinatal-related factors, and exposure to inhalable environmental elements during pregnancy and after birth (occupational exposure to inhalable particles and/or volatile vapor, exposure to cigarette smoke, and the presence of industrial activities or gas stations near the home, work, daycare, or school). Tropospheric pollutants included particulate matter (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), and carbon monoxide (CO). RESULTS: During pregnancy, intrauterine cigarette smoke exposure (OR 3.43, 95% CI 1.45-8.12, p = 0.005) and maternal occupational exposure (OR 13.69, 95% CI 4.4-42.3, p < 0.001) were significant independent risk factors for JIA diagnosis. In contrast, maternal employment (OR 0.06, 95% CI 0.02-0.2, p < 0.001) and ideal maternal weight gain (OR 0.36, 95% CI 0.2-0.8, p = 0.017) presented negative associations. Secondhand smoke exposure from birth to JIA diagnosis (OR 3.6, 95% CI 1.8-7.3, p < 0.001) and exposure to O3 during the second year of life (OR 2.76, 95% CI 1.20-6.37, p = 0.017) were independent and significant risk factors for the pathogenesis of JIA. CONCLUSION: In our study, cigarette smoke exposure (intrauterine and after birth), exposure to O3 in the second year of life, and maternal occupational exposure were identified as potential risk factors for JIA, warranting further study. PMID- 29142040 TI - Use of Disease-modifying Antirheumatic Drugs for Inflammatory Arthritis in US Veterans: Effect of Specialty Care and Geographic Distance. AB - OBJECTIVE: To evaluate the effect of access to and distance from rheumatology care on the use of disease-modifying antirheumatic drugs (DMARD) in US veterans with inflammatory arthritis (IA). METHODS: Provider encounters and DMARD dispensations for IA (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) were evaluated in national Veterans Affairs (VA) datasets between January 1, 2015, and December 31, 2015. RESULTS: Among 12,589 veterans with IA, 23.5% saw a rheumatology provider. In the general IA population, 25.3% and 13.6% of veterans were exposed to a synthetic DMARD (sDMARD) and biologic DMARD (bDMARD), respectively. DMARD exposure was 2.6- to 3.4-fold higher in the subpopulation using rheumatology providers, compared to the general IA population. The distance between veterans' homes and the closest VA rheumatology site was < 40 miles (Near) for 55.9%, 40-99 miles (Intermediate) for 31.7%, and >= 100 miles (Far) for 12.4%. Veterans in the Intermediate and Far groups were less likely to see a rheumatology provider than veterans in the Near group (RR = 0.72 and RR = 0.49, respectively). Exposure to bDMARD was 34% less frequent in the Far group than the Near group. In the subpopulation who used rheumatology care, the bDMARD exposure discrepancy did not persist between distance groups. CONCLUSION: Use of rheumatology care and DMARD was low for veterans with IA. DMARD exposure was strongly associated with rheumatology care use. Veterans in the general IA population living far from rheumatology sites accessed rheumatology care and bDMARD less frequently than veterans living close to rheumatology sites. PMID- 29142041 TI - Occurrence of Serious Infection in Patients with Rheumatoid Arthritis Treated with Biologics and Denosumab Observed in a Clinical Setting. AB - OBJECTIVE: Previous studies combining biologic disease-modifying antirheumatic drugs (bDMARD) to treat rheumatoid arthritis (RA) have shown an increased risk of infection. However, the risk of infection with concurrent use of denosumab, a biologic agent for the treatment of osteoporosis, and a bDMARD remains unclear. Here, we evaluated the incidence of serious and opportunistic infections in patients treated concurrently with denosumab and a bDMARD and patients treated with a bDMARD alone. METHODS: A chart review of patients with RA from 2 Canadian rheumatology practices between July 1, 2010, and July 31, 2014, identified 2 groups of patients: those taking denosumab and a bDMARD concurrently (concurrent group) and those taking only a bDMARD (biologic-alone group). Patients were followed from the time of initiation of denosumab, or a matched index date for the biologic-alone group, to the end of the study or loss to followup. Instances of serious or opportunistic infections were recorded. RESULTS: A total of 308 patients (n = 102 for the concurrent group and n = 206 for the biologic-alone group) were evaluated. Within the concurrent group, 3 serious infection events occurred. Within the biologic-alone group, 4 serious infection events and 1 opportunistic infection event occurred. In both groups, all patients with serious or opportunistic infection recovered, and there were no instances of death during the study period. CONCLUSION: This study demonstrated a low occurrence of serious and opportunistic infections in patients with RA taking bDMARD, including patients with concurrent denosumab use. PMID- 29142043 TI - The higher the farther: distance-specific referential gestures in chimpanzees (Pan troglodytes). AB - Referential signals, such as manual pointing or deictic words, allow individuals to efficiently locate a specific entity in the environment, using distance specific linguistic and/or gestural units. To explore the evolutionary prerequisites of such deictic ability, the present study investigates the ability of chimpanzees to adjust their communicative signals to the distance of a referent. A food-request paradigm in which the chimpanzees had to request a close or distant piece of food on a table in the presence/absence of an experimenter was employed. Our main finding concerns the chimpanzees adjusting their requesting behaviours to the distance of the food such that higher manual gestures and larger mouth openings were used to request the distant piece of food. To the best of our knowledge, this is the first study to demonstrate that chimpanzees are able to use distance-specific gestures. PMID- 29142044 TI - Thermoregulatory role of insensible evaporative water loss constancy in a heterothermic marsupial. AB - 'Insensible' evaporative water loss of mammals has been traditionally viewed as a passive process, but recent studies suggest that insensible water loss is under regulatory control, although the physiological role of this control is unclear. We test the hypothesis that regulation of insensible water loss has a thermoregulatory function by quantifying for the first time evaporative water loss control, along with metabolic rate and body temperature, of a heterothermic mammal during normothermia and torpor. Evaporative water loss was independent of ambient relative humidity at ambient temperatures of 20 and 30 degrees C, but not at 25 degrees C or during torpor at 20 degrees C. Evaporative water loss per water vapour pressure deficit had a positive linear relationship with relative humidity at ambient temperatures of 20 and 30 degrees C, but not at 25 degrees C or during torpor at 20 or 25 degrees C. These findings suggest that insensible water loss deviates from a physical model only during thermoregulation, providing support for the hypothesis that regulation of insensible evaporative water loss has a thermoregulatory role. PMID- 29142045 TI - Rapid Assay for Detection of the Epidemiologically Important Central Asian/Russian Strain of the Mycobacterium tuberculosis Beijing Genotype. PMID- 29142046 TI - Quantitative Analysis of Gamma Interferon Release Assay Response in Children with Latent and Active Tuberculosis. AB - The use of interferon gamma (IFN-gamma) release assays (IGRAs) for the diagnosis of tuberculosis (TB) infection in children is still under debate because of concerns about the immature immune response in children. The aim of this study was to investigate quantitative values of the QuantiFERON-TB Gold In-Tube (QFT IT) test, a commercially available IGRA, in a large cohort of children screened for TB infection. A retrospective analysis was conducted on samples from 517 children aged 0 to 14 years old at the Pediatric Unit of S. Orsola-Malpighi University Hospital of Bologna (Italy); quantitative responses to QFT-IT stimuli were analyzed according to diagnosis and age. Elevated IFN-gamma values in the QFT-IT nil (background) tube were statistically associated with diagnosis of active TB. Quantitative IFN-gamma response to Mycobacterium tuberculosis-specific antigens (TB Ag) was not significantly different in children with active TB compared to those with latent TB infection (LTBI), even though the median values were higher in the first group. When children were grouped by age, those less than 5 years old produced significantly higher levels of IFN-gamma in response to TB Ag if they had active TB (median 10 IU/ml) than those with LTBI (median 1.96 IU/ml). IFN-gamma response to mitogen increased with age. The overall rate of indeterminate results was low (3.9%), and no indeterminate QFT-IT values were observed in active or latent TB patients. In conclusion, quantitative QFT-IT values could provide further information to clinicians to manage TB in children, and these observations could be transferred to the new version of the test, QuantiFERON-TB Gold Plus, which to date lacks data from the pediatric population. PMID- 29142047 TI - Multicenter Evaluation of the Vitek MS v3.0 System for the Identification of Filamentous Fungi. AB - Invasive fungal infections are an important cause of morbidity and mortality affecting primarily immunocompromised patients. While fungal identification to the species level is critical to providing appropriate therapy, it can be slow and laborious and often relies on subjective morphological criteria. The use of matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry has the potential to speed up and improve the accuracy of identification. In this multicenter study, we evaluated the accuracy of the Vitek MS v3.0 system in identifying 1,601 clinical mold isolates compared to identification by DNA sequence analysis and supported by morphological and phenotypic testing. Among the 1,519 isolates representing organisms in the v3.0 database, 91% (n = 1,387) were correctly identified to the species level. An additional 27 isolates (2%) were correctly identified to the genus level. Fifteen isolates were incorrectly identified, due to either a single incorrect identification (n = 13) or multiple identifications from different genera (n = 2). In those cases, when a single identification was provided that was not correct, the misidentification was within the same genus. The Vitek MS v3.0 was unable to identify 91 (6%) isolates, despite repeat testing. These isolates were distributed among all the genera. When considering all isolates tested, even those that were not represented in the database, the Vitek MS v3.0 provided a single correct identification 98% of the time. These findings demonstrate that the Vitek MS v3.0 system is highly accurate for the identification of common molds encountered in the clinical mycology laboratory. PMID- 29142048 TI - Accurate PCR Detection of Influenza A/B and Respiratory Syncytial Viruses by Use of Cepheid Xpert Flu+RSV Xpress Assay in Point-of-Care Settings: Comparison to Prodesse ProFlu. AB - The Xpert Flu+RSV Xpress Assay is a fast, automated in vitro diagnostic test for qualitative detection and differentiation of influenza A and B viruses and respiratory syncytial virus (RSV) performed on the Cepheid GeneXpert Xpress System. The objective of this study was to establish performance characteristics of the Xpert Flu+RSV Xpress Assay compared to those of the Prodesse ProFlu+ real time reverse transcription-PCR (RT-PCR) assay (ProFlu+) for the detection of influenza A and B viruses as well as RSV in a Clinical Laboratory Improvement Amendments (CLIA)-waived (CW) setting. Overall, the assay, using fresh and frozen nasopharyngeal (NP) swabs, demonstrated high concordance with results of the ProFlu+ assay in the combined CW and non-CW settings with positive percent agreements (PPA) (100%, 100%, and 97.1%) and negative percent agreements (NPA) (95.2%, 99.5%, and 99.6%) for influenza A and B viruses and RSV, respectively. In conclusion, this multicenter study using the Cepheid Xpert Flu+RSV Xpress Assay demonstrated high sensitivities and specificities for influenza A and B viruses and RSV in ~60 min for use at the point-of-care in the CW setting. PMID- 29142049 TI - Occurrence and Nature of Double Alleles in Variable-Number Tandem-Repeat Patterns of More than 8,000 Mycobacterium tuberculosis Complex Isolates in The Netherlands. AB - Since 2004, variable-number tandem-repeat (VNTR) typing of Mycobacterium tuberculosis complex isolates has been applied on a structural basis in The Netherlands to study the epidemiology of tuberculosis (TB). Although this technique is faster and technically less demanding than the previously used restriction fragment length polymorphism (RFLP) typing, reproducibility remains a concern. In the period from 2004 to 2015, 8,532 isolates were subjected to VNTR typing in The Netherlands, with 186 (2.2%) of these exhibiting double alleles at one locus. Double alleles were most common in loci 4052 and 2163b. The variables significantly associated with double alleles were urban living (odds ratio [OR], 1.503; 95% confidence interval [CI], 1.084 to 2.084; P = 0.014) and pulmonary TB (OR, 1.703; 95% CI, 1.216 to 2.386; P = 0.002). Single-colony cultures of double allele strains were produced and revealed single-allele profiles; a maximum of five single nucleotide polymorphisms (SNPs) was observed between the single- and double-allele isolates from the same patient when whole-genome sequencing (WGS) was applied. This indicates the presence of two bacterial populations with slightly different VNTR profiles in the parental population, related to genetic drift. This observation is confirmed by the fact that secondary cases from TB source cases with double-allele isolates sometimes display only one of the two alleles present in the source case. Double alleles occur at a frequency of 2.2% in VNTR patterns in The Netherlands. They are caused by biological variation rather than by technical aberrations and can be transmitted either as single- or double-allele variants. PMID- 29142051 TI - Improved Detection of HER2 by a Quasi-Targeted Proteomics Approach Using Aptamer Peptide Probe and Liquid Chromatography-Tandem Mass Spectrometry. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive type of the disease. To date, much evidence has indicated that accurate HER2 status detection is crucial for prognosis and treatment strategy selection. Thus, bioanalytical techniques for early and accurate detection of HER2 have the potential to improve patient care. Currently, the widely used immunohistochemical staining normally has problems with reproducibility and lack of standardization, resulting in poor concordance between laboratories. Aptamers are a good alternative, but the extent of their use in quantitative analysis of HER2 is limited because of the lack of effective detection methods. METHODS: We developed a quasi-targeted proteomics assay and converted the HER2 signal into the mass response of reporter peptide by a combination of aptamer-peptide probe and LC-MS/MS. RESULTS: The selected aptamer peptide probe consisted of aptamer HB5 and the substrate peptide GDKAVLGVDPFR that contained the reporter peptide AVLGVDPFR. After characterization of this newly synthesized probe (e.g., conjugation efficiency, stability, binding affinity, specificity, and digestion efficiency), probe binding and trypsin shaving conditions were optimized. The resulting limit of quantification for HER2 was 25 pmol/L. Then, the quasi-targeted proteomics assay was applied to determine the HER2 concentrations in the HER2-positive breast cancer cells BT474 and SK-BR 3, the HER2-negative breast cancer cells MDA-MB-231 and MCF-7, and 36 pairs of human breast primary tumors and adjacent normal tissue samples. The results were highly concordant with those obtained by immunohistochemistry with reflex testing by fluorescent in situ hybridization. CONCLUSIONS: Quasi-targeted proteomics can be a quantitative alternative for HER2 detection. PMID- 29142050 TI - Collectin-11 Promotes the Development of Renal Tubulointerstitial Fibrosis. AB - Collectin-11 is a recently described soluble C-type lectin, a pattern recognition molecule of the innate immune system that has distinct roles in host defense, embryonic development, and acute inflammation. However, little is known regarding the role of collectin-11 in tissue fibrosis. Here, we investigated collectin-11 in the context of renal ischemia-reperfusion injury. Compared with wild-type littermate controls, Collec11 deficient (CL-11-/- ) mice had significantly reduced renal functional impairment, tubular injury, renal leukocyte infiltration, renal tissue inflammation/fibrogenesis, and collagen deposition in the kidneys after renal ischemia-reperfusion injury. In vitro, recombinant collectin-11 potently promoted leukocyte migration and renal fibroblast proliferation in a carbohydrate-dependent manner. Additionally, compared with wild-type kidney grafts, CL-11-/-mice kidney grafts displayed significantly reduced tubular injury and collagen deposition after syngeneic kidney transplant. Our findings demonstrate a pathogenic role for collectin-11 in the development of tubulointerstitial fibrosis and suggest that local collectin-11 promotes this fibrosis through effects on leukocyte chemotaxis and renal fibroblast proliferation. This insight into the pathogenesis of tubulointerstitial fibrosis may have implications for CKD mediated by other causes as well. PMID- 29142052 TI - Early post-treatment risk stratification of differentiated thyroid cancer: comparison of three high-sensitive Tg assays. AB - OBJECTIVE: To assess the diagnostic performance of three high-sensitive assays in a cohort of TgAb-negative and TgAb-positive differentiated thyroid cancer (DTC) patients. DESIGN: Retrospective study on prospectively selected DTC patients. METHODS: Serum samples from 154 DTC patients were obtained 6-12 months after radioiodine ablation and tested by Beckman, Roche, BRAHMS Tg and TgAb assays, respectively. Receiver operating characteristics curves for Tg were plotted using outcome over time as benchmark and assay-specific Tg thresholds were obtained for TgAb-negative and TgAb-positive patients. RESULTS: The frequency of positive TgAb was 21, 20 and 20% for Beckman, Roche and BRAHMS, respectively. In TgAb-negative patients, clinical sensitivities and specificities of 100% and 85-95%, respectively, were observed across all assays. In TgAb-positive patients, clinical sensitivities and specificities of 80-100% and 92-96%, respectively, were observed using lower thresholds than in patients without TgAb. CONCLUSIONS: Adopting appropriate thresholds, lower than those for TgAb-negative patients, is possible to reliably follow TgAb-positive patients using highly sensitive Tg assays. PMID- 29142053 TI - Rab35 GTPase recruits NDP52 to autophagy targets. PMID- 29142056 TI - Familiarity with a vocal category biases the compartmental expression of Arc/Arg3.1 in core auditory cortex. AB - Learning to recognize a stimulus category requires experience with its many natural variations. However, the mechanisms that allow a category's sensorineural representation to be updated after experiencing new exemplars are not well understood, particularly at the molecular level. Here we investigate how a natural vocal category induces expression in the auditory system of a key synaptic plasticity effector immediate early gene, Arc/Arg3.1, which is required for memory consolidation. We use the ultrasonic communication system between mouse pups and adult females to study whether prior familiarity with pup vocalizations alters how Arc is engaged in the core auditory cortex after playback of novel exemplars from the pup vocal category. A computerized, 3D surface-assisted cellular compartmental analysis, validated against manual cell counts, demonstrates significant changes in the recruitment of neurons expressing Arc in pup-experienced animals (mothers and virgin females "cocaring" for pups) compared with pup-inexperienced animals (pup-naive virgins), especially when listening to more familiar, natural calls compared to less familiar but similarly recognized tonal model calls. Our data support the hypothesis that the kinetics of Arc induction to refine cortical representations of sensory categories is sensitive to the familiarity of the sensory experience. PMID- 29142057 TI - Morphofunctional experience-dependent plasticity in the honeybee brain. AB - Repeated or prolonged exposure to an odorant without any positive or negative reinforcement produces experience-dependent plasticity, which results in habituation and latent inhibition. In the honeybee (Apis mellifera), it has been demonstrated that, even if the absolute neural representation of an odor in the primary olfactory center, the antennal lobe (AL), is not changed by repeated presentations, its relative representation with respect to unfamiliar stimuli is modified. In particular, the representation of a stimulus composed of a 50:50 mixture of a familiar and a novel odorant becomes more similar to that of the novel stimulus after repeated stimulus preexposure. In a calcium-imaging study, we found that the same functional effect develops following prolonged odor exposure. By analyzing the brains of the animals subjected to this procedure, we found that such functional changes are accompanied by morphological changes in the AL (i.e., a decrease in volume in specific glomeruli). The AL glomeruli that exhibited structural plasticity also modified their functional responses to the three stimuli (familiar odor, novel odor, binary mixture). We suggest a model in which rebalancing inhibition within the AL glomeruli may be sufficient to elicit structural and functional correlates of experience-dependent plasticity. PMID- 29142058 TI - Juvenile female rats, but not male rats, show renewal, reinstatement, and spontaneous recovery following extinction of conditioned fear. AB - Anxiety disorders emerge early, and girls are significantly more likely to develop anxiety compared to boys. However, sex differences in fear during development are poorly understood. Therefore, we investigated juvenile male and female rats in the relapse behaviors following extinction of conditioned fear. In all experiments, 18-d-old rats first received three white-noise-footshock pairings on day 1. On day 2, extinction involved 60 white-noise alone trials. In experiment 1, we examined renewal by testing the rats in either the same or different context as extinction on day 3. Male rats did not show renewal, however, female rats showed renewal. Experiment 2 investigated reinstatement by giving rats either a mild reminder footshock or context exposure on day 3. When tested the next day, male rats did not show reinstatement, whereas female rats showed reinstatement. Experiment 3 investigated spontaneous recovery by testing the rats either 1 or 5 d following extinction. Male rats did not show any spontaneous recovery whereas female rats did. Taken together, fear regulation appear to be different in males versus females from early in development, which may explain why girls are more prone to suffer from anxiety disorders compared to boys. PMID- 29142059 TI - Recovery of attention with renewal. AB - One experiment determined the relationship between renewed associative strength and attention. Following cue1-outcome pairings in Context A, cue1 was extinguished in Context B while cue2 was conditioned. On test cue2 was chosen as a predictor of the outcome in Context B. Both cues were chosen equally often as predictors in Context A. Consistent with attributing attention to effective associative strength (as noted in a previous study), participants could locate only cue2 in Context B while both were located in Context A, regardless of having been chosen as a predictor. Attention varied as a function of both cues' associative strengths across contexts. PMID- 29142060 TI - Sleep increases explicit solutions and reduces intuitive judgments of semantic coherence. AB - Sleep fosters the generation of explicit knowledge. Whether sleep also benefits implicit intuitive decisions about underlying patterns is unclear. We examined sleep's role in explicit and intuitive semantic coherence judgments. Participants encoded sets of three words and after a sleep or wake period were required to judge the potential convergence of these words on a common fourth associate. Compared with wakefulness, sleep increased the number of explicitly named common associates and decreased the number of intuitive judgments. This suggests that sleep enhances the extraction of explicit knowledge at the expense of the ability to make intuitive decisions about semantic coherence. PMID- 29142061 TI - Effects of regulatory BC1 RNA deletion on synaptic plasticity, learning, and memory. AB - Nonprotein coding dendritic BC1 RNA regulates translation of mRNAs in neurons. We examined two lines of BC1 knockout mice and report that loss of BC1 RNA exaggerates group I mGluR-stimulated LTD of the Schaffer collateral synapse, with one of the lines showing a much more enhanced DHPG-induced LTD than the other. When the animals were given the hippocampus-synaptic plasticity-dependent active place avoidance task, learning and memory were impaired in the BC1-KO line with the more severely altered DHPG-induced LTD. These findings indicate a role for BC1 RNA control of mGluR-dependent synaptic function in hippocampus and associated cognitive ability. PMID- 29142064 TI - The resurrection of the PIDDosome - emerging roles in the DNA-damage response and centrosome surveillance. AB - The PIDDosome is often used as the alias for a multi-protein complex that includes the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the pro-form of an endopeptidase belonging to the caspase family, i.e. caspase-2. Yet, PIDD1 variants can also interact with a number of other proteins that include RIPK1 (also known as RIP1) and IKBKG (also known as NEMO), PCNA and RFC5, as well as nucleolar components such as NPM1 or NCL. This promiscuity in protein binding is facilitated mainly by autoprocessing of the full-length protein into various fragments that contain different structural domains. As a result, multiple responses can be mediated by protein complexes that contain a PIDD1 domain. This suggests that PIDD1 acts as an integrator for multiple types of stress that need instant attention. Examples are various types of DNA lesion but also the presence of extra centrosomes that can foster aneuploidy and, ultimately, promote DNA damage. Here, we review the role of PIDD1 in response to DNA damage and also highlight novel functions of PIDD1, such as in centrosome surveillance and scheduled polyploidisation as part of a cellular differentiation program during organogenesis. PMID- 29142065 TI - Maintaining centrosomes and cilia. AB - Centrosomes and cilia are present in organisms from all branches of the eukaryotic tree of life. These structures are composed of microtubules and various other proteins, and are required for a plethora of cell processes such as structuring the cytoskeleton, sensing the environment, and motility. Deregulation of centrosome and cilium components leads to a wide range of diseases, some of which are incompatible with life. Centrosomes and cilia are thought to be very stable and can persist over long periods of time. However, these structures can disappear in certain developmental stages and diseases. Moreover, some centrosome and cilia components are quite dynamic. While a large body of knowledge has been produced regarding the biogenesis of these structures, little is known about how they are maintained. In this Review, we propose the existence of specific centrosome and cilia maintenance programs, which are regulated during development and homeostasis, and when deregulated can lead to disease. PMID- 29142062 TI - The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior. AB - The serine protease inhibitor neuroserpin regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin expression is particularly prominent at late stages of neuronal development in most regions of the central nervous system (CNS), whereas it is restricted to regions related to learning and memory in the adult brain. The physiological expression pattern of neuroserpin, its high degree of colocalization with tPA within the CNS, together with its dysregulation in neuropsychiatric disorders, suggest a role in formation and refinement of synapses. In fact, studies in cell culture and mice point to a role for neuroserpin in dendritic branching, spine morphology, and modulation of behavior. In this study, we investigated the physiological role of neuroserpin in the regulation of synaptic density, synaptic plasticity, and behavior in neuroserpin-deficient mice. In the absence of neuroserpin, mice show a significant decrease in spine-synapse density in the CA1 region of the hippocampus, while expression of the key postsynaptic scaffold protein PSD-95 is increased in this region. Neuroserpin-deficient mice show decreased synaptic potentiation, as indicated by reduced long-term potentiation (LTP), whereas presynaptic paired-pulse facilitation (PPF) is unaffected. Consistent with altered synaptic plasticity, neuroserpin-deficient mice exhibit cognitive and sociability deficits in behavioral assays. However, although synaptic dysfunction is implicated in neuropsychiatric disorders, we do not detect alterations in expression of neuroserpin in fusiform gyrus of autism patients or in dorsolateral prefrontal cortex of schizophrenia patients. Our results identify neuroserpin as a modulator of synaptic plasticity, and point to a role for neuroserpin in learning and memory. PMID- 29142066 TI - Characterization of SGN-CD123A, A Potent CD123-Directed Antibody-Drug Conjugate for Acute Myeloid Leukemia. AB - Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Ralpha, or CD123) is expressed on the majority of AML blasts, and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here, we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate using the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A-mediated potent cytotoxicity of 11/12 CD123+ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248). Mol Cancer Ther; 17(2); 554-64. (c)2017 AACR. PMID- 29142067 TI - JQ1 Induces DNA Damage and Apoptosis, and Inhibits Tumor Growth in a Patient Derived Xenograft Model of Cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a fatal disease with a 5-year survival of <30%. For a majority of patients, chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the first-line agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ~8 months. Combining this agent with cisplatin increases survival by ~3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the antitumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2 and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis and downregulated multiple c-Myc transcriptional targets that regulate cell-cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA. Mol Cancer Ther; 17(1); 107-18. (c)2017 AACR. PMID- 29142069 TI - CAT-02-106, a Site-Specifically Conjugated Anti-CD22 Antibody Bearing an MDR1 Resistant Maytansine Payload Yields Excellent Efficacy and Safety in Preclinical Models. AB - Hematologically derived tumors make up ~10% of all newly diagnosed cancer cases in the United States. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1. CD22 is a clinically validated target for the treatment of NHL, but no anti-CD22 agents have yet been approved for this indication. Recent approval of an anti-CD22 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory ALL supports the rationale for targeting this protein. An opportunity exists for a next-generation anti-CD22 antibody-drug conjugate (ADC) to address unmet medical needs in the relapsed/refractory NHL population. We describe a site-specifically conjugated antibody-drug conjugate, made using aldehyde tag technology, targeted against CD22 and bearing a noncleavable maytansine payload that is resistant to MDR1 mediated efflux. The construct was efficacious against CD22+ NHL xenografts and could be repeatedly dosed in cynomolgus monkeys at 60 mg/kg with no observed significantly adverse effects. Exposure to total ADC at these doses (as assessed by AUC0-inf) indicated that the exposure needed to achieve efficacy was below tolerable limits. Together, the data suggest that this drug has the potential to be used effectively in patients with CD22+ tumors that have developed MDR1 related resistance to prior therapies. Mol Cancer Ther; 17(1); 161-8. (c)2017 AACR. PMID- 29142068 TI - Pharmacologic Inhibition of the Menin-MLL Interaction Leads to Transcriptional Repression of PEG10 and Blocks Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) accounts for approximately 85% of malignant liver tumors and results in 600,000 deaths each year, emphasizing the need for new therapies. Upregulation of menin was reported in HCC patients and high levels of menin correlate with poor patient prognosis. The protein-protein interaction between menin and histone methyltransferase mixed lineage leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients. Here, we demonstrate that the menin-MLL inhibitor MI-503 shows antitumor activity in in vitro and in vivo models of HCC and reveals the potential mechanism of menin contribution to HCC. Treatment with MI-503 selectively kills various HCC cell lines and this effect is significantly enhanced by a combination of MI-503 with sorafenib, the standard-of-care therapy for HCC. Furthermore, MI-503 reduces sphere formation and cell migration in in vitro HCC models. When applied in vivo, MI-503 gives a strong antitumor effect both as a single agent and in combination with sorafenib in mice xenograft models of HCC. Mechanistically, treatment with MI-503 downregulates expression of several genes known to play a critical role in proliferation and migration of HCC cells, including PEG10, and displaces the menin-MLL1 complex from the PEG10 promoter, resulting in reduced H3K4 methylation and transcriptional repression. Overall, our studies reveal a mechanistic link between menin and genes involved in HCC and demonstrate that pharmacologic inhibition of the menin-MLL interaction might represent a promising therapeutic approach for HCC. Mol Cancer Ther; 17(1); 26-38. (c)2017 AACR. PMID- 29142070 TI - Gfap and Osmr regulation by BRG1 and STAT3 via interchromosomal gene clustering in astrocytes. AB - Long-range chromatin interactions between gene loci in the cell nucleus are important for many biological processes, including transcriptional regulation. Previously, we demonstrated that several genes specifically cluster with the astrocyte-specific gene for glial fibrillary acidic protein (Gfap) during astrocyte differentiation; however, the molecular mechanisms for gene clustering remain largely unknown. Here we show that brahma-related gene 1 (BRG1), an ATP dependent chromatin remodeling factor, and the transcription factor STAT3 are required for Gfap and oncostatin M receptor (Osmr) clustering and enhanced expression through recruitment to STAT3 recognition sequences and that gene clustering occurs prior to transcriptional up-regulation. BRG1 knockdown and JAK STAT signaling inhibition impaired clustering, leading to transcriptional down regulation of both genes. BRG1 and STAT3 were recruited to the same Gfap fragment; JAK-STAT signaling inhibition impaired BRG1 recruitment. Our results suggest that BRG1 and STAT3 coordinately regulate gene clustering and up-regulate Gfap and Osmr transcription. PMID- 29142071 TI - Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins. AB - Nuclear shape and architecture influence gene localization, mechanotransduction, transcription, and cell function. Abnormal nuclear morphology and protrusions termed "blebs" are diagnostic markers for many human afflictions including heart disease, aging, progeria, and cancer. Nuclear blebs are associated with both lamin and chromatin alterations. A number of prior studies suggest that lamins dictate nuclear morphology, but the contributions of altered chromatin compaction remain unclear. We show that chromatin histone modification state dictates nuclear rigidity, and modulating it is sufficient to both induce and suppress nuclear blebs. Treatment of mammalian cells with histone deacetylase inhibitors to increase euchromatin or histone methyltransferase inhibitors to decrease heterochromatin results in a softer nucleus and nuclear blebbing, without perturbing lamins. Conversely, treatment with histone demethylase inhibitors increases heterochromatin and chromatin nuclear rigidity, which results in reduced nuclear blebbing in lamin B1 null nuclei. Notably, increased heterochromatin also rescues nuclear morphology in a model cell line for the accelerated aging disease Hutchinson-Gilford progeria syndrome caused by mutant lamin A, as well as cells from patients with the disease. Thus, chromatin histone modification state is a major determinant of nuclear blebbing and morphology via its contribution to nuclear rigidity. PMID- 29142072 TI - Salt bridges gate alpha-catenin activation at intercellular junctions. AB - Cadherin complexes transduce force fluctuations at junctions to activate signals that reinforce stressed intercellular contacts. alpha-Catenin is an identified force transducer within cadherin complexes that is autoinhibited under low tension. Increased force triggers a conformational change that exposes a cryptic site for the actin-binding protein vinculin. This study tested predictions that salt bridges within the force-sensing core modulate alpha-catenin activation. Studies with a fluorescence resonance energy transfer (FRET)-based alpha-catenin conformation sensor demonstrated that each of the salt-bridge mutations R551A and D503N enhances alpha-catenin activation in live cells, but R551A has a greater impact. Under dynamic force loading at reannealing cell-cell junctions, the R551A mutant bound more vinculin than wild-type alpha-catenin. In vitro binding measurements quantified the impact of the R551A mutation on the free-energy difference between the active and autoinhibited alpha-catenin conformers. A 2-MUs constant-force, steered molecular dynamics simulation of the core force-sensing region suggested how the salt-bridge mutants alter the alpha-catenin conformation, and identified a novel load-bearing salt bridge. These results reveal key structural features that determine the force-transduction mechanism and the force sensitivity of this crucial nanomachine. PMID- 29142073 TI - GGA1 regulates signal-dependent sorting of BACE1 to recycling endosomes, which moderates Abeta production. AB - The diversion of the membrane-bound beta-site amyloid precursor protein-(APP) cleaving enzyme (BACE1) from the endolysosomal pathway to recycling endosomes represents an important transport step in the regulation of amyloid beta (Abeta) production. However, the mechanisms that regulate endosome sorting of BACE1 are poorly understood. Here we assessed the transport of BACE1 from early to recycling endosomes and have identified essential roles for the sorting nexin 4 (SNX4)-mediated, signal-independent pathway and for a novel signal-mediated pathway. The signal-mediated pathway is regulated by the phosphorylation of the DXXLL-motif sequence DISLL in the cytoplasmic tail of BACE1. The phosphomimetic S498D BACE1 mutant was trafficked to recycling endosomes at a faster rate compared with wild-type BACE1 or the nonphosphorylatable S498A mutant. The rapid transit of BACE1 S498D from early endosomes was coupled with reduced levels of amyloid precursor protein processing and Abeta production, compared with the S498A mutant. We show that the adaptor, GGA1, and retromer are essential to mediate rapid trafficking of phosphorylated BACE1 to recycling endosomes. In addition, the BACE1 DISLL motif is phosphorylated and regulates endosomal trafficking, in primary neurons. Therefore, post-translational phosphorylation of DISLL enhances the exit of BACE1 from early endosomes, a pathway mediated by GGA1 and retromer, which is important in regulating Abeta production. PMID- 29142074 TI - STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis posttranscriptionally, and is essential for lung myofibroblast differentiation. AB - Fibroblast differentiation is a key cellular process that underlies the process of fibrosis, a deadly complication of fibrotic diseases like scleroderma (SSc). This transition coincides with the overproduction of collagen type I (COL1) and other extracellular matrix proteins. High-level expression of the collagen type 1alpha2 subunit (COL1A2), requires the engagement of a far-upstream enhancer, whose activation is strongly dependent on the AP1 factor JunB. We now report that STAT3 also binds the COL1A2 enhancer and is essential for RNA polymerase recruitment, without affecting JunB binding. STAT3 is required for the increased COL1A2 expression observed in myofibroblasts. We also report that TGFbeta partially activates STAT3 and show that inhibiting STAT3 potently blocks TGFbeta signaling, matrix remodeling, and TGFbeta-induced myofibroblast differentiation. Activation of STAT3 with IL6 transsignaling alone, however, only increased COL1A2 protein expression, leaving COL1A2 mRNA levels unchanged. Our results suggest that activated STAT3 is not the limiting factor for collagen enhancer activation in human lung fibroblasts. Yet, a certain threshold level of STAT3 activity is essential to support activation of the COL1A2 enhancer and TGFbeta signaling in fibroblasts. We propose that STAT3 operates at the posttranscriptional as well as the transcriptional level. PMID- 29142075 TI - Cone myoid elongation involves unidirectional microtubule movement mediated by dynein-1. AB - Teleosts and amphibians exhibit retinomotor movements, morphological changes in photoreceptors regulated by light and circadian rhythms. Cone myoid elongation occurs during dark adaptation, leading to the positioning of the cone outer segment closer to the retinal pigment epithelium. Although it has been shown that microtubules are essential for cone myoid elongation, the underlying mechanism has not been established. In this work, we generated a transgenic line of zebrafish expressing a photoconvertible form of alpha-tubulin (tdEOS-tubulin) specifically in cone photoreceptors. Using superresolution structured illumination microscopy in conjunction with both pharmacological and genetic manipulation, we show that cytoplasmic dynein-1, which localizes to the junction between the ellipsoid and myoid, functions to shuttle microtubules from the ellipsoid into the myoid during the course of myoid elongation. We propose a novel model by which stationary complexes of cytoplasmic dynein-1 are responsible for the shuttling of microtubules between the ellipsoid and myoid is the underlying force for the morphological change of myoid elongation. PMID- 29142076 TI - Spatial cues and not spindle pole maturation drive the asymmetry of astral microtubules between new and preexisting spindle poles. AB - In many asymmetrically dividing cells, the microtubule-organizing centers (MTOCs; mammalian centrosome and yeast spindle pole body [SPB]) nucleate more astral microtubules on one of the two spindle poles than the other. This differential activity generally correlates with the age of MTOCs and contributes to orienting the mitotic spindle within the cell. The asymmetry might result from the two MTOCs being in distinctive maturation states. We investigated this model in budding yeast. Using fluorophores with different maturation kinetics to label the outer plaque components of the SPB, we found that the Cnm67 protein is mobile, whereas Spc72 is not. However, these two proteins were rapidly as abundant on both SPBs, indicating that SPBs mature more rapidly than anticipated. Superresolution microscopy confirmed this finding for Spc72 and for the gamma tubulin complex. Moreover, astral microtubule number and length correlated with the subcellular localization of SPBs rather than their age. Kar9-dependent orientation of the spindle drove the differential activity of the SPBs in astral microtubule organization rather than intrinsic differences between the spindle poles. Together, our data establish that Kar9 and spatial cues, rather than the kinetics of SPB maturation, control the asymmetry of astral microtubule organization between the preexisting and new SPBs. PMID- 29142077 TI - Syndromic Panel-Based Testing in Clinical Microbiology. AB - The recent development of commercial panel-based molecular diagnostics for the rapid detection of pathogens in positive blood culture bottles, respiratory specimens, stool, and cerebrospinal fluid has resulted in a paradigm shift in clinical microbiology and clinical practice. This review focuses on U.S. Food and Drug Administration (FDA)-approved/cleared multiplex molecular panels with more than five targets designed to assist in the diagnosis of bloodstream, respiratory tract, gastrointestinal, or central nervous system infections. While these panel based assays have the clear advantages of a rapid turnaround time and the detection of a large number of microorganisms and promise to improve health care, they present certain challenges, including cost and the definition of ideal test utilization strategies (i.e., optimal ordering) and test interpretation. PMID- 29142078 TI - Candida auris: a Review of the Literature. AB - The emerging pathogen Candida auris has been associated with nosocomial outbreaks on five continents. Genetic analysis indicates the simultaneous emergence of separate clades of this organism in different geographical locations. Invasive infection and colonization have been detected predominantly in patients in high dependency settings and have garnered attention due to variable antifungal resistance profiles and transmission within units instituting a range of infection prevention and control measures. Issues with the identification of C. auris using both phenotypic and molecular techniques have raised concerns about detecting the true scale of the problem. This review considers the literature available on C. auris and highlights the key unknowns, which will provide direction for further work in this field. PMID- 29142080 TI - Human Parechovirus: an Increasingly Recognized Cause of Sepsis-Like Illness in Young Infants. AB - Human parechovirus (HPeV) is increasingly being recognized as a potentially severe viral infection in neonates and young infants. HPeV belongs to the family Picornaviridae and is currently divided into 19 genotypes. HPeV-1 is the most prevalent genotype and most commonly causes gastrointestinal and respiratory disease. HPeV-3 is clinically the most important genotype due to its association with severe disease in younger infants, which may partly be explained by its distinct virological properties. In young infants, the typical clinical presentation includes fever, severe irritability, and rash, often leading to descriptions of "hot, red, angry babies." Infants with severe central nervous system (CNS) infections are at an increased risk of long-term sequelae. Considering the importance of HPeV as a cause of severe viral infections in young infants, we recommend that molecular diagnostic techniques for early detection be included in the standard practice for the investigation of sepsis-like illnesses and CNS infections in this age group. PMID- 29142079 TI - Laboratory Diagnosis of Parasites from the Gastrointestinal Tract. AB - This Practical Guidance for Clinical Microbiology document on the laboratory diagnosis of parasites from the gastrointestinal tract provides practical information for the recovery and identification of relevant human parasites. The document is based on a comprehensive literature review and expert consensus on relevant diagnostic methods. However, it does not include didactic information on human parasite life cycles, organism morphology, clinical disease, pathogenesis, treatment, or epidemiology and prevention. As greater emphasis is placed on neglected tropical diseases, it becomes highly probable that patients with gastrointestinal parasitic infections will become more widely recognized in areas where parasites are endemic and not endemic. Generally, these methods are nonautomated and require extensive bench experience for accurate performance and interpretation. PMID- 29142083 TI - Evidence of CNS beta-amyloid deposition in Nasu-Hakola disease due to the TREM2 Q33X mutation. PMID- 29142082 TI - Nonalcoholic fatty liver disease in spinal and bulbar muscular atrophy. AB - OBJECTIVE: To determine the prevalence and features of fatty liver disease in spinal and bulbar muscular atrophy (SBMA). METHODS: Two groups of participants with SBMA were evaluated. In the first group, 22 participants with SBMA underwent laboratory analysis and liver imaging. In the second group, 14 participants with SBMA were compared to 13 female carriers and 23 controls. Liver biopsies were done in 4 participants with SBMA. RESULTS: Evidence of fatty liver disease was detected by magnetic resonance spectroscopy in all participants with SBMA in the first group, with an average dome intrahepatic triacylglycerol of 27% (range 6% 66%, ref <=5.5%). Liver dome magnetic resonance spectroscopy measurements were significantly increased in participants with SBMA in the second group relative to age- and sex-matched controls, with average disease and male control measurements of 17% and 3%, respectively. Liver biopsies were consistent with simple steatosis in 2 participants and nonalcoholic steatohepatitis in 2 others. CONCLUSIONS: We observed evidence of nonalcoholic liver disease in nearly all of the participants with SBMA evaluated. These observations expand the phenotypic spectrum of the disease and provide a potential biomarker that can be monitored in future studies. PMID- 29142084 TI - Impaired vestibular responses in internuclear ophthalmoplegia: Association and dissociation. AB - OBJECTIVE: To determine the role of the medial longitudinal fasciculus (MLF) in conveying vestibular signals. METHODS: In 10 patients with isolated acute unilateral internuclear ophthalmoplegia (INO) due to an acute stroke, we performed comprehensive vestibular evaluation using video-oculography, head impulse tests with a magnetic search coil technique, bithermal caloric tests, tests for the ocular tilt reaction, and measurements of subjective visual vertical and cervical and ocular vestibular evoked myogenic potentials (VEMPs). RESULTS: The head impulse gain of the vestibulo-ocular reflex (VOR) was decreased invariably for the contralesional posterior canal (PC) (n = 9; 90%) and usually for the ipsilesional horizontal canal (n = 5; 50%). At least one component of contraversive ocular tilt reaction (n = 9) or contraversive tilt of the subjective visual vertical (n = 7) were common along with ipsitorsional nystagmus (n = 5). Cervical or ocular VEMPs were abnormal in 5 patients. CONCLUSIONS: The MLF serves as the main passage for the high-acceleration VOR from the contralateral PC. The associations and dissociations of the vestibular dysfunction in our patients indicate variable combinations of damage to the vestibular fibers ascending or descending in the MLF even in strokes causing isolated unilateral INO. PMID- 29142081 TI - Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy. AB - GABA-A receptors play a pivotal role in many brain diseases. Epilepsy is caused by acquired conditions and genetic defects in GABA receptor channels regulating neuronal excitability in the brain. The latter is referred to as GABA channelopathies. In the last two decades, major advances have been made in the genetics of epilepsy. The presence of specific GABAergic genetic abnormalities leading to some of the classic epileptic syndromes has been identified. Advances in molecular cloning and recombinant systems have helped characterize mutations in GABA-A receptor subunit genes in clinical neurology. GABA-A receptors are the prime targets for neurosteroids (NSs). However, GABA-A receptors are not static but undergo rapid changes in their number or composition in response to the neuroendocrine milieu. This review describes the recent advances in the genetic and neuroendocrine control of extrasynaptic and synaptic GABA-A receptors in epilepsy and its impact on neurologic conditions. It highlights the current knowledge of GABA genetics in epilepsy, with an emphasis on the neuroendocrine regulation of extrasynaptic GABA-A receptors in network excitability and seizure susceptibility. Recent advances in molecular regulation of extrasynaptic GABA-A receptor-mediated tonic inhibition are providing unique new therapeutic approaches for epilepsy, status epilepticus, and certain brain disorders. The discovery of an extrasynaptic molecular mechanism represents a milestone for developing novel therapies such as NS replacement therapy for catamenial epilepsy. PMID- 29142085 TI - OCT as a window to the MS brain: The view becomes slightly clearer. PMID- 29142086 TI - Shortage of generic neurologic therapeutics: An escalating threat to patient care. AB - OBJECTIVE: To assess longitudinal trends in shortages of generic drugs used for neurologic conditions over a 15-year period in the United States. METHODS: Drug shortage data from the University of Utah Drug Information Service (UUDIS) from 2001 to 2015 were analyzed. Medications were included that were likely to be prescribed by a neurologist to treat a primary neurologic condition or critical for care of a patient with a neurologic condition. Trends in shortage length were assessed using standard descriptive statistics. RESULTS: A total of 2,081 shortages were reported by UUDIS and 311 (15%) involved medications for neurologic conditions. After excluding discontinued products, 291 shortages were analyzed. The median number of neurologic drugs in shortage was 21 per month with a median duration of 7.4 months. During the three 5-year periods of 2001-2005, 2006-2010, and 2011-2015, a median of 12.5, 14, and 45 drugs were in shortage, respectively. A maximum of 50 drugs in shortage was reached in December 2012 and December 2014. By the end of the study period, 30 neurologic drugs remained in shortage. In over half of the shortages, manufacturers did not provide a reason for the shortage. When reported, manufacturing delays, followed by supply/demand issues, raw material shortages, regulatory issues, and business decisions were cited. CONCLUSIONS: Continued drug shortages may compromise the care of patients with neurologic conditions. Manufacturers, together with professional organizations, patient advocacy groups, and the government, need to continue to address this issue, which may escalate with a growing burden of neurologic disease. PMID- 29142087 TI - No evidence of disease activity is associated with reduced rate of axonal retinal atrophy in MS. AB - OBJECTIVE: To explore, in a longitudinal study, the usefulness of optical coherence tomography (OCT) in monitoring people with multiple sclerosis (MS) by testing the association between retinal nerve fiber layer (RNFL) thinning and clinical and brain MRI criteria of no evidence of disease activity (NEDA). METHODS: OCT, visual evoked potentials (VEPs), and disability, using the Expanded Disability Status Scale (EDSS), were tested at baseline and after 2 years in 72 patients, 63 with routine yearly brain MRI. RESULTS: Longitudinal mean binocular RNFL thinning, in absence of optic neuritis during follow-up, was correlated with EDSS worsening, also controlling for baseline EDSS, RNFL, disease duration, and MS subtype (Spearman rho -0.462, p < 0.001; partial correlation coefficient 0.437, p < 0.001). At follow-up, patients classified as NEDA (20; 31.7%) had RNFL loss of -0.93 MUm +/- 1.35 SD, while patients with active disease had -2.83 MUm +/- 2 SD thinning (t test; p < 0.001). At logistic regression, mean RNFL reduction correctly classified 76.2% of patients as NEDA at 2 years (R2 0.355; p = 0.003). A cutoff of -1.25 MUm RNFL loss classified NEDA status with specificity 81.4% and sensitivity 80% (receiver operating characteristic curve: area under the curve 0.8; p < 0.001). No significant longitudinal correlations were found between changes in RNFL and in VEP latencies or scores. CONCLUSIONS: NEDA is associated with a relatively preserved RNFL over 2 years. A greater neuroretinal loss was detected even in patients with clinical evidence of disease activity independently from changes in brain MRI lesions, prompting further validation of OCT as an additional tool in MS monitoring. PMID- 29142088 TI - Muscle glycogen synthesis and breakdown are both impaired in glycogenin-1 deficiency. AB - OBJECTIVE: To study fat and carbohydrate metabolism during exercise in patients with glycogenin-1 (GYG1) deficiency, and to study whether IV glucose supplementation can alleviate exercise intolerance in these patients. METHODS: This is a case-control study with 4 patients with GYG1 deficiency and 4 healthy controls. Patients performed 1 hour of cycling at 50% of their maximal workload capacity, while controls cycled at the same absolute workloads as patients. Heart rate was measured continuously, and production and utilization of fat and glucose was assessed by stable isotope technique. The following day, patients repeated the exercise, this time receiving an IV 10% glucose supplement. RESULTS: Glucose utilization during exercise was similar in patients and controls, while palmitate utilization was greater in patients compared to controls. However, exercise induced increases in lactate were attenuated to about half normal in patients. This was also the case during a handgrip exercise test. Glucose infusion improved exercise tolerance in patients, and lowered heart rate by on average 11 beats per minute during exercise. CONCLUSIONS: The findings suggest that patients with GYG1 deficiency not only have abnormal formation of glycogen, but also have impaired muscle glycogenolysis, as suggested by impaired lactate production during exercise and improved exercise tolerance with glucose infusion. PMID- 29142091 TI - Physiological and pathophysiological firing properties of single postganglionic sympathetic neurons in humans. AB - It has long been known from microneurographic recordings in human subjects that the activity of postganglionic sympathetic axons occurs as spontaneous bursts, with muscle sympathetic nerve activity (MSNA) exhibiting strong cardiac rhythmicity via the baroreflex and skin sympathetic nerve activity showing much weaker cardiac modulation. Here we review the firing properties of single sympathetic neurons, obtained using highly selective microelectrodes. Individual vasoconstrictor neurons supplying muscle or skin, or sudomotor neurons supplying sweat glands, always discharge with a low firing probability (~30%) and at very low frequencies (~0.5 Hz). Moreover, they usually fire only once per cardiac interval but can fire greater than four times within a burst. Modeling has shown that this pattern can best be explained by individual neurons being driven by, on average, two preganglionic inputs. Unitary recordings of muscle vasoconstrictor neurons have been made in several pathophysiological states, including heart failure, hypertension, obstructive sleep apnea, bronchiectasis, chronic obstructive pulmonary disease, depression, and panic disorder. The augmented MSNA in each of these diseases features an increase in firing probability and discharge frequency of individual muscle vasoconstrictor neurons above that seen in healthy subjects, yet firing rates rarely exceed 1 Hz. However, unlike patients with heart failure, all patients with respiratory disease or panic disorder, and patients with hyperhidrosis, exhibited an increase in multiple within-burst firing, which emphasizes the different modes by which the sympathetic nervous system grades its output in pathophysiological states of high sympathetic nerve activity. PMID- 29142090 TI - Virtual Reality Training for Upper Extremity in Subacute Stroke (VIRTUES): A multicenter RCT. AB - OBJECTIVE: To compare the effectiveness of upper extremity virtual reality rehabilitation training (VR) to time-matched conventional training (CT) in the subacute phase after stroke. METHODS: In this randomized, controlled, single blind phase III multicenter trial, 120 participants with upper extremity motor impairment within 12 weeks after stroke were consecutively included at 5 rehabilitation institutions. Participants were randomized to either VR or CT as an adjunct to standard rehabilitation and stratified according to mild to moderate or severe hand paresis, defined as >=20 degrees wrist and 10 degrees finger extension or less, respectively. The training comprised a minimum of sixteen 60-minute sessions over 4 weeks. The primary outcome measure was the Action Research Arm Test (ARAT); secondary outcome measures were the Box and Blocks Test and Functional Independence Measure. Patients were assessed at baseline, after intervention, and at the 3-month follow-up. RESULTS: Mean time from stroke onset for the VR group was 35 (SD 21) days and for the CT group was 34 (SD 19) days. There were no between-group differences for any of the outcome measures. Improvement of upper extremity motor function assessed with ARAT was similar at the postintervention (p = 0.714) and follow-up (p = 0.777) assessments. Patients in VR improved 12 (SD 11) points from baseline to the postintervention assessment and 17 (SD 13) points from baseline to follow-up, while patients in CT improved 13 (SD 10) and 17 (SD 13) points, respectively. Improvement was also similar for our subgroup analysis with mild to moderate and severe upper extremity paresis. CONCLUSIONS: Additional upper extremity VR training was not superior but equally as effective as additional CT in the subacute phase after stroke. VR may constitute a motivating training alternative as a supplement to standard rehabilitation. CLINICALTRIALSGOV IDENTIFIER: NCT02079103. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with upper extremity motor impairment after stroke, compared to conventional training, VR training did not lead to significant differences in upper extremity function improvement. PMID- 29142092 TI - Response of supraoculomotor area neurons during combined saccade-vergence movements. AB - Combined saccade-vergence movements allow humans and other primates to align their eyes with objects of interest in three-dimensions. In the absence of saccades, vergence movements are typically slow, symmetrical movements of the two eyes in opposite directions. However, combined saccade-vergence movements produce vergence velocities that exceed values observed during vergence alone. This phenomenon is often called "vergence enhancement", or "saccade-facilitated vergence," though it is important to consider that rapid vergence changes, known as "vergence transients," are also observed during conjugate saccades. We developed a visual target array that allows monkeys to make saccades in all directions between targets spaced at distances that correspond to ~1 degrees intervals of vergence angle relative to the monkey. We recorded the activity of vergence-sensitive neurons in the supra-oculomotor area (SOA), located dorsal and lateral to the oculomotor nucleus while monkeys made saccades with vergence amplitudes ranging from 0 to 10 degrees . The primary focus of this study was to test the hypothesis that neurons in the SOA fire a high frequency burst of spikes during saccades that could generate the enhanced vergence. We found that individual neurons encode vergence velocity during both saccadic and non-saccadic vergence, yet firing rates were insufficient to produce the observed enhancement of vergence velocity. Our results are consistent with the hypothesis that slow vergence changes are encoded by the SOA while fast vergence movements require an additional contribution from the saccadic system. NEW & NOTEWORTHY Research into combined saccade-vergence movements has so far focused on exploring the saccadic neural circuitry, leading to diverging hypotheses regarding the role of the vergence system in this behavior. In this study, we report the first quantitative analysis of the discharge of individual neurons that encode vergence velocity in the monkey brain stem during combined saccade-vergence movements. PMID- 29142093 TI - Developmental changes in spinal neuronal properties, motor network configuration, and neuromodulation at free-swimming stages of Xenopus tadpoles. AB - We describe a novel preparation of the isolated brain stem and spinal cord from prometamorphic tadpole stages of the South African clawed frog ( Xenopus laevis) that permits whole cell patch-clamp recordings from neurons in the ventral spinal cord. Previous research on earlier stages of the same species has provided one of the most detailed understandings of the design and operation of a central pattern generator circuit. Here we have addressed how development sculpts complexity from this more basic circuit. The preparation generates bouts of fictive swimming activity either spontaneously or in response to electrical stimulation of the optic tectum, allowing an investigation into how the neuronal properties, activity patterns, and neuromodulation of locomotor rhythm generation change during development. We describe an increased repertoire of cellular responses compared with younger larval stages and investigate the cellular-level effects of nitrergic neuromodulation as well as the development of a sodium pump-mediated ultraslow afterhyperpolarization (usAHP) in these free-swimming larval animals. NEW & NOTEWORTHY A novel in vitro brain stem-spinal cord preparation is described that enables whole cell patch-clamp recordings from spinal neurons in prometamorphic Xenopus tadpoles. Compared with the well-characterized earlier stages of development, spinal neurons display a wider range of firing properties during swimming and have developed novel cellular properties. This preparation now makes it feasible to investigate in detail spinal central pattern generator maturation during the dramatic switch between undulatory and limb-based locomotion strategies during amphibian metamorphosis. PMID- 29142094 TI - Standardized automated training of rhesus monkeys for neuroscience research in their housing environment. AB - Teaching nonhuman primates the complex cognitive behavioral tasks that are central to cognitive neuroscience research is an essential and challenging endeavor. It is crucial for the scientific success that the animals learn to interpret the often complex task rules and reliably and enduringly act accordingly. To achieve consistent behavior and comparable learning histories across animals, it is desirable to standardize training protocols. Automatizing the training can significantly reduce the time invested by the person training the animal. In addition, self-paced training schedules with individualized learning speeds based on automatic updating of task conditions could enhance the animals' motivation and welfare. We developed a training paradigm for across-task unsupervised training (AUT) of successively more complex cognitive tasks to be administered through a stand-alone housing-based system optimized for rhesus monkeys in neuroscience research settings (Calapai A, Berger M, Niessing M, Heisig K, Brockhausen R, Treue S, Gail A. Behav Res Methods 5: 1-11, 2016). The AUT revealed interindividual differences in long-term learning progress between animals, helping to characterize learning personalities, and commonalities, helping to identify easier and more difficult learning steps in the training protocol. Our results demonstrate that 1) rhesus monkeys stay engaged with the AUT over months despite access to water and food outside the experimental sessions but with lower numbers of interaction compared with conventional fluid controlled training; 2) with unsupervised training across sessions and task levels, rhesus monkeys can learn tasks of sufficient complexity for state-of-the art cognitive neuroscience in their housing environment; and 3) AUT learning progress is primarily determined by the number of interactions with the system rather than the mere exposure time. NEW & NOTEWORTHY We demonstrate that highly structured training of behavioral tasks, as used in neuroscience research, can be achieved in an unsupervised fashion over many sessions and task difficulties in a monkey housing environment. Employing a predefined training strategy allows for an observer-independent comparison of learning between animals and of training approaches. We believe that self-paced standardized training can be utilized for pretraining and animal selection and can contribute to animal welfare in a neuroscience research environment. PMID- 29142095 TI - Patterns of intermuscular inhibitory force feedback across cat hindlimbs suggest a flexible system for regulating whole limb mechanics. AB - Prior work has suggested that Golgi tendon organ feedback, via its distributed network linking muscles spanning all joints, could be used by the nervous system to help regulate whole limb mechanics if appropriately organized. We tested this hypothesis by characterizing the patterns of intermuscular force-dependent feedback between the primary extensor muscles spanning the knee, ankle, and toes in decerebrate cat hindlimbs. Intermuscular force feedback was evaluated by stretching tendons of selected muscles in isolation and in pairwise combinations and then measuring the resulting force-dependent intermuscular interactions. The relative inhibitory feedback between extensor muscles was examined, as well as symmetry of the interactions across limbs. Differences in the directional biases of inhibitory feedback were observed across cats, with three patterns identified as points on a spectrum: pattern 1, directional bias of inhibitory feedback onto the ankle extensors and toe flexors; pattern 2, convergence of inhibitory feedback onto ankle extensors and mostly balanced inhibitory feedback between vastus muscle group and flexor hallucis longus, and pattern 3, directional bias of inhibitory feedback onto ankle and knee extensors. The patterns of inhibitory feedback, while different across cats, were symmetric across limbs of individual cats. The variable but structured distribution of force feedback across cat hindlimbs provides preliminary evidence that inhibitory force feedback could be a regulated neural control variable. We propose the directional biases of inhibitory feedback observed experimentally could provide important task dependent benefits, such as directionally appropriate joint compliance, joint coupling, and compensation for nonuniform inertia. NEW & NOTEWORTHY Feedback from Golgi tendon organs project widely among extensor motor nuclei in the spinal cord. The distributed nature of force feedback suggests these pathways contribute to the global regulation of limb mechanics. Analysis of this network in individual animals indicates that the strengths of these pathways can be reorganized appropriately for a variety of motor tasks, including level walking, slope walking, and landing. PMID- 29142097 TI - Fast oscillation dynamics during hypsarrhythmia as a localization biomarker. AB - Hypsarrhythmia in West syndrome, although hard to define, is characterized by chaotic and disorganized electrical activity of the brain and is often regarded as a generalized EEG pattern without any localization value. Using event-related spectral perturbation (ERSP), we tried to determine the brain dynamics during hypsarrhythmia. Routine 1-h scalp EEGs were retrieved from 31 patients with infantile spasms and 20 age-matched controls. Using the EEGLAB toolbox of MATLAB 2015b, the ERSPs of fast oscillations (FOs; 20-100 Hz) of selected channels were analyzed and compared among groups according to their MRI lesions. FO-ERSP cutoff values for predicting the pathologic foci were estimated. The mean FO-ERSPs across all analyzed electrodes of patients with spasms were significantly higher than those of controls. When the patients were categorized into nonlesional, focal/multifocal, or diffuse lesional groups, the FO-ERSP of patients in the focal/multifocal lesional group was significantly lower than that of those in the nonfocal or diffuse lesional groups. In the focal/multifocal lesional group, seven patients (7/9, 77.8%) showed that the locations of channels with high FO ERSPs were matched to the pathologic MRI lesions. Thus, the localization of high FO-ERSPs is closely associated with the location of pathologic brain lesions. Further research is required to prove the value of the FO-ERSP as an important quantitative localizing biomarker of West syndrome. NEW & NOTEWORTHY The locations of high fast oscillation-event-related spectral perturbations (FO ERSPs) are closely associated with brain pathologic lesions, and high FO-ERSPs can be used as a localization biomarker of pathologic brain lesions in patients with hypsarrhythmia. With further validation, FO-ERSP might be useful as a biomarker for the localization of hidden pathologies in conditions with generalized epileptiform activities such as West syndrome. PMID- 29142096 TI - Novel Ca2+-dependent mechanisms regulate spontaneous release at excitatory synapses onto CA1 pyramidal cells. AB - Although long thought to simply be a source of synaptic noise, spontaneous, action potential-independent release of neurotransmitter from presynaptic terminals has multiple roles in synaptic function. We explored whether and to what extent the two predominantly proposed mechanisms for explaining spontaneous release, stochastic activation of voltage-gated Ca2+ channels (VGCCs) or activation of Ca2+-sensing receptors (CaSRs) by extracellular Ca2+, played a role in the sensitivity of spontaneous release to the level of extracellular Ca2+ concentration at excitatory synapses at CA1 pyramidal cells of the adult male mouse hippocampus. Blocking VGCCs with Cd2+ had no effect on spontaneous release, ruling out stochastic activation of VGCCs. Although divalent cation agonists of CaSRs, Co2+ and Mg2+, dramatically enhanced miniature excitatory postsynaptic current (mEPSC) frequency, potent positive and negative allosteric modulators of CaSRs had no effect. Moreover, immunoblot analysis of hippocampal lysates failed to detect CaSR expression, ruling out the CaSR. Instead, the increase in mEPSC frequency induced by Co2+ and Mg2+ was mimicked by lowering postsynaptic Ca2+ levels with BAPTA. Together, our results suggest that a reduction in intracellular Ca2+ may trigger a homeostatic-like compensatory response that upregulates spontaneous transmission at excitatory synapses onto CA1 pyramidal cells in the adult hippocampus. NEW & NOTEWORTHY We show that the predominant theories for explaining the regulation of spontaneous, action potential independent synaptic release do not explain the sensitivity of this type of synaptic transmission to external Ca2+ concentration at excitatory synapses onto hippocampal CA1 pyramidal cells. In addition, our data indicate that intracellular Ca2+ levels in CA1 pyramidal cells regulate spontaneous release, suggesting that excitatory synapses onto CA1 pyramidal cells may express a novel, rapid form of homeostatic plasticity. PMID- 29142098 TI - Acquisition of skilled finger movements is accompanied by reorganization of the corticospinal system. AB - Dexterous finger movements are often characterized by highly coordinated movements. Such coordination might be derived from reorganization of the corticospinal system. In this study, we investigated 1) the manner in which finger movement covariation patterns are acquired, by examining the effects of the implicit and explicit learning of a serial reaction time task (SRTT), and 2) how such changes in finger coordination are represented in the corticospinal system. The subjects learned a button press sequence in both implicit and explicit learning conditions. In the implicit conditions, they were naive about what they were learning, whereas in the explicit conditions the subjects consciously learned the order of the sequence elements. Principal component analysis decomposed both the voluntary movements produced during the SRTT and the passive movements evoked by transcranial magnetic stimulation (TMS) over the primary motor cortex into a set of five finger joint covariation patterns. The structures of the voluntary and passive TMS-evoked movement patterns were reorganized by implicit learning but not explicit learning. Furthermore, in the implicit learning conditions the finger covariation patterns derived from the TMS evoked and voluntary movements spanned similar movement subspaces. These results provide the first evidence that skilled sequential finger movements are acquired differently through implicit and explicit learning, i.e., the changes in finger coordination patterns induced by implicit learning are accompanied by functional reorganization of the corticospinal system, whereas explicit learning results in faster recruitment of individual finger movements without causing any changes in finger coordination. NEW & NOTEWORTHY Skilled sequential multifinger movements are characterized as highly coordinated movement patterns. These finger coordination patterns are represented in the corticospinal system, yet it still remains unclear how these patterns are acquired through implicit and explicit motor sequence learning. A direct comparison of learning-related changes between actively generated finger movements and passively evoked finger movements by TMS provided evidence that finger coordination patterns represented in the corticospinal system are reorganized through implicit, but not explicit, sequence learning. PMID- 29142099 TI - Assessing TMS-induced D and I waves with spinal H-reflexes. AB - Transcranial magnetic stimulation (TMS) of motor cortex produces a series of descending volleys known as D (direct) and I (indirect) waves. In the present study, we questioned whether spinal H-reflexes can be used to dissect D waves and early and late I waves from TMS. We therefore probed H-reflex facilitation at arrival times of D and I waves at the spinal level and thereby changed TMS parameters that have previously been shown to have selective effects on evoked D and different I waves. We changed TMS intensity and current direction and applied a double-pulse paradigm known as short-interval intracortical inhibition (SICI). Experiments were conducted in flexor carpi radialis (FCR) in the arm and soleus (SOL) in the leg. There were two major findings: 1) in FCR, H-reflex facilitation showed characteristic modulations with altered TMS parameters that correspond to the changes of evoked D and I waves; and 2) H-reflexes in SOL did not, possibly because of increased interference from other spinal circuits. Therefore, the most significant outcome of this study is that in FCR, H-reflexes combined with TMS seem to be a useful technique to dissect TMS-induced D and I waves. NEW & NOTEWORTHY Questions that relate to corticospinal function in pathophysiology and movement control demand sophisticated techniques to provide information about corticospinal mechanisms. We introduce a noninvasive electrophysiological technique that may be useful in describing such mechanisms in more detail by dissecting D and I waves from transcranial magnetic stimulation (TMS). Based on the combination of spinal H-reflexes and TMS in the flexor carpi radialis muscle, the technique was shown to measure selective effects on D and I waves from changing TMS parameters. PMID- 29142089 TI - Motor, cognitive, and functional declines contribute to a single progressive factor in early HD. AB - OBJECTIVE: To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials. METHODS: We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up. RESULTS: The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy. CONCLUSIONS: Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures. PMID- 29142100 TI - Abnormal visual gain control and excitotoxicity in early-onset Parkinson's disease Drosophila models. AB - The excitotoxic theory of Parkinson's disease (PD) hypothesizes that a pathophysiological degeneration of dopaminergic neurons stems from neural hyperactivity at early stages of disease, leading to mitochondrial stress and cell death. Recent research has harnessed the visual system of Drosophila PD models to probe this hypothesis. Here, we investigate whether abnormal visual sensitivity and excitotoxicity occur in early-onset PD (EOPD) Drosophila models DJ-1alphaDelta72, DJ-1betaDelta 93, and PINK15. We used an electroretinogram to record steady-state visually evoked potentials driven by temporal contrast stimuli. At 1 day of age, all EOPD mutants had a twofold increase in response amplitudes compared with w controls. Furthermore, we found that excitotoxicity occurs in older EOPD models after increased neural activity is triggered by visual stimulation. In an additional analysis, we used a linear discriminant analysis to test whether there were subtle variations in neural gain control that could be used to classify Drosophila into their correct age and genotype. The discriminant analysis was highly accurate, classifying Drosophila into their correct genotypic class at all age groups at 50-70% accuracy (20% chance baseline). Differences in cellular processes link to subtle alterations in neural network operation in young flies, all of which lead to the same pathogenic outcome. Our data are the first to quantify abnormal gain control and excitotoxicity in EOPD Drosophila mutants. We conclude that EOPD mutations may be linked to more sensitive neuronal signaling in prodromal animals that may cause the expression of PD symptomologies later in life. NEW & NOTEWORTHY Steady-state visually evoked potential response amplitudes to multivariate temporal contrast stimuli were recorded in early-onset PD Drosophila models. Our data indicate that abnormal gain control and a subsequent visual loss occur in these PD mutants, supporting a broader excitotoxicity hypothesis in genetic PD. Furthermore, linear discriminant analysis could accurately classify Drosophila into their correct genotype at different ages throughout their lifespan. Our results suggest increased neural signaling in prodromal PD patients. PMID- 29142101 TI - Loss of ADAM9 expression impairs beta1 integrin endocytosis, focal adhesion formation and cancer cell migration. AB - The transmembrane protease ADAM9 is frequently upregulated in human cancers, and it promotes tumour progression in mice. In vitro, ADAM9 regulates cancer cell adhesion and migration by interacting with integrins. However, how ADAM9 modulates integrin functions is not known. We here show that ADAM9 knockdown increases beta1 integrin levels through mechanisms that are independent of its protease activity. In ADAM9-silenced cells, adhesion to collagen and fibronectin is reduced, suggesting an altered function of the accumulated integrins. Mechanistically, ADAM9 co-immunoprecipitates with beta1 integrin, and both internalization and subsequent degradation of beta1 integrin are significantly decreased in ADAM9-silenced cells, with no effect on beta1 integrin recycling. Accordingly, the formation of focal adhesions and actin stress fibres in ADAM9 silenced cells is altered, possibly explaining the reduction in cell adhesion and migration in these cells. Taken together, our data provide mechanistic insight into the ADAM9-integrin interaction, demonstrating that ADAM9 regulates beta1 integrin endocytosis. Moreover, our findings indicate that the reduced migration of ADAM9-silenced cells is, at least in part, caused by the accumulation and altered activity of beta1 integrin at the cell surface. PMID- 29142102 TI - Prolines in the alpha-helix confer the structural flexibility and functional integrity of importin-beta. AB - The karyopherin family of nuclear transport receptors is composed of a long array of amphiphilic alpha-helices and undergoes flexible conformational changes to pass through the hydrophobic crowding barrier of the nuclear pore. Here, we focused on the characteristic enrichment of prolines in the middle of the outer alpha-helices of importin-beta. When these prolines were substituted with alanine, nuclear transport activity was reduced drastically in vivo and in vitro, and caused a severe defect in mitotic progression. These mutations did not alter the overall folding of the helical repeat or affect its interaction with cargo or the regulatory factor Ran. However, in vitro and in silico analyses revealed that the mutant lost structural flexibility and could not undergo rapid conformational changes when transferring from a hydrophilic to hydrophobic environment or vice versa. These findings reveal the essential roles of prolines in ensuring the structural flexibility and functional integrity of karyopherins. PMID- 29142103 TI - An intracellular activation of Smoothened that is independent of Hedgehog stimulation in Drosophila. AB - Smoothened (Smo), a GPCR family protein, plays a critical role in the reception and transduction of Hedgehog (Hh) signal. Smo is phosphorylated and activated on the cell surface; however, it is unknown whether Smo can be intracellularly activated. Here, we demonstrate that inactivation of the ESCRT-III causes dramatic accumulation of Smo in the ESCRT-III/MVB compartment, and subsequent activation of Hh signaling. In contrast, inactivation of ESCRTs 0-II induces mild Smo accumulation in the ESCRT-III/MVB compartment. We provide evidence that Kurtz (Krz), the Drosophila beta-arrestin2, acts in parallel with the ESCRTs 0-II pathway to sort Smo to the multivesicular bodies and lysosome-mediated degradation. Additionally, upon inactivation of ESCRT-III, all active and inactive forms of Smo are accumulated. Endogenous Smo accumulated upon ESCRT-III inactivation is highly activated, which is induced by phosphorylation but not sumoylation. Taken together, our findings demonstrate a model for intracellular activation of Smo, raising the possibility for tissue overgrowth caused by an excessive amount, rather than mutation of Smo. PMID- 29142104 TI - Constraints on lateral gene transfer in promoting fimbrial usher protein diversity and function. AB - Fimbriae are long, adhesive structures widespread throughout members of the family Enterobacteriaceae. They are multimeric extrusions, which are moved out of the bacterial cell through an integral outer membrane protein called usher. The complex folding mechanics of the usher protein were recently revealed to be catalysed by the membrane-embedded translocation and assembly module (TAM). Here, we examine the diversity of usher proteins across a wide range of extraintestinal (ExPEC) and enteropathogenic (EPEC) Escherichia coli, and further focus on a so far undescribed chaperone-usher system, with this usher referred to as UshC. The fimbrial system containing UshC is distributed across a discrete set of EPEC types, including model strains like E2348/67, as well as ExPEC ST131, currently the most prominent multi-drug-resistant uropathogenic E. coli strain worldwide. Deletion of the TAM from a naive strain of E. coli results in a drastic time delay in folding of UshC, which can be observed for a protein from EPEC as well as for two introduced proteins from related organisms, Yersinia and Enterobacter We suggest that this models why the TAM machinery is essential for efficient folding of proteins acquired via lateral gene transfer. PMID- 29142105 TI - The NDE1 genomic locus can affect treatment of psychiatric illness through gene expression changes related to microRNA-484. AB - Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes, DISC1, NDE1, NDEL1, PDE4B and PDE4D, the 'DISC1 network'. Here, we use gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, while prescription medication information has been collected over a 10-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2908 probes (2542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p = 3.0 * 10-8), located on a non-coding exon of NDE1 Variants within the NDE1 locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression of CYP2C19 in a cell culture system. Thus, variation at the NDE1 locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment. PMID- 29142106 TI - Soluble Abeta aggregates can inhibit prion propagation. AB - Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrPC). Ligands that bind to PrPC can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid beta-protein (Abeta) can tightly bind to PrPC, and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Abeta assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Abeta preparations, we found that the form of Abeta assemblies which most avidly bound to PrP in vitro also inhibited prion infection and propagation. By contrast, forms of Abeta which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Abeta can compete with prions for binding to PrPC and emphasize the bidirectional nature of the interplay between Abeta and PrPC in Alzheimer's and prion diseases. Such inhibitory effects of Abeta on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Abeta deposition is common. PMID- 29142107 TI - Is inflammatory micronucleation the key to a successful anti-mitotic cancer drug? AB - Paclitaxel is a successful anti-cancer drug that kills cancer cells in two dimensional culture through perturbation of mitosis, but whether it causes tumour regression by anti-mitotic actions is controversial. Drug candidates that specifically target mitosis, including inhibitors of kinesin-5, AurkA, AurkB and Plk1, disappointed in the clinic. Current explanations for this discrepancy include pharmacokinetic differences and hypothetical interphase actions of paclitaxel. Here, we discuss post-mitotic micronucleation as a special activity of taxanes that might explain their higher activity in solid tumours. We review data showing that cells which exit mitosis in paclitaxel are highly micronucleated and suffer post-mitotic DNA damage, and that these effects are much stronger for paclitaxel than kinesin-5 inhibitors. We propose that post mitotic micronucleation promotes inflammatory signalling via cGAS-STING and other pathways. In tumours, this signalling may recruit cytotoxic leucocytes, damage blood vessels and prime T-cell responses, leading to whole-tumour regression. We discuss experiments that are needed to test the micronucleation hypothesis, and its implications for novel anti-mitotic targets and enhancement of taxane-based therapies. PMID- 29142108 TI - Growth and size control during development. AB - The size and shape of organs are characteristic for each species. Even when organisms develop to different sizes due to varying environmental conditions, such as nutrition, organ size follows species-specific rules of proportionality to the rest of the body, a phenomenon referred to as allometry. Therefore, for a given environment, organs stop growth at a predictable size set by the species's genotype. How do organs stop growth? How can related species give rise to organs of strikingly different size? No definitive answer has been given to date. One of the major models for the studies of growth termination is the vinegar fly Drosophila melanogaster. Therefore, this review will focus mostly on work carried out in Drosophila to try to tease apart potential mechanisms and identify routes for further investigation. One general rule, found across the animal kingdom, is that the rate of growth declines with developmental time. Therefore, answers to the problem of growth termination should explain this seemingly universal fact. In addition, growth termination is intimately related to the problems of robustness (i.e. precision) and plasticity in organ size, symmetric and asymmetric organ development, and of how the 'target' size depends on extrinsic, environmental factors. PMID- 29142110 TI - Global reef fish richness gradients emerge from divergent and scale-dependent component changes. AB - Biodiversity varies from place to place due to environmental and historical factors. To improve our understanding of how history and the environment influence observed patterns, we need to address the limitations of the most commonly used biodiversity metric, species richness. Here, we show that scale dependent dissections of species richness into components of total abundance, species relative abundances and spatial aggregations of species reveal that two well-known biogeographic reef fish species richness gradients emerge from very different underlying component patterns. Latitudinal richness is underpinned by scale-independent patterns of total and relative abundances, suggesting ecological constraints scale up to determine abundances within communities. In contrast, the longitudinal gradient of species richness typically attributed to historical biogeography only emerges at the largest scale and is accompanied by a similar pattern of relative abundances, suggesting that site-to-site compositional variation leading to species aggregation (i.e. a component of beta diversity) underlies this gradient. Examining relationships among the components that underpin biodiversity gradients reveals new patterns that can better identify processes influencing patterns of biodiversity. PMID- 29142109 TI - The Ndc80 complex targets Bod1 to human mitotic kinetochores. AB - Regulation of protein phosphatase activity by endogenous protein inhibitors is an important mechanism to control protein phosphorylation in cells. We recently identified Biorientation defective 1 (Bod1) as a small protein inhibitor of protein phosphatase 2A containing the B56 regulatory subunit (PP2A-B56). This phosphatase controls the amount of phosphorylation of several kinetochore proteins and thus the establishment of load-bearing chromosome-spindle attachments in time for accurate separation of sister chromatids in mitosis. Like PP2A-B56, Bod1 directly localizes to mitotic kinetochores and is required for correct segregation of mitotic chromosomes. In this report, we have probed the spatio-temporal regulation of Bod1 during mitotic progression. Kinetochore localization of Bod1 increases from nuclear envelope breakdown until metaphase. Phosphorylation of Bod1 at threonine 95 (T95), which increases Bod1's binding to and inhibition of PP2A-B56, peaks in prometaphase when PP2A-B56 localization to kinetochores is highest. We demonstrate here that kinetochore targeting of Bod1 depends on the outer kinetochore protein Ndc80 and not PP2A-B56. Crucially, Bod1 depletion functionally affects Ndc80 phosphorylation at the N-terminal serine 55 (S55), as well as a number of other phosphorylation sites within the outer kinetochore, including Knl1 at serine 24 and 60 (S24, S60), and threonine T943 and T1155 (T943, T1155). Therefore, Ndc80 recruits a phosphatase inhibitor to kinetochores which directly feeds forward to regulate Ndc80, and Knl1 phosphorylation, including sites that mediate the attachment of microtubules to kinetochores. PMID- 29142111 TI - Can birds do it too? Evidence for convergence in evaporative water loss regulation for birds and mammals. AB - Birds have many physiological characteristics that are convergent with mammals. In the light of recent evidence that mammals can maintain a constant insensible evaporative water loss (EWL) over a range of perturbing environmental conditions, we hypothesized that birds might also regulate insensible EWL, reflecting this convergence. We found that budgerigars (Melopsittacus undulatus) maintain EWL constant over a range of relative humidities at three ambient temperatures. EWL, expressed as a function of water vapour pressure deficit, differed from a physical model where the water vapour pressure deficit between the animal and the ambient air is the driver of evaporation, indicating physiological control of EWL. Regulating EWL avoids thermoregulatory impacts of varied evaporative heat loss; changes in relative humidity had no effect on body temperature, metabolic rate or thermal conductance. Our findings that a small bird can regulate EWL are evidence that this is a common feature of convergently endothermic birds and mammals, and may therefore be a fundamental characteristic of endothermy. PMID- 29142112 TI - Give one species the task to come up with a theory that spans them all: what good can come out of that? AB - Does the progress in understanding evolutionary theory depend on the species that is doing the investigation? This question is difficult to answer scientifically, as we are dealing with an n = 1 scenario: every individual who has ever written about evolution is a human being. I will discuss, first, whether we get the correct answer to questions if we begin with ourselves and expand outwards, and second, whether we might fail to ask all the interesting questions unless we combat our tendencies to favour taxa that are close to us. As a whole, the human tendency to understand general biological phenomena via 'putting oneself in another organism's shoes' has upsides and downsides. As an upside, our intuitive ability to rethink strategies if the situation changes can lead to ready generation of adaptive hypotheses. Downsides occur if we trust this intuition too much, and particular danger zones exist for traits where humans are an unusual species. I argue that the levels of selection debate might have proceeded differently if human cooperation patterns were not so unique, as this brings about unique challenges in biology teaching; and that theoretical insights regarding inbreeding avoidance versus tolerance could have spread faster if we were not extrapolating our emotional reactions to incest disproportionately depending on whether we study animals or plants. I also discuss patterns such as taxonomic chauvinism, i.e. less attention being paid to species that differ more from human-like life histories. Textbooks on evolution reinforce such biases insofar as they present, as a default case, systems that resemble ours in terms of life cycles and other features (e.g. gonochorism). Additionally, societal norms may have led to incorrect null hypotheses such as females not mating multiply. PMID- 29142113 TI - Chromatic and achromatic monocular deprivation produce separable changes of eye dominance in adults. AB - Temporarily depriving one eye of its input, in whole or in part, results in a transient shift in eye dominance in human adults, with the patched eye becoming stronger and the unpatched eye weaker. However, little is known about the role of colour contrast in these behavioural changes. Here, we first show that the changes in eye dominance and contrast sensitivity induced by monocular eye patching affect colour and achromatic contrast sensitivity equally. We next use dichoptic movies, customized and filtered to stimulate the two eyes differentially. We show that a strong imbalance in achromatic contrast between the eyes, with no colour content, also produces similar, unselective shifts in eye dominance for both colour and achromatic contrast sensitivity. Interestingly, if this achromatic imbalance is paired with similar colour contrast in both eyes, the shift in eye dominance is selective, affecting achromatic but not chromatic contrast sensitivity and revealing a dissociation in eye dominance for colour and achromatic image content. On the other hand, a strong imbalance in chromatic contrast between the eyes, with no achromatic content, produces small, unselective changes in eye dominance, but if paired with similar achromatic contrast in both eyes, no changes occur. We conclude that perceptual changes in eye dominance are strongly driven by interocular imbalances in achromatic contrast, with colour contrast having a significant counter balancing effect. In the short term, eyes can have different dominances for achromatic and chromatic contrast, suggesting separate pathways at the site of these neuroplastic changes. PMID- 29142114 TI - Female vervet monkeys fine-tune decisions on tolerance versus conflict in a communication network. AB - Group living promotes opportunities for both cooperation and competition. Selection on the ability to cope with such opposing social opportunities has been proposed as a driving force in the evolution of large brains in primates and other social species. However, we still know little about the degree of complexity involved in such social strategies. Here, we report advanced social strategies in wild vervet monkeys. Building on recent experimental evidence that subordinate females trade grooming for tolerance from higher-ranking individuals during foraging activities, we show that the audience composition strongly affects this trade. First, tolerance was lower if the audience contained individuals that outranked the subordinate partner, independently of audience size and kinship relationships. Second, we found a significant interaction between previous grooming and relative rank of bystanders: dominant subjects valued recent grooming by subordinates while intermediate ranked subjects valued the option to aggress subordinate partners in the presence of a dominant audience. Aggressors were also more likely to emit coalition recruitment calls if the audience contained individuals that outranked the subordinate partner. In conclusion, vervet monkeys include both recent grooming and knowledge about third party relationships to make complex decisions when trading grooming for tolerance, leading to a finely balanced trade-off between reciprocation and opportunities to reinforce rank relationships. PMID- 29142115 TI - Males harm females less when competing with familiar relatives. AB - Sexual conflict occurs when reproductive partners have different fitness optima, and can lead to the evolution of traits in one sex that inflict fitness costs on the opposite sex. Recently, it has been proposed that antagonism by males towards females should be reduced when they compete with relatives, because reducing the future productivity of a female would result in an indirect fitness cost for a harmful male. We tested this prediction in the seed beetle Callosobruchus maculatus, the males of which harm females with genital spines and pre-copulatory harassment. We compared lifespan, lifetime egg production and lifetime offspring production among females housed with groups of males that varied in their familiarity and relatedness. Females produced significantly more eggs and offspring when grouped with males who were both related and familiar to each other. There was no effect of male relatedness or familiarity on female lifespan. Our results suggest that males plastically adjust their harmfulness towards females in response to changes in inclusive fitness payoffs, and that in this species both genetic relatedness and social familiarity mediate this effect. PMID- 29142116 TI - Indirectly connected: simple social differences can explain the causes and apparent consequences of complex social network positions. AB - Animal societies are often structurally complex. How individuals are positioned within the wider social network (i.e. their indirect social connections) has been shown to be repeatable, heritable and related to key life-history variables. Yet, there remains a general lack of understanding surrounding how complex network positions arise, whether they indicate active multifaceted social decisions by individuals, and how natural selection could act on this variation. We use simulations to assess how variation in simple social association rules between individuals can determine their positions within emerging social networks. Our results show that metrics of individuals' indirect connections can be more strongly related to underlying simple social differences than metrics of their dyadic connections. External influences causing network noise (typical of animal social networks) generally inflated these differences. The findings demonstrate that relationships between complex network positions and other behaviours or fitness components do not provide sufficient evidence for the presence, or importance, of complex social behaviours, even if direct network metrics provide less explanatory power than indirect ones. Interestingly however, a plausible and straightforward heritable basis for complex network positions can arise from simple social differences, which in turn creates potential for selection to act on indirect connections. PMID- 29142117 TI - Long necks enhance and constrain foraging capacity in aquatic vertebrates. AB - Highly specialized diving birds display substantial dichotomy in neck length with, for example, cormorants and anhingas having extreme necks, while penguins and auks have minimized necks. We attached acceleration loggers to Imperial cormorants Phalacrocorax atriceps and Magellanic penguins Spheniscus magellanicus, both foraging in waters over the Patagonian Shelf, to examine the difference in movement between their respective heads and bodies in an attempt to explain this dichotomy. The penguins had head and body attitudes and movements that broadly concurred throughout all phases of their dives. By contrast, although the cormorants followed this pattern during the descent and ascent phases of dives, during the bottom (foraging) phase of the dive, the head angle differed widely from that of the body and its dynamism (measured using vectorial dynamic acceleration) was over four times greater. A simple model indicated that having the head on an extended neck would allow these cormorants to half the energy expenditure that they would expend if their body moved in the way their heads did. This apparently energy-saving solution is likely to lead to greater heat loss though and would seem tenable in slow-swimming species because the loss of streamlining that it engenders would make it detrimental for fast-swimming taxa such as penguins. PMID- 29142118 TI - Climate and foraging mode explain interspecific variation in snake metabolic rates. AB - The energy cost of self-maintenance is a critical facet of life-history strategies. Clarifying the determinant of interspecific variation in metabolic rate (MR) at rest is important to understand and predict ecological patterns such as species distributions or responses to climatic changes. We examined variation of MR in snakes, a group characterized by a remarkable diversity of activity rates and a wide distribution. We collated previously published MR data (n = 491 observations) measured in 90 snake species at different trial temperatures. We tested for the effects of metabolic state (standard MR (SMR) versus resting MR (RMR)), foraging mode (active versus ambush foragers) and climate (temperature and precipitation) while accounting for non-independence owing to phylogeny, body mass and thermal dependence. We found that RMR was 40% higher than SMR, and that active foragers have higher MR than species that ambush their prey. We found that MR was higher in cold environments, supporting the metabolic cold adaptation hypothesis. We also found an additive and positive effect of precipitation on MR suggesting that lower MR in arid environments may decrease dehydration and energetic costs. Altogether, our findings underline the complex influences of climate and foraging mode on MR and emphasize the relevance of these facets to understand the physiological impact of climate change. PMID- 29142120 TI - The Role of DNA Polymerase beta in Neural Genome Stability. PMID- 29142119 TI - Landscape predictors of pathogen prevalence and range contractions in US bumblebees. AB - Several species of bumblebees have recently experienced range contractions and possible extinctions. While threats to bees are numerous, few analyses have attempted to understand the relative importance of multiple stressors. Such analyses are critical for prioritizing conservation strategies. Here, we describe a landscape analysis of factors predicted to cause bumblebee declines in the USA. We quantified 24 habitat, land-use and pesticide usage variables across 284 sampling locations, assessing which variables predicted pathogen prevalence and range contractions via machine learning model selection techniques. We found that greater usage of the fungicide chlorothalonil was the best predictor of pathogen (Nosema bombi) prevalence in four declining species of bumblebees. Nosema bombi has previously been found in greater prevalence in some declining US bumblebee species compared to stable species. Greater usage of total fungicides was the strongest predictor of range contractions in declining species, with bumblebees in the northern USA experiencing greater likelihood of loss from previously occupied areas. These results extend several recent laboratory and semi-field studies that have found surprising links between fungicide exposure and bee health. Specifically, our data suggest landscape-scale connections between fungicide usage, pathogen prevalence and declines of threatened and endangered bumblebees. PMID- 29142121 TI - The Role of Kappa Opioid Receptors in Glutamate Input Selection in the Ventral Striatum. PMID- 29142123 TI - Initiation, elongation and realignment during influenza virus mRNA synthesis. AB - The RNA-dependent RNA polymerase (RdRp) of the influenza A virus replicates and transcribes the viral genome segments in the nucleus of the host cell. To transcribe these viral genome segments, the RdRp 'snatches' capped RNA oligonucleotides from nascent host cell mRNAs and aligns these primers to the ultimate or penultimate nucleotide of the segments for the initiation of viral mRNA synthesis. It has been proposed that this initiation process is not processive and that the RdRp uses a prime-realign mechanism during transcription. Here we provide in vitro evidence for the existence of this transcriptional prime realign mechanism, but show that it only functions efficiently for primers that are short or can not stably base pair with the template. In addition, we demonstrate that transcriptional elongation is dependent on the priming loop of the PB1 subunit of the RdRp. We propose that the prime-realign mechanism may be used to rescue abortive transcription initiation events or cope with sequence variation among primers. Overall, these observations advance our mechanistic understanding of how the influenza A virus initiates transcription correctly and efficiently.ImportanceThe influenza A virus causes severe disease in humans and is considered a major global health threat. The virus replicates and transcribes its genome using an enzyme called the RNA polymerase. To ensure that the genome is amplified faithfully and abundant viral mRNAs are made for viral protein synthesis, the viral RNA polymerase must transcribe the viral genome efficiently. In this report, we characterise a structure inside the polymerase that contributes to the efficiency of viral mRNA synthesis. PMID- 29142122 TI - Adaptive Immune Responses following Senecavirus A Infection in Pigs. AB - Senecavirus A (SVA), an emerging picornavirus of swine, causes vesicular disease (VD) that is clinically indistinguishable from foot-and-mouth disease (FMD) in pigs. Many aspects of SVA interactions with the host and the host immune responses to infection, however, remain unknown. In the present study, humoral and cellular immune responses to SVA were evaluated following infection in pigs. We show that SVA infection elicited an early and robust virus-neutralizing (VN) antibody response, which coincided and was strongly correlated with VP2- and VP3 specific IgM responses. Notably, the neutralizing antibody (NA) responses paralleled the reduction of viremia and resolution of the disease. Analysis of the major porcine T-cell subsets revealed that during the acute/clinical phase of SVA infection (14 days postinfection [p.i.]), T-cell responses were characterized by an increased frequency of alphabeta T cells, especially CD4+ T cells, which were first detected by day 7 p.i. and increased in frequency until day 14 p.i. Additionally, the frequency of CD8+ and double-positive CD4+ CD8+ T cells (effector/memory T cells) expressing interferon gamma (IFN-gamma) or proliferating in response to SVA antigen stimulation increased after day 10 p.i. Results presented here show that SVA elicits B- and T-cell activation early upon infection, with IgM antibody levels being correlated with early neutralizing activity against the virus and peak B- and T-cell responses paralleling clinical resolution of the disease. The work provides important insights into the immunological events that follow SVA infection in the natural host.IMPORTANCE Senecavirus A (SVA) has recently emerged in swine, causing outbreaks of vesicular disease (VD) in major swine-producing countries around the world, including the United States, Brazil, China, Thailand, and Colombia. Notably, SVA-induced disease is clinically indistinguishable from other high-consequence VDs of swine, such as FMD, swine vesicular disease, vesicular stomatitis, and vesicular exanthema of swine. Despite the clinical relevance of SVA-induced VD, many aspects of the virus infection biology remain unknown. Here, we assessed host immune responses to SVA infection. The results show that SVA infection elicits early B- and T-cell responses, with the levels of VN antibody and CD4+ T-cell responses paralleling the reduction of viremia and resolution of the disease. SVA specific CD8+ T cells are detected later during infection. A better understanding of SVA interactions with the host immune system may allow the design and implementation of improved control strategies for this important pathogen of swine. PMID- 29142124 TI - Truncating the gp41 Cytoplasmic Tail of Simian Immunodeficiency Virus Decreases Sensitivity to Neutralizing Antibodies without Increasing the Envelope Content of Virions. AB - An incomplete understanding of native human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) envelope glycoproteins (Envs) impedes the development of structural models of Env and vaccine design. This shortcoming is due in part to the low number of Env trimers on virus particles. For SIV, this low expression level can be counteracted by truncating the cytoplasmic tail (CT) of Env. CT truncation has been shown to increase Env incorporation into the virion and is commonly used in vaccine and imaging studies, but its effects on viral antigenicity have not been fully elucidated. To study the effects of a CT truncation of Env in viruses in similar genetic contexts, we introduced stop codons into the CT of a SIVsmE660 molecular clone and two neutralizing antibody (NAb) escape variants. These viruses shared 98% sequence identity in Env but were characterized as either tier 1 (sensitive to neutralization), tier 2 (moderately resistant to neutralization), or tier 3 (resistant to neutralization). However, the introduction of premature stop codons in Env at position Q741/Q742 converted all three transfection-derived viruses to a tier 3-like phenotype, and these viruses were uniformly resistant to neutralization by sera from infected macaques and monoclonal antibodies (MAbs). These changes in neutralization sensitivity were not accompanied by an increase in either the virion Env content of infection derived viruses or the infectivity of transfection-derived viruses in human cells, suggesting that CT mutations may result in global changes to the Env conformation. Our results demonstrate that some CT truncations can affect viral antigenicity and, as such, may not be suitable surrogate models of native HIV/SIV Env.IMPORTANCE Modifications to the SIV envelope protein (Env) are commonly used in structural and vaccine studies to stabilize and increase the expression of Env, often without consideration of effects on antigenicity. One such widespread modification is the truncation of the Env C-terminal tail. Here, we studied the effects of a particular cytoplasmic tail truncation in three SIVsm strains that have highly similar Env sequences but exhibit different sensitivities to neutralizing antibodies. After truncation of the Env CT, these viruses were all very resistant to neutralization by sera from infected macaques and monoclonal antibodies. The viruses with a truncated Env CT also did not exhibit the desired and typical increase in Env expression. These results underscore the importance of carefully evaluating the use of truncated Env as a model in HIV/SIV vaccine and imaging studies and of the continued need to find better models of native Env that contain fewer modifications. PMID- 29142125 TI - Emergence of Double- and Triple-Gene Reassortant G1P[8] Rotaviruses Possessing a DS-1-Like Backbone after Rotavirus Vaccine Introduction in Malawi. AB - To combat the high burden of rotavirus gastroenteritis, multiple African countries have introduced rotavirus vaccines into their childhood immunization programs. Malawi incorporated a G1P[8] rotavirus vaccine (Rotarix) into its immunization schedule in 2012. Utilizing a surveillance platform of hospitalized rotavirus gastroenteritis cases, we examined the phylodynamics of G1P[8] rotavirus strains that circulated in Malawi before (1998 to 2012) and after (2013 to 2014) vaccine introduction. Analysis of whole genomes obtained through next generation sequencing revealed that all randomly selected prevaccine G1P[8] strains sequenced (n = 32) possessed a Wa-like genetic constellation, whereas postvaccine G1P[8] strains (n = 18) had a DS-1-like constellation. Phylodynamic analyses indicated that postvaccine G1P[8] strains emerged through reassortment events between human Wa- and DS-1-like rotaviruses that circulated in Malawi from the 1990s and hence were classified as atypical DS-1-like reassortants. The time to the most recent common ancestor for G1P[8] strains was from 1981 to 1994; their evolutionary rates ranged from 9.7 * 10-4 to 4.1 * 10-3 nucleotide substitutions/site/year. Three distinct G1P[8] lineages chronologically replaced each other between 1998 and 2014. Genetic drift was the likely driver for lineage turnover in 2005, whereas replacement in 2013 was due to reassortment. Amino acid substitution within the outer glycoprotein VP7 of G1P[8] strains had no impact on the structural conformation of the antigenic regions, suggesting that it is unlikely that they would affect recognition by vaccine-induced neutralizing antibodies. While the emergence of DS-1-like G1P[8] rotavirus reassortants in Malawi was therefore likely due to natural genotype variation, vaccine effectiveness against such strains needs careful evaluation.IMPORTANCE The error prone RNA-dependent RNA polymerase and the segmented RNA genome predispose rotaviruses to genetic mutation and genome reassortment, respectively. These evolutionary mechanisms generate novel strains and have the potential to lead to the emergence of vaccine escape mutants. While multiple African countries have introduced a rotavirus vaccine, there are few data describing the evolution of rotaviruses that circulated before and after vaccine introduction. We report the emergence of atypical DS-1-like G1P[8] strains during the postvaccine era in Malawi. Three distinct G1P[8] lineages circulated chronologically from 1998 to 2014; mutation and reassortment drove lineage turnover in 2005 and 2013, respectively. Amino acid substitutions within the outer capsid VP7 glycoprotein did not affect the structural conformation of mapped antigenic sites, suggesting a limited effect on the recognition of G1-specific vaccine-derived antibodies. The genes that constitute the remaining genetic backbone may play important roles in immune evasion, and vaccine effectiveness against such atypical strains needs careful evaluation. PMID- 29142126 TI - Human Papillomavirus Replication Regulation by Acetylation of a Conserved Lysine in the E2 Protein. AB - The papillomavirus (PV) E2 protein is a sequence-specific DNA binding protein that recruits cellular factors to its genome in infected epithelial cells. E2 also binds to and loads the viral E1 DNA helicase at the origin of replication. Posttranslational modifications (PTMs) of PV E2 have been identified as potential regulators of E2 functions. We recently reported lysine 111 (K111) as a target of p300 acetylation in bovine PV (BPV). The di-lysines at 111 and 112 are conserved in almost all papillomaviruses. We pursued a mutational approach to query the functional significance of lysine in human PV (HPV) E2. Amino acid substitutions that prevent acetylation, including arginine, were unable to stimulate transcription and E1-mediated DNA replication. The arginine K111 mutant retained E2 transcriptional repression, nuclear localization, DNA and chromatin binding, and association with E2 binding partners involved in PV transcription and replication. While the replication-defective E2-K111R mutant recruited E1 to the viral replication origin, surprisingly, unwinding of the duplex DNA did not occur. In contrast, the K111 glutamine (K111Q) mutant increased origin melting and stimulated replication compared to wild-type E2. These experiments reveal a novel activity of E2 necessary for denaturing the viral origin that likely depends on acetylation of highly conserved lysine 111.IMPORTANCE HPV is one of the most common sexually transmitted infections in the United States. Over 200 HPVs have been described, and they manifest in a variety of ways; they can be asymptomatic or can result in benign lesions (papillomas) or progress to malignancy. Although 90% of infections are asymptomatic and resolve easily, HPV16 and -18 alone are responsible for 70% of all cervical cancers, which are almost entirely caused by HPV infection. Interestingly, 60 to 90% of other cancers have been linked to HPV. The goal of this research is to further elucidate the mechanisms that regulate and mediate viral replication. PMID- 29142127 TI - Epstein-Barr Virus Protein EB2 Stimulates Translation Initiation of mRNAs through Direct Interactions with both Poly(A)-Binding Protein and Eukaryotic Initiation Factor 4G. AB - Epstein-Barr virus (EBV) expresses several mRNAs produced from intronless genes that could potentially be unfavorably translated compared to cellular spliced mRNAs. To overcome this situation, the virus encodes an RNA-binding protein (RBP) called EB2, which was previously found to both facilitate the export of nuclear mRNAs and increase their translational yield. Here, we show that EB2 binds both nuclear and cytoplasmic cap-binding complexes (CBC and eukaryotic initiation factor 4F [eIF4F], respectively) as well as the poly(A)-binding protein (PABP) to enhance translation initiation of a given messenger ribonucleoparticle (mRNP). Interestingly, such an effect can be obtained only if EB2 is initially bound to the native mRNPs in the nucleus. We also demonstrate that the EB2-eIF4F-PABP association renders translation of these mRNPs less sensitive to translation initiation inhibitors. Taken together, our data suggest that EB2 binds and stabilizes cap-binding complexes in order to increase mRNP translation and furthermore demonstrate the importance of the mRNP assembly process in the nucleus to promote protein synthesis in the cytoplasm.IMPORTANCE Most herpesvirus early and late genes are devoid of introns. However, it is now well documented that mRNA splicing facilitates recruitment on the mRNAs of cellular factors involved in nuclear mRNA export and translation efficiency. To overcome the absence of splicing of herpesvirus mRNAs, a viral protein, EB2 in the case of Epstein-Barr virus, is produced to facilitate the cytoplasmic accumulation of viral mRNAs. Although we previously showed that EB2 also specifically enhances translation of its target mRNAs, the mechanism was unknown. Here, we show that EB2 first is recruited to the mRNA cap structure in the nucleus and then interacts with the proteins eIF4G and PABP to enhance the initiation step of translation. PMID- 29142128 TI - Interaction between a Unique Minor Protein and a Major Capsid Protein of Bluetongue Virus Controls Virus Infectivity. AB - Among the Reoviridae family of double-stranded RNA viruses, only members of the Orbivirus genus possess a unique structural protein, termed VP6, within their particles. Bluetongue virus (BTV), an important livestock pathogen, is the prototype Orbivirus BTV VP6 is an ATP-dependent RNA helicase, and it is indispensable for virus replication. In the study described in this report, we investigated how VP6 might be recruited to the virus capsid and whether the BTV structural protein VP3, which forms the internal layer of the virus capsid core, is involved in VP6 recruitment. We first demonstrated that VP6 interacts with VP3 and colocalizes with VP3 during capsid assembly. A series of VP6 mutants was then generated, and in combination with immunoprecipitation and size exclusion chromatographic analyses, we demonstrated that VP6 directly interacts with VP3 via a specific region of the C-terminal portion of VP6. Finally, using our reverse genetics system, mutant VP6 proteins were introduced into the BTV genome and interactions between VP6 and VP3 were shown in a live cell system. We demonstrate that BTV strains possessing a mutant VP6 are replication deficient in wild-type BSR cells and fail to recruit the viral replicase complex into the virus particle core. Taken together, these data suggest that the interaction between VP3 and VP6 could be important in the packaging of the viral genome and early stages of particle formation.IMPORTANCE The orbivirus bluetongue virus (BTV) is the causative agent of bluetongue disease of livestock, often causing significant economic and agricultural impacts in the livestock industry. In the study described in this report, we identified the essential region and residues of the unique orbivirus capsid protein VP6 which are responsible for its interaction with other BTV proteins and its subsequent recruitment into the virus particle. The nature and mechanism of these interactions suggest that VP6 has a key role in packaging of the BTV genome into the virus particle. As such, this is a highly significant finding, as this new understanding of BTV assembly could be exploited to design novel vaccines and antivirals against bluetongue disease. PMID- 29142129 TI - Entry of Human Coronavirus NL63 into the Cell. AB - The first steps of human coronavirus NL63 (HCoV-NL63) infection were previously described. The virus binds to target cells by use of heparan sulfate proteoglycans and interacts with the ACE2 protein. Subsequent events, including virus internalization and trafficking, remain to be elucidated. In this study, we mapped the process of HCoV-NL63 entry into the LLC-Mk2 cell line and ex vivo three-dimensional (3D) tracheobronchial tissue. Using a variety of techniques, we have shown that HCoV-NL63 virions require endocytosis for successful entry into the LLC-MK2 cells, and interaction between the virus and the ACE2 molecule triggers recruitment of clathrin. Subsequent vesicle scission by dynamin results in virus internalization, and the newly formed vesicle passes the actin cortex, which requires active cytoskeleton rearrangement. Finally, acidification of the endosomal microenvironment is required for successful fusion and release of the viral genome into the cytoplasm. For 3D tracheobronchial tissue cultures, we also observed that the virus enters the cell by clathrin-mediated endocytosis, but we obtained results suggesting that this pathway may be bypassed.IMPORTANCE Available data on coronavirus entry frequently originate from studies employing immortalized cell lines or undifferentiated cells. Here, using the most advanced 3D tissue culture system mimicking the epithelium of conductive airways, we systematically mapped HCoV-NL63 entry into susceptible cells. The data obtained allow for a better understanding of the infection process and may support development of novel treatment strategies. PMID- 29142130 TI - Effective Priming of Herpes Simplex Virus-Specific CD8+ T Cells In Vivo Does Not Require Infected Dendritic Cells. AB - Resolution of virus infections depends on the priming of virus-specific CD8+ T cells by dendritic cells (DC). While this process requires major histocompatibility complex (MHC) class I-restricted antigen presentation by DC, the relative contribution to CD8+ T cell priming by infected DC is less clear. We have addressed this question in the context of a peripheral infection with herpes simplex virus 1 (HSV). Assessing the endogenous, polyclonal HSV-specific CD8+ T cell response, we found that effective in vivo T cell priming depended on the presence of DC subsets specialized in cross-presentation, while Langerhans cells and plasmacytoid DC were dispensable. Utilizing a novel mouse model that allows for the in vivo elimination of infected DC, we also demonstrated in vivo that this requirement for cross-presenting DC was not related to their infection but instead reflected their capacity to cross-present HSV-derived antigen. Taking the results together, this study shows that infected DC are not required for effective CD8+ T cell priming during a peripheral virus infection.IMPORTANCE The ability of some DC to present viral antigen to CD8+ T cells without being infected is thought to enable the host to induce killer T cells even when viruses evade or kill infected DC. However, direct experimental in vivo proof for this notion has remained elusive. The work described in this study characterizes the role that different DC play in the induction of virus-specific killer T cell responses and, critically, introduces a novel mouse model that allows for the selective elimination of infected DC in vivo Our finding that HSV-specific CD8+ T cells can be fully primed in the absence of DC infection shows that cross presentation by DC is indeed sufficient for effective CD8+ T cell priming during a peripheral virus infection. PMID- 29142131 TI - Single Dose Trivalent Vesiculovax Vaccine Protects Macaques from Lethal Ebolavirus and Marburgvirus Challenge. AB - Previous studies demonstrated that a single intramuscular (IM) dose of an attenuated vesicular stomatitis virus vector (VesiculovaxTM, rVSV-N4CT1) expressing the glycoprotein (GP) from the Mayinga strain of Zaire ebolavirus (EBOV) protected nonhuman primates (NHP) from lethal challenge with EBOV Kikwit and Makona strains. Here we studied the immunogenicity of an expanded range of attenuated rVSV vectors expressing filovirus GP in mice. Based on data from those studies an optimal attenuated tri-valent rVSV vector formulation was identified which included rVSV vectors expressing EBOV, Sudan ebolavirus (SUDV) or Angola strain of Marburg marburgvirus (MARV) GPs. NHPs were then vaccinated with a single dose of the tri-valent formulation, followed by lethal challenge 28 days later with each of the three corresponding filoviruses. At day 14 post vaccination, a serum IgG response specific for all three GPs was detected in all vaccinated macaques. A modest and balanced cell-mediated immune response specific for each GP protein was also detected in a majority of vaccinated macaques. No matter the level of total GP-specific immune response detected post vaccination, all vaccinated macaques were protected from disease and death following lethal challenge with each of the three filoviruses. These findings indicate that vaccination with a single dose of attenuated rVSV-N4CT1 vectors each expressing a single filovirus GP may provide protection against those filoviruses most commonly responsible for outbreaks of hemorrhagic fever in sub-Saharan Africa.IMPORTANCE The West African Ebola Zaire outbreak in 2013 showed that this disease was not only a regional concern, but a worldwide problem and highlighted the need for a safe and efficacious vaccine to be administered to the populace. However, other endemic pathogens like Ebola Sudan and Marburg also pose an important health risk to the public and therefore require development of a vaccine prior to the occurrence of an outbreak. The significance of our research was the development of a blended tri-valent filovirus vaccine that would elicit a balanced immune response when administered as a single dose and provide complete protection against a lethal challenge of all three filovirus pathogens. PMID- 29142132 TI - Identification of a small molecule that compromises the structural integrity of viroplasms and rotavirus double-layered particles. AB - Despite the availability of two attenuated vaccines, rotavirus (RV) gastroenteritis remains an important cause of mortality among children in developing countries causing about 215,000 infant deaths annually. Currently, there are no specific antiviral therapies available. RV is a non-enveloped virus with a segmented double-stranded RNA genome. Viral genome replication and assembly of transcriptionally active double-layered particles (DLPs) take place in cytoplasmic viral structures called viroplasms. In this study, we describe strong impairment of the early stages of RV replication induced by a small molecule known as RNA polymerase III inhibitor, ML-60218 (ML). This compound was found to disrupt already assembled viroplasms and hamper the formation of new ones without the need of de novo transcription of cellular RNAs. This phenotype correlated with reduction in accumulated viral proteins and newly made viral genome segments, disappearance of the hyperphosphorylated isoforms of the viroplasm-resident protein NSP5 and inhibition of infectious progeny virus production. In in vitro transcription assays with purified DLPs, ML showed a dose dependent inhibitory activity indicating the viral nature of its target. ML was found to interfere with the formation of higher order structures of VP6, the protein forming the DLP outer layer, without compromising its ability to trimerize. Electron microscopy of ML-treated DLPs showed a dose-dependent structural damage. Our data suggest that interactions between VP6 trimers are essential not only for DLP stability but also for the structural integrity of viroplasms in infected cells.IMPORTANCE Rotavirus gastroenteritis is responsible for a large number of infant deaths in developing countries. Unfortunately, in those countries where effective vaccines are urgently needed, the efficacy of the available vaccines is particularly low. Therefore, the development of antivirals is an important goal, as they might complement the available vaccines or represent an alternative option. Moreover, they may be decisive in fighting the acute phase of infection. This work describes the inhibitory effect on rotavirus replication of a small molecule initially reported as an RNA polymerase III inhibitor. The molecule is the first chemical compound identified able to disrupt viroplasms, the viral replication machinery, and to compromise the stability of DLPs by targeting the viral protein VP6. This molecule thus represents a starting point towards the development of more potent and less cytotoxic compounds against rotavirus infection. PMID- 29142133 TI - Human Adenovirus Infection Causes Cellular E3 Ubiquitin Ligase MKRN1 Degradation Involving the Viral Core Protein pVII. AB - Human adenoviruses (HAdVs) are common human pathogens encoding a highly abundant histone-like core protein, VII, which is involved in nuclear delivery and protection of viral DNA as well as in sequestering immune danger signals in infected cells. The molecular details of how protein VII acts as a multifunctional protein have remained to a large extent enigmatic. Here we report the identification of several cellular proteins interacting with the precursor pVII protein. We show that the cellular E3 ubiquitin ligase MKRN1 is a novel precursor pVII-interacting protein in HAdV-C5-infected cells. Surprisingly, the endogenous MKRN1 protein underwent proteasomal degradation during the late phase of HAdV-C5 infection in various human cell lines. MKRN1 protein degradation occurred independently of the HAdV E1B55K and E4orf6 proteins. We provide experimental evidence that the precursor pVII protein binding enhances MKRN1 self ubiquitination, whereas the processed mature VII protein is deficient in this function. Based on these data, we propose that the pVII protein binding promotes MKRN1 self-ubiquitination, followed by proteasomal degradation of the MKRN1 protein, in HAdV-C5-infected cells. In addition, we show that measles virus and vesicular stomatitis virus infections reduce the MKRN1 protein accumulation in the recipient cells. Taken together, our results expand the functional repertoire of the HAdV-C5 precursor pVII protein in lytic virus infection and highlight MKRN1 as a potential common target during different virus infections.IMPORTANCE Human adenoviruses (HAdVs) are common pathogens causing a wide range of diseases. To achieve pathogenicity, HAdVs have to counteract a variety of host cell antiviral defense systems, which would otherwise hamper virus replication. In this study, we show that the HAdV-C5 histone-like core protein pVII binds to and promotes self-ubiquitination of a cellular E3 ubiquitin ligase named MKRN1. This mutual interaction between the pVII and MKRN1 proteins may prime MKRN1 for proteasomal degradation, because the MKRN1 protein is efficiently degraded during the late phase of HAdV-C5 infection. Since MKRN1 protein accumulation is also reduced in measles virus- and vesicular stomatitis virus-infected cells, our results signify the general strategy of viruses to target MKRN1. PMID- 29142135 TI - Autographa californica Nucleopolyhedrovirus AC141 (Exon0), a Potential E3 Ubiquitin Ligase, Interacts with Viral Ubiquitin and AC66 To Facilitate Nucleocapsid Egress. AB - During the infection cycle of Autographa californica multiple nucleopolyhedrovirus (AcMNPV), two forms of virions are produced, budded virus (BV) and occlusion-derived virus (ODV). Nucleocapsids that form BV have to egress from the nucleus, whereas nucleocapsids that form ODV remain inside the nucleus. The molecular mechanism that determines whether nucleocapsids remain inside or egress from the nucleus is unknown. AC141 (a predicted E3 ubiquitin ligase) and viral ubiquitin (vUbi) have both been shown to be required for efficient BV production. In this study, it was hypothesized that vUbi interacts with AC141, and in addition, that this interaction was required for BV production. Deletion of both ac141 and vubi restricted viral infection to a single cell, and BV production was completely eliminated. AC141 was ubiquitinated by either vUbi or cellular Ubi, and this interaction was required for optimal BV production. Nucleocapsids in BV, but not ODV, were shown to be specifically ubiquitinated by vUbi, including a 100-kDa protein, as well as high-molecular-weight conjugates. The viral ubiquitinated 100-kDa BV-specific nucleocapsid protein was identified as AC66, which is known to be required for BV production and was shown by coimmunoprecipitation and mass spectrometry to interact with AC141. Confocal microscopy also showed that AC141, AC66, and vUbi interact at the nuclear periphery. These results suggest that ubiquitination of nucleocapsid proteins by vUbi functions as a signal to determine if a nucleocapsid will egress from the nucleus and form BV or remain in the nucleus to form ODV.IMPORTANCE Baculoviruses produce two types of virions called occlusion-derived virus (ODV) and budded virus (BV). ODVs are required for oral infection, whereas BV enables the systemic spread of virus to all host tissues, which is critical for killing insects. One of the important steps for BV production is the export of nucleocapsids out of the nucleus. This study investigated the molecular mechanisms that enable the selection of nucleocapsids for nuclear export instead of being retained within the nucleus, where they would become ODV. Our data show that ubiquitination, a universal cellular process, specifically tags nucleocapsids of BV, but not those found in ODV, using a virus-encoded ubiquitin (vUbi). Therefore, ubiquitination may be the molecular signal that determines if a nucleocapsid is destined to form a BV, thus ensuring lethal infection of the host. PMID- 29142136 TI - Size, Composition, and Evolution of HIV DNA Populations during Early Antiretroviral Therapy and Intensification with Maraviroc. AB - Residual viremia is common during antiretroviral therapy (ART) and could be caused by ongoing low-level virus replication or by release of viral particles from infected cells. ART intensification should impact ongoing viral propagation but not virion release. Eighteen acutely infected men were enrolled in a randomized controlled trial and monitored for a median of 107 weeks. Participants started ART with (n = 9) or without (n = 9) intensification with maraviroc (MVC) within 90 days of infection. Levels of HIV DNA and cell-free RNA were quantified by droplet digital PCR. Deep sequencing of C2-V3 env, gag, and pol (454 Roche) was performed on longitudinally collected plasma and peripheral blood mononuclear cell (PBMC) samples while on ART. Sequence data were analyzed for evidence of evolution by (i) molecular diversity analysis, (ii) nonparametric test for panmixia, and (iii) tip date randomization within a Bayesian framework. There was a longitudinal decay of HIV DNA after initiation of ART with no difference between MVC intensification groups (-0.08 +/- 0.01 versus -0.09 +/- 0.01 log10 copies/week in MVC+ versus MVC- groups; P = 0.62). All participants had low-level residual viremia (median, 2.8 RNA copies/ml). Across participants, medians of 56 (interquartile range [IQR], 36 to 74), 29 (IQR, 25 to 35), and 40 (IQR, 31 to 54) haplotypes were generated for env, gag, and pol regions, respectively. There was no clear evidence of viral evolution during ART and no difference in viral diversity or population structure from individuals with or without MVC intensification. Further efforts focusing on elucidating the mechanism(s) of viral persistence in various compartments using recent sequencing technologies are still needed, and potential low-level viral replication should always be considered in cure strategies.IMPORTANCE Residual viremia is common among HIV infected people on ART. It remains controversial if this viremia is a consequence of propagating infection. We hypothesized that molecular evolution would be detectable during viral propagation and that therapy intensified with the entry inhibitor maraviroc would demonstrate less evolution. We performed a randomized double-blinded treatment trial with 18 acutely infected men (standard ART versus standard ART plus maraviroc). From longitudinally collected blood plasma and cells, levels of HIV DNA and cell-free HIV RNA were quantified by droplet digital PCR, and HIV DNA (env, gag, and pol coding regions) was deep sequenced (454 Roche). Investigating people who started ART during the earliest stages of their HIV infection, when viral diversity is low, provides an opportunity to detect evidence of viral evolution. Despite using a battery of analytical techniques, no clear and consistent evidence of viral propagation for over 90 weeks of observation could be discerned. PMID- 29142134 TI - Tumor Necrosis Factor-Mediated Survival of CD169+ Cells Promotes Immune Activation during Vesicular Stomatitis Virus Infection. AB - Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169+ cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169+ cells during viral infections remain unclear. Here, we show that tumor necrosis factor is produced by CD11b+ Ly6C+ Ly6G+ cells following infection with VSV. The absence of TNF or TNF receptor 1 (TNFR1) resulted in reduced numbers of CD169+ cells and in reduced type I interferon (IFN-I) production during VSV infection, with a severe disease outcome. Specifically, TNF triggered RelA translocation into the nuclei of CD169+ cells; this translocation was inhibited when the paracaspase MALT-1 was absent. Consequently, MALT1 deficiency resulted in reduced VSV replication, defective innate immune activation, and development of severe disease. These findings indicate that TNF mediates the maintenance of CD169+ cells and innate and adaptive immune activation during VSV infection.IMPORTANCE Over the last decade, strategically placed CD169+ metallophilic macrophages in the marginal zone of the murine spleen and lymph nodes (LN) have been shown to play a very important role in host defense against viral pathogens. CD169+ macrophages have been shown to activate innate and adaptive immunity via "enforced virus replication," a controlled amplification of virus particles. However, the factors regulating the CD169+ macrophages remain to be studied. In this paper, we show that after vesicular stomatitis virus infection, phagocytes produce tumor necrosis factor (TNF), which signals via TNFR1, and promote enforced virus replication in CD169+ macrophages. Consequently, lack of TNF or TNFR1 resulted in defective immune activation and VSV clearance. PMID- 29142139 TI - Multidisciplinary clinic for functional movement disorders (FMD): 1-year experience from a single centre. PMID- 29142138 TI - Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression. AB - OBJECTIVES: Neurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1). METHODS: Altogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer's disease (AD), Parkinson's disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression. RESULTS: In ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, FTLD p<0.0001) except CJD. CHIT1 concentrations were correlated with ALS disease progression and severity but not with the survival time, as did neurofilaments. Serum CHIT1 levels were not different in ALS compared with any other study group. In the spinal cord of patients with ALS, but not Con, AD or CJD cases, CHIT1 was expressed in the corticospinal tract and CHIT1 staining colocalised with markers of microglia (IBA1) and macrophages (CD68). CONCLUSIONS: CHIT1 concentrations in the CSF of patients with ALS may reflect the extent of microglia/macrophage activation in the white matter of the spinal cord. CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials. PMID- 29142137 TI - The Epstein-Barr virus episome maneuvers between nuclear chromatin compartments during reactivation. AB - The human genome is structurally organized in three-dimensional space to facilitate functional partitioning of transcription. We learned that the latent episome of the human Epstein-Barr virus (EBV) preferentially associates with gene poor chromosomes and avoids gene-rich chromosomes. Kaposi's sarcoma-associated herpesvirus behaves similarly, but human papillomavirus does not. Contacts localize on the EBV side to OriP, the latent origin of replication. This genetic element, and the EBNA1 protein that binds there, are sufficient to reconstitute chromosome association preferences of the entire episome. Contacts localize on the human side to gene-poor and AT-rich regions of chromatin distant from transcription start sites. Upon reactivation from latency, however, the episome moves away from repressive heterochromatin and toward active euchromatin. Our work adds three-dimensional relocalization to the molecular events that occur during reactivation. Involvement of a myriad of interchromosomal associations also suggests a role for this type of long-range association in gene regulation.IMPORTANCE The human genome is structurally organized in three dimensional space, and this structure functionally affects transcriptional activity. We set out to investigate whether a double stranded DNA virus, Epstein Barr virus (EBV), uses similar mechanisms as the human genome to regulate transcription. We found that the EBV genome associates with repressive compartments of the nucleus during latency and active compartments during reactivation. This study is advances our knowledge of the EBV life cycle, adding three-dimensional re-localization as a novel component to the molecular events that occur during reactivation. Furthermore, the data adds to our understanding of nuclear compartments, showing that disperse interchromosomal interactions may be important for regulating transcription. PMID- 29142140 TI - Imaging and CSF analyses effectively distinguish CJD from its mimics. AB - OBJECTIVE: To review clinical and investigation findings in patients referred to a specialist prion clinic who were suspected to have sporadic Creutzfeldt-Jakob disease (sCJD) and yet were found to have an alternative final diagnosis. METHODS: Review the clinical findings and investigations in 214 patients enrolled into the UK National Prion Monitoring Cohort Study between October 2008 and November 2015 who had postmortem confirmed sCJD and compare these features with 50 patients referred over the same period who had an alternative final diagnosis (CJD mimics). RESULTS: Patients with an alternative diagnosis and those with sCJD were of similar age, sex and frequency of dementia but CJD mimics had a longer clinical history. Myoclonus, rigidity and hallucinations were more frequent in patients with sCJD but these features were not helpful in classifying individual patients. Alzheimer's disease, dementia with Lewy bodies and genetic neurodegenerative disorders were alternative diagnoses in more than half of the CJD mimic cases, and 10% had an immune-mediated encephalopathy; lymphoma, hepatic encephalopathy and progressive multifocal leukoencephalopathy were seen more than once. Diffusion-weighted MRI was the most useful readily available test to classify cases correctly (92% CJD, 2% CJD mimics). The CSF cell count, 14-3-3 protein detection and S100B were of limited value. A positive CSF RT-QuIC test, introduced during the course of the study, was found in 89% of tested CJD cases and 0% CJD mimics. CONCLUSION: The combination of diffusion-weighted MRI analysis and CSF RT-QuIC allowed a perfect classification of sCJD versus its mimics in this study. PMID- 29142141 TI - Pragmatic approach to muscle MRI biomarkers in motor neuron disease. PMID- 29142142 TI - Purkinje cell cytoplasmic antibody type I (anti-Yo): predictive of gastrointestinal adenocarcinomas in men. PMID- 29142143 TI - DHA supplementation improves cognitive function via enhancing Abeta-mediated autophagy in Chinese elderly with mild cognitive impairment: a randomised placebo controlled trial. AB - BACKGROUND: Higher docosahexaenoic acid (DHA) intake is inversely correlated with relative risk of Alzheimer's disease. The potential benefits of DHA supplementation in people with mild cognitive impairment (MCI) have not been fully examined. OBJECTIVE: Our study aimed to assess the effect of a 24-month DHA supplementation on cognitive function and amyloid beta (Abeta)-mediated autophagy in elderly subjects with MCI. METHODS: This was a randomised, double-blind, placebo-controlled trial in Tianjin, China. A total of 240 individuals with MCI were identified and randomly divided into intervention (DHA 2 g/day, n=120) and control (corn oil as placebo, n=120) groups. Cognitive function and blood Abeta related biomarkers were measured at baseline, 6, 12, 18 and 24 months. Data were analysed using generalised estimating equation. RESULTS: A total of 217 participants (DHA: 109, placebo: 108) completed the trial. During the follow-up, scores of full-scale IQ, verbal IQ and subdomains of information and digit span were significantly higher in the intervention group than the convention group (p<0.05). In the intervention group, blood Abeta-42 level and expression of Abeta protein precursor mRNA were decreased (p<0.05), while Beclin-1 and LC3-II levels and expression of LC3-II mRNA were increased (p<0.05). CONCLUSION: Daily oral DHA supplementation (2 g/day) for 24 months may improve cognitive function and change blood biomarker-related Abeta-mediated autophagy in people with MCI. Larger longer-term confirmatory studies are warranted. TRIAL REGISTRATION NUMBER: ChiCTR IOR-15006058. PMID- 29142144 TI - Plasma creatinine: a potential prognostic biomarker in amyotrophic lateral sclerosis? PMID- 29142146 TI - Inflammatory natalizumab-associated PML: baseline characteristics, lesion evolution and relation with PML-IRIS. AB - BACKGROUND AND OBJECTIVE: Natalizumab-associated progressive multifocal leukoencephalopathy (NTZ-PML) patients may show imaging signs suggestive of inflammation at diagnosis ('inflammatory PML'), reminiscent of PML-immune reconstitution inflammatory syndrome (PML-IRIS). We investigated the imaging characteristics of inflammatory NTZ-PML lesions and PML-IRIS to determine differentiating and overlapping features. METHODS: We scored the presence, localisation and pattern of imaging characteristics of inflammation on brain MRI scans of inflammatory NTZ-PML patients. The imaging characteristics were followed up until the occurrence of PML-IRIS. RESULTS: Ten out of the 44 NTZ-PML patients included showed signs suggestive of inflammation at the time of diagnosis. The inflammation pattern at diagnosis was similar to the pattern seen at PML-IRIS, with contrast enhancement representing the most frequent sign of inflammation (90% at diagnosis, 100% at PML-IRIS). However, the severity of inflammation differed, with absence of swelling and low frequency of perilesional oedema (10%) at diagnosis, as compared with the PML-IRIS stage (40%). CONCLUSION: Patterns of inflammation at the time of PML diagnosis and at the PML-IRIS stage overlap but differ in their severity of inflammation. This supports histopathological evidence that the inflammation seen at both stages of the same disease shares a similar underlying pathophysiology, representing the immune response to the JC virus to a variable extend. PMID- 29142145 TI - Clinical course, therapeutic responses and outcomes in relapsing MOG antibody associated demyelination. AB - OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of >=2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation. PMID- 29142147 TI - Accidental afloqualone intoxication in two dogs. AB - Two dogs presented to the emergency service after accidental ingestion of afloqualone tablets, a muscle relaxant used for back pain in humans. Toxic effects of the drug in these dogs included vomiting, respiratory depression, seizures, ataxia, bradycardia, and hematuria. Treatment consisted of fluid diuresis, furosemide, and propofol. Flumazenil, a gamma-amino butyric acid antagonist, was administered intravenously; however, it was not effective in stopping the seizures in these dogs. Both dogs recovered with supportive treatment. To the authors' knowledge, this is the first documented report of afloqualone intoxication in dogs. PMID- 29142148 TI - Seasonal changes in serum oxidative stress biomarkers in dairy and beef cows in a daytime grazing system. AB - This study aims to evaluate the oxidative stress during hot summer season using serum oxidative stress biomarkers and elucidate the effects of serum antioxidant vitamin levels in dairy and beef cows in a daytime grazing system. Blood samples were collected once a month from eight Holstein Friesian (HF) and 10 Japanese Black (JB) cows from November 2013 to October 2014. Serum values of derivatives of reactive oxygen metabolites (d-ROMs) tended to be higher in March in both breeds and those in HF cows were kept at higher (P<0.001) levels than those in JB cows during the study period. Serum levels of biological antioxidant potential (BAP) in both breeds were maintained at almost the same values during study period. The OSI [(d-ROMs/BAP) * 100] values in both breeds showed similar seasonal changes, i. e. increase from December to March and decrease from March to August or September. In addition, the OSI values in HF cows were kept at higher (P<0.01) levels than those in JB cows during the study period. Serum concentrations of alpha-tocopherol, beta-carotene, blood urea nitrogen and total cholesterol showed similar seasonal changes in both breeds, low in the winter and high from spring to summer, which may be attributed to the pasture grass intake. Opposite changes in OSI values and serum concentrations of alpha-tocopherol and beta-carotene indicated that antioxidant vitamin levels could affect oxidative stress status. PMID- 29142149 TI - Liposarcoma of the spermatic cord in a Toy Poodle. AB - Liposarcoma of the spermatic cord is extremely rare in dogs and humans. This report describes the clinical signs, typical diagnostic imaging including ultrasound and computed tomography, and treatment of a liposarcoma of the spermatic cord of a Toy Poodle confirmed by histological examination after a surgical procedure. This case highlights the importance of preoperative diagnostic imaging and histopathological examination in dogs with an inguinal or scrotal mass. PMID- 29142150 TI - Effect of maternal supplementation with seaweed powder on immune status of liver and lymphoid organs of piglets. AB - This study was performed to evaluate the effect of maternal supplementation with seaweed powder (SWP) on the immune status of piglets. Sows were supplementary fed SWP from 85-days of gestation until delactation. Forty-days old piglets were euthanized and lymphocyte subsets were analyzed. The results showed a significantly higher relative population of CD4+CD8+ T cells in the thymus, lymph node, tonsil (P<0.05), peripheral blood mononuclear cells, spleen and liver (P<0.01) of piglets derived from treated sows. A higher relative population of CD8+ T cells was also observed in the liver and spleen (P<0.05) of the piglets. The data suggested the enhancing effects of maternal supplementation with SWP on immune status of piglets. PMID- 29142151 TI - Two cases of liver cirrhosis treated with lusutrombopag before partial splenic embolization. AB - Lusutrombopag, a small molecule thrombopoietin receptor agonist, has been approved for the treatment of chronic liver disease-associated thrombocytopenia due to hypersplenism in patients scheduled to undergo elective invasive procedures in Japan. We performed partial splenic embolization (PSE) after administration of lusutrombopag in two patients with thrombocytopenia due to cirrhosis. Case 1 involved a 50-year-old man who developed cirrhosis due to hepatitis B virus (HBV) infection and alcohol consumption. Case 2 involved a 30 year-old woman who developed cirrhosis due to HBV infection only. Lusutrombopag administration led to an increase in platelet count in both patients, and PSE was performed safely. However, in Case 2, the patient developed disseminated intravascular coagulation. Further study with a larger population is required to investigate the indications for and risks of the use of lusutrombopag. PMID- 29142152 TI - Indirect Proton MR Imaging and Kinetic Analysis of 17O-Labeled Water Tracer in the Brain. AB - PURPOSE: The feasibility of steady-state sequences for 17O imaging was evaluated based on a kinetic analysis of the brain parenchyma and cerebrospinal fluid (CSF). MATERIALS AND METHODS: The institutional review board approved this prospective study with written informed consent. Dynamic 2D or 3D steady-state sequences were performed in five and nine participants, respectively, with different parameters using a 3T scanner. During two consecutive dynamic scans, saline was intravenously administered for control purposes in the first scan, and 20% 17O-labeled water (1 mL/Kg) was administered in the second scan. Signal changes relative to the baseline were calculated, and kinetic analyses of the curves were conducted for all voxels. Region of interest analysis was performed in the brain parenchyma, choroid plexus, and CSF spaces. RESULTS: Average signal drops were significantly larger in the 17O group than in the controls for most of the imaging parameters. Different kinetic parameters were observed between the brain parenchyma and CSF spaces. Average and maximum signal drops were significantly larger in the CSF spaces and choroid plexus than in the brain parenchyma. Bolus arrival, time to peak, and the first moment of dynamic curves of 17O in the CSF space were delayed compared to that in the brain parenchyma. Significant differences between the ventricle and subarachnoid space were also noted. CONCLUSION: Steady-state sequences are feasible for indirect 17O imaging with reasonable temporal resolution; this result is potentially important for the analysis of water kinetics and aquaporin function for several disorders. PMID- 29142153 TI - Prognostic Impact and Post-operative Evaluation of Volumetric Measurement of the Cerebellopontine Cistern in Trigeminal Neuralgia Using 3 Tesla Magnetic Resonance Imaging. AB - The aim of this study was to evaluate the importance of pre- and post-operative volumetric measurement of the cerebellopontine angle (CPA) using 3 Tesla (3T) magnetic resonance imaging (MRI). Between April 2012 and December 2015, a total of 87 consecutive patients underwent microvascular decompression (MVD) for trigeminal neuralgia (TN), of whom 51 with primary TN caused by arterial compression were enrolled in this study. Bilateral CPA cistern volume was evaluated using 3T MRI before and after surgery; the Cistern Deviation Index was used to represent the degree of deviation of the CPA cistern. The relationships between CPA cistern volume and the etiology of TN were assessed, and post operative changes in anatomical parameters were examined to determine differences between recurrent and non-recurrent patients with TN. The mean volume of the CPA cistern on the affected side was significantly smaller than the unaffected side (P < 0.001). Five of 51 (10%) patients experienced TN recurrence. The recurrent cases demonstrated significantly lower pre-operative Cistern Deviation Index scores than non-recurrent cases (P = 0.035). On the unaffected side-but not the affected side-post-operative volume reduction was significantly greater in the recurrence group than in the non-recurrence group (P = 0.004). The pre-operative Cistern Deviation Index was a useful parameter to predict the recurrence of TN. In recurrent patients, post-operative inflammatory reaction may extend to not only the operated side but also the healthy side and reduce the volume of the CPA cistern. PMID- 29142154 TI - The Choroid Plexus of the Lateral Ventricle As the Origin of CSF Pulsation Is Questionable. AB - The advent of magnetic resonance imaging (MRI) enables noninvasive measurement of cerebrospinal fluid (CSF) motion, and new information about CSF motion has now been acquired. The driving force of the CSF has long been thought to be choroid plexus (CP) pulsation, but to investigate whether this phenomenon actually occurs, CSF motion was observed in the ventricular system and subarachnoid space using MRI. Eleven healthy volunteers, ranging in age from 23 to 58 years, participated in this study. The MRI sequences used were four-dimensional phase contrast (4D-PC) and time-spatial labeling inversion pulse (t-SLIP). The 4D-PC images included sagittal images in the cranial midline, coronal images focusing on the foramen of Monro (FOM), and oblique coronal images of the trigone to quantify CSF velocity and acceleration. These values were compared and analyzed as non-parametric data using the Kolmogorov-Smirnov test and the Mann-Whitney U test. 4D-PC showed that the median CSF velocity was significantly lower in the posterior part of the lateral ventricle than in other regions. The quantitative analysis of velocity and acceleration showed that they were decreased around the CP in the trigone. Image analysis of both velocity mapping and t-SLIP showed suppressed CSF motion around the CP in the trigone. These findings cast doubt on CP pulsation being the driving force for CSF motion. PMID- 29142155 TI - Modulation of High-Density Lipoprotein Function via Cardiac Rehabilitation. PMID- 29142156 TI - Outcomes of Rate-Control Treatment in Patients With Atrial Fibrillation and Heart Failure - A Nationwide Cohort Study. AB - BACKGROUND: Rate control is now a front-line therapy in the management of atrial fibrillation (AF). However, the survival benefits of different rate-control medications remain controversial, so we assessed the efficacy of rate-control medications in AF patients with concomitant heart failure (HF).Methods and Results:From January 2002 to December 2008, a total of 7,034 AF patients with a single type of rate-control drug or without rate-control treatment were enrolled from the Korea National Health Insurance Service database. The death rates over a mean follow-up of 4.5+/-1.2 years were 12.6% (580 of 4,593) and 29.0% (709 of 2,441) in non-HF and HF patients, respectively. Among the total subjects, the risk of death was lower in patients receiving beta-blockers (adjusted hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.64-0.88) and calcium-channel blockers (adjusted HR 0.74, 95% CI 0.55-0.98) compared with those who did not receive rate-control medications. In patients without HF, use of rate-control medications did not affect the risk of death. In patients with HF, beta-blockers significantly decreased the mortality risk (adjusted HR 0.63, 95% CI 0.50-0.79), whereas use of calcium-channel blockers or digoxin was not associated with death. The results were observed consistently among the cohorts after propensity matching. CONCLUSIONS: Use of beta-blockers was associated with a reduced mortality rate for AF patient with HF but not for those without HF. These findings should be examined in a large randomized trial. PMID- 29142157 TI - Intracoronary Acetylcholine Provocation Test via Coronary Bypass Graft. PMID- 29142158 TI - Computed tomography, magnetic resonance imaging and a novel surgical approach of atlanto-axial instability with incongruence in dogs. AB - Atlanto-axial (AA) instability due to ligament insufficiency is a common cause of cervical spinal cord compression in toy breeds. However, in some dogs a difference in size between the atlas and the axis leads to joint incongruence that exacerbates AA subluxation and makes surgical treatment challenging. Twelve dogs with AA instability with incongruence were enrolled in a single institution prospective observational study. Computed tomography (CT) and magnetic resonance imaging (MRI) of the AA joint were compared to a retrospectively reviewed control group. A novel surgical approach consisting of a dorsal internal fixation technique was performed in six dogs. For affected dogs, the mean normalised difference between the dorso-ventral atlas canal and the dorso-ventral axis canal was 29.67% (median of 35.07%, standard deviation 25.64%), while in normal dogs a mean difference of 4.67% (median of 3.95%, standard deviation 5.21%) was observed. On MRI, 12/12 affected dogs had spinal cord compression, which was classified as reducible (3/12), partially reducible (6/12) and non-reducible (3/12). In surgically operated dogs, follow-up CT showed a partial or complete reduction of the previous spinal cord compression with a consistent amelioration or resolution of the presenting complaints. The proposed surgical technique was safe and effective in dogs with partially or completely reducible spinal cord compression. PMID- 29142159 TI - Systemic cytokine response in pigs infected orally with a Lawsonia intracellularis isolate of South Korean origin. AB - In the swine industry, Lawsonia intracellularis is one of the main enteric pathogens; it causes acute intestinal hemorrhage (proliferative hemorrhagic enteropathy) in naive adult pigs and a wasting disease (proliferative enteropathy) in growing pigs. Among many kinds of cytokines, interferon-gamma (IFN-gamma) has previously been reported to play a significant role in limiting intracellular infection and increasing cellular proliferation associated with L. intracellularis. However, the levels of various circulating inflammatory cytokines, including IFN-gamma, in animals infected with L. intracellularisis is still an area of considerable interest for understanding immunity against this bacterium. In addition, there has been no information on cytokine response in animals infected with any L. intracellularis isolate of South Korean origin or Asian origin. To determine the relationship between the changes in the systemic inflammatory cytokine response in the peripheral blood of the host after L. intracellularis infection, we measured the levels of some pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IFN-gamma), anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor-beta (TGF-beta)), and a chemokine (IL-8) in pigs infected with L. intracellularis isolated from South Korea. This study demonstrated that a L. intracellularis isolate of South Korean origin induced cytokine (TNF-alpha, IL-6, and IFN-gamma) responses in infected animals within 15 days post-infection although the circulating levels of IL-4, IL-10, IL-8 and TGF-beta were induced relatively late. PMID- 29142160 TI - Immunogenicity and protective efficacy of Vibrio vulnificus flagellin protein FlaB in a wound infection model. AB - Vibrio vulnificus is known as an opportunistic bacterial pathogen that causes primary septicemia and wound infection in humans. Recently, the incidence of wound infection by V. vulnificus is increasing in warm countries. In this study, we examined a vaccine antigen against V. vulnificus in mice. FlaB, a component protein of the V. vulnificus flagellum, was expressed as a recombinant protein, named rFlaB. After immunization of mice with rFlaB, the mice were challenged by subcutaneous inoculation with V. vulnificus. Bacterial burdens in muscular tissue at the infection site in rFlaB-immunized mice were significantly decreased compared with those of control mice. We found that rFlaB immunization can partially suppress proliferation of V. vulnificus at the local infection site. PMID- 29142161 TI - Treatment and Outcomes of Carcinoma of the External and Middle Ear: The Validity of En Bloc Resection for Advanced Tumor. AB - Carcinoma of the external and middle ear is a very rare disease. Despite the various treatment modalities available, its prognosis is still poor. We aimed to analyze the treatment modalities, outcomes, and validity of surgical approaches, especially in advanced tumors in the ear. Twenty-five patients with carcinoma of the external and middle ear were retrospectively analyzed. The modified Pittsburgh staging system was used for staging of the patients. Overall and disease-free survival was estimated using of Kaplan-Meier method. In our cohort of 25 patients, the majority (76%) had tumor located in external auditory meatus. The most common histologic subtype was squamous cell carcinoma (80%). More than half of patients (56%) had tumor stage IV. In the stage IV group, five patients underwent subtotal temporal bone resection and ipsilateral neck dissection. Seven patients underwent definitive radiotherapy. The remaining two patients underwent palliative chemotherapy. The 2-year overall and disease-free survival for patients with tumor stage IV was 67.7% and 57.8%, respectively. In patients with tumor stage IV, the 2-year overall survival for patients who underwent surgery was 80.0% versus 53.6% for those who underwent radiotherapy (P = 0.16). The 2 year disease-free survival for patients who underwent surgery was 80.0% versus 28.6% for those who underwent radiotherapy (P = 0.15). In the present study, the outcome of patients who received surgical treatment tended to be better than that of patients who received radiation therapy. Our results suggest that en bloc resection could be the first choice even in the advanced disease stage. PMID- 29142162 TI - Chloroform extract of turmeric inhibits biofilm formation, EPS production and motility in antibiotic resistant bacteria. AB - In the form of biofilms, bacteria exhibit more resistance to antibiotics. Biofilm formers can withstand severe conditions and the host's defense system. Therefore, it is necessary to search for effective biofilm inhibitors. In this study, we investigated the effect of a chloroform extract of turmeric on biofilm formation against antibiotic resistant bacteria. The extract exhibited its antibiofilm effect by altering adherence, motility, extracellular polymeric substance (EPS) production and cell surface hydrophobicity; important attributes of biofilm formation. Cell attachment assays indicated that a chloroform extract resulted in a 38.9-60.2% inhibition of cell adherence to a polystyrene surface, and a 44.5 58.3% inhibition to a glass surface. Static biofilm formation assays indicated that a chloroform extract resulted in a 23-74.5% reduction in biofilm formation. The chloroform extract inhibited flagella-directed swarming and swimming motility and pilus-directed twitching motility in a dose-dependent manner. In addition to repression of motility, a chloroform extract also significantly (p < 0.05) altered the hydrophobic behavior, and bacterial strains such as K. pneumoniae and E. cloacae exhibited hydrophilic behavior after the addition of the extract, as compared with control cells. The presence of the extract also significantly (p < 0.05) increased the detachment of biofilms by a surfactant as compared with controls. Fourier transformed infrared spectroscopy (FTIR) had indicated a loss of vital functional groups of polysaccharides and proteins from the EPS of cells treated with a chloroform extract. Gas chromatography mass spectrometry (GC-MS) analysis indicated the presence of many phytochemical constituents, mainly sesquiterpenes and fatty acid groups. These results clearly suggested that turmeric could affect multiple cellular activities in biofilm formers exhibiting antibiotic resistance by modulating adherence, EPS production, motility and surface hydrophobicity. PMID- 29142163 TI - Strain improvement studies on Microbacterium foliorum GA2 for production of alpha amylase in solid state fermentation: Biochemical characteristics and wash performance analysis at low temperatures. AB - Microbacterium foliorum GA2, an alkali-tolerant bacterium, was randomly mutated using UV radiation and sodium azide to obtain a mutant with a higher cold-active extracellular amylolytic activity. A mutant, designated as MFSD20, was selected owing to its higher amylase activity at 20 degrees C. Under optimized conditions, amylase production was achieved best with raw banana peels (5000 units) in solid state fermentation (SSF). The enzyme was purified by salt precipitation and chromatographic methods and afterwards characterized biochemically. The purified enzyme showed maximal activity at temperatures between 15-25 degrees C and at pH 8.0. Interestingly, this mutant biocatalyst (MFSD20) displays higher catalytic activity under conditions of low temperature (4 degrees C) and high pH (10.0), in the presence of SDS (0.1 and 1%), and exhibited 85% and 50% requirement of divalent metallic ions Ca2+ and Mg2+, respectively. This mutant enzyme extract in combination with "Wheel detergent" was highly effective in the removal of tomato sauce and chocolate stains from white cotton fabric was demonstrated by ~50% additional reflectance compared with detergent alone, in a wash performance analysis at 20 +/- 2 degrees C. The features shown by mutant M. foliorum GA2 make it a promising candidate for industrial applications involving starch degradation at low temperatures. PMID- 29142164 TI - Bacterial degradation of spermine and expression of spermidine/spermine acetyltransferase in Bacillus subtilis (natto) under liquid cultivation. PMID- 29142165 TI - Possible mechanism for the polychlorinated bipheny-linduced liver-selective accumulation of thyroxine in rats. AB - We have previously reported that decrease in level of serum thyroxine T4 by Kanechor 500 (KC500) in rats would occur through the increase in hepatic T4 accumulation rather than the increase in hepatic T4-glucuronyl transferase activity. In the present study, to understand the mechanism underlying the KC500 mediated increase in hepatic T4 accumulation, we examined the relationship between the KC500-mediated changes in hepatic T4 accumulation and the expression levels of mRNAs of hepatic transporters including T4 transporters. [125I]T4 was intravenously injected into KC500-pretreated and control (KC500-untreated) Wistar rats, and [125I]T4 uptake levels of liver parenchymal cells were comparatively examined. The amount of [125I]T4 uptake by hepatic cells increased in a time dependent manner up to 96 hr after KC500 treatment. Following KC500 treatment, a time-dependent increase in the mRNA level of hepatic T4 influx transporter LAT1 was observed up to 96 hr later, while a significant increase in hepatic T4 influx transporter Oatp2 mRNA occurred only at 96 hr later. No KC500-mediated increases in the mRNAs of other hepatic transporters (Oatp1, Oatp3, Oatp4, Ntcp, LAT2, and Mrp2) were observed at any timepoints, although the mRNA expression of the T4 conjugate(s) efflux transporter Mrp3 significantly increased in a time-dependent manner 24-96 hr following KC500 treatment. The present findings suggest that KC500-mediated increase in hepatic T4 accumulation occurs, at least in part, through the increase in the expression of hepatic T4-transporters, such as LAT1 and Oatp2. PMID- 29142166 TI - Fish oil feeding reverses hepatomegaly and disrupted hepatic function due to the lack of FXR signaling. AB - Mice lacking farnesoid X receptor (FXR) are used as a model for nonalcoholic fatty liver disease because their livers exhibit hepatomegaly, hepatic steatosis, and hepatic inflammation. The influence of fish oil feeding on hepatomegaly and disrupted hepatic function was investigated using female Fxr-null mice and wild type mice fed a fish oil diet (2% fish oil and 2% corn oil) or a control diet (4% corn oil) for 4 weeks. Hepatic n-3 polyunsaturated fatty acid (PUFA) levels, including 22:6 n-3 docosahexaenoic acid (DHA) and 20:5 n-3 eicosapentaenoic acid (EPA) were significantly higher in the fish oil group than those in the control group of Fxr-null mice and wild-type mice. Fxr-null mouse livers of the control group showed a whitish brown coloration, whereas Fxr-null mouse livers of the fish oil group showed a dark brown coloration similar to that of wild-type mice. The liver in Fxr-null mice of the fish oil group was smaller than that of the control group. There was a significant decrease in the levels of hepatic damage associated diagnostic markers, hepatic and serum bile acids, triglycerides, free fatty acids, and total cholesterol levels in Fxr-null mice because of fish oil feeding. It also reversed elevated mRNA levels of oxidative stress-related genes (Hmox1, Gsta1, and Gsta2) and reduced mRNA levels of transcriptional factors (Pparalpha and Shp) in Fxr-null mice. These results suggest that fish oil feeding reverses hepatomegaly and disrupted hepatic function due to the lack of FXR signaling. PMID- 29142167 TI - Synergistic cytotoxicity caused by forming a complex of copper and 2,9-dimethyl 1,10-phenanthroline in cultured vascular endothelial cells. AB - Organic-inorganic hybrid molecules, which are composed of organic-ligand(s) and metal(s), are indispensable as synthetic reagents in chemistry, but they have made very little in the way of contributions to biological research. Previously, we reported that the cytotoxicity of organic-inorganic hybrid molecules in vascular endothelial cells depends on interactions between the intramolecular metal and ligand, but remains independent of the hydrophobicity of the intramolecular metal(s). Herein, we show a synergistic cytotoxicity produced by forming a complex of copper and 2,9-dimethyl-1,10-phenanthroline in vascular endothelial cells that depends on the intracellular accumulation of copper. PMID- 29142169 TI - The effects of ethylene glycol monomethyl ether on female reproductive system in juvenile rats. AB - Ethylene glycol monomethyl ether (EGME), which is widely used in various industrial products, is known for adverse effects on the reproductive system in adult rats. However, the effects of EGME on reproductive development in juvenile rats have not been demonstrated. In order to investigate the effects of EGME on the female reproductive system and pubertal development in juvenile rats, EGME was administered to female Sprague Dawley rats from postnatal day 21 to 41 at a dose level of 0, 50, 100, or 300 mg/kg. The animals were examined for general condition, body weight, vaginal opening (VO), estrous cyclicity, and histopathology of reproductive organs. EGME treatment resulted in a prolonged estrous cycle interval characterized by persistent diestrus at 50 mg/kg without effects on body weight, timing of VO, or histology of the reproductive organs. EGME at 100 mg/kg induced decreases in body weight gain, a delay of VO, and irregular estrous cycle with absence of corpora lutea and hypertrophy of uterine epithelium indicating disturbance of the ovulatory process associated with hormonal effect. At 300 mg/kg, there was significant delay of puberty due to severe growth retardation. The present results revealed that irregular estrous cycle is a first indicator of the effects of EGME on the female reproductive system in juvenile rats, with delayed pubertal onset and ovulatory process disturbance at a higher dose. PMID- 29142168 TI - Background data on NOD/Shi-scid IL-2Rgammanull mice (NOG mice). AB - To obtain background data of NOD/Shi-scid IL-2Rgammanull (NOG) mice, severely immunedeficient mice, a total of 120 animals were examined at 7, 26 and 52 weeks old (20 mice/sex/group). The survival rate at 52 weeks-old was 95% (19/20) in both sexes. Clinically, circling behavior in one direction along the cage wall was observed in males after 8 weeks and females after 47 weeks-old, and hunchback position was found in males after 32 weeks-old. Hematologically, lymphocyte count markedly decreased at all ages, while white blood cell count increased in several mice at 52 weeks-old. Blood chemistry results revealed high values of aspartate aminotransferase, lactate dehydrogenase and creatine phosphokinase in some females at 26 weeks-old, without any related histological change. Histologically, lymphoid hypoplasia characterized by severe lymphocyte depletion with poorly developed tissue architectures was observed. In addition, spongiotic change in the nerve tissue was observed in both sexes at 7 and 26 weeks-old, and intracytoplasmic materials known as tubular aggregates in the skeletal muscles were found in males terminated at 26 and 52 weeks-old and in females at 52 weeks old. Malignant lymphoma was found in one female euthanized at 20 weeks-old. Further, small intestinal adenoma, hepatocellular adenoma, leukemia, cerebral lipomatous hamartoma, Harderian gland adenoma and uterine polyp were also observed, and their incidences were low except for that of uterine polyp. This study provided detailed background data on NOG mice up to 52 weeks-old and provided information on appropriate use of NOG mice in the various research fields. PMID- 29142170 TI - Characterization of a rat model of moderate liver dysfunction based on alpha naphthylisothiocyanate-induced cholestasis. AB - Plasma amino acid level changes occur in mild, moderate and severe stages of liver injury in human patients. In animal models, however, data are mainly restricted to severe liver injury models in rats. Here we present the characterization of a rat model of moderate liver dysfunction secondary to alpha napthylisothiocyanate (ANIT)-induced cholestasis. Rats treated with 30 mg/kg/day ANIT for 3 weeks exhibited a time-dependent increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin levels and a decrease in albumin concentration. According to a liver dysfunction evaluation based on the human Child-Pugh-Score, animals developed a moderate liver dysfunction in the first two weeks of ANIT treatment, while only a mild dysfunction was observed at the end of week 3 despite ongoing ANIT administration. Univariate analysis of branched-chain amino acid plasma levels indicated that reduced levels of branched chain amino acids were associated with the ANIT treatment. These data may set the stage for further research of amino acid disturbances and requirements in non-severe cholestasis. PMID- 29142171 TI - Sub-toxic concentrations of nano-ZnO and nano-TiO2 suppress neurite outgrowth in differentiated PC12 cells. AB - Nanomaterials have been extensively used in our daily life, and may also induce health effects and toxicity. Nanomaterials can translocate from the outside to internal organs, including the brain. For example, both nano-ZnO and nano-TiO2 translocate into the brain via the olfactory pathway in rodents, possibly leading to toxic effects on the brain. Although the effects of nano-ZnO and nano-TiO2 on neuronal viability or neuronal excitability have been studied, no work has focused on how these nanomaterials affect neuronal differentiation and development. In this study, we investigated the effects of nano-ZnO and nano-TiO2 on neurite outgrowth of PC12 cells, a useful model system for neuronal differentiation. Surprisingly, the number, length, and branching of differentiated PC12 neurites were significantly suppressed by the 7-day exposure to nano-ZnO (in the range of 1.0 * 10-4 to 1.0 * 10-1 ug/mL), at which the cell viability was not affected. The number and length were also significantly inhibited by the 7-day exposure to nano-TiO2 (1.0 * 10-3 to 1.0 ug/mL), which did not have cytotoxic effects. These results demonstrate that the neurite outgrowth in differentiated PC12 cells was suppressed by sub-cytotoxic concentrations of nano-ZnO or nano-TiO2. PMID- 29142172 TI - Change in redox state and heat shock protein expression in an Indian major carp Cirrhinus cirrhosus exposed to zinc and lead. AB - Fish are exposed to different heavy metals that may induce numerous physiological changes. In the present study, we examined the redox state in response to a severe stress resulting from two heavy metals (Zinc and Lead) contamination in carp Cirrhinus cirrhosus. Fish were exposed to 1/10th of LC50 of the respective metals [zinc chloride (2.72 mg/L) and lead acetate (2.53 mg/L)] for 30 days and allowed to recover for another 30 days without any metal exposure. Concentration of metals, different enzymatic and non-enzymatic antioxidant agents and expression levels of heat shock protein (HSP) 70 and 90 were measured in the liver and the kidney of fish. The lipid peroxide levels in fish tissues gradually increased with duration of treatment for both metals. After 15 days of treatment, glutathione (GSH) levels had increased, but decreased as the treatment continued for 30 days and returned to basal levels after a 30-day recovery period. Activities of all the anti-oxidant enzymes, except glutathione peroxidase, in stressed fish were significantly increased compared to those in the control at 15 days and continued till the 30th day of treatment, showing a tendency to return to basal levels after the recovery period. Expression levels of HSP70 and HSP90 gradually increased after zinc and lead treatment, respectively. The expression of HSP was higher in the liver. The results suggest that different heavy metals may have differential effects on the redox state and induction of oxidative stress in carp, in vivo. PMID- 29142173 TI - Effect of dibutyltin on placental and fetal toxicity in rat. AB - In order to elucidate the effect of chorioallantoic and yolk sac placenta on the embryonic/fetal toxicity in dibutyltin dichloride (DBTCl)-exposed rats, we examined the histopathological changes and the tissue distribution of dibutyltin in the placentas and embryos. DBTCl was orally administered to the groups at doses of 0 mg/kg during gestation days (GD)s 7-9 (control group) and 20 mg/kg during GDs 7-9 (GD7-9 treated group), and GDs 10-12 (GD10-12 treated group). The total fetal mortality was increased, and malformations characterized by craniofacial dysmorphism were detected in the GD7-9 treated group. The embryonic/fetal weight and placental weight showed a decrease in both DBTCl treated groups. Histologically, some embryos on GD 9.5 in the GD7-9 treated group underwent apoptosis without any changes of yolk sac. In the laser ablation inductively coupled plasma-mass spectrometry analysis (LA-ICP-MS), tin was detected in the embryo, allantois, yolk sac, ectoplacental cone and decidual mass surrounding the conceptus on GD 9.5 in the GD7-9 treated group. Thus, it is considered that the embryo in this period is specifically sensitive to DBTCl induced apoptosis, compared with other parts. The chorioallantoic placentas in both DBTCl-treated groups showed the developmental delay and hypoplasia in the fetal parts of placenta, resulting from apoptosis and mitotic inhibition. Thus, it was speculated that the DBTCl-induced malformations and fetal resorption resulted from the apoptosis in the embryo caused by the direct effect of DBTCl. The DBTCl-induced lesions in the chorioallantoic placenta were a non-specific transient developmental retardation in the fetal parts of placenta, leading to intrauterine growth retardation. PMID- 29142174 TI - Evaluation system for arrhythmogenic potential of drugs using human-induced pluripotent stem cell-derived cardiomyocytes and gene expression analysis. AB - In recent years, human-induced pluripotent stem cell-derived cardiomyocytes (hiPS CMs) have been widely used to develop evaluation systems for drug cardiotoxicity, including the arrhythmia caused by QT prolongation. To accurately assess the arrhythmogenic potential of drugs, associated with QT prolongation, we developed an evaluation system using hiPS-CMs and gene expression analysis. hiPS-CMs were treated with 8 arrhythmogenic and 17 non-arrhythmogenic drugs at several concentrations for 24 hr to comprehensively analyze gene expression. The results showed that 19 genes were upregulated in the arrhythmogenic drug-treated cells compared with their expression levels in the non-treated and non-arrhythmogenic drug-treated cells. The arrhythmogenic risks of the drugs were evaluated by scoring gene expression levels. The results indicated that arrhythmogenic risks could be inferred when cells were treated at a concentration 100 times higher than the maximum blood concentration of the drug. Thus, we succeeded in developing a system for evaluation of the arrhythmogenic potential of drugs using gene expression analysis. PMID- 29142175 TI - Macrophage differentiation induced by PMA is mediated by activation of RhoA/ROCK signaling. AB - In order to investigate the effects of RhoA/ROCK signaling in macrophage differentiation, we used 100 ng/mL PMA to induce macrophage differentiation from U937 cells in vitro. The observation of cell morphology and the expression of CD68 and SR-A were performed to confirm the differentiation induced by PMA. Western blot analysis showed that the expression of ROCK1 and ROCK2 and the phosphorylation of MYPT1 were significantly increased after PMA treatment. Pulldown assay showed that the activation of RhoA was obviously enhanced when U937 cells were treated with PMA. In order to further demonstrate whether RhoA/ROCK signaling could mediate the macrophage differentiation induced by PMA, we successfully suppressed the expression of RhoA, ROCK1 and ROCK2 by performing siRNA technology in U937 cells, respectively. The macrophage differentiation and the expression of CD68 and SR-A were significantly inhibited by the suppression of RhoA, ROCK1 or ROCK2 in PMA-induced U937 cells, indicating that the macrophage differentiation induced by PMA is associated with RhoA/ROCK signaling pathway. In addition, we pretreated U937 cells with Y27632 (ROCK inhibitor, 20 MUM) for 30 min and then observed the macrophage differentiation induced by PMA. The result illustrated that Y27632 pretreatment obviously inhibited PMA-induced differentiation and the expression of CD68 and SR-A. In conclusion, the activation of RhoA/ROCK signaling is responsible for the macrophage differentiation induced by PMA. PMID- 29142176 TI - Evaluation of the human relevance of the constitutive androstane receptor mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin. AB - High dietary levels of the non-genotoxic synthetic pyrethroid momfluorothrin increased the incidence of hepatocellular tumors in male and female Wistar rats. Mechanistic studies have demonstrated that the mode of action (MOA) for momfluorothrin-induced hepatocellular tumors is constitutive androstane receptor (CAR)-mediated. In the present study, to evaluate the potential human carcinogenic risk of momfluorothrin, the effects of momfluorothrin (1-1,000 uM) and a major metabolite Z-CMCA (5-1,000 uM) on hepatocyte replicative DNA synthesis and CYP2B mRNA expression were examined in cultured rat and human hepatocyte preparations. The effect of sodium phenobarbital (NaPB), a prototypic rodent hepatocarcinogen with a CAR-mediated MOA, was also investigated. Human hepatocyte growth factor (hHGF) produced a concentration-dependent increase in replicative DNA synthesis in rat and human hepatocytes. However, while NaPB and momfluorothrin increased replicative DNA synthesis in rat hepatocytes, NaPB, momfluorothrin and Z-CMCA did not increase replicative DNA synthesis in human hepatocytes. NaPB, momfluorothrin and Z-CMCA increased CYP2B1/2 mRNA levels in rat hepatocytes. NaPB and momfluorothrin also increased CYP2B6 mRNA levels in human hepatocytes. Overall, while momfluorothrin and NaPB activated CAR in cultured human hepatocytes, neither chemical increased replicative DNA synthesis. Furthermore, to confirm whether the findings observed in vitro were also observed in vivo, a humanized chimeric mouse study was conducted. Replicative DNA synthesis was not increased in human hepatocytes of chimeric mice treated with momfluorothrin or its close structural analogue metofluthrin. As human hepatocytes are refractory to the mitogenic effects of momfluorothrin, in contrast to rat hepatocytes, the data support the hypothesis that the MOA for momfluorothrin-induced rat liver tumor formation is not relevant for humans. PMID- 29142177 TI - Perinatal exposure to tetrabromobisphenol A (TBBPA), a brominated flame retardant, exacerbated the pneumonia in respiratory syncytial virus (RSV) infected offspring mice. AB - To investigate the effects of perinatal exposure to tetrabromobisphenol A (TBBPA), a brominated flame retardant, on the immune system, a respiratory syncytial virus (RSV) infection mouse model was utilized. Female mice were exposed to TBBPA mixed with the diet from 10 days after conception to weaning on postnatal day 21. Offspring mice were infected intranasally with A2 strain of RSV. Although no general toxicological sign was observed, the pulmonary viral titers of offspring mice exposed to 0.1% TBBPA were significantly increased compared with the control on day 5 post-infection. TBBPA did not affect RSV growth in vitro. Histopathological analysis confirmed that the exacerbation of interstitial pneumonia was due to TBBPA- exposure in the lung tissues in RSV infected offspring. Moreover, gene expression of interleukin (IL)-24 was shown to be elevated typically in the lung tissues of TBBPA-treated offspring by a DNA microarray and was also confirmed by immunohistopathological analysis using an anti-IL-24 antibody. Thus, developmental exposure to TBBPA affected the immune response to RSV infection, resulting in the exacerbation of pneumonia. Thus, IL 24 should be a key molecule to understand the mechanism of action of TBBPA. PMID- 29142178 TI - Actual consumption amount of personal care products reflecting Japanese cosmetic habits. AB - Safety assessments of cosmetics are carried out by identifying possible harmful effects of substances in cosmetic products and assessing the exposure to products containing these substances. The present study provided data on the amounts of cosmetic products consumed in Japan to enhance and complement the existing data from Europe and the United States, i.e., the West. The outcomes of this study increase the accuracy of exposure assessments and enable more sophisticated risk assessment as a part of the safety assessment of cosmetic products. Actual amounts of products applied were calculated by determining the difference in the weight of products before and after use by approximately 300 subjects. The results of the study of skincare products revealed that in comparison with the West, large amounts of lotions and emulsions were applied, whereas lower amounts of cream and essence were applied in Japan. In the study of sunscreen products, actual measured values during outdoor leisure use were obtained, and these were lower than the values from the West. The study of the use of facial mask packs yielded data on typical Japanese sheet-type impregnated masks and revealed that high amounts were applied. Furthermore, data were obtained on cleansing foams, makeup removers and makeup products. The data from the present study enhance and complement existing information and will facilitate more sophisticated risk assessments. The present results should be extremely useful in safety assessments of newly developed cosmetic products and to regulatory authorities in Japan and around the world. PMID- 29142179 TI - Usefulness of a Short Dietary Propensity Questionnaire in Japan. AB - AIM: There is a growing need for nutritional education for prevention and non pharmacological treatment of risk factors for cardiovascular diseases (CVD). We compared the results of a short dietary propensity questionnaire (SDPQ) with those from the food frequency and quantity survey (FF Quantity), which had been previously quantitatively assessed by comparison with the 24-hr dietary recall (24hr-DR), to examine the usefulness of the SDPQ. The SDPQ was designed to assess dietary propensities of 12 food/nutrients relevant to CVD risk factors. METHODS: We conducted a dietary survey using the SDPQ on Japanese men and women. After 2-3 weeks, we conducted the FF Quantity survey with the same participants. For each of the 12 food/nutrient categories, the relationships between quintiles of results from the SDPQ and FF Quantity were examined. Results from 79 participants who completed both surveys were used. RESULTS: Spearman's correlation coefficients (r) were significant for all food/nutrient categories. Good correlations were found with alcohol (r=0.792), starchy foods (r=0.566), and milk and dairy products (r=0.687), for which good correlations between the FF Quantity and 24hr-DR had been observed previously. Moderate correlations were found for vegetables (r=0.386) and high-salt foods (r=0.505), although the FF Quantity survey poorly correlated with the 24hr-DR. CONCLUSION: The SDPQ may be useful for assessment of dietary propensities for alcohol, starchy foods, and milk and dairy products in Japan. PMID- 29142180 TI - Review on Recent Topics in Hypophysitis. AB - The number of cases of lymphocytic hypophysitis is small, although the condition is not rare. For optimal therapy, the correct diagnosis from imaging, immunological studies, and pathological findings from a pituitary biopsy is important. Recently, anti-Rabphilin antibody has been proposed to be a biomarker for lymphocytic infundibulo-neurohypophysitis. Immunological disorders such as anti-Pit-1 antibody syndrome are similar to the pathogenesis of lymphocytic hypophysitis. Moreover, recent immune checkpoint blockade such ipilimumab has been shown to induce anti-CTLA-4-related hypophysitis. In the future, elucidating the immunological mechanism and establishing a suitable therapy will be necessary for accurate long-term prognosis. PMID- 29142181 TI - Treatment Strategy for Standard-Dose Proton Pump Inhibitor-Resistant Reflux Esophagitis. AB - Reflux esophagitis is characterized by excessive esophageal acid exposure. To treat reflux esophagitis, it is necessary to reduce excessive esophageal acid exposure to within the normal range. The first-line drug for the treatment of reflux esophagitis is a standard-dose proton-pump inhibitor (PPI), which is also recommended by the Evidence-based Clinical Practice Guidelines 2015 for gastroesophageal disease of the Japanese Society of Gastroenterology. It has been reported that the response to a standard dose of PPI in patients with mild reflux esophagitis is 90-100%, and that in patients with severe reflux esophagitis is 80 85%. However, PPI-resistant reflux esophagitis has been increasing. When the standard dose of PPI is not effective, modification of the lifestyle with PPI therapy, switching to another PPI, or a change in the administration method (before meals), as well as double-dose PPI (in divided doses), may be effective. In addition, vonoprazan (potassium-competitive acid blocker), which has rapid and potent acid-suppressive effects, became available in February 2015 in Japan. In the clinical trial data, vonoprazan is very effective for reflux esophagitis. However, clinical data on vonoprazan are still insufficient. The establishment of a new treatment for reflux esophagitis taking advantage of the rapid and potent acid-suppressive effects is awaited. PMID- 29142182 TI - A Real-World Retrospective Cohort Study of Combined Therapy with Bevacizumab and Paclitaxel in Japanese Patients with Metastatic Breast Cancer. AB - OBJECTIVE: Combined therapy with bevacizumab and paclitaxel (BP regimen) as a first-line treatment has proven highly effective with good tolerance for patients with metastatic breast cancer (MBC). The objective of this study was to examine the efficacy and safety of the BP regimen for Japanese patients with MBC in real world clinical settings. METHODS: From June 2012 through May 2014, we recruited 94 patients at 10 medical institutions. The primary endpoint was time to treatment failure (TTF), and the secondary endpoints were overall survival (OS) and safety. Objective response was assessed according to the Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0-Japan Clinical Oncology Group. RESULTS: Nighty patients with MBC (mean 58 years, range: 34-80 years) were enrolled, and 60 (66.6%) and 52 (57.7%) had undergone prior chemotherapy as adjuvant treatment and treatment for MBC, respectively. Median TTF was 6.2 months (95% confidence interval [CI], 4.2-8.3 months), and median OS was 15.4 months (95% CI, 12.0-18.9 months). The overall response rate was 67.8% (95% CI: 57.1-77.2%). A total of 28 patients (31.1%) required a dose reduction of paclitaxel. Forty-five, 42, and 3 patients received the initial doses of 90, 80, and 60 mg/m2, respectively. Among patients who received the initial doses of 90 mg/m2, 13 patients (28.9%) unexpectedly required a dose reduction of >=20 mg/m2. The BP regimen was discontinued for 66 (73.3%) of the 90 patients, 52 (57.7%) of whom experienced "disease progression." Grade 3/4 hematologic AEs developed in 51 patients (56.6%), with leukopenia and neutropenia in 16 patients (17.8%) and 21 patients (23.3%), respectively. Grade 3 nonhematologic AEs developed in 8 patients (8.9%), with the most common nonhematologic AE of peripheral neuropathy in 4 patients (4.4%). No Grade 4 nonhematologic AEs developed. Peripheral neuropathy [56 patients (62.2%) ], nail discoloration [53 patients (58.9%) ], and fatigue [51 patients (56.7%) ] were the most predominant AEs-the known AEs of paclitaxel. CONCLUSIONS: The BP regimen was active and well tolerated in the real-world clinical settings. As many as 28.9% of patients who received the initial dose of 90 mg/m2 required a dose reduction of paclitaxel by 20 mg/m2. Therefore, there is a need to find a therapeutic regimen that is less likely to result in dose reductions for patients with MBC who undergo a BP regimen using the initial paclitaxel dose of 90 mg/m2. PMID- 29142183 TI - Worse Preoperative Status Based on Inflammation and Host Immunity Is a Risk Factor for Surgical Site Infections in Colorectal Cancer Surgery. AB - OBJECTIVE: The modified Glasgow Prognostic Score (mGPS) is an inflammation-based measure of malnutrition that reflects a state of cachexia in cancer patients. We evaluated mGPS as an index to predict surgical site infection (SSI) incidence in patients undergoing colorectal cancer surgery. SUBJECTS AND METHODS: We retrospectively analyzed 351 patients who underwent colon cancer resection. Factors correlated with the incidence of SSIs were identified by logistic analysis and stepwise selection. RESULTS: SSIs were observed in 32 patients, with an incidence of 9.1%. Univariate logistic analysis revealed mGPS (Score 2), laparotomy, resection of other organs, colostomy, excessive blood loss (>423 mL), long duration of surgery (>279 minutes), pulmonary dysfunction, prognostic nutritional index (PNI) <=40, neutrophil lymphocyte ratio (NLR)(>4), and controlling nutritional status (CONUT) >=2 to be associated with an increased incidence of SSIs. Multivariate analysis with variables selected by the stepwise procedure also revealed mGPS (Score 2) (Odds ratio (OR) =3.55, 95% Confidence interval (CI) 1.30-9.56; p=0.01), colostomy (OR=6.56, 95%CI 1.60-31.38; p=0.01), excessive blood loss (OR=3.20, 95%CI 1.23-8.42; p=0.02), and NLR (>4)(OR=3.24, 95%CI 1.31-8.17; p=0.01) to be independent risk factors. CONCLUSION: mGPS is an independent risk factor for SSIs. Our results suggest that cachexia before surgery in patients with colorectal cancer might predict the incidence of SSIs. PMID- 29142184 TI - Efficacy of Cell-Free and Concentrated Ascites Reinfusion Therapy for Palliative Care in a Patient with Malignant Pleural Mesothelioma: A Case Report. AB - Cell-free and concentrated ascites reinfusion therapy (CART) is recognized as a useful treatment to improve the symptoms caused by refractory ascites. Recently, a few clinical studies have reported the effects of CART for malignant ascites, especially in gynecological and gastrointestinal cancers. We report the case of malignant ascites in a patient with malignant pleural mesothelioma (MPM) whose symptoms were relieved by CART. A 59-year-old Japanese male with MPM who had undergone pleural decortication had pleural and peritoneal recurrence. His general status deteriorated as he developed massive ascites due to peritoneal metastases. With the initiation of CART, he recovered well enough to receive cisplatin-based systemic chemotherapy. Repeated use of CART contributed to the maintenance of his good general condition and enabled him to undergo successive systemic chemotherapy, which might have lengthened his life. This is the first report that demonstrates the efficacy of CART for palliative care in a patient with MPM. Our experience indicates that CART should be considered as a treatment option to control refractory malignant ascites regardless of the type of cancer. PMID- 29142185 TI - Anesthesia Procedure for Congenital Insensitivity to Pain in a Child with Anhidrosis Syndrome: A Rare Case. AB - Congenital insensitivity to pain with anhidrosis (CIPA) syndrome is a neuropathy characterized by insensitivity to pain, impaired thermoregulation, anhidrosis, and mental retardation. A 9-year old boy with CIPA syndrome, underwent 2 operations for a calcaneal ulcer. During the first operation standard monitorization was performed. In the second operation, Bispectral Index (BIS) monitoring was added and temperature was monitored with an esophageal probe. In the first operation, in which anesthesia induction was applied with ketamine and midazolam, extremity movements with surgical stimuli were seen. Despite pain insensitivity, as extremity movements were seen with surgical stimuli, propofol was administered in the second operation. Throughout the operation, the BIS values varied from 19-58 and body temperature was measured as 36.1 degrees C-36.9 degrees C. In conclusion, despite the absence of pain sensitivity in CIPA syndrome cases, there is an absolute need for the administration of anesthesia in surgical procedures because of tactile hyperesthesia. PMID- 29142186 TI - Endoscopic Treatment of Boerhaave Syndrome Using Polyglycolic Acid Sheets and Fibrin Glue: A Report of Two Cases. AB - Boerhaave syndrome, the spontaneous perforation of the esophagus, is an emergency, life-threatening condition. Current endoscopic treatment options include clipping and stenting, but the use of polyglycolic acid (PGA) sheets for treating the condition has not been reported. In recent years, PGA sheets have been used after endoscopic submucosal dissection to prevent perforations and stricture formation in patients treated for early-stage carcinoma. We report the cases of two patients with Boerhaave syndrome who were successfully treated using PGA sheets. The present clinical outcomes suggest that the use of PGA sheets is feasible and safe for treating patients with Boerhaave syndrome, and that they may be another treatment option. PMID- 29142187 TI - An ATP2A2 Missense Mutation in a Japanese Family with Darier Disease: A Case Report and Review of the Japanese Darier Disease Patients with ATP2A2 Mutations. AB - Darier disease (DD) is a rare autosomal dominant skin disorder due to mutations in the ATP2A2 gene, which encodes sarco/endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2). The clinical manifestations of DD are characterized by warty papules and plaques in seborrheic areas, and association with neuropsychiatric abnormalities has also been reported in a few families with DD. We herein report a classic Japanese DD case with a previously described mutation (p.C560R) in ATP2A2. In Japan, 26 mutations in the ATP2A2 gene in 7 pedigrees and 19 sporadic cases with DD have been reported, among which one pedigree and one sporadic case were accompanied by neuropsychiatric symptoms. A review of the reports confirmed that most mutations were of the missense type and no consistent genotype phenotype correlations were found. PMID- 29142188 TI - A Case of Microscopic Polyangiitis with Subarachnoid Hemorrhage and Cardiovascular Complications. AB - Microscopic polyangiitis (MPA) is a primary systemic vasculitis that predominantly affects small and medium vessels. MPA is rarely complicated with central nervous system or cardiovascular disease. We report a very rare case of MPA complicated with cerebral infarction, cardiovascular disease, and fatal subarachnoid hemorrhage in a 54-year-old man. During the first six days of hospitalization the patient was diagnosed with rapid progressive glomerulonephritis (RPGN), cerebral infarction, and unstable angina. According to patient's symptoms and laboratory findings, were consisted with a diagnosis of severe MPA. Steroid pulse therapy was immediately introduced. However, the patient developed massive subarachnoid hemorrhage on the 8th day of hospitalization. The condition progressively deteriorated, and the patient died on the 33rd hospital day. PMID- 29142189 TI - A Carbamazepine-induced Brugada-type Electrocardiographic Pattern in a Patient with Schizophrenia. AB - We report the case of a 61-year-old man with schizophrenia who was treated with carbamazepine, in whom electrocardiography showed transient Brugada-type ST elevation. He had been hospitalized our hospital's Department of Psychiatry and had been diagnosed with pneumonia. On the following day, electrocardiography showed coved-type ST elevation in the right precordial leads and a blood examination revealed that the patient's carbamazepine concentration was at the upper limit of the standard range, as well as hypothyroidism. The patient's electrocardiogram normalized after the withdrawal of carbamazepine. We demonstrated that the patient's carbamazepine concentration-and not hypothyroidism-was associated with the serial electrocardiographic changes by monitoring the patient's blood concentration of carbamazepine and his thyroid function. PMID- 29142190 TI - Detection of Atherosclerotic Plaques in the Rabbit Aorta Using Ultrasound Microbubbles Conjugated to Interleukin-18 Antibodies. AB - BACKGROUND The purpose of the study was to investigate the ability of microbubbles (MBs) targeting interleukin-18 (IL-18) to detect plaques in a rabbit atherosclerotic plaque model. MATERIAL AND METHODS A rabbit atherosclerotic plaque model was established. The locations of the atherosclerotic plaques were verified by two-dimensional scanning and color Doppler flow imaging. An IL-18 antibody was conjugated to naked MBs (MBc) using the biotin-streptavidin conjugation method, resulting in the formation of MBIL-18. MBc and MBIL-18 were then used for contrast-enhanced ultrasound (CEUS) studies. The locations of CD34 and IL-18 within the plaques were determined by immunohistochemistry, and IL-18 expression levels in the plaques were determined by Western blot analysis. The relationships between IL-18 expression and the contrast intensity of the 2 MBs were analyzed. RESULTS MBc and MBIL-18 were both uniformly dispersed. Fluorescence microscopy and flow cytometry revealed that IL-18 was successfully conjugated to MBs. CEUS images showed that the intensity of the MBIL-18 signal was substantially enhanced and prolonged compared with that of the MBc signal. Immunohistochemistry showed that CD34 expression was significantly increased in the plaques and that IL-18 was mainly located in the inner parts and base of the atherosclerotic plaques. Western blot analysis revealed that IL-18 expression was higher in the plaque regions. Correlation analysis showed that IL-18 expression was correlated with the contrast intensity of MBIL-18 (r=0.903, P<0.05) but not with MBc (r=0.540, P>0.05). CONCLUSIONS MBs targeting IL-18 may be a novel, noninvasive method of diagnosing atherosclerotic plaques. PMID- 29142191 TI - Immune-Neuroendocrine Interactions: Evolution, Ecology, and Susceptibility to Illness. AB - The integration between immune and neuroendocrine systems is crucial for maintaining homeostasis from invertebrates to humans. In the first, the phagocytic cell, i.e., the immunocyte, is the main actor, while in the latter, the principle player is the lymphocyte. Immunocytes are characterized by the presence of pro-opiomelanocortin (POMC) peptides, CRH, and other molecules that display a significant similarity to their mammalian counterparts regarding their functions, as both are mainly involved in fundamental functions such as immune (chemotaxis, phagocytosis, cytotoxicity, etc.) and neuroendocrine (stress) responses. Furthermore, the immune-neuroendocrine system provides vital answers to ecological and immunological demands in terms of economy and efficiency. Finally, susceptibility to disease emerges as the result of a continuous dynamic interaction between the world within and the world outside. New fields such as ecological immunology study the susceptibility to pathogens in an evolutionary perspective while the field of neuro-endocrine-immunology studies the susceptibility from a more immediate perspective. PMID- 29142192 TI - Successful Post-Transplant Psychiatric Interventions During Long-Term Follow-Up of Patients Receiving Liver Transplants for Alcoholic Liver Disease. AB - BACKGROUND Around 20-30% of patients who undergo liver transplantation (LT) for alcoholic liver disease (ALD) will resume heavy drinking after LT. It is crucial to control post-transplant relapse of alcohol use, because alcoholic recidivism has been shown to have a negative impact on post-transplant compliance and long term outcomes of LT recipients. However, there is currently no specific, effective psychiatric intervention for preventing additional alcohol consumption in clinical practice. CASE REPORT We present 3 patients who underwent LT for ALD at Nagoya University Hospital who were followed up for prolonged periods (7.2, 8.8, and 11.3 years, respectively), and review the psychiatric interventions employed to address critical situations. Additional alcohol consumption was noted in Case 1, but prompt collaborative care led to stable abstinence. In Case 2, marked anger and irritation were exacerbated as a result of work, but the anger was controlled by anger management. Case 3 abused a minor tranquilizer, but limit setting resulted in adequate medical adherence. CONCLUSIONS Transplant teams need to provide comprehensive treatment for alcoholic recidivism to improve long-term health after LT for ALD. PMID- 29142193 TI - PTEN is a protein phosphatase that targets active PTK6 and inhibits PTK6 oncogenic signaling in prostate cancer. AB - PTEN activity is often lost in prostate cancer. We show that the tyrosine kinase PTK6 (BRK) is a PTEN substrate. Phosphorylation of PTK6 tyrosine 342 (PY342) promotes activation, while phosphorylation of tyrosine 447 (PY447) regulates auto inhibition. Introduction of PTEN into a PTEN null prostate cancer cell line leads to dephosphorylation of PY342 but not PY447 and PTK6 inhibition. Conversely, PTEN knockdown promotes PTK6 activation in PTEN positive cells. Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342. Conditional disruption of Pten in the mouse prostate leads to tumorigenesis and increased phosphorylation of PTK6 Y342, and disruption of Ptk6 impairs tumorigenesis. In human prostate tumor tissue microarrays, loss of PTEN correlates with increased PTK6 PY342 and poor outcome. These data suggest PTK6 activation promotes invasive prostate cancer induced by PTEN loss. PMID- 29142194 TI - Transient cardiomyocyte fusion regulates cardiac development in zebrafish. AB - Cells can sacrifice their individuality by fusing, but the prevalence and significance of this process are poorly understood. To approach these questions, here we generate transgenic reporter lines in zebrafish to label and specifically ablate fused cells. In addition to skeletal muscle cells, the reporters label cardiomyocytes starting at an early developmental stage. Genetic mosaics generated by cell transplantation show cardiomyocytes expressing both donor- and host-derived transgenes, confirming the occurrence of fusion in larval hearts. These fusion events are transient and do not generate multinucleated cardiomyocytes. Functionally, cardiomyocyte fusion correlates with their mitotic activity during development as well as during regeneration in adult animals. By analyzing the cell fusion-compromised jam3b mutants, we propose a role for membrane fusion in cardiomyocyte proliferation and cardiac function. Together, our findings uncover the previously unrecognized process of transient cardiomyocyte fusion and identify its potential role in cardiac development and function. PMID- 29142195 TI - Structural basis for tRNA-dependent cysteine biosynthesis. AB - Cysteine can be synthesized by tRNA-dependent mechanism using a two-step indirect pathway, where O-phosphoseryl-tRNA synthetase (SepRS) catalyzes the ligation of a mismatching O-phosphoserine (Sep) to tRNACys followed by the conversion of tRNA bounded Sep into cysteine by Sep-tRNA:Cys-tRNA synthase (SepCysS). In ancestral methanogens, a third protein SepCysE forms a bridge between the two enzymes to create a ternary complex named the transsulfursome. By combination of X-ray crystallography, SAXS and EM, together with biochemical evidences, here we show that the three domains of SepCysE each bind SepRS, SepCysS, and tRNACys, respectively, which mediates the dynamic architecture of the transsulfursome and thus enables a global long-range channeling of tRNACys between SepRS and SepCysS distant active sites. This channeling mechanism could facilitate the consecutive reactions of the two-step indirect pathway of Cys-tRNACys synthesis (tRNA dependent cysteine biosynthesis) to prevent challenge of translational fidelity, and may reflect the mechanism that cysteine was originally added into genetic code. PMID- 29142196 TI - DJ-1 controls bone homeostasis through the regulation of osteoclast differentiation. AB - Receptor activator of NF-kB ligand (RANKL) generates intracellular reactive oxygen species (ROS), which increase RANKL-mediated signaling in osteoclast (OC) precursor bone marrow macrophages (BMMs). Here we show that a ROS scavenging protein DJ-1 negatively regulates RANKL-driven OC differentiation, also called osteoclastogenesis. DJ-1 ablation in mice leads to a decreased bone volume and an increase in OC numbers. In vitro, the activation of RANK-dependent signals is enhanced in DJ-1-deficient BMMs as compared to wild-type BMMs. DJ-1 suppresses the activation of both RANK-TRAF6 and RANK-FcRgamma/Syk signaling pathways because of activation of Src homology region 2 domain-containing phosphatase-1, which is inhibited by ROS. Ablation of DJ-1 in mouse models of arthritis and RANKL-induced bone disease leads to an increase in the number of OCs, and exacerbation of bone damage. Overall, our results suggest that DJ-1 plays a role in bone homeostasis in normal physiology and in bone-associated pathology by negatively regulating osteoclastogenesis. PMID- 29142198 TI - Shock Synthesis of Decagonal Quasicrystals. AB - The Khatyrka meteorite contains both icosahedral and decagonal quasicrystals. In our previous studies, icosahedral quasicrystals have been synthesized and recovered from shock experiments at the interface between CuAl5 and stainless steel 304 alloys. In this study, we report a new shock recovery experiment aimed at synthesizing decagonal quasicrystals similar to decagonite, natural Al71Ni24Fe5. Aluminum 2024 and permalloy 80 alloys were stacked together and shocked in a stainless steel 304 recovery chamber. Abundant decagonal quasicrystals of average composition Al73Ni19Fe4Cu2Mg0.6Mo0.4Mn0.3 with traces of Si and Cr were found along the recovered interface between the Al and permalloy. The experiment also synthesized AlNiFe alloy with the B2 (CsCl-type) structure and the metastable Al9Ni2 phase. We present chemical (scanning electron microscopy and electron microprobe) and structural (electron backscatter diffraction and transmission electron microscopy) characterization of the recovered phases and discuss the implications of this shock synthesis for the stability of quasicrystals during high-pressure shocks and for the interpretation of the phase assemblage found in Khatyrka. PMID- 29142197 TI - Proteotoxicity in cardiac amyloidosis: amyloidogenic light chains affect the levels of intracellular proteins in human heart cells. AB - AL amyloidosis is characterized by widespread deposition of immunoglobulin light chains (LCs) as amyloid fibrils. Cardiac involvement is frequent and leads to life-threatening cardiomyopathy. Besides the tissue alteration caused by fibrils, clinical and experimental evidence indicates that cardiac damage is also caused by proteotoxicity of prefibrillar amyloidogenic species. As in other amyloidoses, the damage mechanisms at cellular level are complex and largely undefined. We have characterized the molecular changes in primary human cardiac fibroblasts (hCFs) exposed in vitro to soluble amyloidogenic cardiotoxic LCs from AL cardiomyopathy patients. To evaluate proteome alterations caused by a representative cardiotropic LC, we combined gel-based with label-free shotgun analysis and performed bioinformatics and data validation studies. To assess the generalizability of our results we explored the effects of multiple LCs on hCF viability and on levels of a subset of cellular proteins. Our results indicate that exposure of hCFs to cardiotropic LCs translates into proteome remodeling, associated with apoptosis activation and oxidative stress. The proteome alterations affect proteins involved in cytoskeletal organization, protein synthesis and quality control, mitochondrial activity and metabolism, signal transduction and molecular trafficking. These results support and expand the concept that soluble amyloidogenic cardiotropic LCs exert toxic effects on cardiac cells. PMID- 29142199 TI - SensorFRET: A Standardless Approach to Measuring Pixel-based Spectral Bleed through and FRET Efficiency using Spectral Imaging. AB - Fluorescence microscopy of FRET-based biosensors allow nanoscale interactions to be probed in living cells. This paper describes a novel approach to spectrally resolved fluorescence microscopy, termed sensorFRET, that enables quantitative measurement of FRET efficiency. This approach is an improvement on existing methods (FLIM, sRET, luxFRET, pFRET), as it does not require single fluorophore standards to be measured with every experiment and the acquisition is intensity independent, allowing the laser power to be optimized for varying levels of fluorophore expression. Additionally, it was found that all spectral based methods, including sensorFRET, fail at specific fluorophore-excitation wavelength combinations. These combinations can be determined a priori using sensorFRET, whereas other methods would give no indication of inaccuracies. This method was thoroughly validated and compared to existing methods using simulated spectra, Fluorescein and TAMRA dye mixtures as a zero FRET control, and Cerulean-Venus FRET standards as positive FRET controls. Simulations also provided a means of quantifying the uncertainty in each measurement by relating the fit residual of noisy spectra to the standard deviation of the measured FRET efficiency. As an example application, Teal-Venus force sensitive biosensors integrated into E cadherin were used to resolve piconewton scale forces along different parts of an individual cell junction. PMID- 29142200 TI - Potassium fertilisation reduces radiocesium uptake by Japanese cypress seedlings grown in a stand contaminated by the Fukushima Daiichi nuclear accident. AB - We analysed suppressive effects of potassium (K) fertilisation on radiocesium (137Cs) uptake by hinoki cypress (Chamaecyparis obtusa) seedlings from soils contaminated after the Fukushima Daiichi Nuclear Power Plant accident. Three-year old seedlings were planted in a clear-cut forest (ca. 4 ha) during June-July 2014, and potassium chloride fertiliser (83 kg K ha-1) was applied twice (August 2014 and April 2015). 137Cs concentrations in the needles in the fertilised plots were one-eighth of those in the control (unfertilised) plots at the end of the second growing season (October 2015). Our results clearly indicated that K fertilisation reduced radiocesium transfer from soil to planted cypress seedlings. A linear mixed model analysis revealed that 137Cs concentrations in the needles were significantly affected by 137Cs inventory in the soil (Bq m-2) adjacent to the sampled seedlings, exchangeable K concentrations in surface mineral soils (0-5 cm) and fertilisation. The exchangeable K concentrations in surface soils in October 2015 did not differ from those in August 2014 (before fertilisation) in the fertilised plots and in the control plots. These results suggested that the levels of exchangeable K would temporarily increase by fertilisation during the growing season, and radiocesium uptake by tree roots was suppressed. PMID- 29142201 TI - Assessment of Genetic Diversity and Population Structure in Iranian Cannabis Germplasm. AB - Cannabis sativa has a complex history reflected in both selection on naturally occurring compounds and historical trade routes among humans. Iran is a rich resource of natural populationswhich hold the promise to characterize historical patterns of population structure and genetic diversity within Cannabis. Recent advances in high-throughput DNA sequencing technologies have dramatically increased our ability to produce information to the point that it is now feasible to inexpensively obtain population level genotype information at a large scale. In the present investigation, we have explored the use of Genotyping-By Sequencing (GBS) in Iranian cannabis. We genotyped 98 cannabis samples 36 from Iranian locations and 26 accessions from two germplasm collections. In total, 24,710 high-quality Single Nucleotide Polymorphisms (SNP) were identified. Clustering analysis by Principal Component Analysis (PCA) identified two genetic clusters among Iranian populations and fineSTRUCTURE analysis identified 19 populations with some geographic partitioning. We defined Iranian cannabis in two main groups using the results of the PCA and discovered some strong signal to define some locations as population according to fineSTRUCTURE analyses. However, single nucleotide variant analysis uncovered a relatively moderate level of variation among Iranian cannabis. PMID- 29142203 TI - Mode of delivery and child and adolescent psychological well-being: Evidence from Hong Kong's "Children of 1997" birth cohort. AB - Mode of delivery (vaginal or cesarean section) is thought to affect gut microbiota, which in turn may affect psychological well-being. As such, mode of delivery is potentially a modifiable factor for psychological well-being. Here we examined the association of mode of delivery with child and adolescent psychological well-being. We used multivariable linear regression in a population representative Hong Kong Chinese birth cohort, "Children of 1997," to examine the adjusted associations of mode of delivery with behavioral problems assessed from parent-reported Rutter score at ~7 (n = 6294) and ~11 years (n = 5598), self esteem assessed from self-reported Culture-Free Self-Esteem Inventory score at ~11 years (n = 6937) and depressive symptoms assessed from self-reported Patient Health Questionnaire-9 score at ~13 years (n = 5797). Cesarean Section (CS) was associated with children born in private hospitals, boys, and firstborns, higher maternal body mass index, higher maternal age, preeclampsia, higher socioeconomic position (SEP) and maternal birth in Hong Kong. CS was unrelated to behavior, self-esteem and depressive symptoms adjusted for infant characteristics (sex, gestational age, birthweight, parity and breast feeding), maternal characteristics (mother's age and place of birth) and SEP. In a developed non Western setting, mode of delivery was not clearly associated with childhood or early adolescent psychological well-being. PMID- 29142202 TI - Genomic mosaicism in paternal sperm and multiple parental tissues in a Dravet syndrome cohort. AB - Genomic mosaicism in parental gametes and peripheral tissues is an important consideration for genetic counseling. We studied a Chinese cohort affected by a severe epileptic disorder, Dravet syndrome (DS). There were 56 fathers who donated semen and 15 parents who donated multiple peripheral tissue samples. We used an ultra-sensitive quantification method, micro-droplet digital PCR (mDDPCR), to detect parental mosaicism of the proband's pathogenic mutation in SCN1A, the causal gene of DS in 112 families. Ten of the 56 paternal sperm samples were found to exhibit mosaicism of the proband's mutations, with mutant allelic fractions (MAFs) ranging from 0.03% to 39.04%. MAFs in the mosaic fathers' sperm were significantly higher than those in their blood (p = 0.00098), even after conditional probability correction (p' = 0.033). In three mosaic fathers, ultra-low fractions of mosaicism (MAF < 1%) were detected in the sperm samples. In 44 of 45 cases, mosaicism was also observed in other parental peripheral tissues. Hierarchical clustering showed that MAFs measured in the paternal sperm, hair follicles and urine samples were clustered closest together. Milder epileptic phenotypes were more likely to be observed in mosaic parents (p = 3.006e-06). Our study provides new insights for genetic counseling. PMID- 29142204 TI - Sociospatial structure explains marked variation in brucellosis seroprevalence in an Alpine ibex population. AB - In a context of (re)emerging infectious diseases with wildlife reservoirs, understanding how animal ecology shapes epidemiology is a key issue, particularly in wild ungulates that share pathogens with domestic herbivores and have similar food requirements. For the first time in Europe, brucellosis (Brucella melitensis), a virulent zoonosis, persisted in an Alpine ibex (Capra ibex) population and was transmitted to cattle and humans. To better understand disease dynamics, we investigated the relationships between the spatial ecology of ibex and the epidemiology of brucellosis. Combining home range overlap between 37 GPS collared individuals and visual observations of 148 visually-marked individuals monitored during the 2013-2016 period, we showed that females were spatially segregated in at least 4 units all year round, whereas males were more prone to move between female units, in particular during the rutting period. In addition to ibex age, the spatial structure in females largely contributed to variation in seroprevalence in the whole population. These results suggest that non-sexual routes are the most likely pathways of intraspecific transmission, crucial information for management. Accounting for wildlife spatial ecology was hence decisive in improving our ability to better understand this health challenge involving a wildlife reservoir. PMID- 29142205 TI - Coupling of emergent octahedral rotations to polarization in (K,Na)NbO3 ferroelectrics. AB - Perovskite potassium sodium niobates, K1-xNaxNbO3, are promising lead-free piezoelectrics. Their dielectric and piezoelectric characteristics peak near x = 0.5, but the reasons for such property enhancement remain unclear. We addressed this uncertainty by analyzing changes in the local and average structures across the x = 0.5 composition, which have been determined using simultaneous Reverse Monte Carlo fitting of neutron and X-ray total-scattering data, potassium EXAFS, and diffuse-scattering patterns in electron diffraction. Within the A-sites, Na cations are found to be strongly off-centered along the polar axis as a result of oversized cube-octahedral cages determined by the larger K ions. These Na displacements promote off-centering of the neighboring Nb ions, so that the Curie temperature and spontaneous polarization remain largely unchanged with increasing x, despite the shrinking octahedral volumes. The enhancement of the properties near x = 0.5 is attributed to an abrupt increase in the magnitude and probability of the short-range ordered octahedral rotations, which resembles the pre transition behavior. These rotations reduce the bond tension around Na and effectively soften the short Na-O bond along the polar axis - an effect that is proposed to facilitate reorientation of the polarization as external electric field is applied. PMID- 29142206 TI - EGFR conjunct FSCN1 as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer. AB - Emerging evidence indicates that Fascin-1 (FSCN1) may possess a causal role in the development of several types of cancers and serves as a novel biomarker of aggressiveness in certain carcinomas. However, the regulatory mechanism of FSCN1 in triple-negative breast cancer (TNBC) cell invasion and migration is still largely unknown. In our study, we observed that the FSCN1 expression rates were significantly higher in invasive ductal carcinoma, compared with both usual ductal hyperplasia and ductal carcinoma in situ. FSCN1 expression was significantly higher in cases of TNBC compared with the non-TNBC subtype. Overexpression of FSCN1 promoted TNBC cell migration and invasion. Epidermal growth factor induced the expression of FSCN1 through activation of MAPK, which subsequently promoted cell migration and invasion. A significant decrease in FSCN1 expression following the co-treatment of FSCN1 siRNA and Gefitinib, compared with the separate treatment of FSCN1 siRNA or Gefitinib. Furthermore, we found that there was a significant association between FSCN1 expression and poor relapse-free survival and overall survival. Therefore, we suggest that co targeting epidermal growth factor receptor and FSCN1 dual biomarker may be used as a novel therapeutic strategy for TNBC. PMID- 29142207 TI - Phosphorylation Dynamics Dominate the Regulated Proteome during Early Xenopus Development. AB - The earliest stages of animal development are largely controlled by changes in protein phosphorylation mediated by signaling pathways and cyclin-dependent kinases. In order to decipher these complex networks and to discover new aspects of regulation by this post-translational modification, we undertook an analysis of the X. laevis phosphoproteome at seven developmental stages beginning with stage VI oocytes and ending with two-cell embryos. Concurrent measurement of the proteome and phosphoproteome enabled measurement of phosphosite occupancy as a function of developmental stage. We observed little change in protein expression levels during this period. We detected the expected phosphorylation of MAP kinases, translational regulatory proteins, and subunits of APC/C that validate the accuracy of our measurements. We find that more than half the identified proteins possess multiple sites of phosphorylation that are often clustered, where kinases work together in a hierarchical manner to create stretches of phosphorylated residues, which may be a means to amplify signals or stabilize a particular protein conformation. Conversely, other proteins have opposing sites of phosphorylation that seemingly reflect distinct changes in activity during this developmental timeline. PMID- 29142208 TI - Transient increases in intracellular calcium and reactive oxygen species levels in TCam-2 cells exposed to microgravity. AB - The effects of microgravity on functions of the human body are well described, including alterations in the male and female reproductive systems. In the present study, TCam-2 cells, which are considered a good model of mitotically active male germ cells, were used to investigate intracellular signalling and cell metabolism during exposure to simulated microgravity, a condition that affects cell shape and cytoskeletal architecture. After a 24 hour exposure to simulated microgravity, TCam-2 cells showed 1) a decreased proliferation rate and a delay in cell cycle progression, 2) increased anaerobic metabolism accompanied by increased levels of intracellular Ca2+, reactive oxygen species and superoxide anion and modifications in mitochondrial morphology. Interestingly, all these events were transient and were no longer evident after 48 hours of exposure. The presence of antioxidants prevented not only the effects described above but also the modifications in cytoskeletal architecture and the activation of the autophagy process induced by simulated microgravity. In conclusion, in the TCam-2 cell model, simulated microgravity activated the oxidative machinery, triggering transient macroscopic cell events, such as a reduction in the proliferation rate, changes in cytoskeleton-driven shape and autophagy activation. PMID- 29142209 TI - Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma. AB - The Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCFFbxo4 complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCFFbxo4. Consistent with a substrate relationship, Fxr1 is overexpressed in Fbxo4 knockout cells, tissues and in human cancer cells, harbouring inactivating Fbxo4 mutations. Critically, in head and neck squamous cell carcinoma, Fxr1 overexpression correlates with reduced Fbxo4 levels in the absence of mutations or loss of mRNA, suggesting the potential for feedback regulation. Direct analysis reveals that Fbxo4 translation is attenuated by Fxr1, indicating the existence of a feedback loop that contributes to Fxr1 overexpression and the loss of Fbxo4. Ultimately, the consequence of Fxr1 overexpression is the bypass of senescence and neoplastic progression. PMID- 29142210 TI - Millisecond dynamics of BTK reveal kinome-wide conformational plasticity within the apo kinase domain. AB - Bruton tyrosine kinase (BTK) is a key enzyme in B-cell development whose improper regulation causes severe immunodeficiency diseases. Design of selective BTK therapeutics would benefit from improved, in-silico structural modeling of the kinase's solution ensemble. However, this remains challenging due to the immense computational cost of sampling events on biological timescales. In this work, we combine multi-millisecond molecular dynamics (MD) simulations with Markov state models (MSMs) to report on the thermodynamics, kinetics, and accessible states of BTK's kinase domain. Our conformational landscape links the active state to several inactive states, connected via a structurally diverse intermediate. Our calculations predict a kinome-wide conformational plasticity, and indicate the presence of several new potentially druggable BTK states. We further find that the population of these states and the kinetics of their inter-conversion are modulated by protonation of an aspartate residue, establishing the power of MD & MSMs in predicting effects of chemical perturbations. PMID- 29142211 TI - The microbiota protects against respiratory infection via GM-CSF signaling. AB - The microbiota promotes resistance to respiratory infection, but the mechanistic basis for this is poorly defined. Here, we identify members of the microbiota that protect against respiratory infection by the major human pathogens Streptococcus pneumoniae and Klebsiella pneumoniae. We show that the microbiota enhances respiratory defenses via granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which stimulates pathogen killing and clearance by alveolar macrophages through extracellular signal-regulated kinase signaling. Increased pulmonary GM-CSF production in response to infection is primed by the microbiota through interleukin-17A. By combining models of commensal colonization in antibiotic-treated and germ-free mice, using cultured commensals from the Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria phyla, we found that potent Nod-like receptor-stimulating bacteria in the upper airway (Staphylococcus aureus and Staphylococcus epidermidis) and intestinal microbiota (Lactobacillus reuteri, Enterococcus faecalis, Lactobacillus crispatus and Clostridium orbiscindens) promote resistance to lung infection through Nod2 and GM-CSF. Our data reveal the identity, location, and properties of bacteria within the microbiota that regulate lung immunity, and delineate the host signaling axis they activate to protect against respiratory infection. PMID- 29142212 TI - Dye-sensitized solar cells based on a push-pull zinc phthalocyanine bearing diphenylamine donor groups: computational predictions face experimental reality. AB - Computational studies have suggested that the integration of secondary amine as donor groups in the structure of unsymmetrical zinc phthalocyanine (ZnPc) should have positive effects on photovoltaic performance, once the molecule is integrated as light harvester in dye sensitized solar cells (DSSCs). Aiming at obtaining experimental confirmation, we synthesized a peripherally substituted push-pull ZnPc bearing three electron donating diphenylamine substituents and a carboxylic acid anchoring group and integrated it as sensitizer in TiO2-based DSSCs. Detailed functional characterization of solar energy converting devices resulted in ruling out the original hypothesis. The causes of this discrepancy have been highlighted, leading to a better understanding of the conditions for an effective design of push-pull diarylamino substituted ZnPcs for DSSCs. PMID- 29142213 TI - Exploring the alpha desynchronization hypothesis in resting state networks with intracranial electroencephalography and wiring cost estimates. AB - This paper addresses a fundamental question, are eyes closed and eyes open resting states equivalent baseline conditions, or do they have consistently different electrophysiological signatures? We compare the functional connectivity patterns in an eyes closed resting state with an eyes open resting state to investigate the alpha desynchronization hypothesis. The change in functional connectivity from eyes closed to eyes open, is here, for the first time, studied with intracranial recordings. We perform network connectivity analysis in iEEG and we find that phase-based connectivity is sensitive to the transition from eyes closed to eyes open only in interhemispheral and frontal electrodes. Power based connectivity, on the other hand, consistently discriminates between the two conditions in temporal and interhemispheral electrodes. Additionally, we provide a calculation for the wiring cost, defined in terms of the connectivity between electrodes weighted by distance. We find that the wiring cost variation from eyes closed to eyes open is sensitive to the eyes closed and eyes open conditions. We extend the standard network-based approach using the filtration method from algebraic topology which does not rely on the threshold selection problem. Both the wiring cost measure defined here and this novel methodology provide a new avenue for understanding the electrophysiology of resting state. PMID- 29142214 TI - Plastic deformation mechanisms in a severely deformed Fe-Ni-Al-C alloy with superior tensile properties. AB - Nanostructured metals have high strength while they usually exhibit limited uniform elongation. While, a yield strength of approximately 2.1 GPa and a uniform elongation of about 26% were achieved in a severely deformed Fe-24.8%Ni 6.0%Al-0.38%C alloy in the present work. The plastic deformation mechanisms for the coarse-grained (CG) sample and the cold-rolled (CR) samples of this alloy were investigated by a series of mechanical tests and microstructure characterizations before and after tensile tests. No obvious phase transformation was observed during the tensile deformation for the CG sample, and the plastic deformation was found to be mainly accommodated by deformation twins and dislocation behaviors. While significant phase transformation occurs for the CR samples due to the facts that the deformed grains by CR are insufficient to sustain the tensile deformation themselves and the flow stress for the CR samples is high enough to activate the martensite transformation. The amount of phase transformation increases with increasing thickness reduction of CR, resulting in excellent tensile ductility in the severely deformed alloy. The back stress hardening was found to play a more important role in the CR samples than in the CG sample due to the dynamically reinforced heterogeneous microstructure by phase transformation. PMID- 29142215 TI - The effects of artocarpin on wound healing: in vitro and in vivo studies. AB - The skin protects the body against harmful substances and microorganisms. When the skin is damaged, wound healing must be finely regulated to restore the normal function of skin tissue. Artocarpin (ARTO), a prenylated flavonoid purified from the plant Artocarpus communis, has been reported to have anti-inflammatory and anti-cancer properties. The aim of the present study was to evaluate the wound healing potential and therapeutic mechanism of ARTO. Immunohistochemical staining of neutrophils and macrophages and mouse cytokine array analysis demonstrated that ARTO accelerates inflammatory progression and subsequently decreases persistent inflammation. ARTO increases collagen production and increases human fibroblast proliferation and migration by activating the P38 and JNK pathways. Moreover, ARTO increases the proliferation and migration of human keratinocytes through the ERK and P38 pathways and augments human endothelial cell proliferation and tube formation through the Akt and P38 pathways. Together, our data suggested that ARTO enhances skin wound healing, possibly by accelerating the inflammatory phase and by increasing myofibroblast differentiation, proliferation and migration of fibroblasts and keratinocytes, collagen synthesis and maturation, re-epithelialization, and angiogenesis. These findings indicate that ARTO has potential as a potent therapeutic agent for the treatment of skin wounds. PMID- 29142216 TI - Polymer mimics of biomacromolecular antifreezes. AB - Antifreeze proteins from polar fish species are remarkable biomacromolecules which prevent the growth of ice crystals. Ice crystal growth is a major problem in cell/tissue cryopreservation for transplantation, transfusion and basic biomedical research, as well as technological applications such as icing of aircraft wings. This review will introduce the rapidly emerging field of synthetic macromolecular (polymer) mimics of antifreeze proteins. Particular focus is placed on designing polymers which have no structural similarities to antifreeze proteins but reproduce the same macroscopic properties, potentially by different molecular-level mechanisms. The application of these polymers to the cryopreservation of donor cells is also introduced. PMID- 29142218 TI - Correspondence: On the bonding in ligand-protected gold clusters. PMID- 29142217 TI - FBXO32 promotes microenvironment underlying epithelial-mesenchymal transition via CtBP1 during tumour metastasis and brain development. AB - The set of events that convert adherent epithelial cells into migratory cells are collectively known as epithelial-mesenchymal transition (EMT). EMT is involved during development, for example, in triggering neural crest migration, and in pathogenesis such as metastasis. Here we discover FBXO32, an E3 ubiquitin ligase, to be critical for hallmark gene expression and phenotypic changes underlying EMT. Interestingly, FBXO32 directly ubiquitinates CtBP1, which is required for its stability and nuclear retention. This is essential for epigenetic remodeling and transcriptional induction of CtBP1 target genes, which create a suitable microenvironment for EMT progression. FBXO32 is also amplified in metastatic cancers and its depletion in a NSG mouse xenograft model inhibits tumor growth and metastasis. In addition, FBXO32 is essential for neuronal EMT during brain development. Together, these findings establish that FBXO32 acts as an upstream regulator of EMT by governing the gene expression program underlying this process during development and disease. PMID- 29142219 TI - Electroacupuncture Attenuates Induction of Inflammatory Pain by Regulating Opioid and Adenosine Pathways in Mice. AB - Although inflammatory pain is a common clinical condition, its mechanisms are still unclear. Electroacupuncture (EA), a well-known method of pain management, may reduce inflammatory pain by regulating neurons, astrocytes, and inflammatory signaling pathways. Injections of complete Freund's adjuvant (CFA), which can initiate cell-mediated inflammatory pain, resulted in significant hyperalgesia, which was subsequently prevented by EA. In CFA-injected mice, a dramatic increase was observed in the expression of the following proteins in the dorsal root ganglion and spinal cord dorsal horn: the astrocytic marker GFAP, S100B, RAGE, pPKCepsilon, COX-2, pERK, and pNFkappaB. These effects were reversed by EA. In addition, mechanical hyperalgesia was significantly reduced in the N6 cyclopentyladenosine (CPA) i.p. or i.m. and endomorphin (EM) i.p. groups. Neither EM i.m. nor EM i.p. exhibited any analgesic effect on thermal hyperalgesia. However, both CPA i.m. and CPA i.p. attenuated thermal hyperalgesia in the mouse inflammatory pain model. We showed that CPA reduced COX-2 and pPKCepsilon expression. However, EM administration did not reduce COX-2 levels. Combined administration of naloxone and rolofylline increased pPKCepsilon and COX-2 pathways. Taken together, our study results revealed a novel and detailed mechanism of EA-induced analgesia that involves the regulation of the opioid and adenosine pathways. PMID- 29142220 TI - Imaging spectroscopy of solar radio burst fine structures. AB - Solar radio observations provide a unique diagnostic of the outer solar atmosphere. However, the inhomogeneous turbulent corona strongly affects the propagation of the emitted radio waves, so decoupling the intrinsic properties of the emitting source from the effects of radio wave propagation has long been a major challenge in solar physics. Here we report quantitative spatial and frequency characterization of solar radio burst fine structures observed with the Low Frequency Array, an instrument with high-time resolution that also permits imaging at scales much shorter than those corresponding to radio wave propagation in the corona. The observations demonstrate that radio wave propagation effects, and not the properties of the intrinsic emission source, dominate the observed spatial characteristics of radio burst images. These results permit more accurate estimates of source brightness temperatures, and open opportunities for quantitative study of the mechanisms that create the turbulent coronal medium through which the emitted radiation propagates. PMID- 29142221 TI - Biogenic selenium and its hepatoprotective activity. AB - Elemental selenium nanoparticles (SeNPs) have multiple biological activities. In this study, we investigated the protective effects of biogenic SeNPs (BioSeNPs) on CCl4-induced liver damage in mice. The results showed that: (i) when compared to sodium selenite (SS), BioSeNPs has a similar tissue distribution after intragastrical administration to mice; (ii) BioSeNPs and SS showed comparable efficacy in increasing the activities of glutathione peroxidase and thioredoxin reductase in liver cell lines, mice blood and liver; (iii) pretreatment with BioSeNPs inhibiting the elevation of activities of various enzymes significantly which included aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and liver lipid peroxide (p < 0.05 or p < 0.01) in CCl4-treated mice; (iv) activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) were significantly increased (p < 0.05 or p < 0.01) after a pretreatment with BioSeNPs in CCl4-treated mice; (v) histopathological damages in the liver from CCl4-treated mice were ameliorated by a pretreatment with BioSeNPs. In conclusion, these results have shown that BioSeNPs is able to protect the liver from CCl4-induced hepatic damage via increasing the antioxidant capacity and inhibiting oxidative damage. BioSeNPs may have the potential to be used as a trace element food supplement inducing antioxidant bioactivities. PMID- 29142222 TI - Human ATG3 binding to lipid bilayers: role of lipid geometry, and electric charge. AB - Specific protein-lipid interactions lead to a gradual recruitment of AuTophaGy related (ATG) proteins to the nascent membrane during autophagosome (AP) formation. ATG3, a key protein in the movement of LC3 towards the isolation membrane, has been proposed to facilitate LC3/GABARAP lipidation in highly curved membranes. In this work we have performed a biophysical study of human ATG3 interaction with membranes containing phosphatidylethanolamine, phosphatidylcholine and anionic phospholipids. We have found that ATG3 interacts more strongly with negatively-charged phospholipid vesicles or nanotubes than with electrically neutral model membranes, cone-shaped anionic phospholipids (cardiolipin and phosphatidic acid) being particularly active in promoting binding. Moreover, an increase in membrane curvature facilitates ATG3 recruitment to membranes although addition of anionic lipid molecules makes the curvature factor relatively less important. The predicted N-terminus amphipathic alpha helix of ATG3 would be responsible for membrane curvature detection, the positive residues Lys 9 and 11 being essential in the recognition of phospholipid negative moieties. We have also observed membrane aggregation induced by ATG3 in vitro, which could point to a more complex function of this protein in AP biogenesis. Moreover, in vitro GABARAP lipidation assays suggest that ATG3-membrane interaction could facilitate the lipidation of ATG8 homologues. PMID- 29142223 TI - Active diffusion and advection in Drosophila oocytes result from the interplay of actin and microtubules. AB - Transport in cells occurs via a delicate interplay of passive and active processes, including diffusion, directed transport and advection. Despite progress in super-resolution microscopy, discriminating and quantifying these processes is a challenge, requiring tracking of rapidly moving, sub-diffraction objects in a crowded, noisy environment. Here we use differential dynamic microscopy with different contrast mechanisms to provide a thorough characterization of the dynamics in the Drosophila oocyte. We study the movement of vesicles and the elusive motion of a cytoplasmic F-actin mesh, a known regulator of cytoplasmic flows. We find that cytoplasmic motility constitutes a combination of directed motion and random diffusion. While advection is mainly attributed to microtubules, we find that active diffusion is driven by the actin cytoskeleton, although it is also enhanced by the flow. We also find that an important dynamic link exists between vesicles and cytoplasmic F-actin motion, as recently suggested in mouse oocytes. PMID- 29142224 TI - Health and disease phenotyping in old age using a cluster network analysis. AB - Human ageing is a complex trait that involves the synergistic action of numerous biological processes that interact to form a complex network. Here we performed a network analysis to examine the interrelationships between physiological and psychological functions, disease, disability, quality of life, lifestyle and behavioural risk factors for ageing in a cohort of 3,270 subjects aged >=55 years. We considered associations between numerical and categorical descriptors using effect-size measures for each variable pair and identified clusters of variables from the resulting pairwise effect-size network and minimum spanning tree. We show, by way of a correspondence analysis between the two sets of clusters, that they correspond to coarse-grained and fine-grained structure of the network relationships. The clusters obtained from the minimum spanning tree mapped to various conceptual domains and corresponded to physiological and syndromic states. Hierarchical ordering of these clusters identified six common themes based on interactions with physiological systems and common underlying substrates of age-associated morbidity and disease chronicity, functional disability, and quality of life. These findings provide a starting point for indepth analyses of ageing that incorporate immunologic, metabolomic and proteomic biomarkers, and ultimately offer low-level-based typologies of healthy and unhealthy ageing. PMID- 29142226 TI - People with higher interoceptive sensitivity are more altruistic, but improving interoception does not increase altruism. AB - People consistently show preferences and behaviors that benefit others at a cost to themselves, a phenomenon termed altruism. We investigated if perception of one's body signals - interoception - may be underlying such behaviors. We tested if participants' sensitivity to their own heartbeat predicted their decision on a choice between self-interest and altruism, and if improving this sensitivity through training would make participants more altruistic. Across these two experiments, interoceptive sensitivity predicted altruism measured through monetary generosity. Improving interoceptive sensitivity did, however, not lead to more altruistic behaviour. We conclude that there is a unique link between interoception and altruistic behaviour, likely established over an individual's history of altruistic acts, and the body responses they elicit. The findings suggest that humans might literally 'listen to their heart' to guide their altruistic behavior. PMID- 29142225 TI - Comparative genomic analysis of esophageal squamous cell carcinoma between Asian and Caucasian patient populations. AB - Esophageal squamous cell carcinoma is a major histological type of esophageal cancer, with distinct incidence and survival patterns among races. Although previous studies have characterized somatic mutations in this disease, a rigorous comparison between different patient populations has not been conducted. Here we sequence the samples of 316 Chinese patients, combine them with those from The Cancer Genome Atlas, and perform a comparative analysis between Asian and Caucasian patients. We find that mutated CSMD3 is associated with better prognosis in Asian patients. Applying a robust computational strategy that adjusts for both technical and biological confounding factors, we find that TP53, EP300, and NFE2L2 show higher mutational frequencies in Asian patients. Moreover, NFE2L2 mutations correlate with the allele status of a nearby high-Fst SNP, suggesting their potential interaction. Our study provides insights into the molecular basis underlying the striking racial disparities of this disease, and represents a general computational framework for such a cross-population comparison. PMID- 29142227 TI - Population genetic structure of the land snail Camaena cicatricosa (Stylommatophora, Camaenidae) in China inferred from mitochondrial genes and ITS2 sequences. AB - The phylogeographic structure of the land snail Camaena cicatricosa was analyzed in this study based on mitochondrial gene (COI and 16srRNA, mt DNA) and internal transcribed spacer (ITS2) sequences in 347 individuals. This snail is the vector of the zoonotic food-borne parasite Angiostrongylus cantonensis and one of the main harmful snails distributed exclusively in China. The results revealed significant fixation indices of genetic differentiation and high gene flow between most populations except several populations. An isolation-by-distance test showed no significant correlation between genetic distance and geographical distance among C. cicatricosa populations, which suggested that gene flow was not restricted by distance. The levels of haplotype and nucleotide diversity of C. cicatricosa were generally high, except those in some special populations, according to the mt DNA and ITS2 data. Furthermore, the phylogenetic trees and asteroid networks of haplotypes indicated nonobvious genetic structure, the same as results got based on the synonymous and non synonymous sites of 347 sequences of the COI gene. All lines of evidence indicated that climatic changes and geographical and human barriers do not substantially affect the current population structure and distribution of the investigated snails. PMID- 29142229 TI - Impact of deforestation and climate on the Amazon Basin's above-ground biomass during 1993-2012. AB - Since the 1960s, large-scale deforestation in the Amazon Basin has contributed to rising global CO2 concentrations and to climate change. Recent advances in satellite observations enable estimates of gross losses of above-ground biomass (AGB) stocks due to deforestation. However, because of simultaneous regrowth, the net contribution of deforestation emissions to rising atmospheric CO2 concentrations is poorly quantified. Climate change may also reduce the potential for forest regeneration in previously disturbed regions. Here, we address these points of uncertainty with a machine-learning approach that combines satellite observations of AGB with climate data across the Amazon Basin to reconstruct annual maps of potential AGB during 1993-2012, the above-ground C storage potential of the undisturbed landscape. We derive a 2.2 Pg C loss of AGB over the study period, and, for the regions where these losses occur, we estimate a 0.7 Pg C reduction in potential AGB. Thus, climate change has led to a decline of ~1/3 in the capacity of these disturbed forests to recover and recapture the C lost in disturbances during 1993-2012. Our approach further shows that annual variations in land use change mask the natural relationship between the El Nino/Southern Oscillation and AGB stocks in disturbed regions. PMID- 29142228 TI - Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus. AB - Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the cis-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify cis-meQTLs at 14,118 CpG methylation sites and cis-eQTLs for 302 3'-mRNA transcripts of 288 genes. Hippocampal cis-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. Cis-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of cis-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non coding genetic variants in the molecular genetic dissection of brain disorders. PMID- 29142230 TI - Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis. AB - Spondyloarthritis encompasses a group of common inflammatory diseases thought to be driven by IL-17A-secreting type-17 lymphocytes. Here we show increased numbers of GM-CSF-producing CD4 and CD8 lymphocytes in the blood and joints of patients with spondyloarthritis, and increased numbers of IL-17A+GM-CSF+ double-producing CD4, CD8, gammadelta and NK cells. GM-CSF production in CD4 T cells occurs both independently and in combination with classical Th1 and Th17 cytokines. Type 3 innate lymphoid cells producing predominantly GM-CSF are expanded in synovial tissues from patients with spondyloarthritis. GM-CSF+CD4+ cells, isolated using a triple cytokine capture approach, have a specific transcriptional signature. Both GM-CSF+ and IL-17A+GM-CSF+ double-producing CD4 T cells express increased levels of GPR65, a proton-sensing receptor associated with spondyloarthritis in genome wide association studies and pathogenicity in murine inflammatory disease models. Silencing GPR65 in primary CD4 T cells reduces GM-CSF production. GM-CSF and GPR65 may thus serve as targets for therapeutic intervention of spondyloarthritis. PMID- 29142231 TI - Evaluation of Critical Flicker-Fusion Frequency Measurement Methods for the Investigation of Visual Temporal Resolution. AB - Recent studies highlight the importance of the temporal domain in visual processing. Critical Flicker-Fusion Frequency (CFF), the frequency at which a flickering light is perceived as continuous, is widely used for evaluating visual temporal processing. However, substantial variability in the psychophysical paradigms, used for measuring CFF, leads to substantial variability in the reported results. Here, we report on a comprehensive comparison of CFF measurements through three different psychophysical paradigms: methods of limits; method of constant stimuli, and staircase method. Our results demonstrate that the CFF can be reliably measured with high repeatability by all three psychophysics methods. However, correlations (r = 0.92, p?0.001) and agreement (Bland Altman test indicated 95% confidence limit variation of +/-3.6 Hz), were highest between the staircase and the constant stimuli methods. The time required to complete the test was significantly longer for the constant stimuli method as compared to other methods (p < 0.001). Our results highlight the suitability of the adaptive paradigm for efficiently measuring temporal resolution in the visual system. PMID- 29142233 TI - Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. AB - CDC73/Parafibromin is a critical component of the Paf1 complex (PAF1C), which is involved in transcriptional elongation and histone modifications. Mutations of the human CDC73/HRPT2 gene are associated with hyperparathyroidism-jaw tumor (HPT JT) syndrome, an autosomal dominant disorder. CDC73/parafibromin was initially recognized as a tumor suppressor by inhibiting cell proliferation via repression of cyclin D1 and c-myc genes. In recent years, it has also shown oncogenic features by activating the canonical Wnt/beta-catenin signal pathway. Here, through limited proteolysis analysis, we demonstrate that the evolutionarily conserved human CDC73 N-terminal 111 residues form a globularly folded domain (hCDC73-NTD). We have determined a crystal structure of hCDC73-NTD at 1.02 A resolution, which reveals a novel protein fold. CDC73-NTD contains an extended hydrophobic groove on its surface that may be important for its function. Most pathogenic CDC73 missense mutations associated with the HPT-JT syndrome are located in the region encoding CDC73-NTD. Our crystal and biochemical data indicate that most CDC73 missense mutations disrupt the folding of the hydrophobic core of hCDC73-NTD, while others such as the K34Q mutant reduce its thermostability. Overall, our results provide a solid structural basis for understanding the structure and function of CDC73 and its association with the HPT-JT syndrome and other diseases. PMID- 29142232 TI - TDP-43 misexpression causes defects in dendritic growth. AB - Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) share overlapping genetic causes and disease symptoms, and are linked neuropathologically by the RNA binding protein TDP-43 (TAR DNA binding protein-43 kDa). TDP-43 regulates RNA metabolism, trafficking, and localization of thousands of target genes. However, the cellular and molecular mechanisms by which dysfunction of TDP-43 contributes to disease pathogenesis and progression remain unclear. Severe changes in the structure of neuronal dendritic arbors disrupt proper circuit connectivity, which in turn could contribute to neurodegenerative disease. Although aberrant dendritic morphology has been reported in non-TDP-43 mouse models of ALS and in human ALS patients, this phenotype is largely unexplored with regards to TDP-43. Here we have employed a primary rodent neuronal culture model to study the cellular effects of TDP-43 dysfunction in hippocampal and cortical neurons. We show that manipulation of TDP-43 expression levels causes significant defects in dendritic branching and outgrowth, without an immediate effect on cell viability. The effect on dendritic morphology is dependent on the RNA-binding ability of TDP-43. Thus, this model system will be useful in identifying pathways downstream of TDP-43 that mediate dendritic arborization, which may provide potential new avenues for therapeutic intervention in ALS/FTD. PMID- 29142234 TI - Ultra-high quality factor metallic micro-cavity based on concentric double metal insulator-metal rings. AB - We propose and numerically investigate a novel ultra-high quality (Q) factor metallic micro-cavity based on concentric double metal-insulator-metal (MIM) rings (CDMR). In this CDMR cavity, because of the angular momentum matching, the strong coupling occurs between the same order modes of the inner and outer rings with huge resonance frequency difference. Consequently, the energy distribution between in the inner and outer rings presents enormous difference. Especially, for the quasi-in-phase CDMR modes, the energy is confined in the inner ring mainly, which suppresses the radiation loss greatly and results in ultra-narrow resonance dips and ultra-high Q factors. The full width at half-maximum (FWHM) of this CDMR cavity can be less than 2 nm and the Q factor can be higher than 300. Moreover, the character of this CDMR metallic micro-cavity can be modulated by varying the gap width between the two MIM rings. Our CDMR metallic micro-cavity provides a new perspective to design the advanced optical cavity with high Q factor and small mode volumes. PMID- 29142235 TI - Proteomic study revealed cellular assembly and lipid metabolism dysregulation in sepsis secondary to community-acquired pneumonia. AB - Sepsis is a life-threatening disorder characterized by organ dysfunction and a major cause of mortality worldwide. The major challenge in studying sepsis is its diversity in such factors as age, source of infection and etiology. Recently, genomic and proteomic approaches have improved our understanding of its complex pathogenesis. In the present study, we use quantitative proteomics to evaluate the host proteome response in septic patients secondary to community-acquired pneumonia (CAP). Samples obtained at admission and after 7 days of follow-up were analyzed according to the outcomes of septic patients. The patients' proteome profiles were compared with age- and gender-matched healthy volunteers. Bioinformatic analyses of differentially expressed proteins showed alteration in the cytoskeleton, cellular assembly, movement, lipid metabolism and immune responses in septic patients. Actin and gelsolin changes were assessed in mononuclear cells using immunofluorescence, and a higher expression of gelsolin and depletion of actin were observed in survivor patients. Regarding lipid metabolism, changes in cholesterol, HDL and apolipoproteins were confirmed using enzymatic colorimetric methods in plasma. Transcriptomic studies revealed a massive change in gene expression in sepsis. Our proteomic results stressed important changes in cellular structure and metabolism, which are possible targets for future interventions of sepsis. PMID- 29142236 TI - Circulating miR-210 and miR-22 combined with ALT predict the virological response to interferon-alpha therapy of CHB patients. AB - Interferon-alpha (IFN-alpha) therapy of chronic hepatitis B (CHB) patients is constrained by limited response and side effects. We described a panel of circulating microRNAs (miRNAs) which could potentially predict outcome of IFN alpha therapy. Here, we report development of a simplified scoring model for personalized treatment of CHB patients. 112 CHB patients receiving IFN-alpha treatment were randomly divided into a training (n = 75) or a validation group (n = 37). The expression of 15 candidate miRNAs was detected in training group with 5 miRNAs exhibiting significantly different levels (p < 0.0001) between early virological response (EVR) and non-early virological response (N-EVR). These 5 miRNAs were further tested in validation phase. Refinement analyses of results from training phase established a model composed of miR-210, miR-22 and alanine aminotransferase (ALT), with area under ROC curve (AUC) of 0.874 and 0.816 in training and validation groups, respectively. In addition, this model showed prognostic value for sustained virological response (SVR) (AUC = 0.821). Collectively, this simplified scoring model composed of miR-210, miR-22 and ALT can reproducibly predict the EVR and SVR of IFN-alpha therapy in CHB patients. The model should help to forecast the outcome of IFN-alpha treatment prior to therapy decision involving nucleoside analogs or IFNs. PMID- 29142237 TI - Inner Ear Otolith Asymmetry in Late-Larval Cichlid Fish (Oreochromis mossambicus, Perciformes) Showing Kinetotic Behaviour Under Diminished Gravity. AB - The inner ears of all vertebrates are designed to perceive auditory and vestibular inputs. Although a tremendous diversity in the inner ear can be found even among bony fishes, the morphologies of the utricle and of the semicircular canals are rather conservative among vertebrates. Fish show kinetoses under reduced gravity (spinning movements and looping responses) and are regarded model organisms concerning the performance of the otolithic organs. Otoliths can be analysed easily because they are compact, in contrast to the otoconial masses of other vertebrates. Here, late-larval Oreochromis mossambicus were subjected to 0.0001 * g and 0.04 * g aboard a sounding rocket, their behaviour was observed and morphometrical analyses on otoliths were carried out. Fish swimming kinetotically at 0.0001 * g had a higher asymmetry of utricular otoliths (gravity perception) but not of saccular otoliths (hearing process) than specimens behaving normally at this gravity level (p = 0.0055). Also, asymmetries of lapilli in animals swimming normally at 0.0001 * g were lower than asymmetries in specimens swimming normally at 0.04 * g (p = 0.06). This supports the "otolith asymmetry hypothesis", an explanation for the susceptibility to kinetosis, particularly concerning the utricular otoliths. It would be interesting to identify processes generating asymmetric otoliths, also in regard to human motion sickness. PMID- 29142238 TI - Mapping QTLs conferring salt tolerance and micronutrient concentrations at seedling stagein wheat. AB - Soil salinization and degradation is one of the consequences of climate change. Identification of major salt tolerance genes and marker assisted selection (MAS) can accelerate wheat breeding for this trait. We genotyped 154 wheat F2 lines derived from a cross between salt tolerant and susceptible cultivars using the Axiom Wheat Breeder's Genotyping Array. A high-density linkage map of 988 single nucleotide polymorphisms (SNPs) was constructed and utilized for quantitative trait loci (QTL) mapping for salt tolerance traits and mineral concentrations under salinity. Of 49 mapped QTLs, six were for Na+ exclusion (NAX) and two QTLs (qSNAX.2 A.1, qSNAX.2 A.2) on chromosome 2 A coincided with a reported major NAX QTL (Nax1 or HKT1;4). Two other major NAX QTLs were mapped on 7 A, which contributed 11.23 and 18.79% of the salt tolerance respectively. In addition to Ca+2 and Mg+2 QTLs, twenty-seven QTLs for tissue Phosphorus, Zinc, Iron, Manganese, Copper, Sulphur and Boron concentrations under salinity were also mapped. The 1293 segregating SNPs were annotated/located within genes for various ion channels, signalling pathways, transcription factors (TFs), metabolic pathways and 258 of them showed differential expression in silico under salinity. These findings will create new opportunities for salt tolerance breeding programs. PMID- 29142239 TI - Differential overexpression of SERPINA3 in human prion diseases. AB - Prion diseases are fatal neurodegenerative disorders with sporadic, genetic or acquired etiologies. The molecular alterations leading to the onset and the spreading of these diseases are still unknown. In a previous work we identified a five-gene signature able to distinguish intracranially BSE-infected macaques from healthy ones, with SERPINA3 showing the most prominent dysregulation. We analyzed 128 suitable frontal cortex samples, from prion-affected patients (variant Creutzfeldt-Jakob disease (vCJD) n = 20, iatrogenic CJD (iCJD) n = 11, sporadic CJD (sCJD) n = 23, familial CJD (gCJD) n = 17, fatal familial insomnia (FFI) n = 9, Gerstmann-Straussler-Scheinker syndrome (GSS)) n = 4), patients with Alzheimer disease (AD, n = 14) and age-matched controls (n = 30). Real Time-quantitative PCR was performed for SERPINA3 transcript, and ACTB, RPL19, GAPDH and B2M were used as reference genes. We report SERPINA3 to be strongly up-regulated in the brain of all human prion diseases, with only a mild up-regulation in AD. We show that this striking up-regulation, both at the mRNA and at the protein level, is present in all types of human prion diseases analyzed, although to a different extent for each specific disorder. Our data suggest that SERPINA3 may be involved in the pathogenesis and the progression of prion diseases, representing a valid tool for distinguishing different forms of these disorders in humans. PMID- 29142240 TI - Robust Segmentation of the Full Cerebral Vasculature in 4D CT of Suspected Stroke Patients. AB - A robust method is presented for the segmentation of the full cerebral vasculature in 4-dimensional (4D) computed tomography (CT). The method consists of candidate vessel selection, feature extraction, random forest classification and postprocessing. Image features include among others the weighted temporal variance image and parameters, including entropy, of an intensity histogram in a local region at different scales. These histogram parameters revealed to be a strong feature in the detection of vessels regardless of shape and size. The method was trained and tested on a large database of 264 patients with suspicion of acute ischemia who underwent 4D CT in our hospital in the period January 2014 to December 2015. Five subvolumes representing different regions of the cerebral vasculature were annotated in each image in the training set by medical assistants. The evaluation was done on 242 patients. A total of 16 (<8%) patients showed severe under or over segmentation and were reported as failures. One out of five subvolumes was randomly annotated in 159 patients and was used for quantitative evaluation. Quantitative evaluation showed a Dice coefficient of 0.91 +/- 0.07 and a modified Hausdorff distance of 0.23 +/- 0.22 mm. Therefore, robust vessel segmentation in 4D CT is feasible with good accuracy. PMID- 29142241 TI - Diverse Marinimicrobia bacteria may mediate coupled biogeochemical cycles along eco-thermodynamic gradients. AB - Microbial communities drive biogeochemical cycles through networks of metabolite exchange that are structured along energetic gradients. As energy yields become limiting, these networks favor co-metabolic interactions to maximize energy disequilibria. Here we apply single-cell genomics, metagenomics, and metatranscriptomics to study bacterial populations of the abundant "microbial dark matter" phylum Marinimicrobia along defined energy gradients. We show that evolutionary diversification of major Marinimicrobia clades appears to be closely related to energy yields, with increased co-metabolic interactions in more deeply branching clades. Several of these clades appear to participate in the biogeochemical cycling of sulfur and nitrogen, filling previously unassigned niches in the ocean. Notably, two Marinimicrobia clades, occupying different energetic niches, express nitrous oxide reductase, potentially acting as a global sink for the greenhouse gas nitrous oxide. PMID- 29142242 TI - Emergent patterns of collective cell migration under tubular confinement. AB - Collective epithelial behaviors are essential for the development of lumens in organs. However, conventional assays of planar systems fail to replicate cell cohorts of tubular structures that advance in concerted ways on out-of-plane curved and confined surfaces, such as ductal elongation in vivo. Here, we mimic such coordinated tissue migration by forming lumens of epithelial cell sheets inside microtubes of 1-10 cell lengths in diameter. We show that these cell tubes reproduce the physiological apical-basal polarity, and have actin alignment, cell orientation, tissue organization, and migration modes that depend on the extent of tubular confinement and/or curvature. In contrast to flat constraint, the cell sheets in a highly constricted smaller microtube demonstrate slow motion with periodic relaxation, but fast overall movement in large microtubes. Altogether, our findings provide insights into the emerging migratory modes for epithelial migration and growth under tubular confinement, which are reminiscent of the in vivo scenario. PMID- 29142243 TI - Genetic risk scores for body fat distribution attenuate weight loss in women during dietary intervention. AB - OBJECTIVE: The well-established link between body fat distribution and metabolic health has been suggested to act through an impact on the remodeling capacity of the adipose tissue. Remodeling of the adipose tissue has been shown to affect body fat distribution and might affect the ability to lose weight. We aimed to study the effect of weighted genetic risk scores (GRSs) on weight loss based on single-nucleotide polymorphisms (SNPs) associated with waist-hip-ratio adjusted for body mass index (WHRadjBMI). DESIGN: We included 707 participants (533 women and 174 men) from the NUGENOB multi-center 10-week diet intervention study with weekly weight measurements. We created 3 GRSs, one including all reported WHRadjBMI SNPs (GRStotal), one including only SNPs with genome-wide significance in women or with significantly greater effect in women (GRSwomen), and one excluding SNPs in the GRSwomen (GRSmen). The data were analyzed in a mixed linear model framework. RESULTS: The GRStotal and GRSwomen attenuated weight loss in women. The effect was strongest for the GRSwomen with an effect of 2.21 g per risk allele per day (95% confidence intereval (CI) (0.90;3.52), P=0.0009). Adjustment for WHR, basal metabolic rate or diet compliance did not affect the result. The GRSs had no effect on weight loss in men. The VEGFA rs1358980-T strongly attenuated weight loss in both men and women (beta=15.95 g per risk allele per day, (3.16;26.74), P=0.013) and (beta=15.95 g per risk allele per day, (2.58;13.53), P=0.004), respectively). CONCLUSION: Our findings suggest that genetic variants influencing body fat distribution attenuate weight loss in women independently on the effect on WHR. The stronger effect of the GRSwomen implies heterogenic effects of the WHRadjBMI variants on weight loss. A strong effect of rs1358980-T in the VEGFA locus suggests that angiogenesis plays a role, but this needs confirmation from functional studies. PMID- 29142244 TI - Body size phenotypes comprehensively assess cardiometabolic risk and refine the association between obesity and gut microbiota. AB - OBJECTIVE: The gut microbiota associates with obesity and related disorders, but recent meta-analyses have found that this association is, at best, of small effect. We argue that such analyses are flawed by the use of body mass index (BMI) as sole proxy for disease, and explore a classification method that distinguishes the cardiometabolic health status of individuals to look for more comprehensive associations between gut microbes and health. DESIGN: We analyzed a 441 community-dwelling cohort on which we obtained demographic and health information, anthropometry and blood biochemistry data that served to categorize participants according to BMI, cardiometabolic health status and body size phenotypes. In addition, the participants donated fecal samples from which we performed 16S rRNA gene sequencing to analyze the gut microbiota. RESULTS: We observed that health-related variables deteriorate with increased BMI, and that there are further discrepancies within a given BMI category when distinguishing cardiometabolically healthy and unhealthy individuals. Regarding the gut microbiota, both obesity and cardiovascular disease associate with reductions in alpha-diversity; having lean, healthy individuals the most diverse microbiotas. Moreover, the association between the gut microbiota and health stems from particular consortia of microbes; the prevalence of consortia involving pathobionts and Lachnospiraceae are increased in obese and cardiometabolically abnormal subjects, whereas consortia including Akkermansia muciniphila and Methanobrevibacter, Oscillospira and Dialister have higher prevalence in cardiometabolically healthy and normoweight participants. CONCLUSIONS: The incorporation of cardiometabolic data allows a refined identification of dissimilarities in the gut microbiota; within a given BMI category, marker taxa associated with obesity and cardiometabolic disease are exacerbated in individuals with abnormal health status. Our results highlight the importance of the detailed assessment and classification of individuals that should be carried out prior to the evaluation of obesity treatments targeting the gut microbiota. PMID- 29142245 TI - Obese and overweight individuals are less sensitive to information about meal times in portion-size judgements. AB - BACKGROUND: Obesity is related to a tendency to discount the future. Information regarding inter-meal interval (IMI) allows meal planning. We sought to assess how obese, overweight and lean people select portion sizes based on the length of an IMI. We hypothesised that individuals with a high body mass index (BMI) would discount information about the IMI. In addition, we investigated how reduced sensitivity to IMIs relates to monetary temporal discounting. METHODS: Participants (lean, n=35; overweight, n=31; obese, n=22) selected lunchtime portion sizes in response to information about the timings of their next meal. In seven trials, the time of the IMI was systematically manipulated, ranging from 'right now' to '8 h'. Participants then completed a monetary temporal discounting task. BMI was included as a continuous measure. For each participant, we conducted a linear regression of portion size on IMI to yield a gradient that reflected reduced sensitivity to future meal timings. RESULTS: As expected, participants selected larger portion sizes in response to a long IMI. Consistent with our hypothesis, individuals with a high BMI discounted information about the IMI (beta=-3.49, P=0.015; confidence interval (CI) 6.29 to -0.70). Monetary discounting also negatively predicted BMI (beta=-8.1, P=0.003; CI=-13.43 to 2.77), but did not correlate with IMI sensitivity (P>0.05). CONCLUSIONS: These results are the first to demonstrate that temporal discounting operates in planning from one meal to the next, and is more prevalent in obese and overweight, relative to lean individuals. Participants with a high BMI discounted concerns about potential future fullness and hunger in the IMI. Our observations might begin to explain associations between obesity and irregular meal timings or help to form the basis for a targeted intervention that promotes future thinking in meal planning. PMID- 29142247 TI - Visual processing: Silent motion detectors. PMID- 29142246 TI - A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family. AB - The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality. PMID- 29142248 TI - The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function. AB - Psoriasis is a TH17-driven inflammatory disease affecting a significant proportion of the world population. The molecular consequences of IL-17 signaling in the skin are only partially understood. Therefore, we evaluated the IL-17A effects on organotypic 3-dimensional skin models and observed that IL-17A interfered with keratinocyte differentiation. In agreement with this phenotype, IL-17A repressed the expression of many genes encoding structural proteins. Moreover, genes encoding anti-microbial peptides were induced, resulting in a strengthening of the chemical barrier. Finally, we observed enhanced expression of the three IL-36 cytokines IL-36alpha, beta and gamma. We found that IL-36gamma was secreted from keratinocytes in an inactive form and that neutrophilic proteases, including elastase, were capable of activating this cytokine. Functionally and similar to IL-17A, truncated IL-36 cytokines interfered with keratinocyte differentiation in 3D models. The molecular analysis revealed strong cooperative effects of IL-17A and IL-36 cytokines in regulating target genes, which was dependent on the proteolytic activation of the latter. Together these findings suggest an amplification cycle that can be initiated by IL-17A, involving IL-36 cytokines and immune cell derived proteases and resulting in active IL-36 cytokines which synergize with IL-17A. This amplification cycle might be relevant for a persistent psoriatic phenotype. PMID- 29142249 TI - A magnetoelastic biosensor based on E2 glycoprotein for wireless detection of classical swine fever virus E2 antibody. AB - A wireless magnetoelastic (ME) biosensor immobilized with E2 glycoprotein was first developed to detect classical swine fever virus (CSFV) E2 antibody. The detection principle is that a sandwich complex of CSFV E2 - rabbit anti-CSFV E2 antibody - alkaline phosphatase (AP) conjugated goat anti-rabbit IgG formed on the ME sensor surface, with biocatalytic precipitation used to amplify the mass change of antigen-antibody specific binding reaction, induces a significant change in resonance frequency of the biosensor. Due to its magnetostrictive feature, the resonance vibrations and resonance frequency can be actuated and wirelessly monitored through magnetic fields. The experimental results show that resonance frequency shift increases with the augmentation of the CSFV E2 antibody concentration. Scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS) and fluorescence microscopy analysis proved that the modification and detection process were successful. The biosensor shows a linear response to the logarithm of CSFV E2 antibody concentrations ranging from 5 ng/mL to 10 MUg/mL, with a detection limit (LOD) of 2.466 ng/mL and the sensitivity of 56.2 Hz/MUg.mL 1. The study provides a low-cost yet highly-sensitive and wireless method for selective detection of CSFV E2 antibody. PMID- 29142250 TI - Loss of lamin B1 is a biomarker to quantify cellular senescence in photoaged skin. AB - Skin ageing is an inevitable consequence of life and accelerated by exposure to ultraviolet (UV) rays. Senescence is an irreversible growth arrest and senescent cells accumulate in ageing tissues, at sites of age-related pathologies and in pre-neoplastic lesions. Conventionally, senescent cells have been detected by senescence associated-beta-galactosidase (SA-beta-gal) staining, a procedure that requires enzymatic activity, which is lost in fixed tissue samples. We previously demonstrated that loss of lamin B1 is a novel marker to identify senescent cells. Here, we demonstrate that loss of lamin B1 facilitates the detection and quantification of senescent cells upon UV-exposure in vitro and upon chronic UV exposure and skin regeneration in vivo. Taken together, this marker enables the study of environmental conditions on tissue ageing and regeneration in vivo, serves as a diagnostic tool to distinguish senescent from proliferating cells in pre-neoplastic lesions, and facilitates investigating the role of senescent cells in various age-related pathologies. PMID- 29142251 TI - Reverse stress testing interbank networks. AB - We reverse engineer dynamics of financial contagion to find the scenario of smallest exogenous shock that, should it occur, would lead to a given final systemic loss. This reverse stress test can be used to identify the potential triggers of systemic events, and it removes the arbitrariness in the selection of shock scenarios in stress testing. We consider in particular the case of distress propagation in an interbank market, and we study a network of 44 European banks, which we reconstruct using data collected from banks statements. By looking at the distribution across banks of the size of smallest exogenous shocks we rank banks in terms of their systemic importance, and we show the effectiveness of a policy with capital requirements based on this ranking. We also study the properties of smallest exogenous shocks as a function of the parameters that determine the endogenous amplification of shocks. We find that the size of smallest exogenous shocks reduces and that the distribution across banks becomes more localized as the system becomes more unstable. PMID- 29142252 TI - Gallic Acid Reduces Blood Pressure and Attenuates Oxidative Stress and Cardiac Hypertrophy in Spontaneously Hypertensive Rats. AB - Gallic acid (GA) has been reported to have beneficial effects on cancer, vascular calcification, and diabetes-induced myocardial dysfunction. We hypothesized that GA controls hypertension via oxidative stress response regulation in an animal model for essential hypertension. Spontaneously hypertensive rats (SHRs) were administered GA for 16 weeks. GA treatment lowered elevated systolic blood pressure in SHRs through the inhibition of vascular contractility and components of the renin-angiotensin II system. In addition, GA administration reduced aortic wall thickness and body weight in SHRs. In SHRs, GA attenuated left ventricular hypertrophy and reduced the expression of cardiac-specific transcription factors. NADPH oxidase 2 (Nox2) and GATA4 mRNA expression was induced in SHR hearts and angiotensin II-treated H9c2 cells; this expression was downregulated by GA treatment. Nox2 promoter activity was increased by the synergistic action of GATA4 and Nkx2-5. GA seems to regulate oxidative stress by inhibiting the DNA binding activity of GATA4 in the rat Nox2 promoter. GA reduced the GATA4-induced Nox activity in SHRs and angiotensin II-treated H9c2 cells. GA administration reduced the elevation of malondialdehyde levels in heart tissue obtained from SHRs. These findings suggest that GA is a potential therapeutic agent for treating cardiac hypertrophy and oxidative stress in SHRs. PMID- 29142253 TI - Protruding organic surfaces triggered by in-plane electric fields. AB - Coatings with a dynamic surface topography are of interest for applications in haptics, soft robotics, cell growth in biology, hydro- and air dynamics and tribology. Here we propose a design for creating oscillating surface topographies in thin liquid crystal polymer network coatings under an electric field. By applying an alternating electric field, the coating surface deforms, and pre designed local corrugations appear. The continuous AC electric field further initiates oscillations superimposed on the formed topographies. This effect is based on microscopic free volume creation. By exciting the liquid crystal network at its resonance frequency, maximum free volume is generated and large surface topographies are formed. Molecular simulation is used to examine this behaviour in microscopic detail as a function of oscillation frequency. Surface topography formation is fast and reversible. Excess free volume is energetically unfavourable, thus the surface topographies disappear within seconds once the electric field is removed. PMID- 29142254 TI - A soft selective sweep during rapid evolution of gentle behaviour in an Africanized honeybee. AB - Highly aggressive Africanized honeybees (AHB) invaded Puerto Rico (PR) in 1994, displacing gentle European honeybees (EHB) in many locations. Gentle AHB (gAHB), unknown anywhere else in the world, subsequently evolved on the island within a few generations. Here we sequence whole genomes from gAHB and EHB populations, as well as a North American AHB population, a likely source of the founder AHB on PR. We show that gAHB retains high levels of genetic diversity after evolution of gentle behaviour, despite selection on standing variation. We observe multiple genomic loci with significant signatures of selection. Rapid evolution during colonization of novel habitats can generate major changes to characteristics such as morphological or colouration traits, usually controlled by one or more major genetic loci. Here we describe a soft selective sweep, acting at multiple loci across the genome, that occurred during, and may have mediated, the rapid evolution of a behavioural trait. PMID- 29142255 TI - A Nonredundant Role for the TRPM6 Channel in Neural Tube Closure. AB - In humans, germline mutations in Trpm6 cause autosomal dominant hypomagnesemia with secondary hypocalcemia disorder. Loss of Trpm6 in mice also perturbs cellular magnesium homeostasis but additionally results in early embryonic lethality and neural tube closure defects. To define the mechanisms by which TRPM6 influences neural tube closure, we functionally characterized the role of TRPM6 during early embryogenesis in Xenopus laevis. The expression of Xenopus TRPM6 (XTRPM6) is elevated at the onset of gastrulation and is concentrated in the lateral mesoderm and ectoderm at the neurula stage. Loss of XTRPM6 produced gastrulation and neural tube closure defects. Unlike XTRPM6's close homologue XTRPM7, whose loss interferes with mediolateral intercalation, depletion of XTRPM6 but not XTRPM7 disrupted radial intercalation cell movements. A zinc influx assay demonstrated that TRPM6 has the potential to constitute functional channels in the absence of TRPM7. The results of our study indicate that XTRPM6 regulates radial intercalation with little or no contribution from XTRPM7 in the region lateral to the neural plate, whereas XTRPM7 is mainly involved in regulating mediolateral intercalation in the medial region of the neural plate. We conclude that both TRPM6 and TRPM7 channels function cooperatively but have distinct and essential roles during neural tube closure. PMID- 29142256 TI - Quantitative analysis of protein-protein interactions and post-translational modifications in rare immune populations. AB - In spite of recent advances in proteomics, quantitative analyses of protein protein interactions (PPIs) or post-translational modifications (PTMs) in rare cell populations remain challenging. This is in particular true for analyses of rare immune and/or stem cell populations that are directly isolated from humans or animal models, and which are often characterized by multiple surface markers. To overcome these limitations, here we have developed proximity ligation imaging cytometry (PLIC), a protocol for proteomic analysis of rare cells. Specifically, by employing PLIC on medullary thymic epithelial cells (mTECs), which serve as a paradigm for a rare immune population, we demonstrate that PLIC overcomes the inherent limitations of conventional proteomic approaches and enables a high resolution detection and quantification of PPIs and PTMs at a single cell level. PMID- 29142257 TI - Using a quantitative quadruple immunofluorescent assay to diagnose isolated mitochondrial Complex I deficiency. AB - Isolated Complex I (CI) deficiency is the most commonly observed mitochondrial respiratory chain biochemical defect, affecting the largest OXPHOS component. CI is genetically heterogeneous; pathogenic variants affect one of 38 nuclear encoded subunits, 7 mitochondrial DNA (mtDNA)-encoded subunits or 14 known CI assembly factors. The laboratory diagnosis relies on the spectrophotometric assay of enzyme activity in mitochondrially-enriched tissue homogenates, requiring at least 50 mg skeletal muscle, as there is no reliable histochemical method for assessing CI activity directly in tissue cryosections. We have assessed a validated quadruple immunofluorescent OXPHOS (IHC) assay to detect CI deficiency in the diagnostic setting, using 10 um transverse muscle sections from 25 patients with genetically-proven pathogenic CI variants. We observed loss of NDUFB8 immunoreactivity in all patients with mutations affecting nuclear-encoding structural subunits and assembly factors, whilst only 3 of the 10 patients with mutations affecting mtDNA-encoded structural subunits showed loss of NDUFB8, confirmed by BN-PAGE analysis of CI assembly and IHC using an alternative, commercially-available CI (NDUFS3) antibody. The IHC assay has clear diagnostic potential to identify patients with a CI defect of Mendelian origins, whilst highlighting the necessity of complete mitochondrial genome sequencing in the diagnostic work-up of patients with suspected mitochondrial disease. PMID- 29142258 TI - In situ detection of the protein corona in complex environments. AB - Colloidal nanoparticles (NPs) are a versatile potential platform for in vivo nanomedicine. Inside blood circulation, NPs may undergo drastic changes, such as by formation of a protein corona. The in vivo corona cannot be completely emulated by the corona formed in blood. Thus, in situ detection in complex media, and ultimately in vivo, is required. Here we present a methodology for determining protein corona formation in complex media. NPs are labeled with 19F and their diffusion coefficient measured using 19F diffusion-ordered nuclear magnetic resonance (NMR) spectroscopy. 19F diffusion NMR measurements of hydrodynamic radii allow for in situ characterization of NPs in complex environments by quantification of protein adsorption to the surface of NPs, as determined by increase in hydrodynamic radius. The methodology is not optics based, and thus can be used in turbid environments, as in the presence of cells. PMID- 29142259 TI - Drip tectonics and the enigmatic uplift of the Central Anatolian Plateau. AB - Lithospheric drips have been interpreted for various regions around the globe to account for the recycling of the continental lithosphere and rapid plateau uplift. However, the validity of such hypothesis is not well documented in the context of geological, geophysical and petrological observations that are tested against geodynamical models. Here we propose that the folding of the Central Anatolian (Kirsehir) arc led to thickening of the lithosphere and onset of "dripping" of the arc root. Our geodynamic model explains the seismic data showing missing lithosphere and a remnant structure characteristic of a dripping arc root, as well as enigmatic >1 km uplift over the entire plateau, Cappadocia and Galatia volcanism at the southern and northern plateau margins since ~10 Ma, respectively. Models show that arc root removal yields initial surface subsidence that inverts >1 km of uplift as the vertical loading and crustal deformation change during drip evolution. PMID- 29142260 TI - Possible nematic to smectic phase transition in a two-dimensional electron gas at half-filling. AB - Liquid crystalline phases of matter permeate nature and technology, with examples ranging from cell membranes to liquid-crystal displays. Remarkably, electronic liquid-crystal phases can exist in two-dimensional electron systems (2DES) at half Landau-level filling in the quantum Hall regime. Theory has predicted the existence of a liquid-crystal smectic phase that breaks both rotational and translational symmetries. However, previous experiments in 2DES are most consistent with an anisotropic nematic phase breaking only rotational symmetry. Here we report three transport phenomena at half-filling in ultra-low disorder 2DES: a non-monotonic temperature dependence of the sample resistance, dramatic onset of large time-dependent resistance fluctuations, and a sharp feature in the differential resistance suggestive of depinning. These data suggest that a sequence of symmetry-breaking phase transitions occurs as temperature is lowered: first a transition from an isotropic liquid to a nematic phase and finally to a liquid-crystal smectic phase. PMID- 29142261 TI - Selective Blocking Property of Microporous Polymer Membranes Fabricated by Chemical Vapor Deposition. AB - Poly-p-xylylene films have been utilized as protective and barrier layers for gases and solvents on electronic and implantable devices. Here we report a new approach to create highly permeable and selective nanofiltration membranes coated with microporous poly-p-xylylene nanofilms fabricated through a dry chemical vapor deposition process by using [2.2]paracyclophanes derivatives on ultrafiltration membranes. The introduction of crosslinking points into rigid poly-p-xylylenes enhanced microporosity and mechanical strength due to insufficient packing and depression of structural relaxation among polymer chains in three-dimensional networks. Crosslinked nanofilms with thicknesses down to 50 nm showed outstanding permeability for water and alcohols at a pressure difference of 0.5 MPa and exhibited higher rejection ratios for water-soluble organic dyes than non-crosslinked nanofilms. Poly-p-xylylene nanofilms also showed an excellent blocking property for non-polar organic solvent permeation through specific interaction of hydrophilic pores with organic solvents. PMID- 29142262 TI - Observation of replica symmetry breaking in disordered nonlinear wave propagation. AB - A landmark of statistical mechanics, spin-glass theory describes critical phenomena in disordered systems that range from condensed matter to biophysics and social dynamics. The most fascinating concept is the breaking of replica symmetry: identical copies of the randomly interacting system that manifest completely different dynamics. Replica symmetry breaking has been predicted in nonlinear wave propagation, including Bose-Einstein condensates and optics, but it has never been observed. Here, we report the experimental evidence of replica symmetry breaking in optical wave propagation, a phenomenon that emerges from the interplay of disorder and nonlinearity. When mode interaction dominates light dynamics in a disordered optical waveguide, different experimental realizations are found to have an anomalous overlap intensity distribution that signals a transition to an optical glassy phase. The findings demonstrate that nonlinear propagation can manifest features typical of spin-glasses and provide a novel platform for testing so-far unexplored fundamental physical theories for complex systems. PMID- 29142263 TI - Hyaluronic acid 35 normalizes TLR4 signaling in Kupffer cells from ethanol-fed rats via regulation of microRNA291b and its target Tollip. AB - TLR4 signaling in hepatic macrophages is increased after chronic ethanol feeding. Treatment of hepatic macrophages after chronic ethanol feeding with small specific sized hyaluronic acid 35 (HA35) normalizes TLR4 signaling; however, the mechanisms for HA35 action are not completely understood. Here we used Next Generation Sequencing of microRNAs to identify negative regulators of TLR4 signaling reciprocally modulated by ethanol and HA35 in hepatic macrophages. Eleven microRNAs were up-regulated by ethanol; only 4 microRNAs, including miR291b, were decreased by HA35. Bioinformatics analysis identified Tollip, a negative regulator of TLR4, as a target of miR291b. Tollip expression was decreased in hepatic macrophages from ethanol-fed rats, but treatment with HA35 or transfection with a miR291b hairpin inhibitor restored Tollip expression and normalized TLR4-stimulated TNFalpha expression. In peripheral blood monocytes isolated from patients with alcoholic hepatitis, expression of TNFalpha mRNA was robustly increased in response to challenge with lipopolysaccharide. Importantly, pre-treatment with HA35 reduced TNFalpha expression by more than 50%. Taken together, we have identified miR291b as a critical miRNA up-regulated by ethanol. Normalization of the miR291b -> Tollip pathway by HA35 ameliorated ethanol induced sensitization of TLR4 signaling in macrophages/monocytes, suggesting that HA35 may be a novel therapeutic agent in the treatment of ALD. PMID- 29142264 TI - Impairment of BKca channels in human placental chorionic plate arteries is potentially relevant to the development of preeclampsia. AB - Preeclampsia has known associations with insufficient placental perfusion. The large-conductance Ca2+-activated K+ (BKca) channels that have recently been found to play important roles in cellular growth and vasodilatation could potentially participate in the development of preeclampsia. However, the mechanisms by which downregulated BKca channels are involved in the development of preeclampsia remain unknown. In this study, we investigated the mechanism(s) underlying the impairment of vascular tone regulation by BKca channels in human placental chorionic plate arteries (CPAs) in preeclampsia. The levels of BKca channel alpha and beta1 subunits were compared using immunohistochemistry, western blotting, and RT-PCR in CPAs of normal and preeclamptic pregnant women. To explore the role of BKca channels in the regulation of proliferation and apoptosis in human placental CPA smooth muscle cells (SMCs), a specific BKca opener, NS1619, was used to investigate proliferative reduction and apoptotic induction in human placental chorionic plate arterie smooth muscle cells (CPASMCs) collected from normal pregnancies. The vasodilator effects of BKca channels and their response to SNP (an NO donor) in both groups were also evaluated by wire myography. We found that BKca channel beta1 subunits were less expressed in preeclamptic CPAs. After pretreatment with NS1619, cellular proliferation was significantly suppressed, and cellular apoptosis was dramatically promoted in cultured CPASMCs, demonstrating a relationship between increased Bax expression and decreased Bcl-2 expression in CPASMCs. Downregulated BKca is also associated with decreased vasodilatation and reduced susceptibility to NO donors. In conclusion, the decreased expression or activation of BKca channels may induce pathologic remodeling of human CPAs, weaken the vasodilation response, and decrease vascular sensitivity to vasoactive substances, thereby reducing fetal-placental blood flow and leading to the future development of preeclampsia. PMID- 29142265 TI - Publisher Correction: Tropical explosive volcanic eruptions can trigger El Nino by cooling tropical Africa. AB - A correction to this article has been published and is linked from the HTML version of this article. PMID- 29142266 TI - Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer's disease patients. AB - Neuritic plaques and neurofibrillary tangles are crucial morphological criteria for the definite diagnosis of Alzheimer's disease. We evaluated 12 unstained frontal cortex and hippocampus samples from 3 brain donors with Alzheimer's disease and 1 control with hyperspectral Raman microscopy on samples of 30 * 30 um. Data matrices of 64 * 64 pixels were used to quantify different tissue components including proteins, lipids, water and beta-sheets for imaging at 0.47 um spatial resolution. Hierarchical cluster analysis was performed to visualize regions with high Raman spectral similarities. The Raman images of proteins, lipids, water and beta-sheets matched with classical brain morphology. Protein content was 2.0 times, the beta-sheet content 5.6 times and Raman broad-band autofluorescence was 2.4 times higher inside the plaques and tangles than in the surrounding tissue. The lipid content was practically equal inside and outside. Broad-band autofluorescence showed some correlation with protein content and a better correlation with beta-sheet content. Hyperspectral Raman imaging combined with hierarchical cluster analysis allows for the identification of neuritic plaques and neurofibrillary tangles in unstained, label-free slices of human Alzheimer's disease brain tissue. It permits simultaneous quantification and distinction of several tissue components such as proteins, lipids, water and beta sheets. PMID- 29142267 TI - In vivo characterization of the electrophysiological and astrocytic responses to a silicon neuroprobe implanted in the mouse neocortex. AB - Silicon neuroprobes hold great potential for studies of large-scale neural activity and brain computer interfaces, but data on brain response in chronic implants is limited. Here we explored with in vivo cellular imaging the response to multisite silicon probes for neural recordings. We tested a chronic implant for mice consisting of a CMOS-compatible silicon probe rigidly implanted in the cortex under a cranial imaging window. Multiunit recordings of cortical neurons with the implant showed no degradation of electrophysiological signals weeks after implantation (mean spike and noise amplitudes of 186 +/- 42 uVpp and 16 +/- 3.2 uVrms, respectively, n = 5 mice). Two-photon imaging through the cranial window allowed longitudinal monitoring of fluorescently-labeled astrocytes from the second week post implantation for 8 weeks (n = 3 mice). The imaging showed a local increase in astrocyte-related fluorescence that remained stable from the second to the tenth week post implantation. These results demonstrate that, in a standard electrophysiology protocol in mice, rigidly implanted silicon probes can provide good short to medium term chronic recording performance with a limited astrocyte inflammatory response. The precise factors influencing the response to silicon probe implants remain to be elucidated. PMID- 29142268 TI - Influence of Large Reservoir Operation on Water-Levels and Flows in Reaches below Dam: Case Study of the Three Gorges Reservoir. AB - The Three Gorges Project (TGP) is the world's largest water conservation project. The post-construction low-flow water level at the same discharge below the dam has declined, but there remains disagreement over whether the flood level has increased. Measured water levels and upstream and downstream flow data from 1955 to 2016 show that, post-construction: (1) the low-flow water level at the same discharge decreased, and the lowest water level increased due to dry-season reservoir discharge; (2) the decline of the low-flow water level below the dam was less than the undercutting value of the flow channel of the river; (3) the flood level at the same discharge below the dam was slightly elevated, although peak water levels decreased; (4) flood characteristics changed from a high discharge-high flood level to a medium discharge - high flood level; and (5) an expected decline in the flood level downstream was not observed. Channel erosion and the adjustment of rivers and lakes tend to reduce flood levels, while river bed coarsening, vegetation, and human activities downstream increase the flood level. Although the flood control benefits of the Three Gorges Dam (TGD) and the upstream reservoirs are obvious, increased elevation of the downstream flood level remains a concern. PMID- 29142269 TI - Sex-specific association between asthma and hypertension in nationally representative young Korean adults. AB - It has been reported that people with asthma have an increased risk of hypertension. However, little is known about the specific relationship between asthma and hypertension in young adults. Among subjects who participated in the Korea National Health and Nutrition Examination Survey conducted in 2008-2013, a total of 10,138 young adults (4,226 men and 5,912 women) aged 19-39 years were analyzed. Multiple logistic regression analysis was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). The prevalence of ever asthma was 11.1% in men and 8.4% in women. The mean diastolic blood pressure (DBP) was lower in men with asthma than in men without asthma (p = 0.03), whereas the mean DBP was higher in women with asthma than in women without asthma (p = 0.04). Having asthma was inversely associated with hypertension in men (OR: 0.62, 95% CI: 0.41-0.91). In contrast, having asthma was positively associated with hypertension in women (OR: 2.19, 95% CI: 1.19-4.02). Our results suggest that asthma pathophysiology might be differentially associated with hypertension in young adults depending on sex. PMID- 29142270 TI - Shock Synthesis of Five-component Icosahedral Quasicrystals. AB - Five-component icosahedral quasicrystals with compositions in the range Al68 73Fe11-16Cu10-12Cr1-4Ni1-2 were recently recovered after shocking metallic CuAl5 and (Mg0.75Fe0.25)2SiO4 olivine in a stainless steel 304 chamber, intended to replicate a natural shock that affected the Khatyrka meteorite. The iron in those quasicrystals might have originated either from reduction of Fe2+ in olivine or from the stainless steel chamber. In this study, we clarify the shock synthesis mechanism of icosahedral quasicrystals through two new shock recovery experiments. When CuAl5 and Fe2+-bearing olivine were isolated in a Ta capsule, no quasicrystals were found. However, with only metallic starting materials, numerous micron-sized five-component icosahedral quasicrystals, average composition Al72Cu12Fe12Cr3Ni1, were found at the interface between CuAl5 and stainless steel, demonstrating nucleation of quasicrystals under shock without any redox reaction. We present detailed characterization of recovered quasicrystals and discuss possible mechanisms for generating sufficiently high temperatures to reach melting with relatively weak shocks. We discuss the implications of our five-component quasicrystal for the stability of quasicrystals, which have previously only been considered in alloy systems with four or fewer components. Even small amounts of additional metals expand the stability range of the icosahedral phase and facilitate routine syntheses without extraordinary precision in preparation of starting mixtures. PMID- 29142271 TI - Structural and functional differences in gut microbiome composition in patients undergoing haemodialysis or peritoneal dialysis. AB - Complications of end-stage renal disease (ESRD) are critically related to inflammation. The gut microbiome is a key driver of inflammation. Since dialysis modalities may differently influence the gut microbiome, we aimed to compare the effects of haemodialysis (HD) and peritoneal dialysis (PD) on patients' gut microbiome composition and function. We therefore studied faecal microbiome composition and function as well as inflammation and gut permeability in 30 patients with ESRD (15 HD, 15 PD) and compared to 21 healthy controls. We found an increase in potentially pathogenic species and a decrease in beneficial species in patients on HD and to a lesser extend in patients on PD when compared to controls. These changes in taxonomic composition also resulted in differences in predicted metagenome functions of the faecal microbiome. In HD but not in PD, changes in microbiome composition were associated with an increase in c-reactive protein (CRP) but not with intestinal inflammation or gut permeability. In conclusion microbiome composition in ESRD differs from healthy controls but also between modes of dialysis. These differences are associated with systemic inflammation and cannot completely be explained by dialysis vintage. The mode of renal replacement therapy seems to be an important driver of dysbiosis in ESRD. PMID- 29142272 TI - Individuals of the common Namib Day Gecko vary in how adaptive simplification alters sprint biomechanics. AB - Locomotion inextricably links biomechanics to ecology as animals maneuver through mechanically challenging environments. Faster individuals are more likely to escape predators, surviving to produce more offspring. Fast sprint speed evolved several times in lizards, including geckos. However, the underlying mechanisms determining performance await discovery in many clades. Novel morphological structures influence these mechanisms by adding complexity to the government of locomotion. Gecko adhesion coevolves with modified muscles, tendons, and reflexes. We explored how the Namib Day Gecko, Rhoptropus afer, sprints on ecologically relevant substrates. Locomotion requires that many moving parts of the animal work together; we found knee and ankle extension are the principal drivers of speed on a level surface while contributions to sprinting uphill are more evenly distributed among motions of the femur, knee, and ankle. Although geckos are thought to propel themselves with specialized, proximally located muscles that retract and rotate the femur, we show with path analysis that locomotion is altered in this secondarily terrestrial gecko. We present evidence of intraspecific variation in the use of adhesive toe pads and suggest that the subdigital adhesive toe pad may increase sprint speed in this species. We argue kinematics coevolve with the secondarily terrestrial lifestyle of this species. PMID- 29142273 TI - A Novel Medium for Enhancing Callus Growth of Hazel (Corylus avellana L.). AB - Paclitaxel is a powerful antimitotic agent with excellent activity against a range of cancers. Hazel has been described as a paclitaxel-producing species among angiosperms. Fast-growing callus is a prerequisite for the success of callus production and then paclitaxel production. Therefore, optimizing the medium culture for enhancing callus growth is a crucial step for paclitaxel production. In this research, Murashige and Skoog (1962) (MS) medium was optimized for improving callus growth of hazel (Corylus avellana L.). The M10 medium (MS medium with pH 6.0 and supplemented with 1000 mg l-1 spirulina powder, 1000 mg l-1 casein hydrolysate and 3 g l-1 gelrite) significantly improved hazel callus growth. This modified MS medium increased callus fresh weight (55.8%) as compared to the control. M10 medium increased fatty acids yield of callus (66.7%) as compared to the control. Liquid M10 medium maintained growth over a longer period of time and also increased slightly, the paclitaxel production as compared to the control. This novel medium is promising for facilitating the mass production of hazel callus as a source of valuable metabolites including paclitaxel, linoleic and oleic acids. PMID- 29142274 TI - Super-achromatic monolithic microprobe for ultrahigh-resolution endoscopic optical coherence tomography at 800 nm. AB - Endoscopic optical coherence tomography (OCT) has emerged as a valuable tool for advancing our understanding of the histomorphology of various internal luminal organs and studying the pathogenesis of relevant diseases. To date, this technology affords limited resolving power for discerning subtle pathological changes associated with early diseases. In addition, it remains challenging to access small luminal organs or pass through narrow luminal sections without potentially causing trauma to tissue with a traditional OCT endoscope of a 1-1.5 mm diameter. Here we report an ultracompact (520 um in outer diameter and 5 mm in rigid length) and super-achromatic microprobe made with a built-in monolithic fiber-optic ball lens, which achieves ultrahigh-resolution (1.7 um axial resolution in tissue and 6 um transverse resolution) for endoscopic OCT imaging at 800 nm. Its performance and translational potential are demonstrated by in vivo imaging of a mouse colon, a rat esophagus, and small airways in sheep. PMID- 29142276 TI - Detecting the relevance to performance of whole-body movements. AB - Goal-directed whole-body movements are fundamental in our daily life, sports, music, art, and other activities. Goal-directed movements have been intensively investigated by focusing on simplified movements (e.g., arm-reaching movements or eye movements); however, the nature of goal-directed whole-body movements has not been sufficiently investigated because of the high-dimensional nonlinear dynamics and redundancy inherent in whole-body motion. One open question is how to overcome high-dimensional nonlinear dynamics and redundancy to achieve the desired performance. It is possible to approach the question by quantifying how the motions of each body part at each time point contribute to movement performance. Nevertheless, it is difficult to identify an explicit relation between each motion element (the motion of each body part at each time point) and performance as a result of the high-dimensional nonlinear dynamics and redundancy inherent in whole-body motion. The current study proposes a data-driven approach to quantify the relevance of each motion element to the performance. The current findings indicate that linear regression may be used to quantify this relevance without considering the high-dimensional nonlinear dynamics of whole-body motion. PMID- 29142275 TI - NF-kappaB Protects NKT Cells from Tumor Necrosis Factor Receptor 1-induced Death. AB - Semi-invariant natural killer T (NKT) cells are innate-like lymphocytes with immunoregulatory properties. NKT cell survival during development requires signal processing by activated RelA/NF-kappaB. Nonetheless, the upstream signal(s) integrated by NF-kappaB in developing NKT cells remains incompletely defined. We show that the introgression of Bcl-xL-coding Bcl2l1 transgene into NF-kappaB signalling-deficient IkappaBDeltaN transgenic mouse rescues NKT cell development and differentiation in this mouse model. We reasoned that NF-kappaB activation was protecting developing NKT cells from death signals emanating either from high affinity agonist recognition by the T cell receptor (TCR) or from a death receptor, such as tumor necrosis factor receptor 1 (TNFR1) or Fas. Surprisingly, the single and combined deficiency in PKC-theta or CARMA-1-the two signal transducers at the NKT TCR proximal signalling node-only partially recapitulated the NKT cell deficiency observed in IkappaBDeltaN tg mouse. Accordingly, introgression of the Bcl2l1 transgene into PKC-theta null mouse failed to rescue NKT cell development. Instead, TNFR1-deficiency, but not the Fas-deficiency, rescued NKT cell development in IkappaBDeltaN tg mice. Consistent with this finding, treatment of thymocytes with an antagonist of the inhibitor of kappaB kinase -which blocks downstream NF-kappaB activation- sensitized NKT cells to TNF alpha-induced cell death in vitro. Hence, we conclude that signal integration by NF-kappaB protects developing NKT cells from death signals emanating from TNFR1, but not from the NKT TCR or Fas. PMID- 29142277 TI - Genetic, metabolomic and transcriptomic analyses of the de novo L-cysteine biosynthetic pathway in the enteric protozoan parasite Entamoeba histolytica. AB - The de novo L-cysteine biosynthetic pathway is critical for the growth, antioxidative stress defenses, and pathogenesis of bacterial and protozoan pathogens, such as Salmonella typhimurium and Entamoeba histolytica. This pathway involves two key enzymes, serine acetyltransferase (SAT) and cysteine synthase (CS), which are absent in mammals and therefore represent rational drug targets. The human parasite E. histolytica possesses three SAT and CS isozymes; however, the specific roles of individual isoforms and significance of such apparent redundancy remains unclear. In the present study, we generated E. histolytica cell lines in which CS and SAT expression was knocked down by transcriptional gene silencing. The strain in which CS1, 2 and 3 were simultaneously silenced and the SAT3 gene-silenced strain showed impaired growth when cultured in a cysteine lacking BI-S-33 medium, whereas silencing of SAT1 and SAT2 had no effects on growth. Combined transcriptomic and metabolomic analyses revealed that, CS and SAT3 are involved in S-methylcysteine/cysteine synthesis. Furthermore, silencing of the CS1-3 or SAT3 caused upregulation of various iron-sulfur flavoprotein genes. Taken together, these results provide the first direct evidence of the biological importance of SAT3 and CS isoforms in E. histolytica and justify the exploitation of these enzymes as potential drug targets. PMID- 29142278 TI - Diet selection and n-3 polyunsaturated fatty acid deposition in lambs as affected by restricted time at pasture. AB - This study investigates the effects of restricted grazing time on forage selectivity and meat fatty acid deposition of lambs compared to a traditional grazing system. Results showed that the animals preferred to graze pasture species that were more palatable and lower in fibre, while demonstrating a partial preference for species with high protein levels. Leymus chinensis was more preferentially selected by lambs grazing pasture for shorter periods than longer periods. Lambs that grazed for 4 h per day had a high LNA (alpha-linolenic acid) intake. The accumulation of LNA and its elongation products in tissue was closely related to the LNA level in diet. Therefore, allowing lambs to graze for at least 4 h per day resulted in a meat fatty acid profile that is richer in health-promoting fatty acids. In particular, the highest DHA (docosahexaenoic acid) was observed in meat from lambs which grazed pasture for 4-h versus 8- and 12-h. It can be concluded that, in grassland systems, a healthier meat fatty acid profile for humans and the potential for better pasture management is achieved by limiting the grazing of lambs to 4 h per day rather than grazing over longer time periods. PMID- 29142279 TI - Modifying response times in the Simon task with transcranial random noise stimulation. AB - Perceptual decisions pervade our every-day lives, and can align or conflict with inbuilt biases. We investigated these conflicting biases by applying transcranial random noise stimulation (tRNS) while subjects took part in a visual Simon task - a paradigm where irrelevant spatial cues influence the response times of subjects to relevant colour cues. We found that tRNS reduces the response time of subjects independent of the congruence between spatial and colour cues, but dependent on the baseline response time, both between subjects and across conditions within subjects. We consider the reduction in response time to be non-specific to the Simon task, and cast our interpretations in terms of drift-diffusion models, which have been previously used as mechanistic explanations for decision-making processes. However, there have been few extensions of the drift-diffusion model to the Simon effect, and so we first elaborate on this interpretation, and further extend it by incorporating the potential action of tRNS. PMID- 29142281 TI - The phase diagram and stability of trapped D-dimensional spin-orbit coupled Bose Einstein condensate. AB - By variational analysis and direct numerical simulation, we study the phase transition and stability of a trapped D-dimensional Bose-Einstein condensate with spin-orbit coupling. The complete phase and stability diagrams of the system are presented in full parameter space, while the collapse dynamics induced by the mean-filed attraction and the mechanism for stabilizing the collapse by spin orbit coupling are illustrated explicitly. Particularly, a full and deep understanding of the dependence of phase transition and stability mechanism on geometric dimensionality and external trap potential is revealed. It is shown that the spin-orbit coupling can modify the dispersion relations, which can balance the mean-filed attractive interaction and result in a spin polarized or overlapped state to stabilize the collapse, then changes the collapsing threshold dependent on the geometric dimensionality and external trap potential. Moreover, from 2D to 3D system, the mean-field attraction for inducing the collapse is reduced and the collapse speed is enhanced, namely, the collapse can be more easily stabilized in 2D system. That is, the collapse can be manipulated by adjusting the spin-orbit coupling, Raman coupling, geometric dimensionality and the external trap potential, which can provide a possible way for elaborating the collapse dynamics experimentally. PMID- 29142280 TI - Mild heat induces a distinct "eustress" response in Chinese Hamster Ovary cells but does not induce heat shock protein synthesis. AB - The current research on cellular heat stress management focuses on the roles of heat shock proteins (HSPs) and the proteostasis network under severe stress conditions. The mild, fever-type stress and the maintenance of membrane homeostasis are less well understood. Herein, we characterized the acute effect of mild, fever-range heat shock on membrane organization, and HSP synthesis and localization in two mammalian cell lines, to delineate the role of membranes in the sensing and adaptation to heat. A multidisciplinary approach combining ultrasensitive fluorescence microscopy and lipidomics revealed the molecular details of novel cellular "eustress", when cells adapt to mild heat by maintaining membrane homeostasis, activating lipid remodeling, and redistributing chaperone proteins. Notably, this leads to acquired thermotolerance in the complete absence of the induction of HSPs. At higher temperatures, additional defense mechanisms are activated, including elevated expression of molecular chaperones, contributing to an extended stress memory and acquired thermotolerance. PMID- 29142282 TI - Spatial distribution of tree species in evergreen-deciduous broadleaf karst forests in southwest China. AB - Understanding the spatial distribution of tree species in subtropical evergreen deciduous broadleaf karst forest is fundamental to studying species coexistence and karst species diversity. Here, complete spatial randomness and heterogeneous Poisson process models were used to analyze the spatial distribution patterns of 146 species with at least one individual per ha in a 25-ha plot in southwest China. We used canonical correspondence analysis (CCA) and the torus-translation test (TTT) to explain the distributions of observed species. Our results show that an aggregated distribution was the dominant pattern in Mulun karst forests; the percentage and intensity of aggregated decreased with increasing spatial scale, abundance, mean diameter at breast height (DBH), and maximum DBH. Rare species were more aggregated than intermediately abundant and abundant species. However, functional traits (e.g., growth form and phenological guild) had no significant effects on the distributions of species. The CCA revealed that the four analyzed topographic variables (elevation, slope, aspect, and convexity) had significant influences on species distributions. The TTT showed that not all species have habitat preferences and that 68.5% (100 out of 146 species) show a strongly positive or negative association with at least one habitat. Most species were inclined to grow on slopes and hilltops. PMID- 29142283 TI - A mobile device-based imaging spectrometer for environmental monitoring by attaching a lightweight small module to a commercial digital camera. AB - Spatially-explicit data are essential for remote sensing of ecological phenomena. Lately, recent innovations in mobile device platforms have led to an upsurge in on-site rapid detection. For instance, CMOS chips in smart phones and digital cameras serve as excellent sensors for scientific research. In this paper, a mobile device-based imaging spectrometer module (weighing about 99 g) is developed and equipped on a Single Lens Reflex camera. Utilizing this lightweight module, as well as commonly used photographic equipment, we demonstrate its utility through a series of on-site multispectral imaging, including ocean (or lake) water-color sensing and plant reflectance measurement. Based on the experiments we obtain 3D spectral image cubes, which can be further analyzed for environmental monitoring. Moreover, our system can be applied to many kinds of cameras, e.g., aerial camera and underwater camera. Therefore, any camera can be upgraded to an imaging spectrometer with the help of our miniaturized module. We believe it has the potential to become a versatile tool for on-site investigation into many applications. PMID- 29142284 TI - Bone: Extracellular vesicles in bone cell crosstalk. PMID- 29142285 TI - Blockade of CB1 cannabinoid receptor alters gut microbiota and attenuates inflammation and diet-induced obesity. AB - Obesity is characterized by chronic low-grade, systemic inflammation, altered gut microbiota, and gut barrier disruption. Additionally, obesity is associated with increased activity of endocannabinoid system (eCB). However, the clear connection between gut microbiota and the eCB system in the regulation of energy homeostasis and adipose tissue inflammation and metabolism, remains to be established. We investigated the effect of treatment of mice with a cannabinoid receptor 1 (CB1) antagonist on Diet-Induced Obesity (DIO), specifically whether such a treatment that blocks endocannabinoid activity can induce changes in gut microbiota and anti-inflammatory state in adipose tissue. Blockade of CB1 attenuated DIO, inflammatory cytokines and trafficking of M1 macrophages into adipose tissue. Decreased inflammatory tone was associated with a lower intestinal permeability and decreased metabolic endotoxemia as evidenced by reduced plasma LPS level, and improved hyperglycemia and insulin resistance. 16S rRNA metagenomics sequencing revealed that CB1 blockade dramatically increased relative abundance of Akkermansia muciniphila and decreased Lanchnospiraceae and Erysipelotrichaceae in the gut. Together, the current study suggests that blocking of CB1 ameliorates Diet-Induced Obesity and metabolic disorder by modulating macrophage inflammatory mediators, and that this effect is associated with alterations in gut microbiota and their metabolites. PMID- 29142286 TI - Discovery of Bladder Cancer-related Genes Using Integrative Heterogeneous Network Modeling of Multi-omics Data. AB - In human health, a fundamental challenge is the identification of disease-related genes. Bladder cancer (BC) is a worldwide malignant tumor, which has resulted in 170,000 deaths in 2010 up from 114,000 in 1990. Moreover, with the emergence of multi-omics data, more comprehensive analysis of human diseases become possible. In this study, we propose a multi-step approach for the identification of BC related genes by using integrative Heterogeneous Network Modeling of Multi-Omics data (iHNMMO). The heterogeneous network model properly and comprehensively reflects the multiple kinds of relationships between genes in the multi-omics data of BC, including general relationships, unique relationships under BC condition, correlational relationships within each omics and regulatory relationships between different omics. Besides, a network-based propagation algorithm with resistance is utilized to quantize the relationships between genes and BC precisely. The results of comprehensive performance evaluation suggest that iHNMMO significantly outperforms other approaches. Moreover, further analysis suggests that the top ranked genes may be functionally implicated in BC, which also confirms the superiority of iHNMMO. In summary, this study shows that disease-related genes can be better identified through reasonable integration of multi-omics data. PMID- 29142287 TI - Targeted next generation sequencing in Italian patients with Usher syndrome: phenotype-genotype correlations. AB - We report results of DNA analysis with next generation sequencing (NGS) of 21 consecutive Italian patients from 17 unrelated families with clinical diagnosis of Usher syndrome (4 USH1 and 17 USH2) searching for mutations in 11 genes: MYO7A, CDH23, PCDH15, USH1C, USH1G, USH2A, ADGVR1, DFNB31, CLRN1, PDZD7, HARS. Likely causative mutations were found in all patients: 25 pathogenic variants, 18 previously reported and 7 novel, were identified in three genes (USH2A, MYO7A, ADGRV1). All USH1 presented biallelic MYO7A mutations, one USH2 exhibited ADGRV1 mutations, whereas 16 USH2 displayed USH2A mutations. USH1 patients experienced hearing problems very early in life, followed by visual impairment at 1, 4 and 6 years. Visual symptoms were noticed at age 20 in a patient with homozygous novel MYO7A missense mutation c.849G > A. USH2 patients' auditory symptoms, instead, arose between 11 months and 14 years, while visual impairment occurred later on. A homozygous c.5933_5940del;5950_5960dup in USH2A was detected in one patient with early deafness. One patient with homozygous deletion from exon 23 to 32 in USH2A suffered early visual symptoms. Therefore, the type of mutation in USH2A and MYO7A genes seems to affect the age at which both auditory and visual impairment occur in patients with USH. PMID- 29142288 TI - Identification of small RNAs abundant in Burkholderia cenocepacia biofilms reveal putative regulators with a potential role in carbon and iron metabolism. AB - Small RNAs play a regulatory role in many central metabolic processes of bacteria, as well as in developmental processes such as biofilm formation. Small RNAs of Burkholderia cenocepacia, an opportunistic pathogenic beta proteobacterium, are to date not well characterised. To address that, we performed genome-wide transcriptome structure analysis of biofilm grown B. cenocepacia J2315. 41 unannotated short transcripts were identified in intergenic regions of the B. cenocepacia genome. 15 of these short transcripts, highly abundant in biofilms, widely conserved in Burkholderia sp. and without known function, were selected for in-depth analysis. Expression profiling showed that most of these sRNAs are more abundant in biofilms than in planktonic cultures. Many are also highly abundant in cells grown in minimal media, suggesting they are involved in adaptation to nutrient limitation and growth arrest. Their computationally predicted targets include a high proportion of genes involved in carbon metabolism. Expression and target genes of one sRNA suggest a potential role in regulating iron homoeostasis. The strategy used for this study to detect sRNAs expressed in B. cenocepacia biofilms has successfully identified sRNAs with a regulatory function. PMID- 29142289 TI - Comprehensive genomic analysis of a plant growth-promoting rhizobacterium Pantoea agglomerans strain P5. AB - In this study, we provide a comparative genomic analysis of Pantoea agglomerans strain P5 and 10 closely related strains based on phylogenetic analyses. A next generation shotgun strategy was implemented using the Illumina HiSeq 2500 technology followed by core- and pan-genome analysis. The genome of P. agglomerans strain P5 contains an assembly size of 5082485 bp with 55.4% G + C content. P. agglomerans consists of 2981 core and 3159 accessory genes for Coding DNA Sequences (CDSs) based on the pan-genome analysis. Strain P5 can be grouped closely with strains PG734 and 299 R using pan and core genes, respectively. All the predicted and annotated gene sequences were allocated to KEGG pathways. Accordingly, genes involved in plant growth-promoting (PGP) ability, including phosphate solubilization, IAA and siderophore production, acetoin and 2,3 butanediol synthesis and bacterial secretion, were assigned. This study provides an in-depth view of the PGP characteristics of strain P5, highlighting its potential use in agriculture as a biofertilizer. PMID- 29142290 TI - Characterizing the conformational landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations. AB - The conformational landscapes of p53 peptide variants and phage derived peptide (12/1) variants, all known to bind to MDM2, are studied using hamiltonian replica exchange molecular dynamics simulations. Complementing earlier observations, the current study suggests that the p53 peptides largely follow the 'conformational selection' paradigm in their recognition of and complexation by MDM2 while the 12/1 peptides likely undergo some element of conformational selection but are mostly driven by 'binding induced folding'. This hypothesis is further supported by pulling simulations that pull the peptides away from their bound states with MDM2. This data extends the earlier mechanisms proposed to rationalize the entropically driven binding of the p53 set and the enthalpically driven binding of the 12/1 set. Using our hypothesis, we suggest mutations to the 12/1 peptide that increase its helicity in simulations and may, in turn, shift the binding towards conformational selection. In summary, understanding the conformational landscapes of the MDM2-binding peptides may suggest new peptide designs with bespoke binding mechanisms. PMID- 29142291 TI - Resveratrol modulates cocaine-induced inhibitory synaptic plasticity in VTA dopamine neurons by inhibiting phosphodiesterases (PDEs). AB - Resveratrol is a natural phytoalexin synthesized by plants, including grapes. It displays a wide range of neuroprotective benefits associated with anti-aging. Recent studies have shown that resveratrol regulates dopaminergic transmission and behavioral effects of drugs of abuse. The goal of the present study is to investigate whether and how resveratrol alters basal inhibitory synaptic transmission and cocaine-induced inhibitory synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA). We report that resveratrol elevated cAMP levels by itself and further potentiated a forskolin-induced increase in cAMP levels in midbrain slices, consistent with reported effects of inhibition of phosphodiesterases (PDEs). Resveratrol potentiated GABAA and GABAB-mediated inhibitory postsynaptic currents (IPSCs) in VTA dopamine neurons, and these effects were mediated by a protein kinase A (PKA)-dependent enhancement of presynaptic GABA release. In addition, we found that resveratrol blocked endocannabinoid-mediated long-term synaptic depression in VTA dopamine neurons. Resveratrol pretreatments attenuated cocaine-induced conditioned place preference and blocked the cocaine-induced reduction of GABAergic inhibition in VTA dopamine neurons. Together, these results provide evidence that resveratrol modulates basal inhibitory synaptic transmission, cocaine-induced synaptic plasticity, and drug-cue associative learning. PMID- 29142292 TI - Urinary volatile organic compounds in overweight compared to normal-weight children: results from the Italian I.Family cohort. AB - Accumulating evidence shows that urinary volatile organic compounds (VOCs) could be perturbed in many physiological and pathological states, including several diseases and different dietary exposures. Few studies investigated the urinary metabolic signature associated to excess body weight and obesity in adult populations, while a different VOCs profile was found in exhaled breath in obese as compared to lean children. Aim of this study was to evaluate the VOCs profile in the urine of 21 overweight/obese (OW/Ob) and 28 normal-weight (NW) children belonging to the Italian cohort of the I. Family study. Urine samples were analysed by Solid Phase Micro-Extraction (SPME) GC-MS under both acidic and alkaline conditions, in order to profile a wider range of urinary volatiles with different physicochemical properties. Multivariate statistics techniques were applied to bioanalytical data to visualize clusters of cases and detect the VOCs able to differentiate OW/Ob from NW children. Under alkaline conditions, fourteen VOCs were identified, distinguishing OW/Ob from NW children. Our results suggest that VOCs signatures differ between OW/Ob and NW children. However, the biological and pathophysiological meaning of the observed differences needs to be elucidated, in order to better understand the potential of urinary VOCs as early metabolic biomarkers of obesity. PMID- 29142293 TI - Neural pathways for colorectal control, relevance to spinal cord injury and treatment: a narrative review. AB - STUDY DESIGN: Narrative review. OBJECTIVES: The purpose is to review the organisation of the nerve pathways that control defecation and to relate this knowledge to the deficits in colorectal function after SCI. METHODS: A literature review was conducted to identify salient features of defecation control pathways and the functional consequences of damage to these pathways in SCI. RESULTS: The control pathways for defecation have separate pontine centres under cortical control that influence defecation. The pontine centres connect, separately, with autonomic preganglionic neurons of the spinal defecation centres and somatic motor neurons of Onuf's nucleus in the sacral spinal cord. Organised propulsive motor patterns can be generated by stimulation of the spinal defecation centres. Activation of the somatic neurons contracts the external sphincter. The analysis aids in interpreting the consequences of SCI and predicts therapeutic strategies. CONCLUSIONS: Analysis of the bowel control circuits identifies sites at which bowel function may be modulated after SCI. Colokinetic drugs that elicit propulsive contractions of the colorectum may provide valuable augmentation of non-pharmacological bowel management procedures. PMID- 29142294 TI - Administration of increasing doses of gonadotropin-releasing hormone in men with spinal cord injury to investigate dysfunction of the hypothalamic-pituitary gonadal axis. AB - STUDY DESIGN: Prospective. OBJECTIVES: To determine the optimum gonadotropin releasing hormone (GnRH) dose to identify dysfunction of the hypothalamic pituitary-gonadal axis in men with spinal cord injury (SCI). SETTING: Metropolitan Area Hospitals, New York and New Jersey, USA. METHODS: SCI men (16 hypogonadal (HG = serum testosterone <12.1 nmol/l) and 14 eugonadal (EG)) and able-bodied (AB) men (27 HG and 11 EG) were studied. GnRH (10, 50, and 100 MUg) was randomly administered intravenously on three separate visits. Blood samples were collected post-GnRH for serum-luteinizing hormone (LH) and follicular stimulating hormone (FSH). RESULTS: HG and EG men had a similar proportion of clinically acceptable gonadotropin responses to all three GnRH doses. The incremental gonadotropin responses to GnRH were not significantly different across the groups. However, in the SCI-HG group, GnRH of 100 MUg resulted in the greatest integrated FSH response, and in the SCI-EG group, GnRH of 50 MUg resulted in the greatest integrated LH response compared with the AB groups. A consistent, but not significant, absolute increase in gonadotropin release was observed in the SCI groups at all GnRH doses. CONCLUSIONS: Lower doses of GnRH did not improve the ability to identify the clinical dysfunction of the hypothalamic-pituitary-gonadal axis. However, the absolutely higher SCI-HG FSH response to GnRH of 100 MUg and a higher SCI-EG LH response to GnRH of 50 MUg, along with a higher gonadotropin release at all GnRH doses, albeit not significant, suggests a hypothalamic-pituitary dysfunction in persons with SCI. PMID- 29142297 TI - 5-Aminolevulinic Acid Guided Sampling of Glioblastoma Microenvironments Identifies Pro-Survival Signaling at Infiltrative Margins. AB - Glioblastoma (GBM) contains diverse microenvironments with uneven distributions of oncogenic alterations and signaling networks. The diffusely infiltrative properties of GBM result in residual tumor at neurosurgical resection margins, representing the source of relapse in nearly all cases and suggesting that therapeutic efforts should be focused there. To identify signaling networks and potential druggable targets across tumor microenvironments (TMEs), we utilized 5 ALA fluorescence-guided neurosurgical resection and sampling, followed by proteomic analysis of specific TMEs. Reverse phase protein array (RPPA) was performed on 205 proteins isolated from the tumor margin, tumor bulk, and perinecrotic regions of 13 previously untreated, clinically-annotated and genetically-defined high grade gliomas. Differential protein and pathway signatures were established and then validated using western blotting, immunohistochemistry, and comparable TCGA RPPA datasets. We identified 37 proteins differentially expressed across high-grade glioma TMEs. We demonstrate that tumor margins were characterized by pro-survival and anti-apoptotic proteins, whereas perinecrotic regions were enriched for pro-coagulant and DNA damage response proteins. In both our patient cohort and TCGA cases, the data suggest that TMEs possess distinct protein expression profiles that are biologically and therapeutically relevant. PMID- 29142295 TI - Regenerating CNS myelin - from mechanisms to experimental medicines. AB - Although the core concept of remyelination - based on the activation, migration, proliferation and differentiation of CNS progenitors - has not changed over the past 20 years, our understanding of the detailed mechanisms that underlie this process has developed considerably. We can now decorate the central events of remyelination with a host of pathways, molecules, mediators and cells, revealing a complex and precisely orchestrated process. These advances have led to recent drug-based and cell-based clinical trials for myelin diseases and have opened up hitherto unrecognized opportunities for drug-based approaches to therapeutically enhance remyelination. PMID- 29142298 TI - Shaping bacterial population behavior through computer-interfaced control of individual cells. AB - Bacteria in groups vary individually, and interact with other bacteria and the environment to produce population-level patterns of gene expression. Investigating such behavior in detail requires measuring and controlling populations at the single-cell level alongside precisely specified interactions and environmental characteristics. Here we present an automated, programmable platform that combines image-based gene expression and growth measurements with on-line optogenetic expression control for hundreds of individual Escherichia coli cells over days, in a dynamically adjustable environment. This integrated platform broadly enables experiments that bridge individual and population behaviors. We demonstrate: (i) population structuring by independent closed-loop control of gene expression in many individual cells, (ii) cell-cell variation control during antibiotic perturbation, (iii) hybrid bio-digital circuits in single cells, and freely specifiable digital communication between individual bacteria. These examples showcase the potential for real-time integration of theoretical models with measurement and control of many individual cells to investigate and engineer microbial population behavior. PMID- 29142296 TI - The dopamine motive system: implications for drug and food addiction. AB - Behaviours such as eating, copulating, defending oneself or taking addictive drugs begin with a motivation to initiate the behaviour. Both this motivational drive and the behaviours that follow are influenced by past and present experience with the reinforcing stimuli (such as drugs or energy-rich foods) that increase the likelihood and/or strength of the behavioural response (such as drug taking or overeating). At a cellular and circuit level, motivational drive is dependent on the concentration of extrasynaptic dopamine present in specific brain areas such as the striatum. Cues that predict a reinforcing stimulus also modulate extrasynaptic dopamine concentrations, energizing motivation. Repeated administration of the reinforcer (drugs, energy-rich foods) generates conditioned associations between the reinforcer and the predicting cues, which is accompanied by downregulated dopaminergic response to other incentives and downregulated capacity for top-down self-regulation, facilitating the emergence of impulsive and compulsive responses to food or drug cues. Thus, dopamine contributes to addiction and obesity through its differentiated roles in reinforcement, motivation and self-regulation, referred to here as the 'dopamine motive system', which, if compromised, can result in increased, habitual and inflexible responding. Thus, interventions to rebalance the dopamine motive system might have therapeutic potential for obesity and addiction. PMID- 29142299 TI - The Immunomodulatory Drug Glatiramer Acetate is Also an Effective Antimicrobial Agent that Kills Gram-negative Bacteria. AB - Classic drug development strategies have failed to meet the urgent clinical needs in treating infections with Gram-negative bacteria. Repurposing drugs can lead to timely availability of new antibiotics, accelerated by existing safety profiles. Glatiramer acetate (GA) is a widely used and safe formulation for treatment of multiple sclerosis. It contains a large diversity of essentially isomeric polypeptides with the cationic and amphiphilic character of many antimicrobial peptides (AMP). Here, we report that GA is antibacterial, targeting Gram-negative organisms with higher activity towards Pseudomonas aeruginosa than the naturally occurring AMP LL-37 in human plasma. As judged from flow cytometric assays, bacterial killing by GA occurred within minutes. Laboratory strains of Escherichia coli and P. aeruginosa were killed by a process of condensing intracellular contents. Efficient killing by GA was also demonstrated in Acinetobacter baumannii clinical isolates and approximately 50% of clinical isolates of P. aeruginosa from chronic airway infection in CF patients. By contrast, the Gram-positive Staphylococcus aureus cells appeared to be protected from GA by an increased formation of nm-scale particulates. Our data identify GA as an attractive drug repurposing candidate to treat infections with Gram negative bacteria. PMID- 29142302 TI - THERE MUST BE BLOOD. AB - It is argued that in the effective psychotherapy of patients suffering with severe trauma, there is always blood that is shed. This blood may be metaphorical but is often literal. In its absence, it is unlikely that anything of real value has occurred. PMID- 29142300 TI - Structure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein. AB - Human metapneumovirus (hMPV) is a frequent cause of bronchiolitis in young children. Its F glycoprotein mediates virus-cell membrane fusion and is the primary target of neutralizing antibodies. The inability to produce recombinant hMPV F glycoprotein in the metastable pre-fusion conformation has hindered structural and immunological studies. Here, we engineer a pre-fusion-stabilized hMPV F ectodomain and determine its crystal structure to 2.6 A resolution. This structure reveals molecular determinants of strain-dependent acid-induced fusion, as well as insights into refolding from pre- to post-fusion conformations. A dense glycan shield at the apex of pre-fusion hMPV F suggests that antibodies against this site may not be elicited by host immune responses, which is confirmed by depletion studies of human immunoglobulins and by mouse immunizations. This is a major difference with pre-fusion F from human respiratory syncytial virus (hRSV), and collectively our results should facilitate development of effective hMPV vaccine candidates. PMID- 29142301 TI - Alteration of the intestinal microbiome characterizes preclinical inflammatory arthritis in mice and its modulation attenuates established arthritis. AB - Perturbations of the intestinal microbiome have been observed in patients with new-onset and chronic autoimmune inflammatory arthritis. However, it is currently unknown whether these alterations precede the development of arthritis or are rather a consequence of disease. Modulation of intestinal microbiota by oral antibiotics or germ-free condition can prevent arthritis in mice. Yet, the therapeutic potential of modulation of the microbiota after the onset of arthritis is not well characterized. We here show that the intestinal microbial community undergoes marked changes in the preclinical phase of collagen induced arthritis (CIA). The abundance of the phylum Bacteroidetes, specifically families S24-7 and Bacteroidaceae was reduced, whereas Firmicutes and Proteobacteria, such as Ruminococcaceae, Lachnospiraceae and Desulfovibrinocaceae, were expanded during the immune-priming phase of arthritis. In addition, we found that the abundance of lamina propria Th17, but not Th1, cells is highly correlated with the severity of arthritis. Elimination of the intestinal microbiota during established arthritis specifically reduced intestinal Th17 cells and attenuated arthritis. These effects were associated with reduced serum amyloid A expression in ileum and synovial tissue. Our observations suggest that intestinal microbiota perturbations precede arthritis, and that modulation of the intestinal microbiota after the onset of arthritis may offer therapeutic opportunities. PMID- 29142303 TI - FUS toxicity is rescued by the modulation of lncRNA hsromega expression in Drosophila melanogaster. AB - FUS is an aggregation-prone hnRNP involved in transcriptional and post transcriptional regulation that aberrantly forms immunoreactive inclusion bodies in a range of neurological diseases classified as FUS-proteinopathies. Although FUS has been extensively examined, the underlying molecular mechanisms of these diseases have not yet been elucidated in detail. We previously reported that RNAi of the lncRNA hsromega altered the expression and sub-cellular localization of Drosophila FUS in the central nervous system of the fly. In order to obtain a clearer understanding of the role of hsromega in FUS toxicity, we herein drove the expression of human FUS in Drosophila eyes with and without a hsromega RNAi background. We found that hFUS was largely soluble and also able to form aggregates. As such, hFUS was toxic, inducing an aberrant eye morphology with the loss of pigmentation. The co-expression of hsromega double-stranded RNA reduced hFUS transcript levels and induced the formation of cytoplasmic non-toxic hFUS LAMP1-insoluble inclusions. The combination of these events caused the titration of hFUS molar excess and a removal of hFUS aggregates to rescue toxicity. These results revealed the presence of a lncRNA-dependent pathway involved in the management of aggregation-prone hnRNPs, suggesting that properly formed FUS inclusions are not toxic to cells. PMID- 29142304 TI - Maternal Exposure to Iodine Excess Throughout Pregnancy and Lactation Induces Hypothyroidism in Adult Male Rat Offspring. AB - This study aimed to investigate the consequences of maternal exposure to iodine excess (IE; 0.6 mg NaI/L) throughout pregnancy and lactation on the hypothalamus pituitary-thyroid axis of the male offspring in adulthood. Maternal IE exposure increased hypothalamic Trh mRNA expression and pituitary Tsh expression and secretion in the adult male offspring. Moreover, the IE-exposed offspring rats presented reduced thyroid hormones levels, morphological alterations in the thyroid follicles, increased thyroid oxidative stress and decreased expression of thyroid differentiation markers (Tshr, Nis, Tg, Tpo, Mct8) and thyroid transcription factors (Nkx2.1, Pax8). Finally, the data presented here strongly suggest that epigenetic mechanisms, as increased DNA methylation, augmented DNA methyltransferases expression, hypermethylation of histone H3, hypoaceylation of histones H3 and H4, increased expression/activity of histone deacetylases and decreased expression/activity of histone acetyltransferases are involved in the repression of thyroid gene expression in the adult male offspring. In conclusion, our results indicate that rat dams' exposure to IE during pregnancy and lactation induces primary hypothyroidism and triggers several epigenetic changes in the thyroid gland of their male offspring in adulthood. PMID- 29142305 TI - Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors. AB - Many compounds with potentially reactive chemical motifs and poor physicochemical properties are published as selective modulators of biomolecules without sufficient validation and then propagated in the scientific literature as useful chemical probes. Several histone acetyltransferase (HAT) inhibitors with these liabilities are now routinely used to probe epigenetic pathways. We profile the most commonly used HAT inhibitors and confirm that the majority of them are nonselective interference compounds. Most (15 out of 23, 65%) of the inhibitors are flagged by ALARM NMR, an industry-developed counter-screen for promiscuous compounds. Biochemical counter-screens confirm that most of these compounds are either thiol-reactive or aggregators. Selectivity panels show many of these compounds modulate unrelated targets in vitro, while several also demonstrate nonspecific effects in cell assays. These data demonstrate the usefulness of performing counter-screens for bioassay promiscuity and assay interference, and raise caution about the utility of many widely used, but insufficiently validated, compounds employed in chemical biology. PMID- 29142306 TI - An exome sequencing based approach for genome-wide association studies in the dog. AB - Genome-wide association studies (GWAS) are widely used to identify loci associated with phenotypic traits in the domestic dog that has emerged as a model for Mendelian and complex traits. However, a disadvantage of GWAS is that it always requires subsequent fine-mapping or sequencing to pinpoint causal mutations. Here, we performed whole exome sequencing (WES) and canine high density (cHD) SNP genotyping of 28 dogs from 3 breeds to compare the SNP and linkage disequilibrium characteristics together with the power and mapping precision of exome-guided GWAS (EG-GWAS) versus cHD-based GWAS. Using simulated phenotypes, we showed that EG-GWAS has a higher power than cHD to detect associations within target regions and less power outside target regions, with power being influenced further by sample size and SNP density. We analyzed two real phenotypes (hair length and furnishing), that are fixed in certain breeds to characterize mapping precision of the known causal mutations. EG-GWAS identified the associated exonic and 3'UTR variants within the FGF5 and RSPO2 genes, respectively, with only a few samples per breed. In conclusion, we demonstrated that EG-GWAS can identify loci associated with Mendelian phenotypes both within and across breeds. PMID- 29142307 TI - Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease. AB - Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III-IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait loci (QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1beta, IFNgamma, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations. PMID- 29142308 TI - The evolution of a rare mammalian trait - benefits and costs of male philopatry in proboscis bats. AB - While inbreeding avoidance is widely accepted as the major driver of female natal dispersal, the evolution of male philopatry is still poorly understood and discussed to be driven by male mating strategy, mate competition among male kin and kin cooperation. During a twelve-year study, we gathered detailed genetic and observational data of individually marked proboscis bats to assess the degree of male philopatry as well as its costs and benefits to improve the understanding of its evolution. Our results reveal several patrilines with simultaneous presence of closely related males and a small proportion of unrelated immigrant males in their colonies. Philopatric males benefit from avoiding the costs of immigration into foreign colonies through significantly longer tenure, better integration (i.e. frequent nocturnal presence in the colonies) and consequently significantly higher reproductive success compared to immigrant males. Finally, we illustrate that despite a high proportion of philopatric males in the groups, the number of closely related competing males is low. Thus, the hypothesised costs of mate competition among male kin seem to be low in promiscuous mammalian societies with unrelated females and a small degree of male immigration and are readily outweighed by the benefits of staying in the natal group. PMID- 29142309 TI - Hypercholesterolemia Enhances T Cell Receptor Signaling and Increases the Regulatory T Cell Population. AB - Hypercholesterolemia promotes the inflammation against lipoproteins in atherosclerosis. Development of atherosclerosis is affected by the balance between pro-inflammatory effector T cells and anti-inflammatory regulatory T (Treg) cells. However, phenotype and function of T cell subpopulations in hypercholesterolemia remain to be investigated. Here, we found that cholesterol containing diet increased the expression of the Treg cell lineage-defining transcription factor FoxP3 among thymocytes and splenocytes. Hypercholesterolemia elevated the FoxP3 expression level and population size of peripheral Treg cells, but did not prevent enhanced proliferation of stimulated T cells. Moreover, cholesterol supplementation in diet as well as in cell culture medium promoted T cell antigen receptor (TCR) signaling in CD4+ T cells. Our results demonstrate that hypercholesterolemia enhances TCR stimulation, Treg cell development as well as T cell proliferation. Thus, our findings may help to understand why hypercholesterolemia correlates with altered CD4+ T cell responses. PMID- 29142310 TI - Sodium channel NaV1.3 is important for enterochromaffin cell excitability and serotonin release. AB - In the gastrointestinal (GI) epithelium, enterochromaffin (EC) cells are enteroendocrine cells responsible for producing >90% of the body's serotonin (5 hydroxytryptamine, 5-HT). However, the molecular mechanisms of EC cell function are poorly understood. Here, we found that EC cells in mouse primary cultures fired spontaneous bursts of action potentials. We examined the repertoire of voltage-gated sodium channels (NaV) in fluorescence-sorted mouse EC cells and found that Scn3a was highly expressed. Scn3a-encoded NaV1.3 was specifically and densely expressed at the basal side of both human and mouse EC cells. Using electrophysiology, we found that EC cells expressed robust NaV1.3 currents, as determined by their biophysical and pharmacologic properties. NaV1.3 was not only critical for generating action potentials in EC cells, but it was also important for regulating 5-HT release by these cells. Therefore, EC cells use Scn3a-encoded voltage-gated sodium channel NaV1.3 for electrical excitability and 5-HT release. NaV1.3-dependent electrical excitability and its contribution to 5-HT release is a novel mechanism of EC cell function. PMID- 29142311 TI - A standardized herbal extract mitigates tumor inflammation and augments chemotherapy effect of docetaxel in prostate cancer. AB - Activation of the NFkappaB pathway is often associated with advanced cancer and has thus been regarded as a rational therapeutic target. Wedelia chinensis is rich in luteolin, apigenin, and wedelolactone that act synergistically to suppress androgen receptor activity in prostate cancer. Interestingly, our evaluation of a standardized Wedelia chinensis herbal extract (WCE) concluded its efficacy on hormone-refractory prostate cancer through systemic mechanisms. Oral administration of WCE significantly attenuated tumor growth and metastasis in orthotopic PC-3 and DU145 xenografts. Genome-wide transcriptome analysis of these tumors revealed that WCE suppressed the expression of IKKalpha/beta phosphorylation and downstream cytokines/chemokines, e.g., IL6, CXCL1, and CXCL8. Through restraining the cytokines expression, WCE reduced tumor-elicited infiltration of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and endothelial cells into the tumors, therefore inhibiting angiogenesis, tumor growth, and metastasis. In MDSCs, WCE also reduced STAT3 activation, downregulated S100A8 expression and prevented their expansion. Use of WCE in combination with docetaxel significantly suppressed docetaxel-induced NFkappaB activation, boosted the therapeutic effect and reduced the systemic toxicity caused by docetaxel monotherapy. These data suggest that a standardized preparation of Wedelia chinensis extract improved prostate cancer therapy through immunomodulation and has potential application as an adjuvant agent for castration-resistant prostate cancer. PMID- 29142312 TI - Understanding the anticorrosive protective mechanisms of modified epoxy coatings with improved barrier, active and self-healing functionalities: EIS and spectroscopic techniques. AB - The present investigation adopted long-term in-situ electrochemical and spectroscopic approaches to study the combined active, self-healing and passive protective mechanisms of a new class of innovative anti-corrosive coatings based on epoxy doped with clay nanotubes impregnated with active species for the protection of carbon steel in 3.5% NaCl solution. The suitability of the as received clay nanotubes to encapsulate the active agents was confirmed by different spectroscopic measurements. Tube end stopper with Ferric ion and polymer encapsulation with chitosan cross-linked with glutaraldehyde were adopted to tunnel the release of the active agents loaded into the nanotubes. The improved passive barrier performances of the various innovative coatings were revealed by the electrochemical impedance spectroscopic, while their active feedback and self-healing abilities were revealed by the optical and spectroscopic techniques. The optical/spectroscopic techniques revealed the degree of pit formation at the steel/coating interface and the iron rust formation around the artificially marked defects, including the ability of the marked defects to self-heal over exposure times. Adhesion and impacts tests were adopted to compare the physical/mechanical properties of the various coatings. The results afforded insights into the effects of exposure time on the protective and failure behaviours of both the reference and modified coatings. PMID- 29142313 TI - Effects of exosome on the activation of CD4+ T cells in rhesus macaques: a potential application for HIV latency reactivation. AB - Exosomes are small extracellular vesicles (EVs), released by a wide variety of cell types, carry donor origin-proteins, cytokines, and nucleic acids, transport these cargos to adjacent or distant specific recipient cells, and thereby regulate gene expression and activation of target cells. In this study, we isolated and identified exosomes in rhesus macaques, and investigated their effects on cell tropism and activation, especially their potential to reactivate HIV latency. The results indicated that plasma-derived exosomes preferentially fuse to TCR-activated T cells and autologous parent cells. Importantly, the uptake of exosomes, derived from IL-2 stimulated CD4+ T cells, effectively promoted reactivation of resting CD4+ T-cell, as indicated by an increased viral transcription rate in these cells. These findings provide premise for the potential application of exosome in the reactivation of HIV latency, in combination its use as functional delivery vehicles with antiretroviral therapy (ART). PMID- 29142314 TI - Magnetoresistance and robust resistivity plateau in MoAs2. AB - We have grown the MoAs2 single crystal which crystallizes in a monoclinic structure with C2/m space group. Transport measurements show that MoAs2 displays a metallic behavior at zero field and undergoes a metal-to-semiconductor crossover at low temperatures when the applied magnetic field is over 5 T. A robust resistivity plateau appears below 18 K and persists for the field up to 9 T. A large positive magnetoresistance (MR), reaching about 2600% at 2 K and 9 T, is observed when the field is perpendicular to the current. The MR becomes negative below 40 K when the field is rotated to be parallel to the current. The Hall resistivity shows the non-linear field-dependence below 70 K. The analysis using two-band model indicates a compensated electron-hole carrier density at low temperatures. A combination of the breakdown of Kohler's rule, the abnormal drop and the cross point in Hall data implies that a possible Lifshitz transition has occurred between 30 K and 60 K, likely driving the compensated electron-hole density, the large MR as well as the metal-semiconductor transition in MoAs2. Our results indicate that the family of centrosymmetric transition-metal dipnictides has rich transport behavior which can in general exhibit variable metallic and topological features. PMID- 29142315 TI - HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration. AB - While beta-amyloid (Abeta), a classic hallmark of Alzheimer's disease (AD) and dementia, has long been known to be elevated in the human immunodeficiency virus type 1 (HIV-1)-infected brain, why and how Abeta is produced, along with its contribution to HIV-associated neurocognitive disorder (HAND) remains ill defined. Here, we reveal that the membrane-associated amyloid precursor protein (APP) is highly expressed in macrophages and microglia, and acts as an innate restriction against HIV-1. APP binds the HIV-1 Gag polyprotein, retains it in lipid rafts and blocks HIV-1 virion production and spread. To escape this restriction, Gag promotes secretase-dependent cleavage of APP, resulting in the overproduction of toxic Abeta isoforms. This Gag-mediated Abeta production results in increased degeneration of primary cortical neurons, and can be prevented by gamma-secretase inhibitor treatment. Interfering with HIV-1's evasion of APP-mediated restriction also suppresses HIV-1 spread, offering a potential strategy to both treat infection and prevent HAND. PMID- 29142316 TI - Sedentary behavior and altered metabolic activity by AgNPs ingestion in Drosophila melanogaster. AB - Among several nanoparticles, silver nanoparticles (AgNPs) are extensively used in a wide variety of consumer products due to its unique antimicrobial property. However, dosage effect of AgNPs on behavior and metabolic activity in an in vivo condition is not well studied. Therefore, to elucidate the impact of AgNPs on behavior and metabolism, systematic and detailed dosages study of AgNPs was performed by rearing Drosophila melanogaster on food without and with AgNPs. We found that dietary intake of AgNPs at early larval stage leads to behavioral abnormalities such as poor crawling and climbing ability of larvae and adults respectively. Interestingly, intake of higher dosage of AgNPs at larval stage significantly altered metabolic activity that includes lipid, carbohydrate and protein levels in adult flies. Further, detailed analysis revealed that AgNPs causes remarkable reduction in the number of lipid droplets (LDs) which are lipid storage organelles in Drosophila. We also observed an increased production of reactive oxygen species (ROS) in AgNPs ingested larval tissues. These results strongly imply that higher dosage of AgNPs ingestion from early larval stage of Drosophila is inimical and thereby draws concern towards the usage of AgNPs in consumer goods. PMID- 29142319 TI - DNA metabarcoding for high-throughput monitoring of estuarine macrobenthic communities. AB - Morphology-based profiling of benthic communities has been extensively applied to aquatic ecosystems' health assessment. However, it remains a low-throughput, and sometimes ambiguous, procedure. Despite DNA metabarcoding has been applied to marine benthos, a comprehensive approach providing species-level identifications for estuarine macrobenthos is still lacking. Here we report a combination of experimental and field studies to assess the aptitude of COI metabarcoding to provide robust species-level identifications for high-throughput monitoring of estuarine macrobenthos. To investigate the ability of metabarcoding to detect all species present in bulk DNA extracts, we contrived three phylogenetically diverse communities, and applied four different primer pairs to generate PCR products within the COI barcode region. Between 78-83% of the species in the contrived communities were recovered through HTS. Subsequently, we compared morphology and metabarcoding-based approaches to determine the species composition from four distinct estuarine sites. Our results indicate that species richness would be considerably underestimated if only morphological methods were used: globally 27 species identified through morphology versus 61 detected by metabarcoding. Although further refinement is required to improve efficiency and output of this approach, here we show the great aptitude of COI metabarcoding to provide high quality and auditable species identifications in estuarine macrobenthos monitoring. PMID- 29142318 TI - The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD. AB - The natural product carolacton is a macrolide keto-carboxylic acid produced by the myxobacterium Sorangium cellulosum, and was originally described as an antibacterial compound. Here we show that carolacton targets FolD, a key enzyme from the folate-dependent C1 metabolism. We characterize the interaction between bacterial FolD and carolacton biophysically, structurally and biochemically. Carolacton binds FolD with nanomolar affinity, and the crystal structure of the FolD-carolacton complex reveals the mode of binding. We show that the human FolD orthologs, MTHFD1 and MTHFD2, are also inhibited in the low nM range, and that micromolar concentrations of carolacton inhibit the growth of cancer cell lines. As mitochondrial MTHFD2 is known to be upregulated in cancer cells, it may be possible to use carolacton as an inhibitor tool compound to assess MTHFD2 as an anti-cancer target. PMID- 29142317 TI - The maternal genetic make-up of the Iberian Peninsula between the Neolithic and the Early Bronze Age. AB - Agriculture first reached the Iberian Peninsula around 5700 BCE. However, little is known about the genetic structure and changes of prehistoric populations in different geographic areas of Iberia. In our study, we focus on the maternal genetic makeup of the Neolithic (~ 5500-3000 BCE), Chalcolithic (~ 3000-2200 BCE) and Early Bronze Age (~ 2200-1500 BCE). We report ancient mitochondrial DNA results of 213 individuals (151 HVS-I sequences) from the northeast, central, southeast and southwest regions and thus on the largest archaeogenetic dataset from the Peninsula to date. Similar to other parts of Europe, we observe a discontinuity between hunter-gatherers and the first farmers of the Neolithic. During the subsequent periods, we detect regional continuity of Early Neolithic lineages across Iberia, however the genetic contribution of hunter-gatherers is generally higher than in other parts of Europe and varies regionally. In contrast to ancient DNA findings from Central Europe, we do not observe a major turnover in the mtDNA record of the Iberian Late Chalcolithic and Early Bronze Age, suggesting that the population history of the Iberian Peninsula is distinct in character. PMID- 29142320 TI - Biocompatibility and biodegradation studies of a commercial zinc alloy for temporary mini-implant applications. AB - In this study, the biocompatibility and in vitro degradation behaviour of a commercial zinc-based alloy (Zn-5 Al-4 Mg) were evaluated and compared with that of pure zinc for temporary orthopaedic implant applications. Biocompatibility tests were conducted using human alveolar lung epithelial cells (A549), which showed that the zinc alloy exhibits similar biocompatibility as compared to pure zinc. In vitro degradation evaluation was performed using weight loss and electrochemical methods in simulated body fluid (SBF) at 37 degrees C. Weight loss measurements revealed that the degradation of the zinc alloy was slightly lower during the initial immersion period (1-3 days), but marginally increased after 5 and 7 days immersion as compared to pure zinc. Potentiodynamic polarisation experiments showed that the zinc alloy exhibits higher degradation rate than pure zinc. However, electrochemical impedance spectroscopy analysis suggests that pure zinc is susceptible to localized degradation, whereas the zinc alloy exhibited passivation behaviour. Post-degradation analysis revealed localized degradation in both pure zinc and the zinc alloy. PMID- 29142321 TI - Design of Cultured Neuron Networks in vitro with Predefined Connectivity Using Asymmetric Microfluidic Channels. AB - The architecture of neuron connectivity in brain networks is one of the basic mechanisms by which to organize and sustain a particular function of the brain circuitry. There are areas of the brain composed of well-organized layers of neurons connected by unidirectional synaptic connections (e.g., cortex, hippocampus). Re-engineering of the neural circuits with such a heterogeneous network structure in culture may uncover basic mechanisms of emergent information functions of these circuits. In this study, we present such a model designed with two subpopulations of primary hippocampal neurons (E18) with directed connectivity grown in a microfluidic device with asymmetric channels. We analysed and compared neurite growth in the microchannels with various shapes that promoted growth dominantly in one direction. We found an optimal geometric shape features of the microchannels in which the axons coupled two chambers with the neurons. The axons grew in the promoted direction and formed predefined connections during the first 6 days in vitro (DIV). The microfluidic devices were coupled with microelectrode arrays (MEAs) to confirm unidirectional spiking pattern propagation through the microchannels between two compartments. We found that, during culture development, the defined morphological and functional connectivity formed and was maintained for up to 25 DIV. PMID- 29142322 TI - Bilateral 5 Hz transcranial alternating current stimulation on fronto-temporal areas modulates resting-state EEG. AB - Rhythmic non-invasive brain stimulations are promising tools to modulate brain activity by entraining neural oscillations in specific cortical networks. The aim of the study was to assess the possibility to influence the neural circuits of the wake-sleep transition in awake subjects via a bilateral transcranial alternating current stimulation at 5 Hz (theta-tACS) on fronto-temporal areas. 25 healthy volunteers participated in two within-subject sessions (theta-tACS and sham), one week apart and in counterbalanced order. We assessed the stimulation effects on cortical EEG activity (28 derivations) and self-reported sleepiness (Karolinska Sleepiness Scale). theta-tACS induced significant increases of the theta activity in temporo-parieto-occipital areas and centro-frontal increases in the alpha activity compared to sham but failed to induce any online effect on sleepiness. Since the total energy delivered in the sham condition was much less than in the active theta-tACS, the current data are unable to isolate the specific effect of entrained theta oscillatory activity per se on sleepiness scores. On this basis, we concluded that theta-tACS modulated theta and alpha EEG activity with a topography consistent with high sleep pressure conditions. However, no causal relation can be traced on the basis of the current results between these rhythms and changes on sleepiness. PMID- 29142323 TI - Nkx6.1 decline accompanies mitochondrial DNA reduction but subtle nucleoid size decrease in pancreatic islet beta-cells of diabetic Goto Kakizaki rats. AB - Hypertrophic pancreatic islets (PI) of Goto Kakizaki (GK) diabetic rats contain a lower number of beta-cells vs. non-diabetic Wistar rat PI. Remaining beta-cells contain reduced mitochondrial (mt) DNA per nucleus (copy number), probably due to declining mtDNA replication machinery, decreased mt biogenesis or enhanced mitophagy. We confirmed mtDNA copy number decrease down to <30% in PI of one-year old GK rats. Studying relations to mt nucleoids sizes, we employed 3D superresolution fluorescent photoactivable localization microscopy (FPALM) with lentivirally transduced Eos conjugate of mt single-stranded-DNA-binding protein (mtSSB) or transcription factor TFAM; or by 3D immunocytochemistry. mtSSB (binding transcription or replication nucleoids) contoured "nucleoids" which were smaller by 25% (less diameters >150 nm) in GK beta-cells. Eos-TFAM-visualized nucleoids, composed of 72% localized TFAM, were smaller by 10% (immunochemically by 3%). A theoretical ~70% decrease in cell nucleoid number (spatial density) was not observed, rejecting model of single mtDNA per nucleoid. The beta-cell maintenance factor Nkx6.1 mRNA and protein were declining with age (>12-fold, 10 months) and decreasing with fasting hyperglycemia in GK rats, probably predetermining the impaired mtDNA replication (copy number decrease), while spatial expansion of mtDNA kept nucleoids with only smaller sizes than those containing much higher mtDNA in non-diabetic beta-cells. PMID- 29142324 TI - An algorithm for the beat-to-beat assessment of cardiac mechanics during sleep on Earth and in microgravity from the seismocardiogram. AB - Seismocardiogram, SCG, is the measure of precordial vibrations produced by the beating heart, from which cardiac mechanics may be explored on a beat-to-beat basis. We recently collected a large amount of SCG data (>69 recording hours) from an astronaut to investigate cardiac mechanics during sleep aboard the International Space Station and on Earth. SCG sleep recordings are characterized by a prolonged duration and wide heart rate swings, thus a specific algorithm was developed for their analysis. In this article we describe the new algorithm and its performance. The algorithm is composed of three parts: 1) artifacts removal, 2) identification in each SCG waveform of four fiducial points associated with the opening and closure of the aortic and mitral valves, 3) beat-to-beat computation of indexes of cardiac mechanics from the SCG fiducial points. The algorithm was tested on two sleep recordings and yielded the identification of the fiducial points in more than 36,000 beats with a precision, quantified by the Positive Predictive Value, >=99.2%. These positive findings provide the first evidence that cardiac mechanics may be explored by the automatic analysis of SCG long-lasting recordings, taken out of the laboratory setting, and in presence of significant heart rate modulations. PMID- 29142325 TI - Origin of methane-rich natural gas at the West Pacific convergent plate boundary. AB - Methane emission from the geosphere is generally characterized by a radiocarbon free signature and might preserve information on the deep carbon cycle on Earth. Here we report a clear relationship between the origin of methane-rich natural gases and the geodynamic setting of the West Pacific convergent plate boundary. Natural gases in the frontal arc basin (South Kanto gas fields, Northeast Japan) show a typical microbial signature with light carbon isotopes, high CH4/C2H6 and CH4/3He ratios. In the Akita-Niigata region - which corresponds to the slope stretching from the volcanic-arc to the back-arc -a thermogenic signature characterize the gases, with prevalence of heavy carbon isotopes, low CH4/C2H6 and CH4/3He ratios. Natural gases from mud volcanoes in South Taiwan at the collision zone show heavy carbon isotopes, middle CH4/C2H6 ratios and low CH4/3He ratios. On the other hand, those from the Tokara Islands situated on the volcanic front of Southwest Japan show the heaviest carbon isotopes, middle CH4/C2H6 ratios and the lowest CH4/3He ratios. The observed geochemical signatures of natural gases are clearly explained by a mixing of microbial, thermogenic and abiotic methane. An increasing contribution of abiotic methane towards more tectonically active regions of the plate boundary is suggested. PMID- 29142326 TI - Complex organic molecules in strongly UV-irradiated gas. AB - We investigate the presence of complex organic molecules (COMs) in strongly UV irradiated interstellar molecular gas. We have carried out a complete millimetre (mm) line survey using the IRAM 30 m telescope towards the edge of the Orion Bar photodissociation region (PDR), close to the H2 dissociation front, a position irradiated by a very intense far-UV (FUV) radiation field. These observations have been complemented with 8.5" resolution maps of the H2CO JKa,Kc = 51,5 -> 41,4 and C18O J = 3 -> 2 emission at 0.9 mm. Despite being a harsh environment, we detect more than 250 lines from COMs and related precursors: H2CO, CH3OH, HCO, H2CCO, CH3CHO, H2CS, HCOOH, CH3CN, CH2NH, HNCO, [Formula: see text] and HC3N (in decreasing order of abundance). For each species, the large number of detected lines allowed us to accurately constrain their rotational temperatures (Trot) and column densities (N). Owing to subthermal excitation and intricate spectroscopy of some COMs (symmetric- and asymmetric-top molecules such as CH3CN and H2CO, respectively), a correct determination of N and Trot requires building rotational population diagrams of their rotational ladders separately. The inferred column densities are in the 1011 - 1013cm-2 range. We also provide accurate upper limit abundances for chemically related molecules that might have been expected, but are not conclusively detected at the edge of the PDR (HDCO, CH3O, CH3NC, CH3CCH, CH3OCH3, HCOOCH3, CH3CH2OH, CH3CH2CN, and CH2CHCN). A non-thermodynamic equilibrium excitation analysis for molecules with known collisional rate coefficients suggests that some COMs arise from different PDR layers but we cannot resolve them spatially. In particular, H2CO and CH3CN survive in the extended gas directly exposed to the strong FUV flux (Tk = 150 - 250 K and Td ? 60 K), whereas CH3OH only arises from denser and cooler gas clumps in the more shielded PDR interior (Tk = 40 - 50 K). The non-detection of HDCO towards the PDR edge is consistent with the minor role of pure gas-phase deuteration at very high temperatures. We find a HCO/H2CO/CH3OH ? 1/5/3 abundance ratio. These ratios are different from those inferred in hot cores and shocks. Taking into account the elevated gas and dust temperatures at the edge of the Bar (mostly mantle-free grains), we suggest the following scenarios for the formation of COMs: (i) hot gas-phase reactions not included in current models; (ii) warm grain-surface chemistry; or (iii) the PDR dynamics is such that COMs or precursors formed in cold icy grains deeper inside the molecular cloud desorb and advect into the PDR. PMID- 29142327 TI - The circumstellar envelope around the S-type AGB star W Aql. Effects of an eccentric binary orbit. AB - Context: Recent observations at subarcsecond resolution, now possible also at submillimeter wavelengths, have shown intricate circumstellar structures around asymptotic giant branch (AGB) stars, mostly attributed to binary interaction. The results presented here are part of a larger project aimed at investigating the effects of a binary companion on the morphology of circumstellar envelopes (CSEs) of AGB stars. Aims: AGB stars are characterized by intense stellar winds that build CSEs around the stars. Here, the CO(J = 3->2) emission from the CSE of the binary S-type AGB star W Aql has been observed at subarcsecond resolution using ALMA. The aim of this paper is to investigate the wind properties of the AGB star and to analyse how the known companion has shaped the CSE. Methods: The average mass-loss rate during the creation of the detected CSE is estimated through modelling, using the ALMA brightness distribution and previously published single dish measurements as observational constraints. The ALMA observations are presented and compared to the results from a 3D smoothed particle hydrodynamics (SPH) binary interaction model with the same properties as the W Aql system and with two different orbital eccentricities. Three-dimensional radiative transfer modelling is performed and the response of the interferometer is modelled and discussed. Results: The estimated average mass-loss rate of W Aql is M = 3.0*10-6 M? yr-1 and agrees with previous results based on single-dish CO line emission observations. The size of the emitting region is consistent with photodissociation models. The inner 10" of the CSE is asymmetric with arc-like structures at separations of 2-3" scattered across the denser sections. Further out, weaker spiral structures at greater separations are found, but this is at the limit of the sensitivity and field of view of the ALMA observations. Conclusions: The CO(J = 3->2) emission is dominated by a smooth component overlayed with two weak arc patterns with different separations. The larger pattern is predicted by the binary interaction model with separations of ~10" and therefore likely due to the known companion. It is consistent with a binary orbit with low eccentricity. The smaller separation pattern is asymmetric and coincides with the dust distribution, but the separation timescale (200 yrs) is not consistent with any known process of the system. The separation of the known companions of the system is large enough to not have a very strong effect on the circumstellar morphology. The density contrast across the envelope of a binary with an even larger separation will not be easily detectable, even with ALMA, unless the orbit is strongly asymmetric or the AGB star has a much larger mass loss rate. PMID- 29142328 TI - Discovery of methyl silane and confirmation of silyl cyanide in IRC +10216. AB - We report the discovery in space of methyl silane, CH3SiH3, from observations of ten rotational transitions between 80 and 350 GHz (Ju from 4 to 16) with the IRAM 30 m radio telescope. The molecule was observed in the envelope of the C-star IRC +10216. The observed profiles and our models for the expected emission of methyl silane suggest that the it is formed in the inner zones of the circumstellar envelope, 1-40 R*, with an abundance of (0.5-1) * 10-8 relative to H2. We also observed several rotational transitions of silyl cyanide (SiH3CN), confirming its presence in IRC +10216 in particular, and in space in general. Our models indicate that silyl cyanide is also formed in the inner regions of the envelope, around 20 R*, with an abundance relative to H2 of 6*10-10. The possible formation mechanisms of both species are discussed. We also searched for related chemical species but only upper limits could be obtained. PMID- 29142329 TI - Evidence for disks at an early stage in class 0 protostars? AB - Aims: The formation epoch of protostellar disks is debated because of the competing roles of rotation, turbulence, and magnetic fields in the early stages of low-mass star formation. Magnetohydrodynamics simulations of collapsing cores predict that rotationally supported disks may form in strongly magnetized cores through ambipolar diffusion or misalignment between the rotation axis and the magnetic field orientation. Detailed studies of individual sources are needed to cross check the theoretical predictions. Methods: We present 0.06 - 0.1 " resolution images at 350 GHz toward B1b-N and B1b-S, which are young class 0 protostars, possibly first hydrostatic cores. The images have been obtained with ALMA, and we compare these data with magnetohydrodynamics simulations of a collapsing turbulent and magnetized core. Results: The submillimeter continuum emission is spatially resolved by ALMA. Compact structures with optically thick 350 GHz emission are detected toward both B1b-N and B1b-S, with 0.2 and 0.35" radii (46 and 80 au at the Perseus distance of 230 pc), within a more extended envelope. The flux ratio between the compact structure and the envelope is lower in B1b-N than in B1b-S, in agreement with its earlier evolutionary status. The size and orientation of the compact structure are consistent with 0.2" resolution 32 GHz observations obtained with the Very Large Array as a part of the VANDAM survey, suggesting that grains have grown through coagulation. The morphology, temperature, and densities of the compact structures are consistent with those of disks formed in numerical simulations of collapsing cores. Moreover, the properties of B1b-N are consistent with those of a very young protostar, possibly a first hydrostatic core. These observations provide support for the early formation of disks around low-mass protostars. PMID- 29142330 TI - Accurate Frequency Determination of Vibration-Rotation and Rotational Transitions of SiH. AB - The fundamental 28SiH+ ion has been characterized in a collaborative work, utilizing a hollow-cathode-discharge laser-spectrometer and a cryogenic ion trap spectrometer. Twenty-three vibration-rotation transitions around 4.75 MUm have been detected with high accuracy. This has facilitated the first direct measurement of the pure rotational transition J = 1 <- 0 at 453056.3632(4) MHz in the trap spectrometer. The measured and accurately predicted transitions enable the search for this ion in space with IR and sub-mm telescopes. PMID- 29142331 TI - Electrode Reactions Coupled with Chemical Reactions of Oxygen, Water and Acetaldehyde in an Ionic Liquid: New Approaches for Sensing Volatile Organic Compounds. AB - Water and oxygen are ubiquitous present in ambient conditions. This work studies the unique oxygen, trace water and a volatile organic compound (VOC) acetaldehyde redox chemistry in a hydrophobic and aprotic ionic liquid (IL), 1-butyl-1 methylpyrrolidinium bis(trifluoromethanesulfonyl)imide ([Bmpy] [NTf2]) by cyclic voltammetry and potential step methods. One electron oxygen reduction leads to superoxide radical formation in the IL. Trace water in the IL acts as a protic species that reacts with the superoxide radical. Acetaldehyde is a stronger protic species than water for reacting with the superoxide radical. The presence of trace water in the IL was also demonstrated to facilitate the electro oxidation of acetaldehyde, with similar mechanism to that in the aqueous solutions. A multiple-step coupling reaction mechanism between water, superoxide radical and acetaldehyde has been described. The unique characteristics of redox chemistry of acetaldehyde in [Bmpy][NTf2] in the presence of oxygen and trace water can be controlled by electrochemical potentials. By controlling the electrode potential windows, several methods including cyclic voltammetry, potential step methods (single-potential, double-potential and triple-potential step methods) were established for the quantification of acetaldehyde. Instead of treating water and oxygen as frustrating interferents to ILs, we found that oxygen and trace water chemistry in [Bmpy][NTf2] can be utilized to develop innovative electrochemical methods for electroanalysis of acetaldehyde. PMID- 29142332 TI - The interstellar chemistry of C3H and C3H2 isomers. AB - We report the detection of linear and cyclic isomers of C3H and C3H2 towards various starless cores and review the corresponding chemical pathways involving neutral (C3Hx with x=1,2) and ionic (C3Hx+ with x = 1,2,3) isomers. We highlight the role of the branching ratio of electronic Dissociative Recombination (DR) reactions of C3H2+ and C3H3+ isomers showing that the statistical treatment of the relaxation of C3H* and C3H2* produced in these DR reactions may explain the relative c,l-C3H and c,l-C3H2 abundances. We have also introduced in the model the third isomer of C3H2 (HCCCH). The observed cyclic-to-linear C3H2 ratio vary from 110 +/- 30 for molecular clouds with a total density around 1*104 molecules.cm-3 to 30 +/- 10 for molecular clouds with a total density around 4*105 molecules.cm-3, a trend well reproduced with our updated model. The higher ratio for low molecular cloud densities is mainly determined by the importance of the H + l-C3H2 -> H + c-C3H2 and H + t-C3H2 -> H + c-C3H2 isomerization reactions. PMID- 29142333 TI - Approaches to Macroevolution: 1. General Concepts and Origin of Variation. AB - Approaches to macroevolution require integration of its two fundamental components, i.e. the origin and the sorting of variation, in a hierarchical framework. Macroevolution occurs in multiple currencies that are only loosely correlated, notably taxonomic diversity, morphological disparity, and functional variety. The origin of variation within this conceptual framework is increasingly understood in developmental terms, with the semi-hierarchical structure of gene regulatory networks (GRNs, used here in a broad sense incorporating not just the genetic circuitry per se but the factors controlling the timing and location of gene expression and repression), the non-linear relation between magnitude of genetic change and the phenotypic results, the evolutionary potential of co opting existing GRNs, and developmental responsiveness to nongenetic signals (i.e. epigenetics and plasticity), all requiring modification of standard microevolutionary models, and rendering difficult any simple definition of evolutionary novelty. The developmental factors underlying macroevolution create anisotropic probabilities-i.e., an uneven density distribution-of evolutionary change around any given phenotypic starting point, and the potential for coordinated changes among traits that can accommodate change via epigenetic mechanisms. From this standpoint, "punctuated equilibrium" and "phyletic gradualism" simply represent two cells in a matrix of evolutionary models of phenotypic change, and the origin of trends and evolutionary novelty are not simply functions of ecological opportunity. Over long timescales, contingency becomes especially important, and can be viewed in terms of macroevolutionary lags (the temporal separation between the origin of a trait or clade and subsequent diversification); such lags can arise by several mechanisms: as geological or phylogenetic artifacts, or when diversifications require synergistic interactions among traits, or between traits and external events. The temporal and spatial patterns of the origins of evolutionary novelties are a challenge to macroevolutionary theory; individual events can be described retrospectively, but a general model relating development, genetics, and ecology is needed. An accompanying paper (Jablonski in Evol Biol 2017) reviews diversity dynamics and the sorting of variation, with some general conclusions. PMID- 29142335 TI - Network Influences on Behavior: A Summary of Tom Valente's Keynote Address at Sunbelt XXXV: The Annual Meeting of the International Network for Social Network Analysis. PMID- 29142337 TI - Consequences of grouped data for testing for departure from circular uniformity. AB - Limits to the precision of circular data often cause grouping of data points into discrete categories, but the effects of grouping on tests for circular uniformity have been little explored. The Rayleigh test is often applied to grouped circular data, despite it being designed for continuous data and the statistical literature recommending a suite of alternative tests specifically designed for grouped data. Here, we investigated the performance of the Rayleigh test relative to four alternatives for testing the null hypothesis of uniformity in grouped circular data. We employed simulation, grouping data into a discrete number of same-sized categories and with samples drawn from a range of different distributions. We found that grouping had little effect on the type I error rate or the power of the Rayleigh test, and that the power of the Rayleigh test was very similar to that of the previously recommended alternative tests designed specifically for grouped circular data. It may thus be appropriate to apply the Rayleigh test to grouped data, provided the situation is one in which the test has substantial statistical power. PMID- 29142336 TI - Multi-atlas-based CT synthesis from conventional MRI with patch-based refinement for MRI-based radiotherapy planning. AB - Accurate CT synthesis, sometimes called electron density estimation, from MRI is crucial for successful MRI-based radiotherapy planning and dose computation. Existing CT synthesis methods are able to synthesize normal tissues but are unable to accurately synthesize abnormal tissues (i.e., tumor), thus providing a suboptimal solution. We propose a multi-atlas-based hybrid synthesis approach that combines multi-atlas registration and patch-based synthesis to accurately synthesize both normal and abnormal tissues. Multi-parametric atlas MR images are registered to the target MR images by multi-channel deformable registration, from which the atlas CT images are deformed and fused by locally-weighted averaging using a structural similarity measure (SSIM). Synthetic MR images are also computed from the registered atlas MRIs by using the same weights used for the CT synthesis; these are compared to the target patient MRIs allowing for the assessment of the CT synthesis fidelity. Poor synthesis regions are automatically detected based on the fidelity measure and refined by a patch-based synthesis. The proposed approach was tested on brain cancer patient data, and showed a noticeable improvement for the tumor region. PMID- 29142338 TI - Aging Out in the Queer Community: Silence to Sanctuary to Activism in Faith Communities: A conversation with Barbara Satin. AB - In this article, Generations Guest Editor Karen Fredriksen-Goldsen interviews Barbara Satin, a transgender woman with a national leadership role in the United Church of Christ. Satin addresses the history, challenges, and hopes for LGBT older adults seeking sanctuary in modern faith communities as they age. PMID- 29142334 TI - Approaches to Macroevolution: 2. Sorting of Variation, Some Overarching Issues, and General Conclusions. AB - Approaches to macroevolution require integration of its two fundamental components, within a hierarchical framework. Following a companion paper on the origin of variation, I here discuss sorting within an evolutionary hierarchy. Species sorting-sometimes termed species selection in the broad sense, meaning differential origination and extinction owing to intrinsic biological properties can be split into strict-sense species selection, in which rate differentials are governed by emergent, species-level traits such as geographic range size, and effect macroevolution, in which rates are governed by organism-level traits such as body size; both processes can create hitchhiking effects, indirectly causing the proliferation or decline of other traits. Several methods can operationalize the concept of emergence, so that rigorous separation of these processes is increasingly feasible. A macroevolutionary tradeoff, underlain by the intrinsic traits that influence evolutionary dynamics, causes speciation and extinction rates to covary in many clades, resulting in evolutionary volatility of some clades and more subdued behavior of others; the few clades that break the tradeoff can achieve especially prolific diversification. In addition to intrinsic biological traits at multiple levels, extrinsic events can drive the waxing and waning of clades, and the interaction of traits and events are difficult but important to disentangle. Evolutionary trends can arise in many ways, and at any hierarchical level; descriptive models can be fitted to clade trajectories in phenotypic or functional spaces, but they may not be diagnostic regarding processes, and close attention must be paid to both leading and trailing edges of apparent trends. Biotic interactions can have negative or positive effects on taxonomic diversity within a clade, but cannot be readily extrapolated from the nature of such interactions at the organismic level. The relationships among macroevolutionary currencies through time (taxonomic richness, morphologic disparity, functional variety) are crucial for understanding the nature of evolutionary diversification. A novel approach to diversity-disparity analysis shows that taxonomic diversifications can lag behind, occur in concert with, or precede, increases in disparity. Some overarching issues relating to both the origin and sorting of clades and phenotypes include the macroevolutionary role of mass extinctions, the potential differences between plant and animal macroevolution, whether macroevolutionary processes have changed through geologic time, and the growing human impact on present-day macroevolution. Many challenges remain, but progress is being made on two of the key ones: (a) the integration of variation-generating mechanisms and the multilevel sorting processes that act on that variation, and (b) the integration of paleontological and neontological approaches to historical biology. PMID- 29142339 TI - Direct Air Capture of CO2 with an Amine Resin: A Molecular Modeling Study of the CO2 Capturing Process. AB - Several reactions, known from other amine systems for CO2 capture, have been proposed for Lewatit R VP OC 1065. The aim of this molecular modeling study is to elucidate the CO2 capture process: the physisorption process prior to the CO2 capture and the reactions. Molecular modeling yields that the resin has a structure with benzyl amine groups on alternating positions in close vicinity of each other. Based on this structure, the preferred adsorption mode of CO2 and H2O was established. Next, using standard Density Functional Theory two catalytic reactions responsible for the actual CO2 capture were identified: direct amine and amine-H2O catalyzed formation of carbamic acid. The latter is a new type of catalysis. Other reactions are unlikely. Quantitative verification of the molecular modeling results with known experimental CO2 adsorption isotherms, applying a dual site Langmuir adsorption isotherm model, further supports all results of this molecular modeling study. PMID- 29142340 TI - Clinical Pearls: Etiologies of Superscan Appearance on Fluorine-18 Fludeoxyglucose Positron Emission Tomography-Computed Tomography. AB - The term "superscan" usually refers to a characteristic pattern on skeletal scintigraphy consisting of symmetrically intense and diffuse radiotracer uptake in the skeleton with absent or diminished visualization of the genitourinary system and soft tissues. Superscans and superscan-like appearances have also been described on fluorine-18-fludeoxyglucose positron emission tomography-computed tomography (18-F-FDG PET/CT). We review reported cases of 18-F-FDG PET/CT superscans and propose criteria for differentiating pathologic superscans from physiologic causes. Knowledge of the 18-F-FDG PET/CT superscan, its reported pathologic causes, its benign imitators, and its clinical implications is important to the nuclear medicine physician or radiologist specializing in the interpretation of nuclear studies to avoid several diagnostic pitfalls. PMID- 29142341 TI - In-house Preparation and Quality Control of Tc99m TRODAT 1 for Diagnostic Single photon Emission Computed Tomography/Computed Tomography Imaging in Parkinson's Disease. AB - Purpose of Study: Loss of dopamine neurons in the brain is a characteristic feature of Parkinson's disease (PD). TRODAT-1 is a tropane derivative that binds to dopamine transporter (DAT) receptors. It can be used for noninvasive in vivo imaging of DAT receptors leading to the early detection of PD. The present study aims to optimize the in-house radiolabeling of TRODAT-1 with Tc-99 m in hospital radiopharmacy set up along with performing single-photon emission computed tomography/computed tomography imaging in patients with PD. Materials and Methods: Radiolabeling was performed through transchelation method. For optimization studies, varied amount of glucoheptonate (GHA) and stannous chloride was incubated with Tc-99 m for 10 min at room temperature. TRODAT-1 was added to the reaction mixture followed by incubation at 95 degrees C for various time intervals. Phosphate buffer saline was added to maintain the pH of the final product. After performing the quality checks, whole-body imaging was performed to check the biodistribution in 4 patients at 1 h postinjection of 20-25 mCi (740 925 MBq) of Tc-99 m-TRODAT-1. Regional brain imaging was performed at 3-4 h. Clinical evaluation was done in control (n = 5) and in patients with PD (n = 5). Results: Radiolabeling yield of 100% was achieved by incubating TRODAT-1 with Tc 99 m GHA. All the quality control indicated the suitability of radiopharmaceutical for the intravenous administration. Good uptake of Tc-99 m TRODAT-1 was observed in the striatum of normal patients. However, decreased uptake was seen in patients with PD. Conclusion: Tc-99 m TRODAT-1 is a potential radiopharmaceutical for the diagnosis and staging PD which can be radiolabeled in house with good yield leading to its easy availability. PMID- 29142342 TI - Prevalence of Subclinical Peripheral Vascular Disease in Obese Egyptian Patients. AB - Objective: To detect subclinical peripheral vascular disease in obese Egyptian patients and establish relations between obesity, metabolic risk factors, and PVD. Methods: This was a prospective case-control study including 100 obese patients (BMI >30) (G1). In addition, 100 age and sex matched non-obese healthy subjects as a control group (G2). Both groups were subjected to duplex ultrasound, Radionuclide muscle scan. Angiography was done for 17 patients. Results: The image pattern of 99mTc-MIBI muscles uptake was studied and perfusion reserve (PR%) was calculated in (G1) and (G2). Comparison between the two groups showed statistically significant difference (P < 0.001) as regarding laboratory findings. Patients were categorized according to PR% into +ve for ischemia (mean PR% was 28.4 +/- 20.3) and -ve for ischemia (mean PR% was 65.0 +/- 11.4). Among (G1) 64 patients positive for ischemia by both PR% and Doppler, 36 patients were negative by Doppler and 22 of them were positive for ischemia by PR%. Angiography was done for 17 of them and proved ischemia in all of them. Conclusion: The Tc 99m sestamibi muscle scan can be used as a screening and diagnostic tool of preclinical atherosclerosis in obese patients. PMID- 29142343 TI - Calculating Gamma Camera Uniformity Parameters: Beyond the Vendor-specific Protocol. AB - Objectives: The aim of this study was to develop and verify a personal computer based software tool for calculating uniformity indices of gamma camera. Materials and Methods: The program was developed in MATLAB R2013b under Microsoft Windows operating system. Noise-less digital phantoms with known uniformity parameters were used to verify the accuracy of the program. Two hundred and forty-four Co-57 flood source images were acquired on Symbia T6 and Discovery nuclear medicine/computed tomography 670. The uniformity indices of these images were determined with their respective vendor's software and also by the tool developed. Bland-Altman plots were used for measuring the agreements between the developed program and the vendor's program for the calculation of uniformity indices. Results: The tool for calculating uniformity indices was found to be accurate. Uniformity indices measured with the tool revealed a very good correlation with vendor's software based on Bland-Altman analysis, as almost all measurements were within the +/-2 standard deviation range. Conclusion: The software tool for calculation of uniformity indices is accurate, and the uniformity indices calculated by it are in agreement with uniformity indices calculated by the vendor's software. PMID- 29142344 TI - Investigating the Role of Global Histogram Equalization Technique for 99mTechnetium-Methylene diphosphonate Bone Scan Image Enhancement. AB - Purpose of the Study: 99mTechnetium-methylene diphosphonate (99mTc-MDP) bone scan images have limited number of counts per pixel, and hence, they have inferior image quality compared to X-rays. Theoretically, global histogram equalization (GHE) technique can improve the contrast of a given image though practical benefits of doing so have only limited acceptance. In this study, we have investigated the effect of GHE technique for 99mTc-MDP-bone scan images. Materials and Methods: A set of 89 low contrast 99mTc-MDP whole-body bone scan images were included in this study. These images were acquired with parallel hole collimation on Symbia E gamma camera. The images were then processed with histogram equalization technique. The image quality of input and processed images were reviewed by two nuclear medicine physicians on a 5-point scale where score of 1 is for very poor and 5 is for the best image quality. A statistical test was applied to find the significance of difference between the mean scores assigned to input and processed images. Results: This technique improves the contrast of the images; however, oversaturation was noticed in the processed images. Student's t-test was applied, and a statistically significant difference in the input and processed image quality was found at P < 0.001 (with alpha = 0.05). However, further improvement in image quality is needed as per requirements of nuclear medicine physicians. Conclusion: GHE techniques can be used on low contrast bone scan images. In some of the cases, a histogram equalization technique in combination with some other postprocessing technique is useful. PMID- 29142345 TI - In vitro Protective Effect of Rutin and Quercetin against Radiation-induced Genetic Damage in Human Lymphocytes. AB - Purpose of the Study: Rutin (RUT) and quercetin (QRT) which are dietary compounds were investigated for their ability to protect against ionizing radiation (IR) induced genotoxicity in human lymphocytes. Materials and Methods: The radiation antagonistic potential of RUT and QRT was assessed by alkaline comet and cytokinesis-block micronucleus (CBMN) assay. Results: Treatment of lymphocytes with RUT and QRT (25 MUg/ml) prior exposure to 2 Gy gamma radiation resulted in a significant reduction of frequency of micronuclei as compared to the control set of cells evaluated by CBMN assay. Similarly, treatment of lymphocytes with RUT and QRT before radiation exposure showed significant decrease in the DNA damage as assessed by comet parameters, such as percent tail DNA and olive tail moment. Conclusion: The study demonstrates the protective effect of RUT and QRT against IR-induced DNA damage in human lymphocytes, which may be partly attributed to scavenging of IR-induced free radicals and also by the inhibition of IR-induced oxidative stress. PMID- 29142346 TI - Conjugation of Antibodies with Radiogold Nanoparticles, as an Effector Targeting Agents in Radiobioconjugate Cancer Therapy: Optimized Labeling and Biodistribution Results. AB - Purpose of the Study: Drug accessibility to the tumor cells is an important area of concern with an anticipation of increasing the efficacy of the drug to be delivered to a specific site. The biogenesis of gold nanoparticles using plant mediated phytochemical extracts and their possible linkage to cancer antibodies with an aim at delivering the conjugate specifically to the tumor-associated antigen is the basic objective of the research. Materials and Methodology: Radiolabeling of antibodies with gold nanoparticles was carried out by a protocol, and the labeling extent of antibodies was compared with that of a radiogold solution to ordinary particulate size (AuNO-Ab). The amount of radiolabeling was estimated by subjecting the reaction mixtures to thin layer chromatography (ITLC-Silica-gel) in different solvent mediums, both by visual inspection of images of the Siemens Orbitor Gamma Camera ZLC-7500 and also by in vitro counting of the radioactive counts in different quarters of the chromatographic strips. Biodistribution relating to the deposition of injected dose in nontargeting sites (reticuloendothelial system [RES]-localization) was studied and efforts were made for reducing the same. Results: Much improved gold incorporation was confirmed at various molar ratios of gold to immunoglobulin (antibody) using nanogold solution (>85%). The RES uptake in the liver, spleen etc., was observed as a problem and the prior administration of unlabeled nonspecific gammaglobulin (before the actual radiolabeled product) was identified as the suitable blocking agent for this purpose. Conclusion: The study signifies the potential for PEGylated gold nanoparticles of a precise size range, suitable to use as a delivery vehicle for targeting small biomolecules (antibody etc.) to the tumor site. The stability of this labeled immunoconjugate and other toxicity effects under physiological conditions needs further evaluation. If successful, this could be a role model for attaining high tumor/nontumor ratio. PMID- 29142348 TI - 18F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography in Tuberculosis: Spectrum of Manifestations. AB - The objective of this article is to provide an illustrative tutorial highlighting the utility of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging to detect spectrum of manifestations in patients with tuberculosis (TB). FDG-PET/CT is a powerful tool for early diagnosis, measuring the extent of disease (staging), and consequently for evaluation of response to therapy in patients with TB. PMID- 29142347 TI - Disease- and Treatment-related Complication on F-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Oncology Practice: A Pictorial Review. AB - F-18-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is routinely performed in oncology patients for various indications including staging, restaging, recurrence detection, and treatment response evaluation. Many disease- and treatment-related complications can be incidentally detected on PET/CT, which may be due to the complication of radiotherapy, chemotherapy, intervention, or primary tumor itself. Some of these complications could be life threatening and need urgent intervention. Therefore, these incidental findings should be recognized on PET/CT and immediately informed to the treating physicians if required urgent intervention. PMID- 29142349 TI - Interesting Skeletal Radiologic and Scintigraphic Outcomes and Their Logical Clinical Conclusions. AB - Skeletal scintigraphy with 99mTc-methylene diphosphonate and 18-fluorine-fluoride the main stay in cancer follow-up for early detection of skeletal metastasis often reveal confusing and conflicting findings requiring proper interpretation in conjunction with clinical-radiological correlation. A series of commonly encountered findings are presented for elucidation. PMID- 29142350 TI - Bone Scan in Detection of Biological Activity in Nonhypertrophic Fracture Nonunion. AB - Biological activity of the fracture site is very important factor in treatment planning of fracture nonunion. If no biological activity is detected, then an autologous bone graft can be supplemented or osteogenic supplementations, such as bone morphogenetic protein is given. If biological activity is present, then secure fixation is sufficient to achieve bony union. Biological activity of nonunions is usually assessed by conventional radiographs. The presence of callus formation is usually assessed as the presence of biological activity. However, high number of radiologically nonhypertrophic nonunion demonstrates intense, uniform tracer uptake on bone scan, a sign of biological activity. Poor or absent callus visualization on radiographs does not always mean a lack of biological activity and it underestimates it. Uptake in bone scintigraphy reflects blood flow and new bone formation and being functional imaging technique, it is more suitable for assessing biological activity. PMID- 29142351 TI - Development of a Simple Image Processing Application that Makes Abdominopelvic Tumor Visible on Positron Emission Tomography/Computed Tomography Image. AB - Introduction: In this study, we have developed a simple image processing application in MATLAB that uses suprathreshold stochastic resonance (SSR) and helps the user to visualize abdominopelvic tumor on the exported prediuretic positron emission tomography/computed tomography (PET/CT) images. Methods: A brainstorming session was conducted for requirement analysis for the program. It was decided that program should load the screen captured PET/CT images and then produces output images in a window with a slider control that should enable the user to view the best image that visualizes the tumor, if present. The program was implemented on personal computer using Microsoft Windows and MATLAB R2013b. Results: The program has option for the user to select the input image. For the selected image, it displays output images generated using SSR in a separate window having a slider control. The slider control enables the user to view images and select one which seems to provide the best visualization of the area(s) of interest. Conclusion: The developed application enables the user to select, process, and view output images in the process of utilizing SSR to detect the presence of abdominopelvic tumor on prediuretic PET/CT image. PMID- 29142352 TI - Localized Pontine Uptake in Fluorine-18-Fuorodeoxyglucose Positron Emission Tomography/Computed Tomography in a Case of Hyponatremia: A Case Report and Review of Literature. AB - A rare acquired demyelinating lesion of the pons central pontine myelinolysis (CPM) typically occurs after rapid correction of hyponatremia. There is disruption of blood-brain barrier due to osmotic stress allowing access for inflammatory mediators in extravascular brain tissue, which most likely attracts glial cells of the brain, attracts macrophages, and activates astrocytes. We present a case of female with a known history of inflammatory bowel disease who presented with altered sensorium and hyponatremia. Fluorine-18-fuorodeoxyglucose (F-18-FDG) positron emission tomography/computed tomography (PET/CT) was performed which showed localized FDG uptake in the pons, consistent with the CPM findings observed on magnetic resonance imaging. Pontine uptake in F-18-FDG PET CT in hyponatremic patients who were clinically deteriotating even after correction of hyponatremic status aids for the diagnosis of CPM. PMID- 29142353 TI - Metabolic Imaging as a Novel Strategy in Evaluation of Mycotic Abdominal Aortic Aneurysm: A Case Report and Brief Clinical Review. AB - Abdominal aortic aneurysm (AAA) is an uncommon entity with high mortality. Etiologically, they are classified as inflammatory and infective (mycotic), the latter being less common. Clinical presentation, laboratory investigations, and treatment for these may considerably overlap. However, choice of management and the need for surgical intervention depends on factors such as size and progression of aneurysm, persistent symptoms, and presence or absence of distant pathology. Although computed tomography (CT) is the gold standard for AAA, in selected cases, especially in infected AAA, fluorodeoxyglucose positron emission tomography-CT can provide valuable information. PMID- 29142354 TI - Primary Pleuropulmonary Synovial Sarcoma on Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography Scan. AB - Primary pleuropulmonary synovial sarcoma, a mesenchymal tumor of lung and pleura, is very rare and highly aggressive condition among the primary lung malignancies. As role of fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) has been established in lung malignancies in terms of staging, restaging, biopsy guidance, and treatment response evaluation, there is also role of FDG PET-contrast-enhanced CT (CECT) to raise suspicion or increase confidence in reporting of sarcomatous lung malignancy by studying characteristics of CECT scan features. We present a case of a 57-year-old female patient having large lung mass, who underwent FDG PET-CT scan and findings raised strong suspicious of noncarcinomatous pattern of lung mass and may have sarcomatous primary lung malignancy which was later proven on histopathological and immunohistochemistry report. PMID- 29142355 TI - Severe Hypercalcemia Related to Silicone Granulomas, as Discovered by FDG-PET. AB - Silicone injected for cosmetic purposes can provoke an inflammatory granulomatous response. In turn, silicone granulomas can lead to hypercalcemia, which is a rare, though potentially life-threatening condition. Hypercalcemia is a nonspecific laboratory finding with many potential etiologies. It may be difficult for clinicians to diagnose silicone-induced hypercalcemia, since the history of cosmetic silicone injections may not be elicited from the patient. Positron emission tomography using F-18-fluorodeoxyglucose (FDG-PET) can be used to evaluate patients with unexplained hypercalcemia as a means of searching for an occult malignancy or granulomatous process. FDG-PET findings may be the initial and perhaps only indication of silicone granulomas as the cause of hypercalcemia. Nuclear medicine physicians should have a low threshold for suggesting this diagnosis, particularly in the setting of unexplained hypercalcemia. This case report highlights the value of FDG-PET in diagnosing silicone granuloma-induced hypercalcemia. PMID- 29142356 TI - Clinically Occult Rectal Carcinoma Identified in a Case of Streptococcus bovis Endocarditis on Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography: A Case Report and Review of Literature. AB - Numerous studies over past four decades have implicated a strong association of Streptoccus bovis infection with colorectal carcinomas. Strong is this association that a screening colonoscopy for identifying malignancy is considered mandatory in patients whose blood/fecal cultures show growth of this particular pathogen. Here, we report an interesting case of a 61-year-old female patient who presented with pyrexia of unknown origin for 3 weeks. Positron emission tomography/computed tomography, in addition to helping diagnose mitral valve endocarditis, also identified a clinically occult T2N0 rectal carcinoma. PMID- 29142357 TI - Single Coronary Artery Demonstrating Slightly Decreased 13NH3 Stress Flows in its Distal Flow Territories. AB - A 54-year-old male patient was referred for computed tomography angiography to rule out cardiovascular disease. The examination revealed a single coronary artery originating from the right sinus of Valsalva, extending to the normal left circumflex artery and left anterior descending artery domains. The computed tomography showed only mild coronary sclerosis. The myocardial stress flow on the subsequently performed 13NH3 myocardial perfusion positron emission tomography demonstrated a relative stress flow reduction in the distal segments along the monocoronary. In the presented patient without significant coronary disease and a benign course of the monocoronary, the relative inability to increase blood flow during stress in the distal segments of the artery is a remarkable finding. PMID- 29142358 TI - Transitional Cell Carcinoma of Urinary Bladder Manifesting as Extensive Retroperitoneal and Axillary Lymph Node Metastasis: An Extremely Rare Case Scenario Detected by 18F-Fluorodeoxyglucose Positron Emission Tomography Scan. AB - Transitional cell carcinoma (TCC) urinary bladder is known to metastasize to regional lymph nodes (LNs), liver, lung, bone, adrenal glands, and intestine. However, an asymptomatic TCC bladder manifesting as metastatic axillary LN mass and extensive retroperitoneal lymphadenopathy is rarely heard of. A 46-year-old male, smoker, presented with 8 cm * 6 cm right axillary swelling of 1-month duration. Aspiration cytology revealed metastatic deposits of poorly differentiated carcinoma favoring TCC. Metastatic evaluation with 18F fluorodeoxyglucose positron emission tomography (18FDG-PET) scan showed mass lesion urinary bladder, conglomerate right axillary mass and extensive retroperitoneal LNs with significant metabolic activity, biopsy from which revealed deposits of TCC. Transurethral-resection of bladder confirmed TCC and was exhibited palliative chemotherapy on which he progressed. Received palliative radiotherapy to axilla to which he showed significant symptomatic clinical response. He developed obstructive uropathy and was kept on supportive care. Review of literature reveals that our case may be the second case of TCC bladder with generalized lymphadenopathy and the first case of asymptomatic bladder carcinoma manifesting with upfront disseminated abdominopelvic lymphadenopathy detected by 18FDG-PET scan ever reported in world literature. PMID- 29142359 TI - Non-Hodgkin's Lymphoma with Pelvic Skeletal Muscle Involvement Presenting as Low Back Ache: An Uncommon Presentation of a Rather Common Malignancy. AB - Lymphoma with skeletal muscle involvement is a rare clinical presentation. They may occur as primary skeletal muscle lymphoma, contiguous spread from bones or by metastatic spread. We present a rare case of non-Hodgkin's lymphoma with pelvic skeletal muscle involvement presenting as low back ache. Lymphoma as the first differential diagnosis in this case was clinched after an 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and confirmed as diffuse large B-cell lymphoma on histopathology. We seek to present an uncommon manifestation of lymphoma and highlight the role of 18F-FDG PET CT in the diagnosis, staging, and management of lymphoma. PMID- 29142360 TI - Abnormal Fluorodeoxyglucose Uptake in Lung without Structural Abnormality on Computed Tomography. AB - Fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET CT) is a useful proven imaging modality in the management of many types of cancers. It is being used at various stages of treatment of cancer. Knowledge regarding the physiological biodistribution and false-positive findings should be kept in mind for correct interpretation. Pulmonary FDG uptake can be due to different causes such as infection, inflammation, and metastases which are invariably associated with structural abnormality on CT. In rare circumstances, there can be a focus of FDG uptake in the lung with no corresponding structural abnormality which might be due to an inflammatory vascular microthrombus or due to iatrogenic microembolism caused during the injection of radiotracer. It is important to be aware of this as it can cause difficulty in interpreting the scan and can lead to false-positive findings. It also highlights the importance of hybrid imaging in the form of PET-CT as there is a definite possibility of misinterpreting this as a site of metastasis in a known carcinoma patient if there was no corresponding CT image. PMID- 29142361 TI - Tubular Intestinal Duplication Harboring Gastric Ectopia Accurately Diagnosed by Tc-99m Pertechnetate Single-photon Emission Computed Tomography/Computed Tomography Meckel's Scan. AB - A 7-year-old girl with an episode of hematochezia and melena, suspicious for bleeding Meckel's diverticulum, was referred for a Tc-99m pertechnetate Meckel's scan. On dynamic planar scan, apart from prompt gastric visualization an oval shaped, area of inhomogeneous tracer uptake was observed in the left lower quadrant of the abdomen. Subsequent single-photon emission computed tomography/computed tomography localized this to intestinal lumen, thus establishing the diagnosis of intestinal duplication (ID) with functional gastric mucosa. Surgical exploration confirmed the presence of a tubular ID in a distance of 1.5 m from the ileocecal valve and pathologic examination showed gastric mucosa lining the lumen of the duplication. PMID- 29142362 TI - Primitive Neuroectodermal Tumor of Nasal Cavity on 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography. AB - Primitive neuroectodermal tumor is a malignant small round cell tumor of presumed neural crest origin, usually affecting the bony structures of the nasal cavity and its clinical and radiological features may be confused with those of infection and malignancy. I report a case with primitive neuroectodermal tumor of the nasal cavity showing increased tracer uptake on 18F-fluorodeoxyglucose positron emission tomography-computed tomography mimicking an another primary malignancy in a 17-year-old boy. PMID- 29142363 TI - Multiple Colorectal Adenomas Syndrome with Malignant Degeneration in Multiple Colorectal Polyps: 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography Findings. AB - Multiple colorectal adenomas (MCRAs) syndrome is a genetic syndrome characterized by multiple colorectal polyps. Patients usually present late in late fourth or fifth decade of life. They have a high risk for developing malignancy. We here present such case of a 61-year-old man with MCRAs who developed malignant degeneration of multiple colorectal polyps, which was demonstrated on 18F fluorodeoxyglucose positron emission tomography-computed tomography. PMID- 29142364 TI - Bone Scan in Evaluation of Bone Viability in Severe Frostbite of the Hand. AB - A 39-year-old male presented to the emergency department (ED) with frostbite to the fingers of both hands. In the ED, he received warm baths, acetylsalicylic acid, clopidogrel, and heparin. A three-phase bone scintigraphy with technetium 99m-methylene diphosphonate revealed absent radiotracer uptake in distal phalanges of both hands. The patient received acetylsalicylic acid, clopidogrel and wound care for the next 5 days and made an excellent recovery with satisfactory wound healing in both hands. Early rapid rewarming and reperfusion can improve the prognosis significantly and therefore bone scan done within first 1-2 days may give spurious results. PMID- 29142365 TI - Superscan on Methylene Diphosphonate Skeletal Scintigraphy in Prostatic Adenocarcinoma: A Common Finding but Rare Etiology. AB - Excessive skeletal radioisotope uptake in relation to soft tissues along with absent or faint activity in the genitourinary tract on skeletal scintigraphy is known as a "superscan." Prostate cancer is the most common cause of superscan in skeletal scintigraphy due to diffuse skeletal metastases. However, prostate cancer may cause secondary renal osteodystrophy leading to metabolic superscan also. Differentiating between these two entities are important as treatment options are different. We, hereby, describe a case of prostatic adenocarcinoma presented with metabolic superscan on methylene diphosphonate skeletal scintigraphy and demonstrate the utility of single emission computed tomography computed tomography in differentiating between two entities. PMID- 29142366 TI - Nested Stromal-epithelial Tumor of Liver with Recurrent Extrahepatic Metastasis: Role of Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. AB - Nested stromal-epithelial tumor (NSET) is a very rare nonhepatocytic and nonbiliary primary tumor of the liver. An 8-year-old boy was incidentally detected with hepatic lesions, involving both lobes of the liver for which he later underwent orthotopic liver transplant. The hepatic lesions were confirmed to be NSET following histopathological examination of explant liver specimen. He later developed recurrence with multiple metastatic lesions, including multi station nodal and right talar bone involvement. We here present the case highlighting the importance of 18F-fludeoxyglucose positron emission tomography/computed tomography in the management of this rare tumor, in particular for monitoring disease progression and/or recurrence. PMID- 29142367 TI - Case of Carcinoma Breast with Unusually Large Tumor Thrombus in Superior Vena Cava Detected on 18F-Fluorodeoxyglucose Positron Emission Tomography Computed Tomography Scan. AB - A 60-year-old female with triple negative breast cancer, postsurgery, neoadjuvant chemotherapy and radiotherapy, on follow-up had facial puffiness and giddiness. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) done for suspected recurrence evaluation revealed a large tumor thrombus (TT) in superior vena cava (SVC) with radiological evidence of SVC obstruction. 18F-FDG PET/CT also showed evidence of FDG avid brain metastases, lymph nodal metastases, and metastatic soft tissue deposits. This case of unusually large TT in SVC detected on 18F-FDG PET/CT highlights the ability of 18F-FDG PET/CT to identify TT and clearly demonstrate the pattern of disease in suspected recurrence in triple negative breast cancer patients. PMID- 29142368 TI - Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in Disseminated Cryptococcosis. AB - Disseminated cryptococcosis without pulmonary involvement is a very rare phenomenon. Patterns of organ involvement in cryptococcosis resemble various other infective conditions as well as malignant conditions on fluorodeoxyglucose positron emission tomography-computed tomography. We present a case of a 43-year old male patient who had disseminated cryptococcosis. The rarity of the case being noninvolvement of lungs and meninges and resembling more like lymphoma due to the diffuse involvement of the lymph nodes on both sides of the diaphragm. PMID- 29142369 TI - Utility of 18F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Imaging in the Diagnosis of Cardiac Paraganglioma. AB - Cardiac paragangliomas are rare tumors of neural crest origin, most frequently seen in the left atrium. There are mixed opinions regarding the most appropriate imaging study for diagnosis and evaluation. We describe the novel utility of 18-F Fluorodeoxyglucose positron emission tomography/magnetic resonance imaging in the case of a 42-year-old male with cardiac paraganglioma. PMID- 29142370 TI - Radio-guided Minimally Invasive Parathyroidectomy: A Descriptive Report of the Experience from Tertiary Center. PMID- 29142371 TI - Reply by the Author. PMID- 29142372 TI - Mapping the Characteristics of Critical Care Facilities: Assessment, Distribution, and Level of Critical Care Facilities from Central India. AB - Background: In low- and middle-income countries such as India, where health systems are weak, the number of available Critical Care Unit (Intensive Care Unit [ICU]) beds is expected to be low. There is no study from the Indian subcontinent that has reported the characteristics and distribution of existing ICUs. We performed this study to understand the characteristics and distribution of ICUs in Madhya Pradesh (MP) state of Central India. We also aimed to develop a consensus scoring system and internally validate it to define levels of care and to improve health system planning and to strengthen referral networks in the state. Methods: We obtained a list of potential ICU facilities from various sources and then performed a cross-sectional survey by visiting each facility and determining characteristics for each facility. We collected variables with respect to infrastructure, human resources, equipment, support services, procedures performed, training courses conducted, and in-place policies or standard operating procedure documents. Results: We identified a total of 123 ICUs in MP. Of 123 ICUs, 35 were level 1 facilities, 74 were level 2 facilities, and only 14 were level 3 facilities. Overall, there were 0.17 facilities per 100,000 population (95* confidence interval [CI] 0.14-0.20 per 100,000 populations). There were a total of 1816 ICU beds in the state, with an average of 2.5 beds per 100,000 population (95* CI 2.4-2.6 per 100,000 population). Of the total number of ICU beds, 250 are in level 1, 1141 are in level 2, and 425 are in level 3 facilities. This amounts to 0.34, 1.57, and 0.59 ICU beds per 100,000 population for levels 1, 2, and 3, respectively. Conclusion: This study could just be an eye opener for our healthcare authorities at both state and national levels to estimate the proportion of ICU beds per lac population. Similar mapping of intensive care services from other States will generate national data that is hitherto unknown. PMID- 29142373 TI - A Pilot Study of Nebulized Heparin for Prevention of Ventilator Induced Lung Injury: Comparative Effects with an Inhaled Corticosteroid. AB - Background: Ventilator-induced lung injury (VILI) is a side effect of mechanical ventilation. Lung inflammation and pulmonary activation of coagulation are induced by mechanical stress. Clinical and preclinical studies show that heparin possesses anti-inflammatory properties. Therefore, we assessed the effects of nebulized heparin in VILI. Methods: Sixty critically ill adult patients who require mechanical ventilation for more than 48 h were included in this prospective, nonrandomized controlled study. Patients received nebulized heparin (10,000 U every 6 h) for 5 days. The matched control group received nebulized budesonide as routine practice in our center. This study assessed changes in partial pressure of oxygen to inspired fraction of oxygen ratio (PaO2/FiO2) and rapid shallow breathing index (RSBI) during the study as primary endpoints. Results: The average daily PaO2/FiO2 ratio was not statistically significant between both groups (187 +/- 11.6 vs. 171 +/- 11.6, P = 0.35). The RSBI also did not differ between groups (P = 0.58). Heparin administration was associated with a higher number of ventilator-free days among survivors but not significantly (7.7 +/- 10.6 vs. 5.1 +/- 8, 95% confidence interval - 2.2-7.5, P = 0.28). Successful weaning from mechanical ventilation was higher in the heparin group (P = 0.42). We did not observe any serious or increased adverse effects from nebulized heparin. Conclusion: The results of this study show that the overall effectiveness of nebulized heparin is at least as comparable with a potent corticosteroid (budesonide). Heparin could be a safe and effective modality for patients who at risk of VILI. PMID- 29142374 TI - Enhancing Hospital Well-being and Minimizing Intensive Care Unit Trauma: Cushioning Effects of Psychosocial Care. AB - Context: Hospitalization has the potential to induce hospital anxiety, while admission in the Intensive Care Unit (ICU) is found to surpass the anxiety and result in what is termed as "ICU Trauma." Aims: This study aimed to determine the impact of psychosocial care and quality of ICU on ICU trauma and hospital well being in patients who underwent coronary artery bypass grafting (CABG). Settings and Design: This correlational study involved 250 CABG patients, who were recruited from five major corporate hospitals. Participants and Methods: The ICU Psychosocial Care Scale, Hospital Wellbeing Scale, and ICU Trauma Scale were used. Each of the participants was assessed individually. The ICU Practices Checklist was used to assess the environment of the ICU in the hospital. Statistical Analysis Used: Descriptive statistics, correlation, and simple and multiple linear regression analyses were done. Results: The results revealed the significant contribution of psychosocial care in ICU in enhancing hospital well being as well as minimizing ICU trauma of patients who underwent CABG. The results of multiple regressions clearly indicated that psychosocial care was a powerful predictor of hospital well-being and ICU trauma. Conclusions: Although psychosocial care was not a component of hospital well-being and had a negative correlation with ICU trauma, it contributed significantly with a cushioning effect to minimize trauma and helped enhance the feelings and experiences of well being among patients in ICU. PMID- 29142375 TI - The Effects of Atorvastatin on Inflammatory Responses and Mortality in Septic Shock: A Single-center, Randomized Controlled Trial. AB - Aim of the Study: Pleiotropic effect of statins can modulate inflammation in septic shock. We tested the hypothesis whether statins can reduce mortality in septic shock. Patients and Methods: We conducted a randomized double-blinded trial with treatment (40 mg dose of atorvastatin for 7 days) and control (placebo) arm in adult septic shock patients admitted to the Intensive Care Unit. Primary (28-day mortality) and secondary (vasopressor-, ventilation-, and renal replacement therapy-free days) outcomes, with lipid profile and adverse effects, were documented. Inflammatory biomarkers (interleukin [IL]-1, IL-6, tumor necrosis-factor [TNF]-alpha, interferon [IFN], and C-reactive protein [CRP]), were also measured before (day 1 [D1]) and after start of trial drug (D4 and D7). Results: Seventy-three septic shock patients with 36 and 37 included in the atorvastatin and placebo group, respectively. Both groups were equally matched. Twenty-eight-day mortality, event-free days, lipid profile, and adverse effects were also not significantly different between groups. Reduced levels of IL-1, IL 6, TNF-alpha, IFN, and CRP were observed in the atorvastatin group. Also observed were significant day-wise changes in inflammatory biomarkers. Conclusions: Atorvastatin-induced changes in inflammatory biomarkers did not confer mortality benefit in septic shock (ClinicalTrials.govNCT02681653). PMID- 29142376 TI - Intensive Care Nurses' Attitude on Palliative and End of Life Care. AB - Background: Intensive Care Unit (ICU) nurses have a vital role in the implementation of end of life (EOL) care. There is limited data on the attitude of ICU nurses toward EOL and palliation. Aim: This study aimed to investigate knowledge, attitude, and beliefs of intensive care nurses in eastern India toward EOL. Materials and Methods: A self-administered questionnaire was distributed to delegates in two regional critical care nurses' training programs. Results: Of 178 questionnaires distributed, 138 completed, with a response rate of 75.5*. About half (48.5*) had more than 1 year ICU experience. A majority (81.9*) agreed that nurses should be involved in and initiate (62.3*) EOL discussions. Terms "EOL care or palliative care in ICU" were new for 19.6*; 21* and 55.8* disagreed with allowing peaceful death in terminal patients and unrestricted family visits, respectively. Work experience was associated with wanting unrestricted family visitation, discontinuing monitoring and investigations at EOL, equating withholding and withdrawal of treatment, and being a part of EOL team discussions (P = 0.005, 0.01, 0.01, and 0.001), respectively. Religiousness was associated with a greater desire to initiate EOL discussions (P = 0.001). Conclusion: Greater emphasis on palliative care in critical care curriculum may improve awareness among critical care nurses. PMID- 29142377 TI - Serum Vitamin D Status and Outcome in Critically Ill Children. AB - Background: Vitamin D is a pleiotropic hormone essential for optimal health. Critical illness in children is a major cause of significant health-care utilization and mortality around the world. The association of Vitamin D deficiency (VDD) in critically ill adults has been well-studied, in comparison, the importance of Vitamin D in pediatric critical illness has been much less studied. Aim and Objectives: This study aimed to assess Vitamin D status and its determinants in patients admitted to a pediatric intensive care unit (PICU) in North of Turkey. We also investigated the association between Vitamin D status and clinical outcomes. Materials and Methods: All patients aged 1 month to 18 years admitted to the PICU of a tertiary care hospital who had levels of 25 hydroxy Vitamin D available within 24 h of admission were included in this retrospective study. VDD was defined as <20 ng/mL levels. Results: VDD was observed in 120 (58.5*) children. In multivariable linear regression model, only identified patient age and winter season as statistically associated with VDD. Vitamin D deficient patients were older and heavier and were more likely to receive catecholamine. There was no association between Vitamin D deficiency and other illness severity factors including mortality. Conclusions: Hypovitaminosis D occurrence was high in critically ill children and was associated with higher vasopressor requirement but not with other markers of illness severity including mortality. PMID- 29142378 TI - Comparison of Awareness of Patient Parameters between Two Groups of Caregivers in Intensive Care Unit. AB - Aim of the Study: The overlap in the scope of duties performed by two core groups of Intensive Care Unit caregivers, the doctors and nurses may lead to gaps in awareness of patient-related parameters among them. Our study tested the hypothesis that there is no difference in the awareness of patient-related parameters between the two study groups (doctors and nurses). Materials and Methods: A questionnaire-based study, incorporating various aspects of a patient's medical care was designed. Pro forma for 100 patients was filled by doctors and nurses divided into two groups of 100 each (50 junior residents [JRs] and 50 senior residents [SRs] in the doctors' group). Statistical analysis of categorical data was done by Chi-squared test and interval data by t-test. A subgroup analysis was done for comparison between nurses SRs and JRs as independent groups. P < 0.05 was considered statistically significant. Results: There was no statistically significant difference between the two groups (doctors and nurses) in terms of percentage of correct responses in the questionnaire (P = 0.655). A highly significant difference between the knowledge of SRs and nurses was found with a P = 0.0001. P < 0.0001 was calculated for the SRs versus JRs which was highly significant. Conclusions: As a group, doctors (SRs and JRs) did not reflect any difference in awareness of patient-related parameters when compared to nurses. However, SRs were more knowledgeable about the patient related parameters when compared independently with the JRs and the nurses. PMID- 29142379 TI - Dyspnea, Eosinopenia, Consolidation, Acidemia and Atrial Fibrillation Score and BAP-65 Score, Tools for Prediction of Mortality in Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Comparative Pilot Study. AB - Introduction: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) being common and often fatal, prognostic tools in AECOPD are lacking. Materials and Methods: A prospective, observational study was carried out in fifty patients of AECOPD admitted in A and E department. Dyspnea, Eosinopenia, Consolidation, Acidemia and atrial Fibrillation (DECAF) score and elevated blood urea nitrogen, altered mental status, pulse >109, age >65 (BAP-65) score were calculated. Dyspnea was scored using extended Medical Research Council Dyspnoea score. Data were collected and analyzed using SPSS 17.0 software. Results: Forty one patients were discharged and 9 (18%) died during treatment. Patients who were discharged and patients who died during hospital stay were compared. There was no significant difference in terms of sociodemographic variables, presence of comorbidities, and other markers of disease severity. A significant difference was found in blood counts, blood urea, serum creatinine, acidotic respiratory failure, and atrial fibrillation. A higher value of DECAF score and BAP-65 score was found more commonly in patients who died. Sensitivity for prediction of mortality for DECAF score and BAP-65 score was 100% and specificity was 34.1% and 63.4%, respectively. Sensitivity for prediction of need for invasive ventilation for DECAF score and BAP-65 score was 80% and 100%, respectively, and specificity was 80% and 60%, respectively. Conclusion: Both DECAF and BAP-65 scores were found to be good predictors of mortality and need for ventilation in this pilot study. PMID- 29142380 TI - Epidemiological Study of Patients of Road Traffic Injuries Attending Emergency Department of a Trauma Center in New Delhi. AB - Background and Aims: There is paucity of data regarding some of the lesser known contextual and epidemiological factors with respect to road traffic injuries (RTIs). The objective was to study the epidemiological profile of RTI victims attending an emergency department of a tertiary care trauma center. Methods: The present study was a hospital-based cross-sectional study conducted in the emergency department of a tertiary care trauma center in New Delhi. All patients of RTI attending the emergency department during the designated data collection days were included in the study. Patients brought dead were excluded from the study. A semi-structured interview schedule was developed for collecting data on various domains such as sociodemographic characteristics, vehicle-related factors, accident site-related factors, personal protection measures, contextual factors, and prehospital care-related factors. Results: A total of 984 patients and informants were approached and finally data of 900 participants were analyzed after excluding those who refused participation and those for whom incomplete data were available. Out of 900 RTI victims, 756 were male (84.0%) and 144 (16.0%) were female. Mean age of the victims was 32.7 years. Most of the victims, i.e., 377 out of 900 (41.9%) were occupants rather than drivers. Majority of victim's vehicle meeting accidents were motorized two-wheelers (53.4%), and majority of the colliding vehicle was a four-wheeler (39.3*). Helmet use was found to be low (63.3%), but seat belt use was particularly low (32.4%). Most accidents (28%) happened between midnight and 6 A.M. More than half of the victims were in a hurry on the day of the accident. An ambulance was used to transport the victims in only 14.6% cases. Conclusion: In road traffic accidents some lesser known epidemiological data were generated that may be useful in defining preventive measures. PMID- 29142381 TI - Nursing Management of Adults with Severe Traumatic Brain Injury: A Narrative Review. AB - Effective nursing management strategies for adults with severe traumatic brain injury (STBI) are still a remarkable issue and a difficult task for neurologists, neurosurgeons, and neuronurses. A list of justified indications and scientific rationale for nursing management of these patients are continuously evolving. The objectives of the study are to analyze the pertinently available research and clinical studies that demonstrate the nursing management strategies for adults with STBI and to synthesize the available evidence based on the review. A comprehensive literature search was made in following databases such as Google Scholar, Cochrane, J-Gate, ProQuest, and ScienceDirect for retrieving the related studies. In the included studies, data were extracted and evaluated according to the objective. Narrative analysis was adopted to write this review. Patients with STBI have poor prognosis and require quality care for maximizing patients' survival. With a thorough knowledge and discernment of care of such patients, nurses can improve these patients' neurological outcomes. PMID- 29142382 TI - Capillary Leak Syndrome Following Snakebite Envenomation. AB - Capillary leak syndrome is a unique complication that follows Russell's viper envenomation. This syndrome has a very high fatality rate and is characterized by parotid swelling, chemosis, periorbital edema, hypotension, albuminuria, hypoalbuminemia, and hemoconcentration. This syndrome is frequently recognized from the southern parts of India, especially from the state of Kerala. It has been postulated that a vascular apoptosis inducing component of Russell's viper venom that is not neutralized by the commercially available anti-snake venom (ASV) is responsible for this complication as it occurs even after adequate doses of ASV administration in most cases. Acute kidney injury often requiring dialysis is invariably present in all patients because of reduced renal perfusion and ischemic acute tubular necrosis as a result of hypotension. Management mainly involves aggressive fluid resuscitation to maintain adequate tissue perfusion. There are no other proven effective treatment modalities, except a few reports of successful treatment with plasmapheresis. Methylprednisolone pulse therapy, terbutaline, aminophylline, and intravenous immunoglobulin are other treatment modalities tried. PMID- 29142383 TI - Assessment of Doripenem, Meropenem, and Imipenem against Respiratory Isolates of Pseudomonas aeroginosa in a Tertiary Care Hospital of North India. AB - Objective: Pseudomonas aeruginosa is one of the leading pathogen causing healthcare-associated infections, particularly in immunocompromised and critically ill patients. The development of carbapenem resistance in P. aeruginosa infections is worrisome. Data specifically comparing the susceptibility of the three available carbapenems are lacking in the Indian subcontinent. Materials and Methods: We evaluated the minimum inhibitory concentrations (MICs) of the three commonly used carbapenems- imipenem, meropenem, and doripenem against, 435 P. aeruginosa isolates obtained from respiratory samples and compared their susceptibility patterns to determine the best possible carbapenem among those available that may be used in combination regimes. Results: Overall, 222 (51.0%) of isolates were susceptible to doripenem followed by imipenem 206 (47.3%) and meropenem 195 (44.8%), respectively. Two hundred and sixty-two (60.23%) strains were intermediate or resistant to at least one carbapenem. The MIC90 of all three carbapenems was >32 MUg/ml while the MIC50 of meropenem was 16 MUg/ml which was higher than MIC50 of both imipenem (4 MUg/ml) and doripenem (2 MUg/ml). Conclusion: Our study revealed that doripenem exerted better in vitro activity against the tested bacteria compared to imipenem and meropenem, but the difference was not statistically significant. PMID- 29142384 TI - Hypercapnic Respiratory Failure in Case of Chiari 1.5 Malformation: Case Report and Review of the Literature. AB - Type 2 respiratory failure is defined as hypercapnia associated with hypoxia. Chiari 1.5 is known as herniation of the cerebellar tonsils along with brain stem and fourth ventricle. We report a 35-year-old male who presented with acute hypercapnic respiratory failure (Type 2), without any preexisting neurological or respiratory abnormality. Analysis of blood gases in emergency revealed a pH of 7.12, pCO2 of 132 mmHg, and arterial oxygen tension of 118 mm Hg. He was intubated and ventilated. Magnetic resonance imaging brain revealed herniation of the cerebellar tonsils along with brain stem and fourth ventricle. The patient underwent surgery and gradually weaned off. He was mobilized and discharged on day 6. Acute respiratory failure has not been reported with Chiari 1.5 malformation. The lesson to be learned from this case is that craniospinal pathology must be looked for in a patient with hypercapnic respiratory failure. PMID- 29142385 TI - Blowing Bubbles Helps Intubation. AB - Rocuronium is commonly used in preference to suxamethonium for rapid sequence induction in the Intensive Care Unit (ICU). We describe a patient who suffered significant neck trauma following a suicide attempt. On initial presentation to accident and emergency, he was an easy intubation with a Grade 1 view obtained at laryngoscopy. After surgery to repair his neck laceration, he was extubated and discharged from ICU. He later developed a severe aspiration pneumonia and required reintubation. After induction and paralysis with suxamethonium, the best view at laryngoscopy was a Grade 3 despite the use of different laryngoscopes. As the muscle paralysis wore off the patient began breathing. This produced bubbles in the back of the patient's pharynx which directed the clinician to the laryngeal inlet to allow successful intubation. In this case, the short duration of action of suxamethonium significantly aided intubation due to the return of spontaneous breathing by the patient. PMID- 29142386 TI - Polymicrobial Blood Stream Infection: Consensus Definition is Required. PMID- 29142387 TI - FAST HUGS BID: Modified Mnemonic for Surgical Patient. PMID- 29142388 TI - Analysis of Free Amino Acids in Different Extracts of Orthosiphon stamineus Leaves by High-Performance Liquid Chromatography Combined with Solid-Phase Extraction. AB - Background: Orthosiphon stamineus (OS) Benth is a medicinal plant and native in Southeast Asia. Previous studies have shown that OS leaves possess antioxidant, cytotoxic, diuretic, antihypertensive, and uricosuric effects. These beneficial effects have been attributed to the presence of primary and secondary metabolites such as polyphenols, amino acids, and flavonoids. Objective: To develop and validate an high-performance liquid chromatography (HPLC)-diode array detector (DAD) method combined with solid-phase extraction that involves precolumn derivatization with O-phthaladehyde for simultaneous analysis of free amino acids in OS leaves extracts. Materials and Methods: OS leaves were extracted with water (OS-W), ethanol (OS-E), methanol (OS-M), 50% ethanol (OS-EW), and 50% methanol (OS-MW). The extracts were treated by C18 cartridge before derivatization, resulting in great improvement of separation by Zorbox Eclipse XDB-C18 column. Results: The HPLC-DAD method was successfully developed and validated for analyzing the contents of free amino acids in OS extracts. The results showed that l-aspartic acid with 0.93 +/- 0.01 nmol/mg was the major free amino acid in OS-W extract. However, in OS-E, OS-M, OS-EW, and OS-MW, l-glutamic acid with 3.53 +/- 0.16, 2.17 +/- 0.10, 4.01 +/- 0.12, and 2.49 +/- 0.12 nmol/mg, respectively, was the major free amino acid. Subsequently, l-serine, which was detected in OS W, OS-E, and OS-M, was the minor free amino acid with 0.33 +/- 0.02, 0.12 +/- 0.01, and 0.06 +/- 0.01 nmol/mg, respectively. However, l-threonine with 0.26 +/- 0.02 and 0.19 +/- 0.08 nmol/mL in OS-EW and OS-MW, respectively, had the lowest concentration compared with other amino acid components. Conclusion: All validation parameters of the developed method indicate that the method is reliable and efficient to simultaneously determine the free amino acids content for routine analysis of OS extracts. SUMMARY: The HPLC-DAD method combined with solid phase extraction was successfully developed and validated for simultaneous determination and quantification of 17 free amino acids in Orthosiphon stamineus (OS) Benth extractsOS extracts were found to be rich in free amino acid contentL aspartic acid was the major free amino acid in OS water extract while, in OS ethanol, methanol, 50% ethanol and 50% methanol extracts, L-glutamic acid was the major free amino acidL-serine was the minor free amino acid in OS water, ethanol and methanol extracts while, in OS 50% ethanol and 50% methanol extracts, L threonine had the lowest concentration compared to other amino acid components. Abbreviations used: HPLC-DAD: High-Performance Liquid Chromatography with Diode Array Detection, OS: Orthosiphon stamineus, OS-W: Orthosiphon stamineus water extract, OS-E: Orthosiphon stamineus ethanol extract, OS-M: Orthosiphon stamineus methanol extract, OS-EW: Orthosiphon stamineus 50% ethanol extract, OS-MW: Orthosiphon stamineus 50% methanol extract, OPA: O-phthaladehyde, SPE: Solid Phase Extraction, UV: Ultraviolet, LOD: Limit of Detection, LOQ: Limit of Quantification, RSD: Relative Standard Deviation. PMID- 29142389 TI - Bioactive Constituents, Radical Scavenging, and Antibacterial Properties of the Leaves and Stem Essential Oils from Peperomia pellucida (L.) Kunth. AB - Background: Peperomia pellucida is an annual herbaceous ethnomedicinal plant used in the treatment of a variety of communicable and noncommunicable diseases in the Amazon region. Objective: The study aimed at profiling the bioactive constituents of the leaves and stem essential oils (LEO and SEO) of P. pellucida, their in vitro antibacterial and radical scavenging properties as probable lead constituents in the management of oxidative stress and infectious diseases. Materials and. Methods: The EOs were obtained from the leaves and stem P. pellucida using modified Clevenger apparatus and characterized by a high resolution gas chromatography-mass spectrometry, while the radicals scavenging and antibacterial effects on four oxidants and six reference bacteria strains were examined by spectrophotometric and agar diffusion techniques, respectively. Results: The EOs exhibited strong antibacterial activities against six bacteria (Escherichia coli [180], Enterobacter cloacae, Mycobacterium smegmatis, Listeria ivanovii, Staphylococcus aureus, Streptococcus uberis, and Vibrio paraheamolyticus) strains. The SEO antibacterial activities were not significantly different (P < 0.05) from the LEO against most of the test bacteria with minimum inhibitory concentration ranging between 0.15 and 0.20 mg/mL for both EOs. The two oils were bactericidal at 0.20 mg/mL against S. aureus while the minimum bactericidal concentration (0.15 mg/mL) of LEO against L. ivanovii was lower than of SEO (0.20 mg/mL) after 24 h. The LEO IC50 value (1.67 mg/mL) revealed more radical scavenging activity than the SEO (2.83 mg/mL) and reference compounds against 2,2-diphenyl-1-picrylhydrazyl radical. The EOs also scavenged three other different radicals (2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical, lipid peroxyl radical, and nitric oxide radical) in concentration-dependent manner. Conclusion: Our results suggest that apart from the indigenous uses of the plant extracts, the EO contains strong bioactive compounds with antibacterial and radicals scavenging properties and may be good alternative candidates in the search for novel potent antibiotics in this present era of increasing multidrug-resistant bacterial strains as well as effective antioxidants agents. SUMMARY: Established gas chromatography-mass spectrometry technique was applied to quantitatively and qualitatively analyze the volatile constituents in Peperomia pellucida essential oil (EO)The Clinical and Laboratory Standards Institute (2014) guidelines were employed to evaluate the antibacterial effects of the EOsAmong the known prominent bioactive terpenoids, linalool 17.09%, limonene 14.25%, beta-caryophyllene 12.52%, and linalyl acetate 10.15% were the main constituents of the EOs in this current studyThe leaf and stem EOs were bactericidal at a concentration below 0.23 mg/mL against three multidrug resistant bacteria and significantly scavenged known free radicals reported to be associated with contagious and oxidative stress-related disorders. Abbreviations used: GC-MS: Gas chromatography-mass spectrometry, DPPH: 2,2-diphenyl-1 picrylhydrazyl, ABTS: 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, DMSO: Dimethyl sulfoxide, LP*: Lipid peroxide radical, NO*: Nitric oxide radical, LEO: Leaf essential oil, SEO: Stem essential oil, RC: Reference compound, TBARS: Thiobarbituric acid. PMID- 29142390 TI - A Comprehensive Study on Fast Dispersible and Slow-Releasing Characteristic of Orange Peel Pectin in Relation to Established Synthetic Polymer. AB - Introduction: In the present work, the method to extract, isolate, and characterize orange peel pectin using soxhlation, and thereafter, the use of this polymer-polymer in the formulation of fast dispersable and slow-releasing tablet has been studied. Thereafter, the evaluation and comparison of fast dispersible/slow-releasing tablets using orange peel pectin versus prepared using sodium starch glycolate (SSG) were carried out. Materials and Methods: In the present investigation, extraction methodology was employed for isolation of pectin from orange peels. Four different batches with each polymer were prepared with varying concentration of superdisintegrant and bulking agent using diclofenac sodium as model drug. Diclofenac sodium stands as easily available, cheap, and good candidate to demonstrate disintegrant property. The formulation involved wet granulation method for the preparation of tablets of each batch. The tablets were evaluated for hardness, friability, thickness, wetting time, deaggregation time, and in vitro release characteristic data. Results: It was observed that parameters for batch O2* were comparable with that of synthetic superdisintegrant. This batch gave around 92.12% drug release in period of 90 min. The study showed that orange peel pectin could be a potential candidate for formulation of orodispersible dosage forms in competence to SSG, which is established superdisintegrant. Conclusion: The results led to the conclusion that the use of natural polymers in formulation of pharmaceutical dosage form can be put into practice on industrial scale meeting the similar requirements as done by synthetic polymers. SUMMARY: The present work aims to demonstrate and establish the use of naturally derived polymer, i.e., orange peel pectin as a superdisintegrant. The extraction methodology has been discussed followed by comparative analysis with a synthetic polymer. Abbreviations used: O1-O2: Batches Containing Orange peel pectin, S1-S2: Batches containing SSG, SSG: Sodium starch glycolate, NDDS: Novel drug delivery system. PMID- 29142391 TI - Acacia catechu Ethanolic Seed Extract Triggers Apoptosis of SCC-25 Cells. AB - Background: Acacia catechu Willd (Fabaceae), commonly known as catechu, cachou, and black cutch, has been studied for its hepatoprotective, antipyretic, antidiarrheal, hypoglycemic, anti-inflammatory, immunomodulatory, antinociceptive, antimicrobial, free radical scavenging, and antioxidant activities. Objective: We evaluated the cytotoxic activity of ethanol extract of A. catechu seed (ACS) against SCC-25 human oral squamous carcinoma cell line. Methods: Cytotoxic effect of ACS extract was determined by 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide assay, using concentrations of 0.1-1000 MUg/mL for 24 h. A. catechu ethanol seed extract was treated SCC-25 cells with 25 and 50 MUg/mL. At the end of treatment period, apoptotic marker gene expressions such as caspase 8, 9, Bcl-2, Bax, and cytochrome c were evaluated by semiquantitative reverse transcription-polymerase chain reaction. Morphological changes of ACS treated SCC-25 cells was evaluated by acridine orange/ethidium bromide (AO/EB) dual staining. Nuclear morphology and DNA fragmentation was evaluated by propidium iodide (PI) staining. Results: A. catechu ethanol seed extract treatment caused cytotoxicity in SCC-25 cells with an IC50 value of 100 MUg/mL. Apoptotic markers caspases 8 and 9, cytochrome c, Bax gene expressions were significantly increased upon ACS extract treatment indicate the apoptosis induction in SCC-25 cells. This treatment also caused significant downregulation of Bcl-2 gene expression. Staining with AO/EB and PI shows membrane blebbing, and nuclear membrane distortion further confirms the apoptosis induction by ACS treatment in SCC-25 cells. Conclusion: The ethanol seed extracts of A. catechu was found to be cytotoxic at lower concentrations and induced apoptosis in human oral squamous carcinoma SCC-25 cells. SUMMARY: Acacia catechu ethanolic seed extract contains phytochemicals such as epicatechin, rutin, and quercetinAcacia catechu seed (ACS) extract significantly (P < 0.001) inhibits the active proliferation of human oral squamous carcinoma (SCC-25) cellsACS extract treatment to SCC-25 cells significantly modulated the gene expressions pertaining to apoptosis and propidium iodide and acridine orange/ethidium bromide staining also confirm the apoptosis inductionAntiproliferative and apoptosis inducing activities of ACS extract is correlated with phytochemical contents. Abbreviations used: ACS: Acacia catechu seed extract; MTT: 3 (4,5 dimethylthiazol 2 yl) 2,5 diphenyltetrazolium bromide; DMSO: Dimethyl sulfoxide; AO/EO: Acridine orange/ethidium bromide; LC MS: Liquid chromatography mass spectrometry. PMID- 29142392 TI - Quantitative Analysis of Benzyl Isothiocyanate in Salvadora persica Extract and Dental Care Herbal Formulations Using Reversed Phase C18 High-Performance Liquid Chromatography Method. AB - Context: Benzyl isothiocyanate is the active antimicrobial agent in Salvadora persica (siwak) widely used in Islamic countries for oral hygiene. Aims: Quantification of benzyl isothiocyanate in the ethanol extract of S. persica and some dental care herbal formulations labeled to contain siwak. Settings and Design: Simple and sensitive high-performance liquid chromatography method was designed. Subjects and Methods: Separation was achieved on reverse phase C18 (250 mm * 4.6 mm, 5 MU) column with a mobile phase comprising acetonitrile and water (1:1). The detection was carried out at 190 nm using ultra violet-visible detector. The flow rate was kept at 1 mL/min. Results: A sharp and well-defined peak was obtained at the retention time of 9.322 +/- 0.3 min. Linear regression analysis data for the calibration plot showed a good linear relationship between response and concentration in the range of 0.5-500 MUg/mL with a regression coefficient (r2) of 0.9977. The method was validated for accuracy, precision, robustness, and sensitivity. All the parameters examined met the current recommendations for the International Conference on Harmonization guidelines for method validation. Conclusions: The method was applied for the quantification of benzyl isothiocyanate in siwak extract, dental care powder, mouth wash, and toothpaste claimed to contain siwak. The developed method was found specific, simple, selective, and reliable for routine use in quality control analysis of different commercially available herbal care products. SUMMARY: A simple, accurate and precise method was developed for the analysis of the antimicrobial agent benzyl isothiocyanate in Salvadora persica (Siwak) extract and selected dental care herbal formulations using RP18 HPLCAmount of benzyl isothiocyanate will indicate the efficacy of Siwak productsThe method subject to ICH validation guidelines. Abbreviations used: RP18: Reversed phase C18, HPLC: High performance liquid chromatography, UV: Ultra violet, r2: regression coefficient, ICH: international conference on harmonization, TLC: Thin layer chromatography, CHCl3: Chloroform, v/v: volume/volume, RSD: Relative standard deviation, LOD: Limit of detection, LOQ: Limit of quantification. PMID- 29142393 TI - Investigation of Antihyperglycaemic Activity of Banana (Musa sp. Var. Nanjangud rasa bale) Flower in Normal and Diabetic Rats. AB - Background: The vital enzymes of starch digestion and absorption are intestinal alpha-glucosidases and their inhibition improves postprandial hyperglycaemia, constituting an effective mode of therapy in diabetes. Objectives: The present study was designed to assess the inhibitory potential of ethanol extract of banana flower (EF) on mammalian alpha-glucosidases and its pharmacological effects on postprandial hyperglycaemia in normal and alloxan-induced diabetic rats. Materials and Methods: EF was evaluated for its inhibitory potential and mode of inhibition on mammalian alpha-glucosidases. Further, the role of EF and its constituents Umbelliferone (C1) and Lupeol (C2) on glucose uptake using isolated rat hemi-diaphragm and insulinotropic activity using RINm5F (rat insulinoma) cell lines were determined. The phytocomponents in EF were also evaluated using GC-MS. Results: EF illustrated a dose-dependent inhibition for rat intestinal sucrase, maltase and p-nitrophenyl-alpha-D-glucopyranoside (pNPG) hydrolysis (IC50 values: 18.76+/-0.22, 25.54+/-0.10 and 76.42+/-1.12 ug/ml, respectively) and the mode of inhibition was non-competitive with low Ki values. Oral administration (100-200 mg/kg b.wt.) of EF significantly improved the maltose/glucose-induced postprandial hyperglycaemia in normal and alloxan-induced diabetic rats. EF, C1 and C2 exhibited stimulation of glucose uptake and a dose dependent glucose-induced insulin secretion at both 4.5 and 16.7 mM glucose concentrations. Further, GC-MS analysis revealed significant levels of steroids (25.61%), diazoprogesterone (21.31%), sesquiterpene (11.78%) and other phytocomponents. Conclusion: EF inhibited alpha-glucosidases besides promoting glucose uptake and insulin secretion, resulting in antihyperglycaemic effect determining EF as a potent anti-diabetic agent.Abbreviations used: mg/dl: milligramsper deciliter, mM: millimolar, b.wt.: body weight. PMID- 29142394 TI - Antioxidant Phytochemicals of Opuntia ficus-indica (L.) Mill. Cladodes with Potential Anti-spasmodic Activity. AB - Background: Opuntia ficus-indica (OFI) (L.) Mill. (Cactaceae), a plant widespread in dry regions of the world, shows interesting biological activities (cicatrizant, antiulcer, anti-inflammatory, and hypolipidemic) and is widely used in traditional medicine. Objectives: Phytochemical analysis and antispasmodic effect of wild OFI cladodes were carried out. Material and Methods: Polyphenols and Vitamin E occurrence, in antioxidant pool of OFI cladodes, were quantified by high-performance liquid chromatography. The antispasmodic effect of OFI cladodes was assessed in isolated rabbit smooth muscle tissues. The experiments were carried out with preparations of rabbit jejunum and uterus with the spontaneous contractile activity, to evaluate the effect of cumulative concentrations of the extract on basal tone, amplitude, and frequency of contractions. Results: Catechin, quercetin, kaempferol, isorhamnetin and chlorogenic, ferulic, and p coumaric acid were identified. alpha-, beta-, and gamma-tocopherols have been highlighted and alpha-tocopherol is the major component. OFI cladodes contain significant amount of polyphenols and tocopherols that are effective radical scavengers and inhibited ethanol 1,1-diphenyl-2-picrylhydrazyl formation by 50%. OFI cladodes caused a light inhibition of amplitude and frequency of spontaneous contractions and a marked decrease in muscle basal tone of rabbit jejunum preparations. On spontaneously contracting uterus preparations, the addition of increasing concentrations of cladode extract caused uterine muscle relaxation. Conclusion: The contraction of smooth muscle preparations depends on an increase in cytoplasmic free calcium ion concentration, which activates the contractile elements. The flavonoids may suppress the contractility of smooth myocytes, by an inhibition of availability of Ca2+ for muscle contraction. SUMMARY: Opuntia ficus indica (OFI) cladodes contain significant amount of polyphenols and tocopherols that are effective radical scavengers and inhibited ethanol 1,1-diphenyl-2 picrylhydrazyl formation by 50%Polyphenols and Vitamin E complex occurrence in OFI cladodes were characterized by high-performance liquid chromatographyOFI cladodes exhibited significative antispasmodic activity. The antispasmodic effect was assessed in isolated rabbit smooth muscle tissues. The experiments were carried out with preparations of rabbit jejunum and uterus with the spontaneous contractile activity, to evaluate the effect of cumulative concentrations of the extract on basal tone, amplitude, and frequency of contractions. Abbreviations used: OFI: Opuntia ficus-indica, DPPH: Ethanol 1,1-diphenyl-2-picrylhydrazyl. PMID- 29142395 TI - Biological Effect of Cynara cardunculus on Kidney Status of Hypercholesterolemic Rats. AB - Context: Cynara cardunculus or artichoke thistle belongs to the sunflower family and has a variety of cultivable forms. Historically, it was cultivated as a vegetable, but more recently, it is being used in cheese and biofuel preparation. Artichoke leaf extracts are also known for its medicinal purposes, particularly in reducing the elevated cholesterol levels in blood. Hypercholesterolemia (HC) is also associated with other complications such as impaired renal function and diabetes mellitus. A remedy without major side effects for HC and its associated complications is highly desirable. Aims: We explored the effect of artichoke on the kidneys of hypercholesterolemic adult male Sprague-Dawley albino rats. Subjects and Methods: Oral administration of 200 mg/kg and 400 mg/kg body weight (b.wt.) of C. cardunculus leaf extract (CCL) and C. cardunculus pulp extract (CCP) was made to male Sprague-Dawley albino hypercholesterolemic rats and investigated the levels of glucose, creatinine, uric acid, and urea in their blood. Results: We observed that both CCL and CCP significantly reduced the creatinine and uric acid levels in the blood in a dose-dependent manner (P < 0.05). Both CCL and CCP significantly reduced the blood glucose levels (P < 0.05). Further, the histopathological investigation of the kidney sections showed that CCL treatment resolved HC-associated kidney damage. Conclusion: CCL not only has cholesterol-reducing capacity but also reduces the blood glucose levels and repairs the impaired kidney functions and damages. These findings are significant particularly because HC results in further complications such as diabetes and kidney damage, both of which can be treated effectively with artichoke. SUMMARY: C. cardunculus leaf extract (CCL) not only has cholesterol-reducing capacity but also reduces the blood glucose levels and repairs the impaired kidney functions and damages. This study evaluated the nephroprotective role of CCL and CCP in hypercholesterolemic rats and observed that both CCL and CCP significantly reduced the creatinine and uric acid levels in hypercholesterolemic rats in a dose-dependent manner. Abbreviations used: HC: Hypercholesterolemia, WHO: World Health Organization, BAS: Bile acid sequestrant, PCSK9: Proprotein convertase subtilisin kexin type 9, ALE: Artichoke leaf extract, CCL: Cynara cardunculus leaf extract, CCP: Cynara cardunculus pulp extract, BWG%: Body weight gain%, FER: Food-efficiency ratio. PMID- 29142396 TI - Antioxidant and Cholinesterase Inhibitory Activities of Ethyl Acetate Extract of Terminalia chebula: Cell-free In vitro and In silico Studies. AB - Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder clinically characterized by memory loss and impaired cognitive function. Cholinergic enzyme deficiency and oxidative stress are the two major factors implicated in the pathogenesis of AD. The symptomatic treatment, as of now, is the use of cholinesterase inhibitors toward cholinergic "downturn." Therefore, there is a search for compounds that will be useful in focused therapies. There has been suggestion that Terminalia chebula fruit would be a potential source. Objective: To assess the anticholinesterase and antioxidant activities of T. chebula fruit which is widely practiced in the Ayurvedic medicines for memory enhancement. Materials and Methods: Ethyl acetate extract of T. chebula fruit (TCEA) was subjected to phytochemical investigation of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities and cell-free antioxidant activity. TCEA was further subjected to gas chromatography-mass spectrum (GC-MS) analysis. The bioactive compounds were analyzed for molecular docking with AChE and BuChE proteins. Results: TCEA exhibited potent AChE and BuChE inhibitory activities comparable to the standard drug donepezil. In vitro cell-free antioxidant assays demonstrated that TCEA possesses excellent free radical scavenging activity, reducing power, and potent metal-chelating activity. Total polyphenolic content of TCEA was 596.75 +/- 0.35 ug gallic acid equivalents/mg of extract, which correlates with the antioxidant activity of TCEA. Molecular docking of compounds expounded in GC-MS analysis for AChE and BuChE enzyme activities revealed that methyl N-(N-benzyloxycarbonyl-beta-l aspartyl)-beta-d-glucosaminide as the most potent compound with good predicted activities. Conclusion: Overall, the results revealed that the bioactive molecule methyl N-(N-benzyloxycarbonyl-beta-l-aspartyl)-beta-d-glucosaminide present in TCEA is a potential depressant for the treatment of AD and related neurodegenerative disorders. SUMMARY: The present study was carried out to assess the neuroprotective effect of Terminalia chebula fruit and its phytoconstituent. Phytochemical analysis of fruit ethyl acetate extract of T. chebula (TCEA) showed the presence of alkaloid, cardiac glycoside, and tannin. TCEA showed potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities when compared to standard drug donepezil. Results of in vitro antioxidant assays revealed excellent free radical scavenging activity, reducing power, and potent metal-chelating activity. Gas chromatography-mass spectrum analysis illustrated the presence of 22 active compounds, among which methyl N-(N benzyloxycarbonyl-beta-l-aspartyl)-beta-d-glucosaminide exhibited potent AChE and BuChE inhibition analyzed through in silico studies. Abbreviations used: AD: Alzheimer's disease; TCEA: Ethyl acetate extract of Terminalia chebula; GC-MS: Gas chromatography-mass spectrum; ROS: Reactive oxygen species; RNS: Reactive nitrogen species; AChE: Acetylcholinesterase; BuChE: Butyrylcholinesterase; NFT: Neurofibrillary tangles; AMU: MU-amyloid; NSAIDS: Nonsteroidal anti-inflammatory drugs; FDA: Food and Drug Administration; RT: Room temperature; HCl: Hydrochloric acid; ATCI: Acetylthiocholine iodide; BTCI: Butyrylthiocholine iodide; BHT: Butylated hydroxytoluene; DPPH: 2,2-diphenyl-1-picrylhydrazyl; TCA: Trichloroacetic acid; GAE: Gallic acid equivalent; NICT: National Institute of Information and Communications Technology; 3D: Three-dimensional; PDB: Protein data bank; OPLS: Optimized potentials for liquid simulations; XP: Extra precision; SD: Standard deviation; ANOVA: Analysis of variance; EDTA: Ethylenediaminetetraacetic acid. PMID- 29142397 TI - Chemical Composition, Antimicrobial and Antitumor Potentiality of Essential Oil of Ferula tingitana L. Apiaceae Grow in Libya. AB - Background: Ferula tingitana L. (Apiaceae) has been considered to have abortive and menstruation-inducing properties. It used to treat sore throat, fever, indigestion, and pains. Objectives: The objective of this study is to establish the chemical composition of the essential oil of flower, leaves of F. tingitana, and to throw light on antimicrobial, cytotoxic activities of Libyan plant. Materials and Methods: The chemical composition of the essential oil of flower (0.06% w/v) and leaves (0.1% w/v) of F. tingitana was comparatively analyzed by gas chromatography/mass spectrometry using nonpolar column DB-5. Results: A total of 28-32 components were identified, 15 being common in both samples. The main constituents of both flower- and leave-derived oil samples were alpha-thujene (13.5%-2.3%), elemol (8.9%-8.3%), eudesmol (0.6%-9.7%) and cadinol (2.2%-13.8%), respectively. The principle difference was a considerably more pronounced sesquiterpenes presence in the leaves-oil, amounting to 74.0%, than in the flower counterpart (39.9%). Caryophyllene (5.6%) and elemol (8.9%) were the major sesquiterpenes detected in flower-oil while leaves-oil showed less amounts of sesquiterpenoid hydrocarbons (27.7%) and represented by eudesmadiene (9.0%). On the contrary, while remaining the dominant group in both oil samples, monoterpenoids are relatively more abundant in flower-derived oil constituting 57.7% versus 24.5% detected in leaves. Conclusion: Leaves-oil sample being mostly efficient as antibacterial against Bacillus subtilis and Neisseria gonorrhoeae with potency 48.3, 41.9% compared to tetracycline standard antibacterial drug. The essential oil samples revealed marked in vitro cytotoxicity against breast (MCF7), cervical (HELA) and liver(HEPG2) carcinoma cell lines with IC50% (6.9, 4.8), (8.6, 10.9), and (4.4, 4.2) for the flower-, leaves-derived oil sample, respectively. SUMMARY: Comparative analysis of the investigated oil samples indicates more pronounced monoterpene contents in Ferula tingitana flower. The principle monoterpenoid constituents of both oils are alpha-thujene. Sesquiterpenes presence is considerably more pronounced in the leaves-derived oil sampleElemol, cadinol, alpha-thujene and a-terpinoline, the major components of the flower- and leaves-derived oil in the present work and were not detected in the Turkish sample. The differences may be due to climatic and other extrinsic conditions such as where and when the samples were collectedWhen screened for antimicrobial activity, the flower- and leaves-derived oil of F. tingitana exhibited a mild effect against all tested Gram-negative and Gram-positive microorganisms. However, not displayed growth inhibitory effect against the fungus Aspergillus flavus and Candida albicansOn assessing the cytotoxic activity, the flower- and leaves-derived oil exhibited specific and significant effects on the viability of the selected human cell lines, viz., hormone responsive breast carcinoma cell line (MCF7), cervical carcinoma cell line (HELA), and liver carcinoma cell line (HEPG2). Abbreviations used: F: Flower derived oil of F. tingitana; L: Leaves-derived oil of F. tingitana; IPP: Isopentenyl pyrophosphate or also isopentenyl diphosphate; DMAPP: Dimethylally pyrophosphate or also dimethylallyl diphosphate; GPP: Geranyl pyrophosphate; GGPP: Geranylgeranyl pyrophosphate; MEP: Methylerythritol phosphate pathway; FPP: Farnesyl pyrophosphate; GC/MS: Analysis gas chromatography/mass spectroscopy; SRB: Sulforhodamine B. PMID- 29142398 TI - Cytotoxic, Antimitotic, and Antiproliferation Studies on Rasam: A South Indian Traditional Functional Food. AB - Background: Rasam is a traditional South Indian food, prepared using tamarind juice as a base, with a variety of spices. Rasam, with all its ingredients medicinally claimed for various ailments, is a functional food. Systematic consumption of traditional functional food provides an excellent preventive measure to ward off many diseases. Objective: To study rasam for cytotoxic, antimitotic, and antiproliferation potential beyond its culinary and nutritional effect. Materials and Methods: Brine shrimp lethality assay, onion root tip inhibition assay, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in Calu-6, HeLa, MCF-7 cell lines for four stage-wise samples in the preparation of rasam (RS1, RS2, RS3, and RS4) were studied. Results: RS4, the end product of rasam showed high lethality with an LC50 value of 38.7 MUL/mL. It showed maximum antimitotic activity in a dose-dependent manner compared to other samples with an IC50 value of 189.86 MUL/mL. RS4 also showed an IC50 value of 350.22 and 410.15 MUL/mL in MCF-7 and Calu-6 cell lines, respectively. Conclusion: From this study, we suggest that rasam is a classic example of traditional functional food and it can treat breast and lung cancer on chronic use. SUMMARY: Rasam, a South Indian traditional functional food, showed high lethality (LC50 = 38.7 mL/mL) against brine shrimpsRasam also showed potential antimitotic activity (IC50 = 189.86 mL/mL) by inhibiting the onion root tipsRasam showed an IC50 value of 350.22 and 410.15 mL/mL against MCF-7 and Calu-6 cell lines respectivelyRasam, when consumed on daily dietary basis, can treat breast and lung cancer. Abbreviations used: SS 316: Stainless Steel 316 grade; MTT: 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DMEM: Dulbecco's modified Eagle medium; FBS: Fetal bovine serum media; TPVG: Trypsin phosphate versene glucose; EDTA: Ethylene diamine tetra acetic acid; PBS: Phosphate buffered saline; DMSO: Dimethyl sulfoxide. PMID- 29142399 TI - The Effect of Thymoquinone on Nuclear Factor Kappa B Levels and Oxidative DNA Damage on Experimental Diabetic Rats. AB - Background: Thymoquinone (TQ), the basic bioactive phytochemical constituent of seed oil of Nigella sativa, is one of these herbal drugs known for antidiabetic effects. This study was carried out to assess the effects of the possible role of TQ on nuclear factor kappa B (NF-kappaB) and oxidative DNA damage levels in experimental diabetic rats. Materials and Methods: Twenty-eight male Wistar Albino rats (200-250 g) were used as experimental subjects. The rats were divided into four groups, including the control, control supplemented with TQ (CT), diabetic (D), and diabetic supplemented with TQ (DT), each containing seven rats. The D and the DT groups were treated with 45 mg/kg streptozotocin (STZ) (intraperitoneal). TQ was administered 30 mg/kg/day for 21 days by oral gavage in the DT and the T groups. Results: It was determined that glucose, glycosylated hemoglobin (HbA1c) levels and alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase activities were decreased significantly and approached the control group in the DT group after TQ supplement (P < 0.05). Urea levels were the lowest in CT (P < 0.05). Oxidative DNA damage (8 hydroxy-2-deoxyguanosine) was increased in both of the diabetic groups (D and DT). The NF-kappaB levels were the highest in Group D (P < 0.05). Conclusion: It was observed that increased glucose and HbA1c levels and the indicators of liver and kidney damages were decreased significantly after TQ supplementation. Oxidative DNA damage and NF-kappaB levels were increased in the diabetic group, and TQ administration caused a statistically insignificant reduction. SUMMARY: In this study, the effects of thymoquinone (TQ), the basic bioactive phytochemical constituent of seed oil of Nigella sativa, on nuclear factor kappa B (NF-kappaB), oxidative DNA damage levels, and, some biochemical parameters was invesigated. It was observed that some biochemical parameters (glucose, glycosylated hemoglobin (HbA1c), ALT, AST, GGT) were close to the control group after TQ treatment in diabetic group. Oxidative DNA damage (8 hydroxy 2 deoxyguanosine) and NF-kappaB were highest levels and TQ implementation caused statistically insignificant decrease, in the diabetic group. Abbreviations used: 8-OHdG: 8 hydroxi-2-deoxiguanosin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; HbA1c: Glycosylated hemoglobin; NF-kappaB: Nuclear factor kappa protein; STZ: Streptozotocin; TQ: Thymoquinone. PMID- 29142400 TI - Chemical Composition of Moringa oleifera Ethyl Acetate Fraction and Its Biological Activity in Diabetic Human Dermal Fibroblasts. AB - Background: Moringa oleifera (MO), commonly known as the drumstick tree, is used in folklore medicine for the treatment of skin disease. Objective: The objective of this study is to evaluate the ethyl acetate (EtOAc) fraction of MO leaves for in vitro antibacterial, antioxidant, and wound healing activities and conduct gas chromatography-mass spectrometry (GC-MS) analysis. Materials and Methods: Antibacterial activity was evaluated against six Gram-positive bacteria and 10 Gram-negative bacteria by disc diffusion method. Free radical scavenging activity was assessed by 1, 1-diphenyl-2-picryl hydrazyl (DPPH) radical hydrogen peroxide scavenging and total phenolic content (TPC). Wound healing efficiency was studied using cell viability, proliferation, and scratch assays in diabetic human dermal fibroblast (HDF-D) cells. Results: The EtOAc fraction showed moderate activity against all bacterial strains tested, and the maximum inhibition zone was observed against Streptococcus pyogenes (30 mm in diameter). The fraction showed higher sensitivity to Gram-positive strains than Gram-negative strains. In the quantitative analysis of antioxidant content, the EtOAc fraction was found to have a TPC of 65.81 +/- 0.01. The DPPH scavenging activity and the hydrogen peroxide assay were correlated with the TPC value, with IC50 values of 18.21 +/- 0.06 and 59.22 +/- 0.04, respectively. The wound healing experiment revealed a significant enhancement of cell proliferation and migration of HDF-D cells. GC-MS analysis confirmed the presence of 17 bioactive constituents that may be the principal factors in the significant antibacterial, antioxidant, and wound healing activity. Conclusion: The EtOAc fraction of MO leaves possesses remarkable wound healing properties, which can be attributed to the antibacterial and antioxidant activities of the fraction. SUMMARY: Moringa oleifera (MO) leaf ethyl acetate (EtOAc) fraction possesses antibacterial activities toward Gram positive bacteria such as Streptococcus pyogenes, Streptococcus faecalis, Bacillus subtilis, Bacillus cereus and Staphylococcus aureus, and Gram-negative bacteria such as Proteus mirabilis and Salmonella typhimuriumMO leaf EtOAc fraction contained the phenolic content of 65.81 +/- 0.01 and flavonoid content of 37.1 +/- 0.03, respectively. In addition, the fraction contained 17 bioactive constituents associated with the antibacterial, antioxidant, and wound healing properties that were identified using gas chromatography-mass spectrometry analysisMO leaf EtOAc fraction supports wound closure rate about 80% for treatments when compared with control group. Abbreviations used: MO: Moringa oleifera; EtOAc: Ethyl acetate; GC-MS: Gas Chromatography-Mass Spectrometry; HDF D: Diabetic Human Dermal Fibroblast cells. PMID- 29142401 TI - Phytochemical Compositions and In vitro Assessments of Antioxidant and Antidiabetic Potentials of Fractions from Ehretia cymosa Thonn. AB - Background: Ehretia cymosa Thonn. is a popular medicinal plant used in different parts of West Africa for the treatment of various ailments including diabetes mellitus. Objective: The current study investigates bioactive constituents and in vitro antioxidant and antidiabetic potentials of fractions from extract of E. cymosa. Materials and Methods: Phytochemical investigation and antioxidant assays were carried out using standard procedures. Antidiabetic potential was assessed by evaluating the inhibitory effects of the fractions on the activities of alpha amylase and alpha-glucosidase, while bioactive constituent's identification was carried out using gas chromatography-mass spectrometric (GC-MS) analysis. Results: The phytochemistry tests of the fractions revealed the presence of tannins, phenols, flavonoids, steroids, terpene, alkaloid, and cardiac glycosides. Methanol fraction shows higher phenolic (27.44 mg gallic acid/g) and flavonoid (235.31 mg quercetin/g) contents, while ethyl acetate fraction revealed higher proanthocyanidins (28.31 mg catechin/g). Methanol fraction displayed higher (P < 0.05) 1,1-diphenyl-2-picryl-hydrazyl (0.47 mg/mL), 2,2-azino-bis (3 ethylbenzothiazoline)-6-sulfonic acid (0.49 mg/mL), and hydroxyl radical (0.55 mg/mL) scavenging activities, while ethyl acetate exhibited strong metal chelating (0.61 mg/mL) and superoxide anion (1.68 mg/mL) scavenging activity. Methanol and ethyl acetate fractions displayed higher inhibition (P < 0.05) against alpha-glucosidase (0.60 mg/mL) and alpha-amylase (2.11 mg/mL), respectively. Methanol fraction also inhibited alpha-amylase and alpha glucosidase in competitive and noncompetitive modes, respectively. The GC-MS chromatogram of the methanol fraction revealed 24 compounds, which include phytol (1.78%), stearic acid (1.02%), and 2-hexadecyloxirane (34.18%), which are known antidiabetic and antioxidant agents. Conclusion: The results indicate E. cymosa leaves as source of active phytochemicals with therapeutic potentials in the management of diabetes. SUMMARY: E. cymosa fractions possess antioxidant and antidiabetic activities. Hence, it is a source of active phytochemicals with therapeutic potentials in the management of diabetesThe high flavonoid, phenolic, and proanthocyanidin contents of fractions from E. cymosa also contribute to its antioxidant and antidiabetic propertiesMethanol fraction of E. cymosa displayed better antidiabetic activities compared to acarbose as revealed by their half maximal inhibitory concentration valuesMethanol fraction of E. cymosa extract contains phytol, hexadecyl oxirane, and stearic acid, which are reported to possess antidiabetic and antioxidant potentials. Abbreviations used: ABTS: 2,2- Azino-bis (3-ethylbenzothiazoline)-6-sulfonic acid, DPPH: 1,1-diphenyl-2-picryl hydrazyl, PMS: Phenazine methosulfate, NBT: Nitroblue tetrazolium, NADH: Nicotinamide adenine dinucleotide, TCA: Trichloroacetic acid, TBA: Thiobarbituric acid, DNS: Dinitrosalicylic acid. PMID- 29142402 TI - Chromosomal Fragmentation: A Possible Marker for the Selection of High Gymnemic Acid Yielding Accessions of Gymnema sylvestre R. Br. AB - Background: Gymnema sylvestre R. Br. a member of family Asclepiadaceae as mentioned in Indian Pharmacopoeia popular among the researchers because of stimulatory effect of its phytoconstituent on pancreatic cells and potential to treat Type I and II type of diabetes. Objectives: Development of cost-effective marker system for the selection of high gymnemic acid yielding accessions of G. sylvestre. Materials and Methods: Presoaked seeds of Brassica campestris treated with different dilutions of gymnemagenin and 10% leaf extract of twenty different accessions of G. sylvestre. Root tips of germinated seeds were fixed, and chromosomal studies were made by root tip bioassay method. Results: Exposure of seeds to treatment solutions promotes various types of chromosomal anomalies in root meristem, and surprisingly, direct correlation between the percentage of chromosomal fragmentation and the percentage of gymnemic acid shared by treatment solution were observed. Conclusion: Later finding may be explored for the development of a novel methodology or marker system for the selection of high active principle yielding accessions of G. sylvestre. SUMMARY: An experiment was carried out using root tip bioassay method for the study of effect of different dilutions of standard gymnemic acid and 10% leaf extract of twenty different accessions of Gymnema sylvestre on root tip meristem of Brassica campestris. Various types of chromosomal anomalies were observed. Of which, percentage of chromosomal fragmentation was showed a direct (infinity) relationship with the percentage of gymnemic acid shared by treatment solution. This interesting result after more and more exploration and revalidation could be utilized for the development of a novel methodology for the selection of high active principle yielding accessions of G. sylvestre. Abbreviations used: MI: Mitotic index; CP: Condensed prophase; CM: Clumped metaphase; MC: Metaphase cleft; FR: Fragmentation; AP: Anaphase with persistent nucleolous; LA: Laggard, BR: Bridge; BI: Bi-nucleated cell; DA: Disturbed anaphasic polarity. PMID- 29142403 TI - Flavonoidal Constituents, Antioxidant, Antimicrobial, and Cytotoxic Activities of Dipterygium glaucum Grown in Kingdom of Saudi Arabia. AB - Background: Dipterygium glaucum Decne. herb is one of the common traditional plants with multiple medicinal uses. Objective: To isolate the major constituents and to investigate the antioxidant, antimicrobial, and cytotoxic activities of this herb. Materials and Methods: Methanolic extract of D. glaucum herb was fractionated using n-hexane, dichloromethane, and n-butanol. Butanol fraction was chromatographed using column chromatography and preparative thin layer chromatography to isolate the major constituents. Isolated compounds were elucidated by means of spectroscopic methods, including 1D, 2D NMR (1H, 13C, DEPT, COSY, HSQC, HMBC, NEOSY) and MS analysis. Total phenolic content using Folin-Ciocalteu reagent and antioxidant activity using 1,1-diphenyl-2 picrylhydrazyl (DPPH) assay of the total methanolic extract were evaluated. Cytotoxic potential of both methanolic extract and butanol fraction was tested using a crystal violet viability assay. Antimicrobial activities of both extracts were investigated using diffusion agar technique. Results: Apigenin 6, 8-di-C glucopyranoside (vicenin-2), quercetin-3'-O-methyl-3-O-glucopyranoside, quercetin 3'-O-methyl-3-O-galactopyranoside, quercetin-3-O-beta-D-glucopyranoside, and quercetin-3-O-beta-D-galactopyranoside were isolated and elucidated. Total phenolic content was (83.89 mg gallic acid equivalent/g extract). The EC50 value of scavenging DPPH radical was 152.0 +/- 2 mg/mL. Butanol fraction showed the highest cytotoxic activity against cervical and breast carcinoma cells (IC50 3.6 and 6.1 mg/mL, respectively). Both methanolic extract and butanol fraction showed wide spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria and some fungi. The highest activity was from methanolic extract against Enterococcus faecalis (83.25%) and against Candida tropicalis (77.03%) as compared to reference antibiotics. Conclusion: Data obtained from this study demonstrate that D. glaucum possesses significant antioxidant, cytotoxic, and antimicrobial activities which could be ascribed to its flavonoidal content. SUMMARY: Dipterygium glaucum Decne. herb is one of the common traditional plants with multiple medicinal uses in KSAFive flvonidal glycosides were isolated and elucidatedThis study demonstrated that D. glaucum possesses significant antioxidant, cytotoxic, and antimicrobial activities. Abbreviations used: KSA: Kingdom of Saudi Arabia; TLC: Thin Layer Chromatography; DPPH: 2,2'-diphenyl-1 picrylhydrazyl; EC50: Half maximal effective concentration; IC50: Half maximal inhibitory concentration; DMSO: dimethyl sulfoxide; NMR: Nuclear Magnetic Resonance; ESIMS: Electrospray ionization mass spectrometry; MeOH: Methyl alcohol. PMID- 29142404 TI - Chalepin: A Compound from Ruta angustifolia L. Pers Exhibits Cell Cycle Arrest at S phase, Suppresses Nuclear Factor-Kappa B (NF-kappaB) Pathway, Signal Transducer and Activation of Transcription 3 (STAT3) Phosphorylation and Extrinsic Apoptotic Pathway in Non-small Cell Lung Cancer Carcinoma (A549). AB - Background: Plants have been a major source of inspiration in developing novel drug compounds in the treatment of various diseases that afflict human beings worldwide. Ruta angustifolia L. Pers known locally as Garuda has been conventionally used for various medicinal purposes such as in the treatment of cancer. Objective: A dihydrofuranocoumarin named chalepin, which was isolated from the chloroform extract of the plant, was tested on its ability to inhibit molecular pathways of human lung carcinoma (A549) cells. Materials and Methods: Cell cycle analysis and caspase 8 activation were conducted using a flow cytometer, and protein expressions in molecular pathways were determined using Western blot technique. Results: Cell cycle analysis showed that cell cycle was arrested at the S phase. Further studies using Western blotting technique showed that cell cycle-related proteins such as cyclins, cyclin-dependent kinases (CDKs), and inhibitors of CDKs correspond to a cell cycle arrest at the S phase. Chalepin also showed inhibition in the expression of inhibitors of apoptosis proteins. Nuclear factor-kappa B (NF-kappaB) pathway, signal transducer and activation of transcription 3 (STAT-3), cyclooxygenase-2, and c-myc were also downregulated upon treatment with chalepin. Chalepin was found to induce extrinsic apoptotic pathway. Death receptors 4 and 5 showed a dramatic upregulation at 24 h. Analysis of activation of caspase 8 with the flow cytometer showed an increase in activity in a dose- and time-dependent manner. Activation of caspase 8 induced cleavage of BH3-interacting domain death agonist, which initiated a mitochondrial-dependent or -independent apoptosis. Conclusion: Chalepin causes S phase cell cycle arrest, NF-kappaB pathway inhibition, and STAT 3 inhibition, induces extrinsic apoptotic pathway, and could be an excellent chemotherapeutic agent. SUMMARY: This study reports the capacity of an isolated bioactive compound known as chalepin to suppress the nuclear factor kappa-light chain-enhancer of activated B cells pathway, signal transducer and activation of transcription 3, and extrinsic apoptotic pathway and also its ability to arrest cell cycle in S phase. This compound was from the leaves of Ruta angustifolia L. Pers. It provides new insight on the ability of this plant in suppressing certain cancers, especially the nonsmall cell lung carcinoma according to this study. Abbreviations used: degrees C: Degree Celsius, ANOVA: Analysis of variance, ATCC: American Type Culture Collection, BCL-2: B-Cell CLL/Lymphoma 2, Bcl-xL: B cell lymphoma extra-large, BH3: Bcl-2 homology 3, BID: BH3-interacting domain death agonist, BIR: Baculovirus inhibitor of apoptosis protein repeat, Caspases: Cysteinyl aspartate-specific proteases, CDK: Cyclin-dependent kinase, CO2: Carbon dioxide, CST: Cell signaling technologies, DISC: Death-inducing signaling complex, DMSO: Dimethyl sulfoxide, DNA: Deoxyribonucleic acid, DR4: Death receptor 4, DR5: Death receptor 5, E1a: Adenovirus early region 1A, ECL: Enhanced chemiluminescence, EDTA: Ethylenediaminetetraacetic acid, ELISA: Enzyme-linked immunosorbent assay, etc.: Etcetera, FADD: Fas-associated protein with death domain, FBS: Fetal bovine serum, FITC: Fluorescein isothiocyanate, G1: Gap 1, G2: Gap 2, HPLC: High-performance liquid chromatography, HRP: Horseradish peroxidase, IAPs: Inhibitor of apoptosis proteins, IC50: Inhibitory concentration at half maximal inhibitory, IKK-alpha: Inhibitor of nuclear factor kappa-B kinase subunit alpha, IKK-beta: Inhibitor of nuclear factor kappa-B kinase subunit beta, IKK gamma: Inhibitor of nuclear factor kappa-B kinase subunit gamma, IKK: IkappaB kinase, IkBalpha: Nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha, m: Meter, M: Mitotic, mm: Millimeter, mRNA: Messenger ribonucleic acid, NaCl: Sodium chloride, NaVO4: Sodium orthovanadate, NEMO: NF Kappa-B essential modulator, NF-kappaB: Nuclear factor kappa-light chain-enhancer of activated B cells, NSCLC: Nonsmall cell lung carcinoma, PBS: Phosphate buffered saline, PGE2: Prostaglandin E2, PI: Propidium iodide, PMSF: Phenylmethylsulfonyl fluoride, pRB: Phosphorylated retinoblastoma, R. angustifolia: Ruta angustifolia L. Pers, Rb: Retinoblastoma, rpm: Rotation per minute, RPMI: Roswell Park Memorial Institute, S phase: Synthesis phase, SD: Standard deviation, SDS-PAGE: Sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Smac: Second mitochondria-derived activator of caspase, SPSS: Statistical Package for the Social Sciences, STAT3: Signal transducer and activation of transcription 3, tBID: Truncated BID, TNF: Tumor necrosis factor, TRADD: Tumor necrosis factor receptor type-1 associated death domain, TRAIL: TNF related apoptosis- inducing ligand, USA: United States of America, v/v: Volume over volume. PMID- 29142405 TI - Antihyperglycemic Activity of Caralluma fimbriata: An In vitro Approach. AB - Background: An increase in prevalence of diabetes mellitus necessitates the need to develop new drugs for its effective management. Plants and their bioactive compounds are found to be an alternative therapeutic approach. Caralluma fimbriata, used in this study, is well known for its various biological effects. Objective: The present study was designed to investigate the antihyperglycemic effect of the ethanolic leaf extract of C. fimbriata. Materials and Methods: Different concentrations (1-1000 mg/mL) of the ethanolic leaf extract of C. fimbriata were subjected to alpha-amylase and alpha-glucosidase inhibitory assay with acarbose as control. Cytotoxicity was assessed by 3-(4,5 dimethylthiazol-2 yl)-2,5-diphenyl tetrazolium bromide assay. Glucose uptake assay was performed on L6 myotubes using the extract in 1 MUg-100 MUg/mL, using metformin and insulin as control. Results: The C. fimbriata extract showed potent inhibitory activity on enzymes of glucose metabolism in a dose-dependent manner. The maximum alpha amylase inhibitory effect was 77.37% +/- 3.23% at 1000 MUg/mL with an IC50 value of 41.75 MUg/mL and alpha-glucosidase inhibitory effect was 83.05% +/- 1.69% at 1000 MUg/mL with an IC50 value of 66.71 MUg/mL. The maximum glucose uptake was found to be 66.32% +/- 0.29% for the Caralluma extract at 100 MUg/mL and that of metformin (10 MUg/mL) was 74.44% +/- 1.72% and insulin (10 mM) 85.55% +/- 1.14%. The extract was found to be safe as the IC50 of extract and metformin was found to be >=1000 MUg/mL and >=1000 MUM, respectively, in the cell line tested. Conclusion: The study concludes that C. fimbriata has promising antihyperglycemic activity. SUMMARY: Caralluma fimbriata extract exhibited effective dose dependent inhibitory activity against alpha-amylase and alpha- glucosidaseEnhanced glucose uptake from L6 myotubes was appreciated in the presence of the extract, comparable to Insulin and metforminCaralluma fimbriata has potent antihyperglycemic properties. Abbreviations used: GLUT: Glucose transporter; MTT: 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. PMID- 29142406 TI - Biological Activity and Isolation of Compounds from Stem Bark of Plumeria acutifolia. AB - Background: Plumeria acutifolia (Apocynaceae) is an ornamental plant, used in the traditional medicine and known to have a variety of constituents as alkaloids, flavonoids, and iridoids. Extracts of this plant were proved to have antimicrobial and anticancer activities. Objectives: This research was conducted for the evaluation of the biological activities of P. acutifolia stem bark and isolation and structural elucidation of various chemical compounds from the biologically active fractions. Materials and Methods: Methanol extract of stem bark of P. acutifolia was successively fractionated with petroleum ether, dichloromethane, ethyl acetate, and n-butanol. The fractions were evaluated for their antimicrobial, cytotoxic, and antioxidant activities. Fractions with promising biological activities were subjected to chromatographic techniques for the isolation of compounds, followed by structural elucidation using several spectroscopic techniques. Results: P. acutifolia stem bark showed a significant antimicrobial activity, where the ethyl acetate fraction was active against Syncephalastrum racemosum (7.81 MUg/ml) and Escherichia coli (3.9 MUg/ml). The cytotoxic activity against HEPG-2, HCT-116, and MCF-7 cell lines was highest in the petroleum ether fraction, using concentrations of 1, 2.5, 5, and 10 MUl/ml. The antioxidant activity was concentration dependent; ethyl acetate fraction showed the most predominant effect, with an IC50 of 197.1 MUg/ml. Five compounds were identified as narcissin (1), quercitrin (2), sweroside (3), gaertneroside (4), and plumieride (5). Conclusion: P. acutifolia was proved to have significant antimicrobial, cytotoxic, and antioxidant activities; the isolated compounds were flavonoids, iridoids, and secoiridoid, some of which were reported for the first time in genus Plumeria and/or family Apocynaceae. SUMMARY: P. acutifolia stem bark showed a significant antimicrobial activity, where the ethyl acetate fraction was active against Syncephalastrum racemosum and Escherichia coli. The cytotoxic activity against HEPG-2, HCT-116, and MCF-7 cell lines was highest in the petroleum ether fraction. The antioxidant activity was concentration dependent; ethyl acetate fraction showed the most predominant effect. Five compounds were identified as narcissin (1), quercitrin (2), sweroside (3), gaertneroside (4), and plumieride (5). Abbreviations used: mp: Melting point, NMR: Nuclear magnetic resonance, s: Singlet, d: Double, t: Triplet, q: Quartet, dd: Double-double, m: Multiplet, br: Broad. PMID- 29142407 TI - Molecular Docking Analysis of Phytic Acid and 4-hydroxyisoleucine as Cyclooxygenase-2, Microsomal Prostaglandin E Synthase-2, Tyrosinase, Human Neutrophil Elastase, Matrix Metalloproteinase-2 and -9, Xanthine Oxidase, Squalene Synthase, Nitric Oxide Synthase, Human Aldose Reductase, and Lipoxygenase Inhibitors. AB - Background: The phytoconstituents phytic acid and 4-hydroxyisoleucine have been reported to posses various biological properties. Objective: This prompted us to carry out the docking study on these two ligands (phytic acid & 4 hydroxyisoleucine) against eleven targeted enzymes. Materials and Methods: Phytic acid & 4-hydroxyisoleucine were evaluated on the docking behaviour of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-2 (mPGES-2), tyrosinase, human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and 9), xanthine oxidase (XO), squalene synthase (SQS), nitric oxide synthase (NOS), human aldose reductase (HAR) and lipoxygenase (LOX) using Discovery Studio Version 3.1 (except for LOX, where Autodock 4.2 tool was used). Results: Docking and binding free energy analysis revealed that phytic acid exhibited the maximum binding energy for four target enzymes such as COX-2, mPGES-2, tyrosinase and HNE. Interestingly, we found that 4-hydroxyisoleucine has the potential to dock and bind with all of the eleven targeted enzymes. Conclusion: This present study has paved a new insight in understanding 4-hydroxyisoleucine as potential inhibitor against COX-2, mPGES-2, tyrosinase, HNE, MMP 2, MMP 9, XO, SQS, NOS, HAR and LOX. SUMMARY: 4-hydroxyisoleucine has the potential to dock and bind with all 11targeted enzymes such as (cyclooxygenase-2 [COX-2], microsomal prostaglandin E synthase-2 [mPGES-2], tyrosinase, human neutrophil elastase [HNE], matrix metalloproteinase [MMP-2 and -9], xanthine oxidase, squalene synthase, nitric oxide synthase, human aldose reductase, and lipoxygenase)Moreover, docking studies and binding free energy calculations revealed that phytic acid exhibited the maximum binding energy for four target enzymes such as COX-2, mPGES-2, tyrosinase, and HNE; however, for other six target enzymes, it fails to dock. Abbreviations used: COX-2: Cyclooxygenase-2, mPGES-2: Microsomal prostaglandin E synthase-2, HNE: Human neutrophil elastase, MMP-2 and -9: Matrix metalloproteinase-2 and -9, XO: Xanthine oxidase, SQS: Squalene synthase, NOS: Nitric oxide synthase, HAR: Human aldose reductase, LOX: Lipoxygenase, ADME: Absorption, distribution, metabolism, and excretion, TOPKAT: Toxicity Prediction by Computer-assisted Technology. PMID- 29142408 TI - Correlation Between Polyphenol Oxidase (PPO) Activity and Total Phenolic Contents in Crocus sativus L. Corms During Dormancy and Sprouting Stages. AB - : Purification and characterization of polyphenol oxidase (PPO) enzyme and determination of total phenolic contents during dormancy and sprouting stages in Crocus sativus corms were performed. PPO enzyme was purified by ammonium sulfate precipitation and ion-exchange chromatography using DEAE-Sephadex A25 and two isoenzymes were obtained on the SDS-PAGE, which corresponded to molecular weights of 70 and 54 kDa. The Km values of the enzyme were 4.87 and 2.12 mM for l-DOPA in dormancy and waking stages, respectively. Also, enzyme showed higher Vmax values of 0.026 (DeltaOD.min-1) in dormancy compared with the value of 0.019 (DeltaOD.min-1) in waking corms. Results showed an inverse correlation between phenolic contents and PPO activity. Accordingly, it can be concluded that as plant progressed through sprouting stage, in contrast to polyphenol oxidase activity, there was a significant increase in total amount of phenolic compounds, as determined by Folin-Ciocalteu method and water and aqueous ethanol extractions. SUMMARY: Purification of polyphenol oxidase enzyme using DEAE Sephadex A25 in Crocus sativus corms.Characterization of polyphenol oxidase enzyme.Comparison of PPO enzyme characteristics in two different physiologic stages of dormancy and sprouting.Determination of phenolic contents.Correlation between phenolic contents and PPO activity during sprouting and dormancy. Abbreviations used: PPO: Polyphenol Oxidase, DEAE-Sephadex: Diethylaminoethyl Sephadex, SDS-PAGE: Sodium Dodecyl Sulfate- Polyacrylamide Gel Electrophoresis, DOPA: Dihydroxyphenylalanine, PEG: Polyethylene Glycol. PMID- 29142410 TI - Methanolic Extract of Costus pictus D. DON Induces Cytotoxicity in Liver Hepatocellular Carcinoma Cells Mediated by Histone Deacetylase Inhibition. AB - Background: Leaves of Costus pictus D. Don, (insulin plant) are used as dietary supplement for the treatment of diabetes. Objective: The antidiabetic activity of this plant is well documented, but its activity on different cell types and mechanism remains unknown. Thus, the present study evaluates the cytotoxicity of C. pictus methanolic extract (CPME) against various cancer and normal cells. Materials and Methods: Dried leaves of C. pictus were extracted using methanol and were subjected to histone deacetylase (HDAC) inhibition and toxicity studies. Results: The CPME displayed a selective toxicity toward tested cancer cells in a dose- and time-dependent manner. CPME exhibited significant cytotoxicity on Liver hepatocellular carcinoma cells (Hep G2) (half maximal inhibitory concentration IC50 = 6.7 mg/ml). Since CPME demonstrates both antidiabetic, anticancer activity, and HDAC enzyme play a detrimental role in both the complications, we have evaluated the CPME-induced HDAC regulation on Hep G2 cell lines. CPME showed a notable HDAC inhibition (55%). Furthermore, CPME did not show any genotoxicity or membrane instability at the tested concentrations. Conclusion: CPME demonstrates selective cytotoxicity toward tumor cells at a lower concentration through HDAC inhibition. SUMMARY: C. pictus is used as munching supplementary food for the treatment of diabetesCPME selectively induces cytotoxicity in cancer cells leaving normal cells healthySelective toxicity to cancer cells are attributed by the inhibition of HDAC enzymeCPME did not show any genotoxicity and membrane instability in blood cellsCPME could be potential source of HDAC inhibitor. Abbreviations used: A549: Human lung carcinoma cells, CPME: Costus pictus methanolic extract, DMEM: Dulbecco's modified eagle's medium, DMSO: Dimethyl sulfoxide, ELISA: Enzyme-linked immunosorbent assay, 5-FU: 5 Fluorouracil, Hep G2: Liver hepatocellular carcinoma cells, HEK-293: Human embryonic kidney cells, Hela: Human cervical carcinoma cells, HT-29: Human colorectal adenocarcinoma cells, HDAC: Histone deacetylase, IC50: Half maximal inhibitory concentration, MCF-7: Human breast adenocarcinoma cells, MDA-MB-435S: Human breast cancer cells, MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazoliumbromide, NFF: Neonatal foreskin fibroblasts, PHA: Phytohemagglutinin, PBS: Phosphate buffer saline, RPMI-1640: Roswell Park Memorial Institute Medium. PMID- 29142409 TI - Reversible Testicular Toxicity of Piperine on Male Albino Rats. AB - Background: Piperine was widely used in traditional medicine for inducing sterility and abortion. Objective: To evaluate the effect of the piperine on testis of male albino rats. Materials and Methods: Adult male rats were divided into four groups (n = 12). Group I (control): Rats were given vehicle p.o. i.e. 0.5% carboxymethyl cellulose in normal saline daily for 60 days, Group II (ED): Rats received piperine at a dose of 10 mg/kg body weight (b.w.) daily, Group III (E4D): Rats received piperine at a dose of 10 mg/kg b.w. on every 4th day, Group IV (E7D): Rats received piperine at a dose of 10 mg/kg b.w. on every 7th day. Half of the animals from each group were sacrificed after the treatment period (60 days), and the remaining were kept for drug-free withdrawal period (60 days) and then sacrificed. Results: Piperine significantly decreased the reproductive organ weights in groups ED and E4D. Piperine induced hormonal imbalance by altering the serum levels of follicle-stimulating hormone, luteinizing hormone, sex hormone binding globulin, serum, and testicular testosterone in groups ED and E4D. Furthermore, piperine decreased the activity of germ cell markers and Leydig cellular steroidogenic enzymes in the groups ED and E4D after 60 days. All the above-altered values returned to normal levels after withdrawal period. Histopathological findings also supported the above findings. Conclusion: From the above data, it can be concluded that piperine could be a good lead molecule for the development of reversible oral male contraceptive. SUMMARY: Piperine was employed for the contraceptive purposes in traditional medicinePiperine significantly impaired the spermatogenesis by decreasing the testicular hormone synthesis in groups ED and E4DPiperine disrupted the testicular antioxidant system by promoting the ROS production and hydroxyl radical generation in rat testis in groups ED and E4DHistopathological evidence supported the disruption of spermatogenesis by piperineAll the effects of piperine after the treatment period (i.e. 60 days) were back to normal after the withdrawal period (i.e., after 120 days). PMID- 29142411 TI - The Effect of Polyherbal Medicines Used for the Treatment of Tuberculosis on Other Opportunistic Organisms of Humans Infected with Tuberculosis. AB - Background: In many immunocompromised patients, opportunistic bacterial and fungal infections are common. Polyherbal medicines examined in this study are used by the indigenous people of South Africa for the treatment of tuberculosis (TB) and other opportunistic infections associated with TB. Objective: To evaluate the antibacterial and antifungal activity of nine polyherbal remedies against four Gram-positive and Gram-negative bacteria respectively and three fungi. Materials and Methods: Agar dilution method was used to determine the minimum inhibitory concentration (MIC) of the remedies against the organisms. Results: The inhibitory activity of the polyherbal medicines based on the overall MIC revealed that HBfs and FB remedies were the most active remedies against the bacterial isolates at the concentration of 2.5 mg/mL, followed by HBts remedy at 5.0 mg/mL. However, the MIC valves of KWTa, KWTb, KWTc, HBss, EL and AL remedies were higher than 5.0 mg/mL which was the highest concentration used. Only KWTa remedy showed activity against Aspergillus niger and Aspergillus fumigatus with the MIC value of 2.5 mg/mL. While KWTc and HBts had the highest activity at 1.25 mg/mL against Candida albicans, the remaining remedies were active at 2.5 mg/mL. Conclusion: This study revealed that some of these polyherbal formulations have activities against some of the opportunistic bacterial and fungal isolates associated with TB patients. The capability of these remedies to inhibit the organisms is an indication that they are a potential broad-spectrum antimicrobial agent. However, the remedies that are inactive might contain stimulant effects on the immune system. SUMMARY: In the Eastern Cape Province of South Africa, no study has been reported on the effect of polyherbal remedies used for the treatment of TB on the opportunistic pathogen. This study therefore revealed that some of the polyherbal medicines possess activity against bacterial and fungal pathogens. Abbreviations used: TB: Tuberculosis; MIC: Minimum Inhibitory Concentration; CFU/ML: Colony Forming Unit Per Mill. PMID- 29142412 TI - Tyrosinase Inhibitory Activities of Carissa opaca Stapf ex Haines Roots Extracts and Their Phytochemical Analysis. AB - Objective: Carissa opaca is a medicinal plant with rich folkloric applications. The present research was conducted to explore the tyrosinase inhibitory potential of aqueous decoction (AD) and methanolic extract (ME) of roots of C. opaca and its fractions in various solvents and their phytochemical analysis. Materials and Methods: AD of the dried powdered roots of C. opaca was prepared by boiling in water. ME was prepared by cold maceration. Its fractions were obtained in solvents of increasing polarity, i.e., hexane, chloroform, ethyl acetate, n butanol, and water. The biomass left after extraction with methanol was boiled in water to get its decoction Biomass aqueous decoction (BAD). Tyrosinase inhibitory activities of the samples were studied according to a reported method. Chemical compounds in the samples were identified by gas chromatography-mass spectrometry (GC-MS). Results: The AD, BAD, and ME and its fractions displayed remarkable tyrosinase inhibitory activity. The IC50 of AD was 23.33 MUg/mL as compared to 15.80 MUg/mL of the standard arbutin and that of BAD was 21.24 MUg/mL. The IC50 of ME was 34.76 MUg/mL while that of hexane, chloroform, ethyl acetate, n butanolic, and aqueous fractions was 21.0, 44.73, 43.40, 27.66, and 25.06 MUg/mL, respectively. The hexane fraction was thus most potent followed by aqueous fraction. By phytochemical analysis, campesterol, stigmasterol, gamma-sitosterol, alpha-amyrin, 9,19-cyclolanostan-3-ol, 24-methylene-,(3 beta)-, lupeol, lup 20(29)-en-3-one, lup-20(29)-en-3-ol, acetate,(3 beta)-, 2(1H) naphthalenone, 3,5,6,7,8,8a-hexahydro-4,8a-dimethyl-6-(1-methylethenyl)-, and 2,3,3-trimethyl-2 (3-methylbuta-1,3-dienyl)-6-methylenecyclohexanone were identified in the extracts by GC-MS. Other compounds included fatty acids and their esters. Some of these compounds are being first time reported here from this plant. Conclusions: The roots extracts exhibited considerable tyrosinase inhibitory activities, alluding to a possible application of the plant in cosmetic as whitening agent subject to further pharmacological studies. SUMMARY: The present study aimed to explore the tyrosinase inhibitory potential of aqueous decoction and methanolic extract of roots of Carissa opaca and its fractions in various solvents and their phytochemical constituents. GCMS analysis was conducted to identify the phytochemicals. The extracts and fractions of C. opaca roots showed remarkable anti-tyrosinase activities alluding to their possible application to treat disorders related to overproduction of melanin. Abbreviations used: AD: Aqueous decoction; ME: Methanolic extract; BAD: Biomass aqueous decoction; GC-MS: Gas chromatography-mass spectrometry. PMID- 29142413 TI - Antiurolithiatic Potential of Neeri against Calcium-Oxalate Stones by Crystallization Inhibition, Free Radicals Scavenging, and NRK-52E Cell Protection from Oxalate Injury. AB - Background: Neeri is a well-established polyherbal formulation prescribed for renal stones by the physicians but has not been experimentally evaluated for its antiurolithiatic potential using cell-lines. Objective: This study is aimed to scientifically substantiate the antiurolithiatic effect of Neeri extract (NRE) through calcium oxalate (CaOx) crystallization inhibition, scavenging of free radicals, and protection of renal tubular epithelial NRK-52E cells from oxalate induced injury. Materials and Methods: The crystallization inhibition was studied by turbidimetric assay while the free radical scavenging potential was determined for superoxide and nitric oxide (NO) radicals. The cytoprotective effect against oxalate-induced injury was assessed by estimating lactate dehydrogenase (LDH) leakage and determining cell viability using 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Results: NRE significantly inhibited the CaOx crystallization in a concentration-dependent manner and also scavenged superoxide (IC50 302.88 MUg/ml) and NO (IC50 300.45 MUg/ml) free radicals. It did not show any significant cytotoxicity for NRK-52E cells till the highest dose (500 MUg/ml) and found to be safe. When NRK-52E cells, injured by exposing to oxalate crystals for 24 h, were treated with NRE, it appreciably prevented the cell injury in a dose-dependent manner. It significantly decreased the elevated LDH leakage toward normal range and improved renal cell viability (82.37% +/- 0.87%), hence, prevented growth and retention of crystals. Conclusion: The experimental findings concluded that Neeri is a potent antiurolithiatic formulation that inhibited CaOx crystallization and prevented tubular retention of crystals by protecting the renal cells against oxalate-induced injury as well as reducing the oxidative stress by scavenging free radicals. SUMMARY: Neeri extract significantly (P < 0.001) inhibited the in vitro crystallization (88.11% +/- 7.70%) of calcium oxalateIt reduced oxidative stress by scavenging superoxide and nitric oxide free radicalsIt significantly (P < 0.001) improved the cell viability by inhibiting the leakage of lactate dehydrogenase in a dose-dependent manner. Abbreviations used: Ac: Absorbance of control, At: Absorbance of test, ANOVA: Analysis of variance, CaOx: Calcium oxalate, DMEM: Dulbecco's Modified Eagle's Medium, DMSO: Dimethyl sulfoxide, EDTA: Ethylenediaminetetraacetic acid, FBS: Fetal bovine serum, INT: Iodonitrotetrazolium, LDH: Lactate dehydrogenase, M: Molar, ml: Milliliter, mM: Millimolar, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, NAD: Nicotinamide adenine dinucleotide, NADPH: Nicotinamide adenine dinucleotide phosphate, NBT: Nitro blue tetrazolium, nm: Nanometer, NO: Nitric oxide, NRE: Neeri extract, PMS: Phenazine methosulfate, ROS: Reactive oxygen species, Sc: Slope of the graph of control, SEM: Standard error of mean, Si: Slope of the graph with inhibitor, U/I: International unit, mg: Microgram, ml: Microliter. PMID- 29142414 TI - Growth-arresting Activity of Acmella Essential Oil and its Isolated Component D Limonene (1, 8 P-Mentha Diene) against Trichophyton rubrum (Microbial Type Culture Collection 296). AB - Background: Spilanthes acmella is used as a remedy in toothache complaints by the tribal people of Western part of Odisha, India. Objective: The objective of this study was to study the growth-arresting activity of an indigenous Acmella essential oil (EO) (S. acmella Murr, Asteraceae) and its isolated component, d limonene against Trichophyton rubrum (microbial type culture collection 296). Materials and Methods: The EO was extracted from flowers of indigenous S. acmella using Clevenger's apparatus and analyzed by gas chromatography-mass spectrometry (GC-MS). High pressure liquid chromatography (HPLC) was carried out to isolate the major constituent. The isolated fraction was subjected to fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). The antidermatophytic activity was screened for using "disc diffusion" and "slant dilution" method followed by optical, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) studies. The molecular dockings were made between d-limonene with cell wall synthesis-related key enzymes (14 methyl deaminase and monooxygenase). Results: The GC-MS analysis EO had inferred the presence of 7 number of major (>=2%) components. The component with highest peak area (%) was found to be 41.02. The HPLC-isolated fraction was identified as d limonene (1,8 p-Mentha-diene) by FTIR and NMR. Qualitative and quantitative assays had suggested the growth inhibitory activity of Acmella EO and its component. Shrinkage, evacuation, cell wall puncture, and leakage of cellular constituents by the activity of Acmella oil and d-limonene were evidenced from optical, SEM, and TEM studies. The computer simulation had predicted the binding strengths of d-limonene and fluconazole with dermatophyte cell wall enzymes. Conclusion: There could have been synergistic action of all or some of compounds present in indigenous Acmella EO. SUMMARY: There was presence of seven number of (d-limonene, ocimene, beta-myrcene, cyclohexene, 3-(1, 5-dimethyl-4-hexenyl)-6 methylene, beta-caryophyllene, and beta-sesquiphellandrene and beta-phellandrene) major components in the indigenous Acmella essential oilThe d-limonene content was 41.02% in the indigenous oilThe antidermatophytic activity of Acmella essential oil could have been attributable to its chemotypes. Abbreviations used: degrees C: Degree centigrade; w/v: Weight/volume; TS: Transverse section; min: minute; Hz: hertz: h: Hr. PMID- 29142415 TI - Are Polyunsaturated Fatty Acid Metabolites, the Protective Effect of 4 hydroxytyrosol on Human Red Blood Cell Membranes and Oxidative Damage (4 hydroxyalkenals) Compatible in Hypertriglyceridemic Patients? AB - Background: Increased levels of malondialdehyde (MDA) and 4-hydroxynonenal (HNE) are demonstrated in plasma of uremic patients. A study showed that the comparison of erythrocytes of healthy and diseased patients (obese, hypertensive, and Type 2 diabetics) with age is associated to a disturbed oxidant/antioxidant balance when obesity is associated with hypertension. 4-hydroxytyrosol is shown to significantly protect red blood cells (RBCs) from oxidative damage (4-HNE). In literature, there are partial discussions on the role of lipids and their oxidation products. The products of degradation of membrane proteins are observed as self-consisting products without interrelations with membrane lipids. Objective: The aim of this study is to evaluate the role of polyunsaturated fatty acid (PUFA) metabolites on oxidative damage (4-hydroxy-alkenals) in RBCs of hypertriglyceridemic patients after membrane treatment with 4-hydroxytyrosol. Materials and Methods: The authors optimize the isolation of RBC ghosts and spectrophotometric method to measure free 4-hydroxyalkenals in human RBC membranes and investigated the effect on oxidative damage in human erythrocyte membranes and in vitro 4-hydroxytyrosol treatment to evaluate the membrane lipids reducible by this phenol. Results: Plasma triglyceride levels in patients are clearly higher than in controls. Moreover, total membrane proteins data are similar to previous described. The normalized alkenals levels are significantly enhanced in hyperlipemic patients in comparison to normoglyceridemic controls. After the 4-hydroxytyrosol action, lipid metabolites substantially decrease. The ratio of oxidized lipids (MDA + HNE) and membrane proteins data are similar to previously described ones. Conclusion: According to experimental data, the accumulation of the alkenals in RBC membrane could be produced either by partial PUFA oxidation contained in glycerides and plasma glycerides and by glycerides into plasma membrane recycled RBC. SUMMARY: Hypertriglyceridemia induces oxidative stress in human red blood cell (RBC) membranesOxidative stress causes increased plasma membrane total protein concentration and hydroxynonenal and malondialdehyde levelsThe authors optimize the isolation of RBC ghosts and spectrophotometric method to measure free 4-hydroxyalkenals in human RBC membranesAfter the reduction with 4-hydroxytyrosol, oxidized lipid concentration significantly decrease. Abbreviations used: RBC: Red blood cell; MDA: Malondialdehyde; HNE?HAE: 4-hydroxyalkenals; LPO: Lipid peroxidation; ROS: Reactive oxygen species; ORAC: Oxygen Radical Absorbance Capacity. PMID- 29142416 TI - Protective Effect of Pluchea lanceolata against Aluminum Chloride-induced Neurotoxicity in Swiss Albino Mice. AB - Background: Aluminum chloride (AlCl3) is a known potent environmental neurotoxin causing progressive neurodegenerative changes in the brain. The herb Pluchea lanceolata is commonly known as "Rasana" and used as a nerve tonic in neuroinflammatory conditions in Indian system of medicine. Objective: To evaluate the neuroprotective activity of hydroalcoholic extract of P. lanceolata in chronic AlCl3-induced neurotoxicity in Swiss albino mice. Materials and Methods: Albino mice were categorized into four different groups; Group 1served as vehicle control, Group 2 mice were administered with AlCl3, 40 mg/kg body weight by intraperitoneal route for 45 consecutive days. Groups 3 and 4 mice were administered with AlCl3, 40 mg/kg body weight intraperitoneal for 45 consecutive days along with hydroalcoholic extract of P. lanceolata at 200 and 400 mg/kg body weight. Results: Chronic administration of AlCl3 resulted in behavioral deficits, triggered lipid peroxidation, increased acetylcholinesterase (AChE) activity, and histological alterations. Co-administration of hydroalcoholic extract of P. lanceolata attenuated many of the AlCl3-induced alterations such as behavioral, lipid peroxidation, AChE, and histological changes of brain tissue. Conclusion: The results of the present study have demonstrated the protective role of hydroalcoholic extract of P. lanceolata against AlCl3-induced neurotoxicity in Swiss albino mice. The neuroprotective efficacy of P. lanceolata can help reduce the symptoms caused by toxic protein aggregates in several degenerative diseases. SUMMARY: The hydro alcoholic extract of Pluchea lanceolata showed neuroprotective activity in albino mice against AlCl3 toxicityThe benefits of Pluchea lanceolata against AlCl3 toxicity includes reduced lipid peroxidation and acetylcholine esterase activity with improved behavioral functionsThe hydro alcoholic extract of Pluchea lanceolata rendered protection against AlCl3 in forebrain, midbrain, cerebellum and hippocampusTherefore Pluchea lanceolata holds pharmacological potentials for treating diseases associated with neuronal toxicity. Abbreviations used: HAPL: Hydro alcoholic extract of Pluchea lanceolata; CAT: Catalase; GSH-Px: Glutathione peroxidase; SOD: Superoxide dismutase; TBARS: Thio-barbituric acid reactive substances; MDA: Malondialdehyde; AChE: Acetylcholine esterase; AOT: Acute oral toxicity; CNS: Central nervous system; H2O2: Hydrogen peroxide; ML: molecular layer; GL: granular layer; MC: microcytic changes; BV: blood vessels; DG: dentate gyrus; PC: pyramidal cells; LD: Lethal dose; ANOVA: Analysis of variance; SEM: Standard error of mean; PCL: Pyramidal cell layer; OCL: Outer granular layer; BV: blood vessels; PM: Pia mater. PMID- 29142417 TI - Inhibition of Phosphorylated c-Jun NH(2)-terminal Kinase by 2',4'-dihydroxy-6 methoxy-3,5-dimethylchalcone Isolated from Eugenia aquea Burm f. Leaves in Jurkat T-cells. AB - Background: Indonesian medicinal plants have been used for their anticancer activity for decades. However, the therapeutic effects of medicinal plants have not been fully examined scientifically. As cancer is a major health problem worldwide, searching for a new anticancer compound has attracted considerable attention. Our previous study found that 2',4'-dihydroxy-6-methoxy-3,5 dimethylchalcone, an active compound isolated from leaves of Indonesian medicinal plants Eugenia aquea Burm f. (Myrtaceae), had anticancer activity in MCF-7 human breast cancer cells through induction of apoptosis. Objective: To investigate the molecular mechanism of 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone antiproliferative activity. Materials and Methods: Leaves of E. aquea were extracted by ethanol, fractionated by ethyl acetate, n-hexane, or water, and isolated for its active compound. Jurkat T-cells were treated with 2',4' dihydroxy-6-methoxy-3,5-dimethylchalcone for 12 and 24 h, and a cell viability assay and real-time-reverse transcriptase polymerase chain reaction for interleukin-2 (IL-2) mRNA measurement were performed. The effects of active compound to mitogen-activated protein kinases were also examined to investigate the mechanism of its antiproliferative activity. Results: 2',4'-dihydroxy-6 methoxy-3,5-dimethylchalcone inhibited Jurkat T-cell proliferation with a half maximal inhibitory concentration of 59.5 mM. Although IL-2 mRNA expression was slightly increased after treatment, it inhibited c-Jun N-terminal kinase expression but not p38 and extracellular signal-regulated kinase expression. Conclusions: Our study indicated that the molecular mechanism mediating the antiproliferative activity of 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone may be attributed to the stimulation of an immunological microenvironment in the cells. SUMMARY: 2',4'-dihydroxy-6-methoxy-3,5-dimethylchalcone was isolated from Eugenia aquea. The antiproliferative activity of 2',4'-dihydroxy-6- methoxy-3,5 dimethylchalcone significantly showed in Jurkat T-cells with a half maximal inhibitory concentration of 59.5 mM through inhibition of c-Jun N-terminal kinase phosphorylation. Interleukin-2 mRNA expression was also slightly increased after treatment with the compound, and this result may be indicated to the stimulation of the immunological microenvironment in T-cells. Abbreviations used:E. aquea: Eugenia aquea, IL-2: Interleukin-2, MAPK: Mitogen-activated protein kinase, ERKs: Extracellular signal-regulated kinases, JNKs: c-Jun N-terminal kinases, p38: p38 MAPK, PI3K: Phosphatidylinositol-3 kinase, IC50: Half maximal inhibitory concentration. PMID- 29142418 TI - Marantodes pumilum (Blume) Kuntze Inhibited Secretion of Lipopolysaccharide- and Monosodium Urate Crystal-stimulated Cytokines and Plasma Prostaglandin E2. AB - Background: Marantodes pumilum is traditionally used for dysentery, gonorrhea, and sickness in the bones. Previous studies revealed its antibacterial and xanthine oxidase inhibitory activities. Objective: To evaluate the inhibitory effects of three M. pumilum varieties on the secretion of lipopolysaccharide (LPS)- and monosodium urate crystal (MSU)-induced cytokines and plasma prostaglandin E2 (PGE2) in vitro. Materials and Methods: The leaves and roots of M. pumilum var. alata (MPA), M. pumilum var. pumila (MPP), and M. pumilum var. lanceolata (MPL) were successively extracted with dichloromethane (DCM), methanol, and water. Human peripheral blood mononuclear cells and ELISA technique were used for the cytokine assay, whereas human plasma and radioimmunoassay technique were used in the PGE2 assay. Flavonoids content was determined using a reversed-phase high-performance liquid chromatography. Results: DCM extract of MPL roots showed the highest inhibition of LPS-stimulated cytokine secretion with IC50 values of 29.87, 7.62, 5.84, 25.33, and 5.40 MUg/mL for interleukin (IL) 1alpha, IL-1beta, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha, respectively; while that of plasma PGE2 secretion was given by DCM extract of MPP roots (IC50 31.10 MUg/mL). Similarly, the DCM extract of MPL roots demonstrated the highest inhibition against MSU-stimulated IL-1alpha, IL-1beta, IL-6, IL-8, TNF-alpha, and PGE2 secretion with IC50 values of 11.2, 8.92, 12.29, 49.51, 9.60, and 31.58 MUg/mL, respectively. Apigenin in DCM extracts of MPL (0.051 mg/g) and MPP (0.064 mg/g) roots could be responsible for the strong inhibitory activity against IL-1beta, IL-6, TNF-alpha, and PGE2. Conclusion: The results suggested that DCM extracts of MPL and MPP roots are potential anti-inflammatory agents by inhibiting the secretion of LPS- and MSU-stimulated pro-inflammatory cytokines and PGE2. SUMMARY: Amongst 18 tested extracts, DCM extracts of MPL and MPP roots remarkably inhibited LPS- and MSU-stimulated pro-inflammatory cytokines and PGE2 secretionPhytochemical analysis was performed for the active extracts using RP HPLC systemThe presence of flavonoids particularly apigenin could be responsible for the anti-inflammatory activity. Abbreviations used: BSA: Bovine serum albumin, COX-2: Cyclooxygenase-2, CPM: Count per minute, DAMP: Danger-associated molecular pattern, DCM: Dichloromethane, DMSO: Dimethyl sulfoxide, ELISA: Enzyme linked immunosorbent assay, FBS: Fetal bovine serum, H2O: Water, HEPES: 4-(2 Hydroxyethyl)piperazine-1-ethanesulfonic acid, HMC-1: Human mast cell-1, HMGB1: High-mobility group box 1, ICAM: Intercellular adhesion molecule, IFN: Interferon, IgG: Immunoglobulin G, IKK: IkB kinase, IL: Interleukin, iNOS: Inducible nitric oxide synthase, LPS: Lipopolysaccharide, MeOH: Methanol, MPA: Marantodes pumilum var. alata, MPL: Marantodes pumilum var. lanceolata, MPP: Marantodes pumilum var. pumila, MSU: Monosodium urate, MTT: Methylthiazole tetrazolium, NF-kappaB: Nuclear factor-kappa B, NLR: NOD-like receptor, NLRP3: NLR family pyrin domain containing protein 3, NO: Nitric oxide, NOD: Nucleotide binding oligomerization domain, NSAID: Nonsteroidal anti-inflammatory drug, PAMP: Pathogen-associated molecular pattern, PBMC: Peripheral blood mononuclear cell, PBS: Phosphate buffered saline, PGE2: Prostaglandin E2, PMACI: Phorbol-12 myristate 13-acetate and calcium ionosphere A23187, PRR: Pathogen recognition receptor, PTFE: Polytetrafluoroethylene, RIA: Radioimmunoassay, RIG: Retinoic acid-inducible gene I, RLR: RIG I-like receptor, RP-HPLC: Reversed-phase high performance liquid chromatography, RPMI-1640: Roswell Park Memorial Institute 1640, TLR: Toll-like receptor, TNF: Tumor necrosis factor, VCAM: Vascular cell adhesion molecule. PMID- 29142419 TI - Antipsoriatic and Anti-inflammatory Studies of Berberis aristata Extract Loaded Nanovesicular Gels. AB - Objective: Novel nanovesicular gel of Berberis aristata extract was developed and evaluated for its anti-inflammatory and antipsoriatic activity. Materials and Methods: Transferosomes were prepared using soya phosphatidylcholine and edge activators (Tween 80, Span 80, and sodium deoxycholate) by a modified lipid film hydration technique using rotary evaporator and evaluated for various parameters. The quantification and standardization of extract have been carried out using its alkaloid content as berberine as biomarker. Topical application of imiquimod (IMQ) (immune modifier) on the shaved back of mice developed psoriasis-like inflammation followed by histopathological study of inflamed skin. Results: The size of transferosomes was in the range of 265-345 nm whereas polydispersity index ranges from 0.10 to 0.63, and for zeta potential, it was from -19.3 to 43.3 mV. Transferosomes were further added to Carbopol 934P for gel formation and subsequently evaluated for their physicochemical properties. Their efficacy against inflammation, IMQ-induced psoriasis, and skin sensitivity was compared with conventional formulation (commercial formulation-Angle Gloss, Phytolab Pvt. Ltd.). Percent inhibition of edema by transferosomal gel (55.76%) was more as compared to conventional gel of extract (33.5%) found out by Carrageenan-induced paw edema method. Primary irritation index was found to be <0.4 inferring its safe use for topical formulation. Conclusion: Histopathological report showed that, in psoriasis-induced animal treated with topical application of extract loaded transferosomal gel showed a marked reduction in thickness of epidermis, length of rete ridges as compared to conventional gel formulation. It can be inferred that B. aristata extract loaded transferosomal gel can function as potential anti-inflammatory and antipsoriatic formulation. SUMMARY: The objective of the present research work was to prepare Berberis aristata extracts (roots, ethanolic 70%v/v) loaded transferosomal gel, to perform in vitro characterization and in vivo evaluation of their efficacy against inflammation as well as imiquimod (IMQ)-induced psoriasis in animalsThe remarkable enhancement in the in vitro release efficiency of B. aristata extract loaded transferosomal gel resulted in improved anti-inflammatory activity. The prepared novel formulation of B. aristata has also shown its efficacy against IMQ-induced psoriasis. Abbreviations used: SPC: Soyaphosphatidylcholine, PDI: Polydispersity index, IMQ: Imiquimod, EA: Edge activator, BE: Berberine, TEM: Transmission electron microscopy, PBS: Phosphate buffered saline, H and E: Hematoxylin and eosin, ZP: Zeta potential, EE: Entrapment efficiency. PMID- 29142420 TI - Exploring the Cytotoxic Potential of Triterpenoids-enriched Fraction of Bacopa monnieri by Implementing In vitro, In vivo, and In silico Approaches. AB - Background: Bacopa monnieri (BM) is a herbaceous plant traditionally used from time immemorial in Ayurvedic and folklore medicines. We hypothesized that the extract of the whole plant might contain numerous molecules with having antitumor activities that could be very effective in killing of human cancer cells. Objectives: This work investigated anticancer activity of bioactive fraction of BM. Materials and Methods: The hydroalcoholic extract of BM was fractionated with different solvent, namely, hexane, dichloromethane (DCM), acetone, methanol, and water. The in vitro anticancer activity was performed against various Human Cancer Cell lines, namely, Colon (HT29, Colo320, and Caco2), Lung (A549), Cervix (HeLa, SiHa), and Breast (MCF-7, MDAMB-231). Further, DCM fraction was evaluated in vivo for anticancer activity against Ehrlich ascites carcinoma (EAC) tumor bearing mice since it showed the best cytotoxicity at 72 h (IC50 41.0-60.0 ug/mL). The metabolic fingerprinting of these extract were carried out using high performance thin-layer chromatography along with quantification of bacoside A, bacoside B, cucurbitacin B, cucurbitacin E, and bittulinic acid. Results: Oral administration of DCM fraction at a dose of 40 mg/kg rendered prominent reduction of tumor regression parameters such as tumor weight, packed cell volume, tumor volume and viable tumor cell count as compared to the untreated mice of the EAC control group. The anticancer activity of DCM fraction may be due to the presence of large amount of bacoside A, B and cucurbitacins. The molecular docking studies of major metabolites with targeted proteins predicted the anticancer activity of DCM fraction which was in support of in vivo activity. Conclusion: The in vitro, in vivo, analytical and in silico studies on DCM fraction of Bacopa monieri has proved its great potential for development of anticancer phytopharmaceuticals. SUMMARY: A new HPTLC method has been developed and validated for the qualitative and quantitative analysis of bacoside A, B, cucurbitacin B, D, E and bittulinic acid in Bacopa monnieri extract. Enrichment of active anticancer metabolites was done by polarity based fractionations of hydroalcoholic extract of Bacopa. DCM fraction of a hydroalcoholic extract of Bacopa showed anticancer potential against human cancer cell line (IC50 41.0-60.0 ug/mL) and in EAC treated mice (at a dose of 40 mg/kg body weight). The anticancer activity of Bacopa may be due to the presence of bacosides and cucurbitacin and it was confirmed by in silico screening. Abbreviations used: DBM: DCM fraction of Bacopa monnieri; DCM: Dichloromethane; EAC: Ehrlich ascites carcinoma; HCT: Hematocrit; HGB: Hemoglobin; HPTLC: High performance thin layer chromatography; ICH: International council for Harmonisation; LOD: Limit of detection; LOQ: Limit of quantification; LYM: Lymphocytes; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular haemoglobin concentration (MCHC); MCV: Mean corpuscular volume; MTT: 3-(4, 5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PLT: Platelet; RBC: Red blood cell; RDW: Red blood cell distribution width; RSD: Relative standard deviation; WBC: White blood cells. PMID- 29142421 TI - Extract of Bauhinia vahlii Shows Antihyperglycemic Activity, Reverses Oxidative Stress, and Protects against Liver Damage in Streptozotocin-induced Diabetic Rats. AB - Background: Several studies have affirmed the effectiveness of some Bauhinia plants as antihyperglycemic agents. Objective: We investigated the possible effect of Bauhinia vahlii leaves extract in reducing hyperglycemia and reversing signs of organ damage associated with diabetes in streptozotocin (STZ) rat model. Materials and Methods: Both polar fraction of the B. vahlii leaves (defatted ethanolic extract [DEE]) and nonpolar fraction (n-hexane extract) were evaluated in vitro for alpha-glucosidase inhibition and 2,2-diphenyl-1-picrylhydrazyl radical scavenging potential. DEE was selected for further in vivo studies and was administered at two doses, i.e., 150 or 300 mg/kg to STZ-diabetic rats for 4 weeks. Results: Only DEE exhibited in vitro antioxidant and antihyperglycemic activities and its oral administration at both dose levels resulted in significant reduction in fasting blood glucose and glycated hemoglobin. Furthermore, signs of oxidative stress as indicated by hepatic reduced glutathione, nitric oxide, and malondialdehyde levels were completely reversed. In addition, histopathological examination and measurement of serum aspartate transaminase and alanine transaminase levels showed that DEE protected the liver from signs of liver pathogenesis when compared to diabetic untreated animals and those treated with metformin. Phytochemical analysis of DEE showed high flavonoids content with quercitrin as the major constituent along with other quercetin glycosides. Conclusion: This study strongly highlights the possible beneficial effect of B. vahlii leaves extract in relieving hyperglycemia and liver damage in STZ-diabetic rats and recommends further investigation of the value of quercetin derivatives in controlling diabetes and ameliorating liver damage associated with it. SUMMARY: The polar fraction of the Bauhinia vahlii leaves (defatted ethanolic extract [DEE]) exhibited both in vitro antioxidant activity in 2,2-diphenyl-1-picrylhydrazyl scavenging assay and strong alpha glucosidase inhibition while the nonpolar fraction (n-hexane extract) failed to show any activity in both assays. DEE was further investigated in streptozotocin induced diabetic rat model where oral administration of DEE at 2 doses (150 and 300 mg/kg) for 4 weeks resulted in significant reduction in fasting blood glucose and glycated hemoglobin and reversal of oxidative stress signs as indicated by measurement of hepatic reduced glutathione, nitric oxide, and malondialdehyde levels. In addition, histopathological examination and measurement of serum aspartate transaminase and alanine transaminase levels showed that DEE protected the liver from signs of pathogenesis observed in diabetic untreated rats. Phytochemical analysis of DEE showed high flavonoid content with quercitrin as the major constituent (62.9 +/- 0.18 mg/mg). Abbreviations used: ALT: Alanine transaminase, AST: Aspartate transaminase, DEE: Defatted ethanol extract, DPPH: 2,2-diphenyl-1-picrylhydrazyl, FBG: Fasting blood glucose, GAE: Gallic acid equivalent, GSH: Reduced glutathione, Hb1Ac: Glycated hemoglobin, HE: Hexane extract MDA: Malondialdehyde, QE: Quercetin equivalent, STZ: Streptozotocin, TAC: Total antioxidant capacity. PMID- 29142422 TI - Chemotaxonomic Diversity of Three Ficus Species: Their Discrimination Using Chemometric Analysis and Their Role in Combating Oxidative Stress. AB - Background: Genus Ficus (Moraceae) constitutes more than 850 species and about 2000 varieties and it acts as a golden mine that could afford effective and safe remedies combating many health disorders. Objectives: Discrimination of Ficus cordata, Ficus ingens, and Ficus palmata using chemometric analysis and assessment of their role in combating oxidative stress. Materials and Methods: Phytochemical profiling of the methanol extracts of the three Ficus species and their successive fractions was performed using high-performance liquid chromatography/electrospray ionization mass spectrometry. Their discrimination was carried out using the obtained spectral data applying chemometric unsupervised pattern-recognition techniques, namely, principal component analysis and hierarchical cluster analysis. In vitro hepatoprotective and antioxidant evaluation of the samples was performed using human hepatocellular carcinoma cells challenged by carbon tetrachloride (CCl4). Results: Altogether, 22 compounds belonging to polyphenolics, flavonoids, and furanocoumarins were identified in the three Ficus species. Aviprin is the most abundant compound in F. cordata while chlorogenic acid and psoralen were present in high percentages in F. ingens and F. palmata, respectively. Chemometric analyses showed that F. palmata and F. cordata are more closely related chemically to each other rather than F. ingens. The ethyl acetate fractions of all the examined species showed a marked hepatoprotective efficacy accounting for 54.78%, 55.46%, and 56.42% reduction in serum level of alanine transaminase and 56.82%, 54.16%, and 57.06% suppression in serum level of aspartate transaminase, respectively, at 100 MUg/mL comparable to CCl4-treated cells. Conclusion: Ficus species exhibited a no table antioxidant and hepatoprotective activity owing to their richness in polyphenolics and furanocoumarins. SUMMARY: Ficus cordata, Ficus ingens, and Ficus palmata were analyzed using high-performance liquid chromatography/electrospray ionization mass spectrometry that revealed their richness with polyphenolics and furanocoumarinsDiscrimination of the three species was performed using spectral data coupled with chemometrics that showed that F. palmata and F. cordata are chemically related to each other rather than F. ingensIn vitro hepatoprotective and antioxidant evaluation was performed using human hepatocellular carcinoma cells. The ethyl acetate fractions of all the examined species showed a marked hepatoprotective efficacyFicus species exhibited notable activities due to polyphenolics and furanocoumarins. Abbreviations used: ALT: Alanine transaminase, AST: Aspartate transaminase, CCl4: Carbon tetrachloride, DMEM: Dulbecco's Modified Eagle's medium, DMSO: Dimethyl sulfoxide, EDTA: Ethylenediaminetetraacetic acid, FBS: Fetal bovine serum, FCA: Ficus cordata remaining aqueous fraction, FCB: Ficus cordata n-butanol fraction, FCE: Ficus cordata ethyl acetate fraction, FCP: Ficus cordata petroleum ether fraction, FCT: Ficus cordata total methanol extract, FIA: Ficus ingens remaining aqueous fraction, FIB: Ficus ingens n-butanol fraction, FIE: Ficus ingens ethyl acetate fraction, FIP: Ficus ingens petroleum ether fraction, FIT: Ficus ingens total methanol extract, FPA: Ficus palmata remaining aqueous fraction, FPB: Ficus palmata n-butanol fraction, FPE: Ficus palmata ethyl acetate fraction, FPP: Ficus palmata petroleum ether fraction, FPT: Ficus palmata total methanol extract, GSH: Reduced glutathione, HepG2 cells: Human hepatocellular carcinoma, HPLC-ESI-MS: High-performance liquid chromatography/electrospray ionization mass spectrometry, and SOD: Superoxide dismutase. PMID- 29142423 TI - Bioactive Turmerosaccharides from Curcuma longa Extract (NR-INF-02): Potential Ameliorating Effect on Osteoarthritis Pain. AB - Background: Curcuma longa has long history of medicinal use in Ayurveda. A unique product NR-INF-02 was prepared from C. longa that was standardized to contain turmerosaccharides. Objective: The present study investigated the effect of turmerosaccharides rich fraction of NR-INF-02 on monosodium iodoacetate (MIA) induced OA pain animal model that mimics human OA. Further, the analgesic effect of turmerosaccharides rich fraction was compared to turmerosaccharides less fraction of NR-INF-02. Materials and Methods: OA pain was chemically induced by intra-articular administration of single dose of 25 MUl of 0.9% saline containing 0.3 mg MIA into the right knee of male albino Wistar rat. Turmerosaccharides rich fraction and turmerosaccharides less fraction (at 22.5, 45 and 90 mg/kg rat body weight dose levels) were administered as a single dose orally on day 5 of post MIA injection. OA pain was measured using hind limb weight-bearing ability at 1, 3, 6, and 24 h post-test substance administration on day 5. Results: Oral administration of turmerosaccharides rich fraction and turmerosaccharides less fraction (at 45 and 90 mg/kg) although significantly decreased the OA pain at all the intervals, the effect of turmerosaccharides rich fraction (57%) on OA pain was superior to turmerosaccharides less fraction (35%). Conclusion: Bioactive turmerosaccharides from C. longa extract contribute to the observed anti arthritic effect in rats. SUMMARY: Osteoarthritic pain was induced by intra articular injection of MIA into the right kneeSingle administration of TRF/TLF on day 5 resulted in dose-dependent significant reduction of OA painTRF showed better analgesic activity than TLFTRF at 45 and 90 mg/kg has similar effects on OA pain as that of tramadolTurmerosaccharides identified as bioactive constituents of C. longa extract. Abbreviations used: MIA: Monosodium iodoacetate; i.ar: Intra-articular; OA: Osteoarthritis; TRF: Turmerosaccharides rich fraction; TLF: Turmerosaccharides less fraction; PGE2: Prostaglandin E2; ROS: Reactive oxygen species. PMID- 29142424 TI - Apoptotic Effect of Nigella sativa on Human Lymphoma U937 Cells. AB - Objective: Nigella sativa is from botanical Ranunculaceae family and commonly known as black seed. Apoptotic effect of N. sativa and its apoptotic signaling pathways on U937 lymphoma cells are unknown. Materials and Methods: In this study, we investigated selective cytotoxic and apoptotic effects of N. sativa extract and its apoptotic mechanisms on U937 cells. In addition, we also studied selective cytotoxic activity of thymoquinone that is the most active essential oil of N. sativa. Results: Our results showed that N. sativa extract has selective cytotoxicity and apoptotic effects on U937 cells but not ECV304 control cells. However, thymoquinone had no significant cytotoxicity against on both cells. N. sativa extract increased significantly caspase-3, BAD, and p53 gene expressions in U937 cells. Conclusions: N. sativa may have anticancer drug potential and trigger p53-induced apoptosis in U937 lymphoma cells. SUMMARY: This is the first study showing the apoptotic effect of Nigella sativa extract on U937 cells. Abbreviations used: CI: Cytotoxicity index, DMEM: Dulbecco's Modified Eagle Medium, HL: Hodgkin's lymphoma, MTT: 3-(4,5-dimethy lthiazol-2yl)-2,5 diphenyl tetrazolium bromide, RPMI: Roswell Park Memorial Institute medium. PMID- 29142425 TI - Hypoglycemic, Hypolipidemic, and Wound Healing Potential of Quercetin in Streptozotocin-Induced Diabetic Rats. AB - Background: Among the dietary polyphenolic, quercetin is the most common compound available in vegetables and fruits. The phytochemicals are used to treat diabetic wounds and diabetes, and specifically dietary polyphenols are being extensively studied for their anti-inflammatory and antioxidant abilities. Objective: The objective of the study was to assess the hypoglycemic, hypolipidemic, and wound healing potential of quercetin in streptozotocin (STZ)-induced diabetic Wistar rats. Materials and Methods: Induction of diabetes was done by intraperitoneally administration of STZ at the dose of 55 mg/kg in Wistar rats. An excision wound was created in diabetic rats that were treated with quercetin (100 mg/kg) orally and quercetin ointment topically to evaluate the antidiabetic and wound healing potential of quercetin. Results: Repeated oral administration of quercetin along with topical application of quercetin ointment in diabetic rats normalized the altered blood glucose, hydroxyproline, and glucosamine levels. Topical application of quercetin ointment alone on the excised wound was sufficient enough to heal the wound area in diabetic rats. Conclusions: The result of the present study indicates that quercetin produces hypoglycemic effect in STZ induced diabetic rats and normalized plasma lipids and protein profiles. Besides, this quercetin also has an excellent wound healing property when applied topically on the wound area in diabetic rats. SUMMARY: Quercetin has hypoglycaemic and hypolipidemic potential in streptozotocin induced diabetes in wistar ratsDermal application along with oral administrations of quercetin has more effective in wound healing in diabetic animalsHistopathological studies of pancreas, skin and liver shows significant reduction in archaeological alterations on quercetin administrations in diabetic rats. Abbreviation used: STZ: Streptozotocin; CMC: Carboxy methyl cellulose; HDL: High density lipoproteins; LDL: low density lipoproteins. PMID- 29142426 TI - In Silico and In Vitro Anticancer Activity of Isolated Novel Marker Compound from Chemically Modified Bioactive Fraction from Curcuma longa (NCCL). AB - Background: Turmeric (Curcuma longa) is reported to possess wide array of biological activities. Herbal Medicament (HM) is a standardized hexane-soluble fraction of C. longa and is well known for its neuroprotective effect. Objective: In this study, we attempted to synthesize a novel chemically modified bioactive fraction from HM (NCCL) along with isolation and characterization of a novel marker compound (I). Materials and Methods: NCCL was prepared from HM. The chemical structure of the marker compound isolated from NCCL was determined from 1D/2D nuclear magnetic resonance, mass spectroscopy, and Fourier transform infrared. The compound so isolated was subjected to in silico and in vitro screenings to test its inhibitory effect on estrogen receptors. Results: Molecular docking studies revealed that the binding poses of the compound I was energetically favorable. Among NCCL and compound I taken for in vitro studies, NCCL had exhibited good anti-cancer activity over compound I against MCF-7, MDA MB-231, DU-145, and PC-3 cells. Conclusion: This is the first study about the synthesis of a chemically modified bioactive fraction which used a standardized extract since the preparation of the HM. It may be concluded that NCCL fraction having residual components induce more cell death than compound I alone. Thus, NCCL may be used as a potent therapeutic drug. SUMMARY: In the present paper, a standardized hexane soluble fraction of Curcuma longa (HM) was chemically modified to give a novel bioactive fraction (NCCL). A novel marker compound was isolated from NCCL and was characerized using various spectral techniques. The compound so isolated was investigated for in-silico screenings. NCCL and isolated compound was subjected to in-vitro anti-cancer screenings against MCF 7, MDA MB 231 (breast adenocarcinoma) and DU 145 and PC 3 cell lines (androgen independent human prostate cancer cells). The virtual screenings reveals that isolated compound has shown favourable drug like properties. NCCL fraction having residual components induces more cell death in these four cancer cell lines than isolated compound alone. Abbreviations used: HM: Herbal Medicament; NCCL: Chemically modified HM; FT-IR: Fourier transform-infrared spectroscopy; NMR: Nuclear magnetic resonance spectroscopy; MS: Mass spectroscopy; HPLC: High-performance liquid chromatography; ER: Estrogen receptor; MTT: 3-(4,5 dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide; MIC: Minimum inhibitory concentration; TAM: Tamoxifen KBr: Potassium bromide; DMSO: Dimethyl sulfoxide; ACN: Acetonitrile; PDB: Protein Data Bank; PDA: Photodiode array detector. PMID- 29142427 TI - Cinnamaldehyde, Cinnamic Acid, and Cinnamyl Alcohol, the Bioactives of Cinnamomum cassia Exhibit HDAC8 Inhibitory Activity: An In vitro and In silico Study. AB - Background: The altered expression of histone deacetylase family member 8 (HDAC8) has been found to be linked with various cancers, thereby making its selective inhibition a potential strategy in cancer therapy. Recently, plant secondary metabolites, particularly phenolic compounds, have been shown to possess HDAC inhibitory activity. Objective: In the present work, we have evaluated the potential of cinnamaldehyde (CAL), cinnamic acid (CA), and cinnamyl alcohol (CALC) (bioactives of Cinnamomum) as well as aqueous cinnamon extract (ACE), to inhibit HDAC8 activity in vitro and in silico. Materials and Methods: HDAC8 inhibitory activity of ACE and cinnamon bioactives was determined in vitro using HDAC8 inhibitor screening kit. Trichostatin A (TSA), a well-known anti-cancer agent and HDAC inhibitor, was used as a positive control. In silico studies included molecular descriptor Analysis molecular docking absorption, distribution, metabolism, excretion, and toxicity prediction, density function theory calculation and synthetic accessibility program. Results: Pharmacoinformatics studies implicated that ACE and its Bioactives (CAL, CA, and CALC) exhibited comparable activity with that of TSA. The highest occupied molecular orbitals and lowest unoccupied molecular orbitals along with binding energy of cinnamon bioactives were comparable with that of TSA. Molecular docking results suggested that all the ligands maintained two hydrogen bond interactions within the active site of HDAC8. Finally, the synthetic accessibility values showed that cinnamon bioactives were easy to synthesize compared to TSA. Conclusion: It was evident from both the experimental and computational data that cinnamon bioactives exhibited significant HDAC8 inhibitory activity, thereby suggesting their potential therapeutic implications against cancer. SUMMARY: Pharmacoinformatics studies revealed that cinnamon bioactives bound to the active site of HDAC8 enzyme in a way similar to that of TSAThe molecular descriptors of cinnamon compounds successfully correlated with TSA values. The binding interactions and energies were also found to be close to TSASynthetic accessibility values showed that cinnamon bioactives were easy to synthesize compared to TSA. Abbreviations used: ACE: Aqueous Cinnamon Extract; DFT: Density Function Theory; CAL: Cinnamaldehyde; CA: Cinnamic Acid; CALC: Cinnamyl Alcohol; MW: Molecular Weight; ROTBs: Rotatable Bonds; ROF: Lipinski's Rule of Five; TSA: Trichostatin A; PDB: Protein Data Bank; RMSD: Root Mean Square Deviation; HBA: Hydrogen Bond Acceptor; HBD: Hydrogen Bond Donor; ADMET: Absorption, Distribution, Metabolism, Excretion and Toxicity; FO: Frontier Orbital; HOMOs: Highest Occupied Molecular Orbitals; LUMOs: Lowest Unoccupied Molecular Orbitals; BE: Binding Energy. PMID- 29142428 TI - In vitro Protoscolicidal Effects of Cinnamomum zeylanicum Essential Oil and Its Toxicity in Mice. AB - Background: This study investigates the scolicidal effects of Cinnamomum zeylanicum essential oil against the protoscoleces of hydatid cysts and its toxicity in the mice model. Materials and Methods: Gas chromatography/mass spectroscopy analyses were used to identify the constituents of essential oil. Protoscoleces were treated with different concentrations of the essential oil (6.25-100 uL/mL) in each test tube for 5-30 min. The viability of protoscoleces was confirmed using eosin exclusion test (0.1% eosin staining). Forty-eight male NMRI mice were also used to determine the toxicity of C. zeylanicum essential oil (0.5-4 mL/kg). Results: The main components were found to be cinnamaldehyde (91.8%), rho metoxicinamate (1.57%), and alpha pinene (1.25%). Findings indicate that C. zeylanicum essential oil with the concentrations of 100 and 50 uL/mL killed 100% of protoscoleces after 5 min of exposure. Also, the lower concentrations of C. zeylanicum essential oil motivated a late protoscolicidal effect. The LD50 value of intraperitoneal injection of C. zeylanicum essential oil was 2.07 mL/kg body weight after 48 h, and the maximum nonfatal dose was 1.52 mL/kg body weight. The results also showed that there was no significant toxicity following oral administration of C. zeylanicum essential oil for 2 weeks. Conclusion: The results exhibited the favorable scolicidal activity of C. zeylanicum, which could be applied as a natural scolicidal agent in hydatid cyst surgery. SUMMARY: We evaluated the efficacy of Cinnamomum zeylanicum essential oil against hydatid cyst protoscolecesThe viability of protoscoleces was confirmed using eosin exclusion test (0.1% eosin staining)Forty-eight male NMRI mice were also used to determine the toxicity of C. zeylanicum essential oilC. zeylanicum with potent scolicidal activity could be applied as a natural scolicidal agent in surgery. Abbreviations used: GC/MS: Gas chromatography/mass spectrometry analysis; CE: Cystic echinococcosis; LD50: Lethal dose 50%; I.p: Intraperitoneally. PMID- 29142429 TI - Antioxidant and Hepatoprotective Potential of Swaras and Hima Extracts of Tinospora cordifolia and Boerhavia diffusa in Swiss albino Mice. AB - Background: In Ayurveda, five basic extraction procedures are mentioned in order of their decreasing potency. Swaras is considered as the most potent followed by, kalka, kwatha, fanta and hima. Objective: Present study was carried out to investigate the antioxidant and hepatoprotective potential of swaras and hima extracts of T.cordifolia and B. diffusa. Materials and Methods: Swaras and hima extracts of T. cordifolia and B. diffusa were prepared. Phytochemical screening and in vitro antioxidant activities was carried out using standard methods. Hepatoprotective efficacy of extracts were carried out in Swiss albino mice using paracetamol induced hepatotoxicity. Animals were administered with swaras and hima extracts of both plants at 200 mg/kg BW dose for 7 days and on 8th day hepatotoxicity was induced by intraperitoneal injection of paracetamol at 500 mg/kg BW. The degree of liver protection was determined by measuring the levels of liver enzymes followed by histopathology. Results and Discussion: The results of phytochemical, antioxidant and hepatoprotective activities showed that there were no significant difference between swaras and hima extracts. Both the extract of T. cordifolia were equally potent in reducing SGOT (P < 0.01) and ALP level (P < 0.001). Similar effects were observed with the Swaras and hima extracts of B. diffusa. Both the extracts reduced SGOT and ALP (P < 0.01). Histopathological findings among all the extracts were also more or less similar in lowering the paracetamol mitigated necrosis. Conclusion: The present study suggested that T. cordifolia and B. diffusa possess potential hepatoprotective activity irrespective of the extraction procedure. SUMMARY: Aqueous extracts of Tinospora cordifolia and Boerhavia diffusa exhibited significant antioxidant and hepatoprotective activitiesAqueous extracts of both the plants were extracted using different extraction procedures mentioned in AyurvedaSwaras and hima extracts of both the plants significantly reduced the deleterious effects of paracetamol, suggesting that both the plant extracts are equipotentAcute toxicity of both the plant extracts did not produce any toxic effects. Abbreviations used: TC swaras: T. cordifolia swaras; TC hima: T. cordifolia hima; BD swaras: B. diffusa swaras; BD hima: B. diffusa hima; BW: Body weight; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; SGOT: Serum glutamate oxaloacetate transminase; SGPT: Serum glutamate pyruvate transminase; ALP: Alkaline phosphatase; I.P: Intraperitoneal; TAC: Total antioxidant capacity; DPPH: 2,2 diphenyl-1-picrylhydrazyl; TCA: Trichloro acetic acid; NO: Nitric oxide; TPC: Total phenolic content; NAPQI: N-acetyl-p-benzoquinone imine; PCM: Paracetamol. PMID- 29142430 TI - Topical Delivery of Withania somnifera Crude Extracts in Niosomes and Solid Lipid Nanoparticles. AB - Background: Withania somnifera is a medicinal plant native to India and is known to have anticancer properties. It has been investigated for its anti-melanoma properties, and since melanoma presents on the skin, it is prudent to probe the use of W. somnifera in topical formulations. To enhance topical drug delivery and to allow for controlled release, the use of niosomes and solid lipid nanoparticles (SLNs) as delivery vesicles were explored. Objective: The objective of this study is to determine the stability and topical delivery of W. somnifera crude extracts encapsulated in niosomes and SLNs. Materials and Methods: Water, ethanol, and 50% ethanol crude extracts of W. somnifera were prepared using 24 h soxhlet extraction which were each encapsulated in niosomes and SLNs. Franz cell diffusion studies were conducted with the encapsulated extracts to determine the release and skin penetration of the phytomolecules, withaferin A, and withanolide A. Results: The niosome and SLN formulations had average sizes ranging from 165.9 +/- 9.4 to 304.6 +/- 52.4 nm with the 50% ethanol extract formulations having the largest size. A small particle size seemed to have correlated with a low encapsulation efficiency (EE) of withaferin A, but a high EE of withanolide A. There was a significant difference (P < 0.05) between the amount of withaferin A and withanolide A that were released from each of the formulations, but only the SLN formulations managed to deliver withaferin A to the stratum corneum-epidermis and epidermis-dermis layers of the skin. Conclusion: SLNs and niosomes were able to encapsulate crude extracts of W. somnifera and release the marker compounds, withaferin A, and withanolide A, for delivery to certain layers in the skin. SUMMARY: Withania somnifera crude extracts were prepared using ethanol, water, and 50% ethanol as solvents. These three extracts were then incorporated into niosomes and solid lipid nanoparticles (SLNs) for use in skin diffusion studies, thus resulting in six formulations (ethanol niosome, water niosome, 50% ethanol niosome, ethanol SLN, water SLN, and 50% ethanol SLN). The diffusion of two marker compounds (withaferin A and withanolide A) from the formulations into the skin was then determined. Abbreviations used: API: Active pharmaceutical ingredient, ANOVA: Analysis of variance, ED: Epidermis-dermis, HPLC: High performance liquid chromatography, HLB: Hydrophilic-lipophilic balance, NMR: Nuclear magnetic resonance spectroscopy, PDI: Polydispersity index, SLN: Solid lipid nanoparticle, SD: Standard deviation, SCE: Stratum corneum-epidermis, TEM: Transmission electron microscopy. PMID- 29142431 TI - Characterization of Leaf Extracts of Schinus terebinthifolius Raddi by GC-MS and Chemometric Analysis. AB - Background: Schinus terebinthifolius Raddi belongs to Anacardiacea family and is widely known as "aroeira." This species originates from South America, and its extracts are used in folk medicine due to its therapeutic properties, which include antimicrobial, anti-inflammatory, and antipyretic effects. The complexity and variability of the chemical constitution of the herbal raw material establishes the quality of the respective herbal medicine products. Objective: Thus, the purpose of this study was to investigate the variability of the volatile compounds from leaves of S. terebinthifolius. Materials and Methods: The samples were collected from different states of the Northeast region of Brazil and analyzed with a gas chromatograph coupled to a mass spectrometer (GC-MS). The collected data were analyzed using multivariate data analysis. Results: The samples' chromatograms, obtained by GC-MS, showed similar chemical profiles in a number of peaks, but some differences were observed in the intensity of these analytical markers. The chromatographic fingerprints obtained by GC-MS were suitable for discrimination of the samples; these results along with a statistical treatment (principal component analysis [PCA]) were used as a tool for comparative analysis between the different samples of S. terebinthifolius. Conclusion: The experimental data show that the PCA used in this study clustered the samples into groups with similar chemical profiles, which builds an appropriate approach to evaluate the similarity in the phytochemical pattern found in the different leaf samples. SUMMARY: The leave extracts of Schinus terebinthifolius were obtained by turbo-extractionThe extracts were partitioned with hexane and analyzed by GC-MSThe chromatographic data were analyzed using the principal component analysis (PCA)The PCA plots showed the main compounds (phellandrene, limonene, and carene), which were used to group the samples from a different geographical location in accordance to their chemical similarity. Abbreviations used: AL: Alagoas, BA: Bahia, CE: Ceara, CPETEC: Center for Weather Forecasting and Climate Studies, GC-MS: Gas chromatograph coupled to a mass spectrometer, MA: Maranhao, MVA: Multivariate data analysis, PB: Paraiba, PC1: Direction that describes the maximum variance of the original data, PC2: Maximum direction variance of the data in the subspace orthogonal to PC1, PCA: Principal component analysis, PE: Pernambuco, PI: Piaui, RN: Rio Grande do Norte, SE: Sergipe. PMID- 29142432 TI - Inhibition of Glycation-induced Cytotoxicity, Protein Glycation, and Activity of Proteolytic Enzymes by Extract from Perovskia atriplicifolia Roots. AB - Background: Protein glycation and glycotoxicity belong to the main oxidative stress related complications in diabetes. Perovskia species are used in Asian folk medicine as antidiabetic herbs. Objective: The aim of this study was to verify the ability of the methanolic extract from Perovskia atriplicifolia Benth. roots to diminish glycation of albumin and to prevent cell damage in vitro. Furthermore, we tested the extract for in vitro antioxidant activity and inhibition of elastase and collagenase. Material and Methods: The aqueous methanol extract was analyzed by UHPLC-MS for the content of polyphenols and terpenoids. The prevention of glycated albumin-induced cell damage was tested in four mammalian cell lines (peripheral blood mononuclear cells, human embryonic kidney cells - HEK293, normal human fibroblasts, and Chinese hamster ovary cells) with the 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazoly)-3-(4-sulfophenyl) tetrazolium assay. Results: Glycated albumin is significantly more toxic than native human serum albumin (LC50 from 35.00 to 48.34 MUg/mL vs. 5.47-9.10 MUg/mL, respectively). The extract, rich in rosmarinic acid (344.27 mg/g dry mass), mitigated the glycated albumin toxicity, and increased glycated albumin-treated cell survival by more than 50%. The inhibition of advanced glycation endproduct formation was confirmed by monitoring conformational changes. The free radical scavenging activity was higher than Trolox and metal reducing power was one-third to half that of ascorbic acid. The activity of elastase and collagenase was inhibited by 54.75% +/- 6.87% and 60.03% +/- 7.22%, respectively. Conclusions: The results confirm antiglycative and antiglycotoxic potential of Perovskia root and its traditional antidiabetic use. The high activity can be attributed to rosmarinic acid abundance. SUMMARY: Perovskia is a small genus of aromatic shrubby plants growing in arid regions of Central and South Asia. Different parts are used in folk medicine as antiparasitic, anti-infectious and antidiabetic remedy. Here, we have studied the extract from roots for inhibition of: glycation induced cytotoxicity, human serum albumin glycation, inflammation-related enzymes, as well as for antioxidant activity. Result: the extract from P. atriplicifolia roots inhibited protein glycation and AGE-induced toxicity in cell cultures. The mechanism is likely to rely on the antioxidant activity of high content of rosmarinic acid. Abbreviations used: AGE: advanced glycation end products; DPPH: 2,2-diphenyl-1-picrylhydrazyl; HSA: human serum albumin. PMID- 29142433 TI - Prosopis juliflora Pods Alkaloid-rich Fraction: In vitro Anthelmintic Activity on Goat Gastrointestinal Parasites and Its Cytotoxicity on Vero Cells. AB - Background: This study was designed to assess the in vitro anthelmintic activity of the fraction containing alkaloid from Prosopis juliflora pods on goat gastrointestinal nematodes using the egg hatch assay (EHA), larval migration inhibition assay (LMIA), and larval motility assay (LMA). Materials and Methods: The alkaloid-rich fraction (AF) - content juliprosopine as major alkaloid - was obtained from ethyl acetate extract after fractionation in Sephadex LH-20 chromatography column and its characterization were made by nuclear magnetic resonance analysis together with literature data comparison. The concentrations tested were 4.0, 2.67, 1.78, 1.19, and 0.79 mg/mL (EHA) and 4 mg/mL (LMIA and LMA). The in vitro cytotoxicity on Vero cell cultures was determined with the 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and trypan blue tests. Results: High ovicidal activity was observed with IC50 and IC90 values at 1.1 and 1.43 mg/mL for AF. On the other hand, this fraction showed low larvicidal activity and high toxic effect. Conclusion: Thus, P. juliflora pod alkaloid rich fraction has ovicidal activity in vitro against goat gastrointestinal nematodes and cytotoxic in Vero cell cultures. SUMMARY: Prosopis juliflora alkaloid-rich fraction (AF) showed in vitro anthelmintic effect against gastrointestinal nematodes of goatsThe AF was more effective against eggs than third larval stage (L3) of gastrointestinal nematodesThe AF showed cytotoxicity activity on Vero cell lineThe juliprosopine was the main alkaloid found in the AF from P. juliflora pods. Abbreviations used: AF: Alkaloid-rich fraction; DMSO: Dimethyl sulfoxide; EE: Ethyl acetate extract; EHA: Egg hatch assay; IC50: Inhibitory concentration 50%; IC90: Inhibitory concentration 90%; L3: Infective larvae; LMA: Larval motility assay; LMIA: Larval migration inhibition assay; MTT: Bromide 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NMR: Nuclear magnetic resonance; PBS: Phosphate buffered saline; RPMI: Roswell Park Memorial Institute medium; TLC: Thin Layer Chromatography. PMID- 29142434 TI - Melastoma malabathricum Ethyl Acetate Fraction Induces Secondary Necrosis in Human Breast and Lung Cancer Cell Lines. AB - Background: Melastoma malabathricum (MM) is a traditional plant used in the Borneo region. The cytotoxic effects of methanol extracts from MM leaves have been reported in a number of human cancer cell lines. However, the mode of cell death by MM has not been investigated. Objective: We investigated the cytotoxic effects of MM in both human breast and lung cancer cell lines, MCF-7 and A549, respectively, and defined the mode of cell death. Materials and Methods: Cell viability was measured using the 3-(4-, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Annexin-V/propidium iodide (PI) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining was done to determine the mode of cell death. Results: The MTT assay revealed that MM extract had an IC50 of >400 MUg/ml on both cell lines at 24 h posttreatment. Flow cytometric and fluorescence microscopy analysis of Annexin-V/PI stained MM treated cells revealed that the majority of the cells underwent secondary necrosis/late apoptosis. TUNEL assay showed that little to no DNA nicks were present in MM-treated cells, suggesting that cells have undergone secondary necrosis, not late apoptosis, at that time point. Conclusion: MCF-7 and A549 cells undergoes secondary necrosis 24 h post-treatment with MM extract. MM leaf extract could be a potential source for a novel anti-tumor agent for cancer therapy. SUMMARY: Melastoma malabathricum (MM) extract was toxic on human breast and lung cancer cell linesMajority of MM-treated cells died by either secondary necrosis or late apoptosis at 24 h post-treatmentTerminal deoxynucleotidyl transferase dUTP nick-end labeling assay confirmed that MM-treated cells underwent secondary necrosis, not late apoptosis. Abbreviations used: DMSO: Dimethyl sulfoxide; MM: Melastoma malabathricum; MTT: 3-(4-, 5-dimethylthiazol-2 yl)-2,5-diphenyl tetrazolium bromide; PI: Propidium iodide; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick-end labeling. PMID- 29142435 TI - Characterization of the Phenolic Compound, Gallic Acid from Sansevieria roxburghiana Schult and Schult. f. Rhizomes and Antioxidant and Cytotoxic Activities Evaluation. AB - Background: Sansevieria roxburghiana Schult. and Schult. f. (Asparagaceae) grows in India, Indonesia, Sri Lanka, and tropical Africa. Even though the plant has been traditionally used for the treatment of many ailments, the antioxidant and antiproliferative activities of S. roxburghiana methanol extract and its fractions have not yet been explored. Materials and Methods: Quantitative estimation of phenols and different antioxidant assays were performed using standard methods. Anti-proliferative effect of the extract and fractions were evaluated in HCT-116, HeLa, MCF-7, HepG2, and A-549 cancer cell lines by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and sulforhodamine B (SRB) assay methods. High-performance liquid chromatography (HPLC) and high performance thin layer chromatography (HPTLC) fingerprint profiling were carried out for extract and different fractions. Results: Significant antioxidant and anti-proliferate activity were detected in ethyl acetate fraction. Ethyl acetate fraction showed prominent scavenging activity in 1,1-diphenyl-2-picrylhydrazyl, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, and nitric oxide antioxidant assays with an concentration yielding 50% inhibition (IC50) 15.33 +/- 1.45, 45.3 +/- 1.93 and 48.43 +/- 0.46 mg/ml, respectively. Cytotoxicity of ethyl acetate fraction was the highest among other fractions against HCT-116, HeLa, and MCF-7cancer cell lines with IC50 values 16.55 +/- 1.28, 12.38 +/- 1.36, and 8.03 +/- 1.9 MUg/ml, respectively, by MTT assay and 15.57 +/- 0.70, 13.19 +/- 0.49, and 10.34 +/- 0.9 MUg/ml, respectively, by SRB assay. The presence of gallic acid in the ethyl acetate fraction of S. roxburghiana rhizomes was confirmed by HPLC and HPTLC analysis. Conclusion: Results suggested that ethyl acetate fraction exhibited effective antioxidant and antiproliferative activities. The phenolic compounds identified in ethyl acetate fraction could be responsible for the activities. SUMMARY: Sansevieria roxburghiana has been selected for in vitro antioxidant and cytotoxicity screeningEthyl acetate fraction of methanol extract of S. roxburghiana exhibited effective antioxidant and antiproliferative activitiesThe activity of ethyl acetate fraction may be due to the presence of phenolic compound which is identified by high-performance liquid chromatography and high-performance thin layer chromatography techniques. Abbreviations used: %: Percent, oC: Celsius, mg: Microgram, ml-Microlitre, ANOVA: Analysis of variance, DMSO: Dimethyl sulfoxide, g: Grams, IC50: Concentration yielding 50% inhibition, Kg: Kilogram, mg: Milligram, min: Minutes, ml: Milliliter, HPLC: High-performance liquid chromatography, HPTLC: High-performance thin layer chromatography, DPPH: 1,1 diphenyl-2-picrylhydrazyl, ABTS: 2,2'-azino-bis (3-ethylbenzothiazoline-6 sulfonic acid) diammonium salt, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, GAE: Gallic acid equivalents, SRME: Methanol extract of S. roxburghiana, ROS: Reactive oxygen species, SRPE: Petroleum ether fraction of S. roxburghiana, SREA: Ethyl acetate fraction of S. roxburghiana, SRAQ: Aqueous fraction of S. roxburghiana, DMEM: Dulbecco's Minimum Essential Medium, FBS: Fetal bovine serum, OD: Optical density, TPC: Total phenolic content, SRBU: Butanol fraction of S. roxburghiana. PMID- 29142436 TI - High-performance Thin-layer Chromatographic-densitometric Quantification and Recovery of Bioactive Compounds for Identification of Elite Chemotypes of Gloriosa superba L. Collected from Sikkim Himalayas (India). AB - Background: Gloriosa superba L. (Colchicaceae) is used as adjuvant therapy in gout for its potential antimitotic activity due to high colchicine(s) alkaloids. Objective: This study aimed to develop an easy, cheap, precise, and accurate high performance thin-layer chromatographic (HPTLC) validated method for simultaneous quantification of bioactive alkaloids (colchicine and gloriosine) in G. superba L. and to identify its elite chemotype(s) from Sikkim Himalayas (India). Methods: The HPTLC chromatographic method was developed using mobile phase of chloroform: acetone: diethyl amine (5:4:1) at lambdamax of 350 nm. Results: Five germplasms were collected from targeted region, and on morpho-anatomical inspection, no significant variation was observed among them. Quantification data reveal that content of colchicine (Rf: 0.72) and gloriosine (Rf: 0.61) varies from 0.035% 0.150% to 0.006%-0.032% (dry wt. basis). Linearity of method was obtained in the concentration range of 100-400 ng/spot of marker(s), exhibiting regression coefficient of 0.9987 (colchicine) and 0.9983 (gloriosine) with optimum recovery of 97.79 +/- 3.86 and 100.023% +/- 0.01%, respectively. Limit of detection and limit of quantification were analyzed, respectively, as 6.245, 18.926 and 8.024, 24.316 (ng). Two germplasms, namely NBG-27 and NBG-26, were found to be elite chemotype of both the markers. Conclusion: The developed method is validated in terms of accuracy, recovery, and precision studies as per the ICH guidelines (2005) and can be adopted for the simultaneous quantification of colchicine and gloriosine in phytopharmaceuticals. In addition, this study is relevant to explore the chemotypic variability in metabolite content for commercial and medicinal purposes. SUMMARY: An easy, cheap, precise, and accurate high performance thin layer chromatographic (HPTLC) validated method for simultaneous quantification of bioactive alkaloids (colchicine and gloriosine) in G. superba L.Five germplasms were collected from targeted region, and on morpho anatomical inspection, no significant variation was observed among themQuantification data reveal that content of colchicine (Rf: 0.72) and gloriosine (Rf: 0.61) varies from 0.035%-0.150% to 0.006%-0.032% (dry wt. basis)Two germplasms, namely NBG 27 and NBG 26, were found to be elite chemotype of both the markers. PMID- 29142437 TI - Docking-based Screening of Ficus religiosa Phytochemicals as Inhibitors of Human Histamine H2 Receptor. AB - Background: Ficus religiosa L. is generally known as Peepal and belongs to family Moraceae. The tree is a source of many compounds having high medicinal value. In gastrointestinal tract, histamine H2 receptors have key role in histamine stimulated gastric acid secretion. Their over stimulation causes its excessive production which is responsible for gastric ulcer. Objective: This study aims to screen the range of phytochemicals present in F. religiosa for binding with human histamine H2 and identify therapeutics for a gastric ulcer from the plant. Materials and Methods: In this work, a 3D-structure of human histamine H2 receptor was modeled by using homology modeling and the predicted model was validated using PROCHECK. Docking studies were also performed to assess binding affinities between modeled receptor and 34 compounds. Molecular dynamics simulations were done to identify most stable receptor-ligand complexes. Absorption, distribution, metabolism, excretion, and screening was done to evaluate pharmacokinetic properties of compounds. Results: The results suggest that seven ligands, namely, germacrene, bergaptol, lanosterol, Ergost-5-en-3beta ol, alpha-amyrin acetate, bergapten, and gamma-cadinene showed better binding affinities. Conclusion: Among seven phytochemicals, lanosterol and alpha-amyrin acetate were found to have greater stability during simulation studies. These two compounds may be a suitable therapeutic agent against histamine H2 receptor. SUMMARY: This study was performed to screen antiulcer compounds from F. religiosa. Molecular modeling, molecular docking and MD simulation studies were performed with selected phytochemicals from F. religiosa. The analysis suggests that Lanosterol and alpha-amyrin may be a suitable therapeutic agent against histamine H2 receptor. This study facilitates initiation of the herbal drug discovery process for the antiulcer activity. Abbreviations used: ADMET: Absorption, distribution, metabolism, excretion and toxicity, DOPE: Discrete Optimized Potential Energy, OPLS: Optimized potential for liquid simulations, RMSD: Root-mean-square deviation, HOA: Human oral absorption, MW: Molecular weight, SP: Standard-precision, XP: Extra-precision, GPCRs: G protein-coupled receptors, SASA: Solvent accessible surface area, Rg: Radius of gyration, NHB: Number of hydrogen bond. PMID- 29142438 TI - Molecular Simulation-based Combinatorial Modeling and Antioxidant Activities of Zingiberaceae Family Rhizomes. AB - Objective: The main aim of this scientific report was to investigate a series of phytochemicals in silico and the pharmacology of four plants found at higher altitude in the ginger family, Zingiberaceae (incl. Costaceae) from North-East India, particularly Sikkim. First, the goal was to determine the biological activities of the four herbs (used under Zingiberaceae family) using antioxidant assays to identify the best species. Second, previously reported compounds in litero were subsequently screened for their anticancerous activities using in silico methods. Materials and Methods: Using the methanolic extracts of herbs, quantitative detection of phytochemicals such as total phenols and total flavonoids was detected, and the free radical scavenging activity was also studied using 2,2-diphenyl-1-picryl-hydrazyl (DPPH) assay. Docking process was studied, using Discovery Studio version 3.5, to identify suitable molecules at the protein-binding sites through annealing and genetic simulation algorithms. Grids centered on active sites were obtained with spacing of 54 * 55 * 56, and 0.503 grid spacing was calculated. The methods adopted and used in this study were comparisons of Global and Local Search Methods to determine the parameters such as maximum number of 250,000 energy evaluations as well as generations of 27,000, followed by mutation and crossover rates of 0.02 and 0.80. The number of docking runs was set to 10. Molecular dynamics study was done to check the stability of the complex. Results: Among all the genus of Zingiberaceae family investigated in this study, Curcuma angustifolia and Hedychium sp. exhibited the highest 537 +/- 12.45; 292 +/- 9.16 mg gallic acid equivalent/g total polyphenols and 38 +/- 1.54; 75 +/- 6.75 mg quercetin equivalent/g flavonoids, respectively. Depending on the concentration, the Hedychium sp. extract exerted the highest scavenging activity on DPPH radical (IC50 36.4 MUg/mL). In silico result demonstrated that the synergetic effects of beta-phellandrene with other compounds might be responsible for its anticancerous activity. beta-phellandrene and farnesene epoxide showed bonding with Leu298, Ala302, Met336, Leu339, Leu343, Phe356, Ala302, Glu305, Met340, Leu343, Arg346, Phe356, Ile373, Ile376, Leu380, His475, Leu476, and Leu491. Conclusion: Based on the current available literature, this is the first study to understand the interaction of compounds found in the rhizomes of Zingiberaceae family. SUMMARY: The aqueous methanolic extract of Zingiberaceae family Curcuma angustifolia and Hedychium sp. has potent antioxidant activity as assessed by 2,2-diphenyl-1-picryl-hydrazyl assaysHedychium sp. is understood to possess more active compounds than other varietiesIn silico studies indicated synergetic effects of beta-phellandrene and other compounds for its anticancerous activity. Abbreviations used: CADD: Computer-aided drug designing; ROS: Reactive oxygen species; ADMET: Absorption, distribution, metabolism, and excretion-toxicity; FeCl3: Ferric chloride; DPPH: 2,2-diphenyl-1-picryl-hydrazyl; NaNO2: Sodium nitrite; TCA: Trichloroacetic acid; K2HPO4: Di-potassium hydrogen phosphate; H2O2: Hydrogen peroxide; KH2PO4: Potassium di-hydrogen phosphate, K2Fe (CN)6: Potassium ferricyanide; KOH: Potassium hydroxide; NaOH: Sodium hydroxide; Na2CO3: Sodium carbonate; CH3COONa: Sodium acetate; AlCl3: Aluminum chloride. PMID- 29142439 TI - Screening of Norharmane from Seven Cyanobacteria by High-performance Liquid Chromatography. AB - Background: Cyanobacteria, including pharmaceutically and medicinally valuable compounds attract the great attention lately. Norharmane (9H-pyrido (3,4-b) indole found in some cyanobacteria revealed a great number of biological effects. Objective: Seven cyanobacteria were isolated and identified from Yesilirmak River and Gaziosmanpasa University Campus to determine the norharmane content. Materials and Methods: Cyanobacteria collected from Tokat, Turkey were isolated and identified by morphologically. Norharmane (9H-pyrido [3,4-b] indole) quantities were presented for seven cyanobacteria, Chroococcus minutus (Kutz.) Nageli, Geitlerinema carotinosum (Geitler) Anagnostidis, Nostoc linckia Bornet ex Bornet and Flahault, Anabaena oryzae F. E. Fritsch, Oscillatoria limnetica Lemmermann, Phormidium sp. Kutzing ex Gomont, and Cylindrospermum sp. Kutzing ex E. Bornet and C. Flahault by high-performance liquid chromatography. Results: The norharmane amount indicated for cyanobacterial culture media altered in a species dependent kind in the range of 0.81-10.87 MUg/g. C. minutus produced the most norharmane among the investigated cyanobacteria as 10.87 MUg/g. Conclusion: Cyanobacteria could be an important source of norharmane as well as pharmaceutically valuable compounds. SUMMARY: Seven cyanobacteria were isolated and identified from Yesilirmak RiverQuantitative analysis of norharmane was executed on isolated cyanobacteriaFour cyanobecteria species included the norharmaneChroococcus minutus contained the most norharmane (10.87 MUg/g). Abbreviations used: HPLC: High performance liquid chromatograph. PMID- 29142440 TI - Constituents and Antioxidant Activity of Bleeding Sap from Various Xinjiang Grapes. AB - Objective: Wine grape sap or bleeding sap of grapes (GBS) is commonly used in Xinjiang (China) for therapeutic aims. Do variations in composition related to region and variety affect its properties? Methods: GBS samples originating in various parts of Xinjiang (Turpan, Hotan, Kashgar, and Atush) were tested for phenols and polyphenols, polysaccharides, saponin, proteins, individual amino acids, and minerals. Their antioxidant activity was measured using ascorbic acid as reference. Results: Polyphenol content varied from 2.6 to 6.6 mg/L, polysaccharides 18.3-816 mg/L, saponin 6.25-106 mg/L, and protein 3.0-22.4 mg/L. Mineral elements and amino acids ranged from 6.20 to 201.2 mg/L and 0.06-118.7 mg/L, respectively. .OH scavenging ability varied from 70% to over 90%, higher than Vitamin C. Grapes from Turpan had lower antioxidant activity than other grapes even though the polyphenol content was generally higher. Conclusion: Bleeding sap of Xinjiang grape is rich in amino acids, polysaccharides, polyphenols, and protein. The contents are different according to the origin, related possibly to species, climate, and environment. Antioxidant effects were not correlated with polyphenol content. SUMMARY: Antioxidant activity of plants or plant extracts is often associated with polyphenolsBleeding sap of grapes has strong antioxidant propertiesBleeding sap from different grape varieties from different parts of Xinjiang (China) had different polyphenol concentrationsThere was no correlation of polyphenol concentrations with antioxidant activity. Abbreviations used: GBS: Bleeding sap of grapes; PITC: phenyl isothiocyanate. PMID- 29142441 TI - From the Editor's Desk. PMID- 29142442 TI - Debates Regarding Lean Patients with Polycystic Ovary Syndrome: A Narrative Review. AB - Polycystic ovary syndrome (PCOS) is a complex syndrome showing the clinical features of an endocrine/metabolic disorder, including hyperinsulinemia and hyperandrogenism. Two phenotypes are present, either lean or obese, with different biochemical, hormonal, and metabolic profiles. Evidence suggests many treatment modalities that can be applied. However, many of these modalities were found to be not suitable for the lean phenotype of PCOS. Much contradictory research was found regarding lean patients with PCOS. The aim of this narrative review is to shed light on the debate prevailing regarding characteristics, as well as metabolic, hematological, and potential management modalities. Literature review was performed from January 1, 2000 to March 31, 2017 with specific word search such as lean PCOS, hormonal abnormalities in lean PCOS, and the management of lean PCOS. All retrieved articles were carefully assessed, and data were obtained. We could conclude that the debate is still prevailing regarding this specific lean population with PCOS, especially with regard to their characteristics and management modalities. Further studies are still required to resolve this debate on the presence of PCOS in lean women. PMID- 29142443 TI - Oral Health and Erectile Dysfunction. AB - Ample evidence strongly supports the fact that periodontal disease is a major risk factor for various systemic diseases namely cardio-vascular disease, diabetes mellitus, etc. Recently, investigators focussed on exploring the link between chronic periodontitis (CP) and erectile dysfunction (ED) by contributing to the endothelial dysfunction. Both the diseases share common risk factors. Various studies conducted in different parts of the world in recent years reported the evidence linking this relationship as well as improvement in ED with periodontal treatment. Systemic exposure to the periodontal pathogen and periodontal infection-induced systemic inflammation was thought to associate with these conditions. The objective of this review was to highlight the evidence of the link between CP and ED and the importance of oral health in preventing the systemic conditions. PMID- 29142444 TI - Correlations Between Anthropometry and Lipid Profile in Women With PCOS. AB - Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive age women and is associated with both reproductive and metabolic abnormalities. Recent studies have demonstrated an early onset of abnormal cardiovascular risk profile in women with PCOS. Abnormal lipid profile patterns are common in women with PCOS, and these abnormalities are not uniform in all populations. Anthropometry is a simple and commonly used research tool for assessing metabolic risk in women with PCOS. Therefore, this study examined the correlations between anthropometric parameters and lipid profile in women with PCOS. Objectives: The objectives of the study were (1) To study the anthropometric profile of women with PCOS, (2) To examine the lipid profile pattern of these women with PCOS and (3) To see whether there exists any correlation between these anthropometric parameters and lipid profile. Materials and Methods: This observational cross-sectional study examined anthropometry and lipid profile in 86 married women with PCOS in the age group of 18-35 years and correlated them by using Pearson's correlation coefficient. Results: More than 80% of the women with PCOS demonstrated abnormal anthropometric parameters, and in more than 70% women, lipid abnormalities such as low levels of high-density lipoprotein (HDL) cholesterol and high levels of triglycerides and low-density lipoprotein cholesterol were observed. Significant positive correlations were seen between body mass index (BMI) and triglycerides (P <= 0.001) and waist circumference (WC) and triglycerides (P <= 0.029). Negative correlations were observed between BMI and HDL cholesterol (P <= 0.013). Conclusion: This study revealed that BMI and WC are the most important anthropometric parameters correlated to dyslipidemia in the south Indian women with PCOS. PMID- 29142445 TI - A Study of Controlled Ovarian Stimulation with Clomiphene Citrate or Letrozole in Combination with Gonadotropins and IUI in Unexplained Infertility. AB - Aim: To compare the effect of clomiphene citrate (CC) + human menopausal gonadotropin (hMG) with letrozole + hMG on size, number of follicles, endometrial thickness, serum levels of oestradiol and progesterone and pregnancy rate. Settings and Design: Non-randomised interventional study. Patients and Methods: A total number of 60 patients in the age group of 20-35 years with unexplained infertility were divided into two groups, 30 in each. Group A received CC + hMG and group B received letrozole + hMG. In both the groups, ovulation was triggered by hCG followed by intrauterine insemination. Results: The number of follicles on day 8 were significantly higher in the CC + hMG group than that in the letrozole + hMG group. Serum oestradiol level was significantly higher in the CC + hMG group on day 10 and on the day of hCG administration. Pregnancy rate in the CC + hMG group was 23.3% and 13.3% in the letrozole + hMG group. Conclusion: The sequential protocol was cost-effective. CC + hMG could be a preferred ovarian stimulation protocol in couples with unexplained infertility with the added advantage of having no significant complications in properly monitored cycles. PMID- 29142446 TI - Hysterosalpingographic (HSG) Pattern of Infertility in Women of Reproductive Age. AB - Background: Infertility is a complex disorder with significant medical, psychological and economic problems. Aims: The aim of the study is to evaluate the structural abnormalities of the uterus and fallopian tubes in infertile women as elucidated by hysterosalpingography. Setting and Design: A retrospective study, conducted at the Radiology and Obstetric and Gynaecologic Departments of a tertiary health care institution. Materials and Methods: Evaluation of all consecutive patients in whom hysterosalpingographic (HSG) was performed for infertility between July 2013 and June 2015 in the Department of Radiology. For the biodata, indications for the investigation and the HSG findings were obtained. Statistical Analysis: The data were analyzed using IBM Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) for Windows, version 20 software. Results: A total of 299 patients were evaluated. Of these, 250 were for infertility with primary and secondary infertility constituting 18.4 and 81.6%, respectively. Seventy percent of the cases for infertility had abnormalities on the HSG. Normal uterine cavity was found in 123 (49.2%) cases. Uterine filling defects were the most common uterine abnormality. Fallopian tube occlusion, loculated contrast material spillage and hydrosalpinx were more common on the right, and bilateral tubal occlusion was seen only in 11.2%. All cases of intravasation were associated with either unilateral or bilateral fallopian tube blockage or irregularity of the uterus. Conclusion: There was a high incidence of tubal disease in the women presenting with infertility. This was commonly as a result of infection and inflammatory process. This study showed that HSG is very vital in detecting birth canal pathologies; hence, the facility for this important procedure, especially fluoroscopy, should be made available in the health centres for adequate assessment of the women with infertility. PMID- 29142447 TI - A Prospective Randomized Study Comparing Unipolar Versus Bipolar Hysteroscopic Myomectomy in Infertile Women. AB - Study Objective: To compare the operative and reproductive outcome of hysteroscopic myomectomy using unipolar resectoscope versus bipolar resectoscope in patients with infertility and menorrhagia. Design: Randomized, prospective, parallel, comparative, single-blinded study. Design Classification: Canadian Task Force classification I. Setting: Tertiary care institute. Patients: Sixty women with submucous myoma and infertility. Interventions: Hysteroscopic myomectomy performed with unipolar resectoscope or bipolar resectoscope. Measurements: Primary outcome measures were the pregnancy-related indicators. Secondary outcome measures were the operative parameters, harmful outcomes related to the procedure, and comparison of improvement levels in the menstrual pattern after surgery between the two groups. Main Results: A total of 60 patients were randomized into two groups of equal size. Baseline characteristics were not significantly different between the two groups. Reduction in sodium level from pre- to postsurgery was significantly (P = 0.001) higher in the unipolar group. Nine patients (30%) in the unipolar group had hyponatremia in the postoperative period compared to none in the bipolar group (P = 0.002). However, there was no significant difference in the other operative parameters between the two groups. In both the groups, a significant improvement in the menstrual symptoms was observed after myomectomy. Pregnancy-related outcomes were similar in both the groups. Conclusion: The use of bipolar resectoscope for hysteroscopic myomectomy is associated with lesser risk of hyponatremia compared to unipolar resectoscope. Bipolar resectoscopic myomectomy is found to be an effective and safer alternative to unipolar resectoscopy with similar reproductive outcome. PMID- 29142448 TI - Expression of the Bone Morphogenetic Protein-2 (BMP2) in the Human Cumulus Cells as a Biomarker of Oocytes and Embryo Quality. AB - Background: The members of the transforming growth factor-B superfamily, as the bone morphogenetic proteins (BMPs) subfamily and anti-Mullerian hormone (AMH), play a role during follicular development, and the bone morphogenetic protein-2 (BMP2), AMH, and THY1 are expressed in ovaries. Aim: This study was designed to define whether or not the expressions of these proteins in human cumulus cells (CCs) can be used as predictors of the oocyte and embryo competence. Settings and Design: The study included nine female patients who were diagnosed as idiopathic infertility, aged 25-33 years (median 30 years) and underwent Assisted Reproductive Technologies. Materials and Methods: The CCs from 60 oocyte-cumulus complexes obtained from the nine patients were evaluated with immunofluorescence staining in respect of BMPs, AMH and THY1 markers. The CCs surrounding the same oocytes were evaluated separately according to the oocyte and embryo quality. Statistical Analysis: Quantitative data were statistically analyzed for differences using the two-sided Mann-Whitney U test (P < 0.05). Results and Conclusions: Significant differences in immunofluorescence staining were observed in oocyte quality and embryo quality for the BMP2 only (P < 0.05). No significant differences were observed for AMH or CD90/THY1. Conclusion: These results demonstrated that there is a significant difference in the expression of BMP2 in the CCs of good quality oocytes and subsequently a good embryo. PMID- 29142449 TI - Single Blastocyst Transfer: The Key to Reduce Multiple Pregnancy Rates Without Compromising the Live Birth Rate. AB - Background: Historically, to achieve higher pregnancy rates, multiple embryos were transferred after an in-vitro fertilisation (IVF). However, this practice is being reassessed, because it leads to multiple pregnancies that is known to cause adverse maternal and fetal outcomes. Aim: To compare the pregnancy outcomes in fresh IVF or intracytoplasmic sperm injection (ICSI) cycles among women undergoing elective single blastocyst transfer (eSBT) vs. those undergoing double blastocyst transfer (DBT). Settings and Design: It is a retrospective data analysis of 582 patients undergoing fresh IVF/ICSI cycles performed from January 2012 to June 2015. Materials and Methods: Patients, who underwent IVF/ICSI and developed more than one blastocyst, were included in the study. Donor cycles were excluded from the study. All the embryos were cultured to blastocyst stage in sequential media followed by transfer of two blastocysts (DBT) or eSBT and cryopreservation of the remaining. Statistical Analysis: Statistical analysis was performed using chi square test. Results: Out of 582 patients, in 149 patients one blastocyst was transferred and in 433 patients two blastocysts were transferred. There was no statistical difference in the biochemical pregnancy rate, clinical pregnancy rate and live birth rate in both the groups. Statistics demonstrated a significant drop in miscarriage rate in eSBT group. There was no incidence of twins in eSBT group, whereas twin birth rate per clinical pregnancy was 29.02% in DBT group. Conclusion: Single blastocyst transfer is an effective method to reduce the risk of multiple births without compromising the pregnancy outcomes. Given the promising potential of vitrification; the remaining blastocyst can be cryopreserved. PMID- 29142450 TI - Autologous Intrauterine Platelet-Rich Plasma Instillation for Suboptimal Endometrium in Frozen Embryo Transfer Cycles: A Pilot Study. AB - Introduction: This pilot study was to evaluate the effectiveness of intrauterine infusion of autologous platelet-rich plasma (PRP) in infertile women undergoing frozen embryo transfer cycles with suboptimal endometrium. Material and Methods: Intrauterine instillation of autologous PRP was done in 68 women between 22 and 40 years, over 8 months, with suboptimal endometrial growth, and patients with repeated cycle cancellations, in addition to Estradiol valerate. Frozen embryo transfer was performed when the endometrium reached an optimal pattern in terms of thickness, appearance, and vascularity. Results: The mean pre-PRP endometrial thickness (ET) was 5 mm which significantly increased to 7.22 mm post-PRP. There was a significant increase in vascularity, seen by the number of vascular signals seen on Power Doppler, reaching the zones 3 and 4 of the endometrium. The positive beta Human Chorionic Gonadotropin (hCG) rate was 60.93% and the clinical pregnancy rate was 45.31%. A total of 13 women are in the second trimester, 13 are in the first trimester with a healthy intrauterine pregnancy, one patient had an ectopic gestation, three had blighted ova, two had missed abortions, and two biochemical pregnancies. Conclusion: This study suggests that the use of autologous PRP holds promise in the treatment of women with suboptimal ET and vascularity for embryo transfer. It would help to reduce the incidence of cycle cancellations and thus even help reduce the financial and psychological burden of repeated cancelled cycles. PMID- 29142451 TI - Sexual Functioning, Beliefs About Sexual Functioning and Quality of Life of Women with Infertility Problems. AB - Background: The study was conducted in the background of paucity of studies examining the sexual and psychosocial functioning of women with infertility. Aims: The study explored sexual functioning in women with infertility problems, their beliefs about sexuality and their quality of life. Settings and Design: A single group exploratory design with non-probability purposive sampling was used. A total of 30 participants diagnosed with primary infertility were included in the study. Materials and Methods: The data were obtained by individual administration of the following tools: Semi-structured interview schedule, Female Sexual Functioning Inventory, Sexual Dysfunctional Beliefs Questionnaire, World Health Organization Quality of Life Scale - BREF Version and General Health Questionnaire-12. The data obtained were analyzed using descriptive statistics and non-parametric tests. Results: About half of the participants had sexual dysfunction. Pain-related problems were most commonly reported (50%). Factors contributing to dysfunction included inadequate knowledge about sex, sexual stimulation and sexual communication. Along with inadequate self-image, negative childhood experiences, financial difficulties and marital discord in parents influenced the perception of self. Majority of the women had dysfunctional beliefs about sexuality (56%), and greater beliefs were found to be in the domain of sexual conservatism. The overall quality of life was poor, and 56% of women experienced psychological distress. There was significant positive correlation between sexual conservatism and experience of pain and overall sexual functioning. Conclusion: Women with infertility bear dysfunctional beliefs and suffer from problems in sexual functioning, have low quality of life and high psychological distress. PMID- 29142452 TI - Infertility Stress in Couples Undergoing Intrauterine Insemination and In Vitro Fertilization Treatments. AB - Aim: The main aim of the study was to assess the stress levels of husbands and wives undergoing intrauterine insemination (IUI) and in vitro fertilization (IVF) treatments, and also to observe whether the stress levels differed between the methods of treatments. Materials and Methods: This research focused on 120 infertile couples who underwent IUI and In Vitro Fertilization-Intra Sperm Cytoplasmic sperm Injection (IVF-ICSI) at an infertility clinic from April 2014 to November 2014. Sixty couples who underwent each method of treatment were selected using purposive sampling technique. Fertility Problem Inventory (Newton et al., 1999) was used to collect the data after obtaining their consent. Statistical Analysis: Statistical analysis was performed at descriptive (mean, standard deviation, and Kolmogorov test) and inferential (analysis of variance, ANOVA) levels. Results and Conclusion: The prevalence of global stress was very high in couples undergoing IUI and IVF treatments, as found by descriptive analysis [mean = 149.95, standard deviation (SD) = 29.76]. Considering the various subscales, stress related to the need for parenthood was found to be high (mean = 45.95, SD = 9.53). Infertility stress (global) was higher among wives when compared to their husbands (f = 9.408; P = 0.002), and the same was noted on the domains of need for parenthood (f = 10.145; P = 0.002), social concern (f = 11.107; P = 0.001), and sexual concern (f = 4.013; P = 0.046). No difference in the levels of global stress was observed when both the modes of treatments were compared (f = 0.180, P = 0.672). For couples, infertility stress showed no significant difference irrespective of whether they underwent IUI or IVF. PMID- 29142453 TI - Ectopic Ovary With Dermoid Cyst as a Result of Possible Asymptomatic Autoamputation. AB - A 32-year-old woman, who presented for laparoscopic sterilization after two full term normal deliveries, was incidentally diagnosed to have a left-sided complex cyst in the pouch of Douglas (POD). She had no history of previous surgeries or any symptoms of lower abdominal pain, nausea, or vomiting in the past. She underwent laparoscopy, and the left ovary and distal portion of the fallopian tube were absent in their normal position. An ectopic left ovary with dermoid cyst was noted in the POD. The right ovary and tube were in their normal position. I attribute this to be a very rare case of asymptomatic torsion and autoamputation of the ovary resulting in an ectopic ovary. PMID- 29142454 TI - Successful Reproductive Outcome After Laparoscopic Strassmann's Metroplasty. AB - Mullerian anomalies cause a significant impact on the reproductive outcomes. A bicornuate uterus is a type of lateral fusion defect, which constitutes 26% of all uterine anomalies. Strassmann's metroplasty is a unification procedure performed to correct the two smaller uterine cavities into a more spacious single cavity. Improved reproductive performance was reported after unification metroplasty. Laparoscopic route can be adopted for this procedure with all the advantages of minimally invasive surgery. Here, we report a success story of a woman who suffered with six miscarriages and secondary infertility who underwent laparoscopic Strassmann's metroplasty in a tertiary care center and later delivered a baby by caesarean section. PMID- 29142455 TI - Large-Volume Paracentesis, up to 27 L, With Adjuvant Vaginal Cabergoline in the Case of Severe Ovarian Hyperstimulation Syndrome with Successful Pregnancy Outcome: A Case Report. AB - Severe ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproductive technology. Herein, we report the case of an infertile couple, with the husband being azoospermic, who underwent in-vitro fertilisation and intracytoplasmic sperm injection at our institute. The woman presented with late OHSS 7 days after embryo transfer. Inpatient management was performed with intensive surveillance. Oral cabergoline was started prophylactically but was replaced by the vaginal route due to intolerance. Transvaginal paracentesis was performed five times over 20 days, and a total of 27 L of ascitic fluid was drained. The patient improved substantially and had a further uneventful pregnancy course. This case report helped us theorise that large-volume paracentesis is safe and efficacious in the management of severe OHSS. In addition, the vaginal route of cabergoline administration is more favourable than the oral route in view of lesser side effects and better patient compliance. PMID- 29142456 TI - Secretory carcinoma - impact of translocation and gene fusions on salivary gland tumor. AB - Secretory carcinoma (SC), previously described as mammary analogue secretory carcinoma (MASC), is a recently described salivary gland tumor which morphologically resembles mammary secretory carcinoma. The first description of SC/MASC, reported by Skalova et al. in 2010, was as a rare salivary carcinoma imitating secretory carcinoma of the breast. SC/MASC is a unique salivary gland tumor with morphological overlap with acinic cell carcinoma (AciCC), mucoepidermoid carcinoma (MEC), and adenocarcinoma not otherwise specified (ADC NOS). SC/MASC shares similar clinicopathological features with AciCC. As a critical difference between SC/MASC and AciCC, SC/MASC characteristically has the chromosomal translocation t(12;15)(p13;q25) which leads to a fusion gene between the ETV6 gene on chromosome 12 and the NTRK3 gene on chromosome 15. This genetic background is an important differential diagnostic finding for excluding other salivary gland tumors and may be a critical factor determining the prognosis for patients with SC/MASC. Research in recent years has provided a large body of new data on SC/MASC and suggests the possibility that the ETV6-NTRK3 translocation could be a therapeutic target. Here, we review the morphological and clinicopathological features of SC/MASC and discuss new directions for therapy. PMID- 29142457 TI - Comparison of cancer incidence and mortality in three GDP per capita levels in China, 2013. AB - Objective: In this research, the patterns of cancer incidence and mortality in areas with different gross domestic product per capita (GDPPC) levels in China were explored, using data from population-based cancer registries in 2013, collected by the National Central Cancer Registry (NCCR). Methods: Data from 255 cancer registries were qualified and included in this analysis. Based on the GDPPC data of 2014, cities/counties were divided into 3 levels: high-, middle- and low-GDPPC areas, with 40,000 and 80,000 RMB per year as cut points. We calculated cancer incidences and mortalities in these three levels, stratified by gender and age group. The national population of the Fifth Census in 2000 and Segi's population were applied for age-standardized rates. Results: The crude incidence and mortality rates as well as age-standardized incidence rate (ASIR) showed positive associations with GDPPC level. The age-standardized mortality rate (ASMR) nevertheless showed a negative association with GDPPC level. The ASMR in high-, middle- and low-GDPPC areas was 103.12/100,000, 112.49/100,000 and 117.43/100,000, respectively. Lung cancer was by far the most common cancer in all three GDPPC levels. It was also the leading cause of cancer death, regardless of gender and GDPPC level. Negative associations with GDPPC level were found for the ASIRs of lung, stomach, esophageal and liver cancer, whereas colorectal and breast cancer showed positive associations. Except for breast cancer, the ASMRs of the other five cancers were always higher in middle- and low-GDPPC areas than in high-GDPPC areas. Conclusions: The economic development is one of the main factors of the heavy cancer burden on Chinese population. It would be reasonable to implement cancer control strategies referring to the local GDPPC level. PMID- 29142458 TI - Widening socioeconomic disparity in lung cancer incidence among men in New South Wales, Australia, 1987-2011. AB - Objective: We assessed the trends in lung cancer incidence over a 25-year period by socioeconomic groups for men in New South Wales (NSW), Australia. Methods: Men diagnosed with lung cancer between 1987 and 2011 were divided into five quintiles according to an Index of Education and Occupation (IEO). We assessed relative socioeconomic differences over time by calculating age-standardized incidence ratios (SIRs) by 5-year period of diagnosis, and estimated absolute differences by comparing the observed and expected numbers of cases using the highest IEO quintile as the reference. Results: Lung cancer incidence for men decreased from 1987 to 2011 for all IEO quintiles, with a greater rate of decline for men living in the highest IEO areas. Thus, the relative disparity increased significantly over the 25-year period (P=0.0006). For example, the SIR for the lowest IEO quintile increased from 1.28 during 1987-1991 to 1.74 during 2007-2011. Absolute differences also increased with the proportion of " potentially preventable" cases doubling from 14.5% in 1987-1991 to 30.2% in 2007-2011. Conclusions: Despite the overall decline in lung cancer incidence among men in NSW over the past 25 years, there was a significant increase in disparity across socioeconomic areas in both relative and absolute terms. PMID- 29142459 TI - A phase I study of different doses and frequencies of pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) in patients with standard dose chemotherapy-induced neutropenia. AB - Objective: The recommended dose of prophylactic pegylated recombinant human granulocyte-colony stimulating factor (PEG rhG-CSF) is 100 MUg/kg once per cycle for patients receiving intense-dose chemotherapy. However, few data are available on the proper dose for patients receiving less-intense chemotherapy. The aim of this phase I study is to explore the proper dose and administration schedule of PEG rhG-CSF for patients receiving standard-dose chemotherapy. Methods: Eligible patients received 3-cycle chemotherapy every 3 weeks. No PEG rhG-CSF was given in the first cycle. Patients experienced grade 3 or 4 neutropenia would then enter the cycle 2 and 3. In cycle 2, patients received a single subcutaneous injection of prophylactic PEG rhG-CSF on d 3, and received half-dose subcutaneous injection in cycle 3 on d 3 and d 5, respectively. Escalating doses (30, 60, 100 and 200 MUg/kg) of PEG rhG-CSF were investigated. Results: A total of 26 patients were enrolled and received chemotherapy, in which 24 and 18 patients entered cycle 2 and cycle 3 treatment, respectively. In cycle 2, the incidence of grade 3 or 4 neutropenia for patients receiving single-dose PEG rhG-CSF of 30, 60, 100 and 200 MUg/kg was 66.67%, 33.33%, 22.22% and 0, respectively, with a median duration less than 1 (0-2) d. No grade 3 or higher neutropenia was noted in cycle 3 in all dose cohorts. Conclusions: The pharmacokinetic and pharmacodynamic profiles of PEG rhG-CSF used in cancer patients were similar to those reported, as well as the safety. Double half dose administration model showed better efficacy result than a single dose model in terms of grade 3 neutropenia and above. The single dose of 60 MUg/kg, 100 MUg/kg and double half dose of 30 MUg/kg were recommended to the phase II study, hoping to find a preferable method for neutropenia treatment. PMID- 29142460 TI - Efficacy and safety of duloxetine in Chinese breast cancer patients with paclitaxel-induced peripheral neuropathy. AB - Objective: Chemotherapy with paclitaxel is associated with significant neurotoxicity that may offset patients' quality of life and therapeutic benefits. This prospective, non-randomized control study evaluated the efficacy and safety of an antidepressant drug, duloxetine, at 30 or 60 mg/d, in the treatment of paclitaxel-induced peripheral neuropathy (PIPN) in Chinese breast cancer patients. Methods: A total of 102 patients with a median age of 50 (range, 25-60) years, treated in the Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, between November 2014 and January 2017 were finally enrolled. Stratified by baseline characteristics, the patients were classified into two groups, receiving either duloxetine or alternative anti-neurotoxicity drugs. During the course of the paclitaxel regimen, the eligibility criteria included sensory neuropathy, as evaluated by the National Cancer Institute-Common Toxicity Criteria for Adverse Events. The treatment consisted of receiving 30 mg duloxetine (for the first 4 weeks) and 60 mg duloxetine for an additional 8 weeks, or any other anti-neurotoxicity drug daily during the same crossover period. The improvement associated with PIPN from the patient's perspective were assessed by the Functional Assessment of Cancer Therapy-Taxane (FACT-Tax) Scales, which contained questions scored from 0 to 4 (0, not at all; 4, very much; total score range, 0-44). Results: Duloxetine was more effective in decreasing PIPN (odds ratio=5.426; 95% confidence interval, 1.898-15.514; P=0.002). Between duloxetine group and control group, the median (25th-75th percentiles) decreasing difference in the FACT-Tax pain score was 4 (2-6) vs. 1 (0-4) (P=0.005). Conclusions: Duloxetine is a promising and safe option with tolerable toxicity at a dose of 60 mg/d for Chinese breast cancer patients with PIPN. Non-neuropathy adverse events were mild and similar in both groups. The major toxicities of duloxetine included nausea, constipation, somnolence, dizziness and distention of the eyes. Further examination of the benefits of duloxetine in the prevention of PIPN is required. PMID- 29142461 TI - Analysis of inpatient payments of breast cancer patients with different medical insurance coverages in China (mainland) in 2011-2015. AB - Objective: An understanding of the levels and trends of medical cost is made for breast cancer patients with different medical insurance coverages in China (mainland), in an attempt to offer a clue to further control the costs. Methods: The inpatient payments of 9,716,180 breast cancer patients spent in medical institutions of different types and grades during 2011-2015 were collected from the inpatient medical record home page (IMRHP) dataset. The data were then processed with SAS (Version 9.3; SAS Institute, Cary, NC, USA). Indicators like means, increase (decrease) percentages were used to descriptively analyze the average hospitalization expense of each time (AHEET) and its trends of breast cancer patients with different medical insurance coverages treated in medical institutions of different types and grades. Results: In 2011-2015, the AHEET borne by breast cancer patients in China had been constantly increasing. Specifically, the self-pay inpatients had the largest increase, inpatients covered by Urban Employee Basic Medical Insurance (UEBMI) and Urban Resident Basic Medical Insurance (URBMI) were the next, and those covered by New Rural Cooperative Medical System (NRCMS) had the least increase. Breast cancer inpatient treated in public hospitals had quite greater increase and higher expenditure level than those in private hospitals. The AHEET borne by the inpatients in Grade 3 hospitals had greater increase and higher cost than those in Grade 2 hospitals. Conclusions: The inpatient payments of breast cancer patients will be wisely controlled by reducing the number of self-pay inpatients, taking advantage of restriction mechanism of the medical insurances, and promoting healthy competition between private hospitals and public hospitals. The economic burden imposed on the society by breast cancer can be relieved through further control of inpatient payments of UEBMI- and URBMI-covered breast cancer patients and of Grade 3 hospitals. PMID- 29142462 TI - A national report from China Liver Transplant Registry: steroid avoidance after liver transplantation for hepatocellular carcinoma. AB - Objective: We aimed to evaluate the efficacy and safety of steroid-free immunosuppression after liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods: We retrospectively analyzed HCC recipients without steroids after LT (SF group, n=368) based on the China Liver Transplant Registry (CLTR) database. These recipients were matched 1:2 with patients using steroids (S group, n=736) for the same period after LT for HCC, according to propensity scores. Results: Multivariate analysis indicates that recipients with younger age [odds ratio (OR), 1.053; P=0.011], preoperative hepatitis B virus (HBV) DNA >=1,000 copies/mL (OR, 2.597; P=0.004) and beyond Milan criteria (OR, 4.255; P<0.001) were identified as the risk factors associated with tumor recurrence in steroid avoidance recipients after LT. The patients fulfilling the Milan criteria in the SF group presented higher overall and tumor-free survival rates than those in the S group (P<0.05). Multivariate analysis revealed that recipient beyond Milan criteria was an independent prognostic factor for overall survival (OR, 1.690; P<0.001) and tumor-free survival (OR, 2.066; P<0.001). The incidences of new-onset diabetes mellitus (21.20%vs. 33.29%, P<0.001), new-onset hypertension (10.05%vs. 18.61%, P<0.001) and hyperlipidemia (4.08%vs. 7.20%, P=0.042) were significantly lower in the SF group. Conclusions: Steroid-free immunosuppression could be safe and feasible for HBV-related HCC patients in LT. Age, HBV DNA level and Milan criteria maybe risk factors associated with tumor recurrence in steroid avoidance recipients. Recipient beyond Milan criteria was an independent prognostic factor and recipient fulfilling Milan criteria can benefit the most from steroid-free immunosuppression. PMID- 29142463 TI - Management of extramedullary plasmacytoma: Role of radiotherapy and prognostic factor analysis in 55 patients. AB - Objective: To investigate potential prognostic factors affecting patient outcomes and to evaluate the optimal methods and effects of radiotherapy (RT) in the management of extramedullary plasmacytoma (EMP). Methods: Data from 55 patients with EMP between November 1999 and August 2015 were collected. The median age was 51 (range, 22-77) years. The median tumor size was 3.5 (range, 1.0-15.0) cm. The median applied dose was 50.0 (range, 30.0-70.0) Gy. Thirty-nine patients (70.9%) presented with disease in the head or neck region. Twelve patients received RT alone, 9 received surgery (S) alone, 3 received chemotherapy (CT) alone, and 3 patients did not receive any treatment. Combination therapies were applied in 28 patients. Results: The median follow-up duration was 56 months. The 5-year local recurrence-free survival (LRFS), multiple myeloma-free survival (MMFS), progression-free survival (PFS) and overall survival (OS) rates were 79.8%, 78.6%, 65.2% and 76.0%, respectively. Univariate analysis revealed that RT was a favourable factor for all examined endpoints. Furthermore, head and neck EMPs were associated with superior LRFS, MMFS and PFS. Tumor size <4 cm was associated with superior MMFS, PFS and OS; serum M protein negativity was associated with superior MMFS and PFS; age >=50 years and local recurrence were associated with poor MMFS. The dose >=45 Gy group exhibited superior 5-year LRFS, MMFS and PFS rates (94.7%, 94.4%, 90.0%, respectively), while the corresponding values for the dose <45 Gy group were 62.5% (P=0.008), 53.3% (P=0.036) and 41.7% (P<0.001). Conclusions: Involved-site RT of at least 45 Gy should be considered for EMP. Furthermore, patients with head and neck EMP, tumor size <4 cm, age <50 years and serum M protein negativity had better outcomes. PMID- 29142464 TI - BMPR2 and HIF1-alpha overexpression in resected osteosarcoma correlates with distant metastasis and patient survival. AB - Objective: Bone morphogenetic protein receptor 2 (BMPR2) and hypoxia-inducible factor 1-alpha (HIF1-alpha) existed abnormal expression in several types of cancer. However, their expressions and related roles in osteosarcoma are largely unknown. Methods: To investigate the clinical significance of BMPR2 and HIF1 alpha in osteosarcoma, we analyzed their expression levels in 103 osteosarcoma specimens by immunochemistry. Meanwhile, we conducted a follow-up to examine the metastatic behavior and overall survival (OS) of osteosarcoma patients. Results: Among 103 tissues, 61 cases had BMPR2-positive expression and 57 cases had HIF1 alpha positive expression. A significant correlation was noticed between BMPR2 and HIF1-alpha expression in osteosarcoma specimens (P=0.035). Receiver-operating characteristic (ROC) curves were calculated to investigate the predictive value of the two markers in tumor metastasis. By means of univariate and multivariate analysis, BMPR2 and HIF1-alpha expression, as well as higher tumor grade, were identified as significant risk factors for OS in patients with osteosarcoma. Kaplan-Meier survival analysis revealed that the patients with BMPR2 and HIF1 alpha positive expression had worse OS compared with patients with BMPR2-negative or HIF1-alpha-negative staining. Conclusions: It can be concluded that BMPR2 and HIF1-alpha expression is highly correlated with metastatic behavior in patients with osteosarcoma and can serve as predictive markers for metastasis and OS of these patients. PMID- 29142465 TI - Efficacy of vinorelbine combined with low-dose methotrexate for treatment of inoperable desmoid tumor and prognostic factor analysis. AB - Objective: To assess the efficacy of conservative chemotherapy for inoperable desmoid tumor (DT) and analyze the prognostic factors. Methods: From November 2008 to April 2016, 71 patients of inoperable DT were treated with vinorelbine and low-dose methotrexate in the Department of Bone and Soft Tissue Tumors, Peking University Cancer Hospital & Institute, and enrolled in this retrospective study. The chemotherapy duration is one year. The efficacy of chemotherapy and the prognosis were observed. Results: Of the 71 patients, 55% were female. Age of onset varied from 1 to 47 years, and the median age was 14 years. Only 11 (15.5%) cases suffered primary tumor. The distribution of the site of tumors was: 31 (43.7%) in the trunk, 36 (50.7%) in the limbs, and 4 (5.6%) in the peritoneal and pelvic cavity. The size of tumor (the maximum diameter) differed from 2 to 37 cm with a mean of 9.3 cm. The median follow-up duration was 28 (range, 6-87) months. Common side effects included: nausea and vomiting, liver injury, bone marrow suppression and oral ulcers. When the chemotherapy finished, 1 (1.4%) case achieved complete response, 24 (33.8%) achieved partial response, 37 (52.1%) achieved stable disease and 9 (12.7%) had progressive disease. The overall response rate was 87.3%. The progression-free survival (PFS) of the participants were from 6 to 87 months, and the 2-, 3- and 5-year PFS was 79.9%, 68.4% and 36.3%, respectively. No significant difference was identified in PFS in subgroups of gender, age of onset, age of chemotherapy, tumor site and tumor size. Conclusions: For recurrent, inoperable and progressive DT, enough course of chemotherapy with vinorelbine combined with low-dose methotrexate was an optional choice for local control. PMID- 29142466 TI - Higher PD-1 expression concurrent with exhausted CD8+ T cells in patients with de novo acute myeloid leukemia. AB - Objective: To investigate the association between the T cell inhibitory receptor programmed death 1 (PD-1) and T cell exhaustion status in T cells from patients with de novo acute myeloid leukemia (AML) and AML in complete remission (CR). Methods: Surface expression of PD-1 and the exhaustion and immunosenescence markers CD244 and CD57 on CD3+, CD4+ and CD8+ T cells from peripheral blood samples from 20 newly diagnosed, untreated AML patients and 10 cases with AML in CR was analyzed by flow cytometry. Twenty-three healthy individuals served as control. Results: A significantly higher percentage of PD-1+ cells were found for CD3+ T cells in the de novo AML group compared with healthy controls. In addition, an increased level of PD-1+CD8+ T cells, but not PD-1+CD4+, was found for CD3+ T cells in the de novo AML and AML-CR samples. A higher percentage of CD244+CD4+, CD244+CD8+, CD57+CD4+ and CD57+CD8+ T cells was found in CD3+ T cells in samples from those with de novo AML compared with those from healthy controls. Strong increased PD-1+CD244+ and PD-1+CD57+ co-expression was found for CD4+ and CD8+ T cells in the de novo AML group compared with healthy controls. Conclusions: We characterized the major T cell defects, including co-expression of PD-1 and CD244, CD57-exhausted T cells in patients with de novo AML, and found a particular influence on CD8+ T cells, suggesting a poor anti-leukemia immune response in these patients. PMID- 29142467 TI - Non-celiac gluten sensitivity: All wheat attack is not celiac. AB - Currently, 1% of the United States population holds a diagnosis for celiac disease (CD), however, a more recently recognized and possibly related condition, "non-celiac gluten sensitivity" (NCGS) has been suggested to affect up to 6% of the United States public. While reliable clinical tests for CD exist, diagnosing individuals affected by NCGS is still complicated by the lack of reliable biomarkers and reliance upon a broad set of intestinal and extra intestinal symptoms possibly provoked by gluten. NCGS has been proposed to exhibit an innate immune response activated by gluten and several other wheat proteins. At present, an enormous food industry has developed to supply gluten-free products (GFP) with GFP sales in 2014 approaching $1 billion, with estimations projecting sales to reach $2 billion in the year 2020. The enormous demand for GFP also reflects a popular misconception among consumers that gluten avoidance is part of a healthy lifestyle choice. Features of NCGS and other gluten related disorders (e.g., irritable bowel syndrome) call for a review of current distinctive diagnostic criteria that distinguish each, and identification of biomarkers selective or specific for NCGS. The aim of this paper is to review our current understanding of NCGS, highlighting the remaining challenges and questions which may improve its diagnosis and treatment. PMID- 29142468 TI - Glucagon-like peptide-2 modulates the nitrergic neurotransmission in strips from the mouse gastric fundus. AB - AIM: To investigate whether glucagon-like peptide-2 (GLP-2) influences the neurally-induced responses in gastric strips from mice, since no data are available. METHODS: For functional experiments, gastric fundal strips were mounted in organ baths containing Krebs-Henseleit solution. Mechanical responses were recorded via force-displacement transducers, which were coupled to a polygraph for continuous recording of isometric tension. Electrical field stimulation (EFS) was applied via two platinum wire rings through which the preparation was threaded. The effects of GLP-2 (2 and 20 nmol/L) were evaluated on the neurally-induced contractile and relaxant responses elicited by EFS. Neuronal nitric oxide synthase (nNOS) enzyme was evaluated by immunohistochemistry. RESULTS: In the functional experiments, electrical field stimulation (EFS, 4-16 Hz) induced tetrodotoxin (TTX)-sensitive contractile responses, which were reduced in amplitude by GLP-2 (P < 0.05). In the presence of the nitric oxide (NO) synthesis inhibitor L-NNA, GLP-2 no longer influenced the neurally-evoked contractile responses (P > 0.05). The direct smooth muscle response to methacholine was not influenced by GLP-2 (P > 0.05). In the presence of guanethidine and carbachol, the addition of GLP-2 to the bath medium evoked TTX-sensitive relaxant responses that were unaffected by L-NNA (P > 0.05). EFS induced a fast NO-mediated relaxation, whose amplitude was enhanced in the presence of the hormone (P < 0.05). Immunohistochemical experiments showed a significant increase (P < 0.05) in nNOS immunoreactivity in the nerve structures after GLP-2 exposure. CONCLUSION: The results demonstrate that in gastric fundal strips, GLP-2 influences the amplitude of neurally-induced responses through the modulation of the nitrergic neurotransmission and increases nNOS expression. PMID- 29142469 TI - Hypothermic machine perfusion with metformin-University of Wisconsin solution for ex vivo preservation of standard and marginal liver grafts in a rat model. AB - AIM: To compare the effect of University of Wisconsin (UW) solution with or without metformin, an AMP-activated protein kinase (AMPK) activator, for preserving standard and marginal liver grafts of young and aged rats ex vivo by hypothermic machine perfusion (HMP). METHODS: Eighteen young (4 mo old) and 18 aged (17 mo old) healthy male SD rats were selected and randomly divided into three groups: control group, UW solution perfusion group (UWP), and UW solution with metformin perfusion group (MUWP). Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), interleukin-18 (IL-18), and tumor necrosis factor-alpha (TNF-alpha) in the perfused liquid were tested. The expression levels of AMPK and endothelial nitric oxide synthase (eNOS) in liver sinusoidal endothelial cells were also examined. Additionally, microscopic evaluation of the harvested perfused liver tissue samples was done. RESULTS: AST, ALT, LDH, IL-18 and TNF-alpha levels in the young and aged liver-perfused liquid were, respectively, significantly lower in the MUWP group than in the UWP group (P < 0.05), but no significant differences were found between the young and aged MUWP groups. Metformin increased the expression of AMPK and eNOS protein levels, and promoted the extracellular release of nitric oxide through activation of the AMPK-eNOS mediated pathway. Histological examination revealed that in the MUWP group, the extent of liver cells and tissue damage was significantly reduced compared with the UWP group. CONCLUSION: The addition of metformin to the UW preservative solution for ex vivo HMP can reduce rat liver injury during cold ischemia, with significant protective effects on livers, especially of aged rats. PMID- 29142470 TI - Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer. AB - AIM: To investigate the relationship between autophagy and perineural invasion (PNI), clinical features, and prognosis in patients with pancreatic cancer. METHODS: Clinical and pathological data were retrospectively collected from 109 patients with pancreatic ductal adenocarcinoma who underwent radical resection at the First Affiliated Hospital of Zhengzhou University from January 2011 to August 2016. Expression levels of the autophagy-related protein microtubule-associated protein 1A/1B-light chain 3 (LC3) and PNI marker ubiquitin carboxy-terminal hydrolase (UCH) in pancreatic cancer tissues were detected by immunohistochemistry. The correlations among LC3 expression, PNI, and clinical pathological features in pancreatic cancer were analyzed. The patients were followed for further survival analysis. RESULTS: In 109 cases of pancreatic cancer, 68.8% (75/109) had evidence of PNI and 61.5% (67/109) had high LC3 expression. PNI was associated with lymph node metastasis, pancreatitis, and CA19 9 levels (P < 0.05). LC3 expression was related to lymph node metastasis (P < 0.05) and was positively correlated with neural invasion (P < 0.05, r = 0.227). Multivariate logistic regression analysis indicated that LC3 expression, lymph node metastasis, pancreatitis, and CA19-9 level were factors that influenced neural invasion, whereas only neural invasion itself was an independent factor for high LC3 expression. Univariate analysis showed that LC3 expression, neural invasion, and CA19-9 level were related to the overall survival of pancreatic cancer patients (P < 0.05). Multivariate COX regression analysis indicated that PNI and LC3 expression were independent risk factors for poor prognosis in pancreatic cancer (P < 0.05). CONCLUSION: PNI in patients with pancreatic cancer is positively related to autophagy. Neural invasion and LC3 expression are independent risk factors for pancreatic cancer with a poor prognosis. PMID- 29142471 TI - Dachaihu decoction ameliorates pancreatic fibrosis by inhibiting macrophage infiltration in chronic pancreatitis. AB - AIM: To explore the role of macrophages in chronic pancreatitis (CP) and the effect of Dachaihu decoction (DCHD) on pancreatic fibrosis in mice. METHODS: KunMing mice were randomly divided into a control group, CP group, and DCHD group. In the CP and DCHD groups, mice were intraperitoneally injected with 20% L arginine (3 g/kg twice 1 d/wk for 6 wk). Mice in the DCHD group were administered DCHD intragastrically at a dose of 14 g/kg/d 1 wk after CP induction. At 2 wk, 4 wk and 6 wk post-modeling, the morphology of the pancreas was observed using hematoxylin and eosin, and Masson staining. Interleukin-6 (IL-6) serum levels were assayed using an enzyme-linked immunosorbent assay. Double immunofluorescence staining was performed to observe the co-expression of F4/80 and IL-6 in the pancreas. Inflammatory factors including monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha) and IL-6 were determined using real time-polymerase chain reaction. Western blot analysis was used to detect fibronectin levels in the pancreas. RESULTS: Compared with the control group, mice with 20% L-arginine-induced CP had obvious macrophage infiltration and a higher level of fibrosis. IL-6 serum concentrations were significantly increased. Double immunofluorescence staining showed that IL-6 and F4/80 were co-expressed in the pancreas. With the administration of DCHD, the infiltration of macrophages and degree of fibrosis in the pancreas were significantly attenuated; IL-6, MCP-1 and MIP-1alpha mRNA, and fibronectin levels were reduced. CONCLUSION: The dominant role of macrophages in the development of CP was mainly related to IL-6 production. DCHD was effective in ameliorating pancreatic fibrosis by inhibiting macrophage infiltration and inflammatory factor secretion in the pancreas. PMID- 29142472 TI - Prostaglandin E1 protects hepatocytes against endoplasmic reticulum stress induced apoptosis via protein kinase A-dependent induction of glucose-regulated protein 78 expression. AB - AIM: To investigate the protective effect of prostaglandin E1 (PGE1) against endoplasmic reticulum (ER) stress-induced hepatocyte apoptosis, and to explore its underlying mechanisms. METHODS: Thapsigargin (TG) was used to induce ER stress in the human hepatic cell line L02 and hepatocarcinoma-derived cell line HepG2. To evaluate the effects of PGE1 on TG-induced apoptosis, PGE1 was used an hour prior to TG treatment. Activation of unfolded protein response signaling pathways were detected by western blotting and quantitative real-time RT-PCR. Apoptotic index and cell viability of L02 cells and HepG2 cells were determined with flow cytometry and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. RESULTS: Pretreatment with 1 MUmol/L PGE1 protected against TG-induced apoptosis in both L02 cells and HepG2 cells. PGE1 enhanced the TG-induced expression of C/EBP homologous protein (CHOP), glucose-regulated protein (GRP) 78 and spliced X box binding protein 1 at 6 h. However, it attenuated their expressions after 24 h. PGE1 alone induced protein and mRNA expressions of GRP78; PGE1 also induced protein expression of DNA damage-inducible gene 34 and inhibited the expressions of phospho-PKR-like ER kinase, phospho-eukaryotic initiation factor 2alpha and CHOP. Treatment with protein kinase A (PKA)-inhibitor H89 or KT5720 blocked PGE1 induced up-regulation of GRP78. Further, the cytoprotective effect of PGE1 on hepatocytes was not observed after blockade of GRP78 expression by H89 or small interfering RNA specifically targeted against human GRP78. CONCLUSION: Our study demonstrates that PGE1 protects against ER stress-induced hepatocyte apoptosis via PKA pathway-dependent induction of GRP78 expression. PMID- 29142473 TI - Genetic associations with adverse events from anti-tumor necrosis factor therapy in inflammatory bowel disease patients. AB - AIM: To study the type and frequency of adverse events associated with anti-tumor necrosis factor (TNF) therapy and evaluate for any serologic and genetic associations. METHODS: This study was a retrospective review of patients attending the inflammatory bowel disease (IBD) centers at Cedars-Sinai IBD Center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at Cedars-Sinai using Illumina Infinium Immunochipv1 array per manufacturer's protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population structure. RESULTS: Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients (21%) were found to have adverse events to an anti-TNF-alpha agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the anti-TNF agent. In total: n = 66 (5%) infusion reactions; n = 49 (4%) allergic/serum sickness reactions; n = 19 (1.5%) lupus-like reactions, n = 52 (4%) rash, n = 18 (1.4%) infections. In Crohn's disease, IgA ASCA (P = 0.04) and IgG-ASCA (P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions (P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT (Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine cytokine receptor interaction, and toxoplasmosis for any adverse event. CONCLUSION: Our study shows 1 in 5 IBD patients experience an adverse event to anti-TNF therapy with novel serologic, genetic , and pathways associations. PMID- 29142474 TI - Clinical features of alcoholic hepatitis in latinos and caucasians: A single center experience. AB - AIM: To study differences of presentation, management, and prognosis of alcoholic hepatitis in Latinos compared to Caucasians. METHODS: We retrospectively screened 876 charts of Caucasian and Latino patients who were evaluated at University of California Davis Medical Center between 1/1/2002-12/31/2014 with the diagnosis of alcoholic liver disease. We identified and collected data on 137 Caucasians and 64 Latinos who met criteria for alcoholic hepatitis, including chronic history of heavy alcohol use, at least one episode of jaundice with bilirubin >= 3.0 or coagulopathy, new onset of liver decompensation or acute liver decompensation in known cirrhosis within 12 wk of last drink. RESULTS: The mean age at presentation of alcoholic hepatitis was not significantly different between Latinos and Caucasians. There was significant lower rate of overall substance abuse in Caucasians compared to Latinos and Latinos had a higher rate of methamphetamine abuse (12.5% vs 0.7%) compared to Caucasians. Latinos had a higher mean number of hospitalizations (5.3 +/- 5.6 vs 2.7 +/- 2.7, P = 0.001) and mean Emergency Department visits (9.5 +/- 10.8 vs 4.5 +/- 4.1, P = 0.017) for alcohol related issues and complications compared to Caucasians. There was significantly higher rate of complications of portal hypertension including gastrointestinal bleeding (79.7% vs 45.3%, P < 0.001), spontaneous bacterial peritonitis (26.6% vs 9.5%, P = 0.003), and encephalopathy (81.2% vs 55.5%, P = 0.001) in Latinos compared to Caucasians. CONCLUSION: Latinos have significant higher rates of utilization of acute care services for manifestations alcoholic hepatitis and complications suggesting poor access to outpatient care. PMID- 29142475 TI - Predictive factors associated with carcinoid syndrome in patients with gastrointestinal neuroendocrine tumors. AB - AIM: To discover unknown factors associated with carcinoid syndrome (CS) with the goal of earlier diagnosis of CS. METHODS: In this retrospective case-control study using United States administrative claims, patients (>= 18 years) newly diagnosed with gastrointestinal neuroendocrine tumors (GI NETs) without CS (controls) were exactly matched to patients with CS (cases) based on NET diagnosis date at a 3-to-1 ratio. Study index date was first CS diagnosis (controls: same distance from NET diagnosis as cases). The most observed conditions, excluding CS-associated symptoms/diagnoses, during the year before index date were assessed. Forward-stepwise logistic regression models were used to derive predictors, and were validation within another claims database. RESULTS: In the development database, 1004 patients with GI NETs were identified; 251 (25%) had CS and 753 (75%) were controls. In the validation database, 724 patients with GI NETs were identified; 181 (25%) had CS and 543 (75%) were controls. A total of 33 common diagnoses (excluding conditions already known to be associated with CS) in the development database were entered in forward step wise logistic regression models. In the final, validated logistic regression model, three factors prior to CS diagnosis were found consistently associated with higher risks for CS, including liver disorder [odds ratio (95%CI): 3.38 (2.07-5.51)], enlargement of lymph nodes [2.13 (1.10-4.11)], and abdominal mass [3.79 (1.87-7.69)]. CONCLUSION: GI NET patients with CS were 2-4 times as likely to have preexisting diagnoses (i.e., liver disorder, enlarged lymph nodes, abdominal mass) than non-CS patients. PMID- 29142476 TI - Clinical and pathological characterization of Epstein-Barr virus-associated gastric carcinomas in Portugal. AB - AIM: To determine the prevalence of Epstein-Barr virus (EBV)-associated gastric carcinomas in the North Region of Portugal and to study its clinicopathological characteristics. METHODS: We have performed a retrospective study including a total of 179 consecutive patients with gastric cancer (GC) submitted to gastrectomy during 2011 at the Portuguese Oncology Institute of Porto. Clinical and pathological data was collected from individual clinical records and inserted on a database with unique codification. Tumour tissues were collected from the institutional tumour bank. EBV was detected by in situ hybridization for the detection of EBV-encoded small RNAs (EBERs) and EBV latent proteins (LMP1 and LMP2A) were detected by immunohistochemistry. RESULTS: The analysis showed that EBV-associated gastric carcinomas (EBVaGC) represents 8.4% (15/179) of all GC cases, with a significant differential distribution among histological types (P < 0.001): 100% (3/3) of medullary carcinomas, 100% (1/1) of adenosquamous carcinoma, 8.7% (8/92) of tubular adenocarcinomas, 8.0% (2/25) of mixed carcinomas and 2% (1/51) in poorly cohesive carcinomas. The analysis revealed a higher predominance of EBVaGC in the upper third and middle (cardia, fundus and body) of the stomach (P = 0.041), a significant lower number of regional lymph nodes invasion (P = 0.025) and a tendency for better prognosis (P = 0.222). EBV latent protein expression revealed that all EBVaGC cases were LMP1-negative, nevertheless 6 cases (40%) expressed LPM2A, which reveals that these cases show a distinct EBV-Latency profile (latency II-like). CONCLUSION: EBVaGC represents 8.4% of all GC in the North Region of Portugal. The EBV-infected patients have specific clinic-pathological features that should be further explored to develop new strategies of management and treatment. PMID- 29142477 TI - Modified model for end-stage liver disease improves short-term prognosis of hepatitis B virus-related acute-on-chronic liver failure. AB - AIM: To investigate whether the short-term prognosis of hepatitis B virus (HBV) related acute-on-chronic liver failure (ACLF) could be improved by using a modified model for end-stage liver disease (MELD) including serum lactate. METHODS: This clinical study was conducted at the First Affiliated Hospital, Fujian Medicine University, China. From 2009 to 2015, 236 patients diagnosed with HBV-related ACLF at our center were recruited for this 3-month follow-up study. Demographic data and serum lactate levels were collected from the patients. The MELD scores with or without serum lactate levels from survival and non-survival groups were recorded and compared. RESULTS: Two hundred and thirty-six patients with HBV-ACLF were divided into two groups: survival group (S) and non-survival group (NS). Compared with the NS group, the patients in survival the S group had a significantly lower level of serum lactate (3.11 +/- 1.98 vs 4.67 +/- 2.43, t = 5.43, P < 0.001) and MELD score (23.33 +/- 5.42 vs 30.37 +/- 6.58, t = 9.01, P = 0.023). Furthermore, serum lactate level was positively correlated with MELD score (r = 0.315, P < 0.001). Therefore, a modified MELD including serum lactate was developed by logistic regression analysis (0.314 * lactate + 0.172 * MELD - 5.923). In predicting 3-month mortality using the MELD-LAC model, the patients from the S group had significantly lower baseline scores (-0.930 +/- 1.34) when compared with those from the NS group (0.771 +/- 1.32, t = 9.735, P < 0.001). The area under the receiver operating characteristic curve (AUROC) was 0.859 calculated by using the MELD-LAC model, which was significantly higher than that calculated by using the lactate level (0.790) or MELD alone (0.818). When the cutoff value was set at -0.4741, the sensitivity, specificity, positive predictive value and negative predictive value for predicting short-term mortality were 91.5%, 80.10%, 94.34% and 74.62%, respectively. When the MELD-LAC scores at baseline level were set at -0.5561 and 0.6879, the corresponding mortality rates within three months were 75% and 90%, respectively. CONCLUSION: The short-term prognosis of HBV-related ACLF was improved by using a modified MELD including serum lactate from the present 6-year clinical study. PMID- 29142478 TI - Chronic opioids in gastroparesis: Relationship with gastrointestinal symptoms, healthcare utilization and employment. AB - AIM: To examine the relationship of chronic scheduled opioid use on symptoms, healthcare utilization and employment in gastroparesis (Gp) patients. METHODS: Patients referred to our tertiary care academic center from May 2016 to July 2017, with established diagnosis or symptoms suggestive of Gp filled out the Patient Assessment of Upper GI Symptoms, abdominal pain and demographics questionnaires, and underwent gastric emptying and blood tests. They were asked about taking pain medicines and the types, doses, and duration. We used Mann Whitney U test, Analysis of Variance, Student's t test and chi2 tests where appropriate for data analyses. RESULTS: Of 223 patients with delayed gastric emptying, 158 (70.9%) patients were not taking opioids (GpNO), 22 (9.9%) were taking opioids only as needed, while 43 (19.3%) were on chronic (> 1 mo) scheduled opioids (GpCO), of which 18 were taking opioids for reasons that included gastroparesis and/or stomach pain. Median morphine equivalent use was 60 mg per day. GpCO reported higher severities of many gastrointestinal symptoms compared to GpNO including nausea (mean +/- SE of mean of 4.09 +/- 0.12 vs 3.41 +/- 0.12, P = 0.011), retching (2.86 +/- 0.25 vs 1.98 +/- 0.14, P = 0.003), vomiting (2.93 +/- 0.24 vs 2.07 +/- 0.15, P = 0.011), early satiety (4.17 +/- 0.19 vs 3.57 +/- 0.12, P = 0.004), post-prandial fullness (4.14 +/- 0.18 vs 3.63 +/- 0.11, P = 0.022), loss of appetite (3.64 +/- 0.21 vs 3.04 +/- 0.13, P = 0.039), upper abdominal pain (3.86 +/- 0.20 vs 2.93 +/- 0.13, P = 0.001), upper abdominal discomfort (3.74 +/- 0.19 vs 3.09 +/- 0.13, P = 0.031), heartburn during day (2.55 +/- 0.27 vs 1.89 +/- 0.13, P = 0.032), heartburn on lying down (2.76 +/- 0.28 vs 1.94 +/- 0.14, P = 0.008), chest discomfort during day (2.42 +/ 0.20 vs 1.83 +/- 0.12, P = 0.018), chest discomfort at night (2.40 +/- 0.23 vs 1.61 +/- 0.13, P = 0.003), regurgitation/reflux during day (2.77 +/- 0.25 vs 2.18 +/- 0.13, P = 0.040) and bitter/acid/sour taste in the mouth (2.79 +/- 0.27 vs 2.11 +/- 0.14, P = 0.028). GpCO had a longer duration of nausea per day (median of 7 h vs 4 h for GpNO, P = 0.037), and a higher number of vomiting episodes per day (median of 3 vs 2 for GpNO, P = 0.002). Their abdominal pain more frequently woke them up at night (78.1% vs 57.3%, P = 0.031). They had a lower employment rate (33.3% vs 54.2%, P = 0.016) and amongst those who were employed less number of working hours per week (median of 23 vs 40, P = 0.005). They reported higher number of hospitalizations in the last 1 year (mean +/- SE of mean of 2.90 +/- 0.77 vs 1.26 +/- 0.23, P = 0.047). CONCLUSION: GpCO had a higher severity of many gastrointestinal symptoms, compared to GpNO. Hospitalization rates were more than 2-fold higher in GpCO than GpNO. GpCO also had lower employment rate and working hours, when compared to GpNO. PMID- 29142479 TI - Medication beliefs predict medication adherence in ambulatory patients with decompensated cirrhosis. AB - AIM: To investigate the impact of medication beliefs, illness perceptions and quality of life on medication adherence in people with decompensated cirrhosis. METHODS: One hundred adults with decompensated cirrhosis completed a structured questionnaire when they attended for routine outpatient hepatology review. Measures of self-reported medication adherence (Morisky Medication Adherence Scale), beliefs surrounding medications (Beliefs about Medicines Questionnaire), perceptions of illness and medicines (Brief Illness Perception Questionnaire), and quality of life (Chronic Liver Disease Questionnaire) were examined. Clinical data were obtained via patient history and review of medical records. Least absolute shrinkage and selection operator and stepwise backwards regression techniques were used to construct the multivariable logistic regression model. Statistical significance was set at alpha = 0.05. RESULTS: Medication adherence was "High" in 42% of participants, "Medium" in 37%, and "Low" in 21%. Compared to patients with "High" adherence, those with "Medium" or "Low" adherence were more likely to report difficulty affording their medications (P < 0.001), lower perception of treatment helpfulness (P = 0.003) and stronger medication concerns relative to medication necessity beliefs (P = 0.003). People with "Low" adherence also experienced greater symptom burden and poorer quality of life, including more frequent abdominal pain (P = 0.023), shortness of breath (P = 0.030), and emotional disturbances (P = 0.050). Multivariable analysis identified having stronger medication concerns relative to necessity beliefs (Necessity-Concerns Differential <= 5, OR = 3.66, 95%CI: 1.18-11.40) and more frequent shortness of breath (shortness of breath score <= 3, OR = 3.87, 95%CI: 1.22-12.25) as independent predictors of "Low"adherence. CONCLUSION: The association between "Low" adherence and patients having strong concerns or doubting the necessity or helpfulness of their medications should be explored further given the clinical relevance. PMID- 29142480 TI - Case of familial hyperlipoproteinemia type III hypertriglyceridemia induced acute pancreatitis: Role for outpatient apheresis maintenance therapy. AB - Hypertriglyceridemic pancreatitis (HTGP) accounts for up to 10% of acute pancreatitis presentations in non-pregnant individuals and is the third most common cause of acute pancreatitis after alcohol and gallstones. There are a number of retrospective studies and case reports that have suggested a role for apheresis and insulin infusion in the acute inpatient setting. We report a case of HTGP in a male with hyperlipoproteinemia type III who was treated successfully with insulin and apheresis on the initial inpatient presentation followed by bi monthly outpatient maintenance apheresis sessions for the prevention of recurrent HTGP. We also reviewed the literature for the different inpatient and outpatient management modalities of HTGP. Given that there are no guidelines or randomized clinical trials that evaluate the outpatient management of HTGP, this case report may provide insight into a possible role for outpatient apheresis maintenance therapy. PMID- 29142482 TI - S-Adenosyl-L-methionine towards hepatitis C virus expression: Need to consider S Adenosyl-L-methionine's chemistry, physiology and pharmacokinetics. AB - S-Adenosyl-L-methionine (SAM) is a cofactor serving as a methyl donor in numerous enzymatic reactions. It has been reported that SAM has the potential to modify antioxidant-enzymes, glutathione-biosynthesis and methionine adenosyltransferases 1/2 in hepatitis C virus -expressing cells at millimolar concentrations. The efficacy of SAM at micromolar concentrations and the underlying mechanisms remain to be demonstrated. PMID- 29142481 TI - Rescue case of low birth weight infant with acute hepatic failure. AB - : We report a case involving a rescued low birth weight infant (LBWI) with acute liver failure. CASE: The patient was 1594 g and 323/7 gestational wk at birth. At the age of 11 d, she developed acute liver failure due to gestational alloimmune liver disease. Exchange transfusion and high-dose gamma globulin therapy were initiated, and body weight increased with enteral nutrition. Exchange transfusion was performed a total of 33 times prior to living donor liver transplantation (LDLT). Her liver dysfunction could not be treated by medications alone. At 55 d old and a body weight of 2946 g, she underwent LDLT using an S2 monosegment graft from her mother. Three years have passed with no reports of intellectual disability or liver dysfunction. LBWIs with acute liver failure may be rescued by LDLT after body weight has increased to over 2500 g. PMID- 29142483 TI - New results on the continuous Weinstein wavelet transform. AB - We consider the continuous wavelet transform [Formula: see text] associated with the Weinstein operator. We introduce the notion of localization operators for [Formula: see text]. In particular, we prove the boundedness and compactness of localization operators associated with the continuous wavelet transform. Next, we analyze the concentration of [Formula: see text] on sets of finite measure. In particular, Benedicks-type and Donoho-Stark's uncertainty principles are given. Finally, we prove many versions of Heisenberg-type uncertainty principles for [Formula: see text]. PMID- 29142484 TI - Contemporary Management of Pulmonary Arteriovenous Malformations. AB - Pulmonary arteriovenous malformations (PAVMs) are atypical vascular structures involving a direct connection between the pulmonary arterial and venous circulations. While PAVMs are a relatively uncommon disorder, unmanaged cases are at risk for the development of serious complications including embolization and infection. Since their first description in 1897, PAVMs have been identified and treated in a variety of ways. Advancements in diagnostic methods and operative techniques have allowed for more effective treatment of the disease. Most recently, the use of vascular plug transcatheter embolization has been described as an effective therapeutic procedure in the management of PAVMs. In this report, we present our experience with nine cases of PAVMs treated at the University of Kentucky, including special consideration of an exemplary case that illustrates the typical course of treatment for the disease. PMID- 29142485 TI - Unexpected Inflammation in the Sympathetic Ganglia in Thromboangiitis Obliterans. AB - The aim of this study was to inspect more closely the microscopic and molecular sympathetic ganglia histology in thromboangiitis obliterans (TAO). The paraffin block and frozen RNAlater-treated tissue of the lumbar sympathetic ganglia of 19 TAO Caucasian male patients were evaluated. The gene expression of cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) markers in the frozen RNAlater-treated sympathetic ganglia tissues were evaluated by real-time polymerase chain reaction. Unexpectedly, lymphocyte infiltration was observed in all of the histological sections, ranging from scattered to moderate lymphocyte infiltration. In seven patients, five of them underwent below-knee amputation, neutrophil infiltration was observed in addition to lymphocyte infiltration. The gene expression of the CD8 marker in all of the samples with the expression of CD4 markers in only four tissue samples was demonstrated. The expression of CD8 in comparison to CD4 was approximately 4.37-fold changes using Pfaffle method. It appears that inflammation of the sympathetic ganglia plays a role in the pathophysiology of TAO and its outcome. Sympathetic ganglia inflammation may be responsible for general vasoconstriction, vascular inflammation, and the increased risk of thrombotic events, by activating the platelets. The dominant infiltration of T cytotoxic lymphocytes and neutrophils in sympathetic ganglia may probably support the idea of possible intracellular infectious pathogen trigger for TAO and consequently infiltration of pathogen-specific T cells into the sympathetic ganglia in TAO. PMID- 29142486 TI - Vitronectin and Urokinase-Type Plasminogen Activator Gene Expression Levels Are Increased in Patients with Coronary Artery In-Stent Restenosis. AB - Neointimal hyperplasia is known as a main factor contributing to in-stent restenosis (ISR). Monocytes may play a central role in vessel restenosis process after stent implantation. The aim of this study was to investigate the relationships between the urokinase-type plasminogen activator (PLAU) and vitronectin (Vtn) gene expression levels in peripheral blood mononuclear cell samples isolated from whole blood of 66 patients undergoing coronary artery angiography (22 controls, stenosis < 0.05%; 22 with stent no-restenosis and stenosis < 70%; and 22 with ISR and stenosis > 70%). The Vtn and PLAU gene expression levels were measured by real-time quantitative polymerase chain reaction technique. The age- and gender-independent increases in the expression levels of Vtn (17-fold; p < 0.001) and PLAU (27-fold; p < 0.0001) genes were found in the patients with ISR as compared with the control group. The results suggested that the Vtn and PLAU genes may be involved in the coronary artery ISR. PMID- 29142487 TI - Preliminary Investigations Showing Venous Thromboembolism Recurrence in Patients with Residual Venous Obstruction in Singaporean Population. AB - This study aims to determine the association of residual venous obstruction (RVO) with recurrent venous thromboembolism (VTE). A retrospective cohort study was conducted determining if RVO on ultrasonography is associated with recurrent VTE in a Singaporean population. The subjects were identified from the Vascular Diagnostic Laboratory patients' record of Tan Tock Seng Hospital (TTSH), Singapore between 2008 and 2013. All the patients included had RVO after 3 months of anticoagulation. Data such as age, gender, race, thrombus location, etiology, history of malignancy, thrombophilia screen, treatment duration, and follow-up were recorded for analysis. Statistical analysis was performed using Stata/SE 13.1 (StataCorp LLC). The study was approved by the National Healthcare Group Domain Specific Review Board (DSRB), Singapore. Out of the 34 patients who had RVO, 6 (17.6%) developed VTE recurrence. Patients were treated with anticoagulation for a mean time of 24.5 months. The mean follow-up time for VTE recurrence was 25.4 months. Out of the six patients who had VTE recurrence, one had common iliac vein involvement, four had superficial femoral vein and common femoral vein involvement, zero had popliteal vein involvement, and one had calf veins involvement. There was a significant association between thrombophilia ( p = 0.0195) and malignancy ( p = 0.020) at inclusion with the risk of recurrent VTE. The presence of RVO after 3 months of anticoagulation is likely to increase the risk of VTE recurrence. Larger studies with RVO are needed to evaluate if there is an increased risk of VTE recurrence in the Asian population. PMID- 29142488 TI - Usefulness of a Nonsuture Closure Device in Patients Undergoing Diagnostic Coronary and Peripheral Angiography. AB - Vascular access site complications can follow diagnostic coronary and peripheral angiography. We compared the complication rates of the Catalyst vascular closure device, with the complication rates after manual compression in patients undergoing diagnostic angiographic procedures via femoral access. We studied 1,470 predominantly male patients undergoing diagnostic coronary and peripheral angiography. Catalyst closure devices were used in 436 (29.7%) patients and manual compression was used in 1,034 (70.3%) patients. The former were allowed to ambulate after 2 hours, while the latter were allowed to ambulate after 6 hours. Major complications occurred in 4 (0.9%) patients who had a Catalyst device and in 14 (1.4%) patients who had manual compression (odds ratio [OR]: 0.67, 95% confidence interval [CI]: 0.22-2.1, p = 0.49). Any complications occurred in 51 (11.7%) patients who had a Catalyst closure device and in 64 (6.2%) patients who had manual compression (OR: 2, CI: 1.4-3, p < 0.01). After adjustment for other variables and for a propensity score reflecting the probability to receive the closure device, the association of major complications with the use of the closure device remained not significant (OR: 0.54, 95% CI: 0.17-1.7, p = 0.29), while the association of any complications with the use of the Catalyst device remained significant (OR: 1.9, 95% CI: 1.3-2.9, p < 0.01). The Catalyst device was not associated with an increased risk of major groin complications but was associated with an increased risk of any complications compared with manual compression. Patients receiving the closure device ambulated sooner. PMID- 29142489 TI - Correlation between Osteoprotegerin Serum Level and Coronary Calcification Using Coronary Artery Calcium Score in Patient with Moderate-Severe Cardiovascular Risk Factor. AB - Coronary artery calcification is a part of atherosclerosis process associated with coronary heart disease. Recently, coronary artery calcification assessment using computed tomography (CT) is still the best noninvasive imaging with high sensitivity and specificity. Osteoprotegerin (OPG) is one of vascular calcification marker that through its role to bind receptor activator of nuclear factor-kappabeta ligand and inhibit osteoclastogenesis is suspected of playing a role for coronary calcification in atherosclerosis process. The objective of this study was to prove a positive correlation between OPG serum level and coronary calcification using coronary artery calcium (CAC) score in patient with moderate severe cardiovascular (CV) risk factor. This is a cross-sectional study with purposive sampling technique. Thirty-three subjects participate in this research and each subject underwent a multislice computed tomography (MSCT) examination to assess coronary calcification and their blood samples were collected for OPG measurement. This study is analyzed with Spearman's correlation test. The mean of OPG serum level in this study was 5.89 +/- 2.1 pmol/L for moderate-risk Framingham risk score (FRS) and the mean of OPG serum level for high-risk FRS was 7.27 +/- 3.4. There was a positive, moderate, and significant correlation between OPG serum level and coronary calcification using CAC score in patient with moderate-severe CV risk factor ( r = 0.694; p < 0.001). PMID- 29142490 TI - Postoperative Elevated Resistive Indices Do Not Predict Hepatic Artery Thrombosis in Extended Criteria Donor Livers. AB - Postoperative transplant liver ultrasounds were analyzed in standard criteria donor (SCD), extended criteria donor (ECD), and donation after cardiac death (DCD) liver allografts to determine if elevated resistive indices (RIs) are consistently present and if they are pathological. Postoperative transplant liver ultrasounds were reviewed from 115 consecutive patients. Hepatic arterial RIs were stratified based on the type of donor: DCD, macrosteatosis (>30%), or standard criteria. In all patients with elevated RI, subsequent ultrasounds were reviewed to demonstrate RI normalization. The mean RI for all 115 patients was 0.64, DCD was 0.67, macrosteatosis was 0.81, and SCD was 0.61 ( p = 0.033). The RI on subsequent liver ultrasounds for DCD and macrosteatosis normalized without any intervention. There were no incidences of early hepatic artery thrombosis (HAT) observed in the cohort. Hepatic arterial RI in ECDs and DCDs are elevated in the immediate postoperative period but are not predictive of HAT. It represents interparenchymal graft stiffness and overall graft edema rather than an impending technical complication. The results of our study do not support the routine use of anticoagulation or routine investigation with computed tomography angiography for elevated RIs as these findings are self-limiting and normalize over a short period of time. We hope that this information helps guide the clinical management of liver transplant patients from expanded criteria donors. PMID- 29142491 TI - Impact of Remote Ischemic Postconditioning during Primary Percutaneous Coronary Intervention on Left Ventricular Remodeling after Anterior Wall ST-Segment Elevation Myocardial Infarction: A Single-Center Experience. AB - The role of remote ischemic postconditioning (RIPostC) in improving left ventricular (LV) remodeling after primary percutaneous coronary intervention (PCI) is not well established. To determine the efficacy and safety of RIPostC in improving LV remodeling and cardiovascular outcomes after primary PCI for anterior ST-elevation myocardial infarction (STEMI). Seventy-one patients with anterior STEMI were randomized to primary PCI with RIPostC protocol ( n = 36) versus conventional primary PCI ( n = 35). Primary outcomes included LV remodeling and LV ejection fraction (LVEF) at 6 month follow-up using transthoracic echocardiography. Secondary outcomes included infarct size, ST segment resolution (STR) >=70%, Thrombolysis in Myocardial Infarction (TIMI) flow grade, and myocardial blush grade (MBG). Major adverse cardiac events (MACEs) were also assessed at 6 months. Safety outcome included incidence of acute kidney injury (AKI) postprimary PCI. Sixty patients completed the study. At 6 months, there was no significant decrease in the incidence of LV remodeling with RIPostC group ( p = 0.42). Similarly, RIPostC failed to show significant improvement in LVEF. However, STR >= 70% after primary PCI was achieved more in the RIPostC group ( p = 0.04), with a trend toward less AKI in the RIPostC group ( p = 0.08). All other secondary end points, including MACEs at 6 months, were similar in both groups. RIPostC might be associated with better STR after reperfusion as well as less incidence of AKI in patients undergoing primary PCI for anterior wall STEMI, indicating potential benefit in those patients. Whether this role can be translated to better outcomes after primary PCI warrants further investigation. PMID- 29142492 TI - Early Changes in Platelet Size and Number in Patients with Acute Coronary Syndrome. AB - A strong relationship exists between acute coronary syndrome (ACS) and platelets (PLTs) volume. Mean platelet volume (MPV) is a parameter of PLT functions and a marker for increased PLT activation. The aim of this study was to determine early changes in number of total PLT and MPV in different manifestation of ACS and to find out predictive value of MPV in the spectrum of ACS. This was a prospective study. One hundred thirty-four ACS patients were enrolled, 76 of them finished the study. PLT and MPV in patients with unstable angina, non-ST elevation, and ST elevation myocardial infarctions were determined on arrival and 1, 3, 72 hours, and 7 days after the admission to hospital. There was decrease in PLT and MPV in all three groups after 3 hours of arrival in hospital in comparison with admission values. In the later time period (72 hours and 7 days), there was an increase in PLT and MPV only in patients with acute myocardial infarction (AMI). We have revealed completely new dynamics in early changes in MPV and PLT count in patients with AMI. Biphasic changes were found in early phase after admission to the hospital. Fast response in these parameters raises new questions about their origin. PMID- 29142493 TI - Cervical Arterial Fibromuscular Dysplasia in a Biethnic Population: A Retrospective Study in the U.S.-Mexican Border. AB - Background There have been studies trying to characterize Fibromuscular Dysplasia (FMD); however, most of them are based in mainly non-Hispanic sample. The objective of this study is to better understand the epidemiology and clinical characteristics of craniocervical FMD in the Hispanic population. Methods We retrospectively reviewed the cerebral angiograms performed in our center in a period of 3.5 years under any indication looking for angiographic patterns of FMD. Exclusion criteria consisted of cases in which the first angiogram was done when the patients were younger than 18 years. Patients were subdivided based on those with FMD and those without it for baseline characteristics and were looked for any associations. We further compared the same baseline characteristics among Hispanic FMD and non-Hispanic FMD population. A chart review was conducted looking for clinical features and vascular events. Results We analyzed 448 angiograms among patients younger than 18 years. We identified 47 patients with evidence of FMD involving the cervical arteries and 401 patients without FMD. Of the 47 patients with FMD in our neuroendovascular registry, we found that 76.6% were women and 57.4% were Hispanics. There was no statistical significant difference when comparing the variables across ethnicities, except history of cigarette smoking and dyslipidemia. The most common associated supra-aortic arterial lesions seen in the FMD group were intracranial aneurysm and arterial dissections. We then used same variables to compare Hispanic FMD with non Hispanic FMD. We have found that there has been a positive association of cigarette smoking and dyslipidemia with FMD ( p <= 0.05). Conclusion Our study suggests that FMD affecting the carotid and vertebral arteries has similar demographic pattern across ethnicities in the United States. In Hispanics, the disease appears to have a predilection for women and history of cigarette smoking. Intracranial aneurysm and arterial dissection were the most commonly associated arterial lesions. PMID- 29142494 TI - Endovascular Treatment of Abdominal Aortic Aneurysm with Complete Iliac Occlusion: Case Series and Literature Review. AB - In patients with abdominal aortic aneurysms (AAA) and complete iliac occlusion, endovascular aortic aneurysm repair (EVAR) using a bifurcated stent graft has clear advantages over aortouniiliac stent grafts. Bifurcated stent grafts had improved hemodynamic flow and increased primary and secondary patency rates compared with aortouniiliac stent grafts. The use of aortouniiliac stent grafts with femorofemoral crossover bypass is associated with complications including infection of the prosthesis, steal phenomenon, and the associated difficulties for further endovascular access at the site of the femoral anastomosis. Recanalization of occluded iliac arteries at the time of EVAR avoids the complications mentioned above. We report three cases of patients with AAA and iliac occlusion who were successfully treated with iliac recanalization at the time of EVAR. PMID- 29142495 TI - Thoracic Origin of Single Right Renal Artery: Some Interesting Facets. AB - Two cases of thoracic origin of the right renal artery, arising from the level of D11 vertebrae detected on an incidental computed tomography examination are reported. A brief review of embryology is presented. Simultaneous variation of the origin of the right inferior phrenic artery is highlighted as a unique feature of our cases. The importance of this relatively uncommon anomaly in the clinical context is discussed. PMID- 29142496 TI - Precipitous Resolution of Type-A Intramural Hematoma with Medical Management in a Patient with Metastatic Stage 4 Renal Cell Carcinoma. AB - Intramural hematoma (IMH) is a variant form of aortic dissection characterized by involvement of the aortic media without the presence of an overt intimal flap. Surgical extirpation is the standard of care for type-A IMH in the Western world. However, a conservative approach with anti-impulse therapy has been advocated especially in Japan as a viable alternative. Here, we report a case of an elderly male patient with a history of metastatic stage 4 renal cell carcinoma who was treated with anti-impulse therapy for an acute type-A IMH. Blood pressure stabilization and continuous monitoring resulted in complete resolution of the IMH within 6 days. This report illustrates how immediate medical management in patients with acute type-A IMH who are not surgical candidates can alleviate the progression or even lead to regression as early as 1 week after initiating anti impulse therapy. PMID- 29142498 TI - Event and Apparent Horizon Finders for 3 + 1 Numerical Relativity. AB - Event and apparent horizons are key diagnostics for the presence and properties of black holes. In this article I review numerical algorithms and codes for finding event and apparent horizons in numerically-computed spacetimes, focusing on calculations done using the 3 + 1 ADM formalism. The event horizon of an asymptotically-flat spacetime is the boundary between those events from which a future-pointing null geodesic can reach future null infinity and those events from which no such geodesic exists. The event horizon is a (continuous) null surface in spacetime. The event horizon is defined nonlocally in time: it is a global property of the entire spacetime and must be found in a separate post processing phase after all (or at least the nonstationary part) of spacetime has been numerically computed. There are three basic algorithms for finding event horizons, based on integrating null geodesics forwards in time, integrating null geodesics backwards in time, and integrating null surfaces backwards in time. The last of these is generally the most efficient and accurate. In contrast to an event horizon, an apparent horizon is defined locally in time in a spacelike slice and depends only on data in that slice, so it can be (and usually is) found during the numerical computation of a spacetime. A marginally outer trapped surface (MOTS) in a slice is a smooth closed 2-surface whose future-pointing outgoing null geodesics have zero expansion Theta. An apparent horizon is then defined as a MOTS not contained in any other MOTS. The MOTS condition is a nonlinear elliptic partial differential equation (PDE) for the surface shape, containing the ADM 3-metric, its spatial derivatives, and the extrinsic curvature as coefficients. Most "apparent horizon" finders actually find MOTSs. There are a large number of apparent horizon finding algorithms, with differing trade-offs between speed, robustness, accuracy, and ease of programming. In axisymmetry, shooting algorithms work well and are fairly easy to program. In slices with no continuous symmetries, spectral integral-iteration algorithms and elliptic-PDE algorithms are fast and accurate, but require good initial guesses to converge. In many cases, Schnetter's "pretracking" algorithm can greatly improve an elliptic-PDE algorithm's robustness. Flow algorithms are generally quite slow but can be very robust in their convergence. Minimization methods are slow and relatively inaccurate in the context of a finite differencing simulation, but in a spectral code they can be relatively faster and more robust. PMID- 29142497 TI - Expression of CCL2 and its receptor in activation and migration of microglia and monocytes induced by photoreceptor apoptosis. AB - Purpose: To explore the effect of the CCL2 and CCR2 system on the activation and migration of microglia and monocytes in light-induced photoreceptor apoptosis. Methods: At 1 day, 3 days, 7 days, and 14 days after light exposure, OX42 and ED1 immunostaining were used to label the activation and migration of microglia and monocytes. Double immunostaining of CCL2 with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), OX42, or glial fibrillary acidic protein (GFAP) was applied to explore the relationships among CCL2, apoptotic photoreceptors, activated microglia and monocytes, and macroglial cells (Muller cells and astrocytes). Real-time PCR was used to evaluate the mRNA levels of retinal CCL2 and CCR2 and the proinflammatory factors interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha. Results: Real-time PCR analyses showed that CCL2 and CCR2 expression gradually increased after light exposure and peaked at 3 days, coinciding with the infiltration of OX42-positive cells and the expression of IL-1 beta and TNF-alpha in the outer retina. Double immunostaining of CCL2 with TUNEL revealed that CCL2 was expressed robustly in about 30% of the apoptotic photoreceptors at the early stage. As degeneration progressed, immunostaining of CCL2 with OX42 showed that activated and migrated microglia and monocytes expressed CCL2. At the late stage, Muller cells became the main source of CCL2, which was illustrated by CCL2 immunostaining with GFAP. Conclusions: Light exposure led to apoptosis of photoreceptors, which expressed CCL2, accelerating an inflammation-mediated cascade by activating and attracting microglia and monocytes and promoting their secretion of CCL2 in the injured position. PMID- 29142499 TI - Null Geodesic Congruences, Asymptotically-Flat Spacetimes and Their Physical Interpretation. AB - A priori, there is nothing very special about shear-free or asymptotically shear free null geodesic congruences. Surprisingly, however, they turn out to possess a large number of fascinating geometric properties and to be closely related, in the context of general relativity, to a variety of physically significant effects. It is the purpose of this paper to try to fully develop these issues. This work starts with a detailed exposition of the theory of shear-free and asymptotically shear-free null geodesic congruences, i.e., congruences with shear that vanishes at future conformal null infinity. A major portion of the exposition lies in the analysis of the space of regular shear-free and asymptotically shear-free null geodesic congruences. This analysis leads to the space of complex analytic curves in an auxiliary four-complex dimensional space, [Formula: see text]-space. They in turn play a dominant role in the applications. The applications center around the problem of extracting interior physical properties of an asymptotically-flat spacetime directly from the asymptotic gravitational (and Maxwell) field itself, in analogy with the determination of total charge by an integral over the Maxwell field at infinity or the identification of the interior mass (and its loss) by (Bondi's) integrals of the Weyl tensor, also at infinity. More specifically, we will see that the asymptotically shear-free congruences lead us to an asymptotic definition of the center-of-mass and its equations of motion. This includes a kinematic meaning, in terms of the center-of-mass motion, for the Bondi three-momentum. In addition, we obtain insights into intrinsic spin and, in general, angular momentum, including an angular-momentum-conservation law with well-defined flux terms. When a Maxwell field is present, the asymptotically shear-free congruences allow us to determine/define at infinity a center-of-charge world line and intrinsic magnetic dipole moment. PMID- 29142501 TI - Initial Data for Numerical Relativity. AB - Initial data are the starting point for any numerical simulation. In the case of numerical relativity, Einstein's equations constrain our choices of these initial data. We will examine several of the formalisms used for specifying Cauchy initial data in the 3 + 1 decomposition of Einstein's equations. We will then explore how these formalisms have been used in constructing initial data for spacetimes containing black holes and neutron stars. In the topics discussed, emphasis is placed on those issues that are important for obtaining astrophysically realistic initial data for compact binary coalescence. PMID- 29142502 TI - The Einstein-Vlasov System/Kinetic Theory. AB - The main purpose of this article is to provide a guide to theorems on global properties of solutions to the Einstein-Vlasov system. This system couples Einstein's equations to a kinetic matter model. Kinetic theory has been an important field of research during several decades in which the main focus has been on nonrelativistic and special relativistic physics, i.e. to model the dynamics of neutral gases, plasmas, and Newtonian self-gravitating systems. In 1990, Rendall and Rein initiated a mathematical study of the Einstein-Vlasov system. Since then many theorems on global properties of solutions to this system have been established. The Vlasov equation describes matter phenomenologically, and it should be stressed that most of the theorems presented in this article are not presently known for other such matter models (i.e. fluid models). This paper gives introductions to kinetic theory in non-curved spacetimes and then the Einstein-Vlasov system is introduced. We believe that a good understanding of kinetic theory in non-curved spacetimes is fundamental to good comprehension of kinetic theory in general relativity. PMID- 29142500 TI - Cosmology and Fundamental Physics with the Euclid Satellite. AB - Euclid is a European Space Agency medium-class mission selected for launch in 2019 within the Cosmic Vision 2015-2025 program. The main goal of Euclid is to understand the origin of the accelerated expansion of the universe. Euclid will explore the expansion history of the universe and the evolution of cosmic structures by measuring shapes and red-shifts of galaxies as well as the distribution of clusters of galaxies over a large fraction of the sky. Although the main driver for Euclid is the nature of dark energy, Euclid science covers a vast range of topics, from cosmology to galaxy evolution to planetary research. In this review we focus on cosmology and fundamental physics, with a strong emphasis on science beyond the current standard models. We discuss five broad topics: dark energy and modified gravity, dark matter, initial conditions, basic assumptions and questions of methodology in the data analysis. This review has been planned and carried out within Euclid's Theory Working Group and is meant to provide a guide to the scientific themes that will underlie the activity of the group during the preparation of the Euclid mission. PMID- 29142503 TI - Stochastic Gravity: Theory and Applications. AB - Whereas semiclassical gravity is based on the semiclassical Einstein equation with sources given by the expectation value of the stress-energy tensor of quantum fields, stochastic semiclassical gravity is based on the Einstein Langevin equation, which has in addition sources due to the noise kernel. The noise kernel is the vacuum expectation value of the (operatorvalued) stress energy bi-tensor which describes the fluctuations of quantum matter fields in curved spacetimes. In the first part, we describe the fundamentals of this new theory via two approaches: the axiomatic and the functional. The axiomatic approach is useful to see the structure of the theory from the framework of semiclassical gravity, showing the link from the mean value of the stress-energy tensor to their correlation functions. The functional approach uses the Feynman Vernon influence functional and the Schwinger-Keldysh closed-time-path effective action methods which are convenient for computations. It also brings out the open systems concepts and the statistical and stochastic contents of the theory such as dissipation, fluctuations, noise, and decoherence. We then focus on the properties of the stress-energy bi-tensor. We obtain a general expression for the noise kernel of a quantum field defined at two distinct points in an arbitrary curved spacetime as products of covariant derivatives of the quantum field's Green function. In the second part, we describe three applications of stochastic gravity theory. First, we consider metric perturbations in a Minkowski spacetime. We offer an analytical solution of the Einstein-Langevin equation and compute the two-point correlation functions for the linearized Einstein tensor and for the metric perturbations. Second, we discuss structure formation from the stochastic gravity viewpoint, which can go beyond the standard treatment by incorporating the full quantum effect of the inflaton fluctuations. Third, we discuss the backreaction of Hawking radiation in the gravitational background of a quasi static black hole (enclosed in a box). We derive a fluctuation-dissipation relation between the fluctuations in the radiation and the dissipative dynamics of metric fluctuations. PMID- 29142504 TI - What if? Exploring the multiverse through Euclidean wormholes. AB - We present Euclidean wormhole solutions describing possible bridges within the multiverse. The study is carried out in the framework of third quantisation. The matter content is modelled through a scalar field which supports the existence of a whole collection of universes. The instanton solutions describe Euclidean solutions that connect baby universes with asymptotically de Sitter universes. We compute the tunnelling probability of these processes. Considering the current bounds on the energy scale of inflation and assuming that all the baby universes are nucleated with the same probability, we draw some conclusions about which universes are more likely to tunnel and therefore undergo a standard inflationary era. PMID- 29142505 TI - Targeting deubiquitinating enzymes in cancer stem cells. AB - Cancer stem cells (CSCs) are rare but accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. Ubiquitination and deubiquitination of stemness-related proteins are essential for CSC maintenance and differentiation, even leading to execute various stem cell fate choices. Deubiquitinating enzymes (DUBs), specifically disassembling ubiquitin chains, are important to maintain the balance between ubiquitination and deubiquitination. In this review, we have focused on the DUBs regulation of stem cell fate determination. For example, we discuss deubiquitinase inhibition may lead stem cell transcription factors and CSCs-related protein degradation. Also, CSCs microenvironment is regulated by DUBs activity. Our review provides a new insight into DUBs activity by emphasizing their cellular role in regulating stem cell fate and illustrates the opportunities for the application of DUBs inhibitors in the CSC-targeted therapy. PMID- 29142506 TI - Detection of circulating natural antibodies to inflammatory cytokines in type-2 diabetes and clinical significance. AB - Background: Inflammatory cytokines have been demonstrated to be involved in developing insulin resistance and type-2 diabetes (T2D). Natural antibodies in the circulation have protective effects on common diseases in humans. The present study was thus designed to test the hypothesis that natural antibodies against inflammatory cytokines could be associated with T2D. Methods: An enzyme-linked immunosorbent assay (ELISA) was developed in-house to detect plasma IgG against peptide antigens derived from interleukin 1alpha (IL1alpha), IL1beta, IL6, IL8 and tumor necrosis factor-alpha (TNF-alpha) in 200 patients with T2D and 220 control subjects. Results: Binary regression showed that compared with control subjects, T2D patients had a decreased level of plasma anti-IL6 IgG (adjusted r2=0.034, p=0.0001), anti-IL8 IgG (adjusted r2=0.021, p=0.002) and anti-TNF-alpha IgG (adjusted r2=0.017, p=0.003). Female patients mainly contributed to decreased levels of anti-IL6 IgG (adjusted r2=0.065, p=0.0008) and anti-IL8 IgG (adjusted r2=0.056, p=0.003), while male patients mainly contributed to decreased anti-TNF alpha IgG levels (adjusted r2=0.024, p=0.005). ROC curve analysis revealed a sensitivity of 16.5% against specificity of 95.5% for anti-IL6 IgG assay and a sensitivity of 19.5% against specificity of 95.9% for anti-IL8 IgG assay. Glycated hemoglobin levels measured after 6-month glucose-lowering treatment appeared to be inversely correlated with plasma anti-IL1alpha IgG (r=-0.477, df=17, p=0.039) and anti-IL6 IgG (r=-0.519, df=17, p=0.023) although such correlation failed to survive the Bonferroni correction. Conclusions: Deficiency of natural IgG against inflammatory cytokines is likely to be a risk factor for T2D development and detection of such antibodies may be useful for personalized treatment of the disease. PMID- 29142507 TI - Suicidal ideation and attempts among court-involved, non-incarcerated youth. AB - Over the past decade, suicide remains one of the leading causes of death among adolescents and a public health priority. Court-involved non-incarcerated juvenile justice youth frequently present with risk factors for suicide. Among these court-involved youth, 14% (n=50) endorsed a lifetime history of suicide ideation and attempts. Three main factors were associated with increased risk: prior offense, substance use, and childhood sexual abuse histories. This study highlights the importance of understanding suicidal behavior among non-detained juvenile justice populations. Community-based court involvement provides a rare opportunity to coordinate screening and suicide prevention efforts for youth and their families. PMID- 29142508 TI - Proteomic characterisation of bovine and avian purified protein derivatives and identification of specific antigens for serodiagnosis of bovine tuberculosis. AB - Background: Bovine purified protein derivative (bPPD) and avian purified protein derivative (aPPD) are widely used for bovine tuberculosis diagnosis. However, little is known about their qualitative and quantitative characteristics, which makes their standardisation difficult. In addition, bPPD can give false-positive tuberculosis results because of sequence homology between Mycobacterium bovis (M. bovis) and M. avium proteins. Thus, the objective of this study was to carry out a proteomic characterisation of bPPD, aPPD and an immunopurified subcomplex from bPPD called P22 in order to identify proteins contributing to cross-reactivity among these three products in tuberculosis diagnosis. Methods: Trypsin digests of bPPD, aPPD and P22 were analysed by nanoscale liquid chromatography-electrospray ionization tandem mass spectrometry. Mice were immunised with bPPD or aPPD, and their serum was tested by indirect ELISA for reactivity against these preparations as well as against P22. Results: A total of 456 proteins were identified in bPPD, 1019 in aPPD and 118 in P22; 146 of these proteins were shared by bPPD and aPPD, and 43 were present in all three preparations. Candidate proteins that may cause cross-reactivity between bPPD and aPPD were identified based on protein abundance and antigenic propensity. Serum reactivity experiments indicated that P22 may provide greater specificity than bPPD with similar sensitivity for ELISA-type detection of antibodies against M. tuberculosis complex. Conclusion: The subpreparation from bPPD called P22 may be an alternative to bPPD for serodiagnosis of bovine tuberculosis, since it shares fewer proteins with aPPD than bPPD does, reducing risk of cross-reactivity with anti-M. avium antibodies. PMID- 29142510 TI - Role of capsule endoscopy in suspected or established Crohn's disease in real practice. PMID- 29142509 TI - Using an NMR metabolomics approach to investigate the pathogenicity of amyloid beta and alpha-synuclein. AB - Introduction: The pathogenicity at differing points along the aggregation pathway of many fibril-forming proteins associated with neurodegenerative diseases is unclear. Understanding the effect of different aggregation states of these proteins on cellular processes is essential to enhance understanding of diseases and provide future options for diagnosis and therapeutic intervention. Objectives: To establish a robust method to probe the metabolic changes of neuronal cells and use it to monitor cellular response to challenge with three amyloidogenic proteins associated with neurodegenerative diseases in different aggregation states. Method: Neuroblastoma SH-SY5Y cells were employed to design a robust routine system to perform a statistically rigorous NMR metabolomics study into cellular effects of sub-toxic levels of alpha-synuclein, amyloid-beta 40 and amyloid-beta 42 in monomeric, oligomeric and fibrillar conformations. Results: This investigation developed a rigorous model to monitor intracellular metabolic profiles of neuronal cells through combination of existing methods. This model revealed eight key metabolites that are altered when neuroblastoma cells are challenged with proteins in different aggregation states. Metabolic pathways associated with lipid metabolism, neurotransmission and adaptation to oxidative stress and inflammation are the predominant contributors to the cellular variance and intracellular metabolite levels. The observed metabolite changes for monomer and oligomer challenge may represent cellular effort to counteract the pathogenicity of the challenge, whereas fibrillar challenge is indicative of system shutdown. This implies that although markers of stress are more prevalent under oligomeric challenge the fibrillar response suggests a more toxic environment. Conclusion: This approach is applicable to any cell type that can be cultured in a laboratory (primary or cell line) as a method of investigating how protein challenge affects signalling pathways, providing additional understanding as to the role of protein aggregation in neurodegenerative disease initiation and progression. PMID- 29142511 TI - Medication adherence in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory condition with intestinal and extraintestinal manifestations. Medications are the cornerstone of treatment of IBD. However, patients often adhere to medication poorly. Adherence to medications is defined as the process by which patients take their medications as prescribed. Treatment non-adherence is a common problem among chronic diseases, averaging 50% in developed countries and is even poorer in developing countries. In this review, we will examine the adherence data in IBD which vary greatly depending on the study population, route of administration, and methods of adherence measurement used. We will also discuss the adverse clinical outcomes related to non-adherence to medical treatment including increased disease activity, flares, loss of response to anti-tumor necrosis factor therapy, and so forth. There are many methods to measure medication adherence namely direct and indirect methods, each with their advantages and drawbacks. Finally, we will explore different intervention strategies to improve adherence to medications. PMID- 29142512 TI - Non-steroidal anti-inflammatory drug-induced enteropathy. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are well known to be associated with serious upper gastrointestinal complications, such as peptic ulcer, bleeding, perforation, and obstruction. Recently, attention has been mainly focused on the small bowel injuries caused by NSAIDs, and new endoscopic techniques such as capsule endoscopy and double balloon endoscopy can help in detecting such injuries. This article reviewed the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of small bowel injuries caused by NSAIDs. Small bowel injures by NSAIDs might occur with a similar frequency and extent as those observed in the upper gastrointestinal tract. The pathogenesis of NSAID-induced enteropathy is complex and not clearly understood. The various lesions observed in the small bowel, including petechiae, reddened folds, loss of villi, erosions, and ulcers can be detected by capsule endoscopy. A drug that could prevent or treat NSAID-induced enteropathy has not yet been developed. Therefore, further investigations should be performed to elucidate the pathogenesis of such enteropathy and develop suitable preventive and treatment strategies. PMID- 29142513 TI - Sedation for routine gastrointestinal endoscopic procedures: a review on efficacy, safety, efficiency, cost and satisfaction. AB - Most gastrointestinal endoscopic procedures are now performed with sedation. Moderate sedation using benzodiazepines and opioids continue to be widely used, but propofol sedation is becoming more popular because its unique pharmacokinetic properties make endoscopy almost painless, with a very predictable and rapid recovery process. There is controversy as to whether propofol should be administered only by anesthesia professionals (monitored anesthesia care) or whether properly trained non-anesthesia personnel can use propofol safely via the modalities of nurse-administered propofol sedation, computer-assisted propofol sedation or nurse-administered continuous propofol sedation. The deployment of non-anesthesia administered propofol sedation for low-risk procedures allows for optimal allocation of scarce anesthesia resources, which can be more appropriately used for more complex cases. This can address some of the current shortages in anesthesia provider supply, and can potentially reduce overall health care costs without sacrificing sedation quality. This review will discuss efficacy, safety, efficiency, cost and satisfaction issues with various modes of sedation for non-advanced, non-emergent endoscopic procedures, mainly esophagogastroduodenoscopy and colonoscopy. PMID- 29142514 TI - Practice patterns and clinical significance of use of capsule endoscopy in suspected and established Crohn's disease. AB - Background/Aims: Although the role of capsule endoscopy (CE) in Crohn's disease (CD) has expanded, CE is not used routinely for diagnosing and evaluating CD in Korea. We aimed to investigate current patterns of practice and evaluate the clinical significance of the use of CE in CD in Korean patients. Methods: Among 651 CE procedures performed for various indications, we retrospectively analyzed the medical records of patients who underwent CE in 57 cases of suspected CD (sCD) and 14 cases of established CD (eCD). Results: In the sCD group, CE was most commonly used for the initial diagnosis of CD (54.4%). Capsule retention was found in only 1 patient in the eCD group (1/71, 1.4%). In the sCD group, 28.1% of patients were diagnosed with CD on the basis of CE findings; other diseases diagnosed included tuberculous enteritis (7.0%), non-steroidal anti-inflammatory drug-induced enteropathy (5.3%), and other enteritis (17.5%). Only 11.5% of patients with eCD (14/122) underwent CE. The indication for CE in the 14 patients with eCD was to assess disease extent and activity. The overall diagnostic yield of CE was 59.7%. Therapeutic strategies were changed in 70.2% of patients in the sCD group and 50% of those in the eCD group based on CE findings. Conclusions: In clinical practice, CE was most commonly indicated for the initial diagnosis of CD and was not generally performed in patients with eCD. CE appears to be an effective diagnostic modality for evaluating sCD and is useful for determining therapeutic strategies for patients with sCD and those with eCD. PMID- 29142515 TI - Efficacy and safety of ustekinumab in Japanese patients with moderately to severely active Crohn's disease: a subpopulation analysis of phase 3 induction and maintenance studies. AB - Background/Aims: Efficacy and safety of ustekinumab were evaluated in a Japanese subpopulation with moderately to severely active Crohn's disease (CD) in UNITI-1, UNITI-2 and IM-UNITI studies and results were compared with the overall population. Methods: Overall, patients in UNITI-1 (Japan, n=56; failed response to tumor necrosis factor antagonist) and UNITI-2 (Japan, n=26; failed response to prior conventional therapy) were randomized to placebo or ustekinumab intravenous induction (130 mg or ~6 mg/kg) at week 0. Responders to ustekinumab induction therapy (Japan, n=21) were randomized to placebo or ustekinumab (90 mg, subcutaneous) maintenance (every 12 weeks [q12w] or 8 weeks [q8w]) in IM-UNITI. The primary endpoint was clinical response at week 6 for induction studies and clinical remission at week 44 for maintenance study. Results: Percentage of patients achieving clinical response at week 6 was greater in ustekinumab 130 mg and ~6 mg/kg groups than in the placebo group (UNITI-1: 36.8% and 31.6% vs. 27.8%, respectively, for Japanese; 34.3% and 33.7% vs. 21.5%, respectively, for overall; UNITI-2: 37.5% and 55.6% vs. 11.1%, respectively, for Japanese; 51.7% and 55.5% vs. 28.7%, respectively, for overall). Clinical remission rate at week 44 during maintenance was greater in the ustekinumab 90 mg SC q12w and q8w groups than in the placebo group (50.0% and 55.6% vs. 25.0%, respectively, for Japanese; 48.8% and 53.1% vs. 35.9%, respectively, for overall). Efficacy and safety results observed in the Japanese subpopulation were generally consistent with those in the overall population. Conclusions: Ustekinumab could be considered as a new therapeutic option for moderately to severely active CD in Japanese patients. Both ustekinumab induction and maintenance treatments were generally well tolerated (Clinical Trial Registration: NCT01369329, NCT01369342, NCT01369355). PMID- 29142516 TI - Outcomes of limited period of adalimumab treatment in moderate to severe Crohn's disease patients: Taiwan Society of Inflammatory Bowel Disease Study. AB - Background/Aims: In Taiwan, due to budget limitations, the National Health Insurance only allows for a limited period of biologics use in treating moderate to severe Crohn's disease (CD). We aimed to access the outcomes of CD patients following a limited period use of biologics, specifically focusing on the relapse rate and remission duration; also the response rate to second use when applicable. Methods: This was a multicenter, retrospective, observational study and we enrolled CD patients who had been treated with adalimumab (ADA) according to the insurance guidelines from 2009 to 2015. Results: A total of 54 CD patients, with follow-up of more than 6 months after the withdrawal of ADA, were enrolled. The average period of treatment with ADA was 16.7+/-9.7 months. After discontinuing ADA, 59.3% patients suffered a clinical relapse. In the univariate analysis, the reason for withdrawal was a risk factor for relapse (P=0.042). In the multivariate analysis, current smoker became an important risk factor for relapse (OR, 3.9; 95% CI, 1.2-14.8; P=0.044) and male sex was another risk factor (OR, 2.9; 95% CI, 1.1-8.6; P=0.049). For those 48 patients who received a second round of biologics, the clinical response was seen in 60.4%, and 1 anaphylaxis occurred. Conclusions: Fifty-nine percent of patients experienced a relapse after discontinuing the limited period of ADA treatment, and most of them occurred within 1 year following cessation. Male sex and current smoker were risk factors for relapse. Though 60.4% of the relapse patients responded to ADA again. PMID- 29142517 TI - Is methylation analysis of SFRP2, TFPI2, NDRG4, and BMP3 promoters suitable for colorectal cancer screening in the Korean population? AB - Background/Aims: Colorectal cancer (CRC) screening using stool DNA was recently found to yield good detection rates. A multi-target stool DNA test (Cologuard(r), Exact Sciences), including methylated genes has been recently approved by the U.S. Food and Drug Administration. The aim of this study was to validate these aberrantly methylated genes as stool-based DNA markers for detecting CRC and colorectal advanced adenoma (AA) in the Korean population. Methods: A single center study was conducted in 36 patients with AA; 35 patients with CRC; and 40 endoscopically diagnosed healthy controls using CRC screening colonoscopy. The methylation status of the SFRP2, TFPI2, NDRG4, and BMP3 promoters was investigated blindly using bisulfate-modified stool DNA obtained from 111 participants. Methylation status was investigated by methylation-specific polymerase chain reaction. Results: Methylated SFRP2, TFPI2, NDRG4, and BMP3 promoters were detected in 60.0%, 31.4%, 68.8%, and 40.0% of CRC samples and in 27.8%, 27.8%, 27.8%, and 33.3% of AA samples, respectively. The sensitivities obtained using 4 markers to detect CRC and AA were 94.3% and 72.2%, respectively. The specificity was 55.0%. Conclusions: Our results demonstrate that the SFRP2, TFPI2, NDRG4, and BMP3 promoter methylation analysis of stool sample DNA showed high sensitivity but low specificity for detecting CRC and AA. Because of the low specificity, 4 methylated markers might not be sufficient for CRC screening in the Korean population. Further large-scale studies are required to validate the methylation of these markers in the Asian population and to find new markers for the Asian population. PMID- 29142518 TI - Local recurrence and subsequent endoscopic treatment after endoscopic piecemeal mucosal resection with or without precutting in the colorectum. AB - Background/Aims: Precutting before endoscopic piecemeal mucosal resection (EPMR) may increase colorectal polyp resection effectiveness. We aimed to identify risk factors for recurrence after conventional EPMR (CEPMR) and precut EPMR (PEPMR) and investigated endoscopic treatment outcomes for recurrent cases. Methods: The medical records of patients with colorectal polyps treated by EPMR were analyzed. Patients without follow-up surveillance colonoscopies were excluded. Results: Among 359 lesions, the local recurrence rate on the first surveillance colonoscopy was 5.8% (18/312) and 6.4% (3/47) after CEPMR and PEPMR, respectively. Among lesions without recurrence at the first surveillance colonoscopy, the rates of late recurrence on subsequent surveillance colonoscopy were 3.9% (6/152) and 0% after CEPMR and PEPMR, respectively. Larger tumor size was the only independent risk factor for recurrence (odds ratio, 7.93; 95% confidence interval, 1.95-32.30; P<0.001). Endoscopic treatment was performed for all 27 recurrences. A combination of >=2 endoscopic treatment modalities was used in 19 of 27 recurrences (70.4%). Surveillance colonoscopies were performed in 20 of 27 recurrences after endoscopic treatment. One (5.0%) had a re-recurrence and was treated by surgical resection because recurrence occurred at the appendiceal orifice. Nineteen of 20 lesions (95.0%) could be cured endoscopically, although 3 of the 19 showed second or third recurrences and were treated by repeat endoscopic resection. Conclusions: The local recurrence rates after CEPMR and PEPMR were similar. Larger tumor size was an independent risk factor for local recurrence after EPMR. Endoscopic treatment of recurrences resulted in high cure rates, although combination methods were necessary in many cases. PMID- 29142519 TI - High C-reactive protein level is associated with high-risk adenoma. AB - Background/Aims: There is substantial evidence supporting a role of inflammation in the pathogenesis of colorectal cancer; however, little is known about the association between serum C-reactive protein (CRP) and the risk of colorectal adenoma. This study was conducted to investigate the association between serum CRP and colorectal adenoma risk. Methods: A retrospective cross-sectional study was performed on first-time screening colonoscopies in asymptomatic subjects who also had their serum CRP level measured during a routine health check-up between September 2006 and September 2009 in Korea. Serum CRP level was compared between high-risk and low-risk adenoma groups and independent predictors of high-risk adenoma were analyzed using multivariate regression analysis. Results: Among the 3,309 eligible patients, the high-risk adenoma group had higher serum CRP levels than the low-risk adenoma group (P=0.000). In addition, patients with a high-risk adenoma were more frequently included in the high CRP group than in the low CRP group (8.6% vs. 4.0%, P<0.001). The prevalence of high-risk adenoma was 3.5 times higher in the highest quartile of CRP level (P=0.000) compared with that in the lowest quartile. In logistic regression analysis, a higher quartile CRP level was found to be an independent risk factor for high-risk adenoma (odds ratio, 1.8; 95% confidence interval, 1.3-2.5; P=0.000). Conclusions: High CRP level is associated with high-risk adenoma in both men and women. Our data may support the association between chronic inflammation and colorectal neoplasia, which warrants further investigation. PMID- 29142520 TI - Predictive factors for malignancy in undiagnosed isolated small bowel strictures. AB - Background/Aims: Patients with small bowel strictures have varied etiologies, including malignancy. Little data are available on the demographic profiles and etiologies of small bowel strictures in patients who undergo surgery because of intestinal obstruction but do not have a definitive pre-operative diagnosis. Methods: Retrospective data were analyzed for all patients operated between January 2000 and October 2014 for small bowel strictures without mass lesions and a definite diagnosis after imaging and endoscopic examinations. Demographic parameters, imaging, endoscopic, and histological data were extracted from the medical records. Univariate and multivariate analyses were conducted to identify factors that could differentiate between intestinal tuberculosis (ITB) and Crohn's disease (CD) and between malignant and benign strictures. Results: Of the 7,425 reviewed medical records, 89 met the inclusion criteria. The most common site of strictures was the proximal small intestine (41.5%). The most common histological diagnoses in patients with small bowel strictures were ITB (26.9%), CD (23.5%), non-specific strictures (20.2%), malignancy (15.5%), ischemia (10.1%), and other complications (3.4%). Patients with malignant strictures were older than patients with benign etiologies (47.6+/-15.9 years vs. 37.4+/-16.4 years, P=0.03) and age >50 years had a specificity for malignant etiology of 80%. Only 7.1% of the patients with malignant strictures had more than 1 stricture and 64% had proximally located strictures. Diarrhea was the only factor that predicted the diagnosis of CD 6.5 (95% confidence interval, 1.10-38.25; P=0.038) compared with the diagnosis of ITB. Conclusions: Malignancy was the cause of small bowel strictures in approximately 16% patients, especially among older patients with a single stricture in the proximal location. Empirical therapy should be avoided and the threshold for surgical resection is low in these patients. PMID- 29142521 TI - Fatal infections in older patients with inflammatory bowel disease on anti-tumor necrosis factor therapy. AB - Anti-tumor necrosis factor (anti-TNF) is highly effective in inflammatory bowel disease (IBD); however, it is associated with an increased risk of infections, particularly in older adults. We reviewed 349 patients with IBD, who were observed over a 12-month period, 74 of whom had received anti-TNF therapy (71 patients were aged <60 years and 3 were aged >=60 years). All the 3 older patients developed serious infectious complications after receiving anti-TNFs, although all of them were also on concomitant immunosuppressive therapy. One patient developed disseminated tuberculosis, another patient developed cholera diarrhea followed by nosocomial pneumonia, while the third patient developed multiple opportunistic infections (Pneumocystis pneumonia, cryptococcal septicemia and meningitis, Klebsiella septicemia). All 3 patients died within 1 year from the onset of the infection(s). We recommend that anti-TNF, especially when combined with other immunosuppressive therapy, should be used with extreme caution in older adult patients with IBD. PMID- 29142522 TI - Drug-induced eosinophilic pneumonia in a patient with Crohn's disease: diagnosis and treatment using fraction of exhaled nitric oxide. AB - Oral 5-aminosalicylic acid agents (mesalazine and sulfasalazine) and azathioprine are the mainstays of treatment for inflammatory bowel disease. Reports of pulmonary toxicity induced by oral 5-aminosalicylic acid agents or azathioprine in patients with inflammatory bowel disease are very rare; to date, only 38 cases have been reported worldwide. We, herein, report a case involving a 26-year-old man who was diagnosed with eosinophilic pneumonia after using mesalazine and azathioprine for the treatment of Crohn's disease and recovered after treatment. We also found that the fraction of exhaled nitric oxide level was elevated in this patient. After treatment, the fraction of exhaled nitric oxide level decreased and the symptoms improved. The present case shows that fraction of exhaled nitric oxide is related to the disease activity and treatment effectiveness of druginduced eosinophilic pneumonia. PMID- 29142523 TI - Steroid-refractory extensive enteritis complicated by ulcerative colitis successfully treated with adalimumab. AB - Extracolonic involvement of the gastrointestinal tract is extremely uncommon in ulcerative colitis (UC) and rarely found in the upper gastrointestinal tract or in postoperative cases since it typically responds to steroids. Here we report a case of UC complicated by extensive ileal inflammation that was refractory to steroids. A 20-year-old man was diagnosed with UC of typical pancolitis without ileal involvement and started treatment with pH-dependent mesalazine and oral prednisolone. Although his symptoms transiently resolved, the condition flared when the steroid dose was tapered down. Computed tomography revealed marked thickening of the ileal wall, and capsule endoscopy and balloon-assisted enteroscopy found diffuse mucosal inflammation with ulcers in the ileum. On the contrary, the inflammation in the colon and rectum was improving. Since the response to the second steroid course was inadequate, treatment with adalimumab and 6-mercaptopurine was initiated and finally achieved clinical and endoscopic remission. The investigation of small intestinal lesions is necessary in patients with UC whose clinical deterioration cannot be explained by colonic lesions. PMID- 29142524 TI - A case of celiac disease with neurologic manifestations misdiagnosed as amyotrophic lateral sclerosis. AB - Celiac disease (CD) is an immune-mediated enteropathy and is a rare disease in Asia, including in Korea. However, the ingestion of wheat products, which can act as a precipitating factor of CD, has increased rapidly. CD is a common cause of malabsorption, but many patients can present with various atypical manifestations as first presented symptoms, including anemia, osteopenia, infertility, and neurological symptoms. Thus, making a diagnosis is challenging. We report a case of CD that mimicked amyotrophic lateral sclerosis (ALS). The patient was a sexagenary man with a history of progressive motor weakness for 2 years. He was highly suspected as having ALS. During evaluation of his neurological symptoms, esophagogastroduodenoscopy (EGD) was performed because he had experienced loose stools and weight loss for the previous 7 months. On EGD, the duodenal mucosa appeared smooth. A biopsy revealed severe lymphoplasma cell infiltration with flattened villi. His serum endomysial antibody (immunoglobulin A) titer was 1:160 (reference, <1:40). Finally, he was diagnosed as having CD, and a gluten-free diet was immediately begun. At a 4-month follow-up, his weight and the quality of his stool had improved gradually, and the neurological manifestations had not progressed. PMID- 29142525 TI - Irritable bowel syndrome-like symptoms associated with endoscopic activity predict ulcerative colitis relapse in patients with clinical remission. PMID- 29142526 TI - Monomorphic epitheliotropic intestinal T-cell lymphoma complicated by common variable immunodeficiency. PMID- 29142527 TI - A massive bleeding from a duodenal mass: what treatment option should be chosen? PMID- 29142528 TI - Is colorectal cancer screening necessary before 50 years of age? PMID- 29142529 TI - Comments on clinical outcomes of sigmoid colon volvulus: identification of the factors associated with successful endoscopic detorsion. PMID- 29142530 TI - Author's Reply. PMID- 29142532 TI - A longitudinal study of the relationship between receptivity to e-cigarette advertisements and e-cigarette use among baseline non-users of cigarettes and e cigarettes, United States. AB - Background: We investigated the relationship between receptivity to electronic cigarette (e-cigarette) advertisements at baseline and e-cigarette use at follow up among adult baseline non-users of cigarettes and e-cigarettes. Methods: A nationally representative online panel was used to survey non-users of cigarettes and e-cigarettes (n = 2191) at baseline and 5-month follow-up. At baseline, respondents were shown an e-cigarette advertisement and asked if they were aware of it (exposure). Among those exposed, receptivity was self-rated for each ad using a validated scale of 1 to 5 for agreement with each of six items: "worth remembering," "grabbed my attention," "powerful," "informative," "meaningful," and "convincing." Logistic regression was used to measure the relationship between receptivity at baseline and e-cigarette use at follow-up. Results: Among baseline non-users of cigarettes and e-cigarettes, 16.6% reported exposure to e cigarette advertisements at baseline; overall mean receptivity score was 2.77. Among baseline non-users who reported exposure to e-cigarette advertisements, incidence of e-cigarette use at follow-up was 2.7%; among baseline non-users who reported not being exposed to e-cigarette advertisements, incidence of e cigarette use at follow-up was 1.3%. The attributable risk percentage for e cigarette initiation from e-cigarette advertisement exposure was 59.3%; the population attributable risk percentage from e-cigarette advertisement exposure was 22.6%. Receptivity at baseline was associated with e-cigarette use at follow up (aOR = 1.57; 95% CI = 1.04-2.37). Conclusions: Receptivity to e-cigarette advertisements at baseline was associated with greater odds of e-cigarette use at follow-up among baseline non-users of cigarettes and e-cigarettes. Understanding the role of advertising in e-cigarette initiation could help inform public health policy. PMID- 29142531 TI - Factors associated with implementation of the 5A's smoking cessation model. AB - Background: Several health organizations have adopted the 5A's brief intervention model (Ask, Advise, Assess, Assist, Arrange), based on evidence-based guidelines for smoking cessation. We examine individual, cognitive, behavioral, and organizational factors associated with the 5A's performance among clinical healthcare workers in Catalonia. We also investigate how these factors interact and potentially predict the implementation of each component of the 5A's. Methods: A cross-sectional survey was conducted among clinical health workers enrolled in an online smoking cessation training course (n = 580). The survey included questions about individual characteristics as well as cognitive, behavioral, and organizational factors previously identified in research. We assessed self-reported performance of the 5A's, assessed on a scale from 0 to 10, and used Multivariate regression to examine factors associated with its performance. Results: The performance means (standard deviation) were moderate for the first 3A's [Ask: 6.4 (3.1); Advise: 7.1 (2.7); Assess: 6.3 (2.8)] and low for the last 2A's [Assist: 4.4 (2.9); Arrange: 3.2 (3.3)]. We observed a high correlation between Assist and Arrange (r = 0.704, p < 0.001). Having positive experiences and feeling competent were positively associated with performing the 5A's model and having organizational support with Assist and Arrange. Personal tobacco use among healthcare workers was negatively associated with Advice and Arrange. Conclusions: Our study found that clinical healthcare workers do not perform the 5A's completely. The main barriers identified suggest the need of training and making available practical guidelines in healthcare services. Organizational support is essential for moving towards the implementation of Assist and Arrange. PMID- 29142533 TI - Corrigendum: RNA-Seq Comparison of Larval and Adult Malpighian Tubules of the Yellow Fever Mosquito Aedes aegypti Reveals Life Stage-Specific Changes in Renal Function. AB - [This corrects the article on p. 283 in vol. 8, PMID: 28536536.]. PMID- 29142534 TI - Corrigendum: Hauntings, homeopathy, and the Hopkinsville Goblins: using pseudoscience to teach scientific thinking. AB - [This corrects the article on p. 336 in vol. 5, PMID: 24860520.]. PMID- 29142535 TI - Corrigendum (2): Overexpression of Rice Glutaredoxin OsGrx_C7 and OsGrx_C2.1 Reduces Intracellular Arsenic Accumulation and Increases Tolerance in Arabidopsis thaliana. AB - [This corrects the article on p. 740 in vol. 7, PMID: 27313586.]. PMID- 29142536 TI - Professional competencies required for Editors of Biomedical Journals. PMID- 29142537 TI - Pneumatic Balloon Dilatation for Achalasia Cardia; Early & late results, a single center study. AB - Objective: Achalasia Cardia is treated by Pneumatic balloon dilatation, Heller's Myotomy and recently, by Peroral Esophagaeal Myotomy. This study reports the efficacy of pneumatic balloon dilatation as a non-surgical motility in achieving relief of dysphagia, clinical improvement and recurrence. Long-term complications were reported. Methods: Eight hundred ninety two adult achalasia patients of both genders were treated from January 1988 till December 2011, with pneumatic balloon (Rigiflex Microvasive(r)) dilatation, under fluoroscopy Barium swallow was obtained prior to and five minutes after dilatation to evaluate for efficacy of dilatation as well as for complications. Patients not responding to 30 mm balloon had repeat dilatation with 35 mm balloon after 8 weeks. All patients were enrolled in regular follow up at one, six months and yearly intervals up to a period of five years. Recurrence was defined as an increase in symptom score at 8 weeks greater than 50% of their baseline value. These patients were treated with 35 mm balloon or referred for surgical intervention. Results: Of 892 patients, follow up was obtained in 50% for 5 years, 9.2% for 4-years), 9.3% for 3-years, 10% for 2-years and 21.5% for 1-year of patients. One patient died after repeat dilatation. Eighty-eight patients were excluded from this analysis (20 died due to non-procedure related causes and another 68 were lost during follow up). Statistically significant improvement was noted in reduction in height and width of barium column and symptom score coupled with weight gain during follow up. Forty-eight patients were subjected to repeat dilatation with 35 mm balloon, two of these developed post-procedure perforations with one mortality. Three non responsive patients required surgical laparoscopic myotomy. No carcinoma of esophagus was reported during follow up. One patient post dilatation, developed esophageal bezoar. A single pneumatic dilatation achieved a remission rate of 93% at four years, 90% at three years, 95% at two years and 92% at one year post dilatation. Conclusion: Achalasia of esophagus can be effectively and safely treated with balloon dilatation to achieve adequate short and long-term symptomatic relief with a low complication rate. PMID- 29142538 TI - Patient safety awareness among postgraduate students and nurses in a tertiary health care facility. AB - Objective: To determine the knowledge of patient safety among postgraduate residents (PGR) and nurses in a tertiary care hospital. Methods: This casual comparative study was conducted among the postgraduate residents and nurses working at The Children's Hospital Lahore in the month of July, August 2017. Both PGR and nurses were asked to complete APSQ-IV questionnaire about patient safety on 7 point Likert scale. Data was analyzed using SPSS version 20 and t-test was used to compare the mean score between two groups. The names of the participants were kept confidential. Results: A total of 150 residents and 150 nurses were included. The scores of both postgraduate residents and nurses were similar in all domains having positively worded questions with insignificant difference in mean score (p=0.141). In the reverse coded questions the nurses showed positive perception with higher mean score as compared to postgraduate residents (p=0.004). The postgraduate residents in the early years of residency had higher mean score in positively worded question as compared to residents who were in last years of training (p=0.006). There was no difference in the mean score of nurses as regard to their years of experience (p=0.733). Medical error disclosure domain was reported lowest by both postgraduate residents and nurses. Conclusion: Both postgraduate residents and nurses showed positive attitude with good knowledge and perception towards patient safety. Lowest rated scores were from error disclosure confidence domain. PMID- 29142539 TI - Values of magnetic Resonance imaging and Cerebrospinal fluid analysis in the diagnosis of Central Nervous System associated infectious diseases. AB - Objective: To discuss the roles of magnetic resonance imaging (MRI) and cerebrospinal fluid analysis in the identification of central nervous system associated infection and provide a reference for the diagnosis and treatment of central nervous system associated infectious diseases. Methods: Seventy-six patients who developed central nervous system infection and were admitted into the Henan People's Hospital between June 2014 and October 2015 were randomly selected as an observation group. Patients in the observation group were subdivided according to purulent meningitis, cryptococcal meningitis, viral meningitis and tubercular meningitis. Moreover, 35 headache patients who were admitted in the same period were selected as a control group. The MRI results and cerebrospinal fluid examination indicators were compared between the two groups. Results: MRI results suggested that the positive rate of the observation group was 96.05% (73/76), much higher than 8.57% in the control group (3/35), and the difference had statistical significance (P<0.05). The analysis results of cerebrospinal fluid demonstrated that the concentration of lactate dehydrogenase (LDH) in the cerebrospinal fluid of the patients with tubercular meningitis was the highest, the concentration of creatine kinase (CK) in the cerebrospinal fluid of the patients with purulent meningitis was the highest, and the concentration of lactic acid (LA) in the cerebrospinal fluid of the patients with tubercular meningitis and purulent meningitis was higher than that of the other patients; the differences were statistically significant (P<0.05). The analysis on the diagnostic efficacy of MRI in combination with cerebrospinal fluid analysis suggested that the sensitivity of the diagnostic scheme was high in diagnosing meningitis except purulent meningitis, and the specificity and accuracy of the scheme was high in diagnosing meningitis except cryptococcal meningitis. Conclusion: MRI in combination with cerebrospinal fluid analysis is effective in diagnosing central nervous system associated infectious diseases. It can also effectively identify the types of infection besides improving accuracy, which provides an important reference for clinical treatment. PMID- 29142540 TI - Clinical Audit of Dengue Related Deaths in 2011-Mayo Hospital Lahore Pakistan. AB - Background and Objective: Dengue infection has evolved into an epidemic during last few years in Pakistan and has been associated with poor outcomes. Literature with respect to mortality risk factors in Dengue infection is not sufficient. This compelled us to conduct this study to find out major contributory factors to death in patients with dengue viral infection at one of Asia's ancient hospital setting with an aim to recognize complications at earliest and improve case management in future. Methods: A retrospective observational study of 95 adult dengue deaths was performed at Mayo Hospital Lahore from July 1st 2011 to 31st December 2011 during a major dengue epidemic. Patients who tested positive by dengue IgM in the presence of acute fever fulfilling the World Health Organization criteria for Dengue Fever, Dengue Hemorrhagic Fever or Dengue Shock Syndrome and died within same setting, were included. Data regarding demographic profile, clinical and laboratory parameters along with treatment details were obtained and analysed. All records examined were anonymized. Results: Median age was 36 years (range13-80 years) among 95 deaths due to Dengue. Male gender comprised 60 (63.1%). Co-morbidities existed in 74 (77.9%) with hypertension in 21 (22.1%) diabetes in 11 (11.58%), liver disease in 9 (9.47%) and ischemic heart disease in 8(8.4%) cases. Patients presented at second day of fever for admission (range 1-8 days) and death occurred at a median of 4 days (range 30 minutes to 23 days). Hospital stay was for less than a week for seventy nine (83.2%) patients and 16 (16.8%) were admitted for more than 7 days. Critical care was required in 67(71%). Severe hepatitis occurred in 41 (43.1%), acute renal impairment occurred in 32 (33.7%) and disseminated intravascular coagulation in 16 (16.8%). Deaths were due to prolonged shock 49 (51.5%) fluid overload 46 (48.4%) and massive bleeding 18(19%) leading to organ failure. Conclusion: Decompensated shock complicated by either massive plasma leakage, frank bleeding, multi organ failure or deranged clotting profile results in enhanced mortality in Dengue infection. Co-morbidities especially Diabetes are poor prognostic factors in predicting Dengue mortality. PMID- 29142541 TI - Is it safe to have multiple repeat cesarean sections? A high volume tertiary care center experience. AB - Objective: To compare the obstetric outcomes of cesarean section in women who had a history of four or more previous cesarean sections with those who had a history of two or three previous cesarean sections. Methods: Total 1318 women who underwent repeat cesarean section between January 2013 and January 2016 were retrospectively reviewed. Of these, 244 (18.5%) had previously had four or more cesarean sections (multiple repeat cesarean section group) and 1074 (81.5%) had previously had two or three cesarean sections (control group). Demographic characteristics and obstetric outcomes were compared using the Independent t and chi-square tests. Results: The adhesion rate (p < 0.001), number of blood transfusion (p = 0.044), operation time (p = 0.012), length of hospital stay (p < 0.001) and tubal ligation surgery (p < 0.001) were significantly higher in multiple repeat cesarean section group compared to control group. Conclusion: Although multiple repeat cesarean section are asscociated with adhesion occurrence, higher number of blood transfusion, increased operation time and length of hospital stay, there is no remarkable difference in serious morbidity associated with multiple repeat cesarean section. PMID- 29142542 TI - Predictors and correlations of emotional intelligence among medical students at King Abdulaziz University, Jeddah. AB - Objectives: To determine the predictors of Emotional Intelligence (EI), and its relationship with academic performance, leadership capacity, self-efficacy and the perceived stress between medical students at King Abdulaziz University, Jeddah, Saudi Arabia. Methods: A cross-sectional study was done among 540 students selected through a multi-stage stratified random sampling method during 2015/2016. A standardized, confidential data collection sheet was used. It included Schutte Self-Report Emotional Intelligence (SSREI) scale, Authentic Leadership questionnaire, General Self-Efficacy Scale and the short version of Perceived Stress Scale (PSS-4). Both descriptive and inferential statistics were done, and a multiple linear regression model was constructed. Results: The predictors of high EI were gender (female), increasing age, and being non-smoker. EI was positively associated with better academic performance, leadership capacity and self-efficacy. It was negatively correlated to perceived-stress. Conclusion: Female gender, age, non-smoking were the predictors of high EI. Conduction of holistic training programs on EI, leadership and self-efficacy are recommended. More smoking control programs and stress management courses are required. PMID- 29142543 TI - Career Choices of Medical doctors at Graduate level - A Multicenter Study. AB - Objective: To find out the specialty choices being taken by Final year Medical students and graduate Doctors. Method: This is a cross sectional survey study which was conducted over two months from 1st November to 31st December 2016. Final year students and house job doctors were asked for the filling of Performa, after filling the consent form. A self-developed, anonymous questionnaire was used to conduct the study using close ended type of questions. This was a multi center study conducted at Dow International Medical College and Jinnah Medical and Dental College. An IRB approval was taken for the study. A total of 317 individuals completed the Performa. Demaographic data included information regarding the year of passing, number of family members already in the medical profession, then specific questions were asked regarding their future career choice and the reason for choosing that particular speciality. After collection of data from both the centers a single operator entered the Data on SPSS 16 version. Frequencies and chi-square test were performed and p-valves were tabulated. Results: A total of 317 individuals completed the Performa. Two hundred and nine participants (65.9%) were females and one hundred and eight (34.1%) were male participants. The age ranged from 22-29 years mean of 25.15 and SD of 1.348. One hundred and twenty one (38%) had a family member as a doctor in the family. Medicine and allied was the most sought after specialty 184(58%), followed by surgery and allied in 108(34%). Non-Clinical Specialty such as radiology, basic sciences was taken up by 27(7.9%). Conclusion: The working hours followed by passion for the chosen field were the important reasons for selecting any specialty. The next most important reason was higher income and other family responsibilities of an individual. The ladies are opting more for fields with a controllable life style. PMID- 29142544 TI - Effect of oil gauze silver dressings on diabetic foot ulcers in the elderly. AB - Objective: To compare the clinical efficacy and safety of oil gauze silver dressing and silver ions dressing on diabetic ulcers in elderly outpatients. Methods: Twenty-two patients with Type-2 diabetic foot ulcers were included in the study conducted at Yantai Yuhuangding Hospital between April 2013 and April 2014. At the time of enrolment they were divided into the silver ions and oil gauze silver groups based on the order of admission. Dressings were changed twice weekly until the ulcer had healed. Clinical efficacy measures were healing outcomes and speed of healing. Adverse events were recorded. Results: The silver ions and oil gauze silver groups were comparable at baseline (P>0.05). Before treatment, the fasting blood glucose (FBG) and two hour postprandial blood glucose (2h PBG) levels were 6.88+/-0.50 mmol /L and 15.55+/-2.47 mmol/L in the oil gauze silver group, and 6.93+/-0.41 mmol/L and 15.23+/-2.58 mmol/L in the silver ions group, respectively. After treatment, the FBG and 2h PBG levels were 6.82+/-0.32 mmol/L and 8.67+/-0.86 mmol/L in the oil gauze silver group, and 6.85+/-0.27 mmol/L and 8.83 +/- 0.61 mmol/L in the silver ions group, respectively. The healing time of foot ulcers was 23.8+/-2.7 days in the silver ions group and 15.8+/-2.5 days in the oil gauze silver group (P<0.05). Conclusion: Oil gauze silver dressings for diabetic foot ulcers were associated with favorable clinical outcomes compared with silver ion dressings, especially with respect to ulcer healing speed. PMID- 29142545 TI - Rapid screening of pyogenic Staphylococcus aureus for confirmation of genus and species, methicillin resistance and virulence factors by using two novel multiplex PCR. AB - Objectives: Emergence of methicillin resistant Staphylococcus aureus (MRSA) is a major medical problem of current era. These bacteria are resistant to most drugs and rapid diagnosis can provide a clear guideline to clinicians. They possess specific virulence factors and relevant information can be very useful. We designed this study to develop multiplex PCRs to provide rapid information. Methods: We studied 60 Staphylococcus aureus isolates and detected methicillin resistance by cefoxitin sensitivity and targeting of mecA gene. After initial studies with uniplex PCRs we optimized two multiplex PCRs with highly reproducible results. The first multiplex PCR was developed to confirm genus, species and methicillin resistance simultaneously, and the second multiplex PCR was for screening of virulence factors. Results: We found 38.33% isolates as methicillin resistant. alpha -toxin, the major cytotoxic factor, was detected in 40% whereas beta-hemolysin was found in 25% cases. Panton Valentine leucocidin was detected in 8.33% and toxic shock syndrome toxin in5% cases. The results of uniplex and multiplex PCRs were highly compatible. Conclusions: These two multiplex PCRs when run simultaneously can provide vital information about methicillin resistance and virulence status of the isolate within a few hours as compared to several days needed by routine procedures. PMID- 29142546 TI - Comparison of analgesic effect of preoperative topical Diclofenac versus Ketorolac on postoperative pain after Corneal Collagen Cross Linkage. AB - Objective: To compare post-operative pain relieving effect of topical diclofenac 0.1% versus ketorolac 0.5% in Corneal Collagen Cross Linking (CXL) for patients diagnosed with keratoconus. Methods: This randomized controlled trial was carried out for six months from October 2016 to March 2017. We included young patients having keratoconus with k-readings greater than 47D and central corneal thickness more than 400 microns. All the patients received single dose one drop of topical diclofenac 0.1% to (Group-A) and ketorolac 0.5% to (Group-B) 30 minutes in advance of the corneal collagen cross linking (CXL) procedure. The CXL was performed with topical 0.1% riboflavin eye drops in 20% dextran as a photo sensitizer. After 36 hours of the CXL procedure, the postoperative intensity of pain was assessed verbally by patients with the help of visual analog scale (VAS) numbers from zero to five where 0 designated no pain & 5 symbolized worst pain. Results: The study comprised sixty eyes of forty one patients. Out of total 16 were male while 25 female patients. The mean age of the patients was 24.27 +/- 2.93 years (range 20 to 29 years). In the conclusive analysis, diclofenac 0.1% was used on 30 patients in Group-A and ketorolac 0.5% on 30 subjects in Group-B. Pain relieving scores in Group-A (diclofenac 0.1%) was 2.57 +/- 0.67 while in Group-B (ketorolac 0.4% treated arm) was 3.20 +/- 0.61. Conclusion: Topical diclofenac 0.1% is statistically comparable to topical ketorolac 0.5% in precluding severity of pain after corneal collagen cross linkage operation. PMID- 29142547 TI - An evaluation of thyroid autoimmunity in patients with beta thalassemia minor: A case-control study. AB - Objective: The tendency to autoimmune diseases has been reported to be increased in beta thalassemia minor (BTM). The aim of this study was to evaluate whether thyroid autoimmunity is higher in BTM. Methods: Patients with BTM (n=86) and a healthy control group (n=93) were included in this cross-sectional case-control study. The two groups were compared in terms of anti-thyroglobulin (anti-TG) and anti-thyroid peroxidase (anti-TPO) and thyroid hormones. Results: In the BTM group, thyroid hormones and serum anti-TG and anti-TPO antibody levels were not statistically different from those of the control group. The BTM and control groups were similar in terms of anti-thyroid antibody (ATA) positivity prevalence. In the BTM group, anti-TG was 11.6% and anti-TPO was 14% positive, while these values were 14% and 12.9% positive, respectively in the control group (p=0.806 and p=0.989, respectively). The proportion of anti-TG and/or anti-TPO antibody positive subjects was found to be 20.9% in the BTM group, and 20.4% in the control group (p=0.919). The ratios of subjects with euthyroidism, hyperthyroidism and hypothyroidism were similar in both groups. Conclusions: As the thyroid autoimmunity prevalence in the BTM group was not increased compared to the control group, it can be considered that there is no necessity for routine ATA and thyroid hormone testing in subjects with BTM. PMID- 29142548 TI - Doubly committed Subarterial Ventricular Septal defect repair: An experience of 51 cases. AB - Objective: To review the surgical outcome of doubly committed subarterial (DCSA) ventricular septal defect repair. Method: Data of 51 patients of doubly committed sub arterial Ventricular septal defect from January 2012 to June 2017 that were referred to Chaudhary Pervaiz Elahi institute of Cardiology Multan was retrospectively reviewed using electronic database. All patients were operated by first author. In our study, we segregated patients into four main groups depending on presence or absence of aortic structural defect and degree of aortic valve regurgitation. Group-A comprised of nineteen (37%) patients who neither had aortic structural nor functional abnormality while Group-B had six (11.7%) patients, having aortic valve cusp prolapse without aortic regurgitation. Group-C and Group-D consists of seventeen (33.3%) and nine (17.6%) patients respectively depending upon degree of aortic regurgitation. Furthermore, six (11.7%) patients among these 51 had associated defects as well. Results: Group-A patients had no aortic valve regurgitation post operatively and at follow up of 22.6 months (1.8 years) as well. In Group-B, aortic valve was not addressed and aortic regurgitation was also not present post operatively or on follow up of 33.6 months (2.8 years). Similarly, in Group-C aortic valve was not addressed, these patients also did not show progression of disease on regular follow up of 18 months (1.5 year). While, in Group-D, eight patients underwent aortic valve repair and one patient had aortic valve replacement. Aortic regurgitation improved significantly in all patients of this group and remained unchanged on follow up of 22.7 months (1.8 years). Conclusion: Early closure of doubly committed subarterial ventricular septal defect with appropriate management of aortic valve disease can halt the process of disease progression. PMID- 29142549 TI - Comparison of pressure vs. volume controlled ventilation on oxygenation parameters of obese patients undergoing laparoscopic cholecystectomy. AB - Background & Objective: There is no special guideline for the best ventilation mode during laparoscopic anesthesia in obese patients and there are too many studies with different controversial points. The aim of this study was to compare the effect of pressure controlled ventilation (PCV) vs. volume controlled ventilation (VCV) on respiratory and oxygenation parameters in patients undergoing laparoscopic cholecystectomy. Methods: Seventy patients with 30 0.05). Genotype frequencies were compared by Chi-square test. Results: There was prevalence of Omentin-1 Val109Asp polymorphism in both case and control groups. However, Val/Asp (heterozygous mutant) genotype was detected more frequently in patients with CAD, OR(95%)=1.921; CI=1.173-3.1469 in comparison of Asp/Asp and Val/Val genotypes. Conclusion: Individuals having Val/Asp heterozygous gemotype of omentin-1 gene polymorphism are at more risk of developing CAD in Pakistani population, further studies are required in different populations and ethnicities to confirm our findings. PMID- 29142552 TI - Atypical Chemokine Receptor 1 polymorphism cannot be used as an indicator of liver fibrosis progression in Hepatitis C virus positive patients. AB - Background & Objective: Atypical chemokine receptor 1(ACKR1) represents an atypical chemokine receptor that can bind promiscuously to various chemokines. Chemokines play a crucial role to recruit leukocyte subsets migration through the endothelium and into liver against the virus during the progression of hepatitis C virus (HCV) infection. Most HCV positive patients can lead to liver fibrosis. Hyaluronic acid (HA), laminin (LN), collagen IV(C-IV) and amino-terminal pro peptide of Type-III pro-collagen (PIII NP) are indices of the extent of liver fibrosis. The aim of this study was to investigate the association between ACKR1 polymorphism and liver fibrosis with these four serum liver markers in HCV positive patients. Methods: From April 2015 to December 2015, a total of 210 patients (109 males and 101 females) with chronic HCV infection at Dalian Infectious Hospital were recruited to participate in this study. ACKR1 genotyping was using TaqMan probes method. HA, LN, C-IV and PIII NP were detected by using diagnostic kits. Results: We compared serum levels of HA, LN, C-IV and PIII NP between FY*A/FY*A and FY*A/FY*B patients and the differences were not significant (P=0.905, P=0.298, P=0.880 and P=0.470, respectively). Conclusions: This study has attempted to elucidate the role of ACKR1 polymorphism in liver fibrosis progression of HCV infection, our results demonstrated that ACKR1 polymorphism is not directly associated with the fibrogenesis in HCV positive patients. PMID- 29142553 TI - Psychometric analysis of Anatomy MCQs in Modular examination. AB - Objective: To analyze the psychometric indices of Anatomy question items in modular system assessment. Methods: A quantitative study was done to determine the quality of MCQs and to analyze the performance of 1st year 100 MBBS students. Each module covers different subjects of MBBS curriculum but psychometric analysis was done on the subject of Anatomy only. The assessment results of 3 modules were taken and checked by item analysis to see the mean differences between the modules using ANOVA. Post hoc analysis was determined by using Tukey HSD test. Results: A total of 140 one best (OB) Anatomy MCQ items were calculated for difficulty index, discriminatory index and reliability. Difficulty index was found to be higher in module I when compared with module II and III. Discriminatory index comparatively showed higher results in module II whereas reliability of module III was significantly higher than the other modules. Results were considered to be significant with p value<= 0.05. Conclusions: The psychometric analysis of Anatomy MCQs showed average difficulty, good discrimination and reliability. PMID- 29142554 TI - Vitamin D supplementation improves FEV1 in patients of Bronchial Asthma. AB - Background and Objective: Vitamin D deficiency has strong association with various respiratory disorders in which bronchial asthma is one of them. The objective was to determine the efficacy of vitamin D supplementation in cases with bronchial asthma. Methods: This case control study was conducted at private clinical set up of district, Rahim Yar Khan from August to October 2016 in which 100 cases of bronchial asthma were randomly divided into Group-A and Group-B each contained 50 patients. Group-A was given placebo and Group-B with vitamin D in a dose of 50,000 units per day orally. Both the groups were followed in terms of improvement in FEV1 at 1, 2 and 3 months. Results: There was no significant difference in both groups in terms of BMI and duration of asthma at start of study. The mean pre treatment vitamin D level of Group-A was 14.23+/-1.66 and of Group-B, 15.30+/-2.05 ng/dl (p= 0.23). FEV1 in pre treatment Group-A was 64.35+/ 3.16 and of Group-B was 62.35+/-2.16 with p= 0.95. There was no significant difference in terms of FEV1 in both the groups at one month (p= 0.32). While at two months it was significantly higher in Group-B with p= 0.04. At 3 months the final outcome was seen where the post treatment FEV1 in Group-A was 66.13+/-2.75 and in Group-B, 75.15+/-2.04 with p value of 0.001. Conclusion: Vitamin D supplementation improves FEV1 significantly at two months and these can be even highly significant if it is extended up to 3 months. PMID- 29142555 TI - Exclusive breastfeeding practices in working women of Pakistan: A cross sectional study. AB - Objective: To determine the prevalence of exclusive breast feeding in working women and to identify the factors effecting exclusive breast feeding in working women. Methods: This cross-sectional survey was conducted in Faisalabad city within a period of six months from June 2016 to December 2016. Working women of age 18 to 45 years, working as doctors, teachers, nurses and bankers in public (government) setup were included. The data was collected using interview method by pre-structured questionnaire. Multi-variable logistic regression model was developed considering EBF practice as dependent and the significant independent variables. Results were reported as Crude Odds Ratio (COR) or Adjusted Odds Ratio (AOR) with 95% Confidence Intervals (CIs). Results: Prevalence of exclusive breast feeding (EBF) was 166 (41.5%). EFB practice was significantly less in doctors and bankers as compared to nurses and teachers (p-value <0.001). Women working as nurses and teachers, having one or two children and short working hours had higher prevalence of exclusive breast feeding. Women having prior knowledge about EBF, training of EBF and women who had previously heard about EBF had five time higher rate of breast feeding. Women having knowledge of colostrum had three times higher EBF practice [odds ratio: 3.02 (1.86-4.91)]. Women having knowledge about hazards of bottle feeding had 12.7 times higher prevalence of EBF [odds ratio: 12.72 (5.70-28.38)]. Those who knew about expression of breast milk had three times higher prevalence of EBF [odds ratio: 3.0 (1.98-4.55)]. Mothers working in organizations that support EBF had 4.1 times higher prevalence of EBF [odds ratio: 4.1 (2.67-6.21)]. And proper training of mothers about correct expression technique of breast milk had 12 time [odds ratio: 12.06 (4.97-29.23)] higher prevalence of EBF. Conclusion: Long working hours, banking profession, family income and lack of proper knowledge about exclusive breast feeding are responsible for non-EBF practice in working women. Proper Knowledge and awareness about exclusive breastfeeding and provision of facilities for exclusive breastfeeding (EBF) by the organizations can play a significant role in promoting it. PMID- 29142556 TI - Occurrence of oral habits among preschool children with Autism Spectrum Disorder. AB - Objective: To determine occurrence of oral habits among Saudi preschool children with autism spectrum disorder (ASD) and compare it with healthy preschool children. Methods: This study was conducted over a 14-months period in Riyadh, Saudi Arabia. The sample consisted of two groups; a study group (SG) of 150 ASD children, and a control group (CG) of age- and gender-matched 150 healthy children. The parents of the children in both the groups were administered a questionnaire that included questions about the children's demographic information and previous or persistent oral habits. Results: The prevalence of oral habits was higher (87.3%) among the SG children as compared to CG children (49.3%). The most prevalent oral habit among the SG was bruxism (n = 82; 54.7%), followed by object biting (n = 67; 44.7%) and mouth breathing (n = 40; 26.7 %). Among the CG; the most prevalent oral habit was mouth breathing (n = 40; 26.7%) followed by nail biting (n=18; 12%) and object biting (n = 7; 4.7%). The prevalence of bruxism, object biting, thumb sucking and tongue biting was significantly (p<0.05) higher in the SG than the CG. Conclusions: The prevalence of oral habits was higher in the ASD group children than the healthy children. PMID- 29142557 TI - Outcome of burr-hole aspiration of brain abscess. AB - Objective: To determine the clinical outcome of burr-hole aspiration of brain abscess. Methods: We analyzed 100 cases of intracranial abscess, treated surgically from January 2015 and October 2016 at Jinnah Postgraduate Medical Centre (JPMC). All patients were treated with burr hole aspiration. Medical records were analyzed for demographics, clinical presentation, predisposing factors, abscess location on imaging and clinical outcomes were charted. Results: The study included 100 patients with 73 (73%) males and 27 (27%) females with a mean age of 36.69+/-10.96 years. Mean duration of signs and symptoms was 8.50+/ 4.2 days. The most common presenting complaint was altered sensorium in 70 (70%) patients and commonest source of infection was otitis media seen in 27 patients (27%). The GCS on presentation was 13 in 57 (57%) cases. The parietal region was the most common site in 43 patients (43%), followed by frontal region in 33 patients (33%). Complete resolution of abscess with recovery of preoperative neuro-deficit was seen in 77 (77%) patients and recovery with major neuro-deficit was observed in 10 (10%) cases while 13 (13%) patients expired. Conclusion: Early diagnosis, optimum follow-up and timely burr-hole aspiration are the keys in the proper management of brain abscess. PMID- 29142558 TI - Transpedical Interbody Bone Grafting in the Treatment of Senile Osteoporotic Vertebral Fracture. AB - Objective: To evaluate the clinical effect of transpedical interbody bone grafting in the treatment of senile osteoporotic vertebral fracture. Methods: Eighty-six elders with osteoporotic vertebral fracture were selected and divided into a control group and a test group using random double-blind method. Patients in the control group were treated by short-segment transpedicular screw system internal fixation, while patients in the test group were treated by short-segment transpedicular screw system internal fixation in combination with transpedical interbody bone grafting. Operation related indexes and fracture recovery condition were compared between the two groups. Results: The overall effective rate of the test group was 93.02%, much higher than the control group (76.74%) (P<0.05). The difference of operation duration, intraoperative bleeding volume, length of hospital stay, fracture healing time, preoperative vertebral height loss and preoperative Cobb's angle between the two groups had no statistical significance (P>0.05). The postoperative pain score of the test group was lower than that of the control group, and the difference was statistically significant (P<0.05). The vertebral height loss and Cobb's angle of the test group were superior to those of the control group at the last follow up, and the difference had statistical significance (P<0.05). The incidence of internal fixator loosening of the test group was much lower than that of the control group (P<0.05). Conclusion: Short-segment transpedicular screw system internal fixation in combination with transpedical interbody bone grafting shows favorable effects in the treatment senile osteoporotic vertebral fracture, resulting in mild pain and less loss of vertebral height and angle; hence it is worth promotion in clinic. PMID- 29142559 TI - Visual and anatomical outcome of macular hole surgery at a tertiary healthcare facility. AB - Objective: To assess visual and anatomical outcome of full thickness macular hole (FTMH) surgery with ILM peeling using brilliant blue G dye. Methods: Thirty patients who had clinically evident macular hole were selected. Pre-operative Optical Coherence Tomography (OCT) was done. In all cases vitrectomy was performed via 23guage 3 ports pars plana (3PPV) vitrectomy system and Brilliant blue G dye, 0.5ml dye was injected over macula which resulted in light blue stain of ILM and peeling was performed around hole in circular motion and after gas fluid exchange gas tamponade with SF6 was done. Final visual and anatomical outcome was measured as postoperative BCVA and postoperative OCT at three months respectively. Descriptive statistics were computed. Paired t-test was applied. P value<=0.05 were considered as significant. Results: There were 12 male and 18 female patients. The mean age was 57.40+/-4.76 years. The mean size of macular hole was 452.20+/-242.33MUm. The mean duration of symptoms was 16.73+/-13.49 weeks. Mean pre operative BCVA was 1.30+/-0.73 log MAR and post operative was 0.51+/-0.23 log MAR. Mean increased BCVA was found to be 0.22+/-0.13 log MAR. Primary closure of hole was achieved in 29(96.7%). Significant mean difference was found in pre operative and post operative BCVA. Conclusion: Brilliant blue G exhibits sufficient staining qualities and safety profile to peel ILM in the management of full thickness macular hole with significant visual and anatomical improvement. PMID- 29142560 TI - Changes in Empathy during Medical Education: An Example from Turkey. AB - Objective: Empathy is a key element of patient- physician communication; it is relevant to and positively influences patients' health. In this study we aimed to present the Turkey example for the empathy change during the medical faculty training. Methods: This cross-sectional study was carried out at Ondokuz Mayis University, Faculty of Medicine, Department of Family Medicine, Samsun, Turkey. in first three years students of medicine during September 2014 to June 2015. Turkish adapted form of the student version of Jefferson empathy scale and sociodemographic questionnaire was used and data was assessed with the SPSS program. Results: Total 511 students (52.5% female, 47.5% male), from first three years of medical faculty participated in the study. Two hundred thirty three (44.5%) students were from the First Year class, while 130 (27.1%) and 148 (28.4%) of them were from Second and Third Year respectively. The mean age was 20.63+/-2.73 years. Significant differences in the empathy scores were observed among first three years in medical school as like as between gender. Conclusion: Although medical schools tend to raise students with higher empathy levels, medical education itself is more scientific based than humanistic approach, and makes medical students more tough and insensitive to the problems of patients. Patient-centered approach and empathy training should be implemented in the curriculum during whole medical education. PMID- 29142561 TI - Feto-maternal outcomes and Glycemic control in Metformin versus insulin treated Gestational Diabetics. AB - Objective: To evaluate and compare feto-maternal outcomes and glycemic control in metformin versus insulin treated gestational diabetics. Methods: The study was conducted in 2010- 2012 as a part of M. Phil at Civil hospital, Lyari General Hospital and Mamji Hospital in Karachi. After written informed consent, 71 GDM diagnosed females with WHO criteria were enrolled. They were divided into two groups. Group-A, 32 females were given oral metformin 500 mg TDS while Group-B, 39 females were given insulin 0.8-0.9 mg/kg/day in two divided doses subcutaneously. Patients were followed till term. Feto-maternal outcomes were evaluated in 25 patients in each group who completed the study. Results: When groups were compared, newborns in Group-B were significantly more in weight (p=0.01). Significant numbers of babies were delivered after 38 weeks of pregnancy in Group-B (P=0.021). There were two intrauterine deaths and significantly higher HbA1C at term in Group-B. (P=0.03). FBS at term was non significant (p=0.079) and there was more number of cesarean sections due to feto maternal disproportion in Group-B (28% vs.2%). Results analyzed for glycemic control before and after the treatment revealed that FBS was statistically less in Group-A (p=0.00) whereas for Group-B the value of FBS and HbA1C was statistically high. (p=0.002 & 0.04 respectively). Conclusion: Metformin has produced better effects on feto-maternal outcomes and glycemic control in comparison to Insulin in GDM. PMID- 29142562 TI - Drug poisoning and associated factors in western Saudi Arabia: A five-year retrospective chart review (2011-2016). AB - Objective: Drug poisoning is a globally common cause of emergency-room admissions. This study explores drug-poisoning prevalence patterns, associated risk factors (gender, age and exposure circumstances), and outcomes in western Saudi Arabia. Methods: Retrospective analysis of Clinical drug poisoning cases (2011-2016). The data were retrieved from the Saudi Ministry of Health's record and Patients' medical charts were analyzed. Results: The Ministry of Health received 1,474 reports of drug poisoning during 2011-2016. More than half involved females (n=885, 60%) or young children (0-4 years old) (n=764, 51.8%) and occurred accidentally (n=786, 53.3%); almost all had an oral route of poisoning (n=1,466, 99.5%). The cases most frequently involved analgesic and non steroidal anti-inflammatory drugs (n=373, 25.2%); antiepileptic, antipsychotic, psychoactive, and anxiolytic drugs (n=229, 16.3%); antihistamine, asthma, flu, and cough drugs (n=157, 12.0%); and antibiotic, anti-fungal; and antiprotozoal drugs (n=74, 5.0%). Antidotes were administered in only 2.2% of cases, and no deaths were reported. Conclusion: The drug poisoning cases involved females and young children (younger than 5 years old) and the most cases were accidental, and the most commonly used drugs were analgesics (Panadol), followed by antipsychotics, antihistamines, and antiepileptics (Tegretol). PMID- 29142563 TI - Posterior occipito cervical decompression with fixation and fusion in Cranio vertebral junction compression. AB - Objective: To find out the clinical outcome of posterior decompression with occipitocervical fixation and fusion in patients with Craniovertebral junction instability. Methods: Eighty consecutive patients of cranio vertebral junction (CVJ) compression were treated in the department of neurosurgery, Jinnah Postgraduate Medical Centre (JPMC), Karachi over a period of 05 years from 1st January 2012 till 31st August 2016. All patients underwent posterior decompression with occipitocervical fusion (OCF) and fixation. The clinical outcome was assessed by Japanese Orthopedic Association (JOA) score and grading. Results: Out of 80 patients with CVJ instability, 64 (80%) were due to non traumatic causes, while 16 (20%) were secondary to trauma. All 80 patients(100%) showed post operative relief in pain. Sixty four (80%) patients showed improvement in power post operatively while six (7.5%) had no change, four (5%) showed deterioration and six (7.5%) patients expired. Sixty four (80%) patients had improvement of the JOA scores at last follow-up. According to etiology, the JOA score for patients with trauma improved in 12(75%) patients and 52(81.25%) for non traumatic causes while six patients (7.5%) expired. Fusion was achieved in 64 (80%) patients at last follow-up. Conclusion: Posterior decompression with occipitocervical fusion and fixation is safe and can be recommended in cases of CVJ compression. PMID- 29142564 TI - Clinical effects of Ganglioside and fructose-1, 6-diphosphate on neonatal heart and brain injuries after Asphyxia. AB - Objective: To study the clinical effect of ganglioside (GM) and fructose-1, 6 diphosphate (FDP) on neonatal heart and brain injuries after asphyxia. Methods: Ninety-one neonates with asphyxia neonatal heart and brain injuries were randomly divided into an observation group and a control group. Both groups were given symptomatic treatment as soon as possible. On this basis, the observation group was given 200 mL of 5% glucose injection and 20 mg of GM and 250 mg/kg.d FDP by intravenous infusion. The above two drugs were given once a day for 14 days. The control group was given 20 mL of 5% glucose injection, 2 mL of cerebrolysin and 250 mg/kg.d FDP by intravenous infusion, once a day for 14 days. Both groups were administered on the first day after admission, and the course of treatment was 14 days. The treatment outcomes of the two groups were compared by detecting the levels of glycogen phosphorylase isoenzyme BB (GPBB), cTn-I and CK-MB, MRI results and Neonatal Behavioral Neurological Assessment (NBNA) scores before and after treatment. Results: The levels of GPBB, cTn-I and CK-MB in the observation group were significantly higher than those of normal neonates. After treatment, the levels of cTn-I and CK-MB in the observation group were closer to those of normal neonates compared with the control group, with significant differences (P<0.05). There was a significant difference in the brain MRI examination between the two groups (P<0.05). The NBNA scores of the two groups were significantly different before and after treatment (P<0.05). The total effective rate of the observation group was significantly higher than that of the control group (P<0.05). Conclusion: Neonatal heart and brain injuries after asphyxia can be well treated by combining GM with FDP. PMID- 29142565 TI - Correlation between Hyperhomocysteinemia and Common Carotid Artery Intima media Thickness in Carbamazepine treated Epileptic patients using Ultrasonography. AB - Objective: The objective was to assess the role of homocysteine in the development of atherosclerosis in common carotid artery in the carbamazepine treated epileptic patients. Methods: This study was conducted in the Department of Biochemistry, Basic Medical Sciences Institute (BMSI), Jinnah Postgraduate Medical Center (JPMC), Karachi. Three hundred individuals, aged 34 +/- 9.5 years were selected and divided into three groups. Each group comprised of 100 subjects labeled as Group-A (control group had healthy individuals), Group-B (newly diagnosed epileptic patients without antiepileptic therapy), Group-C (epileptic patients on Carbamazepine therapy, which was further subdivided into C-I having epileptic patients on Carbamazepine therapy less than 1 year n=33, C-II had epileptic patients on Carbamazepine therapy 1-2 years n = 33 and C-III comprised of epileptic patients on Carbamazepine therapy more than 2 years n = 34). Blood concentration of homocysteine was measured and ultrasound of Common Carotid Artery for intima-media thickness was performed. Results: Significantly elevated level of homocysteine was observed in epileptic patients on CBZ therapy. Common Carotid Artery Intima-media thickness (CCA IMT) was observed significantly high throughout group C but it was more profound in Group-C-III. Homocysteine was found positively correlated with right CCA IMT, left CCA IMT and mean CCA IMT. Conclusion: Hyperhomocysteinemia was linked with increased risk of atherosclerosis in CBZ treated epileptic patients. PMID- 29142566 TI - Operating room professionals' attitudes towards patient safety and the influencing factors. AB - Objective: To determine operating room professionals'attitudes towards patient safety and the influencing factors. Methods: This study was conducted in research hospitals in Izmir, Turkey using descriptive, cross-sectional and correlation research designs. The sample of this study consisted of 477 individuals including nurses, physicians and anesthesia technicians. Data were collected using the Sociodemographic and Working Characteristics Form and the Safety Attitudes Questionnaire. Descriptive statistics method, and Pearson's correlation and the multiple regression models were used for data analysis. Results: Operating room professionals' attitudes towards patient safety were at moderate levels. Regarding the influencing factors, team cooperation obtained the highest score, whereas stress recognition obtained the lowest score. As a result of the regression analysis, age, male gender and receiving patient safety training explains 15.4% of the professionals' safety attitudes. Conclusions: Receiving patient safety training was found to be the most important variable of all. PMID- 29142567 TI - Outcomes of intravitreal bevacizumab and macular photocoagulation for treatment of diabetic macular edema in a tertiary care eye hospital, Karachi. AB - Objective: To study the outcomes of intravitreal injection of Bevacizumab and laser photocoagulation in the treatment of diabetic macular edema (DME). Methods: Seventy-two eyes of 59 patients with diabetic macular edema were divided into two groups of 41 eyes (Group-A) and 31 eyes (Group-B). Subjects in group-A were treated with three intravitreal injections of Bevacizumab (IVB), and that of group-B with macular photocoagulation. Duration of study was 9 months. Follow up pattern for both groups was1, 2, 3 and 6 months. Best Corrected Visual acuity on log MAR (BCVA) for distance as well as near in each visitwas recorded. Retinal OCT for central macular thickness (CMT) was performed on baseline. SPSS version 20.0 was used to analyze the data. Results: Mean age of the patients was 53.76 +/ 8.82 ranging to 36-71 years. Out of 59 patients, 40 (67.8%) were male and 19 (32.2%) female. It was observed that the difference of results among both groups was not significant. Fig.2 documents visual acuity recorded as Improved; Stable and Worse. Conclusion: The improvement in BCVA was significant at 6 months in both treatments. The final improvements in BCVA has been almost similar between both the treatment groups although it was noted that IVB group showed early improvement in BCVA at follow-ups of 1 and 3 months. A long term follow-up is required in these cases to see the effect of both these treatment strategies. PMID- 29142568 TI - Echocardiographic evaluation of cardiovascular complications after birth asphyxia in term neonates. AB - Objectives: After birth asphyxia, a variety of hemodynamic disorders may be noted in the neonatal intensive care unit; these require appropriate recognition and management. The present study was designed to demonstrate the prevalence of heart complications amongst asphyxiated newborns. Methods: Through a cohort study, 29 asphyxiated term neonates were followed since birth until amelioration of pulmonary hypertension and compared with 31 well born neonates. Both groups were evaluated for their heart anatomy and hemodynamic with meticulous assessment through echocardiography. This study was conducted in Besat Medical Center since August 2010 until February 2012. Results: Hemodynamic and anatomic disorders including myocardial dysfunction, pulmonary hypertension and patent arterial duct (PDA) were strongly associated with birth asphyxia (P< 0.05). Conclusion: Birth asphyxia was associated with systolic and diastolic dysfunction and pulmonary hypertension which demands precise evaluation, early recognition and appropriate management. PMID- 29142569 TI - Prevalence and Predictors of Non-Suicidal Self-Injury among Children with Autism Spectrum Disorder. AB - Objectives: To find the prevalence as well as to identify the predictors as protective and risk factors of Non-Suicidal Self-Injury (NSSI) among children with autism spectrum disorder (ASD). Methods: In this analytical cross sectional survey 83 children with ASD age range from 8 to 18 years were selected through convenient sampling technique from five special schools of Lahore city. The Urdu form of a standardized tool was used to assess NSSI. Results: Statistical analysis indicated overall point prevalence of NSSI was 33%. Moreover banging/self-beating (47%), scratching (38), pinching (35%), picking scabs (33%), self-biting (32%), pulling hair (30%) and rubbing skin (19%) emerged as common forms of challenging behavior. Further regression analysis showed that age B(1.68*, P<.05), gender B(3.72, P<.001) and severity level of ASD B(1.85***, p<.0001) as risk factors/positive predictors of NSSI. However early intervention (-0.66***, P<.0001) and involvement of parents in counselling (-2.66*, P<.05) emerged as protective factors/negative predictors of NSSI among children with ASD. Conclusion: Non-suicidal self-injury is a serious challenge among children with ASD. Early intervention, counselling and parental involvement in managing the children with ASD will not only prevent but reduce the challenging behaviors. PMID- 29142570 TI - Assessment of work-related Asthma cases: Our three-year experience. AB - Objective: Work-related asthma (WRA) is one of the most common occupational diseases. In this study, we aimed to review diagnosing procedures and the characteristics of patients who were diagnosed with WRA. Methods: Between November 2013 and June 2016; 214 patients were referred to our clinic with WRA suspicion by an occupational health specialist, personal visit, chest disease specialists [61 (28%), 51 (23%), and 102 (47%) respectively]. Occupational history, functional and radiological assessment, skin prick test, PEF monitoring were done. Results: Fifty-four patients (25%) were diagnosed with OA, and 24 (11%) with WEA, total 78 workers were diagnosed with WRA. Twenty-five (32.1%) had allergic rhinitis, 13 (16.7%) had allergic dermatitis, and 8 (10%) had both diseases. Conclusion: WRA can be seen in many areas. Complaints are the basic route for admission to physician, and the diagnosis can be delayed for a long time as one year. Lower rates of referral by occupational health physicians are the signs of limitations on management of cases. Non-specific BPT and skin prick test for selected cases would be sufficient besides occupational history and clinical examination for the diagnosis of WRA. PEF assessment, one of the most important tests for the diagnosis of WRA, must be performed. PMID- 29142571 TI - In-Vitro Transcription analysis of NS5A from HCV-3a circulating in Pakistani patients with chronic hepatitis C and their differential response to antiviral therapy. AB - Objective: Mutations in HCV nonstructural protein 5A (NS5A) play a vital role in virus resistance. The aim of this study was to develop a correlation between NS5A mutations (genotype 3a) and virological response towards interferon alpha (IFN alpha) plus ribavirin therapy. Methods: In this study, which was conducted from 09-02-2013 to 25-11-2015 in the rural area of Province Sindh - Pakistan, total patients' responses to peg-IFN therapy were investigated. Patients were given peg IFN therapy for 24 to 48 weeks and categorized as sustained virologic responders (SVR) or non-responders (NR) to HCV infection. HCV NS5A region (2215-2335) of genotype 3a was identified in both responders and non-responders. Results: Twenty four NR with 24 SVR isolates showed significant mutations within the nonstructural protein 5A region in HCV genotype 3a. The New Zealand (NZL1) (GenBank D17763) differences were observed by using gene. The ISDR mutations for nonstructural protein 5A in non-responders have been reported as a possible explanation of HCV interferon resistance. Conclusion: Based on these results, it is suggested that decreased SVR is caused by the increased mutations in nonstructural protein 5A sequences. When the sequence outside the Protein kinases R binding domain (PKRBD) (2281-2335) was examined, significant differentiations were observed among the SVR and NR classes at few amino acid strains. PMID- 29142572 TI - Clinicopathological features associated to MiRNA-195 expression in patients with breast cancer: Evidence of a potential biomarker. AB - Background & Objective: MiRNAs are a systematic class of small non-coding RNAs with impending role as tumor biomarkers. Our objective was to identify the level of expression of Mir-195 in patients with breast cancer along with its correlation with clinicopathologic features. Methods: A total of 209 females in which 139 histologically diagnosed breast cancer (BC) cases and 70 healthy controls matched for age, their relative clinical and histopathological findings were recorded from their laboratory reports and hospital record of the patients. Plasma was used for extraction of total RNA and cDNA was prepared by using both miR-195 stem loop RT primers and gene specific antisense primers while U6 IT was used as control. Quantitative real-time PCR (qRT-PCR) for miR-195 expression status was performed and amplification (down regulation) was recorded. Results: Of 139 samples the expression of miR-195 was down regulated in 72.6% cases and the remaining 27.3% cases behaved same as 70 healthy or normal controls. Significant correlation of low miR-195 expression with higher differentiation grade, lymph node metastasis and clinical stage was found. Conclusion: Significant correlation between miR-195 expression and some clinicopathological features were recognized. MiR-195 could be used as potential non-invasive, molecular biomarker for early detection of breast cancer. PMID- 29142573 TI - Standing out with Professionalism: How do Students and Faculty of two different Medical Schools perceive it? AB - Background and Objectives: Medical professionalism is an essential aspect of medical education and practice worldwide. Our objective was to explore and compare the perception as recommended sanctions about professionalism lapses, using the "Dundee Polyprofessionalism Inventory I: Academic Integrity", among the faculty and the students' of two different medical schools in Saudi Arabia. Methods: Respondents from the two medical schools in Saudi Arabia, recommended sanctions for the first time, absolute lapses in academic professionalism were determined by using the "Dundee Polyprofessionalism Inventory 1: Academic Integrity". Results: On comparing the faculty and students' responses (from College of Medicine, King Saud University) with the published data (from another, unidentified medical school in Saudi Arabia) we found alignments in recommending sanctions for 14 (46.66%) behaviours among faculty and again concerning the11(36.66%) behaviours among the students of both cohorts. Conclusion: The results can be used to emphasise on the improved teaching and learning strategies in undergraduate medical students' understanding of professionalism. PMID- 29142574 TI - Frequency of Type-2 diabetes mellitus in Nephropathic patients and comparison of mean magnesium levels in Nephropathic patients with and without Type-2 diabetes mellitus. AB - Objective: The objective of this study was to determine the frequency of Type 2 diabetes mellitus (T2DM) in patients with nephropathy (i.e. Chronic Kidney Disease Stage 1 to 3) and to compare the mean magnesium levels in diabetic nephropathic patients and non-diabetic nephropathic patients. Methods: This cross sectional study was conducted in department of Medicine, Mayo Hospital Lahore from August 2014 to February 2015. Using non-probability purposive sampling 200 nephropathic (Chronic Kidney Disease Stage 1 to 3) patients were selected. Patients were assessed for T2DM and divided in two groups on the basis of presence or absence of DM. Magnesium levels were recorded in both groups. Percentages, mean, standard deviation and unpaired t-test was used to assess the data. SPSS was used for analysis of information. Results: Total number of cases were 200, 43.5% (n=87) out of them were between 25-50 years of age while 56.5% (n=113) patients were between 51-70 years. The Mean+SD was calculated to be 51.38+11.51 years. The male patients were 48.5 %(n=109) while 51.5 %(n=91) were females. The frequency of DM in patients with nephropathy was 25.5% (n=51). Comparison of mean magnesium levels in nephropathic patients with and without diabetes was done. The results showed nephropathic patients having diabetes had 1.54+0.301 mg/dL magnesium levels while cases without diabetes had 1.92+0.313 mg/dL levels of magnesium, p value was calculated as 0.001 showing a significant difference between the two groups. Conclusion: The frequency of diabetes mellitus is higher among patients with nephropathy while on comparison of mean magnesium levels, nephropathic patients with diabetes had significant lower levels of magnesium as compared to without diabetes. PMID- 29142575 TI - The attitudes of fertile and infertile women to Oocyte donation in a Muslim and Secular population. AB - Objective: To determine general attitudes of fertile and infertile women to oocyte donation in a Muslim and secular population. Methods: The participants consisted of fertile women (n=133) who had at least one healthy living child spontaneously conceived without any fertility treatment and infertile women (n=133) who were diagnosed with primary infertility. Both groups were evaluated with charts comprised of 34 questions addressing demographic characteristics and the social aspects of oocyte and sperm donation. Results: Although the age of fertile women was significantly greater than infertile women, there was no significant difference in terms of duration of marriage, education level, or employment status between the two groups. Most of the women in each group reported that they did not have enough knowledge about oocyte donation to make a decision. Only 12% of fertile women and 18% of infertile women declared that they would have oocytes from another woman if they did not have or could not have a child (p=0.004). Only 9.0% of fertile women and 18.8% of infertile women declared that they would donate oocytes to anyone who is infertile (p=0.021). Conclusion: Despite improvement in health care, most fertile and infertile women are still against oocyte donation. This situation may be related to the conservative leanings of Turkish society in recent decades. PMID- 29142576 TI - Frequency and the risk factors of hepatitis C virus in pregnant women; A hospital based descriptive study in Gadap Town Karachi. AB - Objective: To determine the frequency and the risk factors of hepatitis C virus in pregnant women at Al-Tibri Medical College & Hospital in Gadap Town Karachi. Methods: This was a descriptive cross sectional study conducted at Obstetrics & Gynecology OPD of Al-Tibri Medical College & Hospital, Isra University Karachi Campus from 10th June to 10th September 2016. A total of 400 pregnant women of 16 45 years of age, who came in outpatient department for antenatal checkup were selected for the study. The diagnosed cases of Hepatitis C were excluded from the study. Detailed history including age, parity, risk factor like history of transfusion, previous surgeries, vaginal deliveries was taken and relevant examination was performed. Patients on routine antenatal investigation if found to have Anti HCV positive on Immunochromatography Test (ICT) method were further confirmed by Elisa. A well designed proforma was used for data collection. Results: During the period of 3 months 400 women in antenatal clinic were tested for hepatitis C, out of which 27 (6.6%) were positive for HCV antibodies. The age of the women included ranges from 16-45 years. Thirteen (7.9%) pregnant women having HCV +ve antibodies fell in 26-30 years of age group. From 27 HCV +ve patients, 19 (70.3%) were multigravida & 8 (29.6%) were primigravida. Majority of the patients (77%) had history of injections. Conclusion: There is high prevalence of Hepatitis C infection among pregnant female in our setup. The possible risk factors are injection, blood transfusion and surgery. PMID- 29142577 TI - Congenital Hypothyroidism in Neonates of a Tertiary Care Hospital. AB - Objective: To determine neonatal congenital hypothyroidism among neonates born in a tertiary care hospital of Lahore Pakistan. Methods: This cross-sectional study was carried out at Pathology Department of Allama Iqbal Medical College, Lahore in collaboration with Pediatrics and Gynecology & Obstetrics Department, Jinnah Hospital, Lahore Pakistan. A total of 770 babies were included in this study, both male and female. About 2 ml venous blood samples were collected aseptically from the neonates in sterile clotted tube. Serum was separated and serum TSH was determined by ELISA method. Results: Out of total 770 neonates, 48.9% were female and 51.0% were males with the ratio of 1:1.04. Neonatal congenital hypothyroidisim (TSH, >30 mIU/L), was observed in 0.4% (Frequency, 1:257) nenates, with the incidence rate of 1:257. Female to male ratio of hypothyroid neonates was 2:1. The mode of delivery vise distribution showed, among n=251 neonates born by normal delivery, only a single case of hypothyroidism was detected, and among n=519 neonates delivered by cesarean section, only two neonates were belong to hypothyroidism. Conclusion: The frequency of Congenital Hypothyroidism is notably higher in pediatric community than reported in most other countries. This result emphasizes the necessity of a nationwide screening program. PMID- 29142578 TI - Food Exchange List and Dietary Management of Non-Communicable Diseases in Cultural Perspective. AB - This review focuses at highlighting the importance of Food Exchange List in cultural perspective, as an effective dietary tool to help individuals' manage their dietary modifications in relation to non communicable diseases whilst specifying measures that can help improve the quality of Food Exchange Lists for combating various non communicable diseases and addressing adherence related issues to specialized diets. A search was done using PubMed & Google Scholar till June 2016. Search terms used were food exchange list AND disease, diet AND non communicable diseases. We included only studies that discussed Food Exchange List (FEL) in relation to non-communicable diseases; in addition to factors like cultural relevance and adherence. Out of the 837 papers accessed 57 were identified as relevant to the Food Exchange List, out of which 39 papers were focused to the concept and development of the Food Exchange List. Only 18 discussed FEL in relation to non communicable diseases and were thus included in the review. Food exchange list is a user friendly tool for dietary modification due to disease. This tool may help to customize meals for people as it provides information regarding various food items in different groups. This tool is helpful in reducing blood & plasma glucose levels, maintaining lipid profile & effectively combating other diet related diseases & those ailments in which diet plays a significant role in maintenance & prevention from reoccurrences. However, better management and adherence to modified diets for non communicable diseases can be ensured by keeping cultural relevance under consideration before using Food Exchange Lists for such diseases. PMID- 29142579 TI - Pakistan's Recommendations for Optimal Management of diabetes from Primary to Tertiary care level (PROMPT). AB - Pakistan is a developing country with limited resources and diverse socio economic standards. Pakistan has high prevalence of diabetes and its complications, which is a great challenge to the existing health care system. National action plans for control of diabetes have been developed and initiatives have been taken but not at an ideal pace. First National Practice Guidelines for Pakistan were published in 1999. It was very helpful in standardizing the management of Type-2 diabetes. In view of important developments in the field of diabetes during the recent years, it was felt that 1999 National Clinical Practice Guidelines edited, should be revised. Also with rapidly increasing number of diabetic patients and the escalating burden on health economy, it is essential to develop a primary to secondary / tertiary care referral system. These guidelines are developed after an extensive research and cover many aspects of diabetes management. This special communication is an extract of a PROMPT document that has already been published as a Supplement in Pakistan Journal of Medical Sciences in 2017. We hope that these guidelines will help in improving the diabetes care in Pakistan. PMID- 29142580 TI - Medical Education Journal Club: Two years' experience at King Saud University. AB - Objective: Medical Education Journal Club is an evidence-based approach to teach and learn critical appraisal techniques on available literature. This study evaluates the implementation and experience of two academic years of Journal club at Medical Education Department, King Saud University. Methods: We started JC in 2015 at medical education department, KSU. An invitation with a published paper and event poster were sent 2 weeks prior of the session to participants. A traditional one-group posttest design with open item survey were conducted at the end of every session. Results: A total of 12 sessions were conducted in total. The average attendance of 26 (Male: 42/79, 53.1%) and (Female: 31/79, 39.2%) with mix of professors, associate and assistant professors. The MEJC had a positive effect on participant's session expectations (45/79, 92.4%), and had increased their knowledge of the field (73/79, 92.4%). It was observed that the attendance of event depends on the speaker for the event. The sessions have also arisen the need of trainings and other scientific activities. Conclusions: MEJC is an educational activity that can play important aspect in providing high quality healthcare teachings. We conclude that the success and consistency of MEJC depends on speaker. It commensurate the audience interest to attend and learn. While proper advertisement of event, and regular attendance also plays a vital role in this regard. PMID- 29142581 TI - An Unexpected Reason for Isolated Foot Drop: Acute Stroke. AB - The differential diagnosis of acute weakness (AW) in emergency departments (ED) is broad and includes both neurological and medical reasons. We describe an 81 year-old female patient with cortical infarct presenting with sudden onset isolated foot drop, which to the best of our knowledge, was the third case in English literature. An 81-year-old female was admitted to our ED with a 12-hour history of left-sided foot drop. Her motor strength was normal throughout the upper and lower extremities, except for weakness in the left ankle and toe dorsiflexors. Other examination findings were unremarkable. Diffusion-weighted magnetic resonance imaging (DWI-MR) revealed a focal high intensity signal in the right precentral gyrus at high convexity with a cerebral infarct. Detailed physical examinations and histories are extremely important for exact diagnosis and differentials of patients with AW. This case reminds us that a small infarct area of central nervous system may mimic peripheral nerve lesions, especially in elderly patients. Although the presentation of such complaints may play a distracting role to emergency physicians, strokes must always be taught regarding elderly patients and, if necessary, infarct areas should be confirmed with DWI MR. PMID- 29142582 TI - Pseudoaneurysm of Left proximal Common Carotid Artery following penetrating trauma. AB - A 33-year male with history of penetrating trauma to left upper chest in 2006, presented through Medical unit to Radiology Department with complain of hemoptysis. Chest X-ray showed a soft tissue lesion in left upper lobe with a linear metallic foreign body. Contrast enhanced CT scan of chest and later CTA was performed which showed a saccular aneurysm arising from mediastinal part of left common aortic artery surrounded by thrombosis with a cylindrical linear metallic foreign body. He was planned for endovascular repair with stenting which he could not afford due to financial constraints. He is currently on conservative follow up. Vascular lesions can be serious complications resulting from blunt or penetrating trauma, when presenting with hemoptysis due to pseudaoneurysms formation even after so many years of trauma. PMID- 29142583 TI - Primary Gastric Burkitt's lymphoma. AB - The primary gastrointestinal non-Hodgkin's lymphoma is a rare entity. Burkitt's lymphoma (BL) is an aggressive form of B-cell lymphoma which is endemic in Africa, while in rest of the world non-endemic cases has been reported. Primary gastric BL is extremely rare and only around 53 cases have been reported till now. Here we present the case of a middle-aged male, immunocompetent who presented with anorexia weight loss and diarrhea. His upper gastrointestinal endoscopy and biopsy revealed a large primary gastric Burkitt lymphoma. After chemotherapy, he remains in remission. PMID- 29142584 TI - Viability of five different pre- and intraoperative imaging methods for autologous breast reconstruction. AB - Background: Autologous breast reconstruction is an integral part in the treatment of breast cancer. While computed tomography angiography (CTA) is an established preoperative diagnostic tool for microsurgeons, no study has so far evaluated and compared five different imaging methods and their value for the reconstructive team. In order to determine the feasibility of each of the tools for routine or specialized diagnostic application, the methods' efficiency and informative value were analyzed. Methods: We retrospectively analyzed imaging data of 41 patients used for perforator location and assessment for regional perfusion and vessel patency in patients undergoing autologous breast reconstruction with deep inferior epigastric perforator flap (DIEP), transverse rectus abdominis muscle flap (TRAM), or transverse myocutaneous gracilis flap (TMG). Five different imaging techniques were used: hand held Doppler (HHD), CT angiography (CTA), macroscopic indocyanine green (ICG) video angiography, microscope-integrated ICG video angiography, and laser Doppler imaging (LDI). Results: CTA proved to be the best tool for preoperative determination of the highly variable anatomy of the abdominal region, whereas HHD showed the same information on perforator localization with some false-positive results. Intraoperative HHD was an excellent tool for dissection and vessel patency judgment. Microscope-integrated ICG was an excellent tool to document the patency of microanastomoses. In our series, macroscopic perfusion measurement with ICG or LDI was only justified in special situations, where information on perfusion of abdominal or mastectomy flaps was required. LDI did not add any additional information. Conclusion: Preoperative assessment should be performed by CTA with verification of the perforator location by HHD. Intraoperative HHD and microscope-integrated ICG contribute most toward the evaluation of vessel patency. ICG and LDI should only be used for special indications. PMID- 29142585 TI - Trade-offs in the production of animal vocal sequences: insights from the structure of wild chimpanzee pant hoots. AB - Background: Vocal sequences - utterances consisting of calls produced in close succession - are common phenomena in animal communication. While many studies have explored the adaptive benefits of producing such sequences, very little is known about how the costs and constraints involved in their production affect their form. Here, we investigated this issue in the chimpanzee (Pan troglodytes schweinfurthii) pant hoot, a long and structurally complex vocal sequence comprising four acoustically distinct phases - introduction, build-up, climax and let-down. Results: We found that in each of these phases, and for the sequence as a whole, there was a negative relationship between the number of calls produced and their average duration. There was also a negative relationship between the total duration of some adjacent phases. Significant relationships between the fundamental frequency of calls and their number or duration were found for some phases of the sequence, but the direction of these relationships differed between particular phases. Conclusions: These results indicate that there are trade-offs in terms of signal duration at two levels in pant-hoot production: between call number and duration, and between the relative durations of successive phases. These trade-offs are likely to reflect biomechanical constraints on vocal sequence production. Phase-specific trade-offs also appear to occur between fundamental frequency and call number or duration, potentially reflecting that different phases of the sequence are associated with distinct types of information, linked in different ways to call pitch. Overall, this study highlights the important role of costs and constraints in shaping the temporal and acoustic structure of animal vocal sequences. PMID- 29142586 TI - Determinants of exclusive breastfeeding in infants less than six months of age in Hawassa, an urban setting, Ethiopia. AB - Background: The World Health Organization (WHO) recommends exclusive breastfeeding (EBF) for the first six months of life. However, the proportion of EBF in Ethiopia is 58%. The EBF practice and factors affecting it have not been studied in Hawassa, Southern Ethiopia. The aim of this study was to assess the prevalence and determinants of EBF practice among infants less than six months age in Hawassa city, Ethiopia. Methods: A total of 529 mothers with infants aged 0-6 months were involved in this study between November 2015 and January 2016. Trained interviewers collected data from the mothers of the infants. Exclusive breastfeeding was assessed based on infant feeding practice in the prior 24 h. Multivariable logistic regression analysis was conducted. Results: Infants aged 0 5.9 months were studied with comparable gender composition (51.4% females). The exclusive breastfeeding prevalence was 60.9% (95% CI 56.6, 65.1). Mothers with infants aged 0-1.9 months and 2-3.9 months practiced EBF more likely than mothers with infants aged 4-6 months (Adjusted odds ratio [AOR] 3.59; 95% CI 2.07, 6.2) and (AOR 2.08; 95% CI 1.23, 3.5), respectively. Married mothers practiced EBF more likely than singles (AOR 2.04; 95% CI 1.03, 4.06). Housewives practiced EBF more likely than employed mothers (AOR 2.57; 95% CI 1.34, 4.9). Mothers who had a vaginal birth were more likely to practice EBF than mothers who gave birth via Cesarean section (AOR 2.8; 95% CI 1.7, 4.6). Mothers who gave birth at a healthcare facility were more likely to practice EBF than mothers who gave birth at home (AOR 8.8; 95% CI 5.04, 15.4). Mothers without a breast complication practiced exclusive breastfeeding more than mothers with breast complications (AOR 2.05; 95% CI 1.5, 4.1). Conclusions: This study showed a low prevalence of exclusive breastfeeding. Younger infants, babies born to married women, who are housewives, having a vaginal birth in a health facility, and whose mother's breasts were healthy, were predictors for EBF. The promotion of an institutional delivery, optimal breastfeeding practices, and designing strategies to better support employed mothers are recommended. PMID- 29142589 TI - FLIM-FRET analyzer: open source software for automation of lifetime-based FRET analysis. AB - Background: Despite the broad use of FRET techniques, available methods for analyzing protein-protein interaction are subject to high labor and lack of systematic analysis. We propose an open source software allowing the quantitative analysis of fluorescence lifetime imaging (FLIM) while integrating the steady state fluorescence intensity information for protein-protein interaction studies. Findings: Our developed open source software is dedicated to fluorescence lifetime imaging microscopy (FLIM) data obtained from Becker & Hickl SPC-830. FLIM-FRET analyzer includes: a user-friendly interface enabling automated intensity-based segmentation into single cells, time-resolved fluorescence data fitting to lifetime value for each segmented objects, batch capability, and data representation with donor lifetime versus acceptor/donor intensity quantification as a measure of protein-protein interactions. Conclusions: The FLIM-FRET analyzer software is a flexible application for lifetime-based FRET analysis. The application, the C#. NET source code, and detailed documentation are freely available at the following URL: http://FLIM-analyzer.ip-korea.org. PMID- 29142588 TI - Characterization of hormonal receptors and human epidermal growth factor receptor 2 in tissues of women with breast cancer at Muhimbili National Hospital, Dar es salaam, Tanzania. AB - Background: Breast cancer is a leading cause of morbidity and deaths among women worldwide. In Tanzania there is no published data on human epidermal growth receptor-2 (HER2/neu) expression in breast carcinoma. Hormonal receptors and HER2/neu status reportedly influence post-mastectomy adjuvant therapy and predict treatment outcome and prognosis. Here we evaluate hormonal receptors and HER-2 status in biopsies of women with breast cancer at Muhimbili National Hospital (MNH). Methods: A cross-sectional study of female breast post-modified radical mastectomy (MRM)/incisional biopsies confirmed to be carcinoma at the Histopathology Unit (January-December 2013). Tissue blocks having poor morphology, without tumor, secondary tumors, cases outside the study period and male patients were excluded. Routine staining was done followed by immunohistochemistry for estrogen (ER), and progesterone (PgR) receptors and HER2. Data analyzed using Statistical Package for Social Sciences (SPSS). Results: A total of 218 cases were confirmed to be carcinoma including 70 meeting inclusion criteria. Age at diagnosis ranged 18-75 years and mean age was 48.36 years. Majority (64.3%) were in the 36-55 years age-group. Histologically, most (88.6%) women had invasive ductal carcinoma including 43.1% of intermediate grade. A great majority (78%) were stage three. Due to logistical constrains, 75.7% (n = 53/70) cases where immunostained for hormones including 43.4% (ER+), 26.4% (PgR+), and 28% (ER+/PgR+). Furthermore, 65.7% (n = 46/70) cases were immunostained for HER-2 and 15.2% (n = 7/46) were positive, 45.6% were triple negative (ER-,PgR-,HER2-), 23.9% (ER+,PgR+,HER2-) or luminal B, 2.2% (ER+,PgR ,HER2+),13% (ER-,PgR-,HER2+) and 15% (ER+,PgR-,HER2-) with none being triple positive. Conclusions: Hormonal receptors and HER2 expression at MNH appears to be comparable to previous Africans/African Americans reports but not with studies among Caucasians and the current proportion of triple negative breast carcinomas (TNBC) is higher than in a previous Tanzanian report and majority are luminal. HER2 over-expression is relatively common. It is strongly recommended that receptor status assessment be made routine for breast cancer patients at MNH. PMID- 29142590 TI - Birdcage volume coils and magnetic resonance imaging: a simple experiment for students. AB - Background: This article explains some simple experiments that can be used in undergraduate or graduate physics or biomedical engineering laboratory classes to learn how birdcage volume radiofrequency (RF) coils and magnetic resonance imaging (MRI) work. For a clear picture, and to do any quantitative MRI analysis, acquiring images with a high signal-to-noise ratio (SNR) is required. With a given MRI system at a given field strength, the only means to change the SNR using hardware is to change the RF coil used to collect the image. RF coils can be designed in many different ways including birdcage volume RF coil designs. The choice of RF coil to give the best SNR for any MRI study is based on the sample being imaged. Results: The data collected in the simple experiments show that the SNR varies as inverse diameter for the birdcage volume RF coils used in these experiments. The experiments were easily performed by a high school student, an undergraduate student, and a graduate student, in less than 3 h, the time typically allotted for a university laboratory course. Conclusions: The article describes experiments that students in undergraduate or graduate laboratories can perform to observe how birdcage volume RF coils influence MRI measurements. It is designed for students interested in pursuing careers in the imaging field. PMID- 29142587 TI - Factors associated with the high prevalence of oesophageal cancer in Western Kenya: a review. AB - Oesophageal carcinoma (OC) is highly prevalent in Western Kenya especially among the members of the Kalenjin community who reside in the Northern and Southern areas of the Rift Valley. Previous authors have suggested potential association of environmental and genetic risk factors with this high prevalence. The environmental factors that have been suggested include contamination of food by mycotoxins and/or pesticides, consumption of traditional alcohol (locally referred to "Busaa" and "Chan'gaa"), use of fermented milk ("Mursik"), poor diet, tobacco use and genetic predisposition. The aim of this paper is to critically examine the potential contribution of each of the factors that have been postulated to be associated with the high prevalence of the disease in order to establish the most likely cause. We have done this by analyzing the trends, characteristics and behaviours that are specifically unique in the region, and corroborated this with the available literature. From our findings, the most plausible cause of the high incidence of OC among the Kalenjin community is mycotoxins, particularly fumonisins from the food chain resulting from poor handling of cereals; particularly maize combined with traditional alcohol laced with the toxins interacting synergistically with other high-risk factors such as dietary deficiencies associated alcoholism and viral infections, especially HPV. Urgent mitigating strategies should be developed in order to minimize the levels of mycotoxins in the food chain. PMID- 29142591 TI - A novel, highly efficient beta-glucosidase with a cellulose-binding domain: characterization and properties of native and recombinant proteins. AB - Background: Cellulose, the most abundant biopolymer on earth, is an alternative for fossil fuels as a renewable feedstock for the production of second-generation biofuels and other chemicals. The discovery of novel, highly efficient beta glucosidases remains as one of the major bottlenecks for cellulose degradation. In this context, the ascomycete Talaromyces amestolkiae, isolated from cereal samples, has been studied as a promising source for these enzymes. Results: BGL-2 is the major beta-glucosidase secreted by this fungus in the presence of cellulosic inductors. This enzyme possesses a CBD (Cellulose Binding Domain), an unusual feature among this type of proteins. Besides, when growing on cellulose, the fungus produced two different bgl-2 mRNAs that were cloned and expressed in Pichia pastoris. A complete recombinant protein (BGL-2*) and its truncated form, lacking CBD (BGL-2T*), have been purified, characterized and compared with the native enzyme (BGL-2). The three BGL-2 forms studied are highly stable in a wide pH range, but BGL-2T* showed an improved thermal stability at 50 degrees C after 72 h. Using p-nitrophenyl-beta-d-glucopyranoside as a substrate, the steady-state kinetic characterization of the three proteins showed a similar Km and kcat for BGL-2 and BGL-2*, while the truncated protein displayed a threefold higher value for kcat . All tested BGL-2 enzymes were as well highly efficient using cellobiose and other short oligosaccharides as a substrate. In view of biotechnological applications, the recombinant T. amestolkiae enzymes in saccharification of brewers' spent grain were studied, being comparable to commercial beta-glucosidase cocktails. Conclusion: A new beta-glucosidase from T. amestolkiae has been studied. The enzyme, containing a functional CBD, has been expressed in P. pastoris. The comparative analyses of the native protein and its recombinant forms, with and without CBD, suggest that they could be suitable tools for valorization of lignocellulosic biomass. PMID- 29142593 TI - Prevailing clone (ST69) of Vibrio cholerae O139 in India over 10 years. AB - Vibrio cholerae is responsible for the cause of severe life-threatening infection known as cholera. The study aimed to analyze the genetic make-up of V. cholerae O139 isolates from India and compare its phylogeny with the global strains. The genome data revealed that all isolates were of same sequence type (ST69) which belongs to seventh pandemic clone, with same virulence gene profile and, antimicrobial resistance gene profile except for two isolates. No known CRISPR repeats were identified in any of these isolates. Three different phages were identified among the isolates. All the isolates were found to harbour intSXT and seventh pandemic-specific gene (VC2346). Results from this study enhance our understanding on the persistence of ST69 V. cholerae O139 over 20 years. PMID- 29142594 TI - MicroRNAs, a subpopulation of regulators, are involved in breast cancer progression through regulating breast cancer stem cells. AB - Cancer stem cells (CSCs; also known as tumor-initiating cells) are essential effectors of tumor progression due to their self-renewal capacity, differentiation potential, tumorigenic ability and resistance to chemotherapy, all of which contribute to cancer relapse, metastasis and a poor prognosis. Breast cancer stem cells (BCSCs) have been identified to be involved in the processes of BC initiation, growth and recurrence. MicroRNAs (miRNAs) are a class of non-coding small RNAs of 19-23 nucleotides in length that regulate gene expression at the post-transcriptional level through various mechanisms, and serve critical roles in cancer progression. miRNAs have been demonstrated to elicit effects on BCSCs characteristics via the targeting of oncogenes or tumor suppressor genes. The present study focused on the effect of miRNAs on BCSC, including BCSC formation, self-renewal and differentiation, by which miRNAs may inhibit BCSC invasion and metastasis, modulate clonogenicity and tumorigenicity of BCSCs as well as regulate chemotherapy resistance to BC. Through an improved understanding of the association between BCSCs and miRNAs, a novel and safer therapeutic target for BC may be identified. PMID- 29142592 TI - Advances in Age-related Macular Degeneration Understanding and Therapy. AB - While the development of anti-vascular endothelial growth factor (anti-VEGF) as a therapy for neovascular age-related macular degeneration (AMD) was a great success, the pathologic processes underlying dry AMD that eventually leads to photoreceptor dysfunction, death, and vision loss remain elusive to date, with a lack of effective therapies and increasing prevalence of the disease. There is an overwhelming need to improve the classification system of AMD, to increase our understanding of cell death mechanisms involved in both neovascular and non neovascular AMD, and to develop better biomarkers and clinical endpoints to eventually be able to identify better therapeutic targets-especially early in the disease process. There is no doubt that it is a matter of time before progress will be made and better therapies will be developed for non-neovascular AMD. PMID- 29142595 TI - Current status of submucosal tunneling endoscopic resection for gastrointestinal submucosal tumors originating from the muscularis propria layer. AB - Gastrointestinal submucosal tumors (SMTs) have been increasingly identified via the use of endoscopic ultrasonography, and removal is often recommended for SMTs that are >2 cm in diameter or symptomatic. Submucosal tunneling endoscopic resection (STER), also known as submucosal endoscopic tumor resection, endoscopic submucosal tunnel dissection or tunneling endoscopic muscularis dissection, is a novel endoscopic technique for treating gastrointestinal SMTs originating from the muscularis propria layer, and has been demonstrated to be effective in the removal of SMTs with a decreased rate of recurrence by clinical studies. STER may be performed for patients with esophageal or cardia SMTs, and its application has expanded beyond these types of SMTs due to modifications to the technique. The present study reviewed the applications, procedure, efficacy and complications associated with STER. PMID- 29142596 TI - Role and underlying mechanisms of the interstitial protein periostin in the diagnosis and treatment of malignant tumors. AB - Invasion and metastasis are the major characteristics of malignant tumors and are complex processes involving multiple genes. Gene regulation is a precise, large and complex biological control system, and its underlying mechanisms remain to be elucidated. Mesenchymal-specific genes are expressed primarily by mesenchymal cells, and the expression products of these genes are molecules with various structures and functions, including secreted proteins and extracellular matrix proteins. The periostin gene has been newly identified as a mesenchymal-specific gene and an extracellular-matrix secreted protein. Periostin is able to bind to various subtypes of integrin receptors on the surface of the cell membrane. This triggers relevant signal transduction pathways to alter the microenvironment of cancer cells in order to facilitate their survival, invasion, metastasis and angiogenesis as well as enhance the tolerance to hypoxia and chemicals. Therefore, periostin is associated with the grade of malignancy, level of invasion and prognosis of malignant tumors. The in-depth study of periostin may provide an effective marker for tumor diagnosis and prognosis, as well as a novel treatment target. PMID- 29142597 TI - MicroRNA-193a-3p inhibits cell proliferation in prostate cancer by targeting cyclin D1. AB - MicroRNAs (miRNAs) are small non-coding RNAs that affect various biological processes by altering the expression of a target gene. An miRNA microarray analysis has previously revealed a significant decrease in miR-193a-3p levels in prostate cancer tissues compared with that in their benign prostate hyperplasia counterparts. However, the role of miR-193a-3p has yet to be elucidated. In the present study, reverse transcription-quantitative polymerase chain reaction (RT qPCR) was used to evaluate the expression levels of miR-193a-3p in two human prostate cancer cell lines. Forced overexpression of miR-193a-3p was established by transfecting mimics into DU-145 and PC3 cell lines. Cell proliferation and the cell cycle were assessed using a cell viability assay, flow cytometry and a colony formation assay. In addition, the target gene of miR-193a-3p was determined by a luciferase assay, RT-qPCR and western blot analysis. The regulation of the cell cycle by miR-193a-3p was also evaluated by western blotting. The results demonstrated that miR-193a-3p expression levels were lower in prostate cancer cell lines as compared with the RWPE normal prostate epithelium cell line. Subsequent gain-of-function studies revealed that stable miR-193a-3p transfection inhibited cell viability, proliferation and colony formation, and induced G1 phase arrest in prostate cancer cells. A luciferase assay and western blot analysis identified cyclin D1 (CCND1) as a direct target gene of miR-193a-3p. In addition, the forced expression of CCND1 was able to counter the inhibitory effects of miR-193a-3p transfection in the prostate cancer cells. In summary, the results suggest that miR-193a-3p may inhibit the viability, proliferation and survival of prostate cancer cells by regulating the expression profile of CCND1, and that miR-193a-3p may be a novel therapeutic biomarker for prostate cancer. PMID- 29142598 TI - Expression profile of Oct-4 lung cancer-specific marker prior and subsequent to a salirasib treatment regime. AB - Lung cancer is one of the leading types of cancer that lead to mortalities in the male and female populations. The existing lung cancer-specific markers are not able to accurately predict the condition of the disease, and the response of these markers can vary under various pathological conditions. The ability for tumors to regenerate following treatment can be more aggressive, and this may be due to the remaining lung cancer-specific stem cells, which are resistant to chemotherapeutic drugs. Evaluating cancer stem cells under various pathological conditions, as well as prior and subsequent to treatment, can help to increase the understanding of the underlying mechanisms. In the present study, a mouse model with initial and advanced forms of lung cancer was developed using tobacco smoke carcinogen. It was observed from tissue sections that there were many actively dividing cells spread throughout the mouse lung tissue with the initial stages of lung cancer, and these cells aggregated in advanced stages of lung cancer. Furthermore, immunohistochemical staining indicated that there was an increased number of octamer-binding protein 4 (Oct-4)-positive cells present in mouse tissues with advanced stages of the disease compared with tissues without lung cancer or at the initial stages of disease. The cancer stem cell population following salirasib treatment was also investigated in two groups. The mice in the early treatment group were administered with salirasib following 1 month of tumor growth, and the delayed treatment group was treated following 2 months of tumor growth. The number of cancer stem cells was markedly reduced in the early treatment group. However, salirasib failed to have any observable effect in the delayed treatment group. Cancer stem cells were analyzed using the marker Oct-4 to improve an understanding of the proliferative ability of cancer stem cells under various pathological conditions, which may lead to the development of novel cancer therapeutics. PMID- 29142599 TI - Large Wolffian adnexal tumor of the ovary: A case report and literature review. AB - Female Wolffian adnexal tumor (WAT) is a rare neoplasm arising from the remnants of the mesonephric duct and <100 cases have been reported globally. The present case report describes a 73-year-old female patient with WAT in the left ovary which, to the best of our knowledge, is the largest benign WAT tumor to be reported. In addition, the present case report reviewed previous studies on the clinical characteristics and therapy for WAT and the surgery methods for female WAT of ovary were summarized. WATs are typically benign; however, a number factors may increase the risk of malignancy. PMID- 29142600 TI - Co-activation of Hedgehog and Wnt signaling pathways is associated with poor outcomes in triple negative breast cancer. AB - Hedgehog (HH) and Wnt pathway activation have been implicated in poor prognosis of breast cancer. Crosstalk between these two pathways has been demonstrated to be important in breast cancer progression, however the association between these two pathways and breast cancer survival rate is unknown. The present study comprised a cohort of 36 patients with triple negative breast cancer (TNBC) to investigate co-activation of HH and canonical Wnt pathway in association to patient outcome. All patients had varying degrees of cytoplasmic sonic HH and glioma-associated oncogene homolog (Gli)-1 staining, which positively correlated with tumor stage. Nuclear beta-catenin was additionally correlated to tumor stage. A significant association was observed between nuclear Gli-1 and nuclear beta-catenin. Co-activation of HH and Wnt pathways was associated with poorer prognosis in TNBC patients resulting in a greater risk of early recurrence and decreased overall survival rate compared with patients with only one pathway activated. Therefore, the combined activation status of the HH and Wnt pathways may be a useful prognostic marker for TNBC patients at risk for early recurrence. PMID- 29142601 TI - Application of spontaneously closing cannula ileostomy in laparoscopic anterior resection of rectal cancer. AB - An anastomotic leak (AL) is the most serious complication observed in laparoscopic anterior resection of rectal cancer (LARRC). In order to protect anastomosis from AL and avoid stoma reversal surgery in patients with ileostomy, spontaneously closing cannula ileostomy (SCCI) was used in LARRC and its safety and feasibility were assessed in the present study. To the best of our knowledge, this is the first time that SCCI has been used in such a case. A total of 41 patients who underwent LARRC with SCCI or ileostomy procedures between November 2013 and August 2014 were retrospectively analyzed. The patient demographics, clinical features and surgical data were evaluated using a Mann-Whitney U-test, Fisher's exact test or linear-by-linear association. Demographics, surgical data and the majority of clinical features of the two groups were consistently similar. In the SCCI group, the length of postoperative stay, total cost and stoma period were significantly improved compared with those in the ileostomy group. Additionally, the median protective period in the SCCI group was 22 days [interquartile range (IQR), 19-22 days], the median time to cannula removal was 23 days (IQR, 20-24 days) and the median time to cannula stoma closure was 12 days (IQR, 11-13 days). No SCCI-associated complications occurred. No significant differences in routine complications, including staple-line bleeding, anastomotic leak, anastomotic dehiscence, anastomotic stenosis and wound infection, were identified between the two groups. In LARRC, the SCCI procedure was demonstrated to be a safe and feasible diverting technique to protect anastomosis from AL. In contrast to ileostomy, the SCCI procedure obviated the requirement for stoma reversal surgery, which resulted in decreased lengths of postoperative hospital stay, hospitalization costs and stoma periods. PMID- 29142602 TI - Combined aspirin and apatinib treatment suppresses gastric cancer cell proliferation. AB - Gastric cancer (GC), one of the types of tumor most prone to malignancy, is characterized by high lethality. Numerous molecular mediators of GC have been identified, including transcription factors, signaling molecules and non-coding RNAs. Recently, inhibition of angiogenesis has emerged as a potential strategy for GC therapy. In the present study, the levels of vascular endothelial growth factor (VEGF), peroxisome proliferator-activated receptor-alpha (PPARalpha) and miR-21 in GC patients and individuals without cancer, and the correlation between VEGF and miR-21, and PPARalpha and miR-21 expression were analyzed. In addition, the GC MKN45 cell line was treated with apatinib (a tyrosine kinase inhibitor) and aspirin (an activator of the transcription factor, PPARalpha) to investigate the effects of these compounds on tumorigenesis. Furthermore, the present study attempted to elucidate the molecular mechanisms of alteration of GC tumorigenesis by aspirin and apatinib. The results of the current study demonstrated that there was a higher expression of VEGF and miR-21 in GC tissues compared with that in morphologically adjacent normal tissues whereas PPARalpha expression was decreased. These results were confirmed in vitro, as treatment of MKN45 cells with VEGF resulted in a significant increase in miR-21 expression and a significant reduction in PPARalpha protein expression. Furthermore, the inhibitory effects of VEGF on PPARalpha mRNA and protein expression were demonstrated to be mediated by miR-21. Suppression of PPARalpha protein expression attenuated the inhibitory effects of miR-21 on the level of PPARalpha mRNA, thereby enhancing tumorigenesis in gastric cancer. Treatment of MKN45 cells with aspirin reduced the levels of phosphorylated AKT by activating PPARalpha, whereas treatment with apatinib inhibited the phosphorylation of vascular endothelial growth factor receptor 2 and phosphoinositide-3 kinase in MKN45 cells. Finally, treatment of MKN45 cells with apatinib and aspirin suppressed tumorigenesis by inhibiting cell proliferation, migration, invasion and colony formation. Taken together, the results of the present study indicate that treatment with a combination of aspirin and apatinib may be a potential therapeutic strategy for GC treatment. PMID- 29142603 TI - Expression and significance of secreted protein acidic and rich in cysteine in human osteosarcoma. AB - Osteosarcoma is the most common primary malignancy of bone, and is a high-grade malignant mesenchymal tumor with high recurrence and metastatic rates. Increased expression of secreted protein, acidic and rich in cysteine (SPARC) indicates poor prognosis in a number of malignances. However, the expression level of SPARC in human osteosarcoma and its associated mechanism remains unclear. To analyze the expression of SPARC in human osteosarcoma and its potential application in the diagnosis and treatment of osteosarcoma, the clinical records and samples of 20 cases of osteosarcoma were collected. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis applied to detect SPARC expression levels in osteosarcoma tissues, with normal bone tissue as control. Immunofluorescence detection was used to examine the distribution of SPARC. The association between SPARC level and clinical factors was analyzed. RT-qPCR (P=0.002) indicated that the SPARC level in osteosarcoma tissues was significantly increased compared with that in normal tissues. Immunofluorescence detection indicated that SPARC was widely distributed in tumor tissues. SPARC protein expression level was positively associated with lung metastasis (P=0.016). The results indicated that SPARC tends to be highly expressed in human osteosarcoma tissues. The expression level of SPARC is associated with lung metastasis, which may be an indicator of prognosis. Thus, SPARC may be a potential tumor marker and therapeutic target in osteosarcoma. PMID- 29142604 TI - Klotho expression is correlated to molecules associated with epithelial mesenchymal transition in lung squamous cell carcinoma. AB - Klotho is known as an anti-aging gene. We previously reported that the expression of Klotho is a postoperative prognostic factor for patients with lung large cell neuroendocrine carcinoma and lung small cell carcinoma. Recently, Klotho was shown to suppress the epithelial-mesenchymal transition (EMT). In the present study, we examined the association between the expression of Klotho and the regulation of EMT in lung squamous cell carcinoma. We immunohistochemically examined the expression of Klotho in patients with lung squamous cell carcinoma who had undergone surgical resection or photodynamic therapy. The immunohistochemical analysis showed that Klotho expression was observed not only in normal bronchial epithelial cells, but also in centrally located early lung cancers, which were all carcinomas in situ and were treated using PDT. However, in lung cancer patients with invasive and or advanced squamous cell carcinoma who had undergone a complete surgical resection, Klotho expression was observed in only 4 patients (13%). To elucidate the associations between the expression of Klotho and the expressions of EMT-related proteins, such as E-cadherin, N cadherin, vimentin, and Snail, we transiently transfected GFP-Klotho plasmid DNA into the human squamous lung cancer cell line SQ5 and examined the expressions of these proteins of GFP-positive cells after sorting using flow cytometry. In SQ5 cells overexpressing GFP-Klotho, the expression of N-cadherin, which is a mesenchymal marker, was completely inhibited, compared with that in SQ5 cells transfected with the GFP vector. The overexpression of Klotho did not affect the regulation of either other mesenchymal markers (such as vimentin and Snail) or the regulation of an epithelial marker (E-cadherin). We concluded that the expression of Klotho was related to the degree of cancer invasiveness and that Klotho inhibits the expression of N-cadherin and regulates the EMT in lung cancer. PMID- 29142605 TI - Aviscumine, a recombinant ribosomal inhibitor, increases the antitumor activity of natural killer cells. AB - Aviscumine, a recombinant lectin I, has been identified as an immunomodulatory agent within a new class of ribotoxic stress-inducing anticancer substances that have demonstrated efficacy in phase I/II trials. The aim of the present study was to elucidate the presumed effect of aviscumine on enhancing human natural killer (NK) cell antitumor cytotoxicity. To measure the effect of aviscumine on human NK cell cytotoxicity, chromium-51-release assays against K-562 cells were performed with isolated NK cells from the whole blood of 34 healthy volunteers. Two effector-to-target cell ratios (12.5:1 and 25:1) were used by two independent investigators with a focus on the concentration-dependent effect (0.5 vs. 1 ng/ml aviscumine), reproducibility (first vs. second investigator) and the specificity of the effect by comparison to a heat-inactivated aliquot and interleukin 2 (IL 2) stimulation (10 ng/ml). The mediation of the effect via degranulation was demonstrated by flow cytometric analyses of CD107alpha expression. Statistics were performed with SPSS using Student's t-tests for normally distributed data. Aviscumine induced a significant and reproducible, concentration-dependent increase in NK cell cytotoxicity (n=22; P<0.01 for both concentrations and ratios), which was also demonstrated when administered in combination with IL-2 (n=12; 12.5:1 ratio, P<0.001; 25:1 ratio, P=0.025) and when compared with the heat-inactivated aliquots (n=12; 12.5:1, P=0.004; 25:1 ratio, P=0.007). The mediation of its effect via interferon gamma degranulation was demonstrated by significantly enhanced CD107alpha expression (n=7; P=0.005). Taken together, the results indicate that aviscumine induced an increase in NK cell anticancer cytotoxicity. These results highlight its clinical potential as an immunostimulatory agent, particularly with regard to combined use with chemotherapeutics or immune checkpoint inhibitors. However, further studies are required. PMID- 29142606 TI - Hesperidin inhibits ovarian cancer cell viability through endoplasmic reticulum stress signaling pathways. AB - Hesperidin is a vitamin P flavonoid compound primarily present in citrus fruits. The aim of the present study was to investigate whether hesperidin inhibits ovarian cancer cell viability via endoplasmic reticulum stress signaling pathways. A2780 cells were treated with various doses of hesperidin for 6, 12 or 24 h, and the viability of A2780 cells was assessed using the MTT assay. Hesperidin decreased the viability of A2780 cells and increased cytotoxicity in a dose- and time-dependent manner. In addition, hesperidin induced apoptosis and increased cleaved caspase-3 protein expression levels in A2780 cells. Furthermore, hesperidin markedly increased the protein expression of anti-growth arrest- and DNA damage-inducible gene 153, anti-CCAAT'enhancer-binding protein homologous protein, glucose-regulated protein 78 and cytochrome c in A2780 cells. The results of the present study indicated that hesperidin inhibits cell viability and induces apoptosis in ovarian cancer cells via endoplasmic reticulum stress signaling pathways. Thus, hesperidin may offer a novel therapeutic tool for ovarian carcinoma. PMID- 29142607 TI - Curcumin inhibits MCF-7 cells by modulating the NF-kappaB signaling pathway. AB - The present study investigated the inhibitory effect of curcumin on human breast cancer MCF-7 cells and investigated the potential underlying molecular mechanisms. MCF-7 cells were cultured with curcumin at different concentrations and time points. The effects of curcumin treatment on breast cancer cell proliferation were studied using a MTT assay. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to assess the mRNA and protein expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax), nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kappaB) and inhibitor of NF-kappaB-alpha (IkappaBalpha). The proliferation of MCF-7 cells in the group treated with curcumin was markedly decreased compared with the control, with the greatest inhibitory effect at a concentration of 20 uM. The expression of Bax mRNA was increased and Bcl-2 mRNA expression was decreased compared with the control. Additionally, protein expression of NF-kappaB and IkappaB was increased. The data indicate that curcumin is able to inhibit breast cancer cell proliferation, possibly by regulating the NF-kappaB signaling pathway. PMID- 29142608 TI - Upregulation of microRNA-18b induces phosphatase and tensin homolog to accelerate the migration and invasion abilities of ovarian cancer. AB - Ovarian cancer (OC) is the most common cause of mortality from malignant gynecological cancers. Its lethality is mainly a result of tumors that are difficult to detect at the early stage and a lack of effective systemic therapy for advanced status cancer. MicroRNAs (miRNAs/miRs) are a category of single stranded non-coding small RNAs that bind to their target mRNAs, and aberrant expression levels of miRNAs may serve key roles in regulating cell migration and invasion of various types of human cancer. Previous studies have demonstrated that miR-18b may function as an oncogene in numerous types of tumors, but its role and molecular mechanism in OC remained unclear. The present study demonstrated for the first time that miR-18b expression was significantly upregulated in OC tissues and cells. An increased miR-18b expression level was positively associated with tumor grade and lymph node metastasis. An in vitro assay revealed that exogenous inhibition of miR-18b expression may markedly inhibit OC cell migratory and invasive activities, whereas overexpression of miR 18b enhanced cell migratory and invasive abilities. Of note, using in silico methodologies and luciferase reporter assays, it was demonstrated that phosphatase and tensin homolog (PTEN) was a direct target of miR-18b in OC cells. Furthermore, knockdown of miR-18b expression may significantly decrease mRNA and protein expression levels of endogenous PTEN. The results of the present study highlighted that upregulation of miR-18b was involved in OC cell metastasis by directly targeting PTEN. Inhibition of miR-18b may be a novel effective diagnostic and therapeutic measure for OC. PMID- 29142609 TI - Role of 5-Aza-CdR in mitomycin-C chemosensitivity of T24 bladder cancer cells. AB - Chemotherapeutic insensitivity is one of key obstacles to effectively treating muscle invasive bladder cancer. 5-Aza-2'-deoxycytidine (5-Aza-CdR) has been identified as a tumor suppressive agent in various types of cancer. The aim of the present study was to identify the effects of 5-Aza-CdR on the mitomycin-C (MMC) chemosensitivity of T24 bladder cancer cells and investigate the underlying mechanisms. T24 cells were treated with a combination of MMC and 5-Aza-CdR at various concentrations. The rates of proliferation and apoptosis were assessed by an MTT assay and flow cytometry, respectively. The expression of drug resistance associated proteins, including P-glycoprotein (P-gp) and multidrug resistance associated protein 1 (MRP1), and autophagy-associated proteins, including beclin 1, nucleoporin 62 (p62) and autophagy protein 5 (ATG5) were detected with western blotting. Treatment with 5-Aza-CdR significantly promoted the MMC chemosensitivity of T24 cells. The proliferation of T24 cells was significantly inhibited with increasing 5-Aza-CdR concentration, whereas apoptosis was significantly increased. This was associated with the decreased expression of P gp, MRP1, beclin 1, p62 and ATG5. In conclusion, 5-Aza-CdR enhanced MMC chemosensitivity in bladder cancer T24 cells, which may be caused by the suppression of drug resistance- and autophagy-associated proteins. PMID- 29142610 TI - Erratum: A novel t(9;22;11) translocation involving 11q24 in a patient with chronic myeloid leukemia: A case report. AB - [This corrects the article DOI: 10.3892/ol.2017.5668.]. PMID- 29142611 TI - Dissociating morphological and form priming with novel complex word primes: Evidence from masked priming, overt priming, and event-related potentials. AB - Recent research suggests that visually-presented words are initially morphologically segmented whenever the letter-string can be exhaustively assigned to existing morphological representations, but not when an exhaustive parse is unavailable; e.g., priming is observed for both hunter->HUNT and brother ->BROTH, but not for brothel->BROTH. Few studies have investigated whether this pattern extends to novel complex words, and the results to date (all from novel suffixed words) are mixed. In the current study, we examine whether novel compounds (drugrack->RACK) yield morphological priming which is dissociable from that in novel pseudoembedded words (slegrack->RACK). Using masked priming, we find significant and comparable priming in reaction times for word-final elements of both novel compounds and novel pseudoembedded words. Using overt priming, however, we find greater priming effects (in both reaction times and N400 amplitudes) for novel compounds compared to novel pseudoembedded words. These results are consistent with models assuming across-the-board activation of putative constituents, while also suggesting that morpheme activation may persevere despite the lack of an exhaustive morpheme-based parse when an exhaustive monomorphemic analysis is also unavailable. These findings highlight the critical role of the lexical status of the pseudoembedded prime in dissociating morphological and orthographic priming. PMID- 29142612 TI - Trends and patterns of air quality in Santa Cruz de Tenerife (Canary Islands) in the period 2011-2015. AB - Air quality trends and patterns in the coastal city of Santa Cruz de Tenerife (Canary Islands, Spain) for the period 2011-2015 were analyzed. The orographic and meteorological characteristics, the proximity to the African continent, and the influence of the Azores anticyclone in combination with the anthropogenic (oil refinery, road/maritime traffic) and natural emissions create specific dispersion conditions. SO2, NO2, PM10, PM2.5, and O3 pollutants were assessed. The refinery was the primary source of SO2; EU hourly and daily average limit values were exceeded during 2011 and alert thresholds were reached in 2011 and 2012. WHO daily mean guideline was occasionally exceeded. Annual averages in the three stations that registered the highest concentrations in 2011 and 2012 were between 9.3 and 20.4 MUg/m3. The spatial analysis of SO2 concentrations with respect to prevailing winds corroborates a clear influence of the refinery to the SO2 levels. In 2014 and 2015, the refinery did not operate and the concentrations fell abruptly to background levels of 2.5-7.1 MUg/m3 far below from WHO AQG. NO2 EU limit values, as well as WHO AQG for the period 2011-2015, were not exceeded. The progressive dieselization of the vehicle fleet caused an increment on NO2 annual mean concentrations (from 2011 to 2015) measured at two stations close to busy roads 25 to 31 MUg/m3 (+21%) and 27 to 35 MUg/m3 (+29%). NO x daily and weekly cycles (working days and weekends) were characterized. An anti-correlation was found between NO x and O3, showing that O3 is titrated by locally emitted NO. Higher O3 concentrations were reported because less NO x emitted during the weekends showing a clear weekend effect. Saharan dust intrusions have a significant impact on PM levels. After subtracting natural sources contribution, none of the stations reached the EU maximum 35 yearly exceedances of daily means despite seldom exceedances at some stations. None of the stations exceeded the annual mean EU limit values; however, many stations exceeded the annual mean WHO AQG. Observed PM10 annual average concentrations in all the stations fluctuated between 10.1 and 35.3 MUg/m3, where background concentrations were 6.5-24.4 MUg/m3 and natural contributions: 4.2-9.1 MUg/m3. No PM10 temporal trends were identified during the period except for an effect of washout due to the rain: concentrations were lower in 2013 and 2014 (the most rainy years of the period). None of the stations reached the PM2.5 annual mean EU 2015 limit value. However, almost all the stations registered daily mean WHO AQG exceedances. During 2015, PM2.5 concentrations were higher than the previous years (2015, 8.8-12.3 MUg/m3; 2011-2014, 3.7-9.6 MUg/m3). O3 complied with EU target values; stricter WHO AQG were sometimes exceeded in all the stations for the whole time period. PMID- 29142613 TI - Surface data assimilation of chemical compounds over North America and its impact on air quality and Air Quality Health Index (AQHI) forecasts. AB - The aim of this paper is to analyze the impact of initializing GEM-MACH, Environment and Climate Change Canada's air quality (AQ) forecast model, with multi-pollutant surface objective analyses (MPSOA). A series of 48-h air quality forecasts were launched for July 2012 (summer case) and January 2014 (winter case) for ozone, NO2, and PM2.5. In this setup, the GEM-MACH model (version 1.3.8.2) was initialized with surface analysis increments (from MPSOA) which were projected in the vertical by applying an appropriate fractional weighting in order to obtain 3D analyses in the lower troposphere. Here, we have used a methodology based on sensitivity tests to obtain the optimum vertical correlation length (VCL). Overall, results showed that for PM2.5, more specifically for sulfate and crustal materials, AQ forecasts initialized with MPSOA showed a very significant improvement compared to forecasts without data assimilation, which extended beyond 48 h in all seasons. Initializing the model with ozone analyses also had a significant impact but on a shorter time scale than that of PM2.5. Finally, assimilation of NO2 was found to have much less impact than longer-lived species. The impact of simultaneous assimilation of the three pollutants (PM2.5, ozone, and NO2) was also examined and found very significant in reducing the total error of the Air Quality Health Index (AQHI) over 48 h and beyond. We suggest that the period over which there is a significant improvement due to assimilation could be an adequate measure of the pollutant atmospheric lifetime. PMID- 29142614 TI - Repeatability analysis of airborne electromagnetic surveys. AB - Purpose: We provide methods for determining the repeatability of airborne electromagnetic surveys when conducted at different altitudes over a number of repeated flights. Our data arise from the TELLUS project carried out by the Geological Surveys of Ireland and Northern Ireland and we examine the repeatability of the apparent resistivity at different frequencies. Methods: After considering a number of issues with the data, we propose two different models from the functional data analysis literature; a Weiner process with random effects, and a penalised spline smoother. Results: Both methods arrive at the same conclusion regarding repeatability of the data; results obtained are more repeatable for flights at lower altitudes. Conclusions: The target altitude for aircraft carrying out airborne electromagnetic surveys should be as low as possible. PMID- 29142615 TI - Understanding hand hygiene behavior in a pediatric oncology unit in a low- to mid income country. AB - Background/Objective: A qualitative method study identified perceived barriers and motivations for hand hygiene (HH) practice in a pediatric oncology unit in Guatemala. Methods: Data collection included focus groups with participants grouped by job type. Focus group responses were assessed using content analysis. Participants included nurse supervisors, registered nurses, auxiliary nurses, physicians, and auxiliary and support staff and volunteers (n=55). Results: Themes emerged from participant responses, providing a framework to develop and implement targeted interventions to improve HH. Perceived barriers to HH included the following themes: inconsistent HH supplies, time pressures related to workload, lack of HH training for some healthcare workers and patients' families; negative social reactions after reminding others to practice HH; and cultural traditions shaping patients' families' hygiene. Motivations for HH practice included two themes: patient protection and self-protection. Some of these themes were unique to this culture and clinical setting. Recommendations included a preference for visual aids rather than verbal reminders (e.g. HH promotion signage, demonstrations of HH), and disclosure of compliance rates. Conclusions: The research team concluded that the main barriers and motivations for HH, including culturally-unique and site-specific factors, were identified and used for subsequent HH compliance improvement such as education. Intervention post focus group concentrated in HH education of healthcare providers using e-learning methodology. PMID- 29142616 TI - Scaling Relations for Acidity and Reactivity of Zeolites. AB - Zeolites are widely applied as solid acid catalysts in various technological processes. In this work we have computationally investigated how catalytic reactivity scales with acidity for a range of zeolites with different topologies and chemical compositions. We found that straightforward correlations are limited to zeolites with the same topology. The adsorption energies of bases such as carbon monoxide (CO), acetonitrile (CH3CN), ammonia (NH3), trimethylamine (N(CH3)3), and pyridine (C5H5N) give the same trend of acid strength for FAU zeolites with varying composition. Crystal orbital Hamilton populations (COHP) analysis provides a detailed molecular orbital picture of adsorbed base molecules on the Bronsted acid sites (BAS). Bonding is dominated by strong sigma donation from guest molecules to the BAS for the adsorbed CO and CH3CN complexes. An electronic descriptor of acid strength is constructed based on the bond order calculations, which is an intrinsic parameter rather than adsorption energy that contains additional contributions due to secondary effects such as van der Waals interactions with the zeolite walls. The bond order parameter derived for the CH3CN adsorption complex represents a useful descriptor for the intrinsic acid strength of FAU zeolites. For FAU zeolites the activation energy for the conversion of pi-adsorbed isobutene into alkoxy species correlates well with the acid strength determined by the NH3 adsorption energies. Other zeolites such as MFI and CHA do not follow the scaling relations obtained for FAU; we ascribe this to the different van der Waals interactions and steric effects induced by zeolite framework topology. PMID- 29142617 TI - Acute Strenuous Exercise Induces an Imbalance on Histone H4 Acetylation/Histone Deacetylase 2 and Increases the Proinflammatory Profile of PBMC of Obese Individuals. AB - This study evaluated the response of global histone H4 acetylation (H4ac), histone deacetylase 2 (HDAC2) activity, as well as the production of proinflammatory cytokines and monocyte phenotypes of lean and obese males after exercise. Ten lean and ten obese sedentary men were submitted to one session of strenuous exercise, and peripheral blood mononuclear cells (PBMC) were stimulated in vitro with lipopolysaccharide (LPS). Global H4ac levels, HDAC2 activity in PBMC, and IL-6, IL-8, and TNF-alpha production were analyzed. Monocyte phenotype was determined in accordance with the expression of CD14 and CD16. At rest, obese individuals presented higher frequency of proinflammatory CD14+CD16+ monocytes. LPS induced a significant augment in global H4ac and in the production of IL-6, IL-8, and TNF-alpha mainly in obese individuals. After exercise, the increased production of IL-8 and TNF-alpha and peripheral frequency of CD14+CD16+ were observed in both groups. In addition, exercise also induced a significant hyperacetylation of histone H4 and decreased HDAC2 activity in both nonstimulated and LPS-stimulated PBMC of obese individuals. Our data indicate that the obesity impacts on H4ac levels and that strenuous exercise leads to an enhanced chronic low-grade inflammation profile in obesity via an imbalance on H4ac/HDAC2. PMID- 29142619 TI - The Formation of Extragraft Bone Bridging after Anterior Cervical Discectomy and Fusion: A Finite Element Analysis. AB - Objective: In addition to bone bridging inside a cage or graft (intragraft bone bridging, InGBB), extragraft bone bridging (ExGBB) is commonly observed after anterior cervical discectomy and fusion (ACDF) with a stand-alone cage. However, solid bony fusion without the formation of ExGBB might be a desirable condition. We hypothesized that an insufficient contact area for InGBB might be a causative factor for ExGBB. The objective was to determine the minimal area of InGBB by finite element analysis. Methods: A validated 3-dimensional, nonlinear ligamentous cervical segment (C3-7) finite element model was used. This study simulated a single-level ACDF at C5-6 with a cylindroid interbody graft. The variables were the properties of the incorporated interbody graft (cancellous bone [Young's modulus of 100 or 300 MPa] to cortical bone [10000 MPa]) and the contact area between the vertebra and interbody graft (Graft-area, from 10 to 200 mm2). Interspinous motion between the flexion and extension models of less than 2 mm was considered solid fusion. Results: The minimal Graft-areas for solid fusion were 190 mm2, 140 mm2, and 100 mm2 with graft properties of 100, 300, and 10000 MPa, respectively. The minimal Graft-areas were generally unobtainable with only the formation of InGBB after the use of a commercial stand-alone cage. Conclusion: ExGBB may be formed to compensate for insufficient InGBB. Although various factors may be involved, solid fusion with less formation of ExGBB may be achieved with refinements in biomaterials, such as the use of osteoinductive cage materials; changes in cage design, such as increasing the area of polyetheretherketone or the inside cage area for bone grafts; or surgical techniques, such as the use of plate/screw systems. PMID- 29142618 TI - Melatonin Supplementation Lowers Oxidative Stress and Regulates Adipokines in Obese Patients on a Calorie-Restricted Diet. AB - Obesity is one of the major global health problems. Melatonin deficiency has been demonstrated to correlate with obesity. The aim of the study was to estimate the effect of melatonin on oxidative stress and adipokine levels in obese patients on a calorie-restricted diet. Thirty obese patients were supplemented with a daily dose of 10 mg of melatonin (n = 15) or placebo (n = 15) for 30 days with a calorie-restricted diet. Serum levels of melatonin, 4-hydroxynonenal (HNE), adiponectin, omentin-1, leptin, and resistin, as well as erythrocytic malondialdehyde (MDA) concentration and Zn/Cu-superoxide dismutase, catalase, and glutathione peroxidase (GPx) activities, were measured at baseline and after supplementation. Significant body weight reduction was observed only in the melatonin group. After melatonin supplementation, the adiponectin and omentin-1 levels and GPx activities statistically increased, whereas the MDA concentrations were reduced. In the placebo group, a significant rise in the HNE and a drop in the melatonin concentrations were found. The results show evidence of increased oxidative stress accompanying calorie restriction. Melatonin supplementation facilitated body weight reduction, improved the antioxidant defense, and regulated adipokine secretion. The findings strongly suggest that melatonin should be considered in obesity management. This trial is registered with CTRI/2017/07/009093. PMID- 29142620 TI - Elevated Blood Urea Nitrogen/Creatinine Ratio Is Associated with Venous Thromboembolism in Patients with Acute Ischemic Stroke. AB - Objective: Although venous thromboembolism (VTE) is frequently related to dehydration, the impact of dehydration on VTE in acute ischemic stroke (AIS) is not clear. This study investigated whether dehydration, as measured by blood urea nitrogen (BUN)/creatinine (Cr) ratio, influences the occurrence of VTE in patients with AIS. Methods: This is a retrospective study of patients with AIS between January 2012 and December 2013. Patients with newly diagnosed AIS who experienced prolonged hospitalization for at least 4 weeks were included in this study. Results: Of 182 patients included in this study, 17 (9.3%) suffered VTE during the follow-up period; in two cases, VTE was accompanied by deep vein thrombosis and pulmonary embolism. Patients with VTE were more frequently female and had higher National Institutes of Health Stroke Scale (NIHSS) score, more lower limb weakness, and elevated blood urea nitrogen BUN/Cr ratio on admission. In a multivariate analysis, BUN/Cr ratio >15 (odds ratio [OR] 8.75) and severe lower limb weakness (OR 4.38) were independent risk factors for VTE. Conclusion: Dehydration on admission in cases of AIS might be a significant independent risk factor for VTE. PMID- 29142621 TI - Mechanical Thrombectomy with Solitaire Stent Retrieval for Acute Cardioembolic Stroke. AB - Objective: Few studies have reported the outcome of mechanical thrombectomy with Solitaire stent retrival (MTSR) in subtypes of acute ischemic stroke. The purpose of this study was to evaluate the efficacy and result of MTSR in acute cardioembolic stroke. Methods: Twenty consecutive patients with acute cardioembolic stroke were treated by MTSR. The angiographic outcome was assessed by thrombolysis in cerebral infarction (TICI) grade. TICI grade 2a, 2b, or 3 with a measurable thrombus that was retrieved was considered as a success when MTSR was performed in the site of primary vessel occlusion, and TICI grade 2b or 3 was considered as a success when final result was reported. Clinical and radiological results were compared between two groups divided on the basis of final results of MTSR. Persistent thrombus compression sign on angiogram was defined as a stenotic, tapered arterial lumen whenever temporary stenting was performed. The clinical outcomes were assessed by the modified Rankin Scale (mRS) at 3 months. Results: The failure rate of MTSR was 20% (4/20) and other modalities, such as permanent stenting, were needed. Final successful recanalization (TICI grade 2b or 3) was 80% when other treatments were included. The rate of good outcome (mRS<=2) was 35% at the 3-month follow-up. Failure of MTSR was significantly correlated with persistent thrombus compression sign (p=0.001). Conclusion: Some cases of cardioembolic stroke are resistant to MTSR and may need other treatment modalities. Careful interpretation of angiogram may be helpful to the decision. PMID- 29142622 TI - Effectiveness and Safety of Mechanical Thrombectomy with Stent Retrievers in Basilar Artery Occlusion: Comparison with Anterior Circulation Occlusions. AB - Objective: Acute basilar artery occlusion (BAO) is associated with severe neurological dysfunction and high mortality rates. The benefits of mechanical thrombectomy in BAO have not been explored in recent clinical trials. Therefore, we analyzed outcomes of stent retriever mechanical thrombectomy for BAO, and compared with anterior circulation occlusions (ACO). Methods: In total, 161 consecutive patients (24 BAO, 137 ACO) who underwent mechanical thrombectomy with the stent retriever between January 2013 and August 2016 enrolled in our study. All patients underwent clinical assessment with the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS). Radiological results were used to evaluate thrombolysis in cerebral infarction (TICI) scores and successful recanalization was defined by TICI 2b or 3. Results: Mean NIHSS scores at 24 hours and 30 days were significantly higher in the BAO group than the ACO group (p=0.021, p=0.001). mRS at 90 days was significantly higher in the BAO group (4.2) compared with the ACO group (3.0) (p=0.003). The BAO group (2.0) performed fewer stent retriever passages than the ACO group (2.7) (p=0.049). There were no significant differences between the two groups in terms of complications, but the BAO patients experienced a higher mortality (16.6%) rate than ACO patients (5.8%) (p=0.001). In subgroup analysis of BAO, patients with short procedure times achieved successful recanalization (p=0.001) and successfully recanalized patients exhibited more favorable mRS at 90 days (p=0.027). Conclusion: In our study, mechanical thrombectomy of BAO patients showed worse clinical outcome and higher mortality rate than ACO patients. However, mechanical thrombectomy with a stent retriever in BAO is an effective treatment, because successfully recanalized patients showed good clinical outcome in BAO patients. PMID- 29142623 TI - Simple Coiling versus Stent-Assisted Coiling of Paraclinoid Aneurysms: Radiological Outcome in a Single Center Study. AB - Objective: Paraclinoid aneurysms are a group of aneurysms arising at the distal internal carotid artery. Due to a high incidence of small, wide-necked aneurysms in this zone, it is often challenging to achieve complete occlusion when solely using detachable coils, thus stent placement is often required. In the present study, we aimed to investigate the effect of stent placement in endovascular treatment of paraclinoid aneurysms. Methods: Data of 98 paraclinoid aneurysms treated by endovascular approach in our center from August 2005 to June 2016 were retrospectively reviewed. They were divided into two groups: simple coiling and stent-assisted coiling. Differences in the recurrence and progressive occlusion between the two groups were mainly analyzed. The recurrence was defined as more than one grade worsening according to Raymond-Roy Classification or major recanalization that is large enough to permit retreatment in the follow-up study compared to the immediate post-operative results. Results: Complete occlusion was achieved immediately after endovascular treatment in eight out of 37 patients (21.6%) in the stent-assisted group and 18 out of 61 (29.5%) in the simple coiling group. In the follow-up imaging studies, the recurrence rate was lower in the stent-assisted group (one out of 37, 2.7%) compared to the simple coiling group (13 out of 61, 21.3%) (p=0.011). Multivariate logistic regression model showed lower recurrence rate in the stent-assisted group than the simple coiling group (odds ratio [OR] 0.051, 95% confidence interval [CI] 0.005-0.527). Furthermore there was also a significant difference in the rate of progressive occlusion between the stent-assisted group (16 out of 29 patients, 55.2%) and the simple coiling group (10 out of 43 patients, 23.3%) (p=0.006). The stent-assisted group also exhibited a higher rate of progressive occlusion than the simple coiling group in the multivariate logistic regression model (OR 3.208, 95% CI 1.106-9.302). Conclusion: Use of stents results in good prognosis not only by reducing the recurrence rate but also by increasing the rate of progressive occlusion in wide-necked paraclinoid aneurysms. Stent-assisted coil embolization can be an important treatment strategy for paraclinoid aneurysms when considering the superiority of long term outcome. PMID- 29142624 TI - Significances and Outcomes of Mechanical Thrombectomy for Acute Infarction in Very Elderly Patients: A Single Center Experience. AB - Objective: Mechanical thrombectomy is increasingly being used for the treatment of acute ischemic stroke. The population over 80 years of age is growing, and many of these patients have acute infarction; however, these patients are often excluded from clinical trials, so the aim of this study was to compare the functional outcomes and complication rates in very elderly patients (age >=80 years) and aged patients (60-79 years) treated with mechanical thrombectomy. Methods: Between January 2010 and June 2015, we retrospectively reviewed 113 senior patients (over 60 years old) treated at our institution for acute ischemic stroke with mechanical thrombectomy. They were divided into a very elderly (>=80 years) and aged (60-79 years) group, with comparisons in recanalization rates, complications, death and disability on discharge be reported. Results: The mean age was 70.3 years in the aged group and 83.4 years in the very elderly group. Elderly patients had higher rates of mechanical thrombectomy failure than the younger group (40% vs. 14%; odds ratio [OR] 4.1; 95% confidence interval [CI] 1.4 11.9; p=0.012). Results from thrombolysis in cerebral ischemia and modified Rankin scale at discharge were worse in the older group (p=0.005 and 0.023 respectively). There were no differences in mortality rate or other complications, but infarction progression rates were significantly higher in the very elderly group. (15% vs. 2.2%; OR 8.0; 95% CI 1.2-51.7; p=0.038). The majority (92.3%) of the patients who failed in aged group were not successful after several trials. However, in half (4 of 8) of the very elderly group, the occlusion site could not be accessed. Conclusion: Patients older than 80 years of age undergoing mechanical thrombectomy for acute infarction were more difficult to recanalize due to inaccessible occlusion sites and had a higher rate of infarction progression, However, mortality and other complications were similar to those in younger patients. PMID- 29142625 TI - Prognostic Factors of Atypical Meningioma: Overall Survival Rate and Progression Free Survival Rate. AB - Objective: Atypical meningioma is rare tumor and there is no accurate guide line for optimal treatment. This retrospective study analyzed the prognostic factors, the effect of different methods of treatments and the behavior of atypical meningioma. Methods: Thirty six patients were diagnosed as atypical meningioma, among 273 patients who were given a diagnosis of meningioma in the period of 2002 to 2015. Age, gender, tumor location, Ki 67, Simpson grade and treatment received were analyzed. We studied the correlation between these factors with recurrence, overall survival rate and progression free survival. Results: Median overall survival time and progression free survival time are 60 and 53 (months). Better survival rate was observed for patients less than 50 years old but with no statistical significance (p=0.322). And patients with total resection compared with subtotal resection also showed better survival rate but no statistical significance (p=0.744). Patients with a tumor located in skull base compared with patients with a tumor located in brain convexity and parasagittal showed better progression free survival (p=0.048). Total resection is associated with longer progression-free survival than incomplete resection (p=0.018). Conclusion: We confirmed that Simpson grade was significant factor for statistically affect to progression free survival in univariate analysis. In case of skull base atypical tumor, it is analyzed that it has more recurrence than tumor located elsewhere. Overall survival was not affected statistically by patient age, gender, tumor location, Ki 67, Simpson grade and treatment received in this study. PMID- 29142626 TI - Resection and Observation for Brain Metastasis without Prompt Postoperative Radiation Therapy. AB - Objective: Total resection without consecutive postoperative whole brain radiation therapy is indicated for patients with a single or two sites of brain metastasis, with close follow-up by serial magnetic resonance imaging (MRI). In this study, we explored the effectiveness, usefulness, and safety of this follow up regimen. Methods: From January 2006 to December 2015, a total of 109 patients (76 males, 33 females) underwent tumor resection as the first treatment for brain metastases (97 patients with single metastases, 12 with two metastases). The mean age was 59.8 years (range 27-80). The location of the 121 tumors in the 109 patients was supratentorial (n=98) and in the cerebellum (n=23). The origin of the primary cancers was lung (n=45), breast (n=17), gastrointestinal tract (n=18), hepatobiliary system (n=8), kidney (n=7), others (n=11), and unknown origin (n=3). The 121 tumors were totally resected. Follow-up involved regular clinical and MRI assessments. Recurrence-free survival (RFS) and overall survival (OS) after tumor resection were analyzed by Kaplan-Meier methods based on clinical prognostic factors. Results: During the follow-up, MRI scans were done for 85 patients (78%) with 97 tumors. Fifty-six of the 97 tumors showed no recurrence without adjuvant local treatment, representing a numerical tumor recurrence-free rate of 57.7%. Mean and median RFS was 13.6 and 5.3 months, respectively. Kaplan-Meier analysis revealed the cerebellar location of the tumor as the only statistically significant prognostic factor related to RFS (p=0.020). Mean and median OS was 15.2 and 8.1 months, respectively. There were no significant prognostic factors related to OS. The survival rate at one year was 8.2% (9 of 109). Conclusion: With close and regular clinical and image follow-up, initial postoperative observation without prompt postoperative radiation therapy can be applied in patients of brain metastasi(e)s when both the tumor(s) are completely resected. PMID- 29142627 TI - A Comparison of Anterior Cervical Discectomy and Fusion versus Fusion Combined with Artificial Disc Replacement for Treating 3-Level Cervical Spondylotic Disease. AB - Objective: The purpose of this study is to evaluate the efficacy and safety of 3 level hybrid surgery (HS), which combines fusion and cervical disc replacement (CDR), compared to 3-level fusionin patient with cervical spondylosis involving 3 levels. Methods: Patients in the anterior cervical discectomy and fusion (ACDF) group (n=30) underwent 3-level fusion and the HS group (n=19) underwent combined surgery with fusion and CDR. Clinical outcomes were evaluated using the visual analogue scale for the arm, the neck disability index (NDI), Odom criteria and postoperative complications. The cervical range of motion (ROM), fusion rate and adjacent segments degeneration were assessed with radiographs. Results: Significant improvements in arm pain relief and functional outcome were observed in ACDF and HS group. The NDI in the HS group showed better improvement 6 months after surgery than that of the ACDF group. The ACDF group had a lower fusion rate, higher incidence of device related complications and radiological changes in adjacent segments compared with the HS group. The better recovery of cervical ROM was observed in HS group. However, that of the ACDF group was significantly decreased and did not recover. Conclusion: The HS group was better than the ACDF group in terms of NDI, cervical ROM, fusion rate, incidence of postoperative complications and adjacent segment degeneration. PMID- 29142628 TI - Perioperative Results and Complications after Posterior Lumbar Interbody Fusion for Spinal Stenosis in Geriatric Patients over than 70 Years Old. AB - Objective: As increasing the size of the geriatric population, the number of elderly patients, who need the surgery for painful degenerative spinal stenosis has been increasing. The geriatric population may be relatively high complications, because of age and age-associated medical conditions. However, there is a lack of studies addressing the perioperative complications and outcomes in elderly patients with posterior lumbar inter body fusion with screw augmentation (PLIF). Methods: We retrospectively reviewed the medical records and radiographic studies of geriatric patients who had spine surgery of PLIF due to spinal stenosis for 11 years. We divided into 2 groups (A; 70-75 years, B; over then 76 years) according to the age. Surgical level of each groups, hospital day and postoperative day, co-morbidities, complications, clinical outcomes were analyzed. Operative reports, hospital and outpatient clinic charts, and radiographic studies were reviewed. Results: Group A was composed of 80 patients, their mean age was 72.21 and female dominant (n=46), and their mean surgically fused level was 1.52 level. Group B was 36 patients, their mean age was 78.83 and female dominant (n=20), and their mean surgically fused level was 1.36 level. Comparing between two groups, complications, postoperative hospital stay were slightly increase in group B and co-morbidity was statistically high in group B, however clinical outcomes were similar between two groups. Conclusion: Increasing age might be an important risk factor for complications in patients undergoing PLIF, however, we would like to recommend that if the situation of spine of extreme geriatric patients need PLIF, it should be in the surgeon's consideration after careful selection and clinical judgement. PMID- 29142629 TI - A Prospective Study with Cage-Only or Cage-with-Plate Fixation in Anterior Cervical Discectomy and Interbody Fusion of One and Two Levels. AB - Objective: The authors prospectively analyzed the effect of one-level or two level anterior cervical discectomy and fusion (ACDF), comparing stand-alone cages and cage-with-plate fixation constructs with respect to clinical outcomes and radiologic changes. Methods: A total of 84 patients who underwent one-level (n=52) or two-level ACDF (n=32) for cervical disc disease and who completed 2 years of follow-up were included in this study. The patients were divided by cervical level and grouped into ACDF-Cage-only and ACDF-Cage-with-plate groups. The following parameters were assessed using radiographs: subsidence, C2-C7 lordosis angle, fusion segment angle, adjacent disc space narrowing, and fusion status. Clinical outcomes were assessed using the neck disability index (NDI) and visual analog scale scores for arm pain. Results: In the comparison of one-level ACDF-cage-only and ACDF-cage-with-plate groups, the NDI score was better in the cage-only group at the 3-, 12-, and 24-month follow-ups: however, no significant difference in clinical outcomes was observed. In the comparison of two-level ACDF cage-only and ACDF-cage-with-plate groups, no difference in any clinical outcome was observed between the two groups. At the 24-month follow-up, subsidence was observed in 45.8% of patients in the one-level cage-only group and 32.1% of patients in the one-level cage-with-plate fixation group. There was no statistically significant difference in the incidence rate between the two groups (p=0.312). Subsidence in the two-level cage-only group (66.6%) was significantly more frequent than in the two-level cage-with-plate fixation group (30%; p=0.049). The fusion rate for patients in the one-level cage-only group was not significantly different from that in the one-level cage-with-plate fixation group (cage-only, 87.5%; cage-with-plate fixation, 92.9%; p=0.425); fusion rate in the two-level patients were also similar between groups (cage-only, 83.3%; cage-with plate fixation, 95%; p=0.31). Conclusion: Our clinical results showed that for single-level cases, plate fixation had no additional benefit versus cage-only; for two-level ACDF cases, the fusion rate and clinical outcomes were similar, although the cage-with-plate fixation group had a lower incidence of cage subsidence than did the cage-only group. We conclude that physicians should be aware of this possible disadvantage associated with using cervical plates in one level ACDF. However, in two-level ACDF, subsidence is more likely to occur without plate fixation, and thus the addition of plate fixation should be considered. PMID- 29142630 TI - Predictive Factors for Recurrence after Burr-Hole Craniostomy of Chronic Subdural Hematoma. AB - Objective: Chronic subdural hematoma is a common and relatively benign disease. However, recurrence is common after surgical treatment, and the recurrence rate varies from 5% to 33%. The aim of this study was to investigate the predictive factors for recurrence of chronic subdural hematoma. Methods: We analyzed data from 248 patients with chronic subdural hematoma who were treated by burr-hole craniostomy with a closed drainage system for hematoma evacuation in this five year retrospective study. Results: Thirty-one (12.6%) patients underwent re operation for recurrence of chronic subdural hematoma. Univariate analysis revealed that anticoagulation (p=0.0279), headache (p=0.0323), and preoperative midline shifting (p=0.0321) showed significant differences with respect to recurrent chronic subdural hematoma. We performed a multivariate logistic regression analysis and found that diabetes mellitus (odds ratio [OR], 2.618; 95% confidence interval [CI], 1.0899-6.2898; p=0.0314), anticoagulation (OR, 6.739; 95% CI, 1.1287-40.2369; p=0.0364), headache (OR, 2.951; 95% CI, 1.1464-7.5964; p=0.0249), and preoperative midline shifting (OR, 1.0838; 95% CI, 1.0040-1.1699; p=0.0391) were independent predictive factors for recurrence of chronic subdural hematoma. Conclusion: We showed that diabetes mellitus, anticoagulation, headache, and preoperative midline shifting were independent predictors of recurrence of chronic subdural hematoma. PMID- 29142631 TI - Mortality and Epidemiology in 256 Cases of Pediatric Traumatic Brain Injury: Korean Neuro-Trauma Data Bank System (KNTDBS) 2010-2014. AB - Objective: Among pediatric injury, brain injury is a leading cause of death and disability. To improve outcomes, many developed countries built neurotrauma databank (NTDB) system but there was not established nationwide coverage NTDB until 2009 and there have been few studies on pediatric traumatic head injury (THI) patients in Korea. Therefore, we analyzed epidemiology and outcome from the big data of pediatric THI. Methods: We collected data on pediatric patients from 23 university hospitals including 9 regional trauma centers from 2010 to 2014 and analyzed their clinical factors (sex, age, initial Glasgow coma scale, cause and mechanism of head injury, presence of surgery). Results: Among all the 2617 THI patients, total number of pediatric patients was 256. The average age of the subjects was 9.07 (standard deviation+/-6.3) years old. The male-to female ratio was 1.87 to 1 and male dominance increases with age. The most common cause for trauma were falls and traffic accidents. Age (p=0.007), surgery (p<0.001), mechanism of trauma (p=0.016), subdural hemorrhage (SDH) (p<0.001), diffuse axonal injury (DAI) (p<0.001) were statistically significant associated with severe brain injury. Conclusion: Falls were the most common cause of trauma, and age, surgery, mechanism of trauma, SDH, DAI increased with injury severity. There is a critical need for effective fall and traffic accidents prevention strategies for children, and we should give attention to these predicting factors for more effective care. PMID- 29142632 TI - Delayed Burr Hole Surgery in Patients with Acute Subdural Hematoma: Clinical Analysis. AB - Objective: To evaluate the effectiveness and efficacy of delayed burr hole surgery in relation to the reduction of postoperative subdural hematoma (SDH) volume in patients with acute SDH. Methods: We retrospectively analyzed patients with acute SDH who received delayed burr hole surgery at our institute. Age, sex, Glasgow coma scale, maximal SDH thickness, volume of SDH, midline shifts, hounsfield unit (HU), and medical history of anticoagulant agent usage were recorded. Outcome measures were delayed operation day, reduction of SDH volume after operation, and the Glasgow outcome scale (GOS) score at discharge. The patients were divided two groups according to the post-operative reduction of volume of SDH (>=50%, group A; <50%, group B). We also analyzed variables and differences between two groups. Results: Eighteen patients were available for this analysis. The mean delayed of surgery was 13.9+/-7.5 days. Maximal thickness of SDH was changed from 10.0+/-3.5 mm to 12.2+/-3.7 mm. Volume of SDH was changed from 38.7+/-28.0 mL to 42.6+/-29.6 mL. Midline shifts were changed from 5.8+/-3.3 mm to 6.6+/-3.3 mm. HU were changed from 66.4+/-11.2 to 53.2+/-20.6. Post operative reduction of SDH volume was 52.1+/-21.1%. Eleven patients (61%) had a discharge GOS score of 1 (good recovery). Ten patients (56%) were enrolled in group A. Midline shifting was greater in group A than in group B (7.4+/-3.3 vs. 3.0+/-2.4 mm; p<0.02). The delay of surgery was shorter for group A than group B (9.2+/-2.3 vs. 19.8+/-7.7 days; p<0.0008). Conclusion: Among well selected patients, delayed burr hole surgery in patients with acute SDH may be effective for reduction of SDH volume. Further studies will be necessary to establish the effectiveness and safety of delayed burr hole surgery in patients with acute SDH. PMID- 29142633 TI - Risk Factors of Delayed Surgical Intervention after Conservatively Treated Acute Traumatic Subdural Hematoma. AB - Objective: Acute subdural hematoma (ASDH) is generally considered a condition that should be managed surgically. However, some patients initially receive conservative treatment, a subset of whom require surgical intervention later. This study aimed to evaluate the predictors of delayed surgical intervention in ASDH patients who are initially managed conservatively. Methods: From January 2007 to December 2015, 842 patients diagnosed with ASDH were treated at our institution. Among them, 158 patients with convexity ASDH were initially treated conservatively. Patients were divided into a delayed surgery group and a conservative group. Demographic characteristics, past medication and medical histories, and radiological and laboratory data were collected by retrospective chart review. Independent risk factors were identified with univariate and multivariate analyses. Results: Twenty-eight patients (17.7%) underwent delayed surgical intervention. Their mean age was 69.0 years, and 82.1% were male. Hypertension, diabetes mellitus, and heart disease prevalence and use of anti platelet agents did not significantly differ from the conservative group. However, age (p=0.024), previous cerebral infarction history (p=0.026), increased maximal hematoma thickness (p<0.001), midline shifting (p=0.001) and accompanying subarachnoid hemorrhage (p=0.022) on initial brain computed tomography (CT) scan, low hemoglobin level (p<0.001), high leukocyte count (p=0.004), and low glucose level (p=0.002) were significantly associated with delayed surgical intervention. In multivariate analysis, increased maximal hematoma thickness (odds ratio [OR]=1.279, 95% confidence interval [CI] 1.075-1.521; p=0.006), low hemoglobin level (OR=0.673, 95% CI 0.467-0.970; p=0.034), and high leukocyte count (OR=1.142, 95% CI 1.024-1.272; p=0.017) were independent risk factors for delayed surgical intervention. Conclusion: Due to the high likelihood of delayed surgical intervention among minimal ASDH patients with a thicker hematoma on initial brain CT, lower hemoglobin level, and higher leukocyte count, these patients should receive more careful observation. PMID- 29142634 TI - Factors Associated Postoperative Hydrocephalus in Patients with Traumatic Acute Subdural Hemorrhage. AB - Objective: Postoperative hydrocephalus is a common complication following craniectomy in patients with traumatic brain injury, and affects patients' long term outcomes. This study aimed to verify the risk factors associated with the development of hydrocephalus after craniectomy in patients with acute traumatic subdural hemorrhage (tSDH). Methods: Patients with acute traumatic SDH who had received a craniectomy between December 2005 and January 2016 were retrospectively assessed by reviewing the coexistence of other types of hemorrahges, measurable variables on computed tomography (CT) scans, and the development of hydrocephalus during the follow-up period. Results: Data from a total of 63 patients who underwent unilateral craniectomy were analyzed. Postoperative hydrocephalus was identified in 34 patients (54%) via brain CT scans. Preoperative intraventricular hemorrhage (IVH) was associated with the development of hydrocephalus. Furthermore, the thickness of SDH (p=0.006) and the extent of midline shift before craniectomy (p=0.001) were significantly larger in patients with postoperative hydrocephalus. Indeed, multivariate analyses showed that the thickness of SDH (p=0.019), the extent of midline shift (p<0.001) and the coexistence of IVH (p=0.012) were significant risk factors for the development of postoperative hydrocephalus. However, the distance from the midline to the craniectomy margin was not an associated risk factor for postoperative hydrocephalus. Conclusion: In patients with acute traumatic SDH with coexisting IVH, a large amount of SDH, and a larger midline shift, close follow-up is necessary for the early prediction of postoperative hydrocephalus. Furthermore, craniectomy margin need not be limited in acute traumatic SDH patients for the reason of postoperative hydrocephalus. PMID- 29142635 TI - Microvascular Decompression for Glossopharyngeal Neuralgia: Clinical Analyses of 30 Cases. AB - Objective: We present our experience of microvascular decompression (MVD) for glossopharyngeal neuralgia (GPN) and evaluate the postoperative outcomes in accordance with four different operative techniques during MVD. Methods: In total, 30 patients with intractable primary typical GPN who underwent MVD without rhizotomy and were followed for more than 2 years were included in the analysis. Each MVD was performed using one of four different surgical techniques: interposition of Teflon pieces, transposition of offending vessels using Teflon pieces, transposition of offending vessels using a fibrin-glue-coated Teflon sling, and removal of offending veins. Results: The posterior inferior cerebellar artery was responsible for neurovascular compression in 27 of 30 (90%) patients, either by itself or in combination with other vessels. The location of compression on the glossopharyngeal nerve varied; the root entry zone (REZ) only (63.3%) was most common, followed by both the REZ and distal portion (26.7%) and the distal portion alone (10.0%). In terms of detailed surgical techniques during MVD, the offending vessels were transposed in 24 (80%) patients, either using additional insulation, offered by Teflon pieces (15 patients), or using a fibrin glue-coated Teflon sling (9 patients). Simple insertion of Teflon pieces and removal of a small vein were also performed in five and one patient, respectively. During the 2 years following MVD, 29 of 30 (96.7%) patients were asymptomatic or experienced only occasional pain that did not require medication. Temporary hemodynamic instability occurred in two patients during MVD, and seven patients experienced transient postoperative complications. Neither persistent morbidity nor mortality was reported. Conclusion: This study demonstrates that MVD without rhizotomy is a safe and effective treatment option for GPN. PMID- 29142636 TI - Bone Flap Resorption Following Cranioplasty with Autologous Bone: Quantitative Measurement of Bone Flap Resorption and Predictive Factors. AB - Objective: To quantitatively measure the degree of bone flap resorption (BFR) following autologous bone cranioplasty and to investigate factors associated with BFR. Methods: We retrospectively reviewed 29 patients who underwent decompressive craniectomy and subsequent autologous bone cranioplasty between April 2005 and October 2014. BFR was defined as: 1) decrement ratio ([the ratio of initial BF size/craniectomy size]-[the ratio of last BF/craniectomy size]) >0.1; and 2) bone flap thinning or geometrical irregularity of bone flap shape on computed tomographic scan or skull plain X-ray. The minimal interval between craniectomy and cranioplasty was one month and the minimal follow-up period was one year. Clinical factors were compared between the BFR and no-BFR groups. Results: The time interval between craniectomy and cranioplasty was 175.7+/-258.2 days and the mean period of follow up was 1364+/-886.8 days. Among the 29 patients (mean age 48.1 years, male: female ratio 20: 9), BFR occurred in 8 patients (27.6%). In one patient, removal of the bone flap was carried out due to severe BFR. The overall rate of BFR was 0.10+/-0.11 over 3.7 years. Following univariate analysis, younger age (30.5+/-23.2 vs. 54.9+/-13.4) and longer follow-up period (2204.5+/ 897.3 vs. 1044.1+/-655.1) were significantly associated with BFR (p=0.008 and 0.003, respectively). Conclusion: The degree of BFR following autologous bone cranioplasty was 2.7%/year and was associated with younger age and longer follow up period. PMID- 29142637 TI - Lateral Lumbar Interbody Fusion and in Situ Screw Fixation for Rostral Adjacent Segment Stenosis of the Lumbar Spine. AB - Objective: The purpose of this study is to describe the detailed surgical technique and short-term clinical and radiological outcomes of lateral lumbar interbody fusion (LLIF) and in situ lateral screw fixation using a conventional minimally invasive screw fixation system (MISF) for revision surgery to treat rostral lumbar adjacent segment disease. Methods: The medical and radiological records were retrospectively reviewed. The surgery was indicated in 10 consecutive patients with rostral adjacent segment stenosis and instability. After the insertion of the interbody cage, lateral screws were inserted into the cranial and caudal vertebra using the MISF through the same LLIF trajectory. The radiological and clinical outcomes were assessed preoperatively and at 1, 3, 6, and 12 months postoperatively. Results: The median follow-up period was 13 months (range, 3-48 months). Transient sensory changes in the left anterior thigh occurred in 3 patients, and 1 patient experienced subjective weakness; however, these symptoms normalized within 1 week. Back and leg pain were significantly improved (p<0.05). In the radiological analysis, both the segmental angle at the operated segment and anterior disc height were significantly increased. At 6 months postoperatively, solid bony fusion was confirmed in 7 patients. Subsidence and mechanical failure did not occur in any patients. Conclusion: This study demonstrates that LLIF and in situ lateral screw fixation may be an alternative surgical option for rostral lumbar adjacent segment disease. PMID- 29142638 TI - Analysis of dimensions and shapes of maxillary and mandibular dental arch in Korean young adults. AB - PURPOSE: The aim of this study was to investigate dental arch dimensions and to classify arch shape in Korean young adults. MATERIALS AND METHODS: The sample included 50 Koreans with age ranging from 24 to 32 years. Maxillary and mandibular casts were fabricated using irreversible hydrocolloid and type III dental stones. Incisor-canine distance, incisor-1st molar distance, incisor-2nd molar distance, intercanine distance, inter-1st molar distance, and inter-2nd molar distance in both the maxillary and mandibular arch were measured using a three-dimensional measuring device. The dental arch was classified into three groups using five ratios from the measured values by the K-means clustering method. The data were analyzed with one-way analysis of variance. RESULTS: Arch lengths (IM2D, incisal-2nd molar distance) were 44.13 mm in the maxilla and 40.40 mm in the mandible. Arch widths (M2W, inter 2nd molar width) were 64.12 mm in the maxilla and 56.37 mm in the mandible. Distribution of the dental arch form was mostly ovoid shape (maxilla 52% and mandible 56%), followed by the V-shape and the U-shape. The arch width for the U-shape was broader than for the other forms. CONCLUSION: This study establishes new reference data for dental arch dimensions for young Korean adults. The most common arch form is the ovoid type in the maxilla and mandible of Koreans. Clinicians should be aware of these references and classify arch type before and during their dental treatment for effective and harmonized results in Koreans. PMID- 29142639 TI - Effect of ferrule on the fracture resistance of mandibular premolars with prefabricated posts and cores. AB - PURPOSE: This study evaluated fracture resistance with regard to ferrule lengths and post reinforcement on endodontically treated mandibular premolars incorporating a prefabricated post and resin core. MATERIALS AND METHODS: One hundred extracted mandibular premolars were randomly divided into 5 groups (n=20): intact teeth (NR); endodontically treated teeth (ETT) without post (NP); ETT restored with a prefabricated post with ferrule lengths of either 0 mm (F0), 1 mm (F1), or 2 mm (F2). Prepared teeth were restored with metal crowns. A thermal cycling test was performed for 1,000 cycles. Loading was applied at an angle of 135 degrees to the axis of the tooth using a universal testing machine with a crosshead speed of 2.54 mm/min. Fracture loads were analyzed by one-way ANOVA and Tukey HSD test using a statistical program (alpha=.05). RESULTS: There were statistical differences in fracture loads among groups (P<.001). The fracture load of F2 (237.7 +/- 83.4) was significantly higher than those of NP (155.6 +/- 74.3 N), F0 (98.8 +/- 43.3 N), and F1 (152.8 +/- 78.5 N) (P=.011, P<.001, and P=.008, respectively). CONCLUSION: Fracture resistance of ETT depends on the length of the ferrule, as shown by the significantly increased fracture resistance in the 2 mm ferrule group (F2) compared to the groups with shorter ferrule lengths (F0, F1) and without post (NP). PMID- 29142640 TI - Evaluation of C. Albicans and S. Mutans adherence on different provisional crown materials. AB - PURPOSE: Bacterial adhesion on provisional crown materials retained for a long time can influence the duration for which permanent prosthetic restorations can be healthily worn in the oral cavity. The aim of this study was to compare seven different commonly used provisional crown materials with regard to Streptococcus mutans and Candida albicans surface adhesion. MATERIALS AND METHODS: For each group, twenty specimens of the provisional fixed prosthodontic materials TemDent (Schutz), Imident (Imicryl), Tab 2000 (Kerr), Structur Premium (Voco), Systemp (Ivoclar Vivadent), Acrytemp (Zhermack), and Takilon-BBF (Takilon) were prepared (diameter, 10.0 mm; height, 2.0 mm). Surface roughness was assessed by atomic force microscopy. Each group was then divided into 2 subgroups (n=10) according to the microbial suspensions used: S. mutans and C. albicans. The specimens were incubated at 37C with S. mutans or C. albicans for seven days. Bacterial adherence on surfaces was assessed using the 2,3-bis[2-methyloxy-4-nitro-5 sulfophenyl]-2H-tetrazolium-5-carboxanilide (XTT) assay. RESULTS: S. mutans showed maximum adhesion to Structur, followed by Systemp, Acrytemp, Takilon, Tab 2000, Imident, and TemDent (P<.05). The highest vital C. albicans adhesion was noted on Takilon, followed by Imident and Tab 2000; the lowest adhesion was noted on Systemp (P<.05). CONCLUSION: The materials showed significant differences in the degree of bacterial adhesion. C. albicans showed higher surface adhesion than S. mutans on provisional crown and fixed partial denture denture materials. PMID- 29142641 TI - Accuracy of several implant bite registration techniques: an in-vitro pilot study. AB - PURPOSE: This study evaluated the accuracies of different bite registration techniques for implant-fixed prostheses using three dimensional file analysis. MATERIALS AND METHODS: Implant fixtures were placed on the mandibular right second premolar, and the first and second molar in a polyurethane model. Aluwax (A), Pattern Resin (P), and Blu-Mousse (B) were used as the bite registration materials on the healing abutments (H) or temporary abutments (T). The groups were classified into HA, HP, HB, TA, TP, and TB according to each combination. The group using the bite impression coping was the BC group; impression taking and bite registration were performed simultaneously. After impression and bite taking, the scan bodies were connected to the lab analogs of the casts. These casts were scanned using a model scanner. The distances between two reference points in three-dimensional files were measured in each group. One-way ANOVA and Duncan's test were used at the 5% significance level. RESULTS: The smallest distance discrepancy was observed in the TB group using the temporary abutments. The Blu-Mousse and HP groups showed the largest distance discrepancy. The TB and BC groups showed a lower distance discrepancy than the HP group (P=.001), and there was no significant difference between the groups using the temporary abutments and healing abutments (P>.05). CONCLUSION: Although this study has limitations as an in-vitro investigation, the groups using the temporary abutments to hold the Blu-Mousse record and bite impression coping showed greater accuracy than the group using the healing abutments to hold the pattern resin record. PMID- 29142642 TI - Shear bond strength of composite resin to high performance polymer PEKK according to surface treatments and bonding materials. AB - PURPOSE: The object of the present study was to evaluate the shear bonding strength of composite to PEKK by applying several methods of surface treatment associated with various bonding materials. MATERIALS AND METHODS: One hundred and fifty PEKK specimens were assigned randomly to fifteen groups (n = 10) with the combination of three different surface treatments (95% sulfuric acid etching, airborne abrasion with 50 um alumina, and airborne abrasion with 110 um silica coating alumina) and five different bonding materials (Luxatemp Glaze & Bond, Visio.link, All-Bond Universal, Single Bond Universal, and Monobond Plus with Heliobond). After surface treatment, surface roughness and contact angles were examined. Topography modifications after surface treatment were assessed with scanning electron microscopy. Resin composite was mounted on each specimen and then subjected to shear bond strength (SBS) test. SBS data were analyzed statistically using two-way ANOVA, and post-hoc Tukey's test (P<.05). RESULTS: Regardless of bonding materials, mechanical surface treatment groups yielded significantly higher shear bonding strength values than chemical surface treatment groups. Unlike other adhesives, MDP and silane containing self-etching universal adhesive (Single Bond Universal) showed an effective shear bonding strength regardless of surface treatment method. CONCLUSION: Mechanical surface treatment behaves better in terms of PEKK bonding. In addition, self-etching universal adhesive (Single Bond Universal) can be an alternative bonding material to PEKK irrespective of surface treatment method. PMID- 29142643 TI - Verification of a computer-aided replica technique for evaluating prosthesis adaptation using statistical agreement analysis. AB - PURPOSE: The purpose of this study was to evaluate the reliability of computer aided replica technique (CART) by calculating its agreement with the replica technique (RT), using statistical agreement analysis. MATERIALS AND METHODS: A prepared metal die and a metal crown were fabricated. The gap between the restoration and abutment was replicated using silicone indicator paste (n = 25). Gap measurements differed in the control (RT) and experimental (CART) groups. In the RT group, the silicone replica was manually sectioned, and the marginal and occlusal gaps were measured using a microscope. In the CART group, the gap was digitized using optical scanning and image superimposition, and the gaps were measured using a software program. The agreement between the measurement techniques was evaluated by using the 95% Bland-Altman limits of agreement and concordance correlation coefficients (CCC). The least acceptable CCC was 0.90. RESULTS: The RT and CART groups showed linear association, with a strong positive correlation in gap measurements, but without significant differences. The 95% limits of agreement between the paired gap measurements were 3.84% and 7.08% of the mean. The lower 95% confidence limits of CCC were 0.9676 and 0.9188 for the marginal and occlusal gap measurements, respectively, and the values were greater than the allowed limit. CONCLUSION: The CART is a reliable digital approach for evaluating the fit accuracy of fixed dental prostheses. PMID- 29142644 TI - Repair bond strengths of non-aged and aged resin nanoceramics. AB - PURPOSE: To explore the influence of different surface conditionings on surface changes and the influence of surface treatments and aging on the bond strengths of composites to non-aged and aged resin nanoceramics. MATERIALS AND METHODS: Rectangular-shaped non-aged and aged (5000 thermocycles) resin nanoceramic specimens (Lava Ultimate) (n=63, each) were divided into 3 groups according to surface treatments (untreated, air abrasion, or silica coating) (n=21). The surface roughness was measured and scanning electron microscopy was used to examine one specimen from each group. Afterwards, the specimens were repaired with a composite resin (Filtek Z550) and half were sent for aging (5000 thermocycles, n=10, each). Shear bond strengths and failure types were evaluated. Roughness and bond strength were investigated by two- and three-way analysis of variance, respectively. The correlation between the roughness and bond strength was investigated by Pearson's correlation test. RESULTS: Surface-treated samples had higher roughness compared with the untreated specimens (P=.000). For the non aged resin nanoceramic groups, aging was a significant factor for bond strength; for the aged resin nanoceramic groups, surface treatment and aging were significant factors. The failures were mostly adhesive after thermal cycling, except in the non-aged untreated group and the aged air-abraded group, which had mostly mixed failures. Roughness and bond strength were positively correlated (P=.003). CONCLUSION: Surface treatment is not required for the repair of non aged resin nanoceramic; for the repair of aged resin nanoceramic restorations, air abrasion is recommended. PMID- 29142645 TI - Effect of implant- and occlusal load location on stress distribution in Locator attachments of mandibular overdenture. A finite element study. AB - PURPOSE: The aim of this study is to evaluate and compare the stress distribution in Locator attachments in mandibular two-implant overdentures according to implant locations and different loading conditions. MATERIALS AND METHODS: Four three-dimensional finite element models were created, simulating two osseointegrated implants in the mandible to support two Locator attachments and an overdenture. The models simulated an overdenture with implants located in the position of the level of lateral incisors, canines, second premolars, and crossed implant. A 150 N vertical unilateral and bilateral load was applied at different locations and 40 N was also applied when combined with anterior load at the midline. Data for von Mises stresses in the abutment (matrix) of the attachment and the plastic insert (patrix) of the attachment were produced numerically, color-coded, and compared between the models for attachments and loading conditions. RESULTS: Regardless of the load, the greatest stress values were recorded in the overdenture attachments with implants at lateral incisor locations. In all models and load conditions, the attachment abutment (matrix) withstood a much greater stress than the insert plastic (patrix). Regardless of the model, when a unilateral load was applied, the load side Locator attachments recorded a much higher stress compared to the contralateral side. However, with load bilateral posterior alone or combined at midline load, the stress distribution was more symmetrical. The stress is distributed primarily in the occlusal and lateral surface of the insert plastic patrix and threadless area of the abutment (matrix). CONCLUSION: The overdenture model with lateral incisor level implants is the worst design in terms of biomechanical environment for the attachment components. The bilateral load in general favors a more uniform stress distribution in both attachments compared to a much greater stress registered with unilateral load in the load side attachments. Regardless of the implant positions and the occlusal load application site, the stress transferred to the insert plastic is much lower than that registered in the abutment. PMID- 29142646 TI - Integrating 3D facial scanning in a digital workflow to CAD/CAM design and fabricate complete dentures for immediate total mouth rehabilitation. AB - PURPOSE: To integrate extra-oral facial scanning information with CAD/CAM complete dentures to immediately rehabilitate terminal dentition. MATERIALS AND METHODS: Ten patients with terminal dentition scheduled for total extraction and immediate denture placement were recruited for this study. The patients were submitted to a facial scanning procedure using the in-office PritiMirror scanner with bite registration records in-situ. Definitive stone cast models and bite records were subsequently submitted to a lab scanning procedure using the lab scanner (iSeries DWOS; Dental Wings). The scanned models were used to create a virtual teeth setup of a complete denture. Using the intra-oral bite records as a reference, the virtual setup was incorporated in the facial scan thereby facilitating a virtual clinical evaluation (teeth try-in) phase. After applying necessary adjustments, the virtual setup was submitted to a CAM procedure where a 5-axis industrial milling machine (M7 CNC; Darton AG General) was used to fabricate a full-milled PMMA immediate provisional prosthesis. RESULTS: Total extractions were performed, the dentures were immediately inserted, and subjective clinical fit was evaluated. The immediate provisional prostheses were inserted and clinical fit, occlusion/articulation, and esthetics were subjectively assessed; the results were deemed satisfactory. All provisional prostheses remained three months in function with no notable technical complications. CONCLUSION: Ten patients with terminal dentition were treated using a complete digital approach to fabricate complete dentures using CAD/CAM technology. The proposed technique has the potential to accelerate the rehabilitation procedure starting from immediate denture to final implant supported prosthesis leading to more predictable functional and aesthetics outcomes. PMID- 29142647 TI - Effects of staining liquids and finishing methods on translucency of a hybrid ceramic material having two different translucency levels. AB - PURPOSE: Beverages may affect the translucency of esthetic dental restorative materials. The aim of the present study was to investigate the effects of coffee and red wine on the translucency of a PICN material with two translucency levels, and finished with different methods. MATERIALS AND METHODS: 2M2 high translucent and translucent VITA Enamic hybrid ceramic blocks were investigated. Rectangular specimens with the dimensions of 12 mm * 14 mm * 2 mm were prepared. The specimens were finished and polished with different methods as suggested by the manufacturer. The translucency parameters of the specimens were evaluated before and after 24 hours, 7 days, and 28 days immersion in distilled water, coffee and red wine. Translucency parameters were measured using a portable spectrophotometer. RESULTS: At the end of 28 days, there was no statistically significant difference between the groups of specimens kept in coffee (P>.05). In the red wine groups, there was a statistically significant difference between the control group and all other groups (P<.05) at the end of 28 days. CONCLUSION: The translucency of hybrid ceramic for a restoration may not be important regarding the effects of coffee on translucency change because the specimens with different translucencies and finishing methods that were immersed to coffee had similar translucency parameters at the end of 28 days. The translucency of hybrid ceramic may be important in the case of red wine, however, since the results showed that highly translucent specimens exposed to red wine demonstrated better translucency parameters than specimens made from translucent blocks at the end of 28 days. PMID- 29142648 TI - Comparison of the optical properties of pre-colored dental monolithic zirconia ceramics sintered in a conventional furnace versus a microwave oven. AB - PURPOSE: The purpose of this study was to compare the optical properties of pre colored dental monolithic zirconia ceramics of various thicknesses sintered in a microwave and those in a conventional furnace. MATERIALS AND METHODS: A2-shade of pre-colored monolithic zirconia ceramic specimens (22.0 mm * 22.0 mm) in 3 thickness groups of 0.5, 1.0, and 1.5 mm were divided into 2 subgroups according to the sintering methods (n=9): microwave and conventional sintering. A spectrophotometer was used to obtain CIELab color coordinates, and translucency parameters and CIEDE2000 color differences (DeltaE00) were measured. The relative amount of monoclinic phase (Xm) was estimated with x-ray diffraction. The surface topography was analyzed by atomic force microscope and scanning electron microscope. Statistical analyses were conducted with two-way ANOVA (alpha=.05). RESULTS: There were small interaction effects on CIE L*, a*, and TP between sintering method and thickness (P<.001): L* (partial eta squared etap2=0.115), a* (etap2=0.136), and TP (etap2=0.206), although higher b* values were noted for microwave sintering regardless of thickness. Color differences between two sintering methods ranged from 0.52 to 0.96 DeltaE00 units. The Xm values ranged from 7.03% to 9.89% for conventional sintering, and from 7.31% to 9.17% for microwave sintering. The microwave-sintered specimen demonstrated a smoother surface and a more uniform grain structure compared to the conventionally sintered specimen. CONCLUSION: With reduced processing time, microwave-sintered pre-colored dental monolithic zirconia ceramics can exhibit similar color perception and translucency to those by conventional sintering. PMID- 29142649 TI - Adherence of Candida to complete denture surfaces in vitro: A comparison of conventional and CAD/CAM complete dentures. AB - PURPOSE: The goal of this study was to compare the adhesion of Candida albicans to the surfaces of CAD/CAM and conventionally fabricated complete denture bases. MATERIALS AND METHODS: Twenty discs of acrylic resin poly (methyl methacrylate) were fabricated with CAD/CAM and conventional procedures (heat-polymerized acrylic resin). The specimens were divided into two groups: 10 discs were fabricated using the CAD/CAM procedure (Wieland Digital Denture Ivoclar Vivadent), and 10 discs were fabricated using a conventional flasking and pressure-pack technique. Candida colonization was performed on all the specimens using four Candida albicans isolates. The difference in Candida albicans adhesion on the discs was evaluated. The number of adherent yeast cells was calculated by the colony-forming units (CFU) and by Fluorescence microscopy. RESULTS: There was a significant difference in the adhesion of Candida albicans to the complete denture bases created with CAD/CAM and the adhesion to those created with the conventional procedure. The CAD/CAM denture bases exhibited less adhesion of Candida albicans than did the denture bases created with the conventional procedure (P<.05). CONCLUSION: The CAD/CAM procedure for fabricating complete dentures showed promising potential for reducing the adherence of Candida to the denture base surface. Clinical Implications. Complete dentures made with the CAD/CAM procedure might decrease the incidence of denture stomatitis compared with conventional dentures. PMID- 29142651 TI - Prevention of Insulin Resistance by Dietary Intervention among Pregnant Mothers: A Randomized Controlled Trial. AB - Background: Chronic insulin resistance (IR) is a basic part of the pathophysiology of gestational diabetes mellitus. Nutrition significantly impacts IR and weight loss reduces insulin levels, whereas weight gain increases the concentrations. Therefore, we surveyed the effect of nutrition intervention on IR in pregnant women and whether this effect is irrespective of weight gaining in accordance with Institute of Medicine limits. Methods: This prospective, randomized clinical trial was carried out among 150 primiparous pregnant mothers in fifteen health centers, five hospitals, and 15 private obstetrical offices in Isfahan. The nutrition intervention included education of healthy diet with emphasize on 50%-55% of total energy intake from carbohydrate (especially complex carbohydrates), 25%-30% from fat (to increase mono unsaturated fatty acids and decrease saturated and trans-fatty acids), and 15%-20% from protein during pregnancy for experimental group. The controls received the usual prenatal care by their health-care providers. Results: This trial decreased pregnancy-induced insulin increases (P = 0.01) and IR marginally (P = 0.05). ANCOVA demonstrated that control of gestational weight gaining was more effective to decrease IR (P = 0.02) while insulin values decreased by nutrition intervention and irrespective of weight control (P = 0.06). Fasting plasma glucose (FPG) concentrations did not decrease by intervention (P = 0.56) or weight management (P = 0.15). Conclusions: The current intervention was effective to decrease pregnancy-induced insulin increases and IR. Considering study results on FPG levels and incidence of GDM, we suggest repeat of study design in a larger sample. PMID- 29142650 TI - Early Childhood Development and Iranian Parents' Knowledge: A Qualitative Study. AB - Background: Early childhood is the most important step throughout the lifespan and it is a critical period continuing to the end of 8-year-old. Mothers' knowledge is one of the important aspects of child development. The goals of this study were to determine the situation of knowledge in Iranian parents about the concept and the importance of early childhood development (ECD) and determining the sources of parental knowledge about ECD from the perspective of parents and grandparents. Methods: This qualitative study was conducted based on the directional content analysis in 2016. The purposive sampling method is utilized to select 24 participants among parents and grandparents in Tehran. The inclusion criteria consisted of speaking in Persian and having a child or grandchild <3 year-old. Data were collected through four focus group discussions and four individual interviews. Results: Iranian parental knowledge about integrative ECD is not enough, their knowledge about motor development and speech and language are relatively better, about cognitive development is little and socialemotional is very little. They said parents and other caregivers influence the process of children's development. Parents' knowledge resources about ECD included human resources, physical resources, virtual space, and the media. According to the majority of participants, "pediatricians are the most reliable source of parents' knowledge about ECD" even though the main focus of pediatricians is on treating diseases, physical health, and growth of children. Conclusions: According to the results, the knowledge of Iranian parent is not enough about ECD; therefore, actions must be taken to increase their knowledge in these domains. Parents look for reliable and valid sources to enhance their knowledge and they rely the most on pediatricians in this regard. Therefore, more studies on assessing parents' knowledge in community and the practical methods for knowledge promotion in this field is recommended. PMID- 29142652 TI - The Association between Risk Factors and Chronic Obstructive Pulmonary Disease in Canada: A Cross-sectional Study Using the 2014 Canadian Community Health Survey. AB - Background: The global prevalence of chronic obstructive pulmonary disease (COPD) is expected to increase and the disease is projected to be the third leading cause of death by the year 2020. The purpose of this study was to measure the prevalence and determine the risk factors for COPD in Canada. Methods: This is a cross-sectional study that uses data from a nationally generalizable survey, the Canadian Community Health Survey, 2014. There were 46,924 respondents aged 35 years or older. Uni- and multi-variate logistic regression analyses were conducted to determine the risk factors associated with COPD. Results: The overall prevalence of COPD in the surveyed population was 5.69%. Results from multivariate logistic regression showed that COPD was significantly higher among individuals who were 65 years or older (odds ratio [OR] =4.43; 95% confidence interval [CI]: 3.69-5.33), current smokers (OR = 5.13; 95% CI: 4.43-5.95), underweight or obese by body mass index ([OR = 1.81; 95% CI: 1.38-2.38] and [OR = 1.58; 95% CI: 1.41-1.77], respectively), with a total personal income of <$20,000 (OR = 3.67; 95% CI: 2.95-4.57,), and some postsecondary education (OR = 1.42; 95% CI: 1.14-1.76). Immigrants were less likely to have COPD compared to Canadian born respondents (OR = 0.67; 95% CI: 0.57-0.79). Conclusions: COPD is a growing and serious public health issue in Canada. The risk factors identified in this study provide useful targets to health promotion and education initiatives, health-care providers, and public health organizations to decrease the prevalence of COPD. PMID- 29142653 TI - Oral Cancer around Dental Implants Appearing in Patients with?without a History of Oral or Systemic Malignancy: a Systematic Review. AB - Objectives: The purpose of this article is to systematically review the circumstance of oral cancer around osseointegrated dental implants. Material and Methods: An electronic literature search was conducted through the MEDLINE (PubMed) and EMBASE databases. The search was restricted for articles published during the last 21 years from January 1996 to April 2017 and articles were limited to English language. Results: A total of 35 articles were reviewed, and 19 of the most relevant articles that are suitable to the criteria were selected. Case reports were analysed when oral cancer was present in patients with dental implants. Finally, the present data included 28 patients. Conclusions: A direct link between dental implants and oral cancer was not found. It was observed that there were no significant differences in number of incidences of oral cancer between patients with history of malignancy and those without. More research should be made to document such cases. It was noticed that in many cases oral cancer around dental implant present itself as peri-implantitis, correct differential diagnosis is essential in such cases. PMID- 29142654 TI - Correlation between Nasoalveolar Molding and Surgical, Aesthetic, Functional and Socioeconomic Outcomes Following Primary Repair Surgery: a Systematic Review. AB - Objectives: The authors performed a systematic review to evaluate the potential beneficial effects of the nasoalveolar molding appliance on nonsyndromic unilateral clefts of the lip and/or palate prior to primary lip repair. Material and Methods: A literature search was performed using three electronic databases (PubMed, Embase, Web of Science) and three journals ("Cleft Palate-Craniofacial Journal", "Plastic and Reconstructive Surgery Journal" and "American Journal of Orthodontics and Dentofacial Orthopaedic") from January 1980 to April 2017. Data extraction was performed with tables treating different subjects: surgical, aesthetical, functional, socio-economical effects of nasoalveolar molding (NAM) appliances and the evolution of NAM appliances, especially three-dimensional technology. Results: Of the 145 articles retrieved in the literature surveys, 28 were qualified for the final analysis and 20 studies were excluded because of their small sample size (less than 10 patients) and/or too long follow-up (exceeded 18 months). Four randomized controlled trials were available. Although literature allowed discussing the short-term benefits of NAM appliance and the three-dimensional technology, scientific evidence is lacking. Conclusions: Based on the results, nasoalveolar molding appliances have positive surgical, aesthetical, functional and socio-economical effects on unilateral clefts of the lip and/or palate treatment before the primary repair surgeries. Three dimensional technology results in a more efficient and predictable nasoalveolar molding appliance treatment. However, nasoalveolar molding appliance effect in a short term remains unclear with the available literature. Further studies that integrate three-dimensional technology in a large scale are still needed. PMID- 29142655 TI - Maxillary Sinus Floor Augmentation: a Review of Selected Treatment Modalities. AB - Objectives: The objective of the present study is to present the current best evidence for enhancement of the vertical alveolar bone height and oral rehabilitation of the atrophic posterior maxilla with dental implants and propose some evidence-based treatment guidelines. Material and Methods: A comprehensive review of the English literature including MEDLINE (PubMed), Embase and Cochrane Library search was conducted assessing the final implant treatment outcome after oral rehabilitation of the atrophic posterior maxilla with dental implants. No year of publication restriction was applied. The clinical, radiological and histomorphometric outcome as well as complications are presented after maxillary sinus floor augmentation applying the lateral window technique with a graft material, maxillary sinus membrane elevation without a graft material and osteotome-mediated sinus floor elevation with or without the use of a graft material. Results: High implant survival rate and new bone formation was reported with the three treatment modalities. Perforation of the Schneiderian membrane was the most common complication, but the final implant treatment outcome was not influenced by a Schneiderian membrane perforation. Conclusions: The different surgical techniques for enhancement of the vertical alveolar bone height in the posterior part of the maxilla revealed high implant survival with a low incidence of complications. However, the indication for the various surgical techniques is not strictly equivalent and the treatment choice should be based on a careful evaluation of the individual case. Moreover, further high evidence-based and well reported long-term studies are needed before one treatment modality might be considered superior to another. PMID- 29142656 TI - Pharyngeal Airway Dimensions and Head Posture in Obstructive Sleep Apnea Patients with and without Morphological Deviations in the Upper Cervical Spine. AB - Objectives: The aim of the study was to analyse differences in pharyngeal airway dimensions and head posture between obstructive sleep apnea patients with and without morphological deviations in the upper cervical spine and to analyse associations between pharyngeal airway dimensions and head posture in the total sample. Material and Methods: The sample comprised 53 obstructive sleep apnea (OSA) patients of which 32.1% had upper spine morphological deviations. Accordingly two groups were defined: 17 OSA patients with morphological deviations in the upper spine and 36 without upper spine deviations. Pharyngeal airway dimensions in terms of distances, cross-sectional areas and volume and upper spine morphological deviations were evaluated on cone-beam computed tomography. Head posture was evaluated on two-dimensional generated lateral cephalograms. Differences were analysed and adjusted for age and gender by multiple linear regression analysis. Results: OSA patients with upper spine morphological deviations had a significantly more backward and curved neck posture (OPT/HOR, P < 0.01; OPT/CVT, P < 0.05) compared to OSA patients without spine deviations. No significant differences were found in airway dimensions between patients with and without upper spine deviations. In the total group significant associations were found between head posture and pharyngeal airway distances and cross-sectional area at the nasal floor, epiglottis and hyoid bone level (P < 0.05, P < 0.01, P < 0.001). No significant association was found between head posture and airway volume. Conclusions: The results may contribute to differentiate obstructive sleep apnea patients and thereby may prove valuable in diagnosis and treatment planning of obstructive sleep apnea patients. PMID- 29142657 TI - Extraction Socket Preservation Using Porcine-Derived Collagen Membrane Alone or Associated with Porcine-Derived Bone. Clinical Results of Randomized Controlled Study. AB - Objectives: The aim of present randomized controlled clinical trial was to clinically evaluate hard tissue changes after extraction socket preservation procedures compared to natural spontaneous healing. Material and Methods: Thirty patients were enrolled in the present study and underwent single-tooth extraction in the premolar/molar areas. Ten sites were grafted with porcine-derived bone covered by collagen membrane, 10 covered by porcine-derived collagen membrane alone, and 10 underwent natural spontaneous healing. Vertical and horizontal bone changes after 3-month were evaluated at implant placement. Results: The vertical and horizontal bone changes at the extraction sockets treated with collagen membrane alone (vertical: -0.55 [SD 0.11] mm, and horizontal: -1.21 [SD 0.69] mm) and collagen membrane plus porcine-derived bone (vertical: -0.37 [SD 0.7] mm, and horizontal: -0.91 [SD 0.53] mm) were found significantly lower (P < 0.001), when compared to non-grafted sockets (vertical: -2.09 [SD 0.19] mm, and horizontal: 3.96 [SD 0.87] mm).In type 1 extraction sockets, in premolar sites, and in presence of vestibular bone thicknesses >= 1.5 mm, the use of collagen membrane alone revealed similar outcomes to those with additional graft material. Conclusions: At the re-entry surgery, extraction sockets grafted with porcine derived bone and covered by collagen membrane, and extraction sockets covered by porcine-derived collagen membrane alone, showed significantly lower vertical and horizontal bone changes, compared to extraction sockets sites underwent natural spontaneous healing. However, a complete prevention of remodelling is not achievable, irrespective of the technique used. PMID- 29142659 TI - Actinic Prurigo in Scandinavian Adolescent Successfully Treated with Cyclosporine A. AB - Actinic prurigo is a pruritic sun-induced dermatosis classified among the immunologically mediated photodermatoses. The disease is a well-known entity among Native Americans and in Central and South America, however rare in Caucasians with only a few reports from Australia, Britain and France. We report the first case of actinic prurigo in a Scandinavian patient, responding favorably to systemic treatment with cyclosporine A. PMID- 29142658 TI - Magnetic resonance imaging of pineal tumors and drop metastases: a review approach. PMID- 29142660 TI - Considering the hypothesis of the pathophysiology of cellulite in its treatment. PMID- 29142661 TI - Adverse effects of electroconvulsive therapy on cognitive performance. PMID- 29142662 TI - Clinical response of clozapine as a treatment for delirious mania. PMID- 29142663 TI - Changing focus of symptoms: A rare case report of Munchhausen's syndrome. PMID- 29142664 TI - Effective and underprescribed: what about clozapine? PMID- 29142665 TI - Treatment of 22q11.2 deletion syndrome-associated schizophrenia with comorbid anxiety and panic disorder. PMID- 29142666 TI - Social cognition in schizophrenia. PMID- 29142667 TI - Towards a further understanding of prenatal thyroid theory of homosexuality: Autoimmune thyroiditis, polycystic ovary syndrome, autism and low birth weight. PMID- 29142668 TI - Redox-induced umpolung of transition metal carbenes. AB - Metal carbene complexes have been at the forefront of organic and organometallic synthesis and are instrumental in guiding future sustainable chemistry efforts. While classical Fischer and Schrock type carbenes have been intensely studied, compounds that do not fall within one of these categories have attracted attention only recently. In addition, applications of carbene complexes rarely take advantage of redox processes, which could open up a new dimension for their use in practical processes. Herein, we report an umpolung of a nucleophilic palladium carbene complex, [{PC(sp2)P} tBuPd(PMe3)] ({PC(sp2)P} tBu = bis[2-(di iso-propylphosphino)-4-tert-butylphenyl]methylene), realized by successive one electron oxidations that generated a cationic carbene complex, [{PC(sp2)P} tBuPdI]+, via a carbene radical, [{PC(sp2)P} tBuPdI]. An EPR spectroscopic study of [{PC(sp2)P} tBuPdI] indicated the presence of a ligand-centered radical, also supported by the results of reactions with 9,10-dihydroanthracene and PhSSPh. The cationic carbene complex shows electrophilic behavior toward nucleophiles such as NaH, p TolNHLi, PhONa, and PMe3, resulting from an inversion of the electronic character of the Pd-Ccarbene bond in [{PC(sp2)P} tBuPd(PMe3)]. The redox induced umpolung is reversible and unprecedented. PMID- 29142670 TI - The gold(i)...lead(ii) interaction: a relativistic connection. AB - The crystal structure of complex [Pb{HB(pz)3}Au(C6Cl5)2] 1 displays an unsupported Au(i)...Pb(ii) interaction. This complex emits at 480 nm in the solid state due to an aurate(i) to lead(ii) charge transfer, in which the existence of a metallophilic interaction is a pre-requisite. Ab initio calculations show a very strong Au(i)...Pb(ii) closed-shell interaction of -390 kJ mol-1, which has an ionic plus a dispersive (van der Waals) nature strengthened by large relativistic effects (>17%). PMID- 29142669 TI - A faux hawk fullerene with PCBM-like properties. AB - Reaction of C60, C6F5CF2I, and SnH(n-Bu)3 produced, among other unidentified fullerene derivatives, the two new compounds 1,9-C60(CF2C6F5)H (1) and 1,9 C60(cyclo-CF2(2-C6F4)) (2). The highest isolated yield of 1 was 35% based on C60. Depending on the reaction conditions, the relative amounts of 1 and 2 generated in situ were as high as 85% and 71%, respectively, based on HPLC peak integration and summing over all fullerene species present other than unreacted C60. Compound 1 is thermally stable in 1,2-dichlorobenzene (oDCB) at 160 degrees C but was rapidly converted to 2 upon addition of Sn2(n-Bu)6 at this temperature. In contrast, complete conversion of 1 to 2 occurred within minutes, or hours, at 25 degrees C in 90/10 (v/v) PhCN/C6D6 by addition of stoichiometric, or sub stoichiometric, amounts of proton sponge (PS) or cobaltocene (CoCp2). DFT calculations indicate that when 1 is deprotonated, the anion C60(CF2C6F5)- can undergo facile intramolecular SNAr annulation to form 2 with concomitant loss of F-. To our knowledge this is the first observation of a fullerene-cage carbanion acting as an SNAr nucleophile towards an aromatic C-F bond. The gas-phase electron affinity (EA) of 2 was determined to be 2.805(10) eV by low-temperature PES, higher by 0.12(1) eV than the EA of C60 and higher by 0.18(1) eV than the EA of phenyl-C61-butyric acid methyl ester (PCBM). In contrast, the relative E1/2(0/ ) values of 2 and C60, -0.01(1) and 0.00(1) V, respectively, are virtually the same (on this scale, and under the same conditions, the E1/2(0/-) of PCBM is 0.09 V). Time-resolved microwave conductivity charge-carrier yield * mobility values for organic photovoltaic active-layer-type blends of 2 and poly-3 hexylthiophene (P3HT) were comparable to those for equimolar blends of PCBM and P3HT. The structure of solvent-free crystals of 2 was determined by single crystal X-ray diffraction. The number of nearest-neighbor fullerene-fullerene interactions with centroid...centroid (?...?) distances of <=10.34 A is significantly greater, and the average ?...? distance is shorter, for 2 (10 nearest neighbors; ave. ?...? distance = 10.09 A) than for solvent-free crystals of PCBM (7 nearest neighbors; ave. ?...? distance = 10.17 A). Finally, the thermal stability of 2 was found to be far greater than that of PCBM. PMID- 29142671 TI - Visible light photocatalytic reduction of aldehydes by Rh(iii)-H: a detailed mechanistic study. AB - The chemoselective photoreduction of aldehydes in the presence of ketones was achieved using triethanolamine (TEOA) as sacrificial electron donor, proflavine (PF) as photocatalyst and [Cp*Rh(iii)(bpy)Cl]Cl (Rhcat) as mediator. The reducing agent, which reacts with the carbonyl group was found to be [Cp*Rh(iii)(bpy)H]Cl (Rh(iii)-H). Contrary to formate-based reduction, its slow photochemical in situ generation enables to kinetically distinguish aldehydes from ketones. The inherent reactivity difference of the carbonyl compounds is transferred by the method into synthetically useful reaction selectivities. The substrate scope is broad with excellent yields. A detailed study of the reaction mechanism reveals that the photoreduction of the PF triplet and the subsequent reduction of the Rhcat leading to Rh(iii)-H represents the major reaction pathway, which is highly oxygen sensitive. The oxidative quenching of the PF singlet state by Rhcat is a competing mechanism, which prevails in non-degassed systems. PMID- 29142672 TI - A heterobimetallic complex featuring a Ti-Co multiple bond and its application to the reductive coupling of ketones to alkenes. AB - To explore metal-metal multiple bonds between first row transition metals, Ti/Co complexes supported by two phosphinoamide ligands have been synthesized and characterized. The Ti metalloligand Cl2Ti(XylNPiPr2)2 (1) was treated with CoI2 under reducing conditions, permitting isolation of the Ti/Co complex [(MU Cl)Ti(XylNPiPr2)2CoI]2 (2). One electron reduction of complex 2 affords ClTi(XylNPiPr2)2CoPMe3 (3), which features a metal-metal triple bond and an unprecedentedly short Ti-Co distance of 2.0236(9) A. This complex is shown to promote the McMurry coupling reaction of aryl ketones into alkenes, with concomitant formation of the tetranuclear complex [Ti(MU3-O)(NXylPiPr2)2CoI]2 (4). A cooperative mechanism involving bimetallic C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 O bond activation and a cobalt carbene intermediate is proposed. PMID- 29142673 TI - A noble metal-free proton-exchange membrane fuel cell based on bio-inspired molecular catalysts. AB - Hydrogen is a promising energy vector for storing renewable energies: obtained from water-splitting, in electrolysers or photoelectrochemical cells, it can be turned back to electricity on demand in fuel cells (FCs). Proton exchange membrane (PEM) devices with low internal resistance, high compactness and stability are an attractive technology optimized over decades, affording fast start-up times and low operating temperatures. However, they rely on the powerful catalytic properties of noble metals such as platinum, while lower cost, more abundant materials would be needed for economic viability. Replacing these noble metals at both electrodes has long proven to be a difficult task, so far incompatible with PEM technologies. Here we take advantage of newly developed bio inspired molecular H2 oxidation catalysts and noble metal-free O2-reducing materials, to fabricate a noble metal-free PEMFC, with an 0.74 V open circuit voltage and a 23 MUW cm-2 output power under technologically relevant conditions. X-ray absorption spectroscopy measurements confirm that the catalysts are stable and retain their structure during turnover. PMID- 29142674 TI - Bimetallic lanthanide complexes that display a ratiometric response to oxygen concentrations. AB - A pair of hetero-bimetallic lanthanide complexes containing terbium and europium ions have been prepared by coupling kinetically stable complexes together using an Ugi methodology to incorporate a naphthyl chromophore. Both complexes exhibit emission from terbium and europium in solution. The terbium centred emission varies with dissolved oxygen concentration, while the europium intensity remains essentially constant in one of the complexes. PMID- 29142675 TI - Adaptive binding and selection of compressed 1,omega-diammonium-alkanes via molecular encapsulation in water. AB - Guest molecules confined inside hollow molecular assemblies and thus protected from their environment can show unexpected structural behavior or special reactivity compared to their behavior in a bulk, unprotected environment. A special case is the coiling behavior of variable-length alkane chains in rigid hydrogen-bonded molecular cages. It has been found before that coiling may occur in such circumstances, but no experimental evidence concerning the exact conformation of the chains has yet been presented. We reveal in this study the self-assembly of a molecular cage in water and the crystalline state from three distinct components in which linear 1,omega-diammonium-alkanes chains are confined with different degrees of compression. The exact coiling behavior is determined from atomic resolution X-ray diffraction showing crenel-like conformations in the compressed state. Chemical selection can be obtained from mixtures of alkane chains via the encapsulation of kinetically stable conformations observed during the encapsulation of pure components. Moreover, it was found that uncompressed and compressed chains can be competitively trapped inside the capsule. These findings may provide insight in areas to a better understanding of biological processes, such as the fatty acid metabolism. PMID- 29142676 TI - Interfacial chemical oxidative synthesis of multifunctional polyfluoranthene. AB - A novel polyfluoranthene (PFA) exhibiting strong visual fluorescence emission, a highly amplified quenching effect, and widely controllable electrical conductivity is synthesized by the direct cationic oxidative polymerization of fluoranthene in a dynamic interface between n-hexane and nitromethane containing fluoranthene and FeCl3, respectively. A full characterization of the molecular structure signifies that the PFAs have a degree of polymerization from 22-50 depending on the polymerization conditions. A polymerization mechanism at the interface of the hexane/nitromethane biphasic system is proposed. The conductivity of the PFA is tunable from 6.4 * 10-6 to 0.074 S cm-1 by doping with HCl or iodine. The conductivity can be significantly enhanced to 150 S cm-1 by heat treatment at 1100 degrees C in argon. A PFA-based chemosensor shows a highly selective sensitivity for Fe3+ detection which is unaffected by other common metal ions. The detection of Fe3+ likely involves the synergistic effect of well-distributed pi-conjugated electrons throughout the PFA helical chains that function as both the fluorophore and the receptor units. PMID- 29142677 TI - Enhancing H2 evolution performance of an immobilised cobalt catalyst by rational ligand design. AB - The catalyst [CoIIIBr((DO)(DOH)(4-BnPO3H2)(2-CH2py)pn)]Br, CoP3 , has been synthesised to improve the stability and activity of cobalt catalysts immobilised on metal oxide surfaces. The CoP3 catalyst contains an equatorial diimine-dioxime ligand, (DOH)2pn = N2,N2'-propanediyl-bis(2,3-butanedione-2-imine-3-oxime), with a benzylphosphonic acid (4-BnPO3H2) group and a methylpyridine (2-CH2py) ligand covalently linked to the bridgehead of the pseudo-macrocyclic diimine-dioxime ligand. The phosphonic acid functionality provides a robust anchoring group for immobilisation on metal oxides, whereas the pyridine is coordinated to the Co ion to enhance the catalytic activity of the catalyst. Electrochemical investigations in solution confirm that CoP3 shows electrocatalytic activity for the reduction of aqueous protons between pH 3 and 7. The metal oxide anchor provides the catalyst with a high affinity for mesostructured Sn-doped In2O3 electrodes (mesoITO; loading of approximately 22 nmol cm-2) and the electrostability of the attached CoP3 was confirmed by cyclic voltammetry. Finally, immobilisation of the catalyst on ruthenium-dye sensitised TiO2 nanoparticles in aqueous solutions in the presence of a hole scavenger establishes the activity of the catalyst in this photocatalytic scheme. The advantages of the elaborate catalyst design in CoP3 in terms of stability and catalytic activity are shown by direct comparison with previously reported phosphonated Co catalysts. We therefore demonstrate that rational ligand design is a viable route for improving the performance of immobilised molecular catalysts. PMID- 29142678 TI - Increasing the rate of hydrogen oxidation without increasing the overpotential: a bio-inspired iron molecular electrocatalyst with an outer coordination sphere proton relay. AB - Oxidation of hydrogen (H2) to protons and electrons for energy production in fuel cells is currently catalyzed by platinum, but its low abundance and high cost present drawbacks to widespread adoption. Precisely controlled proton removal from the active site is critical in hydrogenase enzymes in nature that catalyze H2 oxidation using earth-abundant metals (iron and nickel). Here we report a synthetic iron complex, (CpC5F4N)Fe(PEtN(CH2)3NMe2 PEt)(Cl), that serves as a precatalyst for the oxidation of H2, with turnover frequencies of 290 s-1 in fluorobenzene, under 1 atm of H2 using 1,4-diazabicyclo[2.2.2]octane (DABCO) as the exogenous base. The inclusion of a properly tuned outer coordination sphere proton relay results in a cooperative effect between the primary, secondary and outer coordination spheres for moving protons, increasing the rate of H2 oxidation without increasing the overpotential when compared with the analogous complex featuring a single pendant base. This finding emphasizes the key role of pendant amines in mimicking the functionality of the proton pathway in the hydrogenase enzymes. PMID- 29142679 TI - Theoretical studies on a carbonaceous molecular bearing: association thermodynamics and dual-mode rolling dynamics. AB - The thermodynamics and dynamics of a carbonaceous molecular bearing comprising a belt-persistent tubular molecule and a fullerene molecule have been investigated using density functional theory (DFT). Among ten representative methods, two DFT methods afforded an association energy that reasonably reproduced the experimental enthalpy of -12.5 kcal mol-1 at the unique curved pi-interface. The dynamics of the molecular bearing, which was assembled solely with van der Waals interactions, exhibited small energy barriers with maximum values of 2-3 kcal mol 1 for the rolling motions. The dynamic motions responded sensitively to the steric environment and resulted in two distinct motions, precession and spin, which explained the unique NMR observations that were not clarified in previous experimental studies. PMID- 29142680 TI - Remote functionalization of hydrocarbons with reversibility enhanced stereocontrol. AB - Remote functionalization of hydrocarbons could be achieved through successive zirconocene-mediated allylic C-H bond activations followed by a selective C-C bond cleavage. Determination of the reaction mechanism by density functional theory (DFT) calculations shows that the high stereocontrol observed in this process results from a large number of energetically accessible equilibria feeding a preferred reactive channel that leads to the major product. A distinctive consequence of this pattern is that stereoselectivity is enhanced upon heating. PMID- 29142681 TI - In vitro and in vivo comparative and competitive activity-based protein profiling of GH29 alpha-l-fucosidases. AB - GH29 alpha-l-fucosidases catalyze the hydrolysis of alpha-l-fucosidic linkages. Deficiency in human lysosomal alpha-l-fucosidase (FUCA1) leads to the recessively inherited disorder, fucosidosis. Herein we describe the development of fucopyranose-configured cyclophellitol aziridines as activity-based probes (ABPs) for selective in vitro and in vivo labeling of GH29 alpha-l-fucosidases from bacteria, mice and man. Crystallographic analysis on bacterial alpha-l-fucosidase confirms that the ABPs act by covalent modification of the active site nucleophile. Competitive activity-based protein profiling identified l fuconojirimycin as the single GH29 alpha-l-fucosidase inhibitor from eight configurational isomers. PMID- 29142682 TI - Mixed-valent, heteroleptic homometallic diketonates as templates for the design of volatile heterometallic precursors. AB - A novel series of mixed-valent, heteroleptic transition metal diketonates that can be utilized as prospective single-source precursors for the low-temperature preparation of oxide materials are reported. The first mixed-valent iron beta diketonates with different FeIII/FeII ratios have been synthesized by applying the mixed-ligand approach. Based on nearly quantitative reaction yields and analysis of iron-oxygen bonds, these compounds were formulated as [FeIII(acac)3][FeII(hfac)2] (1) and [FeII(hfac)2][FeIII(acac)3][FeII(hfac)2] (2). In the above heteroleptic complexes, the Lewis acidic, coordinatively unsaturated FeII centers chelated by two hfac (hexafluoroacetylacetonate) ligands with electron-withdrawing substituents maintain bridging interactions with oxygen atoms of electron-donating acac (acetylacetonate) groups that chelate the neighboring FeIII atoms. Switching the ligands on FeIII and FeII atoms in starting reagents resulted in the instant ligand exchange between iron centers and in yet another polynuclear homometallic diketonate [FeII(hfac)2][FeIII(acac)2(hfac)][FeII(hfac)2] (3) that adheres to the same bonding pattern as in complexes 1 and 2. The proposed synthetic methodology has been extended to design heterometallic diketonates with different M : M' ratios. Homometallic parent molecules have been used as templates to obtain heterometallic mixed-valent [FeIII(acac)3][MnII(hfac)2] (4) and [NiII(hfac)2][FeIII(acac)3][NiII(hfac)2] (5) complexes. The combination of two different diketonate ligands with electron-donating and electron-withdrawing substituents was found to be crucial for maintaining the above mixed-valent heterometallic assemblies. Theoretical investigation of two possible "isomers", [FeIII(acac)3][MnII(hfac)2] (4) and [MnIII(acac)3][FeII(hfac)2] (4') provided an additional support for the metal site assignment giving a preference of 9.78 kcal mol-1 for the molecule 4. Heterometallic complexes obtained in the course of this study have been found to act as effective single-source precursors for the synthesis of mixed-transition metal oxide materials M x M'2-xO3 and M x M'1-xO. The title highly volatile precursors can be used for the low-temperature preparation of both amorphous and crystalline heterometallic oxides in the form of thin films or nanosized particles that are known to operate as efficient catalysts in oxygen evolution reaction. PMID- 29142683 TI - Exceptionally long-lived light-emitting electrochemical cells: multiple intra cation pi-stacking interactions in [Ir(C^N)2(N^N)][PF6] emitters. AB - A series of cyclometalated iridium(iii) complexes [Ir(C^N)2(N^N)][PF6] (N^N = 2,2'-bipyridine (1), 6-phenyl-2,2'-bipyridine (2), 4,4'-di-tert-butyl-2,2' bipyridine (3), 4,4'-di-tert-butyl-6-phenyl-2,2'-bipyridine (4); HC^N = 2-(3 phenyl)phenylpyridine (HPhppy) or 2-(3,5-diphenyl)phenylpyridine (HPh2ppy)) are reported. They have been synthesized using solvento precursors so as to avoid the use of chlorido-dimer intermediates, chloride ion contaminant being detrimental to the performance of [Ir(C^N)2(N^N)][PF6] emitters in light-electrochemical cell (LEC) devices. Single crystal structure determinations and variable temperature solution 1H NMR spectroscopic data confirm that the pendant phenyl domains engage in multiple face-to-face pi-interactions within the coordination sphere of the iridium(iii) centre. The series of [Ir(Phppy)2(N^N)]+ and [Ir(Ph2ppy)2(N^N)]+ complexes investigated include those with and without intra-cation face-to-face pi-stacking. All the complexes display excellent luminescent properties, in particular when employed in thin solid films. The most important observation is that all the LECs using the [Ir(Phppy)2(N^N)]+ and [Ir(Ph2ppy)2(N^N)]+ emitters (i.e. with and without intra-cation pi-stacking interactions) exhibit very stable luminance outputs over time, even when driven at elevated current densities. The most stable LEC had an extrapolated lifetime of more than 2500 hours under accelerated testing conditions. PMID- 29142684 TI - N6-Hydroperoxymethyladenosine: a new intermediate of chemical oxidation of N6 methyladenosine mediated by bicarbonate-activated hydrogen peroxide. AB - N6-Methyladenosine (m6A) represents a relatively abundant modification in eukaryotic RNA. Because m6A has similar properties to adenosine and a low reactivity, limited research has been focused on this nucleoside. In this study, we revealed an important intermediate in the oxidation of m6A through the bicarbonate-activated peroxide system. Over the course of oxidation, we found a new mechanism in which N6-hydroxymethyladenosine (hm6A), N6-formyladenosine (f6A) and N6-hydroperoxymethyladenosine (oxm6A) were intermediate products, and adenosine was the final product. In this study, oxm6A was isolated using HPLC and characterized by mass spectrometry, NMR and diphenyl-1-pyrenylphosphine (DPPP) fluorescence detection. This study provides a new modified nucleoside and demonstrates oxidative demethylation of m6A by reactive oxygen species at the nucleobase level and in RNA strands. PMID- 29142685 TI - Design of two-photon molecular tandem architectures for solar cells by ab initio theory. AB - An extensive database of spectroscopic properties of molecules from ab initio calculations is used to design molecular complexes for use in tandem solar cells that convert two photons into a single electron-hole pair, thereby increasing the output voltage while covering a wider spectral range. Three different architectures are considered: the first two involve a complex consisting of two dye molecules with appropriately matched frontier orbitals, connected by a molecular diode. Optimized combinations of dye molecules are determined by taking advantage of our computational database of the structural and energetic properties of several thousand porphyrin dyes. The third design is a molecular analogy of the intermediate band solar cell, and involves a single dye molecule with strong intersystem crossing to ensure a long lifetime of the intermediate state. Based on the calculated energy levels and molecular orbitals, energy diagrams are presented for the individual steps in the operation of such tandem solar cells. We find that theoretical open circuit voltages of up to 1.8 V can be achieved using these tandem designs. Questions about the practical implementation of prototypical devices, such as the synthesis of the tandem molecules and potential loss mechanisms, are addressed. PMID- 29142686 TI - Probing the vibrational spectroscopy of the deprotonated thymine radical by photodetachment and state-selective autodetachment photoelectron spectroscopy via dipole-bound states. AB - Deprotonated thymine can exist in two different forms, depending on which of its two N sites is deprotonated: N1[T-H]- or N3[T-H]-. Here we report a photodetachment study of the N1[T-H]- isomer cooled in a cryogenic ion trap and the observation of an excited dipole-bound state. Eighteen vibrational levels of the dipole-bound state are observed, and its vibrational ground state is found to be 238 +/- 5 cm-1 below the detachment threshold of N1[T-H]-. The electron affinity of the deprotonated thymine radical (N1[T-H]) is measured accurately to be 26 322 +/- 5 cm-1 (3.2635 +/- 0.0006 eV). By tuning the detachment laser to the sixteen vibrational levels of the dipole-bound state that are above the detachment threshold, highly non-Franck-Condon resonant-enhanced photoelectron spectra are obtained due to state- and mode-selective vibrational autodetachment. Much richer vibrational information is obtained for the deprotonated thymine radical from the photodetachment and resonant-enhanced photoelectron spectroscopy. Eleven fundamental vibrational frequencies in the low-frequency regime are obtained for the N1[T-H] radical, including the two lowest-frequency internal rotational modes of the methyl group at 70 +/- 8 cm-1 and 92 +/- 5 cm-1. PMID- 29142687 TI - Fiber-optic array using molecularly imprinted microspheres for antibiotic analysis. AB - In this article we describe a new class of high-density optical microarrays based on molecularly imprinted microsphere sensors that directly incorporate specific recognition capabilities to detect enrofloxacin (ENRO), an antibiotic widely used for both human and veterinary applications. This approach involves the preparation of highly cross-linked polymer microspheres by thermal precipitation polymerization in the presence and absence of the target analyte ENRO to generate either molecularly imprinted (MIP) or non-imprinted polymer (NIP) microspheres, respectively. Each polymer type of tailor-made microsphere is fluorescently encoded with either coumarin-30 or tris(4,7-diphenyl-1,10 phenanthroline)ruthenium(ii) dichloride [Ru(dip)3]Cl2 to enable the microspheres to be distinguished. The new MIP-based sensing platform utilizes an optical fiber bundle containing approximately 50 000 individual 3.1 MUm diameter fibers that are chemically etched to create microwells in which MIP and NIP microspheres can be deposited and imaged using an epi-fluorescence microscope. The method enables multiplexed detection by independently addressing both types of beads through their separate light channels. The unique response to the presence of ENRO is manifested on the basis of a competitive immunoassay. A red-fluorescent dye tagged ENRO, labeled with BODIPY(r) TR Cadaverine, competes with ENRO for specific binding sites. The developed immuno-like assay displayed a limit of detection (LOD) of 0.04 MUM (10% binding inhibition) and a dynamic range of 0.29 21.54 MUM (20-80% binding inhibition). The selectivity of the assay was evaluated by measuring the cross-reactivity of other fluoroquinolones (ciprofloxacin, norfloxacin, danofloxacin, and flumequine) and non-related antibiotics (penicillin G and doxycycline). This work demonstrates, for the first time, the applicability of MIPs, as an alternative to biomolecule receptors, for the development of multiplexed detection fiber-optic microarrays paving the way for a new generation of biomimetic sensors. PMID- 29142688 TI - A divergent route to core- and peripherally functionalized diazacoronenes that act as colorimetric and fluorescence proton sensors. AB - Combining core annulation and peripheral group modification, we have demonstrated a divergent synthesis of a family of highly functionalized coronene derivatives from a readily accessible dichlorodiazaperylene intermediate. Various reactions, such as aromatic nucleophilic substitution, Kumada coupling and Suzuki coupling proceed effectively on alpha-positions of the pyridine sites, giving rise to alkoxy, thioalkyl, alkyl or aryl substituted polycyclic aromatic hydrocarbons. In addition to peripheral group modulation, the aromatic core structures can be altered by annulation with thiophene or benzene ring systems. Corresponding single crystal X-ray diffraction and optical studies indicate that the heteroatom linkages not only impact the solid state packing, but also significantly influence the optoelectronic properties. Moreover, these azacoronene derivatives display significant acid-induced spectroscopic changes, suggesting their great potential as colorimetric and fluorescence proton sensors. PMID- 29142689 TI - Copper-catalyzed intermolecular C(sp3)-H bond functionalization towards the synthesis of tertiary carbamates. AB - We describe the development of an intermolecular unactivated C(sp3)-H bond functionalization towards the direct synthesis of tertiary carbamates. The transformation proceeded using a readily available, abundant first-row transition metal catalyst (copper), and isocyanates as the source of the amide moiety. This is a novel strategy for direct transformation of a variety of unactivated hydrocarbon feedstocks to N-alkyl-N-aryl and N,N-dialkyl carbamates without pre functionalization or installation of a directing group. The reaction had a broad substrate scope with 3 degrees > 2 degrees > 1 degrees site selectivity. The reaction proceeded even on a gram scale, and a corresponding free amine was directly obtained when the reaction was performed at high temperature. Kinetic studies suggested that radical-mediated C(sp3)-H bond cleavage was the rate determining step. PMID- 29142690 TI - Is a polymer semiconductor having a "perfect" regular structure desirable for organic thin film transistors? AB - This study utilized high temperature NMR and matrix-assisted laser desorption/ionization time-of-flight (MALDI-ToF) mass spectrometry to reveal that appreciable amounts of structural defects are present in the diketopyrrolopyrrole (DPP)-quaterthiophene copolymers (PDQT) synthesized by the Stille coupling polymerization with Pd(PPh3)2Cl2, Pd2(dba)3/P(o-tol)3, and Pd(PPh3)4 catalyst systems. It was proposed that these structural defects were produced via homocoupling side reactions of the C-Br bonds and the organostannane species. Model Stille coupling reactions further substantiated that the amount of structural defects are catalyst-dependent following the order of Pd(PPh3)2Cl2 > Pd2(dba)3/P(o-tol)3 > Pd(PPh3)4. To verify the structural assignments, "perfect" structurally regular PDQT polymers were prepared using Yamamoto coupling polymerization. When compared to the structurally regular polymers, the polymers containing defects exhibited notable redshifts in their absorption spectra. Surprisingly, the "perfect" structurally regular polymers showed poor molecular ordering in thin films and very low charge transport performance as channel semiconductors in organic thin film transistors (OTFTs). On the contrary, all the "defected" polymers exhibited much improved molecular ordering and significantly higher charge carrier mobility. PMID- 29142692 TI - Boronic acids facilitate rapid oxime condensations at neutral pH. AB - We report here the discovery and development of boron-assisted oxime formation as a powerful connective reaction for chemical biology. Oximes proximal to boronic acids form in neutral aqueous buffer with rate constants of more than 104 M-1 s 1, the largest to date for any oxime condensation. Boron's dynamic coordination chemistry confers an adaptability that seems to aid a number of elementary steps in the oxime condensation. In addition to applications in bioconjugation, the emerging importance of boronic acids in chemical biology as carbohydrate receptors or peroxide probes, and the growing list of drugs and drug candidates containing boronic acids suggest many potential applications. PMID- 29142691 TI - Palladium(0) NHC complexes: a new avenue to highly efficient phosphorescence. AB - We report the first examples of highly luminescent di-coordinated Pd(0) complexes. Five complexes of the form [Pd(L)(L')] were synthesized, where L = IPr, SIPr or IPr* NHC ligands and L' = PCy3, or IPr and SIPr NHC ligands. The photophysical properties of these complexes were determined in degassed toluene solution and in the solid state and contrasted to the poorly luminescent reference complex [Pd(IPr)(PPh3)]. Organic light-emitting diodes were successfully fabricated but attained external quantum efficiencies of between 0.3 and 0.7%. PMID- 29142694 TI - Spying on the boron-boron triple bond using spin-spin coupling measured from 11B solid-state NMR spectroscopy. AB - There is currently tremendous interest in the previously documented example of a stable species exhibiting a boron-boron triple bond (Science, 2012, 336, 1420). Notably, it has recently been stated using arguments based on force constants that this diboryne may not, in reality, feature a boron-boron triple bond. Here, we use advanced solid-state NMR and computational methodology in order to directly probe the orbitals involved in multiple boron-boron bonds experimentally via analysis of 11B-11B spin-spin (J) coupling constants. Computationally, the mechanism responsible for the boron-boron spin-spin coupling in these species is found to be analogous to that for the case of multiply-bonded carbon atoms. The trend in reduced J coupling constants for diborenes and a diboryne, measured experimentally, is in agreement with that known for alkenes and alkynes. This experimental probe of the electronic structure of the boron-boron multiple bond provides strong evidence supporting the originally proposed nature of the bonds in the diboryne and diborenes, and demonstrates that the orbitals involved in boron-boron bonding are equivalent to those well known to construct the multiple bonds between other second-row elements such as carbon and nitrogen. PMID- 29142693 TI - Accurate molecular weight determination of small molecules via DOSY-NMR by using external calibration curves with normalized diffusion coefficients. AB - Determination of the aggregation and solvation numbers of organometallic complexes in solution is an important task to increase insight in reaction mechanisms. Thus knowing which aggregates are formed during a reaction is of high interest to develop better selectivity and higher yields. Diffusion-ordered spectroscopy (DOSY), which separates NMR signals according to the diffusion coefficient, finds increasing use to identify species in solution. However, there still is no simple relationship between diffusion coefficient and molecular weight (MW). Some methods have been developed to estimate the MW but still with a significant error of +/-30%. Here we describe a novel development of MW determination by using an external calibration curve (ECC) approach with normalized diffusion coefficients. Taking the shape of the molecules into account enables accurate MW-predictions with a maximum error of smaller than +/-9%. Moreover we show that the addition of multiple internal references is dispensable. One internal reference (that also can be the solvent) is sufficient. If the solvent signal is not accessible, 16 other internal standards (aliphatics and aromatics) are available to avoid signal overlapping problems and provide flexible choice of analytes. This method is independent of NMR-device properties and diversities in temperature or viscosity and offers an easy and robust method to determine accurate MWs in solution. PMID- 29142695 TI - Self-organisation of dodeca-dendronized fullerene into supramolecular discs and helical columns containing a nanowire-like core. AB - Twelve chiral and achiral self-assembling dendrons have been grafted onto a [60]fullerene hexa-adduct core by copper-catalyzed alkyne azide "click" cycloaddition. The structure adopted by these compounds was determined by the self-assembling peripheral dendrons. These twelve dendrons mediate the self organisation of the dendronized [60]fullerene into a disc-shaped structure containing the [60]fullerene in the centre. The fullerene-containing discs self organise into helical supramolecular columns with a fullerene nanowire-like core, forming a 2D columnar hexagonal periodic array. These unprecedented supramolecular structures and their assemblies are expected to provide new developments in chiral complex molecular systems and their application to organic electronics and solar cells. PMID- 29142697 TI - Unveiling the nature of supramolecular crown ether-C60 interactions. AB - A series of exTTF-(crown ether)2 receptors, designed to host C60, has been prepared. The size of the crown ether and the nature of the heteroatoms have been systematically changed to fine tune the association constants. Electrochemical measurements and transient absorption spectroscopy assisted in corroborating charge transfer in the ground state and in the excited state, leading to the formation of radical ion pairs featuring lifetimes in the range from 12 to 21 ps. To rationalize the nature of the exTTF-(crown ether)2.C60 stabilizing interactions, theoretical calculations have been carried out, suggesting a synergetic interplay of donor-acceptor, pi-pi, n-pi and CH...pi interactions, which is the basis for the affinity of our novel receptors towards C60. PMID- 29142696 TI - Molecular understandings on the activation of light hydrocarbons over heterogeneous catalysts. AB - Due to the depletion of petroleum and the recent shale gas revolution, the dropping of the price for light alkanes makes alkanes an attractive feedstock for the production of light alkenes and other valuable chemicals. Understanding the mechanism for the activation of C-H bonds in hydrocarbons provides fundamental insights into this process and a guideline for the optimization of catalysts used for the processing of light alkanes. In the last two decades, density functional theory (DFT) has become a powerful tool to explore elementary steps and mechanisms of many heterogeneously catalyzed processes at the atomic scale. This review describes recent progress on computational understanding of heterogeneous catalytic dehydrogenation reactions of light alkanes. We start with a short description on basic concepts and principles of DFT as well as its application in heterogeneous catalysis. The activation of C-H bonds over transition metal and alloy surfaces are then discussed in detail, followed by C-H activation over oxides, zeolites and catalysts with single atoms as active sites. The origins of coking formation are also discussed followed by a perspective on directions of future research. PMID- 29142698 TI - Crystallization-induced dual emission from metal- and heavy atom-free aromatic acids and esters. AB - Pure organic materials exhibiting room temperature phosphorescence (RTP) have significant fundamental importance and promising optoelectronic and biological applications. Exploration of metal- and heavy atom-free pure organic phosphors, however, remains challenging because achieving emissive triplet relaxation that outcompetes the vibrational loss is difficult without metal or heavy atoms. In this contribution, in contrast to aggregation-caused quenching (ACQ) normally observed in conventional chromophores, a unique phenomenon of crystallization induced dual emission (CIDE), namely, simultaneously boosted fluorescence and phosphorescence upon crystallization, is observed in a group of pure organic aromatic acids and esters at ambient conditions. Moreover, two triplet-involved relaxations of delayed fluorescence (DF) and phosphorescence are activated. Such efficient intrinsic emission from both singlet and triplet states in a single compound without employing metal or heavy atoms is suitable for a variety of fundamental research and applications. PMID- 29142699 TI - Small molecular logic systems can draw the outlines of objects via edge visualization. AB - The recently-discovered ability of small logical molecules to recognize edges is exploited to achieve outline drawing from binary templates. Outlines of arbitrary curvature, several colours and thicknesses down to 1 mm are drawn in around 30 min or less by employing a common laboratory two-colour ultraviolet lamp. The outlines and the light dose-driven XOR logic with fluorescence output or 'off-on off' action which is observed in the irradiated regions are modelled by combining foundational principles of photochemistry, acid-base neutralization and diffusion. PMID- 29142700 TI - Cofactor composition and function of a H2-sensing regulatory hydrogenase as revealed by Mossbauer and EPR spectroscopy. AB - The regulatory hydrogenase (RH) from Ralstonia eutropha H16 acts as a sensor for the detection of environmental H2 and regulates gene expression related to hydrogenase-mediated cellular metabolism. In marked contrast to prototypical energy-converting [NiFe] hydrogenases, the RH is apparently insensitive to inhibition by O2 and CO. While the physiological function of regulatory hydrogenases is well established, little is known about the redox cycling of the [NiFe] center and the nature of the iron-sulfur (FeS) clusters acting as electron relay. The absence of any FeS cluster signals in EPR had been attributed to their particular nature, whereas the observation of essentially only two active site redox states, namely Ni-SI and Ni-C, invoked a different operant mechanism. In the present work, we employ a combination of Mossbauer, FTIR and EPR spectroscopic techniques to study the RH, and the results are consistent with the presence of three [4Fe-4S] centers in the small subunit. In the as-isolated, oxidized RH all FeS clusters reside in the EPR-silent 2+ state. Incubation with H2 leads to reduction of two of the [4Fe-4S] clusters, whereas only strongly reducing agents lead to reduction of the third cluster, which is ascribed to be the [4Fe-4S] center in 'proximal' position to the [NiFe] center. In the two different active site redox states, the low-spin FeII exhibits distinct Mossbauer features attributed to changes in the electronic and geometric structure of the catalytic center. The results are discussed with regard to the spectral characteristics and physiological function of H2-sensing regulatory hydrogenases. PMID- 29142701 TI - Ligand-enabled Ir-catalyzed intermolecular diastereoselective and enantioselective allylic alkylation of 3-substituted indoles. AB - An Ir-catalyzed asymmetric allylic alkylation of 3-substituted indoles is reported. The reaction provides indoline products containing multiple contiguous stereocenters with high site-, regio-, diastereo- and enantioselectivities in one step from a wide range of readily available starting materials. The key to this method is the high level of diastereocontrol enabled by an iridium catalyst derived from a N-aryl phosphoramidite ligand (Me-THQphos, 1c). PMID- 29142702 TI - A new quinoxaline-containing peptide induces apoptosis in cancer cells by autophagy modulation. AB - The synthesis of a new small library of quinoxaline-containing peptides is described. After cytotoxic evaluation in four human cancer cell lines, as well as detailed biological studies, it was found that the most active compound, RZ2, promotes the formation of acidic compartments, where it accumulates, blocking the progression of autophagy. Further disruption of the mitochondrial membrane potential and an increase in mitochondrial ROS was observed, causing cells to undergo apoptosis. Given its cytotoxic activity and protease-resistant features, RZ2 could be a potential drug candidate for cancer treatment and provide a basis for future research into the crosstalk between autophagy and apoptosis and its relevance in cancer therapy. PMID- 29142703 TI - Mechanisms and energetics of free radical initiated disulfide bond cleavage in model peptides and insulin by mass spectrometry. AB - We investigate the mechanism of disulfide bond cleavage in gaseous peptide and protein ions initiated by a covalently-attached regiospecific acetyl radical using mass spectrometry (MS). Highly selective S-S bond cleavages with some minor C-S bond cleavages are observed by a single step of collisional activation. We show that even multiple disulfide bonds in intact bovine insulin are fragmented in the MS2 stage, releasing the A- and B-chains with a high yield, which has been challenging to achieve by other ion activation methods. Yet, regardless of the previous reaction mechanism studies, it has remained unclear why (1) disulfide bond cleavage is preferred to peptide backbone fragmentation, and why (2) the S-S bond that requires the higher activation energy conjectured in previously suggested mechanisms is more prone to be cleaved than the C-S bond by hydrogen deficient radicals. To probe the mechanism of these processes, model peptides possessing deuterated beta-carbon(s) at the disulfide bond are employed. It is suggested that the favored pathway of S-S bond cleavage is triggered by direct acetyl radical attack at sulfur with concomitant cleavage of the S-S bond (SH2). The activation energy for this process is substantially lower by ~9-10 kcal mol-1 than those of peptide backbone cleavage processes determined by density functional quantum chemical calculations. Minor reaction pathways are initiated by hydrogen abstraction from the alpha-carbon or the beta-carbon of a disulfide, followed by beta-cleavages yielding C-S or S-S bond scissions. The current mechanistic findings should be generally applicable to other radical-driven disulfide bond cleavages with different radical species such as the benzyl and methyl pyridyl radicals. PMID- 29142704 TI - Luminescent zinc(ii) and copper(i) complexes for high-performance solution processed monochromic and white organic light-emitting devices. AB - The synthesis and spectroscopic properties of luminescent tetranuclear zinc(ii) complexes of substituted 7-azaindoles and a series of luminescent copper(i) complexes containing 7,8-bis(diphenylphosphino)-7,8-dicarba-nido-undecaborate ligand are described. These complexes are stable towards air and moisture. Thin film samples of the luminescent copper(i) complexes in 2,6-dicarbazolo-1,5 pyridine and zinc(ii) complexes in poly(methyl methacrylate) showed emission quantum yields of up to 0.60 (for Cu-3) and 0.96 (for Zn-1), respectively. Their photophysical properties were examined by ultrafast time-resolved emission spectroscopy, temperature dependent emission lifetime measurements and density functional theory calculations. Monochromic blue and orange solution-processed OLEDs with these Zn(ii) and Cu(i) complexes as light-emitting dopants have been fabricated, respectively. Maximum external quantum efficiency (EQE) of 5.55% and Commission Internationale de l'Eclairage (CIE) coordinates of (0.16, 0.19) were accomplished with the optimized Zn-1-OLED while these values were, respectively 15.64% and (0.48, 0.51) for the optimized Cu-3-OLED. Solution-processed white OLEDs having maximum EQE of 6.88%, CIE coordinates of (0.42, 0.44), and colour rendering index of 81 were fabricated by using these luminescent Zn(ii) and Cu(i) complexes as blue and orange light-emitting dopant materials, respectively. PMID- 29142705 TI - Regioselective thioacetylation of chitosan end-groups for nanoparticle gene delivery systems. AB - Chitosan (CS) end-group chemistry is a conjugation strategy that has been minimally exploited in the literature to date. Although the open-chain form of the CS reducing extremity bears a reactive aldehyde moiety, the most common method to generate a reactive end-group on CS is nitrous acid depolymerization, which produces a 2,5-anhydro-d-mannose unit (M-Unit) bearing also an aldehyde moiety. However, the availability of the latter might be low, since previous literature suggests that its hydrated and non-reactive form, namely the gem-diol form, is predominant in acidic aqueous conditions. Oxime-click chemistry has been used to react on such aldehydes with various degrees of success, but the use of a co-solvent and additional chemical reagents remain necessary to obtain the desired and stable covalent linkage. In this study, we have assessed the availability of the aldehyde reactive form on chitosan treated with nitrous acid. We have also assessed its reactivity towards thiol-bearing molecules in acidic conditions where CS amino groups are fully protonated and thus unreactive towards aldehyde. LC-MS and NMR spectroscopy methods (1H and DOSY, respectively) confirmed the regioselective thioacetylation of the reactive aldehyde with conversion rates between 55 and 70% depending on the thiol molecule engaged. The stabilization of the hemithioacetal intermediates into the corresponding thioacetals was also found to be facilitated upon freeze-drying of the reaction medium. The PEGylation of the CS M-Unit aldehyde by thioacetylation was also performed as a direct application of the proposed conjugation approach. CS-b-PEG2 block copolymers were successfully synthesized and were used to prepare block ionomer complexes with plasmid DNA, as revealed by their spherical morphology vs. the rod-like/globular/toroidal morphology observed for polyplexes prepared using native unmodified chitosan. This novel aqueous thiol-based conjugation strategy constitutes an alternative to the oxime-click pathway; it could be applicable to other polymers. PMID- 29142706 TI - Reaction-activated palladium catalyst for dehydrogenation of substituted cyclohexanones to phenols and H2 without oxidants and hydrogen acceptors. AB - It is widely believed that the dehydrogenation of organic compounds is a thermodynamically unfavorable process, and thus requires stoichiometric oxidants such as dioxygen and metal oxides or sacrificial hydrogen acceptors to remove the hydrogen from the reaction mixture to drive the equilibrium towards the products. Here we report a previously unappreciated combination of common commercial Pd/C and H2 which dehydrogenates a wide range of substituted cyclohexanones and 2 cyclohexenones to their corresponding phenols with high isolated yields, with H2 as the only byproduct. The reaction requires no oxidants or hydrogen acceptors because instead of removing the generated hydrogen with oxidants or hydrogen acceptors, we demonstrated it can be used as a cocatalyst to help power the reaction. This method for phenol synthesis manifests a high atom economy, and is inherently devoid of the complications normally associated with oxidative dehydrogenations. PMID- 29142707 TI - Systematic and site-specific analysis of N-sialoglycosylated proteins on the cell surface by integrating click chemistry and MS-based proteomics. AB - Glycoproteins on the cell surface are ubiquitous and essential for cells to interact with the extracellular matrix, communicate with other cells, and respond to environmental cues. Although surface sialoglycoproteins can dramatically impact cell properties and represent different cellular statuses, global and site specific analysis of sialoglycoproteins only on the cell surface is extraordinarily challenging. An effective method integrating metabolic labeling, copper-free click chemistry and mass spectrometry-based proteomics was developed to globally and site-specifically analyze surface N-sialoglycoproteins. Surface sialoglycoproteins metabolically labeled with a functional group were specifically tagged through copper-free click chemistry, which is ideal because it is quick, specific and occurs under physiological conditions. Sequentially tagged sialoglycoproteins were enriched for site-specific identification by mass spectrometry. Systematic and quantitative analysis of the surface N sialoglycoproteome in cancer cells with distinctive invasiveness demonstrated many N-sialoglycoproteins up-regulated in invasive cells, the majority of which contained cell adhesion-related domains. This method is very effective to globally and site-specifically analyze N-sialoglycoproteins on the cell surface, and will have extensive applications in the biological and biomedical research communities. Site-specific information regarding surface sialoglycoproteins can serve as biomarkers for disease detection, targets for vaccine development and drug treatment. PMID- 29142708 TI - Insight into the strong aggregation-induced emission of low-conjugated racemic C6 unsubstituted tetrahydropyrimidines through crystal-structure-property relationship of polymorphs. AB - Racemic C6-unsubstituted tetrahydropyrimidines (THPs) are a series of fluorophores with a strong aggregation-induced emission (AIE) effect. However, they do not possess the structural features of conventional AIE compounds. In order to understand their AIE mechanism, here, the influences of the molecular packing mode and the conformation on the optical properties of THPs were investigated using seven crystalline polymorphs of three THPs (1-3). The racemic THPs 1-3 have low-conjugated and highly flexible molecular structures, and hence show practically no emission in different organic solvents. However, the fluorescence quantum yields of their polymorphs are up to 93%, and the maximum excitation (lambdaex) and emission (lambdaem) wavelengths of the polymorphs are long at 409 and 484 nm, respectively. Single-crystal structures and theoretical calculation of the HOMOs and LUMOs based on the molecular conformations of these polymorphs indicate that the polymorphs with the shortest lambdaex and lambdaem values possess a RS-packing mode (R- and S-enantiomers self-assemble as paired anti-parallel lines) and a more twisted conformation without through-space conjugation between the dicarboxylates, but the polymorphs with longer lambdaex and lambdaem values adopt a RR/SS-packing mode (R- and S-enantiomers self assemble as unpaired zigzag lines) and a less twisted conformation with through space conjugation between the dicarboxylates. The molecular conformations of 1-3 in all these polymorphs are stereo and more twisted than those in solution. Although 1-3 are poorly conjugated, the radiative rate constants (kr) of their polymorphs are as large as conventional fluorophores (0.41-1.03 * 108 s-1) because of improved electronic conjugation by both through-bond and through-space interactions. Based on the obtained results, it can be deduced that the strong AIE arises not only from the restriction of intramolecular motion but also from enhanced electronic coupling and radiatively-favored inter-crossed local excitation (LE) and intramolecular charge transfer (ICT) excitation states. The abnormal molecular structures, easily-controllable self-assembly of the R- and S enantiomers, and the strong AIE effect make THPs very useful fluorophores for applications and theoretical research. PMID- 29142709 TI - Profluorescent verdazyl radicals - synthesis and characterization. AB - The synthesis and characterization of various 6-oxo-verdazyl radicals and their diamagnetic styryl radical trapping products are presented. It is shown that styryl radical trapping products derived from N-phenyl verdazyls show fluorescence whereas the N-methyl congeners are non-fluorescent. In the parent N phenyl verdazyls fluorescence is fully quenched which renders these compounds highly valuable profluorescent radical probes. PMID- 29142710 TI - Fe(iv) alkylidenes via protonation of Fe(ii) vinyl chelates and a comparative Mossbauer spectroscopic study. AB - Treatment of cis-Me2Fe(PMe3)4 with di-1,2-(E-2-(pyridin-2-yl)vinyl)benzene ((bdvp)H2), a tetradentate ligand precursor, afforded (bdvp)Fe(PMe3)2 (1-PMe3) and 2 equiv. CH4, via C-H bond activation. Similar treatments with tridentate ligand precursors PhCH 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 NCH2(E-CHCHPh) ((pipp)H2) and PhCHN(2-CCMe-Ph) ((pipa)H) under dinitrogen provided trans-(pipp)Fe(PMe3)2N2 (2) and trans (pipvd)Fe(PMe3)2N2 (3), respectively; the latter via one C-H bond activation, and a subsequent insertion of the alkyne into the remaining Fe-Me bond. All three Fe(ii) vinyl species were protonated with H[BArF4] to form the corresponding Fe(iv) alkylidene cations, [(bavp)Fe(PMe3)2][BArF4] (4-PMe3), [(piap)Fe(PMe3)3][BArF4] (5), and [(pipad)Fe(PMe3)3][BArF4] (6). Mossbauer spectroscopic measurements on the formally Fe(ii) and Fe(iv) derivatives revealed isomer shifts within 0.1 mm s-1, reflecting the similarity in their bond distances. PMID- 29142711 TI - A nitrogen-base catalyzed generation of organotin(ii) hydride from an organotin trihydride under reductive dihydrogen elimination. AB - Since their first description over a decade ago, organotin(ii) hydrides have been an iconic class of compounds in molecular main group chemistry. Among other approaches they have been accessed from the hydrogenation of distannynes. We herein report their accessibility from the other direction by dehydrogenation of organotin trihydride. On reacting pyridine and amine bases with the bulky substituted organotin trihydride Ar*SnH3 (Ar* = 2,6-trip2(C6H3)-, trip = 2,4,6 triisopropylphenyl) hydrogen evolution was observed. In case of catalytic amounts of base the dehydro-coupling product diorganodistannane Ar*H2SnSnH2Ar* was obtained quantitatively whilst for excessive amounts (>4 eq.) the monomeric base adduct to known Ar*SnH was obtained almost exclusively. The base adducts were found to be remarkably thermally robust. They readily react with polar fulvenic C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 C-bonds in hydro-stannylenylation reactions. The resulting half-sandwich complex Ar*SnCp* was structurally characterized. Moreover, on application of less nucleophilic amine bases, the uncoordinated, in solution dimeric [Ar*SnH]2 is formed. NMR spectroscopic studies on the kinetics of the DMAP-catalysed reductive elimination of dihydrogen were performed. The activation energy was approximated to be 13.7 kcal mol-1. Solvent dependencies and a kinetic isotope effect KIE of kH/kD = 1.65 in benzene and 2.04 in THF were found and along with DFT calculations support a polar mechanism for this dehydrogenation. PMID- 29142712 TI - Integrating proteomics with electrochemistry for identifying kinase biomarkers. AB - We present an integrated approach for highly sensitive identification and validation of substrate-specific kinases as cancer biomarkers. Our approach combines phosphoproteomics for high throughput cancer-related biomarker discovery from patient tissues and an impedimetric kinase activity biosensor for sensitive validation. Using non-small-cell lung cancer (NSCLC) as a proof-of-concept study, label-free quantitative phosphoproteomic analysis of a pair of cancerous and its adjacent normal tissues revealed 198 phosphoproteins that are over-phosphorylated in NSCLC. Among the differentially regulated phosphorylation sites, the most significant alteration was in residue S165 in the Hepatoma Derived Growth Factor (HDGF) protein. Hence, HDGF was selected as a model system for the electrochemical studies. Further motif-based analysis of this altered phosphorylation site revealed that extracellular-signal-regulated kinase 1/2 (ERK1/2) are most likely to be the corresponding kinases. For validation of the kinase-substrate pair, densely packed peptide monolayers corresponding to the HDGF phosphorylation site were coupled to a gold electrode. Phosphorylation of the monolayer by ERK2 and dephosphorylation by alkaline phosphatase (AP) were detected by electrochemical impedance spectroscopy (EIS) and surface roughness analysis. Compared to other methods for quantification of kinase concentration, this label-free electrochemical assay offers the advantages of ultra-sensitivity as well as higher specificity for the detection of cancer-related kinase substrate pair. With implementation of multiple kinase-substrate biomarker pairs, we expect this integrated approach to become a high throughput platform for discovery and validation of phosphorylation-mediated biomarkers. PMID- 29142714 TI - Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors. AB - Src-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe rhodium(ii) conjugates that deliver both potent and selective inhibition of Src-family SH3 domains. Rhodium(ii) conjugates offer dramatic affinity enhancements due to interactions with specific and unique Lewis-basic histidine residues near the SH3 binding interface, allowing predictable, structure-guided inhibition of SH3 targets that are recalcitrant to traditional inhibitors. In one example, a simple metallopeptide binds the Lyn SH3 domain with 6 nM affinity and exhibits functional activation of Lyn kinase under biologically relevant concentrations (EC50 ~ 200 nM). PMID- 29142713 TI - A novel 18F-labelled high affinity agent for PET imaging of the translocator protein. AB - The translocator protein (TSPO) is an important target for imaging focal neuroinflammation in diseases such as brain cancer, stroke and neurodegeneration, but current tracers for non-invasive imaging of TSPO have important limitations. We present the synthesis and evaluation of a novel 3-fluoromethylquinoline-2 carboxamide, AB5186, which was prepared in eight steps using a one-pot two component indium(iii)-catalysed reaction for the rapid and efficient assembly of the 4-phenylquinoline core. Biological assessment and the implementation of a physicochemical study showed AB5186 to have low nanomolar affinity for TSPO, as well as optimal plasma protein binding and membrane permeability properties. Generation of [18F]-AB5186 through 18F incorporation was achieved in good radiochemical yield and subsequent in vitro and ex vivo autoradiography revealed the ability of this compound to bind with specificity to TSPO in mouse glioblastoma xenografts. Initial positron emission tomography imaging of a glioma bearing mouse and a healthy baboon support the potential for [18F]-AB5186 use as a radiotracer for non-invasive TSPO imaging in vivo. PMID- 29142715 TI - Access to enantioenriched 2,3- and 2,5-dihydrofurans with a fully substituted C2 stereocenter by Pd-catalyzed asymmetric intermolecular Heck reaction. AB - A palladium-catalyzed intermolecular asymmetric Heck reaction with dihydrofurans with a trisubstituted double bond is reported. The use of two different chiral ligands provides access to valuable 2,3- and 2,5-dihydrofurans with a fully substituted C2 stereocenter with high levels of regio- and enantiocontrol. PMID- 29142716 TI - Hydrophilic sulfonated bis-1,2,4-triazine ligands are highly effective reagents for separating actinides(iii) from lanthanides(iii) via selective formation of aqueous actinide complexes. AB - We report the first examples of hydrophilic 6,6'-bis(1,2,4-triazin-3-yl)-2,2' bipyridine (BTBP) and 2,9-bis(1,2,4-triazin-3-yl)-1,10-phenanthroline (BTPhen) ligands, and their applications as actinide(iii) selective aqueous complexing agents. The combination of a hydrophobic diamide ligand in the organic phase and a hydrophilic tetrasulfonated bis-triazine ligand in the aqueous phase is able to separate Am(iii) from Eu(iii) by selective Am(iii) complex formation across a range of nitric acid concentrations with very high selectivities, and without the use of buffers. In contrast, disulfonated bis-triazine ligands are unable to separate Am(iii) from Eu(iii) in this system. The greater ability of the tetrasulfonated ligands to retain Am(iii) selectively in the aqueous phase than the corresponding disulfonated ligands appears to be due to the higher aqueous solubilities of the complexes of the tetrasulfonated ligands with Am(iii). The selectivities for Am(iii) complexation observed with hydrophilic tetrasulfonated bis-triazine ligands are in many cases far higher than those found with the polyaminocarboxylate ligands previously used as actinide-selective complexing agents, and are comparable to those found with the parent hydrophobic bis triazine ligands. Thus we demonstrate a feasible alternative method to separate actinides from lanthanides than the widely studied approach of selective actinide extraction with hydrophobic bis-1,2,4-triazine ligands such as CyMe4-BTBP and CyMe4-BTPhen. PMID- 29142717 TI - How to split a G-quadruplex for DNA detection: new insight into the formation of DNA split G-quadruplex. AB - Here, we get a new insight into the formation of a split G-quadruplex from the viewpoints of the split mode and guanine base number. An unusual result is that the split mode 4 : 8 performed best in six split modes, including the frequently used mode 1 : 3 and 2 : 2 in the split G-quadruplex enhanced fluorescence assay. Circular dichroism spectra verified the conclusion. The application of the split G-quadruplex based assay in DNA detection was performed on the point mutations of the JAK2 V617F and HBB genes. A multi-target analysis method based on a pool of G segments split from T30695 (GGGTGGGTGGGTGGGT) by the magic "law of 4 : 8" was established. PMID- 29142718 TI - Heterologous expression of the avirulence gene ACE1 from the fungal rice pathogen Magnaporthe oryzae. AB - The ACE1 and RAP1 genes from the avirulence signalling gene cluster of the rice blast fungus Magnaporthe oryzae were expressed in Aspergillus oryzae and M. oryzae itself. Expression of ACE1 alone produced a polyenyl pyrone (magnaporthepyrone), which is regioselectively epoxidised and hydrolysed to give different diols, 6 and 7, in the two host organisms. Analysis of the three introns present in ACE1 determined that A. oryzae does not process intron 2 correctly, while M. oryzae processes all introns correctly in both appressoria and mycelia. Co-expression of ACE1 and RAP1 in A. oryzae produced an amide 8 which is similar to the PKS-NRPS derived backbone of the cytochalasans. Biological testing on rice leaves showed that neither the diols 6 and 7, nor amide 8 was responsible for the observed ACE1 mediated avirulence, however, gene cluster analysis suggests that the true avirulence signalling compound may be a tyrosine-derived cytochalasan compound. PMID- 29142719 TI - Wide bandgap OPV polymers based on pyridinonedithiophene unit with efficiency >5. AB - We report the properties of a new series of wide band gap photovoltaic polymers based on the N-alkyl 2-pyridone dithiophene (PDT) unit. These polymers are effective bulk heterojunction solar cell materials when blended with phenyl-C71 butyric acid methyl ester (PC71BM). They achieve power conversion efficiencies (up to 5.33%) high for polymers having such large bandgaps, ca. 2.0 eV (optical) and 2.5 eV (electrochemical). Grazing incidence wide-angle X-ray scattering (GIWAXS) reveals strong correlations between pi-pi stacking distance and regularity, polymer backbone planarity, optical absorption maximum energy, and photovoltaic efficiency. PMID- 29142720 TI - Spontaneous head-to-tail cyclization of unprotected linear peptides with the KAHA ligation. AB - The alpha-ketoacid-hydroxylamine (KAHA) ligation with 5-oxaproline enables the direct cyclization of peptides upon cleavage from a solid support, without coupling reagents, protecting groups, or purification of the linear precursors. This Fmoc SPPS-based method was applied to the synthesis of a library of 24 homoserine-containing cyclic peptides and was compared side-by-side with the synthesis of the same products using a standard method for cyclizing side-chain protected substrates. A detailed mechanistic study including 2H and 18O labeling experiments and the characterization of reaction intermediates by NMR and mass spectrometry is reported. PMID- 29142721 TI - C-H bond activation induced by thorium metallacyclopropene complexes: a combined experimental and computational study. AB - Inter- and intramolecular C-H bond activations by thorium metallacyclopropene complexes were comprehensively studied. The reduction of [eta5-1,2,4 (Me3C)3C5H2]2ThCl2 (1) with potassium graphite (KC8) in the presence of internal alkynes (PhC 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 CR) yields the corresponding thorium metallacyclopropenes [eta5-1,2,4-(Me3C)3C5H2]2Th(eta2-C2Ph(R)) (R = Ph (2), Me (3), iPr (4), C6H11 (5)). Complexes 3-5 derived from phenyl(alkyl)acetylenes are very reactive resulting in an intramolecular C-H bond activation of the 1,2,4 (Me3C)3C5H2 ligand. In contrast, no intramolecular C-H bond activation is observed for the diphenylacetylene derived complex 2, but it does activate alpha C-H bonds in pyridine or carbonyl derivatives upon coordination. Density functional theory (DFT) studies complement the experimental studies and provide additional insights into the observed reactivity. PMID- 29142723 TI - Remote stereoselective deconjugation of alpha,beta-unsaturated esters by simple amidation reactions. AB - The thermodynamically disfavored isomerization of alpha,beta-unsaturated esters to deconjugated beta,gamma-unsaturated analogues occurs readily when coupled to an amidation. Within the framework of macrocyclic derivatives, it is shown that 15, 16, and 18 membered macrocycles react with tBuOK and anilines to generate, in one-pot, beta,gamma-unsaturated amides (yields up to 88%). Importantly, single (chiral) diastereomers are isolated (d.r. > 49 : 1, 1H NMR) irrespective of the size and nature of the rings, showing an effective transmission of remote stereochemistry during the isomerization process. CSP-chromatographic resolution and absolute configuration determination by VCD are achieved. PMID- 29142722 TI - Highly enantioselective construction of tertiary thioethers and alcohols via phosphine-catalyzed asymmetric gamma-addition reactions of 5H-thiazol-4-ones and 5H-oxazol-4-ones: scope and mechanistic understandings. AB - Phosphine-catalyzed highly enantioselective gamma-additions of 5H-thiazol-4-ones and 5H-oxazol-4-ones to allenoates have been developed for the first time. With the employment of amino-acid derived bifunctional phosphines, a wide range of substituted 5H-thiazol-4-one and 5H-oxazol-4-one derivatives bearing heteroatom (S or O)-containing tertiary chiral centers were constructed in high yields and excellent enantioselectivities. The reported method provides facile access to enantioenriched tertiary thioethers/alcohols. The mechanism of the gamma-addition reaction was investigated by performing DFT calculations, and the hydrogen bonding interactions between the Bronsted acid moiety of the phosphine catalysts and the "C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 O" unit of the donor molecules were shown to be crucial in asymmetric induction. PMID- 29142724 TI - An enzyme-responsive metal-enhanced near-infrared fluorescence sensor based on functionalized gold nanoparticles. AB - Near-infrared (NIR) fluorescence imaging is promising due to the high penetration depths and minimal levels of autofluorescence in living systems. However, it suffers from low fluorescent quantum yield, and metal-enhanced fluorescence (MEF) is considered to be a promising technique to overcome this. Stimuli-responsive NIR fluorescence enhancement shows remarkable potential for applications in medical imaging and diagnosis. Herein, we successfully fabricated an enzyme responsive near-infrared sensor based on MEF by functionalizing gold nanoparticles with NIR fluorophores and enzyme-responsive self-aggregation moieties. The NIR fluorescence of fluorophores on the gold nanoparticles was significantly enhanced due to increases both in the light scattering intensity and in the radiative decay rate (kr) of the NIR fluorophores, along with relatively small variation in the nonradiative decay rate. This novel strategy for NIR fluorescent sensors should be particularly promising for NIR fluorescence imaging of enzyme activities and early diagnosis based on rationally designed nanomaterials. PMID- 29142725 TI - Bioinspired design of redox-active ligands for multielectron catalysis: effects of positioning pyrazine reservoirs on cobalt for electro- and photocatalytic generation of hydrogen from water. AB - Mononuclear metalloenzymes in nature can function in cooperation with precisely positioned redox-active organic cofactors in order to carry out multielectron catalysis. Inspired by the finely tuned redox management of these bioinorganic systems, we present the design, synthesis, and experimental and theoretical characterization of a homologous series of cobalt complexes bearing redox-active pyrazines. These donor moieties are locked into key positions within a pentadentate ligand scaffold in order to evaluate the effects of positioning redox non-innocent ligands on hydrogen evolution catalysis. Both metal- and ligand-centered redox features are observed in organic as well as aqueous solutions over a range of pH values, and comparison with analogs bearing redox inactive zinc(ii) allows for assignments of ligand-based redox events. Varying the geometric placement of redox non-innocent pyrazine donors on isostructural pentadentate ligand platforms results in marked effects on observed cobalt catalyzed proton reduction activity. Electrocatalytic hydrogen evolution from weak acids in acetonitrile solution, under diffusion-limited conditions, reveals that the pyrazine donor of axial isomer 1-Co behaves as an unproductive electron sink, resulting in high overpotentials for proton reduction, whereas the equatorial pyrazine isomer complex 2-Co is significantly more active for hydrogen generation at lower voltages. Addition of a second equatorial pyrazine in complex 3-Co further minimizes overpotentials required for catalysis. The equatorial derivative 2-Co is also superior to its axial 1-Co congener for electrocatalytic and visible-light photocatalytic hydrogen generation in biologically relevant, neutral pH aqueous media. Density functional theory calculations (B3LYP-D2) indicate that the first reduction of catalyst isomers 1-Co, 2-Co, and 3-Co is largely metal-centered while the second reduction occurs at pyrazine. Taken together, the data establish that proper positioning of non-innocent pyrazine ligands on a single cobalt center is indeed critical for promoting efficient hydrogen catalysis in aqueous media, akin to optimally positioned redox-active cofactors in metalloenzymes. In a broader sense, these findings highlight the significance of electronic structure considerations in the design of effective electron-hole reservoirs for multielectron transformations. PMID- 29142726 TI - Signal transduction and amplification through enzyme-triggered ligand release and accelerated catalysis. AB - Signal transduction and signal amplification are both important mechanisms used within biological signalling pathways. Inspired by this process, we have developed a signal amplification methodology that utilises the selectivity and high activity of enzymes in combination with the robustness and generality of an organometallic catalyst, achieving a hybrid biological and synthetic catalyst cascade. A proligand enzyme substrate was designed to selectively self-immolate in the presence of the enzyme to release a ligand that can bind to a metal pre catalyst and accelerate the rate of a transfer hydrogenation reaction. Enzyme triggered catalytic signal amplification was then applied to a range of catalyst substrates demonstrating that signal amplification and signal transduction can both be achieved through this methodology. PMID- 29142727 TI - Tertiary amine mediated aerobic oxidation of sulfides into sulfoxides by visible light photoredox catalysis on TiO2. AB - The selective oxidation of sulfides into sulfoxides receives much attention due to industrial and biological applications. However, the realization of this reaction with molecular oxygen at room temperature, which is of importance towards green and sustainable chemistry, remains challenging. Herein, we develop a strategy to achieve the aerobic oxidation of sulfides into sulfoxides by exploring the synergy between a tertiary amine and titanium dioxide via visible light photoredox catalysis. Specifically, titanium dioxide can interact with triethylamine (TEA) to form a visible-light harvesting surface complex, preluding the ensuing selective redox reaction. Moreover, TEA, whose stability was demonstrated by a turnover number of 32, plays a critical role as a redox mediator by shuttling electrons during the oxidation of sulfide. This work suggests that the addition of a redox mediator is highly functional in establishing visible-light-induced reactions via heterogeneous photoredox catalysis. PMID- 29142728 TI - Metal influence on the iso- and hetero-selectivity of complexes of bipyrrolidine derived salan ligands for the polymerisation of rac-lactide. AB - In this paper we have prepared a series of Ti(iv), Hf(iv) and Al(iii) complexes based on bipyrrolidine salan pro-ligands. The Hf(iv) complexes have all been characterised in the solid-state, the chiral ligands coordinate to Hf(iv) in an alpha-cis manner whereas the meso ligand coordinates in a beta-cis geometry. The Hf(iv) complexes are all active for the ROP of rac-lactide in the melt, with the fluxional meso complex affording a strong isotactic bias Pm = 0.84. As expected Hf(3)(OiPr)2 polymerised l-LA faster than rac-LA (kapp = 5.9 * 10-3 min-1vs. 3.8 * 10-3 min-1). For Ti(iv) complexes atactic PLA was formed. The salan pro-ligands have also been complexed to Al(iii), and the novel Al-Me and Al-OiPr complexes were characterised in the solid and solution state. Al(1)(OiPr) was fluxional on the NMR timescale, whereas Al(3)(OiPr) was locked in solution with no exchange. Interestingly, the Al(iii) complexes of 3H2 produce PLA with a very strong heterotactic bias Pr upto 0.87, whereas atactic PLA is produced with 1H2. For Al(3)(OiPr) a linear relationship is observed with Mn and conversion. Experiments with the addition of an equivalent of rac-LA to the selective initiators have also been performed and are discussed. PMID- 29142729 TI - Electrochemical detection of single micelles through 'nano-impacts'. AB - A new class of 'soft' particles, micelles, is detected electrochemically via 'nano-impacts' for the first time. Short, sharp bursts of current are used to indicate the electrical contact of a single CTAB (cetyltrimethylammonium bromide) micelle with an electrode via the oxidation of the bromide content. The variation in CTAB concentration for such 'nano-impact' experiments shows that a significant number of 'spikes' are observed above the CMC (critical micelle concentration) and this is attributed to the formation of micelles. A comparison with dynamic light scattering is also reported. PMID- 29142730 TI - Selective glycoprotein detection through covalent templating and allosteric click imprinting. AB - Many glycoproteins are intimately linked to the onset and progression of numerous heritable or acquired diseases of humans, including cancer. Indeed the recognition of specific glycoproteins remains a significant challenge in analytical method and diagnostic development. Herein, a hierarchical bottom-up route exploiting reversible covalent interactions with boronic acids and so called click chemistry for the fabrication of glycoprotein selective surfaces that surmount current antibody constraints is described. The self-assembled and imprinted surfaces, containing specific glycoprotein molecular recognition nanocavities, confer high binding affinities, nanomolar sensitivity, exceptional glycoprotein specificity and selectivity with as high as 30 fold selectivity for prostate specific antigen (PSA) over other glycoproteins. This synthetic, robust and highly selective recognition platform can be used in complex biological media and be recycled multiple times with no performance decrement. PMID- 29142731 TI - Fluorescence spectroscopy and microscopy as tools for monitoring redox transformations of uranium in biological systems. AB - We report a study of redox reactions of uranium in model conditions using luminescence spectroscopy, which with its ease and wide availability has the potential to offer new insights into a bioremediation strategy of particular interest - the enzymatic reduction of UVIO22+ by bacteria such as Geobacter sulfurreducens. The inherent luminescent properties of UVIO22+ have been combined with confocal fluorescence microscopy techniques and lifetime image mapping to report directly on uranium concentration, localisation and oxidation state in cellular systems during uranium bioreduction, suggesting that localisation of uranyl species on the cell membrane surface plays an important role and that extracellular biogenic features form alongside uranyl sorbed cellular species during early stages of the bioreduction. The use of confocal microscopy in tandem with lifetime image mapping offers both improved temporal and spatial resolution (nanoseconds to microseconds and sub-micron respectively) than more conventional X-ray based techniques and offers the potential to image redox reactions occurring in situ. Together, these techniques provide an excellent and sensitive probe to assess the coordination environment of uranium during bioreduction processes that are currently being considered for remediation strategies of redox active radionuclides present in contaminated land. PMID- 29142732 TI - Biomimetic versus enzymatic high-potential electrocatalytic reduction of hydrogen peroxide on a functionalized carbon nanotube electrode. AB - We report the non-covalent functionalization of a multi-walled carbon nanotube (MWCNT) electrode with a biomimetic model of the horseradish peroxidase (HRP) active site. By modifying the MWCNT electrode surface with imidazole-modified polypyrrole, a new biomimetic complex of HRP was synthesized on the MWCNT sidewalls via the coordination of imidazole (Im) to the metal centre of iron protoporphyrin IX, affording (Im)(PP)FeIII . Compared to the pi-stacking of non coordinated (PP)FeIII on a MWCNT electrode, the (Im)(PP)FeIII -modified MWCNT electrode exhibits higher electrocatalytic activity with an Imax = 0.52 mA cm-2 for the reduction of H2O2, accompanied by a high onset potential of 0.43 V vs. Ag/AgCl. The performances of these novel surface-confined HRP mimics were compared to those of a MWCNT electrode modified by HRP. Although the enzyme electrode displays a higher electrocatalytic activity towards H2O2 reduction, the (Im)(PP)FeIII -modified MWCNT electrode exhibits a markedly higher operational stability, retaining 63% of its initial activity after one month. PMID- 29142733 TI - Enhancing electron affinity and tuning band gap in donor-acceptor organic semiconductors by benzothiadiazole directed C-H borylation. AB - Electrophilic borylation using BCl3 and benzothiadiazole to direct the C-H functionalisation of an adjacent aromatic unit produces fused boracyclic materials with minimally changed HOMO energy levels but significantly reduced LUMO energy levels. In situ alkylation and arylation at boron using Al(alkyl)3 or Zn(aryl)2 is facile and affords boracycles that possess excellent stability towards protic solvents, including water, and display large bathochromic shifts leading to far red/NIR emission in the solid state with quantum yields of up to 34%. Solution fabricated OLEDs with far red/NIR electroluminescence are reported with EQEs > 0.4%. PMID- 29142734 TI - Methanol-to-hydrocarbons conversion over MoO3/H-ZSM-5 catalysts prepared via lower temperature calcination: a route to tailor the distribution and evolution of promoter Mo species, and their corresponding catalytic properties. AB - A series of MoO3/H-ZSM-5 (Si/Al = 25) catalysts were prepared via calcination at a lower-than-usual temperature (400 degrees C) and subsequently evaluated in the methanol-to-hydrocarbon reaction at that same temperature. The catalytic properties of those catalysts were compared with the sample prepared at the more conventional, higher temperature of 500 degrees C. For the lower temperature preparations, molybdenum oxide was preferentially dispersed over the zeolite external surface, while only the higher loading level of MoO3 (7.5 wt% or higher) led to observable inner migration of the Mo species into the zeolite channels, with concomitant partial loss of the zeolite Bronsted acidity. On the MoO3 modified samples, the early-period gas yield, especially for valuable propylene and C4 products, was noticeably accelerated, and is gradually converted into an enhanced liquid aromatic formation. The 7.5 wt% MoO3/H-ZSM-5 sample prepared at 400 degrees C thereby achieved a balance between the zeolite surface dispersion of Mo species, their inner channel migration and the corresponding effect on the intrinsic Bronsted acidity of the acidic zeolite. That loading level also possessed the highest product selectivity (after 5 h reaction) to benzene, toluene and xylenes, as well as higher early-time valuable gas product yields in time-on-stream experiments. However, MoO3 loading levels of 7.5 wt% and above also resulted in earlier catalyst deactivation by enhanced coke accumulation at, or near, the zeolite channel openings. Our research illustrates that the careful adoption of moderate/lower temperature dispersion processes for zeolite catalyst modification gives considerable potential for tailoring and optimizing the system's catalytic performance. PMID- 29142735 TI - Enantioselective palladium(0)-catalyzed intramolecular cyclopropane functionalization: access to dihydroquinolones, dihydroisoquinolones and the BMS 791325 ring system. AB - Taddol-based phosphoramidite ligands enable enantioselective palladium(0) catalyzed C-H arylation of cyclopropanes. The cyclized products are obtained in high yields and enantioselectivities. The reported method provides efficient access to a broad range of synthetically attractive cyclopropyl containing dihydroquinolones and dihydroisoquinolones as well as allows for an efficient enantioselective construction of the 7-membered ring of the cyclopropyl indolobenzazepine core of BMS-791325. PMID- 29142736 TI - Strain differences in cuprizone induced demyelination. AB - Background: Multiple sclerosis (MS) is a severe neurological disorder, characterized by demyelination of the central nervous system (CNS), and with a prevalence of greater than 2 million people worldwide. In terms of research in MS pathology, the cuprizone toxicity model is widely used. Here we investigated the contribution of genetic differences in response to cuprizone-induced demyelination in two genetically different mouse strains: CD1 and C57BL/6. Results: We demonstrate that exposure to a diet containing 0.2% cuprizone resulted in less severe demyelination in the midline of the corpus callosum over the fornix in CD1 mice than C57BL/6 mice. With continuous cuprizone feeding, demyelination in CD1 mice was not prominent until after 7 weeks, in contrast to C57BL/6 mice, which showed prominent demyelination after 4 weeks of exposure. Concomitantly, immunohistochemical analysis demonstrated more oligodendrocytes, as well as fewer oligodendrocyte progenitor cells, microglia and astrocytes in cuprizone treated CD1 mice. We also analyzed 4-weeks-cuprizone treated corpus callosum tissue samples and found that cuprizone treated CD1 mice showed a smaller reduction of myelin-associated glycoprotein (MAG) and a smaller increase of Iba1 and NG2. Conclusions: These observations suggest that CD1 mice are less vulnerable to cuprizone-induced demyelination than C57BL/6 mice and thus genetic background factors appear to influence the susceptibility to cuprizone-induced demyelination. PMID- 29142737 TI - Cloning, expression and identification of KTX-Sp4, a selective Kv1.3 peptidic blocker from Scorpiops pococki. AB - Background: Specific and selective peptidic blockers of Kv1.3 channels can serve as a valuable drug lead for treating T cell-mediated autoimmune diseases, and scorpion venom is an important source of kv1.3 channel inhibitors. Through conducting transcriptomic sequencing for the venom gland of Scorpiops pococki from Xizang province of China, this research aims to discover a novel functional gene encoding peptidic blocker of Kv1.3, and identify its function. Results: We screened out a new peptide toxin KTX-Sp4 which had 43 amino acids including six cysteine residues. Electrophysiological experiments indicated that recombinant expression products of KTX-Sp4 blocked both endogenous and exogenous Kv1.3 channel concentration-dependently, and exhibited good selectivity on Kv1.3 over Kv1.1, Kv1.2, respectively. Mutation experiments showed that the Kv1 turret region was responsible for the selectivity of KTX-Sp4 peptide on Kv1.3 over Kv1.1. Conclusions: This work not only provided a novel lead compound for the development of anti autoimmune disease drugs, but also enriched the molecular basis for the interaction between scorpion toxins and potassium channels, serving as an important theoretical basis for designing high selective Kv1.3 peptide inhibitors. PMID- 29142739 TI - Classification of amyotrophic lateral sclerosis disease based on convolutional neural network and reinforcement sample learning algorithm. AB - Electromyogram (EMG) signals contain useful information of the neuromuscular diseases like amyotrophic lateral sclerosis (ALS). ALS is a well-known brain disease, which can progressively degenerate the motor neurons. In this paper, we propose a deep learning based method for efficient classification of ALS and normal EMG signals. Spectrogram, continuous wavelet transform (CWT), and smoothed pseudo Wigner-Ville distribution (SPWVD) have been employed for time-frequency (T F) representation of EMG signals. A convolutional neural network is employed to classify these features. In it, Two convolution layers, two pooling layer, a fully connected layer and a lost function layer is considered in CNN architecture. The CNN architecture is trained with the reinforcement sample learning strategy. The efficiency of the proposed implementation is tested on publicly available EMG dataset. The dataset contains 89 ALS and 133 normal EMG signals with 24 kHz sampling frequency. Experimental results show 96.80% accuracy. The obtained results are also compared with other methods, which show the superiority of the proposed method. PMID- 29142738 TI - Methods and approaches of utilizing ionic liquids as gas sensing materials. AB - Gas monitoring is of increasing significance for a broad range of applications in the fields of environmental and civil infrastructures, climate and energy, health and safety, industry and commerce. Even though there are many gas detection devices and systems available, the increasing needs for better detection technologies that not only satisfy the high analytical standards but also meet additional device requirements (e.g., being robust to survive under field conditions, low cost, small, smart, more mobile), demand continuous efforts in developing new methods and approaches for gas detection. Ionic Liquids (ILs) have attracted a tremendous interest as potential sensing materials for the gas sensor development. Being composed entirely of ions and with a broad structural and functional diversity, i.e., bifunctional (organic/inorganic), biphasic (solid/liquid) and dual-property (solvent/electrolyte), they have the complementing attributes and the required variability to allow a systematic design process across many sensing components to enhance sensing capability especially for miniaturized sensor system implementation. The emphasis of this review is to describe molecular design and control of IL interface materials to provide selective and reproducible response and to synergistically integrate IL sensing materials with low cost and low power electrochemical, piezoelectric/QCM and optical transducers to address many gas detection challenges (e.g., sensitivity, selectivity, reproducibility, speed, stability, cost, sensor miniaturization, and robustness). We further show examples to justify the importance of understanding the mechanisms and principles of physicochemical and electrochemical reactions in ILs and then link those concepts to developing new sensing methods and approaches. By doing this, we hope to stimulate further research towards the fundamental understanding of the sensing mechanisms and new sensor system development and integration, using simple sensing designs and flexible sensor structures both in terms of scientific operation and user interface that can be miniaturized and interfaced with modern wireless monitoring technologies to achieve specifications heretofore unavailable on current markets for the next generation of gas sensor applications. PMID- 29142740 TI - Combined empirical mode decomposition and texture features for skin lesion classification using quadratic support vector machine. AB - Purpose: Basal cell carcinoma is one of the most common malignant skin lesions. Automated lesion identification and classification using image processing techniques is highly required to reduce the diagnosis errors. Methods: In this study, a novel technique is applied to classify skin lesion images into two classes, namely the malignant Basal cell carcinoma and the benign nevus. A hybrid combination of bi-dimensional empirical mode decomposition and gray-level difference method features is proposed after hair removal. The combined features are further classified using quadratic support vector machine (Q-SVM). Results: The proposed system has achieved outstanding performance of 100% accuracy, sensitivity and specificity compared to other support vector machine procedures as well as with different extracted features. Conclusion: Basal Cell Carcinoma is effectively classified using Q-SVM with the proposed combined features. PMID- 29142741 TI - Statistical sleep pattern modelling for sleep quality assessment based on sound events. AB - A good sleep is important for a healthy life. Recently, several consumer sleep devices have emerged on the market claiming that they can provide personal sleep monitoring; however, many of them require additional hardware or there is a lack of scientific evidence regarding their reliability. In this paper we proposed a novel method to assess the sleep quality through sound events recorded in the bedroom. We used subjective sleep quality as training label, combined several machine learning approaches including kernelized self organizing map, hierarchical clustering and hidden Markov model, obtained the models to indicate the sleep pattern of specific quality level. The proposed method is different from traditional sleep stage based method, provides a new aspect of sleep monitoring that sound events are directly correlated with the sleep of a person. PMID- 29142742 TI - Supporting breast cancer decisions using formalized guidelines and experts decision patterns: initial prototype and evaluation. AB - Transparent decisions and its documentation of breast cancer patients' therapy are getting more important especially since modern therapeutic approaches favor personalized forms of treatment. The medical decisions for a treatment are very complex, because there are rules and different options for each patient. To support the decision process, we analyzed the current decision rules and implemented them in a prototype of a rule-based expert system. Thus, this system shall support the quality assurance regarding transparent documentation of individualized therapeutic decisions. For evaluating the system, we used data from a state tumor center and compared the decisions suggested by our system with expert ones. The system and the expert approach will be compared with each other as well as the differences in the treatment decisions. The first preliminary results show us that the human factor-like must be considered by creating a decision support system. The prototype delivers first results, which are restricted, but the results are promising for further developments. PMID- 29142743 TI - Anti-Candida activity of antimicrobial impregnated central venous catheters. AB - Background: Whenever the rate of central line-associated bloodstream infections (CLABSIs) remains high even after the implementation of preventive strategies, the use of chlorhexidine/silver sulfadiazine (CSS) or minocycline/rifampin (MR) impregnated central venous catheters (CVCs) is currently recommended. Nevertheless, the efficacy of such CVCs against Candida albicans and other emerging non-albicans spp. has been insufficiently studied. This study aims to compare the activity of CSS and MR-impregnated CVCs against the yeasts most frequently isolated from CLABSIs. Methods: For biofilm formation assays, type strains and clinical isolates of C. albicans, C. glabrata and C. parapsilosis sensu stricto were used. Segments of standard polyurethane, MR and second generation CSS-CVCs were tested. The biofilm metabolic activity was measured by a semi-quantitative XTT reduction assay. Results: CSS catheter segments significantly reduced the biofilm metabolic activity by all tested Candida spp., with inhibition ranging from 60% to 100%. The MR catheter segments promoted C. albicans and C. parapsilosis biofilm formation and exhibited an inconspicuous effect against C. glabrata. Conclusions: Among the recommended antimicrobial CVCs, CSS-CVCs proved to be superior in the inhibition of biofilm formation by the most frequent yeasts causing CLABSIs. Data from this in vitro study may suggest that patients at high risk for invasive candidosis could benefit from the use of CSS-CVCs. PMID- 29142744 TI - "Who has to do it at the end of the day? Programme officials or hospital authorities?" Airborne infection control at drug resistant tuberculosis (DR-TB) centres of Karnataka, India: a mixed-methods study. AB - Background: Drug resistant tuberculosis (DR-TB) centers admit patients with DR-TB for initiation of treatment and thereby concentrate the patients under one setting. It becomes imperative to assess the compliance of DR-TB centres to national airborne infection control (AIC) guidelines and explore the provider perspectives into reasons for unsatisfactory compliance. Methods: This mixed methods study (triangulation design) was carried out across all the six DR-TB centers of Karnataka state, India, between November 2016 and April 2017. Non participant observation using a structured format was carried out at the DR-TB wards (n = 6), outpatient departments (n = 6), patient waiting areas outside outpatient departments (n = 6) and culture and drug susceptibility testing laboratories (n = 3). Structured interviews of admitted patients (n = 30) were done to assess the knowledge on cough hygiene and sputum disposal. Key informant interviews (KIIs) of health care providers (n = 20) were done. Manual descriptive content analysis was done to analyse the transcripts of KIIs. Results: The findings related to compliance in non-participant observation were corroborated by KIIs. All the laboratories were consistently implementing the AIC guidelines. Compliance to hand hygiene, wet mopping and ventilation measures were satisfactory in four or more DR-TB wards. The non-availability of N95 masks in wards as well as outpatient departments was staggering. Sputum disposal without prior disinfection and the lack of display materials on cough hygiene and patient education was common. Patient fast tracking in outpatient department waiting areas and visitor restrictions in wards were lacking. Trainings on AIC measures were uncommon. About half and one-third of patients admitted had satisfactory knowledge regarding sputum disposal and situations demanding mask respectively. The reasons for unsatisfactory compliance to AIC guidelines were poor coordination between programme and hospital authorities leading to lack of ownership; ineffective or non-existent infection control committees; vacant posts of medical officers; and attitudes of health care delivery staff. Conclusion: Compliance with AIC guidelines in DR-TB centers of Karnataka was sub-optimal. The reasons identified require urgent attention of the programme managers and hospital authorities. PMID- 29142745 TI - Determinants of prenatal anemia in Ethiopia. AB - Background: Anemia is responsible for 20% of maternal mortality worldwide, and it is associated with premature birth, low birth weight, and infant mortality. In Ethiopia, about 22% of pregnant women are anemic. However, literatures are limited, therefore, this study aimed to investigate the prevalence and associated factors of anemia among pregnant women attending antenatal care (ANC) in Asossa Zone Public Health Institutions, northwest Ethiopia. Methods: A facility based cross-sectional study was conducted from February to March 2016. Data were collected by interviewer administered, pretested and structured questionnaires. A multi-stage sampling technique was used to select 762 pregnant women. The hemoglobin level was determined by taking 5 ml of venous blood using Sahli's method. A multivariate binary logistic regression model was fitted to identify factors associated with anemia. Adjusted Odds Ratio (AOR) with a 95% Confidence Interval (CI) was computed to show the strength of association and statistical significance was determined at a P-value of <0.05. Results: The prevalence of anemia was 31.8% [95% CI: 28.9, 35.5]. In the adjusted analysis, maternal age of 30-34 years [AOR = 0.34, 95% CI: 0.14, 0.86], household size of >=6 [AOR = 4.27, 95% CI: 1.58, 11.45], dietary diversity [AOR = 0.58, 95% CI: 0.38, 0.93], no meat consumption [AOR = 1.80, 95% CI: 1.11, 2.91], not drinking soft beverages [AOR =1.96, 95% CI: 1.19, 3.23], undernutrition [AOR = 7.38, 95% CI: 4.22, 12.91], not consuming fruits [AOR = 3.29, 95% CI: 1.59, 6.82], inter-pregnancy interval of >=2 years [AOR = 0.59, 95% CI: 0.34, 0.99], and third trimester of pregnancy [AOR = 0.33, 95% CI: 0.20, 0.57] were significantly associated with anemia. Conclusions: The prevalence of prenatal anemia is high in the Asossa Zone; suggesting a moderate public health concern. Socio-demographic and dietary intake characteristics were significantly associated with anemia. Therefore, improving dietary diversity and animal food consumption are the key to reduce the high burden of anemia. It is also important to strengthen interventions aiming to reduce closed birth interval and teenage pregnancy. PMID- 29142746 TI - Interaction between Merkel cell carcinoma and the immune system: Pathogenetic and therapeutic implications. AB - Merkel cell carcinoma (MCC) is a rare, aggressive primary cutaneous neuroendocrine carcinoma. It usually appears on the face and neck of elderly Caucasian people as a flesh-colored, erythematous or violaceous dome-shaped, non tender nodule with a smooth surface. In immunocompromised patients with T-cell dysfunction, such as patients with acquired immunodeficiency syndrome (AIDS) or solid organ transplant recipients, the incidence of this disease is markedly increased. This suggests a link between the development of MCC and the immune system. Merkel cell polyolmavirus (MCPyV) is clonally integrated into the majority of MCCs, suggesting its causative role in the pathogenesis of the majority of these tumors. Despite wide local excision, sentinel lymph node biopsy, and eventually, adjuvant radiation therapy, which remains the first-line treatment for MCC, the identification of MCPyV has opened novel therapeutic insights. Novel therapeutic strategies could be to inhibit MCPyV oncoproteins and to stimulate immune responses against virus-infected tumor cells by immunostimulatory cytokines, including interferons and interleukin-2. PMID- 29142747 TI - Clinical characteristics of critically ill cancer patients who are undergoing isolated limb perfusion. AB - The aim of the present study was to investigate the incidence of organ dysfunction, and to describe the clinical characteristics and intensive care unit (ICU) outcomes of critically ill cancer patients who were admitted to an oncological ICU during the isolated limb perfusion post-operative period. The present study was an observational investigation of 42 critically ill cancer patients who were admitted to the ICU of the Instituto Nacional de Cancerologia, during the isolated limb perfusion post-operative period, between July 2010 and February 2016. The mean age of the patients was 45.7+/-16.9 years, and 45.2% (19 cases) were female. Soft tissue sarcoma was the most common pre-operative diagnosis (38.1%), and the mean duration of surgery was 267.6+/-50.1 min. Furthermore, a mean blood loss volume of 732.3+/-526.1 ml during the procedure was recorded, and the patients received a mean volume of 3.88+/-1.28 l crystalloid fluid during the surgical procedure, subsequently requiring an additional 2.95+/-6.28 l on the first post-operative day. The incidence of organ dysfunction was 90.5% and was most frequently noted in the respiratory (81%), hepatic (33%), hematologic (31%) and renal (11.9%) systems. No patients succumbed to the disease during the ICU and hospital stay. Nevertheless, <10% of the patients required vasopressors. Additionally, <5% of the patients required invasive mechanical ventilation. Therefore, ICU admission directly following isolated limb perfusion should not be standardized. PMID- 29142748 TI - Intraoperative prediction of the two axillary lymph node macrometastases threshold in patients with breast cancer using a one-step nucleic acid cytokeratin-19 amplification assay. AB - The aim of the present study was to assess the sensitivity, specificity and practicality of using a one-step nucleic acid amplification (OSNA) assay during breast cancer staging surgery to predict and discriminate between at least 2 involved nodes and more than 2 involved nodes and facilitate the decision to provide axillary conservation in the presence of a low total axillary node tumour burden. A total of 700 consecutive patients, not treated with neo-adjuvant chemotherapy, received intraoperative sentinel lymph node (SLN) analysis using OSNA for cT1-T3 cN0 invasive breast cancer. Patients with at least one macrometastasis on whole-node SLN analysis underwent axillary lymph node dissection (ALND). The total tumour load (TTL) of the macrometastatic SLN sample was compared with the non-sentinel lymph node (NSLN) status of the ALND specimen using routine histological assessment. In total, 122/683 patients (17.9%) were found to have an OSNA TTL indicative of macrometastasis. In addition, 45/122 (37%) patients had NSLN metastases on ALND with a total positive lymph node burden exceeding the American College of Surgeons Oncology Group Z0011 trial threshold of two macrometastatic nodes. The TTL negative predictive value was 0.975 [95% confidence interval (CI), 0.962-0.988]. The area under the curve for the receiver operating characteristic curve was 0.86 (95% CI, 0.81-0.91), indicating that SLN TTL was associated with the prediction (and partitioning) of total axillary disease burden. OSNA identifies a TTL threshold value where, in the presence of involved SLNs, ALND may be avoided. This technique offers objective confidence in adopting conservative management of the axilla in patients with SLN macrometastases. PMID- 29142749 TI - Urine metabolomics as a predictor of patient tolerance and response to adjuvant chemotherapy in colorectal cancer. AB - Colorectal cancer is the third leading cause of cancer-associated mortality in the western world. The ability to predict a patient's response to chemotherapy may be of great value for clinicians and patients when planning cancer treatment. The aim of the current study was to develop a urine metabolomics-based biomarker panel to predict adverse events and response to chemotherapy in patients with colorectal cancer. A retrospective chart review of patients diagnosed with stage III or IV colorectal cancer between 2008 and 2012 was performed. The exclusion criteria included chemotherapy for palliation and patients living outside of Alberta. Data was collected concerning the chemotherapy regimen, adverse events associated with chemotherapy, disease progression and recurrence and 5-year survival. Adverse events were subdivided as follows: Delays in treatment, dose reductions, hospitalizations and chemotherapy regime changes. Patients provided urine samples for analysis prior to any intervention. Nuclear magnetic resonance (NMR) spectra of urine samples were acquired. The 1H NMR spectrum of each urine sample was analyzed using Chenomx NMRSuite v7.0. Using machine learning, predictors were generated and evaluated using 10-fold cross-validation. Urine spectra were obtained for 62 patients. The best predictors resulted in area under the receiver operating characteristic curve values of: 0.542 for chemotherapy dose reduction, 0.612 for 5-year survival, 0.650 for cancer recurrence and 0.750 for treatment delay. Therefore, predictors were developed for response to and adverse events from chemotherapy for patients with colorectal cancer patients. The predictor for treatment delay has the most promise, and further studies will aid its refinement and improvement of its accuracy. PMID- 29142750 TI - Evaluation of epidermal growth factor receptor serum levels and their association with clinicopathological characteristics in patients with colorectal cancer. AB - Colorectal cancer (CRC) is a major public health concern and one of the leading causes of cancer-related mortality worldwide. The aim of the present study was to determine the serum epidermal growth factor receptor (sEGFR) levels in healthy volunteers and patients with CRC, to determine the association between tumor marker levels and clinicopathological findings, and investigate its prognostic value. A total of 140 patients with CRC were enrolled in the present study. Pre treatment sEGFR levels were determined using ELISA. A total of 40 age- and sex matched healthy controls were included in the analysis. The median age of patients was 60 years (range, 24-84 years); the majority of the tumor localization was to the colon (n=81, 58%). The median follow-up time was 14 months, while 43 (31%) patients experienced disease progression and 31 (22%) succumbed to the disease. A total of 81 patients (58%) were in the early stages of disease (stage II and III), and 42% of the patients had stage IV disease. The estimated 2-year overall and 1-year progression-free survival rates for the whole patient group were 70% [95% confidence interval (CI): 58.8-81.2] and 26.2% (95% CI: 12.9-39.5), respectively. The number of patients who received neoadjuvant treatment was 37. Of the patients who were administered palliative treatment, 24 received oxaliplatin, whereas 22 received irinotecan and 9 received fluorouracil/capecitabine. A total of 36 and 15 of the patients who received targeted therapy were administered bevacizumab and cetuximab, respectively. Of the 55 patients with metastatic disease who received palliative chemotherapy (CTx), 31% were CTx-responsive. The baseline median sEGFR levels were significantly higher in patients with CRC compared with the healthy control group (P=0.002). In addition, established clinical variables, including no surgical resection, metastatic stage, higher pathological tumor stage, poorer regression score (3-4) and higher lactate dehydrogenase levels, were found to be associated with higher sEGFR levels (P=0.03, P=0.009, P=0.05, P=0.05 and P=0.05, respectively). The results of the present study did not reveal statistically significant associations between sEGFR concentrations and overall and progression free survival rates. In conclusion, sEGFR concentrations may be diagnostic markers in patients with CRC; however, their predictive and prognostic values were not determined. PMID- 29142751 TI - Hepatic epithelioid hemangioendothelioma with metastasis to the mesentery of the small intestine: A case report. AB - Epithelioid hemangioendothelioma (EHAE) is a vascular tumor which, due to its rarity, is often misdiagnosed as other hepatic tumors based on radiological characteristics. We herein report a case of EHAE in the liver and the mesentery of the small intestine. A 64-year-old asymptomatic woman was admitted to the hospital due to a hepatic tumor identified using computed tomography (CT). An enhanced CT scan revealed multiple tumors in the liver and a tumor in the mesentery. One of the hepatic tumors and the mesenteric tumor were resected and histologically examined. The two tumors exhibited similar histological characteristics and were diagnosed as EHAE. When multiple tumors are found in the liver, EHAE should be included in the differential diagnosis, as the prognosis of EHAE differs from that of carcinoma or benign tumors. PMID- 29142752 TI - Protective effect of hydrogen-rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy. AB - The present study was conducted to investigate the protective effect of hydrogen rich water on the liver function of colorectal cancer (CRC) patients treated with mFOLFOX6 chemotherapy. A controlled, randomized, single-blind clinical trial was designed. A total of 152 patients with CRC were recruited by the Department of Oncology of Taishan Hospital (Taian, China) between June 2010 and February 2016, among whom 146 met the inclusion criteria. Subsequently, 144 patients were randomized into the treatment (n=80) and placebo (n=64) groups. At the end of the study, 76 patients in the hydrogen treatment group and 60 patients in the placebo group were included in the final analysis. The changes in liver function after the chemotherapy, such as altered levels of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase, indirect bilirubin (IBIL) and direct bilirubin, were observed. The damaging effects of the mFOLFOX6 chemotherapy on liver function were mainly represented by increased ALT, AST and IBIL levels. The hydrogen-rich water group exhibited no significant differences in liver function before and after treatment, whereas the placebo group exhibited significantly elevated levels of ALT, AST and IBIL. Thus, hydrogen-rich water appeared to alleviate the mFOLFOX6-related liver injury. PMID- 29142753 TI - Long-term survival in a patient with metastatic squamous cell lung carcinoma: A case report. AB - Non-small-cell lung cancer (NSCLC) is the most common malignancy in industrialized countries, with a 5-year survival rate of only ~15%, as the majority of the patients have advanced-stage disease at diagnosis and the treatment options are limited. Squamous cell carcinoma the second most frequent type of NSCLC and is closely associated with cigarette smoking. We herein present the case of a 72-year-old male smoker, diagnosed with stage IV squamous cell lung carcinoma, with a solitary brain metastasis. After the diagnosis, stereotactic radiotherapy was performed on the brain metastasis. Following radiotherapy, chemotherapy with carboplatin + paclitaxel was initiated. However, after 2 cycles of chemotherapy, disease progression in the lung was observed. Therefore, second line treatment with pemetrexed was started, which was discontinued after 2 cycles due to further disease progression. Third-line treatment with erlotinib was then administered, with notable benefit, as the patient remains alive after 6 years of treatment with a good performance status. The mutation status of EGFR was unknown. PMID- 29142754 TI - Inviting eating disorder patients to discuss the academic literature: a model program for psychoeducation. AB - Background: Psychoeducation initiatives in which patients read primary scientific literature have not yet been studied as a treatment intervention for eating disorders. In this paper, we discuss and evaluate the acceptability of a novel psychoeducational journal club for individuals with anorexia and bulimia nervosa in inpatient and partial hospitalization program settings. Primary literature about eating disorders is presented and discussed with patients. By presenting scientifically-supported information, our "Psychoeducational Research Group" is designed to help patients restructure disordered thoughts and encourage adherence to evidence-based treatment. Methods: Using a Likert scale questionnaire (0 = not at all; 5 = very much), participants provided ratings for how much they liked the group and felt that it helped them across several domains. Results: Average scores from 33 participants (26 inpatient, 7 partial hospital patients) indicated they would recommend this group to others receiving eating disorder treatment (4.8 +/- 0.6). Scores also suggested patients' likeability (4.6 +/- 0.8), benefit regarding challenging eating disorder thoughts (4.1 +/- 1.1), improved motivation for eating behavior change (4.0 +/- 1.0) and completion of prescribed nutritional plan (3.6 +/- 1.0), and usefulness in working towards treatment goals (4.2 +/- 0.9) associated with group participation. Conclusions: Preliminary findings support the acceptability of this psychoeducational group and that it may serve as a useful adjunct to larger evidence-based programming across eating disorder treatment settings. PMID- 29142755 TI - Time versus energy minimization migration strategy varies with body size and season in long-distance migratory shorebirds. AB - Background: Migrants have been hypothesised to use different migration strategies between seasons: a time-minimization strategy during their pre-breeding migration towards the breeding grounds and an energy-minimization strategy during their post-breeding migration towards the wintering grounds. Besides season, we propose body size as a key factor in shaping migratory behaviour. Specifically, given that body size is expected to correlate negatively with maximum migration speed and that large birds tend to use more time to complete their annual life-history events (such as moult, breeding and migration), we hypothesise that large-sized species are time stressed all year round. Consequently, large birds are not only likely to adopt a time-minimization strategy during pre-breeding migration, but also during post-breeding migration, to guarantee a timely arrival at both the non-breeding (i.e. wintering) and breeding grounds. Methods: We tested this idea using individual tracks across six long-distance migratory shorebird species (family Scolopacidae) along the East Asian-Australasian Flyway varying in size from 50 g to 750 g lean body mass. Migration performance was compared between pre and post-breeding migration using four quantifiable migratory behaviours that serve to distinguish between a time- and energy-minimization strategy, including migration speed, number of staging sites, total migration distance and step length from one site to the next. Results: During pre- and post-breeding migration, the shorebirds generally covered similar distances, but they tended to migrate faster, used fewer staging sites, and tended to use longer step lengths during pre-breeding migration. These seasonal differences are consistent with the prediction that a time-minimization strategy is used during pre-breeding migration, whereas an energy-minimization strategy is used during post-breeding migration. However, there was also a tendency for the seasonal difference in migration speed to progressively disappear with an increase in body size, supporting our hypothesis that larger species tend to use time-minimization strategies during both pre- and post-breeding migration. Conclusions: Our study highlights that body size plays an important role in shaping migratory behaviour. Larger migratory bird species are potentially time constrained during not only the pre- but also the post-breeding migration. Conservation of their habitats during both seasons may thus be crucial for averting further population declines. PMID- 29142756 TI - Usefulness of central venous saturation as a predictor of thiamine deficiency in critically ill patients: a case report. AB - Background: Central venous oxygen saturation (ScvO2) reflects the balance of oxygen delivery and consumption. Low ScvO2 indicates the presence of inadequate oxygen delivery, while high ScvO2 indicates reduced oxygen consumption and is sometimes associated with a high mortality rate in critically ill patients from dysoxia. Thiamine is an essential cofactor in cellular aerobic metabolism. Thiamine deficiency is more prevalent than was previously thought, and underlies severe conditions in critically ill patients. However, currently, there is no rapid diagnostic test for thiamine deficiency. Considering oxygen flux, high ScvO2 might be associated with thiamine deficiency. Case presentation: A 70-year old man admitted to the hospital with chief complaint of malaise and edema. He was diagnosed with heart failure with preserved ejection function and was treated with loop diuretics, which resulted in shock. Venoarterial extracorporeal membrane oxygenation and intra-aortic balloon pumping was indicated. The right heart catheter showed high ScvO2, normal cardiac output, and low systemic vascular resistance. Thiamine deficiency was suspected and we started the thiamine infusion. His hemodynamic status improved after thiamine replacement. After his recovery, it was discovered that he had a 1-month history of anorexia and thiamine deficiency. His final diagnosis was beriberi. Conclusions: The current case showed the relation between thiamine deficiency and high ScvO2. A literature review also suggested that thiamine deficiency is associated with high ScvO2. Thiamine deficiency causes impaired tissue oxygen extraction, which could lead to high ScvO2. In this context, high ScvO2 might serve as a predictor of thiamine deficiency in critically ill patients. PMID- 29142757 TI - Correlates of maternal mortality in developing countries: an ecological study in 82 countries. AB - Background: Maternal mortality is a major public health issue in developing countries due to its shocking magnitude and lower declining pattern. With appropriate strategy and intensive implementation programs, some countries have made remarkable progress, however in developing countries where 99% of maternal death is occurring; little or no progress has been made. Identifying determinants and designing intervention will have important role to overcome the problem. Therefore this study aimed to identify correlates of maternal mortality in developing countries. Methods: This study was conducted using international data bases of health metrics from 2008 to 2016 using aggregates of health indicator data from WHO, World Bank, UNDP and UNICEF data bases for 82 developing countries. The dependent variable was the maternal mortality ratio, while the independent variable was socio-economic, health care related and morbidity variables. Data was compiled in excel and analyzed using SPSS version 21. Results: Maternal mortality ratio is very high in developing countries and enormously varies among countries. A significant relationship between the maternal mortality ratio and socio-economic, health care and morbidity indicator variables was observed. There was an inverse and significant correlation of the maternal mortality ratio with Antenatal care coverage, skilled birth attendance, access to an improved water source and sanitation, adult literacy rate, the Gross National Income per capita and positive relation with disease incidence, unmet need and others. Conclusions: Maternal mortality is correlated with multiples of socio-economic factors, health care system associated factors, disease burden and their complex interactions. Therefore Policy and programs targeted to improve maternal health and reduce maternal deaths should consider population dynamics, socio-economic influence and health system factors that impose a major risk on mothers. PMID- 29142758 TI - Ethnic differences in patients' perceptions towards isolated orthopedic injuries: a pilot study. AB - Background: Patients' perceptions of their healthcare have been reported to influence clinical outcomes following orthopedic trauma. Findings across clinical outcomes have demonstrated significant differences in perceptions towards healthcare between Hispanics and non-Hispanic whites. However, ethnic disparities in perceptions towards orthopedic injuries have not been examined in the literature. Aim of study: The aim of this pilot study is to explore whether Hispanic patients with isolated orthopedic injuries will demonstrate different perceptions towards their injury as compared to non-Hispanic white patients. The pilot data will be used to inform a subsequent larger clinical investigation and interventional study. Methods: A total of 43 patients (31 Hispanics and 12 non Hispanic whites) with isolated orthopedic injuries requiring surgical treatment were enrolled in this cross-sectional observational pilot study. Outcome measures included the Questionnaire of Perceived Injustice (QPI), Short-Form 36 Health Survey (SF-36v2), Pain Catastrophizing Scale, and Consumer Assessment of Healthcare Providers and Systems (CAHPS) Cultural Competence (CC) item set. Results: The CAHPS was completed by 34 patients, and the remaining scoring systems were completed by all 43 subjects enrolled in this study. Hispanic patients trended towards higher QPI scores indicating poorer outcomes than non Hispanic whites (mean difference [MD] 5.4, 95%; confidence interval [CI] - 4.4, 15.2). The mental component summary score of the SF-36 trended lower in Hispanics as compared to non-Hispanic white (MD - 6.8, 95%; CI - 15.0, 1.4). Hispanic patients also expressed less trust in their doctor on a scale from 0 to 10 (MD - 1.0, 95%; CI - 1.9, - 0.1). Conclusions: Our study suggests ethnic differences in patients' perceptions towards isolated orthopedic injuries. These results must be interpreted cautiously given the limited number of subjects in this pilot examination. We collected sufficient data to allow a sample size calculation for a subsequent larger clinical investigation. Future clinical investigations may determine the influence of ethnic differences in patients' perceptions towards orthopedic injuries, identify their impact on the functional outcomes, and establish intervention strategies. PMID- 29142759 TI - Forced migrants involved in setting the agenda and designing research to reduce impacts of complex emergencies: combining Swarm with patient and public involvement. AB - Plain English summary: The UK's National Institute for Health Research (NIHR) Health Protection Research Unit in Emergency Preparedness and Response was asked to undertake research on how to reduce the impact of complex national/international emergencies on public health. How to focus the research and decide on priority topics was challenging, given the nature of complex events. Using a type of structured brain-storming, the researchers identified the ongoing UK, European and international migration crisis as both complex and worthy of deeper research. To further focus the research, two representatives of forced migrant communities were invited to join the project team as patient and public (PPI) representatives. They attended regular project meetings, insightfully contributed to and advised on practical aspects of potential research areas. The representatives identified cultural obstacles and community needs and helped choose the final research study design, which was to interview forced migrants about their strategies to build emotional resilience and prevent mental illness. The representatives also helped design recruitment documents, and undertake recruitment and interviewer training. Abstract: Background: Many events with wide-ranging negative health impacts are notable for complexity: lack of predictability, non-linear feedback mechanisms and unexpected consequences. A multi-disciplinary research team was tasked with reducing the public health impacts from complex events, but without a pre-specified topic area or research design. This report describes using patient and public involvement within an adaptable but structured development process to set research objectives and aspects of implementation. Methods: An agile adaptive development approach, sometimes described as swarm, was used to identify possible research areas. Swarm is meant to quickly identify strengths and weaknesses of any candidate project, to accelerate early failure before resources are invested. When aspects of the European migration crisis were identified as a potential priority topic area, two representatives of forced migrant communities were recruited to explore possible research ideas. These representatives helped set the specific research objectives and advised on aspects of implementation, still within the swarm framework for project development. Results: Over ten months, many research ideas were considered by the collaborative working group in a series of six group meetings, supplemented by email contact in between. Up to four possible research ideas were scrutinised at any one meeting, with a focus on identifying practical or desirable aspects of each proposed project. Interest settled on a study to solicit original data about successful strategies that forced migrants use to adapt to life in the UK, with an emphasis on successfully promoting resilience and minimizing emotional distress. "Success in resettlement" was identified to be a more novel theme than "barriers to adaption" research. A success approach encourages participation when individuals may find discussion of mental illness stigmatising. The patient representatives helped with design of patient-facing and interview training materials, interviewer training (mock interviews), and aspects of the recruitment. Conclusion: Using patient and public involvement (PPI) within an early failure development approach that itself arises from theory on complex adaptive systems, we successfully implemented a dynamic development process to determine research topic and study design. The PPI representatives were closely involved in setting research objectives and aspects of implementation. PMID- 29142760 TI - Outcomes of primary endoresection for choroidal melanoma. AB - Purpose: To review long time treatment results in patients with small or medium sized choroidal melanoma who underwent surgical tumor endoresection as a primary treatment when plaque radiotherapy was unable and patients declined enucleation. Materials and methods: Patients were evaluated for best corrected visual acuity (BCVA), and underwent biomicroscopy, indirect ophthalmoscopy, retinography and ultrasound as well as the usual systemic workup. Study inclusion required the absence of scleral invasion or metastasis and an anterior margin not exceeding the pars plana or the ciliary body. Surgery consisted of a clear lens phacoemulsification with a PC-IOL, and a 23-gauge pars plana vitrectomy with anterior vitreous shave, lesional choroidal endodiathermy, followed by 23-gauge probe tumor endoresection and continuous endolaser. Patients were followed at post-operative 1 day, 1 week, 1, 3, and 6 months and then every 6 months with a complete ophthalmological exam including ultrasound biomicroscopy and systemic follow-up at 3, 6 and every 6 months thereafter. Results: Fourteen patients with choroidal melanoma were included the study. Pre-operative BCVA ranged from 20/20 to hand motion (HM): 20/20 (n = 2); 20/60 (n = 1); and HM (n = 10). Pathological analysis confirmed the diagnosis of uveal melanoma in all cases. Mean follow-up was 54.5 months (45-66 months) with a final BCVA ranging from 20/60 to HM: 20/60 (n = 1); 20/60 to 20/200 (n = 10); and HM (n = 2). The eye retention rate in our study was 100%. No intraocular recurrence was observed. One patient died 12 months after surgery from metastatic disease. Conclusion: Endoresection appears to be an acceptable alternative to enucleation for the treatment of posteriorly localized uveal melanoma, with excellent local control and eye salvage rates. PMID- 29142761 TI - Aeromonas hydrophila utilizes TLR4 topology for synchronous activation of MyD88 and TRIF to orchestrate anti-inflammatory responses in zebrafish. AB - Toll-like receptor 4 (TLR4) plays a critical role in host immunity against Gram negative bacteria. It transduces signals through two distinct TIR-domain containing adaptors, MyD88 and TRIF, which function at the plasma membrane and endosomes, respectively. Using zebrafish Aeromonas hydrophila infection model, we demonstrate that synchronization of MyD88 and TRIF dependent pathways is critical for determining the fate of infection. Zebrafish were infected with A. hydrophila, and bacterial recovery studies suggested its effective persistence inside the host. Histopathological assessment elucidates that A. hydrophila did not provoke inflammatory responses in the spleen. Immunofluorescence revealed the presence of TLR4-bound A. hydrophila on the plasma membrane at 3 h post-infection (p.i.), and inside endosomes 1 day p.i. Quantitative PCR studies suggest that TLR4 activates the downstream pathway of MyD88-IRAK4 axis at early stages followed by a shift to TRIF-TRAF6 axis at late stages of infection coupled with fold increase in NFkappaB. Our results implicated the involvement of p110delta isoform of PI(3)Kinase in this transition. Coupled to this, we noted that the TLR4-TRIF-NFkappaB axis prompted burgeoned secretion of anti-inflammatory cytokines. We observed that A. hydrophila inhibits endosome maturation and escapes to cytoplasm. Significant downregulation of cytosolic-NLR receptors further suggested that A. hydrophila represses pro-inflammatory responses in cytosol aiding its persistence. Our findings suggest a novel role of 'TLR4 topology' in A. hydrophila-induced pathogenesis. We propose that A. hydrophila manipulates translocation of TLR4 and migrates to endosome, where it triggers TRIF-dependent anti-inflammatory responses, interferes with endosomal maturation and escapes to cytosol. Inside the cytosol, A. hydrophila avoids detection by suppressing NLRs, facilitating its survival and ensuing pathogenesis. PMID- 29142762 TI - Analysis of CYP1B1 Gene Mutations in Patients with Primary Congenital Glaucoma. AB - Primary congenital glaucoma (PCG) is the most common type of infantile glaucoma, yet it remains a relatively rare disease, because the disease is often transmitted in an autosomal recessive pattern. However, PCG occurs up to 10 times more frequently in certain ethnic and geographical groups where consanguineous relationships are common. The aim of this study was to investigate the distribution of mutations in the cytochrome P450 1B1 gene ( CYP1B1 ) in patients with PCG among different populations around the world from 2011 until May 2016. We referred to the electronic databases, such as Medline, Clinicalkey, Scopus, and ScienceDirect, to search for articles that were published in this area. Nineteen records were included in this qualitative synthesis. CYP1B1 mutations were assessed in 1,220 patients with PCG and identified in 41.6% of them. According to these studies, 99 mutations including 60 novel mutations were found. Nonsignificant difference in the sex ratio has been reported. This current review shows that consanguinity plays an important role in the PCG pathogenesis and transmission; however, sporadic mutations have been found in some cases. A difference in penetrance was highlighted by some mutations. The CYP1B1 mutations were mostly found in the Middle East and the Maghreb with a rate of 64.8 and 54.4%, respectively, followed by Europe (34.7%), Asia (21.3%), and finally the United States (14.9%). Founder mutations in different geographical areas have been discovered. For instance, the p.Gly61Glu, p.Arg390His, p.Gly61Glu, c.4,339delG, p.E387Lys, and p.Val320Leu were considered founder mutations for Iran/Saudi Arabia, Pakistan, Lebanon, Morocco, Europe, and Vietnam/South Korea, respectively. Many common mutations in different countries were found, such as in Morocco, where its mutations were similar to seven other countries. These findings suggest that the ethnic differences and the geographical distribution of PCG give us a large CYP1B1 mutation pattern. Genetic tests looking for founder and common mutations should be the first step in genetic screening for patients with PCG. PMID- 29142763 TI - Array Characterization of Prenatally Diagnosed 15q26 Microdeletion and 2q37.1 Duplication: Report of a New Case with Multicystic Kidneys and Review of the Literature. AB - We report on a molecular cytogenetic characterization of 15q26 deletion and 2q37.1 duplication in a fetus presenting with intrauterine growth restriction (IUGR), diaphragmatic hernia, multicystic kidneys, left kidney pyelectasis, and clubfeet. A terminal 15q26 deletion and a terminal 2q duplication of at least 10 and 9 Mb, respectively, derived from a maternal translocation, were found. The 15q26 deletion represents a contiguous gene deletion syndrome mainly characterized by IUGR, congenital diaphragmatic hernia, and less frequently kidney defects. This deletion encompasses the IGF1R and COUPTF2 genes, known to lead to fetal growth retardation syndrome. However, kidney malformations are less well known in such conditions, and to the best of our knowledge, no candidate gene has been proposed to date. Here, we review the literature of the 15q26 deletion syndrome and suggest that hypoplastic and multicystic kidneys, the most commonly observed anomalies in this condition, should be considered in the prenatal diagnosis setting. Based on COUPTF2 protein function, we hypothesize that its haploinsufficiency might be responsible for the renal pathology. PMID- 29142764 TI - Determining Nt-proBNP Levels with Diastolic Dysfunction in Thalassemia Major Patients. AB - Beta thalassemia is an autosomal, recessive disorder, characterized by ineffective erythropoiesis. Chronic transfusions and inability of body to eliminate iron lead to an iron overload, thereby causing damage to heart. Natriuretic peptides (NPs) are produced within the heart, which are then released into the circulation in response to ventricular wall stress. We, therefore, aimed to study the relation between ventricular dysfunction and N-terminal pro-B-type natriuretic peptides (NT-proBNPs). We enrolled 105 patients with increased serum ferritin levels and echocardiography was performed. We collected blood samples and NT-proBNP levels were measured in them. Though we found that the studied group had no significant difference in the mean serum NT-proBNP levels, in patients with or without hypertrophy ( n = 37, p = 0.992), the NT-proBNP levels were found to be significantly increased in patients with diastolic dysfunction ( n = 24, p < 0.0001 with mean values of 577.67 +/- 122.01 and 456.50 +/- 48.40 pg/mL in patients with and without diastolic dysfunction, respectively). The NT proBNP levels correlated well with the echocardiography indices, such as left ventricular end-systolic diameter (LVESD), ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/E' ratio), and ratio of the early (E) to late (A) ventricular filling velocities (E/A ratio), and were found to have significant positive correlation with the serum ferritin levels. The NT-proBNP levels correlated significantly with diastolic dysfunction; thus, serum ferritin levels could be useful for assessing the diastolic dysfunction in patients with beta thalassemia. PMID- 29142765 TI - Duplication of 19p13.3 in 11-Year-Old Male Patient with Dysmorphic Features and Intellectual Disability: A Review. AB - We present a clinical report of an 11-year-old male patient with an interstitial duplication of 19p13.3 (829 kb in size) at genomic coordinates 3,804,495 4,033,722 bp (hg19) identified by chromosomal microarray analysis and review the literature from nine published reports adding knowledge regarding this chromosomal anomaly and clinical outcomes. The size of the duplication ranged from 0.83 to 8.9 Mb in the nine individuals. The young boy in our report was dysmorphic with microcephaly, abnormal craniofacial features, intellectual disability, aggression, and a heart murmur. All patients were found to have a psychomotor developmental delay and/or intellectual disability with the majority having microcephaly, intrauterine growth retardation, and hypotonia. Common craniofacial findings included a tall, prominent forehead, an elongated face, epicanthal folds, hypertelorism, prominent low-set ears, philtrum anomaly, and a small mouth. Other less common features included abnormal digits, sparse hair, and cardiac defects. Clinical features, chromosome duplication sizes, locations, and the number of genes will be summarized in a tabular form. PMID- 29142766 TI - Mutations in NSD1 and NFIX in Three Patients with Clinical Features of Sotos Syndrome and Malan Syndrome. AB - Mutations in nuclear receptor SET domain-containing protein 1 gene ( NSD1 ) are related to Sotos syndrome, which is characterized by overgrowth, macrocephaly, distinctive features, and neurodevelopmental disabilities. On the other hand, mutations in the nuclear factor I/X gene ( NFIX ) can lead to Malan syndrome, also known as Sotos-like syndrome, or to the Marshall-Smith syndrome. In this study, using next generation sequencing (NGS), we identified de novo mutations in NSD1 and NFIX in three patients with developmental disabilities associated with overgrowth or macrocephaly. Overall, we confirmed that clinical entities of congenital malformation syndromes can be expanded by molecular diagnoses via NGS. PMID- 29142767 TI - Could Congenital Insensitivity to Pain with Anhidrosis Be Misdiagnosed as Papillon-Lefevre Syndrome? AB - Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder characterized by early loss of teeth with hyperkeratosis of the palms and soles. Congenital insensitivity to pain with anhidrosis (CIPA) is a disorder of decreased pain sensation, decreased sweating, recurrent infections, and fever. Here, we report a 5-year-old girl born to consanguineous parents with a family history of a similarly affected sibling. The girl presented with early loss of teeth and palmoplantar hyperkeratosis, hence, provisionally diagnosed as PLS. Further clinical examination and detailed history taking shifted the diagnosis to CIPA. CIPA could be misdiagnosed as PLS. Congenital insensitivity to pain with anhidrosis, although rare, should be considered in the differential diagnosis of PLS. PMID- 29142768 TI - A Rare Double Aneuploidy Case (Down-Klinefelter). AB - Down's syndrome has its own dysmorphic findings and is accompanied by mental retardation and hypotonia. Klinefelter's syndrome is a syndrome caused by a numerical abnormality that affects male physical and cognitive development. This case reports a unique finding of 48,XXY, + 21 and a current literature review. A 4-month-old male patient presented with typical clinical features of Down's syndrome with hypothyroidism, atrial septal defect, ventricular septal defect, and patent ductus arteriosus without any phenotypic signs of Klinefelter's syndrome. PMID- 29142769 TI - Plexiform Neurofibroma of Clitoris. AB - The most frequent genital presentation of neurofibromatosis in females is clitoromegaly. We report a case of a 5-year-old girl with neurofibromatosis type 1 with clitoral plexiform neurofibromatosis. Clitoroplasty was done, and the histopathology confirmed the diagnosis. Though rare, plexiform neurofibroma of clitoris should always be considered as a differential diagnosis in children with clitoromegaly before embarking on detailed investigations. PMID- 29142770 TI - Placental Teratoma, Omphalomesenteric Duct Remnant, or Intestinal Organoid (Enteroid) Differentiation: A Diagnostic Dilemma. AB - We report an unusual case of fully developed fetal intestinal segment(s) within a nodule on the chorionic plate of the placenta of a 27-year-old female patient at 37 weeks gestation with spontaneous vaginal delivery. Gross examination of the placenta revealed a chorionic plate nodule near the insertion of the umbilical cord, which, upon microscopic evaluation, raised the differential diagnostic possibilities of placental teratoma, vitelline/omphalomesenteric duct anomaly, and intestinal organoid differentiation. We discuss the distinguishing features, morphogenesis, and clinical significance of the aforementioned entities and review the pertinent medical literature. PMID- 29142771 TI - A Peruvian Child with 18p-/18q+ Syndrome and Persistent Microscopic Hematuria. AB - Chromosome 18 pericentric inversion carriers could have offspring with recombinant chromosomes, leading to patients with clinical variable manifestations. Patients with 18p-/18q+ rearrangements share some clinical characteristics, while other characteristics differ. Factors for such divergence include the length of the inverted segment, among others. Here, we describe a Peruvian child with dysmorphic features, intellectual disability persistent microscopic hematuria, aortic pseudocoarctation, and descending aorta arteritis, among others. Karyotype analysis of family members determined the mother as the carrier of a pericentric inversion: 18[inv(18)(p11.2q21.3)]. This child carries a recombinant chromosome 18, with chromosomal microarray analysis detecting two genomic imbalances in patient's chromosome 18: one duplicated region and one deleted segment in the large and the short arms, respectively. Persistent microscopic hematuria has not been reported among 18p-/18q+ phenotypes. Our patient elucidates that other factors play significant and yet unknown roles for not fulfilling the proposed genotype-phenotype correlation associated with hemizygosity in this type of recombinant chromosome 18 or presenting these features as the patient ages. PMID- 29142772 TI - Rare case of an extraosseous cervical chordoma with both intradural and extensive extraspinal involvement. AB - Background: Chordomas must be considered among the differential diagnoses for extradural spinal tumors, especially involving the clival or sacrococcygeal regions. They are often locally invasive and destructive to the osseous structures from which they arise, but rarely extend intradurally. Here, we report a unique chordoma that was intradural and spanned nearly four subaxial cervical vertebral levels. Case Description: We report the case of an atypical intradural chordoma that spanned four subaxial levels of the cervical spine in an 81-year old female. It also extended through multiple neural foramina but did not invade or destroy the bony elements of the cervical vertebrae. Notably, it demonstrated sizable extension into the deep carotid triangle abutting the internal jugular vein. Conclusion: This case involved an extraosseous, intradural, four-level subaxial cervical chordoma that demonstrated significant extraspinal extension into the anterior soft tissues of the neck. PMID- 29142773 TI - Suprasellar and third ventricular cavernous malformation: Lessons learned in differential diagnosis and surgical planning. AB - Background: While craniopharyngiomas (CPs) are the most common cystic suprasellar lesions in adults, cavernous malformations (CMs) only exceptionally occur in this location and are seldom considered in the differential diagnosis of such lesions. However, unlike CPs, suprasellar CMs are not typically approached via an endoscopic endonasal approach. Case Description: We present a unique clinical case of suprasellar and third ventricular CM mimicking a CP, posing a major decision-making dilemma at the levels of both preoperative diagnosis and surgical planning. Conclusion: This case highlights the importance of carefully considering all the differential diagnoses of sellar pathology to select the most appropriate management strategy and surgical approach. PMID- 29142774 TI - Urgent look: Why Neurosurgeons are being evaluated primarily by subjective patient's satisfaction survey rather than objective neurological outcomes. PMID- 29142775 TI - [Relevance of Simpson's grades in the resection of grade I meningiomas]. AB - Objective: Compare the number of recurrences in patients with WHO Grade I meningiomas that underwent microsurgical resection. Introduction: In 1957 Simpson established five grades for surgical resection for intracranial meningiomas and recurrence rate. He thought that an aggressive removal of these tumors with dura and bone was necessary to cure them. Development of new diagnostic methods, advances in anatomopathology and microsurgical technique lead us to question if this scale has a value nowadays. Methods: A retrospective analysis was performed. All patients operated from grade I meningiomas between February 2006 to December 2015 were included. Pre and postoperative MRI as well as histology were analyzed. A multivariate analysis was performed, a P < 0.05 was considered statistically significant. Results: There was no statistical significant difference between patients undergoing Simpson Grade I, II, III or IV resection (P = 0,3117). This could be best stated for Simpson Grade I and II resection, where the number of patients included in the study was higher. When we analyze tumor location there was not significant difference in recurrence between groups (P = 0,2203). Conclusion: For grade I meningiomas there is no significant difference in the recurrence between patients with a Simpson Grade I or II resection, thus increasing morbidity of the surgery is not justified. A new resection scale should be designed taking into account the WHO classification. PMID- 29142776 TI - [Surgical treatment of intradural extramedullary lesions by hemilaminectomy]. AB - Objective: To evaluate the usefulness of hemilaminectomy as a surgical approach in patients with intradural-extramedullary tumors. Methods: Retrospective analysis of patients in which hemilaminectomy was as surgical approach in intradural-extramedullary tumors between June 2006 and December 2015. Demographics, preoperative symptoms, imaging characteristics, intraoperative findings, histological lineage, and postsurgical complications were analyzed. The average follow-up was 48.9 months (6-120 months). Results: Fifty-three patients underwent hemilaminectomy. Tumor was located in the cervical level in 5 cases, in the dorsal level in 24, and in the lumbar region in 24 cases. Histological analysis revealed 28 neuromas, 11 meningiomas, 7 ependymomas, and 7 "multiple injuries." Total resection without postsurgical neurologic deficit was possible in 96% of the patients. There were no recurrences on follow-up. Conclusion: Hemilaminectomy is an effective approach for the resection of lateralized cervicodorsal intradural-extramedullary tumors. It can also be used to treat midline lesions located in the lumbar level. PMID- 29142777 TI - [Trajectory of lumbar and sacral pedicular screws: Comparison between midline versus wiltse approach]. AB - Objectives: To compare the posterolateral Wiltse approach and conventional Midline approach in short lumbosacral fusions in terms of the angle of convergence of pedicle screws. Methods: We retrospectively reviewed computed tomography (CT) images of 76 lumbar and sacral pedicular screws that had been placed using a conventional midline approach (CA) (n = 38) and a Wiltse posterolateral approach (WA) (n = 38). All patients underwent short lumbosacral fusions from L3 to S1 for degenerative spinal disease. Screws with a bone gap >4 mm in any direction, cases with previous pedicular implants, and those with coronal plane curves >20 degrees were excluded. Results: Considering all implants, the angle of convergence was 23.3 degrees (+/-15.8). The mean angulation in the WA group was 29.3 degrees (+/-9.7), whereas in the CA group it was 17.2 degrees (+/-0.6). This difference was statistically significant (P < 0.05). Conclusions: In short, lumbosacral fusion employing the Wiltse approach allowed placement of pedicle implants with more convergence than the conventional midline approach. The clinical relevance of this is unknown, and prospective randomized studies are needed to clarify this. PMID- 29142778 TI - [Foramen magnum meningiomas: A report of 12 cases and literature review]. AB - Objectives: The primary aim of this study was to assess the results attained for 12 patients with an anterior or lateral foramen magnum meningioma, treated microsurgically. Methods: Between June 2005 and December 2016, 12 patients with foramen magnum meningiomas underwent microsurgical resection. Patients' age and gender, tumor localization (anterior or lateral), symptoms, approach, and postoperative results were analyzed. Results: Eight of the 12 patients were women. The average age of the patients was 47 years. In 8 patients, the tumor was located anteriorly and in 4 patients laterally. The main symptom was occipitocervical pain (8 patients), followed by tetraparesia (3 patients). For all the anterior foramen magnum meningiomas, an extreme-lateral transcondylar approach was performed. In cases where the tumor was lateral, an extreme-lateral retrocondylar approach was adopted. Total and subtotal resection was achieved in 10 and 2 patients, respectively. In the latter instances, a very small piece of tumor remained around the vertebral artery or inside the jugular foramen. Three patients exhibited postoperative cranial nerve XII palsy and 2 cranial nerve XI palsy. One patient experienced cerebrospinal fluid leakage. Conclusions: Microsurgery for both anterior and lateral foramen magnum meningiomas can be performed safely and effectively. What is necessary is: (a) good anatomical knowledge of the region; (b) two-step muscle dissection to expose the suboccipital triangle and vertebral artery; (c) to adopt an extreme-lateral retrocondylar approach for lateral meningiomas, and an extreme-lateral transcondylar approach for anterior tumors; and (d) good microsurgical techniques. PMID- 29142779 TI - [Comparative analysis of Grade I vs Grade II intracranial Meningiomas in a retrospective series of 63 patients]. AB - Objective: We aimed to demonstrate the differences between grade I and II (OMS classification) of intracranial meningiomas. We evaluate their location, Simpson resection grade, re-operations rate, adjuvant treatment and patient outcomes. Methods: We conduct a retrospective review of Sixty- three clinical records of patients who were diagnosed with meningiomas grade I and II (OMS) between 2009 2015 and received surgical treatment at our Hospital. We evaluated different variables such as age, sex, histological type, Simpson grade resection, location, symptoms, radiotherapy, follow-up, mortality rate and patient outcome. The main aim was to establish the differences between these intracranial tumors. Results: A total of sixty-three patients diagnosed with meningiomas and received surgical treatment; fifty-one were grade I and thirteen with grade II. There were no differences in the rate between man and women. The average age for both types of meningiomas was 57 years old. The typical meningiomas were located in 55% of the cases outside the cranial base vs. 91.6% of the atypical meningiomas (P = 0.03). Typical meningioma had a Simpson resection grade of I, II and III in 74.5% against 58.3% of the atypical (P = 0.2). The atypical meningioma in 33% had more than one-stage surgery vs. 9.8% of the typical (P = 0.03). The patients with a typical meningioma showed a good outcome in 86.2% vs. 53.8 of the grade II (P = 0, 01). The typical meningiomas showed a good outcome in 82.2% of the cases vs. 53.8% of the atypical. The grade II meningiomas received adjuvant treatment in 33.3%, while the grade I only 1.9%. Conclusions: The atypical intracranial meningiomas have a worse outcome compared with the typical kind and a higher incidence of re-operations. These tumors have a preference for a location outside the cranial base. Concluding that the location could be a risk factor. PMID- 29142781 TI - Snapping Pes Anserinus and the Diagnostic Utility of Dynamic Ultrasound. AB - Snapping pes anserinus syndrome is an often encountered cause of medial knee snapping. It results from impingement and translation of the gracilis tendon or semitendinosus tendon over the osseous structures of the knee during active flexion and extension. Ultrasonography is often the diagnostic imaging test of choice in cases of mechanical snapping. We report 2 cases of painful snapping pes anserinus and highlight the value of dynamic ultrasound in making an accurate diagnosis so as to direct care. PMID- 29142780 TI - Molecular Mechanism of Enzymatic Chlorite Detoxification: Insights from Structural and Kinetic Studies. AB - The heme enzyme chlorite dismutase (Cld) catalyzes the degradation of chlorite to chloride and dioxygen. Although structure and steady-state kinetics of Clds have been elucidated, many questions remain (e.g., the mechanism of chlorite cleavage and the pH dependence of the reaction). Here, we present high-resolution X-ray crystal structures of a dimeric Cld at pH 6.5 and 8.5, its fluoride and isothiocyanate complexes and the neutron structure at pH 9.0 together with the pH dependence of the Fe(III)/Fe(II) couple, and the UV-vis and resonance Raman spectral features. We demonstrate that the distal Arg127 cannot act as proton acceptor and is fully ionized even at pH 9.0 ruling out its proposed role in dictating the pH dependence of chlorite degradation. Stopped-flow studies show that (i) Compound I and hypochlorite do not recombine and (ii) Compound II is the immediately formed redox intermediate that dominates during turnover. Homolytic cleavage of chlorite is proposed. PMID- 29142782 TI - Massive Left-sided Congestive Colitis Due to Idiopathic Inferior Mesenteric Arteriovenous Malformation. AB - Arteriovenous malformations (AVM) of the inferior mesenteric artery are rare. They may be primary (congenital or idiopathic) or secondary (acquired) after trauma or of iatrogenic origin. Of the abdominal AVM, the inferior mesenteric trunk is the least commonly involved. Most reported cases are of iatrogenic origin, resulting from colon surgery. Only 17 cases have been described and published in the literature. The objective of this work is to make known a case treated in our center. We present a case of 73-year old male, who came to the emergency service with symptoms of abdominal distension, pain lasting 48 hours along with months of diarrhoea. CT scan and an abdominal CT angiography showed a massive left-sided congestive colitis due to idiopathic inferior mesenteric arteriovenous malformation. In our case, the decision was to carry out the treatment in two stages. Embolisation was performed in the first stage in order to decrease the blood flow and the risk of intraoperative bleeding, followed by resective surgery of the affected colon. PMID- 29142783 TI - Birth Order and Maternal Age for Reported Cases of Severe Prenatal Cortical Hyperostosis (Caffey-Silverman Disease) AB - The spectrum of prenatal cortical hyperostosis includes a mild phenotype that typically presents after 35 weeks of gestation, and a severe form that presents earlier. The skeletal and systemic manifestations of the severe phenotype remain unexplained. A review of reported cases indicates that older mothers and firstborn infants are overrepresented. This combination suggests decreased fertility. Fourteen years after the birth of the present case, his mother presented with renal failure from multiple myeloma raising the possibility that a maternal antibody may play a role in the etiology of severe prenatal Caffey disease. The present case report is also intended to alert clinicians to potential difficulties with tracheal intubation secondary to micrognathia from mandibular involvement during a critical growth period. PMID- 29142784 TI - The Value of Implementing Multidisciplinary Perinatal Care Conference in the Private Practice Setting. AB - Objective The objective of this study was to estimate the impact of multidisciplinary (Multi-D) perinatal care conference (PCC) implementation in the private practice setting. Methods After the initial 12-month period following implementation of the monthly PCC by private maternal-fetal medicine and neonatology practitioners, conference attendees were asked to completed a modified version of the Attitudes Toward Health Care Teams Scale, involving 19 questions assessing their attitudes and opinions toward Multi-D team care on a five-point Likert's scale. Results Of the 51 average attendees to the PCC, 82.3% completed the survey. A majority of respondents agreed that Multi-D team care resulted in improved care for patients and family, was not overly complex to coordinate, and resulted in significant job satisfaction and improved medical knowledge. Conclusion Multi-D care is an effective approach to the complicated needs of maternal-fetal medicine patients which may lead to improved patient and family outcomes, high provider satisfaction, and can easily be implemented and utilized within a private practice or community hospital setting. PMID- 29142785 TI - Role of cord blood and bone marrow mesenchymal stem cells in recent deep burn: a case-control prospective study. AB - RATIONALE: Burn injuries represent one of the major worldwide public health problems causing more severe physiological stress than other traumas. Effective treatment of burn injuries is mandatory to prevent the numerous life-threatening complications and possible disabilities. Stem cells, a population of multipotent cells retaining the properties of self-renewal and differentiation, are the main player in tissue regeneration after major trauma. Thus, they are thought to play a key role in wound healing inducing efficient and physiological skin regeneration. Stem cell-based regeneration is quickly gaining scientific grounds. OBJECTIVE: This study was designed as a comparative prospective study to evaluate and compare the regenerative effect of bone marrow derived mesenchymal stem cells (BM-MSCs) and umbilical cord blood derived mesenchymal stem cells (UC-MSCs) compared to conventional early excision and graft (EE&G) in recent thermal full thickness burned patients. SUBJECT & METHODS: Recruited burned patients were randomly divided into three groups (20 patients on each group) having recent thermal full thickness percentage ranging from 10% to 25% total body surface area (TBSA). After receiving allocated treatment, they were assessed as regards: rate of burn healing, presence of post-burn complications both early (such as loss of graft and infections) and late (as hypertrophic scars, keloid, hypo- or hyperpigmentation or contracture of the wound), hospitalization time and cost. RESULTS: This study showed significantly improved rate of healing in both BM-MSC and UC-MSC groups as compared to EE&G group with no significant difference between bone marrow and umbilical cord groups. Comparing the incidence of early complications, partial and total loss of graft occurred in 50% patients in (EE&G) group, while infection complication appeared in 25% of patients of (BM-MSCs) group and in 70% of patients in (UC-MSCS) group. The late complications (hypertrophic scars) were observed in 40% of (EE&G) patients group, in 15% of (BM MSCs) treated patients group and 20% of (UC-MSCS) patients group. Contractured scars were present in 15% in (EE&G) group, 10% in (BM-MSCs) group, 10% in (UC MSCS) group. Hypopigmentation occurred in 20% of patients in (EE&G) group, 20% in (BM-MSCs) group and 10% in (UC-MSCS) group. Hyperpigmentation was present in 20% of patient in (EE&G) group, 30% in (UC-MSCS) group but no hyperpigmentation occurred in (BM-MSCs) group. There was no late complication in 5% of patient in (EE&G) group, 55% in (BM-MSCs) group and 30% in (UC-MSCS) group. The results of this study revealed that the hospitalization period was significantly reduced in both (BM-MSCs) group and (UC-MSCS) group as compared to (EE&G) group. CONCLUSION: this study proves that mesenchymal stem cells, both from bone marrow and cord blood origin, can effectively improve healing of burn injuries. PMID- 29142786 TI - Extraordinary clinical benefit to sequential treatment with targeted therapy and immunotherapy of a BRAF V600E and PD-L1 positive metastatic lung adenocarcinoma. AB - Background: The treatment algorithm for metastatic non-small cell lung cancers (NSCLCs) has been evolving rapidly due to the development of new therapeutic agents. Although guidelines are provided by National Comprehensive Cancer Network (NCCN) for treatment options according to biomarker testing results, sequentially applying the three main modalities (chemotherapy, targeted therapy and immunotherapy) remains an ad hoc practice in clinic. In light of recent FDA approval of dabrafenib and trametinib combination for metastatic NSCLCs with BRAF V600E mutation, one question arises due to insufficient clinical data is if the targeted therapy should be used before immunotherapy in patients with both BRAF V600E and PD-L1 expression. Case presentation: We present a case of 74-year-old female, former smoker with metastatic lung adenocarcinoma. The BRAF V600E mutation among other abnormalities was identified by comprehensive genomic profiling. The patient had an excellent 2-year response to the combination of pemetrexed and sorafenib. The patient was then treated with dabrafenib due to the presence of the BRAF V600E mutation and intolerance to cytotoxic chemotherapy. Not only the patient had an 18-month durable response to dabrafenib, she experienced outstanding quality of life with no serious adverse effects. At the time of symptomatic progression, the patient was then treated with two cycles of pembrolizumab based on her positive PD-L1 staining (90%). She had early response and came off pembrolizumab due to side effects. Seven months after initiation of pembrolizumab, the patient is off all the therapy and is currently asymptomatic. The patient is surviving with metastatic disease for over 7 years as of to date. Conclusions: By appropriately sequencing the three main modalities of systemic therapies, we are able to achieve long-term disease control with minimal side effects even in a geriatric patient with multiple comorbidities. We argue that it is reasonable to first use a BRAF inhibitor before considering immunotherapy for NSCLCs positive for both BRAF V600E and PD-L1. PMID- 29142787 TI - Sleep Apnea Symptoms and Cardiovascular Disease Risks among Haitian Medical Students. AB - Sleep apnea is a prevalent sleep disorder that disproportionately affects blacks and has been previously studied among Caribbean-born blacks in Brooklyn, New York, but there has been negligible research in the Caribbean, specifically Haiti, and developing countries on this pressing health issue. A total of 373 medical students (mean age=20.6 years +/- 2.3 years) from a medical school in Haiti participated in this study. Participants were administered a questionnaire assessing their sleep health and cardiovascular outcomes. The rate of sleep apnea symptoms was: snoring (13.2%), excessive daytime sleepiness (73.7%), and difficulty maintaining sleep (25.3%). Many reported falling asleep while watching television (68.2%) or while driving (7.8%). Based on logistic regression analysis, reported nocturnal breathing pauses was the most important predictor of the likelihood of reporting a history of cardiac disease (14.96; 95% CI=1.27 76.07). Findings suggest that more aggressive effort should be made to increase screening of sleep apnea among Haitians, thereby increasing the likelihood for early detection and treatment to reduce sleep-related risk of cardiovascular disease. PMID- 29142788 TI - A unified approach to model peripheral nerves across different animal species. AB - Peripheral nerves are extremely complex biological structures. The knowledge of their response to stretch is crucial to better understand physiological and pathological states (e.g., due to overstretch). Since their mechanical response is deterministically related to the nature of the external stimuli, theoretical and computational tools were used to investigate their behaviour. In this work, a Yeoh-like polynomial strain energy function was used to reproduce the response of in vitro porcine nerve. Moreover, this approach was applied to different nervous structures coming from different animal species (rabbit, lobster, Aplysia) and tested for different amount of stretch (up to extreme ones). Starting from this theoretical background, in silico models of both porcine nerves and cerebro abdominal connective of Aplysia were built to reproduce experimental data (R2 > 0.9). Finally, bi-dimensional in silico models were provided to reduce computational time of more than 90% with respect to the performances of fully three-dimensional models. PMID- 29142789 TI - Catalytic Depolymerization of Lignin and Woody Biomass in Supercritical Ethanol: Influence of Reaction Temperature and Feedstock. AB - The one-step ethanolysis approach to upgrade lignin to monomeric aromatics using a CuMgAl mixed oxide catalyst is studied in detail. The influence of reaction temperature (200-420 degrees C) on the product distribution is investigated. At low temperature (200-250 degrees C), recondensation is dominant, while char forming reactions become significant at high reaction temperature (>380 degrees C). At preferred intermediate temperatures (300-340 degrees C), char-forming reactions are effectively suppressed by alkylation and Guerbet and esterification reactions. This shifts the reaction toward depolymerization, explaining high monomeric aromatics yield. Carbon-14 dating analysis of the lignin residue revealed that a substantial amount of the carbon in the lignin residue originates from reactions of lignin with ethanol. Recycling tests show that the activity of the regenerated catalyst was strongly decreased due to a loss of basic sites due to hydrolysis of the MgO function and a loss of surface area due to spinel oxide formation of the Cu and Al components. The utility of this one-step approach for upgrading woody biomass was also demonstrated. An important observation is that conversion of the native lignin contained in the lignocellulosic matrix is much easier than the conversion of technical lignin. PMID- 29142790 TI - An Active Giant Cell Tumor of the Patella: A Case Report. AB - Primary neoplasms of the patella account for less than 1% of all primary bone tumors of the lower extremity, the most frequent of them being the giant cell tumor of bone, the chondroblastoma, and the aneurysmal bone cyst. Herein, we report the case of a 29-year-old woman with an active giant cell tumor of the patella (GCTP) with its clinical and radiological features and a brief review of the literature. PMID- 29142791 TI - Management of Massively Enlarged Multiple Hydatid Cysts in the Liver of a Pediatric Patient. AB - Multiple hydatid cysts in the liver are a very rare occurrence in childhood. We present a similar case in a nine-year-old girl, a resident in a rural community, who presented with two hydatid cysts in her liver. The cysts were operated upon by a pediatric surgeon. The laboratory findings of this patient showed peripheral blood eosinophilia, elevated white blood cells, and liver enzymes. The serology was positive. The ultrasonography showed cystic masses in the liver, and the diagnosis of hydatid cysts was eventually confirmed by computed tomography (CT) of the abdomen. PMID- 29142792 TI - Spinal Muscular Atrophy: The Treatment Approved. AB - Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder resulting in progressive muscle weakness and atrophy. It is universally fatal, especially if the respiratory muscles are involved leading to repetitive aspiration and respiratory failure. Historically, the treatment for this disease was only supportive. Herein we describe an adult patient who presented with worsening weakness and fatigue and was subsequently diagnosed with spinal muscular atrophy. Increased awareness of this condition and a new treatment modality is required. PMID- 29142793 TI - A Ruptured Extra-dural Spinal Arterio-venous Malformation Presenting as Horner's Syndrome: The First Case Report. AB - We report the first case of a young patient who presented with the features of Horner's syndrome following a spinal extradural hematoma resulting from a ruptured arterio-venous malformation (AVM). Since there were features of early compressive myelopathy as well, urgent magnetic resonance imaging (MRI) scan of the spine revealed features suggestive of an extradural hematoma in the cervico thoracic junction. The patient underwent an emergent laminectomy with an evacuation of the hematoma. The histological features were consistent with that of an AVM. PMID- 29142795 TI - Comorbid Post-Traumatic Stress Disorder and Opioid Dependence. AB - Post-traumatic stress disorder (PTSD) is predominant amongst individuals addicted to opioids and obscures the course of illness and the treatment outcome. We report the case of a patient with major depressive disorder and opioid dependence, who experienced post-traumatic stress disorder symptoms during a recent visit to the inpatient unit. The similarity of symptoms between post traumatic stress disorder and opioid dependence is so high that, sometimes, it is a challenge to differentiate between these conditions. Since opioid withdrawal symptoms mimic hyper vigilance, this results in an exaggeration of the response of patients with post-traumatic stress disorder. This comorbidity is associated with worse health outcomes, as its pathophysiology involves a common neurobiological circuit. Opioid substitution therapy and psychotherapeutic medications in combination with evidence-based cognitive behavioral therapy devised for individuals with comorbid post-traumatic stress disorder and opioid dependence may improve treatment outcomes in this population. Therefore, we conclude that the screening for post-traumatic stress disorder in the opioid abusing population is crucial. To understand the underlying mechanisms for this comorbidity and to improve the treatment response, further research should be encouraged. PMID- 29142794 TI - Gastrointestinal Side Effects of Antiarrhythmic Medications: A Review of Current Literature. AB - Antiarrhythmic drugs are commonly prescribed cardiac drugs. Due to their receptor mimicry with several of the gastrointestinal tract receptors, they can frequently lead to gastrointestinal side effects. These side effects are the most common reasons for discontinuation of these drugs by the patients. Knowledge of these side effects is important for clinicians that manage antiarrhythmic drugs. This review focuses on the gastrointestinal side effects of these drugs and provides a detailed up-to-date literature review of the side effects of these drugs. The review provides case reports reported in the literature as well as possible mechanisms that lead to gastrointestinal side effects. PMID- 29142796 TI - Impact of Depression on Hospitalization and Related Outcomes for Parkinson's Disease Patients: A Nationwide Inpatient Sample-Based Retrospective Study. AB - Background Major Depressive Disorder (MDD) is a common comorbidity that significantly affects the quality of life and disease outcomes in Parkinson's disease (PD) patients. No studies have been conducted to our knowledge to address the health care utilization and its outcomes in these patients. The aim of this study is to analyze and discern the differences in the hospitalization outcomes, comorbid conditions, and utilization of procedures in PD patients versus patients with comorbid MDD. Methods We used the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project from year's 2010-2014. We identified PD and MDD as a primary and secondary diagnosis respectively using validated International Classification of Diseases, 9th Revision, and Clinical Modification codes. Pearson's chi-square test and independent sample T-test were used for categorical data and continuous data, respectively. All statistical analysis was done by SPSS 22.0 in this study. Results Extensive analysis was performed on 63,912 patients with PD and 1445 patients with PD having MDD. Patients with comorbid depression had three times greater chances of disposition to acute care hospital (3.1% vs. 1.1%, p < 0.001). Median length of hospitalization was higher in Parkinson's patients with depression (5.85 vs. 4.08 days; p < 0.001) though the median cost of hospitalization was low ($ 31,039 vs. $ 39,464; p < 0.001). This could be because therapeutic procedures performed during the hospitalization were lower in Parkinson's patients with depression (0.53 vs. 0.89, p < 0.001). Utilization of Deep Brain Stimulation (DBS) was lower in Parkinson's patients with depression (9.4% vs. 25.6%, p < 0.001). In--hospital mortality was significantly higher in Parkinson's patients with depression (1.4% vs. 1.1%; p < 0.001). Conclusion Our study establishes the negative impact of depression in PD with regards to hospitalization-related outcomes including the illness severity, comorbid conditions, risk of mortality, utilization of diagnostic and therapeutic procedures, the length of stay and disposition as compared to PD without depression. PMID- 29142797 TI - Cervical Funneling: Potential Pitfall of Point-of-Care Pelvic Ultrasound. AB - Though point-of-care ultrasound applications continue to expand, there are findings that are not within the scope of emergency ultrasound. It is important for emergency physicians to be aware of incidental findings that can be identified on comprehensive ultrasounds performed by other imaging departments in order to fully understand the limitations of bedside ultrasound. In this case, a gravid patient presented to the emergency department with pelvic cramping and vaginal bleeding. Point-of-care transabdominal pelvic ultrasound examination was performed and demonstrated cervical funneling. In the appropriate patient, cervical insufficiency due to cervical funneling may be an indication for cerclage in a pregnant patient. PMID- 29142798 TI - Verification of Diagnosis in Tuberculosis: A Case Report and Discussion. AB - Tuberculosis (TB), caused by strains of Mycobacterium tuberculosis complex (M. tuberculosis), is a pulmonary infection that is spread by airborne droplet transmission. The development and spread of drug-resistant strains of M. tuberculosisgreatly jeopardize TB control efforts. We report the case of a previously healthy 43-year-old male, visiting from China, who presented to the emergency department complaining of hemoptysis of 10 days' duration. Cultures were positive for acid fast bacteria and negative for fungi. M. tuberculosis infection was confirmed by a deoxyribonucleic acid (DNA) probe. The patient was initially started on first-line therapy of isoniazid, rifampin, pyrazinamide, and ethambutol, with pyridoxine. His country of origin, China, increased suspicion for drug-resistant tuberculosis. Two weeks later, susceptibility testing of the M. tuberculosis isolate showed resistance to isoniazid, pyrazinamide, and ethambutol. Therapy was subsequently changed to amikacin, linezolid, moxifloxacin, and rifampin. The isolate was subsequently sent to the Center for Disease Control (CDC) for evaluation. Repeat testing showed that the isolate was susceptible to rifampin, pyrazinamide, and ethambutol. The patient was then restarted on his initial anti-TB regimen and was able to return to China. The main goals for the treatment of TB are to treat the individual patient and to minimize transmission. Clues that point to the possibility of multiple drug resistant tuberculosis (MDR-TB) include contact with a patient with MDR-TB, origin from an endemic region, or failure of therapy with documented supervision. Collaboration with experts was imperative in ensuring appropriate patient care. PMID- 29142799 TI - Respiratory Failure Following Organophosphate Poisoning: A Literature Review. AB - Organophosphates (OPs) account for a large portion of suicides globally. OP manifests as cholinergic crises, which underlie respiratory failure. There are many pathways by which respiration is inhibited secondary to organophosphate poisoning. These include central as well as peripheral mechanisms, with central mechanisms predominating. We conducted a literature review in June 2017. PubMed, Embase, and Google Scholar were searched for studies that reported acute organophosphate poisoning in humans. In our review, data were collected from studies published during the years 2001 to 2016. The data consisted of 1,996 patients with organophosphate poisoning, of which 491 (24.6%) required ventilatory support secondary to respiratory failure. Treatment offered to OP poisoning patients should focus on its pathophysiology to benefit from the future outcomes. Recent advances direct the need for a central nervous system (CNS) protective strategy for future prevention and treatment of events associated with cholinergic crises. PMID- 29142800 TI - Rapid Fulminant Case of Aspergillus Prosthetic Valve Endocarditis. AB - A 74-year-old male presented to the emergency department 46 days after undergoing an aortic valve replacement. He presented with nonspecific symptoms developed over the previous 15 days, with a new onset of a systolic panfocal murmur. Echocardiography revealed a great vegetation measuring 15 mm by 23 mm causing a severe obstruction of the bioprosthesis. The patient underwent an emergency surgical procedure due to his hemodynamic unsteadiness. During the procedure, we noted an obstruction of the left ventricle outflow tract with pseudoaneurysm of the aortomitral continuity. We debrided the aortic annulus, reconstructed the aortomitral continuity, and replaced the prosthesis, but the patient died. We present a rare fulminant case of Aspergillus endocarditis. PMID- 29142801 TI - Idiopathic Acquired Dacryocystocele Presenting Only with Epiphora: A Very Rare Case Report. AB - A 42-years-old male presented with left medial canthal swelling, accompanied with only mild epiphora. There was no history of dacryocystitis, mid-facial trauma, surgery, or bloody tears. On examination, there was an immobile, subcutaneous, non-inflammatory mass below the medial canthal tendon. Lacrimal irrigation showed blockade at the nasolacrimal duct. A computerized axial tomography (CAT) scan revealed a non-enhancing, low-density, cystic lesion at the inferomedial margin of the orbit. There were no signs of bony erosion, consistent with idiopathic acquired dacryocystocele. The patient underwent external dacryocystorhinostomy (DCR) with silicone tube intubation. The patient's symptoms of epiphora resolved after surgery. Idiopathic acquired dacryocystocele with only epiphora, although rare, should be considered in differential diagnosis of medial canthal, non inflammatory swellings. In areas with insufficient endoscopic facilities, external dacryocystorhinostomy gives similar promising results. PMID- 29142802 TI - Metastatic HER2+ Breast Cancer: A Potentially Curable Disease? AB - The advent of trastuzumab and other human epidermal growth factor receptor 2 (HER2)-directed therapies has revolutionized the treatment of metastatic HER2 positive breast cancer, leading to prolonged survival and appreciable clinical benefit for a substantial subset of patients. Previously, in a retrospective study at our institution, we observed that nearly 10% of patients achieved a durable complete remission (DCR) following a combination of HER2-directed therapy and cytotoxic chemotherapy. We are currently expanding this study to include patients who were treated since the initial introduction of trastuzumab. From our ongoing study, we present a selected case series of three patients with metastatic HER2-positive breast cancer who achieved a DCR. It is theorized that metastatic HER2-positive breast cancer may be potentially curable in certain patients with favorable clinicopathological and molecular factors, which the patients within our case series mostly demonstrate. These include de novo presentation, estrogen receptor (ER)-negative status, limited disease burden, and absence of deleterious gene or pathway mutations. More research is needed in order to incorporate these findings into clinical practice. PMID- 29142803 TI - Unprovoked Pulmonary Embolism in a Young Patient with Marfan Syndrome. AB - Marfan syndrome is a rare connective tissue disorder with a prevalence of approximately 2 to 3 per 10,000 individuals. There have been some reports of young patients with Marfan syndrome developing arteriovenous thromboembolism. These events were unprovoked and recurrent. Owing to its rarity, hypercoagulopathy and other metabolic derangement in patients with Marfan syndrome remains largely unknown. Herein, we report a case of a young man with Marfan syndrome who had myocardial infarction and pulmonary embolism. We hope that this case adds to the scant body of knowledge about this patient population. PMID- 29142804 TI - Analytical study of effective biodegradation of p-cresol using Serratia marcescens ABHI001: application in bioremediation. AB - This study evaluated the capability of Serratia marcescens ABHI001 to effectively degrade p-cresol through different techniques. The molecular identity of the laboratory isolate S. marcescens ABHI001 was confirmed through the 16S ribosomal DNA gene pattern, and its morphological features were investigated through field emission scanning electron microscopy. In addition, the degradation behavior of the isolate for cresol was verified using several techniques, including UV visible spectroscopy, followed by high-performance liquid chromatography (HPLC), gas chromatography, and Fourier transform infrared spectroscopy. The maximum degradation percentage of 85% for p-cresol could be achieved after 18 h of incubation with S. marcescens ABHI001. The formation of p-hydroxybenzaldehyde, p hydroxybenzoate, and protocatechuate metabolites was confirmed through HPLC. The study results indicate that S. marcescens ABHI001 may have applications in the bioremediation of organic pollutants, such as p-cresol. PMID- 29142805 TI - Role of Adjuvant Treatment in Sinonasal Mucosal Melanoma. AB - Purpose Sinonasal mucosal melanoma (SNMM) is a locally aggressive tumor. This study aimed to define the role of adjuvant treatment and its association with survival outcomes of SNMM. Methods This retrospective study investigated 152 patients with SNMM treated between 1991 and 2016 in MD Anderson Cancer Center. Patients were divided into the following treatment groups: surgery alone, surgery with postoperative radiotherapy (PORT), surgery with postoperative chemoradiation (POCRT), and induction chemotherapy followed by surgery and PORT. Overall survival (OS), disease-specific survival, and relapse-free survival were compared. Survival between the groups was compared using univariate and multivariate analyses. Results The median follow-up was 28 months (range: 2-220 months). Five-year OS rates were 39, 42, 47, and 27% for the surgery only, PORT, POCRT, and neoadjuvant chemotherapy groups, respectively (log rank p = 0.73). Distant metastasis was the most common form of treatment failure and occurred in 59 (39%) patients. Five-year distant metastasis rates were 51, 45, and 58% for patients treated with surgery alone, PORT, and POCRT, respectively (log rank p = 0.21) but unable to be estimated in the neoadjuvant chemotherapy group due to low OS rates. Multivariate analysis demonstrated tumor site (hazard ratio [HR] = 2.32, 95% confidence interval [CI] = 1.24-4.15) and smoking status (HR = 1.77, 95% CI = 1.02-3.1) to be significant prognostic factors for survival. Conclusion Tumor site and smoking status were significant prognosticators in SNMM. A high rate of distant metastatic disease suggests that further investigation into novel, systemic therapies is required to improve outcomes in this disease entity. PMID- 29142806 TI - Synthesis and gas sensing properties of membrane template-grown hollow ZnO nanowires. AB - One-dimensional, hollow nanostructured materials are among the most promising materials for sensing applications owing to their high surface area that facilitates the adsorption of target gases. Accordingly, for gas sensing studies, hollow ZnO nanowires (NWs) with different surface areas were successfully synthesized herein by using polycarbonate membranes with different pore sizes as templates, and deposition of ZnO via the atomic layer deposition technique. The sensing properties of the synthesized hollow ZnO NWs were examined for CO and NO2, revealing their comparative sensing performances with ZnO nanomaterials based sensors reported in literature. This study highlights a novel way of synthesizing hollow ZnO NWs by using membrane template and their promising sensing properties as well. PMID- 29142807 TI - Silver nanoparticle-human hemoglobin interface: time evolution of the corona formation and interaction phenomenon. AB - In this paper, we have used spectroscopic and electron microscopic analysis to monitor the time evolution of the silver nanoparticles (Ag NP)-human hemoglobin (Hb) corona formation and to characterize the interaction of the Ag NPs with Hb. The time constants for surface plasmon resonance binding and reorganization are found to be 9.51 and 118.48 min, respectively. The drop of surface charge and the increase of the hydrodynamic diameter indicated the corona of Hb on the Ag NP surface. The auto correlation function is found to broaden with the increasing time of the corona formation. Surface zeta potential revealed that positively charged Hb interact electrostatically with negatively charged Ag NP surfaces. The change in alpha helix and beta sheet depends on the corona formation time. The visualization of the Hb corona from HRTEM showed large number of Hb domains aggregate containing essentially Ag NPs and without Ag NPs. Emission study showed the tertiary deformation, energy transfer, nature of interaction and quenching under three different temperatures. PMID- 29142808 TI - Analyzing microtomography data with Python and the scikit-image library. AB - The exploration and processing of images is a vital aspect of the scientific workflows of many X-ray imaging modalities. Users require tools that combine interactivity, versatility, and performance. scikit-image is an open-source image processing toolkit for the Python language that supports a large variety of file formats and is compatible with 2D and 3D images. The toolkit exposes a simple programming interface, with thematic modules grouping functions according to their purpose, such as image restoration, segmentation, and measurements. scikit image users benefit from a rich scientific Python ecosystem that contains many powerful libraries for tasks such as visualization or machine learning. scikit image combines a gentle learning curve, versatile image processing capabilities, and the scalable performance required for the high-throughput analysis of X-ray imaging data. PMID- 29142809 TI - Is Left Atrial Function Affected by Coronary Slow Flow? A Two-dimensional Speckle Tracking Echocardiographic Study. AB - Background: The coronary slow flow phenomenon (CSFP) is the slow passage of the angiographic contrast agent to the distal portion of the coronary artery in the absence of significant stenosis. We evaluated the left atrial (LA) function in patients with the CSFP using two-dimensional speckle-tracking echocardiography (2DSTE). Methods: The LA function was compared through 2DSTE between 36 patients with the CSFP and 36 participants with a normal coronary flow. The two groups were matched for age, sex, hypertension, diabetes mellitus, and the left ventricular function. Results: There were no statistically significant differences between the CSFP group and the control group regarding longitudinal systolic strain, early and late diastolic strains, and the strain rate of the LA myocardium. Conclusions: The LA function as evaluated with 2DSTE was not different between the CSFP group and the normal coronary flow group when they were matched for age, sex, hypertension, diabetes, and the left ventricular function. PMID- 29142810 TI - The role of Ivabradine in Diastolic Heart Failure with preserved Ejection Fraction. A Doppler-Echocardiographic study. AB - Background: Ivabradine (IVA) is effective in patients with coronary artery disease (CAD) or systolic heart failure in sinus rhythm. Its action consists in reducing heart rate (HR) and improving the time of left ventricular (LV) diastolic filling. The aim of this study was to evaluate the effects of IVA added to conventional therapy on patients with diastolic heart failure (DHF) and preserved ejection fraction (HFpEF). Methods: We evaluated 25 patients with DHF in the New York Heart Association (NYHA) Class II-III and sinus rhythm. In these, IVA per os (5 mg/twice a day) was added to the conventional medical therapy and given for 12 weeks. Immediately before the beginning of IVA therapy and 3 months later, patients underwent echocardiographic evaluation by two-dimensional (2D) ultrasound and tissue Doppler imaging (TDI). The patterns of diastolic mitral inflow and pulmonary venous flow were recorded using 2D echocardiography, while the diastolic phase of mitral flow was recorded by TDI, from the lateral mitral annulus. Results: Three months after the addition of IVA to conventional treatment, HR significantly decreased in comparison to the baseline values. On the contrary, the echocardiographic indexes of LV diastolic dysfunction improved. Conclusions: These results testify that the addition of IVA to conventional therapy in patients with HFpEF can improve LV diastolic function evaluated by 2D and tissue Doppler-echocardiographic patterns. These Doppler-echocardiographic results match with the clinical improvement of patients evaluated. PMID- 29142812 TI - Left Ventricle Relative Apical Sparing in Cardiac Amyloidosis. AB - Amyloidosis is a disease characterized by the extracellular deposition of the protein amyloid. It is a multiorgan disease, and cardiac involvement is not uncommon, generally in the form of a restrictive cardiomyopathy. Typical aspects of cardiac amyloidosis have been described at echocardiography and magnetic resonance imaging (MRI). In particular, the relative apical sparing at two dimensional speckle-tracking echocardiography has been reported to be specific for cardiac amyloidosis. In our case, we report for the first time that this echocardiographic sign is related to lack of hyperenhancement at late gadolinium enhancement imaging in cardiac MRI. PMID- 29142811 TI - Carotid Artery Stiffness and Development of Hypertension in People with Paraplegia and No Overt Cardiovascular Disease: A 7-year Follow-up Study. AB - Objectives: The aim of this study was to compare arterial stiffness between people with paraplegia and able-bodied persons (ABPs) and to assess cardiovascular markers that may be predictive of the development of arterial hypertension in people with spinal cord injury (SCI). Setting: This study was conducted at rehabilitation Hospital, Udine (Italy). Methods: Fifty-seven patients with SCI were prospectively enrolled and compared with 88 healthy ABPs. All patients underwent comprehensive transthoracic echocardiography, and one point left common carotid artery (CCA) color-Doppler study for arterial stiffness. Results: Patients with SCI had significantly lower body mass index (BMI) and diastolic blood pressure (BP) compared with ABPs, and significantly higher carotid stiffness values (and lower arterial compliance) (P < 0.05) after adjustment for age, sex, BMI, physical activity, and heart rate. The SCI patients had lower values of the right ventricular function parameters (tricuspid annular plane systolic excursion and right Sm; P < 0.0001), increased wall thickness, and impaired diastolic function. At 7-year follow-up, 10.5% of SCI patients showed high BP; they were significantly heavier with a tendency toward increased abdominal obesity after adjustment for age and systolic BP. BMI was found to be an independent predictor of the development of hypertension. Conclusions: Patients with posttraumatic chronic SCI and no overt cardiovascular disease exhibit higher CCA stiffness along with the left and right ventricular involvement, compared with ABPs. People with paraplegia who develop arterial hypertension show increased CCA stiffness mediated by obesity. Lifestyle modifications and weight control should be promoted in all patients with SCI, even at a very early stage. PMID- 29142813 TI - Aortopulmonary Window with Crisscross Pulmonary Arteries: Anatomically Type 1, Physiologically Type 2. AB - Aortopulmonary window (APW) is a rare congenital anomaly. We report an association of APW with crisscross pulmonary arteries (hitherto unreported) in a 6-month-old child. There was differential flow to the right pulmonary artery was evident by the chest X-ray. We discuss the pathophysiology of the differential pulmonary blood flow in a case of APW. PMID- 29142814 TI - A Membranous Septal Aneurysm Causing Right Ventricular Outflow Tract Obstruction in an Adult. AB - We describe a case of a 69-year-old female referred for the evaluation of exertional dyspnea, with a small membranous ventricular septal defect (VSD) and right ventricle (RV) outflow tract obstruction. Using transthoracic echo was diagnosed VSD with left to right shunting and transesophageal echo (TEE) was used to a better anatomical characterization. TEE showed a perimembranous subaortic VSD that developed a high-velocity flow in RV. Pulmonary valve appears normal and right ventricular infundibular hypertrophy or double-chambered RV was excluded from the study. Furthermore, TEE showed a malaligned VSD and the presence of perimembranous mobile tissue protruding in RV. We hypothesized that this tissue can be attributed to broken septum aneurysm and protruding during systole, it causes a dynamic RV output tract obstruction. PMID- 29142815 TI - Multifactorial Genesis of a Seeming Case of Pulmonary Hypertension. AB - Herein, we report the case of a 44-year-old female with end-stage renal disease on hemodialysis. She was admitted to our hospital to evaluate if she was eligible for a kidney transplant. Transthoracic echocardiography showed a markedly dilated coronary sinus and an unexpected finding of increased right ventriculoatrial gradient. A saline contrast echocardiography to confirm the presence of persistent left superior vena cava (PLSVC) was not performed because of arteriovenous fistula (FAV) for hemodialysis on the left forearm. Therefore, computed tomography angiography was performed, and it showed the PLSVC. We also proceeded with a transesophageal echocardiography which showed an atrial septal defect (ASD) of the sinus venous type hemodynamically significant. In this case, we identified a rare association of PLSVC with a ASD; therefore, there is a right ventricular volume overload because of the ASD hemodynamically significant and high flow FAV leading to a condition of a seeming pulmonary hypertension. PMID- 29142816 TI - Unilateral Pulmonary Edema in a Patient with Worsening Tricuspid Valve Regurgitation: A Secret Inside Pulmonary Veins. AB - We present the case of a 69-year-old patient who was referred to the Department of Echocardiography for surgical treatment of severe tricuspid valve regurgitation (TVR) with advanced congestive heart failure. In 2013 the patient underwent unsuccessful percutaneous ablation for permanent atrial fibrillation. In 2015, following numerous episodes of atrial fibrillation and congestive heart failure with left pleural effusion, the patient was admitted to another center. A transthoracic echocardiogram showed severe TVR and moderate precapillary pulmonary hypertension, confirmed at right cardiac catheterization. He showed bilateral ankle swelling, mild systolic cardiac murmur and localized leftmost decreased breath sounds. Chest X-ray revealed left-sided pulmonary edema and ipsilateral large pleural effusion. Following percutaneous drainage of the left pulmonary effusion, the patient underwent transthoracic and transesophageal echocardiography (TEE), confirming severe TVR due to annular dilation, severe pulmonary hypertension (60 mmHg) and right ventricular overload. At TEE, we found a narrowed single left pulmonary vein. Coronary artery angiography showed no critical stenosis. The patient underwent cardiac magnetic resonance and Angiography that confirmed ostial stenosis of a single left pulmonary vein. We performed successful bare-metal stent implantation. After the procedure, we observed progressive improvement in the patient's clinical condition, concomitant with reverse pulmonary hypertension, significant TVR reduction and chest X-ray normalization. This is a rare case of unilateral pulmonary edema following percutaneous ablation of atrial fibrillation. PMID- 29142817 TI - An Unusual Case of Aortic-Right Atrium Fistula: A Diagnostic and Therapeutic Challenge. AB - An aorta-to-right atrium (RA) fistula is an anomalous communication between the ascending or descending thoracic aorta and the RA. In this report, we describe a case of an idiopathic aortic root-to-RA fistula occasionally found during a coronary angiography performed in a young patient admitted for acute chest pain with evidence of multivessel coronary artery disease. The anatomical peculiarity of this fistulous communication is that it gave origin to collateral vessels furnishing the inferolateral wall of the left ventricle. The case represented a diagnostic and therapeutic challenge that required a multimodality imaging and a multidisciplinary team approach. PMID- 29142818 TI - Shortness of Breath on Exertion: A (Cardiac Magnetic Resonance) Picture is Worth a Thousand Words. AB - This is the case of a 78-year-old male patient that underwent a cardiac magnetic resonance (CMR) due to shortness of breath. An unanticipated diagnosis of a giant pseudoaneurysm with a "guitar-like" appearance was made and patient was sent for urgent ventriculoplasty. CMR offered striking illustrative images allowing for previously unsuspected diagnosis to be made and patient's therapeutic management modified. Moreover, in this case, we emphasize the paramount importance of differentiating between true aneurysms, pseudoaneurysms, clefts, and diverticuli since each pathology has completely different management and prognosis that vary from benign to potentially fatal if not immediately treated. PMID- 29142819 TI - Liposomes modified with cardiolipin can act as a platform to regulate the potential flux of NADP+-dependent isocitrate dehydrogenase. AB - Cardiolipin (CL) is a phospholipid found in the outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM) in animal cells. Isocitrate dehydrogenase (ICDH) is an important catalytic enzyme that is localized at the cytosol and mitochondria; the metabolic pathway catalyzed by ICDH differs between the OMM and IMM. To estimate the possible role of lipid membrane in the enzymatic activity of NADP+-dependent ICDH, CL-modified liposomes were prepared using CL/1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/cholesterol (Ch), and their characteristics were analyzed based on the fluorescent probe method. The relative enzymatic activity of ICDH decreased in the presence of CL/DPPC/Ch=(30/50/20) liposome, whereas activity increased in the presence of CL/DPPC/Ch=(5/75/20) liposome. NADP+ had the greatest substrate affinity and was dominant in the regulation of ICDH activity. Analysis of membrane properties indicated that membranes in CL-modified liposomes were dehydrated by ICDH binding. Using circular dichroism analysis, CL/DPPC/Ch=(30/50/20) liposome induced a conformational change in ICDH, indicating that CL-rich membrane domains could inhibit ICDH activity. These results suggest that lipid membranes, including CL molecules, could act as a platform to regulate ICDH-related metabolic pathways such as the tricarboxylic acid cycle and lipid synthesis. PMID- 29142820 TI - Excessive by-product formation: A key contributor to low isobutanol yields of engineered Saccharomyces cerevisiae strains. AB - It is theoretically possible to engineer Saccharomyces cerevisiae strains in which isobutanol is the predominant catabolic product and high-yielding isobutanol-producing strains are already reported by industry. Conversely, isobutanol yields of engineered S. cerevisiae strains reported in the scientific literature typically remain far below 10% of the theoretical maximum. This study explores possible reasons for these suboptimal yields by a mass-balancing approach. A cytosolically located, cofactor-balanced isobutanol pathway, consisting of a mosaic of bacterial enzymes whose in vivo functionality was confirmed by complementation of null mutations in branched-chain amino acid metabolism, was expressed in S. cerevisiae. Product formation by the engineered strain was analysed in shake flasks and bioreactors. In aerobic cultures, the pathway intermediate isobutyraldehyde was oxidized to isobutyrate rather than reduced to isobutanol. Moreover, significant concentrations of the pathway intermediates 2,3-dihydroxyisovalerate and alpha-ketoisovalerate, as well as diacetyl and acetoin, accumulated extracellularly. While the engineered strain could not grow anaerobically, micro-aerobic cultivation resulted in isobutanol formation at a yield of 0.018+/-0.003 mol/mol glucose. Simultaneously, 2,3 butanediol was produced at a yield of 0.649+/-0.067 mol/mol glucose. These results identify massive accumulation of pathway intermediates, as well as overflow metabolites derived from acetolactate, as an important, previously underestimated contributor to the suboptimal yields of 'academic' isobutanol strains. The observed patterns of by-product formation is consistent with the notion that in vivo activity of the iron-sulphur-cluster-requiring enzyme dihydroxyacid dehydratase is a key bottleneck in the present and previously described 'academic' isobutanol-producing yeast strains. PMID- 29142821 TI - Tet-On lentiviral transductants lose inducibility when silenced for extended intervals in mammary epithelial cells. AB - Silencing of virally transduced genes by promoter methylation and histone deacetylation has been a chronic problem both experimentally and therapeutically. We observed frequent silencing of the tetracycline-inducible Tet-On promoter borne by the Tripz lentivirus in mammary epithelial cell lines. We found that silencing could be prevented by continuous induction, but uninduced Tet-On gradually became uninducible, suggesting promoter modification. Accordingly, silencing was reversible by a common inhibitor of histone deacetylases, sodium butyrate. The effect was cell-line dependent, as HEK293 cells exhibited only moderate silencing that could be partly reversed by extended induction. These results indicate the need to test individual cell lines prior to using this system for studies that require induction after long periods of repression such as in animal models or RNA interference screens. PMID- 29142822 TI - Development of a plasmid-based expression system in Clostridium thermocellum and its use to screen heterologous expression of bifunctional alcohol dehydrogenases (adhEs). AB - Clostridium thermocellum is a promising candidate for ethanol production from cellulosic biomass, but requires metabolic engineering to improve ethanol yield. A key gene in the ethanol production pathway is the bifunctional aldehyde and alcohol dehydrogenase, adhE. To explore the effects of overexpressing wild-type, mutant, and exogenous adhEs, we developed a new expression plasmid, pDGO144, that exhibited improved transformation efficiency and better gene expression than its predecessor, pDGO-66. This new expression plasmid will allow for many other metabolic engineering and basic research efforts in C. thermocellum. As proof of concept, we used this plasmid to express 12 different adhE genes (both wild type and mutant) from several organisms. Ethanol production varied between clones immediately after transformation, but tended to converge to a single value after several rounds of serial transfer. The previously described mutant C. thermocellum D494G adhE gave the best ethanol production, which is consistent with previously published results. PMID- 29142823 TI - Investigation of useful carbon tracers for 13C-metabolic flux analysis of Escherichia coli by considering five experimentally determined flux distributions. AB - The 13C-MFA experiments require an optimal design since the precision or confidence intervals of the estimated flux levels depends on factors such as the composition of 13C-labeled carbon sources, as well as the metabolic flux distribution of interest. In this study, useful compositions of 13C-labeled glucose for 13C-metabolic flux analysis (13C-MFA) of Escherichia coli are investigated using a computer simulation of the stable isotope labeling experiment. Following the generation of artificial mass spectra datasets of amino acid fragments using five literature-reported flux distributions of E. coli, the best fitted flux distribution and the 95% confidence interval were estimated by the 13C-MFA procedure. A comparison of the precision scores showed that [1, 2 13C]glucose and a mixture of [1-13C] and [U-13C]glucose at 8:2 are one of the best carbon sources for a precise estimation of flux levels of the pentose phosphate pathway, glycolysis and the TCA cycle. Although the precision scores of the anaplerotic and glyoxylate pathway reactions were affected by both the carbon source and flux distribution, it was also shown that the mixture of non-labeled, [1-13C], and [U-13C]glucose at 4:1:5 was specifically effective for the flux estimation of the glyoxylate pathway reaction. These findings were confirmed by wet 13C-MFA experiments. PMID- 29142824 TI - System wide cofactor turnovers can propagate metabolic stability between pathways. AB - Metabolic homeostasis, or low-level metabolic steady state, has long been taken for granted in metabolic engineering, and research priority has always been given to understand metabolic flux control and regulation of the reaction network. In the past, this has not caused concerns because the metabolic networks studied were invariably associated with living cells. Nowadays, there are needs to reconstruct metabolic networks, and so metabolic homeostasis cannot be taken for granted. For metabolic steady state, enzyme feedback control has been known to explain why metabolites in metabolic pathways can avoid accumulation. However, we reasoned that there are further contributing mechanisms. As a new methodology developed, we separated cofactor intermediates (CIs) from non-cofactor intermediates, and identified an appropriate type of open systems for operating putative reaction topologies. Furthermore, we elaborated the criteria to tell if a multi-enzyme over-all reaction path is of in vivo nature or not at the metabolic level. As new findings, we discovered that there are interactions between the enzyme feedback inhibition and the CI turnover, and such interactions may well lead to metabolic homeostasis, an emergent property of the system. To conclude, this work offers a new perspective for understanding the role of CIs and the presence of metabolic homeostasis in the living cell. In perspective, this work might provide clues for constructing non-natural metabolic networks using multi-enzyme reactions or by degenerating metabolic reaction networks from the living cell. PMID- 29142825 TI - Creating metabolic demand as an engineering strategy in Pseudomonas putida - Rhamnolipid synthesis as an example. AB - Metabolic engineering of microbial cell factories for the production of heterologous secondary metabolites implicitly relies on the intensification of intracellular flux directed toward the product of choice. Apart from reactions following peripheral pathways, enzymes of the central carbon metabolism are usually targeted for the enhancement of precursor supply. In Pseudomonas putida, a Gram-negative soil bacterium, central carbon metabolism, i.e., the reactions required for the synthesis of all 12 biomass precursors, was shown to be regulated at the metabolic level and not at the transcriptional level. The bacterium's central carbon metabolism appears to be driven by demand to react rapidly to ever-changing environmental conditions. In contrast, peripheral pathways that are only required for growth under certain conditions are regulated transcriptionally. In this work, we show that this regulation regime can be exploited for metabolic engineering. We tested this driven-by-demand metabolic engineering strategy using rhamnolipid production as an example. Rhamnolipid synthesis relies on two pathways, i.e., fatty acid de novo synthesis and the rhamnose pathway, providing the required precursors hydroxyalkanoyloxy-alkanoic acid (HAA) and activated (dTDP-)rhamnose, respectively. In contrast to single pathway molecules, rhamnolipid synthesis causes demand for two central carbon metabolism intermediates, i.e., acetyl-CoA for HAA and glucose-6-phosphate for rhamnose synthesis. Following the above-outlined strategy of driven by demand, a synthetic promoter library was developed to identify the optimal expression of the two essential genes (rhlAB) for rhamnolipid synthesis. The best rhamnolipid synthesizing strain had a yield of 40% rhamnolipids on sugar [CmolRL/CmolGlc], which is approximately 55% of the theoretical yield. The rate of rhamnolipid synthesis of this strain was also high. Compared to an exponentially growing wild type, the rhamnose pathway increased its flux by 300%, whereas the flux through de novo fatty acid synthesis increased by 50%. We show that the central carbon metabolism of P. putida is capable of meeting the metabolic demand generated by engineering transcription in peripheral pathways, thereby enabling a significant rerouting of carbon flux toward the product of interest, in this case, rhamnolipids of industrial interest. PMID- 29142826 TI - Microbial synthesis of a branched-chain ester platform from organic waste carboxylates. AB - Processing of lignocellulosic biomass or organic wastes produces a plethora of chemicals such as short, linear carboxylic acids, known as carboxylates, derived from anaerobic digestion. While these carboxylates have low values and are inhibitory to microbes during fermentation, they can be biologically upgraded to high-value products. In this study, we expanded our general framework for biological upgrading of carboxylates to branched-chain esters by using three highly active alcohol acyltransferases (AATs) for alcohol and acyl CoA condensation and modulating the alcohol moiety from ethanol to isobutanol in the modular chassis cell. With this framework, we demonstrated the production of an ester library comprised of 16 out of all 18 potential esters, including acetate, propionate, butanoate, pentanoate, and hexanoate esters, from the 5 linear, saturated C2-C6 carboxylic acids. Among these esters, 5 new branched-chain esters, including isobutyl acetate, isobutyl propionate, isobutyl butyrate, isobutyl pentanoate, and isobutyl hexanoate were synthesized in vivo. During 24 h in situ fermentation and extraction, one of the engineered strains, EcDL208 harnessing the SAAT of Fragaria ananassa produced ~63 mg/L of a mixture of butyl and isobutyl butyrates from glucose and butyrate co-fermentation and ~127 mg/L of a mixture of isobutyl and pentyl pentanoates from glucose and pentanoate co fermentation, with high specificity. These butyrate and pentanoate esters are potential drop-in liquid fuels. This study provides better understanding of functional roles of AATs for microbial biosynthesis of branched-chain esters and expands the potential use of these esters as drop-in biofuels beyond their conventional flavor, fragrance, and solvent applications. PMID- 29142827 TI - Overexpression of the primary sigma factor gene sigA improved carotenoid production by Corynebacterium glutamicum: Application to production of beta carotene and the non-native linear C50 carotenoid bisanhydrobacterioruberin. AB - Corynebacterium glutamicum shows yellow pigmentation due to biosynthesis of the C50 carotenoid decaprenoxanthin and its glycosides. This bacterium has been engineered for production of various non-native cyclic C40 and C50 carotenoids such as beta-carotene, astaxanthin or sarcinaxanthin. In this study, the effect of modulating gene expression more broadly by overexpression of sigma factor genes on carotenoid production by C. glutamicum was characterized. Overexpression of the primary sigma factor gene sigA improved lycopene production by recombinant C. glutamicum up to 8-fold. In C. glutamicum wild type, overexpression of sigA led to 2-fold increased accumulation of the native carotenoid decaprenoxanthin in the stationary growth phase. Under these conditions, genes related to thiamine synthesis and aromatic compound degradation showed increased RNA levels and addition of thiamine and the aromatic iron chelator protocatechuic acid to the culture medium enhanced carotenoid production when sigA was overexpressed. Deletion of the gene for the alternative sigma factor SigB, which is expected to replace SigA in RNA polymerase holoenzymes during transition to the stationary growth phase, also increased carotenoid production. The strategy of sigA overexpression could be successfully transferred to production of the non-native carotenoids beta-carotene and bisanhydrobacterioruberin (BABR). Production of the latter is the first demonstration that C. glutamicum may accumulate a non-native linear C50 carotenoid instead of the native cyclic C50 carotenoid decaprenoxanthin. PMID- 29142829 TI - Recent developments in the follow-up, prevention and management of complications in thyroid surgery. PMID- 29142828 TI - Metabolic engineering of Ustilago trichophora TZ1 for improved malic acid production. AB - Ustilago trichophora RK089 has been found recently as a good natural malic acid producer from glycerol. This strain has previously undergone adaptive laboratory evolution for enhanced substrate uptake rate resulting in the strain U. trichophora TZ1. Medium optimization and investigation of process parameters enabled titers and rates that are able to compete with those of organisms overexpressing major parts of the underlying metabolic pathways. Metabolic engineering can likely further increase the efficiency of malate production by this organism, provided that basic genetic tools and methods can be established for this rarely used and relatively obscure species. Here we investigate and adapt existing molecular tools from U. maydis for use in U. trichophora. Selection markers from U. maydis that confer carboxin, hygromycin, nourseothricin, and phleomycin resistance are applicable in U. trichophora. A plasmid was constructed containing the ip-locus of U. trichophora RK089, resulting in site-specific integration into the genome. Using this plasmid, overexpression of pyruvate carboxylase, two malate dehydrogenases (mdh1, mdh2), and two malate transporters (ssu1, ssu2) was possible in U. trichophora TZ1 under control of the strong P etef promoter. Overexpression of mdh1, mdh2, ssu1, and ssu2 increased the product (malate) to substrate (glycerol) yield by up to 54% in shake flasks reaching a titer of up to 120 g L-1. In bioreactor cultivations of U. trichophora TZ1 P etefssu2 and U. trichophora TZ1 P etefmdh2 a drastically lowered biomass formation and glycerol uptake rate resulted in 29% (Ssu1) and 38% (Mdh2) higher specific production rates and 38% (Ssu1) and 46% (Mdh2) increased yields compared to the reference strain U. trichophora TZ1. Investigation of the product spectrum resulted in an 87% closed carbon balance with 134 g L-1 malate and biomass (73 g L-1), succinate (20 g L-1), CO2 (17 g L-1), and alpha ketoglutarate (8 g L-1) as main by-products. These results open up a wide range of possibilities for further optimization, especially combinatorial metabolic engineering to increase the flux from pyruvate to malic acid and to reduce by product formation. PMID- 29142830 TI - Parathyroid hormone and serum calcium levels measurements as predictors of postoperative hypocalcemia in total thyroidectomy. AB - Background: The rules of quantitative measures such as parathyroid hormone (PTH) levels in the first hours following total thyroidectomy have since been validated repeatedly. Such measures play an integral rule in identifying patients at significant risk for hypocalcaemia and have allowed for earlier supplementation of these patients with calcium with or without vitamin D. Methods: A retrospective analysis was conducted of 40 consecutive patients with well differentiated thyroid cancer (WDTC) who underwent total thyroidectomy without central neck dissection (CND) as an initial surgery and no comorbidity at King Abdulaziz Medical City (National Guard hospital), between July 2011 and July 2012. A blood testing protocol was applied for all patients that measured serum calcium PTH at 6 hours postoperatively. Results: Following total thyroidectomy, women were found to experience transient hypocalcaemia in 12.5% of cases (4/32), whereas no men cases encountered this postoperative complication (0/8). However, most probably due to small sample size, this difference was not statistically significant. PTH level was significantly associated with post thyroidectomy hypocalcaemia (43.7+/-39.3 versus 13.40+/-24.9 ng/L), P=0.014. Only negligible differences in the length of hospital stay were observed with and without post thyroidectomy hypocalcaemia. Conclusions: Using post-thyroidectomy PTH levels to predict hypocalcaemia has been confirmed in the current study. So, the use of PTH levels allows for early risk stratification of our patients and we feel this has resulted in better patient satisfaction. PMID- 29142831 TI - What adds Valsalva maneuver to hemostasis after Trendelenburg's positioning during thyroid surgery? AB - Background: Bleeding after thyroidectomy is life-threatening. The aim of the study was to evaluate whether controlling of further bleeding with Valsalva maneuver following Trendelenburg's positioning has an impact on hemostasis. Methods: This prospective study included 68 consecutive patients undergoing thyroidectomy. Study protocol consisted of performing manual intra-abdominal pressure increase and Valsalva maneuver to check hemostasis and treating any bleeding point identified, after Trendelenburg's positioning. All identified bleeding points and treatments were recorded. Results: Total number of bleeding points identified in Trendelenburg's tilt was 49, while it was 41 when using Valsalva maneuver. Abdominal pressure increase, carried out before Valsalva maneuver, identified 14 bleeding points, which was less than bleeding after Trendelenburg's positioning and Valsalva maneuver (P<0.05). All bleeding points, except 1 for Trendelenburg's positioning and 1 for Valsalva maneuver, were minor (<2 mm). Only 4.4% bleeding vessels required ties or stitching. Conclusions: Valsalva maneuver helps to detect any further bleeding following Trendelenburg's positioning. PMID- 29142832 TI - Chyle fistula in advanced and metastatic thyroid cancer. AB - Background: Chyle fistula (CF) is a rare but challenging condition for the surgeon and the patient's health. Methods: A retrospective review of single surgeon's case load in a 12-year period is presented, reviewing the case of those patients presenting with a CF. Results: Three patients were found during this study period from more than 1,050 surgeries performed due to thyroid cancer. Patients underwent extensive lymph node dissection for advanced, metastatic and infiltrative disease. In all patients, a long hospital stay and surgical re interventions were required. Conclusions: A description of the management of CF is presented along with a review of current Literature. PMID- 29142833 TI - The effect of long-term thyroid-stimulating hormone suppressive therapy on the gonadal steroid hormones of patients with thyroid carcinoma after surgery. AB - Background: To analyze the effect of long-term thyroid-stimulating hormone (TSH) suppressive therapy on the gonadal hormones and related symptoms in patients after surgery. Methods: From 2008 to 2011, totally 238 patients were recruited, who underwent thyroid surgery and subsequent TSH suppression treatment in Department of thyroid Surgery, China-Japan Union hospital, Jilin University. Then their postoperative follow-up data (3-8 years) were collected, including operational method, pathological diagnosis, whether processed radioiodine therapy and the period/dose of TSH suppression treatment. In addition, the menstrual cycle, menstruation quantity, whether accompanied with dysmenorrheal and menstrual disorder or not, date of last menstrual period, ages of menopause and so on were also collected. Results: (I) Neither the level nor the duration of TSH treatment had any function on estradiol (E2) and testosterone (T) in male patients; (II) in the subgroup of patients with TSH treatment for 3-5 years, patients who took high dose of TSH (TSH >=0.5 U/L) obtained the lower T level compared with the group of medium dose (1.08+/-0.34 vs. 1.36+/-0.46 nmol/L, P=0.001); (III) in the medium dose (0.1 IU/L <= TSH <0.5 IU/L) of TSH treatment, patients in luteal phase showed significant difference between two separate durations as the E2 level was 196.0 pmol/L in 3-5 years group vs. 442.5 pmol/L in 6-8 years group, P=0.018; (IV) the level of follicle-stimulating hormone (FSH) did not show any change in terms of the dose and the duration of TSH treatment; (V) the menstrual volume, dysmenorrhea condition, menstrual cycle and menopause related indicators did not show any difference in terms of doses and duration of TSH treatment (P=0.701, 0.412 and 0.507 respectively). Conclusions: The long term of TSH repressive therapy after surgery did not affect T and E2 level in male patients. As for female patients, the impact was mainly reflected in the T and E2 levels especially in female sexual maturity but not FSH level. In addition, TSH treatment did not play any role on menstruation or menopause. PMID- 29142834 TI - Two-stage thyroidectomy in the era of intraoperative neuromonitoring. AB - Background: The use of intraoperative neuromonitoring (IONM) provides surgeons with real time information about recurrent laryngeal nerves (RLN) functional integrity. Hence, allowing them to modify the initially scheduled bilateral procedure, to a two-stage thyroidectomy in cases of loss of signal (LOS) on the first side of resection resulting in minimization of bilateral RLN injury. The purpose of our study was to present our results since the implementation of the above mentioned process in both malignant and benign thyroid disease. Methods: We conducted a retrospective, observational cohort study of prospectively collected data from all patients who underwent a scheduled total thyroidectomy with or without neck dissection in our Department over the last 4 years [2013-2016]. From the 1,138 patients who received surgical treatment during that period, 284 were excluded since they did not meet the criteria. Exclusion criteria involved previous neck operation, parathyroid surgery, pre-existing vocal cord palsy (VCP) and unilateral surgery. A total of 854 patients were eligible for our study. All patients were subjected to pre- and postoperative indirect laryngoscopy by the same experienced ENT specialist team and all the surgeries were performed by the same experienced team. The whole procedure followed the International Neural Monitoring Study Group's (INMSG) Guideline Statement. Results: We experienced 70 cases (70/854, 8.2%) with postoperative VCP. Two of them (0.23%) had permanent VCP and the rest of those patients (7.97%) experienced transient VCP. Twenty three (2.7%) patients were candidates for staged thyroidectomy after LOS on the first side of resection, including ten patients with papillary or medullary thyroid carcinoma and one with toxic multinodular goiter (MNG). Of those patients, 22 incidents of VCP (95.7%) have recovered within two months and one of them persisted for more than six months (permanent VCP). We did not experience any permanent bilateral RLN palsy after the implementation of the staged procedure. Conclusions: Staged thyroidectomy seems a very attractive and promising procedure for both patient and surgeon, since it nearly eliminates one of the most fearful complications in thyroid surgery. We suggest staged thyroidectomy in all cases with first side of resection signal loss, even in malignancies, since the benefits are much more than the disabilities in a patient's morbidity and quality of life. PMID- 29142835 TI - Trachway video intubating stylet allows for optimization of electromyographic endotracheal tube placement for monitored thyroidectomy. AB - Background: Endotracheal tube-based surface electrodes are now commonly applied to measure evoked electromyographic (EMG) response of the vocal cord during monitored thyroidectomy. The aim of the study was to determine the incidence of difficult intubation and to assess the effectiveness of using video-assisted intubating stylet (Trachway) for EMG tube placement in patients undergoing monitored thyroidectomy. Methods: Medical records were collected from consecutive patients undergoing thyroid surgery before and after implementation of the protocol. A total of 748 patients intubated with EMG tube for monitored thyroidectomy by the same team were enrolled in this study. Patient allocation was based on intubation technique either conventional direct laryngoscopy (n=336) or Trachway (n=412). The intubation difficulty was assessed and analyzed. Results: The overall incidence of difficult intubation was 4.4%. Incidence of difficult intubation was significantly lower in patients with the Trachway procedure (2.7%) than direct laryngoscopy (6.5%, P=0.01). The incidence of "unable to intubate" (>3 attempts, or change airway device or anesthesiologist) also significantly reduced from 2.3% to 0.5% after introduction of the Trachway intubating stylet (P=0.02). Conclusions: We conclude that the incidence of difficult intubation was significantly lower with Trachway than direct laryngoscopy. The Trachway video-intubating stylet is useful and helpful to reduce EMG tube intubation difficulty for monitored thyroidectomy. PMID- 29142837 TI - Preoperative management in patients with Graves' disease. AB - Graves' disease is the most frequent cause of hyperthyroidism in iodine sufficient geographical areas and is characterized by the presence in patients' serum of autoantibodies directed against the thyrotropin receptor (TRAb) that cause overproduction and release of thyroid hormones. Clinical presentation results from both hyperthyroidism and underlying autoimmunity. The diagnosis is based on characteristic clinical features and biochemical abnormalities. If serum thyrotropin (TSH) is low, serum free thyroxine (FT4) and free triiodothyronine (FT3) concentrations should be measured to distinguish between subclinical (with normal circulating thyroid hormones) and overt hyperthyroidism (with increased circulating thyroid hormones). Graves' disease is treated with any of three effective and relatively safe initial treatment options: antithyroid drugs (ATDs), radioactive iodine ablation (RAIU), and surgery. Total thyroidectomy is favored in several clinical situations, such as intolerance, ineffectiveness or recurrence after ATD treatment, radioiodine therapy contraindicated, documented or suspected thyroid malignancy, one or more large thyroid nodules, coexisting moderate-to-severe active Graves' orbitopathy, women planning a pregnancy within 6 months. Whenever surgery is selected as treatment, selection of an expert high volume thyroid surgeons is fundamental and careful preoperative management is essential to optimize surgical outcomes. Pretreatment with ATDs in order to promptly achieve the euthyroid state is recommended to avoid the risk of precipitating thyroid storm during surgery. For the majority of patients, euthyroidism is achieved after few weeks of ATD treatment. Beta-blockers, such as propranolol, are often added effectively to control hyperthyroid symptoms. Saturated solution of potassium iodide (SSKI) or potassium iodine (Lugol's solution), given for a short period prior to surgery, in order to reduce both thyroid hormone release and thyroid gland vascularity, is beneficial to decrease intra-operative blood loss. PMID- 29142836 TI - Preoperative, intraoperative and postoperative anesthetic prospective for thyroid surgery: what's new. AB - The aim of this review is to analyze what's new on anesthetic prospective to perioperative management for thyroid surgery. For recent decades intraoperative neuromonitoring (IONM) during thyroid and parathyroid surgery has obtained more and more popularity. New modality of anesthetic technique was also developed to incorporate into surgical teamwork. For example, the precise position of EMG tube and optimal use of neuromuscular blocking agents (NMBAs) play key roles in successful IONM system. Special focus is paid to following issues: (I) preoperative airway evaluation and pre-op preparation; (II) anesthetic managements including advanced intubation tools, NMBAs and sugammadex; and (III) post-op adverse events such as pain and postoperative nausea vomiting. PMID- 29142838 TI - Preoperative information for thyroid surgery. AB - The preoperative information necessary to communicate to the patient to obtain informed consent in thyroid surgery is not detailed in length in the current medical literature. Advances in technology and the advent of remote access approaches in thyroid surgery have increased the need for a detailed communication of risks, benefits and alternatives to achieve an informed consent. In this review article, we outline the indications for thyroid surgery, risks of thyroid surgery, different approaches to thyroidectomy, and possible consequences of using advanced technology using intraoperative nerve monitoring (IONM) as an example. A truly detailed informed consent in the modern age of thyroid surgery is crucial. This article not only details the risks, benefits and alternatives of thyroid surgery, but also incorporates new practices, guidelines and technologies to allow patients to achieve a comprehensive preoperative understanding of treatment recommendations. PMID- 29142839 TI - Morbidity from minimally invasive video-assisted thyroidectomy: a general review. AB - Minimally invasive video-assisted thyroidectomy (MIVAT) is known and used worldwide, it combines the advantages associated with endoscopic magnification with those due with traditional surgery. In selected patients, it should be considered a safe and valid alternative. Indeed, a lot of comparative studies have demonstrated the advantages of MIVAT in terms of low rate of complications, reduced postoperative pain, improved cosmetic results and higher patient satisfaction over traditional surgery. Anyway, for obtaining the best results, with similar or even less complication rate than traditional surgery, surgeons should be well trained, acquired confidence with a smaller surgical incision and with the use of endoscopic instruments. PMID- 29142841 TI - Speech therapy after thyroidectomy. AB - Common complaints of patients who have received thyroidectomy include dysphonia (voice dysfunction) and dysphagia (difficulty swallowing). One cause of these surgical outcomes is recurrent laryngeal nerve paralysis. Many studies have discussed the effectiveness of speech therapy (e.g., voice therapy and dysphagia therapy) for improving dysphonia and dysphagia, but not specifically in patients who have received thyroidectomy. Therefore, the aim of this paper was to discuss issues regarding speech therapy such as voice therapy and dysphagia for patients after thyroidectomy. Another aim was to review the literature on speech therapy for patients with recurrent laryngeal nerve paralysis after thyroidectomy. Databases used for the literature review in this study included, PubMed, MEDLINE, Academic Search Primer, ERIC, CINAHL Plus, and EBSCO. The articles retrieved by database searches were classified and screened for relevance by using EndNote. Of the 936 articles retrieved, 18 discussed "voice assessment and thyroidectomy", 3 discussed "voice therapy and thyroidectomy", and 11 discussed "surgical interventions for voice restoration after thyroidectomy". Only 3 studies discussed topics related to "swallowing function assessment/treatment and thyroidectomy". Although many studies have investigated voice changes and assessment methods in thyroidectomy patients, few recent studies have investigated speech therapy after thyroidectomy. Additionally, some studies have addressed dysphagia after thyroidectomy, but few have discussed assessment and treatment of dysphagia after thyroidectomy. PMID- 29142840 TI - Morbidity of central neck dissection for papillary thyroid cancer. AB - Thyroid cancer has a very well-known propensity for nodal involvement, either in the central and lateral neck compartments. Neck dissection addressing the central compartment may be performed with an elective or therapeutic intent, the former concomitantly to a thyroidectomy whereas the latter may be accomplished also as a revision procedure for recurrent disease. In this paper complications of central compartment neck dissection will be described, analyzing separately primary and revision procedures. PMID- 29142842 TI - Prevention and management of bleeding in thyroid surgery. AB - Post-thyroidectomy neck hematoma represents a major concern for surgeons because it can result in severe and even life-threatening complications. In fact, postoperative hemorrhage may result in airway compression and respiratory distress, and therefore, effective hemostasis is an important goal in thyroid surgery. Postoperative hematoma occurs at a rate of approximately 0.1% to 1.1%. Almost all cases occur in the first 6 h after surgery and can be the result of several surgeon or patient factors. For many years the clamp-and-tie technique has been the most common way to divide the main vascular pedicles of the thyroid gland. Alternatively, bipolar electrocautery has been used for only very small vessels. Other hemostatic systems have been introduced and proved to be potentially very useful in neck surgery and, in particular, for thyroid surgery. This new class of instruments is generally known as "energy devices" because they use different forms of energy, such as advanced bipolar (LigaSureTM Small Jaw Medtronic, Covidien product, Mineapolis, MN, USA) and ultrasound (Harmonic Focus; Ethicon, Johnson and Johnson, Cincinnati, OH, USA), and hybrid devices that join these two technologies (Thunderbeat by Olympus, Japan). Although they all generate a significant elevation of temperature in the tissues, as in any form of energy, the temperatures reached by these instruments are never as high as the standard monopolar electrocautery. For small bleeding very close to critical structures, where energy devices are too dangerous to be used and clamp and tie is not possible, several studies have assessed the use of adjunctive hemostatic agents. In conclusion, all energy devices have been shown to significantly decrease operative times without increasing costs or complications. Adjunctive hemostatic agents have shown equivalent differences when added to standard methods from a clinically significant perspective. PMID- 29142843 TI - Intraoperative real-time localization of parathyroid gland with near infrared fluorescence imaging. AB - Surgeons have cited difficulties in identifying the parathyroid glands (PG) during thyroidectomy. To overcome the limitation of naked eye, many studies on near-infrared fluorescence imaging of PGs have been introduced and suggested that fluorescence imaging is useful for both localizing PGs and evaluating their function. This imaging technique has been reported in two ways: (I) imaging using a fluorescent material called indocyanine green (ICG); and (II) autofluorescence using intrinsic fluorophores. These innovative and novel techniques are expected to have a significant impact on performing thyroid or parathyroid surgery. In this article, current papers that describe ICG fluorescence and autofluorescence imaging of PG during thyroid and parathyroid surgery are reviewed. PMID- 29142844 TI - Antibiotic prophylaxis in thyroid surgery. AB - Use of antibiotic prophylactic (AP) in clean surgery is still controversial. We reviewed the literature of the last 10 years to identify the best way to approach the use of prophylactic antibiotic in thyroid surgery. In thyroid surgery, it is a highly controversial topic primarily due to the lack of evidence in "support" of or "against" antibiotic use. In this review, the authors analyze the literature on the use of AP in thyroid surgery in order to evaluate if the available data support or contradict this use routinely. PMID- 29142845 TI - Parathyroid transplantation in thyroid surgery. AB - Permanent hypoparathyroidism following thyroid surgery is rare. Its prevalence is reported to be below 1-2% if surgery is performed by experienced thyroid surgeons. Parathyroid identification and preservation in situ with good vascular supply is the mainstay of safe thyroid surgery. However, if the parathyroid glands are damaged, autotransplantation should be undertaken to preserve their function. Parathyroid transplantation can be considered in three distinct modes of application: (I) fresh parathyroid tissue autotransplantation during thyroidectomy in order to reduce the risk of permanent hypoparathyroidism; (II) cryopreserved parathyroid tissue autotransplantation in patients with permanent hypoparathyroidism; (III) parathyroid allotransplantation in patients with permanent hypoparathyroidism when cryopreserved parathyroid tissue is not available for grafting. Nowadays, allotransplantation of cultured parathyroid cells without immunosuppression should be taken into consideration in selected patients as an alternative to calcium and vitamin D3 supplementation in management of permanent hypoparathyroidism. This paper is aimed to provide a review of current status of various parathyroid transplantation techniques in thyroid surgery. PMID- 29142846 TI - Opportunities and challenges of intermittent and continuous intraoperative neural monitoring in thyroid surgery. AB - The number of thyroid operations and there radically continues to rise in the western hemisphere, bringing prevention of recurrent laryngeal nerve (RLN) palsy to the fore. Overall, the incidence of RLN palsy is fairly low but continues to prompt litigation for malpractice. In an effort to diminish transient, and more importantly permanent, RLN palsy rates, intraoperative neuromonitoring (IONM) has been advocated as a risk minimization tool. Recent meta-analyses of studies, many of which were limited by poor study design and the sole use of intermittent nerve stimulation, were unable to demonstrate superiority of IONM over mere anatomic RLN dissection. This is where continuous IONM (CIONM) comes into play: this technology enables the surgeon to (I) identify impending nerve injury as it unfolds; (II) release distressed nerves by reversing causative surgical maneuvers; and (III) verify functional nerve recovery after intraoperative loss of the electromyographic signal. Despite this superiority, CIONM is not devoid of methodological limitations, which need to be accounted for. This review summarizes the current key achievements of IONM; outlines opportunities for improvement regarding clinical implementation; and suggests areas of future research in this rapidly evolving field. PMID- 29142847 TI - Predictive features associated with thyrotoxic storm and management. AB - Thyroid storm (TS) is an endocrine emergency characterized by rapid deterioration, associated with high mortality rate therefore rapid diagnosis and emergent treatment is mandatory. In the past, thyroid surgery was the most common cause of TS, but recent preoperative medication creates a euthyroid state before performing surgery. An active approach during perioperative period could determine an effective clinical treatment of this life-threating diseases. Recently, the Japan Thyroid Association and Japan Endocrine Society developed diagnostic criteria for TS focusing on premature and prompt diagnosis avoiding inopportune e useless drugs. This review analyses predictive features associated with thyrotoxic storm highlighting recent literature to optimize the patient quality of care. PMID- 29142849 TI - The application of drains in thyroid surgery. AB - It has been shown that the use of drain in thyroid surgery does not reduce the reoperation rate for hemorrhage. The aim of this systematic review was to update the knowledge of the role of drain in thyroid surgery in term of postoperative complications, pain and hospital length of stay (LOS). A systematic search was performed in the PubMed and Embase database to identify all randomized controlled trials (RCTs) comparing clinical outcomes in patients who underwent thyroidectomy or lobectomy with or without drainage. The primary outcome was reoperation rate for bleeding; the secondary outcomes were development of hematoma, seroma, and wound infection; postoperative pain evaluated by Visual Analogue Scale (VAS) at the postoperative day (POD) 1, and hospital LOS. Risk ratios (RRs) and 95% confident intervals (95% CI) were used for dichotomous variables; mean differences (MDs) and 95% CI for continuous variables. Statistical heterogeneity was evaluated and its degree was quantified by the I2 statistic. Twenty RCTs were included, with 2,204 patients enrolled. No difference was found between the two groups in term of reoperation [RR 1.13 (0.43, 2.95); I2 =0%], hematoma [RR 1.18 (0.71, 1.95); I2 =0%], and seroma [RR 0.82 (0.44, 1.53); I2 =0%]. Patients with drain had higher postoperative pain [MD 1.91 (1.30, 2.53); I2 =97%], prolonged hospital LOS [MD 1.34 (0.91, 1.76) days; I2 =98%], and increased wound infection rate [RR 2.82 (1.36, 5.86); I2 =0%], even though the latter was not confirmed in the sensitivity analysis including only studies with >=100 patients per trial. The use of drain after thyroid surgery increase postoperative pain and hospital LOS, with no decrease of reoperation rate, hematoma and seroma formation. An increased wound infection rate in patients with drain is suggested, but a large RCT should be performed to confirm this correlation. PMID- 29142848 TI - Injury of the external branch of the superior laryngeal nerve in thyroid surgery. AB - The external branch of the superior laryngeal nerve (EBSLN) innervates the cricothyroid muscle (CTM) to promote lengthening and thinning of the vocal fold, thus increasing voice pitch. The close relation with the superior thyroid vessels (STV) puts the EBSLN in risk every time the superior pole of the thyroid is dissected. It travels downward to innervate the CTM, lateral to the thyroid cartilage and to the inferior pharyngeal constrictor muscle (IPCM), being eventually covered by this muscle fibers as it approaches its entry point. During its descending course, the EBSLN curves and crosses the STV posteriorly. The lower this crossing occurs in the neck, the higher the risk of surgical damage to the nerve by transection, traction, entrapment, thermal damage or disrupted blood supply. The chances of surgical trauma are also increased by size and weight of the specimen, shorter neck length and non-white ethnicity. Voice changes following thyroid surgery are common and multifactorial. The actual rate of vocal impairment due to EBSLN injury is unclear, since changes to the everyday speaking voice can be minimal and laryngeal findings are usually subtle and controversial. CTM electroneuromyography (EMG) is the most accurate tool to diagnose abnormal EBSLN conductivity, but it is technically difficult and barely applicable in routine practice. Recommended approaches to prevent injury include: (I) individual distal ligature of the STV by the thyroid capsule; (II) visual identification of the nerve and its trajectory and (III) electrostimulation with either observation of CTM twitch or intraoperative nerve monitoring (IONM) via dedicated endotracheal tube electrodes. There is accumulating evidence that a combination of visual and standardized electrophysiological EBSLN identification with meticulous division of the STV improves preservation rates. IONM bears the additional benefits of prognostication, quantification and documentation of neural function once it allows intraoperative laryngeal EMG. PMID- 29142850 TI - Complications from tracheal resection for thyroid carcinoma. AB - Thyroidectomy associated to en bloc tracheal resection with end-to-end anastomosis is the treatment of choice of thyroid tumor invading the tracheal wall and is associated with a good prognosis. However, the postoperative morbidity is not irrelevant. The present review aims to discuss the complications occurring after this aggressive surgical procedure. The search was performed using PubMed through an overarching for the following terms: "complication of tracheal resection [AND] invasive thyroid cancer". Postoperative complications rate after tracheal sleeve resection with end-to-end anastomosis for thyroid cancer invading tracheal wall range from 15% to 39%. Postoperative mortality is about 1.2%. The most common postoperative complications are: anastomotic dehiscence, airway stenosis, infections and bleeding. Tumor local recurrence can be considered a late on set complication. To conclude, in locally invasive thyroid cancer, en bloc resection of the thyroid with the tracheal segment interested by the tumor provides a good prognosis despite the non-negligible postoperative morbidity rate. Patients' selection and accurate surgical technique performing a tracheal tension-free anastomosis are mandatory to reduce postoperative morbidity and mortality. PMID- 29142851 TI - The use of ICG enhanced fluorescence for the evaluation of parathyroid gland preservation. AB - Indocyanine green (ICG) enhanced fluorescence imaging is recent innovation as the "real-time intraoperative imaging" technique. Many clinical studies have been reported in the literature which use different devices and techniques that employ various doses and usages of ICG as a non-specific contrast agent. Several groups have performed studies in endocrine surgery, especially with regards to parathyroid-related outcomes after thyroid and parathyroid surgery. However, there is no consensus on the technical details that should be applied. With this study, we aimed to review the current literature on potential use of intraoperative ICG angiography for evaluating parathyroid gland (PTG) preservation. PMID- 29142852 TI - Thyroidectomy in elderly patients aged >=70 years. AB - Worldwide, the indications for thyroid surgery have been continuously extended among elderly patients in the last 20 years. The balance between treatment indication and surgical risk is certainly an interesting topic for every thyroid surgeon. This paper is a review of recent literature from January 2005 up to April 2017. We analyzed three principal subjects: indications for surgical treatment, medical complications and surgical complications. We can summarize the conclusions of our analysis, stating that age could not be considered as an absolute factor, but in relation to the comorbidities and the general clinical condition of the patient. Special risk indices dedicated to geriatric patients could be very useful in order to facilitate the decision-making process; however, relying on the current knowledge, we could state that there is value in providing surgery to geriatric patients in highly specialized and high-volume centers, where access to technology and its systematic use, coupled with surgeons' experience, could certainly avail the geriatric patient management. PMID- 29142853 TI - Silk suture reaction in thyroid surgery. AB - Silk suture reaction (i.e., a benign granulomatous inflammatory foreign body reaction) is a rare complication of thyroid surgery. Here, two cases of post thyroidectomy suture reaction are presented. Both of the patients were female, one is 48 and the other is 34 years old. The patients were presented with neck swelling and leakage of serous fluid from the Kocher's incision. Both patients had normal free T4, free T3, and TSH values. The 48-year-old female patient had a right subtotal and left near-total thyroidectomy 6 years ago and the other had bilateral total thyroidectomy 6 years ago. In the physical examination a mobile, painless, red, swelling was palpated in front of neck. In the ultrasound of both patients, a heterogeneous nodule with hypoechoic rim was seen, however, in scintigraphy no radiopharmaceutical involvement was observed in thyroid region. Due to suspicion of thyroid malignancy, a fine needle aspiration biopsy was performed and foreign body reaction was revealed cytologically. A suture reaction can vary from an erythematous swelling to chronic granulomatous reaction. The time interval between the operation and formation of suture reaction was 6 years in both of the cases thus these patients were considered as chronic patients. Foreign body reaction diagnosis was confirmed with fine needle aspiration biopsy. It is important to diagnose these chronic inflammation cases since these cases can mimic recurrence in thyroid malignancies. A post-thyroidectomy suture reaction is diagnosed cytologically with fine needle aspiration biopsy and by surgical removal of suture, this chronic inflammatory reaction can be cured. PMID- 29142854 TI - Skin metastasis on the neck: an unusual presentation of recurrence of papillary thyroid carcinoma. AB - Skin metastasis of papillary thyroid carcinoma (PTC) is rare. Here, two cases of skin metastases of PTC are presented. Both of the patients were females, one is 83 and the other is 65 years old. The patients were admitted to the hospital with a movable skin lesion on anterior neck region. Free T3 and T4 levels were in normal levels and TSH levels were low in both patients. The 83-year-old patient underwent total thyroidectomy due to papillary thyroid cancer and received 131I ablation therapy and then thyroid suppression therapy. After the surgery, the patient lived without evidence of disease for 3 years and then skin metastasis occurred. The 65-year-old patient had a total thyroidectomy 5 years ago due to PTC then neck dissection due to metastasis 3 years later and then received 131I ablation therapy. Thyroid ultrasonography of both patients showed hypoechoic nodules with central vascularization. In the histological examination of both patients, cystic lesions filled with papillary structures were seen. Fine needle aspiration biopsy (FNAB) taken from both patients were papillary carcinoma with solid trabecular pattern. PTC tends to metastasize to regional lymph nodes but distant metastasis is rare. When distant metastasis develops, prognosis of the disease is poor. Therefore, skin metastasis of papillary thyroid cancer is a poor prognostic factor. If the patient does not have a thyroid malignancy history, diagnosis of PTC metastatic to the skin may be difficult since primary skin tumors such as apocrine tumors have similar histopathological features. However, in the presented cases since there was a PTC history, the diagnosis was easier with the help of histopathological examination. Skin metastasis of PTC should be kept in mind when differential diagnosis of atypical skin lesions are made especially in the patients with thyroid malignancy history. PMID- 29142855 TI - Single port thoracoscopic treatment of thoracic duct injury after thyroidectomy with neck dissection. AB - Chylous leakage is a complication of thyroidectomy accompanied by bilateral neck dissection with incidence of 0.5-6.2%. A 51-year-old female patient underwent total thyroidectomy, bilateral and central neck dissection for papillary thyroid carcinoma. In post-operative 4th day, left sided chylous leakage was observed as 1,500 cc/day through neck drain. Leakage did not cease after 1-month conservative treatment so single port thoracoscopic intervention was performed. Under general anesthesia, patient was placed in left lateral decubitus position. An Alexis(r) retractor was placed through sixth intercostal space. Thoracic cavity was visualized with 30o scope. Posteroinferior edge of lower lobe was retracted superior posteriorly with a Foerster clamp to display inferior pulmonary ligament, which was then divided with electrocautery. Posterior mediastinal pleura between azygous vein and chest wall was incised to mobilize the vein. After that, mediastinal pleura between azygous vein and esophagus was cut longitudinally and esophagus was retracted anteriorly to dissect towards aorta. By dissection, thoracic duct was revealed as a thin tubular structure with occasional peristalsis. After isolation of the duct, it was clipped using Hem-o lok(r). Finally, fibrin sealant was applied to decrease risk of recurrence. One chest tube was placed to ensure adequate drainage of thoracic cavity and complete re-expansion of lung. Neck drain and chest tube was extracted in postoperative second and fourth day respectively and patient was discharged at 8th day. Single port thoracoscopy is a safe choice for treatment of chylous leakages due to cervical ductus thoracicus injury with faster recovery. PMID- 29142856 TI - Erratum to the role of the physiotherapy in the plastic surgery patients after oncological breast surgery. AB - [This corrects the article on p. 43 in vol. 3, PMID: 25083493.]. PMID- 29142858 TI - Notice of Retraction. AB - [This retracts the article on p. 13 in vol. 38.]. PMID- 29142857 TI - Advances in Imaging: Brain Tumors to Alzheimer's Disease. AB - Professor Black and colleagues have been working to improve the quality and sensitivity of imaging in the early detection of conditions from brain tumors to Alzheimer's disease to enhance treatment protocols and patient management. Professor Black et al introduced nanoparticles to improve MRI imaging. These nanoparticles consist of poly (b-L- malic acid (PMLA)) conjugates with monoclonal antibodies ((mAbs)) and Gd-DOTA. These are known as MRI nano-imaging agents (NIA). Most importantly, they can penetrate the endothelial blood-brain barrier (BBB) to reach brain tumors (primary or metastasis). This is effective in cases of brain tumors or breast cancer or other cancers such as lung cancer and gastric cancer having HER2 and/or EGFR positive crossing BBB. By the covalent conjugation of MR contrast (NIA), the MRI virtual biopsy can differentiate brain tumors from infections or other brain pathological conditions. The brain's intrinsic natural fluorescence such as NADH, FAD, lipopigments and porphyrin in the brain tissue can be identified by using time resolved fluorescence spectroscopy (TRFS) which is operated through the use of ultra-short laser. TRFS produces various color bands to differentiate the tumor from normal brain tissue in real time and registers the data on a 3D map. This is significant, as this will provide a greatly improved assessment methodology of tissue type. Consequently, this will potentially result in shorter operation times as well as more satisfactory tumor removal. In the detection of Alzheimer disease, amyloid plaque is deposited in retina tissue (including the RGC, RNFL and inner plexiform layer) which can produce a fluorescence effect by using curcumin as a contrast. This is then shown by human retina amyloid imaging device. Immunotherapies with glatiramer acetate (GA) have been shown to reduce amyloid deposits in brain and retinal AB deposits in mice. The study of advanced imaging technology and techniques including NIA, TRFS and the detection of amyloid plaque in Alzheimer disease are very important approaches to create a new era for diagnostic and therapeutic management of brain tumors and other cancers (HER2 and/or EGFR positive). This pioneering work by Professor Black, and colleagues, gives rise to a new hope for cancer patients for targeted therapy and for immunotherapies in Alzheimer's disease. PMID- 29142859 TI - Notice of Retraction. AB - [This retracts the article on p. 101 in vol. 38.]. PMID- 29142860 TI - Notice of Retraction. AB - [This retracts the article on p. 661 in vol. 38.]. PMID- 29142861 TI - The use of buccal fat pad in oral and maxillofacial reconstruction. PMID- 29142863 TI - Rabbit submandibular salivary gland replantation. AB - Objectives: To test the feasibility of submandibular salivary gland (SMG) replantation techniques and the survival of the replanted glands. Such a study can provide a rationale for later allotransplantation procedures, along with implementation of conventional and advanced immunosuppression therapy. Materials and Methods: Six SMG replantations were performed in New Zealand white rabbits. One week postoperatively, 99mTc scintigraphy was performed and the uptake ratio and salivary excretion fraction were calculated. Two to four weeks later, submandibular glands were excised, fixed, and stained with H&E for histomorphometric evaluation. Results: Intraoperatively, all glands showed patent blood perfusion except gland 5. Positive tracer uptake and saliva excretion were documented by scintigraphy. On excision, all of the glands except glands 4 and 5 looked viable, with a red color and patent pedicles. Gland 4 was infected and filled with creamy pus, while gland 5 looked pale and necrotic. Histologically, glands 1, 2, 3, and 6 had preserved normal glandular tissue with slight variations from the contralateral normal glands, as their parenchyma was composed of mildly atrophic acini. Conclusion: Four out of six replanted SMGs successfully survived. The glands maintained good viability and function. Such success depends on safe harvesting, short anastomosis time, and strict control of infection. PMID- 29142862 TI - Three-dimensional printing for craniomaxillofacial regeneration. AB - Craniomaxillofacial injuries produce complex wound environments involving various tissue types and treatment strategies. In a clinical setting, care is taken to properly irrigate and stabilize the injury, while grafts are molded in an attempt to maintain physiological functionality and cosmesis. This often requires multiple surgeries and grafts leading to added discomfort, pain and financial burden. Many of these injuries can lead to disfigurement and resultant loss of system function including mastication, respiration, and articulation, and these can lead to acute and long-term psychological impact on the patient. A main causality of these issues is the lack of an ability to spatially control pre injury morphology while maintaining shape and function. With the advent of additive manufacturing (three-dimensional printing) and its use in conjunction with biomaterial regenerative strategies and stem cell research, there is an increased potential capacity to alleviate such limitations. This review focuses on the current capabilities of additive manufacturing platforms, completed research and potential for future uses in the treatment of craniomaxillofacial injuries, with an in-depth discussion of regeneration of the periodontal complex and teeth. PMID- 29142864 TI - Count of platelet and mean platelet volume score: serologic prognostic factor in patients with oral squamous cell carcinoma. AB - Objectives: TNM staging, especially for lymph node metastasis, is the scoring system most widely used among prognostic factors for cancer survival. Several biomarkers have been studied as serologic markers, but their specificity is low and clinical applications are difficult. This study aimed to establish a scoring system for patients with oral squamous cell carcinoma (OSCC) using platelet (PLT) and mean platelet volume (MPV) levels measured postoperatively and to evaluate their significance as prognostic factors. Materials and Methods: We studied 40 patients admitted to the Department of Oral and Maxillofacial Surgery of Dankook University Hospital who were diagnosed with primary OSCC histopathologically between May 2006 and May 2012. Clinical pathological information obtained from the medical records of each patient included age, sex, height, weight, tumor location, degree of differentiation, tumor diameter, lymph node metastasis, TNM stage, and other test values including white blood cell, MPV, PLT, C-reactive protein (CRP), and albumin obtained through a test conducted within 7 days before surgery. Count of platelet (COP)-MPV Score: Patients with both PLT and MPV values below the cut-off values were defined as score 0 (group A). Patients with at least one of the two higher than the cut-off value were defined as score 1 (group B). Results: Univariate analyses showed N-metastasis, COP-MPV (A vs B), PLT, platelet-lymphocyte ratio, and CRP were statistically significant prognostic factors. A multivariate Cox proportional hazards model showed N-metastasis (hazard ratio [HR] 6.227, P=0.016) and COP-MPV (A vs B) (HR 18.992, P=0.013) were independent prognostic factors with a significant effect on survival. Conclusion: COP-MPV score is a simple and cost-effective test method and is considered a more effective prognostic factor than other considered factors in predicting the prognosis of OSCC patients. PMID- 29142865 TI - Osteosarcoma of the jaws in Koreans: analysis of 26 cases. AB - Objectives: In order to assess clinical behavior, response to treatment, and factors influencing prognosis of Korean patients with osteosarcoma of the jaws (OSJ). Materials and Methods: A retrospective study of clinical, and pathological records of 26 patients with OSJ treated at the Department of Oral and Maxillofacial Surgery in Yonsei University Dental Hospital from 1990 to March 2017. Results: Of 26 patients, there were 9 men (34.6%) and 17 women (65.4%). Twenty-one of 26 patients had osteosarcoma of the mandible, and 5 of 26 patients had osteosarcoma of the maxilla. The histopathology of OSJ is highly variable, ranging from chondroblastic type (6 out of 26), osteoblastic type (10 out of 26), fibroblastic type (2 out of 26), to the rare variants like mixed type, small cell osteosarcoma types and more. All patients underwent gross total excision and only a few patients underwent neoadjuvant chemotherapy. Postoperative chemotherapy was given to most of the patients as adjuvant treatment or in combination with radiotherapy. The overall survival rate was 73.1% with an overall 2-year survival rate of 83.3%. The overall 5-,10-,15-year survival rates in this study were 73.5%, 73.5%, 49%, respectively. Using Kaplan-Meier analysis with log rank tests, the size of tumor (T-stage), and resection margins were found to affect the survival rate significantly. The chemotherapy was not significantly associated with improved survival rate. Conclusion: Surgical resection with a clear margin is the most important factor in disease survival. The role of chemotherapy and radiotherapy in OSJ remains controversial, and deserves further studies. PMID- 29142866 TI - Inferior alveolar nerve cutting; legal liability versus desired patient outcomes. AB - Objectives: Mandibular angle reduction or reduction genioplasty is a routine well known facial contouring surgery that reduces the width of the lower face resulting in an oval shaped face. During the intraoral resection of the mandibular angle or chin using an oscillating saw, unexpected peripheral nerve damage including inferior alveolar nerve (IAN) damage could occur. This study analyzed cases of damaged IANs during facial contouring surgery, and asked what the basic standard of care in these medical litigation-involved cases should be. Materials and Methods: We retrospectively reviewed a total of 28 patients with IAN damage after mandibular contouring from August 2008 to July 2015. Most of the patients did not have an antipathy to medical staff because they wanted their faces to be ovoid shaped. We summarized three representative cases according to each patient's perceptions and different operation procedures under the approvement by the Institutional Review Board of Seoul National University. Results: Most of the patients did not want to receive any further operations not due to fear of an operation but because of the changes in their facial appearance. Thus, their fear may be due to a desire for a better perfect outcome, and to avoid unsolicited patient complaints related litigation. Conclusion: This article analyzed representative IAN cutting cases that occurred during mandibular contouring esthetic surgery and evaluated a questionnaire on the standard of care for the desired patient outcomes and the specialized surgeon's position with respect to legal liability. PMID- 29142867 TI - Immunohistochemical evaluation of p63 and cyclin D1 in oral squamous cell carcinoma and leukoplakia. AB - Objectives: There are only a limited number of studies on cyclin D1 and p63 expression in oral squamous cell carcinoma (OSCC) and leukoplakia. This study compared cyclin D1 and p63 expression in leukoplakia and OSCC to investigate the possible correlation of both markers with grade of dysplasia and histological grade of OSCC. Materials and Methods: The study included a total of 60 cases, of which 30 were diagnosed with OSCC and 30 with leukoplakia, that were evaluated immunohistochemically for p63 and cyclin D1 expression. Protein expression was correlated based on grades of dysplasia and OSCC. Results: Out of 30 cases of OSCC, 23 cases (76.7%) were cyclin D1 positive and 30 cases (100%) were p63 positive. Out of 30 cases of leukoplakia, 21 cases (70.0%) were cyclin D1 positive and 30 (100%) were p63 positive (P<0.05). Conclusion: The overall expression of cyclin D1 and p63 correlated with tumor differentiation, and increases were correlated with poor histological grades, from well-differentiated to poorly-differentiated SCC. Increased cyclin D1 and p63 expression was associated with the severity of leukoplakia. Based on these results cyclin D1 and p63 products can be a useful tool for improved leukoplakia prognosis. PMID- 29142868 TI - Protrusive maxillomandibular fixation for intracapsular condylar fracture: a report of two cases. AB - Clinical limitations following closed reduction of an intracapsular condylar fracture include a decrease in maximum mouth opening, reduced range of mandibular movements such as protrusion/lateral excursion, and reduced occlusal stability. Anteromedial and inferior displacement of the medial condyle fragment by traction of the lateral pterygoid muscle can induce bone overgrowth due to distraction osteogenesis between the medial and lateral condylar fragments, causing structural changes in the condyle. In addition, when conventional maxillomandibular fixation (MMF) is performed, persistent interdental contact sustains masticatory muscle hyperactivity, leading to a decreased vertical dimension and premature contact of the posterior teeth. To resolve the functional problems of conventional closed reduction, we designed a novel method for closed reduction through protrusive MMF for two weeks. Two patients diagnosed with intracapsular condylar fracture had favorable occlusion after protrusive MMF without premature contact of the posterior teeth. This particular method has two main advantages. First, in the protrusive position, the lateral condylar fragment is moved in the anterior-inferior direction closer to the medial fragment, minimizing bone formation between the two fragments and preventing structural changes. Second, in the protrusive position, posterior disclusion occurs, preventing masticatory muscle hyperactivity and the subsequent gradual decrease in ramus height. PMID- 29142869 TI - Temporomandibular joint synovial chondromatosis extending to the temporal bone: a report of two cases. AB - Synovial chondromatosis is a rare benign lesion originating from the synovial membrane. It presents as adhesive or non-adhesive intra-articular cartilaginous loose bodies. Although the causes of synovial chondromatosis have not been fully elucidated, inflammation, external injury, or excessive use of joints have been suggested as possible causes. Synovial chondromatosis has been reported to occur most frequently at large joints that bear weights, with a rare occurrence at the temporomandibular joint (TMJ). When synovial chondromatosis develops at TMJ, clinical symptoms, including pain, joint sounds, and mouth opening may common. Moreover, synovial chondromatosis rarely spreads to the mandibular condyle, glenoid cavity, or articular eminence of TMJ. The goal of this study was to discuss the methods of surgery and other possible considerations by reviewing cases of patients who underwent surgery for synovial chondromatosis that extended to the temporal bone. PMID- 29142870 TI - Intracorporeal reduction of condylar fracture using both pedicled condylar and seperated ramal fragments after vertical ramal osteotomy. AB - The aim of this study is to introduce a surgical technique that can maintain blood supply to prevent condylar resorption in the extracorporeal reduction of condylar fracture. Neither the medial pterygoid muscle on the ramal bone nor the lateral pterygoid muscle on the condylar fragment was detached after vertical ramal osteotomy. Thus, reduction was performed in the intracorporeal state. Therefore, blood supply was expected to be maintained to the fragments of both the condylar and ramal bones. On postoperative radiographs, the anatomical outline of the fractured condyle was well restored, and the occlusion was stable. In the unilateral case, there were no signs of mandibular condylar resorption until postoperative 3 weeks. In the 2 bilateral cases, condylar displacements with plate fractures and screw loosening were observed at postoperative 1 month or 5 months, but radiodensity at the displaced fracture site increased during the follow-up period. Finally, complete remodeling of the condylar fragments with restored anatomic appearance was observed on 8-month or 2-year follow-up radiographs. All cases exhibited good healing aspects with no signs or symptoms of mandibular condylar dysfunction during the postoperative remodeling period after intracorporeal reduction of condylar fracture. PMID- 29142871 TI - Cavernous sinus thrombosis following dental extraction: a rare case report and forgotten entity. AB - Prior to the advent of efficacious antimicrobial agents, the mortality rate from cavernous sinus thrombosis (CST) was effectively 100%. There have been very few reports of CST associated with tooth extraction. A 40-year-old female presented to the emergency room with swelling over the right side of the face and history of extraction in the upper right region by an unregistered dental practitioner. The patient presented with diplopia, periorbital ecchymosis, and chemosis of the right eye. A computed tomography scan revealed venous dilatation of the right superior ophthalmic vein. The patient was immediately treated with incision and drainage, intravenous antibiotics, and heparin (low molecular weight). Unfortunately, the patient died two days after surgery due to complications from the disease. CST is a rare disease with a high mortality rate. Therefore, dental health education in rural areas, legal action against unregistered dental practitioners, early diagnosis, and aggressive antibiotic treatment can prevent future mortality resulting from CST. PMID- 29142872 TI - Isolated tympanic plate fracture detected by cone-beam computed tomography: report of four cases with review of literature. AB - The tympanic plate is a small part of the temporal bone that separates the mandibular condyle from the external auditory canal. Fracture of this small plate is rare and usually associated with other bony fractures, mainly temporal and mandibular bone. There is a limited amount of literature on this subject, which increases the chance of cases being overlooked by physicians and radiologists. This is further supported by purely isolated cases of tympanic plate fracture without evidence of other bony fractures. Cone-beam computed tomography is an investigative three-dimensional imaging modality that can be used to detect fine structures and fractures in maxillofacial trauma. This article presents four cases of isolated tympanic plate fracture diagnosed by cone-beam computed tomography with no evidence of fracture involving other bones and review of the literature. PMID- 29142873 TI - Microhybrid versus nanofill composite in combination with a three step etch and rinse adhesive in occlusal cavities: five year results. AB - Objectives: The aim of the study was to evaluate the 5-year clinical performance of occlusal carious restorations using nanofill and microhybrid composites, in combination with 3-step etch-and-rinse adhesives, in patients who were going to commence orthodontic treatment. Materials and Methods: A total of 118 restorations for occlusal caries were conducted prior to orthodontic treatment. Occlusal restorations were performed both with Filtek Supreme XT (3M ESPE) and Filtek Z250 (3M ESPE) before beginning orthodontic treatment with fixed orthodontic bands. Restorations were clinically evaluated at baseline and at 1, 2, 3, 4, and 5-year recalls. Results: None of the microhybrid (Filtek Z250) and nanofill (Filtek Supreme XT) composite restorations was clinically unacceptable with respect to color match, marginal discoloration, wear or loss of anatomical form, recurrent caries, marginal adaptation, or surface texture. A 100% success rate was recorded for both composite materials. There were no statistically significant differences in any of the clinical evaluation criteria between Filtek Z250 and Filtek Supreme XT restorations for each evaluation period. Conclusions: The composite restorations showed promising clinical results relating to color matching, marginal discoloration, wear or loss of anatomical form, recurrent caries, marginal adaptation, and surface texture at the end of the 5-year evaluation period. PMID- 29142874 TI - Evaluation of antimicrobial activity and efficacy of herbal oils and extracts in disinfection of gutta percha cones before obturation. AB - Objectives: Literature has shown that micro-organisms contaminate gutta percha (GP) during storage and manipulation. Till date herbal extracts are not explored as an alternative medicament for pre-operative chairside disinfection of GP cones. The purpose of our study was to evaluate the antimicrobial activity and efficacy of lemon grass oil (LG), basil oil (BO), and obicure tea extract (OT) in disinfecting GP cones before obturation. Materials and Methods: Agar diffusion method was used to evaluate the antimicrobial efficacy of LG, BO, OT, and sodium hypochlorite (control) against common contaminants, namely, Enterococcus faecalis, Staphylococcus aureus, and Candida albicans. One hundred and twenty GP cones were contaminated and cut into 2. First half was placed in the broth and incubated; whereas the second was treated with herbal extracts for 1 minute and then incubated for 24 hours in the broth. Any inhibition in bacterial growth was noted with presence/absence of turbidity. Two-way analysis of variance and chi2 test were used to assess the effectiveness of herbal extracts to decontaminate GP. Results: LG showed the highest inhibition zones (29.9 +/- 6.9 mm) for all tested organisms, followed by OT extract (16.3 +/- 1.8 mm), sodium hypochlorite (16.0 +/- 1.6 mm), and BO (14.5 +/- 5.3 mm). Statistically significant difference was observed between LG and other herbal extracts (p < 0.05). Conclusions: All extracts proved to be potential rapid chairside disinfectants of GP cones with LG showing the highest antimicrobial activity. PMID- 29142875 TI - Quantification of the tug-back by measuring the pulling force and micro computed tomographic evaluation. AB - Objectives: The aims of this study were to quantify tug-back by measuring the pulling force and investigate the correlation of clinical tug-back pulling force with in vitro gutta-percha (GP) cone adaptation score using micro-computed tomography (uCT). Materials and Methods: Twenty-eight roots from human single rooted teeth were divided into 2 groups. In the ProTaper Next (PTN) group, root canals were prepared with PTN, and in the ProFile (PF) group, root canals were prepared using PF (n = 14). The degree of tug-back was scored after selecting taper-matched GP cones. A novel method using a spring balance was designed to quantify the tug-back by measuring the pulling force. The correlation between tug back scores, pulling force, and percentage of the gutta-percha occupied area (pGPOA) within apical 3 mm was investigated using uCT. The data were analyzed using Pearson's correlation analysis, one-way analysis of variance (ANOVA) and Tukey's test. Results: Specimens with a strong tug-back had a mean pulling force of 1.24 N (range, 0.15-1.70 N). This study showed a positive correlation between tug-back score, pulling force, and pGPOA. However, there was no significant difference in these factors between the PTN and PF groups. Regardless of the groups, pGPOA and pulling force were significantly higher in the specimens with a higher tug-back score (p < 0.05). Conclusions: The degree of subjective tug-back was a definitive determinant for master cone adaptation in the root canal. The use of the tug-back scoring system and pulling force allows the interpretation of subjective tug-back in a more objective and quantitative manner. PMID- 29142876 TI - In vitro comparison of the cyclic fatigue resistance of HyFlex EDM, One G, and ProGlider nickel titanium glide path instruments in single and double curvature canals. AB - Objectives: It was aimed to compare the cyclic fatigue resistances of ProGlider (PG), One G (OG), and HyFlex EDM (HEDM) nickel titanium glide path files in single- and double-curved artificial canals. Materials and Methods: 40 PG (16/0.02), 40 OG (14/0.03), and 40 HEDM (10/0.05) single-file glide path files were used in the present study. Sixty files were subjected to cyclic fatigue test by using double-curved canals and 60 files by using single-curved canal (n = 20). The number of cycles to fracture (NCF) was calculated and the length of the fractured fragment (FL) was determined by a digital micro-caliper. Twelve pieces of fractured files were examined with scanning electron microscope to determine fracture types of the files (n = 2). The NCF and the FL data were analyzed using one-way analysis of variance and post hoc Tukey test using SPSS 21 software (p < 0.05). Results: In all of the groups, NCF values were significantly lower in double-curved canals when compared to single-curved canals (p < 0.05). For both of single- and double-curved canals, NCF values of HEDM group in apical and coronal curvatures were found to be significantly higher than NCF values of PG and OG groups (p < 0.05). In both of single- and double-curved canals, NCF value of PG group was found significantly higher than OG group (p < 0.05). Conclusions: Within the limitations of this study, HEDM glide path files were found to have the highest cyclic fatigue resistance in both of single- and double-curved canals. PMID- 29142877 TI - Removal efficacy and cytotoxicity of a calcium hydroxide paste using N-2-methyl pyrrolidone as a vehicle. AB - Objectives: This study investigated the removal efficacy and cytotoxicity of a newly developed calcium hydroxide paste (cleaniCal, Maruchi) using N-2-methyl pyrrolidone (NMP) as a vehicle in comparison with ApexCal (Ivoclar Vivadent) and Calcipex II (Nishika), which use different vehicles such as polyethylene glycol and propylene glycol, respectively. Materials and Methods: Thirty maxillary premolars with oval-shaped canals were divided into 3 groups and the teeth were filled with one of the pastes. After removal of the paste, micro-computed tomographic (MU-CT) imaging was obtained to assess the volume of residual paste in the root canal of each tooth. The teeth were then split longitudinally and the area of the paste-coated surface was evaluated by stereomicroscopy. The cytotoxicity of each product was assessed using an agar overlay assay. The effect of each vehicle on cell viability was evaluated using the 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The data were analyzed using one-way analysis of variance and Tukey's tests to detect any significance (p < 0.05). Results: In the MU-CT and stereomicroscopic analysis, cleaniCal exhibited less remnants of medicament than ApexCal and Calcipex. cleaniCal showed a higher cytotoxicity than the other pastes in the agar overlay assay. Furthermore, NMP exhibited lower cell viability compared to the other vehicles. Conclusions: cleaniCal showed better removal efficacy compared to the other products. However, clinicians should be aware of the higher cytotoxicity of the NMP-based material and consider its possible adverse effects on periradicular tissue when it is overfilled. PMID- 29142879 TI - Effect of water storage on flexural strength of silorane and methacrylate-based composite resins. AB - Objectives: This study assessed the effect of water storage on the flexural strength (FS) of low shrinkage composites. Materials and Methods: A total of 165 bar-shaped specimens (2 * 2 * 25 mm) were fabricated of 2 low shrinkage composites (Filtek P90 [3M ESPE], GC Kalore [GC International]) and a conventional methacrylate-based composite (Filtek Z250 [3M ESPE]). The specimens were subjected to 3-point bending test at 6 time intervals, namely: immediately after curing, at 24 hours, 1 week, 1 month, 6 months, and 1 year following storage in wet and dry conditions. The FS of the specimens were measured by applying compressive load at a crosshead speed of 1.0 mm/min. Data was analyzed using 3-way analysis of variance (ANOVA) and Tukey's test. Results: Three-way ANOVA revealed significant interactions between time, type of composite, and storage condition (p = 0.001). Tukey's multiple comparison test revealed significant reductions in FS of all composites after 6 months and 1 year of storage in distilled water compared to dry condition. Conclusions: Filtek P90 showed the highest and GC Kalore showed the lowest FS after 1 year storage in distilled water. The immediate high strength of Filtek Z250 significantly decreased at 1 year and its final value was lower than that of Filtek P90. PMID- 29142878 TI - The effects of autoclave sterilization on the cyclic fatigue resistance of ProTaper Universal, ProTaper Next, and ProTaper Gold nickel-titanium instruments. AB - Objectives: It was aimed to compare the cyclic fatigue resistances of ProTaper Universal (PTU), ProTaper Next (PTN), and ProTaper Gold (PTG) and the effects of sterilization by autoclave on the cyclic fatigue life of nickel-titanium (NiTi) instruments. Materials and Methods: Eighty PTU, 80 PTN, and 80 PTG were included to the present study. Files were tested in a simulated canal. Each brand of the NiTi files were divided into 4 subgroups: group 1, as received condition; group 2, pre-sterilized instruments exposed to 10 times sterilization by autoclave; group 3, instruments tested were sterilized after being exposed to 25%, 50%, and 75% of the mean cycles to failure, then cycled fatigue test was performed; group 4, instruments exposed to the same experiment with group 3 without sterilization. The number of cycles to failure (NCF) was calculated. The data was statistically analyzed by using one-way analysis of variance and post hoc Tukey tests. Results: PTG showed significantly higher NCF than PTU and PTN in group 1 (p < 0.05). Sterilization significantly increased the NCF of PTN and PTG (p < 0.05) in group 2. PTN in group 3 had significantly higher cyclic fatigue resistance than PTN group 4 (p < 0.05). Also, significantly higher NCF was observed for PTG in group 2 than in groups 3 and 4 (p < 0.05). Conclusions: PTG instrument made of new gold alloy was more resistant to fatigue failure than PTN and PTU. Autoclaving increased the cyclic fatigue resistances of PTN and PTG. PMID- 29142880 TI - Comparison of apical extrusion of intracanal bacteria by various glide-path establishing systems: an in vitro study. AB - Objectives: This study compared the amount of apically extruded bacteria during the glide-path preparation by using multi-file and single-file glide-path establishing nickel-titanium (NiTi) rotary systems. Materials and Methods: Sixty mandibular first molar teeth were used to prepare the test apparatus. They were decoronated, blocked into glass vials, sterilized in ethylene oxide gas, infected with a pure culture of Enterococcus faecalis, randomly assigned to 5 experimental groups, and then prepared using manual stainless-steel files (group KF) and glide path establishing NiTi rotary files (group PF with PathFiles, group GF with G Files, group PG with ProGlider, and group OG with One G). At the end of canal preparation, 0.01 mL NaCl solution was taken from the experimental vials. The suspension was plated on brain heart infusion agar and colonies of bacteria were counted, and the results were given as number of colony-forming units (CFU). Results: The manual instrumentation technique tested in group KF extruded the highest number of bacteria compared to the other 4 groups (p < 0.05). The 4 groups using rotary glide-path establishing instruments extruded similar amounts of bacteria. Conclusions: All glide-path establishment instrument systems tested caused a measurable apical extrusion of bacteria. The manual glide-path preparation showed the highest number of bacteria extruded compared to the other NiTi glide-path establishing instruments. PMID- 29142881 TI - Smear layer removal by different chemical solutions used with or without ultrasonic activation after post preparation. AB - Objectives: This study evaluated smear layer removal by different chemical solutions used with or without ultrasonic activation after post preparation. Materials and Methods: Forty-five extracted uniradicular human mandibular premolars with single canals were treated endodontically. The cervical and middle thirds of the fillings were then removed, and the specimens were divided into 9 groups: G1, saline solution (NaCl); G2, 2.5% sodium hypochlorite (NaOCl); G3, 2% chlorhexidine (CHX); G4, 11.5% polyacrylic acid (PAA); G5, 17% ethylenediaminetetraacetic acid (EDTA). For the groups 6, 7, 8, and 9, the same solutions used in the groups 2, 3, 4, and 5 were used, respectively, but activated with ultrasonic activation. Afterwards, the roots were analyzed by a score considering the images obtained from a scanning electron microscope. Results: EDTA achieved the best performance compared with the other solutions evaluated regardless of the irrigation method (p < 0.05). Conclusions: Ultrasonic activation did not significantly influence smear layer removal. PMID- 29142883 TI - Statistical notes for clinical researchers: logistic regression. PMID- 29142882 TI - Incidence of apical crack formation and propagation during removal of root canal filling materials with different engine driven nickel-titanium instruments. AB - Objectives: To determine the incidence of crack formation and propagation in apical root dentin after retreatment procedures performed using ProTaper Universal Retreatment (PTR), Mtwo-R, ProTaper Next (PTN), and Twisted File Adaptive (TFA) systems. Materials and Methods: The study consisted of 120 extracted mandibular premolars. One millimeter from the apex of each tooth was ground perpendicular to the long axis of the tooth, and the apical surface was polished. Twenty teeth served as the negative control group. One hundred teeth were prepared, obturated, and then divided into 5 retreatment groups. The retreatment procedures were performed using the following files: PTR, Mtwo-R, PTN, TFA, and hand files. After filling material removal, apical enlargement was done using apical size 0.50 mm ProTaper Universal (PTU), Mtwo, PTN, TFA, and hand files. Digital images of the apical root surfaces were recorded before preparation, after preparation, after obturation, after filling removal, and after apical enlargement using a stereomicroscope. The images were then inspected for the presence of new apical cracks and crack propagation. Data were analyzed with chi2 tests using SPSS 21.0 software. Results: New cracks and crack propagation occurred in all the experimental groups during the retreatment process. Nickel-titanium rotary file systems caused significantly more apical crack formation and propagation than the hand files. The PTU system caused significantly more apical cracks than the other groups after the apical enlargement stage. Conclusions: This study showed that retreatment procedures and apical enlargement after the use of retreatment files can cause crack formation and propagation in apical dentin. PMID- 29142884 TI - LDL-cholesterol measurement in diabetic type 2 patients: a comparison between direct assay and popular equations. AB - Background: Low density lipoprotein -Cholesterol (LDL-C) is one of the main factors for assessment of cardiovascular disease risk and it is more important in diabetic patients. Various methods are currently used for LDL-C measurements which are compared in this study. Methods: This study was conducted in Diabetes Research Center based on laboratory results of 1721 diabetic patients who referred to laboratory for regular follow-up of lipid profile. LDL-C was measured directly and also estimated according to Friedwald, Anandraja and Chen formulas. Results: Results of direct LDL-C measurements were lower than all calculations at triglycerides (TG) levels less than 150 mg/dL while in higher TG levels direct measurement values were higher than Friedwald and Anandraja formula. Friedwald and Chen formula results had better correlation(r) with direct measurement than Anandraja in different levels of TG and also were able to define LDL-C > 100 mg/dL more accurately. Conclusions: Although we observed excellent correlation between the studied formulas with direct measurement, using the formula can misclassified diabetic patients with LDL-C values near threshold (100 mg/dL). However calculated LDL-C based on Chen and Friedwald formula can be a suitable alternative for direct measurement especially in regions with limited resources. PMID- 29142885 TI - Successful glycemic control using a flash glucose monitoring system for a pregnant woman with diabetes: a case report. AB - Background: Glucose control for pregnant women with glucose intolerance is important, as hyperglycemia may adversely affect the mother and the fetus. Case presentation: We report the case of a pregnant Japanese woman who experienced gestational diabetes mellitus during her first pregnancy and developed impaired glucose tolerance after the delivery. During her second pregnancy with twins, she required up to 75 units of injected insulin to control her postprandial hyperglycemia and occasionally experienced hypoglycemia. We used a newly developed flash glucose monitoring system, which allowed her to successfully achieve ideal glycemic control and experience an uncomplicated delivery. Conclusion: We suggest that this flash glucose monitoring system may be clinically effective for similar cases that involve pregnant women with abnormal glucose tolerance. PMID- 29142886 TI - Toric Intraocular Lens for Astigmatism Correction in Cataract Patients. AB - Background: To assess the clinical consequences of AcrySof toric intraocular lens (IOL) and Hoya toric IOL implantation to correct preexisting corneal astigmatism in patients undergoing cataract surgery. Materials and Methods: In this study, we examined 55 eyes of 45 patients with at least 1.00 D corneal astigmatism who were scheduled for cataract surgery. After phacoemulsification, toric IOL was inserted and axis was aligned. We observed the patients, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), keratometry, manifest refraction, and IOL axis alignment 6 months after surgery. Results: After 6 months, the UDVA was 0.17 +/- 0.17 logMAR in the AcrySof group and 0.17 +/- 0.18 logMar in the Hoya group. More than 78% of eyes in the AcrySof group and 80% of eyes in the Hoya toric IOL achieved a UDVA of 20/40 or better. In the AcrySof group, the mean preoperative corneal astigmatism was 2.73 +/- 0.92 D. The mean postoperative refractive astigmatism was 0.84 +/- 0.63 D. In the Hoya group, the preoperative corneal astigmatism was 2.58 +/- 0.76 D and the postoperative refractive astigmatism was 0.87 +/- 0.66 D (P < 0.05). The mean AcrySof IOL axis rotation was 1.88 degrees +/- 3.05 degrees . In the Hoya group, the mean axis rotation was 1.53 degrees +/- 3.66 degrees . All changes in visual and refractive data before and after surgery were statistically significant (P < 0.05). There was no significant difference between the two groups regarding refractive and visual outcome after surgery (P > 0.05 for all). Conclusion: Implantation of AcrySof toric IOL and Hoya toric IOL was an effective way to correct preexisting corneal astigmatism in cataract surgery. PMID- 29142887 TI - Comparison of the Serum Level of Cancer Antigen 125 and Human Epididymis Protein 4 in Ovarian Cancer Patients and Healthy Groups in Isfahan City. AB - Background: Ovarian cancer is the most common fatal malignancy of the gynecology tract. The purpose of this study was to compare serum levels of tumor markers cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in both healthy groups and patients with ovarian cancer. Materials and Methods: this case-control study was performed on Seyed Al-Shohada Hospital in Isfahan. Research on the treatment of 44 patients with ovarian cancer and 44 healthy controls was performed. CA125 and HE4 were measured in serum by sandwich ELISA method. Results: Average CA125 in ovarian cancer patients (83.30 +/- 43.99 MU/ml) was significantly higher than in healthy controls (12.39 +/- 5.50 MU/ml) (P < 0.001). Average HE4 in ovarian cancer patients (295.41 +/- 133.33 PM) was significantly higher than in healthy controls (114.64 +/- 17.31 PM) (P < 0.001). Conclusions: HE4 test is complementary of CA125 test in women with epithelial ovarian cancer. It is also used to study the disease process. PMID- 29142888 TI - Effect of Intravitreal Injection of Bevacizumab on Acute Central Serous Chorioretinopathy Patients Who Visited Feiz Hospital during 2014-2015 Period. AB - Background: Aim of this clinical trial is the evaluation of the effect of intravitreal injection of bevacizumab on acute central serous chorioretinopathy (CSC). Materials and Methods: In a nonrandomized clinical trial, 36 CSC eyes (with <1-month disease history) were examined. Initially, all the patients underwent posterior and anterior segment examinations as well as complete eye examination to evaluate the best spectacle-corrected visual acuity (BSCVA). Then, optical coherence tomography was performed to confirm the diagnosis. The patients were divided to the two groups each of 18 subjects, which 18 patients received intravitreal injection of bevacizumab (1.25 mg) and the rest of them did not receive any treatment (control group). The patients were health checked by the end of the 1st and 3rd months. Significance level was considered as P < 0.05. Results: In the BSCVA, no significant difference in visual improvement was observed in baseline vision compared to each other (P = 0.481). There was also no significant difference in the vision of intervention and control groups 1 and 3 months after injection (P = 0.379 and P = 0.557). A significant decrement existed in the intervention group compared with the control group in the maximum central macular thickness at 1 month after injection (P = 0.001); however, the difference was not significant when comparing the two groups at baseline and 3 months after injection (P = 0.925 and P = 0.338). Conclusion: In general, according to the results of this study, intravitreal injection of bevacizumab was not effective in improvement of patients with acute CSC, although it had no side effects. PMID- 29142889 TI - Rapid Detection of Streptomycin-Resistant Mycobacterium tuberculosis by rpsL Restriction Fragment Length Polymorphism. AB - Background: Molecular methods for the detection of drug-resistant tuberculosis (DR-TB) are potentially more rapid than conventional culture-based drug susceptibility testing, facilitating the commencement of appropriate treatment for patients with DR-TB. The aim of this study was to evaluate and develop polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays for the detection of mutations within rpsL, and for the determination of streptomycin (STR) resistance in Mycobacterium tuberculosis. Materials and Methods: Clinical specimens were collected from individuals with suspected TB referred to the TB Center of Isfahan, from which 205 M. tuberclosis were isolated and identified by conventional phenotypic methods. The minimum inhibitory concentration of STR for all isolates was determined using the proportion method and 10 isolates were recognized as STR resistant M. tuberculosis. The effect of genetic alterations in the rpsL gene for these resistant isolates were investigated by PCR-RFLP method. Results: Three (30%) isolates showed point mutation at codon 43 by RLFP analysis. Conclusion: Our results suggest that RFLP analysis of the rpsL gene is useful for the rapid prediction of STR resistant strains of M. tuberculosis. PMID- 29142890 TI - Comparing the Effect of Labetalol versus Morphine on Controlling Blood Pressure and Pulse Rate during Emergence from Anesthesia after Craniotomy. AB - Background: Emergence from anesthesia is associated with sympathetic stimulation, increase in pulse and blood pressure. There are different methods, but the most appropriate method should be selected regarding the differences in nationalities. This study aimed to compare the efficacy of morphine and labetalol in controlling blood pressure and pulse during emergence from anesthesia in brain tumors craniotomy. Materials and Methods: This study was conducted at Al-Zahra Hospital of Isfahan - Iran on 60 patients suffering from brain tumor candidated for craniotomy and randomly classified into two groups of 30. One group received labetalol with dose of 10 mg over 10 min from 45 min before finishing dressing and then 0.75 mg/min until 35 min later; another group received morphine in bolus dose of 0.1 mg/kg during 2-3 min. Blood pressure and pulse were measured every 10 min over 40 min. After operation, they were measured every 5 min over 15 min. Results: The morphine group had higher systolic (133.3 +/- 18.8) and diastolic blood pressure (87.1 +/- 13.6) (P = 0.021 and 0.028, respectively) at extubation and during 45 min before dressing, the diastolic blood pressure was significantly higher in compares with labetalol (75.3 +/- 10.5) (P < 0.05). And extubation time was significantly shorter in labetalol group (7.7 +/- 0.84) (P < 0.001). Pulse had no significant difference in both groups. In labetalol group, blood pressure and pulse fluctuations were more stable. Conclusion: Administration of labetalol 45 min before finishing dressing can significantly control blood pressure during emergence from anesthesia and also shorten the time of extubation during emergence in patients undergoing craniotomy. PMID- 29142891 TI - Assessment of Severity of Malnutrition in Peritoneal Dialysis Patients via Malnutrition: Inflammatory Score. AB - Background: Regarding to the complications of malnutrition in dialysis patients, using an easy and reliable method for evaluating of malnutrition is important in patients with the end-stage renal disease. Based on the effect of inflammatory factors in malnutrition, A new scale has been designed which is called malnutrition-inflammatory scale (MIS). We designed current study to assess the severity of malnutrition in peritoneal dialysis patients in Isfahan via MIS. Materials and Methods: In this cross-sectional MIS was used for evaluation of malnutrition. MIS includes 10 components: dry weight changes, dietary intake, functional capacity, comorbidity, muscle wasting and loss of subcutaneous fat as well as body mass index (BMI), serum albumin level and total iron binding capacity (TIBC). Each component has four levels of severity from 0 (normal) to 3 (severely abnormal). All analyses were performed using Statistical Package for Social Sciences version 20 (SPSS 20) and P < 0.05 were considered statistically significant. Results: Results showed no significant difference in MIS between male and female participants. Mean of minimum inhibitory concentration in this study was calculated about 4.1 (MIS <9) which means no or mild malnutrition. Significant correlation between MIS and weight (P < 0.001), BMI (P < 0.001), TIBC (P < 0.001), triglyseride (P = 0.04) and arm circumference (P < 0.001) was seen. Conclusion: We suggest That MIS is being used as a valuable tool for prevention of fatal outcomes in chronic dialysis patients. PMID- 29142892 TI - Evaluation of miR-362 Expression in Astrocytoma of Human Brain Tumors. AB - Background: Patients affected by gliomas have a poor prognosis. Astrocytoma is a subtype of glioma. Identification of biomarkers could be an effective way to an early diagnosis of tumor or to distinguish more aggressive tumors that need more intensive therapy. In this study, we investigated whether the expression of miR 362 was increased or decreased in patients with different grades of astrocytoma. Materials and Methods: miR-362 expression was compared in 25 patients with astrocytoma with that of 4 normal nonneoplastic brain tissues. Results: In all tumor tissues, the expression of miR-362 was significantly decreased relative to its expression in normal brain tissues. However, there was no significant difference between miR-362 expressions in high and low grades of astrocytoma. Conclusions: In conclusion, miR-362 showed a down-regulation pattern in astrocytoma tissues that was different from the pattern obtained from previously published microarray studies. PMID- 29142893 TI - Evaluation of Polymerase Chain Reaction for Detecting Coliform Bacteria in Drinking Water Sources. AB - Background: Coliform bacteria are used as indicator organisms for detecting fecal pollution in water. Traditional methods including microbial culture tests in lactose-containing media and enzyme-based tests for the detection of beta galactosidase; however, these methods are time-consuming and less specific. The aim of this study was to evaluate polymerase chain reaction (PCR) for detecting coliform. Materials and Methods: Totally, 100 of water samples from Isfahan drinking water source were collected. Coliform bacteria and Escherichia coli were detected in drinking water using LacZ and LamB genes in PCR method performed in comparison with biochemical tests for all samples. Results: Using phenotyping, 80 coliform isolates were found. The results of the biochemical tests illustrated 78.7% coliform bacteria and 21.2% E. coli. PCR results for LacZ and LamB genes were 67.5% and 17.5%, respectively. Conclusion: The PCR method was shown to be an effective, sensitive, and rapid method for detecting coliform and E. coli in drinking water from the Isfahan drinking water sources. PMID- 29142894 TI - Comparison of Energy and Nutrient Contents of Commercial and Noncommercial Enteral Nutrition Solutions. AB - Background: Nutritional support plays a major role in the management of critically ill patients. This study aimed to compare the nutritional quality of enteral nutrition solutions (noncommercial vs. commercial) and the amount of energy and nutrients delivered and required in patients receiving these solutions. Materials and Methods: This cross-sectional study was conducted among 270 enterally fed patients. Demographic and clinical data in addition to values of nutritional needs and intakes were collected. Moreover, enteral nutrition solutions were analyzed in a food laboratory. Results: There were 150 patients who fed noncommercial enteral nutrition solutions (NCENS) and 120 patients who fed commercial enteral nutrition solutions (CENSs). Although energy and nutrients contents in CENSs were more than in NCENSs, these differences regarding energy, protein, carbohydrates, phosphorus, and calcium were not statistically significant. The values of energy and macronutrients delivered in patients who fed CENSs were higher (P < 0.001). Energy, carbohydrate, and fat required in patients receiving CENSs were provided, but protein intake was less than the required amount. In patients who fed NCENSs, only the values of fat requirement and intake were not significantly different, but other nutrition delivered was less than required amounts (P < 0.001). CENSs provided the nutritional needs of higher numbers of patients (P < 0.001). In patients receiving CENSs, nutrient adequacy ratio and also mean adequacy ratio were significantly higher than the other group (P < 0.001). Conclusion: CENSs contain more energy and nutrients compared with NCENSs. They are more effective to meet the nutritional requirements of entirely fed patients. PMID- 29142895 TI - Towards a global policy against alcohol marketing to youth: Challenges and recommendations for research. PMID- 29142896 TI - Sodium variability is associated with increased mortality in severe burn injury. AB - Background: Dysnatremias are associated with increased mortality in critically ill patients. Hypernatremia in burn patients is also associated with poor survival. Based on these findings, we hypothesized that high plasma sodium variability is a marker for increased mortality in severely burn-injured patients. Methods: We performed a retrospective review of adult burn patients with a burn injury of 15% total body surface area (TBSA) or greater from 2010 to 2014. All patients included in the study had at least three serum sodium levels checked during admission. We used multivariate logistic regression analysis to determine if hypernatremia, hyponatremia, or sodium variability independently increased the odds ratio (OR) for death. Results: Two hundred twelve patients met entry criteria. Mean age and %TBSA for the study was 45 +/- 18 years and 32 +/- 19%. Twenty-nine patients died for a mortality rate of 14%. Serum sodium was measured 10,310 times overall. The median number of serum sodium measurements per patient was 22. Non-survivors were older (59 +/- 19 vs. 42 +/- 16 years) and suffered from a more severe burn injury (50 +/- 25% vs. 29 +/- 16%TBSA). While mean sodium was significantly higher for non-survivors (138 +/- 3 milliequivalents/liter (meq/l)) than for survivors (135 +/- 2 meq/l), mean sodium levels remained within the laboratory reference range (135 to 145 meq/l) for both groups. Non-survivors had a significantly higher median number of hypernatremic (> 145 meq/l) measurements (2 vs. 0). Coefficient of variation (CV) was significantly higher in non-survivors (2.85 +/- 1.1) than survivors (2.0 +/- 0.7). Adjusting for TBSA, age, ventilator days, and intensive care unit (ICU) stay, a higher CV of sodium measurements was associated with mortality (OR 5.8 (95% confidence interval (CI) 1.5 to 22)). Additionally, large variation in sodium ranges in the first 10 days of admission may be associated with increased mortality (OR 1.35 (95% CI 1.06 to1.7)). Conclusions: Increased variability in plasma sodium may be associated with death in severely burned patients. PMID- 29142897 TI - Drug-induced activation of "junk" DNA - A path to combat cancer therapy resistance? PMID- 29142898 TI - Intrinsic and environmental factors in intrahepatic cholangiocarcinoma development. PMID- 29142899 TI - Enhancing the antitumor potency of T cells redirected by bispecific antibodies. PMID- 29142900 TI - A novel DNA damage-induced alternative splicing pathway that regulates p53 and cellular senescence markers. PMID- 29142901 TI - Exposing the deadly dark side of apoptotic cancer stem cells. PMID- 29142902 TI - GM-CSF promotes a supportive adipose and lung microenvironment in metastatic breast cancer. PMID- 29142903 TI - BETi induction of mitotic catastrophe: towing the LIN9. PMID- 29142904 TI - KrasG12D upregulates Notch signaling to induce gallbladder tumorigenesis in mice. AB - Background: Kras mutations and increased Notch activation occur frequently in gallbladder cancer. However, their roles in gallbladder carcinogenesis have not been defined. This study was aimed at determining whether expression of mutant Kras was sufficient to induce gallbladder carcinoma and whether Notch deregulation played a role in this context. Methods: We determined Cre recombination activity of Pdx1-Cre in the gallbladder using a reporter strain and examined gallbladder tumor development in the KrasLSL- G12D/+;Pdx1-Cre mice. We analyzed expression of Notch pathway genes in the mouse gallbladder by immunohistochemistry, quantitative RT-PCR, and Western blot analysis. We also determined the effect of Jag1 deletion on Kras-induced gallbladder tumor development. Results: Pdx1-Cre exhibits robust recombination activity in the gallbladder epithelium. KrasLSL-G12D/+;Pdx1-Cre mice form early onset adenoma in the gallbladder and adjacent biliary tract with complete penetrance, albeit short of invasive adenocarcinoma. KrasG12D upregulates expressions of Notch2, Notch3, Notch4, Jag1 and downstream target genes Hes1, Hey1 and Hey2, and deletion of Jag1 partially suppresses KrasG12D-induced adenoma development. Conclusions: KrasG12D induces gallbladder adenoma and Notch plays a key role in Kras-initiated gallbladder tumorigenesis. PMID- 29142905 TI - P-Cadherin (CDH3) is overexpressed in colorectal tumors and has potential as a serum marker for colorectal cancer monitoring. AB - Introduction: Placental-Cadherin (CDH3) is a cell adhesion molecule vital to cellular localization and tissue integrity. It is highly expressed in the placenta (PLC)and is overexpressed by many types of cancer. P-cadherin levels in colorectal cancer (CRC) remains poorly characterized. This study's purpose was to determine P-cadherin expression in CRC and normal tissues and to assess plasma CDH3 levels in order to determine the relationship, if any, between cancer stage, P-cadherin expression and plasma CDH3 levels. Methods: An IRB approved plasma, tumor, and prospective data bank was utilized. CRC patients for whom tumor and normal colon tissue samples were available were enrolled. Tumor samples were OCT embedded and stored at -80C degrees . Total purified RNA was isolated from tissue samples and cDNA synthesized. CDH3 expression was analyzed by quantitative PCR (QPCR) using the SYBR Green platform. Tumor expression levels were determined and compared to levels in normal colonic tissue and PLC. Expression in 22 different normal tissues was also assessed by RT-PCR. Plasma CDH3 levels were determined via ELISA in patients for whom preoperative blood samples were available. Results: A total of 77 paired CRC and normal colon specimens (36 M/ 41 F, age 67.3+/-14.5) were assessed (82% colon, 18% rectal; Cancer Stage 2, 44; Stage 3, 33). All tested tumors had CDH3 expression levels over 0.1% of the PLC level and tumor to normal colon ratios greater than 1. CDH3 expression was noted in 14/22 normal organ tissues. There was a positive correlation between tumor CDH3 QPCR and preoperative CDH3 blood levels (n=57, P= 0.038). Expression levels were significantly higher in rectal vs. colon tumors (p=0.019). Conclusion: CDH3 expression was elevated in CRC tumors as compared to normal tissue. CDH3 was expressed by numerous normal organs and, thus, is not a viable vaccine target, however, the correlation between plasma and tumor CDH3 levels suggests CDH3 may have value as a diagnostic or prognostic marker. PMID- 29142906 TI - Hierarchical Modeling of Patient and Physician Determinants of Blood Pressure Outcomes in Hypertensive Patients with and without Diabetes: Pooled Analysis of Six Observational Valsartan Studies with 15,282 Evaluable Patients. AB - We pooled data from 6 valsartan-related studies including 3,658 diabetic and 11,624 nondiabetic patients to evaluate blood pressure (BP) outcomes after approximately 90 days of second- or later-line valsartan treatment. Hierarchical linear and logistic regressions were applied to identify determinants of BP outcomes. Similar reductions in BP values and similar BP control rates were achieved in both groups after approximately 90 days of therapy. The modeling analyses identified several common and different patient- and physician-related determinants of BP outcomes for both groups, many of which are modifiable or clinically manageable. Through varying in terms of association and influence between the diabetic and nondiabetic groups, patient-related determinants included age, BP at diagnosis of hypertension, risk factors, valsartan regimen, concomitant antihypertensive treatment, and adherence; and physician-related determinants included gender, years in practice, and hypertension management. In summary, in both diabetic and nondiabetic patients, the use of valsartan-centric treatment regimens in second- or later-line antihypertensive treatment is associated with significant reductions in BP level and improvement in BP control. The determinants identified in modeling provide guidance to clinicians in the common and differential management of hypertension in diabetic and nondiabetic patients. PMID- 29142907 TI - Social Effects of Health Care Reform: Medicaid Expansion under the Affordable Care Act and changes in Volunteering. AB - Do public health policy interventions result in pro-social behaviors? The Affordable Care Act (ACA)'s Medicaid expansions were responsible for the largest gains in public insurance coverage since its inception in 1965. These gains were concentrated in states that opted to expand Medicaid eligibility and provide a unique opportunity to study not just medical but also social consequences of increased public health coverage. This article examines the association between Medicaid and volunteer work. Volunteerism is implicated in individuals' health and well-being yet it is highly correlated with a person's existing socioeconomic resources. Medicaid expansions improved financial security and a sense of health two factors that predict volunteer work-for a socioeconomic group that has had low levels of volunteerism. Difference-in-difference analyses of the Volunteer Supplement of the Current Population Survey (2010-2015) find increased reports of formal volunteering for organizations as well as informal helping behaviors between neighbors for low-income non-elderly adults who would have likely benefited from expansions. Furthermore, increased volunteer work associated with Medicaid was greater among minority groups and narrowed existing ethnic differences in volunteerism in states that expanded Medicaid eligibility. PMID- 29142908 TI - A Rare Ureteral Injury Following Posterior Approach Lumbar Discectomy. AB - Iatrogenic ureteral injuries account for ~75% of all ureteral injuries and occur primarily during urologic, gynecologic, general, and vascular surgery procedures. Ureteral injury during spine surgery is a rare complication with only occasional reports in the literature. In this case report, we present a case of unrecognized left ureteral injury during an open right lumbar discectomy with a delayed presentation, and discuss the steps required for diagnosis and management. This report highlights a rare complication during laminectomy and serves to better inform patients and surgeons about this potential complication and the management options. PMID- 29142909 TI - Transgender Women's Drug Use in the Dominican Republic. AB - Purpose: Studies on drug use in transgender populations, particularly those in resource-limited settings, are scarce. Considering that drug use can be a coping mechanism to deal with stigma and traumatic experiences, we examined associations between stigma, trauma, and drug use in a national sample of transgender women from the Dominican Republic. Methods: Bivariate analyses examined differences between drug users and abstainers (n=287). Multivariate analyses reported odds ratios (OR) with general drug, marijuana, and cocaine use as outcomes (n=243). Results: A quarter of respondents (24.5%) experienced sexual abuse, 12.1% were tortured, and 20.1% experienced a murder attempt. More than a quarter reported using illegal drugs (26.1%). Drug users had lower socioeconomic status; 30.0% of drug users had a primary level of education or less (18.2% of abstainers) and 17.6% of drug users had higher income, defined as greater than 10,001 pesos (~$210 United States Dollars, USD) per month (28.1% of abstainers). More than half of drug users experienced some form of trauma (51.4%) compared to 43.5% of abstainers, and 28.4% of drug users, compared to 17.1% of abstainers, experienced a murder attempt on her life. Independent sample t-tests found significant differences between drug users and abstainers. Transgender women who experienced sexual abuse had three times high odds of using cocaine. Drug users were more likely to have experienced sexual abuse and attempted suicide (p<0.05 for both). Respondents who attempted suicide had higher odds of using drugs generally and using marijuana specifically, compared to respondents who had not attempted suicide (OR=2.665 and 3.168, respectively). Higher scores on the stigma scale were associated with higher odds of any drug use and cocaine use (OR=1.132 and 1.325, respectively). Conclusions: Although some nations have implemented antidiscrimination policies protecting transgender citizens, these policies are not consistently enforced. Eliminating stigma and stigmatizing policies may reduce rates of drug use as a coping mechanism. PMID- 29142910 TI - Induction and Maintenance of Amenorrhea in Transmasculine and Nonbinary Adolescents. AB - The treatment of persistent uterine bleeding in those patients who identify as transmasculine or nonbinary is often straightforward, but can be difficult in a subset of patients. This article reviews the physiology of the normal menstrual cycle and the hormonal influences on the endometrium, and then explores options for the treatment of persistent bleeding for people both already on testosterone and for those who are either not ready for or who do not desire testosterone. PMID- 29142912 TI - The Launch of Kidney International Reports. PMID- 29142911 TI - Fluorescent Alloy CsPb x Mn1-x I3 Perovskite Nanocrystals with High Structural and Optical Stability. AB - CsPbI3 nanocrystals are still limited in their use because of their phase instability as they degrade into the yellow nonemitting delta-CsPbI3 phase within a few days. We show that alloyed CsPb x Mn1-x I3 nanocrystals have essentially the same optical features and crystal structure as the parent alpha-CsPbI3 system, but they are stable in films and in solution for periods over a month. The stabilization stems from a small decrease in the lattice parameters slightly increasing the Goldsmith tolerance factor, combined with an increase in the cohesive energy. Finally, hybrid density functional calculations confirm that the Mn2+ levels fall within the conduction band, thus not strongly altering the optical properties. PMID- 29142914 TI - Renal Stress Testing in the Assessment of Kidney Disease. AB - As part of human evolutionary development, many human organ systems have innate mechanisms to adapt to increased "work demand" or stress. This reserve capacity can be informative and is used commonly in cardiology to assess cardiac function (e.g., treadmill test). Similarly, the kidney possesses reserve capacity, which can be demonstrated in at least 2 of the following renal domains: glomerular and tubular. When appropriate stimulants are used, healthy patients with intact kidneys can significantly increase their glomerular filtration rate and their tubular secretion. This approach has been used to develop diagnostics for the assessment of renal function. This article reviews both glomerular and tubular kidney stress tests and their respective diagnostic utility. PMID- 29142913 TI - The Unappreciated Role of Extrarenal and Gut Sensors in Modulating Renal Potassium Handling: Implications for Diagnosis of Dyskalemias and Interpreting Clinical Trials. AB - In addition to the classic and well-established "feedback control" of potassium balance, increasing investigative attention has focused on a novel and not widely recognized complementary regulatory paradigm for maintaining potassium homeostasis-the "feed-forward control" of potassium balance. This regulatory mechanism, initially defined in rumen, has recently been validated in normal human subjects. Studies are being conducted to determine the location for this putative potassium sensor and to evaluate potential signals, which might increase renal potassium excretion. Awareness of this more updated integrative control mechanism for potassium homeostasis is ever more relevant today, when the medical community is increasingly focused on the challenges of managing the hyperkalemia provoked by renin-angiotensin-aldosterone system inhibitors (RAASis). Recent studies have demonstrated a wide gap between RAASi prescribing guidelines and real-world experience and have highlighted that this gap is thought to be attributable in great part to hyperkalemia. Consequently we require a greater knowledge of the complexities of the regulatory mechanisms subserving potassium homeostasis. Sodium polystyrene sulfonate has long been the mainstay for treating hyperkalemia, but its administration is fraught with challenges related to patient discomfort and colonic necrosis. The current and imminent availability of newer potassium binders with better tolerability and more predictive dose response potassium removal should enhance the management of hyperkalemia. Consequently it is essential to better understand the intricacies of mammalian colonic K+ handling. We discuss colonic transport of K+ and review evidence for potassium (BK) channels being responsible for increased stool K+ in patients with diseases such as ulcerative colitis. PMID- 29142915 TI - The Relationship Between Presentation and the Time of Initial Administration of Antibiotics With Outcomes of Peritonitis in Peritoneal Dialysis Patients: The PROMPT Study. AB - Introduction: The impact of time to treatment on clinical outcome is an established precept in infectious disease but is not established in peritoneal dialysis-related peritonitis (PDRP). Methods: In a prospective multicenter study of PDRP, symptom-to-contact time (SC), contact-to-treatment time (CT), defined as the time from health care presentation to initial antibiotic, and symptom-to treatment time (ST) were determined. Results: One hundred sixteen patients had 159 episodes of PDRP. Median SC for all episodes was 5.0 hours (first to third quartile [Q1-Q3]: 1.3-13.9); CT, 2.3 hours (Q1-Q3: 1.2-4.0); and ST, 9.0 hours (Q1-Q3: 4.7-25.3). Thirty-eight (23.9%) patient episodes (28 catheter removals and 10 deaths) met the primary composite outcome of PD failure at 30 days (PD fail). The risk of PD-fail increased by 5.5% for each hour of delay of administration of antibiotics (odds ratio [OR] for CT: 1.055; 95% confidence interval [CI]: 1.005-1.109; P = 0.032). Neither SC (OR: 1.00; 95% CI: 0.99-1.01; P = 0.74) nor ST (OR: 1.00; 95% CI: 0.99-1.01; P = 0.48) was associated with PD fail. In a multivariable analysis, only CT for presentation to a hospital-based facility compared with a community facility (OR: 1.068; 95% CI: 1.013-1.126; P = 0.015) and female sex (OR: 2.4; 95% CI: 1.1-5.4; P = 0.027) were independently associated with PD-fail. Each hour of delay in administering antibacterial therapy from the time of presentation to a hospital facility increased the risk of PD failure or death by 6.8%. Discussion: Strategies targeted to expedited antibiotic treatment should be implemented to improve outcomes from PDRP. PMID- 29142916 TI - A Case of Continuous Venovenous Hemofiltration for Anuric Acute Kidney Injury With Severe Hyponatremia: A Simple Method Involving Flexible Adjustment of Sodium Replacement Solution. PMID- 29142917 TI - Acute Tubular Necrosis in a Patient With Myeloma Treated With Carfilzomib. PMID- 29142918 TI - Laparoscope Is a Useful Tool for Reducing and Drawing off a Peritoneal Dialysis Catheter in Peritoneal Dialysis Patients. PMID- 29142919 TI - Implantation of Autologous Selected Renal Cells in Diabetic Chronic Kidney Disease Stages 3 and 4-Clinical Experience of a "First in Human" Study. AB - Introduction: Animal models of chronic kidney disease demonstrate that a redundant population of therapeutically bioactive selected renal cells (SRCs) can be delivered to the kidney through intraparenchymal injection and arrest disease progression. Direct injection of SRCs has been shown to attenuate nuclear factor kappaB, which is known to drive tissue inflammation, as well as the transforming growth factor-beta-mediated plasminogen activator inhibitor-1 response that drives tissue fibrosis. Methods: We present experience from the first-in-human clinical study with SRCs. Seven male type 2 diabetic patients (63 +/- 2 years of age) with chronic kidney disease stage 3 to 4 (estimated glomerular filtration rate 25 +/- 2 ml/min) were recruited. After blood and urine sampling, iohexol clearance, magnetic resonance imaging, and renal scintigraphy, patients underwent ultrasound-guided renal biopsy. Two cores of renal tissue were shipped to the manufacturing plant for cell isolation, culture, and product preparation. Formulated SRCs were transported back to study sites (range 59-87 days after biopsy) for intracortical injection using a retroperitoneoscopic technique. Results: Laparoscopically assisted implantation of SRCs was uneventful in all patients. However, postoperative complications were common and suggest that other techniques of SRC delivery should be used. Kidney volume, split function, and glomerular filtration rate did not change during 12 months of follow-up. An extended 24-month follow-up in 5 of the patients showed a decline in estimated glomerular filtration rate (cystatin C). Discussion: Postoperative complications following retroperitoneoscopic implantation of SRC in the kidney cortex seem to be related to the surgical procedure rather than to injection of the cell product. No changes in renal function were observed during the original 12-month protocol. Beyond the first 12 months after cell implantation, individual renal function began to deteriorate during further follow-up. PMID- 29142921 TI - Leishmaniasis-Associated Membranoproliferative Glomerulonephritis With Massive Complement Deposition. PMID- 29142920 TI - Urinary NGAL-Positive Acute Kidney Injury and Poor Long-term Outcomes in Hospitalized Patients. AB - Introduction: Neutrophil gelatinase-associated lipocalin (NGAL) is a widely studied biomarker of renal tubular injury. Urinary NGAL (uNGAL) during acute kidney injury (AKI) predicts short-term adverse outcomes. However, the long-term predictive value is unknown. Methods: We performed a prospective observational study of 145 patients with hospital-acquired AKI according to Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) criteria and analyzed the long-term predictive value of uNGAL at the time of AKI. We defined a composite outcome of all-cause mortality and the development of end stage renal disease (ESRD). Results: In all, 61 AKI patients died and 22 developed ESRD within 6 months. The uNGAL levels were significantly higher in patients with poor long-term outcomes. uNGAL levels >=362 MUg/l (highest quartile) and uNGAL levels between 95 and 362 MUg/l (third quartile) were associated with hazard ratios of 3.7 (95% confidence interval, 2.1-6.5) and 1.9 (1.1-3.5), respectively, compared with uNGAL levels <95 MUg/l (lower quartiles). After 6 months, 67% and 43% of patients within the highest and third uNGAL quartile, respectively, had either progressed to ESRD or died, compared to only 21% of patients with uNGAL in the lower 2 quartiles (P < 0.001). In multivariable Cox regression analyses accounting for conventional predictors, uNGAL was the strongest independent predictor of adverse long-term outcomes. The association of uNGAL levels and poor long-term outcomes remained significant in the subgroup of 107 AKI survivors discharged without requiring dialysis (P = 0.002). Discussion: These data indicate that elevated uNGAL levels at AKI diagnosis predict poor long term outcomes. PMID- 29142922 TI - Beneficial Effect of Rituximab in the Treatment of Esophageal Cancer-Associated Pauci-Immune Glomerulonephritis. PMID- 29142923 TI - Pediatric Nephrology Training Worldwide 2016: Quantum Educatus? PMID- 29142925 TI - Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease. PMID- 29142924 TI - Complement-Mediated Glomerular Diseases: A Tale of 3 Pathways. AB - A renewed interest in the role of complement in the pathogenesis of glomerular diseases has improved our understanding of their basic, underlying physiology. All 3 complement pathways-classical, lectin, and alternative-have been implicated in glomerular lesions both rare (e.g., dense deposit disease) and common (e.g., IgA nephropathy). Here we review the basic function of these pathways and highlight, with a disease-specific focus, how activation can lead to glomerular injury. We end by exploring the promise of complement-targeted therapies as disease-specific interventions for glomerular diseases. PMID- 29142926 TI - Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease: The TEMPO 3:4 Clinical Trial. AB - Introduction: Patients with slowly progressive autosomal dominant polycystic kidney disease (ADPKD) are unlikely to experience outcomes during randomized controlled trials (RCTs). An image classification of ADPKD into typical (diffuse cyst distribution) class 1A to E (by age- and height-adjusted total kidney volume [TKV]) and atypical (asymmetric cyst distribution) class 2 was proposed for prognostic enrichment design, recommending inclusion of only classes 1C to 1E in RCTs. Methods: A post hoc exploratory analysis was conducted of the TEMPO 3:4 Trial, a prospective, randomized, double-blinded, controlled clinical trial in adult subjects with ADPKD, an estimated creatinine clearance >60 ml/min and total kidney volume >750 ml. Results: Due to the entry criteria, the study population of TEMPO 3:4 was enriched for classes 1C-E (89.5 % of 1436 patients with baseline magnetic resonance images) compared to unselected populations (e.g., 60.5% of 590 Mayo Clinic patients). The effects of tolvaptan on TKV and eGFR slopes were greater in classes 1C to E than in 1B. In TEMPO 3:4, tolvaptan reduced TKV and eGFR slopes from 5.51% to 2.80% per year and from -3.70 to -2.78 ml/min/1.73 m2 per year, and lowered the risk for a composite endpoint of clinical progression events (hazard ratio = 0.87). Restricting enrollment to classes 1C to E would have reduced TKV and eGFR slopes from 5.78% to 2.91% per year and from -3.93 to 2.82 ml/min/1.73 m2 per year, and the risk of the composite endpoint (hazard ratio = 0.84, P = 0.003), with 10.5% fewer patients. Discussion: Prognostic enrichment strategies such as the entry criteria used for TEMPO 3:4 or preferably the proposed image classification should be used in RCTs for ADPKD to increase power and to reduce cost. PMID- 29142927 TI - Ex Vivo Normothermic Perfusion Induces Donor-Derived Leukocyte Mobilization and Removal Prior to Renal Transplantation. AB - Introduction: Ex vivo normothermic perfusion offers an alternative method of organ preservation, allowing donor kidneys to be reanimated and evaluated prior to transplantation. Beyond preservation, it can be used to characterize the immunological contribution of the donor kidney in isolation. Furthermore, it has the potential to be used as an immunomodulatory strategy to manipulate donor kidneys prior to transplantation. Methods: Explanted porcine kidneys underwent 6 hours of perfusion. Sequential perfusate samples were collected and leukocytes characterized via flow cytometry. An inflammatory profile was generated via cytokine quantification. Cell-free DNA was also determined as markers of cell death. Results: All kidneys functioned within normal parameters and met the criteria for transplantation at the end of perfusion. Throughout perfusion there were continuous increases in pro-inflammatory cytokines, including large concentrations of interferon-gamma, suggesting that perfusion drives a significant inflammatory response. Increasing concentrations in cell-free DNA were also observed, suggesting cell death. During perfusion there was a marked cellular diapedesis of T cells, B cells, natural killer (NK) cells, and monocytes from the kidney into the circuit. Minor populations of granulocytes and macrophages were also detected. Discussion: We demonstrate that ex vivo normothermic perfusion initiates an inflammatory cytokine storm and release of mitochondrial and genomic DNA. This is likely to be responsible for immune cell activation and mobilization into the circuit prior to transplantation. Interestingly this did not have an impact on renal function. These data therefore suggest that normothermic perfusion can be used to immunodeplete and to saturate the pro-inflammatory capacity of donor kidneys prior to transplantation. PMID- 29142928 TI - The Burden of Cognitive Impairment in Patients With End-Stage Renal Disease and Impact on Dialysis Modality Choice. AB - Introduction: Kidney disease is associated with significant cognitive dysfunction. Subjective reports of cognitive ability have not been studied extensively in chronic kidney disease. We investigated the association between objective and subjective cognitive functions in predialysis patients and their association with self-care dialysis modality choice. Methods: Cross-sectional data from the Barriers to Successful Implementation of Care in Home Haemodialysis study were used for the study of cognition in 220 predialysis patients. The data were used to ascertain the demographics, clinical, laboratory, and neuropsychometric variables. The latter includes Trail Making Tests (TMT) parts A and B, Modified Mini Mental State Examination, and metacognition questionnaire for subjective assessment of one's cognitive ability. The outcome variable was fully assisted and self-care dialysis modality choice. Results: Within the study cohort, 90 patients chose fully assisted hemodialysis and 114 patients chose self care dialysis. The median Modified Mini Mental State Examination, TMT part A, and TMT part B scores were greater for the assisted versus the self-care group. Metamemory was not significantly different between groups, but the metaconcentration score was significantly worse in the group choosing assisted dialysis. Higher (i.e., better) metaconcentration scores were significantly associated with the self-care modality choice in the univariate and hierarchical regression analyses. Adjusted and unadjusted analyses showed a significant association between perceived concentration and TMT part B scores (P < 0.01). With every 1.6-minute increase in TMT part B score, there was a 1-unit reduction in metaconcentration score, and the latter was associated with 20% lower odds of choosing self-care dialysis over a fully assisted dialysis modality. Discussion: Patients' self-perception of cognitive ability is a significant predictor of self care dialysis modality choice. Subjective report of "metaconcentration" is also strongly associated with poorer outcome on the TMT part B. PMID- 29142929 TI - Glomerulopathy Associated With Moderate Obesity. AB - Introduction: Obesity-related glomerulopathy is an established secondary glomerular disease that may occur in obese individuals with a body mass index (BMI) of >=30 kg/m2. However, patients with moderate obesity (BMI <= 30 kg/m2) may also develop this disease. Methods: A total of 20 patients with grade 1 obesity (25 <= BMI < 30 kg/m2) with persistent proteinuria, without evidence of other renal diseases, were analyzed retrospectively. These patients were compared with 20 patients with grade 2 or higher obesity (BMI >= 30 kg/m2) with persistent proteinuria. Biopsies of 31 kidney transplant donors as healthy controls were used to compare histologic parameters. Results: Similar to the grade 2 or higher obesity group, the grade 1 obesity group had a male predominance (85%) and showed a high incidence of hypertension (80%). Urinary protein excretion and renal outcome parameters were comparable between the groups. Patients with grade 1 obesity showed typical histologic features of obesity-related glomerulopathy: low glomerular density with glomerulomegaly. The glomerular density and mean glomerular volume in the grade 1 group, the grade 2 or higher group, and the kidney transplant donors with grade 1 obesity were 1.6 +/- 0.8 versus 1.4 +/- 0.6 versus 3.0 +/- 1.1 (per mm2) and 6.1 +/- 2.1 versus 6.4 +/- 1.6 versus 2.9 +/- 0.8 (*106 MUm3), respectively. Discussion: A glomerulopathy similar to obesity related glomerulopathy can occur in moderately obese individuals. Renal factor(s), such as low glomerular density, may thus underlie susceptibility to this disease entity as well as BMI. PMID- 29142930 TI - Statin Use and Survival After Acute Kidney Injury. AB - Introduction: The incidence of acute kidney injury (AKI) in hospitalized patients is rising, and survivors are at high risk for cardiovascular events and mortality. Effective strategies that improve long-term outcomes of AKI are unknown. Methods: A retrospective cohort study was performed between 2008 and 2011. All subjects were followed until 31 March 2013, with a minimum follow-up of 2 years. Participants were adults 18 years of age or older, who developed AKI during a hospitalization and had chronic kidney disease (CKD) following discharge (n = 19,707 mean age 69.9 years, mean postdischarge estimated glomerular filtration rate (eGFR) 43.0 ml/min/1.73 m2). Exposure to statins was examined prior to the index hospitalization as well as within 2 years following hospital discharge. The primary outcome was mortality; secondary outcomes included all cause re-hospitalization and cardiovascular events. Results: Within 2 years of discharge, only 38.3% of the participants were prescribed a statin. After adjustment for comorbidities, statin use prior to admission, demographics, baseline kidney function, and a number of other factors, statin use was associated with lower mortality (hazard ratio, 0.74; 95% confidence interval, 0.69, 0.79) in AKI survivors with CKD. Patients who received a statin also had a lower risk of all cause rehospitalization (adjusted hazarad ratio, 0.90; 95% confidence interval, 0.85, 0.94). Statin use was not associated with a reduction in cardiovascular events. Discussion: Among AKI survivors with CKD, statin use was associated with a lower risk of mortality and rehospitalization rates. This finding suggests that there is an opportunity to improve postdischarge care in AKI survivors. PMID- 29142931 TI - Rationale and Design of the Genetic Contribution to Drug Induced Renal Injury (DIRECT) Study. AB - Introduction: Nephrotoxicity from drugs accounts for 18% to 27% of cases of acute kidney injury. Determining a genetic predisposition may potentially be important in minimizing risk. The aims of this study are as follows: to determine whether a genetic predisposition exists for the development of drug-induced kidney disease (DIKD), using genome-wide association and whole-genome sequencing studies; to describe the frequency, course, risk factors, resolution and outcomes of DIKD cases; to investigate the role of ethnic/racial variability in the genetics of DIKD; and to explore the use of different tools establishing causality of DIKD. Methods: A total of 800 patients will be enrolled worldwide and blood samples for DNA collected. Data on the patient risk factors, vital signs, laboratory parameters, drug exposure, and DIKD course will be recorded. A panel of nephrologists will adjudicate all cases. Genome-wide association studies will be conducted using population controls matched on biogeographic ancestry to determine whether there is a genetic predisposition to DIKD. The primary endpoint is the identification of specific drug-related polymorphisms associated with DIKD. Secondary endpoints include the following: frequency of DIKD by causal drug and drug combinations; DIKD genetic variability; exploration of causality assessment tools; risk factor identification; description of the course of DIKD, including mortality and dialysis dependency at hospital discharge and 28 and 90 days post-event. Results: Data are currently being analyzed. Results are pending. Discussion: The Genetic Contribution to Drug Induced Renal Injury (DIRECT) study will be the first observational cohort study to investigate the genetic determinants of DIKD. If the trial is positive, its findings will potentially translate into safer patient outcomes, by genotypic individualization of therapy and minimization of harm. PMID- 29142932 TI - Clinicopathologic Features of Membranous-Like Glomerulopathy With Masked IgG Kappa Deposits. AB - Introduction: Ig deposits identified on renal biopsy samples by paraffin immunofluorescence that show negative staining by routine immunofluorescence on frozen tissue have become known as "masked" deposits. Membranous-like glomerulopathy with masked IgG kappa (kappa) deposits is a recently recognized pattern of immune complex deposition characterized by masked deposits that show IgG kappa restriction and are subepithelial and mesangial by electron microscopy. Based on the frequent presence of C3-only staining by routine immunofluorescence microscopy (IF), these cases could be misdiagnosed as C3 glomerulonephritis in the absence of paraffin immunofluorescence evaluation. Methods: The clinicopathologic details of all cases of membranous-like glomerulopathy with masked IgG kappa deposits diagnosed in our laboratory were included, beginning with the initial recognition of this entity in 2011 through the end of 2015. Inclusion was based on renal biopsy sample morphologic features including glomerular deposits that stain for IgG kappa and have a staining intensity that is significantly brighter by paraffin IF than by routine IF on frozen tissue. Results: This pattern of immune complex deposition has been seen in 41 patients in our laboratory over a 5-year period. The patients with these biopsy findings are most commonly young female individuals with a mean age of 27.5 years, with 88% being less than 40 years. All patients had proteinuria with a mean 24-hour urine protein of 3.5 g (range 0.5-12.8 years) and 35% with nephrotic-range proteinuria. Hematuria was present in 88% of patients, and 29% had elevated serum creatinine at presentation. Autoimmune serologic tests were positive in 55% of patients, with a weakly positive antinuclear antibody being most common. Despite this, only 1 patient (2%) fulfilled the diagnostic criteria for systemic lupus erythematosus. The outcome data were mixed, as some patients showed spontaneous remission and mild disease whereas others progressed to end-stage renal disease. There was no apparent correlation between the treatment used and outcome in this retrospective analysis. One patient underwent transplantation and developed biopsy-proven recurrence of disease in the graft 42 months posttransplantation. The etiology of this entity remains unknown. Discussion: We provide an expanded case series detailing the clinicopathologic findings of patients with membranous like glomerulopathy with masked IgG kappa deposits. Patients are most commonly young female individuals <40 years of age and commonly have positive autoimmune serologic studies such as antinuclear antibody, although few carry a diagnosis of any well-defined autoimmune disease such as lupus. The outcome data were mixed, as some patients showed spontaneous remission and mild disease whereas others progressed to ESRD. There was no apparent correlation between the treatment used and outcome in this retrospective analysis. PMID- 29142933 TI - Lambda Light Chain Crystalline Cast Nephropathy and Proximal Tubulopathy. PMID- 29142934 TI - Marked Elevation of Plasma Levels of Oxidative Stress-Responsive Apoptosis Inducing Protein in Dialysis Patients. PMID- 29142935 TI - Needle Size and the Risk of Kidney Biopsy Bleeding Complications. PMID- 29142936 TI - Tackling the Fallout From Chronic Kidney Disease of Unknown Etiology: Why We Need to Focus on Providing Peritoneal Dialysis in Rural, Low-Resource Settings. PMID- 29142937 TI - Geographic Variation and US County Characteristics Associated With Rapid Kidney Function Decline. AB - Introduction: Geographic variation in the prevalence of chronic kidney disease and incidence of end-stage renal disease has been previously reported. However, the geographic epidemiology of rapid estimated glomerular filtration rate (eGFR) decline has not been examined. Methods: We built a longitudinal cohort of 2,107,570 US veterans to characterize the spatial epidemiology of and examine the associations between US county characteristics and rapid eGFR decline. Results: There were 169,029 (8.02%) with rapid eGFR decline (defined as eGFR slope < -5 ml/min per 1.73 m2/year). The prevalence of rapid eGFR decline adjusted for age, race, gender, diabetes, and hypertension varied by county from 4.10%-6.72% in the lowest prevalence quintile to 8.41%-22.04% in the highest prevalence quintile (P for heterogeneity < 0.001). Examination of adjusted prevalence showed substantial geographic variation in those with and without diabetes and those with and without hypertension (P for heterogeneity < 0.001). Cohort participants had higher odds of rapid eGFR decline when living in counties with unfavorable characteristics in domains including health outcomes (odds ratio [OR] = 1.15; confidence interval [CI] = 1.09-1.22), health behaviors (OR = 1.08; CI = 1.03 1.13), clinical care (OR = 1.11; CI = 1.06-1.16), socioeconomic conditions (OR = 1.15; CI = 1.09-1.22), and physical environment (OR = 1.15; CI = 1.01-1.20); living in counties with high percentage of minorities and immigrants was associated with rapid eGFR decline (OR = 1.25; CI = 1.20-1.31). Spatial analyses suggest the presence of cluster of counties with high prevalence of rapid eGFR decline. Discussion: Our findings show substantial geographic variation in rapid eGFR decline among US veterans; the variation persists in analyses stratified by diabetes and hypertension status; results show associations between US county characteristics in domains capturing health, socioeconomic, environmental, and diversity conditions, and rapid eGFR decline. PMID- 29142938 TI - Epidemiological Transition of End-Stage Kidney Disease in Oman. AB - Introduction: The number of persons receiving renal replacement therapy (RRT) is estimated at more than 2.5 million worldwide, and is growing by 8% annually. Registries in the developing world are not up to standards compared to the United States Renal Data System (USRDS). Herein we examine the causes, progression, and magnitude of end-stage kidney disease (ESKD) over 3 decades in Oman. Methods: We examined ESKD data from 1983 to 2013. Data from 1998 to 2013 were obtained through an Information Management System. Data before 2008 were collected from patients' files. A questionnaire based on USRDS form 2728 was completed by nephrologists once a citizen reached ESKD. Results: A total of 4066 forms were completed, with a response rate of 90% (52% male). The mean (SD) age was 50.1 (14.0) years. By 31 December 2013, there were 2386 patients alive on RRT, of whom 1206 were on hemodialysis (50.5%), 1080 were living with a functioning kidney transplant (45.3%), and 100 were receiving peritoneal dialysis (4.2%). The incidence of ESKD on RRT was 21, 75, and 120 per million population in 1983, 2001, and 2013, respectively. Similarly, the prevalence of ESKD was 49, 916, and 2386 in 1983, 2001, and 2013 respectively. Among patients with ESKD on RRT, a progressive rise was seen in diabetic nephropathy, with 5.8%, 32.1%, and 46% in 1983, 2001, and 2013 respectively. Discussion: The incidence and prevalence of ESKD has increased progressively over last 30 years. This is anticipated to continue at an even higher rate in view of the progressive rise in noncommunicable diseases. Continuous improvement in registries is required to improve capturing of ESKD patients for providing accurate data to health authorities, and enhancing public awareness of the magnitude, future trends, treatments, and outcomes regarding ESKD. PMID- 29142939 TI - Negative Staining for COL4A5 Correlates With Worse Prognosis and More Severe Ultrastructural Alterations in Males With Alport Syndrome. AB - Introduction: Alport syndrome (AS) is a genetic disorder characterized by progressive hematuric nephropathy with or without sensorineural hearing loss and ocular lesions. Previous studies on AS included mostly children. Methods: To determine the prognostic value of loss of staining for collagen type IV alpha 5 (COL4A5) and its relationship with the ultrastructural glomerular basement membrane alterations, we performed direct immunofluorescence using a mixture of fluorescein isothiocyanate-conjugated and Texas-red conjugated antibodies against COL4A5 and COL4A2, respectively, on renal biopsies of 25 males with AS (including 16 who were diagnosed in adulthood). Results: All patients showed normal positive staining of glomerular basement membranes and tubular basement membranes for COL4A2. Of the 25 patients, 10 (40%) patients showed loss of staining for COL4A5 (including 89% of children and 13% of adults) and the remaining 15 (60%) had intact staining for COL4A5. Compared with patients with intact staining for COL4A5, those with loss of staining had more prominent ultrastructural glomerular basement membrane alterations and were younger at the time of biopsy. By Kaplan Meier survival analysis and Cox regression analysis, loss of staining for COL4A5 predicted earlier progression to overt proteinuria and stage 2 chronic kidney disease or worse. By multivariate Cox regression analysis, loss of staining for COL4A5 was an independent predictor of the development of overt proteinuria and stage 2 chronic kidney disease or worse. Discussion: Thus, the COL4A5 expression pattern has an important prognostic value and it correlates with the severity of ultrastructural glomerular basement membrane alterations in males with AS. Loss of COL4A5 staining is uncommon in patients with AS diagnosed in their adulthood. PMID- 29142940 TI - Transplantation of Renal Allografts From Organ Donors Reactive for HCV Antibodies to HCV-Negative Recipients: Safety and Clinical Outcome. AB - Introduction: Because of the shortage of available organs for renal transplantation, strategies enabling the safe use of organs from donors with potential chronic infections such as hepatitis C are necessary. The aim of this study was to analyze the outcome of renal transplant donation from hepatitis C virus (HCV)-positive donors. Methods: Between September 2002 and May 2007, 51 kidneys (34 donors) reactive for HCV antibodies were further evaluated. Six kidneys (5 donors) were transplanted to 6 recipients with known chronic HCV infection. The remaining 29 donors underwent extended virological testing. Nine donors were HCV RNA positive and thus not suitable for HCV-negative patients. Twenty donors (21 kidneys) did not have detectable HCV RNA copies and were transplanted into 21 HCV-negative recipients. Clinical outcomes focusing on safety, allograft function, and de novo HCV infection in the recipient were collected. Results: There were no de novo HCV infections detected in recipients who were HCV negative before transplantation. The extended virological donor screening did not have an impact on median cold ischemia time. Five-year graft survival was 75%. Discussion: Organs from anti-HCV-reactive, nonviremic donors can be transplanted safely to HCV-negative recipients. PMID- 29142941 TI - The Longitudinal Study of Liver Cysts in Patients With Autosomal Dominant Polycystic Kidney Disease and Polycystic Liver Disease. AB - Introduction: Although polycystic liver disease (PCLD) is one of the extrarenal complications in patients with autosomal dominant polycystic kidney disease (ADPKD), longitudinal changes and the association with total liver volume (TLV) have not been clearly elucidated yet. Methods: Patients with ADPKD were chosen who underwent computed tomography or magnetic resonance imaging twice or more during August 2003 through December 2015. TLV, each cyst volume, and the proportion of parenchyma were measured. The natural history of liver cysts and the association between TLV and liver cysts were evaluated. To compare with liver cysts in ADPKD patients with PCLD, simple liver cysts in patients without ADPKD were also evaluated. Results: TLV at baseline and its growth rate in all the patients with ADPKD, whose serum creatinine, estimated glomerular filtration rate, and total kidney volume were 1.45 mg/dl (0.76-2.32 mg/dl), 38.5 ml/min per 1.73 m2 (18.7-57.9 ml/min per 1.73 m2), and 1394 ml (773-2861 ml), were 1431 ml (1062-1749 ml) and -0.95%/yr (-3.16 to 4.94%/yr), respectively, in the observation period (median, 1063 days). Neither TLV nor its growth rate was significantly different between ADPKD patients with PCLD and those without PCLD. The growth rate of 79 liver cysts was 39.5%/yr (17.5-80.8%/yr) in PCLD patients with ADPKD. It was significantly larger than that of 60 simple liver cysts in the non-ADPKD group, 11.0%/yr (-2.2 to 33.1%/yr). Moreover, the proportion of parenchyma reduced, whereas that of total cyst volume increased significantly (P = 0.001). Discussion: The reduction of parenchyma was accompanied by the growth of liver cysts during time course in PCLD patients with ADPKD. PMID- 29142943 TI - Ischemic Monomelic Neuropathy: Diagnosis, Pathophysiology, and Management. PMID- 29142942 TI - Complement Activation Induces Neutrophil Adhesion and Neutrophil-Platelet Aggregate Formation on Vascular Endothelial Cells. AB - Introduction: Atypical hemolytic uremic syndrome is a thrombotic microangiopathy, which is linked to hereditary or autoimmune defects in complement activators or regulators present in blood and on vascular endothelial cells. Acute thrombotic microangiopathy episodes are typically preceded by infections, which by themselves would not be expected to manifest HUS. Thus, it is possible that the host immune response contributes to the precipitation of aHUS. However, the mechanisms involved are not fully understood. We hypothesized that neutrophils trigger aHUS via initiating platelet aggregate formation on complement-activated endothelial cells. Methods: We investigated neutrophil adhesion to complement activated endothelial cells under static and flow conditions in vitro and ex vivo. Results: Our results show that complement activation on endothelial cells promotes neutrophil adhesion, which is significantly reduced when the complement terminal pathway is blocked. When neutrophils and platelets are perfused simultaneously, neutrophils adhering to endothelial cells also induce the formation of platelet-neutrophil aggregates on these cells. Sera from patients with aHUS recapitulated these results. Discussion: Therefore, our findings of (i) neutrophils adhering to complement-activated endothelial cells, (ii) the formation of neutrophil-platelet aggregates on endothelial cells, and (iii) the ability of aHUS serum to induce similar effects identify a possible role for neutrophils in aHUS manifestation. PMID- 29142944 TI - Atypical Antiglomerular Basement Membrane Disease With IgG1-kappa Staining. PMID- 29142945 TI - Lysozyme-Induced Nephropathy. PMID- 29142946 TI - CD19 Targeted Low-Dose Rituximab Is Effective in the Management of Refractory Phospholipase A2 Receptor Antibody-Associated Membranous Nephropathy. PMID- 29142947 TI - How Well Does Serum Albumin Correlate With Dietary Protein Intake in Dialysis Patients? PMID- 29142948 TI - KI Reports and World Kidney Day. PMID- 29142949 TI - Rhabdomyolysis in Earthquake Victims in Nepal. PMID- 29142950 TI - A Familial Infantile Renal Failure. PMID- 29142951 TI - Severe Acute Interstitial Nephritis: Response to Therapy With Antithymocyte Globulin. PMID- 29142952 TI - Serum NGAL and Cystatin C Comparison With Urinary Albumin-to-Creatinine Ratio and Inflammatory Biomarkers as Early Predictors of Renal Dysfunction in Patients With Type 2 Diabetes. AB - Introduction: Diabetic nephropathy is associated with specific histological changes. Early detection of poor glomerular and tubular function can be achieved with biomarkers of diabetes. The aim of this study was to evaluate the accuracy of kidney dysfunction biomarkers in type 2 diabetes (T2D). Methods: Patients with T2D were grouped according to their glycated hemoglobin level. Patients' urine and blood samples were taken to measure cystatin C (CysC), neutrophil gelatinase associated lipocalin, beta-trace protein levels, and the first morning void albumin-to-creatinine ratio. Patients in the end stage of renal disease or receiving dialysis were not included. Receiver operating characteristic curves were generated, and the areas under the curve were compared with the performance of the biomarkers used to evaluate kidney dysfunction in T2D. Results: Ninety patients with T2D were chosen. CysC was positively correlated with creatinine (P < 0.001), estimated glomerular filtration rate (P < 0.001), and urinary beta trace protein (P = 0.01). The area under the curve was 0.635 for CysC, 0.621 for serum neutrophil gelatinase-associated lipocalin, and 0.660 for the albumin-to creatinine ratio. A crude logistic regression model showed a positive association between serum CysC (P = 0.01) and serum neutrophil gelatinase-associated lipocalin (P < 0.001). A linear regression model showed a positive association between serum CysC, creatinine, and estimated glomerular filtration rate (P < 0.001) but did not show a positive association with glycated hemoglobin (P = 0.892). Discussion: Neutrophil gelatinase-associated lipocalin and serum CysC were positively associated with the presence of renal dysfunction and had better performance on receiver operating characteristic analysis than the other markers evaluated in patients with T2D without kidney dysfunction. PMID- 29142953 TI - Absence of HIV-Associated Nephropathy Among Antiretroviral Naive Adults With Persistent Albuminuria in Western Kenya. AB - Introduction: HIV-associated nephropathy (HIVAN) has been strongly linked to African ancestry. However, studies have demonstrated wide variability in the prevalence of HIVAN in different sub-Saharan African populations. Accurate assessment of the disease burden is important because antiretroviral therapy (ART) is increasingly available and may prevent progression to end-stage renal disease. Methods: We prospectively screened ART-naive, afebrile, nonhypertensive, and nondiabetic adults attending a large HIV care program in Western Kenya for the presence of albuminuria (dipstick albumin >= trace or urine albumin to creatinine ratio [UACR] >= 30 mg/g). Those with albuminuria confirmed on 2 occasions, subject to consent, underwent kidney biopsy. Results: Among 523 subjects screened, 85 (16.3%) had albuminuria on the initial screen, and persistent albuminuria was confirmed in 32 of the 53 (60%) who returned for confirmatory testing. A total of 27 subjects with persistent albuminuria underwent biopsy. The median age was 34 years (interquartile range [IQR] 30-42 years), and 63% were female. The median CD4 count was 369 cells/MUl (IQR 89-492 cells/MUl). Renal function was normal in 92%. Median UACR was 257.5 mg/g (IQR 93.5-543 mg/g), and 92% had UACR < 1 g/g. No subject had histologic features consistent with HIVAN; 41% had acute interstitial nephritis (AIN); 33% had nonspecific findings, and 2 patients had arteriosclerosis. Focal segmental glomerulosclerosis, acute postinfectious glomerulonephritis, chronic interstitial nephritis, pyelitis, and papillary sickling were seen in 1 patient each. Discussion: Among ART-naive adults with persistent albuminuria at a referral center in Western Kenya, we observed no cases of HIVAN. AIN was the most common cause of persistent proteinuria in this setting. PMID- 29142954 TI - Asymmetric Dimethylarginine (ADMA) Levels Are Lower in Hemodialysis Patients Treated With Paricalcitol. AB - Introduction: Chronic kidney disease is a major public health problem. In the last decade, it has been shown that the early stages of chronic kidney disease are associated with an inflammatory condition involving an increased risk of cardiovascular morbidity and long-term mortality. In patients with chronic kidney disease and more specifically those on hemodialysis, cardiovascular events are the most common cause of death. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and may be an independent risk factor for endothelial dysfunction and cardiovascular disease. Methods: We performed a cross-sectional analysis to identify factors that were associated with ADMA such as certain medications related to cardiovascular disease in dialysis patients. Results: Patients who were treated with paricalcitol had significantly lower levels of ADMA (0.21 +/- 0.19 MUmol/l) compared with those not treated with paricalcitol (0.42 +/- 0.35 MUmol/l) (P = 0.00027). Dividing ADMA levels by quartiles, patients treated with paricalcitol were less likely to have very high level ADMA (P = 0.014), whereas there were no significant differences with other medications. Higher dose of paricalcitol was also related to lower levels of ADMA noting an inverse correlation (r = -0.36, P = 0.013). Discussion: Hemodialysis patients treated with paricalcitol presented significantly decreased ADMA levels compared with those who did not receive this treatment. Possible beneficial effects in terms of cardiovascular morbidity and mortality by paricalcitol and its association with ADMA and nitric oxide synthesis are unknown. Studies to confirm this effect and determine the underlying pathophysiological mechanism are necessary. PMID- 29142955 TI - Improving the Prediction of Cardiac Surgery-Associated Acute Kidney Injury. AB - Introduction: Acute kidney injury (AKI) is a potentially fatal complication of cardiac surgery. The inability to predict cardiac surgery-associated AKI is a major barrier to prevention and early treatment. Current clinical risk models for the prediction of cardiac surgery-associated AKI are insufficient, particularly in patients with preexisting kidney dysfunction. Methods: To identify intraoperative variables that might improve the performance of a validated clinical risk score (Cleveland Clinic Score, CCS) for the prediction of cardiac surgery-associated AKI, we conducted a prospective cohort study in 289 consecutive elective cardiac surgery patients at a tertiary care center. We compared the area under the receiver operator characteristic curve (AUC) of a base model including only the CCS with models containing additional selected intraoperative variables including mean arterial pressure, hematocrit, duration of procedure, blood transfusions, and fluid balance. AKI was defined by the Kidney Disease Improving Global Outcomes 2012 criteria. Results: The CCS alone gave an AUC of 0.72 (95% confidence interval, 0.62-0.82) for postoperative AKI. Nadir intraoperative hematocrit was the only variable that improved AUC for postoperative AKI when added to the CCS (AUC = 0.78; 95% confidence interval, 0.70-0.87; P = 0.002). In the subcohort of patients without preexisting chronic kidney disease (n = 214), where the CCS underperformed (AUC, 0.60 [0.43-0.76]), the improvement with the addition of nadir hematocrit was more marked (AUC, 0.74 [0.62-0.86]). Other variables did not improve discrimination. Discussion: Nadir intraoperative hematocrit is useful in improving discrimination of clinical risk scores for AKI, and may provide a target for intervention. PMID- 29142956 TI - Hypertension Control, Apparent Treatment Resistance, and Outcomes in the Elderly Population With Chronic Kidney Disease. AB - Introduction: Chronic kidney disease (CKD) is often associated with poor hypertension control and treatment resistance, but whether CKD modifies the effect of hypertension control on outcomes is unknown. Methods: We studied 10 year mortality and cardiovascular events according to hypertension control status and CKD (glomerular filtration rate <60 ml/min/1.73m2) in 4262 community-dwelling individuals (40% men) more than 65 years of age. Results: At baseline, 19% had CKD, and 31.2% had controlled hypertension on <=3 antihypertensive drugs, 62.3% uncontrolled hypertension >=140/90 mm Hg on <=2 drugs, and 6.5% apparent treatment-resistant hypertension (aTRH) >=140/90 mm Hg with >=3 drugs or use of >=4 drugs regardless of level. There were 1115 deaths (305 total cardiovascular deaths) and 274 incident nonfatal or fatal strokes or coronary events. Compared to the reference group (controlled hypertension and no CKD), participants without CKD and with uncontrolled hypertension or aTRH had adjusted hazard ratios for all cause mortality of 0.86 (0.74-1.01) and 1.09 (0.82-1.46), and those with CKD and controlled or uncontrolled hypertension, or aTRH, of 1.33 (1.06-1.68), 1.14 (0.93 1.39), and 1.34 (0.98-1.85), respectively. Participants with aTRH and CKD had a risk of coronary death more than 3 times higher than that of the reference group; participants with aTHR, with or without CKD, had a risk of stroke more than twice as high, and those with CKD but controlled hypertension a 2 times higher risk for cardiovascular deaths from other causes. Discussion: CKD does not appear to amplify the risk of stroke and coronary events associated with aTRH in this older population. The reasons for excess cardiovascular mortality from other causes associated with controlled hypertension require further study. PMID- 29142957 TI - Identifying Factors That Influence Physicians' Recommendations for Dialysis and Conservative Management in Indonesia. AB - Introduction: For elderly end-stage renal disease (ESRD) patients with multiple comorbidities, dialysis may offer little survival benefit compared to conservative management (CM). Yet, many elderly ESRD patients undergo dialysis, partly due to physicians' recommendations regarding treatment choice. This study aims to elucidate the factors that influence these recommendations. Methods: We surveyed a convenience sample of physicians who attended the 9th Asian Forum of Chronic Kidney Disease Initiative conference. We used vignettes that vary by age and comorbidity status, and asked physicians to recommend dialysis or CM for a hypothetical patient with that profile and to predict survival with both treatment options. We also compared the physician's recommendations to patients for what they would recommend for themselves if they were diagnosed with ESRD. Results: On average, physicians believed that dialysis extends life relative to CM. Yet, a large subset believed that CM confers greater survival. Estimates range from 17.3% (for a 65-year-old with diabetes and CHF) to 50% for patients with advanced cancer. Results further reveal high discordance regarding treatment recommendations. For a 65-year-old patient with diabetes, 62% recommended dialysis and 38% did not. For advanced cancer, the split was 25% and 75%. Physicians were far more likely to recommend dialysis for themselves than for their patients. Discussion: This study suggests that physicians would benefit from a greater understanding of survival benefits of dialysis and CM for elderly patients with different comorbidity profiles. This would allow patients to make more informed decisions. PMID- 29142958 TI - Diagnostic Performance of a Saliva Urea Nitrogen Dipstick to Detect Kidney Disease in Malawi. AB - Introduction: Kidney disease (KD), including acute kidney injury, is common, severe and leads to significant mortality in the developing world. However, simple tools to facilitate diagnosis and guide treatment are lacking. We studied the diagnostic performance of saliva urea nitrogen (SUN) measured by dipstick to diagnose KD in a low-resource setting. Methods: Medical admissions to a tertiary hospital in Malawi had serum creatinine tested at presentation; SUN was measured using a dipstick. Patients with serum creatinine above normal range underwent serial measurements of SUN and blood urea nitrogen for up to 7 days. Hospital outcome was recorded in all patients. Results: A total of 742 patients were included (age 41 +/- 17.3 years, 56.1% male); 146 (19.7%) had KD, including 114 (15.4%) with acute kidney injury. SUN >14 mg/dl had a sensitivity of 0.72 and a specificity of 0.87 to diagnose KD; specificity increased to 0.97 when SUN levels were combined with self-reported urine output. The diagnostic performance of SUN was comparable with the one of blood urea nitrogen (SUN area under curve, 0.82; 95% confidence interval, 0.78-0.87; blood urea nitrogen area under curve, 0.82; 95% confidence interval, 0.59-1.0). SUN >14 mg/dl on admission was an independent predictor of all-cause mortality (hazard ratio = 2.43 [95% confidence interval, 1.63-3.62]). Discussion: SUN measured by dipstick can be used to identify patients with KD in a low-resource setting. SUN is an independent predictor of mortality in this population. PMID- 29142959 TI - Hemodialysis Infection Prevention Protocols Ontario-Shower Technique (HIPPO-ST): A Pilot Randomized Trial. AB - Introduction: We developed the Hemodialysis Infection Prevention Protocols Ontario-Shower Technique (HIPPO-ST) to permit hemodialysis (HD) patients with central venous catheters (catheters) to shower without additional infection risk. Our primary objective was to determine the feasibility of conducting a parallel randomized controlled trial (RCT) to evaluate the impact of HIPPO-ST on catheter related bacteremia (CRB) in adult HD patients. Methods: Adult HD patients using catheters were recruited from 11 HD units. Patients were randomized to receive HIPPO-ST or standard care and were followed up for 6 months. Only CRB-outcome assessors were blinded. For the study to be considered feasible, 4 of 5 feasibility outcomes, each with its own statistical threshold for success, must have been achieved. Results: A total of 68 patients were randomized (33 HIPPO-ST and 35 control) and were followed up to 6 months. Of 5 measures of feasibility, 4 were achieved: (1) accurate CRB rate documented (threshold: kappa level >0.80); (2) 97.8% (279/285) of satellite HD patients with catheters were screened (threshold: >95%); (3) 88% (23/26) in the HIPPO-ST arm were successfully educated by 6 months (threshold: >80%); and (4) 0% (0/29) patients in the control arm were "contaminated," that is, using HIPPO-ST (threshold: <5%). However, only 44.2% (72/163) of eligible patients consented to participate (threshold: >80%). The rate of CRB was similarly low in HIPPO-ST and control groups (0.68 vs. 0.88/1000 catheter days). Discussion: This HIPPO-ST pilot study demonstrated the feasibility of the larger HIPPO-ST study, especially given the high levels of education success with the HIPPO-ST arm and the low levels of contamination in the control arm. PMID- 29142960 TI - Depression and Immunosuppressive Therapy Adherence Following Renal Transplantation in Military Healthcare System Beneficiaries. PMID- 29142961 TI - The Renal Pathology of Obesity. AB - Obesity causes various structural, hemodynamic, and metabolic alterations in the kidney. Most of these are likely to be compensatory responses to the systemic increase in metabolic demand that is seen with obesity. In some cases, however, renal injury becomes clinically apparent as a result of compensatory failure. Obesity-related glomerulopathy is the best known of such disease states. Factors that may sensitize obese individuals to renal compensatory failure and associated injury include the severity and number of obesity-associated conditions or complications, including components of metabolic syndrome, and the mismatch of body size to nephron mass, due to nephron reductions of congenital or acquired origin. PMID- 29142963 TI - Understanding Electronic AKI Alerts: Characterization by Definitional Rules. AB - Introduction: Automated acute kidney injury (AKI) electronic alerts are based on comparing creatinine with historic results. Methods: We report the significance of AKI defined by 3 "rules" differing in the time period from which the baseline creatinine is obtained, and AKI with creatinine within the normal range. Results: A total of 47,090 incident episodes of AKI occurred between November 2013 and April 2016. Rule 1 (>26 MUmol/l increase in creatinine within 48 hours) accounted for 9.6%. Rule 2 (>=50% increase in creatinine within previous 7 days) and rule 3 (>=50% creatinine increase from the median value of results within the last 8-365 days) accounted for 27.3% and 63.1%, respectively. Hospital-acquired AKI was predominantly identified by rules 1 and 2 (71.7%), and community-acquired AKI (86.3%) by rule 3. Stages 2 and 3 were detected by rules 2 and 3. Ninety-day mortality was higher in AKI rule 2 (32.4%) than rule 1 (28.3%, P < 0.001) and rule 3 (26.6%, P < 0.001). Nonrecovery of renal function (90 days) was lower for rule 1 (7.9%) than rule 2 (22.4%, P < 0.001) and rule 3 (16.5%, P < 0.001). We found that 19.2% of AKI occurred with creatinine values within normal range, in which mortality was lower than that in AKI detected by a creatinine value outside the reference range (22.6% vs. 29.6%, P < 0.001). Discussion: Rule 1 could only be invoked for stage 1 alerts and was associated with acute on chronic kidney disease acquired in hospital. Rule 2 was also associated with hospital-acquired AKI and had the highest mortality and nonrecovery. Rule 3 was the commonest cause of an alert and was associated with community-acquired AKI. PMID- 29142962 TI - What Genetics Tells Us About the Pathogenesis of IgA Nephropathy: The Role of Immune Factors and Infection. AB - Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis, which is characterized by IgA1-containing immune-deposits in the glomerular mesangium. The epidemiologic observations of familial clustering as well as ethnic and regional discrepancies indicate a genetic component to IgAN. Large, international, genome-wide association studies have identified several susceptibility genes and loci for IgAN, many of which have been implicated in immune regulation and are shared with other autoimmune diseases. Notably, increasing numbers of genes involved in mucosal immunity have been detected; such genes may impact the susceptibility and progression of IgAN through interaction with environmental stimuli (especially infection). Here, we discuss the innate and adaptive immune mechanisms that drive protective immunity against pathogens. Our goal is to provide a representative overview of the synergistic roles between genetic predisposition and infection in IgAN pathogenesis. We anticipate that these results will provide potential therapeutic agents and advances in precision medicine. PMID- 29142964 TI - Impact of the End Stage Renal Disease Prospective Payment System on the Use of Peritoneal Dialysis. AB - Introduction: The End Stage Renal Disease (ESRD) Prospective Payment System (PPS), implemented by the Centers for Medicare and Medicaid Services in January 2011, encouraged use of peritoneal dialysis (PD) through various financial incentives. Our goal was to determine whether PPS effectively increased PD use in incident dialysis patients. Methods: Our study used the United States Renal Data System (USRDS) to identify 430,927 adult patients who initiated dialysis between 2009 and 2012. The interrupted time series method was used to evaluate the association Centers for Medicare and Medicaid Services of PPS with PD use at dialysis initiation. We further stratified by patient demographics, predialysis care, and facility chain and profit status. Results: Interrupted time series analysis indicated PPS was associated with increased PD use in the 2-year period after PPS (change in slope = 0.04, P < 0.0001), although there was no immediate change in the level of PD use at the beginning of PPS (P = 0.512). Stratified analyses indicated PPS led to increased PD use across all age, race, and sex groups (P < 0.05) although marginally among females (P = 0.09). Notably, small dialysis organizations and nonprofit organizations appeared to increase use of PD faster compared to large dialysis organizations and for-profit units, respectively. Discussion: Implementation of the Centers for Medicare and Medicaid Services ESRD payment reform was associated with an increased use of PD in the 2 years after PPS. Our findings highlight the role of financial incentives in changing practice patterns to increase use of a dialysis modality considered to be both more cost-effective and empowering to ESRD patients. However, even after PPS, rates of PD use remain low among the dialysis population in the USA. PMID- 29142965 TI - Ferritin Elevation and Improved Responsiveness to Erythropoiesis-Stimulating Agents in Patients on Ferric Citrate Hydrate. AB - Introduction: In hemodialysis patients on ferric citrate hydrate, the increase in ferritin level is mainly due to the administration of the compound. We investigated possible other factors associated with ferritin level and how erythropoietin resistance index and erythropoiesis in those patients were affected. We looked at ferritin-elevating factors using data from a Japanese phase III long-term clinical trial of ferric citrate hydrate. Methods: The factors with a strong association with ferritin levels at week 28 were selected by the process of variable selection. In addition, selected factors were analyzed by Mixed Model for Repeated Measurement. Subjects were divided into 3 groups by quantiles (28 ml/min per 1.73 m2. In contrast, the C/V ratio increased with worsening renal function in patients with eGFR <=28 ml/min per 1.73 m2. During hemodialysis, the initial decrease in vasopressin levels was greater compared with copeptin and, consequently, the C/V ratio increased. This was, at least in part, explained by a greater dialytic clearance of vasopressin compared with copeptin. Discussion: Our data indicate that copeptin is a reliable substitute for vasopressin in subjects with an eGFR >28 ml/min per 1.73 m2, whereas at an eGFR <=28 ml/min per 1.73 m2, that is, CKD stages 4 and 5, a correction for renal function is required in epidemiological studies that use copeptin as a marker for vasopressin. Intradialytic copeptin levels do not adequately reflect vasopressin levels because vasopressin clearance by hemodialysis is higher than that of copeptin. PMID- 29142969 TI - Elucidation of Renal Scars in Children With Vesicoureteral Reflux Using Contrast Enhanced Ultrasound: A Pilot Study. AB - Introduction: Vesicoureteral reflux is a common disorder in children but can result in kidney scarring following acute pyelonephritis. The gold standard diagnostic to detect renal scars in children is 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy. DMSA has a number of limitations including radiation exposure, need for sedation, and radiotracer supply shortages. Contrast-enhanced ultrasound (CEUS) is a technique whereby biocompatible microspheres of inert gas are administered i.v. that reflect ultrasonography sound waves and do not involve radiation. Because the contrast agent is rapidly cleared, contrast images must be obtained within minutes of administration. CEUS has been used in a variety of organ systems, but its use in pediatric kidney diseases is limited. Methods: In this study, we performed CEUS in 7 children with documented renal scars by radiographic imaging consistent with reflux nephropathy. Results: In all subjects, CEUS detected all previously known radiologic abnormalities as well as detecting new areas of hypoenhancing renal parenchyma. None of the patients experienced any serious adverse events. Discussion: This study represents the first report of using CEUS to characterize renal scars in children with reflux nephropathy. We conclude that CEUS is a highly sensitive, rapid, and cost effective diagnostic imaging modality for detecting and monitoring renal scars in children with vesicoureteral reflux. PMID- 29142970 TI - Cardiovascular Disease Biomarkers and suPAR in Predicting Decline in Renal Function: A Prospective Cohort Study. AB - Introduction: Soluble urokinase-type plasminogen activator receptor (suPAR) strongly predicts outcomes and incident chronic kidney disease (CKD) in patients with cardiovascular disease (CVD). Whether the association between suPAR and CKD is a reflection of its overall association with chronic inflammation and poor CVD outcomes is unclear. We examined whether CVD biomarkers, including high sensitivity C-reactive protein (hs-CRP), fibrin-degradation products (FDPs), heat shock protein 70 (HSP-70), and high-sensitivity troponin I (hs-TnI) were associated with a decline in kidney function in the Emory Cardiovascular Biobank cohort, in which suPAR levels were shown to be predictive of both incident CKD and CVD outcomes. Methods: We measured suPAR, hs-CRP, HSP-70, FDP, and hs-TnI plasma levels in 3282 adults (mean age 63 years, 64% male, 75% estimated glomerular filtration rate [eGFR] >60 ml/min per 1.73 m2). Glomerular filtration rate was estimated using Chronic Kidney Disease-Epidemiology Collaboration (eGFR) at enrollment (n = 3282) and follow-up (n = 2672; median 3.5 years). Urine protein by dipstick at baseline was available for 1335 subjects. Results: There was a weak correlation among biomarkers (r range: 0.17-0.28). hs-CRP, FDPs, hs TnI, and suPAR were independently associated with baseline eGFR and proteinuria. The median yearly decline in eGFR was -0.6 ml/min per 1.73 m2. hs-CRP (beta: 0.04; P = 0.46), FDPs (beta: -0.13; P = 0.08), HSP-70 (beta: 0.05; P = 0.84), or hs-TnI (beta: -0.01; P = 0.76) were associated with eGFR decline. suPAR remained predictive of eGFR decline even after adjusting for all biomarkers. Discussion: hs-CRP, FDP, HSP-70, and hs-TnI were not associated with eGFR decline. The specific association of suPAR with eGFR decline supported its involvement in pathways specific to the pathogenesis of kidney disease. PMID- 29142971 TI - Total Kidney Volume Is a Prognostic Biomarker of Renal Function Decline and Progression to End-Stage Renal Disease in Patients With Autosomal Dominant Polycystic Kidney Disease. AB - Introduction: Autosomal dominant polycystic kidney disease is the most common hereditary kidney disease. TKV is a promising imaging biomarker for tracking and predicting the natural history of autosomal dominant polycystic kidney disease. The prognostic value of TKV was evaluated, in combination with age and eGFR, for the outcomes of 30% decline in eGFR and progression to ESRD. Observational data including 2355 patients with TKV measurements were available. Methods: Multivariable Cox models were developed to assess the prognostic value of age, TKV, height-adjusted TKV, eGFR, sex, race, and genotype for the probability of a 30% decline in eGFR or ESRD. Results: TKV was the most important prognostic term for 30% decline in eGFR in autosomal dominant polycystic kidney disease patients with and without preserved baseline eGFR. For a 40-year-old subject with preserved eGFR (70 ml/min per 1.73 m2), the adjusted hazard ratios for a 30% decline in eGFR were 1.86 (95% CI, 1.65-2.10) for a 2-fold larger TKV (600 vs. 1200 ml) and 2.68 (95% CI, 2.22-3.24) for a 3-fold larger TKV (600 vs. 1800 ml), respectively. Hazard ratios for progression to ESRD for 2- and 3-fold larger TKV were 1.72 (95% CI, 1.49-1.99) and 2.36 (95% CI, 1.88-2.97), respectively. Discussion: The capability to predict 30% decline in eGFR is a novel aspect of this study. TKV was formally qualified, both by FDA and EMA, as a prognostic enrichment biomarker for selecting patients at high risk for a progressive decline in renal function for inclusion in interventional clinical trials. PMID- 29142972 TI - A Drug Development Tool for Trial Enrichment in Patients With Autosomal Dominant Polycystic Kidney Disease. AB - Introduction: Total kidney volume (TKV) is a promising imaging biomarker for tracking and predicting the natural history of patients with autosomal dominant polycystic kidney disease. Methods: A drug development tool was developed by linking longitudinal TKV measurements to the probability of a 30% decline of estimated glomerular filtration rate (eGFR) or end-stage renal disease. Drug development tools were developed based on observational data collected over multiple decades for an eGFR decline and end-stage renal disease in 641 and 866 patients with autosomal dominant polycystic kidney disease, respectively. Results: The statistical association between predicted TKV at the time of a 30% decline of eGFR and that at the time of end-stage renal disease were both highly significant (P < 0.0001). The drug development tool was applied to demonstrate the utility of trial enrichment according to prespecified baseline TKV, age, and eGFR as enrollment criteria in hypothetical clinical trials. Patients with larger TKV (>=1000 ml) displayed steeper slopes of hazard, which translated into a higher risk of a 30% decline of eGFR within each baseline age (< or >=40 years) or baseline eGFR (< or >=50 ml/min per 1.73 m2) subgroups. Discussion: These results suggest that, when eGFR is preserved, patients with larger TKV are more likely to progress to a 30% decline of eGFR within the course of a clinical trial, whereas eGFR and age displayed limited predictive value of disease progression in early disease. Pharmaceutical sponsors and academic investigators are encouraged to prospectively employ the above drug development tool to optimize trial designs in patients with autosomal dominant polycystic kidney disease. PMID- 29142973 TI - Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein. AB - Introduction: Fibrinogen A alpha chain amyloidosis is an autosomal dominant disease associated with mutations in the fibrinogen A alpha chain (FGA) gene, and it is the most common cause of hereditary renal amyloidosis in the UK. Patients typically present with kidney impairment and progress to end-stage renal disease over a median time of 4.6 years. Methods: Six patients presented with proteinuria, hypertension, and/or lower limb edema and underwent detailed clinical and laboratory investigations. Results: A novel FGA gene mutation was identified in each case: 2 frameshift mutations F521Sfs*27 and G519Efs*30 and 4 single base substitutions G555F, E526K, E524K, R554H. In 5 subjects, extensive amyloid deposits were found solely within the glomeruli, which stained specifically with antibodies to fibrinogen A alpha chain, and in one of these cases, we found coexistent fibrinogen A alpha chain amyloidosis and anti glomerular basement membrane antibody disease. One patient was diagnosed with light-chain amyloidosis after a bone marrow examination revealed a small clonal plasma cell population, and laser microdissection of the amyloid deposits followed by liquid chromatography and tandem mass spectrometry identified kappa light chain as the fibril protein. Discussion: We report 6 novel mutations in the FGA gene: 5 were associated with renal fibrinogen A alpha chain amyloidosis and 1 was found to be incidental to light-chain amyloid deposits discovered in a patient with a plasma cell dyscrasia. Clinical awareness and suspicion of hereditary amyloidosis corroborated by genetic analysis and adequate typing using combined immunohistochemistry and laser microdissection and mass spectrometry is valuable to avoid misdiagnosis, especially when a family history of amyloidosis is absent. PMID- 29142974 TI - Profiling of Plasma Metabolites Suggests Altered Mitochondrial Fuel Usage and Remodeling of Sphingolipid Metabolism in Individuals With Type 2 Diabetes and Kidney Disease. AB - Introduction: Pathophysiology of diabetic kidney disease (DKD) is incompletely understood. We aim to elucidate metabolic abnormalities associated with DKD in type 2 diabetes mellitus (T2DM) by targeted plasma metabolomics. Methods: A total of 126 T2DM participants with early DKD (urinary albumin-to-creatinine ratio [ACR] 30-299 mg/g and eGFR >= 60 ml/min/1.73 m2), 154 overt DKD (ACR >= 300 mg/g or eGFR < 60 ml/min/1.73 m2), and 129 non-DKD T2DM controls (ACR < 30 mg/g and eGFR >= 60 ml/min/1.73 m2) were included in discovery study. Findings were subsequently validated in 149 T2DM with macroalbuminuria (ACR >= 300 mg/g) and 149 matched non-DKD T2DM controls. Plasma amino acid, acylcarnitine, Krebs cycle organic acid, and sphingolipids/ceramide levels were quantified by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Results: Of 123 metabolites included in the data analysis, 24 differed significantly between DKD and controls in the same direction in both discovery and validation subpopulations. A number of short acylcarnitines including their dicarboxylic derivatives (C2-C6) were elevated in DKD, suggesting abnormalities in fatty acids and amino acids metabolic pathways. Five phosphatidylcholines were lower whereas 4 metabolites in the sphingomyelin-ceramide subfamily were higher in DKD. Principal component regression revealed that long-chain ceramides were independently associated with ACR but not eGFR. Conversely, essential amino acids catabolism and short dicarboxylacylcarnitine accumulation were associated with eGFR but not ACR. Discussion: DKD is associated with altered fuel substrate use and remodeling of sphingolipid metabolism in T2DM with DKD. Associations of albuminuria and impaired filtration function with distinct metabolomic signatures suggest different pathophysiology underlying these 2 manifestations of DKD. PMID- 29142975 TI - Sclerostin?A Debutant on the Autosomal Dominant Polycystic Kidney Disease Scene? AB - Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease originating from a mutation in genes encoding polycystin 1 and 2. Recent evidence suggests that these polycystins mediate mechanosensation not only in the primary cilium of kidney cells but also in bone cells. The Wnt/beta-catenin signaling pathway plays a central role in mechanotransduction in osteocytes. Mechanical unloading causes the upregulation of the Wnt inhibitor sclerostin. We tested the hypothesis that ADPKD associates with higher circulating sclerostin levels. Methods: In this observational, cross-sectional study, circulating levels of sclerostin and other laboratory parameters of mineral and bone disease, including intact parathyroid hormone (PTH), calcium, phosphate, magnesium, 25(OH) D-vitamin, 1,25 (OH)2 D-vitamin, and bone specific alkaline phosphatase (BALP) were assessed in 100 patients with end-stage renal disease recruited from an ongoing longitudinal cohort study in Stockholm, Sweden. Results: Patients with ADPKD had higher sclerostin levels and lower BALP levels as compared to patients with other primary renal disease. In multivariate analysis, ADPKD associated with circulating sclerostin levels, independent of the established determinants including age, gender, body mass index, diabetes, phosphate, PTH, and 1,25 (OH)2 D-vitamin. Discussion: Circulating sclerostin levels are increased in ADPKD, possibly reflecting impaired mechanosensation. The clinical relevance of this finding, especially with regard to bone health, remains to be investigated. Our finding draws attention to the etiology of kidney disease as an important, yet neglected, confounder of the association between renal failure and mineral and bone disease. PMID- 29142976 TI - An Early Immediate Early Protein IE-1-Specific T-Cell Polyfunctionality Is Associated With a Better Control of Cytomegalovirus Reactivation in Kidney Transplantation. PMID- 29142977 TI - von Brunn Nests Hyperplasia as a Cause of Ureteral Stenosis After Kidney Transplantation. PMID- 29142978 TI - Severe Adverse Effects Associated With Corticosteroid Treatment in Patients With IgA Nephropathy. AB - Introduction: Few data are available on the risk of SAEs in corticosteroid users in IgAN populations. We describe the prevalence and risk factors of corticosteroid-related SAEs in a Chinese cohort. Methods: A total of 1034 IgAN patients were followed up in our renal center from 2003 to 2014. Prevalence of corticosteroid use and corticosteroid-related SAEs were noted. Logistic regression was used to search for risk factors of SAEs in corticosteroid users. Results: Of the 369 patients with steroids therapy, 46 patients (12.5%) with 58 events suffered SAEs, whereas only 18 patients (2.7%) without corticosteroids suffered SAEs (OR: 5.45; 95% CI: 3.07-9.68; P < 0.001). SAEs included diabetes mellitus (n = 19, 5.1%), severe or fatal infection (n = 18, 4.9%), osteonecrosis of the femoral head or bone fracture (n = 6, 1.6%), cardiocerebral vascular disease (n = 4, 1.1%), cataract (n = 3, 0.8%), and gastrointestinal hemorrhage (n = 1, 0.3%). Multivariable logistic regression analysis revealed that advanced age (OR: 1.05; 95% CI: 1.02-1.07; P < 0.001) and hypertension (OR: 1.04; 95% CI: 1.01 1.06; P = 0.009) were risk factors for corticosteroid-related SAEs. Impaired kidney function (estimated GFR: OR: O.98; 95% CI: 0.96-0.99; P = 0.036) was a risk factor for severe infection. Accumulated dosages of corticosteroids were not identified as a risk factor of SAEs (OR: 1.09; 95% CI: 0.91-1.30; P = 0.365). Discussion: Corticosteroid use is associated with a high risk of SAEs in IgAN patients, especially those who are older, have hypertension, or impaired renal function. Current guidelines on corticosteroid regimens in IgAN should be reviewed with regard to safety. PMID- 29142979 TI - Two-Year Follow-up Study of Membranous Nephropathy Treated With Tacrolimus and Corticosteroids Versus Cyclical Corticosteroids and Cyclophosphamide. AB - Introduction: Both cCTX/GCs and CNIs are recommended as first-line agents in the management of PMN. The present study is an extended report of patients randomized to receive TAC/GCs or cCTX/GCs at 2 years post randomization. Methods: Seventy patients enrolled in the clinical trial Tacrolimus Combined With Corticosteroids Versus Modified Ponticelli Regimen in Treatment of Idiopathic Membranous Nephropathy: Randomized Control Trial were followed quarterly between 12 and 24 months. At the end of 24 months, 3 patients were lost to follow-up. Results: At 18 months, 66% and 89% (P = 0.04) were in remission in TAC/GCs and cCTX/GCs groups, respectively. At 18 and 24 months, 60% and 86% (P = 0.03) of cases were in remission in the TAC/GCs and cCTX/GCs groups, respectively. At 18 months, 57% and 83% (P = 0.03) of the patients in TAC/GCs and cCTX/GCs groups were in remission without need of any additional immunosuppression (persistent remission) and, at 24 months, 43% and 80% (P = 0.002) were in persistent remission in TAC/GCs and cCTX/GCs groups, respectively. Relapse rate after any remission was 40% and 6.7% in TAC/GCs and cCTX/GCs groups, respectively (P = 0.007). There was an association of aPLA2R titers with remission or resistance (P = 0.006) in relapsing PMN. The significant decrease in eGFR after 12 months of TAC/GCs therapy normalized at 18 and 24 months. Discussion: At 2 years after randomization, relapse rates are higher for TAC/GCs compared with cCTX/GCs in PMN patients. Thus, cCTX/GCs are better than TAC/GCs in the longer term in PMN patients. PMID- 29142980 TI - Effectiveness of Multifaceted Care Approach on Adverse Clinical Outcomes in Nondiabetic CKD: A Systematic Review and Meta-analysis. AB - Introduction: The risk of major adverse events associated with chronic kidney disease (CKD) could potentially be reduced with effective medical interventions. The impact of multifaceted interventions as compared with usual care in patients with nondiabetic CKD is unclear. We performed a systematic review to analyze the impact of multifaceted interventions on reducing the risk of major adverse events in this population. Methods: Systematic review and meta-analysis. We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library databases for medical literature published up to November 2016. Published original studies and abstracts were reviewed that reported on adult patients in a community or specialty care setting, with 2 or more CKD risk factors, treated with a combination of more than 2 interventions. We included randomized controlled trials, observational studies, and systematic reviews. Studies focused on diabetic patients were excluded. The intervention was defined as a treatment with a combination of 2 or more interventions compared with the usual care. The outcomes were defined as a reduction in the risk of adverse clinical outcomes (renal replacement therapy, all-cause hospitalizations, all-cause and cardiovascular mortality, cardiovascular events) as primary outcomes. Secondary outcomes were optimal risk factor control (attaining guideline concordant blood pressure, reduction of proteinuria, smoking cessation). Results: Five of the 5846 unique citations from our initial literature search met our study criteria. All identified studies reported on patients with CKD and their management. In comparison with usual care, multifaceted interventions tended to reduce all-cause mortality (risk ratio: 0.81, 95% confidence interval: 0.63-1.03) and were associated with a lower risk of progression to kidney failure requiring dialysis (risk ratio: 0.57, 95% confidence interval: 0.35-0.94). Multifaceted interventions were not associated with reducing risk of all-cause hospitalizations (risk ratio: 0.93, 95% confidence interval: 0.71-1.23) or improved blood pressure control (mean difference: -0.48, range: -2.5 to 1.55 mm Hg). Discussion: Multifaceted interventions targeting multiple risk factors tended to reduce the risk of all cause mortality and reduced the risk to progress to end-stage kidney failure in patients with CKD. There is a need for high-quality studies that can rigorously evaluate a set of interventions targeting multiple domains of CKD management in the population with nondiabetic CKD due to paucity of data in the current published literature. PMID- 29142981 TI - Commercial Kidney Transplantation: Attitude, Knowledge, Perception, and Experience of Recipients. AB - Introduction: Kidney transplantation is the gold standard for patients with end stage kidney disease. In view of shortages of available organs, long wait times for possible transplantation, and strict regulation, many patients opt for commercial transplantation. This study elicits the reasons and motivations for patients with end-stage kidney disease to elect for commercial transplant. Methods: A questionnaire-based evaluation was conducted during the period from July 2015 until late December 2015. It consisted of 29 multiple choice questions and was distributed to all patients who underwent commercial kidney transplantation. Results: One hundred and fifty patients were approached to participate and 106 agreed. Of the participants, 60% were male with an average age of 41.5 (SD 14.8) years and ranged from 18 to 83 years. The majority (82%) of our participants were educated ranging from primary to college level. The major reason (71%) for these participants to obtain commercial transplants was stated as the unavailability of a live related donor. Thirteen percent stated that they objected to getting a kidney donated from a family member, and 9% stated that they were worried about taking a kidney from a family member. Finally, 3% of participants stated that they needed prompt transplant and could not wait for a long time for transplant investigations and the workup associated with this program. Discussion: The study showed that the most common underlying cause for seeking commercial transplantation is the unavailability of a national transplant program, particularly transplantation from deceased sources. All western ethical arguments turn out to become of vital importance in developing countries, because transplantation is the cheapest renal replacement therapy. However, it must be emphasized that commercial transplants should not be an alternative to building a national transplant initiative. The national diseased program must be a priority with full financial and administrative support. All government agencies including religious affairs must work together to support the program and to provide the citizens with a good transplantation service and ameliorate the impact of commercial transplantation. PMID- 29142982 TI - A Single- and Multiple-Dose, Multicenter Study of Etelcalcetide in Japanese Hemodialysis Patients With Secondary Hyperparathyroidism. AB - Introduction: The pharmacokinetics, pharmacodynamics, and safety and tolerability profile of etelcalcetide (ONO-5163/AMG 416), a novel, i.v., long-acting calcium sensing receptor agonist, were studied in Japanese hemodialysis patients with secondary hyperparathyroidism. Methods: This multicenter, randomized, double blind, placebo-controlled, parallel-group study consisted of a single dose part and a multiple dose (3 times weekly for 4 weeks) part. Major inclusion criteria were hemodialysis for at least 90 days, serum intact parathyroid hormone (iPTH) >= 300 pg/ml, and serum albumin-corrected Ca (cCa) >= 9.0 mg/dl. There were 3 single-dose cohorts (n = 6 each) randomized 2:1 to 5, 10, or 20 mg etelcalcetide or placebo, and 2 multiple-dose cohorts (n = 11 each) randomized 8:3 to 2.5 or 5 mg etelcalcetide or placebo. Results: Etelcalcetide plasma concentration decreased rapidly after i.v. administration, generally remained stable from 24 hours postdose to the next dialysis, and then decreased by dialysis. Etelcalcetide exposure increased dose proportionally. Etelcalcetide plasma predialysis concentration reached almost steady state at week 4. A single dose of etelcalcetide dose-dependently reduced serum iPTH in 30 minutes, and the reduction reached a plateau at 1 hour that lasted until 8 hours. The percent change from baseline serum iPTH thereafter showed a trend to gradually decrease; it was still -30% or greater on day 3. Similar results were obtained at the last injection (days 27-29) of the multiple dose. The effect of the multiple dose was sustained during the interdialytic period. Etelcalcetide decreased serum cCa in a more gradual but dose-dependent and sustained manner. Discussion: Etelcalcetide dose-dependently reduced serum iPTH and serum cCa. Moreover, the effect was sustained in the interdialytic period. PMID- 29142983 TI - Efficacy and Safety of Sparsentan Compared With Irbesartan in Patients With Primary Focal Segmental Glomerulosclerosis: Randomized, Controlled Trial Design (DUET). AB - Introduction: Primary focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease. There are no US Food and Drug Administration-approved therapies for FSGS, and treatment often fails to reduce proteinuria. Endothelin is an important factor in the pathophysiology of podocyte disorders, including FSGS. Sparsentan is a first-in-class, orally active, dual-acting angiotensin receptor blocker (ARB) and highly selective endothelin Type A receptor antagonist. This study is designed to evaluate whether sparsentan lowers proteinuria compared with an ARB alone and has a favorable safety profile in patients with FSGS. Methods: DUET is a phase 2, randomized, active-control, dose-escalation study with an 8-week, fixed-dose, double-blind period followed by 136 weeks of open-label sparsentan treatment. Patients aged 8 to 75 years with primary FSGS will be randomized to treatment with sparsentan or irbesartan for 8 weeks. Results: The primary efficacy objective is to test the hypothesis that sparsentan over the dose range (200 mg, 400 mg, or 800 mg daily) is superior to irbesartan (300 mg daily) in decreasing the urinary protein-to creatinine ratio (UPC) from baseline to 8 weeks postrandomization. As secondary objectives, the trial will evaluate the proportion of patients who achieve prespecified targets of UPC reduction, changes in laboratory and quality-of-life indices, and detailed safety analysis. Analyses will be conducted at the end of the double-blind (week 8) and open-label (week 144) periods. Discussion: This study will provide important evidence on whether dual ARB and endothelin blockade may be an effective therapeutic strategy for FSGS and may provide the rationale for next-phase trials. PMID- 29142984 TI - The Combination of Beta Blockers and Renin-Angiotensin System Blockers Improves Survival in Incident Hemodialysis Patients: A Propensity-Matched Study. AB - Introduction: Although several studies suggest that the prognosis of hypertensive dialysis patients can be improved by using antihypertensive drug therapy, it is unknown whether the prescription of a particular class or combination of antihypertensive drugs is beneficial during hemodialysis. Methods: We performed a propensity score matching study to compare the effectiveness of various classes of antihypertensive drugs on cardiovascular (CV) mortality in 2518 incident hemodialysis patients in Spain. The patients had initially received antihypertensive therapy with a renin-angiotensin system (RAS) blocker (728 patients), a beta-blocker (679 patients), antihypertensive drugs other than a RAS blocker or a beta-blocker (787 patients), or the combination of a beta-blocker and a RAS inhibitor (324 patients). These patients were followed for a maximum of 5 years (median: 2.21 yr; range: 1.04-3.34 yr). Results: After adjustment for baseline CV risk covariates, no significant differences were observed in the risk of CV mortality between patients taking a RAS blocker and patients treated with beta-blocker-based antihypertensive therapy. The combination of a RAS blocker with a beta-blocker was associated with better CV survival than either agent alone (RAS blocker: hazard ratio [HR]: 1.68; 95% confidence interval [CI] 1.05 2.69; beta-blocker: HR: 1.59; 95% CI: 1.01-2.50; antihypertensive medication other than a RAS blocker or beta-blocker: HR: 1.67; 95% CI: 1.08-2.58). Discussion: Our data suggested that the combination of a RAS blocker and a beta blocker could improve survival in hemodialysis patients. Further prospective randomized controlled trials are necessary to confirm the beneficial effects of this combination of antihypertensive drugs in patients undergoing hemodialysis. PMID- 29142985 TI - Low Urinary Creatinine Excretion Is Associated With Self-Reported Frailty in Patients With Advanced Chronic Kidney Disease. AB - Introduction: Frailty and muscle wasting, a component of frailty, are common in advanced stage chronic kidney disease (CKD). Whether frailty is associated with low urinary creatinine excretion (UCrE) as a measure of muscle mass in this population is unknown. Furthermore, reference values of UCrE are lacking. We first defined low UCrE and studied correlates of low UCrE, and subsequently studied cross-sectional associations of frailty with low UCrE in patients with advanced CKD. Methods: A total of 2748 healthy individuals of the general population-based PREVEND study were included to define low UCrE (UCrE indexed for height, below the age- and sex-specific 5th percentile of the distribution). Frailty was defined using a modification of the Fried frailty phenotype. In a CKD population that included 320 and 967 participants of the PREPARE-2 and NECOSAD studies, respectively, cross-sectional associations of self-reported frailty, the individual components that define self-reported frailty, and frailty-associated variables with low UCrE were evaluated using multivariate logistic and linear regression models. Results: Low UCrE was found in 38% of the CKD patients. A lower glomerular filtration rate was strongly associated with low UCrE. Self reported frailty (adjusted odds ratio: 2.19; 95% confidence interval: 1.28-3.77) and the individual components were associated with low UCrE, independent of comorbidities. The frailty-associated variables hemoglobin and albumin were inversely associated with low UCrE, and parathyroid hormone was positively associated with low UCrE. Discussion: Lower kidney function is a strong correlate of low UCrE and self-reported frailty, and the individual frailty components are associated with low UCrE as well, independent of comorbidities. PMID- 29142986 TI - Cardiac Autonomic Neuropathy Predicts All-Cause and Cardiovascular Mortality in Patients With End-Stage Renal Failure: A 5-Year Prospective Study. AB - Introduction: Chronic renal disease is associated with increased cardiovascular (CV) mortality. Cardiac autonomic neuropathy (CAN) is predictive of mortality for diseases that affect the autonomic nervous system. We prospectively evaluated the prognostic value of indexes of left ventricular (LV) function and CAN in all cause and CV mortality of patients with end-stage renal failure (ESRF). Methods: A total of 133 patients with ESRF were recruited. LV function was evaluated by echocardiography, whereas cardiac autonomic function was assessed using the battery of the 4 standardized tests proposed by Ewing. Results: A total of 123 of 133 (92.5%) patients completed the study and were followed for a mean of 4.9 +/- 2.6 years. Mean LV ejection fraction (LVEF) was 50.9 +/- 6.9%, whereas 70 (57.9%) patients had CAN. Sixty-nine all-cause and 36 CV deaths were recorded. The survival rates at 3, 5, and 7 years were 77.2%, 57.4%, and 33.7%, respectively. Multivariate analysis after adjustment for waist circumference, current smoking, history of diabetes, and coronary artery disease demonstrated that the only independent predictors of all-cause mortality during follow-up were age, serum triglycerides, LVEF, and presence of CAN. Competing risk regression analysis, after adjusting for waist circumference, coronary heart disease, serum glucose, and triglycerides, indicated that age and presence of CAN were independent risk factors for CV mortality. Discussion: Age and presence of CAN are independent predictors of all-cause and CV mortality in patients with ESRF. The functionality of the cardiac autonomic nervous system activity can be used for the risk stratification in patients with ESRF. PMID- 29142987 TI - Prospective Study of Routine Heparin Avoidance Hemodialysis in a Tertiary Acute Care Inpatient Practice. AB - Introduction: Extracorporeal circuit (EC) anticoagulation with heparin is a key advance in hemodialysis (HD), but anticoagulation is problematic in inpatients at risk of bleeding. We prospectively evaluated a heparin-avoidance HD protocol, clotting of the EC circuit (CEC), impact on dialysis efficiency, and associated risk factors in our acute care inpatients who required HD (January 17, 2014 to May 31, 2015). Methods: HD sessions without routine EC heparin were performed using airless dialysis tubing. Patients received systemic anticoagulation therapy and/or antiplatelets for non-HD indications. We observed patients for indications of CEC (interrupted HD session, circuit loss, or inability to return blood). The primary outcome was CEC. Logistic regression with generalized estimating equations assessed associations between CEC and other variables. Results: HD sessions (n = 1200) were performed in 338 patients (204 with end-stage renal disease; 134 with acute kidney injury); a median session was 211 minutes (interquartile range [IQR]: 183-240 minutes); delivered dialysis dose measured by Kt/V was 1.4 (IQR: 1.2 Kt/V 1.7). Heparin in the EC was prescribed in only 4.5% of sessions; EC clotting rate was 5.2%. Determinants for CEC were temporary catheters (odds ratio [OR]: 2.8; P < 0.01), transfusions (OR: 2.4; P = 0.04), therapeutic systemic anticoagulation (OR: 0.2; P < 0.01), and antiplatelets (OR: 0.4; P < 0.01). CEC was associated with a lower delivered Kt/V (difference: 0.39; P < 0.01). Most CEC events during transfusions (71%) occurred with administration of blood products through the HD circuit. Discussion: We successfully adopted heparin avoidance using airless HD tubing as our standard inpatient protocol. This protocol is feasible and safe in acute care inpatient HD. CEC rates were low and were associated with temporary HD catheters and transfusions. Antiplatelet agents and systemic anticoagulation were protective.ClinicalTrials.gov Identifier:NCT02086682. PMID- 29142988 TI - Proximal Tubular Expression Patterns of Megalin and Cubilin in Proteinuric Nephropathies. AB - Introduction: Receptor-mediated endocytosis is responsible for protein reabsorption in the proximal tubules. For albumin this process involves at least 2 interacting receptors, megalin and cubilin. Albumin is not usually present in the urine, indicating a highly efficient tubular reuptake under physiological conditions. However, early appearance of albuminuria may mean that the tubular system is overwhelmed by large quantities of albumin or that the function is impaired. Methods: To better understand the physiological role of megalin and cubilin in human renal disease, renal biopsies from 15 patients with a range of albuminuria and 3 healthy living donors were analyzed for proximal tubular expression of megalin and cubilin using immunohistochemistry (IHC) and semiquantitative immune-electron microscopy. Their expression in proteinuric zebrafish was also studied. Results: Megalin and cubilin were expressed in brush border and cytoplasmic vesicles. Patients with microalbuminuric IgA nephropathy and thin membrane disease had significantly higher megalin in proximal tubules, whereas those with macro- or nephrotic-range albuminuria had unchanged levels. Cubilin expression was significantly higher in all patients. In a proteinuric zebrafish nphs2 knockdown model, we found a dose-dependent increase in the expression of tubular megalin and cubilin in response to tubular protein uptake. Discussion: Megalin and cubilin show different expression patterns in different human diseases, which indicates that the 2 tubular proteins differently cooperate in cleaning up plasma proteins in kidney tubules. PMID- 29142989 TI - Recommended Standards for Assessing Blood Pressure in Human Research Where Blood Pressure or Hypertension Is a Major Focus. AB - Introduction: Although inaccurate, nonreproducible blood pressure values can result from nonstandardized assessments, recommended approaches to standardize blood pressure measurement are often not followed in research studies. Methods: An expert consensus of national and international health and scientific organizations developed recommended minimum standards for assessing blood pressure in research subjects where: (i) blood pressure or hypertension is a major endpoint, or (ii) blood pressure is likely a major mediator of the research outcome. Results: Minimum research standards are presented for training of observers, technical aspects of assessing blood pressure, and equipment for both adults and children. Discussion: The standards are based on prior recommendations, some of which did not conform to current evidence-based methods. All new research should require adherence to these minimum standards on the patient populations described above. Readers need to use caution in interpreting studies if the standards are not met in the defined populations. PMID- 29142991 TI - A Patient Navigation System to Minimize Barriers for Peritoneal Dialysis in Rural, Low-Resource Settings: Case Study From Guatemala. PMID- 29142990 TI - The Chemical Chaperone, PBA, Reduces ER Stress and Autophagy and Increases Collagen IV alpha5 Expression in Cultured Fibroblasts From Men With X-Linked Alport Syndrome and Missense Mutations. AB - Introduction: X-linked Alport syndrome (OMIM 301050) is caused by COL4A5 missense variants in 40% of families. This study examined the effects of chemical chaperone treatment (sodium 4-phenylbutyrate) on fibroblast cell lines derived from men with missense mutations. Methods: Dermal fibroblast cultures were established from 2 affected men and 3 normals. Proliferation rates were examined, the collagen IV alpha5 chain localized with immunostaining, and levels of the intra- and extracellular chains quantitated with an in-house enzyme-linked immunosorbent assay. COL4A5 mRNA was measured using quantitative reverse transcriptase polymerase chain reaction. Endoplasmic reticulum (ER) size was measured on electron micrographs and after HSP47 immunostaining. Markers of ER stress (ATF6, HSPA5, DDIT3), autophagy (ATG5, BECN1, ATG7), and apoptosis (CASP3, BAD, BCL2) were also quantitated by quantitative reverse transcriptase polymerase chain reaction. Measurements were repeated after 48 hours of incubation with 10 mM sodium 4-phenylbutyrate acid. Results: Both COL4A5 missense variants were associated with reduced proliferation rates on day 6 (P = 0.01 and P = 0.03), ER enlargement, and increased mRNA for ER stress and autophagy (all P values < 0.05) when compared with normal. Sodium 4-phenylbutyrate treatment increased COL4A5 transcript levels (P < 0.01), and reduced ER size (P < 0.01 by EM and P < 0.001 by immunostaining), ER stress (p HSPA5 and DDIT3, all P values < 0.01) and autophagy (ATG7, P < 0.01). Extracellular collagen IV alpha5 chain was increased in the M1 line only (P = 0.06). Discussion: Sodium 4-phenylbutyrate increases collagen IV alpha5 mRNA levels, reduces ER stress and autophagy, and possibly facilitates collagen IV alpha5 extracellular transport. Whether these actions delay end-stage renal failure in men with X-linked Alport syndrome and missense mutations will only be determined with clinical trials. PMID- 29142992 TI - A Dialysis Patient With Hyperphosphatemia, Hyperkalemia, and Azotemia Without an Excessive Intake. PMID- 29142993 TI - Shunt Nephritis and Pyogenic Spondylitis With a Positive PR3-ANCA Associated With Chronically Infected Ventriculoatrial Shunt. PMID- 29142994 TI - Re: Timely Referral to Outpatient Nephrology Care Slows Progression and Reduces Treatment Costs of Chronic Kidney Diseases. PMID- 29142995 TI - Screening of novel RGD peptides to modify nanoparticles for targeted cancer therapy. AB - New targeted RGD peptides obtained by solid phase peptide synthesis (SPPS) were successfully screened by Molecular Operating Environment (MOE) and used for the building of the 6-O-carboxymethyl chitosan based carrier with an active target on the surface. CRGDYC-6-O-carboxymethyl chitosan based nanoparticles (NPs) loaded with doxorubicin hydrochloride (DOX) were successfully prepared by an ionic gelation method with the carrier synthesized before. Synthesis conditions and formulation parameters were optimized by determining the characteristics of nanoparticles including the particle size and drug encapsulation efficiency. 6-O Carboxymethyl chitosan concentration, calcium chloride concentration and calcium chloride/6-O-carboxymethyl chitosan ratio all had effects on the particle size and drug encapsulation efficiency. Nanoparticles with an average diameter of 193.4 nm, an average drug loading efficiency of up to 69.5% and an average drug loading of up to 0.395% were prepared successfully with the optimal formulation. Flow cytometry and confocal microscopy analyses showed that the cellular uptake of DOX in human breast cancer cell lines (MCF-7) was higher in the CRGDYC modified nanoparticles compared with the unmodified nanoparticles. In vivo imaging showed that the distribution of CRGDYC-modified nanoparticles in the tumor site was higher compared with the unmodified nanoparticles. These results suggest that CRGDYC-6-O-carboxymethyl chitosan may be a promising cancer targeting carrier which can enhance the intracellular uptake and cytotoxicity of the drug-loaded nanoparticles. PMID- 29142996 TI - Selective phosphatidylcholine double bond fragmentation and localisation using Paterno-Buchi reactions and ultraviolet photodissociation. AB - The effect of double bond functionalisation for selective double bond localisation by ultraviolet photodissociation of phosphatidylcholines is investigated. Paterno-Buchi reactions in nanoESI emitter tips enable attachment of acetophenone to double bonds of unsaturated phosphatidylcholines after 100 s of 254 nm light irradiation with about 50-80% reaction yield. Functionalized phosphatidylcholines dissociate upon 266 nm irradiation yielding double bond selective fragment ions in contrast to results for ultraviolet photodissociation of unmodified lipids. Ultraviolet photodissociation of Paterno-Buchi modified lipids results in a selectivity increase of up to 2.2 towards double bond localisation compared collision-induced dissociation experiments. Double bond localisation is also possible with ultraviolet photodissociation when alkali metal ion attachment to Paterno-Buchi modified phosphatidylcholines occurs in contrast to classic collision-induced dissociation experiments. The developed methodology is used to differentiate lipid double bond isomers and applied to phosphatidylcholines from egg yolk to identify 15 phosphatidylcholines. Results from this study demonstrate that locally depositing energy in close vicinity to cleavable bonds via ultraviolet photodissociation can result in increased dissociation selectivity. This method can help to disentangle contributions from different structural elements in complex tandem mass spectra of lipids and aid to the structural characterization of phospholipids in a "top-down" approach. PMID- 29142998 TI - Covalent post-assembly modification in metallosupramolecular chemistry. AB - A growing variety of covalent reactions have been employed to achieve the post assembly modification (PAM) of self-assembled metallosupramolecular complexes. Covalent PAM enables the late-stage derivatisation of pre-assembled parent complexes in a modular fashion, thus expanding the chemical space available for supramolecular synthesis. The oldest and most widespread implementation of covalent PAM is in metal-preorganised covalent synthesis. Recent work, however, has broadened the scope of covalent PAM to include: protocols for efficiently grafting new functionalities onto supramolecular architectures, reactions that permanently 'lock-down' metastable complexes, and covalent bond-forming stimuli that trigger controlled structural transformations between distinct supramolecular species. This review highlights key examples of each of these distinct kinds of covalent PAM in metallosupramolecular chemistry, before providing a perspective upon future challenges and opportunities. PMID- 29142999 TI - Highlights from Faraday Discussion FDSERS17: Surface Enhanced Raman Scattering - SERS, Glasgow, UK, 30th August-1st September 2017. AB - The 2017 Faraday Discussion on Surface Enhanced Raman Scattering (SERS) attracted more than a hundred delegates from a broad spectrum of backgrounds and experience levels, bringing together leading scientists involved in the long living field of SERS. The meeting gave an overview of the liveliness of the topic, characterised by open questions and fascinating science still to discover. In the following, we discuss the topics covered during this meeting and briefly highlight the content of each presentation. PMID- 29143000 TI - Parametric amplification in MoS2 drum resonator. AB - Parametric amplification is widely used in diverse areas from optics to electronic circuits to enhance low level signals by varying relevant system parameters. Parametric amplification has also been performed in several micro nano resonators including nano-electromechanical system (NEMS) resonators based on a two-dimensional (2D) material. Here, we report the enhancement of mechanical response in a MoS2 drum resonator using degenerate parametric amplification. We use parametric pumping to modulate the spring constant of the MoS2 resonator and achieve a 10 dB amplitude gain. We also demonstrate quality factor enhancement in the resonator with parametric amplification. We investigate the effect of cubic nonlinearity on parametric amplification and show that it limits the gain of the mechanical resonator. Amplifying ultra-small displacements at room temperature and understanding the limitations of the amplification in these devices is key for using these devices for practical applications. PMID- 29142997 TI - Advanced smart-photosensitizers for more effective cancer treatment. AB - Photodynamic therapy (PDT) based upon the use of light and photosensitizers (PSs) has been used as a novel treatment approach for a variety of tumors. It, however, has several major limitations in the clinic: poor water solubility, long-term phototoxicity, low tumor targeting efficacy, and limited light penetration. With advances in nanotechnology, materials science, and clinical interventional imaging procedures, various smart-PSs have been developed for improving their cancer-therapeutic efficacy while reducing the adverse effects. Here, we briefly review state-of-the-art smart-PSs and discuss the future directions of PDT technology. PMID- 29143001 TI - Easily fabricated and lightweight PPy/PDA/AgNW composites for excellent electromagnetic interference shielding. AB - Conductive polymer composites (CPCs) containing nanoscale conductive fillers have been widely studied for their potential use in various applications. In this paper, polypyrrole (PPy)/polydopamine (PDA)/silver nanowire (AgNW) composites with high electromagnetic interference (EMI) shielding performance, good adhesion ability and light weight are successfully fabricated via a simple in situ polymerization method followed by a mixture process. Benefiting from the intrinsic adhesion properties of PDA, the adhesion ability and mechanical properties of the PPy/PDA/AgNW composites are significantly improved. The incorporation of AgNWs endows the functionalized PPy with tunable electrical conductivity and enhanced EMI shielding effectiveness (SE). By adjusting the AgNW loading degree in the PPy/PDA/AgNW composites from 0 to 50 wt%, the electrical conductivity of the composites greatly increases from 0.01 to 1206.72 S cm-1, and the EMI SE of the composites changes from 6.5 to 48.4 dB accordingly (8.0-12.0 GHz, X-band). Moreover, due to the extremely low density of PPy, the PPy/PDA/AgNW (20 wt%) composites show a superior light weight of 0.28 g cm-3. In general, it can be concluded that the PPy/PDA/AgNW composites with tunable electrical conductivity, good adhesion properties and light weight can be used as excellent EMI shielding materials. PMID- 29143002 TI - Nanotopography-based strategy for the precise manipulation of osteoimmunomodulation in bone regeneration. AB - Immune cells play vital roles in regulating bone dynamics. Successful bone regeneration requires a favourable osteo-immune environment. The high plasticity and diversity of immune cells make it possible to manipulate the osteo-immune response of immune cells, thus modulating the osteoimmune environment and regulating bone regeneration. With the advancement in nanotechnology, nanotopographies with different controlled surface properties can be fabricated. On tuning the surface properties, the osteo-immune response can be precisely modulated. This highly tunable characteristic and immunomodulatory effects make nanotopography a promising strategy to precisely manipulate osteoimmunomdulation for bone tissue engineering applications. This review first summarises the effects of the immune response during bone healing to show the importance of regulating the immune response for the bone response. The plasticity of immune cells is then reviewed to provide rationales for manipulation of the osteoimmune response. Subsequently, we highlight the current types of nanotopographies applied in bone biomaterials and their fabrication techniques, and explain how these nanotopographies modulate the immune response and the possible underlying mechanisms. The effects of immune cells on nanotopography-mediated osteogenesis are emphasized, and we propose the concept of "nano-osteoimmunomodulation" to provide a valuable strategy for the development of nanotopographies with osteoimmunomodulatory properties that can precisely regulate bone dynamics. PMID- 29143003 TI - A mixed-dimensional light-emitting diode based on a p-MoS2 nanosheet and an n CdSe nanowire. AB - The construction of the mixed-dimensional van der Waals (vdW) heterostructures with two-dimensional (2D) and one-dimensional (1D) materials can advantageously integrate their respective dimensional properties to produce new device functionalities and/or enhance device performance. In this case, a single semiconductor nanowire (NW) can function as an optical cavity and a gain medium, while the atomically thin 2D material does not strongly absorb the NW's light emission or disturb the optical propagation mode. Therefore, the mixed dimensional 2D/1D vdW heterostructure might provide a new route to realize high efficiency light-emitting diodes (LEDs) and/or even electrically driven lasers. Here, we report a LED based on a p-type MoS2 nanosheet and an n-type CdSe NW. The 2D/1D vdW heterojunction diode exhibits a rectification ratio of ~24 at Vds = +/ 3 V, and a low turn-on voltage of ~1.5 V. Under the forward bias exceeding the turn-on voltage, the 2D/1D vdW heterojunction exhibits strong electroluminescence centered at ~709 nm, corresponding to the band-edge emission of the CdSe NW. This novel 2D/1D vdW device, which takes advantages of both 2D and 1D semiconductors, enables potential future applications in electrically driven lasers, high sensitivity sensors, and transparent flexible devices. PMID- 29143004 TI - Adsorption parameters and phase behaviour of non-ionic surfactants at liquid interfaces. AB - A reasonable adsorption model is one that allows all adsorption parameters (adsorption constant, hard-disc area alpha, attraction parameter beta) of a surfactant at a liquid interface to be predicted accurately as a function of the molecular structure and medium conditions. However, the established adsorption models of van der Waals and Frumkin lead to inconsistencies, such as negative beta at water|oil, alpha significantly larger than the crystallographic area of the molecule, and phase behaviour that contradicts the experimental observations. Several less popular models that are better suited for liquid interfaces are investigated. It is shown that the sticky disc model agrees with the observed adsorption behaviour of several homologous series of surfactants, both at water|air and water|oil interfaces. The area alpha is independent of the interface and agrees within 6% to what follows from collapse and crystallographic data. A model of the lateral attraction is proposed, from which it follows that beta has a strongly non-linear dependence on the hydrocarbon chain length, the area of the head group and the temperature. Using the model of beta, experimental data, and the law of corresponding states, the critical point of the adsorbed layer could be determined. Depending on the value of beta, the adsorption behaviour of the surfactants at liquid interfaces can be classified into distinct categories: cohesive or non-cohesive, based on their Boyle points (where beta = 2), and sub-critical or super-critical, based on their critical points (where beta = 38.1). PMID- 29143005 TI - Photodissociation of the CH3O and CH3S radical molecules: an ab initio electronic structure study. AB - The electronic states and the spin-orbit couplings between them involved in the photodissociation process of the radical molecules CH3X, CH3X -> CH3 + X (X = O, S), taking place after the A(2A1) <- X[combining tilde](2E) transition, have been investigated using highly correlated ab initio techniques. A two-dimensional representation of both the potential-energy surfaces (PESs) and the couplings is generated. This description includes the C-X dissociative mode and the CH3 umbrella mode. Spin-orbit effects are found to play a relevant role in the shape of the excited state potential-energy surfaces, particularly in the CH3S case where the spin-orbit couplings are more than twice more intense than in CH3O. The potential surfaces and couplings reported here for the present set of electronic states allow for the first complete description of the above photodissociation process. The different photodissociation mechanisms are analyzed and discussed in light of the results obtained. PMID- 29143006 TI - Cooperative supramolecular polymerization of a perylene diimide derivative and its impact on electron-transporting properties. AB - H-bonding-promoted supramolecular polymerization of a perylene diimide (PDI) building block and its impact on charge carrier mobility were studied. PDI-1, containing a carboxylic acid group, exhibits H-aggregation in a non-polar solvent decalin while in THF or chloroform it remains in the monomeric form. In contrast, the control molecule PDI-2, containing an ester group does not show aggregation even in decalin, indicating that H-bonding among the carboxylic acid is primarily responsible for H-aggregation, which is further verified by the FT-IR study. A variable temperature UV/Vis study establishes a cooperative pathway for the supramolecular polymerization of PDI-1. Microscopy images show a short fibrillar morphology. Flash-photolysis time-resolved microwave conductivity (FP-TRMC) measurements reveal significantly higher electrical conductivity for the PDI-1 film prepared from decalin compared with that prepared from THF/MeOH or the film of non-aggregated PDI-2 prepared from decalin. By combining the transient absorption spectroscopy data (that estimate the charge carrier generation efficiency) and the TRMC evaluated conductivity, the 1D charge carrier mobility of PDI-1 (MUe,1D) is estimated to be 0.24 cm2 V-1 s-1, which is among the top values reported for any PDI derivative measured using the same technique. PMID- 29143010 TI - Exploring what prompts ITIC to become a superior acceptor in organic solar cell by combining molecular dynamics simulation with quantum chemistry calculation. AB - The interface characteristic is a crucial factor determining the power conversion efficiency of organic solar cells (OSCs). In this work, our aim is to conduct a comparative study on the interface characteristics between the very famous non fullerene acceptor, ITIC, and a fullerene acceptor, PC71BM by combining molecular dynamics simulations with density functional theory. Based on some typical interface models of the acceptor ITIC or PC71BM and the donor PBDB-T selected from MD simulation, besides the evaluation of charge separation/recombination rates, the relative positions of Frenkel exciton (FE) states and the charge transfer states along with their oscillator strengths are also employed to estimate the charge separation abilities. The results show that, when compared with those for the PBDB-T/PC71BM interface, the CT states are more easily formed for the PBDB-T/ITIC interface by either the electron transfer from the FE state or direct excitation, indicating the better charge separation ability of the former. Moreover, the estimation of the charge separation efficiency manifests that although these two types of interfaces have similar charge recombination rates, the PBDB-T/ITIC interface possesses the larger charge separation rates than those of the PBDB-T/PC71BM interface. Therefore, the better match between PBDB-T and ITIC together with a larger charge separation efficiency at the interface are considered to be the reasons for the prominent performance of ITIC in OSCs. PMID- 29143011 TI - Iron-catalyzed peroxidation-carbamoylation of alkenes with hydroperoxides and formamides via formyl C(sp2)-H functionalization. AB - A reaction protocol in which FeCl3 and tert-butyl hydroperoxide facilitated a selective radical coupling reaction of aryl alkenes or 1,3-enynes with tert-butyl hydroperoxide and formamides to prepare an array of beta-peroxy amides has been achieved. The beta-peroxy amide could serve as a synthetic precursor which was facilely converted to beta-hydroxy amide, beta-keto amide and beta-lactam following subsequent chemical transformation. PMID- 29143013 TI - Shape-dependent effective diffusivity in packings of hard cubes and cuboids compared with spheres and ellipsoids. AB - We performed computational screening of effective diffusivity in different configurations of cubes and cuboids compared with spheres and ellipsoids. In total, more than 1500 structures are generated and screened for effective diffusivity. We studied simple cubic and face-centered cubic lattices of spheres and cubes, random configurations of cubes and spheres as a function of volume fraction and polydispersity, and finally random configurations of ellipsoids and cuboids as a function of shape. We found some interesting shape-dependent differences in behavior, elucidating the impact of shape on the targeted design of granular materials. PMID- 29143012 TI - beta-Alanine and N-terminal cationic substituents affect polyamide-DNA binding. AB - Minor-groove binding hairpin polyamides (PAs) bind specific DNA sequences. Synthetic modifications can improve PA-DNA binding affinity and include flexible modules, such as beta-alanine (beta) motifs to replace pyrroles (Py), and increasing compound charge using N-terminal cationic substituents. To better understand the variations in kinetics and affinities caused by these modifications on PA-DNA interactions, a comprehensive set of PAs with different numbers and positions of beta and different types of N-cationic groups was systematically designed and synthesized to bind their cognate sequence, the lambdaB motif. The lambdaB motif is also a strong binding promoter site of the major groove targeting transcription factor PU.1. The PA binding affinities and kinetics were evaluated using a spectrum of powerful biophysical methods: thermal melting, biosensor surface plasmon resonance and circular dichroism. The results show that beta inserts affect PA-DNA interactions in a number and position dependent manner. Specifically, a beta replacement between two imidazole heterocycles (ImbetaIm) generally strengthens binding. In addition, N-terminal cationic groups can accelerate the association between PA and DNA, but the bulky size of TMG can cause steric hindrance and unfavourable repulsive electrostatic interactions in some PAs. The future design of stronger binding PA requires careful combination of betas and cationic substituents. PMID- 29143014 TI - Synthesis, characterization, and anticancer activity of two mixed ligand copper(ii) complexes by regulating the VEGF/VEGFR2 signaling pathway. AB - The single crystals of two novel mixed-ligand copper(ii)-based complexes were obtained and characterized. These complexes can remarkably induce apoptosis, inhibit proliferation, suppress migration and metastasis, and inhibit angiogenesis to inhibit the growth of cervical cancer by down-regulating the expressions of the important proteins FAK, Akt and Erk1/2 or their phosphorylated proteins p-FAK, p-Akt, and p-Erk1/2 downstream of the VEGF/VEGFR2 signaling pathway. PMID- 29143019 TI - Half-sandwich ruthenium(ii) complexes containing N^N-chelated imino-pyridyl ligands that are selectively toxic to cancer cells. AB - Chemotherapy is limited by its poor selectivity towards cancer cells over normal cells. Herein, we designed half-sandwich ruthenium imino-pyridyl complexes [(eta6 bz)Ru(N^N)Cl]PF6 to achieve selective cytotoxicity to cancer cells. This kind of ruthenium complex has unique characteristics and is worthy of further exploration in the design of new anticancer drugs. PMID- 29143020 TI - Correction: Synthesis by free radical polymerization and properties of BN polystyrene and BN-poly(vinylbiphenyl). AB - Correction for 'Synthesis by free radical polymerization and properties of BN polystyrene and BN-poly(vinylbiphenyl)' by Wen-Ming Wan et al., Chem. Commun., 2016, 52, 13616-13619. PMID- 29143021 TI - Reversing the undesirable pH-profile of doxorubicin via activation of a di substituted maleamic acid prodrug at tumor acidity. AB - The acid-labile behavior of di-substituted maleamic acid (DMA) and its equilibrium with di-substituted maleimide (DMI) are exploited to build an ultra acid-sensitive, small molecule prodrug that can be activated by tumor extracellular pH (pHe) in the range of 6.5-6.9. Such a DMA prodrug reversed the unfavorable pH-profile of doxorubicin (Dox), which may improve its therapeutic window. PMID- 29143022 TI - High CO2 absorption capacity by chemisorption at cations and anions in choline based ionic liquids. AB - The effect of CO2 absorption on the aromaticity and hydrogen bonding in ionic liquids is investigated. Five different ionic liquids with choline based cations and aprotic N-heterocyclic anions were synthesized. Purity and structures of the synthesized ionic liquids were characterized by 1H and 13C NMR spectroscopy. CO2 capture performance was studied at 20 degrees C and 40 degrees C under three different pressures (1, 3, 6 bar). The IL [N1,1,6,2OH][4-Triz] showed the highest CO2 capture capacity (28.6 wt%, 1.57 mol of CO2 per mol of the IL, 6.48 mol of CO2 per kg of the ionic liquid) at 20 degrees C and 1 bar. The high CO2 capture capacity of the [N1,1,6,2OH][4-Triz] IL is due to the formation of carbonic acid (-OCO2H) together with carbamate by participation of the -OH group of the [N1,1,6,2OH]+ cation in the CO2 capture process. The structure of the adduct formed by CO2 reaction with the IL [N1,1,6,2OH][4-Triz] was probed by using IR, 13C NMR and 1H-13C HMBC NMR experiments utilizing 13C labeled CO2 gas. 1H and 13C PFG NMR studies were performed before and after CO2 absorption to explore the effect of cation-anion structures on the microscopic ion dynamics in ILs. The ionic mobility was significantly increased after CO2 reaction due to lowering of aromaticity in the case of ILs with aromatic N-heterocyclic anions. PMID- 29143023 TI - Self-assembled [2]catenane in trapezoidal metallacycles with [Cp*Ir]-corners. AB - A series of trapezoidal metallacycles were synthesized by the selective combination of a rigid with a flexible arm. [2]Catenane 3 was obtained by self assembly when the cavity size of the trapezoidal rings was optimised. PMID- 29143024 TI - An analysis of the explosion limits of hydrogen/oxygen mixtures with nonlinear chain reactions. AB - The ignition boundary of hydrogen/oxygen mixtures is a Z-shaped curve in the pressure-temperature space, demonstrating the existence of three explosion limits. In this study, a general analysis governing all the three explosion limits in an isothermal environment is performed by considering both linear chain reactions (reactant-radical reactions) and nonlinear chain reactions (radical radical reactions), in addition to the zeroth-order reactant-reactant reactions. For the nonlinear reactions, it is further shown that the linear-nonlinear coupling has the major influence, while the effect of nonlinear-nonlinear coupling is negligible. Phenomenologically, at low pressures, the competition between linear branching and linear termination as well as wall destruction determines the first and second explosion limits, while the nonlinear chain reactions are unimportant because of the small radical concentrations under these conditions. However, at higher pressures, both linear and nonlinear chain reactions are needed to accurately describe the third limit, which would be underpredicted by considering the linear chain reactions alone. For intermediate and high pressures, the dominant species are HO2 and H2O2, respectively. Mechanistically, the concentration of HO2 becomes higher at higher pressures due to the three-body recombination reaction, H + O2 + M -> HO2 + M, such that the radical-radical reactions involving HO2 become important, while the reaction HO2 + HO2 -> H2O2 + O2 renders HO2 nonessential at the third limit, with the H2O2 radical generated by the nonlinear chain reactions becoming the controlling species. PMID- 29143025 TI - Efficient Ni-catalyzed conversion of phenols protected with 2,4,6-trichloro-1,3,5 triazine (TCT) to olefins. AB - An efficient Ni(COD)2/dppf catalyzed olefination of Ar-O-TCT as synthetic equivalents of aryl halides is described. Activation of C-O bonds in phenols as readily available compounds was achieved with 2,4,6-trichloro-1,3,5-triazine (TCT). This method provides practical access to 1,2-disubstituted olefins in high yields and high functional group compatibility. PMID- 29143026 TI - Tunable synthetic control of soft polymeric nanoparticle morphology. AB - With a growing variety of nanoparticles available, research probing the influence of particle deformability, morphology, and topology on the behavior of all polymer nanocomposites is also increasing. In particular, the behavior of soft polymeric nanoparticles in polymer nanocomposites has displayed unique behavior, but their precise performance depends intimately on the internal structure and morphology of the nanoparticle. With the goal of providing guidelines to control the structure and morphology of soft polymeric nanoparticles, we have examined monomer starved semi-batch nano-emulsion polymerizations that form organic, soft nanoparticles, to correlate the precise structure of the nanoparticle to the rate of monomer addition and crosslinking density. The synthesis method produces 5-20 nm radii polystyrene nanoparticles with tunable morphologies. We report small angle neutron scattering (SANS) results that correlate synthetic conditions to the structural characteristics of soft polystyrene nanoparticles. These results show that the measured molecular weight of the nanoparticles is controlled by the monomer addition rate, the total nanoparticle radius is controlled by the excess surfactant concentration, and the crosslinking density has a direct effect on the topology of each nanoparticle. These studies thus provide pathways to control these 3 structural characteristics of the nanoparticle. This research, therefore provides a conduit to thoroughly investigate the effect of structural features of soft nanoparticles on their individual properties and those of their polymer nanocomposites. PMID- 29143027 TI - Surface-confined [2 + 2] cycloaddition towards one-dimensional polymers featuring cyclobutadiene units. AB - Surface-confined synthesis has been offering a wide range of opportunities for the construction of novel molecular nanostructures. Exploring new types of on surface coupling reactions is considered essential for being able to deliberately tune the materials properties. Here, we report on the formation of a covalent C-C bonding motif, namely 1,3-cyclobutadiene, via surface-confined [2 + 2] cycloaddition between pyrene moieties using low temperature scanning tunneling microscopy (LT-STM) and X-ray photoemission spectroscopy (XPS) measurements. By employing a hydrogen dosing treatment together with low-temperature activation, we were able to both eliminate residual byproducts and obtain covalent 1D polymers through the formation of 1,3-cyclobutadiene units. The resulting C-C bonding motif has so far hardly been explored in surface chemistry and substantial evidence is provided that the hydrogen treatment is crucial towards the removal of byproducts in surface-confined polymerization. PMID- 29143028 TI - Frame, metric and geodesic evolution in shape-changing nematic shells. AB - Non-uniform director fields in flat, responsive, glassy nematic sheets lead to the induction of shells with non-trivial topography on the application of light or heat. Contraction along the director causes metric change, with, in general, the induction of Gaussian curvature, that drives the topography change. We describe the metric change, the evolution of the director field, and the transformation of reference state material curves, e.g. spirals into radii, as curvature develops. The non-isometric deformations associated with heat or light change the geodesics of the surface, intriguingly even in regions where no Gaussian curvature results. PMID- 29143029 TI - Triphenylsulfonium topophotochemistry. AB - The products from the 193 nm irradiation of triphenylsulfonium nonaflate (TPS) embedded in a poly(methyl methacrylate) (PMMA) film have been characterized. The analysis of the photoproduct formation was performed using chromatographic techniques including HPLC, GPC and GC-MS as well as UV-vis and NMR spectroscopic methods. Two previously unreported TPS photoproducts, triphenylene and dibenzothiophene, were detected; additionally, GPC and DOSY-NMR spectroscopic analyses after irradiation suggested that TPS fragments had been incorporated into the polymer film. The irradiation of acetonitrile solutions containing 10% w/v PMMA and 1% w/v TPS in a 1 cm-path-length cuvette showed only a trace amount of triphenylene or dibenzothiophene, indicating that topochemical factors were important for the formation of these molecules. The accumulated evidence indicates that both products were formed by in-cage, secondary photochemical reactions: 2-(phenylthio)biphenyl to triphenylene, and diphenylsulfide to dibenzothiophene. PMID- 29143030 TI - Quantitative chemoproteomic profiling reveals multiple target interactions of spongiolactone derivatives in leukemia cells. AB - The spongiolactones are marine natural products with an unusual rearranged spongiane skeleton and a fused beta-lactone ring. These compounds have potential anticancer properties but their mode of action has yet to be explored. Here we employ activity-based protein profiling to identify the targets of a more potent spongiolactone derivative in live cancer cells, and compare these to the targets of a simpler beta-lactone. These hits provide the first insights into the covalent mechanism of action of this natural product class. PMID- 29143031 TI - Acid-base machines: electrical work from neutralization reactions. AB - We have developed an electrochemical system that performs electrical work due to changes in alkaline ion and proton activities associated with acidic solution neutralization. This system can be used to treat wastewater, contributing to sustainable growth. The system includes an electrochemical machine that operates between an acidic and a basic reservoir to produce work in cycles comprising four stages: two isothermal ionic insertion/de-insertion steps and two steps involving acid and base injection. On the basis of the mixing free energy associated with the reaction free energy, we have developed the thermodynamic formalism by considering reversible electrochemical processes to determine the maximum work performed by this acid-base machine and the efficiency. Electrochemical methods in the time and frequency domains helped in investigating the kinetics of sodium ions and proton insertion in host matrices consisting of copper hexacyanoferrate and phosphomolybdic acid, respectively, to improve our understanding of the factors underlying dissipation as a function of pH and pNa. The full cell composed of these insertion electrodes was used as a proof of concept. It performed a maximum work of 26.4 kJ per mol of electro-inserted ion from HCl solution neutralization with the addition of NaOH, to simulate acidic wastewater treatment in a profitable and sustainable way. PMID- 29143032 TI - Reaction monitoring reveals poisoning mechanism of Pd2(dba)3 and guides catalyst selection. AB - We have discovered that the dba ligand in the commonly used Pd2(dba)3.CHCl3 cross coupling pre-catalyst is susceptible to bis-arylation when used in the presence of aryl iodides. The in situ formed dbaAr2 ligands result in Pd-species with altered catalytic activity. In the case of study, the room temperature C3 arylation of benzo[b]thiophenes with aryl iodides, we have observed a marked catalyst deactivation when dba is arylated with electron-deficient aryl iodides, accounting for the poor yields obtained in the C3 arylation reactions with these aryl iodides. Based on these studies, we report a new catalytic system, employing a dba-free Pd catalyst, which allows for the first time the direct C3 arylation of benzo[b]thiophenes with electron-deficient aryl iodides at room temperature. PMID- 29143033 TI - Correction: Key role of surface oxidation and reduction processes in the coarsening of Pt nanoparticles. AB - Correction for 'Key role of surface oxidation and reduction processes in the coarsening of Pt nanoparticles' by Eduardo Solano et al., Nanoscale, 2017, 9, 13159-13170. PMID- 29143037 TI - Measurement of long range attractive forces between hydrophobic surfaces produced by vapor phase adsorption of palmitic acid. AB - Extensive research into the surface forces between hydrophobic surfaces has produced experimentally measured interaction forces that vary widely in range and in magnitude. This variability is attributed to interference from surface nanobubbles and the nature of the hydrophobic surface. Whilst the effects of nanobubbles are now recognised and can be addressed, the precise nature of the surface remains a confounding factor in measurements between hydrophobic surfaces. Here we show that a monolayer coating with hydrophobic properties is formed by exposing metal oxide surfaces to palmitic acid vapour. Surface forces measured between these smooth hydrophobic surfaces exhibited an exponential attraction. Neither patchy surface charges, nor surface nanobubbles could explain the measured forces. However, the observed interaction may be explained by the interaction of a single patch of bilayered palmitic acid molecules interacting with an exposed patch of the hafnia surface. Such an interaction is consistent with the observed exponential nature of the attraction and the agreement between the measured decay of the exponential attraction with the Debye length of the solution. PMID- 29143038 TI - Optical nonlinearity engineering of a bismuth telluride saturable absorber and application of a pulsed solid state laser therein. AB - Saturable absorbers (SAs) have interesting applications for the realization of pulsed lasers in various wavelengths of fiber and solid-state lasers. Topological insulators (TIs) have been recently discovered to feature saturable absorption due to their unique band structure. In this study, high-purity layers of Bi2Te3 thin film SA have been successfully prepared using the spin coating-coreduction approach (SCCA). Compared with the typical method of preparing SAs, the SCCA can be used to prepare topological insulator saturable absorbers (TISAs) with high optical quality, large area consistency, and controllable thickness, which is critical for pulsed lasers. To the best of our knowledge, this study is the first observation and discussion of clear thickness-dependent optical nonlinearity. In this study, a Q-switched bulk Nd:YAG laser is demonstrated and investigated using the prepared TISA as the absorber. The timing jitter and amplitude fluctuation of the stable pulse laser indicated that the SCCA is suitable for fabricating a Bi2Te3 SA. Furthermore, the SCCA enables the establishment of a pulsing laser through saturation intensity engineering. PMID- 29143039 TI - Copper nitrate-catalyzed oxidative coupling of unactivated C(sp3)-H bonds of ethers and alkanes with N-hydroxyphthalimide: synthesis of N-hydroxyimide esters. AB - A copper nitrate-catalyzed cross-dehydrogenative coupling reaction between N hydroxyphthalimide (NHPI) and ethers/alkanes has been described. The reaction is accomplished smoothly by using simple and green molecular oxygen as the oxidant, providing an alternative for the efficient synthesis of N-alkoxyphthalimides. In addition, it was found that when tert-butyl ethers were used as substrates, unexpected N-hydroxyimide ester derivatives were obtained in moderate to excellent yields. To further understand this unusual transformation, control experiments were performed and a plausible mechanism was proposed. PMID- 29143040 TI - Probing optical excitations in chevron-like armchair graphene nanoribbons. AB - The bottom-up fabrication of graphene nanoribbons (GNRs) has opened new opportunities to specifically tune their electronic and optical properties by precisely controlling their atomic structure. Here, we address excitation in GNRs with periodic structural wiggles, the so-called chevron GNRs. Based on reflectance difference and high-resolution electron energy loss spectroscopies together with ab initio simulations, we demonstrate that their excited-state properties are of excitonic nature. The spectral fingerprints corresponding to different reaction stages in their bottom-up fabrication are also unequivocally identified, allowing us to follow the exciton build-up from the starting monomer precursor to the final GNR structure. PMID- 29143041 TI - Joint experimental and theoretical studies of the surprising stability of the aryl pentazole upon noncovalent binding to beta-cyclodextrin. AB - Herein, binding of the beta-cyclodextrin (beta-CD) host to the unstable aryl pentazole guest has been confirmed experimentally and theoretically. After the confinement of aryl pentazole, electron density reorganization was studied by M06 2X dispersion-corrected DFT and further reflected in the characteristic shift in the NMR spectra. Among the host-guest complexes, the inclusion complex is favored with the phenyl ring expectedly encapsulated within the cavity through noncovalent interactions such as hydrogen bonding, C-Hpi, and the special Csp2-HH Csp3 bonding discovered by the NBO, QTAIM, and NCI-RDG theories. The host-guest binding renders the enhancement of the nitrogen-ring aromatic character; this has been analyzed by employing nucleus-independent chemical shift (NICS)-based profiles. The non-covalent interaction largely enhances the thermal stability of the guest through a change of the decomposition reaction path whether the guest is encapsulated or not by the host. By comparison of the structures of B1-B4, the enhancement could be assigned to the ion-type transition structure stabilized by the C-H bonds of the host. PMID- 29143043 TI - Multi-functional micromotor: microfluidic fabrication and water treatment application. AB - Micromotors are important for a wide variety of applications. Here, we develop a microfluidic approach for one-step fabrication of a Janus self-propelled micromotor with multiple functions. By fine tuning the fabrication parameters and loading functional nanoparticles, our micromotor reaches a high speed and achieves an oriented function to promote the water purification efficiency and recycling process. PMID- 29143042 TI - Synthesis and characterization of the first inhibitor of N acylphosphatidylethanolamine phospholipase D (NAPE-PLD). AB - N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is a membrane associated zinc enzyme that catalyzes the hydrolysis of N acylphosphatidylethanolamines (NAPEs) into fatty acid ethanolamides (FAEs). Here, we describe the identification of the first small-molecule NAPE-PLD inhibitor, the quinazoline sulfonamide derivative 2,4-dioxo-N-[4-(4-pyridyl)phenyl]-1H quinazoline-6-sulfonamide, ARN19874. PMID- 29143044 TI - Electrocatalytic oxygen evolution with a cobalt complex. AB - The development of an earth-abundant, first-row water oxidation catalyst that operates at a high TOF and a low overpotential remains a fundamental chemical challenge. Cobalt complexes are important members of water oxidation catalysts. Herein, we report a cobalt-based robust homogeneous water oxidation catalyst, which can electrocatalyze water oxidation at a high pH and a low overpotential (eta = 520 mV) in phosphate buffer. This homogeneous system exhibits a high turnover frequency (about 5 s-1) of catalyzing water oxidation to produce oxygen at eta = 720 mV. We speculate the mechanism of the reaction that O-O bond formation prefers a HO-OH coupling in catalytic water oxidation. PMID- 29143045 TI - Long-wavelength fluorescent boronate probes for the detection and intracellular imaging of peroxynitrite. AB - Two boronate fluorescent probes have been developed for the detection of peroxynitrite (TCFB1 and TCFB2). TCFB1 was shown to have a low sensitvity towards peroxynitrite and have a poor solubility in aqueous solution whereas TCFB2 demonstrated high sensitivity towards peroxynitrite and mitochondria localisation with the ability to detect exogenous and endogenous peroxynitrite in live cells (Hep-G2, RAW 264.7, HeLa and A459). PMID- 29143046 TI - Shaping membrane vesicles by adsorption of a semiflexible polymer. AB - The adsorption of polymers onto fluid membranes is a problem of fundamental interest in biology and soft materials, in part because the flexibility of membranes can lead to nontrivial coupling between polymer and membrane configurations. Here, we use Monte Carlo computer simulations to study the adsorption of a semiflexible polymer onto a fluid membrane vesicle. Polymer adsorption can significantly impact both the vesicle and polymer shapes, and we identify distinct classes of configurations that emerge as a function of polymer persistence length, membrane bending rigidity, adsorption strength, and vesicle size. Large-scale deformations of the vesicle include invaginations of the membrane that internalize the polymer in a membrane bud. The buds range from disk like shapes surrounding a collapsed polymer to tubular deformations enveloping rod-like polymers. For small vesicles, polymer adsorption also induces dumbbell like vesicle shapes with a narrow membrane constriction circled by the polymer. Vesicles with sufficiently small or large bending rigidities adopt configurations similar to those without the polymer present. We further characterize statistical properties of the membrane and polymer configurations and identify distinct classes of polymer configurations that emerge within membrane buds. Analysis of idealized polymer-membrane configurations provides additional insight into transitions between bud shapes. PMID- 29143051 TI - An open holey structure enhanced rate capability in a NaTi2(PO4)3/C nanocomposite and provided ultralong-life sodium-ion storage. AB - Sodium-ion battery (SIB) technology is competitive in the fields of transportation and grid storage, which require electrode materials showing rapid energy conversion (high rate capability) and long cycle life. In this work, a NaTi2(PO4)3/C (NTP/C) nanocomposite with an open holey-structured framework was successfully prepared for the first time using a solvothermal reaction followed by pyrolysis. The nanocomposite realized fast sodium-ion transport and thus preferable battery performances. Within the wide rate range of 0.5-50C, only a very small decrease in capacity from 124 to 120 mA h g-1 was observed. A high discharge capacity of 103 mA h g-1 (88.3% retention of the 1st cycle) was delivered even after 10 000 cycles at an ultrahigh rate of 50C without any obvious morphological change and without structural pulverization. Forming open channels for ion transport proved to contribute to such performance enhancement and therefore has the potential to become a universal model for the development of sustainable electrode materials in SIBs and other battery systems. PMID- 29143052 TI - Photo-enhanced antibacterial activity of ZnO/graphene quantum dot nanocomposites. AB - Synthesis of new, highly active antibacterial agents has become increasingly important in light of emerging antibiotic resistance. In the present study, ZnO/graphene quantum dot (GQD) nanocomposites were produced by a facile hydrothermal method and characterized by an array of microscopic and spectroscopic measurements, including transmission electron microscopy, X-ray photoelectron spectroscopy, UV-vis and photoluminescence spectroscopy. Antibacterial activity of the ZnO/GQD nanocomposites was evaluated with Escherichia coli within the context of minimum inhibitory concentration and the reduction of the number of bacterial colonies in a standard plate count method, in comparison to those with ZnO and GQD separately. It was found that the activity was markedly enhanced under UV photoirradiation as compared to that in ambient light. This was ascribed to the enhanced generation of reactive oxygen species under UV photoirradiation, with minor contributions from membrane damage, as manifested in electron paramagnetic resonance and fluorescence microscopic measurements. The results highlight the significance of functional nanocomposites based on semiconductor nanoparticles and graphene derivatives in the development of effective bactericidal agents. PMID- 29143053 TI - Recent advances in microfluidic technologies for cell-to-cell interaction studies. AB - Microfluidic cell cultures are ideally positioned to become the next generation of in vitro diagnostic tools for biomedical research, where key biological processes such as cell signalling and dynamic cell-to-cell interactions can be reliably analysed under reproducible physiological cell culture conditions. In the last decade, a large number of microfluidic cell analysis systems have been developed for a variety of applications including drug target optimization, drug screening and toxicological testing. More recently, advanced in vitro microfluidic cell culture systems have emerged that are capable of replicating the complex three-dimensional architectures of tissues and organs and thus represent valid biological models for investigating the mechanism and function of human tissue structures, as well as studying the onset and progression of diseases such as cancer. In this review, we present the most important developments in single-cell, 2D and 3D microfluidic cell culture systems for studying cell-to-cell interactions published over the last 6 years, with a focus on cancer research and immunotherapy, vascular models and neuroscience. In addition, the current technological development of microdevices with more advanced physiological cell microenvironments that integrate multiple organ models, namely, the so-called body-, human- and multi-organ-on-a-chip, is reviewed. PMID- 29143054 TI - Amidoboranes of rubidium and caesium: the last missing members of the alkali metal amidoborane family. AB - We report the synthesis and physicochemical characterization of two ammonia borane derivatives: rubidium amidoborane (RbNH2BH3) and caesium amidoborane (CsNH2BH3). Both compounds undergo solid-solid phase transition upon heating and then evolve pure hydrogen at temperatures lower than 125 degrees C. The phase transition is clearly seen in the Raman spectra. We present crystal structures of both low- and high-temperature forms of the title compounds which were solved from powder X-ray data. PMID- 29143055 TI - Use of azidonaphthalimide carboxylic acids as fluorescent templates with a built in photoreactive group and a flexible linker simplifies protein labeling studies: applications in selective tagging of HCAII and penicillin binding proteins. AB - This work describes the synthesis of azidonaphthalimide carboxylic acids which act as fluorescent templates with a built-in photoreactive group and a linker thus simplifying the design of protein labeling agents. These were separately connected to selectivity hands like a sulfonamide and ampicillin for successful labeling/detection of HCAII and PBPs, respectively. PMID- 29143056 TI - Controlling the length of self-assembled nanotubes by sonication followed by polymer wrapping. AB - This work demonstrates that sonication, followed by polymer-wrapping, is an effective strategy to modulate the length of self-assembled nanotubes. The length distributions of the nanotubes were controlled by varying the amplitude of sonication. Wrapping the nanotubes with ionic polymers suspended the propensity of the nanotube fragments to re-assemble over time into their elongated precursors. PMID- 29143057 TI - Accelerating ion diffusion with unique three-dimensionally interconnected nanopores for self-membrane high-performance pseudocapacitors. AB - Herein, a unique three-dimensionally interconnected nanoporous structure (3-D INPOS) pseudocapacitor electrode, which possesses a large surface area, an efficient electron and ion transport, together with a remarkable structural stability, has been constructed via soft anodization of an aluminum alloy, cost effective ultrasonic spray pyrolysis (USP)-assisted deposition of fluorine-doped tin oxide (FTO), and controllable electrochemical deposition of nanostructured manganese dioxide (MnO2). Taking the advantage of large surface area, the as built 3-D INPOS pseudocapacitor electrode exhibits the highest areal capacitance of 540 mF cm-2 and a volumetric capacitance of 135 F cm-3, which is 53% higher than that achieved from the conventional 3-D nanopore pseudocapacitor electrode and 17.6 times higher than that of the planar electrode. More interestingly, the unique 3-D interconnected structure offers an unrestricted space for the diffusion of electrolyte ions. Thus, the 3-D INPOS electrode achieves a higher rate capability than the 3-D nanopore electrode. As a proof of concept, a symmetric self-membrane pseudocapacitor device was constructed by simply stacking two pieces of the 3-D INPOS electrodes. Without an added separator, the device possesses a largely reduced dead volume and achieves the highest volumetric capacitance of 28.9 F cm-3 and a specific energy of 2.36 mW h cm-3. The largely enhanced capacitance, rate capability, and specific energy certainly make the 3-D INPOS an ideal architecture for the fabrication of high-performance pseudocapacitors. PMID- 29143058 TI - Membrane environment drives cytochrome P450's spin transition and its interaction with cytochrome b5. AB - Heme's spin-multiplicity is key in determining the enzymatic function of cytochrome P450 (cytP450). The origin of the low-spin state in ferric P450 is still under debate. Here, we report the first experimental demonstration of P450's membrane interaction altering its spin equilibrium which is accompanied by a stronger affinity for cytochrome b5. These results highlight the importance of lipid membrane for the function of P450. PMID- 29143059 TI - Short-lived intermediates in photochemistry of an OsCl62- complex in aqueous solutions. AB - Two mechanisms of OsIVCl62- photolysis were studied by means of quantum chemical calculations in gas and aqueous phases. The difference between these mechanisms is in the nature of the possible Os(iv) key intermediates (KI). According to calculations, the intermediate is an OsIVCl5- complex of square pyramidal coordination geometry. The calculations do not give an opportunity to make an unambiguous choice between the triplet and quintet multiplicities of OsIVCl5-. The calculated CASSCF/IMCP-SR1 transition energies for 5OsIVCl5- are lower than for 3OsIVCl5-, while the calculated XMC-QDPT2/SBKJC spectra for the triplet state are in better agreement with the experimental absorption spectrum of the KI than for the quintet state. PMID- 29143060 TI - How to realize a spin-dependent Seebeck diode effect in metallic zigzag gamma graphyne nanoribbons? AB - The spin-dependent Seebeck effect (SDSE) is one of the core topics of spin caloritronics. In the traditional device designs of spin-dependent Seebeck rectifiers and diodes, finite spin-dependent band gaps of materials are required to realize the on-off characteristic in thermal spin currents, and nearly zero charge current should be achieved to reduce energy dissipation. Here, we propose that two ferromagnetic zigzag gamma-graphyne nanoribbons (ZgammaGNRs) without any spin-dependent band gaps around the Fermi level can not only exhibit the SDSE, but also display rectifier and diode effects in thermal spin currents characterized by threshold temperatures, which originates from the compensation effect occurring in spin-dependent transmissions but not from the spin-splitting band gaps in materials. The metallic characteristics of ZgammaGNRs bring about an advantage that the gate voltage is an effective route to adjust the symmetry of spin-splitting bands to obtain pure thermal spin currents. The results provide a new mechanism to realize spin-Seebeck rectifier and diode effects in 2D materials and expand material candidates towards spin-Seebeck device applications. PMID- 29143061 TI - The Origins of Verb Learning: Preverbal and Postverbal Infants' Learning of Word Action Relations. AB - Purpose: This experiment examined English- or Spanish-learning preverbal (8-9 months, n = 32) and postverbal (12-14 months, n = 40) infants' learning of word action pairings prior to and after the transition to verb comprehension and its relation to naturally learned vocabulary. Method: Infants of both verbal levels were first habituated to 2 dynamic video displays of novel word-action pairings, the words /wem/ or /baef/, spoken synchronously with an adult shaking or looming an object, and tested with interchanged (switched) versus same word-action pairings. Mothers of the postverbal infants were asked to report on their infants' vocabulary on the MacArthur-Bates Communicative Development Inventories (Fenson et al., 1994). Results: The preverbal infants looked longer to the switched relative to same pairings, suggesting word-action mapping, but not the postverbal infants. Mothers of the postverbal infants reported a noun bias on the MacArthur-Bates Communicative Development Inventories; infants learned more nouns than verbs in the natural environment. Further analyses revealed marginal word action mapping in postverbal infants who learned fewer nouns and only comprehended verbs (post-verb comprehension), but not in those who learned more nouns and also produced verbs (post-verb production). Conclusions: These findings on verb learning from inside and outside the laboratory suggest a developmental shift from domain-general to language-specific mechanisms. Long before they talk, infants learning a noun-dominant language learn synchronous word-action relations. As a postverbal language-specific noun bias develops, this learning temporarily diminishes. Supplemental Materials: https://doi.org/10.23641/asha.5592637. PMID- 29143062 TI - [Intracranial cystic lesions]. AB - CLINICAL PROBLEM: Intracerebral cysts are common findings in imaging of the neurocranium and are not always clinically significant. The pathological spectrum of intracerebral cysts is, however, very broad and in addition to incidental findings includes developmental disorders, malformation tumors, primary and secondary neoplasms and infectious etiologies, such as cerebral abscess formation, cysticercosis or residuals after congenital cytomegalovirus infections. Intracerebral cystic defects may be caused by inflammatory central nervous system (CNS) diseases, such as multiple sclerosis as well as by mitochondriopathies, leukodystrophy, electrolyte disturbances or osmotic demyelination syndrome or brain infarctions, e.g. after lacunar infarctions or as encephalomalacic changes after severe traumatic brain injury. RADIOLOGICAL STANDARD PROCEDURES: In addition to the radiological findings of cysts in magnetic resonance imaging (MRI) or in computed tomography (CT), the localization, patient age, patient medical history and laboratory diagnostics are helpful for the differential diagnostics. METHODICAL INNOVATION: In addition to the morphological assessment, advanced MRI techniques, such as diffusion-weighted imaging for epidermoids or the use of MR spectroscopy, can provide valuable information for the differential diagnosis. PERFORMANCE/ASSESSMENT: Intracranial cysts can be subdivided into intraventricular and periventricular cysts, intra axial cysts and cysts in the external fluid-filled spaces. Associated tumor nodules and the contrast medium behavior of the cyst walls and/or associated soft tissue components as well as the reaction of the adjacent parenchyma are helpful for the diagnosis and assessment. PMID- 29143064 TI - Exercise training response heterogeneity: statistical insights. PMID- 29143065 TI - [Complex joint reconstruction and joint transplantation with the FLOCSAT concept planning and surgical implementation]. AB - Cartilage defects in adult patients are so far incurable. Fresh osteochondral allograft (OCA) transplantation is based on the insertion of mature, living, mechanically sound hyaline cartilage into an osteochondral defect where it undergoes osseointegration. Intact hyaline cartilage of OCA does not cause immune reactions in the recipient. Many reports show that small OCA have good osseointegration and show good long-term results. These observations have been incorporated into the development of the fresh large (> 10 cm2) osteochondral shell allograft transplantation (FLOCSAT) concept, which is based on the following principles: 1) the thickness of the osseous layer should be kept as thin as possible (target < 6-8 mm) so that the transplant remains stable and fixable. This results in reduced segments of vascularization, simplified ossification and reduced immunogenic bone volume. 2) The bone surface is processed and enlarged (oscillating saw: pie crust technique, drill holes) and areas of sclerosis are simultaneously broken off. 3) Cell reduction and washing out of the bony layer with a pulsatile jet lavage. 4) Prevention of impaction and dessication: cartilage with its living chondrocytes are very sensitive to mechanical contusion and dessication. When introducing the transplant, the tissue must therefore be continually moistened and the pressure acting on the cartilage must be controlled. 5) Stable fixation: extensive uniplanar osteochondral transplants cannot be inserted by the press-fit method; therefore, fixation is carried out with small implants. In this publication we demonstrate how severe and complex posttraumatic or degenerative delayed problems can be solved using FLOCSAT. PMID- 29143063 TI - Translating aetiological insight into sustainable management of type 2 diabetes. AB - Using a low-energy diet as a tool, it has been possible to elucidate the sequence of pathophysiological changes that lead to the onset of type 2 diabetes. Negative energy balance in type 2 diabetes causes a profound fall in liver fat content resulting in normalisation of hepatic insulin sensitivity within 7 days. As the period of negative energy balance extends and liver fat levels fall to low normal, the rate of export of triacylglycerol from the liver falls. Consequent to this, the raised pancreas fat content falls and in early type 2 diabetes, normal first-phase insulin secretion becomes re-established with normal plasma glucose control. This research, driven by the predictions of the 2008 twin cycle hypothesis, has led to a paradigm shift in understanding. Studying the reversed sequence of pathophysiological changes, the linked abnormalities in liver and pancreas have been revealed. Early type 2 diabetes is a potentially reversible condition. Surprisingly, it was observed that the diet devised as an experimental tool was actually liked by research participants. It was associated neither with hunger nor tiredness in most people, but with rapidly increased wellbeing. A defined period of weight loss followed by carefully planned weight maintenance the 'One, Two' approach-has since been applied in clinical practice. Motivated individuals can reverse their type 2 diabetes and remain normoglycaemic over years. A large study is underway to evaluate the applicability of this general approach to routine primary care practice as a long-term management strategy. PMID- 29143066 TI - [Thoracolumbar spinal fractures in the elderly : Classification and treatment]. AB - Thoracolumbar fractures in the elderly are frequently associated with osteoporosis. Osteoporosis can cause fractures or be a significant comorbidity in traumatic fractures. The OF classification is based on conventional X-ray, computed tomography (CT) scan and magnetic resonance imaging (MRI). It is easy to use and provides a clinically relevant classification of the fractures. Therapeutic decisions are made based on the clinical and radiological situation by using the OF score. The score takes the current clinical situation including patient-specific comorbidities into consideration. The treatment recommendations are based on an expert consensus opinion and include conservative and operative options. If surgery is indicated, vertebral body augmentation, percutaneous stabilization and even open surgery can be used. PMID- 29143069 TI - Hemin/G-Quadruplex Horseradish Peroxidase-Mimicking DNAzyme: Principle and Biosensing Application. AB - Enzymes are macromolecular biological catalysts that accelerate chemical reactions. Enzyme labels are commonly used to obtain signal amplification in sensors and biosensors on the basis of reactions of some enzymes such as horseradish peroxidase (HRP). However, use of natural enzymes can encounter some challenges. Lately, nucleic acids that exhibit catalytic properties have attracted growing interest because they have certain advantages in comparison with traditional protein enzymes. DNAzymes are DNA-based catalysts, representing an important class of functional DNA, which have been widely used because of their excellent activity, programmability, signal amplification through catalytic turnover, high chemical stability, simple synthesis, and easy modification. Considering these remarkable properties, the hemin/G-quadruplex DNAzyme is extensively used in electrochemical, colorimetric, and chemiluminescence sensors and biosensors for detection of various targets. Graphical Abstract. PMID- 29143067 TI - Characterization and fine mapping of qkc7.03: a major locus for kernel cracking in maize. AB - KEY MESSAGE: A major locus conferring kernel cracking in maize was characterized and fine mapped to an interval of 416.27 kb. Meanwhile, combining the results of transcriptomic analysis, the candidate gene was inferred. Seed development requires a proper structural and physiological balance between the maternal tissues and the internal structures of the seeds. In maize, kernel cracking is a disorder in this balance that seriously limits quality and yield and is characterized by a cracked pericarp at the kernel top and endosperm everting. This study elucidated the genetic basis and characterization of kernel cracking. Primarily, a near isogenic line (NIL) with a B73 background exhibited steady kernel cracking across environments. Therefore, deprived mapping populations were developed from this NIL and its recurrent parent B73. A major locus on chromosome 7, qkc7.03, was identified to be associated with the cracking performance. According to a progeny test of recombination events, qkc7.03 was fine mapped to a physical interval of 416.27 kb. In addition, obvious differences were observed in embryo development and starch granule arrangement within the endosperm between the NIL and its recurrent parent upon the occurrence of kernel cracking. Moreover, compared to its recurrent parent, the transcriptome of the NIL showed a significantly down-regulated expression of genes related to zeins, carbohydrate synthesis and MADS-domain transcription factors. The transcriptomic analysis revealed ten annotated genes within the target region of qkc7.03, and only GRMZM5G899476 was differently expressed between the NIL and its recurrent parent, indicating that this gene might be a candidate gene for kernel cracking. The results of this study facilitate the understanding of the potential mechanism underlying kernel cracking in maize. PMID- 29143068 TI - Patient characteristics and outcomes in adolescents and young adults with classical Philadelphia chromosome-negative myeloproliferative neoplasms. AB - Little is known about the outcomes of Philadelphia-negative myeloproliferative neoplasms (MPNs) in adolescents and young adults (AYA). We reviewed all patients with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) treated at our institution from 1988 to 2016 who were aged 16 to 39 years (AYA) and described their outcomes in comparison to older MPN population. Of 2206 patients, 185 (8.3%) were identified as AYA: 105 (57%) ET, 43 (23%) PV, and 37 (20%) MF. The median age was 33 years [range, 16-39], and median follow-up time 3 years [range, 0.04-25]. JAK2 allele burdens were significantly lower among AYA JAK2V617F-mutated patients in both PV (p = 0.001) and MF (p = 0.005). Seven percent of MPN AYA patients were diagnosed with a thrombotic event at, or prior to, diagnosis. Over the short median follow-up, 4 thrombotic (PV = 1, MF = 3) and 3 leukemia (ET = 2, MF = 1) events occurred. In multivariate analysis, AYA did not predict for thrombotic or transformational events across three cohorts. In the MF cohort, there was a reduced frequency of negative prognostic variables of anemia (p = 0.011) and leukocytosis (p = 0.048) in AYA when compared with non AYA. Overall survival was significantly superior in the AYA cohorts in all three MPN groups, namely MF (p < 0.001), PV (p < 0.001), and ET (p = 0.002). Our findings suggest that MPN AYA patients exhibit an indolent clinical phenotype characterized by favorable survival outcomes. PMID- 29143070 TI - The use of critical incident technique in population health intervention research: lessons learned. PMID- 29143071 TI - Cluster of risk and protective factors for obesity among Brazilian adolescents. AB - OBJECTIVES: This study aims to identify and analyze clusters formed by risk and protective factors for obesity among Brazilian adolescents. METHODS: Cross sectional data collected in a national representative sample of adolescents by the Brazilian National School Health Survey of 2012 were used (n = 109,104). Cluster analysis was applied to identify clusters involving dietary intake, eating behavior, physical activity and sedentary behaviors. Logistic regression was employed to contextualize the clusters according to students' sociodemographics and schools' characteristics. RESULTS: Two clusters were identified. Cluster 1 was predominantly characterized by the low frequency of both risk and protective factors for obesity; Cluster 2 was characterized by high frequency of both of these factors. None was essentially healthy or unhealthy. Adolescents from less developed regions and with mothers with lower education level were associated to Cluster 1. CONCLUSIONS: The identification of two mixed clusters indicate wide spread obesity risk among scholars in the country. The association between the clusters and sociodemographic characteristics of the population allows a greater refinement of health promotion and obesity prevention and combat actions in Brazil. PMID- 29143072 TI - The extent of ground-glass attenuation is a risk factor of chemotherapy-related exacerbation of interstitial lung disease in patients with non-small cell lung cancer. AB - OBJECTIVES: Chemotherapy-related acute exacerbation (AE) of interstitial lung disease (ILD) is observed in certain patients with non-small cell lung cancer (NSCLC) who have ILD. Although the prognosis of AE-ILD is extremely poor, there are no established risk factors for its occurrence. Therefore, we retrospectively investigated whether high-resolution computed tomography (HRCT) findings could identify risk factors for AE-ILD. MATERIALS AND METHODS: Between January 2005 and December 2016, 35 patients with NSCLC who received chemotherapy at Hiroshima University Hospital and were diagnosed with ILD on HRCT were enrolled. The extent of ground-glass attenuation (GGA), reticulation, honeycomb appearance, and emphysema, as well as the presence of micronodules, traction bronchiectasis, and consolidation were evaluated in five levels of the lung bilaterally. The HRCT scores of GGA, reticulation, honeycomb appearance, and emphysema were determined by the following formula: 100 * sum of the extent of the HRCT findings/lung area. RESULTS: Thirty-five patients underwent various first- to fifth-line chemotherapy regimens. Nine patients (25.7%) developed AE-ILD. The median HRCT scores of GGA and reticulation were significantly higher in patients with AE-ILD than in those without. On univariate analysis, a GGA area score >= 24.8, reticulation area score >= 19.5, and KL-6 level >= 946 U/mL were significant risk factors. Multivariate logistic analysis revealed that only a GGA area score >= 24.8 was an independent risk factor of AE-ILD. CONCLUSIONS: The GGA area on HRCT is a risk factor for chemotherapy-related AE-ILD. Therefore, this parameter can be used to predict the risk of AE-ILD before administering chemotherapy. PMID- 29143073 TI - Correction to: HLA class I molecular variation and peptide-binding properties suggest a model of joint divergent asymmetric selection. AB - The above article originally published with an incomplete bibliographic information for Bitarello et al. (2016) and presented correctly in this article. PMID- 29143075 TI - The black garland sign in ovarian fibromatosis. PMID- 29143074 TI - [Additional emergency medical measures in trauma-associated cardiac arrest]. AB - INTRODUCTION: More than half of all traumatic deaths happen in prehospital settings. Until now, there have been no long-term studies examining the actual additive treatment during trauma-associated cardiopulmonary resuscitation (tCPR), including pleural decompression, pericardiocentesis, tourniquets and external stabilization of the pelvis. The present cohort study evaluated forensic autopsy reports of trauma deaths occurring at the scene with respect to additive actions in preclinical tCPR as well as the potentially preventable nature of the individual death cases. MATERIAL AND METHODS: All autopsy protocols from the Institutes of Legal Medicine in Leipzig and Chemnitz, Germany within the years 2011-2017 were retrospectively examined and all trauma deaths with professional prehospital tCPR at the scene, during transport or shortly after arriving at the emergency room were analyzed. In addition to epidemiological parameters all forms of medical procedure performed by emergency physicians and the injury patterns were recorded. Thus, the questions whether any of the trauma deaths were preventable and if failures in work-flow management were evident could be retrospectively answered through a structured Delphi method. RESULTS: Overall, 3795 autopsy protocols were listed containing 154 trauma cases (4.1%) with various preclinical tCPR attempts (male patients 70.1%; mean age 48 +/- 21 years). Most of them died at the accident site (84.4%), some during transport (2.6%) or directly after admission to a hospital (13.0%). Only 23 patients (14.9%) received 25 additional interventions exceeding the normal scope (pleural decompression 80.0%, pericardiocentesis 8.0% and external stabilization of the pelvis 12.0%). A relevant number of potentially reversible causes for trauma associated cardiac arrest was determined. There were deficits in the performance of pleural decompression in cases of tension pneumothorax. Even if isolated traumatic hemopericardium was a rare occurrence in the examined cases, the rate of pericardiocentesis was still too low. Also, more focus needs to be placed on provisional external pelvic stabilization of trauma patients which was performed too rarely even though an instable pelvic ring was apparent during the postmortem external examination. None of the cases received a rescue thoracotomy even if a few patients might have derived benefit from this and none of the cases showed injury patterns with tourniquet indications. Furthermore, no single case of death due to incorrect or missing airway management was determined. Errors in work-flow management were found in 37.0% and potentially preventable deaths occurred cumulatively in 12.3% of the cases. The potentially preventable deaths were particularly related to penetrating chest injuries caused by a sharp force. DISCUSSION: The percentage of patients who might benefit from additive treatment implemented in tCPR efforts was shown to be equal between the local situations in Leipzig and Chemnitz compared to previous reports in Berlin. A need for optimizing the professional resuscitation process still remains as not all reversible causes were appropriately addressed. Further training and education should intensively address the mentioned deficits and continuous awareness of necessary additional medical procedures in the preclinical setting in cases of traumatic cardiac arrest is inevitable. Cooperation with forensic institutes can help to impart particular issues and treatment options of emergency medicine in cases of potentially reversible causes of traumatic cardiac arrest. PMID- 29143076 TI - Magnetic resonance elastography: beyond liver fibrosis-a case-based pictorial review. AB - Magnetic resonance elastography (MRE) has been introduced for clinical evaluation of liver fibrosis for nearly a decade. MRE has proven to be a robust and accurate technique for diagnosis and staging of liver fibrosis. As clinical experience with MRE grows, the possible role in evaluation of other diffuse and focal disorders of liver is emerging. Stiffness maps provide an opportunity to evaluate mechanical properties within a large volume of liver tissue. This enables appreciation of spatial heterogeneity of stiffness. Stiffness maps may reveal characteristic and differentiating features of chronic liver diseases and focal liver lesions and therefore provide useful information for clinical management. The objective of this pictorial review is to recapture the essentials of MRE technique and illustrate with examples, the utility of stiffness maps in other chronic liver disorders and focal liver lesions. PMID- 29143078 TI - Adverse outcome pathways. PMID- 29143077 TI - Calcein Release from Cells In Vitro via Reversible and Irreversible Electroporation. AB - The aim of this study was to investigate the dependence of calcein extraction and cell viability on the parameters of pulsed electric field (PEF). Two different approaches concerning PEF parameters were investigated: (1) extraction efficiency and cell viability dependence on pulse number, exploiting 1200 V/cm 100 us duration high voltage (HV) electric pulses and (2) extraction efficiency and cell viability dependence on the pulses with different duration (44-400 us) and electric field strength (600-1800 V/cm) that result in the same amount of electric field energy delivered to Chinese hamster ovary cells. Extraction efficiency was evaluated as a percentage ratio of calcein fluorescence intensity prior and after PEF treatment. Cell viability was evaluated using PI test and cell clonogenic assay. Moreover, calcein release dynamics from cells after 600 V/cm 400 us, 1200 V/cm 100 us, and 1800 V/cm 44 us was evaluated. Our results show that HV pulses induce instant calcein extraction due to reversible electroporation; however, subsequent calcein leakage over time was only observed when 9 HV pulses of 1800 V/cm 44 us were used. The increased number of pulses resulted in more efficient total calcein extraction. With the same total energy delivered via electric pulses, the increase of calcein extraction efficiency was more dependent on pulse strength rather than pulse duration. The highest calcein extraction efficiency (84.5 +/- 7.4%) was obtained using 9 electric field pulses of 1800 V/cm, 44 us at 1 Hz. Furthermore, the extraction efficiency can be significantly enhanced if external mechanical stress (pipetting) is applied to cells. Cell viability was determined to be dependent on different PEF exposure parameters. It varied from 96.8 +/- 4.8 to 31.2 +/- 8.9%, implying the possibility to adjust PEF parameter combinations to maintain high cell viability. PMID- 29143079 TI - Stem cells in toxicological research. PMID- 29143080 TI - Combined presence of four individually weak genetic variants strongly increases cancer risk. PMID- 29143081 TI - Generation in yeast and antigenic characterization of hepatitis E virus capsid protein virus-like particles. AB - Hepatitis E is a globally distributed human disease caused by hepatitis E virus (HEV). In Europe, it spreads through undercooked pork meat or other products and with blood components through transfusions. There are no approved or golden standard serologic systems for HEV diagnostics. Commercially available HEV tests often provide inconsistent results which may differ among the assays. In this study, we describe generation in yeast and characterization of HEV genotype 3 (HEV-3) and rat HEV capsid proteins self-assembled into virus-like particles (VLPs) and the development of HEV-specific monoclonal antibodies (MAbs). Full length HEV-3 and rat HEV capsid proteins and their truncated variants comprising amino acids (aa) 112-608 were produced in yeast S. cerevisiae. The yeast expressed rat HEV capsid protein was found to be glycosylated. The full-length HEV-3 capsid protein and both full-length and truncated rat HEV capsid proteins were capable to self-assemble into VLPs. All recombinant proteins contained HEV genotype-specific linear epitopes and cross-reactive conformational epitopes recognized by serum antibodies from HEV-infected reservoir animals. Two panels of MAbs against HEV-3 and rat HEV capsid proteins were generated. Their cross reactivity pattern was investigated by Western blot, ELISA, and immunofluorescence assay on HEV-3-infected cell cultures. The analysis revealed cross-reactive, genotype-specific, and virus-reactive MAbs. MAb epitopes were localized within S, M, and P domains of HEV-3 and rat HEV capsid proteins. Yeast generated recombinant VLPs of HEV-3 and rat HEV capsid proteins and HEV-specific MAbs might be employed to develop novel HEV detection systems. PMID- 29143082 TI - Spatial separation of photosynthesis and ethanol production by cell type-specific metabolic engineering of filamentous cyanobacteria. AB - Cyanobacteria, which perform oxygenic photosynthesis, have drawn attention as hosts for the direct production of biofuels and commodity chemicals from CO2 and H2O using light energy. Although cyanobacteria capable of producing diverse chemicals have been generated by metabolic engineering, anaerobic non photosynthetic culture conditions are often necessary for their production. In this study, we conducted cell type-specific metabolic engineering of the filamentous cyanobacterium Anabaena sp. PCC 7120, which forms a terminally differentiated cell called a heterocyst with a semi-regular spacing of 10-15 cells. Because heterocysts are specialized cells for nitrogen fixation, the intracellular oxygen level of heterocysts is maintained very low even when adjacent cells perform oxygenic photosynthesis. Pyruvate decarboxylase of Zymomonas mobilis and alcohol dehydrogenase of Synechocystis sp. PCC 6803 were exclusively expressed in heterocysts. Ethanol production was concomitant with nitrogen fixation in genetically engineered Anabaena sp. PCC 7120. Engineering of carbon metabolism in heterocysts improved ethanol production, and strain ET14, with an extra copy of the invB gene expressed from a heterocyst-specific promoter, produced 130.9 mg L-1 of ethanol after 9 days. ET14 produced 1681.9 mg L-1 of ethanol by increasing the CO2 supply. Ethanol production per heterocyst cell was approximately threefold higher than that per cell of unicellular cyanobacterium. This study demonstrates the potential of heterocysts for anaerobic production of biofuels and commodity chemicals under oxygenic photosynthetic conditions. PMID- 29143084 TI - Can We Do Even Better? Preoperative Imaging Overestimates the Tumor Size in Pancreatic Neuroendocrine Neoplasms Associated with Multiple Endocrine Neoplasia Type 1. PMID- 29143083 TI - The Polyphyletic Origins of Primase-Helicase Bifunctional Proteins. AB - We studied the evolutionary relationships of different primase-helicase bifunctional proteins, found mostly in viruses, virophages, plasmids, and organellar genomes, by phylogeny and correlation analysis. Our study suggests independent origins of primase-helicase bifunctional proteins resulting from multiple fusion events between genes encoding primase and helicase domains of different families. The correlation analysis further indicated strong functional dependencies of domains in the bifunctional proteins that are part of smaller genomes and plasmids. Bifunctional proteins found in some bacterial genomes exhibited weak coevolution probably suggesting that these are the non-functional remnants of the proteins acquired via horizontal transfer. We have put forward possible scenarios for the origin of primase-helicase bifunctional proteins in large eukaryotic DNA viruses and virophages. PMID- 29143085 TI - Clinical Significance of New Magnetic Resonance Thoracic Ductography Before Thoracoscopic Esophagectomy for Esophageal Cancer. AB - BACKGROUND: Preoperative simulation of the thoracic duct using magnetic resonance thoracic ductography (MRTD) would enable a safe lymph node dissection near the thoracic duct and the prevention of chylothorax after an esophagectomy. The aim of this study was to determine whether MRTD is useful for preventing injury to the thoracic duct during surgery and for reducing the incidence of chylothorax after surgery. METHODS: We evaluated 130 patients who underwent preoperative MRTD followed by a thoracoscopic esophagectomy for the treatment of thoracic esophageal cancer between August 2014 and April 2017 (MRTD group). These patients were then compared with 160 patients with esophageal cancer who underwent a thoracoscopic esophagectomy without preoperative MRTD (non-MRTD group). RESULTS: Four patients in the non-MRTD group developed Type IIIB chylothorax (International Consensus on Standardization), while none of the patients in the MRTD group developed Type III chylothorax. Some type of abnormal finding was found during MRTD in 24 patients (18.5%). Among them, 13 patients (10.0%) exhibited abnormal divergence, which was the most frequent finding, followed by 5 patients (3.8%) with window formation and 2 patients (1.5%) with stitch formation. CONCLUSIONS: The present study revealed the frequencies of abnormal findings of the thoracic duct and of patients with false-negative MRTD findings. Injury to the thoracic duct can be avoided through the use of appropriate care during procedures performed in patients with abnormal findings on preoperative MRTD. PMID- 29143086 TI - Derivation and Validation of a Novel Physiological Emergency Surgery Acuity Score (PESAS): Reply. PMID- 29143087 TI - Factors Associated with Premalignant Epithelial Changes in Chronic Calculous Cholecystitis: A Case-Control Study. AB - INTRODUCTION: Gallstones are known to be associated with premalignant changes in the gallbladder epithelium that range from atypical hyperplasia, metaplasia, dysplasia to carcinoma. Recognition of factors associated with these changes in patients with gallstones can potentially be helpful in identifying patients to whom prophylactic cholecystectomy can be offered to reduce the chances of developing carcinoma. OBJECTIVE: To identify factors associated with premalignant epithelial changes including atypical hyperplasia, metaplasia, and dysplasia in gallbladder mucosa in patients with chronic calculus cholecystitis. MATERIALS AND METHODS: This was retrospective case-control study conducted over a period of 10 years from 2004 to 2014. Cases were patients with reported histopathological premalignant epithelial changes along with chronic calculus cholecystitis, and controls were patients without premalignant epithelial changes but chronic calculus cholecystitis. Controls were twice the number of the cases. RESULTS: Over study period, 92 patients were reported to have premalignant epithelial changes on gall bladder histopathology for whom 184 controls were selected. Of cases, 61 (66%) patients had atypical hyperplasia, while metaplasia and dysplasia were present in 26 (28%) and 5 (5%) cases, respectively. Mean age was 47.5 +/- 14.5 years, and 74% of the study population were female. Wall thickness of more than 3 mm (OR = 4.14, p value < 0.001) turned out to be statistically significant independent variables associated with premalignant lesions in gallbladder mucosa. CONCLUSION: Odds of premalignant epithelial change in gall bladder mucosa in patients with gall bladder wall thickness of more than 3 mm is four times the odds of patients with wall thickness less than 3 mm, and the effect is statistically significant. Prophylactic cholecystectomy should be considered for this group of patients. PMID- 29143088 TI - The Association of Preoperative Hematocrit and Transfusion with Mortality in Patients Undergoing Elective Non-cardiac Surgery. AB - BACKGROUND: Patients with anemia frequently undergo surgery, as it is unclear at what threshold clinicians should consider delaying surgery for preoperative anemia optimization. The primary objective of this study was to determine whether there is an association of varying degrees of anemia and transfusion with 30-day mortality. METHODS: This is a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program database from 2011 to 2013. Cohorts were analyzed based on preoperative hematocrit range patients with: (1) no anemia, (2) hematocrit >=33% and <36% in females or <39% in males, (3) hematocrit >=30% and <33%, (4) hematocrit >=27% and <30%, (5) hematocrit >=24% and <27%, and (6) hematocrit >=21% and less than 24%. Multivariable logistic regression was used to analyze the association of anemia and transfusion with 30-day in-hospital mortality. RESULTS: The odds for 30-day mortality increased incrementally as the hematocrit ranges decreased, in which preoperative hematocrit between 21 and 24% had the highest odds for this outcome (odds ratio [OR] 6.50, p < 0.0001) compared to the reference group (no anemia). The use of transfusion increased the odds of mortality even further (OR 5.57, p < 0.0001). Among patients that received an intra-/postoperative transfusion, preoperative anemia was not predictive of mortality. CONCLUSIONS: Healthcare providers making preoperative clinical decisions for patients undergoing elective surgery should consider the degree of preoperative anemia and likelihood of perioperative transfusion. PMID- 29143089 TI - Surgical Treatment of Gastro-Pulmonary Fistula Following Bariatric Surgery: Possible and Safe. AB - BACKGROUND: Laparoscopic sleeve gastrectomy is a common surgical management of morbid obesity. Major complication rate is 3-8%. Staple line leak is one of the most serious complications. In a small group of patients, a gastro-pulmonary fistula is formed. Endoscopic and minimally invasive measures are the first line of treatment with considerable success rate. There are very poor data in the literature what should be done in cases of failure. In this paper, we report our positive experience with definitive surgical repair. METHODS: Retrospective evaluation of 13 consecutive patients referred to the general thoracic surgery department for gastro-pulmonary fistula following sleeve gastrectomy. RESULTS: Prior to their referral, all patients underwent surgical or percutaneous drainage and multiple treatment attempts including stent insertion, pyloric dilatation, endo-clip/ring closure, endoscopic argon ablation and glue injection. Two patients underwent emergency thoracotomy for sepsis and bile empyema. One died in the early postoperative period. Eleven patients underwent semi-elective definitive surgery. Surgery included left lower lobectomy, partial diaphragmectomy and digestive system reconstruction. There was no mortality or major complications in this group. Complication rate was 45% mostly local wound infection and pneumonia. CONCLUSIONS: Gastro-pulmonary fistula is a rare devastating complication of sleeve gastrectomy. When minimally invasive measures fail, there is no place for nihilism. Surgical repair is possible and safe. The data presented herein support this treatment policy. PMID- 29143090 TI - Pattern of Lower Intestinal Ostomies in a Low-Income Country: Case of Southeast of Niger Republic. AB - BACKGROUND: Intestinal ostomies are common surgical procedures performed in visceral surgery as part of management for several gastrointestinal diseases. This study aims to report the socio-demographic characteristics, indications and prognosis of intestinal ostomies in low-income country. METHODS: This was a 4 year retrospective study (January 2013 to December 2016) at Zinder National Hospital (Niger). All patients with a digestive ostomy on an ileum or colic segment were included in the study. RESULTS: During the study period, 2437 patients underwent digestive surgery, including 328 gastrointestinal stomas (13.5%). Patients classified ASA3 were 60.7% (n = 199). The median age was 12 years (IQ: 7-25). Children represent 64% (n = 210) of patients with ostomy. The sex ratio was 2.60. The stoma was performed in emergency in 96.3% (n = 316) of cases. Acute peritonitis was the main indication of the stoma in 70.73% (n = 232). The ileostomies accounted for 75.61% (n = 248). Ostomy was intended as temporary in 97.3% of cases (n = 319). Complications were observed in 188 patients (57.3%). Mortality was 14.02% (n = 46). The indigent status (OR: 4.15 [2.20-7.83], P = 000), ASA score 4 (OR: 2.53 [1.54-4.15], P = 0.0003), Altemeier class IV (OR: 4.03 [2.10-7.73], P = 0.0000) and ileostomy (OR: 2.7853 [1.47 5.29], P = 0.0018) were statistically associated with the occurrence of major complications. The mean time for stoma closure was 59.3 +/- 14.5 days. CONCLUSION: Acute peritonitis was the main indication of digestive ostomy. The occurrence of major complications was associated with bad socioeconomic status, ASA4 score, Altemeier class IV and ileostomy. PMID- 29143091 TI - Risk of Catastrophic Health Expenditure in Rwandan Surgical Patients with Peritonitis. AB - BACKGROUND: Surgical procedures are cost-effective compared with various medical and public health interventions. While peritonitis often requires surgery, little is known regarding the associated costs, particularly in low- and middle-income countries. The aim of this study was to determine in-hospital charges for patients with peritonitis and if patients are at risk of catastrophic health expenditure. METHODS: As part of a larger study examining the epidemiology and outcomes of patients with peritonitis at a referral hospital in Rwanda, patients undergoing operation for peritonitis were enrolled and hospital charges were examined. The primary outcome was the percentage of patients at risk for catastrophic health expenditure. Logistic regression was used to determine the association of various factors with risk for catastrophic health expenditure. RESULTS: Over a 6-month period, 280 patients underwent operation for peritonitis. In-hospital charges were available for 245 patients. A total of 240 (98%) patients had health insurance. Median total hospital charges were 308.1 USD, and the median amount paid by patients was 26.9 USD. Thirty-three (14%) patients were at risk of catastrophic health expenditure based on direct medical expenses. Estimating out-of-pocket non-medical expenses, 68 (28%) patients were at risk of catastrophic health expenditure. Unplanned reoperation was associated with increased risk of catastrophic health expenditure (p < 0.001), whereas patients with community-based health insurance had decreased risk of catastrophic health expenditure (p < 0.001). CONCLUSIONS: The median hospital charges paid out-of pocket by patients with health insurance were small in relation to total charges. A significant number of patients with peritonitis are at risk of catastrophic health expenditure. PMID- 29143092 TI - Laparoscopic Appendectomy: Minimally Invasive Surgery Training Improves Outcomes in Basic Laparoscopic Procedures. AB - BACKGROUND: To determine whether minimally invasive surgery (MIS) training improves outcomes in laparoscopic appendectomy, a procedure that is commonly performed in general surgery training. METHODS: Retrospective review was conducted of all patients undergoing laparoscopic appendectomy for suspected acute appendicitis between 2014 and 2015 at a single-center, tertiary-care academic institution. Patients operated on by MIS-trained surgeons (MIS group) were compared to those operated on by general surgeons (GS group). Single incision and multiport laparoscopic appendectomies were included; open approach, known malignancy, and interval appendectomies were excluded. RESULTS: A total of 507 patients were included in the study: 181 patients in the MIS group and 326 in the GS group. There were no differences in patient demographics or medical comorbidities between groups and most patients were ASA class 1 or 2. Patients operated on by MIS-trained surgeons had significantly shorter operative time (43 min, IQR 32-60 vs. 58 min, IQR 44-81; p < 0.001) and fewer intra-operative adverse events (0/181 vs. 8/326, 2.5%; p = 0.03). There was no difference in number of postoperative adverse events between groups (6/181, 3.3% vs. 21/326, 6.4%; p = 0.13). In the MIS group, subgroup analysis of single-incision versus multiport appendectomy showed no differences in intra-operative or postoperative adverse events. On multivariable linear regression, lack of MIS training and traditional multiport approach had the greatest effects on prolonging operative time (11.2 and 12.8 min, respectively; p = 0.001). CONCLUSIONS: MIS fellowship improves operative metrics and patient outcomes even in basic laparoscopy. PMID- 29143093 TI - Response to: Post-hepatectomy Lactate: Should We Add More? And Assessing Predictive Value of Post-operative Elevated Lactate for Adverse Outcomes Following Hepatectomy. PMID- 29143094 TI - The Application of a Performance-Based Self-Administered Intra-procedural Checklist on Surgical Trainees During Laparoscopic Cholecystectomy. AB - INTRODUCTION: Surgical checklists are in use to reduce errors for safer surgery. We aimed to study the effect of a previously designed performance-based self administered intra-procedural checklist on the performance of trainees during elective laparoscopic cholecystectomy. METHODS: Twenty-four laparoscopic cholecystectomies were enrolled into the study. Six surgical trainees each performed four procedures, two without the checklist and directly followed by two procedures with the checklist. A soft beeping sound reminded each trainee to apply the checklist every 4 min during the procedures. The unedited videos were analysed using the human reliability analysis technique for the number of consequential errors, number of interventions by the trainer, number of instrument movements and time execution. The trainees' satisfaction was assessed on a 5-point Likert scale questionnaire. Nonparametric test was used for data analysis. p value was defined as significant when p < 0.05. RESULTS: Participants performed statistically better with the application of the checklist compared to when no checklist was used, respectively: Median [IQR] total number of errors 1.51 [0.80] versus 3.84 [1.42] (p = 0.002) and consequential errors 0.20 [0.12] versus 0.45 [0.42] (p = 0.005), and the number of instrument movements per time decreased from 11.90 [5.34] to 10.38 [5.16] (p = 0.04). With the introduction of the checklist, the number of interventions by the trainer per time decreased from 2.79 [1.85] to 0.43 [1.208] (p = 0.003). The trainees satisfaction score was 4.5 [1] for the first question, 4 [1] for the second question and 4 [2] for the third question. CONCLUSION: The self-administered intra-procedural checklist improved the performance of surgical trainees and decreased the number of interventions by the trainer during laparoscopic cholecystectomy. The trainees were generally satisfied using the checklist during the procedures. PMID- 29143095 TI - Areca nut chewing is associated with common mental disorders: a population-based study. AB - INTRODUCTION: Forms of habitual substance use including cigarette smoking and alcohol consumption have been documented as risk factors of common mental disorders (CMDs). The effects of areca nut chewing on biophysiological tests, metabolic syndromes, and liver function have been reported previously; however, the relationship between areca nut chewing and CMDs remains unclear. This study examined the association between areca nut chewing and CMDs and explored the relationships between areca nut chewing and biophysiological indicators. METHODS: A total of 4477 community dwellers who had enrolled in a cohort study and participated in health examinations in 2 consecutive years were selected for analysis in the present study. The community cohort was established in northern Taiwan during 2006-2012. The Chinese health questionnaire (CHQ-12) was used as a self-reported screening instrument to assess the potential for developing psychotic mental disorders (CHQ-12 score >= 3) among the community residents. Biophysiological tests performed 1 year before CMD assessment were analyzed to examine the causal pathways between areca nut chewing and CMDs. Multiple logistic regression and stratified analyses were performed. RESULTS: A total of 18.23% of the participants were diagnosed as having CMDs. Factors including areca nut chewing [odds ratio (OR) 1.828; 95% confidence interval (CI) 1.165-2.869], sex (women; OR 1.828; 95% CI 1.165-2.869), age (30-49; OR 1.302; 95% CI 1.073-1.579), and socioeconomic status (lower status; OR 1.373; 95% CI 1.084-1.738) were associated with CMDs in a multiple logistic regression model. Areca nut chewers exhibited significantly more triglycerides (220.04 vs. 124.16 mg/dL) and white blood cells (65.17 102/MUL vs. 60.36 102/MUL) and significantly higher diastolic blood pressure (78.83 vs. 75.84 mmHg) and glutamic oxaloacetic transaminase (30.30 vs. 25.45 U/L) than did the controls. CONCLUSIONS: This study demonstrated the association between areca nut chewing and CMDs and its effects on biophysiological tests in a community-based population in Taiwan. The findings suggest the existence of mechanistic effects of areca nut chewing on CMDs exerted through multiple pathways that may interact with pre-existing biophysiological abnormalities. Lifestyle variables should be considered for the prevention and management of mental disorders in the future. PMID- 29143096 TI - [Neurofeedback for the treatment of chronic tinnitus : Review and future perspectives]. AB - Neurofeedback is a noninvasive neuromodulation technique employing real-time display of brain activity in terms of electroencephalography (EEG) signals to teach self-regulation of distinct patterns of brain activity or influence brain activity in a targeted manner. The benefit of this approach for control of symptoms in attention deficit disorders, hyperactivity, depression, and migraine has been proven. Studies in recent years have also repeatedly shown this treatment to improve tinnitus symptoms, although it has not become established as routine therapy. The primary focus of this review is the rational of EEG neurofeedback for tinnitus treatment and the currently available data from published studies. Furthermore, alternative neurofeedback protocols using real time functional magnetic resonance imaging (fMRI) measurements for tinnitus control are considered. Finally, this article highlights how modern EEG analysis (source localization, connectivity) and the improving understanding of tinnitus pathology can contribute to development of more focused neurofeedback protocols for more sustainable control of tinnitus. PMID- 29143097 TI - [Concurrent once-daily or twice-daily chemoradiotherapy in limited-stage small cell lung cancer?] PMID- 29143098 TI - Cervicofacial and mediastinal emphysema after balloon eustachian tuboplasty (BET): a retrospective multicenter analysis. AB - PURPOSE: Balloon Eustachian tuboplasty (BET) is a new treatment modality addressing chronic obstructive dysfunction of the Eustachian tube (ET). So far, BET has been deemed a safe procedure under general anesthesia with only minor adverse effects. However, individual cases of postoperative emphysema have been reported. In the present retrospective multicenter analysis we determined the incidence rate of this potentially life threatening complication after BET. METHODS: In total we collected data from 3,670 BET procedures performed on 2,272 patients in four tertiary care ENT departments. RESULTS: Ten cases of postoperative cervicofacial emphysema were documented, whereas only in 3 of them a pneumomediastinum was developed. None of the affected patients developed at any time serious clinical signs or symptoms besides cutaneous crepitations. A complete resolution and recovery of the emphysema occurred in all patients under antibiotic prophylaxis and abstinence from Valsalva maneuver within the first 2-6 postoperative days. CONCLUSIONS: Possible causes for the development of these postinterventional emphysemas are considered to be mucosal injuries of the ET during manipulations for the correct position of the insertion instrument, through a "kinking" of the balloon catheter or even due to the relative rigid catheter itself, although its form is regarded to be atraumatic. The complication rate of postoperative emphysema was 0.27% (95% CI 0.13-0.50%). The above facts in addition to only minor and transient overall complications after BET reported in literature, can label this procedure as a safe treatment with a low risk profile. PMID- 29143099 TI - [Left atrial appendage clusure in nonvalvular atrial fibrillation : Clinical evidence 2017]. AB - Nonvalvular atrial fibrillation (AF) is the most common arrhythmia with a prevalence of 1-2% and affects approximately 15-20% of all octogenarians. Patients are at increased risk of thromboembolic stroke, with an overall risk of 5% per year. Thrombi form almost exclusively in the left atrial appendage (LAA), a blind sac-like heterogeneous structure trabeculated by pectinate muscles. In the past five decades, life-long oral anticoagulation (OAC) with vitamin K antagonists (VKA) has been the state-of-the art treatment to prevent stroke and systemic embolism from thrombi in AF. In the last decade, nonvitamin K dependent oral anticoagulants (NOAC) have been shown to be superior to VKA. Given the safety issues of indefinite OAC with either VKA or NOAC, it is plausible to consider left atrial appendage closure (LAAC) as an alternative strategy to prevent death, stroke or other systemic embolization, and bleeding. In recent years, LAAC has been compared to VKA in prospective randomized trials, yielding superior results regarding efficacy and noninferiority regarding safety in the mid-term. This review provides an update on the current state of LAAC in the field of prevention of death, stroke, and bleedings in patients suffering from nonvalvular AF. We elucidate the evidence and limitations of anticoagulation as the classical treatment paradigm, and review devices and techniques for LAAC. Most importantly, the current clinical evidence on efficacy and safety is outlined. PMID- 29143100 TI - Infrarenal aortic diameter, aortoiliac bifurcation level and lumbar disc degenerative changes: a cross-sectional MR study. AB - PURPOSE: To examine a possible correlation of infrarenal aortic diameter and aortoiliac bifurcation level with lumbar disc degenerative changes. METHODS: This was a cross-sectional, single-center retrospective study on lumbar magnetic resonance images of patients with low back pain (n = 496). Lumbar disc degenerative changes were reported on the basis of the Pfirrmann grading system and accordingly, patients were grouped as with grade I-II findings (n = 192), with grade III findings (n = 64) and with grade IV-V findings (n = 240). The groups were matched for sex, body mass index and the history of diabetes mellitus, hypertension, hyperlipidemia and smoking. Infrarenal aortic diameter and aortoiliac bifurcation level were compared between the three groups. RESULTS: Pairwise comparisons between the three groups of patients with Pfirrmann grades of I-II, III and IV-V revealed significant differences (p < 0.05) in terms of the median infrarenal aortic diameter (17 mm [interquartile range 4], 18 mm [4] and 19 mm [4], respectively) and the median aortoiliac bifurcation level (3 [2], 4 [2] and 5 [3], respectively; the higher the value, the more the caudal displacement). These associations were independent of conventional risk factors of atherosclerosis (including age) and from each other. CONCLUSIONS: This study showed a significant, direct correlation of the infrarenal aortic diameter and the level of aortoiliac bifurcation with lumbar intervertebral degenerative changes according to the Pfirrmann grading system. The associations were independent of well-known risk factors of atherosclerosis and from each other. PMID- 29143102 TI - Diagnostic performance of HPV E6/E7 mRNA assay for detection of cervical high grade intraepithelial neoplasia and cancer among women with ASCUS Papanicolaou smears. AB - PURPOSE: The aim of this study was to investigate the clinical performance of high risk (HR) HPV E6/E7 mRNA assay in detecting cervical high-grade intraepithelial neoplasia and cancer among women with atypical squamous cells of undetermined significance (ASCUS) Papanicolaou (Pap) smears. METHODS: A total of 160 patients with ASCUS who underwent HR-HPV DNA assay, HR-HPV E6/E7 mRNA assay and colposcopy biopsy at Third Affiliated Hospital of Zhengzhou University, China, from December 2015 to March 2017, were enrolled. Logistic regression analysis was used to evaluate the relationship between pathological results with clinical biologic factors. RESULTS: Univariate analysis showed that the qualitative results of HR-HPV DNA, qualitative results of HR-HPV E6/E7 mRNA and expression levels of HR-HPV E6/E7 mRNA were risk factors of high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer (all P < 0.05). Multivariable analysis found that only the expression levels of HR-HPV E6/E7 mRNA was associated with high-grade CIN and cervical cancer (OR = 8.971, 95% CI = 2.572 31.289, P = 0.001). An optimal cut-off value of >= 558.26 copies/ml was determined using receiver operating characteristic curve, and specificity of cut off value were higher than E6/E7 mRNA qualitative assay and DNA qualitative assay. CONCLUSION: HPV E6/E7 mRNA quantitative assay may be a valuable tool in triage of ASCUS pap smears. A high specificity of E6/E7 mRNA quantitative assay as a triage test in women with ASCUS can be translated into a low referral for colposcopy. PMID- 29143103 TI - Combined assessment of left ventricular end-diastolic pressure and ejection fraction by left ventriculography predicts long-term outcomes of patients with ST segment elevation myocardial infarction. AB - In patients with ST-segment elevation myocardial infarction (STEMI), it is unclear if combined assessment of left ventricular end-diastolic pressure (LVEDP) and left ventricular ejection fraction (LVEF) improves prediction of major adverse cardiac events (MACE). We analyzed data from 266 STEMI patients who underwent successful percutaneous coronary intervention and subsequent left ventriculography (LVG). Patients were divided into 4 groups, as follows: Group 1, LVEDP < 21 mmHg and LVEF >= 55%; Group 2, LVEDP < 21 mmHg and LVEF < 55%; Group 3, LVEDP >= 21 mmHg and LVEF >= 55%; and Group 4, LVEDP >= 21 mmHg and LVEF < 55%. Multivariate Cox proportional hazards analysis was used to determine if LVEDP and LVEF were associated with MACE (including cardiac death, non-fatal myocardial infarction, and heart failure requiring hospitalization). Change in LV parameters was assessed in the subset of 183 patients who underwent serial LVG (mean interval 6.3 +/- 1.6 months). During a mean follow-up of 43 +/- 31 months, 29 patients (10.9%) had a MACE. As compared to Group 1, MACE risk was significantly higher in Group 3 [hazard ratio (HR) 3.26; 95% confidence interval (CI) 1.05-10.0] and Group 4 (HR 3.99; 95% CI 1.44-11.0), but not in Group 2 (HR 0.46, 95% CI 0.54-3.96). In sub-analyses, LV end-systolic volume index after PCI was significantly higher in Group 4 than in the other groups and remained higher during follow-up. Combined LVEDP/LVEF assessment was useful in predicting MACE after successful PCI for STEMI patients and could facilitate risk stratification, as it predicts LV remodeling. PMID- 29143101 TI - Candidate biomarkers in the cervical vaginal fluid for the (self-)diagnosis of cervical precancer. AB - PURPOSE: Despite improvement in vaccines against human papilloma virus (HPV), the causative agent of cervical cancer, screening women for cervical precancer will remain indispensable in the coming 30-40 years. A simple test that could be performed at home or at a doctor's practice and that informs the woman whether she is at risk would significantly help make a broader group of patients who aware that they need medical treatment. Cervical vaginal fluid (CVF) is a body fluid that is very well suited for such a test. METHODS: Narrative review of cervical (pre)cancer candidate biomarkers from cervicovaginal fluid, is based on a detailed review of the literature. We will also discuss the possibilities that these biomarkers create for the development of a self-test or point-of-care test for cervical (pre)cancer. RESULTS: Several DNA, DNA methylation, miRNA, and protein biomarkers were identified in the cervical vaginal fluid; however, not all of these biomarkers are suited for development of a simple diagnostic assay. CONCLUSIONS: Proteins, especially alpha-actinin-4, are most suited for development of a simple assay for cervical (pre)cancer. Accuracy of the test could further be improved by combination of several proteins or by combination with a new type of biomarker, e.g., originating from the cervicovaginal microbiome or metabolome. PMID- 29143104 TI - Left ventricular end-diastolic dimension and septal e' are predictors of cardiac index at rest, while tricuspid annular plane systolic excursion is a predictor of peak oxygen uptake in patients with pulmonary hypertension. AB - Little is known regarding a correlation of hemodynamics at rest or exercise capacity with echocardiographic parameters in patients with pulmonary hypertension (PH). To clarify these potential correlations, we performed transthoracic echocardiography, right heart catheterization, and cardiopulmonary exercise testing in 53 patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Left ventricular end diastolic dimension (LVDd), early diastolic velocity of the septal mitral annulus (septal e'), tricuspid regurgitation peak gradient (TRPG), and tricuspid annular plane systolic excursion (TAPSE) were significantly correlated with cardiac index (LVDd; r = 0.477, P < 0.001, septal e'; r = 0.463, P = 0.001, TRPG; r = - 0.455, P = 0.001 and TAPSE; r = 0.406, P = 0.003, respectively). Multiple regression analysis revealed that LVDd and septal e' were significantly associated with cardiac index (CI) and stroke volume index at rest. Among the exercise capacity markers evaluated, TAPSE, TRPG, and LVDd were significantly correlated with peak oxygen uptake (TAPSE; r = 0.534, P < 0.001, TRPG; r = - 0.466, P = 0.001 and LVDd; r = 0.411, P = 0.002, respectively). Multiple regression analysis showed that TAPSE was significantly associated with peak oxygen uptake (VO2). In PAH and CTEPH patients, LVDd and septal e' were significantly associated with CI at rest, whereas TAPSE was significantly associated with peak VO2. Echocardiographic parameters may predict the prognostic factors of PAH and CTEPH patients. PMID- 29143105 TI - Application of DWIBS in malignant lymphoma: correlation between ADC values and Ki 67 index. AB - OBJECTIVES: We investigated the correlation between the apparent diffusion coefficient (ADC) and Ki-67 index using diffusion-weighted whole-body imaging with background body signal suppression (DWIBS), and their utility in evaluating malignant lymphoma cell proliferation. MATERIALS AND METHODS: Seventy-four patients with malignant lymphoma underwent DWIBS within 1 week before pathological confirmation. The ADC value was measured at the site of the pathological examination, and specimens were also stained with Ki-67. The ADC values and Ki-67 indices in aggressive non-Hodgkin's lymphoma (NHL), indolent NHL, and Hodgkin's lymphoma (HL) were compared using Spearman's rank correlation coefficient and the Kruskal-Wallis test. RESULTS: The Ki-67 indices and ADC values were inversely correlated (r = -0.289, p = 0.0125); the differences in the Ki-67 index between aggressive NHL, indolent NHL, and HL were significant (p < 0.001); this was confirmed by the Nemenyi test except for indolent NHL vs. HL. The ADC values were significantly different between the types of lymphoma (p = 0.013); the Nemenyi test showed a significant difference only between aggressive NHL and HL. CONCLUSIONS: The Ki-67 indices and ADC values are inversely correlated in patients with lymphoma, combining DWIBS and ADC values can evaluate the proliferation level of malignant lymphoma cells noninvasively. KEY POINTS: * By using DWIBS, malignant lymphoma cell proliferation can be assessed noninvasively. * The ADC value and Ki-67 index are significantly and inversely correlated. * The ADC values were lower in aggressive NHL than in HL. * The ADC values of aggressive and indolent NHL were not significantly different. PMID- 29143107 TI - How I do it: endoscopic microvascular decompression for hemifacial spasm associated with the vertebral artery. AB - BACKGROUND: Microvascular decompression (MVD) of hemifacial spasm (HFS) associated with the vertebral artery (VA) shows higher rates of incomplete cure and complications compared to non-VA-related HFS. METHOD: Purely endoscopic MVD for VA-associated HFS via a retrosigmoid keyhole was performed. Neurovascular conflicts by a directly offending artery and VA around the root exit zone of the facial nerve were clearly demonstrated under 30 degrees endoscopic view without significant cerebellar retraction. The VA and directly offending artery were safely transposed with preservation of perforators under excellent view. CONCLUSION: Endoscopic MVD offers reliable decompression for VA-associated HFS with minimal invasiveness. PMID- 29143106 TI - Nonsuppressing normal thymus on chemical-shift MR imaging and anterior mediastinal lymphoma: differentiation with diffusion-weighted MR imaging by using the apparent diffusion coefficient. AB - OBJECTIVES: To prospectively evaluate usefulness of the apparent diffusion coefficient (ADC) in differentiating anterior mediastinal lymphoma from nonsuppressing normal thymus on chemical-shift MR, and to look at the relationship between patient age and ADC. METHODS: Seventy-three young subjects (25 men, 48 women; age range, 9-29 years), who underwent chemical-shift MR and diffusion-weighted MR were divided into a normal thymus group (group A, 40 subjects), and a lymphoma group (group B, 33 patients). For group A, all subjects had normal thymus with no suppression on opposed-phase chemical-shift MR. Two readers measured the signal intensity index (SII) and ADC. Differences in SII and ADC between groups were tested using t-test. ADC was correlated with age using Pearson correlation coefficient. RESULTS: Mean SII+/-standard deviation was 2.7+/ 1.8% for group A and 2.2+/-2.4% for group B, with no significant difference between groups (P=.270). Mean ADC was 2.48+/-0.38x10-3mm2/s for group A and 1.24+/-0.23x10-3mm2/s for group B. A significant difference between groups was found (P<.001), with no overlap in range. Lastly, significant correlation was found between age and ADC (r=0.935, P<.001) in group A. CONCLUSIONS: ADC of diffusion-weighted MR is a noninvasive and accurate parameter for differentiating lymphoma from nonsuppressing thymus on chemical-shift MR in young subjects. KEY POINTS: * SII cannot differentiate mediastinal lymphoma from nonsuppressing normal thymus at visual assessment * ADC is useful for distinguishing nonsuppressing normal thymus from mediastinal lymphoma * ADC is more accurate than transverse-diameter and surface-area in this discrimination * ADC of normal thymus is age dependent and increases with increasing age. PMID- 29143108 TI - Immune checkpoint inhibitor colitis: the flip side of the wonder drugs. AB - Immune checkpoint inhibitors block the co-inhibitory receptors on T cells to activate their cytotoxic immune function and are rapidly being explored for the treatment of various advanced-stage malignancies. These novel drugs have already significantly increased survival rates. The first available immune checkpoint inhibitors were cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors (such as ipilimumab), followed by programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) inhibitors (such as pembrolizumab and nivolumab). Anti-PD-1 and anti-PD-L1 therapies have demonstrated better efficacy and tolerability and less severe adverse effects compared to anti-CTLA-4 agents. Idelalisib, a PI3Kdelta isoform inhibitor, is another immunotherapeutic agent that is often classified separately and is currently used in treatment of chronic lymphocytic leukemia and non-Hodgkin lymphomas. Despite successful therapeutic responses, immune-related adverse events have been reported with the use of these agents. The gastrointestinal side effects, particularly diarrhea, are among the most commonly reported symptoms. The histologic features of immune checkpoint inhibitor-associated colitis show a spectrum of patterns of injury among various drug classes. There is significant overlap between immune checkpoint inhibitor associated colitis and other colitides, making the differential diagnosis difficult-especially in the absence of clinical history. The histopathology data on immune checkpoint inhibitor-associated colitis are limited. Here we review clinical features as well as various histologic patterns of colitis associated with these groups of medications. PMID- 29143109 TI - Correction to: Abstracts : 29th European Congress of Pathology. AB - Due to an error with the registration system, the following abstract was regrettably omitted from the Poster Sessions. The abstract should have been included as PS-13-116 and displayed on page S199. PMID- 29143110 TI - Correction to: Abstracts : 29th European Congress of Pathology. AB - In Poster Sessions, the first-author name was missing from the authorship group originally listed for Abstract PS-01-004 (page S52), entitled "Clinicopathological features of microinvasive breast cancer". The correct authorship group is shown above. PMID- 29143111 TI - Correction to: Abstracts : 29th European Congress of Pathology. AB - In Poster Sessions, the first-author name was missing from the authorship group originally listed for Abstract PS-13-001 (page S176), entitled "Gastric carcinoma with lymphoid stroma: Analysis of microsatellite instability and Epstein-Barr virus status". The correct authorship group is shown above. PMID- 29143112 TI - Assessment of the zonal variation of perfusion parameters in the femoral head: a 3-T dynamic contrast-enhanced MRI pilot study. AB - OBJECTIVE: The objective was to describe MR perfusion characteristics of the femoral head, with a focus on the subchondral bone. MATERIALS AND METHODS: This prospective monocentric study was approved by our local Ethics Committee. Written informed consent was obtained from all subjects. Dynamic contrast-enhanced MRI of the right hip was performed in 59 adults with suspected spondyloarthritis (32 women, 28 men). Mean age was 37.5 (+/-12.5) years. Regions of interest were drawn in the femoral head epiphysis, in the subchondral areas the most exposed to mechanical load (superolateral, anterosuperior, and posterior zones) and in areas less exposed to mechanical load (inferior subchondral zone and center of the femoral head). Semi-quantitative and pharmacokinetic parameters were calculated using the Tofts model. Statistical analysis was performed with a linear mixed model to compare the perfusion parameters in the different femoral head zones. RESULTS: Extravascular extracellular volume and area under the curve were lower in the superolateral zone than in the inferior zone (p = 0.0135 and p < 0.0001 respectively) and the central zone (p = 0.007 and p = 0.0134 respectively). Extravascular extracellular volume and rate constant were lower in the anterosuperior zone than in the inferior zones (p = 0.011 and p = 0.029). In the anterosuperior zone, extravascular extracellular volume was lower, and time to peak was higher than in the central zones (p = 0.0056 and p = 0.0013 respectively). No significant differences were found for any values between other paired zones. CONCLUSION: The perfusion of femoral head subchondral bone assessed with dynamic contrast-enhanced magnetic resonance imaging is not homogeneous: the areas exposed to more mechanical loading are less perfused. PMID- 29143113 TI - Percutaneous CT-guided sacroiliac joint sampling for infection: aspiration, biopsy, and technique. AB - OBJECTIVE: To evaluate methods of CT-guided sacroiliac joint sampling in patients with suspected infection. MATERIALS AND METHODS: All CT-guided sacroiliac joint sampling procedures for suspected infection were reviewed for sampling type (aspiration, lavage aspiration, biopsy), microbiology results, and clinical and imaging follow-up. The primary gold standard was anatomic pathology. If pathology was not available, then positive blood culture with the same organism as SIJ sampling, imaging and clinical follow-up, or clinical follow-up only were used. Anterior and posterior joint distention was evaluated by MRI within 7 days of the procedure. RESULTS: A total of 34 patients (age 39 +/- 20 (range, 6-75) years; 21 F, 13 M) were included. Aspiration samples only were obtained in 13/34 (38%) cases, biopsy samples only in 9/34 (26%) cases, and both samples in 12/34 (35%) cases. There was an overall 54% sensitivity and 86% specificity. For the aspiration samples, sensitivity and specificity were 60 and 81%, respectively, compared to 45 and 90% for the biopsy samples. In cases with both samples, biopsy did not add additional microbial information. Seventeen (17/34, 50%) patients had an MRI. The anterior joint was more distended than the posterior joint in 15/17 (88%) of patients, and this difference was significant (P = 0.0003). All of these 17 patients had an attempted aspiration by a posterior approach; 6/17 (35%) resulted in a successful aspiration. CONCLUSIONS: Aspiration of the sacroiliac joint has a higher sensitivity than biopsy and should always be attempted first. MRI may be helpful for procedure planning. PMID- 29143114 TI - Cancer vaccine strategies: translation from mice to human clinical trials. AB - We translated two cancer vaccine strategies from mice into human clinical trials. (1) In preclinical studies on TARP, an antigen expressed in most prostate cancers, we mapped epitopes presented by HLA-A*0201, modified them to increase affinity and immunogenicity in HLA transgenic mice, and induced human T cells that killed human cancer cells ("epitope enhancement"). In a clinical trial, HLA A2+ prostate cancer patients with PSA biochemical recurrence (Stage D0) were vaccinated with two peptides either in Montanide-ISA51 or on autologous dendritic cells (DCs). In stage D0, the Prostate-Specific Antigen (PSA) slope is prognostic of time to radiographic evidence of metastases and death. With no difference between arms, 74% of combined subjects had a decreased PSA slope at 1 year compared to their own baseline slopes (p = 0.0004). For patients vaccinated with DCs, response inversely correlated with a tolerogenic DC signature. A randomized placebo-controlled phase II trial is underway. (2) HER2 is a driver surface oncogene product expressed in multiple tumors. We made an adenoviral vector vaccine expressing the extracellular and transmembrane domains of HER2 and cured mice with large established HER2+ tumors, dependent on antibodies to HER2, not T cells. The mechanism differed from that of trastuzumab. We tested a human version in advanced metastatic cancer patients naive to HER2-directed therapies. At the second and third dose levels, 45% of evaluable patients showed clinical benefit. Circulating tumor cells also declined in some vaccinated patients. Thus, cancer vaccines developed in mice were successfully translated to humans with promising early results. PMID- 29143115 TI - Hydrocephalus associated to congenital Zika syndrome and shunting. PMID- 29143116 TI - Cerebral venous sinus thrombosis after cranial surgery in children. PMID- 29143118 TI - [Chronic pain disorder with somatic and psychological factors (F45.41) : Validation criteria on operationalization of the ICD-10-GM diagnosis]. AB - In 2009 the diagnosis chronic pain disorder with somatic and psychological factors (F45.41) was integrated into the German version of the International Classification of Diseases, version 10 (ICD-10-GM). In 2010 Paul Nilges and Winfried Rief published operationalization criteria for this diagnosis. In the present publication the ad hoc commission on multimodal interdisciplinary pain therapy of the German Pain Society now presents a formula for a clear validation of these operationalization criteria of the ICD code F45.41. PMID- 29143117 TI - The expression of VE-cadherin in breast cancer cells modulates cell dynamics as a function of tumor differentiation and promotes tumor-endothelial cell interactions. AB - The cadherin switch has profound consequences on cancer invasion and metastasis. The endothelial-specific vascular endothelial cadherin (VE-cadherin) has been demonstrated in diverse cancer types including breast cancer and is supposed to modulate tumor progression and metastasis, but underlying mechanisms need to be better understood. First, we evaluated VE-cadherin expression by tissue microarray in 392 cases of breast cancer tumors and found a diverse expression and distribution of VE-cadherin. Experimental expression of fluorescence-tagged VE-cadherin (VE-EGFP) in undifferentiated, fibroblastoid and E-cadherin-negative MDA-231 (MDA-VE-EGFP) as well as in differentiated E-cadherin-positive MCF-7 human breast cancer cell lines (MCF-VE-EGFP), respectively, displayed differentiation-dependent functional differences. VE-EGFP expression reversed the fibroblastoid MDA-231 cells to an epithelial-like phenotype accompanied by increased beta-catenin expression, actin and vimentin remodeling, increased cell spreading and barrier function and a reduced migration ability due to formation of VE-cadherin-mediated cell junctions. The effects were largely absent in both MDA-VE-EGFP and in control MCF-EGFP cell lines. However, MCF-7 cells displayed a VE-cadherin-independent planar cell polarity and directed cell migration that both developed in MDA-231 only after VE-EGFP expression. Furthermore, VE-cadherin expression had no effect on tumor cell proliferation in monocultures while co culturing with endothelial cells enhanced tumor cell proliferation due to integration of the tumor cells into monolayer where they form VE-cadherin mediated cell contacts with the endothelium. We propose an interactive VE cadherin-based crosstalk that might activate proliferation-promoting signals. Together, our study shows a VE-cadherin-mediated cell dynamics and an endothelial dependent proliferation in a differentiation-dependent manner. PMID- 29143119 TI - Infectious and Non-Infectious Diseases Causing the Air Crescent Sign: A State-of the-Art Review. AB - Aspergilloma, also known as mycetoma or fungus ball, is characterized by a round or oval mass with soft-tissue attenuation within a preexisting lung cavity. The typical computed tomography (CT) aspect of an aspergilloma is a mass separated from the wall of the cavity by an airspace of variable size and shape, resulting in the air crescent sign, also known as the meniscus sign. This CT feature is non specific and can be simulated by several other entities that result in intracavitary masses. This review describes the main clinical and imaging aspects of the infectious and non-infectious diseases that may present with fungus-ball appearance, including pulmonary hydatid cyst, Rasmussen aneurysm, pulmonary gangrene, intracavitary clot, textiloma, lung cancer, metastasis, and teratoma, focusing on the differential diagnosis. PMID- 29143120 TI - Epigenetic silencing of ADAMTS5 is associated with increased invasiveness and poor survival in patients with colorectal cancer. AB - PURPOSE: A disintegrin and metalloprotease with motif 5(ADAMTS5) has been involved in colorectal cancer (CRC) with hypermethylation in the promoter. However, its role in CRC remains unclear. The aim of this study was to explore the clinical significance and biological effect of ADAMTS5 on colorectal carcinogenesis. Through MSP, qRT-PCR, WB and IHC analysis, followed by a variety of in vitro assays, we report the function of ADAMTS5 in CRC. ADAMTS5 was markedly hypermethylaed and downregulated in tumor tissues compared with non tumor tissues (p < 0.001). Negative expression of ADAMTS5 was much more common in tumor tissues than that in normal tissues (p < 0.001) and correlated with histologic types (p = 0.002), poor OS (p = 0.029) and DFS (p = 0.018). In vitro assay revealed that overexpression of ADAMTS5 inhibited the capabilities of migration and invasion of CRC cells, and no effect on cell growth, cell cycle and apoptosis. ADAMTS5 is hypermethylated and inhibits cancer cells invasion and migration in colorectal cancer, and correlates with OS and DFS, indicating that ADAMTS5 might be a useful biomarker in colorectal cancer therapy. PMID- 29143121 TI - Telomere length of gallbladder epithelium is shortened in patients with congenital biliary dilatation: measurement by quantitative fluorescence in situ hybridization. AB - BACKGROUND: Congenital biliary dilatation (CBD) is a congenital malformation involving both dilatation of the extrahepatic bile duct and pancreaticobiliary maljunction. Persistent reflux of pancreatic juice injures the biliary tract mucosa, resulting in chronic inflammation and higher rates of carcinogenesis in the biliary tract, including the gallbladder. Telomeres are repetitive DNA sequences located at the ends of chromosomes. Chromosomal instability due to telomere dysfunction plays an important role in the carcinogenesis of many organs. This study was performed to determine whether excessive shortening of telomeres occurs in the gallbladder mucosa of patients with CBD. METHODS: Resected gallbladders were obtained from 17 patients with CBD, ten patients with cholecystolithiasis without pancreatic juice reflux, and 17 patients with normal gallbladders (controls) (median age of each group of patients: 37, 50, and 53 years, respectively). The telomere lengths of the gallbladder epithelium were measured by quantitative fluorescence in situ hybridization using tissue sections, and the normalized telomere-to-centromere ratio (NTCR) was calculated. RESULTS: The NTCRs in the CBD, cholecystolithiasis, and control groups were 1.24 [interquartile range (IQR) 1.125-1.52], 1.96 (IQR 1.56-2.295), and 1.77 (IQR 1.48 2.53), respectively. The NTCR in the CBD group was significantly smaller than that in the cholecystolithiasis and control groups (p = 0.003 and 0.004, respectively), even in young patients. CONCLUSIONS: Our findings indicate that telomere shortening in the gallbladder mucosa plays an important role in the process of carcinogenesis in patients with CBD. These results support the recommendation of established guidelines for prophylactic surgery in patients with CBD because CBD is a premalignant condition with excessive telomere shortening. PMID- 29143122 TI - Vitamin D supplementation attenuates oxidative stress in paraspinal skeletal muscles in patients with low back pain. AB - PURPOSE: The aim of the study was to evaluate markers of oxidative stress and vitamin D receptor in paraspinal muscles in low back pain patients with vitamin D deficiency, with normal level of vitamin D, and after 5 weeks of vitamin D supplementation. METHODS: Patients were divided into three groups: supplemented (SUP) with vitamin D, placebo with normal concentration of vitamin D (SUF), and the placebo group with vitamin D deficiency (DEF). The concentration of serum vitamin D was measured before and after the supplementation with vitamin D (3200 IU/ day for 5 weeks). Markers of lipid and protein peroxidation, the activity of antioxidant enzymes, and protein content of vitamin D receptor was determined in multifidus muscle of patients. RESULTS: Vitamin D supplementation increased serum level of 25(OH)D3 (p < 0.001). In paraspinal muscle level of 8-isoprostanes and protein carbonyls was higher in DEF group as compared to the SUP group (p < 0.05). Antioxidant enzyme activity and vitamin D receptor in paraspinal muscle altered between the groups with different serum vitamin D concentration. The cytosolic superoxide dismutase and glutathione peroxidase activities were significantly higher in DEF group as compared to the SUP group (p < 0.05). CONCLUSIONS: An attenuation of markers of free radical damage of lipids and proteins was observed in participants supplemented with Vitamin D. Antioxidant enzyme activities in skeletal muscle differ among patients with different serum vitamin D concentration. Monitoring oxidative stress and VDR protein content might be useful for future studies on the mechanism(s) of vitamin D action in muscle. PMID- 29143123 TI - Recovery of the cardiac autonomic nervous and vascular system after maximal cardiopulmonary exercise testing in recreational athletes. AB - OBJECTIVE: The body's adaptation to physical exercise is modulated by sympathetic and parasympathetic (vagal) branches of the autonomic nervous system (ANS). Heart rate variability (HRV), the beat-to-beat variation of the heart, is a proxy measure for ANS activity, whereas blood pressure (BP) is an indicator for cardiovascular function. Impaired vagal activity and lower BP is already described after exercise. However, inconsistent results exist about how long vagal recovery takes and how long post-exercise hypotension persists. Therefore, the aim of this study was to assess HRV and BP 1 h after maximal cardiopulmonary exercise testing (CPET). PATIENTS AND METHODS: HRV (Polar RS800CX), peripheral and central BP (Mobil-O-Graph(r)) were prospectively studied in 107 healthy volunteers (47 female, median age 29.0 years) in supine position, before and 60 min after maximal CPET. RESULTS: One hour after terminating CPET measures of HRV were still impaired and post-exercise BP was significantly reduced suggesting an improved vascular function compared to pre levels. HRV parameters post-exercise were 34.7% (RMSSD), 67.2% (pNN50), 57.2% (HF), and 42.7% (LF) lower compared to pre-exercise levels (for all p < 0.001). Median reduction in BP was 5 mmHg for systolic BP (p < 0.001), and 4 mmHg for diastolic BP (p = 0.016) and central systolic post-exercise (p = 0.005). CONCLUSIONS: One hour after terminating strenuous exercise, autonomic nervous regulation seems to be postponed which is reflected in reduced HRV, whereas the early recovery of the vasculature, post exercise hypotension, is still preserved over the recovery period of 1 h. PMID- 29143124 TI - The effect of inhibition on stimulus-specific adaptation in the inferior colliculus. AB - The inferior colliculus is a center of convergence for inhibitory and excitatory synaptic inputs that may be activated simultaneously by sound stimulation. Stimulus repetition may generate response habituation by changing the efficacy of neuron's synaptic inputs. Specialized IC neurons reduce their response to repetitive tones, but restore their firing when a different and infrequent tone occurs, a phenomenon known as stimulus specific adaptation. Here, using the microiontophoresis technique, we determined the role of GABAA-, GABAB-, and glycinergic receptors in stimulus-specific adaptation (SSA). We found that blockade of postsynaptic GABAB receptors selectively modulated response adaptation to repetitive sounds, whereas blockade of presynaptic GABAB receptors exerted a gain control effect on neuron excitability. Adaptation decreased when postsynaptic GABAB receptors were blocked, but increased if the blockade affected the presynaptic GABAB receptors. A dual, paradoxical effect was elicited by blockade of glycinergic receptors, i.e., both increase and decrease in adaptation. Moreover, simultaneous co-application of GABAA, GABAB, and glycinergic antagonists demonstrated that local GABA- and glycine-mediated inhibition contributes to only about 50% of SSA. Therefore, inhibition via chemical synapses dynamically modulate the strength and dynamics of stimulus specific adaptation, but does not generate it. PMID- 29143126 TI - [Spinal orthoses in the treatment of vertebral fractures with osteoporosis : A systematic review article]. AB - This literature search concerning the potential role of spinal orthoses for rehabilitation and treatment of atraumatic vertebral fractures between Th4 and L5 with osteoporosis and without any evidence for a secondary cause, provided no evidence for the benefits of traditional rigid thoracolumbar corsets, which only had a poor compliance. In addition, there are indications that these rigid corsets may even worsen the disease condition especially in the long-term. Wearing these corsets can result in further loss of muscle mass and strength followed by loss of bone and bone mass. Both together can worsen the functional capabilities of patients. On the other hand the functional capabilities of patients suffering from acute or subacute vertebral fractures due to osteoporosis can be improved by flexible backpack orthoses. These spinal orthoses generate an extension moment about the spine, increase perception of one's own body posture via biofeedback and therefore lead to improved posture. This results in a strengthening of the trunk musculature, a more stable equilibrium and a reduction of pain, which are associated with an increase in functional capabilities and improvement in the parameters of the quality of life. During a long-term phase of rehabilitation individually tailored spinal orthoses guarantee a high level of compliance and adherence. Finally, there is high-quality evidence that spinal orthoses with additional weighting can improve the equilibrium in women with vertebral osteoporosis and hyperkyphosis. Future studies should also be carried out with other groups of patients. PMID- 29143125 TI - Rapid temporal recalibration to visuo-tactile stimuli. AB - For a comprehensive understanding of the environment, the brain must constantly decide whether the incoming information originates from the same source and needs to be integrated into a coherent percept. This integration process is believed to be mediated by temporal integration windows. If presented with temporally asynchronous stimuli for a few minutes, the brain adapts to this new temporal relation by recalibrating the temporal integration windows. Such recalibration can occur even more rapidly after exposure to just a single trial of asynchronous stimulation. While rapid recalibration has been demonstrated for audio-visual stimuli, evidence for rapid recalibration of visuo-tactile stimuli is lacking. Here, we investigated rapid recalibration in the visuo-tactile domain. Subjects received visual and tactile stimuli with different stimulus onset asynchronies (SOA) and were asked to report whether the visuo-tactile stimuli were presented simultaneously. Our results demonstrate visuo-tactile rapid recalibration by revealing that subjects' simultaneity reports were modulated by the temporal order of stimulation in the preceding trial. This rapid recalibration effect, however, was only significant if the SOA in the preceding trial was smaller than 100 ms, while rapid recalibration could not be demonstrated for SOAs larger than 100 ms. Since rapid recalibration in the audio-visual domain has been demonstrated for SOAs larger than 100 ms, we propose that visuo-tactile recalibration works at shorter SOAs, and thus faster time scales than audio visual rapid recalibration. PMID- 29143127 TI - Decreased serum vitamin B12 and vitamin D levels affect sleep quality in children with familial Mediterranean fever. AB - Familial Mediterranean fever is an autoinflammatory disorder characterized by recurrent fever and serositis. We aimed to describe serum vitamin B12 and vitamin D levels and their correlation with self-reported sleep quality of pediatric FMF patients. Sixty-three children with FMF were enrolled to the study. Information on sleep quality was obtained using self-administration of Pittsburg Sleep Quality Index (PSQI). The patients were divided into subgroups depending on vitamin D serum concentrations: >= 20 and < 20 ng/ml. We also grouped patients according to their serum B12 concentration: >= 200, < 200 pg/ml. B12 levels were not correlated with PSQI scores, whereas significant correlation was found between vitamin D and total PSQI scores and daytime sleepiness. Total PSQI score, sleep disorders and daytime sleepiness sub-scores were statistically high in patients with serum D vitamin levels below 20 ng/ml. Sleep efficiency was found lower in patients with serum B12 levels below 200 pg/ml. B12 may have a positive role on effective sleep. More importantly, we suggest that vitamin D is protective against sleep disorders and poor sleep, it may also improve daytime activities. PMID- 29143128 TI - The evolution of androgen receptor expression and behavior in Anolis lizard forelimb muscles. AB - The motor systems that produce behavioral movements are among the primary targets for the action of steroid hormones, including androgens. Androgens such as testosterone bind to androgen receptors (AR) to induce physiological changes in the size, strength, and energetic capacity of skeletal muscles, which can directly influence the performance of behaviors in which those muscles are used. Because tissues differentially express AR, resulting in tissue-specific sensitivity to androgens, AR expression may be a major target of selection for the evolution of behavior. Anolis lizards (i.e., anoles) provide a robust system for the study of androgen-regulated traits, including the behavioral traits that facilitate social display and locomotion. In this study, we examined six anole species that demonstrate significant variation in the behavioral use of the forelimbs to measure the proportion of myonuclei in the bicep muscles that express AR. Using phylogenetic comparative analyses, we found that species with a greater proportion of nuclei positive for AR expression in the biceps exhibited greater frequencies of locomotor movements and pushup displays. These results suggest that AR expression in skeletal muscles may influence the evolution of androgen-regulated behaviors in this group. PMID- 29143129 TI - Competitive/co-operative interactions in acid base sandwich: role of cation vs. substituents. AB - The cation-pi interaction can be envisaged as a lewis acid base interaction, and it is in line with Pearson's acid base concept. The critical examination of interactions between the pi-acids (alkali metal cations - Li+, Na+ and alkaline earth metal cations Mg2+, Ca2+) on one face and tripodal Cr(CO)3 moiety on the other pi face of substituted arenes demonstrates the role of cation and substitutents in manipulating the interactions between them. The interaction of the two pi acids on both faces of arene is not expectedly additive, rather it shows either depreciation of interaction energy revealing the competition of acids toward the base or enhancement of interaction energy denoting a cooperative effect. Among the metal cations under study, Mg2+ shows a cooperative gesture. Although the substituents play a meek role, they unfailingly exert their electronic effects and are amply documented by excellent correlation of various parameters with the Hammett constant sigmam. The elusive switching of lambdamax from the UV to IR region on binding Mg2+ with substituted arene-Cr(CO)3 complex is a characteristic clue that TDDFT can help design the ionic sensors for Mg2+ cations. PMID- 29143130 TI - Two threshold levels of vitamin D and the prevalence of comorbidities in outpatients of a tertiary hospital. AB - : This study evaluated the number of comorbidities between two normal values of 25OHD in outpatients during 1 year of 25OHD measurements. Five hundred twenty nine outpatients were included, patients with 25OHD >= 20 and < 30 ng/mL had the higher number of comorbidities, suggesting that for this specific population, 25OHD >= 30 ng/mL would be more appropriate. INTRODUCTION : This study evaluated the comorbidities between two values of 25OHD in outpatients of a tertiary hospital. METHODS: This is a cross-sectional study with measures of 25OHD in 1 year period, excluding 25OHD < 20 and > 50 ng/mL, clinical research participants, and liver disease and chronic renal failure patients. Patients were divided into two groups: group 1 (G1), 25OHD >= 20 and < 30 ng/mL; and group 2 (G2), 250HD >= 30 and <= 50 ng/mL. Medical records were reviewed for demographic, laboratory, and comorbidity data. RESULTS: From 529 outpatients included, 319 were in G1 (53.3 +/- 15.8 years, 85% women), mean 25OHD 24.8 +/- 2.8 ng/mL; and 210 outpatients in G2 (56.7 +/- 16.0 years, 83% women), mean 25OHD was 36.8 +/- 4.8 ng/mL. G1 had the higher number of comorbidities, including altered glycemia, dyslipidemia, hypothyroidism, urinary tract diseases, arthropathy, secondary hyperparathyroidism, anemia, and neurological and psychiatric disorders. Osteoporosis and hypothyroidism were more prevalent in G2. After binary logistic regression, the variables age (OR 0.988, CI 0.97-1.00, p = 0.048), osteoporosis (OR 0.54, CI 0.36-0.80, p = 0.003), dyslipidemia (OR 1.61, CI 1.10-2.39, p = 0.015), arthropathy (OR 2.60, CI 1.40-5.10, p = 0.003), anemia (OR 15.41, CI 3.09 280.08, p = 0.008), and neurological and psychiatric diseases (OR 3.78, CI 1.98 7.88, p = 0.001) maintained significance. CONCLUSION: Patients with serum 25OHD >= 20 and < 30 ng/mL had higher prevalence of comorbidities compared to >= 30 ng/mL. PMID- 29143131 TI - Vertebral fractures and their association with health-related quality of life, back pain and physical function in older women. AB - : Studies investigating prevalent vertebral fracture (VF) diagnosed using densitometry-based VF assessment (VFA) and associations with physical function, assessed by performance-based measures, are lacking. In this population-based study of 1027 older women, we found that prevalent VF, identified by VFA, was associated with inferior physical health, back pain and inferior physical function. PURPOSE: Several studies have investigated the associations between health-related quality of life (HRQL) and back pain with prevalent VF, detected by spine radiographs, but just a few have been population-based and have used vertebral fracture assessment (VFA) for diagnosing VF. The aims of this study were to investigate associations between prevalent VF, detected by VFA, with HRQL, back pain and physical function, and investigate if also mild VFs were associated with these clinical parameters. METHODS: One thousand twenty-seven women aged 75-80 years participated in this population-based cross-sectional study. VF was identified by VFA using dual-energy X-ray absorptiometry. HRQL was assessed by SF-12, back pain during the past 12 months using a questionnaire, and physical function was tested with one leg standing (OLS), Timed Up and Go (TUG), walking speed, 30-s chair stand test and maximum grip strength. RESULTS: Physical health (Physical Component Summary, PCS), derived from SF-12, was worse (43.5 +/- 11.3 vs. 46.2 +/- 10.5, p < 0.001) and back pain more frequent in women with any VF than in women without (69.0 vs. 59.9%, p = 0.008). PCS and physical function (OLS, 30-s chair stand test), were significantly worse for mild VF compared to no VF (43.8 +/- 10.9 vs. 46.2 +/- 10.5, p < 0.001, 12.7 +/- 9.9 vs. 15.3 +/- 10.4 s, p = 0.038, 10.7 +/- 3.2 vs. 11.4 +/- 3.4 times, p = 0.021, respectively). In multivariable adjusted linear regression models, VF prevalence was associated with PCS (beta = - 0.079, p = 0.007), TUG (beta = 0.067, p = 0.021), walking speed (beta = - 0.071, p = 0.009) and 30-s chair stand test (beta = - 0.075, p = 0.012). CONCLUSIONS: In conclusion, prevalent VF, diagnosed by VFA, was associated with inferior physical health, back pain and inferior physical function, indicating VFA is useful for diagnosing clinically relevant vertebral fractures. Also, mild VF was associated with inferior physical health and inferior physical function. PMID- 29143132 TI - Thermostable and highly specific L-aspartate oxidase from Thermococcus litoralis DSM 5473: cloning, overexpression, and enzymological properties. AB - We successfully expressed the L-aspartate oxidase homolog gene (accession no: OCC_06611) of Thermococcus litoralis DSM 5473 in the soluble fraction of Escherichia coli BL21 (DE3) using a pET21b vector with 6X His tag at its C terminus. The gene product (Tl-LASPO) showed L-aspartate oxidase activity in the presence of FAD in vitro, and this report is the first that details an L aspartate oxidase derived from a Thermococcus species. The homologs of Tl-LASPO existed mainly in archaea, especially in the genus of Thermococcus, Pyrococcus, Sulfolobus, and Halobacteria. The quaternary structure of Tl-LASPO was homotrimeric with a subunit molecular mass of 52 kDa. The enzyme activity of Tl LASPO increased with temperature up to 70 degrees C. Tl-LASPO was active from pH 6.0 to 9.0, and its highest activity was at pH 8.0. Tl-LASPO was stable at 80 degrees C for 1 h. The highest k cat/K m value was observed in assays at 70 degrees C. Tl-LASPO was highly specific for L-aspartic acid. Tl-LASPO utilized fumaric acid, 2,6-dichlorophenolindophenol, and ferricyanide in addition to FAD as a cofactor under anaerobic conditions. The absorption spectrum of holo-Tl LASPO exhibited maxima at 380 and 450 nm. The FAD dissociation constant, K d, of the FAD-Tl-LASPO complex was determined to be 5.9 * 10-9 M. PMID- 29143133 TI - Association of DNA repair genes polymorphisms and mutations with increased risk of head and neck cancer: a review. AB - DNA repair mechanisms allow maintain genomic stability and proper functioning within the cells. Any aberrations may cause an increased risk of many diseases such as cancer. The most crucial risk factors for head and neck squamous cell carcinoma are behavioral factors, predominantly chronic exposure to tobacco, alcohol addiction, and infection with human papillomavirus or Epstein-Barr virus. These agents can induce DNA damage; therefore, cells must activate appropriate mechanisms in order to function correctly. Cancer cells are marked with genomic instability, which is associated with a greater tendency for the accumulation of a DNA damage and increased chemo- and radioresistance. Multiple studies have assessed the correlation of increased head and neck cancer (HNC) risk with polymorphism in the DNA repair genes. However, they suggest that interaction of DNA repair genes mutations with susceptibility to HNC depends on a patient's race and risk factors, especially tobacco smoking. Further identification of these sequence variations must be performed. In this review, we discuss the current knowledge about the DNA repair genes mutations and polymorphisms associated with the high risk of head and neck treatment. PMID- 29143134 TI - Reduced population size does not affect the mating strategy of a vulnerable and endemic seabird. AB - Bottleneck episodes may occur in small and isolated animal populations, which may result in decreased genetic diversity and increased inbreeding, but also in mating strategy adjustment. This was evaluated in the vulnerable and socially monogamous Monteiro's Storm-petrel Hydrobates monteiroi, a seabird endemic to the Azores archipelago which has suffered a dramatic population decline since the XVth century. To do this, we conducted a genetic study (18 microsatellite markers) in the population from Praia islet, which has been monitored over 16 years. We found no evidence that a genetic bottleneck was associated with this demographic decline. Monteiro's Storm-petrels paired randomly with respect to genetic relatedness and body measurements. Pair fecundity was unrelated to genetic relatedness between partners. We detected only two cases of extra-pair parentage associated with an extra-pair copulation (out of 71 offspring). Unsuccessful pairs were most likely to divorce the next year, but genetic relatedness between pair mates and pair breeding experience did not influence divorce. Divorce enabled individuals to improve their reproductive performances after re-mating only when the new partner was experienced. Re-pairing with an experienced partner occurred more frequently when divorcees changed nest than when they retained their nest. This study shows that even in strongly reduced populations, genetic diversity can be maintained, inbreeding does not necessarily occur, and random pairing is not risky in terms of pair lifetime reproductive success. Given, however, that we found no clear phenotypic mate choice criteria, the part played by non-morphological traits should be assessed more accurately in order to better understand seabird mating strategies. PMID- 29143135 TI - The mediating role of spirituality (meaning, peace, faith) between psychological distress and mental adjustment in cancer patients. AB - OBJECTIVE: The objectives of this study were (a) to determine the psychometric properties of the Functional Assessment of Chronic Illness Therapy-Spiritual Well Being (FACIT-Sp) scale and (b) to provide that FACIT scores behave one dimensional to establish the mediating role of spiritual well-being in psychological distress and mental adjustment in a sample of patients with non metastatic, resected cancer. METHOD: A total of 504 consecutive patients completed the FACIT-Sp, Brief Symptom Inventory, and Mini-Mental Adjustment to Cancer scales. The dimensionality and structure of the scale were assessed by semi-confirmatory factor analysis; the reliability of the derived scale scores was evaluated using the omega coefficient, and regression analysis appraised the FACIT-Sp's mediating role between psychological distress and mental adjustment. RESULTS: A clear and theoretically interpretable solution in two factors that agreed generally with solutions reported in other languages was obtained for the FACIT item scores and omega reliabilities of the derived Meaning/Peace (0.85) and Faith (0.86) scales were acceptable. The oblique solution in two factors was compatible with an essentially unidimensional solution of general well-being and associated strongly with psychological distress and mental adjustment. Spiritual well-being acted as a partial mediator between psychological distress and mental adjustment strategies, such as fighting spirit, hope, and cognitive avoidance. CONCLUSIONS: The Spanish version of the FACIT-Sp scale is a reliable and valid clinical evaluation tool, and further highlights the potential clinical implications of spirituality for improving quality of life and adjustment to cancer. PMID- 29143136 TI - Investigation of arginine A-specific cysteine proteinase gene expression profiling in clinical Porphyromonas gingivalis isolates against photokilling action of the photo-activated disinfection. AB - Porphyromonas gingivalis is a significant root canal pathogen capable of causing endodontic infections, which during their treatment may receive sub-lethal doses of photo-activated disinfection (sPAD). As sPAD can influence microbial virulence, this study was designed to evaluate the effect of sPAD on gene expression level of arginine A-specific cysteine proteinase (rgpA), as one of the underlying virulence factors involved in the development of endodontic infection via P. gingivalis strains. To find out the sPAD against 16 clinical isolates of PAD-resistant P. gingivalis that were isolated in vivo, we used toluidine blue O (TBO), methylene blue (MB), and indocyanine green (ICG) as the photosensitizers, which were excited with specific wavelength of light in vitro. Quantitative real time PCR (qRT-PCR) was then applied to monitor gene expression of rgpA in P. gingivalis isolates to characterize its virulence agent and understand the effect of sPAD on its pathogenicity. Maximal sPAD that could not decrease the count of P. gingivalis isolates were 6.25, 15.6, and 25 MUg/mL at fluencies of 171.87, 15.6, and 93.75 J/cm2 for TBO, ICG, and MB, respectively. ICG-sPAD could suppress the rgpA gene expression about 14-fold, while MB and TBO-mediated sPAD could cause the attenuation of rgpA expression about 4.9- and 11.6-fold, respectively. ICG-sPAD with the maximum ability to reduce rgpA gene expression compared with other photosensitizers can be an appropriate candidate for the treatment of endodontic infections. PMID- 29143137 TI - Segmental biventricular analysis of myocardial function using high temporal and spatial resolution tissue phase mapping. AB - OBJECTIVE: Myocardial dysfunction of the right ventricle (RV) is an important indicator of RV diseases, e.g. RV infarction or pulmonary hypertension. Tissue phase mapping (TPM) has been widely used to determine function of the left ventricle (LV) by analyzing myocardial velocities. The analysis of RV motion is more complicated due to the different geometry and smaller wall thickness. The aim of this work was to adapt and optimize TPM to the demands of the RV. MATERIALS AND METHODS: TPM measurements were acquired in 25 healthy volunteers using a velocity-encoded phase-contrast sequence and kt-accelerated parallel imaging in combination with optimized navigator strategy and blood saturation. Post processing was extended by a 10-segment RV model and a detailed biventricular analysis of myocardial velocities was performed. RESULTS: High spatio-temporal resolution (1.0 * 1.0 * 6 mm3, 21.3 ms) and the optimized blood saturation enabled good delineation of the RV and its velocities. Global and segmental velocities, as well as time to peak velocities showed significant differences between the LV and RV. Furthermore, complex timing of the RV could be demonstrated by segmental time to peak analysis. CONCLUSION: High spatio-temporal resolution TPM enables a detailed biventricular analysis of myocardial motion and might provide a reliable tool for description and detection of diseases affecting left and right ventricular function. PMID- 29143138 TI - [Pseudarthroses of the long bones]. AB - Pseudarthrosis development is dependent on the presence of individual risk factors in approximately 10% as a result of fractures and are more frequently located in the region of the long bones. The development of non-union regularly results in prolonged pain and reduced functionality of the affected limb. The resulting clearly increased socioeconomic costs are caused by the complex operative treatment strategies and increased indirect costs, which include lost wages, social benefits and compensation. Altogether, non-unions require a differentiated therapeutic treatment strategy. The analysis of the non-union based on the diamond concept is the key for a successful planning and therapy. In this context, the use of focused, high-energy extracorporeal shock waves may be possible under specific circumstances; however, in most cases an operative revision is necessary to optimize the biomechanical stability and/or improve the local biology. PMID- 29143139 TI - Effect of protein adsorption layers and solution treatments on hydroxyapatite deposition on polystyrene plate surfaces in simulated body fluids. AB - We have developed a method to functionalize polystyrene (PS) cell culture plates with hydroxyapatite (HAp) via protein adsorption layers such as human serum albumin (HSA) in simulated body fluids (SBFs). In order to investigate the versatility the method, in this study the effect of protein adsorption layers on HAp deposition on PS plate surfaces in SBF was evaluated. Pretreatments with alternate soaking process (ASP) using solutions containing calcium ions and phosphate ions followed by incubation with SBF for 24 h resulted in HAp deposition on PS plates with adsorption layers of HSA, type I collagen, hen egg white lysozyme, and poly L-glutamic acid, an acidic protein analogue: the deposition behaviors were correlated with adsorption ability and charge state of proteins. We also demonstrated that commercially available tissue culture-treated PS (TCPS) were directly coated with bone-like HAp using the same ASP and SBF processes. Human mesenchymal stem cells adhered and stretched on the HAp-coated TCPS plates in a similar manner to the case of the HAp-coated PS plates prepared via HSA adsorption layers. The results indicate that the present methods are useful for preparing bone-like HAp-coated cell culture plates that can be utilized function of adsorbed proteins and that are obtainable conveniently and at low-cost. PMID- 29143140 TI - Impact of Conventional Medical Therapy on Bone Mineral Density and Bone Turnover in Adult Patients with X-Linked Hypophosphatemia: A 6-Year Prospective Cohort Study. AB - X-linked hypophosphatemia (XLH) is a rare, inheritable disorder manifesting as rickets in children and osteomalacia in adults. While conventional medical treatment with oral phosphate and alfacalcidol is recommended in childhood, it is undecided whether adults should continue therapy. The aim of this 6-year prospective study was to determine the impact of conventional medical treatment on areal bone mineral density (aBMD), bone turnover markers (BTMs) and measures of calcium homeostasis in 27 adult patients with XLH, 11 of whom received medical treatment. Lumbar spine and total hip aBMD, as assessed by DXA, and biochemical measures of calcium, phosphate, PTH, 1,25 dihydroxyvitamin D2+3 (1,25(OH)2D), fibroblast growth factor 23 (FGF23), P1NP and CTX were measured at baseline and at follow-up. The renal tubular reabsorption of PO4 (TmPO4/GFR) was calculated at both time points. Multilevel mixed-effects linear regression models were used for analyses. During the study period, spine and hip aBMD did not change significantly between treated and non-treated XLH patients. There was a trend towards a decrease in calcium, phosphate and TmPO4/GFR in the treatment group (p = 0.057, p = 0.080 and p = 0.063, respectively), whereas PTH, FGF23, 1,25(OH)2D and P1NP did not change significantly in either groups. However, CTX increased significantly in the treated compared to non-treated group (p = 0.044). Continuing conventional medical therapy in adulthood, although associated with increased bone resorption, does not promote or prevent loss of bone mass as evidenced from the stable aBMD of the hip and spine in XLH patients. PMID- 29143141 TI - Prevalence and genomic characteristics of canine kobuvirus in southwest China. AB - To investigate canine kobuvirus (CaKoV) infection in southwest China, 107 fecal samples were collected from dogs with obvious diarrhea in Sichuan and Chongqing regions, China. CaKoV infection was detected in 54 diarrheic samples (50.46%) by RT-PCR targeting a partial fragment (504 bp) of the 3D gene. Comparison of these partial 3D gene sequences from 14 of these CaKoV-positive samples show 95.4% 99.0% nucleotide (nt) identity within this group, and nt identities ranging from 93.1% to 98.2% with previously reported CaKoV 3D gene sequences. Additionally, we amplified five VP1 gene sequences and analyzed the inferred phylogeny. Amino acid (aa) identities of the five VP1 gene sequences were 81.5%-89.4% with those previously reported. Furthermore, one complete CaKoV genome was successfully obtained from a positive sample and designated SMCD-59/CHN/2015. This genome consisted of 8,184 nt, and shared 92.9%-96.6% nt identity (97.6%-98.1% aa identity) with other reported CaKoV genomes. This study provides proof that CaKoV circulates in diarrheic dogs in southwest China, and that these viruses exhibit unique genetic characteristics. PMID- 29143142 TI - Prevalence of NS5B resistance-associated variants in treatment-naive Asian patients with chronic hepatitis C. AB - There is little information on the association between baseline non-structural protein (NS) 5b resistance-associated variants (RAVs) and treatment failure in hepatitis C patients. This study examined the frequencies of natural hepatitis C virus (HCV) NS5B resistance-associated variants (RAVs) in an Asian cohort. Samples from Asian HCV patients enrolled between October 2009 and September 2014 were analyzed for NS5B RAVs within the region from amino acid 230 to 371. Serum samples were tested by PCR genotyping, with sequence alignment performed using the neighbor-joining method. NS5B was detected by Sanger sequencing followed by Geno2pheno analysis. NS5B RAVs were detected in 80.52% (1199/1489) of patients; 68.4% (1019/1489) and 79.7% (1186/1489) were associated with resistance to sofosbuvir (SOF) and dasabuvir (DSV), respectively. These RAVs were present in 95% (1004/1058) of genotype 1b patients. When genotypes 1b and 2a were compared, SOF-associated RAVs were detected at a higher frequency in genotype 1b (94.8% [1004/1058] vs. 2.9% [9/309]; chi2 = 1054.433, P < 0.001), C316H/N was more common in genotype 1b (94.7% [1002/1058] vs. 0% [0/309]; chi2 = 1096.014, P < 0.001), M289F/L/I/W/V had a higher frequency in genotype 2a (0.7% [7/309] vs. 2.3% [7/1058]; chi2 = 4.589, P = 0.032), DSV-associated RAVs were most often found in genotype 1b (95.0% [1005/1058] vs. 40.1% 124/309]; chi2 = 500.577, P < 0.001), and frequency of C316Y/H/N/W was higher in genotype 1b (94.7% [1002/1058] vs. 0% [0/309]; chi2 = 1096.014, P < 0.001). In conclusion, baseline SOF and DSV RAVs are common in Asian HCV patients and predominantly occur in genotype 1b. PMID- 29143143 TI - Soil respiration patterns and rates at three Taiwanese forest plantations: dependence on elevation, temperature, precipitation, and litterfall. AB - BACKGROUND: Soil respiration contributes to a large quantity of carbon emissions in the forest ecosystem. In this study, the soil respiration rates at three Taiwanese forest plantations (two lowland and one mid-elevation) were investigated. We aimed to determine how soil respiration varies between lowland and mid-elevation forest plantations and identify the relative importance of biotic and abiotic factors affecting soil respiration. RESULTS: The results showed that the temporal patterns of soil respiration rates were mainly influenced by soil temperature and soil water content, and a combined soil temperature and soil water content model explained 54-80% of the variation. However, these two factors affected soil respiration differently. Soil temperature positively contributed to soil respiration, but a bidirectional relationship between soil respiration and soil water content was revealed. Higher soil moisture content resulted in higher soil respiration rates at the lowland plantations but led to adverse effects at the mid-elevation plantation. The annual soil respiration rates were estimated as 14.3-20.0 Mg C ha-1 year-1 at the lowland plantations and 7.0-12.2 Mg C ha-1 year-1 at the mid-elevation plantation. When assembled with the findings of previous studies, the annual soil respiration rates increased with the mean annual temperature and litterfall but decreased with elevation and the mean annual precipitation. A conceptual model of the biotic and abiotic factors affecting the spatial and temporal patterns of the soil respiration rate was developed. Three determinant factors were proposed: (i) elevation, (ii) stand characteristics, and (iii) soil temperature and soil moisture. CONCLUSION: The results indicated that changes in temperature and precipitation significantly affect soil respiration. Because of the high variability of soil respiration, more studies and data syntheses are required to accurately predict soil respiration in Taiwanese forests. PMID- 29143144 TI - Carcinosarcoma of the ovary compared to ovarian high-grade serous carcinoma: impact of optimal cytoreduction and standard adjuvant treatment. AB - OBJECTIVE: The purpose of this retrospective study was to compare the prognoses of women with ovarian carcinosarcoma (OCS) who had optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy to those of women with ovarian high-grade serous carcinoma (HGSC) treated in the same manner. METHODS: A multicenter, retrospective department database review was performed to identify patients with OCS at eight gynecologic oncology centers in Turkey. A total of 54 women with OCS who had undergone optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy between 1999 and 2017 were included in this case-control study. Each case was matched to two women with ovarian HGSC who had undergone optimal cytoreductive surgery followed by platinum plus taxane combination chemotherapy. The Kaplan-Meier method was used to generate survival data. Factors predictive of outcome were analysed using Cox proportional hazards models. RESULTS: Median disease-free survival (DFS) was 29 months [95% confidence interval (CI) 0-59, standard error (SE) 15.35] versus 27 months (95% CI 22.6 31.3, SE 2.22; p = 0.765) and median overall survival (OS) was 62 versus 82 months (p = 0.53) for cases and controls, respectively. For the entire cohort, the presence of ascites [hazard ratio (HR) 2.32; 95% CI 1.02-5.25, p = 0.04] and platinum resistance [HR 5.05; 95% CI 2.32-11, p < 0.001] were found to be independent risk factors for decreased OS. CONCLUSION: DFS and OS rates of patients with OCS and HGSC seem to be similar whenever optimal cytoreduction is achieved and followed by platinum plus taxane combination chemotherapy. PMID- 29143145 TI - Duration of viral shedding and factors associated with prolonged shedding among inpatients with influenza treated with oseltamivir: a prospective cohort study. AB - The purpose of this study was to determine the rate of decline in the diagnostic yield of influenza PCR assay after oseltamivir administration, and to identify risk factors for prolonged shedding. This was a prospective observational study. We included adult inpatients with clinical signs of influenza during the influenza seasons 2015 and 2016, who had positive influenza PCR tests and who were treated with oseltamivir. Clinical follow-up and repeat PCR testing were performed on days 2, 4 and 6 after the first positive test. We defined prolonged shedders as patients who still required hospitalization and had a positive PCR assay on day 4. Risk factors for prolonged shedding were assessed in univariate and multivariate analyses. A total of 215 patients were included in our study. The median age was 64 years and 49.3% were men. The main influenza type was H1N1 (50.1%). Rates of PCR positivity among evaluable patients on days 2, 4 and 6 were 142/215 (66%), 50/78 (64.1%) and 20/30 (66.6%), respectively. Independent risk factors for prolonged shedding (50 patients) included hypoxemia [odds ratio (OR) 2.55, 95% confidence interval (1.3-5.1)] and lower diastolic blood pressure [OR 0.94, 95% CI (0.92-0.97)] on admission. Negative PCR tests taken more than 48 h after initiation of treatment had low diagnostic yield. More severe disease, manifested by hypoxemia and lower blood pressure, is associated with prolonged shedding on oseltamivir treatment. PMID- 29143146 TI - Screening transferable microsatellite markers across genus Phalaenopsis (Orchidaceae). AB - BACKGROUND: Molecular identification based on microsatellite loci is an important technology to improve the commercial breeding of the moth orchid. There are more than 30,000 cultivars have been enrolled at the Royal Horticultural Society (RHS). In this study, genomic microsatellite primer sets were developed from Phalaenopsis aphrodite subsp. formosana to further examine the transferability of across 21 Phalaenopsis species. METHODS AND RESULTS: Twenty-eight polymorphic microsatellite markers were obtained using the magnetic bead enrichment method, with high transferability of the 21 species of the genus Phalaenopsis, especially in the subgenus Phalaenopsis. The 28 newly developed polymorphic microsatellite markers with high polymorphism information content values. The best and second fit grouping (K) are inferred as two and four by the DeltaK evaluation in the assignment test. This result indicates that these microsatellite markers are discernible to subgenus Phalaenopsis. CONCLUSIONS: Our results indicate that these new microsatellite markers are useful for delimiting species within genus Phalaenopsis. As expected, the genetic relationships between species of subgenus Phalaenopsis can be well distinguished based on the assignment test. These molecular markers could apply to assess the paternity of Phalaenopsis as well as investigating hybridization among species of genus Phalaenopsis. PMID- 29143147 TI - [ESC guidelines 2017 on peripheral arterial diseases : Summary of the most important recommendations and innovations]. AB - The current European Society of Cardiology (ESC) guidelines on peripheral arterial diseases include recommendations on diagnostics and treatment of atherosclerotic manifestations in peripheral arteries. Because of the high coincidence of atherosclerosis in different arterial territories, screening for other atherosclerotic lesions is necessary in patients with clinical symptoms in one vascular bed. Consistent treatment of cardiovascular risk factors is important in all patients with peripheral atherosclerosis. This includes smoking cessation, statin therapy and control of blood pressure and blood glucose. All patients with carotid artery stenosis should be treated with antiplatelet drugs. In patients with symptomatic carotid artery stenosis and low periprocedural risk, early revascularization is recommended when the degree of stenosis is more than 50%. In asymptomatic carotid artery stenosis revascularization should only be considered if the risk for cerebral embolization is high and the periprocedural risk is low. Patients with peripheral arterial occlusive disease should only be treated with an antiplatelet drug if they are symptomatic. In cases of intermittent claudication supervised exercise training is strongly recommended. When activities of daily life are compromised despite training, revascularization by endovascular therapy first should be considered. In chronic limb-threatening ischemia early revascularization should be considered, preferably by venous bypass surgery. In patients with arterial hypertension and specific risk factors screening for renal artery stenosis is recommended. Particularly in patients with atherosclerotic renal artery stenosis, the indications for revascularization should be assessed very carefully. PMID- 29143148 TI - Antecedent diffuse cerebellar lesions on diffusion-weighted MRI in nonalcoholic Wernicke's encephalopathy. PMID- 29143149 TI - Effects of intraspecific and intra-individual differences in plant quality on preference and performance of monophagous aphid species. AB - Plant chemistry is one of the main drivers of herbivore distribution. Monophagous herbivore species are highly specialized, but even within their only host species the chemistry varies. The herbivore's choice is initially mainly guided by volatile plant compounds. Once on the plant, particularly for aphids the phloem quality affects their performance. However, little is known about the intraspecific and intra-individual variation in phloem sap and their influences on monophagous aphids. To determine potential mechanisms involved in aphid colonization, we tested the effects of intraspecific chemical variation in Tanacetum vulgare, which produces different chemotypes, on the preference of two monophagous aphid species. Moreover, we measured the performance of the aphids on different plant parts (stem close to the inflorescence, young and old leaves) of these chemotypes and analyzed their phloem sap composition. Both species preferred the beta-thujone (THU) over the trans-carvyl acetate (CAR) chemotype in dual-choice assays. Survival of Macrosiphoniella tanacetaria was neither affected by intraspecific nor intra-individual variation, whereas the reproduction was highest on stems. In contrast, Uroleucon tanaceti survived and reproduced best on old leaves of the preferred chemotype. The sugar, organic acid and amino acid composition pronouncedly differed between phloem exudates of different plant parts, but less between chemotypes. Unexpectedly, high concentrations of amino acids did not necessarily enhance aphid performance. These different performance optima may cause niche differentiation and, therefore, enable co-existence. In conclusion, the tremendous variation in plant chemistry even within one species can affect the distribution of highly specialized aphids at various scales aphid species-specifically. PMID- 29143150 TI - The impact of sea ice conditions on breeding decisions is modulated by body condition in an arctic partial capital breeder. AB - Determining how environmental conditions interact with individual intrinsic properties is important for unravelling the underlying mechanisms that drive variation in reproductive decisions among migratory species. We investigated the influence of sea ice conditions and body condition at arrival on the breeding propensity, i.e. the decision to reproduce or not within a single breeding season, and timing of laying in migrating common eiders (Somateria mollissima) breeding in the Arctic. Using Radarsat satellite images acquired from 2002 to 2013, we estimated the proportion of open water in the intertidal zone in early summer to track the availability of potential foraging areas for pre-breeding females. Timing of ice-breakup varied by up to 20 days across years and showed strong relationship with both breeding propensity and the timing of laying of eiders: fewer pre-breeding individuals were resighted nesting in the colony and laying was also delayed in years with late ice-breakup. Interestingly, the effect of sea ice dynamics on reproduction was modulated by the state of individuals at arrival on the breeding grounds: females arriving in low condition were more affected by a late ice-breakup. Open water accessibility in early summer, a likely proxy of food availability, is thus crucial for reproductive decisions in a (partial) capital breeder. Our predictive capacity in determining how Arctic breeding seabirds respond to changes in environmental conditions will require incorporating such cross-seasonal cumulative effects. PMID- 29143151 TI - Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment. AB - The clinical success of anti-CD20 monoclonal antibody (mAb)-mediated B cell depletion therapy has contributed to the understanding of B cells as major players in several autoimmune diseases. The first therapeutic anti-CD20 mAb, rituximab, is a murine-human chimera to which many patients develop antibodies and/or experience infusion-related reactions. A second generation of anti-CD20 mAbs has been designed to be more effective, better tolerated, and of lower immunogenicity. These include the humanized versions: ocrelizumab, obinutuzumab, and veltuzumab, and the fully human, ofatumumab. We conducted a literature search of relevant randomized clinical trials in the PubMed database and ongoing trials in Clinicaltrials.gov. Most of these trials have evaluated intravenous ocrelizumab or subcutaneous ofatumumab in rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus. Understanding how newer anti-CD20 mAbs compare with rituximab in terms of efficacy, safety, convenience, and cost is important for guiding future management of anti-CD20 mAb therapy in autoimmune diseases. PMID- 29143152 TI - Electrochemical and theoretical studies of the interactions of a pyridyl-based corrosion inhibitor with iron clusters (Fe15, Fe30, Fe45, and Fe60). AB - The capacity of 2,6-bis[((2-pyridylmethyl)oxy)methyl)]pyridine (BPMMP) to inhibit the corrosion of mild carbon steel in HCl was analyzed. In a polarization study, both the cathodic and anodic currents were appreciably decreased in the presence of BPMMP, suggesting that this ligand is effective at inhibiting corrosion at the metal surface. This conclusion is consistent with the results of impedance analysis, where only one time constant corresponding to one depressed capacitive loop was detected, and the diameter of the impedance plot was directly related to the concentration of BPMMP. Furthermore, when recurrence analysis was performed, a decrease in regular noise was observed due to the change of Shannon entropy when the inhibitor was present in the corrosive medium, showing that a high degree of recurrence increases the entropy of the system. Electrochemical data on some pyridyl-based inhibitors were collected from the literature and used to plot (i) I corr (A/cm2) vs. inhibition efficiency (eta%) and (ii) DeltaG degrees ads vs. inhibition efficiency (n%) in order to examine the general relationships between these parameters. Furthermore, the interactions of the ligand BPMMP with different iron clusters (Fe15, Fe30, Fe45, and Fe60) were analyzed theoretically using density functional theory (DFT). The structural and electronic properties of BPMMP and its protonated form BPMMPH+ were studied before and after the interactions of BPMMP with the iron clusters. The first protonation was found to occur at pyridine nitrogen atom N1, resulting in a Gibbs free energy DeltaG of 10.2 kcal/mol, with an energy difference of 5.3 kcal/mol between the two possible protonated conformers. Graphical abstract Recurrence and Noise signal performance of BPMMP as corrosion inhibitor. PMID- 29143153 TI - Statewide mental health training for probation officers: improving knowledge and decreasing stigma. AB - BACKGROUND: The large and growing number of probationers with mental illnesses pose significant challenges to the probationer officers who supervise them. Stigma towards mental illnesses among probation officers is largely unstudied and the effectiveness of training initiatives designed to educate probation officers about mental illness is unknown. To address these gaps in the literature, we report findings from a statewide mental health training initiative designed to improve probation officers' knowledge of mental illnesses. A single-group pretest posttest design was used and data about stigma towards mental illnesses and knowledge of mental illnesses were collected from 316 probation officers. Data were collected prior to and shortly after officers viewed a series of educational training modules about mental illnesses. RESULTS: Officers' knowledge of mental illnesses increased and officers demonstrated lower levels of stigma towards persons with mental illnesses as evidenced by scores on a standardized scale. CONCLUSION: Mental health education can help decrease stigma and increase knowledge of mental illnesses among probation officers. More research is needed to assess the impact of these trainings on probationers' mental health and criminal justice outcomes. PMID- 29143154 TI - Deciphering the molecular events during arsenic induced transcription signal cascade activation in cellular milieu. AB - Anthropogenic sources of arsenic poses and creates unintentional toxico pathological concerns to humans in many parts of the world. The understanding of toxicity of this metalloid, which shares properties of both metal and non-metal is principally structured on speciation types and holy grail of toxicity prevention. Visible symptoms of arsenic toxicity include nausea, vomiting, diarrhea and abdominal pain. In this review, we focused on the dermal cell stress caused by trivalent arsenic trioxide and pentavalent arsanilic acid. Deciphering the molecular events involved during arsenic toxicity and signaling cascade interaction is key in arsenicosis prevention. FoxO1 and FoxO2 transcription factors, members of the Forkhead/Fox family, play important roles in this aspect. Like Foxo family proteins, ATM/CHK signaling junction also plays important role in DNA nuclear factor guided cellular development. This review will summarize and discuss current knowledge about the interplay of these pathways in arsenic induced dermal pathogenesis. PMID- 29143155 TI - Language and social-emotional and behavioural wellbeing from 4 to 7 years: a community-based study. AB - Language disorder (LD) and social-emotional and behavioural (SEB) difficulties are common childhood problems that often co-occur. While there is clear evidence of these associations from clinical samples, less is known about community samples. This paper examines these associations in children aged 4-7 years from a community-based longitudinal study. 771 families provided questionnaire and assessment data at 4, 5 and 7 years. Parent-reported SEB difficulties were measured at each point (SDQ). Child language was directly assessed at 4 (CELF P2), 5 and 7 years (CELF-4). Linear regression analysis was used to compare cross sectional differences in mean SDQ scores between children with and without LD at each time point. Linear regression was then used to examine how patterns of language development (language disordered at three time points; never disordered; disordered at one or two time points, i.e. 'unstable' group) related to SEB difficulties at each age, adjusted for potential confounders, as in the previous analyses. Higher hyperactivity/inattention scores were associated with LD at each age. In fully adjusted models, there was little difference in mean emotional symptoms scores between children with and without LD. The 'never' LD group had lower mean SDQ scores at each time point than the 'unstable' group. Findings highlight that children with persistent LD from preschool to early primary school may be more likely to have concomitant SEB difficulties, particularly behavioural difficulties. Those with unstable LD may also have co-occurring SEB difficulties, showing a need for education and health professionals to monitor early language and SEB development. PMID- 29143156 TI - Social Distance and Community Attitudes Towards People with Psycho-Social Disabilities in Uttarakhand, India. AB - Stigma is an important contributor to the large treatment gap for people with mental and psycho-social disabilities (PPSD) in India. Social distance as assessed by willingness to engage in relationships with PPSD is a proxy measure of stigma and potential discrimination. In North India, investigations of community attitudes towards PPSD have been limited. To describe attitudes towards people with depression and psychosis, a community sample of 960 adults in Dehradun district, India from 30 randomised clusters, was surveyed using a validated tool to assess social distance, beliefs and attitudes related to mental illness. Participants preferred greater social distance from a person with psychosis than a person with depression. Beliefs and attitudes around mental illness were diverse reflecting a wide spread of belief frameworks. After controlling for confounding, there was increased social distance among people who believed PPSD were dangerous. Factors that reduced social distance included familiarity with PPSD, and belief that PPSD can recover. Attitudes to PPSD, stigma and social distance are complex and likely to require complex responses that include promoting awareness of mental health and illness, direct contact with PPSD and increasing access to care for PPSD. PMID- 29143157 TI - Evaluation of HIV Disclosure Behavior Following a Randomized Controlled Disclosure Intervention for Men Who Have Sex with Men Living with HIV. AB - Preventing the transmission of HIV, especially among high-risk populations, is a U.S. public health priority. Interventions aimed at easing the burden of HIV disclosure to casual sexual partners among men who have sex with men (MSM) living with HIV are essential in this endeavor. This randomized controlled study evaluated differences in disclosure behavior between a disclosure intervention (DI) and attention control case management (ACCM) group for MSM living with HIV (N = 315) and determinants (self-efficacy, outcome expectancy) of disclosure. Mixed-effects models results showed no significant differences in disclosure behavior between the DI and ACCM groups. Further, disclosure behavior changed in a curvilinear manner over 12 months and benefited from a booster session. Both disclosure self-efficacy and outcome expectancy predicted disclosure behavior. Interventions targeting HIV disclosure among MSM living with HIV should focus on improving perceptions of disclosure self-efficacy and outcome expectancy and include a booster session to facilitate HIV disclosure. PMID- 29143158 TI - Being a Young Migrant in Italy: The Effect of Perceived Social Support in Adolescence. AB - Parental and peer support seems to be a favourable determining factor in the acculturation process among young immigrants. We aimed to assess the level of perceived support among first- and second-generation adolescent immigrants and compare it to that perceived by the adolescents from the host population. Using Italian HBSC survey data collected in 2013-2014, first- and second-generation immigrants aged 11, 13 and 15 years were classified according to their ethnic background as being from Western countries, Eastern European countries, or from non-Western/non-European countries. The domains of teacher, classmate, family, and peer support was measured through multidimensional, standardised, validated scales. Analyses were run on a 47,399 valid responses (2195 from Western countries, 2424 from Eastern European countries, and 2556 from non-Western/non European countries). Adolescent immigrants from Eastern European countries and non-Western/non-European countries reported significantly lower support than their peers from the host population in all explored domains. Girls perceived a lower level of classmate and family support compared to boys across all ethnic backgrounds. We observed two different immigration patterns: the Western pattern, from more affluent countries, and the Eastern pattern. Among the latter, second generation immigrants showed the lowest level of support in all domains. Increasing family connections and developing peer networks should favour the acculturation process among adolescent immigrants. PMID- 29143159 TI - Six-year outcome in subjects diagnosed with attention-deficit/hyperactivity disorder as adults. AB - There are very few studies on the long-term outcome in subjects diagnosed with ADHD as adults. The objective of the present study was to assess this and relate the outcome to whether there was current medication or not and to other potential predictors of favourable outcome. A prospective clinical cohort of adults diagnosed with ADHD according to DSM-IV criteria was followed-up on an average of 6 years after first evaluation (n = 124; mean age 42 years, 51% males). ADHD symptom trajectories were assessed as well as medication, global functioning, disability, health-related quality of life, and alcohol and drug consumption at follow-up. Ninety percent of those diagnosed were initially treated pharmacologically and half of them discontinued treatment. One-third reported remission, defined as not fulfilling any ADHD subtype and a GAF-value last year >= 70, which was not affected by comorbidity at baseline. Current medication was not associated with remission. Subjects evaluated and first diagnosed with ADHD as adults are functionally improved at follow-up 6 years later despite a high percentage of psychiatric comorbidity at baseline. Half dropped out of medication, and there was no difference in ADHD remission between subjects with on-going medication at follow-up or subjects without medication, although current medication was related to a higher degree of self-reported global improvement. PMID- 29143160 TI - Solvent-free synthesis and anticancer activity evaluation of benzimidazole and perimidine derivatives. AB - Benzimidazoles and perimidines are subsidiary structures for research and development of new biologically active molecules and have established prominence because of their promising biological activities. Two series of diversified heterocyclic molecules, tetracyclic benzimidazole derivatives, tetracyclic and pentacyclic perimidine derivatives have been synthesized in good yields by condensation of acid anhydrides and diacids with various diamines using microwave irradiation. All synthesized derivatives were fully characterized and evaluated for in vitro antiproliferative activity against five human cancer cell lines. Compounds 3a (breast T47D, lung NCl H-522), 3b (colon HCT-15), 3d (lung NCl H 522, ovary PA-1), 3f (breast T47D, liver HepG2) and 5a (breast T47D) exhibited good anticancer activity with [Formula: see text] values ranging from [Formula: see text] to [Formula: see text]. PMID- 29143162 TI - Anti-retroviral Status and HIV Transmission Risk Behaviors are Associated with Age, Time Since Diagnosis, and Psychosocial Factors Among Women Living with HIV/AIDS Enrolling in the WILLOW Intervention at Community-Based Organizations. AB - Safe sexual behaviors and anti-retroviral use help prevent HIV transmission. In this cross-sectional study, we assessed correlates of anti-retroviral (ART) status and transmission risk (a constructed variable) among a convenience sample of n = 1041 HIV-positive women (pre-intervention) enrolled in an evidence-based intervention at four CBOs. Multinomial logistic regression models were used. Younger women and those diagnosed with HIV in the last 5 years more often reported that they had not been prescribed ART. Self-reported non-adherence to ART was less frequently reported among women who were older, had a higher HIV knowledge, and those with attitudes/beliefs supportive of condom use. The highest risk transmission group (condomless sex with HIV-negative/unknown partner and not prescribed or non-adherent to ART) was associated with younger age, attitudes/beliefs less supportive of condom use, and low self-efficacy discussing condom use. Our findings inform HIV prevention efforts among similar populations of HIV-positive women enrolled in interventions at CBOs. PMID- 29143161 TI - Point-of-care B-type natriuretic peptide and portable echocardiography for assessment of patients with suspected heart failure in primary care: rationale and design of the three-part Handheld-BNP program and results of the training study. AB - BACKGROUND: Patients with suspected heart failure (HF) often present first to general practitioners (GPs). Timely and accurate HF diagnosis and reliable prognostic information have remained unmet goals in primary care, where patient evaluation often relies on clinical assessment only. The Handheld-BNP program investigates whether additional use of portable echocardiography (ECHO) and point of-care determination of B-type natriuretic peptide (BNP) improves the accuracy of HF diagnosis and aids risk prediction in primary care. METHODS AND RESULTS: A research network was established between 2 academic centers, 2 * 6 cardiologists, and 2 * 24 GPs inexperienced with ECHO and BNP. The Training Study investigates the feasibility of implementing GP use and interpretation of ECHO and BNP. After training, competence is assessed using multiple-choice testing (pass mark: > 80% correct diagnoses). In the cluster-randomized four-arm Screening Study, each GP passes in random order through four study arms: clinical assessment (CA), CA + BNP, CA + ECHO, and CA + ECHO + BNP. Cardiologists' diagnoses serve as reference. Primary endpoint is the rate of correct GP diagnoses per study arm. In the Prognostic Follow-Up Study, patients are followed up centrally for 72 months. Forty-four GPs were successfully trained. With 225 +/- 34 (75 +/- 3) and 233 +/- 28 (81 +/- 7) min, respectively, total ECHO (BNP) training times were similar between centers I and II. Furthermore, training results did not differ between centers. CONCLUSIONS: Standardized training of limited duration enabled GPs to use ECHO and BNP for HF diagnosis. The Handheld-BNP program will provide robust evaluation of the diagnostic effectiveness and prognostic value of these tools in primary care. TRIAL REGISTRATION: http://www.controlled-trials.com (ISRCTN23325295). PMID- 29143163 TI - Sex, PrEP, and Stigma: Experiences with HIV Pre-exposure Prophylaxis Among New York City MSM Participating in the HPTN 067/ADAPT Study. AB - The HPTN 067/Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking (ADAPT) study evaluated daily and non-daily dosing schedules for oral pre exposure prophylaxis (PrEP) to prevent HIV. A qualitative sub-study including focus groups and in-depth interviews was conducted among men who have sex with men participating in New York City to understand their experience with PrEP and study dosing schedules. The 37 sub-study participants were 68% black, 11% white, and 8% Asian; 27% were of Hispanic/Latino ethnicity. Mean age was 34 years. Themes resulting from qualitative analysis include: PrEP is a significant advance for HIV prevention; non-daily dosing of PrEP is congruent with HIV risk; and pervasive stigma connected to HIV and risk behavior is a barrier to PrEP adherence, especially for non-daily dosing schedules. The findings underscore how PrEP intersects with other HIV prevention practices and highlight the need to understand and address multidimensional stigma related to PrEP use. PMID- 29143164 TI - Upregulation of Myelin Gene Expression by a Physically-Modified Saline via Phosphatidylinositol 3-Kinase-Mediated Activation of CREB: Implications for Multiple Sclerosis. AB - An increase in central nervous system (CNS) remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis (MS). RNS60 is a bioactive aqueous solution generated by subjecting normal saline to Taylor-Couette-Poiseuille flow under elevated oxygen pressure. Recently we have demonstrated that RNS60 exhibits anti-inflammatory properties. Here, we describe promyelinating property of RNS60. RNS60, but not normal saline (NS), RNS10.3 (TCP-modified saline without excess oxygen) or PNS60 (saline containing excess oxygen without TCP modification), stimulated the expression of myelin specific genes and proteins (myelin basic protein, MBP; myelin oligodendrocyte glycoprotein, MOG and proteolipid protein, PLP) in primary mouse oligodendroglia and mixed glial cells. While investigating the mechanisms, we found that RNS60 treatment induced the activation of cAMP response element binding protein (CREB) in oligodendrocytes, ultimately leading to the recruitment of CREB to the promoters of myelin-specific genes. Furthermore, activation of type 1A p110beta/alpha, but not type 1B p110gamma, phosphatidylinositol-3 (PI-3) kinase by RNS60 together with abrogation of RNS60-mediated activation of CREB and upregulation of myelin genes by LY294002 (a specific inhibitor of PI-3 kinase) suggest that RNS60 upregulates the activation of CREB and the expression of myelin-specific molecules in oligodendrocytes via activation of PI3 kinase. These results highlight a novel promyelinating property of RNS60, which may be of benefit for MS and other demyelinating disorders. PMID- 29143166 TI - The time has come; good-bye to all this. PMID- 29143165 TI - Structure of monomeric Interleukin-8 and its interactions with the N-terminal Binding Site-I of CXCR1 by solution NMR spectroscopy. AB - The structure of monomeric human chemokine IL-8 (residues 1-66) was determined in aqueous solution by NMR spectroscopy. The structure of the monomer is similar to that of each subunit in the dimeric full-length protein (residues 1-72), with the main differences being the location of the N-loop (residues 10-22) relative to the C-terminal alpha-helix and the position of the side chain of phenylalanine 65 near the truncated dimerization interface (residues 67-72). NMR was used to analyze the interactions of monomeric IL-8 (1-66) with ND-CXCR1 (residues 1-38), a soluble polypeptide corresponding to the N-terminal portion of the ligand binding site (Binding Site-I) of the chemokine receptor CXCR1 in aqueous solution, and with 1TM-CXCR1 (residues 1-72), a membrane-associated polypeptide that includes the same N-terminal portion of the binding site, the first trans membrane helix, and the first intracellular loop of the receptor in nanodiscs. The presence of neither the first transmembrane helix of the receptor nor the lipid bilayer significantly affected the interactions of IL-8 with Binding Site-I of CXCR1. PMID- 29143167 TI - Effectiveness of concurrent procedures during high tibial osteotomy for medial compartment osteoarthritis: a systematic review and meta-analysis. AB - INTRODUCTION: The purpose of this systematic review and meta-analysis was to evaluate the efficacy of concurrent cartilage procedures during high tibial osteotomy (HTO) for medial compartment osteoarthritis (OA) by comparing the outcomes of studies that directly compared the use of HTO plus concurrent cartilage procedures versus HTO alone. MATERIALS AND METHODS: Results that are possible to be compared in more than two articles were presented as forest plots. A 95% confidence interval was calculated for each effect size, and we calculated the I 2 statistic, which presents the percentage of total variation attributable to the heterogeneity among studies. The random effects model was used to calculate the effect size. RESULTS: Seven articles were included to the final analysis. Case groups were composed of HTO without concurrent procedures and control groups were composed of HTO with concurrent procedures such as marrow stimulation procedure, mesenchymal stem cell transplantation, and injection. The case group showed a higher hospital for special surgery score and mean difference was 4.10 [I 2 80.8%, 95% confidence interval (CI) - 9.02 to 4.82]. Mean difference of the mechanical femorotibial angle in five studies was 0.08 degrees (I 2 0%, 95% CI - 0.26 to 0.43). However, improved arthroscopic, histologic, and MRI results were reported in the control group. CONCLUSION: Our analysis support that concurrent procedures during HTO for medial compartment OA have little beneficial effect regarding clinical and radiological outcomes. However, they might have some beneficial effects in terms of arthroscopic, histologic, and MRI findings even though the quality of healed cartilage is not good as that of original cartilage. Therefore, until now, concurrent procedures for medial compartment OA have been considered optional. Nevertheless, no conclusions can be drawn for younger patients with focal cartilage defects and concomitant varus deformity. This question needs to be addressed separately. PMID- 29143168 TI - Limited influence of blunt aortic injuries on the outcome of polytraumatized patients: a matched pair analysis. AB - INTRODUCTION: Traumatic lesions of great vessels such as the aorta are life threatening injuries. There is limited evidence about the influence of traumatic aortic injuries in multiple trauma patients in particular with regard to posttraumatic complications. The aim of this study was to evaluate the influence of blunt thoracic aortic injuries in multiple trauma patients compared to a multiple trauma cohort without this specific injury. In addition, the safety of Thoracic Endovascular Aortic Repair (TEVAR) in multiple trauma patients was analyzed. MATERIALS AND METHODS: A retrospective study was performed. We included all multiple trauma patients (ISS >= 16, age > 14 years) between 2005 and 2014 with (group BTAI) and without (group nBTAI) blunt traumatic aortic injuries who were treated at our level-1 trauma center. Demographic as well as clinical parameters were analyzed including injury pattern, mechanism of injury, posttraumatic complications such as ARDS, multiple organ dysfunction syndrome (MODS) and others. A matched pair analysis was performed by propensity score matching. RESULTS: In total, 721 patients were enrolled (group BTAI: n = 45; nBTAI: n = 676). In the initial study population, surgical intervention was done in n = 32 (71.1%) patients (TEVAR: n = 25; 78.1%), there was an increased AISChest and overall injury severity in group BTAI with associated significantly more posttraumatic complications in group BTAI. The matched pair analysis consisted of 42 patients per group. Beside an increased ventilation time, no significant differences were evident after the matching process. There was a trend to increased risk for SIRS using binary logistic regression analysis. CONCLUSIONS: Multiple trauma patients with blunt thoracic aortic injuries who are treated at a level-1 trauma center show a comparable outcome matched to their counterparts without aortic injuries. Our study confirms that using TEVAR in polytraumatized patients is a safe procedure. In all patients treated with TEVAR, there were no procedure-related complications, especially no neurological deficit. PMID- 29143169 TI - Predictors and Patterns of Psychiatric Treatment Dropout During Pregnancy Among Low-Income Women. AB - Objective This study compared psychiatric treatment discontinuation rates among pregnant women using psychotropic medications, outpatient psychotherapy, or both before conception. Methods Using data from Pennsylvania Medicaid Fee-For-Service and Managed Care Organization claims and Medicaid enrollment, 3030 women were identified who gave birth between 2007 and 2009, had >= 1 claim for psychiatric treatment during the 120 days prior to pregnancy, and were enrolled in Medicaid until they delivered. Kaplan-Meier and Cox regression analyses were used to estimate psychiatric treatment dropout rate during pregnancy and examine relationships between treatment dropout and age, race/ethnicity, and pre pregnancy psychiatric diagnosis and treatment pattern. Results After the first trimester, the probability of discontinuing psychotropic medications was 83 versus 37.8% for cessation of psychotherapy among combined treatment users. Two or more psychotherapy sessions in the 4 months prior to pregnancy were associated with decreased psychotherapy dropout during pregnancy. Psychotherapy during pregnancy was associated with prenatal psychotropic medication adherence. Conclusions To retain women in treatment during pregnancy, when discontinuation from care is common, innovative models of care should consider type of pre pregnancy mental healthcare and individual characteristics. PMID- 29143170 TI - Circumferential strain acquired by CMR early after acute myocardial infarction adds incremental predictive value to late gadolinium enhancement imaging to predict late myocardial remodeling and subsequent risk of sudden cardiac death. AB - PURPOSE: Late adverse myocardial remodeling after acute myocardial infarction (AMI) is strongly associated with sudden cardiac death (SCD). Cardiac magnetic resonance (CMR) performed early after AMI can predict late remodeling and SCD risk with moderate accuracy. This study assessed the ability of CMR-measured circumferential strain (CS) to add incremental predictive information to late gadolinium enhancement (LGE). METHODS: Patients with an AMI and LVEF < 50% were screened for inclusion. A total of 27 patients, totaling 432 myocardial segments, prospectively underwent CMR 7 +/- 5 days after percutaneous coronary intervention (PCI). LGE, microvascular obstruction (MVO), and myocardial CS were measured for each segment. The primary endpoint was late segmental adverse remodeling defined as segmental wall motion score (WMS) > 1 measured by echocardiography 3 months after PCI. RESULTS: A total of 141 segments experienced the primary endpoint at 3 months. The mean LGE volume was higher in these segments, but LGE was also present in many segments with normal WMS (40 +/- 28 versus 20 +/- 26%, p < 0.01). Segments that met the primary endpoint also showed greater impairment of CS. Segments with both LGE > 17% and impaired CS >- 7.2% on CMR were more likely to experience late adverse remodeling (73%) as compared to segments with neither (9%, p < 0.001) or one abnormal parameter (36%, p < 0.001). CS >- 7.2% also added incremental accuracy to LGE > 17% for predicting late adverse remodeling (AUC 0.81 from 0.70, p < 0.001). CONCLUSIONS: When performed early after AMI, LGE is a moderate predictor of late remodeling and CS is a powerful predictor of late myocardial remodeling. When combined, they can predict late remodeling, a surrogate of SCD, with high accuracy. PMID- 29143171 TI - Neonicotinoid insecticides in pollen, honey and adult bees in colonies of the European honey bee (Apis mellifera L.) in Egypt. AB - Honeybee losses have been attributed to multiple stressors and factors including the neonicotinoid insecticides (NIs). Much of the study of hive contamination has been focused upon temperate regions such as Europe, Canada and the United States. This study looks for the first time at honey, pollen and bees collected from across the Nile Delta in Egypt in both the spring and summer planting season of 2013. There is limited information upon the frequency of use of NIs in Egypt but the ratio of positive identification and concentrations of NIs are comparable to other regions. Metabolites of NIs were also monitored but given the low detection frequency, no link between matrices was possible in the study. Using a simple hazard assessment based upon published LD50 values for individual neonicotinoids upon the foraging and brood workers it was found that there was a potential risk to brood workers if the lowest reported LD50 was compared to the sum of the maximum NI concentrations. For non-lethal exposure there was significant risk at the worst case to brood bees but actual exposure effects are dependant upon the genetics and conditions of the Egyptian honeybee subspecies that remain to be determined. PMID- 29143172 TI - Identification of key genes and construction of microRNA-mRNA regulatory networks in bladder smooth muscle cell response to mechanical stimuli using microarray expression profiles and bioinformatics analysis. AB - PURPOSE: To identify keys genes and elucidate miRNA-mRNA regulatory networks in Bladder smooth muscle cell (BSMC) response to mechanical stimuli. METHODS: Human BSMCs, seeded on a silicone membrane, were subjected to mechanical stretch or without stretch. Microarray was used to analyze the differential expression of mRNAs and miRNAs between human BSMCs under mechanical stretch and control static control group. Differentially expressed genes(DEGs) and miRNAs (DEMs) in these two groups were identified. Subsequently, differentially expressed DEGs were conducted with functional analysis, and then PPI network was constructed. Finally, miRNA-mRNA regulatory network was visualized using Cytoscape. RESULTS: 1639 significant DEGs and three DEMs were identified between the stretch group and control static group. The PPI network of DEGs was constructed by STRING, which was composed of 1459 nodes and 1481 edges, including 188 upregulated genes and 255 downregulated genes. Moreover, 36 genes in the PPI network were identified as hub genes in BSMCs response to mechanical stretch, e.g. CCNH, CPSF2, TSNAX, ARPC5 and PSMD3 genes. Subsequently, 39 clusters were selected from PPI network using MCODE, and it was shown that the most significant cluster consisted of 14 nodes and 91 edges. Besides, miR-503HG was the most significantly downregulated miRNA and was predicted to target five upregulated genes, including SMAD7, CCND3, WIPI2, NYNRIN and PVRL1. CONCLUSIONS: Our data mining and integration help reveal the mechanotransduction mechanism of BSMCs' response to mechanical stimulation and contribute to the early diagnosis of bladder outlet obstruction (BOO) as well as the improvement of pathogenesis of BOO treatment. PMID- 29143173 TI - Individualized Progress Measures Are More Acceptable to Clinicians Than Standardized Measures: Results of a National Survey. AB - Despite research supporting measurement-based care grounded in standardized progress measures, such measures are underutilized by clinicians. Individualized measures of client-specific targets present an alternative, but little is known about their acceptability or use. We compared attitudes toward and use of standardized and individualized progress measures in a national sample of 504 clinicians. Clinicians reported neutral to positive attitudes toward both types of measures, but strongly preferred and were more likely to use individualized measures. Clinician attitudes, theoretical orientation, and work setting predicted assessment preferences and practices. Implications for dissemination and implementation of measurement-based care are discussed. PMID- 29143174 TI - Single-Cell Imaging Using Radioluminescence Microscopy Reveals Unexpected Binding Target for [18F]HFB. AB - PURPOSE: Cell-based therapies are showing great promise for a variety of diseases, but remain hindered by the limited information available regarding the biological fate, migration routes and differentiation patterns of infused cells in trials. Previous studies have demonstrated the feasibility of using positron emission tomography (PET) to track single cells utilising an approach known as positron emission particle tracking (PEPT). The radiolabel hexadecyl-4 [18F]fluorobenzoate ([18F]HFB) was identified as a promising candidate for PEPT, due to its efficient and long-lasting labelling capabilities. The purpose of this work was to characterise the labelling efficiency of [18F]HFB in vitro at the single-cell level prior to in vivo studies. PROCEDURES: The binding efficiency of [18F]HFB to MDA-MB-231 and Jurkat cells was verified in vitro using bulk gamma counting. The measurements were subsequently repeated in single cells using a new method known as radioluminescence microscopy (RLM) and binding of the radiolabel to the single cells was correlated with various fluorescent dyes. RESULTS: Similar to previous reports, bulk cell labelling was significantly higher with [18F]HFB (18.75 +/- 2.47 dpm/cell, n = 6) than 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) (7.59 +/- 0.73 dpm/cell, n = 7; p <= 0.01). However, single-cell imaging using RLM revealed that [18F]HFB accumulation in live cells (8.35 +/- 1.48 cpm/cell, n = 9) was not significantly higher than background levels (4.83 +/- 0.52 cpm/cell, n = 12; p > 0.05) and was 1.7-fold lower than [18F]FDG uptake in the same cell line (14.09 +/- 1.90 cpm/cell, n = 13; p < 0.01). Instead, [18F]HFB was found to bind significantly to fragmented membranes associated with dead cell nuclei, suggesting an alternative binding target for [18F]HFB. CONCLUSION: This study demonstrates that bulk analysis alone does not always accurately portray the labelling efficiency, therefore highlighting the need for more routine screening of radiolabels using RLM to identify heterogeneity at the single-cell level. PMID- 29143175 TI - Vectors for Expression of Signal Peptide-Dependent Proteins in Baculovirus/Insect Cell Systems and Their Application to Expression and Purification of the High Affinity Immunoglobulin Gamma Fc Receptor I in Complex with Its Gamma Chain. AB - Integral membrane proteins play a central role in various cellular functions and are important therapeutic targets. However, technical challenges in the overexpression and purification of membrane proteins often represent a limiting factor for biochemical and structural studies. Here, we constructed a set of vectors, derivatives of MultiBac vectors that can be used to express proteins with a cleavable N-terminal signal peptide in insect cells. We propose these vectors for expression of type I membrane proteins and other secretory pathway proteins that require the signal recognition particle for translocation to the endoplasmic reticulum (ER). The vectors code for N-terminal and C-terminal affinity tags including 3 * FLAG and Twin-Strep, which represent tags compatible with efficient translocation to the ER as well as with purification under mild conditions that preserve protein structure and function. As a model, we used our system to express and purify the engineered high-affinity immunoglobulin gamma Fc receptor I (CD64) in complex with its gamma subunit (gamma-chain). We demonstrate that CD64 expressed in complex with the gamma-chain is functional in immunoglobulin G (IgG) binding. The sedimentation of CD64 in complex with IgG suggests individual CD64/IgG complexes in addition to formation of high-molecular weight complexes. In summary, our vectors can be used as a tool for expression of membrane proteins, other secretory pathway proteins and their protein complexes. PMID- 29143177 TI - The RISK pathway and beyond. AB - Research on cardioprotection has attracted considerable attention during the past 30 years following the discovery of ischemic preconditioning with great advances being made in the field, particularly in the description of the molecular signalling behind this cardioprotective intervention. In a time when basic research is struggling to translate its findings into therapies in the clinical setting, this viewpoint has the intention of presenting to clinical and basic scientists how the reperfusion injury salvage kinase pathway has been described and dissected, as well as highlighting its relevance in cardioprotection. PMID- 29143178 TI - Transgenic cotton co-expressing chimeric Vip3AcAa and Cry1Ac confers effective protection against Cry1Ac-resistant cotton bollworm. AB - Wide planting of transgenic Bt cotton in China since 1997 to control cotton bollworm (Helicoverpa armigera) has increased yields and decreased insecticide use, but the evolution of resistance to Bt cotton by H. armigera remains a challenge. Toward developing a new generation of insect-resistant transgenic crops, a chimeric protein of Vip3Aa1 and Vip3Ac1, named Vip3AcAa, having a broader insecticidal spectrum, was specifically created previously in our laboratory. In this study, we investigated cross resistance and interactions between Vip3AcAa and Cry1Ac with three H. armigera strains, one that is susceptible and two that are Cry1Ac-resistant, to determine if Vip3AcAa is a good candidate for development the pyramid cotton with Cry1Ac toxin. Our results showed that evolution of insect resistance to Cry1Ac toxin did not influence the sensitivity of Cry1Ac-resistant strains to Vip3AcAa. For the strains examined, observed mortality was equivalent to the expected mortality for all the combinations of Vip3AcAa and Cry1Ac tested, reflecting independent activity between these two toxins. When this chimeric vip3AcAa gene and the cry1Ac gene were introduced into cotton, mortality rates of Cry1Ac resistant H. armigera larvae strains that fed on this new cotton increased significantly compared with larvae fed on non-Bt cotton and cotton producing only Cry1Ac. These results suggest that the Vip3AcAa protein is an excellent option for a "pyramid" strategy for pest resistance management in China. PMID- 29143179 TI - Diagnostic work-up in steroid myopathy. AB - INTRODUCTION: Steroid myopathy is a well-known sign of endogenous Cushing's syndrome as well as a side effect of glucocorticoid administration. The clinical finding of muscle weakness and the clinical inspection of the muscle size are the most commonly used diagnostic tools, sometimes in combination with needle electromyography, but there are no means to detect the myopathy before the appearance of clinical or electrodiagnostic signs. Until now, no guidelines have been produced for a disease-specific evaluation of muscle impairment in patients with Cushing's syndrome. REVIEW: We reviewed the measurement properties and limitations of the following tools that are currently adopted in clinical research and routine care for diagnosis and monitoring of steroid myopathy: muscle strength assessment; needle biopsy; intramuscular and surface electromyography; laboratory assays; muscle mass assessments (through bioelectrical impedance analysis, dual-energy X-ray absorptiometry, and computed tomography). CONCLUSIONS: We suggest that the management of steroid myopathy patients in clinical research and practice would benefit from a multidisciplinary approach based on the combined assessment of muscle mass, strength, and performance. However, further studies are required to establish an operational definition of steroid myopathy and to identify population-specific criteria for diagnosis of the myopathic process. PMID- 29143176 TI - The Treatment Landscape and New Opportunities of Molecular Targeted Therapies in Gastroenteropancreatic Neuroendocrine Tumors. AB - Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that originate from neuroendocrine stem cells and express both neural and endocrine markers. They are found in almost every organ, and while NENs are mostly associated with slow growth, complications due to the uncontrolled secretion of active peptides, and metastatic disease, may significantly impair the quality of life and can ultimately lead to the death of affected individuals. Expanding knowledge of the genetic, epigenetic, and proteomic landscapes of NENs has led to a better understanding of their molecular pathology and consequently increased treatment options for patients. Here, we review the principal breakthroughs in NEN treatment management, owing largely to omics technologies over the last few years, current recommendations of systemic treatment, and ongoing research into the identification of predictive and response biomarkers based on molecular targeted therapies. PMID- 29143180 TI - Oxidative stress in adult growth hormone deficiency: different plasma antioxidant patterns in comparison with metabolic syndrome. AB - BACKGROUND AND AIMS: Growth hormone deficiency (GHD) is a condition associated with increased cardiovascular risk and insulin-resistance. Oxidative stress (OS) could be a mechanism underlying both these phenomena. In order to investigate plasma antioxidant defenses in such condition, we evaluated adults with GHD, compared with controls and metabolic syndrome patients (MetS), studying plasma total antioxidant capacity (TAC) and coenzyme Q10 (CoQ10, lipophilic antioxidant) levels, both in its oxidized and reduced forms, correlating this data with metabolic and hormonal pattern. MATERIALS AND METHODS: In this case-control study, 51 GHD, 36 controls, and 35 MetS were enrolled. An evaluation of hormonal and metabolic parameters was performed. TAC was measured using the system metmyoglobin -H202 and the chromogen ABTS, whose radical form is spectroscopically revealed; latency time (LAG) in the appearance of ABTS? is proportional to antioxidant in sample. CoQ10 was assayed by electrochemical method. RESULTS: Despite HOMA index was higher in both GHD and MetS (2.2 +/- 0.3 and 3.1 +/- 0.3 vs. 1.2 +/- 0.2 in controls), only in MetS we observed lower LAG levels (64.5 +/- 3.1 s vs. 82.8 +/- 5.8 in GHD and 80.6 +/- 6.6 in controls), suggesting an increased consumption of antioxidants. LAG significantly correlated with uric acid only in MetS (r 2 = 0.65, p < 0.001), suggesting a different pattern of antioxidants. CoQ10 exhibited a trend toward lower levels in GHD, although not significant. CONCLUSIONS: Our data indicate that GHD, although sharing with MetS various metabolic features, including increased HOMA levels, showed a different pattern of plasma antioxidants, suggesting inadequate reactivity toward radical production rather than an antioxidants consumption as in MetS. PMID- 29143181 TI - HLA-DQ2 and -DQ8 haplotypes frequency and diagnostic utility in celiac disease patients of Gaza strip, Palestine. AB - PURPOSE: Celiac disease (CD) diagnosis can be established by serological and small bowel biopsy (SBB), while absence of HLA-DQ2 and -DQ8 haplotypes excludes the disease. The present study aims at evaluating the diagnosis of a representative sample of pediatric and adult CD patients of Gaza strip in light of DQ2 and DQ8 haplotypes expression. METHODS: Unrelated CD patients (n = 101) and matched healthy controls (n = 97) were genotyped for DQA1*05, DQB1*02 and DQB1*03:02 alleles by allele-specific real-time PCR. The diagnosis was re evaluated according to the patient laboratory tests and HLA-DQ genotype. RESULTS: The diagnosis of 35 patients who have been managed for CD could not be confirmed. Twenty-five of them were diagnosed upon their clinical presentation only. The remaining were either negative for serological and SBB tests or negative for HLA DQ haplotypes. The HLA-DQ alleles were negative in 4 SBB and one Anti-EMA positive patients. The frequency of DQ2 and DQ8 haplotypes among the remaining 65 confirmed cases was 70.8 and 15.4%, respectively, compared to 17.5 and 27.8% in the controls. The DQB1*02 allele was the most common in the cases (84.6%) followed by DQA1*05 allele (80%) and DQB1*03:02 allele (20%). The DQA1*05 allele was commonest in the control group (54.6%) followed by DQB1*02 allele (42.3%) and DQB1*03:02 allele (28.9%). CONCLUSIONS: Absence of HLA-DQ2 and HLA-DQ8 genotyping in the workup of patients may result in CD misdiagnosis, particularly in a setting with poor histopathological diagnostic capacity. PMID- 29143184 TI - Measuring the Unmeasurable : The Psychometrics of Life History Strategy. AB - Within evolutionary biology, life-history theory is used to explain cross-species differences in allocation strategies regarding reproduction, maturation, and survival. Behavioral scientists have recently begun to conceptualize such strategies as a within-species individual characteristic that is predictive of behavior. Although life history theory provides an important framework for behavioral scientists, the psychometric approach to life-history strategy measurement-as operationalized by K-factors-involves conceptual entanglements. We argue that current psychometric approaches attempting to identify K-factors are based on an unwarranted conflation of functional descriptions and proximate mechanisms-a conceptual mix-up that may generate unviable hypotheses and invites misinterpretation of empirical findings. The assumptions underlying generic psychometric methodology do not allow measurement of functionally defined variables; rather these methods are confined to Mayr's proximate causal realm. We therefore conclude that K-factor scales lack validity, and that life history strategy cannot be identified with psychometrics as usual. To align theory with methodology, suggestions for alternative methods and new avenues are proposed. PMID- 29143182 TI - Noncoding RNAs in the Regulation of Pluripotency and Reprogramming. AB - Pluripotent stem cells have great potential for developmental biology and regenerative medicine. Embryonic stem cells, which are obtained from blastocysts, and induced pluripotent stem cells, which are generated by the reprogramming of somatic cells, are two main types of pluripotent cells. It is important to understand the regulatory network that controls the pluripotency state and reprogramming process. Various types of noncoding RNAs (ncRNAs) have emerged as substantial components of regulatory networks. The most studied class of ncRNAs in the context of pluripotency and reprogramming is microRNAs (miRNAs). In addition to canonical microRNAs, other types of small RNAs with miRNA-like function are expressed in PSCs. Another class of ncRNAs, long ncRNAs, are also involved in pluripotency and reprogramming regulation. Thousands of ncRNAs have been annotated to date, and a significant number of the molecules do not have known function. In this review, we briefly summarized recent advances in this field and described existing genome-editing approaches to study ncRNA functions. PMID- 29143183 TI - MicroRNAs: Important Regulators of Induced Pluripotent Stem Cell Generation and Differentiation. AB - Induced pluripotent stem (iPS) cells can differentiate into nearly all types of cells. In contrast to embryonic stem cells, iPS cells are not subject to immune rejection because they are derived from a patient's own cells without ethical concerns. These cells can be used in regenerative medical techniques, stem cell therapy, disease modelling and drug discovery investigations. However, this application faces many challenges, such as low efficiency, slow generation time, partially reprogrammed colonies and tumourigenicity. Numerous techniques have been formulated in the past decade to improve reprogramming efficiency and safety, including the use of different transcription factors, small molecule compounds and non-coding RNAs. Recently, microRNAs (miRNAs) were found to promote the generation and differentiation of iPS cells. The miRNAs can more effectively and safely generate iPS cells than transcription factors. This process ultimately leads to the development of iPSC-based therapeutics for future clinical applications. In this comprehensive review, we summarise advances in research and the application of iPS cells, as well as recent progress in the use of miRNAs for iPS cell generation and differentiation. We examine possible clinical applications, especially in cardiology. PMID- 29143185 TI - Osteogenic prospective of deriving human dental stem cells in collagen matrix boost. AB - Stem cells derived from oral tissue represent a highly attractive alternative source for clinical bone regeneration because they can be collected by non invasive or minimally invasive procedures. Herein, we describe the human dental stem cells (DSCs) deriving from buccal fat pads (BFP), dental pulp (DP) of impacted teeth, and periodontal ligaments (PDL) to obtain BFPSCs, DPSCs, and PDLSCs, respectively. Cells were purified with selected medium and expanded through passages in stem cell culture medium. Purified cells were characterized for stemness by their growth rate, immunostaining, and multilineage differentiation ability. They showed plastic adherence, expression of stemness specific markers, and multilineage differentiation potential. Immunocytochemistry analysis confirmed that DPSCs had more osteogenic potential than BFSCs and PDLSCs. Calcium-rich deposits, evaluated by von Kossa and Alizarin red staining, showed greater mineralization when DPSCs were cultured on collagen type I matrix than without collagen. Furthermore, DPSC-seeded collagen type I matrix maintained consistent osteogenesis and boosted mineral formation by 1-2 weeks over that in DPSCs cultured without collagen. Radiographic analysis of DPSC-seeded collagen type I matrix transplanted into rat cranial defects showed significant bone regeneration after 8 weeks. These results suggested that the redundant oral tissue can be used as a source of adult multipotent stem cells for clinical bone regeneration. Triple overlay images with biomarkers (red), nuclei (blue) and bright field morphology of DPSCs. The specifically osteo-differentiation shown by osteocalcin (left) expression and lack of sox9 (right) expressed in the images below which were cultured with collagen matrix, contrast with no collagen matrix group above. PMID- 29143186 TI - Identification of an anellovirus and genomoviruses in ixodid ticks. AB - Ticks are blood-feeding arachnids that are vectors of several important human and animal pathogens. Little is known about single-stranded DNA (ssDNA) viruses that are associated with these ectoparasites. As part of a pilot study to identify ssDNA viruses present in ticks, female American dog ticks (Dermacentor variabilis) and blacklegged ticks (Ixodes scapularis) were collected in eastern Pennsylvania (USA), and the extracted viral DNA was analyzed using viral metagenomics approaches. Three genomoviruses were recovered from pooled samples of D. variabilis (n = 2) and I. scapularis (n = 1): two belonging to the genus Gemycircularvirus, sharing < 63% pairwise identity with other members within the genus; and the third belonging to the genus Gemykolovirus, sharing < 70% pairwise identity to other gemykoloviruses. Furthermore, a genome of an anellovirus belonging to the sharing 62-65% nucleotide identity with torque teno canis viruses (genus Thetatorquevirus) was also recovered from a D. variabilis pooled sample. PMID- 29143187 TI - Multi-locus sequence typing of African swine fever viruses from endemic regions of Kenya and Eastern Uganda (2011-2013) reveals rapid B602L central variable region evolution. AB - The central variable region (CVR) within the B602L gene of the African swine fever virus (ASFV) is highly polymorphic within the 23 ASFV genotypes defined by sequencing of the C-terminal end of the p72 locus. Sequencing the p54 gene further discriminates ASFV genotypes that are conserved at the p72 locus. Variation in the thymidine kinase locus is a novel additional tool for ASFV genotyping whose application for this purpose is described for the first time herein. We evaluated genetic variation at these four polymorphic loci in 39 ASFV isolates obtained from outbreaks in Kenya and a region of Eastern Uganda between 2011 and 2013. Analysis of the p72 and p54 loci revealed high genetic conservation among these isolates; all clustered within p72 genotype IX and were similar to isolates associated with earlier outbreaks in East Africa. The thymidine kinase gene of the Kenyan isolates in this study were distinct relative to Southern African isolates and synonymous substitutions were observed among viruses from central Kenya. Analysis of the CVR within the B602L gene revealed two previously unknown polymorphisms that were restricted to Western Kenya and Eastern Uganda. A novel variant was revealed within CVR subgroup XXIV and a novel CVR subgroup XXIVa that contains tetrameric repeat F which has previously only been associated with p72 genotype I, was also identified for the first time in East Africa. Phylogeographic analysis of isolates based on CVR polymorphisms revealed rapid evolution and dissemination of variants present within ASFV genotype IX in East Africa. PMID- 29143188 TI - Power to the People? PMID- 29143189 TI - Oral hygiene and oral health in older people with dementia: a comprehensive review with focus on oral soft tissues. AB - BACKGROUND: The number of older people with dementia and a natural dentition is growing. Recently, a systematic review concerning the oral health of older people with dementia with the focus on diseases of oral hard tissues was published. OBJECTIVE: To provide a comprehensive literature overview following a systematic approach of the level of oral hygiene and oral health status in older people with dementia with focus on oral soft tissues. METHODS: A literature search was conducted in the databases PubMed, CINAHL, and the Cochrane Library. The following search terms were used: dementia and oral health or stomatognathic disease. A critical appraisal of the included studies was performed with the Newcastle-Ottawa scale (NOS) and Delphi list. RESULTS: The searches yielded 549 unique articles, of which 36 were included for critical appraisal and data extraction. The included studies suggest that older people with dementia had high scores for gingival bleeding, periodontitis, plaque, and assistance for oral care. In addition, candidiasis, stomatitis, and reduced salivary flow were frequently present in older people with dementia. CONCLUSIONS: The studies included in the current systematic review suggest that older people with dementia have high levels of plaque and many oral health problems related to oral soft tissues, such as gingival bleeding, periodontal pockets, stomatitis, mucosal lesions, and reduced salivary flow. SCIENTIFIC RATIONALE FOR STUDY: With the aging of the population, a higher prevalence of dementia and an increase in oral health problems can be expected. It is of interest to have an overview of the prevalence of oral problems in people with dementia. PRINCIPAL FINDINGS: Older people with dementia have multiple oral health problems related to oral soft tissues, such as gingival bleeding, periodontal pockets, mucosal lesions, and reduced salivary flow. PRACTICAL IMPLICATIONS: The oral health and hygiene of older people with dementia is not sufficient and could be improved with oral care education of formal and informal caregivers and regular professional dental care to people with dementia. PMID- 29143190 TI - Role of magnetic resonance imaging in the management of perianal Crohn's disease. AB - : Perianal fistulas are a major problem in many patients with Crohn's disease. These are usually complex fistulas that adversely affect patients' quality of life, and their clinical management is difficult. Medical treatment sometimes achieves cessation of discharge and closure of the external opening; however, it is difficult to assess the status of the rest of the fistula tract. Magnetic resonance imaging is the method of choice with which to evaluate the condition of perianal fistulas and allows for assessment of the status of inaccessible areas. Magnetic resonance imaging also allows the clinician to evaluate other perianal manifestations of Crohn's disease that differ from the fistulas. This imaging technique is therefore a fundamental means of patient monitoring. When used in conjunction with assessment of the patient's morphological findings, it provides information that allows for both quantification of disease severity and evaluation of the response to treatment. New types of magnetic resonance sequences are emerging, such as diffusion, perfusion, and magnetisation transfer. These sequences may serve as biomarkers because they provide information reflecting the changes taking place at the molecular level. This will help to shape a new scenario in the early assessment of the response to treatments such as anti-tumour necrosis factor drugs. TEACHING POINTS: * MRI is the method of choice with which to evaluate perianal fistulas. * In perianal Crohn's disease, MRI is a fundamental means of patient monitoring. * The usefulness of the Van Assche score for patient monitoring remains unclear. * New MRI sequences' diffusion, perfusion, and magnetisation transfer may serve as biomarkers. PMID- 29143191 TI - Evaluation of the solitary pulmonary nodule: size matters, but do not ignore the power of morphology. AB - : Subsequent to the widespread use of multidetector computed tomography and growing interest in lung cancer screening, small pulmonary nodules are more frequently detected. The differential diagnosis for a solitary pulmonary nodule is extremely broad and includes both benign and malignant causes. Recognition of early lung cancers is vital, since stage at diagnosis is crucial for prognosis. Estimation of the probability of malignancy is a challenging task, but crucial for follow-up and further work-up. In addition to the clinical setting and metabolic assessment, morphological assessment on thin-section computed tomography is essential. Size and growth are key factors in assessment of the malignant potential of a nodule. The likelihood of malignancy positively correlates with nodule diameter: as the diameter increases, so does the likelihood of malignancy. Although there is a considerable overlap in the features of benign and malignant nodules, the importance of morphology however should not be underestimated. Features that are associated with benignity include a perifissural location and triangular morphology, internal fat and benign calcifications. Malignancy is suspected in nodules presenting with spiculation, lobulation, pleural indentation, vascular convergence sign, associated cystic airspace, bubble-like lucencies, irregular air bronchogram, and subsolid morphology. Nodules often show different features and combination of findings is certainly more powerful. TEACHING POINTS: * Size of a pulmonary nodule is important, but morphological assessment should not be underestimated. * Lung nodules should be evaluated on thin section CT, in both lung and mediastinal window setting. * Features associated with benignity include a triangular morphology, internal fat and calcifications. * Spiculation, pleural retraction and notch sign are highly suggestive of a malignant nature. * Complex features (e.g. bubble-like lucencies) are highly indicative of a malignant nature. PMID- 29143193 TI - Cigarette demand among smokers with elevated depressive symptoms: an experimental comparison with low depressive symptoms. AB - RATIONALE: Individuals with depression smoke more than smokers without depression. Research has shown that cigarette demand is a useful tool for quantifying tobacco reinforcement and supposes a clinical predictor of treatment outcomes. Despite previous studies examining the relative reinforcing efficacy of nicotine among different populations of smokers, to date, no study has assessed cigarette demand among individuals with elevated depressive symptoms. OBJECTIVE: The aim of this study was to compare cigarette demand among samples of smokers with low and elevated depressive symptoms. Further, it also sought to examine the relationship between depressive symptomatology and the individual CPT demand indices. METHODS: Participants (80 non-depressed smokers and 85 depressed smokers) completed the 19-item version of the Cigarette Purchase Task (CPT). Depression symptomatology was assessed using the Beck Depression Inventory-Second Edition (BDI-II). Depressed smokers needed to present at least moderate depressive symptoms as indicated by scoring >= 20 on the BDI-II. RESULTS: Depressive symptomatology and nicotine dependence were significantly associated with elasticity of demand (R 2 = 0.112; F(2, 155) = 9.756, p = <= 0.001). Depressive symptoms, cigarettes per day, and years of regular smoking also predicted breakpoint scores (R 2 = 0.088; F(4, 153) = 3.697, p = 0.007). CONCLUSION: As smokers with elevated depressive symptoms are less sensitive to increases in cigarette prices than those with low depressive symptomatology, future studies should consider these cigarette demand indices when designing depression-focused smoking cessation treatments. Providing this difficult-to treat population with interventions that promote both pleasurable and alternative reinforcing activities is highly encouraged. PMID- 29143194 TI - The role of crowding in parallel search: Peripheral pooling is not responsible for logarithmic efficiency in parallel search. AB - Recent results from our laboratory showed that, in fixed-target parallel search tasks, reaction times increase in a logarithmic fashion with set size, and the slope of this logarithmic function is modulated by lure-target similarity. These results were interpreted as being consistent with a processing architecture where early vision (stage one) processes elements in the display in exhaustive fashion with unlimited capacity and with a limitation in resolution. Here, we evaluate the contribution of crowding to our recent logarithmic search slope findings, considering the possibility that peripheral pooling of features (as observed in crowding) may be responsible for logarithmic efficiency. Factors known to affect the strength of crowding were varied, specifically: item spacing and similarity. The results from three experiments converge on the same pattern of results: reaction times increased logarithmically with set size and were modulated by lure target similarity even when crowding was minimized within displays through an inter-item spacing manipulation. Furthermore, we found logarithmic search efficiencies were overall improved in displays where crowding was minimized compared to displays where crowding was possible. The findings from these three experiments suggest logarithmic efficiency in efficient search is not the result peripheral pooling of features. That said, the presence of crowding does tend to reduce search efficiency, even in "pop-out" search situations. PMID- 29143195 TI - Normal Values of High-Resolution Manometry in Supine and Upright Positions in a Thai Population. AB - BACKGROUND: Although cut-off values used in high-resolution manometry (HRM) to diagnose esophageal motility disorders are based on representative samples of the US population and assume a supine position, differences in population and body positioning can reportedly affect results. AIMS: To establish normal HRM values for Thai people in both supine and upright positions. METHODS: Forty-one healthy subjects were recruited, each of whom underwent solid-state HRM with ten 5-mL swallows of water in both the supine and upright positions. Measuring parameters according to the Chicago classification criteria (CC v3.0) were included, for which the mean, median and 5th and 95th percentiles (PCTLs) were calculated. RESULTS: The results corresponded with the CC v3.0 criteria, except for the mean, and 5th PCTL of the distal contractile integral (DCI), which were lower for this population. In the upright position, the mean and median values for DCI, intrabolus pressure and integrated relaxation pressure were significantly decreased, whereas the length of the transitional zone was significantly increased. The limitations of this study include: (1) the relatively low number of participants, (2) the limited recruitment of participants only at Ramathibodi Hospital and (3) the limited recruitment of only young and middle-aged participants. CONCLUSIONS: We established normal values for the HRM parameters in a representative sample of the Thai population. Our supine results still prove that the use of the CC v3.0 is preferable. HRM testing in patients measured in the upright position should be analyzed based on the normative values obtained from upright swallow studies. PMID- 29143197 TI - Three Cases of Hereditary Tyrosinaemia Type 1: Neuropsychiatric Outcomes and Brain Imaging Following Treatment with NTBC. AB - AIM: To examine neuropsychiatric outcomes in adults with hereditary tyrosinaemia type I (HT-1), treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione (NTBC) and correlate these with functional imaging as well as with tyrosine and phenylalanine-tyrosine (Phe:Tyr) ratios. DESIGN: We retrospectively reviewed the medical records of three adult HT-1 patients with a particular focus on their FDG PET/CT brain scans, neuropsychiatric assessment (including neurocognitive assessment and mood and anxiety ratings) as well as mean tyrosine and phenylalanine levels and Phe:Tyr ratios for 3-month period. The patients had been referred to a specialist joint inherited metabolic disorder and neuropsychiatry clinic. They were all on NTBC; two since 6 weeks of age, and one since 9 years of age. RESULTS: All patients performed below the expectation on the formal neurocognitive testing and had raised plasma tyrosine levels and reduced plasma Phe:Tyr ratios. FDG PET/CT-brain scans were normal in two patients and the third patient (treated with NTBC from 6 weeks) had reduced metabolism in temporal and medial frontal areas bilaterally which correlated with the neurocognitive performance. CONCLUSIONS: All three HT-1 patients treated with NTBC had high tyrosine levels, reduced Phe:Tyr ratios and underperformed in neurocognitive testing regardless of the point when the NTBC was first started. One had imaging abnormalities which also correlated with neurocognitive performance. The patient who struggled the most in neurocognitive testing had the highest average plasma tyrosine levels and the lowest Phe:Tyr ratio. Overall, these cases appear to support the previous hypothesis that either the high tyrosine levels or abnormal phenylalanine hydroxylase (PAH) function may well be the causative factor for poor neurocognitive performance. Further systematic, multi-centre studies with a longer follow-up are required to further clarify the relationship between HT-1, NTBC treatment, tyrosine and phenylalanine levels and neurocognitive outcomes. PMID- 29143196 TI - Effect of Low-Dose Aspirin on Chronic Acid Reflux Esophagitis in Rats. AB - BACKGROUND: Clinical role of low-dose aspirin (LDA) in pathogenesis of gastroesophageal reflux disease is by far controversial. This can be attributed to the paucity of basic research detailing the mechanism of LDA-induced esophageal mucosal injury (EI) on underlying chronic acid reflux esophagitis (RE). AIM: The aim of this study was to clarify the effect of LDA on chronic RE in rats. METHODS: Esophagitis was induced in 8-week-old male Wistar rats by ligating the border between forestomach and glandular portion with a 2-0 silk tie and covering the duodenum with a small piece of 18-Fr Nelaton catheter. Seventy eight chronic RE rat models were divided into five treatment groups, consisting of orally administered vehicle (controls), and aspirin doses of 2, 5, 50 or 100 mg/kg once daily for 28 days. EI was assessed by gross area of macroscopic mucosal injury, severity grade of esophagitis and microscopic depth of infiltration by inflammatory cells. RESULTS: Area of esophagitis in animals with aspirin dose of 100 mg/kg/day showed a 36.5% increase compared with controls, although it failed to achieve statistical significance (p = 0.812). Additionally, the rate of severe EI was increased in animals with aspirin dose of 100 mg/kg/day as compared with controls (p < 0.05). The grade of severity correlated with the depth of inflammation (r s = 0.492, p < 0.001). CONCLUSIONS: Maximal dose aspirin (100 mg/kg/day) contributed in exacerbating preexisting EI. LDA (2 and 5 mg/kg/day), on the other hand, did not affect chronic RE in this model. LDA seems to be safe for use in patients with chronic RE. PMID- 29143192 TI - Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies. AB - No specific antivirals are currently available for two emerging infectious diseases, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). A literature search was performed covering pathogenesis, clinical features and therapeutics, clinically developed drugs for repurposing and novel drug targets. This review presents current knowledge on the epidemiology, pathogenesis and clinical features of the SARS and MERS coronaviruses. The rationale for and outcomes with treatments used for SARS and MERS is discussed. The main focus of the review is on drug development and the potential that drugs approved for other indications provide for repurposing. The drugs we discuss belong to a wide range of different drug classes, such as cancer therapeutics, antipsychotics, and antimalarials. In addition to their activity against MERS and SARS coronaviruses, many of these approved drugs have broad spectrum potential and have already been in clinical use for treating other viral infections. A wealth of knowledge is available for these drugs. However, the information in this review is not meant to guide clinical decisions, and any therapeutic described here should only be used in context of a clinical trial. Potential targets for novel antivirals and antibodies are discussed as well as lessons learned from treatment development for other RNA viruses. The article concludes with a discussion of the gaps in our knowledge and areas for future research on emerging coronaviruses. PMID- 29143198 TI - The effect of parental age on NF1 patients in Turkey. AB - Neurofibromatosis type 1 (NF1) is the most common neurogenetic disorder worldwide, and its clinical presentations are highly variable. NF1 is caused by mutations in the NF1 gene, and 50% of NF1 cases are sporadic, which occur in the absence of a family history of the disease and usually result from a new mutation in the germline of a parent. Advanced paternal age may increase the risk for germinal NF1 mutations; however, some dominant conditions, including neurofibromatosis, have shown a lesser association with paternal age, although there are conflicting reports in the literature. We investigated the effects of paternal and maternal age in 241 NF1 patients (121 sporadic and 120 familial cases) who were seen in Hacettepe hospital, a reference center for genetic diseases in Turkey. For statistical analysis, Spearman's and Chi-square tests were used. In this study, we evaluated paternal and maternal age at birth in sporadic and familial cases of NF1. We also compared the effect of parental age on the appearance and coexistence of various NF1 symptoms. There were no significant statistical differences between paternal age and coexistence of the NF1 symptoms. However, a slightly negative correlation was observed between paternal age and the coexistence of NF1 symptoms in familial cases (p < 0.05). We did not find strong evidence for the effect of parental age on the clinical severity of NF1. PMID- 29143199 TI - Cone-beam CT in paediatric dentistry: DIMITRA project position statement. AB - DIMITRA (dentomaxillofacial paediatric imaging: an investigation towards low-dose radiation induced risks) is a European multicenter and multidisciplinary project focused on optimizing cone-beam CT exposures for children and adolescents. With increasing use of cone-beam CT for dentomaxillofacial diagnostics, concern arises regarding radiation risks associated with this imaging modality, especially for children. Research evidence concerning cone-beam CT indications in children remains limited, while reports mention inconsistent recommendations for dose reduction. Furthermore, there is no paper using the combined and integrated information on the required indication-oriented image quality and the related patient dose levels. In this paper, therefore, the authors initiate an integrated approach based on current evidence regarding image quality and dose, together with the expertise of DIMITRA's members searching for a state of the art. The aim of this DIMITRA position statement is to provide indication-oriented and patient specific recommendations regarding the main cone-beam CT applications in the pediatric field. The authors will review this position statement document when results regarding multidisciplinary approaches evolve, in a period of 5 years or earlier. PMID- 29143200 TI - Structural and perfusion magnetic resonance imaging of the lung in cystic fibrosis. AB - BACKGROUND: Because of its absence of ionising radiation and possibility for obtaining functional information, MRI is promising for assessing lung disease in children who require repetitive imaging for long-term follow-up. OBJECTIVE: To describe MRI findings in children with cystic fibrosis and evaluate semi quantitative dynamic contrast-enhanced lung perfusion. MATERIALS AND METHODS: We retrospectively compared lung MRI in 25 children and young adults with cystic fibrosis (median age 3.7 years) to 12 children (median age 2 years) imaged for other pathologies. MRI at 1.5 T included respiratory-gated sequences and contrast enhanced lung perfusion imaging. We described and graded any morphologic change. Signal enhancement and time to peak values of perfusion abnormalities were compared to those of normally enhancing lung parenchyma. RESULTS: Frequent findings in patients with cystic fibrosis were bronchial wall thickening (24/25, 96%), areas of consolidation (22/25, 88%), enlarged lymph nodes (20/25, 80%), bronchiectasis (5/25, 20%) and mucus plugging (3/25, 12%). Compared to normally enhancing lung, perfusion defects (21/25, 84%), characterised by decreased enhancement, showed prolonged time to peak. Areas of consolidation showed increased enhancement. While time to peak of procedure-related atelectasis was not significantly different from that of normal lung, disease-related consolidation showed prolonged time to peak (P=0.01). CONCLUSION: Lung MRI demonstrates structural and perfusion abnormalities in children and young people with cystic fibrosis. Semi-quantitative assessment of dynamic contrast-enhanced perfusion imaging might allow differentiation between procedure-related atelectasis and disease-related consolidation. PMID- 29143201 TI - Newborn screening for lysosomal storage disorders by tandem mass spectrometry in North East Italy. AB - BACKGROUND: Lysosomal storage diseases (LSDs) are inborn errors of metabolism resulting from 50 different inherited disorders. The increasing availability of treatments and the importance of early intervention have stimulated newborn screening (NBS) to diagnose LSDs and permit early intervention to prevent irreversible impairment or severe disability. We present our experience screening newborns in North East Italy to identify neonates with Mucopolysaccharidosis type I (MPS I) and Pompe, Fabry, and Gaucher diseases. METHODS: Activities of acid beta-glucocerebrosidase (ABG; Gaucher), acid alpha-glucosidase (GAA; Pompe), acid alpha-galactosidase (GLA; Fabry), and acid alpha-L-iduronidase (IDUA; MPS-I) in dried blood spots (DBS) from all newborns during a 17-month period were determined by multiplexed tandem mass spectrometry (MS/MS) using the NeoLSD(r) assay system. Enzymatic activity cutoff values were determined from 3500 anonymous newborn DBS. In the screening study, samples were retested if the value was below cutoff and a second spot was requested, with referral for confirmatory testing and medical evaluation if a low value was obtained. RESULTS: From September 2015 to January 2017, 44,411 newborns were screened for the four LSDs. We recalled 40 neonates (0.09%) for collection of a second DBS. Low activity was confirmed in 20, who had confirmatory testing. Ten of 20 had pathogenic mutations: two Pompe, two Gaucher, five Fabry, and one MPS-I. The incidences of Pompe and Gaucher diseases were similar (1/22,205), with Fabry disease the most frequent (1/8882) and MPS-I the rarest (1/44411). The combined incidence of the four disorders was 1/4411 births. CONCLUSIONS: Simultaneously determining multiple enzyme activities by MS/MS, with a focus on specific biochemical markers, successfully detected newborns with LSDs. The high incidence of these disorders supports this screening program. PMID- 29143203 TI - Relapse of nephrotic syndrome triggered by Kawasaki disease. AB - Minor infections, allergies, insect bites, and bee stings are commonly reported causes of nephrotic syndrome (NS). Herein, we report, to the best of our knowledge, the first case of NS relapse due to Kawasaki disease (KD). An 8-year old boy presented with high fever of 4-day duration. He had developed steroid dependent NS at the age of 4 years and remained in remission after steroid and mizonbin therapy. Renal biopsy, performed at the age of four, showed minimal change (MC) disease. Upon examination, the patient fulfilled 5 of 6 criteria for KD under the Japanese diagnostic guidelines, with positive proteinuria. He was diagnosed with NS relapse caused by KD. Proteinuria resolved after treatment with intravenous immunoglobulin and cyclosporine A. We present the case of an 8-year old boy, whose NS relapsed due to KD. To the best of our knowledge, this is the first case report. It is necessary to recognize that KD can trigger relapse of MCNS. PMID- 29143202 TI - Tobacco plants expressing the maize nitrate transporter ZmNrt2.1 exhibit altered responses of growth and gene expression to nitrate and calcium. AB - BACKGROUND: Nitrate uptake is a highly regulated process. Understanding the intricate interactions between nitrate availability and genetically-controlled nitrate acquisition and metabolism is essential for improving nitrogen use efficiency and increasing nitrate uptake capacity for plants grown in both nitrate-poor and nitrate-enriched environments. In this report, we introduced into tobacco (Nicotiana tabacum) the constitutively expressed maize high-affinity transporter ZmNrt2.1 gene that would bypass the tight control for the endogenous nitrate-responsive genes. By using calcium inhibitors and varying levels of NO3-, Ca2+ and K+, we probed how the host plants were affected in their nitrate response. RESULTS: We found that the ZmNrt2.1-expressing plants had better root growth than the wild type plants when Ca2+ was deficient regardless of the nitrate levels. The growth restriction associated with Ca2+-deficiency can be alleviated with a high level of K+. Furthermore, the transgenic plants exhibited altered expression patterns of several endogenous, nitrate-responsive genes, including the high- and low-affinity nitrate transporters, the Bric-a Brac/Tramtrack/Broad protein BT2 and the transcription factor TGA-binding protein TGA1, in responding to treatments of NO3-, K+ or inhibitors for the calcium channel and the cytosolic Ca2+-regulating phospholipase C, as compared to the wild type plants under the same treatments. Their expression was not only responsive to nitrate, but also affected by Ca2+. There were also different patterns of gene expression between roots and shoots. CONCLUSION: Our results demonstrate the ectopic effect of the maize nitrate transporter on the host plant's overall gene expression of nitrate sensing system, and further highlight the involvement of calcium in nitrate sensing in tobacco plants. PMID- 29143204 TI - Eric Heinz Lenneberg (1921-1975). PMID- 29143205 TI - Ugo Cerletti (1877-1963). PMID- 29143206 TI - Characteristics of two distinct clinical phenotypes of functional (psychogenic) dystonia: follow-up study. AB - BACKGROUND: The fixed dystonia phenotype was originally established as a prototype of functional dystonia. Nevertheless, in recent reports different functional dystonia phenotypes have been recognized with dystonic movement comprising phasic instead of tonic contraction. OBJECTIVES: To examine clinical characteristic in all patients with dystonia who fulfilled the criteria for functional movement disorders irrespective of phenotype in an attempt to determine parameters of clinical presentations that might impact the disease progression pattern and outcome. METHODS: Patients presented with dystonia features incompatible with organic disease without other features required for the diagnosis of functional movement disorders were analyzed and prospectively followed-up. The two-step cluster analysis was performed to obtain the subgroups of dystonia phenotypes. RESULTS: The two-step cluster analysis extracted two subgroup of patients. Patients of the first cluster (68.8%) presented with "mobile" dystonia (84.9%), of cranial/neck/trunk localization (90.9%), fluctuated clinical course (69.7%), with frequent additional movement or other functional neurological disorders (63.6%) during follow-up. In the second cluster (31.2%) all of the patients presented with "fixed" dystonia of extremities, and the clinical course was characterized by either the disease progression (60%), or continuous without improvement (26.7%), and rare occurrence of additional functional neurological disorders (13.3%). CONCLUSION: In terms of clinical and demographic features as well as pattern of disease progression there are two clinical phenotypes in patients with functional dystonia. Distinctive features of incongruence and inconstancy are characteristic for "mobile" functional dystonia subgroup of patients. PMID- 29143207 TI - Contribution of EEG in transient neurological deficits. AB - Identification of stroke mimics and 'chameleons' among transient neurological deficits (TND) is critical. Diagnostic workup consists of a brain imaging study, for a vascular disease or a brain tumour and EEG, for epileptiform discharges. The precise role of EEG in this diagnostic workup has, however, never been clearly delineated. However, this could be crucial in cases of atypical or incomplete presentation with consequences on disease management and treatment. We analysed the EEG patterns on 95 consecutive patients referred for an EEG within 7 days of a TND with diagnostic uncertainty. Patients were classified at the discharge or the 3-month follow-up visit as: 'ischemic origin', 'migraine aura', 'focal seizure', and 'other'. All patients had a brain imaging study. EEG characteristics were correlated to the TND symptoms, imaging study, and final diagnosis. Sixty four (67%) were of acute onset. Median symptom duration was 45 min. Thirty two % were 'ischemic', 14% 'migraine aura', 19% 'focal seizure', and 36% 'other' cause. EEGs were recorded with a median delay of 1.6 day after symptoms onset. Forty EEGs (42%) were abnormal. Focal slow waves were the most common finding (43%), also in the ischemic group (43%), whether patients had a typical presentation or not. Epileptiform discharges were found in three patients, one with focal seizure and two with migraine aura. Non-specific EEG focal slowing is commonly found in TND, and may last several days. We found no difference in EEG presentation between stroke mimics and stroke chameleons, and between other diagnoses. PMID- 29143209 TI - The medial vestibular nuclei, a vulnerable target in thiamine deficiency. AB - BACKGROUND: Bilateral medial vestibular nuclei (MVN) is a common target in thiamine depletion and results in acute vestibular failure. Involvement of the MVN was present in 27 out of 38 brainstem sections reported in the largest thiamine deficiency autopsy cohort with Wernicke's encephalopathy. METHOD: Serial clinical, imaging and vestibulo-ocular reflex gain measured with the video head impulse (vHIT) in one patient with acute thiamine deficiency. RESULTS: Low horizontal VOR gain correlated with an abnormal manual head impulse and with MRI evidence of MVN in an alcohol-dependent patient with low thiamine levels. The vertical VOR gain was either normal or mildly abnormal. Thiamine replacement and normal diet restored the VOR gain and MRI signal changes to normal. CONCLUSION: This single case study provides clinical-imaging correlation for symmetric MVN compromise in thiamine deficiency, its effect on the VOR gain and the favorable response to thiamine and diet replacement when identified early. PMID- 29143210 TI - Jean-Alexandre Barre (1880-1967). PMID- 29143208 TI - A new measure for end of life planning, preparation, and preferences in Huntington disease: HDQLIFE end of life planning. AB - BACKGROUND: Huntington disease is a fatal inherited neurodegenerative disease. Because the end result of Huntington disease is death due to Huntington disease related causes, there is a need for better understanding and caring for individuals at their end of life. AIM: The purpose of this study was to develop a new measure to evaluate end of life planning. DESIGN: We conducted qualitative focus groups, solicited expert input, and completed a literature review to develop a 16-item measure to evaluate important aspects of end of life planning for Huntington disease. Item response theory and differential item functioning analyses were utilized to examine the psychometric properties of items; exploratory factor analysis was used to establish meaningful subscales. PARTICIPANTS: Participants included 508 individuals with pre-manifest or manifest Huntington disease. RESULTS: Item response theory supported the retention of all 16 items on the huntington disease quality of life ("HDQLIFE") end of life planning measure. Exploratory factor analysis supported a four-factor structure: legal planning, financial planning, preferences for hospice care, and preferences for conditions (locations, surroundings, etc.) at the time of death. Although a handful of items exhibited some evidence of differential item functioning, these items were retained due to their relevant clinical content. The final 16-item scale includes an overall total score and four subscale scores that reflect the different end of life planning constructs. CONCLUSIONS: The 16-item HDQLIFE end of life planning measure demonstrates adequate psychometric properties; it may be a useful tool for clinicians to clarify patients' preferences about end of life care. PMID- 29143211 TI - Redirecting T cells to glypican-3 with 28.41BB.zeta and 28.zeta-41BBL CARs for hepatocellular carcinoma treatment. PMID- 29143212 TI - Rhodococcus psychrotolerans sp. nov., isolated from rhizosphere of Deschampsia antarctica. AB - A novel actinobacterium, designated strain CMAA 1533T, was isolated from the rhizosphere of Deschampsia antarctica collected at King George Island, Antarctic Peninsula. Strain CMAA 1533T was found to grow over a wide range of temperatures (4-28 degrees C) and pH (4-10). Macroscopically, the colonies were observed to be circular shaped, smooth, brittle and opaque-cream on most of the culture media tested. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CMAA 1533T belongs to the family Nocardiaceae and forms a distinct phyletic line within the genus Rhodococcus. Sequence similarity calculations indicated that the novel strain is closely related to Rhodococcus degradans CCM 4446T, Rhodococcus erythropolis NBRC 15567T and Rhodococcus triatomae DSM 44892T (<= 96.9%). The organism was found to contain meso-diaminopimelic acid, galactose and arabinose in whole cell hydrolysates. Its predominant isoprenologue was identified as MK-8(H2) and the polar lipids as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannosides. The major fatty acids were identified as Summed feature (C16:1 omega6c and/or C16:1 omega7c), C16:0, C18:1 omega9c and 10-methyl C18:0. The G+C content of genomic DNA was determined to be 65.5 mol%. Unlike the closely related type strains, CMAA 1533T can grow at 4 degrees C but not at 37 degrees C and was able to utilise adonitol and galactose as sole carbon sources. Based on phylogenetic, chemotaxonomic and physiological data, it is concluded that strain CMAA 1533T (= NRRL B-65465T = DSM 104532T) represents a new species of the genus Rhodococcus, for which the name Rhodococcus psychrotolerans sp. nov. is proposed. PMID- 29143213 TI - Colorectal Surgery Fellowship Improves In-hospital Mortality After Colectomy and Proctectomy Irrespective of Hospital and Surgeon Volume. AB - BACKGROUND: General surgery residents are increasingly pursuing sub-specialty training in colorectal (CR) surgery. However, the majority of operations performed by CR surgeons are also performed by general surgeons. This study aimed to assess in-hospital mortality stratified by CR training status after adjusting for surgeon and hospital volume. METHODS: The Statewide Planning and Research Cooperative system database was used to identify all patients who underwent colectomy/proctectomy from January 1, 2000, to December 31, 2014, in the state of New York. Operations performed by board-certified CR surgeons were identified. The relationships between CR board certification and in-hospital mortality, in hospital complications, length of stay, and ostomy were assessed using multivariate regression models. RESULTS: Two hundred seventy thousand six hundred eighty-four patients underwent colectomy/proctectomy over the study period. Seventy-two thousand two hundred seventy-nine (26.7%) of operations were performed by CR surgeons. Without adjusting for hospital and surgeon volume, in hospital mortality was lower for those undergoing colectomy/proctectomy by a CR surgeon (OR 0.49, CI 0.44-0.54, p = 0.001). After controlling for hospital and surgeon volume, the odds of inpatient mortality after colectomy/proctectomy for those operated on by CR surgeons weakened to 0.76 (CI 0.68-0.86, p = 0.001). Hospital and surgeon volume accounted for 53% of the reduction in in-hospital mortality when CR surgeons performed colectomy/proctectomy. Patients who underwent surgery by a CR surgeon had a shorter inpatient stay (0.8 days, p = 0.001) and a decreased chance of colostomy (OR 0.86, CI 0.78-0.95, p < 0.001). CONCLUSIONS: For patients undergoing colectomy/proctectomy, in-hospital mortality decreased when the operation was performed by a CR surgeon even after accounting for hospital and surgeon volume. PMID- 29143214 TI - Cellular processing of gold nanoparticles: CE-ICP-MS evidence for the speciation changes in human cytosol. AB - The cellular uptake of gold nanoparticles (AuNPs) may (or may not) affect their speciation, but information on the chemical forms in which the particles exist in the cell remains obscure. An analytical method based on the use of capillary electrophoresis hyphenated with inductively coupled plasma mass spectrometry (ICP MS) has been proposed to shed light on the intracellular processing of AuNPs. It was observed that when being introduced into normal cytosol, the conjugates of 10 50 nm AuNPs with albumin evolved in human serum stayed intact. On the contrary, under simulated cancer cytosol conditions, the nanoconjugates underwent decomposition, the rate of which and the resulting metal speciation patterns were strongly influenced by particle size. The new peaks that appeared in ICP-MS electropherograms could be ascribed to nanosized species, as upon ultracentrifugation, they quantitatively precipitated whereas the supernatant showed only trace Au signals. Our present study is the first step to unravel a mystery of the cellular chemistry for metal-based nanomedicines. PMID- 29143215 TI - Combining cationic and anionic mixed-mode sorbents in a single cartridge to extract basic and acidic pharmaceuticals simultaneously from environmental waters. AB - The aim of the present study is to broaden the applications of mixed-mode ion exchange solid-phase extraction sorbents to extract both basic and acidic compounds simultaneously by combining the sorbents in a single cartridge and developing a simplified extraction procedure. Four different cartridges containing negative and positive charges in the same configuration were evaluated and compared to extract a group of basic, neutral, and acidic pharmaceuticals selected as model compounds. After a thorough optimization of the extraction conditions, the four different cartridges showed to be capable of retaining basic and acidic pharmaceuticals simultaneously through ionic interactions, allowing the introduction of a washing step with 15 mL methanol to eliminate interferences retained by hydrophobic interactions. Using the best combined cartridge, a method was developed, validated, and further applied to environmental waters to demonstrate that the method is promising for the extraction of basic and acidic compounds from very complex samples. PMID- 29143216 TI - Self-perception and determinants of color vision in Parkinson's disease. AB - Visual dysfunction is common in patients with Parkinson's disease (PD). The objective of this study was to investigate the perceived impact of visual dysfunction and especially color vision loss on PD patients, and to identify retinal and disease factors associated with color vision. Thirty PD patients and thirty-four healthy controls were included. Participants performed the Farnsworth Munsell Hue-100 test (FMT). Patients answered the National Eye Institute Visual Function Questionnaire (NEI-VFQ), Unified Parkinson's Disease Rating Scale (UPDRS) assessment, and underwent optical coherence tomography with measurement of retinal nerve fiber layer, ganglion cell layer + inner plexiform layer (GCIPL), and outer nuclear and photoreceptor layer. Dopaminergic treatment was assessed as levodopa equivalent dose (LED). Vision domains significantly worse in PD patients compared to normative data were General Vision, Near Activities, Distance Activities, Vision-Specific Dependency, Driving, and Peripheral Vision. Worse NEI-VFQ total scores were associated with worse UPDRS, higher LED, and higher age, but not with FMT, visual acuity, or OCT measures. Only two patients (7%) reported problems with color vision. In contrast, patients performed significantly worse in the FMT than healthy controls and 17 (56.7%) patients were outside the 95th percentile of normative data. In multiple regression analyses, lower LED and higher age were associated with worse color vision in the FMT. PD patients are not aware of color vision deficits. Given the impact of color vision loss on everyday tasks in other conditions, future research should investigate the impact of vision deficits on disease burden in PD. PMID- 29143217 TI - Fluid biomarker agreement and interrelation in dementia due to Alzheimer's disease. AB - The cerebrospinal fluid (CSF) levels of beta-amyloid 42, total tau, and phosphorylated tau 181 are supposed to be all continuously abnormal in dementia due to Alzheimer's disease (AD), being the most advanced disease stage. The aim of the present study, which included a monocentric and a multicentric sample (N = 119 and 178, respectively), was to investigate the degree of CSF biomarker agreement and interrelation in AD dementia. Based on previously published cut-off values, biomarker values were categorized as positive or negative for AD (dichotomization strategy) and as either positive, negative, or borderline (trichotomization strategy). The statistical analyses relied on distance correlation analysis and kappa (k) statistics. Poor agreement (k < 0.4) and low interrelations between the studied biomarkers were detected in all cases with the exception of the interrelation between the markers total tau and phosphorylated tau 181, especially in the monocentric sample. Interestingly, lower interrelation and agreement degrees were observed in carriers of the Apolipoprotein E epsilon4 allele compared to non-carriers. The clinical phenotype currently referred to as "AD dementia" is characterized by an inhomogeneous CSF biomarker profile, possibly mirroring the complex genesis of AD-typical dementia symptoms and pointing to the necessity of shedding more light on the hypothesis of biomarker stability over time in symptomatic AD. PMID- 29143218 TI - Reactions to online colorectal cancer risk estimates among a nationally representative sample of adults who have never been screened. AB - Data on the public's reactions to online tailored colorectal cancer (CRC) risk estimates are sparse. We assessed among 560 men and women aged 50-75 with no CRC screening history reactions to online tailored CRC estimated comparative risk (i.e., self vs. other their age and sex). Assessed were reactions to estimate (i.e., repeating back estimate, match between perceived comparative risk and estimate, accuracy and usefulness of estimate, emotional reactions), risk appraisals and screening intentions. 73% of the sample accurately repeated back their estimate; the match between perceived comparative risk and the estimate was lowest among those informed of being at higher risk. Higher estimates were viewed as less useful and evoked more negative emotions. Viewing the estimate as more useful and experiencing more negative emotions were related with higher risk appraisals and, in turn, screening intentions. These data indicate that adults at higher comparative risk resist accepting a higher risk status. PMID- 29143220 TI - Validation of the 8th AJCC prognostic staging system for breast cancer in a population-based setting. AB - OBJECTIVES: To validate the newly proposed American Joint Committee on Cancer (AJCC) prognostic staging system for breast cancer. METHODS: Surveillance, epidemiology, and end results (SEER) database (2010-2014) was accessed. Cumulative incidence function was conducted (through assessment of sub distribution hazard) according to both anatomical and prognostic stages. Likewise, Cox cause-specific hazard ratio with pairwise hazard ratio comparisons were also assessed for both anatomical and prognostic stages. Survival analyses according to both anatomical and prognostic staging systems were conducted through Kaplan-Meier analysis/log-rank testing. RESULTS: A total of 209,304 patients with non-metastatic breast cancer and upfront surgical treatment were included. According to anatomical stages, pairwise Cox hazard ratio comparisons between different stages were significant (P < 0.0001) except between stage IIIB and stage IIIC, while according to prognostic stages, all pairwise hazard ratio comparisons between different stages were significant (P < 0.05). Sub distribution hazard ratio (using breast cancer death as the primary failure endpoint and using other causes of death as competing causes of death) adjusted for age, race, and surgery was as follows: for the anatomical groups, it was 1.671 (95% CI 1.627-1.716; P < 0.0001) indicating increasing risk of death from breast cancer with increasing stage; however, for the prognostic groups it was 1.790 (95% CI 1.744-1.838; P < 0.0001) indicating increasing risk of death from breast cancer with increasing stage. C-statistic was assessed using breast cancer death as the dependent variable; and the findings for the two staging systems were as follows: anatomical staging: 0.767 (SE 0.004; 95% CI 0.759-0.776); prognostic staging: 0.814 (SE 0.004; 95% CI 0.807-0.822). CONCLUSIONS: The current analysis showed an improvement in the discriminatory value for the prognostic staging system compared to the anatomical staging system and endorsed its routine use in clinical practice. PMID- 29143219 TI - Glutamatergic, GABAergic, and endocannabinoid neurotransmissions within the dorsal hippocampus modulate the cardiac baroreflex function in rats. AB - The dorsal hippocampus (DH) is involved in the modulation of the cardiac baroreflex function. There is a wide expression of the NMDA and AMPA/Kainate receptors within the DH. Glutamate administration into the DH triggers both tachycardia and pressor responses. Moreover, GABAergic interneurons and endocannabinoid system play an important role in modulation of the activity of glutamatergic neurons within the DH. Therefore, the present work aimed to evaluate the involvement of the glutamatergic, GABAergic, and endocannabinoid neurotransmissions within the DH in cardiac baroreflex function in rats. We have used the technique of vasoactive drugs infusion to build both sigmoidal curves and linear regressions to analyze the cardiac baroreflex function. Bilateral injection into the DH of DL-AP7, a NMDA receptor antagonist (10 or 50 nmol/500 nL), or NBQX, an AMPA/Kainate antagonist (100 nmol/ 500 nL), reduced the cardiac baroreflex function. On the other hand, bilateral injection of Bicuculline, a GABAA receptor antagonist (1 nmol/500 nL), or AM251, a CB1 receptor antagonist (10 or 100 pmol/500 nL), increased the cardiac baroreflex function. Furthermore, 1 nmol/500 nL of the NMDA receptor antagonist, when administrated alone, was ineffective to change baroreflex function, but it was able to inhibit the alteration in the cardiac baroreflex function elicited by the dose of 100 pmol/500 nL of the CB1 receptor antagonist. Taken together, these findings suggest that glutamatergic, GABAergic, and endocannabinoid neurotransmissions interact each other within the DH to modulate the cardiac baroreflex function. PMID- 29143221 TI - Controlling Streptococcus mutans and Staphylococcus aureus biofilms with direct current and chlorhexidine. AB - Microbial biofilms formed on biomaterials are major causes of chronic infections. Among them, Gram-positive bacteria Streptococcus mutans and Staphylococcus aureus are important pathogens causing infections associated with dental caries (tooth decay) and other medical implants. Unfortunately, current antimicrobial approaches are ineffective in disrupting established biofilms and new methods are needed to improve the efficacy. In this study, we report that the biofilm cells of S. mutans and S. aureus can be effectively killed by low-level direct current (DC) and through synergy in concurrent treatment with DC and chlorhexidine (CHX) at low concentrations. For example, after treatment with 28 uA/cm2 DC and 50 ug/mL CHX for 1 h, the viability of biofilm cells was reduced by approximately 4 and 5 logs for S. mutans and S. aureus, respectively. These results are useful for developing more effective approaches to control pathogenic biofilms. PMID- 29143222 TI - Quantitative analysis of the level of readability of online emergency radiology based patient education resources. AB - PURPOSE: The vast amount of information found on the internet, combined with its accessibility, makes it a widely utilized resource for Americans to find information pertaining to medical information. The field of radiology is no exception. In this paper, we assess the readability level of websites pertaining specifically to emergency radiology. METHODS: Using Google, 23 terms were searched, and the top 10 results were recorded. Each link was evaluated for its readability level using a set of ten reputable readability scales. The search terms included the following: abdominal ultrasound, abdominal aortic aneurysm, aortic dissection, appendicitis, cord compression, CT abdomen, cholecystitis, CT chest, diverticulitis, ectopic pregnancy, epidural hematoma, dural venous thrombosis, head CT, MRI brain, MR angiography, MRI spine, ovarian torsion, pancreatitis, pelvic ultrasound, pneumoperitoneum, pulmonary embolism, subarachnoid hemorrhage, and subdural hematoma. Any content that was not written for patients was excluded. RESULTS: The 230 articles that were assessed were written, on average, at a 12.1 grade level. Only 2 of the 230 articles (1%) were written at the third to seventh grade recommended reading level set forth by the National Institutes of Health (NIH) and American Medical Association (AMA). Fifty two percent of the 230 articles were written so as to require a minimum of a high school education (at least a 12th grade level). Additionally, 17 of the 230 articles (7.3%) were written at a level that exceeded an undergraduate education (at least a 16th grade level). CONCLUSIONS: The majority of websites with emergency radiology-related patient education materials are not adhering to the NIH and AMA's recommended reading levels, and it is likely that the average reader is not benefiting fully from these information outlets. With the link between health literacy and poor health outcomes, it is important to address the online content in this area of radiology, allowing for patient to more fully benefit from their online searches. PMID- 29143223 TI - Accelerating and Strengthening Native American Health Research Through a Collaborative NIH Initiative. AB - This paper is intended to provide an overview of the considerations that informed the development of a National Institutes of Health funding opportunity to promote health and prevent disease in Native Americans, including American Indian, Alaska Native, and Native Hawaiian communities. NIH Institute staff thoughtfully considered epidemiologic research findings and feedback from constituents regarding the need for more published research overall and stronger prevention efforts to address persistent health concerns affecting many Native communities. This led to the publication of four funding announcements supported by multiple NIH Institutes and one NIH Office. Through the efforts of researchers, tribal leaders, community collaborators, and NIH leadership and staff, a growing body of knowledge regarding culturally informed approaches to supporting health in Native Americans is emerging. This article describes how staff who developed the funding opportunities envisioned a process to support high impact science through ensuring methodological rigor, responsiveness to prevention needs, and respect for community heritage, values, and history with non-Native peoples. In addition, this article highlights the growth of the researchers and collaborators within a community of scientists expanding the knowledge base further by sharing their research resources, instruments, and strategies for engaging in scientific inquiry that meets the needs of Native communities and those of funding organizations. PMID- 29143224 TI - Investigation of DNA transfer onto clothing during regular daily activities. AB - Low levels of DNA from an unidentified human source, often referred to as trace DNA, are ubiquitous, can be transferred onto objects by either direct or indirect methods and have an unknown longevity in situ. Clothing items from crime scenes are often submitted for trace DNA analysis, usually in attempt to identify a person of interest. This study examined the transfer of DNA onto three 10 * 10 cm areas located on the front, back and shoulder of an individual's external clothing (n = 300) during a regular day's activity. After wearing for a day, the DNA quantity on all three areas increased approximately 8-fold, which usually corresponded with an increase in the endogenous DNA from the wearer on the front area of the shirt. However, the back area of the shirt was more likely to demonstrate mixtures of endogenous and extraneous DNA. An additional study was also carried out to examine whether domestic laundering is a possible mechanism for the transfer of foreign DNA onto freshly laundered items and revealed that 74% of UV-treated cotton swatch samples produced DNA profiles after laundry with household garments. In summary, this study highlights the ease of DNA transfer onto an individual's external clothing during a regular day, and that extraneous DNA may be already on the clothing item prior to it being worn. The study provides empirical data to assist in the interpretation of trace DNA profiles and support a Bayesian approach to estimate statistical likelihoods for the transfer of foreign DNA. Graphical abstract ?. PMID- 29143225 TI - Diurnal regulation of the floral scent emission by light and circadian rhythm in the Phalaenopsis orchids. AB - BACKGROUND: Phalaenopsis bellina and its closely related species, P. violacea, emit linalool, geraniol and their derivatives as the predominant monoterpenes at the full-bloom stages. Geranyl diphosphate synthase (PbGDPS) is the key enzyme that converts precursors for monoterpene biosynthesis. Besides the monoterpenes being synthesized in concert with floral development stages, we noticed that the scent emission of P. bellina and P. violacea was detected mainly in the daytime. RESULTS: The monoterpenes of P. violacea flowers displayed a diurnal emission pattern, which was regulated by an internal oscillator in the treatment of constant light. In contrast, constant dark diminished the scent emission levels, indicating that light also affects monoterpene emission in P. violacea. Further treating P. violacea with various light wavelengths showed that the monoterpene emission was greatest in white light condition. Other Phalaenopsis hybrids, including P. I-Hsin Venus 'KHM2212' and P. Meidarland Bellina Age 'LM128', responded differently to various light wavelengths but most of them still showed the highest scent emission under the whole spectra of light. A great number of light-responsive, HY5-interacting, and circadian-responsive elements was enriched on the promoters of both structural genes and transcription factors for monoterpene biosynthesis. Furthermore, several putative genes encoding components involved in light and circadian signaling pathways were also identified in the transcriptome of P. bellina flowers at consecutive stages (from the anthesis day to day 7 post anthesis). CONCLUSIONS: Taken together, both circadian clock and light factors had positive effects on orchid floral scent emission, and the regulation resided on the control of both structural genes and transcription factors for monoterpene biosynthesis. PMID- 29143226 TI - Aligned ovine diaphragmatic myoblasts overexpressing human connexin-43 seeded on poly (L-lactic acid) scaffolds for potential use in cardiac regeneration. AB - Diaphragmatic myoblasts (DMs) are precursors of type-1 muscle cells displaying high exhaustion threshold on account that they contract and relax 20 times/min over a lifespan, making them potentially useful in cardiac regeneration strategies. Besides, it has been shown that biomaterials for stem cell delivery improve cell retention and viability in the target organ. In the present study, we aimed at developing a novel approach based on the use of poly (L-lactic acid) (PLLA) scaffolds seeded with DMs overexpressing connexin-43 (cx43), a gap junction protein that promotes inter-cell connectivity. DMs isolated from ovine diaphragm biopsies were characterized by immunohistochemistry and ability to differentiate into myotubes (MTs) and transduced with a lentiviral vector encoding cx43. After confirming cx43 expression (RT-qPCR and Western blot) and its effect on inter-cell connectivity (fluorescence recovery after photobleaching), DMs were grown on fiber-aligned or random PLLA scaffolds. DMs were successfully isolated and characterized. Cx43 mRNA and protein were overexpressed and favored inter-cell connectivity. Alignment of the scaffold fibers not only aligned but also elongated the cells, increasing the contact surface between them. This novel approach is feasible and combines the advantages of bioresorbable scaffolds as delivery method and a cell type that on account of its features may be suitable for cardiac regeneration. Future studies on animal models of myocardial infarction are needed to establish its usefulness on scar reduction and cardiac function. PMID- 29143227 TI - PDGFR inhibition mediated intracellular signalling in C6 glioma growth and migration: role of ERK and ROCK pathway. AB - Aberrant PDGFR (Platelet derived growth factor receptor) signalling in brain tumors and gliomas is one of the primary cause of tumor progression. PDGFR stimulation by its ligand and the role of its downstream mediators such as extracellular regulated kinases (ERK1/2), PI3K and ROCK pathways have not been thoroughly investigated. The present study sought to investigate the role of PDGF receptor signalling inhibition on suppression of rat C6 glioma growth and migration. Treatment of C6 cells with PDGFR inhibitor, AG1295 caused a significant reduction in migration and proliferation by regulating the ERK and ROCK signalling. Subsequently, PDGFR blocking was demonstrated to regulate cytoskeleton reorganization by modulating the Actin-pMLC reorganization and pERK FAK-Paxillin complex formation which may further regulate the C6 glioma migration. Further, other malignant behaviour of C6 glioma such as anchorage independent growth, adhesion, invasion and sphere forming abilities were found to be impaired by PDGFR blocking. PDGFR inhibition further regulates the C6 glioma tumor behaviour by inducing gene expression of GFAP, BDNF, and MECP2 and down regulating FAK expression. In conclusion, our data elucidate novel mechanisms involve in PDGFR inhibition mediated inhibition of C6 glioma growth and migration which can be a future potential target for the treatment of glioma. PMID- 29143228 TI - Effect of exosome biomarkers for diagnosis and prognosis of breast cancer patients. AB - PURPOSE: Exosomes are gradually detected as an indicator for diagnosis and prognosis of breast cancer in clinic and a systematic review was conducted. METHODS: A search for clinical studies published before July 1, 2017 was performed. Methods of exosome purification and identification from all studies were extracted. For diagnosis evaluation, the comparison of exosome biomarkers expression between breast cancer patients and healthy women was obtained; for prognosis prediction, the correlation between exosome biomarkers expression and chemotherapy resistance, overall survival (OS), disease-free survival (DFS), recurrence and metastasis of breast cancer was also extracted. RESULTS: A total of 11 studies with 921 breast cancer patients were included. Ultracentrifugation is the most frequent method to purify exosomes and transmission electron microscopy is commonly used to identify exosomes. Exosome biomarkers (such as HER2, CD47, Del-1, miR-1246 and miR-21) in breast cancer patients are significantly higher than those in healthy controls, exosomal GSTP1 and TRPC5 are related to chemotherapy resistance, exosome-carrying TRPC5, NANOG, NEUROD1, HTR7, KISS1R and HOXC are correlated to PFS, DFS or OS, and some exosomal proteins (HER2, KDR, CD49d, CXCR4 and CD44) as well as miRNAs (miR-340-5p, miR-17-5p, miR 130a-3p, miR-93-5p) are associated with tumor recurrence or distant organ metastasis. CONCLUSIONS: Exosome biomarkers can be used for early diagnosis and prognosis of breast cancer patients in clinic. PMID- 29143229 TI - Meta-analysis of survival benefit with postoperative chemoradiotherapy in patients of lymph node positive esophageal carcinoma. AB - BACKGROUND: The effect of postoperative chemoradiotherapy (CRT) for esophageal carcinoma (EC) was investigated. Patients who can obtain benefit from this treatment modality have not yet been well identified. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library for studies published from January 1993 to July 2016. Research comparing surgery alone (SA) with postoperative CRT in patients with resectable EC was procured; collected articles were written in English. RESULTS: Nine studies comparing of postoperative CRT versus SA (n = 1650) in patients with resectable EC met the inclusion criteria. No survival benefit was achieved for postoperative CRT compared with SA. Subgroup analysis was conducted for patients under resection with positive lymph node carcinoma; there was a significant survival benefit at 1 year [risk ratio (RR) = 0.55 95% CI: 0.37-0.82; P = 0.003], 3 years (RR = 0.71 95% CI: 0.61-0.83; P<0.0001), as well as 5 years (RR = 0.86 95% CI: 0.78-0.94; P = 0.0007). Subgroup analysis by tumor histology of squamous cell carcinoma (SCC) was also performed, but there was no significant survival benefit when postoperative CRT was compared with SA. Fail models after surgery were performed; the RR for local control rate and distant metastasis rate were 0.64 (95% CI 0.49-0.85; P = 0.002) and 0.87 (95% CI 0.67-1.15; P = 0.34), which indicates lower local recurrence rates of post-CRT than that of SA. CONCLUSION: This meta-analysis demonstrated a survival benefit of postoperative CRT over SA in resectable EC patients with positive lymph nodes. Improvements of local control rates with postoperative CRT were also detected. PMID- 29143231 TI - Correction to: Combination Therapy with Pirfenidone plus Prednisolone Ameliorates Paraquat-Induced Pulmonary Fibrosis. AB - Unfortunately, the original publication of this article contained mistakes, and the authors would like to correct them. The corrected details are given below. PMID- 29143230 TI - The Efficacy of Biologic Therapy for the Management of Palmoplantar Psoriasis and Palmoplantar Pustulosis: A Systematic Review. AB - INTRODUCTION: Palmoplantar psoriasis (PP) and palmoplantar pustulosis (PPP) are diseases affecting the hands and/or feet that can cause marked physical discomfort and functional disability. The tumor necrosis factor-alpha antagonists adalimumab, etanercept, and infliximab, the interleukin (IL)-17A inhibitors ixekizumab and secukinumab, and the IL-23 or IL-12/IL-23 inhibitors guselkumab and ustekinumab have been well studied for the treatment of moderate to severe plaque psoriasis. Less is known about the efficacy and safety of these agents for the treatment of PP (hyperkeratotic and pustular forms) and PPP. The aim of this review was to investigate the efficacy of biologic therapy for the treatment of hyperkeratotic PP, pustular PP, and PPP. METHODS: A systematic search of the medical electronic databases (Medline, Embase, and Cochrane Library) was conducted to identify studies or case reports which both used biologic therapy for the treatment of hyperkeratotic PP, pustular PP, and PPP and reported treatment outcomes. RESULTS: The systematic search identified 579 published articles, of which 44 were included in the analysis. Seven of the articles involved randomized placebo-controlled trials, two were open label trials, and the remaining were cohort studies, case series, or case reports. In the randomized controlled trials on the treatment of hyperkeratotic PP, adalimumab, guselkumab, infliximab, ixekizumab, and secukinumab each demonstrated superiority to placebo at 16, 16, 14, 12, and 12 or 16 weeks, respectively (p < 0.05). For the treatment of pustular PP, ustekinumab 45 mg was not superior to placebo at 12 and 16 weeks, respectively (p > 0.05), although an open label study demonstrated that four of five patients on a therapeutic regimen of ustekinumab 90 mg achieved clinical clearance at 16 weeks. For the treatment of PPP, etanercept and ustekinumab 45 mg were not superior to placebo at 12 and 16 weeks, respectively (p > 0.05). A combined analysis of studies for hyperkeratotic PP demonstrated that 94.7%, 90.0%, 82.5%, 89.1%, and 86.7% of patients experienced an improvement of at least 50% upon treatment with adalimumab, guselkumab, ixekizumab, secukinumab, and ustekinumab, respectively. In a combined analysis of case reports examining PPP, infliximab showed the greatest efficacy at 100.0% clinical improvement of patients from case reports, followed by ustekinumab at 58.8% clinical improvement. Few serious adverse events were reported, but several were reported in patients treated with infliximab or secukinumab. CONCLUSION: Biologic therapy is effective and well-tolerated for the treatment of hyperkeratotic PP, but less data are available on the treatment of pustular PP or PPP. Adalimumab, guselkumab, ixekizumab, secukinumab, and ustekinumab all showed > 80% efficacy for the treatment of hyperkeratotic PP, while infliximab and ustekinumab showed moderate efficacy for the treatment of pustular PP, and infliximab was the most efficacious treatment for PPP. PMID- 29143232 TI - Assessment of gastrointestinal nematode infection, anthelmintic usage and husbandry practices on two small-scale goat farms in Malaysia. AB - Haemonchosis is a common problem on goat farms in tropical countries such as Malaysia. Prevention of production losses generally depends on the use of anthelmintic drugs, but is threatened by the emergence of anthelmintic resistance. This study investigates anthelmintic efficacy on small-scale Malaysian goat farms and describes putative risk factors. Adult goats had moderate to high pre-treatment faecal trichostrongyle egg counts, despite being housed on slatted floors and fed on cut-and-carry forage, raising questions about the source of nematode infection. Our results show multiple resistance to benzimidazole and macrocyclic lactone anthelmintic drugs and allow us to discuss the genetic origins of resistance with reference to farm husbandry and management. We conclude that improvement in Malaysian goat production efficiency will require the development of sustainable helminth control strategies, underpinned by a better understanding of the origins and population genetics of anthelmintic resistance. PMID- 29143233 TI - Etoposide Upregulates Survival Favoring Sphingosine-1-Phosphate in Etoposide Resistant Retinoblastoma Cells. AB - Improved knowledge of retinoblastoma chemotherapy resistance is needed to raise treatment efficiency. The objective of this study was to test whether etoposide alters glucosyl-ceramide, ceramide, sphingosine, and sphingosine-1-phosphate (sphingosine-1-P) levels in parental retinoblastoma cells (WERI Rb1) or their etoposide-resistant subclones (WERI EtoR). WERI Rb1 and WERI EtoR were incubated with 400 ng/ml etoposide for 24 h. Levels of glucosyl-ceramides, ceramides, sphingosine, sphingosine-1-P were detected by Q-TOF mass spectrometry. Statistical analysis was done by ANOVA followed by Tukey post-hoc test (p < 0.05). The mRNA expression of sphingolipid pathways enzymes in WERI Rb1, WERI EtoR and four human retinoblastoma tissue samples was analyzed by quantitative real-time PCR. Pathways enzymes mRNA expression confirmed similarities of human sphingolipid metabolism in both cell lines and tissue samples, but different relative expression. Significant up-regulation of sphingosine was seen in both cell lines (p < 0.001). Only sphingosine-1-P up-regulation was significantly increased in WERI EtoR (p < 0.01), but not in WERI Rb1 (p > 0.2). Both cell lines upregulate pro-apoptotic sphingosine after etoposide incubation, but only WERI EtoR produces additional survival favorable sphingosine-1-P. These data may suggest a role of sphingosine-1-P in retinoblastoma chemotherapy resistance, although this seems not to be the only resistance mechanism. PMID- 29143236 TI - The Making of Informed Choice in Midwifery: A Feminist Experiment in Care. AB - This paper is about the clinical principle of informed choice-the hallmark feature of the midwifery model of care in Ontario, Canada. Drawing on ethnographic history interviews with midwives, I trace the origins of the idea of informed choice to its roots in the social movement of midwifery in North America in the late 1960s and 1970s. At that time informed choice was not the distinctive feature of midwifery but was deeply embedded what I call midwifery's feminist experiment in care. But as midwifery in Ontario transitioned from a social movement to a full profession within the formal health care system, informed choice was strategically foregrounded in order to make the midwifery model of care legible and acceptable to a skeptical medical profession, conservative law makers, and a mainstream clientele. As mainstream biomedicine now takes up the rhetoric of patient empowerment and informed choice, this paper is at once a nuanced history of the making of the concept and also a critique of the ascendant 'regime of choice' in contemporary health care, inspired by the reflections of the midwives in my study for whom choice is impossible without care. PMID- 29143237 TI - John Henryism, Gender and Self-reported Health Among Roma/Gypsies in Serbia. AB - We describe how self-reported health (SRH) varies with gender and John Henryism (a strong behavioral predisposition to engage in high-effort coping to overcome adversity) in a low income sample of Serbian Roma. Data were collected in 2016 in several Roma settlements around Belgrade, Serbia. The sample consisted of 90 men and 112 women. In addition to John Henryism (JH), measured by a Serbian version of the John Henryism Scale, demographic data and data on SRH and family relationships dynamics were collected. SRH was positively correlated with age and JH, and negatively correlated with a history of chronic disease. Roma males and females differed significantly on JH and a number of other variables. For Roma women, multiple regression analyses revealed that a history of chronic disease, unemployment, age and daily stress level were negatively associated with SRH, while JH, SES and harmonious relationships with one's family/children were positively associated with SRH. For Roma men, there was no association between JH and SRH, but older age, being on welfare, a diagnosis of hypertension and extended family disputes were associated with poorer SRH. Hence, despite economic disadvantage and social exclusion from mainstream society, some Roma report good health and the ability to cope actively with economic disadvantage and social exclusion. This study adds to the literature on the cross-cultural relevance of JH theory for understanding health variations within socially and economically marginalized populations. PMID- 29143238 TI - Yeasts and bacterial biosurfactants as demulsifiers for petroleum derivative in seawater emulsions. AB - Oil sludge or waste generated in transport, storage or refining forms highly stable mixtures due to the presence and additives with surfactant properties and water forming complex emulsions. Thus, demulsification is necessary to separate this residual oil from the aqueous phase for oil processing and water treatment/disposal. Most used chemical demulsifiers, although effective, are environmental contaminants and do not meet the desired levels of biodegradation. We investigated the application of microbial biosurfactants as potential natural demulsifiers of petroleum derivatives in water emulsions. Biosurfactants crude extracts, produced by yeasts (Candida guilliermondii, Candida lipolytica and Candida sphaerica) and bacteria (Pseudomonas aeruginosa, Pseudomonas cepacia and Bacillus sp.) grown in industrial residues, were tested for demulsification capacity in their crude and pure forms. The best results obtained were for bacterial biosurfactants, which were able to recover about 65% of the seawater emulsified with motor oil compared to 35-40% only for yeasts products. Biosurfactants were also tested with oil-in-water (O/W) and water-in-oil (W/O) kerosene model emulsions. No relationship between interfacial tension, cell hydrophobicity and demulsification ratios was observed with all the biosurfactants tested. Microscopic illustrations of the emulsions in the presence of the biosurfactants showed the aspects of the emulsion and demulsification process. The results obtained demonstrate the potential of these agents as demulsifiers in marine environments. PMID- 29143239 TI - Improving cellulase production in submerged fermentation by the expression of a Vitreoscilla hemoglobin in Trichoderma reesei. AB - Trichoderma reesei is well known as an industrial workhorse fungus in cellulase production. The low dissolved oxygen supply in the highly viscous medium of T. reesei remains a major bottleneck that hampers growth and cellulase production in submerged fermentation. Vitreoscilla hemoglobin (VHb) has been demonstrated to improve metabolism and protein production in different heterologous hosts under hypoxic conditions, but the use of VHb in T. reesei remains uninvestigated. This study examines the effect of VHb in improving T. reesei performance in submerged fermentation. The VHb gene (vgb)-expressing cassette was successfully transformed into the TU-6 strain, integrated into the genome of T. reesei, and functionally expressed with biological activity, which was confirmed by carbon monoxide difference analysis. Compared to the parent strain, the expression of VHb increased the glucose consumption rate of the transformant. Moreover, in cellulase-inducing medium total protein secretion of the VHb expressing strain was 2.2-fold of the parental strain and the filter paper cellulase activity was increased by 58% under oxygen-limiting conditions. In summary, our results demonstrate that VHb has beneficial effects on improving total protein secretion and cellulase activity of T. reesei in submerged fermentation. PMID- 29143240 TI - Dynamic infrared thermography (DIRT) for assessment of skin blood perfusion in cranioplasty: a proof of concept for qualitative comparison with the standard indocyanine green video angiography (ICGA). AB - PURPOSE: Complications in wound healing after neurosurgical operations occur often due to scarred dehiscence with skin blood perfusion disturbance. The standard imaging method for intraoperative skin perfusion assessment is the invasive indocyanine green video angiography (ICGA). The noninvasive dynamic infrared thermography (DIRT) is a promising alternative modality that was evaluated by comparison with ICGA. METHODS: The study was carried out in two parts: (1) investigation of technical conditions for intraoperative use of DIRT for its comparison with ICGA, and (2) visual and quantitative comparison of both modalities in a proof of concept on nine patients. Time-temperature curves in DIRT and time-intensity curves in ICGA for defined regions of interest were analyzed. New perfusion parameters were defined in DIRT and compared with the usual perfusion parameters in ICGA. RESULTS: The visual observation of the image data in DIRT and ICGA showed that operation material, anatomical structures and skin perfusion are represented similarly in both modalities. Although the analysis of the curves and perfusion parameter values showed differences between patients, no complications were observed clinically. These differences were represented in DIRT and ICGA equivalently. CONCLUSIONS: DIRT has shown a great potential for intraoperative use, with several advantages over ICGA. The technique is passive, contactless and noninvasive. The practicability of the intraoperative recording of the same operation field section with ICGA and DIRT has been demonstrated. The promising results of this proof of concept provide a basis for a trial with a larger number of patients. PMID- 29143241 TI - A Highly Selective Naphthalimide-Based Chemosensor: "Naked-Eye" Colorimetric and Fluorescent Turn-On Recognition of Al3+ and Its Application in Practical Samples, Test Paper and Logic Gate. AB - A novel naphthalimide-based colorimetric and fluorescent turn-on chemosensor for Al3+ was synthesized and characterized with spectroscopic techniques. In MeOH solution, BPAM showed high selectivity and sensitivity to Al3+ by a 60-fold fluorescence enhancement and blue-shift absorption with visible color changes attributed to the contribution of chelation enhanced fluorescence (CHEF) and inhibition of intramolecular charge transfer (ICT). A 1:1 BPAM-Al3+ complex confirmed by job's plot and HRMS with a binding constant of 6.37 * 104 M- 1, and the detection limit for Al3+ was as low as 1.59 * 10- 7 M. BPAM was successfully applied in real sample detection and assessing the existence of Al3+ by a colorimetric method on filter paper. Furthermore, the fluorescent signals of BPAM were designed to construct an INHIBIT molecular logic gate. PMID- 29143242 TI - Comparing reactive oxygen species and DNA fragmentation in semen samples of unexplained infertile and healthy fertile men. AB - BACKGROUND: Male factor infertility has increased to more than 40% during the last decade. About 30% of these couples are diagnosed with unexplained infertility. In fact, reactive oxygen species (ROS), especially superoxide anion (O2-.) and hydrogen peroxide (H2O2), play a crucial role in regulation of physiological and pathological processes in spermatozoa. Moreover, since the diagnosis of unexplained infertility just through semen analysis is a matter of much controversy; we aimed to evaluate the levels of ROS and sperm DNA fragmentation in the semen samples of unexplained infertile and fertile control couples. METHODS: The semen samples of 28 unexplained infertile couples and 30 fertile control couples were analyzed according to WHO criteria. The intracellular levels of H2O2 and O2-. were detected by flow cytometry with 2',7' Dichlorodihydrofluorescin diacetate and Dihydroethidium, respectively, and DNA fragmentation was evaluated by sperm chromatin dispersion test. RESULTS: In unexplained infertile group, sperm motility and normal morphology were significantly lower than the control. The levels of sperm H2O2, O2-., and DNA fragmentation were significantly higher in unexplained infertile men compared to fertile. Moreover, a positive correlation was found between the level of H2O2 and sperm DNA fragmentation in the unexplained infertile group. Besides, reduced sperm motility in the unexplained infertile group was significantly correlated with elevated levels of ROS. CONCLUSIONS: The higher levels of intracellular ROS and DNA fragmentation in the semen samples of unexplained infertile couples and their causes might be considered as an important factor related to diagnosis and treatment of the unexplained infertile couples. PMID- 29143244 TI - Correction to: The role of nuclear medicine in assessments of cardiac dyssynchrony. AB - Some of the values in Table 3 of the original publication inadvertently contained discrepancies with the literature from which they were taken. A corrected version of Table 3 can be found below; the values which have been corrected now appear in bold text (row: Romero-Farina G). PMID- 29143243 TI - Seasonal variation and diet quality among Spanish people aged over 55 years. AB - There is evidence supporting the importance of a healthy diet; however, there are few studies analyzing the seasonal variation of food intake. The present study was aimed to evaluate seasonal variation of food and energy intake in Spanish elderly also to investigate diet quality based on the Healthy Eating Index (HEI) score. From a cross-sectional study, 28 individuals (39% males) aged over 55 years volunteered for a longitudinal follow-up. Dietary assessment was evaluated through 24-h dietary recalls. Energy and nutrient intake were calculated using DIAL software. Furthermore, diet quality was measured using HEI. Data was analyzed considering the interaction of sex, age, fitness status, and body composition. Cereals intake was significantly lower in summer than in winter and autumn (both p < 0.05); whereas, drinks intake was significantly higher in summer than in winter, spring, and autumn (all p < 0.01). Daily energy intake was significant higher in spring than in summer, and in autumn than in summer (p < 0.05), and energy intake from lunch was also statistically higher in spring than in summer (p < 0.01). The HEI was classified as good; however, a negative and significant association was observed between HEI and cholesterol, alcohol, and monounsaturated fatty acids intake (p < 0.01). Cereals and drinks intake and total daily energy intake changed according to seasons. This should be considered in nutritional studies. Diet quality seems not to be affected by these seasonal changes, and HEI did not show a good association with the majority of foods and macro- and micronutrients. PMID- 29143245 TI - Accuracy of PET/CT for detection of infective endocarditis: Where are we now? PMID- 29143246 TI - Isolated right ventricular ischemia by SPECT myocardial perfusion imaging in a patient with coronary artery disease and pulmonary hypertension. PMID- 29143247 TI - Using circulating tumor cells to evaluate the efficacy of irreversible electroporation for unresectasble pancreatic cancer. AB - We used circulating tumor cells (CTCs) as biomarkers to evaluate the efficacy of pre-irreversible electroporation (IRE) and post-IRE for unresectable pancreatic cancer (PC). Real-time qPCR was used to detect potential biomarker genes in CTCs, and magnetic-activated cell sorting (MACS) and fluorescence-activated cell sorting (FACS) were performed on 43 patients with PC who underwent IRE. Some patients experienced adverse reactions within 30 days of the operation, including arrhythmia (6.9%), intraoperative transient change of blood pressure (25.5%), cough (11.6%), nausea and vomiting (23.3%), ascites (25.6%), fever (9.3%), and pain of puncture point (60.5%). The number of CTCs decreased significantly with postoperative time (P < 0.01). Delta cycle threshold values for the CTC-related genes CEA, Ep-CAM, and CK19 increased significantly after IRE. Furthermore, the expression of CEA, Ep-CAM, and CK19 decreased significantly with time after IRE (P < 0.01). Detecting CTCs by RT-qPCR and FACS combined with MACS has significant diagnostic and prognostic value for evaluating the efficacy of IRE in patients with unresectable PC. PMID- 29143248 TI - What do dogs (Canis familiaris) see? A review of vision in dogs and implications for cognition research. AB - Over the last 20 years, a large amount of research has been conducted in an attempt to uncover the cognitive abilities of the domestic dog. While substantial advancements have been made, progress has been impeded by the fact that little is known about how dogs visually perceive their external environment. It is imperative that future research determines more precisely canine visual processing capabilities, particularly considering the increasing number of studies assessing cognition via paradigms requiring vision. This review discusses current research on visual cognition and emphasizes the importance of understanding dog visual processing. We review several areas of vision research in domestic dogs, such as sensitivity to light, visual perspective, visual acuity, form perception, and color vision, with a focus on how these abilities may affect performance in cognition tasks. Additionally, we consider the immense diversity seen in dog morphology and explore ways in which these physical differences, particularly in facial morphology, may result in, or perhaps even be caused by, different visual processing capacities in dogs. Finally, we suggest future directions for research in dog vision and cognition. PMID- 29143249 TI - Next-Generation Chimeric Antigen Receptor T-Cell Therapy: Going off the Shelf. AB - Autologous, patient-specific chimeric antigen receptor T-cell (CART) therapy has emerged as a powerful and potentially curative therapy for cancer, especially for CD19-positive hematological malignancies. Indeed, on August 30, 2017, the University of Pennsylvania-designed CD19-directed CART (CART-19) cell therapy (CTL019, tisagenlecleucel-t, Kymriah - Novartis) became the first CART therapy approved by the Food and Drug Administration (FDA) for acute lymphoblastic leukemia. However, the development of CART technology and its wider application is partly limited by the patient-specific nature of such a platform and by the time required for manufacturing. The efficacious generation of universal allogeneic CART cells would overcome these limitations and represent a major advance in the field. However, several obstacles in the generation of universal CART cells need to be overcome, namely the risk of CART rejection and the risk of graft-versus-host disease mediated by the allogeneic CART. In this review, we discuss the different strategies being employed to generate universal CART and provide our perspective on the successful development of a truly off-the-shelf CART product. PMID- 29143251 TI - Service Evaluation of an Exercise on Referral Scheme for Adults with Existing Health Conditions in the United Kingdom. AB - PURPOSE: This paper outlines a service evaluation of an exercise referral scheme for adults suffering from a variety of physical or mental health conditions or who were deemed are at risk of developing such conditions. The evaluation aimed to assess the impact of the scheme at increasing physical activity and at reducing BMI and waist circumference. METHOD: This was a retrospective evaluation looking at levels of physical activity and changes to anthropometric measures over a period of 6 months. Each participant self-reported their levels of physical activity for the previous 7 days at three time points: baseline (T1), at 12-week exit from the scheme (T2), and at 6-month follow-up (T3). Waist circumference and BMI were also recorded by either a health professional or self reported at these time points. RESULTS: Six hundred seventy participants were referred during the evaluation period, of whom 494 were eligible. Of those 494, 211 completed the 12-week scheme and 135 completed a 6-month follow-up. Significant increases in levels of physical activity were recorded between T1 and T2 and between T1 and T3. Furthermore, significant reductions in waist circumference were noted between T1 and T2 and between T1 and T3, and BMI significantly decreased between T1 and T2 but significantly increased between T2 and T3. CONCLUSION: The service has proven effective at increasing levels of physical activity among participants and has had a positive impact on waist circumference and body for clients who remain engaged with the programme. PMID- 29143250 TI - Cliques and cavities in the human connectome. AB - Encoding brain regions and their connections as a network of nodes and edges captures many of the possible paths along which information can be transmitted as humans process and perform complex behaviors. Because cognitive processes involve large, distributed networks of brain areas, principled examinations of multi-node routes within larger connection patterns can offer fundamental insights into the complexities of brain function. Here, we investigate both densely connected groups of nodes that could perform local computations as well as larger patterns of interactions that would allow for parallel processing. Finding such structures necessitates that we move from considering exclusively pairwise interactions to capturing higher order relations, concepts naturally expressed in the language of algebraic topology. These tools can be used to study mesoscale network structures that arise from the arrangement of densely connected substructures called cliques in otherwise sparsely connected brain networks. We detect cliques (all-to-all connected sets of brain regions) in the average structural connectomes of 8 healthy adults scanned in triplicate and discover the presence of more large cliques than expected in null networks constructed via wiring minimization, providing architecture through which brain network can perform rapid, local processing. We then locate topological cavities of different dimensions, around which information may flow in either diverging or converging patterns. These cavities exist consistently across subjects, differ from those observed in null model networks, and - importantly - link regions of early and late evolutionary origin in long loops, underscoring their unique role in controlling brain function. These results offer a first demonstration that techniques from algebraic topology offer a novel perspective on structural connectomics, highlighting loop-like paths as crucial features in the human brain's structural architecture. PMID- 29143252 TI - Infertility Centrality in the Woman's Identity and Goal Adjustment Predict Psychological Adjustment Among Women in Ongoing Fertility Treatments. AB - PURPOSE: Some of the women that go through repeated fertility treatments will not adjust well to the treatments and will experience increased distress. The present study examined how centrality of the fertility problem in the woman's identity and dispositional goal adjustment (disengagement and reengagement) are associated with the woman's psychological adjustment. These issues are examined in a context of a pro-natal society (Israel) where parenthood is a major life goal. METHODS: One hundred ninety-three women in ongoing fertility treatments filled out questionnaires, and follow-up on their psychological well-being was carried out after 3 months (N = 130). RESULTS: Women who perceived their fertility problem as more central to their identity experienced greater distress (beta = 0.34, p < 0.01) and less well-being (beta = - 0.31, p < 0.01). Concurrently, high ability for goal disengagement was a resource that protected women from these feelings. Women high on goal disengagement who were low on goal reengagement experienced greater distress (beta of interaction = - 0.24, p < 0.01), probably because they remained with feelings of emptiness and lack of purpose. These findings were found in both cross-sectional and longitudinal analyses. Finally, the models predicting well-being and distress at T2 using centrality, goal adjustment, and T1 well-being/distress explained 42 and 47.5% of the variance, respectively. CONCLUSIONS: Much research and therapeutic attention has been invested in coping with fertility treatments, while the options of reducing investment in treatments and finding alternative goals did not receive adequate attention. This study discusses these issues and their possible clinical implications especially in a pro-natal context. PMID- 29143253 TI - Ruling out clinically significant prostate cancer with negative multi-parametric MRI. AB - PURPOSE: To evaluate the negative predictive value (NPV) of a negative prostate multi-parametric magnetic resonance imaging (mpMRI) in ruling out clinically significant prostate upon 12-core systematic biopsy. METHODS: We retrospectively reviewed 114 men evaluated at our institution who underwent systematic 12-core biopsy within 1 year of a negative prostate mpMRI. Clinicopathologic features were evaluated and NPV was calculated for detection of clinically significant (Gleason >= 7) cancer. Regression analysis was performed to identify clinical predictors of biopsy outcome. RESULTS: Overall, 88 (77.2%) patients in our cohort had no cancer detected upon biopsy. The highest pathologic grade was Gleason 6 (3 + 3) in 22 (19.3%) patients, and Gleason >= 7 in 4 (3.6%) patients. NPV for detecting Gleason >= 7 cancer was 96.5% (95% CI 93.1-99.9%) in the entire negative MRI cohort, 100% in those who were prostate biopsy naive (n = 20), 100% in those with a prior negative biopsy (n = 53), and 90% in those who have had a previous positive biopsy and on active surveillance (n = 41). Regression analysis identified no predictors of significant cancer in our cohort. CONCLUSION: In our cohort of men with no lesions detected on prostate mpMRI, we found very low rates of clinically significant cancer on systematic 12-core biopsy. In the few patients who diagnosed with prostate cancer, the majority had low-risk disease and could remain on active surveillance. Although validation studies and greater sample size is needed before clinical recommendations can be made, our data suggest patients with negative mpMRI evaluated by experienced radiologists may avoid unnecessary prostate biopsy and potential overtreatment. PMID- 29143254 TI - Chronic Inflammatory Demyelinating Polyneuropathy: A Case Series. PMID- 29143255 TI - PCB exposure and potential future cancer incidence in Slovak children: an assessment from molecular finger printing by Ingenuity Pathway Analysis (IPA(r)) derived from experimental and epidemiological investigations. AB - The risk of cancer due to PCB exposure in humans is highly debated. In eastern Slovakia, high exposure of the population to organochlorines (especially PCBs) was associated with various disease and disorder pathways, viz., endocrine disruption, metabolic disorder & diabetes, and cancer, thereby disturbing several cellular processes, including protein synthesis, stress response, and apoptosis. We have evaluated a Slovak cohort (45-month children, at lower and higher levels of PCB exposure from the environment) for disease and disorder development to develop early disease cancer biomarkers that could shed new light on possible mechanisms for the genesis of cancers under such chemical exposures, and identify potential avenues for prevention.Microarray studies of global gene expression were conducted from the 45-month-old children on the Affymetrix platform followed by Ingenuity Pathway Analysis (IPA(r)) to associate the affected genes with their mechanistic pathways. High-throughput qRT-PCR TaqMan low-density array (TLDA) was performed to further validate the selected genes on the whole blood cells of the most highly exposed children from the study cohort (n = 71). TP53, MYC, BCL2, and LRP12 differential gene expressions suggested strong relationships between potential future tumor promotion and PCB exposure in Slovak children. The IPA analysis further detected the most important signaling pathways, including molecular mechanism of cancers, prostate cancer signaling, ovarian cancer signaling, P53 signaling, oncostatin M signaling, and their respective functions (viz., prostate cancer, breast cancer, progression of tumor, growth of tumor, and non-Hodgkin's disease). The results suggest that PCB exposures, even at the early age of these children, may have lifelong consequences for the future development of chronic diseases. PMID- 29143256 TI - Toxic effects of Solanum xanthocarpum Sch &Wendle against Helicoverpa armigera (Hub.), Culex quinquefasciatus (Say.) and Eisenia fetida (Savigny, 1826). AB - Many commercially available agro and household chemicals are used as pesticides, repellents, and growth inhibitors against insect pests. The repeated uses of these chemicals against insect pests have caused the development of resistance in them; they also cause ill effects on nontarget organisms. The present study was aimed to evaluate the antifeedant, larvicidal, pupicidal, and biochemical effects of the solvent extracts of Solanum xanthocarpum against third instar larvae of Helicoverpa armigera. Hexane, chloroform and ethyl acetate extracts were subjected to phytochemical analysis. The results revealed the presence of terpenoids, flavonoid, and quinone. Maximum antifeedant activity of 72.30% was recorded in chloroform extract followed by hexane (69.02%) and ethyl acetate (57.40%) extracts against H. armigera. Chloroform extracts of S. xanthocarpum showed more than 60% larvicidal and pupicidal activity against H. armigera. The effective chloroform extract was fractionated with increasing polarity of solvent system (hexane, chloroform, and ethyl acetate extracts). Based on the TLC profile, nine major fractions were isolated. The fourth fraction showed higher antifeedant, larvicidal, and pupicidal activity against H. armigera. The effective fraction reduced the hemolymph and gut protein concentration in a concentration-dependent manner (r 2 0.99). The effective fraction 4 showed 100% larvicidal activity at 500 ppm concentration with LC50 value of 227.95 ppm. The fourth fraction did not show any toxic symptom or mortality of earthworm. Based on these results, this effective fraction could be used in the development of a pesticide formulation to control insect. PMID- 29143257 TI - Environmental characteristics and changes of sediment pore water dissolved organic matter in four Chinese lakes. AB - Sediment pore waters were examined in four Chinese lakes (Bosten, Qinghai, Chenghai and Dianchi) to characterise the sources of dissolved organic matter (DOM) and their microbial changes in the sediment depth profiles. Parallel factor (PARAFAC) modelling on the sample fluorescence spectra confirmed that the pore water DOM was mostly composed of two components with a mixture of both allochthonous and autochthonous fulvic acid-like substances in three lakes, except Lake Dianchi, and protein-like components in Lake Bosten. However, DOM in Lake Dianchi was composed of three components, including a fulvic acid-like, and two unidentified components, which could originate from mixed sources of either sewerage-impacted allochthonous or autochthonous organic matter (OM). Dissolved organic carbon (DOC) concentrations were typically high (583-7410 MUM C) and fluctuated and increased vertically in the depth profile. The fluorescence intensity of the fulvic acid-like substance and absorbance at 254 nm increased vertically in the sediment pore waters of three lakes. A significant relationship between DOC and the fluorescence intensity of the fulvic acid-like component in the sediment pore waters of three lakes, except Lake Dianchi, suggested that the fulvic acid-like component could significantly contribute to total DOM and could originate via complex microbial processes in early diagenesis on OM (ca. phytoplankton, terrestrial plant material) in these lakes. Pore water DOM components could therefore be a useful indicator to assess the DOM sources of the lake sediment during sedimentation over the past several decades, which have been heavily affected by ambient terrestrial vegetation and human activities. PMID- 29143258 TI - Improvement of nitrogen utilization and soil properties by addition of a mineral soil conditioner: mechanism and performance. AB - A mineral soil conditioner (MSC) composed of activated potash feldspar, gypsum, and calcium carbonate and containing an amount of available mineral nutrients, is shown to be effective for plant growth and acidic soil amelioration. In this study, a field test was conducted over four rice seasons by examining treatment with control check (CK), MSC, biological active carbon, and lime to investigate the nitrogen-use efficiency and mechanism of soil characteristic variations due to the desilicification and allitization of soil as well as the unrestrained use of nitrogen (N) fertilizer in recent years. Influences of MSC on the xylem sap intensity and mean rice yields were evaluated, and the soil type was also analyzed using the FactSage 6.1 Reaction, phase diagram, and Equilib modules. The results of the field trial showed that MSC application increased the xylem sap intensity and nitrogen export intensity by 37.33-39.85% and 31.40-51.20%, respectively. A significant increase (5.63-15.48%) in mean grain yields was achieved with MSC application over that with biological active carbon and lime application. The effects of MSC had a tendency to increase with time in the field experiment results, and grain yields increased after the initial application. The new formation of clay minerals exhibits a significant influence on [Formula: see text] fixation, especially for 2:1 phyllosilicates with illite, owing to the interlayers of the clay minerals. Our preliminary results showed that kaolinite, the main 1:1 phyllosilicate clay mineral in ferralsol, transformed to illite at room temperature as a consequence of the presence of H4SiO4 and available K+ supplied by MSC. This indicated that improving the soil quality combined with reducing N losses from soils is an efficient way to control non-point source pollution from agriculture without the risk of decreased in grain yield. PMID- 29143259 TI - Adsorption/reduction of Hg(II) and Pb(II) from aqueous solutions by using bone ash/nZVI composite: effects of aging time, Fe loading quantity and co-existing ions. AB - In this research, a versatile and highly efficient method for the stabilization of nanoscale zerovalent iron particles (nZVI) on the surface of ostrich bone ash (OBA) was presented as a novel inorganic adsorbent (OBA/nZVI) for the removal of Hg(II) and Pb(II) ions from aqueous solutions, even after 1 year of storage under room conditions. The removal behavior of the OBA/nZVI was assessed as a function of the initial pH, contact time, initial pollutants concentration, temperature, amount of adsorbent, effect of competitive metal ions, and ionic strength. The synthesized adsorbent was characterized by several techniques including N2 adsorption at - 196 degrees C, FT-IR spectroscopy, scanning electron microscopy, X-ray diffraction, and zeta potential. The results confirmed that the OBA is a good candidate as support of nZVI. The maxima adsorption capacity for Hg(II) and Pb(II) ions found from experimental results were 170 and 160 mg g-1, when the loading quantities of Fe were 20%. The equilibrium sorption data obeyed a Langmuir-Freundlich isotherm type model. The kinetic data of the adsorption followed the mechanism of the pseudo-second-order model. The thermodynamic experiments indicated that the removal of metal ions were feasible, endothermic, and spontaneous. It can be found that fresh and aged OBA/nZVI maintained its usability even after five cycles in the order: fresh (OBA/nZVI)-Hg(II) > fresh (OBA/nZVI)-Pb(II) > aged (OBA/nZVI)-Hg(II) > aged (OBA/nZVI)-Pb(II), which indicate that OBA/nZVI can be regenerated as adsorbent. The existence of Fe in the OBA/nZVI was proved by SEM-EDX results and X-ray diffraction analysis also confirmed adsorption/reduction of some of the Hg(II) to Hg0 and Pb(II) to Pb0. PMID- 29143260 TI - Combining stable carbon isotope analysis and petroleum-fingerprinting to evaluate petroleum contamination in the Yanchang oilfield located on loess plateau in China. AB - This study evaluated petroleum contamination in the Yanchang (Shaanxi Yanchang Petroleum (Group) Co., Ltd.) oilfield, located in the loess plateau region of northern Shaanxi, China. Surface soil and sediment samples were collected from the wasteland, farmland, and riverbed in this area to assess the following parameters: total petroleum hydrocarbon (TPH), n-alkanes, polycyclic aromatic hydrocarbons (PAHs), and carbon isotope ratios (delta13C). The results showed that TPH and PAH levels in the study area were 907-3447 mg/kg and 103.59-563.50 MUg/kg, respectively, significantly higher than the control samples (TPH 224 mg/kg, PAHs below method quantification limit, MQL). Tests using delta13C to detect modified TPH (2238.66 to 6639.42 mg/kg) in the wastelands adjacent to the oil wells revealed more significant contamination than tests using extraction gravimetric analysis. In addition, "chemical fingerprint" indicators, such as low to high molecular weight (LMW/HMW) hydrocarbons, carbon preference index (CPI), and pristine/phytane (Pr/Ph), further confirmed the presence of heavy petroleum contamination and weathering. This has resulted in a nutrient imbalance and unsuitable pH and moisture conditions for microbial metabolic activities. This study evaluates petroleum contamination, which can inform contamination remediation on a case by case basis. PMID- 29143261 TI - River sediment metal and nutrient variations along an urban-agriculture gradient in an arid austral landscape: implications for environmental health. AB - The effect of metals on environmental health is well documented and monitoring these and other pollutants is considered an important part of environmental management. Developing countries are yet to fully appreciate the direct impacts of pollution on aquatic ecosystems and as such, information on pollution dynamics is scant. Here, we assessed the temporal and spatial dynamics of stream sediment metal and nutrient concentrations using contaminant indices (e.g. enrichment factors, pollution load and toxic risk indices) in an arid temperate environment over the wet and dry seasons. The mean sediment nutrient, organic matter and metal concentration were highest during the dry season, with high values being observed for the urban environment. Sediment contaminant assessment scores indicated that during the wet season, the sediment quality was acceptable, but not so during the dry season. The dry season had low to moderate levels of enrichment for metals B, Cu, Cr, Fe, Mg, K and Zn. Overall, applying the sediment pollution load index highlighted poor quality river sediment along the length of the river. Toxic risk index indicated that most sites posed no toxic risk. The results of this study highlighted that river discharge plays a major role in structuring temporal differences in sediment quality. It was also evident that infrastructure degradation was likely contributing to the observed state of the river quality. The study contributes to our understanding of pollution dynamics in arid temperate landscapes where vast temporal differences in base flow characterise the riverscape. Such information is further useful for contrasting sediment pollution dynamics in aquatic environments with other climatic regions. PMID- 29143262 TI - Influences of graphene oxide on biofilm formation of gram-negative and gram positive bacteria. AB - In this study, we evaluated the influences of graphene oxide (GO) on biofilm formation. Escherichia coli MG1655 and Bacillus subtilis 168 were used as models for Gram-negative and Gram-positive bacteria. The growth profiles and viability assays indicated that GO exhibited a high antibacterial activity, of which the negative effects on bacteria growth raised with the increasing GO concentration. The antibacterial activity of GO was mainly attributed to the membrane stress and ROS-independent oxidative stress. Moreover, it was worthy to note that the biofilm formation was enhanced in the presence of GO at low dosage whereas inhibited in the high-concentration GO environment. These results could be explained by the roles of the dead cells, which were inactivated by GO. When the concentration of GO was limited, only a part of the cells would be inactivated, which may then serve as a protection barrier as well as the necessary nutrient to the remaining living cells for the formation of biofilm. In contrast, with a sufficient presence of GO, almost all cells can be inactivated completely and thus the formation of biofilm could no longer be triggered. Overall, the present work provides significant new insights on the influence of carbon nanomaterials towards biofilm formation, which has far-reaching implications in the field of biofouling and membrane bioreactor. Graphical abstract ?. PMID- 29143263 TI - Enhanced stabilization of Pb, Zn, and Cd in contaminated soils using oxalic acid activated phosphate rocks. AB - Phosphate amendments, especially phosphate rock (PR), are one of the most commonly used materials to stabilize heavy metals in contaminated soils. However, most of PR reserve consists of low-grade ore, which limits the efficiency of PR for stabilizing heavy metals. This study was to enhance the stabilization of heavy metals through improving the available phosphorous (P) release of PR by oxalic acid activation. Raw PR and activated PR (APR) were characterized by scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS), X ray powder diffraction (XRD), Brunauer-Emmett-Teller (BET) surface analysis, and laser diffraction to determine the changes of structure and composition of APR. The stabilization effectiveness of lead (Pb), zinc (Zn), and cadmium (Cd) in soils by APR was investigated through toxicity leaching test and speciation analysis. The results indicated that after treatment by oxalic acid, (1) the crystallinity of the fluorapatite phase of PR transformed into the weddellite phase; (2) the surface area of PR increased by 37%; (3) the particle size of PR became homogenized (20-70 MUm); and (4) the available P content in PR increased by 22 times. These changes of physicochemical characteristics of PR induced that APR was more effective to transform soil heavy metals from the non-residual fraction to the residual fraction and enhance the stabilization efficiency of Pb, Zn, and Cd than PR. These results are significant for the future use of low-grade PR to stabilize heavy metals. PMID- 29143264 TI - Carbon emissions-income relationships with structural breaks: the case of the Middle Eastern and North African countries. AB - This article revisits the carbon dioxide (CO2) emissions-GDP causal relationships in the Middle Eastern and North African (MENA) countries by employing the Rossi (Economet Theor 21:962-990, 2005) instability-robust causality test. We show evidence of significant causality relationships for all considered countries within the instability context, whereas the standard Granger causality test fails to detect causal links in any direction, except for Egypt, Iran, and Morocco. An important policy implication resulting from this robust analysis is that the income is not affected by the cuts in the CO2 emissions for only two MENA countries, the UAE and Syria. PMID- 29143265 TI - Is Caenorhabditis elegans representative of freshwater nematode species in toxicity testing? AB - Multi-species toxicity tests were conducted using a broad range of freshwater nematode species to assess interspecific differences in sensitivity to chemical stress and to compare the toxicity to that on the standard test organism Caenorhabditis elegans. The lethal effects of nine different chemical treatments, including metals and polycyclic aromatic hydrocarbons (PAHs) in single and mixture application, were determined for nematodes exposed for 48 h to spiked aqueous solutions. The investigated freshwater nematodes exhibited distinct differences in their sensitivity. Ranking of the susceptibility of 27 species to chemical stress showed that the effects were largely independent of the tested chemical compounds. Overall, the responses of C. elegans were well within the range of those of freshwater nematode species, being slightly less tolerant to metals, but more tolerant to PAHs than the average freshwater species response. Therefore, this study justified the use of C. elegans as representative model for freshwater nematode species in toxicity testing. PMID- 29143266 TI - 'Measuring' Physical Literacy and Related Constructs: A Systematic Review of Empirical Findings. AB - BACKGROUND: The concept of physical literacy has received increased research and international attention recently. Where intervention programs and empirical research are gaining momentum, their operationalizations differ significantly. OBJECTIVE: The objective of this study was to inform practice in the measure/assessment of physical literacy via a systematic review of research that has assessed physical literacy (up to 14 June, 2017). METHODS: Five databases were searched using the Preferred Reporting Items for Systematic Reviews and Meta Analyses for Protocols guidelines, with 32 published articles meeting the inclusion criteria. English-language, peer-reviewed published papers containing empirical studies of physical literacy were analyzed using inductive thematic analysis. RESULTS: Qualitative methods included: (1) interviews; (2) open-ended questionnaires; (3) reflective diaries; (4) focus groups; (5) participant observations; and (6) visual methods. Quantitative methods included: (1) monitoring devices (e.g., accelerometers); (2) observations (e.g., of physical activity or motor proficiency); (3) psychometrics (e.g., enjoyment, self perceptions); (4) performance measures (e.g., exergaming, objective times/distances); (5) anthropometric measurements; and (6) one compound measure. Of the measures that made an explicit distinction: 22 (61%) examined the physical domain, eight (22%) the affective domain; five (14%) the cognitive domain; and one (3%) combined three domains (physical, affective, and cognitive) of physical literacy. Researchers tended to declare their philosophical standpoint significantly more in qualitative research compared with quantitative research. CONCLUSIONS: Current research adopts diverse often incompatible methodologies in measuring/assessing physical literacy. Our analysis revealed that by adopting simplistic and linear methods, physical literacy cannot be measured/assessed in a traditional/conventional sense. Therefore, we recommend that researchers are more creative in developing integrated philosophically aligned approaches to measuring/assessing physical literacy. Future research should consider the most recent developments in the field of physical literacy for policy formation. PMID- 29143268 TI - Skin Cancer Awareness and Sun Protection Behavior Before and Following Treatment Among Skin Cancer-Treated Patients. AB - There is little known about illness perception in patients with skin tumors. We conducted this study to investigate Iranian patients' understanding of skin tumors, and to evaluate their sun-protective behavior changes after treatment of skin cancer. Patients with a skin biopsy of basal cell carcinoma were asked to complete questionnaires. A total of 110 patients were enrolled in the study. Patients were mostly referred to our tumor clinic from rural areas. At the skin cancer perception investigation, 63% of patients did not consider their disease as a long-lasting situation. Besides, 45.4% of patients consider their illness as a serious condition which significantly affecting their lives. Our patients had a strong belief in treatment control (81%) and 81% of them also described worries about their skin cancer. The leading causes of skin cancer as assumed by patients were: history of skin cancer (37.4%), poor medical care in the past (36.4%), extreme sun exposure (31.5%), and lack of sun protection (27.5%). In regard to sun-protective behavior after treatment of skin cancer, 55.4% of patients showed no changes or even negative change in their sun-protective behavior, But 44.5% of the patients changed their sun-protective behavior in a positive way which was statically significant (P <= 0.001). Our study demonstrates how our patients with skin cancer perceive their disease and we need to educate our patients, considering diseases' aspects, causes and symptoms. This is of great value as dermatologists should be aware of patients' perceptions of their disease in order to improve patients' knowledge through educating more about different aspects of disease. PMID- 29143269 TI - Defining Information Security. AB - This article proposes a new definition of information security, the 'Appropriate Access' definition. Apart from providing the basic criteria for a definition correct demarcation and meaning concerning the state of security-it also aims at being a definition suitable for any information security perspective. As such, it bridges the conceptual divide between so-called 'soft issues' of information security (those including, e.g., humans, organizations, culture, ethics, policies, and law) and more technical issues. Because of this it is also suitable for various analytical purposes, such as analysing possible security breaches, or for studying conflicting attitudes on security in an organization. The need for a new definition is demonstrated by pointing to a number of problems for the standard definition type of information security-the so-called CIA definition. Besides being too broad as well as too narrow, it cannot properly handle the soft issues of information security, nor recognize the contextual and normative nature of security. PMID- 29143267 TI - Hamstring Injury Prevention Practices in Elite Sport: Evidence for Eccentric Strength vs. Lumbo-Pelvic Training. AB - Hamstring strain injuries are endemic in running-based sports. Given the economic and performance implications of these injuries, a significant body of research has emerged in recent years in an attempt to identify risk factors and develop or optimise injury prevention strategies. Surveys of injury prevention practices among medical and conditioning staff in elite sport suggest that many sporting clubs invest significant efforts in eccentric hamstring conditioning and lumbo pelvic or trunk stability programmes. The purpose of this narrative review was to critically evaluate the evidence underpinning these practices. Single-exercise eccentric training interventions have proven effective in the prevention of primary and recurrent hamstring strains, when compliance is adequate. However, despite its almost universal acceptance, the authors are aware of only one, very recent, prospective risk factor study examining the effect of lumbo-pelvic motion during sprinting on hamstring injury risk. Furthermore, the interventions exploring the effect of lumbo-pelvic training on hamstring injury rates have not measured stability in any way. An improved understanding of the evidence underpinning commonly employed hamstring injury prevention practices may enable clinicians and coaches to better prioritise effective strategies in the increasingly complex environment of elite sport. PMID- 29143270 TI - An efficient computer-aided structural elucidation strategy for mixtures using an iterative dynamic programming algorithm. AB - The identification of chemical structures in natural product mixtures is an important task in drug discovery but is still a challenging problem, as structural elucidation is a time-consuming process and is limited by the available mass spectra of known natural products. Computer-aided structure elucidation (CASE) strategies seek to automatically propose a list of possible chemical structures in mixtures by utilizing chromatographic and spectroscopic methods. However, current CASE tools still cannot automatically solve structures for experienced natural product chemists. Here, we formulated the structural elucidation of natural products in a mixture as a computational problem by extending a list of scaffolds using a weighted side chain list after analyzing a collection of 243,130 natural products and designed an efficient algorithm to precisely identify the chemical structures. The complexity of such a problem is NP-complete. A dynamic programming (DP) algorithm can solve this NP-complete problem in pseudo-polynomial time after converting floating point molecular weights into integers. However, the running time of the DP algorithm degrades exponentially as the precision of the mass spectrometry experiment grows. To ideally solve in polynomial time, we proposed a novel iterative DP algorithm that can quickly recognize the chemical structures of natural products. By utilizing this algorithm to elucidate the structures of four natural products that were experimentally and structurally determined, the algorithm can search the exact solutions, and the time performance was shown to be in polynomial time for average cases. The proposed method improved the speed of the structural elucidation of natural products and helped broaden the spectrum of available compounds that could be applied as new drug candidates. A web service built for structural elucidation studies is freely accessible via the following link ( http://csccp.cmdm.tw/ ). PMID- 29143271 TI - Collision-Induced Dissociation of Deprotonated Peptides. Relative Abundance of Side-Chain Neutral Losses, Residue-Specific Product Ions, and Comparison with Protonated Peptides. AB - High-accuracy MS/MS spectra of deprotonated ions of 390 dipeptides and 137 peptides with three to six residues are studied. Many amino acid residues undergo neutral losses from their side chains. The most abundant is the loss of acetaldehyde from threonine. The abundance of losses from the side chains of other amino acids is estimated relative to that of threonine. While some amino acids lose the whole side chain, others lose only part of it, and some exhibit two or more different losses. Side-chain neutral losses are less abundant in the spectra of protonated peptides, being significant mainly for methionine and arginine. In addition to the neutral losses, many amino acid residues in deprotonated peptides produce specific negative ions after peptide bond cleavage. An expanded list of fragment ions from protonated peptides is also presented and compared with those of deprotonated peptides. Fragment ions are mostly different for these two cases. These lists of fragments are used to annotate peptide mass spectral libraries and to aid in the confirmation of specific amino acids in peptides. Graphical Abstract ?. PMID- 29143272 TI - Preliminary results of immune modulating antibody MDV9300 (pidilizumab) treatment in children with diffuse intrinsic pontine glioma. AB - Diffuse intrinsic pontine glioma (DIPG) is an incurable disease with a median overall survival of 10 months. Immune modulating antibodies have recently emerged as a highly promising treatment modality in multiple cancer types. We present results from the first study to evaluate the immune modulating antibody MDV9300 (pidilizumab) in pediatric patients with DIPG. All patients aged 3 years and older, diagnosed with DIPG between February 2014 and June 2015 in Israel, were offered to participate in the study. Enrolled patients were started on biweekly 6 mg/kg MDV9300 after radiation completion. Treatment was continued until disease progression on imaging. Patients were followed biweekly for the occurrence of neurological deficit toxicities and side effects. Secondary endpoints were event free survival and overall survival. Of 13 children diagnosed with DIPG during the study period, nine were enrolled in the study. The patients underwent radiotherapy and none had chemotherapy. A total of 83 cycles of MDV9300 (range 2 16) were applied. The main side effects were neutropenia (CTCAE grade 1-3), mild to moderate fatigue, and acute elevation of blood pressure. Four patients died within 1 year of the diagnosis, another three died within 2 years and two children are still alive nearly 30 months from diagnosis, with stable disease. The median event free survival is 9.3 months (range 6.8-24) and the median overall survival is 15.6 months (range 6.9-28). Preliminary results demonstrate that MDV9300 treatment is safe and may be effective in the treatment of children with DIPG. PMID- 29143273 TI - Meningioma recurrence rates following treatment: a systematic analysis. AB - Recurrence rates of meningiomas have been widely reported in the literature, but it remains challenging for clinicians to predict recurrence rate depending on treatment, patient demographics and tumor characteristics. To address these needs, we performed a systematic analysis of the literature to determine the recurrence rate ranges of meningiomas following surgery or radiation. Our search yielded 13 studies that met all criteria for inclusion, allowing us to include 1539 patients in the assessment. Recurrence rates ranged from 0.00 to 2.36 per 100-person-years for WHO grade I meningiomas; and from 7.35 to 11.46 per 100 person-years for WHO grade II meningiomas. Our findings suggest that (1) reported recurrence rates are variable and complicated by the heterogeneity of study populations; (2) as expected, WHO grade II meningiomas generally have a higher recurrence rate than WHO grade I, when controlling for time of diagnosis (by employing person-years); and (3) there is a need for more rigorous reporting of recurrence rates, WHO grade, and Simpson grading for individual patients in order to determine a robust mean of recurrence across WHO grades. PMID- 29143274 TI - Clinical features, surgical management, and prognostic factors of secretory meningiomas: a single-center case series of 149 patients. AB - Secretory meningioma (SM) is a rare histological subtype of the meningioma family. Few reports investigating SM have been published due to its extremely low incidence; thus, the current understanding of this disease is poor. We analyzed the incidence and clinical, radiological, pathological, and prognostic features of SM. Approximately 12,380 intracranial meningiomas were surgically resected at Beijing Tiantan Hospital between April 2008 and January 2017. All pathologically confirmed SM cases were identified. SMs accounted for approximately 1.2% of the intracranial meningiomas (149 of 12,380). The patients with SM had a mean age of 51.0 years and were predominantly female (112 female and 37 male). Radiologically, peritumoral brain edema was observed in 49 (32.9%) patients. Gross total resection was achieved in 115 (77.2%) cases. At the 35-months median follow-up (range 4-109 months), six patients had tumor recurrence, and one patient died from the tumor recurrence. The 5-year progression-free survival rates were 95.9%, and the 5-year overall survival rate was 99.3%. A skull base location and a tumor size >= 3.5 cm were significantly associated with poor short term outcomes, and a skull base location was significantly associated with an increased risk of poor long-term outcomes (P < 0.05). A skull base location (OR 3.797; 95% CI 1.071-13.468; P = 0.039) and tumor size >= 3.5 cm (OR 2.616; 95% CI 1.107-6.181; P = 0.028) were independent risk factors for non-gross total resection. A son-skull base location (OR 0.070; 95% CI 0.028-0.177; P = 0.001) was the only independent risk factor that correlated with more severe peritumoral brain edema. SM is a rare subtype of meningiomas with a female predominance and low recurrence. Our results highlight the risk factors for short- and long-term outcomes, which can be useful for selecting treatments and predicting prognosis. Microsurgical treatment of a skull base SM remains a formidable challenge due to a large tumor size and critical neurovascular structure encasement. PMID- 29143275 TI - Increasing time to postoperative stereotactic radiation therapy for patients with resected brain metastases: investigating clinical outcomes and identifying predictors associated with time to initiation. AB - We sought to determine the impact of time to initiation (TTI) of post-operative radiosurgery on clinical outcomes for patients with resected brain metastases and to identify predictors associated with TTI. All patients with resected brain metastases treated with postoperative SRS or fractionated stereotactic radiation therapy (fSRT) from 2012 to 2016 at a single institution were reviewed. TTI was defined as the interval from resection to first day of radiosurgery. Receiver operating characteristic (ROC) curves were used to identify an optimal threshold for TTI with respect to local failure (LF). Survival outcomes were estimated using the Kaplan-Meier method and analyzed using the log-rank test and Cox proportional hazards models. Logistic regression models were used to identify factors associated with ROC-determined TTI covariates. A total of 79 resected lesions from 73 patients were evaluated. An ROC curve of LF and TTI identified an optimal threshold for TTI of 30.5 days, with an area under the curve of 0.637. TTI > 30 days was associated with an increased hazard of LF (HR 4.525, CI 1.239 16.527) but was not significantly associated with survival (HR 1.002, CI 0.547 1.823) or distant brain failure (DBF, HR 1.943, CI 0.989-3.816). Fifteen patients (20.5%) required post-operative inpatient rehabilitation. Post-operative rehabilitation was associated with TTI > 30 days (OR 1.48, CI 1.142-1.922). In our study of resected brain metastases, longer time to initiation of post operative radiosurgery was associated with increased local failure. Ideally, post op SRS should be initiated within 30 days of resection if feasible. PMID- 29143276 TI - Long-term impact of temozolomide on 1p/19q-codeleted low-grade glioma growth kinetics. AB - Although upfront temozolomide (TMZ) has been widely-used to treat 1p/19q codeleted diffuse low-grade gliomas (LGG), its long-term impact on the growth kinetics of these tumors has not been determined. Based on serial magnetic resonance images we retrospectively evaluated the evolution of the mean tumor diameter (MTD) in 36 progressive 1p/19q-codeleted LGG treated with upfront TMZ. After TMZ onset, all but two patients (94.4%) presented a progressive MTD decrease that lasted for a median duration of 23 months (range 3-114). In 10 patients (27%) MTD regrowth occurred during TMZ treatment and in 22 patients (66%) after TMZ discontinuation. In these patients, median time to MTD regrowth after TMZ discontinuation was 12 months (range 1-88). The rate of MTD regrowth at 3 and 5 years after TMZ onset was 77 and 94%, respectively. Time to tumor progression (TTP) based on volumetric analysis was shorter than TTP based on Response Assessment in Neuro-Oncology (RANO) bidimensional criteria (23 vs. 35 months, p = 0.05) and shorter than time to next oncological treatment (23 vs. 46 months, p = 0.001). In 10 patients (27%), absence of volumetric analysis led to continue TMZ for a median of 10 cycles after MTD had started to regrow. Volumetric analysis is important to precisely assess chemotherapy efficacy in 1p/19q-codeleted LGG, identify early tumor progression and avoid futile chemotherapy continuation. In the present series, although some long-lasting volumetric responses were observed, most tumors resumed their growth within 3 years after TMZ onset. PMID- 29143278 TI - Is it really good for you to eat fat as much as you could? PMID- 29143277 TI - Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma. AB - It is sometimes difficult to distinguish gliomas from other tumors on routine imaging. In this study, we assessed whether 3-T magnetic resonance spectroscopy (MRS) with LCModel software might be useful for discriminating glioma from other brain tumors, such as primary central nervous system lymphomas (PCNSLs) and metastatic tumors. A total of 104 cases of brain tumor (66 gliomas, 20 PCNSLs, 6 metastatic tumors, 12 other tumors) were preoperatively investigated with short echo time (35 ms) single-voxel 3-T MRS. LCModel software was used to evaluate differences in the absolute concentrations of choline, N-acetylaspartate, N acetylaspartylglutamate, glutamate + glutamine, myo-inositol (mIns), and lipid. mIns levels were significantly increased in high-grade glioma (HGG) compared with PCNSL (p < 0.001). In multivariate logistic regression analysis, mIns was the best marker for differentiating HGG from PCNSL (p < 0.0001, odds ratio 1.9927, 95% confidence interval 1.3628-3.2637). Conventional MRS detection of mIns resulted in a high diagnostic accuracy (sensitivity, 64%; specificity, 90%; area under the receiver operator curve, 0.80) for HGG. The expression of inositol 3 phosphate synthase (ISYNA1) was significantly higher in gliomas than in PCNSLs (p < 0.05), suggesting that the increased level of mIns in glioma is due to high expression of ISYNA1, the rate-limiting enzyme in the mIns-producing pathway. In conclusion, noninvasive analysis of mIns using single-voxel MRS may be useful in distinguishing gliomas from other brain tumors, particularly PCNSLs. PMID- 29143279 TI - Arabidopsis noncoding RNA modulates seedling greening during deetiolation. AB - Seedling greening is essential for the survival of plants emerging from the soil. The abundance of chlorophyll precursors, including protochlorophyllide (Pchlide), is precisely controlled during the dark-to-light transition, as over-accumulation of Pchlide can lead to cellular photooxidative damage. Previous studies have identified and characterized multiple regulators controlling this important process. HID1 (hidden treasure 1) is the first noncoding RNA (ncRNA) found in photomorphogenesis. Under continuous red light, HID1 has been shown to inhibit hypocotyl elongation by repressing the transcription of PIF3 (phytochrome interacting factor 3). Here, we report that HID1 acts as a negative regulator of cotyledon greening. Knockdown of HID1 resulted in an increased greening rate of etiolated seedlings relative to wild type when exposed to white light. Genetically, HID1 acts downstream of PIF3 during the dark-to-light transition. The expression of HID1 is not regulated by PIF3 in the dark. Molecularly, the Pchlide content was reduced in dark-grown hid1 mutants than WT. Meanwhile, transcript levels of the protochlorophyllide oxidoreductases known to catalyze Pchlide to chlorophyllide conversion were significantly increased in hid1 seedlings. Thus, our study reveals an additional role of HID1 in the dark-to light transition in Arabidopsis. Moreover, these results suggest HID1 could regulate distinct targets in different light-mediated developmental processes, and thus is essential to the control of these mechanisms. PMID- 29143280 TI - Genome sequencing and phylogenetic analysis of Banna virus (genus Seadornavirus, family Reoviridae) isolated from Culicoides. AB - In an investigation of blood-sucking insects and arboviruses, a virus (YN12243) was isolated from Culicoides samples collected in the Sino-Burmese border region of Yunnan Province, China. The virus caused cytopathic effect (CPE) in C6/36 cells and passaged stably. Polyacrylamide gel analysis showed that the genome of YN12243 was composed of 12 segments of double-stranded RNA (dsRNA), with a distribution pattern of 6-6. The nucleotide and amino acid sequences of the coding region (1-12 segments) were 17,803 bp and 5,925 amino acids in length, respectively. The phylogenetic analysis of VP1 protein (RdRp) revealed that YN12243 belonged to genus Seadornavirus of family Reoviridae, and further analysis indicated that YN12243 belongs to the Banna virus (BAV) genotype A2. Additionally, YN12243 was located in the same evolutionary cluster as BAV strains isolated from different mosquito species, suggesting that the BAV isolated from Culicoides does not have species barriers. These results indicate that Culicoides can also be a vector for BAV. In view of the hematophagous habits of Culicoides on cattle, horses, deer, and other large animals, as well as the possibility of spreading and causing a variety of animal arboviral diseases, it is important to improve infection detection and monitor the BAV in large livestock. PMID- 29143281 TI - Long-term outcome in patients treated at home during the pancytopenic phase after allogeneic haematopoietic stem cell transplantation. AB - Patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) were given the option to be treated at home during the pancytopenic phase. Daily visits by a nurse and phone calls from a physician from the unit were part of the protocol. During almost two decades, 252 patients with haematological malignancies and non-malignant disorders were included. Median age was 47 (range 0-72) years. Myeloablative conditioning was given to 102 patients and reduced intensity to 150. Donors were matched unrelated (n = 160), HLA-identical siblings (n = 71), or HLA-mismatched (n = 21). Cumulative incidence of acute graft-versus host disease (GVHD) was 35% and that of chronic GVHD was 46%. Non-relapse mortality was 14% 10 years after HSCT. In patients with haematological malignancies (n = 229), the 10-year probability of relapse was 34%. No patients died at home. Overall survival was 59% and relapse-free survival was 50% after 10 years. We conclude that patients treated at home after HSCT have an encouraging long-term outcome. PMID- 29143283 TI - Evaluation of sequential SPECT and CT for targeted radionuclide therapy dosimetry. AB - PURPOSE: In targeted radionuclide therapy (TRT), a prior knowledge of the absorbed dose biodistribution is essential for pre-therapy treatment planning. Previously, we showed that non-rigid organ-by-organ registration in sequential quantitative SPECT images improved dose estimation. This study aims to investigate if sequential CT can further improve TRT dosimetric accuracy. METHODS: We simulated SPECT/CT acquisitions at 1, 12, 24, 72 and 144 h In-111 Zevalin post-injection using an analytical MEGP projector, modeling attenuation, scatter and collimator-detector response. We later recruited a patient injected with 222 MBq In-111 DTPAOC imaged at 3 SPECT/CT sessions for clinical evaluations. Four registration schemes were evaluated: whole-body-based registration performed on sequential (1) SPECT (WB-SPECT) or (2) CT (WB-CT) images; organ-based registration applied on organs individually segmented from sequential (3) SPECT (O-SPECT) or (4) CT (O-CT) images. Voxel-by-voxel integration was performed followed by Y-90 voxel-S-kernel convolution. Organ absorbed doses, iso-dose curves, dose-volume histograms (DVHs) were generated for targeted organs for analysis. RESULTS: In simulation study, organ-absorbed dose errors were (- 8.66 +/- 2.83)%, (- 2.51 +/- 3.69)%, (- 9.23 +/- 3.28)%, (- 7.17 +/- 2.53)% for liver, (- 14.81 +/- 4.91)%, (- 3.60 +/- 4.37)%, (- 18.13 +/- 4.44)%, (- 11.34 +/- 4.22)% for spleen, for O-SPECT, O-CT, WB-SPECT and WB-CT registrations, respectively. For all organs, O-CT showed superior results. Results of iso-dose contour, DVHs were in accordance with the organ-absorbed doses. In clinical studies, the results were also consistent which showed O-CT method deviated the most from the result with no registration. CONCLUSIONS: We conclude that if both sequential SPECT/CT scans are available, CT organ-based registration method can more effectively improve the 3D dose estimation. Sequential low-dose CT scans might be considered to be included in the standard TRT protocol. PMID- 29143282 TI - Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation. AB - Despite the curative potential of allogeneic stem cell transplantation (allo-SCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), many patients will relapse. Until recently therapeutic options mainly consisted of palliative care, chemotherapy, donor lymphocyte infusions and second transplantation in selected cases. Still many patients either do not tolerate intensive therapies or do not achieve durable remissions and will finally succumb. Given this unmet medical need the hypomethylating agents (HMA), Azacitidine (Aza) and Decitabine (DAC) have been tested as salvage therapy in patients with myeloid malignancies relapsing after allo-SCT. Furthermore, they have also been incorporated into prophylactic and pre-emptive approaches to avoid haematological relapse. In this review, we summarize the evidence from retrospective studies but also from a few prospective trials regarding the use of HMA after transplant. To aid clinicians in their daily clinical practice, we also comment on some practical aspects such as dosing and schedule, the choice of HMA and the use of complementary cellular therapies. Finally, this review also gives an overview on potential mechanisms mediating the efficacy of HMA after transplant as well as ongoing preclinical research and clinical activities aiming to further improve this treatment approach. PMID- 29143284 TI - Development and characterization of 79 nuclear markers amplifying in viviparous and oviparous clades of the European common lizard. AB - The European common lizard (Zootoca vivipara) is a widely distributed species across Europe and Asia exhibiting two reproductive modes (oviparity/viviparity), six major lineages and several sublineages. It has been used to tackle a large variety of research questions, nevertheless, few nuclear DNA sequence markers have been developed for this species. Here we developed 79 new nuclear DNA sequence markers using a clonation protocol. These markers were amplified in several oviparous and viviparous specimens including samples of all extant clades, to test the amplification success and their diversity. 49.4% of the markers were polymorphic and of those, 51.3% amplified in all and 94.9% amplified in 5-7 of the extant Z. vivipara clades. These new markers will be very useful for the study of the population structure, population dynamics, and micro/macro evolution of Z. vivipara. Cross-species amplification in four lizard species (Psammodromus edwardsianus, Podarcis muralis, Lacerta bilineata, and Takydromus sexlineatus) was positive in several of the markers, and six makers amplified in all five species. The large genetic distance between P. edwardsianus and Z. vivipara further suggests that these markers may as well be employed in many other species. PMID- 29143285 TI - Comment on: "Adverse Drug Reaction-Related Hospitalizations in Elderly Australians: A Prospective Cross-Sectional Study in Two Tasmanian Hospitals". PMID- 29143286 TI - Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model. AB - HIV-1 Tat is known to be neurotoxic and important for HIV/neuroAIDS pathogenesis. However, the overwhelming majority of the studies involved use of recombinant Tat protein. To understand the contributions of Tat protein to HIV/neuroAIDS and the underlying molecular mechanisms of HIV-1 Tat neurotoxicity in the context of a whole organism and independently of HIV-1 infection, a doxycycline-inducible astrocyte-specific HIV-1 Tat transgenic mouse (iTat) was created. Tat expression in the brains of iTat mice was determined to be in the range of 1-5 ng/ml and led to astrocytosis, loss of neuronal dendrites, and neuroinflammation. iTat mice have allowed us to define the direct effects of Tat on astrocytes and the molecular mechanisms of Tat-induced GFAP expression/astrocytosis, astrocyte mediated Tat neurotoxicity, Tat-impaired neurogenesis, Tat-induced loss of neuronal integrity, and exosome-associated Tat release and uptake. In this review, we will provide an overview about the creation and characterization of this model and its utilities for our understanding of Tat neurotoxicity and the underlying molecular mechanisms. PMID- 29143287 TI - Lipoic Acid Stimulates cAMP Production in Healthy Control and Secondary Progressive MS Subjects. AB - Lipoic acid (LA) exhibits antioxidant and anti-inflammatory properties; supplementation reduces disease severity and T lymphocyte migration into the central nervous system in a murine model of multiple sclerosis (MS), and administration in secondary progressive MS (SPMS) subjects reduces brain atrophy compared to placebo. The mechanism of action (MOA) of LA's efficacy in suppression of MS pathology is incompletely understood. LA stimulates production of the immunomodulator cyclic AMP (cAMP) in vitro. To determine whether cAMP could be involved in the MOA of LA in vivo, we performed a clinical trial to examine whether LA stimulates cAMP production in healthy control and MS subjects, and whether there are differences in the bioavailability of LA between groups. We administered 1200 mg of oral LA to healthy control, relapsing remitting MS (RRMS) and SPMS subjects, and measured plasma LA and cAMP levels in peripheral blood mononuclear cells (PBMCs). There were no significant differences between the groups in pharmacokinetic (PK) parameters. Healthy and SPMS subjects had increased cAMP at 2 and 4 h post-LA treatment compared to baseline, while RRMS subjects showed decreases in cAMP. Additionally, plasma concentrations of prostaglandin E2 (PGE2, a known cAMP stimulator) were significantly lower in female RRMS subjects compared to female HC and SPMS subjects 4 h after LA ingestion. These data indicate that cAMP could be part of the MOA of LA in SPMS, and that there is a divergent response to LA in RRMS subjects that may have implications in the efficacy of immunomodulatory drugs. This clinical trial, "Defining the Anti-inflammatory Role of Lipoic Acid in Multiple Sclerosis," NCT00997438, is registered at https://clinicaltrials.gov/ct2/show/record/NCT00997438 . PMID- 29143288 TI - GSK3beta Controls mTOR and Prosurvival Signaling in Neurons. AB - Glycogen synthase kinases-3beta (GSK3beta) is a key regulator of cell homeostasis. In neurons, GSK3beta contributes to control of neuronal transmission and plasticity. Despite extensive studies in non-neuronal cells, crosstalk between GSK3beta and other signaling pathways remains not well defined in neurons. In the present study, we report that GSK3beta positively affected the activity of effectors of mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2), in mature neurons in vitro and in vivo. GSK3beta also promoted prosurvival signaling and attenuated kainic acid-induced apoptosis. Our study identified GSK3beta as a positive regulator of prosurvival signaling, including the mTOR pathway, and indicates the possible neuroprotective role of GSK3beta in models of pharmacologically induced excitotoxicity. PMID- 29143289 TI - Agents in Development for Childhood Acute Lymphoblastic Leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood. Standard chemotherapy has afforded outstanding outcomes for many patients; however, there remain some sub-groups with high-risk features, refractory disease, and patients that relapse who have a poor prognosis with conventional treatments. Over the past decade, there have been significant advances in newer treatment options, including improved monoclonal antibody therapies, T cell engagers, and chimeric antigen T-cell receptor products, all of which have changed the landscape for patients who relapse. These are now being introduced more frequently and at earlier stages of therapy. We present a brief overview of the biology and etiology of childhood ALL, treatment strategies currently in use, and discuss some newer strategies and their possible role in the future of ALL therapy for children. PMID- 29143291 TI - Professor Martin Fried, MD, PhD. PMID- 29143290 TI - Increased Free Testosterone Levels in Men with Uncontrolled Type 2 Diabetes Five Years After Randomization to Bariatric Surgery. AB - Hypogonadism frequently occurs in male patients with type 2 diabetes (T2DM) and is linked to insulin resistance and inflammation. Testosterone levels rise acutely in obese patients following bariatric surgery, though long-term changes have not been investigated in a randomized controlled trial. This study evaluated obese men with T2DM randomized to either bariatric surgery or medical therapy. Testosterone, gonadotropins, body composition, insulin sensitivity, and inflammatory markers were evaluated in 32 patients at baseline and at 5 years. Surgical patients had 47.4% increase in free testosterone compared to medical therapy patients who had 2.2% decrease (P = 0.013). Increase in free testosterone correlated with reduction in body weight, high-sensitivity C-reactive protein (hsCRP), and leptin levels. Prolonged improvements in testosterone levels after bariatric surgery in T2DM are found to be related to reduction in body weight and adipogenic inflammation. PMID- 29143292 TI - Tribute to Professor Quirino Maggiore (December 17, 1933-September 2, 2017) founder and first editor in chief of the Journal of Nephrology. PMID- 29143293 TI - Acute motor axonal neuropathy and transverse myelitis overlap: the importance of history taking. AB - In young adults, acute motor axonal neuropathy and transverse myelitis rarely occur as associated conditions. Clinical reasoning, symptoms, laboratory and ancillary investigations (electroneurographic and radiological findings), should properly address the physician to the correct diagnosis. PMID- 29143294 TI - Reply to the letter by Jasmin Zvornicanin on the article Prefoveal floaters as a differential diagnosis to optic neuritis: "mouches dormantes". PMID- 29143296 TI - Erratum to: Progress in Motor Control. PMID- 29143295 TI - Posterior circulation involvement in pediatric and adult patients with moyamoya disease: a single center experience in 574 patients. AB - The importance of the posterior cerebral artery (PCA) involvement in moyamoya disease has been highlighted in recent years. However, few studies compared the impact of PCA lesions in moyamoya disease between pediatric and adult patients. We conducted this study to summarize the clinical features of moyamoya patients with PCA lesions and describe the difference between pediatric and adult patients. We reviewed the records of 696 consecutive moyamoya vasculopathy patients from 2009 to 2015. The Suzuki and the Miyamoto stages were used to evaluate the steno-occlusive lesions of the anterior and posterior arteries. Clinical and radiographic features were compared between those with and without PCA involvement, also between pediatric and adult patients. A total of 574 angiograms (140 pediatrics and 434 adults) were reviewed. The prevalence of PCA steno-occlusion did not differ significantly between pediatric patients and adult patients (35.0% vs. 30.4%, P = 0.347). Pediatric patients had more advanced PCA stages compared to adult patients (P = 0.045). There was a significant correlation of the PCA angiographic stages with the ipsilateral internal carotid artery (ICA) stages, both in pediatrics and in adults (both P < 0.001). The frequency of ipsilateral cerebral infarction positively correlated with the advancement of PCA stages in adult patients (P < 0.001), but not significant in pediatric patients (P = 0.106). Pediatric patients tend to have more advanced PCA lesions than adult patients. The degree of PCA steno-occlusion positively correlates with the ipsilateral ICA stage, both in pediatrics and in adults. PMID- 29143297 TI - Impact of Trimetazidine Treatment on 5-year Clinical Outcomes in Patients with Significant Coronary Artery Spasm: A Propensity Score Matching Study. AB - OBJECTIVE: We aimed to evaluate the additive benefit of trimetazidine with well known antispasmodic agents such as calcium channel blockers and nitrate in patients with significant coronary artery spasm (CAS) as assessed by acetylcholine provocation test up to 5 years. METHODS: A total 1727 patients with significant CAS were enrolled. They were divided into two groups: a trimetazidine group (trimetazidine, diltiazem, and nitrate, n = 695), and control group (diltiazem and nitrate, n = 473). After propensity score matching analysis, two matched groups (441 pairs, n = 882, C-statistic = 0.673) were generated. The individual and composite clinical end points [mortality, myocardial infarction (MI), revascularization, cerebrovascular accident (CVA), major adverse cardiac events (MACE), major adverse cardiac or cerebrovascular events (MACCE), and recurrent angina] were assessed up to 5 years for the two groups. RESULTS: At 5 years, there were similar incidences of individual and composite hard endpoints including mortality, MI, revascularization, CVA, MACE, MACCE, and recurrent angina in the two groups. CONCLUSIONS: Additional long-term (5-year) treatment with trimetazidine in combination with diltiazem and nitrate in patients with significant CAS was not associated with improved clinical outcomes compared with combination therapy with diltiazem and nitrate only (without trimetazidine). PMID- 29143298 TI - A single nucleotide mutation of IspF gene involved in the MEP pathway for isoprenoid biosynthesis causes yellow-green leaf phenotype in rice. AB - KEY MESSAGE: We identified IspF gene through yellow-green leaf mutant 505ys in rice. OsIspF was expressed in all tissues detected, and its encoded protein was targeted to the chloroplast. On expression levels of genes in this mutant, OsIspF itself and the genes encoding other enzymes of the MEP pathway and chlorophyll synthase were all up-regulated, however, among eight genes associated with photosynthesis, only psaA, psaN and psbA genes for three reaction center subunits of photosystem obviously changed. Isoprenoids are the most abundant natural compounds in all organisms, which originate from the basic five-carbon units isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). In plants, IPP and DMAPP are synthesized through two independent pathways, the mevalonic acid pathway in cytoplasm and the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway in plastids. The MEP pathway comprises seven enzymatic steps, in which IspF is the fifth enzyme. So far, no IspF gene has been identified in monocotyledonous plants. In this study, we isolated a leaf-color mutant, 505ys, in rice (Oryza sativa). The mutant displayed yellow-green leaf phenotype, reduced level of photosynthetic pigments, and arrested development of chloroplasts. By map-based cloning of this mutant, we identified OsIspF gene (LOC_Os02g45660) showing significant similarity to IspF gene of Arabidopsis, in which a missense mutation occurred in the mutant, resulting in an amino acid change in the encoded protein. OsIspF gene was expressed in all tissues detected, and its encoded protein was targeted to the chloroplast. Further, the mutant phenotype of 505ys was complemented by transformation with the wild-type OsIspF gene. Therefore, we successfully identified an IspF gene in monocotyledonous plants. In addition, real-time quantitative RT-PCR implied that a positive regulation could exist between the OsIspF gene and the genes encoding other enzymes of the MEP pathway and chlorophyll synthase. At the same time, it also implied that the individual genes involved in the MEP pathway might differentially regulated expression levels of the genes associated with photosynthesis. PMID- 29143300 TI - Effect of Restraining the Base of Support on the Other Biomechanical Features in Patients with Cerebellar Ataxia. AB - This study aimed to analyze the biomechanical consequences of reducing the base of support in patients with ataxia. Specifically, we evaluated the spatio temporal parameters, upper- and lower-body kinematics, muscle co-activation, and energy recovery and expenditure. The gaits of 13 patients were recorded using a motion analysis system in unperturbed and perturbed walking conditions. In the latter condition, patients had to walk using the same step width and speed of healthy controls. The perturbed walking condition featured reduced gait speed, step length, hip and knee range of motion, and energy recovery and increased double support duration, gait variability, trunk oscillation, and ankle joint muscle co-activation. Narrowing the base of support increased gait instability (e.g., gait variability and trunk oscillations) and induced patients to further use alternative compensatory mechanisms to maintain dynamic balance at the expense of a reduced ability to recover mechanical energy. A widened step width gait is a global strategy employed by patients to increase dynamic stability, reduce the need for further compensatory mechanisms, and thus recover mechanical energy. Our findings suggest that rehabilitative treatment should more specifically focus on step width training. PMID- 29143301 TI - Potentially inappropriate medication use in elderly non-Hodgkin lymphoma patients is associated with reduced survival and increased toxicities. AB - Survival outcomes for elderly lymphoma patients are disproportionally inferior to those of younger patients. We examined medication usage at diagnosis for 171 elderly patients (median age 70 years) with aggressive non-Hodgkin lymphoma treated between 2009 and 2014. At least one potentially inappropriate medication was used in 47% of patients according to the Beers Criteria, 59% experienced treatment delays and/or dose reduction and 65% experienced >= grade 3 treatment related toxicities. We report here for the first time that potentially inappropriate medication use was associated with reduced progression-free survival and overall survival, and increased >= grade 3 treatment-related toxicities in multivariate analysis. PMID- 29143302 TI - Convergent selection pressures drive the evolution of rhodopsin kinetics at high altitudes via nonparallel mechanisms. AB - Convergent evolution in response to similar selective pressures is a well-known phenomenon in evolutionary biology. Less well understood is how selection drives convergence in protein function, and the underlying mechanisms by which this can be achieved. Here, we investigate functional convergence in the visual system of two distantly related lineages of high-altitude adapted Andean and Himalayan catfishes. Statistical analyses revealed in the two high-altitude lineages, a parallel acceleration of evolutionary rates in rhodopsin, the dim-light visual pigment. However, the elevated rates were found to be accompanied by substitutions at different sites in the protein. Experiments substituting Andean- or Himalayan-specific residues significantly accelerated the kinetic rates of rhodopsin, destabilizing the ligand-bound forms. As found in cold-adapted enzymes, this phenotype likely compensates for a cold-induced decrease in kinetic rates, properties of rhodopsin mediating rod sensitivity and visual performance. Our study suggests that molecular convergence in protein function can be driven by parallel shifts in evolutionary rates but via nonparallel molecular mechanisms. Signatures of natural selection may therefore be a powerful guide for identifying complex instances of functional convergence across a wider range of protein systems. PMID- 29143299 TI - A comparative transcriptomic approach to understanding the formation of cork. AB - KEY MESSAGE: The transcriptome comparison of two oak species reveals possible candidates accounting for the exceptionally thick and pure cork oak phellem, such as those involved in secondary metabolism and phellogen activity. Cork oak, Quercus suber, differs from other Mediterranean oaks such as holm oak (Quercus ilex) by the thickness and organization of the external bark. While holm oak outer bark contains sequential periderms interspersed with dead secondary phloem (rhytidome), the cork oak outer bark only contains thick layers of phellem (cork rings) that accumulate until reaching a thickness that allows industrial uses. Here we compare the cork oak outer bark transcriptome with that of holm oak. Both transcriptomes present similitudes in their complexity, but whereas cork oak external bark is enriched with upregulated genes related to suberin, which is the main polymer responsible for the protective function of periderm, the upregulated categories of holm oak are enriched in abiotic stress and chromatin assembly. Concomitantly with the upregulation of suberin-related genes, there is also induction of regulatory and meristematic genes, whose predicted activities agree with the increased number of phellem layers found in the cork oak sample. Further transcript profiling among different cork oak tissues and conditions suggests that cork and wood share many regulatory mechanisms, probably reflecting similar ontogeny. Moreover, the analysis of transcripts accumulation during the cork growth season showed that most regulatory genes are upregulated early in the season when the cork cambium becomes active. Altogether our work provides the first transcriptome comparison between cork oak and holm oak outer bark, which unveils new regulatory candidate genes of phellem development. PMID- 29143303 TI - Is food intolerance a factor underlying chronic immune thrombocytopenia (ITP)? PMID- 29143304 TI - Inter-individual variability in phospholipid-dependent interference of C-reactive protein on activated partial thromboplastin time. PMID- 29143305 TI - In response: fluids in neurosurgery. PMID- 29143306 TI - Long-term evaluation of painful symptoms and fertility after surgery for large rectovaginal endometriosis nodule: a retrospective study. AB - INTRODUCTION: Optimal surgical treatment of rectovaginal endometriosis remains a controversial topic. The objective of this study was to evaluate long-term postoperative outcomes after rectal shaving or colorectal resection for rectovaginal endometriosis. MATERIAL AND METHODS: 195 patients underwent surgery (172 managed by shaving, 23 by colorectal resection) between January 2000 and June 2013 for rectovaginal endometriosis (>2 cm) involving at least the serosa of the rectum. Primary outcome measures were pain and fertility. Secondary outcome measures were complications, recurrence rates and quality of life. RESULTS: Mean follow-up was 60 +/- 42 months in the shaving group and 67 +/- 47 months in the resection group. The mean VAS score for pelvic pain between the pre and postoperative period decreased from 5.5 +/- 3.5 (shaving group) and 7.3 +/- 2.9 (resection group) to 2.3 +/- 2.4 (p < 0.001) and 2.0 +/- 1.8 (p < 0.001), respectively. For dysmenorrhea, the mean baseline VAS score fell postoperatively from 7.7 +/- 2.8 (shaving group) and 8.2 +/- 2.6 (resection group) to 3.3 +/- 2.9 (p < 0.001) and 2.7 +/- 2.7 (p < 0.001), respectively. Pregnancy rates were 73% for shaving and 69% for resection. Major complications occurred in 4% of patients in the shaving group and in 26% in the resection group (p = 0.001). Thirteen patients (7.6%) from the shaving group and none from the resection group were reoperated for suspicion of endometriosis recurrence (p = 0.37). Postoperative quality of life scores revealed no differences between the two groups. CONCLUSION: Our study demonstrates that rectal shaving, when feasible for rectovaginal nodule (>2 cm) infiltrating the digestive serosa, has equal impact on pain and pregnancy rates compared with colorectal resection at long-term follow-up, with low complication and favorable pregnancy rates. PMID- 29143307 TI - Considerations in performing and analyzing the responses of cortico-cortical evoked potentials in stereo-EEG. AB - This review aims to highlight key considerations when performing cortico-cortical evoked potentials (CCEPs) using stereo-electroencephalography (SEEG) for network mapping and show its clinical applicability to presurgical evaluations. The parameters for performing stimulation and safety aspects have been investigated in electrocorticography (ECoG) and deep brain stimulation (DBS), but not as extensively in SEEG. A review of current literature was performed, with an attempt made to emphasize practical insights from all modalities of intracranial stimulation. This paper reviews physical stimulation parameters, highlights safety limits, and considers the influence of changing common stimulation parameters. These factors are put into the context of CCEPs in SEEG. Given the paucity of direct research in this area, studies utilizing low frequency stimulation, DBS, and ECoG are incorporated along with the fundamental principles of electrical engineering. In addition, postprocessing considerations are reviewed, including electrode localization, application of digital filters, baseline selection, application of connectivity metrics, and higher order network analysis. The aim is to guide CCEP stimulation as well as to provide an understanding of the underlying principles of this technique. At present, there are few articles detailing the design of low-frequency stimulation paradigms, especially in the setting of SEEG. Providing a review of the fundamentals and postprocessing considerations when performing CCEPs in SEEG will increase the accessibility of this technique. PMID- 29143308 TI - Bone marrow Dikkopf-1 levels are a new independent risk factor for progression in patients with smouldering myeloma. PMID- 29143309 TI - A comparison of paternity data and relative testes size as measures of level of sperm competition in the Hominoidea. AB - OBJECTIVES: The phrase "level of sperm competition" is used only vaguely in the primate literature. There is also little distinction between the important elements of frequency and intensity of sperm competition, largely because the two current forms of measurement (socio-sexual system and relative testes size) are both proxies which allow neither precision nor fine distinctions. Both measures have critics, socio-sexual system in particular being branded subjective, misleading, and changeable. Testes size is considered the more reliable despite its validation resting on correlations with the other, less reliable, proxy. Recently, genetic paternity studies have been mooted to provide a potentially superior third measure of sperm competition but so far lack a formal interpretive framework. Here we use the published and relatively comprehensive genetic field studies of the Hominoidea to develop such a framework. MATERIALS AND METHODS: Formulae are derived to convert paternity data into a direct measure of the frequency, intensity, and overall level of sperm competition. We then compare these measures with relative testes size at the study, species, and phylogenetic levels. RESULTS: A significant correlation between level of sperm competition and relative testes size was obtained at each level. These correlations provide independent support for the continuing use of testes size as a proxy measure when such a measure is sufficient. However, they also suggest that paternity data and our formulae yield a viable alternative measure. DISCUSSION: This alternative measure based on paternity data has a number of advantages. Not only is it a potentially direct measure of the level of sperm competition but it also allows the roles of frequency and intensity to be studied separately when of interest. PMID- 29143310 TI - Clinical features and outcomes of secondary intraocular lymphoma. PMID- 29143312 TI - Erythrophagocytosis by T-cell lymphoma cells in a patient with hereditary spherocytosis post-splenectomy. PMID- 29143311 TI - Interleukin-12 and its procoagulant effect on erythrocytes, platelets and fibrin(ogen): the lesser known side of inflammation. AB - Inflammation, with its associated inflammatory molecules, is integral to most chronic diseases, including the various cardiovascular diseases. Interleukin 12 (IL12) is one of the inflammatory cytokines that is upregulated during inflammation; however, we know very little about its exact effect on red blood cells (RBCs), platelets and fibrin(ogen). IL12 is an important pleiotropic cytokine in early inflammatory responses and has potent immunomodulatory, antitumour and anti-infection activity. Here we investigate how low levels of circulating IL12, comparable to levels found during chronic inflammation, affect coagulation parameters, platelets and RBCs. We used thromboelastography, scanning electron microscopy, refractometery and wide-field microscopy. Our results show that IL12 caused hypercoagulation, platelet activation and spreading, as well as RBC agglutination. This phenomenon has far-reaching implications for treatment of the plethora of conditions where IL12 is upregulated, since it suggests aberrant haemorheology as agglutination affects blood flow. This information might be used in future to target the lowering of IL12 in inflammatory conditions, as well as address RBC agglutination. PMID- 29143313 TI - Polyglucosan myopathy and functional characterization of a novel GYG1 mutation. AB - OBJECTIVES: Disorders of glycogen metabolism include rare hereditary muscle glycogen storage diseases with polyglucosan, which are characterized by storage of abnormally structured glycogen in muscle in addition to exercise intolerance or muscle weakness. In this study, we investigated the etiology and pathogenesis of a late-onset myopathy associated with glycogenin-1 deficiency. MATERIALS AND METHODS: A family with two affected siblings, 64- and 66-year-olds, was studied. Clinical examination and whole-body MRI revealed weakness and wasting in the hip girdle and proximal leg muscles affecting ambulation in the brother. The sister had weakness and atrophy of hands and slight foot dorsiflexion difficulties. Muscle biopsy and whole-exome sequencing were performed in both cases to identify and characterize the pathogenesis including the functional effects of identified mutations. RESULTS: Both siblings demonstrated storage of glycogen that was partly resistant to alpha-amylase digestion. Both were heterozygous for two mutations in GYG1, one truncating 1-base deletion (c.484delG; p.Asp163Thrfs*5) and one novel missense mutation (c.403G>A; p.Gly135Arg). The mutations caused reduced expression of glycogenin-1 protein, and the missense mutation abolished the enzymatic function as analyzed by an in vitro autoglucosylation assay. CONCLUSION: We present functional evidence for the pathogenicity of a novel GYG1 missense mutation located in the substrate binding domain. Our results also demonstrate that glycogenin-1 deficiency may present with highly variable distribution of weakness and wasting also in the same family. PMID- 29143314 TI - Skills among young and elderly laypersons during simulated dispatcher assisted CPR and after CPR training. AB - BACKGROUND: Dispatcher assisted cardiopulmonary resuscitation (DA-CPR) increase the rate of bystander CPR. The aim of the study was to compare the performance of DA-CPR and attainable skills following CPR training between young and elderly laypersons. METHODS: Volunteer laypersons (young: 18-40 years; elderly: > 65 years) participated. Single rescuer CPR was performed in a simulated DA-CPR cardiac arrest scenario and after CPR training. Data were obtained from a manikin and from video recordings. The primary endpoint was chest compression depth. RESULTS: Overall, 56 young (median age: 26, years since last CPR training: 6) and 58 elderly (median age: 72, years since last CPR training: 26.5) participated. Young laypersons performed deeper (mean (SD): 56 (14) mm vs. 39 (19) mm, P < 0.001) and faster (median (25th-75th percentile): 107 (97-112) per min vs. 84 (74 107) per min, P < 0.001) chest compressions compared to elderly. Young laypersons had shorter time to first compression (mean (SD): 71 (11) seconds vs. 104 (38) seconds, P < 0.001) and less hands-off time (median (25th-75th percentile): 0 (0 1) seconds vs. 5 (2-10) seconds, P < 0.001) than elderly. After CPR training chest compressions were performed with a depth (mean (SD): 64 (8) mm vs. 50 (14) mm, P < 0.001) and rate (mean (SD): 111 (11) per min vs. 93 (18) per min, P < 0.001) for young and elderly laypersons respectively. CONCLUSION: Despite long CPR retention time for both groups, elderly laypersons had longer retention time, and performed inadequate DA-CPR compared to young laypersons. Following CPR training the attainable CPR level was of acceptable quality for both young and elderly laypersons. PMID- 29143316 TI - Psychometric properties of parent and child reported sleep assessment tools in children with cerebral palsy: a systematic review. AB - AIM: To determine whether any parent and child report sleep measure tools have been validated in children aged 0-18 years with cerebral palsy (CP). METHOD: A systematic search of five databases was performed up to June 2017. Studies were included if a sleep measure tool was used to evaluate sleep in children 0-18 years with CP based on international classifications of sleep. Sleep measures were assessed for psychometric data in children with CP. RESULTS: Only one paper which used the Schlaffragebogen fur Kinder mit Neurologischen und Anderen Komplexen Erkrankungen (SNAKE) questionnaire met the study criteria. The four other measures frequently used in children with CP had no psychometric data available for their use in children with CP. The SNAKE questionnaire has been validated only in children with CP in Gross Motor Function Classification System level V. The Sleep Disturbance Scale for Children and the Pediatric Sleep Questionnaire had the strongest psychometric properties in typically developing children, but has not yet been validated in children with CP. INTERPRETATION: Current sleep measures being administered in typically developing children are also often used in children with CP, but have not been well validated in this group of children. WHAT THIS PAPER ADDS: There are no condition specific measures of sleep in children with cerebral palsy (CP). The Schlaffragebogen fur Kinder mit Neurologischen und Anderen Komplexen Erkrankungen (SNAKE) questionnaire is validated for children with CP in Gross Motor Function Classification System level V. A framework to design a CP specific sleep questionnaire is provided. PMID- 29143317 TI - Castleman disease: delineating the spectrum. PMID- 29143315 TI - Fetal haemoglobin induction in sickle cell disease. AB - Fetal haemoglobin (HbF, alpha2gamma2) induction has long been an area of investigation, as it is known to ameliorate the clinical complications of sickle cell disease (SCD). Progress in identifying novel HbF-inducing strategies has been stymied by limited understanding of gamma (gamma)-globin regulation. Genome wide association studies (GWAS) have identified variants in BCL11A and HBS1L-MYB that are associated with HbF levels. Functional studies have established the roles of BCL11A, MYB, and KLF1 in gamma-globin regulation, but this information has not yielded new pharmacological agents. Several drugs are under investigation in clinical trials as HbF-inducing agents, but hydroxycarbamide remains the only widely used pharmacologic therapy for SCD. Autologous transplant of edited haematopoietic stem cells holds promise as a cure for SCD, either through HbF induction or correction of the causative mutation, but several technical and safety hurdles must be overcome before this therapy can be offered widely, and pharmacological therapies are still needed. PMID- 29143318 TI - Calcineurin inhibitor-induced complement system activation via ERK1/2 signalling is inhibited by SOCS-3 in human renal tubule cells. AB - One factor that significantly contributes to renal allograft loss is chronic calcineurin inhibitor (CNI) nephrotoxicity (CIN). Among other factors, the complement (C-) system has been proposed to be involved CIN development. Hence, we investigated the impact of CNIs on intracellular signalling and the effects on the C-system in human renal tubule cells. In a qPCR array, CNI treatment upregulated C-factors and downregulated SOCS-3 and the complement inhibitors CD46 and CD55. Additionally, ERK1/-2 was required for these regulations. Following knock-down and overexpression of SOCS-3, we found that SOCS-3 inhibits ERK1/-2 signalling. Finally, we assessed terminal complement complex formation, cell viability and apoptosis. Terminal complement complex formation was induced by CNIs. Cell viability was significantly decreased, whereas apoptosis was increased. Both effects were reversed under complement component-depleted conditions. In vivo, increased ERK1/-2 phosphorylation and SOCS-3 downregulation were observed at the time of transplantation in renal allograft patients who developed a progressive decline of renal function in the follow-up compared to stable patients. The progressive cohort also had lower total C3 levels, suggesting higher complement activity at baseline. In conclusion, our data suggest that SOCS-3 inhibits CNI-induced ERK1/-2 signalling, thereby blunting the negative control of C-system activation. PMID- 29143319 TI - The full spectrum of Castleman disease: 273 patients studied over 20 years. AB - The spectrum of Castleman disease (CD) has considerably extended since its first description in 1956. Recently, an international collaborative working group has reached consensus on the diagnostic criteria and classification of CD. We herein report 273 patients with lymph node histopathology consistent with CD and investigate the newly established diagnostic criteria. Twenty of these patients with Castleman-like histopathology were removed from analyses, because they were diagnosed with an exclusionary disorder (18 with haematological malignancy). Among the 253 remaining patients, 57 were considered unicentric CD (UCD), 169 were multicentric CD associated with Human Herpesvirus 8 (HHV-8+MCD), including 140 patients with human immunodeficiency virus (HIV) infection and 29 patients without HIV infection, and 27 were HHV-8 negative/idiopathic multicentric CD (iMCD). 2-(18 F)fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography was useful in 62 patients for staging/classification of the disease and for excluding associated lymphoma. UCD was mainly associated with hyaline vascular histopathological features, and most patients were asymptomatic. Of the 27 patients that we had originally diagnosed with iMCD, 26 met the newly established diagnostic criteria. Patients with iMCD and HHV-8+ MCD demonstrated similar characteristics, including fever, splenomegaly, cytopenia and inflammatory symptoms. However, the disease was more aggressive in HHV-8+ MCD, particularly in HIV-infected patients. PMID- 29143320 TI - Accelerometer-Measured Physical Activity and Mortality in Women Aged 63 to 99. AB - OBJECTIVES: To prospectively examine associations between accelerometer-measured physical activity (PA) and mortality in older women, with an emphasis on light intensity PA. DESIGN: Prospective cohort study with baseline data collection between March 2012 and April 2014. SETTING: Women's Health Initiative cohort in the United States. PARTICIPANTS: Community-dwelling women aged 63 to 99 (N = 6,382). MEASUREMENTS: Minutes per day of usual PA measured using hip-worn triaxial accelerometers, physical functioning measured using the Short Physical Performance Battery, mortality follow-up for a mean 3.1 years through September 2016 (450 deaths). RESULTS: When adjusted for accelerometer wear time, age, race ethnicity, education, smoking, alcohol, self-rated health, and comorbidities, relative risks (95% confidence intervals) for all-cause mortality across PA tertiles were 1.00 (referent), 0.86 (0.69, 1.08), 0.80 (0.62, 1.03) trend P = .07, for low light; 1.00, 0.57 (0.45, 0.71), 0.47 (0.35, 0.61) trend P < .001, for high light; and, 1.00, 0.63 (0.50, 0.79), 0.42 (0.30, 0.57) trend P < .001, for moderate-to-vigorous PA (MVPA). Associations remained significant for high light-intensity PA and MVPA (P < .001) after further adjustment for physical function. Each 30-min/d increment in light-intensity (low and high combined) PA and MVPA was associated, on average, with multivariable relative risk reductions of 12% and 39%, respectively (P < .01). After further simultaneous adjusting for light intensity and MVPA, the inverse associations remained significant (light intensity PA: RR = 0.93, 95% CI = 0.89-0.97; MVPA: RR = 0.67, 95% CI = 0.58 0.78). These relative risks did not differ between subgroups for age or race and ethnicity (interaction, P >= .14, all). CONCLUSION: When measured using accelerometers, light-intensity and MVPA are associated with lower mortality in older women. These findings suggest that replacing sedentary time with light intensity PA is a public health strategy that could benefit an aging society and warrants further investigation. PMID- 29143321 TI - Interobserver agreement on standardized ultrasound and histopathologic signs for the prenatal diagnosis of placenta accreta spectrum disorders. AB - OBJECTIVE: To evaluate interobserver agreement in assessment of ultrasound signs and histopathologic findings associated with placenta accreta spectrum (PAS) disorders. METHODS: A retrospective study was conducted using data for patients prenatally diagnosed with PAS disorders at a UK hospital between January 31, 2012, and March 30, 2017. Ultrasound images (including gray-scale and color Doppler imaging [CDI] parameters) and histopathologic slides were reviewed by two observers; the level of agreement was calculated. RESULTS: Among 25 patients, 11 had placenta creta, 10 had placenta increta, and four had placenta percreta. Interobserver agreement for ultrasound imaging in the second and third trimesters and histopathologic diagnosis of PAS was rated as good-to-excellent. The highest level of interobserver agreement for ultrasound signs was found for loss of clear zone (100%) and substantial myometrial thinning (96%-100%) on gray-scale imaging, the presence of lacunar feeder vessels (100%) on two-dimensional CDI, and crossing vessels and lacunae (92%-95%) on three-dimensional CDI. CONCLUSION: Standardized ultrasound signs might prove useful for prenatal screening of women at risk of PAS disorders and should enable remote evaluation of images when PAS is suspected. PMID- 29143322 TI - Certifying Death in the United States. AB - Accurately identifying death and its causes is integral to the compilation of mortality data and ultimately to the operation of the criminal justice and public health systems. A clear understanding of who is in charge of such processes is paramount to establishing the quality, or lack thereof, of the information provided in death certificates. Our study provides a comprehensive overview of all state statutes identifying death investigators charged with classifying and certifying death in the United States. We found that state statutes designate a broad range of individuals as responsible for the classification and certification of death. Those vary by state and set of circumstances and can include medical examiners, coroners, pathologists, other physicians, registered nurses, and more. Our findings highlight the important need for a unified standard of qualifications in the medico-legal system, as well as, regulatory reform at the state level regarding who can complete and sign death certificates. PMID- 29143323 TI - Regarding "Implicit Review Instrument to Evaluate Quality of Care Delivered by Physicians to Children in Emergency Departments". PMID- 29143324 TI - Bioelectrical Impedance as a Technique for Estimating Postmortem Interval,. AB - Estimation of postmortem interval (PMI) is a critical component of death investigation. A cadaver can be hypothesized to be a resistor-capacitor (RC) circuit the impedance (Z) of which changes in a quantifiable manner as the cadaver decomposes. This hypothesis was tested using bioelectrical impedance analysis (BIA) equipment to apply a current with a fixed amplitude at a single frequency to four cadavers over time and measuring two components of Z, resistance (R) and reactance (Xc ). Quadratic regression analysis between Z and accumulated degree days (ADD) showed a statistically significant parabolic relationship. The parabolic relationship poses an initial challenge to the use of the method, and additional research is needed to address this issue. However, the results of the reported research support the hypothesis that Z measured using BIA has a relationship to PMI. PMID- 29143325 TI - Physician Practice Transitions to System Ownership Do Not Result in Diminished Practice Responsiveness to Patients. AB - OBJECTIVE: To examine the extent to which physician-to-system ownership transitions are associated with declines in practice-reported patient responsiveness (PRPR). DATA SOURCES: A longitudinal cohort of practices (n = 897) from the National Survey of Large Physician Organizations/National Survey of Small- and Medium-Sized Physician Organizations (2006/08) and the National Survey of All-Size Physician Organizations (2012/13). STUDY DESIGN: Multivariable regression estimated the effect of ownership on changes in PRPR, controlling for practice size, specialty composition, other practice, and market characteristics. DATA COLLECTION/EXTRACTION METHODS: Data were collected from three nationally representative surveys of physician organizations consisting of 40-minute interviews with the medical director, president, or chief executive officer. PRINCIPAL FINDINGS: Nine percent of organizations transitioned to system ownership. Compared to practices that were continuously physician-owned, practices that switched to system ownership did not have significantly lower PRPR at baseline but continuously system-owned practices did. Transitions to system ownership were associated with increased PRPR compared to continuously physician ownership. Increased practice size and changes in specialty composition, however, were associated with diminished PRPR. CONCLUSIONS: Practices can maintain or improve strategies to address patient concerns when transferring ownership to systems with careful attention to the impact of increased size and changes in specialty composition. PMID- 29143326 TI - LncRNA RP11-670E13.6 Regulates Cell Cycle Progression in UVB Damaged Human Dermal Fibroblasts. AB - Long noncoding RNAs (lncRNAs) have gained extensive attention in recent years, however, their effects on ultraviolet (UV) radiation-induced skin photodamage remain to be elucidated. In this study, we performed high-throughput RNA sequencing and comprehensive bioinformatics analyses to characterize the transcriptome profiles including lncRNAs and mRNAs in UVB-irradiated primary human dermal fibroblasts (HDFs) and to explore the roles of lncRNAs in photoaging. Quantitative reverse transcription-polymerase chain reaction amplification was performed to verify the differentially expressed genes. We subsequently found that knocking down of RP11-670E13.6, an up-regulated lncRNA in UVB-irradiated HDFs, promoted a robust senescence phenotype, including increased numbers of the senescence-associated beta-galactosidase-positive cells, decreased cell proliferation, accumulation of cells in G0/G1 phase and a characteristic gene expression signature of senescent cells. In addition, Western blot analysis showed that knocking down of RP11-670E13.6 activated the p16-pRB senescence pathway independent of the p53-p21 pathway. Therefore, we propose that RP11 670E13.6 may delay cellular senescence in UVB damaged HDFs through the p16-pRB pathway. PMID- 29143327 TI - Location of Artifacts Deposited by the Blow Fly Lucilia cuprina After Feeding on Human Blood at Simulated Indoor Crime Scenes. AB - Human DNA profiles can be obtained from fly artifacts (feces and regurgitant) when a fly has been feeding on biological material, sometimes 2 years after deposition. Morphological similarity between artifacts and spots of unaltered biological material make it difficult to distinguish between them, and presumptive and confirmatory forensic tests are unreliable in making the distinction. Knowing possible artifact locations will assist investigators in recognizing where DNA contamination might occur. Flies were released into a house with human blood available under a variety of different climatic and lighting conditions. The location of flies and artifacts was recorded after 72 h. It was found flies may move toward warm or well-lit areas and deposit artifacts there, but artifacts were predominantly located around food sources and were often found in low positions. Factors such as ambient temperature, and the proximity of light and food sources, had an impact on where artifacts were deposited. PMID- 29143328 TI - Efficacy and safety of anti-EGFR agents administered concurrently with standard therapies for patients with head and neck squamous cell carcinoma: a systematic review and meta-analysis of randomized controlled trials. AB - Agents targeting epidermal growth factor receptor (EGFR) are used to treat head and neck squamous cell carcinoma (HNSCC); however, their efficacy and safety is poorly understood. Here we evaluated the efficacy and safety of anti-EGFR agents administered concurrently with standard therapies for HNSCC. Randomized controlled trials that evaluated addition of EGFR targeted therapy versus standard therapy alone were included. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate (ORR), locoregional control, and severe adverse events (SAEs, grade >= 3). Sixteen eligible trials with 4031 patients were included. Addition of anti-EGFR regimens to standard therapy significantly improved OS of patients with HNSCC (HR = 0.89; 95% CI, 0.82-0.96), with a moderately elevated rate of SAEs (RR = 1.08; 95% CI, 1.03-1.13). Subgroup analysis indicated that the survival benefit was observed when cetuximab was administered concurrently with radiotherapy (RT) for stage III/IV patients (HR = 0.76; 95% CI, 0.61-0.94; p = 0.01), or with chemotherapy for recurrent or metastatic (R/M) HNSCC (HR = 0.86; 95% CI, 0.78 0.95; p = 0.005). Significantly increased ORR (RR = 1.51; 95% CI 1.05-2.18) and PFS (HR = 0.72; 95% CI, 0.59-0.88) were found in R/M HNSCC patients treated with anti-EGFR plus chemotherapy, while no significant improvements were found in stage III/IV patients treated with anti-EGFR plus standard therapy. In conclusion, addition of cetuximab to standard therapy may improve outcomes for R/M HNSCC patients, while causing a moderate increase in SAEs. For stage III/IV patients, anti-EGFR mAb plus RT can improve OS compared with RT alone, while replacement of chemotherapy with EGFR mAb or adding EGFR mAb to combined chemotherapy and RT did not improve outcomes. PMID- 29143329 TI - Matsubara-Takahashi cervix-holding technique for massive postpartum hemorrhage in patients with placenta previa with or without placenta accreta spectrum disorders. AB - OBJECTIVE: To determine the efficacy and safety of the Matsubara-Takahashi cervix holding technique (MT-holding) for achieving hemostasis for postpartum hemorrhage (PPH). METHODS: The present retrospective observational study included data from deliveries that occurred between January 1, 2004, and December 31, 2014, at the Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Japan. Deliveries were included where patients experienced blood loss greater than 2500 mL and MT-holding was used. The success rates of the technique in patients with placenta accreta spectrum (PAS) disorders and PPH were determined; subsequent pregnancy outcomes were also examined. RESULTS: There were 53 deliveries included in the study; 29 patients had placenta previa and 8 of these patients also had PAS disorders. MT-holding achieved hemostasis in 15 (71%) and 4 (50%) patients with placenta previa without and with PAS disorders, respectively; the placenta was removed in the latter. Overall, MT-holding achieved hemostasis in 40 (75%) deliveries. Of nine patients who became pregnant after this procedure, six went on to have full-term deliveries. CONCLUSION: MT-holding achieved hemostasis in 50% of patients with PAS disorders and had an overall success rate of 75% for PPH, comparable to other uterus-sparing procedures. MT holding is suggested as a simple, effective, safe technique available to less experienced obstetrician; these findings require confirmation in larger studies. PMID- 29143330 TI - Short-term high-fat diet primes excitatory synapses for long-term depression in orexin neurons. AB - KEY POINTS: High-fat diet consumption is a major cause of obesity. Orexin neurons are known to be activated by a high-fat diet and in turn promote further consumption of a high-fat diet. Our study shows that excitatory synapses to orexin neurons become amenable to long-term depression (LTD) after 1 week of high fat diet feeding. However, this effect reverses after 4 weeks of a high-fat diet. This LTD may be a homeostatic response to a high-fat diet to curb the activity of orexin neurons and hence caloric consumption. Adaptation seen after prolonged high-fat diet intake may contribute to the development of obesity. ABSTRACT: Overconsumption of high-fat diets is one of the strongest contributing factors to the rise of obesity rates. Orexin neurons are known to be activated by a palatable high-fat diet and mediate the activation of the mesolimbic reward pathway, resulting in further food intake. While short-term exposure to a high fat diet is known to induce synaptic plasticity within the mesolimbic pathway, it is unknown if such changes occur in orexin neurons. To investigate this, 3-week old male rats were fed a palatable high-fat western diet (WD) or control chow for 1 week and then in vitro patch clamp recording was performed. In the WD condition, an activity-dependent long-term depression (LTD) of excitatory synapses was observed in orexin neurons, but not in chow controls. This LTD was presynaptic and depended on postsynaptic metabotropic glutamate receptor 5 (mGluR5) and retrograde endocannabinoid signalling. WD also increased extracellular glutamate levels, suggesting that glutamate spillover and subsequent activation of perisynaptic mGluR5 may occur more readily in the WD condition. In support of this, pharmacological inhibition of glutamate uptake was sufficient to prime chow control synapses to undergo a presynaptic LTD. Interestingly, these WD effects are transient, as extracellular glutamate levels were similar to controls and LTD was no longer observed in orexin neurons after 4 weeks of WD. In summary, excitatory synapses to orexin neurons become amenable to LTD under a palatable high-fat diet, which may represent a homeostatic mechanism to prevent overactivation of these neurons and to curtail high-fat diet consumption. PMID- 29143332 TI - Accurate prediction and elucidation of drug resistance based on the robust and reproducible chemoresponse communities. AB - Selecting the available treatment for each cancer patient from genomic context is a core goal of precision medicine, but innovative approaches with mechanism interpretation and improved performance are still highly needed. Through utilizing in vitro chemotherapy response data coupled with gene and miRNA expression profiles, we applied a network-based approach that identified markers not as individual molecules but as functional groups extracted from the integrated transcription factor and miRNA regulatory network. Based on the identified chemoresponse communities, the predictors of drug resistance achieved high accuracy in cross-validation and were more robust and reproducible than conventional single-molecule markers. Meanwhile, as candidate communities not only enriched abundant cellular process but also covered a variety of drug enzymes, transporters, and targets, these resulting chemoresponse communities furnished novel models to interpret multiple kinds of potential regulatory mechanism, such as dysregulation of cancer cell apoptosis or disturbance of drug metabolism. Moreover, compounds were linked based on the enrichment of their common chemoresponse communities to uncover undetected response patterns and possible multidrug resistance phenotype. Finally, an omnibus repository named ChemoCommunity (http://www.jianglab.cn/ChemoCommunity/) was constructed, which furnished a user-friendly interface for a convenient retrieval of the detailed information on chemoresponse communities. Taken together, our method, and the accompanying database, improved the performance of classifiers for drug resistance and provided novel model to uncover the possible regulatory mechanism of individual response to drug. PMID- 29143333 TI - The Effect of Alcohol-Based Hand Sanitizer Vapors on Evidential Breath Alcohol Test Results. AB - This study was undertaken to determine if the application of alcohol-based hand sanitizers (ABHSs) to the hands of a breath test operator will affect the results obtained on evidential breath alcohol instruments (EBTs). This study obtained breath samples on three different EBTs immediately after application of either gel or foam ABHS to the operator's hands. A small, but significant, number of initial analyses (13 of 130, 10%) resulted in positive breath alcohol concentrations, while 41 samples (31.5%) resulted in a status code. These status codes were caused by ethanol vapors either in the room air or their inhalation by the subject, thereby causing a mouth alcohol effect. Replicate subject samples did not yield any consecutive positive numeric results. As ABHS application can cause a transitory mouth alcohol effect via inhalation of ABHS vapors, EBT operators should forego the use of ABHS in the 15 min preceding subject testing. PMID- 29143331 TI - Implicit Review Instrument to Evaluate Quality of Care Delivered by Physicians to Children in Emergency Departments. AB - OBJECTIVE: To evaluate the consistency, reliability, and validity of an implicit review instrument that measures the quality of care provided to children in the emergency department (ED). DATA SOURCES/STUDY SETTING: Medical records of randomly selected children from 12 EDs in the Pediatric Emergency Care Applied Research Network (PECARN). STUDY DESIGN: Eight pediatric emergency medicine physicians applied the instrument to 620 medical records. DATA COLLECTION/EXTRACTION METHODS: We determined internal consistency using Cronbach's alpha and inter-rater reliability using the intraclass correlation coefficient (ICC). We evaluated the validity of the instrument by correlating scores with four condition-specific explicit review instruments. PRINCIPAL FINDINGS: Individual reviewers' Cronbach's alpha had a mean of 0.85 with a range of 0.76-0.97; overall Cronbach's alpha was 0.90. The ICC was 0.49 for the summary score with a range from 0.40 to 0.46. Correlations between the quality of care score and the four condition-specific explicit review scores ranged from 0.24 to 0.38. CONCLUSIONS: The quality of care instrument demonstrated good internal consistency, moderate inter-rater reliability, high inter-rater agreement, and evidence supporting validity. The instrument could be useful for systems' assessment and research in evaluating the care delivered to children in the ED. PMID- 29143335 TI - Self-perceived Coparenting of Nonresident Fathers: Scale Development and Validation. AB - This study reports on the development and validation of the Fatherhood Research and Practice Network coparenting perceptions scale for nonresident fathers. Although other measures of coparenting have been developed, this is the first measure developed specifically for low-income, nonresident fathers. Focus groups were conducted to determine various aspects of coparenting. Based on this, a scale was created and administered to 542 nonresident fathers. Participants also responded to items used to examine convergent and predictive validity (i.e., parental responsibility, contact with the mother, father self-efficacy and satisfaction, child behavior problems, and contact and engagement with the child). Factor analyses and reliability tests revealed three distinct and reliable perceived coparenting factors: undermining, alliance, and gatekeeping. Validity tests suggest substantial overlap between the undermining and alliance factors, though undermining was uniquely related to child behavior problems. The alliance and gatekeeping factors showed strong convergent validity and evidence for predictive validity. Taken together, results suggest this relatively short measure (11 items) taps into three coparenting dimensions significantly predictive of aspects of individual and family life. PMID- 29143334 TI - PK/PD modeling of flunixin meglumine in a kaolin-induced inflammation model in piglets. AB - Flunixin is marketed in several countries for analgesia in adult swine but little is known about its efficacy in piglets. Thirty-two piglets (6-8 days old) were randomized to receive placebo saline (n = 11, group CONTROL) or flunixin meglumine intravenously at 2.2 (n = 11, group MEDIUM) or 4.4 (n = 10, group HIGH) mg/kg, 10 hr after subcutaneous injection of kaolin in the left metacarpal area. A hand-held algometer was used to determine each piglet's mechanical nociceptive threshold (MNT) from both front feet up to 50 hr after treatment (cut-off value of 24.5 newton). Serial venous blood samples were obtained to quantify flunixin in plasma using LC-MS/MS. A PKPD model describing the effect of flunixin on the mechanical nociceptive threshold was obtained based on an inhibitory indirect response model. A two-compartmental PK model was used. A significant effect of flunixin was observed for both doses compared to control group, with 4.4 mg/kg showing the most relevant (6-10 newton) and long-lasting effect (34 hr). The median IC50 was 6.78 and 2.63 mg/ml in groups MEDIUM and HIGH, respectively. The ED50 in this model was 6.6 mg/kg. Flunixin exhibited marked antinociceptive effect on kaolin-induced inflammatory hyperalgesia in piglets. PMID- 29143336 TI - Inter-filament co-operativity is crucial for regulating muscle contraction. PMID- 29143338 TI - Extracellular Matrix Containing in vitro Three-dimensional Tumor Models in Photodynamic Therapy-related Research. AB - Three-dimensional (3D) tumor models have been intensively evaluated for their use in cancer research, and there is a strong rationale behind using 3D cell cultures in photodynamic therapy (PDT)-related experimentation. In this contribution, it is explained why 3D cell cultures containing extracellular matrix (ECM) are preferred for this purpose. Results of experimental studies utilizing ECM containing 3D cellular models in PDT research are summarized. Finally, the design of in vitro 3D models that would provide clinically relevant information is discussed. PMID- 29143337 TI - Intraductal papillary mucinous neoplasm of the pancreas rapidly xenografts in chicken eggs and predicts aggressiveness. AB - Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has a high risk of progressing to invasive pancreatic ductal adenocarcinoma (PDA), but experimental models for IPMN are largely missing. New experimental systems for the molecular characterization of IPMN and for personalized prognosis and treatment options for IPMN are urgently needed. We analyzed the potential use of fertilized chicken eggs for the culture of freshly resected IPMN tissue. We transplanted 49 freshly resected IPMN tissues into eggs and compared the growth characteristics to IPMN tissues transplanted into mice; this was followed by an analysis of histology, morphology, and marker expression. Of the IPMN tissues transplanted into eggs, 63% formed tumor xenografts within 4 days, while none of the 12 IPMN tissues transplanted into immunodeficient mice engrafted. In the eggs, the grafting efficiency of high-grade (n = 14) and intermediate-grade (n = 17) dysplasia was 77% and was significantly higher than the 39% grafting efficiency of low-grade dysplasia (n = 18). According to mucinous expression, 46 IPMN tissues were classified into gastric (n = 6), intestinal (n = 3), oncocytic (n = 23), and pancreatobiliary (n = 14) subtypes. The grafting efficiency was highest for the pancreatobiliary subtype (86%), followed by the oncocytic (70%), gastric (33%) and intestinal (33%) subtypes. The morphology and expression patterns of mucins, progression markers and pancreatic ductal markers were comparable between the primary IPMN tissues and their xenograft copies. The individual tumor environment was largely maintained during subtransplantation, as evaluated upon passage 6. This new IPMN model may facilitate experimental studies and treatment decisions for the optimal personalized management of IPMN. PMID- 29143339 TI - Cell Death Pathways Associated with Photodynamic Therapy: An Update. AB - Photodynamic therapy (PDT) has the potential to make a significant impact on cancer treatment. PDT can sensitize malignant tissues to light, leading to a highly selective effect if an appropriate light dose can be delivered. Variations in light distribution and drug delivery, along with impaired efficacy in hypoxic regions, can reduce the overall tumor response. There is also evidence that malignant cells surviving PDT may become more aggressive than the initial tumor population. Promotion of more effective direct tumor eradication is therefore an important goal. While a list of properties for the "ideal" photosensitizing agent often includes formulation, pharmacologic and photophysical elements, we propose that subcellular targeting is also an important consideration. Perspectives relating to optimizing PDT efficacy are offered here. These relate to death pathways initiated by photodamage to particular subcellular organelles. PMID- 29143341 TI - A toxicogenomics approach to screen chlorinated flame retardants tris(2 chloroethyl) phosphate and tris(2-chloroisopropyl) phosphate for potential health effects. AB - Tris(2-chloroethyl) phosphate (TCEP) is a pervasive flame retardant that has been identified as a chemical of concern given its health effects and therefore its use has since been tightly regulated. Tris(2-chloroisopropyl) phosphate (TCIPP), an analogue of TCEP, is believed to be its replacement. However, compared to TCEP, little is known of the toxicological impacts of TCIPP. We used RNA sequencing as unbiased and sensitive tool to identify and compare effects on a transcriptome level of TCEP and TCIPP in the human hepatocellular carcinoma cell line, HepG2. We identified that compared to other flame retardants, TCEP and TCIPP had little cytotoxicity. Treatment with sub-cytotoxic concentrations of the two compounds revealed that both chemicals elicited similar effects; both compounds were found to affect genes involved in immune responses and steroid hormone biosynthesis, while also affecting xenobiotic metabolism pathways in a similar manner. Specifically for effects on immune responses, both compounds were shown to alter the expression of the receptor of the potent and pleiotropic complement component, C5a. Additionally, expression of genes encoding for effector proteins involved in the complement cascade along with other potent inflammatory regulators were found altered in response to TCEP and TCIPP, further emphasizing their potential effects on immune function. Taken together, given that TCIPP elicited similar effects compared to TCEP, and at lower concentrations, the potential health effects of TCIPP need to be further studied for a complete risk assessment of the compound. PMID- 29143340 TI - K2P TASK-2 and KCNQ1-KCNE3 K+ channels are major players contributing to intestinal anion and fluid secretion. AB - KEY POINTS: K+ channels are important in intestinal epithelium as they ensure the ionic homeostasis and electrical potential of epithelial cells during anion and fluid secretion. Intestinal epithelium cAMP-activated anion secretion depends on the activity of the (also cAMP dependent) KCNQ1-KCNE3 K+ channel, but the secretory process survives after genetic inactivation of the K+ channel in the mouse. Here we use double mutant mice to investigate which alternative K+ channels come into action to compensate for the absence of KCNQ1-KCNE3 K+ channels. Our data establish that whilst Ca2+ -activated KCa 3.1 channels are not involved, K2P two-pore domain TASK-2 K+ channels are major players providing an alternative conductance to sustain the intestinal secretory process. Work with double mutant mice lacking both TASK-2 and KCNQ1-KCNE3 channels nevertheless points to yet-unidentified K+ channels that contribute to the robustness of the cAMP-activated anion secretion process. ABSTRACT: Anion and fluid secretion across the intestinal epithelium, a process altered in cystic fibrosis and secretory diarrhoea, is mediated by cAMP-activated CFTR Cl- channels and requires the simultaneous activity of basolateral K+ channels to maintain cellular ionic homeostasis and membrane potential. This function is fulfilled by the cAMP activated K+ channel formed by the association of pore-forming KCNQ1 with its obligatory KCNE3 beta-subunit. Studies using mice show sizeable cAMP-activated intestinal anion secretion in the absence of either KCNQ1 or KCNE3 suggesting that an alternative K+ conductance must compensate for the loss of KCNQ1-KCNE3 activity. We used double mutant mouse and pharmacological approaches to identify such a conductance. Ca2+ -dependent anion secretion can also be supported by Ca2+ -dependent KCa 3.1 channels after independent CFTR activation, but cAMP-dependent anion secretion is not further decreased in the combined absence of KCa 3.1 and KCNQ1-KCNE3 K+ channel activity. We show that the K2P K+ channel TASK-2 is expressed in the epithelium of the small and large intestine. Tetrapentylammonium, a TASK-2 inhibitor, abolishes anion secretory current remaining in the absence of KCNQ1-KCNE3 activity. A double mutant mouse lacking both KCNQ1-KCNE3 and TASK-2 showed a much reduced cAMP-mediated anion secretion compared to that observed in the single KCNQ1-KCNE3 deficient mouse. We conclude that KCNQ1-KCNE3 and TASK-2 play major roles in the intestinal anion and fluid secretory phenotype. The persistence of an, admittedly reduced, secretory activity in the absence of these two conductances suggests that further additional K+ channel(s) as yet unidentified contribute to the robustness of the intestinal anion secretory process. PMID- 29143342 TI - BonnMag: Computer program for ligand-field analysis of f n systems within the angular overlap model. AB - The program BonnMag has been developed to calculate the absorption spectra and temperature dependent magnetic susceptibilities of f n systems. The computations of the transition energies are performed within the angular overlap model. Using Judd-Ofelt theory BonnMag allows estimation of the relative absorption coefficients of the electronic transitions with reasonable accuracy. A description of the theoretical background of the implemented methods is given. Using Slater-Condon-Shortley parameters and spin-orbit coupling coefficients for free Ln3+ ions from ab initio calculations, the transition energies of all Ln3+ ions are calculated and compared to the results from CASSCF/NEV-PT2 calculations. Splitting due to the ligand field as well as transition energies of all Cs2 NaLnCl6 (except Gd and Pm) are calculated using parameters reported in the literature. Based on the comparison between theory and experiment, the potential and limitations of the program BonnMag are shown. (c) 2017 Wiley Periodicals, Inc. PMID- 29143343 TI - Secrets and disclosure in donor conception. AB - This article considers the disclosure, sharing and exchange of information on being donor conceived within families, drawing on data from a study undertaken with donor-conceived adults registered with UK Donor Link (a voluntary DNA linking register). This paper considers the narratives of how respondents found out they were donor-conceived and what events triggered disclosure of this information. This paper then goes on to examine the role secrecy played in their family life and uses the concept of 'display' to explore how secrecy affected their relationships with their immediate and extended family. Secrets are notoriously 'leaky' and we found complex patterns of knowing and uncertainty about whom in the family knew that the person was donor-conceived. We argue that what is kept secret and from whom provides insights into the multifaceted web of social relationships that can be created by donor-conception, and how knowledge can be managed and controlled in attempts to display and maintain family narratives of biogenetic connection. PMID- 29143344 TI - Down-regulation of p16 and MGMT promotes the anti-proliferative and pro-apoptotic effects of 5-Aza-dC and radiation on cervical cancer cells. AB - Cervical cancer is one of the most common malignancies of the female reproductive system. Therefore, it is critical to investigate the molecular mechanisms involved in the development and progression of cervical cancer. In this study, we stimulated cervical cancer cells with 5-aza-2'-deoxycytidine (5-Aza-dC) and found that this treatment inhibited cell proliferation and induced apoptosis; additionally, methylation of p16 and O-6-methylguanine-DNA methyltransferase (MGMT) was reversed, although their expression was suppressed. 5-Aza-dC inhibited E6 and E7 expression and up-regulated p53, p21, and Rb expression. Cells transfected with siRNAs targeting p16 and MGMT as well as cells stimulated with 5 Aza-dC were arrested in S phase, and the expression of p53, p21, and Rb was up regulated more significantly. However, when cells were stimulated with 5-Aza-dC after transfection with siRNAs targeting p16 and MGMT, proliferation decreased significantly, and the percentage of cells in the sub-G1 peak and in S phase was significantly increased, suggesting a marked increase in apoptosis. But E6 and E7 overexpression could rescue the observed effects in proliferation. Furthermore, X ray radiation caused cells to arrest in G2/M phase, but cells transfected with p16- and MGMT-targeted siRNAs followed by X-ray radiation exhibited a significant decrease in proliferation and were shifted toward the sub-G1 peak, also indicating enhanced apoptosis. In addition, the effects of 5-Aza-dC and X-ray radiation were most pronounced when MGMT expression was down-regulated. Therefore, down-regulation of p16 and MGMT expression enhances the anti proliferative effects of 5-Aza-dC and X-ray radiation. This discovery may provide novel ideas for the treatment of cervical cancer. PMID- 29143345 TI - Lin28a enhances in vitro osteoblastic differentiation of human periosteum-derived cells. AB - Despite a capacity for proliferation and an ability to differentiate into multiple cell types, in long-term culture and with ageing, stem cells show a reduction in growth, display a decrease in differentiation potential, and enter senescence without evidence of transformation. The Lin28a gene encodes an RNA binding protein that plays a role in regulating stem cell activity, including self-renewal and differentiation propensity. However, the effect of the Lin28a gene on cultured human osteoprecursor cells is poorly understood. In the present study, alkaline phosphatase activity, alizarin red-positive mineralization, and calcium content, positive indicators of osteogenic differentiation, were significantly higher in cultured human periosteum-derived cells (hPDCs) with Lin28a overexpression compared with cells without Lin28a overexpression. Lin28a overexpression by hPDCs also increased mitochondrial activity, which is essential for cellular proliferation, as suggested by a reduced presence of reactive oxygen species and significantly enhanced lactate levels and ATP production. Our results suggest that, in hPDCs, the Lin28a gene enhances osteoblastic differentiation and increases mitochondrial activity. Although Lin28a is known as a marker of undifferentiated human embryogenic stem cell, there is limited evidence regarding the influence of Lin28a on osteoblastic differentiation of cultured osteoprecursor cells. This study was to examine the impact of Lin28a on osteogenic phenotypes of human periosteum-derived cells. Their phenotypes can be similar to those of mesenchymal stem cells. Our results suggest that the Lin28a gene enhances the osteoblastic differentiation of human periosteum-derived cells. In addition, the Lin28a gene increases mitochondrial activity in human periosteum derived cells. PMID- 29143346 TI - A comparative view on the potential acting on an electron in a molecule and the electrostatic potential through the typical halogen bonds. AB - This work considers the features of the electrostatic potential (ESP), and the potential acting on an electron in a molecule (PAEM) for the series of isolated dihalide molecules and for their molecular complexes. The joint analysis of these functions enriches the vision of atomic predispositions to the halogen bond formation and reveals details for their characterization. The account for the exchange-correlation interaction in PAEM retains the specific anisotropy of the ESP, which is commonly used for the halogen bonding explanation within sigma-hole concept. Along the halogen bonds, the curvatures of PAEM and ESP functions are opposite. Being jointly mapped on the closed isosurfaces of the reduced density gradient, placed between bound atoms, they are significantly differed from the side facing the halogen atom and from the side looking at the electron donor atom. (c) 2017 Wiley Periodicals, Inc. PMID- 29143347 TI - Validation of a tool for reporting pharmacists' interventions in everyday community pharmacy. AB - WHAT IS KNOWN AND OBJECTIVE: The French Society of Clinical Pharmacy (SFPC) asked a group of experts to adapt the SFPC hospital pharmacists' interventions reporting tool for use in community pharmacy practice. This study aimed to develop and validate a tool for the routine reporting of pharmacists' interventions in French community settings. METHODS: Two groups of community pharmacists coded reports of 60 typical pharmacists' interventions. One group was "experts" (n = 4) who had participated in the development of the tool (internal validation) and the other were "external" community pharmacists (n = 6), naive to the tool (external validation). The Kappa coefficient was used to assess the inter-reliability of classification between participants. A 4-level Likert scale was used to evaluate ease of use and acceptability. RESULTS AND DISCUSSION: The tool we developed for recording and classifying PIs has 19 items; 11 non-ordered categories describing drug-related problems; and 7 items describing interventions. Two tables of definitions were provided to help community pharmacists in the classification. The mean kappa statistic was (i) 0.63 for experts and 0.73 for external community pharmacists in categorizing drug-related problems and (ii) 0.69 for experts and 0.75 for external community pharmacists in categorizing interventions. WHAT IS NEW AND CONCLUSION: A specific tool for the documentation of pharmacists' interventions in community pharmacies is now available in French. Besides being useful to describe pharmacists' interventions in studies in community settings, it can be used to document the pharmaceutical patient record and to support the traceability process. PMID- 29143348 TI - RUNX-2, OPN and OCN expression induced by grey and white mineral trioxide aggregate in normal and hypertensive rats. AB - AIM: To investigate whether hypertension affects mineralization associated with white and grey mineral trioxide aggregate (MTA Angelus(r) ) implanted subcutaneously into rats by assaying osteoblastic biomarkers. METHODOLOGY: Polyethylene tubes containing grey MTA Angelus(r) , white MTA Angelus(r) , intermediate restorative material (IRM; positive control) or an empty tube (negative control) were implanted into the dorsal connective tissue of spontaneous hypertensive (n = 12) and Wistar (normotensive; n = 10) rats. Half of the rats in each group were killed after 7 days, and the remaining after 30 days. Tubes with surrounding tissue were removed, and immunostaining was performed to detect RUNX-2, OPN and OCN proteins. The normality of data was analysed using the Shapiro-Wilk test. Comparison of two independent groups was performed using the Mann-Whitney U-test, to detect a significant difference. A post hoc test accounting for multiple comparisons was performed following Tukey's test (P < 0.05). RESULTS: Under hypertensive conditions after 30 days, both MTA materials were associated with immunolabelling for RUNX-2 from low to moderate, which was less than that observed at normal blood pressure and the 7-day groups (P < 0.05). The expression of OPN and OCN proteins under both MTA conditions was considered low after both 7 and 30 days for the hypertensive condition, and was less than that in animals with normal blood pressure after 30 days (P < 0.05). No immunostaining for any biomarkers in the control and IRM groups was observed (P < 0.05). CONCLUSION: Hypertension decreased the immunostaining of RUNX-2, OPN and OCN biomarkers in response to MTA. Thus, hypertension can jeopardize the mineralization ability of MTA and may have a negative impact on endodontic treatment outcomes. PMID- 29143349 TI - Growth rate rather than growth duration drives growth heterosis in maize B104 hybrids. AB - Research in maize is often performed using inbred lines that can be readily transformed, such as B104. However, because the B104 line flowers late, the kernels do not always mature before the end of the growing season, hampering routine seed yield evaluations of biotech traits introduced in B104 at many geographical locations. Therefore, we generated five hybrids by crossing B104 with the early-flowering inbred lines CML91, F7, H99, Mo17, and W153R and showed in three consecutive years that the hybrid lines proved to be suitable to evaluate seed yield under field conditions in a temperate climate. By assessing the two main processes driving maize leaf growth, being rate of growth (leaf elongation rate or LER) and the duration of growth (leaf elongation duration or LED) in this panel of hybrids, we showed that leaf growth heterosis was mainly the result of increased LER and not or to a lesser extent of LED. Ectopic expression of the transgenes GA20-oxidase (GA20-OX) and PLASTOCHRON1 (PLA1), known to stimulate the LER and LED, respectively, in the hybrids showed that leaf length heterosis can be stimulated by increased LER, but not by LED, indicating that LER rather than LED is the target for enhancing leaf growth heterosis. PMID- 29143350 TI - DNA variants and organophosphate neurotoxicity among emerging farmers in the Western Cape of South Africa. AB - BACKGROUND: Previous epidemiological studies investigating modification of organophosphate (OP) neurotoxicity by xenobiotic metabolizing enzymes (XMEs) polymorphisms have produced inconsistent results. METHODS: A cross-sectional study of 301 emerging farmers was conducted. Neurotoxicity testing included forward and backward recall, digit span, and vibration sensitivity testing. Questionnaire data included demography, potential confounders, and work history of pesticide exposures. Genomic DNA was analyzed from study participants for DNA variants of two glutathione S-transferases (GSTM1 and GSTT1), N-acetyltransferase 2 (NAT2), and Paraoxonase 1 (PON1). RESULTS: There was evidence of OP pesticide neurotoxicity modification by rs1799931 (NAT2), rs662 (PON1), and the null allele of GSTM1 in multivariate analysis. The strongest evidence of modification was observed for rs1799931 (NAT2) on the relationship between pesticide poisoning and impaired vibration sense. CONCLUSIONS: DNA variants of NAT2, PON1, and GSTM1 may modify OP neurotoxicity, and this requires further exploration. PMID- 29143351 TI - Apoptotic and antiproliferative properties of 3beta-hydroxy-Delta5-steroidal congeners from a partially purified column fraction of Dendronephthya gigantea against HL-60 and MCF-7 cancer cells. AB - Organisms belonging to the genus Dendronephthya are among a group of marine invertebrates that produce a variety of terpenoids with biofunctional properties. Many of these terpenoids have been proven effective as anticancer drugs. Here, we report the antiproliferative effect of 3beta-hydroxy-Delta5-steroidal congeners against the proliferation of HL-60 human leukemia cells and MCF-7 human breast cancer cells. The sterol-rich fraction (DGEHF2-1) inhibited the growth of HL-60 and MCF-7 cells with IC50 values of 13.59 +/- 1.40 and 29.41 +/- 0.87 MUg ml-1 respectively. Treatment with DGEHF2-1 caused a dose-dependent increase in apoptotic body formation, DNA damage and the sub-G1 apoptotic cell population. Moreover, DGEHF2-1 downregulated the expression of Bcl-xL while upregulating Bax, caspase-9, and PARP cleavage in both HL-60 and MCF-7 cells. The steroid fraction was found to act via the mitochondria-mediated apoptosis pathway. Identification of the sterols was performed via gas chromatography-tandem mass spectrometry analysis. Studying the mechanism of the anticancer effect caused by these sterol derivatives could lead to the identification of other natural products with anticancer properties. PMID- 29143352 TI - Assessment of exposure to radio frequency electromagnetic fields from smart utility meters in GB; part II) numerical assessment of induced SAR within the human body. AB - Human body exposure to radiofrequency electromagnetic waves emitted from smart meters was assessed using various exposure configurations. Specific energy absorption rate distributions were determined using three anatomically realistic human models. Each model was assigned with age- and frequency-dependent dielectric properties representing a collection of age groups. Generalized exposure conditions involving standing and sleeping postures were assessed for a home area network operating at 868 and 2,450 MHz. The smart meter antenna was fed with 1 W power input which is an overestimation of what real devices typically emit (15 mW max limit). The highest observed whole body specific energy absorption rate value was 1.87 mW kg-1 , within the child model at a distance of 15 cm from a 2,450 MHz device. The higher values were attributed to differences in dimension and dielectric properties within the model. Specific absorption rate (SAR) values were also estimated based on power density levels derived from electric field strength measurements made at various distances from smart meter devices. All the calculated SAR values were found to be very small in comparison to International Commission on Non-Ionizing Radiation Protection limits for public exposure. Bioelectromagnetics. 39:200-216, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29143354 TI - Synthesis and biological properties of radiohalogenated alpha,alpha-disubstituted amino acids for PET and SPECT imaging of amino acid transporters (AATs). AB - Fluorine-18 and iodine-123 labeled nonnatural alicyclic and methyl branched disubstituted alpha,alpha-amino acids are a diverse and useful class of tumor imaging agents suitable for positron emission tomography and single photon emission computed tomography. These tracers target the increased expression of the cell membrane amino acid transporter systems L, ASC, and A exhibited by many human tumor cells. The most established clinical use for these radiolabeled amino acids is imaging primary and recurrent gliomas and primary, recurrent, and metastatic prostate cancer. This review focuses on the synthesis, radiolabeling, and amino acid transport mechanism of a series of nonnatural fluorine-18 and iodine-123 labeled analogs of 1-aminocyclobutane-1-carboxylic acid, 1 aminocyclopentane-1-carboxylic acid, alpha-aminoisobutyric acid, and alpha methylaminoisobutyric acid. PMID- 29143353 TI - Prospective Study of Concordance Between Hysterosalpingo-Contrast Sonography and Hysteroscopy for Evaluation of the Uterine Cavity in Patients Undergoing Infertility Studies. AB - OBJECTIVES: The purpose of the study was to assess the accuracy of hysterosalpingo-contrast sonography (HyCoSy) for evaluation of the uterine cavity. METHODS: Hysterosalpingo-contrast sonography was compared with hysteroscopy for assessment of the uterine cavity. This work was a descriptive prospective study to assess the concordance between pathologic intrauterine findings using the Cohen kappa coefficient. Ninety infertile patients from Puerta de Hierro University Hospital were included in the study. They underwent HyCoSy between June 2016 and April 2017. Fifteen of them had pathologic findings in the uterine cavity during HyCoSy and therefore underwent hysteroscopy. Clinical and sonographic findings were compared in those 15 patients by to evaluate the agreement between both techniques. RESULTS: In this study, intrauterine sonographic findings on HyCoSy and hysteroscopic features of the uterine cavity reached 100% concordance, with a kappa coefficient of 1.000 and a 100% agreement rate. CONCLUSIONS: Hysterosalpingo-contrast sonography permits a very accurate evaluation of the uterine cavity, which could be of interest for infertile patients who might be examined for tubal patency. PMID- 29143355 TI - Short-term changes in chewing efficiency and subjective evaluation in normal dentate subjects after insertion of oral appliances with an occlusal flat table. AB - Oral appliances with an occlusal flat table are used as treatment dentures. However, the short-term effect of insertion of such oral appliances on chewing has not been reported. This study aimed to determine whether experimental and continuous insertion of oral appliances with an occlusal flat table has an effect on chewing efficiency and Oral Health Impact Profile (OHIP) in healthy participants. Ten participants each in the oral-appliance and control (no oral appliance insertion) groups attended six data collection sessions for 5 consecutive days. Participants answered the OHIP questionnaire and underwent the chewing efficiency test. For each parameter, intergroup differences were investigated in terms of change from baseline to immediately after oral-appliance insertion (0 hour; P < .05) and from 0 hour to 24, 48, 72 and 96 hours after oral appliance insertion (P < .05). There were significant differences between groups in the degree of change in chewing efficiency and OHIP scores for functional limitation, physical pain, physical disability and handicap from baseline to 0 hour (all, P < .001); among these, only OHIP scores for functional limitation and physical pain demonstrated significant differences in degree of change between the two groups at 96 hours after appliance insertion (P = .477 and .275, respectively). Differences between the two groups in the degree of change in other parameters were not significant. Insertion of oral appliances caused a decrease in chewing efficiency and an increase in OHIP scores. Continuous insertion improved functional limitation and physical pain within 96 hours. PMID- 29143356 TI - On-the-ground application of the 'temporary recommendation for use' regulatory measure on off-label use of baclofen for alcohol dependence in France: a regional survey of community pharmacies. AB - The 'temporary recommendation for use' (TRU) is a French novel regulatory measure for off-label drug. The first TRU to be issued by the French drug agency (in March 2014) pertained to the off-label use of baclofen for alcohol dependence (AD). We performed a questionnaire-based survey of the on-the-ground application of the baclofen TRU among community pharmacies in northern France. A pharmacist from 70 of the 219 pharmacies contacted (response rate: 32.0%) completed the questionnaire. The mean +/- standard deviation number of off-label baclofen prescriptions for AD was 2.3 +/- 2.2 per pharmacy per month. 65.2% of these prescriptions were issued by primary care physicians. 65.7% of the pharmacists had never seen 'TRU' written on the prescription, and 80.3% delivered a prescription without checking whether the patient had been included by the prescriber in the TRU. The main criterion used to identify off-label prescribing was the patient's medical history (according to 74.6% of pharmacists) and the prescription of an above-threshold dose (73.1%). 87.1% of the pharmacists were aware of the baclofen TRU, and 42.9% had actually read the document. 17.9% of the pharmacists estimated that the TRU had changed their attitude to off-label baclofen prescription, and 29.9% (20 out of 67) of them wanted to be more involved in the TRU process. Community pharmacists were well informed about the off-label use of baclofen for AD and the TRU. However, a majority of baclofen prescribers did not fulfill the TRU requirements while a majority of pharmacists did not exert any control over these off-label prescriptions. In practice, in 2015 the TRU measure had thus a limited impact on both the baclofen prescribing and delivery practices. PMID- 29143357 TI - Influence of phosphatidylserine and phosphatidylethanolamine on farnesol tolerance in Candida albicans. AB - Candida albicans is among the most common human fungal pathogens. The ability to undergo the morphological transition from yeast to hyphal growth is critical for its pathogenesis. Farnesol, a precursor in the isoprenoid/sterol pathway, is a quorum-sensing molecule produced by C. albicans that inhibits hyphal growth in this polymorphic fungus. Interestingly, C. albicans can tolerate farnesol concentrations that are toxic to other fungi. We hypothesized that changes in phospholipid composition are one of the factors contributing to farnesol tolerance in C. albicans. In this study, we found that loss of enzymes that synthesize the phospholipids phosphatidylserine (PS) and/or phosphatidylethanolamine (PE) compromise the tolerance of C. albicans to farnesol. Compared with wild type, the phospholipid mutant cho1?/? (loss of PS and decreased PE synthesis) shows greater inhibition of growth, loss of ATP production, increased consumption of oxygen, and increased formation of reactive oxygen species in the presence of farnesol. The cho1?/? mutant also exhibits decreased sensitivity to mitochondrial ATPase inhibition, suggesting that cells lacking PS and/or downstream PE rely less on mitochondrial function for ATP synthesis. These data reveal that PS and PE play roles in farnesol tolerance and maintaining mitochondrial respiratory function. PMID- 29143358 TI - Melatonin improves survival and respiratory activity of yeast cells challenged by alpha-synuclein and menadione. AB - One of the hallmarks of Parkinson disease is alpha-synuclein aggregate deposition that leads to endoplasmic reticulum stress, Golgi fragmentation and impaired energy metabolism with consequent redox imbalance. In the last decade, many studies have used Saccharomyces cerevisiae as a model in order to explore the intracellular consequences of alpha-synuclein overexpression. In this study we propose to evaluate the respiratory outcome of yeast cells expressing alpha synuclein. Cell viability or growth on selective media for respiratory activity was mainly affected in the alpha-synuclein-expressing cells if they were also treated with menadione, which stimulates reactive oxygen species production. We also tested whether melatonin, a natural antioxidant, would counteract the deleterious effects of alpha-synuclein and menadione. In fact, melatonin addition improved the respiratory growth of alpha-synuclein/menadione-challenged cells, presented a general improvement in the enzymatic activity of the respiratory complexes and finally elevated the rate of mitophagy, an important cellular process necessary for the clearance of damaged mitochondria. Altogether, our data confirms that alpha-synuclein impairs respiration in yeast, which can be rescued by melatonin addition. PMID- 29143359 TI - Indolent T-lymphoblastic proliferation concomitant with acinic cell carcinoma mimicking T-lymphoblastic lymphoma: case report and literature review. AB - AIMS: Indolent T-lymphoblastic proliferation (iT-LBP) is a non-clonal benign condition showing extrathymic proliferation of T-lymphoblasts positive for CD3, CD4, CD8, and TdT. Isolated iT-LBP has been observed, but the majority of iT-LBPs have been seen in conjunction with other disorders, including Castleman disease, hepatocellular carcinoma, follicular dendritic cell tumours, angioimmunoblastic T cell lymphoma, myasthenia gravis, and acinic cell carcinoma (ACC). The clinical course of iT-LBP is indolent, and no therapy is usually required. A major concern is misdiagnosis as T-lymphoblastic lymphoma, and a correct diagnosis of iT-LBP often requires not only pathological analysis but also careful monitoring of the clinical course. The aim of this study was to broaden the knowledge of pathologists and physicians concerning this as yet not well-recognised entity. METHODS AND RESULTS: We report a case of iT-LBP concomitant with ACC, along with a literature review of all 14 cases of iT-LBP reported to date. CONCLUSIONS: iT LBP should always be considered as a differential diagnosis of T-lymphoblastic lymphoma, as the two disorders show extremely similar traits. PMID- 29143360 TI - Identification of a pyridine derivative inducing senescence in ovarian cancer cell lines via P21 activation. AB - Cellular senescence is a state of irreversible cell growth arrest. Increasing evidence suggests that cellular senescence contribute to tumour suppression in vivo. However, only a few anti-cancer drugs have been discovered to induce cellular senescence. Searching for new compounds which can inhibit cancer cell growth by inducing senescence is becoming one of the most attractive research fields. To test the effects of candidate compounds on cancer cell growth, cell proliferation assays, senescence-associated beta-galactosidase (SA-beta-gal) staining, and flow cytometry assay were performed. Immunofluorescence, western blot, and qRT-PCR experiments were used to further study the molecular mechanisms of the candidate compounds. We demonstrated that a pyridine derivative, 4-(4 fluorophenyl)-2-phenyl-5, 6, 7, 8-tetrahydroquinoline (FPTHQ), from a pool of 46 compounds can induce senescence of ovarian cancer cells in a dose-dependent manner. FPTHQ caused growth inhibition by inducing G0/G1 cell cycle arrest in A2780 cells. Increased activities of SA-beta-gal were observed in FPTHQ-treated A2780, OVCAR-3 and SKOV-3 cell lines. In addition, FPTHQ treatment increased the protein levels of MMP3 and the mRNA levels of IL-6 and IL-8 in A2780 cells, indicating the appearance of senescence-associated secretary phenotype (SASP) in the cells. Furthermore, we found that p21 was up-regulated and DNA damage was accumulated in FPTHQ-treated ovarian cancer cells. So far, our data suggest that FPTHQ can induce senescence in multiple ovarian cancer cell lines through activation of p21 signalling pathway by causing excessive DNA damage. PMID- 29143361 TI - 2-Alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles: An Overview on Synthetic Strategies and Biological Activity. AB - 2-Alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles represent an important class of ATP-competitive protein kinase inhibitors, offering the possibility of multiple interactions with different regions of the target enzyme. The necessity of exploring the effects of diverse chemical decorations around the imidazole core prompted the design of several synthetic routes aimed at achieving both efficiency and flexibility. Additionally, the optimization of established protocols and the extensive use of transition metal-catalyzed cross-coupling reactions have been broadening the spectrum of preparative methodologies within the last decade. This review summarizes the progress in the development of synthetic strategies leading to 2-alkylsulfanyl-4(5)-aryl-5(4) heteroarylimidazoles and 1-alkyl-2-alkylsulfanyl-4(5)-aryl-5(4) heteroarylimidazoles and offers a glance at the biological activities of this class of compounds. PMID- 29143362 TI - MicroRNA-26a inhibits proliferation and tumorigenesis via targeting CKS2 in laryngeal squamous cell carcinoma. AB - Laryngeal squamous cell carcinoma (LSCC) is one of the most common head and neck cancers, with high mortality and incidence. MicroRNA-26a (miR-26a) is involved in the development and progression of several tumours. However, the roles of miR-26a and its target CKS2 in LSCC progression are not yet clear. The mRNA and protein expression was determined using RT-PCR and Western blotting assay, respectively. Cell proliferation was detected using a Cell Counting kit-8 assay (CCK-8). Transwell assay was used to evaluate cell migration and invasion. Dual-luciferase reporter assay was applied to determine the relationship between miR-26a and CKS2. In addition, a tumour xenograft model in nude mice was established to further determine the effects of miR-26a on tumourigenesis. In this study, we found that miR-26a level was down-regulated in LSCC tissues and cell lines, while CKS2 expression was increased. Cell proliferation, migration, invasion and the expression of MMP2 and MMP9 was suppressed by miR-26a overexpression, but enhanced by inhibition of miR-26a. Dual-luciferase reporter assay demonstrated that CKS2 is a direct target of miR-26a in AMC-HN-8 cells. Overexpression of miR 26a caused a significant reduction in CKS2 expression, and reinforced expression of CKS2 abolished the tumour-suppressive function of miR-26a. Moreover, miR-26a inhibited tumour growth in vivo. Taken together, miR-26a inhibited proliferation and tumourigenesis of LSCC via targeting CKS2 in vitro and in vivo. PMID- 29143363 TI - Utility of Shear Wave Elastography for Assessing Allograft Fibrosis in Renal Transplant Recipients: A Pilot Study. AB - OBJECTIVES: To evaluate the utility of ultrasound-based shear wave elastography (SWE) as a noninvasive method to accurately detect and potentially stage the severity of renal allograft fibrosis and assess its user reproducibility. METHODS: In this Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant prospective study, 70 renal transplant recipients underwent an SWE evaluation of their allograft followed directly by biopsy. Two radiologists performed separate SWE measurement acquisitions and the mean, median, and standard deviation of 10 SWE measurements, obtained separately within the cortex and the medulla, were automatically computed. Each patient's SWE results were subsequently compared to their histologic fibrosis scores. The Fisher exact test and univariate logistic regression models were fit to test for associations between the presence of fibrosis (yes/no) as well as categorical SWE results based on the fibrosis severity, ranging from F0 (no fibrosis) to F3 (severe fibrosis), correlating with histologic scores according to the 2007 Banff classification system. Interobserver and intraobserver correlations were also examined. RESULTS: Our median medulla SWE values reached statistical significance (P = .04) in association with fibrosis. Furthermore, for every unit increase in the median medulla SWE measurement, the odds of fibrosis increased by approximately 20%. No statistical significance was found for mean cortical, median cortical, or mean medullary SWE values (P = .32, .37, and .06, respectively) in association with fibrosis. CONCLUSIONS: The use of SWE for assessing renal allograft fibrosis is challenging but promising. Further investigation with a larger sample size remains to validate our initial results and establish clinical relevance. PMID- 29143364 TI - Automated preparation of 2-[18 F]fluoropropionate labeled peptides using a flexible, multi-stage synthesis platform (iPHASE Flexlab). AB - Radiolabelled peptides are vital tools used in positron emission tomography imaging for the diagnosis of disease, drug discovery, and biomedical research. Peptides are typically labeled through conjugation to a radiolabelled prosthetic group, which usually necessitates complex, multi-step procedures, especially for fluorine-18 labeled peptides. Herein, we describe the automated synthesis and formulation of 2-[18 F]fluoropropionate labeled RGD-peptides through use of the iPHASE Flexlab as an effective dual-stage radiochemical synthesis module. The fully automated preparation of the monomeric RGD-peptides, [18 F]FP-GalactoRGD and [18 F]FP-c(RGDy(SO3 )K), was accomplished in under 90 minutes with n.d.c. radiochemical yields ca. 7% from fluoride. Similarly, the automated preparation of the dimeric RGD-peptides, [18 F]F-PRGD2 and [18 F]FP-E(RGDy(SO3 )K)2 , was accomplished in under 105 minutes with n.d.c. yields ca. 4% from fluoride. PMID- 29143365 TI - Epigenetic down-regulation of SOX2 is an independent poor prognostic factor for hypopharyngeal cancers. AB - AIMS: We recently reported that a small subset (7%) of oesophageal squamous cell carcinomas completely lacking SOX2 expression had unique clinicopathological features and a dismal prognosis. The aim of the present study was to elucidate whether the findings obtained in oesophageal cancers are applicable to hypopharyngeal squamous cell carcinomas (HPSCCs) or oropharyngeal squamous cell carcinomas (OPSCCs). METHODS AND RESULTS: The study cohort consisted of consecutive patients with HPSCC (n = 130) and OPSCC (n = 65) who underwent surgery without preoperative therapy. On immunostaining, SOX2 was almost entirely negative in 10 of 130 HPSCCs (8%) and seven of 65 OPSCCs (11%). No significant differences were observed in clinicopathological features, including p16 status, between SOX2-positive and SOX2-negative cancers. However, patients with SOX2 negative HPSCC had significantly worse overall and recurrence-free survival than those with SOX2-positive HPSCC, whereas such a prognostic relationship was not confirmed in patients with OPSCC. In a multivariate analysis, the loss of SOX2 expression appeared to be an independent poor prognostic factor for patients with HPSCC. In a sequencing analysis, no mutation was found in SOX2. As SOX2 is known to contain an extensive CpG island before the transcription start site, methylation-specific polymerase chain reaction for the SOX2 promoter was performed. Methylated alleles were found in nine of 10 SOX2-negative HPSCCs but in none of SOX2-positive HPSCCs. CONCLUSIONS: Similarly to oesophageal cancers, a small subset (8%) of HPSCCs characteristically almost completely lacking SOX2 expression appeared to be aggressive neoplasms with high recurrence rates. Promoter hypermethylation was determined to be a major mechanism underlying epigenetic SOX2 silencing. PMID- 29143366 TI - Patch testing in Israeli children with suspected allergic contact dermatitis: A retrospective study and literature review. AB - BACKGROUND/OBJECTIVES: Childhood allergic contact dermatitis is recognized as a significant clinical problem. The objective was to evaluate the rate of positive patch tests in Israeli children with clinically suspected allergic contact dermatitis, identify possible sex and age differences, compare results with those in Israeli adults, and review pediatric studies in the literature. METHODS: The study sample included 343 children and adolescents (197 female, 146 male; 1-18 years of age, mean age 11.8 years) with clinically suspected allergic contact dermatitis who underwent patch testing with a standard pediatric series of 23 allergens at a tertiary medical center from 1999 to 2012. Data on clinical characteristics and test results were collected retrospectively from the medical files. RESULTS: Ninety-eight subjects (28.6%) (75 girls [38.1%], 23 boys [15.8%]) had at least one positive reaction. The most frequent reactions were to nickel sulfate, followed by potassium dichromate and cobalt chloride. Nickel sulfate sensitivity was more common in girls, especially those younger than 3 years and older than 12 years. The prevalence of contact sensitization was similar in subjects with and without atopic dermatitis (50% and 51%, respectively). CONCLUSION: Nickel is the most common allergen in Israeli children, especially girls. Patch testing should be performed in children with clinically suspected allergic contact dermatitis regardless of atopic background. PMID- 29143367 TI - Risk of death associated with new benzodiazepine use among persons with Alzheimer disease: A matched cohort study. AB - OBJECTIVE: To investigate the risk of death associated with new benzodiazepine and related drug (BZDR) use in a nationwide cohort of persons with Alzheimer disease (AD). METHODS: The register-based MEDALZ cohort, including all community dwelling Finns diagnosed with AD during 2005 to 2011 (n = 70 718), was used. Clinically verified AD diagnoses were obtained from the Special Reimbursement Register. Drug use periods were modeled from BZDR purchases, derived from the Prescription Register. To study new users, persons who had any BZDR use during the year preceding the AD diagnosis were excluded. For each person initiating BZDR use (n = 10 380), 2 nonusers (n = 20 760) were matched on age, gender, and time since AD diagnosis. The outcome was 180-day mortality, and BZDR use was compared with nonuse with Cox regression. Multivariable analyses were adjusted for Charlson comorbidity index, socioeconomic position, hip fractures, psychiatric disorders, substance abuse, stroke, and other psychotropic drug use. RESULTS: During the follow-up, 5 excess deaths per 100 person-years occurred during BZDR use in comparison to nonuse, and mortality rates were 13.4 (95% confidence interval [CI], 12.2-14.5) and 8.5 (95% CI, 7.9-9.1), respectively. Benzodiazepine and related drug use was associated with an increased risk of death (adjusted hazard ratio = 1.4 [95% CI, 1.2-1.6]), and the association was significant from the initiation of use. Benzodiazepine use was associated with an increased risk of death, whereas benzodiazepine-related drug use was not. CONCLUSIONS: Benzodiazepine and related drug use was associated with an increased risk of death in persons with AD. Our results support treatment guidelines stating that nonpharmacological approaches should be the first-line option for symptomatic treatment of AD. PMID- 29143368 TI - Re-thinking the role of radiometal isotopes: Towards a future concept for theranostic radiopharmaceuticals. AB - The potential and future role of certain metal radionuclides, for example, 44 Sc, 89 Zr, 86 Y, 64 Cu, 68 Ga, 177 Lu, 225 Ac, and 213 Bi, and several terbium isotopes has been controversially discussed in the past decades. Furthermore, the possible benefits of "matched pairs" of isotopes for tandem applications of diagnostics and therapeutics (theranostics) have been emphasized, while such approaches still have not made their way into routine clinical practice. Analysis of bibliographical data illustrates how popularity of certain nuclides has been promoted by cycles of availability and applications. We furthermore discuss the different practical requirements for diagnostic and therapeutic radiopharmaceuticals and the resulting consequences for efficient development of clinically useful pairs of radionuclide theranostics, with particular emphasis on the underlying economical factors. Based on an exemplary assessment of overall production costs for 68 Ga and 18 F radiopharmaceuticals, we venture a look into the future of theranostics and predict that high-throughput PET applications, that is, diagnosis of frequent conditions, will ultimately rely on 18 F tracers. PET radiometals will occupy a niche in the clinical low-throughput sector (diagnosis of rare diseases), but above all, dominate preclinical research and clinical translation. Matched isotope pairs will be of lesser relevance for theranostics but may become important for future PET-based therapeutic dosimetry. PMID- 29143369 TI - Detection of adverse drug reactions: evaluation of an automatic data processing applied in oncology performed in the French Diagnosis Related Groups database. AB - The aim of this study was to assess an automated detection method of serious adverse reactions induced by oral targeted therapy (OTT) in patients with cancer, performed in the French Diagnosis Related Groups (DRG) database. Patients with cancer of the Poitiers hospital who started an OTT between 2014 and 2015 were included. This study focused on adverse drug reaction which required inpatient hospitalization (ADRh ). All diagnoses coded in the DRG database for hospital stays that occurred within 3 months after OTT initiation were collected (potential ADRh ). Filters (exclusion criteria) were automatically applied on potential ADRh to exclude diagnoses that were not adverse drug reactions (false positives). A pharmacovigilance review was carried out to identify ADRh in the medical records (reported ADRh ). The sensitivity and specificity of the detection method were estimated for each filter combinations by comparison between potential and reported ADRh . This study included 129 patients. The medical records review led to identify 19 ADRh (all coded in the DRG database) in 14 patients. To maintain a 100% sensitivity of the method detection, the best specificity obtained was 58.3% (95% IC: [55.2-61.4]).The use of restrictive filters ('drug' in the diagnostic label, specific diagnosis code for adverse cancer drug reaction) resulted in a 97.8% specificity (95% IC: [96.6-98.5]) with a 38.2% sensitivity (95% IC: [23.9-55.0]). Our method has detected the third of ADRh with an excellent specificity. Complementary experimentations in pharmacovigilance centers are necessary to evaluate the interest of this tool in routine in addition to spontaneous reporting. PMID- 29143371 TI - Editorial Comment from Dr Taguchi to Demographics, management and treatment outcomes of benign and malignant retroperitoneal tumors in Japan. PMID- 29143370 TI - Coronary artery bypass graft surgery in a patient with a giant pericardial cyst. PMID- 29143372 TI - A critical role of TRPM2 channel in Abeta42 -induced microglial activation and generation of tumor necrosis factor-alpha. AB - Amyloid beta (Abeta)-induced neuroinflammation plays an important part in Alzheimer's disease (AD). Emerging evidence supports a role for the transient receptor potential melastatin-related 2 (TRPM2) channel in Abeta-induced neuroinflammation, but how Abeta induces TRPM2 channel activation and this relates to neuroinflammation remained poorly understood. We investigated the mechanisms by which Abeta42 activates the TRPM2 channel in microglial cells and the relationships to microglial activation and generation of tumor necrosis factor-alpha (TNF-alpha), a key cytokine implicated in AD. Exposure to 10-300 nM Abeta42 induced concentration-dependent microglial activation and generation of TNF-alpha that were ablated by genetically deleting (TRPM2 knockout ;TRPM2-KO) or pharmacologically inhibiting the TRPM2 channel, revealing a critical role of this channel in Abeta42 -induced microglial activation and generation of TNF-alpha. Mechanistically, Abeta42 activated the TRPM2 channel via stimulating generation of reactive oxygen species (ROS) and activation of poly(ADPR) polymerase-1 (PARP 1). Abeta42 -induced generation of ROS and activation of PARP-1 and TRPM2 channel were suppressed by inhibiting protein kinase C (PKC) and NADPH oxidases (NOX). Abeta42 -induced activation of PARP-1 and TRPM2 channel was also reduced by inhibiting PYK2 and MEK/ERK. Abeta42 -induced activation of PARP-1 was attenuated by TRPM2-KO and moreover, the remaining PARP-1 activity was eliminated by inhibiting PKC and NOX, but not PYK2 and MEK/ERK. Collectively, our results suggest that PKC/NOX-mediated generation of ROS and subsequent activation of PARP 1 play a role in Abeta42 -induced TRPM2 channel activation and TRPM2-dependent activation of the PYK2/MEK/ERK signalling pathway acts as a positive feedback to further facilitate activation of PARP-1 and TRPM2 channel. These findings provide novel insights into the mechanisms underlying Abeta-induced AD-related neuroinflammation. PMID- 29143373 TI - Saphenous vein graft pseudoaneurysm: Treatment with a covered stent graft. PMID- 29143374 TI - Asthma and lung function in adulthood after a viral wheezing episode in early childhood. AB - BACKGROUND: Viral aetiology of infection has a significant role in the long-term outcome of early-childhood wheezing. OBJECTIVE: This study examines asthma and lung function in adulthood after early-childhood wheezing induced by respiratory syncytial virus (RSV) and rhinovirus (RV). METHODS: A total of 100 children were hospitalized for a wheezing episode at less than 24 months of age from 1992 to 1993 in Kuopio University Hospital (Finland). Adenovirus, influenza A and B virus, parainfluenza (1-3) virus, and RSV were tested on admission using antigen detection and antibody assays, and RSV and RV were tested by polymerase chain reaction (PCR). In 2010, 49 cases and 60 population controls attended a follow-up study, which included spirometry with bronchodilation test and fractionally exhaled nitric oxide (FENO ) measurements. RESULTS: Current asthma was present in 64% of the cases with RV-induced wheezing (OR 17.0 [95%CI 3.9-75.3] vs controls), in 43% of the cases with RSV-induced wheezing episode (6.1 [1.5-24.9] vs controls), and in 12% of the controls. The RV group showed significantly higher mean FENO values than the RSV group and controls. RV-positive cases had lower MEF50 before bronchodilation and higher MEF50, FEV1, and FEV1/FVC bronchodilation responses than controls. RSV-positive cases had lower FVC than controls before bronchodilation. CONCLUSION: Cases with RV- and RSV-induced early-childhood wheezing had increased risk for asthma in adulthood, and RV-positive cases had significantly higher FENO values than RSV-positive cases and controls. Compared to controls, RV-positive cases showed more bronchial reactivity, and RSV-positive cases showed lower FVC before bronchodilation in lung function testing. CLINICAL RELEVANCE: Children with RV- or RSV-induced wheezing in early childhood have an increased risk for asthma and lung function abnormalities in adulthood. PMID- 29143375 TI - An immunoinformatics approach to define T cell epitopes from polyketide and non ribosomal peptide synthesis proteins of Mycobacterium tuberculosis as potential vaccine candidates. AB - The role of polyketide and non-ribosomal proteins from the class of small molecule metabolism of Mycobacterium tuberculosis is well documented in envelope organization, virulence, and pathogenesis. Consequently, the identification of T cell epitopes from these proteins could serve to define potential antigens for the development of vaccines. Fourty-one proteins from polyketide and non ribosomal peptide synthesis of small molecule metabolism proteins of M tuberculosis H37Rv were analyzed computationally for the presence of HLA class I binding nanomeric peptides. All possible overlapping nanomeric peptide sequences from 41 small molecule metabolic proteins were generated through in silico and analyzed for their ability to bind to 33 alleles belonging to A, B, and C loci of HLA class I molecule. Polyketide and non-ribosomal protein analyses revealed that 20% of generated peptides were predicted to bind HLA with halftime of dissociation T1/2 >= 100 minutes, and 77% of them were mono-allelic in their binding. The structural bases for recognition of nanomers by different HLA molecules were studied by structural modeling of HLA class I-peptide complexes. Pathogen peptides that could mimic as self-peptides or partially self-peptides in the host were excluded using a comparative study with the human proteome; thus, subunit or DNA vaccines will have more chance of success. PMID- 29143376 TI - Evaluating the nutritional value of date pits and demonstrating their application in laying hen diets. AB - This experiment was carried out to study the feeding value of ground date pits (DP) (Phoenix dactylifera L.) with and without enzyme supplementation on laying hens' performance. Apparent metabolizable energy value of DP was determined by the total collection method using 10 adult Leghorn cockerels. After that, a total number of 144 Lohmann 50-week-old LSL-Lite hens were randomly allocated into six groups consisting of four replicates of six birds, based on a 3 * 2 factorial arrangement of the treatments. Six iso-caloric and iso-nitrogenous experimental diets including I-corn-soya bean meal-based control, II-corn-soya bean meal oil based control and III- corn-soya bean meal-based diet (180 g/kg DP) were formulated. Each of the diets was supplemented with two levels of an enzyme (0.0 and 0.07 g/kg Natozim Plus). The experiment lasted 10 weeks after 7 days of adaptation. The results revealed that there was no significant difference in feed intake, feed conversion ratio, egg production, egg mass, eggshell weight, eggshell thickness and Haugh unit among the treatments. Dietary inclusion of DP significantly decreased body weight gain (BWG), egg weight and yolk colour score. On the other hand, corn-soya bean meal-based control diet with vegetable oil significantly increased egg weight and BWG of birds in comparison with other treatments. The serum biochemical metabolites were not affected by DP and enzyme supplementation. Thus, DP can be used as alternative feedstuff in laying hen diets, up to 18% of the diet with little effect on the performance of hens, including egg weight, and also, it had an adverse effect on yolk colour. Eventually, in terms of performance, the results failed to demonstrate any positive effect of Natozim Plus on either the controls or 18% DP diets. PMID- 29143377 TI - Long-term outcomes following transatrial versus transventricular repair on right ventricular function in tetralogy of Fallot. AB - BACKGROUND AND AIM OF THE STUDY: Outcomes after repair of tetralogy of Fallot (TOF) are good with either a transventricular (TV) or transatrial (TA) approach. We sought to determine if there is a relationship between the TV or TA approach and right ventricular (RV) function, and the role of residual pulmonary regurgitation (PR) on the long-term outcomes. METHODS: This was a retrospective cohort multicentric study on survivors after surgical repair of TOF (TA versus TV approach, +/-transannular patch) between 1990 and 2004. All patients underwent magnetic resonance imaging to assess RV volume, function, and PR. Patients were matched for length of follow-up and age. Clinical adverse events were retrieved from institutional databases. RESULTS: Seventy-nine patients (TA/TV = 37/42, median age 0.3 and 1.0 yrs, respectively) were included. At a median follow-up of 16.6 years (12.5-20.3), there were no differences in freedom from reintervention (either catheter or surgical), RV volumes, function, and PR between the TA and TV groups. Pulmonary valve (PV) replacement was significantly less frequent in the TA subgroup (P = 0.033) and patients with a preserved PV showed significantly lower RV volumes and less adverse events at follow-up. CONCLUSIONS: There is no significant difference in RV volumes and function between the TA and TV. However, the TA approach seems to be protective against PV replacement in the long-term. When PV is not preserved at repair, residual pulmonary regurgitation is a significant cause of late RV dysfunction and dilation, and is associated with a higher rate of late adverse events. PMID- 29143378 TI - Management of coronary obstruction following transcatheter aortic valve replacement. AB - Although occlusion of the coronary arteries during transcatheter aortic valve replacement is rare, the mortality is high. In this review, we discuss the prevention and management of this complication. Occlusion of coronary ostia is a very rare, but serious, complication of transcatheter aortic valve replacement (TAVR). Although reported as only occurring in <1% of TAVR cases, it carries a high risk of fatality, with some series reporting a mortality rate as high as 40%. We present the management of an occluded left coronary artery after a self expanding TAVR, and review the incidence, prevention, and management of this complication. PMID- 29143379 TI - Region-dependent hamstrings activity in Nordic hamstring exercise and stiff-leg deadlift defined with high-density electromyography. AB - Recent studies suggest region-specific metabolic activity in hamstring muscles during injury prevention exercises, but the neural representation of this phenomenon is unknown. The aim of this study was to examine whether regional differences are evident in the activity of biceps femoris long head (BFlh) and semitendinosus (ST) muscles during two common injury prevention exercises. Twelve male participants without a history of hamstring injury performed the Nordic hamstring exercise (NHE) and stiff-leg deadlift (SDL) while BFlh and ST activities were recorded with high-density electromyography (HD-EMG). Normalized activity was calculated from the distal, middle, and proximal regions in the eccentric phase of each exercise. In NHE, ST overall activity was substantially higher than in BFlh (d = 1.06 +/- 0.45), compared to trivial differences between muscles in SDL (d = 0.19 +/- 0.34). Regional differences were found in NHE for both muscles, with different proximal-distal patterns: The distal region showed the lowest activity level in ST (regional differences, d range = 0.55-1.41) but the highest activity level in BFlh (regional differences, d range = 0.38-1.25). In SDL, regional differences were smaller in both muscles (d range = 0.29-0.67 and 0.16-0.63 in ST and BFlh, respectively) than in NHE. The use of HD-EMG in hamstrings revealed heterogeneous hamstrings activity during typical injury prevention exercises. High-density EMG might be useful in future studies to provide a comprehensive overview of hamstring muscle activity in other exercises and high-injury risk tasks. PMID- 29143380 TI - Polo-like kinase 1 inhibition results in misaligned chromosomes and aberrant spindles in porcine oocytes during the first meiotic division. AB - Polo-like kinase 1 (Plk1), a type of serine/threonine protein kinase, has been implicated in various functions in the regulation of mitotic processes. However, these kinase's roles in meiotic division are not fully understood, particularly in the meiotic maturation of porcine oocytes. In this study, the expression and spatiotemporal localization of Plk1 were initially assessed in the meiotic process of pig oocytes by utilizing Western blotting with immunofluorescent staining combined with confocal microscopy imaging technique. The results showed that Plk1 was expressed and exhibited a dynamic subcellular localization throughout the meiotic process. After germinal vesicle breakdown (GVBD), Plk1 was detected prominently around the condensed chromosomes and subsequently exhibited a similar subcellular localization to alpha-tubulin throughout subsequent meiotic phases, with particular enrichment being observed near spindle poles at MI and MII. Inhibition of Plk1 via a highly selective inhibitor, GSK461364, led to the failure of first polar body extrusion in porcine oocytes, with the majority of the treated oocytes being arrested in GVBD. Further subcellular structure examination results indicated that Plk1 inhibition caused the great majority of oocytes with spindle abnormalities and chromosome misalignment during the first meiotic division. The results of this study illustrate that Plk1 is critical for the first meiotic division in porcine oocytes through its influence on spindle organization and chromosome alignment, which further affects the ensuing meiotic cell cycle progression. PMID- 29143381 TI - Comparing dermoscopy and histological examination of normal equine skin. AB - BACKGROUND: Dermoscopy is a noninvasive diagnostic technique that allows visualization of structures of the superficial dermis not visible with the naked eye. HYPOTHESIS/OBJECTIVES: To assess the usefulness and applicability of dermoscopy for evaluation of healthy equine skin. ANIMALS: Twelve healthy horses from a research herd. METHODS: Five regions (cheek, lateral neck, dorsum, flank and abdomen) were examined with contact dermoscopy using both nonpolarized and polarized light at both 17-fold and 24-fold magnification. These findings were compared to histological features of skin biopsies cut both longitudinally and transversely. RESULTS: Using a hand-held dermatoscope with nonpolarized light, epidermal ridges were observed. Using polarized light, follicular openings and distinctly separate epidermal openings of sweat gland ducts were observed in some but not all individuals. Similarities were noted between histological and dermoscopic results. CONCLUSIONS: Although not ideal for visualizing many structures in the superficial dermis of healthy equine skin, dermoscopy allowed visualization of epidermal ridges, hair shafts in the infundibular portion of the hair follicles and sweat gland duct openings. Dermoscopy could potentially be useful in the evaluation of diseases affecting the sweat glands, epidermis and hair shaft. PMID- 29143382 TI - The effect of resveratrol on the developmental competence of porcine oocytes vitrified at germinal vesicle stage. AB - We tested the effects of resveratrol both as a pre-treatment and as a recovery treatment after warming during in vitro maturation (IVM) on the viability and developmental competence of porcine oocytes vitrified at the germinal vesicle stage. Pre-treatment before vitrification of oocytes for 3 hr with 2 MUM resveratrol did not affect survival, oocyte maturation and embryo developmental competence to the blastocyst stage after parthenogenetic activation. However, supplementation of the medium with resveratrol during subsequent IVM after vitrification and warming significantly improved the ability of surviving oocytes to develop to the blastocyst stage, and this effect was observed only on vitrified, but not on non-vitrified oocytes. The intracellular levels of glutathione and hydrogen peroxide in oocytes were not affected by vitrification and resveratrol treatment. Also, there was no significant difference in the occurrence of apoptosis measured by annexin V binding between vitrified and non vitrified oocytes, regardless of the resveratrol treatment. In conclusion, resveratrol did not prevent the cellular damages in immature porcine oocytes during vitrification; however, when added to the IVM medium, it specifically improved the developmental competence of vitrified oocytes. Further research will be necessary to clarify the mechanisms of action of resveratrol on the recovery of vitrified oocytes from vitrification-related damages. PMID- 29143384 TI - Enhanced ventricular-arterial coupling during a 2-year physical activity programme in patients with rheumatoid arthritis: a prospective substudy of the physical activity in rheumatoid arthritis 2010 trial. AB - OBJECTIVE: To establish how guided physical activity in patients with rheumatoid arthritis (RA) without known cardiovascular disease affected vascular and cardiac function, and how these two entities were prospectively interconnected in this patient group. METHODS: Prospective substudy of 29 participants in the Physical Activity in RA (PARA) 2010 trial. All subjects were examined at baseline, at year 1 and 2 with measures of pulse wave velocity and arterial augmentation index, as well as echocardiographic evaluation of diastolic parameters and ventricular arterial coupling. Muscle strength and aerobic exercise capacity were assessed at baseline and yearly. All participants performed physiotherapist-guided aerobic and muscle strength exercise during 2 years and were reminded through SMS to report physical activity progress. RESULTS: This cohort of patients with RA exhibited increased vascular stiffness despite normal blood pressure. At baseline, lower muscle strength was associated with increased vascular stiffness (beta = 0.68; P = 0.004), whereas lower aerobic working capacity was associated with left ventricular diastolic dysfunction (beta = 0.85; P = 0.03). There was a significant positive correlation between vascular stiffness and diastolic dysfunction at baseline (R2 = 0.64) and for the changes in those parameters observed during 2 years of guided physical activity. Finally, a significant improvement in ventricular-arterial coupling was observed after exercise (P < 0.001). CONCLUSION: These results indicate that although differentially associated with physical capacity parameters, improved vascular stiffness and improved diastolic dysfunction are interrelated, and that an optimization of the ventricular-arterial coupling may contribute to the beneficial effects of physical activity in patients with RA. PMID- 29143383 TI - Who Performs Colonoscopy? Workforce Trends Over Space and Time. AB - PURPOSE: With the increased availability of colonoscopy to average risk persons due to insurance coverage benefit changes, we sought to identify changes in the colonoscopy workforce. We used outpatient discharge records from South Carolina between 2001 and 2010 to examine shifts over time and in urban versus rural areas in the types of medical providers who perform colonoscopy, and the practice settings in which they occur, and to explore variation in colonoscopy volume across facility and provider types. METHODS: Using an all-payer outpatient discharge records database from South Carolina, we conducted a retrospective analysis of all colonoscopy procedures performed between 2001 and 2010. FINDINGS: We identified a major shift in the type of facilities performing colonoscopy in South Carolina since 2001, with substantial gains in ambulatory surgery settings (2001: 15, 2010: 34, +127%) versus hospitals (2001: 58, 2010: 59, +2%), particularly in urban areas (2001: 12, 2010: 27, +125%). The number of internists (2001: 46, 2010: 76) and family physicians (2001: 34, 2010: 106) performing colonoscopies also increased (+65% and +212%, respectively), while their annual procedures volumes stayed fairly constant. Significant variation in annual colonoscopy volume was observed across medical specialties (P < .001), with nongastroenterologists having lower volumes versus gastroenterologists and colon and rectal surgeons. CONCLUSIONS: There have been substantial changes over time in the number of facilities and physicians performing colonoscopy in South Carolina since 2001, particularly in urban counties. Findings suggest nongastroenterologists are meeting a need for colonoscopies in rural areas. PMID- 29143386 TI - A survey of exercise professionals' barriers and facilitators to working with stroke survivors. AB - Stroke survivors (SSs) are largely inactive despite the benefits of exercise. Exercise professionals (EPs), skilled in exercise prescription and motivation, may have a role in promoting exercise among SSs. However, the number of EPs working with SSs is estimated to be low. This study aimed to investigate EPs' opinions on working with SSs by rating their agreement of barriers and facilitators to working with SSs. The study also investigated EPs skills, interest and experience working with SSs and the relationship between EPs' barriers and facilitators with their training on stroke. A descriptive cross sectional study was conducted using a researcher-designed online survey between October and December 2015. Purposive sampling was used to survey EPs on the Register of Exercise Professionals in Ireland (n = 277). The response rate was 31% (87/277). Only 22% (19/86) of EPs had experience working with SSs. The primary barriers rated by EPs included insufficient training on psychological problems post-stroke (84%; 61/73), unsuitable equipment for SSs (69%; 50/73) and the level of supervision SSs require (56%; 41/73). The primary facilitators rated included access to suitable equipment (97%; 69/71), practical (100%; 71/71) and theoretical training (93%; 66/71) on stroke. Respondents with no training on stroke were significantly more likely to agree that insufficient training on psychological problems post-stroke and lack of experience were barriers. Seventy six per cent of EPs (58/76) were interested in one-to-one exercise sessions with SSs but only 53% (40/76) were interested in group sessions. Eighty-two per cent of EPs (62/76) rated their motivational skills as good or very good but 42% (32/76) indicated having only acceptable skills dealing with psychological problems. Results indicate that EPs are interested in working with SSs despite limited experience and practical barriers. Training opportunities on stroke need to be developed; taking into account EPs' barriers, facilitators and skills along with access to suitable equipment. PMID- 29143385 TI - Patterns of allergic sensitization and atopic dermatitis from 1 to 3 years: Effects on allergic diseases. AB - BACKGROUND: While allergic sensitization and atopic dermatitis (AD) are known to increase the risk for allergic diseases, the impact of different temporal and clinical patterns of sensitization and AD is less well defined. OBJECTIVE: We investigated patterns of sensitization and AD from early infancy to age 3, and the differential risk of developing allergic diseases within each pattern in a general cohort. METHODS: Children (n = 2629) from the Canadian Healthy Infant Longitudinal Development (CHILD) Study underwent skin prick tests and were assessed clinically for AD at ages 1 and 3 years. We applied an unsupervised latent class analysis (LCA) to the following 5 factors at these ages: AD, food sensitization, inhalant sensitization, poly-sensitization to foods and poly sensitization to inhalants. The risks for developing asthma, allergic rhinitis and food allergy at 3 years were evaluated for each identified group. RESULTS: Five distinct classes were revealed by LCA: healthy (81.8%), atopic dermatitis (7.6%), inhalant sensitization (3.5%), transient sensitization (4.1%) and persistent sensitization (3.2%). Using healthy children as the baseline, children in the "atopic dermatitis" group had the next lowest risk for all allergic outcomes at 3 years; those in the "inhalant sensitization" group had the highest risk for allergic rhinitis; children in the "transient sensitization" group were at an increased risk for food allergy; while children in the "persistent sensitization" group had the highest risk for all allergic diseases. CONCLUSION AND CLINICAL RELEVANCE: There is substantial heterogeneity among allergen sensitized children. Researchers and clinicians need to be aware of the non specificity associated with labelling children simply as "atopic" and "non atopic" without considering the timing of their atopic history, type of sensitization and AD status. Children with AD who were poly-sensitized to foods at an early age appear to be at greatest risk of developing other allergic diseases. PMID- 29143388 TI - In Vitro Assessment of Retention and Resistance Failure Loads of Teeth Restored with a Complete Coverage Restoration and Different Core Materials. AB - PURPOSE: To investigate in vitro the retention and the resistance form, as well as the failure modes of maxillary premolars restored with cast metal crowns and different core materials. MATERIALS AND METHODS: Sixty human extracted maxillary premolars were selected according to their size and were embedded in PMMA resin blocks. After removing a part of their clinical crowns, the teeth were randomly divided into 3 groups of 20 teeth and were either left unrestored, or they were restored with amalgam or composite resin. All teeth were prepared for a cast metal complete coverage restoration. The restorations were cemented on the prepared teeth with a resin-modified glass ionomer luting agent (GC Fuji Plus). All specimens were subjected to static loading at 1 mm/min by a universal testing machine, until failure. Half the specimens of each group were subjected to tensile loading along the long axis of the teeth. The other half were subjected to compressive loading at a 30 degrees angle. Failure loads and failure modes for each tooth were recorded. The statistical analysis included descriptive statistics, one-way ANOVA, and Tukey's HSD test. RESULTS: One-way ANOVA revealed statistically significant differences among the 3 tested groups (p < 0.05) for both tests. The group of teeth with no core material presented the highest failure loads for both the tensile and the compressive loading tests, with mean loads of 381.02 Nu and 741.21 Nu, respectively. Mean tensile and compressive failure loads for the amalgam group were 277.34 Nu and 584.75 Nu, while the composite resin group presented the lowest tensile and compressive failure values, which were 250.77 Nu and 465.78 Nu, respectively. The compression loading test resulted in the same failure mode for all specimens, which included unfavorable fracture of the teeth in combination with detachment of the cast metal complete coverage restorations. The tensile loading test resulted in different failure modes between the groups that used a core material and the group with no core material. CONCLUSIONS: Teeth that lost more than half of their coronal structure presented better retention and resistance form if no core material was used, provided that a minimum of 2-mm axial wall height was present at the missing part. Teeth that have lost more than half of their coronal structure and were restored with amalgam core presented better retention and resistance form than those restored with composite resin. Catastrophic fractures, extending to the root, were associated with compression forces but not with tensile forces. PMID- 29143387 TI - Cytomegalovirus is still in intensive care. PMID- 29143389 TI - Clinical and Radiologic Outcomes of Submerged and Nonsubmerged Bone-Level Implants with Internal Hexagonal Connections in Immediate Implantation: A 5-Year Retrospective Study. AB - PURPOSE: To evaluate the 5-year clinical and radiologic outcome of immediate implantation using submerged and nonsubmerged techniques with bone-level implants and internal hexagonal connections and the effects of potential influencing factors. MATERIALS AND METHODS: A total of 114 bone-level implants (XiVE S plus) with internal hexagonal connections inserted into 72 patients were included. Patients were followed up for 5 years. A t-test was used to statistically evaluate the marginal bone loss between the submerged and nonsubmerged groups. The cumulative survival rate (CSR) was calculated according to the life table method and illustrated with Kaplan-Meier survival curves. Comparisons of the CSR between healing protocols, guided bone regeneration, implants with different sites, lengths, and diameters were performed using log-rank tests. RESULTS: The 5 year cumulative implant survival rates with submerged and nonsubmerged healing were 94% and 96%, respectively. No statistically significant differences in terms of marginal bone loss, healing protocol, application of guided bone regeneration, implant site, or length were observed. CONCLUSIONS: High CSRs and good marginal bone levels were achieved 5 years after immediate implantation of bone-level implants with internal hexagonal connections using both the submerged and nonsubmerged techniques. Factors such as implant length, site, and application of guided bone regeneration did not have an impact on the long-term success of the implants. PMID- 29143390 TI - Chemotherapy and healthcare utilisation near the end of life in patients with cancer. AB - The quality of medical care delivered to patients with cancer near the end of life is a significant issue. Previous studies have defined several areas suggestive of aggressive cancer treatment as potentially representing poor quality care. The primary objective of current analysis was to examine chemotherapy and healthcare utilisation in the last 3 months of life among patients with cancer that received palliative chemotherapy. Patients were selected from the hospital administration database of the Diakonessenhuis Utrecht, the Netherlands. Data were extracted from the medical files. A total of 604 patients were included for analysis (median age: 64 years). For 300 patients (50%) chemotherapy was given in the last 3 months (CT+). For 76% (n = 229) of CT+ patients unplanned hospital admissions were made in these last 3 months, compared to 44% (n = 133) of CT- patients (p < .001). Visits to the emergency room in last 3 months were made by 67% (n = 202) of CT+ patients compared to 43% (n = 132) of CT- patients (p < .001). Healthcare consumption was significantly higher in patients who received chemotherapy in the last 3 months of life. Being able to inform our patients about these aspects of treatment can help to optimise both the quality of life and the quality of dying in patients with cancer. PMID- 29143391 TI - An All-Zirconia Crown Discovered 2 Years Following Aspiration. AB - Accidental aspiration or ingestion can occur in dental treatment, as most procedures are performed with the patient in a supine position or semi-recumbent position. Aspiration of foreign bodies commonly causes acute symptoms such as violent coughing, choking, and dyspnea; however, if foreign bodies are stuck distally to the lower lobe bronchi or the bronchus intermedius, acute presentation can be rare. This clinical report documents a 68-year-old male patient who accidentally aspirated an all-zirconia crown during the try-in procedure. The case was initially surmised as ingestion. The crown remained in the lower lobe of the left lung for about 2 years without any significant symptoms. This report cautions the importance of airway protection during dental procedures. PMID- 29143392 TI - Is Dr von Magnus to blame for the withdrawal of live attenuated influenza vaccine? PMID- 29143393 TI - An algorithm to detect unexpected increases in frequency of reports of adverse events in EudraVigilance. AB - PURPOSE: The European Medicines Agency developed an algorithm to detect unexpected increases in frequency of reports, to enhance the ability to detect adverse events that manifest as increases in frequency, in particular quality defects, medication errors, and cases of abuse or misuse. METHODS: An algorithm based on a negative binomial time-series regression model run on 6 sequential observations prior to the monitored period was developed to forecast monthly counts of reports. A heuristic model to capture increases in counts when the previous 4 observations were null supplemented the regression. Count data were determined at drug-event combination. Sensitivity analyses were run to determine the effect of different methods of pooling or stratifying count data. Positive retrospective detections and positive predictive values (PPVs) were determined. RESULTS: The algorithm detected 8 of the 13 historical concerns, including all concerns of quality defects. The highest PPV (1.29%) resulted from increasing the lower count threshold from 3 to 5 and including literature reports in the counts. Both the regression model and the heuristic model components to the algorithm contributed to the detection of concerns. Sensitivity analysis indicates that stratification by commercial product reduces the PPV but suggests that pooling counts of related events may improve it. CONCLUSION: The results are encouraging and suggest that the algorithm could be useful for the detection of concerns that manifest as changes in frequency of reporting; however, further testing, including in prospective use, is warranted. PMID- 29143394 TI - Bactericera cockerelli vitellogenin-6 like, a vitellogenin without a direct reproductive function? AB - Vitellogenin-like proteins are members of the large lipid transfer proteins, a family of proteins involved in reproduction, lipid circulation and immune defences. In this study, we identified a new Bactericera cockerelli vitellogenin like (Vg-like) transcript, and named it BcVg6-like based on its similarity to Acyrthosiphon pisum Vg6. In silico analyses predicted different conserved domains in BcVg6-like compared with the conventional Ba. cockerelli vitellogenin, BcVg1 like, previously described by our research group. Phylogenetic analyses determined that BcVg6-like clustered with Vg-like-B proteins and not the conventional vitellogenins involved in vitellogenesis. Also, the expression analyses showed differences in BcVg6-like transcript expression between 7-day-old males and 3- and 7-day-old females. BcVg6-like was not upregulated after exogenous application of juvenile hormone III, but its relative expression increased significantly in alimentary canals of adult females exposed to tomato plants infected by the bacterial plant pathogen 'Candidatus Liberibacter solanacearum'. Our results suggest that in Ba. cockerelli, both vitellogenin genes may have different functions: BcVg1-like is a conventional vitellogenin that conserved its ancestral function as an egg yolk precursor whereas BcVg6-like might have acquired a function in lipid and/or other molecule transport, and could potentially play a role in immune defence. PMID- 29143395 TI - A novel classification scheme to decline the mortality rate among women due to breast tumor. AB - Early screening of skeptical masses or breast carcinomas in mammograms is supposed to decline the mortality rate among women. This amount can be decreased more on development of the computer-aided diagnosis with reduction of false suppositions in medical informatics. Our aim is to provide a robust tumor detection system for accurate classification of breast masses using normal, abnormal, benign, or malignant classes. The breast carcinomas are classified on the basis of observed classes. This is highly dependent on feature extraction process. In propose work, a novel algorithm for classification based on the combination of top Hat transformation and gray level co-occurrence matrix with back propagation neural network. The aim of this study is to present a robust classification model for automated diagnosis of the breast tumor with reduction of false assumptions in medical informatics. The proposed method is verified on two datasets MIAS and DDSM. It is observed that rate of false positives decreased by the proposed method to improve the performance of classification, efficiently. PMID- 29143396 TI - Sustained release of stem cell factor in a double network hydrogel for ex vivo culture of cord blood-derived CD34+ cells. AB - OBJECTIVES: Stem cell factor (SCF) is considered as a commonly indispensable cytokine for proliferation of haematopoietic stem cells (HSCs), which is used in large dosages during ex vivo culture. The work presented here aimed to reduce the consumption of SCF by sustained release but still support cells proliferation and maintain the multipotency of HSCs. MATERIALS AND METHODS: Stem cell factor was physically encapsulated within a hyaluronic acid/gelatin double network (HGDN) hydrogel to achieve a slow release rate. CD34+ cells were cultured within the SCF loaded HGDN hydrogel for 14 days. The cell number, phenotype and functional capacity were investigated after culture. RESULTS: The HGDN hydrogels had desirable properties and encapsulated SCF kept being released for more than 6 days. SCF remained the native bioactivity, and the proliferation of HSCs within the SCF-loaded HGDN hydrogel was not affected, although the consumption of SCF was only a quarter in comparison with the conventional culture. Moreover, CD34+ cells harvested from the SCF-loaded HGDN hydrogels generated more multipotent colony-forming units (CFU-GEMM). CONCLUSION: The data suggested that the SCF loaded HGDN hydrogel could support ex vivo culture of HSCs, thus providing a cost effective culture protocol for HSCs. PMID- 29143397 TI - Marginal Fit Comparison of CAD/CAM Crowns Milled from Two Different Materials. AB - PURPOSE: To evaluate the marginal fit of CAD/CAM copings milled from hybrid ceramic (Vita Enamic) blocks and lithium disilicate (IPS e.max CAD) blocks, and to evaluate the effect of crystallization firing on the marginal fit of lithium disilicate copings. MATERIALS AND METHODS: A standardized metal die with a 1-mm wide shoulder finish line was imaged using the CEREC AC Bluecam. The coping was designed using CEREC 3 software. The design was used to fabricate 15 lithium disilicate and 15 hybrid ceramic copings. Design and milling were accomplished by one operator. The copings were seated on the metal die using a pressure clamp with a uniform pressure of 5.5 lbs. A Macroview Microscope (14*) was used for direct viewing of the marginal gap. Four areas were imaged on each coping (buccal, distal, lingual, mesial). Image analysis software was used to measure the marginal gaps in MUm at 15 randomly selected points on each of the four surfaces. A total of 60 measurements were made per specimen. For lithium disilicate copings the measurements for marginal gap were made before and after crystallization firing. Data were analyzed using paired t-test and Kruskal-Wallis test. RESULTS: The overall mean difference in marginal gap between the hybrid ceramic and crystallized lithium disilicate copings was statistically significant (p < 0.01). Greater mean marginal gaps were measured for crystallized lithium disilicate copings. The overall mean difference in marginal gap before and after firing (precrystallized and crystallized lithium disilicate copings) showed an average of 62 MUm increase in marginal gap after firing. This difference was also significant (p < 0.01). CONCLUSIONS: A significant difference exists in the marginal gap discrepancy when comparing hybrid ceramic and lithium disilicate CAD/CAM crowns. Also crystallization firing can result in a significant increase in the marginal gap of lithium disilicate CAD/CAM crowns. PMID- 29143398 TI - A retrospective cohort study of the health of children prenatally exposed to methadone, buprenorphine or naltrexone compared with non-exposed control children. AB - BACKGROUND AND OBJECTIVES: Little is known about the health of children exposed to opioid pharmacotherapies in utero. This study aims to examine the health of children from birth to 5 years of age, who were exposed to methadone, buprenorphine, or naltrexone with non-exposed children. METHODS: Children were identified by linking the treatment records of women treated with one of the three opioid pharmacotherapies with midwife notifications. Live-born children exposed to methadone (n = 198), buprenorphine (n = 122), naltrexone (n = 67) in utero, and neonates not prenatally exposed to opioids (n = 387) born between 2001 and 2011 in Western Australia were included in the study. The children were then linked to state mortality, hospital, emergency department (ED), mental health, cancer, and reportable diseases from birth up to their 5th birthday. RESULTS: Overall rates of hospital admission were elevated in all three treatments as compared with the control children, while rates of ED attendances were only significantly elevated in the methadone (p = .002) and naltrexone (p = .044) exposed children. In terms of both hospital and ED attendances, the differences between the exposed and control children was most apparent in the neonatal period. Rates of mental health out-patient attendances were elevated in buprenorphine-exposed children as compared with the control (p = .005). DISCUSSION AND CONCLUSIONS: The study provides evidence to suggest a disparity in the health of children exposed to opioid pharmacotherapies in utero compared with non-exposed control children. SCIENTIFIC SIGNIFICANCE: Exposure to opioid pharmacotherapies in utero may influence the health of children beyond the neonatal period. (Am J Addict 2017;26:845-851). PMID- 29143399 TI - Buprenorphine-naloxone treatment responses differ between young adults with heroin and prescription opioid use disorders. AB - BACKGROUND AND OBJECTIVES: Opioid use disorder among young adults is rising sharply with an increase in morbidity and mortality. This study examined differences in treatment response to a fixed dose of buprenorphine-naloxone between heroin (HU) and prescriptions opioids (POU) users. METHODS: Eighty opioid dependent young adults (M = 22 years) were treated with buprenorphine-naloxone 16 4 mg/day for 8 weeks. Differences between HU (N = 17) and POU (N = 63) on changes in weekly opioid use, opioid craving, withdrawal, and depression symptoms were analyzed with mixed-effects regression models. RESULTS: The HU had an overall mean proportion of weekly opioid use of .32 (SD = .14) compared to POU's weekly mean of .24 (SD = .15) showing a significant main effect (Z = 2.21, p = .02). Depressive symptoms (CES-D scores) were elevated at baseline for both groups (HU: M = 23.1, SD = 11.9; PO: M = 22.2, SD = 9.4), but only POU improved significantly to a score of 9.88 (SD = 7.4) compared to HU's score of 18.58 (SD = 10.3) at week 8 (Z = 2.24, p = .02). There were no significant differences in treatment retention, craving, or withdrawal symptoms. DISCUSSION AND CONCLUSIONS: Treatment response to 16-4 mg/day of buprenorphine-naloxone was significantly diminished for heroin users relative to opioid prescription users in weekly opioid use. Heroin users also had persistent depressive symptoms suggesting the need for close monitoring. SCIENTIFIC SIGNIFICANCE: These data suggest that young heroin users might require higher doses of buprenorphine. (Am J Addict 2017;26:838-844). PMID- 29143401 TI - Assessment of risk behaviors in patients with opioid prescriptions: A study of indiana's inspect data. AB - BACKGROUND AND OBJECTIVES: Prescription Drug Monitoring Programs (PDMPs) can serve as screening tools and support the clinical decision-making process in patients receiving opioids. The objective of the study was to utilize 2014 INSPECT (Indiana's PDMP) data to identify factors that increase patients' likelihood to engage in opioid-related risk behaviors. METHODS: Based on a literature review, four risk behaviors were identified: Receiving >90 morphine milligram equivalents (MME), having >4 opioid prescribers, obtaining opioids from >4 pharmacies, and concurrent use of opioids and benzodiazepines. Two binary logistic regression analyses (engaging in at least one risk behaviors; engaging in all four risk behaviors) and an ordinal regression analysis (engaging in 0-4 risk behaviors) were conducted to identify factors associated with these opioid related risk behaviors. RESULTS: Of the 1,538,120 unique opioid patients included in the study, 18.4% engaged in one, 5.3% in two, 1.6% in three, and .4% in all four risk behaviors. Depending on the model, prescribing a second monthly opioid increased patients' odds to engage in risk behaviors by a factor of 10 or more and prescribing two or more benzodiazepines annually increased the odds at least 13-fold. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: About one-fourth of all patients consuming opioids engaged in one or more risk behaviors; higher number of opioid prescriptions and addition of even a small number of benzodiazepine prescriptions dramatically increased these odds. PDMPs can be helpful in identifying opioid users at high-risk for misuse. This information could be used to target efforts to reduce the prescription drug epidemic. (Am J Addict 2017;26:822-829). PMID- 29143400 TI - Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study. AB - BACKGROUND AND AIMS: Take-home naloxone can prevent death from heroin/opioid overdose, but pre-provision is difficult because naloxone is usually given by injection. Non-injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability. DESIGN: Open label, randomized, five-way cross-over PK study. SETTING: Clinical trials facility (Croydon, UK). PARTICIPANTS: Thirty-eight healthy volunteers (age 20-54 years; 11 female). INTERVENTION AND COMPARATOR: Three doses of i.n. (1 mg/0.1 ml, 2 mg/0.1 ml, 4 mg/0.2 ml) versus 0.4 mg i.m. (reference) and 0.4 mg intravenous (i.v.) naloxone. MEASUREMENTS: Regular blood samples were taken, with high frequency sampling during the first 15 minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration. FINDINGS: Mean peak concentration (Cmax ) values for 1 mg (1.51 ng/ml), 2 mg (2.87 ng/ml) and 4 mg (6.02 ng/ml) i.n. exceeded 0.4 mg i.m. (1.27 ng/ml) naloxone. All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15-30 minutes (Tmax ). For comparison, the i.m. reference reached Tmax at 10 minutes. Mean bioavailability was 47-51% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2 * 2 mg i.n. versus 5 * 0.4 mg i.m. doses) at 3-minute intervals showed that comparable plasma naloxone concentrations would be anticipated. CONCLUSIONS: Concentrated 2 mg intranasal naloxone is well-absorbed and provides early exposure comparable to 0.4 mg intramuscular naloxone, following the 0.4 mg intramuscular curve closely in the first 10 minutes post-dosing and maintaining blood levels above twice the intramuscular reference for the next 2 hours. PMID- 29143402 TI - Association between objectively measured sedentary behavior and a criterion measure of obesity among adults. AB - OBJECTIVE: Results of published studies on the association between sedentary behavior (SB) and obesity are inconsistent, possibly due to reliance on subjective measures of SB and inappropriate measures of obesity. The aim of this study was to examine the relationship between objectively measured SB and criterion-measured obesity among adults. METHODS: A total of 2284 adults (>=18 years) from the 2003 to 2004 National Health and Nutrition Examination Survey were included in the analysis. The participants were categorized into tertiles of SB time measured by accelerometry. Obesity was determined using body fat percentage measured by dual-energy X-ray absorptiometry. RESULTS: Increased SB was significantly associated with obesity when controlling for covariates related to demographics, health behaviors, energy intake, and physical activity (P for trends = .025). CONCLUSIONS: This finding suggests that avoiding SB may be beneficial for lowering the risk of obesity in adults. PMID- 29143403 TI - Effect of Distal Implant Inclination on Dislodging Forces of Different Locator Attachments Used for Mandibular Overdentures: An In Vitro Study. AB - PURPOSE: To evaluate the effect of distal implant inclination on axial and nonaxial retentive forces of different Locator attachments used to retain mandibular overdentures. MATERIALS AND METHODS: Four duplicate mandibular edentulous acrylic models received 2 implants in the canine areas with 0 degrees , 5 degrees , 10 degrees , and 20 degrees distal inclinations. Experimental overdentures were connected to the implants with Locator extra light retention (Le), Locator light retention (Ll), and Locator medium retention (Lm). For the 20 degrees model, extended range Locator extra-light retention (Lee) and Locator medium retention (Lem) were used. Axial and nonaxial (anterior, posterior, lateral) retentive forces were measured initially and after 540 cycles of denture insertion and removal. Three-way mixed ANOVA was used to analyze axial and nonaxial retentive forces RESULTS: After wear simulation, 20 degrees angulation showed the highest axial retention for Le and Ll while 5 degrees showed the highest retention for Lm; 0 degrees and 5 degrees showed the highest anterior and posterior retention for Lm; 20 degrees showed the highest lateral retention for Le and Ll. For all implant inclinations, Lm showed the highest axial and nonaxial retention, and Le and Lee showed the lowest retention for 10 degrees and 20 degrees inclined implants, respectively. CONCLUSIONS: Axial and nonaxial retention of Locator attachments for implant-retained overdentures are significantly affected by the degree of distal implant inclination and the type of nylon inserts. Lm is recommended to retain overdentures when implants have 5 degrees or 10 degrees distal inclination, and Le and Ll are recommended with 20 degrees inclination to maintain high axial and nonaxial retention after wear. PMID- 29143404 TI - Tool for osteoarthritis risk prediction (TOARP) over 8 years using baseline clinical data, X-ray, and MRI: Data from the osteoarthritis initiative. AB - BACKGROUND: Osteoarthritis (OA), a multifactorial disease causing joint degeneration, often leads to severe disability. The rising rates of disability highlight the need for implementing preventative measures at early stages of the disease, which would especially benefit subjects at high risk for OA development. PURPOSE: To develop a risk prediction tool for moderate-severe OA (TOARP) over 8 years based on subject characteristics, knee radiographs, and MRI data at baseline using data from the Osteoarthritis Initiative (OAI). STUDY TYPE: Retrospective. SUBJECTS: 641 subjects with no/mild radiographic OA (Kellgren Lawrence [KL] 0-2) and no clinically significant symptoms (Western Ontario and McMaster Universities Arthritis Index [WOMAC] 0-1) were selected from the OAI. FIELD STRENGTH/SEQUENCE: MR images were obtained using 3.0T. ASSESSMENT: Compartment-specific cartilage and meniscus morphology and cartilage T2 were assessed. Baseline subject demographics, risk factors, KL score, cartilage WORMS score, presence of meniscus tear, and cartilage T2 were used to predict the development of moderate/severe OA (KL = 3-4 or WOMAC pain >=5 or total knee replacement [TKR]) over 8 years. STATISTICAL TESTS: Best subsets variable selection followed by cross-validation were used to assess which combinations of variables best predict moderate/severe OA. RESULTS: Model 1 included KL score, previous knee injury in the last 12 months, age, gender, and BMI. Model 2 included all variables in Model 1 plus presence of cartilage defects in the lateral femur and patella, and presence of a meniscal tear. Model 3 included all variables in Models 1 and 2, plus cartilage T2 in the medial tibia and medial femur. Compared to Model 1 (cross-validated AUC = 0.67), Model 3 performed significantly better (AUC = 0.72, P = 0.04), while Model 2 showed a statistical trend (AUC = 0.71, P = 0.08). DATA CONCLUSION: We established a risk calculator for the development of moderate/severe knee OA over 8 years that includes radiographic and MRI data. The inclusion of MRI-based morphological abnormalities and cartilage T2 significantly improved model performance. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1517-1526. PMID- 29143405 TI - Cost-Effectiveness Modeling of Repetitive Transcranial Magnetic Stimulation Compared to Electroconvulsive Therapy for Treatment-Resistant Depression in Singapore. AB - BACKGROUND: Compared to electroconvulsive therapy (ECT), the cost-effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the management of treatment-resistant depression (TRD) remains unclear. OBJECTIVE/HYPOTHESIS: This study evaluated the cost-effectiveness of rTMS vs. ECT for TRD from Singapore societal perspective. METHODS: We constructed a Markov model to project the cost and benefit of rTMS compared with ECT over one year in patients with TRD. The relative treatment effects between rTMS and ECT were obtained from meta-analyses of published trials. The effectiveness and quality of life data for patients using ECT, resource use for TRD and their associated costs were derived from the national tertiary mental institution in Singapore. RESULTS: At one year, rTMS was cost-effective relative to ECT. The incremental cost-effectiveness ratio (ICER) associated with ECT was Singapore dollars (SGD) 311,024 per quality-adjusted life year (QALY) gained. This exceeded the willingness-to-pay threshold of SGD 70,000 per QALY gained. A similar trend was observed for ICER per remission achieved (i.e., SGD 143,811 per remission achieved with ECT). In the subgroup analysis, rTMS was found to be less costly and more effective than ECT in nonpsychotic depressive patients. In the scenario analysis, ECT employed as an ambulatory service yielded a much smaller ICER (i.e., SGD 78,819 per QALY gained) compared to the standard inpatient setting. CONCLUSIONS: rTMS was a cost-effective treatment compared to ECT in TRD over one year. The cost-effectiveness of rTMS was attenuated when ECT was used in the outpatient setting. PMID- 29143407 TI - Emerging role of viral and bacterial co-infection in early childhood. PMID- 29143406 TI - Oncogenic spiral by infectious pathogens: Cooperation of multiple factors in cancer development. AB - Chronic infection is one of the major causes of cancer, and there are several mechanisms for infection-mediated oncogenesis. Some pathogens encode gene products that behave like oncogenic factors, hijacking cellular pathways to promote the survival and proliferation of infected cells in vivo. Some of these viral oncoproteins trigger a cellular damage defense response leading to senescence; however, other viral factors hinder this suppressive effect, suggesting that cooperation of those viral factors is important for malignant transformation. Coinfection with multiple agents is known to accelerate cancer development in certain cases. For example, parasitic or bacterial infection is a risk factor for adult T-cell leukemia-lymphoma induced by human T-cell leukemia virus type 1, and Epstein-Barr virus and malaria are closely associated with endemic Burkitt lymphoma. Human immunodeficiency virus type 1 infection is accompanied by various types of infection-related cancer. These findings indicate that these oncogenic pathogens can cooperate to overcome host barriers against cancer development. In this review, the authors focus on the collaborative strategies of pathogens for oncogenesis from two different points of view: (i) the cooperation of two or more different factors encoded by a single pathogen; and (ii) the acceleration of oncogenesis by coinfection with multiple agents. PMID- 29143409 TI - Chronnectome fingerprinting: Identifying individuals and predicting higher cognitive functions using dynamic brain connectivity patterns. AB - The human brain is a large, interacting dynamic network, and its architecture of coupling among brain regions varies across time (termed the "chronnectome"). However, very little is known about whether and how the dynamic properties of the chronnectome can characterize individual uniqueness, such as identifying individuals as a "fingerprint" of the brain. Here, we employed multiband resting state functional magnetic resonance imaging data from the Human Connectome Project (N = 105) and a sliding time-window dynamic network analysis approach to systematically examine individual time-varying properties of the chronnectome. We revealed stable and remarkable individual variability in three dynamic characteristics of brain connectivity (i.e., strength, stability, and variability), which was mainly distributed in three higher order cognitive systems (i.e., default mode, dorsal attention, and fronto-parietal) and in two primary systems (i.e., visual and sensorimotor). Intriguingly, the spatial patterns of these dynamic characteristics of brain connectivity could successfully identify individuals with high accuracy and could further significantly predict individual higher cognitive performance (e.g., fluid intelligence and executive function), which was primarily contributed by the higher order cognitive systems. Together, our findings highlight that the chronnectome captures inherent functional dynamics of individual brain networks and provides implications for individualized characterization of health and disease. PMID- 29143408 TI - Automated synthesis of PET radiotracers by copper-mediated 18 F-fluorination of organoborons: Importance of the order of addition and competing protodeborylation. AB - In this paper, we describe the use of Cu-mediated [18 F]fluorodeboronation for the automated production of positron emission tomography radiotracers suitable for clinical use. Two recurrent issues with the method, low radiochemical conversion on automation and protoarene byproduct purification issues, have been successfully addressed. The new method was utilized to produce sterile injectable doses of [18 F]-(+/-)-IPMICF17, a positron emission tomography radiotracer for tropomyosin receptor kinase B/C, using an automated synthesis module. The product was isolated in 1.9 +/- 0.1% isolated radiochemical yield, excellent radiochemical purity (>99%), and high specific activity (5294 +/- 1227 Ci/mmol). Quality control testing confirmed that doses were suitable for clinical use. PMID- 29143410 TI - Early contributions to infants' mental rotation abilities. AB - Some cognitive abilities exhibit reliable gender differences, with females outperforming males in specific aspects of verbal ability, and males showing an advantage on certain spatial tasks. Among these cognitive gender differences, differences in mental rotation are the most robust, and appear to be present even in infants. A large body of animal research suggests that gonadal hormones, particularly testosterone, during early development could contribute to this gender difference in mental rotation. Also, substantial evidence supports an influence of socialization on mental rotation performance. The present study investigated the relationship of two types of factors, early postnatal testosterone exposure and parental attitudes about gender, to mental rotation performance in 61 healthy infants (29 males, 32 females). We measured salivary testosterone at two time points: 1-2.5 months of age and 5-6 months of age. Infants' mental rotation performance and parents' attitudes about gender were assessed at 5-6 months of age. As predicted, testosterone concentrations were significantly higher in boys than girls in early infancy (d = 0.54), and boys performed significantly better than girls on mental rotation (d = 0.64). A significant positive correlation between testosterone at age 1-2.5 months and mental rotation was found only in boys (r = 0.50, p = .01). A significant negative correlation between parents' gender-stereotypical attitudes and mental rotation performance was found only in girls (r = -.57, p = .002). These findings suggest that the early postnatal testosterone surge (also known as "mini puberty") may have organizational influences on mental rotation performance in boys, and that parents may influence their daughters' mental rotation abilities beginning very early in life. PMID- 29143411 TI - Spontaneous neural activity differences in posttraumatic stress disorder: A quantitative resting-state meta-analysis and fMRI validation. AB - Identifying the pathophysiology of posttraumatic stress disorder (PTSD) is a critical step toward reducing its debilitating impact. Spontaneous neural activity, measured at rest using various neuroimaging techniques (e.g., regional homogeneity [ReHo], amplitude of low frequency fluctuations [ALFF]), can provide insight about baseline neurobiological factors influencing sensory, cognitive, or behavioral processes associated with PTSD. The present study used activation likelihood estimation (ALE) to conduct the largest-to-date quantitative meta analysis of spontaneous neural activity in PTSD, including 457 PTSD cases, 292 trauma-exposed controls (TECs), and 293 non-traumatized controls (NTCs) across 22 published studies. Five regions-of-interest (ROIs) were identified where activity differed between PTSD cases and controls: one when compared to all controls (left globus pallidus), two when compared to TECs (left inferior parietal lobule [IPL] and right lingual gyrus), and two when compared to NTCs (left amygdala and right caudate head). To corroborate these results, a second analysis was conducted using resting-state functional magnetic resonance imaging on an independent sample of 205 previously-deployed US military veterans. In this analysis, converging evidence from ReHo and ALFF showed that spontaneous neural activity in the left IPL alone was positively correlated with PTSD symptom severity. This result is consistent with theoretical accounts that link left IPL activity with PTSD-relevant processes such as processing of emotional stimuli (e.g., fearful faces) and the extent that attention is captured by salient autobiographical memories. By modeling the neurobiological correlates of PTSD, we can increase our understanding of this debilitating disorder and guide the development of future clinical innovations. PMID- 29143412 TI - Reverse production effect: children recognize novel words better when they are heard rather than produced. AB - This research investigates the effect of production on 4.5- to 6-year-old children's recognition of newly learned words. In Experiment 1, children were taught four novel words in a produced or heard training condition during a brief training phase. In Experiment 2, children were taught eight novel words, and this time training condition was in a blocked design. Immediately after training, children were tested on their recognition of the trained novel words using a preferential looking paradigm. In both experiments, children recognized novel words that were produced and heard during training, but demonstrated better recognition for items that were heard. These findings are opposite to previous results reported in the literature with adults and children. Our results show that benefits of speech production for word learning are dependent on factors such as task complexity and the developmental stage of the learner. PMID- 29143413 TI - Bioinspired Chemical Communication between Synthetic Nanomotors. AB - While chemical communication plays a key role in diverse natural processes, the intelligent chemical communication between synthetic nanomotors remains unexplored. The design and operation of bioinspired synthetic nanomotors is presented. Chemical communication between nanomotors is possible and has an influence on propulsion behavior. A chemical "message" is sent from a moving activator motor to a nearby activated (receiver) motor by release of Ag+ ions from a Janus polystyrene/Ni/Au/Ag activator motor to the activated Janus SiO2 /Pt nanomotor. The transmitted silver signal is translated rapidly into a dramatic speed change associated with the enhanced catalytic activity of activated motors. Selective and successive activation of multiple nanomotors is achieved by sequential localized chemical communications. The concept of establishing chemical communication between different synthetic nanomotors paves the way to intelligent nanoscale robotic systems that are capable of cooperating with each other. PMID- 29143414 TI - Central pain processing in "drug-naive" pain-free patients with Parkinson's disease. AB - BACKGROUND: Despite its clinical relevance, the pathophysiology of pain in Parkinson's disease (PD) is still largely unknown, and both central and peripheral mechanisms have been invoked. OBJECTIVES: To investigate whether central pain processing is altered in "drug-naive" pain-free PD (dnPD) patients. METHODS: Using event-related functional MRI (fMRI), functional response to forearm heat stimulation (FHS) at two different intensities (41 degrees C and 53 degrees C) was investigated in 20 pain-free dnPD patients, compared with 18 healthy controls (HCs). Secondary analyses were performed to evaluate associations between BOLD signal changes and PD clinical features and behavioral responses. RESULTS: During low-innocuous FHS (41 degrees C), no activation differences were found between dnPD patients and HCs. During high-noxious FHS (53 degrees C) a significantly increased activation in the left somatosensory cortex, left cerebellum, and right low pons was observed in dnPD patients compared to HCs. In the latter experimental condition, fMRI BOLD signal changes in the right low pons (p < .0001; R = -0.8) and in the cerebellum (p = .004; R = -0.7) were negatively correlated with pain intensity ratings only in dnPD patients. No statistically significant difference in experimental pain perception was detected between dnPD patients and HCs. CONCLUSIONS: Our findings suggest that a functional remodulation of pain processing pathways occurs even in the absence of clinically overt pain symptoms in dnPD patients. These mechanisms may eventually become dysfunctional over time, contributing to the emergence of pain symptoms in more advanced PD stages. The comprehension of pain-related mechanisms may improve the clinical approach and therapeutic management of this disabling nonmotor symptom. PMID- 29143415 TI - Severe BK polyomavirus-induced hemorrhagic cystitis in a kidney transplant recipient with the absence of renal allograft involvement. AB - BK polyomavirus mostly manifests as polyomavirus-associated nephropathy (PyVAN) in kidney transplant patients and polyoma virus-associated hemorrhagic cystitis (PyVHC) in bone marrow transplant patients. PyVHC in kidney transplant patients is only reported in four cases in the literature. Our patient had severe hemorrhagic cystitis without renal involvement. We postulate that our patient's exposure to ifosfamide and radiation 8 years prior transplantation might predispose him to this disease. PMID- 29143416 TI - Plasma renin activity, response to aliskiren, and clinical outcomes in patients hospitalized for heart failure: the ASTRONAUT trial. AB - AIMS: The direct renin inhibitor, aliskiren, is known to reduce plasma renin activity (PRA), but whether the efficacy of aliskiren varies based on an individual's baseline PRA in patients hospitalized for heart failure (HF) is presently unknown. We characterized the prognostic value of PRA and determined if this risk is modifiable with use of aliskiren. METHODS AND RESULTS: This pre specified neurohormonal substudy of ASTRONAUT analysed all patients hospitalized for HF with ejection fraction (EF) <=40% with available baseline PRA data (n = 1306, 80.9%). Risk associated with baseline PRA and short-term changes in PRA from baseline to 1 month was modelled with respect to 12-month clinical events. Median baseline PRA was 3.0 (interquartile range 0.6-16.4) ng/mL/h. Aliskiren significantly reduced PRA early after treatment initiation through 12-month follow-up compared with placebo (P < 0.001). The lowest baseline PRA quartile (<0.6 ng/mL/h) was independently predictive of lower all-cause mortality [adjusted hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31-0.81] and the composite of cardiovascular mortality and HF hospitalization (adjusted HR 0.57, 95% CI 0.40-0.79). Delta log-normalized PRA (from baseline to 1 month) was not predictive of either primary endpoint at 12 months (P >= 0.43). The prognostic value of baseline PRA and short-term changes in PRA did not vary by randomization to aliskiren or placebo (interaction P >= 0.13). CONCLUSIONS: Plasma renin activity is reduced early and durably by aliskiren, but this did not translate into improved clinical outcomes in ASTRONAUT. Baseline PRA or short-term reduction in PRA do not identify a subgroup who may preferentially benefit from direct renin inhibition. Clinical Trial Registration ClinicalTrials.gov Unique Identifier: NCT00894387. PMID- 29143417 TI - Can Antarctic lichens acclimatize to changes in temperature? AB - The Antarctic Peninsula, a tundra biome dominated by lichens and bryophytes, is an ecozone undergoing rapid temperature shifts. Such changes may demand a high physiological plasticity of the local lichen species to maintain their role as key drivers in this pristine habitat. This study examines the response of net photosynthesis and respiration to increasing temperatures for three Antarctic lichen species with different ecological response amplitudes. We hypothesize that negative effects caused by increased temperatures can be mitigated by thermal acclimation of respiration and/or photosynthesis. The fully controlled growth chamber experiment simulated intermediate and extreme temperature increases over the time course of 6 weeks. Results showed that, in contrast to our hypothesis, none of the species was able to down-regulate temperature-driven respiratory losses through thermal acclimation of respiration. Instead, severe effects on photobiont vitality demonstrated that temperatures around 15 degrees C mark the upper limit for the two species restricted to the Antarctic, and when mycobiont demands exceeded the photobiont capacity they could not survive within the lichen thallus. In contrast, the widespread lichen species was able to recover its homoeostasis by rapidly increasing net photosynthesis. We conclude that to understand the complete lichen response, acclimation processes of both symbionts, the photo- and the mycobiont, have to be evaluated separately. As a result, we postulate that any acclimation processes in lichen are species-specific. This, together with the high degree of response variability and sensitivity to temperature in different species that co-occur spatially close, complicates any predictions regarding future community composition in the Antarctic. Nevertheless, our results suggest that species with a broad ecological amplitude may be favoured with on-going changes in temperature. PMID- 29143418 TI - Identification of swallowing disorders in early and mid-stage Parkinson's disease using pattern recognition of pharyngeal high-resolution manometry data. AB - BACKGROUND: Parkinson's disease (PD) can cause severe dysphagia, especially later in disease progression. Early identification of swallowing dysfunction may lead to earlier intervention. Pharyngeal high-resolution manometry (HRM) provides complementary information to videofluoroscopy, with advantages of being quantitative and objective. Artificial neural network (ANN) classification can examine non-linear relationships among multiple variables with relatively low bias. We evaluated if ANN techniques could differentiate between patients with PD and healthy controls. METHODS: Simultaneous videofluoroscopy and pharyngeal HRM were performed on 31 patients with early to mid-stage PD and 31 age- and sex matched controls during thin-liquid swallows of 2 cc, 10 cc and comfortable sip volume. We performed multilayer-perceptron analyses on only videofluoroscopic data, only HRM data or a combination of the two. We also evaluated variability based parameters, representing variability in manometric parameters across multiple swallows. We hypothesized that patients with PD and controls would be classified with at least 80% accuracy, and that combined videofluoroscopic and HRM data would classify participants better than either alone. KEY RESULTS: Classification rates were highest with all parameters considered. Maximum classification rate was 82.3 +/- 5.2%, recorded for 2 cc swallows. Inclusion of variability-based parameters improved classification rates. Classification rates using only manometric parameters were similar to those using all parameters, and rates were substantially lower for the comfortable sip volumes. CONCLUSIONS & INFERENCES: Results from these classifications highlight the differences between swallowing function in patients with early and mid-stage PD and healthy controls. Early identification of swallowing dysfunction is key to developing preventative swallowing treatments for those with PD. PMID- 29143419 TI - Long Noncoding RNA RP11-380D23.2 Drives Distal-Proximal Patterning of the Lung by Regulating PITX2 Expression. AB - Early lung development is a tightly orchestrated process encompassing (a) formation of definitive endoderm, (b) anteriorization of definitive endoderm, followed by (c) specification and maturation of both proximal and distal lung precursors. Several reports detailing the interaction of genes and proteins during lung development are available; however, studies reporting the role(s) of long noncoding RNAs (lncRNA) in lung morphogenesis are limited. To investigate this, we tailored a protocol for differentiation of human-induced pluripotent stem cells into distal and proximal lung progenitors to mimic in vivo lung development. The authenticity of differentiated cells was confirmed by expression of key lung markers such as FoxA2, Sox-17, Nkx2.1, Pitx2, FoxJ1, CC10, SPC, and via scanning as well as transmission electron microscopy. We employed next generation sequencing to identify lncRNAs and categorized them based on their proximity to genes essential for lung morphogenesis. In-depth bioinformatical analysis of the sequencing data enabled identification of a novel lncRNA, RP11 380D23.2, which is located upstream of PITX2 and includes a binding site for PARP1. Chromatin immunoprecipitation and other relevant studies revealed that PARP1 is a repressor for PITX2. Whole genome microarray analysis of RP11 380D23.2/PITX2 knockdown populations of progenitors demonstrated enrichment in proximal progenitors and indicated altered distal-proximal patterning. Dysregulation of WNT effectors in both knockdowns highlighted direct modulation of PITX2 by RP11-380D23.2. Most of these results were validated in four independent hiPSC lines (including a patient-specific CFTR mutant line). Taken together, these findings offer a mechanistic explanation underpinning the role of RP11-380D23.2 during lung morphogenesis via WNT signaling. Stem Cells 2018;36:218 229. PMID- 29143421 TI - PTRHD1 and possibly ADORA1 mutations contribute to Parkinsonism with intellectual disability. PMID- 29143420 TI - Investigation of Surface Sulfurization in CuIn1-x Gax S2-y Sey Thin Films by Using Kelvin Probe Force Microscopy. AB - CuIn1-x Gax S2-y Sey (CIGSSe) thin films have attracted a great deal of attention as promising absorbing materials for solar cell applications, owing to their favorable optical properties (e.g. a direct band gap and high absorption coefficients) and stable structure. Many studies have sought to improve the efficiency of solar cells using these films, and it has been found that surface modification through post-heat treatment can lead to surface passivation of surface defects and a subsequent increase in efficiency. The surface properties of solution-processed CIGSSe films are considered to be particularly important in this respect, owing to the fact that they are more prone to defects. In this work, CIGSSe thin films with differing S/Se ratios at their surface were synthesized by using a precursor solution and post-sulfurization heat treatment. These CIGSSe thin films were investigated with current-voltage and Kelvin probe force microscope (KPFM) analyses. Surface photovoltage (SPV), which is the difference in the work function in the dark and under illumination, was measured by using KPFM, which can examine the screening and the modification of surface charge through carrier trapping. As the concentration of S increases on the CIGSSe film surface, higher work functions and more positive SPV values were observed. Based on these measurements, we inferred the band-bending behavior of CIGSSe absorber films and proposed reasons for the improvement in solar cell performance. PMID- 29143422 TI - Atropoenantioselective Redox-Neutral Amination of Biaryl Compounds through Borrowing Hydrogen and Dynamic Kinetic Resolution. AB - We report herein a novel atropoenantioselective redox-neutral amination of biaryl compounds triggered by a cascade of borrowing hydrogen and dynamic kinetic resolution under the cooperative catalysis of a chiral iridium complex and an achiral Bronsted acid. This protocol features broad substrate scope and good functional-group tolerance, and allows the rapid assembly of axially chiral biaryl compounds in good to high yields and with high to excellent enantioselectivity. PMID- 29143423 TI - Treatment and biology of pediatric acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. In the past ALL was intractable but now the survival probability is as high as 80 90%. Improved supportive care, treatment stratification based on relapse risk, biological features of leukemic cells, and optimization of treatment regimens by nationwide and international collaboration have contributed to this dramatic improvement. While including traditional risk factors (e.g. age and leukocyte count at diagnosis), the treatment has been modified based on biological characteristics (aneuploidy and translocation) and treatment response (assessed by minimal residual disease). Treatment for pediatric ALL typically consists of induction therapy with steroids, vincristine, and asparaginase with or without anthracycline, followed by multi-agent consolidation including high-dose methotrexate and re-induction therapy. After consolidation, less intensive maintenance therapy is required for 1-2 years to maintain event-free survival. Recently, using advanced genomic analysis technology, novel sentinel genomic alterations that may provide more precise stratification or therapeutic targets, were identified. Moreover, in the last decade germline variations have been recognized as similarly important contributors to understanding the etiology and sensitivity of ALL to treatment. A more individualized approach based on genomic features (somatic and germline) and treatment response, the introduction of newly developed agents such as molecular targeted drugs or immunotherapy, and social support including long-term follow up are required for further improvement. PMID- 29143424 TI - Restoration of Ribozyme Tertiary Contact and Function by Using a Molecular Glue for RNA. AB - Some RNA classes require folding into the proper higher-order structures to exert their functions. Hammerhead ribozyme (HHR) requires a folding conformation stabilized by tertiary interaction for full activity. A rationally engineered HHR was developed that was inactive, but could be activated by a synthetic RNA binding ligand, naphthyridine carbamate tetramer with Z-stilbene linker (Z-NCTS). Binding of Z-NCTS could induce the formation of an active folding structure and thereby restore ribozyme activity, where Z-NCTS acts as a molecular glue to bring two isolated RNA loops into contact with each other. Next, we designed a Z-NCTS responsive genetic switch using the HHR sequence inserted into the 3' untranslated region as a cis-acting element. We demonstrated that the rationally designed ribozyme switch enabled regulation of gene expression by Z-NCTS and was functional in mammalian cells. PMID- 29143427 TI - Effectiveness of educational program using printed educational material on care burden distress among staff of residential aged care facilities without medical specialists and/or registered nurses: Cluster quasi-randomization study. AB - AIM: Behavioral and psychological symptoms of dementia are an important source of distress for caregivers. The aim of the present study was to evaluate the effectiveness of educational intervention using printed educational material for reducing distress induced by behavioral and psychological symptoms of dementia among caregivers working at facilities without medical specialists and/or registered nurses. METHODS: A cluster quasi-randomized, controlled comparative trial was carried out at 17 facilities in Japan. Our intervention was an educational program administered at baseline using printed educational material for the care staff. The primary outcome was evaluated using the Japanese version of the Neuropsychiatric Inventory Questionnaire. The secondary outcome measures were caregiver burnout evaluated using the Japanese version of the Maslach Burnout Inventory and the care dependency of residents measured using the Japanese version of the Care Dependency Scale. RESULTS: The total Neuropsychiatric Inventory Questionnaire score decreased significantly in the intervention group (F [1355] = 6.57, P = 0.01), and the difference between the intervention and control groups was also significant (F [1355] = 4.78, P = 0.03). There were no significant changes in the Maslach Burnout Inventory or Care Dependency Scale scores in the intervention group, while the Maslach Burnout Inventory subscale (personal accomplishment) score decreased significantly in the control group. CONCLUSIONS: Our intervention achieved a significant reduction of distress among caregivers working at care homes without medical specialists and/or registered nurses. The findings of this research show that educational intervention can make a valuable contribution to training programs for care staff. Geriatr Gerontol Int 2018; 18: 487-494. PMID- 29143428 TI - Combination of alfacalcidol and calcium improved handgrip strength and mobility among Indonesian older women: A randomized controlled trial. AB - AIM: To determine the effect of alfacalcidol on muscle strength and functional mobility in Indonesian older women whose handgrip strength was low. METHODS: A randomized, double-blind controlled trial was carried out among 95 older women whose handgrip strength was <=22 kg. Participants were randomized into two groups: 47 participants received alfacalcidol 0.5 MUg/day and 48 participants received a placebo. Each participant in both groups was given calcium 500 mg/day. Handgrip strength as well as the Timed-Up and Go test were measured before and after 90 days of intervention. Per protocol analysis after intervention between two groups was carried out. RESULTS: There was a significant improvement of handgrip strength in the group that received alfacalcidol compared with the placebo group (15.50 vs 13.75; P = 0.003). The median time for the Timed-Up and Go test in the alfacalcidol group also improved significantly compared with the placebo group (9.01 vs 10.07, P = 0.028). CONCLUSIONS: Alfacalcidol with daily doses of 0.5 MUg significantly improved muscle strength and functional mobility in Indonesian older women. Geriatr Gerontol Int 2018; 18: 434-440. PMID- 29143429 TI - An overview of methods to mitigate artifacts in optical coherence tomography imaging of the skin. AB - BACKGROUND: Optical coherence tomography (OCT) of skin delivers three-dimensional images of tissue microstructures. Although OCT imaging offers a promising high resolution modality, OCT images suffer from some artifacts that lead to misinterpretation of tissue structures. Therefore, an overview of methods to mitigate artifacts in OCT imaging of the skin is of paramount importance. Speckle, intensity decay, and blurring are three major artifacts in OCT images. Speckle is due to the low coherent light source used in the configuration of OCT. Intensity decay is a deterioration of light with respect to depth, and blurring is the consequence of deficiencies of optical components. METHOD: Two speckle reduction methods (one based on artificial neural network and one based on spatial compounding), an attenuation compensation algorithm (based on Beer Lambert law) and a deblurring procedure (using deconvolution), are described. Moreover, optical properties extraction algorithm based on extended Huygens Fresnel (EHF) principle to obtain some additional information from OCT images are discussed. RESULTS: In this short overview, we summarize some of the image enhancement algorithms for OCT images which address the abovementioned artifacts. The results showed a significant improvement in the visibility of the clinically relevant features in the images. The quality improvement was evaluated using several numerical assessment measures. CONCLUSION: Clinical dermatologists benefit from using these image enhancement algorithms to improve OCT diagnosis and essentially function as a noninvasive optical biopsy. PMID- 29143430 TI - Power, discourse, and resistance: Poststructuralist influences in nursing. AB - Based on our respective research programs (psychiatry, forensic psychiatry, public health, HIV/AIDS, harm reduction) this article aims to use purposely non conventional means to present the substantial contribution of poststructuralist perspectives to knowledge development in nursing science in general and in our current research in particular. More specifically, we call on the work of Michel Foucault and Deleuze & Guattari to politicize nursing science using examples from our empirical research programs with marginal and often highly marginalized populations. We discuss the concepts of power, discourse, and resistance to illustrate the essential contribution of poststructuralism to marginal, even "nomadic", nursing research. PMID- 29143431 TI - Multinuclear NMR and diffusion studies of quaternary amine-based ionic liquids. PMID- 29143432 TI - Primary myxoid mesenchymal tumour with intracranial location: report of a case with a EWSR1-ATF1 fusion. PMID- 29143433 TI - Psychological correlates of fear of falling: Findings from the German Aging Survey. AB - AIM: The aim of the present study was to identify general psychological factors related to fear of falling. METHODS: Data drawn from national probability sampling of the German population aged >=40 years were used (German Aging Survey; n = 7779). The fear of falling and the psychological factors of loneliness, life satisfaction, positive affect, negative affect, optimism, self-efficacy, self esteem, self-regulation and perceived stress were collected in self-administered questionnaires. Multiple logistic regression models controlling for sociodemographic, lifestyle and health-related variables were used to determine the psychological correlates of fear of falling. RESULTS: The prevalence of fear of falling was 18% for all individuals. All psychological factors showed strong bivariate associations with fear of falling. In the multiple regression analyses, higher levels of loneliness, lower life satisfaction, lower positive affect and higher negative affect, as well as lower levels of optimism, self-efficacy, self esteem, self-regulation and more perceived stress, were associated with increased fear of falling after controlling for sociodemographic factors, various lifestyle factors and morbidity. CONCLUSIONS: The psychological factors considered in the present study are important for characterizing people with fear of falling. Because effective interventions to treat the fear of falling are available, our study might help to address this target group more accurately. Geriatr Gerontol Int 2018; 18: 396-406. PMID- 29143434 TI - Community structure of insect herbivores is driven by conservatism, escalation and divergence of defensive traits in Ficus. AB - Escalation (macroevolutionary increase) or divergence (disparity between relatives) in trait values are two frequent outcomes of the plant-herbivore arms race. We studied the defences and caterpillars associated with 21 sympatric New Guinean figs. Herbivore generalists were concentrated on hosts with low protease and oxidative activity. The distribution of specialists correlated with phylogeny, protease and trichomes. Additionally, highly specialised Asota moths used alkaloid rich plants. The evolution of proteases was conserved, alkaloid diversity has escalated across the studied species, oxidative activity has escalated within one clade, and trichomes have diverged across the phylogeny. Herbivore specificity correlated with their response to host defences: escalating traits largely affected generalists and divergent traits specialists; but the effect of escalating traits on extreme specialists was positive. In turn, the evolution of defences in Ficus can be driven towards both escalation and divergence in individual traits, in combination providing protection against a broad spectrum of herbivores. PMID- 29143435 TI - Risk factors for falls among older Aboriginal and Torres Strait Islander people in urban and regional communities. AB - OBJECTIVE: To examine associations between fall risk factors identified previously in other populations and falls among Aboriginal people aged 60 years and older, living in New South Wales, Australia. METHODS: Interviews were conducted with older Aboriginal people in five urban and regional communities. Associations between past falls and 22 fall predictor variables were examined using linear and multiple regression analyses. RESULTS: Of the 336 participants, 80 people (24%) reported at least one fall in the past year, and 34 (10%) reported two or more falls. Participants had an increased fall risk if they were female; used three or more medications; had arthritis, macular degeneration, depression, history of stroke; were unable to do their own housework; or were unable to do their own shopping. CONCLUSION: Falls were experienced by one quarter of study participants. Fall risk factors identified for older Aboriginal people appear to be similar to those identified in the general population. Understanding of fall risk factors may assist with the development of appropriate and effective community-led fall prevention programs. PMID- 29143436 TI - Eco-energetic consequences of evolutionary shifts in body size. AB - Size imposes physiological and ecological constraints upon all organisms. Theory abounds on how energy flux covaries with body size, yet causal links are often elusive. As a more direct way to assess the role of size, we used artificial selection to evolve the phytoplankton species Dunaliella tertiolecta towards smaller and larger body sizes. Within 100 generations (c. 1 year), we generated a fourfold difference in cell volume among selected lineages. Large-selected populations produced four times the energy than small-selected populations of equivalent total biovolume, but at the cost of much higher volume-specific respiration. These differences in energy utilisation between large (more productive) and small (more energy-efficient) individuals were used to successfully predict ecological performance (r and K) across novel resource regimes. We show that body size determines the performance of a species by mediating its net energy flux, with worrying implications for current trends in size reduction and for global carbon cycles. PMID- 29143437 TI - Profiles of needs satisfaction and thwarting in older people living at home: Relationships with well-being and ill-being indicators. AB - AIM: To examine the profiles of basic psychological needs satisfaction (BPNS) and thwarting (BPNT) in older people living at home, their relationship with well being and ill-being indicators, and how BPNS and BPNT needs were related to these indicators using regression analyses. METHODS: Participants (n = 182; mean age 73.33 years; SD 7.07 years) completed the measures of BPNS, BPNT, purpose in life, personal growth, subjective vitality, self-esteem, positive and negative affective states, and depressive feelings. Sociodemographic data were collected. RESULTS: Cluster analyses show two distinct profiles: (i) high degrees of BPNS and low degrees of BPNT; and (ii) moderate degrees of both BPNS and BPNT. No effect of cluster membership on demographic characteristics was reported. Multivariate analysis of variance (manova) results showed that participants in profile 1 had a higher level of well-being (personal growth, purpose in life, subjective vitality, self-esteem and positive affective states) and a lower level of ill-being (negative affective state and depressive feelings) than those in profile 2. For all participants, the findings showed that competence and relatedness need satisfactions were significantly and positively related to well being indicators (positive affective states, purpose of life and subjective vitality respectively). Autonomy and competence need thwarting were significantly and positively related to negative affective states. CONCLUSIONS: The present results suggest using the BPNS and BPNT scales simultaneously to better understand the mechanisms that contribute to well-being and ill-being in older people. Geriatr Gerontol Int 2018; 18: 470-478. PMID- 29143439 TI - Use of and satisfaction with Community Aged Care Packages in the eastern suburbs of Sydney. AB - OBJECTIVE: The pilot study aimed to examine the accessibility and the flexibility of the Community Aged Care Package (CACP) program, and provide recommendations for further improvement. METHOD: Data were collected using structured interviews with 80 CACP recipients, and mail surveys with nine service coordinators of CACP services. Descriptive statistics and chi2 analysis were used for quantitative information, and thematic analysis for qualitative data. RESULTS: CACPs were utilised more frequently and for longer periods by clients with English-speaking backgrounds and those living alone. The average level of client satisfaction with CACP was high, over 62% rating extremely satisfied. Participants expressed concerns related to CACPs including inflexibility, lack of communication between service providers and other health services, poor continuity and quality of care, inadequate funding, problems with recruitment, retention and support for staff. CONCLUSION: While the clients' overall satisfaction levels were rated high, qualitative information suggested a need for improvement of the current delivery of the CACP program. PMID- 29143438 TI - Protective effects of coenzyme Q10 nanoparticles on dichlorvos-induced hepatotoxicity and mitochondrial/lysosomal injury. AB - Development of biocompatible antioxidant nanoparticles for xenobiotic-induced liver disease treatment by oral or parenteral administration is of great interest in medicine. In the current study, we demonstrate the protective effects of coenzyme Q10 nanoparticles (CoQ10-NPs) on hepatotoxicity induced by dichlorvos (DDVP) as an organophosphate. Although CoQ10 is an efficient antioxidant, its poor bioavailability has limited the applications of this useful agent. First, CoQ10-NPs were prepared then characterized using dynamic light scattering (DLS) and transmission electron microscopy (TEM). In DDVP-treated and non-treated hepatocytes in the presence of CoQ10-NPs, cell viability, the level of reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial membrane potential (MMP), lysosome membrane integrity, and cellular glutathione (GSH) content were measured. The prepared CoQ10-NPs were mono-dispersed and had narrow size distribution with average diameter of 54 nm. In the in vivo study, we evaluated the enzymes, which are involved in the antioxidant system for maintenance of normal liver function. In comparison to nonparticulate CoQ10, the CoQ10-NPs efficiently decreased the ROS formation, lipid peroxidation and cell death. Also, particulate form of CoQ10 improved MMP, GSH level and lysosome membrane integrity. In the in vivo, study, we revealed that CoQ10-NPs were better hepatoprotective than its nonparticulate form (P < .05). Altogether, we propose that the CoQ10-NPs have potential capability to be used as a therapeutic and prophylactic agent for poisoning that is induced by organophosphate agents, especially in the case of DDVP. Furthermore, these positive remarks make this nanoparticle amenable for the treatment of xenobiotic-induced liver diseases. PMID- 29143440 TI - Use of Innovative (Micro)Extraction Techniques to Characterise Harpagophytum procumbens Root and its Commercial Food Supplements. AB - INTRODUCTION: For the determination of harpagoside and the wide phenolic pattern in Harpagophytum procumbens root and its commercial food supplements, dispersive liquid-liquid microextraction (DLLME), ultrasound-assisted DLLME (UA-DLLME), and sugaring-out liquid-liquid extraction (SULLE) were tested and compared. OBJECTIVES: In order to optimise the extraction efficiency, DLLME and UA-DLLME were performed in different solvents (water and aqueous solutions of glucose, beta-cyclodextrin, (2-hydroxypropyl)-beta-cyclodextrin, sodium chloride, natural deep eutectic solvent, and ionic liquid). MATERIAL AND METHODS: The plant material was ground and sieved to obtain a uniform granulometry before extraction. Commercial food supplements, containing H. procumbens are commercially available in Italy. RESULTS: The most effective sodium chloride aided-DLLME was then optimised and applied for analyses followed by HPLC-PDA. For comparison, microwave-assisted extraction was performed using the same solvents and the best results were obtained using 1% of beta-cyclodextrin or 15% of sodium chloride. CONCLUSION: All commercial samples respected the European Pharmacopoeia monograph for this plant material, showing a harpagoside content >= 1.2%. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29143441 TI - Cellular aging dynamics after acute malaria infection: A 12-month longitudinal study. AB - Accelerated cellular aging and reduced lifespan have recently been shown in birds chronically infected with malaria parasites. Whether malaria infection also affects cellular aging in humans has not been reported. Here, we assessed the effect of a single acute Plasmodium falciparum malaria infection on cellular aging dynamics in travelers prospectively followed over one year in Sweden. DNA and RNA were extracted from venous blood collected at the time of admission and repeatedly up to one year. Telomere length was measured using real-time quantitative PCR, while telomerase activity and CDKN2A expression were measured by reverse transcriptase (RT)-qPCR. Our results show that acute malaria infection affects cellular aging as reflected by elevated levels of CDKN2A expression, lower telomerase activity, and substantial telomere shortening during the first three months postinfection. After that CDKN2A expression declined, telomerase activity increased and telomere length was gradually restored over one year, reflecting that cellular aging was reversed. These findings demonstrate that malaria infection affects cellular aging and the underlying cellular mechanism by which pathogens can affect host cellular aging and longevity need to be elucidated. Our results urge the need to investigate whether repeated malaria infections have more pronounced and long-lasting effects on cellular aging and lifespan (similarly to what was observed in birds) in populations living in malaria endemic areas. PMID- 29143443 TI - Multiscale characterization of cortical bone composition, microstructure, and nanomechanical properties in experimentally induced osteoporosis. AB - Cortical bone plays a vital role in determining overall bone strength. We investigate the structural, compositional, and nanomechanical properties of cortical bone following ovariectomy (OVX) of 12-week-old Sprague Dawley rats, since this animal model is frequently employed to evaluate the performance of implantable biomaterials in compromised bone healing conditions. Morphological parameters and material properties of bone in the geometrical center of the femoral cortex were investigated four and eight weeks post-OVX and in unoperated controls (Ctrl), using X-ray micro-computed tomography, backscattered electron scanning electron microscopy, Raman spectroscopy, and nanoindentation. The OVX animals showed increase in body weight, diminished bone mineral density, increased intracortical porosity, but increased bone mass through periosteal apposition (e.g., increases in periosteal perimeter, cortical cross-sectional thickness, and cross-sectional area). However, osteocyte densities, osteocyte lacunar dimensions, and the nanomechanical behavior on the single mineralized collagen fibril level remained unaffected. Our correlative multiscale investigation provides structural, chemical, and nanomechanical evidence substantiating earlier reports suggesting that rats ovariectomized at 12 weeks undergo simultaneous bone loss and growth, resulting in the effects of OVX being less obvious. Periosteal apposition contradicts the conventional view of bone loss in osteoporosis but appears advantageous for the greater functional demand imposed on the skeleton by increased body weight and fragility induced by increased intracortical porosity. Through a variety of morphological changes, it is likely that 12-week-old rats are able to adapt to OVX-related microstructural and compositional alterations. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 997-1007, 2018. PMID- 29143442 TI - Development of biomimetic thermoplastic polyurethane/fibroin small-diameter vascular grafts via a novel electrospinning approach. AB - A new electrospinning approach for fabricating vascular grafts with a layered, circumferentially aligned, and micro-wavy fibrous structure similar to natural elastic tissues has been developed. The customized electrospinning collector was able to generate wavy fibers using the dynamic "jump rope" collecting process, which also solved the sample removal problem for mandrel-type collectors. In this study, natural silk fibroin and synthetic thermoplastic polyurethane (TPU) were combined at different weight ratios to produce hybrid small-diameter vascular grafts. The purpose of combining these two materials was to leverage the bioactivity and tunable mechanical properties of these natural and synthetic materials. Results showed that the electrospun fiber morphology was highly influenced by the material compositions and solvents employed. All of the TPU/fibroin hybrid grafts had mechanical properties comparable to natural blood vessels. The circumferentially aligned and wavy biomimetic configuration provided the grafts with a sufficient toe region and the capacity for long-term usage under repeated dilatation and contraction. Cell culture tests with human endothelial cells (EC) also revealed high cell viability and good biocompatibility for these grafts. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 985-996, 2018. PMID- 29143444 TI - The subversion of Mill and the ultimate aim of nursing. AB - This is lightly edited and referenced version of a presentation given at the 20th International Philosophy of Nursing conference in Quebec on 23rd August 2016. Philosophical texts are not given the same prominence in nurse education as their more valued younger sibling, primary research evidence, but they can influence practice through guidelines, codes and espoused values. John Stuart Mill's harm principle, found in On Liberty, is not a universal law, and only a thoroughgoing libertarian would defend it as such, though it, or its remnants, can be seen can be seen in policy documents. But its influence is weakening. Smoking bans in enclosed spaces were initially justified with other-regarding considerations, but judgements from unsuccessful legal challenges from patients in UK psychiatric hospitals rely on preventing harm to the smoker, even when smoking outside, which does not harm others. In the wake of legislation, no-smoking policies enacted by hospitals are becoming more aggressive, banning smoking both inside and outside, and extending the use of power gained through employment to prevent nurses assisting patients enjoy a lawful habit. Mill's dictum has been subverted, and this speaks to the fundamental purpose of nursing. Should nurses collude and willingly exert their power for their version of the good of the patient? Or should they instead reaffirm values that support and facilitate life choices made by autonomous people? The paper supports the latter option, and this has wider application for nursing which can be illuminated, if not settled, by revisiting Mill and his famous dictum. PMID- 29143445 TI - Glycyrrhiza uralensis and Semilicoisoflavone B Reduce Abeta Secretion by Increasing PPARgamma Expression and Inhibiting STAT3 Phosphorylation to Inhibit BACE1 Expression. AB - SCOPE: Glycyrrhiza uralensis extract (GUE) has been reported to improve amyloid beta (Abeta)-induced cognitive deficits in mice. However, the mechanisms underlying this effect and the components involved have not been previously explored. Extracellular Abeta plaques are one of the major pathological hallmarks of Alzheimer's disease (AD). Therefore, decreasing Abeta levels is one strategy for preventing the etiology of AD. This study aims to test the effect of GUE and semilicoisoflavone B (SB) on Abeta secretion and investigates the mechanism underlying this effect. METHODS AND RESULTS: GUE and its bio-activated compound SB reduce Abeta secretion. We find that this effect contribute to the downregulation of the beta-secretase-1 (BACE1) protein and mRNA. In a subsequent mechanism study, we find that GUE and SB regulate BACE1 transcription factors by inducing the expression of peroxisome proliferator activated receptor gamma (PPARgamma) and inhibiting the phosphorylation of signal transducer and activator of transcription 3. In addition, the effect of GUE and SB on BACE1 expression and Abeta secretion are attenuated by treatment with PPARgamma-siRNA or its antagonist, GW9662. CONCLUSION: These findings indicate that GUE and SB may function as PPARgamma agonists, thereby inhibiting BACE1 expression and ultimately reducing the secretion of Abeta. PMID- 29143446 TI - Realism in paediatric emergency simulations: A prospective comparison of in situ, low fidelity and centre-based, high fidelity scenarios. AB - OBJECTIVE: To measure scenario participant and faculty self-reported realism, engagement and learning for the low fidelity, in situ simulations and compare this to high fidelity, centre-based simulations. METHODS: A prospective survey of scenario participants and faculty completing in situ and centre-based paediatric simulations. RESULTS: There were 382 responses, 276 from scenario participants and 106 from faculty with 241 responses from in situ and 141 from centre-based simulations. Scenario participant responses showed significantly higher ratings for the centre-based simulations for respiratory rate (P = 0.007), pulse (P = 0.036), breath sounds (P = 0.002), heart sounds (P < 0.001) and patient noises (P < 0.001). There was a significant difference in overall rating of the scenario reality by scenario participants in favour of the centre-based simulations (P = 0.005); however, there was no significant difference when rating participant engagement (P = 0.11) and participant learning (P = 0.77). With the centre-based scenarios, nurses rated the reality of the respiratory rate (P < 0.001), blood pressure (P = 0.016) and abdominal signs (P = 0.003) significantly higher than doctors. Nurses rated the overall reality higher than doctors for the centre simulations (96.8% vs 84.2% rated as realistic, P = 0.041), which was not demonstrated in the in situ scenarios (76.2% vs 73.5%, P = 0.65). CONCLUSION: Some aspects of in situ simulations may be less 'real' than centre-based simulations, but there was no significant difference in self-reported engagement or learning by scenario participants. Low fidelity, in situ simulation provides adequate realism for engagement and learning. PMID- 29143447 TI - Investigation of the interactions between aptamer and misfolded proteins: From monomer and oligomer to fibril by single-molecule force spectroscopy. AB - Increasing knowledge on the understanding interactions of aptamer with misfolded proteins (including monomer, oligomer, and amyloid fibril) is crucial for development of aggregation inhibitors and diagnosis of amyloid diseases. Herein, the interactions of lysozyme monomer-, oligomer-, and amyloid fibril-aptamer were investigated using single-molecule force spectroscopy. The results revealed that the aptamer screened against lysozyme monomer could also bind to oligomer and amyloid fibril, in spite of the recognition at a lower binding probability. It may be attributed to the inherent structural differences of misfolded proteins and the flexible conformation of aptamer. In addition, dynamic force spectra showed that there were similar dissociation paths in the dissociation process of lysozyme monomer-, oligomer-, and amyloid fibril-aptamer complexes. It showed that the dissociation only passed 1 energy barrier from the binding state to the detachment. However, the dynamic parameters suggested that the oligomer- and amyloid fibril-aptamer were more stable than lysozyme monomer-aptamer. The phenomena may result from the exposure of aptamer-recognized sequences on the surface and the electrostatic interactions. This work demonstrated that single molecule force spectroscopy could be a powerful tool to study the binding behavior of the aptamer with misfolded proteins at single-molecule level, providing abundant information for researches and comprehensive applications of aptamer probes in diagnosis of amyloid diseases. PMID- 29143448 TI - Prospective observational study of predicted usage of intravenous cannulas inserted in a tertiary paediatric emergency department. AB - OBJECTIVES: To determine the proportion of unused peripheral intravenous cannulas (PIVCs) inserted in a paediatric emergency department (PED) and to assess clinicians' abilities to predict future usage of PIVC. METHODS: Prospective concealed observational study in a tertiary PED. Healthcare workers (HCWs) completed questionnaires upon insertion and removal of PIVC with review of patient notes if required. The primary outcome was the number of unused, unnecessary PIVCs. Secondary outcomes included demographic factors affecting unused cannulas, a clinician's ability to predict PIVC use and the incidence of complications from PIVC insertion. RESULTS: From 806 returned questionnaires, 719 patients were recruited. Twenty-two per cent of PIVCs remained unused after initial insertion for all patients. There was no significant difference in the rate of unused cannulas among any age or sex category, with the lowest rate of unused PIVCs in triage category 2 patients. HCW seniority when deciding to insert a PIVC did not affect usage rates. Likert scale analyses showed that HCWs could correctly predict ongoing use of PIVCs in 90% of cases. The overall rate of PIVCs removed for infected or inflamed insertion sites was low at 0.8%. CONCLUSION: This study is consistent with the idle PIVC rates observed in PEDs but there is potential to further reduce this rate with targeted insertion. The paediatric clinicians' reliability in predicting PIVC use has been demonstrated for the first time and we have identified four groups where targeted phlebotomy rather than i.v. cannulation would reduce unused cannulas. PMID- 29143449 TI - Osteoinductivity of nanostructured hydroxyapatite-functionalized gelatin modulated by human and endogenous mesenchymal stromal cells. AB - The demand of new strategies for the induction of bone regeneration is continuously increasing. Biomimetic porous gelatin-nanocrystalline hydroxyapatite scaffolds with tailored properties were previously developed, showing a positive response in terms of cell adhesion, proliferation, and differentiation. In the present paper, we focused on their osteoinductive properties. The effect of scaffolds on osteogenic differentiation of human mesenchymal stromal cells (hMSCs) was investigated in vitro. hMSCs were seeded on GEL (type A gelatin) and GEL containing 10 wt% hydroxyapatite (GEL-HA) and cultured in osteogenic medium. Results showed that GEL and GEL-HA10 sustained hMSC differentiation, with an increased ALP activity and a higher expression of bone specific genes. The osteoinductive ability of these scaffolds was then studied in vivo in a heterotopic bone formation model in nude mice. The influence of hMSCs within the implants was examined as well. Both GEL and GEL-HA10 scaffolds mineralized when implanted without hMSCs. On the contrary, the presence of hMSC abolished or reduced mineralization of GEL and GEL-HA10 scaffolds. However, we could observe a species-specific response to the presence of HA, which stimulated osteogenic differentiation of human cells only. In conclusion, the scaffolds showed promising osteoinductive properties and may be suitable for use in confined critical defects. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 914-923, 2018. PMID- 29143450 TI - Co-design of technology-enhanced learning resources. PMID- 29143451 TI - Using Intraoral Scanning Technology for Three-Dimensional Printing of Kennedy Class I Removable Partial Denture Metal Framework: A Clinical Report. AB - Removable partial dentures (RPDs) are used to restore missing teeth and are traditionally fabricated using the lost-wax casting technique. The casting process is arduous, time-consuming, and requires a skilled technician. The development of intraoral scanning and 3D printing technology has made rapid prototyping of the RPD more achievable. This article reports a completed case of direct fabrication of a maxillary RPD metal framework (Kennedy Class I) using intraoral scanning and 3D printing techniques. Acceptable fit and satisfactory clinical outcome were demonstrated. Intraoral scanning and 3D printing for fabrication of the RPD metal framework is a useful alternative to conventional impression and casting techniques, especially for patients suffering from nasal obstruction or intolerance. PMID- 29143452 TI - Engineering improved variants of the antifungal peptide histatin 5 with reduced susceptibility to Candida albicans secreted aspartic proteases and enhanced antimicrobial potency. AB - Candida albicans is an opportunistic fungal pathogen and a commensal organism that commonly colonizes mucosal surfaces, including those inside the human mouth. To help control C. albicans, human saliva contains the antifungal peptide histatin 5 (Hst-5), which has strong antifungal activity against C. albicans. However, the pathogen produces secreted aspartic proteases (Saps) that cleave Hst 5 at lysine residues and eliminate its antifungal properties. We designed variants of Hst-5 with its lysine residues substituted with arginine or leucine to evaluate the effect on proteolysis by Saps. We found site-, residue-, and Sap dependent effects from single amino acid substitutions. The K17R and K17L modifications led to dramatic results, with over 77% and 100% intact peptide remaining after incubation with Sap9 and Sap2, respectively, compared to 47% and 61% of Hst-5. This decrease in proteolysis was accompanied by a reduction in cleavage on the C-terminal side of K17, suggesting the Saps prefer lysine at K17 for cleavage. Incubation with C. albicans cells and culture supernatant corroborated the results with purified Saps and highlighted their biological relevance. The modifications to Hst-5 do not diminish the antifungal activity of Hst-5, and, in fact, the K17R, K17L, and K11R peptides retained significantly more antifungal activity after treatment with Saps than Hst-5. Our results indicate that single amino acid modifications drastically impact both proteolysis at the modification sites and the overall level of proteolysis of the peptide, demonstrating the potential of designing peptides for resistance to proteolysis as a means for improving therapeutic efficacy. PMID- 29143453 TI - Professional competencies and work-related support in relation to periodontal therapy and work satisfaction: A questionnaire study among Swedish Dental Hygienists. AB - OBJECTIVES: To analyse dental hygienists' (DHs) views on professional competencies and behavioural interventions in the treatment of periodontitis patients, perceived work-related support and work satisfaction. METHODS: A Web based questionnaire was distributed to all DHs employed at the public dental service in the county of Vastra Gotaland, Sweden. 302 (83%) responded to the questionnaire; 291 of these DHs stated that they on regular basis treated periodontitis patients and thus constituted the sample for analyses. Based on initial correlation and bivariate analyses of the questionnaire data, multiple logistic regression models were formulated to estimate perceived competencies to treat patients with periodontitis and work satisfaction. RESULTS: The multiple analyses revealed that DHs who worked with specific methods for behavioural intervention, like motivational interviewing, were more likely to rate themselves as "definitely possessing the competencies required to treat patients with periodontitis" (OR 4.0). Likewise, this group of DHs did not consider it more difficult to charge their patients the financial costs for such a behavioural intervention than for scaling therapy (OR 3.1). The perception that one's professional competencies were utilized well in daily practice was associated with high work satisfaction (OR 4.1). More years in the profession (OR 1.03) and a good support by colleagues (OR 1.9) had also a positive impact on work satisfaction. CONCLUSIONS: Dental hygienists' considered that competencies in the treatment of periodontitis patients were related to the practice of behavioural interventions as part of therapy. A stimulating and supportive work environment, with opportunities for professional development, is important for work satisfaction. PMID- 29143454 TI - High Prevalence of Drug-Drug Interactions in Primary Health Care is Caused by Prescriptions from other Healthcare Units. AB - Drug-drug interactions are increasingly common, as patients are getting older and the number of drugs per patient is increasing. In this study, we investigated to which extent potential drug-drug interactions originated from single or multiple prescribers. All patients attending any of 20 primary healthcare centres were included in a retrospective observational cohort study. Data on all prescriptions to these patients, irrespectively of the prescriber, were collected for two 4 month periods. Potential drug interactions were identified using the drug-drug interaction database SFINX. Interactions were classified with respect to the workplace of the prescriber, and the prevalence of interactions according to origin was analysed. We found that the drug interactions were significantly more common when the drugs were prescribed from different healthcare centres, compared with drugs prescribed from the patients' primary healthcare centre only. One explanation for this increased risk of drug interactions could be that the prescribers at different primary healthcare centres do not share the same information concerning the total medication list of the patient. PMID- 29143455 TI - Understanding the functional role of microRNA-214-3p in atherosclerosis for the identification of novel targeted therapies to prevent or reverse endothelial cell dysfunction and stimulate autophagy. PMID- 29143456 TI - Early intervention in psychosis: From clinical intervention to health system implementation. AB - AIM: Early intervention in psychosis (EIP) is a well-established approach with the intention of early detection and treatment of psychotic disorders. Its clinical and economic benefits are well documented. This paper presents basic aspects of EIP services, discusses challenges to their implementation and presents ideas and strategies to overcome some of these obstacles. METHODS: This paper is a narrative review about the evidence supporting EIP, with examples of successful implementation of EIP and of cases where major obstacles still need to be overcome. RESULTS: Experience from successfully implemented EIP services into the mental healthcare system have generated evidence, concepts and specific strategies that might serve as guidance or inspiration in other countries or systems where EIP is less well developed or not developed at all. Previous experience has made clear that evidence of clinical benefits alone is not enough to promote implementation, as economic arguments and political and social pressure have shown to be important elements in efforts to achieve implementation. CONCLUSIONS: Users' narratives, close collaboration with community organizations and support from policy-makers and known people within the community championing early intervention (EI) services are just a few of the approaches that should be considered in campaigns for implementation of EI services. Fast progress in implementation is possible. PMID- 29143457 TI - Microhaplotypes provide increased power from short-read DNA sequences for relationship inference. AB - The accelerating rate at which DNA sequence data are now generated by high throughput sequencing instruments provides both opportunities and challenges for population genetic and ecological investigations of animals and plants. We show here how the common practice of calling genotypes from a single SNP per sequenced region ignores substantial additional information in the phased short-read sequences that are provided by these sequencing instruments. We target sequenced regions with multiple SNPs in kelp rockfish (Sebastes atrovirens) to determine "microhaplotypes" and then call these microhaplotypes as alleles at each locus. We then demonstrate how these multi-allelic marker data from such loci dramatically increase power for relationship inference. The microhaplotype approach decreases false-positive rates by several orders of magnitude, relative to calling bi-allelic SNPs, for two challenging analytical procedures, full sibling and single parent-offspring pair identification. We also show how the identification of half-sibling pairs requires so much data that physical linkage becomes a consideration, and that most published studies that attempt to do so are dramatically underpowered. The advent of phased short-read DNA sequence data, in conjunction with emerging analytical tools for their analysis, promises to improve efficiency by reducing the number of loci necessary for a particular level of statistical confidence, thereby lowering the cost of data collection and reducing the degree of physical linkage amongst markers used for relationship estimation. Such advances will facilitate collaborative research and management for migratory and other widespread species. PMID- 29143458 TI - COMP report: CPQR technical quality control guidelines for CT simulators. AB - The Canadian Organization of Medical Physicists (COMP), in close partnership with the Canadian Partnership for Quality Radiotherapy (CPQR) has developed a series of Technical Quality Control (TQC) guidelines for radiation treatment equipment. These guidelines outline the performance objectives that equipment should meet in order to ensure an acceptable level of radiation treatment quality. The TQC guidelines have been rigorously reviewed and field tested in a variety of Canadian radiation treatment facilities. The development process enables rapid review and update to keep the guidelines current with changes in technology (the most updated version of this guideline can be found on the CPQR website). This particular TQC details recommended quality control testing of CT simulators. PMID- 29143459 TI - The spatial patterning of RGD and BMP-2 mimetic peptides at the subcellular scale modulates human mesenchymal stem cells osteogenesis. AB - Engineering artificial extracellular matrices, based on the biomimicry of the spatial distribution of proteins and growth factors within their native microenvironment, is of great importance for understanding mechanisms of bone tissue regeneration. Herein, photolithography is used to decorate glass surfaces with subcellular patterns of RGD and BMP-2 ligands; two mimetic peptides recognized to be involved in stem cells osteogenesis. The biological relevance of well-defined RGD and BMP-2 patterned surfaces is evaluated by investigating the differentiation of human mesenchymal stem cells (hMSCs) into osteoblasts, in the absence of induction media. The extent of hMSCs differentiation is revealed to be dependent on both the pattern shape and the ligand type. Indeed, the spatial patterning of BMP-2, but not RGD peptide, significantly enhances the extent of hMSCs differentiation, suggesting that geometric cues guide stem cells specification into specialized cells in a ligand type dependent manner. Such cell culture models provide an interesting tool to investigate how stem cells perceive and respond to their microenvironment and may contribute to the development of next-generation biomaterials capable of producing clinically relevant volume of bone tissue. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 959-970, 2018. PMID- 29143460 TI - Transient neonatal zinc deficiency in exclusively breastfed preterm infants. PMID- 29143461 TI - Do animal exhibitors support and follow recommendations to prevent transmission of variant influenza at agricultural fairs? A survey of animal exhibitor households after a variant influenza virus outbreak in Michigan. AB - Influenza A viruses circulate in swine and can spread rapidly among swine when housed in close proximity, such as at agricultural fairs. Youth who have close and prolonged contact with influenza-infected swine at agricultural fairs may be at increased risk of acquiring influenza virus infection from swine. Animal and human health officials have issued written measures to minimize influenza transmission at agricultural exhibitions; however, there is little information on the knowledge, attitudes, and practice (KAP) of these measures among animal exhibitors. After an August 2016 outbreak of influenza A(H3N2) variant ("H3N2v") virus infections (i.e., humans infected with swine influenza viruses) in Michigan, we surveyed households of animal exhibitors at eight fairs (including one with known H3N2v infections) to assess their KAP related to variant virus infections and their support for prevention measures. Among 170 households interviewed, most (90%, 151/167) perceived their risk of acquiring influenza from swine to be low or very low. Animal exhibitor households reported high levels of behaviours that put them at increased risk of variant influenza virus infections, including eating or drinking in swine barns (43%, 66/154) and hugging, kissing or snuggling with swine at agricultural fairs (31%, 48/157). Among several recommendations, including limiting the duration of swine exhibits and restricting eating and drinking in the animal barns, the only recommendation supported by a majority of households was the presence of prominent hand-washing stations with a person to monitor hand-washing behaviour (76%, 129/170). This is a unique study of KAP among animal exhibitors and highlights that animal exhibitor households engage in behaviours that could increase their risk of variant virus infections and have low support for currently recommended measures to minimize infection transmission. Further efforts are needed to understand the lack of support for recommended measures and to encourage healthy behaviours at fairs. PMID- 29143462 TI - Evaluation of Immediate Implants Augmented with Autogenous Bone/Melatonin Composite Graft in the Esthetic Zone: A Randomized Controlled Trial. AB - PURPOSE: To evaluate the clinical and radiographic outcomes following the application of autogenous bone (ABG)/melatonin composite graft around immediate implants in the esthetic zone compared to ABG alone. MATERIALS AND METHODS: Twenty-six patients with two nonrestorable anterior/premolar teeth were randomly classified into two equal groups. Dental implants were immediately inserted either with ABG (control group) or ABG/melatonin (test group). Outcome measures were peri-implant sulcus depth (PD), gingival index (GI), and wound healing scores. Cone beam computed tomography (CBCT) was recorded at baseline, 6, and 9 months. RESULTS: At the end of the study, a significant difference was shown in the mean of marginal bone loss between the control group (1.91 mm +/- 0.42) and the test group (0.84 mm +/- 0.34) at p = 0.0001. The test group showed a significant gain in bone density, 500.73 +/- 40.92, versus 420.14 +/- 38.33 in the control group (p = 0.0001). There was a statistically significant difference between the control group (0.68 +/- 0.42) versus the test group (0.45 +/- 0.49; p = 0.044) in GI. PD was significantly reduced at the end of the study in the test group (0.42 mm +/- 0.50; p = 0.002), with a similar significant improvement in the healing scores (p = 0.026). CONCLUSION: Within the limitations of this study, immediate implants augmented with ABG/melatonin composite graft would be a valuable option in the esthetic zone. PMID- 29143463 TI - Advances in chronic cerebral circulation insufficiency. AB - Chronic cerebral circulation insufficiency (CCCI) may not be an independent disease; rather, it is a pervasive state of long-term cerebral blood flow insufficiency caused by a variety of etiologies, and considered to be associated with either occurrence or recurrence of ischemic stroke, vascular cognitive impairment, and development of vascular dementia, resulting in disability and mortality worldwide. This review summarizes the features and recent progress of CCCI, mainly focusing on epidemiology, experimental research, pathophysiology, etiology, clinical manifestations, imaging presentation, diagnosis, and potential therapeutic regimens. Some research directions are briefly discussed as well. PMID- 29143464 TI - Mean platelet diameter measurements to classify inherited thrombocytopenias. AB - INTRODUCTION: Mean platelet volume (MPV) assists the differential diagnosis of inherited thrombocytopenia (IT) but lacks standardisation and varies between automated analysers. Classification of IT based on mean platelet diameter (MPD) has been proposed by an international collaborative study but has not been validated. METHODS: To assess the applicability of MPD to classify forms of IT, digital images of blood films from patients with established genetic causes for IT were generated, and the MPD measured (ZEISS Axio-scanner and Image J software) by a blinded reviewer. Comparison was made to the proposed classification system. RESULTS: Mean platelet volume was measured in thrombocytopenia with different genetic aetiologies, bilallelic BSS (bBSS) (n = 1), monoallelic BSS (mBSS) (n = 2), MYH9-related disorders (MYH9-RD) (n = 11), GFI1B-related thrombocytopenia (RT) (n = 15), FLI1-RT (n = 2), TUBB1-RT (n = 3), ITGA2B/ITGB3-RT (n = 1), RUNX1 RT (n = 2) and controls (n = 54). bBSS and 82% of MYH9-RD samples had MPD >4 MUm which correlated with "IT with giant platelets." Only 55% of samples expected in the "large platelet group" had MPD meeting the classification cut-off (MPD >3.2 MUm). FLI1-RT MPD were significantly larger than expected whilst ITGA2B/ITGB3-RT MPD were smaller than proposed. MPD in FPD/AML were "normal." CONCLUSION: Platelet MPD measurements are a useful guide to classify IT, but the time taken to record measurements may limit clinical applicability. PMID- 29143466 TI - Tuberculosis serosurveillance and management practices of captive African elephants (Loxodonta africana) in the Kavango-Zambezi Transfrontier Conservation Area. AB - Transfrontier conservation areas represent an international effort to encourage conservation and sustainable development. Their success faces a number of challenges, including disease management in wildlife, livestock and humans. Tuberculosis (TB) affects humans and a multitude of non-human animal species and is of particular concern in sub-Saharan Africa. The Kavango-Zambezi Transfrontier Conservation Area encompasses five countries, including Zimbabwe, and is home to the largest contiguous population of free-ranging elephants in Africa. Elephants are known to be susceptible to TB; thus, understanding TB status, exposure and transmission risks to and from elephants in this area is of interest for both conservation and human health. To assess risk factors for TB seroprevalence, a questionnaire was used to collect data regarding elephant management at four ecotourism facilities offering elephant-back tourist rides in the Victoria Falls area of Zimbabwe. Thirty-five working African elephants were screened for Mycobacterium tuberculosis complex antibodies using the ElephantTB Stat-Pak and the DPP VetTB Assay for elephants. Six of 35 elephants (17.1%) were seropositive. The risk factor most important for seropositive status was time in captivity. This is the first study to assess TB seroprevalence and risk factors in working African elephants in their home range. Our findings will provide a foundation to develop guidelines to protect the health of captive and free-ranging elephants in the southern African context, as well as elephant handlers through simple interventions. Minimizing exposure through shared feed with other wildlife, routine TB testing of elephant handlers and regular serological screening of elephants are recommended as preventive measures. PMID- 29143465 TI - Migratory birds in southern Brazil are a source of multiple avian influenza virus subtypes. AB - BACKGROUND: There is insufficient knowledge about the relation of avian influenza virus (AIV) to migratory birds in South America. Accordingly, we studied samples obtained over a 4-year period (2009-2012) from wild birds at a major wintering site in southern Brazil. METHODS: We obtained 1212 oropharyngeal/cloacal samples from wild birds at Lagoa do Peixe National Park and screened them for influenza A virus by RT-PCR amplification of the matrix gene. Virus isolates were subjected to genomic sequencing and antigenic characterization. RESULTS: Forty-eight samples of 1212 (3.96%) contained detectable influenza virus RNA. Partial viral sequences were obtained from 12 of these samples, showing the presence of H2N2 (1), H6Nx (1), H6N1 (8), H9N2 (1), and H12N5 (1) viruses. As H6 viruses predominated, we generated complete genomes from all 9 H6 viruses. Phylogenetic analyses showed that they were most similar to viruses of South American lineage. The H6N1 viruses caused no disease signs in infected ferrets and, despite genetic differences, were antigenically similar to North American isolates. CONCLUSIONS: Lagoa do Peixe National Park is a source of multiple AIV subtypes, with the levels of influenza virus in birds being highest at the end of their wintering period in this region. H6N1 viruses were the predominant subtype identified. These viruses were more similar to viruses of South American lineage than to those of North American lineage. PMID- 29143467 TI - Kawasaki disease: An ongoing challenge. PMID- 29143468 TI - Predictive QSAR modeling study on berberine derivatives with hypolipidemic activity. AB - Berberine (BBR), isolated from a Chinese herb, is identified as a new cholesterol lowering small molecule, and hundreds of berberine derivatives have been obtained for optimization of their hypolipidemic activities in recent years. However, so far there is no available quantitative structure-activity relationship (QSAR) model used for the development of novel BBR analogues with hypolipidemic activities, mainly due to lack of lipid-lowering molecular mechanisms and target identification of BBR. In this paper, the tactics using ligand efficiency indice instead of pIC50 as the activity could be adopted for the development of BBR QSAR models. A series of 59 BBR derivatives with hypolipidemic activities have been studied and split randomly into three sets of training and test sets. Statistical quality of most building models shows obviously robust. Best calculated model that employs LLE indice as the activity (Model 6) has the following statistical parameters: for training set R2 = .984, Q2 = 0.981, RMSE = 0.1160, and for test set R2 = .989, RMSE = 0.0067. This model would be used for the development of novel BBR analogues with lipid-lowering activities as a hit discovery tool. PMID- 29143469 TI - Reaction of Thiocarbonyl Fluoride Generated from Difluorocarbene with Amines. AB - The reaction of thiocarbonyl fluoride, generated from difluorocarbene, with various amines under mild conditions is described. Secondary amines, primary amines, and o-phenylenediamines are converted to thiocarbamoyl fluorides, isothiocyanates, and difluoromethylthiolated heterocycles, respectively. Thiocarbamoyl fluorides were further transformed into trifluoromethylated amines by using a one-pot process. Thiocarbonyl fluoride is generated in situ and is rapidly fully converted in one pot under mild conditions; therefore, no special safety precautions are needed. PMID- 29143470 TI - November 2017 at a glance: quality of care and disease management. PMID- 29143471 TI - Ethnic differences in stratum corneum functions between Chinese and Thai infants residing in Bangkok, Thailand. AB - BACKGROUND/OBJECTIVES: Ethnic and racial differences in infant skin have not been well characterized. The purpose of this study was to establish whether there are ethnic differences and similarities in the stratum corneum (SC) functions of Thai and Chinese infants. METHODS: Healthy infants 6 to 24 months of age (N = 60; 30 Thai, 30 Chinese) who resided in Bangkok, Thailand, were enrolled. Transepidermal water loss (TEWL) and SC hydration (capacitance) on the thigh, buttock, and upper arm were measured. Ceramide content was determined in the SC on the upper arm. RESULTS: SC hydration was not remarkably different between the two ethnicities at any site measured, but TEWL was significantly higher in Chinese infants than in Thai infants at all sites. Hydration of the SC was not significantly correlated with age in either ethnicity. TEWL had significant but weak correlations with age on the thigh and upper arm in Thai infants. Ceramide content was significantly higher in Chinese SC than in Thai SC. No relationship between ceramide content and TEWL or hydration was observed in either ethnicity. CONCLUSION: The significant differences in TEWL and ceramide contents between Chinese and Thai infant skin could prove useful in designing skin care and diapering products that are best suited for each ethnicity. PMID- 29143472 TI - Mindreading and Psycholinguistic Approaches to Perspective Taking: Establishing Common Ground. AB - In this commentary on "Memory and Common Ground Processes in Language Use," I draw attention to relevant work on mindreading. The concerns of research on common ground and mindreading have significant overlap, but these literatures have worked in relative isolation of each other. I attempt an assimilation, pointing out shared and distinctive concerns and mutually informative results. PMID- 29143473 TI - Synthesis and Application of Rylene Imide Dyes as Organic Semiconducting Materials. AB - Rylene imide dyes have been among the most promising organic semiconducting materials for several years due to their remarkable optoelectronic properties and high chemical/thermal stability. In the past decades, various excellent rylene imide dyes have been developed for optoelectronic devices, such as organic solar cells (OSCs) and organic field-effect transistors (OFETs). Recently, tremendous progress of perylene diimides (PDIs) and their analogues for use in OSCs has been achieved, which can be attributed to their ease of functionalization. In this review, we will mainly focus on the synthetic strategies toward to latest PDI dyes and higher rylene imide analogues. A variety of compounds synthesized from different building blocks are summarized, and some properties and applications are discussed. PMID- 29143474 TI - Chronic intestinal pseudo-obstruction: Progress in management? AB - Chronic intestinal pseudo-obstruction (CIPO) is a severe form of gastrointestinal dysmotility (often due to derangement of the innervation/smooth muscle/interstitial cells of Cajal) with recurrent episodes of intestinal subocclusion mimicking a mechanical obstruction. Because of its complexity and heterogeneity, CIPO is often misdiagnosed or remains unrecognized until advanced stages. Management is a critical aspect in CIPO patient care. So far, most prokinetic drugs have not proven efficacy in restoring intestinal propulsion, thus nutritional support, fluid/electrolyte replacement, and antibiotics are the mainstay of treatment. In this issue of the journal, Ohkubo et al showed promising data indicating that percutaneous endoscopic gastro-jejunostomy (PEG-J) can be proposed as a measure for intestinal decompression, thereby improving CIPO associated abdominal symptoms, including pain. In addition to a concise update of clinical and diagnostic features, the present minireview tackles management options, with a major emphasis on PEG-J, for CIPO patients. PMID- 29143476 TI - Differences in innervated neurons of the internal anal sphincter based on age and sex: A histological study. AB - AIM: Previous studies have shown sex and age differences in anal sphincter function, but few morphological studies have focused on the quality and quantity of the nerves that control the sphincter muscles. The present study aimed to determine whether there are morphological and quantitative sex and age differences in the nerves in the conjoined longitudinal muscle. METHODS: This was a single-center, retrospective study using surgical specimens from 44 patients who underwent abdominoperineal resection between 2003 and 2012. Hematoxylin-eosin and S-100-stained peripheral nerves (nerve fibers and ganglion cells) in the conjoined longitudinal muscle beneath the dentate line were observed microscopically. A qualitative examination assessed the degeneration score, which was based on the presence or absence of karyopyknosis, vacuolar degeneration, acidophilic degeneration of the cytoplasm, denucleation and adventitial neuronal changes. For quantitative examinations, each neuronal and muscular area was traced to calculate the neuronal area ratio in S-100-immunostained photomicrographs at the observation site. RESULTS: Women had a significantly lower quantity of nerves than men. Older individuals (aged >=80 years) had a significantly lower quantity of nerves than younger individuals. Furthermore, older individuals tended to show greater morphological changes that appeared to be a result of degeneration. CONCLUSIONS: The present findings suggest that anal hypofunction in women and older individuals might result from differences in the quantity and quality of the neurons controlling the anal sphincter muscle. Geriatr Gerontol Int 2018; 18: 495-500. PMID- 29143475 TI - Amygdala sub-regional functional connectivity predicts anxiety in children with reading disorder. AB - Pediatric reading disorder (RD) is associated with an increased risk of anxiety symptoms, yet understudied are the neurobiological factors that might underlie anxiety in children with RD. Given the role of the amygdala in anxiety, we assessed resting state functional connectivity of amygdalar subregions in children with RD to identify functional correlates of anxiety and reading impairment. We collected resting state functional MRI data from 22 children with RD and 21 typically developing (TD) children, ages 7 to 13 years. We assessed group differences in resting state functional connectivity (RSFC) from amygdalar subregions. Associations of amygdalar RSFC and volume with reading impairment, reading fluency scores, and anxiety symptoms were explored. Relative to TD children, those with RD showed increased RSFC from amygdalar nuclei to medial prefrontal cortex. Across all subjects, RSFC from right centromedial amygdala to left medial prefrontal cortex positively predicted both reading impairment and self-reported anxiety, and anxiety mediated the relationship between RSFC and reading impairment. These findings are consistent with amygdalar functional abnormalities in pediatric anxiety disorders, suggesting a common neurobiological mechanism underlying anxiety and reading impairment in children. Thus, aberrant patterns of RSFC from amygdalar subregions may serve as potential targets for the treatment of anxiety symptoms that typically co-occur with RD. Our dimensional approach to studying anxiety in RD revealed how amygdalar connectivity underlies anxiety and reading impairment across a continuum from normal to abnormal. PMID- 29143478 TI - Regio- and Stereoselective Iron-Catalyzed Oxyazidation of Enamides Using a Hypervalent Iodine Reagent. AB - A novel regio- and diastereoselective iron-catalyzed intermolecular oxyazidation of enamides using various azidobenziodoxolone (ABX) derivatives is presented. A variety of alpha-N3 amino derivatives and of alpha-N3 piperidines were synthesized in good yields and under mild reaction conditions. The reaction involves a radical process using cheap FeCl2 as the initiator. PMID- 29143477 TI - Gastric venous congestion and bleeding in association with total pancreatectomy. AB - BACKGROUND: Gastric venous congestion and bleeding in association with total pancreatectomy (TP) were evaluated. METHODS: Thirty-eight patients of TP were retrospectively analyzed. TP was classified as TP with distal gastrectomy (TPDG), pylorus-preserving TP (PPTP), subtotal stomach-preserving TP (SSPTP), and TP with segmental duodenectomy (TPSD). RESULTS: Portal vein or superior mesenteric vein resection and reconstruction was performed in 24 patients (62.2%). Gastric bleeding occurred immediately after tumor resection in one of eight patients who underwent SSPTP, and urgent anastomosis between the right gastroepiploic and left ovarian vein stopped the bleeding. Another case of gastric bleeding was observed a few hours after TP in one of nine patients who underwent PPTP, and hemostasis was achieved after conservative therapy. Gastric bleeding was not observed in 16 patients who underwent TPDG and five who underwent TPSD. Some patients underwent preservation of gastric drainage veins (left gastric vein, right gastric vein, or right gastroepiploic vein). Neither patient with bleeding underwent preservation of a gastric drainage vein. CONCLUSIONS: To preserve the subtotal or whole stomach when performing TP, one of the gastric drainage veins should undergo preservation or reconstruction, and anastomosis between the right gastroepiploic vein and left ovarian vein may be beneficial. PMID- 29143479 TI - Encapsulation of rifampin in a polymeric layer-by-layer structure for drug delivery. AB - Rifampin (RIF) is a bactericidal antibiotic drug and potent inducer of hepatic and intestinal cytochrome P-450 (CYP-450) enzyme systems. Given by mouth or intravenously, it can cause numerous clinical drug interactions; thus, alternative systems of drug delivery that bypass some or all of its toxic effects are well worth investigating. In this study, a controlled layer-by-layer (LBL) process of encapsulating RIF in biocompatible alginate and chitosan polymers loaded onto Fe3 O4 nanoparticles was developed. Fe3 O4 nanoparticles were synthesized from FeCl3 .6H2 O using a hydrothermal procedure. Fluorescent molecular beacons containing RIF molecules and Texas Red were loaded onto the surfaces of Fe3 O4 nanoparticles. The loaded nanoparticles were encapsulated in alginate and chitosan layers with alternating negative and positive surface charge using an LBL self-assembly method. Subsequently, by removing the Fe3 O4 template particles, polymeric capsules containing RIF were obtained. Ultraviolet visible spectrophotometry employed to determine optimized conditions for loading RIF, measure the amount of RIF loaded onto the surface of the nanoparticles under optimized conditions, and study drug-release capability. Scanning electron microscopy was used to characterize the morphology of unloaded and loaded nanoparticles. X-ray diffraction and Fourier transform infrared spectroscopy were applied to demonstrate the production of nanoparticles and loading of RIF onto them. Zeta potential analysis was used to determine the size and surface potential of the loaded polymeric layers. After removal of the core template, confocal fluorescence microscopy was used to isolate polymeric capsules containing RIF. The average size of the nanoparticles obtained was 23 nm. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 905-913, 2018. PMID- 29143480 TI - Telephone discharge support for frail, vulnerable older people discharged from hospital: Impact on readmission rates - Participant and general practitioner feedback. AB - OBJECTIVE: To assess the use and acceptability to older participants and general practitioners (GPs) of telephone support postdischarge to reduce readmissions. METHODS: A prospective cohort study of older people after discharge from a specialist geriatric unit, and comparison with a previous cohort. Telephone follow-up calls were made fortnightly for three months. Structured questionnaires were used to obtain feedback from participants and GPs. RESULTS: Readmission rates were high, 40%, despite the intervention. This rate had significantly increased since the earlier cohort. Almost one-fifth of the sample (19%) were readmitted before the first telephone call. Subsequent readmissions were not related to whether participants had reported deteriorating health during the preceding telephone call. Feedback on the intervention from both participants and GPs was supportive. CONCLUSIONS: Telephone follow-up as we used it did not reduce readmission rates. However, it was well received and appreciated by participants. It is possible the telephone calls were not made early enough or frequently enough to achieve the desired outcome. PMID- 29143481 TI - Decisional regret and choice of breast reconstruction following mastectomy for breast cancer: A systematic review. AB - OBJECTIVE: Women facing mastectomy for breast cancer should have the option of considering whether they would like breast reconstruction (BR), and if so, what type and when. Previous research has demonstrated that some women will come to regret their decision about BR. We aim to summarise the evidence about the prevalence of decisional regret (DR) associated with BR choices and identify factors influencing vulnerability to DR. METHODS: A systematic review of the literature reporting BR-related DR published between January 1994 and February 2017 identified 254 initial search results. Thirteen publications from 12 studies (5672 participants) met the selection criteria and were included in the final review. Each article was allocated a quality score out of 24. RESULTS: Overall, DR levels were reported as low and stable, although direct comparison across studies was limited by inconsistencies in measurement and reporting methods. Estimates of DR scores ranged from 9.3/100 to 5.4/20. All studies identified a relationship between higher levels of DR and an insufficient amount, inadequate quality, or unclear nature of information provided to women prior to undergoing mastectomy. A major determinant of DR was new or recurrent cancer, while psychosocial characteristics including depression, distress, and negative body image increased the likelihood of DR. CONCLUSION: The available research is yet to provide a clear understanding of the many interrelated issues involved in DR. Given the consensus that presurgical information was inadequate, making standardised educational material more widely available and increasing use of breast care nurses in preoperative patient education roles may be useful. PMID- 29143482 TI - Incorporating emerging fields in medical education. PMID- 29143483 TI - The impact of mental health comorbidities on adherence to buprenorphine: A claims based analysis. AB - BACKGROUND AND OBJECTIVES: Previous research has been inconclusive about whether opioid-dependent patients with psychiatric comorbidities have shorter treatment retention and higher relapse rates. This study aims to evaluate the impact of mental health comorbidities on adherence to buprenorphine using a large, national health insurance claims data base. METHODS: We used MarketScan(r) data from 2012 to 2014 to perform this analysis. Inclusion criteria included all patients with an opioid use disorder-related ICD-9 code who had been prescribed buprenorphine (n = 2947). Medication adherence was defined using the Medication Possession Ratio >=.8 (MPR) and logistic regression was used to examine the association between medication adherence and mental health diagnoses, which included Alzheimer's/dementia, schizophrenia, other psychosis, major depressive disorder/bipolar disorder (MDDBP), anxiety disorder, personality disorder, and mental health disorder not elsewhere specified (NOS). RESULTS: Of the 2947 patients included in our analysis, the most common diagnoses were anxiety disorder: n = 648 (22.0%), MDDBP: n = 467 (15.9%), and mental health disorder NOS: n = 959 (32.5%). Patients diagnosed with MDDBP were significantly less likely to adhere to opioid pharmacotherapy (OR = .805, 95%CI = .651, .994) than patients without MDDBP. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The presence of a psychiatric comorbidity can significantly affect adherence to buprenorphine. These trends illustrate the need for clinicians treating opioid use disorder with buprenorphine to screen for psychiatric disorders and monitor their medication adherence. There may also be opportunities to design interventions to help this vulnerable population adhere to buprenorphine and other forms of opioid pharmacotherapy. (Am J Addict 2017;26:859-863). PMID- 29143484 TI - Response of Red Blood Cell Folate to Supplementation in Nonpregnant Women is Predictable: A Proposal for Personalized Supplementation. AB - SCOPE: We modeled red blood cell (RBC)-folate response to supplementation and developed personalized folate supplementation concepts. METHODS AND RESULTS: The changes of RBC-folate were modeled in a time- (4 or 8 weeks) and dose- (400 or 800 MUg d-1 folate) dependent manner. Post-supplementation RBC-folate levels were predicted from folate-loading capacities (= measured RBC-folate - [baseline RBC folate * RBC-survival]). The prediction equations were validated in 119 participants. The median increase of RBC-folate was higher in the 800 MUg d-1 than in the 400 MUg d-1 group (275 vs 169 nmol L-1 after 4 weeks, and 551 vs 346 nmol L-1 after 8 weeks). Medians (interquartile range) of RBC-folate loading were (4 weeks: 299 (160) vs 409 (237) nmol L-1 ) and (8 weeks: 630 (134) versus 795 (187) nmol L-1 ) in the 400 and 800 MUg d-1 group, respectively. The individual measured and predicted RBC-folate values (after 4 weeks/400 MUg d-1 = 25 + 1.27 * baseline RBC-folate) and (after 4 weeks/800 MUg d-1 = 65 + 1.41 * baseline RBC folate) did not differ significantly. The measured and predicted concentrations showed high agreement in the validation cohort. CONCLUSIONS: The models can guide nutritional recommendations in women when baseline RBC-folate concentrations are measured and the time to pregnancy between 4 and 8 weeks. PMID- 29143485 TI - Synthesis, molecular modeling, and biological evaluation of 4-[5-aryl-3-(thiophen 2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides toward acetylcholinesterase, carbonic anhydrase I and II enzymes. AB - In this study, 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides were synthesized, and inhibition effects on AChE, hCA I, and hCA II were evaluated. Ki values of the compounds toward hCA I were in the range of 24.2 +/- 4.6-49.8 +/- 12.8 nm, while they were in the range of 37.3 +/- 9.0 65.3 +/- 16.7 nm toward hCA II. Ki values of the acetazolamide were 282.1 +/- 19.7 nm and 103.60 +/- 27.6 nm toward both isoenzymes, respectively. The compounds inhibited AChE with Ki in the range of 22.7 +/- 10.3-109.1 +/- 27.0 nm, whereas the tacrine had Ki value of 66.5 +/- 13.8 nm. Electronic structure calculations at M06-L/6-31 + G(d,p)//AM1 level and molecular docking studies were also performed to enlighten inhibition mechanism and to support experimental findings. Results obtained from calculations of molecular properties showed that the compounds obey drug-likeness properties. The experimental and computational findings obtained in this study might be useful in the design of novel inhibitors against hCA I, hCA II, and AChE. PMID- 29143486 TI - Violent behaviour in early psychosis patients: Can we identify clinical risk profiles? AB - AIMS: The objective of this study is to explore, within a sample of early psychosis patients (EPP), if subgroups regarding rate of violent behaviour (VB) against others can be identified on the basis of dynamic risk factors (treatment modifiable characteristics). METHODS: In a sample of 265 EPP, treated at the Treatment and Early Intervention in Psychosis Program in Lausanne, we conducted a latent-class analysis on the basis of the main dynamic VB risk factors (substance use disorder [SUD], positive symptoms, insight, and impulsivity). VB were restricted to "serious violence" and were assessed through patients self-report, interview with relatives or forensic services and with a standardized instrument. RESULTS: The analysis confirmed the heterogeneity of the sample regarding rate of VB. Patients could be stratified within 4 subgroups, 3 of which were at increased risk of VB. The two groups with the highest rates of VB displayed specific clinical profiles. The first one was characterized by high levels of impulsivity, hostility, positive symptoms and SUD, and the second, by low level of insight and low social functioning. These patterns suggest that significant difficulties in social interaction may contribute to the emergence of aggressive reactions against others. CONCLUSIONS: Identification of EPP at increased risk of VB seems possible on the basis of dynamic risk factors. If confirmed prospectively, this could pave the way to the development of preventive strategies and specific interventions. PMID- 29143487 TI - Nurses' implementation of ventilator-associated pneumonia prevention guidelines: an observational study in Jordan. AB - BACKGROUND: Ventilator-associated pneumonia prevention guidelines from the Center for Disease Control and Prevention, the American Thoracic Society, and the Institute for Health Care and Improvement have been published to reduce the rate of ventilator-associated pneumonia in the clinical settings; however, nurses' compliance with these guidelines is still questionable. AIMS: The purpose of this study was to assess nurses' compliance with ventilator-associated pneumonia prevention guidelines and the factors that influence their compliance. DESIGN: A structured observational design with a non-participant approach. METHOD: One hundred nurses were observed during their care for patients on mechanical ventilator. The observers documented nurses' implementation of ventilator associated pneumonia prevention guidelines using a structured observational sheet. RESULTS: Compliance of nurses was found to be unsatisfactory. Of the participants, 63% showed 'insufficient compliance'. Nurses working in units with a 1:1 nurse:patient ratio and lower beds' capacity demonstrated higher compliance and their intensive care units had a lower rate of ventilator-associated pneumonia and shorter intensive care unit stay in comparison with their counterparts working with a 1:2 nurse:patient ratio and higher beds' capacity. CONCLUSION: Nurses' compliance with ventilator-associated pneumonia prevention guidelines was insufficient. Low nurse-patient ratio and large intensive care unit beds capacity were found to affect nurses' compliance and patients' outcomes. This study expanded knowledge about important aspects of nursing care; nurses' compliance with ventilator-associated pneumonia prevention guidelines and the factors that affect their compliance. This knowledge can be used by health professional to guide the clinical practice and to improve the quality of care. PMID- 29143488 TI - Isolation and characterization of novel goose parvovirus-related virus reveal the evolution of waterfowl parvovirus. AB - Short beak and dwarfism syndrome (SBDS) has been constantly breaking out in China since 2015. It is caused by a novel goose parvovirus-related virus (NGPV) and can severely restrict the growth of ducks. In this study, seven NGPV stains were isolated from different regions in China between 2015 and 2016. To better understand the correlation between NGPV and goose parvovirus (GPV), we conducted complete genome sequencing and a comprehensive analysis of the NGPV genome. The phylogenetic and alignment analysis showed that NGPV is a branch of GPV, sharing 92.2%-97.1% nucleotide identity with GPV. Compared with classical GPV, five consensus nucleotide mutations in all the seven NGPV isolates and two 14 nucleotide-pair deletions in six NGPV isolates were found in the inverted terminal repeats, twelve and eight synchronous amino acid changes were found in the replication protein and capsid protein of NGPV, respectively, which might be important for viral gene regulation, humoral immune responses, and host transfer. Notably, SDLY1602 was demonstrated a recombinant strain, with the potential major parent GPV vaccine strain 82-0321v and the minor parent GPV wild strain GDaGPV. This is the first report showing that the recombination between two classical GPV strains generated a NGPV strain circulating in nature. This study will advance our understanding of NGPV molecular biology and facilitate to elucidate the evolutionary characteristics of GPV. PMID- 29143489 TI - Spatial variation in the parasite communities and genomic structure of urban rats in New York City. AB - Brown rats (Rattus norvegicus) are a globally distributed pest. Urban habitats can support large infestations of rats, posing a potential risk to public health from the parasites and pathogens they carry. Despite the potential influence of rodent-borne zoonotic diseases on human health, it is unclear how urban habitats affect the structure and transmission dynamics of ectoparasite and microbial communities (all referred to as "parasites" hereafter) among rat colonies. In this study, we use ecological data on parasites and genomic sequencing of their rat hosts to examine associations between spatial proximity, genetic relatedness and the parasite communities associated with 133 rats at five sites in sections of New York City with persistent rat infestations. We build on previous work showing that rats in New York carry a wide variety of parasites and report that these communities differ significantly among sites, even across small geographical distances. Ectoparasite community similarity was positively associated with geographical proximity; however, there was no general association between distance and microbial communities of rats. Sites with greater overall parasite diversity also had rats with greater infection levels and parasite species richness. Parasite community similarity among sites was not linked to genetic relatedness of rats, suggesting that these communities are not associated with genetic similarity among host individuals or host dispersal among sites. Discriminant analysis identified site-specific associations of several parasite species, suggesting that the presence of some species within parasite communities may allow researchers to determine the sites of origin for newly sampled rats. The results of our study help clarify the roles that colony structure and geographical proximity play in determining the ecology of R. norvegicus as a significant urban reservoir of zoonotic diseases. Our study also highlights the spatial variation present in urban rat parasite communities, indicating that rats across New York City are not reservoirs for a homogenous set of parasites and pathogens. As a result, the epidemiological risks may be similarly heterogeneous for people in urban habitats. PMID- 29143490 TI - Rock glaciers in crystalline catchments: Hidden permafrost-related threats to alpine headwater lakes. AB - A global warming-induced transition from glacial to periglacial processes has been identified in mountainous regions around the world. Degrading permafrost in pristine periglacial environments can produce acid rock drainage (ARD) and cause severe ecological damage in areas underlain by sulfide-bearing bedrock. Limnological and paleolimnological approaches were used to assess and compare ARDs generated by rock glaciers, a typical landform of the mountain permafrost domain, and their effects on alpine headwater lakes with similar morphometric features and underlying bedrock geology, but characterized by different intensities of frost action in their catchments during the year. We argue that ARD and its effects on lakes are more severe in the alpine periglacial belt with mean annual air temperatures (MAAT) between -2 degrees C and +3 degrees C, where groundwater persists in the liquid phase for most of the year, in contrast to ARD in the periglacial belt where frost action dominates (MAAT < -2 degrees C). The findings clearly suggest that the ambient air temperature is an important factor affecting the ARD production in alpine periglacial environments. Applying the paleoecological analysis of morphological abnormalities in chironomids through the past millennium, we tested and rejected the hypothesis that unfavorable conditions for aquatic life in the ARD-stressed lakes are largely related to the temperature increase over recent decades, responsible for the enhanced release of ARD contaminants. Our results indicate that the ARDs generated in the catchments are of a long-lasting nature and the frequency of chironomid morphological deformities was significantly higher during the Little Ice Age (LIA) than during pre- or post-LIA periods, suggesting that lower water temperatures may increase the adverse impacts of ARD on aquatic invertebrates. This highlights that temperature-mediated modulations of the metabolism and life cycle of aquatic organisms should be considered when reconstructing long-term trends in the ecotoxicological state of lakes. PMID- 29143491 TI - Fine needle aspiration evaluation of pancreatic lymphoma: A retrospective study of 25 cases in a single institution. AB - BACKGROUND: Accurate diagnosis of pancreatic lymphoma is crucial for clinical management. We evaluate the role of fine-needle aspiration (FNA) in the diagnosis of pancreatic lymphoma with the aid of flow cytometry and/or immunohistochemistry on the cell block. METHODS: Cases of pancreatic lymphoma were collected by searching our pathology laboratory information system over a period of 16 years. The clinical findings, cytologic features, and immunophenotypic results were reviewed. The diagnoses of FNA were correlated with surgical specimens in a subset of FNA cases. RESULTS: A total of 25 FNA cases of pancreatic lymphoma were included. The most common type of pancreatic lymphoma was large B cell lymphoma followed by follicular lymphoma. With the aid of flow cytometry and immunohistochemical work-up on cell block, 72% (18/25) of the cases were diagnosed as lymphoma and 16% of the cases (4/25) were diagnosed as suspicious for lymphoma by FNA. Only two cases (8%) including one false negative and one nondiagnostic aspirate missed the lymphoma diagnosis and 1 case (4%) was indeterminate by FNA evaluation. CONCLUSION: FNA demonstrated high accuracy in rendering diagnosis of pancreatic lymphoma. The overall sensitivity is 88% and the false negative and nondiagnostic rates are 4%, respectively. Further subtyping of certain lymphomas can be difficult due to the lack of architectural features of FNA specimens. PMID- 29143492 TI - Molecular epidemiological survey and phylogenetic analysis of bovine influenza D virus in Japan. AB - The influenza D virus, a new member of the Orthomyxoviridae family, is predominantly found in cattle. Although viral pathology and clinical disease in cattle appear mild, this virus plays an important role as a trigger of bovine respiratory disease (BRD). BRD is a costly illness worldwide. Thus, epidemiological surveys of the influenza D virus are necessary. Here, we conducted a molecular epidemiological survey for the influenza D virus in healthy and respiratory-diseased cattle in Japan. We found that 2.1% (8/377) of the cattle were infected with influenza D. The cattle with and without respiratory symptoms had approximately equal amounts of the virus. A full-genome sequence analysis revealed that the influenza D virus that was isolated in Japan formed an individual cluster that was distinct from the strains found in other countries. These results suggest that this virus might have evolved uniquely in Japan over a long period of time and that the viral pathology of Japanese strains might be different from the strains found in other countries. Continuous surveillance is required to determine the importance of this virus and to characterize its evolution. PMID- 29143493 TI - Recurrent sublethal warming reduces embryonic survival, inhibits juvenile growth, and alters species distribution projections under climate change. AB - The capacity to tolerate climate change often varies across ontogeny in organisms with complex life cycles. Recently developed species distribution models incorporate traits across life stages; however, these life-cycle models primarily evaluate effects of lethal change. Here, we examine impacts of recurrent sublethal warming on development and survival in ecological projections of climate change. We reared lizard embryos in the laboratory under temperature cycles that simulated contemporary conditions and warming scenarios. We also artificially warmed natural nests to mimic laboratory treatments. In both cases, recurrent sublethal warming decreased embryonic survival and hatchling sizes. Incorporating survivorship results into a mechanistic species distribution model reduced annual survival by up to 24% compared to models that did not incorporate sublethal warming. Contrary to models without sublethal effects, our model suggests that modest increases in developmental temperatures influence species ranges due to effects on survivorship. PMID- 29143495 TI - Palliative care in residential aged care: An overview. AB - OBJECTIVE: To measure how care needs, health and length of stay in permanent residential aged care differs by assessed need for palliative care. METHODS: On entry into permanent residential aged care, people's care needs and health conditions are assessed on the Aged Care Funding Instrument. Data for the period 2008-2009 and 2015-2016 were analysed for trends in care needs, health conditions, length of stay and separation reason across assessed need for palliative care. RESULTS: Assessed care needs have increased for all people in residential aged care over this period, and people appraised for palliative care were more likely to be rated 'high' in need for support in activities of daily living. People appraised for palliative care had a higher prevalence of cancer and shorter length of stays. CONCLUSION: Palliative care appraisal is associated with increased complexity in assessed care needs, different profiles of health and shorter length of stays in permanent residential aged care. PMID- 29143496 TI - Does the Serotonin2C receptor segregate circuits of the basal ganglia responding to cingulate cortex stimulation? PMID- 29143494 TI - Continental mapping of forest ecosystem functions reveals a high but unrealised potential for forest multifunctionality. AB - Humans require multiple services from ecosystems, but it is largely unknown whether trade-offs between ecosystem functions prevent the realisation of high ecosystem multifunctionality across spatial scales. Here, we combined a comprehensive dataset (28 ecosystem functions measured on 209 forest plots) with a forest inventory dataset (105,316 plots) to extrapolate and map relationships between various ecosystem multifunctionality measures across Europe. These multifunctionality measures reflected different management objectives, related to timber production, climate regulation and biodiversity conservation/recreation. We found that trade-offs among them were rare across Europe, at both local and continental scales. This suggests a high potential for 'win-win' forest management strategies, where overall multifunctionality is maximised. However, across sites, multifunctionality was on average 45.8-49.8% below maximum levels and not necessarily highest in protected areas. Therefore, using one of the most comprehensive assessments so far, our study suggests a high but largely unrealised potential for management to promote multifunctional forests. PMID- 29143497 TI - Detection and monitoring of driver mutations by next-generation sequencing in squamous cell lung cancer patient and possible predictive biomarker of third generation EGFR-tyrosine kinase inhibitors. AB - Driver mutation detection and the development of targeted drugs have significantly improved survival of advanced lung adenocarcinoma patients with driver mutations. However, we still lack understanding of druggable mutations in patients with advanced squamous cell lung cancer (SQCLC). Less than 10% of SQCLC patients have EGFR gene mutations, thus we have limited knowledge of biological molecular changes with first generation EGFR-tyrosine kinase inhibitor (TKI) resistance. We report a case of an SQCLC patient treated with first-line platinum doublet chemotherapy. After disease progression, the patient was administered first generation EGFR-TKI gefitinib based on next generation sequencing results. After five months, a second biopsy was performed and both the tumor and plasma samples indicated an acquired EGFR exon 20 T790M mutation. The patient was subsequently administered AZD9291, which resulted in disease control for a time. Our results indicate that a TP53 exon 8 mutation might act as a negative predictive biomarker for third generation EGFR-TKIs. PMID- 29143499 TI - ? PMID- 29143498 TI - Rationale and opportunities in estimating the economic burden of seasonal influenza across countries using a standardized WHO tool and manual. AB - Influenza disease burden is recognized as one of the major public health problems globally. Much less is known about the economic burden of influenza especially in low- and middle-income countries (LMICs). A recent systematic review on the economic burden of influenza in LMICs suggests that information is scarce and/or incomplete and that there is a lack of standardized approaches for cost evaluations in LMICs. WHO commissioned and publicized a Manual for estimating the economic burden of seasonal influenza to support the standardization of estimates of the economic burden of seasonal influenza across countries. This article aims to describe the rationale of this manual development and opportunities that lie in collecting data to help policymakers estimate the economic burden of seasonal influenza. It describes a manual developed by WHO to help such estimation and also links to relevant literature and tools to ensure robustness of applied methods to assess the economic burden associated with seasonal influenza, including direct medical costs, direct non-medical costs and indirect costs. PMID- 29143500 TI - [Pulmonary hypertension and pregnancy]. AB - Pregnancy in the context of pulmonary hypertension is characterised by high mortality for the mother and the foetus and is therefore strongly discouraged ; contraception has to be prescribed to patients in reproductive age. Women who decide to continue their pregnancy should be followed by multidisciplinary teams in specialised centres. A specific treatment should be defined with no delay. In case of clinical deterioration, the early, intravenous administration of prostacyclin should be considered. The ideal time and method of delivery are still disputed. PMID- 29143501 TI - [The place of balloon pulmonary angioplasty in the management of chronic thromboembolic pulmonary hypertension]. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is uncommon. Its diagnosis should not be delayed as its prognosis is poor if not treated. In most cases, an acute pulmonary embolism is found in the medical history of the patient. Once suspected, a specific work-up should be performed in a pulmonary hypertension (PH) center. The ventilation/perfusion scan has a central role in this workup but the emergence of non invasive imaging technologies provides morphological and functional information which take part in the therapeutic decision making, such as operability. Surgical endarterectomy remains the only curative treatment. In some specific patients, percutaneous transluminal pulmonary angioplasty (AAP) is performed. This developing technique is a safe and efficient treatment on a clinical and hemodynamic standpoint. The main complication after AAP is lung reperfusion edema. PMID- 29143502 TI - [Exercise-induced bronchoconstriction: epidemiology, physiopathology and management]. AB - Exercise-induced bronchoconstriction, associated or not with asthma, describes a transient limitation of airflow in the airways occurring during or after physical activity, regardless of age or training. Bronchoconstriction on exertion is principally induced by thermal and fluid losses of the bronchial mucosa by hyperventilation of large air volumes. Respiratory symptoms are variable and not specific. Among bronchial provocation test, eucapnic voluntary hyperventilation owns the best sensitivity and specificity in the diagnosis of exercise-induced bronchoconstriction. Therapeutic management consists in an adjustment of the environment and training, as well as bronchodilators. PMID- 29143503 TI - [Lung and pleural space ultrasonography for pulmonologist]. AB - In the past twenty years ultrasound has been the subject of renewed interest in lung exploration in the broad sense. The necessity of accessing a means of rapid exploration at the bed of the patient in a critical situation has led to the development of a pleuro-pulmonary ultrasound semiology to make it a diagnostic tool of choice which exceeds the strict framework intensive care units and emergency services. With the diagnosis of thoracic tumors or the exploration of interstitial syndromes, it tends to integrate more into the daily practice of the pulmonologist. This article is a review of the possibilities offered by ultrasound in the field with its advantages and limitations. PMID- 29143504 TI - [Living with bronchiectasis]. AB - Bronchiectasis is a chronic condition with a prevalence continuously on the rise. Bronchiectasis have a considerable impact on morbidity, healthcare utilization and quality of life. Pulmonary function tests, microbiological variables and exacerbation rate are useful in the initial and follow-up evaluation. Scores that combine those variables with chest CT findings have been established to predict hospitalizations and mortality. Assessment of health-related quality of life cannot rely on physiological variables measurement. Dedicated questionnaires are therefore needed for that purpose. PMID- 29143505 TI - [Inhaled antibiotics for the management of non cystic fibrosis bronchiectasis]. AB - Bronchiectasis is irreversible bronchial dilatation associated with chronic respiratory symptoms. Management is aimed at reducing symptoms and slowing the progression of the disease by interrupting the vicious circle: bronchial infection, inflammation, altered mucociliary clearance, lung destruction. Unlike the literature on inhaled antibiotics in cystic fibrosis, literature data are limited and of low quality for bronchiectasis of other causes. However, new recommendations from the European Respiratory Society propose the conditional use of inhaled antibiotics to prevent repeated infectious exacerbations and to eradicate Pseudomonas aeruginosa colonization. PMID- 29143507 TI - ? PMID- 29143506 TI - ? PMID- 29143508 TI - ? PMID- 29143509 TI - ? PMID- 29143510 TI - ? PMID- 29143512 TI - ? PMID- 29143511 TI - ? PMID- 29143513 TI - Safety of Degludec versus Glargine in Type 2 Diabetes. PMID- 29143514 TI - Safety of Degludec versus Glargine in Type 2 Diabetes. PMID- 29143515 TI - Safety of Degludec versus Glargine in Type 2 Diabetes. PMID- 29143516 TI - Cognitive Function in a Randomized Trial of Evolocumab. PMID- 29143517 TI - Advanced Non-Small-Cell Lung Cancer. PMID- 29143518 TI - Advanced Non-Small-Cell Lung Cancer. PMID- 29143519 TI - Advanced Non-Small-Cell Lung Cancer. PMID- 29143520 TI - Health Insurance Coverage and Health. PMID- 29143521 TI - Health Insurance Coverage and Health. PMID- 29143522 TI - MMP-2-Sensitive HA End-Conjugated Poly(amidoamine) Dendrimers via Click Reaction To Enhance Drug Penetration into Solid Tumor. AB - Currently, the limited penetration of nanoparticles remains a major challenge for antitumor nanomedicine to penetrate into the tumor tissues. Herein, we propose a size-shrinkable drug delivery system based on a polysaccharide-modified dendrimer with tumor microenvironment responsiveness for the first time to our knowledge, which was formed by conjugating the terminal glucose of hyaluronic acid (HA) to the superficial amidogen of poly(amidoamine) (PAMAM), using a matrix metalloproteinase-2 (MMP-2)-cleavable peptide (PLGLAG) via click reaction. These nanoparticles had an initial size of ~200 nm, but once deposited in the presence of MMP-2, they experienced a dramatic and fast size change and dissociated into their dendrimer building blocks (~10 nm in diameter) because of cleavage of PLGLAG. This rapid size-shrinking characteristic not only promoted nanoparticle extravasation and accumulation in tumors benefited from the enhanced permeability and retention effect but also achieved faster nanoparticle diffusion and penetration. We have further conducted comparative studies of MMP-2-sensitive macromolecules (HA-pep-PAMAM) and MMP-2-insensitive macromolecules (HA-PAMAM) synthesized with a similar particle size, surface charge, and chemical composition and evaluated in both monolayer cells and multicellular spheroids. The results confirmed that the enzyme-responsive size shrink is an implementable strategy to enhance drug penetration and to improve therapeutic efficacy. Meanwhile, macromolecule-based nanoparticles with size-variable characteristics not only promote drug penetration, but they can also be used as gene delivery systems, suggesting great potential as nano-delivery systems. PMID- 29143523 TI - New Insights into the Electronic Structure and Photoelectrochemical Properties of Nitrogen-Doped HNb3O8 via a Combined in Situ Experimental and DFT Investigation. AB - The nitrogen-doping approach has been intensively adopted to improve various properties of metal oxides, especially for adjusting the energy band structure and extending the photoresponse range of oxide photocatalysts. However, the nitrogen doping behavior is still unintelligible and complex due to the diversity of compositions and crystal structures. In this work, new insights into the electronic structure and photoelectrochemical (PEC) properties of nitrogen-doped HNb3O8 were presented. On the one hand, we utilized an in situ experimental strategy to ascertain the effect of nitrogen doping on the energy band and photoelectrochemical (PEC) properties of HNb3O8 and nitrogen-doped HNb3O8 (N HNb3O8). Their energy band level, donor densities, and interfacial charge transfer properties were studied by Mott-Schottky plots and electrochemical impedance spectroscopy. After nitrogen doping, the conduction band position is unusually descended by 0.23 eV, the valance band position is raised by 0.51 eV, the donor density (Nd) is increased from 3.71 * 1021 to 6.46 * 1021 cm-3, and interfacial charge transfer efficiency is reduced, though. On the other hand, density functional theoretical calculations were also conducted, so as to understand the electronic structures of HNb3O8 and N-HNb3O8. After nitrogen doping, the electronic structure is modified due to the upshift of the valance band edge consisting of hybrid N 2p and O 2p orbitals and the downshift of the conduction band edge consisting of the H 1s and Nb 4d orbitals. Furthermore, these insights into the behavior of nitrogen-doped semiconductors have important guiding significance toward their potential applications. PMID- 29143524 TI - Injectable Shear-Thinning CaSO4/FGF-18-Incorporated Chitin-PLGA Hydrogel Enhances Bone Regeneration in Mice Cranial Bone Defect Model. AB - For craniofacial bone regeneration, shear-thinning injectable hydrogels are favored over conventional scaffolds because of their improved defect margin adaptability, easier handling, and ability to be injected manually into deeper tissues. The most accepted method, after autografting, is the use of recombinant human bone morphogenetic protein-2 (BMP-2); however, complications such as interindividual variations, edema, and poor cost-efficiency in supraphysiological doses have been reported. The endogenous synthesis of BMP-2 is desirable, and a molecule which induces this is fibroblast growth factor-18 (FGF-18) because it can upregulate the BMP-2 expression by supressing noggin. We developed a chitin poly(lactide-co-glycolide) (PLGA) composite hydrogel by regeneration chemistry and then incorporated CaSO4 and FGF-18 for this purpose. Rheologically, a 7-fold increase in the elastic modulus was observed in the CaSO4-incorporated chitin PLGA hydrogels as compared to the chitin-PLGA hydrogel. Shear-thinning Herschel Bulkley fluid nature was observed for both hydrogels. Chitin-PLGA/CaSO4 gel showed sustained release of FGF-18. In vitro osteogenic differentiation showed an enhanced alkaline phosphatase (ALP) expression in the FGF-18-containing chitin PLGA/CaSO4 gel when compared to cells alone. Further, it was confirmed by studying the expression of osteogenic genes [RUNX2, ALP, BMP-2, osteocalcin (OCN), and osteopontin (OPN)], immunofluorescence staining of BMP-2, OCN, and OPN, and alizarin red S staining. Incorporation of FGF-18 in the hydrogel increased the endothelial cell migration. Further, the regeneration potential of the prepared hydrogels was tested in vivo, and longitudinal live animal MU-CT was performed. FGF-18-loaded chitin-PLGA/CaSO4 showed early and almost complete bone healing in comparison with chitin-PLGA/CaSO4, chitin-PLGA/FGF-18, chitin-PLGA, and sham control systems, as confirmed by hematoxylin and eosin and osteoid tetrachrome stainings. This shows that the CaSO4 and FGF-18-incorporated hydrogel is a potential candidate for craniofacial bone defect regeneration. PMID- 29143525 TI - Sweritranslactones A-C: Unusual Skeleton Secoiridoid Dimers via [4 + 2] Cycloaddition from Swertiamarin. AB - Skeleton-diversity-oriented chemical conversion from pure natural products is a valuable method to obtain natural product-like compounds, especially those with novel architecture. The application of phytochemical methods to iridoids yielded three novel secoiridoid dimers: sweritranslactones A-C (1-3). These molecules possess a 6/6/6/6/6/6-fused hexacyclic skeleton and were obtained from swertiamarin, one of the major constituents of the genus Swertia, via a [4 + 2] cycloaddition and intramolecular nucleophilic addition under aqueous conditions. The structures were established based on extensive spectroscopic characterization and X-ray crystallographic diffraction analysis. PMID- 29143526 TI - Two-Dimensional Semiconducting Boron Monolayers. AB - The two-dimensional boron monolayers were reported to be metallic both in previous theoretical predictions and experimental observations. Unexpectedly, we have first found a family of boron monolayers with the novel semiconducting property as confirmed by the first-principles calculations with the quasi particle G0W0 approach. We demonstrate that the connected network of hexagonal vacancies dominates the gap opening for both the in-plane s+px,y and pz orbitals, with which various semiconducting boron monolayers are designed to realize the band gap engineering for the potential applications in electronic devices. The semiconducting boron monolayers in our predictions are expected to be synthesized on the proper substrates, due to the similar stabilities to the ones observed experimentally. PMID- 29143527 TI - Origins of Enantioselectivity in Asymmetric Radical Additions to Octahedral Chiral-at-Rhodium Enolates: A Computational Study. AB - The origin of asymmetric induction in the additions of carbon- and nitrogen centered radicals to octahedral centrochiral rhodium enolates has been investigated with density functional theory calculations. Computed free energies of activation reproduce the preference for the experimentally observed major enantiomer. Good levels of enantioselectivity are maintained upon replacement of the bulky tert-butyl substituents on the ligands with methyl groups. Distortion interaction analysis indicates that for both carbon- and nitrogen-centered radicals, which have relatively early and late transition states, respectively, the difference in the distortion energies controls the enantioselectivity. In the enolate derived from the Lambda-configured catalyst, the tert-butyl group that shields the si face of the substrate plays the most sterically significant steric role by directly hindering access to the enolate double bond. Exploration of the effect of the N substituent size and shape on the imidazole substrate shows that compared to N-Me, N-iPr and N-Ph variants, the N-o-tolyl variant of the rhodium enolate results in the most substantial improvement in stereodiscrimination, a finding that is in agreement with experimental ee values. PMID- 29143529 TI - Hexavalent Chromium as an Electrocatalyst in DNA Sensing. AB - We report for the first time the use of hexavalent chromium (Cr(VI)) as an electrocatalyst in electrochemical DNA sensing. For both stem-loop probe and linear probe electrochemical DNA sensors, the increase in probe rigidity upon target hybridization alters the accessibility of Cr(VI) to the methylene blue label on the surface-immobilized DNA probes. This change results in an enhancement in the electrocatalytic current when the sensors are interrogated using cyclic voltammetry at a slow scan rate. The incorporation of this electrocatalyst does not affect the normal "signal-off" sensing behavior observed in alternating current voltammetry; instead it enables simultaneous "signal-on" and "signal-off" detection of the target, while maintaining noted attributes of this class of folding- and dynamics-based sensors such as reusability and high selectivity. It is also capable of improving the limit of detection of the sensors by an order of magnitude. Importantly, this accessibility-based electrocatalytic sensing strategy is versatile and can potentially be used with other folding- and dynamics-based electrochemical biosensors. PMID- 29143528 TI - Ellagitannins from Strawberries with Different Degrees of Polymerization Showed Different Metabolism through Gastrointestinal Tract of Rats. AB - The present paper describes a comparative study of the metabolism of (1) ellagic acid, (2) monomeric ellagitannins (a mixture of alpha- and beta-bis hexahydroxydiphenoyl-d-glucose), and (3) dimeric ellagitannins (mainly agrimoniin with both glucose residues being esterified with hexahydroxydiphenoyl) in rats fed polyphenol-rich diets. Their metabolites were identified and quantified in selected parts of the gastrointestinal tract, i.e., the stomach, small intestine, and cecum, on the second, fourth, and seventh days of the experiment, as well as in the rats' feces, blood serum, and urine. Significant differences between the metabolites of strawberry ellagitannins and ellagic acid were observed in all parts of the gastrointestinal tract. Urolithin A was the predominant polyphenolic metabolite of rats fed a diet supplemented with ellagic acid. On the other hand, in rats fed low degree of polymerization (DP) ellagitannins, the main metabolite was nasutin followed by urolithin A, while ellagitannins with a higher DP led to nasutin only. PMID- 29143530 TI - Modulation of Spatiotemporal Particle Patterning in Evaporating Droplets: Applications to Diagnostics and Materials Science. AB - Spatiotemporal particle patterning in evaporating droplets lacks a common design framework. Here, we demonstrate autonomous control of particle distribution in evaporating droplets through the imposition of a salt-induced self-generated electric field as a generalized patterning strategy. Through modeling, a new dimensionless number, termed "capillary-phoresis" (CP) number, arises, which determines the relative contributions of electrokinetic and convective transport to pattern formation, enabling one to accurately predict the mode of particle assembly by controlling the spontaneous electric field and surface potentials. Modulation of the CP number allows the particles to be focused in a specific region in space or distributed evenly. Moreover, starting with a mixture of two different particle types, their relative placement in the ensuing pattern can be controlled, allowing coassemblies of multiple, distinct particle populations. By this approach, hypermethylated DNA, prevalent in cancerous cells, can be qualitatively distinguished from normal DNA of comparable molecular weights. In other examples, we show uniform dispersion of several particle types (polymeric colloids, multiwalled carbon nanotubes, and molecular dyes) on different substrates (metallic Cu, metal oxide, and flexible polymer), as dictated by the CP number. Depending on the particle, the highly uniform distribution leads to surfaces with a lower sheet resistance, as well as superior dye-printed displays. PMID- 29143531 TI - The Population Mean Mood Predicts The Prevalence of Depression in an Australian Context. AB - BACKGROUND: The mean population mood has been demonstrated to strongly correlate with the prevalence of depression in European populations. Mean population mood has, therefore, been proposed as both a metric to measure the impact of population-level interventions to prevent depression and a target for public health policy. AIM: To demonstrate the relationship between mean population mood and the prevalence of depression using Australian data in order to broaden the applicability of this finding to the Australian population. METHODS: We used data from the Geelong Osteoporosis Study to assess the relationship between population mean mood and depression. Participants reported mood symptoms via questionnaire (the Hospital Anxiety and Depression Scale or General Health Questionnaire-12). Depression was diagnosed by semi-structured clinical interview ( Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Non-patient Edition). Stratification by age and socio-economic status was used to create subpopulation groups. Socio-economic status was measured using Index of Relative Socio-economic Advantage and Disadvantage quintiles, an area-based measure based on Australian census data and published by the Australian Bureau of Statistics. The mean subpopulation questionnaire scores and subpopulation prevalence of depression were then analysed using regression and predictive models. RESULTS: Mean subpopulation questionnaire scores correlated well with the prevalence of depression across socio-economic status groups in women but not age groups. Questionnaire scores tended to underestimate the prevalence of depression in the young and overestimate it in the elderly. CONCLUSION: The mean population mood was demonstrated to correlate with the population prevalence of depression in Australia for women, but not for men. Due to the issues of questionnaire validity and sample size in the oldest age groups, the age analysis is unlikely to be a representative of population characteristics. Further work to identify population determinants of mean mood could potentially create policy targets to reduce the prevalence of depression. PMID- 29143532 TI - The clue in the face: An unusual first episode psychosis presentation. PMID- 29143533 TI - Revising the diagnosis of personality disorder: Can it be single, clinical and factorial? PMID- 29143534 TI - Decreased activation and subsyndromal manic symptoms predict lower remission rates in bipolar depression. AB - OBJECTIVE: Activation encompasses energy and activity and is a central feature of bipolar disorder. However, the impact of activation on treatment response of bipolar depression requires further exploration. The aims of this study were to assess the association of decreased activation and sustained remission in bipolar depression and test for factors that could affect this association. METHODS: We assessed participants with Diagnostic and Statistical Manual of Mental Disorders (4th ed) bipolar depression ( n = 303) included in a comparative effectiveness study of lithium- and quetiapine-based treatments (the Bipolar CHOICE study). Activation was evaluated using items from the Bipolar Inventory of Symptoms Scale. The selection of these items was based on a dimension of energy and interest symptoms associated with poorer treatment response in major depression. RESULTS: Decreased activation was associated with lower remission rates in the raw analyses and in a logistic regression model adjusted for baseline severity and subsyndromal manic symptoms (odds ratio = 0.899; p = 0.015). The manic features also predicted lower remission (odds ratio = 0.934; p < 0.001). Remission rates were similar in the two treatment groups. CONCLUSION: Decreased activation and subsyndromal manic symptoms predict lower remission rates in bipolar depression. Patients with these features may require specific treatment approaches, but new studies are necessary to identify treatments that could improve outcomes in this population. PMID- 29143535 TI - Cytotoxic triterpene saponins from the mangrove Aegiceras corniculatum. AB - Using various chromatographic separations, sixteen compounds, including one new triterpene saponin named aegicoroside A (1), were isolated from the leaves of the Vietnamese mangrove Aegiceras corniculatum. Their structures were determined by spectroscopic methods such as 1D and 2D NMR and HR-ESI-MS. The cytotoxic activities of the isolated compounds against MCF7 (breast), HCT116 (colon), B16F10 (melanoma), and A549 (adenocarcinoma) cancer cell lines were also evaluated. Strong cytotoxicity was observed for sakurasosaponin (2) against all four cancer cell lines and for sakurasosaponin methyl ester (3) against MCF7, A549, and HCT116 cell lines with IC50 values ranging from 2.89 +/- 0.02 to 9.86 +/- 0.21 MUM. PMID- 29143536 TI - Time for a new zeitgeist in perinatal mental health. AB - Perinatal depression, and to a lesser extent anxiety, has been the focus of interest for perinatal psychiatrists for several decades. Policy and substantial funding has supported this. We argue that it is now time to change this focus and to invest greater funding to support clinical and research effort in 'high-risk' caregivers and their infants. We define high-risk caregivers as those who are likely to have attachment and relationship difficulties with their infant as a result of their own developmental experiences, personality difficulties and/or trauma-related mental disorders, often complicated by substance abuse, depression and anxiety. We propose that early intervention with such caregivers, focussing on both maternal mental health and on the needs of the infant for responsive and sensitive interaction and emotional care, would contribute to prevention of infant developmental disorders, with real gains to be made in breaking the transgenerational cycle of development of severe personality disorder. PMID- 29143538 TI - Dynamics of postural control during repetitive transcranial magnetic stimulation in an adult with major depressive disorder. PMID- 29143539 TI - Psychiatric care of children with autism spectrum disorder - What do their siblings think about it? A qualitative study. AB - The expectations and role of families in the care of children with autism spectrum disorder are increasingly important. Nonetheless, no study has thus far explored the perspectives of siblings about the care received by a brother or sister with this disorder. The objective of this study was to fill this gap in the literature. This multicentre qualitative study took place in France, where we conducted semi-structured interviews with adolescents who were older siblings of children receiving care in a day hospital for an autism spectrum disorder. Data collection by purposive sampling continued until we reached 'theoretical sufficiency', and data analysis was thematic. The study included 20 participants: 13 sisters and 7 brothers. Four themes emerged in the data analysis: (1) the treatment targets, (2) the treatment's perceived effectiveness, (3) the complex questions it raises and (4) the role of intrafamily relationships. Our results allowed us to report original aspects of the experience of siblings, in particular, their confusion with regard to the treatment, their difficulty in separating themselves from their parents' discourse and their assertion of their role as caregivers for their younger brothers and sisters. PMID- 29143537 TI - Camphor sulphonic acid mediated quantitative 1,3-diol protection of major Labdane diterpenes isolated from Andrographis paniculata. AB - Phytochemical survey of the methanol extract of the dried aerial parts of Andrographis paniculata led to the isolation of major labdane diterpenes, namely 14-deoxy-11,12-didehydroandrographolide, andrographolide and neoandrographolide. Andrographolide was found to be the major phytoconstituent of the plant which was biologically active. For better physiochemical characteristics and bioefficacy, andrographolide is subjected to semi-synthetic modifications. However, presence of several free hydroxyl groups associated with this molecule make it quite polar and poorly soluble in many organic solvents and hence unsuitable for synthetic modifications. One way of resolving its solubility issue is to protect 1,3-diol quantitatively under mild reaction condition without effecting other functional groups. Reaction conditions were optimised using different solvent systems and catalysts towards this direction. X-ray structure of 3,19-isopropylidene-14-deoxy 11,12-didehydroandrographolide is being reported here for the first time. Isolated compounds and derivatives were confirmed by spectral analysis or X-ray data analysis. PMID- 29143541 TI - The efficacy of cognitive behavioral therapy for Chinese people: A meta-analysis. AB - OBJECTIVE: Over the past decade, cognitive behavioral therapy has been applied to an increasingly wider range of disorders and problems in Chinese societies. However, no meta-analysis has been conducted to synthesize the studies on cognitive behavioral therapy for Chinese clients. The purpose of this meta analytic study was to examine the overall efficacy of cognitive behavioral therapy for Chinese people. METHOD: A literature search was conducted using electronic databases, including Web of Science, PsycINFO and PubMed. Pooled mean effect sizes were calculated using the random-effects model. RESULTS: The literature search identified 55 studies with 6763 Chinese participants. The overall short-term effect of cognitive behavioral therapy on the primary outcome was medium in size. Effect sizes were medium for anxiety, depression/well-being and caregiving stress and small for psychotic symptoms and addictive behaviors. The effects of cognitive behavioral therapy on process variables, dysfunctional thoughts and coping, were in the small range. The overall longer-term effect of cognitive behavioral therapy on the primary outcome was medium in size. Moderator analyses showed that the short-term effect was stronger for culturally adapted cognitive behavioral therapy than for unadapted cognitive behavioral therapy. Type of primary outcome, type of control group, recruitment method, study design, the format of delivery and region were found to moderate the efficacy of cognitive behavioral therapy. CONCLUSION: The findings of this study provide evidence for the overall efficacy of cognitive behavioral therapy for Chinese people and the benefit of cultural adaptation of cognitive behavioral therapy to Chinese culture. PMID- 29143540 TI - Association Between Nutrition Resource Stress and Dietary Consumption: Results From a U.S. Nationally Representative Survey. AB - BACKGROUND: There is little research on how affective reactions (e.g., stress) to perceptions of nutritious food accessibility contribute to dietary behaviors. AIMS: This study explores whether stress associated with limited access to nutritious foods-termed nutrition resource stress (NRS)-contributes to diet outcomes, and whether these associations are mediated by health-related self efficacy. METHOD: Using data from the cross-sectional National Cancer Institute's Health Information National Trends Survey, analyses were conducted to examine whether reported NRS was associated with specific dietary behaviors (i.e., fewer servings of fruit/vegetables; more servings of sugar-sweetened soda; N = 3,112). RESULTS: Analyses revealed a main association such that NRS was negatively associated with fruit/vegetable consumption (beta = -0.08, p = .016). There was a negative association between NRS and self-efficacy (beta = -0.11, p < .001). There was no significant association between NRS and soda consumption. Mediation analyses revealed a significant indirect association between NRS and fruit/vegetable consumption, mediated by perceived health-related self-efficacy (beta = -0.03, 95% confidence interval [-.04, -.01], p < .0001). Given that self efficacy (the mediator) was not significantly associated with soda consumption (beta = 0.01, p = .912), mediation analyses were not conducted for this outcome. CONCLUSION: This study suggests that stress associated with perceptions of inability to access nutritious foods may influence dietary behaviors, and points to a psychological mechanism (i.e., self-efficacy) that may explain the association. In addition to improving objective barriers of access to healthy foods, future interventions might address ways of improving nutritious food related self-efficacy or perceived stress related to obtaining healthy foods. PMID- 29143542 TI - Structure, longitudinal invariance, and stability of the Child Behavior Checklist 11/2-5's Diagnostic and Statistical Manual of Mental Disorders-Autism Spectrum Disorder scale: Findings from Generation R (Rotterdam). AB - Although the Child Behavior Checklist 11/2-5's 12-item Diagnostic and Statistical Manual of Mental Disorders-Autism Spectrum Problems Scale (formerly called Pervasive Developmental Problems scale) has been used in several studies as an autism spectrum disorder screener, the base rate and stability of its items and its measurement model have not been previously studied. We therefore examined the structure, longitudinal invariance, and stability of the Child Behavior Checklist 11/2-5's Diagnostic and Statistical Manual of Mental Disorders-Autism Spectrum Problems Scale in the diverse Generation R (Rotterdam) sample based on mothers' ratings at 18 months ( n = 4695), 3 years ( n = 4571), and 5 years ( n = 5752). Five items that seemed especially characteristic of autism spectrum disorder had low base rates at all three ages. The rank order of base rates for the 12 items was highly correlated over time ( Qs ? 0.86), but the longitudinal stability of individual items was modest (phi coefficients = 0.15-0.34). Confirmatory factor analyses indicated that the autism spectrum disorder scale model manifested configural, metric, and scalar longitudinal invariance over the time period from 18 months to 5 years, with large factor loadings. Correlations over time for observed autism spectrum disorder scale scores (0.25-0.50) were generally lower than the correlations across time of the latent factors (0.45-0.68). Results indicated significant associations of the autism spectrum disorder scale with later autism spectrum disorder diagnoses. PMID- 29143543 TI - Marsha Sharp: A Modern-day Pioneer. PMID- 29143544 TI - Transparency in Peer Review. PMID- 29143545 TI - TAZ responds to fluid shear stress to regulate the cell cycle. AB - Physical forces associated with tumor growth and drainage alter cancer cell invasiveness and metastatic potential. We previously showed that fluid frictional force, or shear stress, typical of lymphatic flow induces YAP1/TAZ activation in prostate cancer cells to promote motility dependent upon YAP1 but not TAZ. Here, we show that shear stress elevates TAZ protein levels and promotes TAZ nuclear localization. Increased TAZ activity drives increased DNA synthesis and induces AMOTL2, ANKRD1, and CTGF gene transcription independently of YAP1. Ectopic expression of constitutively activated TAZ increases expression of these TAZ target genes and promotes cell proliferation of prostate cancer cells. Conversely, silencing of TAZ results in reduced proliferation. Together, our data show that force-induced TAZ regulates signaling that dictates cell division, and suggest that TAZ may govern cellular proliferation of cancer cells traveling through the lymphatics in response to biophysical cues. PMID- 29143546 TI - Is the proximal bone resorption around the femoral stem after hip arthroplasty really caused by reduced stress? PMID- 29143547 TI - From individual to global: Human rights and aphasia. AB - This commentary marks the 70th anniversary of the Universal Declaration of Human Rights by examining Article 19 and its application to people with aphasia. This group of people still face lack of access, stigmatisation, exclusion, disadvantage and social withdrawal as well as poor public awareness of aphasia and inadequate prioritisation of support and resources. Nevertheless, a range of creative initiatives at individual, healthcare, local community, national and global levels have helped to connect and empower people with aphasia. Such initiatives include provision of accessible information in a range of media, inclusion of people with aphasia in decision-making and as research partners, awareness raising campaigns to counter attitudinal barriers, organisation of community aphasia groups, development of guidelines for best practice, national aphasia associations and international collaborations such as Aphasia United. While ongoing work and resourcing is needed to expand these efforts further, they have helped people with aphasia to be heard and to protect their sense of dignity which underlies human rights. A human rights approach can unite, politicise and refocus these efforts, and highlight the essential role of communication in fostering a better quality of life. PMID- 29143548 TI - Evaluation on the thyroid disrupting mechanism of malathion in Fischer rat thyroid follicular cell line FRTL-5. AB - Thyroid hormones are involved in many important physiological activities including regulation of energy metabolism, development of nervous system, maintenance of cerebral functions, and so on. Endocrine-disrupting chemicals (EDCs) that interfere with thyroid functions raise serious concerns due to their frequent misuse in areas where regulations are poorly implemented. In addition, chemicals that are originally regarded safe may now be considered as toxic with the development of life sciences. Malathion is an organophosphate insecticide that is widely applied and distributed in agricultural and residential settings. Due to the low acute toxicity and rapid degradation, malathion is not listed as a primary thyroid disrupting chemical. However, emerging evidences reported that malathion affected thyroperoxidase catalyzed iodide oxidation which in turn influenced thyroid hormone transportation, and enhanced parathyroid hyperplasia prevalence. Nevertheless, direct effect of malathion on thyroid hormone biosynthesis remains to be elucidated. This study investigated the effects of thyroid disruption of malathion in Fischer rat thyroid follicular cell line, FRTL 5. Transcriptional and translational analyses on thyroglobulin demonstrated that both mRNA and protein expression levels were significantly inhibited by malathion. Cellular cAMP level and TSH receptor expression were distinctly reduced by malathion (6.0 ug/ml). These results suggested that malathion directly disrupted the biosynthesis of thyroid hormone and the mechanism involved down regulation of TSH receptor and cellular cAMP. This subsequently led to the suppression of TSH dependent signal transduction, TG transcription inhibition, and obstruction of thyroid hormone biosynthesis. PMID- 29143550 TI - Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study. AB - BACKGROUND: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells. OBJECTIVES: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. METHODS: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ?80 cells/uL. RESULTS: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively. CONCLUSION: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions. PMID- 29143549 TI - Negative impact of hyperglycaemia on mouse alveolar development. AB - Diabetes mellitus in pregnancy has been known to affect the embryonic development of various systems, including cardiovascular and nervous systems. However, whether this disease could have a negative impact on embryonic respiratory system remains controversial. In this study, we demonstrated that pregestational diabetes mellitus (PGDM)-induced defects in lung development in mice are mainly characterized by the changes in the morphological structure of the lung. Immunostaining and Western blotting showed that proliferation increased and apoptosis decreased in PGDM. Hyperglycaemia caused pulmonary tissue fibrationas manifested by an increase in Masson staining and decorin expression in PGDM lungs, and the immunofluorescent pro-SPC+ type II pulmonary epithelial cell number was decreased. The alteration of pulmonary epithelial cell differentiation might be due to hyperglycaemia-activated Wnt signalling and suppressed GATA6 expression in PGDM mouse lung tissues and MLE-12 cells. The treatment of MLE-12 cells with high glucose in the presence/absence of XAV939 or su5402 further proved that hyperglycaemia suppressed the expression of GATA6 and pro-SPC by activating Wnt signalling and induced the expression of decorin, alpha-SMA and TGF-beta by activating Fgf signalling. Therefore, in this study, we revealed that hyperglycemia induced dysfunctional pulmonary cell apoptosis and proliferation, as well as pulmonary myofibroblast hyperplasia, which contributed to the formation of aberrant structure of alveolar walls. Furthermore, the hyperglycaemia also inhibited the differentiation of pulmonary epithelial cells through the canonical Wnt and Fgf signalling, and the alteration of Fgf and Wnt signalling activated TGF-beta, which would promote the AECII EMT process. PMID- 29143551 TI - Independent validation of the ICU requirement score in a cohort of acutely poisoned adults. AB - OBJECTIVE: To independently validate the predictive value of the intensive care requirement score (IRS) in unselected poisoned patients. DESIGN: Retrospective chart review. PATIENTS AND METHODS: Five hundred and seventeen out of 585 admissions for acute intoxications could be analyzed. Eleven were excluded for a condition already requiring intensive care unit (ICU) support at admission (e.g., preclinical intubation). A further 57 admissions were excluded due to missing data. The IRS was calculated using a point-scoring system including age, Glasgow Coma Scale, heart rate, type of intoxication, and preexisting conditions. It was then compared to a composite endpoint indicating an ICU requirement (death in hospital, vasopressors, need for ventilation). The endpoint and the point-scoring system were identical to the original publication of the score. RESULTS AND CONCLUSION: Twenty-three out of 517 patients had a complicated clinical course as defined by meeting the endpoint definition. Twenty-one out of 23 complicated courses had a positive IRS (defined as greater or equal 6 points), as compared to 255/494 patients with an uncomplicated clinical course (p < .001, Fisher's exact test). One patient (with a positive IRS) died. The negative predictive value of the IRS was 0.99 (95% CI: 0.97-1), the sensitivity was 0.91 and the specificity 0.48. In conclusion, the IRS is significantly linked to outcome. While a negative IRS virtually excludes the need for ICU care, a positive IRS has a positive predictive value too low to be used for risk stratification. The IRS could also be applied to unselected admissions of poisoned patients. PMID- 29143552 TI - Metabonomics analysis of serum from rats given long-term and low-level cadmium by ultra-performance liquid chromatography-mass spectrometry. AB - 1. This study evaluated the toxicity of chronic exposure to low-level cadmium (Cd) in rats using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Forty male Sprague-Dawley rats were randomly assigned to four groups, namely, the control group, low-dose group (0.13 mg/kg.bw), middle-dose group (0.8 mg/kg.bw) and high-dose group (4.89 mg/kg.bw). The rats continuously received CdCl2 via drinking water for 24 weeks. Serum samples were collected for metabonomics analysis. The data generated from the UPLC-MS was analysed using principal components analysis (PCA) and partial least-squares discriminant analysis (PLS-DA). PLS-DA model with satisfactory explanatory and predictive ability is capable of discriminating the treatment groups from the control group. 2. Finally, the 10 metabolites were identified and showed significant changes in some treatment groups compared with that in the control group (p < 0.0167 or p < 0.003). Exposure to Cd resulted in increased intensities of lysophosphatidic acid (P-16:0e/0:0), glycocholic acid, bicyclo-prostaglandin E2, lithocholyltaurine, sulfolithocholylglycine, lysophosphatidylethanolamine (20:5/0:0) and lysophosphatidylcholine (20:0), as well as decreased intensities of 3 indolepropionic acid, phosphatidylcholine (18:4/18:0) and 15S hydroxyeicosatrienoic acid in rat serum. 3. Results suggest that exposure to Cd can cause disturbances in the lipid metabolism, amino acid metabolism, nervous system, antioxidant defence system, liver and kidney function. PMID- 29143553 TI - Cognitive function is a major determinant of income among multiple sclerosis patients in Sweden acting independently from physical disability. AB - BACKGROUND: In multiple sclerosis (MS), various aspects of cognitive function can be detrimentally affected, thus patients' employment and social functioning is commonly impacted. OBJECTIVE: To analyse income among MS patients in relation to cognitive function, assessed with the Symbol Digit Modalities Test (SDMT). METHODS: A cross-sectional study including 2080 MS patients was conducted linking national register-based data. Descriptive statistics and a two-part model were used to estimate differences in earnings and social benefits. RESULTS: MS patients in the highest SDMT score quartile earned more than twice annually compared to patients in the lowest quartile, whereas patients in the lowest quartile received three times more income through social benefits. The difference in earnings and benefits across the SDMT performance quartiles remained statistically significant after adjusting for various clinical and socio demographic variables, including physical disability. The corrected prevalence ratios for MS patients in the highest quartile for having income from earnings and benefits were 1.40 (95% confidence interval (CI): 1.29-1.49) and 0.81 (95% CI: 0.71-0.90), respectively, when compared to the patients in the lowest quartile. CONCLUSION: Cognitive function affects the financial situation of MS patients negatively and independently of physical disability. This warrants cognitive testing as a routine measure in health care services for MS patients. PMID- 29143554 TI - The octanoylated energy regulating hormone ghrelin: An expanded view of ghrelin's biological interactions and avenues for controlling ghrelin signaling. AB - Ghrelin is a small peptide hormone that requires a unique post-translational modification, serine octanoylation, to bind and activate the GHS-R1a receptor. Initially demonstrated to stimulate hunger and appetite, ghrelin-dependent signaling is implicated in a variety of neurological and physiological processes influencing diseases such as diabetes, obesity, and Prader-Willi syndrome. In addition to its cognate receptor, recent studies have revealed ghrelin interacts with a range of binding partners within the bloodstream. Defining the scope of ghrelin's interactions within the body, understanding how these interactions work in concert to modulate ghrelin signaling, and developing molecular tools for controlling ghrelin signaling are essential for exploiting ghrelin for therapeutic effect. In this review, we discuss recent findings regarding the biological effects of ghrelin signaling, outline binding partners that control ghrelin trafficking and stability in circulation, and summarize the current landscape of inhibitors targeting ghrelin octanoylation. PMID- 29143555 TI - Qualitative and quantitative prediction of human in vivo metabolic pathways in a human hepatocyte-murine stromal cell co-culture model. AB - 1. This study assessed the value of a static in vitro human hepatocyte-murine stromal cell co-culture model to qualitatively and quantitatively predict human in vivo metabolic clearance pathways using 14C-labeled test compounds and compared these results to an in vitro suspended human hepatocyte model and the in vivo human 14C ADME studies. 2. Test compounds represented a diverse set of clearance pathways (Phase I and Phase II). Compounds were incubated for 4 h in suspended human hepatocytes and for 24 and 168 h in the human co-culture model. Multivariate analysis revealed that long-term (168 h) incubation of test compounds in the co-culture had reasonable quantitative prediction of the in vivo human clearance pathways as compared to the 4 h suspended hepatocytes or the 24 h co-culture incubation. 3. In vivo and in vitro disconnects were observed in cases where extra-hepatic metabolism or urinary excretion was observed in vivo. Differences in the relative percentages of Phase I and Phase II metabolites observed were likely due to microbial beta-glucuronidase hydrolysis of conjugates and microflora mediated metabolism in the gut not present in the in vitro systems. PMID- 29143556 TI - daTALbase: A Database for Genomic and Transcriptomic Data Related to TAL Effectors. AB - Transcription activator-like effectors (TALEs) are proteins found in the genus Xanthomonas of phytopathogenic bacteria. These proteins enter the nucleus of cells in the host plant and can induce the expression of susceptibility genes (S genes), triggering disease. TALEs bind the promoter region of S genes following a specific code, which allows the prediction of binding sites based on TALEs amino acid sequences. New candidate S genes can then be discovered by finding the intersection between genes induced in the presence of TALEs and genes containing predicted effector binding elements. By contrasting differential expression data and binding site predictions across different datasets, patterns of TALE diversification or convergence may be unveiled, but this requires the seamless integration of different genomic and transcriptomic data. With this in mind, we present daTALbase, a curated relational database that integrates TALE-related data including bacterial TALE sequences, plant promoter sequences, predicted TALE binding sites, transcriptomic data of host plants in response to TALE-harboring bacteria, and other associated data. The database can be explored to uncover new candidate S genes as well as to study variation in TALE repertories and their corresponding targets. The first version of the database here presented includes data for Oryza sp.-Xanthomonas pv. oryzae interactions. Future versions of the database will incorporate information for other pathosystems involving TALEs. PMID- 29143557 TI - Particle disease really does exist. PMID- 29143558 TI - Perturbation of RNA Polymerase I transcription machinery by ablation of HEATR1 triggers the RPL5/RPL11-MDM2-p53 ribosome biogenesis stress checkpoint pathway in human cells. AB - Ribosome biogenesis is an energy consuming process which takes place mainly in the nucleolus. By producing ribosomes to fuel protein synthesis, it is tightly connected with cell growth and cell cycle control. Perturbation of ribosome biogenesis leads to the activation of p53 tumor suppressor protein promoting processes like cell cycle arrest, apoptosis or senescence. This ribosome biogenesis stress pathway activates p53 through sequestration of MDM2 by a subset of ribosomal proteins (RPs), thereby stabilizing p53. Here, we identify human HEATR1, as a nucleolar protein which positively regulates ribosomal RNA (rRNA) synthesis. Downregulation of HEATR1 resulted in cell cycle arrest in a manner dependent on p53. Moreover, depletion of HEATR1 also caused disruption of nucleolar structure and activated the ribosomal biogenesis stress pathway - RPL5 / RPL11 dependent stabilization and activation of p53. These findings reveal an important role for HEATR1 in ribosome biogenesis and further support the concept that perturbation of ribosome biosynthesis results in p53-dependent cell cycle checkpoint activation, with implications for human pathologies including cancer. PMID- 29143559 TI - K+-Cl- co-transporter 2 (KCC2) - a membrane trafficking perspective. AB - K+-Cl- co-transporter 2 (KCC2/SLC12A5) is a neuronal specific cation chloride co transporter which is active under isotonic conditions, and thus a key regulator of intracellular Cl- levels. It also has an ion transporter-independent structural role in modulating the maturation and regulation of excitatory glutamatergic synapses. KCC2 levels are developmentally regulated, and a postnatal upregulation of KCC2 generates a low intracellular chloride concentration that allows the neurotransmitters gamma-aminobutyric acid (GABA) and glycine to exert inhibitory neurotransmission through its Cl- permeating channel. Functional expression of KCC2 at the neuronal cell surface is necessary for its activity, and impairment in KCC2 cell surface transport and/or internalization may underlie a range of neuropathological conditions. Although recent advances have shed light on a range of cellular mechanisms regulating KCC2 activity, little is known about its membrane trafficking itinerary and regulatory proteins. In this review, known membrane trafficking signals, pathways and mechanisms pertaining to KCC2's functional surface expression are discussed. PMID- 29143561 TI - Beyond lip service: Towards human rights-driven guidelines for South African speech-language pathologists. AB - Developed with a strong awareness of past injustices, South Africa's progressive constitution emphasises a full spectrum of human rights. While the constitution celebrates many languages and cultures, speech-language pathologists (SLPs) face challenges in translating these values into practice with a diverse clientele. Similarly, Article 19 of the Universal Declaration of Human Rights focuses on freedom of expression in one's language of choice, but is often perceived as a "Cinderella" right (i.e. one that is frequently neglected). This paper presents a literature review undertaken in association with the Health Professions Council of South Africa to produce guidelines to support SLPs in their practice with diverse linguistic and cultural groups. The aim was to identify key points for inclusion in a set of human rights-driven guidelines. Specific objectives were to critique: (1) current guidelines for SLPs working with diverse cultural and linguistic groups; and (2) equivalent guidelines for related professions. Content analysis of the datasets revealed key themes which formed the basis of an initial skeleton, to be further developed through a consultative process and discussion, ultimately aiming to provide supportive, practical guidelines to better equip South African SLPs to serve all the people of the country. PMID- 29143560 TI - Induced pluripotent stem cells derived from human amnion in chemically defined conditions. AB - Fetal stem cells are a unique type of adult stem cells that have been suggested to be broadly multipotent with some features of pluripotency. Their clinical potential has been documented but their upgrade to full pluripotency could open up a wide range of cell-based therapies particularly suited for pediatric tissue engineering, longitudinal studies or disease modeling. Here we describe episomal reprogramming of mesenchymal stem cells from the human amnion to pluripotency (AM iPSC) in chemically defined conditions. The AM-iPSC expressed markers of embryonic stem cells, readily formed teratomas with tissues of all three germ layers present and had a normal karyotype after around 40 passages in culture. We employed novel computational methods to determine the degree of pluripotency from microarray and RNA sequencing data in these novel lines alongside an iPSC and ESC control and found that all lines were deemed pluripotent, however, with variable scores. Differential expression analysis then identified several groups of genes that potentially regulate this variability in lines within the boundaries of pluripotency, including metallothionein proteins. By further studying this variability, characteristics relevant to cell-based therapies, like differentiation propensity, could be uncovered and predicted in the pluripotent stage. PMID- 29143562 TI - Pathological cut-offs of global and regional brain volume loss in multiple sclerosis. AB - BACKGROUND: Volumetric MRI surrogate markers of disease progression are lacking. OBJECTIVE: To establish cut-off values of brain volume loss able to discriminate between healthy controls and MS patients. METHODS: In total, 386 patients after first demyelinating event suggestive of MS (CIS), 964 relapsing-remitting MS (RRMS) patients, 63 secondary-progressive MS (SPMS) patients and 58 healthy controls were included in this longitudinal study. A total of 11,438 MRI scans performed on the same MRI scanner with the same protocol were analysed. Annualised percentage changes of whole brain, grey matter, thalamus and corpus callosum volumes were estimated. We investigated cut-offs able to discriminate between healthy controls and MS patients. RESULTS: At a predefined specificity of 90%, the annualised percentage change cut-off of corpus callosum volume (-0.57%) was able to distinguish between healthy controls and patients with the highest sensitivity (51% in CIS, 48% in RRMS and 42% in SPMS patients). Lower sensitivities (22%-49%) were found for cut-offs of whole brain, grey matter and thalamic volume loss. Among CIS and RRMS patients, cut-offs were associated with greater accumulation of disability. CONCLUSION: We identified cut-offs of annualised global and regional brain volume loss rates able to discriminate between healthy controls and MS patients. PMID- 29143564 TI - Advancing the human rights of children with communication needs in school. AB - Article 19 of the Universal Declaration of Human Rights states that everyone has the right to freedom of opinion and expression. However, due to difficulties in communicating, children with speech, language and communication needs (SLCN) are at particular risk of not being heard. Although it is recommended that children with SLCN can and should be actively involved as equal partners in decision making about their communication needs, speech-language pathologists (SLPs) can lose sight of the importance of supporting communication as a tool for the child to shape and influence choices available to them in their lives. Building these skills is particularly important for SLPs working in mainstream educational contexts. In this commentary, the authors argue the need for a shift in emphasis in current practice to a rights-based approach and for SLPs to take more of an active role in supporting children with SLCN to develop agency and be heard. We also present some concepts and frameworks that might guide SLPs to work in a right-based way in schools with this population. PMID- 29143563 TI - Mammalian target of rapamycin complex 2 (mTORC2) controls glycolytic gene expression by regulating Histone H3 Lysine 56 acetylation. AB - Metabolic reprogramming is a hallmark of cancer cells, but the mechanisms are not well understood. The mammalian target of rapamycin complex 2 (mTORC2) controls cell growth and proliferation and plays a critical role in metabolic reprogramming in glioma. mTORC2 regulates cellular processes such as cell survival, metabolism, and proliferation by phosphorylation of AGC kinases. Components of mTORC2 are shown to localize to the nucleus, but whether mTORC2 modulates epigenetic modifications to regulate gene expression is not known. Here, we identified histone H3 lysine 56 acetylation (H3K56Ac) is regulated by mTORC2 and show that global H3K56Ac levels were downregulated on mTORC2 knockdown but not on mTORC1 knockdown. mTORC2 promotes H3K56Ac in a tuberous sclerosis complex 1/2 (TSC1/2) mediated signaling pathway. We show that knockdown of sirtuin6 (SIRT6) prevented H3K56 deacetylation in mTORC2 depleted cells. Using glioma model consisting of U87EGFRvIII cells, we established that mTORC2 promotes H3K56Ac in glioma. Finally, we show that mTORC2 regulates the expression of glycolytic genes by regulating H3K56Ac levels at the promoters of these genes in glioma cells and depletion of mTOR leads to increased recruitment of SIRT6 to these promoters. Collectively, these results identify mTORC2 signaling pathway positively promotes H3K56Ac through which it may mediate metabolic reprogramming in glioma. PMID- 29143566 TI - Electromyographic evaluation in children orthodontically treated for skeletal Class II malocclusion: Comparison of two treatment techniques. AB - Objective To compare the clinical efficacy of two techniques for fabricating a Bimler device by assessing the patient's surface electromyography (sEMG) activity at rest before treatment and six months after treatment. Methods Twenty-four patients undergoing orthodontic treatment were enrolled in the study; 12 formed the test group and wore a Bimler device fabricated with a Myoprint impression using neuromuscular orthodontic technique and 12 formed the control group and were treated by traditional orthodontic technique with a wax bite in protrusion. The "rest" sEMG of each patient was recorded prior to treatment and six months after treatment. Results The neuromuscular-designed Bimler device was more comfortable and provided better treatment results than the traditional Bimler device. Conclusion This study suggests that the patient group subjected to neuromuscular orthodontic treatment had a treatment outcome with more relaxed masticatory muscles and better function versus the traditional orthodontic treatment. PMID- 29143565 TI - HIV-1 resistance rarely observed in patients using darunavir once-daily regimens across clinical studies. AB - BACKGROUND: Darunavir 800 mg once daily (QD) is indicated for HIV-1-infected treatment-naive and treatment-experienced (without darunavir resistance associated mutations [RAMs]) individuals, and has been evaluated in phase 2/3 studies with durations between 48 and 192 weeks. OBJECTIVE: To summarize the development (or identification) of post-baseline resistance (RAMs and antiretroviral phenotypic susceptibility) among patients receiving darunavir QD dosing. METHODS: Seven phase 2/3 studies with available genotypes/phenotypes for subjects treated with ritonavir- or cobicistat-boosted darunavir 800 mg QD regimens were assessed: ARTEMIS (NCT00258557; n = 343), GS-US-299-0102 (NCT01565850; n = 153), GS-US-216-0130 (NCT01440569; n = 313), ODIN (NCT00524368; n = 294), INROADS (NCT01199939; n = 54), MONET (NCT00458302; n = 256), and PROTEA (NCT01448707; n = 273). Genotypic analyses were conducted at baseline (except switch studies enrolling virologically suppressed subjects [MONET, PROTEA]). Criteria for post-baseline resistance testing and evaluation of the development (or identification [switch studies]) of RAMs (respective IAS-USA mutations) varied slightly across studies. RESULTS: Among 1686 subjects treated with darunavir 800 mg QD regimens, 184 had protocol-defined virologic failure; 182 had post-baseline genotypes analyzed. Overall, 4/1686 (0.2%) developed (or had identified [switch studies]) primary protease inhibitor and/or darunavir RAMs (ARTEMIS, n = 1; GS-US-216-0130, n = 1; ODIN, n = 1; MONET, n = 1). Only 1/1686 (<0.1%) subject lost darunavir phenotypic susceptibility (ODIN; possibly related to prior ritonavir-boosted lopinavir virologic failure). Among 1103 subjects using a nucleos(t)ide reverse transcriptase inhibitor (N[t]RTI) backbone, 10 (0.9%) developed >= 1 N(t)RTI RAM (8 had the emtricitabine RAM M184I/V). CONCLUSIONS: Darunavir has a high genetic barrier to resistance. Across a diverse population of HIV-1-infected subjects treated with darunavir 800 mg QD regimens, the development of darunavir resistance was rare (<0.1%). PMID- 29143567 TI - Couple relationship quality and offspring attachment security: a systematic review with meta-analysis. AB - This paper provides a meta-analytic examination of strength and direction of association between parents' couple relationship quality and early childhood attachment security (5 years and under). A comprehensive search of four EBSCOhost databases, Informit, Web of Science, and grey literature yielded 24 studies meeting eligibility criteria. Heterogeneity of the couple quality construct and measurement was marked. To disaggregate potentially differentially acting factors, we grouped homogeneous studies, creating two predictor variables defined as "positive dyadic adjustment" and "inter-parental conflict". Associations of each construct with offspring attachment security were examined in two separate meta-analyses. Inter-parental conflict was inversely associated (8 studies, k = 17, r = -0.28, CI = [-0.39 to -0.18]), and dyadic adjustment was not associated with offspring attachment security (5 studies, k = 12, r = 0.14, CI = [-0.03 to 0.32]). The study supports finer distinctions of couple relationship constructs and measurement in developmental research, assessment, and intervention. PMID- 29143569 TI - Prevalence of temporomandibular symptoms and parafunctional habits in a university dental clinic and association with gender, age, and missing teeth. AB - Objective To assess the prevalence of symptoms of temporomandibular disorder (TMD) and parafunctional habits as well as to investigate their association with age, gender, and number of missing teeth. Methods This retrospective study is based on 4204 randomly selected patients who were examined to determine their symptoms of TMD, such as clicking, difficulty chewing, difficulty opening/closing, as well self-reported joint pain and parafunctional habits. Results Clenching/grinding was reported by 26.5% of the examined population, clicking by 14.8%, and difficulty chewing and closing by 3.6%. Significant associations between the number of missing teeth with clenching/grinding (p = 0.05) and difficulty chewing (p < 0.001) were detected. Age and gender showed significant effects on the examined parameters (p < 0.05). Discussion Understanding the TMD subjective symptoms in relation to age, gender, and tooth loss would be of great value for treatment planning and could provide other perspectives to establish preventive measures. PMID- 29143568 TI - The inter-rater reliability and prognostic value of coma scales in Nepali children with acute encephalitis syndrome. AB - Background Acute encephalitis syndrome (AES) is a common cause of coma in Nepali children. The Glasgow coma scale (GCS) is used to assess the level of coma in these patients and predict outcome. Alternative coma scales may have better inter rater reliability and prognostic value in encephalitis in Nepali children, but this has not been studied. The Adelaide coma scale (ACS), Blantyre coma scale (BCS) and the Alert, Verbal, Pain, Unresponsive scale (AVPU) are alternatives to the GCS which can be used. Methods Children aged 1-14 years who presented to Kanti Children's Hospital, Kathmandu with AES between September 2010 and November 2011 were recruited. All four coma scales (GCS, ACS, BCS and AVPU) were applied on admission, 48 h later and on discharge. Inter-rater reliability (unweighted kappa) was measured for each. Correlation and agreement between total coma score and outcome (Liverpool outcome score) was measured by Spearman's rank and Bland Altman plot. The prognostic value of coma scales alone and in combination with physiological variables was investigated in a subgroup (n = 22). A multivariable logistic regression model was fitted by backward stepwise. Results Fifty children were recruited. Inter-rater reliability using the variables scales was fair to moderate. However, the scales poorly predicted clinical outcome. Combining the scales with physiological parameters such as systolic blood pressure improved outcome prediction. Conclusion This is the first study to compare four coma scales in Nepali children with AES. The scales exhibited fair to moderate inter rater reliability. However, the study is inadequately powered to answer the question on the relationship between coma scales and outcome. Further larger studies are required. PMID- 29143570 TI - The perceptual responses to high-velocity, low-load and low-velocity, high-load resistance exercise in older adults. AB - The present study examined exercise affect during volume-load matched, high velocity, low-load and low-velocity, high-load resistance exercise conditions in older adults. Ten older adults completed three sets of eight exercises on six separate occasions (three high-velocity, low-load and three low-velocity, high load sessions) in a crossover study design. High-velocity, low-load was performed at 40% of predicted one repetition maximum, and low-velocity, high-load at 80%. The Physical Activity Affect Scale, Felt Arousal Scale, Feeling Scale, Rating of Perceived Exertion, Visual Analogue Scales, and the Physical Activity Enjoyment Scale examined exercise intensity and affect. There were moderate effects of exercise condition on positive exercise affect (P = 0.067; [Formula: see text] = 0.33), and trivial effects on negative exercise affect (P = 0.904; [Formula: see text] = 0.002). Rating of perceived exertion (P < 0.001; [Formula: see text] = 0.41) and fatigue (P = 0.012; [Formula: see text] = 0.52) were greater during low velocity, high-load. Furthermore, high-velocity, low-load facilitated statistically insignificant, favourable changes (less exertion, more enjoyment etc.) for all other measures. These findings combined with emerging evidence that high-velocity, low-load is superior for improving muscle power and/or functional performance, indicates that high-velocity, low-load should be prescribed preferentially. However, both exercise conditions were enjoyed similarly, demonstrating that individual preference is an important consideration. PMID- 29143571 TI - Enabling positive change: Progress and setbacks in HIV and sexual and reproductive health and rights. AB - At a point in history when the future of sexual and reproductive health including HIV looks particularly uncertain, it is helpful to recognise that many of the challenges currently faced are neither new nor insurmountable. Reflecting on past achievements and lessons learned helps us to have confidence that positive change is feasible. This paper reflects on some of the changes observed in countries like India and Mozambique and identifies a range of factors which need to coalesce to enable these developments, along with specific contextual factors. It is the combination of these influences rather than any one of them alone that brought about the change in the three instances described - fostering a positive political response to HIV in its early years in India; bringing about policy reform on abortion in Mozambique; and increasing contraceptive prevalence and age at marriage in some districts in Bihar, India. Change is always fragile and susceptible to setbacks, but change-seekers can learn in the process and gain renewed hope that progress can and often does take place if they persevere. PMID- 29143572 TI - Socio-economic integration of the informal recycling sector through an NGO intervention at the Andralanitra dumpsite in Antananarivo, Madagascar. AB - The social status improvement and the degree of integration of the informal recycling sector, by using InteRa, made by the AKAMASOA association interventions at the Andralanitra dumpsite (Antananarivo, Madagascar) was assessed. 20% of the workers from the three activities at the site were interviewed: 325 scavengers, 12 compost producers and three soap manufacturers. It was found that the incomes of Andralanitra workers are relatively low compared to that of people working in the same field in other countries (30-60 USD/month). However, with the social support from AKAMASOA, their living conditions were greatly improved, allowing them to own their house, have access to water and sanitation facilities and send their children to school or subscribe to health insurance and bank savings. Though they do not experience the common socio-economic issues faced by informal workers at dumpsites and their works are highly appreciated by the solid waste management (SWM) stakeholders, there is no official planned intervention to formalise their situation. Thus, InteRa has shown low scores in SWM and organisational interfaces and high scores in materials/value chain and social interfaces. AKAMASOA actions are good examples of successful NGO interventions to improve the dumpsites' informal recycling social status. The findings suggest that full integration into the SWM system should be supported by municipalities through the setting of policy and regulations on the access to dumpsites and the exploitation of the wastes. PMID- 29143573 TI - Current Treatment Concepts for Stress Urinary Incontinence. AB - Initially, stress urinary incontinence should be treated by conservative measures, such as weight reduction, hormonal substitution, physiotherapy, pelvic floor exercise and/or the use of pessaries. Incontinence surgeries are only recommended in case of unsuccessful conservative therapy. Today, tension-free suburethral sling insertions represent the gold standard of incontinence surgery yielding very good outcomes (cure rates of 80-90 %). Pelvic-floor sonography provides important information on decision of surgical methods and the management of complications. Furthermore, intra- or paraurethral injection of bulking agents is a promising, minimally invasive surgical alternative. This article discusses treatment concepts, pre-, intra- and post-operative examinations, decision on surgical methods, operational details for surgical success, and the prevention and management of complications. PMID- 29143574 TI - Investigating the preventive effects of baicalin and gallocatechin against glyoxal-induced cystatin aggregation. AB - Several mammalian proteins form pathological deposits under nonphysiological conditions that are associated with many degenerative diseases. Protein aggregation is associated with aging, as well as a variety of diseases, including cystic fibrosis, amyotrophic lateral sclerosis (ALS), and hypertrophic cardiomyopathy. There is a lack of any potential anti-amyloidogenic agents and therapeutics till date. Polyphenols have been accredited with myriad biological effects. An analysis of the effects of natural agents like baicalin (BC) and gallocatechin (GC) on aggregation process can open new avenues for the treatment of protein misfolding diseases. Thus, investigation of the effects of these flavonoids on Buffalo Heart Cystatin (BHC) aggregation induced by a reactive metabolic dialdehyde, glyoxal (GO), was taken up. Results have shown that elevated concentration of GO forms aggregates of BHC, which was characterized by an increase in the ANS fluorescence intensity, an increase in ThT fluorescence intensity, red shift in Congo red absorbance, negative ellipticity peak at 217 nm in the far-UVCD and BHC aggregates displaying by TEM. Using fluorescence spectroscopic analysis with Thioflavin T, CD and electron microscopic studies, anti-aggregation effects of polyphenols, BC and GC were analyzed. The study showed that BC and GC produced concentration-dependent anti-aggregation effects with GC producing a more pronounced effect than BC. The study proposed a mechanistic approach assuming structural constraints and specific aromatic interactions of polyphenols with sheets of BHC aggregates. PMID- 29143575 TI - Determination of illegal adulteration of dietary supplements with synthetic hair growth compounds by UPLC and LC-Q-TOF/MS. AB - In this study, we developed a UPLC-PDA and LC-Q-TOF/MS method to identify and measure the following prohibited substances that may be found in dietary supplements:triaminodil, minoxidil, bimatoprost, alimemazine, diphenylcyclopropenone, alpha-tradiol, finasteride, methyltestosterone, spironolatone, flutamide, cyproterone, dutasteride, and testosterone 17 propionate.The method was validated according to International Conference on Harmonization guidelines in terms of specificity, linearity, accuracy, precision, LOD, LOQ, recovery, and stability. The method was completely validated showing satisfactory data for all method validation parameters. The linearity was good (R2 > 0.999) with intra- and inter-day precision values of 0.2-3.4% and 0.3-2.9%, respectively. Moreover, the intra- and inter-day accuracies were 87-102% and 86 103%, respectively, and the precision was better than 9.4% (relative standard deviation).Hence, the proposed method is precise and has high quality,and can be utilised to comprehensively and continually monitor illegal drug adulteration in various forms of dietary supplements. Furthermore, to evaluate the applicability of the proposed method, we analysed 13 hair-growth compounds in 78 samples including food and dietary supplements. Minoxidil and triaminodil were detected in capsules at concentrations of 4.69 mg/g and 6.54 mg/g. In addition, finasteride was detected in a tablet at 13.45 mg/g. In addition, the major characteristic fragment ions were confirmed once again using LC-Q-TOF/MS for higher accuracy. PMID- 29143576 TI - A nationwide study of health-related quality of life, stress, pain or discomfort and the use of medicine among problem gamblers. AB - AIM: The aim of this study was to investigate the associations between problem gambling and health-related quality of life, stress, pain or discomfort and the use of analgesics and sleeping pills. METHODS: Data derives from the Danish Health and Morbidity Survey 2010. The survey was based on a random sample of 25,000 adult Danes (response rate: 61%), and data were collected via a self administered questionnaire. The Lie/Bet Questionnaire was used as the screening instrument for problem gambling. Respondents were categorised as current, previous or non-problem gamblers. The questionnaire also included topics such as health-related quality of life (Short Form-12), perceived stress, pain and discomforts within the past two weeks, as well as the use of medication within the past two weeks. RESULTS: Current problem gambling was strongly associated with negative outcomes such as poor mental health, high perception of stress, headache, fatigue and sleeping problems. Furthermore, previous problem gambling was generally associated with poorer health outcomes. Thus, current and previous problem gamblers had 2.36 times (95% confidence interval [CI] 1.44-3.87) and 1.66 times (95% CI 1.07-2.55) higher odds than non-problem gamblers of reporting fair or poor health, respectively. The data revealed no clear association between problem gambling and the use of analgesics. CONCLUSIONS: Both current and previous problem gambling were negatively associated with physical and mental health problems. Health professionals should be alert to any signs of these complicating factors when planning the treatment of problem gamblers. PMID- 29143577 TI - Lipedema. PMID- 29143578 TI - Non-participation modestly increased with distance to the examination clinic among adults in Finnish health examination surveys. AB - AIMS: Health examination surveys (HES) provide important information about population health and health-related factors, but declining participation rates threaten the representativeness of collected data. It is hard to conduct national HESs at examination clinics near to every sampled individual. Thus, it is interesting to look into the possible association between the distance from home to the examination clinic and non-participation, and whether there is a certain distance after which the participation activity decreases considerably. METHODS: Data from two national HESs conducted in Finland in 2011 and 2012 were used and a logistic regression model was fitted to investigate how distance was related to non-participation. RESULTS: We found out that non-participation modestly increased with distance to the examination clinic. An additional analysis indicated that the option of having an examination at home may decrease the effect of distance to participation. CONCLUSIONS: Long distances from home to the examination clinic are one reason for low participation activity. Possible bias caused by these differences in participation could be decreased by providing the option of a home examination. PMID- 29143579 TI - MRI for multiple sclerosis diagnosis and prognosis. PMID- 29143580 TI - Neuroplasticity and its relevance for multiple sclerosis. PMID- 29143581 TI - Multiple sclerosis symptoms and spasticity management: new data. AB - Spasticity, perceived by patients as muscle rigidity and spasms, is a common symptom in multiple sclerosis (MS). It is associated with functional impairment that can exacerbate other MS symptoms and reduce quality of life. Pharmacological treatment options are limited and frequently ineffective. Treatment adherence is a key issue to address in these patients. The efficacy and safety of 9-delta tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray for treatment of MS spasticity were demonstrated in four Phase III trials. Observational studies and registry data subsequently confirmed the effectiveness and tolerability of THC:CBD oromucosal spray under everyday practice conditions. Among patients who respond to treatment, THC:CBD oromucosal spray has been shown to produce positive improvements in gait parameters and to normalize muscle fibers. PMID- 29143582 TI - Personalized medicine in multiple sclerosis. AB - The therapeutic approach in multiple sclerosis (MS) requires a personalized medicine frame beyond the precision medicine concept, which is not currently implementable due to the lack of robust biomarkers and detailed understanding of MS pathogenesis. Personalized medicine demands a patient-focused approach, with disease taxonomy informed by characterization of pathophysiological processes. Important questions concerning MS taxonomy are: when does MS begin? When does the progressive phase begin? Is MS really two or three diseases? Does a therapeutic window truly exist? Newer evidence points to a disease spectrum and a therapeutic lag of several years for benefits to be observed from disease-modifying therapy. For personalized treatment, it is important to ascertain disease stage and any worsening of focal inflammatory lesions over time. PMID- 29143583 TI - Cognition in multiple sclerosis. PMID- 29143584 TI - Pediatric multiple sclerosis: epidemiology, clinical aspects, diagnosis and treatment. PMID- 29143585 TI - Having the conversation about work with people with multiple sclerosis: a guide for healthcare professionals. AB - The ability to work is important for people with multiple sclerosis (MS). However, only 37% of those with mild MS are in work. Across Europe, lost work productivity accounts for a third of the ?15 billion total annual cost of MS. Supporting people with MS into employment should be a clinical care priority in order to maximize work productivity, inclusiveness and therapeutic benefit. A guide for healthcare professionals on having conversations about work with people with MS has been developed through the 'Ready for Work' project. Work should be considered as a clinical outcome. The focus should be on what patients can do, rather than what they cannot do, at work. Effective communication is fundamental in supporting patients' return to work. PMID- 29143586 TI - Break-out session highlights. AB - A popular feature of the Multiple Sclerosis Experts Summit is interactive break out sessions to discuss various aspects of multiple sclerosis (MS), including MS spasticity and general management of MS patients. The format encourages participation and active discussion, thus providing attendees with the opportunity to exchange their experiences of the day-to-day management of MS in clinical practice. Following feedback provided by each session leader, key messages are summarized and presented in a plenary session by the Summit chair. Topics covered in this year's country break-out sessions included: triggering factors for MS; decision-making in MS and the importance of patients' risk perception; assessment and management of MS spasticity. PMID- 29143587 TI - Foreword. PMID- 29143588 TI - What's new in multiple sclerosis spasticity research? Poster session highlights. AB - Each year at the Multiple Sclerosis Experts Summit, relevant research in the field of multiple sclerosis spasticity is featured in poster sessions. The main studies presented at this year's meeting are summarized herein. PMID- 29143589 TI - Biomarkers in the evolution of multiple sclerosis. AB - Nonimaging biomarkers can be applied in differential diagnosis, evaluation of disease progression and therapy monitoring of multiple sclerosis (MS). Presence of oligoclonal IgG bands in cerebrospinal fluid is a diagnostic element and a negative predictor of MS evolution. AQP4 antibodies are pathogenic and diagnostic for neuromyelitis optica spectrum disorder. Antibodies to myelin oligodendrocyte glycoprotein develop in about 50% of predominantly pediatric patients with acute disseminated encephalomyelitis, but their possible role in pathogenesis is unknown. Currently, there are no individualized biomarkers suitable to track disease progression. Neutralizing antibodies against IFN-beta, natalizumab and daclizumab arise with variable frequency and reduce treatment efficacy. The anti John Cunningham virus antibody index has potential as a biomarker for risk of progressive multifocal leukoencephalopathy. PMID- 29143590 TI - Exercise therapy in multiple sclerosis and its effects on function and the brain. AB - Exercise therapy is a promising nonpharmacological therapy in people with multiple sclerosis (MS). Although exercise training may induce a transient worsening of symptoms in some MS patients, it is generally considered safe and does not increase the risk of relapses. Exercise training can lead to clinically relevant improvements in physical function, but should be considered an adjunct to specific task-based training. Exercise has also shown positive effects on the brain, including improvements in brain volume and cognition. In summary, exercise therapy is a safe and potent nonpharmacological intervention in MS, with beneficial effects on both functional capacity and the brain. PMID- 29143591 TI - The machine in the market: Computers and the infrastructure of price at the New York Stock Exchange, 1965-1975. AB - This article traces the development and expansion of early computer systems for managing and disseminating 'real-time' market data at the most influential stock market in the United States, the New York Stock Exchange (NYSE). It follows electronic media at the NYSE over a roughly ten-year period, from the time of the deployment of a computer called the Market Data System (MDS) through debates surrounding the National Market System and the passage of the 1975 Securities Acts Amendments. Building on research at the archives of the NYSE and the Securities and Exchange Commission (SEC), this history emphasizes the regulatory and managerial contexts in which market data became computerized. The SEC viewed market automation as both necessary for the viability of the securities industry and a mechanism for expanding regulatory oversight over the venues of stock trading. Moving from the MDS to later technical projects in the late 1960s and early 1970s, this article charts the changing meaning of electronic governance in a market increasingly conceptualized as a technical object. Adding to recent work in the social studies of finance and financial technologies, this history sites early NYSE computerization programs within managerial efforts to consolidate control over the clerical labor of financial markets, and in contests between regulatory and market institutions. It concludes by exploring the differing forms of electronic governance activated in these efforts to bring computers into the market. PMID- 29143592 TI - COL5A1 gene variants previously associated with reduced soft tissue injury risk are associated with elite athlete status in rugby. AB - BACKGROUND: Two common single nucleotide polymorphisms within the COL5A1 gene (SNPs; rs12722 C/T and rs3196378 C/A) have previously been associated with tendon and ligament pathologies. Given the high incidence of tendon and ligament injuries in elite rugby athletes, we hypothesised that both SNPs would be associated with career success. RESULTS: In 1105 participants (RugbyGene project), comprising 460 elite rugby union (RU), 88 elite rugby league athletes and 565 non-athlete controls, DNA was collected and genotyped for the COL5A1 rs12722 and rs3196378 variants using real-time PCR. For rs12722, the injury protective CC genotype and C allele were more common in all athletes (21% and 47%, respectively) and RU athletes (22% and 48%) than in controls (16% and 41%, P <= 0.01). For rs3196378, the CC genotype and C allele were overrepresented in all athletes (23% and 48%) and RU athletes (24% and 49%) compared with controls (16% and 41%, P <= 0.02). The CC genotype in particular was overrepresented in the back and centres (24%) compared with controls, with more than twice the odds (OR = 2.25, P = 0.006) of possessing the injury-protective CC genotype. Furthermore, when considering both SNPs simultaneously, the CC-CC SNP-SNP combination and C-C inferred allele combination were higher in all the athlete groups (>=18% and >=43%) compared with controls (13% and 40%; P = 0.01). However, no genotype differences were identified for either SNP when RU playing positions were compared directly with each other. CONCLUSION: It appears that the C alleles, CC genotypes and resulting combinations of both rs12722 and rs3196378 are beneficial for rugby athletes to achieve elite status and carriage of these variants may impart an inherited resistance against soft tissue injury, despite exposure to the high-risk environment of elite rugby. These data have implications for the management of inter-individual differences in injury risk amongst elite athletes. PMID- 29143593 TI - Preface: genomics and biology of exercise is undergoing a paradigm shift. PMID- 29143594 TI - The gene SMART study: method, study design, and preliminary findings. AB - The gene SMART (genes and the Skeletal Muscle Adaptive Response to Training) Study aims to identify genetic variants that predict the response to both a single session of High-Intensity Interval Exercise (HIIE) and to four weeks of High-Intensity Interval Training (HIIT). While the training and testing centre is located at Victoria University, Melbourne, three other centres have been launched at Bond University, Queensland University of Technology, Australia, and the University of Brighton, UK. Currently 39 participants have already completed the study and the overall aim is to recruit 200 moderately-trained, healthy Caucasians participants (all males 18-45 y, BMI < 30). Participants will undergo exercise testing and exercise training by an identical exercise program. Dietary habits will be assessed by questionnaire and dietitian consultation. Activity history is assessed by questionnaire and current activity level is assessed by an activity monitor. Skeletal muscle biopsies and blood samples will be collected before, immediately after and 3 h post HIIE, with the fourth resting biopsy and blood sample taken after four weeks of supervised HIIT (3 training sessions per week). Each session consists of eight to fourteen 2-min intervals performed at the pre-training lactate threshold (LT) power plus 40 to 70% of the difference between pre-training lactate threshold (LT) and peak aerobic power (Wpeak). A number of muscle and blood analyses will be performed, including (but not limited to) genotyping, mitochondrial respiration, transcriptomics, protein expression analyses, and enzyme activity. The participants serve as their own controls. Even though the gene SMART study is tightly controlled, our preliminary findings still indicate considerable individual variability in both performance (in-vivo) and muscle (in-situ) adaptations to similar training. More participants are required to allow us to better investigate potential underlying genetic and molecular mechanisms responsible for this individual variability. PMID- 29143595 TI - Why nature prevails over nurture in the making of the elite athlete. AB - While the influence of nature (genes) and nurture (environment) on elite sporting performance remains difficult to precisely determine, the dismissal of either as a contributing factor to performance is unwarranted. It is accepted that a complex interaction of a combination of innumerable factors may mold a talented athlete into a champion. The prevailing view today is that understanding elite human performance will require the deciphering of two major sources of individual differences, genes and the environment. It is widely accepted that superior performers are endowed with a high genetic potential actualised through hard and prodigious effort. Heritability studies using the twin model have provided the basis to disentangle genetic and environmental factors that contribute to complex human traits and have paved the way to the detection of specific genes for elite sport performance. Yet, the heritability for most phenotypes essential to elite human performance is above 50% but below 100%, meaning that the environment is also important. Furthermore, individual differences can potentially also be explained not only by the impact of DNA sequence variation on biology and behaviour, but also by the effects of epigenetic changes which affect phenotype by modifying gene expression. Despite this complexity, the overwhelming and accumulating evidence, amounted through experimental research spanning almost two centuries, tips the balance in favour of nature in the "nature" and "nurture" debate. In other words, truly elite-level athletes are built - but only from those born with innate ability. PMID- 29143596 TI - Genetic testing for exercise prescription and injury prevention: AIS-Athlome consortium-FIMS joint statement. AB - BACKGROUND: There has been considerable growth in basic knowledge and understanding of how genes are influencing response to exercise training and predisposition to injuries and chronic diseases. On the basis of this knowledge, clinical genetic tests may in the future allow the personalisation and optimisation of physical activity, thus providing an avenue for increased efficiency of exercise prescription for health and disease. RESULTS: This review provides an overview of the current status of genetic testing for the purposes of exercise prescription and injury prevention. As such there are a variety of potential uses for genetic testing, including identification of risks associated with participation in sport and understanding individual response to particular types of exercise. However, there are many challenges remaining before genetic testing has evidence-based practical applications; including adoption of international standards for genomics research, as well as resistance against the agendas driven by direct-to-consumer genetic testing companies. Here we propose a way forward to develop an evidence-based approach to support genetic testing for exercise prescription and injury prevention. CONCLUSION: Based on current knowledge, there is no current clinical application for genetic testing in the area of exercise prescription and injury prevention, however the necessary steps are outlined for the development of evidence-based clinical applications involving genetic testing. PMID- 29143597 TI - Genotypic and phenotypic features of all Spanish patients with McArdle disease: a 2016 update. AB - BACKGROUND: We recently described the genotype/phenotype features of all Spanish patients diagnosed with McArdle disease as of January 2011 (n = 239, prevalence of ~1/167,000) (J Neurol Neurosurg Psychiatry 2012;83:322-8). Several caveats were however identified suggesting that the prevalence of the disease is actually higher. METHODS: We have now updated main genotype/phenotype data, as well as potential associations within/between them, of all Spanish individuals currently diagnosed with McArdle disease (December 2016). RESULTS: Ninety-four new patients (all Caucasian) have been diagnosed, yielding a prevalence of ~1/139,543 individuals. Around 55% of the mutated alleles have the commonest PYGM pathogenic mutation p.R50X, whereas p.W798R and p.G205S account for 10 and 9% of the allelic variants, respectively. Seven new mutations were identified: p.H35R, p.R70C, p.R94Q, p.L132WfsX163, p.Q176P, p.R576Q, and c.244-3_244-2CA. Almost all patients show exercise intolerance, the second wind phenomenon and high serum creatine kinase activity. There is, however, heterogeneity in clinical severity, with 8% of patients being asymptomatic during normal daily life, and 21% showing limitations during daily activities and fixed muscle weakness. A major remaining challenge is one of diagnosis, which is often delayed until the third decade of life in 72% of new patients despite the vast majority (86%) reporting symptoms before 20 years. An important development is the growing proportion of those reporting a 4-year improvement in disease severity (now 34%) and following an active lifestyle (50%). Physically active patients are more likely to report an improvement after a 4-year period in the clinical course of the disease than their inactive peers (odds ratio: 13.98; 95% confidence interval: 5.6, 34.9; p < 0.001). Peak oxygen uptake is also higher in the former (20.7 +/- 6.0 vs. 16.8 +/ 5.3 mL/kg/min, p = 0.0013). Finally, there is no association between PYGM genotype and phenotype manifestation of the disease. CONCLUSIONS: The reported prevalence of McArdle disease grows exponentially despite frequent, long delays in genetic diagnosis, suggesting that many patients remain undiagnosed. Until a genetic cure is available (which is not predicted in the near future), current epidemiologic data support that adoption of an active lifestyle is the best medicine for these patients. PMID- 29143598 TI - GWAS for plant growth stages and yield components in spring wheat (Triticum aestivum L.) harvested in three regions of Kazakhstan. AB - BACKGROUND: Spring wheat is the largest agricultural crop grown in Kazakhstan with an annual sowing area of 12 million hectares in 2016. Annually, the country harvests around 15 million tons of high quality grain. Despite environmental stress factors it is predicted that the use of new technologies may lead to increases in productivity from current levels of 1.5 to up to 3 tons per hectare. One way of improving wheat productivity is by the application of new genomic oriented approaches in plant breeding projects. Genome wide association studies (GWAS) are emerging as powerful tools for the understanding of the inheritance of complex traits via utilization of high throughput genotyping technologies and phenotypic assessments of plant collections. In this study, phenotyping and genotyping data on 194 spring wheat accessions from Kazakhstan, Russia, Europe, and CIMMYT were assessed for the identification of marker-trait associations (MTA) of agronomic traits by using GWAS. RESULTS: Field trials in Northern, Central and Southern regions of Kazakhstan using 194 spring wheat accessions revealed strong correlations of yield with booting date, plant height, biomass, number of spikes per plant, and number of kernels per spike. The accessions from Europe and CIMMYT showed high breeding potential for Southern and Central regions of the country in comparison with the performance of the local varieties. The GGE biplot method, using average yield per plant, suggested a clear separation of accessions into their three breeding origins in relationship to the three environments in which they were evaluated. The genetic variation in the three groups of accessions was further studied using 3245 polymorphic SNP (single nucleotide polymorphism) markers. The application of Principal Coordinate analysis clearly grouped the 194 accessions into three clades according to their breeding origins. GWAS on data from nine field trials allowed the identification of 114 MTAs for 12 different agronomic traits. CONCLUSIONS: Field evaluation of foreign germplasm revealed its poor yield performance in Northern Kazakhstan, which is the main wheat growing region in the country. However, it was found that EU and CIMMYT germplasm has high breeding potential to improve yield performance in Central and Southern regions. The use of Principal Coordinate analysis clearly separated the panel into three distinct groups according to their breeding origin. GWAS based on use of the TASSEL 5.0 package allowed the identification of 114 MTAs for twelve agronomic traits. The study identifies a network of key genes for improvement of yield productivity in wheat growing regions of Kazakhstan. PMID- 29143599 TI - Epistasis, physical capacity-related genes and exceptional longevity: FNDC5 gene interactions with candidate genes FOXOA3 and APOE. AB - BACKGROUND: Forkhead box O3A (FOXOA3) and apolipoprotein E (APOE) are arguably the strongest gene candidates to influence human exceptional longevity (EL, i.e., being a centenarian), but inconsistency exists among cohorts. Epistasis, defined as the effect of one locus being dependent on the presence of 'modifier genes', may contribute to explain the missing heritability of complex phenotypes such as EL. We assessed the potential association of epistasis among candidate polymorphisms related to physical capacity, as well as antioxidant defense and cardiometabolic traits, and EL in the Japanese population. A total of 1565 individuals were studied, subdivided into 822 middle-aged controls and 743 centenarians. RESULTS: We found a FOXOA3 rs2802292 T-allele-dependent association of fibronectin type III domain-containing 5 (FDNC5) rs16835198 with EL: the frequency of carriers of the FOXOA3 rs2802292 T-allele among individuals with the rs16835198 GG genotype was significantly higher in cases than in controls (P < 0.05). On the other hand, among non-carriers of the APOE 'risk' epsilon4-allele, the frequency of the FDNC5 rs16835198 G-allele was higher in cases than in controls (48.4% vs. 43.6%, P < 0.05). Among carriers of the 'non-risk' APOE epsilon2-allele, the frequency of the rs16835198 G-allele was higher in cases than in controls (49% vs. 37.3%, P < 0.05). CONCLUSIONS: The association of FDNC5 rs16835198 with EL seems to depend on the presence of the FOXOA3 rs2802292 T allele and we report a novel association between FNDC5 rs16835198 stratified by the presence of the APOE epsilon2/epsilon4-allele and EL. More research on 'gene*gene' and 'gene*environment' effects is needed in the field of EL. PMID- 29143600 TI - Characterizing the pathotype structure of barley powdery mildew and effectiveness of resistance genes to this pathogen in Kazakhstan. AB - BACKGROUND: Powdery mildew of barley is a wind-borne and obligate biotrophic pathogen, which ranks among the most widespread barley pathogens worldwide. However, purposeful research towards studying the structure of the barley powdery mildew populations, of their virulence and of effectiveness of certain resistance genes against the infection was not conducted in Kazakhstan till present time. This paper is the first to describe characteristics of the pathotype structure of Blumeria graminis f.sp. hordei (Bgh) population and effectiveness of resistance genes in two regions of barley cultivation in the republic. RESULTS: One hundred and seven isolates of Bgh were obtained from seven populations occurring on cultivated barley at two geographically locations in Kazakhstan during 2015 and 2016. Their virulence frequency was determined on 17 differential lines Pallas. All isolates were virulent on the resistance gene Mla8 and avirulent for the resistance genes Mla9, Mla1 + MlaAl2, Mla6 + Mla14, Mla13 + MlRu3, Mla7 + MlNo3, Mla10 + MlDu2, Mla13 + MlRu3 and Mlo-5. The frequencies of isolates overcoming the genes Mla3, Mla22, Mlat Mlg + MlCP and Mla12 + MlEm2 were 0.0-33.33%, and frequencies of isolates overcoming the genes Mlra, Mlk, MlLa and Mlh ranged from 10.0 to 78.6%. Based on reactions of differential lines possessing the genes Mla22, Mlra, Mlk, Mlat, MlLa and Mlh, pathotypes were identified. In total, 23 pathotypes with virulence complexity ranging from 1 to 6 were identified. During both years in all populations of South Kazakhstan and Zhambyl regions pathotypes 24 and 64 mainly prevailed. CONCLUSIONS: Obtained data suggest that low similarity of populations Bgh in Kazakhstan to European, African, Australian and South-East Asian populations. The present study provides a foundation for future studies on the pathogenic variability within of Bgh populations in Kazakhstan and addresses the knowledge gap on the virulence structure of Bgh in Central Asia. Complete effectiveness of the resistance genes, for which no corresponding virulence was found, will allow Kazakhstanean breeders to access many modern barley cultivars that those possessing the resistance effectiveness genes. PMID- 29143601 TI - Morphological description and DNA barcoding study of sand rice (Agriophyllum squarrosum, Chenopodiaceae) collected in Kazakhstan. AB - BACKGROUND: Sand rice (Agriophyllum squarrosum (L.) Moq.) is an annual shrub-like plant adapted to the mobile sand dunes in desert and semi-desert regions of Asia. It has a balanced nutrient composition with relatively high concentration of lipids and proteins, which results in its nutrition being similar to legumes. Sand rice's proteins contain the full range of essential amino acids. However, calories content is more similar to wheat. These features together with desert stress resistance make sand rice a potential food crop resilient to ongoing climate change. It is also an important fodder crop (on young stages of growth) for cattle in arid regions of Kazakhstan. In our work, sand rice samples were collected from two distant regions of Kazakhstan as a part of the nation-wide project to determine genetic variation of the native flora. RESULTS: Samples were collected in western and southeastern parts of Kazakhstan separated by distances of up to 1300 km. Sequences of the nuclear ribosomal DNA ITS1-5.8S-ITS2 region and the chloroplast matK gene confirmed the identity of species defined by morphological traits. Comparison with GenBank sequences revealed polymorphic sequence positions among Kazakh populations and GenBank references, and suggested a distinction among local populations of sand rice. The phylogenetic analysis of nucleotide sequences showed a clear partition of A. squarrosum (L.) Moq. from Agriophyllum minus Fisch. & C.A. Mey, which grows in the same sand dunes environment. CONCLUSIONS: DNA barcoding analyses of ITS and matK sequences showed a segregation of A. squarrosum from A. minus into separate clades in Maximum Likelhood dendrograms. ITS analysis can be successfully used to characterize A. squarrosum populations growing quite distant from each other. The data obtained in this work provide the basis for further investigations on A. squarrosum population structure and may play a role in the screening of sand rice plants growing in desert and semi-desert environments of Central Asia and China. PMID- 29143602 TI - Molecular and agro-morphological characterization of ancient wheat landraces of turkey. AB - BACKGROUND: Turkey is one of the important gene centers for many crop species. In this research, some ancient wheats such as tetraploid and diploid hulled wheats together with hexaploid tir wheats (Triticum aestivum ssp. leucospermum Korn.) landraces mainly adapted to harsh winter conditions of Eastern Anatolian region of Turkey were characterized at agro-morphological and molecular level. Totally 50 hulled wheat population from Kastamonu, Konya and Kayseri provinces and 15 tir wheats from Kars provinces of Turkey were in-situ collected for characterization in 2013. Some quantitative and qualitative traits of each population were determined. RESULTS: Twenty three hulled wheat population collected from Kastamonu province were distinguished into nine emmer and 14 einkorn wheats at morphological level. Additionally, Konya, Kayseri and Kars population were characterized as einkorn, emmer and tir wheat, respectively. Among the evaluated traits, protein ratios of hulled wheats were strikingly higher than registered cultivars. All the populations were also examined by molecular level by using fluorescently labelled 11 polymorphic SSRs primers. The primers exhibited 104 bands, ranging from 6 to 16 with a mean value 9.45 per loci. The clustering analysis separated the germplasm into two clusters which were also divided into two subclusters based on genetic similarity coefficient. Sixty-five population and five checks were analyzed to estimate mean number of alleles (N), expected and observed heterozygoties (He and Ho), polymorphism information content (PIC), Wright fix index (F), genetic deviation from Hardy-Weinberg expectation (Fit-Fis) and genetic variation (Fst) were determined as 9.45, 0.71, 0.07, 0.67, 0.90, 0.39, 0.87 and 0.39, respectively. A clear genetic deviation from Hardy - Weinberg expectation was observed among population in particular. These results showed considerable genetic variation among landraces rather than within population. CONCLUSIONS: These molecular information has revealed genetically diverse einkorn, emmer wheat and tir wheat population could be used as parents for further breeding studies in both Turkey and abroad. Furthermore, the molecular analysis has also generally discriminated the germplasm into ploidy level. PMID- 29143603 TI - Evolution of VRN-1 homoeologous loci in allopolyploids of Triticum and their diploid precursors. AB - BACKGROUND: The key gene in genetic system controlling the duration of the vegetative period in cereals is the VRN1 gene, whose product under the influence of low temperature (vernalization) promotes the transition of the apical meristem cells into a competent state for the development of generative tissues of spike. As early genetic studies shown, the dominant alleles of this gene underlie the spring forms of plants that do not require vernalization for this transition. In wheat allopolyploids various combinations of alleles of the VRN1 homoeologous loci (VRN1 homoeoalleles) provide diversity in such important traits as the time to heading, height of plants and yield. Due to genetical mapping of VRN1 loci it became possible to isolate the dominant VRN1 alleles and to study their molecular structure compared with the recessive alleles defining the winter type of plants. Of special interest is the process of divergence of VRN1 loci in the course of evolution from diploid ancestors to wheat allopolyploids of different levels of ploidy. RESULTS: Molecular analysis of VRN1 loci allowed to establish that various dominant alleles of these loci appeared as a result of mutations in two main regulatory regions: the promoter and the first intron. In the diploid ancestors of wheat, especially, in those of A- genome (T. boeoticum, T. urartu), the dominant VRN1 alleles are rare in accordance with a limited distribution of spring forms in these species. In the first allotetraploid wheat species including T. dicoccoides, T. araraticum (T. timopheevii), the spring forms were associated with a new dominant alleles, mainly, within the VRN-A1 locus. The process of accumulation of new dominant alleles at all VRN1 loci was significantly accelerated in cultivated wheat species, especially in common, hexaploid wheat T. aestivum, as a result of artificial selection of spring forms adapted to different climatic conditions and containing various combinations of VRN1 homoeoalleles. CONCLUSIONS: This mini-review summarizes data on the molecular structure and distribution of various VRN1 homoeoalleles in wheat allopolyploids and their diploid predecessors. PMID- 29143604 TI - Fine organization of genomic regions tagged to the 5S rDNA locus of the bread wheat 5B chromosome. AB - BACKGROUND: The multigene family encoding the 5S rRNA, one of the most important structurally-functional part of the large ribosomal subunit, is an obligate component of all eukaryotic genomes. 5S rDNA has long been a favored target for cytological and phylogenetic studies due to the inherent peculiarities of its structural organization, such as the tandem arrays of repetitive units and their high interspecific divergence. The complex polyploid nature of the genome of bread wheat, Triticum aestivum, and the technically difficult task of sequencing clusters of tandem repeats mean that the detailed organization of extended genomic regions containing 5S rRNA genes remains unclear. This is despite the recent progress made in wheat genomic sequencing. Using pyrosequencing of BAC clones, in this work we studied the organization of two distinct 5S rDNA-tagged regions of the 5BS chromosome of bread wheat. RESULTS: Three BAC-clones containing 5S rDNA were identified in the 5BS chromosome-specific BAC-library of Triticum aestivum. Using the results of pyrosequencing and assembling, we obtained six 5S rDNA- containing contigs with a total length of 140,417 bp, and two sets (pools) of individual 5S rDNA sequences belonging to separate, but closely located genomic regions on the 5BS chromosome. Both regions are characterized by the presence of approximately 70-80 copies of 5S rDNA, however, they are completely different in their structural organization. The first region contained highly diverged short-type 5S rDNA units that were disrupted by multiple insertions of transposable elements. The second region contained the more conserved long-type 5S rDNA, organized as a single tandem array. FISH using probes specific to both 5S rDNA unit types showed differences in the distribution and intensity of signals on the chromosomes of polyploid wheat species and their diploid progenitors. CONCLUSION: A detailed structural organization of two closely located 5S rDNA-tagged genomic regions on the 5BS chromosome of bread wheat has been established. These two regions differ in the organization of both 5S rDNA and the neighboring sequences comprised of transposable elements, implying different modes of evolution for these regions. PMID- 29143605 TI - Impact of the 7-bp deletion in HvGA20ox2 gene on agronomic important traits in barley (Hordeum vulgare L.). AB - BACKGROUND: Alike to Reduced height-1 (Rht-1) genes in wheat and the semi dwarfing (sd-1) gene in rice, the sdw1/denso locus involved in the metabolism of the GA, was designated as the 'Green Revolution' gene in barley. The recent molecular characterization of the candidate gene HvGA20ox2 for sdw1/denso locus allows to estimate the impact of the functional polymorphism of this gene on the variation of agronomically important traits in barley. RESULTS: We investigated the effect of the 7-bp deletion in exon 1 of HvGA20ox2 gene (sdw1.d mutation) on the variation of yield-related and malting quality traits in the population of DHLs derived from cross of medium tall barley Morex and semi-dwarf barley Barke. Segregation of plant height, flowering time, thousand grain weight, grain protein content and grain starch was evaluated in two diverse environments separated from one another by 15 degrees of latitude. The 7-bp deletion in HvGA20ox2 gene reduced plant height by approximately 13 cm and delayed flowering time by 3-5 days in the barley segregating DHLs population independently on environmental cue. On other hand, the sdw1.d mutation did not affect significantly either grain quality traits (protein and starch content) or thousand grain weight. CONCLUSIONS: The beneficial effect of the sdw1.d allele could be associated in barley with lodging resistance and extended period of vegetative growth allowing to accumulate additional biomass that supports higher yield in certain environments. However, no direct effect of the sdw1.d mutation on thousand grain weight or grain quality traits in barley was detected. PMID- 29143606 TI - Metabolic pathways and genes identified by RNA-seq analysis of barley near isogenic lines differing by allelic state of the Black lemma and pericarp (Blp) gene. AB - BACKGROUND: Some plant species have 'melanin-like' black seed pigmentation. However, the chemical and genetic nature of this 'melanin-like' black pigment have not yet been fully explored due to its complex structure and ability to withstand almost all solvents. Nevertheless, identification of genetic networks participating in trait formation is key to understanding metabolic processes involved in the expression of 'melanin-like' black seed pigmentation. The aim of the current study was to identify differentially expressed genes (DEGs) in barley near-isogenic lines (NILs) differing by allelic state of the Blp (black lemma and pericarp) locus. RESULTS: RNA-seq analysis of six libraries (three replicates for each line) was performed. A total of 957 genome fragments had statistically significant changes in expression levels between lines BLP and BW, with 632 fragments having increased expression levels in line BLP and 325 genome fragments having decreased expression. Among identified DEGs, 191 genes were recognized as participating in known pathways. Among these were metabolic pathways including 'suberin monomer biosynthesis', 'diterpene phytoalexins precursors biosynthesis', 'cutin biosynthesis', 'cuticular wax biosynthesis', and 'phenylpropanoid biosynthesis, initial reactions'. Differential expression was confirmed by real time PCR analysis of selected genes. CONCLUSIONS: Metabolic pathways and genes presumably associated with black lemma and pericarp colour as well as Blp associated resistance to oxidative stress and pathogens, were revealed. We suggest that the black pigmentation of lemmas and pericarps is related to increased level of phenolic compounds and their oxidation. The effect of functional Blp on the synthesis of ferulic acid and other phenolic compounds can explain the increased antioxidant capacity and biotic and abiotic stress tolerance of black-grained cereals. Their drought tolerance and resistance to diseases affecting the spike may also be related to cuticular wax biosynthesis. In addition, upregulated synthesis of phytoalexins, suberin and universal stress protein (USP) in lemmas and pericarps of the Blp carriers may contribute to their increased disease resistance. Further description of the DEGs haplotypes and study of their association with physiological characteristics may be useful for future application in barley pre-breeding. PMID- 29143607 TI - Features of Ppd-B1 expression regulation and their impact on the flowering time of wheat near-isogenic lines. AB - BACKGROUND: Photoperiod insensitive Ppd-1a alleles determine early flowering of wheat. Increased expression of homoeologous Ppd-D1a and Ppd-A1a result from deletions in the promoter region, and elevated expression of Ppd-B1a is determined by an increased copy number. RESULTS: In this study, using bread wheat cultivars Sonora and PSL2, which contrast in flowering time, and near-isogenic lines resulting from their cross, "Ppd-m" and "Ppd-w" with Ppd-B1a introgressed from Sonora, we investigated the putative factors that influence Ppd-B1a expression. By analyzing the Ppd-B1a three distinct copies, we identified an indel and the two SNPs, which distinguished the investigated allele from other alleles with a copy number variation. We studied the expression of the Ppd-A1, Ppd-B1a, and Ppd-D1 genes along with genes that are involved in light perception (PhyA, PhyB, PhyC) and the flowering initiation (Vrn-1, TaFT1) and discussed their interactions. Expression of Ppd-B1a in the "Ppd-m" line, which flowered four days earlier than "Ppd-w", was significantly higher. We found PhyC to be up regulated in lines with Ppd-B1a alleles. Expression of PhyC was higher in "Ppd m". Microsatellite genotyping demonstrated that in the line "Ppd-m", there is an introgression in the pericentromeric region of chromosome 5B from the early flowering parental Sonora, while the "Ppd-w" does not have this introgression. FHY3/FAR1 is known to be located in this region. Expression of the transcription factor FHY3/FAR1 was higher in the "Ppd-m" line than in "Ppd-w", suggesting that FHY3/FAR1 is important for the wheat flowering time and may cause earlier flowering of "Ppd-m" as compared to "Ppd-w". CONCLUSIONS: We propose that there is a positive bidirectional regulation of Ppd-B1a and PhyC with an FHY3/FAR1 contribution. The bidirectional regulation can be proposed for Ppd-A1a and Ppd D1a. Using in silico analysis, we demonstrated that the specificity of the Ppd-B1 regulation compared to that of homoeologous genes involves not only a copy number variation but also distinct regulatory elements. PMID- 29143608 TI - Physical activity in the prevention of human diseases: role of epigenetic modifications. AB - Epigenetic modification refers to heritable changes in gene function that cannot be explained by alterations in the DNA sequence. The current literature clearly demonstrates that the epigenetic response is highly dynamic and influenced by different biological and environmental factors such as aging, nutrient availability and physical exercise. As such, it is well accepted that physical activity and exercise can modulate gene expression through epigenetic alternations although the type and duration of exercise eliciting specific epigenetic effects that can result in health benefits and prevent chronic diseases remains to be determined. This review highlights the most significant findings from epigenetic studies involving physical activity/exercise interventions known to benefit chronic diseases such as metabolic syndrome, diabetes, cancer, cardiovascular and neurodegenerative diseases. PMID- 29143609 TI - Survey of programmatic experiences and challenges in delivery of hepatitis B and C testing in low- and middle-income countries. AB - BACKGROUND: There have been few reports on programmatic experience of viral hepatitis testing and treatment in resource-limited settings. To inform the development of the 2017 World Health Organization (WHO) viral hepatitis testing guidance and in particular the feasibility of proposed recommendations, we undertook a survey across a range of organisations engaged with hepatitis testing in low- and middle-income countries (LMICs). Our objective was to describe current hepatitis B and C testing practices across a range of settings in different countries, as well as key barriers or challenges encountered and proposed solutions to promote testing scale-up. METHODS: Hepatitis testing programmes in predominantly LMICs were identified from the WHO Global Hepatitis Programme contacts database and through WHO regional offices, and invited to participate. The survey comprised a six-part structured questionnaire: general programme information, description of hepatitis testing, treatment and care services, budget and funding, data on programme outcomes, and perceptions on key barriers encountered and strategies to address these. RESULTS: We interviewed 22 viral hepatitis testing programmes from 19 different countries. Nine were from the African region; 6 from the Western Pacific; 4 from South-East Asia; and 3 from Eastern Europe. All but four of the programmes were based in LMICs, and 10 (45.5%) were supported by non-governmental or international organizations. All but two programmes undertook targeted testing of specific affected populations such as people living with HIV, people who inject drugs, sex workers, health care workers, and pregnant women. Only two programmes focussed on routine testing in the general population. The majority of programmes were testing in hospital-based or other health facilities, particularly HIV clinics, and community-based testing was limited. Nucleic acid testing (NAT) for confirmation of HCV and HBV viraemia was available in only 30% and 18% of programmes, respectively. Around a third of programmes required some patient co-payment for diagnosis. The most commonly identified challenges in scale-up of hepatitis testing were: limited community awareness about viral hepatitis; lack of facilities or services for hepatitis testing; no access to low cost treatment, particularly for HCV; absence of national guidance and policies; no dedicated budget for hepatitis; and lack of trained health care and laboratory workers. CONCLUSIONS: At this early stage in the global scale-up of testing for viral hepatitis, there is a wide variation in testing practices and approaches across different programmes. There remains limited access to NAT to confirm viraemia, and patient self-payment for testing and treatment is common. There was consensus from implementing organizations that scale-up of testing will require increased community awareness, health care worker training, development of national strategies and guidelines, and improved access to low cost NAT virological testing. PMID- 29143610 TI - Development of F1 hybrid population and the high-density linkage map for European aspen (Populus tremula L.) using RADseq technology. AB - BACKGROUND: Restriction-site associated DNA sequencing (RADseq) technology was recently employed to identify a large number of single nucleotide polymorphisms (SNP) for linkage mapping of a North American and Eastern Asian Populus species. However, there is also the need for high-density genetic linkage maps for the European aspen (P. tremula) as a tool for further mapping of quantitative trait loci (QTLs) and marker-assisted selection of the Populus species native to Europe. RESULTS: We established a hybrid F1 population from the cross of two aspen parental genotypes diverged in their phenological and morphological traits. We performed RADseq of 122 F1 progenies and two parents yielding 15,732 high quality SNPs that were successfully identified using the reference genome of P. trichocarpa. 2055 SNPs were employed for the construction of maternal and paternal linkage maps. The maternal linkage map was assembled with 1000 SNPs, containing 19 linkage groups and spanning 3054.9 cM of the genome, with an average distance of 3.05 cM between adjacent markers. The paternal map consisted of 1055 SNPs and the same number of linkage groups with a total length of 3090.56 cM and average interval distance of 2.93 cM. The linkage maps were employed for QTL mapping of one-year-old seedlings height variation. The most significant QTL (LOD = 5.73) was localized to LG5 (96.94 cM) of the male linkage map, explaining 18% of the phenotypic variation. CONCLUSIONS: The set of 15,732 SNPs polymorphic in aspen and high-density genetic linkage maps constructed for the P. tremula intra-specific cross will provide a valuable source for QTL mapping and identification of candidate genes facilitating marker-assisted selection in European aspen. PMID- 29143611 TI - One or two serological assay testing strategy for diagnosis of HBV and HCV infection? The use of predictive modelling. AB - BACKGROUND: Initial serological testing for chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is conducted using either rapid diagnostic tests (RDT) or laboratory-based enzyme immunoassays (EIA)s for detection of hepatitis B surface antigen (HBsAg) or antibodies to HCV (anti-HCV), typically on serum or plasma specimens and, for certain RDTs, capillary whole blood. WHO recommends the use of standardized testing strategies - defined as a sequence of one or more assays to maximize testing accuracy while simplifying the testing process and ideally minimizing cost. Our objective was to examine the diagnostic outcomes of a one- versus two-assay serological testing strategy. These data were used to inform recommendations in the 2017 WHO Guidelines on hepatitis B and C testing. METHODS: Few published studies have compared diagnostic outcomes for one assay versus two-assay serological testing strategies for HBsAg and anti-HCV. Therefore, the principles of Bayesian statistics were used to conduct a modelling exercise to examine the outcomes of a one-assay versus two-assay testing strategy when applied to a hypothetical population of 10,000 individuals. The resulting model examined the diagnostic outcomes (true and false positive diagnoses; true and false negative diagnoses; positive and negative predictive values as a function of prevalence; and total tests required) for both one-assay and two assay testing strategies. The performance characteristics assumed for assays used within the testing strategies were informed by WHO prequalification assessment findings and systematic reviews for diagnostic accuracy studies. Each of the presumptive testing strategies (one-assay or two-assay) was modelled at varying prevalences of HBsAg (10%, 2% and 0.4%) and of anti-HCV (40%, 10%, 2% and 0.4%), aimed at representing the range of testing populations typically encountered in WHO Member States. When the two-assay testing strategy was considered, the model assumed the independence of the two assays. RESULTS: Modeling demonstrated that applying a single assay (HBsAg or anti-HCV), even with high specificity (99%), may result in considerable numbers of false positive diagnoses and low positive predictive values (PPV), particularly in lower prevalence settings. Even at very low prevalences shifting to a two-assay testing strategy would result in a PPV approaching 1.0. When test sensitivity is high (>99%) false negative reactions are rare at all but the highest prevalences; but a two-test strategy might yield more false negative diagnoses. The order in which the tests are used has no impact on the overall accuracy of a two-assay strategy though it may impact the total number of tests needed to complete the diagnostic strategy, incurring added cost and complexity. HBsAg assays may have a low sensitivity (<90%), and result in large numbers of false negative diagnoses, particularly in high prevalence settings, which would be exacerbated in the two-assay testing strategy. In contrast, most anti-HCV assays have high sensitivity and lead to fewer false negative results, both in the one-assay and two-assay testing strategies. At prevalences <=2% the number of tests needed using a second assay was nearly always small, at <300 per 10,000 individuals tested, making sustainability of a second assay uncertain in such a setting. CONCLUSIONS: A key public health objective of an effective testing strategy is to identify all individuals who would benefit from treatment. Therefore, a strategy that prioritizes a high NPV (minimal false negatives) may be acceptable even if the PPV is suboptimal (some false positives) as the implementation of such a public health programme must also take account of other factors such as costs, feasibility, impact on testing uptake and linkage to care, and consequences of a false-positive test. This rationale informed the development of the WHO Viral Hepatitis Testing Guidelines, with a conditional recommendation for a one-assay serological testing strategy in most testing settings and populations (>=0.4% prevalence in population tested). A one-test strategy results in few failures to diagnose infection and, although it is associated under most assumptions with a sub-optimal PPV, benefits include greater simplicity, easier implementation, lower costs and better feasibility, uptake and linkage to care. Furthermore, prior to antiviral therapy all those diagnosed either HBsAg or anti-HCV positive will require confirmation of viraemia, preventing unnecessary treatment of those who may be false positive on serology. For HBsAg, in low-prevalence settings (<=0.4%), a second recommendation was made to consider a two-assay testing strategy, using a confirmatory neutralization step or a second different HBsAg assay. PMID- 29143613 TI - WHO guidelines on testing for hepatitis B and C - meeting targets for testing. PMID- 29143612 TI - Values, preferences and current hepatitis B and C testing practices in low- and middle-income countries: results of a survey of end users and implementers. AB - BACKGROUND: Access to hepatitis B virus (HBV) and hepatitis C virus (HCV) diagnostics remains a key bottleneck in scale-up of access to HBV and HCV treatment, particularly in low- and middle-income countries (LMICs) that lack laboratory resources and skilled personnel. To inform the development of World Health Organization (WHO) testing guidelines on who to test and how to test, we performed a "values and preferences" survey of end users and implementers of hepatitis testing in LMICs on current hepatitis B and C testing practices and acceptability of diagnostic approaches, as well as preferences for the future. METHODS: The survey consisted of a four-part, 28 question online survey tool using SurveyMonkey software. The invitation to participate was sent via email to a network of contacts in hepatitis clinical care, research, advocacy and industry. RESULTS: The survey collected responses on current testing practices from 48 respondents in 23 LMICs. Only a small proportion of hepatitis testing is currently funded through government-supported programmes. Most limit their testing programmes to blood donor screening and although testing is recommended in several populations, this is not well implemented. Also, there is still very limited access to virological testing. CONCLUSIONS: The survey showed that HBV and HCV testing programmes in LMICs are inadequate and/or scarce. Lack of affordable diagnostic tests; lack of funding, public education and awareness; absence of national policies and guidelines; and a dearth of skilled health professionals are the most important barriers to scaling up HBV and HCV diagnosis and treatment. PMID- 29143614 TI - Composite measures of women's empowerment and their association with maternal mortality in low-income countries. AB - BACKGROUND: Maternal mortality has declined significantly since 1990. While better access to emergency obstetrical care is partially responsible, women's empowerment might also be a contributing factor. Gender equality composite measures generally include various dimensions of women's advancement, including educational parity, formal employment, and political participation. In this paper, we compare several composite measures to assess which, if any, are associated with maternal mortality ratios (MMRs) in low-income countries, after controlling for other macro-level and direct determinants. METHODS: Using data from 44 low-income countries (half in Africa), we assessed the correlation of three composite measures - the Gender Gap Index, the Gender Equity Index (GEI), and the Social Institutions and Gender Index (SIGI) - with MMRs. We also examined two recognized contributors to reduce maternal mortality (skilled birth attendance (SBA) and total fertility rate (TFR)) as well as several economic and political variables (such as the Corruption Index) to see which tracked most closely with MMRs. We examined the countries altogether, and disaggregated by region. We then performed multivariate analysis to determine which measures were predictive. RESULTS: Two gender measures (GEI and SIGI) and GDP per capita were significantly correlated with MMRs for all countries. For African countries, the SIGI, TFR, and Corruption Index were significant, whereas the GEI, SBA, and TFR were significant in non-African countries. After controlling for all measures, SBA emerged as a predictor of log MMR for non-African countries (beta = -0.04, P = 0.01). However, for African countries, only the Corruption Index was a predictor (beta = -0.04, P = 0.04). No gender measure was significant. CONCLUSIONS: In African countries, corruption is undermining the quality of maternal care, the availability of critical drugs and equipment, and pregnant women's motivation to deliver in a hospital setting. Improving gender equality and SBA rates is unlikely to reduce MMR in Africa unless corruption is addressed. In other regions, increasing SBA rates can be expected to lower MMRs. PMID- 29143617 TI - Introduction: reporting on updates in the scientific basis for the Lives Saved Tool (LiST). PMID- 29143615 TI - Diagnostic accuracy of tests to detect Hepatitis C antibody: a meta-analysis and review of the literature. AB - BACKGROUND: Although direct-acting antivirals can achieve sustained virological response rates greater than 90% in Hepatitis C Virus (HCV) infected persons, at present the majority of HCV-infected individuals remain undiagnosed and therefore untreated. While there are a wide range of HCV serological tests available, there is a lack of formal assessment of their diagnostic performance. We undertook a systematic review and meta-analysis to evaluate he diagnostic accuracy of available rapid diagnostic tests (RDT) and laboratory based EIA assays in detecting antibodies to HCV. METHODS: We used the PRISMA checklist and Cochrane guidance to develop our search protocol. The search strategy was registered in PROSPERO (CRD42015023567). The search focused on hepatitis C, diagnostic tests, and diagnostic accuracy within eight databases (MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, SCOPUS, Literatura Latino Americana e do Caribe em Ciencias da Saude and WHO Global Index Medicus. Studies were included if they evaluated an assay to determine the sensitivity and specificity of HCV antibody (HCV Ab) in humans. Two reviewers independently extracted data and performed a quality assessment of the studies using the QUADAS tool. We pooled test estimates using the DerSimonian-Laird method, by using the software R and RevMan. 5.3. RESULTS: A total of 52 studies were identified that included 52,673 unique test measurements. Based on five studies, the pooled sensitivity and specificity of HCV Ab rapid diagnostic tests (RDTs) were 98% (95% CI 98-100%) and 100% (95% CI 100-100%) compared to an enzyme immunoassay (EIA) reference standard. High HCV Ab RDTs sensitivity and specificity were observed across screening populations (general population, high risk populations, and hospital patients) using different reference standards (EIA, nucleic acid testing, immunoblot). There were insufficient studies to undertake subanalyses based on HIV co-infection. Oral HCV Ab RDTs also had excellent sensitivity and specificity compared to blood reference tests, respectively at 94% (95% CI 93 96%) and 100% (95% CI 100-100%). Among studies that assessed individual oral RDTs, the eight studies revealed that OraQuick ADVANCE(r) had a slightly higher sensitivity (98%, 95% CI 97-98%) compared to the other oral brands (pooled sensitivity: 88%, 95% CI 84-92%). CONCLUSIONS: RDTs, including oral tests, have excellent sensitivity and specificity compared to laboratory-based methods for HCV antibody detection across a wide range of settings. Oral HCV Ab RDTs had good sensitivity and specificity compared to blood reference standards. PMID- 29143616 TI - Diagnostic accuracy of detection and quantification of HBV-DNA and HCV-RNA using dried blood spot (DBS) samples - a systematic review and meta-analysis. AB - BACKGROUND: The detection and quantification of hepatitis B (HBV) DNA and hepatitis C (HCV) RNA in whole blood collected on dried blood spots (DBS) may facilitate access to diagnosis and treatment of HBV and HCV infection in resource poor settings. We evaluated the diagnostic performance of DBS compared to venous blood samples for detection and quantification of HBV-DNA and HCV-RNA in two systematic reviews and meta-analyses on the diagnostic accuracy of HBV DNA and HCV RNA from DBS compared to venous blood samples. METHODS: We searched MEDLINE, Embase, Global Health, Web of Science, LILAC and Cochrane library for studies that assessed diagnostic accuracy with DBS. Heterogeneity was assessed and where appropriate pooled estimates of sensitivity and specificity were generated using bivariate analyses with maximum likelihood estimates and 95% confidence intervals. We also conducted a narrative review on the impact of varying storage conditions or different cut-offs for detection from studies that undertook this in a subset of samples. The QUADAS-2 tool was used to assess risk of bias. RESULTS: In the quantitative synthesis for diagnostic accuracy of HBV-DNA using DBS, 521 citations were identified, and 12 studies met the inclusion criteria. Overall quality of studies was rated as low. The pooled estimate of sensitivity and specificity for HBV-DNA was 95% (95% CI: 83-99) and 99% (95% CI: 53-100), respectively. In the two studies that reported on cut-offs and limit of detection (LoD) - one reported a sensitivity of 98% for a cut-off of >=2000 IU/ml and another reported a LoD of 914 IU/ml using a commercial assay. Varying storage conditions for individual samples did not result in a significant variation of results. In the synthesis for diagnostic accuracy of HCV-RNA using DBS, 15 studies met the inclusion criteria, and this included six additional studies to a previously published review. The pooled sensitivity and specificity was 98% (95% CI:95-99) and 98% (95% CI:95-99.0), respectively. Varying storage conditions resulted in a decrease in accuracy for quantification but not for reported positivity. CONCLUSIONS: These findings show a high level of diagnostic performance for the use of DBS for HBV-DNA and HCV-RNA detection. However, this was based on a limited number and quality of studies. There is a need for development of standardized protocols by manufacturers on the use of DBS with their assays, as well as for larger studies on use of DBS conducted in different settings and with varying storage conditions. PMID- 29143618 TI - Using the missed opportunity tool as an application of the Lives Saved Tool (LiST) for intervention prioritization. AB - BACKGROUND: The Missed Opportunity tool was developed as an application in the Lives Saved Tool (LiST) to allow users to quickly compare the relative impact of interventions. Global Financing Facility (GFF) investment cases have been identified as a potential application of the Missed Opportunity analyses in Democratic Republic of the Congo (DRC), Ethiopia, Kenya, and Tanzania, to use 'lives saved' as a normative factor to set priorities. METHODS: The Missed Opportunity analysis draws on data and methods in LiST to project maternal, stillbirth, and child deaths averted based on changes in interventions' coverage. Coverage of each individual intervention in LiST was automated to be scaled up from current coverage to 90% in the next year, to simulate a scenario where almost every mother and child receive proven interventions that they need. The main outcome of the Missed Opportunity analysis is deaths averted due to each intervention. RESULTS: When reducing unmet need for contraception is included in the analysis, it ranks as the top missed opportunity across the four countries. When it is not included in the analysis, top interventions with the most total deaths averted are hospital-based interventions such as labor and delivery management in the CEmOC and BEmOC level, and full treatment and supportive care for premature babies, and for sepsis/pneumonia. CONCLUSIONS: The Missed Opportunity tool can be used to provide a quick, first look at missed opportunities in a country or geographic region, and help identify interventions for prioritization. While it is a useful advocate for evidence-based priority setting, decision makers need to consider other factors that influence decision making, and also discuss how to implement, deliver, and sustain programs to achieve high coverage. PMID- 29143619 TI - Diagnostic accuracy of tests to detect hepatitis B surface antigen: a systematic review of the literature and meta-analysis. AB - BACKGROUND: Chronic Hepatitis B Virus (HBV) infection is characterised by the persistence of hepatitis B surface antigen (HBsAg). Expanding HBV diagnosis and treatment programmes into low resource settings will require high quality but inexpensive rapid diagnostic tests (RDTs) in addition to laboratory-based enzyme immunoassays (EIAs) to detect HBsAg. The purpose of this review is to assess the clinical accuracy of available diagnostic tests to detect HBsAg to inform recommendations on testing strategies in 2017 WHO hepatitis testing guidelines. METHODS: The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using 9 databases. Two reviewers independently extracted data according to a pre specified plan and evaluated study quality. Meta-analysis was performed. HBsAg diagnostic accuracy of rapid diagnostic tests (RDTs) was compared to enzyme immunoassay (EIA) and nucleic-acid test (NAT) reference standards. Subanalyses were performed to determine accuracy among brands, HIV-status and specimen type. RESULTS: Of the 40 studies that met the inclusion criteria, 33 compared RDTs and/or EIAs against EIAs and 7 against NATs as reference standards. Thirty studies assessed diagnostic accuracy of 33 brands of RDTs in 23,716 individuals from 23 countries using EIA as the reference standard. The pooled sensitivity and specificity were 90.0% (95% CI: 89.1, 90.8) and 99.5% (95% CI: 99.4, 99.5) respectively, but accuracy varied widely among brands. Accuracy did not differ significantly whether serum, plasma, venous or capillary whole blood was used. Pooled sensitivity of RDTs in 5 studies of HIV-positive persons was lower at 72.3% (95% CI: 67.9, 76.4) compared to that in HIV-negative persons, but specificity remained high. Five studies evaluated 8 EIAs against a chemiluminescence immunoassay reference standard with a pooled sensitivity and specificity of 88.9% (95% CI: 87.0, 90.6) and 98.4% (95% CI: 97.8, 98.8), respectively. Accuracy of both RDTs and EIAs using a NAT reference were generally lower, especially amongst HIV-positive cohorts. CONCLUSIONS: HBsAg RDTs have good sensitivity and excellent specificity compared to laboratory immunoassays as a reference standard. Sensitivity of HBsAg RDTs may be lower in HIV infected individuals. PMID- 29143620 TI - Optimising diagnosis of viraemic hepatitis C infection: the development of a target product profile. AB - BACKGROUND: The current low access to virological testing to confirm chronic viraemic HCV infection in low- and middle-income countries (LMIC) is limiting the rollout of hepatitis C (HCV) care. Existing tests are complex, costly and require sophisticated laboratory infrastructure. Diagnostic manufacturers need guidance on the optimal characteristics a virological test needs to have to ensure the greatest impact on HCV diagnosis and treatment in LMIC. Our objective was to develop a target product profile (TPP) for diagnosis of HCV viraemia using a global stakeholder consensus-based approach. METHODS: Based on the standardised process established to develop consensus-based TPPs, we followed five key steps. (i) Identifying key potential global stakeholders for consultation and input into the TPP development process. (ii) Informal priority-setting exercise with key experts to identify the needs that should be the highest priority for the TPP development; (iii) Defining the key TPP domains (scope, performance and operational characteristics and price). (iv) Delphi-like process with larger group of key stakeholder to facilitate feedback on the key TPP criteria and consensus building based on pre-defined consensus criteria. (v) A final consensus gathering meeting for discussions around disputed criteria. A complementary values and preferences survey helped to assess trade-offs between different key characteristics. RESULTS: The following key attributes for the TPP for a test to confirm HCV viraemic infection were identified: The scope defined is for both HCV detection as well as confirmation of cure. The timeline of development for tests envisioned in the TPP is 5 years. The test should be developed for use by health care workers or laboratory technicians with limited training in countries with a medium to high prevalence of HCV (1.5-3.5% and >3.5%) and in high-risk populations in low prevalence settings (<1.5%). A clinical sensitivity at a minimum of 90% is considered sufficient (analytical sensitivity of the equivalent of 3000 IU/ml), particularly if the test increases access to testing through an affordable price, increase ease-of-use and feasibility on capillary blood. Polyvalency would be optimal (i.e. ability to test for HIV and others). The only characteristic that full agreement could not be achieved on was the price for a virological test. Discussants felt that to reach the optimal target price substantial trade-offs had to be made (e.g. in regards to sensitivity and integration). CONCLUSION: The TPP and V&P survey results define the need for an easy-to-use, low cost test to increase access to diagnosis and linkage to care in LMIC. PMID- 29143621 TI - Identification and characterization of regulatory network components for anthocyanin synthesis in barley aleurone. AB - BACKGROUND: Among natural populations, there are different colours of barley (Hordeum vulgare L.). The colour of barley grains is directly related to the accumulation of different pigments in the aleurone layer, pericarp and lemma. Blue grain colour is due to the accumulation of anthocyanins in the aleurone layer, which is dependent on the presence of five Blx genes that are not sequenced yet (Blx1, Blx3 and Blx4 genes clustering on chromosome 4HL and Blx2 and Blx5 on 7HL). Due to the health benefits of anthocyanins, blue-grained barley can be considered as a source of dietary food. The goal of the current study was to identify and characterize components of the anthocyanin synthesis regulatory network for the aleurone layer in barley. RESULTS: The candidate genes for components of the regulatory complex MBW (consisting of transcription factors MYB, bHLH/MYC and WD40) for anthocyanin synthesis in barley aleurone were identified. These genes were designated HvMyc2 (4HL), HvMpc2 (4HL), and HvWD40 (6HL). HvMyc2 was expressed in aleurone cells only. A loss-of-function (frame shift) mutation in HvMyc2 of non-coloured compared to blue-grained barley was revealed. Unlike aleurone-specific HvMyc2, the HvMpc2 gene was expressed in different tissues; however, its activity was not detected in non-coloured aleurone in contrast to a coloured aleurone, and allele-specific mutations in its promoter region were found. The single-copy gene HvWD40, which encodes the required component of the regulatory MBW complex, was expressed constantly in coloured and non-coloured tissues and had no allelic differences. HvMyc2 and HvMpc2 were genetically mapped using allele-specific developed CAPS markers developed. HvMyc2 was mapped in position between SSR loci XGBS0875-4H (3.4 cM distal) and XGBM1048-4H (3.4 cM proximal) matching the region chromosome 4HL where the Blx-cluster was found. In this position, one of the anthocyanin biosynthesis structural genes (HvF3'5'H) was also mapped using an allele-specific CAPS-marker developed in the current study. CONCLUSIONS: The genes involved in anthocyanin synthesis in the barley aleurone layer were identified and characterized, including components of the regulatory complex MBW, from which the MYC-encoding gene (HvMyc2) appeared to be the main factor underlying variation of barley by aleurone colour. PMID- 29143622 TI - Lives Saved Tool (LiST) costing: a module to examine costs and prioritize interventions. AB - BACKGROUND: Achieving the Sustainable Development Goals will require careful allocation of resources in order to achieve the highest impact. The Lives Saved Tool (LiST) has been used widely to calculate the impact of maternal, neonatal and child health (MNCH) interventions for program planning and multi-country estimation in several Lancet Series commissions. As use of the LiST model increases, many have expressed a desire to cost interventions within the model, in order to support budgeting and prioritization of interventions by countries. A limited LiST costing module was introduced several years ago, but with gaps in cost types. Updates to inputs have now been added to make the module fully functional for a range of uses. METHODS: This paper builds on previous work that developed an initial version of the LiST costing module to provide costs for MNCH interventions using an ingredients-based costing approach. Here, we update in 2016 the previous econometric estimates from 2013 with newly-available data and also include above-facility level costs such as program management. The updated econometric estimates inform percentages of intervention-level costs for some direct costs and indirect costs. These estimates add to existing values for direct cost requirements for items such as drugs and supplies and required provider time which were already available in LiST Costing. RESULTS: Results generated by the LiST costing module include costs for each intervention, as well as disaggregated costs by intervention including drug and supply costs, labor costs, other recurrent costs, capital costs, and above-service delivery costs. These results can be combined with mortality estimates to support prioritization of interventions by countries. CONCLUSIONS: The LiST costing module provides an option for countries to identify resource requirements for scaling up a maternal, neonatal, and child health program, and to examine the financial impact of different resource allocation strategies. It can be a useful tool for countries as they seek to identify the best investments for scarce resources. The purpose of the LiST model is to provide a tool to make resource allocation decisions in a strategic planning process through prioritizing interventions based on resulting impact on maternal and child mortality and morbidity. PMID- 29143623 TI - The impact of eliminating within-country inequality in health coverage on maternal and child mortality: a Lives Saved Tool analysis. AB - BACKGROUND: Inequality in healthcare across population groups in low-income countries is a growing topic of interest in global health. The Lives Saved Tool (LiST), which uses health intervention coverage to model maternal, neonatal, and child health outcomes such as mortality rates, can be used to analyze the impact of within-country inequality. METHODS: Data from nationally representative household surveys (98 surveys conducted between 1998 and 2014), disaggregated by wealth quintile, were used to create a LiST analysis that models the impact of scaling up health intervention coverage for the entire country from the national average to the rate of the top wealth quintile (richest 20% of the population). Interventions for which household survey data are available were used as proxies for other interventions that are not measured in surveys, based on co-delivery of intervention packages. RESULTS: For the 98 countries included in the analysis, 24 32% of child deaths (including 34-47% of neonatal deaths and 16-19% of post neonatal deaths) could be prevented by scaling up national coverage of key health interventions to the level of the top wealth quintile. On average, the interventions with most unequal coverage rates across wealth quintiles were those related to childbirth in health facilities and to water and sanitation infrastructure; the most equally distributed were those delivered through community-based mass campaigns, such as vaccines, vitamin A supplementation, and bednet distribution. CONCLUSIONS: LiST is a powerful tool for exploring the policy and programmatic implications of within-country inequality in low-income, high-mortality-burden countries. An "Equity Tool" app has been developed within the software to make this type of analysis easily accessible to users. PMID- 29143624 TI - Randomized controlled pilot of a group antenatal care model and the sociodemographic factors associated with pregnancy-related empowerment in sub Saharan Africa. AB - BACKGROUND: The links between empowerment and a number of health-related outcomes in sub-Saharan Africa have been documented, but empowerment related to pregnancy is under-investigated. Antenatal care (ANC) is the entry point into the healthcare system for most women, so it is important to understand how ANC affects aspects of women's sense of control over their pregnancy. We compare pregnancy-related empowerment for women randomly assigned to the standard of care versus CenteringPregnancy-based group ANC (intervention) in two sub-Saharan countries, Malawi and Tanzania. METHODS: Pregnant women in Malawi (n = 112) and Tanzania (n = 110) were recruited into a pilot study and randomized to individual ANC or group ANC. Retention at late pregnancy was 81% in Malawi and 95% in Tanzania. In both countries, individual ANC, termed focused antenatal care (FANC), is the standard of care. FANC recommends four ANC visits plus a 6-week post-birth visit and is implemented following the country's standard of care. In group ANC, each contact included self- and midwife-assessments in group space and 90 minutes of interactive health promotion. The number of contacts was the same for both study conditions. We measured pregnancy-related empowerment in late pregnancy using the Pregnancy-Related Empowerment Scale (PRES). Independent samples t-tests and multiple linear regressions were employed to assess whether group ANC led to higher PRES scores than individual ANC and to investigate other sociodemographic factors related to pregnancy-related empowerment. RESULTS: In Malawi, women in group ANC had higher PRES scores than those in individual ANC. Type of care was a significant predictor of PRES and explained 67% of the variation. This was not so in Tanzania; PRES scores were similar for both types of care. Predictive models including sociodemographic variables showed religion as a potential moderator of treatment effect in Tanzania. Muslim women in group ANC had a higher mean PRES score than those in individual ANC; a difference not observed among Christian women. CONCLUSIONS: Group ANC empowers pregnant women in some contexts. More research is needed to identify the ways that models of ANC can affect pregnancy-related empowerment in addition to perinatal outcomes globally. PMID- 29143625 TI - Trends in hepatitis B virus testing practices and management in HIV clinics across sub-Saharan Africa. AB - BACKGROUND: Approximately 8% of HIV-infected individuals are co-infected with hepatitis B virus (HBV) in sub-Saharan Africa (SSA). Knowledge of HBV status is important to guide optimal selection of antiretroviral therapy (ART) and monitor/prevent liver-related complications. We describe changes in testing practices and management of HBV infection over a 3-year period in HIV clinics across SSA. METHODS: A medical chart review was conducted in large urban HIV treatment centers in Cote d'Ivoire (3 sites), Benin, Burkina Faso, Cameroon, Kenya, Senegal, South Africa, Togo, Uganda and Zambia (1 site each). Of the patients who started ART between 2010 and 2012, 100 per year were randomly selected from each clinic. Demographic, clinical and laboratory information as well as individual treatment histories were collected using a standardized questionnaire. We examined changes over time in the proportion of patients screened for HBV infection (HBV surface antigen [HBsAg]-positivity), identified predictors of HBV testing using logistic regression, and assessed the proportion of patients initiating a tenofovir (TDF)-containing ART regimen. RESULTS: Overall, 3579 charts of patients initiating ART (64.4% female, median age 37 years) were reviewed in 12 clinics. The proportion of patients screened for HBsAg increased from 17.8% in 2010 to 24.4% in 2012 overall, and ranged from 0.7% in Kenya to 96% in South Africa. In multivariable analyses, age and region were associated with HBsAg screening. Among 759 individuals tested, 88 (11.6%; 95% confidence interval [CI] 9.4-14.1) were HBV-infected, of whom 71 (80.7%) received a TDF-containing ART regimen. HBsAg-positive individuals were twice as likely to receive a TDF-containing first-line ART regimen compared to HBsAg-negative patients (80.7% vs. 40.3%, p < 0.001). The proportion of patients on TDF containing ART increased from 57.9% in 2010 to 90.2% in 2012 in HIV/HBV-co infected patients (Chi-2 test for trend: p = 0.01). Only 114 (5.0%) patients were screened for anti-HCV antibodies and one of them (0.9%, 95% CI 0.02-4.79) had a confirmed HCV infection. CONCLUSIONS: The systematic screening for HBV infection in HIV-positive patients before ART initiation was limited in most African countries and its uptake varied widely across clinics. Overall, the prescription of TDF increased over time, with 90% of HIV/HBV-coinfected patients receiving this drug in 2012. PMID- 29143626 TI - Methodological challenges in appraising evidence on diagnostic testing for WHO guidelines on hepatitis B and hepatitis C virus infection. AB - Linking persons with hepatitis B (HBV) and hepatitis C (HCV) infection with appropriate prevention and treatment requires that they first be diagnosed. The World Health Organization (WHO) has developed its first guidelines on testing for chronic HBV and HCV infection, using a framework based on methods from the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group for the formulation of recommendations, including determining the strength of recommendations and quality of evidence. Recommendations were formulated based on the overall quality of the evidence, in addition to other considerations, including the balance between benefits and harms, values and preferences, feasibility and resource implications. This article summarizes methodological challenges and additional considerations encountered in applying these procedures to diagnostic testing for viral hepatitis, and strategies to address these. Direct evidence on the effects of tests and test strategies on clinical outcomes was not available. Given the availability of effective treatments for HBV and HCV that are generally acceptable to patients, the Guidelines Development Group (GDG) considered diagnostic accuracy a reasonable surrogate for clinical outcomes. In order to increase the number of patients identified with chronic HBV and HCV infection who could benefit from treatments, the GDG determined that tests and testing strategies associated with slightly lower diagnostic accuracy could be recommended when associated with lower costs; increased testing access, uptake, and linkage to care; greater feasibility; or if preferred by patients. PMID- 29143628 TI - Do the status and empowerment of mothers predict their daughters' reproductive outcomes? AB - BACKGROUND: Despite increased recognition of the important influences of women's status and empowerment on social and health outcomes for women and their families, there are few investigations that examine the extent to which any gains in women's empowerment may be transmitted intergenerationally, that is, between mothers and their daughters. METHODS: This study seeks to address this gap by using data from a unique, longitudinal, and intergenerational dataset from Cebu, Philippines (1994-2009), to examine potential influences of the status of mothers on subsequent reproductive health outcomes among their daughters. Using data from 648 mother-daughter dyads, we examine a multidimensional set of women's status and empowerment measures among the mothers to predict three outcomes among their daughters: sexual onset by 2009 (ages 25-26), use of family planning, and experience of an unintended pregnancy. RESULTS: We find that that while some of the mothers' characteristics and measures of empowerment and status were predictive of their daughters' sexual initiation, these effects were not consistent across empowerment indicators, nor were there significant effects on two of the outcomes: use of family planning or occurrence of an unintended pregnancy. Older mothers (45+ years in 1994) and mothers who were considered to be "well-kept", a locally defined measure of empowerment, were more likely to have daughters who had not engaged in sex by 2009 (ages 25-26). Daughters with higher educational levels were also more likely to delay sex, as compared to their peers. Among young women who had become sexually active, 54% reported an unintended pregnancy (mistimed or unwanted) by the age of 25-26, yet their mothers' empowerment and status were not predictive of daughters' reports of an unintended pregnancy. CONCLUSIONS: Overall, these findings suggest that further research is needed to explore more proximal impacts on young women's reproductive behavior in this setting, given other related investigations on women's empowerment and its linkages to sexual debut and educational attainment in this setting. Findings from this examination of daughters' reproductive outcomes suggest that there are likely additional intervening mechanisms between onset on sexual activity and mistimed or unintended pregnancy that need further elaboration. PMID- 29143629 TI - From erasure to opportunity: a qualitative study of the experiences of transgender men around pregnancy and recommendations for providers. AB - BACKGROUND: Some transgender men retain their uterus, get pregnant, and give birth. However, societal attitudes about gender have erected barriers to openly being pregnant and giving birth as a transgender man. Little research exists regarding transgender men's reproductive needs. Anecdotal observations suggest that social change and increasing empowerment of transgender men may result in increasing frequency and openness about pregnancy and birth. Specific needs around conception, pregnancy, and newborn care may arise from transphobia, exogenous testosterone exposure, or from having had (or desiring) gender affirming surgery. We undertook a qualitative study to understand the needs of transgender men who had given birth. METHODS: We interviewed 10 transgender men who had been recruited for a recently published online cross-sectional survey of individuals (n = 41). Subjects had given birth while identifying as male. Interviews were recorded, transcribed, and systematically coded. Analysis used a priori and emergent codes to identify central themes and develop a framework for understanding participant experiences. RESULTS: Participants reported diverse experiences and values on issues including prioritization and sequencing of transition versus reproduction, empowerment in healthcare, desire for external affirmation of their gender and/or pregnancy, access to social supports, and degree of outness as male, transgender, or pregnant. We identified structural barriers that disempowered participants and describe healthcare components that felt safe and empowering. We describe how patients' strategies, and providers' behaviors, affected empowerment. Anticipatory guidance from providers was central in promoting security and empowerment for these individuals as patients. CONCLUSIONS: Recognizing diverse experiences has implications in supporting future patients through promoting patient-centered care and increasing the experiential legibility. Institutional erasure creates barriers to transgender men getting routine perinatal care. Identifying this erasure helps shape recommendations for how providers and clinics can provide appropriate care. Specific information regarding reproduction can be helpful to patients. We provide recommendations for providers' anticipatory guidance during the pre transition, pre-conception, prenatal, and postpartum periods. Ways to support and bring visibility to the experience of transgender men are identified. Improving clinical visibility and affirming gender will likely enhance patient experience and may support patient-centered perinatal healthcare services. PMID- 29143627 TI - Conceptualizing pathways linking women's empowerment and prematurity in developing countries. AB - BACKGROUND: Globally, prematurity is the leading cause of death in children under the age of 5. Many efforts have focused on clinical approaches to improve the survival of premature babies. There is a need, however, to explore psychosocial, sociocultural, economic, and other factors as potential mechanisms to reduce the burden of prematurity. Women's empowerment may be a catalyst for moving the needle in this direction. The goal of this paper is to examine links between women's empowerment and prematurity in developing settings. We propose a conceptual model that shows pathways by which women's empowerment can affect prematurity and review and summarize the literature supporting the relationships we posit. We also suggest future directions for research on women's empowerment and prematurity. METHODS: The key words we used for empowerment in the search were "empowerment," "women's status," "autonomy," and "decision-making," and for prematurity we used "preterm," "premature," and "prematurity." We did not use date, language, and regional restrictions. The search was done in PubMed, Population Information Online (POPLINE), and Web of Science. We selected intervening factors-factors that could potentially mediate the relationship between empowerment and prematurity-based on reviews of the risk factors and interventions to address prematurity and the determinants of those factors. RESULTS: There is limited evidence supporting a direct link between women's empowerment and prematurity. However, there is evidence linking several dimensions of empowerment to factors known to be associated with prematurity and outcomes for premature babies. Our review of the literature shows that women's empowerment may reduce prematurity by (1) preventing early marriage and promoting family planning, which will delay age at first pregnancy and increase interpregnancy intervals; (2) improving women's nutritional status; (3) reducing domestic violence and other stressors to improve psychological health; and (4) improving access to and receipt of recommended health services during pregnancy and delivery to help prevent prematurity and improve survival of premature babies. CONCLUSIONS: Women's empowerment is an important distal factor that affects prematurity through several intervening factors. Improving women's empowerment will help prevent prematurity and improve survival of preterm babies. Research to empirically show the links between women's empowerment and prematurity is however needed. PMID- 29143630 TI - Examining the mechanisms by which women's status and empowerment affect skilled birth attendant use in Senegal: a structural equation modeling approach. AB - BACKGROUND: Despite the reduction in maternal deaths globally, maternal mortality rates remain unacceptably high, particularly in some regions of the world. In sub Saharan Africa, maternal mortality rates have even increased recently, with 201,000 deaths in 2015 as compared to 179,000 in 2013. Use of a skilled birth attendant (SBA) at delivery has remained low, despite evidence of the effectiveness of SBAs in reducing maternal deaths. Women's empowerment is increasingly recognized as a key determinant of maternal health care-seeking and outcomes, yet empirical examinations of the linkages between women's empowerment and delivery care use are particularly limited, especially from sub-Saharan Africa. METHODS: Using data from the 2010 Senegal Demographic and Health Survey (n = 7451), in this study we employed structural equation modeling (SEM) to investigate the complex and multidimensional pathways by which three women's empowerment domains (household decision-making, attitudes towards violence, and sex negotiation) directly and indirectly affect SBA use. RESULTS: Although variations were observed across measures, many of the women's status and empowerment measures were positively related to SBA use. Notably, women's education demonstrated a substantial indirect effect: higher education was related to older age at first marriage, which was associated with higher levels of empowerment and SBA use. In addition to age at first marriage, gender-role attitudes (e.g., progressive attitudes towards violence and sex negotiation) were significant mediators in the relationship between education and SBA use. However, household decision-making was not significantly associated with SBA use. CONCLUSIONS: Findings indicate significant effects of women's education, early marriage, and some dimensions of women's empowerment on SBA use. SEM was particularly useful in examining the complex and multidimensional constructs of women's empowerments and their effects. This study informs policy recommendations and programmatic efforts to reduce maternal mortality in sub-Saharan Africa by strengthening support for women's access to higher education, delaying marriage and childbearing among girls and young women, and supporting more equitable gender norms. PMID- 29143631 TI - First birth and the trajectory of women's empowerment in Egypt. AB - BACKGROUND: Women's empowerment is often used to explain changes in reproductive behavior, but no consideration is given to how reproductive events can shape women's empowerment over time. Fertility may cause changes in women's empowerment, or they may be mutually influencing. Research on women's empowerment and fertility relies on cross-sectional data from South Asia, which limits the understanding of the direction of association between women's empowerment and fertility in other global contexts. This study uses two waves of a panel survey from a prominent Middle Eastern country, Egypt, to examine the trajectory of women's empowerment and the relationship between first and subsequent births and empowerment over time. METHODS: Using longitudinal data from the 2006 and 2012 Egyptian Labor Market Panel Survey, a nationally representative sample of households in Egypt, for 4660 married women 15 to 49 years old, multilevel negative binomial, ordinary least squares, and logistic regression models estimate women's empowerment and consider whether a first and subsequent births are associated with empowerment later in life. Women's empowerment is operationalized through four measures of agency: individual household decision making, joint household decision-making, mobility, and financial autonomy. RESULTS: A first birth and subsequent births are significantly positively associated with all measures of empowerment except financial autonomy in 2012. Women who have not had a birth make 30% fewer individual household decisions and 14% fewer joint household decisions in 2012 compared to women with a first birth. There is also a positive relationship with mobility, as women with a first birth have more freedom of movement compared to women with no births. Earlier empowerment is also an important predictor of empowerment later in life. CONCLUSIONS: Incorporating the influence of life events like first and subsequent births helps account for the possibility that empowerment is dynamic and that life course experiences shape women's empowerment. This and the notion that empowerment builds over time helps portray women's lives more completely, demonstrates the importance of empowerment early in the life course, and addresses issues of temporality in empowerment fertility research. PMID- 29143632 TI - A method for estimating maternal and newborn lives saved from health-related investments funded by the UK government Department for International Development using the Lives Saved Tool. AB - BACKGROUND: In 2010, the UK Government Department for International Development (DFID) committed through its 'Framework for results for reproductive, maternal and newborn health (RMNH)' to save 50,000 maternal lives and 250,000 newborn lives by 2015. They also committed to monitoring the performance of this portfolio of investments to demonstrate transparency and accountability. Methods currently available to directly measure lives saved are cost-, time-, and labour intensive. The gold standard for calculating the total number of lives saved would require measuring mortality with large scale population based surveys or annual vital events surveillance. Neither is currently available in all low- and middle-income countries. Estimating the independent effect of DFID support relative to all other effects on health would also be challenging. METHODS: The Lives Saved Tool (LiST) is an evidence based software for modelling the effect of changes in health intervention coverage on reproductive, maternal, newborn and child mortality. A multi-country LiST-based analysis protocol was developed to retrospectively assess the total annual number of maternal and newborn lives saved from DFID aid programming in low- and middle-income countries. RESULTS: Annual LiST analyses using the latest program data from DFID country offices were conducted between 2013 and 2016, estimating the annual number of maternal and neonatal lives saved across 2010-2015. For each country, independent project results were aggregated into health intervention coverage estimates, with and in the absence of DFID funding. More than 80% of reported projects were suitable for inclusion in the analysis, with 151 projects analysed in the 2016 analysis. Between 2010 and 2014, it is estimated that DFID contributed to saving the lives of 15,000 women in pregnancy and childbirth with health programming and 88,000 with family planning programming. It is estimated that DFID health programming contributed to saving 187,000 newborn lives. CONCLUSIONS: It is feasible to estimate the overall contribution and impact of DFID's investment in RMNH from currently available information on interventions and coverage from individual country offices. This utilization of LiST, with estimated population coverage based on DFID program inputs, can be applied to similar types of datasets to quantify programme impact. The global data were used to estimate DFID's progress against the Framework for results targets to inform future programming. The identified limitations can also be considered to inform future monitoring and evaluation program design and implementation within DFID. PMID- 29143633 TI - Predicting high risk births with contraceptive prevalence and contraceptive method-mix in an ecologic analysis. AB - BACKGROUND: Increased contraceptive use has been associated with a decrease in high parity births, births that occur close together in time, and births to very young or to older women. These types of births are also associated with high risk of under-five mortality. Previous studies have looked at the change in the level of contraception use and the average change in these types of high-risk births. We aim to predict the distribution of births in a specific country when there is a change in the level and method of modern contraception. METHODS: We used data from full birth histories and modern contraceptive use from 207 nationally representative Demographic and Health Surveys covering 71 countries to describe the distribution of births in each survey based on birth order, preceding birth space, and mother's age at birth. We estimated the ecologic associations between the prevalence and method-mix of modern contraceptives and the proportion of births in each category. Hierarchical modelling was applied to these aggregated cross sectional proportions, so that random effects were estimated for countries with multiple surveys. We use these results to predict the change in type of births associated with scaling up modern contraception in three different scenarios. RESULTS: We observed marked differences between regions, in the absolute rates of contraception, the types of contraceptives in use, and in the distribution of type of birth. Contraceptive method-mix was a significant determinant of proportion of high-risk births, especially for birth spacing, but also for mother's age and parity. Increased use of modern contraceptives is especially predictive of reduced parity and more births with longer preceding space. However, increased contraception alone is not associated with fewer births to women younger than 18 years or a decrease in short-spaced births. CONCLUSIONS: Both the level and the type of contraception are important factors in determining the effects of family planning on changes in distribution of high-risk births. The best predictions for how birth risk changes with increased modern contraception and for different contraception methods allow for more nuanced predictions specific to each country and can aid better planning for the scaling up of modern contraception. PMID- 29143634 TI - Efficacy of oral moxidectin against susceptible and resistant isolates of Dirofilaria immitis in dogs. AB - BACKGROUND: Monthly topical and sustained-release injectable formulations of moxidectin are currently marketed; however, an oral formulation, while approved at a dose of 3 MUg/kg, is not currently marketed in the United States. Although resistance of heartworms to all macrocyclic lactone (ML) heartworm preventives (ivermectin, milbemycin, selamectin and moxidectin) has been demonstrated, to date no data have been reported on the effectiveness of oral moxidectin against recent isolates of Dirofilaria immitis. METHODS: A total of nine studies were conducted to determine the efficacy of moxidectin against a range of older and recently sourced heartworm isolates. Dogs (groups of three to eight) were inoculated with 50 D. immitis infective larvae (L3) from nine different isolates (MP3, Michigan, JYD-34, ZoeMO-2012, ZoeKy-2013, ZoeLA-2013, GCFL-2014, AMAL-2014 and ZoeAL-2015) and treated 28-30 days later with single oral doses of 3 MUg/kg of moxidectin. Additionally, one group of dogs that was inoculated with JYD-34 was treated monthly for 3 consecutive months beginning 30 days post inoculation. Dogs were held for approximately 4 months after the initial (or only) treatment and then necropsied for recovery of adult heartworms. RESULTS: A single dose of 3 MUg/kg of moxidectin was 100% effective in preventing the development of five of nine heartworm isolates (MP3, Michigan, ZoeKy, GCFL and ZoeAL isolates), confirming their susceptibility to oral moxidectin at this dose. MP3 and Michigan are isolates sourced from the field more than 9 years ago, while ZoeKy, ZoeAL and GCFL were isolated from the field within the past 2 to 3 years. Against JYD-34, ZoeMO, ZoeLA and AMAL isolates, a single dose of 3 MUg/kg of moxidectin was not completely effective, with efficacies of 19%, 82%, 54% and 62%, respectively, demonstrating resistance of these heartworm isolates to oral moxidectin at this dosage. Three consecutive monthly doses of 3 MUg/kg of moxidectin were also incompletely effective against the JYD-34 isolate, with an efficacy of 44%. JYD 34 was originally isolated in 2010, while ZoeMO, ZoeLA and AMAL were isolated within the past 2 to 3 years. CONCLUSIONS: A single oral dose (3 MUg/mg) of moxidectin was 100% effective in preventing the development of ML-susceptible heartworm isolates while being incompletely effective against ML-resistant isolates. PMID- 29143635 TI - A systematic review of concepts related to women's empowerment in the perinatal period and their associations with perinatal depressive symptoms and premature birth. AB - BACKGROUND: The perinatal period, which we here define as pregnancy and the first year postpartum, is a time in women's lives that involves significant physiological and psychosocial change and adjustment, including changes in their social status and decision-making power. Supporting women's empowerment at this particular time in their lives may be an attractive opportunity to create benefits for maternal and infant health outcomes such as reductions in perinatal depressive symptoms and premature birth rates. Thus, we here systematically review and critically discuss the literature that investigates the effects of empowerment, empowerment-related concepts and empowerment interventions on reductions in perinatal depressive symptoms, preterm birth (PTB), and low birthweight (LBW). METHODS: For this systematic review, we conducted a literature search in PsychInfo, PubMed, and CINAHL without setting limits for date of publication, language, study design, or maternal age. The search resulted in 27 articles reporting on 25 independent studies including a total of 17,795 women. RESULTS: The majority of studies found that, for the most part, measures of empowerment and interventions supporting empowerment are associated with reduced perinatal depressive symptoms and PTB/LBW rates. However, findings are equivocal and a small portion of studies found no significant association between empowerment-related concepts and perinatal depressive symptoms and PTB or LBW. CONCLUSION: This small body of work suggests, for the most part, that empowerment related concepts may be protective for perinatal depressive symptoms and PTB/LBW. We recommend that future theory-driven and integrative work should include an assessment of different facets of empowerment, obtain direct measures of empowerment, and address the relevance of important confounders, including for example, ethnicity and socioeconomic status. PMID- 29143636 TI - A review of measures of women's empowerment and related gender constructs in family planning and maternal health program evaluations in low- and middle-income countries. AB - BACKGROUND: Evidence suggests that gender-integrated interventions, which actively seek to identify and integrate activities that address the role of gender norms and dynamics, improve family planning (FP) and maternal health (MH). To understand the link between the gender components of interventions and FP and MH outcomes, it is critical to examine the gender measures used in evaluations. METHODS: We conducted a systematic review of evaluations of gender-integrated FP and MH interventions in low- and middle-income countries. We examine characteristics of the interventions and their evaluations, and summarize women's empowerment and related gender measures. RESULTS: Out of 16 evaluation articles, five reported the theoretical or conceptual model that guided the intervention. Twelve described how gender was quantitatively measured and identified 13 women's empowerment and related gender constructs. Gender scales or indexes were used in five evaluations, three of which noted that their scales had been validated. Less than one third of articles reported examining the effect of gender on FP or MH. CONCLUSIONS: Evaluations of gender-integrated FP and MH interventions do not consistently describe how gender influences FP and MH outcomes or include validated gender measures within their studies. As a result, examining the pathways through which interventions empower women and the manner in which women's empowerment leads to changes in FP and MH outcomes remains a challenge. Valid measures of commonly reported women's empowerment and gender constructs, such as gender-equitable attitudes and women's decision-making power, must be adapted and used within evaluations to examine how empowerment and improvements in gender-related factors can produce positive FP and MH outcomes. PMID- 29143637 TI - Impact of malaria interventions on child mortality in endemic African settings: comparison and alignment between LiST and Spectrum-Malaria model. AB - BACKGROUND: In malaria-endemic countries, malaria prevention and treatment are critical for child health. In the context of intervention scale-up and rapid changes in endemicity, projections of intervention impact and optimized program scale-up strategies need to take into account the consequent dynamics of transmission and immunity. METHODS: The new Spectrum-Malaria program planning tool was used to project health impacts of Insecticide-Treated mosquito Nets (ITNs) and effective management of uncomplicated malaria cases (CMU), among other interventions, on malaria infection prevalence, case incidence and mortality in children 0-4 years, 5-14 years of age and adults. Spectrum-Malaria uses statistical models fitted to simulations of the dynamic effects of increasing intervention coverage on these burdens as a function of baseline malaria endemicity, seasonality in transmission and malaria intervention coverage levels (estimated for years 2000 to 2015 by the World Health Organization and Malaria Atlas Project). Spectrum-Malaria projections of proportional reductions in under five malaria mortality were compared with those of the Lives Saved Tool (LiST) for the Democratic Republic of the Congo and Zambia, for given (standardized) scenarios of ITN and/or CMU scale-up over 2016-2030. RESULTS: Proportional mortality reductions over the first two years following scale-up of ITNs from near-zero baselines to moderately higher coverages align well between LiST and Spectrum-Malaria -as expected since both models were fitted to cluster-randomized ITN trials in moderate-to-high-endemic settings with 2-year durations. For further scale-up from moderately high ITN coverage to near-universal coverage (as currently relevant for strategic planning for many countries), Spectrum-Malaria predicts smaller additional ITN impacts than LiST, reflecting progressive saturation. For CMU, especially in the longer term (over 2022-2030) and for lower endemic settings (like Zambia), Spectrum-Malaria projects larger proportional impacts, reflecting onward dynamic effects not fully captured by LiST. CONCLUSIONS: Spectrum-Malaria complements LiST by extending the scope of malaria interventions, program packages and health outcomes that can be evaluated for policy making and strategic planning within and beyond the perspective of child survival. PMID- 29143639 TI - Linking household surveys and health facility assessments to estimate intervention coverage for the Lives Saved Tool (LiST). AB - BACKGROUND: Calls have been made for improved measurement of coverage for maternal, newborn and child health interventions. Recently, methods linking household and health facility surveys have been used to improve estimation of intervention coverage. However, linking methods rely the availability of household and health facility surveys which are temporally matched. Because nationally representative health facility assessments are not yet routinely conducted in many low and middle income countries, estimates of intervention coverage based on linking methods can be produced for only a subset of countries. Estimates of intervention coverage are a critical input for modelling the health impact of intervention scale-up in the Lives Saved Tool (LiST). The purpose of this study was to develop a data-driven approach to estimate coverage for a subset of antenatal care interventions modeled in LiST. METHODS: Using a five step process, estimates of population level coverage for syphilis detection and treatment, case management of diabetes, malaria infection, hypertensive disorders, and pre-eclampsia, were computed by linking household and health facility surveys. Based on data characterizing antenatal care and estimates of coverage derived from the linking approach, predictive models for intervention coverage were developed. Updated estimates of coverage based on the predictive models were compared, first with current default proxies, then with estimates based on the linking approach. Model fit and accuracy were assessed using three measures: the coefficient of determination, Pearson's correlation coefficient, and the root mean square error (RMSE). RESULTS: The ability to predict intervention coverage was fairly accurate across all interventions considered. Predictive models accounted for 20-63% of the variance in intervention coverages, and correlation coefficients ranged from 0.5 to 0.83. The predictive model used to estimate coverage of management of pre-eclampsia performed relatively better (RMSE = 0.11) than the model estimating coverage of diabetes case management (RMSE = 0.19). CONCLUSIONS: The new approach to estimate coverage represents an improvement over current default proxies in LiST. As the availability of reliable coverage data improves, impact estimates generated by LiST will improve. This study underscores the need for continued efforts to improve coverage measurement, while bringing to the fore the importance of health facility assessments as complementary data sources. PMID- 29143638 TI - Water, sanitation and hygiene interventions for acute childhood diarrhea: a systematic review to provide estimates for the Lives Saved Tool. AB - BACKGROUND: In the Sustainable Development Goals (SDGs) era, there is growing recognition of the responsibilities of non-health sectors in improving the health of children. Interventions to improve access to clean water, sanitation facilities, and hygiene behaviours (WASH) represent key opportunities to improve child health and well-being by preventing the spread of infectious diseases and improving nutritional status. METHODS: We conducted a systematic review of studies evaluating the effects of WASH interventions on childhood diarrhea in children 0-5 years old. Searches were run up to September 2016. We screened the titles and abstracts of retrieved articles, followed by screening of the full text reports of relevant studies. We abstracted study characteristics and quantitative data, and assessed study quality. Meta-analyses were performed for similar intervention and outcome pairs. RESULTS: Pooled analyses showed diarrhea risk reductions from the following interventions: point-of-use water filtration (pooled risk ratio (RR): 0.47, 95% confidence interval (CI): 0.36-0.62), point-of use water disinfection (pooled RR: 0.69, 95% CI: 0.60-0.79), and hygiene education with soap provision (pooled RR: 0.73, 95% CI: 0.57-0.94). Quality ratings were low or very low for most studies, and heterogeneity was high in pooled analyses. Improvements to the water supply and water disinfection at source did not show significant effects on diarrhea risk, nor did the one eligible study examining the effect of latrine construction. CONCLUSIONS: Various WASH interventions show diarrhea risk reductions between 27% and 53% in children 0-5 years old, depending on intervention type, providing ample evidence to support the scale-up of WASH in low and middle-income countries (LMICs). Due to the overall low quality of the evidence and high heterogeneity, further research is required to accurately estimate the magnitude of the effects of these interventions in different contexts. PMID- 29143640 TI - How is the Lives Saved Tool (LiST) used in the global health community? Results of a mixed-methods LiST user study. AB - BACKGROUND: The Lives Saved Tool (LiST) is a computer-based model that estimates the impact of scaling up key interventions to improve maternal, newborn and child health. Initially developed to inform the Lancet Child Survival Series of 2003, the functionality and scope of LiST have been expanded greatly over the past 10 years. This study sought to "take stock" of how LiST is now being used and for what purposes. METHODS: We conducted a quantitative survey of LiST users, qualitative interviews with a smaller sample of LiST users and members of the LiST team at Johns Hopkins University, and a literature review of studies involving LiST analyses. RESULTS: LiST is being used by donors, international organizations, governments, NGOs and academic institutions to assist program evaluation, inform strategic planning and evidenced-based decision-making, and advocate for high-impact interventions. Some organizations have integrated LiST into internal workflows and built in-house capacity for using LiST, while other organizations rely on the LiST team for support and to outsource analyses. In addition to being a popular stand-alone software, LiST is used as a calculation engine for other applications. CONCLUSIONS: The Lives Saved Tool has been reported to be a useful model in maternal, newborn, and child health. With continued commitment, LiST should remain as a part of the international health toolkit used to assess maternal, newborn and child health programs. PMID- 29143641 TI - Effects of deworming on child and maternal health: a literature review and meta analysis. AB - BACKGROUND: Soil-transmitted helminth infections are widespread. Many studies have been published on the topic of deworming. The Lives Saved Tool (LiST) is a software package that uses a deterministic mathematical model to estimate the effect of scaling up interventions on maternal and child health outcomes. This review investigates the scope of available evidence for benefits of deworming treatments in order to inform a decision about possible inclusion of deworming as an intervention in LiST. METHODS: We searched PubMed, the Cochrane Library, and Google Scholar. We included studies that reported pre/post data in children younger than 5 years or pregnant women for outcomes related to mortality and growth. We excluded studies that compared different anthelminthic treatments but did not include a placebo or non-treatment group, and those that did not report post-intervention outcomes. We categorized articles by treated population (children younger than 5 years and pregnant women), experimental versus observational, mass drug administration (MDA) versus treatment, and reported outcome. RESULTS: We identified 58 relevant trials; 27 investigated children younger than 5 years and 11 investigated pregnant women; one reported on both children younger than 5 years and pregnant women. We conducted meta-analyses of relevant outcomes in children younger than 5 years. CONCLUSIONS: Deworming did not show consistent benefits for indicators of mortality, anemia, or growth in children younger than five or women of reproductive age. We do not recommend including the effect of deworming in the LiST model. PMID- 29143642 TI - A diagnostic algorithm for evaluating cases of potential macrocyclic lactone resistant heartworm. AB - BACKGROUND: The emergence of macrocyclic lactone resistance in canine heartworm poses a substantial threat to what is currently the only effective, FDA-approved available method of prevention. Further study of the biotypes is necessary to understand the mechanism of resistance and evaluate novel prevention options. Identifying cases of drug-resistant infection remains problematic, however, especially when poor compliance and insufficient testing are concerns. Furthermore, a definitive demonstration of resistance requires experimental infection and treatment, which is prohibitively costly. METHODS: With the aim of identifying likely cases of macrocyclic lactone-resistant heartworm and preventing their continued spread, we describe an algorithm for determining the likelihood of drug resistance and appropriate treatment strategies for each case. RESULTS: This algorithm relies on the microfilarial suppression test (MFST), which has been used previously as an efficient and discrete measure of suspected resistance. By standardizing this method in a format that is readily available to practitioners, it could become possible to preliminarily survey the emergence and spread of resistance. CONCLUSION: Heartworm isolates identified through this method can be used in research to better understand macrocyclic lactone resistance so prevention strategies can be adapted. PMID- 29143643 TI - Subcutaneous dirofilariosis (Dirofilaria repens): an infection spreading throughout the old world. AB - BACKGROUND: Two main Dirofilaria species infect dogs: D. immitis and D. repens. While D. immitis has a worldwide distribution, D. repens is currently found only in Europe, Asia, and Africa. Adult D. repens are located in subcutaneous tissues of natural hosts where they survive for long periods of time. First-stage larvae, microfilariae, circulate in the peripheral bloodstream, where they are taken up by the mosquito intermediate hosts. Infected mosquitoes then transmit infective third-stage (L3) larvae to new hosts through the blood meal. In dogs, most infections are asymptomatic, although cutaneous disorders such as pruritus, dermal swelling, subcutaneous nodules, and ocular conjunctivitis can be observed. Currently, two factors have increased the concerns about this parasitic infection 1) its spread throughout the European countries and to other continents and its prevalence in dog populations, where in some cases it has overcome D. immitis; and 2) its zoonotic potential, which is much greater than that of D. immitis. RESULTS: Different hypotheses can be put forward to explain these concerns. First, climate change has allowed more favorable conditions for survival of culicid vectors. Second, accidental hosts such as humans may have a less efficient immune reaction against a parasite that is located in subcutaneous tissues, and thus less exposed to the host's immune response than, for instance, D. immitis. Furthermore, the absence of clinical signs in the majority of canine infections and the difficulty in diagnosing the infection, due to the lack of serologic tests and thus the reliance on the identification of microfilariae and differentiation from D. immitis to confirm the presence of the parasite, favor the further spread of this species. Finally, among the macrocyclic lactones currently used to prevent heartworm infection, only moxidectin has been found to be fully effective against the infective larvae transmitted by mosquitoes and partially effective (efficacy 96%) against adult D. repens in experimental studies. CONCLUSIONS: Dirofilaria repens infection is much more difficult than D. immitis to diagnose and control in the reservoir population (microfilaremic dogs). In addition, lack of familiarity with D. repens infection could lead to lack of vigilance underestimation for this parasite. The number of human cases in Europe and Asia is currently a serious public health concern. Medical doctors and veterinarians must collaborate closely for better control and surveillance of D. repens infection. PMID- 29143644 TI - The effects of family planning and other factors on fertility, abortion, miscarriage, and stillbirths in the Spectrum model. AB - BACKGROUND: The Lives Saved Tool (LiST) estimates the effects of maternal and child health interventions on mortality rates and the number of deaths. The family planning module in Spectrum interacts with LiST by providing estimates of the effects of scaling up family planning use on the number of live births, miscarriages, abortions, and stillbirths. METHODS: We use the proximate determinants of fertility framework to estimate the effects of changes in contraceptive use, proportion married, postpartum insusceptibility, abortion and sterility on the total fertility rate. We extend this framework to estimate the number of intended and unintended pregnancies and the resulting live births, abortions, stillbirths, and miscarriages. RESULTS: We apply the model to four countries (Mali, Kenya, Indonesia, and Ukraine) to demonstrate possible trends with a range of family planning and fertility levels. In high-fertility countries, such as Mali, increases in contraceptive use will partially compensate for the increasing number of women of reproductive age to reduce the annual increases in pregnancies and births. Most unintended pregnancies occur to women defined as having unmet need for contraception. In low-fertility countries, increases in contraceptive use may reduce abortion rates and low levels of unmet need mean that most unintended pregnancies are due to method failure. CONCLUSIONS: The family planning module in Spectrum provides a useful framework to incorporate changes in contraceptive practices and pregnancy outcomes in the LiST calculations of mortality rates and deaths. PMID- 29143645 TI - Impact of heat treatment on Dirofilaria immitis antigen detection in shelter dogs. AB - BACKGROUND: The diagnosis and management of canine heartworm disease is a growing concern for shelter veterinarians. Although the accuracy of commercial antigen test kits has been widely studied, recent reports have renewed interest in antigen blocking as a causative factor for false "no antigen detected" results. The objectives of this study were to determine the prevalence of false "no antigen detected" results in adult dogs entering shelters in northern, southern, and western regions of the country and to identify historical and clinical risk factors for such results. METHODS: Serum samples were evaluated for Dirofilaria immitis antigen using a commercially available point-of-care ELISA; samples in which no antigen was detected underwent a heat treatment protocol and repeat antigen testing. Whole blood samples underwent Knott testing to identify the presence of microfilariae. Historical and clinical findings were analyzed using exact logistic regression. RESULTS: A total of 616 samples were analyzed. Overall prevalence of positive antigen test results (prior to heat treatment) was 7.3% and frequency of false "no antigen detected" results due to antigen blocking (ie, samples with no antigen detected prior to heat treatment and positive after heat treatment) was 5.2%. Among dogs that had no detectable antigen on the initial tests, dogs that had microfilariae detected via modified Knott testing (OR = 32.30, p-value = 0.013) and dogs that previously received a heartworm preventive (OR = 3.81, p-value = 0.016) had greater odds of antigen blocking than dogs without these factors. Among dogs that were heartworm positive, those without microfilariae detected had greater odds of antigen blocking than dogs with this factor (OR = 11.84, p-value = 0.0005). Geographic region of origin was significantly associated with occurrence of antigen blocking (p = 0.0036); however, blocking occurred in all regions sizably contributing to heartworm diagnoses. Of the 74 dogs found to be infected with heartworms in this study, 39.2% (29) had no detectable antigen prior to heat treatment. CONCLUSIONS: Heat treatment of serum samples should be considered to improve diagnostic test accuracy, particularly in dogs that reportedly received a heartworm preventive prior to antigen testing regardless of region of origin. PMID- 29143646 TI - Validation of immune complex dissociation methods for use with heartworm antigen tests. AB - BACKGROUND: Antigen testing is routinely used to diagnose canine Dirofilaria immitis infections. Immune complex dissociation (ICD) methods, which were employed in the original heartworm antigen tests to release antigen that was bound by endogenous canine antibodies, were discontinued with improvements in assay reagents. The purpose of this study was to evaluate different ICD methods for detection of heartworm antigen by microtiter plate ELISA and assess the performance in samples from pet dogs. METHODS: The original PetChek(r) Heartworm Test (IDEXX Laboratories, Inc.) utilized pepsin at an acidic pH for ICD prior to antigen testing. Performance and characteristics of the pepsin ICD method were compared with those for heat treatment (with and without EDTA) and acid treatment. RESULTS: All four methods released complexed antigen in serum samples when tested using microtiter plate ELISA. Heat treatment required >=600 MUL of serum or plasma, whereas pepsin and acid methods needed only a 50-MUL sample. Samples from 1115 dogs submitted to IDEXX Laboratories between 2014 and 2016 for investigation of discrepant heartworm results were evaluated with and without pepsin ICD using the PetChek Heartworm Test. Samples from 10% (n = 112) of the dogs were antigen positive with the ICD protocol only while 90% of the results remained unchanged. In a prospective study, antigen levels with and without ICD were evaluated for 12 dogs receiving pre-adulticide heartworm treatment with a macrocyclic lactone and doxycycline for 28 days. Serial samples revealed that three dogs had a reduction in detectable heartworm antigen within 4 weeks of initiating treatment. In these cases, heartworm antigen levels could be recovered with ICD. CONCLUSIONS: Heartworm antigen testing with ICD can be a valuable diagnostic tool for patients with discrepant results that have had intermittent use of a preventive, or have been treated with a macrocyclic lactone and doxycycline. Heartworm therapies may reduce antigen production and favor immune complexing in some dogs, resulting in false-negative results. Therefore, it is important to confirm positive heartworm antigen test results before initiating therapy. PMID- 29143647 TI - Modelling stillbirth mortality reduction with the Lives Saved Tool. AB - BACKGROUND: The worldwide burden of stillbirths is large, with an estimated 2.6 million babies stillborn in 2015 including 1.3 million dying during labour. The Every Newborn Action Plan set a stillbirth target of <=12 per 1000 in all countries by 2030. Planning tools will be essential as countries set policy and plan investment to scale up interventions to meet this target. This paper summarises the approach taken for modelling the impact of scaling-up health interventions on stillbirths in the Lives Saved tool (LiST), and potential future refinements. METHODS: The specific application to stillbirths of the general method for modelling the impact of interventions in LiST is described. The evidence for the effectiveness of potential interventions to reduce stillbirths are reviewed and the assumptions of the affected fraction of stillbirths who could potentially benefit from these interventions are presented. The current assumptions and their effects on stillbirth reduction are described and potential future improvements discussed. RESULTS: High quality evidence are not available for all parameters in the LiST stillbirth model. Cause-specific mortality data is not available for stillbirths, therefore stillbirths are modelled in LiST using an attributable fraction approach by timing of stillbirths (antepartum/ intrapartum). Of 35 potential interventions to reduce stillbirths identified, eight interventions are currently modelled in LiST. These include childbirth care, induction for prolonged pregnancy, multiple micronutrient and balanced energy supplementation, malaria prevention and detection and management of hypertensive disorders of pregnancy, diabetes and syphilis. For three of the interventions, childbirth care, detection and management of hypertensive disorders of pregnancy, and diabetes the estimate of effectiveness is based on expert opinion through a Delphi process. Only for malaria is coverage information available, with coverage estimated using expert opinion for all other interventions. Going forward, potential improvements identified include improving of effectiveness and coverage estimates for included interventions and addition of further interventions. CONCLUSIONS: Known effective interventions have the potential to reduce stillbirths and can be modelled using the LiST tool. Data for stillbirths are improving. Going forward the LiST tool should seek, where possible, to incorporate these improving data, and to continually be refined to provide an increasingly reliable tool for policy and programming purposes. PMID- 29143648 TI - A statistical approach for evaluating the effectiveness of heartworm preventive drugs: what does 100% efficacy really mean? AB - BACKGROUND: Initial studies of heartworm preventive drugs all yielded an observed efficacy of 100% with a single dose, and based on these data the US Food and Drug Administration (FDA) required all products to meet this standard for approval. Those initial studies, however, were based on just a few strains of parasites, and therefore were not representative of the full assortment of circulating biotypes. This issue has come to light in recent years, where it has become common for studies to yield less than 100% efficacy. This has changed the landscape for the testing of new products because heartworm efficacy studies lack the statistical power to conclude that finding zero worms is different from finding a few worms. METHODS: To address this issue, we developed a novel statistical model, based on a hierarchical modeling and parametric bootstrap approach that provides new insights to assess multiple sources of variability encountered in heartworm drug efficacy studies. Using the newly established metrics we performed both data simulations and analyzed actual experimental data. RESULTS: Our results suggest that an important source of modeling variability arises from variability in the parasite establishment rate between dogs; not accounting for this can overestimate the efficacy in more than 40% of cases. We provide strong evidence that ZoeMo-2012 and JYD-34, which both were established from the same source dog, have differing levels of susceptibility to moxidectin. In addition, we provide strong evidence that the differences in efficacy seen in two published studies using the MP3 strain were not due to randomness, and thus must be biological in nature. CONCLUSION: Our results demonstrate how statistical modeling can improve the interpretation of data from heartworm efficacy studies by providing a means to identify the true efficacy range based on the observed data. Importantly, these new insights should help to inform regulators on how to move forward in establishing new statistically and scientifically valid requirements for efficacy in the registration of new heartworm preventative products. Furthermore, our results provide strong evidence that heartworm 'strains' can change their susceptibility phenotype over short periods of time, providing further evidence that a wide diversity of susceptibility phenotypes exists among naturally circulating biotypes of D. immitis. PMID- 29143649 TI - Modelling stunting in LiST: the effect of applying smoothing to linear growth data. AB - BACKGROUND: The Lives Saved Tool (LiST) is a widely used resource for evidence based decision-making regarding health program scale-up in low- and middle-income countries. LiST estimates the impact of specified changes in intervention coverage on mortality and stunting among children under 5 years of age. We aimed to improve the estimates of the parameters in LiST that determine the rate at which the effects of interventions to prevent stunting attenuate as children get older. METHODS: We identified datasets with serial measurements of children's lengths or heights and used random effects models and restricted cubic splines to model the growth trajectories of children with at least six serial length/height measurements. We applied WHO growth standards to both measured and modelled (smoothed) lengths/heights to determine children's stunting status at multiple ages (1, 6, 12, 24 months). We then calculated the odds ratios for the association of stunting at one age point with stunting at the next ("stunting-to stunting ORs") using both measured and smoothed data points. We ran analyses in LiST to compare the impact on intervention effect attenuation of using smoothed rather than measured stunting-to-stunting ORs. RESULTS: A total of 21,786 children with 178,786 length/height measurements between them contributed to our analysis. The odds of stunting at a given age were strongly related to whether a child is stunted at an earlier age, using both measured and smoothed lengths/heights, although the relationship was stronger for smoothed than measured lengths/heights. Using smoothed lengths/heights, we estimated that children stunted at 1 month have 45 times the odds of being stunted at 6 months, with corresponding odds ratios of 362 for the period 6 to 12 months and 175 for the period 12 to 24 months. Using the odds ratios derived from the smoothed data in LiST resulted in a somewhat slower attenuation of intervention effects over time, but substantial attenuation was still observed in the LiST outputs. For example, in Mali the effect of effectively eliminating SGA births reduced prevalence of stunting at age 59 months from 44.4% to 43.7% when using odds ratios derived from measured lengths/heights and from 44.4% to 41.9% when using odds ratios derived from smoothed lengths/heights. CONCLUSIONS: Smoothing of children's measured lengths/heights increased the strength of the association between stunting at a given age and stunting at an earlier age. Using odds ratios based on smoothed lengths/heights in LiST resulted in a small reduction in the attenuation of intervention effects with age and thus some increase in the estimated benefits, and may better reflect the true benefits of early nutritional interventions. PMID- 29143650 TI - Microfilarial reduction following ProHeart(r) 6 and ProHeart(r) SR-12 treatment in dogs experimentally inoculated with a resistant isolate of Dirofilaria immitis. AB - BACKGROUND: Emerging resistance of heartworms (Dirofilaria immitis) to macrocyclic lactone (ML) preventives is an increasing concern for veterinarians, pet owners and animal health companies that supply heartworm preventives, with recent reports of resistant isolates identified from the Mississippi Delta region of the United States. Products that are effective in eliminating microfilariae (MF) in dogs harboring resistant heartworm infections could be important in reducing the spread of heartworm resistance. The current study was conducted to investigate the potential for ProHeart(r) 6 (PH 6; Zoetis) and ProHeart(r) SR-12 (PH 12; Zoetis) to reduce MF in dogs experimentally inoculated with an isolate of D. immitis (ZoeMo-2012) confirmed to be resistant to MLs. METHODS: Twenty-three dogs with preexisting heartworm infections (via surgical transplantation) were randomly allocated to four groups based on pretreatment (Day -14) MF counts. On Day 0, dogs received a subcutaneous injection of either saline (placebo-treated control, 6 dogs), PH 6 (0.17 mg/kg, 6 dogs), PH 12 (0.5 mg/kg, 5 dogs) or a single oral dose of moxidectin powder in a gelatin capsule (0.25 mg/kg, 6 dogs). All dogs were bled for MF counts (modified Knott's test) on Days 0 (pretreatment), 1, 3, 7, 14, 21, 28, 42, 56, and 84. Dogs in control and PH 6 groups were also bled for MF counts on Days 112, 140, and 168. No adverse events associated with treatment were observed for any dog. RESULTS: Average reductions in MF counts compared with controls for PH 6 were 9.7% on Day 1, increasing to 75.0% on Day 7, and further to 86.5% on Day 28. On Day 42, average MF reduction increased to 90.3%. Reductions increased further over the next several months with reductions of 91.3, 96.8, 96.6, and 98.9% on Days 56, 84, 112, and 140, respectively. On Day 168, the reduction was 99.3% (P < 0.0001). Average reductions in MF counts compared with controls for PH 12 were 20.9% on Day 1, increasing to 78.9% on Day 7, and further to 91.2% on Day 28. On Day 84, the reduction was 96.9%. For dogs receiving a single oral moxidectin (0.25 mg/kg) on Day 0, reductions in MF were 86.3% on Day 1 and fluctuated between 74.4 and 83.6% through Day 28. On Days 42 and 56, percentage reductions were 87.1 and 81.8%, respectively, and 92.6% at the final time point (Day 84). CONCLUSION: Both PH 6 and PH 12 were highly effective in reducing the MF levels of a confirmed ML resistant heartworm isolate following a single dose. PMID- 29143651 TI - Blocking the transmission of heartworm (Dirofilaria immitis) to mosquitoes (Aedes aegypti) by weekly exposure for one month to microfilaremic dogs treated once topically with dinotefuran-permethrin-pyriproxyfen. AB - BACKGROUND: This study assessed the influence of a topical ectoparasiticide (dinotefuran-permethrin-pyriproxyfen, DPP, Vectra(r)3D, Ceva Animal Health) on the acquisition of heartworm microfilariae by mosquitoes exposed to microfilaremic dogs weekly for 1 month. METHODS: Six beagle dogs (9.2 +/- 1.6 kg body weight) infected with Dirofilaria immitis were allocated to two groups of three dogs: an untreated control group and a DPP-treated group. Dogs were treated on Day 0 and exposed under sedation for 1 h to 80 +/- 20 unfed Aedes aegypti. Each dog was exposed to mosquitoes released into mosquito-proof containers on Days -7 (pretreatment), 7, 14, 21 and 28. Up to 20 engorged mosquitoes were aspirated from the cage as soon as they were blood-fed. They were dissected and the blood from each midgut was stained for a microfilaria (MF) count. After each exposure, mosquitoes were classified as live, moribund or dead and engorged or nonengorged. The number of dead mosquitoes was recorded daily for 16 days, when the live mosquitoes were dissected to count the infective third-stage larvae (L3). RESULTS: Prior to treatment, 95% of the engorged mosquitoes in both groups had MF. After treatment, engorgement rates for the treated group were 0%, 2.3%, 2.7% and 2.2% for Days 7, 14, 21 and 28, respectively, with anti-feeding efficacy (repellency) of 100%, 98.0%, 95.8% and 97.0%, respectively. A total of 22 mosquitoes fed on treated dogs; most of them were dead within 24 h, and all were dead within 72 h. Only 2 unfed mosquitoes exposed to treated dogs survived the incubation period and no L3 were found in them. A total of 121 of the 132 (91.6%) surviving mosquitoes that had engorged on untreated dogs had an average of 12.3 L3 per mosquito (range, 0-39). CONCLUSIONS: DPP was more than 95% effective in inhibiting blood-feeding and killing both engorged and nonengorged mosquitoes exposed weekly to microfilaremic dogs for 28 days after treatment. Treatment with DPP was completely effective in killing the few mosquitoes that fed on the treated dogs before they lived long enough for the microfilariae to develop to L3 and, consequently, was completely effective in blocking the transmission of L3 to other animals. DPP can break the life cycle of D. immitis and prevent infected dogs and infected mosquitoes from being effective reservoirs and can slow down the spread of heartworms, even those resistant to macrocyclic lactone preventives. PMID- 29143652 TI - Genetic profiles of ten Dirofilaria immitis isolates susceptible or resistant to macrocyclic lactone heartworm preventives. AB - BACKGROUND: For dogs and cats, chemoprophylaxis with macrocyclic lactone (ML) preventives for heartworm disease is widely used in the United States and other countries. Since 2005, cases of loss of efficacy (LOE) of heartworm preventives have been reported in the U.S. More recently, ML-resistant D. immitis isolates were confirmed. Previous work identified 42 genetic markers that could predict ML response in individual samples. For field surveillance, it would be more appropriate to work on microfilarial pools from individual dogs with a smaller subset of genetic markers. METHODS: MiSeq technology was used to identify allele frequencies with the 42 genetic markers previously reported. Microfilaria from ten well-characterized new isolates called ZoeKY, ZoeMI, ZoeGCFL, ZoeAL, ZoeMP3, ZoeMO, ZoeAMAL, ZoeLA, ZoeJYD-34, and Metairie were extracted from fresh blood from dogs. DNA were extracted and sequenced with MiSeq technology. Allele frequencies were calculated and compared with the previously reported susceptible, LOE, and resistant D. immitis populations. RESULTS: The allele frequencies identified in the current resistant and susceptible isolates were in accordance with the allele frequencies previously reported in related phenotypes. The ZoeMO population, a subset of the ZoeJYD-34 population, showed a genetic profile that was consistent with some reversion towards susceptibility compared with the parental ZoeJYD-34 population. The Random Forest algorithm was used to create a predictive model using different SNPs. The model with a combination of three SNPs (NODE_42411_RC, NODE_21554_RC, and NODE_45689) appears to be suitable for future monitoring. CONCLUSIONS: MiSeq technology provided a suitable methodology to work with the microfilarial samples. The list of SNPs that showed good predictability for ML resistance was narrowed. Additional phenotypically well characterized D. immitis isolates are required to finalize the best set of SNPs to be used for large scale ML resistance screening. PMID- 29143653 TI - Phylogenetic study of the endemic species Oxytropis almaatensis (Fabaceae) based on nuclear ribosomal DNA ITS sequences. AB - BACKGROUND: Oxytropis almaatensis Bajt. is a rare, narrow endemic species of the Trans-Ili Alatau mountains in Kazakhstan. Up to now, no studies regarding the taxonomy and variation of key morphological traits of O. almaatensis were undertaken. The purpose of this analysis was to evaluate phenotypic variation of O. almaatensis and assess the position of the species within the genus based on nucleotide sequences of the nuclear ribosomal DNA internal transcribed spacer (ITS) region. RESULTS: Two populations of O. almaatensis were collected in neighboring gorges of the Trans-Ili Alatau Mountains. The ITS sequences from the samples of two populations of O. almaatensis were identical. The phylogenetic analysis indicated that O. almaatensis is within Oxytropis genetically close to O. glabra as these species formed a separate subclade. The phenotypic variation of populations was assessed using nine morphological traits and compared to descriptions of O. glabra. The range of variation for the traits between two populations was established. A clear morphological difference of O. almaatensis and O. glabra was found in peduncle length to leaf length ratio. This was in O. almaatensis 1.56, while in O. glabra, it was 1.0. CONCLUSIONS: The study provides the first phenotypic description and phylogenetic placement of the rare endemic species O. almaatensis. The morphological traits in two O. almaatensis populations showed a high level of phenotypic variability. Although clearly different from O. glabra, the ITS phylogeny grouped these species in a subclade within the genus. PMID- 29143654 TI - Evaluation of the efficacy of ProHeart(r) 6 (moxidectin) against a resistant isolate of Dirofilaria immitis (JYD-34) in dogs. AB - BACKGROUND: In a previous study, it was demonstrated that ProHeart(r) 6 (PH6) (moxidectin, Zoetis) provided only about 20% efficacy in a small six-dog study against a macrocyclic lactone -resistant Dirofilaria immitis isolate (Jd2009-2) when dogs were inoculated with infective third-stage larvae (L3) at the end of the dosing period (ie, 180 days post treatment). The objective of the current study was to determine the prophylactic efficacy of a moxidectin sustained release formulation (PH6) against a confirmed macrocyclic lactone-resistant isolate of D. immitis (JYD-34) in dogs when administered by subcutaneous injection at the labeled dose of 0.17 mg/kg 2 days before L3 inoculation. This was intended to model the scenario where dogs become infected with resistant heartworms at the end of the PH6 treatment period (ie, 6 months post treatment) when dogs would routinely be given another injection under normal field use. METHODS: Twelve purpose-bred Beagle dogs (six males and six females) were selected and randomly allocated to two groups, untreated controls and PH6-treated dogs in groups of six each. The dogs were >=8 months old at the start of the study, and using blood samples collected on Day -7 were shown to be negative for adult heartworm antigen and microfilariae. On Day 0, the dogs in the untreated control group were administered saline subcutaneously by injection, and the dogs in the treated group were administered PH6 according to label instructions. On Day 2, each dog was inoculated in the inguinal area with 50 L3 of D. immitis. The dogs were necropsied on Day 150 (148 days post infection), and the worms were collected and counted. RESULTS: All of the six control dogs were infected and harbored a range of 21 to 37 worms (geometric mean, 25.4; 10.9 males and 13.9 females). Only one of the six PH6 dogs was found to be infected, harboring a single male worm. Efficacy was 99.5% (geometric mean). CONCLUSION: ProHeart(r) 6 was highly effective in preventing the development of heartworms in dogs challenged with a confirmed macrocyclic lactone-resistant heartworm isolate (JYD 34) 2 days prior to treatment. PMID- 29143655 TI - Consent, ethics and genetic biobanks: the case of the Athlome project. AB - This article provides a critical overview of the ethics and governance of genetic biobank research, using the Athlome Consortium as a large scale instance of collaborative sports genetic biobanking. We present a traditional model of written informed consent for the acquisition, storage, sharing and analysis of genetic data and articulate the challenges to it from new research practices such as genetic biobanking. We then articulate six possible alternative consent models: verbal consent, blanket consent, broad consent, meta consent, dynamic consent and waived consent. We argue that these models or conceptions of consent must be articulated in the context of the complexities of international legislation and non legislative national and international biobank governance frameworks and policies, those which govern research in the field of sports genetics. We discuss the tensions between individual rights and public benefits of genomic research as a critical ethical issue, particularly where benefits are less obvious, as in sports genomics. The inherent complexities of international regulation and biobanking governance are challenging in a relatively young field. We argue that there is much nuanced ethical work still to be done with regard to governance of sports genetic biobanking and the issues contained therein. PMID- 29143656 TI - Does evaluation of in vitro microfilarial motility reflect the resistance status of Dirofilaria immitis isolates to macrocyclic lactones? AB - BACKGROUND: Several reports have confirmed that macrocyclic lactone-resistant isolates of Dirofilaria immitis are circulating in the United States; however, the prevalence and potential impact of drug resistance is unknown. We wished to assess computer-aided measurements of motility as a method for rapidly assessing the resistance status of parasite isolates. METHODS: Blood containing microfilariae (MF) from two clinical cases with a high suspicion of resistance was fed to mosquitoes and the resultant L3 injected into dogs that were then treated with six doses of Heartgard(r) Plus (ivermectin + pyrantel; Merial Limited) at 30-day intervals. In both cases patent heartworm infections resulted despite the preventive treatment. Microfilariae isolated from these dogs and other isolates of known resistance status were exposed to varying concentrations of ivermectin in vitro and their motility assessed 24 h later using computer processed high-definition video imaging. RESULTS: We produced two isolates, Yazoo 2013 and Metairie-2014, which established patent infections despite Heartgard(r) Plus treatments. Measurements of the motility of MF of these and other isolates (Missouri, MP3 and JYD-27) following exposure to varying concentrations of ivermectin did not distinguish between susceptible and resistant heartworm populations. There was some evidence that the method of MF isolation had an influence on the motility and drug susceptibility of the MF. CONCLUSIONS: We confirmed that drug-resistant heartworms are circulating in the southern United States, but that motility measurements in the presence of ivermectin are not a reliable method for their detection. This implies that the drug does not kill the microfilariae via paralysis. PMID- 29143657 TI - Clinical benefits of incorporating doxycycline into a canine heartworm treatment protocol. AB - BACKGROUND: The objective of heartworm treatment is to improve the clinical condition of the patient and to eliminate pre-cardiac, juvenile, and adult worm stages with minimal complications. Pulmonary thromboembolisms are an inevitable consequence of worm death and can result in severe pulmonary reactions and even death of the patient. To minimize these reactions, various treatment protocols involving melarsomine, the only adulticidal drug approved by the US Food and Drug Administrations (FDA), in conjunction with macrocyclic lactone heartworm preventives and glucocorticosteroids have been advocated. The discovery of the bacterial endosymbiont Wolbachia in Dirofilaria immitis has led to several experimental studies examining the effects of administering doxycycline to reduce or eliminate Wolbachia organism. These studies have shown a decrease in gross and microscopic pathology of pulmonary parenchyma in experimental heartworm infections pretreated with doxycycline before melarsomine administration. METHODS: Electronic medical records from a large veterinary practice in northeast Alabama were searched to identify dogs treated for heartworms with melarsomine from January 2005 through December 2012. The search was refined further to select for dogs that met the following criteria: 1) received two or three doses of ivermectin heartworm preventive prior to melarsomine injections, 2) received one injection of melarsomine followed by two injections 4 to 8 weeks later, and 3) were treated with prednisone following melarsomine injections. The dogs were then divided into those that also were treated with doxycycline 10 mg/kg BID for 4 weeks (Group A, n = 47) and those that did not receive doxycycline (Group B, n = 47). The medical notes of all 94 cases were then reviewed for comments concerning coughing, dyspnea, or hemoptysis in the history, physical exam template, or from telephone conversations with clients the week following each visit. Any dog that died within one year of treatment from either cardiovascular or pulmonary problems was noted. RESULTS: Dogs from Group A receiving doxycycline had fewer respiratory complications (6.52%) and heartworm disease-related deaths (0%) than Group B (19.14% and 4.25%, respectively). CONCLUSIONS: Although there are not enough cases to indicate statistical significance, the results strongly suggest that including doxycycline into canine heartworm treatment protocols decreases post-treatment complications and mortality in naturally infected clinical cases. PMID- 29143658 TI - A key enzyme of animal steroidogenesis can function in plants enhancing their immunity and accelerating the processes of growth and development. AB - BACKGROUND: The initial stage of the biosynthesis of steroid hormones in animals occurs in the mitochondria of steroidogenic tissues, where cytochrome P450SCC (CYP11A1) encoded by the CYP11A1 gene catalyzes the conversion of cholesterol into pregnenolone - the general precursor of all the steroid hormones, starting with progesterone. This stage is missing in plants where mitochondrial cytochromes P450 (the mito CYP clan) have not been found. Generating transgenic plants with a mitochondrial type P450 from animals would offer an interesting option to verify whether plant mitochondria could serve as another site of P450 monooxygenase reaction for the steroid hormones biosynthesis. RESULTS: For a more detailed comparison of steroidogenic systems of Plantae and Animalia, we have created and studied transgenic tobacco and tomato plants efficiently expressing mammalian CYP11A1 cDNA. The detailed phenotypic characterization of plants obtained has shown that through four generations studied, the transgenic tobacco plants have reduced a period of vegetative development (early flowering and maturation of bolls), enlarged biomass and increased productivity (quantity and quality of seeds) as compared to the only empty-vector containing or wild type plants. Moreover, the CYP11A1 transgenic plants show resistance to such fungal pathogen as Botrytis cinerea. Similar valuable phenotypes (the accelerated course of ontogenesis and/or stress resistance) are also visible in two clearly distinct transgenic tomato lines expressing CYP11A1 cDNA: one line (No. 4) has an accelerated rate of vegetative development, while the other (No. 7) has enhanced immunity to abiotic and biotic stresses. The progesterone level in transgenic tobacco and tomato leaves is 3-5 times higher than in the control plants of the wild type. CONCLUSIONS: For the first time, we could show the compatibility in vivo of even the most specific components of the systems of biosynthesis of steroid hormones in Plantae and Animalia. The hypothesis is proposed and substantiated that the formation of the above-noted special phenotypes of transgenic plants expressing mammalian CYP11A1 cDNA is due to the increased biosynthesis of progesterone that can be considered as a very ancient bioregulator of plant cells and the first real hormone common to plants and animals. PMID- 29143659 TI - Effect of heartworm disease and heartworm-associated respiratory disease (HARD) on the right ventricle of cats. AB - BACKGROUND: Dirofilaria immitis infection occurs in dogs and cats, both of which species are clinically affected by mature adult infections. Cats are uniquely affected by immature-adult infections with an inflammatory pulmonary disease called Heartworm-Associated Respiratory Disease (HARD). D. immitis infection causes pulmonary parenchymal and vascular pathology in the dog and cat. Dogs develop pulmonary hypertension and cor pulmonale, whereas the development of pulmonary hypertension is rare in the cat. D. immitis infection in the dog causes alteration of the right ventricular (RV) extracellular matrix, including a decrease in myocardial collagen. In this study, the RV myocardial changes of cats infected with adult and immature-adult D. immitis were assessed. METHODS: The cardiopulmonary systems of six groups of SPF cats (n = 9-10 per group) were examined 8 or 18 months after infection with L3 D. immitis. Two groups were untreated and allowed to develop adult HW; two groups were treated with ivermectin starting 3 months post infection, thus allowing HARD but no mature adult heartworms; and two groups were treated with selamectin beginning 1 month post infection, preventing development of L5 or adult heartworms. A group of specific pathogen free (SPF) normal cats was utilized as a negative control (n = 12). Lung pathologic lesions were objectively assessed, and both RV and left ventricular (LV) weights were obtained to calculate an RV/LV ratio. Intramural RV myocardial collagen content was quantitatively assessed. RESULTS: RV/LV weight ratios were not different between groups. Negative control cats had significantly greater RV collagen content than all other affected groups (P = 0.032). Analysis of the RV/LV ratios and collagen content revealed no significant relationship (r = 0.03, P = 0.723, respectively). Collagen content had a modest, but significant, negative correlation, however, with both pulmonary vascular pathology (r = -0.25, P = 0.032) as well as the total pulmonary parenchymal and vascular pathology (r = -0.26, P = 0.025). CONCLUSIONS: Cats infected with mature and immature D. immitis did not develop RV hypertrophy but did demonstrate loss of RV myocardial collagen content. The collagen loss was present at 8 and 18 months after infection in all infected cats. This loss of RV myocardial collagen was correlated with the severity of pulmonary parenchymal and vascular pathology. PMID- 29143660 TI - Efficacy of 10% imidacloprid + 2.5% moxidectin topical solution (Advantage Multi(r) for Dogs) for the prevention of heartworm disease and infection all month long. AB - BACKGROUND: Prior work has shown that the levels of moxidectin in dogs treated with Advantage Multi(r) for Dogs (Bayer Animal Health) remain at a high plasma concentration for the full month after application. The objective of this study was to demonstrate the efficacy of 10% imidacloprid + 2.5% moxidectin topical solution (Advantage Multi(r) for Dogs, also known as Advocate(r) for Dogs) for the prevention of heartworm infection and disease 30 days after just one application. METHODS: Two groups of eight dogs each were included. Dogs in Group 1 received the product (Advantage Multi(r) for Dogs) while those in Group 2 remained as nontreated controls. All dogs entering the study completed a physical examination including examination for Dirofilaria immitis antigen and circulating microfilariae. Dogs in Group 1 were treated on Study Day (SD) -30 as per the label recommendation. Thirty days later (SD 0) dogs in Groups 1 and 2 were subcutaneously infected in the inguinal region with approximately 50 infective third-stage D. immitis larvae ("Missouri" isolate). Blood was collected on SDs 120 and 147 for examination for D. immitis antigen and circulating microfilariae. On SD 148, all animals were euthanized and necropsied for recovery of adult heartworms. All procedures were performed in accordance with the VICH GL9 guidelines. RESULTS: Examination and worm counts made at necropsy showed no heartworms in the treated dogs (Group 1) compared with six of eight nontreated dogs (Group 2) with heartworms (range of 2-33). The treated dogs (Group 1) had significantly fewer heartworms (p < 0.05) compared with the nontreated controls (Group 2). CONCLUSION: The results demonstrated that 10% imidacloprid + 2.5% moxidectin topical solution (Advantage Multi(r) for Dogs) is efficacious for the prevention of heartworm infection and disease all month long with no observation of treatment-related adverse events. PMID- 29143661 TI - Heartworm-associated respiratory disease (HARD) induced by immature adult Dirofilaria immitis in cats. AB - BACKGROUND: A controlled, blind research study was conducted to define the initial inflammatory response and lung damage associated with the death of immature adult Dirofilaria immitis in cats as compared with cats developing adult heartworm infections and cats on preventive medication. METHODS: Three groups of cats were utilized, 10 per group. All cats were infected with 100 third-stage (L3) larvae by subcutaneous injection. Group A cats were treated topically with selamectin (Revolution(r); Zoetis) per label directions at 28 days post infection (PI) and once monthly for 8 months. Group B cats were treated orally with ivermectin (Ivomec(r); Merial) at 150 MUg/kg at 70 days PI, then every 2 weeks for 5 months. Group C cats were untreated PI. At baseline (Day 0) and on Days 70, 110, 168, and 240 PI, peripheral blood, serum, bronchial lavage, and thoracic radiographic images were collected on all cats. Upon completion of the study (Day 245), cats were euthanized and necropsies were conducted. RESULTS: Results were analyzed statistically between groups by ANOVA and by paired sample T testing for changes within the group over time. The selamectin-treated cats (Group A) did not develop radiographically evident changes throughout the study and were free of adult heartworms or worm fragments at necropsy. The heartworm life cycle was abbreviated with oral doses of ivermectin (Group B), shown by the absence of adult heartworms or worm fragments at necropsy. The early stage of immature adult worm in Group B cats, however, did induce severe pulmonary airway, interstitial, and arterial lung lesions, revealing that the abbreviated infection is a significant cause of respiratory pathology in cats. Cats in Groups B and C could not be differentiated based on radiographic changes, serologic antibody titers, complete blood count, or bronchoalveolar lavage cytology at any time point throughout the study. Eighty percent of cats in Group A and 100% of cats in Groups B and C became heartworm antibody positive at some time point post infection. CONCLUSIONS: The clinical implications of this study are that cats that become infected with immature adult heartworms may not develop fully mature heartworms and are only transiently heartworm antibody positive, but do develop Heartworm-Associated Respiratory Disease (HARD). PMID- 29143662 TI - Heat treatment and false-positive heartworm antigen testing in ex vivo parasites and dogs naturally infected by Dirofilaria repens and Angiostrongylus vasorum. AB - BACKGROUND: Heartworm antigen testing is considered sensitive and specific. Currently available tests are reported as detecting a glycoprotein found predominantly in the reproductive tract of the female worm and can reach specificity close to 100%. Main concerns regard sensitivity in the case of light infections, the presence of immature females or cases of all-male infections. Research and development have been aimed at increasing sensitivity. Recently, heat treatment of serum prior to antigen testing has been shown to result in an increase in positive antigen test results, presumably due to disruption of natural antigen-antibody complexes. Cross-reactions in dogs with both natural and experimental infections with Angiostrongylus vasorum and Spirocerca lupi have been reported, but cross-reactions with other helminths have not been extensively studied. In order to evaluate potential cross-reactivity with other canine and feline parasites, two studies were performed. Study 1: Live adults of Dirofilaria immitis, Dirofilaria repens, Toxocara canis, Toxocara cati, Dipylidium caninum, Taenia taeniaeformis and Mesocestoides spp. larvae were washed and incubated in tubes with saline solution. All worms were alive at the time of removal from the saline. Saline solutions containing excretory/secretory antigens were then tested for heartworm with six different, commercially available antigen tests. All results were evaluated blind by three of the authors. Study 2: Sera from dogs with natural infections by A. vasorum or D. repens, living in areas free of heartworm disease, were tested with the same tests before and after heat treatment (103 degrees C for 10 min). RESULTS: Results suggest that antigens detected by currently available tests are not specific for D. immitis. They may give positive results through detection of different parasites' antigens that are normally not released into the bloodstream or released in a low amount and/or bound to antibodies. Tests may even detect antigens released by male D. immitis adult worms. D. repens appears to release more detectable antigens than the other worms studied. CONCLUSIONS: Cross-reaction with A. vasorum and D. repens does occur in the field and could potentially occur with other helminths. Heat treatment decreases specificity by enhancing cross-reactivity. PMID- 29143663 TI - Dirofilaria immitis JYD-34 isolate: whole genome analysis. AB - BACKGROUND: Macrocyclic lactone (ML) anthelmintics are used for chemoprophylaxis for heartworm infection in dogs and cats. Cases of dogs becoming infected with heartworms, despite apparent compliance to recommended chemoprophylaxis with approved preventives, has led to such cases being considered as suspected lack of efficacy (LOE). Recently, microfilariae collected from a small number of LOE isolates were used as a source of infection of new host dogs and confirmed to have reduced susceptibility to ML in controlled efficacy studies using L3 challenge in dogs. A specific Dirofilaria immitis laboratory isolate named JYD-34 has also been confirmed to have less than 100% susceptibility to ML-based preventives. For preventive claims against heartworm disease, evidence of 100% efficacy is required by FDA-CVM. It was therefore of interest to determine whether JYD-34 has a genetic profile similar to other documented LOE and confirmed reduced susceptibility isolates or has a genetic profile similar to known ML-susceptible isolates. METHODS: In this study, the 90Mbp whole genome of the JYD-34 strain was sequenced. This genome was compared using bioinformatics tools to pooled whole genomes of four well-characterized susceptible D. immitis populations, one susceptible Missouri laboratory isolate, as well as the pooled whole genomes of four LOE D. immitis populations. Fixation indexes (FST), which allow the genetic structure of each population (isolate) to be compared at the level of single nucleotide polymorphisms (SNP) across the genome, have been calculated. Forty-one previously reported SNP, that appeared to differentiate between susceptible and LOE and confirmed reduced susceptibility isolates, were also investigated in the JYD-34 isolate. RESULTS: The FST analysis, and the analysis of the 41 SNP that appeared to differentiate reduced susceptibility from fully susceptible isolates, confirmed that the JYD-34 isolate has a genome similar to previously investigated LOE isolates, and isolates confirmed to have reduced susceptibility, and to be dissimilar to the susceptible isolates. CONCLUSIONS: These results provide additional evidence for the link between genotype and the reduced susceptibility phenotype observed in such isolates as JYD-34. Further work on other isolates showing reduced susceptibility to ML is required to demonstrate the value of genetic analysis in predicting the response to ML chemoprophylaxis. The authors suggest that genetic analysis may be useful in helping to interpret the results of in vivo efficacy testing of ML heartworm preventives against D. immitis isolates. PMID- 29143664 TI - Evaluation of Dirofilaria immitis antigen detection comparing heated and unheated serum in dogs with experimental heartworm infections. AB - BACKGROUND: To evaluate whether heated serum allows for earlier detection of Dirofilaria immitis antigen, dogs with experimental D. immitis infections underwent weekly blood sampling to compare antigen results using both heated and unheated serum. METHODS: One of two isolates (JYD-34 or Big HeadTM) were used to infect naive laboratory beagle dogs. Serum was collected from dogs weekly and divided into two aliquots, heated and unheated. The samples designated as heated were placed in a heat block at 104 degrees C for 10 min then centrifuged with collection of the resulting supernatant. Two commercial ELISAs, DiroCHEK(r) (Synbiotics Corporation, Zoetis) and PetChek(r) (IDEXX Laboratories, Inc.), were used to conduct D. immitis antigen testing on all serum samples. RESULTS: There was no statistical difference in the mean number of days from infection to positive D. immitis antigen status between the two commercial testing kits (DiroCHEK(r) versus PetChek(r)) with either heated or unheated serum. When unheated serum was utilized, very strong agreement between the two assays was demonstrated using Lin's concordance correlation coefficient (R c = 0.98). However, when heated serum was compared, Lin's concordance correlation coefficient was only R c = 0.64, showing a lesser agreement. There was a statistical difference in the mean number of days from infection to a positive test result for unheated serum when compared to mean days to positive status with heated serum. For DiroCHEK(r) the heated serum yielded a positive result 126.9 +/ 18.9 days postinfection while the unheated serum yielded a positive result 162.6 +/- 23.0 days postinfection; this was a significant 35.7 +/- 32.2 days longer, on average, compared with heated serum. With PetChek(r) the heated serum yielded a positive result 131.5 +/- 11.7 days postinfection while the unheated serum yielded a positive result 162.8 +/- 23.8 days postinfection; this was a significant 31.3 +/- 25.5 days longer, on average, compared with heated serum. The detection of D. immitis antigen earlier using heated serum was consistent for both heartworm isolates. CONCLUSION: Our results suggest heat treatment of serum may allow earlier detection of D. immitis antigen but with less consistency demonstrated across two testing platforms as compared with antigen detection using unheated serum. PMID- 29143666 TI - Comparative evaluation of commercially available point-of-care heartworm antigen tests using well-characterized canine plasma samples. AB - BACKGROUND: Dirofilaria immitis is a worldwide parasite that is endemic in many parts of the United States. There are many commercial assays available for the detection of D. immitis antigen, one of which was modified and has reentered the market. Our objective was to compare the recently reintroduced Witness(r) Heartworm (HW) Antigen test Kit (Zoetis, Florham Park, NJ) and the SNAP(r) Heartworm RT (IDEXX Laboratories, Inc., Westbrook, ME) to the well-based ELISA DiroChek(r) Heartworm Antigen Test Kit (Zoetis, Florham Park, NJ). METHODS: Canine plasma samples were either received at the Auburn Diagnostic Parasitology Laboratory from veterinarians submitting samples for additional heartworm testing (n = 100) from 2008 to 2016 or purchased from purpose-bred beagles (n = 50, presumed negative) in 2016. Samples were categorized as "positive," "borderline" or "negative" using our established spectrophotometric cutoff value with the DiroChek(r) assay when a sample was initially received and processed. Three commercially available heartworm antigen tests (DiroChek(r), Witness(r) HW, and SNAP(r) RT) were utilized for simultaneous testing of the 150 samples in random order as per their package insert with the addition of spectrophotometric optical density (OD) readings of the DiroChek(r) assay. Any samples yielding discordant test results between assays were further evaluated by heat treatment of plasma and retesting. Chi-square tests for the equality of proportions were utilized for statistical analyses. RESULTS: Concordant results occurred in 140/150 (93.3%) samples. Discrepant results occurred in 10/150 samples tested (6.6%): 9/10 occurring in the borderline heartworm (HW) category and 1/10 occurring in the negative HW category. The sensitivity and specificity of each test compared to the DiroChek(r) read by spectrophotometer was similar to what has been reported previously (Witness(r): sensitivity 97.0% [94.1-99.4%], specificity 96.4% [95.5 100.0%]; SNAP(r) RT: sensitivity 90.9% [78.0-100.0%], specificity 98.8% [96.0 100.0%]). There were significant differences detected when comparing the sensitivities of the SNAP(r) RT and the Witness(r) HW to the DiroChek(r) among the 150 total samples (p = 0.003) and the 50 "borderline" samples (p = 0.001). CONCLUSIONS: In this study, the sensitivity of the Witness(r) HW was higher than the sensitivity of the SNAP(r) RT when compared with the DiroChek(r) test results prior to heat treatment of samples. PMID- 29143665 TI - Cardiopulmonary and inflammatory biomarkers in heartworm disease. AB - In heartworm disease, several biomarkers of cardiopulmonary injury and inflammatory activity have been studied during the recent years. D-dimer is a fibrin degradation product present after a clot is degraded, which has been reported to provide support for the diagnosis of pulmonary thromboembolism in heartworm disease. Furthermore, concentrations increment with increased disease severity and during the adulticide treatment. This increase in concentration has proved to be valuable. Cardiac biomarkers troponin I, myoglobin and NT-proBNP demonstrated presence of myocardial injury and heart failure, especially in chronic infections, which in some cases, slightly improve after the adulticide treatment. An acute phase response in dogs with Dirofilaria immitis, characterized by variations of acute phase proteins (APP), has been reported, indicating inflammatory processes that could contribute to disease progression. Among them, C-reactive protein (CRP) increases according to the severity of the disease; and a strong correlation between pulmonary hypertension and CRP has been observed. In cats, little work has been done to ascertain the utility of these biomarkers in feline heartworm; the only published study in D. immitis seropositive cats reported significantly higher concentrations in positive APP serum amyloid A, haptoglobin and ceruloplasmin. PMID- 29143667 TI - Validation of whole-blood transcriptome signature during microdose recombinant human erythropoietin (rHuEpo) administration. AB - BACKGROUND: Recombinant human erythropoietin (rHuEpo) can improve human performance and is therefore frequently abused by athletes. As a result, the World Anti-Doping Agency (WADA) introduced the Athlete Biological Passport (ABP) as an indirect method to detect blood doping. Despite this progress, challenges remain to detect blood manipulations such as the use of microdoses of rHuEpo. METHODS: Forty-five whole-blood transcriptional markers of rHuEpo previously derived from a high-dose rHuEpo administration trial were used to assess whether microdoses of rHuEpo could be detected in 14 trained subjects and whether these markers may be confounded by exercise (n = 14 trained subjects) and altitude training (n = 21 elite runners and n = 4 elite rowers, respectively). Differential gene expression analysis was carried out following normalisation and significance declared following application of a 5% false discovery rate (FDR) and a 1.5 fold-change. Adaptive model analysis was also applied to incorporate these markers for the detection of rHuEpo. RESULTS: ALAS2, BCL2L1, DCAF12, EPB42, GMPR, SELENBP1, SLC4A1, TMOD1 and TRIM58 were differentially expressed during and throughout the post phase of microdose rHuEpo administration. The CD247 and TRIM58 genes were significantly up- and down-regulated, respectively, immediately following exercise when compared with the baseline both before and after rHuEpo/placebo. No significant gene expression changes were found 30 min after exercise in either rHuEpo or placebo groups. ALAS2, BCL2L1, DCAF12, SLC4A1, TMOD1 and TRIM58 tended to be significantly expressed in the elite runners ten days after arriving at altitude and one week after returning from altitude (FDR > 0.059, fold-change varying from 1.39 to 1.63). Following application of the adaptive model, 15 genes showed a high sensitivity (>= 93%) and specificity (>= 71%), with BCL2L1 and CSDA having the highest sensitivity (93%) and specificity (93%). CONCLUSIONS: Current results provide further evidence that transcriptional biomarkers can strengthen the ABP approach by significantly prolonging the detection window and improving the sensitivity and specificity of blood doping detection. Further studies are required to confirm, and if necessary, integrate the confounding effects of altitude training on blood doping. PMID- 29143668 TI - Women's empowerment and experiences of mistreatment during childbirth in facilities in Lucknow, India: results from a cross-sectional study. AB - BACKGROUND: Recent evidence has found widespread reports of women experiencing abuse, neglect, discrimination, and poor interpersonal care during childbirth around the globe. Empowerment may be a protective mechanism for women against facility mistreatment during childbirth. The majority of previous research on mistreatment during childbirth has been qualitative in nature. METHODS: In this analysis, we use quantitative data from 392 women who recently gave birth in a facility in the slums of Lucknow, India, to explore whether measures of women's empowerment are associated with their experiences of mistreatment at their last childbirth. We use the Gender Equitable Men (GEM) scale to measure women's views of gender equality. RESULTS: We find that women who had more equitable views about the role of women were less likely to report experiencing mistreatment during childbirth. These findings suggest that dimensions of women's empowerment related to social norms about women's value and role are associated with experiences of mistreatment during childbirth. CONCLUSIONS: This expands our understanding of empowerment and women's health, and also suggests that the GEM scale can be used to measure certain domains of empowerment from a women's perspective in this setting. PMID- 29143669 TI - Considerations for using minocycline vs doxycycline for treatment of canine heartworm disease. AB - BACKGROUND: Doxycycline has been considered the first drug of choice for treating Wolbachia, a member of the Rickettsiaceae, which has a symbiotic relationship with filarial worms, including heartworms. Wolbachia, is susceptible to tetracyclines, which have been used as adjunctive treatments for heartworm disease. Treatment with doxycycline reduces Wolbachia numbers in all stages of heartworms and improves outcomes and decreased microfilaremia in dogs treated for heartworm disease. The American Heartworm Society recommends treatment with doxycycline in dogs diagnosed with heartworm disease at a dose of 10 mg/kg twice daily for 28 days. If doxycycline is not available, minocycline can be considered as a substitute. However, minocycline has not undergone an evaluation in dogs with heartworm disease, nor has an effective dose been established. Minocycline is an attractive option because of the higher cost of doxycycline and new pharmacokinetic information for dogs that provides guidance for appropriate dosage regimens to achieve pharmacokinetic-pharmacodynamic (PK-PD) targets. RESULTS: Published reports from the Anti-Wolbachia Consortium (A-WOL) indicate superior in vitro activity of minocycline over doxycycline. Studies performed in mouse models to measure anti-Wolbachia activity showed that minocycline was 1.7 times more effective than doxycycline, despite a 3-fold lower pharmacokinetic exposure. To achieve the same exposure as achieved in the mouse infection model, a pharmacokinetic-pharmacodynamic (PK-PD) analysis was conducted to determine optimal dosages for dogs. The analysis showed that an oral minocycline dose of 3.75 to 5 mg/kg administered twice daily would attain similar targets as observed in mice and predicted for human infections. CONCLUSIONS: There are potentially several advantages for use of minocycline in animals. It is well absorbed from oral administration, it has less protein binding than doxycycline (65% vs 92%) allowing for better distribution into tissue, and it is approximately two times more lipophilic than doxycycline, which may result in better intracellular penetration. More work is needed to document efficacy of minocycline for treating canine heartworm disease. PMID- 29143670 TI - Genes to predict VO2max trainability: a systematic review. AB - BACKGROUND: Cardiorespiratory fitness (VO2max) is an excellent predictor of chronic disease morbidity and mortality risk. Guidelines recommend individuals undertake exercise training to improve VO2max for chronic disease reduction. However, there are large inter-individual differences between exercise training responses. This systematic review is aimed at identifying genetic variants that are associated with VO2max trainability. METHODS: Peer-reviewed research papers published up until October 2016 from four databases were examined. Articles were included if they examined genetic variants, incorporated a supervised aerobic exercise intervention; and measured VO2max/VO2peak pre and post-intervention. RESULTS: Thirty-five articles describing 15 cohorts met the criteria for inclusion. The majority of studies used a cross-sectional retrospective design. Thirty-two studies researched candidate genes, two used Genome-Wide Association Studies (GWAS), and one examined mRNA gene expression data, in addition to a GWAS. Across these studies, 97 genes to predict VO2max trainability were identified. Studies found phenotype to be dependent on several of these genotypes/variants, with higher responders to exercise training having more positive response alleles than lower responders (greater gene predictor score). Only 13 genetic variants were reproduced by more than two authors. Several other limitations were noted throughout these studies, including the robustness of significance for identified variants, small sample sizes, limited cohorts focused primarily on Caucasian populations, and minimal baseline data. These factors, along with differences in exercise training programs, diet and other environmental gene expression mediators, likely influence the ideal traits for VO2max trainability. CONCLUSION: Ninety-seven genes have been identified as possible predictors of VO2max trainability. To verify the strength of these findings and to identify if there are more genetic variants and/or mediators, further tightly-controlled studies that measure a range of biomarkers across ethnicities are required. PMID- 29143671 TI - GWAS of agronomic traits in soybean collection included in breeding pool in Kazakhstan. AB - BACKGROUND: In recent years soybean is becoming one of the most important oilseed crops in Kazakhstan. Only within the last ten years (2006-2016), the area under soybean is expanded from 45 thousand hectares (ha) in 2006 to 120 thousand ha in 2016. The general trend of soybean expansion is from south-eastern to eastern and northern regions of the country, where average temperatures are lower and growing seasons are shorter. These new soybean growing territories were poorly examined in terms of general effects on productivity level among the diverse sample of soybean accessions. In this study, phenotypic data were collected in three separate regions of Kazakhstan and entire soybean sample was genotyped for identification of marker-trait associations (MTA). RESULTS: In this study, the collection of 113 accessions representing five different regions of the World was planted in 2015-2016 in northern, eastern, and south-eastern regions of Kazakhstan. It was observed that North American accessions showed the highest yield in four out of six trials especially in Northern Kazakhstan in both years. The entire sample was genotyped with 6 K SNP Illumina array. 4442 SNPs found to be polymorphic and were used for whole genome genotyping purposes. Obtained SNP markers data and field data were used for GWAS (genome-wide association study). 30 SNPs appear to be very significant in 42 MTAs in six studied environments. CONCLUSIONS: The study confirms the efficiency of GWAS for the identification of molecular markers which tag important agronomic traits. Overall thirty SNP markers associated with time to flowering and maturation, plant height, number of fertile nodes, seeds per plant and yield were identified. Physical locations of 32 identified out of 42 total MTAs coincide well with positions of known analogous QTLs. This result indicates importance of revealed MTAs for soybean growing regions in Kazakhstan. Obtained results would serve as required prerequisite for forming and realization of specific breeding programs towards effective adaptation and increased productivity of soybean in three different regions of Kazakhstan. PMID- 29143672 TI - Diagnostic accuracy of serological diagnosis of hepatitis C and B using dried blood spot samples (DBS): two systematic reviews and meta-analyses. AB - BACKGROUND: Dried blood spots (DBS) are a convenient tool to enable diagnostic testing for viral diseases due to transport, handling and logistical advantages over conventional venous blood sampling. A better understanding of the performance of serological testing for hepatitis C (HCV) and hepatitis B virus (HBV) from DBS is important to enable more widespread use of this sampling approach in resource limited settings, and to inform the 2017 World Health Organization (WHO) guidance on testing for HBV/HCV. METHODS: We conducted two systematic reviews and meta-analyses on the diagnostic accuracy of HCV antibody (HCV-Ab) and HBV surface antigen (HBsAg) from DBS samples compared to venous blood samples. MEDLINE, EMBASE, Global Health and Cochrane library were searched for studies that assessed diagnostic accuracy with DBS and agreement between DBS and venous sampling. Heterogeneity of results was assessed and where possible a pooled analysis of sensitivity and specificity was performed using a bivariate analysis with maximum likelihood estimate and 95% confidence intervals (95%CI). We conducted a narrative review on the impact of varying storage conditions or limits of detection in subsets of samples. The QUADAS-2 tool was used to assess risk of bias. RESULTS: For the diagnostic accuracy of HBsAg from DBS compared to venous blood, 19 studies were included in a quantitative meta-analysis, and 23 in a narrative review. Pooled sensitivity and specificity were 98% (95%CI:95%-99%) and 100% (95%CI:99-100%), respectively. For the diagnostic accuracy of HCV-Ab from DBS, 19 studies were included in a pooled quantitative meta-analysis, and 23 studies were included in a narrative review. Pooled estimates of sensitivity and specificity were 98% (CI95%:95-99) and 99% (CI95%:98-100), respectively. Overall quality of studies and heterogeneity were rated as moderate in both systematic reviews. CONCLUSION: HCV-Ab and HBsAg testing using DBS compared to venous blood sampling was associated with excellent diagnostic accuracy. However, generalizability is limited as no uniform protocol was applied and most studies did not use fresh samples. Future studies on diagnostic accuracy should include an assessment of impact of environmental conditions common in low resource field settings. Manufacturers also need to formally validate their assays for DBS for use with their commercial assays. PMID- 29143674 TI - The role of human rights litigation in improving access to reproductive health care and achieving reductions in maternal mortality. AB - BACKGROUND: Improving maternal health, reducing global maternal mortality, and working toward universal access to reproductive health care are global priorities for United Nations agencies, national governments, and civil society organizations. Human rights lawyers have joined this global movement, using international law and domestic constitutions to hold nations accountable for preventable maternal death and for failing to provide access to reproductive health care services. CASE PRESENTATION: This article discusses three decisions in which international treaty bodies find the nations of Brazil and Peru responsible for violations of the Convention on the Elimination of All Forms of Discrimination Against Women and the International Covenant on Civil and Political Rights and also two domestic decisions alleging constitutional violations in India and Uganda. CONCLUSIONS: The authors analyze the impact of these decisions on access to maternal and other reproductive health services in Brazil, Peru, India, and Uganda and conclude that litigation is most effective when aligned with ongoing efforts by the public health community and civil society organizations. In filing these complaints and cases on behalf of individual women and their families, legal advocates highlight health system failures and challenge the historical structures and hierarchies that discriminate against and devalue women. These international and domestic decisions empower women and their communities and inspire nations and other stakeholders to commit to broader social, economic, and political change. Human rights litigation brings attention to existing public health campaigns and supports the development of local and global movements and coalitions to improve women's health. PMID- 29143673 TI - The HepTestContest: a global innovation contest to identify approaches to hepatitis B and C testing. AB - BACKGROUND: Innovation contests are a novel approach to elicit good ideas and innovative practices in various areas of public health. There remains limited published literature on approaches to deliver hepatitis testing. The purpose of this innovation contest was to identify examples of different hepatitis B and C approaches to support countries in their scale-up of hepatitis testing and to supplement development of formal recommendations on service delivery in the 2017 World Health Organization hepatitis B and C testing guidelines. METHODS: This contest involved four steps: 1) establishment of a multisectoral steering committee to coordinate a call for contest entries; 2) dissemination of the call for entries through diverse media (Facebook, Twitter, YouTube, email listservs, academic journals); 3) independent ranking of submissions by a panel of judges according to pre-specified criteria (clarity of testing model, innovation, effectiveness, next steps) using a 1-10 scale; 4) recognition of highly ranked entries through presentation at international conferences, commendation certificate, and inclusion as a case study in the WHO 2017 testing guidelines. RESULTS: The innovation contest received 64 entries from 27 countries and took a total of 4 months to complete. Sixteen entries were directly included in the WHO testing guidelines. The entries covered testing in different populations, including primary care patients (n = 5), people who inject drugs (PWID) (n = 4), pregnant women (n = 4), general populations (n = 4), high-risk groups (n = 3), relatives of people living with hepatitis B and C (n = 2), migrants (n = 2), incarcerated individuals (n = 2), workers (n = 2), and emergency department patients (n = 2). A variety of different testing delivery approaches were employed, including integrated HIV-hepatitis testing (n = 12); integrated testing with harm reduction and addiction services (n = 9); use of electronic medical records to support targeted testing (n = 8); decentralization (n = 8); and task shifting (n = 7). CONCLUSION: The global innovation contest identified a range of local hepatitis testing approaches that can be used to inform the development of testing strategies in different settings and populations. Further implementation and evaluation of different testing approaches is needed. PMID- 29143675 TI - Economic evaluations of HBV testing and treatment strategies and applicability to low and middle-income countries. AB - BACKGROUND: Many people living with chronic HBV infection remain undiagnosed until later stages of disease. Increasing testing and treatment rates form part of the strategy to respond to the WHO goal of eliminating viral hepatitis as a public health threat by 2030. However, achieving these ambitious targets is dependent on finding effective and cost-effective methods of scale up strategies. The aim of this study was to undertake a narrative review of the literature on economic evaluations of testing and treatment for HBV infection, to help inform the development of the 2017 WHO Hepatitis Testing Guidelines. METHODS: We undertook a focussed literature review for economic evaluations on testing for HBV accompanied by antiviral treatment. The search was carried out in Pubmed and included only articles published after 2000 and written in English. We narratively synthesise the results and discuss the key drivers of cost effectiveness and their applicability to low and middle-income countries (LMICs). RESULTS: Nine published studies were included in this review, only one of which was performed in a low or middle-income setting in West Africa. Eight studies were performed in high-income settings, seven among high risk groups and one among the general population. The studies were heterogeneous in many respects including the population and testing strategy under consideration, model structure and baselines parameters, willingness to pay thresholds and outcome measures used. However, most studies found HBV testing and treatment to be cost effective, even at low HBsAg prevalence levels. CONCLUSIONS: Currently economic evaluations of HBV testing and treatment strategies in LMICs is lacking, therefore limiting the ability to provide formal recommendations on the basis of cost-effectiveness alone. Further implementation research is needed in order to help guide national policy planning. PMID- 29143676 TI - The future of viral hepatitis testing: innovations in testing technologies and approaches. AB - A large burden of undiagnosed hepatitis virus cases remains globally. Despite the 257 million people living with chronic hepatitis B virus infection, and 71 million with chronic viraemic HCV infection, most people with hepatitis remain unaware of their infection. Advances in rapid detection technology have created new opportunities for enhancing access to testing and care, as well as monitoring of treatment. This article examines a range of other technological innovations that can be leveraged to provide more affordable and simplified approaches to testing for HBV and HCV infection and monitoring of treatment response. These include improved access to testing through alternative sampling methods (use of dried blood spots, oral fluids, self-testing) and combination rapid diagnostic tests for detection of HIV, HBV and HCV infection; more affordable options for confirmation of virological infection (HBV DNA and HCV RNA) such as point-of-care molecular assays, HCV core antigen and multi-disease polyvalent molecular platforms that make use of existing centralised laboratory based or decentralised TB and HIV instrumentation for viral hepatitis testing; and finally health system improvements such as integration of laboratory services for procurement and sample transportation and enhanced data connectivity to support quality assurance and supply chain management. PMID- 29143677 TI - Women's empowerment related to pregnancy and childbirth: introduction to special issue. PMID- 29143678 TI - Shifting the paradigm in Dirofilaria immitis prevention: blocking transmission from mosquitoes to dogs using repellents/insecticides and macrocyclic lactone prevention as part of a multimodal approach. AB - BACKGROUND: This study assessed the influence of a topical ectoparasiticide (dinotefuran-permethrin-pyriproxyfen, DPP, Vectra(r) 3D, Ceva Animal Health) combined with a macrocyclic lactone (milbemycin oxime, MBO, Interceptor(r), Virbac) on transmission of heartworm L3 from mosquitoes to dogs and subsequent development of worms in treated dogs exposed to infected mosquitoes. METHODS: Thirty-two beagle dogs were allocated to four groups of eight: Group 1, untreated controls; Group 2, treated topically with DPP on Day 0; Group 3, treated orally with MBO on Day 51; and Group 4, treated with DPP on Day 0 and MBO on Day 51. Dogs were exposed under sedation for 1 h to Dirofilaria immitis (JYD-34)-infected Aedes aegypti on Days 21 and 28. At the end of each exposure, mosquitoes were classified as live, moribund, or dead and engorged or non-engorged. Live or moribund mosquitoes were incubated for daily survival assessment for 3 days. Mosquitoes were dissected before and after exposure to estimate the number of L3 transmitted to each dog. Dogs were necropsied 148 to 149 days postinfection. RESULTS: A total of 418 mosquitoes fed on the 16 dogs in Groups 1 and 3, while only 6 fed on the 16 DPP-treated dogs in Groups 2 and 4. Mosquito anti-feeding (repellency) effect in Groups 2 and 4 was 98.1 and 99.1%, respectively. The estimated numbers of L3 transmitted to controls, DPP-treated, MBO-treated and DPP + MBO-treated dogs were 76, 2, 78, and 1, respectively. No heartworms were detected in any of the DPP + MBO-treated dogs (100% efficacy), while 8 out of 8 were infected in the control group (range, 21-66 worms per dog), 8 out of 8 were infected in the MBO-treated group (58% efficacy), and 3 out of 8 were infected in the DPP-treated group (96% efficacy). CONCLUSIONS: DPP repelled and killed most mosquitoes that were capable of transmitting heartworm L3 to dogs. The "Double Defense" protocol of DPP + MBO had better efficacy for protecting dogs against heartworm transmission and infection than MBO alone. This added DPP benefit is more pronounced when macrocyclic lactone-resistant strains of heartworms are involved or lack of compliance in macrocyclic lactone administration is known or suspected. PMID- 29143679 TI - All things to all people: trade-offs in pursuit of an ideal modeling tool for maternal and child health. AB - BACKGROUND: Modeling tools have potential to aid decision making for program planning and evaluation at all levels, but are still largely the domain of technical experts, consultants, and global-level staff. One model that can improve decision making for maternal and child health is the Lives Saved Tool (LiST). We examined respondents' perceptions of LiST's strengths and weaknesses, to identify ways in which LiST - and similar modeling tools - can adapt to be more accessible and helpful to policy makers. METHODS: We interviewed 21 purposefully sampled LiST users. First, we identified the characteristics that respondents explicitly stated, or implicitly implied, were important in a modeling tool, and then used these results to create a framework for reviewing a modeling tool. Second, we used this framework to categorize the strengths and weaknesses of LiST that respondents articulated. RESULTS: Two overarching qualities were important to respondents: usability and accuracy. For some users, LiST already meets these criteria: it allows for customized input parameters to increase specificity; the interface is intuitive; the assumptions and calculations are scientifically sound; and the standard metric of "additional lives saved" is understood and comparable across settings. Other respondents had different views, although their complaints were typically not that the tool is unusable or inaccurate, but that aspects of the tool could be better explained or easier to understand. CONCLUSION: Government and agency staff at all levels should be empowered to use the data available to them, including the use of models to make full use of these data. For this, we need tools that meet a threshold of both accuracy, so results clarify rather than mislead, and usability, so tools can be used readily and widely, not just by select experts. With these ideals in mind, there are ways in which LiST might continue to be improved or adapted to further advance its uptake and impact. PMID- 29143680 TI - Abortion as empowerment: reproductive rights activism in a legally restricted context. AB - BACKGROUND: This paper analyzes the strategies used by activist health professionals in Argentina who justify providing abortion despite legal restrictions on the procedure. These "insider activists" make a case for abortion rights by linking pregnancy termination to a woman's ability to exert agency at a key point in her reproductive life, and argue that refusing women access to the procedure constitutes a grievous health risk. This argument frames pregnancy termination as an issue of empowerment and also as a medical necessity. METHODS: This article is based on ethnographic research conducted in Argentina in 2013 and 2015, which includes in-depth interviews with abortion activists and health professionals and ethnographic observation at activist events and in clinics. RESULTS: During the period of my field research, the medical staff in one clinic shifted from abortion counseling, based on a harm reduction model, to legal pregnancy termination, a new mode of abortion provision where they directly provided abortions based on the legal health exception. These insider activists formalized the latter approach by creating a diagnostic instrument that frames women's "bio-psycho-social" reasons for wishing to terminate a pregnancy as medically justified. CONCLUSIONS: The clinical practice analyzed in this article raises important questions about the potential for health professionals to take on an activist role by making safe abortion accessible, even in a context where the procedure is highly restricted. PMID- 29143681 TI - Economic evaluation of HCV testing approaches in low and middle income countries. AB - BACKGROUND: Hepatitis C virus (HCV) infection represents a major public health burden with diverse epidemics worldwide, but at present, only a minority of infected persons have been tested and are aware of their diagnosis. The advent of highly effective direct acting antiviral (DAA) therapy, which is becoming available at increasingly lower costs in low and middle income countries (LMICs), represents a major opportunity to expand access to testing and treatment. However, there is uncertainty as to the optimal testing approaches and who to prioritize for testing. We undertook a narrative review of the cost-effectiveness literature on different testing approaches for chronic hepatitis C infection to inform decision-making and formulation of recommendations in the 2017 World Health Organization (WHO) viral hepatitis testing guidelines. METHODS: We undertook a focused search and narrative review of the literature for cost effectiveness studies of testing approaches in three main groups:- 1) focused testing of specific high-risk groups (defined as those who are part of a population with higher seroprevalence or who have a history of exposure or high risk behaviours); 2) "birth cohort" testing among easily identified age groups (i.e. specific birth cohorts) known to have a high prevalence of HCV infection; and 3) routine testing in the general population. Articles included were those published in PubMed, written in English and published after 2000. RESULTS: We identified 26 eligible studies. Twenty-four of them were from Europe (n = 14) or the United States (n = 10). There was only one study from a LMIC (Egypt) and this evaluated general population testing. Thirteen studies evaluated focused testing among specific groups at high risk for HCV infection, including nine in persons who inject drugs (PWID); five among people in prison, and one among HIV-infected men who have sex with men (MSM). Eight studies evaluated birth cohort testing, and five evaluated testing in the general population. Most studies were based on a one-time testing intervention, but in one study testing was undertaken every 5 years and in another among HIV-infected MSM there was more frequent testing. Comparators were generally either: 1) no testing, 2) the status quo, or 3) multiple different strategies. Overall, we found broad agreement that focused testing of high risk groups such as persons who inject drugs and men who have sex with men was cost-effective, as was birth cohort testing. Key drivers of cost effectiveness were the prevalence of HCV infection in these groups, efficacy and cost of treatment, stage of disease and linkage to care. The evidence for routine population testing was mixed, and the cost-effectiveness depends largely on the prevalence of HCV. CONCLUSIONS: The evidence base for different HCV testing approaches in LMICs is limited, minimizing the contribution of cost-effectiveness data alone to decision-making and recommendations on testing approaches in the 2017 WHO viral hepatitis testing guidelines. Overall, the guidelines recommended focused testing in high risk-groups, particularly PWID, prisoners, and men who have sex with men; with consideration of two other approaches:- birth cohort testing in those countries with epidemiological evidence of a significant birth cohort effect; and routine access to testing across the general population in those countries with a high HCV seroprevalence above 2% - 5% in the general population. Further implementation research on different testing approaches is needed in order to help guide national policy planning. PMID- 29143682 TI - Using the Lives Saved Tool to aid country planning in meeting mortality targets: a case study from Mali. AB - BACKGROUND: Mali is one of four countries implementing a National Evaluation Platform (NEP) to build local capacity to answer evaluation questions for maternal, newborn, child health and nutrition (MNCH&N). In 2014-15, NEP-Mali addressed questions about the potential impact of Mali's MNCH&N plans and strategies, and identified priority interventions to achieve targeted mortality reductions. METHODS: The NEP-Mali team modeled the potential impact of three intervention packages in the Lives Saved Tool (LiST) from 2014 to 2023. One projection included the interventions and targets from Mali's ten-year health strategy (PDDSS) for 2014-2023, and two others modeled intervention packages that included scale up of antenatal, intrapartum, and curative interventions, as well as reductions in stunting and wasting. We modeled the change in maternal, newborn and under-five mortality rates under these three projections, as well as the number of lives saved, overall and by intervention. RESULTS: If Mali were to achieve the MNCH&N coverage targets from its health strategy, under-5 mortality would be reduced from 121 per 1000 live births to 93 per 1000, far from the target of 69 deaths per 1000. Projections 1 and 2 produced estimated mortality reductions from 121 deaths per 1000 to 70 and 68 deaths per 1000, respectively. With respect to neonatal mortality, the mortality rate would be reduced from 39 to 32 deaths per 1000 live births under the current health strategy, and to 25 per 1000 under projections 1 and 2. CONCLUSIONS: This study revealed that achieving the coverage targets for the MNCH&N interventions in the 2014-23 PDDSS would likely not allow Mali to achieve its mortality targets. The NEP-Mali team was able to identify two packages of MNCH&N interventions (and targets) that achieved under-5 and neonatal mortality rates at, or very near, the PDDSS targets. The Malian Ministry of Health and Public Hygiene is using these results to revise its plans and strategies. PMID- 29143683 TI - The progression of heartworm associated respiratory disease (HARD) in SPF cats 18 months after Dirofilaria immitis infection. AB - BACKGROUND: Heartworm-associated respiratory disease (HARD) in cats is induced by the arrival and death of immature adult Dirofilaria immitis in the pulmonary system and is indistinguishable from mature adult heartworm infection. METHODS: A controlled, blind research study investigated the long-term (18 months post infection, PI) consequences of the inflammatory response associated with the death of immature adult heartworms in cats. Three groups of cats, 10 per group, were infected with 100 third-stage (L3) larvae by subcutaneous injection. Group A cats were treated with selamectin (Revolution(r); Zoetis) per label directions at 28 days PI and once monthly for 17 months. Group B cats were treated orally with ivermectin (Ivomec(r); Merial) at 150 MUg/kg) at 70 days PI, then every 2 weeks for 15 months. Group C cats were untreated PI. At baseline (Day 0) and on Days 70, 110, 168, 240, 309, 380, and 505 PI, peripheral blood, serum, bronchial lavage, and thoracic radiographic images were collected. RESULTS: The selamectin treated cats (Group A) and ivermectin-treated cats (Group B) were free of heartworms or heartworm fragments at necropsy. All cats became heartworm antibody positive at some time point in the study except for one cat in Group A. Only cats in Group C (all with adult heartworms) were heartworm antigen positive. The heartworm antibody titer for Group B was highest on Days 110 to 168 and then decreased over time and 50% were serologically antibody negative on Day 240. Eosinophilic bronchoalveolar lavage (BAL) cytology and peripheral eosinophilia were most pronounced on Day 110 in all cats. Randomly distributed myofibrocytes in the lungs of some Group A cats suggest that precardiac larval stages were affecting the lungs. Radiographs in Group B cats demonstrated partial resolution of the initial HARD reaction but chronic myofibrocyte proliferation was histologically evident 18 months after infection. CONCLUSION: HARD was induced by immature adult worm infection with progressive improvement starting 6 to 8 months after infection but histologic lesions were evident in some cats 18 months after infection. The serologic antibody assay was negative in 50% of cats at 8 months and 100% of cats at 18 months post infection. Abnormal radiographic lung patterns continued in a subset of Group B cats for months after heartworm antibody serology and BAL cytology returned to normal. PMID- 29143684 TI - Evaluation of cardiopulmonary and inflammatory markers in dogs with heartworm infection during treatment with the 2014 American Heartworm Society recommended treatment protocol. AB - BACKGROUND: Heartworm disease in dogs is a life-threatening parasitic disease. Although adulticide treatment with melarsomine has been proven to be the most effective, complications associated with adulticide treatment are major concerns for clinicians. METHODS: This study evaluated the change in levels of D-dimer, interleukin-6, C-reactive protein and cardiac troponin I in 12 dogs with different severities of heartworm infection treated by the American Heartworm Society (AHS) recommended protocol during the treatment period. The serum levels of several markers were measured on the day of diagnosis (T-60), before the initiation of melarsomine therapy (T0), 1 day after the first injection (T1), 1 week after the first injection (T7), 1 month after the first injection (T30), 1 day after the second injection (T31), 1 day after the third injection (T32), 1 week after the third injection (T39), 1 month after the third injection (T62), 2 months after the third injection (T92), 3 months after the third injection (T122), and 6 months after the third injection (T182). RESULTS: The serum levels of these markers were significantly different at the test time point after melarsomine treatment and also differed significantly according to the stage of heartworm disease in the dogs. CONCLUSION: This study found that monitoring of inflammatory and hemostatic markers in dogs with heartworm disease being treated with melarsomine might be beneficial in predicting the clinical outcomes and complications associated with melarsomine treatment. PMID- 29143685 TI - Available studies fail to provide strong evidence of increased risk of diarrhea mortality due to measles in the period 4-26 weeks after measles rash onset. AB - BACKGROUND: Measles vaccination effectiveness studies showed dramatic decreases in all-cause mortality in excess of what would be expected from the prevention of measles disease alone. This invited speculation that measles infection may increase the risk of diarrhea morbidity and mortality subsequent to the acute phase of the disease. The aim of the present systematic review is to summarize the existing evidence in the publically available literature pertaining to the putative causal link between measles and diarrhea in the period 4-26 weeks following measles rash onset. METHODS: We searched the PubMed, Embase, Open Grey and Grey Literature Report databases for relevant literature using broad search terms. Prospective, retrospective and case-control studies in low- and middle income countries involving children under five wherein relevant evidence were presented were included. Data were extracted from the articles and summarized. RESULTS: Fifty abstracts retrieved through the database searches met the initial screening criteria. Twelve additional documents were identified by review of the references of the documents found in the initial searches. Six documents representing five unique studies that presented evidence relevant to the research question were found. Four of the included studies took place in Bangladesh. One of the included studies took place in Sudan. Some measles vaccine effectiveness studies show lower diarrhea morbidity and mortality among the vaccinated. However, children who received vaccine may have differed in important ways from children who did not, such as health service utilization. Additionally, cohort studies following unvaccinated children showed no difference in diarrhea morbidity and mortality between cases and controls more than 4 weeks after measles rash onset. One study showed some evidence that severe measles may predispose children to gastroenteritis, but was not able to show a corresponding increase in the risk of diarrhea mortality. CONCLUSIONS: The available evidence suggests that the risk of measles-associated diarrhea mortality is largely limited to the 5-week period 1 week prior to and 4 weeks after measles rash onset, and that there is no increased risk of diarrhea mortality in the longer term caused by measles. PMID- 29143686 TI - Acute phase proteins and markers of oxidative stress to assess the severity of the pulmonary hypertension in heartworm-infected dogs. AB - BACKGROUND: Canine heartworm infection is characterized by pulmonary endarteritis and pulmonary hypertension (PH). The aim of the present study was to evaluate the relationship between PH with the concentrations of different positive (C-reactive protein [CRP] and haptoglobin [Hp]) and negative (albumin and paraoxonase-1 [PON 1]) acute phase proteins (APP), as well as the oxidative stress, by measuring glutathione peroxidase (GPx) and total antioxidant capacity (TAC) in 27 heartworm infected dogs on Day 0 (diagnosis) and Day 120 (1 month after the last adulticide injection). Presence/absence of PH was determined by the Right Pulmonary Artery Distensibility (RPAD) Index. RESULTS: On Day 0, 62.9% of the dogs showed PH. Concentrations of CRP and Hp were higher in dogs with PH, especially in dogs with moderate-severe PH (P < 0.005 and P < 0.05, respectively). Albumin and PON-1 concentrations were higher in dogs without PH (P < 0.05 for albumin). On Day 120, 59.2% of the dogs presented with PH; CRP decreased while Hp increased (P < 0.005 and P < 0.05, respectively). Also, albumin and PON-1 rose, especially in absence of PH. There were not significant changes in the serum values of GPx and TAC. CONCLUSIONS: CRP and Hp have a potential prognostic role in dogs with dirofilariasis because increases in positive APP correlated with presence and severity of PH. CRP decreased, but Hp persisted at an elevated level in dogs with PH 1 month after the end of the adulticide treatment. CRP and Hp could work as early biomarkers of PH and be useful to stage the disease and to monitor the evolution of the patient and indirectly evaluate the persistence of arterial damage after the parasites have been eliminated. Albumin and PON-1 also showed potential value as markers of PH, although further research is necessary to determine its utility. PMID- 29143687 TI - Prevalence and epidemiology of canine and feline heartworm infection in Taiwan. AB - BACKGROUND: Heartworm, Dirofilaria immitis, has long been recognized in Taiwanese dogs but feline heartworm infection has been largely overlooked by veterinarians and pet owners. The main goal of this study was to determine the prevalence and epidemiology of canine and feline heartworm infection in Taiwan. METHODS: Household dogs and cats were selected from 103 veterinary hospitals in 13 cities throughout Taiwan. All animals were at least 1 year old, had received no heartworm prevention for more than 1 year, and had lived in the same city for at least 1 year. Client consent was obtained and an owner questionnaire was completed for each patient. Blood samples were collected from each canine patient and tested at each veterinary hospital for microfilariae and for circulating antigen. A positive result on either test was considered to confirm mature heartworm infection. Blood was collected from each feline patient and examined for microfilariae and a feline heartworm antigen/antibody test was performed. Descriptive statistics were used for heartworm prevalence. Multivariate logistic regression analysis was used to determine the relationships between heartworm infection and multiple risk factors. RESULTS: A total of 2064 household dogs and 616 household cats from 103 veterinary hospitals throughout Taiwan were included in the study. The overall prevalence of canine heartworm disease was 22.8% (471/2064). In heartworm-positive dogs, 63% were both microfilaria positive and antigen positive, 35% were microfilaria negative and antigen positive, and only 2% were microfilaria positive and antigen negative. In the comparison of different life style groups, outdoor dogs (N = 797) had significantly higher heartworm prevalence rate than indoor dogs (N = 1267; p = 0.000). The heartworm prevalence rate in dogs presented with dyspnea and cough was as high as 51%. The overall prevalence of antibody-positive cats was 6.7% (41/616) and the antigen positive prevalence rate was 3.1% (19/616). In 41 antibody-positive cats, 6 of them were also antigen-positive. In 19 antigen-positive cats, 13 of them were antibody negative. In antibody-positive and antigen-negative cats, half had no clinical signs. In antigen-positive cats, 21% had no clinical signs and only 38% had classic heartworm clinical signs (dyspnea, cough, or gastrointestinal signs). CONCLUSIONS: Our canine study showed that southern and eastern Taiwan have the highest heartworm prevalence. Dogs not receiving preventive and living outdoors or those that have either cough or dyspnea have a high incidence of heartworm infection. We also confirmed that feline heartworm exposure exists in most cities in Taiwan. The diagnosis of feline heartworm infection will remain challenging for clinicians, however, without a consistent relationship between the presence of heartworm infection and clinical signs and the vagaries of microfilaria and antigen/antibody testing. PMID- 29143688 TI - Investigating management choices for canine heartworm disease in northern Mississippi. AB - BACKGROUND: There are concerns that the chronic use of macrocyclic lactone preventives to kill adult heartworms ("soft-" or "slow-kill") may have contributed to the development of macrocyclic lactone resistance. This prospective analysis was designed to expand our understanding of currently employed treatment decisions, protocols utilized in a "slow-kill" methodology, and trends in heartworm prevention in a region with concerns about macrocyclic lactone resistance. We tested the hypothesis that practitioners underestimate the actual percentage of heartworm-positive dogs treated with "slow-kill" therapy. Owners' financial concerns and veterinarians' efforts at meeting client preferences are the primary reasons for employment of "soft-kill" treatment. METHODS: A prospective analysis of dogs determined to be heartworm-positive when presented to a mixed-animal practice in northern Mississippi was conducted for the second quarter of 2016. Client records were scrutinized for heartworm preventive purchase history. Veterinarians in the four-doctor practice completed a questionnaire regarding their beliefs and practices of heartworm treatment. RESULTS: Forty of 321 canine patients tested heartworm-positive with a commercial antigen test kit. Of these, two were considered to be due to possible product failure. The majority (75.0%) of patients received a "slow-kill" method, a percentage greater than that estimated by the practitioners. Patients were equally likely to have received adulticidal treatment as they were to receive no treatment (12.5%). Injectable moxidectin was the most common preventive used in "slow-kill" treatment (80.65%). Client financial concerns were cited as the primary reason for choosing "slow-kill" treatment (79.0%). CONCLUSIONS: Despite American Heartworm Society recommendations, clients and veterinarians prefer the "slow-kill" method of heartworm treatment. Trends in patient heartworm preventive history show that poor client compliance remains the predominant explanation for heartworm infection. Thus, consistent use of existing, effective heartworm preventives should be the primary goal in reducing prevalence of heartworm infection, regardless of the recognized threat of resistance. It is also noteworthy that practitioner estimates may be suspect in their accuracy. Further study is needed on the risks and efficacy of "slow-kill" treatment and the effects of different ML preventives for this off-label use. PMID- 29143689 TI - Examination of the "susceptibility gap" in the treatment of canine heartworm infection. AB - BACKGROUND: The "susceptibility gap" in a dog diagnosed with adult heartworms has been defined as the period of time in which some Dirofilaria immitis stages are not susceptible to treatment with either macrocyclic lactones or melarsomine dihydrochloride. This was previously defined within the American Heartworm Society guidelines as a period of about 3 months "as per product labels." It can be postulated, however, that a susceptibility gap does not exist with the combination of continued macrocyclic lactone therapy coupled with a three-dose melarsomine dihydrochloride protocol where the first intramuscular treatment is near the time of first diagnosis. DISCUSSION: Melarsomine dihydrochloride was originally also investigated as a "preventive" as well as a treatment for adult heartworm infection where it would be given to dogs by intramuscular injection every 4 months; therefore, there was early interest in its ability to kill younger worms. A single intramuscular injection of 2.5 mg melarsomine dihydrochloride/kg has an efficacy of 82.1% against 4-month-old worms. When it was given to dogs with older heartworms, 7 and 12 months of age, a single injection was only 55.6% and 51.7% effective, respectively. Thiacetarsamide has been shown to be 99.7% effective against 2-month-old heartworms and other work has shown that melarsomine dihydrochloride is 100% efficacious against these younger forms. With the development and US Food and Drug Administration (FDA) approval of spinosad + milbemycin oxime (Trifexis(r), Elanco), milbemycin oxime + praziquantel (Interceptor(r) Plus, Novartis, now Elanco), and milbemycin oxime + lufenuron + praziquantel (Sentinel(r) Spectrum(r), Novartis, now Virbac), it was shown that repeated treatments of dogs with milbemycin oxime also has efficacy against 3-month-old heartworms. Thus, no improvement in efficacy is expected with a delay in initiating therapy with both melarsomine dihydrochloride and macrocyclic lactones, even with the presence of younger heartworms. Starting treatment at diagnosis appears to be acceptable for maximal heartworm clearance based on published data. Delaying treatment has the disadvantage of allowing disease progression and continued heartworm growth. CONCLUSIONS: The collective data that has been reviewed indicates that continued macrocyclic lactone administration with two additional injections of melarsomine dihydrochloride a month later will protect dogs against all heartworm stages, including those heartworms 2 months of age or younger at diagnosis, when both treatments are started upon diagnosis. PMID- 29143690 TI - Standardisation of the Japanese diet for use in animal experiments. AB - The aim of this study was to develop a purified diet that mimics the characteristics of the Japanese diet using readily available materials with a simpler composition and a focus on quality, with the goal of facilitating performance of studies on the Japanese diet worldwide. The utility of the new diet was examined as a mimic of the standard Japanese diet for use in animal experiments. We examined whether a key characteristic of the Japanese diet of being less likely to cause obesity could be reproduced. The mimic diet had a balance of protein, fat and carbohydrate based on the 1975 Japanese diet, which is the least likely to cause obesity, and materials chosen with reference to the National Health and Nutrition Survey (NHNS). To examine similarities of the mimic diet with the model 1975 Japanese diet, we created a menu of the 1975 diet based on the NHNS and prepared the freeze-dried and powdered diet. The mimic diet, the 1975 Japanese diet, a control AIN-93G diet and a Western diet were fed to mice for 4 weeks. As a result, the mimic diet and the 1975 diet resulted in less accumulation of visceral fat and liver fat. Mice given these two diets showed similar effects. This indicates that the mimic diet used in this study has characteristics of the 1975 Japanese diet and could be used as a standard Japanese diet in animal experiments. PMID- 29143691 TI - Health claims and product endorsements on child-oriented beverages in Guatemala. AB - OBJECTIVE: We sought to describe front-of-package marketing strategies and nutritional quality of child-oriented beverages in Guatemala. DESIGN: We purchased all child-oriented ready-to-drink fruit drinks, milks and carbonated beverages in three convenience stores and one supermarket in Guatemala City. Front-of-package marketing was defined as the presence of spokes-characters, cartoons, celebrities, or health-related images, words, claims or endorsements on beverage packaging. We used the UK Nutrition Profiling Model (NPM) to classify beverages as healthy or less healthy. SETTING: Guatemala City, Guatemala. RESULTS: We purchased eighty-nine beverages; most were fruit drinks (n 52, 58 %), milk (15, 17 %), carbonated beverages (5, 17 %), rice/soya products (5, 6.0 %), water (1, 1 %) and energy drinks (1, 1 %). Two-thirds (57, 64 %) had health claims. Of those with a nutrition facts label (85, 96 %), nearly all (76, 89 %) were classified as less healthy. No association between the presence of health claims and NPM score (P=0.26) was found. Eight beverages had health-related endorsements. However, only one beverage was classified as healthy. CONCLUSIONS: In this sample of beverages in Guatemala City, health claims and health-related endorsements are used to promote beverages with poor nutritional quality. Our data support evidence-based policies to regulate the use of front-of-package health claims and endorsements based on nutritional quality. PMID- 29143692 TI - Non-pharmacological interventions for Lewy body dementia: a systematic review. AB - Lewy body dementia (consisting of dementia with Lewy bodies and Parkinson's disease dementia) is a common neurodegenerative disease characterised by visual hallucinations, fluctuating attention, motor disturbances, falls, and sensitivity to antipsychotics. This combination of features presents challenges for pharmacological management. Given this, we sought to review evidence for non pharmacological interventions with patients with Lewy body dementia and their carers. Bibliographic databases were searched using a wide range of search terms and no restrictions were placed on study design, language, or clinical setting. Two reviewers independently assessed papers for inclusion, rated study quality, and extracted data. The search identified 21 studies including two randomised controlled trials with available subgroup data, seven case series, and 12 case studies. Most studies reported beneficial effects of the interventions used, though the only sizeable study was on dysphagia, showing a benefit of honey thickened liquids. Given the heterogeneity of interventions and poor quality of the studies overall, no quantitative synthesis was possible. Overall, identified studies suggested possible benefits of non-pharmacological interventions in Lewy body dementia, but the small sample sizes and low quality of studies mean no definite recommendations can be offered. Our findings underscore the clear and urgent need for future research on this topic. PMID- 29143693 TI - A rare case of extra-nasopharyngeal angiofibroma of the septum in a female child. AB - BACKGROUND: Extra-nasopharyngeal angiofibroma is a rare but distinct clinical entity, different from juvenile angiofibroma. METHODS: This clinical record elucidates the only case of extra-nasopharyngeal angiofibroma arising from the septum in a female child, who presented with epistaxis. RESULTS: The histopathological diagnosis was confirmed by immunohistochemistry, and the case was managed surgically with no recurrence. CONCLUSION: In a female paediatric patient presenting with epistaxis, extra-nasopharyngeal angiofibroma (of the inferior turbinate) is a rare albeit important differential diagnosis, as it challenges the hormonal theory of angiofibroma aetiopathogenesis. PMID- 29143694 TI - Cryo-Scanning Electron Microscopy (SEM) and Scanning Transmission Electron Microscopy (STEM)-in-SEM for Bio- and Organo-Mineral Interface Characterization in the Environment. AB - Understanding biofilm interactions with surrounding substratum and pollutants/particles can benefit from the application of existing microscopy tools. Using the example of biofilm interactions with zero-valent iron nanoparticles (nZVI), this study aims to apply various approaches in biofilm preparation and labeling for fluorescent or electron microscopy and energy dispersive X-ray spectrometry (EDS) microanalysis for accurate observations. According to the targeted microscopy method, biofilms were sampled as flocs or attached biofilm, submitted to labeling using 4',6-diamidino-2-phenylindol, lectins PNA and ConA coupled to fluorescent dye or gold nanoparticles, and prepared for observation (fixation, cross-section, freezing, ultramicrotomy). Fluorescent microscopy revealed that nZVI were embedded in the biofilm structure as aggregates but the resolution was insufficient to observe individual nZVI. Cryo-scanning electron microscopy (SEM) observations showed nZVI aggregates close to bacteria, but it was not possible to confirm direct interactions between nZVI and cell membranes. Scanning transmission electron microscopy in the SEM (STEM-in SEM) showed that nZVI aggregates could enter the biofilm to a depth of 7-11 um. Bacteria were surrounded by a ring of extracellular polymeric substances (EPS) preventing direct nZVI/membrane interactions. STEM/EDS mapping revealed a co localization of nZVI aggregates with lectins suggesting a potential role of EPS in nZVI embedding. Thus, the combination of divergent microscopy approaches is a good approach to better understand and characterize biofilm/metal interactions. PMID- 29143695 TI - An overview of systematic reviews of pharmacological and non-pharmacological interventions for the treatment of behavioral and psychological symptoms of dementia. AB - : ABSTRACTBackground:This systematic overview reports findings from systematic reviews of randomized controlled trials of pharmacological and non pharmacological interventions for behavioural and psychological symptoms of dementia (BPSD). METHODS: The Cochrane Database of Systematic Reviews, DARE, Medline, EMBASE, and PsycINFO were searched to September 2015. RESULTS: Fifteen systematic reviews of eighteen different interventions were included. A significant improvement in BPSD was seen with: functional analysis-based interventions (GRADE quality of evidence moderate; standardized mean difference (SMD) -0.10, 95%CI -0.20 to 0.00), music therapy (low; SMD -0.49, 95%CI -0.82 to 0.17), analgesics (low; SMD -0.24, 95%CI -0.47 to -0.01), donepezil (high; SMD 0.15 95% CI -0.29 to -0.01), galantamine (high; SMD -0.15, 95%CI -0.28 to -0.03), and antipsychotics (high; SMD -0.13, 95%CI -0.21 to -0.06). The estimate of effect size for most interventions was small. CONCLUSIONS: Although some pharmacological interventions had a slightly larger effect size, current evidence suggests functional analysis-based interventions should be used as first line management of BPSD whenever possible due to the lack of associated adverse events. Music therapy may also be beneficial, but further research is required as the quality of evidence to support its use is low. Cholinesterase inhibitors donepezil and galantamine should be trialled for the management of BPSD where non pharmacological treatments have failed. Low-quality evidence suggests that assessment of pain should be conducted and a stepped analgesic approach trialled when appropriate. Antipsychotics have proven effectiveness but should be avoided where possible due to the high risk of serious adverse events and availability of safer alternatives. PMID- 29143696 TI - From 'ah' to 'bah': social feedback loops for speech sounds at key points of developmental transition. AB - Social feedback is a driving force for speech development. A recent study provided a key finding to explain how contingent responses influence developmental change: infant speech-related vocalizations are contingent on responses to prior speech-related vocalizations (Warlaumont et al., 2014). However, the study did not distinguish between different speech-related vocalizations, vowel-like (V) and consonant-vowel (CV) vocalizations, which is important because CV vocalizations are a precursor to words. The present study explored parents' responses to infants' vocalizations and infants' subsequent vocal production at a point when vocalizations become more like adult speech. The relative proportion of CVs following contingent responses to CV did not differ between 10- and 12-months-olds; however, there was only a significant contingent relationship between responses to CV and subsequent CV production in 12-month olds. Results suggest a developmental transition and a social feedback loop for the production of more developmentally advanced sounds when infants are learning their first words. PMID- 29143697 TI - Stroke and food groups: an overview of systematic reviews and meta-analyses. AB - OBJECTIVE: Numerous systematic reviews of prospective studies on the association of stroke risk with the consumption of various food groups have been published. A review of the evidence across the existing systematic reviews and meta-analyses of prospective studies was conducted to provide an overview of the range and validity of the reported associations of food groups with stroke risk. DESIGN: The PubMed, EMBASE and Cochrane Library databases were searched for articles published up to September 2015 to identify systematic reviews of prospective studies. RESULTS: A total of eighteen studies published from 2008 to 2015 were eligible for analysis. Overall, thirteen specific foods were studied for an association with stroke outcome, including nuts, legumes, fruits and vegetables, refined grains, whole grains, dairy products, eggs, chocolate, red and/or processed meat, fish, tea, sugar-sweetened beverages and coffee. Whereas a high consumption of nuts, fruits, vegetables, dairy foods, fish and tea, and moderate consumption of coffee and chocolate demonstrated a protective effect, a high consumption of red and/or processed meat was associated with increased stroke risk. Refined grain, sugar-sweetened beverage, legume, egg and whole grain intake showed no effect on stroke outcome. CONCLUSIONS: The current overview provided a high level of evidence to support the beneficial effect of specific foods on stroke outcome. Clinicians and policy makers could inform clinical practice and policy based on this overview. PMID- 29143698 TI - USING THE INTEGRATE-HTA GUIDANCE: EXPERIENCE FROM CADTH. AB - OBJECTIVES: The aim of this study was to describe an initial exploration by CADTH, Canada's pan-Canadian health technology assessment (HTA) agency, in using the INTEGRATE-HTA guidance in the production of an HTA that examined the use of both in-center and in-home dialysis modalities for the treatment of end-stage kidney disease in adults in Canada. METHODS AND RESULTS: We outline CADTH's standard HTA production process and context and then describe the experience of the assessment team in using the INTEGRATE-HTA guidance, specifically to help structure and guide the use of a logic model, the identification of implementation issues, and the identification and examination of ethical issues. For each of the aspects, we describe and reflect on how the assessment team used the guidance, challenges that were encountered in its use, and whether and how we might address these challenges when using the INTEGRATE-HTA guidance in the future. CONCLUSIONS: INTEGRATE-HTA provided detailed and helpful guidance for truly integrating wide-ranging aspects of HTA. Our agency was challenged by a steep learning curve for assessment team members, tight project timelines, and a misalignment of current HTA processes with those required to implement the guidance. Nevertheless, using the guidance initiated a dialogue about what might be needed to assess complex interventions and the potential process changes that could facilitate conducting more integrated assessments. PMID- 29143699 TI - Are there distinct cognitive and motivational sub-groups of children with ADHD? AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is proposed to be a neuropsychologically heterogeneous disorder that encompasses two distinct sub groups, one with executive function (EF) deficits and one with delay aversion (DA). However, such claims have often been based on studies that have operationalized neuropsychological deficits using a categorical approach - using intuitive but rather arbitrary, clinical cut-offs. The current study applied an alternative empirical approach to sub-grouping in ADHD, latent profile analysis (LPA), and attempted to validate emerging subgroups through clinically relevant correlates. METHODS: One-hundred medication-naive children with ADHD and 96 typically developing children (6-14 years) completed nine EF and three DA tasks as well as an odor identification test. Parents and teachers provided reports of the children's behavior (ADHD and EF). Models of the latent structure of scores on EF and DA tests were contrasted using confirmatory factor analysis (CFA). LPA was carried out based on factor scores from the CFA and sub-groups were compared in terms of odor identification and behavior. RESULTS: A model with one DA and two EF factors best fit the data. LPA resulted in four sub-groups that differed in terms of general level of neuropsychological performance (ranging from high to very low), odor identification, and behavior. The sub-groups did not differ in terms of the relative EF and DA performance. Results in the ADHD group were replicated in the control group. CONCLUSIONS: While EF and DA appear to be dissociable constructs; they do not yield distinct sub-groups when sub-grouping is based on a statistical approach such as LPA. PMID- 29143700 TI - Improved Three-Dimensional (3D) Resolution of Electron Tomograms Using Robust Mathematical Data-Processing Techniques. AB - Electron tomography has become an essential tool for three-dimensional (3D) characterization of nanomaterials. In recent years, advances have been made in specimen preparation and mounting, acquisition geometries, and reconstruction algorithms. All of these components work together to optimize the resolution and clarity of an electron tomogram. However, one important component of the data processing has received less attention: the 2D tilt series alignment. This is challenging for a number of reasons, namely because the nature of the data sets and the need to be coherently aligned over the full range of angles. An inaccurate alignment may be difficult to identify, yet can significantly limit the final 3D resolution. In this work, we present an improved center-of-mass alignment model that allows us to overcome discrepancies from unwanted objects that enter the imaging area throughout the tilt series. In particular, we develop an approach to overcome changes in the total mass upon rotation of the imaging area. We apply our approach to accurately recover small Pt nanoparticles embedded in a zeolite that may otherwise go undetected both in the 2D microscopy images and the 3D reconstruction. In addition to this, we highlight the particular effectiveness of the compressed sensing methods with this data set. PMID- 29143701 TI - Modelling interactions between farmer practices and fattening pig performances with an individual-based model. AB - European pig production continues to encounter economic and environmental challenges. To address these issues, methods have been developed to assess performances of pig production systems. Recent studies indicate that considering variability in performances among pigs improves the accuracy and reliability of results compared with modelling an average animal. Our objective was to develop a pig fattening unit model able to (i) simulate individual pig performances, including their variability in interaction with farmers' practices and management, and (ii) assess their effects on technical, economic and environmental performances. Farmer practices included in the model were chosen from a typology generated from on-farm surveys focused on batch management, pig allocation to pens, pig feeding practices, practices of shipping to the slaughterhouse, and management of the remaining pigs. Pigs are represented using an individual-based model adapted from the InraPorc(r) model. To illustrate the model's abilities, four scenarios were simulated that combine two feed rationing plans (ad libitum, restricted to 2.5 kg/day) and two feed sequence plans (two phase, 10-phase). Analysis of variance was performed on the simulated technical, economic and environmental indicators (calculated via Life Cycle Assessment). The feed rationing plan and feed sequence plan significantly affected all indicators except for the premium per pig, for which the feed sequence plan did not have a significant effect. The 'restricted 10-phase' scenario maximised gross margin of the fattening unit (14.2 ?/pig) and minimised environmental impacts per kg of pig produced. In contrast, the 'ad libitum two-phase' scenario generated the lowest margin (8.20 ?/pig) and the highest environmental impacts. The model appears to be a promising tool to assess effects of farmers' practices, pig characteristics and farm infrastructure on technical, economic and environmental performances of the fattening unit, and to investigate the potential of improvement. However, further work is needed, based on virtual experiments, in order to evaluate the effects of a larger diversity of practices. PMID- 29143702 TI - Association between altered neurochemical metabolites and apathy in patients with Alzheimer's disease. AB - : ABSTRACTBackground:Apathy is a condition characterized by a lack of motivation that manifests in emotional, behavioral, and cognitive domains. Although previous studies have indicated that apathy is associated with frontal lesions, few studies have focused on the different subdomains of apathy, and no in vivo human biochemical data have been obtained to examine the neurochemical changes related to apathy in patients with Alzheimer's disease (AD). Thus, we investigated the frontal neurochemical alterations related to apathy among patients with AD using proton magnetic resonance spectroscopy (1H MRS). METHODS: Apathy was assessed through the Apathy Evaluation Scale (AES). 1H MRS was performed to measure neurochemical metabolite levels in the anterior cingulate region and right orbitofrontal region. Associations between neurochemical metabolites and the total score and subscores of each domain of the AES were analyzed. RESULTS: Altogether, 36 patients completed the study. Patients with lower N acetylaspartate/creatine ratios (NAA/Cr) in the anterior cingulate region demonstrated higher total apathy scores (beta = -0.56, p = 0.003) with adjustments for age, gender, educational level, dementia severity, and depression severity. In a further analysis, a lower NAA/Cr in the anterior cingulate region was associated with all subdomains of apathy, including cognition (beta = -0.43, p = 0.028), behavior (beta = -0.55, p = 0.002), and emotion (beta = -0.50, p = 0.005). No statistically significant associations were discovered in the right orbitofrontal region. CONCLUSIONS: Our results suggest that apathy, in each of its cognitive, behavioral, or emotional subdomains is associated with brain neurochemical alterations in the anterior cingulate region. Abnormal neuronal integrity over the anterior cingulate cortex may exhibit a central role in causing all aspects of apathy in patients with AD. PMID- 29143703 TI - Dose-response evaluation of the standardized ileal digestible tryptophan : lysine ratio to maximize growth performance of growing-finishing gilts under commercial conditions. AB - Environmental regulations as well as economic incentives have resulted in greater use of synthetic amino acids in swine diets. Tryptophan is typically the second limiting amino acid in corn-soybean meal-based diets. However, using corn-based co-products emphasizes the need to evaluate the pig's response to increasing Trp concentrations. Therefore, the objective of these studies was to evaluate the dose-response to increasing standardized ileal digestible (SID) Trp : Lys on growth performance of growing-finishing gilts housed under large-scale commercial conditions. Dietary treatments consisted of SID Trp : Lys of 14.5%, 16.5%, 18.0%, 19.5%, 21.0%, 22.5% and 24.5%. The study was conducted in four experiments of 21 days of duration each, and used corn-soybean meal-based diets with 30% distillers dried grains with solubles. A total of 1166, 1099, 1132 and 975 gilts (PIC 337*1050, initially 29.9+/-2.0 kg, 55.5+/-4.8 kg, 71.2+/-3.4 kg and 106.2+/-3.1 kg BW, mean+/-SD) were used. Within each experiment, pens of gilts were blocked by BW and assigned to one of the seven dietary treatments and six pens per treatment with 20 to 28 gilts/pen. First, generalized linear mixed models were fit to data from each experiment to characterize performance. Next, data were modeled across experiments and fit competing dose-response linear and non-linear models and estimate SID Trp : Lys break points or maximums for performance. Competing models included broken-line linear (BLL), broken-line quadratic and quadratic polynomial (QP). For average daily gain (ADG), increasing the SID Trp : Lys increased growth rate in a quadratic manner (P<0.02) in all experiments except for Exp 2, for which the increase was linear (P<0.001). Increasing SID Trp : Lys increased (P<0.05) feed efficiency (G : F) quadratically in Exp 1, 3 and 4. For, ADG the QP was the best fitting dose-response model and the estimated maximum mean ADG was obtained at a 23.5% (95% confidence interval (CI): [22.7, 24.3%]) SID Trp : Lys. For maximum G : F, the BLL dose-response models had the best fit and estimated the SID Trp : Lys minimum to maximize G : F at 16.9 (95% CI: [16.0, 17.8%]). Thus, the estimated SID Trp : Lys for 30 to 125 kg gilts ranged from a minimum of 16.9% for maximum G : F to 23.5% for maximum ADG. PMID- 29143704 TI - Identification of Clostridium difficile Reservoirs in The Patient Environment and Efficacy of Aerial Hydrogen Peroxide Decontamination. AB - OBJECTIVE To identify, using a novel enhanced method of recovery, environmental sites where spores of Clostridium difficile persist despite cleaning and hydrogen peroxide aerial decontamination. DESIGN Cohort study. SETTING Tertiary referral center teaching hospital. METHODS In total, 16 sites representing high-frequency contact or difficult-to-clean surfaces in a single-isolation room or bed area in patient bed bays were sampled before and after terminal or hydrogen peroxide disinfection using a sponge swab. In some rooms, individual sites were not present (eg, there were no en-suite rooms in the ICU). Swab contents were homogenized, concentrated by membrane-filtration, and plated onto selective media. Results of C. difficile sampling were used to focus cleaning. RESULTS Over 1 year, 2,529 sites from 146 rooms and 44 bays were sampled. Clostridium difficile was found on 131 of 572 surfaces (22.9%) before terminal cleaning, on 105 of 959 surfaces (10.6%) after terminal cleaning, and on 43 of 967 surfaces (4.4%) after hydrogen peroxide disinfection. Clostridium difficile persisted most frequently on floor corners (97 of 334; 29.0%) after disinfection. Between the first and third quarters, we observed a significant decrease in the number of positive sites (25 of 390 vs 6 of 256). However, no similar change in the number of isolates before terminal cleaning was observed. CONCLUSION Persistence of C. difficile in the clinical environment was widespread. Although feedback of results did not improve the efficacy of manual disinfection, numbers of C. difficile following hydrogen peroxide gradually declined. Infect Control Hosp Epidemiol 2017;38:1487-1492. PMID- 29143705 TI - Rumination time and monitoring of health disorders during early lactation. AB - The objective was to evaluate the association between changes in daily rumination time (dRT) and early stages of disease during early lactation and to assess the performance of two proposed disease detection indices. This cohort study included 210 multiparous Holstein cows at the University of Florida Dairy Unit. Cows were affixed with a neck collar containing rumination loggers providing rumination time. The occurrence of health disorders (mastitis, metritis, clinical hypocalcemia, depression/dehydration/fever (DDF), digestive conditions, lameness and clinical ketosis) was assessed until 60 days in milk. Two indices were developed to explore the association between dRT and disease: (i) Cow index (CIx), based on changes in dRT in the affected cow during the days before the diagnosis of health disorders; (ii) Mates index (MIx), index based on deviations in dRT relative to previous days and healthy pen mate cohorts. Subsequently, an alert model was proposed for each index (ACIx and AMIx) considering the reference alert cut-off values as the differences between average index values in healthy and sick cows for each specific disease. The sensitivity (SE) of ACIx detecting disease ranged from 42% (digestive conditions and DDF) to 80% (clinical hypocalcemia) with 84% specificity (SP). The SE of AMIx ranged from 46% (digestive conditions and DDF) to 100% (clinical hypocalcemia) with 85% SP. Consistent reductions in rumination activity, both within cow and relative to healthy mate cohorts, were observed for each health disorder at the day of diagnosis. However, the ability of the proposed algorithms for detecting each specific disease was variable. PMID- 29143706 TI - Potential sensitivity of pork production situations aiming at high-quality products to the use of entire male pigs as an alternative to surgical castrates. AB - The perspective of a possible ban on surgical castration of male pigs in the EU is a real challenge for pork production systems aiming at (very) high-quality products. Information was collected from a total of 272 situations in 16 European countries, including 170 situations related to EU protected designations (Database of Origin & Registration (DOOR) database) and 102 other situations related to high-quality products or differentiated production systems, in order to evaluate their potential sensitivity to the use of entire male pigs along four dimensions: BT_Inc, likelihood of increased levels of boar taint compounds compared with conventional production of entire males; BT_Per, extent to which (some of) the associated pork product(s) are susceptible to perception of boar taint by consumers; FatQQ, likelihood that the quality of (some of) the related products is decreased due to the lower fat quantity and quality in entire males; Manag, increased likelihood of animal management and welfare problems compared with conventional production of entire males. Situations corresponding to EU protected designations (DOOR situations) were on average more sensitive to entire male production but 11% of the non-DOOR situations were highly potentially sensitive, whereas one-third of the DOOR situations had low potential sensitivity. In total, 37% of the situations where castration is not formally specified as mandatory exhibited high potential sensitivity to entire male production. Three main patterns of situations were identified via ascending hierarchical clustering. A first pattern including 31% of the DOOR situations and 74% of the other ones, had potentially no increased risk compared with conventional production of entire males. A second pattern including 28% of the DOOR situations and 16% of the other ones had a high, moderate and low potential sensitivity for FatQQ, BT_Inc and Manag, respectively. The third pattern including 41% of the DOOR situations and 11% of the other situations had high potential sensitivity for BT_Inc and FatQQ, associated with moderate to high sensitivity for Manag. The approach used to evaluate the sensitivity to entire male pig production from the limited information collected for this study has many limitations. More precise approaches using more specific information are needed to evaluate the actual sensitivity of individual situations to the use of entire male pigs. Still, the present study provides a first global insight on the capacity of European production systems aiming at high-quality products to use entire male pigs as an alternative to surgical castration. PMID- 29143707 TI - Effect of multi-micronutrient-fortified rice on cognitive performance depends on premix composition and cognitive function tested: results of an effectiveness study in Cambodian schoolchildren. AB - OBJECTIVE: Even though current policy is strongly focused on the crucial first '1000 days', it might be still possible to enhance cognitive function during the pre-adolescent and adolescent years by improving micronutrient status. In Cambodia, nutritional status is poor. Provision of rice fortified with micronutrients through a school meal programme (SMP) could be a cost-effective strategy to help improve health and school performance. The present study aimed to evaluate the effect of three different micronutrient-fortified rice formulations on cognitive function in Cambodian children. SETTING: Sixteen Cambodian schools receiving SMP. DESIGN: The FORISCA-UltraRice(r)+NutriRice(r) study was a randomized, double-blind, placebo-controlled trial. Four groups of four schools were randomly allocated to receive normal rice, UltraRice(r)Original, UltraRice(r)New or NutriRice(r). Within each school, 132 children were randomly selected. Data on cognitive performance (picture completion, block design and Raven's coloured progressive matrices (RCPM)), anthropometry, parasite infestation and micronutrient status were collected before the intervention and after 6 months. SUBJECTS: Cognitive data were available for 1796 children aged 6-16 years. RESULTS: All cognitive scores improved after 6 months (P<0.001). Block design score improvement was significantly higher in children consuming UltraRice(r)Original (P=0.03) compared with the other fortified rice groups and placebo. No difference among groups was found on RCPM or picture completion scores. Stunting, parasite infestation and inflammation negatively affected the impact of the intervention. CONCLUSIONS: Combined with other interventions, using SMP to distribute fortified rice to schoolchildren may be a cost-effective way to increase cognitive performance and thereby improve school performance and educational achievements. PMID- 29143708 TI - Genome-wide association study for growth traits in Nelore cattle. AB - The objective of this study was to investigate the association of single nucleotide polymorphisms (SNPs) with birth weight, weight gain from birth to weaning and from weaning to yearling, yearling height and cow weight in Nelore cattle. Data from 5064 animals participating in the DeltaGen and PAINT breeding programs were used. The animals were genotyped with a panel of 777 962 SNPs (Illumina BovineHD BeadChip) and 412 993 SNPs remained after quality control analysis of the genomic data. A genome-wide association study was performed using a single-step methodology. The analyses were processed with the BLUPF90 family of programs. When applied to a genome-wide association studies, the single-step GBLUP methodology is an iterative process that estimates weights for the SNPs. The weights of SNPs were included in all analyses by iteratively applying the single-step GBLUP methodology and repeated twice so that the effect of the SNP and the effect of the animal were recalculated in order to increase the weight of SNPs with large effects and to reduce the weight of those with small effects. The genome-wide association results are reported based on the proportion of variance explained by windows of 50 adjacent SNPs. Considering the two iterations, only windows with an additive genetic variance >1.5% were presented in the results. Associations were observed with birth weight on BTA 14, with weight gain from birth to weaning on BTA 5 and 29, with weight gain from weaning to yearling on BTA 11, and with yearling height on BTA 8, showing the genes TMEM68 (transmembrane protein 8B) associated with birth weight and yearling height, XKR4 (XK, Kell blood group complex subunit-related family, member 4) associated with birth weight, NPR2 (natriuretic peptide receptor B) associated with yearling height, and REG3G (regenerating islet-derived 3-gamma) associated with weight gain from weaning to yearling. These genes play an important role in feed intake, weight gain and the regulation of skeletal growth. PMID- 29143709 TI - Acute and chronic cold exposure differentially affects the browning of porcine white adipose tissue. AB - Piglets are characteristically cold intolerant and thus susceptible to high mortality. However, browning of white adipose tissue (WAT) can induce non shivering thermogenesis as a potential strategy to facilitate the animal's response to cold. Whether cold exposure can induce browning of subcutaneous WAT (sWAT) in piglets in a similar manner as it can in humans remains largely unknown. In this study, piglets were exposed to acute cold (4 degrees C, 10 h) or chronic cold exposure (8 degrees C, 15 days), and the genes and proteins of uncoupling protein 1 (UCP1)-dependent and independent thermogenesis, mitochondrial biogenesis, lipogenic and lipolytic processes were analysed. Interestingly, acute cold exposure induced browning of porcine sWAT, smaller adipocytes and the upregulated expression of UCP1, PGC1alpha, PGC1beta, C/EBPbeta, Cidea, UCP3, CKMT1 and PM20D1. Conversely, chronic cold exposure impaired the browning process, reduced mitochondrial numbers and the expression of browning markers, including UCP1, PGC1alpha and PRDM16. The present study demonstrated that acute cold exposure (but not chronic cold exposure) induces porcine sWAT browning. Thus, browning of porcine sWAT could be a novel strategy to balance the body temperature of piglets, and thus could be protective against cold exposure. PMID- 29143710 TI - Importance of determining the climatic domains of sheep breeds. AB - The main purpose of the study was to compare the capacity of the major sheep breeds in Morocco to cope with climate changes through the ranges of several climate parameters in which they can be found. We first delimitated the climatic 'domains' of each breed by constructing a database including altitude and climatic parameters (minima mean of the coldest month, maxima mean of the hottest month, annual rainfall, pluviothermic coefficient of Emberger Q 2, annual minima mean and annual maxima mean) on a 30-year period using the representative stations of each breed distribution. The overlap between each breed combination was quantified through a canonical analysis that extracted the most discriminant parameters. The variance analysis of each climatic parameter evidenced two breeds remarkable by their tolerance. The first one is the Timahdite, mainly settled in areas over 1100 m, which can tolerate the greatest variations in annual rainfall and pluviothermic coefficient. In spite of this feature, this breed is endangered owing to the decreasing quality of pastures. The second one is the D'man which apparently can support high variations in extreme temperatures. In fact, this breed is not well adapted to pastures and requires a special microclimate offered by oases. The information reported in this study will be the basis for the establishment of characterization and selection strategies for Moroccan sheep. PMID- 29143711 TI - Defining the breeding goal for a sheep breed including production and functional traits using market data. AB - In this study, the economic values for production and functional traits of dairy sheep are estimated through the application of a profit function model using farm level technical and economic data. The traits incorporated in the model were milk production, prolificacy, fertility, milking speed, longevity and mastitis occurrence. The economic values for these traits were derived as the approximate partial derivative of the specified profit function. A sensitivity analysis was also conducted in order to examine how potential changes in input and output prices would affect the breeding goal. The estimated economic values of the traits revealed their economic impact on the definition of the breeding goal for the specified production system. Milk production and fertility had the highest economic values (?40.30 and ?20.28 per standard genetic deviation (SDa)), while, mastitis only had a low negative value of -0.57 ?/SDa. Therefore, breeding for clinical mastitis will have a minor impact on farm profitability because it affects a small proportion of the flock and has low additive variance. The production traits, which include milk production, prolificacy and milking speed, contributed most to the breeding goal (70.0%), but functional traits still had a considerable share (30.0%). The results of this study highlight the importance of the knowledge of economic values of traits in the design of a breeding program. It is also suggested that the production and functional traits under consideration can be categorized as those which can be efficiently treated through genetic improvement (e.g. milk production and fertility) while others would be better dealt with through managerial interventions (e.g. mastitis occurrence). Also, sub-clinical mastitis that affects a higher proportion of flocks could have a higher contribution to breeding goals. PMID- 29143712 TI - Accuracy and bias of genomic prediction with different de-regression methods. AB - Genomic selection has become increasingly important in the breeding of animals and plants. The response variable is an important factor, influencing the accuracy of genomic selection. The de-regressed proof (DRP) based on traditional estimated breeding value (EBV) is commonly used as response variable. In the current study, simulated data from 16th QTL-MAS Workshop and real data from Chinese Holstein cattle were used to compare accuracy and bias of genomic prediction with two methods of calculating DRP. Our results with simulated data showed that the correlation between genomic EBV and true breeding value achieved using the Jairath method (DRP_J) was superior to that achieved using the Garrick method (DRP_G) for simulated trait 1 but the reverse was true for simulated trait 3, and these two methods performed comparably for simulated trait 2. For all three simulated traits, DRP_J yielded larger bias of genomic prediction. However, DRP_J outperformed DRP_G in both accuracy and unbiasedness for four milk production traits in Chinese Holstein. In the estimation of genomic breeding value using genomic BLUP model, two methods for weighting diagonal elements of incidence matrix associated with residual error were also compared. With increasing the proportion of genetic variance unexplained by markers, the accuracy of genomic prediction was decreased and the bias was increased. Weighting by the reliability of DRP produced accuracy comparable to the evaluation where the proportion of genetic variance unexplained by markers was considered, but with smaller bias in general. PMID- 29143713 TI - Expanding the evidence: key priorities for research on mental health interventions for refugees in high-income countries. PMID- 29143714 TI - New insights into mitogenomic phylogeny and copy number in eight indigenous sheep populations based on the ATP synthase and cytochrome c oxidase genes. AB - The origins and phylogeny of different sheep breeds has been widely studied using polymorphisms within the mitochondrial hypervariable region. However, little is known about the mitochondrial DNA (mtDNA) content and phylogeny based on mtDNA protein-coding genes. In this study, we assessed the phylogeny and copy number of the mtDNA in eight indigenous (population size, n=184) and three introduced (n=66) sheep breeds in China based on five mitochondrial coding genes (COX1, COX2, ATP8, ATP6 and COX3). The mean haplotype and nucleotide diversities were 0.944 and 0.00322, respectively. We identified a correlation between the lineages distribution and the genetic distance, whereby Valley-type Tibetan sheep had a closer genetic relationship with introduced breeds (Dorper, Poll Dorset and Suffolk) than with other indigenous breeds. Similarly, the Median-joining profile of haplotypes revealed the distribution of clusters according to genetic differences. Moreover, copy number analysis based on the five mitochondrial coding genes was affected by the genetic distance combining with genetic phylogeny; we also identified obvious non-synonymous mutations in ATP6 between the different levels of copy number expressions. These results imply that differences in mitogenomic compositions resulting from geographical separation lead to differences in mitochondrial function. PMID- 29143715 TI - Scar satisfaction and body image in thyroidectomy patients: prospective study in a tertiary referral centre. AB - BACKGROUND: This study is the first to evaluate scar satisfaction and body image in thyroidectomy patients using validated assessment tools. METHODS: A total of 123 thyroidectomy patients were recruited over 8 months. Both patients and clinicians completed assessment tools that included: the Manchester Scar Scale (to measure scar perception), Dysmorphic Concern Questionnaire (to assess body image), Body Dysmorphic Concern Questionnaire (to screen for body dysmorphic disorder) and EQ-5D (to measure life quality). A separate image panel comprising experts and non-experts assessed 15 scar photographs. The results were analysed using non-parametric descriptive statistics. RESULTS: Poor body image was associated with poor scar perception (rho = 0.178, p = 0.05). Poor life quality correlated with poor scar perception (rho = -0.292, p = 0.001). Scar length did not affect scar perception. Prevalence of body dysmorphic disorder among patients was found to be 8.94 per cent, which is higher than general population rates. CONCLUSION: Negative body image and life quality impact negatively upon scar perception. PMID- 29143716 TI - The shelf space and strategic placement of healthy and discretionary foods in urban, urban-fringe and rural/non-metropolitan Australian supermarkets. AB - OBJECTIVE: Supermarkets are a key influence on eating behaviours, but it is unknown if the promotion of food within stores varies on a geographic gradient from urban, to urban-fringe and non-metropolitan areas. The present study aimed to assess the shelf space and strategic placement of healthy and discretionary foods in each of urban, urban-fringe and non-metropolitan Australian supermarkets. Design/Setting In-store audits were conducted in stores from one of the two major Australian supermarket chains in urban (n 19), urban-fringe (n 20) and non-metropolitan (n 26) areas of Victoria. These audits examined selected food items (crisps/chips, chocolate, confectionery, soft drinks/sodas, fruits and vegetables) and measured the shelf space and the proportion of end-of-aisle and cash register displays containing these products. Store size was measured as the sum of aisle length. Differences in the supermarket food environment with respect to location were assessed, before and after adjustment for neighbourhood socio economic position. RESULTS: The strategic placement of discretionary foods was commonly observed in all supermarkets. Adjusting for store size (larger in urban fringe and rural areas), urban stores had greater shelf space devoted to fruits and vegetables, and less checkouts with soft drinks, than urban-fringe and rural/non-metropolitan areas. Differences remained following adjustment for neighbourhood socio-economic position. No clear pattern was observed for end-of aisle displays, or the placement of chocolate and confectionery at checkouts. CONCLUSIONS: The shelf space of healthy and discretionary foods in urban-fringe and rural stores parallels the prevalence of overweight and obesity in these areas. Interventions in urban-fringe and rural stores targeting the shelf space of healthy foods and the placement of soft drinks at key displays may be useful obesity prevention initiatives. PMID- 29143717 TI - White matter abnormalities in 22q11.2 deletion syndrome patients showing cognitive decline. AB - BACKGROUND: Decline in cognitive functioning precedes the first psychotic episode in the course of schizophrenia and is considered a hallmark symptom of the disorder. Given the low incidence of schizophrenia, it remains a challenge to investigate whether cognitive decline coincides with disease-related changes in brain structure, such as white matter abnormalities. The 22q11.2 deletion syndrome (22q11DS) is an appealing model in this context, as 25% of patients develop psychosis. Furthermore, we recently showed that cognitive decline also precedes the onset of psychosis in individuals with 22q11DS. Here, we investigate whether the early cognitive decline in patients with 22q11DS is associated with alterations in white matter microstructure. METHODS: We compared the fractional anisotropy (FA) of white matter in 22q11DS patients with cognitive decline [n = 16; -18.34 (15.8) VIQ percentile points over 6.80 (2.39) years] to 22q11DS patients without cognitive decline [n = 18; 17.71 (20.17) VIQ percentile points over 5.27 (2.03) years] by applying an atlas-based approach to diffusion-weighted imaging data. RESULTS: FA was significantly increased (p < 0.05, FDR) in 22q11DS patients with a cognitive decline in the bilateral superior longitudinal fasciculus, the bilateral cingulum bundle, all subcomponents of the left internal capsule and the left superior frontal-occipital fasciculus as compared with 22q11DS patients without cognitive decline. CONCLUSIONS: Within 22q11DS, the early cognitive decline is associated with microstructural differences in white matter. At the mean age of 17.8 years, these changes are reflected in increased FA in several tracts. We hypothesize that similar brain alterations associated with cognitive decline take place early in the trajectory of schizophrenia. PMID- 29143718 TI - Prediction of a new body shape index and body adiposity estimator for development of type 2 diabetes mellitus: The Rural Chinese Cohort Study. AB - To compare the ability of a body shape index (ABSI) and body adiposity estimator (BAE) to BMI, waist circumference (WC) and waist:height ratio (WHtR) for predicting development of type 2 diabetes mellitus (T2DM) in rural adult Chinese. The prospective cohort study included 11 687 eligible participants who were free of T2DM at baseline. The risk of new-onset T2DM for ABSI, BAE, BMI, WC and WHtR quintiles was estimated by Cox proportional-hazards regression at follow-up. We also compared the power of ABSI and BAE to BMI, WC and WHtR for predicting the development of T2DM. With increasing ABSI, BAE, BMI, WC and WHtR, T2DM incidence was substantially increased (P trend<0.0001). After adjustment for multi covariates, risk of T2DM was increased from the second to fifth quintile as compared with first quintile for ABSI (1.27; 95 % CI 0.95, 1.69; 1.35; 95 % CI 1.00, 1.82; 1.75; 95 % CI 1.33, 2.32 and 1.87; 95 % CI 1.40, 2.49; P trend<0.0001); BAE (1.82; 95 % CI 1.38, 2.41; 1.93; 95 % CI 1.38, 2.68; 2.73; 95 % CI 1.94, 3.84 and 4.18; 95 % CI 2.98, 5.87; P trend<0.0001); BMI (1.42; 95 % CI 1.03, 1.97; 1.62; 95 % CI 1.18, 2.23; 2.59; 95 % CI 1.92, 3.50 and 3.90; 95 % CI 2.90, 5.26; P trend<0.0001); WC (1.53; 95 % CI 1.08, 2.17; 1.66; 95 % CI 1.18, 2.33; 2.72; 1.97, 3.76 and 4.09; 95 % CI 2.97, 5.62; P trend<0.0001); and WHtR (1.40; 95 % CI 0.98, 1.99; 2.06; 95 % CI 1.47, 2.88; 2.90; 95 % CI 2.10, 4.01 and 4.22; 95 % CI 3.05, 5.85; P trend<0.0001). ABSI, BAE, BMI, WC and WHR were effective and comparable in discriminating cases from non-cases of T2DM. Risk of T2DM was increased with elevated ABSI and BAE, but the predictive ability for T2DM did not differ than that of BMI, WC and WHtR in a rural Chinese population. PMID- 29143719 TI - Microbial protein targets: towards understanding and intervention. AB - The rise of antimicrobial resistance, coupled with a lack of industrial focus on antimicrobial discovery over preceding decades, has brought the world to a crisis point. With both human and animal health set to decline due to increased disease burdens caused by near untreatable microbial pathogens, there is an urgent need to identify new antimicrobials. Central to this is the elucidation of new, robustly validated, drug targets. Informed by industrial practice and concerns, the use of both biological and chemical tools in validation is key. In parallel, repurposing approved drugs for use as antimicrobials may provide both new treatments and identify new targets, whilst improved understanding of pharmacology will help develop and progress good 'hits' with the required rapidity. In recognition of the need to increase research efforts in these areas, in 14-16 September 2017, the British Society for Parasitology (BSP) Autumn Symposium was hosted at Durham University with the title: Microbial Protein Targets: towards understanding and intervention. Staged in collaboration with the Royal Society of Chemistry (RSC) Chemistry Biology Interface Division (CBID), the core aim was to bring together leading researchers working across disciplines to imagine novel approaches towards combating infection and antimicrobial resistance. Sessions were held on: 'Anti-infective discovery, an overview'; 'Omic approaches to target validation'; 'Genetic approaches to target validation'; 'Drug target structure and drug discovery'; 'Fragment-based approaches to drug discovery'; and 'Chemical approaches to target validation'. Here, we introduce a series of review and primary research articles from selected contributors to the Symposium, giving an overview of progress in understanding antimicrobial targets and developing new drugs. The Symposium was organized by Paul Denny (Durham) for the BSP and Patrick Steel (Durham) for RSC CBID. PMID- 29143720 TI - Epidemiological investigation of a severe rumen fluke outbreak on an Irish dairy farm. AB - Although the rumen fluke, Calicophoron daubneyi is now very common and widespread throughout Western Europe, reports of clinical cases are still rare. This study explores the epidemiological background to a severe rumen fluke outbreak in 6 month-old heifers on a dairy farm in Ireland. Sequence analysis of the cytochrome oxidase subunit 1 (Cox1) gene of the rumen fluke metacercariae on pasture failed to identify predominant, possibly pathogenic subtypes. However, estimates of metacercarial load indicated that the animals were exposed to a daily dose of about 5334 C. daubneyi metacercariae for a period of 3 weeks resulting in the build-up of very large numbers of immature worms in the small intestine. It is hypothesized that specific environmental conditions may favour this parasite over its competitor, the liver fluke, Fasciola hepatica, possibly by allowing it to emerge earlier. The possibility that C. daubneyi may be better adapted to the Irish climate than F. hepatica together with the fact that selective treatment against F. hepatica effectively frees the niche for C. daubneyi, may result in the gradual replacement of F. hepatica by C. daubneyi. PMID- 29143721 TI - Bio-economic and operational feasibility of introducing oestrus synchronization and artificial insemination in simulated smallholder sheep breeding programmes. AB - Low selection intensity due to few selection candidates available at any one time due to thinly spread year-round lambings in villages and prohibitively large nucleus requirements to provide sufficient improved rams to the production tier are the major challenges for designing effective village-based and central nucleus-based breeding programmes, respectively, for smallholder sheep farmers. To tackle these challenges, we used deterministic simulation to design three schemes in village-based programmes introducing hormonal oestrus synchronization (natural oestrus (VNE), single oestrus synchronization (VSE1) and double oestrus synchronization (VSE2)) and three schemes in central nucleus programme introducing artificial insemination (AI) (natural mating with nucleus sizes of 5% (CNM1) and 1% (CNM2) of the total ewe population and natural mating in breeding tier and AI in production tier (CAI)). The schemes were evaluated for their bio economic and operational feasibility, taking Bonga sheep of Ethiopia as a case study. The selection intensities achieved in VNE, VSE1 and VSE2 were 2.0, 2.3 and 2.4, respectively, for selecting rams for the breeding tier and 0.0, 0.8 and 1.0, respectively, for the production tier. The profits per ewe per year from VNE, VSE1 and VSE2 were Birr 12.2, 21.7 and 24.5, but the profit from VNE for the production tier was zero. CAI generated more genetic gains in the breeding objective (Birr 4.8) than CNM1 (Birr 2.5) and CNM2 (Birr 0.0) in the production tier. However, CAI was less profitable than CNM1 and CNM2. In conclusion, hormonal oestrus synchronization was found to be a feasible technological aide to accelerate genetic progress in village-based programmes. CNM1 and CNM2 could not be recommended as CNM1 requires large nucleus of 10 325 ewes and CNM2 results in zero genetic gain in the production tier. CAI could overcome the challenge in central nucleus programmes, namely unaffordable large nucleus, but the scheme needs to be subsidized by the public sector to be economically feasible for farmers. PMID- 29143722 TI - Relationship between the number of behavioral symptoms in dementia and caregiver distress: what is the tipping point? AB - : ABSTRACTBackground:Behavioral and psychological symptoms of dementia (BPSD) are a primary manifestation of brain dysfunction in dementia and a great challenge in caregiving. While BPSD are historically associated with caregiver distress, it is unclear whether there is an identifiable point where BPSD number is associated with heightened caregiver distress. The purpose of this study was to determine if such a tipping point exists to assist clinicians in identifying caregiver compromise. METHODS: Analyses were performed with three datasets totaling 569 community-dwelling persons with dementia and their caregivers. Each included identical demographic, BPSD, cognitive, and caregiver well-being measures. Linear regression was performed with 16 BPSD symptoms on caregiver well-being measures and predictive values determined with receiver operating characteristic (ROC) curves and pre-defined scores for clinically significant distress. RESULTS: Of the 569 persons with dementia, 549 (96%) displayed at least one BPSD, mean of 5.7 (SD = 3.06) symptoms in the past month. After controlling for covariates, BPSD symptom number was significantly associated with caregiver depression and burden (p < 0.01 for both models). Findings indicate >= 4 BPSD has strong predictive values for depression (sensitivity 85%, specificity 44%, area under ROC curve 0.62, p < 0.01), and burden (sensitivity 84%, specificity 43%, area under ROC curve 0.67, p < 0.01). CONCLUSIONS: Caring for persons with four or more BPSD appears to reflect a tipping point for clinically meaningful distress. Findings have implications for clinicians working with persons with dementia and their caregivers and suggest need for continuous monitoring of BPSD and identification of at risk caregivers. PMID- 29143723 TI - Food insecurity among people with severe mental disorder in a rural Ethiopian setting: a comparative, population-based study. AB - AIM: In low-income African countries, ensuring food security for all segments of the population is a high priority. Mental illness is associated consistently with poverty, but there is little evidence regarding the association with food insecurity. The aim of this study was to compare the levels of food insecurity in people with severe mental disorders (SMD) with the general population in a rural African setting with a high burden of food insecurity. METHOD: Households of 292 community-ascertained people with a specialist-confirmed diagnosis of SMD (including schizophrenia and bipolar disorder) were compared with 284 households without a person with SMD in a rural district in south Ethiopia. At the time of the study, no mental health services were available within the district. Food insecurity was measured using a validated version of the Household Food Insecurity Access Scale. Disability was measured using the World Health Organisation Disability Assessment Schedule 2.0. RESULT: Severe household food insecurity was reported by 32.5% of people with SMD and 15.9% of respondents from comparison households: adjusted odds ratio 2.82 (95% confidence interval 1.62 to 4.91). Higher annual income was associated independently with lower odds of severe food insecurity. When total disability scores were added into the model, the association between SMD and food insecurity became non-significant, indicating a possible mediating role of disability. CONCLUSION: Efforts to alleviate food insecurity need to target people with SMD as a vulnerable group. Addressing the disabling effects of SMD would also be expected to reduce food insecurity. Access to mental health care integrated into primary care is being expanded in this district as part of the Programme for Improving Mental health carE (PRIME). The impact of treatment on disability and food insecurity will be evaluated. PMID- 29143724 TI - Gastric lymphoma: association with Helicobacter pylori outer membrane protein Q (HopQ) and cytotoxic-pathogenicity activity island (CPAI) genes. AB - B-cell non-Hodgkin lymphoma (B-cell NHL) is the second commonest malignancy in the stomach. We determined the distribution of Helicobacter pylori outer membrane protein Q (HopQ) allelic type, cytotoxin-associated gene (cag)-pathogenicity activity island (cag-PAI) and vacuolation activating cytotoxin A (vacA) genes, respectively, in patients with B-cell NHL. We also compared them with their distribution in non-ulcer dyspepsia (NUD). H. pylori was cultured from gastric biopsy tissue obtained at endoscopy. Polymerase chain reaction was performed. Of 170 patients enrolled, 114 (63%) had NUD and 56 (37%) had B-cell NHL. HopQ type 1 was positive in 66 (58%) in NUD compared with 46 (82%) (P = 0.002) in B-cell NHL; HopQ type 2 was positive in 93 (82%) with NUD compared with 56 (100%) (P < 0.001) in B-cell NHL. Multiple HopQ types were present in 46 (40%) in NUD compared with 46 (82%) (P < 0.001) in B-cell NHL. CagA was positive in 48 (42%) in NUD vs. 50 (89%) (P < 0.001) in B-cell NHL; cagT was positive in 35 (31%) in NUD vs. 45 (80%) (P < 0.001) in B-cell NHL; left end of the cagA gene (LEC)1 was positive in 23 (20%) in NUD vs. 43 (77%) (P < 0.001) in B-cell NHL. VacAs1am1 positive in B cell NHL in 48 (86%) (P < 0.001) vs. 50 (44%) in NUD, while s1am2 was positive in 20 (17%) in NUD vs. 46 (82%) (P < 0.001) in B-cell NHL. H. pylori strains with multiple HopQ allelic types, truncated cag-PAI evidenced by expression of cagA, cagT and cag LEC with virulent vacAs1 alleles are associated with B-cell NHL development. PMID- 29143725 TI - Thalassotalea atypica sp. nov., isolated from seawater, and emended description of Thalassotalea eurytherma. AB - A novel Gram-stain-negative, straight or slightly curved rod-shaped, non-spore forming, non-flagellated, strictly aerobic strain, designated RZG4-3-1T, was isolated from coastal seawater of Rizhao, China (119.625 degrees E 35.517 degrees N). The organism grew optimally at 24-28 degrees C, at pH 7.0 and in the presence of 2.0 % (w/v) NaCl. The strain required seawater or artificial seawater for growth, and NaCl alone did not support growth. Strain RZG4-3-1T contained ubiquinone 8 (Q-8) as the major respiratory quinone and contained C16 : 1omega7c and/or C16 : 1omega6c and C16 : 0 as the dominant fatty acids. The polar lipids of strain RZG4-3-1T were phosphatidylethanolamine, phosphatidylglycerol and one unidentified aminophospholipid. The DNA G+C content of strain RZG4-3-1T was 40.1 mol%. Strain RZG4-3-1T exhibited the highest 16S rRNA gene sequence similarity value (96.0 %) to Thalassotalea eurytherma JCM 18482T. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain RZG4-3-1T belonged to the genus Thalassotalea. On the basis of polyphasic analyses, strain RZG4-3-1T represents a novel species of the genus Thalassotalea, for which the name Thalassotalea atypica sp. nov. is proposed. The type strain is RZG4-3-1T (=JCM 31894T=KCTC 52745T=MCCC 1K03276T). An emended description of Thalassotalea eurytherma is also provided. PMID- 29143727 TI - Characterization of clinically isolated thymidine-dependent small-colony variants of Escherichia coli producing extended-spectrum beta-lactamase. AB - PURPOSE: Thymidine-dependent small-colony variants (TD-SCVs) are difficult to detect or test for antimicrobial susceptibility. We investigated the characteristics of clonal TD-SCVs of Escherichia coli, both with and without blaCTX-M-3, isolated from a patient. METHODOLOGY: Mutation in the thyA gene was analysed by sequencing, and morphological abnormalities in the colonies and cells of the isolates were examined. Additionally, conjugational transfer experiments were performed to prove the horizontal transferability of plasmids harbouring resistance genes. RESULTS: The TD-SCVs contained a single nucleotide substitution in the thyA gene, c.62G>A, corresponding to p.Arg21His. Morphologically, their colonies were more translucent and flattened than those of the wild-type strain. In addition, cells of the TD-SCVs were swollen and elongated, sometimes with abnormal and incomplete divisions; a large amount of cell debris was also observed. Changing c.62G>A back to the wild-type sequence reversed these abnormalities. Conjugational transfer experiments showed that the TD-SCV of E. coli with blaCTX-M-3 failed to transfer blaCTX-M-3 to E. coli CSH2. However, the TD-SCV of E. coli without blaCTX-M-3 experimentally received the plasmid encoding blaSHV-18 from Klebsiella pneumoniae ATCC 700603 and transferred it to E. coli CSH2. CONCLUSION: Mutation in the thyA gene causes morphological abnormalities in the colonies and cells of E. coli, as well as inducing thymidine auxotrophy. In addition, TD-SCVs horizontally transmit plasmids encoding resistance genes. It is important to detect TD-SCVs based on their characteristics because they serve as reservoirs of transferable antibiotic resistance plasmids. PMID- 29143728 TI - Streptomyces tritici sp. nov., a novel actinomycete isolated from rhizosphere soil of wheat (Triticum aestivum L.). AB - Two novel actinomycete isolates, designated strains NEAU-A4T and NEAU-A3, were isolated from rhizosphere soil of wheat (Triticumaestivum L.) and characterized using a polyphasic approach. Morphological and chemotaxonomic characteristics of the two strains coincided with those of the genus Streptomyces. The 16S rRNA gene sequence analysis showed that the two isolates exhibited 99.6 % 16S rRNA gene sequence similarity with each other and that they were most closely related to Streptomyces violaceorectus DSM 40279T (98.8, 99.0 %). Phylogenetic analysis based on 16S rRNA gene sequences indicated that the two strains clustered together and formed a separate subclade. Furthermore, a combination of DNA-DNA hybridization results and some physiological and biochemical properties demonstrated that the two strains could be distinguished from its closest relative. Therefore, it is proposed that strains NEAU-A4T and NEAU-A3 should be classified as representatives of a novel species of the genus Streptomyces, for which the name Streptomycestritici sp. nov. is proposed. The type strain is NEAU A4T (=CGMCC 4.7393T=DSM 104540T). PMID- 29143726 TI - Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5 year update. AB - Oncolytic virus (OV) therapy is an anti-cancer approach that uses viruses that preferentially infect, replicate in and kill cancer cells. Vesicular stomatitis virus (VSV, a rhabdovirus) is an OV that is currently being tested in the USA in several phase I clinical trials against different malignancies. Several factors make VSV a promising OV: lack of pre-existing human immunity against VSV, a small and easy to manipulate genome, cytoplasmic replication without risk of host cell transformation, independence of cell cycle and rapid growth to high titres in a broad range of cell lines facilitating large-scale virus production. While significant advances have been made in VSV-based OV therapy, room for improvement remains. Here we review recent studies (published in the last 5 years) that address 'old' and 'new' challenges of VSV-based OV therapy. These studies focused on improving VSV safety, oncoselectivity and oncotoxicity; breaking resistance of some cancers to VSV; preventing premature clearance of VSV; and stimulating tumour-specific immunity. Many of these approaches were based on combining VSV with other therapeutics. This review also discusses another rhabdovirus closely related to VSV, Maraba virus, which is currently being tested in Canada in phase I/II clinical trials. PMID- 29143729 TI - Thalassotalea coralli sp. nov., isolated from the torch coral Euphyllia glabrescens. AB - Strain Eup a-8T, isolated from a torch coral Euphyllia glabrescens, was characterized using a polyphasic taxonomy approach. Cells of strain Eup a-8T were Gram-staining-negative, aerobic, motile by means of a single polar flagellum, poly-beta-hydroxybutyrate-containing, rod-shaped and formed white colonies. Optimal growth occurred at 25-30 degrees C, pH 7-8, and in the presence of 2 % NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Eup a-8T belonged to the genus Thalassotalea and showed the highest levels of sequence similarity with respect to Thalassotalea ganghwensis JC2041T (97.1 %). Strain Eup a-8T contained C17 : 1omega8c, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), iso-C14 : 0 and iso-C16 : 0 as the predominant fatty acids. The only isoprenoid quinone was Q-8. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and one uncharacterized phospholipid. Genomic DNA G+C content of strain Eup a-8T was 41.5 mol%. The DNA DNA hybridization value for strain Eup a-8T with Thalassotalea ganghwensis JC2041T was less than 70 %. Differential phenotypic properties, together with the phylogenetic inference, demonstrate that strain Eup a-8T should be classified as a novel species of the genus Thalassotalea, for which the name Thalassotalea coralli sp. nov. is proposed. The type strain is Eup a-8T (=BCRC 80967T=LMG 29478T=KCTC 52169T). PMID- 29143730 TI - Genetic diversity and symbiotic effectiveness of Bradyrhizobium strains nodulating selected annual grain legumes growing in Ethiopia. AB - Vigna unguiculata, Vigna radiata and Arachis hypogaea growing in Ethiopia are nodulated by a genetically diverse group of Bradyrhizobium strains. To determine the genetic identity and symbiotic effectiveness of these bacteria, a collection of 36 test strains originating from the root nodules of the three hosts was investigated using multilocus sequence analyses (MLSA) of core genes including 16S rRNA, recA, glnII, gyrB, atpD and dnaK. Sequence analysis of nodA and nifH genes along with tests for symbiotic effectiveness using delta15N analysis were also carried out. The phylogenetic trees derived from the MLSA grouped most test strains into four well-supported distinct positions designated as genospecies I IV. The maximum likelihood (ML) tree that was constructed based on the nodA gene sequences separated the entire test strains into two lineages, where the majority of the test strains were clustered on one of a well-supported large branch that comprise Bradyrhizobium species from the tropics. This clearly suggested the monophyletic origin of the nodA genes within the bradyrhizobia of tropical origin. The delta15N-based symbiotic effectiveness test of seven selected strains revealed that strains GN100 (delta15N=0.73) and GN102 (delta15N=0.79) were highly effective nitrogen fixers when inoculated to cowpea, thus can be considered as inoculants in cowpea production. It was concluded that Ethiopian soils are a hotspot for rhizobial diversity. This calls for further research to unravel as yet unknown bradyrhizobia nodulating legume host species growing in the country. In this respect, prospective research should also address the mechanisms of symbiotic specificity that could lead to high nitrogen fixation in target legumes. PMID- 29143731 TI - The Treatment of Depression in Primary Care. AB - BACKGROUND: General practitioners play a key role in the care of patients with depressive disorders. We studied the frequency and type of treatment of depressive disorders in primary care. METHODS: In a cross-sectional epidemiological study on a particular day in six different regions in Germany, 253 physicians and 3563 unselected patients were asked to fill in a questionnaire assessing the diagnosis and treatment of depression. A total of 3431 usable patient data sets and 3211 sets of usable data from both the patient and the physician were subjected to further analysis. RESULTS: 68.0% of the 490 patients in primary care who were classified as depressed according to the Depression Screening Questionnaire received treatment from their general practitioner or in other care settings; the probability of being treated by the general practitioner was higher for patients whose diagnosis was recognized by the general practitioner (92.8%) than for the remaining depressed patients (47.8%). On the day of data recording, 54.1% of the depressed patients were under treatment by the general practitioner and 21.2% had been referred to specialized treatment. Approximately 60% of the depressed patients were not being treated, as recommended in the guidelines, with antidepressant drugs, psychotherapy, or both. The likelihood of being treated in conformity with the guidelines depended on whether or not the general practitioner had made the diagnosis of depression (odds ratio [OR] = 7.5; 95% confidence interval = [4.9; 11.6]; p <0,001); it was also higher if the general practitioner had an additional qualification in psychotherapy (OR = 1.9; [1.1; 3.4]; p = 0.022). CONCLUSION: The finding that a relevant proportion of patients with depressive disorders in primary care are inadequately treated indicates the need to improve general practitioners' ability to diagnose these conditions and determine the indication for treatment. PMID- 29143732 TI - Surgical and Endovascular Treatment of Extracranial Carotid Stenosis. AB - BACKGROUND: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) can be used to prevent stroke due to arteriosclerotic lesions of the carotid artery. In Germany, legally mandated quality assurance (QA) enables the evaluation of outcome quality after CEA and CAS performed under routine conditions. METHODS: We analyzed data on all elective CEA and CAS procedures performed over the periods 2009-2014 and 2012-2014, respectively. The endpoints of the study were the combined in-hospital stroke and death rate, stroke rate and mortality separately, local complications, and other complications. We analyzed the raw data with descriptive statistics and carried out a risk-adjusted analysis of the association of clinically unalterable variables with the risk of stroke and death. All analyses were performed separately for CEA and CAS. RESULTS: Data were analyzed from 142 074 CEA procedures (67.8% of them in men) and 13 086 CAS procedures (69.7% in men). The median age was 72 years (CEA) and 71 years (CAS). The periprocedural rate of stroke and death after CEA was 1.4% for asymptomatic and 2.5% for symptomatic stenoses; the corresponding rates for CAS were 1.7% and 3.7%. Variables associated with increased risk included older age, higher ASA class (ASA = American Society of Anesthesiologists), symptomatic vs. asymptomatic stenosis, 50-69% stenosis, and contralateral carotid occlusion (for CEA only). CONCLUSION: These data reveal a low periprocedural rate of stroke or death for both CEA and CAS. This study does however not permit any conclusions as to the superiority or inferiority of CEA and CAS. PMID- 29143733 TI - Amendment Necessary. PMID- 29143734 TI - Data-based Assessment of the Maintenance of Sterility. PMID- 29143735 TI - In Reply. PMID- 29143736 TI - Apparent Swelling of the Tongue. PMID- 29143737 TI - Validation of ELISA methods for quantification of the major birch allergen Bet v 1 (BSP090). AB - To date, the potency of allergen products in Europe is expressed in manufacturer specific units relative to a product-specific in-house reference. Consequently, cross-product comparability of allergen products from different manufacturers with respect to strength and efficacy is impossible. The Biological Standardisation Programme (BSP) project BSP090 addresses this issue via the establishment of reference standards in conjunction with ELISA methods for the quantification of major allergens in allergen products. Since the initiation of BSP090, the recombinant major allergen Bet v 1 has been adopted by the European Pharmacopoeia Commission as a Chemical Reference Substance (CRS). In parallel, two sandwich ELISA systems for quantification of Bet v 1 were found suitable in preliminary phases of BSP090 to be validated in a large collaborative study. In this study, the candidate ELISA systems were compared with respect to accuracy, precision and variability. Thirteen participating laboratories tested model samples containing the CRS as well as spiked and unspiked birch pollen extracts. Both in pre-testing and in the collaborative study, the 2 candidate ELISA systems confirmed their suitability to quantify recombinant and native Bet v 1. As no clear-cut decision for one of the ELISA systems could be made based on the results of the collaborative study, a post-study testing was performed. Bet v 1 content of 30 birch pollen allergen products was determined in parallel in both ELISA systems. Consequently, 1 candidate ELISA system was selected to be proposed as the future European Pharmacopoeia standard method for Bet v 1 quantification. PMID- 29143739 TI - An inaccurate automated device negatively impacts the diagnosis and treatment of gestational hypertension. AB - OBJECTIVES: Automated blood pressure devices are frequently introduced in maternity care without prior validation for their accuracy in pregnancy. Our objectives were to, firstly, establish the accuracy in pregnancy of a locally used device (Welch Allyn 300) and, secondly, to audit its impact on the diagnosis and treatment of hypertension. STUDY DESIGN: Validation study: The device was evaluated using the grading criteria of the European Society of Hypertension International Protocol (ESH-IP) (2010). Two observers took nine same-arm measurements alternating between the Welch Allyn and the mercury sphygmomanometer. Thirty-three women of any gestation were included. Clinical audit: One observer took three same-arm measurements alternating between the Welch Allyn and the mercury sphygmomanometer. One hundred women of any gestation referred with suspected hypertension were included. The main outcome measures were the proportion diagnosed with hypertension or commenced on anti-hypertensive treatment on the presenting visit when using either the manual or the automated device. MAIN OUTCOME MEASURES: Grading criteria of the ESH-IP (2010) and proportion of women diagnosed with hypertension or commenced on antihypertensive therapy at the presenting visit when using either manual sphygmomanometry or the Welch Allyn device. RESULTS: The Welch Allyn 300 series failed to meet the criteria of the ESH-IP (2010) for pregnancy. Compared to the mercury device, it under diagnosed hypertension by 48% and need for treatment by 80%. CONCLUSIONS: The Welch Allyn 300 cannot be recommended for the measurement of blood pressure in pregnancy. Its use leads to the under-diagnosis and under-treatment of gestational hypertension. PMID- 29143738 TI - Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator activated receptors to drive urothelial proliferation. AB - RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20-25% of human bladder cancers. Here, we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers in human bladder cancer cells. Structure-function studies indicate that the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In mouse urothelial organoids, PPAR agonism is sufficient to drive growth-factor-independent growth in the context of concurrent tumor suppressor loss. Similarly, mutant RXRA stimulates growth-factor-independent growth of Trp53/Kdm6a null bladder organoids. Mutant RXRA-driven growth of urothelium is reversible by PPAR inhibition, supporting PPARs as targetable drivers of bladder cancer. PMID- 29143740 TI - Corrections. PMID- 29143741 TI - Eliminating viral hepatitis: time to match visions with action. PMID- 29143742 TI - Support for a publicly funded health system in the USA. PMID- 29143743 TI - The case for action on childhood pneumonia. PMID- 29143744 TI - Hidden conflicts of interest in continuing medical education. PMID- 29143745 TI - Offline: Planetary health's next frontier-biodiversity. PMID- 29143746 TI - Trump administration begins to confront the opioid crisis. PMID- 29143747 TI - The digitised clinical trial. PMID- 29143748 TI - Patients are denied care because of corruption in Romania. PMID- 29143749 TI - Ocular gene therapy for neovascular AMD: a new era? PMID- 29143750 TI - Ocular gene therapy for neovascular AMD: a new era? - Authors' reply. PMID- 29143751 TI - Intravitreal aflibercept for proliferative diabetic retinopathy. PMID- 29143752 TI - Intravitreal aflibercept for proliferative diabetic retinopathy - Authors' reply. PMID- 29143753 TI - Intravitreal aflibercept for proliferative diabetic retinopathy. PMID- 29143754 TI - Department of Error. PMID- 29143755 TI - Corrections. PMID- 29143756 TI - Corrigendum to Real-time path-integral approach for dissipative quantum dot cavity quantum electrodynamics: impure dephasing-induced effects (Davoud G Nahri et al 2017 J. Phys.: Condens. Matter 29 055701). AB - We have noticed of one ambiguity and two errors in our original published paper [1], which we modify in this corrigendum. However, the errors do not affect the results and discussion of the original paper. PMID- 29143757 TI - Simultaneous Determination of Seven Anthraquinone Aglycones of Crude and Processed Semen Cassiae Extracts in Rat Plasma by UPLC-MS/MS and Its Application to a Comparative Pharmacokinetic Study. AB - Semen cassiae is the ripe seed of Cassia obtusifolia L. or Cassia tora L. of the family Leguminosae. In traditional Chinese medicine, the two forms of Semen cassiae are raw Semen cassiae (R-SC) and parched Semen cassiae (P-SC). To clarify the processing mechanism of Semen cassiae, the pharmacokinetics of R-SC and P-SC extracts were examined. A simple, rapid, sensitive ultra-high-performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) method was developed and validated for the simultaneous determination of seven anthraquinone aglycones of Semen cassiae (aurantio-obtusin, obtusifolin, questin, 2-hydroxyemodin-1-methyl ether, rhein, emodin, 1,2,7-trimethoxyl-6,8-dihydroxy-3-methylanthraquinone) to compare the pharmacokinetics of raw and parched Semen cassiae in rat plasma. Compared with the R-SC group, Cmax and AUC0-12 tended to be higher in the P-SC group. In particular, Cmax values for aurantio-obtusin, obtusifolin, questin, 2 hydroxyemodin-1-methyl-ether and rhein were significantly higher in the P-SC group (p < 0.05). Meanwhile, Tmax and MRT0-12 tended to be lower in the P-SC group. Specifically, Tmax for aurantio-obtusin and 2-hydroxyemodin-1-methyl-ether and MRT0-12 for obtusifolin and rhein were significantly higher in the P-SC group (p < 0.05). PMID- 29143758 TI - Determination of the Bridging Ligand in the Active Site of Tyrosinase. AB - Tyrosinase is a type-3 copper enzyme that is widely distributed in plants, fungi, insects, and mammals. Developing high potent inhibitors against tyrosinase is of great interest in diverse fields including tobacco curing, food processing, bio insecticides development, cosmetic development, and human healthcare-related research. In the crystal structure of Agaricus bisporus mushroom tyrosinase, there is an oxygen atom bridging the two copper ions in the active site. It is unclear whether the identity of this bridging oxygen is a water molecule or a hydroxide anion. In the present study, we theoretically determine the identity of this critical bridging oxygen by performing first-principles hybrid quantum mechanics/molecular mechanics/Poisson-Boltzmann-surface area (QM/MM-PBSA) calculations along with a thermodynamic cycle that aim to improve the accuracy. Our results show that the binding with water molecule is energy favored and the QM/MM-optimized structure is very close to the crystal structure, whereas the binding with hydroxide anions causes the increase of energy and significant structural changes of the active site, indicating that the identity of the bridging oxygen must be a water molecule rather than a hydroxide anion. The different binding behavior between water and hydroxide anions may explain why molecules with a carboxyl group or too many negative charges have lower inhibitory activity. In light of this, the design of high potent active inhibitors against tyrosinase should satisfy both the affinity to the copper ions and the charge neutrality of the entire molecule. PMID- 29143759 TI - The Role of Food Antioxidants, Benefits of Functional Foods, and Influence of Feeding Habits on the Health of the Older Person: An Overview. AB - This overview was directed towards understanding the relationship of brain functions with dietary choices mainly by older humans. This included food color, flavor, and aroma, as they relate to dietary sufficiency or the association of antioxidants with neurodegenerative diseases such as dementia and Alzheimer's disease. Impairment of olfactory and gustatory function in relation to these diseases was also explored. The role of functional foods was considered as a potential treatment of dementia and Alzheimer's disease through inhibition of acetylcholinesterase as well as similar treatments based on herbs, spices and antioxidants therein. The importance of antioxidants for maintaining the physiological functions of liver, kidney, digestive system, and prevention of cardiovascular diseases and cancer has also been highlighted. Detailed discussion was focused on health promotion of the older person through the frequency and patterns of dietary intake, and a human ecology framework to estimate adverse risk factors for health. Finally, the role of the food industry, mass media, and apps were explored for today's new older person generation. PMID- 29143760 TI - Nano-Aptasensing in Mycotoxin Analysis: Recent Updates and Progress. AB - Recent years have witnessed an overwhelming integration of nanomaterials in the fabrication of biosensors. Nanomaterials have been incorporated with the objective to achieve better analytical figures of merit in terms of limit of detection, linear range, assays stability, low production cost, etc. Nanomaterials can act as immobilization support, signal amplifier, mediator and artificial enzyme label in the construction of aptasensors. We aim in this work to review the recent progress in mycotoxin analysis. This review emphasizes on the function of the different nanomaterials in aptasensors architecture. We subsequently relate their features to the analytical performance of the given aptasensor towards mycotoxins monitoring. In the same context, a critically analysis and level of success for each nano-aptasensing design will be discussed. Finally, current challenges in nano-aptasensing design for mycotoxin analysis will be highlighted. PMID- 29143761 TI - Antibody Cross-Reactivity between Porcine Cytomegalovirus (PCMV) and Human Herpesvirus-6 (HHV-6). AB - Porcine cytomegalovirus (PCMV) infection is widely prevalent among pigs, and PCMV is one of the viruses which may be transmitted during xenotransplantation using pig cells, tissues, or organs. While human cytomegalovirus (HCMV) is a major risk factor for allotransplantation, it is still unclear whether PCMV is able to infect human cells or pose a risk for xenotransplantation. Previously, it was shown that transmission of PCMV after pig kidney to non-human primate transplantations resulted in a significantly reduced survival time of the transplanted organ. To detect PCMV, PCR-based and immunological methods were used. Screening of pigs by Western blot analyses using recombinant viral proteins revealed up to 100% of the tested animals to be infected. When the same method was applied to screen human sera for PCMV-reactive antibodies, positive Western blot results were obtained in butchers and workers in the meat industry as well as in normal blood donors. To exclude an infection of humans with PCMV, the sera were further investigated. PCMV is closely related to human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7), and a sequence alignment of glycoprotein B suggests that the antibodies may cross-react with identical epitope sequences. HCMV is not related with PCMV, and no correlation between antibody reactivity against PCMV and HCMV was detected. These data indicate that antibodies against PCMV found in humans are cross-reactive antibodies against HHV-6. PMID- 29143762 TI - Executive Function Capacities, Negative Driving Behavior and Crashes in Young Drivers. AB - Motor vehicle crashes remain a leading cause of injury and death in adolescents, with teen drivers three times more likely to be in a fatal crash when compared to adults. One potential contributing risk factor is the ongoing development of executive functioning with maturation of the frontal lobe through adolescence and into early adulthood. Atypical development resulting in poor or impaired executive functioning (as in Attention-Deficit/Hyperactivity Disorder) has been associated with risky driving and crash outcomes. However, executive function broadly encompasses a number of capacities and domains (e.g., working memory, inhibition, set-shifting). In this review, we examine the role of various executive function sub-processes in adolescent driver behavior and crash rates. We summarize the state of methods for measuring executive control and driving outcomes and highlight the great heterogeneity in tools with seemingly contradictory findings. Lastly, we offer some suggestions for improved methods and practical ways to compensate for the effects of poor executive function (such as in-vehicle assisted driving devices). Given the key role that executive function plays in safe driving, this review points to an urgent need for systematic research to inform development of more effective training and interventions for safe driving among adolescents. PMID- 29143764 TI - Road Lane Detection Robust to Shadows Based on a Fuzzy System Using a Visible Light Camera Sensor. AB - Recently, autonomous vehicles, particularly self-driving cars, have received significant attention owing to rapid advancements in sensor and computation technologies. In addition to traffic sign recognition, road lane detection is one of the most important factors used in lane departure warning systems and autonomous vehicles for maintaining the safety of semi-autonomous and fully autonomous systems. Unlike traffic signs, road lanes are easily damaged by both internal and external factors such as road quality, occlusion (traffic on the road), weather conditions, and illumination (shadows from objects such as cars, trees, and buildings). Obtaining clear road lane markings for recognition processing is a difficult challenge. Therefore, we propose a method to overcome various illumination problems, particularly severe shadows, by using fuzzy system and line segment detector algorithms to obtain better results for detecting road lanes by a visible light camera sensor. Experimental results from three open databases, Caltech dataset, Santiago Lanes dataset (SLD), and Road Marking dataset, showed that our method outperformed conventional lane detection methods. PMID- 29143763 TI - Intellectual Functioning in Offspring of Parents with Bipolar Disorder: A Review of the Literature. AB - Impaired intellectual functioning is an important risk factor for the emergence of severe mental illness. Unlike many other forms of mental disorder however, the association between bipolar disorder and intellectual deficits is unclear. In this narrative review, we examine the current evidence on intellectual functioning in children and adolescents at risk for developing bipolar disorder. The results are based on 18 independent, peer-reviewed publications from 1980 to 2017 that met criteria for this study. The findings yielded no consistent evidence of lower or higher intellectual quotient (IQ) in offspring of parents diagnosed with bipolar disorder. Some tentative evidence was found for lower performance IQ in offspring of bipolar parents as compared to controls. It is recommended that future research examine variability in intellectual functioning and potential moderators. These findings demonstrate the need to examine how intellectual functioning unfolds across development given the potential role of IQ as a marker of vulnerability or resilience in youth at high risk for affective disorders. PMID- 29143765 TI - Relative Influence of Socioeconomic, Psychological and Sensory Characteristics, Physical Activity and Diet on 5-Year Weight Gain in French Adults. AB - Individual characteristics, dietary intake and physical activity influence weight status; however, the contribution of each factor to weight change has not been studied. The objective was to confirm a conceptual framework by simultaneously assessing the relative influence of socioeconomic, psychological and sensory characteristics, physical activity, and dietary intake on five-year weight gain in French adults. Individual characteristics, physical activity, and dietary data were assessed at baseline in 8014 participants in the NutriNet-Sante cohort. Self reported anthropometric data were collected at baseline and five years later. Structural equation models, stratified by baseline body mass index (BMI), were used to perform analyses. Dietary restraint was a direct predictor of weight gain, with a stronger effect than age or intake of energy-dense foods, both in non-overweight and overweight participants. In non-overweight individuals only, intake of nutrient-dense foods and physical activity were inversely associated with weight gain. Regarding dietary intake, fat liking was the most important predictor of nutrient-dense food intake and was also related to energy-dense food intake. In these models, dietary restraint appears to be a direct predictor of weight gain and fat liking is a strong determinant of dietary intake. The influence of dietary restraint on weight gain, not explained by diet, warrants further investigation. PMID- 29143767 TI - Distributed Channel Allocation and Time Slot Optimization for Green Internet of Things. AB - In sustainable smart cities, power saving is a severe challenge in the energy constrained Internet of Things (IoT). Efficient utilization of limited multiple non-overlap channels and time resources is a promising solution to reduce the network interference and save energy consumption. In this paper, we propose a joint channel allocation and time slot optimization solution for IoT. First, we propose a channel ranking algorithm which enables each node to rank its available channels based on the channel properties. Then, we propose a distributed channel allocation algorithm so that each node can choose a proper channel based on the channel ranking and its own residual energy. Finally, the sleeping duration and spectrum sensing duration are jointly optimized to maximize the normalized throughput and satisfy energy consumption constraints simultaneously. Different from the former approaches, our proposed solution requires no central coordination or any global information that each node can operate based on its own local information in a total distributed manner. Also, theoretical analysis and extensive simulations have validated that when applying our solution in the network of IoT: (i) each node can be allocated to a proper channel based on the residual energy to balance the lifetime; (ii) the network can rapidly converge to a collision-free transmission through each node's learning ability in the process of the distributed channel allocation; and (iii) the network throughput is further improved via the dynamic time slot optimization. PMID- 29143768 TI - An Electronic System for the Contactless Reading of ECG Signals. AB - The aim of this work is the development of a contactless capacitive sensory system for the detection of (Electrocardiographic) ECG-like signals. The acquisition approach is based on a capacitive coupling with the patient body performed by electrodes integrated in a front-end circuit. The proposed system is able to detect changes in the electric charge related to the heart activity. Due to the target signal weakness and to the presence of other undesired signals, suitable amplification stages and analogue filters are required. Simulated results allowed us to evaluate the effectiveness of the approach, whereas experimental measurements, recorded without contact to the skin, have validated the practical effectiveness of the proposed architecture. The system operates with a supply voltage of +/-9 V with an overall power consumption of about 10 mW. The analogue output of the electronic interface is connected to an ATmega328 microcontroller implementing the A/D conversion and the data acquisition. The collected data can be displayed on any multimedia support for real-time tracking applications. PMID- 29143769 TI - Senescent Nephropathy: The New Renal Syndrome. AB - Chronic kidney disease (CKD) is a condition characterized by progressive and irreversible deterioration of renal function due to the reduction of nephron mass for a period of at least three months. The prevalence of CKD is roughly 10% in the general population but increases with age, affecting more than one-third of people older than 65. Frailty is a condition usually found in elderly people, characterized by weakness, motility, and balance issues, with a declined ability to resist stressors leading to increased risks of adverse health outcomes including falls, fracture, hospitalization, institutionalization, disability, dependence, dementia, poor quality of life, and death. There is interdependence between CKD and normal ageing whereby CKD makes ageing more accelerated and pronounced (senescence), whereas senescence accelerates chronic nephropathy's progression. Frailty status catalyzes this spiral, with renal and systemic consequences, phenomenon which can be named senescent nephropathy. In conclusion, senescent nephropathy is a new renal syndrome that should be taken into account, and we must try to handle its appearance and progression not only by applying nephron prevention measurements but also by diagnosis and treating frailty in the CKD population. PMID- 29143766 TI - Assessment of Micronutrient Status in Critically Ill Children: Challenges and Opportunities. AB - Micronutrients refer to a group of organic vitamins and inorganic trace elements that serve many functions in metabolism. Assessment of micronutrient status in critically ill children is challenging due to many complicating factors, such as evolving metabolic demands, immature organ function, and varying methods of feeding that affect nutritional dietary intake. Determination of micronutrient status, especially in children, usually relies on a combination of biomarkers, with only a few having been established as a gold standard. Almost all micronutrients display a decrease in their serum levels in critically ill children, resulting in an increased risk of deficiency in this setting. While vitamin D deficiency is a well-known phenomenon in critical illness and can predict a higher need for intensive care, serum concentrations of many trace elements such as iron, zinc, and selenium decrease as a result of tissue redistribution in response to systemic inflammation. Despite a decrease in their levels, supplementation of micronutrients during times of severe illness has not demonstrated clear benefits in either survival advantage or reduction of adverse outcomes. For many micronutrients, the lack of large and randomized studies remains a major hindrance to critically evaluating their status and clinical significance. PMID- 29143770 TI - Surface-Relief Gratings in Halogen-Bonded Polymer-Azobenzene Complexes: A Concentration-Dependence Study. AB - In recent years, supramolecular complexes comprising a poly(4-vinylpyridine) backbone and azobenzene-based halogen bond donors have emerged as a promising class of materials for the inscription of light-induced surface-relief gratings (SRGs). The studies up to date have focused on building supramolecular hierarchies, i.e., optimizing the polymer-azobenzene noncovalent interaction for efficient surface patterning. They have been conducted using systems with relatively low azobenzene content, and little is known about the concentration dependence of SRG formation in halogen-bonded polymer-azobenzene complexes. Herein, we bridge this gap, and study the concentration dependence of SRG formation using two halogen-bond-donating azobenzene derivatives, one functionalized with a tetrafluoroiodophenyl and the other with an iodoethynylphenyl group. Both have been previously identified as efficient molecules in driving the SRG formation. We cover a broad concentration range, starting from 10 mol % azobenzene content and going all the way up to equimolar degree of complexation. The complexes are studied as spin-coated thin films, and analyzed by optical microscopy, atomic force microscopy, and optical diffraction arising during the SRG formation. We obtained diffraction efficiencies as high as 35%, and modulation depths close to 400 nm, which are significantly higher than the values previously reported for halogen-bonded polymer-azobenzene complexes. PMID- 29143771 TI - Doxorubicin-Wrapped Zinc Oxide Nanoclusters for the Therapy of Colorectal Adenocarcinoma. AB - Doxorubicin (DOX)-wrapped zinc oxide nanoclusters (ZnO NCs) were developed for the therapy of colorectal cancer. DOX was coated onto the agglomerates of ZnO nanoparticles using a facile coating process. DOX-ZnO NCs with a hydrodynamic size of 170 nm, narrow size distribution, and positive zeta potential were fabricated. The aggregated shape of developed DOX-ZnO NCs was observed by transmission electron microscopy (TEM) imaging. The result of Fourier-transform infrared (FT-IR) analysis suggested the interaction between DOX and ZnO in DOX ZnO NCs. The existence of DOX in the outer surface of DOX-ZnO NCs was further identified by X-ray powder diffractometer (XRD) and X-ray photoelectron spectroscopy (XPS) analyses. Cellular uptake efficiency and antiproliferation efficacy of developed DOX-ZnO NCs were tested in Caco-2 (human colorectal adenocarcinoma) cells. The cellular accumulated amount of DOX-ZnO NCs was 3.19 fold higher than that of free DOX (p < 0.05). The DOX-ZnO NCs group also exhibited improved antiproliferation potentials, compared with the DOX and ZnO groups, in Caco-2 cells at 0.5 and 1 MUg/mL DOX concentrations. All these findings imply that developed DOX-ZnO NCs can be efficient hybrid nanoformulations for the therapy of colorectal cancers. PMID- 29143772 TI - Fault Detection of Bearing Systems through EEMD and Optimization Algorithm. AB - This study proposes a fault detection and diagnosis method for bearing systems using ensemble empirical mode decomposition (EEMD) based feature extraction, in conjunction with particle swarm optimization (PSO), principal component analysis (PCA), and Isomap. First, a mathematical model is assumed to generate vibration signals from damaged bearing components, such as the inner-race, outer-race, and rolling elements. The process of decomposing vibration signals into intrinsic mode functions (IMFs) and extracting statistical features is introduced to develop a damage-sensitive parameter vector. Finally, PCA and Isomap algorithm are used to classify and visualize this parameter vector, to separate damage characteristics from healthy bearing components. Moreover, the PSO-based optimization algorithm improves the classification performance by selecting proper weightings for the parameter vector, to maximize the visualization effect of separating and grouping of parameter vectors in three-dimensional space. PMID- 29143773 TI - Phonon Confinement Induced Non-Concomitant Near-Infrared Emission along a Single ZnO Nanowire: Spatial Evolution Study of Phononic and Photonic Properties. AB - The impact of mixed defects on ZnO phononic and photonic properties at the nanoscale is only now being investigated. Here we report an effective strategy to study the distribution of defects along the growth direction of a single ZnO nanowire (NW), performed qualitatively as well as quantitatively using energy dispersive spectroscopy (EDS), confocal Raman-, and photoluminescence (PL) mapping technique. A non-concomitant near-infrared (NIR) emission of 1.53 +/- 0.01 eV was observed near the bottom region of 2.05 +/- 0.05 MUm along a single ZnO NW and could be successfully explained by the radiative recombination of shallowly trapped electrons V_O^(**) with deeply trapped holes at V_Zn^''. A linear chain model modified from a phonon confinement model was used to describe the growth of short-range correlations between the mean distance of defects and its evolution with spatial position along the axial growth direction by fitting the E2H mode. Our results are expected to provide new insights into improving the study of the photonic and photonic properties of a single nanowire. PMID- 29143774 TI - Disrupting VEGF-VEGFR1 Interaction: De Novo Designed Linear Helical Peptides to Mimic the VEGF13-25 Fragment. AB - The interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFR) has important implications in angiogenesis and cancer, which moved us to search for peptide derivatives able to block this protein-protein interaction. In a previous work we had described a collection of linear 13-mer peptides specially designed to adopt helical conformations (Ac-SSEEX5ARNX8AAX12N NH2), as well as the evaluation of seven library components for the inhibition of the interaction of VEGF with its Receptor 1 (VEGFR1). This study led to the discovery of some new, quite potent inhibitors of this protein-protein system. The results we found prompted us to extend the study to other peptides of the library. We describe here the evaluation of a new selection of peptides from the initial library that allow us to identify new VEGF-VEGFR1 inhibitors. Among them, the peptide sequence containing F, W, and I residues at the 5, 9, and 12 positions, show a very significant nanomolar IC50 value, competing with VEGF for its receptor 1, VEGFR1 (Flt-1), which could represent a new tool within the therapeutic arsenal for cancer detection and therapy. PMID- 29143775 TI - Low-Cost Air Quality Monitoring Tools: From Research to Practice (A Workshop Summary). AB - In May 2017, a two-day workshop was held in Los Angeles (California, U.S.A.) to gather practitioners who work with low-cost sensors used to make air quality measurements. The community of practice included individuals from academia, industry, non-profit groups, community-based organizations, and regulatory agencies. The group gathered to share knowledge developed from a variety of pilot projects in hopes of advancing the collective knowledge about how best to use low cost air quality sensors. Panel discussion topics included: (1) best practices for deployment and calibration of low-cost sensor systems, (2) data standardization efforts and database design, (3) advances in sensor calibration, data management, and data analysis and visualization, and (4) lessons learned from research/community partnerships to encourage purposeful use of sensors and create change/action. Panel discussions summarized knowledge advances and project successes while also highlighting the questions, unresolved issues, and technological limitations that still remain within the low-cost air quality sensor arena. PMID- 29143776 TI - Gastric Cancer Cell Glycosylation as a Modulator of the ErbB2 Oncogenic Receptor. AB - Aberrant expression and hyperactivation of the human epidermal growth factor receptor 2 (ErbB2) constitute crucial molecular events underpinning gastric neoplastic transformation. Despite ErbB2 extracellular domain being a well-known target for glycosylation, its glycosylation profile and the molecular mechanisms through which it actively tunes tumorigenesis in gastric cancer (GC) cells remain elusive. We aimed at disclosing relevant ErbB2 glycan signatures and their functional impact on receptor's biology in GC cells. The transcriptomic profile of cancer-relevant glycosylation enzymes, and the expression and activation of the ErbB receptors were characterized in four GC cell lines. Cellular- and receptor-specific glycan profiling of ErbB2-overexpressing NCI-N87 cells unveiled a heterogeneous glycosylation pattern harboring the tumor-associated sialyl Lewis a (SLea) antigen. The expression of SLea and key enzymes integrating its biosynthetic pathway were strongly upregulated in this GC cell line. An association between the expression of ERBB2 and FUT3, a central gene in SLea biosynthesis, was disclosed in GC patients, further highlighting the crosstalk between ErbB2 and SLea expression. Moreover, cellular deglycosylation and CA 19.9 antibody-mediated blocking of SLea drastically altered ErbB2 expression and activation in NCI-N87 cells. Altogether, NCI-N87 cell line constitutes an appealing in vitro model to address glycan-mediated regulation of ErbB2 in GC. PMID- 29143777 TI - Margination of Fluorescent Polylactic Acid-Polyaspartamide based Nanoparticles in Microcapillaries In Vitro: the Effect of Hematocrit and Pressure. AB - The last decade has seen the emergence of vascular-targeted drug delivery systems as a promising approach for the treatment of many diseases, such as cardiovascular diseases and cancer. In this field, one of the major challenges is carrier margination propensity (i.e., particle migration from blood flow to vessel walls); indeed, binding of these particles to targeted cells and tissues is only possible if there is direct carrier-wall interaction. Here, a microfluidic system mimicking the hydrodynamic conditions of human microcirculation in vitro is used to investigate the effect of red blood cells (RBCs) on a carrier margination in relation to RBC concentration (hematocrit) and pressure drop. As model drug carriers, fluorescent polymeric nanoparticles (FNPs) were chosen, which were obtained by using as starting material a pegylated polylactic acid-polyaspartamide copolymer. The latter was synthesized by derivatization of alpha,beta-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) with Rhodamine (RhB), polylactic acid (PLA) and then poly(ethyleneglycol) (PEG) chains. It was found that the carrier concentration near the wall increases with increasing pressure drop, independently of RBC concentration, and that the tendency for FNP margination decreases with increasing hematocrit. This work highlights the importance of taking into account RBC-drug carrier interactions and physiological conditions in microcirculation when planning a drug delivery strategy based on systemically administered carriers. PMID- 29143780 TI - Who Participates in Running Events? Socio-Demographic Characteristics, Psychosocial Factors and Barriers as Correlates of Non-Participation-A Pilot Study in Belgium. AB - In Western countries, the popularity of running events has increased exponentially during the last three decades. However, little is known about the profile of non-participants. This knowledge is crucial to tailor promotional actions towards people who are currently not participating. Therefore, this study aimed: (1) to examine which socio-ecological factors are related to participation in running events, (2) to give an overview of the barriers towards participation, and (3) to examine differences in barriers depending on gender, age and educational level. Flemish adults (n = 308) completed an online questionnaire about their socio-demographic and psychosocial characteristics, physical activity levels, participation in running events and barriers towards participation. Results showed that motivation, family social support, knowledge about running events and physical activity levels were associated with participation in running events. Among non-participants, the main barriers were bad physical condition, lack of time and lack of interest. In participants, lack of time, distance to the event and financial barriers were most prevalent. With some exceptions, barriers were relatively similar across socio-demographic subgroups. This study confirmed a democratization among participants of running events and provided evidence about which barriers should be tackled to increase participation among population subgroups that are currently underrepresented in such events. PMID- 29143779 TI - Regenerative Therapies in Dry Eye Disease: From Growth Factors to Cell Therapy. AB - Dry eye syndrome is a complex and insidious pathology with a high level of prevalence among the human population and with a consequently high impact on quality of life and economic cost. Currently, its treatment is symptomatic, mainly based on the control of lubrication and inflammation, with significant limitations. Therefore, the latest research is focused on the development of new biological strategies, with the aim of regenerating affected tissues, or at least restricting the progression of the disease, reducing scar tissue, and maintaining corneal transparency. Therapies range from growth factors and cytokines to the use of different cell sources, in particular mesenchymal stem cells, due to their multipotentiality, trophic, and immunomodulatory properties. We will review the state of the art and the latest advances and results of these promising treatments in this pathology. PMID- 29143781 TI - Biological Properties of Low-Toxic PLGA and PLGA/PHB Fibrous Nanocomposite Scaffolds for Osseous Tissue Regeneration. Evaluation of Potential Bioactivity. AB - Abstracts: The aim of the study was to evaluate the biocompatibility and bioactivity of two new prototype implants for bone tissue regeneration made from biodegradable fibrous materials. The first is a newly developed poly(l-lactide-co glycolide), (PLGA), and the second is a blend of PLGA with synthetic poly([R,S]-3 hydroxybutyrate) (PLGA/PHB). The implant prototypes comprise PLGA or PLGA/PHB nonwoven fabrics with designed pore structures to create the best conditions for cell proliferation. The bioactivity of the proposed implants was enhanced by introducing a hydroxyapatite material and a biologically active agent, namely, growth factor IGF1, encapsulated in calcium alginate microspheres. To assess the biocompatibility and bioactivity, allergenic tests and an assessment of the local reaction of bone tissue after implantation were performed. Comparative studies of local tissue response after implantation into trochanters for a period of 12 months were performed on New Zealand rabbits. Based on the results of the in vivo evaluation of the allergenic effects and the local tissue reaction 12 months after implantation, it was concluded that the two implant prototypes, PLGA + IGF1 and PLGA/PHB + IGF1, were characterized by high biocompatibility with the soft and bone tissues of the tested animals. PMID- 29143778 TI - The Forty-Sixth Euro Congress on Drug Synthesis and Analysis: Snapshot ?. AB - The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5-8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, "Drug Synthesis and Analysis," meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting. PMID- 29143782 TI - Sustainable Bio-Based Phenol-Formaldehyde Resoles Using Hydrolytically Depolymerized Kraft Lignin. AB - In this study bio-based bio-phenol-formaldehyde (BPF) resoles were prepared using hydrolytically depolymerized Kraft lignin (DKL) as bio-phenol to partially substitute phenol. The effects of phenol substitution ratio, weight-average molecular weight (Mw) of DKL and formaldehyde-to-phenol (F/P) ratio were also investigated to find the optimum curing temperature for BPF resoles. The results indicated that DKL with Mw ~ 1200 g/mol provides a curing temperature of less than 180 degrees C for any substitution level, provided that F/P ratios are controlled. Incorporation of lignin reduced the curing temperature of the resin, however, higher Mw DKL negatively affected the curing process. For any level of lignin Mw, the curing temperature was found to increase with lower F/P ratios at lower phenol substitution levels. At 25% and 50% phenol substitution, increasing the F/P ratio allows for synthesis of resoles with lower curing temperatures. Increasing the phenol substitution from 50% to 75% allows for a broader range of lignin Mw to attain low curing temperatures. PMID- 29143783 TI - Metformin Potentiates the Benefits of Dietary Restraint: A Metabolomic Study. AB - Prevention of the metabolic consequences of a chronic energy-dense/high-fat diet (HFD) represents a public health priority. Metformin is a strong candidate to be incorporated in alternative therapeutic approaches. We used a targeted metabolomic approach to assess changes related to the multi-faceted metabolic disturbances provoked by HFD. We evaluated the protective effects of metformin and explored how pro-inflammatory and metabolic changes respond when mice rendered obese, glucose-intolerant and hyperlipidemic were switched to diet reversal with or without metformin. Mice treated with metformin and diet-reversal showed a dramatically improved protection against HFD-induced hepatic steatosis, a beneficial effect that was accompanied by a lowering of liver-infiltrating pro inflammatory macrophages and lower release of pro-inflammatory cytokines. Metformin combined with diet reversal promoted effective weight loss along with better glucose control, lowered levels of circulating cholesterol and triglycerides, and reduced adipose tissue content. Our findings underscored the ability of metformin to target the contribution of branched chain amino acids to adipose tissue metabolism while suppressing mitochondrial-dependent biosynthesis in hepatic tissue. The relationship between adipose tissue and liver might provide clinical potential for combining metformin and dietary modifications to protect against the metabolic damage occurring upon excessive dietary fat intake. PMID- 29143785 TI - Waterborne Polyurethane Coatings with Covalently Linked Black Dye Sudan Black B. AB - Colored waterborne polyurethanes have been widely used in paintings, leathers, textiles, and coatings. Here, a series of black waterborne polyurethanes (WPUs) with different ratios of black dye, Sudan Black B (SDB), were prepared by step growth polymerization. WPU emulsions as obtained exhibit low particle sizes and remarkable storage stability at the same time. At different dye loadings, essential structural, statistical and thermal properties are characterized. FTIR (fourier transform infrared) spectra indicate that SDB is covalently linked into waterborne polyurethane chains. All of the WPUs with covalently linked SDB show better color fastness and resistance of thermal migration than those with SDB mixed physically. Besides, WPUs incorporated SDB covalently with different polymeric diols, polytetramethylene ether glycol (PTMG), polypropylene glycol (PPG), poly-1, 4-butylene adipate glycol (PBA) and polycaprolactone glycol (PCL), were prepared to obtain different properties to cater to a variety of practical demands. By a spraying method, the black WPUs can be directly used as metal coatings without complex dyeing process by simply mixing coating additive and other waterborne resins, which exhibit excellent coating performance. PMID- 29143784 TI - Primary Cilium-Dependent Signaling Mechanisms. AB - Primary cilia are hair-like organelles and play crucial roles in vertebrate development, organogenesis, health, and many genetic disorders. A primary cilium is a mechano-sensory organelle that responds to mechanical stimuli in the micro environment. A cilium is also a chemosensor that senses chemical signals surrounding a cell. The overall function of a cilium is therefore to act as a communication hub to transfer extracellular signals into intracellular responses. Although intracellular calcium has been one of the most studied signaling messengers that transmit extracellular signals into the cells, calcium signaling by various ion channels remains a topic of interest in the field. This may be due to a broad spectrum of cilia functions that are dependent on or independent of utilizing calcium as a second messenger. We therefore revisit and discuss the calcium-dependent and calcium-independent ciliary signaling pathways of Hedgehog, Wnt, PDGFR, Notch, TGF-beta, mTOR, OFD1 autophagy, and other GPCR-associated signaling. All of these signaling pathways play crucial roles in various cellular processes, such as in organ and embryonic development, cardiac functioning, planar cell polarity, transactivation, differentiation, the cell cycle, apoptosis, tissue homeostasis, and the immune response. PMID- 29143787 TI - Limitation of Studies on Food Intake and Dietary Pattern in Iran and other Middle East Countries: Lack of Alcohol Intake Assessment. PMID- 29143786 TI - Dietary Factors Associated with Plasma Thyroid Peroxidase and Thyroglobulin Antibodies. AB - The knowledge about dietary habits and their influence in the development of autoimmune thyroid disease is insufficient. The aim of this study was to analyse the association of dietary factors and plasma thyroid peroxidase antibodies (TPO Ab) and/or thyroglobulin antibodies (Tg-Ab). The study enrolled 1887 participants originating from the South Croatia. Participants with elevated plasma TPO-Ab and/or Tg-Ab were defined as cases (n = 462) and those with TPO-Ab and/or Tg-Ab within referent values were defined as controls (n = 1425). Dietary intake was evaluated according to a food frequency questionnaire containing 58 food items. Principal component analysis was used to group food items into dietary groups. We used logistic regression analysis to examine dietary groups associated with positive plasma TPO-Ab and/or Tg-Ab. The results indicate that the dietary group with frequent consumption of animal fats and butter is associated with positive plasma TPO-Ab and/or Tg-Ab (p = 0.01). The dietary group with frequent consumption of vegetables as well as the dietary group with high consumption of dried fruit, nuts, and muesli are associated with negative findings of TPO-Ab and/or Tg-Ab (p = 0.048 and p = 0.02, respectively). We showed that the anti inflammatory dietary groups are associated with the negative findings of plasma TPO-Ab and/or Tg-Ab. PMID- 29143788 TI - Thermal Degradation Kinetics of Sugarcane Bagasse and Soft Wood Cellulose. AB - The properties of untreated sugar cane bagasse (SCB) and soft wood (SW) and their respective celluloses were investigated. The celluloses indicated improved crystallinity index values and decreased concentration of lignin and hemicellulose compared to their untreated counterparts. Three degradation models, Kissinger-Akahira-Sunose (KAS), Flynn-Wall-Ozawa (OFW), and Kissinger (KGR) methods were employed to determine apparent activation energy values. Generally, the thermal degradation processes of both sugarcane bagasse and soft wood included dehydration, degradation of hemicellulose and cellulose, whereas the lignin degraded from the degradation temperature of hemicellulose to the end of the cellulose. The apparent activation energy values obtained from the OFW and KAS models vary with the degree of conversion, and showed similar trends. The activation energies obtained by KGR were relatively lower than those obtained from the KAS and OFW methods. PMID- 29143789 TI - Real-Time Observation of the Interaction between Thioflavin T and an Amyloid Protein by Using High-Sensitivity Rheo-NMR. AB - Amyloid fibril formation is associated with numerous neurodegenerative diseases. To elucidate the mechanism of fibril formation, the thioflavin T (ThT) fluorescence assay is widely used. ThT is a fluorescent dye that selectively binds to amyloid fibrils and exhibits fluorescence enhancement, which enables quantitative analysis of the fibril formation process. However, the detailed binding mechanism has remained unclear. Here we acquire real-time profiles of fibril formation of superoxide dismutase 1 (SOD1) using high-sensitivity Rheo-NMR spectroscopy and detect weak and strong interactions between ThT and SOD1 fibrils in a time-dependent manner. Real-time information on the interaction between ThT and fibrils will contribute to the understanding of the binding mechanism of ThT to fibrils. In addition, our method provides an alternative way to analyze fibril formation. PMID- 29143790 TI - Deep Eutectic Solvents (DESs) for the Isolation of Willow Lignin (Salix matsudana cv. Zhuliu). AB - Deep eutectic solvents (DESs) are a potentially high-value lignin extraction methodology. DESs prepared from choline chloride (ChCl) and three hydrogen-bond donors (HBD)-lactic acid (Lac), glycerol, and urea-were evaluated for isolation of willow (Salix matsudana cv. Zhuliu) lignin. DESs types, mole ratio of ChCl to HBD, extraction temperature, and time on the fractionated DES-lignin yield demonstrated that the optimal DES-lignin yield (91.8 wt % based on the initial lignin in willow) with high purity of 94.5% can be reached at a ChCl-to-Lac molar ratio of 1:10, extraction temperature of 120 degrees C, and time of 12 h. Fourier transform infrared spectroscopy (FT-IR) , 13C-NMR, and 31P-NMR showed that willow lignin extracted by ChCl-Lac was mainly composed of syringyl and guaiacyl units. Serendipitously, a majority of the glucan in willow was preserved after ChCl-Lac treatment. PMID- 29143792 TI - Polyphosphates as Inhibitors for Poly(vinyl Chloride) Photodegradation. AB - Three polyphosphates were used as inhibitors for poly(vinyl chloride) (PVC) photodegradation. The polyphosphates were added to PVC at a concentration of 0.5% by weight. The PVC films (40 um thickness) were irradiated at room temperature with ultraviolet (UV) light for up to 300 h. The changes in PVC films after irradiation were monitored by Fourier transform infrared spectroscopy, weight loss, viscosity-average molecular weight determination, and atomic force microscopy. These changes were very noticeable in the blank PVC films compared to the ones obtained when additives were used. The polyphosphates can inhibit the PVC photodegradation through direct absorption of UV light, interactions with PVC chains, and acting as radical scavengers. PMID- 29143793 TI - Marrubium vulgare L. Leave Extract: Phytochemical Composition, Antioxidant and Wound Healing Properties. AB - Several factors contribute in wound generation, e.g., accidental traumas or surgery, and in certain cases, this dermal injury may have a devastating outcome. When skin damage occurs, the human body puts in place a sophisticated choreography, which involves numerous repairing processes to restore physiological conditions. Nevertheless, natural healing mechanisms are ineffective towards chronic or non-healing wounds and thus, therapeutic strategies may represent the only beneficial alternative to counteract these tissue insults. Over the years, numerous studies showed the great potential of plants in promoting wound healing, by virtue of their high contents in antioxidant species. These compounds trigger a molecular cascade that collimate into the promotion of reparative processes. In this article, we report on the potential effect on wound healing of Marrubium vulgare L., a medicinal plant well known for several pharmaceutical activities. To this aim, the methanolic extract was prepared and subjected to a phytochemical investigation, quantifying the amount of marrubiin via NMR and drawing the phytochemical fingerprint via high performance liquid chromatography-ultra violet/photodiode-array detection electrospray/mass (HPLC-UV/PAD-ESI/MS) analysis. Lastly, the antioxidant properties and wound healing potential have been evaluated. PMID- 29143791 TI - Dietary and Endogenous Sphingolipid Metabolism in Chronic Inflammation. AB - Chronic inflammation is a common underlying factor in many major metabolic diseases afflicting Western societies. Sphingolipid metabolism is pivotal in the regulation of inflammatory signaling pathways. The regulation of sphingolipid metabolism is in turn influenced by inflammatory pathways. In this review, we provide an overview of sphingolipid metabolism in mammalian cells, including a description of sphingolipid structure, biosynthesis, turnover, and role in inflammatory signaling. Sphingolipid metabolites play distinct and complex roles in inflammatory signaling and will be discussed. We also review studies examining dietary sphingolipids and inflammation, derived from in vitro and rodent models, as well as human clinical trials. Dietary sphingolipids appear to influence inflammation-related chronic diseases through inhibiting intestinal lipid absorption, altering gut microbiota, activation of anti-inflammatory nuclear receptors, and neutralizing responses to inflammatory stimuli. The anti inflammatory effects observed with consuming dietary sphingolipids are in contrast to the observation that most cellular sphingolipids play roles in augmenting inflammatory signaling. The relationship between dietary sphingolipids and low-grade chronic inflammation in metabolic disorders is complex and appears to depend on sphingolipid structure, digestion, and metabolic state of the organism. Further research is necessary to confirm the reported anti-inflammatory effects of dietary sphingolipids and delineate their impacts on endogenous sphingolipid metabolism. PMID- 29143794 TI - Berberine Activates Aryl Hydrocarbon Receptor but Suppresses CYP1A1 Induction through miR-21-3p Stimulation in MCF-7 Breast Cancer Cells. AB - Berberine and the methylenedioxy ring-opening derivatives palmatine and jatrorrhizine are active ingredients in immunomodulatory plants, such as goldenseal. This study aimed to illustrate the effects of protoberberines on aryl hydrocarbon receptor (AhR) activation and cytochrome P450 (CYP) 1 in the estrogen receptor (ER)alpha(+) MCF-7 breast cancer cells. Among protoberberines at non cytotoxic concentrations (<=10 MUM), berberine had the most potent and statistically significant effects on AhR activation and CYP1A1/1A2/1B1 mRNA induction. The 24-h exposure to 10 MUM berberine did not change CYP1A1 mRNA stability, protein level and function. Berberine significantly increased micro RNA (miR)-21-3p by 36% and the transfection of an inhibitor of miR-21-3p restored the induction of CYP1A1 protein with a 50% increase. These findings demonstrate that the ring opening of the methylenedioxyl moiety in berberine decreased AhR activation in MCF-7 cells. While CYP1A1 mRNA was elevated, berberine-induced miR 21-3p suppressed the increase of functional CYP1A1 protein expression. PMID- 29143795 TI - DEEP-SEE: Joint Object Detection, Tracking and Recognition with Application to Visually Impaired Navigational Assistance. AB - In this paper, we introduce the so-called DEEP-SEE framework that jointly exploits computer vision algorithms and deep convolutional neural networks (CNNs) to detect, track and recognize in real time objects encountered during navigation in the outdoor environment. A first feature concerns an object detection technique designed to localize both static and dynamic objects without any a priori knowledge about their position, type or shape. The methodological core of the proposed approach relies on a novel object tracking method based on two convolutional neural networks trained offline. The key principle consists of alternating between tracking using motion information and predicting the object location in time based on visual similarity. The validation of the tracking technique is performed on standard benchmark VOT datasets, and shows that the proposed approach returns state-of-the-art results while minimizing the computational complexity. Then, the DEEP-SEE framework is integrated into a novel assistive device, designed to improve cognition of VI people and to increase their safety when navigating in crowded urban scenes. The validation of our assistive device is performed on a video dataset with 30 elements acquired with the help of VI users. The proposed system shows high accuracy (>90%) and robustness (>90%) scores regardless on the scene dynamics. PMID- 29143797 TI - Indoor Air Quality Analysis Using Deep Learning with Sensor Data. AB - Indoor air quality analysis is of interest to understand the abnormal atmospheric phenomena and external factors that affect air quality. By recording and analyzing quality measurements, we are able to observe patterns in the measurements and predict the air quality of near future. We designed a microchip made out of sensors that is capable of periodically recording measurements, and proposed a model that estimates atmospheric changes using deep learning. In addition, we developed an efficient algorithm to determine the optimal observation period for accurate air quality prediction. Experimental results with real-world data demonstrate the feasibility of our approach. PMID- 29143796 TI - Angelica sinensis Polysaccharides Ameliorate Stress-Induced Premature Senescence of Hematopoietic Cell via Protecting Bone Marrow Stromal Cells from Oxidative Injuries Caused by 5-Fluorouracil. AB - Myelosuppression is the most common complication of chemotherapy. Decline of self renewal capacity and stress-induced premature senescence (SIPS) of hematopoietic stem cells (HSCs) induced by chemotherapeutic agents may be the cause of long term myelosuppression after chemotherapy. Whether the mechanism of SIPS of hematopoietic cells relates to chemotherapeutic injury occurred in hematopoietic microenvironment (HM) is still not well elucidated. This study explored the protective effect of Angelica sinensis polysaccharide (ASP), an acetone extract polysaccharide found as the major effective ingredients of a traditional Chinese medicinal herb named Chinese Angelica (Dong Quai), on oxidative damage of homo sapiens bone marrow/stroma cell line (HS-5) caused by 5-fluorouracil (5-FU), and the effect of ASP relieving oxidative stress in HM on SIPS of hematopoietic cells. Tumor-suppressive doses of 5-FU inhibited the growth of HS-5 in a dose dependent and time-dependent manner. 5-FU induced HS-5 apoptosis and also accumulated cellular hallmarks of senescence including cell cycle arrest and typical senescence-associated beta-galactosidase positive staining. The intracellular reactive oxygen species (ROS) was increased in 5-FU treated HS-5 cells and coinstantaneous with attenuated antioxidant capacity marked by superoxide dismutase and glutathione peroxidase. Oxidative stress initiated DNA damage indicated by increased gammaH2AX and 8-OHdG. Oxidative damage of HS-5 cells resulted in declined hematopoietic stimulating factors including stem cell factor (SCF), stromal cell-derived factor (SDF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), however, elevated inflammatory chemokines such as RANTES. In addition, gap junction channel protein expression and mediated intercellular communications were attenuated after 5-FU treatment. Significantly, co-culture on 5-FU treated HS-5 feeder layer resulted in less quantity of human umbilical cord blood-derived hematopoietic cells and CD34+ hematopoietic stem/progenitor cells (HSPCs), and SIPS of hematopoietic cells. However, it is noteworthy that ASP ameliorated SIPS of hematopoietic cells by the mechanism of protecting bone marrow stromal cells from chemotherapeutic injury via mitigating oxidative damage of stromal cells and improving their hematopoietic function. This study provides a new strategy to alleviate the complication of conventional cancer therapy using chemotherapeutic agents. PMID- 29143798 TI - Skullcap (Scutellaria Baicalensis) Hexane Fraction Inhibits the Permeation of Ovalbumin and Regulates Th1/2 Immune Responses. AB - Skullcap (Scutellaria baicalensis) is well known for its anti-inflammatory and anti-allergic effects. In our previous study, we found that skullcap could inhibit allergen permeation and regulate Th1/2 immune balance. To reveal the key fractions and components of skullcap, we fractionated skullcap extract into five fractions: hexane, chloroform, ethyl acetate, butanol, and water fraction. Among these fractions, the hexane fraction significantly suppressed the production of Th2-mediated cytokines (Interleukin (IL)-4, 5, 10 and 13) and increased Th1 mediated cytokines (Interferon (IFN)-gamma and IL-12). Furthermore, the hexane fraction inhibited the permeation of ovalbumin (OVA), used as an allergen, across the intestinal epithelial cell monolayer. To confirm the active compounds in the hexane fraction, fatty acids were analyzed. Linoleic acid (LA, C18:2 (>59.7%)) was identified as the most important fatty acid in the skullcap hexane fraction. LA significantly suppressed IL-4 production and increased IFN-gamma secretion, as well as inhibiting OVA permeation. Thus, LA significantly diminished the permeation of allergen by enhancing intestinal barrier function and regulated allergic responses to maintain Th1/Th2 immune balance. PMID- 29143799 TI - Effect of a Partially Hydrolysed Whey Infant Formula Supplemented with Starch and Lactobacillus reuteri DSM 17938 on Regurgitation and Gastric Motility. AB - Functional regurgitation (FR) is common in early infancy and represents a major drain on healthcare resources. This double-blind, randomized controlled trial investigated the effects of a formula containing partially hydrolysed, 100% whey protein, starch and Lactobacillus reuteri (DSM 17938) on gastric emptying rate (GErate) and regurgitation frequency in infants with FR. Enrolled infants were randomly allocated to receive either the test formula or a standard starter formula for four weeks. Ultrasound GErate assessment was performed at baseline (week 0) and at week 4; the number of regurgitations, feed volumes and potential adverse events were recorded in a daily diary. Eighty infants aged four weeks to five months were enrolled; 72 (test group = 37; control group = 35) completed the study. Compared to controls, the test group showed greater percentage changes in GErate (12.3% vs. 9.1%, p < 0.01). Mean daily regurgitations decreased from 7.4 (0.8) at week 0 to 2.6 (1.0) at week 4 in the test group and from 7.5 (1.0) to 5.3 (1.0) in controls (between-group difference, p < 0.0001). Compared to a standard formula, a starch-thickened partially hydrolysed whey protein formula supplemented with Lactobacillus reuteri is more effective in decreasing the frequency of regurgitation and improving GErate, and can be of benefit to infants with FR. PMID- 29143800 TI - Hungry Neurons: Metabolic Insights on Seizure Dynamics. AB - Epilepsy afflicts up to 1.6% of the population and the mechanisms underlying the appearance of seizures are still not understood. In past years, many efforts have been spent trying to understand the mechanisms underlying the excessive and synchronous firing of neurons. Traditionally, attention was pointed towards synaptic (dys)function and extracellular ionic species (dys)regulation. Recently, novel clinical and preclinical studies explored the role of brain metabolism (i.e., glucose utilization) of seizures pathophysiology revealing (in most cases) reduced metabolism in the inter-ictal period and increased metabolism in the seconds preceding and during the appearance of seizures. In the present review, we summarize the clinical and preclinical observations showing metabolic dysregulation during epileptogenesis, seizure initiation, and termination, and in the inter-ictal period. Recent preclinical studies have shown that 2-Deoxyglucose (2-DG, a glycolysis blocker) is a novel therapeutic approach to reduce seizures. Furthermore, we present initial evidence for the effectiveness of 2-DG in arresting 4-Aminopyridine induced neocortical seizures in vivo in the mouse. PMID- 29143801 TI - Novel Molecular Challenges in Targeting Anaplastic Lymphoma Kinase in ALK Expressing Human Cancers. AB - Targeting anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase receptor initially identified as a potent oncogenic driver in anaplastic large-cell lymphoma (ALCL) in the form of nucleophosmin (NPM)-ALK fusion protein, using tyrosine kinase inhibitors has shown to be a promising therapeutic approach for ALK-expressing tumors. However, clinical resistance to ALK inhibitors invariably occurs, and the molecular mechanisms are incompletely understood. Recent studies have clearly shown that clinical resistance to ALK inhibitors is a multifactorial and complex mechanism. While few of the mechanisms of clinical resistance to ALK inhibitors such as gene mutation are well known, there are others that are not well covered. In this review, the molecular mechanisms of cancer stem cells in mediating resistance to ALK inhibitors as well as the current understanding of the molecular challenges in targeting ALK in ALK-expressing human cancers will be discussed. PMID- 29143802 TI - The Inhibitory Effects of Cobalt Protoporphyrin IX and Cannabinoid 2 Receptor Agonists in Type 2 Diabetic Mice. AB - The activation of the transcription factor Nrf2 inhibits neuropathy and modulates the activity of delta-opioid receptors (DOR) in type 2 diabetic mice but the impact of Nrf2/HO-1 pathway on the antinociceptive actions of cannabinoid 2 receptors (CB2R) has not been assessed. Using male mice BKS.Cg-m+/+Leprdb/J (db/db) we investigated if treatment with cobalt protoporphyrin IX (CoPP), an HO 1 inductor, inhibited mechanical allodynia, hyperglycemia and obesity associated to type 2 diabetes. The antinociceptive effects of JWH-015 and JWH-133 (CB2R agonists) administered with and without CoPP or sulforaphane (SFN), a Nrf2 transcription factor activator, have been also evaluated. The expression of Nrf2, HO-1, NAD(P)H: quinone oxidoreductase 1 (NQO1) and c-Jun N-terminal kinase (JNK) in sciatic nerve and that of the CB2R on the dorsal root ganglia from animals treated with CoPP and/or SFN were assessed. CoPP treatment inhibited allodynia, hyperglycemia and body weight gain in db/db mice by enhancing HO-1/NQO1 levels and reducing JNK phosphorylation. Both CoPP and SFN improved the antiallodynic effects of JWH-015 and JWH-133 and expression of CB2R in db/db mice. Therefore, we concluded that the activation of antioxidant Nrf2/HO-1 pathway potentiate the effects of CB2R agonists and might be suitable for the treatment of painful neuropathy linked to type 2 diabetes. PMID- 29143803 TI - Use of Novel High-Protein Functional Food Products as Part of a Calorie Restricted Diet to Reduce Insulin Resistance and Increase Lean Body Mass in Adults: A Randomized Controlled Trial. AB - Significant reductions in insulin resistance (IR) can be achieved by either calorie restriction or by the increase of lean mass. However, calorie restriction usually results in significant loss of lean mass. A 6-week randomized controlled feeding trial was conducted to determine if a calorie-restricted, high-protein diet (~125 g protein/day consumed evenly throughout the day) using novel functional foods would be more successful for reducing IR in comparison to a conventional diet (~80 g protein/day) with a similar level of calorie restriction. Healthy adults (age 20-75 years; body mass index, 20-42 kg/m2) with raised triglyceride/high-density lipoprotein ratios were randomly assigned to the control group (CON: test foods prepared using gluten-free commercial pasta and cereal) or to the high-protein group (HPR: test foods prepared using novel high protein pasta and cereal both rich in wheat gluten). Mean weight loss did not differ between groups (-2.7 +/- 2.6 and -3.2 +/- 3.0 kg for CON (n = 11) and HPR (n = 10) respectively, p = 0.801); however, the 6-week change in fat-free mass (FFM) differed significantly between groups (-0.5 +/- 1.5 and +1.5 +/- 3.8 kg for CON and HPR respectively, p = 0.008). IR improved in HPR vs. CON participants (homeostasis model assessment-estimated insulin resistance [HOMAIR] change: -1.7 +/- 1.4 and -0.7 +/- 0.7 respectively; p = 0.020). The change in HOMA-IR was related to the change in FFM among participants (r = -0.511, p = 0.021). Thus, a high-protein diet using novel functional foods combined with modest calorie restriction was 140% more effective for reducing HOMA-IR in healthy adults compared to a lower protein, standard diet with an equal level of calorie restriction. PMID- 29143807 TI - Urinary incontinence in women. AB - This corrects the article DOI: 10.1038/nrdp.2017.42. PMID- 29143804 TI - Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions. AB - Leukocyte telomere length (TL) has been suggested as a marker of biological age in healthy individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML), indicates clinical outcomes in chronic lymphocytic leukemia (CLL), and can be used as screening tool for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes (BMFS). In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast, the elevation in telomerase levels through treatment with androgens has become an exciting clinical intervention for patients with BMFS. Here, we review recent developments, which highlight the impact of telomeres and telomerase targeted therapies in hematologic dysfunctions. PMID- 29143805 TI - Mechanisms of Acupuncture Therapy in Ischemic Stroke Rehabilitation: A Literature Review of Basic Studies. AB - Acupuncture is recommended by the World Health Organization (WHO) as an alternative and complementary strategy for stroke treatment and for improving stroke care. Clinical trial and meta-analysis findings have demonstrated the efficacy of acupuncture in improving balance function, reducing spasticity, and increasing muscle strength and general well-being post-stroke. The mechanisms underlying the beneficial effects of acupuncture in stroke rehabilitation remain unclear. The aim of this study was to conduct a literature review, summarize the current known mechanisms in ischemic stroke rehabilitation through acupuncture and electroacupuncture (EA) therapy, and to detail the frequently used acupoints implicated in these effects. The evidence in this review indicates that five major different mechanisms are involved in the beneficial effects of acupuncture/EA on ischemic stroke rehabilitation: (1) Promotion of neurogenesis and cell proliferation in the central nervous system (CNS); (2) Regulation of cerebral blood flow in the ischemic area; (3) Anti-apoptosis in the ischemic area; (4) Regulation of neurochemicals; and, (5) Improvement of impaired long term potentiation (LTP) and memory after stroke. The most frequently used acupoints in basic studies include Baihui (GV20), Zusanli (ST36), Quchi (LI11), Shuigou (GV26), Dazhui (GV14), and Hegu (LI4). Our findings show that acupuncture exerts a beneficial effect on ischemic stroke through modulation of different mechanisms originating in the CNS. PMID- 29143809 TI - Hypertension: Promising mitochondria-targeting drug for PAH. PMID- 29143808 TI - Corrigendum: A simple and versatile design concept for fluorophore derivatives with intramolecular photostabilization. AB - This corrects the article DOI: 10.1038/ncomms10144. PMID- 29143811 TI - Surgery: Circadian rhythms influence surgical outcomes. PMID- 29143810 TI - Next-generation pacemakers: from small devices to biological pacemakers. AB - Electrogenesis in the heart begins in the sinoatrial node and proceeds down the conduction system to originate the heartbeat. Conduction system disorders lead to slow heart rates that are insufficient to support the circulation, necessitating implantation of electronic pacemakers. The typical electronic pacemaker consists of a subcutaneous generator and battery module attached to one or more endocardial leads. New leadless pacemakers can be implanted directly into the right ventricular apex, providing single-chamber pacing without a subcutaneous generator. Modern pacemakers are generally reliable, and their programmability provides options for different pacing modes tailored to specific clinical needs. Advances in device technology will probably include alternative energy sources and dual-chamber leadless pacing in the not-too-distant future. Although effective, current electronic devices have limitations related to lead or generator malfunction, lack of autonomic responsiveness, undesirable interactions with strong magnetic fields, and device-related infections. Biological pacemakers, generated by somatic gene transfer, cell fusion, or cell transplantation, provide an alternative to electronic devices. Somatic reprogramming strategies, which involve transfer of genes encoding transcription factors to transform working myocardium into a surrogate sinoatrial node, are furthest along in the translational pipeline. Even as electronic pacemakers become smaller and less invasive, biological pacemakers might expand the therapeutic armamentarium for conduction system disorders. PMID- 29143812 TI - The NLRP3 inflammasome in acute myocardial infarction. AB - The heart is extremely sensitive to ischaemic injury. During an acute myocardial infarction (AMI) event, the injury is initially caused by reduced blood supply to the tissues, which is then further exacerbated by an intense and highly specific inflammatory response that occurs during reperfusion. Numerous studies have highlighted the central role of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in this process. The inflammasome, an integral part of the innate immune system, is a macromolecular protein complex that finely regulates the activation of caspase 1 and the production and secretion of powerful pro-inflammatory cytokines such as IL-1beta and IL-18. In this Review, we summarize evidence supporting the therapeutic value of NLRP3 inflammasome targeted strategies in experimental models, and the data supporting the role of the NLRP3 inflammasome in AMI and its consequences on adverse cardiac remodelling, cytokine-mediated systolic dysfunction, and heart failure. PMID- 29143813 TI - SHIP1, but not an AML-derived SHIP1 mutant, suppresses myeloid leukemia growth in a xenotransplantation mouse model. AB - Constitutive activation of the PI3K/AKT signaling pathway is found in ~50-70% of AML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP1) is a negative regulator of PI3K/AKT signaling in hematopoietic cells. SHIP1 knockout mice develop a myeloproliferative syndrome and concomitant deletion of SHIP1 and the tumor suppressor PTEN leads to the development of lethal B-cell lymphomas. In the study presented here, we investigated the role of SHIP1 as a tumor suppressor in myeloid leukemia cells in an in vivo xenograft transplantation model. NSG Mice transplanted with UKE-1 cells derived from a secondary AML showed a significantly extended lifespan after lentiviral-mediated overexpression of SHIP1 in comparison to the vector control cohort. In contrast, the AML-derived SHIP1Y643H mutant, which has a strongly reduced enzymatic activity showed a significant reversion of the SHIP1-induced prolongation of the survival time. In addition, the analysis of 290 AML patients revealed a correlation between expression of SHIP1 and overall survival of the AML patients. These results indicate that SHIP1 can act as a tumor suppressor in acute myeloid leukemia cells and that higher SHIP1 expression is associated with prolonged overall survival in AML patients. SHIP1 may be an interesting candidate for gene therapy. PMID- 29143814 TI - Structural basis of nucleotide sugar transport across the Golgi membrane. AB - Glycosylation is a fundamental cellular process that, in eukaryotes, occurs in the lumen of both the Golgi apparatus and the endoplasmic reticulum. Nucleotide sugar transporters (NSTs) are an essential component of the glycosylation pathway, providing the diverse range of substrates required for the glycosyltransferases. NSTs are linked to several developmental and immune disorders in humans, and in pathogenic microbes they have an important role in virulence. How NSTs recognize and transport activated monosaccharides, however, is currently unclear. Here we present the crystal structure of an NST, the GDP mannose transporter Vrg4, in both the substrate-free and the bound states. A hitherto unobserved requirement of short-chain lipids in activating the transporter supports a model for regulation within the highly dynamic membranes of the Golgi apparatus. Our results provide a structural basis for understanding nucleotide sugar recognition, and provide insights into the transport and regulatory mechanism of this family of intracellular transporters. PMID- 29143816 TI - Quantitative microbiome profiling links gut community variation to microbial load. AB - Current sequencing-based analyses of faecal microbiota quantify microbial taxa and metabolic pathways as fractions of the sample sequence library generated by each analysis. Although these relative approaches permit detection of disease associated microbiome variation, they are limited in their ability to reveal the interplay between microbiota and host health. Comparative analyses of relative microbiome data cannot provide information about the extent or directionality of changes in taxa abundance or metabolic potential. If microbial load varies substantially between samples, relative profiling will hamper attempts to link microbiome features to quantitative data such as physiological parameters or metabolite concentrations. Saliently, relative approaches ignore the possibility that altered overall microbiota abundance itself could be a key identifier of a disease-associated ecosystem configuration. To enable genuine characterization of host-microbiota interactions, microbiome research must exchange ratios for counts. Here we build a workflow for the quantitative microbiome profiling of faecal material, through parallelization of amplicon sequencing and flow cytometric enumeration of microbial cells. We observe up to tenfold differences in the microbial loads of healthy individuals and relate this variation to enterotype differentiation. We show how microbial abundances underpin both microbiota variation between individuals and covariation with host phenotype. Quantitative profiling bypasses compositionality effects in the reconstruction of gut microbiota interaction networks and reveals that the taxonomic trade-off between Bacteroides and Prevotella is an artefact of relative microbiome analyses. Finally, we identify microbial load as a key driver of observed microbiota alterations in a cohort of patients with Crohn's disease, here associated with a low-cell-count Bacteroides enterotype (as defined through relative profiling). PMID- 29143815 TI - Genome sequence of the progenitor of the wheat D genome Aegilops tauschii. AB - Aegilops tauschii is the diploid progenitor of the D genome of hexaploid wheat (Triticum aestivum, genomes AABBDD) and an important genetic resource for wheat. The large size and highly repetitive nature of the Ae. tauschii genome has until now precluded the development of a reference-quality genome sequence. Here we use an array of advanced technologies, including ordered-clone genome sequencing, whole-genome shotgun sequencing, and BioNano optical genome mapping, to generate a reference-quality genome sequence for Ae. tauschii ssp. strangulata accession AL8/78, which is closely related to the wheat D genome. We show that compared to other sequenced plant genomes, including a much larger conifer genome, the Ae. tauschii genome contains unprecedented amounts of very similar repeated sequences. Our genome comparisons reveal that the Ae. tauschii genome has a greater number of dispersed duplicated genes than other sequenced genomes and its chromosomes have been structurally evolving an order of magnitude faster than those of other grass genomes. The decay of colinearity with other grass genomes correlates with recombination rates along chromosomes. We propose that the vast amounts of very similar repeated sequences cause frequent errors in recombination and lead to gene duplications and structural chromosome changes that drive fast genome evolution. PMID- 29143817 TI - Greater post-Neolithic wealth disparities in Eurasia than in North America and Mesoamerica. AB - How wealth is distributed among households provides insight into the fundamental characters of societies and the opportunities they afford for social mobility. However, economic inequality has been hard to study in ancient societies for which we do not have written records, which adds to the challenge of placing current wealth disparities into a long-term perspective. Although various archaeological proxies for wealth, such as burial goods or exotic or expensive-to manufacture goods in household assemblages, have been proposed, the first is not clearly connected with households, and the second is confounded by abandonment mode and other factors. As a result, numerous questions remain concerning the growth of wealth disparities, including their connection to the development of domesticated plants and animals and to increases in sociopolitical scale. Here we show that wealth disparities generally increased with the domestication of plants and animals and with increased sociopolitical scale, using Gini coefficients computed over the single consistent proxy of house-size distributions. However, unexpected differences in the responses of societies to these factors in North America and Mesoamerica, and in Eurasia, became evident after the end of the Neolithic period. We argue that the generally higher wealth disparities identified in post-Neolithic Eurasia were initially due to the greater availability of large mammals that could be domesticated, because they allowed more profitable agricultural extensification, and also eventually led to the development of a mounted warrior elite able to expand polities (political units that cohere via identity, ability to mobilize resources, or governance) to sizes that were not possible in North America and Mesoamerica before the arrival of Europeans. We anticipate that this analysis will stimulate other work to enlarge this sample to include societies in South America, Africa, South Asia and Oceania that were under-sampled or not included in this study. PMID- 29143819 TI - Archaeology: Inequality has deep roots in Eurasia. PMID- 29143818 TI - Visualization of chemical modifications in the human 80S ribosome structure. AB - Chemical modifications of human ribosomal RNA (rRNA) are introduced during biogenesis and have been implicated in the dysregulation of protein synthesis, as is found in cancer and other diseases. However, their role in this phenomenon is unknown. Here we visualize more than 130 individual rRNA modifications in the three-dimensional structure of the human ribosome, explaining their structural and functional roles. In addition to a small number of universally conserved sites, we identify many eukaryote- or human-specific modifications and unique sites that form an extended shell in comparison to bacterial ribosomes, and which stabilize the RNA. Several of the modifications are associated with the binding sites of three ribosome-targeting antibiotics, or are associated with degenerate states in cancer, such as keto alkylations on nucleotide bases reminiscent of specialized ribosomes. This high-resolution structure of the human 80S ribosome paves the way towards understanding the role of epigenetic rRNA modifications in human diseases and suggests new possibilities for designing selective inhibitors and therapeutic drugs. PMID- 29143820 TI - Microbiota: A high-pressure situation for bacteria. PMID- 29143821 TI - Erratum: The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. AB - This corrects the article DOI: 10.1038/nature24029. PMID- 29143822 TI - Cancer immunotherapy: The dark side of PD-1 receptor inhibition. PMID- 29143825 TI - Corrigendum: Transcriptome Analysis of Maize Immature Embryos Reveals the Roles of Cysteine in Improving Agrobacterium Infection Efficiency. AB - [This corrects the article on p. 1778 in vol. 8, PMID: 29089955.]. PMID- 29143824 TI - PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. AB - T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor programmed death-1 (PD-1), as a master gene that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre malignant cells. By contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation, and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology. PMID- 29143826 TI - Redox non-innocent bis(2,6-diimine-pyridine) ligand-iron complexes as anolytes for flow battery applications. AB - Diiminepyridines are a well-known class of "non-innocent" ligands that confer additional redox activity to coordination complexes beyond metal-centred oxidation/reduction. Here, we demonstrate that metal coordination complexes (MCCs) of diiminepyridine (DIP) ligands with iron are suitable anolytes for redox flow battery applications, with enhanced capacitance and stability compared with bipyridine analogs, and access to storage of up to 1.6 electron equivalents. Substitution of the ligand is shown to be a key factor in the cycling stability and performance of MCCs based on DIP ligands, opening the door to further optimization. PMID- 29143823 TI - Salt-responsive gut commensal modulates TH17 axis and disease. AB - A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt sensitive conditions. PMID- 29143828 TI - Large stretchability and failure mechanism of graphene kirigami under tension. AB - From the macro- to the nanoscale, kirigami structures show novel and tunable properties by tailoring the original two-dimensional sheets. In this study, the large stretchability and failure behavior in graphene nanoribbon kirigami (GNR-k) are obtained using the finite element (FE) method and molecular dynamics (MD) simulations. The carbon-carbon bond in the FE method is equivalent to a nonlinear Timoshenko beam based on the Tersoff-Brenner potential. All the results from the present FE method are in reasonable agreement with those from our MD simulations using the REBO potential. These results from the two methods show that the maximum ultimate strain of GNR-k (around 100%) is around 4 times higher than that of a pristine graphene nanoribbon (GNR), whereas the minimum ultimate stress of GNR-k is around one order of magnitude lower than that of the GNR. In particular, the large stretchability of GNR-k is indirectly proven to be mainly derived from the out-of-plane bending deformation by measuring the nonlinear mechanical properties of paper kirigami. Our results provide physical insights into the origins of the large stretchability of GNR-k and make GNR-k applicable to flexible nanodevices. PMID- 29143827 TI - Digestion under saliva, simulated gastric and small intestinal conditions and fermentation in vitro of polysaccharides from the flowers of Camellia sinensis induced by human gut microbiota. AB - In the present study, digestion under saliva, simulated gastric and small intestinal conditions and fermentation in vitro of polysaccharides from the flowers of Camellia sinensis (TFPS) by human gut microbiota were investigated. The results indicated that human saliva and simulated gastric and intestinal juices had no effect on TFPS, while TFPS could be utilized by human fecal microbiota, which was proved from the decreased molecular weight and lower content of total or reducing sugars after fermentation under anaerobic conditions. It was found that pH in the fermentation system decreased, and the production of short-chain fatty acids was significantly enhanced. Furthermore, in vitro fermentation of TFPS altered the composition of gut microbiota, specifically in elevating the ratio of Bacteroidetes to Firmicutes and enriching Prevotella. The present results suggest that TFPS has the potential to be developed as functional foods to modify gut microbiota. PMID- 29143829 TI - Spectral properties of ionic benzotristhiazole based donor-acceptor NLO-phores in polymer matrices and their one- and two-photon cellular imaging ability. AB - A series of ionic benzotristhiazolium (BTT) push-pull chromophores, with different nitrogen donor groups and different lengths of conjugated bridges, was successfully doped in polar polymer matrices (PVC and PSS). The spectral (photophysical) properties of their low concentration thin polymeric films are compared with those in solution and are discussed in terms of matrix polarity/viscosity influence, specific polymer-chromophore interaction, structure spectral property relationship and Twisted Intramolecular Charge-Transfer (TICT) state formation. The elimination of a non-emissive phantom and TICT state formation by restricted intramolecular rotations in the polymer matrix or viscous solvent results in a relatively high PhiF of all the investigated NLO-phores; particularly for near-infrared NIR molecular rotors bearing diphenylamino and julolidine donor groups. Because of cationic characteristics, small molecular weight, calculated high second hyperpolarizability and significant emission efficiency dependence on surroundings' viscosity (rigidochromic effect), two dyes were chosen as candidates for potential fluorescent probes for one-photon (1P) and two photon (2P) cellular imaging. The selected BTT NLO-phore with a julolidine donor is promising as a mitochondria-specific fluorescent small molecular probe for live cell super-resolution imaging with low cytotoxicity and good photostability, and is also potentially suitable for super-resolution STED imaging. PMID- 29143830 TI - Gramicidin ion channels in a lipid bilayer supported on polyelectrolyte multilayer films: an electrochemical impedance study. AB - Supported membranes on polymer cushions are of fundamental interest as models for cell membranes. The use of polyelectrolyte multilayers (PEMs) assembled by the layer by layer (LbL) technique as supports for a bilayer allows for easy integration of the lipid bilayer on surfaces and devices and for nanoscale tunable spacing of the lipid bilayer. Controlling ionic permeability in lipid bilayers supported on PEMs triggers potential applications in sensing and as models for transport phenomena in cell membranes. Lipid bilayers displaying gramicidin channels are fabricated on top of polyallylamine hydrochloride (PAH) and polystyrene sulfonate (PSS) multilayer films, by the assembly of vesicles of phosphatidylcholine and phosphatidylserine, 50 : 50 M/M, carrying gramicidin (GA). Quartz crystal microbalance with dissipation shows that the vesicles with GA fuse into a bilayer. Atomic force microscopy reveals that the presence of GA alters the bilayer topography resulting in depressions in the bilayer of around 70 nm in diameter. Electrochemical impedance spectroscopy (EIS) studies show that supported bilayers carrying GA have smaller resistances than the bilayers without GA. Lipid layers carrying GA display a higher conductance for K+ than for Na+ and are blocked in the presence of Ca2+. PMID- 29143834 TI - Cobalt, nickel, and iron complexes of 8-hydroxyquinoline-di(2-picolyl)amine for light-driven hydrogen evolution. AB - Novel cobalt, nickel, and iron complexes based on the pentadentate 8 hydroxyquinoline-di(2-picolyl)amine ligand were synthesized and thoroughly characterized. X-ray structures of both the cobalt and iron complexes were also obtained, showing the tendency to adopt a pseudo-octahedral geometry by coordination of an additional sixth ligand. These metal complexes were then studied as potential hydrogen-evolving catalysts (HECs) under both electrochemical and light-driven conditions. In particular, two different photochemical systems were tested involving either Ru(bpy)32+/ascorbic acid or Ir(ppy)2(bpy)+/TEA sensitizer/sacrificial donor couples. The electrochemical results showed that these metal complexes may behave as competent HECs. However, under photochemical conditions, only the cobalt compound displayed substantial hydrogen-evolving activity in both ruthenium- and iridium-based systems. The nickel and iron complexes, on the other hand, exhibited appreciable photocatalytic activity only in the iridium-based photochemical system, while showing negligible hydrogen evolution ability when employed in the ruthenium based one. PMID- 29143835 TI - Recent advances in quantum scattering calculations on polyatomic bimolecular reactions. AB - This review surveys quantum scattering calculations on chemical reactions of polyatomic molecules in the gas phase published in the last ten years. These calculations are useful because they provide highly accurate information on the dynamics of chemical reactions which can be compared in detail with experimental results. They also serve as quantum mechanical benchmarks for testing approximate theories which can more readily be applied to more complicated reactions. This review includes theories for calculating quantities such as rate constants which have many important scientific applications. PMID- 29143836 TI - Synthesis and properties of [7]helicene and [7]helicene-like compounds with a cyclopenta[1,2-b:4,3-b']dithiophene or dithieno[2,3-b:3',2'-d]heterole skeleton. AB - A series of [7]helicene and [7]helicene-like compounds composed of a cyclopenta[1,2-b:4,3-b']dithiophene or dithieno[2,3-b:3',2'-d]heterole moiety and two naphthalene moieties were successfully synthesized from a common synthetic intermediate, 1,1'-binaphtho[2,1-b]thiophene. Their helical structures were confirmed by X-ray crystallographic analysis. The photophysical properties of them and their benzene analogues were investigated via absorption and fluorescence spectroscopy and theoretical calculations to correlate the effect of the five-membered rings in their pi-conjugated skeleton. Through these investigations, the photophysical properties were found to largely depend on a combination of the central five-membered ring and the neighboring two aromatic rings. In particular, a combination of the central five-membered ring with electron-withdrawing character and the two neighboring thiophene rings was revealed to induce red-shifted emission. PMID- 29143837 TI - Development of a label-free Raman imaging technique for differentiation of malaria parasite infected from non-infected tissue. AB - During malarial infection, the host uses the spleen to clear the malaria parasites, however, the parasites have evolved the ability to bind to endothelial receptors in blood vessels of tissues to avoid removal, known as sequestration, and this is largely responsible for the symptoms and severity of infection. So a technique which could non-invasively diagnose tissue burden could be utilised as an aid for localised malaria diagnosis within tissue. Raman spectroscopy is a label-free imaging technique and can provide unique and chemically specific Raman 'fingerprint' spectrum of biological samples such as tissue. Within this study, Raman imaging was used to observe the changes to the molecular composition of mice spleen tissue under malarial infection, compared with non-infected samples. From analysis of the Raman imaging data, both tissue types showed very similar spectral profiles, which highlighted that their biochemical compositions were closely linked. Principal component analysis showed very clear separation of the two sample groups, with an associated increase in concentration of heme-based Raman vibrations within the infected dataset. This was indicative of the presence of hemozoin, the malaria pigment, being detected within the infected spleen. Separation also showed that as the hemozoin content within the tissue increased, there was a corresponding change to hemoglobin and some lipid/nucleic acid vibrations. These results demonstrate that Raman spectroscopy can be used to easily discriminate the subtle changes in tissue burden upon malarial infection. PMID- 29143838 TI - Organocatalyst-assisted Ar-18F bond formation: a universal procedure for direct aromatic radiofluorination. AB - A metal free, phosphane-catalysed protocol for C-F bond formation based on ipso elimination of iodanes is described. The reaction proceeds in significantly higher yield and with markedly reduced variability of yields (yield range) than previously described procedures. Rapid and efficient radiofluorination is achieved using unobjectionable chemical reagents with precedence in routine radiotracer production. With operational ease and mild conditions, the method promises a high potential for radiolabelling of biomolecules. PMID- 29143839 TI - Real-time observation of the photoionization-induced water rearrangement dynamics in the 5-hydroxyindole-water cluster by time-resolved IR spectroscopy. AB - Solvation plays an essential role in controlling the mechanism and dynamics of chemical reactions in solution. The present study reveals that changes in the local solute-solvent interaction have a great impact on the timescale of solvent rearrangement dynamics. Time-resolved IR spectroscopy has been applied to a hydration rearrangement reaction in the monohydrated 5-hydroxyindole-water cluster induced by photoionization of the solute molecule. The water molecule changes the stable hydration site from the indolic NH site to the substituent OH site, both of which provide a strongly attractive potential for hydration. The rearrangement time constant amounts to 8 +/- 2 ns, and is further slowed down by a factor of more than five at lower excess energy. These rearrangement times are slower by about three orders of magnitude than those reported for related systems where the water molecule is repelled from a repulsive part of the interaction potential toward an attractive well. The excess energy dependence of the time constant is well reproduced by RRKM theory. Differences in the reaction mechanism are discussed on the basis of energy relaxation dynamics. PMID- 29143840 TI - Nonaffine deformation and tunable yielding of colloidal assemblies at the air water interface. AB - Silica nanoparticles trapped at the air-water interface form a 2D solid state with amorphous order. We propose a theoretical model to describe how this solid like state deforms under a shear strain ramp up to and beyond a yielding point which leads to plastic flow. The model accounts for all the particle-level and many-body physics of the system: nonaffine displacements, local connectivity and its evolution in terms of cage-breaking, and interparticle interactions mediated by the particle chemistry and colloidal forces. The model is able to reproduce experimental data with only two non-trivial fitting parameters: the relaxation time of the cage and the viscous relaxation time. The interparticle spring constant contains information about the strength of interparticle bonding which is tuned by the amount of surfactant that renders the particles hydrophobic and mutually attractive. This framework opens up the possibility of quantitatively tuning and rationally designing the mechanical response of colloidal assemblies at the air-water interface. Also, it provides a mechanistic explanation for the observed non-monotonic dependence of yield strain on surfactant concentration. PMID- 29143841 TI - Ionic liquids as stationary phases for fatty acid analysis by gas chromatography. AB - The present paper provides an overview of the application of ionic liquid (IL) columns for GC analysis of fatty acid methyl esters (FAMEs). Although their separation can be carried out utilizing GC columns containing polar stationary phases, some ILs have been employed as stationary phases, either commercial or laboratory made, in GC analysis. Monodimensional and bidimensional GC methods have been optimized in order to achieve the best separation especially considering the geometric and positional isomers of unsaturated fatty acids. Several methods for the analysis of trans-fatty acids have also been reported. The use of GC-GC, using either the same IL columns or different columns in the first and second dimensions, allowed the separation of a large number of FAMEs. The application of the IL columns for GC analysis of FAMEs in different types of real samples is described, e.g., oil of different nature (fish, flaxseed, and olive), margarine and butter, biodiesel, milk, bacteria etc. PMID- 29143842 TI - Wrinkling formation in simply-supported graphenes under tension and compression loadings. AB - Wrinkles in supported graphenes can be formed either by uniaxial compression or uniaxial tension beyond a certain critical load depending on the mode of loading. In the first case, the wrinkling direction is normal to the compression axis whereas in tension, wrinkles of the same pattern are formed parallel to the loading direction due to Poisson's (lateral) contraction. Herein we show by direct AFM observations that in simply-supported graphenes such instabilities appear as periodic wrinkles over existing stochastic undulations caused by the underlying-substrate-roughness. The critical strain for the generation of these wrinkles in both tension and compression is less than 1% which particularly for the former is far lower than the predicted tensile strain to fracture of suspended graphene estimated at ~30%. Based on these findings, a constitutive model that provides the critical tensile strain for induced buckling in the lateral direction is proposed that depends only on the graphene-support interaction and not on the nature of the substrate. Understanding the wrinkling failure of graphenes under strain is of paramount importance as it leads to new threshold limits beyond which the physical-mechanical properties of graphene are impaired. PMID- 29143843 TI - Mitochondria-targetable carbon quantum dots for differentiating cancerous cells from normal cells. AB - In this study, a series of fluorescent carbon quantum dots (or carbon dots, CDs) with inherent mitochondrial targeting/imaging and cancerous/normal cell differentiation capabilities were prepared by a one-pot solvothermal treatment of glycerol and a silane molecule. Glycerol acted as a solvent and carbon source, and the silane molecule acted as a passivation agent. The as-prepared CDs could specifically and stably (for at least 24 h) visualize mitochondria of various types of cells without the introduction of mitochondria-targeting ligands (such as triphenylphosphonium). In addition, the CDs exhibited extraordinary features including facile synthesis, good water solubility, favorable biocompatibility, and excellent photostability as compared to commercial mitochondrial probes. Moreover, the CDs could efficiently distinguish cancerous cells from normal cells with high fluorescence contrast due to differences in their mitochondrial membrane potentials and substance uptake efficiencies. More importantly, to the best of our knowledge, the present study provides the first example of using CDs to distinguish cancerous cells from normal cells. The remarkable features of mitochondria-targeted imaging and cancerous cell recognition make the CDs an excellent fluorescent probe for various biomedical applications. PMID- 29143844 TI - Charged probes: turn-on selective fluorescence for RNA. AB - RNA controls many biological processes. The selective detection and imaging of RNA molecules can provide information about their location, kinetics, and functions at the cellular level. The imidazolium-based positively charged probes would play a significant role in the deep investigation of RNA biomolecules to check their therapeutic potential and aid in the future rational molecular and drug design. PMID- 29143845 TI - Pulse laser-induced fragmentation of carbon quantum dots: a structural analysis. AB - Carbon quantum dots (CQDs) have attracted enormous interest in recent years owing to their low cytotoxicity, excellent biocompatibility and strong fluorescence. They have been successfully employed in sensor, bio-imaging, and drug carrier applications. A complete understanding of their core-surface structure is essential for tuning their physical and chemical properties for various applications. Conventional characterizations of CQDs are conducted with electron microscopy or spectroscopy, such as transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy and Raman spectroscopy. However, these techniques cannot fully resolve the core-surface structure of CQDs. In this study, we attempt to analyze the structures of CQDs by laser desorption/ionization mass spectrometry (LDI-MS) using three model CQDs synthesized from citric acid (CA-CQDs), diammonium citrate (AC-CQDs) and spermidine trihydrochloride (Spd-CQDs). Both CA-CQDs and AC-CQDs produced anionic carbon cluster ions ([Cn]-, n = 4-9) during the laser desorption/ionization process. Additionally, AC-CQDs produced fragments containing C, N, and O that appeared at m/z values of 41.999, 91.015, and 107.008, which were identified by 15N isotopes as [CNO]-, [CH3N2O3]-, and [CH3N2O4]-, respectively. By contrast, subjecting Spd-CQDs to the same analysis did not yield carbon cluster ions ([Cn] ); instead, strong chlorine-associated ions with a unique isotopic pattern were observed, strongly implying that Spd-CQDs contain chlorine. The lack of carbon cluster ion formation in nitrogen- and chlorine-doped Spd-CQDs indicates that nitrogen and chlorine are abundantly and homogenously doped in the CQDs. We also found a shot-dependent fragmentation behavior for AC-CQDs that produces nitrogen- and oxygen-containing ions and carbon cluster ions ([Cn]-) during initial fragmentation of the surface, with a gradual destruction of the nanocrystalline carbon core after additional shots. These results suggest that LDI-MS can be used as a tool for analyzing the core-surface structure of CQDs, particularly when it contains a heteroatom doped carbon core with various surface functional groups containing nitrogen, oxygen and halogens. PMID- 29143846 TI - Organocatalytic umpolung annulative dimerization of ynones for the synthesis of 5 alkylidene-2-cyclopentenones. AB - A novel phosphine-catalyzed umpolung [3 + 2]-annulative dimerization of ynones was developed to furnish functionally rich 5-alkylidene-2-cyclopentenones. In this protocol, ynone acts as both C2 and C3 synthons, which undergo [3 + 2] annulative dimerization. PMID- 29143847 TI - 1,3-Dibromo-5,5-dimethylhydantoin mediated oxidative amidation of terminal alkenes in water. AB - A variety of terminal alkenes were converted to the corresponding amides in yields of 25 to 86% in water via treatment with 1,3-dibromo-5,5 dimethylhydantoin, followed by reaction with molecular iodine and aq. NH3 (or amine) in one pot. This metal- and organic solvent-free protocol is not only suitable for styrene derivatives, but also, for the first time, works well on terminal aliphatic alkenes. PMID- 29143848 TI - Spirals and helices by asymmetric active surface growth. AB - We show that spiral and helical Au nanowires can be directly grown via the active surface growth mechanism. The formation of spiral nanowires as opposed to straight nanowires is not triggered by the presence of a particular reactant, but controlled by the ratio of reactant concentrations. We propose that the asymmetric blocking of the Au-substrate interface induces imbalanced growth of the nanowire, causing it to curve. Blocking a single corner of the active interface leads to spiral nanowires whereas blocking two corners leads to helical nanowires. Spiral and helical nanowires become more frequent when the diffusion of Au is the limiting factor, as the reactant ratio falls below a critical value. The transition from helices to spirals and finally to nearly straight nanowires indicates a gradual loss of the blocked sites, hence supporting the asymmetric blocking mechanism. PMID- 29143849 TI - Water system unreliability and diarrhea incidence among children in Guatemala. AB - OBJECTIVES: This article examines the effect of water system unreliability on diarrhea incidence among children aged 0-5 in Guatemala. METHODS: We use secondary data from a nationally representative sample of 7579 children to estimate the effects of uninterrupted and interrupted water services on diarrhea incidence. The national scope of this study imposes some methodological challenges due to unobserved geographical heterogeneity. To address this issue, we estimate mixed-effects logit models that control for unobserved heterogeneity by estimating random effects of selected covariates that can vary across geographical areas (i.e. water system reliability). RESULTS: Compared to children without access to piped water, children with uninterrupted water services have a lower probability of diarrhea incidence by approximately 33 percentage points. Conversely, there is no differential effect between children without access and those with at least one day of service interruptions in the previous month. Results also confirm negative effects of age, female gender, spanish language, and garbage disposal on diarrhea incidence. CONCLUSIONS: Public health benefits of piped water are realized through uninterrupted provision of service, not merely access. Policy implications are discussed. PMID- 29143850 TI - ? PMID- 29143851 TI - Phylogenetic diversity and distribution of bacterial and archaeal amoA genes in the East China Sea during spring. AB - Microbial nitrification is a key process in the nitrogen cycle in the continental shelf ecosystems. The genotype compositions and abundance of the ammonia monooxygenase gene, amoA, derived from ammonia-oxidizing archaea (AOA) and bacteria (AOB) in two size fractions (2-10 and 0.2-2 um), were investigated in the East China Sea (ECS) in May 2008 using PCR-denaturing gradient gel electrophoresis (DGGE) and quantitative PCR (qPCR). Four sites were selected across the continental shelf edge: continental shelf water (CSW), Kuroshio branch water (KBW), transition between CSW and KBW (TCSKB) and coastal KBW (CKBW). The gene copy numbers of AOA-amoA were higher than those of AOB-amoA in ECS. The relative abundance of amoA to the total 16S rRNA gene level reached approximately 15% in KBW and CKBW for the free-living fraction of AOA, whereas the level was less than 0.01% throughout ECS for the AOB. A cluster analysis of the AOA-amoA DGGE band pattern showed distinct genotype compositions in CSW in both the size fractions and in the surface of the TCSKB and KBW. Sequences of the DGGE bands were assigned to two clades. One of the clades exclusively consisted of sequences derived from the 2-10-um fraction. This study revealed that AOA-amoA abundance dominated over AOB-amoA throughout the ECS, whereas the genotype composition of AOA-amoA were distributed heterogeneously across the water masses. Additionally, this is the first report showing the distribution of AOA-amoA genotypes characteristic to particle-associated AOA in the offshore of the East China Sea. PMID- 29143852 TI - Exposure to Sublethal Ammonia Concentrations Alters the Duration and Intensity of Agonistic Interactions in the Crayfish, Orconectes rusticus. AB - Crayfish extract information from chemical stimuli during social interactions. Commercial fertilizers increase background ammonia concentrations which may interfere with chemical communication. Background pollution can disrupt perception of chemical stimuli in three ways: masking, sensory impairment, physiological impairment or in combination. We investigated whether exposure to ammonia alters agonistic behavior. Crayfish pairs exposed to 0.9 mg/L ammonia fought for a longer duration, while crayfish exposed to 9.0 mg/L ammonia fought for a shorter duration. Altering activity patterns of crayfish may alter crayfish populations leading to a nonproportional impact because of their importance to the structure and function of aquatic ecosystems. PMID- 29143853 TI - Sex-specific risk assessment of PFHxS using a physiologically based pharmacokinetic model. AB - Perfluorohexanesulfonate (PFHxS), which belongs to the group of perfluoroalkyl and polyfluoroalkyl substances (PFASs), has been extensively used in industry and subsequently detected in the environment. Its use may be problematic, as PFHxS is known to induce neuronal cell death, and has been associated with early onset menopause in women and with attention deficit/hyperactivity disorder. Due to these impending issues, the aim of this study is to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for PFHxS in male and female rats, and apply this to a human health risk assessment. We conducted this study in vivo after the oral or intravenous administration of PFHxS in male (dose of 10 mg/kg) and female rats (dose of 0.5-10 mg/kg). The biological samples consisted of plasma, nine tissues, urine, and feces. We analyzed the sample using ultra liquid chromatography coupled tandem mass spectrometry (UPLC-MS/MS). Our findings showed the tissue-plasma partition coefficients for PFHxS were highest in the liver. The predicted rat plasma and tissue concentrations using a simulation fitted well with the observed values. We extrapolated the PBPK model in male and female rats to a human PBPK model of PFHxS based on human physiological parameters. The reference doses of 0.711 ug/kg/day (male) and 0.159 ug/kg/day (female) and external doses of 0.007 ug/kg/day (male) and 0.006 ug/kg/day (female) for human risk assessment were estimated using Korean biomonitoring values. This study provides valuable insight into human health risk assessment regarding PFHxS exposure. PMID- 29143854 TI - In vitro biotransformation of pyrrolizidine alkaloids in different species. Part I: Microsomal degradation. AB - Pyrrolizidine alkaloids (PA) are secondary metabolites of certain flowering plants. The ingestion of PAs may result in acute and chronic effects in man and livestock with hepatotoxicity, mutagenicity, and carcinogenicity being identified as predominant effects. Several hundred PAs sharing the diol pyrrolizidine as a core structure are formed by plants. Although many congeners may cause adverse effects, differences in the toxic potency have been detected in animal tests. It is generally accepted that PAs themselves are biologically and toxicologically inactive and require metabolic activation. Consequently, a strong relationship between activating metabolism and toxicity can be expected. Concerning PA susceptibility, marked differences between species were reported with a comparatively high susceptibility in horses, while goat and sheep seem to be almost resistant. Therefore, we investigated the in vitro degradation rate of four frequently occurring PAs by liver enzymes present in S9 fractions from human, pig, cow, horse, rat, rabbit, goat, and sheep liver. Unexpectedly, almost no metabolic degradation of any PA was observed for susceptible species such as human, pig, horse, or cow. If the formation of toxic metabolites represents a crucial bioactivation step, the found inverse conversion rates of PAs compared to the known susceptibility require further investigation. PMID- 29143856 TI - Correction to: The all-inside meniscal repair technique has less risk of injury to the lateral geniculate artery than the inside-out repair technique when suturing the lateral meniscus. AB - The author claims that his name is incorrectly listed on PubMed. The first name should be Jorge and the last name should be Diaz Heredia. PMID- 29143857 TI - Correction to: Effect of patient positioning in axillary nerve safety during arthroscopic inferior glenohumeral ligament plication. AB - The author claims that his name is incorrectly listed on PubMed. The first name should be Jorge and the last name should be Diaz Heredia. On SpringerLink the name is listed correctly, but on PubMed he is listed as Heredia JD. PMID- 29143855 TI - Considerations and guidelines for mouse metabolic phenotyping in diabetes research. AB - Mice are the most commonly used species in preclinical research on the pathophysiology of metabolic diseases. Although they are extremely useful for identifying pathways, mechanisms and genes regulating glucose and energy homeostasis, the specificities of the various mouse models and methodologies used to investigate a metabolic phenotype can have a profound impact on experimental results and their interpretation. This review aims to: (1) describe the most commonly used experimental tests to assess glucose and energy homeostasis in mice; (2) provide some guidelines regarding the design, analysis and interpretation of these tests, as well as for studies using genetic models; and (3) identify important caveats and confounding factors that must be taken into account in the interpretation of findings. PMID- 29143858 TI - Correction to: Young athletes return too early to knee-strenuous sport, without acceptable knee function after anterior cruciate ligament reconstruction. AB - The author claims that his name is incorrectly listed on PubMed. The first name should be Eric and the last name should be Hamrin Senorski. On SpringerLink the name is listed correctly, but on PubMed he is listed as Senorski EH. PMID- 29143859 TI - Socioeconomic risk factors for hospital admittance due to a suicide attempt in Belgium: a population-based study using administrative data. AB - PURPOSE: This population-based study aims to investigate socio-economic factors, depression and psychosis as independent risk factors for a suicide attempt that requires hospitalization, and estimate the incidence of suicide attempts. METHODS: Individual-level administrative data were analysed that were collected for all members of the Socialist Health Insurance Schemes in Belgium during the period 2011-2013 (N = 3,156,030) in the context of the financing of the health care services provided. Bivariate and multivariate odds ratios were calculated for multiple socio-economic factors, socio-demographic factors and the presence of depression and psychosis. RESULTS: During the study period, 4063 persons were hospitalized due to a suicide attempt. The incidence of suicide attempts with hospital admittance was 48.0/100,000 persons/year. Being unemployed, incapable of work over a shorter or longer period with substitute income, living on social welfare, having an increased healthcare reimbursement, living alone and using antidepressants or antipsychotics were identified as independent factors that contributed to the risk of hospitalization due to a suicide attempt. CONCLUSIONS: Persons from low income groups, however defined, those living alone, or persons using antidepressants or antipsychotics are at an increased risk of attempting suicide and needing hospitalization for it. A social policy that focuses on the improvement of these factors or their consequences may be expected to have a favourable effect on the number of suicide attempts. Funding of mental health care should also better match population needs. PMID- 29143861 TI - Migraine with prolonged aura: phenotype and treatment. AB - We review the published literature on migraine with prolonged aura (PA), specifically with regards to the phenotype and treatment options. PA is not uncommon. A recent study found that about 17% of migraine auras are prolonged and that 26% of patients with migraine with aura have experienced at least one PA. The characteristics of PA are similar to most typical auras with the exception of a higher number of aura symptoms (in particular sensory and/or dysphasic). There are no well-established treatments at present which target the aura component of migraine. Other than case reports, there have been open-label studies of lamotrigine and greater occipital nerve blocks. The only randomised, blinded, controlled trial to date has been of nasal ketamine showing some reduction in aura severity but not duration. A small open-labelled pilot study of amiloride was also promising. Larger randomised, controlled trials are needed to establish whether any of the existing or novel compounds mentioned are significantly effective and safe. PMID- 29143862 TI - A20 prevents obesity-induced development of cardiac dysfunction. AB - : Obesity and an increased free fatty acid (FFA) level are tightly linked, leading to aberrant oxidative stress, inflammation, apoptosis, and progression to cardiovascular disorders. A20 is a ubiquitin-modifying enzyme that plays a significant role in the negative regulation of inflammatory response. Here, we study the role of A20 in obesity-induced heart injury and explore the underlying mechanisms. A20 expression was first increased in mouse hearts after 4 weeks of a high-fat diet (HFD) and then was gradually decreased in the following 20 weeks. Cardiac-specific supplementation with A20 via recombinant adeno-associated virus subtype 9 (rAAV9) could reverse myocardial dysfunction, hypertrophy and fibrosis in mice exposed to 24 weeks of HFD, along with reduced cardiac apoptosis and inflammation. The beneficial actions of A20 were closely associated with its ability to repress TAK1 activation and the downstream inhibition of P38, JNK1/2, and the NF-kappaB pathway. TAK1 over-expression could efficiently retard the above-mentioned positive effects of A20. Therefore, our data uncovered a novel function of A20 in obesity-induced heart injury and presented a therapeutic approach for the treatment of obesity-related cardiovascular disorders. KEY MESSAGES: A20 expression is downregulated in obesity-related hearts. A20 ameliorates HFD-induced lipid accumulation, ROS, inflammation, apoptosis, hypertrophy, fibrosis, and cardiac dysfunction. A20 represses TAK1 activation and the downstream inhibition of P38, JNK1/2, and the NF-kappaB pathway. TAK1 overexpression retards the beneficial effects of A20. PMID- 29143863 TI - Morphometric properties of the latissimus dorsi muscle in human fetuses for flap surgery. AB - PURPOSE: Although latissimus dorsi (LD) flaps are extensively used in a wide range of interventions, fetus studies on this subject are quite limited. This study aims to obtain detailed information about the morphometric features of LD, thoracodorsal artery (TDA) and nerve (TDN). METHODS: The study was carried out on both sides of 50 formalin-fixed human fetuses (22 male/28 female) with a mean gestational age of 24.5 +/- 4.7 (range 18-36) weeks, which were in the inventory of Anatomy Department of Mersin University Faculty of Medicine. Dimensions of LD, lengths and width of TDA and TDN were measured. Surface area of LD was calculated using digital image analysis software. RESULTS: All samples had LD muscle. Neither gender nor side-significant differences were observed in relation with the numerical data of LD, TDN and TDA. Linear function of surface area was calculated as "y = - 1767.532 + 114.582 * Age (weeks)". LD was attached directly to the posterior part of iliac crest in 59 of 100 sides meanwhile in the rest 41, it was attached by the thoracolumbar fascia. TDA gave a branch to serratus anterior in 96 cases and 2 branches in 4 cases. TDN passed superficial to TDA in 84 and deep to TDA in 16 samples. TDN had bifurcation in 93, trifurcation in 6 and tetrafurcation in 1 side. CONCLUSION: Data obtained from this study can be useful for estimating the sizes of LD and related neurovascular structures, especially in neonate surgeries. Linear function of LD surface area can be helpful to design the flap dimensions in newborn surgeries. A throughout knowledge about the branching pattern of TDN and its location-wise relation with TDA should be kept in mind to prevent possible complications during harvesting LD flaps and TDN grafts. PMID- 29143864 TI - Correction to: Cell type-specific localization of Ephs pairing with ephrin-B2 in the rat postnatal pituitary gland. AB - The published online version contains mistakes in Table 1, Table 2 and Fig. 2. See below for the corrected Tables and Figure. PMID- 29143865 TI - Paraneoplastic pemphigus without detectable anti-plakin antibodies in a patient with non-Hodgkin lymphoma. PMID- 29143867 TI - Correction to: Metoclopramide role in preventing ileus after cesarean, a clinical trial. AB - The original publication of this paper contains an error. PMID- 29143866 TI - Haplotype analysis of the germacrene A synthase gene and association with cynaropicrin content and biological activities in Cynara cardunculus. AB - Cynara cardunculus: L. represents a natural source of terpenic compounds, with the predominant molecule being cynaropicrin. Cynaropicrin is gaining interest since it has been correlated to anti-hyperlipidaemia, antispasmodic and cytotoxicity activity against leukocyte cancer cells. The objective of this work was to screen a collection of C. cardunculus, from different origins, for new allelic variants in germacrene A synthase (GAS) gene involved in the cynaropicrin biosynthesis and correlate them with improved cynaropicrin content and biological activities. Using high-resolution melting, nine haplotypes were identified. The putative impact of the identified allelic variants in GAS protein was evaluated by bioinformatic tools and polymorphisms that putatively lead to protein conformational changes were described. Additionally, cynaropicrin and main pentacyclic triterpenes contents, and antithrombin, antimicrobial and antiproliferative activities were also determined in C. cardunculus leaf lipophilic-derived extracts. In this work we identified allelic variants with putative impact on GAS protein, which are significantly associated with cynaropicrin content and antiproliferative activity. The results obtained suggest that the identified polymorphisms should be explored as putative genetic markers correlated with biological properties in Cynara cardunculus. PMID- 29143868 TI - Fishtail deformity of the distal humerus: association with osteochondritis dissecans of the capitellum. AB - BACKGROUND: Fishtail deformity is a rare deformity of the humerus exhibiting concavity of the lateral trochlea, resulting in ulnotrochlear joint derangement. We wanted to share our experience that osteochondritis dissecans of the capitellum is a common associated complication. OBJECTIVE: To summarize imaging of fishtail deformity in children centered on complications of the radiocapitellar joint. MATERIALS AND METHODS: From the radiology information system, we identified all patients <18 years with the diagnosis of fishtail deformity. We included only patients with V-shaped deformity of the distal humerus due to concavity at the lateral trochlea (fishtail deformity). Each patient's initial injury, most recent radiograph and available MRI were evaluated for radiocapitellar joint derangement. RESULTS: Seven patients (4 males) with a mean age of 12.9 years (range: 9.7 to 14.4 years) were identified. Radiocapitellar joint abnormalities were identified in six patients including osteoarthritis (n=5), flattened and sclerotic capitellum (n=4), osteochondritis dissecans (2 associated with loose body, n=4) and radial head subluxation (n=2). In 4 patients, MRI detected changes of osteoarthritis (n=4), osteochondritis dissecans (n=2) and loose body (n=1) not identified on radiography. Two patients with osteochondritis dissecans underwent surgery and one patient has planned surgery. CONCLUSION: Radiocapitellar joint abnormalities (particularly, capitellar osteochondritis dissecans) are common in patients with fishtail deformities. MRI should be performed in these patients since some abnormalities, possibly requiring surgery, are not detected on elbow radiographs. PMID- 29143869 TI - Peripheral endocannabinoid concentrations are not associated with verbal memory impairment during MDMA intoxication. AB - BACKGROUND: Preclinical data have suggested involvement of the endocannabinoid (eCB) system in MDMA-induced memory impairment. Clinical research has shown that blockade of the 5-HT2 receptor nulls memory impairment during MDMA intoxication. Interestingly, studies have demonstrated that the eCB and the 5-HT system interact. It was hypothesized that MDMA would cause an increase in eCB concentrations together with a decrease in memory performance, and that combining MDMA with a 5-HT2 receptor blocker ketanserin would lead to a counteraction of the MDMA effects on eCB concentrations and memory. METHODS: Twenty healthy recreational polydrug users entered a double-blind placebo-controlled within subject study. Participants received a pre-treatment (ketanserin 40 mg, placebo) followed 30 min later by a treatment (MDMA 75 mg, placebo). Verbal memory was tested by means of a 30-word learning test. Endocannabinoid concentrations (anandamide (2-AG); N-arachidonylethanolamine (AEA)) were assessed in blood at baseline, before (90 min post-treatment) and after cognitive tests (150 min post treatment). RESULTS: Findings showed that MDMA impaired memory 90 min post treatment in the word learning task. This effect was a replication of previous studies using the same dose of MDMA (75 mg) and the same learning paradigm. Contrary to our hypothesis, MDMA did not affect eCB concentrations, nor did ketanserin block MDMA-induced memory impairment. Ketanserin caused an increase in AEA concentrations, 180 min after administration. CONCLUSION: Current findings suggest that peripherally measured endocannabinoids are not associated with the verbal memory deficit during MDMA intoxication. TRIAL REGISTRATION NUMBER: NTR3691. PMID- 29143870 TI - Head to head comparison of [18F] AV-1451 and [18F] THK5351 for tau imaging in Alzheimer's disease and frontotemporal dementia. AB - PURPOSE: Tau accumulation is a core pathologic change in various neurodegenerative diseases including Alzheimer's disease and frontotemporal lobar degeneration-tau. Recently, tau positron emission tomography tracers such as [18F] AV-1451 and [18F] THK5351 have been developed to detect tau deposition in vivo. In the present study, we performed a head to head comparison of these two tracers in Alzheimer's disease and frontotemporal dementia cases and aimed to investigate which tracers are better suited to image tau in these disorders. METHODS: A cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We recruited eight participants (two Alzheimer's disease, four frontotemporal dementia and two normal controls) who underwent magnetic resonance image, amyloid positron emission tomography with [18F] Florbetaben and tau positron emission tomography with both THK5351 and AV-1451. To measure regional AV1451 and THK5351 uptakes, we used the standardized uptake value ratios by dividing mean activity in target volume of interest by mean activity in the cerebellar hemispheric gray matter. RESULTS: Although THK5351 and AV-1451 uptakes were highly correlated, cortical uptake of AV-1451 was more striking in Alzheimer's disease, while cortical uptake of THK5351 was more prominent in frontotemporal dementia. THK5351 showed higher off-target binding than AV-1451 in the white matter, midbrain, thalamus, and basal ganglia. CONCLUSIONS: AV-1451 is more sensitive and specific to Alzheimer's disease type tau and shows lower off-target binding, while THK5351 may mirror non-specific neurodegeneration. PMID- 29143871 TI - Head and neck rhabdomyosarcoma in children: a 20-year retrospective study at a tertiary referral center. AB - OBJECTIVE: The purpose of this study was to assess rhabdomyosarcomas (RMS) of the head and neck in pediatric patients with regard to clinical presentation, treatment, and survival. METHODS: Data were retrospectively obtained from patient charts with regard to RMS of the head and neck diagnosed between 1996 and 2016 at a tertiary referral center. Clinical course, treatment modalities, and side effects were analyzed. Survival analysis was carried out using the Kaplan-Meier method. RESULTS: Twenty-eight patients (17 male, 11 female) with a mean age at diagnosis of 6.8 +/- 5.0 years have been included. Fourteen patients (50%) presented with painless swelling in the head and neck region and nine patients (32.1%) presented with cranial nerve deficit at initial diagnosis. The location of the majority of rhabdomyosarcomas was orbital (N = 9; 32.1%), followed by parapharyngeal (n = 4; 14.2%) and sinonasal (n = 3; 10.7%). All patients (n = 28; 100%) received polychemotherapy, additional adjuvant radiation therapy was carried out in 24 patients (85.7%), and surgery was performed in 12 cases (42.9%). The 5-year overall survival was 91.3%, and median progression-free survival was 46 +/- 67.4 months. Common side effects resulting from chemotherapy and radiation therapy included neutropenia, mucositis, nausea and vomiting, and radiodermatitis, long-term side effects included microsomia and facial mutilation. CONCLUSION: Multimodality treatment of rhabdomyosarcomas of the head and neck in pediatric patients may lead to a 5-year overall survival of up to 91.3%. PMID- 29143874 TI - Letter to the editor. PMID- 29143872 TI - Concomitant hook of hamate fractures in patients with scaphoid fracture: more common than you might think. AB - OBJECTIVE: The scaphoid is the most commonly fractured carpal bone. The presence of a concomitant hook of hamate fracture is of particular relevance given that it is often occult on routine wrist/scaphoid radiographs and that hook of hamate fractures are prone to symptomatic non-union, resulting in chronic ulnar wrist pain. Prompt diagnosis and immobilisation/fixation may minimise such complications. Our study is aimed at assessing the frequency of concomitant hook of hamate fractures in patients with scaphoid fractures. METHODS: Hook of hamate fracture is often occult on wrist/scaphoid radiographs. Hence, we identified all 2,568 CT and MRI studies performed to investigate scaphoid fracture at our institution from April 2005 to March 2016. Three hundred and twelve out of 2,568 cases were confirmed to have a scaphoid fracture. Images were then retrospectively reviewed by a Consultant Musculoskeletal Radiologist and Musculoskeletal Radiologist Trainee to assess for the presence of concomitant hook of hamate fracture and, if present, whether this was identified on initial reporting. RESULTS: Concomitant hook of hamate fracture was identified in 10.3% of cases (32 out of 312, 30 on CT, 2 on MRI); most were minimally/non-displaced. Sixty percent of fractures identified on CT were missed on the initial review (18 out of 30). Both cases identified on MRI had been initially reported. CONCLUSION: Scaphoid fracture is associated with higher than expected rates of concomitant hook of hamate fracture. Given the potential morbidity associated with hook of hamate fracture, this should be considered a review area when investigating scaphoid injury. These fractures are often minimally displaced, hence easily overlooked on CT. MRI may therefore be superior when investigating radiographically occult scaphoid fractures. PMID- 29143875 TI - The Role of 18F-FDG PET/CT and PET/MRI in Pancreatic Ductal Adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) remains a difficult disease to treat and continues to portend a poor prognosis, as most patients are unresectable at diagnosis. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with CT (PET/CT) has been a cornerstone in oncological imaging of different cancers; however, the role of PET/CT in PDAC is continually evolving and currently not well established. Studies have shown the potential of PET/CT in guiding the management of patients with PDAC, with possible added benefit over anatomic imaging with CT or MRI in certain scenarios. PET/CT may be useful in diagnosis, initial staging, treatment response assessment, differentiation of recurrent tumor from post-treatment fibrosis, and radiotherapy planning. Additionally, PET/CT may be a cost-effective modality due to upstaging of patients originally deemed as surgical candidates. Recently, the advent of simultaneous PET/MRI represents an exciting advancement in hybrid functional imaging with potential applications in the imaging of PDAC. The advantages of PET/MRI include simultaneous acquisition to improve registration of fusion images, lower radiation dose, superior soft tissue contrast, and availability of multiparametric imaging. Studies are underway to evaluate the utility of PET/MRI in PDAC, including in initial staging and treatment response assessment and to determine the subgroup of patients that will benefit from PET/MRI. Further studies are warranted in both PET/CR and PET/MRI to better understand the role of these modalities in PDAC. PMID- 29143876 TI - Deregulation of Genes Associated with Alternate Drug Resistance Mechanisms in Mycobacterium tuberculosis. AB - Alternate mechanisms of drug resistance involving intrinsic defense pathways play an important role in development of drug resistance. Deregulation of drug efflux, cellular metabolism, and DNA repair have been indicated to have effect on drug tolerance and persistence. Here we chose eight genes from these pathways to investigate their association with development of multidrug resistance (MDR). We generated mono drug resistant and MDR strains of rifampicin and isoniazid and examined the differential expression of genes belonging to efflux, DNA repair and cell wall lipid synthesis pathways. Rv1687c, recB, ppsD and embC genes showed significant (P <0.05) upregulation in mono-resistant (both rifampicin and isoniazid) as well as MDR strains. mmr showed significant upregulation with rifampicin resistance while Rv1457c showed significant upregulation only with mono-resistant strains. Highest expression change was observed with Rv1687c and ppsD. The study identified potential key genes that are significantly associated with development of drug resistance in vitro. These genes may help identify clinical strains predisposed to acquiring drug resistance in patients during the course of treatment or help in management of MDR forms of tuberculosis. PMID- 29143877 TI - FT-MIR and NIR spectral data fusion: a synergetic strategy for the geographical traceability of Panax notoginseng. AB - Three data fusion strategies (low-llevel, mid-llevel, and high-llevel) combined with a multivariate classification algorithm (random forest, RF) were applied to authenticate the geographical origins of Panax notoginseng collected from five regions of Yunnan province in China. In low-level fusion, the original data from two spectra (Fourier transform mid-IR spectrum and near-IR spectrum) were directly concatenated into a new matrix, which then was applied for the classification. Mid-level fusion was the strategy that inputted variables extracted from the spectral data into an RF classification model. The extracted variables were processed by iterate variable selection of the RF model and principal component analysis. The use of high-level fusion combined the decision making of each spectroscopic technique and resulted in an ensemble decision. The results showed that the mid-level and high-level data fusion take advantage of the information synergy from two spectroscopic techniques and had better classification performance than that of independent decision making. High-level data fusion is the most effective strategy since the classification results are better than those of the other fusion strategies: accuracy rates ranged between 93% and 96% for the low-level data fusion, between 95% and 98% for the mid-level data fusion, and between 98% and 100% for the high-level data fusion. In conclusion, the high-level data fusion strategy for Fourier transform mid-IR and near-IR spectra can be used as a reliable tool for correct geographical identification of P. notoginseng. Graphical abstract The analytical steps of Fourier transform mid-IR and near-IR spectral data fusion for the geographical traceability of Panax notoginseng. PMID- 29143878 TI - Sensitive mass spectrometric assay for determination of 15-deoxy-Delta12,14 prostaglandin J2 and its application in human plasma samples of patients with diabetes. AB - The determination of individual prostaglandins (PG) in humans is mainly performed in urine samples. The quantification of PGs in human plasma could improve the understanding of particular PG species under various physiological and pathological conditions. 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) is a dehydrated downstream product of PGD2 and is of high interest due to its recently discovered anti-inflammatory effects. Increasing availability of highly sensitive mass spectrometry allows the quantification of low abundant biomarkers like 15d PGJ2 in human plasma samples. Herein, a sensitive LC-MS/MS method for the determination of 15d-PGJ2 was established. The method was validated according to the guidance of the American Food and Drug Administration and tested in plasma samples from patients with poorly controlled diabetes, considered to be a pro inflammatory condition. Extraction of 15d-PGJ2 was achieved with an easy-to-use liquid-liquid extraction by ethyl acetate following a methanol precipitation. The lower limit of quantification was 2.5 pg mL-1 and linearity (R 2 = 0.998) was guaranteed between 2.5 and 500 pg mL-1 for 15d-PGJ2. Selectivity was assured by the use of two individual mass transitions (qualifier and quantifier). Precision and accuracy were validated in an inter- and intraday assay with a coefficient of variation below 11.8% (intraday) and 14.7% (interday). In diabetic patients with an HbA1C > 9%, increased plasma concentrations of 15d-PGJ2 compared to control plasma were measured. 15d-PGJ2 correlated negatively with the inflammation marker C-reactive protein. The developed LC-MS/MS method represents a new possibility to quantify 15d-PGJ2 with high specificity in human plasma samples. This may contribute to a better understanding of the potential anti-inflammatory effects of 15d-PGJ2 in severe long-term pro-inflammatory disorders like diabetes, cancer, or cardiovascular disease. PMID- 29143879 TI - Comparison of analytical tools appropriate for identification of proteinaceous additives in historical mortars. AB - Natural organic additives such as eggs, lard, resins, and oils have been added to mortars since ancient times, because the ancient builders knew of their positive effect on the mortar quality. The tradition of adding organic materials to mortars was commonly handed down only verbally for thousands years. However, this practice disappeared in the nineteenth century, when the usage of modern materials started. Today, one of the most recent topics in the industry of building materials is the reusing of natural organic materials and searching for the forgotten ancient recipes. The research of the old technological approaches involves currently the most advanced analytical techniques and methods. This paper is focussed on testing the possibility of identification of proteinaceous additives in historical mortars and model mortar samples containing blood, bone glue, curd, eggs and gelatine, by Fourier transform infrared (FTIR) and Raman spectroscopy, gas chromatography - mass spectrometry (GC-MS), matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS), liquid chromatography-electrospray ionisation-quadrupole-time of flight mass spectrometry (LC-ESI-Q-TOF MS) and enzyme-linked immunosorbent assay (ELISA). All these methods were applied to the mortar sample taken from the interior of the medieval (sixteenth century) castle in Namest nad Oslavou in the Czech Republic and their comparison contributed to the rough estimation of the protein additive content in the mortar. The obtained results demonstrate that only LC-ESI-Q-TOF MS, MALDI-TOF MS and ELISA have the sufficiently low detection limits that enable the reliable identification of collagens in historical mortars. Graphical abstract Proteomics analyses of historical mortars. PMID- 29143880 TI - Effects of heat waves on daily excess mortality in 14 Korean cities during the past 20 years (1991-2010): an application of the spatial synoptic classification approach. AB - The aims of this study are to explore the "offensive" summer weather types classified under the spatial synoptic classification (SSC) system and to evaluate their impacts on excess mortality in 14 Korean cities. All-cause deaths per day for the entire population were examined over the summer months (May-September) of 1991-2010. Daily deaths were standardized to account for long-term trends of subcycles (annual, seasonal, and weekly) at the mid-latitudes. In addition, a mortality prediction model was constructed through multiple stepwise regression to develop a heat-health warning system based on synoptic climatology. The result showed that dry tropical (DT) days during early summer caused excess mortality due to non-acclimatization by inhabitants, and moist tropical (MT) plus and double plus resulted in greater spikes of excess mortality due to extremely hot and humid conditions. Among the 14 Korean cities, highly excess mortality for the elderly was observed in Incheon (23.2%, 95%CI 5.6), Seoul (15.8%, 95%CI 2.6), and Jeonju (15.8%, 95%CI 4.6). No time lag effect was observed, and excess mortality gradually increased with time and hot weather simultaneously. The model showed weak performance as its predictions were underestimated for the validation period (2011-2015). Nevertheless, the results clearly revealed the efficiency of relative and multiple-variable approaches better than absolute and single variable approaches. The results indicate the potential of the SSC as a suitable system for investigating heat vulnerability in South Korea, where hot summers could be a significant risk factor. PMID- 29143881 TI - RMCE-based insect cell platform to produce membrane proteins captured on HIV-1 Gag virus-like particles. AB - Conformationally complex membrane proteins (MPs) are therapeutic targets in many diseases, but drug discovery has been slowed down by the lack of efficient production tools. Co-expression of MPs with matrix proteins from enveloped viruses is a promising approach to obtain correctly folded proteins at the surface of virus-like particles (VLPs), preserving their native lipidic environment. Here, we implemented a site-specific recombinase-mediated cassette exchange (RMCE) strategy to establish a reusable HIV-1 Gag-expressing insect cell line for fast production of target MPs on the surface of Gag-VLPs. The Sf9 cell line was initially tagged with a Gag-GFP-expressing cassette incorporating two flipase recognition target sites (FRTs), one within the fusion linker of Gag-GFP. The GFP cassette was afterwards replaced by a Cherry cassette via flipase (Flp) recombination. The fusion of Gag to fluorescent proteins enabled high-throughput screening of cells with higher Gag expression and Flp-mediated cassette exchange ability, while keeping the functionality of the VLP scaffold unaltered. The best cell clone was then Flp-recombinated to produce Gag-VLPs decorated with a human beta2-adrenergic receptor (beta2AR). Release of a fluorescently labeled beta2AR into the culture supernatant was confirmed by immunoblotting, and its co localization with Gag-VLPs was visualized by confocal microscopy. Furthermore, the differential avidity of beta2AR-dsplaying Gag-VLPs versus "naked" Gag-VLPs to an anti-beta2AR antibody measured by ELISA corroborated the presence of beta2AR at the surface of the Gag-VLPs. In conclusion, this novel insect cell line represents a valuable platform for fast production of MPs in their native conformation, which can accelerate small-molecule and antibody drug discovery programs. PMID- 29143882 TI - Enzymatic properties of beta-N-acetylglucosaminidases. AB - beta-N-Acetylglucosaminidases (GlcNAcases) hydrolyse N-acetylglucosamine containing oligosaccharides and proteins. These enzymes produce N acetylglucosamine (GlcNAc) and have a wide range of promising applications in the food, energy, and pharmaceutical industries, such as synergistic degradation of chitin with endo-chitinases and using GlcNAc to produce sialic acid, bioethanol, single-cell proteins, and pharmaceutical therapeutics. GlcNAcases also play an important role in the dynamic balance of cellular O-linked GlcNAc levels, catabolism of ganglioside storage in Tay-Sachs disease, and bacterial cell wall recycling and flagellar assembly. In view of these important biological functions and the wide range of industrial applications of GlcNAcases, this review aims to provide a better understanding of various advances for these enzymes. It focuses on enzymatic properties of GlcNAcases, including substrate specificity, catalytic activity, pH optimum, temperature optimum, thermostability, the effects of various metal ions and organic reagents, and transglycosylation. PMID- 29143883 TI - Rooting depth varies differentially in trees and grasses as a function of mean annual rainfall in an African savanna. AB - A significant fraction of the terrestrial biosphere comprises biomes containing tree-grass mixtures. Forecasting vegetation dynamics in these environments requires a thorough understanding of how trees and grasses use and compete for key belowground resources. There is disagreement about the extent to which tree grass vertical root separation occurs in these ecosystems, how this overlap varies across large-scale environmental gradients, and what these rooting differences imply for water resource availability and tree-grass competition and coexistence. To assess the extent of tree-grass rooting overlap and how tree and grass rooting patterns vary across resource gradients, we examined landscape level patterns of tree and grass functional rooting depth along a mean annual precipitation (MAP) gradient extending from ~ 450 to ~ 750 mm year-1 in Kruger National Park, South Africa. We used stable isotopes from soil and stem water to make inferences about relative differences in rooting depth between these two functional groups. We found clear differences in rooting depth between grasses and trees across the MAP gradient, with grasses generally exhibiting shallower rooting profiles than trees. We also found that trees tended to become more shallow-rooted as a function of MAP, to the point that trees and grasses largely overlapped in terms of rooting depth at the wettest sites. Our results reconcile previously conflicting evidence for rooting overlap in this system, and have important implications for understanding tree-grass dynamics under altered precipitation scenarios. PMID- 29143884 TI - Biominerals and waxes of Calamagrostis epigejos and Phragmites australis leaves from post-industrial habitats. AB - Vascular plants are able to conduct biomineralization processes and collect synthesized compounds in their internal tissues or to deposit them on their epidermal surfaces. This mechanism protects the plant from fluctuations of nutrient levels caused by different levels of supply and demand for them. The biominerals reflect both the metabolic characteristics of a vascular plant species and the environmental conditions of the plant habitat. The SEM/EDX method was used to examine the surface and cross-sections of the Calamagrostis epigejos and Phragmites australis leaves from post-industrial habitats (coal and zinc spoil heaps). The results from this study have showed the presence of mineral objects on the surfaces of leaves of both grass species. The calcium oxalate crystals, amorphous calcium carbonate spheres, and different silica forms were also found in the inner tissues. The high variety of mineral forms in the individual plants of both species was shown. The waxes observed on the leaves of the studied plants might be the initializing factor for the crystalline forms and structures that are present. For the first time, wide range of crystal forms is presented for C. epigejos. The leaf samples of P. australis from the post industrial areas showed an increased amount of mineral forms with the presence of sulfur. PMID- 29143885 TI - Consensus-driven in-hospital cortisol assessment after ACTH-secreting pituitary adenoma resection. AB - PURPOSE: Remission from Cushing disease (CD) after pituitary adenoma resection may be predicted by a postoperative reduction in serum cortisol level. A 2008 consensus statement recommends assessing morning cortisol levels during the first postoperative week, and replacing glucocorticoid (GC) if cortisol nadir of < 2 or < 5 ug/dL is achieved. We sought to evaluate adherence to consensus recommendations following adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma resection at our tertiary medical center, and assess time to cortisol nadir to better define the window for assessment and intervention. METHODS: We retrospectively analyzed data extracted from in-hospital electronic medical records for CD surgeries between January 1991 and September 2015. We compared cortisol levels and collection times, ACTH measurement, and postoperative and discharge GC treatment before and after consensus statement publication in July 2008. RESULTS: 107 surgeries were performed in 92 patients with CD. After 2008, more surgeries had at least one cortisol value assessed (67.9% before vs. 91.3% after, p = 0.033), with median initial cortisol measurement at 14 h post-surgery. However, ACTH measurement remained unchanged (42.9% vs. 43.5%; p > 0.99). Cortisol collection during GC treatment tended to increase (32.7% vs. 57.1%; p = 0.068). Of surgeries performed without prior GC treatment, 31.7 and 55.0% had a cortisol nadir of < 2 and < 5 ug/dL, respectively, within 72 h postoperative. CONCLUSIONS: Our physicians were more diligent in measuring in-hospital postoperative cortisol levels consistent with 2008 consensus recommendations. Better management of cortisol measurements and their timing is an opportunity for improvement. PMID- 29143886 TI - Rapid in situ assessment for predicting soil quality using an algae-soaked disc seeding assay. AB - The soil quality of remediated land is altered and this land consequently exerts unexpected biological effects on terrestrial organisms. Therefore, field evaluation of such land should be conducted using biological indicators. Algae are a promising new biological indicator since they are a food source for organisms in higher soil trophic levels and easily sampled from the soil. Field evaluation of soil characteristics is preferred to be testing in laboratory conditions because many biological effects cannot be duplicated during laboratory evaluations. Herein, we describe a convenient and rapid algae-soaked disc seeding assay for assessing soil quality in the field based on soil algae. The collection of algae is easy and rapid and the method predicts the short-term quality of contaminated, remediated, and amended farm and paddy soils. The algae-soaked disc seeding assay is yet to be extensively evaluated, and the method cannot be applied to loamy sand soil in in situ evaluations. The algae-soaked disc seeding assay is recommended for prediction of soil quality in in situ evaluations because it reflects all variations in the environment. The algae-soaked disc seeding assay will help to develop management strategies for in situ evaluation. PMID- 29143888 TI - 'The Art of Insulin Treatment:' Diabetes, Insulin, and the 1920s. AB - Soon after the discovery of insulin in the early 1920s, the popular press celebrated the miraculous discovery. Although insulin had no curative effect on the chronic state of diabetes, it was frequently heralded as a "cure." This paper examines how the discovery of insulin intersected with the rise of diabetic technology and the transfer of medical technology to the home setting. By analyzing diabetic manuals written for patients and physicians, letters exchanged between patient and physician, medical journals, magazines and newspapers, I trace how patients learned about insulin and more significantly how patients adopted measurement technologies designed to allow better home administration of insulin. This included acquiring knowledge about nutritional content and scales, maintaining sterile glass syringes, sharpening needles, using chemistry to measure sugar in the urine, and recording various measurements into meaningful text for patient-physician dialogue. As diabetes was re-imagined as a chronic and controllable illness, patients and physicians alike grappled with the promises and limitations of new medical technologies. This historical perspective offers a lens for better understanding the process of implementing diabetic treatment plans that required home testing, measurement, and recording of medical data. Such processes centered the importance of patient-centered work and the value of diabetic technologies. Much of this discourse is outlined in diabetic manuals of the 1920s. PMID- 29143887 TI - Diagnosis and Treatment of Aplastic Anemia. AB - OPINION STATEMENT: Acquired aplastic anemia (AA) is a rare, life-threatening bone marrow failure (BMF) disorder that affects patients of all ages and is caused by lymphocyte destruction of early hematopoietic cells. Diagnosis of AA requires a comprehensive approach with prompt evaluation for inherited and secondary causes of bone marrow aplasia, while providing aggressive supportive care. The choice of frontline therapy is determined by a number of factors including AA severity, age of the patient, donor availability, and access to optimal therapies. For newly diagnosed severe aplastic anemia, bone marrow transplant should be pursued in all pediatric patients and in younger adult patients when a matched sibling donor is available. Frontline therapy in older adult patients and in all patients lacking a matched sibling donor involves immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine A. Recent improvements in upfront therapy include encouraging results with closely matched unrelated donor transplants in younger patients and the emerging benefits of eltrombopag combined with initial IST, with randomized studies underway. In the refractory setting, several therapeutic options exist, with improving outcomes of matched unrelated donor and haploidentical bone marrow transplantation as well as the addition of eltrombopag to the non-transplant AA armamentarium. With the recent appreciation of frequent clonal hematopoiesis in AA patients and with the growing use of next-generation sequencing in the clinic, utmost caution should be exercised in interpreting the significance of somatic mutations in AA. Future longitudinal studies of large numbers of patients are needed to determine the prognostic significance of somatic mutations and to guide optimal surveillance and treatment approaches to prevent long-term clonal complications. PMID- 29143889 TI - Beyond Pathologizing Harm: Understanding PTSD in the Context of War Experience. AB - An alternative to objectifying approaches to understanding Post-traumatic Stress Disorder (PTSD) grounded in hermeneutic phenomenology is presented. Nurses who provided care for soldiers injured in the Iraq and Afghanistan wars, and sixty seven wounded male servicemen in the rehabilitation phase of their recovery were interviewed. PTSD is the one major psychiatric diagnosis where social causation is established, yet PTSD is predominantly viewed in terms of the usual neuro physiological causal models with traumatic social events viewed as pathogens with dose related effects. Biologic models of causation are applied reductively to both predisposing personal vulnerabilities and strengths that prevent PTSD, such as resiliency. However, framing PTSD as an objective disease state separates it from narrative historical details of the trauma. Personal stories and cultural meanings of the traumatic events are seen as epiphenomenal, unrelated to the understanding of, and ultimately, the therapeutic treatment of PTSD. Most wounded service members described classic symptoms of PTSD: flashbacks, insomnia, anxiety etc. All experienced disturbance in their sense of time and place. Rather than see the occurrence of these symptoms as decontextualized mechanistic reverberations of war, we consider how these symptoms meaningfully reflect actual war experiences and sense of displacement experienced by service members. PMID- 29143890 TI - Paternal Anxiety in Relation to Toddler Anxiety: The Mediating Role of Maternal Behavior. AB - Despite robust investigations examining the impact of maternal anxiety and parenting behaviors and child anxiety risk, less is understood about the impact of paternal anxiety and parenting behaviors on child anxiety risk, particularly within the broader family context. An Actor Partner Interdependence Model (APIM) was used to examine whether paternal anxiety longitudinally predicted child anxiety risk indirectly through maternal and paternal parenting behaviors, while controlling for maternal anxiety. Both fathers and mothers of 12- to 30-month olds (n = 94) provided self-report of their anxiety and parenting behaviors. Child inhibited temperament (i.e., anxiety risk) was coded. Two APIMs separately considering encouragement of independence and overprotection were examined. These models revealed no direct relation between parent and child anxiety while controlling for parenting behaviors. Models did suggest that paternal anxiety is indirectly linked with future child anxiety through lower maternal encouragement of independence, but not through maternal overprotection or paternal parenting behaviors. PMID- 29143891 TI - In Search of the Ideal Promotility Agent: Optimal Use of Currently Available Promotility Agents for Nutrition Therapy of the Critically Ill Patient. AB - PURPOSE OF REVIEW: Enteral nutrition therapy is essential in the management of critically ill patients. Prokinetic agents have been used successfully to aid in the delivery of nutrition and improve feeding tolerance in patients in the intensive care unit (ICU). The aim of this report is to review the existing promotility agents available for use in the critically ill as well as outline the role of potential investigative drugs in order to provide a guide to the management of this difficult and important clinical dilemma. RECENT FINDINGS: While no single currently available agent currently meets all of the desired goals in the critical care setting, there are an increasing number of available agents from which to choose including motilin receptor agonists, 5HT4 receptor agonists, D2 receptor antagonists, and Mu opioid receptor antagonists. We recommend a multifaceted approach to optimizing enteral nutrition in the critical care setting which should include the early, prophylactic use of promotility agents and should focus on the management of reversible causes of impaired gastrointestinal motility. PMID- 29143892 TI - Update in the Therapy of Advanced Neuroendocrine Tumors. AB - OPINION STATEMENT: Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of ~ 6.9/100,000. NETs arise throughout the body from cells of the diffuse endocrine system. More than half originate from endocrine cells of the gastrointestinal tract and the pancreas, thus being referred to as gastroenteropancreatic NETs (GEP-NETs). The only treatment that offers a cure is surgery; however, most patients are diagnosed with metastatic disease, and curative surgery is usually not an option. These patients can be offered long term systemic treatment, for both symptomatic relief and tumor growth suppression. Evidence-based treatment options include somatostatin analogs, everolimus (a mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor), and peptide receptor radionuclide therapy, alone or combined with cytoreductive procedures (surgery or liver-directed procedures). Other treatment options being investigated are immunotherapy and epigenetic assessment that may lead to more personalized interventions. We believe that each patient should be thoroughly evaluated and their case discussed by a multidisciplinary team that is up-to-date with all treatment modalities including ongoing clinical trials, before selecting the proper treatment option. PMID- 29143894 TI - Mechanism of Resistance in Gastrointestinal Stromal Tumors. AB - Imatinib has revolutionized the treatment of GIST since this drug is able to inhibit tumoral growth by blocking the activity of receptor tyrosine kinases, KIT or PDGFRA, that in these tumors are constitutively activated because of the presence of mutations that alters their catalytic activity. However, despite this enormous improvement in the RFS and OS and in the quality of life of GIST patients, imatinib is not able to eradicate the disease: recurrences occur and acquired resistance is a common event which develops during targeted treatments. Several mechanisms have been demonstrated to be responsible for tumoral growth reactivation which is due to the reactivation of the altered KIT/PDGFRA receptors, no more blocked by the drug. Secondary point mutations are generally observed in the regrowing tumors, and it has been demonstrated that they alter the architectural structure of the site in which the interaction between the drug and the receptor happens. Other mechanisms causing drug resistance have been investigated, indicating that many aspects need to be still explicated and fully understood in order to define a strategy able to fight definitively GIST growth. PMID- 29143893 TI - The Role of Systemic Therapy in Resectable Gastric and Gastro-oesophageal Junction Cancer. AB - OPINION STATEMENT: Approximately 20% of patients with cancer of the stomach or gastro-oesophageal junction (GOJ) present with resectable disease. Long-term outcome after surgery alone in these patients is poor, and a combined treatment approach is the standard of care. The two approaches to managing patients with cancer of the GOJ are perioperative chemotherapy or preoperative chemoradiotherapy. Based upon the most recent evidence, patients treated with a perioperative approach and deemed suitable for a triplet regimen should be considered for pre- and post-operative FLOT (5-fluorouracil [5-FU], leucovorin, oxaliplatin and docetaxel) and those suitable for a doublet regimen should be considered for a fluoropyrimidine/platinum combination such as capecitabine and oxaliplatin. Alternatively, such patients may be considered for preoperative chemoradiotherapy according to the CROSS regimen. True gastric cancers may be treated with a perioperative approach or, as is commonly used in Asia, postoperative adjuvant chemotherapy. PMID- 29143895 TI - Genetic Approaches to the Study of Gene Variants and Their Impact on the Pathophysiology of Type 2 Diabetes. AB - Diabetes mellitus is an incurable progressive disease, characterized by elevated blood glucose levels, which lead to the development of micro- and macrovascular complications. Although the etiopathology of the disease remains unclear, it seems to be multifactorial, with an important interaction between genetics and environmental causes. Currently, the genetics of type 2 diabetes (T2D) is poorly understood. The recent advance of the genetic technologies and with a better understanding of genetics, more than 120 distinct genetic loci, with more than 150 variants, have been identified that may be involved in the pathogenesis of T2D. However, as these variants can account for only approximately 20% of the heritability of T2D, there is an obvious need for additional approaches to identify susceptibility genes or genetic mechanisms involved in the development of this disease. There is a growing number of genes found to be related to T2D; however, their individual impact on the pathogenesis of the disease appears to be low, while silencing of protective genes may also contribute to the development of this disease. The present review attempts to summarize our current knowledge in the field of genetics of T2D, highlighting the possible practical applications for each approach. PMID- 29143896 TI - Modulation of Stimulator of Interferon Genes (STING) Expression by Interferon gamma in Human Keratinocytes. AB - Infection of microbial pathogen triggers the innate immune system, and the induction of interferons (IFNs) play a vital role in host antiviral response. Stimulator of interferon genes (STING) was identified as a crucial regulator of the DNA sensing pathway, and activates both nuclear factor-kappaB and interferon regulatory factor 3 transcription pathways to evoke IFNs production. In this study, we studied the upregulation of STING mRNA expression, induced by IFN-gamma in human keratinocytes (HaCaT). STING promoter assays clarified that a gamma activated sequence (GAS), located at - 7 to - 15-bp, is required for IFN-gamma upregulated promoter activity. Furthermore, an electrophoretic mobility shift assay showed that signal transducers and activators of transcription 1 (STAT1) attach to the GAS motif on the human STING promoter region. This indicates that IFN-gamma/Janus kinases/STAT1 signaling is essential for the STING upregulation in human keratinocytes. PMID- 29143897 TI - Anaplastic Lymphoma Kinase Testing: IHC vs. FISH vs. NGS. AB - OPINION STATEMENT: Personalized targeted therapy has emerged as a promising strategy in lung cancer treatment, with current attention focused on elucidation and detection of oncogenic drivers responsible for tumor initiation and maintenance and development of drug resistance. In lung cancer, several oncogenic drivers have been reported, triggering the application of tyrosine kinase inhibitors (TKIs) to target these dysfunctional genes. The anaplastic lymphoma kinase (ALK) rearrangement is responsible for about 4-7% of all non-small cell lung cancers (NSCLCs) and perhaps as high as a third in specific patient populations such as younger, male, non-smokers with advanced stage, epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS) wild type, and signet ring cell adenocarcinoma with abundant intracytoplasmic mucin. The selection of patients based on their ALK status is vital on account of the high response rates with the ALK-targeted agents in this subset of patients. Standardization and validation of ALK rearrangement detection methods is essential for accurate and reproducible results. There are currently three detection methods widely available in clinical practice, including fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), and polymerase chain reaction (PCR)-based next generation sequencing (NGS) technology. However, the choice of diagnostic methodology for ALK rearrangement detection in clinical practice remains a matter of debate. With accumulating data enumerating the advantages and disadvantages of each of the three methods, combining more than one testing method for ALK fusion detection may be beneficial for patients. In this review, we will discuss the current methods used in ALK rearrangement detection with emphasis on their key advantages and disadvantages. PMID- 29143898 TI - The Multidisciplinary Approach to Localized Pancreatic Adenocarcinoma. AB - OPINION STATEMENT: Pancreatic adenocarcinoma 2030 (PCa) is predicted to be the second leading cause of cancer death in USA by 2030. To date, attempts at early detection have been unsuccessful. Therapies for resectable PCa include surgery followed by adjuvant chemotherapy with or without radiotherapy. Unfortunately, most patients with PCa present with advanced disease and thus only 20% of patients are potentially resectable upon presentation. Improved surgical techniques along with adjuvant combination chemotherapy have improved outcomes for patients with resectable disease. The optimal treatment approach for borderline resectable and locally advanced unresectable PCa has not yet been defined. Despite significant advances in the palliative treatment of PCa, long term survival of early stage disease continues to be sobering. The key to improving outcomes for this largely fatal disease is to identify multidisciplinary therapeutic interventions including surgical, medical, and radiation techniques tailored to the patient and their disease characteristics. The neoadjuvant approach provides an in vivo platform to test novel treatment options to help us understand tumor biology and surrounding microenvironment, which may ultimately help us achieve the goal of improvement in long-term survival. While the neoadjuvant approach remains popular as a way to optimally select patients that might benefit most from surgery, randomized trials utilizing adjuvant and neoadjuvant novel therapies hold the key to truly personalizing the ideal treatment strategy for localized PCa. PMID- 29143899 TI - Headache in Resource-Limited Settings. AB - PURPOSE OF REVIEW: This review summarizes the unmet need of headache burden and management in resource-limited settings. It provides a general overview of the nuances and peculiarities of headache disorders in resource-limited settings. The review delivers perspectives and explanations for the emerging burden of both primary and secondary headache disorders. Important discussion on demographic and epidemiologic transition pertinent to low-resource settings is included. A critical analysis of headache disorders is made within the context of growing burden non-communicable disorders in low-resource countries. Challenges are examined and prospective feasible solutions tailored to existing resources are provided to address headache disorders in resource-limited settings. RECENT FINDINGS: Many low-resource countries are entering into the third epidemiological transition featuring increasing burden of non-communicable disorders of which headache disorders contribute a significant proportion. Exponential population growth involving youthful demographic and massive rural-urban migration is taking place in low-resource countries. Youthful demographic is the natural cohort for primary headache such as migraine. Socioeconomic mobility and lifestyle changes are leading to higher levels of physical inactivity and obesity, both of which are related to headache. Life expectancy is rising in some resource-restricted countries; this increases prevalence of secondary headache attributed to neurovascular causes. Many low-resource countries are still burdened with tropical infectious causes of secondary headache. Health care facilities are primarily designed to respond to infectious epidemic and not to chronic burden such as headache. Many low-resource-restricted settings are plagued by poor and corrupt governance, ill-equipped regimes with malfunctioning health policies, war, and poverty. Many low-resource settings do not have access to generic headache medications such as triptans. Headache training and expertise is low. Healthy lifestyle changes emphasizing on improving regular exercise can be inexpensive method to reducing primary headache burden and its comorbidities (e.g. obesity). Addressing the increasing burden of headache disorders in resource-limited settings is important to avert accrued disability which in turn lowers productivity and socioeconomic performance in a young booming population. PMID- 29143900 TI - An Innovative Mobile Health System to Improve and Standardize Antenatal Care Among Underserved Communities: A Feasibility Study in an Italian Hosting Center for Asylum Seekers. AB - Innovative migrant-friendly tools are needed to assist health personnel manage the high number of pregnancies within reception centers. This study tests functionality and acceptability of a new mHealth system in providing antenatal care amongst migrants. The study, carried out between 2014 and 2016, involved 150 pregnant women residing in the largest European migrant reception center in Sicily. A ticket tracking system assessed the system's functionality and a questionnaire assessed women's acceptability. The system facilitated the collection of clinical data, enabling the creation of electronic patient records and identifying 10% of pregnancies as high-risk. The application's digital format increased health providers' adherence to antenatal-care recommendations, while the graphic interface facilitated women's engagement and retention of the health education modules. The study recorded a 91.9% patient satisfaction rate. The system was efficient in providing comprehensive and high-quality antenatal care amongst migrants, facilitating the continuity of care for a population undergoing frequent relocations. PMID- 29143902 TI - A new aerobic chemolithoautotrophic arsenic oxidizing microorganism isolated from a high Andean watershed. AB - Biological arsenic oxidation has been suggested as a key biogeochemical process that controls the mobilization and fate of this metalloid in aqueous environments. To the best of our knowledge, only four aerobic chemolithoautotrophic arsenite-oxidizing (CAO) bacteria have been shown to grow via direct arsenic oxidation and to have the essential genes for chemolithoautotrophic arsenite oxidation. In this study, a new CAO bacterium was isolated from a high Andean watershed evidencing natural dissolved arsenic attenuation. The bacterial isolate, designated TS-1, is closely related to the Ancylobacter genus, in the Alphaproteobacteria class. Results showed that TS-1 has genes for arsenite oxidation and carbon fixation. The dependence of bacterial growth from arsenite oxidation was demonstrated. In addition, a mathematical model was suggested and the kinetic parameters were obtained by simultaneously fitting the biomass growth, arsenite depletion curves, and arsenate production. This research increases the knowledge of chemolithoautotrophic arsenic oxidizing microorganisms and its potential role as a driver for natural arsenic attenuation. PMID- 29143901 TI - Combined Vertebral Augmentation and Radiofrequency Ablation in the Management of Spinal Metastases: an Update. AB - OPINION STATEMENT: Spinal metastases are the most commonly encountered tumour of the spine, occurring in up to 40% of patients with cancer. Each year, approximately 5% of cancer patients will develop spinal metastases. This number is expected to increase as the life expectancy of cancer patients increases. Patients with spinal metastases experience severe and frequently debilitating pain, which often decreases their remaining quality of life. With a median survival of less than 1 year, the goals of treatment in spinal metastases are reducing pain, improving or maintaining level of function and providing mechanical stability. Currently, conventional treatment strategies involve a combination of analgesics, bisphosphonates, radiotherapy and/or relatively extensive surgery. Despite these measures, pain management in patients with spinal metastases is often suboptimal. In the last two decades, minimally invasive percutaneous interventional radiology techniques such as vertebral augmentation and radiofrequency ablation (RFA) have shown progressive success in reducing pain and improving function in many patients with symptomatic spinal metastases. Both vertebral augmentation and RFA are increasingly being recognised as excellent alternative to medical and surgical management in carefully selected patients with spinal metastases, namely those with severe refractory pain limiting daily activities and stable pathological vertebral compression fractures. In addition, for more complicated lesions such as spinal metastasis with soft tissue extension, combined treatments such as vertebral augmentation in conjunction with RFA may be helpful. While combined RFA and vertebral augmentation have theoretical benefits, comparative trials have not been performed to establish superiority of combined therapy. We believe that a multidisciplinary approach as well as careful pre-procedure evaluation and imaging will be necessary for effective and safe management of spinal metastases. RFA and vertebral augmentation should be considered during early stages of the disease so as to maintain the remaining quality of life in this patient population group. PMID- 29143903 TI - Whole community transcriptome of a sequencing batch reactor transforming 2,4 dinitroanisole (DNAN) and 3-nitro-1,2,4-triazol-5-one (NTO). AB - Two sequencing batch reactors (SBRs) were run to bio-mineralize 2,4 dinitroanisole (DNAN) and 3-nitro-1,2,4-triazol-5-one (NTO) in lab scale settings. The reactors were shown to reproducibly biotransform these munitions under aerobic and anaerobic conditions during the operations of these SBRs. Complete removal (100% biotransformation) of DNAN (initially 17.7 +/- 5.4 mg L-1) and NTO (initially 15.0 +/- 7.1 mg L-1) was observed in an anaerobic SBR when Luria-Bertani (LB) broth was present. In contrast, an aerobic SBR degraded only 58 +/- 22% of DNAN (initially 19.7 +/- 6.2 mg L-1) and 45 +/- 24% of NTO (initially 9.7 +/- 6.3 mg L-1) when either LB or glucose was also added indicating that anaerobic conditions are more favorable for biotransformation of these munitions. Transcriptomic analysis of the DNAN and NTO degrading anaerobic SBR revealed upregulation of a putative nitroreductase, hydroxylaminophenol mutases, 4-hydroxylphenyl acetate associated genes, and quinone oxioreductases. Major Bacterial populations included Bacteroidales, Campylobacterales, Enterobacteriales, Pseudomonadales, Burkholderiales and Clostridiales. Results from this study can be used to inform investigation of munition degrading organisms and the functional genes responsible. PMID- 29143904 TI - Exploring Peer Support Needs of Caregivers for Youth with Mental Illness or Addictions Concerns in Family Navigation Services. AB - Roles for peer support workers are increasingly recognized as a valuable component of mental health and addictions (MHA) services. In youth MHA care, caregivers are often closely involved in finding and accessing services and may also require support for themselves, yet caregiver peer support is not readily available in existing service delivery models. In order to understand the potential role and value of a caregiver peer support worker in a Family Navigation service, a descriptive qualitative study was conducted to explore the needs and potential value of a peer worker from caregiver client perspectives. Study findings indicate that a caregiver peer support worker can provide support for engaging in the caregiving role, utilize lived experience as a skill, and complement navigation support through lived experience. The discussion highlights implications for the implementation of a caregiver peer role at a family-focused service as well as implications for peer work within the MHA system. PMID- 29143905 TI - Measurement invariance of the WHOQOL-AGE questionnaire across three European countries. AB - PURPOSE: Developing valid and reliable instruments that can be used across countries is necessary. The present study aimed to test the comparability of quality of life scores across three European countries (Finland, Poland, and Spain). METHOD: Data from 9987 participants interviewed between 2011 and 2012 were employed, using nationally representative samples from the Collaborative Research on Ageing in Europe project. The WHOQOL-AGE questionnaire is a 13-item test and was employed to assess the quality of life in the three considered countries. First of all, two models (a bifactor model and a two-correlated factor model) were proposed and tested in each country by means of confirmatory factor models. Second, measurement invariance across the three countries was tested using multi-group confirmatory factor analysis for that model which showed the best fit. Finally, differences in latent mean scores across countries were analyzed. RESULTS: The results indicated that the bifactor model showed more satisfactory goodness-of-fit indices than the two-correlated factor model and that the WHOQOL-AGE questionnaire is a partially scalar invariant instrument (only two items do not meet scalar invariance). Quality of life scores were higher in Finland (considered as the reference category: mean = 0, SD = 1) than in Spain (mean = - 0.547, SD = 1.22) and Poland (mean = - 0.927, SD = 1.26). CONCLUSIONS: Respondents from Finland, Poland, and Spain attribute the same meaning to the latent construct studied, and differences across countries can be due to actual differences in quality of life. According to the results, the comparability across the different considered samples is supported and the WHOQOL AGE showed an adequate validity in terms of cross-country validation. Caution should be exercised with the two items which did not meet scalar invariance, as potential indicator of differential item functioning. PMID- 29143906 TI - Surgery for diverticular disease results in a higher hernia rate compared to colorectal cancer: a population-based study from Ontario, Canada. AB - BACKGROUND: Incisional hernias are a well described complication of abdominal surgery. Previous studies identified malignancy and diverticular disease as risk factors. We compared incisional hernia rates between colon resection for colorectal cancer (CRC) and diverticular disease (DD). STUDY DESIGN: We performed a retrospective, population-based, matched cohort study. Provincial databases were linked through the Institute for Clinical Evaluative Sciences. These databases include all patients registered under the universal Ontario Health Insurance Plan. Patients aged 18-105 undergoing open colon resection, without ostomy formation between April 1, 2002 and March 31, 2009, were included. We excluded those with previous surgery, hernia, obstruction, and perforation. The primary outcomes were surgery for hernia repair, or diagnosis of hernia in clinic. RESULTS: We identified 4660 cases of DD. These were matched 2:1 by age and gender to 8933 patients with CRC for a total of 13,593. At 5 years, incisional hernias occurred in 8.3% of patients in the CRC cohort, versus 13.1% of those undergoing surgery for DD. After adjusting for important confounders (comorbidity score, wound infection, age, diabetes, prednisone and chemotherapy), hernias were still more likely in patients with DD [HR 1.58, 95% Confidence Interval (CI) 1.43-1.76, P < 0.001]. The only significant covariate was wound infection (HR 1.63, 95% CI 1.43-1.87, P < 0.001). CONCLUSION: Our study found that incisional hernias occur more commonly in patients with DD than CRC. PMID- 29143907 TI - Invited comment to: Minimal modulation of the host immune response to small intestinal submucosa by mesenchymal stem cells from the amniotic fluid. F. Lesagne, S. Pranpanus, F.M. Bosisio, M. Jacobs, S. Ospitalieri, J. Toelen, J. Deprest. PMID- 29143908 TI - The HP10 Taenia monoclonal antibody-based ELISA detects a similar protein in the vesicular fluid of Taenia hydatigena. AB - Diagnosis of Taenia solium cysticercosis in endemic rural communities depends on serological tests, as typically there is no access to imaging facilities. The HP10 antigen ELISA (HP10 Ag ELISA), which detects a high molecular weight secreted protein of viable metacestodes, has been employed for the diagnosis of both human and porcine cysticercosis in such communities. In this communication, we formally demonstrate that the HP10 Ag ELISA, already known to function for the detection of T. saginata and T. solium cysticercosis, also detects a similar high molecular weight antigen of T. hydatigena. Thus, the HP10 Ag assay, while specific for human cysticercosis, may not be recommended for the diagnosis of porcine cysticercosis where there is co-infection of pigs with T. solium and T. hydatigena. PMID- 29143909 TI - Design of an optimum Poincare plane for extracting meaningful samples from EEG signals. AB - Biosignals are considered as important sources of data for diagnosing and detecting abnormalities, and modeling dynamics in the body. These signals are usually analyzed using features taken from time and frequency domain. In theory' these dynamics can also be analyzed utilizing Poincare plane that intersects system's trajectory. However' selecting an appropriate Poincare plane is a crucial part of extracting best Poincare samples. There is no unique way to choose a Poincare plane' because it is highly dependent to the system dynamics. In this study, a new algorithm is introduced that automatically selects an optimum Poincare plane able to transfer maximum information from EEG time series to a set of Poincare samples. In this algorithm' EEG time series are first embedded; then a parametric Poincare plane is designed and finally the parameters of the plane are optimized using genetic algorithm. The presented algorithm is tested on EEG signals and the optimum Poincare plane is obtained with more than 99% data information transferred. Results are compared with some typical method of creating Poinare samples and showed that the transferred information using with this method is higher. The generated samples can be used for feature extraction and further analysis. PMID- 29143910 TI - The effect of SMS (text message) reminders on attendance at a community adult mental health service clinic: do SMS reminders really increase attendance? AB - BACKGROUND: Non-attendance at outpatient clinics is common and costly. AIMS: This study aimed to determine if sending SMS ('short message service' or text message) reminders to patients before appointments reduced non-attendance. METHODS: We collected outpatient data at Ballyfermot and Lucan Community Adult Mental Health Service, Dublin, Ireland during 6-month periods (a) immediately prior to the introduction of SMS reminders for outpatient appointments; (b) immediately following the introduction of SMS reminders; and (c) two and a half years later. RESULTS: In the 6-month period prior to SMS reminders, 2170 outpatient appointments were offered and there was a 22.2% non-attendance rate. In the 6 months following the introduction of SMS reminders, 2092 appointments were offered and the non-attendance rate fell to 13.9% (p < 0.001), with the lower non attendance rate among those who did not receive SMS reminders (9.7%) rather than those who did (15.7%) (p = 0.0002). There were 98 appointment cancellations during this period (73% via SMS messaging). In the 6-month period two and a half years after the introduction of SMS reminders, 2474 appointments were offered and the non-attendance rate rose to 19.3%; this did not differ between those who received SMS reminders (19.3%) and those who did not (19.1%) (p = 0.38209) and was still lower than the rate prior to SMS reminders (p = 0.01321). During this period, 197 appointments were cancelled (75% via SMS messaging). CONCLUSIONS: The chief value of SMS reminders lies not in reminding patients of appointments but in providing a convenient way to cancel them, thus allowing more appointments to be offered. PMID- 29143911 TI - Decreased interhemispheric coordination in the posterior default-mode network and visual regions as trait alterations in first-episode, drug-naive major depressive disorder. AB - Decreased homotopic connectivity has been implicated in the neurophysiology of major depressive disorder (MDD) with inconsistent findings. A combination of clinical and methodological variabilities may account for the inconsistency, and thus limiting the reproducibility of the findings. The present study aims to examine voxel-mirrored homotopic connectivity (VMHC) alterations in two independent samples of patients with first-episode, drug-naive MDD. The samples included 59 patients and 31 controls from Sample 1 and 29 patients and 24 controls from Sample 2. VMHC was evaluated in both samples with an overlapping technique, which was used to define regions of abnormality common to both samples. Moreover, receiver operating characteristic curve and support vector machine were employed to differentiate the patients from the controls in both samples. Compared with the controls, the patients in both samples exhibited decreased VMHC in overlapped brain clusters, including the posterior cingulate cortex (PCC) and cuneus. Moreover, the VMHC values in the PCC and cuneus and a combination of the VMHC values in these two clusters could robustly discriminate between patients and controls with good sensitivities and specificities in both samples. This study is the first to examine VMHC abnormalities in first-episode, drug-naive patients with MDD in two independent samples by using an overlapped technique. The patients exhibit decreased VMHC in overlapping clusters in the posterior default-mode network and visual regions, which may be trait alterations for MDD. The present study provides a new perspective for understanding the neurophysiologic abnormalities of VMHC in MDD. PMID- 29143912 TI - Determination of splenomegaly by coronal oblique length on CT. AB - PURPOSE: The aims of this study were (a) to determine whether a coronal oblique length (COL) > 12 cm, which is often used to detect splenomegaly (SM) on ultrasound, can be used as a marker of SM on computed tomography (CT), (b) to compare the diagnostic accuracy of COL with other unidimensional linear measurements (ULM) in identifying SM, (c) to determine which ULM most closely correlates with splenic volume (SVol) according to the splenic index on CT, (d) to assess the relationship between SVol and patient's gender, age and body parameters (height, weight), and (e) to determine whether there is a difference between non-contrast-enhanced and contrast-enhanced CT images in identifying SM. MATERIALS AND METHODS: The body parameters and ULM (width, length, thickness, COL) were obtained from patients who underwent CT for various indications from April 2016 to April 2017. SVol and body mass indexes were calculated for each patient. RESULTS: Of the 1078 patients [male/female = 526/552; 47.57 (mean) +/- 19.21 (standard deviation) years], 392 patients had SM. The sensitivity, specificity, positive and negative predictive values of COL > 12 cm for diagnosing SM were 44.6, 95.6, 85.3 and 75.1%, respectively (p < 0.001). SVol correlated with all ULM (p < 0.001). In the non-SM group (n = 686), the mean SVol was 331.7 +/- 92.2 cm3 and females had smaller spleens than males (p < 0.001). SVol showed correlation with gender, age and height (p < 0.001). CONCLUSION: COL > 12 cm is not superior to other ULM for the detection of SM, but it is very successful in determining normal spleens. The unidimensional measurements and volume of the spleen should be calculated by taking gender and body parameters into account for different ethnic populations. Non-contrast-enhanced CT can also be used to detect SM. PMID- 29143913 TI - Chylothorax post thoracoscopic surgery for an anterior mediastinal tumor. AB - Chylothorax after anterior mediastinal surgery is rare. We treated a 39-year-old woman who presented with progressive dyspnea over 6 months. Chest computed tomography revealed a 12-cm round mass in the right anterior mediastinum. She underwent video-assisted thoracoscopic surgery for successful excision of the tumor; however, the surgery was complicated by the development of chylothorax. It was treated surgically with no recurrence of the tumor and/or chylothorax for 2 years. Chylothorax should be recognized as a postsurgical complication of anterior mediastinal tumors. PMID- 29143914 TI - Sclerosing mesenteritis diagnosed with computed tomography and ultrasound-guided needle biopsy: the utility of the coaxial technique. AB - Here we report a case of sclerosing mesenteritis that we diagnosed with needle biopsy under the guidance of computed tomography (CT) and ultrasound (US) observation. An 82-year-old woman presented with appetite loss, weight loss and epigastric pain. CT of the abdomen and pelvis revealed increased density of the mesentery adjacent to the small bowel and enlarged lymph nodes. Sclerosing mesenteritis was suspected, but malignancies, such as lymphoma, were also considered. We performed CT and US-guided needle biopsy with the coaxial technique. An introducer needle was inserted, its correct location was documented with CT, and multiple specimens were taken with a finer needle passed through the introducer without incident. Adequate specimens were obtained, and the histological diagnosis of sclerosing mesenteritis was made. We treated the patient with corticosteroids and her symptoms and the radiographic findings improved. The coaxial technique was a useful and minimally invasive tool for making the diagnosis of sclerosing mesenteritis. PMID- 29143916 TI - A Real-World Comparison of FOLFIRINOX, Gemcitabine Plus nab-Paclitaxel, and Gemcitabine in Advanced Pancreatic Cancers. AB - PURPOSE: FOLFIRINOX (FFN), nab-paclitaxel plus gemcitabine (GN), and gemcitabine are three systemic therapies that provide clinically meaningful benefit to patients with unresectable pancreatic cancer (UPC). There are no clinical trials that directly compare the efficacy of all three regimens. In this study, we aim to examine and compare the real-world effectiveness of these treatments. METHODS: Patients diagnosed with UPC who initiated palliative chemotherapy from August 2014 to January 2016 at any one of six cancer centers in British Columbia were identified from the provincial pharmacy. Clinical, pathological, treatment, and outcome characteristics were compared. RESULTS: Two hundred twenty-five patients were included: 55% men, 68% Eastern Cooperative Oncology Group 0/1, 58% metastatic disease. Patients who received FFN were younger (p < 0.001) and in better performance status (p < 0.001). Patients treated with FFN or GN experienced significantly longer median overall survival (OS) when compared to those treated with gemcitabine (14.1 vs 10.5 vs 4.2 months, respectively, p < 0.001). Progression-free survival (PFS) was also longer among patients on FFN or GN in comparison to gemcitabine (FFN, HR 0.44, 95% CI 0.24 to 0.814, p = 0.008; GN, HR 0.30, 95% CI 0.19 to 0.47, p < 0.001). A significantly higher proportion of patients require two or more dose modifications on FFN (40%) compared to GN (14%) or gemcitabine (9%) (p < 0.001). CONCLUSIONS: Receipt of modified FFN and GN portends a better prognosis than gemcitabine alone. In the absence of a randomized comparison of all three regimens, our population-based study reveals that the introduction of modified FFN and GN confers real-world effectiveness for UPC patients. PMID- 29143915 TI - Effects of Aging on Fracture Healing. AB - PURPOSE OF REVIEW: This review summarizes research on the physiological changes that occur with aging and the resulting effects on fracture healing. RECENT FINDINGS: Aging affects the inflammatory response during fracture healing through senescence of the immune response and increased systemic pro-inflammatory status. Important cells of the inflammatory response, macrophages, T cells, mesenchymal stem cells, have demonstrated intrinsic age-related changes that could impact fracture healing. Additionally, vascularization and angiogenesis are impaired in fracture healing of the elderly. Finally, osteochondral cells and their progenitors demonstrate decreased activity and quantity within the callus. Age related changes affect many of the biologic processes involved in fracture healing. However, the contributions of such changes do not fully explain the poorer healing outcomes and increased morbidity reported in elderly patients. Future research should address this gap in understanding in order to provide improved and more directed treatment options for the elderly population. PMID- 29143917 TI - Lambda phage nanoparticles displaying HER2-derived E75 peptide induce effective E75-CD8+ T response. AB - We have investigated the in vitro immunogenicity and in vivo prophylactic and therapeutic potential of lambda (lambda) phage particles displaying the E75 peptide (derived from HER2 protein) in an implantable TUBO breast tumor model of BALB/c mice. The mice were immunized with the E75-displaying phage (lambdaF7 gpD::E75) every 2-week intervals over a 6-week period, and the generated immune responses were studied. Results showed in vitro induction of immune responses by the lambdaF7 (gpD::E75) construct compared to the control lambdaF7 and buffer groups. In the in vivo prophylactic study, all the control and vaccinated mice groups developed tumors. However, in the therapeutic experiments, we observed a significant difference in tumor size at days 14-36 for mice immunized with lambdaF7 (gpD::E75) compared to control groups (P < 0.05). Moreover, the survival time prolonged in mice immunized with lambdaF7 (gpD::E75). The discrepancy between the results obtained from the in vitro and in vivo studies may have been a result of the induction of Foxp3 CD4+CD25+ which has been previously reported to hamper effective T cell functionality. In conclusion, we observed a significant immune stimulatory response in the in vitro study, while in vivo, the vaccine was not able to exert significant tumor inhibitory effects. We suggest that the presence of Foxp3+ CD4+CD25+ cells may have impaired the anti-tumor response in mice challenged in vivo with the TUBO xenograft tumor. PMID- 29143918 TI - Induction of CD4+CD25+Foxp3+ regulatory T cells by mesenchymal stem cells is associated with RUNX complex factors. AB - Among the particular immunomodulation properties of mesenchymal stem cells (MSCs), one relies on their capacity to regulatory T cell (Treg) induction from effector T cells. Stable expression of Foxp3 has a dominant role in suppressive phenotype and stability of induced regulatory T cells (iTregs). How MSCs induce stable Foxp3 expression in iTregs remains unknown. We previously showed MSCs could enhance demethylation of Treg-specific demethylated region (TSDR) in iTregs in cell-cell contact manner (unpublished data). Here, we evaluated the possible effect of MSCs on the mRNA expression of Runx complex genes (Runx1, Runx3, and CBFB) that perch on TSDR in iTregs and play the main role in suppressive properties of Tregs, a regulatory pathway that has not yet been explored by MSCs. Also, we investigated the mRNA expression of MBD2 that promotes TSDR demethylation in Tregs. We first showed that in vitro MSC-iTreg induction was associated with strong mRNA modifications of genes involved in Runx complex. We next injected high doses of MSCs in a murine model of C57BL/6 into Balb/C allogeneic skin transplantation to prolong allograft survival. When splenocytes of grafted mice were analyzed, we realized that the Foxp3 expression was increased at day 5 and 10 post-graft merely in MSC-treated mice. Furthermore, Foxp3 mRNA expression was associated with modified Runx complex mRNA expression comparable to what was shown in in vitro studies. Hence, our data identify a possible mechanism in which MSCs convert conventional T cells to iTreg through strong modifications of mRNA of genes that are involved in Runx complex of Foxp3. PMID- 29143919 TI - iGlarLixi Reduces Glycated Hemoglobin to a Greater Extent Than Basal Insulin Regardless of Levels at Screening: Post Hoc Analysis of LixiLan-L. AB - INTRODUCTION: The treatment of patients with type 2 diabetes uncontrolled on basal insulin and oral glucose-lowering drugs was investigated previously in the LixiLan-L trial. In the LixiLan-L trial, patients experienced a 6-week run-in with insulin glargine U100 (iGlar) as part of the screening phase, followed by treatment with a fixed-ratio combination of iGlar + lixisenatide (iGlarLixi) or iGlar alone over 30 weeks. In the study reported here, we investigated the achievement of glycemic control in those who completed the 30-week LixiLan-L trial, as assessed by change in glycated hemoglobin (HbA1c) levels from screening, both for the overall category and for screening HbA1c subcategories. METHODS: This post hoc analysis of the LixiLan-L trial included both the screening phase and the treatment period for 30-week completers and evaluated the change in HbA1c from screening to Week 30, patients reaching HbA1c < 7% at Week 30, and iGlar and lixisenatide (Lixi) doses at Week 30 overall and according to HbA1c subcategory at screening (HbA1c <= 8%, 8% < HbA1c <= 9%, and HbA1c > 9%). Documented symptomatic hypoglycemia during the treatment period was also assessed. RESULTS: HbA1c reductions (least squares mean) from screening to Week 30 were greater for iGlarLixi than iGlar, both overall (- 1.7 vs. - 1.1%) and in all subgroups (HbA1c <= 8%, 8% < HbA1c <= 9%, and HbA1c > 9%): - 1.1, - 1.4, - 2.4 (iGlarLixi) vs. - 0.5, - 1.0, - 1.8% (iGlar), respectively (all p < 0.0001). The end-of-treatment mean HbA1c level for iGlarLixi across all groups was < 7%. More patients achieved an HbA1c of < 7% with iGlarLixi than with iGlar, both overall (59.9 vs. 31.2%) and within each subgroup [74.2, 54.7, 52.2 (iGlarLixi) vs. 37.2, 31.6, 23.5% (iGlar), respectively]. A higher initial screening HbA1c corresponded with a greater mean reduction in HbA1c for both treatment strategies. In all HbA1c screening categories, the risk of hypoglycemia was not increased with iGlarLixi versus iGlar during the treatment phase. CONCLUSION: iGlarLixi controlled HbA1c levels more effectively than iGlar across all HbA1c screening subgroups and in the overall study population without increasing the risk of hypoglycemia. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02058160. FUNDING: Sanofi. PMID- 29143920 TI - Distinguishing the disease-associated SNPs based on composition frequency analysis. AB - Single-nucleotide polymorphism (SNP) is a basical variation in genome. When SNPs occur at the binding sites of microRNA, they can influence the binding efficiency, cause a fluctuation of the mRNA in vivo, and thus arouse posttranscriptional level abnormality. Therefore, SNP has a strong correlation with diseases. Although enormous SNPs have been experimentally identified, only a tiny proportion of them are truly disease-associated SNPs (dSNPs) that relate to microRNA modification and then are involved in disease causing process. Therefore, it is important to distinguish dSNPs from the usual SNPs. Analysis here shows that composition is different between sequence segments centered by dSNP and SNP. Inspired by the composition, transition and distribution features which are meaningful and effective in characterizing proteins' sequence information, we improved and applied it to represent the frequency and physicochemical properties of a gene sequence. Binary encoding scheme was also used for further labelling four nucleic acids (A, T, C, and G). First, clustering analysis was performed to gain reasonable negative samples. Then, optimization tests were implemented on different ratios of positive vs negative samples and different feature subsets retrieved by evaluation method of F score. The optimal model constructed by random forest achieves an accuracy of more than 90% on the testing data set. Moreover, the promising results of the external validation also demonstrate the practical applicability of our method. Finally, principal component analysis on the features indicates that all features in our method gain the gross contribution to the prediction model. PMID- 29143921 TI - Dichloroacetate induced intracellular acidification in glioblastoma: in vivo detection using AACID-CEST MRI at 9.4 Tesla. AB - Intracellular pH (pHi) plays an important role in the maintenance of normal cell function, and is maintained within a narrow range by the activity of transporters located at the plasma membrane. Modulation of tumor pHi may influence proliferation, apoptosis, chemotherapy resistance, and thermosensitivity. Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is dependent on cellular pH. Amine and amide concentration-independent detection (AACID) is a recently developed CEST contrast method that is intracellular pH (pHi) weighted. Dichloroacetate (DCA) can alter tumor pHi by inhibiting the enzyme pyruvate dehydrogenase kinase causing reduced lactate (increasing pHi), or by decreasing the expression of monocarboxylate transporters and vacuolar ATPase leading to reduced pHi. Since the net in vivo effect of DCA on pHi is difficult to predict, the purpose of this study was to quantify the magnitude of acute pHi change in glioblastoma after a single DCA injection using AACID CEST MRI. Using a 9.4T MRI scanner, CEST spectra were acquired in six mice approximately 14 days after implanting 105 U87 human glioblastoma multiforme (GBM) cells in the brain, before and after intravenous injection of DCA (dose: 200 mg/kg). Three additional mice received only phosphate buffered saline (PBS) injection and were studied as controls. Repeated measures t test was used to compare AACID changes in tumor and contralateral tissue regions of interest. One hour after DCA injection there was a significant increase in tumor AACID level by 0.04 +/- 0.01 corresponding to a 0.16 decrease in pHi, and no change in AACID in contralateral tissue. Inspection of AACID maps following PBS injection showed no differences. The use of DCA to induce a tumor specific pH change detectable by AACID CEST MRI is consistent with previous studies that have shown similar effects for lonidamine and topiramate. This study demonstrates that a single dose of DCA can be used as a pharmacological challenge to induced rapid tumor intracellular acidification. PMID- 29143922 TI - Pre-treatment lymphopenia and indication of tumor-induced systemic immunosuppression in medulloblastoma. AB - The presence of tumor-induced systemic immune suppression, including lymphopenia, has been recognized in adult patients with glioblastoma for several decades, and pre-treatment neutrophil-to-lymphocyte count ratio (NLCR) is associated with inferior clinical outcome in patients with glioblastoma. Whether tumor-induced systemic immune suppression is also present in children with malignant brain tumors is not known. We performed a retrospective analysis of pretreatment neutrophil and lymphocyte counts in pediatric patients with medulloblastoma (MB) compared to a control group of children with posterior fossa pilocytic astrocytoma (PA). Compared to the control group, we observed statistically significantly lower absolute lymphocyte counts (ALCs) and higher NLCRs in the medulloblastoma group. Our findings suggest the presence of tumor-induced systemic immune suppression in MB patients already present at the time of diagnosis, with potential implications for the development of immune therapies in this population. PMID- 29143923 TI - Impact of concurrent versus adjuvant chemotherapy on the severity and duration of lymphopenia in glioma patients treated with radiation therapy. AB - Prolonged severe lymphopenia has been shown to persist beyond a year in glioma patients after radiation therapy (RT) with concurrent and adjuvant chemotherapy. This study examines the differential impact of concurrent versus adjuvant chemotherapy on lymphopenia after RT. WHO grade II-III glioma patients who received RT with concurrent and/or adjuvant chemotherapy from 2007 to 2016 were retrospectively analyzed. Concurrent chemotherapy was temozolomide (TMZ), and adjuvant chemotherapy was either TMZ or procarbazine/lomustine/vincristine (PCV). Absolute lymphocyte count (ALC) was analyzed at baseline, 1.5, 3, 6, and 12 months after the start of RT. Univariable and multivariable logistic regression were used to identify the clinical variables in predicting acute or late lymphopenia. There were 151 patients with evaluable ALC: 91 received concurrent and adjuvant TMZ (CRT + ADJ), 32 received only concurrent TMZ (CRT), and 28 received only adjuvant TMZ or PCV (ADJ). There were 9 (10%) versus 6 (19%) versus 0 (0%) cases of grade 3 lymphopenia (ALC < 500/mm3) at 6 weeks and 4 (6%) versus 0 (0%) versus 3 (17%) cases at 12 months in CRT + ADJ, CRT and ADJ groups, respectively. On multivariable analyses, concurrent chemotherapy (odds ratio [OR] 72.3, p < 0.001), female sex (OR 10.8, p < 0.001), and older age (OR 1.06, p = 0.002) were the most significant predictors for any grade >= 1 lymphopenia (ALC < 1000/mm3) at 1.5 months. Older age (OR 1.08, p = 0.02) and duration of adjuvant chemotherapy (OR 1.19, p = 0.003) were significantly associated with grade >= 1 lymphopenia at 12 months. Thus, concurrent chemotherapy appears as the dominant contributor to the severity of acute lymphopenia after RT in WHO grade II-III glioma patients, and duration of adjuvant chemotherapy appears as the key factor to prolonged lymphopenia. PMID- 29143924 TI - Blood plasma biomarkers of citrinin and ochratoxin A exposure in young adults in Bangladesh. AB - Citrinin (CIT) and Ochratoxin A (OTA) are nephrotoxic mycotoxins which can co occur in food commodities, resulting in internal exposure. Studies in many countries reported on the presence of OTA in human blood; however, such biomonitoring data for CIT is still scarce. This study was conducted to characterize both CIT and OTA biomarker levels in plasma of volunteers since food analysis data are insufficient to assess human exposure in Bangladesh. In total 104 blood samples were collected from university students in 2013 (sampling 1: n = 64, midsummer) and 2014 (sampling 2: n = 40, end winter) for analysis of CIT and OTA and their metabolites HO-CIT and OTalpha by LC-MS/MS and HPLC-FD techniques, respectively. CIT and HO-CIT were detected in 90% (max 2.70 ng/mL) and 85% (max 1.44 ng/mL) of all samples. Mean levels in sampling 2 (CIT 0.47 ng/mL; HO-CIT 0.40 ng/mL) were higher than in sampling 1 (0.25 ng/mL; 0.37 ng/mL) indicative of variable CIT exposure. OTA was present in all (max 6.63 ng/mL) and OTalpha in 98% (max 0.99 ng/mL) of the samples. In sampling 1, mean OTA (0.85 ng/mL) was higher than in sampling 2 (0.51 ng/mL); the reverse situation was found for OTalpha mean levels. The calculated dietary OTA intake among the students (mean 9.9; max 91.7 ng/kg bw/week) was lower than the tolerable weekly intake for this mycotoxin (120 ng/kg bw/week) set by EFSA. But frequent co exposure to CIT should be considered, and the results of this study indicate the necessity to identify major sources of CIT and OTA intake in the Bangladeshi population. PMID- 29143925 TI - Production of fumonisins by endophytic strains of Tolypocladium cylindrosporum and its relation to fungal virus infection. AB - Fumonisins were first discovered in Fusarium verticillioides, a fungus associated to disease and asymptomatic infections in maize. Afterwards, other fungal taxa have been found to produce fumonisins. The entomopathogenic ascomycete Tolypocladium cylindrosporum has been isolated from soil and also as an endophyte from leaves of grasses. The objectives of this work were to determine the in vitro production of fumonisin B (FB) mycotoxins and the immunosuppressive compound cyclosporine A (CyA) in several strains of T. cylindrosporum, and to examine the effect of fungal virus infection and temperature in FB production. FB1 was detected in 30% of the strains, ranging from 0.16 to 5.52 MUg cm-2 in solid media, and FB2 was detected in 78% of the strains, ranging from 0.764 to 40.92 MUg cm-2. CyA was not detected in any strain. The mean FB2 concentration of the endophytic strain Tc37W was three times greater (p < 0.05) than that of any other strain. Up to 34% more of FB2 was detected in strains infected by the virus TcV3 than in the corresponding virus-free versions. The effect of temperature on FB2 content was interactively significantly dependent on fungal strain and growth medium; in the YES medium, the FB2 of virus-infected strains Tc37-1V and Tc37W increased by 67 and 16%, respectively, at 26 degrees C as compared to 20 degrees C. The FB concentration in some fungal strains was similar to that in fungi associated to food and feed intoxications. PMID- 29143926 TI - Prolonging Time to Flare in Pediatric Atopic Dermatitis: A Randomized, Investigator-Blinded, Controlled, Multicenter Clinical Study of a Ceramide Containing Moisturizer. AB - INTRODUCTION: Delaying or preventing flares is important in atopic dermatitis (AD) management. The objective of the study was to evaluate whether using a ceramide-containing moisturizer in addition to a body wash during latent AD can delay flares. METHODS: This was a randomized, investigator-blinded, parallel group, controlled study among Chinese children with a history of mild to moderate AD, within 1 week of successful treatment with a topical corticosteroid. Subjects were randomized to receive moisturizer twice daily and body wash once daily, or body wash alone once daily for 12 weeks. The primary efficacy endpoint was time to flare [necessitating medical therapy and/or Investigator Global Assessment (IGA) > 1 (at least mild AD)]. Other efficacy endpoints were AD characteristics and emollient effects. The patient-reported outcome comprised satisfaction at week 12. The safety endpoint was incidence of undesirable events. RESULTS: A total of 64 subjects aged 2-12 years were randomized. Median time to flare was delayed by nearly 2 months for moisturizer/body wash compared to body wash alone (89 vs. 27 days, respectively). A significantly earlier onset of action in terms of fewer flares favoring moisturizer was found at week 4 (31 vs. 59%, respectively, p = 0.022), and after 12 weeks, fewer flares occurred (50 vs. 72%). At week 12 for flare-free subjects, nearly half in both groups had clear IGA, and an emollient effect in terms of less dryness or burning was more marked for moisturizer/body wash. Both products led to high patient satisfaction and were well tolerated. CONCLUSION: A regimen incorporating a moisturizer plus body wash delayed AD flares by nearly 2 months compared to body wash alone, and yielded high patient satisfaction. FUNDING: Galderma R&D. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02589392. PMID- 29143927 TI - Update on the Treatment of Uveitis in Patients with Juvenile Idiopathic Arthritis: A Review. AB - Chronic uveitis is a common extra-articular manifestation of juvenile idiopathic arthritis. The classic clinical picture is one of chronic anterior uveitis, which usually remains asymptomatic until ocular complications arise. The risk of uveitis is increased in girls with an early onset of oligoarthritis and positive antinuclear antibodies. Even though the inflammation in patients with juvenile idiopathic arthritis is initially limited in the anterior part of the eye, chronic active inflammation may eventually cause significant damage to the posterior pole. Complications may include band keratopathy, cataract, secondary glaucoma, posterior synechiae, cystoid macular edema, and hypotony. The cooperation of ophthalmologists with rheumatologists may help define the best treatment plan. The ophthalmic therapeutic regimen includes topical corticosteroids and mydriatics, while in severe cases immunosuppressive and biological agents are introduced. Surgical management of complications might be needed. PMID- 29143928 TI - Systematic Literature Review of the Impact of Endocrine Monotherapy and in Combination with Targeted Therapy on Quality of Life of Postmenopausal Women with HR+/HER2- Advanced Breast Cancer. AB - INTRODUCTION: A major treatment goal for advanced breast cancer (ABC) is to maintain or ideally improve patient quality of life (QoL). Given the changing disease landscape, this systematic literature review (SLR) aims to assess the impact of endocrine therapies (ET), including ET monotherapy (ET mono) and ET combined with targeted therapy (ET + TT), on QoL of women with HR+/HER2- ABC. METHODS: A SLR was conducted to identify randomized controlled trials (RCTs) meeting the following criteria: (1) included ET mono or ET + TT, (2) reported QoL outcomes, (3) focused on women with HR+/HER2- ABC, and (4) published after 2007 (when standardized HER2 testing became available). The databases searched included MEDLINE, EMBASE, Cochrane Library, and key conference proceedings from 2013 to 2016. QoL outcomes for ET mono, ET + TT, and comparisons between the two were summarized from the identified trials. RESULTS: A total of 11 studies (representing 6 RCTs) were identified. The study populations included first-line (5 studies) and ET-failure settings (6 studies). Across settings, global health status (GHS) maintained or deteriorated slightly on these treatments during the trial period. Time to deterioration (TTD) in QoL measured by GHS was analyzed in 6 studies and 4 RCTs. In the first-line setting, reported median TTD in GHS was similar between ET mono and ET + TT (7.2-13.8 months in ET mono; 11.1 months in ET + TT). In the ET-failure setting, ET + TT showed significantly longer TTD vs. ET mono in GHS (median 5.6-8.4 months in ET mono and 8.3-11.7 months in ET + TT) and some additional domains. CONCLUSIONS: ET + TT users experienced similar QoL in the first-line and ET-failure setting relative to patients on ET mono. Moreover, ET + TT users experienced better QoL outcomes in some domains in the ET failure setting relative to ET mono users. FUNDING: Novartis. PMID- 29143930 TI - Photovoltaic cell electrical heating system for removing snow on panel including verification. AB - Small photovoltaic plants in private ownership are typically rated at 5 kW (peak). The panels are mounted on roofs at a decline angle of 20 degrees to 45 degrees . In winter time, a dense layer of snow at a width of e.g., 10 cm keeps off solar radiation from the photovoltaic cells for weeks under continental climate conditions. Practically, no energy is produced over the time of snow coverage. Only until outside air temperature has risen high enough for a rather long-time interval to allow partial melting of snow; the snow layer rushes down in an avalanche. Following this proposal, snow removal can be arranged electrically at an extremely positive energy balance in a fast way. A photovoltaic cell is a large junction area diode inside with a threshold voltage of about 0.6 to 0.7 V (depending on temperature). This forward voltage drop created by an externally driven current through the modules can be efficiently used to provide well-distributed heat dissipation at the cell and further on at the glass surface of the whole panel. The adhesion of snow on glass is widely reduced through this heating in case a thin water film can be produced by this external short time heating. Laboratory experiments provided a temperature increase through rated panel current of more than 10 degrees C within about 10 min. This heating can initiate the avalanche for snow removal on intention as described before provided the clamping effect on snow at the edge of the panel frame is overcome by an additional heating foil. Basics of internal cell heat production, heating thermal effects in time course, thermographic measurements on temperature distribution, power circuit opportunities including battery storage elements and snow-removal under practical conditions are described. PMID- 29143929 TI - A Comparison of the Energetic Cost of Running in Marathon Racing Shoes. AB - BACKGROUND: Reducing the energetic cost of running seems the most feasible path to a sub-2-hour marathon. Footwear mass, cushioning, and bending stiffness each affect the energetic cost of running. Recently, prototype running shoes were developed that combine a new highly compliant and resilient midsole material with a stiff embedded plate. OBJECTIVE: The aim of this study was to determine if, and to what extent, these newly developed running shoes reduce the energetic cost of running compared with established marathon racing shoes. METHODS: 18 high-caliber athletes ran six 5-min trials (three shoes * two replicates) in prototype shoes (NP), and two established marathon shoes (NS and AB) during three separate sessions: 14, 16, and 18 km/h. We measured submaximal oxygen uptake and carbon dioxide production during minutes 3-5 and averaged energetic cost (W/kg) for the two trials in each shoe model. RESULTS: Compared with the established racing shoes, the new shoes reduced the energetic cost of running in all 18 subjects tested. Averaged across all three velocities, the energetic cost for running in the NP shoes (16.45 +/- 0.89 W/kg; mean +/- SD) was 4.16 and 4.01% lower than in the NS and AB shoes, when shoe mass was matched (17.16 +/- 0.92 and 17.14 +/- 0.97 W/kg, respectively, both p < 0.001). The observed percent changes were independent of running velocity (14-18 km/h). CONCLUSION: The prototype shoes lowered the energetic cost of running by 4% on average. We predict that with these shoes, top athletes could run substantially faster and achieve the first sub-2-hour marathon. PMID- 29143931 TI - Antioxidant enzyme activities of Folsomia candida and avoidance of soil metal contamination. AB - Induction of the antioxidant enzymes catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD) and the avoidance of potentially toxic metals in soil by Folsomia candida were investigated. Both laboratory-spiked and field-polluted agricultural soils were used. Cadmium (Cd) concentrations in body tissues, animal avoidance behaviour and physico-chemical properties of the field soils were also determined. In laboratory Cd-spiked soils, the CAT and SOD activities in the Cd treatments were 71.1-94.7 and 1.31-4.55 times higher than in the control, respectively. In field-polluted agricultural soils, the CAT and POD activities generally increased with increasing pollution index (PI Nemerow ) of soil Cd, Cu, Pb and Zn. The CAT, POD and SOD activities at different PI Nemerow were 65.7-128, 30.1-180 and 36.5-95.8% higher than in the control, respectively. In line with the enzyme activities, Cd concentrations in the animal bodies were 8.31-15.1 and 3.21-10.0 times higher than in the control in spiked and field-polluted soils, respectively. Avoidance behaviour also increased with increasing metal concentrations in both soils. The effects of metals on CAT, POD or SOD activity were influenced by soil properties such as soil texture and pH. These results indicate that the antioxidant enzymes activities of F. candida can be induced by heavy metals and potentially used to assess the toxicity, and also that soil properties must be considered in the analysis of enzyme activities in different types of field soils. PMID- 29143932 TI - Forecasting carbon dioxide emissions based on a hybrid of mixed data sampling regression model and back propagation neural network in the USA. AB - The accurate forecast of carbon dioxide emissions is critical for policy makers to take proper measures to establish a low carbon society. This paper discusses a hybrid of the mixed data sampling (MIDAS) regression model and BP (back propagation) neural network (MIDAS-BP model) to forecast carbon dioxide emissions. Such analysis uses mixed frequency data to study the effects of quarterly economic growth on annual carbon dioxide emissions. The forecasting ability of MIDAS-BP is remarkably better than MIDAS, ordinary least square (OLS), polynomial distributed lags (PDL), autoregressive distributed lags (ADL), and auto-regressive moving average (ARMA) models. The MIDAS-BP model is suitable for forecasting carbon dioxide emissions for both the short and longer term. This research is expected to influence the methodology for forecasting carbon dioxide emissions by improving the forecast accuracy. Empirical results show that economic growth has both negative and positive effects on carbon dioxide emissions that last 15 quarters. Carbon dioxide emissions are also affected by their own change within 3 years. Therefore, there is a need for policy makers to explore an alternative way to develop the economy, especially applying new energy policies to establish a low carbon society. PMID- 29143934 TI - Evaluation of antioxidative and diabetes-preventive properties of an ancient grain, KAMUT(r) khorasan wheat, in healthy volunteers. AB - PURPOSE: Recently, there was an increasing interest on the use of ancient grains because of their better health-related composition. The aim of this study was to evaluate in healthy human subjects the antioxidative and diabetes-preventive properties of ancient KAMUT(r) khorasan wheat compared to modern wheat. METHODS: The study was a randomized, non-blind, parallel arm study where the biochemical parameters of volunteers with a diet based on organic whole grain KAMUT(r) khorasan products, as the only source of cereal products were compared to a similar replacement diet based on organic whole grain modern durum wheat products. A total of 30 healthy volunteers were recruited and the intervention period lasted 16 weeks. Blood analyses were performed before and after the diet intervention. The effect of KAMUT(r) khorasan products on biochemical parameters was analyzed by multiple quantile regression adjusted for age, sex, physical activity and BMI compared to data at baseline. RESULTS: Subjects receiving KAMUT(r) khorasan products showed a significantly greater decrease of fat mass (b = 3.7%; CI 1.6-5.5; p = 0.042), insulin (b = 2.4 uU/ml; CI 0.2-4.2; p = 0.036) and a significant increase of DHA (b = - 0.52%; CI - 1.1 to - 0.12; p = 0.021). CONCLUSIONS: Our study provides evidence that a substitution diet with KAMUT(r) khorasan wheat products can reduce some markers associated to the development of type-2 diabetes compared to a diet of modern wheat. PMID- 29143933 TI - Long-term effectiveness of tocilizumab in patients with rheumatoid arthritis, stratified by number of previous treatment failures with biologic agents: results from the German RABBIT cohort. AB - In Germany, Tocilizumab (TCZ) is used for the treatment of rheumatoid arthritis both in biologic-naive patients and those with previous failures of biologic disease-modifying antirheumatic drugs (bDMARDs). The long-term effectiveness and retention rates of TCZ in patients with different numbers of prior bDMARD failures has rarely been investigated. We included 885 RA patients in the analyses, enrolled with the start of TCZ between 2009 and 2015 in the German biologics register RABBIT. Patients were stratified according to prior bDMARD failures: no prior bDMARD or 1, 2 or >= 3 bDMARD failures. We applied Kaplan Meier methods and Cox-regression to examine treatment adherence as well as linear mixed effects models to investigate effectiveness over 3 years of follow-up. Compared to biologic-naive patients, those with prior bDMARD failures at start of TCZ were younger but had significantly longer disease duration and more comorbidities. DAS28 at baseline and loss of physical function were highest in patients with >= 3 bDMARD failures. During follow-up, patients with up to two bDMARD failures on average reached low disease activity (LDA, DAS28 < 3.2). Those with >= 3 prior bDMARDs had a slightly lower response. However, after 3 years, nearly 50% of them achieved LDA. Treatment continuation on TCZ therapy was similar in patients with <= 2 bDMARD failures but significantly lower in those with >= 3 bDMARD failures. TCZ seems to be similarly effective in patients with no, one or two prior bDMARD failures. The majority of patients achieved LDA already after 6 months and maintained it over a period of 3 years. TCZ proved effective even in the high-risk group of patients with more than two prior bDMARD failures. PMID- 29143936 TI - Retained placenta accreta with marked vascularity, uterine artery pseudoaneurysm, and placental polyp: overlapping clinical entities? PMID- 29143935 TI - A propensity-matched comparison of hard outcomes in children on chronic dialysis. AB - : Data concerning outcomes of children on hemodialysis (HD) and peritoneal dialysis (PD) are scarce and frequently derived from single-center experiences. We sought to compare survival and transplantation rates in a large cohort of PD and HD patients. We extracted all patients initiating dialysis under 16 years of age between 2004 and 2013 from the Italian Registry of Pediatric Chronic Dialysis. Patients on PD were propensity-matched to those on HD based on gender, age, primary cause of ESRD, and the number of co-morbidities. Stratified Cox proportional hazard models were used to compare outcomes by dialysis modality. Three hundred ten patients were matched from 452 incident patients. In the unmatched cohort, PD patients were younger, more likely to be diagnosed with CAKUT, and had a higher urine output than HD patients. In the propensity-matched cohort, covariates were balanced between the two groups. At 2 years, the cumulative hazard ratio for death was similar (CHR 0.95, 95% CI 0.17-5.20) for HD relative to PD patients; and at 5 years, the CHR was lower for HD patients (0.22 95% CI 0.16-0.29). The cumulative incidence of transplantation at 3 years after dialysis initiation was 60.9% in HD patients and 59.7% in PD patients, with a CHR of 1.03 (95% CI 0.73-1.45). CONCLUSIONS: Pediatric PD and HD patients have distinct characteristics. After controlling for treatment-selection biases, children selected to start on PD or HD exhibit a similar mortality risk during the first 2 years on treatment, after which this risk increases in PD children. What is Known: * Few studies have compared hard outcomes in children on maintenance dialysis. * Children started on different dialysis modalities have distinct characteristics that impact on survival. What is New: * After controlling for treatment-selection biases, children selected to start dialysis on PD or HD exhibit a similar mortality risk during the first 2 years on treatment, after which this risk appears to be increased in PD children. * An "integrative care" approach should be used in children on PD, switching them to HD when PD-related morbidity tends to increase. PMID- 29143937 TI - Reply to "Retained placenta accreta with marked vascularity, uterine artery pseudoaneurysm, and placental polyp: overlapping clinical entities?" PMID- 29143938 TI - Short hairpin RNA interference targeting interleukin 1 receptor type I in the paraventricular nucleus attenuates hypertension in rats. AB - Blood pressure is controlled by tonic sympathetic activities, excessive activation of which contributes to the pathogenesis and progression of hypertension. Interleukin (IL)-1beta in the paraventricular nucleus (PVN) is involved in sympathetic overdrive and hypertension. Here, we investigated the therapeutic effects of IL-1 receptor type I (IL-1R1) gene silencing in the PVN on hypertension. Recombinant lentivirus vectors expressing a short hairpin RNA (shRNA) targeting IL-1R1 (Lv-shR-IL-1R1) or a control shRNA were microinjected into PVN of spontaneously hypertensive rats (SHRs) and normotensive WKY rats. The fluorescence of green fluorescent protein-labelled vectors appeared at 2 weeks after injection and persisted for at least 8 weeks. IL-1R1 protein expression in the PVN was reduced 4 weeks after Lv-shR-IL-1R1 injection in SHRs. IL-1R1 interference also reduced basal sympathetic activity, cardiac sympathetic afferent reflex in SHRs. Depressor effects were observed from week 2 to 10 after Lv-shR-IL-1R1 treatment in SHRs, with the most prominent effects seen at the end of week 4. Furthermore, Lv-shR-IL-1R1 treatment decreased the ratio of left ventricular weight to body weight and cross-sectional areas of myocardial cells in SHRs. Additionally, Lv-shR-IL-1R1 treatment prevented an increase in superoxide anion and pro-inflammatory cytokines (PICs, TNF-alpha and IL-1beta) in the PVN of SHR, and upregulated anti-inflammatory cytokine (AIC, IL-10) expression. These results indicate that shRNA interference targeting IL-1R1 in the PVN decreases arterial blood pressure, attenuates excessive sympathetic activity and cardiac sympathetic afferent reflex, and improves myocardial remodelling in SHRs by restoring the balance between PICs and AICs to attenuate oxidative stress. PMID- 29143940 TI - Histogram analysis of diffusion kurtosis imaging derived maps may distinguish between low and high grade gliomas before surgery. AB - OBJECTIVE: To investigate the value of histogram analysis of diffusion kurtosis imaging (DKI) maps in the evaluation of glioma grading. METHODS: A total of 39 glioma patients who underwent preoperative magnetic resonance imaging (MRI) were classified into low-grade (13 cases) and high-grade (26 cases) glioma groups. Parametric DKI maps were derived, and histogram metrics between low- and high grade gliomas were analysed. The optimum diagnostic thresholds of the parameters, area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were achieved using a receiver operating characteristic (ROC). RESULT: Significant differences were observed not only in 12 metrics of histogram DKI parameters (P<0.05), but also in mean diffusivity (MD) and mean kurtosis (MK) values, including age as a covariate (F=19.127, P<0.001 and F=20.894, P<0.001, respectively), between low- and high-grade gliomas. Mean MK was the best independent predictor of differentiating glioma grades (B=18.934, 22.237 adjusted for age, P<0.05). The partial correlation coefficient between fractional anisotropy (FA) and kurtosis fractional anisotropy (KFA) was 0.675 (P<0.001). The AUC of the mean MK, sensitivity, and specificity were 0.925, 88.5% and 84.6%, respectively. CONCLUSIONS: DKI parameters can effectively distinguish between low and high-grade gliomas. Mean MK is the best independent predictor of differentiating glioma grades. KEY POINTS: * DKI is a new and important method. * DKI can provide additional information on microstructural architecture. * Histogram analysis of DKI may be more effective in glioma grading. PMID- 29143941 TI - Peer Victimization during Middle Childhood as a Marker of Attenuated Risk for Adult Arrest. AB - This longitudinal investigation examined interactions between aggression and peer victimization during middle childhood in the prediction of arrest through the adult years for 388 (198 boys, 190 girls) study participants. As part of an ongoing multisite study (i.e., Child Development Project), peer victimization and aggression were assessed via a peer nomination inventory in middle childhood, and juvenile and adult arrest histories were assessed via a self-report questionnaire as well as review of court records. Early aggression was linked to later arrest but only for those youths who were rarely victimized by peers. Although past investigators have viewed youths who are both aggressive and victimized as a high risk subgroup, our findings suggest that the psychological and behavioral attributes of these children may mitigate trajectories toward antisocial problems. PMID- 29143943 TI - The impact of ejaculatory abstinence on semen analysis parameters: a systematic review. AB - OBJECTIVE: The aim of this study was to evaluate recent publications and determine the impact of ejaculatory abstinence on semen analysis parameters as well as fertility outcomes. METHODS: This was a systematic review of 28 recent publications. The focus of this study was the impact of abstinence on semen parameters and fertility outcomes in papers published since the year 2000. The specific parameters evaluated were volume, sperm count, motility, morphology, pH, DNA fragmentation rate, viability, and pregnancy or fertilization rates following assisted reproduction. RESULTS: Twenty-eight recent publications met inclusion criteria. Analysis of publications showed that longer abstinence is associated with increases in semen volume and sperm count. Studies evaluating the effect of abstinence on motility, morphology, and DNA fragmentation rates are contradictory and inconclusive, although a trend appears to exist toward improvements in semen parameters with shorter abstinence. Semen pH was unaffected by abstinence. The majority of publications found no difference in rates of viability with varying abstinence times, although total number of viable sperm increases with increasing abstinence. Some studies evaluating the impact of ejaculatory abstinence on intrauterine insemination (IUI), intracytoplasmic sperm injection (ICSI), and in vitro fertilization (IVF) demonstrated an association between short abstinence and improved outcomes. CONCLUSIONS: The impact of abstinence on sperm quality is complex. While certain semen parameters improve with longer abstinence, others appear to improve with shorter abstinence. No clear recommendations can be made regarding ideal abstinence due to the conflicting nature of current evidence. Going forward, more research is needed to evaluate the impact of abstinence on pregnancy and fertilization rates. PMID- 29143944 TI - One thousand seventy-eight autologous IVF cycles in women 45 years and older: the largest single-center cohort to date. AB - PURPOSE: The purpose of this study was to determine IVF outcomes in women 45 years and older using autologous oocytes. METHODS: This is a retrospective cohort study reviewing all IVF cycles in women >= 45 years old from January 1995 to June 2015 that were conducted at one academic medical center. One thousand seventy eight fresh, autologous IVF cycles met inclusion criteria. PGD/S, natural IVF, and donor egg cycles were excluded. Outcomes were analyzed for the different age groups (age 45, n = 773; age 46, n = 221; age 47, n = 57; age 48, n = 22; age 49, n = 5). Primary outcome measures included IVF cycle characteristics, total pregnancy loss, clinical pregnancy, and live birth rates, and were stratified according to patient age. RESULTS: Mean age of patients in the study cohort was 45.4 +/- 0.72. 11.7% of patients did not start due to an elevated FSH or cyst and 28.5% of patients were canceled prior to oocyte retrieval. The overall pregnancy rate per transfer was 18.7% (117/626), of which 82.1% ended in a pregnancy loss. The overall clinical pregnancy and live birth rates per transfer were 9.6 and 3.4%, respectively, which did not differ between age groups. Per cycle start women aged 45 had significantly higher positive pregnancy rates compared to women aged 46 and 47 (14.1 vs. 8.6 vs. 5.9%, p = 0.04). For women 45 years old, the live birth rate was 2.9% per cycle start and was 4.4% per embryo transfer. Of the 21 live births, 20 were in women aged 45 and one live birth was in a 46-year-old woman. There were no live births in any patient with <= 4 oocytes retrieved. CONCLUSION: Autologous IVF in women aged 45 with acceptable ovarian reserve is not futile; however, it does carry very low prognosis. Patients aged 46 and older should be counseled appropriately that a live birth seems highly unlikely. PMID- 29143945 TI - One evidence of cocaine- and amphetamine-regulated transcript (CART) has the bidirectional effects on appetite in Siberian sturgeon (Acipenser baerii). AB - Cocaine- and amphetamine-regulated transcript (CART), discovered in 1995, with various biological functions, has received much attention recently due to its role in the regulation of appetite in mammals. However, the function of CART on the appetite control in fish species is still not very clear. In this study, Siberian sturgeon (Acipenser baerii Brandt) cart gene was cloned for the first time, and the cart mRNA levels in 11 feeding-related tissues was investigated. The Siberian sturgeon cart gene sequence was 1459 base pairs (bp), including a 3' terminal untranslated region (3'-UTR) of 39 bp, a 5'-terminal untranslated region (5'-UTR) of 52 bp, and an open reading frame (ORF) of 348 bp encoding 115 amino acids. Siberian sturgeon cart gene has three exons and two introns including 341 bp intron 1 and 679 bp intron 2. The result of tissue distribution showed that cart was widely distributed in 11 tissues with the highest expression in the whole brain. The effects of periprandial (pre- and post-feeding), fasting, and re feeding on cart mRNA abundance in the whole brain were assessed. Periprandial result showed the expression of cart mRNA in the whole brain significantly elevated after feeding for 3 h. However, fasting experiment showed that the level of cart significantly decreased after 1 day of fasting, but that significantly increased after 3-17 days of food deprivation and returned to the basic level after 3 days of re-feeding in the fishes which were fasted for 15 days. In conclusion, this study suggests that CART has the bidirectional effects on appetite, which acts as a satiety factor in short-term feeding regulation but as a starvation factor in long-term appetite regulation in Siberian sturgeon. PMID- 29143947 TI - Connexin 30 is expressed in a subtype of mouse brain pericytes. AB - Pericytes are mural cells of blood microvessels which play a crucial role at the neurovascular interface of the central nervous system. They are involved in the regulation of blood-brain barrier integrity, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses, and neuroinflammation, and they demonstrate stem cell activity. Morphological and molecular studies to characterize brain pericytes recently pointed out some heterogeneity in pericyte population. Nevertheless, a clear definition of pericyte subtypes is still lacking. Here, we demonstrate that a fraction of brain pericytes express Connexin 30 (Cx30), a gap junction protein, which, in the brain parenchyma, was thought to be exclusively found in astrocytes. Cx30 could thus be a candidate protein in the composition of the gap junction channels already described between endothelial cells and pericytes. It could also form hemichannels or acts in a channel independent manner to regulate pericyte morphology, as already observed in astrocytes. Altogether, our results suggest that Cx30 defines a novel brain pericyte subtype. PMID- 29143949 TI - [Psychiatry: between fads and facts]. PMID- 29143948 TI - Label-free NMR-based dissociation kinetics determination. AB - Understanding the dissociation of molecules is the basis to modulate interactions of biomedical interest. Optimizing drugs for dissociation rates is found to be important for their efficacy, selectivity, and safety. Here, we show an application of the high-power relaxation dispersion (RD) method to the determination of the dissociation rates of weak binding ligands from receptors. The experiment probes proton RD on the ligand and, therefore, avoids the need for any isotopic labeling. The large ligand excess eases the detection significantly. Importantly, the use of large spin-lock fields allows the detection of faster dissociation rates than other relaxation approaches. Moreover, this experimental approach allows to access directly the off-rate of the binding process without the need for analyzing a series of samples with increasing ligand saturation. The validity of the method is shown with small molecule interactions using two macromolecules, bovine serum albumin and tubulin heterodimers. PMID- 29143946 TI - Multi-scale account of the network structure of macaque visual cortex. AB - Cortical network structure has been extensively characterized at the level of local circuits and in terms of long-range connectivity, but seldom in a manner that integrates both of these scales. Furthermore, while the connectivity of cortex is known to be related to its architecture, this knowledge has not been used to derive a comprehensive cortical connectivity map. In this study, we integrate data on cortical architecture and axonal tracing data into a consistent multi-scale framework of the structure of one hemisphere of macaque vision related cortex. The connectivity model predicts the connection probability between any two neurons based on their types and locations within areas and layers. Our analysis reveals regularities of cortical structure. We confirm that cortical thickness decays with cell density. A gradual reduction in neuron density together with the relative constancy of the volume density of synapses across cortical areas yields denser connectivity in visual areas more remote from sensory inputs and of lower structural differentiation. Further, we find a systematic relation between laminar patterns on source and target sides of cortical projections, extending previous findings from combined anterograde and retrograde tracing experiments. Going beyond the classical schemes, we statistically assign synapses to target neurons based on anatomical reconstructions, which suggests that layer 4 neurons receive substantial feedback input. Our derived connectivity exhibits a community structure that corresponds more closely with known functional groupings than previous connectivity maps and identifies layer-specific directional differences in cortico-cortical pathways. The resulting network can form the basis for studies relating structure to neural dynamics in mammalian cortex at multiple scales. PMID- 29143950 TI - [The effect of a short-term group stabilisation training in patients with complex posttraumatic stress disorder]. AB - BACKGROUND: The international guideline for complex posttraumatic stress disorder (ptsd) from the International Society for Traumatic Stress Studies (istss) recommends treatment in phases, starting with stabilisation treatment. Different forms of stabilisation training have been developed the past few years, one being short-term group stabilisation training.
AIM: To map out the effects of the short-term group training.
METHOD: The research implemented a pre-post design. The training consisted of five group sessions. Questionnaires (bsi, OQ 45 and svl-15) were completed both prior to and after the training. Four domains were assessed: psychosymptomatology in general, depressive symptoms, problems with interpersonal functioning and ptsd-related symptoms. The effect of the training was calculated by paired t-tests.
RESULTS: The questionnaires of the 47 participants who had completed the training were analysed. No significant decrease was observed during the stabilisation training concerning the symptoms of the four evaluated domains.
CONCLUSION: Contrary our expectations, a short-term group-based stabilisation training does not seem to have added value when treating patients with complex ptsd. The results correspond with a recent trend in which the effectiveness of other stabilising methods is questioned. Alternative treatment options are discussed. PMID- 29143951 TI - [Matched care for complex PTSD: what works for whom?] PMID- 29143952 TI - [The effect of mood-stabilising drugs on cytokine levels in bipolar disorder: a systematic review]. AB - ACHTERGROND: Veranderde cytokineconcentraties bij personen met een bipolaire stoornis ten opzichte van controle-personen suggereren een rol van het immuunsysteem in de pathofysiologie van bipolaire stoornis. Farmacotherapie is een belangrijke verstorende factor in klinisch onderzoek naar cytokineconcentraties.
DOEL: Evalueren van cytokineconcentraties bij medicatievrije patienten met een bipolaire stoornis en van het effect van stemmingsstabiliserende geneesmiddelen op deze concentraties.
METHODE: We doorzochten systematisch PubMed en Embase naar klinische studies die cytokineconcentraties bij medicatievrije patienten met een bipolaire stoornis beschrijven of het effect van een individueel stemmingsstabiliserend geneesmiddel op deze concentraties evalueren.
RESULTATEN: Van de 564 gescreende artikelen werden er 17 geincludeerd. Resultaten bij medicatievrije patienten toonden stemmingsgerelateerde cytokineveranderingen. Hoewel geen data over de kortetermijneffecten van lithium beschikbaar waren, was lithiumgebruik langer dan 2 maanden geassocieerd met normale cytokineconcentraties. Twee studies rapporteerden geen effect van valproinezuur. We vonden geen studies over carbamazepine, lamotrigine of antipsychotica.
CONCLUSIE: Dit systematisch literatuuroverzicht toont stemmingsgerelateerde cytokineveranderingen bij medicatievrije patienten met een bipolaire stoornis met de meeste evidentie voor een pro-inflammatoire immuunrespons tijdens manie. Euthymie en langdurig lithiumgebruik zijn geassocieerd met normale cytokineconcentraties. Er is een belangrijke methodologische heterogeniteit en onvoldoende replicatie tussen studies. Longitudinale studies met medicatievrije beginmetingen, gerandomiseerde monotherapeutische behandelprotocollen en nauwkeurige monitoring van stemming zijn noodzakelijk.
BACKGROUND: Alterations of the cytokine level in persons with bipolar disorder - when compared to controls - suggest that the immune system plays a role in the pathophysiology of bipolar disorder. Pharmacotherapy is an important confounding factor in clinical research on cytokine levels.
AIM: To evaluate the evidence on cytokine levels in medication-free bipolar disorder and to study the effects that single mood-stabilising drugs have on these levels.
METHOD: We searched PubMed and Embase systematically in order to single out clinical studies that reported on cytokine levels in medication free bipolar disorder or that commented on the effects of single mood-stabilising drugs on cytokine levels.
RESULTS: Of the 564 articles that we screened, we detected 17 that were particularly relevant for our investigation. Results for medication-free patients point to mood-related alterations in cytokine levels. Although we found no data relating to short-term effects of lithium, the use of lithium in euthymic populations was associated with normal cytokine levels. Two studies reported no effect of valproate. We did not find any studies relating to carbamazepine, lamotrigine or antipsychotics.
CONCLUSION: Our systematic review of the literature suggests the presence of mood-related changes in cytokine levels in medication-free patients with bipolar disorder, with the most evidence for a proinflammatory response during a manic episode. Euthymia and long term use of lithium use are associated with normal cytokine levels. There is considerable heterogeneity in the methods used in these studies and too little replication. Future research will have to include longitudinal studies with medication-free baseline measurements. It will also be necessary to draw up single-drug treatment protocols and to conduct intensive mood-related monitoring. PMID- 29143953 TI - [Older patients with a bipolar disorder, a distinctive group]. AB - BACKGROUND: The number of older adults with bipolar disorders is growing and warrants a specific approach. Recommendations, as in the current guideline, are mostly based on research in samples with younger patients or from the United States, as best available evidence.
AIM: To raise awareness of the limitations of the current guidelines for older adults with bipolar disorder.
METHOD: We present a selection of Dutch studies on older adults with bipolar disorder and compared these findings with research done in younger patients or older patients from the United States.
RESULTS: Psychiatric comorbidity is relatively rare, somatic comorbidity is more frequent as is medication use. Cognition is impaired, but stable after 5 years of follow-up. Social functioning is associated with cognition. Less than half of the older adults with bipolar disorders reported unmet needs, mostly on company and daily activities.
CONCLUSION: Dutch research on older adults with bipolar disorder confirms the differences with younger patients with bipolar disorder and their American peers. Recommendations can't be extrapolated to older adults with bipolar disorders. More research is needed to provide evidence based guidelines for this special population. PMID- 29143955 TI - ? PMID- 29143954 TI - [Why Dutch mental health care practitioners should have second thoughts about adopting the English cluster model]. AB - BACKGROUND: Administrators and policymakers in the Netherlands have concluded, after considerable deliberation, that the existing Dutch diagnosis-related group (drg)-based system of diagnosis treatment combinations for funding mental health care should be replaced by the so-called English model. The details, however, need to be analysed very carefully by Dutch professional health care practitioners.
AIM: To make the reader aware of the reasons why the English model should not be adopted in the Netherlands.
METHOD: We describe and analyse the English cluster model and the referral instrument (the Honos, supplemented by six items) and we demonstrate how it is applied in England. We also describe and analyse the actions and activities pursued by the Dutch Healthcare Authority (nza) to introduce the model in the Netherlands.
RESULTS: There are strong objections to the English model. One of the most important is that the mental health care system will suffer when its connections are severed between its funding sources from internationally recognised and scientifically important classification systems such as dsm, icd and icf. Another major objection is that the proposed clustering system is conceptually weak and is not based on convincing analyses. Furthermore, the Honos is an instrument for measuring outcomes and is not appropriate for assigning patients to specific types of care. In England the model is very rarely used as an instrument for assigning patients to care.
CONCLUSION: Dutch mental health care practitioners should have second thoughts about deciding to adopt the English model. PMID- 29143956 TI - [Intensive home treatment: a first observational evaluation]. AB - BACKGROUND: Yulius intensive home treatment (iht) offers six weeks of home-care to psychiatric patients in crisis who would normally be hospitalised.
AIM: To study patient characteristics and the content and outcomes of iht.
METHOD: We followed the handling of 75 consecutive applications for iht. Details were recorded before and after admission to the treatment.
RESULTS: Fifteen patients were referred in order to shorten the period of hospitalisation, and 60 were referred in order to prevent hospitalisation; 59 of the 75 persons admitted for the treatment received iht, and 41 patients finished the six-week module and provided follow-up data. Psychiatric symptoms improved significantly, suicidality was reduced, the caregiver's burden became much lighter and the evaluation by both patient and caregiver was very positive. iht was sufficient to prevent the need for hospitalisation of 75% of the patients referred for reduced hospitalisation, and it was also adequate to prevent the hospitalisation of more than 91% of patients referred for that particular purpose.
CONCLUSION: iht is highly appreciated and is possibly a good alternative to hospitalisation. However, in the future there will have to be randomised, controlled research in order to determine the effectiveness of iht compared to hospitalisation. PMID- 29143957 TI - [Differences in non-native resident psychiatrists and native residents psychiatrists in completion of the psychiatry residency training programmes]. AB - BACKGROUND: A relatively small number of psychiatrists in the Netherlands have a non-Dutch origin. We suspect that resident psychiatrists who do not have Dutch as their first language are less likely than native Dutch speakers to complete the psychiatry residency training programmes.
AIM: To find out how often and for what reasons resident psychiatrists do not complete the psychiatry residency training programmes.
METHOD: All course coordinators in the Netherlands were asked to participate in a survey to provide information about the residents who had started but had abandoned the psychiatry residency training programmes between the years 2008 and 2015. They were also asked about factors that had influenced residents to abandon the course.
RESULTS: We were able to obtain data on 37% of the trainees. The data revealed that the number of non-native resident psychiatrists who failed to complete the training course was almost four times higher than the number of native trainee psychiatrists who dropped out before the end of the course. According to the coordinators, possible reasons for this discrepancy are lack of proficiency in Dutch, communication problems and cultural differences.
CONCLUSION: The results of our survey could possibly be used to adjust the training programmes. PMID- 29143958 TI - Intraspinal mesenchymal chondrosarcoma: report of a pediatric case and literature review. AB - PURPOSE: Mesenchymal chondrosarcoma (MCS) is an aggressive variant of chondrosarcoma and is a rare tumor, particularly within the pediatric population. Commonly, MCS originates in the bone, but it can also arise in extraskeletal sites, such as the brain and the intraspinal area. Due to the rarity of this tumor, there are no guidelines for its optimal treatment. METHODS: We report a case of intradural extramedullary MCS, located at the T11-T12 level, in a 14-year old male. The tumor was documented by magnetic resonance imaging and treated with gross total resection (GTR) without adjuvant treatment. We further reviewed the relevant pediatric literature and discussed the management and outcome of intracranial and intraspinal MCS. RESULTS: The patient's follow-up showed no evidence of disease 2 years from diagnosis. A total of 51 cases of intracranial and intraspinal MCS have been reported (24 intraspinal and 27 intracranial). Recurrence has been described in only 4 patients with intraspinal MSC, and among them 3 received adjuvant chemotherapy and radiotherapy. GTR seems to reduce the risk of recurrence and, due to a higher cancer-mortality rate for these patients, adjuvant chemotherapy and radiotherapy are recommended in case aggressive surgery is not possible. CONCLUSIONS: According to our single experience, we would suggest that adjuvant therapy might be unnecessary in cases where a localized MCS undergoes GTR. Chemotherapy and radiotherapy should be recommended when GTR cannot be obtained. Further studies are needed to investigate a standard treatment approach for this rare tumor. PMID- 29143959 TI - Intracapsular carcinoma ex-pleomorphic adenoma of the parapharyngeal space: report of two cases and review of the literature. AB - BACKGROUND: Carcinoma ex-pleomorphic adenoma of the parapharyngeal space is an exceedingly rare entity. METHODS: The clinical records of two patients with primary carcinoma ex-pleomorphic adenoma of the parapharyngeal space surgically treated at two different centers were retrospectively analyzed. RESULTS: Despite ultrasound-guided fine-needle aspiration cytology and magnetic resonance imaging, the correct diagnosis was preoperatively missed in both cases. Excision was obtained through a transcervical-transparotid approach in 1 case and a minimally invasive endoscopic-assisted transcervical approach in the other. Definitive histology was consistent with intracapsular carcinoma ex-pleomorphic adenoma. Adjuvant radiotherapy was performed in the case with macroscopic malignant degeneration; both patients are alive and free from disease 36 months after surgery. CONCLUSIONS: Carcinoma ex-pleomorphic adenoma of the parapharyngeal space is a rare disease, and definitive diagnosis may be challenging. Surgery is the mainstay of treatment, but adjuvant radiotherapy also may be required in the presence of specific risk factors. PMID- 29143960 TI - Predicting frequent emergency department use among children with epilepsy: A retrospective cohort study using electronic health data from 2 centers. AB - OBJECTIVE: Among children with epilepsy, to develop and evaluate a model to predict emergency department (ED) use, an indicator of poor disease control and/or poor access to care. METHODS: We used electronic health record data from 2013 to predict ED use in 2014 at 2 centers, benchmarking predictive performance against machine learning algorithms. We evaluated algorithms by calculating the expected yearly ED visits among the 5% highest risk individuals. We estimated the breakeven cost per patient per year for an intervention that reduced ED visits by 10%. We estimated uncertainty via cross-validation and bootstrapping. RESULTS: Bivariate analyses showed multiple potential predictors of ED use (demographics, social determinants of health, comorbidities, insurance, disease severity, and prior health care utilization). A 3-variable model (prior ED use, insurance, number of antiepileptic drugs [AEDs]) performed as well as the best machine learning algorithm at one center (N = 2730; ED visits among top 5% highest risk, 3-variable model, mean = 2.9, interquartile range [IQR] = 2.7-3.1 vs Random Forest, mean = 2.9, IQR = 2.7-3.1), and superior at the second (N = 784; mean = 2.5, IQR = 2.2-2.9 vs mean = 1.9, IQR = 1.6-2.5). The per-patient-per-year breakeven point using this model to identify high-risk individuals was $958 (95% confidence interval [CI] = $568-$1390) at one center and $1086 (95% CI = $886 $1320) at the second. SIGNIFICANCE: Prior ED use, insurance status, and number of AEDs, taken together, predict future ED use for children with epilepsy. Our estimates suggest a program targeting high-risk children with epilepsy that reduced ED visits by 10% could spend approximately $1000 per patient per year and break even. Further work is indicated to develop and evaluate such programs. PMID- 29143961 TI - Upregulation of epidermal gap junctional proteins in patients with venous disease. AB - BACKGROUND: Leg ulceration is a feared complication of venous insufficiency. It is not known whether varicose veins predispose skin to poor wound healing. The expression pattern of gap junctional protein connexin, a known marker of poor wound healing, was investigated across various stages of venous disease. METHODS: Patients undergoing intervention for varicose veins were assessed according to the Clinical Etiologic Anatomic Pathophysiologic (CEAP) classification of varicose veins. Paired 4-mm punch biopsies were taken from above the ankle (pathological) and above the knee (control). Tissues were stained with haematoxylin and eosin, and for connexin 43, connexin 30 and connexin 26. RESULTS: Forty-eight paired biopsies were taken (12 each for CEAP class C0, C2, C4 and C6). The pathological skin showed progressive epithelial hyperthickening, an increase in the number and depth of rete ridges, increased inflammation and loss of dermal architecture with disease progression from C4 onwards. The overall absolute connexin expression and mean connexin expression per cell in the pathological skin similarly increased across the CEAP classes from as early as C2. Increasing levels of connexin in control skin were also noted, indicating progression of the disease proximally. Connexin 43 expression showed the strongest positive correlation between pathological and control skin. CONCLUSION: Connexins were overexpressed in patients with simple varicose veins, with a stepwise increased expression through venous eczema to ulceration. Connexin 43 is a potential biomarker for venous disease. This finding suggests that varicose veins predispose skin to poor wound healing. Surgical relevance The overexpression of connexins, a family of gap junctional proteins, is known to cause poor healing in venous leg ulceration. It is not known whether there is any association with superficial venous disease. Here, connexin proteins were overexpressed in patients with uncomplicated varicose veins, before histological skin changes. Connexin could be a biomarker of venous disease progression. PMID- 29143962 TI - Comparison of gene expression in post-smolt Atlantic salmon challenged by LF-89 like and EM-90-like Piscirickettsia salmonis isolates reveals differences in the immune response associated with pathogenicity. AB - Piscirickettsiosis is the main bacterial disease affecting the Chilean salmon farming industry and is responsible for high economic losses. The aim of this study was to describe and comparatively quantify the immune response of post smolt Atlantic salmon infected by cohabitation with fish bearing LF-89-like and EM-90-like Piscirickettsia salmonis. The expression of 17 genes related to the immune response was studied in head kidney from cohabitant fish by RT-qPCR. Our results at the transcriptomic level suggest that P. salmonis is able to manipulate the kinetics of cytokine production in a way that might constitute a virulence mechanism that promotes intracellular bacterial replication in cells of Atlantic salmon. This strategy involves the creation of an ideal environment for the microorganism based on induction of the inflammatory and IFN-mediated response, modulation of Th1 polarization, reduced antigen processing and presentation, modulation of the evasion of the immune response mediated by CD8+ T cells and promotion of the CD4+ T-cell response during the late stage of infection as a mechanism to escape host defences. This response was significantly exacerbated in fish infected by PS-EM-90 compared with fish infected by PS-LF-89, a finding that is probably associated with the higher pathogenicity of PS-EM-90. PMID- 29143964 TI - Signatures of selection in embryonic transcriptomes of lizards adapting in parallel to cool climate. AB - Populations adapting independently to the same environment provide important insights into the repeatability of evolution at different levels of biological organization. In the 20th century, common wall lizards (Podarcis muralis) from southern and western Europe were introduced to England, north of their native range. Nonnative populations of both lineages have adapted to the shorter season and lower egg incubation temperature by increasing the absolute rate of embryonic development. Here, we tested if this adaptation is accompanied by signatures of directional selection in the transcriptomes of early embryos and, if so, if nonnative populations show adaptive convergence. Embryos from nonnative populations exhibited gene expression profiles consistent with directional selection following introduction, but different genes were affected in the two lineages. Despite this, the functional enrichment of genes that changed their expression following introduction showed substantial similarity between lineages, and was consistent with mechanisms that should promote developmental rate. Moreover, the divergence between nonnative and native populations was enriched for genes that were temperature-responsive in native populations. These results indicate that small populations are able to adapt to new climatic regimes, but the means by which they do so may largely be determined by founder effects and other sources of genetic drift. PMID- 29143963 TI - Expression of paraoxonase types 1, 2 and 3 in reproductive tissues and activity of paraoxonase type 1 in the serum and seminal plasma of bulls. AB - The paraoxonases types 1, 2 and 3 (PON1, PON2 and PON3, respectively) are enzymes that degrade lipid peroxides, preventing oxidative damages relevant for male reproductive function. This study determined the expression of those three paraoxonases in reproductive tissues of bulls and evaluated correlations among the activity of PON1 in the serum and seminal plasma with breeding soundness parameters in bulls. The expression of PON1, PON2 and PON3 was characterised by RT-PCR in samples of testicular parenchyma, vesicular glands and epididymis collected from three slaughtered bulls. All three paraoxonases were expressed in the testicular parenchyma, PON2 and PON3 were both expressed in the epididymis head and PON3 was also expressed in the epididymis tail. The PON1 activity was determined in samples of serum and seminal plasma from 110 bulls submitted to breeding soundness evaluation. There was a strong correlation (r = .90) between the activity of the PON1 in both serum and seminal plasma (p < .0001). The PON1 activity in the seminal plasma was positively correlated with ejaculate's colour, sperm mass activity (p = .04), motility, vigour and viability (all p < .01). Thus, PON1 may be a potential marker for sperm motility and viability in bulls. PMID- 29143965 TI - Display stability of fresh and thawed lamb supplemented with vitamin E or sprayed with an antioxidant borage seed extract. AB - BACKGROUND: The commercialization of thawed lamb packaged in modified atmosphere and maintained on display could serve as an alternative capable of satisfying the requirements of both customers and distributors. However, previous studies have suggested that lipid oxidation may accelerate post-thawing because peroxidation occurs during frozen storage, thereby leading to rapid and severe secondary lipid oxidation. The addition of an antioxidant compound either in the lamb diet or in the packaged meat could resolve this problem. Therefore, the present study aimed to compare the effect of dietary vitamin E (1000 mg of dl-alpha-tocopheryl acetate per kg of basal diet) and the spraying of borage seed aqueous extract (10% p/v) on the quality of fresh and thawed lamb leg chops. RESULTS: Both borage extract and vitamin E improved colour (as measured via instrumental and visual assessment of colour) and lipid stability (thiobarbituric acid reactive substances) of fresh and thawed lamb throughout display, although neither of them had any antimicrobial effect. Freezing/thawing accelerated bone marrow darkening and reduced redness but delayed microbial growth. CONCLUSION: Both of these antioxidant strategies would be very profitable for the preservation of lamb meat, allowing thawed meat packaged in a modified atmosphere to be commercialized. However, additional studies should be carried out to determine how bone darkening in thawed chops can be avoided. (c) 2017 Society of Chemical Industry. PMID- 29143966 TI - Drug interaction at hERG channel: In vitro assessment of the electrophysiological consequences of drug combinations and comparison against theoretical models. AB - Drugs carry a proarrhythmic risk, which gets even greater when they are used in combination. In vitro assessment of the proarrhythmic potential of drugs is limited to one compound and thus neglects the potential of drug-drug interactions, including those involving active metabolites. Here we present the results of an in vitro study of potential drug-drug interactions at the level of the hERG channel for the combination of up to three compounds: loratadine, desloratadine and ketoconazole. Experiments were performed at room temperature on an automated patch-clamp device CytoPatch 2, with the use of heterogeneously, stably transfected HEK cells. Single drugs, pairs and triplets were used. The results provided as the inhibition of the IKr current for pairs were compared against the calculated theoretical interaction. Models applied to calculate the combined effect of inhibitory actions of simultaneously given drugs include: (1) simple additive model with a maximal inhibition limit of 1 (all channels blocked in 100%); (2) Bliss independence; and (3) Loewe additivity. The observed IC50 values for loratadine, desloratadine and ketoconazole were 5.15, 1.95 and 0.74 MUm respectively. For the combination of drugs tested in pairs, the effect was concentration dependent. In lower concentrations, the synergistic effect was observed, while for the highest tested concentrations it was subadditive. To triple the effect, it was subadditive regardless of concentrations. The square root of sum of squares of differences between the observed and predicted total inhibition was calculated to assess the theoretical interaction models. For most of the drugs, the allotopic model offered the best fit. PMID- 29143967 TI - Thirteen week toxicity study of dietary l-tryptophan in rats with a recovery period of 5 weeks. AB - Although l-tryptophan is nutritionally important and widely used in medical applications, toxicity data for its oral administration are limited. The purpose of this study was to evaluate the potential toxicity of an experimental diet containing added l-tryptophan at doses of 0 (basal diet), 1.25%, 2.5% and 5.0% when administered to Sprague-Dawley rats for 13 weeks. There were no toxicological changes in clinical signs, ophthalmology, urinalysis, hematology, necropsy, organ weight and histopathology between control rats and those fed additional l-tryptophan. Body weight gain and food consumption significantly decreased throughout the administration period in males in the 2.5% group and in both sexes in the 5.0% group. At the end of the dosing period, decreases in water intake in males in the 5.0% group and in serum glucose in females in the 5.0% group were observed. The changes described above were considered toxicologically significant; however, they were not observed after a 5 week recovery period, suggesting reversibility. Consequently, the no-observed-adverse-effect level of l tryptophan in the present study was 1.25% for males and 2.5% for females (mean intake of l-tryptophan: 779 mg kg-1 body weight day-1 [males] and 1765 mg kg-1 body weight day-1 [females]). As the basal diet used in this study contained 0.27% of proteinaceous l-tryptophan, the no-observed-adverse-effect level of overall l-tryptophan was 1.52% for males and 2.77% for females (mean intake of overall l-tryptophan: 948 mg kg-1 body weight day-1 (males) and 1956 mg kg-1 body weight day-1 (females)). We conclude that l-tryptophan has a low toxicity profile in terms of human use. PMID- 29143968 TI - Correlating the vibrational spectra of structurally related molecules: A spectroscopic measure of similarity. AB - Using catastrophe theory and the concept of a mutation path, an algorithm is developed that leads to the direct correlation of the normal vibrational modes of two structurally related molecules. The mutation path is defined by weighted incremental changes in mass and geometry of the molecules in question, which are successively applied to mutate a molecule into a structurally related molecule and thus continuously converting their normal vibrational spectra from one into the other. Correlation diagrams are generated that accurately relate the normal vibrational modes to each other by utilizing mode-mode overlap criteria and resolving allowed and avoided crossings of vibrational eigenstates. The limitations of normal mode correlation, however, foster the correlation of local vibrational modes, which offer a novel vibrational measure of similarity. It will be shown how this will open new avenues for chemical studies. (c) 2017 Wiley Periodicals, Inc. PMID- 29143969 TI - The molecular basis of cytotoxicity of alpha-spinasterol from Ganoderma resinaceum: Induction of apoptosis and overexpression of p53 in breast and ovarian cancer cell lines. AB - Despite advances in therapy of breast and ovarian cancers, they still remain among the most imperative causes of cancer death in women. The first can be considered one of the most widespread diseases among females, while the latter is more lethal and needs prompt treatment. Thus, the research field can still benefit from discovery of new compounds that can be of potential use in management of these grave illnesses. We hereby aimed to assess the antitumor activity of the phytosterol alpha-spinasterol isolated from Ganoderma resinaceum mushroom on human breast cancer cell lines (MCF-7, MDA-MB-231), as well as, on human ovarian cancer cell line (SKOV-3). The anti-tumor activity of alpha spinasterol, isolated from the mycelial extract of the Egyptian G. resinaceum, on human breast and ovarian cancer cell lines was evaluated by MTT cell viability assay and AnnexinV/propidium iodide apoptosis assay. The molecular mechanism underlying this effect was assessed by the relative expression of the following markers; tumor suppressor (p53, BRCA1, BRCA2), apoptotic marker (Bax) and cell cycle progression markers (cyclin dependent kinases cdk4/6) using real-time PCR. Cell cycle analysis was performed for the three investigated cancer cell lines to explore the effect on cell cycle progression. Our findings showed that alpha spinasterol exhibited a higher antitumor activity on MCF-7 cells relative to SKOV 3 cells, while its lowest antitumor activity was against MDA-MB-231 cells. A significant increase in the expression of p53 and Bax was observed in cells treated with alpha-spinasterol, while cdk4/6 were significantly down-regulated upon exposure to alpha-spinasterol. Cell cycle analysis of alpha-spinasterol treated cells showed a G0 -G1 arrest. In conclusion, alpha-spinasterol isolated from G. resinaceum mushroom exerts a potent inhibitory activity on breast and ovarian cancer cell lines in a time- and dose-dependent manner. This can be reasonified in lights of the compound's ability to increase p53 and Bax expressions, and to lower the expression of cdk4/6. PMID- 29143970 TI - Sample preparation for large-scale bioanalytical studies based on liquid chromatographic techniques. AB - Quality of the analytical data obtained for large-scale and long term bioanalytical studies based on liquid chromatography depends on a number of experimental factors including the choice of sample preparation method. This review discusses this tedious part of bioanalytical studies, applied to large scale samples and using liquid chromatography coupled with different detector types as core analytical technique. The main sample preparation methods included in this paper are protein precipitation, liquid-liquid extraction, solid-phase extraction, derivatization and their versions. They are discussed by analytical performances, fields of applications, advantages and disadvantages. The cited literature covers mainly the analytical achievements during the last decade, although several previous papers became more valuable in time and they are included in this review. PMID- 29143971 TI - Industry Perspective on Biomarker Development and Qualification. AB - Pharmaceutical and biotechnology companies routinely use biomarkers to obtain quantitative metrics for drug exposure, efficacy, and safety and to inform clinical trial design with regard to patient selection, treatments, and outcomes. Biomarker science has the unique capability to catalyze precompetitive collaborations between academia, industry, regulatory agencies, and other stakeholders with the ultimate goal of accelerating the delivery of safe and effective medicines to patients, particularly in areas of high unmet need. PMID- 29143972 TI - Determination of tubuloside B by LC-MS/MS and its application to a pharmacokinetic study in rats. AB - Tubuloside B, a novel neuroprotective phenylethanoid, is a major active constituent of Cistanche tubulosa and Cistanche deserticola. A specific and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the quantification of tubuloside B in rat plasma. Sample preparation was conducted through a protein-precipitation extraction with methanol using tubuloside A as internal standard (IS). Chromatographic separation was achieved using a Capcell Pak C18 column (2.0 * 50 mm, 5 MUm) with a mobile phase of methanol-10 mm ammonium acetate buffer (70:30, v/v) in an isocratic elution. Mass spectrometry analysis was performed in negative ionization mode with selected reaction monitoring transitions at m/z 665.1 -> 160.9 for tubuloside B, and m/z 827.1 -> 160.9 for IS. Calibration curves were linear over the range of 1.64-1640 ng/mL for plasma samples samples (R2 > 0.990). The lower limit of quantification (LLOQ) was 1.64 ng/mL. The intra- and inter-day accuracy was between 92.3 and 113.0% with the RSD <9.23% at all LLOQ and quality control levels. Finally, this method was successfully applied in the pharmacokinetics study of tubuloside B after intravenous administration. PMID- 29143973 TI - Effects of microRNA-24 targeting C-myc on apoptosis, proliferation, and cytokine expressions in chondrocytes of rats with osteoarthritis via MAPK signaling pathway. AB - To investigate whether microRNA-24 (miR-24) targeting C-myc affects chondrocytes of rats with osteoarthritis (OA) via the MAPK signaling pathway. Thirty rats were assigned as a sham group and an OA group (established as OA rat models by cutting the anterior cruciate ligaments and removing 1/3 medial meniscus). TUNEL staining and immunohistochemistry were conducted for cell apoptosis index (AI) and positive expression rate of C-myc protein. Enzyme-linked immuno sorbent assay (ELISA) was carried out for serum level of IL-1beta and TNF-alpha. Primary chondrocytes were assigned into the blank, negative control (NC), miR-24 mimics, miR-24 inhibitors, siRNA-C-myc, and miR-24 inhibitors+siRNA-C-myc groups. The expressions of miR-24, C-myc, p38, ERK, JNK, IL-1beta, and TNF-alpha in tissues and cells were detected using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and Western blotting. CCK8 assay and flow cytometry were performed for cell proliferation and apoptosis. The OA group showed higher IL-1beta, TNF-alpha, AI, and C-myc than the sham group. C-myc is a target gene of miR-24. Compared with the blank group, the miR-24 mimics and siRNA C-myc groups showed reduced expression of C-myc, IL-1beta, TNF-alpha, p38, p-p38, ERK, p-ERK, JNK, and p-JNK, apoptosis rate yet increased cell proliferation; however, the miR-24 inhibitors group exhibited an opposite trend. The miR-24 inhibitors+siRNA-C-myc group presented a same tendency compared to the siRNA-C myc group. Upregulated miR-24 downregulates C-myc could suppress apoptosis and promote proliferation of chondrocytes to prevent the occurrence and subsequent progression of OA via inactivating the MAPK signaling pathway. PMID- 29143974 TI - gamma-H2AX formation in the urinary bladder of rats treated with two norharman derivatives obtained from o-toluidine and aniline. AB - Aminomethylphenylnorharman (AMPNH) and aminophenylnorharman (APNH) are mutagenic norharman derivatives obtained from o-toluidine and aniline, respectively. APNH is carcinogenic to the urinary bladder of rats and present in urine samples of healthy volunteers, indicating that norharman derivatives may be associated with cancer development in the urinary bladder of humans. To evaluate the possible role of AMPNH and APNH in bladder carcinogenesis, we examined the formation of gamma-H2AX, a DNA damage response marker, in the urinary bladder of rats. Seven week-old male F344 rats were treated with 400 ppm AMPNH or 40 ppm APNH in the diet for 4 weeks. Animals were killed at the end of administration or after 2 weeks of recovery, and immunohistochemistry for gamma-H2AX and Ki67, a cell proliferation marker, was performed. At week 4, gamma-H2AX formation in bladder epithelial cells was significantly increased by APNH treatment as compared with that in controls. AMPNH also induced upregulation of gamma-H2AX formation, although there was no statistical significance. After the recovery period, gamma H2AX-positive cells were reduced but remained significantly higher in AMPNH and APNH groups than in the control group. Ki67-positive cells were significantly increased by AMPNH and APNH at week 4 and reduced to the same level as the control after 2 weeks of recovery. Expression of KRT14, a bladder stem cell marker, was also increased in the basal layer by the two norharman derivatives. Thus, AMPNH and APNH showed in vivo genotoxicity in the bladder epithelium of rats, and APNH may be a potent causative agent of bladder carcinogenesis. PMID- 29143975 TI - Sustained cardiac programming by short-term juvenile exercise training in male rats. AB - KEY POINTS: Cardiac hypertrophy following endurance-training is thought to be due to hypertrophy of existing cardiomyocytes. The benefits of endurance exercise on cardiac hypertrophy are generally thought to be short-lived and regress to sedentary levels within a few weeks of stopping endurance training. We have now established that cardiomyocyte hyperplasia also plays a considerable role in cardiac growth in response to just 4 weeks of endurance exercise in juvenile (5-9 weeks of age) rats. The effect of endurance exercise on cardiomyocyte hyperplasia diminishes with age and is lost by adulthood. We have also established that the effect of juvenile exercise on heart mass is sustained into adulthood. ABSTRACT: The aim of this study was to investigate if endurance training during juvenile life 'reprogrammes' the heart and leads to sustained improvements in the structure, function, and morphology of the adult heart. Male Wistar Kyoto rats were exercise trained 5 days week-1 for 4 weeks in either juvenile (5-9 weeks of age), adolescent (11-15 weeks of age) or adult life (20-24 weeks of age). Juvenile exercise training, when compared to 24-week-old sedentary rats, led to sustained increases in left ventricle (LV) mass (+18%; P < 0.05), wall thickness (+11%; P < 0.05), the longitudinal area of binucleated cardiomyocytes (P < 0.05), cardiomyocyte number (+36%; P < 0.05), and doubled the proportion of mononucleated cardiomyocytes (P < 0.05), with a less pronounced effect of exercise during adolescent life. Adult exercise training also increased LV mass (+11%; P < 0.05), wall thickness (+6%; P < 0.05) and the longitudinal area of binucleated cardiomyocytes (P < 0.05), despite no change in cardiomyocyte number or the proportion of mono- and binucleated cardiomyocytes. Resting cardiac function, LV chamber dimensions and fibrosis levels were not altered by juvenile or adult exercise training. At 9 weeks of age, juvenile exercise significantly reduced the expression of microRNA-208b, which is a known regulator of cardiac growth, but this was not sustained to 24 weeks of age. In conclusion, juvenile exercise leads to physiological cardiac hypertrophy that is sustained into adulthood long after exercise training has ceased. Furthermore, this cardiac reprogramming is largely due to a 36% increase in cardiomyocyte number, which results in an additional 20 million cardiomyocytes in adulthood. PMID- 29143976 TI - Stat3-Atg5 signal axis inducing autophagy to alleviate hepatic ischemia reperfusion injury. AB - In performing our experiment, impaired autophagy increased hepatocellular damage during the reperfusion period. It was demonstrated by the effect of blocking autophagy using bafilomycin A1 or knocking Atg5 gene out reduces the anti apoptotic effect of Stat3. Here we focus on the role of signal transducer and activator of transcription 3 (Stat3) in regulating autophagy to alleviate hepatic IRI. We found that Stat3 was up-regulated during hepatic IRI and was associated with an activation of the autophagic signaling pathway. This increased Stat3 expression, which was allied with high autophagic activity, alleviated liver damage to IR, an effect which was abrogated by Stat3 epletion as demonstrated in both in vivo and in vitro methods. The levels of Atg5 protein were decreased when Stat3 was inhibited by HO 3867 or siStat3. We conclude that Stat3 appeared to exert a pivotal role in hepatic IRI, by activating autophagy to alleviate hepatic IRI, and Atg5 was required for this process. The identification of this novel pathway, that links expression levels of Stat3 with Atg5-mediated autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI. PMID- 29143977 TI - Motivation and treatment credibility predict alliance in cognitive behavioral treatment for youth with anxiety disorders in community clinics. AB - OBJECTIVE: We examined whether motivation and treatment credibility predicted alliance in a 10-session cognitive behavioral treatment delivered in community clinics for youth anxiety disorders. METHOD: Ninety-one clinic-referred youths (meanage = 11.4 years, standard deviation = 2.1, range 8-15 years, 49.5% boys) with anxiety disorders-rated treatment motivation at pretreatment and perceived treatment credibility after session 1. Youths and therapists (YT) rated alliance after session 3 (early) and session 7 (late). Hierarchical linear models were applied to examine whether motivation and treatment credibility predicted YT early alliance, YT alliance change, and YT alliance agreement. RESULTS: Motivation predicted high early YT alliance, but not YT alliance change or alliance agreement. Youth-rated treatment credibility predicted high early youth alliance and high YT positive alliance change, but not early therapist alliance or alliance agreement. CONCLUSION: Conclusion Efforts to enhance youth motivation and treatment credibility early in treatment could facilitate the formation of a strong YT alliance. PMID- 29143978 TI - Production of 1,2-propanediol in photoautotrophic Synechocystis is linked to glycogen turn-over. AB - We utilized a photoautotrophic organism to synthesize 1,2-propanediol from carbon dioxide and water fueled by light. A synthetic pathway comprising mgsA (methylglyoxal synthase), yqhD (aldehyde reductase), and adh (alcohol dehydrogenase) was inserted into Synechocystis sp. PCC6803 to convert dihydroxyacetone phosphate to methylglyoxal, which is subsequently reduced to acetol and then to 1,2-propanediol. 1,2-propanediol could be successfully produced by Synechocystis, at an approximate rate of 55 MUmol h-1 gCDW-1 . Surprisingly, maximal productivity was observed in the stationary phase. The production of 1,2-propanediol was clearly coupled to the turn-over of intracellular glycogen. Upon depletion of the glycogen pool, product formation stopped. Reducing the carbon flux to glycogen significantly decreased final product titers. Optimization of cultivation conditions allowed final product titers of almost 1 g L-1 (12 mM), which belongs to the highest values published so far for photoautotrophic production of this compound. PMID- 29143979 TI - Analysis of anti-tumour necrosis factor-induced skin lesions reveals strong T helper 1 activation with some distinct immunological characteristics. AB - BACKGROUND: Psoriasiform and eczematous eruptions are the most common dermatological adverse reactions linked to anti-tumour necrosis factor (TNF) alpha therapy. Yet, a detailed characterization of their immune phenotype is lacking. OBJECTIVES: To characterize anti-TNF-alpha-induced inflammatory skin lesions at a histopathological, cellular and molecular level, compared with psoriasis, eczema (atopic dermatitis) and healthy control skin. METHODS: Histopathological evaluation, gene expression (quantitative real-time polymerase chain reaction) and computer-assisted immunohistological studies (TissueFAXS) were performed on 19 skin biopsies from patients with inflammatory bowel disease (n = 17) and rheumatoid arthritis (n = 2) with new-onset inflammatory skin lesions during anti-TNF-alpha-therapy. RESULTS: Although most biopsies showed a psoriasiform and/or spongiotic (eczematous) histopathological architecture, these lesions were inconsistent with either psoriasis or eczema on a molecular level using an established chemokine (C-C motif) ligand 27/inducible nitric oxide synthase classifier. Despite some differences in immune skewing depending on the specific histopathological reaction pattern, all anti-TNF-alpha-induced lesions showed strong interferon (IFN)-gamma activation, at higher levels than in psoriasis or eczema. IFN-gamma was most likely produced by CD3/CD4/Tbet-positive T helper 1 lymphocytes. CONCLUSIONS: New-onset anti-TNF-alpha-induced eruptions previously classified as psoriasis or spongiotic dermatitis (eczema) exhibit a molecular profile that is different from either of these disorders. PMID- 29143980 TI - White matter maturation during 12 months in individuals at ultra-high-risk for psychosis. AB - OBJECTIVE: The neurodevelopmental hypothesis of psychosis suggests that disrupted white matter (WM) maturation underlies disease onset. In this longitudinal study, we investigated WM connectivity and compared WM changes between individuals at ultra-high-risk for psychosis (UHR) and healthy controls (HCs). METHOD: Thirty UHR individuals and 23 HCs underwent MR diffusion tensor imaging before and after 12 months of non-manualized standard care. Positive and negative symptoms and level of functioning were assessed. Tract-based spatial statistics were employed. RESULTS: During 12 months, none of the UHR individuals transitioned to psychosis. Both UHR individuals and HCs increased significantly in fractional anisotropy (FA). UHR individuals showed significant FA increases predominantly in the left superior longitudinal fasciculus (SLF) (P = 0.01), and HCs showed significant FA increases in the left uncinate fasciculus (P = 0.03). Within UHR individuals, a significant positive correlation between FA change and age was observed predominantly in the left SLF (P = 0.02). Within HCs, no significant correlation between FA change and age was observed. No significant correlations between baseline FA and clinical outcomes were observed; however, FA changes were significantly positively correlated to changes in negative symptoms (P = 0.04). CONCLUSION: As normal brain maturation occurs in a posterior to frontal direction, our findings could suggest disturbed WM maturation in UHR individuals. PMID- 29143981 TI - High plasma 25-hydroxyvitamin D and high risk of nonmelanoma skin cancer: a Mendelian randomization study of 97 849 individuals. AB - BACKGROUND: High plasma 25-hydroxyvitamin D [25(OH)D] concentration has been associated observationally with a high risk of nonmelanoma skin cancer (NMSC), whereas many studies suggest that vitamin D could have a protective effect against cancer. The true association between vitamin D and risk of skin cancer remains unclear. OBJECTIVES: To test the hypothesis that genetically high plasma 25(OH)D protects against NMSC. METHODS: We included 103 084 individuals from the Danish general population, of whom 35 298 had plasma 25(OH)D measured and 97 849 were genotyped for four genetic variants near DHCR7 and CYP2R1 associated with 25(OH)D concentrations. We tested the association between plasma 25(OH)D levels and NMSC observationally and between genetically determined 25(OH)D levels and NMSC, using an instrumental variable approach. RESULTS: Multivariate-adjusted hazard ratios of NMSC were 3.27 [95% confidence interval (CI) 2.22-4.84] for plasma 25(OH)D >= 50 nmol L-1 vs. < 25 nmol L-1 . Genetic variants around DHCR7 and CYP2R1 were associated with up to 8.2 nmol L-1 higher 25(OH)D concentrations (F = 314). The odds ratio (OR) for a genetically determined 20 nmol L-1 higher plasma 25(OH)D was 1.11 (95% CI 0.91-1.35) for NMSC, with a corresponding observational multivariable adjusted OR of 1.13 (95% CI 1.10-1.17). CONCLUSIONS: Genetically determined high 25(OH)D levels did not appear to protect against NMSC, whereas high plasma 25(OH)D concentrations were associated with an observational high risk of NMSC. Thus, the observational association likely reflects confounding by sun exposure rather than causality. PMID- 29143982 TI - TWEAK/Fn14 interaction induces proliferation and migration in human airway smooth muscle cells via activating the NF-kappaB pathway. AB - Asthma, an increasingly common chronic disease among children, are characterized by airway remodeling, which is partly attributed to the proliferation and migration of airway smooth muscle cell (ASMC). The purpose of the present study was to investigate potential roles and mechanisms of the tumor necrosis factor like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible molecule 14 (Fn14) axis on cell proliferation and migration in HASMCs. Compared to HASMCs from non-asthmatic patients, those from asthmatic patients showed elevated expression levels of both Fn14 and TWEAK. Additionally, similar to the response triggered by platelet-derived growth factor-BB, stimulation with recombinant TWEAK strongly induced cell proliferation and migration in HASMCs. However, depletion of Fn14 remarkably abrogated the enhancement of TWEAK on the cell proliferation and migration of HASMCs. Furthermore, treatment with TWEAK led to the activation of NF-kappaB. This effect was eliminated by silencing Fn14, indicating that TWEAK-induced NF-kappaB signaling was mediated via Fn14. Moreover, the TWEAK/Fn14 interaction promoted cell proliferation and migration. These effects were blocked by NF-kappaB inhibitor SN50, which suggest that the TWEAK/Fn14 signaling system partially depends on NF-kappaB activity. Collectively, we demonstrated that the TWEAK/Fn14 axis accelerated HASMC cell proliferation and migration by activating the NF-kappaB pathway, thereby exacerbating airway remodeling in asthma. Altogether, these findings indicate a novel role for the TWEAK/Fn14/NF-kappaB pathway as a potent option for limiting airway remodeling in asthma. PMID- 29143984 TI - CRISPR/Cas9-mediated knockout of Lim-domain only four retards organ of Corti cell growth. AB - Lim-domain only 4 (LMO4) plays a critical role in mediating the ototoxic side effects of cisplatin, a highly effective anti-cancer drug. However, the signaling mechanism by which cochlear LMO4 mediates otopathology is yet to be fully understood. Knockout cell culture models are useful tools for investigating the functional roles of novel genes and delineating associated signaling pathways. Therefore, LMO4 knockout organ of Corti cells were generated by using the CRISPR (clustered regularly interspersed short palindromic repeats)/Cas9 (CRISPR associated protein 9) system. Successful knockout of LMO4 in UB/OC1 cells was verified by the absence of LMO4 protein bands in immunoblots. Though the Knockout of LMO4 retarded the growth rate and the migratory potential of the cells it did not inhibit their long-term viability as the LMO4 knockout UB/OC1 cells were able to survive, proliferate, and form colonies. In addition, the knockout of LMO4 did not alter the expression of myosin VIIa, a biomarker of hair cells, suggesting that the knockout cells retain important characteristic features of cochlear sensory receptor cells. Thus, the findings of this study indicate that CRISPR/Cas9 system is a simple and versatile method for knocking out genes of interest in organ of Corti cells and that LMO4 knockout UB/OC1 cells are viable experimental models for studying the functional role of LMO4 in ototoxicity. PMID- 29143985 TI - Silencing of COL1A2, COL6A3, and THBS2 inhibits gastric cancer cell proliferation, migration, and invasion while promoting apoptosis through the PI3k Akt signaling pathway. AB - This study explores the effect of COL1A2, COL6A3, and THBS2 gene silencing on proliferation, migration, invasion, and apoptosis of gastric cancer cells through the PI3K-Akt signaling pathway. The gastric cancer microarray expression data (GSE19826, GSE79973, and GSE65801) was analyzed. Gastric cancer tissues and corresponding adjacent normal tissues were extracted from patients. Positive expression rate of PI3K, Akt, and p-Akt was measured with immunohistochemistry. Two cell lines, BGC-823 and SGC-7901, were transfected and cells were grouped into blank, negative control, COL1A2-shRNA, COL6A3-shRNA, and THBS2-shRNA groups. Expressions of COL1A2, COL6A3, and THBS2 in gastric cancer cells transfected with corresponding silencing sequences were evaluated by RT-qPCR and Western blot. MTT assay, Transwell, and cell scratch tests were conducted to evaluate cell proliferation, invasion, and migration capacity, respectively. Flow cytometry was used to evaluate cell cycle distribution and apoptosis. The positive expression of PI3K, Akt, and p-Akt was higher in gastric cancer tissues compared with adjacent normal tissues, and the mRNA expression of COL1A2, COL6A3, and THBS2 was increased in gastric cancer tissues. Akt, p-Akt, and PI3K expression drastically decreased in cells transfected with COL1A2, COL6A3, and THBS2 silencing sequences. Cells transfected with COL1A2, COL6A3, and THBS2 silencing sequences exhibited promoted apoptosis but inhibited proliferation, migration, and invasion. This study demonstrates that COL1A2, COL6A3, and THBS2 gene silencing inhibits gastric cancer cell proliferation, migration, and invasion while promoting apoptosis through the PI3K-Akt signaling pathway. PMID- 29143986 TI - Effect of Second-Order Spin-Orbit Coupling on the Interaction between Spin States in Spin-Crossover Systems. AB - The second-order spin-orbit coupling is evaluated in two transition-metal complexes to establish the effect on the deactivation mechanism of the excited low-spin state in systems that undergo spin transitions under the influence of light. We compare the standard perturbational approach to calculate the second order interaction with a variational strategy based on the effective Hamiltonian theory and show that the former one can only be applied in some special cases and even then gives results that largely overestimate the interaction. The combined effect of geometry distortions and second-order spin-orbit coupling leads to sizeable interactions for states that are nearly uncoupled in the symmetric (average) structure of the complex. This opens the possibility of a direct deactivation from the singlet and triplet states of the metal-to-ligand charge transfer manifold to the final high-spin state as suggested from the interpretation of experimental data but so far not supported by theoretical descriptions of the light-induced spin crossover. PMID- 29143983 TI - Growth of doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase. AB - Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3 : G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine alpha-deamino-gamma-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 +/- 88 mm3 ; DOX (G2): 329.5 +/- 79 mm3 , P = 0.670; rMETase (G3): 162.6 +/- 51 mm3 , P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma. PMID- 29143987 TI - Effect of body temperature on the pharmacokinetics of a triarylmethyl-type paramagnetic contrast agent used in EPR oximetry. AB - PURPOSE: Pharmacokinetics of the tri[8-carboxy-2,2,6,6-tetrakis(2 hydroxymethyl)benzo[1,2-d:4,5-d']bis(1,3)dithio-4-yl]methyl radical (Oxo63) after a single bolus and/or continuous intravenous infusion was investigated in tumor bearing C3H mice with or without body temperature control while under anesthesia. METHOD: The in vivo time course of Oxo63 in blood was measured using X-band electron paramagnetic resonance spectroscopy. Distribution of Oxo63 in normal muscle and tumor tissues was obtained using a surface coil resonator and a 700 MHz electron paramagnetic resonance spectrometer. The whole-body distribution of Oxo63 was obtained by 300-MHz continuous-wave electron paramagnetic resonance imaging. The high-resolution 300-MHz time-domain electron paramagnetic resonance imaging was also carried out to probe the distribution of Oxo63. RESULTS: Urination of mice was retarded at low body temperature, causing the concentration of Oxo63 in blood to attain high levels. However, the concentration of Oxo63 in tumor tissue was lower with no control of body temperature than active body temperature control. The nonsystemized blood flow in the tumor tissues may pool Oxo63 at lower body temperature. CONCLUSIONS: Pharmacokinetics of the contrast agent were found to be significantly affected by body temperature of the experimental animal, and can influence the probe distribution and the image patterns. Magn Reson Med 79:1212-1218, 2018. (c) Published 2017. This article is a U.S. Government work and is in the public domain in the USA. PMID- 29143988 TI - Synthesis and Optical Properties of Phenanthroline-Derived Schiff Base-Like Dinuclear RuII -NiII Complexes. AB - Two phenanthroline-derived Schiff base-like ligands with a covalently linked ruthenium(II) phosphorescent unit were synthesised and converted into bimetallic RuII -NiII complexes. The optical properties were studied to examine a possible photoluminescence quenching through a nonradiative energy-transfer upon a coordination-induced spin-state switch (CISSS) at the nickel(II) centre. Therefore, the metalloligands and the nickel(II) complexes were studied using UV/Vis absorbance, steady-state, and time-resolved emission spectroscopy in solutions of MeCN and pyridine. It is demonstrated that the nature of the bridging ligand between the ruthenium(II) donor and the nickel(II) acceptor strongly influences the photophysical behaviour upon CISSS. For the complex with a phenazine bridge, photoluminescence quenching is observed in the presence of a paramagnetic nickel(II) centre. PMID- 29143989 TI - Nanos2 promotes differentiation of chicken (Gallus gallus) embryonic stem cells to male germ cells. AB - Nanos2 is an evolutionarily conserved RNA-binding protein containing 2 CCHC-type zinc finger motives. Here, we report that Nanos2 is strongly expressed in the testis compared to other tissues in chicken (Gallus gallus). Overexpression and knockout plasmid vectors were constructed, and in-vitro Cas9/gRNA digestion and T7 endonuclease I (T7E1) assay indicated that Nanos2-g1 possessed the highest knockout activity. In vitro and in vivo, Nanos2 overexpression accelerated the production of embryoid bodies (EBs) and SSC-like cells and promoted cvh, c-kit, and integrin alpha6 expression. Immunofluorescence staining, periodic acid schiff (PAS) and flow cytometry (FCM) assay showed that primordial germ cells (PGCs) and spermatogonial stem cells (SSCs) formation were significantly promoted. On the contrary, Nanos2 knockout delayed the production of EBs and SSC-like cells and correspondingly reduced cvh, c-kit, and integrin alpha6 expression. Simultaneously, the quantity of PGCs and SSCs was blocked. Collectively, these results uncovered a novel function of Nanos2 involved in chicken male germ cell differentiation, where it acts as a facilitator. PMID- 29143990 TI - Interpretation of pyuria in children with urinary tract infection. PMID- 29143991 TI - Genetic and non-genetic risk factors for pre-eclampsia: umbrella review of systematic reviews and meta-analyses of observational studies. AB - OBJECTIVE: To summarize evidence from the literature on genetic and non-genetic risk factors associated with pre-eclampsia (PE), assess the presence of statistical bias in the studies and identify risk factors for which there is robust evidence supporting their association with PE. METHODS: PubMed and ISI Web of Science were searched from inception to October 2016, to identify systematic reviews and meta-analyses of observational studies examining associations between genetic or non-genetic risk factors and PE. For each meta-analysis, the summary effect size was estimated using random-effects and fixed-effects models, along with 95% CIs and the 95% prediction interval. Between-study heterogeneity was expressed using the I2 statistic, and evidence of small-study effects (large studies had significantly more conservative results than smaller studies) and evidence of excess significance bias (too many studies with statistically significant results) were estimated. RESULTS: Fifty-eight eligible meta-analyses were identified, which included 1466 primary studies and provided data on 130 comparisons of risk factors associated with PE, covering a wide range of comorbid diseases, genetic factors, exposure to environmental agents and biomarkers. Sixty five (50%) associations had nominally statistically significant findings at P < 0.05, while 16 (12%) were significant at P < 10-6 . Sixty-five (50%) associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in 10 (8%) and 26 (20%) associations, respectively. The only non-genetic risk factor with convincing evidence for an association with PE was oocyte donation vs spontaneous conception, which had a summary odds ratio of 4.33 (95% CI, 3.11-6.03), was supported by 2712 cases with small heterogeneity (I2 = 26%) and 95% prediction intervals excluding the null value, and without hints of small-study effects (P for Egger's test > 0.10) or excess of significance (P > 0.05). Of the statistically significant (P < 0.05) genetic risk factors for PE, only PAI-1 4G/5G (recessive model) polymorphism was supported by strong evidence for a contribution to the pathogenesis of PE. Eleven factors (serum iron level, pregnancy-associated plasma protein-A, chronic kidney disease, polycystic ovary syndrome, mental stress, bacterial and viral infections, cigarette smoking, oocyte donation vs assisted reproductive technology, obesity vs normal weight, severe obesity vs normal weight and primiparity) presented highly suggestive evidence for an association with PE. CONCLUSIONS: A large proportion of meta-analyses of genetic and non-genetic risk factors for PE have caveats that threaten their validity. Oocyte donation vs spontaneous conception and PAI-1 4G/5G polymorphism (recessive model) showed the strongest consistent evidence for an association with risk for PE. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29143993 TI - How to measure size of tubal ectopic pregnancy on ultrasound. AB - OBJECTIVE: To identify the preoperative ultrasound parameters for assessing the size of tubal ectopic pregnancy that correlate best with findings at surgery. METHODS: This was a prospective study of all women attending our center who had a conclusive transvaginal ultrasound diagnosis of tubal ectopic pregnancy over a 10 month period. In each case, the total size of the ectopic pregnancy was measured by placing the calipers on the outer edges of the visible trophoblastic tissue. In ectopic pregnancies presenting with a well-defined gestational sac, the size of the celomic (chorionic) cavity was also measured using the inner borders of the trophoblastic ring as reference points. In women with signs of intra abdominal bleeding, the size of the hematosalpinx and/or hemoperitoneum was measured. Surgeons were blinded to the ultrasound measurements and were asked to estimate the size of the ectopic pregnancy and the amount of hemoperitoneum intraoperatively. RESULTS: A total of 105 women were diagnosed with a tubal ectopic pregnancy on ultrasound examination, of whom 71 (67.6%) were managed surgically. A significant (P < 0.01) positive correlation was found between all ultrasound measurements and the size of the tubal ectopic pregnancy as reported during surgery. In the absence of hematosalpinx, the mean total outer diameter of the ectopic pregnancy had the highest positive correlation with the size of the tubal ectopic pregnancy at surgery (r = 0.65, P < 0.001). In cases complicated by hematosalpinx, the mean diameter of the tube was the only variable that correlated significantly with the estimated size of the ectopic pregnancy at surgery (P < 0.001). There was a significant positive association between the amount of hemoperitoneum on ultrasound and the estimated volume of intraperitoneal blood at surgery (P < 0.001). CONCLUSIONS: The mean size of a hematosalpinx and the total outer mean diameter of an ectopic pregnancy on ultrasound correlate better with the surgical findings than does the size of the celomic cavity. Our findings show that the standard approach of measuring the size of an intrauterine pregnancy on ultrasound should be adapted to include these additional measurements in women diagnosed with a tubal ectopic pregnancy. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29143992 TI - Teaching Old Compounds New Tricks: DDQ-Photocatalyzed C-H Amination of Arenes with Carbamates, Urea, and N-Heterocycles. AB - The C-H amination of benzene derivatives was achieved using DDQ as photocatalyst and BocNH2 as the amine source under aerobic conditions and visible light irradiation. Electron-deficient and electron-rich benzenes react as substrates with moderate to good product yields. The amine scope of the reaction comprises Boc-amine, carbamates, pyrazoles, sulfonimides and urea. Preliminary mechanistic investigations indicate arene oxidation by the triplet of DDQ to radical cations with different electrophilicity and a charge transfer complex between the amine and DDQ as intermediate of the reaction. PMID- 29143994 TI - Intermittent compressive force induces human mandibular-derived osteoblast differentiation via WNT/beta-catenin signaling. AB - Mechanical force induces an efflux of ATP that regulates osteoblast differentiation. However, the effect of mechanical force-induced ATP efflux on WNT/beta-catenin signaling remains unclarified. The aim of this study was to investigate the effect of intermittent compressive force (ICF) and ICF-induced extracellular ATP on osteoblast differentiation via WNT/beta-catenin signaling in human mandibular-derived osteoblast precursors (hMOBPs). The hMOBPs were subjected to ICF (1.5 g/cm2 , 0.3 Hz) for 20 h. To investigate the role of ATP, Apyrase (0.5 units/mL), an enzyme that hydrolyzes ATP, was added 30 min before ICF was applied. The extracellular ATP levels were measured immediately after ICF was removed. The mRNA expression of osteogenic related genes, including WNT was evaluated via quantitative real time polymerase chain reaction. In vitro mineralization was determined by Alizarin Red S staining. The localization of beta-catenin was detected using immunofluorescence staining and lentiviral-TOP dGFP reporter assay. The results demonstrated that ICF increased ATP efflux and in vitro mineralization by hMOBPs. In addition, OSX, ALP, and WNT3A mRNA expression and beta-catenin nuclear translocation increased when ICF was applied. The upregulation of these genes was reduced by Apyrase, suggesting the role of ICF-induced ATP on osteoblast differentiation. Notably, ICF altered the mRNA expression of purinergic 2X receptors (P2XRs). A P2X1R antagonist (NF449) downregulated ICF-induced WNT3A, OSX, and ALP mRNA expression. Moreover, when 25 MUM alpha, beta-meATP, a P2X1R agonist, was added, WNT3A, and OSX expression increased. In conclusion, our results demonstrate that ICF-induced ATP enhanced hMOBP differentiation. This enhancement was associated with WNT/beta-catenin signaling and P2X1R activation. PMID- 29143995 TI - Catalytic Synthesis of Indolines by Hydrogen Atom Transfer to Cobalt(III)-Carbene Radicals. AB - We report a new method for the synthesis of indolines from o-aminobenzylidine N tosylhydrazones proceeding through a cobalt(III)-carbene radical intermediate. This methodology employs the use of inexpensive commercially available reagents and allows for the transformation of easily derivatized benzaldehyde-derived precursors to functionalized indoline products. This transformation takes advantage of the known propensity of radicals to undergo rapid intramolecular 1,5 hydrogen atom transfer (1,5-HAT) to form more stabilized radical intermediates. Computational investigations using density functional theory identify remarkably low barriers for 1,5-HAT and subsequent radical rebound displacement, providing support for the proposed mechanism. We explore the effect of a variety of nitrogen substituents, and highlight the importance of adequate resonance stabilization of radical intermediates to the success of the transformation. Furthermore, we evaluate the steric and electronic effects of substituents on the aniline ring. This transformation is the first reported example of the synthesis of nitrogen-containing heterocycles from cobalt(III)-carbene radical precursors. PMID- 29143996 TI - Long non-coding RNA H19 suppresses retinoblastoma progression via counteracting miR-17-92 cluster. AB - Long non-coding RNAs (lncRNAs) are frequently dysregulated and play important roles in many cancers. lncRNA H19 is one of the earliest discovered lncRNAs which has diverse roles in different cancers. However, the expression, roles, and action mechanisms of H19 in retinoblastoma are still largely unknown. In this study, we found that H19 is downregulated in retinoblastoma tissues and cell lines. Gain-of-function and loss-of-function assays showed that H19 inhibits retinoblastoma cell proliferation, induces retinoblastoma cell cycle arrest and cell apoptosis. Mechanistically, we identified seven miR-17-92 cluster binding sites on H19, and found that H19 directly bound to miR-17-92 cluster via these seven binding sites. Through binding to miR-17-92 cluster, H19 relieves the suppressing roles of miR-17-92 cluster on p21. Furthermore, H19 represses STAT3 activation induced by miR-17-92 cluster. Hence, our results revealed that H19 upregulates p21 expression, inhibits STAT3 phosphorylation, and downregulates the expression of STAT3 target genes BCL2, BCL2L1, and BIRC5. In addition, functional assays demonstrated that the mutation of miR-17-92 cluster binding sites on H19 abolished the proliferation inhibiting, cell cycle arrest and cell apoptosis inducing roles of H19 in retinoblastoma. In conclusion, our data suggested that H19 inhibits retinoblastoma progression via counteracting the roles of miR-17-92 cluster, and implied that enhancing the action of H19 may be a promising therapeutic strategy for retinoblastoma. PMID- 29143997 TI - Epidermal neural crest stem cell-derived glia enhance neurotrophic elements in an ex vivo model of spinal cord injury. AB - Growing evidence that cell-based therapies can improve recovery outcome in spinal cord injury (SCI) models substantiates their application for treatment of human with SCI. To address the effectiveness of these stem cells, potential candidates should be evaluated in proper SCI platform that allows direct real-time monitoring. In this study, the role of epidermal neural crest stem cells (EPI NCSCs) was elucidated in an ex vivo model of SCI, and valproic acid (VPA) was administered to ameliorate the inhospitable context of injury for grafted EPI NCSCs. Here the contusion was induced in organotypic spinal cord slice culture at day seven in vitro using a weight drop device and one hour post injury the GFP- expressing EPI-NCSCs were grafted followed by VPA administration. The evaluation of treated slices seven days after injury revealed that grafted stem cells survived on the injured slices and expressed GFAP, whereas they did not express any detectable levels of the neural progenitor marker doublecortin (DCX), which was expressed prior to transplantation. Immunoblotting data demonstrated that the expression of GFAP, BDNF, neurotrophin-3 (NT3), and Bcl2 increased significantly in stem cell treated slices. This study illustrated that the fate of transplanted stem cells has been directed to the glial lineage in the ex vivo context of injury and EPI-NCSCs may ameliorate the SCI condition through releasing neurotrophic factors directly and/or via inducing resident spinal cord cells. PMID- 29143998 TI - Oxytocin mediates the beneficial effects of the exercise training on breast cancer. AB - NEW FINDINGS: What is the central question of this study? We hypothesized that potential anti-tumour effects of exercise training might be mediated by oxytocin and explored the underlying mechanisms in a mouse model of breast cancer. What is the main finding and its importance? Interval exercise training, by inducing oxytocin secretion, may reduce the activity of the PI3K/Akt and ERK pathways, and consequently, results in a smaller tumour volume in a mouse model of breast cancer. Exercise training can affect the growth of breast tumours. We hypothesized that exercise training might reduce breast tumour growth by inducing oxytocin (OT) secretion and its related signalling pathways, such as PI3K/Akt and ERK. Therefore, 56 BALB/c mice were equally divided into seven groups to study the effects of OT and atosiban (an oxytocin receptor antagonist) together with interval exercise training on mammary tumour growth, as well as tumour-related signalling pathways, including PI3K/Akt and ERK. Animal weight, OT plasma concentration, tumour weight and volume were measured at the end of the study. PI3K/Akt and ERK were evaluated by Western blot and qPCR assays. The results showed that OT plasma concentration was significantly increased in trained animals. The volume and weight of tumours were decreased significantly after both exercise training and OT administration. The expression of genes involved in tumour cell proliferation, such as PI3KR2, Akt and mTOR, was notably lower in the exercise-trained and OT-treated groups. Furthermore, the expression of genes involved in cell apoptosis, such as caspase-3 and Bax, was significantly increased in the tumour tissues. In addition, Western blot results showed that phosphorylated Akt and ERK were significantly decreased in the exercise training and OT groups compared with the tumour group. Interestingly, atosiban reversed these effects. These results indicated that interval exercise training, acting via OT secretion, may reduce PI3K/Akt and ERK axis activities, and consequently, decrease tumour volume and weight in a mouse model of breast cancer. PMID- 29143999 TI - MicroRNA-27a-3p inhibits cell viability and migration through down-regulating DUSP16 in hepatocellular carcinoma. AB - MicroRNA (miRNA or miR) has been shown to play an important role in the initiation and development in many different cancers. Here, we demonstrated down regulated expression of miR-27a-3p in hepatocellular carcinoma (HCC) tissues in comparison with that in adjacent normal liver tissues based on the TCGA database. Cells viability and apoptosis was measured by CCK-8 and flow cytometry assay. Cell invasion and migration was measured by Transwell and wound healing assay. The effect of miR-27a-3p on DUSP16 expression was evaluated by luciferase assays, and western blot assay. miR-27a-3p up-regulation by transfection with miR-27a-3p mimics attenuated SMMC-7721 and HepG2 cell viability, invasion as well as migration, obviously. Moreover, we found that dual specificity phosphatase 16 (DUSP16), also known as mitogen-activated protein kinase phosphatase 7 (MKP-7), is a target of miR-27a-3p. DUSP16 expression was obvious decrease by miR-27a-3p at both transcriptional and protein levels in both SMMC-7721 and HepG2 cells. DUSP16 expression in tissues of HCC was up-regulated in comparison with that in tissues of adjacent liver based on the TCGA database. Overexpression of DUSP16 significantly reversed the cell changes in viability, invasion and migration which resulted from miR-27a-3p up-regulation in SMMC-7721 and HepG2 cells. Our findings contribute to current understanding of the functions of miR-27a-3p and suggest a mechanism by which miR-27a-3p plays an anti-tumor role in the development of HCC by targeting DUSP16. PMID- 29144000 TI - Design, expression and evaluation of novel chimeric protein constructed from colorectal tumor-associated antigen. AB - There were 134,000 new diagnosis and 49,000 deaths in 2016 due to colorectal cancer. Similar to most cancers, early diagnosis increases the chance of successful treatment. Detection of tumor-associated antigens or the immune response against such markers is one of the most common methods of diagnosis. In that regard, we aimed to design and express a chimeric protein from the most common tumor-associated antigens in colorectal cancer and assess its ability to detect the immune response in comparison with the parental tumor-associated antigens in patient's sera. Through bioinformatics approaches a chimeric protein from carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19-9) was designed and expressed in E. coli (BL21DE3). Proper folding, expression levels and immune reactivity were assessed by western blot, ELISA and immunohistochemistry. Recombinant proteins functionality and immune reactivity were confirmed by ELISA and Western blot. Results showed that recombinant CEA, recombinant CA19.9 and chimeric protein of CEA- CA19.9 have strong reactivity with antibodies in the sera of colorectal cancer patients, whereas no reactivity was seen with the sera of healthy volunteers. Significantly stronger immune reactivity was seen with the chimeric protein than each of the CEA or CA19.9 alone. Overall, it was concluded that the designed recombinant proteins in this study could be used to detect autoantibodies produced against the colorectal tumor-associated antigens. The chimeric CEA-CA19.9 protein shows a stronger reactivity with the sera antibodies of colorectal cancer patients that CEA or CA19.9 alone. PMID- 29144001 TI - Biological evaluation and energetic analyses of novel GSK-3beta inhibitors. AB - Glycogen synthase kinase-3 beta (GSK-3beta) is involved in multiple signaling pathways. Consistent with its critical roles in normal cells, abnormalities in GSK-3beta activity have been implicated in diabetes, heart disease, Parkinson disease, and Alzheimer's disease. In this study, a series of new scaffolds of small molecule inhibitors of GSK-3beta were identified by virtual screening and bioassay. Candidates that adhere to drug-like criteria from a virtual library of compounds were tested using computational docking studies. Twenty selected compounds were tested, which led to the discovery of two hits. Compound 14 (IC50 = 8.48 uM) and compound 19 (IC50 = 2.19 uM) were identified with high affinity. Molecular dynamics (MD) simulations, in conjunction with molecular mechanics/Poisson-Boltzmann surface area binding free-energy analysis, were employed to gain insight into the binding modes and energetics of GSK-3beta inhibitors. The detailed analysis of molecular dynamics results shows that Ile62, Val70, Tyr134, and Leu188 in GSK-3beta are key residues responsible to the binding of compound 14 and compound 19. Importantly, our results also validated this combined virtual screening and biophysical technique approach to discovery kinase inhibitors, which may be applied for future inhibitor discovery work for GSK-3beta. PMID- 29144003 TI - Value of social media in advancing surgical research. PMID- 29144005 TI - Multicentre study of the impact of morbidity on long-term survival following hepatectomy for intrahepatic cholangiocarcinoma. PMID- 29144006 TI - Behavioral outcomes of a novel, pelvic nerve damage rat model of fecal incontinence. AB - BACKGROUND: Fecal incontinence (FI) has a multifactorial pathophysiology with a severe social impact. The most common cause for FI is pudendal nerve damage, which mostly occurs in women during or after labor. A better understanding of the pathophysiology is required to optimize treatment of FI. In this study, we evaluate the use of a novel pelvic nerve damage rat model of FI. METHODS: This new model simulates the forces on the pelvic floor during labor by prolonged transvaginal, retro-uterine intrapelvic balloon distention in female rats. Number of fecal pellets produced per day and defecation pattern was compared between the experimental and control group for 2 weeks. The cages of the rats were divided in food, nesting and latrine areas to evaluate changes in defecation pattern. The FI Index (FII) was calculated to assess the ratio of fecal pellets between the non latrine areas and the total number of pellets. A higher score represents more random distribution of feces outside the latrine area. RESULTS: Total number of fecal pellets was higher in the experimental group as compared with the controls. In both groups most fecal pellets were deposited in the nesting area, which is closest to the food area. The experimental group deposited more fecal pellets in the latrine area and had a lower FII indicating less random distribution of feces outside the latrine area. CONCLUSION: Transvaginal, retro-uterine intrapelvic balloon distention is a safe and feasible animal model simulating the human physiologic impact of labor by downwards pressure on the pelvic floor. PMID- 29144007 TI - Analysis of Surface Roughness, Fracture Toughness, and Weibull Characteristics of Different Framework-Veneer Dental Ceramic Assemblies after Grinding, Polishing, and Glazing. AB - PURPOSE: To compare the surface roughness and biaxial flexural strength of dental ceramics obtained after chairside surface modification by mechanical polishing procedures, versus laboratory reglazing. MATERIALS AND METHODS: Discs (16 * 1.5 +/- 1.6 mm) (N = 90) of various framework-veneering combinations were fabricated: D/FC: lithium disilicate/feldspathic ceramic; Z/AL: zirconium dioxide/aluminous ceramic; N/FC: noble alloy/feldspathic ceramic; N/FF: noble alloy feldspathic with fluorapatite; B/FC: base alloy/feldspathic ceramic; B/FF: base alloy/feldspathic ceramic with fluorapatite. In each group 10 specimens were ground using a diamond bur (46 MUm) and five were polished with silicone reinforced disc polishers (25 MUm). Surface roughness (Ra) was measured using contact profilometry. After thermocycling in artificial saliva (6000 cycles, 5 to 55 +/- 5 degrees C), biaxial flexural strength was measured using "piston-on three ball" test. The data (N) were analyzed using one-way ANOVA, Bonferroni, and Tukey's posthoc tests. Weibull distribution values were calculated. RESULTS: Surface roughness was significantly higher in the ground group only (p < 0.0001). Mean fracture toughness was significantly lower for chipping (RK: 287, HS: 22, ISO: 1099 MPa) than for total fracture (p < 0.05), (RK: 841, HS:64, ISO: 3222 MPa). For chipping, Weibull distribution presented the highest shape value (m) for D/FC (3.82-5.07) and for total fracture for B/FC (3.69-4.6). CONCLUSION: Chairside surface polishing restored veneer ceramic roughness and mechanical strength to the level of glazing. Feldspathic ceramic with fluorapatite presented better polishing results than conventional feldspathic ceramic did. Ceramic fused to metal was more resistant than lithium disilicate or zirconium dioxide framework-veneer assemblies. Lithium disilicate framework veneered with feldspathic ceramic presented more durability against chipping. CLINICAL IMPLICATIONS: After chairside occlusal modifications in the surfaces of cemented all-ceramic or fused-to-metal FDPs, mechanical polishing procedures should always be carried out. PMID- 29144008 TI - A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells. AB - The breast cancer stem cell (CSC) and bulk breast cancer cell potency of a series of metallopeptides containing dichloro(1,10-phenanthroline)copper(II) and various organelle-targeting peptide sequences is reported. The mitochondria-targeting metallopeptide 1 exploits the higher mitochondrial load in breast CSCs over the corresponding non-CSCs and the vulnerability of breast CSCs to mitochondrial damage to potently and selectively kill breast CSCs. Strikingly, 1 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-potent agent. Mechanistic studies show that 1 enters CSC mitochondria, induces mitochondrial dysfunction, generates reactive oxygen species (ROS), activates JNK and p38 pathways, and prompts apoptosis. To the best of our knowledge, 1 is the first metallopeptide to selectivity kill breast CSCs in vitro. PMID- 29144009 TI - Immobilization of Superoxide Dismutase on Polyelectrolyte-Functionalized Titania Nanosheets. AB - The superoxide dismutase (SOD) enzyme was successfully immobilized on titania nanosheets (TNS) functionalized with the poly(diallyldimethylammonium chloride) (PDADMAC) polyelectrolyte. The TNS-PDADMAC solid support was prepared by hydrothermal synthesis followed by self-assembled polyelectrolyte layer formation. It was found that SOD strongly adsorbed onto oppositely charged TNS PDADMAC through electrostatic and hydrophobic interactions. The TNS-PDADMAC-SOD material was characterized by light scattering and microscopy techniques. Colloidal stability studies revealed that the obtained nanocomposites possessed good resistance against salt-induced aggregation in aqueous suspensions. The enzyme kept its functional integrity upon immobilization; therefore, TNS-PDADMAC SOD showed excellent superoxide radical anion scavenging activity. The developed system is a promising candidate for applications in which suspensions of antioxidant activity are required in the manufacturing processes. PMID- 29144010 TI - Self-Assembly and Surface Patterning of Polyferrocenylsilane-Functionalized Gold Nanoparticles. AB - Chemical and topographic surface patterning of inorganic polymer-functionalized nanoparticles (NPs) and their self-assembly in nanostructures with controllable architectures enable the design of new NP-based materials. Capping of NPs with inorganic polymer ligands, such as metallopolymers, can lead to new synergetic properties of individual NPs or their assemblies, and enhance NP processing in functional materials. Here, for gold NPs functionalized with polyferrocenylsilane, two distinct triggers are used to induce attraction between the polymer ligands and achieve NP self-assembly or topographic surface patterning of individual polymer-capped NPs. Control of polymer-solvent interactions is achieved by either changing the solvent composition or by the electrooxidation of polyferrocenylsilane ligands. These results expand the range of polymer ligands used for NP assembly and patterning, and can be used to explore new self-assembly modalities. The utilization of electrochemical polymer oxidation stimuli at easily accessible potentials broadens the range of stimuli leading to NP self-assembly and patterning. PMID- 29144011 TI - A Gold-Catalyzed Domino Cyclization Enabling Rapid Construction of Diverse Polyheterocyclic Frameworks. AB - We report herein an efficient gold(I)-catalyzed post-Ugi domino dearomatization/ipso-cyclization/Michael sequence that enables access to libraries of diverse (hetero)arene-annulated tricyclic heterocycles. This process affords novel complex polycyclic scaffolds in moderate to good yields from readily available acyclic precursors with excellent chemo-, regio-, and diastereoselectivity. The power of this strategy has been demonstrated by the rapid synthesis of 40 highly functionalized polyheterocycles bearing indole, pyrrole, (benzo)furan, (benzo)thiophene, pyrazole, and electron-rich arene groups in two operational steps. PMID- 29144012 TI - Uterine cervical adenocarcinoma associated with lobular endocervical glandular hyperplasia: Radiologic-pathologic correlation. AB - AIM: We aimed to identify the radiologic features of uterine cervical adenocarcinoma associated with lobular endocervical glandular hyperplasia (LEGH). METHODS: We retrospectively analyzed magnetic resonance (MR) images and pathologic findings of eight patients who underwent preoperative MR imaging followed by surgical resection and who were pathologically diagnosed with adenocarcinoma (except for adenocarcinoma in situ) associated with LEGH. We assessed the following MR findings: multicystic component (MC), solid component (SC), signal intensity of SC on diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) map, and radiological stage (r-stage) based on the FIGO classification. A pathologist reevaluated the pathological stage (p-stage) according to the FIGO classification. We correlated the MR findings with the pathologic features. RESULTS: Eight patients were classified into the following three types based on the MR findings: type A, MC and SC; type B, only SC; and type C, only MC. In the five patients with type A, diffusion restriction (DR) was seen on DWI and the ADC map. In 80% of type A cases, the r-stage matched the p stage. In the one patient with type B, DR was not seen on DWI or the ADC map, and the r-stage matched the p-stage. In the remaining type C cases, DR was not seen on DWI or the ADC map, and the r-stage was underestimated compared with the p stage. CONCLUSION: On MR imaging, the most common type of adenocarcinoma with LEGH is type A; type C is difficult to diagnose as carcinoma. PMID- 29144013 TI - Photocontrolled Synthesis of Abiotic Sequence-Defined Oligo(Phosphodiester)s. AB - A photoregulated phosphoramidite iterative process is studied for the synthesis of non-natural, digitally encoded oligo(phosphodiester)s. The oligomers are prepared using two reactive phosphoramidite monomers containing a 2-(2 nitrophenyl)propoxycarbonyl (NPPOC) protected OH group. The stepwise synthesis is performed on an OH-functional soluble polystyrene support, which allows recycling by precipitation in a nonsolvent. Repeating cycles involving phosphoramidite coupling, oxidation of phosphite to phosphate, and NPPOC deprotection by light irradiation at lambda = 365 nm are performed in order to prepare oligomers with different lengths and sequences. Synthesis is conducted on a micromolar scale and good recycling yields are obtained in all cases. The use of a soluble polymer support allows an in-depth characterization of the NPPOC photo-deprotection step by 1 H NMR, UV spectroscopy, and size exclusion chromatography, and thus identification of optimal synthesis conditions. After cleavage from the support, the oligo(phosphodiester)s are characterized by tandem mass spectrometry, which confirms preparation of uniform sequence-coded oligomers. PMID- 29144014 TI - Translocation of Precision Polymers through Biological Nanopores. AB - Nanopore analysis, which is, currently, chiefly used for DNA sequencing, is also an appealing technique for characterizing abiotic polymers. As a first step toward this goal, nanopore detection of non-natural monodispersed poly(phosphodiester)s as candidate backbone structures is reported herein. Two model homopolymers containing phosphopropyl repeat units (i.e., 56 or 104 r.u.) and a short thymidine nucleotide sequence are analyzed in the present work. They are tested in two different biological nanopores, alpha-hemolysin from Staphylococcus aureus, and aerolysin from Aeromonas hydrophila. These recordings are performed in aqueous medium at different KCl concentrations and various driving voltages. The data show a complex interaction with evidence for voltage dependence and threading, and underline the influence of the molecular structure and orientation of the precision poly(phosphodiester)s on the observed residual current signal as well as on the translocation dynamics. In particular, they suggest a dominant entropic contribution due to the high flexibility of the phosphodiester homopolymer. PMID- 29144015 TI - Elucidating the Impact of Chalcogen Content on the Photovoltaic Properties of Oxychalcogenide Perovkskites: NaMO3-x Qx (M=Nb, Ta; Q=S, Se, Te). AB - In the quest for nontoxic and stable perovskites for solar cells, we have conducted a systematic study of the effect of chalcogen content in oxychalcogenide perovskite by using DFT and quasi-particle perturbation theory. We explored the changes in the electronic structure due to the substitution of O atoms in NaNbO3 and NaTaO3 perovskite structures with various chalcogens (S, Se, Te) at different concentrations. Interestingly, the introduction of the chalcogen atoms resulted in a drastic reduction in the electronic band gap, which made some of the compounds fall within the visible range of the solar spectrum. In addition, our analysis of the electronic structure shows that the optical transition becomes direct as a result of the strong hybridization between the orbitals of the transition metal and those of the chalcogen ion, in contrast to the indirect band feature of NaNbO3 and NaTaO3 . We identified candidates with a high theoretical solar conversion efficiency that approached the Shockley Queisser limit, which makes them suitable for thin-film solar cell applications. The present work serves as a guideline for experimental efforts by identifying the chalcogen content that should be targeted during the synthetic route of thermodynamically stable and strongly photoactive absorbers for oxychalcogenide perovskites in thin-film solar cells. PMID- 29144016 TI - What is the protective effect of metformin on rat ovary against ischemia reperfusion injury? AB - AIM: The aim of this study was to investigate the protective effect of metformin on the rat ovary against ischemia-reperfusion injury. METHODS: Thirty-seven female Wistar albino rats were used in the study. The rats were divided into five groups, as follows: sham operation group (group 1); torsion group (group 2); torsion/detorsion + saline group (group 3); torsion/detorsion + low-dose metformin group (group 4); and torsion/detorsion + high-dose metformin group (group 5). The right ovary from each rat was evaluated histologically using hematoxylin-eosin staining, and the left ovaries were evaluated for tissue levels of the reduced-glutathione-to-oxidized-glutathione ratio, malondialdehyde (MDA), and caspase-3 activation. RESULTS: The highest damage score was observed in group 3, and the lowest score was observed in group 1. The tissue caspase-3 activity levels of groups 2, 3, and 4 were significantly higher than those of group 1. The difference between group 1 and group 5 in terms of tissue caspase-3 activity was not significant (P = 0.4). The reduced-glutathione-to-oxidized-glutathione ratio of group 1 was significantly higher than the ratios found in groups 2, 3, and 4. The tissue MDA level of group 1 was significantly lower than the levels found in groups 2, 3, 4, and 5. The tissue MDA level of group 5 was significantly lower than the levels in groups 3 and 4. CONCLUSION: From both histopathological and biochemical analyses, the results of the study demonstrated that metformin has beneficial effects when it comes to attenuating ovarian ischemia-reperfusion injury. PMID- 29144018 TI - Navigated retrograde endoscopic myotomy (REM) for the treatment of therapy resistant achalasia. AB - BACKGROUND: In achalasia, muscle spasm may involve the proximal esophagus. When the muscle spasm is located in the proximal esophagus, conventional per oral endoscopic myotomy (POEM) may not be sufficient to relieve symptoms. In this paper, we describe retrograde endoscopic myotomy (REM) as a novel approach to perform myotomy of the proximal esophagus, with the application of a navigation tool for anatomical guidance during REM. We aim to evaluate the feasibility and safety of REM and usefulness of the navigation during REM. METHOD: A 42-year-old male with type III achalasia who was treated with laparoscopic myotomy with fundoplication, multiple pneumatic balloon dilations, Botox injections and anterior POEM of the middle and distal esophagus without symptomatic effect. Repeated high-resolution- manometry (HRM) revealed occluding contractions of high amplitude around and above the aortic arch. A probe-based real-time electromagnetic navigation platform was used to facilitate real-time anatomical orientation and to evaluate myotomy position and length during REM. RESULTS: The navigation system aided in identifying the major structures of the mediastinum, and position and length of the myotomy. Twelve weeks after REM, the Eckardt score fell from seven at baseline seven to two. We also observed improvement with reduction of the pressure at the level of previous spasms in the proximal esophagus from 124 mmHg to 8 mmHg on HRM. CONCLUSION: REM makes the proximal esophagus accessible for endoscopic myotomy. Potential indication for REM is motility disorders in the proximal esophagus and therapy failure after POEM. PMID- 29144017 TI - A new and important relationship between miRNA-147a and PDPK1 in radiotherapy. AB - It was found that the expression level of miR-147a was significantly increased and the pathway of PI3K/AKT was dramatically inhibited after radiation. In view of the relationship between miRNA and target genes, we put forward the question, what is the relationship between PI3K/AKT and miR-147a? In order to find the answer to the question, we used bioinformatics techniques to analyze the relationship between miR-147 (a or b) and PI3K/AKT signaling pathway. miR-147a overexpression plasmid and PDPK1 3'UTR luciferase reporter gene plasmid were constructed. Dual luciferase reporter gene system validation experiments were carried out on miR-147a and PDPK1 relationship. The verification experiments were also carried out. Bioinformatics analysis showed that there is a miR-147a binding site in the non-coding region (3'UTR) of PDPK1. In the experimental groups transfected with wild type PDPK1 gene of 3'UTR plasmid, the luciferase activity decreased (or increased) significantly in miR-147a (or inhibitor) group compared with miR-NC (or anti-miR-NC); There was no significant difference between the miR 147a group (or inhibitor) and the miR-NC group (or anti-miR-NC) in the transfection of PDPK1-3'UTR-Mut gene vector. PDPK1 was a target gene for direct regulation of miR-147a downstream. Verifying test results showed that the expression of PDPK1 mRNA and protein was reduced after overexpression of miR 147a, which was up-regulated after silencing miR-147a in TC, and V79 cells. These results suggest that miR-147a could be involved in the regulation of PDPK1 transcription by binding to the target site in PDPK1 mRNA 3'UTR, and then regulated AKT. PMID- 29144019 TI - PEGylated Precision Segments Based on Sequence-Defined Thiolactone Oligomers. AB - A straightforward access route to multifunctional block copolymers, combining a poly(ethylene glycol) (PEG) block and a monodisperse segment with discrete monomer sequence based on thiolactone chemistry, is described. Exploiting an inverse conjugation strategy on a PEG preloaded poly(styrene) synthesis resin enables the convenient introduction of a predefined PEG-block at the alpha terminus of thiolactone-based sequence-defined oligomers. Reaction conditions for the stepwise, submonomer synthesis at polar solid supports are optimized, using sequential synthesis on a model resin that enables to isolate and determine the purity of the oligomer segments by liquid chromatography-electrospray ionization mass spectrometry analysis. The reaction conditions are used to synthesize PEGylated 5mer precision polymers with defined monomer sequence in good yields and high purity to offer an interesting platform of macromolecules with potential for biomedical applications. PMID- 29144021 TI - Quantitative Extracellular Matrix Proteomics Suggests Cell Wall Reprogramming in Host-Specific Immunity During Vascular Wilt Caused by Fusarium oxysporum in Chickpea. AB - Extracellular matrix (ECM) is the unique organelle that perceives stress signals and reprograms molecular events of host cell during patho-stress. However, our understanding of how ECM dictates plant immunity is largely unknown. Vascular wilt caused by the soil borne filamentous fungus Fusarium oxysporum is a major impediment for global crop productivity. To elucidate the role of ECM proteins and molecular mechanism associated with cell wall mediated immunity, the temporal changes of ECM proteome was studied in vascular wilt resistant chickpea cultivar upon F. oxysporum infection. The 2DE protein profiling coupled with mass spectrometric analysis identified 166 immune responsive proteins (IRPs) involved in variety of functions. Our data suggest that wall remodeling; protein translocation, stabilization, and chitin triggered immunity; and extracellular ATP signaling are major players in early, middle, and later phases of ECM signaling during fungal attack. Furthermore, we interrogated the proteome data using network analysis that identified modules enriched in known and novel immunity-related prognostic proteins centered around nascent aminopolypeptide complex (NAC), amine oxidase, thioredoxin, and chaperonin. This study for the first time provides an insight into the complex network operating in the ECM and impinges on the surveillance mechanism of innate immunity during patho-stress in crop plant. PMID- 29144020 TI - Combining Click Sulfur(VI)-Fluoride Exchange with Photoiniferters: A Facile, Fast, and Efficient Strategy for Postpolymerization Modification. AB - "Click" type reactions represent the currently most prevalent postpolymerization strategy for the preparation of functional polymeric materials. Herein, a novel photoiniferter agent 4-(fluorosulfonyl)benzyl diethylcarbamodithioate (FSB-DECT) containing both dithiocarbamates and sulfonyl fluoride moieties is developed to act as both photoinitiator and click sulfur(VI)-fluoride exchange (SuFEx) agent. The photopolymerization behavior of FSB-DECT is demonstrated via standard photoiniferter-mediated polymerization for various types of monomer including N isopropylacrylamide (NIPAAm), glycidyl methacrylate, and vinyl acetate (VAc). Gel permeation chromatography data show that the polymerization is relatively well controlled, with polydispersity indices of the product homopolymers in the range of 1.3-1.6. 1 H and 19 F NMR spectra and "reinitiated" photopolymerization indicate that the sulfonyl fluoride and diethyldithiocarbamyl groups remain at the respective ends of the homopolymer chains. Furthermore, using the sulfonyl fluoride end-functionalized poly(N-isopropylacrylamide) as a model polymer, the utility of the SuFEx reaction for efficient postpolymerization functionalization is demonstrated. PMID- 29144022 TI - Collagen: A review on its sources and potential cosmetic applications. AB - Collagen is a fibrillar protein that conforms the conjunctive and connective tissues in the human body, essentially skin, joints, and bones. This molecule is one of the most abundant in many of the living organisms due to its connective role in biological structures. Due to its abundance, strength and its directly proportional relation with skin aging, collagen has gained great interest in the cosmetic industry. It has been established that the collagen fibers are damaged with the pass of time, losing thickness and strength which has been strongly related with skin aging phenomena [Colageno para todo. 60 y mas. 2016. http://www.revista60ymas.es/InterPresent1/groups/revistas/documents/binario/ses33 informe.pdf.]. As a solution, the cosmetic industry incorporated collagen as an ingredient of different treatments to enhance the user youth and well-being, and some common presentations are creams, nutritional supplement for bone and cartilage regeneration, vascular and cardiac reconstruction, skin replacement, and augmentation of soft skin among others [J App Pharm Sci. 2015;5:123-127]. Nowadays, the biomolecule can be obtained by extraction from natural sources such as plants and animals or by recombinant protein production systems including yeast, bacteria, mammalian cells, insects or plants, or artificial fibrils that mimic collagen characteristics like the artificial polymer commercially named as KOD. Because of its increased use, its market size is valued over USD 6.63 billion by 2025 [Collagen Market By Source (Bovine, Porcine, Poultry, Marine), Product (Gelatin, Hydrolyzed Collagen), Application (Food & Beverages, Healthcare, Cosmetics), By Region, And Segment Forecasts, 2014 - 2025. Grand View Research. http://www.grandviewresearch.com/industry-analysis/collagen-market. Published 2017.]. Nevertheless, there has been little effort on identifying which collagen types are the most suitable for cosmetic purposes, for which the present review will try to enlighten in a general scope this unattended matter. PMID- 29144023 TI - Resident versus faculty member simulation debriefing. AB - BACKGROUND: Near-peer teaching is effective in graduate medical education, but it has not been compared with faculty member teaching in resident simulation. In this study, we sought to compare debriefing sessions of internal medicine (IM) intern simulation sessions led by academic faculty doctors with those led by senior IM residents in order to measure the effectiveness of near-peer teaching in this setting. Near-peer teaching is effective in graduate medical education, but has not been compared with faculty member teaching in resident simulation METHOD: Internal medicine interns participated in four simulation cases, two of which were debriefed by faculty members and two of which were debriefed by residents. Pre-simulation knowledge assessment was completed prior to the case. Following each debriefing, interns completed a Debriefing Assessment for Simulation in Healthcare (DASH) survey. Post-simulation knowledge assessments were completed 6 months after simulation. Debriefings were recorded and transcribed. Each statement made during debriefing was classified as either correct or erroneous by blinded reviewers. RESULTS: Fifty interns participated in simulation, and the response rate on the DASH survey was 88%. There was no difference between DASH scores (p = 0.13), post-simulation knowledge assessments or error rates during debriefing (p = 0.31) for faculty member and resident instructors. CONCLUSION: Our study suggests that residents and faculty members provide a similar quality of simulation instruction based on qualitative and quantitative evaluation. PMID- 29144025 TI - Detection of atypical porcine pestivirus in semen from commercial boar studs in the United States. AB - Atypical porcine pestivirus (APPV) has recently been identified as a cause of congenital tremor (CT) in pigs and has been detected in semen and preputial swabs from boars that were known to be clinically affected with CT. Accordingly, the objectives of this study were to 1) detect the presence of APPV in semen, preputial fluids and preputial swabs from adult boars by quantitative reverse transcription PCR (qRT-PCR) and 2) genetically characterize a subset of positive samples to better understand the ecology of APPV in commercial boar studs and the potential risk of transmission of APPV via semen. A total of 597 samples of semen, preputial fluid and preputial swabs each representing a different boar were obtained from four commercial boar studs located in three different states in the United States. Viral RNA was detected by qRT-PCR in 90 samples (15.08%; 90/597), with the greatest per cent positive from preputial swabs (23.81%; 5/21) followed by preputial fluid (22.81%; 26/114) and semen (12.91%; 59/457). The mean cycle quantification (Cq) between sample types was similar while eleven semen samples had Cq values lower than 27.0 corresponding to approximately 2 * 106 copies/ml. Based on phylogenetic analysis of the Npro gene, different viral strains can be on the same farm at the same and different times. This is the first report of detection of APPV in semen from commercial boar studs. Studies investigating the role of semen in the transmission of APPV and production of CT are needed. PMID- 29144024 TI - Epidemiology of type 1 diabetes in Polish children: A multicentre cohort study. AB - BACKGROUND: The incidence of childhood type 1 diabetes (T1D) varies greatly between populations, and the estimates and/or predictions of the rates would aid in adequate planning of health care resources. The study's aim was to assess the incidence of T1D in the paediatric population of eastern and central Poland. METHODS: In this cohort study covering the period from January 2010 to December 2014, data were collected for children and adolescents below 18 years of age with newly diagnosed T1D living in eastern and central Poland. A total of 2174 children were included in the analysis. The population estimates were from the Central Statistical Office of Poland. RESULTS: Overall, the annual incidence of T1D increased from 12.84/100,000 in 2010 to 18.46/100,000 in 2014 with the incidence rate (IR) ratio of 1.5 (an increase in the IR by 12.7% per year over 5 years). The lowest increase in the IR by 7.1% per year was seen in 15 to 17-year olds. In the urban population (age 0-17 years), the overall incidence rate was significantly higher than in subjects from rural communities (P < .02). The incidence of T1D in rural areas was significantly higher (p = .004) in voivodeships of higher population density. Such dependence was not observed in urban areas. CONCLUSIONS: The incidence of T1D in children living in eastern and central Poland increased 1.5-fold over the 5-year observation period with the highest rise in 10 to 14-year-olds and significantly higher rates in urban children compared with their peers living in rural areas. PMID- 29144026 TI - Heart rate variability and implication for sport concussion. AB - Finding sensitive and specific markers for sports-related concussion is both challenging and clinically important. Such biomarkers might be helpful in the management of patients with concussion (i.e. diagnosis, monitoring and risk prediction). Among many parameters, blood flow-pressure metrics and heart rate variability (HRV) have been used to gauge concussion outcomes. Reports on the relation between HRV and both acute and prolonged concussion recovery are conflicting. While some authors report on differences in the low-frequency (LF) component of HRV during postural manipulations and postexercise conditions, others observe no significant differences in various HRV measures. Despite the early success of using the HRV LF for concussion recovery, the interpretation of the LF is debated. Recent research suggests the LF power is a net effect of several intrinsic modulatory factors from both sympathetic and parasympathetic branches of the autonomic nervous system, vagally mediated baroreflex and even some respiratory influences at lower respiratory rate. There are only a few well controlled concussion studies that specifically examine the contribution of the autonomic nervous system branches with HRV for concussion management. This study reviews the most recent HRV- concussion literature and the underlying HRV physiology. It also highlights cerebral blood flow studies related to concussion and the importance of multimodal assessment of various biological signals. It is hoped that a better understanding of the physiology behind HRV might generate cost-effective, repeatable and reliable protocols, all of which will improve the interpretation of HRV throughout concussion recovery. PMID- 29144027 TI - Longitudinal Change in Adolescents' Prosocial Behavior Toward Strangers, Friends, and Family. AB - There is little understanding about how prosocial behavior toward different targets might change over time, and what might promote initial levels and age related changes in prosocial behavior. Thus, this study examined longitudinal change in prosocial behavior toward strangers, friends, and family from early adolescence through the transition to adulthood. Participants included 500 adolescents from the United States (age 12 to age 20; 52% female, 65% European American). Latent growth curve models suggested that prosocial behavior toward strangers increased across early to mid-adolescence and then flattened out during the transition to adulthood, prosocial behavior toward friends increased steadily, and prosocial behavior toward family was relatively stable across adolescence and then increased. Predictors of initial levels and growth in prosocial behavior varied by target. PMID- 29144029 TI - Neck circumference: A valuable anthropometric measurement to detect metabolic syndrome among different age groups in China. AB - OBJECTIVES: The aim of this study was to investigate the correlation between neck circumference and metabolic syndrome in Chinese residents and to explore the cut off points of neck circumference for metabolic syndrome in different age groups. METHODS: In all, 4227 Chinese adults (18-90 y) were enrolled in the study and divided into 3 subgroups (young, middle-aged, and elderly) according to their ages. The compared data for the subjects included anthropometric indicators and biochemical detection indices. Neck circumference was compared with other simple anthropometric indices using receiver operating characteristic curves. RESULTS: (1) In all, 362 of the subjects who were diagnosed with metabolic syndrome were young (16.8%), 428 were middle-aged (36.9%), and 485 were elderly people (53.1%). (2) The areas under the curve of neck circumference for metabolic syndrome for the 3 subgroups, young, middle-aged, and elderly, for males were 0.853, 0.792, and 0.828, respectively, and these values were 0.859, 0.780, and 0.725 for females, respectively. (3) Neck circumference cut-offs were 39.05, 39.45, and 38.90 cm in men and 34.15, 33.55, and 33.95 cm in women. CONCLUSIONS: Neck circumference contributed to determining metabolic syndrome risk beyond the classical anthropometric indices among different age groups in China. PMID- 29144030 TI - The role of glucagon in weight loss-mediated metabolic improvement: a systematic review and meta-analysis. AB - Aims This meta-analysis aimed to investigate the role of glucagon suppression in regulating glucose homeostasis following diet or bariatric surgery. Methods A comprehensive search of intervention and observational studies was conducted in Medline, Scopus, Web of Science, PubMed and Embase. Random effects model meta analysis was performed. Primary outcomes were (i) body weight change, (ii) fasting glucagon, (iii) fasting glucose and (iv) fasting insulin concentrations. Results Twenty articles reporting data from 29 interventions were eligible for analysis. Bariatric surgery caused greater weight loss than diet (bariatric -29.7 kg [CI:-36.8, -22.6]; diet -5.8 kg [CI: -8.4, -3.3]; P < 0.00001), an effect that remained significant after adjusting for study duration (P < 0.05). Mean fasting glucagon decreased in parallel with weight loss (-11.8 ng/L [CI: -15.9, -7.8]; P < 0.00001) with no difference between bariatric and diet intervention. Both fasting glucose, and insulin decreased following weight loss (both P < 0.00001; glucose -1.7 mmol/L [CI: -2.0, -1.3]; insulin -50.6 pmol/L [CI: -66.5, -34.7] with greater decrease in fasting insulin between bariatric versus diet (P = 0.01). Conclusions Synergistic suppression of fasting glucagon and insulin resistance may act together to restore normoglycaemia following weight loss. Whether suppression of plasma glucagon may contribute to increased hunger after weight loss and gradual weight regain is not yet known. PMID- 29144028 TI - Efficacy and safety of different regimens for primary open-angle glaucoma or ocular hypertension: a systematic review and network meta-analysis. AB - PURPOSE: To assess the efficacy and safety of different regimens, including monotherapy and double therapy, for primary open-angle glaucoma (POAG) or ocular hypertension. METHODS: We searched PubMed, EMBASE and clinicaltrials.gov for studies that fit our inclusion criteria in this network meta-analysis. Randomized controlled trials that report data on efficacy and safety of medications for POAG or ocular hypertension are included. Data on intra-ocular pressure (IOP) lowering effect and incidence of adverse events including hyperaemia and ocular discomfort were extracted and used in mixed-comparison analysis. RESULTS: This study includes 72 randomized trials. Data were available on 12 medical treatments of POAG or ocular hypertension. Of 66 possible comparisons of outcome efficacy, 15 treatments were compared directly. Compared to prostaglandin analogues (PGA), beta-blockers (BB) showed relatively weaker ability to lower IOP, followed by alpha2-adrenergic agonists (AA) and carbonic anhydrase inhibitors (CAI). For dual therapy, regimens composed of a combination of PGA with another treatment demonstrated more powerful IOP lowering efficacy, while the combination of two non-PGA drugs had lower efficacy in controlling IOP than PGA alone. There was no statistical significance in combinations that did not include PGA on efficacy of IOP control. In terms of tolerance, PGA alone leads to more severe hyperaemia than any other monotherapy regimen, while BBs have the lowest effect on the incidence of hyperaemia. Most dual therapy regimens containing PGA also lead to serious hyperaemia, with the exception of PGA + AA. Compared to regimens containing PGA, those with BB are less likely to cause hyperaemia. CONCLUSION: Our network meta-analysis showed that PGAs provide best IOP lowering effect among all the monotherapy regimen. Combination of PGA and other category of drugs leads to better IOP decrease. Combination of BB and another non-PGA drug may have less ocular side-effects than PGA alone. PMID- 29144031 TI - Error analysis of helmholtz-based MR-electrical properties tomography. AB - PURPOSE: MR electrical properties tomography (MR-EPT) aims to measure tissue electrical properties by computing spatial derivatives of measured B1+ data. This computation is very sensitive to spatial fluctuations caused, for example, by noise and Gibbs ringing. In this work, the error arising from the computation of spatial derivatives using finite difference kernels (FD error) has been investigated. In relation to this FD error, it has also been investigated whether mitigation strategies such as Gibbs ringing correction and Gaussian apodization can be beneficial for conductivity reconstructions. METHODS: Conductivity reconstructions were performed on a phantom (by means of simulations and MR measurements at 3T) and on a human brain model. The accuracy was evaluated as a function of image resolution, FD kernel size, k-space windowing, and signal-to noise ratio. The impact of mitigation strategies was also investigated. RESULTS: The adopted small FD kernel is highly sensitive to spatial fluctuations, whereas the large FD kernel is more noise-robust. However, large FD kernels lead to extended numerical boundary error propagation, which severely hampers the MR-EPT reconstruction accuracy for highly spatially convoluted tissue structures such as the human brain. Mitigation strategies slightly improve the accuracy of conductivity reconstructions. For the adopted derivative kernels and the investigated scenario, MR-EPT conductivity reconstructions show low accuracy: less than 37% of the voxels have a relative error lower than 30%. CONCLUSION: The numerical error introduced by the computation of spatial derivatives using FD kernels is one of the major causes of limited accuracy in Helmholtz-based MR-EPT reconstructions. Magn Reson Med 80:90-100, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29144032 TI - MicroRNA-106b overexpression alleviates inflammation injury of cardiac endothelial cells by targeting BLNK via the NF-kappaB signaling pathway. AB - We aim to investigate whether microRNA-106b (miR-106b) affects the inflammation injury of cardiac endothelial cells (ECs) by targeting B-cell linker (BLNK) via the NF-kappaB signaling pathway. Human cardiac microvascular endothelial cells (HCMECs) were assigned into the control, hypoxia/reoxygenation (H/R), negative control (NC), pyrrolidine dithiocarbamate (PDTC), miR-106b mimic, miR-106b inhibitor, and si-BLNK, and miR-106b inhibitor+si-BLNK groups. Quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting were conducted for miR-106b expression and expressions of BLNK, interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, NF-kappaB, pIkappaBalpha, BTK, and PLC-gamma2. Enzyme-linked immunosorbent assay was applied for levels of IL-6, IL-10, and TNF alpha; cell counting Kit-8 assay for cell proliferation; and flow cytometry for cell cycle and ensuing apoptosis. In-vitro tube formation assay was performed for tube formation ability. Dual-luciferase reporter assay revealed that BLNK was verified as the target gene of miR-106b. Compared with the H/R and NC groups, the PDTC, miR-106b mimic, and si-BLNK groups had declined expressions of IL-6, IL 1beta, TNF-alpha, BTK, PLC-gamma2, NF-kappaB p105/p50, and pIkappaBalpha as well as levels of L-6 and TNF-alpha, but contrarily elevated levels of NF-kappaB p105/p50 and IL-10. The PDTC, miR-106b mimic, and si-BLNK groups had less cell number in G0 /G1 phase but higher cell count in both S and G2 phases, decreased cell apoptosis but increased proliferation and tube formation ability, while opposite trends were observed in the miR-106b inhibitor group. Our findings indicated that the overexpression of miR-106b alleviated the inflammation injury of cardiac ECs by targeting BLNK via the NF-kappaB signaling pathway. PMID- 29144033 TI - Response to "Case series study of the efficacy of compounded antibacterial, steroid, and moisturizer in atopic dermatitis". PMID- 29144034 TI - Considerations in surgical management of a Buschke-Lowenstein tumor in Netherton syndrome: A case report. AB - Netherton syndrome is an autosomal recessive ichthyosis caused by mutations in SPINK5, with the classic triad of linearis circumflexa, trichorrhexis invaginata, and atopy. There are few reports of surgical management in individuals with Netherton syndrome and clinicians may be reluctant to operate for fear of wound healing complications. This report describes a pediatric case of a Buschke Lowenstein tumor of the natal cleft in a patient with Netherton syndrome that had failed to respond to medical management. We reviewed the literature for previous cases of surgery in individuals with Netherton syndrome using MEDLINE and PubMed searches. Our patient underwent surgery to remove the lesion without complication. Using conventional dressings and topical negative-pressure therapy, the wound was managed and healed within a reasonable time frame despite the underlying skin condition. This case indicates that surgery and topical negative pressure therapy is a safe and reasonable treatment for individuals with Netherton syndrome. PMID- 29144035 TI - Multiple ulcerated lesions in a child. PMID- 29144036 TI - Comment on "Case Series Study of the Efficacy of Compounded Antibacterial, Steroid, and Moisturizer in Atopic Dermatitis". PMID- 29144037 TI - A 15-year-old girl with a funky-looking great toenail. PMID- 29144038 TI - A 7-year-old boy with pustules on the upper eyelid. PMID- 29144039 TI - Chronic plaque on the great toe of a 10-year-old boy. PMID- 29144040 TI - Multiple annular plaques on a 9-year-old boy. PMID- 29144041 TI - Persistent pruritic subcutaneous nodules and hypopigmentation in a young boy. PMID- 29144043 TI - A 15-year-old boy with convoluted folds and furrows on the scalp. PMID- 29144042 TI - Palmoplantar keratoderma with curly hair. PMID- 29144044 TI - Patient Perspectives: What is papular urticaria? PMID- 29144045 TI - The triad of pruritus, xanthomas, and cholestasis: Two cases and a brief review of the literature. AB - When encountered in children, xanthomas are most commonly associated with a group of disorders known as familial hyperlipidemias. Aside from cosmetic concerns, these xanthomas are typically asymptomatic, but when generalized pruritus is a prominent associated symptom, clinicians should consider a different set of diagnoses that includes cholestasis of the liver. In this article we present two illustrative cases of children with cholestatic disease, pruritus, and xanthomas and discuss other disorders that may include this triad. PMID- 29144046 TI - Acute induration of the neck in a 16-year-old girl. PMID- 29144047 TI - Evaluation of patient satisfaction in pediatric dermatology. AB - BACKGROUND/OBJECTIVES: There remains a lack of investigation into which factors patients and families value the most in their experience at pediatric dermatology clinics. Most of the current literature on quality improvement in dermatology does not encompass the pediatric population. To determine the drivers that are most predictive of a positive patient experience, we observed the indirect relationship between several factors of the patient experience and their role in patient satisfaction. METHODS: Patient satisfaction surveys were distributed after their visits to patients at four pediatric dermatology clinics in one children's academic health system. Data were collected and organized into the top 30 survey variables with which patients expressed satisfaction on a 5-point Likert scale. Pearson product-moment correlation coefficients (r) for each variable with regard to "likelihood of your recommending our practice to others" were calculated. RESULTS: A total of 516 families completed patient satisfaction surveys. Analyses of top box scores showed that the strongest predictors of patient satisfaction were the likelihood of recommending care provider (r = .77, P = <.001), cheerfulness of practice (r = .76, P = <.001), care provider spoke using clear language (r = .73, P = <.001), patient confidence in care provider (r = .70, P = <.001), and our sensitivity to patient needs (r = .70, P = <.001). CONCLUSION: The patient-physician relationship, along with the environment of the practice and its sensitivity to patients' personal needs, contributes most to the patient experience in pediatric dermatology. Identifying such variables that shape patients' assessments of their experience can guide future quality improvement plans in the specialty. PMID- 29144048 TI - Teenage boy with thickened dorsal hands and feet. PMID- 29144049 TI - Characterization of children with recurrent eczema herpeticum and response to treatment with interferon-gamma. AB - BACKGROUND/OBJECTIVES: Interferon gamma (IFN-gamma) has been used treat severe atopic dermatitis, with equivocal results. Recurrent eczema herpeticum is an underappreciated, therapeutically challenging complication of severe atopic dermatitis. Defects in IFN-gamma and other cytokine pathways have been identified in individuals with confirmed eczema herpeticum. This suggests possible benefit from IFN-gamma treatment for confirmed eczema herpeticum. The objective of the current study was to evaluate immunologic and microbial parameters and response to IFN-gamma treatment in children with confirmed eczema herpeticum. METHODS: We performed a retrospective review of medical records from eight children with confirmed eczema herpeticum and two children with severe atopic dermatitis without a history of eczema herpeticum treated with subcutaneous IFN-gamma. RESULTS: Our cohort of children with confirmed eczema herpeticum was predominantly male and had high total serum immunoglobulin E, evidence of insufficient toll-like receptor responses, and streptococcal skin and pharyngeal colonization. The duration of IFN-gamma administration was 4.5-25 months. Five children had initial control and then relapse. Three had interval flares. Two had no improvement. Injections were well tolerated, without significant adverse effects. Treatment was associated with an increase in total immunoglobulin E. Poor adherence complicated therapy in five patients. All 10 discontinued IFN gamma for poor perceived efficacy. CONCLUSION: Children with confirmed eczema herpeticum have evidence of impaired innate and adaptive immunity. IFN-gamma did not result in dramatic improvement in either subset. Specific evaluation for IFN gamma production, function, or receptor defects may help predict response. PMID- 29144050 TI - Fibroadipose vascular anomaly treated with sirolimus: Successful outcome in two patients. AB - Fibroadipose vascular anomaly (FAVA) is a rare, complex mesenchymal malformation combining fibrofatty replacement of the affected muscles and slow-flow vascular malformation. The condition is characterized by localized swelling, severe pain, phlebectasia, and contracture of the affected limb. Treatment paradigms are not well established for this rare, recently recognized condition. We report two cases of FAVA in which treatment with sirolimus produced rapid, dramatic improvement in pain and quality of life. PMID- 29144051 TI - Infantile hemangiomas with conjunctival involvement: An underreported occurrence. AB - BACKGROUND/OBJECTIVES: Infantile hemangiomas (IHs) involving the conjunctiva are only anecdotally reported in the literature and little is known about their clinical course. In a retrospective case series we aimed to better delineate the clinical presentation, complications, and response to treatment of this uncommon subtype of IH. A classification of conjunctival IH is proposed. METHODS: Medical charts at three academic pediatric dermatology institutions were retrospectively analyzed. Data were collected on the clinical characteristics, ophthalmologic findings, treatments, and outcomes of 22 individuals with conjunctival IH. RESULTS: Growth characteristics of conjunctival IH closely mirrored those of their cutaneous counterparts. Ophthalmologic abnormalities were associated with the IH in six individuals (27%); in three, they were considered severe. Seventeen subjects (77%) required treatment, most commonly because of risk of ocular compromise. All treated individuals responded favorably to topical timolol or systemic propranolol. CONCLUSION: Conjunctival IH have clinical characteristics similar to those of cutaneous IH and respond readily to beta-blocker treatment. Ocular complications may occur in a minority of individuals receiving treatment. PMID- 29144052 TI - Comment on "Prevention of flares in children with atopic dermatitis with regular use of an emollient containing glycerol and paraffin: A randomised controlled study". PMID- 29144054 TI - A Strontium- and Chlorine-Free Pyrotechnic Illuminant of High Color Purity. AB - The development of a red-light-emitting pyrotechnic illuminant has garnered interest from the pyrotechnics community owing to potential regulations by the United States Environmental Protection Agency (U.S. EPA) regarding the use of strontium and chlorinated organic materials. To address these environmental regulatory concerns, the development of lithium-based red-light-emitting pyrotechnic compositions of high purity and color quality is described. These formulations do not contain strontium or chlorinated organic materials. Rather, the disclosed formulations are based on a non-hygroscopic dilithium nitrogen-rich salt that serves as both oxidizer and red colorant. These formulations are likely to draw interest from the civilian fireworks and military pyrotechnics communities for further development as they both have a vested interest in the development of environmentally conscious formulations. PMID- 29144053 TI - The impact of flow PRA on outcome in pediatric heart recipients in modern era: An analysis of the Pediatric Heart Transplant Study database. AB - Data from patients in the Pediatric Heart Transplant Study (PHTS) registry transplanted between 2010 and 2014 were analyzed to determine the association between HLA antibody (PRA) determined by SPA using Luminex or flow cytometry with a positive retrospective cross-match and the post-transplant outcomes of acute rejection and graft survival. A total of 1459 of 1596 (91%) recipients had a PRA reported pretransplant; 26% had a PRA > 20%. Patients with a PRA > 20% were more likely to have CHD, prior cardiac surgery, ECMO support at listing, and waited longer for transplantation than patients with a PRA <20%. Patients with higher PRA% determined by SPA were predictive of a positive retrospective cross-match determined by flow cytometric method (P < .001). A PRA > 50% determined by SPA was independently associated with worse overall graft survival after first month of transplant in both unadjusted and adjusted for all other risk factors. In this large multicenter series of pediatric heart transplant recipients, an elevated PRA determined by SPA remains a significant risk factor in the modern era. PMID- 29144055 TI - Confocal Raman spectroscopic imaging for in vitro monitoring of active ingredient penetration and distribution in reconstructed human epidermis model. AB - Topically applied active cosmetic ingredients (ACI) or active pharmaceutical ingredients (API) efficacy is directly related to their efficiency of penetration in the skin. In vitro reconstructed human epidermis surrogate models offer in vivo like skin samples for transdermal studies. Using Delipidol(r), an ACI currently used in the cosmetics industry, the capabilities to deliver accurate distribution maps and penetration profiles of this molecule by means of confocal Raman spectroscopic imaging have been demonstrated. Using a non-negative constrained least squares (NCLS) approach, contribution of specific molecules can be estimated at each point of spectral maps in order to deliver semi-quantitative heat maps representing the ACI levels in the different skin layers. The concentration profiles obtained are approximately single exponential for all 3 time points evaluated, with a consistent decay constant, which is independent of the sublayer structure. Notably, however, there is no significant penetration into the lower basal layers until a critical concentration is built up, after 3 hours. Combination of Raman confocal imaging with spectral unmixing methods such as NCLS is demonstrated to be a relevant approach for in vitro biological evaluation of cosmetic and pharmaceutical active ingredients and could easily be implemented as a screening tool for industrial use. PMID- 29144056 TI - Oropharyngeal dysphagia profiles in individuals with oculopharyngeal muscular dystrophy. AB - BACKGROUND: Although dysphagia represents a hallmark manifestation of oculopharyngeal muscular dystrophy (OPMD), limited knowledge exists regarding the underlying nature of oropharyngeal swallowing impairments in this patient population. We aimed to delineate global pharyngeal dysphagia profiles in OPMD and identify the prevalence and physiologic associations of impairments in swallowing safety and efficiency. METHODS: Twenty-two individuals with OPMD completed a videofluoroscopic swallowing evaluation. Blinded raters completed validated scales of global dysphagia (dynamic imaging grade of swallowing toxicity, DIGEST), efficiency (normalized residue ratio scale, NRRS), and safety (penetration-aspiration scale, PAS). Degree of laryngeal vestibule closure and aspiration events were described. Descriptives and chi-squared analyses were conducted with alpha set at P < .05. KEY RESULTS: One hundred and thirty-four swallowing trials were analyzed. DIGEST scores revealed that 96% (n = 21) of participants demonstrated pharyngeal dysphagia (score >1). Presence of a cricopharyngeal bar was noted in 10 individuals. The predominant swallowing categorization across patients was safe and inefficient (51%) followed by unsafe and inefficient (32%). 77.3% demonstrated vallecular residue (NRRSv>0.07) and 90.1% piriform sinus residue (NRRSp > .20). 33% (n = 54) of swallows were unsafe (PAS>3) with 45 episodes of penetration and 9 episodes of aspiration. Aspiration occurred during the swallow in 100% of identified occurrences. Incomplete epiglottic inversion was associated with airway compromise and postswallow residue (P < .05). CONCLUSIONS & INFERENCES: These findings highlight the high prevalence of oropharyngeal swallowing impairments in both swallowing efficiency and safety. A high proportion of physiologic impairments in epiglottic inversion and laryngeal vestibule closure were noted that related to functional impairments in swallow safety and inefficiency. PMID- 29144058 TI - Corrigendum. PMID- 29144057 TI - Prepregnancy Body Mass Index, Gestational Weight Gain, and Odds of Cesarean Delivery in Hispanic Women. AB - OBJECTIVE: This study aimed to evaluate the association between prepregnancy body mass index (BMI), gestational weight gain (GWG), and cesarean delivery in Hispanics. METHODS: We examined these associations among 1,215 participants in Proyecto Buena Salud, a prospective cohort of Hispanic women studied from 2006 to 2011. Prepregnancy BMI, GWG, and the mode of delivery were abstracted from medical records. RESULTS: A quarter of the participants entered pregnancy with obesity, 23% delivered via cesarean, and 52% exceeded the Institute of Medicine guidelines for GWG. After adjusting for age, women with obesity had 2.03 times the odds of cesarean delivery compared with women with normal BMI (95% confidence interval [CI]: 1.46-2.82); findings remained significant after adjusting for GWG. Women with excessive total GWG had 1.49 times the odds of cesarean delivery (95% CI: 1.06-2.10) compared with women who gained within guidelines. An excessive rate of third trimester GWG (standard deviation [SD] change in GWG per week) increased the odds of cesarean delivery (odds ratio = 1.66; 95% CI: 1.05-2.62), while an excessive rate of first and third trimester GWG was not associated with increased odds. CONCLUSIONS: Obesity prior to pregnancy was associated with increased odds of cesarean delivery among Hispanics. Excessive GWG across pregnancy and an excessive rate of third trimester GWG were also associated with increased odds. PMID- 29144060 TI - Your journal needs you. PMID- 29144059 TI - Association between smoking and glycemic control in diabetic patients: Results from the Risk Evaluation of cAncers in Chinese diabeTic Individuals: A lONgitudinal (REACTION) study. AB - BACKGROUND: A number of primary studies suggested that active smoking could be independently associated with incident diabetes. However less is known about the effect of active smoking and smoking cessation on glycemic control in patients with diabetes. The aim of this study was to evaluate the associations of active smoking and smoking cessation with glycemic control in diabetic patients. METHODS: The present was a cross-sectional study of 10 551 men and 15 297 women with diabetes from the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. Risk factors for glycemic control and the association of active smoking with glycemic control were evaluated using logistic regression models. Poor glycemic control was defined as HbA1c >=7.0%. RESULTS: Current smokers have an increased risk of poor glycemic control, and the multivariable-adjusted odds ratio (OR) and 95% confidence intervals (CI) of HbA1c >=7.0% with current smoking were 1.49 (1.35-1.66) in men and 1.56 (1.13-2.15) in women. Further analysis demonstrated a dose-dependent relationship between active smoking and the risk of poor glycemic control in men. Former smokers who quit smoking for <10 years remained at increased risk of poor glycemic control, with the risk leveling off after 10 years of smoking cessation compared with non smokers, but risk in former smokers was significantly lower than that in current smokers. CONCLUSIONS: Active smoking is a modifiable risk factor for poor glycemic control in Chinese diabetic patients. PMID- 29144061 TI - Saxagliptin add-on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin with or without metformin: Results from the SUPER study, a randomized, double-blind, placebo-controlled trial. AB - This prospective, multicentre, phase III study (NCT02104804) evaluated the efficacy and safety of saxagliptin add-on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin +/- metformin. Patients with glycated haemoglobin (HbA1c) 7.5% to 10.5% and fasting plasma glucose (FPG) <15 mmol/L (270 mg/dL) on stable insulin therapy (20-150 U/d) were randomized (1:1) to saxagliptin 5 mg once daily (N = 232) or placebo (N = 230) for 24 weeks, stratified by metformin use. The primary efficacy measure was change in HbA1c. Saxagliptin treatment resulted in a greater adjusted mean change in HbA1c from baseline to week 24 than placebo (-0.58%; P < .001), irrespective of metformin use, and a greater mean change in FPG (0.9 mmol/L [-15.9 mg/dL]; P < .001). More patients achieved HbA1c <7% with saxagliptin (11.4%) than with placebo (3.5%, P = .002). Adverse events and incidence of hypoglycaemia were similar in both groups. Overall, add-on saxagliptin 5 mg once daily significantly improved glycaemic control without increasing hypoglycaemia risk and was well tolerated in Chinese patients with type 2 diabetes inadequately controlled by insulin (+/- metformin). PMID- 29144062 TI - Hearing impairment and deafness among HIV infected children and adolescents in Harare, Zimbabwe. AB - Background: Among HIV-infected children ear infections are recurrent and chronic, which may lead to hearing loss. Objective: To determine the prevalence, cause and severity of hearing impairment among HIV-infected children aged 5-17 years attending for HIV care in Harare. Design and Setting: An analytical cross sectional survey conducted at Newlands Clinic, an opportunistic infections clinic in Harare. Materials and Methods: Participants underwent a standardised otoscopic examination of the ear and Pure Tone Audiometry (PTA). Factors associated with hearing impairment were investigated using multivariate logistic regression. Results: Three hundred and eighty (380) participants (55% female and mean age 11 years (SD: 3.3 years)) were consecutively recruited. The vast majority of participants (n=338; 89% were taking antiretroviral therapy (ART) for a median of 3 (IQR: 2-5) years at recruitment, and the most recent median CD4 Count (i.e. CD4 count measured within 6 months of the study recruitment) was 725 (IQR: 497-1000) cells/uL, with no difference by ART status. 61% (n= 231) of participants had an abnormal ear examination. Of the 359 participants who underwent audiometry, the prevalence of hearing impairment was 32.3% (95%CI: 27.5%-37.4%) based on a PTA threshold >=26Db. Hearing impairment was associated with a recent CD4 count <350cell/uL (OR 2.1, P<0.037). Conclusion: There is a high prevalence of hearing impairment among HIV-infected children and adolescents. Low CD4 count remains a risk factor even among those who are on ART. We recommend that HIV infected children and adolescents, particularly those with low CD4 counts, should have routine evaluation of hearing as part of HIV care. PMID- 29144063 TI - Metabolic effects of Carbon Dioxide (CO2) insufflation during laparoscopic surgery: changes in pH, arterial partial Pressure of Carbon Dioxide (PaCo2) and End Tidal Carbon Dioxide (EtCO2). AB - Background: Acid base alterations occur during laparoscopy with carbon dioxide insufflation. The purpose of this study was to investigate the effects of low tidal volume ventilation on acid base status during pneumoperitonium. Materials and Methods: 30 patients undergoing laparoscopic surgery under General Anaesthesia were ventilated with tidal volume of 6 ml/kg and respiratory rate of 12 breaths/minute. Arterial blood gas analysis was done before, during and after C02 pneumoperitoneum. Arterial haemoglobin oxygen saturation by pulse oximetry (SPO2) and EtC02 were monitored continuously throughout the laparoscopy. Respiratory adjustments were done for EtCO2 levels above 60mmHg or SPO2 below 92% or adverse haemodynamic changes. Results: low tidal volume ventilation during pneumoperitoneum resulted in a significant elevation in PaCO2 (p<0.001) and a fall of pH (p <0.001), ion bicarbonate (HCO3-) (p = 0.011), and base excess (ABE) (p <0.001). A correlation was found between the EtCO2 and PaCO2 during pneumoperitoneum. Oxygenation was well maintained during pneumoperitoneum. No ventilatory adjustments were instituted on any of the patients as they maintained EtCO2 below 60mmHg throughout pneumoperitoneum. Conclusion: Ventilation with low tidal volume during pneumoperitoneum causes a mixed respiratory and metabolic acidosis. EtCO2 is still a good non-invasive monitor for estimation of PaCO2 during low tidal volume ventilation during pneumoperitoneum. PMID- 29144065 TI - WHO Expert Committee on Drug Dependence AB - The WHO Expert Committee on Drug Dependence (ECDD) is responsible for assessing psychoactive substances for possible control under the international drug control conventions. The ECDD reviews the therapeutic usefulness, the liability for abuse and dependence, and the public health and socialharm potential of each substance under review. After the ECDD advises the Director-General of WHO as to whether to schedule or to amend the scheduling status of a substance, the Director-General will, as appropriate, communicate the recommendations to the United Nations Secretary-General. The Secretary-General communicates the advice to the Commission on Narcotic Drugs (CND), as appropriate. This report presents the recommendations of the thirty-seventh meeting of the WHO Expert Committee on Drug Dependence. The report summarizes the review of nine substances and the ECDD's recommendations for the scheduling of seven substances. The report also provides updates on ketamine and cannabis, as requested byresolutions of the Commission on Narcotic Drugs. It contains updates on the work of international bodies concerned with controlled substances, as well as summaries of the follow-up discussions on recommendations made at the previous ECDD meeting, and on the discussions on criteria for assessing new psychoactive substances and on terminology. PMID- 29144064 TI - Negative appendicectomy: evaluation of ultrasonography and Alvarado score. AB - Background: High negative appendicectomy rates are no longer acceptable with improvements in imaging techniques and clinical prediction rules. The use of ultrasound and CT scan in addition to clinical assessment and blood investigations has greatly reduced the negative appendicectomy rate to less than 10%. Objectives: The aim of the study was to determine the negative appendicectomy rate at the two major teaching hospitals in Harare and to evaluate the accuracy of the Alvarado score and ultrasound scan in diagnosing acute appendicitis. Design: Prospective observational, cross sectional study. Setting: Parirenyatwa Group of Hospitals and Harare Central Hospital, in Zimbabwe. Materials and Methods: A total of 206 patients undergoing appendicectomy at the two major teaching hospitals in Harare were included in this study between June 2012 and May 2013. Information recorded included: age, sex, clinical features, investigations and treatment. Alvarado score was calculated from the data in the case notes and ultrasound scan results were also captured. All appendices removed at operation were sent for histopathological examination. Appendicitis was confirmed at histology. The positive predictive value of Alvarado score and sensitivity and specificity of ultrasound scan were calculated. Results: The overall negative appendicectomy rate was 16.5%. The negative appendicectomy rate for men was 13.3% and that for females was 24.4%. The negative appendicectomy rate for Parirenyatwa Group of Hospitals was 19.0% and that for Harare Central Hospital was 12.1%. The mean age was 28 years (SD 12.8). Appendicitis was diagnosed commonly in the second and third decades of life. Sensitivity of ultrasound scan in diagnosing acute appendicitis was 89.5% with a positive predictive value of 77.2%. Females were 2.6 times more likely to have an ultrasound scan done to diagnose appendicitis than males. Alvarado score had a sensitivity of 95.3% with a positive predictive value of 90.3%. Conclusion: The negative appendicectomy rate (16.5%) at the two University Teaching Hospitals in Harare is relatively high when compared with modern trends. Alvarado score had a high sensitivity (95.3%) and predictive value (90.3%). Ultrasound scan had a high sensitivity (89.5%) and a relatively low predictive value (77.2%) in diagnosing acute appendicitis. Regular use of these assessment modalities should contribute substantially to reduction in the negative appendicectomy rate in our practice. PMID- 29144066 TI - Neurological manifestation of phenytoin toxicity, resulting from drug interaction with chloramphenicol: a case report. AB - Phenytoin toxicity masquerading as deterioration of neurological symptoms caused by interaction with chloramphenicol is a very rare but real risk. To the authors' knowledge only one such case occurring in humans has been reported in the English literature. No case of clinical phenytoin toxicity occurring at less than double the serum phenytoin therapeutic levels, occurring as a result of chlorampenicol interaction has been documented, hence our report.A 17 year old man, whose frontal subdural empyema had been drained, had his seizures well controlled on phenytoin. Shortly after, he had a parasagital subdural empyema which was also drained. He was put on chloramphenicol. He improved tremendously until he then developed cerebellar symptoms. Phenytoin levels were noted to be almost twice the maximum therapeutic value. On stopping chloramphenicol, phenytoin levels normalized and symptoms resolved.Possibility of phenytoin toxicity should always be entertained in patients who are also taking chlorampenicol, presenting with new or worsening neurological symptoms. PMID- 29144067 TI - Introducing misoprostol for the management of postpartum hemorrhage in Zimbabwe: final report on operational research. AB - Postpartum Haemorrhage (PPH) is the most common cause of maternal mortality globally, leading to a woman's death every seven minutes. In Zimbabwe, there has been a 300% increase in the Maternal Mortality Ratio (MMR) between 1994 and 2010 and the MMR was estimated at 960 maternal deaths per 100,000 live births in 2012.2-3 Overall, 14% of all maternal deaths in Zimbabwe are due to PPH. Ensuring prompt access to high-quality prevention and treatment of PPH for all women who deliver is an essential strategy to combat PPH-related morbidity and mortality and to make progress toward reaching Millennium Development Goal 5, the reduction of maternal mortality by three-quarters by 2015. PMID- 29144068 TI - Going Public: Early Disclosure of Food Risks for the Benefit of Public Health. AB - Often during an outbreak of foodborne illness, there are health officials who have data indicating that there is a risk prior to notifying the public. During the lag period between the first public health signal and some release of public information, there are decision makers who are weighing evidence with the impacts of going public. Multiple agencies and analysts have lamented that there is not a common playbook or decision tree for how public health agencies determine what information to release and when. Regularly, health authorities suggest that how and when public information is released is evaluated on a case-by-case basis without sharing the steps and criteria used to make decisions. Information provision on its own is not enough. Risk communication, to be effective and grounded in behavior theory, should provide control measure options for risk management decisions. There is no indication in the literature that consumers benefit from paternalistic protection decisions to guard against information overload. A review of the risk communication literature related to outbreaks, as well as case studies of actual incidents, are explored and a blueprint for health authorities to follow is provided. PMID- 29144070 TI - Food Safety Program Performance Assessment in Tennessee, 2003-2011. AB - To assess food safety program performance, the Tennessee Department of Health conducted food service surveys of randomly selected establishments and reviewed routine inspection reports by environmental health specialists (EHSs) of the same facilities. The individual restaurant sanitation scores, along with types and frequencies of violations noted by the survey team, were compared with records from the previous year. In addition, EHSs were observed as they each performed two routine inspections. Survey team staff consistently marked more critical violations than did field EHS staff. Differences between survey teams and field EHS staff in marking critical violations were statistically significant for all 10 critical violations in the first review cycle, 8 in the second cycle, and 7 in the third cycle. Over the course of the review period, there was a small but measurable improvement in scoring by field EHS staff. Marking of critical violations increased, sanitation scores decreased, and discrepancies with survey teams in both areas decreased. PMID- 29144071 TI - Evaluation of certain contaminants in food. AB - This report represents the conclusions of a Joint FAO/WHO ExpertCommittee convened to evaluate the safety of various contaminants orgroups of contaminants in food.The first part of the report contains a brief description of generalconsiderations addressed at the meeting, including updates on mattersof interest to the work of the Committee. A summary follows of theCommittee's evaluations of technical, toxicological and/or dietaryexposure data for six contaminants or groups of contaminants (aflatoxins,4,15-diacetoxyscirpenol, fumonisins, glycidyl esters, 3-MCPD esters and3-MCPD, sterigmatocystin) as well as an evaluation of co-exposure offumonisins with aflatoxins.Annexed to the report is a summary of the toxicological and dietaryexposure information as well as the Committee's recommendations on thecontaminants and groups of contaminants considered at this meeting. PMID- 29144072 TI - Relapse and cytogenetic evolution in myeloid neoplasms. AB - Based on the current WHO Classification of Myeloid Neoplasms, cytogenetic findings play a central role in the diagnostic classification of the myeloid malignancies. Cytogenetic abnormalities detected at primary diagnosis may change over time. Karyotype changes can be characterized as cytogenetic evolution, cytogenetic regression or a combination of both. While the exact mechanism of cytogenetic evolution is not completely understood, the process of cytogenetic evolution is not random, but follows different, and often disease-specific patterns during progression and relapse of myeloid neoplasms. Important lessons were learned from the cytogenetic evolution pathways observed over the course of chronic myelogenous leukemia (CML), progressing through chronic phase into accelerated phase and blast crisis. Cytogenetic evolution pathways of CML are divided into major and minor route abnormalities. The major route changes include an extra Ph chromosome (+Ph) trisomy 8 (+8) and the occurrence of an i(17q). The six most common minor route abnormalities include -7, -17, +17, +21 and -Y and one structural change, t(3;21). Recently an increased number of CML cases with karyotype abnormalities in Ph-negative cells have been reported in patients treated with imatinib. These abnormalities include trisomy 8, abnormalities of chromosome 7, and chromosome 20. The significance of the Ph-negative karyotype changes in subsequent development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) is unclear. Nevertheless, the occurrence of clonal abnormalities in Ph-negative cells underlines the importance of conventional cytogenetic studies in monitoring of CML patients. In AML, karyotype changes commonly occur between diagnosis and relapse status post chemotherapy. Karyotype evolution seems more common in patients who had unfavorable aberrations at diagnosis as compared to patients with favorable or intermediate abnormalities. Karyotype evolution results in shortened remission duration as compared to cases without cytogenetic change. Recent studies on cytogenetic evolution at relapse after allogeneic hematopoietic cell transplantation (allo-HCT) were similar to the data observed in chemotherapy-treated AML. Serial bone marrow evaluations after allo-HCT offer insights into the dynamics of karyotype evolution, notably, they demonstrated that a detection of karyotype abnormalities is usually followed by a relapse within the next 90 days. As a contrast, karyotype abnormalities were not observed in patients who do not relapse in the next 3 months. CGE at relapse was associated with significantly decreased postrelapse and post-transplantation survival compared with the non-CGE group. Very few data exist regarding a potential association between the dose or certain types of chemotherapy and cytogenetic evolution. Based on the results of a single study conducted recently, no specific chemotherapy regimen emerged to predispose for cytogenetic evolution. Further studies are necessary to evaluate the impact of the altered bone marrow environment and immunosuppression on karyotype stability. PMID- 29144073 TI - Evaluation of certain food additives. AB - This report represents the conclusions of a Joint FAO/WHO ExpertCommittee convened to evaluate the safety of various food additives,including flavouring agents, with a view to concluding as to safety concernsand to preparing specifications for identity and purity.The first part of the report contains a general discussion of the principlesgoverning the toxicological evaluation of and assessment of dietaryexposure to food additives, including flavouring agents. A summaryfollows of the Committee's evaluations of technical, toxicological anddietary exposure data for 10 food additives (Allura Red AC; carob beangum; lutein esters from Tagetes erecta; octenyl succinic acid (OSA)-modified gum arabic; pectin; Quinoline Yellow; rosemary extract; steviolglycosides; tartrazine; and xanthan gum) and five groups of flavouringagents (alicyclic, alicyclic-fused and aromatic-fused ring lactones;aliphatic and aromatic amines and amides; aliphatic secondary alcohols,ketones and related esters; cinnamyl alcohol and related substances; andtetrahydrofuran and furanone derivatives).Specifications for the following food additives were revised: aspartame;cassia gum; citric and fatty acid esters of glycerol (CITREM); modifiedstarches; octanoic acid; starch sodium octenyl succinate; and totalcolouring matters.Annexed to the report are tables summarizing the Committee'srecommendations for dietary exposures to and toxicological evaluationsof all of the food additives, including flavouring agents, considered at thismeeting. PMID- 29144074 TI - A cluster randomized controlled trial of the non-pneumatic anti-shock garment for obstetric haemorrhage: sub-analysis of the Zimbabwean Arm. AB - Objectives: To determine whether earlier application of the Non-pneumatic Anti Shock Garment (NASG) at clinic level compared to the referral hospital level reduces maternal morbidity and mortality and recovery time from shock due to severe Obstetric Haemorrhage (OH) and to determine the safety of the NASG when applied at clinic level. Design: A cluster Randomized Controlled Trial (RCT) Setting: Harare and Parirenyatwa Referral Hospitals (RH) in Harare and the twelve Harare City Council clinics that offer maternity care. Subjects: Women who had suffered severe OH at clinic level and were being transferred to a Referral Hospital (RH). Iterventions: The clinics were randomized into two groups. In the early NASG group eligible women were given the standard management for OH and had the NASG applied at the clinic level before transport to RH. In the control group, eligible women were given the standard management for OH at the clinic level, transferred to the RH, and received the NASG at the RH. All women received equivalent OH/hypovolemic shock management at the RH. Main Outcome Measures: The main outcome measures were maternal mortality and morbidity, blood loss, recovery from shock and the occurrence of side effects whilst in the NASG. Results: There were few maternal deaths and morbidities, and no statistically significant differences between the two groups were noted. Women in the early NASG group spent a statistically significant shorter time in the NASG at referral hospital level (OR 0.64, 95% CI 0.52 - 0.79, p < 0.001) and had a non-significant 40% faster recovery from shock (HR 1.39; 95% CI 0.98-1.97, p=0.07). There were no differences in reported side effects. Conclusion: Earlier NASG application at the clinic level was associated with faster recovery from shock in women who had suffered severe OH and appears safe to use. PMID- 29144075 TI - WHO Expert Committee on Biological Standardization. AB - This report presents the recommendations of a WHO ExpertCommittee commissioned to coordinate activities leading to theadoption of international recommendations for the productionand control of vaccines and other biological substances, and theestablishment of international biological reference materials.Following a brief introduction, the report summarizes anumber of general issues brought to the attention of theCommittee. The next part of the report, of particular relevanceto manufacturers and national regulatory authorities, outlinesthe discussions held on the development and adoption ofnew and revised WHO Recommendations, Guidelines andguidance documents. Following these discussions, a WHOguidance document on Regulatory assessment of approvedrDNA-derived biotherapeutics was adopted along with WHOGuidelines on the stability evaluation of vaccines for use underextended controlled temperature conditions and on WHO goodmanufacturing practices for biological products. In addition,revised WHO Recommendations to assure the quality, safetyand efficacy of recombinant human papillomavirus virus-likeparticle vaccines were also adopted by the Committee.Subsequent sections of the report provide information on thecurrent status and proposed development of internationalreference materials in the areas of antibiotics; biotherapeuticsother than blood products; blood products and relatedsubstances; in vitro diagnostic device reagents; and vaccinesand related substances.A series of annexes are then presented which include anupdated list of all WHO Recommendations, Guidelines andother documents on biological substances used in medicine(Annex 1). The above four WHO documents adopted onthe advice of the Committee are then published as partof this report (Annexes 2-5). Finally, all additions anddiscontinuations made during the 2015 meeting to the list ofInternational Standards, Reference Reagents and ReferencePanels for biological substances maintained by WHO aresummarized in Annex 6. The updated full catalogue ofWHO International Reference Preparations is available at:http://www.who.int/bloodproducts/catalogue/en/. PMID- 29144076 TI - The Let's Beat the Bug! Campaign--A Statewide Active Public Education Against Bed Bugs in Minnesota. AB - Bed bugs continue to affect society and place a burden on public health systems. Experiences of the Let's Beat the Bug! campaign are presented to help information networks prepare personnel to effectively address questions about this pest. Following recommendations from the Minnesota state bed bug working group, an information line was established and the Web site (www.bedbugs.umn.edu) was revised. Data from both services were analyzed by geographic region and type of information requested. InformationLine primarily assisted people who had issues dealing with failed treatments and landlord reluctance to take effective measures against this pest. Web site visits indicated a preference for learning do-it yourself control methods. There were commonalities in the information sought from both services. People were often looking for reassurance, in addition to information about basic prevention and control of bed bugs. We present here priority topics that public health personnel should be prepared to answer if they receive inquiries about bed bugs. PMID- 29144077 TI - Seasonality and surgical management of intussusception over 10 years at Harare Children's Hospital. AB - Objectives: To determine the number of patients with intussusception treated at HCH over a 10 year period. To describe the ages and sex of children operated for intussusceptions. To determine if there is seasonal variation in the number of cases presenting to HCH. To determine the type and method of treatment of intussusception at HCH. Design: This was a descriptive retrospective study. Theatre records were inspected to identify eligible patients. Information regarding sex, age, anatomical subtype and procedure performed was recorded. Setting: Harare Central Hospital, Zimbabwe. Subjects: Two hundred and seventeen (217) participants were enrolled. All patients who underwent surgery for intussusception between September 2003 and August 2013 were eligible. One re operation was excluded. Results: There were 129 boys and 83 girls. The modal age was 6 months. 61.3% of patients had ileo-colic intussusception, 4.1% colo-colic and 0.5% ileo-ileal. The peak incidence was in September. There was an increase in annual cases in the period under review from 9 cases in 2003/2004 to 34 cases in the 2012/2013 period. 47.5%of patients had resection and primary anastomosis while 24.0% had manual reduction at laparotomy. Conclusion: Intussusception is one of the most common paediatric surgical emergencies at Harare Central Hospital. The age and sex of patients are the same as those found in literature. In contrast with previous data, a strong statistically significant seasonal incidence was observed. The majority of cases were ileo-colic. The most common procedure at laparotomy was resection as opposed to manual reduction. PMID- 29144078 TI - Presence of Household Mold, Children's Respiratory Health, and School Absenteeism: Cause for Concern. AB - A study examining the relationship between housing conditions, respiratory health, and school absenteeism was conducted in the city of Winnipeg in Manitoba, Canada. As part of this study, a survey was completed by 3,424 parents of children in grades 3 and 4 to determine the a) relationship between self-reported visible mold in homes and tested airborne mold; b) relationships of self-reported visible mold, tested airborne mold, and asthma and/or persistent colds; c) school absenteeism rates due to asthma and/or persistent colds; and d) children's socioeconomic status (SES) and incidence of asthma and/or persistent colds. In addition, a complete inspection of a subset of 715 homes was conducted, including the collection of over 1,400 indoor and 500 outdoor air samples for mold analysis. Results indicate a significant association between self-reported visible mold and airborne mold. Additionally, a significant association was found between Cladosporium levels from air samples (the most common genus type found) and children's asthma in combination with persistent colds. Children with persistent colds in combination with asthma miss significantly more school than children who have only asthma or only persistent colds. Children from poorer families reported more persistent colds than children from high-income families. No association was found between income and asthma. Furthermore, SES was not a significant factor for number of school days missed. PMID- 29144079 TI - Occupational therapy needs of adolescents and young adults with cerebral palsy in Zimbabwe: caregivers' perspectives. AB - Objectives: To determine occupational therapy needs of adolescents and young adults with cerebral palsy living in an urban setting, to identify participation levels in activities of daily living and social activities, to identify factors influencing participation and to determine the contribution of occupational therapy in participating in these activities. Design: Descriptive cross sectional. Setting: Community rehabilitation outreach points in Epworth, Mufakose, Glenview, Dzivarasekwa, Mabvuku and Norton. Participants: Thirty-five randomly selected primary caregivers of adolescents and young adults with cerebral palsy. Data analysis: Data collected on the questionnaires was analysed using SPSS/16.0 for frequencies and means. Results: Fourteen (41%) of the adolescents and young adults were independent in self-care activities such as toileting, grooming, dressing, mobility and bathing. Twenty-one (59%) were totally dependent or needed some assistance in performing activities of daily living. Factors reported to influence participation included upper and lower limb contractures, transport challenges, financial constraints and the home environment. Occupational therapy needs of adolescents and young adults as reported by their caregivers included further training in activities of daily living (74%), home adaptations (66%), vocational skills training (20%) and provision of appropriate assistive devices (6%). Conclusion: In light of these findings performance areas that still needed occupational therapy interventions included activities of daily living, vocational skills training, use of assistive devices and home adaptations. Therefore adolescents and young adults with cerebral palsy living in Zimbabwe still have functional performance deficits that can be addressed by provision of follow-up community occupational therapy interventions. PMID- 29144081 TI - Students Can Be an Important Link Between Academia and Practice. PMID- 29144080 TI - Competency based ophthalmology training curriculum for undergraduate medical students in Zimbabwe. AB - Background: The establishment of a credible, defensible and acceptable "formal competency based ophthalmology training curriculum for undergraduate medical and dental students" is fundamental to program recognition, monitoring and evaluation. The University of Zimbabwe College of Health Sciences (UZ-CHS) has never had a formal ophthalmology training curriculum for medical graduates since its inception. This has cast doubts on the quality of medical graduates produced with regards to delivery of basic primary eye care in the community. Objective: The aim of this project was to develop a formal "competency based ophthalmology training curriculum" (CBOTC) for medical graduates in Zimbabwe. Design: Institution based (University of Zimbabwe College of Health Sciences and Parirenyatwa Group of Hospitals), cross-sectional analytic study. Methodology: A review of undergraduate medical training curriculum and literature was done to identify gaps in the ophthalmology training curriculum. A local needs assessment was conducted through interviews of major stake holders in the University of Zimbabwe College of Health Sciences and Parirenyatwa Group of Hospitals. Results: This project confirmed the lack of a formal ophthalmology training curriculum for medical graduates at the UZCHS, ad-hoc training of undergraduate ophthalmology and inconsistent student assessment in knowledge of and care of eye complaints. Cataract, glaucoma, refractive errors, ocular tumours, conjunctivitis, eye infection and eye injuries were suggested as priority conditions every student should learn during the rotation. A formal CBOTC for medical graduates based on identified needs and priority eye diseases has been developed in response. Conclusion: A CBOTC based on identified needs and focused on targeted diseases has been proposed geared towards producing medical graduates with the basic knowledge, skills and attitudes to deliver adequate primary eye care. PMID- 29144082 TI - Left atrial myxoma: a report of two cases and literature review. PMID- 29144083 TI - Emergence of Veterinary Parasitology in the United States: Maurice C. Hall and the Bureau of Animal Industry. AB - By 1883 a Veterinary Division had been established within the United States Department of Agriculture, itself established in 1862. Federal concern about animal health in the U.S.A. emerged as early as 1865 when Congress adopted regulations aimed at controlling importation of livestock. It was not until 1884 that the Bureau of Animal Industry (BAI) was formally created by Act of Congress, and shortly after that the Zoological Laboratory was established and assigned responsibility for study of parasites and the diseases they produce in animals. Classically trained parasitologists working in USDA's BAI soon became internationally recognized for their contributions to basic research and development of programs for prevention and control of parasitic diseases. Leadership by a series of BAI-employed parasitologists led to the emergence of veterinary parasitology as a sub-discipline. Maurice C. Hall who served as president of both the American Society of Parasitologists and the American Veterinary Medical Association was a central figure in development of veterinary parasitology in the U.S.A., which flourished in his country and elsewhere today. PMID- 29144084 TI - The Rise and Fall of "Wonder Drugs": The Story of Antibiotics in Agriculture. PMID- 29144085 TI - The Origin and Legacy of Christian Petersen's Gentle Doctor. PMID- 29144086 TI - Prevalence and the correlates of postnatal depression in an urban high density suburb of Harare. AB - Introduction: Postnatal depression is a common cause of morbidity but is rarely diagnosed or managed in busy primary care settings in most resource limited countries like Zimbabwe. Objectives: This study sought to determine the prevalence of postnatal depression and establish factors associated with postnatal depression. Methods: The study utilized a cross-sectional descriptive design where 295 consenting women (mean age=25.4 years; SD= 5.6 years) attending post natal care services at Mbare Polyclinic were recruited. Data were collected using the validated Shona version of the Edinburgh Postnatal Depression Scale (EPDS) questionnaire. Associations between variables were computed using the chi square test statistic and where appropriate the Fisher's exact statistic. Results: Prevalence for postnatal depression was 34.2% among women in the study. Univariate analysis revealed that there were no statistically significant associations between mother's age (p=0.120), parity (p=0.396), marital status (p=0.523), level of education (p=0.805), and age of child (p=0.489) and postnatal depression. Conclusion: Findings from this study indicate that there is a high prevalence of postnatal depression in women in Mbare, Zimbabwe. This therefore calls for further studies to identify and address the causes of postnatal depression among women attending postnatal care in Zimbabwe. PMID- 29144087 TI - Remembrances of a Student Who Modeled for Christian Petersen's Gentle Doctor. PMID- 29144089 TI - Etiology and risk factors of meningitis in patients admitted at a Central Hospital in Harare. AB - Objective: To determine etiology and risk factors of meningitis in patients admitted a tertiary referral Hospital in Harare. Design: Cross-Sectional Study. Setting: Urban Referral Health Facility. Subjects: Patients suspected of having Meningitis admitted at Parirenyatwa Hospital were consecutively consented and recruited into the study until sample size accrual. Main Outcome Measures: Prevalence of pathogens associated with Meningitis. Risk factors of meningitis. Results: Two Hundred and Ninety Six (296) clinically suspected meningitis patients were recruited into the study, 51.7 %( n=115) were male. Meningitis was confirmed in 20.6% (n=61) cases with the following pathogen proportions, C. neoformans - 45.9 %( n=28), S. pneumoniae - 27.9 % (n=17), TBM - 4.9 %( n=3), probable viral meningitis - 6.6% (n=4 and other bacteria- 14.8% (n=9). Patients from crowded households were also more likely to suffer from meningitis than those from sparsely populated households (p<0.001). Conclusion: The use of Latex agglutination increases the proportion of detected pathogens both fungal and bacterial when used in conjunction with CSF gram stain and culture. Cryptococcus neoformans and S. pneumoniae are the leading causes of meningitis in patients admitted at Parirenyatwa Hospital. PMID- 29144090 TI - Effects of different frequencies of loading on healing in partial rupture of the Achilles tendon in a rat model. AB - Objective: To determine the histological effects of different frequencies of loading in a healing Achilles tendon following partial rupture. Design: Experimental laboratory study. Setting: University of Zimbabwe, Department of Physiology, Animal house. Subjects: Sixty female Sprague-Dawley rats. Intervention: Partial tenotomies of the right Achilles tendon were performed surgically. From day 1 post operatively, the animals were allocated to treadmill running at different frequencies (once (OD), two (BD), three (TDS) and four (QID) times daily) up to 21 days. Histological sides of the tendons were made at days 7,14 and 21 and interpreted by a blinded pathologist. Main outcome measures: Collagen fibre orientation, inflammatory cell populations, fibroblast morphology and neoangiogenesis were observed and scored using the Grande Biomechanical Histological Correlation Score. Results: Mean weight was 209.67g +/-30.14. The best and worst arrangements of collagen were in the QID group (73%) and OD group (46.7%) respectively. These differences were not statistically significant (p=0.487). The BD group had the most mature fibroblast nuclei and the QID tendons had the least mature (p=0.577). Inflammatory cell populations were independent of loading frequency (p=0.132). Conclusion: Changing the frequency of the same type of loading in a healing tendon does not have an effect on the healing process in partially ruptured Achilles tendons during the inflammatory and proliferative phases. PMID- 29144091 TI - The Bovine Infectious Abortion Problem: Efforts toward Identification and Control in the United STates through 1940. PMID- 29144092 TI - DirecTalk: Musings From the 10th Floor: The Journey Into the Future Points Upstream. PMID- 29144093 TI - An echocardiography audit to determine and characterise rheumatic heart disease lesions since 2012. AB - Introduction: Rheumatic heart disease is still a common problem in Zimbabwe. It has a significant mortality rate due to heart failure, stroke or endocarditis. Timely surgical interventions can reduce mortality. An echocardiography audit was performed to determine the proportion of patients referred for echocardiography who had a diagnosis of rheumatic heart disease, the pattern of valvular involvement and the presence of surgical indications on echocardiography. Objective: To determine the number of echocardiograms done in 2012 and the proportion with a diagnosis of rheumatic heart disease. To determine which valve lesions were present and whether there were any echocardiographic indications for surgical intervention. Method: A record review of all echocardiograms performed by the investigator during the period January to December 2012 was performed. A data collection form was used to extract the data and the findings were tabulated and analysed. Results: 308 echocardiograms were performed by the investigator during the year of review. 236 of these were abnormal and rheumatic heart disease was diagnosed in 16% of them. The commonest valve lesion was mitral regurgitation and half of the patients had surgical indications. The common complications were pulmonary hypertension and left atrial enlargement. Conclusion: This audit shows that rheumatic heart disease is still quite common in patients referred for echocardiography. Lesions are severe and the majority of patients are in need of surgical intervention. PMID- 29144094 TI - Bilharzioma of the fallopian tube - A case report. PMID- 29144096 TI - Long-term treatment with etanercept monotherapy in a hemodialyzed patient with moderate-to-severe plaque-type psoriasis and psoriatic arthritis. PMID- 29144097 TI - Simultaneous occurrence of hand foot and mouth disease and pityriasis rosea. PMID- 29144099 TI - Primary cutaneous B-cell lymphoma: narrative review of the literature. AB - Primary Cutaneous B-cell Lymphomas comprehend a group of lymphoproliferative disorders characterized by being monoclonal proliferations of B-cell primarily involving the skin. Despite being recognized as autonomous and distinct clinico pathologic entities since the late 80s, their classification is still an ongoing matter of debate. At the moment, WHO classification recognizes three disorders: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type. Primary cutaneous diffuse large B-cell lymphoma, other has been used to define rare cases which show histologically an infiltrate with diffuse pattern composed by large B cell, but not fitting with criteria for follicle center lymphoma nor for primary cutaneous diffuse large B-cell lymphoma, leg type. Aim of this review is to briefly describe all recognized and provisional entities included in the primary cutaneous B-cell lymphomas and to discuss recent acquisitions that may influence their future classifications. PMID- 29144098 TI - Correlation between plasmatic levels of vitamin D and PASI score. AB - BACKGROUND: Psoriasis is a common, inflammatory, chronic, relapsing skin disease. The pathogenesis is multifactorial and it is involved both innate and acquired immunity. Several studies have shown the important role of vitamin D in the pathogenesis of this disorder. In this study we have evaluated a possible correlation between vitamin D and clinical severity of psoriasis calculated using the Psoriasis Area Severity Score (PASI) score. METHODS: In this case control study we included 141 Caucasian subjects affected by moderate to severe psoriasis and 62 healthy controls. We have calculated PASI score and serum levels of vitamin D. RESULTS: Psoriatic patients had significantly lower serum levels of 25(OH)D than healthy controls. Using no parametric Spearman's coefficient test between serum levels of vitamin D and the PASI score we found a statistical significant correlation. However, the statistical significance was not reached analyzing separately the patients with psoriatic arthritis, while it was confirmed for patients without an articular involvement. CONCLUSIONS: The present study confirm that serum levels of vitamin D are significantly lower in psoriatic patients and correlate with the clinical severity of psoriasis; these data suggest that psoriatic patients could be screened for vitamin D insufficiency for a more comprehensive management. PMID- 29144100 TI - Extramedullary metastatic plasmacytoma in multiple myeloma. PMID- 29144101 TI - Real-life use of phototherapy in early-stage mycosis fungoides from the Cutaneous Lymphoma Commission of the Italian Lymphoma Foundation: results of a web-based survey. PMID- 29144102 TI - Palpable migratory arciform erythema: hydroxychloroquine as a possible therapeutic option. PMID- 29144103 TI - Effects of home-based neuromuscular electrical stimulation in severe chronic obstructive pulmonary disease patients: a randomized controlled clinical trial. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients experience a sustained deterioration of several capacities. Those with severe COPD undergo a considerable decline in their physical and functional capacities, but pulmonary rehabilitation (PR) is used to reduce the weakness of such patients. To date, neuromuscular electrical stimulation (NMES) has been used in acute COPD patients but NMES superimposed onto voluntary muscular contraction has not been tested in COPD patients. AIM: The aim of this study was to evaluate the effects of superimposed NMES on the cardiorespiratory performance and functionality of severe COPD patients undergoing a home-based rehabilitation program. DESIGN: This was a randomized controlled clinical trial. POPULATION: A total of 36 stable severe COPD patients were included in this study and were randomly divided into two groups: an intervention group and a control group. SETTING: The study was conducted as a home-based program. METHODS: The control group received standard medical treatment. The intervention group additionally underwent an individualized physical therapy program. The intervention consisted of a pulmonary rehabilitation (PR) protocol for 8 weeks (2 h/week). The protocol was carried out as follows: 10 minutes of controlled breathing training; 30 minutes of NMES superimposed onto voluntary muscular contraction; and 5 minutes of relaxation/cool-down. The outcome measures were cardiorespiratory performance measured using the 6-Minute Walk Test in the treadmill and functionality assessed with the functional independence measure. RESULTS: In the intervention group, significant improvements were observed after the treatment in cardiorespiratory performance and functionality (P<0.05), while the control group did not show any significant changes (P>0.05). The between-group analysis showed significant differences in cardiorespiratory performance and functionality (P<0.05). CONCLUSIONS: An 8-week individualized home-based PR program including controlled breathing training, aerobic exercise with elastic bands, and NMES superimposed onto voluntary muscle contraction significantly improves cardiorespiratory performance and functionality in stable COPD patients. CLINICAL REHABILITATION IMPACT: A home-based pulmonary rehabilitation program including controlled breathing training, and NMES superimposed onto voluntary muscle contraction significantly improves cardiorespiratory performance and functionality in stable COPD patients. PMID- 29144104 TI - Can we avoid the feeding tube? The use of neuromuscular electrical stimulation in a case of Gerstmann-Straussler-Scheinker syndrome. PMID- 29144105 TI - Motor imagery ability of patients with lower-limb amputation: exploring the course of rehabilitation effects. AB - BACKGROUND: Amputation of a lower-limb results in a severe decrease of functional mobility that deeply alters independent living. Motor imagery (MI) refers to the mental representation of an action without engaging its actual execution. The repetitive use of MI has been shown to contribute to promote motor recovery and phantom-limb pain alleviation. AIM: Given the importance of invoking accurate images to benefit from MI practice, and considering the link between motor capacities and MI, the present study investigated the effect of a rehabilitation program on MI ability in patients with lower-limb amputation. DESIGN: Observational and longitudinal study. POPULATION: Patients with trans-tibial or trans-femoral amputation, following a rehabilitation program as outpatients. METHODS: MI ability of the patients was measured at three different time point along the course of physical therapy. RESULTS: The data revealed i) a positive effect of the rehabilitation program on MI accuracy of locomotor tasks, and ii) greater MI vividness and accuracy for single-joint movements that patients were still able to physically perform. CONCLUSIONS: These findings suggest that MI abilities and actual motor performance are mirrored in a congruent fashion. CLINICAL REHABILITATION IMPACT: Therapists should consider this critical aspect when including MI practice in rehabilitation programs among patients with lower limb amputation. PMID- 29144106 TI - The impact of cognitive reserve on the effectiveness of balance rehabilitation in Parkinson's disease. AB - BACKGROUND: Cognitive reserve (CR) can be considered an active expression of brain resilience in response to a damage. Several studies have shown the influence of CR on cognitive impairment and its relationship with cognitive function in Parkinson's disease (PD). AIM: The aim of the present study was to show if CR influences the effectiveness of balance rehabilitation in PD patients who performed a conventional rehabilitative treatment. DESIGN: Observational longitudinal study. SETTING: Neurology Outpatient Unit, University Hospital. POPULATION: Fifty-three patients affected by idiopathic PD, stage 2-3 at the Hoehn and Yahr Scale. METHODS: Each patient underwent 32 group sessions of conventional rehabilitative treatment. At baseline, patients' CR was assessed by the Cognitive Reserve Index questionnaire (CRIq). The primary outcome was the evaluation of static and dynamic balance modifications, induced by the treatment, through the Berg Balance Scale (BBS), assessed at T0 and T1. Mini Mental State Examination, Unified Parkinson's Disease Rating Scale Part III (clinician-scored monitored motor evaluation) and Brief Intelligence Test were assessed only at T0 and used as descriptive variables. RESULTS: Considering the clinically meaningful change, BBS improved in 26% of patients, worsened in 2% and was unchanged in 72%. BBS score significantly improved in older patients, and in those with lower CRI total score. A significant inverse correlation was observed between changes in BBS and work and education related CR. Patients with lower baseline BBS score showed better improvement in balance. CONCLUSIONS: We found an inverse correlation between CR level and balance improvement in PD patients who underwent conventional rehabilitation: higher improvement in BBS was observed in those with a lower CRI score. This may suggest that patients with higher CRI could benefit from more stimulating types of non-conventional rehabilitation (e.g. robotic, virtual reality). CLINICAL REHABILITATION IMPACT: Rehabilitation should be individually tailored considering CR as a significant variable. PMID- 29144108 TI - Graphical modeling: a tool for describing and understanding the functioning of people living with a health condition. AB - Rehabilitation aims to optimize people's lived experience of health or functioning. A comprehensive understanding of people's functioning is thus fundamental for rehabilitation clinicians and scientists. Over the past ten years it has been shown that graphical modelling is a promising technique for modelling data on people's functioning. It can contribute to our understanding of the complex associations between domains of functioning and the identification of potential targets for rehabilitation interventions both at the level of the person and the environment. The objective of this methodological note is to demonstrate how graphical modeling can be used by rehabilitation clinicians and scientists in the description, understanding and influencing of people's functioning. The application of graphical modelling and the interpretation of results is illustrated using the Spinal Cord Injury Independence Measure - Self Report used in the Swiss Spinal Cord Injury Cohort Study. Finally, we discuss the potential of graphical modelling for the planning of studies that expand our understanding of functioning and for rehabilitation interventions. PMID- 29144107 TI - Safe return to driving following severe acquired brain injury: role of a short neuropsychological assessment. AB - BACKGROUND: Driving is a complex ability requiring a broad range of motor, cognitive-behavioral and visual skills that may be impaired after severe acquired brain injury (sABI). Resumption of driving is perceived as a major need by patients, being closely linked to personal autonomy, work and social activities. AIM: The objective of this study was to identify a short battery of neuropsychological tests with predictive value with regard to safe return to driving after sABI. DESIGN: Observational study. SETTING: Outpatient of a rehabilitation center for sABI. POPULATION: A continuous series of 127 patients with stable sABI, well-reintegrated at a family and social level, dismissed since at least one year from the end of their intensive rehabilitation, enrolled between 2006 and 2014. METHODS: Patients underwent an extensive battery of neuropsychological tests (pencil and paper and specific PC programs), aimed at assessing cognitive functions, in performance and verbal tasks. The results were analyzed in relation to their on-road performance during the driving test conducted by the office of the Italian Government Authority (success or failure of the test). RESULTS: No correlations were found between demographic data, etiology, driving experience, verbal competence and the decision of the competent authority. Significant correlation was found between attention, executive functions, overall visual-spatial exploration and driving performance. CONCLUSIONS: Both "pencil and paper" and computerized tests in the cognitive domains of attentive functions, and those involving performance with visual spatial material, are significantly correlated with the driving test outcome, even if there is not enough evidence of the relative value of off-road compared to direct on-road tests. CLINICAL REHABILITATION IMPACT: We propose a small neuropsychological battery of tests with normative data for Italian population, predictive with respect to the ability to drive safely. We recommend to use it as first screening before submitting patients to more demanding and risky on-road driving tests. PMID- 29144109 TI - Manual therapy RCTs: should we control placebo in placebo control? PMID- 29144110 TI - Effect of stabilization exercise on back pain, disability and quality of life in adults with scoliosis: a systematic review. AB - INTRODUCTION: Adult scoliosis (AS) is the most common spine deformity in adults. Back pain is the main symptom leading patients to seek medical consultation. Stabilization exercise has been shown effective for reducing back pain. No literature review has examined the effects of such exercises in adults with scoliosis. The objective was to systematically review the effects of stabilization exercises on back pain, disability and quality of life in adults with scoliosis. EVIDENCE ACQUISITION: We systematically searched the following databases from inception to March 2017: Medline, CINAHL, Embase, SportDiscus and Cochrane Register of Controlled Trials. Selection criteria included: controlled clinical trials that compare core stabilization exercise to placebo, no treatment or another treatment in participants diagnosed with AS over 18 years old. Studies with participants presenting torso or lower extremity surgery, injection in the last six months, comorbidity that could affect the spine, red flags signs or with a history of spine trauma were excluded. We extracted information about participants, treatments, and results on pain, function and quality of life. We appraised quality using Cochrane risk of bias. We formulated level of evidence summary statements using a priori rules based on quality and consistency of results. EVIDENCE SYNTHESIS: We found 630 unique articles and screened the full text of 98 articles retrieved. Only one article met all selection criteria and was included in this review. Studies were mainly excluded for study design and patient population. The included study presented a low risk of bias for all criteria except for blinding and reporting if the timing of assessments was similar between groups. The literature provides limited evidence from one study with high risk of bias that stabilization exercises in the form of 20 weeks of active self-correction, task-oriented exercises and cognitive-behavioral therapy significantly improves pain, disability and quality of life. CONCLUSIONS: Despite the high prevalence of AS, there is an important gap in the literature with limited evidence reporting the effect of exercise on back pain in adults with scoliosis. This review suggest further experimental research is needed and formulates research recommendations. PMID- 29144112 TI - JEH Quiz #5: Presence of Household Mold, Children's Respiratory Health, and School Absenteeism: Cause for Concern. PMID- 29144111 TI - What Actions Are Health Departments Taking to Improve Safe Drinking Water Programs? PMID- 29144113 TI - [Can we transfer the mechanisms of the generics market to biosimilars?] AB - Personalized medicines such as biologics and their generic equivalents, biosimilars, are pouring onto the pharmaceutical markets. Data of 16 private health insurance companies were used to describe the market shares of selected biosimilars available in 2014 and 2015. The purpose of this study focuses on the question of whether market access of biosimilars will lead to a price competition of the expense of innovation competition. The results show that prescriptions of biosimilars made up 37% of total prescriptions in 2015 compared to 35% in 2014, and that their share of prescription costs went up from 21% to 23% in the same period. Price competition similar to that found in the generic markets has been established for erythropoietin and filgrastim. The same has not been observed for follitropin alfa and somatropin due to the limited number of competitors and products available at this stage. No definitive conclusions can be drown from the results at this stage. Time will tell whether it will be possible for physicians and individuals with private health insurance to fully leverage the savings potential of biosimilars while safeguarding patient safety. PMID- 29144114 TI - Prevalence of Acute Kidney Injury in neonates admitted at a referral hospital, Harare, Zimbabwe. AB - Objectives: To determine prevalence of acute kidney injury and associated factors, among neonates admitted at a referral hospital. Design: Cross sectional study conducted 1 May to 31 July 2010. Setting: Harare Central Hospital, Neonatal Unit. Subjects: 270 neonates >= 37 weeks gestation admitted within 12 hours of birth. Systematic random sampling was used to select study participants. Methods: Maternal details were collected through an interviewer administered questionnaire. Neonatal clinical examination was performed. Blood for serum creatinine was collected within 12 hours of life and repeated 24-48 hours of life. Main Outcome Measure: Acute Kidney Injury (AKI) defined by decrease of estimated Glomerular Filtration Rate (GFR) by >= 25% from baseline value, using RIFLE criteria (an acronym for Risk, Injury, Failure, Loss and End stage). Results: The prevalence of AKI in term neonates was 33.3% (95% CI 0.27; 0.39). Factors significantly associated with AKI were Hypoxic Ischaemic Encephalopathy (HIE) 1(OR 3.05 95%CI 1.56;5.97), HIE 2 and 3 (OR 9.57 95%CI 3.83;23.92), APGAR score <=6 (OR 3.82 95%CI 2.16;6.78), respiratory rate >60 (OR1.96 95%CI 1.09;3.55), chest recessions (OR 2.73 95% CI 1.56;4.75), history of neonatal fits (OR 5.78 95%CI 1.56;4.75),hypothermia (OR 3.05 95%CI 1.56;4.75) and maternal age >=35 years(OR 5.89 95%CI1.11;31.41). Strong determinants of AKI on multivariate logistic regression analysis were HIE 1, hypothermia and chest recessions. Conclusion: The prevalence of AKI in term neonates admitted at a Harare hospital was high. It is recommended to assess for AKI in neonates with identified risk factors and monitor for chronic kidney disease. PMID- 29144115 TI - The relationship between perceived self-efficacy and adherence to self-care activities in type 2 diabetic clients. AB - Objective: The purpose of this study was to determine the relationship between perceived self-efficacy and adherence to self-care activities in type 2 diabetic clients. Low adherence to diabetic self-care activities result in increased risks of developing chronic serious and life-threatening complications with increased morbidity and mortality in diabetic patients. Design: The study was conducted using a descriptive correlational design. The Health Belief Model was utilized as the conceptual framework. Setting: The study was carried out at Parirenyatwa hospital, a central referral health facility located in Harare, the capital city of Zimbabwe. Subjects: The study had a sample of 74 subjects selected through systematic probability sampling with clients aged 40-65 years old suffering from type 2 diabetes mellitus and attending an outpatient diabetic clinic at the study site during the period of study. There were no dropouts they had to be at least one year post diagnosis and being able to speak either English or Shona or both. Interventions: Data was collected through a structured interview. The interviews were conducted between08:00 hrs and 12:00hrs, which are the clinic hours. A questionnaire was used that was divided into three parts namely demographics, adherence and perceived self efficacy. Main Outcome Measures: levels of adherence to self care and perceived self efficacy were the main outcome measures levels of adherence to self care and perceived self efficacy were the main outcome measures Results: 45.9% of the subjects in the study had high adherence level of diabetic self-care activities, and this finding is inconsistent with the desirable adherence level for a chronic condition with potential for serious and life threatening complications. A high perceived self-efficacy level was found in 75.7% of the study subjects. There was a strong positive relationship between perceived self-efficacy and adherence to diabetic self-care activities (r = .964), and regression analysis showed an r squared of .930 which is evident of a strong positive relationship. Conclusions: There is need for the medical-surgical nurses to develop strategies that would further improve diabetic clients' perceived self-efficacy so as to increase adherence to diabetic self-care activities. PMID- 29144116 TI - [The importance of biosimilars medicines for private and statutory health insurance]. AB - Patented biopharmaceuticals generate huge costs for private and statutory health insurance. Exactly ten years ago, off-patent biopharmaceuticals, also referred to as 'biosimilars medicines', became available as a more cost-efficient and therapeutically equivalent alternative in Germany and Europe. Following their approval by all the relevant authorities, biosimilars medicines can therefore be applied in the same way as previously patented biopharmaceuticals. PMID- 29144117 TI - Comparison of Ponseti and Kite's method of treatment for congenital Talipes Equino using the Pirani scoring system. AB - Objective: The study was carried out to compare the effectiveness of the Ponseti manipulation versus the Kite's manipulation in the treatment of idiopathic Congenital Talipes Equino Varus (CTEV) as evaluated by the Pirani score. Design: An intervention study, prospective non randomized trial. Setting: Hospital based study at three central hospitals namely Harare Central Hospital (HCH), Parirenyatwa Group of Hospitals (PGH) and Chitungwiza Central Hospitals (CCH) in Zimbabwe. Subjects: 38 feet in 25 patients, 13 bilateral and 12 unilateral CTEV deformities in children less than one year of age and without prior manipulation or surgical treatment were purposively allocated to either Ponseti (20 feet) or Kite's method (18 feet) at three central hospitals. There were no dropouts. Intervention: Participants in two hospitals were managed using the Ponseti method and one hospital managed participants using the kite's method. Baseline Pirani scores were measured before the first treatment was done. Thereafter they were followed up weekly and analysis was done for three and six week outcomes using the Pirani score. Correction was measured by the difference between the baseline hindfoot, midfoot and total scores and the Pirani scores at three weeks and six weeks. Within group analysis of the data was done using a single student t - test and between groups analysis was done using the independent student t - test. Results: Both methods were effective in correcting CTEV deformity. Feet managed by the Ponseti method showed faster rates of decrease in Pirani score (improvement) as compared to feet treated by Kite's method. The between group analysis (Kite Ponseti) at three weeks was -1,4056 (p = 0.0000) [CI = -1.900 to 0.9103] showing a significantly difference between the methods at three weeks. The between group analysis (Kite Ponseti) at six weeks was -2.2302 (p = 0.0000) [CI = -2.9789 to -1.4815] showing a significantly difference between the methods at six weeks. Conclusion: Ponseti management causes faster improvement in CTEV deformity using the Pirani scores than Kite management at three weeks and six weeks. It would therefore be more efficacious to use the Ponseti method of manipulation in the conservative management of CTEV. Issues of cost effectiveness will need to be researched further. PMID- 29144118 TI - Severe airway obstruction from goitre during pregnancy relieved by Thyroidectomy at Caesarean Section: A case report. PMID- 29144119 TI - Self-Assembly Driven Aggregation-Induced Emission of Copper Nanoclusters: A Novel Technology for Lighting. AB - Because of the specific properties including HOMO-LUMO electronic transition, size-dependent fluorescent emission, and intense light absorption, metal nanoclusters (NCs) have been considered to be one of the most competitive color conversion materials in light-emitting diodes (LEDs). However, the monotonous emission color and the low emission stability and intensity of individual metal NCs strongly limit their universal application. Inspired by the concept of "aggregation-induced emission" (AIE), the utilization of highly ordered metal NC assemblies opens a door to resolve these problems. After self-assembly, the emission stability and intensity of metal NC assemblies are enhanced. At the same time, the emission color of metal NC assemblies become tunable. We termed this process as self-assembly driven AIE of metal NCs. In this review, we use Cu NCs as the example to convey the concept that the compact and ordered arrangement can efficiently improve the metal NCs' emission stability, tunability, and intensity. We first introduce the synthesis of 2D Cu NC self-assemblies and their emissions. We further summarize some of the factors that can affect the emissions of 2D Cu NC self-assemblies. We then discuss the utilization of 2D Cu NC self-assemblies as color conversion materials for LEDs. At last, we outline current challenges and our perspectives on the development of this area. PMID- 29144120 TI - Plasmon-Induced Selective Enhancement of Green Emission in Lanthanide-Doped Nanoparticles. AB - By introducing an 18 nm thick Au nanofilm, selective enhancement of green emission from lanthanide-doped (beta-NaYF4:Yb3+/Er3+) upconversion nanoparticles (UCNPs) is demonstrated. The Au nanofilm is deposited on a microfiber surface by the sputtering method and then covered with the UCNPs. The plasma on the surface of the Au nanofilm can be excited by launching a 980 nm wavelength laser beam into the microfiber, resulting in an enhancement of the local electric field and a strong thermal effect. A 36-fold luminescence intensity enhancement of the UCNPs at 523 nm is observed, with no obvious reduction in the photostability of the UCNPs. Further, the intensity ratios of the emissions at 523-545 nm and at 523-655 nm are enhanced with increasing pump power, which is attributed to the increasing plasmon-induced thermal effect. Therefore, the fabricated device is further demonstrated to exhibit an excellent ability in temperature sensing. By controlling the pump power and the UCNP concentration, a wide temperature range (325-811 K) and a high temperature resolution (0.035-0.046 K) are achieved in the fabricated device. PMID- 29144121 TI - Low-Temperature-Grown KNbO3 Thin Films and Their Application to Piezoelectric Nanogenerators and Self-Powered ReRAM Device. AB - Amorphous KNbO3 (KN) film containing KN nanocrystals was grown on TiN/SiO2/Si substrate at 350 degrees C. This KN film showed a dielectric constant (epsilonr) and a piezoelectric strain constant (d33) of 43 and 80 pm/V at 10 V, respectively, owing to the existence of KN nanocrystals. Piezoelectric nanogenerators (PNGs) were fabricated using KN films grown on the TiN/polyimide/poly(ethylene terephthalate) substrates. The PNG fabricated with the KN film grown at 350 degrees C showed an open-circuit output voltage of 2.5 V and a short-circuit current of 70 nA. The KN film grown at 350 degrees C exhibited a bipolar resistive switching behavior with good reliability characteristics that can be explained by the formation and rupture of the oxygen vacancy filaments. The KN resistive random access memory device powered by the KN PNG also showed promising resistive switching behavior. Moreover, the KN film shows good biocompatibility. Therefore, the KN film can be used for self-powered biomedical devices. PMID- 29144122 TI - Ratio of Polycation and Serum Is a Crucial Index for Determining the RNAi Efficiency of Polyplexes. AB - We report that the mass ratio of the polycation to serum in the medium determines the (RNA interference) RNAi efficiency in vitro by using spermine-modified pullulan (Ps) and spermine-modified dextran (Ds) as polycation models. The high ratio of Ps to serum protein (Ps/Pr) mediated the formation of larger polyplexes, which led to the promoted cellular uptake, enhanced lysosomal escape, and elevated RNAi efficiency. In addition, the supplementary of free Ps also enhanced small interfering RNA transfection because of the elevation of Ps/Pr. Similar results were obtained with Ds. Compared with the adjustment of the nitrogen to phosphate (N/P) ratio in the polyplex, these findings revealed a more applicable strategy to tune the polycation-mediated RNAi efficiency in the serum-containing culture medium. PMID- 29144123 TI - The Sign of Nuclear Magnetic Resonance Chemical Shift Difference as a Determinant of the Origin of Binding Selectivity: Elucidation of the Position Dependence of Phosphorylation in Ligands Binding to Scribble PDZ1. AB - The use of nuclear magnetic resonance chemical shift perturbation to monitor changes taking place around the binding site of a ligand-protein interaction is a routine and widely applied methodology in the field of protein biochemistry. Shifts are often acquired by titrating various concentrations of ligand to a fixed concentration of the receptor and may serve the purpose, among others, of determining affinity constants, locating binding surfaces, or differentiating between binding mechanisms. Shifts are quantified by the so-called combined chemical shift difference. Although the directionality of shift changes is often used for detailed analysis of specific cases, the approach has not been adapted in standard chemical shift monitoring. This is surprising as it would not require additional effort. Here, we demonstrate the importance of the sign of the chemical shift difference induced by ligand-protein interaction. We analyze the sign of the 15N/1H shift changes of the PDZ1 domain of Scribble upon interaction with two pairs of phosphorylated and unphosphorylated peptides. We find that detailed differences in the molecular basis of this PDZ-ligand interaction can be obtained from our analysis to which the classical method of combined chemical shift perturbation analysis is insensitive. In addition, we find a correlation between affinity and millisecond motions. Application of the methodology to Cyclophilin a, a cis-trans isomerase, reveals molecular details of peptide recognition. We consider our directionality vector chemical shift analysis as a method of choice when distinguishing the molecular origin of binding specificities of a class of similar ligands, which is often done in drug discovery. PMID- 29144124 TI - Ionic Liquid Microstrips Impregnated with Magnetic Nanostirrers for Sensitive Gas Sensors. AB - Ionic liquids (IL) have been regarded as promising electrolytes as substitutes for volatile aqueous or organic solvents for electrochemical gas sensors. However, ILs are viscous, and the slow diffusion of gas molecules leads to poor sensitivity and sluggish response times. Herein, we describe a strategy using an array of microstrips of IL containing magnetic nanoparticles as nanostirrers for enhanced mass transport and gas sensing. Magnetic CoFe2O4 nanoparticles are synthesized and dispersed in a hydrophobic IL [BMP][Ntf2]. First, the convection effect of the IL dispersion was studied using the reversible redox couple ferrocene/ferrocenium ion. In a rotating magnetic field, steady-state currents for oxidation of dissolved ferrocene are three to five times greater than that in an unstirred solution. Then, the IL dispersion is micropatterned onto a gold electrode using microcontact printing. A self-assembled monolayer was printed onto a gold surface creating 70 MUm wide hydrophobic lines with a 30 MUm gap between them. Upon applying the IL dispersion into the gap, a 30 MUm wide array of microstrips was successfully fabricated. The system is demonstrated as an oxygen sensor in the range of volume fraction of O2 of 50-500 ppm giving a linear calibration with a sensitivity of 1.94 nA cm-2 ppm-1. PMID- 29144126 TI - Highly Active Carbene Potassium Complexes for the Ring-Opening Polymerization of epsilon-Caprolactone. AB - Herein we report the synthesis of two complexes of potassium employing strongly nucleophilic carbenes, such as cyclic "(alkyl)(amino)carbene (cAAC) and abnormal N-heterocyclic carbene (aNHC). Both complexes are dimeric in the solid state and the two potassium centers are bridged by trimethylsilylamide. In these complexes, the carbene- - -K interaction is predominantly electrostatic in character, which has been probed thoroughly by NBO and AIM analyses. Indeed, the delocalization energy of the cAAC lone pair calculated from the second-order perturbation theory was only 5.21 kcal mol-1, supporting a very weak interaction. The solution-state behavior of these molecules, as inferred from NOESY spectra, hints that the weak carbene- - -K interaction is retained in nonpolar solvents, and the bond is not dissociated at least on the NMR time scale. We took advantage of such a weak interaction to develop highly effective ring-opening polymerization catalysts for epsilon-caprolactone and rac-lactide. The efficacy of these catalysts is prominent from a very high substrate/metal-initiator ratio as well as very low dispersity index of the obtained polymer chains, reflecting significant control over polymerization. PMID- 29144125 TI - Impacts of Repeated Redox Cycling on Technetium Mobility in the Environment. AB - Technetium is a problematic contaminant at nuclear sites and little is known about how repeated microbiologically mediated redox cycling impacts its fate in the environment. We explore this question in sediments representative of the Sellafield Ltd. site, UK, over multiple reduction and oxidation cycles spanning ~1.5 years. We found the amount of Tc remobilised from the sediment into solution significantly decreased after repeated redox cycles. X-ray Absorption Spectroscopy (XAS) confirmed that sediment bound Tc was present as hydrous TcO2 like chains throughout experimentation and that Tc's increased resistance to remobilization (via reoxidation to soluble TcO4-) resulted from both shortening of TcO2 chains during redox cycling and association of Tc(IV) with Fe phases in the sediment. We also observed that Tc(IV) remaining in solution during bioreduction was likely associated with colloidal magnetite nanoparticles. These findings highlight crucial links between Tc and Fe biogeochemical cycles that have significant implications for Tc's long-term environmental mobility, especially under ephemeral redox conditions. PMID- 29144127 TI - Area-Controllable Stamping of Semicrystalline Copolymer Ionogels for Solid-State Electrolyte-Gated Transistors and Light-Emitting Devices. AB - Two types of thin-film electrochemical devices (electrolyte-gated transistors and electrochemical light-emitting cells) are demonstrated using area-controllable ionogel patches generated by transfer-stamping. For the successful transfer of ionogel patches on various target substrates, thermoreversible gelation by phase separated polymer crystals within the ionogel is essential because it allows the gel to form a conformal contact with the acceptor substrate, thereby lowering the overall Gibbs energy of the system upon transfer of the ionogel. This crystallization-mediated stamping provides a much more efficient deposition route for producing thin films of ionically conductive high-capacitance solid ionogel electrolytes. The lateral dimensions of the transferred ionogels range from 1 mm * 1 mm to 40 mm * 40 mm. These ionogel patches are incorporated in organic p-type and inorganic n-type thin-film transistors and electrochemical light-emitting devices. The resulting transistors show sub-1 V device operation with high transconductance currents, and the optoelectronic devices emit orange light through a series of electrochemical redox reactions. These results demonstrate a simple yet versatile route to employ physical ionogels for various solid-state electrochemical device applications. PMID- 29144128 TI - Proton-Driven Intercalation and Ion Substitution Utilizing Solid-State Electrochemical Reaction. AB - The development of an unconventional synthesis method has a large potential to drastically advance materials science. In this research, a new synthesis method based on a solid-state electrochemical reaction was demonstrated, which can be made available for intercalation and ion substitution. It was referred to as proton-driven ion introduction (PDII). The protons generated by the electrolytic dissociation of hydrogen drive other monovalent cations along a high electric field in the solid state. Utilizing this mechanism, Li+, Na+, K+, Cu+, and Ag+ were intercalated into a layered TaS2 single crystal while maintaining high crystallinity. This liquid-free process of ion introduction allows the application of high voltage around several kilovolts to the sample. Such a high electric field strongly accelerates ion substitution. Actually, compared to conventional solid-state reaction, PDII introduced 15 times the amount of K into Na super ionic conductor (NASICON)-structured Na3-xKxV2(PO4)3. The obtained materials exhibited a thermodynamically metastable phase, which has not been reported so far. This concept and idea for ion introduction is expected to form new functional compounds and/or phases. PMID- 29144129 TI - Efficient Mechanochemical Synthesis of Polyoxometalate?ZIF Complexes as Reusable Catalysts for Highly Selective Oxidation. AB - One-pot mechanochemical synthesis was demonstrated to be an efficient strategy to synthesize host-guest POM?rho-ZIF complexes (POM = polyoxometalate; rho-ZIF = zeolitic imidazolate framework with rho topology) with high crystallinity. In this work, the metastable rho-ZIF with large interior cavities and windows was used as host matrix for encapsulating and immobilizing bulky guest molecules with high loading efficiency and chemical stability. As novel catalysts, POM?rho-ZIF complexes were found effective for the selective oxidation of a series of sulfides to sulfoxides. Moreover, the heterogeneity of these composite catalysts was confirmed by leaching tests, and they can be recycled at least four times without significant loss of activity. PMID- 29144130 TI - Structural Phase Transitions in PtIn2 at High Pressure: A Theoretical Investigation. AB - A study of the bonding and electronic properties of intermetallics under pressure is crucial in the design and development of novel materials for useful applications. These properties are largely controlled by the underlying crystal structures. Here we investigated the high-pressure structural behavior of PtIn2 using crystal structure search calculations, which efficiently combine evolutionary algorithms and state-of-the-art density functional theory. Three new crystal structures, namely, Fe2B-type (I4/mcm, Z = 2), cotunnite-type (Pnma, Z = 4), and monoclinic (C2/m, Z = 2), are proposed at about 9.4, 13.5, and 47.5 GPa, respectively. With pressure, the covalent character of the Pt-In pair interaction is found to increase because of enhancement of spd hybridization, and structural transitions are rationalized in terms of the covalency increase. PMID- 29144131 TI - Twisting and Tilting 1,1'-Bis(dialkylphosphino)ferrocene Bound to Low Valent Tricarbonylmaganese(I to -I). AB - Recently we had reported the noninnocent behavior of 1,1' bis(diphenylphosphino)ferrocene (dppf) in Fe(CO)3dppf [Ringenberg et al., Inorg. Chem., 2017, 56, 7501]. Moving to the left in the periodic table, HMn(CO)3(dRpf) where dRpf = dppf (1H) and 1,1'-bis(diisopropylphosphino)ferrocene (dippf) (2H) were synthesized. The hydride ligand was removed by protonation with [(Et2O)2H][B(ArF)4] ([B(ArF)4]- = tetrakis[3,5 bis(trifluoromethyl)phenyl]borate), resulting in the rapid evolution of H2 followed by the formation of an Fe->Mn interaction. The reaction mechanism was determined by in situ IR experiments which show that directly following protonation both [1]+ and [2]+ offer an open manganese coordination site that allows for the formation of an intramolecular Fe->Mn dative bond. This process is significantly faster for [2]+ than for [1]+. The reduction chemistry as studied by cyclic voltammetry (CV) reveals that both complexes change from a distorted octahedral coordination with an Fe->Mn interaction to an open square-pyramidal configuration which is more stable for [1]0 than [2]0. Reoxidation of this square pyramidal species proceeds more reversibly for 2 versus 1 due to the faster ferrocene ligand reorganization. The electrochemical mechanism was studied by in situ spectroscopic techniques, e.g., IR, UV-vis-NIR (near IR), and EPR spectroelectrochemistry (SEC) as well as by CV simulation. The new complexes described offer an exciting platform for the development of electrocatalysts for the reduction of CO2 to CO, or for proton reduction (2H+ + 2e- -> H2). PMID- 29144132 TI - Large Piezoelectric Effect in a Lead-Free Molecular Ferroelectric Thin Film. AB - Piezoelectric materials have been widely used in various applications, such as high-voltage sources, actuators, sensors, motors, frequency standard, vibration reducer, and so on. In the past decades, lead zirconate titanate (PZT) binary ferroelectric ceramics have dominated the commercial piezoelectric market due to their excellent properties near the morphotropic phase boundary (MPB), although they contain more than 60% toxic lead element. Here, we report a lead-free and one-composition molecular ferroelectric trimethylbromomethylammonium tribromomanganese(II) (TMBM-MnBr3) with a large piezoelectric coefficient d33 of 112 pC/N along polar axis, comparable with those of typically one-composition piezoceramics such as BaTiO3 along polar axis [001] (~90 pC/N) and much greater than those of most known molecular ferroelectrics (almost below 40 pC/N). More significantly, the effective local piezoelectric coefficient of TMBM-MnBr3 films is comparable to that of its bulk crystals. In terms of ferroelectric performance, it is the low coercive voltages, combined with the multiaxial characteristic, that ensure the feasibility of piezo film applications. Based on these, along with the common superiorities of molecular ferroelectrics like light weight, flexibility, low acoustical impedance, easy and environmentally friendly processing, it will open a new avenue for the exploration of next-generation piezoelectric devices in industrial and medical applications. PMID- 29144133 TI - Inducing Secondary Metabolite Production by Combined Culture of Talaromyces aculeatus and Penicillium variabile. AB - Four new polyketides, penitalarins A-C (1-3) and nafuredin B (4), together with the known biogenetically related nafuredin A (5) were isolated from a mixed culture of a deep-sea-derived fungus Talaromyces aculeatus and a mangrove-derived fungus Penicillium variabile. Liquid chromatography/mass spectrometry analysis showed that none of compounds 1-5 was produced by either of the two fungi when cultured alone under the same condition. The structures of 1-4, including absolute configurations, were deduced based on the interpretation of MS, NMR data, and time-dependent density functional theory calculations of specific electronic circular dichroism spectra. Compounds 1-3 possess a 3,6 dioxabicyclo[3.1.0]hexane ring, and 4 showed cytotoxicity with IC50 values ranging from 1.2 to 9.8 MUM against a panel of human cancer cell lines. PMID- 29144134 TI - Haloarene-Linked Unsymmetrically Substituted Triarylethenes: Small AIEgens To Detect Nitroaromatics and Volatile Organic Compounds. AB - Unsymmetrically substituted triarylalkenes as aggregation-induced emission-active fluorogens (AIEgens) are sporadically explored by different researchers. In this Article, naphthalene, biphenyl, and haloarene-linked new triarylethenes are conveniently synthesized and presented as unsymmetrically substituted extensive pi-conjugates to continue the discovery of small molecules as new AIEgens. Moreover, fluorophores attached to haloarenes are noteworthy, but such compounds are barely investigated as AIEgens. The possible mechanism underlying this AIE behavior has also been addressed by the support of experimental/theoretical outcomes. Moreover, two of these small AIEgens are fruitfully employed for rapid sensing of nitroaromatic compounds (NACs) where picric acid (PA, as a model explosive) showed a strong quenching efficiency with the detection limit of 39 or 48 ppb along with other nitroaromatics such as p-nitrotoluene and p-nitrophenol. This quenching could be visualized by the naked eye under a UV (365 nm) lamp and performed almost in an aqueous medium. Such alkenes are also proved to exhibit very clean on/off fluorescence switching properties for polar volatile organic compounds (VOCs). PMID- 29144135 TI - Parameterization of Palmitoylated Cysteine, Farnesylated Cysteine, Geranylgeranylated Cysteine, and Myristoylated Glycine for the Martini Force Field. AB - Peripheral membrane proteins go through various post-translational modifications that covalently bind fatty acid tails to specific amino acids. These post translational modifications significantly alter the lipophilicity of the modified proteins and allow them to anchor to biological membranes. Over 1000 different proteins have been identified to date that require such membrane-protein interactions to carry out their biological functions, including members of the Src and Ras superfamilies that play key roles in cell signaling and carcinogenesis. We have used all-atom simulations with the CHARMM36 force field to parameterize four of the most common post-translational modifications for the Martini 2.2 force field: palmitoylated cysteine, farnesylated cysteine, geranylgeranylated cysteine, and myristoylated glycine. The parameters reproduce the key features of clusters of configurations of the different anchors in lipid membranes as well as the water-octanol partitioning free energies of the anchors, which are crucial for the correct reproduction of the expected biophysical behavior of peripheral membrane proteins at the membrane-water interface. Implementation in existing Martini setup tools facilitates the use of the new parameters. PMID- 29144136 TI - Photophysics of J-Aggregate-Mediated Energy Transfer on DNA. AB - Achieving nanoscale spatial and electronic control over the formation of dye aggregates is a major synthetic challenge due to their typically inhomogeneous self-assembly, which limits control over their higher-order organization. To address these challenges, synthetic DNA-templated pseudoisocyanine (PIC) J aggregates were recently introduced. However, the dependence of the photophysics of the superradiant exciton on the underlying DNA template length and the impact of static disorder on energy transfer through these PIC J-aggregates remain unknown. We examine the delocalization length progression of superradiant PIC excitons by varying the length of poly-A DNA tracts that template PIC J aggregates. We then investigate the energy-transfer efficiency from PIC J aggregates with DNA duplex template length, which we found to be limited by static disorder. Utilizing the self-assembled and selective formation of superradiant excitons on DNA provides a platform to determine the function of delocalized excitons in the context of nanoscale energy transport. PMID- 29144138 TI - Doublet-Triplet Energy Transfer-Dominated Photon Upconversion. AB - Stable luminescent pi-radicals with doublet emission have aroused a growing interest for functional molecular materials. We have demonstrated a neutral pi radical dye (4-N-carbazolyl-2,6-dichlorophenyl)bis(2,4,6-trichlorophenyl)-methyl (TTM-1Cz) with remarkable doublet emission, which could be used as triplet sensitizer to initiate the photophysical process of triplet-triplet annihilation photon upconversion (TTA-UC). Dexter-like excited doublet-triplet energy transfer (DTET) was confirmed by theoretical calculation. With the same sensitizer, a mixed solution of TTM-1Cz and aromatic emitters could upconvert red light (lambda = 635 nm) to blue or cyan light. An anti-Stokes energy shift as large as 0.92 eV was observed from red to blue light upconversion. This finding of DTET phenomena offers a new kind of triplet sensitizer for TTA-UC. PMID- 29144137 TI - Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model. AB - In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ~33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads. PMID- 29144139 TI - Multiscale Simulation Platform Linking Lithium Ion Battery Electrode Fabrication Process with Performance at the Cell Level. AB - A novel multiscale modeling platform is proposed to demonstrate the importance of particle assembly during battery electrode fabrication by showing its effect on battery performance. For the first time, a discretized three-dimensional (3D) electrode resulting from the simulation of its fabrication has been incorporated within a 3D continuum performance model. The study used LiNi0.5Co0.2Mn0.3O2 as active material, and the effect of changes of electrode formulation is explored for three cases, namely 85:15, 90:10, and 95:5 ratios between active material and carbon-binder domains. Coarse-grained molecular dynamics is used to simulate the electrode fabrication. The resulting electrode mesostructure is characterized in terms of active material surface coverage by the carbon-binder domains and porosity. The trends observed are nonintuitive, indicating a high degree of complexity of the system. These structures are subsequently implemented into a 3D continuum model which displays distinct discharge behaviors for the three cases. The study offers a method for developing a coherent theoretical understanding of electrode fabrication that can help optimize battery performance. PMID- 29144140 TI - Specific Monitoring of Excited-State Symmetry Breaking by Femtosecond Broadband Fluorescence Upconversion Spectroscopy. AB - Most quadrupolar molecules designed for large two-photon absorption cross section have been shown to undergo symmetry breaking upon excitation to the S1 state. This was originally deduced from their strong fluorescence solvatochromism and later visualized in real time using transient infrared spectroscopy. For molecules not containing clear IR marker modes, however, a specific real-time observation of the symmetry breaking process remains lacking. Here we show that this process can be resolved using broadband fluorescence upconversion spectroscopy by monitoring the instantaneous emission transition dipole moment. This approach is illustrated with measurements performed on two quadrupolar molecules, with only one of them undergoing excited-state symmetry breaking in polar solvents. PMID- 29144141 TI - Experimental Demonstration of a Sizeable Nonclassical CH...G Hydrogen Bond in Cyclohexane Derivatives: Stabilization of an Axial Cyano Group. AB - Base-catalyzed equilibration of anancomeric cyanocyclohexanes demonstrates that replacement of cis-3,5-dimethyl holding groups with electron-withdrawing CF3 groups dramatically increases the proportion of the axial cyano isomer present at equilibrium. The CF3 groups exert an effect on the conformational energy of the cyano group worth about 0.6 kcal/mol. A nonclassical hydrogen bond between the axial CN group and the syn-axial hydrogens is a major contributor to the axial stability of the group. PMID- 29144142 TI - Nanoscale Zirconium-Abundant Surface Layers on Lithium- and Manganese-Rich Layered Oxides for High-Rate Lithium-Ion Batteries. AB - Battery performance, such as the rate capability and cycle stability of lithium transition metal oxides, is strongly correlated with the surface properties of active particles. For lithium-rich layered oxides, transition metal segregation in the initial state and migration upon cycling leads to a significant structural rearrangement, which eventually degrades the electrode performance. Here, we show that a fine-tuning of surface chemistry on the particular crystal facet can facilitate ionic diffusion and thus improve the rate capability dramatically, delivering a specific capacity of ~110 mAh g-1 at 30C. This high rate performance is realized by creating a nanoscale zirconium-abundant rock-salt-like surface phase epitaxially grown on the layered bulk. This surface layer is spontaneously formed on the Li+-diffusive crystallographic facets during the synthesis and is also durable upon electrochemical cycling. As a result, Li-ions can move rapidly through this nanoscale surface layer over hundreds of cycles. This study provides a promising new strategy for designing and preparing a high-performance lithium rich layered oxide cathode material. PMID- 29144143 TI - Study of the Hydrate-Melt/Li4Ti5O12 Interphase by Scanning Electron Microscopy Based Spectroscopy. AB - To develop safe and low-cost Li-ion batteries (LIBs), recently, an aqueous-based electrolyte so-called "hydrate-melt" (HDM) electrolyte is proposed. Li4Ti5O12 is a promising negative electrode material for a LIB with such a HDM electrolyte because of its unexpected reversible Li insertion and extraction properties without usually inevitable water reduction. The solid-electrolyte interphase formation is one of the reasons for this stable reaction, although a detailed analysis is not yet performed. Here, a Li4Ti5O12 electrode surface reacted in a HDM electrolyte is investigated by scanning electron microscopy-based analysis. Surface reaction products are clearly observed on the Li4Ti5O12 surface after the Li insertion reaction in a HDM electrolyte. Energy-dispersive X-ray spectroscopy and Auger electron spectroscopy indicated that the products do not contain any components originated from Li salts, whereas anion-derived passivation films seem to cover a bare surface below the products. Further, the surface products are identified as Li2O by the feature of Li-K-edge reflection electron energy-loss spectrum. The Li2O formation would be one of the key issues for stable Li insertion and extraction of a Li4Ti5O12 electrode in a HDM electrolyte. PMID- 29144144 TI - Structural Emergence in Particle Dispersions. AB - Particle dispersions, such as pigment-based inks, comprise weakly bound, milled nanoparticles. The properties of these pigments depend on both their chemical composition and a rather complex structural hierarchy which emerges from these dispersions. The emergence of structure under semidilute conditions is related to the structure of the dilute particles, the particle spacing (mesh size), processing history, and the interaction potential. Kinetic simulations could predict such emergence using these input parameters. In this paper, organic pigments are studied as an example of the importance of emergent structure to predict properties such as brilliance and opacity. Organic pigments are used to impart color to commercial inks, plastics, coatings, and cosmetics. In many cases, dilute pigments are mass fractal structures consisting of aggregated nanoparticles held together by weak van der Waals forces. In water, surfactant is added to create a pigment dispersion (an ink). The final properties of a pigment emerge from a complex interplay between aggregation and dispersion of aggregates as a function of concentration. Samples of the organic pigment yellow 14, PY14, were milled to four primary particle sizes to study the effect on structural emergence. The interaction between surfactant-stabilized PY14 aggregates in an aqueous medium was quantified by the second virial coefficient, A2, which reflects long-range interactions. The degree of aggregation is associated with short-range attractive interactions between primary particles. In this series of pigments, the degree of aggregation increases dramatically with reduction in primary particle size. Concurrently, the second-order virial coefficient, A2, increases reflecting stronger long-range repulsive interactions with particle size. Structural emergence can be understood through the percolation concentration and the filler mesh size. A2 is translated into a repulsive interaction potential for use in dissipative particle dynamics simulations to enable predictive modeling. This description of the interactions between dispersed pigment aggregates allows for a more scientific and predictive approach to understand structural emergence. PMID- 29144145 TI - A social comparison theory meta-analysis 60+ years on. AB - These meta-analyses of 60+ years of social comparison research focused on 2 issues: the choice of a comparison target (selection) and the effects of comparisons on self-evaluations, affect, and so forth (reaction). Selection studies offering 2 options (up or down) showed a strong preference (and no evidence of publication bias) for upward choices when there was no threat; there was no evidence for downward comparison as a dominant choice even when threatened. Selections became less differentiable when a lateral choice was also provided. For reaction studies, contrast was, by far, the dominant response to social comparison, with ability estimates most strongly affected. Moderator analyses, tests and adjustments for publication bias showed that contrast is stronger when the comparison involves varying participants' standing for ability (effect estimates, -0.75 to -0.65) and affect (-0.83 to -0.65). Novel personal attributes were subject to strong contrast for ability (-0.5 to -0.6) and affect (-0.6 to -0.7). Dissimilarity priming was associated with contrast (-0.44 to 0.27; no publication bias), consistent with Mussweiler (2003). Similarity priming provided modest support for Collins (1996) and Mussweiler (2003), with very weak assimilation effects, depending on the publication bias estimator. Studies including control groups indicated effects in response to upward and downward targets were comparable in size and contrastive. Limitations of the literature (e.g., small number of studies including no-comparison control conditions), unresolved issues, and why people choose to compare upward when the most likely result is self-deflating contrast are discussed. (PsycINFO Database Record PMID- 29144146 TI - Legalization of recreational marijuana and community sales policy in Oregon: Impact on adolescent willingness and intent to use, parent use, and adolescent use. AB - Studies investigating the impact of medical marijuana legalization have found no significant changes in adolescent use. In one of the few studies focused on recreational marijuana, we investigated how recreational marijuana legalization and community sales policy influenced factors that likely impact youth use (youth willingness and intent to use, parent use) as well as youth use. Legalization of recreational marijuana in Oregon coincided with our study on adolescent substance use. Cohort 1 transitioned from 8th to 9th grade prior to legalization and Cohort 2 made this transition during legalization (N = 444; 53% female). Communities were allowed to opt out of sales. Multivariate linear regression models estimated the impact of legalization and community sales policy on changes in attitudes and parent use (2 time points 1 year apart). Zero-inflated Poisson growth curve models estimated the effects on initial levels and rate of change from 8th through 9th grade (4 time points). In communities opting out of sales, the prior to-legalization cohort was less likely to increase their willingness and intent to use marijuana, and the legalization cohort was more likely to increase intent to use. For youth who used marijuana, legalization was associated with increased use, and those in communities opting out of sales had greater growth in marijuana use. Community policy appears to impact youth attitudes toward, and use of, marijuana. Results suggest that legalization of recreational marijuana did not increase marijuana use for youth who did not use marijuana but did increase use in youth who were already using. (PsycINFO Database Record PMID- 29144147 TI - Pursued for their prescription: Exposure to compliance-gaining strategies predicts stimulant diversion in emerging adults. AB - Researchers have begun to identify predictors of who will divert their stimulant prescriptions, as most emerging adults (EAs) who use prescription stimulants nonmedically procure these drugs from a friend or acquaintance with a prescription. Far less research has examined how EAs with attention deficit/hyperactivity disorder (ADHD) are approached for these medications, and their affective and behavioral responses to these requests. We hypothesized that EAs with a stimulant prescription who reported greater exposure to compliance gaining attempts from peers, particularly rational appeals for academic work, would be more likely to divert, as would EAs who reported lower resistance to peer influence. We recruited EAs diagnosed with ADHD (N = 149) through flyers, in class presentations, campus-wide e-mails, and psychology subject pools at 2 demographically dissimilar college campuses. As predicted, a logistic regression showed that greater exposure to compliance-gaining strategies, Greek involvement, Northeast college attendance, and less guilt and worry about diversion predicted diversion (n = 53, 36%). Diverters were no less resistant to peer influence; however, a continuous measure assessing willingness to divert was inversely correlated with resistance to peer influence. An analysis of variance showed that rational appeals for academic work and guilt-inducing strategies for not complying with diversion requests were associated with the greatest likelihood of diversion. Further, negative affective responses (e.g., feeling manipulated, used) among students with a prescription following diversion were relatively common. Interventions to reduce diversion should inoculate EAs with ADHD against a range of compliance-gaining strategies and should help EAs who are experiencing dissonance about diversion to resist their peers' requests more effectively. (PsycINFO Database Record PMID- 29144148 TI - A prospective study of mutual influence for substance use among young adult marital dyads. AB - The purpose of this 2-wave longitudinal study was to specify, test, and evaluate an actor-partner interdependence model (APIM) with young adult marital dyads to test husbands' and wives' mutual influences on each other's substance use. Prospective data were collected from young adults and their spouses at baseline and 5 years later. Data from 237 dyads were used to test spouses' interdependence on alcohol use, alcohol problems, and marijuana use with the APIMs. Marital partners had significant effects on each other's substance use, though the patterns were different contingent on the outcome referenced. Husbands' alcohol use significantly predicted wives' alcohol use and alcohol problems. Wives' alcohol use and marijuana use significantly predicted husbands' alcohol use, alcohol problems, and marijuana use. For these young adult dyads, partner influences were indicated for both spouses, but more pervasive influences were indicated from wives-to-husbands than the reverse. (PsycINFO Database Record PMID- 29144150 TI - Development and psychometric analysis of the Brief DSM-5 Alcohol Use Disorder Diagnostic Assessment: Towards effective diagnosis in college students. AB - The Diagnostic and Statistical Manual of Mental Disorders (5th edition) Alcohol Use Disorder (DSM-5 AUD) criteria have been modified to reflect a single, continuous disorder. It is critical that we develop brief assessment measures that can accurately assess for DSM-5 AUD criteria in college students to assist in screening, referral, and brief intervention services implemented on college campuses. The present study sought to develop and assess for the psychometric properties of a brief 13-item measure designed to capture the full spectrum of the DSM-5 AUD criteria in a sample of college students. Participants were past year drinkers (N = 923) between the ages of 18 to 30 enrolled at 3 universities. Respondents completed a 30-min anonymous battery of questionnaires online. The Brief DSM-5 AUD Assessment consisted of 13 items designed to reflect the DSM-5 AUD criteria. Results indicated a high degree of internal consistency reliability with high item-to-scale correlations. Confirmatory factor analyses indicated that a dominant single factor emerged with good model fit. The Item Response Theory (IRT) analyses indicated that the difficulty parameters for each criterion were intermixed along the upper portion of the underlying AUD severity continuum, and the discrimination parameters were all high. Additional analysis indicated that those with a DSM-5 AUD had greater levels of alcohol and other drug use and problem severity in comparison to those without a DSM-5 AUD. Study findings provide empirical support for the reliability and validity of the Brief 13-item DSM-5 Assessment. It should be routinely included into research and clinical practice efforts. (PsycINFO Database Record PMID- 29144149 TI - Modeling numerosity representation with an integrated diffusion model. AB - Models of the representation of numerosity information used in discrimination tasks are integrated with a diffusion decision model. The representation models assume distributions of numerosity either with means and SD that increase linearly with numerosity or with means that increase logarithmically with constant SD. The models produce coefficients that are applied to differences between two numerosities to produce drift rates and these drive the decision process. The linear and log models make differential predictions about how response time (RT) distributions and accuracy change with numerosity and which model is successful depends on the task. When the task is to decide which of two side-by-side arrays of dots has more dots, the log model fits decreasing accuracy and increasing RT as numerosity increases. When the task is to decide, for dots of two colors mixed in a single array, which color has more dots, the linear model fits decreasing accuracy and decreasing RT as numerosity increases. For both tasks, variables such as the areas covered by the dots affect performance, but if the task is changed to one in which the subject has to decide whether the number of dots in a single array is more or less than a standard, the variables have little effect on performance. Model parameters correlate across tasks suggesting commonalities in the abilities to perform them. Overall, results show that the representation used depends on the task and no single representation can account for the data from all the paradigms. (PsycINFO Database Record PMID- 29144151 TI - Workflow interruptions and employee work outcomes: The moderating role of polychronicity. AB - Workflow interruptions are one of the most commonly experienced stressors at work. This research expands existing literature on workflow interruptions in a diary field study. We apply a within-person approach and investigate detrimental effects of daily workflow interruptions on both daily satisfaction with performance and daily emotional exhaustion. Furthermore, we introduce polychronicity (the trait-like preference of a person to deal with several activities at the same time) as a buffering factor in this relationship. Results of the diary study with knowledge workers over 5 consecutive working days (N = 149, 644 daily observations) showed that on days on which participants experienced a large amount of workflow interruptions, they reported lower levels of satisfaction with their performance and higher levels of emotional exhaustion on that same day. Polychronicity failed to moderate the positive association between interruptions and emotional exhaustion. However, polychronicity significantly moderated the negative association between daily interruptions and daily satisfaction with participants' own performance in a way that for people ranking high on polychronicity this negative association was dissolved. (PsycINFO Database Record PMID- 29144152 TI - New psychometric data from the Spanish versions of the Glasgow Dyspepsia Severity Score and the Dyspepsia-Related Health Scale measures. AB - BACKGROUND AND OBJECTIVE: There are no structural abnormalities in functional dyspepsia, therefore it is essential to have a viable questionnaire to measure treatment outcome according to patient perception. The aim of the study was to extensively document psychometric characteristics of the Glasgow Dyspepsia Severity Score and the Dyspepsia-Related Health Scale that are currently available in Spanish. METHODS: Patients with functional dyspepsia (n = 158) were recruited from a randomized trial that assessed standard vs. standard and psychological treatment. Participants had completed the validation questionnaires and the Medical Outcome Study Short-form 36. Reliability (Cronbach's alpha), validity (Confirmatory Factor Analysis, convergent and known group validity) and responsiveness (minimal clinically important difference) were analyzed. RESULTS: A Confirmatory Factor Analysis of the Glasgow Dyspepsia Severity Score showed a one-factor solution model, but a low Cronbach's alpha (0.61). With regard to the Dyspepsia-Related Health Scale, the Cronbach's alpha (0.80-0.97) and Confirmatory Factor Analysis supported a model with four inter-correlated dimensions and suggested a need to improve the "Satisfaction with dyspepsia-related health" dimension (Cronbach's alpha < 20). Finally, the global scores for both the Glasgow Dyspepsia Severity Score and the Dyspepsia-Related Health Scale were responsive at six months post-treatment, with a minimal clinically important difference of 4 and 6, respectively. CONCLUSIONS: Our findings support the continued application of the Dyspepsia-Related Health Scale and the need to improve the "Satisfaction with dyspepsia-related health" dimension. Although the Glasgow Dyspepsia Severity Score is a promising questionnaire, further review of the content is required to eliminate and add items in order to provide greater consistency to the evaluated construct. PMID- 29144153 TI - Intravoxel incoherent motion diffusion-weighted MR imaging for differentiation of benign and malignant musculoskeletal tumours at 3 T. AB - OBJECTIVE: To evaluate the intravoxel incoherent motion (IVIM) diffusion-weighted (DW) MRI for differentiating between benign and malignant musculoskeletal tumours at 3 T. METHODS: 65 patients with treatment-naive musculoskeletal tumours (47 malignant and 23 benign lesions) who underwent 3 T MRI including IVIM DW imaging were included. IVIM-derived parameters included pure diffusion coefficient (D), perfusion related incoherent microcirculation (D*, pseudodiffusion coefficient), and perfusion fraction (f). IVIM parameters and mono-exponential apparent diffusion coefficient (ADC) were retrospectively measured by two independent musculoskeletal radiologists. RESULTS: D and ADC values of malignant tumours (923 +/- 360, 965 +/- 353 um2 s-1, respectively) were significantly lower than those of benign tumours (1668 +/- 546, 1689 +/- 526 um2 s-1) (p < 0.001). F values of malignant tumours (9.6%) were significantly higher than those of benign tumours (7.2%) (p = 0.021), whereas D* values showed no significant difference (p > 0.05). The area under the receiver operating characteristic (ROC) curve of D, ADC and f were 0.874, 0.880 and 0.671, respectively. Using cut-off values of D and ADC of 1200 um2 s-1, the sensitivity, specificity and accuracy were 92, 83, 89%, 92, 87 and 90%, respectively. CONCLUSION: D and ADC may be more accurate and reliable for differentiation of malignant from benign musculoskeletal tumours than f and D* at 3 T IVIM DW imaging. Advances in knowledge: Among IVIM-derived parameters, D is more accurate and reliable in differentiating malignant from benign musculoskeletal tumours than f and D* at 3.0T IVIM DW imaging. There was no significant difference in the diagnostic performance of D and ADC. PMID- 29144154 TI - Sleep quality and methylation status of selected tumor suppressor genes among nurses and midwives. AB - Chronic sleep restriction may affect metabolism, hormone secretion patterns and inflammatory responses. Limited reports suggest also epigenetic effects, such as changes in DNA methylation profiles. The study aims to assess the potential association between poor sleep quality or sleep duration and the levels of 5 methylcytosine in the promoter regions of selected tumor suppressor genes. A cross-sectional study was conducted on 710 nurses and midwives aged 40-60 years. Data from interviews regarding sleep habits and potential confounders were used. The methylation status of tumor suppressor genes was determined via qMSP reactions using DNA samples derived from leucocytes. No significant findings were observed in the total study population or in the two subgroups of women stratified by the current system of work. A borderline significance association was observed between a shorter duration of sleep and an increased methylation level in CDKN2A among day working nurses and midwives. Further studies are warranted to explore this under-investigated topic. PMID- 29144155 TI - Proposal of cutoff points for pediatric daytime sleepiness scale to identify excessive daytime sleepiness. AB - The objective of the present study was to propose cutoff points for the Pediatric Daytime Sleepiness Scale (PDSS) through sensitivity and specificity analyses in order to identify excessive daytime sleepiness, considering parameters such as duration and quality of sleep, health perception, stress control and depressive moods (feelings of sadness) in adolescents. A total of 1,132 adolescents, aged 14 19 years old, of both sexes, from the public high school of Sao Jose - SC, answered the questionnaire with information on age, daytime sleepiness, sleep duration, health perception, stress management, depressive moods (feelings of sadness) and quality of sleep. The Receiver Operating Characteristic (ROC) curve was used to estimate cutoff points considering the sensitivity and specificity values that best identify adolescents with excessive daytime sleepiness, using independent variables as a reference. The majority of the sample was female (54.2%), aged 14-16 years. The girls presented worse quality of sleep (66.4%), and the boys had a more positive perception of health (74.8%), better stress control (64.8%) and lower depressive moods (feelings of sadness) (63.3%). The largest area in the ROC curve was the one that considered sleep quality as a parameter in both sexes (area of the curve = 0.709 and 0.659, respectively, for boys and girls, p < 0.001). Considering sleep quality as a reference, the cutoff point for excessive daytime sleepiness was 15 points. The other parameters used were also significant (p < 0.005). Poor sleep quality was the parameter most strongly related to daytime sleepiness, and a cutoff of 15 points for the PDSS for both sexes should be used in the definition of excessive daytime sleepiness. For the other parameters, stress management, depressive mood (feelings of sadness) and health perception, different cutoff points are suggested for boys and girls. PMID- 29144156 TI - UPMC Prescription for Wellness: A Quality Improvement Case Study for Supporting Patient Engagement and Health Behavior Change. AB - Addressing patient health and care behaviors that underlie much of chronic disease continues to challenge providers, medical practices, health systems, and insurers. Improving health and care as described by the Quadruple Aim requires innovation at the front lines of clinical care: the doctor-patient interaction and office practice. This article describes the use of Lean Six Sigma in a quality improvement (QI) effort to design an effective and scalable method for physicians to prescribe health coaching for healthy behaviors in a primary care medical home within a large integrated delivery and financing system. Building on the national Agency for Healthcare Research and Quality and Robert Wood Johnson Foundation-funded Prescription for Health multisite demonstration, this QI case study provides important lessons for transforming patient-physician-practice support systems to better address lifestyle and care management challenges critical to producing better outcomes. PMID- 29144157 TI - The influence of sunlight exposure on hospitalization in emergency psychiatry. AB - OBJECTIVE: Environmental conditions during early life may affect individual vulnerability to both physiological changes as well as psychiatric conditions, especially in those with a genetic susceptibility. Among all factors, sunlight exposure intensity has a crucial effect on affecting circadian functions high risk individuals. A potential explanation of this relation is that excessive sunlight exposure is able to impair biological mechanisms, possibly through the dysregulation of serotonin and/or melatonin production/metabolism. The aim of this study was to evaluate the influence of excessive sunlight exposure in a sample of emergency psychiatry inpatients. METHODS: All subjects were consecutively recruited from the Psychiatric Inpatient Unit of San Luigi Gonzaga Hospital, Orbassano (University of Turin, Italy) from September 2013 to August 2015. Socio-demographic and clinical characteristics were carefully collected. RESULTS: We initially screened a sample of 900 patients; however, only 730 subjects voluntary accepted to participate in the study. Patients with admissions in spring/summer (a period in which daylight/darkness ratio is longer) showed a higher prevalence of involuntary admission, an earlier age at illness onset, a longer duration of hospitalization and admission for (hypo)manic episode. CONCLUSIONS: Excessive sunlight exposure may exert a fundamental role on psychopathological conditions presumably affecting biological vulnerability. A better understanding of its effect on the course of bipolar and other psychiatric disorders may assist in tailoring the adequate treatment for patients resulting in a shorter stay within hospitalized settings and a better treatment response. PMID- 29144158 TI - Glycosylation Repurposes Alpha-1 Antitrypsin for Resolution of Community-acquired Pneumonia. PMID- 29144160 TI - High-Flow Nasal Cannula Oxygen in Adults: An Evidence-based Assessment. AB - High-flow nasal cannula oxygenation has distinct advantages over other oxygen devices because of its unique effects on respiratory physiology. In particular, adjustable oxygen delivery and flow-dependent carbon dioxide clearance reduce work of breathing and better match inspiratory demand during respiratory distress. Historically, few studies had evaluated whether the physiologic effects of these devices translated into clinical benefit. However, recent publications have begun to address this knowledge gap. High-flow nasal cannula oxygenation has been shown to have similar, and in some cases superior clinical efficacy compared with conventional low-flow oxygen supplementation and noninvasive positive pressure ventilation in acute hypoxemic respiratory failure. High-flow nasal cannula oxygenation also prevents reintubations in medical and postoperative surgical populations, provides preoxygenation for laryngoscopy, and supports oxygenation during bronchoscopy. This review examines the evidence for high-flow nasal cannula oxygenation use in adults, including a focus on the unique effects of high flow on respiratory physiology and keys for tailoring flow for specific clinical scenarios. PMID- 29144159 TI - Shear-wave elastography quantitative assessment of the male breast: added value to distinguish benign and malignant palpable masses. AB - OBJECTIVE: To evaluate the ability of shear-wave elastography (SWE) to distinguish between benign and malignant palpable masses of the adult male breast. METHODS: Clinical examination, mammography, B-mode and Doppler ultrasound findings and SWE quantitative parameters were compared in 50 benign lesions (including 40 gynaecomastias) and 15 malignant lesions (invasive ductal carcinomas) from 65 patients who were consecutively addressed for specialized advice at our comprehensive cancer centre. Mean elasticity (El mean), maximum elasticity (El max), El mean of the surrounding fatty tissue and lesion to fat ratio (El ratio) were reported for each patient. RESULTS: Malignant masses displayed significantly higher El mean (p < 0.0001), El max (p < 0.0001) and El ratio (p < 0.0001) compared to benign masses without overlap of values between the two groups. By adding SWE to clinical examination, mammography and ultrasound, all the lesions would have been retrospectively correctly diagnosed as benign or malignant. One false positive could have been downstaged, 14/65 undetermined masses could have been correctly reclassified as 4 malignant and 10 benign lesions, for which biopsies could have consequently been avoided. CONCLUSION: Evaluation of male breast palpable masses by SWE demonstrates that malignant masses are significantly stiffer lesions and may improve diagnostic management when clinical examination, mammography and conventional ultrasound are doubtful. Advances in knowledge: Quantitative SWE is feasible in male breast and could be of great interest to help classify doubtful lesions after classical clinical and radiological evaluations, probably because of different anatomy and different tumours epidemiology compared with female breast. PMID- 29144162 TI - Association Between Metformin Adherence and All-Cause Mortality Among New Users of Metformin: A Nested Case-Control Study. AB - BACKGROUND: Metformin presents better survival rates than other oral antidiabetics in the treatment of type 2 diabetes. However, these benefits may be dampened by inadequate treatment adherence. OBJECTIVE: We aimed to investigate the relationship between adherence level to metformin therapy and all-cause mortality over 10 years in incident metformin users. METHODS: A nested case control study was conducted using a large cohort of beneficiaries of the Quebec public drug insurance plan, aged 45 to 85 years, who initiated metformin between 2000 and 2009. Each case of all-cause death during follow-up was matched with up to 10 controls. Adherence to metformin was measured using the medication possession ratio (MPR). Conditional logistic regression models were used to estimate rate ratios (RRs) for mortality between adherent (MPR >= 80%) and nonadherent patients (MPR < 80%). Subgroup analyses were conducted according to age (45-64 and 65-85 years) and comedication use (antihypertensive/cardiovascular drugs and statins). RESULTS: The cohort included 82 720 incident metformin users, followed up for 2.4 [0.8-4.4] years (median [interquartile range]) and 4747 cases of all-cause deaths. Analyses revealed decreased mortality risks after long-term adherence to metformin. Specifically, RRs were 0.84 (95% CI = [0.71-0.98]) and 0.69 [0.57-0.85] after 4 to 6 and >=6 years of adherence to metformin, respectively. Survival benefits of long-term adherence (>=4 years) were also observed across most subgroups and particularly in patients using neither antihypertensive/cardiovascular drugs nor statins (0.57 [0.41-0.77]). CONCLUSIONS: Long-term adherence to metformin is associated with decreased risks of all-cause mortality in incident metformin users. Further research should investigate whether survival benefits vary according to the comorbidity burden of patients. PMID- 29144161 TI - Use of patient outcome endpoints to identify the best functional CT imaging parameters in metastatic renal cell carcinoma patients. AB - OBJECTIVE: To use the patient outcome endpoints overall survival and progression free survival to evaluate functional parameters derived from dynamic contrast enhanced CT. METHODS: 69 patients with metastatic renal cell carcinoma had dynamic contrast-enhanced CT scans at baseline and after 5 and 10 weeks of treatment. Blood volume, blood flow and standardized perfusion values were calculated using deconvolution (BVdeconv, BFdeconv and SPVdeconv), blood flow and standardized perfusion values using maximum slope (BFmax and SPVmax) and blood volume and permeability surface area product using the Patlak model (BVpatlak and PS). Histogram data for each were extracted and associated to patient outcomes. Correlations and agreements were also assessed. RESULTS: The strongest associations were observed between patient outcome and medians and modes for BVdeconv, BVpatlak and BFdeconv at baseline and during the early ontreatment period (p < 0.05 for all). For the relative changes in median and mode between baseline and weeks 5 and 10, PS seemed to have opposite associations dependent on treatment. Interobserver correlations were excellent (r >= 0.9, p < 0.001) with good agreement for BFdeconv, BFmax, SPVdeconv and SPVmax and moderate to good (0.5 < r < 0.7, p < 0.001) for BVdeconv and BVpatlak. Medians had a better reproducibility than modes. CONCLUSION: Patient outcome was used to identify the best functional imaging parameters in patients with metastatic renal cell carcinoma. Taking patient outcome and reproducibility into account, BVdeconv, BVpatlak and BFdeconv provide the most clinically meaningful information, whereas PS seems to be treatment dependent. Standardization of acquisition protocols and post-processing software is necessary for future clinical utilization. Advances in knowledge: Taking patient outcome and reproducibility into account, BVdeconv, BVpatlak and BFdeconv provide the most clinically meaningful information. PS seems to be treatment dependent. PMID- 29144163 TI - Demand for CT scans increases during transition from paediatric to adult care: an observational study from 2009 to 2015. AB - OBJECTIVE: Avoiding unnecessary radiation exposure is a clinical priority in children and young adults. We aimed to explore demand for CT scans in a busy general hospital with particular interest in the period of transition from paediatric to adult medical care. METHODS: We used an observational epidemiological study based in a teaching hospital. Data were obtained on numbers and rates of CT scans from 2009 to 2015. The main outcome was age-stratified rates of receiving a CT scan. RESULTS: There were a total of 262,221 CT scans. There was a large step change in the rate of CT scans over the period of transition from paediatric to adult medical care. Individuals aged 10-15 years experienced 6.7 CT scans per 1000 clinical episodes, while those aged 19-24 years experienced 19.8 CT scans per 1000 clinical episodes (p < 0.001). This difference remained significant for all sensitivity analyses. CONCLUSION: There is almost a threefold increase in rates of CT scans in the two populations before and after the period of transition from paediatric to adult medical care. While we were unable to adjust for case mix or quantify radiation exposure, paediatricians' diagnostic strategies to minimize radiation exposure may have clinical relevance for adult physicians, and hence enable reductions in ionizing radiation to patients. Advances in knowledge: A large increase in rates of CT scans occurs during adolescence, and considering paediatricians' strategies to minimize radiation exposure may enable reductions to all patients. PMID- 29144164 TI - Correlation between obesity and fat-infiltrated axillary lymph nodes visualized on mammography. AB - OBJECTIVE: Using screening mammography, this study investigated the association between obesity and axillary lymph node (LN) size and morphology. METHODS: We conducted a retrospective review of 188 females who underwent screening mammography at an academic medical centre. Length and width of the LN and hilum were measured in the largest, mammographically visible axillary node. The hilo cortical ratio (HCR) was calculated as the hilar width divided by the cortical width. Measurements were performed by a board certified breast radiologist and a resident radiology physician. Inter-rater agreement was assessed with Pearson correlation coefficient. We performed multivariable regression analysis for associations of LN measurements with body mass index (BMI), breast density and age. RESULTS: There was a strong association between BMI and LN dimensions, hilum dimensions and HCR (p < 0.001 for all metrics). There was no significant change in cortex width with increasing BMI (p = 0.15). Increases in LN length and width were found with increasing BMI [0.6 mm increase in length per unit BMI, 95% CI (0.4-0.8), p < 0.001 and0.3 mm increase in width per unit BMI, 95% CI(0.2-0.4), p < 0.001, respectively]. Inter-rater reliability for lymph node and hilum measurements was 0.57-0.72. CONCLUSION: We found a highly significant association between increasing BMI and axillary LN dimensions independent of age and breast density with strong interobserver agreement. The increase in LN size was driven by expansion of the LN hilum secondary to fat infiltration. Advances in knowledge: This preliminary work determined a relationship between fat infiltrated axillary lymph nodes and obesity. PMID- 29144165 TI - Gene therapy: evidence, value and affordability in the US health care system. AB - AIMS: To explore the challenges presented by gene therapies, discuss potential solutions, and present policy recommendations. METHODS: A review of the literature and series of expert interviews were conducted and discussed at a Policy Forum convened by The Institute for Clinical and Economic Review (ICER). The Policy Forum was attended by independent experts and senior representatives from 20 payer organizations and life sciences companies. RESULTS: Three categories of challenges are identified: evidence generation, assessing value and affordability. Possible solutions and policy recommendations are presented for each of the three main categories of challenges. CONCLUSIONS: Gene therapies present exciting opportunities, but also pose major challenges. Dialogue between manufacturers and payers around the issues and possible solutions is crucial. PMID- 29144167 TI - Peer reviewers for International Journal of Speech-Language Pathology December 2011-September 2012. PMID- 29144166 TI - Imaging assessment of acute ischaemic stroke: a review of radiological methods. AB - Acute ischaemic stroke is the second largest cause of death worldwide and a cause of major physical and psychological morbidity. Current evidence based treatment includes intravenous thrombolysis (IVT) and mechanical thrombectomy (MT), both requiring careful patient selection and to be administered as quickly as possible within a limited time window from symptom onset. Imaging plays a crucial role identifying patients who may benefit from MT or IVT whilst excluding those that may be harmed. For IVT, imaging must as a minimum exclude haemorrhage, stroke mimics and provide an estimate of non-viable brain. For MT, imaging must in addition detect and characterize intra-arterial thrombus and assess the intra and extracranial arterial architecture. More advanced imaging techniques may be used to assess more accurately the volume of non-viable and potentially salvageable brain tissue. It is highly likely that further research will identify patients who would benefit from treatment beyond currently accepted time windows for IVT (4.5 h) and MT (6 h) and patients with an unknown time of symptom onset. Current evidence indicates that best outcomes are achieved when treatment is instituted as soon as possible after symptom onset. A rapid, efficient imaging pathway including interpretation is fundamental to achieving the best outcomes. This review summarizes current techniques for imaging assessment of acute stroke, highlighting strengths and limitations of each. The optimum pathway is a balance between diagnostic information, local resources, specialization and the time taken to acquire, process and interpret the data. As new evidence emerges, it is likely that the minimum required imaging data will change. PMID- 29144168 TI - The effects of extended nap periods on cognitive, physiological and subjective responses under simulated night shift conditions. AB - Extended nap opportunities have been effective in maintaining alertness in the context of extended night shifts (+12 h). However, there is limited evidence of their efficacy during 8-h shifts. Thus, this study explored the effects of extended naps on cognitive, physiological and perceptual responses during four simulated, 8-h night shifts. In a laboratory setting, 32 participants were allocated to one of three conditions. All participants completed four consecutive, 8-h night shifts, with the arrangements differing by condition. The fixed night condition worked from 22h00 to 06h00, while the nap early group worked from 20h00 to 08h00 and napped between 00h00 and 03h20. The nap late group worked from 00h00 to 12h00 and napped between 04h00 and 07h20. Nap length was limited to 3 hours and 20 minutes. Participants performed a simple beading task during each shift, while also completing six to eight test batteries roughly every 2 h. During each shift, six test batteries were completed, in which the following measures were taken. Performance indicators included beading output, eye accommodation time, choice reaction time, visual vigilance, simple reaction time, processing speed and object recognition, working memory, motor response time and tracking performance. Physiological measures included heart rate and tympanic temperature, whereas subjective sleepiness and reported sleep length and quality while outside the laboratory constituted the self reported measures. Both naps reduced subjective sleepiness but did not alter the circadian and homeostatic-related changes in cognitive and physiological measures, relative to the fixed night condition. Additionally, there was evidence of sleep inertia following each nap, which resulted in transient reductions in certain perceptual cognitive performance measures. The present study suggested that there were some benefits associated with including an extended nap during 8-h night shifts. However, the effects of sleep inertia need to be effectively managed to ensure that post-nap alertness and performance is maintained. PMID- 29144169 TI - Bright-light exposure during daytime sleeping affects nocturnal melatonin secretion after simulated night work. AB - The guidelines for night and shift workers recommend that after night work, they should sleep in a dark environment during the daytime. However, staying in a dark environment during the daytime reduces nocturnal melatonin secretion and delays its onset. Daytime bright-light exposure after night work is important for melatonin synthesis the subsequent night and for maintaining the circadian rhythms. However, it is not clear whether daytime sleeping after night work should be in a dim- or a bright-light environment for maintaining melatonin secretion. The aim of this study, therefore, was to evaluate the effect of bright light exposure during daytime sleeping on nocturnal melatonin secretion after simulated night work. Twelve healthy male subjects, aged 24.8 +/- 4.6 (mean +/- SD), participated in 3-day sessions under two experimental conditions, bright light or dim light, in a random order. On the first day, the subjects entered the experimental room at 16:00 and saliva samples were collected every hour between 18:00 and 00:00 under dim-light conditions. Between 00:00 and 08:00, they participated in tasks that simulated night work. At 10:00 the next morning, they slept for 6 hours under either a bright-light condition (>3000 lx) or a dim-light condition (<50 lx). In the evening, saliva samples were collected as on the first day. The saliva samples were analyzed for melatonin concentration. Activity and sleep times were recorded by a wrist device worn throughout the experiment. In the statistical analysis, the time courses of melatonin concentration were compared between the two conditions by three-way repeated measurements ANOVA (light condition, day and time of day). The change in dim light melatonin onset (DeltaDLMO) between the first and second days, and daytime and nocturnal sleep parameters after the simulated night work were compared between the light conditions using paired t-tests. The ANOVA results indicated a significant interaction (light condition and3 day) (p = .006). Post hoc tests indicated that in the dim-light condition, the melatonin concentration was significantly lower on the second day than on the first day (p = .046); however, in the bright-light condition, there was no significant difference in the melatonin concentration between the days (p = .560). There was a significant difference in DeltaDLMO between the conditions (p = .015): DLMO after sleeping was advanced by 11.1 +/- 17.4 min under bright-light conditions but delayed for 7.2 +/- 13.6 min after sleeping under dim-light conditions. No significant differences were found in any sleep parameter. Our study demonstrated that daytime sleeping under bright-light conditions after night work could not reduce late evening melatonin secretion until midnight or delay the phase of melatonin secretion without decreasing the quality of the daytime sleeping. Thus, these results suggested that, to enhance melatonin secretion and to maintain their conventional sleep-wake cycle, after night work, shift workers should sleep during the daytime under bright-light conditions rather than dim-light conditions. PMID- 29144170 TI - Night work as a risk factor for future cause-specific disability pension: A prospective twin cohort study in Sweden. AB - The objectives of the study were to investigate the associations between night work and disability pension (DP) due to all causes, cardiovascular (CVD), mental, and other diagnoses, adjusting for familial confounding. The material of the study included comprehensive survey data on 27 165 Swedish twins born in 1935 1958 that were linked with DP data for the survey period (1998-2003) to 2013. Night work was assessed as years of working nights at least every now and then, and categorized into not at all, 1-10 years and over 10 years. For statistical analyses, Cox proportional hazards regressions were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). The results of the study indicated that over 10 years duration of night work had an age- and sex-adjusted HR of 1.48 (95% CI 1.11-1.98) for DP due to CVD and 1-10 years of night work an HR of 1.28 (95% CI 1.06-1.55) for DP due to mental diagnoses, but attenuated when covariates were adjusted for. Both 1-10 years (HR 1.27, 95% CI 1.17-1.39) and >10 years of night work (HR 1.20, 95% CI 1.08-1.34) were associated with DP due to all causes and other diagnoses. These risks remained after adjusting for covariates. To conclude, even modest exposure in terms of duration of night work is a risk factor for all-cause DP, but also for DP due to mental and other diagnoses. The risk of DP due to CVD seems to be associated with longer (>10 years) periods of night work. All the associations between night work and DP seem to be influenced by various covariates. PMID- 29144171 TI - Circadian gene methylation in rotating-shift nurses: a cross-sectional study. AB - Investigating the methylation status of the circadian genes may contribute to a better understanding of the shift work-related circadian disruption in individuals exposed to artificial light at night. In the present study, we determined the methylation status of the circadian genes associated with a shift work pattern among nurses and midwives participating in a cross-sectional study in Lodz, Poland. Quantitative methylation polymerase chain reaction assays were used to assess promoter CpG methylation in PER1, PER2, PER3, CRY1, CRY2, BMAL1, CLOCK, and NPAS2 in genomic DNA from whole blood of 347 women having a rotating shift work schedule and 363 women working days only. The percentage of methylated reference (PMR) was assessed using fluorescent probes for PER1, PER2, PER3, CRY1, and NPAS2, and the percentage of gene methylation, as the methylation index (MI), using two sets of primers for BMAL1, CLOCK, and CRY2. We tested the possible association between current and lifetime rotating night-shift work characteristics and circadian gene methylation by using proportional odds regression model with blood DNA methylation, categorized into tertiles, and adjusted for age, current smoking status, folate intake and blood collection time. The findings indicated that CpG methylation in PER2 promoter was significantly decreased (P < 0.004) among nurses and midwives currently working rotating shifts, as compared with day-working nurses and midwives. The lower percentage of PER2 methylation was associated with a higher monthly frequency of current night duties (2-7 night shifts, and eight or more night shifts per month) (P = 0.012) and was associated at borderline significance (P = 0.092) with the lifetime duration of shift work (>10 <= 20 years and >20 <= 43 years of rotating shift work) among nurses and midwives (N = 710). Moreover, women with a longer lifetime duration of shift work presented a lower status of PER1 methylation (P = 0.040) than did the women with up to 10 years of rotating-shift work. Long lifetime duration of shift work (> 10 years) among current rotating night-shift workers (N = 347) was associated with BMAL1 hypomethylation (P = 0.013). Among eight of the investigated circadian genes, only PER1, PER2, and BMAL1 showed differential methylation attributable to the rotating-shift work of nurses and midwives. The findings on blood-based DNA methylation in the circadian genes may provide a better insight into the mechanistic principles underlying the possible health effects of night-shift work but these should be verified in further studies recruiting larger populations of shift workers. PMID- 29144172 TI - Disruptions in sleep-wake cycles in community-dwelling cancer patients receiving palliative care and their correlates. AB - Significant disruptions in sleep-wake cycles have been found in advanced cancer patients in prior research. However, much remains to be known about specific sleep-wake cycle variables that are impaired in patients with a significantly altered performance status. More studies are also needed to explore the extent to which disrupted sleep-wake cycles are related to physical and psychological symptoms, time to death, maladaptive sleep behaviors, quality of life and 24-h light exposure. This study conducted in palliative cancer patients was aimed at characterizing patients' sleep-wake cycles using various circadian parameters (i.e. amplitude, acrophase, mesor, up-mesor, down-mesor, rhythmicity coefficient). It also aimed to compare rest-activity rhythm variables of participants with a performance status of 2 vs. 3 on the Eastern Cooperative Oncology Group scale (ECOG) and to evaluate the relationships of sleep-wake cycle parameters with several possible correlates. The sample was composed of 55 community-dwelling cancer patients receiving palliative care with an ECOG of 2 or 3. Circadian parameters were assessed using an actigraphic device for seven consecutive 24-h periods. A light recording and a daily pain diary were completed for the same period. A battery of self-report scales was also administered. A dampened circadian rhythm, a low mean activity level, an early mean time of peak activity during the day, a late starting time of activity during the morning and an early time of decline of activity during the evening were observed. In addition, a less rhythmic sleep-wake cycle was associated with a shorter time to death (from the first home visit) and with a lower 24-h light exposure. Sleep wake cycles are markedly disrupted in palliative cancer patients, especially, near the end of life. Effective non-pharmacological interventions are needed to improve patients' circadian rhythms, including perhaps bright light therapy. PMID- 29144173 TI - Chronotype regulates the neural basis of response inhibition during the daytime. AB - Studies have elucidated the various modulatory effects of chronotype and time-of day on task-dependent brain activity, but it is unclear how chronotype and time of-day regulate brain activity in response inhibition tasks. To address this question, we used functional magnetic resonance imaging (fMRI) to explore the effects of chronotype and time-of-day on response inhibition in normal day-night conditions. Morning-type (MT) and evening-type (ET) participants conducted the stop-signal task in morning (08:00-12:00 hours) and evening (19:00-23:00 hours) sessions. The results showed that inhibition-related cerebral responses in the medial frontal gyrus (MFG), middle cingulate cortex (MCC), thalamus and other typical regions for the execution of response inhibition significantly decreased from morning to evening in MT participants, whereas activity in the right inferior frontal gyrus (IFG)/insula, MFG, MCC and thalamus remained stable or increased in ET participants. The chronotypical differences in homeostatic sleep pressure may explain the observed individual differences in maintaining cognition related cortical activation. These results suggest the importance of considering chronotype and time-of-day in the design and analysis of cognitive neuroscience studies. PMID- 29144174 TI - Secondary metabolites from Triclisia gilletii (De Wild) Staner (Menispermaceae) with antimycobacterial activity against Mycobacterium tuberculosis. AB - Triclisinone (2), a new ochnaflavone derivative, was isolated from the aerial parts of Triclisia gilletii, along with known drypemolundein B (1) and eight other known compounds. The chemical shifts of drypemolundein B (1) have been partially revised based on reinterpretation of NMR spectroscopic data. The eight other secondary metabolites are composed of: (+)-nonacosan-10-ol (3); stigmasterol (4), 3-O-beta-D-glucopyranosylsitosterol (5), 3-O-beta-D glucopyranosylstigmasterol (6); oleanic acid (7); myricetin (8), quercetin (9) and 3-methoxyquercetin (10). Their structures were elucidated using IR, MS, NMR 1D and 2D, 1H and 13C and comparison with literature data. Furthermore, compounds 1, 2, 5, 6, 8, 9 and the crude extract were tested against Mycobacterium tuberculosis. Compounds 1, 2, 8 and 9 displayed moderate to very good activity against resistant strain (codified AC 45) of M. tuberculosis with minimum inhibitory concentrations MICs ranging from 3.90 to 62.5 MUg/mL. PMID- 29144176 TI - Correction to: van Bergen, The men with broken faces. Gueules cassees of the first world war. PMID- 29144175 TI - Pregnancy associated plasma protein-A as a prognostic biomarker of all-cause mortality and cardiovascular events in patients presenting with chest pain: a systematic review. AB - AIM: Novel biomarkers have been proposed for identification of patients at greater risk of future adverse events among those presenting with chest pain. In this review, we aim to elucidate the ability of pregnancy associated plasma protein-A (PAPP-A) to predict mortality and other cardiovascular events in this patient population. METHODS: A literature search of the electronic databases Medline, Scopus, Cochrane Library and ClinicalTrials.gov was performed in order to identify studies investigating the utility of PAPP-A to predict mortality and adverse cardiovascular events in patients with chest pain. RESULTS: Eight studies met our inclusion criteria. Five of these studies pertained to patients with confirmed ischemic chest pain, while the rest included patients presenting with chest pain possibly due to acute coronary syndrome, irrespectively of the underlying cause. Although the results for long-term events were inconclusive in both groups of patients, higher PAPP-A concentrations were found to be a significant predictor of short-term adverse events in patients with confirmed ischemic chest pain. CONCLUSIONS: PAPP-A appears to be a potentially useful biomarker for short-term risk stratification of patients presenting with chest pain of ischemic origin. However, there is an eminent need for more standardized clinical studies investigating the prognostic value of this biomarker. PMID- 29144177 TI - Eudesmane and aromadendrane sesquiterpenoids from the Vietnamese soft coral Sinularia erecta. AB - Using various chromatographic separations, eight sesquiterpenoids (1-8), including one new compound 3beta,5alpha-dihydroxyeudesma-4(15),11-diene (1), were isolated from the MeOH extract of the Vietnamese soft coral Sinularia erecta. The structure elucidation was confirmed by spectroscopic experiments including 1D and 2D NMR and HR-ESI-MS. The cytotoxic activities against three human cancer cell lines (A-549, HeLa and PANC-1) of all isolated compounds were evaluated by MTT based colorimetric assays. Compound 1 exhibited selective cytotoxicity against the A549 cell line with IC50 of 14.79 +/- 0.91 MUM. PMID- 29144178 TI - Influence of a dosing-time on toxicities induced by docetaxel, cisplatin and 5 fluorouracil in patients with oral squamous cell carcinoma; a cross-over pilot study. AB - Docetaxel, cisplatin plus fluorouracil (DCF) regimen is a useful chemotherapy, but is sometimes withdrawn due to severe adverse effects (AE). In this study, we examined whether the chronotherapy of DCF regimen could reduce the drugs-induced toxicities in clinical practice. Patients with oral squamous cell carcinoma were enrolled. Chemotherapy started at 10:30 (Morning-dosing) or 18:30 (Evening dosing) for 5 days by a cross-over design. AE were assessed for 14 days after an initiation of each dosing. The grades of nausea, vomiting and neutropenia were smaller during Evening-dosing than during Morning-dosing. These data suggest that the chrono-chemotherapy might provide a merit for reducing the DCF regimen related severe AE. PMID- 29144179 TI - Effects of Active Immunization Against Akirin2 on Muscle Fiber-type Composition in Pigs. AB - The objective of this study was to investigate effects of active immunization against Akirin2 on muscle fiber-type composition in pigs. Here we showed that the titer of Akirin2 antibody in pigs immunized with porcine Akirin2 (pAkirin2) was significantly increased. Active immunization against pAkirin2 decreased succinic dehydrogenase and malate dehydrogenase activities and increased lactate dehydrogenase activity in the longissimus dorsi muscle of pigs. Active immunization against pAkirin2 significantly decreased MyHC I and MyHC IIa mRNA expressions and MyHC I protein expression and increased mRNA expressions of MyHC IIb as well as protein expressions of MyHC IIb and fast-MyHC. mRNA expressions of nuclear factors of activated T cells c1 (NFATc1), transcriptional coactivator PPARgamma coactivator-1alpha, myocyte enhancer factor 2C, and modulatory calcineurin interacting protein 1 exon 4 isform were also notably decreased by active immunization against pAkirin2. Together, our data imply that active immunization against pAkirin2 may result in a slow to fast fiber-type shift in pigs, and which may be mediated by suppression of the calcineurin/NFATc1 signaling pathway. PMID- 29144180 TI - Intraoperative Hemodynamic Instability and Diagnosis of Pheochromocytoma During Excision of Adrenal Incidentaloma With Incomplete Workup: A Case Report. AB - Preoperative evaluation of incidentalomas for pheochromocytoma is imperative. This case report describes a scheduled adrenalectomy in an asymptomatic patient with what was eventually determined to be an incomplete biochemical workup. The intraoperative course was complicated by labile and rapid increases in blood pressure and heart rate, suggesting the missed diagnosis of pheochromocytoma. It is important for anesthesiologists to ensure adequate preoperative biochemical workup before excluding the possibility of coexisting pheochromocytoma. PMID- 29144181 TI - The Prevalence of Amblyopia and Its Determinants in a Population-based Study. AB - PURPOSE: To determine the prevalence of amblyopia and its determinants in a population-based study in Mashhad County, Iran. METHODS: This cross-sectional, population-based study was conducted on the population of Mashhad County aged >1 year using randomized stratified cluster sampling. Examinations were performed after selection of the participants and their free transportation to the sampling site. The examinations included the measurement of uncorrected and corrected visual acuity, cycloplegic and non-cycloplegic refraction, cover testing, slit lamp biomicroscopy, and ophthalmoscopy. In this study, amblyopia was defined as best corrected visual acuity (BCVA) of 20/30 or less or 2-line interocular optotype acuity differences with no pathology. RESULTS: After considering the exclusion criteria, the data of 2739 individuals, 65.6% of whom were women, were analyzed. The mean age of the participants was 29.5+/-17.5 years. The prevalence of amblyopia was 4.6% (95% CI: 3.77%-5.43%) in the total population. The lowest prevalence was 2.24% in the age group 5-15 years (95% CI: 0.99%-3.48%) and the highest prevalence was 7.14% in the age group 55-65 years (95% CI: 2.64%-11.56%). Anisometropic amblyopia was observed in 45.24% of the amblyopic participants. Isometropic, mixed (strabismic/anisometropic), and strabismic amblyopia were other common causes of amblyopia, with a prevalence of 24.6%, 16.67%, and 13.49% in amblyopic patients, respectively. The odds ratio (OR) of having amblyopia for each 1-year increase in age was 1.02 (95% CI: 1.01-1.03). Amblyopia was less common in people with better socioeconomic status. CONCLUSION: This study showed the prevalence of amblyopia in all age groups in a population-based study for the first time. The findings of this study regarding the relatively high prevalence of amblyopia in the older population and its lower prevalence in young people indicate attention to amblyopia in recent years. PMID- 29144182 TI - Plasma-Lyte 148 vs. Hartmann's solution for cardiopulmonary bypass pump prime: a prospective double-blind randomized trial. AB - BACKGROUND: The mechanisms of acid-base changes during cardiopulmonary bypass (CPB) remain unclear. We tested the hypothesis that, when used as CPB pump prime solutions, Plasma-Lyte 148 (PL) and Hartmann's solution (HS) have differential mechanisms of action in their contribution to acid-base changes. METHODS: We performed a prospective, double-blind, randomized trial in adult patients undergoing elective cardiac surgery with CPB. Participants received a CPB prime solution of 2000 mL, with either PL or HS. The primary endpoint was the standard base excess (SBE) value measured at 60 minutes after full CPB flows (SBE60min). Secondary outcomes included changes in SBE, pH, chloride, sodium, lactate, gluconate, acetate, strong ion difference and strong ion gap at two (T2min), five (T5min), ten (T10min), thirty (T30min) and sixty (T60min) minutes on CPB. The primary outcome was measured using a two-tailed Welch's t-test. Repeated measures ANOVA was used to test for differences between time points. RESULTS: Twenty-five participants were randomized to PL and 25 to HS. Baseline characteristics, EURO and APACHE scores, biochemistry, hematology and volumes of cardioplegia were similar. Mean (SD) SBE at T60min was -1.3 (1.4) in the PL group and -0.1 (2.7) in the HS group; p=0.55. No significant differences in SBE between the groups was observed during the first 60 minutes (p=0.48). During CPB, there was hyperacetatemia and hypergluconatemia in the PL group and hyperlactatemia and hyperchloremia in the HS group. No significant difference between the groups in plasma bicarbonate levels and total weak acid levels were found. Complications and intensive care unit and hospital length of stays were similar. CONCLUSIONS: During CPB, PL and HS did not cause a significant metabolic acidosis. There was hyperacetatemia and hypergluconatemia with PL and hyperchloremia and hyperlactatemia with HS. These physiochemical effects appear clinically innocuous. PMID- 29144183 TI - Age and rest-activity rhythm as predictors of survival in patients with newly diagnosed lung cancer. AB - Disruption of the rest-activity rhythm in patients with lung cancer can accelerate cancer progression and affect survival. Rest-activity rhythm changes with age. Therefore, we investigated the effects of rest-activity rhythm and age on patients' survival. A total of 84 patients with lung cancer were recruited, then separated into two groups; younger patients aged under 65 years or elderly patients aged 65 and over. The dichotomy index (I < O) was used to estimate the rest-activity rhythm measured through the actigraphy motion detector. Cox proportional hazards models were adopted to investigate the effects of different variables on the patients' survival. After adjusting for confounding, the risk of earlier mortality in the younger patients with disrupted I < O were 2.52 (95%CI = 1.09-5.82) times higher than that in the younger patients with robust I < O (p = 0.03), the risk of earlier mortality in the elderly patients with disrupted I < O was 4.08 (95%CI = 1.91-8.68) times higher than that in the elderly patients with robust I < O (p < 0.001). Therefore, age and I < O influence the survival period of patients with lung cancer. Moreover, disrupted I < O has a substantial influence on elderly patients. In conclusion, aging and disrupted rest-activity rhythm negatively and jointly influenced the survival period of the patients with lung cancer and significantly increased their death risk. PMID- 29144185 TI - Rest-activity circadian rhythm and sleep quality in patients with binge eating disorder. AB - Recent findings suggest that altered rest-activity circadian rhythms (RARs) are associated with a compromised health status. RARs abnormalities have been observed also in several pathological conditions, such as cardiovascular, neurological, and cancer diseases. Binge eating disorder (BED) is the most common eating disorder, with a prevalence of 3.5% in women and 2% in men. BED and its associate obesity and motor inactivity could induce RARs disruption and have negative consequences on health-related quality of life. However, the circadian RARs and sleep behavior in patients with BED has been so far assessed only by questionnaires. Therefore, the purpose of this study was to determine RARs and sleep parameters by actigraphy in patients with BED compared to a body mass index matched control group (Ctrl). Sixteen participants (eight obese women with and eight obese women without BED diagnosis) were recruited to undergo 5-day monitoring period by actigraphy (MotionWatch 8(r), CamNtech, Cambridge, UK) to evaluate RARs and sleep parameters. In order to determine the RARs, the actigraphic data were analyzed using the single cosinor method. The rhythmometric parameters of activity levels (MESOR, amplitude and acrophase) were then processed with the population mean cosinor. The Actiwatch Sleep Analysis Software (Cambridge Neurotecnology, Cambridge, UK) evaluated the sleep patterns. In each participant, we considered seven sleep parameters (sleep onset: S-on; sleep offset: S-off; sleep duration: SD; sleep latency: SL; movement and fragmentation index: MFI; immobility time: IT; sleep efficiency: SE) calculated over a period of five nights. The population mean cosinor applied to BED and Ctrl revealed the presence of a significant circadian rhythm in both groups (p < 0.001). The MESOR (170.0 vs 301.6 a.c., in BED and Ctrl, respectively; p < 0.01) and amplitude (157.66 vs 238.19 a.c., in BED and Ctrl, respectively p < 0.05) differed significantly between the two groups. Acrophase was not different between BED and Ctrl, as well as all sleep parameters. Both groups displayed a low level of sleep quality (SE 80.7% and 75.7% in BED and Ctrl, respectively). These data provided the first actigraphy-based evidence of RARs disruption and sleep behavior disorder in patients with BED. However, while sleep disorders could be reasonably ascribed to overweight/obesity and the related lower daily physical activity, RARs disruption in this pathology should be ascribed to factors other than reduced physical activity. The circadian timing approach can represent a novel potential tool in the treatment of patients with eating disorders. These data provide exploratory evidence of behavioral association in a small population of patients that, if confirmed in a wider number of subjects and across different populations, may lead to a revision and enhancement of interventions in BED patients. PMID- 29144184 TI - Rates and Predictors of Professional Interpreting Provision for Patients With Limited English Proficiency in the Emergency Department and Inpatient Ward. AB - The provision of professional interpreting services in the hospital setting decreases communication errors of clinical significance and improves clinical outcomes. A retrospective audit was conducted at a tertiary referral adult hospital in Brisbane, Australia. Of 20 563 admissions of patients presenting to the hospital emergency department (ED) and admitted to a ward during 2013-2014, 582 (2.8%) were identified as requiring interpreting services. In all, 19.8% of admissions were provided professional interpreting services in the ED, and 26.1% were provided on the ward. Patients were more likely to receive interpreting services in the ED if they were younger, spoke an Asian language, or used sign language. On the wards, using sign language was associated with 3 times odds of being provided an interpreter compared with other languages spoken. Characteristics of patients including their age and type of language spoken influence the clinician's decision to engage a professional interpreter in both the ED and inpatient ward. PMID- 29144186 TI - "The Whole Is Greater Than the Sum of the Parts": Prison Staff Perceptions of Domestic Violence Rehabilitation Programs. AB - This qualitative study is part of a mixed methods research project that examined the effectiveness of the primary rehabilitation program for domestic violence offenders in the Israeli Prison Services-the "House of Hope." The quantitative part of the study showed that the "House of Hope" program was effective in reducing recidivism among participating inmates. The purpose of this qualitative study was to describe the rehabilitation program according to the perspectives of the program staff. For this purpose, semistructured interviews were conducted with the department staff during the study as well as with past directors. The qualitative findings suggested that the success of the program probably stemmed from a synergistic combination of several components, for example, identifying the characteristics of domestic violence offenders and adjusting treatment programs to their needs, along with exposure to psychological treatment in varied therapies (cognitive behavioral therapy, psychoeducational, and psychodynamic) and formats (group therapy and individual therapy) during a 1-year stay in a hierarchical therapeutic community. Other components mentioned are staff professionalism, stability, and the program's location in a therapeutic-oriented prison that is architecturally designed and built to create a less stressful environment for the inmates and the staff. PMID- 29144188 TI - Corrigendum. PMID- 29144187 TI - Indispensable Points for Research on Antiadhesion Materials. AB - To prevent postoperative abdominal adhesions, many new antiadhesion materials have been developed all over the world. Few studies have analyzed the thickness of antiadhesive materials, but it is an important factor in maximizing adhesion prevention. The aspect of material thickness will needed for the future studies. However, few materials proceeded further than animal experimentation. Comparison tests between the newly developed antiadhesion materials and products already on the market will make it easier to conduct clinical trials. Recently, many new technologies are developed in the field of engineering and medical-engineering collaboration achieved some results, such as electrospinning technique. Application of new technologies to the medical field must be accelerated. PMID- 29144189 TI - Clinical and Personality Disorders in a Danish Treatment-Seeking Sample of Intimate Partner Violence Perpetrators. AB - Intimate partner violence (IPV) is a global public health concern with profound psychological consequences. Perpetrators often have a history of childhood trauma and a range of co-occurring psychiatric problems, which may have implications for treatment. This study examines the prevalence of psychiatric and personality disorders (PD) among perpetrators and the association between a range of demographic, childhood trauma, and adult criminality variables for the most prominent disorders. Data were collected from IPV perpetrators ( n = 529) engaging in a treatment program, ' Dialogue Against Violence'. High rates of childhood trauma were observed. There was significant variation in the prevalence of clinical disorders and PDs, with Antisocial PD and Anxiety Disorder being the most common. A clinical disorder was the strongest predictor of PDs, likewise a PD was the strongest predictor of clinical disorders. Findings demonstrated that IPV perpetrators have a number of personality and clinical disorders and traumatic histories that need to be considered within a treatment perspective. PMID- 29144190 TI - Factors associated with paternal perinatal depression in fathers of newborns in Nigeria. AB - INTRODUCTION: There is a lack of information on paternal postnatal depression in developing countries such as Nigeria. METHODS: This study aims to assess the prevalence of depression in fathers at the birth of their infants and the incidence of paternal postnatal depression at 6 weeks postpartum. We also examined the correlation between paternal postpartum depression (PPD) at 6 weeks and maternal PPD as well as the sociodemographic and other correlates of paternal PPD at 6 weeks. RESULTS: All the 331 fathers recruited at baseline completed the study. Prevalence of depression in fathers at birth of their babies was 10 (3%). After excluding the 3%, the incidence of PPD in fathers (N = 321) at 6 weeks was 19 (5.9%). In all, 29 (8.8%) fathers had PPD. The prevalence of depression in mothers at 6 weeks postpartum was 57 (17.8%). The prevalence of depression in mothers at 6 weeks was significantly higher than the incidence of depression in fathers at 6 weeks (X2 = 26.2, p < .001). There was no significant correlation between maternal PPD and paternal PPD. At baseline, prevalence of PPD among the unemployed fathers was higher than in the employed, 3 (21.4%) versus 7 (2.2%), this was significant (FE p < .01). There was no significant correlate of paternal PPD at 6 weeks. DISCUSSION: Postpartum mental health services should be extended to fathers of newborns especially those who are unemployed. Our findings have implications for family health. PMID- 29144191 TI - Paternal involvement and support and risk of preterm birth: findings from the Boston birth cohort. AB - OBJECTIVE: To investigate to what extent paternal involvement and support during pregnancy were associated with preterm (PTB) and small-for-gestational age (SGA) births. METHODS: Using data from the Boston Birth Cohort (n = 7047), multiple logistic regression models were performed to estimate the log odds of either PTB or SGA birth, with paternal involvement, paternal social support, and family and friend social support variables as the primary independent variables. RESULTS: About 10% of participating mothers reported their husbands not being involved or supportive during their pregnancies. Lack of paternal involvement was associated with 21% higher risk of PTB (OR = 1.21, 95% CI: 1.01-1.45). Similarly, lack of paternal support was borderline associated with PTB (OR = 1.13, 95% CI: 0.94 1.35). Also marginally significant, lack of paternal involvement (OR = 1.18, 95% CI: 0.95-1.47) and father's support (OR = 1.19, 95% CI: 0.96-1.48) were associated with higher odds of SGA birth. No associations were found between familial and friend support during pregnancy and PTB or SGA. CONCLUSIONS: Among predominantly low-income African Americans, lack of paternal involvement and lack of paternal support during pregnancy were associated with an increased risk of PTB, and suggestive of SGA birth. These findings, if confirmed in future research, underscore the important role a father can play in reducing PTB and/or SGA. PMID- 29144192 TI - Seeding of the mucosal leukocytes in the HALT and trachea of White Leghorn chickens. AB - Characterising the immune cells of the head-associated lymphoid tissues (HALT) and trachea during maturation in young birds is critical to understanding the immunological responses to avian respiratory diseases and vaccines. Selected mucosal leukocytes of the conjunctiva-associated lymphoid tissue (CALT), Harderian gland (HG), nasal-associated lymphoid tissue (NALT) and trachea from 4 , 6-, 8-, and 10-week-old chickens were enumerated and phenotyped. HG, NALT, and trachea cellularity increased as the birds aged with cell viability varying by tissue. The results showed that the T cell subset numbers, but not B cell numbers, increased in the mucosal tissues of chickens during aging. PMID- 29144193 TI - Typhi colonization factor (Tcf) genetically conserved yet functionally diverse. PMID- 29144194 TI - An Integrative Behavioral Health Care Model Using Automated SBIRT and Care Coordination in Community Health Care. AB - Efficient and effective integration of behavioral health programs in a community health care practice emphasizes patient-centered medical home principles to improve quality of care. A prospective, 3-period, interrupted time series study was used to explore which of 3 different integrative behavioral health care screening and management processes were the most efficient and effective in prompting behavioral health screening, identification, interventions, and referrals in a community health practice. A total of 99.5% ( P < .001) of medical patients completed behavioral health screenings; brief intervention rates nearly doubled to 83% ( P < .001) and 100% ( P < .001) of identified at-risk patients had referrals made using a combination of electronic tablets, electronic medical record, and behavioral health care coordination. PMID- 29144195 TI - Extraction, purification of prostate-specific antigen (PSA), and establishment of radioimmunoassay system as a diagnostic tool for prostate disorders. AB - This study aimed to provide an easy and effective method for extraction and purification of prostate-specific antigen (PSA) from human seminal fluid with high quantity (14 mg) and high purity (98%). The obtained PSA was injected into rabbits for production of anti-PSA polyclonal antibody (titer 1/1000), labeled with radioactive iodine-125 for preparation of radioactive PSA tracer (purity 98 +/- 1.8% and specific activity 64 +/- 1.9 uCi/ug), and used in preparation of PSA standards. All prepared components can be used in PSA immunoassays specially radioimmunoassay (RIA) kit preparation as a diagnostic tool for prostatic diseases. PMID- 29144196 TI - Quantitative weight of evidence assessment of higher tier studies on the toxicity and risks of neonicotinoids in honeybees. 3. Clothianidin. AB - A quantitative weight of evidence (QWoE) methodology was used to assess higher tier studies on the effects of clothianidin (CTD) on honeybees. Assessment endpoints were population size and viability of commercially managed bees and quantity of hive products. A colony-level no-observed-adverse effect concentration (NOAEC) of 25 ug CTD/kg syrup, equivalent to an oral no-observed adverse effect-dose (NOAED) of 7.3 ng/bee/d for all responses measured. Based on a NOAEC of 19.7 ug/kg pollen, the NOAED for honeybee larvae was 2.4 ng/bee larva/d. For exposures via dust, a no-observed-adverse effect rate of 4 g CTD/ha was used to assess relevance of exposures via deposition of dust. The overall weight of evidence suggested that there is minimal risk to honeybees from exposure to CTD from its use as a seed treatment. For exposures via dust, dust/seed and dust/foliar applications, there were no exposures greater than the NOAED for CTD in nectar and pollen, indicating a de minimis risk to honeybees when the route of exposure was via uptake in plants. Analysis of effect studies in the field indicated a consistent lack of relevant effects, regardless of the way CTD was applied. For exposures via dust, there were no adverse effects because of these applications and there were no exposures greater than the NOAED for CTD in nectar and pollen. The overall weight of evidence based on many studies indicated no adverse effects on colony viability or survival of the colony. Thus, the overall conclusion is that clothianidin, as currently used in good agricultural practices, does not present a significant risk to honeybees at the level of the colony. PMID- 29144197 TI - Evaluation of UMELISA(r) T4 NEONATAL and UMELISA(r) T4 using polystyrene plates coated with anti-thyroxine (T4) monoclonal antibodies. AB - : Congenital hypothyroidism is one of the most common preventable causes of mental retardation. The Center of Immunoassay has developed the UMELISA(r) T4 NEONATAL and UMELISA(r) T4 to determine neonatal T4 levels in dried blood and serum samples. Both reagent kits use the same polystyrene plates coated with anti thyroxine (T4) polyclonal antibodies as solid phase. This work shows the re standardization of the UMELISA(r) T4 NEONATAL and UMELISA(r) T4 using plates coated with anti-T4 monoclonal antibodies (T4Mabs). Polystyrene plates of the modified assays were firstly coated with polyclonal IgG sheep-anti-mouse IgG for 18 hours. T4Mabs were added to the plates and incubated for 2 hours at room temperature. Different performance parameters were evaluated and correlation studies with the commercial kits done. Using polystyrene plates coated with T4Mabs increases the slope of the calibration curve in the clinical interest zone. The assay conjugates work twice diluted in respect to the ones of the commercial kits. Recovery percentages (90.8-110.7 for UMELISA(r) T4 NEONATAL and 92.1-109.3 for UMELISA(r) T4) and intra (7.2-7.6 for UMELISA(r) T4 NEONATAL and 6.9-7.2 for UMELISA(r) T4) and inter (7.4-8.5 for UMELISA(r) T4 NEONATAL and 7.1 8.5 for UMELISA(r) T4) coefficients of variation were similar to the ones described for the commercial kits. Limits of detection and quantification were 9.0 and 21.1 nmol/L for UMELISA(r) T4 NEONATAL, and 8.9 and 20.5 nmol/L for UMELISA(r) T4, respectively. The results also showed high overall concordance between assays (n = 244, r = 0.92, rhoc = 0.91 for UMELISA(r) T4 NEONATAL and n = 492, r = 0.92, rhoc = 0.9 for UMELISA(r) T4). The analytical sensibility of UMELISA(r) T4 NEONATAL and UMELISA(r) T4 is improved by using polystyrene plates coated with T4Mabs, without affecting the precision and accuracy of the results. ABBREVIATIONS: T4: L-Thyroxine; ELISA: Enzyme-linked immunosorbent assay; SUMA: Ultra Micro Analytic System; UMELISA: Ultramicro enzyme-linked immunosorbent assay; TSH: Thyroid-stimulating hormone. PMID- 29144198 TI - Development of novel fluorescent particles applicable for phagocytosis assays with human macrophages. AB - Phagocytosis is a fundamental process for removal of pathogens and for clearance of apoptotic cells. The objective of this work was the preparation of fluorescent microspheres by a simple method and the evaluation of its applicability in phagocytosis assays by using different human derived cells, differentiated THP-1 cell line and blood monocytes, with flow cytometry measurements for functionality assays. Our results show that microparticles are efficiently internalised in a non-opsonised form and in dose-dependent manner by both cellular types. Concerning mechanism we determined that tTG-beta3 integrin signaling could be involved in the uptake of these particles. PMID- 29144199 TI - Effect of High Hydrostatic Pressure Applied Before Cryopreservation on the Survival Rate and Quality of Porcine Mesenchymal Stem Cells After Thawing. AB - : The aim of the present study was to examine the effects of varied high hydrostatic pressure (HHP) values on survival rate, proliferation rate, cell multipotency (transcript expression of SOX2, C-MYC, and REX1) and apoptosis (expression of phosphatidylserine (PS), SURVIVIN at the RNA level and BAX at the protein level) of porcine mesenchymal stem cells (MSCs). MSCs were isolated from porcine bone marrow and cultured in vitro. Before cryopreservation and storage in liquid nitrogen, MSCs were subjected to HHP at the varied pressures of 20, 30, 40, 50, or 60 MPa for 1 h at 24 degrees C. Immediately after thawing and after 8 days of in vitro culture, cells were subjected to trypan blue staining, cell counting, real-time Polymerase Chain Reaction (PCR), western blotting, and fluorescence microscopy. BAX protein expression was only estimated immediately after HHP to exclusively examine the impact of HHP on apoptosis of MSCs. The viability of MSC subjected to 40, 50, and 60 MPa and estimated immediately after thawing increased significantly (P < 0.001 for 60 MPa and P < 0.05 for 40 and 50 MPa) in comparison to control. The proliferation rate of MSCs subjected to 40 MPa HHP was significantly higher than in the control group (P < 0.02) after 8 days of in vitro culture. After 8 days of in vitro culture, no significant differences were noted in the survival rates, PS exposure, or levels of SOX2, C-MYC, REX1, and SURVIVIN gene expression in all analyzed groups compared to control. IN CONCLUSION: 40-60 MPa HHP has a positive impact by improving cell viability in short term. 20-60 MPa HHP does not induce nor decrease apoptosis in MSCs. Fortunately, HHP does not induce differentiation of MSC. Our results calls for further analysis using HHP values higher than 60 MPa. PMID- 29144200 TI - Mechanisms underlying melatonin-mediated prevention of fenvalerate-induced behavioral and oxidative toxicity in zebrafish. AB - The neurotoxic effects attributed to the pesticide fenvalerate (FEN) are well established. The aim of this study was to determine whether melatonin (MLT) was able to protect against FEN-induced behavior, oxidative stress, apoptosis, and neurogenesis using zebrafish (Danio rerio) model. Zebrafish exposed to 100 MUg/L FEN for 120 h exhibited decreased swimming activity accompanied by downregulated expression of neurogenesis-related genes (Dlx2, Shha, Ngn1, Elavl3, and Gfap), suggesting that neurogenesis were impaired. In addition, FEN exposure significantly elevated oxidative stress as evidenced by increased malondialdehyde levels, as well as activities of Cu/Zn superoxide dismutase (Cu/Zn SOD), catalase, and glutathione peroxidase. Acridine orange staining demonstrated that embryos treated with FEN for 120 h significantly enhanced apoptosis mainly in the brain. FEN also produced upregulation of the expression of the pro-apoptotic genes (Bax, Fas, caspase 8, caspase 9, and caspase 3) and decreased expression of the anti-apoptotic gene Bcl-2. MLT significantly attenuated the FEN-mediated oxidative stress, modulated apoptotic-regulating genes, and diminished apoptotic responses. Further, MLT blocked the FEN-induced effects on swimming behavior as well as on neurogenesis-related genes. In conclusion, MLT protected against FEN induced developmental neurotoxicity and apoptosis by inhibiting pesticide mediated oxidative stress in zebrafish. PMID- 29144201 TI - Brucella Lipopolysaccharide and pathogenicity: The core of the matter. PMID- 29144202 TI - A glimpse into the future - new therapeutic targets could transform the way we treat staphylococcal infections. PMID- 29144203 TI - Suppression or Activation of Immune Responses by Predicted Secreted Proteins of the Soybean Rust Pathogen Phakopsora pachyrhizi. AB - Rust fungi, such as the soybean rust pathogen Phakopsora pachyrhizi, are major threats to crop production. They form specialized haustoria that are hyphal structures intimately associated with host-plant cell membranes. These haustoria have roles in acquiring nutrients and secreting effector proteins that manipulate host immune systems. Functional characterization of effector proteins of rust fungi is important for understanding mechanisms that underlie their virulence and pathogenicity. Hundreds of candidate effector proteins have been predicted for rust pathogens, but it is not clear how to prioritize these effector candidates for further characterization. There is a need for high-throughput approaches for screening effector candidates to obtain experimental evidence for effector-like functions, such as the manipulation of host immune systems. We have focused on identifying effector candidates with immune-related functions in the soybean rust fungus P. pachyrhizi. To facilitate the screening of many P. pachyrhizi effector candidates (named PpECs), we used heterologous expression systems, including the bacterial type III secretion system, Agrobacterium infiltration, a plant virus, and a yeast strain, to establish an experimental pipeline for identifying PpECs with immune-related functions and establishing their subcellular localizations. Several PpECs were identified that could suppress or activate immune responses in nonhost Nicotiana benthamiana, N. tabacum, Arabidopsis, tomato, or pepper plants. PMID- 29144204 TI - Specific Hypersensitive Response-Associated Recognition of New Apoplastic Effectors from Cladosporium fulvum in Wild Tomato. AB - Tomato leaf mold disease is caused by the biotrophic fungus Cladosporium fulvum. During infection, C. fulvum produces extracellular small secreted protein (SSP) effectors that function to promote colonization of the leaf apoplast. Resistance to the disease is governed by Cf immune receptor genes that encode receptor-like proteins (RLPs). These RLPs recognize specific SSP effectors to initiate a hypersensitive response (HR) that renders the pathogen avirulent. C. fulvum strains capable of overcoming one or more of all cloned Cf genes have now emerged. To combat these strains, new Cf genes are required. An effectoromics approach was employed to identify wild tomato accessions carrying new Cf genes. Proteomics and transcriptome sequencing were first used to identify 70 apoplastic in planta-induced C. fulvum SSPs. Based on sequence homology, 61 of these SSPs were novel or lacked known functional domains. Seven, however, had predicted structural homology to antimicrobial proteins, suggesting a possible role in mediating antagonistic microbe-microbe interactions in planta. Wild tomato accessions were then screened for HR-associated recognition of 41 SSPs, using the Potato virus X-based transient expression system. Nine SSPs were recognized by one or more accessions, suggesting that these plants carry new Cf genes available for incorporation into cultivated tomato. PMID- 29144205 TI - Lessons in Effector and NLR Biology of Plant-Microbe Systems. AB - A diversity of plant-associated organisms secrete effectors-proteins and metabolites that modulate plant physiology to favor host infection and colonization. However, effectors can also activate plant immune receptors, notably nucleotide-binding domain and leucine-rich repeat region (NLR)-containing proteins, enabling plants to fight off invading organisms. This interplay between effectors, their host targets, and the matching immune receptors is shaped by intricate molecular mechanisms and exceptionally dynamic coevolution. In this article, we focus on three effectors, AVR-Pik, AVR-Pia, and AVR-Pii, from the rice blast fungus Magnaporthe oryzae (syn. Pyricularia oryzae), and their corresponding rice NLR immune receptors, Pik, Pia, and Pii, to highlight general concepts of plant-microbe interactions. We draw 12 lessons in effector and NLR biology that have emerged from studying these three little effectors and are broadly applicable to other plant-microbe systems. PMID- 29144206 TI - C-Jun expression in lichen planus, psoriasis, and cutaneous squamous cell carcinoma, an immunohistochemical study. AB - : The AP-1 transcription factor complex is a key player in regulating inflammatory processes, cell proliferation, differentiation, and cell transformation. The aim of the present study is to investigate C-Jun (one of AP 1complex) expression and its proliferative role in skin samples of lichen planus, psoriasis as common inflammatory skin diseases and squamous cell carcinoma using immunohistochemical method. The present study was carried out on skin biopsies of 15 psoriatic patients, 15 lichen planus patients, 15 SCC, and 15 normal skin biopsies. Nuclear expression of C-Jun was detected in basal and few suprabasal layers of epidermis of normal skin. C-Jun was expressed in the whole epidermal layers of both psoriasis (14/15) and lichen planus (15/15) in addition to its expression in lymphocytic infiltrate in the latter in about half of cases (8/15). C-Jun was also expressed in 93.3% (14/15) of SCC in a percentage lower than that of psoriasis, lichen planus, and normal skin. The percentage of C-Jun expression in SCC was significantly associated with an early stage (p = 0.000), free surgical margins (p = 0.022), and small tumour size (p = 0.003). CONCLUSIONS: The marked reduction of C-Jun in SCC in comparison to normal skin and inflammatory skin dermatoses may refer to its tumour suppressor activity. C-Jun expression in SCC carries favourable prognosis. Absence of significant association between C Jun and Ki-67 either in SCC or inflammatory skin diseases indicates that it does not affect proliferative capacity of cells. PMID- 29144207 TI - Exploring physical activity behaviour - needs for and interest in a technology delivered, home-based exercise programme among patients with intermittent claudication. AB - BACKGROUND: Supervised walking is a first line therapy in peripheral arterial disease (PAD) with complaints of intermittent claudication. However, uptake of supervised programmes is low. Home-based exercise seems an appealing alternative; especially since technological advances, such as tele-coaching and tele monitoring, may facilitate the process and support patients when adopting a physically active lifestyle. To guide the development of such an intervention, it is important to identify barriers of physical activity and the needs and interests for technology-enabled exercise in this patient group. PATIENTS AND METHODS: PAD patients were recruited at the vascular centre of UZ Leuven (Belgium). A questionnaire assessing PA (SF-International Physical Activity Questionnaire), barriers to PA, and interest in technology-supported exercise (Technology Usage Questionnaire) was completed. Descriptive and correlation analyses were performed. RESULTS: Ninety-nine patients (76 men; mean age 69 years) completed the survey. Physical activity levels were low in 48 %, moderate in 29 %, and high in 23 %. Intermittent claudication itself is the most important barrier for enhanced PA, with most patients reporting pain (93 %), need for rest (92 %), and obstacles worsening their pain (74 %) as barriers. A total of 93 % participants owned a mobile phone; 76 % had Internet access. Eighty-seven reported the need for an exercise programme, with 67 % showing interest in tele coaching to support exercise. If technology was available, three-quarter stated they would be interested in home-based tele-coaching using the Internet (preferably e-mails, 86 %); 50 % via mobile phone, 87 % preferred text messages. Both were inversely related to age (rpb = 0.363 and rpb = 0.255, p < 0.05). Acquaintance with elastic bands or gaming platforms was moderate (55 and 49 %, respectively), but patients were interested in using them as alternatives (84 and 42 %). Interest in platforms was age-dependent (rs = -0.508, p < 0.01). CONCLUSIONS: PAD patients show significant interest in technology-delivered exercise, offering opportunities to develop a guided home-based exercise programme. PMID- 29144208 TI - High-throughput sequencing of kDNA amplicons for the analysis of Leishmania minicircles and identification of Neotropical species. AB - Leishmania kinetoplast DNA contains thousands of small circular molecules referred to as kinetoplast DNA (kDNA) minicercles. kDNA minicircles are the preferred targets for sensitive Leishmania detection, because they are present in high copy number and contain conserved sequence blocks in which polymerase chain reaction (PCR) primers can be designed. On the other hand, the heterogenic nature of minicircle networks has hampered the use of this peculiar genomic region for strain typing. The characterization of Leishmania minicirculomes used to require isolation and cloning steps prior to sequencing. Here, we show that high throughput sequencing of single minicircle PCR products allows bypassing these laborious laboratory tasks. The 120 bp long minicircle conserved region was amplified by PCR from 18 Leishmania strains representative of the major species complexes found in the Neotropics. High-throughput sequencing of PCR products enabled recovering significant numbers of distinct minicircle sequences from each strain, reflecting minicircle class diversity. Minicircle sequence analysis revealed patterns that are congruent with current hypothesis of Leishmania relationships. Then, we show that a barcoding-like approach based on minicircle sequence comparisons may allow reliable identifications of Leishmania spp. This work opens up promising perspectives for the study of kDNA minicercles and a variety of applications in Leishmania research. PMID- 29144209 TI - Bidirectional associations between body dissatisfaction and depressive symptoms from adolescence through early adulthood. AB - Body dissatisfaction and depressive symptoms are commonly experienced during adolescence and increase the risk of adverse health outcomes, especially eating disorders. However, the dominant temporal associations between these two experiences (i.e., whether one is a risk factor for the other or the two are mutually reinforcing) has yet to be fully explored. We examined the associations between body dissatisfaction and depressive symptoms assessed at baseline and 5- and 10-year follow-up in younger (M age = 12.9 years at baseline, 56% female, n = 577) and older (M age = 15.9 years at baseline, 57% female, n = 1,325) adolescent cohorts assessed as part of Project Eating Among Teens and Young Adults. Associations between body dissatisfaction and depressive symptoms were examined using cross-lagged models. For females, the dominant directionality was for body dissatisfaction predicting later depressive symptoms. For males, the picture was more complex, with developmentally sensitive associations in which depressive symptoms predicted later body dissatisfaction in early adolescence and early adulthood, but the reverse association was dominant during middle adolescence. These findings suggest that interventions should be tailored to dynamic risk profiles that shift over adolescence and early adulthood, and that targeting body dissatisfaction at key periods during development may have downstream impacts on depressive symptoms. PMID- 29144210 TI - A new allele of the kappa-casein gene in local zebu cattle breeds. PMID- 29144211 TI - Plasmodium knowlesi: experimental model, zoonotic pathogen and golden opportunity? PMID- 29144212 TI - Morphological and molecular characterization of two new species of Andracantha (Acanthocephala: Polymorphidae) from New Zealand shags (Phalacrocoracidae) and penguins (Spheniscidae) with a key to the species. AB - Two new species of Andracantha (Polymorphidae) are described from the intestine of the shags Leucocarbo chalconotus (Gray) and Phalacrocorax punctatus (Sparrman), and the penguin Eudyptula minor (Forster) from southern South Island, New Zealand. Andracantha leucocarboi n. sp. is distinguished from its congeners by having no genital or ventral trunk spines, but possessing a scattering of small spines between the anterior fields of spines. This is the first record of a species of Andracantha from a penguin. Circumbursal papillae are illustrated in a scanning electron micrograph for the first time in the polymorphids. Andracantha sigma n. sp. is distinguished by the sigmoid shape of its largest proboscis hook, hook VIII, and having the ventral field separated from the posterior disc field by an aspinous gap. A Maximum Likelihood tree from cox1 and large ribosomal subunit (LSU) data shows A. leucocarboi n. sp. to be more closely related to A. gravida than A. sigma n. sp. and the genus Andracantha as sister to Corynosoma spp. Genetic distances between species of Andracantha are comparatively large. A key to the species of Andracantha is provided. PMID- 29144213 TI - Timely trigger of caterpillar zombie behaviour: temporal requirements for light in baculovirus-induced tree-top disease. AB - Host behavioural manipulation is a common strategy used by parasites to enhance their survival and/or transmission. Baculoviruses induce hyperactivity and tree top disease (pre-death climbing behaviour) in their caterpillar hosts. However, little is known about the underlying mechanisms of this behavioural manipulation. A previous study showed that the baculovirus Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV) induced tree-top disease at 3 days post infection in third instar S. exigua larvae and that light plays a key role in triggering this behaviour. Here we investigated the temporal requirements for the presence of light to trigger this behaviour and found that light from above was needed between 43 and 50 h post infection to induce tree-top disease. Infected larvae that were not exposed to light from above in this period finally died at low positions. Exposure to light prior to this period did not affect the final positions where larvae died. Overall we conclude that light in a particular time frame is needed to trigger SeMNPV-induced tree-top disease in S. exigua larvae. PMID- 29144214 TI - Circadian rhythms of trematode parasites: applying mixed models to test underlying patterns. AB - Circadian rhythms of parasites and their hosts can influence processes such as transmission, pathology and life cycle evolution. For trematode parasites that depend on free-living infectious stages (i.e. cercariae) to move among host species, the timing of parasite release is hypothesized to increase the likelihood of contacting a host. Yet, a persistent challenge in studying such biorhythms involves selection of appropriate analytical techniques. Here, we extend a generalized linear mixed modelling (GLMM) framework to cosinor analyses, thereby allowing flexibility in the statistical distribution of the response variable, incorporation of multiple covariates and inclusion of hierarchical grouping effects. By applying this approach to 93 snails infected with trematode parasites from freshwater pond ecosystems, we detected non-random rhythms in six of eight species, with variation in both the timing of peak cercariae release (between 5:10 and 21:46 h) and its magnitude (between 13 and 386). The use of GLMM yielded more accurate and precise estimates of the cosinor parameters compared with classical least-squares (LS) based on a simulation-based sensitivity analysis. The sensitivity analysis revealed that the amplitude and rhythm-adjusted mean values from the LS models diverged from the true values at some limits. We highlight the importance of novel analytical approaches for evaluating parasite circadian rhythms and investigating their underlying mechanisms. PMID- 29144215 TI - A filtration-based rapid test using a partially purified third-stage larval antigen to detect specific antibodies for the diagnosis of gnathostomiasis. AB - Human gnathostomiasis is an emerging food-borne parasitic disease caused by nematodes of the genus Gnathostoma. Currently, serological tests are commonly applied to support clinical diagnosis. In the present study, a simple and rapid filtration-based test, dot immune-gold filtration assay (DIGFA) was developed using a partially purified antigen of Gnathostoma third-stage larvae (L3). A total of 180 serum samples were tested to evaluate the diagnostic potential of DIGFA for gnathostomiasis. The diagnostic sensitivity and specificity were 96.7% (29/30) and 100% (25/25), respectively. The cross-reactivity with sera from other helminthiasis patients ranged from 0 to 4%, with an average of 1.6% (2/125). DIGFA using a partially purified L3 antigen was not only simple and rapid, but also more accurate than standard assays for the diagnosis of human gnathostomiasis. DIGFA may represent a promising tool for application in laboratories or in the field, without requiring any instrumentation. PMID- 29144216 TI - The truth about in vitro culture of Cryptosporidium species. AB - Cryptosporidium research has focused on the development of infection control, and effective therapy that has thus far been hampered by the inability to culture Cryptosporidium in vitro. Other limitations include inadequate animal models, cumbersome screening procedures for chemotherapeutic approaches and a lack of tools for genetic manipulation. These limitations can, however, be eased by the improvement and focused development of in vitro cultivation. The ability to culture relevant Cryptosporidium isolates in vitro and to propagate the life cycle stages that are responsible for causing disease in an infected host is still a critical link. This ability will facilitate other relevant approaches, e.g., the ability to knockout genes and the application of broader screening for drug discoveries and vaccine developments, in combination with new discoveries on the parasite's basic biology, genetic manipulation and new life cycle stages. Success in this effort represents an essential step towards significant progress in the control of cryptosporidiosis. PMID- 29144217 TI - Mechanisms of naturally acquired immunity to P. falciparum and approaches to identify merozoite antigen targets. AB - Malaria is one the most serious infectious diseases with over 200 million clinical cases annually. Most cases of the severe disease are caused by Plasmodium falciparum. The blood stage of Plasmodium parasite is entirely responsible for malaria-associated pathology. The population most susceptible to severe malaria are children under the age of 5, with low levels of immunity. It is only after many years of repeated exposure that individuals living in endemic areas develop clinical immunity. This form of protection prevents clinical episodes by substantially reducing parasite burden. Naturally acquired immunity predominantly targets blood-stage parasites with antibody responses being the main mediators of protection. The targets of clinical immunity are the extracellular merozoite and the infected erythrocyte surface, with the extremely diverse PfEMP1 proteins the main target here. This observation provides a strong rationale that an effective anti-malaria vaccine targeting blood-stage parasites is achievable. Thus the identification of antigenic targets of naturally acquired immunity remains an important step towards the formulation of novel vaccine combinations before testing their efficacy in clinical trials. This review summarizes the main findings to date defining antigenic targets present on the extracellular merozoite associated with naturally acquired immunity to P. falciparum malaria. PMID- 29144218 TI - Characterization of a glycine-rich protein from Rhipicephalus microplus: tissue expression, gene silencing and immune recognition. AB - Salivary molecules, as glycine-rich proteins (GRPs), are essential to tick attachment and feeding on the host and are suggested to be involved in the host's immune system evasion, therefore representing natural candidates in the search for protective vaccine antigens. This work shows the molecular characterization of a GRP from Rhipicephalus microplus (RmGRP). The cDNA and putative amino acid sequences were analysed, as well as the transcription level in tick tissues/developmental stages, showing the highest levels of gene expression in 1 day-old larvae and salivary glands of fully engorged females. RmGRP gene silencing resulted in a lower hatching rate of larvae from treated females. In addition, recombinant RmGRP (rRmGRP) was recognized by sera from naturally and experimentally infested bovines, displaying considerable differences among the individuals tested. rRmGRP was recognized by anti-saliva and anti-salivary glands sera, while anti-rRmGRP serum recognized RmGRP in saliva and salivary glands, indicating its secretion into the host. The data collected indicate that RmGRP may present roles other than in the tick-host relationship, especially in embryo development. In addition, the high expression in adult females, antigenicity and presence of shared characteristics with other tick protective GRPs turns RmGRP a potential candidate to compose an anti-tick vaccine cocktail. PMID- 29144219 TI - Trypanosoma sp. diversity in Amazonian bats (Chiroptera; Mammalia) from Acre State, Brazil. AB - Bats are ancient hosts of Trypanosoma species and their flying ability, longevity and adaptability to distinct environments indicate that they are efficient dispersers of parasites. Bats from Acre state (Amazon Biome) were collected in four expeditions conducted in an urban forest (Parque Zoobotanico) and one relatively more preserved area (Seringal Cahoeira) in Rio Branco and Xapuri municipalities. Trypanosoma sp. infection was detected by hemoculture and fresh blood examination. Isolated parasite species were identified by the similarity of the obtained DNA sequence from 18S rDNA polymerase chain reaction and reference strains. Overall, 367 bats from 23 genera and 32 species were examined. Chiropterofauna composition was specific to each municipality, although Artibeus sp. and Carollia sp. prevailed throughout. Trypanosoma sp. infection was detected in 85 bats (23.2%). The most widely distributed and prevalent genotypes were (in order) Trypanosoma cruzi TcI, T. cruzi marinkellei, Trypanosoma dionisii, T. cruzi TcIV and Trypanosoma rangeli. At least one still-undescribed Trypanosoma species was also detected in this study. The detection of T. cruzi TcI and TcIV (the ones associated with Chagas disease in Amazon biome) demonstrates the putative importance of these mammal hosts in the epidemiology of the disease in the Acre State. PMID- 29144221 TI - A Case of Bell's Palsy Complicated by Subsequent Herpes Simplex Virus Encephalitis. PMID- 29144220 TI - Is low cognitive functioning a predictor or consequence of major depressive disorder? A test in two longitudinal birth cohorts. AB - Cognitive impairment has been identified as an important aspect of major depressive disorder (MDD). We tested two theories regarding the association between MDD and cognitive functioning using data from longitudinal cohort studies. One theory, the cognitive reserve hypothesis, suggests that higher cognitive ability in childhood decreases risk of later MDD. The second, the scarring hypothesis, instead suggests that MDD leads to persistent cognitive deficits following disorder onset. We tested both theories in the Dunedin Study, a population-representative cohort followed from birth to midlife and assessed repeatedly for both cognitive functioning and psychopathology. We also used data from the Environmental Risk Longitudinal Twin Study to test whether childhood cognitive functioning predicts future MDD risk independent of family-wide and genetic risk using a discordant twin design. Contrary to both hypotheses, we found that childhood cognitive functioning did not predict future risk of MDD, nor did study members with a past history of MDD show evidence of greater cognitive decline unless MDD was accompanied by other comorbid psychiatric conditions. Our results thus suggest that low cognitive functioning is related to comorbidity, but is neither an antecedent nor an enduring consequence of MDD. Future research may benefit from considering cognitive deficits that occur during depressive episodes from a transdiagnostic perspective. PMID- 29144223 TI - No-Touch Disinfection Methods to Decrease Multidrug-Resistant Organism Infections: A Systematic Review and Meta-analysis. AB - BACKGROUND Recent studies have shown that using no-touch disinfection technologies (ie, ultraviolet light [UVL] or hydrogen peroxide vapor [HPV] systems) can limit the transmission of nosocomial pathogens and prevent healthcare-associated infections (HAIs). To investigate these findings further, we performed a systematic literature review and meta-analysis on the impact of no touch disinfection methods to decrease HAIs. METHODS We searched PubMed, CINAHL, CDSR, DARE and EMBASE through April 2017 for studies evaluating no-touch disinfection technology and the nosocomial infection rates for Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE), and other multidrug-resistant organisms (MDROs). We employed random-effect models to obtain pooled risk ratio (pRR) estimates. Heterogeneity was evaluated with I2 estimation and the Cochran Q statistic. Pooled risk ratios for C. difficile, MRSA, VRE, and MDRO were assessed separately. RESULTS In total, 20 studies were included in the final review: 13 studies using UVL systems and 7 studies using HPV systems. When the results of the UVL studies were pooled, statistically significant reduction ins C. difficile infection (CDI) (pRR, 0.64; 95% confidence interval [CI], 0.49-0.84) and VRE infection rates (pRR, 0.42; 95% CI, 0.28-0.65) were observed. No differences were found in rates of MRSA or gram-negative multidrug-resistant pathogens. CONCLUSIONS Ultraviolet light no-touch disinfection technology may be effective in preventing CDI and VRE infection. Infect Control Hosp Epidemiol 2018;39:20-31. PMID- 29144222 TI - Child language and parenting antecedents and externalizing outcomes of emotion regulation pathways across early childhood: A person-centered approach. AB - Decreases in children's anger reactivity because of the onset of their autonomous use of strategies characterizes the prevailing model of the development of emotion regulation in early childhood (Kopp, 1989). There is, however, limited evidence of the varied pathways that mark this development and their proposed antecedents and consequences. This study used a person-centered approach to identify such pathways, antecedents, and outcomes. A sample of 120 children from economically strained rural and semirural households were observed while waiting to open a gift at ages 24, 36, and 48 months. Multitrajectory modeling of children's anger expressions and strategy use yielded three subgroups. As they aged, typically developing children's strategy use (calm bids and focused distraction) increased while anger expressions decreased. Later developing children, though initially elevated in anger expression and low in strategy use, demonstrated marked growth across indicators and did not differ from typically developing children at 48 months. At-risk children, despite developing calm bidding skills, did not display longitudinal self-distraction increases or anger expression declines. Some predicted antecedents (12-24 month child language skills and language-capitalizing parenting practices) and outcomes (age 5 years externalizing behavior) differentiated pathways. Findings illustrate how indicator-specific departures from typical pathways signal risk for behavior problems and point to pathway-specific intervention opportunities. PMID- 29144224 TI - Violence exposure and neural systems underlying working memory for emotional stimuli in youth. AB - Violence exposure during childhood is common and associated with poor cognitive and academic functioning. However, little is known about how violence exposure influences cognitive processes that might contribute to these disparities, such as working memory, or their neural underpinnings, particularly for cognitive processes that occur in emotionally salient contexts. We address this gap in a sample of 54 participants aged 8 to 19 years (50% female), half with exposure to interpersonal violence. Participants completed a delayed match to sample task for emotional faces while undergoing functional magnetic resonance imaging scanning. Violence-exposed youth performed worse than controls on happy and neutral, but not angry, trials. In whole-brain analysis, violence-exposed youth had reduced activation in the left middle frontal gyrus and right intraparietal sulcus during encoding and the left superior temporal sulcus and temporal-parietal junction during retrieval compared to control youth. Reduced activation in the left middle frontal gyrus during encoding and the left superior temporal sulcus during retrieval mediated the association between violence exposure and task performance. Violence exposure influences the frontoparietal network that supports working memory as well as regions involved in facial processing during working memory for emotional stimuli. Reduced neural recruitment in these regions may explain atypical patterns of cognitive processing seen among violence-exposed youth, particularly within emotional contexts. PMID- 29144225 TI - Prevalence of Genetic Disorders and GLUT1 Deficiency in a Ketogenic Diet Clinic. AB - Between July of 2012 and December of 2014, 39 patients were enrolled prospectively to investigate the prevalence of glucose transporter 1 (GLUT1) deficiency in a ketogenic diet clinic. None of them had GLUT1 deficiency. All patients seen in the same clinic within the same period were reviewed retrospectively. A total of 18 of these 85 patients had a genetic diagnosis, including GLUT1 deficiency, pathogenic copy number variants, congenital disorder of glycosylation, neuronal ceroid lipofuscinosis type II, mitochondrial disorders, tuberous sclerosis, lissencephaly, and SCN1A-, SCN8A-, and STXBP1 associated epileptic encephalopathies. The prevalence of genetic diagnoses was 21% and prevalence of GLUT1 deficiency was 2.4% in our retrospective cohort study. PMID- 29144226 TI - Do executive functions explain the covariance between internalizing and externalizing behaviors? AB - This study examined whether executive functions (EFs) might be common features of internalizing and externalizing behavior problems across development. We examined relations between three EF latent variables (a common EF factor and factors specific to updating working memory and shifting sets), constructed from nine laboratory tasks administered at age 17, to latent growth intercept (capturing stability) and slope (capturing change) factors of teacher- and parent-reported internalizing and externalizing behaviors in 885 individual twins aged 7 to 16 years. We then estimated the proportion of intercept-intercept and slope-slope correlations predicted by EF as well as the association between EFs and a common psychopathology factor (P factor) estimated from all 9 years of internalizing and externalizing measures. Common EF was negatively associated with the intercepts of teacher-rated internalizing and externalizing behavior in males, and explained 32% of their covariance; in the P factor model, common EF was associated with the P factor in males. Shifting-specific was positively associated with the externalizing slope across sex. EFs did not explain covariation between parent rated behaviors. These results suggest that EFs are associated with stable problem behavior variation, explain small proportions of covariance, and are a risk factor that that may depend on gender. PMID- 29144228 TI - List of new names and new combinations previously effectively, but not validly, published. AB - The purpose of this announcement is to effect the valid publication of the following effectively published new names and new combinations under the procedure described in the Bacteriological Code (1990 Revision). Authors and other individuals wishing to have new names and/or combinations included in future lists should send three copies of the pertinent reprint or photocopies thereof, or an electronic copy of the published paper to the IJSEM Editorial Office for confirmation that all of the other requirements for valid publication have been met. It is also a requirement of IJSEM and the ICSP that authors of new species, new subspecies and new combinations provide evidence that types are deposited in two recognized culture collections in two different countries. It should be noted that the date of valid publication of these new names and combinations is the date of publication of this list, not the date of the original publication of the names and combinations. The authors of the new names and combinations are as given below. Inclusion of a name on these lists validates the publication of the name and thereby makes it available in the nomenclature of prokaryotes. The inclusion of a name on this list is not to be construed as taxonomic acceptance of the taxon to which the name is applied. Indeed, some of these names may, in time, be shown to be synonyms, or the organisms may be transferred to another genus, thus necessitating the creation of a new combination. PMID- 29144227 TI - Maternal smoking during pregnancy and offspring executive function: What do we know and what are the next steps? AB - Children exposed to maternal smoking during pregnancy (MSDP) exhibit difficulties in executive function (EF) from infancy through adolescence. Due to the developmental significance of EF as a predictor of adaptive functioning throughout the life span, the MSDP-EF relation has clear public health implications. In this paper, we provide a comprehensive review of the literature on the relationship between MSDP and offspring EF across development; consider brain-based assessments, animal models, and genetically informed studies in an effort to elucidate plausible pathways of effects; discuss implications for prevention and intervention; and make calls to action for future research. PMID- 29144229 TI - Aquaticitalea lipolytica gen. nov., sp. nov., isolated from Antarctic seawater. AB - A Gram-stain-negative, rod-shaped bacterium, designated Ar-125T, was isolated from Antarctic seawater. It produced carotenoid-like pigments and did not produce Bchl a. Ar-125T was positive for hydrolysis of DNA, aesculin, gelatin, starch, Tween 40 and Tween 60. The sole respiratory quinone was MK-6. The major polar lipids were phosphatidylethanolamine, one unidentified aminolipid, one unidentified glycolipid and two unidentified lipids. The principal fatty acids were branched-chain fatty acids, including iso-C15 : 0, iso-C15 : 1 G, summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1omega7c), iso-C16 : 0, iso-C17 : 0 3 OH, iso-C16 : 0 3-OH and iso-C15 : 0 3-OH, as well as C15 : 0. The genomic DNA G+C content was 31.8 mol%. On the basis of 16S rRNA gene sequence analysis, Ar 125T is closely related to the species of the genera Bizionia(with 16S rRNA gene pairwise sequence similarity of 93.7-96.5 %), Formosa(94.3-95.8 %), Gaetbulibacter(94.2-95.7 %), Geojedonia(95.5 %), Gelidibacter (93.3-95.4 %), Meridianimaribacter(95.3 %) and Psychroserpens (94.8-95.3 %), of the family Flavobacteriaceae. Phylogenetic analysis indicated that it represented an independent lineage and that the closest relatives were members of the genus Gelidibacter. Differential phenotypic properties and chemotaxonomic differences, together with phylogenetic distinctiveness, revealed that Ar-125T could be differentiated from members of closely related genera. Therefore, it is proposed that Ar-125T represents a novel species in a new genus, for which the name Aquaticitalea lipolytica gen. nov., sp. nov. (type strain Ar-125T =CGMCC 1.15295T =JCM 30876T) is proposed. PMID- 29144230 TI - Notification that new names of prokaryotes, new combinations and new taxonomic opinions have appeared in volume 65, part 12, of the IJSEM. AB - This listing of names of prokaryotes published in a previous issue of the IJSEM is provided as a service to bacteriology to assist in the recognition of new names and new combinations. This procedure was proposed by the Judicial Commission [Minute 11(ii), Int J Syst Bacteriol41 (1991), p. 185]. The names given herein are listed according to the Rules of priority (i.e. page number and order of valid publication of names in the original articles). PMID- 29144231 TI - Wickerhamomyces orientalis f.a., sp. nov.: an ascomycetous yeast species belonging to the Wickerhamomyces clade. AB - Five closely related yeast strains were isolated from soil in Kharg Island, Persian Gulf, Iran, and from fallen fruits in Galle, Sri Lanka, during separate projects. Morphologically, the strains produced white-coloured yeast colonies, with cells that were ovoid to ellipsoidal, making branched, true hyphae and pseudohyphae. Ascospore formation was not observed. Biochemically, the strains were able to ferment d-glucose and weakly ferment d-galactose. The strains could use a wide variety of carbon sources except methanol and hexadecane. Phylogenetic analyses using combined sequences of the small ribosomal subunit and the D1/D2 domains of the LSU, as well as the internal transcribed spacer regions, suggested that these strains belong to the Wickerhamomyces clade and that together they form one strongly supported phylogenetic clade. Differences in their sequences, biochemistry and morphology suggest they are representatives of distinct species of the genus Wickerhamomyces. Therefore, the name Wickerhamomyces orientalis f.a., sp. nov. is proposed to accommodate these novel strains; the type strain is IBRC-M 30103T (=CBS 13306T). The MycoBank number is MB 807323. PMID- 29144232 TI - Saccharopolyspora aidingensis sp. nov., an actinomycete isolated from a salt lake. AB - A novel halophilic actinomycete strain, designated TRM 46074T, was isolated from Aiding salt lake in Turpan Basin, north-west China. Strain TRM 46074T was aerobic, Gram-stain-positive and grew optimally with 12 % (w/v) NaCl. The strain was observed to produce sparse aerial mycelium with long chains of spores that were non-motile and oval or spherical in shape with a rough or smooth surface; substrate mycelium was branched and well developed. The cell wall was determined to contain meso-diaminopimelic acid; the diagnostic whole-cell sugars were galactose, arabinose and ribose. The diagnostic polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol and phosphatidylinositol. The predominant menaquinones were MK-9(H4), MK-10(H8) and MK-10(H4). The G+C content of the DNA was 70.9 mol%. The major fatty acids were anteiso-C17 : 0, iso-C15 : 0, iso-C16 : 0 and iso-C17 : 0. Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain TRM 46074T belongs to the genus Saccharopolyspora. Strain TRM 46074T had 16S rRNA gene sequence similarity of 99.6 % with the closest described species, Saccharopolyspora ghardaiensis H53T. DNA-DNA hybridization between strain TRM 46074T and Saccharopolysporaghardaiensis H53T showed 58.6 % relatedness. On the basis of the evidence from a polyphasic study, strain TRM 46074T is considered to represent a novel species in the genus Saccharopolyspora, for which the name Saccharopolyspora aidingensis sp. nov. is proposed. The type strain is TRM 46074T (=CCTCC AA 2012014T=JCM 30185T). PMID- 29144235 TI - Speak to me in English, Spanish, or both? PMID- 29144236 TI - Food anaphylaxis has been increasing in New York City schools. PMID- 29144233 TI - A high-resolution mRNA expression time course of embryonic development in zebrafish. AB - We have produced an mRNA expression time course of zebrafish development across 18 time points from 1 cell to 5 days post-fertilisation sampling individual and pools of embryos. Using poly(A) pulldown stranded RNA-seq and a 3' end transcript counting method we characterise temporal expression profiles of 23,642 genes. We identify temporal and functional transcript co-variance that associates 5024 unnamed genes with distinct developmental time points. Specifically, a class of over 100 previously uncharacterised zinc finger domain containing genes, located on the long arm of chromosome 4, is expressed in a sharp peak during zygotic genome activation. In addition, the data reveal new genes and transcripts, differential use of exons and previously unidentified 3' ends across development, new primary microRNAs and temporal divergence of gene paralogues generated in the teleost genome duplication. To make this dataset a useful baseline reference, the data can be browsed and downloaded at Expression Atlas and Ensembl. PMID- 29144238 TI - 50 Years Ago in The Journal of Pediatrics: Cholestyramine Therapy in Patients with a Paucity of Intrahepatic Bile Ducts. PMID- 29144237 TI - Searching for the Best Oral Treatment for Hypoglycemic Newborns. PMID- 29144234 TI - LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis. AB - Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor with diverse physiological roles, ranging from cellular uptake of lipoproteins and other cargo by endocytosis to sensor of the extracellular environment and integrator of a wide range of signaling mechanisms. As a chylomicron remnant receptor, LRP1 controls systemic lipid metabolism in concert with the LDL receptor in the liver, whereas in smooth muscle cells (SMC) LRP1 functions as a co-receptor for TGFbeta and PDGFRbeta in reverse cholesterol transport and the maintenance of vascular wall integrity. Here we used a knockin mouse model to uncover a novel atheroprotective role for LRP1 in macrophages where tyrosine phosphorylation of an NPxY motif in its intracellular domain initiates a signaling cascade along an LRP1/SHC1/PI3K/AKT/PPARgamma/LXR axis to regulate and integrate cellular cholesterol homeostasis through the expression of the major cholesterol exporter ABCA1 with apoptotic cell removal and inflammatory responses. PMID- 29144239 TI - The Unintended Consequences of Marijuana Legalization. PMID- 29144240 TI - Trial of Music, Sucrose, and Combination Therapy for Pain Relief during Heel Prick Procedures in Neonates. AB - OBJECTIVE: To compare the effectiveness of music, oral sucrose, and combination therapy for pain relief in neonates undergoing a heel prick procedure. STUDY DESIGN: This randomized, controlled, blinded crossover clinical trial included stable neonates >32 weeks of postmenstrual age. Each neonate crossed over to all 3 interventions in random order during consecutive heel pricks. A video camera on mute mode recorded facial expressions, starting 2 minutes before until 7 minutes after the heel prick. The videos were later analyzed using the Premature Infant Pain Profile-Revised (PIPP-R) scale once per minute by 2 independent assessors, blinded to the intervention. The PIPP-R scores were compared between treatment groups using Friedman test. RESULTS: For the 35 participants, the postmenstrual age was 35 weeks (SD, 2.3) with an average weight of 2210 g (SD, 710). The overall median PIPP-R scores following heel prick over 6 minutes were 4 (IQR 0 6), 3 (IQR 0-6), and 1 (IQR 0-3) for the music, sucrose, and combination therapy interventions, respectively. The PIPP-R scores were significantly lower at all time points after combination therapy compared with the groups given music or sucrose alone. There was no difference in PIPP-R scores between the music and sucrose groups. CONCLUSIONS: In relatively stable and mature neonates, the combination of music therapy with sucrose provided better pain relief during heel prick than when sucrose or music was used alone. Recorded music in isolation had a similar effect to the current gold standard of oral sucrose. TRIAL REGISTRATION: www.anzctr.org.au ACTRN12615000271505. PMID- 29144241 TI - Shifting Risks and Conflicting Outcomes-ECMO for Neonates with Congenital Diaphragmatic Hernia in the Modern Era. AB - OBJECTIVES: To update previously described trends for neonates with congenital diaphragmatic hernia (CDH) receiving ECMO with changes in recommendations for care, and to determine how recent advancements in respiratory care have affected this patient population. STUDY DESIGN: This study is a retrospective review of more than 2500 neonates with CDH who received ECMO listed in the Extracorporeal Life Support Organization (ELSO) registry. Cochran-Armitage and multivariate regression analyses were used to analyze changes in the patient population over time and in mortality-related risk factors. RESULTS: Almost one-half (48.1%) of the term neonates survived to discharge, representing a 13.8% decline in survival over the past 25 years (P < .0001). Over the past 10 years, the prevalence of respiratory acidosis more than doubled (P < .0001) and the prevalence of major complications increased (P < .001). During the same period, the number of ECMO courses longer than 1 week increased (P < .001), whereas the prevalence of multiple complications (>4) decreased (P < .0001). Surgeries performed on ECMO were associated with worse outcomes than those performed off ECMO. ECMO duration no longer represents a mortality-related risk factor. CONCLUSIONS: Survival rates for neonates with CDH receiving ECMO have continued to drop in the modern era. Although the safety of ECMO has improved over the last decade, the number of patients experiencing significant respiratory acidosis has more than doubled increasing the risk of intracranial hemorrhage and overall mortality. The evidence for permissive hypercapnia remains mixed; nonetheless, we believe that the risks outweigh the rewards in this patient population. PMID- 29144242 TI - Effects of Intrapartum Antibiotic Prophylaxis on Neonatal Acquisition of Group B Streptococci. AB - OBJECTIVES: To assess the incidence of colonization with group B streptococci (GBS) among neonates as influenced by maternal GBS carriage and intrapartum antibiotic prophylaxis (IAP). STUDY DESIGN: Between October 2014 and May 2015, nasopharyngeal and rectal swab samples were collected from 730 neonates at 1 week and 1 month after birth. GBS and capsular serotype were identified by real-time polymerase chain reaction and by culture. IAP at delivery was determined retrospectively from hospital records. RESULTS: Sixty-four neonates (8.8%) were GBS-positive by real-time polymerase chain reaction and culture. Among neonates born to mothers who were GBS carriers (n = 107), 94.4% (101/107) had maternal IAP; 19.6% nonetheless were GBS-positive, compared with 6.5% of neonates born to noncarrier mothers (P <.01). Among neonates born to mothers receiving IAP, more were positive only at 1 month of age than at both 1 week and 1 month. The frequency of GBS in neonates born to mothers receiving IAP was significantly lower than that in neonates born to mothers not receiving IAP (P <.05). Capsular serotypes V (25%) and III (23.4%) were common, followed by Ib (15.6%), Ia (14.1%), II (7.8%), IV (6.3%), nontypeable (4.7%), and VI and VIII (each 1.6%). CONCLUSIONS: Delayed colonization with GBS occurs in infants born to GBS carrier mothers receiving IAP. GBS should be considered in all infants at 1 month after birth with signs of infection. PMID- 29144243 TI - Risk of Mortality into Adulthood According to Gestational Age at Birth. AB - OBJECTIVES: To quantify the independent risks of neonatal (0-28 days), postneonatal (29-364 days), 1- to 5- and 6- to 30-year mortality by gestational age and investigate changes in survival over time in an Australian birth cohort. STUDY DESIGN: Maternal and birth related Western Australian population data (1980 2010) were linked to the state mortality data using a retrospective cohort study design involving 722 399 live-born singletons infants. RESULTS: When compared with 39- to 41-week born infants, the adjusted risk ratio for neonatal mortality was 124.8 (95% CI 102.9-151.3) for 24-31 weeks of gestation, 3.4 (95% CI 2.4-4.7) for 35-36 weeks of gestation, and 1.4 (95% CI 1.1-1.8) for 37-38 weeks of gestation. For 24-31 weeks of gestation infants, the adjusted hazard ratio for postneonatal mortality (29-364 days) was 13.9 (95% CI 10.9-17.6), for 1- to 5 year mortality 1.4 (95% CI 0.7-3.0) and for 6- to 30-year mortality 1.3 (95% CI 0.8-2.3). The risk of neonatal and postneonatal mortality for those born preterm decreased over time. CONCLUSIONS: In Western Australia, late preterm and early term infants experienced higher risk of neonatal and postneonatal mortality when compared with their full-term peers. There was insufficient evidence to show that gestational length was independently associated with mortality beyond 1 year of age. Neonatal and postneonatal mortality improved with each decade of the study period. PMID- 29144245 TI - Long-term follow-up and the future. PMID- 29144246 TI - Caffeine therapy-when and why? PMID- 29144244 TI - Modes of Infant Feeding and the Risk of Childhood Asthma: A Prospective Birth Cohort Study. AB - OBJECTIVE: To determine whether different modes of infant feeding are associated with childhood asthma, including differentiating between direct breastfeeding and expressed breast milk. STUDY DESIGN: We studied 3296 children in the Canadian Healthy Infant Longitudinal Development birth cohort. The primary exposure was infant feeding mode at 3 months, reported by mothers and categorized as direct breastfeeding only, breastfeeding with some expressed breast milk, breast milk and formula, or formula only. The primary outcome was asthma at 3 years of age, diagnosed by trained healthcare professionals. RESULTS: At 3 months of age, the distribution of feeding modes was 27% direct breastfeeding, 32% breastfeeding with some expressed breast milk, 26% breast milk and formula, and 15% formula only. At 3 years of age, 12% of children were diagnosed with possible or probable asthma. Compared with direct breastfeeding, any other mode of infant feeding was associated with an increased risk of asthma. These associations persisted after adjusting for maternal asthma, ethnicity, method of birth, infant sex, gestational age, and daycare attendance (some expressed breast milk: aOR, 1.64, 95% CI, 1.12-2.39; breast milk and formula, aOR, 1.73, 95% CI, 1.17-2.57; formula only: aOR, 2.14, 95% CI, 1.37-3.35). Results were similar after further adjustment for total breastfeeding duration and respiratory infections. CONCLUSIONS: Modes of infant feeding are associated with asthma development. Direct breastfeeding is most protective compared with formula feeding; indirect breast milk confers intermediate protection. Policies that facilitate and promote direct breastfeeding could have impact on the primary prevention of asthma. PMID- 29144247 TI - The Child Opportunity Index and Disparities in Pediatric Asthma Hospitalizations Across One Ohio Metropolitan Area, 2011-2013. AB - OBJECTIVES: To determine whether the Child Opportunity Index (COI), a nationally available measure of relative educational, health/environmental, and social/economic opportunity across census tracts within metropolitan areas, is associated with population- and patient-level asthma morbidity. STUDY DESIGN: This population-based retrospective cohort study was conducted between 2011 and 2013 in a southwest Ohio county. Participants included all children aged 1-16 years with hospitalizations or emergency department visits for asthma or wheezing at a major pediatric hospital. Patients were identified using discharge diagnosis codes and geocoded to their home census tract. The primary population-level outcome was census tract asthma hospitalization rate. The primary patient-level outcome was rehospitalization within 12 months of the index hospitalization. Census tract opportunity was characterized using the COI and its educational, health/environmental, and social/economic domains. RESULTS: Across 222 in-county census tracts, there were 2539 geocoded hospitalizations. The median asthma related hospitalization rate was 5.0 per 1000 children per year (IQR, 1.9-8.9). Median hospitalization rates in very low, low, moderate, high, and very high opportunity tracts were 9.1, 7.6, 4.6, 2.1, and 1.8 per 1000, respectively (P < .0001). The social/economic domain had the most variables significantly associated with the outcome at the population level. The adjusted patient-level analyses showed that the COI was not significantly associated with a patient's risk of rehospitalization within 12 months. CONCLUSIONS: The COI was associated with population-level asthma morbidity. The details provided by the COI may inform interventions aimed at increasing opportunity and reducing morbidity across regions. PMID- 29144248 TI - Recognition of Infantile Spasms Is Often Delayed: The ASSIST Study. AB - OBJECTIVES: To characterize and quantify diagnostic and treatment delay among children with infantile spasms, and to estimate the developmental impact of this delay. STUDY DESIGN: In this cohort study, we surveyed the parents of 100 patients with infantile spasms about their experiences with diagnosis and treatment, and ascertained medical and sociodemographic factors potentially related to care of these infants. We specifically determined the latency to first visit an "effective provider," defined as a provider who identified infantile spasms, and prescribed an appropriate first-line treatment, namely adrenocorticotropic hormone, corticosteroids, or vigabatrin. Time to the first visit to an effective provider was evaluated using Cox proportional hazards regression. RESULTS: The median time from the onset of infantile spasms to first visit with an effective provider was 24.5 days. Only 29% of patients were evaluated by an effective provider within 1 week of infantile spasms onset. The time to first effective provider visit was associated with parental language preference, but with no other sociodemographic characteristics. Parents' suspicions that "something is wrong" were often discounted by healthcare providers, and survey respondents frequently reported that pediatricians and neurologists were unfamiliar with infantile spasms. CONCLUSION: This study demonstrates that substantial delay (ie, >1 week) in appropriate care is common, and suggests that the poor awareness of infantile spasms among healthcare providers is at least partly responsible for preventable and potentially significant delays in treatment. PMID- 29144250 TI - Case Not Closed: Prescription Errors 12 Years after Computerized Physician Order Entry Implementation. AB - OBJECTIVE: To assess the prolonged impact of computerized physician order entry (CPOE) on medication prescription errors in pediatric intensive care patients. STUDY DESIGN: This observational study was conducted at a pediatric intensive care unit in which a CPOE (Metavision, iMDsoft, Israel) with a limited clinical decision support system was implemented between 2004 and 2007. Since then, no changes were made to the systems. We analyzed 2500 electronic prescriptions (1250 prescriptions from 2015 and 1250 prescriptions from 2016). Prescription errors were identified by a pediatric intensive care physician and classified as potential adverse drug events, medication prescription errors, or rule violations. Their prevalence was compared with the rate in 2007, reported in a previous study from the same unit. A randomly selected 10% of the prescriptions were also analyzed by the pediatric intensive care unit pharmacist, and the level of agreement was determined. RESULTS: The rate of prescription errors increased from 1.4% in 2007 to 3.2% in 2015 (P = .03). Following revision of the clinical decision support system tools, prescription errors decreased to 1% in 2016 (P < .0001). The potential adverse drug event rate dropped from 2% in 2015 to 0.7% in 2016 (P = .006), and the medication prescription error rate, from 1% to 0.2% (P = .01). The agreement between the 2 reviewers was excellent (k = 0.96). CONCLUSIONS: The rate of prescription errors may increase with time from implementation of a CPOE. Repeated surveillance of prescription errors is highly advised to plan strategies to reduce them. This approach should be considered in quality improvement of computerized information systems in general. PMID- 29144249 TI - Effect of Antiandrogen, Aromatase Inhibitor, and Gonadotropin-releasing Hormone Analog on Adult Height in Familial Male Precocious Puberty. AB - OBJECTIVE: Antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog (GnRHa) treatment normalizes growth rate and bone maturation and increases predicted adult height (AH) in boys with familial male-limited precocious puberty (FMPP). To evaluate the effect of long-term antiandrogen, aromatase inhibitor, and GnRHa on AH, boys with FMPP who were treated were followed to AH. STUDY DESIGN: Twenty-eight boys with FMPP, referred to the National Institutes of Health, were started on antiandrogen and aromatase inhibitor at 4.9 +/- 1.5 years of age; GnRHa was added at 6.9 +/- 1.5 years of age. Treatment was discontinued at 12.2 +/- 0.5 years of age (bone age, 14.4 +/- 1.3). AH was assessed at 16.4 +/ 1.3 years of age (bone age, 18.5 +/- 0.6). RESULTS: AH (mean +/- SD) for all treated subjects was 173.6 +/- 6.8 cm (-0.4 +/- 1.0 SD relative to adult US males). For 25 subjects with pretreatment predicted AH, AH significantly exceeded predicted AH at treatment onset (173.8 +/- 6.9 vs 164.9 +/- 10.7 cm; P < .001), but fell short of predicted AH at treatment discontinuation (177.3 +/- 9.0 cm; P < .001). For 11 subjects with maternal or sporadic inheritance, the mean AH was 3.1 cm (0.4 SD score) below sex-adjusted midparental height (175.4 +/- 5.8 vs 178.5 +/- 3.1 cm [midparental height]; P = .10). For 16 subjects with affected and untreated fathers, AH was significantly greater than fathers' AH (172.8 +/- 7.4 vs 168.8 +/- 7.2 cm; P < .05). CONCLUSIONS: Long-term treatment with antiandrogen, aromatase inhibitor, and GnRHa in boys with FMPP results in AH modestly below sex-adjusted midparental height and within the range for adult males in the general population. PMID- 29144251 TI - Evaluation of Dorsal Midline Discolorations with Physical Examination and Ultrasound. AB - OBJECTIVE: To assess the association between dorsal midline skin discolorations, tethering of the spinal cord, and the role of ultrasound screening of these stigmata, focusing specifically on vascular lesions. STUDY DESIGN: We conducted a prospective observational study of infants <6 months of age with suspicious dorsal midline skin stigmata. All were evaluated by physical examination and ultrasound scan. A subset also had a magnetic resonance imaging examination. We examined the association between small, red-shaded discolorations and their respective imaging findings. RESULTS: Among 100 cases with discolorations of vascular types, either isolated or combined with low-risk simple dimples or deviated gluteal folds, none had clinically significant pathologic findings requiring surgical intervention. CONCLUSIONS: Midline lumbar discolorations are more benign than previously thought. Despite the very low association of this group of stigmata with surgical implications, we still recommend the routine use of ultrasound scanning. PMID- 29144254 TI - Emicizumab prophylaxis overcomes factor VIII inhibitors in Hemophilia A. PMID- 29144253 TI - Pediatric Orthopedic Hoverboard Injuries: A Prospectively Enrolled Cohort. AB - Hoverboards pose a significant risk of musculoskeletal injury to pediatric riders. A prospectively enrolled cohort yielded 9 pediatric patients injured while riding hoverboards in 2016. Eight of the injuries involved the upper extremity, and one involved the lower extremity. No riders wore any safety equipment and injury patterns modeled those seen in skateboard riders. PMID- 29144255 TI - An egg a day enhances growth in resource-poor communities. PMID- 29144256 TI - Association of ADHD with increased motor vehicle crashes. PMID- 29144257 TI - Clostridium difficile infection and commonly used pediatric medications. PMID- 29144258 TI - Topical antibiotic-glucocorticoid is superior to oral antibiotics in tympanostomy tube otorrhea. PMID- 29144259 TI - Translating Best Evidence into Best Care. PMID- 29144252 TI - Can We Understand the Pathobiology of Bronchopulmonary Dysplasia? PMID- 29144260 TI - Understanding cardiopulmonary resuscitation. PMID- 29144261 TI - Creatine kinase: how an obsolete test for skeletal muscle disease became a risk factor for hypertension. PMID- 29144262 TI - Reply. PMID- 29144263 TI - Public Health Practice and Policy to Improve Child and Adolescent Health in Europe. PMID- 29144264 TI - Please diagnose infantile spasm early! PMID- 29144265 TI - Better beginnings. PMID- 29144266 TI - Alkaline phosphatase and infant cardiopulmonary bypass. PMID- 29144267 TI - "Gelin' it". PMID- 29144268 TI - When increased mortality indicates improved care: CDH ECMO registry data. PMID- 29144269 TI - 50 Years Ago in The Journal of Pediatrics: Diagnosis of Cerebrospinal Fluid Rhinorrhea: Lack of Specificity of the Glucose Oxidase Test Tape. PMID- 29144271 TI - Different cut points in detecting child nutritional disorders-where do we draw the line? PMID- 29144270 TI - Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship to Organ Injury and Major Cardiovascular Events. AB - OBJECTIVES: To determine the kinetics of alkaline phosphatase (AP) activity and concentration after infant cardiopulmonary bypass, including isoform-specific changes, and to measure the association between postoperative AP activity and major postoperative cardiovascular events, organ injury/dysfunction, and postoperative support requirements STUDY DESIGN: Prospective cohort study of 120 infants <=120 days of age undergoing cardiopulmonary bypass. AP total and isoform specific activity was assessed at 6 time points (preoperation, rewarming, 6, 24, 48, and 72 hours postoperation). Low AP activity was defined as <=80 U/L. AP concentrations and biomarkers of organ injury/dysfunction were collected through 24 hours postoperation. Major cardiovascular events were defined as cardiac arrest, mechanical circulatory support, or death. RESULTS: AP activity loss occurred primarily during the operation (median decrease 89 U/L; P < .0001) secondary to decreased bone and liver 2 isoforms. Activity declined through 24 hours in 27% of patients. AP activity strongly correlated with serum concentration (r = 0.87-0.91; P < .0001). Persistent low AP activity at 72 hours was associated independently with occurrence of a major cardiac event (OR 5.6; P < .05). Early AP activity was associated independently with subsequent vasoactive inotropic score (P < .001), peak lactate (P < .0001), peak creatinine (P < .0005), N-terminal pro-brain natriuretic peptide (P < .05), and intestinal fatty acid binding protein (P < .005). CONCLUSIONS: AP activity decreases during infant cardiopulmonary bypass and may continue to decrease for 24 hours. Activity loss is secondary to decreased bone and liver 2 isoform concentrations. Early low AP activity is associated independently with subsequent postoperative support and organ injury/dysfunction, and persistence of AP activity <=80 U/L at 72 hours is associated independently with increased odds of major cardiovascular events. PMID- 29144274 TI - 50 Years Ago in The Journal of Pediatrics: Prenatal Treatment of Cretinism: Preliminary Studies of Its Value in Postnatal Development. PMID- 29144272 TI - Body Composition in Children with Chronic Illness: Accuracy of Bedside Assessment Techniques. AB - OBJECTIVE: To evaluate the accuracy of estimated fat mass and fat-free mass from bedside methods compared with reference methods in children with chronic illnesses. STUDY DESIGN: Fat mass and fat-free mass values were obtained by skinfold, bioelectrical impedance analysis (BIA), dual-energy x-ray absorptiometry (DXA), and deuterium dilution method in children with spinal muscular atrophy, intestinal failure, and post hematopoietic stem cell transplantation (HSCT). Spearman's correlation and agreement analyses were performed between (1) fat mass values estimated by skinfold equations and by DXA and (2) fat-free mass values estimated by BIA equations and by DXA and deuterium dilution methods. Limits of agreement between estimating and reference methods within +/-20% were deemed clinically acceptable. RESULTS: Fat mass and fat-free mass values from 90 measurements in 56 patients, 55% male, and median age of 11.6 years were analyzed. Correlation coefficients between the skinfold-estimated fat mass values and DXA were 0.93-0.94 and between BIA-estimated fat-free mass values and DXA were 0.92-0.97. Limits of agreement between estimated and DXA values of fat mass and fat-free mass were greater than +/-20% for all equations. Correlation coefficients between estimated fat-free mass values and deuterium dilution method in 35 encounters were 0.87-0.91, and limits of agreement were greater than +/-20%. CONCLUSION: Estimated body composition values derived from skinfold and BIA may not be reliable in children with chronic illnesses. An accurate noninvasive method to estimate body composition in this cohort is desirable. PMID- 29144273 TI - The Use of Different International References to Assess Child Anthropometric Status in a Malaysian Population. AB - OBJECTIVE: To assess the prevalence of child underweight, overweight, and obesity in a Malaysian population according to 3 international references because classification of anthropometric status may differ according to the reference used to express body mass index (BMI). STUDY DESIGN: We assessed data from 6414 children aged 6-18 years, collected by the South East Asia Community Observatory. Child underweight, overweight, and obesity were expressed according to 3 internationally used BMI references: World Health Organization 2007, International Obesity Task Force 2012, and Centers for Disease Control and Prevention 2000. We assessed agreement in classification of anthropometric status among the references using Cohen's kappa statistic and estimated underweight, overweight, and obesity prevalence according to each reference using mixed effects Poisson regression. RESULTS: There was poor to moderate agreement between references when classifying underweight, but generally good agreement when classifying overweight and obesity. Underweight, overweight, and obesity prevalence estimates generated using the 3 references were notably inconsistent. Overweight and obesity prevalence estimates were higher using the World Health Organization reference vs the other 2, and underweight prevalence was up to 8.5% higher and obesity prevalence was about 4% lower when using the International Obesity Task Force reference. CONCLUSIONS: The choice of reference to express BMI may influence conclusions about child anthropometric status and malnutrition prevalence. This has implications regarding strategies for clinical management and public health interventions. PMID- 29144275 TI - The Effect of Level of Care on Gastroschisis Outcomes. AB - OBJECTIVE: To examine the relationship between level of care in neonatal intensive care units (NICUs) and outcomes for newborns with gastroschisis. STUDY DESIGN: A retrospective cohort study was conducted at 130 California Perinatal Quality Care Collaborative NICUs from 2008 to 2014. All gastroschisis births were examined according to American Academy of Pediatrics NICU level of care at the birth hospital. Multivariate analyses examined odds of mortality, duration of mechanical ventilation, and duration of stay. RESULTS: For 1588 newborns with gastroschisis, the adjusted odds of death were higher for those born into a center with a level IIA/B NICU (OR, 6.66; P = .004), a level IIIA NICU (OR, 5.95; P = .008), or a level IIIB NICU (OR, 5.85; P = .002), when compared with level IIIC centers. The odds of having more days on ventilation were significantly higher for births at IIA/B and IIIB centers (OR, 2.05 [P < .001] and OR, 1.91 [P < .001], respectively). The odds of having longer duration of stay were significantly higher at IIA/B and IIIB centers (OR, 1.71 [P < .004]; OR, 1.77 [P < .001]). CONCLUSIONS: NICU level of care was associated with significant disparities in odds of mortality for newborns with gastroschisis. PMID- 29144276 TI - Threading the Needle for the Tiniest Babies. PMID- 29144277 TI - Newborn Screening for Spinal Muscular Atrophy and Lysosomal Storage Disorders Takes Advantage of Novel Therapies. PMID- 29144278 TI - Time Trends in Food Allergy Diagnoses, Epinephrine Orders, and Epinephrine Administrations in New York City Schools. AB - OBJECTIVES: To assess time trends in food allergy diagnoses, epinephrine autoinjector (EAI) prescriptions, and EAI administrations in the school setting. STUDY DESIGN: In this retrospective study, deidentified student data from the New York City Department of Health and Mental Hygiene, which oversees >1 million students in 1800 schools, were provided to investigators. Data from school years 2007-2008 to 2012-2013 pertaining to diagnoses of food allergy, student-specific EAI orders, and EAI administrations among students in New York City were analyzed for trends over time, via the use of ORs and chi2 calculation. RESULTS: The prevalences of providing physician documentation of food allergy and EAI orders, and the incidence of EAI administrations, all increased approximately 3-fold over the years of the study. Of 337 EAI administrations, more than one-half used stock EAI, and three-quarters were for students without a student-specific order preceding the incident. CONCLUSIONS: The rise in food allergy diagnoses, EAI prescriptions, and EAI administrations suggest either a true increase in allergic disease, increased reporting, and/or, in the case of EAI administrations, increased appropriate use. As the majority of EAI administrations used stock supply, availability of nonstudent-specific stock EAI appears vital to management of anaphylaxis in schools. Collaboration between physicians, families, and schools is needed to identify students at risk for severe allergic reactions and to ensure preparedness and availability of EAI in the event of anaphylaxis. PMID- 29144279 TI - Engineered superlattices with crossover from decoupled to synthetic ferromagnetic behavior. AB - The extent of interfacial charge transfer and the resulting impact on magnetic interactions were investigated as a function of sublayer thickness in La0.7Sr0.3MnO3/La0.7Sr0.3CoO3 ferromagnetic superlattices. Element-specific soft x-ray magnetic spectroscopy reveals that the electronic structure is altered within 5-6 unit cells of the chemical interface, and can lead to a synthetic ferromagnet with strong magnetic coupling between the sublayers. The saturation magnetization and coercivity depends sensitively on the sublayer thickness due to the length scale of this interfacial effect. For larger sublayer thicknesses, the La0.7Sr0.3MnO3 and La0.7Sr0.3CoO3 sublayers are magnetically decoupled, displaying two independent magnetic transitions with little sublayer thickness dependence. These results demonstrate how interfacial phenomena at perovskite oxide interfaces can be used to tailor their functional properties at the atomic scale. PMID- 29144280 TI - Selective ion-permeation through strained and charged graphene membranes. AB - By means of molecular dynamics simulations and density functional theory calculations, we demonstrate that stretched and charged graphene can act as ion sieve membranes. It is observed that loading 30% strain on graphene can induce pores in the dense electron cloud to allow ions to pass through the aromatic rings. Meanwhile, a charged surface is helpful to peel the hydration layers from the ions and decrease the energy barrier for ion translocation through nanopores. Our results suggest that with a membrane charge density of 6.80 e nm-2, Li+ can be highly purified from the mixed solution including Li+, K+, Na+ and Cl- ions. Further increasing the charge density to 15.78 e nm-2 can obtain excellent Na+/K+ selectivity. The potential of mean force profiles of ion permeation reveal that the potential for each ion is quite different. By fine tuning membrane charge density, pristine monolayer graphene can act as ion sieves with both high permeability and high selectivity. PMID- 29144281 TI - Preparation of Rh/Ag bimetallic nanoparticles as effective catalyst for hydrogen generation from hydrolysis of KBH4. AB - ISOBAM-104 protected Rh/Ag bimetallic nanoparticles (NPs) with average diameter less than 3.0 nm were synthesized by a co-reduction method. Ultraviolet-visible spectroscopy, transmission electron microscopy (TEM), high-resolution TEM and x ray photoelectron spectroscopy (XPS) were employed to characterize the structure, particle size, and electronic structure of the prepared bimetallic NPs. The catalytic activities of prepared bimetallic NPs for hydrogen generation from hydrolysis of a basic KBH4 solution were evaluated in detail. The results indicated that as-prepared Rh/Ag bimetallic NPs showed a higher catalytic activity than corresponding monometallic NPs. Among all the monometallic NPs and bimetallic NPs, Rh80Ag20 bimetallic NPs exhibited the highest catalytic activity with a value of 6010 mol-H2.h-1.mol-catalyst-1 at pH = 12 and 303 K. The high catalytic activities of Rh/Ag bimetallic NPs could be attributed to presence of negatively charged Rh atoms and positively charged Ag atoms, which is supported by the results of XPS and density functional theory calculation. Based on the kinetic study, the apparent activation energy for the hydrolysis reaction of the basic KBH4 solution catalyzed by Rh80Ag20 bimetallic NPs was about 47.0 +/- 3.9 kJ mol-1. PMID- 29144282 TI - Substrate effects in high gain, low operating voltage SnSe2 photoconductor. AB - High gain photoconductive devices find wide spread applications in low intensity light detection. Ultra-thin layered materials have recently drawn a lot of attention from researchers in this regard. However, in general, a large operating voltage is required to obtain large responsivity in these devices. In addition, the characteristics are often confounded by substrate induced trap effects. Here we report multi-layer SnSe2 based photoconductive devices using two different structures: (1) SiO2 substrate supported inter-digitated electrode (IDE), and (2) suspended channel. The IDE device exhibits a responsivity of [Formula: see text] A W-1 and [Formula: see text] A W-1 at operating voltages of 1 mV and 100 mV, respectively-a superior low voltage performance over existing literature on planar 2D structures. However, the responsivity reduces by more than two orders of magnitude, while the transient response improves for the suspended device providing insights into the critical role played by the channel-substrate interface in the gain mechanism. The results, on one hand, are promising for highly sensitive photoconductive applications consuming ultra-low power, and on the other hand, show a generic methodology that could be applied to other layered material based photoconductive devices as well for extracting the intrinsic behavior. PMID- 29144283 TI - Large Purcell enhancement with efficient one-dimensional collection via coupled nanowire-nanorod system. AB - Combining the advantages of both gap surface plasmons (GSPs) and evanescent waves, we demonstrate simultaneously large Purcell enhancement and efficient one dimensional collection of photons at subwavelength scale in the coupled nanowire nanorod system. The spontaneous emission (SE) can be enhanced thousands of times based on the excitation of GSPs with strongly localized electromagnetic field. Emitted photons are directly collected by subwavelength-confined evanescent modes and guided along the nanowire. By optimizing geometry and material parameters, 14 208 times of Purcell enhancement with collection efficiency up to 39.3% can be achieved in the Ag nanowire-Ag nanorod system where the emitted photons can spread more than 25 MUm, or SE is enhanced by 3142 times and up to 53% of emitted photons propagate with low loss in the dielectric nanowire-Ag nanorod system. This proposal that incorporates large Purcell enhancement, efficient nanoscale collection and one-dimensional propagation of photons, promises to have an important impact on bright single photon sources, plasmon-based nanolasers and on chip nanodevices. PMID- 29144284 TI - Integrated assessment and scenarios simulation of urban water security system in the southwest of China with system dynamics analysis. AB - The demand for global freshwater is growing, while global freshwater available for human use is limited within a certain time and space. Its security has significant impacts on both the socio-economic system and ecological system. Recently, studies have focused on the urban water security system (UWSS) in terms of either water quantity or water quality. In this study, water resources, water environment, and water disaster issues in the UWSS were combined to establish an evaluation index system with system dynamics (SD) and geographic information systems (GIS). The GIS method performs qualitative analysis from the perspective of the spatial dimension; meanwhile, the SD method performs quantitative calculation about related water security problems from the perspective of the temporal dimension. We established a UWSS model for Guizhou province, China to analyze influencing factors, main driving factors, and system variation law, by using the SD method. We simulated the water security system from 2005 to 2025 under four scenarios (Guiyang scenario, Zunyi scenario, Bijie scenario and combined scenario). The results demonstrate that: (1) the severity of water security in cities is ranked as follows: three cities are secure in Guizhou province, four cities are in basic security and two cities are in a situation of insecurity from the spatial dimension of GIS through water security synthesis; and (2) the major driving factors of UWSS in Guizhou province include agricultural irrigation water demand, soil and water losses area, a ratio increase to the standard of water quality, and investment in environmental protection. A combined scenario is the best solution for UWSS by 2025 in Guizhou province under the four scenarios from the temporal dimension of SD. The results of this study provide a useful suggestion for the management of freshwater for the cities of Guizhou province in southwest China. PMID- 29144285 TI - Bioenergy recovery from cattle wastewater in an UASB-AF hybrid reactor. AB - New data on biogas production and treatment of cattle wastewater were registered using an upflow anaerobic sludge blanket-anaerobic filter (UASB-AF) hybrid reactor under mesophilic temperature conditions (37 degrees C). The reactor was operated in semi-continuous mode with hydraulic retention times of 6, 5, 3 and 2 days and organic loading rates of 3.8, 4.6, 7.0 and 10.8 kg CODt m-3 d-1. Biogas volumes of 0.6-0.8 m3 m-3 d-1 (3.8-4.6 kg CODt m-3 d-1) and 1.2-1.4 m3 m-3 d-1 (7.0-10.8 kg CODt m-3 d-1), with methane concentrations between 69 and 75%, were attained. The removal of organic matter with values of 60-81% (CODt) and 51-75% (CODs) allowed methane yields of 0.155-0.183 m3 CH4 kg-1 CODt and 0.401-0.513 m3 CH4 kg-1 CODs to be obtained. Volatile solids were removed in 34 to 69%, with corresponding methane yields of 0.27 to 0.42 m3 CH4 kg-1 VSremoved. The good performance of the novel hybrid reactor was demonstrated by biogas outputs higher than reported previously in the literature, along with the quality of the gas obtained in the various experimental phases. The hybrid reactor investigated in this study presents comparative advantages, particularly in relation to conventional complete mixture units, considering economic factors such as energy consumption, reactor volume and installation area. PMID- 29144286 TI - Effects and mechanistic aspects of absorbing organic compounds by coking coal. AB - Coal is a porous medium and natural absorbent. It can be used for its original purpose after adsorbing organic compounds, its value does not reduce and the pollutants are recycled, and then through systemic circulation of coking wastewater zero emissions can be achieved. Thus, a novel method of industrial organic wastewater treatment using adsorption on coal is introduced. Coking coal was used as an adsorbent in batch adsorption experiments. The quinoline, indole, pyridine and phenol removal efficiencies of coal adsorption were investigated. In addition, several operating parameters which impact removal efficiency such as coking coal consumption, oscillation contact time, initial concentration and pH value were also investigated. The coking coal exhibited properties well-suited for organics' adsorption. The experimental data were fitted to Langmuir and Freundlich isotherms as well as Temkin and Redlich-Peterson (R-P) models. The Freundlich isotherm model provided reasonable models of the adsorption process. Furthermore, the purification mechanism of organic compounds' adsorption on coking coal was analysed. PMID- 29144287 TI - Assessment of a Danish sludge treatment reed bed system and a stockpile area, using substance flow analysis. AB - Sludge treatment reed bed (STRB) systems combine dewatering, stabilisation and long-term storage of sludge. The main objective of this study was to investigate how substance concentrations change in the sludge residue during treatment and to conduct substance flow analyses covering the flow of substances in an STRB system over a 12-year treatment period, followed by three months' post-treatment in a stockpile area (SPA). Samples of sludge, reject water and sludge residue of different ages were collected at two Danish STRB system facilities and analysed for content of relevant substances. Concentrations of carbon and nitrogen in the sludge residue residing in an STRB system changed as a function of treatment time, mainly due to mineralisation; only a negligible part was lost to reject water. Considering metals and phosphorus, the main share was accumulated in the sludge residue; only minor fractions were lost to mineralisation or reject water. Post-treatment in an SPA resulted in an increase in dry matter content from 24% to 32%. After treatment, the concentrations of heavy metals (lead, cadmium, nickel, zinc, copper and chromium) in the sludge residue met the threshold values stated by the Danish Environmental Protection Agency and the EU. PMID- 29144288 TI - Gas composition of sludge residue profiles in a sludge treatment reed bed between loadings. AB - Treatment of sludge in sludge treatment reed bed systems includes dewatering and mineralization. The mineralization process, which is driven by microorganisms, produces different gas species as by-products. The pore space composition of the gas species provides useful information on the biological processes occurring in the sludge residue. In this study, we measured the change in composition of gas species in the pore space at different depth levels in vertical sludge residue profiles during a resting period of 32 days. The gas composition of the pore space in the sludge residue changed during the resting period. As the resting period proceeded, atmospheric air re-entered the pore space at all depth levels. The methane (CH4) concentration was at its highest during the first part of the resting period, and then declined as the sludge residue became more dewatered and thereby aerated. In the pore space, the concentration of CH4 often exceeded the concentration of carbon dioxide (CO2). However, the total emission of CO2 from the surface of the sludge residue exceeded the total emission of CH4, suggesting that CO2 was mainly produced in the layer of newly applied sludge and/or that CO2 was emitted from the sludge residue more readily compared to CH4. PMID- 29144289 TI - Removal of chromium(III) from aqueous waste solution by liquid-liquid extraction in a circular microchannel. AB - A new circular microchannel device has been proposed for the removal of chromium(III) from aqueous waste solution by using kerosene as a diluent and (2 ethylhexyl) 2-ethylhexyl phosphonate as an extractant. The proposed device has several advantages such as a flexible and easily adaptable design, easy maintenance, and cheap setup without the requirement of microfabrication. To study the extraction efficiency and advantages of the circular microchannel device in the removal of chromium(III), the effects of various operating conditions such as the inner diameter of the channel, the total flow velocity, the phase ratio, the initial pH of aqueous waste solution, the reaction temperature and the initial concentration of extractant on the extraction efficiency are investigated and the optimal process conditions are obtained. The results show that chromium(III) in aqueous waste solution can be effectively removed with (2-ethylhexyl) 2-ethylhexyl phosphonate in the circular microchannel. Under optimized conditions, an extraction efficiency of chromium(III) of more than 99% can be attained and the aqueous waste solution can be discharged directly, which can meet the Chinese national emission standards. PMID- 29144290 TI - Assessment of coagulation pretreatment of leachate by response surface methodology. AB - Coagulation-flocculation is a relatively simple technique that can be used successfully for the treatment of old leachate by poly-aluminum chloride (PAC). The main objectives of this study are to design the experiments, build models and optimize the operating parameters, dosage m and pH, using the central composite design and response surface method. Developed for chemical organic matter (COD) and turbidity responses, the quadratic polynomial model is suitable for prediction within the range of simulated variables as it showed that the optimum conditions were m of 5.55 g/L at pH 7.05, with a determination coefficient R2 at 99.33%, 99.92% and adjusted R2 at 98.85% and 99.86% for both COD and turbidity. We confirm that the initial pH and PAC dosage have significant effects on COD and turbidity removal. The experimental data and model predictions agreed well and the removal efficiency of COD, turbidity, Fe, Pb and Cu reached respectively 61%, 96.4%, 97.1%, 99% and 100%. PMID- 29144291 TI - Effective adsorption of nitroaromatics at the low concentration by a newly synthesized hypercrosslinked resin. AB - In the present study, a series of hypercrosslinked resins (CH series) was prepared in systematically designed conditions for the adsorption of nitroaromatics from aqueous solution. The newly synthesized CH-10 possesses a Brunauer-Emmett-Teller (BET) surface area up to 1,329.3 m2/g which is larger than that of the widely used hypercrosslinked resin H-103 and it exhibits great advantage over H-103 when subjected to nitrobenzene at low concentrations. The adsorption capacity of CH-10 for nitrobenzene is 1.4 times as much as that of H 103 at the concentration of 100 mg/L. Kinetic study by film diffusion model and intra-particle diffusion model revealed that its distinctive mesoporous structure within pore diameters between 2 and 6 nm played significant role in the mass transfer at low concentrations, and these unique mesopores also resulted in better adsorption capacity, which was confirmed by adsorption thermodynamics study. Moreover, the CH series displayed a good affinity to a wide scope of nitroaromatics and exhibited excellent dynamic adsorption and desorption properties in fixed bed. PMID- 29144292 TI - The response of nitrous oxide emissions to different operating conditions in activated sludge wastewater treatment plants in Southeastern Brazil. AB - The continuous measurements of N2O emissions from the aeration tanks of three activated sludge wastewater treatment plants (WWTPs) operated with biological nitrogen removal (BNR) and non-BNR were performed during the different operating conditions of several parameters, such as aeration, dissolved oxygen (DO) profiling and organic shock loading (with landfill leachate). The nitrification process is the main driving force behind N2O emission peaks. There are indications that the variation of the air flow rate influenced N2O emissions; high N2O emissions denote over-aeration conditions or incomplete nitrification, with accumulation of NO2- concentrations. Thus, continuous measurements of N2O emissions can provide information on aeration adequacy and the efficiency of complete nitrification, with major focus on DO control, in order to reduce N2O emissions. An additional concern is the observed propensity of WWTPs in developing countries to receive landfill leachates in their wastewater systems. This practice could have adverse effects on climate change, since wastewater treatment during periods of organic shock loading emitted significantly higher amounts of N2O than without organic shock loading. In short, non-BNR WWTPs are subject to high N2O emissions, in contrast to BNR WWTP with controlled nitrification and denitrification processes. PMID- 29144293 TI - Facile preparation of a novel catalytic particle electrode from sewage sludge and its electrocatalytic performance in three-dimensional heterogeneous electro Fenton. AB - A novel type of catalytic particle electrode (SAC-Fe) was developed from sewage sludge and iron sludge via a facile method. The catalytic particle electrodes (CPEs) were also supposed to be heterogeneous catalyst for electro-Fenton (EF). The CPEs were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). SAC-Fe showed superior porous structure and higher adsorption capacity and catalytic activity than Fe3O4 magnetic nanoparticles. Catechol and total organic carbon (TOC) removal efficiency can reach 96.7% and 88.3% after three-dimensional (3D) EF with SAC-Fe as CPEs. A possible mechanism was deduced based on adsorption tests and radicals detection. Meanwhile, the stability and reusability of the CPEs were evaluated. PMID- 29144294 TI - Higher alkyl sulfatase activity required by microbial inhabitants to remove anionic surfactants in the contaminated surface waters. AB - Biodegradation of anionic surfactants, like sodium dodecyl sulfate (SDS) are challenged by some bacteria through the function of the enzyme alkyl sulfatases. Therefore, identifying and characterizing bacteria capable of degrading SDS with high alkyl sulfatase enzyme activity are pivotal. In this study, bacteria isolated from surfactant contaminated river water were screened for their potential to degrade SDS. Primary screening carried out by the conventional enrichment culture technique and assessment of SDS-degrading ability through methylene blue active substance assay revealed 12, out of 290, SDS-degrading surface water bacteria with maximum SDS degrading abilities of 46-94% in 24-54 h. The isolates exhibited optimum growth at SDS concentration of 1 g/L, but tolerated up to 15-75 g/L. Eleven isolates were identified as the species of Pseudomonas and one isolate was identified as Aeromonas through 16S rRNA sequencing. Proteolytic activity of alkyl sulfatases in the identified isolates was shown by using native-PAGE analysis. The determined enzyme activities changed in between 1.32 and 2.90 U/mg in the crude extracts. Preliminary experiments showed that the isolates with the alkyl sulfatase enzyme activities >=2.50 U/mg were strong gratuitous degraders. However, their relative importance in soil, sewage, and wastewater treatment plants remains to be assessed. PMID- 29144295 TI - A comparative treatment of bleaching wastewater by physicochemical processes. AB - The bleaching effluent discharged from a pulp and paper mill contains chlorinated organic compounds which are toxic to living matter. Physicochemical treatments such as coagulation and different advanced oxidation processes (AOPs) were employed for combined bleaching effluent generated from the first two stages (i.e. chlorination and alkali extraction) (pH = 3.5, chemical oxygen demand (COD) = 1,920 mg/L, and total organic carbon (TOC) = 663 mg/L). At optimum conditions (pH = 7.5, polyaluminium chloride (PAC) dose = 3.84 g/L and slow mixing time = 25 min), ~68% removal in UV254 and ~23% TOC removal was obtained during coagulation. Among various AOPs, UV/Fe2+/TiO2/H2O2 system showed the highest TOC and COD removals (~78%) after 2 h duration (Fe2+:H2O2 molar ratio = 1:100). After the AOP process, chloride ion concentration and biodegradability of the treated wastewater was increased to 2,762 mg/L and 0.46 from an initial value of 2,131 mg/L and 0.29, respectively. The wastewater and sludge analysis showed oxidation and adsorption as the major mechanisms for organics removal. Upon reuse of the regenerated catalysts, TOC removal was reduced significantly. It was found that three times more sludge per unit TOC removal was generated after coagulation in comparison to that produced after UV/Fe2+/TiO2/H2O2 treatment. PMID- 29144296 TI - Dynamic desorption of arsenic from polymer-supported hydrated iron(III) oxide in a wastewater treatment plant. AB - Polymer-supported hydrated iron(III) oxide (PHIO) was successfully applied as adsorbent for arsenic removal in a wastewater treatment plant in Nandan, China. The practical PHIO adsorbent samples (PHIO-P) were collected from the adsorption column of the wastewater treatment plant, and desorption experiments of the adsorbent were carried out. Our results showed that the formation of precipitates on the surface of PHIO-P might block the porous channel of the adsorbent and decrease its arsenic adsorption capacity. In the dynamic arsenic desorption experiment, the arsenic desorption equilibrium was achieved more quickly at decreasing desorption velocity, and higher arsenic desorption efficiency was obtained at increasing NaOH concentration in regenerant. It was found that the PHIO-P adsorbent could be well regenerated at 1.0 M NaOH solution and desorption velocity of 5 BV h-1. Comparing with the raw adsorbent, the maximum arsenic adsorption capacity of PHIO-P decreased by 41.1% after practical running for 26 months. Additionally, the frequently used waste PHIO adsorbent could be treated as non-hazardous material in the arsenic-containing wastewater treatment process after long-time use. PMID- 29144297 TI - Effect of reagents used during detection and quantification of Ascaris suum in environmental samples on egg viability. AB - Soil-transmitted helminths (STHs) are a major health concern globally. Infection is mostly through contact with contaminated water, food or soil. Therefore to break the cycle of viable transmission STH eggs must be quantitatively detected in the environment. The effect of different reagents on the viability of Ascaris suum eggs during laboratory detection and quantification was assessed and different incubation solutions compared. Sulphuric acid gave a slightly higher recovery percentage of viable eggs (91.2%) than distilled water (90.0%) and 0.5% formalin (87.6%), although the difference was not statistically significant (p > 0.05). Acetoacetic acid, ethyl acetate, ammonium bicarbonate, zinc sulphate, magnesium sulphate and Tween 80, are reagents widely used in test protocols for the detection and quantification of STH eggs. Eggs were exposed to these reagents for different time durations. Acetoacetic acid resulted in the highest loss of viability (3.4 +/- 0.7% viable), while magnesium sulphate resulted in the least effect (88.5 +/- 1.2% viable). In conclusion the use of the selected reagents in the detection of these eggs was found to affect the viability of exposed eggs, especially during prolonged exposures. Therefore we recommended that eggs be exposed for <=5 minutes, to reduce the risk of viability loss. PMID- 29144298 TI - Flood forecasting within urban drainage systems using NARX neural network. AB - Urbanization activity and climate change increase the runoff volumes, and consequently the surcharge of the urban drainage systems (UDS). In addition, age and structural failures of these utilities limit their capacities, and thus generate hydraulic operation shortages, leading to flooding events. The large increase in floods within urban areas requires rapid actions from the UDS operators. The proactivity in taking the appropriate actions is a key element in applying efficient management and flood mitigation. Therefore, this work focuses on developing a flooding forecast system (FFS), able to alert in advance the UDS managers for possible flooding. For a forecasted storm event, a quick estimation of the water depth variation within critical manholes allows a reliable evaluation of the flood risk. The Nonlinear Auto Regressive with eXogenous inputs (NARX) neural network was chosen to develop the FFS as due to its calculation nature it is capable of relating water depth variation in manholes to rainfall intensities. The campus of the University of Lille is used as an experimental site to test and evaluate the FFS proposed in this paper. PMID- 29144299 TI - The modelling of lead removal from water by deep eutectic solvents functionalized CNTs: artificial neural network (ANN) approach. AB - The main challenge in the lead removal simulation is the behaviour of non linearity relationships between the process parameters. The conventional modelling technique usually deals with this problem by a linear method. The substitute modelling technique is an artificial neural network (ANN) system, and it is selected to reflect the non-linearity in the interaction among the variables in the function. Herein, synthesized deep eutectic solvents were used as a functionalized agent with carbon nanotubes as adsorbents of Pb2+. Different parameters were used in the adsorption study including pH (2.7 to 7), adsorbent dosage (5 to 20 mg), contact time (3 to 900 min) and Pb2+ initial concentration (3 to 60 mg/l). The number of experimental trials to feed and train the system was 158 runs conveyed in laboratory scale. Two ANN types were designed in this work, the feed-forward back-propagation and layer recurrent; both methods are compared based on their predictive proficiency in terms of the mean square error (MSE), root mean square error, relative root mean square error, mean absolute percentage error and determination coefficient (R2) based on the testing dataset. The ANN model of lead removal was subjected to accuracy determination and the results showed R2 of 0.9956 with MSE of 1.66 * 10-4. The maximum relative error is 14.93% for the feed-forward back-propagation neural network model. PMID- 29144300 TI - Enhancing dewaterability of waste activated sludge by combined oxidative conditioning process with zero-valent iron and peroxymonosulfate. AB - The enhancement of sludge dewaterability is of great importance for facilitating the sludge disposal during the operation of wastewater treatment plants. In this study, a novel oxidative conditioning approach was applied to enhance the dewaterability of waste activated sludge by the combination of zero-valent iron (ZVI) and peroxymonosulfate (PMS). It was found that the dewaterability of sludge was significantly improved after the addition of ZVI (0-4 g/g TSS) (TSS: total suspended solids) and PMS (0-1 g/g TSS). The optimal addition amount of ZVI and PMS was 0.25 g/g TSS and 0.1 g/g TSS, respectively, under which the capillary suction time of the sludge was reduced by approximately 50%. The decomposition of sludge flocs could contribute to the improved sludge dewaterability. Economic analysis demonstrated that the proposed conditioning process with ZVI and PMS was more economical than the ZVI + peroxydisulfate and the traditional Fenton conditioning processes. PMID- 29144301 TI - Contamination levels and potential sources of organic pollution in an Asian river. AB - The Houjing River has long been an environmental victim of economic development. Industries that have settled along the bank of this river may have largely contributed to severe organic wastes pollution. This study collected water and sediment samples at various points along the river and measured concentrations of 61 volatile organic compounds (VOCs) and 128 semi-volatile organic compounds (SVOCs) for a period of 16 months (Feb 2014-June 2015). Our analyses show that elevated levels of VOCs were observed near two industrial areas, Dashe and Renwu industrial parks. High SVOC concentrations were found in the vicinities of the Nanzih Export Processing Zone (NEPZ) and CingPu station, possibly due to considerable effluent discharges of adjacent industrial and residential areas. Comparing this study's findings with the standard values of different governmental agencies and studies similar to this one, the ecosystem of the Houjing River was seriously contaminated. This study could be used by the government as a basis for future and urgent pollution prevention actions aimed at protecting this ecosystem and reducing the negative impacts of these contaminants on the health and well-being of the local residents and the environment. PMID- 29144302 TI - Fouling mitigation in anaerobic membrane bioreactors using fluidized resin beads. AB - This study focuses on the use of fluidized resin beads to mitigate fouling during ultrafiltration (UF) of the effluent of an anaerobic bioreactor. Two different module configurations were tested: A fluidized bed of resin beads was generated in a tubular UF membrane, and a hollow fiber (HF) UF membrane was submerged into a fluidized bed, respectively. During filtration of anaerobically treated synthetic wastewater using the tubular module, fluidized resin beads with a diameter of 0.5-0.71 mm did not show any beneficial effect. In contrast, the presence of fluidized resin beads (diameter of 0.5-0.71 and 1.00-1.25 mm) in the HF module reduced the fouling rate significantly. Furthermore, particle diameter and the bed voidage affected the cleaning efficiency of a pre-fouled membrane in the HF module. Interestingly, short-term filtration tests (<2 h) of a dextran solution showed that fluidized resin beads are able to minimize concentration polarization of a macromolecule, even in the tubular module. Therefore, it is supposed that fouling of the anaerobically treated synthetic wastewater was mainly attributed to the deposition of colloidal and particulate matter. PMID- 29144303 TI - Zero-valent aluminum-mediated degradation of Bisphenol A in the presence of common oxidants. AB - The use of a commercial, nano-scale zero-valent aluminum (ZVA) powder was explored for the treatment of aqueous Bisphenol A (BPA). The study focused on the (i) activation of hydrogen peroxide (HP) and persulfate (PS) oxidants with ZVA to accelerate BPA degradation, (ii) comparison of the treatment performance in pure and real surface water (SW) samples, (iii) effects on toxicity and (iv) reuse potential of ZVA nanoparticles after ZVA/HP and ZVA/PS treatments. In pure water, ZVA coupled with HP or PS provided an effective means of BPA treatment particularly when PS was employed as the oxidant. On the other hand, in BPA spiked SW, the ZVA/HP treatment combination outperformed ZVA/PS oxidation in terms of BPA removal, whereas ZVA/PS oxidation was superior in terms of organic carbon removal. According to the bioassays conducted in pure and real SW samples with the marine photobacteria Vibrio fischeri and the freshwater microalgae Pseudokirchneriella subcapitata, the toxicity response of BPA and its oxidation products was sensitive to the test organism and water matrix. The inhibitory effect of the reaction solution increased at the early stages of ZVA/PS treatment. The reuse potential of the ZVA/HP treatment system was higher than that of the ZVA/PS treatment system. PMID- 29144304 TI - Low energy consumption vortex wave flow membrane bioreactor. AB - In order to reduce the energy consumption and membrane fouling of the conventional membrane bioreactor (MBR), a kind of low energy consumption vortex wave flow MBR was exploited based on the combination of biofilm process and membrane filtration process, as well as the vortex wave flow technique. The experimental results showed that the vortex wave flow state in the membrane module could be formed when the Reynolds number (Re) of liquid was adjusted between 450 and 1,050, and the membrane flux declined more slowly in the vortex wave flow state than those in the laminar flow state and turbulent flow state. The MBR system was used to treat domestic wastewater under the condition of vortex wave flow state for 30 days. The results showed that the removal efficiency for CODcr and NH3-N was 82% and 98% respectively, and the permeate quality met the requirement of 'Water quality standard for urban miscellaneous water consumption (GB/T 18920-2002)'. Analysis of the energy consumption of the MBR showed that the average energy consumption was 1.90 +/- 0.55 kWh/m3 (permeate), which was only two thirds of conventional MBR energy consumption. PMID- 29144305 TI - Cost minimization in a full-scale conventional wastewater treatment plant: associated costs of biological energy consumption versus sludge production. AB - Energy consumption and sludge production minimization represent rising challenges for wastewater treatment plants (WWTPs). The goal of this study is to investigate how energy is consumed throughout the whole plant and how operating conditions affect this energy demand. A WWTP based on the activated sludge process was selected as a case study. Simulations were performed using a pre-compiled model implemented in GPS-X simulation software. Model validation was carried out by comparing experimental and modeling data of the dynamic behavior of the mixed liquor suspended solids (MLSS) concentration and nitrogen compounds concentration, energy consumption for aeration, mixing and sludge treatment and annual sludge production over a three year exercise. In this plant, the energy required for bioreactor aeration was calculated at approximately 44% of the total energy demand. A cost optimization strategy was applied by varying the MLSS concentrations (from 1 to 8 gTSS/L) while recording energy consumption, sludge production and effluent quality. An increase of MLSS led to an increase of the oxygen requirement for biomass aeration, but it also reduced total sludge production. Results permit identification of a key MLSS concentration allowing identification of the best compromise between levels of treatment required, biological energy demand and sludge production while minimizing the overall costs. PMID- 29144306 TI - Characterization of a hybrid polyacrylamide and its flocculation properties in cyanide tailing suspensions. AB - An inorganic-organic hybrid flocculant Al(OH)3-polyacrylamide (Al-PAM) with narrow molecular weight distribution was synthesized using inverse microemulsion polymerization. The hybrid polymer Al-PAM was characterized by Infrared spectroscopy, thermogravimetric analysis, transmission electron microscopy and scanning electron microscopy, and it was found that it had a 'star-like' structure in which Al(OH)3 colloidal particles acted as cores linking PAM chains. The properties of Al-PAM were investigated in flocculating 10 wt% cyanide tailing suspensions. It was found that as the amount of Al-PAMM1 with high molecular weight and aluminum content increased, the initial settling rate of particles accelerated, achieving the maximum 6.6 m/h, 17.3 times the rate of the control without flocculants. The turbidity of the supernatant decreased to 35 +/- 2 NTU accordingly, compared to 353 +/- 2 NTU of that in the control, which meant that 90.0% of turbidity was removed from the cyanide tailing suspensions. The flocculation mechanism was further explored by floccule size and zeta potential measurements. The superior performance of cationic Al-PAM in flocculating negatively charged particles compared to commercial non-ionic GG indicated that electrostatic repulsion between tailing particles was a crucial factor in deciding the flocculation performance of the polymer. The study demonstrated that both charge neutralization and bridge adsorption were conductive to the particle flocculation. PMID- 29144307 TI - Reduction of chromium (VI) from aqueous solution by biomass of Cladosporium cladosporioides. AB - The capacity of Cladosporium cladosporioides biomass for removal of Cr(VI) in aqueous solutions was evaluated. A 2 * 2 factorial experiment design was used to study the effects of pH and biomass doses. Lower pH values and larger biomass doses increased the capacity of C. cladosporioides biomass for removal of Cr(VI), reaching a reduction capacity of 492.85 mg g-1, a significantly higher value compared to other biomass reported. Cr(VI) removal kinetic rates followed a pseudo-second order model, like other fungal biomass reported previously. The apparent adsorption process was described well by the Freundlich isothermal model. However, determination of total chromium indicated that adsorption of Cr(VI) was followed by a redox reaction that released proportional quantities of Cr(III) into the experimental supernatant, suggesting a parallel adsorption reduction process. Comparison of Fourier transform infrared spectroscopy spectra of C. cladosporioides biomass before and after the reduction process demonstrated the involvement of positively charged amino groups in the Cr(VI) adsorption reduction process. PMID- 29144308 TI - Numerical simulation of filtration performance in submerged membrane bioreactors: effect of particle packed structure. AB - It is widely known that the accumulation of solid matter forming a cake layer on the membrane surface is one of the major limitations of the filtration performance in submerged membrane bioreactors (SMBR). This study is focused on the influence of the cake porosity of different particle microscopic packed structures on the filtration performance of hollow fiber systems. An integrated model based on the finite element method to simulate numerically the flow in an SMBR is presented. The model coupled the Navier-Stokes and Darcy Brinkman equations to simulate a complete filtration run. The cake growth took into consideration not only the deposition with local filtration velocity but also the effect of aeration scouring. A novel solution of mesh deformation was adopted to investigate transient cake growth along the fiber. Comparisons between simulations and experiments are in good agreement. The results show that a higher porosity particle packed structure causes non-uniform filtration and cake thickness but also higher permeate flux. Meanwhile, the proportion of cake resistance to total resistance increases with the decrease of porosity. PMID- 29144309 TI - Combined electrocoagulation and electro-oxidation of industrial textile wastewater treatment in a continuous multi-stage reactor. AB - A combined electrocoagulation (EC) and electrochemical oxidation (EO) industrial textile wastewater treatment potential is evaluated in this work. A fractional factorial design of experiment showed that EC current density, followed by pH, were the most significant factors. Conductivity and number of electrooxidation cells did not affect chemical oxygen demand degradation (DCOD). Aluminum and iron anodes performed similarly as sacrificial anodes. Current density, pH and conductivity were chosen for a Box-Behnken design of experiment to determine optimal conditions to achieve a high DCOD minimizing operating cost (OC). The optimum to achieve a 70% DCOD with an OC of USD 1.47/m3 was: pH of 4, a conductivity of 3.7 mS/cm and a current density of 4.1 mA/cm2. This study also shows the applicability of a combined EC/EO treatment process of a real complex industrial wastewater. PMID- 29144310 TI - Preparation of ureido-functionalized PVA/silica mesoporous fibre membranes via electrospinning for adsorption of Pb2+ and Cu2+ in wastewater. AB - Ureido-functionalized mesoporous polyvinyl alcohol/silica composite nanofibre membranes were prepared by electrospinning technology and their application for removal of Pb2+ and Cu2+ from wastewater was discussed. The characteristics of the membranes were investigated by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and N2 adsorption-desorption analysis. Results show that the membranes have long fibrous shapes and worm-like mesoporous micromorphologies. Fourier transform infrared spectroscopy confirmed the membranes were successfully functionalized with ureido groups. Pb2+ and Cu2+ adsorption behavior on the membranes followed a pseudo-second-order nonlinear kinetic model with approximately 30 minutes to equilibrium. Pb2+ adsorption was modelled using a Langmuir isotherm model with maximum adsorption capacity of 26.96 mg g-1. However, Cu2+ adsorption was well described by a Freundlich isotherm model with poor adsorption potential due to the tendency to form chelating complexes with several ureido groups. Notably, the membranes were easily regenerated through acid treatment, and maintained adsorption capacity of 91.87% after five regeneration cycles, showing potential for applications in controlling heavy metals-related pollution and metals reuse. PMID- 29144311 TI - Velocity-based analysis of sediment incipient deposition in rigid boundary open channels. AB - Drainage systems must be designed in a way to minimize undesired problems such as decrease in hydraulic capacity of the channel, blockage and transport of pollutants due to deposition of sediment. Channel design considering self cleansing criteria are used to solve the sedimentation problem. Incipient deposition is one of the non-deposition self-cleansing design criteria that can be used as a conservative method for channel design. Experimental studies have been carried out in five different cross-section channels, namely trapezoidal, rectangular, circular, U-shape and V-bottom. Experiments were performed in a tilting flume using four different sizes of sands as sediment in nine different channel bed slopes. Two well-known methods, namely the Novak & Nalluri and Yang methods are considered for the analysis of sediment motion. Equations developed using experimental data are found to be in agreement with the literature. It is concluded that the design velocity depends on the shape of the channel cross section. Rectangular and V-bottom channels need lower and higher incipient deposition velocities, respectively, in comparison with other channels. PMID- 29144312 TI - Effectiveness of septage pre-treatment in vertical flow constructed wetlands. AB - Septage is wastewater stored temporarily in cesspools. A periodic supply of its significant quantities to small municipal wastewater treatment plants (WWTPs) may cause many operational problems. In the frame of the research, it has been proposed to utilize vertical flow constructed wetlands for pre-treatment of septage prior to its input to the biological stage of a WWTP. The aim of the work was to assess the effectiveness of pre-treatment in relation to factors such as: seasonality, hydraulic load, pollutants load of the VF bed and interactions between these factors. The results proved that application of a VF bed to septage pre-treatment can significantly reduce the concentration of pollutants (biochemical oxygen demand (BOD5): 82%, chemical oxygen demand (COD): 82%, total suspended solids (TSS): 91%, total nitrogen (TN): 47%, ammonia nitrogen (NH4-N): 70%), and thus decrease the loading of the biological stage of a WWTP. The mathematical models of mass removal process were created. They indicate that in case of all analysed parameters, removed load goes up with the increase of load in the influent. However, with the increase of hydraulic load, a decrease of the removed BOD5, COD, TSS and total phosphorus, and in vegetation period an increase of TN, can be observed in terms of load. There are no statistically significant effects of seasonality. PMID- 29144313 TI - Preliminary results of water quality assessment using phytoplankton and physicochemical approaches in the Huai River Basin, China. AB - Water pollution has been a significant issue in the Huai River Basin (HRB) of China since the late 1970s. In July and December 2013, two field investigations were carried out at 10 sites along the main streams of the basin. The monitoring indices contained both physicochemical variables and the structure and composition of phytoplankton communities. The correlations between communities and physicochemical variables were analyzed using cluster analysis and redundancy analysis. Moreover, water quality was evaluated using the comprehensive nutrition state index (TLI) and Shannon-Wiener diversity index (H). Results indicated that more phytoplankton species were present in December than in July, but total density was less in December. Phytoplankton communities in the midstream of the Shaying River were affected by the same physicochemical factors throughout the year, but ammonia nitrogen and total phosphorus had the greatest influence on these sites in July and December, respectively. The water pollution status of the sampling sites was much greater in the Shaying River midstream than at other sites. TLI was more suitable than H for assessing water quality in the study area. These results provide valuable information for policy makers and stakeholders in water quality assessment, water ecosystem restoration, and sustainable basin management in the HRB. PMID- 29144314 TI - Venereology in India. PMID- 29144315 TI - Juvenile Xanthogranuloma. PMID- 29144316 TI - Basal Cell Carcinoma Nose Simulating Scleroma. PMID- 29144317 TI - Serological Changes in Leprosy. PMID- 29144318 TI - Acute Gonorrhoea Treated with Tetracyclines. PMID- 29144319 TI - Granuloma Annulare (Review of literature with a case report). PMID- 29144320 TI - What is your diagnosis? PMID- 29144321 TI - Analytical Study of 1,054 Genital Lesions. AB - A. PMID- 29144322 TI - Studies on 100 Cases of Urticaria with Particular Reference To the Etiology. PMID- 29144324 TI - Monilethrix. PMID- 29144323 TI - Growth and Behaviour of Keloid Transplants. PMID- 29144325 TI - Syphilitic perforation of the Nasal Septum. PMID- 29144326 TI - Leucomelanoderma in Late Congenital Syphilis. PMID- 29144327 TI - A Clinical and Mycological Study of Tinea Capitis in Nagpur. PMID- 29144328 TI - Hair Penetration Ability of Various Dermatophytes "in Vitro". PMID- 29144329 TI - "Reverin" Therapy in Granuloma Venereum. PMID- 29144330 TI - Principles of Control of Leprosy and National Leprosy Control Programme. PMID- 29144331 TI - C-A note on "Undergraduate Teaching in Dermato-Venereology. PMID- 29144332 TI - Presidential Address. PMID- 29144333 TI - Gumma of the Frontal Region. PMID- 29144335 TI - Pattern of Skin Diseases in Industrial Workers. PMID- 29144334 TI - Industrial Dermatitis Due To Diesel Oil - A Study of 25 Cases. PMID- 29144336 TI - Herpes Zoster - A Clinical Study. PMID- 29144337 TI - A Preliminary Estimate on the Burden of Venereal Disease in India. PMID- 29144338 TI - Porokeratosis of Mibelli with Cutaneous Horns. PMID- 29144339 TI - What is your diagnosis? PMID- 29144340 TI - Porphyria Erythropoietica (A case report). PMID- 29144341 TI - Granuloma Venereum and A.B.O. Blood Groups. PMID- 29144342 TI - Clinical Pattern of Infantile Atopic Eczema in Bihar. PMID- 29144343 TI - Leucomelanoderma - Diagnostic Sign of Syphilis. PMID- 29144344 TI - Dermatomycoses in Rohtak (An analysis of cases). PMID- 29144345 TI - The Clients of the Common Prostitutes. PMID- 29144346 TI - ABO Blood Groups in Leprosy. PMID- 29144347 TI - ABO Blood Groups and Psoriasis. PMID- 29144348 TI - Simultaneous Manifestations of Contact Dermatitis To Multiple Antigens. PMID- 29144349 TI - A case of Focal Hypoplasia (Goltz's Syndrome) with review of Literature. PMID- 29144350 TI - What is your diagnosis? PMID- 29144351 TI - Study of Dyshidrosis. PMID- 29144352 TI - One Dose Treatment of Acute Gonorrhoea with Spiramycin (rovamycin). PMID- 29144355 TI - Tuberous Sclerosis. PMID- 29144354 TI - Topical Buclosamede in Dermatomycosis. PMID- 29144356 TI - Tinea Capitis in Hyderabad. PMID- 29144357 TI - Pyoderma Gangrenosum (A Case Report). PMID- 29144358 TI - Value of Griseofulvin in the Treatment of Herpes Zoster. PMID- 29144359 TI - Immunologic Study in Drug Reactions: Immunoelectrophoretic Analysis of Serum and Bullous Fluid in Some Drug Eruptions. PMID- 29144361 TI - Chloramphenicol Therapy in Granuloma Venereum. PMID- 29144360 TI - Chromoblastomycosis. PMID- 29144362 TI - Filariasis Complicating Reactions in Leprosy. PMID- 29144363 TI - What is your diagnosis? PMID- 29144364 TI - Clinical Evaluation of Flumethasone Pivalate (locacorten) with Neomycin As a Topical Corticosteroid. PMID- 29144365 TI - Spina Bifida Occulta (A case report with Unilateral lesions). PMID- 29144367 TI - Case Report of a Rare Type of Apocrine Gland Tumour of Groin. PMID- 29144366 TI - Topical Management of Atopic Dermatitis by Demeclocycline and Triamcinolone Ointment. PMID- 29144368 TI - Apocrine Gland Carcinoma in Axilla (Report of a case). PMID- 29144369 TI - Reactions in Leprosy. PMID- 29144370 TI - Penicillin Sensitivity of Neisseria Gonorrhoeae Strains From Calicut Kerala. PMID- 29144371 TI - Behcet's Syndrome (A case report). PMID- 29144372 TI - Chromosomal Studies in Psoriatics. PMID- 29144373 TI - Rifampicin (rimactane Ciba ) in Acute Gonorrhoea. PMID- 29144374 TI - Study on Donovanosis. PMID- 29144376 TI - What is your diagnosis? PMID- 29144375 TI - Mycosis fungoides. PMID- 29144377 TI - Symptomatic Purpura following Tuberculin test (A case report). PMID- 29144378 TI - A Comparative Study of Enriched Culture Media and Selective Culture in the Diagnosis of Gonorrhoea. PMID- 29144379 TI - A Digital Microfluidics Platform for Loop-Mediated Isothermal Amplification Detection. AB - Digital microfluidics (DMF) arises as the next step in the fast-evolving field of operation platforms for molecular diagnostics. Moreover, isothermal schemes, such as loop-mediated isothermal amplification (LAMP), allow for further simplification of amplification protocols. Integrating DMF with LAMP will be at the core of a new generation of detection devices for effective molecular diagnostics at point-of-care (POC), providing simple, fast, and automated nucleic acid amplification with exceptional integration capabilities. Here, we demonstrate for the first time the role of coupling DMF and LAMP, in a dedicated device that allows straightforward mixing of LAMP reagents and target DNA, as well as optimum temperature control (reaction droplets undergo a temperature variation of just 0.3 degrees C, for 65 degrees C at the bottom plate). This device is produced using low-temperature and low-cost production processes, adaptable to disposable and flexible substrates. DMF-LAMP is performed with enhanced sensitivity without compromising reaction efficacy or losing reliability and efficiency, by LAMP-amplifying 0.5 ng/uL of target DNA in just 45 min. Moreover, on-chip LAMP was performed in 1.5 uL, a considerably lower volume than standard bench-top reactions. PMID- 29144380 TI - A Passive and Wireless Sensor for Bone Plate Strain Monitoring. AB - This paper reports on a sensor for monitoring bone plate strain in real time. The detected bone plate strain could be used for judging the healing state of fractures in patients. The sensor consists of a magnetoelastic material, which can be wirelessly connected and passively embedded. In order to verify the effectiveness of the sensor, a tibia-bone plate-screw (TBS) model was established using the finite element analysis method. A variation of the bone plate strain was obtained via this model. A goat hindquarter tibia was selected as the bone fracture model in the experiment. The tibia was fixed on a high precision load platform and an external force was applied. Bone plate strain variation during the bone fracture healing process was acquired with sensing coils. Simulation results indicated that bone plate strain decreases as the bone gradually heals, which is consistent with the finite element analysis results. This validated the soundness of the sensor reported here. This sensor has wireless connections, no in vivo battery requirement, and long-term embedding. These results can be used not only for clinical practices of bone fracture healing, but also for bone fracture treatment and rehabilitation equipment design. PMID- 29144381 TI - Comment on Zheng et al. Association between Promoter Methylation of Gene ERCC3 and Benzene Hematotoxicity. Int. J. Environ. Res. Public Health 2017, 14, 921. AB - Benzene is an established carcinogenic substance [1,2].[...]. PMID- 29144382 TI - Treatment Approaches to Moderate to Severe Psoriasis. AB - Psoriasis is a common disease, which has a considerable impact on patients and the health care system. Treatment approaches to the disease may be various because some issues are not definitely addressed. Moreover, the therapeutic paradigms are continuously changing because of the recent approval of new treatments for psoriasis such as interleukin (IL)-17 inhibitors and apremilast. In this review, the factors influencing psoriasis severity, the indications for systemic treatments, the overall parameters to be considered in the treatment choice, life style interventions, and the recommendations for the use, screening, and monitoring of systemic therapies available including acitretin, cyclosporine, methotrexate, apremilast, adalimumab, etanercept, infliximab, secukinumab, ixekizumab, and ustekinumab are discussed. Finally, treatment approaches in special patient populations including children, the elderly, pregnant women, patients with a history of neoplasm, and candidates for surgical procedures are reported. PMID- 29144383 TI - Monitoring for Response to Antineoplastic Drugs: The Potential of a Metabolomic Approach. AB - For most cancers, chemotherapeutic options are rapidly expanding, providing the oncologist with substantial choices. Therefore, there is a growing need to select the best systemic therapy, for any individual, that effectively halts tumor progression with minimal toxicity. Having the capability to predict benefit and to anticipate toxicity would be ideal, but remains elusive at this time. An alternative approach is an adaptive approach that involves close observation for treatment response and emergence of resistance. Currently, response to systemic therapy is estimated using radiographic tests. Unfortunately, radiographic estimates of response are imperfect and radiographic signs of response can be delayed. This is particularly problematic for targeted agents, as tumor shrinkage is often not apparent with these drugs. As a result, patients are exposed to prolonged courses of toxic drugs that may ultimately be found to be ineffective. A biomarker-based adaptive strategy that involves the serial analysis of the metabolome is attractive. The metabolome changes rapidly with changes in physiology. Changes in the circulating metabolome associated with various antineoplastic agents have been described, but further work will be required to understand what changes signify clinical benefit. We present an investigative approach for the discovery and validation of metabolomic response biomarkers, which consists of serial analysis of the metabolome and linkage of changes in the metabolome to measurable therapeutic benefit. Potential pitfalls in the development of metabolomic biomarkers of response and loss of response are reviewed. PMID- 29144384 TI - Mediator Preference of Two Different FAD-Dependent Glucose Dehydrogenases Employed in Disposable Enzyme Glucose Sensors. AB - Most commercially available electrochemical enzyme sensor strips for the measurement of blood glucose use an artificial electron mediator to transfer electrons from the active side of the enzyme to the electrode. One mediator recently gaining attention for commercial sensor strips is hexaammineruthenium(III) chloride. In this study, we investigate and compare the preference of enzyme electrodes with two different FAD-dependent glucose dehydrogenases (FADGDHs) for the mediators hexaammineruthenium(III) chloride, potassium ferricyanide (the most common mediator in commercial sensor strips), and methoxy phenazine methosulfate (mPMS). One FADGDH is a monomeric fungal enzyme, and the other a hetero-trimeric bacterial enzyme. With the latter, which contains a heme-subunit facilitating the electron transfer, similar response currents are obtained with hexaammineruthenium(III), ferricyanide, and mPMS (6.8 uA, 7.5 uA, and 6.4 uA, respectively, for 10 mM glucose). With the fungal FADGDH, similar response currents are obtained with the negatively charged ferricyanide and the uncharged mPMS (5.9 uA and 6.7 uA, respectively, for 10 mM glucose), however, no response current is obtained with hexaammineruthenium(III), which has a strong positive charge. These results show that access of even very small mediators with strong charges to a buried active center can be almost completely blocked by the protein. PMID- 29144385 TI - Preparation and Characterization of Cellulose Triacetate as Support for Lecitase Ultra Immobilization. AB - The use of polymers as supports for enzyme immobilization is a strategy that enables to remove the enzymes from a chemical reaction and improve their efficiency in catalytic processes. In this work, cellulose triacetate (CTA) was used for physical adsorption of phospholipase Lecitase ultra (LU). CTA is more hydrophobic than cellulose, shows good performance in the lipases immobilization being a good candidate for immobilization of phospholipases. We investigated the immobilization of LU in CTA, the stability of the immobilized enzyme (CTA-LU) and the performance of CTA-LU using soybean oil as a substrate. LU was efficiently immobilized in CTA reaching 97.1% in 60 min of contact with an enzymatic activity of 975.8 U.g-1. The CTA-LU system presents good thermal stability, being superior of the free enzyme and increase of the catalytic activity in the whole range of pH values. The difference observed for immobilized enzyme compared to free one occurs because of the interaction between the enzyme and the polymer, which stabilizes the enzyme. The CTA-LU system was used in the transesterification of soybean oil with methanol, with the production of fatty acid methyl esters. The results showed that CTA-LU is a promising system for enzymatic reactions. PMID- 29144386 TI - Creating a World-Class Program through Training and Certification. AB - The animal research field has gotten more sophisticated with the use of genetically engineered animals, biohazardous agents, and advanced technologies. Trained and competent personnel are a cornerstone of any animal care and use program. Individual career success is a combination of education, experience, continuing competence, professional development, and personal commitment. Integration of training and certification into programs demonstrate institutional commitment to quality research and enhance the program by providing staff with knowledge and training to address problems and situation that arise and to perform their job in a professional and effective manner. Professional development programs offered through the American Association for Laboratory Animal Science-including the AALAS Learning Library and the AALAS certification process-will be presented. PMID- 29144388 TI - Hyperspectral Image Enhancement and Mixture Deep-Learning Classification of Corneal Epithelium Injuries. AB - In our preliminary study, the reflectance signatures obtained from hyperspectral imaging (HSI) of normal and abnormal corneal epithelium tissues of porcine show similar morphology with subtle differences. Here we present image enhancement algorithms that can be used to improve the interpretability of data into clinically relevant information to facilitate diagnostics. A total of 25 corneal epithelium images without the application of eye staining were used. Three image feature extraction approaches were applied for image classification: (i) image feature classification from histogram using a support vector machine with a Gaussian radial basis function (SVM-GRBF); (ii) physical image feature classification using deep-learning Convolutional Neural Networks (CNNs) only; and (iii) the combined classification of CNNs and SVM-Linear. The performance results indicate that our chosen image features from the histogram and length-scale parameter were able to classify with up to 100% accuracy; particularly, at CNNs and CNNs-SVM, by employing 80% of the data sample for training and 20% for testing. Thus, in the assessment of corneal epithelium injuries, HSI has high potential as a method that could surpass current technologies regarding speed, objectivity, and reliability. PMID- 29144387 TI - Neighborhood Prices of Healthier and Unhealthier Foods and Associations with Diet Quality: Evidence from the Multi-Ethnic Study of Atherosclerosis. AB - It is known that the price of food influences the purchasing and consumption decisions of individuals; however, little work has examined if the price of healthier food relative to unhealthier food in an individual's neighborhood is associated with overall dietary quality while using data from multiple regions in the United States. Cross-sectional person-level data came from The Multi-Ethnic Study of Atherosclerosis (exam 5, 2010-2012 n = 2765); a food frequency questionnaire assessed diet. Supermarket food/beverage prices came from Information Resources Inc. (n = 794 supermarkets). For each individual, the average price of select indicators of healthier foods (vegetables, fruits, dairy) and unhealthier foods (soda, sweets, salty snacks), as well as their ratio, was computed for supermarkets within three miles of the person's residential address. Logistic regression estimated odds ratios of a high-quality diet (top quintile of Healthy Eating Index 2010) associated with healthy-to-unhealthy price ratio, adjusted for individual and neighborhood characteristics. Sensitivity analyses used an instrumental variable (IV) approach. Healthier foods cost nearly twice as much as unhealthier foods per serving on average (mean healthy-to-unhealthy ratio = 1.97 [SD 0.14]). A larger healthy-to-unhealthy price ratio was associated with lower odds of a high-quality diet (OR = 0.76 per SD increase in the ratio, 95% CI = [0.64-0.9]). IV analyses largely confirmed these findings although-as expected with IV adjustment-confidence intervals were wide (OR = 0.82 [0.57-1.19]). Policies to address the large price differences between healthier and unhealthy foods may help improve diet quality in the United States. PMID- 29144389 TI - Effects of Infrared Optical Trapping on Saccharomyces cerevisiae in a Microfluidic System. AB - Baker's yeast (Saccharomyces cerevisiae) represents a very popular single-celled eukaryotic model organism which has been studied extensively by various methods and whose genome has been completely sequenced. It was also among the first living organisms that were manipulated by optical tweezers and it is currently a frequent subject of optical micromanipulation experiments. We built a microfluidic system for optical trapping experiments with individual cells and used it for the assessment of cell tolerance to phototoxic stress. Using optical tweezers with the wavelength of 1064 nm, we trapped individual Saccharomyces cerevisiae cells for 15 min and, subsequently, observed their stress response in specially designed microfluidic chambers over time periods of several hours by time-lapse video-microscopy. We determined the time between successive bud formations after the exposure to the trapping light, took account of damaged cells, and calculated the population doubling period and cell areas for increasing trapping power at a constant trapping time. Our approach represents an attractive, versatile microfluidic platform for quantitative optical trapping experiments with living cells. We demonstrate its application potential by assessing the limits for safe, non-invasive optical trapping of Saccharomyces cerevisiae with infrared laser light. PMID- 29144390 TI - RNA Sequencing and Coexpression Analysis Reveal Key Genes Involved in alpha Linolenic Acid Biosynthesis in Perilla frutescens Seed. AB - Perillafrutescen is used as traditional food and medicine in East Asia. Its seeds contain high levels of alpha-linolenic acid (ALA), which is important for health, but is scarce in our daily meals. Previous reports on RNA-seq of perilla seed had identified fatty acid (FA) and triacylglycerol (TAG) synthesis genes, but the underlying mechanism of ALA biosynthesis and its regulation still need to be further explored. So we conducted Illumina RNA-sequencing in seven temporal developmental stages of perilla seeds. Sequencing generated a total of 127 million clean reads, containing 15.88 Gb of valid data. The de novo assembly of sequence reads yielded 64,156 unigenes with an average length of 777 bp. A total of 39,760 unigenes were annotated and 11,693 unigenes were found to be differentially expressed in all samples. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, 486 unigenes were annotated in the "lipid metabolism" pathway. Of these, 150 unigenes were found to be involved in fatty acid (FA) biosynthesis and triacylglycerol (TAG) assembly in perilla seeds. A coexpression analysis showed that a total of 104 genes were highly coexpressed (r > 0.95). The coexpression network could be divided into two main subnetworks showing over expression in the medium or earlier and late phases, respectively. In order to identify the putative regulatory genes, a transcription factor (TF) analysis was performed. This led to the identification of 45 gene families, mainly including the AP2-EREBP, bHLH, MYB, and NAC families, etc. After coexpression analysis of TFs with highly expression of FAD2 and FAD3 genes, 162 TFs were found to be significantly associated with two FAD genes (r > 0.95). Those TFs were predicted to be the key regulatory factors in ALA biosynthesis in perilla seed. The qRT-PCR analysis also verified the relevance of expression pattern between two FAD genes and partial candidate TFs. Although it has been reported that some TFs are involved in seed development, more direct evidence is still needed to verify their function. However, these findings can provide clues to reveal the possible molecular mechanisms of ALA biosynthesis and its regulation in perilla seed. PMID- 29144392 TI - Design and Development of a Novel Upper-Limb Cycling Prosthesis. AB - The rise in popularity of the Paralympics in recent years has created a need for effective, low-cost sports-prosthetic devices for upper-limb amputees. There are various opportunities for lower-limb amputees to participate in cycling; however, there are only few options for those with upper-limb amputations. If the individual previously participated in cycling, a cycling-specific prosthesis could allow these activities to be integrated into rehabilitation methods. This article describes the processes involved with designing, developing and manufacturing such a prosthesis. The fundamental needs of people with upper-limb amputation were assessed and realised in the prototype of a transradial terminal device with two release mechanisms, including a sliding mechanism (for falls and minor collisions) and clamping mechanism (for head-on collisions). The sliding mechanism requires the rider to exert approximately 200 N, while the clamping mechanism requires about 700 N. The force ranges can be customised to match rider requirements. Experiments were conducted in a controlled environment to demonstrate stability of the device during normal cycling. Moreover, a volunteer test-rider was able to successfully activate the release mechanism during a simulated emergency scenario. The development of this prosthesis has the potential to enable traumatic upper-limb amputees to participate in cycling for rehabilitation or recreation. PMID- 29144391 TI - Antimicrobial Peptide Epinecidin-1 Modulates MyD88 Protein Levels via the Proteasome Degradation Pathway. AB - The cationic antimicrobial peptide epinecidin-1 was identified from Epinephelus coioides and possesses multiple biological functions, including antibacterial, antifungal, anti-tumor, and immunomodulatory effects. In addition, epinecidin-1 suppresses lipopolysaccharide (LPS)-induced inflammation by neutralizing LPS and ameliorating LPS/Toll-like receptor (TLR)-4 internalization. However, it is unclear whether the actions of epinecidin-1 depend on the regulation of TLR adaptor protein MyD88 or endogenous TLR signaling antagonists, which include A20, interleukin-1 receptor associated kinase (IRAK)-M, and suppressor of cytokine signaling (SOCS)-1. Our results demonstrate that epinecidin-1 alone does not affect A20, IRAK-M, or SOCS-1 protein levels. However, pre-incubation of epinecidin-1 significantly inhibits LPS-induced upregulation of A20, IRAK-M, and SOCS-1. In addition, epinecidin-1 significantly reduces the abundance of MyD88 protein. Both MG132 (a specific proteasome inhibitor) and Heclin (a specific Smurf E3 ligase inhibitor) are able to abolish epinecidin-1-mediated MyD88 degradation. Thus, our data suggest that epinecidin-1 directly inhibits MyD88 via induction of the Smurf E3 ligase proteasome pathway. PMID- 29144394 TI - Estimating Crop Area at County Level on the North China Plain with an Indirect Sampling of Segments and an Adapted Regression Estimator. AB - Image classifications, including sub-pixel analysis, are often used to estimate crop acreage directly. However, this type of assessment often leads to a biased estimation, because commission and omission errors generally do not compensate for each other. Regression estimators combine remote sensing information with more accurate ground data on a field sample, and can result in more accurate and cost-effective assessments of crop acreage. In this pilot study, which aims to produce crop statistics in Guoyang County, the area frame sampling approach is adapted to a strip-like cropping pattern on the North China Plain. Remote sensing information is also used to perform a stratification in which non-agricultural areas are excluded from the ground survey. In order to compute crop statistics, 202 ground points in the agriculture stratum were surveyed. Image classification was included as an auxiliary variable in the subsequent analysis to obtain a regression estimator. The results of this pilot study showed that the integration of remote sensing information as an auxiliary variable can improve the accuracy of estimation by reducing the variance of the estimates, as well as the cost effectiveness of an operational application at the county level in the region. PMID- 29144393 TI - Growth, Gastrointestinal Tolerance and Stool Characteristics of Healthy Term Infants Fed an Infant Formula Containing Hydrolyzed Whey Protein (63%) and Intact Casein (37%): A Randomized Clinical Trial. AB - To investigate whether healthy term infants, fed an infant formula containing hydrolyzed whey protein (HWP-F, hydrolyzed whey/intact casein =63/37), differ in growth, gastrointestinal tolerance and stool characteristics from those fed an infant formula containing intact whey protein (IWP-F, intact whey/intact casein =61/39) or breast milk. Healthy term infants, born within 14 days of the study's commencement, were randomly assigned to be fed IWP-F or HWP-F until 13 weeks of age, and breast-fed (BF) infants were enrolled as a reference group. Anthropometric measurements, gastrointestinal tolerance indexes and stool characteristics were assessed at baseline, and 7 and 13 weeks of age. There were no significant differences in any growth measurements and the occurrence of crying, spit-up and difficult defecation among the three feeding groups during the study period. However, daily feeding frequency was consistently lower in the formula-fed infants than in the BF group throughout the study (p < 0.05), and infants in the HWP-F group consumed more formula than those in the IWP-F group at 7 and 13 weeks of age (p <= 0.002). The HWP-F-fed infants had more similar stool characteristics to the breast-fed infants than infants in the IWP-F group at 13 weeks of age, regardless of frequency, volume, color or consistency of stool. This study demonstrates that the HWP-F could support the normal growth of healthy term infants, to a comparable extent to that of breast-fed infants during the first three months of life. Moreover, stool characteristics of HWP-F-fed infants are much closer to breast-fed infants than IWP-F-fed infants, but no significant gastrointestinal tolerance improvement was observed in HWP-F group. PMID- 29144395 TI - Real-Time Indoor Scene Description for the Visually Impaired Using Autoencoder Fusion Strategies with Visible Cameras. AB - This paper describes three coarse image description strategies, which are meant to promote a rough perception of surrounding objects for visually impaired individuals, with application to indoor spaces. The described algorithms operate on images (grabbed by the user, by means of a chest-mounted camera), and provide in output a list of objects that likely exist in his context across the indoor scene. In this regard, first, different colour, texture, and shape-based feature extractors are generated, followed by a feature learning step by means of AutoEncoder (AE) models. Second, the produced features are fused and fed into a multilabel classifier in order to list the potential objects. The conducted experiments point out that fusing a set of AE-learned features scores higher classification rates with respect to using the features individually. Furthermore, with respect to reference works, our method: (i) yields higher classification accuracies, and (ii) runs (at least four times) faster, which enables a potential full real-time application. PMID- 29144396 TI - Salivary Oxytocin Concentration Changes during a Group Drumming Intervention for Maltreated School Children. AB - Many emotionally-disturbed children who have been maltreated and are legally separated from their parents or primary caregivers live in group homes and receive compulsory education. Such institutions provide various special intervention programs. Taiko-ensou, a Japanese style of group drumming, is one such program because playing drums in a group may improve children's emotional well-being. However, evidence for its efficacy has not been well established at the biological level. In this study, we measured salivary levels of oxytocin (OT), a neuropeptide associated with social memory and communication, in three conditions (recital, practice, and free sessions) in four classes of school-aged children. Following the sessions, OT concentrations showed changes in various degrees and directions (no change, increases, or decreases). The mean OT concentration changes after each session increased, ranging from 112% to 165%. Plasma OT concentrations were equally sensitive to drum playing in school-aged boys and girls. However, the difference between practice and free play sessions was only significant among elementary school boys aged 8-12 years. The results suggest that younger boys are most responsive to this type of educational music intervention. PMID- 29144397 TI - Sulforaphane Alters beta-Naphthoflavone-Induced Changes in Activity and Expression of Drug-Metabolizing Enzymes in Rat Hepatocytes. AB - Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, exerts many beneficial effects on human health such as antioxidant, anti-inflammatory, and anticancer effects. The effect of SFN alone on drug-metabolizing enzymes (DMEs) has been investigated in numerous in vitro and in vivo models, but little is known about the effect of SFN in combination with cytochrome P450 (CYP) inducer. The aim of our study was to evaluate the effect of SFN on the activity and gene expression of selected DMEs in primary cultures of rat hepatocytes treated or non-treated with beta-naphthoflavone (BNF), the model CYP1A inducer. In our study, SFN alone did not significantly alter the activity and expression of the studied DMEs, except for the glutathione S-transferase (GSTA1) mRNA level, which was significantly enhanced. Co-treatment of hepatocytes with SFN and BNF led to a substantial increase in sulfotransferase, aldoketoreductase 1C, carbonylreductase 1 and NAD(P)H:quinone oxidoreductase 1 activity and a marked decrease in cytochrome P450 (CYP) Cyp1a1, Cyp2b and Cyp3a4 expression in comparison to the treatment with BNF alone. Sulforaphane is able to modulate the activity and/or expression of DMEs, thus shifting the balance of carcinogen metabolism toward deactivation, which could represent an important mechanism of its chemopreventive activity. PMID- 29144398 TI - Predict the Relationship between Gene and Large Yellow Croaker's Economic Traits. AB - The importance of a gene's impact on traits is well appreciated. Gene expression will affect the growth, immunity, reproduction and environmental resistance of some fish, and then affect the economic performance of fish-related business. Studying the connection between gene and character can help elucidate the growth of fishes. Thus far, a collected database containing large yellow croaker (Larimichthys crocea) genes does not exist. The gene having to do with the growth efficiency of fish will have a huge impact on research. For example, the protein encoded by the IFIH1 gene is associated with the function of viral infection in the immune system, which affects the survival rate of large yellow croakers. Thus, we collected data through the published literature and combined them with a biological genetic database related to the large yellow croaker. Based on the data, we can predict new gene-trait associations which have not yet been discovered. This work will contribute to research on the growth of large yellow croakers. PMID- 29144399 TI - DNA G-Wire Formation Using an Artificial Peptide is Controlled by Protease Activity. AB - The development of a switching system for guanine nanowire (G-wire) formation by external signals is important for nanobiotechnological applications. Here, we demonstrate a DNA nanostructural switch (G-wire <--> particles) using a designed peptide and a protease. The peptide consists of a PNA sequence for inducing DNA to form DNA-PNA hybrid G-quadruplex structures, and a protease substrate sequence acting as a switching module that is dependent on the activity of a particular protease. Micro-scale analyses via TEM and AFM showed that G-rich DNA alone forms G-wires in the presence of Ca2+, and that the peptide disrupted this formation, resulting in the formation of particles. The addition of the protease and digestion of the peptide regenerated the G-wires. Macro-scale analyses by DLS, zeta potential, CD, and gel filtration were in agreement with the microscopic observations. These results imply that the secondary structure change (DNA G quadruplex <--> DNA/PNA hybrid structure) induces a change in the well-formed nanostructure (G-wire <--> particles). Our findings demonstrate a control system for forming DNA G-wire structures dependent on protease activity using designed peptides. Such systems hold promise for regulating the formation of nanowire for various applications, including electronic circuits for use in nanobiotechnologies. PMID- 29144400 TI - Design and Clinical Evaluation of a Non-Contact Heart Rate Variability Measuring Device. AB - The object of the proposed paper is to design and analyze the performance of a non-contact heart rate variability (HRV) measuring device based on ultrasound transducers. The rationale behind non-contact HRV measurement is the goal of obtaining a means of long term monitoring of a patient's heart performance. Due to its complexity as a non-contact measuring device, influential physical quantities, error source and other perturbations were thoroughly investigated. For medical purposes it is of utmost importance to define the target uncertainty of a measuring method from the side of physicians, while it is the role of scientists to realistically evaluate all uncertainty contributions. Within this paper we present a novelty method of non-contact HRV measurement based on ultrasound transducers operating at two frequencies simultaneously. We report laboratory results and clinical evaluations are given for healthy subjects as well as patients with known heart conditions. Furthermore, laboratory tests were conducted on subjects during a relaxation period, and after 1 min physical activity. PMID- 29144401 TI - Design, Synthesis and Preliminary Biological Evaluation of Novel Benzyl Sulfoxide 2-Indolinone Derivatives as Anticancer Agents. AB - In this work, a series of novel benzyl sulfoxide 2-indolinone derivatives was designed and synthesized as potent anticancer agents. Tyrosine kinase inhibitory activity assay indicated that most of the compounds showed significant activity. The in vitro antiproliferative activity of these compounds was further investigated against five human cancer cell lines (HeLa, HepG2, MCF-7, SCC-15, and A549). Several compounds exhibited evident activities. Among them, (Z)-3-(((4 bromobenzyl)sulfinyl)methylene)indolin-2-one (6j) and (Z)-3 ((benzylsulfinyl)methylene)-5-bromoindolin-2-one (6o) were found to be effective tyrosine kinase inhibitors (IC50 = 1.34 and 2.69 MUM, respectively) in addition to having noteworthy antitumor potential (the average IC50 value of 6j or 6o was less than 40 MUM). This class of novel derivatives has promising potential for further development as anticancer agents. PMID- 29144402 TI - Characterization of Non-Derivatized Cellulose Samples by Size Exclusion Chromatography in Tetrabutylammonium Fluoride/Dimethylsulfoxide (TBAF/DMSO). AB - This paper deals with the use of tetrabutylammonium fluoride/dimethylsulfoxide (TBAF/DMSO) to characterize the molar mass distribution of non-derivatized cellulosic samples by size exclusion chromatography (SEC). Different cellulose samples with various average degree of polymerization (DP) were first solubilized in this solvent system, with increasing TBAF rates, and then analyzed by SEC coupled to a refractive index detector (RID), using DMSO as mobile phase. The Molar Masses (MM) obtained by conventional calibration were then discussed and compared with suppliers' data and MM determined by viscosimetry measurements. By this non-classic method, molar mass of low DP samples (Avicel(r) and cotton fibers) have been determined. For high DP samples (alpha-cellulose and Vitacel(r)), dissolution with TBAF concentration of 10 mg/mL involved elution of cellulose aggregates in the exclusion volume, related to an incomplete dissolution or the dilution of TBAF molecules in elution solvent, preventing the correct evaluation of their molar mass. PMID- 29144403 TI - The Non-Homologous End Joining Protein PAXX Acts to Restrict HSV-1 Infection. AB - Herpes simplex virus 1 (HSV-1) has extensive interactions with the host DNA damage response (DDR) machinery that can be either detrimental or beneficial to the virus. Proteins in the homologous recombination pathway are known to be required for efficient replication of the viral genome, while different members of the classical non-homologous end-joining (c-NHEJ) pathway have opposing effects on HSV-1 infection. Here, we have investigated the role of the recently discovered c-NHEJ component, PAXX (Paralogue of XRCC4 and XLF), which we found to be excluded from the nucleus during HSV-1 infection. We have established that cells lacking PAXX have an intact innate immune response to HSV-1 but show a defect in viral genome replication efficiency. Counterintuitively, PAXX-/- cells were able to produce greater numbers of infectious virions, indicating that PAXX acts to restrict HSV-1 infection in a manner that is different from other c-NHEJ factors. PMID- 29144404 TI - Dietary Magnesium and Incident Frailty in Older People at Risk for Knee Osteoarthritis: An Eight-Year Longitudinal Study. AB - Inadequate magnesium (Mg) intake is associated with lower physical performance, but the relationship with frailty in older people is unclear. Therefore, we aimed to investigate whether higher dietary Mg intake is associated with a lower risk of frailty in a large cohort of North American individuals. Details regarding Mg intake were recorded through a food-frequency questionnaire (FFQ) and categorized as greater than/equal to Recommended Dietary Allowance (RDA) vs. lower. Frailty was defined using the Study of Osteoporotic Fractures index. Multivariable Cox's regression analyses, calculating hazard ratios (HRs) with 95% confidence intervals (CIs), were undertaken by sex. In total, 4421 individuals with knee osteoarthritis or who were at high risk without frailty at baseline (mean age: 61.3, females = 58.0%) were followed for 8 years. After adjusting for 11 potential baseline confounders, reaching the RDA for Mg lowered risk of frailty among men (total n = 1857, HR = 0.51; 95% CI: 0.26-0.93), whilst no significant associations were found in women (total n = 2564). Each 100 mg of dietary Mg intake at baseline corresponded to a 22% reduction in men (HR = 0.78; 95% CI: 0.62-0.97; p = 0.03), but not in women (HR = 1.05; 95% CI: 0.89-1.23). In conclusion, higher dietary Mg intake appears to reduce the risk of frailty in men, but not in women. PMID- 29144405 TI - Genomic Analysis of the ASMT Gene Family in Solanum lycopersicum. AB - Acetylserotonin methyltransferase (ASMT) is the last enzyme of melatonin biosynthesis and may play a rate-limiting role in the melatonin production of plants. In this study, systematic analysis of the ASMT gene family in tomato (Solanum lycopersicum Mill) has been presented by the integration of the structural features, phylogenetic relationships, exon/intron configuration, and expression profile during growth and development, as well as biotic stresses. The results revealed that the tomato genome encoded a minimum of 14 members, containing three probable encoded pseudogenes. Chromosome mapping indicated that the family had probably expanded via tandem duplication events. Genome-wide RNA seq and qRT-PCR based gene expression analysis revealed that almost half of the SlASMT genes were expressed in at least one of the experimental stages studied and also showed differential accumulation. Furthermore, the tandem duplicated SlASMT genes showed differential expression levels, which indicated probable functional divergence during the course of the evolution. Finally, this study also determined that some SlASMT genes were induced by multiple pathogens. The results suggested that these genes could be involved in tomato plant response to biotic stresses. PMID- 29144406 TI - Evaluating Differences in Aluminum Exposure through Parenteral Nutrition in Neonatal Morbidities. AB - Aluminum is a common contaminant in many components of parenteral nutrition, especially calcium and phosphate additives. Although long-term effects have been described in the literature, short-term effects are not well-known. Currently, the Food and Drug Administration recommends maintaining aluminum at <5 mcg/kg/day. This was a single center, retrospective case-control study of 102 neonatal intensive care unit patients. Patients were included if they had a diagnosis of necrotizing enterocolitis, rickets/osteopenia, or seizures and received at least 14 days of parenteral nutrition. Patients were matched 1:1 with control patients by gestational age and birth weight. Mean total aluminum exposure for the 14 days of parenteral nutrition was calculated using manufacturer label information. Differences in mean aluminum exposure between cases and controls, as well as subgroup analysis in those with renal impairment or cholestasis, was conducted. Aluminum exposure in patients meeting inclusion criteria closely mirrored the aluminum exposure of control patients. The difference in aluminum exposure was not found to be statistically significant, except in patients with cholestasis. Although the study found no difference in aluminum exposure in short-term complications with neonates, long-term complications are well established and may warrant the need to monitor and limit neonatal aluminum exposure. PMID- 29144407 TI - The Effects of Various Weather Conditions as a Potential Ischemic Stroke Trigger in Dogs. AB - Stroke is the fifth leading cause of death in the United States, and is the leading cause of serious, long-term disability worldwide. There are at least 795,000 new or recurrent strokes each year, and approximately 85% of all stroke occurrences are ischemic. Unfortunately, companion animals are also at risk for ischemic stroke. Although the exact incidence of ischemic stroke in companion animals is unknown, some studies, and the veterinary information network (VIN), report that approximately 3% of neurological case referrals are due to a stroke. There is a long list of predisposing factors associated with the risk of ischemic stroke in both humans and canines; however, these factors do not explain why a stroke happens at a particular time on a particular day. Our understanding of these potential stroke "triggers" is limited, and the effect of transient environmental exposures may be one such "trigger". The present study investigated the extent to which the natural occurrence of canine ischemic stroke was related to the weather conditions in the time-period immediately preceding the onset of stroke. The results of the present study demonstrated that the change in weather conditions could be a potential stroke trigger, with the strokes evaluated occurring after periods of rapid, large fluctuations in weather conditions. There are currently no epidemiological data on the seasonal variability of ischemic stroke in dogs, and determining whether canine stroke parallels human stroke would further validate the use of companion dogs as an appropriate naturally occurring model. PMID- 29144409 TI - How Well Can We Extract the Permanent Displacement from Low-Cost MEMS Accelerometers? AB - Following the recent establishment of a high-density seismic network equipped with low-cost micro-electro-mechanical system (MEMS) P-wave-alert-device (P Alert) by the earthquake early warning (EEW) research group at the National Taiwan University, a large quantity of strong-motion records from moderate magnitude earthquakes (ML > 6) around Taiwan has been accumulated. Using a data preprocessing scheme to recover the dynamic average embedded within the P-Alert data, we adopted an automatic baseline correction approach for the P-Alert accelerograms to determine the coseismic deformation (Cd). Comparisons between the Cd values determined using global positioning system (GPS) data, strong motion records from the P-Alert network, and data from the Taiwan Strong Motion Instrumentation Program (TSMIP) demonstrates that the near-real-time determination of Cd values (>2 cm), which provide crucial information for seismic hazard mitigation, is possible using records from low-cost MEMS accelerometers. PMID- 29144408 TI - Antioxidant Effect of Barley Sprout Extract via Enhancement of Nuclear Factor Erythroid 2 Related Factor 2 Activity and Glutathione Synthesis. AB - We previously showed that barley sprout extract (BSE) prevents chronic alcohol intake-induced liver injury in mice. BSE notably inhibited glutathione (GSH) depletion and increased inflammatory responses, revealing its mechanism of preventing alcohol-induced liver injury. In the present study we investigated whether the antioxidant effect of BSE involves enhancing nuclear factor-erythroid 2 related factor 2 (Nrf2) activity and GSH synthesis to inhibit alcohol-induced oxidative liver injury. Mice fed alcohol for four weeks exhibited significantly increased oxidative stress, evidenced by increased malondialdehyde (MDA) level and 4-hydroxynonenal (4-HNE) immunostaining in the liver, whereas treatment with BSE (100 mg/kg) prevented these effects. Similarly, exposure to BSE (0.1-1 mg/mL) significantly reduced oxidative cell death induced by t-butyl hydroperoxide (t BHP, 300 MUM) and stabilized the mitochondrial membrane potential (?psi). BSE dose-dependently increased the activity of Nrf2, a potential transcriptional regulator of antioxidant genes, in HepG2 cells. Therefore, increased expression of its target genes, heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase catalytic subunit (GCLC) was observed. Since GCLC is involved in the rate-limiting step of GSH synthesis, BSE increased the GSH level and decreased both cysteine dioxygenase (CDO) expression and taurine level. Because cysteine is a substrate for both taurine and GSH synthesis, a decrease in CDO expression would further contribute to increased cysteine availability for GSH synthesis. In conclusion, BSE protected the liver cells from oxidative stress by activating Nrf2 and increasing GSH synthesis. PMID- 29144410 TI - Evaluation of Different Single-Walled Carbon Nanotube Surface Coatings for Single Particle Tracking Applications in Biological Environments. AB - Fluorescence imaging of biological systems down to the single-molecule level has generated many advances in cellular biology. For applications within intact tissue, single-walled carbon nanotubes (SWCNTs) are emerging as distinctive single-molecule nanoprobes, due to their near-infrared photoluminescence properties. For this, SWCNT surfaces must be coated using adequate molecular moieties. Yet, the choice of the suspension agent is critical since it influences both the chemical and emission properties of the SWCNTs within their environment. Here, we compare the most commonly used surface coatings for encapsulating photoluminescent SWCNTs in the context of bio-imaging applications. To be applied as single-molecule nanoprobes, encapsulated nanotubes should display low cytotoxicity, and minimal unspecific interactions with cells while still being highly luminescent so as to be imaged and tracked down to the single nanotube level for long periods of time. We tested the cell proliferation and cellular viability of each surface coating and evaluated the impact of the biocompatible surface coatings on nanotube photoluminescence brightness. Our study establishes that phospholipid-polyethylene glycol-coated carbon nanotube is the best current choice for single nanotube tracking experiments in live biological samples. PMID- 29144414 TI - Wear Behavior and Microstructure of Mg-Sn Alloy Processed by Equal Channel Angular Extrusion. AB - Mg-5wt.% Sn alloy is often used in portable electronic devices and automobiles. In this study, mechanical properties of Mg-5wt.% Sn alloy processed by Equal Channel Angular Extrusion (ECAE) were characterized. More precisely, its hardness and wear behavior were measured using Vickers hardness test and a pin-on-disc wear test. The microstructures of ECAE-processed Mg-Sn alloys were investigated by scanning electron microscope and X-ray diffraction. ECAE process refined the grain sizes of the Mg-Sn alloy from 117.6 MUm (as-cast) to 88.0 MUm (one pass), 49.5 MUm (two passes) and 24.4 MUm (four passes), respectively. Meanwhile, the hardness of the alloy improved significantly. The maximum wear resistance achieved in the present work was around 73.77 m/mm3, which was obtained from the Mg-Sn alloy treated with a one-pass ECAE process with a grain size of 88.0 MUm. The wear resistance improvement was caused by the grain size refinement and the precipitate of the second phase, Mg2Sn against the oxidation of the processed alloy. The as-cast Mg-Sn alloy with the larger grain size, i.e., 117.6 MUm, underwent wear mechanisms, mainly adhesive wear and abrasive wear. In ECAE processed Mg-Sn alloy, high internal energy occurred due to the high dislocation density and the stress field produced by the plastic deformation, which led to an increased oxidation rate of the processed alloy during sliding. Therefore, the oxidative wear and a three-body abrasive wear in which the oxide debris acted as the three-body abrasive components became the dominant factors in the wear behavior, and as a result, reduced the wear resistance in the multi-pass ECAE processed alloy. PMID- 29144412 TI - Pancreatic Cancer Chemoresistance to Gemcitabine. AB - Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation and overall efficacy, as well as the development of chemoresistance within weeks of treatment initiation. To circumvent gemcitabine resistance in PDAC, several novel therapeutic approaches, including chemical modifications of the gemcitabine molecule generating numerous new prodrugs, as well as new entrapment designs of gemcitabine in colloidal systems such as nanoparticles and liposomes, are currently being investigated. Many of these approaches are reported to be more efficient than the parent gemcitabine molecule when tested in cellular systems and in vivo in murine tumor model systems; however, although promising, their translation to clinical use is still in a very early phase. This review discusses gemcitabine metabolism, activation and chemoresistance entities in the gemcitabine cytotoxicity pathway and provides an overview of approaches to override chemoresistance in pancreatic cancer. PMID- 29144413 TI - Epstein-Barr Virus Hijacks DNA Damage Response Transducers to Orchestrate Its Life Cycle. AB - The Epstein-Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt's lymphoma, Hodgkin's lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has shown that EBV triggers a DNA damage response (DDR) during primary infection and lytic reactivation. The EBV-encoded viral proteins have been implicated in deregulating the DDR signaling pathways. The consequences of DDR inactivation lead to genomic instability and promote cellular transformation. This review summarizes the current understanding of the relationship between EBV infection and the DDR transducers, including ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), and DNA-PK (DNA-dependent protein kinase), and discusses how EBV manipulates the DDR signaling pathways to complete the replication process of viral DNA during lytic reactivation. PMID- 29144415 TI - The Association between Environmental Lead Exposure and High School Educational Outcomes in Four Communities in New South Wales, Australia. AB - The associations between environmental lead exposure and high school educational outcomes in four communities located in New South Wales, Australia, were examined in this ecological study. A mixed model analysis was performed to account for each school's results being more similar than results for other schools. The effect of environmental lead exposure on mean results for five educational outcomes was examined. 'Leaded' schools with more than five per cent of students living in the highest lead risk areas were tested against non-leaded 'comparison' schools that were matched by a pre-defined socio-educational advantage rating. A small disadvantage was found for leaded schools for four out of five outcomes, which was statistically significant for three outcomes: Higher School Certificate English (p < 0.01), School Certificate Mathematics (p < 0.05), and Australian Tertiary Admissions Rank eligibility rate (p < 0.01). This study adds to the large body of evidence in Australia and elsewhere supporting the importance of primary prevention to protect health at multiple stages of development. PMID- 29144411 TI - Nucleic Acid Aptamers: Emerging Applications in Medical Imaging, Nanotechnology, Neurosciences, and Drug Delivery. AB - Recent progresses in organic chemistry and molecular biology have allowed the emergence of numerous new applications of nucleic acids that markedly deviate from their natural functions. Particularly, DNA and RNA molecules-coined aptamers can be brought to bind to specific targets with high affinity and selectivity. While aptamers are mainly applied as biosensors, diagnostic agents, tools in proteomics and biotechnology, and as targeted therapeutics, these chemical antibodies slowly begin to be used in other fields. Herein, we review recent progress on the use of aptamers in the construction of smart DNA origami objects and MRI and PET imaging agents. We also describe advances in the use of aptamers in the field of neurosciences (with a particular emphasis on the treatment of neurodegenerative diseases) and as drug delivery systems. Lastly, the use of chemical modifications, modified nucleoside triphosphate particularly, to enhance the binding and stability of aptamers is highlighted. PMID- 29144416 TI - Environmental Risks Associated with Symptoms of Acute Respiratory Infection among Preschool Children in North-Western and South-Southern Nigeria Communities. AB - The exposure-disease-stress model places young children in their physical and social contexts and considers the extent and intensity of associational links to symptoms of acute respiratory infection (ARI), taking in to account a range of biological, social, and environment components. This study uses the 2013 Nigeria Demographic and Health Survey to assess the individual and environmental risks present in the North-Western and South-Southern Nigerian communities and examines their associations with ARI symptoms. The descriptive findings show that the prevalence of ARI symptoms is significantly higher among preschool children in the North-Western province (5.7%) than in the South-Southern province (1.4%) (p < 0.001). In addition to regional differences, multilevel logistic models further indicate that the increased likelihood of a child suffering from ARI symptoms is significantly associated with the dry season (aOR 1.42; 95% CI: 1.02-1.97) and household poverty (aOR 1.42; 95% CI: 1.01-1.99), even after adjusting for the cooking fuel used and various other characteristics of the children, households, and communities. These findings underscore the importance of taking into account environmental risks when addressing specific regional variations in ARI symptoms, because these determinants differ between communities in Nigeria. As it is imperative to achieve minimum levels of child health, in order to improve economic development across regions, future health policies aiming to promote child health will benefit from taking a region-specific perspective into consideration. PMID- 29144417 TI - Fast, Low-Cost and Non-Destructive Physico-Chemical Analysis of Virgin Olive Oils Using Near-Infrared Reflectance Spectroscopy. AB - Near-Infrared (NIR) Spectroscopy was used for the non-destructive assessment of physico-chemical quality parameters in olive oil. At the same time, the influence of the sample presentation mode (spinning versus static cup) was evaluated using two spectrophotometers with similar optical characteristics. A total of 478 olive oil samples were used to develop calibration models, testing various spectral signal pre-treatments. The models obtained by applying MPLS regression to spectroscopic data yielded promising results for olive oil quality measurements, particularly for acidity, the peroxide index and alkyl and ethyl ester content. The results obtained indicate that this non-invasive technology can be used successfully by the olive oil sector to categorize olive oils, to detect potential fraud and to provide consumers with more reliable information. Although both sample presentation modes yielded comparable results, equations constructed with samples scanned using the spinning mode provided greater predictive capacity. PMID- 29144418 TI - NMR-Based Identification of Metabolites in Polar and Non-Polar Extracts of Avian Liver. AB - Metabolites present in liver provide important clues regarding the physiological state of an organism. The aim of this work was to evaluate a protocol for high throughput NMR-based analysis of polar and non-polar metabolites from a small quantity of liver tissue. We extracted the tissue with a methanol/chloroform/water mixture and isolated the polar metabolites from the methanol/water layer and the non-polar metabolites from the chloroform layer. Following drying, we re-solubilized the fractions for analysis with a 600 MHz NMR spectrometer equipped with a 1.7 mm cryogenic probe. In order to evaluate the feasibility of this protocol for metabolomics studies, we analyzed the metabolic profile of livers from house sparrow (Passer domesticus) nestlings raised on two different diets: livers from 10 nestlings raised on a high protein diet (HP) for 4 d and livers from 12 nestlings raised on the HP diet for 3 d and then switched to a high carbohydrate diet (HC) for 1 d. The protocol enabled the detection of 52 polar and nine non-polar metabolites in 1H NMR spectra of the extracts. We analyzed the lipophilic metabolites by one-way ANOVA to assess statistically significant concentration differences between the two groups. The results of our studies demonstrate that the protocol described here can be exploited for high throughput screening of small quantities of liver tissue (approx. 100 mg wet mass) obtainable from small animals. PMID- 29144420 TI - Visual Positioning Indoors: Human Eyes vs. Smartphone Cameras. AB - Artificial Intelligence (AI) technologies and their related applications are now developing at a rapid pace. Indoor positioning will be one of the core technologies that enable AI applications because people spend 80% of their time indoors. Humans can locate themselves related to a visually well-defined object, e.g., a door, based on their visual observations. Can a smartphone camera do a similar job when it points to an object? In this paper, a visual positioning solution was developed based on a single image captured from a smartphone camera pointing to a well-defined object. The smartphone camera simulates the process of human eyes for the purpose of relatively locating themselves against a well defined object. Extensive experiments were conducted with five types of smartphones on three different indoor settings, including a meeting room, a library, and a reading room. Experimental results shown that the average positioning accuracy of the solution based on five smartphone cameras is 30.6 cm, while that for the human-observed solution with 300 samples from 10 different people is 73.1 cm. PMID- 29144419 TI - Air Pollution and Dispensed Medications for Asthma, and Possible Effect Modifiers Related to Mental Health and Socio-Economy: A Longitudinal Cohort Study of Swedish Children and Adolescents. AB - It has been suggested that children that are exposed to a stressful environment at home have an increased susceptibility for air pollution-related asthma. The aim here was to investigate the association between air pollution exposure and asthma, and effect modification by mental health and by socio-economic status (as markers of a stressful environment). All individuals under 18 years of age in four Swedish counties during 2007 to 2010 (1.2 million people) were included. The outcome was defined as dispensing at least two asthma medications during follow up. We linked data on NO2 from an empirical land use regression to data from national registers on outcome and potential confounders. Data was analyzed with logistic regression. There was an odds ratio (OR) of 1.02 (95% Confidence Interval (CI: 1.01-1.03) for asthma associated with a 10 ug.m-3 increase in NO2. The association only seemed to be present in areas where NO2 was higher than 15 ug.m-3 with an OR of 1.09 (95% CI: 1.07-1.12), and the association seemed stronger in children with parents with a high education, OR = 1.05 (95% CI: 1.02 1.09) and OR = 1.04 (95% CI: 1.01-1.07) in children to mothers and father with a high education, respectively. The association did not seem to depend on medication history of psychiatric disorders. There was weak evidence for the association between air pollution and asthma to be stronger in neighborhoods with higher education levels. In conclusion, air pollution was associated with dispensed asthma medications, especially in areas with comparatively higher levels of air pollution, and in children to parents with high education. We did not observe support for our hypothesis that stressors linked to socio-economy or mental health problems would increase susceptibility to the effects of air pollution on the development of asthma. PMID- 29144421 TI - Paralytic Shellfish Toxins and Cyanotoxins in the Mediterranean: New Data from Sardinia and Sicily (Italy). AB - Harmful algal blooms represent a severe issue worldwide. They affect ecosystem functions and related services and goods, with consequences on human health and socio-economic activities. This study reports new data on paralytic shellfish toxins (PSTs) from Sardinia and Sicily (Italy), the largest Mediterranean islands where toxic events, mainly caused by Alexandrium species (Dinophyceae), have been ascertained in mussel farms since the 2000s. The toxicity of the A. minutum, A. tamarense and A. pacificum strains, established from the isolation of vegetative cells and resting cysts, was determined by high performance liquid chromatography (HPLC). The analyses indicated the highest toxicity for A. pacificum strains (total PSTs up to 17.811 fmol cell-1). The PSTs were also assessed in a strain of A. tamarense. The results encourage further investigation to increase the knowledge of toxic species still debated in the Mediterranean. This study also reports new data on microcystins (MCs) and beta-N-methylamino-L-alanine (BMAA) from a Sardinian artificial lake (Lake Bidighinzu). The presence of MCs and BMAA was assessed in natural samples and in cell cultures by enzyme-linked immunosorbent assay (ELISA). BMAA positives were found in all the analysed samples with a maximum of 17.84 ug L-1. The obtained results added further information on cyanotoxins in Mediterranean reservoirs, particularly BMAA, which have not yet been thoroughly investigated. PMID- 29144422 TI - Atypical Processing of Novel Distracters in a Visual Oddball Task in Autism Spectrum Disorder. AB - Several studies have shown that children with autism spectrum disorder (ASD) show abnormalities in P3b to targets in standard oddball tasks. The present study employed a three-stimulus visual oddball task with novel distracters that analyzed event-related potentials (ERP) to both target and non-target items at frontal and parietal sites. The task tested the hypothesis that children with autism are abnormally orienting attention to distracters probably due to impaired habituation to novelty. We predicted a lower selectivity in early ERPs to target, frequent non-target, and rare distracters. We also expected delayed late ERPs in autism. The study enrolled 32 ASD and 24 typically developing (TD) children. Reaction time (RT) and accuracy were analyzed as behavioral measures, while ERPs were recorded with a dense-array EEG system. Children with ASD showed higher error rate without normative post-error RT slowing and had lower error-related negativity. Parietal P1, frontal N1, as well as P3a and P3b components were higher to novels in ASD. Augmented exogenous ERPs suggest low selectivity in pre processing of stimuli resulting in their excessive processing at later stages. The results suggest an impaired habituation to unattended stimuli that incurs a high load at the later stages of perceptual and cognitive processing and response selection when novel distracter stimuli are differentiated from targets. PMID- 29144423 TI - Lipid Peroxidation Process in Meat and Meat Products: A Comparison Study of Malondialdehyde Determination between Modified 2-Thiobarbituric Acid Spectrophotometric Method and Reverse-Phase High-Performance Liquid Chromatography. AB - The aim of this work was to compare the methods of malondialdehyde detection, as the main secondary product of the lipid peroxidation process, in meat and meat products. Malondialdehyde measurements were performed by two modified methods, the 2-thiobarbituric acid spectrophotometric method and the reverse-phase high performance liquid chromatography in raw, mechanically-deboned chicken meat and in manufactured frankfurters. The malondialdehyde concentrations measured by the 2-thiobarbituric acid spectrophotometric method were found to be overestimated by more than 25% in raw meat and more than 27% in frankfurters in comparison to the results of reverse-phase high-performance liquid chromatography (p < 0.05). The achieved results showed that the presented modified reverse-phase high performance liquid chromatography method was more applicable and more accurate for the quantification of malondialdehyde in samples of meat and meat products. PMID- 29144424 TI - Synthesis, Characterization and Biological Activities of Biopolymeric Schiff Bases Prepared with Chitosan and Salicylaldehydes and Their Pd(II) and Pt(II) Complexes. AB - In an attempt to enhance chitosan biological activities, biopolymeric Schiff bases of chitosan and different salicylaldehydes and their palladium(II) and platinum(II) complexes were synthesized and tested. The chemical structures of these derivatives were characterized using 1H-NMR, FTIR spectroscopy and XPRD. Thermal analysis was done through TGA/DTG-DTA. Electronic absorption spectra and surface morphologies were analyzed by SEM-EDAX. Chitosan and its derivatives were evaluated for their in vitro antimicrobial activity against two common bacterial and fungal plant pathogens Pseudomonas syringae pv. tomato and Fusarium graminearum, respectively, and for their antitumor activity against a human breast cancer cell line (MCF-7). It was found that, compared to the nonmodified chitosan, chitosan modified with Schiff bases and their complexes was highly toxic against the MCF-7 cell line and had antibacterial effects against P. syringea. However, the modified chitosan derivatives had less pronounced antifungal effects against F. graminearum compared to the nonmodified chitosan, suggesting different modes of action. PMID- 29144425 TI - Selective Laser Sintering of Porous Silica Enabled by Carbon Additive. AB - The aim of this study is to investigate the possibility of a freeform fabrication of porous ceramic parts through selective laser sintering (SLS). SLS was proposed to manufacture ceramic green parts because this additive manufacturing technique can be used to fabricate three-dimensional objects directly without a mold, and the technique has the capability of generating porous ceramics with controlled porosity. However, ceramic printing has not yet fully achieved its 3D fabrication capabilities without using polymer binder. Except for the limitations of high melting point, brittleness, and low thermal shock resistance from ceramic material properties, the key obstacle lies in the very poor absorptivity of oxide ceramics to fiber laser, which is widely installed in commercial SLS equipment. An alternative solution to overcome the poor laser absorptivity via improving material compositions is presented in this study. The positive effect of carbon additive on the absorptivity of silica powder to fiber laser is discussed. To investigate the capabilities of the SLS process, 3D porous silica structures were successfully prepared and characterized. PMID- 29144426 TI - Experimental Exploration of Metal Cable as Reinforcement in 3D Printed Concrete. AB - The Material Deposition Method (MDM) is enjoying increasing attention as an additive method to create concrete mortar structures characterised by a high degree of form-freedom, a lack of geometrical repetition, and automated construction. Several small-scale structures have been realised around the world, or are under preparation. However, the nature of this construction method is unsuitable for conventional reinforcement methods to achieve ductile failure behaviour. Sometimes, this is solved by combining printing with conventional casting and reinforcing techniques. This study, however, explores an alternative strategy, namely to directly entrain a metal cable in the concrete filament during printing to serve as reinforcement. A device is introduced to apply the reinforcement. Several options for online reinforcement media are compared for printability. Considerations specific to the manufacturing process are discussed. Subsequently, pull-out tests on cast and printed specimens provide an initial characterisation of bond behaviour. Bending tests furthermore show the potential of this reinforcement method. The bond stress of cables in printed concrete was comparable to values reported for smooth rebar but lower than that of the same cables in cast concrete. The scatter in experimental results was high. When sufficient bond length is available, ductile failure behaviour for tension parallel to the filament direction can be achieved, even though cable slip occurs. Further improvements to the process should pave the way to achieve better post-crack resistance, as the concept in itself is feasible. PMID- 29144427 TI - The Chloroplast Genome of Symplocarpus renifolius: A Comparison of Chloroplast Genome Structure in Araceae. AB - Symplocarpus renifolius is a member of Araceae family that is extraordinarily diverse in appearance. Previous studies on chloroplast genomes in Araceae were focused on duckweeds (Lemnoideae) and root crops (Colocasia, commonly known as taro). Here, we determined the chloroplast genome of Symplocarpus renifolius and compared the factors, such as genes and inverted repeat (IR) junctions and performed phylogenetic analysis using other Araceae species. The chloroplast genome of S. renifolius is 158,521 bp and includes 113 genes. A comparison among the Araceae chloroplast genomes showed that infA in Lemna, Spirodela, Wolffiella, Wolffia, Dieffenbachia and Colocasia has been lost or has become a pseudogene and has only been retained in Symplocarpus. In the Araceae chloroplast DNA (cpDNA), psbZ is retained. However, psbZ duplication occurred in Wolffia species and tandem repeats were noted around the duplication regions. A comparison of the IR junction in Araceae species revealed the presence of ycf1 and rps15 in the small single copy region, whereas duckweed species contained ycf1 and rps15 in the IR region. The phylogenetic analyses of the chloroplast genomes revealed that Symplocarpus are a basal group and are sister to the other Araceae species. Consequently, infA deletion or pseudogene events in Araceae occurred after the divergence of Symplocarpus and aquatic plants (duckweeds) in Araceae and duplication events of rps15 and ycf1 occurred in the IR region. PMID- 29144428 TI - Resistance of Magnesium Alloys to Corrosion Fatigue for Biodegradable Implant Applications: Current Status and Challenges. AB - Magnesium (Mg) alloys are attracting increasing interest as the most suitable metallic materials for construction of biodegradable and bio-absorbable temporary implants. However, Mg-alloys can suffer premature and catastrophic fracture under the synergy of cyclic loading and corrosion (i.e., corrosion fatigue (CF)). Though Mg alloys are reported to be susceptible to CF also in the corrosive human body fluid, there are very limited studies on this topic. Furthermore, the in vitro test parameters employed in these investigations have not properly simulated the actual conditions in the human body. This article presents an overview of the findings of available studies on the CF of Mg alloys in pseudo physiological solutions and the employed testing procedures, as well as identifying the knowledge gap. PMID- 29144429 TI - Does Perception of Dietary Fiber Mediate the Impact of Nutrition Knowledge on Eating Fiber-Rich Bread? AB - The average daily intake of fiber is still too low in relation to nutritional recommendations, as was found in several studies. Therefore, it is necessary to recommend ways to increase fiber intake in the diet. Increasing the consumption of bread rich in fiber as a substitute of white bread is one of the ways to increase fiber intake. The aim of this study was to find out whether nutrition knowledge and perception of dietary fiber affected the frequency of eating wholemeal bread and white bread fortified with fiber. The data were collected in 2014 through a cross-sectional quantitative survey that was performed under the Bioproduct project among a group of 1013 Polish adults. The associations between variables were investigated using multiple regression analysis. The respondents' general knowledge on nutrition influenced their knowledge on fiber intake (correlation coefficient r = 0.30). Respondents with a greater knowledge perceived higher benefits of consuming cereal products that were fortified with fiber (r = 0.78), and attached greater importance to the information on the label (r = 0.39) as well. The nutrition knowledge determined the familiarity with fiber enriched bread and the consumption of this product (r = 0.40) to a greater degree than the frequency of wholemeal bread consumption (r = -0.10). The respondents' perception of dietary fiber was observed to play a partial mediation role between the knowledge on nutrition and the consumption of both kinds of breads, suggesting that it can be an important predictor of bread consumption. To increase the consumption of bread that is rich in fiber, emphasis should be laid on specific information on fiber, referring to food products as well as on individual's perception of those products. The said information should be reinforced along with overall communication regarding nutrition to influence the bread-related decisions. PMID- 29144430 TI - A Correlation Study of DHA Intake Estimated by a FFQ and Concentrations in Plasma and Erythrocytes in Mid- and Late Pregnancy. AB - Adequate docosahexaenoic acid (DHA) is essential for the optimal growth and development of the fetus. Maternal DHA content fluctuates during pregnancy. The correlation of DHA content with dietary intake might be varied over the course of pregnancy. We aimed to compare the dietary DHA intake, estimated by a DHA specific semiquantitative food frequency questionnaire (FFQ) against its blood content, among mid- and late-term pregnant women. A total of 804 Chinese pregnant women completed the tailored FFQ and provided fasting venous blood samples. Dietary DHA intake (mg/day) in the previous month was calculated from the FFQ using Chinese Food Composition Table. DHA concentrations (weight percent of total fatty acids) in plasma and erythrocytes were measured by capillary gas chromatography. Spearman correlation coefficients (rs) between DHA intake and its relative concentrations were calculated. After adjustment for maternal age, pre pregnancy body mass index, stage of pregnancy, parity, education level, ethnicity, and annual family income per capita, the correlation coefficients of DHA intake with its concentrations in plasma and erythrocytes were 0.35 and 0.33, respectively (p < 0.001). The correlations were relatively stronger among women in late pregnancy (rs = 0.44 in plasma and 0.39 in erythrocytes) than those in mid-pregnancy (rs = 0.25 and 0.26). The significant correlations were consistently observed in subgroups stratified by regions, except for erythrocytes in women living in a coastland area. Multiple regression analyses also indicated significant positive linear correlations between DHA intake and its plasma or erythrocytes concentrations (p < 0.001). In conclusion, dietary DHA intake, estimated by the FFQ, was positively correlated with its concentrations in plasma and erythrocytes in Chinese pregnant women, especially for women in late pregnancy, with the exception of the erythrocytes of those living in a coastland area. PMID- 29144431 TI - Bioabsorption and Bioaccumulation of Cadmium in the Straw and Grain of Maize (Zea mays L.) in Growing Soils Contaminated with Cadmium in Different Environment. AB - There is a worldwide increase of heavy metal or potentially toxic element (PTE), contamination in agricultural soils caused mainly by human and industrial action, which leads to food contamination in crops such as in maize. Cadmium (Cd) is a PTE often found in soils and it is ingested through food. It is necessary to determine the bioabsorption, distribution, and accumulation levels in maize to reduce or prevent food chain contamination. Cadmium absorption and accumulation in three maize cultivars were evaluated in three agricultural environments in Chile by increasing CdCl2 rates (0, 1, and 2 mg.kg-1). Evaluation included Cd accumulation and distribution in different plant tissues, bioaccumulation factor (BAF), bioconcentration factor (BCF), translocation factor (TF), and tolerance index (TI). Cadmium whole-plant uptake was only affected by the CdCl2 rate; the highest uptake was obtained with 2 mg.kg-1 CdCl2 (34.4 g.ha-1) (p < 0.05). Cadmium distribution in the maize plant usually exhibited the highest accumulation in the straw (p < 0.05), independently of the environment, Cd rate, and evaluated cultivar. Given the results for TF (TF > 2) and BAF (BAF > 1), the Los Tilos and Chillan environments were classified as having a high capacity to contaminate the food chain for all evaluated cultivars. PMID- 29144432 TI - Climate Change and Schools: Environmental Hazards and Resiliency. AB - The changing climate is creating additional challenges in maintaining a healthy school environment in the United States (U.S.) where over 50 million people, mostly children, spend approximately a third of their waking hours. Chronic low prioritization of funds and resources to support environmental health in schools and lack of clear regulatory oversight in the U.S. undergird the new risks from climate change. We illustrate the extent of risk and the variation in vulnerability by geographic region, in the context of sparse systematically collected and comparable data particularly about school infrastructure. Additionally, we frame different resilience building initiatives, focusing on interventions that target root causes, or social determinants of health. Disaster response and recovery are also framed as resilience building efforts. Examples from U.S. Federal Region 2 (New Jersey, New York, Puerto Rico, and the U.S. Virgin Islands) and nationally are used to illustrate these concepts. We conclude that better surveillance, more research, and increased federal and state oversight of environmental factors in schools (specific to climate risks) is necessary, as exposures result in short- and long term negative health effects and climate change risks will increase over time. PMID- 29144433 TI - The Influence of Family Dog Ownership and Parental Perceived Built Environment Measures on Children's Physical Activity within the Washington, DC Area. AB - Sedentary behavior and physical inactivity are significant contributors to youth obesity in the United States. Neighborhood dog walking is an outlet for physical activity (PA). Therefore, understanding the relationship between built environment, dog ownership, and youth PA is essential. This study examined the influence of dog ownership and parental built environment perceptions on children's PA in the Washington, D.C. area. In 2014, questionnaires were mailed to 2000 parents to assess family dog ownership; children's outdoor dog walking or playing; and parental perceived built environment measures. Chi-square analyses examined differences in parental perceived built environment measures between children with and without family dogs. The sample included 144 children (50% female; average-age 9.7 years; 56.3% White; 23.7% African-American; 10.4% Asian American; 29.9% owned dog). Only 13% and 5.6% of the children walked or played outdoors with the dog daily, respectively. A significantly greater proportion (p value < 0.05) of parents who owned dogs recognized and observed some home built environment measures (e.g., traffic speed on most streets is 30 mph or less) that were PA -promoting for their children. Findings suggest that dog ownership may provide more positive parental perceptions of the neighborhood built environment, which supports children's outdoor PA through dog walking and playing. PMID- 29144434 TI - The Role of Non-Coding RNAs in Cytoplasmic Male Sterility in Flowering Plants. AB - The interactions between mitochondria and nucleus substantially influence plant development, stress response and morphological features. The prominent example of a mitochondrial-nuclear interaction is cytoplasmic male sterility (CMS), when plants produce aborted anthers or inviable pollen. The genes responsible for CMS are located in mitochondrial genome, but their expression is controlled by nuclear genes, called fertility restorers. Recent explosion of high-throughput sequencing methods enabled to study transcriptomic alterations in the level of non-coding RNAs under CMS biogenesis. We summarize current knowledge of the role of nucleus encoded regulatory non-coding RNAs (long non-coding RNA, microRNA as well as small interfering RNA) in CMS. We also focus on the emerging data of non coding RNAs encoded by mitochondrial genome and their possible involvement in mitochondrial-nuclear interactions and CMS development. PMID- 29144436 TI - An In Silico Subject-Variability Study of Upper Airway Morphological Influence on the Airflow Regime in a Tracheobronchial Tree. AB - Determining the impact of inter-subject variability on airflow pattern and nanoparticle deposition in the human respiratory system is necessary to generate population-representative models, useful for several biomedical engineering applications. Thus, the overall research objective is to quantitatively correlate geometric parameters and coupled transport characteristics of air, vapor, and nanoparticles. Focusing on identifying morphological parameters that significantly influence airflow field and nanoparticle transport, an experimentally validated computational fluid-particle dynamics (CFPD) model was employed to simulate airflow pattern in three human lung-airway configurations. The numerical results will be used to generate guidelines to construct a representative geometry of the human respiratory system. PMID- 29144437 TI - Report from the BIT's 1st Annual World Congress of Biomedical Engineering Held in Xi'an, China, 9-11 November 2017. AB - We are delighted to present within this meeting report the abstracts of the "BIT's 1st World Congress of Biomedical Engineering 2017" which has been hold in Xi'an in China [...]. PMID- 29144435 TI - Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-beta1 in Fibroblasts from Idiopathic Pulmonary Fibrosis Patients: Role of FAK/Akt. AB - Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and TGF-beta1 cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from IPF patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide (PAA) gels. We found that TGF-beta1 consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the FAK/Akt pathway, whereas FAK depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and TGF-beta1 that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by TGF-beta1 alone or synergistically with matrix stiffening were higher in IPF-fibroblasts compared to control fibroblasts in association with larger FAK and Akt activities in the former cells. These findings provide new insights on how matrix stiffening and TGF-beta1 cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the FAK/Akt pathway in this cooperation. PMID- 29144438 TI - Bioactive Components in Moringa Oleifera Leaves Protect against Chronic Disease. AB - Moringa Oleifera (MO), a plant from the family Moringacea is a major crop in Asia and Africa. MO has been studied for its health properties, attributed to the numerous bioactive components, including vitamins, phenolic acids, flavonoids, isothiocyanates, tannins and saponins, which are present in significant amounts in various components of the plant. Moringa Oleifera leaves are the most widely studied and they have shown to be beneficial in several chronic conditions, including hypercholesterolemia, high blood pressure, diabetes, insulin resistance, non-alcoholic liver disease, cancer and overall inflammation. In this review, we present information on the beneficial results that have been reported on the prevention and alleviation of these chronic conditions in various animal models and in cell studies. The existing limited information on human studies and Moringa Oleifera leaves is also presented. Overall, it has been well documented that Moringa Oleifera leaves are a good strategic for various conditions associated with heart disease, diabetes, cancer and fatty liver. PMID- 29144439 TI - Cell Line Secretome and Tumor Tissue Proteome Markers for Early Detection of Colorectal Cancer: A Systematic Review. AB - Objective: In order to find low abundant proteins secretome and tumor tissue proteome data have been explored in the last few years for the diagnosis of colorectal cancer (CRC). In this review we aim to summarize the results of studies evaluating markers derived from the secretome and tumor proteome for blood based detection of colorectal cancer. Methods: Observing the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines PubMed and Web of Science databases were searched systematically for relevant studies published up to 18 July 2017. After screening for predefined eligibility criteria a total of 47 studies were identified. Information on diagnostic performance indicators, methodological procedures and validation was extracted. Functions of proteins were identified from the UniProt database and the the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess study quality. Results: Forty seven studies meeting inclusion criteria were identified. Overall, 83 different proteins were identified, with carcinoembryonic Antigen (CEA) being by far the most commonly reported (reported in 24 studies). Evaluation of the markers or marker combinations in blood samples from CRC cases and controls yielded apparently very promising diagnostic performances, with area under the curve >0.9 in several cases, but lack of internal or external validation, overoptimism due to overfitting and spectrum bias due to evaluation in clinical setting rather than screening settings are major concerns. Conclusions: Secretome and tumor proteome-based biomarkers when validated in blood yield promising candidates. However, for discovered protein markers to be clinically applicable as screening tool they have to be specific for early stages and need to be validated externally in larger studies with participants recruited in true screening setting. PMID- 29144440 TI - Field Monitoring of Drosophila suzukii and Associated Communities in South Eastern France as a Pre-Requisite for Classical Biological Control. AB - The spotted wing Drosophila, Drosophila suzukii (Ds), became a major economic pest for fruit production since its establishment in Europe and America. Among potential control methods, only classical biological control appears to be a mean of sustainably regulating Ds in both cultivated and natural habitats. In the frame of risk assessment, pre-release surveys were carried out in a restricted but highly heterogeneous area in the south-east of France using traps and deliberate field exposures of Ds and D. melanogaster larvae/pupae. Although Ds abundance varied according to sampling methods, it was found to be pervasive and to produce offspring and adults in most conditions (spatial and seasonal). Its main limits are some specific abiotic conditions (i.e., desiccation) as well as interspecific competition. Indeed, Ds mostly co-occurred with D. busckii and D. hydei, probably due to common phenology and/or ecological requirements. These two species thus deserve more attention for risk assessment. The main indigenous parasitoids collected belonged to two pupal species, Trichopria cf drosophilae and Pachycrepoideus vindemmiae, but their presence was observed late in the autumn and mainly in cultivated areas. Results are discussed in a comparison of the methodological approaches for monitoring Drosophilids and the benefits-risks assessment of classical biological control. PMID- 29144442 TI - Propagation of Fibrillar Structural Forms in Proteins Stopped by Naturally Occurring Short Polypeptide Chain Fragments. AB - Amyloids characterized by unbounded growth of fibrillar structures cause many pathological processes. Such unbounded propagation is due to the presence of a propagating hydrophobicity field around the fibril's main axis, preventing its closure (unlike in globular proteins). Interestingly, similar fragments, commonly referred to as solenoids, are present in many naturally occurring proteins, where their propagation is arrested by suitably located "stopper" fragments. In this work, we analyze the distribution of hydrophobicity in solenoids and in their corresponding "stoppers" from the point of view of the fuzzy oil drop model (called FOD in this paper). This model characterizes the unique linear propagation of local hydrophobicity in the solenoid fragment and allows us to pinpoint "stopper" sequences, where local hydrophobicity quite closely resembles conditions encountered in globular proteins. Consequently, such fragments perform their function by mediating entropically advantageous contact with the water environment. We discuss examples of amyloid-like structures in solenoids, with particular attention to "stop" segments present in properly folded proteins found in living organisms. PMID- 29144443 TI - A Genomic Survey of SCPP Family Genes in Fishes Provides Novel Insights into the Evolution of Fish Scales. AB - The family of secretory calcium-binding phosphoproteins (SCPPs) have been considered vital to skeletal tissue mineralization. However, most previous SCPP studies focused on phylogenetically distant animals but not on those closely related species. Here we provide novel insights into the coevolution of SCPP genes and fish scales in 10 species from Otophysi. According to their scale phenotypes, these fishes can be divided into three groups, i.e., scaled, sparsely scaled, and scaleless. We identified homologous SCPP genes in the genomes of these species and revealed an absence of some SCPP members in some genomes, suggesting an uneven evolutionary history of SCPP genes in fishes. In addition, most of these SCPP genes, with the exception of SPP1, individually form one or two gene cluster(s) on each corresponding genome. Furthermore, we constructed phylogenetic trees using maximum likelihood method to estimate their evolution. The phylogenetic topology mostly supports two subclasses in some species, such as Cyprinus carpio, Sinocyclocheilus anshuiensis, S. grahamin, and S. rhinocerous, but not in the other examined fishes. By comparing the gene structures of recently reported candidate genes, SCPP1 and SCPP5, for determining scale phenotypes, we found that the hypothesis is suitable for Astyanax mexicanus, but denied by S. anshuiensis, even though they are both sparsely scaled for cave adaptation. Thus, we conclude that, although different fish species display similar scale phenotypes, the underlying genetic changes however might be diverse. In summary, this paper accelerates the recognition of the SCPP family in teleosts for potential scale evolution. PMID- 29144444 TI - Benthic Habitat Mapping Using Multispectral High-Resolution Imagery: Evaluation of Shallow Water Atmospheric Correction Techniques. AB - Remote multispectral data can provide valuable information for monitoring coastal water ecosystems. Specifically, high-resolution satellite-based imaging systems, as WorldView-2 (WV-2), can generate information at spatial scales needed to implement conservation actions for protected littoral zones. However, coastal water-leaving radiance arriving at the space-based sensor is often small as compared to reflected radiance. In this work, complex approaches, which usually use an accurate radiative transfer code to correct the atmospheric effects, such as FLAASH, ATCOR and 6S, have been implemented for high-resolution imagery. They have been assessed in real scenarios using field spectroradiometer data. In this context, the three approaches have achieved excellent results and a slightly superior performance of 6S model-based algorithm has been observed. Finally, for the mapping of benthic habitats in shallow-waters marine protected environments, a relevant application of the proposed atmospheric correction combined with an automatic deglinting procedure is presented. This approach is based on the integration of a linear mixing model of benthic classes within the radiative transfer model of the water. The complete methodology has been applied to selected ecosystems in the Canary Islands (Spain) but the obtained results allow the robust mapping of the spatial distribution and density of seagrass in coastal waters and the analysis of multitemporal variations related to the human activity and climate change in littoral zones. PMID- 29144441 TI - G-Protein Coupled Receptors Targeted by Analgesic Venom Peptides. AB - Chronic pain is a complex and debilitating condition associated with a large personal and socioeconomic burden. Current pharmacological approaches to treating chronic pain such as opioids, antidepressants and anticonvulsants exhibit limited efficacy in many patients and are associated with dose-limiting side effects that hinder their clinical use. Therefore, improved strategies for the pharmacological treatment of pathological pain are urgently needed. G-protein coupled receptors (GPCRs) are ubiquitously expressed on the surface of cells and act to transduce extracellular signals and regulate physiological processes. In the context of pain, numerous and diverse families of GPCRs expressed in pain pathways regulate most aspects of physiological and pathological pain and are thus implicated as potential targets for therapy of chronic pain. In the search for novel compounds that produce analgesia via GPCR modulation, animal venoms offer an enormous and virtually untapped source of potent and selective peptide molecules. While many venom peptides target voltage-gated and ligand-gated ion channels to inhibit neuronal excitability and blunt synaptic transmission of pain signals, only a small proportion are known to interact with GPCRs. Of these, only a few have shown analgesic potential in vivo. Here we review the current state of knowledge regarding venom peptides that target GPCRs to produce analgesia, and their development as therapeutic compounds. PMID- 29144445 TI - Critical Review on the Significance of Olive Phytochemicals in Plant Physiology and Human Health. AB - Olive oil displays remarkable organoleptic and nutritional features, which turn it into a foodstuff appreciated by consumers, and a basic component of the Mediterranean diet. Indeed, the noticed benefits of including olive oil in the diet have been assigned to the presence of diverse bioactive compounds with different molecular structures. These compounds confer a wide range of biological properties to this food matrix, including the prevention of distinct human diseases as well as the modulation of their severity. The most relevant bioactive compounds present in olive oil correspond to benzoic and cinnamic acids, phenolic alcohols and secoiridoids, and also flavonoids. Over the last decades, several studies, devoted to gaining a further insight into the relative contribution of the separate groups and individual compounds for their biological activities, have been conducted, providing relevant information on structure-activity relationships. Therefore, this paper critically reviews the health benefits evidenced by distinct phenolic compounds found in olive oils, thus contributing to clarify the relationship between their chemical structures and biological functions, further supporting their interest as essential ingredients of wholesome foods. PMID- 29144446 TI - Structure and assembly of the Ebola virus nucleocapsid. AB - Ebola and Marburg viruses are filoviruses: filamentous, enveloped viruses that cause haemorrhagic fever. Filoviruses are within the order Mononegavirales, which also includes rabies virus, measles virus, and respiratory syncytial virus. Mononegaviruses have non-segmented, single-stranded negative-sense RNA genomes that are encapsidated by nucleoprotein and other viral proteins to form a helical nucleocapsid. The nucleocapsid acts as a scaffold for virus assembly and as a template for genome transcription and replication. Insights into nucleoprotein nucleoprotein interactions have been derived from structural studies of oligomerized, RNA-encapsidating nucleoprotein, and cryo-electron microscopy of nucleocapsid or nucleocapsid-like structures. There have been no high-resolution reconstructions of complete mononegavirus nucleocapsids. Here we apply cryo electron tomography and subtomogram averaging to determine the structure of Ebola virus nucleocapsid within intact viruses and recombinant nucleocapsid-like assemblies. These structures reveal the identity and arrangement of the nucleocapsid components, and suggest that the formation of an extended alpha helix from the disordered carboxy-terminal region of nucleoprotein-core links nucleoprotein oligomerization, nucleocapsid condensation, RNA encapsidation, and accessory protein recruitment. PMID- 29144447 TI - BCAT1 restricts alphaKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. AB - The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers alpha-amino groups from BCAAs to alpha-ketoglutarate (alphaKG), is a critical regulator of intracellular alphaKG homeostasis. Further to its role in the tricarboxylic acid cycle, alphaKG is an essential cofactor for alphaKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of alphaKG, leading to EGLN1-mediated HIF1alpha protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular alphaKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHWTTET2WT, but not IDHmut or TET2mut AML. Gene sets characteristic for IDHmut AML were enriched in samples from patients with an IDHWTTET2WTBCAT1high status. BCAT1high AML showed robust enrichment for leukaemia stem-cell signatures, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular alphaKG, BCAT1 links BCAA catabolism to HIF1alpha stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA-BCAT1-alphaKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDHWTTET2WT AML. PMID- 29144449 TI - Erratum: Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. AB - This corrects the article DOI: 10.1038/nature24042. PMID- 29144448 TI - Regeneration of the entire human epidermis using transgenic stem cells. AB - Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies. PMID- 29144450 TI - Corrigendum: High-throughput discovery of novel developmental phenotypes. AB - This corrects the article DOI: 10.1038/nature19356. PMID- 29144451 TI - Tidal tomography constrains Earth's deep-mantle buoyancy. AB - Earth's body tide-also known as the solid Earth tide, the displacement of the solid Earth's surface caused by gravitational forces from the Moon and the Sun-is sensitive to the density of the two Large Low Shear Velocity Provinces (LLSVPs) beneath Africa and the Pacific. These massive regions extend approximately 1,000 kilometres upward from the base of the mantle and their buoyancy remains actively debated within the geophysical community. Here we use tidal tomography to constrain Earth's deep-mantle buoyancy derived from Global Positioning System (GPS)-based measurements of semi-diurnal body tide deformation. Using a probabilistic approach, we show that across the bottom two-thirds of the two LLSVPs the mean density is about 0.5 per cent higher than the average mantle density across this depth range (that is, its mean buoyancy is minus 0.5 per cent), although this anomaly may be concentrated towards the very base of the mantle. We conclude that the buoyancy of these structures is dominated by the enrichment of high-density chemical components, probably related to subducted oceanic plates or primordial material associated with Earth's formation. Because the dynamics of the mantle is driven by density variations, our result has important dynamical implications for the stability of the LLSVPs and the long term evolution of the Earth system. PMID- 29144452 TI - Ubiquitination and degradation of GBPs by a Shigella effector to suppress host defence. AB - Interferon-inducible guanylate-binding proteins (GBPs) mediate cell-autonomous antimicrobial defences. Shigella flexneri, a Gram-negative cytoplasmic free living bacterium that causes bacillary dysentery, encodes a repertoire of highly similar type III secretion system effectors called invasion plasmid antigen Hs (IpaHs). IpaHs represent a large family of bacterial ubiquitin-ligases, but their function is poorly understood. Here we show that S. flexneri infection induces rapid proteasomal degradation of human guanylate binding protein-1 (hGBP1). We performed a transposon screen to identify a mutation in the S. flexneri gene ipaH9.8 that prevented hGBP1 degradation. IpaH9.8 targets hGBP1 for degradation via Lys48-linked ubiquitination. IpaH9.8 targets multiple GBPs in the cytoplasm independently of their nucleotide-bound states and their differential function in antibacterial defence, promoting S. flexneri replication and resulting in the death of infected mice. In the absence of IpaH9.8, or when binding of GBPs to IpaH9.8 was disrupted, GBPs such as hGBP1 and mouse GBP2 (mGBP2) translocated to intracellular S. flexneri and inhibited bacterial replication. Like wild-type mice, mutant mice deficient in GBP1-3, 5 and 7 succumbed to S. flexneri infection, but unlike wild-type mice, mice deficient in these GBPs were also susceptible to S. flexneri lacking ipaH9.8. The mode of IpaH9.8 action highlights the functional importance of GBPs in antibacterial defences. IpaH9.8 and S. flexneri provide a unique system for dissecting GBP-mediated immunity. PMID- 29144456 TI - Planetary science: Haze cools Pluto's atmosphere. PMID- 29144454 TI - Dynamics of P-type ATPase transport revealed by single-molecule FRET. AB - Phosphorylation-type (P-type) ATPases are ubiquitous primary transporters that pump cations across cell membranes through the formation and breakdown of a phosphoenzyme intermediate. Structural investigations suggest that the transport mechanism is defined by conformational changes in the cytoplasmic domains of the protein that are allosterically coupled to transmembrane helices so as to expose ion binding sites to alternate sides of the membrane. Here, we have used single molecule fluorescence resonance energy transfer to directly observe conformational changes associated with the functional transitions in the Listeria monocytogenes Ca2+-ATPase (LMCA1), an orthologue of eukaryotic Ca2+-ATPases. We identify key intermediates with no known crystal structures and show that Ca2+ efflux by LMCA1 is rate-limited by phosphoenzyme formation. The transport process involves reversible steps and an irreversible step that follows release of ADP and extracellular release of Ca2+. PMID- 29144458 TI - Biogeochemistry: Ocean hotspots of nitrogen loss. PMID- 29144457 TI - A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair. AB - DNA repair is essential to prevent the cytotoxic or mutagenic effects of various types of DNA lesions, which are sensed by distinct pathways to recruit repair factors specific to the damage type. Although biochemical mechanisms for repairing several forms of genomic insults are well understood, the upstream signalling pathways that trigger repair are established for only certain types of damage, such as double-stranded breaks and interstrand crosslinks. Understanding the upstream signalling events that mediate recognition and repair of DNA alkylation damage is particularly important, since alkylation chemotherapy is one of the most widely used systemic modalities for cancer treatment and because environmental chemicals may trigger DNA alkylation. Here we demonstrate that human cells have a previously unrecognized signalling mechanism for sensing damage induced by alkylation. We find that the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci specifically upon exposure of cells to alkylating agents. These foci associate with alkylated nucleotides, and coincide spatially with elongating RNA polymerase II and splicing components. Proper recruitment of the repair complex requires recognition of K63-linked polyubiquitin by the CUE (coupling of ubiquitin conjugation to ER degradation) domain of the subunit ASCC2. Loss of this subunit impedes alkylation adduct repair kinetics and increases sensitivity to alkylating agents, but not other forms of DNA damage. We identify RING finger protein 113A (RNF113A) as the E3 ligase responsible for upstream ubiquitin signalling in the ASCC pathway. Cells from patients with X-linked trichothiodystrophy, which harbour a mutation in RNF113A, are defective in ASCC foci formation and are hypersensitive to alkylating agents. Together, our work reveals a previously unrecognized ubiquitin-dependent pathway induced specifically to repair alkylation damage, shedding light on the molecular mechanism of X-linked trichothiodystrophy. PMID- 29144459 TI - Geophysics: The buoyancy of Earth's deep mantle. PMID- 29144462 TI - Corrigendum: Superparamagnetic enhancement of thermoelectric performance. AB - This corrects the article DOI: 10.1038/nature23667. PMID- 29144460 TI - Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. AB - The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism. PMID- 29144464 TI - Haze heats Pluto's atmosphere yet explains its cold temperature. AB - Pluto's atmosphere is cold and hazy. Recent observations have shown it to be much colder than predicted theoretically, suggesting an unknown cooling mechanism. Atmospheric gas molecules, particularly water vapour, have been proposed as a coolant; however, because Pluto's thermal structure is expected to be in radiative-conductive equilibrium, the required water vapour would need to be supersaturated by many orders of magnitude under thermodynamic equilibrium conditions. Here we report that atmospheric hazes, rather than gases, can explain Pluto's temperature profile. We find that haze particles have substantially larger solar heating and thermal cooling rates than gas molecules, dominating the atmospheric radiative balance from the ground to an altitude of 700 kilometres, above which heat conduction maintains an isothermal atmosphere. We conclude that Pluto's atmosphere is unique among Solar System planetary atmospheres, as its radiative energy equilibrium is controlled primarily by haze particles instead of gas molecules. We predict that Pluto is therefore several orders of magnitude brighter at mid-infrared wavelengths than previously thought-a brightness that could be detected by future telescopes. PMID- 29144463 TI - A single-cell survey of the small intestinal epithelium. AB - Intestinal epithelial cells absorb nutrients, respond to microbes, function as a barrier and help to coordinate immune responses. Here we report profiling of 53,193 individual epithelial cells from the small intestine and organoids of mice, which enabled the identification and characterization of previously unknown subtypes of intestinal epithelial cell and their gene signatures. We found unexpected diversity in hormone-secreting enteroendocrine cells and constructed the taxonomy of newly identified subtypes, and distinguished between two subtypes of tuft cell, one of which expresses the epithelial cytokine Tslp and the pan immune marker CD45, which was not previously associated with non-haematopoietic cells. We also characterized the ways in which cell-intrinsic states and the proportions of different cell types respond to bacterial and helminth infections: Salmonella infection caused an increase in the abundance of Paneth cells and enterocytes, and broad activation of an antimicrobial program; Heligmosomoides polygyrus caused an increase in the abundance of goblet and tuft cells. Our survey highlights previously unidentified markers and programs, associates sensory molecules with cell types, and uncovers principles of gut homeostasis and response to pathogens. PMID- 29144466 TI - Influenza: A broadly protective antibody. PMID- 29144469 TI - Research reports: An open market for scientific verbiage? PMID- 29144465 TI - Parallel palaeogenomic transects reveal complex genetic history of early European farmers. AB - Ancient DNA studies have established that Neolithic European populations were descended from Anatolian migrants who received a limited amount of admixture from resident hunter-gatherers. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Here we investigate the population dynamics of Neolithization across Europe using a high-resolution genome-wide ancient DNA dataset with a total of 180 samples, of which 130 are newly reported here, from the Neolithic and Chalcolithic periods of Hungary (6000-2900 bc, n = 100), Germany (5500-3000 bc, n = 42) and Spain (5500-2200 bc, n = 38). We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways in which gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time series-based sampling and modelling approaches to elucidate multiple dimensions of historical population interactions. PMID- 29144470 TI - Chemists can help to solve the air-pollution health crisis. PMID- 29144471 TI - Fires: fund research for citizen safety. PMID- 29144467 TI - Progress in and promise of bacterial quorum sensing research. AB - This Review highlights how we can build upon the relatively new and rapidly developing field of research into bacterial quorum sensing (QS). We now have a depth of knowledge about how bacteria use QS signals to communicate with each other and to coordinate their activities. In recent years there have been extraordinary advances in our understanding of the genetics, genomics, biochemistry, and signal diversity of QS. We are beginning to understand the connections between QS and bacterial sociality. This foundation places us at the beginning of a new era in which researchers will be able to work towards new medicines to treat devastating infectious diseases, and use bacteria to understand the biology of sociality. PMID- 29144473 TI - New Delhi smog, death-sentence appeal and a porpoise setback. PMID- 29144472 TI - International funding: Empower Africa's electricity sector. PMID- 29144474 TI - Puerto Rico struggles to assess hurricane's health effects. PMID- 29144475 TI - UK government appoints next chief scientific adviser. PMID- 29144476 TI - China fires up next-generation neutron-science facility. PMID- 29144477 TI - Boycott products from states with dirty energy. PMID- 29144478 TI - World's carbon emissions set to spike by 2% in 2017. PMID- 29144479 TI - Immunization needs a technology boost. PMID- 29144480 TI - Preclinical research: Meet patients to sharpen up research. PMID- 29144481 TI - Chemists get faster on the draw. PMID- 29144482 TI - Graduate students face alarming tax hike. PMID- 29144484 TI - Lab mice's ancestral 'Eve' gets her genome sequenced. PMID- 29144485 TI - Fires: degree courses for fire professionals. PMID- 29144486 TI - Archaeologists say human-evolution study used stolen bone. PMID- 29144487 TI - Biology's beloved amphibian - the axolotl - is racing towards extinction. PMID- 29144488 TI - How China could make the most of its beamlines. PMID- 29144489 TI - Need a paper? Get a plug-in. PMID- 29144490 TI - Neonatal lung ultrasound exam guidelines. AB - Point-of-care ultrasound (POC-US) is increasingly used especially in emergency and critical-care medicine. It is focused, quick and does not expose patients to ionizing radiation. It encompasses all organ systems and has well-defined indications. Lung ultrasound (LUS) represents one of the most exciting applications in the field of POC-US. It is particularly important to emphasize the role of LUS in neonatology due to the specific pathology inherent in lung immaturity as well as in the particular sensitivity of neonates to repeated radiation exposure. One of the main barriers to the more extensive use of the ultrasound technology is a lack of efficient and attractive training solutions followed by the structured quality-check assurance. In an effort to help bridge this gap, based on the most current literature, we developed creative and intuitive neonatal LUS algorithms. We hope they can serve as a clinical imaging guidelines and a valuable complement to the history and physical exam. PMID- 29144491 TI - Corrigendum: Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. AB - This corrects the article DOI: 10.1038/ni.3799. PMID- 29144492 TI - Inflammatory lipids. PMID- 29144494 TI - Modulation of CD46 in T cells. PMID- 29144495 TI - Charles D. Surh 1960-2017. PMID- 29144493 TI - Adaptive Immune Receptor Repertoire Community recommendations for sharing immune repertoire sequencing data. PMID- 29144496 TI - Suppression from beyond the grave. PMID- 29144497 TI - Gut clues to MS. PMID- 29144498 TI - Corrigendum: The RNA helicase DDX46 inhibits innate immunity by entrapping m6A demethylated antiviral transcripts in the nucleus. AB - This corrects the article DOI: 10.1038/ni.3830. PMID- 29144500 TI - Interferons control fungus. PMID- 29144499 TI - Epithelial stem cell memory. PMID- 29144502 TI - Trained macrophages support hygiene hypothesis. PMID- 29144501 TI - Novel mechanisms and functions of complement. AB - Progress at the beginning of the 21st century transformed the perception of complement from that of a blood-based antimicrobial system to that of a global regulator of immunity and tissue homeostasis. More recent years have witnessed remarkable advances in structure-function insights and understanding of the mechanisms and locations of complement activation, which have added new layers of complexity to the biology of complement. This complexity is readily reflected by the multifaceted and contextual involvement of complement-driven networks in a wide range of inflammatory and neurodegenerative disorders and cancer. This Review provides an updated view of new and previously unanticipated functions of complement and how these affect immunity and disease pathogenesis. PMID- 29144504 TI - Tumor control. PMID- 29144503 TI - MAIT cells in type 1 diabetes: a good friend turned bad. PMID- 29144505 TI - Feeling stressed? It might be your T cells. PMID- 29144506 TI - Soluble P-selectin promotes retinal ganglion cell survival through activation of Nrf2 signaling after ischemia injury. AB - Retinal ischemic injuries play an important role in the pathogenesis of several eye disorders. Inflammation and oxidative stress are key players in ischemic injuries. Following retinal ischemia, vascular endothelial cells and leukocytes express several inflammatory adhesion receptors, such as selectins and cell adhesion molecules. P-selectin stimulates leukocyte recruitment to platelet aggregates and has an important role in vascular homeostasis and inflammatory leukocyte extravasation. Soluble P-selectin can be neuroprotective through competitive binding to the receptors of endogenous P-selectin molecules. Here, we demonstrate the neuroprotective effect of a recombinant P-selectin immunoglobin G (P-sel-IgG) chimeric fusion protein in a rat anterior ischemic optic neuropathy (rAION) model. rAION was induced by photodynamic therapy. P-sel-IgG treatment reduced optic nerve edema and stabilized the blood-optic nerve barrier (BONB) in the acute phase of rAION. Further, P-sel-IgG increased the retinal ganglion cell (RGC) survival rate, reduced RGC apoptosis, preserved visual function, maintained retinal nerve fiber layer thickness, and reduced macrophage infiltration in optic nerve tissue in the chronic phase (day 28). Increased NAD(P)H quinone dehydrogenase 1 (NQO1) and heme oxygenase 1(HO-1) expression levels, along with increased transcription factor Nrf2, suggesting an antioxidant role of P-sel-IgG via the Nrf2 signaling pathway. In conclusion, this study is the first to demonstrate that P-sel-IgG treatment promotes RGC survival by stabilizing the BONB and activating the Nrf2 signaling pathway in a rAION model. PMID- 29144507 TI - The fragile X mental retardation protein regulates tumor invasiveness-related pathways in melanoma cells. AB - The fragile X mental retardation protein (FMRP) is lacking or mutated in patients with the fragile X syndrome (FXS), the most frequent form of inherited intellectual disability. FMRP affects metastasis formation in a mouse model for breast cancer. Here we show that FMRP is overexpressed in human melanoma with high Breslow thickness and high Clark level. Furthermore, meta-analysis of the TCGA melanoma data revealed that high levels of FMRP expression correlate significantly with metastatic tumor tissues, risk of relapsing and disease-free survival. Reduction of FMRP in metastatic melanoma cell lines impinges on cell migration, invasion and adhesion. Next-generation sequencing in human melanoma cells revealed that FMRP regulates a large number of mRNAs involved in relevant processes of melanoma progression. Our findings suggest an association between FMRP levels and the invasive phenotype in melanoma and might open new avenues towards the discovery of novel therapeutic targets. PMID- 29144508 TI - Ly6G+ neutrophil-derived miR-223 inhibits the NLRP3 inflammasome in mitochondrial DAMP-induced acute lung injury. AB - MicroRNA (miRNA) mediates RNA interference to regulate a variety of innate immune processes, but how miRNAs coordinate the mechanisms underlying acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in patients with pulmonary inflammatory injury is still unknown. In this study, we demonstrated that miR-223 limits the number of Ly6G+ neutrophils and inhibits the activity of the NLRP3 inflammasome to alleviate ALI induced by mitochondrial damage-associated molecular patterns (DAMPs) (MTDs). miR-223 expression is increased in the lungs of MTD-induced mice or ARDS patients following trauma/transfusion or following the physiological remission of ALI/ARDS. miR-223-/+ mice exhibited more severe ALI and cytokine dysregulation. Other studies have shown that MTD-induced increases in miR-223 expression are mainly contributed by Ly6G+ neutrophils from the haematopoietic system. miR-223 blocks bone marrow-derived Ly6G+ neutrophil differentiation and inhibits peripheral cytokine release. In addition, MTD induced miR-223 expression activates a negative feedback pathway that targets the inhibition of NLRP3 expression and IL-1beta release; therefore, miR-223 deficiency can lead to the sustained activation of NLRP3-IL-1beta. Finally, elimination of peripheral Ly6G+ neutrophils and pharmacological blockade of the miR-223-NLRP3-IL-1beta signalling axis could alleviate MTD-induced ALI. In summary, miR-223 is essential for regulating the pathogenesis of DAMP-induced ALI. PMID- 29144509 TI - Circular RNA expression is suppressed by androgen receptor (AR)-regulated adenosine deaminase that acts on RNA (ADAR1) in human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a heterogeneous malignancy as a result of complex genetic and epigenetic alterations. HCC is characterized by a clear gender disparity for which there is lack of a clear mechanistic understanding. Androgen receptor (AR) is thought to be critical for such bias. Meanwhile, the potential function of circular RNA (circRNA), regulated by RNA editing enzyme, remained largely unknown in malignancy till now. By utilizing circRNA microarray survey coupled with in vitro analysis, we analyzed the influence of AR on circRNA expression in HCC. Our results indicated that AR could suppress circRNA expression by upregulating ADAR1 p110. Such effect is because AR served as a transcriptional activator of ADAR1 promoter. More significantly, data collected from our center strongly suggest that ADAR1 expression can effectively predict HCC patients' prognosis and an abnormal overexpression of ADAR1 is positively correlated with AR in HCC. In addition, we found CircARSP91 (hsa_circ_0085154), one of the circRNAs downregulated by AR in an ADAR1-dependent manner, could inhibit HCC tumor growth both in vitro and in vivo. These findings highlight the fact that AR as a contributing factor for gender disparity in HCC can cause complex consequences though regulation of circRNA expression. Better understanding of the roles of circRNA during HCC initiation and progression will provide a novel angle to develop potential HCC therapies. PMID- 29144510 TI - Characterizing reduced coverage regions through comparison of exome and genome sequencing data across 10 centers. AB - PURPOSE: As massively parallel sequencing is increasingly being used for clinical decision making, it has become critical to understand parameters that affect sequencing quality and to establish methods for measuring and reporting clinical sequencing standards. In this report, we propose a definition for reduced coverage regions and describe a set of standards for variant calling in clinical sequencing applications. METHODS: To enable sequencing centers to assess the regions of poor sequencing quality in their own data, we optimized and used a tool (ExCID) to identify reduced coverage loci within genes or regions of particular interest. We used this framework to examine sequencing data from 500 patients generated in 10 projects at sequencing centers in the National Human Genome Research Institute/National Cancer Institute Clinical Sequencing Exploratory Research Consortium. RESULTS: This approach identified reduced coverage regions in clinically relevant genes, including known clinically relevant loci that were uniquely missed at individual centers, in multiple centers, and in all centers. CONCLUSION: This report provides a process road map for clinical sequencing centers looking to perform similar analyses on their data. PMID- 29144511 TI - Evaluating CHARGE syndrome in congenital hypogonadotropic hypogonadism patients harboring CHD7 variants. AB - PURPOSE: Congenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined. METHODS: Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype-phenotype correlations were evaluated. RESULTS: Of the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features (P = 0.01). CONCLUSION: Pathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management. PMID- 29144512 TI - Ashkenazi Jewish genomic variants: integrating data from the Israeli National Genetic Database and gnomAD. AB - PURPOSE: The aim of the study was to compare the data for mutations related to clinical disorders reported among Ashkenazi Jewish patients in the Israeli National Genetic Database (INGD) with variants included in the Genome Aggregation Database (gnomAD). METHODS: We extracted data for mutations claimed to cause disorders reported among Ashkenazi Jews from the INGD and searched gnomAD for each of them. We compared the allele frequency of each variant in Ashkenazi Jews with that of other delineated populations. RESULTS: Of the 58 INGD-reported mutations related to autosomal-dominant disorders, 19 were present in gnomAD (32.8%). Of the 309 mutations related to autosomal-recessive disorders, 240 (77.7%) were variants found in gnomAD. Of these variants, 202 (84.2%) were documented among one or more Ashkenazi individuals. At this point in the INGD, there are 168 Ashkenazi assumed founder mutations in 128 different genes corresponding to 111 autosomal-recessive disorders. CONCLUSION: Integration of information on mutations among Ashkenazi Jews extracted from the INGD with their population frequency recorded in gnomAD is important for effective straightforward molecular diagnosis as well as for targeted carrier screening either for reproductive decision-making or for implementation of disease modifying behavior. PMID- 29144513 TI - Predictors of heart rhythm disturbances in hypertensive obese patients with obstructive sleep apnea. AB - Objective: To assess the incidence and predictors of heart rhythm and conduction disturbances in hypertensive obese patients with and without obstructive sleep apnea (OSA). Methods: This is an open, cohort, prospective study. Out of 493 screened patients, we selected 279 hypertensive, obese individuals without severe concomitant diseases: 75 patients without sleep-disordered breathing (non-SDB group), and 204 patients with OSA (OSA group). At baseline, all patients underwent examination, including ECG, Holter ECG monitoring, and sleep study. During follow-up (on 3, 5, 7 and 10th years; phone calls once per 6 months), information about new events, changes in therapy and life style was collected, diagnostic procedures were performed. As the endpoints, we registered significant heart rhythm and conduction disorders as following: atrial fibrillation (AF), ventricular tachycardia, atrioventricular block (AV) 2-3 degree, sinoatrial block, significant sinus pauses (> 2000 ms), and the required pacemaker implantation. Results: The median follow-up was 108 (67.5-120) months. The frequency of heart rhythm disorders was higher in OSA patients (29 cases, chi2 = 5.5; R = 0.019) compared to the non-SDB patients (three cases; OR: 3.92, 95% CI: 1.16-13.29). AF was registered in 15 patients (n = 12 in OSA group; R = 0.77). Heart conduction disturbance developed in 16 patients, without an association with the rate of coronary artery disease onset. Regression analysis showed that only hypertension duration was an independent predictor of AF (OR: 1.10, 95% CI: 1.04-1.16; R = 0.001). In case of heart conduction disturbances, apnea duration was the strongest predictor (R = 0.002). Conclusions: Hypertensive obese patients with OSA demonstrate 4-fold higher incidence of heart rhythm and conduction disturbances than subjects without SDB. Hypertension duration is an independent predictor for AF development, while sleep apnea/hypopnea duration is the main factor for heart conduction disorders onset in hypertensive obese patients with OSA. PMID- 29144514 TI - Catheter ablation of atrial fibrillation in elderly population. AB - Background: Although elderly patients have been included in published series of catheter ablation for atrial fibrillation (AF), clinical benefit and safety remain still less defined in this population. A retrospective analysis of the results of catheter ablation for AF in a large volume center focused on comparison of elderly patients with the rest of the patient cohort was conducted in this study. Methods: Consecutive patients who underwent catheter ablation for AF between January 2001 and December 2016 were analysed. A total population of 3197 patients was dichotomized by the age of 70 years (394 elderly vs. 2803 younger subjects). Patients were followed in terms of arrhythmia status and survival for a median period of 18 vs. 21 and 35 vs. 57 months, respectively. Results: Elderly patients were more frequently females (49% vs. 29%, P < 0.0001), had a history of hypertension (79% vs. 57%, P < 0.0001), diabetes (16% vs. 11%, P < 0.01), stroke (9% vs. 6%, P < 0.01), coronary/peripheral artery disease (14% vs. 8%, P < 0.0001), and CHA2DS2-VASc score (3.1 +/- 1.3 vs. 1.5 +/- 1.2 s, P < 0.0001). Major complications were more frequent in elderly (5.3% vs. 3.2%, P = 0.03); however, this difference was driven by vascular complications (3.6% vs. 1.9%, P = 0.04). There were comparable rates of cerebrovascular (0.3 vs. 0.3%) or nonvascular complications (1.8 vs. 1.2%). Good arrhythmia control was inferior in elderly patients as compared with the rest of the cohort, both without and with antiarrhythmic drugs: 44.2% vs. 58.2% (P < 0.0001) and 78.2 vs. 83.2% (P < 0.01), respectively. Poor arrhythmia control was associated with relative risk of all cause mortality of 2.7 (95% CI: 1.1-6.4) in elderly patients and 1.4 (95% CI: 0.9 2.0) in younger subjects. Conclusions: Catheter ablation for AF in elderly patients is safe although somewhat less effective. Good arrhythmia control is associated with better survival, especially in elderly patients. PMID- 29144515 TI - Detection of sepsis in patient blood samples using CD64 expression in a microfluidic cell separation device. AB - A microfluidic affinity separation device was developed for the detection of sepsis in critical care patients. An affinity capture method was developed to capture cells based on changes in CD64 expression in a single, simple microfluidic chip for sepsis detection. Both sepsis patient samples and a laboratory CD64+ expression model were used to validate the microfluidic assay. Flow cytometry analysis showed that the chip cell capture had a linear relationship with CD64 expression in laboratory models. The Sepsis Chip detected an increase in upregulated neutrophil-like cells when the upregulated cell population is as low as 10% of total cells spiked into commercially available aseptic blood samples. In a proof of concept study, blood samples obtained from sepsis patients within 24 hours of diagnosis were tested on the chip to further validate its performance. On-chip CD64+ cell capture from 10 patient samples (619 +/- 340 cells per chip) was significantly different from control samples (32 +/- 11 cells per chip) and healthy volunteer samples (228 +/- 95 cells per chip). In addition, the on-chip cell capture has a linear relationship with CD64 expression indicating our approach can be used to measure CD64 expression based on total cell capture on Sepsis Chip. Our method has proven to be sensitive, accurate, rapid, and cost-effective. Therefore, this device is a promising detection platform for neutrophil activation and sepsis diagnosis. PMID- 29144516 TI - A ratiometric mitochondria-targeting two-photon fluorescent probe for imaging of nitric oxide in vivo. AB - A two-photon ratiometric fluorescent probe (Mito-N) has been developed for monitoring mitochondrial nitric oxide (NO) in vivo. Mito-N exhibited excellent selectivity and sensitivity toward NO among various ROS/RNS. The successful two photon imaging of mitochondrial NO proved that Mito-N is a powerful noninvasive imaging tool in living systems. PMID- 29144522 TI - Assessment of the burden of critical illness in a rural Botswana hospital with the use of an early warning score. AB - Background: There is little data on prevalence of critical illness in Sub Saharan Africa, especially in rural areas, but it is needed to develop critical care services in district hospitals. Methods: We sought to determine the prevalence of patients 'at risk of' critical illness using an Early Warning Score (EWS) in a district hospital in Botswana. During two-month period patients daily vital signs were recorded and EWSs calculated on adult medical or surgical wards to identify patients who scored >=3. Results: EWS on 826 patients were obtained. There were 180 patients with >=3 [8 refused to give consent and were excluded] with mortality 63(37%) and 646 patients scored below 3, mortality of 3 (0.6%). Patients with scores >=3 were medical (63%), surgical (27%) and orthopaedic (9%). Of patients that were transferred to a referral centre [6 (3%)], none were admitted to ICU. Patients who died lived for 6.5 (SD 7.0) days after first score of >=3. HIV prevalence among patients that died was 37%. Other co-morbidities were rare, except hypertension (21%). Cause of death was not clear in 60% of patients. When cause of death could be inferred from clinical records, it was illness related in 75% of cases. Conclusions: Using the EWS we have identified the burden of critical illness in a rural district hospital in Botswana and the 'critical care gap' where patients do not get the intensive care they need. PMID- 29144523 TI - Protein-templated gold nanoparticle synthesis: protein organization, controlled gold sequestration, and unexpected reaction products. AB - Emerging applications that exploit the properties of nanoparticles for biotechnology require that the nanoparticles be biocompatible or support biological recognition. These types of particles can be produced through syntheses that involve biologically relevant molecules (proteins or natural extracts, for example). Many of the protocols that rely on these molecules are performed without a clear understanding of the mechanism by which the materials are produced. We have investigated a previously described reaction in which gold nanoparticles are produced from the reaction of chloroauric acid and proteins in solution. We find that modifications to the starting conditions can alter the product from the expected solution-suspended colloids to a product where colloids are formed within a solid, fibrous protein structure. We have interrogated this synthesis, exploiting the change in products to better understand this reaction. We have evaluated the kinetics and products for 7 different proteins over a range of concentrations and temperatures. The key factor that controls the synthetic outcome (colloid or fiber) is the concentration of the protein relative to the gold concentration. We find that the observed fibrous structures are more likely to form at low protein concentrations and when hydrophilic proteins are used. An analysis of the reaction kinetics shows that AuNP formation occurs faster at lower protein (fiber-forming) concentrations than at higher protein (colloid forming) concentrations. These results contradict traditional expectations for reaction kinetics and protein-fiber formation and are instructive of the manner in which proteins template gold nanoparticle production. PMID- 29144529 TI - Driving dynamic colloidal assembly using eccentric self-propelled colloids. AB - Designing protocols to dynamically direct the self-assembly of colloidal particles has become an important direction in soft matter physics because of promising applications in the fabrication of dynamic responsive functional materials. Here, using computer simulations, we found that in the mixture of passive colloids and eccentric self-propelled active particles, when the eccentricity and self-propulsion of active particles are high enough, the eccentric active particles can push passive colloids to form a large dense dynamic cluster, and the system undergoes a novel dynamic demixing transition. Our simulations show that the dynamic demixing occurs when the eccentric active particles move much faster than the passive particles such that the dynamic trajectories of different active particles can overlap each other while passive particles are depleted from the dynamic trajectories of active particles. Our results suggest that this is in analogy to the entropy-driven demixing in colloid polymer mixtures, in which polymer random coils can overlap with each other while depleting the colloids. More interestingly, we find that by fixing the passive colloid composition at a certain value with increasing density, the system undergoes an intriguing re-entrant mixing, and the demixing only occurs within a certain intermediate density range. This suggests a new way of designing active matter to drive the self-assembly of passive colloids and fabricate dynamic responsive materials. PMID- 29144530 TI - Liddle's syndrome in an African male due to a novel frameshift mutation in the beta-subunit of the epithelial sodium channel gene. AB - Resistant hypertension is a common clinical problem in South Africa and is frequently associated with low renin and aldosterone levels, especially in black Africans. In South Africa, novel variants in the epithelial sodium channel (ENaC) have been described to be associated with varying degrees of hypokalaemia and hypertension due to primary sodium retention. We report here a case of Liddle's syndrome due to a novel c.1709del11 (p.Ser570Tyrfs*20) deletion in the beta subunit of the ENaC in a young black African male. We discuss the likely pathogenesis of hypertension in this setting as well as the treatment options available in South Africa aimed at the ENaC. This case highlights the need for vigilance in detecting and appropriately treating low-renin and low-aldosterone hypertension in view of the frequency of the described variants of the ENaC channel in our country. Specific therapy such as amiloride should be made more widely available. PMID- 29144531 TI - Who is too fat? PMID- 29144532 TI - Is there a role for combination anti-remodelling therapy for heart failure secondary to chronic rheumatic mitral regurgitation? AB - INTRODUCTION: The value of combination anti-remodelling therapy for heart failure (HF) secondary to mitral regurgitation (MR) is unknown. We studied the effect of anti-remodelling therapy on clinical and echocardiographic parameters in patients with severe chronic rheumatic mitral regurgitation (CRMR) presenting in HF. METHODS: Thirty-one patients (29 females) at Chris Hani Baragwanath Academic Hospital, treated with combination therapy for HF due to CRMR and New York Heart Association functional class II-III symptoms, underwent prospective six-month follow up. RESULTS: Mean age was 50.7 +/- 8.5 years. No patients died or were hospitalised for HF during the study period. No worsening of clinical symptoms or functional status, or left and right ventricular echocardiographic parameters (p > 0.05) was noted. Peak left atrial systolic strain improved at six months (18.7 +/- 7.7 vs 23.6 +/- 8.5%, p = 0.02). CONCLUSION: This preliminary analysis suggests that combination anti-remodelling therapy may be beneficial for HF secondary to CRMR. We had no HF-related admissions or deaths, and no deterioration in echocardiographic parameters of ventricular size and function. PMID- 29144534 TI - Building and strengthening capacity for cardiovascular research in Africa through technical training workshops: a report of the joint course on health research methods by the Clinical Research Education Networking and Consultancy and the Ivorian Society of Cardiology. AB - Africa bears a quarter of the global burden of disease but contributes less than 2% of the global research publications on health, partially due to a lack of expertise and skills to carry out scientific research. We report on a short course on research methods organised by the Clinical Research Education Networking and Consultancy (CRENC) during the third international congress of the Ivorian Cardiac Society (SICARD) in Abidjan, Cote d'Ivoire. Results from the pre- and post-test evaluation during this course showed that African researchers could contribute more to scientific research and publications, provided adequate support and investment is geared towards the identification and training of motivated early-career scientists. PMID- 29144535 TI - A health economic outcome evaluation of an internet-based mobile-supported stress management intervention for employees. AB - Objective This study aimed to estimate and evaluate the cost-effectiveness and cost-benefit of a guided internet- and mobile-supported occupational stress management intervention (iSMI) for employees from the employer's perspective alongside a randomized controlled trial. Methods A sample of 264 employees with elevated symptoms of perceived stress (Perceived Stress Scale, PSS-10 >=22) was randomly assigned either to the iSMI or a waitlist control (WLC) group with unrestricted access to treatment as usual. The iSMI consisted of seven sessions of problem-solving and emotion-regulation techniques and one booster session. Self-report data on symptoms of perceived stress and economic data were assessed at baseline, and at six months following randomization. A cost-benefit analysis (CBA) and a cost-effectiveness analysis (CEA) with symptom-free status as the main outcome from the employer's perspective was carried out. Statistical uncertainty was estimated using bootstrapping (N=5000). Results The CBA yielded a net-benefit of EUR181 [95% confidence interval (CI) -6043-1042] per participant within the first six months following randomization. CEA showed that at a willingness-to-pay ceiling of EUR0, EUR1000, EUR2000 for one additional symptom free employee yielded a 67%, 90%, and 98% probability, respectively, of the intervention being cost-effective compared to the WLC. Conclusion The iSMI was cost-effective when compared to WLC and even lead to cost savings within the first six months after randomization. Offering stress-management interventions can present good value for money in occupational healthcare. PMID- 29144533 TI - Anaemia and iron deficiency in heart failure: epidemiological gaps, diagnostic challenges and therapeutic barriers in sub-Saharan Africa. AB - Anaemia and iron deficiency (ID) are common and of prognostic importance in heart failure (HF). In both conditions the epidemiology, diagnosis and therapies have been extensively studied in high-income countries but are still largely unexplored in sub-Saharan Africa (SSA). The lack of adequate and robust epidemiological data in SSA makes it difficult to recognise the significance of anaemia and ID in HF. From a clinical perspective, less attention is paid by clinicians to screening for anaemia in HF, and as far as interventions are concerned, there are no clinical trials in SSA that provide guidance on the appropriate interventional approach. Therefore studies are needed to provide more insight into the burden and peculiarities of and intervention for anaemia and ID in HF in SSA, where the pathophysiology might be different from that in high income countries. There is increasing appreciation that targeting ID may serve as a useful additional treatment strategy for patients with chronic HF in high income countries. However, there is limited information on the diagnosis of and therapy for ID in HF in SSA, where infections and malnutrition are more likely to influence the situation. This article reviews the present epidemiological gap in knowledge about anaemia and ID in HF, as well as the diagnostic and therapeutic challenges in SSA. PMID- 29144537 TI - Thermotolerant mycobiota of Israeli soils. AB - Composition of thermotolerant mycobiota in the soil of Israeli deserts and northern territories was examined in spatiotemporal dynamics. A total of 165 species from 82 genera were isolated at 37 degrees C using the soil dilution plate method. Aspergilli (Aspergillus fumigatus and A. niger) and teleomorphic ascomycetes (Canariomyces notabilis, Chaetomium nigricolor, and Ch. strumarium) comprised the basic part of the thermotolerant communities. The desert communities remarkably differed from the northern communities by a much higher abundance of A. fumigatus and teleomorphic species, as well as by a lower abundance of A. niger and Rhizopus arrhyzus. Seasonal dynamics revealed for the southern Negev was expressed mainly in the variations of species richness (substantially lower in the winter), and abundances of A. fumigatus (dominant in the summer) and A. niger (dominant in the winter). The composition of thermotolerant mycobiota was almost entirely different from the composition of mesophilic mycobiota at 25 degrees C. Melanin-containing fungi with many-celled conidia that dominated mesophilic communities in the deserts did not grow at 37 degrees C, while prevailing aspergilli accompanied by teleomorphic species with perithecial fruit bodies were apparently able not only to survive but also to germinate at this temperature and be active during a long hot period in the desert. PMID- 29144536 TI - Isolation and whole genome sequencing of fetal cells from maternal blood towards the ultimate non-invasive prenatal testing. AB - OBJECTIVE: The purpose of this study were to develop a methodology of isolating fetal cells from maternal blood and use deep sequence demonstrating the promise for complete and accurate genetic screening compared to other non-invasive prenatal testing. METHODS: Here in this study, we developed a double negative selection (DNS) procedure to unbiasedly enrich fetal cells. After validated by short tandem repeat (STR), the isolated circulating fetal cells (CFCs) were subjected to deep whole genome sequencing analysis. RESULTS: Our DNS protocol significantly increasing the purity of the mimic fetal cells from 1 in 1 million nucleated cells in whole blood to 1:8 to 1:30 (12.5%-3.33%) after 2 steps of enrichment. Isolated single fetal cell obtained a coverage rate (86.8%) and allelic dropout rate (24.90%) comparative to the reported results of human cell line. Several disease-associated variants were identified in the whole genome sequencing data of isolated CFCs and further confirmed in the sequencing data of unamplified gDNA. CONCLUSION: In conclusion, the robustness of DNS and STR to collect CFCs from peripheral maternal blood for the first time coupled with deep sequencing technique demonstrates the possibility of comprehensive non-invasive prenatal testing of genetic disorders using isolated CFCs. PMID- 29144538 TI - Control of hemorrhage through the osteotomy gap during tibial plateau leveling osteotomy: 9 cases. AB - OBJECTIVE: To describe a new technique to control intraoperative hemorrhage during tibial plateau leveling osteotomy (TPLO) and report subsequent short-term and long-term complications. STUDY DESIGN: Retrospective case series. ANIMALS: Nine dogs with arterial hemorrhage during TPLO. METHODS: Medical records of dogs with hemorrhage controlled through the osteotomy gap of a TPLO were reviewed at 2 institutions over 8 years. Inclusion criteria included diagnosis of single cranial cruciate ligament rupture, intraoperative arterial hemorrhage during the radial osteotomy controlled with bipolar electrocautery or hemostatic clips placed along the cranial tibial artery through the osteotomy, complete medical records, radiographic follow-up for at least 8 weeks postoperatively, and completion of long-term follow-up questionnaire by the owner. RESULTS: Dogs were 4.6 +/- 1.8 years old and weighed 36.6 +/- 9.7 kg. In total, 3 +/- 1 hemostatic clips were placed per stifle. Intraoperative hemostasis was achieved in all cases. One of the first dogs received a blood transfusion during the procedure and had a postoperative packed cell volume of 37%. The only complication consisted of fibular fracture, which was noticed on radiographs of 1 dog 8 weeks after TPLO. CONCLUSION: Arterial hemorrhage during the radial osteotomy of a TPLO can be controlled by occlusion of the compromised artery through distraction of the osteotomy gap. This technique was not associated with long-term complications. PMID- 29144539 TI - Model-Based Evaluation of Proximal Sodium Reabsorption Through SGLT2 in Health and Diabetes and the Effect of Inhibition With Canagliflozin. AB - Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce glucose levels in diabetes by inhibiting renal glucose reabsorption in the proximal tubule (PT), resulting in urinary glucose excretion. A recent large cardiovascular outcomes trial suggested that the SGLT2i empagliflozin may also decrease risk of renal dysfunction. Because sodium (Na) and glucose reabsorption are coupled through SGLT2, it is hypothesized that the renal benefits may be derived from lowering Na reabsorption in the PT, which would lead to favorable renal hemodynamic changes. However, the quantitative contribution of SGLT2 to PT Na reabsorption, as well as the differences between healthy and diabetic subjects, and the impact of SGLT2i on PT Na reabsorption are unknown. In this study we extended an existing mathematical model of glucose dynamics to account for renal glucose filtration and excretion. We utilized this model to quantify glucose and Na reabsorption through SGLT2 in healthy, controlled, and uncontrolled diabetes and following treatment with canagliflozin. In healthy, controlled diabetic, and uncontrolled diabetic states, Na reabsorption through SGLT2 was found to be 5.7%, 11.5%, and 13.7% of total renal Na reabsorption, and 7.1% to 9.5%, 14.4% to 19.2%, and 17.1% to 22.8% of sodium reabsorption in the PT alone. The model predicted that treatment of controlled diabetes with canagliflozin returns PT Na reabsorption through SGLT2 to normal levels. The degree of increased PT Na reabsorption due to SGLT2 is likely sufficient to drive pathologic changes in renal hemodynamics, and restoration of normal Na reabsorption through SGLT2 may contribute to beneficial renal effects of SGLT2 inhibition. PMID- 29144540 TI - Biosynthetic energy cost of potentially highly expressed proteins vary with niche in selected actinobacteria. AB - Amino acid and protein biosynthesis requires a number of high energy phosphate bonds and includes a dual energy cost for the synthesis of chemical intermediates during the fueling reactions and the conversion of precursor molecules to final products. One popular hypothesis is that the proteins encoded by putative highly expressed genes (hence called PHXPs) generally utilize low energy consuming amino acids to reduce the biosynthetic cost of the essential proteins. In our study, we found that this idea was not supported in the case of actinobacteria. With the actinobacteria, the energy costs of PHXPs varied in relation to their niche. Free living, including aquatic, soil and extremophilic, and plant-associated actinobacteria were found to use energetically expensive amino acids in their PHXPs. An exception occurred with some animal-host-associated actinobacteria that used energy efficient amino acids. One explanation for these results may be due to the diverse metabolic patterns exhibited by actinobacteria under varied niches influenced by nutritional availability and physical environment. PMID- 29144541 TI - Genetic landscape of papillary thyroid carcinoma in the Chinese population. AB - Improvement in the clinical outcome of human cancers requires characterization of the genetic alterations underlying their pathogenesis. Large-scale genomic and transcriptomic characterization of papillary thyroid carcinomas (PTCs) in Western populations has revealed multiple oncogenic drivers which are essential for understanding pathogenic mechanisms of this disease, while, so far, the genetic landscape in Chinese patients with PTC remains uncharacterized. Here, we conducted a large-scale genetic analysis of PTCs from patients in China to determine the mutational landscape of this cancer. By performing targeted DNA amplicon and targeted RNA deep-sequencing, we elucidated the landscape of somatic genetic alterations in 355 Chinese patients with PTC. A total of 88.7% of PTCs were found to harbor at least one candidate oncogenic driver genetic alteration. Among them, around 72.4% of the cases carried BRAF mutations; 2.8% of cases harbored RAS mutations; and 13.8% of cases were characterized with in-frame gene fusions, including seven newly identified kinase gene fusions. TERT promoter mutations were likely to occur in a sub-clonal manner in our PTC cohort. The prevalence of somatic genetic alterations in PTC was significantly different between our Chinese cohort and TCGA datasets for American patients. Additionally, combined analyses of genetic alterations and clinicopathologic features demonstrated that kinase gene fusion was associated with younger age at diagnosis, larger tumor size, and lymph node metastasis in PTC. With the analyses of DNA rearrangement sites of RET gene fusions in PTC, signatures of chromosome translocations related to RET fusion events were also depicted. Collectively, our results provide fundamental insight into the pathogenesis of PTC in the Chinese population. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29144543 TI - Primary Thromboprophylaxis in Individuals without Cancer Admitted to a Geriatric Palliative Care Unit. AB - BACKGROUND/OBJECTIVES: The prevalence of individuals with advanced noncancer disease is increasing on palliative care units (PCUs), but there are no current guidelines to direct venous thromboembolism (VTE) prophylaxis decisions in these individuals. The aim of this study was to compare primary VTE prophylaxis in elderly adults with advanced noncancer diagnoses with that of those with advanced cancer on a dedicated geriatric PCU. DESIGN: Single-center retrospective chart review. SETTING: Baycrest Health Sciences PCU, Toronto, Ontario, Canada. PARTICIPANTS: All 317 individuals admitted to and discharged in 2015 were included in the initial analysis. RESULTS: Three hundred sixteen individuals were included in the final analysis, 56 (17.7%) of whom had a noncancer diagnosis. VTE prophylaxis was administered in 31.8% of participants with cancer and 26.8% of those without (P = .28). Two hundred eleven (66.6%) participants were admitted from the hospital, and 96 (30.3%) were admitted from home. Participants admitted from the hospital were more likely to receive VTE prophylaxis (39.8% vs 13.7%; P < .05). Mean admission PPS score was 31.4 for participants without cancer and 36.0 for those with cancer (P < .05). Length of stay was shorter for participants with a PPS score less than 30 (18.6 vs 33.6 days; P < .05). The rate of VTE prophylaxis in participants who were bedbound was similar to that in those who were ambulatory (29.8% vs 32.2%; P = .36). CONCLUSION: VTE prophylaxis rates were similar in participants with and without cancer on a geriatric PCU. The rate was not significantly less for nonambulatory participants. Further research would help to better guide VTE prophylaxis decisions and minimize suffering at the end of life. PMID- 29144542 TI - Autoimmune diseases and breast cancer risk by tumor hormone-receptor status among elderly women. AB - The female preponderance of many autoimmune diseases suggests a possible hormonal etiology. Little research exists on systemic and organ-specific autoimmune diseases and risk of breast cancer by tumor estrogen receptor (ER)- and progesterone receptor (PR)- status. Here, we evaluate associations between selected systemic and organ-specific autoimmune diseases and breast cancer risk overall and by tumor ER- and PR-status. We used linked Surveillance, Epidemiology and End Results (SEER)-Medicare data, with first female breast cancer cases ages >=66 years identified by SEER registries (years 1992-2011; N = 209,929). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients who were alive and breast cancer-free. We assessed exposures until 12 months before breast cancer diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional and multinomial logistic regression. We found reduced breast cancer risk among those with rheumatoid arthritis (OR = 0.84; 99.9% CI 0.79-0.89), systemic lupus erythematosus (OR = 0.82; 99.9% CI 0.70-0.97) and pernicious anemia (OR = 0.90; 99.9% CI 0.83-0.97) and increased risk among those with psoriasis (OR = 1.16; 99.9% CI 1.06-1.27). Statistically significant alterations in risk for rheumatoid arthritis were limited to ER-positive (+) breast cancer, whereas those for the other three conditions were further limited to ER+/PR+ breast cancer. However, only differences for rheumatoid arthritis by ER-status were statistically significant (p-heterogeneity = 0.0001). The reasons for these associations need to be investigated in future studies accounting for host characteristics and autoimmune disease treatment. PMID- 29144544 TI - Effects of Nicotine on Alcohol Drinking in Female Mice Selectively Bred for High or Low Alcohol Preference. AB - BACKGROUND: Studies show that repeated nicotine use associates with high alcohol consumption in humans and that nicotine exposure sometimes increases alcohol consumption in animal models. However, the relative roles of genetic predisposition to high alcohol consumption, the alcohol drinking patterns, and the timing of nicotine exposure both with respect to alcohol drinking and developmental stage remain unclear. The studies here manipulated all these variables, using mice selectively bred for differences in free-choice (FC) alcohol consumption to elucidate the role of genetics and nicotine exposure in alcohol consumption behaviors. METHODS: In Experiments 1 and 2, we assessed the effects of repeated nicotine (0, 0.5, or 1.5 mg/kg) injections immediately before binge-like (drinking-in-the-dark; Experiment 1) or during FC alcohol access (Experiment 2) on these alcohol drinking behaviors (immediately after injections and during re-exposure to alcohol access 14 days later) in adult high- (HAP2) and low-alcohol-preferring (LAP2) female mice (co-exposure model). In Experiments 3 and 4, we assessed the effects of repeated nicotine (0, 0.5, or 1.5 mg/kg) injections 14 days prior to binge-like and FC alcohol access on these alcohol drinking behaviors in adolescent HAP2 and LAP2 female mice (Experiment 3) or adult HAP2 female mice (Experiment 4). RESULTS: In Experiment 1, we found that repeated nicotine (0.5 and 1.5 mg/kg) and alcohol co-exposure significantly increased binge-like drinking behavior in HAP2 but not LAP2 mice during the re exposure phase after a 14-day abstinence period. In Experiment 2, 1.5 mg/kg nicotine injections significantly reduced FC alcohol intake and preference in the third hour postinjection in HAP2 but not LAP2 mice. No significant effects of nicotine treatment on binge-like or FC alcohol drinking were observed in Experiments 3 and 4. CONCLUSIONS: These results show that the temporal parameters of nicotine and alcohol exposure, pattern of alcohol access, and genetic predisposition for alcohol preference influence nicotine's effects on alcohol consumption. These findings in selectively bred mice suggest that humans with a genetic history of alcohol use disorders may be more vulnerable to develop nicotine and alcohol co-use disorders. PMID- 29144545 TI - Music therapy for depression. AB - BACKGROUND: Depression is a highly prevalent mood disorder that is characterised by persistent low mood, diminished interest, and loss of pleasure. Music therapy may be helpful in modulating moods and emotions. An update of the 2008 Cochrane review was needed to improve knowledge on effects of music therapy for depression. OBJECTIVES: 1. To assess effects of music therapy for depression in people of any age compared with treatment as usual (TAU) and psychological, pharmacological, and/or other therapies.2. To compare effects of different forms of music therapy for people of any age with a diagnosis of depression. SEARCH METHODS: We searched the following databases: the Cochrane Common Mental Disorders Controlled Trials Register (CCMD-CTR; from inception to 6 May 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; to 17 June 2016); Thomson Reuters/Web of Science (to 21 June 2016); Ebsco/PsycInfo, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, and PubMed (to 5 July 2016); the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, the National Guideline Clearing House, and OpenGrey (to 6 September 2016); and the Digital Access to Research Theses (DART)-Europe E-theses Portal, Open Access Theses and Dissertations, and ProQuest Dissertations and Theses Database (to 7 September 2016). We checked reference lists of retrieved articles and relevant systematic reviews and contacted trialists and subject experts for additional information when needed. We updated this search in August 2017 and placed potentially relevant studies in the "Awaiting classification" section; we will incorporate these into the next version of this review as appropriate. SELECTION CRITERIA: All randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing music therapy versus treatment as usual (TAU), psychological therapies, pharmacological therapies, other therapies, or different forms of music therapy for reducing depression. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, and extracted data from all included studies. We calculated standardised mean difference (SMD) for continuous data and odds ratio (OR) for dichotomous data with 95% confidence intervals (CIs). We assessed heterogeneity using the I2 statistic. MAIN RESULTS: We included in this review nine studies involving a total of 421 participants, 411 of whom were included in the meta-analysis examining short-term effects of music therapy for depression. Concerning primary outcomes, we found moderate-quality evidence of large effects favouring music therapy and TAU over TAU alone for both clinician rated depressive symptoms (SMD -0.98, 95% CI -1.69 to -0.27, 3 RCTs, 1 CCT, n = 219) and patient-reported depressive symptoms (SMD -0.85, 95% CI -1.37 to -0.34, 3 RCTs, 1 CCT, n = 142). Music therapy was not associated with more or fewer adverse events than TAU. Regarding secondary outcomes, music therapy plus TAU was superior to TAU alone for anxiety and functioning. Music therapy and TAU was not more effective than TAU alone for improved quality of life (SMD 0.32, 95% CI 0.17 to 0.80, P = 0.20, n = 67, low-quality evidence). We found no significant discrepancies in the numbers of participants who left the study early (OR 0.49, 95% CI 0.14 to 1.70, P = 0.26, 5 RCTs, 1 CCT, n = 293, moderate-quality evidence). Findings of the present meta-analysis indicate that music therapy added to TAU provides short-term beneficial effects for people with depression if compared to TAU alone. Additionally, we are uncertain about the effects of music therapy versus psychological therapies on clinician-rated depression (SMD -0.78, 95% CI -2.36 to 0.81, 1 RCT, n = 11, very low-quality evidence), patient-reported depressive symptoms (SMD -1.28, 95% CI -3.75 to 1.02, 4 RCTs, n = 131, low quality evidence), quality of life (SMD -1.31, 95% CI - 0.36 to 2.99, 1 RCT, n = 11, very low-quality evidence), and leaving the study early (OR 0.17, 95% CI 0.02 to 1.49, 4 RCTs, n = 157, moderate-quality evidence). We found no eligible evidence addressing adverse events, functioning, and anxiety. We do not know whether one form of music therapy is better than another for clinician-rated depressive symptoms (SMD -0.52, 95% CI -1.87 to 0.83, 1 RCT, n = 9, very low quality evidence), patient-reported depressive symptoms (SMD -0.01, 95% CI -1.33 to 1.30, 1 RCT, n = 9, very low-quality evidence), quality of life (SMD -0.24, 95% CI -1.57 to 1.08, 1 RCT, n = 9, very low-quality evidence), or leaving the study early (OR 0.27, 95% CI 0.01 to 8.46, 1 RCT, n = 10). We found no eligible evidence addressing adverse events, functioning, or anxiety. AUTHORS' CONCLUSIONS: Findings of the present meta-analysis indicate that music therapy provides short-term beneficial effects for people with depression. Music therapy added to treatment as usual (TAU) seems to improve depressive symptoms compared with TAU alone. Additionally, music therapy plus TAU is not associated with more or fewer adverse events than TAU alone. Music therapy also shows efficacy in decreasing anxiety levels and improving functioning of depressed individuals.Future trials based on adequate design and larger samples of children and adolescents are needed to consolidate our findings. Researchers should consider investigating mechanisms of music therapy for depression. It is important to clearly describe music therapy, TAU, the comparator condition, and the profession of the person who delivers the intervention, for reproducibility and comparison purposes. PMID- 29144546 TI - Presence of infection and analysis of HPV subtypes in girls younger than 9 years old attended at a referral service in Espirito Santo, Brazil. AB - Human papillomavirus (HPV) is found in adults and adolescents and is associated with genital warts and cervical cancer. However, it has been detected in girls younger than 10 years old. Currently, there are no prevention methods for this age group, since it is not considered a risk group. The aim of this study was to evaluate the presence of infection and HPV subtype in girls under 9 years old attended at a referral service in the State of Espirito Santo, Brazil. Forty three girls younger than 9 years old had gynecological brush samples collected from vulval and perineal/anal regions. Viral detection and subtyping were done using polymerase chain reaction, restriction fragment length polymorphism and DNA sequencing. Statistics was performed using Action Stat 3.1. The mean age of girls was 6.1 years. Sexual activity and abuse were not reported by 95.3%. Family stories showed viral infection in 9.3% of mothers, 4.7% of fathers and 9.3% of caretakers. None of these were related with the children infection. In the only case of mother's gestational HPV infection, the daughter tested negative. Genital warts and infection were observed in 7% and 13.9% of the patients, respectively. Viral subtypes detected were 6, 11, 38, and 42. These results demonstrate the presence of HPV infection in girls under 9 years of age. Prevalence studies are needed in order to evaluate a possible alteration in age of vaccination policy. PMID- 29144547 TI - Research in Nursing & Health Author Guidelines. PMID- 29144548 TI - Anti-Mullerian hormone measurement for the diagnosis of polycystic ovary syndrome. AB - OBJECTIVE: Anti-Mullerian hormone (AMH) is derived from the small antral follicles, and an elevated level has been suggested to add value to the Rotterdam criteria for the diagnosis of PCOS in cases of diagnostic uncertainty. Therefore, the role of AMH in the classical phenotype of PCOS was defined within a Caucasian population. DESIGN: This was a cross-sectional study. PATIENTS: Sixty Five women without PCOS and 110 women with PCOS fulfilling all 3 diagnostic Rotterdam criteria. MEASUREMENTS: The main outcomes were the utility of serum AMH for the diagnosis of PCOS and its relationship to the metabolic parameters. RESULTS: Anti Mullerian hormone was increased in PCOS compared to controls (P < .001). Areas under the receiver operator curve showed AMH to be predictive of PCOS (0.76) using a cut-off AMH of 46 pmol/L, which is derived from the 95th percentile of the controls that gave a 41% sensitivity and 86% specificity; an AMH cut-off of 35 pmol/L gave a 55% sensitivity and 79% specificity. Age- and BMI-adjusted multiple logistic regression showed that AMH was more predictive of PCOS independently of either serum testosterone (T) (OR = 4.04; 95% CI 1.42-11.11; P = .007) or free androgen index (FAI) (OR = 3.90; 95% CI 1.40-10.83; P = .009). CONCLUSION: Whilst an elevated AMH has poor sensitivity, it is fourfold more likely to be associated with a diagnosis of PCOS, and supplementary to biochemical parameters will make a positive diagnosis of PCOS in 22% of patients when neither serum testosterone nor FAI is elevated. PMID- 29144549 TI - Zuclopenthixol dihydrochloride for schizophrenia. AB - BACKGROUND: Oral zuclopenthixol dihydrochloride (Clopixol) is an anti-psychotic treatment for people with psychotic symptoms, especially those with schizophrenia. It is associated with neuroleptic malignant syndrome, a prolongation of the QTc interval, extra-pyramidal reactions, venous thromboembolism and may modify insulin and glucose responses. OBJECTIVES: To determine the effects of zuclopenthixol dihydrochloride for treatment of schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (latest search 09 June 2015). There were no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: All randomised controlled trials (RCTs) focusing on zuclopenthixol dihydrochloride for schizophrenia. We included trials meeting our inclusion criteria and reporting useable data. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We included 20 trials, randomising 1850 participants. Data were reported for 12 comparisons, predominantly for the short term (up to 12 weeks) and inpatient populations. Overall risk of bias for included studies was low to unclear.Data were unavailable for many of our pre-stated outcomes of interest. No data were available, across all comparisons, for death, duration of stay in hospital and general functioning.Zuclopenthixol dihydrochloride versus: 1. placeboMovement disorders (EPSEs) were similar between groups (1 RCT, n = 28, RR 6.07 95% CI 0.86 to 43.04 very low-quality evidence). There was no clear difference in numbers leaving the study early (2 RCTs, n = 100, RR 0.29, 95% CI 0.01 to 6.60, very low-quality evidence). 2. chlorpromazineNo clear differences were found for the outcomes of global state (average CGI-SI endpoint score) (1 RCT, n = 60, MD 0.00, 95% CI -0.49 to 0.49) or movement disorders (EPSEs) (3 RCTs, n = 199, RR 0.94, 95% CI 0.61 to 1.45), both very low-quality evidence. More people left the study early for any reason from the zuclopenthixol group (6 RCTs, n = 766, RR 0.54, 95% CI 0.36 to 0.81, low-quality evidence). 3. chlorprothixeneThere was no clear difference in numbers leaving the study early for any reason (1 RCT, n = 20, RR 1.00, 95% CI 0.34 to 2.93, very low-quality evidence). 4. clozapineNo useable data were presented. 5. haloperidolNo clear differences between treatment groups were found for the outcomes global state score (average CGI endpoint score) (1 RCT, n = 49, MD 0.13, 95% CI -0.30 to 0.55) or leaving the study early (2 RCTs, n = 141, RR 0.99, 95% CI 0.72 to 1.35), both very low-quality evidence. 6. perphenazineThose receiving zuclopenthixol were more likely to require medication in the short term for EPSEs than perphenazine (1 RCT, n = 50, RR 1.90, 95% CI 1.12 to 3.22, very low-quality evidence). Similar numbers left the study early (2 RCTs, n = 104, RR 0.63, 95% CI 0.27 to 1.47, very low-quality evidence). 7. risperidoneThose receiving zuclopenthixol were more likely to require medications for EPSEs than risperidone (1 RCT, n = 98,RR 1.92, 95% CI 1.12 to 3.28, very low quality evidence). There was no clear difference in numbers leaving the study early ( 3 RCTs, n = 154, RR 1.30, 95% CI 0.84 to 2.02) or in mental state (average PANSS total endpoint score) (1 RCT, n = 25, MD -3.20, 95% CI -7.71 to 1.31), both very low-quality evidence). 8. sulpirideNo clear differences were found for global state (average CGI endpoint score) ( 1 RCT, n = 61, RR 1.18, 95% CI 0.49 to 2.85, very low-quality evidence), requiring hypnotics/sedatives (1 RCT, n = 61, RR 0.60, 95% CI 0.27 to 1.32, very low quality evidence) or leaving the study early (1 RCT, n = 61, RR 2.07 95% CI 0.97 to 4.40, very low-quality evidence). 9. thiothixeneNo clear differences were found for the outcomes of 'global state (average CGI endpoint score) (1 RCT, n = 20, RR 0.50, 95% CI 0.17 to 1.46) or leaving the study early (1 RCT, n = 20, RR 0.57, 95% CI 0.24 to 1.35), both very low-quality evidence). 10. trifluoperazineNo useable data were presented. 11. zuclopenthixol depotThere was no clear difference in numbers leaving the study early (1 RCT, n = 46, RR 1.95, 95% CI 0.36 to 10.58, very low-quality evidence). 12. Zuclopenthixol dihydrochloride (cis z isomer) versus zuclopenthixol (cis z/trans e isomer)There were no clear differences in reported side-effects ( 1 RCT, n = 57, RR 1.34, 95% CI 0.82 to 2.18, very low-quality evidence) and in numbers leaving the study early (4 RCTs, n = 140, RR 2.15, 95% CI 0.49 to 9.41, very low-quality evidence). AUTHORS' CONCLUSIONS: Zuclopenthixol dihydrochloride appears to cause more EPSEs than clozapine, risperidone or perphenazine, but there was no difference in EPSEs when compared to placebo or chlorpromazine. Similar numbers required hypnotics/sedatives when zuclopenthixol dihydrochloride was compared to sulpiride, and similar numbers of reported side-effects were found when its isomers were compared. The other comparisons did not report adverse-effect data.Reported data indicate zuclopenthixol dihydrochloride demonstrates no difference in mental or global states compared to placebo, chlorpromazine, chlorprothixene, clozapine, haloperidol, perphenazine, sulpiride, thiothixene, trifluoperazine, depot and isomers. Zuclopenthixol dihydrochloride, when compared with risperidone, is favoured when assessed using the PANSS in the short term, but not in the medium term.The data extracted from the included studies are mostly equivocal, and very low to low quality, making it difficult to draw firm conclusions. Prescribing practice is unlikely to change based on this meta analysis. Recommending any particular course of action about side-effect medication other than monitoring, using rating scales and clinical assessment, and prescriptions on a case-by-case basis, is also not possible.There is a need for further studies covering this topic with more antipsychotic comparisons for currently relevant outcomes. PMID- 29144550 TI - Self-Determination Theory as a Foundation for Personality Researchers. AB - In this introductory article we first describe the impetus for this special issue. What made us think that Self-Determination Theory (SDT) might provide a sort of foundation for the rest of personality psychology? For readers unfamiliar with SDT, we then provide a historical overview which covers the evolution of the six "mini-theories" that currently comprise SDT: cognitive evaluation theory, causality orientations theory, organismic integration theory, basic psychological needs theory, goal contents theory, and relational motivation theory. Following each section are preliminary suggestions about how each mini-theory might be useful or informative in other branches of personality. This special issue contains 9 articles, each of which makes its own attempt to newly link its area of personality research to SDT. Even if SDT is not the appropriate seed for greater consilience in personality psychology, we urge the field not to neglect the search for unifying principles (Sheldon, Chen, & Hilpert, 2011); it may finally be time to renew the search for a "grand theory" in personality. This article is protected by copyright. All rights reserved. PMID- 29144551 TI - Impact of volumetric muscle loss injury on persistent motoneuron axotomy. AB - INTRODUCTION: Volumetric muscle loss (VML) occurs following significant traumatic injury or surgical removal of skeletal muscle, resulting in nonrecoverable loss of tissue and long-term dysfunction. Perhaps less recognized is that VML injuries inherently disrupt the neuromuscular unit, resulting in fiber denervation and presumptive motor unit rearrangement, expansion, and/or loss. To characterize neural dysfunction we quantified motoneuron axotomy, in efforts to understand how this relates to the temporal coordination of neuromuscular and morphological alterations due to injury. METHODS: In an established rat tibialis anterior (TA) VML injury model, we examined the motoneuron, skeletal muscle, and maximal isometric torque at 3, 7, 14, and 21 days postinjury. RESULTS: Significant axotomy of 57-79% of all TA muscle motoneurons was observed through 21 days postinjury, which was coupled with a 45-90% TA maximal torque deficit. DISCUSSION: A ~20% partial ablation of the TA muscle causes disproportionate damage across the motor unit acutely postinjury. Muscle Nerve 57: 799-807, 2018. PMID- 29144552 TI - Simultaneous determination of tilianin and its metabolites in mice using ultra high-performance liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetic study. AB - Tilianin is an active flavonoid glycoside found in many medical plants. Data are lacking regarding its pharmacokinetics and disposition in vivo. The objective of this study was to develop a sensitive, reliable and validated ultra-high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method to simultaneously quantify tilianin and its main metabolites and to determine its pharmacokinetics in wild-type and breast cancer resistance protein knockout (Bcrp1-/-) FVB mice. Chromatographic separation was accomplished on a C18 column by utilizing acetonitrile and 0.5 mm ammonium acetate as the mobile phase. Mass spectrometric detection was performed using electrospray ionization in both positive and negative modes. The results showed that the precision, accuracy and recovery, as well as the stability of tilianin and its metabolites in mouse plasma, were all within acceptable limits. Acacetin-7-glucuronide and acacetin-7-sulfate were the major metabolites of tilianin in mouse plasma. Moreover, systemic exposure of acacetin-7-sulfate was significantly higher in Bcrp1 (-/-) FVB mice compared with wild-type FVB mice. In conclusion, the fully validated UHPLC-MS/MS method was sensitive, reliable, and was successfully applied to assess the pharmacokinetics of tilianin in wild-type and Bcrp1 (-/-) FVB mice. Breast cancer resistance protein had a significant impact on the elimination of the sulfated metabolite of tilianin in vivo. PMID- 29144553 TI - Blocking 17beta-hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach. AB - The enzyme type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD-1), responsible for generating active 17beta-estradiol (E2) from low-active estrone (E1), is overexpressed in endometrial cancer (EC), thus implicating an increased intra tissue generation of E2 in this estrogen-dependent condition. In this study, we explored the possibility of inhibiting 17beta-HSD-1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo, and ex vivo models. We generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of 17beta-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17beta-HSD-1 activity could be blocked by a specific 17beta-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17beta-HSD-1 inhibition. In vivo, tumors grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by 17beta-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17beta-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17beta-HSD-1 enzyme activity (ex vivo in tumor tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the 17beta-HSD-1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumor, we next demonstrated the mRNA expression of the potential drug target, 17beta-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17beta-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17beta-HSD-1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29144554 TI - A sensitive colorimetric DNA biosensor for specific detection of the HBV gene based on silver-coated glass slide and G-quadruplex-hemin DNAzyme. AB - A sensitive colorimetric DNA biosensor for specific detection of single stranded oligonucleotide (ssDNA) is proposed in this paper. The biosensor is based on silver-coated glass (SCGS) and G-quadruplex-hemin DNAzyme. Capture DNA is immobilized on the surface of SCGS by Ag-S bond. Signal DNA can be used to hybridize with the target DNA which is selected from the Hepatitis B virus(HBV) gene as target HBV DNA, and the HRP-mimicking G-quadruplex-hemin DNAzyme can be formed through the function of a guanine-rich fragment from signal DNA to catalyze the oxidation of 2,2-azinobis(3-ethylbenzothiozoline)-6-sulfonicacid (ABTS2- ) by H2 O2 . The reaction will be monitored along the side of absorbance changes at 418 nm and it can be viewed by naked eye with the change of color as well. Upon addition of target Hepatitis B virus(HBV) DNA, signal DNA could bind on the surface of SCGS, and the concentration of G-quadruplex-hemin DNAzyme immobilizing on the surface of SCGS is depended on that of target HBV DNA. Under the optimum conditions, the absorption was proportional to the concentration of target HBV DNA over the range from 0.5 to 100 nM, with a detection limit of 0.2 nM. In addition, the biosensor is target specific and practicability. This assay might open a new avenue for applying in the diagnosis of HBV disease in the future. PMID- 29144555 TI - "CHOP"ing intestinal stem cells on way to cholestatic liver injury. PMID- 29144556 TI - Exercise alters the hepatic immunophenotype to protect against inflammatory liver disease. PMID- 29144557 TI - Penile warty mucoepidermoid carcinoma with features of stratified mucin-producing intra-epithelial lesion and invasive stratified mucin-producing carcinoma. AB - AIMS: Stratified mucin-producing intra-epithelial lesion (SMILE) and invasive stratified mucin-producing carcinoma (ISMC) are recently described cervical and penile lesions. We report an unusual case of mixed variant of penile squamous cell carcinomas with warty, usual and mucoepidermoid SMILE/ISMC features. METHODS AND RESULTS: A 62-year-old Japanese man had a glans penis lesion of one-and-a half years' duration, suggesting malignancy. Partial penectomy and left inguinal lymphadenectomy were performed. Pathological evaluation revealed a mixed squamous cell carcinoma with warty, mucinous and usual features. The mucinous component resembled mucoepidermoid carcinoma (MEC) and SMILE/ISMC. Glandular differentiation was absent. All the diverse tumour components were negative for p16, which was confirmed by negative human papillomavirus (HPV) genotyping. The mucinous component was diffusely positive for cytokeratin 7 and largely negative for cytokeratin 5 and p63. Fluorescence in-situ hybridisation did not detect rearrangement in the MAML2 or EWSR1 genes. The tumour was pathological stage pT2, pN1 (AJCC prognostic stage group IIIA) and was disease-free 26 months after surgery. CONCLUSIONS: The lack of glands in the mucinous areas suggested that MEC should be separated from adenosquamous carcinoma (ASC). Penile SMILE/ISMC may occur without dependence upon HPV status. Further studies will be necessary to determine the pathogenesis and definition of penile SMILE/ISMC, the presence of true MEC arising from the glans penis and the clinicopathological differences of penile ASC, MEC and SMILE/ISMC. Herein, we refer to the SMILE-like penile lesion as 'mucinous penile intra-epithelial neoplasia'. PMID- 29144558 TI - Association of oxidative stress with clinical characteristics in patients with rheumatoid arthritis. AB - BACKGROUND: Few studies examining the association between oxidative stress and clinical parameters or disease activity in patients with rheumatoid arthritis (RA) are available. Therefore, the objective of this study was to test whether oxidative stress has any association with clinical parameters and disease activity in patients with RA. MATERIALS AND METHODS: In this post hoc cross sectional study, 45 patients with RA treated with traditional disease-modifying antirheumatic drugs (DMARDs) +/- low-dose glucocorticoids +/- nonsteroidal analgesics for at least 3 months were analysed. Oxidative stress parameters were malondialdehyde (MDA), superoxide dismutase (SOD), antioxidant potential (AOP) and nonenzymatic superoxide radical scavenger activity (NSSA). Clinical parameters were pain, patient global assessment, physician global assessment, Health Assessment Questionnaire (HAQ), and disease activity score (DAS28). RESULTS: Plasma NSSA levels were significantly inversely correlated with tender joints count (r = -.304; P = .042), swollen joints count (r = -.342; P = .021) and DAS28 (r = -.396; P = .009). There were no significant correlations between MDA/SOD/AOP and any of clinical parameters or DAS28 (P > .05 for all). Multiple regression analysis revealed that NSSA was an independent variable of DAS28 (beta=-.243, P = .016). CONCLUSION: The preliminary results demonstrate that plasma NSSA levels were inversely correlated with tender and swollen joints count and DAS28 and that NSSA was independently associated with DAS28, in patients with RA treated with traditional DMARDs; and provide initial support that NSSA may be used as a biomarker of disease activity in patients with RA. PMID- 29144559 TI - Treatment of Helicobacter pylori infection: A clinical practice update. AB - BACKGROUND: Helicobacter pylori infection is still frequent in the community and all infected subjects should be offered an eradication therapy. Nowadays physicians have to face the challenge of antibiotic resistance in treating Helicobacter pylori-infected individuals. AIM: This review provides an overview of current international guidelines and reports recent evidence from systematic reviews and clinical trials on the treatment of Helicobacter pylori infection and should help physicians to better treat their patients. RESULTS: General rules to optimize the management of Helicobacter pylori infection include: (i) considering previous patient's exposure to antibiotics; (ii) using high dose of proton-pump inhibitors; and (iii) avoiding repeating the same regimen, if it has already failure. Bismuth quadruple therapy and concomitant therapy are the best first line empirical treatments in areas with high clarithromycin resistance and in individuals with previous use of macrolides; otherwise, the 14-day clarithromycin containing triple therapy is a valid regimen. The sequential therapy is no longer a suggested treatment by international guidelines. CONCLUSIONS: Current international guidelines are consistent in defining treatment strategies for Helicobacter pylori infection. The use of national registries to monitor the efficacy and tolerability of different regimens in the real world of clinical practice is now needed. PMID- 29144560 TI - Large Proton-Affinity Enhancements Triggered by Noncovalent Interactions. AB - High affinity: The proton affinity (PA) of the OH group of YHx OH compounds is always increased by noncovalent interaction (NCI) with a Lewis base (LB; see figure). This PA enhancement depends on the type of NCI. Weak NCIs can give rise to PA enhancements equal to or even larger than strong NCIs. The binding energies of protonated species play a major role in the case of sigma-hole interactions. PMID- 29144562 TI - MiR-5100 increases the cisplatin resistance of the lung cancer stem cells by inhibiting the Rab6. AB - Cisplatin-based chemotherapy is the most commonly used treatment regimen for lung cancer. Cancer stem cells (CSCs) are postulated to be important promoters of drug resistance. We previously found that miR-5100 is overexpressed in lung cancer, but it is unknown whether and how miR-5100 regulates cisplatin resistance. Here, we demonstrated that miR-5100 was significantly up-regulated in CD44+ CD133+ lung cancer stem cells (LCSCs) compared with non-CSCs. Additionally, over-expression of miR-5100 increased CSC properties, cell growth, and tumor sphere formation in lung cancer cell line A549 or H1299, and that miR-5100 inhibitor significantly increased sensitivity of LCSCs to cisplatin in vitro. Surprisingly, the combination with miR-5100 inhibitor significantly decreased the IC50 of LCSCs to cisplatin. Furthermore, miR-5100 increased CSC properties and cisplatin resistance by inhibiting Rab6, a direct target gene of miR-5100. We demonstrated that miR-5100 overexpression increases the cisplatin resistance of the LCSCs through the mitochondrial apoptosis pathway. In conclusion, our results suggest that miR-5100 increases the cisplatin resistance of the LCSCs by inhibiting the Rab6. This study provides novel insight into the regulation of LCSCs by miRNA. PMID- 29144563 TI - Reply to Letter to the Editor regarding "Systematic review and meta-analysis of venous thromboembolism in otolaryngology-head and neck surgery". PMID- 29144564 TI - Rotating Iron and Titanium Sandwich Complexes. AB - The origin for the rotational barrier of organometallic versus inorganic sandwich complexes has remained enigmatic for the past decades. Here, we investigate in detail what causes the substantial barrier for titanodecaphosphacene through spin state consistent density functional theory. Orbital interactions are shown to be the determining factor. PMID- 29144565 TI - Rethinking status dystonicus. AB - Status dystonicus is a movement disorder emergency that has been a source of controversy in terms of terminology, phenomenology, and management since it was first described in 1982. Here we argue that the current use of the term status dystonicus falls well short of the precision needed for either clinical or academic use. We performed a critical review on this topic, describing possible pathophysiological mechanisms and areas of uncertainties. This review also addresses the problems derived by the extreme clinical heterogeneity of this condition, as the lack of an objective criterion useful for the definition, or the fact that status dystonicus may present not only in the context of a known dystonic syndrome. We propose a new possible definition that includes not only dystonia but also other hyperkinetic movements in the wide range of movement disorders that can be seen during an episode. The new definition keeps the term status dystonicus and highlights the fact that this is a medical emergency based on the impairment of bulbar and/or respiratory function requiring hospital admission as the principal feature. Furthermore, the new definition should not consider as necessary unspecific features as patient's condition at baseline, the distribution of dystonia, occurrence of systemic symptoms such as fever or laboratory findings. We hope that this proposal will stimulate the debate on this subject among our peers, further developing a clinical and pathophysiological understanding of status dystonicus. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29144566 TI - Reply to Letter to Editor regarding "Economic impact of intraoperative parathyroid hormone assay in primary hyperparathyroidism?" PMID- 29144567 TI - Reliable recognition of lying, sitting, and standing with a hip-worn accelerometer. AB - Hip-worn accelerometers are widely used to estimate physical activity (PA), but the accuracy of acceleration threshold-based analysis is compromised when it comes to identifying stationary and sedentary behaviors, let alone classifying body postures into lying, sitting, or standing. The purpose of this study was to devise a novel method for accurate classification of body posture using triaxial data from hip-worn accelerometer and to evaluate its performance in free-living conditions against a thigh-worn accelerometer. The posture classification rested on 2 facts: constant Earth's gravity vector and upright walking posture. Thirty healthy adults wore a hip-mounted accelerometer and underwent an array of lying, sitting, standing, and walking tasks. Task type, their order, and length were randomly assigned to each participant. During walking, the accelerometer orientation in terms of gravity vector was taken as reference, and the angle for posture estimation (APE) was determined from the incident accelerometer orientation in relation to the reference vector. Receiver operating characteristic (ROC) curve yielded an optimal cut-point APE of 64.9 degrees (sensitivity 100% and specificity 100%) for lying and sitting and 11.6 degrees (94.2%; 94.5%) for sitting and standing. In free-living conditions, high agreement (89.2% for original results and 90.4% for median-filtered results) in identifying sedentary periods (sitting and lying) was observed between the results from hip- and thigh-worn accelerometers. Walking provides a valid reference activity to determine the body posture. The proposed APE analysis of the raw data from hip-worn triaxial accelerometer gives accurate and specific information about daily times spent lying, sitting, and standing. PMID- 29144568 TI - Kinematic analysis of pressing situations in female collegiate football games: New insight into anterior cruciate ligament injury causation. AB - The most common events during which anterior cruciate ligament (ACL) injuries occur in football are pressing situations. This study aimed to describe the knee and hip joint kinematics during pressing situations in football games to identify kinematic patterns in actions with a high risk for ACL injuries. We filmed 5 female collegiate football matches and identified 66 pressing situations. Five situations with a large distance between the trunk and foot placements in the sagittal plane were analyzed using a model-based image-matching technique. The mean knee flexion angle at initial contact (IC) was 13 degrees (range, 8 degrees -28 degrees ) and increased by 11 degrees (95% confidence interval [CI], 3 degrees -14 degrees ) at 40 ms after IC. As for knee adduction and rotation angles, the knee positions were close to neutral at IC, and only minor knee angular changes occurred later in the sequences. The mean hip flexion was 25 degrees (range, 8 degrees -43 degrees ) at IC and increased by 22 degrees (95% CI, 11 degrees -32 degrees ) after 100 ms. The hip was also externally rotated by 7 degrees (range, -19 degrees to 3 degrees ) at IC, and gradually rotated internally, reaching 10 degrees of internal rotation (range, -5 degrees to 27 degrees ) at 100 ms after IC. This study suggests that the observed knee valgus, internal hip and knee rotation, and static hip flexion previously reported in non contact ACL injury events are unique to injury situations. In contrast, neither rapid knee valgus nor increased internal rotation was seen in non-injury pressing maneuvers. PMID- 29144570 TI - LncAPC drives Wnt/beta-catenin activation and liver TIC self-renewal through EZH2 mediated APC transcriptional inhibition. AB - Liver tumor initiating cells (TICs), a small subset cells in tumor bulk, are responsible for liver tumor initiation, metastasis, and relapse. However, the regulatory mechanism of liver TICs remains largely unknown. Here we found a long noncoding RNA lncAPC, locating near from APC locus, was highly expressed in liver cancer and liver TICs. LncAPC was required for liver TIC self-renewal. Silencing and overexpressing lncAPC showed impaired and enhanced sphere formation capacity of liver TICs, respectively. By recruiting EZH2 to APC promoter, LncAPC inhibits APC transcription and thus drives the activation of Wnt/beta-catenin signaling. Attenuate binding between EZH2 and APC promoter was observed upon lncAPC knockdown. What is more, lncAPC-EZH2-APC axis can be targeted to eliminate liver TICs. Altogether, LncAPC promotes liver TIC self-renewal through EZH2-dependent APC transcriptional inhibition. PMID- 29144571 TI - Letter to the Editor regarding "Systematic review and meta-analysis of venous thromboembolism in otolaryngology-head and neck surgery". PMID- 29144569 TI - [11 C]arachidonic acid incorporation measurement in human brain: Optimization for clinical use. AB - Arachidonic acid (AA) is involved in signal transduction, neuroinflammation, and production of eicosanoid metabolites. The AA brain incorporation coefficient (K*) is quantifiable in vivo using [11 C]AA positron emission tomography, although repeatability remains undetermined. We evaluated K* estimates obtained with population-based metabolite correction (PBMC) and image-derived input function (IDIF) in comparison to arterial blood-based estimates, and compared repeatability. Eleven healthy volunteers underwent a [11 C]AA scan; five repeated the scan 6 weeks later, simulating a pre- and post-treatment study design. For all scans, arterial blood was sampled to measure [11 C]AA plasma radioactivity. Plasma [11 C]AA parent fraction was measured in 5 scans. K* was quantified using both blood data and IDIF, corrected for [11 C]AA parent fraction using both PBMC (from published values) and individually measured values (when available). K* repeatability was calculated in the test-retest subset. K* estimates based on blood and individual metabolites were highly correlated with estimates using PBMC with arterial input function (r = 0.943) or IDIF (r = 0.918) in the subset with measured metabolites. In the total dataset, using PBMC, IDIF-based estimates were moderately correlated with arterial input function-based estimates (r = 0.712). PBMC and IDIF-based K* estimates were ~6.4% to ~11.9% higher, on average, than blood-based estimates. Average K* test-retest absolute percent difference values obtained using blood data or IDIF, assuming PBMC for both, were between 6.7% and 13.9%, comparable to other radiotracers. Our results support the possibility of simplified [11 C]AA data acquisition through eliminating arterial blood sampling and metabolite analysis, while retaining comparable repeatability and validity. PMID- 29144572 TI - "Mind the gaps": Cognition and cancer. PMID- 29144573 TI - Letter to the Editor regarding "Does it have a negative economic impact the intraoperative parathyroid hormone assay in primary hyperparathyroidism?" PMID- 29144575 TI - Intimate intimas: Positioning of copulatory organs in mating Drosophila. PMID- 29144574 TI - SGLT-2 inhibitors and ketoacidosis: a disproportionality analysis in the World Health Organization's adverse drug reactions database. AB - SGLT-2 inhibitors, also called gliflozins, are a new class of drugs used in type 2 diabetes. Since their marketing, several cases of ketoacidosis, including life threatening conditions, were reported with their use. The objective of this study was to investigate the disproportionality of pharmacovigilance reports of ketoacidosis between gliflozins and other drugs used for type 2 diabetes. We performed a case-noncase study within the World Health Organization's pharmacovigilance database, VigiBase. We selected all reports of serious adverse drug reaction associated with a glucose-lowering drug in patients aged 40 years and older, from January 2013 to March 2016. Cases were the reports of ketoacidosis and noncases were all other serious adverse drug reactions reported. We studied the disproportionality of reports of ketoacidosis for gliflozins by calculating reporting odds ratios (ROR) with their 95% confidence interval (95% CI). We also measured the disproportionality before the warnings issued by the US and European medicines agencies. A total of 68 555 notifications were selected. We identified 487 cases of ketoacidosis exposed to gliflozins. Ketoacidosis was significantly more frequently reported with gliflozins than with other glucose lowering drugs (adjusted ROR 15.5; 95% CI: 12.8-18.7). The disproportionality of gliflozin reports was also found before the alerts of the medicines agencies. Our study shows a significant and early pharmacovigilance signal which suggests an increased risk of ketoacidosis associated with the use of gliflozins in patients with diabetes. Further studies are needed to confirm this potential risk. PMID- 29144576 TI - Molecular Reproduction & Development Volume 84, Issue 11, November 2017. AB - Ctenophores, also known as comb jellies, are non-bilaterian invertebrates and nearly all are self-fertile hermaphrodites. Mnemiopsis leidyi is a particularly useful model for the study of cellular, tissue, and organ patterning in ctenophores due to their extreme transparency, as seen in these adults. The locomotory ctene rows, highlighted by iridescence, overlie the germ line, from which gametes and embryos are readily available in large numbers. In this issue, Davidson et al. characterize transcript expression and timing of the maternal-to zygotic transition and accompanying zygotic genome activation during early embryogenesis in this ctenophore. PMID- 29144578 TI - Table of Contents, Volume 84, Issue 11, November 2017. PMID- 29144577 TI - The 3 Ws of Bayard T. Storey - Wisdom, wine, and wit. PMID- 29144579 TI - Tailor-Made Molecularly Imprinted Polymer for Selective Recognition of the Urinary Tumor Marker Pseudouridine. AB - Pseudouridine (Psi) is an important urinary cancer biomarker, especially in human colorectal cancer (CRC). Disclosed herein is the first Psi molecularly imprinted polymer (Psi-MIP) material obtained from tailor-engineered functional monomers. The resulting MIP imprint exhibits a remarkable imprinting factor greater than 70. It is successfully used for the selective recognition of Psi in spiked human urine. This selective functionalized material opens the route to the development of inexpensive disposable chemosensors for noninvasive CRC diagnosis and prognosis. PMID- 29144580 TI - Higher retransplantation rate following extended right split-liver transplantation: An analysis from the eurotransplant liver follow-up registry. AB - Split-liver transplantation has been perceived as an important strategy to increase the supply of liver grafts by creating 2 transplants from 1 allograft. The Eurotransplant Liver Allocation System (ELAS) envisages that the extended right lobes (ERLs) after splitting (usually in the pediatric center) are almost exclusively shipped to a second center. Whether the ELAS policy impacts the graft and patient survival of extended right lobe transplantation (ERLT) in comparison to whole liver transplantation (WLT) recipients remains unclear. Data on all liver transplantations performed between 2007 and 2013 were retrieved from the Eurotransplant Liver Follow-up Registry (n = 5351). Of these, 5013 (269 ERL, 4744 whole liver) could be included. The impact of the transplant type on patient and graft survival was evaluated using univariate and multivariate proportional hazard models adjusting for demographics of donors and recipients. Cold ischemia times were significantly prolonged for ERLTs (P < 0.001). Patient survival was not different between ERLT and WLT. In the univariate analysis, ERLT had a significantly higher risk for retransplantation (P = 0.02). For WLT, the risk for death gradually and significantly increased with laboratory Model for End-Stage Liver Disease (MELD) scores of >20. For ERLT, this effect was seen already with laboratory MELD scores of >14. These results mandate a discussion on how to refine the splitting policy to avoid excess retransplant rates in ERL recipients and to further improve transplant outcomes of these otherwise optimal donor organs. Liver Transplantation 24 26-34 2018 AASLD. PMID- 29144581 TI - Corrigendum. PMID- 29144582 TI - A window into the transcriptomic basis of genotype-by-genotype interactions in the legume-rhizobia mutualism. AB - The maintenance of genetic variation in the benefits provided by mutualists is an evolutionary puzzle (Heath & Stinchcombe, ). Over time, natural selection should favour the benefit strategy that confers the highest fitness, eroding genetic variation in partner quality. Yet abundant genetic variation in partner quality exists in many systems (Heath & Stinchcombe, ). One possible resolution to this puzzle is that the genetic identity of both a host and its partner affects the benefits each mutualist provides to the other, a pattern known as a genotype-by genotype interaction (Figure ). Mounting evidence suggests that genotype-by genotype interactions between partners are pervasive at the phenotypic level (Barrett, Zee, Bever, Miller, & Thrall, ; Heath, ; Hoeksema & Thompson, ). Ultimately, however, to link these phenotypic patterns to the maintenance of genetic variation in mutualisms we need to answer two questions: How much variation in mutualism phenotypes is attributable to genotype-by-genotype interactions, and what mutualistic functions are influenced by each partner and by the interaction between their genomes? In this issue of Molecular Ecology, Burghardt et al. (2017) use transcriptomics to address both questions in the legume-rhizobia mutualism. PMID- 29144583 TI - Silicon-Based Dielectric Metamaterials: Focus on the Current Synthetic Challenges. AB - Metamaterials have optical properties that are unprecedented in nature. They have opened new horizons in light manipulation, with the ability to bend, focus, completely reflect, transmit, or absorb an incident wave front. Optically active metamaterials in particular could be used for applications ranging from 3D information storage to photovoltaic cells. Silicon (Si) particles are some of the most promising building blocks for optically active metamaterials, with high scattering efficiency coupled to low light absorption for visible frequencies. However, to date ideal Si building blocks cannot be produced by bulk synthesis techniques. The key is to find a synthetic route to produce Si building blocks between 75-200 nm in diameter of uniform size and shape, that are crystalline, have few impurities, and little to no porosity. This Review provides a theoretical background on Si optical properties for metamaterials, an overview of current synthetic methods and gives direction towards the most promising routes to ideal Si particles for metamaterials. PMID- 29144585 TI - Therapeutic potential of low-dose IL-2 in immune thrombocytopenia: An analysis of 3 cases. AB - Immune thrombocytopenia (ITP) is an acquired immune-mediated disorder with regulatory T cells (Tregs) reduction. Recent studies have shown that low-dose interleukin-2 can preferentially induce Treg expansion in vivo, and therefore offers a therapeutic strategy against immune thrombocytopenia. We have demonstrated in a previous study that Tregs and platelet counts significantly improve in an adult with ITP following low-dose IL-2 treatment. Here we report the efficacy of low-dose IL-2 in another three adults with immune thrombocytopenia who failed the first-line treatment. All patients received a dose of 1.0 million IU IL-2/day for 5 consecutive days per week as a cycle for 2 or 4 weeks. In addition to IL-2, vincristine (2 mg IV weekly * 3 weeks) was added to one patient as a combination therapy. No specific treatment was added in the other two patients. Two cases exhibited significantly increased platelet counts with improved levels of Tregs, while no changes were observed for the remaining patient. In summary, administration of daily subcutaneous low-dose IL-2 was safe, and it may be a new therapeutic option for treatment of ITP, especially refractory ITP. (c) 2017 International Clinical Cytometry Society. PMID- 29144584 TI - 3D Printed Anchoring Sutures for Permanent Shaping of Tissues. AB - Sutures are one of the most widely used devices for adhering separated tissues after injury or surgery. However, most sutures require knotting, which can create a risk of inflammation, and can act as mechanically weak points that often result in breakage and slipping. Here, an anchoring suture is presented with a design that facilitates its propagation parallel to the suturing direction, while maximizing its resistive force against the opposite direction of external force to lock its position in tissues. Different microstructures of suture anchors are systematically designed using orthogonal arrays, and selected based on shape factors associated with mechanical strength. 3D printing is used to fabricate different types of hollow microstructured suture anchors, and optimize their structure for the effective shaping of tissues. To define the structural design for fixing tissues, the maximum force required to pull 3D printed anchors in different directions is examined with tissues. The tissue reshaping function of suture anchors is further simulated ex vivo by using swine ear, nose, and skin, and bovine muscle tendon. This study provides advantages for building functional sutures that can be used for permanently reshaping tissues with enhanced mechanical strength, eliminating the need for knotting to improve surgical efficiency. PMID- 29144586 TI - Relationship Between Hospital-Level Percentage of Midwife-Attended Births and Obstetric Procedure Utilization. AB - INTRODUCTION: Research has shown good outcomes among individual low-risk women who receive perinatal care from midwives, yet little is known about how hospital level variation in midwifery care relates to procedure use and maternal health. This study aimed to document the association between the hospital-level proportion of midwife-attended births and obstetric procedure utilization. METHODS: This analysis used 2 data sources: Healthcare Cost and Utilization Project State Inpatient Database data for New York in 2014, and New York State Department of Health data on the percentage of midwife-attended births at hospitals in the state in 2014. Using logistic regression, we estimated the association between the hospital-level percentage of midwife-attended births and 4 outcomes among low-risk women: labor induction, cesarean birth, episiotomy, and severe maternal morbidity. RESULTS: Hospital-level percentage of midwife-attended births was not associated with reduced odds of labor induction or severe maternal morbidity. Women who gave births at hospitals with more midwife-attended births had lower odds of giving birth by cesarean (eg, adjusted odds ratio [aOR], 0.70; 95% confidence interval [CI], 0.59-0.82 at a hospital with 15% to 40% of births attended by midwives, compared to no midwife-attended births) and lower odds of episiotomy (eg, aOR, 0.41; 95% CI, 0.23-0.74 at a hospital with more than 40% of births attended by midwives, compared to no midwife-attended births). DISCUSSION: Our results indicate that hospitals with more midwife-attended births have lower utilization of some obstetric procedures among low-risk women; this raises the possibility of improving value in maternity care through greater access to midwifery care. PMID- 29144587 TI - Characterization of complex, heterogeneous lipid A samples using HPLC-MS/MS technique III. Positive-ion mode tandem mass spectrometry to reveal phosphorylation and acylation patterns of lipid A. AB - In this study, we report the detailed analysis of the fragmentation patterns of positively charged lipid A species based on their tandem mass spectra obtained under low-energy collision-induced dissociation conditions of an electrospray quadrupole time-of-flight mass spectrometer. The tandem mass spectrometry experiments were performed after the separation of the compounds with a reversed phase high performance liquid chromatography method. We found that both, phosphorylated and nonphosphorylated lipid A molecules can be readily ionized in the positive-ion mode by adduct formation with triethylamine added to the eluent. The tandem mass spectra of the lipid A triethylammonium adduct ions showed several product ions corresponding to inter-ring glycosidic cleavages of the sugar residues, as well as consecutive and competitive eliminations of fatty acids, phosphoric acid, and water following the neutral loss of triethylamine. Characteristic product ions provided direct information on the phosphorylation site(s), also when phosphorylation isomers (ie, containing either a C1 or a C4' phosphate group) were simultaneously present in the sample. Continuous series of high-abundance B-type and low-abundance Y-type inter-ring fragment ions were indicative of the fatty acyl distribution between the nonreducing and reducing ends of the lipid A backbone. The previously reported lipid A structures of Proteus morganii O34 and Escherichia coli O111 bacteria were used as standards. Although, the fragmentation pathways of the differently phosphorylated lipid A species significantly differed in the negative-ion mode, they were very similar in the positive-ion mode. The complementary use of positive-ion and negative-ion mode tandem mass spectrometry was found to be essential for the full structural characterization of the C1-monophosphorylated lipid A species. PMID- 29144588 TI - Varicuothiols A and B, New Fungal Metabolites from Aspergillus versicolor with Anti-Inflammatory Activities. AB - Chemical examination of a coral-associated fungus Aspergillus versicolor LZD-44 03 resulted in the isolation of two new compounds with the trivial names of varicuothiols A (1) and B (2) as a unique scaffold. Their structures were determined through extensive spectroscopic analyses in association with the modified Mosher's method and chemical conversion. Both 1 and 2 exhibited significant inhibition against LPS-induced RAW24.7 cell proliferation, in association with the down regulation of nitrite production and cytokines (MCP-1, IL-6, and TNF-alpha). PMID- 29144589 TI - Sphingosine-1-Phosphate Immobilized on Nanotopographical Scaffolds Improve Myogenic Differentiation. AB - The skeletal muscle consists of highly aligned dense cables of collagen fibers with nanometer feature size to support muscle fibers. The skeletal myocyte can be greatly affected to differentiate by their surrounding topographical structure. To improve myogenic differentiation, we fabricated cell culture platform that sphingosine-1-phosphate (S1P) which regulated myocyte behavior is immobilized on a biomimetic nanopatterned polyurethaneacrylate (PUA) substrate using 3,4 dihydroxyphenylalanine (L-DOPA) for providing topographical and biological cues synergistically. In the present study, we hypothesized that cultured C2C12 cells can be induced to synergistically promote myogenic differenntiation on nanopatterned PUA-L-DOPA-S1P. We confirmed that nanopatterned PUA-L-DOPA-S1P has high hydrophilicity with a suitable range of water contact angle and small intensity of phosphate peak (P2p) by analyses of water contact analyzer and X-ray photoelectron spectroscopy. In addition, C2C12 cells culured on nanopatterned PUA L-DOPA-S1P has well-oriented and organized myodubes formed with greater expression of myogenic regulatory factors such as MyoD and MyoG comapred to flat PUA groups. This functional platform which is not only provided topographical and biological cues has a suitable potential function to apply muscle cell niche as similar structure of muscle fiber but also utilized cell behavior within tissue engineered scaffolds and cellular microenvironment. PMID- 29144590 TI - Metabolic profiling of normal hepatocyte and hepatocellular carcinoma cells via 1 H nuclear magnetic resonance spectroscopy. AB - Hepatocellular carcinoma (HCC) causes death mainly by disseminated metastasis progression from the organ being confined. Different metastatic stages are closely related to cellular metabolic profiles. Normal hepatocyte and HepG2 cell line from low metastatic HCC were studied by NMR-based metabolomic techniques. Multivariate and univariate statistical analyses were utilized to identify characteristic metabolites from cells and cultured media. Elevated levels of acetate, creatine, isoleucine, leucine, and phenylalanine were observed in HepG2 cells, suggesting more active in gathering nutrient components along with altered amino acid metabolisms and enhanced lipid metabolism. High glucose consumption was significantly different in low metastatic cells. A series of characteristic metabolites were identified and served as biomarkers. Relative metabolic pathway analysis shows that low metastatic HepG2 cell line exhibits active behaviors in metabolisms and biosynthesis of specific amino acids and energy metabolism. Moreover, characteristic metabolites-based classification models executed by support vector machines algorithm perform robustly to classify normal hepatocyte and HepG2 cell line. It is concluded that NMR-based metabolomic analyses of cell lines can provide a powerful approach to understand metastasis-related biological alterations. The present study also provides a basis for metabolic markers determination of hepatic carcinoma in the future clinical study. PMID- 29144591 TI - Is it time to abandon care planning in mental health services? A qualitative study exploring the views of professionals, service users and carers. AB - BACKGROUND: It has been established that mental health-care planning does not adequately respond to the needs of those accessing services. Understanding the reasons for this and identifying whose needs care plans serve requires an exploration of the perspectives of service users, carers and professionals within the wider organizational context. OBJECTIVE: To explore the current operationalization of care planning and perceptions of its function within mental health services from the perspectives of multiple stakeholders. SETTINGS AND PARTICIPANTS: Participants included 21 mental health professionals, 29 service users and 4 carers from seven Mental Health Trusts in England. All participants had experience of care planning processes within secondary mental health-care services. METHODS: Fifty-four semi-structured interviews were conducted with participants and analysed utilizing a qualitative framework approach. FINDINGS: Care plans and care planning were characterized by a failure to meet the complexity of mental health needs, and care planning processes were seen to prioritize organizational agendas and risk prevention which distanced care planning from the everyday lives of service users. DISCUSSION AND CONCLUSIONS: Care planning is recognized, embedded and well established in the practices of mental health professionals and service users. However, it is considered too superficial and mainly irrelevant to users for managing mental health in their everyday lives. Those responsible for the planning and delivery of mental health services should consider ways to increase the relevance of care planning to the everyday lives of service users including separating risk from holistic needs assessment, using support aids and utilizing a peer workforce in this regard. PMID- 29144592 TI - Ex vivo reduction of thickness in the left lateral section to tailor the graft size in infantile split deceased donor liver transplantation. PMID- 29144593 TI - Risk factors for seasonal influenza virus detection in stools of patients consulting in general practice for acute respiratory infections in France, 2014 2016. AB - BACKGROUND: Previous studies reported detection of influenza RNA in stools of patients with seasonal influenza infection. While this detection may have a clinical significance, other factors may influence the stools positivity for influenza viruses. OBJECTIVES: The objective of this study was to investigate demographical, clinical and microbiological factors which could favour the presence of influenza viral RNA in the stools of patients with laboratory confirmed influenza infection. METHODS: Acute respiratory infection (ARI) patients were enrolled by general practitioners (GP) during two winter seasons (2014-2016). Nasopharyngeal swabs, stool specimens and clinical data were collected. Samples were tested for 12 respiratory pathogen groups (nasopharyngeal and stool specimens) and for 12 enteric pathogens (stool specimens). RESULTS: Among the 331 patients with ARI enrolled by GP, 114 (34.4%) presented influenza infection. Influenza RNA was detected in stool samples of 21% (24/114) of the 114 stool specimens analysed. Hospitalization [adjusted odds ratio(aOR)=7.8 (95% confidence interval (CI) [1.7-33.7], p=0.02), age between 45-64 years (aOR = 4.8 [1.7-14.5], p=0.01), consumption of raw shellfish and/or molluscs (aOR = 16.7 [3.6-90.9], p=0.00), and use of antibiotics (aOR = 6.4 [2.1-19.8], p=0.006) or antiviral treatment (aOR = 7.4 [1.9-29], p=0.01) were significantly associated with an increased odds of the detection of influenza RNA in stools. Among the 24 stool samples subjected to viral isolation, no one showed virus growth. CONCLUSIONS: These findings will be useful to studies investigating the dissemination route of influenza viruses to gastrointestinal tract. This article is protected by copyright. All rights reserved. PMID- 29144594 TI - On the origin of obesity: identifying the biological, environmental and cultural drivers of genetic risk among human populations. AB - Genetic predisposition to obesity presents a paradox: how do genetic variants with a detrimental impact on human health persist through evolutionary time? Numerous hypotheses, such as the thrifty genotype hypothesis, attempt to explain this phenomenon yet fail to provide a justification for the modern obesity epidemic. In this critical review, we appraise existing theories explaining the evolutionary origins of obesity and explore novel biological and sociocultural agents of evolutionary change to help explain the modern-day distribution of obesity-predisposing variants. Genetic drift, acting as a form of 'blind justice,' may randomly affect allele frequencies across generations while gene pleiotropy and adaptations to diverse environments may explain the rise and subsequent selection of obesity risk alleles. As an adaptive response, epigenetic regulation of gene expression may impact the manifestation of genetic predisposition to obesity. Finally, exposure to malnutrition and disease epidemics in the wake of oppressive social systems, culturally mediated notions of attractiveness and desirability, and diverse mating systems may play a role in shaping the human genome. As an important first step towards the identification of important drivers of obesity gene evolution, this review may inform empirical research focused on testing evolutionary theories by way of population genetics and mathematical modelling. PMID- 29144595 TI - Evaluation of 405-nm monochromatic light for inactivation of Tulane virus on blueberry surfaces. AB - AIM: The study aim was to evaluate the potential of 405-nm light as a virus intervention for blueberries. METHODS AND RESULTS: Tulane virus (TV)-inoculated blueberries were treated with 4.2 mW cm-2 of 405-nm light for 5-30 min. To mitigate thermal heating due to the intense light, a dry ice-chilled, nitrogen based cooling system was utilized. Blueberries were rotated to ensure exposure of all surfaces to 405-nm light. Five-, 15- and 30-min treatments resulted in little or no inactivation of TV on blueberries (average log reductions of -0.18; -0.02; and +0.06 respectively). Since 405-nm light's inactivation mechanism may involve singlet oxygen, two singlet oxygen enhancers, riboflavin and rose bengal, were used to coat the blueberries prior to 405-nm light treatment. When 0.1% riboflavin or rose bengal was added, resulting in an average PFU reduction of 0.51 and -1.01 logs respectively. However, it was noted that the addition of riboflavin and rose bengal in the absence of 405-nm light treatment produced some inactivation. Average untreated log reductions for riboflavin and rose bengal were -0.13 and -0.66 respectively. Also, 60-30-s 405-nm light pulses with 2-min ambient cooling periods without the dry ice nitrogen cooling system did not inactivate TV, suggesting that oxygen limitation by the nitrogen CO2 mixture was not the cause of limited inactivation. CONCLUSIONS: Overall results indicate that 405-nm light has some potential to inactivate viruses if singlet oxygen enhancers are present. SIGNIFICANCE AND IMPACT OF THE STUDY: The potential of visible monochromatic violet/blue light (405 nm) as a nonthermal intervention for viruses on foods, such as berries that are prone to norovirus contamination, had not been previously evaluated. Use of food-grade singlet oxygen enhancer compounds in combination with visible spectra light may offer a means to inactivate foodborne viruses. PMID- 29144596 TI - Controlled Radical Polymerization of Ethylene Using Organotellurium Compounds. AB - The first successfully controlled radical polymerization (CRP) of ethylene is reported using several organotellurium chain-transfer agents (CTAs) under mild conditions (70 degrees C, 200 bar of ethylene) within the concept of organotellurium-mediated radical polymerization (TERP). In contrast to preceding works on CRPs of ethylene applying reversible addition-fragmentation chain transfer (RAFT), the TERP system provided a high livingness and chain-end functionalization of polyethylene chains. Molar-mass distributions with dispersities between 1.3 and 2.1 were obtained up to average molar masses of 5000 g mol-1 . As in the RAFT system, the high reactivity of the growing polyethylenyl radical led to an inherent side reaction. For the presented TERP systems, however, this side reaction did not result in dead chains, while it could even be effectively suppressed by a good choice of the CTA. PMID- 29144597 TI - Melanogenesis-Inhibitory and Cytotoxic Activities of Chemical Constituents from the Leaves of Sauropus androgynus L. Merr. (Euphorbiaceae). AB - A new steroid, 20-hydroxyisofucosterol (stigmasta-5,24(28)-diene-3beta,20beta diol) (7), along with six known compounds 1 - 6 were isolated from the MeOH extract of the leaves of Sauropus androgynus L. Merr. (Euphorbiaceae). The structure of new steroid was determined by HR-APCI-MS and various NMR techniques in combination with literature data. Subsequently, their anti-inflammatory, cytotoxic activities against five human cell lines, as well as inhibitory activities against the alpha-MSH induced melanogenesis on the B16 cell line were evaluated. As the results, steroid compounds, 6 and 7 exhibited moderate cytotoxic to HL60, AZ521, SKBR3, and A549 tumor cell lines (IC50 26.9 - 45.1 MUm) with high tumor selectivity for A549 relative to WI38 cell lines (SI 2.6 and 3.0, resp.). And, flavonoid compounds, 4 and 5 exhibited superior inhibitory activities against melanogenesis (67.0 - 94.7% melanin content), even with no or low toxicity to the cells (90.1 - 99.6% cell viability) at the concentrations from 10 to 100 MUm. Furthermore, Western blot analysis suggested that compound 5 could inhibit melanogenesis by suppressing the protein expressions of MITF, TRP 1, TRP-2, and tyrosinase. PMID- 29144598 TI - Estimating burden of influenza-associated influenza-like illness and severe acute respiratory infection at public healthcare facilities in Romania during the 2011/12-2015/16 influenza seasons. AB - BACKGROUND: Influenza is responsible for substantial morbidity and mortality, but there is limited information on reliable disease burden estimates, especially from middle-income countries in the WHO European Region. OBJECTIVES: To estimate the incidence of medically attended influenza-associated influenza-like illness (ILI) and hospitalizations due to severe acute respiratory infection (SARI) presenting to public healthcare facilities in Romania. PATIENTS/METHODS: Sentinel influenza surveillance data for ILI and SARI from 2011/12-2015/16, including virological data, were used to estimate influenza-associated ILI and SARI incidence/100 000 and their 95% confidence intervals (95% CI). RESULTS: The overall annual incidence of ILI and influenza-associated ILI per 100 000 persons in Romania varied between 68 (95% CI: 61-76) and 318 (95% CI: 298-338) and between 23 (95% CI: 19-29) and 189 (95% CI: 149-240), respectively. The highest ILI and influenza incidence was among children aged 0-4 years. We estimated that SARI incidence per 100 000 persons was 6 (95% CI: 5-7) to 9 (95% CI: 8-10), of which 2 (95% CI: 1-2) to 3 (95% CI: 2-4) were due to influenza. Up to 0.3% of the Romanian population were annually reported with ILI, and 0.01% was hospitalized with SARI, of which as much as one-third could be explained by influenza. CONCLUSIONS: This evaluation was the first study estimating influenza burden in Romania. We found that during each influenza season, a substantial number of persons in Romania suffer from influenza-related ILI or are hospitalized due to influenza-associated SARI. PMID- 29144599 TI - Assessing social values for California's efforts to reduce the overuse of unnecessary medical care. AB - BACKGROUND: A partnership of large health-care purchasers created a workgroup to reduce the overuse of harmful and wasteful medical care in California. OBJECTIVE: Employ a civic engagement process to identify the social values important to the public in considering different strategies to reduce overuse. INTERVENTION: Use of deliberation techniques for 3 case examples that explore possible strategies: physician oversight, physician compensation, increased patient cost-sharing or taking no definitive action. RESULTS: Five themes were identified, including strong support for physicians' leadership role to reduce overuse; nuanced enthusiasm for increasing patient cost-sharing to discourage excessive demand; and marked disapproval of physician compensation as a motivator. CONCLUSION: Most but not all of the perspectives voiced by participants are congruent with efforts to reduce overuse that is being initiated or discussed at the state, provider and health plan level. As health-care policymakers and leaders consider more targeted approaches to reducing overuse, these findings will inform decision-making. PMID- 29144600 TI - Engineering Mammalian Designer Cells for the Treatment of Metabolic Diseases. AB - Synthetic biology applies engineering principles to biological systems and has significantly advanced the design of synthetic gene circuits that can reprogram cell activities to perform new functions. The ability to engineer mammalian designer cells with robust therapeutic behaviors has brought new opportunities for treating metabolic diseases. In this review, the authors highlight the most recent advances in the development of synthetic designer cells uploaded with open or closed-loop gene circuits for the treatment of metabolic disorders including diabetes, hypertension, hyperuricemia, and obesity, and discuss the current technologies and future perspectives in applying these designer cells for clinical applications. In the future, more and more rationally designed cells will be constructed and revolutionized to treat a number of metabolic disorders in an intelligent manner. PMID- 29144601 TI - Antibacterial, antibiofilm and antiquorum sensing effects of Thymus daenensis and Satureja hortensis essential oils against Staphylococcus aureus isolates. AB - AIMS: The present study was conducted to investigate the effects of Thymus daenensis and Satureja hortensis essential oils (EOs) on the planktonic growth, biofilm formation and quorum sensing (QS) of some Staphylococcus aureus isolates (strong biofilm producers). METHODS AND RESULTS: Minimum inhibitory concentration (MIC) of the EOs, inhibition of biofilm formation as well as disruption of preformed Staph. aureus biofilms were assessed. The antibiofilm activity of the EOs was determined using microtitre plate test (MtP) and scanning electron microscope (SEM). The QS inhibitory activity was also examined on the pregrown biofilms by gene expression analysis using quantitative real-time RT-polymerase chain reaction (PCR) of hld gene (RNAIII transcript). Moreover, tetrazolium-based colorimetric assay (MTT) was performed to detect cytotoxic effects of these EOs on the Vero cell line. Finally, the major components of the tested EOs were determined using Gas Chromatography-Mass Spectrometry (GC-MS). The MICs of T. daenensis and S. hortensis EOs against planktonic cells of the isolates were 0.0625 and 0.125 MUl ml-1 respectively. The minimum bactericidal concentrations for both of the EOs was 0.125 MUl ml-1 . The MtP test showed a significant inhibitory effect of the EOs on the biofilm formation and disruption at sub-MIC concentrations. These results were confirmed by SEM. Real-time PCR revealed a significant down-regulation of hld gene following treatment with MIC/2 concentration of S. hortensis EO. GC-MS analysis showed that carvacrol, terpinene and thymol were the major components of the applied EOs. CONCLUSIONS: As selected EOs did not show significant cytotoxic effects even up to tenfold of MIC concentration, the applied EOs seem to be good candidates for preventing of biofilm formation of Staph. aureus cells. SIGNIFICANCE AND IMPACT OF THE STUDY: The present study introduced T. daenensis and S. hortensis EOs as new antibiofilm, and S. hortensis EO as anti-QS herbal agents with natural origin against Staph. aureus. PMID- 29144602 TI - Neuroplasticity following short-term strength training occurs at supraspinal level and is specific for the trained task. AB - AIMS: Different modalities of strength training cause performance enhancements, which are specific for the trained task. However, the involved mechanisms are still largely unknown. It has been demonstrated that strength training could induce neuroplasticity, which might underlie the performance improvements during the first training sessions. Thus, we hypothesized to find task-specific neuroplasticity after a short-term strength training of two distinct strength tasks. METHODS: Young healthy male subjects were exposed to 4 sessions of either maximal isometric explosive (EXPL group, N = 9) or slow sustained (SUS group, N = 10) knee extensions. Pre- and post-training, we measured H-reflexes and motor evoked potentials (MEPs) in the vastus lateralis (VL) at the onset of both strength tasks. RESULTS: Pre- and post-training, H-reflexes remained unchanged in both groups. MEP areas were lower in the trained task in both groups and remained unchanged in the untrained task. CONCLUSION: This study demonstrated that short term strength training induces specific neuroplasticity for the trained task only. The fact that MEPs were lower but H-reflex amplitudes remained unchanged at the onset of the trained tasks suggests that strength training elicited neuroplasticity at supraspinal level that most likely reflect an improved task specific corticospinal efficiency. PMID- 29144603 TI - Hyaluronic Acid-Based Micelles as Ocular Platform to Modulate the Loading, Release, and Corneal Permeation of Corticosteroids. AB - The aim of this work is to prepare hyaluronic acid-based micelles as a platform to load corticosteroid drugs and to improve their corneal permeation after administration on the ocular surface. Three amphiphilic derivatives of hyaluronic acid (HA) are synthesized using different amounts of hexadecylamine (C16 -NH2 ). HAC16 a, HAC16 b, and HAC16 c derivatives are able to form micelles by the cosolvent evaporation method and to entrap corticosteroids (dexamethasone, triamcinolone, triamcinolone acetonide). HAC16 a and HAC16 b micelles show the best results in terms of drug loading and particle size. They are also able to improve drug release compared to free drug solution or suspension. In addition, HAC16 b micelles show an optimal mucoadhesion and compatibility with human corneal epithelial cells. In vitro and ex vivo permeation studies of drug-loaded HAC16 b micelles are performed to understand the ability of these micelles to act as penetration and/or permeation enhancers. PMID- 29144604 TI - Transitions. PMID- 29144605 TI - Assessing the clinical applicability of prior head imaging in patients with chronic rhinosinusitis. AB - BACKGROUND: Patients often have received some modality of head imaging prior to being evaluated for chronic sinonasal complaints, and the clinical significance of these scans on current sinonasal symptomatology is unknown. METHODS: We performed a retrospective, cohort study of 578 patients with chronic sinonasal indications for maxillofacial computed tomography scans (CTs) in 2016. Patients were included if previous head cross-sectional imaging had been performed. Lund McKay (LM) scores were calculated on the prior CT scan for each patient and compared to LM scores of the most recent scan. Scans with LM scores <=3 were deemed normal, scores >3 were deemed positive, and Delta >3 was deemed a significant change. RESULTS: Of 578 patients, 153 (26.5%) patients had previous imaging. Overall, a strong correlation was noted between scans (r = 0.791, p < 0.001). Significant correlations remained with the subset of positive prior scans (r = 0.743, p < 0.001). The 3 most common prior imaging modalities were maxillofacial CT, head CT, and brain magnetic resonance imaging (MRI). Correlations between these modalities and subsequent maxillofacial CTs range from strong to moderately strong. Women were significantly more likely to have negative prior imaging (p = 0.048). Patients with negative prior imaging (80/153) were significantly more likely to remain unchanged (71/80) compared to patients with positive prior scans (56/73) (p = 0.023). CONCLUSION: Prior head imaging highly correlates to future maxillofacial CT in patients with chronic sinonasal complaints, and patients with prior negative scans are likely to remain negative on future imaging. If prior head scans exist, practitioners may want to avoid ordering additional scans in the absence of changing symptoms. PMID- 29144606 TI - Improved Dehydrogenation Properties of LiBH4 Using Catalytic Nickel- and Cobalt based Mesoporous Oxide Nanorods. AB - Lithium borohydride (LiBH4 ) with a theoretical hydrogen storage capacity of 18.5 wt % has attracted intense interest as a high-density hydrogen storage material. However, high dehydrogenation temperatures and limited kinetics restrict its practical applications. In this study, mesoporous nickel- and cobalt-based oxide nanorods (NiCo2 O4 , Co3 O4 and NiO) were synthesized in a controlled manner by using a hydrothermal method and then mixed with LiBH4 by ball milling. It is found that the dehydrogenation properties of LiBH4 are remarkably enhanced by doping the as-synthesized metal oxide nanorods. When the mass ratio of LiBH4 and oxides is 1:1, the NiCo2 O4 nanorods display the best catalytic performance owing to the mesoporous rod-like structure and synergistic effect of nickel and cobalt active species. The initial hydrogen desorption temperature of the LiBH4 -NiCo2 O4 composite decreases to 80 degrees C, which is 220 degrees C lower than that of pure LiBH4 , and 16.1 wt % H2 is released at 500 degrees C for the LiBH4 NiCo2 O4 composite. Meanwhile, the composite also exhibits superior dehydrogenation kinetics, which liberates 5.7 wt % H2 within 60 s and a total of 12 wt % H2 after 5 h at 400 degrees C. In comparison, pure LiBH4 releases only 5.3 wt % H2 under the same conditions. PMID- 29144607 TI - Eustachian tube dysfunction symptoms in patients treated in a tertiary rhinology clinic. AB - BACKGROUND: Ear symptoms are common among patients presenting to a rhinology clinic. Validated inventories are available for patient quality-of-life in sinonasal disease and Eustachian tube dysfunction (ETD). This study sought to determine the extent of ETD symptoms, using validated metrics, in a large population of patients presenting to a tertiary rhinology clinic. METHODS: Seven item Eustachian Tube Dysfunction Questionnaires (ETDQ-7) and 22-item Sino-Nasal Outcome Tests (SNOT-22) were prospectively collected from 492 patients treated in a tertiary rhinology clinic. Patient diagnoses were retrospectively determined from the medical record. Correlation between reported SNOT-22 and ETDQ-7 scores were analyzed, in addition to the number of patients meeting the criterion score for ETD. RESULTS: A total of 213 patients reported mean ETDQ-7 scores >2.1, consistent with a diagnosis of ETD. Overall SNOT-22 scores were strongly correlated with ETDQ-7 scores (r = 0.679, p < 0.001). The SNOT-22 ear subdomain was very strongly correlated with the ETDQ-7 score (r = 0.847, p < 0.001), while there was a moderate correlation with the SNOT-22 rhinologic subdomain (r = 0.486, p < 0.001). Patients with allergic fungal sinusitis had decreased ETDQ-7 scores compared to patients with other rhinologic diagnoses (p = 0.010). CONCLUSION: Symptoms of ETD are common in patients treated in a rhinology clinic, with 43.3% of patients reporting symptom scores consistent with a formal diagnosis of ETD. Increased SNOT-22 scores are correlated with increased ETDQ-7 scores, even when only the SNOT-22 rhinologic subdomain is considered. Patients presenting for treatment of rhinologic symptoms likely have an increased prevalence of otologic symptoms and ETD. PMID- 29144609 TI - Internalization kinetics and cytoplasmic localization of functionalized diatomite nanoparticles in cancer cells by Raman imaging. AB - Porous biosilica nanoparticles obtained from diatomites (DNPs) have been recently demonstrated to be non-toxic nanovectors of therapeutic agents in cancer cells. In this work, the internalization kinetics and intracellular spatial distribution of functionalized DNPs incubated with human lung epidermoid carcinoma cell line (H1355) up to 72 hours are investigated by Raman imaging. The label-free Raman results are compared with confocal fluorescence microscopy and photoluminescence (PL) data. Raman bands specifically assigned to DNPs and cellular components provide evidence that the nanovectors are internalized and co-localize with lipid environments. A considerable DNPs uptake in cells is observed within 6 hours, with equilibrium being achieved after 18 hours. The obtained data show the presence of DNPs up to 72 hours, without damage to cell viability or morphology. The PL measurements performed on DNPs not penetrating the cells at different incubation times are strongly correlated with the results obtained by Raman imaging and confocal microscopy analyses. PMID- 29144610 TI - ? PMID- 29144608 TI - Relationship between urine pH and abnormal glucose tolerance in a community-based study. AB - AIMS/INTRODUCTION: The association between urine pH and abnormal glucose tolerance in men and women is unclear; therefore, we carried out a community based, cross-sectional study to investigate sex-specific associations between these values, possible indicators of prediabetes and type 2 diabetes. MATERIALS AND METHODS: We enrolled 4,945 Japanese individuals (2,490 men and 2,455 women), who had undergone annual health checkups. To investigate the relationship between low urine pH and abnormal glucose tolerance, participants were divided into three groups based on their fasting plasma glucose levels (<6.11 mmol/L, 6.11-6.99 mmol/L and >=6.99 mmol/L), and three groups based on their glycated hemoglobin levels (<=44.3 mmol/mol, 44.3-47.5 mmol/mol and >=47.5 mmol/mol). To examine the effects of urine pH on abnormal glucose tolerance, participants were categorized into five groups based on their urine pH (5.0, 5.5, 6.0, 6.5 and >=7.0). RESULTS: Multivariate analysis adjusted for age, body mass index, systolic blood pressure, triglycerides, high-density lipoprotein cholesterol, uric acid, creatinine and antidiabetic agent use showed significant associations between low urine pH and both high fasting plasma glucose and high glycated hemoglobin levels (P for trend = 0.0260, 0.0075) in men. Furthermore, after the same adjustments, prevalence rates of abnormal glucose tolerance (>=6.11 mmol/L and >=6.99 mmol/L), increased significantly as urine pH levels decreased (P for trend = 0.0483, 0.0181) in men. In women, a similar trend was observed without a significant difference. CONCLUSIONS: Low urine pH is significantly associated with abnormal glucose tolerance; therefore, measuring urine pH might prove useful for identifying patients at high risk for diabetes. PMID- 29144611 TI - ? PMID- 29144613 TI - ? PMID- 29144612 TI - ? PMID- 29144614 TI - ? PMID- 29144616 TI - ? PMID- 29144615 TI - ? PMID- 29144617 TI - A simple qualitive procedure for the detection of chloroquine in urine for use in clinical analytical toxicology in resource poor settings. AB - Objective: To develop and validate a simple procedure for the qualitative determination of chloroquine in urine with potential for use in developing countries lacking sophisticated analytical equipment and expensive reagents. Design: This was a laboratory based study making use of which combines a colorimetric test, Dill-Glazko's test, and UV/Visible absorbance spectrometry to confirm the presence of chloroquine. The spectrophotometric method was cross validated with the standard Baselt's method for quantification of chloroquine in biological fluids. Setting: Pharmacology laboratory at the Department of Clinical Pharmacology, College of Health Sciences, University of Zimbabwe. Main Outcome Measures: Recovery of the methods was assessed by comparing the peak absorbances and the resolution of the peaks at 329nm and 343nm. Sensitivity and specificity was determined by analysing in a blinded manner. The limits of detection of both the Dill-Glazko's test and the confirmatory test was determined. Results: In the prevalidation procedures increasing the volume of the ethylacetate and the volume of the lower aqueous layer extracted was found to increase the recovery of the confirmatory test. There was a significant difference between both the peak absorbances and the peak resolution for the two methods (p<0.0001). The confirmatory test had a sensitivity of 90% and a specificity of 100%, whereas the Baselt's method had a sensitivity of 83.3% and a specificity of 96.7%. The limit of detection of the Dill-Glazko's test was 15mg/Land that of the confirmatory test was 5mg/L. Conclusions: The confirmatory test had better recovery and was more sensitivity compared with the Baselt's method. The limit of detection of the combination method (Dill-Glazko's plus confirmatory test) was 15mg/L. The combination test showed appreciable sensitivity to be suitable for application to clinicaltoxicology. PMID- 29144618 TI - Glucose tolerance study in low and normal birth weight young adults. AB - Objective: To determine blood glucose levels by conducting an oral glucose tolerance test in low and normal birth weight young black adults. Design: Acase control study was done. Seventy students in the College of Health Sciences who had neonatal clinic cards as proof of birth weight were recruited into the study. Blood glucose levels were measured before, during and after the oral glucose tolerance test. Setting: Department of Physiology, University of Zimbabwe, College of Health Sciences, Harare, Zimbabwe. Main Outcome Measures and Results: A total of 70 young adult participants, 47(67%) females and 23(33%)males with mean age 20.28+/-0.19 years were recruited. 30 had Low Birth Weight (LBW, 21 females and 9 males) and 40 had Normal Birth Weight (NBW,26 females and 14 males).LBW individuals had significantly elevated (p<0.05) mean blood glucose levels at 30minutes(9.41+/-0.91 for LBW and 7.24+/-0.28 for NBW, p=0.029) and 60 minutes (9.22+/-0.75 for LBW and 7.57+/-0.36 for NBW, p=0.035) after the oral glucose tolerance test. Oral glucose tolerance testing detected 1case of type II diabetes (LBW individual), 13cases of impaired glucose tolerance (9 LBW and 4 NBW individuals)and 1 case of impaired fasting glucose (LBW individual).LBW was associated with an odds ratio of 3.1 for impaired glucose tolerance and it was statistically significant, p<0.05 (p=0.027). Conclusion: Low birth weight was associated with glucose intolerance and significantly higher mean blood glucose levels at 30 and 60 minutes after glucose loading in young adults. PMID- 29144619 TI - Tetralogy of Fallot and HIV infection in pregnancy: A case report. AB - Tetralogy of Fallot (TOF) is the commonest congenital heart abnormality beyond the age of one year. Cases of Tetralogy of Fallot can present during pregnancy following successful surgical repair in childhood or occasionally as uncorrected TOF presenting for the first time during pregnancy, indeed the most frequently encountered congenital cyanotic heart lesion during pregnancy is cyanotic TOF. Most adult congenital heart disease in Africa is uncorrected due to widespread unavailability of cardiothoracic surgical services on the continent. Pregnancy is associated with significant haemodynamic alterations affecting both the systemic and pulmonary circulatory beds. These are more likely to have deleterious effects in pregnant women with underlying heart disease or with risk factors for pulmonary hypertension.We describe here the case of a 22 year old pregnant woman with acyanotic tetralogy of Fallot and HIV infection who had an uncomplicated parturition. We discuss possible reasons why this potentially fatal combination was well tolerated by the patient. PMID- 29144620 TI - Determinants of premature births in two central hospital Harare, Zimbabwe, 2011. AB - Introduction: Prematurity is a major determinant of neonatal morbidity and mortality in Zimbabwe. Although 8-10% of deliveries are premature , prematurity contributes 33% of neonatal deaths. Identifying local risk factors for prematurity could help incoming up with local intervention and prevention strategies. Design: 1:1 unmatched case control study. Setting: Harare and Parirenyatwa central hospitals maternity units. Subjects: All mothers who delivered in the units June to July 2011. Acase was a mother who had delivered a premature baby and control was a mother who delivered a term baby. Results: We interviewed 188 cases and 188 controls. Independent risk factors for premature delivery were -A previous premature delivery [AOR 3.15 95% CI 1.17 8.49, 4.61] being admitted with a medical complication in pregnancy[AOR 2.15 95% CI 1.18 3.92]. Birth interval > 24 months [AOR 0.26 95% CI 0.12 0.59] being well nourished evidenced by BMI >=20kg/m [ AOR 0.926 95% CI 0.88 0.97] and MUAC >=23cm [AOR 0.95 95% CI 0.91 0.95] reduced the risk of premature delivery. HIV test was done on 87% of participants, 12% were positive (66% controls, 33% cases) (p<=0.001). Conclusion: Birth interval < 24 months, previous premature delivery, only one ANC attendance, maternal under nutrition and being hospitalized with complications in pregnancy were associated with premature delivery. There was no association with HIV infection. Efforts should be made to give food supplements to pregnant undernourished women. PMID- 29144621 TI - Knowledge, attitudes and practices of oral health professionals with regard to the hepatitis B virus in their workplace, Harare. AB - Objective: To assess the knowledge, attitudes and practices of Harare oral health professionals regarding Hepatitis B Virus (HBV) in the workplace. Design: A cross sectional study was conducted using a structured 36 item interviewer administered questionnaire to collect data from consenting participants. Setting: The study was conducted at private and public dental practices in Harare. Participants: Oral health professionals comprising dentists, dental therapists and technicians were purposively sampled and interviewed. Results: Eighty nine study participants were interviewed. Seventy four (83%) and 69 participants (77.5%) knew about the potential transmission through contact with blood and saliva respectively. Forty seven (52.8%) participants knew that HBV infection is incurable. Thirty five participants (39.3%) were unaware of the ability of HBV to remain infective in dried blood. Although 22 participants (25%) stated that there was potential for transmission of HBV to patients at their workplace, 81participants (92%) felt they were at risk of contracting HBV infection at work. Sixty one participants (69%) reported being vaccinated, but on verifying the vaccine doses the participants received, 35 (39.3%) received three doses, 15(17%) two doses and 11 (12.4%) one dose. Forty six per cent of the fully vaccinated participants (16 of 35) had a post-HBV vaccination test. Seventy nine (87%) and 83(93.3%) professionals stated consistent use of face masks and gloves during procedures respectively. Conclusion: Although the oral health professionals in Harare appreciated the risk of HBV transmission in dental settings, they had incomplete knowledge of HBV infection and there was poor uptake of HBV vaccination among these professionals. PMID- 29144622 TI - Non-adherence to highly active antiretroviral therapy in children attending HIV treatment clinic at harare Children's Hospital, Zimbabwe. AB - Background: Non-adherence reduces the effectiveness of antiretroviral therapy. Knowledge of factors associated with non-adherence would assist clinicians and program planners to design and implement interventions to improve adherence and therefore treatment outcomes. Objective: To determine the prevalence and factors associated with non-adherence to Highly Active Antiretroviral Therapy (HAART) in children less than 10 years of age. Methods: A cross-sectional study of 216 caregivers and children less than 10 years of age who had received HAART for at least 60 days prior to this study. Non-adherence was defined as taking less than 95% of prescribed doses. Caregiver self-reports of missed doses in the 30 days preceding a clinic visit, and clinic based pill counts were used to determine non adherence. Results: Of the 228 children selected, 216 (94.7%) study participants were assessed using the self-report method. Pill count assessment was done on only 96 (44%) participants who produced unused pills on their review dates. Caregiver self-reports (n=216) estimated the prevalence of non-adherence to be 7.4% (95%: CI 3.90 10.90) whereas clinic-based pill counts (n=96) yielded a higher estimate of 18.8% (95% CI 10.94 26.56). In a regression analysis based on pill count, two or fewer siblings (OR=6.26, 95% CI 1.64-23.95) or adults (OR=3.73, 95% CI: 1.01-13.78) in the household were independently associated with non-adherence to HAART. Of the 16 participants who were non adherent by pill count the reasons for missing doses were, attending gatherings (funeral, church), caregiver forgetting to give dose, medication running out, not understanding dosing instructions, concurrently taking other medicines such as anti tuberculosis drugs and cotrimoxazole, child visiting relatives during school vacation, and inconsistent supply of drugs in the hospital. Conclusion: The prevalence of non adherence using pill count method was high at this clinic. Caregiver reports of missed doses underestimated the prevalence of non-adherence to HAART. Having fewer siblings or adults in the household to assist with dosing are strongly associated with non-adherence to HAART in this population of children. PMID- 29144623 TI - Cryptococcus gattii: A dilemma in diagnosis and treatment in sub-Saharan Africa an area with high HIV prevalence. AB - Sub-Saharan Africa contributes at least 70% of the global cryptococcal meningoencephalitis cases each year and the majority of cases are caused by the Cryptococcus neoformans species. We present a case of meningoencephalitis due to Cryptococcus gattii in an 18 year old apparently immunocompetent male patient from Zimbabwe. PMID- 29144624 TI - [Assessment of prescriptive therapies and remedies - Experience and results]. AB - In the years 2005-2015, a leading assessment institute conducted numerous assessments on behalf of two major German private health insurance companies concerning the necessity of prescriptive therapies and remedies. The findings are presented in this article, and the results vary significantly, depending on the prescriptive therapy assessed. PMID- 29144625 TI - Acquired Hemophilia presenting as Gross Hematuria following Kidney Stone - A Case Report and Review of the Literature. AB - A rare condition in itself, acquired hemophilia A, seldom presents as isolated gross hematuria. It is a serious condition with a high mortality rate and thus clinical suspicion followed by prompt diagnosis is imperative (1). In fact, only 8 cases of such presentation of this condition have been reported thus far in the literature. Of these, none describe the initial presentation of hematuria with the inciting event of a kidney stone. We present a case of a 67-year-old man with signs and symptoms of nephrolithiasis accompanied by profuse hematuria, who was subsequently found to have developed expression of factor VIII inhibitor leading to acquired hemophilia A. PMID- 29144626 TI - Super-selective robot-assisted partial nephrectomy using near-infrared flurorescence versus early-unclamping of the renal artery: results of a prospective matched-pair analysis. AB - INTRODUCTION: Super-selective clamping of tumor-specific segmental arteries was developed to eliminate ischemia of the remnant kidney while limiting hemorrhage during partial nephrectomy. The objective is to evaluate the benefice of super selective clamping on renal functional outcome, compared to early-unclamping of the renal artery. MATERIALS AND METHODS: From March 2015 to July 2016, data from 30 patients undergoing super-selective robot-assisted PN (RAPN) for a solitary tumor by a single surgeon were prospectively collected. Tumor devascularization was assessed using indocyanine green near-infrared fluorescence. A matched-pair analysis with a retrospective cohort undergoing early-unclamping was conducted, adjusting on tumor complexity and preoperative eGFR. Perioperative, oncologic and functional outcomes using DMSA-renal scintigraphy were assessed. Multivariate analysis was performed to identify predictors of postoperative renal function and de novo chronic kidney disease (CKD). RESULTS: Super-selective RAPN was successful in 23/30 patients (76.7%), 5 requiring secondary main artery clamping due to persistent tumor fluorescence. Matched-pair analysis showed similar operating time, blood loss, positives margins and complication rates. Super selective clamping was associated with an improved eGFR variation at discharge (p=0.002), 1-month (p=0.01) and 6-month post-op (-2%vs-16% p=0.001). It also led to a better relative function on scintigraphy (46%vs40% p=0.04) and homolateral eGFR (p=0.04), and fewer upstaging to CKD stage >=3 (p=0.03). On multivariate analysis, super-selective clamping was a predictor of postoperative renal function. CONCLUSION: Super-selective RAPN leads to an improved preservation of renal function and a reduced risk of de novo CKD stage>=3, while keeping the benefit of main artery clamping on perioperative outcomes. PMID- 29144627 TI - Laparoscopic nephrectomy outside gerota fascia and En bloc ligation of the renal hilum for management of inflammatory renal diseases. AB - OBJECTIVES: This study aims to improve laparoscopic nephrectomy techniques for inflammatory renal diseases (IRD) and to reduce complications. MATERIALS AND METHODS: Thirty-three patients underwent laparoscopic nephrectomy for IRD, with a method of outside Gerota fascia dissection and en-bloc ligation and division of the renal pedicle. Operative time, blood loss, complications, analgesia requirement, post-operative recovery of intestinal function and hospital stay were recorded. The degrees of perinephric adhesion were classified based on the observation during operation and post-operative dissection of the specimen, and the association of different types of adhesion with the difficulty of the procedures was examined. RESULTS: Among 33 cases, three were converted to hand assisted laparoscopy, and one was converted to open surgery. Mean operative time was 99.6+/-29.2min, and blood loss was 75.2+/-83.5 mL. Postoperative recovery time of intestinal function was 1.6+/-0.7 days and average hospital stay was 4.8+/-1.4 days. By classification and comparison of the perinephric adhesions, whether inflammation extending beyond Gerota fascia or involving renal hilum was found to be not only an important factor influencing the operative time and blood loss, but also the main reason for conversion to hand-assisted laparoscopy or open surgery. CONCLUSIONS: In laparoscopic nephrectomy, outside Gerota fascia dissection of the kidney and en-bloc ligation of the renal pedicle using EndoGIA could reduce the difficulty of procedure and operative time, with satisfactory safety and reliability. Inflammation and adhesion extending beyond Gerota fascia or involving renal hilum is an important predictor of the difficulty related to laparoscopic nephrectomy for IRD. PMID- 29144628 TI - Overactive bladder syndrome and bladder wall thickness in patients with obstructive sleep apnea syndrome. AB - OBJECTIVE: The main objective of the present study was to evaluate the presence of overactive bladder (OAB) syndrome, nocturia, urgency, and urge incontinence in patients with obstructive sleep apnea syndrome (OSAS), and measure bladder wall thickness (BWT) in these patients. MATERIALS AND METHODS: The patient group was composed of 38 patients with OSAS. The control group was composed of 15 healthy individuals. All patients were evaluated using the Epworth Sleepiness Scale (ESS) and Overactive Bladder Symptom Score (OABSS). The bladder wall thickness was measured by transabdominal ultrasound (US). The presence of nocturia, urinary urgency, and urge incontinence were also evaluated. RESULTS: The mean OABSS was significantly higher in the patient group compared with the control group (p=0.048). The minimum oxygen saturation (Min.SO2) of patients with urgency was found to be significantly lower (p=0.014). The time spent below 90% of oxygen saturation (SO2) was significantly longer in patients with urinary urgency (p=0.009). There was no difference in BWT measurements between the patient group and the control group. There was a significant relationship between BWT values and OABSS in patients with OSAS (p=0.002). CONCLUSION: The results of the present study suggest that OSAS is associated with OAB syndrome. As a key symptom of OAB, urgency correlates with hypoxia in cases with OSAS. Although the present study did not observe any difference in BWT measurements between the patients and the control group, there was a correlation between BWT measurements and OABSS in patients with OSAS. PMID- 29144629 TI - Single perineal incision placement of artificial urinary sphincter with cadaveric correlation of sub-dartos pump placement. AB - PURPOSE: We present a novel AUS implantation technique using a single perineal incision for single device placement or in combination with an inflatable penile prosthesis (IPP). Urinary and sexual dysfunction following the management of prostate cancer has a significant impact on the quality of life of our patients. While there are marginal changes in the prosthetic devices, we strive to reduce post-operative morbidity while maximizing efficacy. MATERIALS AND METHODS: We retrospectively reviewed the outcomes of 6 patients who underwent single perineal incision placement of a virgin AUS in 2014, 3 with simultaneous IPP placement. In all cases, the pressure regulating balloons (PRB) were placed in a high sub muscular ectopic position and the pumps were placed into a sub-dartos pouch through the perineal incision, which was also validated using a cadaveric model. RESULTS: The mean patient age was 61 (SD, 7.5 years) with mean body mass index of 31 (SD, 5.9). The average pre-operative pad usage was 7.7 (SD 1.63) pads per day. The mean follow-up was 13.9 months (SD 9.45). Four out of the six patients reported utilizing <=1 pad daily at follow-up. The one patient who was not initially dry required downsizing of his cuff to 3.5cm; the remaining patient was lost to follow-up. There were no identifiable perioperative or post-operative complications. CONCLUSIONS: We present our initial report of using a single perineal incision for AUS implantation with a validated sub-dartos pump location, which is safe and effective for implantation of an AUS as a single or double implantation in well-selected patients. PMID- 29144631 TI - [What do company health insurance plans provide?] AB - Company health insurance plans are a voluntary employer benefit and an increasingly important part of company pension and benefits systems. They enable employers to invest in the health of their employees. They are also a useful modular complement to both statutory and private health insurance. Company health insurance plans allow employers to attract first-rate staff and to retain them for the long term. Employees, in turn, are provided with a variety of attractive additional benefits, for instance treatment by chief physicians, single or double-room hospital accommodation, additional aids and remedies, and a variety of screenings and medical check ups. It is expected that, in the next few years, company health insurance will become very widespread. PMID- 29144630 TI - Is circumferential urethral mobilisation an overdo? A prospective outcome analysis of dorsal onlay and dorso - lateral onlay BMGU for anterior urethral strictures. AB - INTRODUCTION: For dorsal onlay graft placement, unilateral urethral mobilization is less invasive than standard circumferential urethral mobilization. Apart from success in terms of patency of urethra, other issues like sexual function, overall quality of life and patient satisfaction remain important issues while comparing outcomes of urethroplasty. AIM: To prospectively compare the objective as well as subjective outcomes of two approaches. MATERIALS AND METHODS: Between July 2011 and January 2015, 136 adult males having anterior urethral stricture with urethral lumen >= 6 Fr. were prospectively assigned between two groups by alternate randomization. Operative time, complications, success rate (no obstructive symptoms, no need of any postoperative intervention, Q max > 15mL/sec), sexual functions (using Brief Male Sexual Function Inventory) were compared. RESULTS: Baseline parameters were similar in both groups (68 in each group). Overall success rate was similar in both groups (89 % and 91 % respectively). Improvement in total LUTS scores was similar in groups. Changes in overall health status (VAS and EQ 5D) was equal in both groups. Erectile function score was significantly decreased in DO than DL group while ejaculatory function and sexual desire remained stable after urethroplasty in both groups. CONCLUSIONS: In anterior urethral stricture buccal mucosa graft provides satisfactory results as onlay technique. No technique whether dorsolateral and dorsal techniques is superior to other. Dorsolateral technique needs minimal urethral mobilization and should be preferred whenever feasible. PMID- 29144716 TI - Mechanism of action of non-invasive cervical vagus nerve stimulation for the treatment of primary headaches. AB - Stimulation of the cervical vagus nerve with implanted vagus nerve stimulation (iVNS) has been used clinically for more than 20 years to treat patients with epilepsy. More recently, a non-invasive cervical vagus nerve stimulation (nVNS), gammaCore, was developed, which has been purported to also stimulate the vagus nerve without the cost and morbidity associated with an iVNS system. gammaCore has been used to acutely treat various types of primary headaches, including migraine and cluster headaches (CH), and for the prevention of episodic, chronic, and menstrual migraines and CH. The gammaCore device was cleared by the FDA for the acute treatment of pain in episodic CH patients. In this review, we summarize the clinical work that has been published in the use of gammaCore for treating primary headache disorders, present an overview of studies demonstrating that nVNS does indeed stimulate similar vagus nerve fibers as the implantable VNS system, and then present several animal headache-related studies that address the mechanism of action of nVNS. PMID- 29144717 TI - Review of non-invasive vagus nerve stimulation (gammaCore): efficacy, safety, potential impact on comorbidities, and economic burden for episodic and chronic cluster headache. AB - The FDA has cleared gammaCore (non-invasive vagus nerve stimulator [nVNS]) for the treatment of episodic cluster headache (eCH). With the exception of subcutaneous sumatriptan, all other treatments are used off label and have many limitations. The FDA approval process for devices differs from that of drugs. We performed a review of the literature to evaluate new evidence on various aspects of gammaCore treatment and impact. The ACute Treatment of Cluster Headache Studies (ACT1 and ACT2), both double-blind sham-controlled randomized trials, did not meet the primary endpoints of the trials but each demonstrated significant superiority of gammaCore among patients with eCH. In ACT1, gammaCore resulted in a higher response rate (RR) (RR, 3.2; 95% CI, 1.6-8.2; P = .014), higher pain free rate for >50% of attacks (RR, 2.3; 95% CI, 1.1-5.2; P = .045), and shorter duration of attacks (mean difference [MD], -30 minutes; P <.01) compared with the sham group. In ACT2, gammaCore resulted in higher odds of achieving pain-free attacks in 15 minutes (OR, 9.8; 95% CI, 2.2-44.1; P = .01), lower pain intensity in 15 minutes (MD, -1.1; P <.01), and higher rate of achieving responder status at 15 minutes for >=50% of treated attacks (RR, 2.8; 95% CI, 1.0-8.1; P = .058) compared with the sham group. The PREVention and Acute Treatment of Chronic Cluster Headache (PREVA) study also demonstrated that gammaCore plus standard of care (SOC) was superior to SOC alone in patients with chronic cluster headache (CH). Medical costs, pharmacy refills, and pharmacy costs were higher in patients coded for CH in claims data compared with controls with nonheadache codes. gammaCore is easy to use, practical, and safe; delivery cannot be wasted; and patients prefer using gammaCore compared with SOC. The treatment improves symptoms and reduces the need for CH rescue medications. Current US reimbursement policies, which predate nVNS and are based on expensive, surgically implanted, and permanent implanted vagus nerve stimulation (iVNS), need to be modified to distinguish nVNS from iVNS. gammaCore, cleared by the FDA in April 2017, provides substantial value to patients and also to payers. There is sufficient evidence to support the need to modify current reimbursement policies to include coverage for gammaCore (nVNS) for eCH. PMID- 29144718 TI - The emerging role of gammaCore(r) in the management of cluster headache: expert panel recommendations. AB - A panel of 9 experts, including neurologists, other headache specialists, and medical and pharmacy directors, from 4 health plans (1 integrated delivery network and 3 plans with commercial, Medicare, and Medicaid lines of business), convened to discuss cluster headache (CH). Topics covered included the current treatment landscape, treatment challenges, economic impact of disease, and gaps in care for patients with CH. One major challenge in the management of CH is that it is underrecognized and frequently misdiagnosed, leading to delays in and suboptimal treatment for patients who suffer from this painful and disabling condition. The management of CH is challenging due to the lack of a robust evidence base for preventive treatment, the adverse events (AEs) associated with conventional preventive treatments, the variability of response to acute treatments, and the challenging reimbursement landscape for well-accepted treatments (eg, oxygen). The lack of effective prevention for many patients may lead to the excessive use of acute therapies, often multiple times each day, which drives the cost of illness up significantly. The goal of the panel discussion was to discuss the role of gammaCore, the recently released first non invasive vagus nerve stimulation (nVNS) therapy in the acute treatment of patients with episodic CH (eCH), in the management of CH. The panel reviewed current practices and formulated recommendations on incorporating a newly released therapy into CH management. The panel explored the role of traditional management strategies as well as that of gammaCore in the acute treatment of patients with eCH. Resources that may be useful in the treatment of patients with CH were also discussed. PMID- 29144719 TI - Real-world health plan claims analysis of differences in healthcare utilization and total cost in patients suffering from cluster headaches and those without headache-related conditions. AB - BACKGROUND: According to the World Health Organization, headache disorders are underappreciated by many health systems. These disorders have a substantial impact on quality of life, yet the true correlation between headache conditions and increased total healthcare utilization is not well understood. This study further explores the impact of headache conditions on healthcare utilization. OBJECTIVES: To assess differences in healthcare utilization and total cost in patients suffering from cluster headaches (CH) compared with patients without headache-related conditions. METHODS: Medical and pharmacy claims data from 4 regional health plans were used to evaluate differences in healthcare utilization and cost in patients with a diagnosis code for CH (chronic, episodic, or unspecified) from International Classification of Diseases, Ninth Revision, Clinical Modification or International Classification of Diseases, Tenth Revision, Clinical Modification compared with a control group of patients without headache-related conditions. Qualifying patients were aged at least 18 years and continuously eligible for their health plan for 3 consecutive years during the study period (January 1, 2009-December 31, 2015). The first date with a diagnosis of CH was considered the index date and the subsequent 3 years of claims data were used for this retrospective analysis. The CH cohort was matched with controls using propensity score matching. Differences between cohorts (CH vs control) were assessed with t test or Fisher's exact test as appropriate. RESULTS: A total of 4174 patients with diagnosis codes for CH met the study criteria and were matched 1:1 with controls (gender: 48% male; mean age: 47 years; mean Charlson Comorbidity Index score: 0.30). Mean medical costs per patient in the CH cohort during the 3-year measurement period were 155% higher than those of the control group ($25,805 vs $10,140, respectively). Unique encounters and cost per patient by medical services type for the CH cohort compared with the control group were as follows (encounters [costs]): emergency department: 2151 ($1986) versus 962 ($1268); hospital inpatient: 900 ($7312) versus 253 ($8528); hospital outpatient: 3422 ($12,459) versus 2141 ($7644); physician office: 4113 ($7379) versus 4089 ($3672); home infusion/specialty medications: 817 ($4977) versus 427 ($1720). Visit counts per patient were significantly higher for CH patients in all categories. Mean pharmacy costs per patient for the CH cohort were more than double that of the control group ($9197 vs $4368), with these patients 2.3 times as likely to fill a prescription for an opioid. CONCLUSIONS: The results of this analysis show that CH patients utilize healthcare resources at a significantly higher rate and cost the healthcare system significantly more than similar patients without headache-related conditions. There is an unmet need for new treatment modalities in this patient population to improve outcomes and contain cost. PMID- 29144720 TI - Cost-effectiveness of gammaCore (non-invasive vagus nerve stimulation) for acute treatment of episodic cluster headache. AB - Cluster headache is a debilitating disease characterized by excruciatingly painful attacks that affects 0.15% to 0.4% of the US population. Episodic cluster headache manifests as circadian and circannual seasonal bouts of attacks, each lasting 15 to 180 minutes, with periods of remission. In chronic cluster headache, the attacks occur throughout the year with no periods of remission. While existing treatments are effective for some patients, many patients continue to suffer. There are only 2 FDA-approved medications for episodic cluster headache in the United States, while others, such as high-flow oxygen, are used off-label. Episodic cluster headache is associated with comorbidities and affects work, productivity, and daily functioning. The economic burden of episodic cluster headache is considerable, costing more than twice that of nonheadache patients. gammaCore adjunct to standard of care (SoC) was found to have superior efficacy in treatment of acute episodic cluster headaches compared with sham gammaCore used with SoC in ACT1 and ACT2 trials. However, the economic impact has not been characterized for this indication. We conducted a cost-effectiveness analysis of gammaCore adjunct to SoC compared with SoC alone for the treatment of acute pain associated with episodic cluster headache attacks. The model structure was based on treatment of acute attacks with 3 outcomes: failures, nonresponders, and responders. The time horizon of the model is 1 year using a payer perspective with uncertainty incorporated. Parameter inputs were derived from primary data from the randomized controlled trials for gammaCore. The mean annual costs associated with the gammaCore-plus-SoC arm was $9510, and mean costs for the SoC alone arm was $10,040. The mean quality-adjusted life years for gammaCore-plus SoC arm were 0.83, and for the SoC-alone arm, they were 0.74. The gammaCore-plus SoC arm was dominant over SoC alone. All 1-way and multiway sensitivity analyses were cost-effective using a threshold of $20,000. gammaCore dominance, representing savings, was driven by superior efficacy, improvement in quality of life (QoL), and reduction in costs associated with successful and consistent abortion of episodic attacks. These findings serve as additional economic evidence to support coverage for gammaCore. Additional real-world data are needed to characterize the long-term impact of gammaCore on comorbidities, utilization, QoL, daily functioning, productivity, and social engagement of these patients, and for other indications. PMID- 29144721 TI - Functionalized Solid-State Nanopore Integrated in a Reusable Microfluidic Device for a Better Stability and Nanoparticle Detection. AB - Electrical detection based on single nanopores is an efficient tool to detect biomolecules, particles and study their morphology. Nevertheless the surface of the solid-state membrane supporting the nanopore should be better controlled. Moreover, nanopore should be integrated within microfluidic architecture to facilitate control fluid exchanges. We built a reusable microfluidic system integrating a decorated membran, rendering the drain and refill of analytes and buffers easier. This process enhances strongly ionic conductance of the nanopore and its lifetime. We highlight the reliability of this device by detecting gold nanorods and spherical proteins. PMID- 29144722 TI - Transport Across Heterointerfaces of Amorphous Niobium Oxide and Crystallographically Oriented Epitaxial Germanium. AB - Because of the high carrier mobility of germanium (Ge) and high dielectric permittivity of amorphous niobium pentoxide (a-Nb2O5), Ge/a-Nb2O5 heterostructures offer several advantages for the rapidly developing field of oxide-semiconductor-based multifunctional devices. To this end, we investigate the growth, structural, band alignment, and metal-insulator-semiconductor (MIS) electrical properties of physical vapor-deposited Nb2O5 on crystallographically oriented (100), (110), and (111)Ge epilayers. The as-deposited Nb2O5 dielectrics were found to be in the amorphous state, demonstrating an abrupt oxide/semiconductor heterointerface with respect to Ge, when examined via low- and high-magnification cross-sectional transmission electron microscopy. Additionally, variable-angle spectroscopic ellipsometry and X-ray photoelectron spectroscopy (XPS) were used to independently determine the a-Nb2O5 band gap, yielding a direct gap value of 4.30 eV. Moreover, analysis of the heterointerfacial energy band alignment between a-Nb2O5 and epitaxial Ge revealed valance band offsets (DeltaEV) greater than 2.5 eV, following the relation DeltaEV(111) > DeltaEV(110) > DeltaEV(100). Similarly, utilizing the empirically determined a-Nb2O5 band gap, conduction band offsets (DeltaEC) greater than 0.75 eV were found, likewise following the relation DeltaEC(110) > DeltaEC(100) > DeltaEC(111). Leveraging the reduced DeltaEC observed at the a-Nb2O5/Ge heterointerface, we also perform the first experimental investigation into Schottky barrier height reduction on n-Ge using a 2 nm a-Nb2O5 interlayer, resulting in a 20* increase in reverse-bias current density and improved Ohmic behavior. PMID- 29144723 TI - Inorganic Strengthened Hydrogel Membrane as Regenerative Periosteum. AB - Periosteum plays the pivotal role in neomineralization, vascularization and protection during bone tissue regeneration. However, many artificial periosteum focused only on protection and lacked of the osteogenesis and angiogenesis functional capacity. In this study, we developed a novelty inorganic strengthened gelatin hydrogel membrane via inorganic and organic co-cross-linked double network as artificial periosteum for enhancing the durable angiogenesis and osteogenesis in bone reconstruction. Mesoporous bioactive glass nanoparticles (MBGNs) chemically modified with photo-cross-linkable gelatin derivative (GelMA) were further incorporated into GelMA to fabricate an organic/inorganic co-cross linked hydrogel membrane (GelMA-G-MBGNs). The GelMA-G-MBGNs hydrogel membrane displayed better mechanical property, durable degradation time, pH stable, biomineralization and long-term ion release. In vitro study demonstrated that, when compared with GelMA or GelMA/MBGNs, the GelMA-G-MBGN membrane significantly promoted osteogenic differentiation while maintaining stable local pH, which is conducive to cell adhesion and proliferation. Finally, the GelMA-G-MBGN membrane shows a superior artificial periosteum with superior capacity in angiogenesis and osteogenesis for accelerating new and mature lamellar bone formation in rat calvarial critical size defect. This co-cross-linked hydrogel membrane implied a promising strategy for the development of advanced periosteum biomaterials with excellent handle and bone repairing properties. PMID- 29144724 TI - Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C beta-Lactamase. AB - Acinetobacter baumannii is a multidrug resistant pathogen that infects more than 12 000 patients each year in the US. Much of the resistance to beta-lactam antibiotics in Acinetobacter spp. is mediated by class C beta-lactamases known as Acinetobacter-derived cephalosporinases (ADCs). ADCs are unaffected by clinically used beta-lactam-based beta-lactamase inhibitors. In this study, five boronic acid transition state analog inhibitors (BATSIs) were evaluated for inhibition of the class C cephalosporinase ADC-7. Our goal was to explore the properties of BATSIs designed to probe the R1 binding site. Ki values ranged from low micromolar to subnanomolar, and circular dichroism (CD) demonstrated that each inhibitor stabilizes the beta-lactamase-inhibitor complexes. Additionally, X-ray crystal structures of ADC-7 in complex with five inhibitors were determined (resolutions from 1.80 to 2.09 A). In the ADC-7/CR192 complex, the BATSI with the lowest Ki (0.45 nM) and greatest Delta Tm (+9 degrees C), a trifluoromethyl substituent, interacts with Arg340. Arg340 is unique to ADCs and may play an important role in the inhibition of ADC-7. The ADC-7/BATSI complexes determined in this study shed light into the unique recognition sites in ADC enzymes and also offer insight into further structure-based optimization of these inhibitors. PMID- 29144725 TI - Inhibition of Acinetobacter-Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel beta-Lactamase Inhibitors. AB - Boronic acids are attracting a lot of attention as beta-lactamase inhibitors, and in particular, compound S02030 ( Ki = 44 nM) proved to be a good lead compound against ADC-7 ( Acinetobacter-derived cephalosporinase), one of the most significant resistance determinants in A. baumannii. The atomic structure of the ADC-7/S02030 complex highlighted the importance of critical structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C3/C4 found in beta lactams, we designed, synthesized, and characterized six derivatives of S02030 (3a). Out of the six compounds, the best inhibitors proved to be those with an explicit negative charge (compounds 3a-c, 3h, and 3j, Ki = 44-115 nM), which is in contrast to the derivatives where the negative charge is omitted, such as the amide derivative 3d ( Ki = 224 nM) and the hydroxyamide derivative 3e ( Ki = 155 nM). To develop a structural characterization of inhibitor binding in the active site, the X-ray crystal structures of ADC-7 in a complex with compounds 3c, SM23, and EC04 were determined. All three compounds share the same structural features as in S02030 but only differ in the carboxy-R2 side chain, thereby providing the opportunity of exploring the distinct binding mode of the negatively charged R2 side chain. This cephalosporinase demonstrates a high degree of versatility in recognition, employing different residues to directly interact with the carboxylate, thus suggesting the existence of a "carboxylate binding region" rather than a binding site in ADC enzymes. Furthermore, this class of compounds was tested against resistant clinical strains of A. baumannii and are effective at inhibiting bacterial growth in conjunction with a beta-lactam antibiotic. PMID- 29144727 TI - Ex Vivo Measurement of Electrically Evoked Dopamine Release in Zebrafish Whole Brain. PMID- 29144728 TI - Simultaneous Analysis of a Non-Lipidated Protein and Its Lipidated Counterpart: Enabling Quantitative Investigation of Protein Lipidation's Impact on Cellular Regulation. AB - Here, we introduce protein-lipidation quantitation (PLQ)-the first method for quantitative analysis of both a substrate and a product of protein lipidation in a biologically relevant context. Such analysis is required to study roles of protein lipidation in cellular regulation. In PLQ, the substrate is fused with a fluorescent protein to facilitate quantitative detection of both the nonlipidated substrate and the lipidated product. When expressed in cells with endogenous lipidation activity, the substrate is intracellularly lipidated. Following cell lysis and sampling crude cell lysate for analysis, the substrate and the product are separated by surfactant-mediated capillary electrophoresis (CE) and quantitated by integrating fluorescence intensity over respective CE peaks. In this work, we prove PLQ in principle and demonstrate its robustness to changes in structures of the substrate and lipid donor. Finally, PLQ analysis confirms a hypothesized link between a mutation in p53 and cellular prenylation activity. PMID- 29144726 TI - Physalis Mottle Virus-Like Particles as Nanocarriers for Imaging Reagents and Drugs. AB - Platform technologies based on plant virus nanoparticles (VNPs) and virus-like particles (VLPs) are attracting the attention of researchers and clinicians because the particles are biocompatible, biodegradable, noninfectious in mammals, and can readily be chemically and genetically engineered to carry imaging agents and drugs. When the Physalis mottle virus (PhMV) coat protein is expressed in Escherichia coli, the resulting VLPs are nearly identical to the viruses formed in vivo. Here, we isolated PhMV-derived VLPs from ClearColi cells and carried out external and internal surface modification with fluorophores using reactive lysine-N-hydroxysuccinimide ester and cysteine-maleimide chemistries, respectively. The uptake of dye-labeled particles was tested in a range of cancer cells and monitored by confocal microscopy and flow cytometry. VLPs labeled internally on cysteine residues were taken up with high efficiency by several cancer cell lines and were colocalized with the endolysosomal marker LAMP-1 within 6 h, whereas VLPs labeled externally on lysine residues were taken up with lower efficiency, probably reflecting differences in surface charge and the propensity to bind to the cell surface. The infusion of dye and drug molecules into the cavity of the VLPs revealed that the photosensitizer (PS), Zn-EpPor, and the drugs crystal violet, mitoxantrone (MTX), and doxorubicin (DOX) associated stably with the carrier via noncovalent interactions. We confirmed the cytotoxicity of the PS-PhMV and DOX-PhMV particles against prostate cancer, ovarian and breast cancer cell lines, respectively. Our results show that PhMV derived VLPs provide a new platform technology for the delivery of imaging agents and drugs, with preferential uptake into cancer cells. These particles could therefore be developed as multifunctional tools for cancer diagnosis and therapy. PMID- 29144729 TI - Optical Nanoantenna for Single Molecule-Based Detection of Zika Virus Nucleic Acids without Molecular Multiplication. AB - Because of the limited signal-to-background ratio, molecular diagnostics requires molecular amplification of the target molecules or molecular signal amplification after target recognition. For direct molecular detection, we demonstrate a purely physical fluorescence enhancement process which can elevate the fluorescence signal of single fluorescent dyes by several orders of magnitude. To this end, DNA origami-based optical antennas with a height of around 125 nm are used, which utilize metallic nanoparticles to create a hotspot where fluorescence signals are enhanced by plasmonic effects. By equipping the hotspot with a molecular beacon like structure, we combine the plasmonic signal enhancement with a specific signal generation, leading to an enhanced and therefore easy to detect signal only in the presence of the specific target nucleic acid. Exemplified with Zika virus detection, we show the applicability of this approach by detecting Zika specific artificial DNA and RNA both in buffer and in heat-inactivated human blood serum. We show the sensitivity against small nucleotide variations of this approach, allowing the discrimination of closely related pathogens. Furthermore, we show how the modularity offered by DNA nanotechnology enables multiplexing by incorporating orthogonal fluorescent labels for the simultaneous detection of different sequences. The achieved signal enhancement will allow technically simplified signal detection, paving the way for single molecule-based point-of care diagnosis. PMID- 29144730 TI - Cancer Protrusions on a Tightrope: Nanofiber Curvature Contrast Quantitates Single Protrusion Dynamics. AB - Cell migration is studied with the traditional focus on protrusion-driven cell body displacement, while less is known on morphodynamics of individual protrusions themselves, especially in fibrous environments mimicking extracellular matrix. Here, using suspended fibers, we report integrative and multiscale abilities to study protrusive behavior independent of cell body migration. By manipulating the diameter of fibers in orthogonal directions, we constrain cell migration along large diameter (2 MUm) base fibers, while solely allowing cells to sense, initiate, and mature protrusions on orthogonally deposited high-curvature/low diameter (~100, 200, and 600 nm) protrusive fibers and low-curvature (~300 and 600 nm width) protrusive flat ribbons. In doing so, we report a set of morphodynamic metrics that precisely quantitate protrusion dynamics. Protrusion growth and maturation occur by rapid broadening at the base to achieve long lengths, a behavior dramatically influenced by curvature. While flat ribbons universally induce the formation of broad and long protrusions, we quantitatively protrutype protrusive behavior of two highly invasive cancer cell lines and find breast adenocarcinoma (MDA-MB-231) to exhibit sensitivity to fiber curvature higher than that of brain glioblastoma DBTRG-05MG. Furthermore, while actin and microtubules localize within protrusions of all sizes, we quantify protrusion size-driven localization of vimentin and, contrary to current understanding, report that vimentin is not required to form protrusions. Using multiple protrusive fibers, we quantify high coordination between hierarchical branches of individual protrusions and describe how the spatial configuration of multiple protrusions regulates cell migratory state. Finally, we describe protrusion-driven shedding and collection of cytoplasmic debris. PMID- 29144731 TI - Zwitterionic Manganese and Gadolinium Metal-Organic Frameworks as Efficient Contrast Agents for in Vivo Magnetic Resonance Imaging. AB - Two water-stable three-dimensional Mn- and Gd-based metal-organic frameworks (MOFs), {[Mn2(Cmdcp)2(H2O)2].H2O}n (1) and {[Gd(Cmdcp)(H2O)3](NO3).3H2O}n (2, H3CmdcpBr = N-(4-carboxy benzyl)-(3,5-dicarboxyl)pyridinium bromide), have been prepared and analyzed. In vitro magnetic resonance imaging indicated that MOFs 1 and 2 possess relaxivity r1 values of 17.50 and 13.46 mM-1.S-1, respectively, which are superior to that of the control Gd-DTPA (r1 = 4.87 mM-1.S-1, DTPA = diethylene triamine pentaacetate). MOFs 1 and 2 also possessed good biocompatibility and low cytotoxicity against a model cell line. In vivo magnetic resonance images of treated Kunming mice indicated that kidneys showed remarkably positive signal enhancement after 15 min with intravenous administration of MOF 1 and the hyperintensity of both kidneys persisted for about 240 min with no obvious tissue damage. MOF 1 is therefore promising in vivo probes for imaging intravascular diseases and renal dysfunction. PMID- 29144732 TI - Ratiometric Detection of Intracellular Lysine and pH with One-Pot Synthesized Dual Emissive Carbon Dots. AB - Recently, the development of new fluorescent probes for the ratiometric detection of target objects inside living cells has received great attention. Normally, the preparation, modification as well as conjugation procedures of these probes are complicated. On this basis, great efforts have been paid to establish convenient method for the preparation of dual emissive nanosensor. In this work, a functional dual emissive carbon dots (dCDs) was prepared by a one-pot hydrothermal carbonization method. The dCDs exhibits two distinctive fluorescence emission peaks at 440 and 624 nm with the excitation at 380 nm. Different from the commonly reported dCDs, this probe exhibited an interesting wavelength dependent dual responsive functionality toward lysine (440 nm) and pH (624 nm), enabling the ratiometric detection of these two targets. The quantitative analysis displayed that a linear range of 0.5-260 MUM with a detection limit of 94 nM toward lysine and the differentiation of pH variation from 1.5 to 5.0 could be readily realized in a ratiometric strategy, which was not reported before with other carbon dots (CDs) as the probe. Furthermore, because of the low cytotoxicity, good optical and colloidal stability, and excellent wavelength dependent sensitivity and selectivity toward lysine and pH, this probe was successfully applied to monitor the dynamic variation of lysine and pH in cellular systems, demonstrating the promising applicability for biosensing in the future. PMID- 29144733 TI - A Mechanism for Symmetry Breaking and Shape Control in Single-Crystal Gold Nanorods. AB - The phenomenon of symmetry breaking-in which the order of symmetry of a system is reduced despite manifest higher-order symmetry in the underlying fundamental laws is pervasive throughout science and nature, playing a critical role in fields ranging from particle physics and quantum theory to cosmology and general relativity. For the growth of crystals, symmetry breaking is the crucial step required to generate a macroscopic shape that has fewer symmetry elements than the unit cell and/or seed crystal from which it grew. Advances in colloid synthesis have enabled a wide variety of nanocrystal morphologies to be achieved, albeit empirically. Of the various nanoparticle morphologies synthesized, gold nanorods have perhaps been the most intensely studied, thanks largely to their unique morphology-dependent optical properties and exciting application potential. However, despite intense research efforts, an understanding of the mechanism by which a single crystal breaks symmetry and grows anisotropically has remained elusive, with many reports presenting seemingly conflicting data and theories. A fundamental understanding of the symmetry breaking process is needed to provide a rational framework upon which future synthetic approaches can be built. Inspired by recent experimental results and drawing upon the wider literature, we present a mechanism for gold nanorod growth from the moments prior to symmetry breaking to the final product. In particular, we describe the steps by which a cuboctahedral seed particle breaks symmetry and undergoes anisotropic growth to form a nanorod. With an emphasis on the evolving crystal structure, we highlight the key geometrical and chemical drivers behind the symmetry breaking process and factors that govern the formation and growth of nanorods, including control over the crystal width, length, and surface faceting. We propose that symmetry breaking is induced by an initial formation of a new surface structure that is stabilized by the deposition of silver, thus preserving this facet in the embryonic nanorod. These new surfaces initially form stochastically as truncations that remove high-energy edge atoms at the intersection of existing {111} facets and represent the beginnings of a {011}-type surface. Crucially, the finely tuned [HAuCl4]:[AgNO3] ratio and reduction potential of the system mean that silver deposition can occur on the more atomically open surface but not on the pre-existing lower-index facets. The stabilized surfaces develop into side facets of the nascent nanorod, while the largely unpassivated {111} facets are the predominant site of Au atom deposition. Growth in the width direction is tightly controlled by a self-sustaining cycle of galvanic replacement and silver deposition. It is the [HAuCl4]:[AgNO3] ratio that directly determines the particle size at which the more open atomic surfaces can be stabilized by silver and the rate of growth in the width direction following symmetry breaking, thus explaining the known aspect ratio control with Ag ion concentration. We describe the evolving surface faceting of the nanorod and the emergence of higher-index facets. Collectively, these observations allow us to identify facet-size and edge atom effects as a simple fundamental driver of symmetry breaking and the subsequent development of new surfaces in the presence of adsorbates. PMID- 29144734 TI - Physically Unclonable Cryptographic Primitives by Chemical Vapor Deposition of Layered MoS2. AB - Physically unclonable cryptographic primitives are promising for securing the rapidly growing number of electronic devices. Here, we introduce physically unclonable primitives from layered molybdenum disulfide (MoS2) by leveraging the natural randomness of their island growth during chemical vapor deposition (CVD). We synthesize a MoS2 monolayer film covered with speckles of multilayer islands, where the growth process is engineered for an optimal speckle density. Using the Clark-Evans test, we confirm that the distribution of islands on the film exhibits complete spatial randomness, hence indicating the growth of multilayer speckles is a spatial Poisson process. Such a property is highly desirable for constructing unpredictable cryptographic primitives. The security primitive is an array of 2048 pixels fabricated from this film. The complex structure of the pixels makes the physical duplication of the array impossible (i.e., physically unclonable). A unique optical response is generated by applying an optical stimulus to the structure. The basis for this unique response is the dependence of the photoemission on the number of MoS2 layers, which by design is random throughout the film. Using a threshold value for the photoemission, we convert the optical response into binary cryptographic keys. We show that the proper selection of this threshold is crucial for maximizing combination randomness and that the optimal value of the threshold is linked directly to the growth process. This study reveals an opportunity for generating robust and versatile security primitives from layered transition metal dichalcogenides. PMID- 29144735 TI - Removal of Pb(II) Ion Using PAMAM Dendrimer Grafted Graphene and Graphene Oxide Surfaces: A Molecular Dynamics Study. AB - The dendrimer polyamidoamine (PAMAM) has been widely applied in environmental applications as adsorbents for wastewater treatment. In this work, molecular dynamics simulations are conducted to understand the effect of dendrimer grafted graphene and graphene oxide on the structural and dynamical properties of the Pb2+ ion. The adsorption capacity of the metal ion is improved significantly, over 60%, using carboxyl terminal groups of a dendrimer molecule grafted on a graphene oxide surface. We examine the self-diffusion coefficient and residence time of Pb2+ ion near graphene and graphene oxide surfaces grafted with PAMAM dendrimers using terminal groups, -COO- and -OH. Further, the potential of mean force is analyzed to understand the role of different surface groups in enhancing the adsorption of the metal ion. PMID- 29144736 TI - Inference of Calmodulin's Ca2+-Dependent Free Energy Landscapes via Gaussian Mixture Model Validation. AB - A free energy landscape estimation method based on the well-known Gaussian mixture model (GMM) is used to compare the efficiencies of thermally enhanced sampling methods with respect to regular molecular dynamics. The simulations are carried out on two binding states of calmodulin, and the free energy estimation method is compared with other estimators using a toy model. We show that GMM with cross-validation provides a robust estimate that is not subject to overfitting. The continuous nature of Gaussians provides better estimates on sparse data than canonical histogramming. We find that diffusion properties determine the sampling method effectiveness, such that diffusion-dominated apo calmodulin is most efficiently sampled by regular molecular dynamics, while holo calmodulin, with its rugged free energy landscape, is better sampled by enhanced sampling methods. PMID- 29144737 TI - Infant and Adult Inhalation Exposure to Resuspended Biological Particulate Matter. AB - Human-induced resuspension of floor dust is a dynamic process that can serve as a major indoor source of biological particulate matter (bioPM). Inhalation exposure to the microbial and allergenic content of indoor dust is associated with adverse and protective health effects. This study evaluates infant and adult inhalation exposures and respiratory tract deposited dose rates of resuspended bioPM from carpets. Chamber experiments were conducted with a robotic crawling infant and an adult performing a walking sequence. Breathing zone (BZ) size distributions of resuspended fluorescent biological aerosol particles (FBAPs), a bioPM proxy, were monitored in real-time. FBAP exposures were highly transient during periods of locomotion. Both crawling and walking delivered a significant number of resuspended FBAPs to the BZ, with concentrations ranging from 0.5 to 2 cm-3 (mass range: ~50 to 600 MUg/m3). Infants and adults are primarily exposed to a unimodal FBAP size distribution between 2 and 6 MUm, with infants receiving greater exposures to super-10 MUm FBAPs. In just 1 min of crawling or walking, 103-104 resuspended FBAPs can deposit in the respiratory tract, with an infant receiving much of their respiratory tract deposited dose in their lower airways. Per kg body mass, an infant will receive a nearly four times greater respiratory tract deposited dose of resuspended FBAPs compared to an adult. PMID- 29144738 TI - Metabolism of an Insecticide Fenitrothion by Cunninghamella elegans ATCC36112. AB - In this study, the detailed metabolic pathways of fenitrothion (FNT), an organophosphorus insecticide by Cunninghamella elegans, were investigated. Approximately 81% of FNT was degraded within 5 days after treatment with concomitant accumulation of four metabolites (M1-M4). The four metabolites were separated by high-performance liquid chromatography, and their structures were identified by mass spectroscopy and/or nuclear magnetic resonance. M3 is confirmed to be an initial precursor of others and identified as fenitrothion oxon. On the basis of their metabolic profiling, the possible metabolic pathways involved in phase I and II metabolism of FNT by C. elegans was proposed. We also found that C. elegans was able to efficiently and rapidly degrade other organophosphorus pesticides (OPs). Thus, these results will provide insight into understanding of the fungal degradation of FNT and the potential application for bioremediation of OPs. Furthermore, the ability of C. elegans to mimic mammalian metabolism would help us elucidate the metabolic fates of organic compounds occurring in mammalian liver cells and evaluate their toxicity and potential adverse effects. PMID- 29144739 TI - Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones? AB - Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this Perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degradation concepts and their resulting applications to medicine discovery. The approach has the potential to bring disruptive change to drug discovery; the many potential advantages and outstanding challenges which lie ahead of this technology are discussed. PMID- 29144740 TI - Identification, Synthesis, and Safety Assessment of Thidiazuron [1-Phenyl-3 (1,2,3-thidiazol-5-yl)urea] and Its Metabolites in Kiwifruits. AB - The quality of kiwifruit became worse as a result of the abuse of plant growth regulators (PGRs). The safety of the fruits treated with PGRs also worried consumers. Therefore, the present study analyzed the structure of thidiazuron [TDZ, (1-phenyl-3-(1,2,3-thidiazol-5-yl)-urea)] (1) and its metabolites of biotransformation in kiwifruits using liquid chromatography hybrid ion trap time of-flight mass spectrometry (LC-IT-TOF-MS). Standard compounds were also synthesized and used for structural identification of those metabolites. In addition, cytotoxicity of TDZ and its metabolites was tested through sulforhodamine B assays against normal Chinese hamster ovary (CHO) cells. Four metabolites were identified. They were 4-hydroxy-thidiazuron (2), 3-hydroxy thidiazuron (3), thidiazuron-4-O-beta-d-glucoside (4), and thidiazuron-3-O-beta-d glucoside (5). Values of IC50 of compounds 1, 2, and 3 to CHO cells were 18.3 +/- 1.8, 37.56 +/- 1.5, and 23.36 +/- 1.59 MUM, respectively. Compounds 4 and 5 had no effect on CHO cells. PMID- 29144741 TI - Spiro-BODIPYs with a Diaryl Chelate: Impact on Aggregation and Luminescence. AB - Spiro-BODIPYs with a diaryl chelate unit have been found to form J-aggregates in methanol-water solvent mixture and brightly emissive in the solid state. The diaryl chelate unit has a significant impact on J-aggregates and fluorescence of BODIPYs. Crystal structural analysis reveals that the spiro-structures facilitate J-stacking in the solid state. PMID- 29144743 TI - Diselaginellin B, an Unusual Dimeric Molecule from Selaginella pulvinata, Inhibited Metastasis and Induced Apoptosis of SMMC-7721 Human Hepatocellular Carcinoma Cells. AB - Two new unusual dimeric selaginellins, diselaginellins A and B (1 and 2), along with two known derivatives, selaginellin (3) and selaginellin B (4), were isolated from Selaginella pulvinata. Their structures were elucidated by extensive NMR and high-resolution ESIMS data analysis. Compound 2 displayed apoptosis-inducing and antimetastatic activities against the human hepatocellular carcinoma cell line SMMC-7721. A microarray analysis revealed that genes related to metabolism, angiogenesis, and metastasis were altered by 2. The up- and down regulation of the mRNA levels of related genes was confirmed by RT-qPCR. Metabolism modulation and metastasis inhibition might be the mechanisms of the antitumor properties of diselaginellin B (2). PMID- 29144742 TI - Successful Identification of Cardiac Troponin Calcium Sensitizers Using a Combination of Virtual Screening and ROC Analysis of Known Troponin C Binders. AB - Calcium-dependent cardiac muscle contraction is regulated by the protein complex troponin. Calcium binds to the N-terminal domain of troponin C (cNTnC) which initiates the process of contraction. Heart failure is a consequence of a disruption of this process. With the prevalence of this condition, a strong need exists to find novel compounds to increase the calcium sensitivity of cNTnC. Desirable are small chemical molecules that bind to the interface between cTnC and the cTnI switch peptide and exhibit calcium sensitizing properties by possibly stabilizing cTnC in an open conformation. To identify novel drug candidates, we employed a structure-based drug discovery protocol that incorporated the use of a relaxed complex scheme (RCS). In preparation for the virtual screening, cNTnC conformations were identified based on their ability to correctly predict known cNTnC binders using a receiver operating characteristics analysis. Following a virtual screen of the National Cancer Institute's Developmental Therapeutic Program database, a small number of molecules were experimentally tested using stopped-flow kinetics and steady-state fluorescence titrations. We identified two novel compounds, 3-(4-methoxyphenyl)-6,7 chromanediol (NSC600285) and 3-(4-methylphenyl)-7,8-chromanediol (NSC611817), that show increased calcium sensitivity of cTnC in the presence of the regulatory domain of cTnI. The effects of NSC600285 and NSC611817 on the calcium dissociation rate was stronger than that of the known calcium sensitizer bepridil. Thus, we identified a 3-phenylchromane group as a possible key pharmacophore in the sensitization of cardiac muscle contraction. Building on this finding is of interest to researchers working on development of drugs for calcium sensitization. PMID- 29144744 TI - Partially Oxidized SnS2 Atomic Layers Achieving Efficient Visible-Light-Driven CO2 Reduction. AB - Unraveling the role of surface oxide on affecting its native metal disulfide's CO2 photoreduction remains a grand challenge. Herein, we initially construct metal disulfide atomic layers and hence deliberately create oxidized domains on their surfaces. As an example, SnS2 atomic layers with different oxidation degrees are successfully synthesized. In situ Fourier transform infrared spectroscopy spectra disclose the COOH* radical is the main intermediate, whereas density-functional-theory calculations reveal the COOH* formation is the rate limiting step. The locally oxidized domains could serve as the highly catalytically active sites, which not only benefit for charge-carrier separation kinetics, verified by surface photovoltage spectra, but also result in electron localization on Sn atoms near the O atoms, thus lowering the activation energy barrier through stabilizing the COOH* intermediates. As a result, the mildly oxidized SnS2 atomic layers exhibit the carbon monoxide formation rate of 12.28 MUmol g-1 h-1, roughly 2.3 and 2.6 times higher than those of the poorly oxidized SnS2 atomic layers and the SnS2 atomic layers under visible-light illumination. This work uncovers atomic-level insights into the correlation between oxidized sulfides and CO2 reduction property, paving a new way for obtaining high efficiency CO2 photoreduction performances. PMID- 29144745 TI - High Efficiency Near-Infrared and Semitransparent Non-Fullerene Acceptor Organic Photovoltaic Cells. AB - The absence of near-infrared (NIR) solar cells with high open circuit voltage (Voc) and external quantum efficiency (EQE) has impeded progress toward achieving organic photovoltaic (OPV) power conversion efficiency PCE > 15%. Here we report a small energy gap (1.3 eV), chlorinated nonfullerene acceptor-based solar cell with PCE = 11.2 +/- 0.4%, short circuit current of 22.5 +/- 0.6 mA cm-2, Voc = 0.70 +/- 0.01 V and fill factor of 0.71 +/- 0.02, which is the highest performance reported to date for NIR single junction OPVs. Importantly, the EQE of this NIR solar cell reaches 75%, between 650 and 850 nm while leaving a transparency window between 400 and 600 nm. The semitransparent OPV using an ultrathin (10 nm) Ag cathode shows PCE = 7.1 +/- 0.1%, with an average visible transmittance of 43 +/- 2%, Commission d'Eclairage chromaticity coordinates of (0.29, 0.32) and a color rendering index of 91 for simulated AM1.5 illumination transmitted through the cell. PMID- 29144746 TI - Oxyprenylated Phenylpropanoids Bind to MT1 Melatonin Receptors and Inhibit Breast Cancer Cell Proliferation and Migration. AB - Oxyprenylated compounds (i.e., ferulic acid and coumarin derivatives) demonstrate neuroprotection and anticancer properties as reported in previous studies. We have tested the affinity of oxyprenylated ferulic acid (1-4) and umbelliferone derivatives (5-11) to melatonin receptors as well as their antiproliferation and antimigratory properties against breast cancer (BC) cell lines. All the compounds except for ferulic acid, boropinic acid, and umbelliferone had binding affinities to melatonin receptors in the nM to MUM range, and both auraptene and umbellinprenin reduced BC cell proliferation and migration in phenotypically diverse BC including triple negative. PMID- 29144747 TI - Structural Variability of 4f and 5f Thiocyanate Complexes and Dissociation of Uranium(III)-Thiocyanate Bonds with Increased Ionicity. AB - A series of complexes [Et4N][Ln(NCS)4(H2O)4] (Ln = Pr, Tb, Dy, Ho, Yb) have been structurally characterized, all showing the same structure, namely a distorted square antiprismatic coordination geometry, and the Ln-O and Ln-N bond lengths following the expected lanthanide contraction. When the counterion is Cs+, a different structural motif is observed and the eight-coordinate complex Cs5[Nd(NCS)8] isolated. The thorium compounds [Me4N]4[Th(NCS)7(NO3)] and [Me4N]4[Th(NCS)6(NO3)2] have been characterized, and high coordination numbers are also observed. Finally, attempts to synthesize a U(III) thiocyanate compound has been unsuccessful; from the reaction mixture, a heterocycle formed by condensation of five MeCN solvent molecules, possibly promoted by U(III), was isolated and structurally characterized. To rationalize the inability to isolate U(III) thiocyanate compounds, thin-layer cyclic voltammetry and IR spectroelectrochemistry have been utilized to explore the cathodic behavior of [Et4N]4[U(NCS)8] and [Et4N][U(NCS)5(bipy)2] along with a related uranyl compound [Et4N]3[UO2(NCS)5]. In all examples, the reduction triggers a rapid dissociation of [NCS]- ions and decomposition. Interestingly, the oxidation chemistry of [Et4N]3[UO2(NCS)5] in the presence of bipy gives the U(IV) compound [Et4N]4[U(NCS)8], an unusual example of a ligand-based oxidation triggering a metal-based reduction. The experimental results have been augmented by a computational investigation, concluding that the U(III)-NCS bond is more ionic than the U(IV)-NCS bond. PMID- 29144748 TI - Chemical Modification for Proteolytic Stabilization of the Selective alphavbeta3 Integrin RGDechi Peptide: in Vitro and in Vivo Activities on Malignant Melanoma Cells. AB - Herein, we report the synthesis and biological characterization of the new peptide psiRGDechi as the first step toward novel-targeted theranostics in melanoma. This pseudopeptide is designed from our previously reported RGDechi peptide, known to bind selectively alphavbeta3 integrin, and differs for a modified amide bond at the main protease cleavage site. This chemical modification drastically reduces the enzymatic degradation in serum, compared to its parental peptide, resulting in an overall magnification of the biological activity on a highly expressing alphavbeta3 human metastatic melanoma cell line. Selective inhibition of cell adhesion, wound healing, and invasion are demonstrated; near-infrared fluorescent psiRGDechi derivative is able to detect alphavbeta3 integrin in human melanoma xenografts in a selective fashion. More, molecular docking studies confirm that psiRGDechi recognizes the receptor similarly to RGDechi. All these findings pave the way for the future employment of this novel peptide as promising targeting probe and therapeutic agent in melanoma disease. PMID- 29144749 TI - Synthesis and Reactivity of a Low-Coordinate Iron(II) Hydride Complex: Applications in Catalytic Hydrodefluorination. AB - A low-coordinate iron hydride complex bearing an unsymmetrical NpN (enamido phosphinimine) ligand scaffold was synthesized and fully characterized. Insertion reactivity with azobenzene, 3-hexyne, and 1-azidoadamantane was explored, and the isolated products were analogous to previously reported beta-diketiminate iron hydride insertion products. Surprisingly, the NpN iron hydride displays unprecedented reactivity toward hexafluorobenzene, affording an NpN iron fluoride complex and pentafluorobenzene as products. The NpN iron hydride is a precatalyst for catalytic hydro-defluorination of perfluorinated aromatics in the presence of silane. Kinetic studies indicated that the rate-determining step during catalysis involved silane. PMID- 29144750 TI - Investigation of the Physical and Bioactive Properties of Bromo- and Iodo Containing Sponge-Derived Compounds Possessing an Oxyphenylethanamine Core. AB - This research set out to identify compounds from marine sponges that can act as bacterial virulence blockers. Extracts from a total of 80 sponges collected from throughout Indonesia were screened in a high-throughput NF-kappaB-based screen that identifies compounds capable of inhibiting the bacterial type III secretion system (T3SS) in Yersinia pseudotuberculosis. An extract that was shown to inhibit T3SS-driven NF-kappaB expression was obtained from an Iotrochota cf. iota sponge and was the source of seven new bromo- and iodo-containing compounds, all of which contain a 2-(4-oxyphenyl)ethan-1-amine core. Five were determined to be new compounds and named enisorines A-E (1-5). The remaining two were determined to be new hemibastadinol analogues named (+)-1-O-methylhemibastadinol 2 (6) and (+)-1-O-methylhemibastadinol 4 (7). All seven compounds inhibited T3SS-dependent YopE secretion and did not affect the growth or metabolic activity of Y. pseudotuberculosis. The most potent inhibitors of T3SS activity were enisorine C (3), enisorine E (5), and (+)-1-O-methylhemibastadinol 2 (6), all of which inhibited YopE secretion by >50% at 30 MUM. PMID- 29144751 TI - Dendrimer-Stabilized Metal Nanoparticles as Efficient Catalysts for Reversible Dehydrogenation/Hydrogenation of N-Heterocycles. AB - Nanoparticles (Pd, Pt, Rh) stabilized by G4OH PAMAM dendrimers and supported in SBA-15 (MNPs/SBA-15 with M = Pd, Pt, Rh) were efficiently used as catalysts in the acceptorless dehydrogenation of tetrahydroquinoline/indoline derivatives in toluene (release of H2) at 130 degrees C. These catalysts are air stable, very active, robust, and recyclable during the process. The reverse hydrogenation reaction of quinoline derivatives (H2 storage) was also optimized and successfully performed in the presence of the same catalysts in toluene at 60 degrees C under only 1 atm of hydrogen gas. Such catalysts may be essential for the adoption of organic hydrogen-storage materials as an alternative to petroleum derived fuels. Hot filtration test confirmed that the reaction follows a heterogeneous pathway. Moreover, PdNPs/SBA-15 was an excellent catalyst for the direct arylation at the C-2 position (via C-H activation) of indole in water in the presense of a hypervalent iodine oxidant. Thus, a one-pot dehydrogenation/direct arylation cascade reaction between indoline and an arylated agent was efficaciously performed in water, demonstrating the potential of the system to catalyze tandem heterogeneous/homogeneous processes by choice of the appropriate oxidant/reductant. PMID- 29144752 TI - Investigation of Iodonium Trifluoroborate Zwitterions as Bifunctional Arene Reagents. AB - The synthesis of a new family of iodonium zwitterions, in which the formal anion is a trifluoroborate moiety, is reported. These reagents present very good stability and have high resistance toward benzyne formation. Their structures were confirmed by X-ray crystallographic analysis and were further investigated using DFT calculations. QTAIM analysis supports an ionic, noncovalent, I+...BF3- interaction, in accordance with a true zwitterionic nature. Preliminary results of synthetic applications, the arylation of phenolates and trifluoroborate group functionalization, are reported. PMID- 29144753 TI - Nonlinear Metasurface for Simultaneous Control of Spin and Orbital Angular Momentum in Second Harmonic Generation. AB - The spin and orbital angular momentum (SAM and OAM) of light is providing a new gateway toward high capacity and robust optical communications. While the generation of light with angular momentum is well studied in linear optics, its further integration into nonlinear optical devices will open new avenues for increasing the capacity of optical communications through additional information channels at new frequencies. However, it has been challenging to manipulate the both SAM and OAM of nonlinear signals in harmonic generation processes with conventional nonlinear materials. Here, we report the generation of spin controlled OAM of light in harmonic generations by using ultrathin photonic metasurfaces. The spin manipulation of OAM mode of harmonic waves is experimentally verified by using second harmonic generation (SHG) from gold meta atom with 3-fold rotational symmetry. By introducing nonlinear phase singularity into the metasurface devices, we successfully generate and measure the topological charges of spin-controlled OAM mode of SHG through an on-chip metasurface interferometer. The nonlinear photonic metasurface proposed in this work not only opens new avenues for manipulating the OAM of nonlinear optical signals but also benefits the understanding of the nonlinear spin-orbit interaction of light in nanoscale devices. PMID- 29144754 TI - Immunogenic Cell Death Amplified by Co-localized Adjuvant Delivery for Cancer Immunotherapy. AB - Despite their potential, conventional whole-cell cancer vaccines prepared by freeze-thawing or irradiation have shown limited therapeutic efficacy in clinical trials. Recent studies have indicated that cancer cells treated with certain chemotherapeutics, such as mitoxantrone, can undergo immunogenic cell death (ICD) and initiate antitumor immune responses. However, it remains unclear how to exploit ICD for cancer immunotherapy. Here, we present a new material-based strategy for converting immunogenically dying tumor cells into a powerful platform for cancer vaccination and demonstrate their therapeutic potential in murine models of melanoma and colon carcinoma. We have generated immunogenically dying tumor cells surface-modified with adjuvant-loaded nanoparticles. Dying tumor cells laden with adjuvant nanodepots efficiently promote activation and antigen cross-presentation by dendritic cells in vitro and elicit robust antigen specific CD8alpha+ T-cells in vivo. Furthermore, whole tumor-cell vaccination combined with immune checkpoint blockade leads to complete tumor regression in ~78% of CT26 tumor-bearing mice and establishes long-term immunity against tumor recurrence. Our strategy presented here may open new doors to "personalized" cancer immunotherapy tailored to individual patient's tumor cells. PMID- 29144755 TI - Holographic Plasmonic Nanotweezers for Dynamic Trapping and Manipulation. AB - We demonstrate dynamic trapping and manipulation of nanoparticles with plasmonic holograms. By tailoring the illumination pattern of an incident light beam with a computer-controlled spatial light modulator, constructive and destructive interference of plasmon waves create a focused hotspot that can be moved across a surface. Specifically, a computer-generated hologram illuminating the perimeter of a silver Bull's Eye nanostructure generates surface plasmons that propagate toward the center. Shifting the phase of the plasmon waves as a function of space gives complete control over the location of the focus. We show that 200 nm diameter nanoparticles trapped in this focus can be moved in arbitrary patterns. This allows, for example, circular motion with linearly polarized light. These results show the versatility of holographically generated surface plasmon waves for advanced trapping and manipulation of nanoparticles. PMID- 29144756 TI - Controlling the Graphene-Bio Interface: Dispersions in Animal Sera for Enhanced Stability and Reduced Toxicity. AB - Liquid phase exfoliation of graphite in six different animal sera and evaluation of its toxicity are reported here. Previously, we reported the exfoliation of graphene using proteins, and here we extend this approach to complex animal fluids. A kitchen blender with a high-turbulence flow gave high quality and maximum exfoliation efficiency in all sera tested, when compared to the values found with shear and ultrasonication methods. Raman spectra and electron microscopy confirmed the formation of three- or four-layer, submicrometer size graphene, independent of the serum used. Graphene prepared in serum was directly transferred to cell culture media without post-treatments. Contrary to many reports, a nanotoxicity study of this graphene fully dispersed to human embryonic kidney cells, human lung cancer cells, and nematodes (Caenorhabditis elegans) showed no acute toxicity for up to 7 days at various doses (50-500 MUg/mL), but prolonged exposure at higher doses (300-500 MUg/mL, 10-15 days) showed cytotoxicity to cells (~95% death) and reproductive toxicity to C. elegans (5-10% reduction in brood size). The origin of toxicity was found to be due to the highly fragmented smaller graphene sheets (<200 nm), while the larger sheets were nontoxic (50-300 MUg/mL dose). In contrast, graphene produced with sodium cholate as the mediator has been found to be cytotoxic to these cells at these dosages. We demonstrated the toxicity of liquid phase exfoliated graphene is attributed to highly fragmented fractions or nonbiocompatible exfoliating agents. Thus, low toxicity graphene/serum suspensions are produced by a facile method in biological media, and this approach may accelerate the much-anticipated development of graphene for biological applications. PMID- 29144757 TI - Versatile Encapsulation Technology Based on Tailored pH-Responsive Amphiphilic Polymers: Emulsion Gels and Capsules. AB - We present a multipurpose technology to encapsulate hydrophobic substances in micron-sized emulsion droplets and capsules. The encapsulating agent is a comblike stimuli-responsive copolymer comprising side-chain surfactants attached to a methacrylic acid/ethyl acrylate polyelectrolyte backbone. The composition and structure of the hydrophobic moieties of the side chains are customized to tune the particle morphology and the processing conditions. The technology exploits the synergy of properties provided by the copolymer: interfacial activity, pH responsiveness, and viscoelasticity. A one-pot process produces emulsion gels or capsule dispersions consisting of a hydrophobic liquid core surrounded by a polymer shell. The dispersions resist high ionic strengths and exhibit long-term stability. The versatility of the method is demonstrated by encapsulating various hydrophobic substances covering a broad range of viscosities and polarities-conventional and technical oils, perfumes, and alkyd paints-with a high degree of morphological and rheological control. PMID- 29144758 TI - On the Density Dependence of the Integral Equation Coarse-Graining Effective Potential. AB - Coarse-graining (CG) procedures provide computationally efficient methods for investigating the corresponding long time- and length-scale processes. In the bottom-up approaches, the effective interactions between the CG sites are obtained using the information from the atomistic simulations, but reliable CG procedures are required to preserve the structure and thermodynamics. In this regard, the integral equation coarse-graining (IECG) method is a promising approach that uses the first-principles Ornstein-Zernike equation in liquid state theory to determine the effective potential between CG sites. In this work, we present the details of the IECG method while treating the density as an intrinsic property and active variable of the CG system. Performing extensive simulations of polymer melts, we show that the IECG theory/simulation and atomistic simulation results are consistent in structural properties such as the pair correlation functions and form factors, and also thermodynamic properties such as pressure. The atomistic simulations of the liquids show that the structure is largely sensitive to the repulsive part of the potential. Similarly, the IECG simulations of polymeric liquids show that the structure can be determined by the relatively short-range CG repulsive interactions, but the pressure is only accurately determined once the long-range, weak CG attractive interactions are included. This is in agreement with the seminal work by Widom on the influence of the potential on the phase diagram of the liquid [Widom, B. Science 1967 , 157 , 375 - 382 ]. Other aspects of the IECG theory/simulations are also discussed. PMID- 29144759 TI - Degree of Unsaturation and Backbone Orientation of Amphiphilic Macromolecules Influence Local Lipid Properties in Large Unilamellar Vesicles. AB - Liposomes have become increasingly common in the delivery of bioactive agents due to their ability to encapsulate hydrophobic and hydrophilic drugs with excellent biocompatibility. While commercial liposome formulations improve bioavailability of otherwise quickly eliminated or insoluble drugs, tailoring formulation properties for specific uses has become a focus of liposome research. Here, we report the design, synthesis, and characterization of two series of amphiphilic macromolecules (AMs), consisting of acylated polyol backbones conjugated to poly(ethylene glycol) (PEG) that can serve as the sole additives to stabilize and control hydrophilic molecule release rates from distearoylphosphatidylcholine (DSPC)-based liposomes. As compared to DSPC alone, all AMs enable liposome formation and stabilize their colloidal properties at low incorporation ratios, and the AM's degree of unsaturation and hydrophobe conformation have profound impacts on stability duration. The AM's chemical structures, particularly hydrophobe unsaturation, also impact the rate of hydrophilic drug release. Course grained molecular dynamics simulations were utilized to better understand the influence of AM structure on lipid properties and potential liposomal stabilization. Results indicate that both hydrophobic domain structure and PEG density can be utilized to fine-tune liposome properties for the desired application. Collectively, AMs demonstrate the potential to simultaneously stabilize and control the release profile of hydrophilic cargo. PMID- 29144760 TI - Multispectroscopic and Theoretical Exploration of the Comparative Binding Aspects of Bioflavonoid Fisetin with Triple- and Double-Helical Forms of RNA. AB - The interactions of RNA triplex (U.A*U) and duplex (A.U) with naturally occurring flavonoid fisetin (FTN) have been examined at pH 7.0 using various spectroscopic, viscometric, and theoretical studies. Experimental observations showed that the ligand binds with both double- and triple-helical forms of RNA, although the binding affinity is greater for the triplex structure (5.94 * 106 M-1) compared to that for the duplex counterpart (1.0 * 105 M-1). Thermal melting experiments revealed that the Hoogsteen base-paired third strand of triplex was stabilized to a greater extent (~14 degrees C) compared with the Watson-Crick base-paired second strand (~4 degrees C) in the presence of FTN. From fluorimetric study, we observed that U.A*U and A.U primarily bind to the photoproduced tautomer of FTN in the excited state. Steady-state and time-resolved anisotropy measurements illustrate considerable modulations of the spectroscopic properties of the tautomeric FTN within the RNA environment. Viscometric, fluorescence quenching, and thermal melting studies all together support the mode of binding to be intercalation. Theoretical study explains the experimental absorption and emission (dual fluorescence) behavior of FTN along with the excited-state intramolecular proton transfer process. PMID- 29144761 TI - Amphiphiles without Head-and-Tail Design: Nanostructures Based on the Self Assembly of Anionic Boron Cluster Compounds. AB - Anionic boron cluster compounds (ABCCs) are intrinsically amphiphilic building blocks suitable for nanochemistry. ABCCs are involved in atypical weak interactions, notably dihydrogen bonding, due to their peculiar polyhedral structure, consisting of negatively charged B-H units. The most striking feature of ABCCs that differentiates them from typical surfactants is the lack of head and-tail structure. Furthermore, their structure can be described as intrinsically amphiphilic or aquaneutral. Therefore, classical terms established to describe self-assembly of classical amphiphiles are insufficient and need to be reconsidered. The opinions and theories focused on the solution behavior of ABCCs are briefly discussed. Moreover, a comparison between ABCCs with other amphiphilic systems is made focusing on the explanation of enthalpy-driven micellization or relations between hydrophobic and chaotropic effects. Despite the unusual structure, ABCCs still show self- and coassembly properties comparable to classical amphiphiles such as ionic surfactants. They self-assemble into micelles in water according to the closed association model. The most typical features of ABCCs solution behavior is demonstrated on calorimetry, NMR spectroscopy, and tensiometry experiments. Altogether, the unique features of ABCCs makes them a valuable inclusion into the nanochemisty toolbox to develop novel nanostructures both alone and with other molecules. PMID- 29144762 TI - Enhancement of CO Evolution by Modification of Ga2O3 with Rare-Earth Elements for the Photocatalytic Conversion of CO2 by H2O. AB - Modification of the surface of Ga2O3 with rare-earth elements enhanced the evolution of CO as a reduction product in the photocatalytic conversion of CO2 using H2O as an electron donor under UV irradiation in aqueous NaHCO3 as a pH buffer, with the rare-earth species functioning as a CO2 capture and storage material. Isotope experiments using 13CO2 as a substrate clearly revealed that CO was generated from the introduced gaseous CO2. In the presence of the NaHCO3 additive, the rare-earth (RE) species on the Ga2O3 surface are transformed into carbonate hydrates (RE2(CO3)3.nH2O) and/or hydroxycarbonates (RE2(OH)2(3 x)(CO3)x) which are decomposed upon photoirradiation. Consequently, Ag-loaded Yb modified Ga2O3 exhibits much higher activity (209 MUmol h-1 of CO) than the pristine Ag-loaded Ga2O3. The further modification of the surface of the Yb modified Ga2O3 with Zn afforded a selectivity toward CO evolution of 80%. Thus, we successfully achieved an efficient Ag-loaded Yb- and Zn-modified Ga2O3 photocatalyst with high activity and controllable selectivity, suitable for use in artificial photosynthesis. PMID- 29144763 TI - Iron-Catalyzed Indolizine Synthesis from Pyridines, Diazo Compounds, and Alkynes. AB - The iron(III)-catalyzed synthesis of indolizines from commercially available alkyne, pyridine, and diazo precursors is reported. This mild, expedient method is tolerant of various solvents and proceeds with as little as 0.25 mol % [Fe(TPP)Cl]. Significantly, this multicomponent reaction is compatible with electrophilic alkynes; control experiments demonstrate the importance of the catalyst in promoting pyridinium ylide formation over background reactivity. PMID- 29144765 TI - Triazoliptycenes: A Twist on Iptycene Chemistry for Regioselective Cross-Coupling To Build Nonstacking Fluorophores. AB - Triazoliptycene fluorophores have been designed and synthesized, in which a three dimensional propeller-like iptycene motif is employed to suppress intermolecular pi-pi stacking in the solid state. Key to the success of this modular synthesis is a stereoelectronic bias imposed by the iptycene scaffold, which assists the desired regioselectivity in the C-N cross-coupling step as the last-stage structure diversification from a common precursor. PMID- 29144764 TI - Synthesis of Polycyclic Imidazolidinones via Amine Redox-Annulation. AB - alpha-Ketoamides undergo redox-annulations with cyclic secondary amines, such as 1,2,3,4-tetrahydroisoquinoline, pyrrolidine, piperidine, and morpholine. Catalytic amounts of benzoic acid significantly accelerate these transformations. This approach provides polycyclic imidazolidinone derivatives in typically good yields. PMID- 29144766 TI - From Ketones, Amines, and Carbon Monoxide to 4-Quinolones: Palladium-Catalyzed Oxidative Carbonylation. AB - A novel method of palladium-catalyzed oxidative carbonylation of ketones, amines, and carbon monoxide for the synthesis of 4-quinolones has been developed. This protocol provides a straightforward route to construct useful 4-quinolone derivatives from inexpensive chemicals. PMID- 29144767 TI - Evaluation of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer nanomicelle for trigeminal ganglion neurons delivering with intranasal administration. AB - Purpose How to deliver enough medical agents to the trigeminal ganglion (TG) neurons conveniently still remains a challenge in pharmaceutics and clinics. The purpose of this study was to reveal that intranasal administration of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG) nanomicelle formulation could efficiently deliver agent to TG neurons in mice. Methods Ocular topical or intranasal administration of nanomicelle coumarin-6 was performed in mice, and tissue distribution after administration (0.25, 1, 2, 4, 6, 8, and 10 h) was analyzed. Fluoro-Gold was used as a retrograde tracer to identify corneal and nasal neurons in the TG. Pharmacokinetic profiles after ocular topical or intranasal administration were explored in detail. Results Coumarin-6 levels in the TG neurons were significantly higher in intranasal administration groups than in topical administration groups, and the difference was statistically significant (P < 0.05) at all time points except for 10 h. Interestingly, in cornea, coumarin-6 was detected after intranasal administration. For intranasal administration groups, it was also interestingly found that coumarin-6 levels in the TG neurons were much higher than that in the brain, suggesting that the TG neurons was a target tissue after the intranasal administration of nanomicelle coumarin-6. These levels also indicated the safety of brain tissue after intranasal administration. Using Fluoro-Gold tract tracing techniques, coumarin-6 was detected in TG neurons after either ocular topical or intranasal administration of nanomicelle coumarin-6, indicating the high colocalization of corneal and nasal neurons in the TG. Conclusions Intranasal administration of PVCL-PVA-PEG nanomicelle formulation could efficiently deliver to TG neurons, and it might be a promising therapy for pathological TG neurons. PMID- 29144769 TI - Detection of Emerging Zoonotic Pathogens: An Integrated One Health Approach. AB - The emergence of novel zoonotic pathogens is one of the greatest challenges to global health security. The advent of increasingly sophisticated diagnostics tools has revolutionized our capacity to detect and respond to these health threats more rapidly than ever before. Yet, no matter how sophisticated these tools become, the initial identification of emerging infectious diseases begins at the local community level. It is here that the initial human or animal case resides, and it is here that early pathogen detection would have maximum benefit. Unfortunately, many areas at highest risk of zoonotic disease emergence lack sufficient infrastructure capacity to support robust laboratory diagnostic systems. Multiple factors are essential for pathogen detection networks, including an understanding of the complex sociological and ecological factors influencing disease transmission risk, community engagement, surveillance along high-risk human-animal interfaces, and a skilled laboratory workforce. Here we discuss factors relevant to the emerging disease paradigm, recent technical advances in diagnostic methods, and strategies for comprehensive and sustainable approaches to rapid zoonotic disease detection. PMID- 29144770 TI - Equine Intestinal Mucosal Pathobiology. AB - The equine intestinal mucosa is intimately involved in maintaining homeostasis both on a systemic level by controlling extracellular fluid movement and at the local level to maintain barrier function. Horses are particularly susceptible to the clinical syndrome of colic, with the most severe cases involving strangulating obstruction that induces ischemia. Because of the mucosal vascular architecture, the mucosal epithelium is particularly susceptible to ischemic injury. The potential for reperfusion injury has been investigated and found to play a minimal role. However, inflammation does affect mucosal repair. Mechanisms of repair, including villus contraction, epithelial restitution, and tight junction closure, are critical to reforming the mucosal barrier. Nonsteroidal anti-inflammatory drugs have an impact on this repair, particularly at the level of the tight junctions. Completion of mucosal regeneration requires proliferation, which is now being actively studied in equine enteroids. All of these aspects of equine mucosal pathobiology are reviewed in depth. PMID- 29144771 TI - Bursal-Sided Rotator Cuff Tears: Simple Versus Everted Type. AB - BACKGROUND: No studies have focused on the everted type of bursal-sided partial thickness rotator cuff tears (PTRCTs). PURPOSE: To evaluate the radiological characteristics, arthroscopic findings, and clinical and structural outcomes after arthroscopic repair of the everted type of bursal-sided PTRCTs. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Two groups of patients with bursal-sided PTRCTs (simple type, 25 shoulders; everted type, 25 shoulders) were enrolled. The mean age was 59.6 years (range, 47-73 years) and 60.8 years (range, 48-72 years) among patients with the simple and everted type, respectively. The mean follow-up period was 2.7 years (range, 2.0-5.1 years). RESULTS: The everted type always exhibited an acromial spur (hat-shaped, 52%; heel-shaped, 48%) and bony changes in the greater tuberosity (bony spur, 52%; sclerotic changes, 48%). Hat-shaped spurs of the acromion were not observed in the simple type. The everted type showed significantly thicker tendon on magnetic resonance imaging (MRI), as the stump was retracted superomedially (mean thickness: 8.1 +/- 1.2 mm vs 5.5 +/- 1.1 mm for the everted and simple type, respectively). During arthroscopic repair, additional sutures were needed more often for the everted type than for the simple type (64% vs 16%, respectively). After repair, the tendon margin was uneven and ragged in 16% of shoulders with the everted type. Preoperatively, the visual analog scale (VAS) score for pain during motion and range of motion (ROM) were significantly worse in patients with the everted type than in those with the simple type (VAS score, 7.2 vs 5.6, respectively; ROM for forward flexion, 146.8 degrees vs 156.4 degrees , respectively). Postoperatively, no significant differences in the VAS score, ROM, or clinical outcomes were observed between the 2 groups, with no retears on follow-up MRI in either group. CONCLUSION: The everted type of bursal-sided PTRCTs showed a characteristic hat-shaped acromion, often with bony spurs of the greater tuberosity. On MRI, the tendon stump appeared thickened because of the everted flap. The everted type was more likely to require additional sutures because of an uneven or ragged tendon margin. However, satisfactory clinical and structural outcomes were observed for both the simple and everted types. PMID- 29144772 TI - Subchondral Bone Degradation After Microfracture for Osteochondral Lesions of the Talus: An MRI Analysis. AB - BACKGROUND: Microfracture is the most common cartilage-reparative procedure for the treatment of osteochondral lesions of the talus (OLTs). Damage to the subchondral bone (SCB) during microfracture may irreversibly change the joint loading support of the ankle, leading to reparative fibrocartilage degradation over time. PURPOSE: To investigate the morphological change in the SCB after microfracture for OLT by developing a novel magnetic resonance imaging (MRI) scoring system specifically for evaluating the SCB. Furthermore, this study assesses the influence of the morphological changes of the SCB on clinical outcomes based on the new score. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Forty-two patients who underwent microfracture for OLT were included. An SCB Health (SCBH) scoring system was developed according to the amount of edema, subchondral cyst diameter, and qualitative and thickness change in the SCB, with a total score of 12 indicating normal SCB. MRI was obtained postoperatively from 6 months to 1 year, 1 to 2 years, 2 to 4 years, and 4 to 6 years. The Foot and Ankle Outcome Score (FAOS) was evaluated preoperatively and at 2 years and final follow-up. RESULTS: The mean patient age was 38.4 +/- 15.6 years, with a mean follow-up of 51.7 +/- 22.8 months. The mean FAOS improved significantly from 57.8 +/- 14.4 preoperatively to 84.3 +/- 7.2 at 24 months ( P < .001) and decreased to a final mean value of 77.1 +/- 12.6 ( P < .001). The mean SCBH score decreased from 8.6 +/- 1.9 preoperatively to 7.1 +/- 1.8 on the first follow-up MRI ( P < .001) and significantly decreased to 5.9 +/- 2.3 on the fourth follow-up MRI ( P < .001). Subchondral cysts were noticeably worse at the fourth follow-up MRI than at the first and second ( P < .001, P = .006, respectively). There was a positive correlation between the final FAOS and the SCBH score on the third and fourth follow-up MRI ( r = 0.55, P < .001; r = 0.70, P < .001, respectively), but no correlation was found on the first and second follow-up. CONCLUSION: The SCBs following microfracture for OLT were not restored at midterm follow-up. There was a significant decrease of the overall SCBH score over time. Noticeably, subchondral cysts deteriorated over time consistently. In addition, the SCBH score at midterm follow-up was positively correlated with clinical outcomes. Lasting morphological changes in the SCB may be indicative of longer-term failure of the microfracture procedure. PMID- 29144773 TI - Cancer Chemopreventive, Antiproliferative, and Superoxide Anion Scavenging Properties of Kluyveromyces marxianus and Saccharomyces cerevisiae var. boulardii Cell Wall Components. AB - This study investigated the cancer chemopreventive, the antiradical, and the antiproliferative properties of polysaccharides extracts from cell wall of Saccharomyces boulardii and Kluyveromyces marxianus. beta-glucan, mannan, and chitin were also quantified to identify the most important extract responsible for these biological properties. Soluble and insoluble glucans as well as mannoprotein were extracted from cell wall using single hot-alkaline method. Superoxide anion scavenging (antiradical capacity), NAD(P)H: quinone reductase (QR) (EC 1.6.99.2) induction, and antiproliferative assays were done for the evaluation of biological properties of those extracts. The insoluble glucan from S. boulardii revealed the most relevant biological properties by increasing QR activity and exhibiting the highest growth inhibition against colorectal cancer cells. Moreover, high amount of glucan, high glucan/total sugars ratios, and low chitin/glucan ratios were shown to have an impact on enhancing cancer chemopreventive and antiproliferative properties. To our knowledge, this is the first study that demonstrates QR activity by yeast cell wall components in a dose dependent manner. PMID- 29144774 TI - Strategies for Enhanced Crop Resistance to Insect Pests. AB - Insect pests are responsible for substantial crop losses worldwide through direct damage and transmission of plant diseases, and novel approaches that complement or replace broad-spectrum chemical insecticides will facilitate the sustainable intensification of food production in the coming decades. Multiple strategies for improved crop resistance to insect pests, especially strategies relating to plant secondary metabolism and immunity and microbiome science, are becoming available. Recent advances in metabolic engineering of plant secondary chemistry offer the promise of specific toxicity or deterrence to insect pests; improved understanding of plant immunity against insects provides routes to optimize plant defenses against insects; and the microbiomes of insect pests can be exploited, either as a target or as a vehicle for delivery of insecticidal agents. Implementation of these advances will be facilitated by ongoing advances in plant breeding and genetic technologies. PMID- 29144775 TI - A three-patient evaluation. PMID- 29144776 TI - Extremely painful venous leg ulcer. PMID- 29144778 TI - Exuding venous leg ulcer with signs of biofilm. PMID- 29144777 TI - UrgoClean Ag: evidence base and mode of action. AB - UrgoClean Ag is indicated for all exuding wounds with signs of increased bioburden and biofilm. This article describes the evidence base supporting its efficacy. PMID- 29144779 TI - Heavily exuding venous leg ulcer with suspected biofilm. PMID- 29144780 TI - Wound on a patient with alcoholic hepatitis recovering from sepsis. PMID- 29144781 TI - Non-healing venous leg ulcer. PMID- 29144782 TI - Foreword. PMID- 29144783 TI - Post-brachytherapy wound. PMID- 29144784 TI - Diabetic foot ulcer. PMID- 29144785 TI - Role of slough and biofilm in delaying healing in chronic wounds. AB - The management of biofilms with maintenance desloughing and antimicrobial therapy is fast becoming the accepted treatment strategy for chronic wounds. PMID- 29144786 TI - Venous leg ulceration in an intravenous drug user. PMID- 29144787 TI - Lessons Learned From a Food Environment Intervention Study: Recruitment and Retention of Participants in Disadvantaged Urban Inner-City Neighborhoods. AB - Growing health inequities have led to calls for population health intervention research that can contribute to improving the health of marginalized populations, but conducting research with these communities can be challenging. When research aims to examine and understand an aspect of health in a population characterized as hard-to-reach or marginalized, recruitment techniques appear to have a significant impact on participation and sample retention in longitudinal studies. We examine and comment on the recruitment and retention techniques used in the Good Food, Healthy Families study conducted in low-income, inner-city neighborhoods in a midsized Canadian city; we hope that this will inform recruitment and retention approaches for population health intervention studies in similar populations. It is a responsibility of researchers who wish to engage with population health interventions that have the potential to improve health equity to gather information in ways that are respectful. PMID- 29144788 TI - Panchakola Reduces Oxidative Stress in MCF-7 Breast Cancer and HEK293 Cells. AB - A large number of studies have proven the efficacy of ayurveda in the field of health and wellness. Panchakola, an ayurvedic formulation, is a general health tonic primarily used to cure fever, inflammation, pain, indigestion, and so on. We investigated effects of panchakola on oxidative stress in MCF-7 breast cancer and human embryonic kidney 293 (HEK293) cells. This work was performed to assess the antineoplastic and free radical-scavenging potential of aqueous extract of panchakola, a polyherbal formulation, in normal and breast cancer cell lines (i.e., HEK and MCF-7, respectively) using MTT assay. Activities of antioxidant enzyme, nitric oxide scavenger, superoxide dismutase, glutathione S-transferase, and glutathione peroxidase were assessed in cell lines incubated with and without panchakola. The outcome was analyzed by spectrophotometer. The results demonstrated increased cytotoxicity in MCF-7 (IC50 16.446 MUg/ml) comparable to the results obtained with standard anticancer control (curcumin) with IC50 10.265 MUg/ml in MCF-7 cell line. Further, the results obtained from antioxidant assays suggested increased antioxidant activity in MCF-7 cells as compared to normal HEK cells. The results derived from this study suggested panchakola is a strong contender in the field of phytomedicines to fight cancer and free radical-related diseases. PMID- 29144789 TI - A comparative study of different amniotic membrane orientations during extraocular muscle surgery in rabbits. AB - PURPOSE: To histopathologically compare the effect of different orientations of cryopreserved human amniotic membrane (AM) transplant during extraocular muscle surgery in rabbits. METHODS: Fifty-two albino rabbit eyes underwent 4-mm resection of the superior rectus. Eyes were randomly divided into four groups. In Group C (Control group, 16 eyes) the muscle was not wrapped with amniotic membrane. In the three AM groups, cryopreserved AM was wrapped around the muscle, oriented with either its stroma (Group S, 15 eyes) or epithelium (Group E, nine eyes) towards the muscle, or folded on itself with the epithelium externally (Group F, 12 eyes). The rabbits were sacrificed and the eyes were enucleated 6 weeks after surgery. Histopathological examination was conducted for periamniotic, foreign body, scleral, and conjunctival inflammation, conjunctival vascularity, adhesions and muscle fibrosis. RESULTS: In all AM eyes, the AM was surrounded by periamniotic inflammation, with no adhesions detected between the muscle and surrounding tissues in the segment where the AM was present, but detected elsewhere. Adhesions were detected in all group C eyes. Foreign body inflammation was significantly less in Group C than in each of the AM groups (p < .05), but was insignificantly different among the three AM groups (p > .05). Scleral inflammation was absent in all specimens. No significant differences were noted among all groups in terms of conjunctival vascularity, conjunctival inflammation, or muscle fibrosis (p > .05). CONCLUSIONS: All AM orientations were equally effective in preventing the development of postoperative adhesions between the extraocular muscle and surrounding tissues. PMID- 29144790 TI - Evaluation of Ki-67 Index in Core Needle Biopsies and Matched Breast Cancer Surgical Specimens. AB - CONTEXT: - The Ki-67 index is strongly prognostic and is used as a surrogate marker to distinguish luminal A from luminal B breast cancer types. OBJECTIVE: - To investigate differences in Ki-67 index between core needle biopsy samples and matched surgical samples in breast cancer. DESIGN: - We included patients with invasive breast cancer who did not receive neoadjuvant therapy. A total of 89 pairs of core needle biopsies and surgical specimens were collected, and the Ki 67 index was assessed in hot spot areas using an image analyzer. We applied a 14% Ki-67 index to define low versus high groups. RESULTS: - The Ki-67 index was significantly higher in core needle biopsies than in surgical specimens ( P < .001), with a median absolute difference of 3.5%. When we applied 14% as a cutoff, 16 of 89 cases (18%) showed discrepancy. Thirteen cases showed a high Ki 67 index in core needle biopsies but a low Ki-67 index in surgical samples. There were 10 cases (11.2%) that showed discordant luminal A/B types between core needle biopsy and the matched surgical specimen. The reasons for the discordance were poor staining of MIB1 accompanied by fixation issues and intratumoral heterogeneity of the Ki-67 index. CONCLUSIONS: - A significant difference in the Ki-67 index between core biopsy and surgical specimens was observed. Our findings indicate that it may be better to perform the Ki-67 assay on the core needle biopsy and the surgical specimen than on only one sample. PMID- 29144791 TI - Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part I-Colorectal Cancer: Microsatellite Instability, Testing, and Clinical Implications. AB - CONTEXT: - Colorectal cancer (CRC) represents the third most-common cancer in developed countries and is a leading cause of cancer deaths worldwide. Two recognized pathways contribute to CRC development: a more-common chromosomal instability pathway and, in 15% of cases, a deficient mismatch repair or microsatellite instability-high (MSI-H) pathway. The MSI-H CRC can be associated with somatic or germline mutations. Microsatellite status has been recognized as a prognostic and predictive biomarker. OBJECTIVES: - To summarize the molecular pathways of CRC, with an emphasis on the MSI (mismatch repair) pathway; the recommended MSI testing algorithms and interpretation; and the prognostic and predictive role of MSI-H status in personalized treatment, including adjuvant chemotherapy, targeted therapy, and immune checkpoint inhibitor therapy. DATA SOURCES: - A PubMed (US National Library of Medicine, Bethesda, Maryland) review was performed for articles pertaining to CRC, MSI and mismatch repair systems, molecular classification, immune response, programmed death receptor-1/programmed death ligand-1, and immunotherapy. CONCLUSIONS: - Although the TNM classification of malignant tumor stage remains the key determinant of CRC prognosis and treatment, there are considerable stage-independent, interindividual differences in clinical outcome and therapy response by patients. In addition, MSI-H status has an important role in CRC management and can be reliably detected by molecular and immunohistochemistry techniques and genetic testing. Efforts must be made to identify whether MSI-H CRC is germline or sporadic to ensure appropriate treatment, accurate prognosis, and risk assessment for relatives. Microsatellite status has been recognized as a good prognostic indicator and is predictive of a poor response to 5-fluorouracil-based chemotherapy and a good response to programmed death ligand-1 inhibitor pembrolizumab in metastatic/refractory MSI-H CRC. PMID- 29144792 TI - Effect of Blood Collection Tube Type and Time to Processing on the Enumeration and High-Content Characterization of Circulating Tumor Cells Using the High Definition Single-Cell Assay. AB - CONTEXT: - As circulating tumor cell (CTC) assays gain clinical relevance, it is essential to address preanalytic variability and to develop standard operating procedures for sample handling in order to successfully implement genomically informed, precision health care. OBJECTIVE: - To evaluate the effects of blood collection tube (BCT) type and time-to-assay (TTA) on the enumeration and high content characterization of CTCs by using the high-definition single-cell assay (HD-SCA). DESIGN: - Blood samples of patients with early- and advanced-stage breast cancer were collected into cell-free DNA (CfDNA), EDTA, acid-citrate dextrose solution, and heparin BCTs. Time-to-assay was evaluated at 24 and 72 hours, representing the fastest possible and more routine domestic shipping intervals, respectively. RESULTS: - We detected the highest CTC levels and the lowest levels of negative events in CfDNA BCT at 24 hours. At 72 hours in this BCT, all CTC subpopulations were decreased with the larger effect observed in high-definition CTCs and cytokeratin-positive cells smaller than white blood cells. Overall cell retention was also optimal in CfDNA BCT at 24 hours. Whole genome copy number variation profiles were generated from single cells isolated from all BCT types and TTAs. Cells from CfDNA BCT at 24-hour TTA exhibited the least noise. CONCLUSIONS: - Circulating tumor cells can be identified and characterized under a variety of collection, handling, and processing conditions, but the highest quality can be achieved with optimized conditions. We quantified performance differences of the HD-SCA for specific preanalytic variables that may be used as a guide to develop best practices for implementation into patient care and/or research biorepository processes. PMID- 29144793 TI - Interprofessional collaboration: An exploration of possible prerequisites for successful implementation. AB - Poor collaboration among professional groups may be a major cause of incoherent patient pathways in hospital settings. For over a decade, interprofessional collaboration (IPC) have been stressed as an effective method to enhance the delivery of patient care. This article presents a theory-based stakeholder evaluation of the implementation of an intervention aiming to implement the concept of IPC in a Danish regional hospital from 2012 to 2015. Involving five departments and eight professions, the intervention aimed at developing coherent practices across health professions by optimising patient pathways with the establishment of interprofessional teams as a core element. The evaluation assessed the professionals' views of the intervention. Data were collected through focus group interviews and document analysis. We found that a strengthened focus on patient pathways, well-trained instructors, and an evidence based strategy for implementation facilitates the success of interventions with a focus on IPC in hospital settings. We furthermore found that cultural and organisational factors are barriers to the implementation of IPC practices, that interruptions of uni-professional work may hamper coordination across professions, and that the interprofessional teams may form new isolated organisational structures. PMID- 29144794 TI - ENDOSCOPIC ULTRASOUND-GUIDED FINE-NEEDLE ASPIRATION IN THE DIAGNOSIS OF ADRENAL METASTASIS IN A HIGH-RISK POPULATION. AB - OBJECTIVE: While the left adrenal gland is readily accessible via endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), data regarding the utility of EUS-FNA in the diagnosis of adrenal lesions remain limited. We aimed to ( 1) describe the clinical context, adverse event rate, and diagnostic performance of EUS-FNA, and ( 2) compare the safety profile and diagnostic accuracy of EUS-FNA with percutaneous adrenal biopsy. METHODS: Single-center, retrospective cohort study. Medical records of patients who underwent adrenal EUS-FNA from 2005-2016 were reviewed. Biopsy outcomes were evaluated using a predefined reference standard. Results were compared to patients who underwent percutaneous biopsy (n = 419; 1994-2014) at the same institution. RESULTS: A total of 121 patients underwent EUS-FNA of 122 adrenal lesions (left [n = 121]; right [n = 1]; mean lesion size, 1.8 cm). Cytology was positive for malignancy in 35 (29%), suspicious for malignancy in 1 (1%), atypical in 1 (1%), negative for malignancy in 81 (66%), and nondiagnostic in 4 (3%). No adverse events were reported. EUS FNA diagnosed metastasis with a sensitivity of 100%, specificity of 97.4%, positive predictive value of 91.7%, and negative predictive value of 100%. When compared to percutaneous biopsy, lesion size (1.8 cm vs. 3.7 cm; P<.001) and biopsy site (99% vs. 62% left adrenal; P<.001) were significantly different. EUS FNA adverse event rate was lower than percutaneous biopsy (0% vs. 4%; P = .024), but nondiagnostic rates were similar (3.3% vs. 4.8%; P = .48). CONCLUSION: EUS FNA is a sensitive technique to sample adrenal lesions in patients at high risk for adrenal metastasis with fewer adverse events compared to percutaneous biopsy. ABBREVIATIONS: CI = confidence interval CT = computed tomography EUS-FNA = endoscopic ultrasound-guided fine-needle aspiration NPV = negative predictive value PPV = positive predictive value TUS = transabdominal ultra-sound. PMID- 29144795 TI - RELATIONSHIP BETWEEN THE EFFECTIVENESS OF INORGANIC IODINE AND THE SEVERITY OF GRAVES THYROTOXICOSIS: A RETROSPECTIVE STUDY. AB - OBJECTIVE: Inorganic iodine is often used to treat patients with Graves thyrotoxicosis who do not tolerate thionamides due to adverse effects. However, predictors of continued inorganic iodine efficacy have not been fully elucidated. This study aimed to investigate the factors affecting the continued efficacy of potassium iodide (KI) in patients with Graves thyrotoxicosis. METHODS: In this study, among 1,197 patients with Graves disease who were initially treated with thionamides, we retrospectively studied 24 consecutive Japanese patients whose treatment was changed to KI alone due to the adverse effects of thionamides. We divided these patients into 2 groups: patients who had maintained euthyroid function for at least 180 days (nonrecurrence group, n = 11), and patients who had not maintained euthyroid function for 180 days (recurrence group, n = 13). RESULTS: Free triiodothyronine (FT3) and free thyroxine (FT4) levels on the day of changing from thionamides to KI were statistically higher in the recurrence group than in the nonrecurrence group (FT3, 9.3 [range, 5.2-11.6] vs. 3.7 [3.3 4.8] pg/mL, P = .02 and FT4, 3.6 [1.8-4.5] vs. 1.4 [1.2-1.9] ng/dL, P = .02). FT4 levels on the day of drug change were significantly higher in the recurrence group, even after adjusting for thionamide or KI dose. In the recurrence group, the duration of KI effect was inversed correlated with FT3 and FT4 levels on the day of drug change. CONCLUSION: Continued efficacy of KI after thionamides might be inversely correlated with thyrotoxicosis severity on the day of drug change. ABBREVIATIONS: ANOVA = analysis of variance eTV = estimated thyroid volume FT3 = free triiodothyronine FT4 = free thyroxine IQR = interquartile range KI = potassium iodide MMI = thiamazole PTU = propylthiouracil RAIT = radioactive iodine therapy TRAb = TSH receptor antibody TSH = thyroid stimulating hormone. PMID- 29144796 TI - VISUAL VIGNETTE. PMID- 29144797 TI - VISUAL VIGNETTE. PMID- 29144798 TI - PANCREAS METASTASES FROM PAPILLARY THYROID CARCINOMA: A REVIEW OF THE LITERATURE. AB - OBJECTIVE: Although locoregional metastases occur in 5 to 10% of patients with papillary thyroid cancer (PTC), distant metastases are rare, especially to the pancreas. Here we review the literature regarding metastases to the pancreas from PTC and present an illustrative patient. METHODS: The literature search was performed through using the PubMed database. The information regarding our illustrative case was obtained from the medical records of our institution. RESULTS: Since 1991, 11 cases of pancreas metastases of PTC have been reported. The average age at diagnosis was 55.3 years. There were 8 males and 3 females. Three had classic PTC histology, 2 had tall cell variant, and 2 had follicular variant. Four had T4 tumors, and 2 had T3 tumors. Seven had thyroid cancer spread to regional lymph nodes. One had distant metastasis. Pancreas metastases were diagnosed from 1 month to 13 years after primary PTC was detected; the average was 7 years. Our patient was an 84-year-old female diagnosed with PTC with a BRAFV600E mutation following total thyroidectomy. A whole-body scan after radioactive iodine (RAI) remnant ablation was negative for metastases. A pancreatic tumor was identified 2 years later on a fluorodeoxyglucose (FDG) positron emission tomography (PET) scan. A biopsy of the tumor was histologically similar to PTC and positive for thyroglobulin, thyroid transcription factor-1, and the BRAFV600E mutation. CONCLUSION: The biological reasons why PTCs metastasize to the pancreas remain to be elucidated. Older patients with non-RAI avid, FDG-PET-positive metastases, and symptoms of pancreatitis are at increased risk of this rare entity. ABBREVIATIONS: FDG = fluorodeoxyglucose FNA = fine-need aspiration PTC = papillary thyroid cancer RAI = radioactive iodine Tg = thyroglobulin TgAb = antithyroglobulin antibodies TNM = tumor-node-metastasis. PMID- 29144799 TI - PARATHYROID FUNCTION AFTER TOTAL THYROIDECTOMY: A RANDOMIZED CLINICAL TRIAL CONCERNING THE INFLUENCE OF THE SURGICAL TECHNIQUE. AB - OBJECTIVE: Thyroidectomy impairs parathyroid function, even if it does not necessarily lead to postoperative clinical hypocalcemia. This study was prospective and evaluated the parathyroid hormone (PTH) function in nonclinically symptomatic patients after total thyroidectomy performed by two different techniques. METHODS: Prospective randomized clinical trial including 269 patients undergoing classic or harmonic scalpel total thyroidectomy. Pre-operatively and at 48 hours, biochemical analysis was performed. Simultaneously, a sodium bicarbonate test (SBT) was performed. RESULTS: Calcium and PTH were altered for both groups ( P<.001). During SBT at 3 minutes after infusion, PTH rose and reached its maximum for both groups ( P<.001) and then decreased at 5 minutes ( P<.001 and P = .004) and at 10 minutes ( P = .006 and P = .043) before returning to baseline levels. At 5 and 10 minutes of the SBT, some differences were observed between the groups. The difference in clinically obvious parathyroid dysfunction between groups was not significant, but there was a difference in the peak PTH levels after bicarbonate stimulation. Similarly, total secretion during the test, as well as total secretion for the first 10 minutes, was practically the same for the two groups. Additionally, partial subclinical postoperative hypoparathyroidism was clearly more common in the harmonic scalpel thyroidectomy group ( P<.001). CONCLUSION: SBT demonstrated more impairment in the harmonic scalpel group, as parathyroid function was altered after thyroidectomy. ABBREVIATIONS: HSTT = harmonic scalpel total thyroidectomy PTH = parathyroid hormone SBIT = sodium bicarbonate infusion test. PMID- 29144800 TI - VISUAL VIGNETTE. PMID- 29144801 TI - UTILITY OF A SINGLE LATE-NIGHT PLASMA CORTISOL AND ACTH FOR THE DIAGNOSIS OF CUSHING SYNDROME. AB - OBJECTIVE: To evaluate the diagnostic efficacy of various screening tests for the diagnosis of Cushing syndrome (CS). METHODS: Thirty-five patients with CS and 16 patients of pseudo-CS were enrolled. Assessment of 24-h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), overnight dexamethasone suppression test (ONDST), late-night plasma cortisol (LNPC), and adrenocorticotropic hormone (ACTH) on outpatient basis, and during sleep as well as in awake state after 48 hours of hospital admission. RESULTS: We found that 24-h UFC performed the best among the screening tests with sensitivity, specificity and areas under the curve (AUCs) of 96.0%, 99%, and 0.988, respectively, at a cut-off of 144.6 MUg/24 h. A cut-off of 10.5 nmol/L for LNSC had sensitivity 85.7%, specificity 88.2%, and an AUC of 0.897. A cut-off of 412.4 nmol/L for LNPC on outpatient basis had sensitivity 88.2%, specificity 91.2%, and an AUC of 0.957. Cut-offs of 215 and 243.3 nmol/L for LNPC during sleep and awake states after acclimatization had sensitivity, specificity, and an AUC of 94.1%, 88.2%, and 0.958, respectively. An ONDST cut-off of 94.6 nmol/L provided sensitivity, specificity, and an AUC of 96.0%, 99.03% and 0.995, respectively. A cut-off of 30.3 pg/mL for late-night ACTH on outpatient basis had sensitivity 67.6%, specificity 99.9%, and an AUC 0.796.A cut-off of 22.6 pg/mL for ACTH during sleep state after acclimatization had sensitivity, specificity, and an AUC of 73.5%, 99.2%, and 0.827, respectively. CONCLUSION: UFC is the best screening test for CS. Furthermore, single measurements of LNPC and ACTH help to establish the diagnosis and ACTH dependency of CS in the majority of patients with CS. ABBREVIATIONS: ACTH = adrenocorticotropic hormone AUC = area under the curve CRH = corticotropin releasing hormone CS = Cushing syndrome ECLIA = electrochemiluminescence immuno assay LDDST = low-dose dexamethasone suppression test LNPC = late-night plasma cortisol LNSC = late-night salivary cortisol ONDST = overnight dexamethasone suppression test RIA = radio-immuno assay UFC = urinary free cortisol. PMID- 29144802 TI - LIPID ACCUMULATION PRODUCT, VISCERAL ADIPOSITY INDEX, AND CHINESE VISCERAL ADIPOSITY INDEX AS MARKERS OF CARDIOMETABOLIC RISK IN ADULT GROWTH HORMONE DEFICIENCY PATIENTS: A CROSS-SECTIONAL STUDY. AB - OBJECTIVE: Adult growth hormone deficiency (AGHD) is associated with cardiometabolic risk factors. Given that cardiovascular disease (CVD) is an important cause of morbidity and mortality in the AGHD population, there is a need for alternative, noninvasive methods of assessing cardiometabolic risk in this population. The Chinese visceral adiposity index (CVAI) is a new marker of visceral fat dysfunction based on age, body mass index (BMI), waist circumference (WC), and metabolic parameters. CVAI is well correlated with insulin resistance (IR) and is better at predicting metabolic syndrome (MS) than BMI and WC. This study aims to examine the reliability of the lipid accumulation product (LAP), visceral adiposity index (VAI), and CVAI as cardiometabolic risk markers in AGHD patients. METHODS: A total of 91 patients diagnosed with AGHD were divided into 4 groups according to CVAI quartile. We investigated the relationship between the patients' clinical and biochemical features, cardiometabolic risk assessed by cardiometabolic risk indices, the Framingham and atherosclerotic cardiovascular disease (ASCVD) risk scores, LAP, VAI, and CVAI. RESULTS: The CVAI scores of patients were significantly higher than those of control patients. Increased CVAI significantly correlated with higher BMI, WC, waist-hip ratio (WHR), and triglycerides (TG), Framingham risk score and atherosclerotic cardiovascular disease lifetime risk score ( P<=.001), with lower growth hormone (GH) and high density lipoprotein cholesterol (HDL-C) levels ( P<=.001). CONCLUSION: Our results suggest that CVAI may be a good marker of cardiometabolic risk in AGHD patients and could be used to diagnose CVD development and vascular accidents. ABBREVIATIONS: AGHD = adult growth hormone deficiency; ASCVD = atherosclerotic cardiovascular disease; AUROC = area under the receiver operating characteristic curve; BMI = body mass index; CVAI = Chinese visceral adiposity index; CVD = cardiovascular disease; DBP = diastolic blood pressure; GH = growth hormone; GHRT = GH replacement therapy; HDL-C = high-density lipoprotein cholesterol; IGF-1 = insulin like factor-1; IGFBP-3 = insulin like factor binding protein-3; IR = insulin resistance; LAP = lipid accumulation product; MS = metabolic syndrome; SBP = systolic blood pressure; TC = total cholesterol; TG = triglycerides; VAI = visceral adiposity index; WC = waist circumference; WHR = waist-to-hip ratio. PMID- 29144803 TI - ENDOCRINE MANIFESTATIONS OF PRIMARY HYPEROXALURIA. AB - OBJECTIVE: Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder of oxalate overproduction. It is associated with urolithiasis and nephrocalcinosis, which progress to end-stage renal disease and systemic oxalosis. As oxalate deposits in tissues, non-parathyroid hormone (nonPTH)-mediated hypercalcemia, oxalate osteopathy, primary hypothyroidism, and primary hypogonadism develop. In this review, we will present a case of PH1 and provide an overview of this clinical entity and its endocrine manifestations. METHODS: We conducted a PubMed search for articles related to PH1. The terms "primary hyperoxaluria," "nonPTH mediated hypercalcemia," "hypothyroidism," and "hypogonadism" were used to identify pertinent literature. RESULTS: Given the rarity of PH1, there is scant literature regarding the incidence and clinical significance of endocrine manifestations of this disorder. There are rare reports of hypercalcemia secondary to osteoclast-stimulating activity of macrophages in bone granulomas, which occur in response to oxalate deposits. We report that hypercalcemia may also be mediated by 1,25-dihydroxyvitamin D and PTH-related protein (PTHrP). Primary hypothyroidism and primary hypogonadism are thought to be due partly to calcium oxalate deposition in thyroid and testicular tissue. The presented case is the first to report PTHrP-mediated hypercalcemia and primary hypogonadism in a patient with PH1. CONCLUSION: PH1 is a metabolic disease with significant morbidity and mortality. Owing to its rarity, it is not widely recognized in the field of endocrinology, despite presenting with several endocrinopathies. Recognition of endocrine disturbances can result in early and successful treatment, limiting morbidity and improving quality of life in these challenging patients. ABBREVIATIONS: 1,25(OH)2D= 1,25-dihydoxyvitamin D AGT = alanine:glyoxylate aminotransferase ESRD = end-stage renal disease GRHPR = glyoxylate reductase-hydroxypyruvate reductase nonPTH = non-parathyroid hormone PH = primary hyperoxaluria pQCT = peripheral quantitative computed tomography PTH = parathyroid hormone PTHrP = parathyroid hormone-related protein T4 = thyroxine TSH = thyroid-stimulating hormone. PMID- 29144804 TI - THE IMPACT OF RESIDENT SENIORITY ON GUIDELINES ADHERENCE: A COMMENTARY ON DIABETES MANAGEMENT IN THE HOSPITAL. PMID- 29144805 TI - DPP4 INHIBITOR SITAGLIPTIN AS A POTENTIAL TREATMENT OPTION IN METFORMIN INTOLERANT OBESE WOMEN WITH POLYCYSTIC OVARY SYNDROME: A PILOT RANDOMIZED STUDY. AB - OBJECTIVE: Metformin has an established role in the management of polycystic ovary syndrome (PCOS). Some patients cannot tolerate it due to associated gastrointestinal adverse events. The present study evaluated the dipeptidyl peptidase 4 inhibitor sitagliptin as a potential treatment option in metformin intolerant PCOS. METHODS: We conducted a 12-week, prospective, randomized, open label study with 30 obese metformin-intolerant women with PCOS (age 35.0 +/- 7.2 years; body mass index, 36.9 +/- 5.5 kg/m2). After metformin withdrawal, they were randomized to lifestyle intervention and sitagliptin 100 mg daily (SITA) or lifestyle intervention alone as controls (CON). All participants underwent anthropometric and endocrine measurements and oral glucose tolerance testing. Model-derived indexes of insulin resistance and beta-cell function were calculated. RESULTS: SITA improved beta-cell function as assessed by the homeostasis model assessment for beta-cell function index (HOMA-B) of 45.9 +/- 35.8 ( P = .001), modified beta-cell function index (MBCI) of 7.9 +/- 7 ( P = .002), and quantitative insulin-sensitivity check index (QUICKI) of -0.03 +/- 0.03 ( P = .002). By contrast, beta-cell function decreased in CON. The between group differences were significant for HOMA-B ( P = 0.001), MBCI ( P = .010), and QUICKI ( P = .025). The conversion rate to impaired glucose homeostasis was prevented in SITA: 3 of 15 subjects had impaired glucose tolerance (IGT) before and after the study. In CON, none had type 2 diabetes (T2D), and 4 had IGT at the beginning. After 12 weeks, IGT was observed in 2 and T2D in 3 subjects. CONCLUSION: SITA improved beta-cell function and prevented a conversion to IGT and T2D in metformin-intolerant obese PCOS patients. ABBREVIATIONS: BMI = body mass index; DPP-4 = dipeptidyl peptidase-4; DXA = dual energy X-ray absorptiometry; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon like peptide-1; HOMA-B = homeostasis model assessment for beta-cell function; HOMA-IR = homeostasis model assessment of insulin resistance; IAI = insulin action index; IGT = impaired glucose tolerance; IR = insulin resistance; MBCI = modified beta-cell function index; OGTT = oral glucose tolerance test; QUICKI = quantitative insulin sensitivity check index; PCOS = polycystic ovary syndrome; SHBG = sex hormone-binding globulin; T2D = type 2 diabetes. PMID- 29144806 TI - DUMBBELL TUMOR WITH APOPLEXY. PMID- 29144807 TI - VISUAL VIGNETTE. PMID- 29144808 TI - OSTEOPOROTIC FRACTURES DURING BISPHOSPHONATE DRUG HOLIDAY. AB - OBJECTIVE: Bisphosphonate (BP) drug holidays are recommended to lower the risk of rare adverse events, such as atypical femoral fractures and osteonecrosis of the jaw. However, there are minimal data on the optimal duration of these holidays. Our aim was to determine the clinical and laboratory parameters associated with increased fracture risk in patients on BP drug holiday. METHODS: A retrospective chart review was conducted of 401 patients with osteopenia or osteoporosis who began a BP drug holiday from 2004 to 2013. Collected parameters included demographics, prior therapy, bone mineral density (BMD), bone turnover markers, parathyroid hormone, calcium & vitamin D status, and clinical reports of fractures. RESULTS: Sixty-two (15.4%) patients developed a fracture during follow up. The yearly incidence of fractures ranged from 3.7 to 9.9%, peaking at 9.9% and 9.8% during years 4 and 5, respectively. The mean age of the fracture group was higher than the nonfracture group, though not significantly different (69.24 +/- 12.26 years vs. 66.42 +/- 10.18 years; P = .09). Compared to the nonfracture group, the fracture group had lower femoral neck BMD (0.75 +/- 0.12 g/cm2 vs. 0.79 +/- 0.10 g/cm2; P = .03) and T-scores (-2.13 +/- 0.99 vs. -1.78 +/- 0.79; P = .01) at baseline. CONCLUSION: Patients who begin BP drug holidays at high risk of fracture based on BMD, age, or other clinical risk factors warrant close follow-up, especially as its duration lengthens. Fracture risk analysis needs to be regularly assessed during the drug holiday and treatment resumed accordingly. ABBREVIATIONS: 25-OHD = 25-hydroxyvitamin D AACE = American Association of Clinical Endocrinologists ACE = American College of Endocrinology BMD = bone mineral density BP = bisphosphonate BSAP = bone-specific alkaline phosphatase BTM = bone turnover marker FN = femoral neck LS = lumbar spine PTH = parathyroid hormone. PMID- 29144809 TI - PRESERVED PROINSULIN SECRETION IN LONG-STANDING TYPE 1 DIABETES. AB - OBJECTIVE: Recent literature has reported preserved residual beta-cell function (C-peptide "microsecretion") in many individuals with long-standing type 1 diabetes (T1D). However, the concentrations of detectable insulin/C-peptide in the serum are usually very low, and beta-cell mass is typically negligible. Proinsulin is measurable in the early years after diagnosis, consistent with the presence of residual functioning beta cells. However, individuals are not expected to secrete significant amounts of proinsulin beyond the early years after diagnosis. Our primary objective was to measure the prohormone, proinsulin, in a heterogeneous cohort of individuals with long-standing T1D. We also sought to assess whether proinsulin secretion might occur in certain individuals despite the absence of measurable C-peptide. METHODS: Random postmeal proinsulin concentrations were measured in 97 subjects with T1D (disease duration >3 years) recruited from within the T1D Exchange Clinic Network participants who took part in the Residual C-peptide Study. RESULTS: Forty-nine of these subjects had undetectable baseline and stimulated C-peptide (C-peptide [-]), and 48 of them had detectable C-peptide concentrations (C-peptide [+]). All the C-peptide (+) subjects had detectable serum proinsulin. Eight (16%) of the C-peptide (-) subjects had detectable serum proinsulin. CONCLUSION: We report the observation that proinsulin secretion persists in a proportion of individuals with long standing T1D, even in the absence of measurable C-peptide. It is not yet clear why certain patients with T1D retain the ability to secrete proinsulin many years after diagnosis. ABBREVIATIONS: CP = C-peptide CV = coefficient of variation ELISA = enzyme-linked immunosorbent assay IQR = inter-quartile range MMTT = mixed meal tolerance test NIBSC = National Institute for Biological Standards and Control PI = proinsulin T1D = type 1 diabetes. PMID- 29144810 TI - THE TIMING OF MEAL INSULIN ADMINISTRATION. PMID- 29144811 TI - CONCORDANCE OF PRE-OPERATIVE CLINICAL STAGE WITH PATHOLOGIC STAGE IN PATIENTS >=45 YEARS OLD WITH WELL-DIFFERENTIATED THYROID CANCER. AB - OBJECTIVE: Clinical stage (cStage) in thyroid cancer determines extent of surgical therapy and completeness of resection. Pathologic stage (pStage) is an important determinant of outcome. The rate of discordance between clinical and pathologic stage in thyroid cancer is unknown. METHODS: The National Cancer Data Base was queried to identify 27,473 patients >=45 years old with cStage I through IV differentiated thyroid cancer undergoing surgery from 2008-2012. RESULTS: There were 16,286 (59.3%) cStage I patients; 4,825 (17.6%) cStage II; 4,329 (15.8%) cStage III; and 2,013 (7.3%) cStage IV patients. The upstage rate was 15.1%, and the downstage rate was 4.6%. For cStage II, there was a 25.5% upstage rate. The change in cStage was a result of inaccurate T-category in 40.8%, N category in 36.3%, and both in 22.9%. On multivariate analysis, the patients more likely to be upstaged had papillary histology, tumors 2.1 to 4 cm, total thyroidectomy, nodal surgery, positive margins, or multifocal disease. Upstaged patients received radioiodine more frequently (75.3% vs. 48.1%; P<.001). CONCLUSION: Approximately 20% of cStage is discordant to pStage. Certain populations are at risk for inaccurate staging, including cT2 and cN0 patients. Upstaged patients are more likely to receive radioactive iodine therapy. ABBREVIATIONS: CI = confidence interval; cStage = clinical stage; DTC = differentiated thyroid cancer; NCDB = National Cancer Data Base; OR = odds ratio; pStage = pathologic stage; RAI = radioactive iodine. PMID- 29144812 TI - INCREASED BONE TURNOVER IN TYPE 2 DIABETES PATIENTS RANDOMIZED TO BARIATRIC SURGERY VERSUS MEDICAL THERAPY AT 5 YEARS. AB - OBJECTIVE: The aim of our study was to determine the 5-year outcomes of bariatric surgery versus intensive medical therapy on bone turnover in patients with type 2 diabetes mellitus (T2DM) from the STAMPEDE trial. METHODS: This was an ancillary investigation of a 5-year randomized control trial at a single tertiary care center involving 95 patients aged 48.5 +/- 8 years with obesity (body mass index [BMI], 36.5 +/- 3.6 kg/m2) and uncontrolled T2DM (glycated hemoglobin 9.3 +/- 1.6% [78 mmol/mol]). Patients were randomized to intensive medical therapy (IMT; n = 25), Roux-en-Y gastric bypass (RYGB; n = 37), or sleeve gastrectomy (SG; n = 33) for diabetes treatment. Bone formation marker osteocalcin (OC), bone resorption marker serum C-telopeptide of type 1 collagen (CTX), and intact parathyroid hormone (PTH) were assessed at baseline and 5 years postintervention. Analysis with key clinical parameters and outcomes (i.e., age, menopausal status, gender, weight loss) was performed. RESULTS: Percent change in CTX at 5 years increased in both surgical groups, by 137 +/- 108% in RYGB ( P<.001) and 61.1 +/- 90% in SG ( P<.001) compared to 29.8 +/- 93% in IMT ( P = .12). OC also increased from baseline in the surgical cohorts, by 138 +/- 19% in RYGB ( P<.001) and 71 +/ 69% in SG ( P<.001) compared to 43.8 +/- 121.1% in IMT ( P = .83). Increases in both CTX and OC correlated linearly with increases in PTH levels in RYGB patients ( P<.001). Increase in CTX correlated with decreased BMI in SG patients ( P = .039). CONCLUSION: In patients with T2DM, bone turnover remains chronically elevated at 5 years following RYGB, and to a lesser extent in SG patients. ABBREVIATIONS: BMI = body mass index; BTM = bone turnover marker; CTX = C telopeptide of type 1 collagen; HbA1c = glycated hemoglobin; IMT = intensive medical therapy; OC = osteocalcin; PPI = proton-pump inhibitor; PTH = parathyroid hormone; RYGB = Roux-en-Y gastric bypass; SG = sleeve gastrectomy; T2DM = type 2 diabetes mellitus; TZD = thiazolidinedione. PMID- 29144813 TI - DIAGNOSING AND MONITORING ENDOCRINE DYSFUNCTION, DIABETES, AND OBESITY IN A COHORT OF ADULT SURVIVORS OF CHILDHOOD CANCER. AB - OBJECTIVE: The 5-year survival rate for childhood cancer has increased to 80%, resulting in a growing population of adult survivors of childhood cancer (ASOCC). Long-term endocrine dysfunction is as high as 63% when screened in research protocols. The purpose of this study was to evaluate the prevalence of endocrine testing, endocrine dysfunction, diabetes, obesity, and endocrinologist visits outside of a research screening protocol. METHODS: A retrospective chart review was performed for 176 ASOCC who were diagnosed with cancer before age 18, followed at least 10 years, were now at least 18, and had survived to the time of chart review. RESULTS: After a mean follow-up of 15.2 years (range 10-21 years), 33.5% of ASOCC had endocrine dysfunction, excluding obesity and diabetes. These outcomes were more common in those with any radiation (64.8%, P<.0001) or cranial radiation (73.1%, P<.0001). Many subjects had never had certain endocrine tests. Over half (54.6%) of subjects were either overweight or obese. Glycated hemoglobin A1C (A1C) testing was rare, but when performed, 38.1% were abnormal. 71% of subjects had never seen an endocrinologist. Even among subjects with cranial radiation, 65.4% had either never seen an endocrinologist or had not seen one in the past 5 years. CONCLUSION: This cohort of ASOCC showed high rates of endocrine dysfunction, overweight or obesity, and diabetes in those who had been tested, combined with low rates of testing and endocrinology evaluation. Endocrinologists need to be aware of the endocrine risks in ASOCC, the need for long-term monitoring, and increase their collaboration with oncology. ABBREVIATIONS: A1C = glycated hemoglobin A1C ASOCC = adult survivors of childhood cancer BMI = body mass index COG = Children's Oncology Group EMR = electronic medical record FSH = follicle-stimulating hormone IGF-1 = insulin-like growth factor 1 LH = luteinizing hormone TSH = thyroid-stimulating hormone. PMID- 29144814 TI - SELF BLOOD GLUCOSE MONITORING UNDERESTIMATES HYPERGLYCEMIA AND HYPOGLYCEMIA AS COMPARED TO CONTINUOUS GLUCOSE MONITORING IN TYPE 1 AND TYPE 2 DIABETES. AB - OBJECTIVE: When glucose records from self blood glucose monitoring (SBGM) do not reflect estimated average glucose from glycosylated hemoglobin (HgBA1) or when patients' clinical symptoms are not explained by their SBGM records, clinical management of diabetes becomes a challenge. Our objective was to determine the magnitude of differences in glucose values reported by SBGM versus those documented by continuous glucose monitoring (CGM). METHODS: The CGM was conducted by a clinical diabetes educator (CDE)/registered nurse by the clinic protocol, using the Medtronic iPRO2TM system. Patients continued SBGM and managed their diabetes without any change. Data from 4 full days were obtained, and relevant clinical information was recorded. De-identified data sets were provided to the investigators. RESULTS: Data from 61 patients, 27 with type 1 diabetes (T1DM) and 34 with T2DM were analyzed. The lowest, highest, and average glucose recorded by SBGM were compared to the corresponding values from CGM. The lowest glucose values reported by SBGM were approximately 25 mg/dL higher in both T1DM ( P = .0232) and T2DM ( P = .0003). The highest glucose values by SBGM were approximately 30 mg/dL lower in T1DM ( P = .0005) and 55 mg/dL lower in T2DM ( P<.0001). HgBA1c correlated with the highest and average glucose by SBGM and CGM. The lowest glucose values were seen most frequently during sleep and before breakfast; the highest were seen during the evening and postprandially. CONCLUSION: SBGM accurately estimates the average glucose but underestimates glucose excursions. CGM uncovers glucose patterns that common SBGM patterns cannot. ABBREVIATIONS: CDE = certified diabetes educator; CGM = continuous glucose monitoring; HgBA1c = glycosylated hemoglobin; MAD = mean absolute difference; SBGM = self blood glucose monitoring; T1DM = type 1 diabetes; T2DM = type 2 diabetes. PMID- 29144815 TI - VISUAL VIGNETTE. PMID- 29144816 TI - VISUAL VIGNETTE. PMID- 29144817 TI - SEASONAL VARIATION OF VITAMIN D AND SERUM THYROTROPIN LEVELS AND ITS RELATIONSHIP IN A EUTHYROID CAUCASIAN POPULATION. AB - OBJECTIVE: It is unclear whether seasonal variations in vitamin D concentrations affect the hypothalamo-pituitary-thyroid axis. We investigated the seasonal variability of vitamin D and serum thyrotropin (TSH) levels and their interrelationship. METHODS: Analysis of 401 patients referred with nonspecific symptoms of tiredness who had simultaneous measurements of 25-hydroxyvitamin D3 (25[OH]D3) and thyroid function. Patients were categorized according to the season of blood sampling and their vitamin D status. RESULTS: 25(OH)D3 levels were higher in spring-summer season compared to autumn-winter (47.9 +/- 22.2 nmol/L vs. 42.8 +/- 21.8 nmol/L; P = .02). Higher median (interquartile range) TSH levels were found in autumn-winter (1.9 [1.2] mU/L vs. 1.8 [1.1] mU/L; P = .10). Across different seasons, 25(OH)D3 levels were observed to be higher in lower quartiles of TSH, and the inverse relationship was maintained uniformly in the higher quartiles of TSH. An independent inverse relationship could be established between 25(OH)D3 levels and TSH by regression analysis across both season groups (autumn-winter: r = -0.0248; P<.00001 and spring-summer: r = 0.0209; P<.00001). We also observed that TSH varied according to 25(OH)D3 status, with higher TSH found in patients with vitamin D insufficiency or deficiency in comparison to patients who had sufficient or optimal levels across different seasons. CONCLUSION: Our study shows seasonal variability in 25(OH)D3 production and TSH secretion in euthyroid subjects and that an inverse relationship exists between them. Further studies are needed to see if vitamin D replacement would be beneficial in patients with borderline thyroid function abnormalities. ABBREVIATIONS: 25(OH)D2 = 25-hydroxyvitamin D2; 25(OH)D3 = 25-hydroxyvitamin D3; AITD = autoimmune thyroid disease; FT4 = free thyroxine; TFT = thyroid function test; TSH = thyrotropin; UVB = ultraviolet B. PMID- 29144818 TI - CLINICAL IMPLICATIONS OF POSTOPERATIVE UPSTAGING OF DIFFERENTIATED THYROID CANCER BASED UPON PATHOLOGIC EVALUATION. PMID- 29144819 TI - VISUAL VIGNETTE. PMID- 29144820 TI - PHEOCHROMOCYTOMA: A GENETIC AND DIAGNOSTIC UPDATE. AB - OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathologic studies are performed to prove, localize, treat, and monitor disease progression. Improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (<1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment. METHODS: This review outlines the most updated approach to PPGL patients and presents a new diagnostic protocol for physicians to increase earlier tumor identification and accurately assess metastatic behavior. CONCLUSION: We present the most recent advances in genetics, epigenetics, metabolomics, biochemical, and imaging diagnoses of this rare tumor to properly assess disease, decide treatment options, and manage follow-up. We also elaborate on new therapeutic perspectives in these very rare neoplastic entities. ABBREVIATIONS: ATRX = ATRX chromatin remodeler; ccRCC = clear cell renal cell carcinoma; c-MYC = MYC proto oncognene; CT = computed tomography; DOTATATE = DOTA-octreotate; EGLN1/2 = egl-9 family hypoxia inducible factor 1/2; EGLN2/PHD1 = egl-9 family hypoxia inducible factor 2; EPAS1/HIF2A = endothelial PAS domain protein 2/hypoxia-inducible factor 2alpha; ERK = extracellular signal regulated kinase; HIFs = hypoxia-inducible factors; HIF-alpha = hypoxia-inducible factor alpha; HNPGLs = head and neck paragangliomas; 177Lu-DOTATATE = lutetium octreotate; MAX = myc-associated factor X; MDH2 = malate dehydrogenase; MIBG = metaiodobenzylguanidine; MN = metanephrine; MRI = magnetic resonance imaging; mTOR = mammalian target of rapamycin; NETs = neuroendocrine tumors; NF1 = neurofibromin 1; NMN = normetanephrine; PHD = prolyl hydroxylase domain protein; PI3K = phosphoinositide 3-kinase; PPGLs = pheochromocytoma and paragangliomas; PRRT = peptide receptor radionuclide therapy; Pvhl = von Hippel-Lindau protein; RAS = rat sarcoma oncogene; RET = rearranged during transfection proto-oncogene; SDH = succinate dehydrogenase; SDHA, -B, -C, -D = succinate dehydrogenase subunits A, B, C, D; SDHAF2 = succinate dehydrogenase complex assembly factor 2; SDHB, C, D = succinate dehydrogenase subunits B, C, D; SDHx = succinate dehydrogenase subunits; SSTRs = somatostatin receptors; VHL = von Hippel-Lindau. PMID- 29144821 TI - PYRAMIDAL LOBE REMNANT. PMID- 29144822 TI - TESTOSTERONE LEVELS ACHIEVED BY MEDICALLY TREATED TRANSGENDER WOMEN IN A UNITED STATES ENDOCRINOLOGY CLINIC COHORT. AB - OBJECTIVE: Most transgender women depend on medical treatment alone to lower testosterone levels in order to align physical appearance with gender identity. The medical regimen in the United States typically includes spironolactone and estrogens. The purpose of this cross-sectional study was to assess the testosterone suppression achieved among transgender women treated with spironolactone and estrogens. METHODS: Testosterone and estradiol levels were extracted from the electronic medical records of 98 anonymized transgender women treated with oral spironolactone and oral estrogen therapy at the Endocrinology Clinic at Boston Medical Center. RESULTS: Patients starting therapy required about 9 months to reach a steady-state testosterone, with significant heterogeneity of levels achieved among patients. Patients with normal body mass index (BMI) had higher testosterone levels, whereas patients with obese BMI had lower testosterone levels throughout treatment. Stratification of patients by age or spironolactone dosage revealed no significant difference in testosterone levels achieved. At steady state, patients in the highest suppressing quartile were able to achieve testosterone levels of 27 ng/dL, with a standard deviation of 21 ng/dL. Measured serum estradiol levels did not change over time and did not correlate with dosage of estradiol administered. CONCLUSION: Among a cohort of transgender women treated with spironolactone and estrogen, the highest suppressing quartile could reliably achieve testosterone levels in the female range at virtually all times. The second highest suppressing quartile could not achieve female levels but remained below the male range virtually all of the time. One quartile was unable to achieve any significant suppression. ABBREVIATIONS: BMC = Boston Medical Center BMI = body mass index CPY = cyproterone acetate LC-MS/MS = liquid chromatography-tandem mass spectrometry Q = quartile. PMID- 29144823 TI - THE RELATIONSHIP OF BRAFV600E MUTATION STATUS TO FDG PET/CT AVIDITY IN THYROID CANCER: A REVIEW AND META-ANALYSIS. AB - OBJECTIVE: Papillary thyroid cancer (PTC) harboring a BRAFV600E gene mutation has been shown to exhibit aggressive tumor behavior and carries higher risks of recurrence and disease-specific death. In this systematic review and meta analysis, we examined published evidence related to the accuracy of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in detection of residual disease in patients with BRAFV600E mutated thyroid cancer. METHODS: We extracted data from PUBMED/MEDLINE and EMBASE published between January 1995 and March 2017. We included studies that compared FDG PET standardized uptake values (SUVs) between BRAFV600E-positive and BRAFV600E negative subjects, as well as those that evaluated the odds of having FDG avidity between BRAFV600E-positive and -negative patients with thyroid cancer. RESULTS: There were a total of 12 studies in the systematic review. Seven studies qualified for the analysis for calculating the pooled odds ratio (OR). The pooled cohort with binary data had 1,144 patients out of which 843 were BRAFV600E positive and 301 were BRAFV600E negative. Those with a BRAFV600E mutation had a significantly greater likelihood of having FDG-avid lesions. The pooled OR was 2.12 (confidence interval [CI] 1.53-3.00, P<.01). The pooled mean SUV (cohort of 315 patients) was significantly higher in BRAFV600E-positive compared to BRAFV600E negative patients, with a pooled mean difference of 5.1 (CI 4.3-5.8). CONCLUSION: Our meta-analysis shows that presence of BRAFV600E mutation in PTC confers a higher likelihood of FDG PET avidity and is associated with higher SUV uptake values compared to BRAFV600E-mutation negative status. ABBREVIATIONS: BRAF = B-Raf proto-oncogene, serine/threonine kinase; CI = confidence interval; CT = computed tomography; DTC = differentiated thyroid cancer; FDG = fluorodeoxyglucose; PET = positron emission tomography; PTC = papillary thyroid cancer; SUV = standardized uptake value. PMID- 29144824 TI - 17alpha-HYDROXYLASE DEFICIENCY IS AN UNDERDIAGNOSED DISEASE: HIGH FREQUENCY OF MISDIAGNOSES IN A LARGE COHORT OF BRAZILIAN PATIENTS. AB - OBJECTIVE: 17alpha-Hydroxylase deficiency (P450c17D) is characterized by hypogonadism and mineralocorticoid hypertension. We aimed to estimate the relative incidence and spectrum of preliminary misdiagnoses in Brazilian P450c17D patients. METHODS: In this cross-sectional study, we reviewed, updated, and analyzed data of 40 P450c17D patients (21 XY, 19 XX). RESULTS: Complete data were unavailable for 2 patients. Seven patients were relatives of an index case. Of the 31 index cases, 29 (94%) received a total of 16 misdiagnoses (1-4 per patient) before confirmation of P450c17D. Essential hypertension (55%), pure gonadal dysgenesis (35%), and androgen resistance syndrome (21%) were the most frequent misdiagnoses. Median ages at initial and final diagnosis were 13.2 and 16.5 years, respectively, with an average interval to diagnosis of 3.2 years. Initially, 38 (95%) patients had hypertension, and 75% had hypokalemia. Primary amenorrhea and sexual infantilism were present in 95% patients, and 73% were at Tanner stage I. All had low-to-undetectable estrogens and androgens with elevated gonadotropins and progesterone (580 +/- 53 ng/dL). Several had recurrent infections in childhood and neurological issues prior to final diagnosis and/or had siblings who died of infectious diseases or unknown causes before puberty. CONCLUSION: The high percentage of prior misdiagnoses in P450c17D patients may be attributable to the rarity of and relative unfamiliarity with the disease, its varied clinical presentation, and the limited access to critical steroid dosages and genotyping. Reduced sex steroids, and elevated gonadotropins and progesterone levels, in addition to mineralocorticoid hypertension, are pathognomonic of P450c17D. CYP17A1 gene mutations provide a definitive diagnosis. ABBREVIATIONS: ACTH = adrenocorticotropic hormone CAH = congenital adrenal hyperplasia CYP17A1 = 17alpha-hydroxylase enzyme DOC = deoxycorticosterone HH = hypergonadotropic hypogonadism P450c17D = 17alpha-hydroxylase deficiency TS = Tanner stage. PMID- 29144826 TI - Cataract Surgery in Patients with Diabetes: Management Strategies. AB - Diabetes is a chronic systemic disease that affects nearly one in eight adults worldwide. Ocular complications, such as cataract, can lead to significant visual impairment. Among the worldwide population, cataract is the leading cause of blindness, and patients with diabetes have an increased incidence of cataracts which mature earlier compared to the rest of the population. Cataract surgery is a common and safe procedure, but can be associated with vision-threatening complications in the diabetic population, such as diabetic macular edema, postoperative macular edema, diabetic retinopathy progression, and posterior capsular opacification. This article is a brief review of diabetic cataract and complications associated with cataract extraction in this population of patients. PMID- 29144827 TI - Management of Delayed Suprachoroidal Hemorrhage after Glaucoma Surgery. AB - PURPOSE: To review the most current treatment recommendations and outcomes for delayed suprachoroidal hemorrhages. METHODS: Article review of management and outcomes of suprachoroidal hemorrhages, with emphasis on delayed suprachoroidal hemorrhages in the setting of glaucoma surgery. CONCLUSION: Time of drainage of suprachoroidal hemorrhages remains controversial. Earlier drainage should be considered with high intraocular pressure, expulsion of intraocular content, or retinal detachment. In clinically stable eyes with suprachoroidal hemorrhage, recommendations range from observation to immediate drainage. Clot lysis occurs at roughly 14 days. PMID- 29144828 TI - Prognostic impact of CD200 and CD56 expression in pediatric B-cell acute lymphoblastic leukemia patients. AB - This study aimed to determine the prognostic impact of CD200 and CD56 expression in pediatric B cell acute lymphoblastic leukemia (B-ALL) patients, both of which have been implicated in immune tolerance and previously suggested as independent risk factors. CD200 has a central role in immune tolerance that protects stem cells and other critical tissues from immune damage. The expression of CD200/CD56 in leukemic blasts were assessed in leukemic blasts before chemotherapy in 43 bone marrow (BM) and/or peripheral blood (PB) samples by flow cytometry. Twenty eight of 43 B-ALL cases (65%) showed CD200 positive expression, 5 of 43 cases (11.6%) showed CD56 expression, and only 2 patients (4.7%) expressed both CD200 and CD56. Patients with CD200+ and CD56+ were significantly associated with lower platelet count; less tendency for induction of remission response as compared to negative ones (p = .01 for both). The overall survival (OS) and DFS were significantly shorter in CD200+ and CD56+ cases as compared to those with CD200- and CD56- expression. In conclusion, CD200 and/or CD56 positive expression in B ALL at diagnosis suggest a poor prognosis and may be associated with biological aggressiveness. PMID- 29144825 TI - Salt, Hypertension, and Immunity. AB - The link between inappropriate salt retention in the kidney and hypertension is well recognized. However, growing evidence suggests that the immune system can play surprising roles in sodium homeostasis, such that the study of inflammatory cells and their secreted effectors has provided important insights into salt sensitivity. As part of the innate immune system, myeloid cells have diverse roles in blood pressure regulation, ranging from prohypertensive actions in the kidney, vasculature, and brain, to effects in the skin that attenuate blood pressure elevation. In parallel, T lymphocyte subsets, as key constituents of the adaptive immune compartment, have variable effects on renal sodium handling and the hypertensive response, accruing from the functions of the cytokines that they produce. Conversely, salt can directly modulate the phenotypes of myeloid and T cells, illustrating bidirectional regulatory mechanisms through which sodium and the immune system coordinately impact blood pressure. This review details the complex interplay between myeloid cells, T cells, and salt in the pathogenesis of essential hypertension. PMID- 29144829 TI - Complications Assoicated with MIRAgel for Treatment of Retinal Detachment. AB - MIRAgel (MIRA, Waltham, MA) is a hydrogel buckle that was introduced in 1979 as a new scleral implant for the treatment of retinal detachment. Long-term follow-up of more than 10 years revealed that the hydrolysis of the synthetic hydrophilic material leads to marked expansion of the substance, causing complications such as buckle extrusion and intrusion, eye motility disorder, cosmetic deformities, and periocular infections. Removal of the implant is the treatment of choice in cases with complications, but it is technically difficult due to the friability of the implant, severe scleral ectasia, and relatively high rate of redetachment after removal. PMID- 29144830 TI - Looking towards the horizon: changing landscapes and a shift to a more equitable future for children, young people and their families. PMID- 29144832 TI - Postoperative Complications of Dermis-Fat Autografts in the Anophthalmic Socket. AB - Reconstruction of the anophthalmic socket allows the use of an ocular prosthesis and rehabilitation of facial appearance. Dermis-fat grafting is one option in volume augmentation of the anophthalmic socket and presents unique benefits, including increased surface area within the socket and the ability to grow with pediatric patients. Postoperative complications of this procedure are relatively common. Minor complications, such as graft hirsutism, keratinization, and conjunctival cysts or granulomas, are managed easily by observation or simple intervention. Major complications, such as graft atrophy, infection, or ulceration, may prevent good prosthesis fit and may require return to the operating room. PMID- 29144831 TI - Attention Deficit Hyperactivity Disorder: Unique Considerations in Athletes. AB - CONTEXT: Attention deficit hyperactivity disorder (ADHD) is a common psychiatric condition in the general population, with evidence suggesting that it may be more common among athletes. EVIDENCE ACQUISITION: Literature searches were performed on PubMed, MEDLINE, and Cochrane databases for the years 2000 to 2016 utilizing the following key search terms: ADHD, ADD, guidelines, diagnosis, athlete, sports, treatment, pharmacotherapy, stimulants, risk, cardiovascular effects, concussion, and traumatic brain injury (TBI). STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: ADHD exists among athletes at all levels of play, and symptomatology overlaps significantly with that of concussion. Treatment with stimulants has cardiovascular effects and may not be permitted by the athlete's governing body. An athlete's level of competition and individual cardiovascular risk factors may therefore affect medication choices. CONCLUSION: ADHD diagnosis and treatment are paramount to optimal quality of life and functioning in affected individuals. Pharmacologic treatment options should not specifically be avoided in athletes; however, stimulant use is an independent risk factor for heat illness. Concussion, a common athletic injury, may have an altered course in those affected by ADHD, specifically with regard to neurocognitive testing and recovery. PMID- 29144835 TI - Modern Systemic Therapy for Metastatic Renal Cell Carcinoma of the Clear Cell Type. AB - In the last 30 years, there have been many advances in the treatment of metastatic renal cell carcinoma of the clear cell type. Renal cell carcinoma has long been understood to have a component of immune mediation and has been responsive to immune-based therapies; in addition to early cytokine therapy, newer checkpoint inhibition therapies have also demonstrated activity. Molecular characterization of the genome of clear cell renal cell carcinoma enabled identification of the roles of angiogenesis and hypoxic stress. This led to development of small-molecule tyrosine kinase inhibitors and inhibitors of mammalian target of rapamycin that have provided additional benefit to patients. Ongoing strategies of combinations of immune and antiangiogenic therapies may lead to further advancements. PMID- 29144834 TI - Clinicopathological and immunohistochemical description of an intrapelvic hepatoid gland carcinoma in a 14-year-old Teckel dog. PMID- 29144833 TI - Low dietary fiber intake increases Collinsella abundance in the gut microbiota of overweight and obese pregnant women. AB - : The gut microbiota contributes to the regulation of glucose metabolism in pregnancy. Abundance of the genus Collinsella is positively correlated with circulating insulin; however, it is unclear what determines Collinsella abundance. This study aims to validate the correlation between Collinsella and insulin and to elucidate if macronutrient intake alters Collinsella abundance and gut microbiota composition. Gut microbiota profiles were assessed by 16S rRNA sequencing in 57 overweight and 73 obese pregnant women from the SPRING (Study of PRobiotics IN Gestational diabetes) trial at 16 weeks gestation and correlated with metabolic hormone levels and macronutrient intake. Gut microbiota composition in the top and bottom 10% of dietary fiber intake was evaluated through network analysis. Collinsella abundance correlated positively with circulating insulin (rho = 0.30, p = 0.0006), independent of maternal BMI, but negatively with dietary fiber intake (rho = -0.20, p = 0.025) in this cohort. Low dietary fiber intake was associated with a gut microbiota favoring lactate fermentation while high fiber intake promotes short-chain fatty acid-producing bacteria. Low dietary fiber may enable overgrowth of Collinsella and alter the overall fermentation pattern in gut microbiota. This suggests that dietary choices during pregnancy can modify the nutritional ecology of the gut microbiota, with potential deleterious effects on the metabolic and inflammatory health of the host. TRIAL REGISTRATION: ANZCTR 12611001208998, registered 23/11/2011. PMID- 29144836 TI - Autophagy and Inflammation. AB - The cellular degradative pathway of autophagy has a fundamental role in immunity. Here, we review the function of autophagy and autophagy proteins in inflammation. We discuss how the autophagy machinery controls the burden of infectious agents while simultaneously limiting inflammatory pathologies, which often involves processes that are distinct from conventional autophagy. Among the newly emerging processes we describe are LC3-associated phagocytosis and targeting by autophagy proteins, both of which require many of the same proteins that mediate conventional autophagy. We also discuss how autophagy contributes to differentiation of myeloid and lymphoid cell types, coordinates multicellular immunity, and facilitates memory responses. Together, these functions establish an intimate link between autophagy, mucosal immunity, and chronic inflammatory diseases. Finally, we offer our perspective on current challenges and barriers to translation. PMID- 29144837 TI - Evolution of Alternative Adaptive Immune Systems in Vertebrates. AB - Adaptive immunity in jawless fishes is based on antigen recognition by three types of variable lymphocyte receptors (VLRs) composed of variable leucine-rich repeats, which are differentially expressed by two T-like lymphocyte lineages and one B-like lymphocyte lineage. The T-like cells express either VLRAs or VLRCs of yet undefined antigen specificity, whereas the VLRB antibodies secreted by B-like cells bind proteinaceous and carbohydrate antigens. The incomplete VLR germline genes are assembled into functional units by a gene conversion-like mechanism that employs flanking variable leucine-rich repeat sequences as templates in association with lineage-specific expression of cytidine deaminases. B-like cells develop in the hematopoietic typhlosole and kidneys, whereas T-like cells develop in the thymoid, a thymus-equivalent region at the gill fold tips. Thus, the dichotomy between T-like and B-like cells and the presence of dedicated lymphopoietic tissues emerge as ancestral vertebrate features, whereas the somatic diversification of structurally distinct antigen receptor genes evolved independently in jawless and jawed vertebrates. PMID- 29144838 TI - Human T Cell Leukemia Virus Type 1: Persistence and Pathogenesis. AB - Human T cell leukemia virus type 1 (HTLV-1), also known as human T lymphotropic virus type 1, was the first exogenous human retrovirus discovered. Unlike the distantly related lentivirus HIV-1, HTLV-1 causes disease in only 5-10% of infected people, depending on their ethnic origin. But whereas HIV-1 infection and the consequent diseases can be efficiently contained in most cases by antiretroviral drug treatment, there is no satisfactory treatment for the malignant or inflammatory diseases caused by HTLV-1. The purpose of the present article is to review recent advances in the understanding of the mechanisms by which the virus persists in vivo and causes disabling or fatal diseases. PMID- 29144839 TI - Distinguishing Benign from Malignant Circumscribed Orbital Tumors in Children. AB - An orbital neoplasm in children is an uncommon clinical finding. Clinical suspicion should be based on many factors, including its location, the nature of onset, associated systemic signs and symptoms, family and social histories, examination findings, and radiographic characteristics. We present two cases of young children of similar age with a rapid-onset orbital mass. In both cases, a circumscribed round lesion was found in the superomedial orbit. An orbital schwannoma, a benign and usually slow growing tumor, was found in the first patient. In contrast, the biopsy of the second patient, who was nearly asymptomatic, revealed a rhabdomyosarcoma. In this review, we have explored the differential diagnosis of relatively common circumscribed round orbital tumors in the pediatric population from both the radiographic (magnetic resonance imaging, MRI) and histopathologic perspectives. A review of highly unusual orbital tumors in children is also provided. PMID- 29144840 TI - Feasibility of Using the General Movements Assessment of Infants in the United States. AB - AIMS: To pilot the practicality of administering the Prechtl General Movements Assessment of infants (GMA) in the Neonatal Intensive Care Unit (NICU) setting and at home to infants at risk for developing cerebral palsy (CP). Additional aims included assessing inter-rater reliability and comparing GMA predictions to AIMS motor assessment at 12 months. METHODS: 12 "at risk" infants were recruited by convenience sample. Video recordings were obtained in the NICU and provided by parents after discharge. These recordings were analyzed by two trained examiners to assess infants in the writhing and fidgety movement periods (birth to 16 weeks). Infants were assessed at 12 months corrected age using the Alberta Infant Motor Scale (AIMS) with scores lower than 5th centile considered a motor delay. RESULTS: 33 of 42 videos (79%) were of sufficient quality to permit interpretation and there was 97% inter-examiner subcategory agreement and 100% overall developmental trajectory (abnormal/normal) agreement. The GMA demonstrated a sensitivity of 60% and a specificity of 100% in predicting AIMS score (age appropriate or delayed). CONCLUSIONS: Clinical feasibility of GMA obtained in the NICU was demonstrated however feasibility of parents providing video samples after discharge was not demonstrated, indicating a need for a parent-friendly method. PMID- 29144844 TI - Corrigendum. PMID- 29144843 TI - Brevicollum, a new genus in Neohendersoniaceae, Pleosporales. AB - A new genus, Brevicollum, is established for two new species, B. hyalosporum on Syzygium samarangense and B. versicolor on Volkameria inermis, in Japan. This genus is characterized by the presence of immersed ascomata with an excentric to central, short cylindrical ostiolar neck, thin ascomatal wall, clavate asci with a shallow ocular chamber, and broadly fusiform, hyaline to pale brown ascospores with a sheath. Molecular phylogenetic analyses based on a combined data set of sequences of 18S and 28S nuc rDNA genes and the second largest subunit of RNA polymerase II (RPB2) revealed that Brevicollum is a member of Neohendersoniaceae (Pleosporales, Dothideomycetes). The genera Brevicollum, Crassiparies, Medicopsis, and Neohendersonia are accepted in Neohendersoniaceae. Revised descriptions of Crassiparies and its type species, C. quadrisporus, are provided based on the holotype and a newly obtained specimen and isolate. An asexual morph of C. quadrisporus is reported for the first time. The nuc rDNA internal transcribed spacer (ITS1-5.8S-ITS2 = ITS) phylogenetic tree of the newly collected species (B. hyalosporum, B. versicolor, and C. quadrisporus), and the unnamed or provisionally identified endophytic species, suggests a broader distribution of Brevicollum and Crassiparies species. PMID- 29144842 TI - A novel fiber chimeric conditionally replicative adenovirus-Ad5/F35 for tumor therapy. AB - Significant progress has been made in the diagnosis and treatment of cancer; however, significant challenges remain. Conditionally replicating adenoviruses (CRAds), which not only kill cancer cells, but also serve as vectors to express therapeutic genes, are a novel and effective method to treat cancer. However, most adenoviruses are Ad5, which infect cells through the coxsackie and adenovirus receptor (CAR). The transduction efficacy of Ad5 is restricted because of the absent or low expression of CAR on several cancer cells. Ad serotype 35 has a different tropism pattern to Ad5. Ad35 attaches to cells via a non-CAR receptor, CD46, which is expressed widely on most tumor cells. Thus, chimeric adenoviral vectors consisting of the knob and shaft of Ad35 combined with Ad5 have been constructed. The chimeric fiber adenoviral vectors can transduce CAR positive and CAR-negative cell lines. In this review, we explore the application of the novel fiber chimeric conditionally replicative adenovirus-Ad5/F35 in tumor therapy in terms of safety, mechanism, transduction efficacy, and antitumor effect. PMID- 29144845 TI - Birdshot Chorioretinopathy. PMID- 29144846 TI - Anticoagulation in Glaucoma Surgery. AB - Anticoagulation medications are used commonly, particularly in an elderly population. There are many systemic diseases and scenarios that require modulation of coagulation to prevent serious adverse outcomes. While there is some consensus about their use in cataract surgery, there is less certainty about their management with glaucoma surgery. Glaucoma surgery presents a unique challenge when considering anticoagulation. Currently, there is great diversity in surgeon practices regarding anticoagulation in glaucoma surgery. Based on available evidence, it is unclear whether it is beneficial to hold anticoagulation, with or without bridging therapy, leading up to a planned surgery. Considering the potential serious adverse outcomes related to holding anticoagulation therapy, altering these medications for glaucoma surgery should be done sparingly and in consultation with the primary prescriber of such medications. PMID- 29144847 TI - Explaining the Sexuality Gap in Protest Participation. AB - This study investigated the relationship between sexual orientations and the protest actions of adults in the United States. Drawing from General Social Survey data from 1996 to 2004, we found that lesbians, gays, and bisexuals were more than twice as likely to protest as heterosexuals. To account for this sexuality gap, we used Patrick Egan's (2008) political distinctiveness theories to identify possible underlying causes of these protesting differences. After running several regressions, we found that sexuality and protesting relationships were moderated by issues of educational attainment, marital statuses, metropolitan residencies, political partisanships, governmental grievances, and gender role expectations. PMID- 29144848 TI - Watching the Evolution of the American Family? Amazon's Transparent, Ecological Systems Theory, and the Changing Dynamics of Public Opinion. AB - Using Bronfenbrenner's (1979) ecological systems theory as an organizing framework, the research closely examines the text of the Amazon Studios hit show Transparent and, by extension, the evolution of public opinion toward transgender individuals. By examining the Pfefferman family in detail and their related microsystem and macrosystem, we are able to closely unpack the transition of Jeffrey Tambor's character from Mort to Maura and the show's connections with broader developments in the Los Angeles LGBT community and the Jewish diaspora in postwar and contemporary Los Angeles. In addition, by focusing on the influence of the chronosystem, we are able to examine how both opinions toward Maura and public opinion toward transgender issues more generally have evolved within the family system and the larger American community over time. PMID- 29144850 TI - Clinical Factors Negatively Impacting Sexual Relationships in Men With Peyronie's Disease. AB - Here, we sought to identify clinical factors associated with a negative impact on the relationships patients with Peyronie's disease (PD) have with their partners. During initial consultation, a detailed sexual questionnaire was administered, which included a question on whether or not PD negatively impacted the current sexual relationship. More than half (146/242; 60.3%) of patients reported that PD negatively impacted their sexual relationship. On multivariate analysis, penile shortening, partner pain with intercourse, and shorter relationship duration were associated with a negative relationship effect. We did not identify significant differences in negative relationship effects based on objective physical examination findings including penile curvature, calcification, hourglass deformity, or penile length. PMID- 29144851 TI - The prejudice against asylum seekers scale: presenting the psychometric properties of a new measure of classical and conditional attitudes. AB - This paper reports the initial psychometric properties for the recently developed prejudice against asylum seekers scale (PAAS)-a new measure of the classical and conditional components of negative attitudes towards asylum seekers. Across three studies the initial psychometric evidence is presented: An exploratory factor analysis suggested that the 16 items of the PAAS accurately factor onto the two hypothesized subscales (Study 1), which was ratified using a confirmatory factor analysis (Study 2). The presented reliability estimates (internal consistency: Studies 1-3; test-retest reliability: Study 3) verified the stability of the measure. Finally, evidence of the validity for the scale (criterion, construct, and known-groups; Study 2) and for the independent predictive validity of each subscale is presented. In summary, the evidence presented here suggests that the PAAS is a psychometrically sound measure of classical and contemporary prejudice against asylum seekers. PMID- 29144852 TI - "Not a Real Family": Microaggressions Directed toward LGBTQ Families. AB - The present study investigates microaggressions toward individuals in lesbian, gay, bisexual, transgender, and queer (LGBTQ) families. Microaggressions are subtle forms of discrimination experienced on a daily basis as verbal or behavioral slights against individuals in oppressed groups. LGBTQ microaggressions are often studied at an individual level and understood as being directed toward an individual based on perceived identity. The present study allows for an understanding of bias directed at the family system level. Participants included 46 adults who identified as being part of an LGBTQ family. Participants completed an online questionnaire and described their experiences of LGBTQ family microaggressions. Thematic analysis revealed that LGBTQ family microaggressions were salient to individuals across multiple family roles. Three specific themes emerged: family legitimacy, conflicts with family values, and gender violation within family. These findings highlight the way LGBTQ microaggressions are influenced by cultural notions of family and impact the family system. PMID- 29144853 TI - Sexual Experiences in Transgender People: The Role of Desire for Gender Confirming Interventions, Psychological Well-Being, and Body Satisfaction. AB - We examined the role of gender-confirming treatment (GCT; i.e., hormonal treatment and genital surgery), psychological well-being, and body satisfaction in the sexual feelings and behaviors of transgender adults. A survey was conducted among a nonclinical sample of 325 male-to-female (MtF) and 251 female to-male (FtM) Dutch adults (17-76 years, Mage = 41.87), divided into those with no GCT desire, those who desired (more) GCT, and those who completed GCT. Findings indicated that whereas GCT may positively affect sexual feelings, particularly in MtF persons, body satisfaction may play an even bigger role. Those without a GCT desire may experience particular difficulties in their sexual experiences. PMID- 29144854 TI - Journal of Agromedicine "Leader in the Field" 2018: Dennis J. Murphy, PhD. PMID- 29144855 TI - Pain Intensity and Sexual Functioning in Men with Genital Pain: The Mediation Role of Sexually Related Thoughts. AB - The comorbidity between male genital pain and sexual dysfunction is highly prevalent. Previous studies have indicated that men with genital pain share some cognitive characteristics with men experiencing other sexual dysfunctions. However, there is little information on the role of these cognitive factors in understanding the relationship between pain intensity and sexual functioning. This study aims to test if negative sexually related thoughts mediate the relationship between pain intensity and sexual functioning in men with genital pain. A total of 50 men with self-reported genital pain completed an online survey assessing pain intensity, thoughts during sexual activity, and sexual functioning. Results showed a significant effect of negative sexually related thoughts on sexual functioning, beta = -.71, t(50) = -4.2, p <.001. Additionally, the Sobel test found a partial mediation effect (z = 2.23, p =.025) and a medium to large indirect effect size was observed (abcs =.474). Findings suggest that negative sexually related thoughts play an important role in explaining the impact of pain intensity on sexual functioning. Overall, the study emphasizes the relevance of cognitions in predicting sexual function/dysfunction in men with genital pain and suggests the use of cognitive techniques in the treatment of this clinical condition. PMID- 29144856 TI - Leadership and Funding: Changes Ahead for Agricultural Safety and Health. AB - For the last several decades, financial support for agricultural safety and health programs and professionals has primarily been covered by public dollars through federal and state government grant programs and appropriations. This federal and state funding provided a tremendous boost to farm safety and health professionals and program efforts for 30+ years and has provided the foundation and structure for current agricultural safety and health efforts and activities. However, there is reason to question long-term sustainability of a sufficient level of federal and state dollars for agricultural safety and health. Public funding for agricultural safety and health has never quite kept up to inflation, but even more ominous is that the entire agricultural safety and health program has been proposed for elimination each year by the White House budget beginning with the fiscal year 2012. It seems prudent, perhaps even imperative, for the agricultural safety and health community to find alternative support mechanisms. We suggest that now is a great time for agricultural businesses, services, and organizations to step up their financial support. Fortunately, several positive examples have recently surfaced within the agricultural community. As the agricultural industry continues to be a dominant enterprise in the United States, the integration of significant funding and the role of leadership from within the industry must continue to expand. PMID- 29144857 TI - A review of tribal best practices in substance abuse prevention. AB - : American Indian youth experience higher rates of substance use than non American Indian youth. Researchers, clinicians, and treatment programs embrace evidence-based practices (EBPs) and practice based evidence (PBE) as a primary method for addressing substance abuse and advancing behavioral health. However, less is known about the use of tribal best practices (TBPs) and how they are implemented in American Indian substance use prevention contexts. OBJECTIVE: The main objective of this systematic review was to determine how TBPs are implemented and shared in the context of tribal substance use prevention. The second objective was to document TBP examples from three tribal communities involved in a 5-year substance use prevention initiative. METHODS: A systematic review of published and grey literature was conducted using funding agencies websites, EBSCO Host and national registries. Three tribal communities involved in the initiative documented current TBPs to highlight characteristics of TBPs, costs, and approval processes. RESULTS: TBPs are very limited in the literature. Despite tribal use for thousands of years, TBPs are underrepresented and misunderstood. This review found that the terminology used to describe TBPs is not consistent across agencies, publications, websites, or reports. There is also variation in how TBPs originate in substance use prevention contexts and there is not a primary resource or protocol for sharing TBPs. Continued efforts are needed to support the use and dissemination of TBPs in substance use prevention. PMID- 29144858 TI - Editorial. PMID- 29144861 TI - Centering on LGBTQ Families: Introduction to the Special Issue. PMID- 29144862 TI - Are Physician Orders for Life-Sustaining Treatments the Answer to the End-of-Life Care Quality Conundrums in Cancer Care? PMID- 29144863 TI - In Response to "Medical Assistance in Dying in Canada". PMID- 29144864 TI - Reply to M. McKenzie et al. PMID- 29144865 TI - MACRA in Oncology Care: Are We Ready? PMID- 29144866 TI - Challenges in the Clinical Application of the American Society of Clinical Oncology Value Framework: A Medicare Cost-Benefit Analysis in Chronic Lymphocytic Leukemia. AB - PURPOSE: The ASCO Value Framework calculates the value of cancer therapies. Given costly novel therapeutics for chronic lymphocytic leukemia, we used the framework to compare net health benefit (NHB) and cost within Medicare of all regimens listed in the National Comprehensive Cancer Network (NCCN) guidelines. METHODS: The current NCCN guidelines for chronic lymphocytic leukemia were reviewed. All referenced studies were screened, and only randomized controlled prospective trials were included. The revised ASCO Value Framework was used to calculate NHB. Medicare drug pricing was used to calculate the cost of therapies. RESULTS: Forty nine studies were screened. The following observations were made: only 10 studies (20%) could be evaluated; when comparing regimens studied against the same control arm, ranking NHB scores were comparable to their preference in guidelines; NHB scores varied depending on which variables were used, and there were no clinically validated thresholds for low or high values; treatment-related deaths were not weighted in the toxicity scores; and six of the 10 studies used less potent control arms, ranked as the least-preferred NCCN-recommended regimens. CONCLUSION: The ASCO Value Framework is an important initial step to quantify value of therapies. Essential limitations include the lack of clinically relevant validated thresholds for NHB scores and lack of incorporation of grade 5 toxicities/treatment-related mortality into its methodology. To optimize its application for clinical practice, we urge investigators/sponsors to incorporate and report the required variables to calculate the NHB of regimens and encourage trials with stronger comparator arms to properly quantify the relative value of therapies. PMID- 29144869 TI - Ocular Redness Measured with the Keratograph 5M in Patients Using Anti-Glaucoma Eye Drops. AB - PURPOSE: To examine correlations between ocular redness measured with the new topographer Keratograph 5M and the use of topical anti-glaucoma medication. METHODS: A total of 211 eyes of 211 patients with open-angle glaucoma or ocular hypertension on topical medication and 51 eyes of 51 healthy volunteers were recruited over 10 months. Outcome variables were keratograph redness scores (RS): overall, bulbar temporal (BT), bulbar nasal (BN), limbar temporal (LT), and limbar nasal (LN). In each subject, we also recorded the intraocular pressure lowering eye drops used, daily doses and daily and cumulative preservative concentrations, fluorescein corneal staining score (OXFORD), lower tear meniscus height (Fourier-domain OCT), non-invasive tear film breakup time (Keratograph 5M), and ocular surface disease questionnaire index (OSDI). RESULTS: Higher RS were recorded in the medication than control group (P < 0.01 all scores). Within the medication group, older patients returned greater RS (P < 0.05 all scores). Prostaglandin was a strong predictor of higher scores, except LN RS. A higher OSDI was associated with a higher LN RS (beta = 0.007; P < 0.05), while the use of beta-blockers was linked to a lower LN RS (beta = -0.225; P < 0.05). The use of >=3 daily eye drops with preservative gave rise to a higher BN RS and >=3 daily eye drops to a higher LN RS (beta = 0.366, P < 0.01; beta = 0.296, P < 0.05, respectively). CONCLUSION: Keratograph 5M can objectively detect the hyperaemia induced by glaucoma medication. The factors contributing to ocular redness were advanced age, more daily eye drops (nasal sectors), a higher OSDI, and prostaglandin as the medication used. PMID- 29144870 TI - Brain Maturation-Differences in Biochemical Composition of Fetal and Child's Brain. AB - INTRODUCTION: The aim of this study was to evaluate differences in 1H MRS spectra of the brain of fetuses and children from 6 to 11 years of age. MATERIAL AND METHODS: 21 healthy fetuses in the third trimester and 22 children were examined using the proton nuclear magnetic resonance. The relative metabolite concentrations to the sum of all metabolites were calculated. RESULTS: In the 1H MRS spectra of the brain from fetuses and children, there are the same characteristic peaks: N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (mI). NAA/Sigma, NAA/Cr, and Cr/Sigma concentrations are significantly higher and Cho/Sigma, Cho/Cr, mI/Sigma, and mI/Cr are significantly lower in children than in the fetuses. CONCLUSIONS: It was found that the brain metabolism changes from fetal life to childhood. The results of this study may provide a valuable basis for further research on brain maturation and "healthy aging." PMID- 29144871 TI - Consistency-ensured parametric tests for critical events of composite endpoints. AB - Composite endpoints (CEs) are commonly used in clinical trials when clinically important events are rare or when the disease is multifaceted. However, components of a CE often differ markedly in their clinical importance. The overall treatment effect on the composite can be driven by less-important, yet more frequently occurring, components, with no effects on some clinically important components. These situations create difficulties in interpreting the results of the CE. The literature has proposed several approaches for handling these conditions, for example, by setting requirements on the results of the clinically important components. However, for a rare event, it can be difficult to draw an appropriate conclusion about its contribution to the overall result of the composite. Here, we propose combining clinically important components to jointly increase their power and to require that their findings meet a prespecified level of evidence, called the consistency criterion. With the increase in power, the study can then be designed with the objectives of establishing efficacy for the composite and/or for the subset of clinically critical components. In this regard, we introduce multiple testing strategies, which account for the consistency requirement and for the correlation between these two endpoints. We illustrate the methodology using the PROactive trial. PMID- 29144874 TI - Evaluation of Interfacial Gap Volume of Two Low-shrinkage Composites Using Micro Computed Tomography. AB - OBJECTIVES: To investigate the efficacy of X-ray micro-computed tomography (MUCT) in the detection and quantification of interfacial gap formation in standardized Class I and Class II resin composite restorations, to compare the interfacial gaps for two low-shrinkage resin composites with a methacrylate composite material, and to determine any correlation between the cavity configuration factor (C-factor) and the volume of gaps formed. METHODS AND MATERIALS: Sixty standardized Class I and Class II cavities were prepared and divided into six groups. Three types of composites, with their recommended self-etching adhesive systems, were used: Filtek Z250 XT; Estelite Sigma Quick; and Filtek P90. Each of the composite materials was placed in 10 Class I and 10 Class II cavities. The specimens were digitized using Skyscan 1172 MUCT. They were examined for gap volume measurements, the thickness of the adhesive layer, and location of interfacial gaps. RESULTS: There was a significant difference in the mean gap volume percentages of the three materials. The gap volume percent of Estelite Sigma quick was significantly lower than that of Filtek P90. No significant difference in the mean gap volume percentages of Class I and Class II restorations was found, except for Estelite Sigma Quick, in which the Class I gap volume percentage was higher than that of the Class II restorations. CONCLUSIONS: MUCT is an efficacious tool for the measurement of volumetric gaps formed at the tooth/restoration interface and for the evaluation of the adhesive layer. The differences in the C-factor do not always have a pronounced effect on the gap volumes of low-shrinkage composites. PMID- 29144876 TI - Effects of At-home Bleaching in Smokers: 30-month Follow-up. AB - OBJECTIVE: This clinical study evaluated the color longevity after 30 months of at-home bleaching with 10% carbamide peroxide (CP) in smokers and nonsmokers. METHODS: Sixty patients, 30 smokers and 30 nonsmokers, were subjected to bleaching with 10% CP (Whiteness Perfect-FGM) for three hours daily for three weeks. The color was measured at baseline and at one month and 30 months after the completion of dental bleaching using the shade guide Vita classical organized by value (DeltaSGU) and the shade guide Vita Bleachedguide 3D-MASTER. At the 30 month recall, the color was assessed before and after dental prophylaxis. Data from color evaluation were analyzed by two-way repeated-measures analysis of variance and Tukey test for the contrast of means (alpha=0.05). RESULTS: Twenty one smokers and 22 nonsmokers attended the 30 month recall. For both shade guides, only the main factor of assessment time was statistically significant (p<0.001). Effective whitening was observed in both groups at the baseline, which was stable at one month. However, color rebound was observed after 30 months for both groups of participants when color was measured before and after dental prophylaxis. CONCLUSION: Thirty months after at-home bleaching with 10% CP gel, dental darkening was detected in both groups, which cannot be solely attributed to stains caused by extrinsic staining from daily food, drinks, and smoke (in smokers). PMID- 29144877 TI - Role of Proteolytic Enzyme Inhibitors on Carious and Eroded Dentin Associated With a Universal Bonding System. AB - OBJECTIVES: The aim of this study was to evaluate the effect of proteolytic inhibitors on the bond strength of a universal adhesive system (etch-and-rinse mode) applied to artificial carious and eroded dentin. METHODS: Ninety molars were prepared and randomly divided into three groups according to the substrate: N, no challenges; ACD, artificial carious dentin simulation and ERO, artificial erosion simulation with orange juice. All groups were redivided into three subgroups according to the dentin pretreatment: W, water; CHX, 2% digluconate chlorhexidine; and E-64 (trans-epoxysuccinyl-L-leucylamido-[4-guanidino] butane), 5 MUM E-64 inhibitor. They constituted a total of nine groups (n=10): N-W, N-CHX, N-E64, ACD-W, ACD-CHX, ACD-E64, ERO-W, ERO-CHX, and ERO-E64. All specimens were restored with Adper Single Bond Universal/Filtek Z250. Beams (0.64 mm2) were obtained and subjected to the microtensile test (MUTBS) in a universal testing machine at 0.5 mm/min. The failure mode of the interfaces was determined by optical microscopy (40* magnification). Data were statistically analyzed by three way analysis of variance and Tukey tests (p<0.05). RESULTS: All individual factors (p<0.0001) and the interaction between substrate and treatment (p=0.0011) and between substrate and time (p=0.0003) were statistically significant. The caries substrate contributed negatively to bond strength. Chlorhexidine reduced bond strength for normal and eroded conditions. Only the normal substrate was negatively affected by time despite the pretreatment. CONCLUSIONS: The universal bonding system appears to be a promising bonding strategy for the maintenance of bond strength to affected dentin. E-64 did not affect bonding to the dentin in contrast to the use of chlorhexidine, which, when associated with the universal system, did affect the microtensile bond strength for artificial carious dentin. PMID- 29144878 TI - Effect of Preparation Designs on the Prognosis of Porcelain Laminate Veneers: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To investigate the association between preparation designs and prognosis of porcelain laminate veneers (PLVs). METHODS: Electronic and manual literature searches were performed in Medline, Embase, CENTRAL, and Scopus databases for randomized controlled trials and retrospective and prospective cohort studies comparing any two of three preparation designs. The quality of the included studies was assessed using the Newcastle-Ottawa scale. Pooled hazard ratios and risk ratios were used to evaluate the difference between two preparation designs. Subgroup analyses, sensitivity analysis, and evaluation of publication bias were performed if possible. RESULTS: Of 415 screened articles, 10 studies with moderate to high quality were included in the meta-analysis. Comparison of preparations with incisal coverage to preparations without coverage revealed a significant result based on time-to-event data (hazard ratio=1.81, 95% confidence interval [CI]=1.18-2.78, I2=12.5%), but the result was insignificant based on dichotomous data (risk ratio=1.04, 95% CI=0.59-1.83, I2=42.3%). The other comparisons between any two of overlap, butt-joint, and window types revealed no statistically significant difference. Subgroup analyses regarding the porcelain materials, location of prosthesis, and tooth vitality could account for only part of the heterogeneity. No evidence of publication bias was observed. CONCLUSIONS: Within the limitation of the present study, it can be concluded that preparation design with incisal coverage for PLVs exhibits an increased failure risk compared to those without incisal coverage. The failure risk of the overlap type may be higher than the butt-joint type but must be validated in further studies. PMID- 29144879 TI - Effectiveness and Impact of the Walking Bleach Technique on Esthetic Self perception and Psychosocial Factors: A Randomized Double-blind Clinical Trial. AB - OBJECTIVE: This trial evaluates the impact of psychosocial and esthetic self perceptions of patients undergoing nonvital tooth bleaching using the walking bleach technique. We also assessed the clinical effectiveness of bleaching tooth discoloration. METHODS: Fifty volunteers with nonvital tooth discoloration were enrolled. Teeth were randomized into two groups: 35% hydrogen peroxide (n=25) and 37% carbamide peroxide (n=25). Intracoronal bleaching was performed over four sessions using the walking bleach technique. Tooth color was evaluated at each session to measure total color variation. The shade guide was arranged from highest (B1) to lowest (C4) values to assess the color and calculate the color change in the number of shade guide units. Subjective and objective assessments were compared with the tooth counterpart. Esthetic self-perception and psychosocial factors were assessed before and after treatment. RESULTS: Color change was 15.48<5.17 for hydrogen peroxide and 14.02<4.85 for carbamide peroxide. There was no significant difference at any time point (p>0.05) except at sessions 3 and 4 (p<0.05). Overall, whitened teeth values were similar to those of counterpart teeth (p>0.05). There was a decrease in Oral Health Impact Profile and Psychosocial Impact of Dental Esthetics questionnaire scores after treatment compared with baseline (p<0.05). CONCLUSION: The walking bleach technique was highly effective on nonvital teeth and had a positive effect on self-esthetic perception and psychological impact for the patients. PMID- 29144880 TI - Online Only Articles. AB - On occasion we receive manuscripts that we would like to publish, but do not have the page room to include in the print journal. For the full article, please go to www.jopdentonline.org or enter the provided address into your address bar. PMID- 29144881 TI - Improving graduation rates for African Americans in drug court: Importance of human relationships and barriers to gaining and sustaining employment. AB - Drug courts have been an important part of the criminal justice system since 1989. They continue to expand throughout the United States because nearly three decades of research has shown that they are more effective than other interventions, such as traditional probation. There is a pattern, though, in some drug courts where African Americans are less likely to graduate than their Caucasian counterparts. This qualitative study explores this phenomenon by asking African American participants (n = 31) their views on the most helpful aspects of drug court and how drug court could be more helpful in supporting them in graduating the program. Participants felt that the respect and compassion they received from the drug court judge and their case managers, as well as the camaraderie they developed with other participants, was an aspect of drug court that supported them in graduating the program. Next, participants felt that graduation rates would improve if drug court better supported them in gaining employment or sustaining the employment they already had. Implications for drug court practice are discussed. PMID- 29144882 TI - Adult Children of Gay Fathers: Parent-Child Relationship Quality and Mental Health. AB - According to family systems theory, parent-child relationships are an important aspect of individual wellbeing. This study explored associations among parental disclosure, parent-child relationships, and wellbeing among 84 adult children with gay fathers. We explored associations between the adult children's wellbeing and the children's ages at sexual orientation disclosure, geographic distance, relationship quality, and closeness with their fathers. We found that when parental disclosure had occurred earlier in the adult child's life, participants reported feeling closer to fathers in adulthood. Those who reported closer relationships with their fathers reported greater wellbeing. Using a stepwise regression, we found that adult children's reports of closeness with fathers were the best predictors of adult children's wellbeing. PMID- 29144883 TI - What was once essential, may become detrimental: The mediating role of depersonalization in the relationship between childhood emotional maltreatment and psychological distress in adults. AB - Depersonalization (DP) is a dissociative phenomenon, characterized by feeling "unreal" or detached from one's own emotions, thoughts, and behavior (APA, 2013). It is considered to be a defense mechanism, employed in response to overwhelming events, whereby thoughts and emotions are suppressed in order to enhance the individual's capacity to function in traumatic environments. DP has been found to co-occur with anxiety and depressive disorders, and childhood emotional maltreatment (EM) has been identified as an important predisposing factor. The study's primary aim was to investigate the mediating role of DP in the relationship between childhood EM and psychological distress in young adults. Additionally, it aimed to confirm that a history of childhood EM (emotional abuse and emotional neglect) predicted current levels of DP and to explore how both a person's attitude towards experiencing and expressing emotions (with an emphasis on the affect phobia model) and their current attachment security are related to current DP. A cross-sectional design was employed, which included young adults (N = 761) aged between 18 and 25 years. Participants completed an online survey that comprised of several self-report measures. Regression and mediation analyses were conducted. The results indicated that: (1) DP significantly mediated the relationship between childhood EM and current psychological distress; (2) that a history of EM, but no other forms of childhood abuse, significantly predicted current DP experiences; and (3) EM, attachment-related anxiety, and negative attitudes toward emotions predicted clinical cutoff levels of DP. The results are discussed in detail, including clinical implications and direction for future research. PMID- 29144884 TI - Adiposity and Asthma in a Nationwide Study of Children and Adults in the United States. AB - RATIONALE: Although obesity has been associated with asthma, body mass index is suboptimal to fully characterize adiposity. OBJECTIVES: We examined the relation between adiposity and asthma in a large sample of the U.S. population, using indices defined by dual-energy X-ray absorptiometry. METHODS: We analyzed data from 8,886 children (aged 8-19 yr) and 12,795 adults (aged 20-69 yr) from the 2001 to 2006 National Health and Nutrition Examination Survey. In addition to body mass index, percent body fat, waist circumference, and waist-to-height ratio, dual-energy X-ray absorptiometry was used to calculate whole-body and local adiposity indices: fat mass index; total, trunk, and legs percent fat; and trunk-to-total fat mass ratio, legs-to-total fat mass ratio, and trunk-to-legs fat mass ratios. Logistic regression was used for the analysis of adiposity measures and asthma. RESULTS: Among children, general adiposity was significantly associated with asthma, with no major differences by sex. Results were driven by nonatopic children, in whom trunk-predominant (central) adiposity (assessed by waist circumference, waist-to-height ratio, trunk-to-total fat mass ratio, and trunk-to-legs fat mass ratio) was also associated with asthma. There were no significant associations among atopic children. Among adults, all adiposity indices were associated with asthma, with central adiposity significant only among women. The results in adults were driven by atopy, especially in women. CONCLUSIONS: Adiposity measured by dual-energy X-ray absorptiometry provides similar information to that obtained by using anthropometric indices among children of both sexes and among adult men. However, dual-energy X-ray absorptiometry provides additional information in adult women, in whom dual energy X-ray absorptiometry-measured central adiposity is significantly associated with asthma, particularly atopic asthma. PMID- 29144885 TI - Systemic and Airway Inflammation after Exposure to Fumes from Military Small Arms. PMID- 29144886 TI - Comparative Effectiveness of Proactive Tobacco Treatment among Smokers with and without Chronic Lower Respiratory Disease. AB - RATIONALE: Adults with chronic lower respiratory disease differ in their barriers to smoking cessation but also suffer from tobacco-related health concerns, which may motivate quit attempts. Few studies have examined differences in tobacco treatment response between smokers with and without chronic lower respiratory disease. OBJECTIVE: We examined the effectiveness of a proactive outreach program for cessation among smokers with and without chronic lower respiratory disease. METHODS: Subgroup analysis of the Veterans Victory over Tobacco Study, a pragmatic randomized controlled trial that demonstrated the effectiveness of proactive outreach and the choice of tobacco treatments compared with usual care. Smokers identified via the electronic medical record were proactively offered phone-based counseling and care coordination to receive medication from their Veterans Affairs providers or in-person care. We compared the response among those with and without an International Classification of Diseases, 9th Revision diagnosis of a chronic lower respiratory disease (chronic obstructive pulmonary disease, chronic bronchitis, emphysema, asthma). We used stratification by propensity scores to adjust for imbalanced covariates between groups with and without chronic lower respiratory disease within each treatment arm, using complete case analysis accounting for the stratified sampling by site. RESULTS: The study participants were predominantly older, white, male smokers. Overall, 19.6% had chronic lower respiratory disease. A total of 3,307 had outcome data with the following assignments to the intervention: proactive care: n = 1,272 without chronic lower respiratory disease, n = 301 with chronic lower respiratory disease; usual care: n = 1,387 without chronic lower respiratory disease, n = 347 with chronic lower respiratory disease. A total of 1,888 had both complete baseline and outcome data and were included in the primary analysis. In unadjusted analyses (n = 3,307), among individuals with chronic lower respiratory disease, 13.1% in the proactive group reported 6-month prolonged abstinence compared with 8.7% of those in the usual care group (odds ratio, 1.57; 95% confidence interval, 0.93-2.65). Among individuals without chronic lower respiratory disease, 13.1% quit in the proactive group compared with 11.0% in the usual care group (odds ratio, 1.22; 95% confidence interval, 0.95-1.55). In adjusted analyses (n = 1,888), the association between treatment arm and quit rate varied by the presence of chronic lower respiratory disease, with a stronger association between allocation to the proactive group and quit rate among those with chronic lower respiratory disease (odds ratio, 3.45; 95% confidence interval, 1.59-7.47) than those without chronic lower respiratory disease (odds ratio, 1.34; 95% confidence interval, 0.95-1.88; P for interaction with chronic lower respiratory disease = 0.03). CONCLUSIONS: Smokers with chronic lower respiratory disease may be more likely to respond to a proactive outreach intervention for tobacco cessation treatment than those without chronic lower respiratory disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608426). PMID- 29144887 TI - Rosiglitazone is superior to resveratrol in inducing the expression of glyceroneogenic genes in adipose tissue from obese participants. AB - We compared the effects of resveratrol and rosiglitazone, alone and in combination, on indices of fatty acid re-esterification in cultured adipose tissue from obese participants (n = 17) undergoing gastric bypass. Rosiglitazone induced PDK4 and PEPCK gene expression to a greater extent than resveratrol. Co treatment with both compounds induced PDK4 and PEPCK expression in parallel with reductions in the fatty acid to glycerol ratio. Our findings suggest beneficial effects of resveratrol and rosiglitazone co-treatment. PMID- 29144888 TI - Energy expenditure and intake during Special Operations Forces field training in a jungle and glacial environment. AB - The purpose of this study was to identify and compare energy requirements specific to Special Operations Forces in field training, in both cool and hot environments. Three separate training sessions were evaluated, 2 in a hot environment (n = 21) and 1 in a cool environment (n = 8). Total energy expenditure was calculated using doubly labeled water. Dietary intake was assessed via self-report at the end of each training mission day, and macronutrient intakes were calculated. Across the 3 missions, mean energy expenditure (4618 +/- 1350 kcal/day) exceeded mean energy intake (2429 +/- 838 kcal/day) by an average of 2200 kcal/day. Macronutrient intakes (carbohydrates (g/(kg.day body weight (bw))-1) = 3.2 +/- 1.2; protein (g/(kg.day bw)-1) = 1.3 +/ 0.7; fat (g/(kg.day bw)-1) = 1.2 +/- 0.7) showed inadequate carbohydrate and possibly protein intake across the study period, compared with common recommendations. Total energy expenditures were found to be similar between hot (4664 +/- 1399 kcal/day) and cool (4549 +/- 1221 kcal/day) environments. However, energy intake was found to be higher in the cool (3001 +/- 900 kcal/day) compared with hot (2200 +/- 711 kcal/day) environments. Based on the identified energy deficit, high variation in energy expenditures, and poor macronutrient intake, a greater attention to feeding practices during similar training scenarios for Special Operations Forces is needed to help maintain performance and health. The differences in environmental heat stress between the 2 climates/environments had no observed effect on energy expenditures, but may have influenced intakes. PMID- 29144889 TI - Effect of dietary fermented mushroom bed on egg production in laying hens. AB - Egg productivity is declined by stress. It has been reported that some food supplements can improve the egg productivity due to a reduction of environmental stress. We evaluated the effect of fermented waste mushroom bed (FWMB) as a dietary additive on egg productivity. Hens were fed control food (control group, n = 100) or 3% FWMB-added food (FWMB group, n = 100) for 16 months. The number of eggs, soft-shelled eggs, and broken eggs were recorded for 15 months. We also evaluated stress-related markers (ovotransferrin, lipid peroxide, and the heterophil-to-lymphocyte ratio). The FWMB group had slightly increased egg production compared with control hens. The FWMB group produced significantly less broken and soft-shelled eggs than the control group. All stress-related markers were significantly lower in the FWMB group than in the control group. Gut flora was also affected by FWMB feeding. The increased egg production and decreased proportion of broken and soft-shelled eggs might be related to the prevention of stressful conditions by FWMB. PMID- 29144890 TI - Comprehensive analysis of patients with neuromyelitis optica spectrum disorder (NMOSD) combined with chronic hepatitis B (CHB) infection and seropositive for anti-aquaporin-4 antibody. AB - Previous research indicated the association between hepatitis B virus (HBV) infection/vaccination and the onset of demyelinating diseases. However, most of these studies were single case reports, and comprehensive data are still scarce. Here we present a comprehensive analysis of 10 patients with neuromyelitis optica spectrum disorder (NMOSD) combined with chronic hepatitis B (CHB) infection and seropositive for anti-aquaporin-4 antibody (AQP4-Ab). Demographic, clinical, laboratory, neuroimaging, outcome, and follow-up data of the 10 patients were retrospectively analyzed. The median age at the onset of NMOSD was 35 years (range 25-43). Nine patients were female (90%). All patients were positive for HBsAg and had been diagnosed with CHB earlier than with NMOSD. One patient had an autoimmune disease. All patients had normal thyroid function. Paresthesia and visual impairment were the most common clinical symptoms. The cerebrospinal fluid (CSF) parameters (protein and glucose) were normal in 10 cases, whereas slightly higher CSF white blood cell count was detected in 3 patients. The brain and spinal cord magnetic resonance imaging findings were abnormal in 8 patients. All patients were treated with hormone and immunosuppressive therapy, and anti-HBV agents. Patients with detectable serum HBV DNA were more prone to liver damage after receiving high doses of corticosteroids. In 8 patients, the symptoms improved before they were discharged. Two patients with optic neuritis (ON) maintained the symptoms. A month later, 1/8 patient had recurrence of symptoms, and one ON patient progressed to NMO. Overall, the characteristics of NMOSD patients with CHB and seropositive for AQP4-Ab are usually nonspecific. Abnormal liver function test results in NMOSD patients should be a warning of possible CHB infection, and the treatment should be modified accordingly. PMID- 29144891 TI - A plea for an extension of the anatomical nomenclature: The locomotor system. AB - Anatomical nomenclature is the main tool of communication in morphology, anatomy and other medical disciplines as well as in medical education, and thus needs to be exact, flawless, elaborate and correct. The Terminologia Anatomica (TA) is a thorough and extensive list of anatomical terms and their definitions, and the current standard for human anatomical terminology. Although several revisions to the TA have been made in the last 20 years, some important anatomical structures are still not included. This article is aimed at correcting and extending the anatomical nomenclature described in the TA. We gathered and presented a list of anatomical terms, with their definitions and explanations, to provoke a discussion about correcting and extending the TA. Our list comprises of 96 terms related to the locomotor system of the human body, i.e., the bones, joints, muscles and related structures. PMID- 29144892 TI - Preventable Tooth Loss in Hawai'i: The Role of Socioeconomic Status, Diabetes, and Dental Visits. AB - INTRODUCTION: Tooth preservation in adults and children is one of the Healthy People 2020 goals for oral health. Although the overall prevalence of tooth loss has been declining in the United States, substantial racial/ethnic differences in preventable tooth loss persist as a public health problem. We examined the strength of the association of health risk factors and tooth loss in Hawai'i. METHODS: We used data from the Hawai'i Behavioral Risk Factor Surveillance System survey collected from 2011 through 2014. Participant responses were included if they self-identified as Native Hawaiian, white, Japanese, or Filipino. Differences in excess tooth loss (6 or more teeth) and known risk factors (demographics, diabetes, and dental visits) were analyzed by using univariate analyses and adjusted stepwise, logistic regression models. RESULTS: We identified oral health inequity among the 4 ethnic groups studied; among the groups, Native Hawaiians had the largest proportion of excess tooth loss. The univariate analyses found differences in the strength of these associations among the 4 racial/ethnic groups. The stepwise analyses found that the associations of excess tooth loss and race/ethnicity were not significant after adjusting for demographics, diabetes status, and dental visits. CONCLUSION: Findings suggest a need for programs and policies that improve access to oral health care in Hawai'i for those with low levels of income and education and those with diabetes. PMID- 29144893 TI - Primary Care Providers' Level of Preparedness for Recommending Physical Activity to Adults With Disabilities. AB - INTRODUCTION: Adults with disabilities are more likely to be physically inactive than those without disabilities. Although receiving a health care provider recommendation is associated with physical activity participation in this population, there is little information on factors associated with primary care providers recommending physical activity to patients with disabilities. METHODS: We used 2014 DocStyles data to assess primary care provider characteristics and perceived barriers to and knowledge-related factors of recommending physical activity to adult patients with disabilities, by how prepared primary care providers felt in making recommendations. We used log-binomial regression to estimate adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) between recommending physical activity at most visits and primary care provider characteristics and preparedness. RESULTS: Most primary care providers strongly (36.3%) or somewhat (43.3%) agreed they felt prepared to recommend physical activity to patients with disabilities. We found significant trends between preparedness and primary care provider age (P = .001) and number of patients with disabilities seen per week (P < .001). Half (50.6%) of primary care providers recommend physical activity to patients with disabilities at most visits. Primary care providers who strongly agreed (adjusted PR, 1.74; 95% CI, 1.44-2.09) or somewhat agreed (adjusted PR, 1.36; 95% CI, 1.22-1.65) they felt prepared were more likely to recommend physical activity at most visits compared with those who were neutral or disagreed. CONCLUSION: Primary care providers are more likely to recommend physical activity to patients with disabilities regularly if they feel prepared. Understanding factors and barriers associated with preparedness can help public health programs develop and disseminate resources for primary care providers to promote physical activity among adults with disabilities. PMID- 29144894 TI - Clinical-Community Partnerships to Identify Patients With Food Insecurity and Address Food Needs. AB - INTRODUCTION: More than 42 million people in the United States are food insecure. Although some health care entities are addressing food insecurity among patients because of associations with disease risk and management, little is known about the components of these initiatives. METHODS: The Systematic Screening and Assessment Method was used to conduct a landscape assessment of US health care entity-based programs that screen patients for food insecurity and connect them with food resources. A network of food insecurity researchers, experts, and practitioners identified 57 programs, 22 of which met the inclusion criteria of being health care entities that 1) screen patients for food insecurity, 2) link patients to food resources, and 3) target patients including adults aged 50 years or older (a focus of this assessment). Data on key features of each program were abstracted from documentation and telephone interviews. RESULTS: Most programs (n = 13) focus on patients with chronic disease, and most (n = 12) partner with food banks. Common interventions include referrals to or a list of food resources (n = 19), case managers who navigate patients to resources (n = 15), assistance with federal benefit applications (n = 14), patient education and skill building (n = 13), and distribution of fruit and vegetable vouchers redeemable at farmers markets (n = 8). Most programs (n = 14) routinely screen all patients. CONCLUSION: The programs reviewed use various strategies to screen patients, including older adults, for food insecurity and to connect them to food resources. Research is needed on program effectiveness in improving patient outcomes. Such evidence can be used to inform the investments of potential stakeholders, including health care entities, community organizations, and insurers. PMID- 29144895 TI - Should the Legal Age for Tobacco Be Raised? Results From a National Sample of Adolescents. AB - Raising the minimum age of legal access to tobacco products may reduce smoking initiation and save lives. In a national telephone survey (2014-2015), US adolescents aged 13 to 17 years (N = 1,125; response rate, 66%) were asked about raising the age of legal access to tobacco products and randomized to hear one of 3 ages (19, 20, or 21 y). Most adolescents, across all US regions, favored raising the minimum age of legal access to 19 (75.7%), 20 (80.6%), or 21 (76.4%). These supportive attitudes may be useful to tobacco prevention and control practitioners who seek to reduce tobacco use among adolescents. PMID- 29144897 TI - Re: Evolution of Primary Care Referrals to Urology. Impact of a Protocol on Prostate Disease and Continuing Education. PMID- 29144898 TI - Re: A Novel Automatic Regulatory Device for Continuous Bladder Irrigation Based on Wireless Sensor in Patients after Transurethral Resection of the Prostate: A Prospective Investigation. PMID- 29144899 TI - Re: Changes in Weight and Metabolic Syndrome are Associated with Prostate Growth Rate over a 5-Year Period. PMID- 29144900 TI - Re: A Relevant Midterm (12 Months) Placebo Effect on Lower Urinary Tract Symptoms and Maximum Flow Rate in Male Lower Urinary Tract Symptom and Benign Prostatic Hyperplasia-A Meta-Analysis. PMID- 29144896 TI - Atg9 antagonizes TOR signaling to regulate intestinal cell growth and epithelial homeostasis in Drosophila. AB - Autophagy is essential for maintaining cellular homeostasis and survival under various stress conditions. Autophagy-related gene 9 (Atg9) encodes a multipass transmembrane protein thought to act as a membrane carrier for forming autophagosomes. However, the molecular regulation and physiological importance of Atg9 in animal development remain largely unclear. Here, we generated Atg9 null mutant flies and found that loss of Atg9 led to shortened lifespan, locomotor defects, and increased susceptibility to stress. Atg9 loss also resulted in aberrant adult midgut morphology with dramatically enlarged enterocytes. Interestingly, inhibiting the TOR signaling pathway rescued the midgut defects of the Atg9 mutants. In addition, Atg9 interacted with PALS1-associated tight junction protein (Patj), which associates with TSC2 to regulate TOR activity. Depletion of Atg9 caused a marked decrease in TSC2 levels. Our findings revealed an antagonistic relationship between Atg9 and TOR signaling in the regulation of cell growth and tissue homeostasis. PMID- 29144901 TI - Re: Quality Improvement in Cystectomy Care with Enhanced Recovery (QUICCER) Study. PMID- 29144902 TI - Re: Incidence and Implications of Silent Hydronephrosis following Percutaneous Nephrolithotomy. PMID- 29144903 TI - Re: Impact of the Lack of Community Urinary Catheter Care Services on the Emergency Department. PMID- 29144904 TI - Re: Prevalence of Antimicrobial Use and Opportunities to Improve Prescribing Practices in U.S. Nursing Homes. PMID- 29144905 TI - Re: Algorithm of Medication Review in Frail Older People: Focus on Minimizing the Use of High-Risk Medications. PMID- 29144906 TI - Re: Medications Associated with Geriatric Syndromes and Their Prevalence in Older Hospitalized Adults Discharged to Skilled Nursing Facilities. PMID- 29144907 TI - Re: Impact of Body Mass Index, Age and Varicocele on Reproductive Hormone Profile from Elderly Men. PMID- 29144908 TI - Re: Prevalence of Sexual Dysfunction in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Meta-Analysis. PMID- 29144909 TI - Re: The Effectiveness of Prophylactic Antibiotics with Oral Levofloxacin against Post-Shock Wave Lithotripsy Infectious Complications: A Randomized Controlled Trial. PMID- 29144910 TI - Re: Pediatric Robot-Assisted Redo Pyeloplasty with Buccal Mucosa Graft: A Novel Technique. PMID- 29144911 TI - Re: Advanced Reconstruction of Vesicourethral Support (ARVUS) during Robot Assisted Radical Prostatectomy: One-Year Functional Outcomes in a Two-Group Randomised Controlled Trial. PMID- 29144912 TI - Re: Does any Association Exist between Chronic Obstructive Pulmonary Disease and Erectile Dysfunction? The DECODED Study. PMID- 29144913 TI - Re: Silodosin versus Naftopidil in the Treatment of Premature Ejaculation: A Prospective Multicenter Trial. PMID- 29144914 TI - Re: Factors Associated with Erectile Dysfunction and the Peyronie's Disease Questionnaire in Patients with Peyronie Disease. PMID- 29144915 TI - Re: Safety and Effectiveness of Collagenase Clostridium Histolyticum in the Treatment of Peyronie's Disease Using a New Modified Shortened Protocol. PMID- 29144916 TI - Re: Bicentric Prospective Evaluation of Corporoplasty with Porcine Small Intestinal Submucosa (SIS) in Patients with Severe Peyronie's Disease. PMID- 29144917 TI - Re: Dietary Patterns, Foods and Nutrients in Male Fertility Parameters and Fecundability: A Systematic Review of Observational Studies. PMID- 29144918 TI - Re: Obesity, Male Infertility, and the Sperm Epigenome. PMID- 29144919 TI - Re: Strong Adherence to a Healthy Dietary Pattern is Associated with Better Semen Quality, Especially in Men with Poor Semen Quality. PMID- 29144920 TI - Re: A High-Fat Diet Impairs Reproduction by Decreasing the IL1beta Level in Mice Treated at Immature Stage. PMID- 29144921 TI - Re: Predictive Value of Different Covariates Influencing Pregnancy Rate following Intrauterine Insemination with Homologous Semen: A Prospective Cohort Study. PMID- 29144922 TI - Re: What is the Outcome of Paediatric Gastrocystoplasty When the Patients Reach Adulthood? PMID- 29144923 TI - Re: Barriers to Transition in Young Adults with Neurogenic Bladder. PMID- 29144924 TI - Re: Enterocystoplasty: The Long-Term Effects on Bone Mineral Density. PMID- 29144925 TI - Re: Does Endoscopy of Difficult to Catheterize Channels Spare Some Patients from Formal Open Revision? PMID- 29144926 TI - Re: Telemedically Supported Case Management of Living-Donor Renal Transplant Recipients to Optimize Routine Evidence-Based Aftercare: A Single-Center Randomized Controlled Trial. PMID- 29144927 TI - Re: Can Separation of the Scrotal Sac in Proximal Hypospadias Reliably Predict the Need for Urethral Plate Transection? PMID- 29144928 TI - Re: A Cost Comparison for Telehealth Utilization in the Kidney Transplant Waitlist Evaluation Process. PMID- 29144929 TI - Re: High Volume is the Key for Improving In-Hospital Outcomes after Radical Prostatectomy: A Total Population Analysis in Germany from 2006 to 2013. PMID- 29144930 TI - Re: Treatment Decision Regret among Long-Term Survivors of Localized Prostate Cancer: Results from the Prostate Cancer Outcomes Study. PMID- 29144931 TI - Re: Variation and Predictors of Surgical Case Costs among Urologists. PMID- 29144932 TI - Re: Radiation-Induced Complex Anterior Urinary Fistulation for Prostate Cancer: A Retrospective Multicenter Study from the Trauma and Urologic Reconstruction Network of Surgeons (TURNS). PMID- 29144933 TI - Re: 36-Month Data for the AdVance XP(r) Male Sling: Results of a Prospective Multicentre Study. PMID- 29144934 TI - Re: The Effect of Urethral Transection on Erectile Function after Anterior Urethroplasty. PMID- 29144935 TI - Re: A Prospective Randomized Comparison of Micropercutaneous Nephrolithotomy (Microperc) and Retrograde Intrarenal Surgery (RIRS) for the Management of Lower Pole Kidney Stones. PMID- 29144936 TI - Re: Vascular Disease and Kidney Stones: Abdominal Aortic Calcifications are Associated with Low Urine pH and Hypocitraturia. PMID- 29144937 TI - Re: Comparison of CROES, S.T.O.N.E, and Guy's Scoring Systems for the Prediction of Stone-Free Status and Complication Rates following Percutaneous Nephrolithotomy in Patients with Chronic Kidney Disease. PMID- 29144938 TI - Re: Partial Nephrectomy versus Radical Nephrectomy for Clinical T1b and T2 Renal Tumors: A Systematic Review and Meta-Analysis of Comparative Studies. PMID- 29144939 TI - Re: Efficacy of Systemic Chemotherapy plus Radical Nephroureterectomy for Metastatic Upper Tract Urothelial Carcinoma. PMID- 29144940 TI - Re: Orthotopic Neobladder vs. Ileal Conduit Urinary Diversion: A Long-Term Quality-of-Life Comparison. PMID- 29144941 TI - Re: The Health Effects of Electronic Cigarettes. PMID- 29144942 TI - Re: Systematic Review Links the Prevalence of Intraductal Carcinoma of the Prostate to Prostate Cancer Risk Categories. PMID- 29144943 TI - Re: Propensity Score Analysis of Radical Cystectomy versus Bladder-Sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic. PMID- 29144944 TI - Re: Impact of Ga-68 PSMA-11 PET on Management in Patients with Biochemically Recurrent Prostate Cancer. PMID- 29144945 TI - Re: Association between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer. PMID- 29144946 TI - Re: Associations of Luminal and Basal Subtyping of Prostate Cancer with Prognosis and Response to Androgen Deprivation Therapy. PMID- 29144947 TI - Re: The Metabolic Co-Regulator PGC1alpha Suppresses Prostate Cancer Metastasis. PMID- 29144948 TI - Re: The World Health Organization 2016 Classification of Testicular Germ Cell Tumours: A Review and Update from the International Society of Urological Pathology Testis Consultation Panel. PMID- 29144949 TI - Re: Genomic Hallmarks of Localized, Non-Indolent Prostate Cancer. PMID- 29144950 TI - Re: Comparison of Retropubic Synthetic Mid-Urethral Slings to Fascia Pubovaginal Slings following Failed Sling Surgery. PMID- 29144951 TI - Re: Smooth Muscle Progenitor Cells Derived from Human Pluripotent Stem Cells Induce Histologic Changes in Injured Urethral Sphincter. PMID- 29144952 TI - Re: Surgical Treatment of Detrusor Underactivity: A Short Term Proof of Concept Study. PMID- 29144953 TI - Re: A Systematic Approach to the Evaluation and Management of the Failed Artificial Urinary Sphincter. PMID- 29144954 TI - Re: Simultaneous In Vivo Comparison of Water-Filled and Air-Filled Pressure Measurement Catheters: Implications for Good Urodynamic Practice. PMID- 29144955 TI - Re: Clinical Effectiveness and Cost-Effectiveness of Surgical Options for the Management of Anterior and/or Posterior Vaginal Wall Prolapse: Two Randomised Controlled Trials within a Comprehensive Cohort Study-Results from the PROSPECT Study. PMID- 29144956 TI - Re: Pelvic Floor Muscle Training for Secondary Prevention of Pelvic Organ Prolapse (PREVPROL): A Multicentre Randomised Controlled Trial. PMID- 29144957 TI - Fluconazole levels in serum and cerebrospinal fluid according to daily dosage in patients with cryptococcosis and other fungal infections. AB - Fluconazole is extensively used for the treatment of candidiasis and cryptococcosis. Among other factors, successful treatment is related to appropriate fluconazole levels in blood and cerebrospinal fluid. In the present study, fluconazole levels were determined in 15 patients, 14 of whom had AIDS and 13 had neurocryptococcosis. The only selection criterion was treatment with fluconazole, which was performed with a generic or similar form of the drug. Fluconazole level was determined by high performance liquid chromatography and the susceptibility profile of Cryptococcus spp. isolated from the patients was assessed by broth microdilution. Blood and cerebrospinal fluid fluconazole levels were found to be related to the fluconazole daily dose, and exceeded the minimum inhibitory concentration of this antifungal for the Cryptococcus spp. isolates. A good correlation was observed between serum and cerebrospinal fluid drug concentration. In conclusion, treatment with non-original fluconazole under usual medical practice conditions results in appropriate blood and cerebrospinal fluid levels of the drug for inhibiting Cryptococcus spp. susceptible to this antifungal drug. The relatively common failures of neurocryptococcosis treatment appear not to be due to insufficient fluconazole levels in the cerebrospinal fluid, especially with the use of daily doses of 400-800mg. PMID- 29144958 TI - Isolation of blaNDM-producing Enterobacteriaceae in a public hospital in Salvador, Bahia, Brazil. AB - Carbapenemases have great importance in the global epidemiological scenario since infections with carbapenemase-producing bacteria are associated with high mortality, especially in hospitalized patients in intensive care units. This study describes two microorganisms producers of the New Delhi Metallo-b lactamase, Klebsiella pneumoniae and Citrobacter freundii, from two patients admitted to a public hospital in Salvador, Bahia. These are the first clinical cases of New Delhi Metallo-b-lactamase described in microorganisms in the north and northeast Brazil. The isolates were characterized by antimicrobial susceptibility test, with resistance to all beta-lactams including carbapenems, negative Modified Hodge Test and the synergy test with Ethylenediaminetetraacetic acid, Phenylboronic Acid and Cloxacillin was positive only with Ethylenediaminetetraacetic acid (difference of >5mm in the inhibition zone between the disk without and with the inhibitor). Analysis by multiplex PCR for blaIMP, blaVIM, blaNDM, blaKPC and blaOXA-48 enzymes confirmed the presence of blaNDM gene. This report of two different New Delhi Metallo-b-lactamase-producing microorganisms in a different region of Brazil confirms the risk of spreading resistance genes between different species and emphasizes the need for prevention and control of infections caused by these pathogens, which have limited treatment options and have been linked to high mortality rates. PMID- 29144961 TI - Current Resources for Evidence-Based Practice, January 2018. PMID- 29144960 TI - Cervical Cancer Screening Experiences Among Chinese American Immigrant Women in the United States. AB - OBJECTIVE: To understand the experiences and perceptions of having cervical cancer screening tests and to explore the extant barriers to having the tests among first-generation Chinese American women in the United States. DESIGN: Qualitative, descriptive, phenomenological research. SETTING: Los Angeles, California. PARTICIPANTS: Snowball and purposive sampling of 12 Chinese American immigrant women ages 20 to 65 years. METHODS: Individual face-to-face, in-depth, semistructured interviews in which participants were asked about their experiences and perceptions about cervical cancer screening. Interviews were audiotaped, transcribed, and translated into English. Data analysis included comparing and distinguishing, collecting and counting, and presupposing and inferring. RESULTS: Through the analysis process, we identified four major themes that reflected the experiences, perceptions, and barriers to having cervical cancer screening among Chinese American women: Belief in a Healthy Lifestyle, Maintaining Privacy for Female Health Problems, Fear of Losing Control, and Feeling Vulnerable in an Unfamiliar Health Care System. These themes indicated that Chinese immigrant women in the United States face challenges to their cultural health beliefs and practices with regard to decision-making and health seeking behaviors related to cervical cancer screening. They felt more vulnerable as immigrants because of systematic barriers to navigation of the unfamiliar health care system and limited resources. CONCLUSION: Women's health care providers should be aware of and give consideration to cultural differences through the provision of more educational information and comfort to Chinese immigrant women who seek cervical cancer screening. Ultimately, the development of culturally appropriate and affordable cancer prevention programs with effective strategies is important to ease Chinese American women's senses of vulnerability. PMID- 29144959 TI - Induction of innervation by encapsulated adipocytes with engineered vitamin A metabolism. AB - Innervation is a fundamental basis for function and survival of tissues. In the peripheral tissues, degenerative diseases create a neurotoxic metabolic milieu that either causes neurodegeneration or fails to sustain regenerative growth and reinnervation of injured/diseased tissues. Encapsulation of cells producing neurotrophic factors can augment axon growth and neuron survival; however, sustained innervation in vivo requires a combination of factors promoting axon growth and guidance pathway that are released in a tissue-specific context. Using novel encapsulation techniques and genetic tools, we manipulated retinoic acid generating enzyme aldehyde dehydrogenase 1a1 (Aldh1a1) in adipocytes that are capable of promoting growth and innervation of white adipose tissue by sympathetic neurons. Aldh1a1-/- adipocytes secrete molecules that regulate axon guidance and markedly stimulate neurite outgrowth in vitro and in vivo. Based on studies with natural and synthetic RAR agonists and antagonists, gene microarray and nanostring arrays, we concluded that ephrin A5/ephrin A4 is a downstream pathway regulated by Aldh1a1. Encapsulation of Aldh1a1-/- adipocytes into alginate poly-L-lysine microcapsules induced functional innervation of adipose tissue in obese wild-type mice. We propose that encapsulated Aldh1a1-/- adipocytes could provide a therapeutic solution for the reinnervation of damaged tissues. PMID- 29144962 TI - Editorial Comment. PMID- 29144963 TI - Translation and validation of Pediatric Quality of Life InventoryTM 3.0 Diabetes Module (PedsQLTM 3.0 Diabetes Module) in Brazil-Portuguese language. AB - OBJECTIVE: The aim of the present study was to create a translated version of the Pediatric Quality of Life InventoryTM 3.0 Diabetes Module (PedsQLTM 3.0 Diabetes Module) in Brazilian Portuguese that was conceptually equivalent to the original American English version and to linguistically validate it in a Brazilian pediatric population with type 1 diabetes mellitus and their parents or caregivers. METHODS: The instrument was translated, back-translated, and then administered to 83 children/adolescents (5-18 years) with type 1 diabetes mellitus and their family members and to 25 parents/caregivers of patients aged between 2 and 4 years. The final translated version was tested for reliability by analyzing internal consistency, intraobserver (test-retest) reliability, and concurrent validity. RESULTS: Cronbach's alpha coefficient for the total score of the questionnaires of children/adolescents (alpha=0.85) and their parents (alpha=0.82) was above the recommended minimum of 0.70 for group comparisons. Intraobserver reliability and concurrent validity exhibited a significant positive correlation (p<0.001), indicating the reliability of the translated instrument. A moderate but significant positive correlation (r=0.40; p<0.001) was demonstrated between the total scores of patient self-report and parent proxy report scales. There was no significant correlation between glycated hemoglobin (HbA1c) levels and the respective scores in the questionnaires answered by patients and their parents/caregivers. CONCLUSION: The analysis of the translated version of the PedsQLTM 3.0 Diabetes Module revealed adequate psychometric characteristics with respect to reliability and validity following administration to a sample of Brazilian children/adolescents with type 1 diabetes mellitus and their caregivers. PMID- 29144964 TI - Biocultural approach of the association between maturity and physical activity in youth. AB - OBJECTIVE: To test the biocultural model through direct and indirect associations between biological maturation, adiposity, cardiorespiratory fitness, feelings of sadness, social relationships, and physical activity in adolescents. METHODS: This was a cross-sectional study conducted with 1,152 Brazilian adolescents aged between 10 and 17 years. Somatic maturation was estimated through Mirwald's method (peak height velocity). Physical activity was assessed through Baecke questionnaire (occupational, leisure, and sport contexts). Body mass index, body fat (sum of skinfolds), cardiorespiratory fitness (20-m shuttle run test), self perceptions of social relationship, and frequency of sadness feelings were obtained for statistical modeling. RESULTS: Somatic maturation is directly related to sport practice and leisure time physical activity only among girls (beta=0.12, p<0.05 and beta=0.09, respectively, p<0.05). Moreover, biological (adiposity and cardiorespiratory fitness), psychological (sadness), and social (satisfaction with social relationships) variables mediated the association between maturity and physical activity in boys and for occupational physical activity in girls. In general, models presented good fit coefficients. CONCLUSION: Biocultural model presents good fit and emotional/biological factors mediate part of the relationship between somatic maturation and physical activity. PMID- 29144965 TI - Role of serum (1,3)-beta-d-glucan assay in early diagnosis of invasive fungal infections in a neonatal intensive care unit. AB - OBJECTIVES: To study the microbiological pattern of late onset neonatal sepsis cultures and to assess the diagnostic performance of serum (1,3)-beta-d-glucan level for early diagnosis of invasive fungemia in high-risk infants admitted to a neonatal intensive care unit. METHODS: A prospective multicenter clinical trial conducted on infants at high risk for invasive fungal infections, with suspected late onset sepsis, admitted to a neonatal intensive care unit at Mansoura University Children's Hospital and Mansoura General Hospital between March 2014 and February 2016. RESULTS: A total of 77 newborn infants with high risk of invasive fungal infection were classified based on blood culture into three groups: no fungemia (41 neonates with proven bacterial sepsis), suspected fungemia (25 neonates with negative blood culture), and definite fungemia group (11 neonates with culture-proven Candida). The growing organisms were Klebsiella spp. (14/54); Escherichia coli (12/54); Staphylococcus spp. (12/54; coagulase negative Staphylococcus [9/54]; Staphylococcus aureus [3/54]); Pseudomonas aerouginosa (3/54); and Proteus spp. (2/54). Moreover, 11/54 presented Candida. Serum (1,3)-beta-d-glucan concentration was significantly lower in the no fungemia group when compared with the definite fungemia group. The best cut-off value of (1,3)-beta-d-glucan was 99pg/mL with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 63.6%, 95.1%, 77.8%, 90.7%, and 88.5%, respectively. CONCLUSION: (1,3)-beta-d-glucan assay has a limited sensitivity with excellent specificity and negative predictive value, which allow its use as an aid in exclusion of invasive neonatal fungal infection. Accurate diagnosis and therapeutic decisions should be based on combining (1,3) beta-d-glucan assay with other clinical, radiological, and microbiological findings. PMID- 29144966 TI - GABAergic Synaptogenesis: A Case for Cooperation. AB - Multiple cell-adhesion molecules contribute to synapse formation by mediating trans-synaptic interactions with presynaptic signaling molecules. In this issue of Neuron, Li et al. (2017) report cooperativity between Neuroligin2 and Slitrk3, exerting distinct effects on GABAergic synapse formation in immature and mature neurons. PMID- 29144967 TI - A Local Rebalancing Act Leads to Global Benefit. AB - Barnes et al. (2017) reveal that in the visual cortex of sensory-deprived mice, dendritic spine enlargement correlates with recent spine loss from the same dendritic branch. Such branch-specific homeostatic plasticity highlights dendritic branches as key computational units. PMID- 29144968 TI - A Synaptic Basis for GLP-1 Action in the Brain. AB - Unraveling the brain control of metabolism may generate opportunities to discover novel precision medicines for obesity and diabetes. In this issue of Neuron, Liu et al. (2017) identify a novel glucagon-like peptide (GLP)-1 receptor-dependent signaling process that exerts anorexigenic action via the regulation of AMPA receptor subunit composition in the hypothalamus. PMID- 29144969 TI - Good Vibrations: Resting-State Functional Connectivity Reflects Entrainment of Vasomotion. AB - In this issue of Neuron,Mateo et al. (2017) suggest that hemodynamic measures of resting-state functional connectivity in cortex are reporting the consequences of entrainment of arteriole vasomotion by neuronal activity. PMID- 29144970 TI - Epimetronomics: m6A Marks the Tempo of Corticogenesis. AB - Yoon et al. (2017) uncover a key role for the m6A RNA mark in regulating the timing of cerebral cortex development in mouse and human. This discovery opens new avenues of exploration into how the epitranscriptome helps orchestrate central nervous system formation. PMID- 29144971 TI - Gender Equality from a European Perspective: Myth and Reality. AB - In the past 50 years, significant progress in women's equality has been made worldwide. Western countries, particularly European countries, have implemented initiatives to attain a more gender-balanced workforce with the introduction of family friendly policies, by trying to narrow the gender pay gap and by promoting women's career progression. In academia, however, fewer women reach top leadership positions than those in the political arena. These findings suggest that academia needs to carefully evaluate why these new policies have not been very effective. In this NeuroView, we report on the progress made in higher education, the shortcomings, and how new initiatives hold great promise for improving gender equality in academia around the globe. PMID- 29144975 TI - The Spatiotemporal Organization of the Striatum Encodes Action Space. PMID- 29144972 TI - Building Bridges through Science. AB - Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge" initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities. PMID- 29144976 TI - Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation. PMID- 29144974 TI - Double-Nanodomain Coupling of Calcium Channels, Ryanodine Receptors, and BK Channels Controls the Generation of Burst Firing. AB - Action potentials clustered into high-frequency bursts play distinct roles in neural computations. However, little is known about ionic currents that control the duration and probability of these bursts. We found that, in cartwheel inhibitory interneurons of the dorsal cochlear nucleus, the likelihood of bursts and the interval between their spikelets were controlled by Ca2+ acting across two nanodomains, one between plasma membrane P/Q Ca2+ channels and endoplasmic reticulum (ER) ryanodine receptors and another between ryanodine receptors and large-conductance, voltage- and Ca2+-activated K+ (BK) channels. Each spike triggered Ca2+-induced Ca2+ release (CICR) from the ER immediately beneath somatic, but not axonal or dendritic, plasma membrane. Moreover, immunolabeling demonstrated close apposition of ryanodine receptors and BK channels. Double nanodomain coupling between somatic plasma membrane and hypolemmal ER cisterns provides a unique mechanism for rapid control of action potentials on the millisecond timescale. PMID- 29144973 TI - Orbitofrontal Cortex: A Neural Circuit for Economic Decisions. AB - Economic choice behavior entails the computation and comparison of subjective values. A central contribution of neuroeconomics has been to show that subjective values are represented explicitly at the neuronal level. With this result at hand, the field has increasingly focused on the difficult question of where in the brain and how exactly subjective values are compared to make a decision. Here, we review a broad range of experimental and theoretical results suggesting that good-based decisions are generated in a neural circuit within the orbitofrontal cortex (OFC). The main lines of evidence supporting this proposal include the fact that goal-directed behavior is specifically disrupted by OFC lesions, the fact that different groups of neurons in this area encode the input and the output of the decision process, the fact that activity fluctuations in each of these cell groups correlate with choice variability, and the fact that these groups of neurons are computationally sufficient to generate decisions. Results from other brain regions are consistent with the idea that good-based decisions take place in OFC and indicate that value signals inform a variety of mental functions. We also contrast the present proposal with other leading models for the neural mechanisms of economic decisions. Finally, we indicate open questions and suggest possible directions for future research. PMID- 29144977 TI - Birthplace in Australia: Processes and interactions during the intrapartum transfer of women from planned homebirth to hospital. AB - OBJECTIVE: the aim of the study was to explore the views and experiences of women, midwives and obstetricians on the intrapartum transfer of women from planned homebirth to hospital in Australia. DESIGN: a Constructivist Grounded Theory approach was taken, to conceptualise the social interactions and processes grounded in the data. SETTING: urban and regional areas in four states of south eastern Australia. PARTICIPANTS: semi-structured qualitative interviews were conducted with 36 women, midwives and obstetricians who had experienced an intrapartum homebirth transfer within three years prior to the interview. Interviews were audio recorded and transcribed verbatim. FINDINGS: women who were transferred to hospital from a planned homebirth made physical and psychological journeys out of their comfort zone, as they faced the uncertainty of changing expectations for their birth. The trusting relationship between a woman and her homebirth midwife was crucial to women's sense of safety and well-being in hospital. Midwives and obstetricians, when congregating in the hospital birthing rooms of transferred women, also felt out of their comfort zones. This was due to the challenges of converging with others who possessed conflicting paradigms of safety and risk in birth that were at odds with their own, and adapting to different routines, roles and responsibilities. These differences were derived from diverse professional, social and personal influences and often manifested in stereotyping behaviours and 'us and them' dynamics. When midwife-woman partnerships were respected as an inclusive part of women's care, collaboration ensued, conflict was ameliorated, and smooth transfers could be celebrated as successes of the maternity care system. KEY CONCLUSIONS: supporting woman centred care in homebirth transfers means acknowledging the social challenges of collaborating in the unique context of a transferred woman's hospital birthing room. Understanding the power of the midwife-woman partnership, and its value to the health and well-being of each woman and her baby, is key to facilitating a successful transfer. IMPLICATIONS FOR PRACTICE: the midwife-woman partnership played a central role in providing the necessary support and advocacy for women transferred out of their comfort zone. When midwives worked together in an integrated system to provide the necessary care and support for women who were transferred, greater levels of collaboration emerged and women's perceptions of their quality of care was high. In practice, this meant health professionals respecting each other's roles, responsibilities and expertise, and ameliorating 'us and them' dynamics. PMID- 29144978 TI - Attendance at prenatal care and adverse birth outcomes in China: A follow-up study based on Maternal and Newborn's Health Monitoring System. AB - OBJECTIVE: to evaluate the independent association between attendance at prenatal care and adverse birth outcomes in China, measured either as the occurrence of preterm birth or low birth weight. DESIGN: a follow-up study. SETTING: the data was collected from maternal and newborn's health monitoring system at 6 provinces in China. PARTICIPANTS: all pregnant women registered in the system at their first prenatal care visit. We included 40152 registered pregnant women who had delivered between October 2013 and September 2014. MEASUREMENTS: attendance at prenatal care was evaluated using Kessner index. chi2 tests were used to examine the correlations between demographic characteristics and preterm birth or low birth weight. The associations between attendance at prenatal care and birth outcomes were explored using multilevel mixed-effects logistic regression models. FINDINGS: the prevalence for preterm birth and low birth weight was 3.31% and 2.55%. The null models showed region clustering on birth outcomes. Compared with women who received adequate prenatal care, those with intermediate prenatal care (adjusted OR 1.62, 95%CI 1.37-1.92) or inadequate prenatal care (adjusted OR 2.78, 95%CI 2.24-3.44) had significantly increased risks for preterm birth, and women with intermediate prenatal care (adjusted OR 1.31, 95%CI 1.10-1.55) or inadequate prenatal care (adjusted OR 1.70, 95%CI 1.32-2.19) had significantly increased risks for low birth weight. We found very significant dose-response patterns for both preterm birth (p-trend<0.001) and low birth weight (p-trend = 0.001). KEY CONCLUSIONS AND IMPLICATION FOR PRACTICE: This study shows that attendance at prenatal care in China has independent effects on both preterm birth and low birth weight. Appropriate timing and number of prenatal care visits can help to reduce the occurrence of preterm birth or low birth weight. PMID- 29144979 TI - Who crosses the norms? Predictors of the readiness for non-normative political participation among adolescents. AB - This study investigated whether adolescents' readiness for non-normative political participation (i.e., readiness to confront social rules for political reasons) was predicted by their interpersonal problems (with parents, teachers, and classmates), low optimism, and political beliefs (political self-efficacy and distrust in public institutions). A structural equation model using two-wave longitudinal data from Czech high school students (N = 768; 54% females; age range at T1 = 14-17, M = 15.97; T2 data collected 1.5 years later) showed that the changes in adolescents' readiness for non-normative participation were predicted by their lower institutional trust. Interpersonal relationships or optimism had no cross-sectional or longitudinal effect on the readiness for non normative participation. These results suggest that the main source of adolescents' readiness for non-normative political actions lies in their political beliefs, while the effect of adolescents' interpersonal problems is less clear. PMID- 29144980 TI - Time attitudes predict changes in adolescent self-efficacy: A 24-month latent transition mover-stayer analysis. AB - Increasingly, the study of temporal psychology is moving away from bivariate analyses towards person-centered analyses, which simultaneously account for scores on past, present and future dimensions. However, longitudinal studies are lacking. This study builds on a developing literature by examining the 24-month relationship between time attitudes and criterion variables. Four latent profiles called Positive, Ambivalent, Moderately Negative, and Negative, were identified. Results showed that time attitude profiles were generally unstable across the first three years of high school. However, those who stayed in the Positive profile developed higher self-efficacy in all domains. Transitioning to the Positive profile was associated with positive outcomes, whereas other transitions among profiles were associated with negative outcomes. There were small-sized, socio-demographic effects such that living in Northern Ireland (compared to Scotland), being male, and not being entitled to a free school meal, were all related to membership of, or transition to, the Positive profile. PMID- 29144981 TI - Barriers to self-compassion for female survivors of childhood maltreatment: The roles of fear of self-compassion and psychological inflexibility. AB - Preliminary evidence has demonstrated the benefits of targeting self-compassion in the treatment of posttraumatic stress disorder (PTSD). However, survivors of childhood maltreatment may present with unique challenges that compromise the effectiveness of these and other PTSD treatments. Specifically, childhood maltreatment victims often exhibit a marked fear and active resistance of self kindness and warmth (i.e., fear of self-compassion). Victims may also attempt to control distressing internal experiences in a way that hinders engagement in value-based actions (i.e., psychological inflexibility). Research suggests that psychological inflexibility exacerbates the negative effects of fear of self compassion. The present study expanded on previous research by examining the relations among childhood maltreatment, fear of self-compassion, psychological inflexibility, and PTSD symptom severity in 288 college women. As expected, moderate to severe levels of childhood maltreatment were associated with greater fear of self-compassion, psychological inflexibility, and PTSD symptom severity compared to minimal or no childhood maltreatment. A mediation analysis showed that childhood maltreatment had a significant indirect effect on PTSD symptom severity via fear of self-compassion, although a conditional process analysis did not support psychological inflexibility as a moderator of this indirect effect. A post hoc multiple mediator analysis showed a significant indirect effect of childhood maltreatment on PTSD symptom severity via psychological inflexibility, but not fear of self-compassion. These findings highlight the importance of addressing fear of self-compassion and psychological inflexibility as barriers to treatment for female survivors of childhood maltreatment. PMID- 29144982 TI - Bone mesenchymal stem cell secretion of sRANKL/OPG/M-CSF in response to macrophage-mediated inflammatory response influences osteogenesis on nanostructured Ti surfaces. AB - Although it has been well established that osteogenic differentiation of bone mesenchymal stem cells (bMSCs) as well as osteoclastic differentiation of macrophages can be manipulated by the nanostructure of biomaterial surfaces, the interactions among the effects of the surface on immune cells and bMSCs remained unknown. Therefore, in this study, the osteogenic behaviors and secretion of osteoclastogenesis-related cytokines of human bMSCs on TiO2 nanotubular (NT) surfaces in conditioned medium (CM) generated by macrophages cultured on the respective NT surfaces (NT-CM) were analyzed. Although bMSCs showed consistent osteogenic behaviors on the NT5 and NT20 surfaces in both standard culture medium and both types of NT-CM, collagen synthesis and extracellular matrix mineralization were partially impeded on the NT20 surface in NT20-CM and bMSC cytokine secretions on the NT20 surface in NT20-CM elicited remarkable multinuclear giant cell and osteoclast formation compared with that observed on the NT5 surface in NT5-CM. After implantation in vivo, mineralized bone formation was significantly delayed around the NT20 implant compared with the NT5 implant, but both surfaces contributed to good bone formation after 12 weeks. The results obtained in this study advance our understanding of the confounding influence of the implant surface nanostructure, macrophage inflammatory response, and osteogenic differentiation of bMSCs as well as the retro-regulative effects of bMSCs on the osteoclastic differentiation of macrophages, and the culture system based on different NT surfaces and CM generated on the respective surfaces may provide a systematic research model for evaluating the performance of endosseous implants as well as a prospective approach for improving implant osseointegration via immune-regulation. PMID- 29144983 TI - Albumin-coordinated assembly of clearable platinum nanodots for photo-induced cancer theranostics. AB - Photoactive noble metal nanoparticles are of increasing importance toward personalized cancer therapy in the field of precision nanomedicine. A critical challenge remains in the exploration of clinically potential noble metal nanoparticles for highly efficient cancer theranostics. Here, we introduce albumin-coordinated assembly of clearable Pt nanodots (Pt-NDs) with monodisperse nanostructure as high-performance theranostic agents for imaging-guided photothermal tumor ablation. We precisely manipulate the reduction and growth of tetravalent Pt ions into ultrasmall nanodots through albumin-directed growth kinetics, thereby leading to the synthesis of monodisperse 6.7 nm Pt-NDs with albumin molecules as the corona. Pt-NDs exhibit the surface plasmon resonance at 225 nm with enhanced near-infrared (NIR) absorbance, ideal resistance to photo bleaching, distinct photoacoustic and X-ray signals, as well as remarkable photothermal effect through non-radiative relaxation under NIR light irradiation. In particular, Pt-NDs possess preferable tumor accumulation, and effective in vivo excretory capability. Thus, these nanodots promote preferable in vivo microscopic photoacoustics and spatially anatomic CT imaging with enhanced contrast, as well as potent hyperthermia-mediated tumor ablation. These findings represent a facile and general approach to fabricate high-performance noble metal nanostructures with clinical potential for cancer theranostics. PMID- 29144984 TI - Developing a scale to assess health regulatory focus. AB - RATIONALE: Regulatory focus (i.e., focus on motivation to achieve gains or avoid losses and non-gains) is used to tailor health behavior change interventions, improving efficacy, but is currently assessed by scales that are not health specific and may capture a version of the construct that is not ideally matched to the rationale for tailoring. OBJECTIVE: We developed and validated a Health Regulatory Focus Scale (HRFS), which assesses tendencies to avoid negative health consequences (prevention focus) or achieve positive health outcomes (promotion focus). METHODS: Across four studies (and a scale development study in supplementary online materials), we established convergent, discriminant, and predictive validity for the HRFS. In studies examining predictive validity, main outcome measures were health behavior intentions, including intentions to reduce alcohol use, quit smoking, eat a healthy diet, exercise, be screened for cancer, and engage in general cancer preventive behaviors. RESULTS: The promotion and prevention sub-scales performed well in confirmatory factor analyses. Single factor models had significantly poorer fit than models delineating promotion and prevention. The sub-scales were differentially (and only modestly) correlated with related constructs (anxiety, optimism, information avoidance, ambiguity/fatalism). Higher HRFS-Promotion focus generally corresponded with greater health behavior intentions. Conversely, higher HRFS-Prevention focus corresponded with lower health behavior intentions. Associations were largely maintained even when controlling for established regulatory focus measures, supporting the assertion that the HRFS would predict unique variance in health behavior intentions. CONCLUSION: The HRFS has the potential to improve the precision with which framed health messages change behavior, as it may assess a version of regulatory focus that is more ideally matched to rationale for tailoring interventions. PMID- 29144985 TI - A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia. AB - This Phase 1/2, dose-escalating study of rigosertib enrolled 22 patients with higher-risk myelodysplastic syndromes (MDS) (n=9) and acute myeloid leukemia (AML; n=13) who had relapsed or were refractory to standard therapy and for whom no second-line therapies were approved. Patients received 3- to 7-day continuous intravenous infusions of rigosertib, an inhibitor of Ras-effector pathways that interacts with the Ras-binding domains, common to several signaling proteins including Raf and PI3 kinase. Rigosertib was administered at doses of 650 1700mg/m2/day in 14-day cycles. Initial dose escalation followed a Fibonacci scheme, followed by recommended phase 2 dose confirmation in an expanded cohort. Rigosertib was well tolerated for up to 23 cycles, with no treatment-related deaths and 18% of patients with related serious adverse events (AEs). Common AEs were fatigue, diarrhea, pyrexia, dyspnea, insomnia, and anemia. Rigosertib exhibited biologic activity, with reduction or stabilization of bone marrow blasts and improved peripheral blood counts in a subset of patients. Ten of 19 evaluable patients (53%) demonstrated bone marrow/peripheral blood responses (n=4 MDS, n=1 AML) or stable disease (n=3 MDS, n=2 AML). Median survival was 15.7 and 2.0 months for responders and non-responders, respectively. Additional studies of rigosertib are ongoing in higher-risk MDS (NCT00854646). PMID- 29144986 TI - Decadal changes in emissions of volatile organic compounds (VOCs) from on-road vehicles with intensified automobile pollution control: Case study in a busy urban tunnel in south China. AB - In the efforts at controlling automobile emissions, it is important to know in what extent air pollutants from on-road vehicles could be truly reduced. In 2014 we conducted tests in a heavily trafficked tunnel in south China to characterize emissions of volatile organic compounds (VOC) from on-road vehicle fleet and compared our results with those obtained in the same tunnel in 2004. Alkanes, aromatics, and alkenes had average emission factors (EFs) of 338, 63, and 42 mg km-1 in 2014 against that of 194, 129, and 160 mg km-1 in 2004, respectively. In 2014, LPG-related propane, n-butane and i-butane were the top three non-methane hydrocarbons (NMHCs) with EFs of 184 +/- 21, 53 +/- 6 and 31 +/- 3 mg km-1; the gasoline evaporation marker i-pentane had an average EF of 17 +/- 3 mg km-1; ethylene and propene were the top two alkenes with average EFs of 16 +/- 1 and 9.7 +/- 0.9 mg km-1, respectively; isoprene had no direct emission from vehicles; toluene showed the highest EF of 11 +/- 2 mg km-1 among the aromatics; and acetylene had an average EF of 7 +/- 1 mg km-1. While EFs of total NMHCs decreased only 9% from 493 +/- 120 mg km-1 in 2004 to 449 +/- 40 mg km-1 in 2014, their total ozone formation potential (OFP) decreased by 57% from 2.50 * 103 mg km-1 in 2004 to 1.10 * 103 mg km-1 in 2014, and their total secondary organic aerosol formation potential (SOAFP) decreased by 50% from 50 mg km-1 in 2004 to 25 mg km-1 in 2014. The large drop in ozone and SOA formation potentials could be explained by reduced emissions of reactive alkenes and aromatics, due largely to fuel transition from gasoline/diesel to LPG for taxis/buses and upgraded vehicle emission standards. PMID- 29144987 TI - Benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide induces human trophoblast Swan 71 cell dysfunctions due to cell apoptosis through disorder of mitochondrial fission/fusion. AB - Benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide (BPDE) is an endocrine disrupter and ultimate carcinogenic product of benzo(a)pyrene (BaP). Numerous studies have shown that BPDE causes trophoblast-related diseases, such as preeclampsia, growth restriction or miscarriages. However, the underlying mechanism, especially the mitochondria-related BPDE-induced trophoblast dysfunction remains unknown. In this study, we examined mitochondrial functions in BPDE-induced human trophoblast cell line Swan 71. BPDE decreased cell ability, attenuated cell invasion and HCG secretion, induced cell apoptosis, decreased mitochondrial membrane potential, increased reactive oxygen species (ROS) and MDA, and decreased SOD activity in a dose-dependent manner. In the mechanism, BPDE significantly increased pro apoptosis protein (P53 and Bak1) and decreased anti-apoptosis protein (Bcl-2). Furthermore, the protein expression levels of mitochondrial fusion genes (Mfn1, Mfn2, and OPA1) were decreased and those of fission genes (Fis1 and Drp1) were increased with increasing concentrations of BPDE and incubation time, resulting in the release of Cyt c and activation of Caspase 3, which irreversibly induced trophoblast cell apoptosis. This study reveals the mechanism of dysfunction of trophoblast cells through cell apoptosis due to the disorder of mitochondrial fission/fusion after exposure to BPDE, providing a further experimental understanding the adverse effects of BaP on trophoblast cells in early pregnancy. PMID- 29144988 TI - Di-(2-ethylhexyl) phthalate enhances melanoma tumor growth via differential effect on M1-and M2-polarized macrophages in mouse model. AB - Phthalates are widely used as plasticizers that influence sexual and reproductive development. Here, we investigated whether di-(2-ethylhexyl) phthalate (DEHP) affects macrophage polarization that are associated with tumor initiation and progression. No changes were observed in LPS- or ConA-stimulated in vitro spleen B or T cell proliferation for 48 h, respectively. In contrast, macrophage functions were inhibited in response to DEHP for 12 h as judged by LPS-induced H2O2 and NO production and zymosan A-mediated phagocytosis. When six weeks old male mice were pre-exposed to 4.0 mg/kg DEHP for 21 days before the injection of B16F10 melanoma cells and post-exposed to 4.0 mg/kg DEHP for 7 days, tumor nodule formation and the changes in tumor volume were higher than those in control group. Furthermore, when male mice were intraperitoneally pretreated with DEHP for 3 or 4 weeks and peritoneal exudate cells (PECs) or bone marrow-derived macrophages (BMDMs) were incubated with lipopolysaccharide (LPS), the expression of COX-2, TNF-alpha, and IL-6 was reduced in DEHP-pretreated cells as compared with that in LPS-stimulated control cells. While the production of nitric oxide (NO) for 18 h was reduced by LPS-stimulated PECs and M1-type BMDMs, IL-4 expression was enhanced in LPS-stimulated BMDMs. When BMDMs were incubated with IL-4 for 30 h, arginase 1 for M2-type macrophages was increased in transcriptional and translational level. Data implicate that macrophages were differentially polarized by DEHP treatment, which reduced M1-polarzation but enhanced M2-polarization. Taken together, these data demonstrate that DEHP could affect in vivo immune responses of macrophages, leading to the suppression of their tumor-preventing ability. This suggests that individuals at high risk for tumor incidence should avoid long-term exposure to various kind of phthalate including DEHP. PMID- 29144990 TI - Effects of childhood trauma on cortisol levels in suicide attempters and ideators. AB - OBJECTIVES: Suicide is a global health issue. Dysregulated hypothalamic-pituitary adrenal (HPA) axis activity, as measured by cortisol levels, has been identified as one potential risk factor for suicide. Recent evidence has indicated that blunted cortisol reactivity to stress is associated with suicidal behavior. The current study investigated whether childhood trauma was associated with blunted cortisol reactivity to a laboratory stressor and resting cortisol levels in suicide attempters and ideators. METHODS: 160 Participants were recruited and grouped according to history of previous suicidal attempt, suicidal ideation or as control participants. Participants completed background questionnaires, including the Childhood Trauma Questionnaire, before completing a laboratory stress task. Cortisol levels were assessed at rest and during the stress task. RESULTS: The highest levels of childhood trauma were reported in those who had attempted suicide (78.7%), followed by those who thought about suicide (37.7%) and then those with no suicidal history (17.8%). Moreover, regression analyses showed that childhood trauma was a significant predictor of blunted cortisol reactivity to stress and resting cortisol levels, such that higher levels of trauma were associated with lower cortisol levels in those with a suicidal history. Family history of suicide did not interact with the effects of childhood trauma on cortisol levels. CONCLUSIONS: These results indicate that childhood trauma is associated with blunted HPA axis activity in vulnerable populations in adulthood. The challenge for researchers is to elucidate the precise causal mechanisms linking trauma, cortisol and suicide risk and to investigate whether the effects of childhood trauma on cortisol levels are amendable to psychological intervention. PMID- 29144989 TI - Cysteine Dioxygenase 1 Mediates Erastin-Induced Ferroptosis in Human Gastric Cancer Cells. AB - BACKGROUND: Ferroptosis is a recently discovered form of iron-dependent nonapoptotic cell death. It is characterized by loss of the activity of the lipid repair enzyme, glutathione peroxidase 4 (GPX4), and accumulation of lethal reactive lipid oxygen species. However, we still know relatively little about ferroptosis and its molecular mechanism in gastric cancer (GC) cells. Here, we demonstrate that erastin, a classic inducer of ferroptosis, induces this form of cell death in GC cells and that cysteine dioxygenase 1 (CDO1) plays an important role in this process. METHODS: We performed quantitative real-time polymerase chain reaction, Western blotting, cell viability assay, reactive oxygen species (ROS) assay, glutathione assay, lipid peroxidation assay, RNAi and gene transfection, immunofluorescent staining, dual-luciferase reporter assay, transmission electron microscopy, and chromatin immunoprecipitation assay to study the regulation of ferroptosis in GC cells. Mouse xenograft assay was used to figure out the mechanism in vivo. RESULTS: Silencing CDO1 inhibited erastin induced ferroptosis in GC cells both in vitro and in vivo. Suppression of CDO1 restored cellular GSH levels, prevented ROS generation, and reduced malondialdehyde, one of the end products of lipid peroxidation. In addition, silencing COO1 maintained mitochondrial morphologic stability in erastin-treated cells. Mechanistically, c-Myb transcriptionally regulated CDO1, and inhibition of CDO1 expression upregulated GPX4 expression. CONCLUSIONS: Our findings give a better understanding of ferroptosis and its molecular mechanism in GC cells, gaining insight into ferroptosis-mediated cancer treatment. PMID- 29144991 TI - Finite element simulation on posterior tibial tendinopathy: Load transfer alteration and implications to the onset of pes planus. AB - BACKGROUND: Posterior tibial tendinopathy is a challenging foot condition resulting in pes planus, which is difficult to diagnose in the early stage. Prior to the deformity, abnormal internal load transfer and soft tissue attenuation are anticipated. The objective of this study was to investigate the internal load transfer and strain of the ligaments with posterior tibial tendinopathy, and the implications to pes planus and other deformities. METHODS: A three-dimensional finite element model of the foot and ankle was reconstructed from magnetic resonance images of a 28-year-old normal female. Thirty bones, plantar fascia, ligaments and tendons were reconstructed. With the gait analysis data of the model subject, walking stance was simulated. The onset of posterior tibial tendinopathy was resembled by unloading the tibialis posterior and compared to the normal condition. FINDINGS: The load transfer of the joints at the proximal medial column was weaken by posterior tibial tendinopathy, which was compromised by the increase along the lateral column and the intercuneiforms during late stance. Besides, the plantar tarsometatarsal and cuboideonavicular ligaments were consistently over-stretched during stance. Particularly, the maximum tensile strain of the plantar tarsometatarsal ligament was about 3-fold higher than normal at initial push-off. INTERPRETATION: Posterior tibial tendinopathy altered load transfer of the medial column and unbalanced the load between the proximal and distal side of the medial longitudinal arch. Posterior tibial tendinopathy also stretched the midfoot plantar ligaments that jeopardized midfoot stability, and attenuated the transverse arch. All these factors potentially contributed to the progress of pes planus and other foot deformities. PMID- 29144992 TI - Intracerebroventricular injection of miR-146a relieves seizures in an immature rat model of lithium-pilocarpine induced status epilepticus. AB - OBJECTIVE: Status epilepticus (SE) is a common, life-threatening neurological emergency that confers a high degree of morbidity and mortality. Increasing evidence indicates that neuroinflammation plays a critical role in the pathogenesis of SE. MicroRNA-146a (miR-146a) has been reported to be an important posttranscriptional inflammation-associated microRNA. The aim of this study was to investigate the effect of miR-146a in SE and the mechanism by which it operates. METHODS: To study the effect of miR-146a in SE, we chose intracerebroventricular injection for rat at 21-28days old, and made a lithium pilocarpine-induced SE rat model. We assessed latency time and Lado grade by behavior observation. We performed qPCR, ELISA and western blot tests on rat hippocampus to measure the expression levels of miR-146a, IL-1beta, TNF-alpha, TLR4 and NF-kappaB. RESULTS: In the miR-146a antagomir injection group, the latency to generalized convulsions was shorter, the duration and degree of seizures were more severe, the expression level of miR-146a was clearly decreased, and IL-1beta, TNF-alpha, TLR4 and NF-kappaB were all significantly up regulated. The opposite was true for rats treated with miR-146a agomir. CONCLUSION: Our findings elucidate the role of inflammation in the pathogenesis of SE in immature rats, and show that regulating the expression level of miR-146a may provide a novel insights into the pathogenesis of SE. PMID- 29144993 TI - Evaluate the effects of antiepileptic drugs on reproductive endocrine system in newly diagnosed female epileptic patients receiving either Valproate or Lamotrigine monotherapy: A prospective study. AB - OBJECTIVE: To investigate the development of reproductive endocrine changes in Indian women with epilepsy initiating on either Valproate (VPA) or Lamotrigine (LTG) monotherapy. METHODS: Reproductive hormonal profiles, hirsutism, ovarian morphology by ultrasonography and menstrual cycle data in newly diagnosed women with epilepsy taking VPA (n=34) or LTG (n=32) monotherapy were compared. None of the women were receiving hormonal contraception. Patients gave details of seizure type and frequency, medical and drug history. Body weight and fasting insulin, glucose, testosterone, dihyroepiandrosterone sulfate (DHEAS), androstenedione, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle stimulating hormone (FSH) were measured. Body mass index, free androgen index and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Longitudinal evaluations were done at 6th month and at 12th month. After 12th month some VPA-treated women were replaced with LTG and further followed-up twice in next six months. RESULTS: The mean testosterone level was significant increased in VPA-treated women at 6th month (p=0.03), then at 12th month (p=0.01). More women in the valproate group than the lamotrigine group developed hirsutism (p=0.06), menstrual disturbances (p=0.02) and PCOS (p=0.001). Before valproate therapy, 32% of the patients were obese, this percentage rose to 47% after treatment (p=0.03). A significant positive correlation was existed between obesity (BMI >25) and the development of menstrual disturbances (p=0.006), serum testosterone levels (p=0.02) and PCOS (p=0.03). Insulin resistance (HOMA-IR >2.5) was significant correlated with menstrual disturbances (p=0.03) and serum testosterone levels (p=0.02). Substitution of VPA with LTG results in significant reduction in mean testosterone levels (p=0.005) and means body weight at 6th month (p=0.01). CONCLUSION: Long-term valproate therapy in Indian women with epilepsy was associated with development of menstrual disturbances, alterations in reproductive hormonal function and increased the risk to developed PCOS. PMID- 29144994 TI - Gene pathways associated with mitochondrial function, oxidative stress and telomere length are differentially expressed in the liver of rats fed lifelong on virgin olive, sunflower or fish oils. AB - This study investigates the effect of lifelong intake of different fat sources rich in monounsaturated (virgin olive oil), n6 polyunsaturated (sunflower oil) or n3 polyunsaturated (fish oil) fatty acids in the aged liver. Male Wistar rats fed lifelong on diets differing in the fat source were killed at 6 and at 24 months of age. Liver histopathology, mitochondrial ultrastructure, biogenesis, oxidative stress, mitochondrial electron transport chain, relative telomere length and gene expression profiles were studied. Aging led to lipid accumulation in the liver. Virgin olive oil led to the lowest oxidation and ultrastructural alterations. Sunflower oil induced fibrosis, ultrastructural alterations and high oxidation. Fish oil intensified oxidation associated with age, lowered electron transport chain activity and enhanced the relative telomere length. Gene expression changes associated with age in animals fed virgin olive oil and fish oil were related mostly to mitochondrial function and oxidative stress pathways, followed by cell cycle and telomere length control. Sunflower oil avoided gene expression changes related to age. According to the results, virgin olive oil might be considered the dietary fat source that best preserves the liver during the aging process. PMID- 29144995 TI - Content analysis of homeless smokers' perspectives on established and alternative smoking interventions. AB - BACKGROUND: Cigarette smoking is 5 times more prevalent among homeless individuals than in the general population, and homeless individuals are disproportionately affected by smoking-related morbidity and mortality. Homeless smokers report interest in changing their smoking behavior; however, established smoking cessation interventions are neither desirable to nor highly effective for most members of this population. The aim of this study was to document homeless smokers' perceptions of established smoking interventions as well as self generated, alternative smoking interventions to elucidate points for intervention enhancement. METHODS: Participants (N=25) were homeless smokers who responded to semistructured interviews regarding smoking and nicotine use as well as experiences with established and alternative smoking interventions. Conventional content analysis was used to organize data and identify themes. RESULTS: Participants appreciated providers' initiation of conversations about smoking. They did not, however, feel simple advice to quit was a helpful approach. Instead, they suggested providers use a nonjudgmental, compassionate style, offer more support, and discuss a broader menu of options, including nonabstinence based ways to reduce smoking-related harm and improve health-related quality of life. Most participants preferred engaging in their own self-defined, alternative smoking interventions, including obtaining nicotine more safely (e.g., vaping, using smokeless tobacco) and using behavioral (e.g., engaging in creative activities and hobbies) and cognitive strategies (e.g., reminding themselves about the positive aspects of not smoking and the negative consequences of smoking). Abrupt, unaided quit attempts were largely unsuccessful. CONCLUSIONS: The vast majority of participants with the lived experience of homelessness and smoking were uninterested in established smoking cessation approaches. They did, however, have creative ideas about alternative smoking interventions that providers may support to reduce smoking-related harm and enhance quality of life. These ideas included providing information about the relative risks of smoking and the relative benefits of alternative strategies to obtaining nicotine and avoiding smoking. PMID- 29144996 TI - New roles and controls of mast cells. AB - Mast cells are innate immune cells implicated in immune surveillance and defense. They are filled with secretory granules where a vast array of molecules endowed with multiple biological activities are stored. The process of granule secretion, named degranulation, is a tightly controlled biological phenomenon that allows mast cells to rapidly and efficiently release bioactive mediators in response to extracellular stimuli. MC degranulation allows fighting pathogens, limiting envenomation and contributes to tissue homeostasis. However, it is also a potentially harmful response that plays a key role in the development of allergy and inflammatory diseases. Recent findings revealed that MC degranulation is a complex modular process that can be controlled at multiple levels. First, mast cells can decode different activation stimuli into two main patterns of degranulation that differently impact inflammatory responses. Second, mast cells in contact with antibody-opsonized cells or parasites form antibody-dependent degranulatory synapse for dedicated secretion and defense. Third, IL-33 fine tunes FcR-mediated degranulation at the single cell level. Together these recent findings show how mast cells adapt their degranulation responses to environmental cues and highlight the remarkable functional plasticity of these cells. PMID- 29144997 TI - Examination of a therapeutic-recreation based clinical placement for undergraduate nursing students: A self-determined perspective. AB - Nursing students across the globe are expected to undertake clinical placements. To date, there have been no studies that have examined the potential educational benefits for undergraduate nursing students engaged in a mental health clinical placement grounded in self-determination theory. The present study examined the experiences of undergraduate students engaged in a mental health clinical placement termed Recovery Camp. An ethnographic methodology within a case study approach was used. The researchers were immersed in the clinical placement, which took place at a YMCA camp facility. Participants were 20 3rd year undergraduate nursing students. To gain insight and understanding, the researchers used interviews, observations, and reflective journals. The constant-comparative method was used to analyse the data. Emergent themes identified from systematic analysis were: (a) social connection and (b) experiential learning. Recovery Camp facilitated a sense of inclusion and positive/supportive behaviour. It also enhanced student learning and understanding of symptoms of mental illness. Findings from this study support and extend findings for the use of therapeutic recreation based work placement experiences in the clinical education of future nurses. Findings demonstrated a link between this type of placement and undergraduate student's development of deeper knowledge of symptoms and experiences associated with mental illness. PMID- 29144998 TI - Work-based learning in health care organisations experienced by nursing staff: A systematic review of qualitative studies. AB - The aim of this review is to systematically summarise qualitative evidence about work-based learning in health care organisations as experienced by nursing staff. Work-based learning is understood as informal learning that occurs inside the work community in the interaction between employees. Studies for this review were searched for in the CINAHL, PubMed, Scopus and ABI Inform ProQuest databases for the period 2000-2015. Nine original studies met the inclusion criteria. After the critical appraisal by two researchers, all nine studies were selected for the review. The findings of the original studies were aggregated, and four statements were prepared, to be utilised in clinical work and decision-making. The statements concerned the following issues: (1) the culture of the work community; (2) the physical structures, spaces and duties of the work unit; (3) management; and (4) interpersonal relations. Understanding the nurses' experiences of work based learning and factors behind these experiences provides an opportunity to influence the challenges of learning in the demanding context of health care organisations. PMID- 29144999 TI - Communicating out loud: Midwifery students' experiences of a simulation exercise for neonatal resuscitation. AB - Midwifery students feel unprepared to deal with commonly encountered emergencies, such as neonatal resuscitation. Clinical simulation of emergencies may provide a safe forum for students to develop necessary skills. A simulation exercise, for neonatal resuscitation, was developed and evaluated using qualitative methods. Pre and post-simulation questions focussed on student confidence and knowledge of resuscitation. Data were analysed using a thematic analysis approach. Pre simulation questions revealed that most students considered themselves not very confident/unsure about their level of confidence in undertaking neonatal resuscitation. Most correctly identified features of the neonate requiring resuscitation. Post-simulation, students indicated that their confidence and knowledge of neonatal resuscitation had improved. Themes included: gaining confidence; understanding when to call for help; understanding the principles of resuscitation; tailoring simulation/education approaches to student needs. Students benefits included improved knowledge, confidence and skills. Participants unanimously suggested a program of simulation exercises, over a longer period of time, to reinforce knowledge and confidence gains. Ideally, students would like to actively participate in the simulation, rather than observe. PMID- 29145000 TI - Proopiomelanocortin processing and prohormone convertase 1 level in dogs with pituitary corticotroph tumors. AB - Preliminary data suggest that prohormone convertase 1 (PC1/3) protein expression and proopiomelanocortin (POMC) processing are altered in large corticotroph tumors. The aim of this study was to characterize the levels of ACTH precursors and PC1/3 protein in small and large corticotroph tumors of dogs with Cushing's disease. Pituitary tumors of dogs with Cushing's disease were collected postmortem 30 min to 12h after natural death or euthanasia, and classified as small or large. POMC, pro-ACTH, and PC1/3 were detected by Western blotting. Five small and 6 large corticotroph tumors were collected. POMC and pro-ACTH signals were visualized in 5/6 large tumors and in 4/5 small tumors. The strongest signal intensity was observed in 2 large tumors. The PC1/3 signal was weak to undetectable in 6/6 large tumors but strong in 5/5 small tumors. These results suggest differences in PC1/3 protein levels and patterns of POMC processing between large and small corticotroph tumors. If confirmed in larger groups of tumors, further studies will be required to characterize the mechanism involved in these differences. PMID- 29145001 TI - In vitro and in vivo evaluation of 10-hydroxycamptothecin-loaded poly (n-butyl cyanoacrylate) nanoparticles prepared by miniemulsion polymerization. AB - In this paper, 10-hydroxycamptothecin (HCPT)-loaded poly (n-butyl cyanoacrylate) nanoparticles (HCPT-PBCA-NPs) co-modified with polysorbate 80, soybean phospholipids, and polyethylene glycol (100) monostearate were successfully prepared via miniemulsion polymerization, and were characterized for particle size, morphology, zeta potential, encapsulation efficiency (EE) and drug loading capacity (DL). The chemical structure of HCPT-PBCA-NPs and the state of HCPT in the PBCA-NPs were investigated by DSC, FTIR and 1H NMR. Additionally, drug release, cytotoxicity, cellular uptake capacity, cellular uptake mechanism, and in vivo behavior of NPs were investigated as well. The particles were 92.7nm in size with a high EE of 94.24%. FTIR, 1H NMR, and DSC demonstrated complete polymerization of BCA monomers and the drug was in a molecular or amorphous form inside the NPs. In vitro release of the drug from HCPT-PBCA-NPs exhibited sustained-release and less than 60% of HCPT was released from the NPs within 24h of dialysis. Cellular uptake study displayed that Caco-2 cell uptake of NPs was governed by active endocytosis, clathrin- and caveolin-mediated process, and increased with the increase of the NPs concentration and the time. The pharmacokinetic study in rats showed that encapsulation of HCPT into PBCA-NPs increased the Cmax and AUC0-t about 6.52 and 7.56 times, respectively, in comparison with the HCPT suspension. It was concluded that HCPT loaded PBCA-NPs prepared by miniemulsion polymerization could be promising in oral drug delivery. PMID- 29145002 TI - Different transport behaviors of Bacillus subtilis cells and spores in saturated porous media: Implications for contamination risks associated with bacterial sporulation in aquifer. AB - In this study, we compared the transport characteristics of Bacillus subtilis cells and their spores in saturated porous media. Both the bacteria cells and spores were readily transported under lower ionic strengths (IS) (1mM), featuring high mass recovery rates (>75%). The bacteria cells recovery rate declined to 58.05% when the IS increased to 100mM; but the spores recovery rate remained at 74.54%. Spores appear to be more mobile than bacterial cells over wide range of IS. Surface properties and breakthrough curves analysis of the two bio-particles (cells and spores) indicated that attachment, straining and blocking mechanisms contribute differently to deposition processes. The extended Derjaguin-Landau Verwey-Overbeek (XDLVO) theory further indicated that the particles attachment may primarily occurred at the secondary energy minimum. More important, XDLVO calculations showed that the dominant forces changed with IS, altering the efficiency of particles attachment. The electric double layer repulsion mainly controlled particle deposition at 1mM. In contrast, the van der Waals attraction and Lewis acid-base interactions dominated particle deposition at 100mM. This study showed that spores are more mobile than bacteria cells in subsurface environment. Given that spores form under harsh environmental conditions, we must consider spore formation and transport when groundwater microbial contamination occurs. PMID- 29145003 TI - The importance of Saprinus semistriatus (Coleoptera: Histeridae) for estimating the minimum post-mortem interval. AB - In forensic science, the use of entomological evidence to estimate the minimum post-mortem interval can be crucial. However, not all cadaver-visiting insects are equally useful. Our focus is on the histerid beetle Saprinus semistriatus (Scriba 1790) (Histeridae; Coleoptera). Histeridae are common predators that feed mainly on dipteran larvae on carrion and dung. We review 23 publications mentioning this species and provide new experimental data on its temporal pattern beneath and on hanging pig cadavers. In a field experiment near Neuchatel, Switzerland, we recorded the abundance of S. semistriatus on ten decomposing pig cadavers (Sus scrofa) over a 32-day period in summer 2013 (July, 01- August; 02). Five cadavers were placed on the ground and five cadavers were hung one metre above the ground. Insects were collected from pitfall traps and by manual sampling. The abundance of S. semistriatus was significantly higher during the active stage than during the fresh and the bloated stages of decomposition in both, ground and hanging pigs. However, S. semistriatus was more abundant on the ground than on the hanging cadavers. The literature and our new data show that S. semistriatus is present on cadavers during a relatively short period of time (approximately two weeks), mainly during the active decay stage, but it may also occasionally occur in the bloated stage. Identifying key indicators such as S. semistriatus can help optimise forensic research by focusing on the most informative taxa. A few key indicators for each decomposition stage may constitute an optimal toolbox for forensic entomologists. PMID- 29145004 TI - Effects of primary care physician density, urologist presence, and insurance status on stage of diagnosis for urologic malignancies. AB - OBJECTIVE: To evaluate effects of PCP density, insurance status, and urologist presence on stage of diagnosis for urologic malignancies. Cancer stage at diagnosis is an important outcome predictor. Studies have shown an inverse relationship to primary care physician (PCP) density and insurance coverage with stage of cancer diagnosis. METHODS: Data was obtained from OK2Share, an Oklahoma Central Cancer Registry, for bladder, kidney, and prostate cancer from 2000 to 2010. Physician data was obtained through the State Licensing Board. The 2010 national census was used for population data. High PCP density was defined as greater than or equal to the median value: 3.17 PCP/10,000 persons. Chi-square and multivariate logistic regressions were used to analyze effects of PCP density, insurance status, and urologist presence on advanced stage diagnosis. RESULTS: 27,086 patients were identified across 77 counties. As PCP density increased by 1 PCP/10,000 persons, the odds ratios (OR) of an advanced stage at diagnosis were 0.383, 0.468, 0.543 for bladder, kidney, and prostate cancer respectively. Compared to private insurance, being uninsured had OR of 1.61 and 2.45 respectively for kidney and prostate cancers. The OR of an advanced stage diagnosis for bladder and prostate cancer were 3.77 and 1.73, respectively, in counties with a urologist. CONCLUSIONS: Increased PCP density and insurance coverage reduced the odds of an advanced diagnosis. Implementation of policies to improve access to healthcare including through increasing PCP density and reducing the number of uninsured patients should result in diagnosis at an earlier stage, which will likely improved cancer-related outcomes. PMID- 29145005 TI - Assessment of long-term spatio-temporal radiofrequency electromagnetic field exposure. AB - As both the environment and telecommunications networks are inherently dynamic, our exposure to environmental radiofrequency (RF) electromagnetic fields (EMF) at an arbitrary location is not at all constant in time. In this study, more than a year's worth of measurement data collected in a fixed low-cost exposimeter network distributed over an urban environment was analysed and used to build, for the first time, a full spatio-temporal surrogate model of outdoor exposure to downlink Global System for Mobile Communications (GSM) and Universal Mobile Telecommunications System (UMTS) signals. Though no global trend was discovered over the measuring period, the difference in measured exposure between two instances could reach up to 42dB (a factor 12,000 in power density). Furthermore, it was found that, taking into account the hour and day of the measurement, the accuracy of the surrogate model in the area under study was improved by up to 50% compared to models that neglect the daily temporal variability of the RF signals. However, further study is required to assess the extent to which the results obtained in the considered environment can be extrapolated to other geographic locations. PMID- 29145007 TI - Sleep preserves original and distorted memory traces. AB - Retrieval facilitates the long-term retention of memories, but may also enable stored representations to be updated with new information that is available at the time of retrieval. However, if information integrated during retrieval is erroneous, future recall can be impaired: a phenomenon known as retrieval-induced distortion (RID). Whether RID causes an "overwriting" of existing memory traces or leads to the co-existence of original and distorted memory traces is unknown. Because sleep enhances memory consolidation, the effects of sleep after RID can provide novel insights into the structure of updated memories. As such, we investigated the effects of sleep on memory consolidation following RID. Participants encoded word locations and were then tested before (T1) and after (T2) an interval of sleep or wakefulness. At T2, the majority of words were placed closer to the locations retrieved at T1 than to the studied locations, consistent with RID. After sleep compared with after wake, the T2-retrieved locations were closer to both the studied locations and the T1-retrieved locations. These findings suggest that RID leads to the formation of an additional memory trace that corresponds to a distorted variant of the same encoding event, which is strengthened alongside the original trace during sleep. More broadly, these data provide evidence for the importance of sleep in the preservation and adaptive updating of memories. PMID- 29145006 TI - A cross-disciplinary evaluation of evidence for multipollutant effects on cardiovascular disease. AB - BACKGROUND: The current single-pollutant approach to regulating ambient air pollutants is effective at protecting public health, but efficiencies may be gained by addressing issues in a multipollutant context since multiple pollutants often have common sources and individuals are exposed to more than one pollutant at a time. OBJECTIVE: We performed a cross-disciplinary review of the effects of multipollutant exposures on cardiovascular effects. METHODS: A broad literature search for references including at least two criteria air pollutants (particulate matter [PM], ozone [O3], oxides of nitrogen, sulfur oxides, carbon monoxide) was conducted. References were culled based on scientific discipline then searched for terms related to cardiovascular disease. Most multipollutant epidemiologic and experimental (i.e., controlled human exposure, animal toxicology) studies examined PM and O3 together. DISCUSSION: Epidemiologic and experimental studies provide some evidence for O3 concentration modifying the effect of PM, although PM did not modify O3 risk estimates. Experimental studies of combined exposure to PM and O3 provided evidence for additivity, synergism, and/or antagonism depending on the specific health endpoint. Evidence for other pollutant pairs was more limited. CONCLUSIONS: Overall, the evidence for multipollutant effects was often heterogeneous, and the limited number of studies inhibited making a conclusion about the nature of the relationship between pollutant combinations and cardiovascular disease. PMID- 29145008 TI - Morphological changes in erythrocytes of people with type 2 diabetes mellitus evaluated with atomic force microscopy: A brief review. AB - : Prevalence of type 2 diabetes mellitus (T2DM) has been increasing worldwide. Cardiovascular diseases are one of the main causes of death among people with T2DM. Morphological changes in erythrocytes have been associated with higher risk of cardiovascular diseases. Atomic force microscopy (AFM) is a new technique that allows non-invasive imaging of cells and the evaluation of changes in mechanical properties. AIM: To evaluate by AFM the erythrocytes morphological changes of people with T2DM METHODS: Search was conducted from in PubMed, ScienceDirect, Scielo, and Lilacs. Erythrocyte, type 2 Diabetes Mellitus and, Microscopy, Atomic Force were the keywords used for the search. Papers included were cross-sectional studies performed in humans. RESULTS: Five of seven articles fulfilled the inclusion criteria. Compared with healthy cells, the erythrocytes from individuals affected by T2DM had morphological changes such as a decreased concave depth, diameter, height and a deformation index, while axial ratio, stiffness, adhesive force, aggregation, and rigidity index were increased. The results regarding the erythrocyte roughness were inconclusive. CONCLUSIONS: The AFM is an excellent instrument to study the altered erythrocytes of subjects affected by T2DM. Morphology changes in erythrocytes could lead to cardiovascular events, which are major complications in people living with this disease. PMID- 29145009 TI - Sperm morphology of predatory pirate bugs Amphiareus constrictus and Blaptostethus pallescens (Heteroptera: Anthocoridae) with phylogenetic inferences. AB - The sperm morphology of two predatory bugs Amphiareus constrictus and Blaptostethus pallescens, representing the tribes Dufouriellini and Blasptostethini, respectively, was described using light and transmission electron microscopy. The spermatozoa of Amphiareus constrictus and Blaptostethus pallescens are fine and long, each measuring 216.6MUm and 181.0MUm in length, of which 37.0MUm and 11.6MUm, respectively, comprise the nuclei. When stained with DAPI (for DNA), the posterior half of the nucleus in B. pallescens exhibited low fluorescence, while in A. constrictus this feature was observed only in the last 6MUm. In both species, as in Heteroptera in general, the spermatozoa have, in the head region, an acrosome and nucleus, and in the flagellar region, an axoneme with 9 accessory tubules, 9 peripheral doublets and 2 central microtubules (9+9+2 microtubules), 2 mitochondrial derivatives (MDs), and a centriolar adjunct in the nucleus-flagellum transition. However, unlike most Heteroptera, in these species, the MDs are asymmetric, and the centriolar adjunct is quite long and encompasses completely the posterior nuclear end and the anterior tips of the MDs. These features are considered as derived, thus supporting the condition derived of Anthocoridae within Cimicomorpha. In addition, several traits of the spermatozoa of these two species easily distinguish one species (and probably a tribe) from the other; for example, the difference of formats in the MDs, and the long anterior projection of the centriolar adjunct parallel to the nucleus in B. pallescens. PMID- 29145010 TI - The use of hardened bone cement as an impaction grafting extender for revision hip arthroplasty. AB - Impaction bone grafting is a method of restoring bone stock to patients who have suffered significant bone loss due to revision total hip surgery. The procedure requires morsellised cancellous bone (MCB) to be impacted into the site of bone loss in order to stabilise the prosthesis with the aim of long term resorption and reintegration of the impacted bone graft. Due to financial cost and the potential to transmit disease, the use of supplementary material, known as an extender, is frequently used to increase the graft material volume. This study investigates the use of hardened Hydroset (Stryker Corp, MA, USA), an injectable bone cement (IBC), as an extender material and compares the performance of the IBC in different weight percent inclusions to a commercially available bone graft extender (GCP, BoneSave, Stryker Corp, MA, USA). The surgical impaction procedure was standardised and samples were evaluated in terms of graft stiffness and height. It was observed that 30wt% IBC extended samples had significantly improved graft stiffness (p = 0.02) and no significant different in height (p = 0.067) over a 100% MCB control sample. Cyclic loading, representative of gait, found that the IBC subsided similarly to the commercial bone substitute in wt% above 10%. Shear testing of the impacted grafts showed no significant differences between GCP and IBC with impaction forces determining the shear parameters of impacted grafts. The effects of the impaction and cyclical loading procedures on extender particle sizes was assessed via particle size analysis. It was found that the IBC extended samples demonstrated reduced friability, evident in the better retention of particle size as a result of both impaction and gait representative loading compared to that of the GCP samples. This indicates a potential reduction in issues arising from small particle migration to joint surfaces. Scanning electron microscopy of the MCB particles with both GCP and IBC as extenders showed retention of the porous trabecular structure post-testing which is essential for revascularisation and bone growth into the graft. PMID- 29145011 TI - Preparation of morselised bone for impaction grafting using a blender method. AB - Impaction bone grafting is a method of restoring bone stock to patients suffering significant bone loss due to revision total hip surgery. The procedure requires morselised bone (MB) to be impacted into the site of bone loss in order to stabilise the prosthesis with the aim of the long term resorption and reintegration of the impacted bone graft. Currently, the method for producing MB requires the use of expensive surgical bone mills or manually-intensive rongeurs that can produce a limited variety of particle sizes and may have a low throughput. This study examines the potential to produce suitable MB using a domestic blender. The method produces a wide range of particle sizes without the need for an adjustment of the system. It was found through packing modelling that this particle distribution resulted in reduced initial graft porosity and thus a theoretical potential to increase the graft stiffness and ability of the graft to stabilise a prosthesis in comparison to a manually prepared roughly cut morselised bone samples. Mechanical testing confirmed the increased mechanical performance of the graft through both impaction testing and subsidence testing. The blended MB was found to exhibit greater graft stiffness under the same impaction conditions. The graft was also found to have subsided less in comparison to the rough cut, less well graded MB. Scanning electron imaging also confirmed the retention of the trabecular structure necessary for revascularisation and host bone ingrowth. In conclusion, the blender method offers a rapid and cheap way of obtaining morselised bone with favourable particle size distribution, particle morphology and mechanical properties with preservation of the bone trabecular structure. PMID- 29145012 TI - The gut-brain interaction in opioid tolerance. AB - The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, includes persistent constipation and paradoxically may also worsen pain symptoms. Recent work has suggested a significant role of the gastrointestinal microbiome in behavioral responses to opioids, including the development of tolerance to its pain-relieving effects. In this review, we present current concepts of gut-brain interaction in analgesic tolerance to opioids and suggest that peripheral mechanisms emanating from the gut can profoundly affect central control of opioid function. PMID- 29145013 TI - Parenting and family adjustment scales (PAFAS): validation of a brief parent report measure for use with families who have a child with a developmental disability. AB - BACKGROUND: Children with a developmental disability are three to four times more likely than their typically developing peers of developing significant emotional and behavioural problems. There is strong evidence to suggest that individual biological and psychological factors interact with family functioning to precipitate and perpetuate these problems. AIMS: This study examined the psychometric properties of a brief measure, the Parent and Family Adjustment Scales (PAFAS) for use with parents of children with a developmental disability. METHODS: A sample of 914 parents of children (M=6.27years) with a developmental disability participated in the study. Disabilities included Autism Spectrum Disorder and Intellectual Disability RESULTS: A confirmatory factor analysis supported a 16-item, four factor model of PAFAS Parenting, and an 11-item, three factor model of PAFAS Family Adjustment. The Parenting Scale measures parental consistency, coercive practices, use of encouragement and the quality of parent child relationship. The Family Adjustment Scale measures parental emotional adjustment and partner and family support in parenting. CONCLUSIONS: The current study indicated that the PAFAS demonstrates promise as a brief measure of multiple domains of family functioning important for families who have a child with a developmental disability. PMID- 29145014 TI - Ecotracer: analyzing concentration of contaminants and radioisotopes in an aquatic spatial-dynamic food web model. AB - Ecotracer is a tool in the Ecopath with Ecosim (EwE) software package used to simulate and analyze the transport of contaminants such as methylmercury or radiocesium through aquatic food webs. Ecotracer solves the contaminant dynamic equations simultaneously with the biomass dynamic equations in Ecosim/Ecospace. In this paper, we give a detailed description of the Ecotracer module and analyze the performance on two problems of differing complexity. Ecotracer was modified from previous versions to more accurately model contaminant excretion, and new numerical integration algorithms were implemented to increase accuracy and robustness. To test the mathematical robustness of the computational algorithm, Ecotracer was tested on a simple problem for which we know an analytical solution. These results demonstrated the effectiveness of the program numerics. A much more complex model, the release of the cesium radionuclide 137Cs from the Fukushima Dai-ichi nuclear accident, was also modeled and analyzed. A comparison of the Ecotracer results to sampled 137Cs measurements in the coastal ocean area around Fukushima show the promise of the tool but also highlight some important limitations. PMID- 29145015 TI - Glial control of neurogenesis. AB - Glial cells are central components of all neurogenic niches in the embryonic as well as in the adult central nervous system. While neural stem cells (NSCs) themselves exhibit glial features the behavior of NSCs is also strongly influenced by niche glial cells. Recently, studies have begun to uncover a large variety of glial cell-extrinsic as well as intrinsic factors that play crucial roles in the control of NSCs and the regulation of the cellular output from the neurogenic niches. In this review, we focus on mechanisms underlying the formation of adult NSCs by embryonic radial glia cells, discuss the influence of niche glia cells on adult NSCs and examine how the neurogenic potential of glial cells is controlled. PMID- 29145016 TI - Thermal effect on the degradation of hIAPP20-29 fibrils. AB - Uncontrolled misfolding of proteins resulting in the formation of amyloid deposits is associated with over 40 types of diseases, for instance, type-2 diabetes. The human Islet amyloid polypeptide (hIAPP) amyloid formation is thought to be the cause of type-2 diabetes occurrence. A possible strategy to the current challenge of reducing the toxicity of its aggregates to pancreatic beta cell is the discovery of an efficient way to degrading amyloid deposits. In this work, hIAPP20-29, a core fibrillating fragment of hIAPP, was selected as model system to explore the thermal effect at different temperature on the degradation of hIAPP20-29 mature fibrils. Insights on the degradation mechanism are obtained by analyzing the morphologies, the mechanical properties, the interactions between the peptides, and the secondary structure of amyloid aggregates. In addition, thermal degradation displayed a possible way to breaking the interaction of peptides and further disassembling the amyloid fibrils. These findings may initiate a new avenue to degrade the amyloid peptide aggregates and enrich and update the current selection of nanostructure modulations. PMID- 29145017 TI - Membrane interactions of microgels as carriers of antimicrobial peptides. AB - Microgels are interesting as potential delivery systems for antimicrobial peptides. In order to elucidate membrane interactions of such systems, we here investigate effects of microgel charge density on antimicrobial peptide loading and release, as well as consequences of this for membrane interactions and antimicrobial effects, using ellipsometry, circular dichroism spectroscopy, nanoparticle tracking analysis, dynamic light scattering and z-potential measurements. Anionic poly(ethyl acrylate-co-methacrylic acid) microgels were found to incorporate considerable amounts of the cationic antimicrobial peptides LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES) and DPK-060 (GKHKNKGKKNGKHNGWKWWW) and to protect incorporated peptides from degradation by infection-related proteases at high microgel charge density. As a result of their net negative z potential also at high peptide loading, neither empty nor peptide-loaded microgels adsorb at supported bacteria-mimicking membranes. Instead, membrane disruption is mediated almost exclusively by peptide release. Mirroring this, antimicrobial effects against several clinically relevant bacteria (methicillin resistant Staphylococcus aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa) were found to be promoted by factors facilitating peptide release, such as decreasing peptide length and decreasing microgel charge density. Microgels were further demonstrated to display low toxicity towards erythrocytes. Taken together, the results demonstrate some interesting opportunities for the use of microgels as delivery systems for antimicrobial peptides, but also highlight several key factors which need to be controlled for their successful use. PMID- 29145018 TI - Nitrogen, phosphorus dual-doped molybdenum-carbide/molybdenum-phosphide-@-carbon nanospheres for efficient hydrogen evolution over the whole pH range. AB - MoO42-@aniline-pyrrole (MoO42-@polymer) spheres as precursors have been used to synthesize unique core-shell nanostructure consisting of molybdenum carbide and molybdenum phosphide composites encapsulated into uniformly dual N, P-doped carbon shells (Mo2C/MoP@NPC) through a facile two-step strategy. Firstly, porous core-shell N-doped Mo2C@C (Mo2C@NC) nanospheres have been synthesized with ultrafine Mo2C nanoparticles as core and ultrathin NC as shell by a annealing route. Secondly, Mo2C/MoP@NPC has been obtained maintaining intact spherical-like morphology through a phosphidation reaction in high temperature. The synergistic effect of Mo2C and MoP may reduce the strong MoH bonding energy of pure Mo2C and provide a fast hydrogen release process. In addition, the dual N, P-doped carbon matrix as shell can not only improve the electroconductivity of catalysts but also prevent the corrosion of Mo2C/MoP nanoparticles during the electrocatalytic process. When used as HER cathode in acids, the resulting Mo2C/MoP@NPC shows excellent catalytic activity and durability, which only needs an overpotential of 160 mV to drive 10 mA cm-2. Moreover, it also exhibits better HER performance in basic and neutral media with the need for overpotentials of only 169 and 228 mV to achieve 10 mA cm-2, respectively. This inorganic-organic combination of Mo based catalysts may open up a new way for water-splitting to produce large-scale hydrogen. PMID- 29145019 TI - Ordered cylindrical micropatterned Petri dishes used as scaffolds for cell growth. AB - Three-dimensional (3D) culture dish patterned with a microwell structure demonstrates a great application potential in biotechnology. This study reports on the easy fabrication of an ordered customizable honeycomb microwell array on the surface of polymer substrates including the commercial Petri dish to create a biological platform for cell culture. The fabrication method is based on a very simple solvent dip-coating technique and the methanol accumulation-induced phase separation in which a binary mixture of chloroform and methanol is used to induce a ternary solution and to guarantee the formation of the ordered pore array on the substrate. The surface topology of the honeycomb substrate is manipulated through varying the experimental conditions; notably, the obtained honeycomb structure is part of the substrate, which reveals an increase in the structure's stability for the practical applications. Honeycomb-structured Petri dish fabricated using this method is applied as a scaffold for cell growth to demonstrate its potential in biomedical applications. PMID- 29145020 TI - Evaluation of 7Be and 133Xe atmospheric radioactivity time series measured at four CTBTO radionuclide stations. AB - Time series analysis of 7Be and 133Xe atmospheric data and meteorological parameters measured at four CTBTO/IMS radionuclide stations have shown great variability in terms of noise structures, harmonic content, cross-correlation patterns and local Hurst exponent behaviour. This study focused on highlighting and characterising both differences and similarities expected for these radionuclides due to their different physical and chemical characteristics along with their different source terms. Detrended crosscorrelation analysis of different meteorological parameters influencing the residuals time series has shown that for Canadian and American stations the parameters mostly affecting radionuclide concentrations in the air seem to be wind direction and atmospheric pressure. PMID- 29145021 TI - Production of chemicals using dynamic control of metabolic fluxes. AB - Engineered microbial cell factories are constantly experiencing metabolic imbalance due to nutrients depletion, metabolites buildup, evolutionary pressure or genetic instability. It is important to equip the engineered cell factory with sensor-regulator system to enable cell adjust metabolism and respond to the changing environment. Dynamically allocating cellular resources and optimally controlling pathway expression have proved as promising strategies to manage the tradeoff between cell growth and product formation as well as improve the cost competitiveness of industrial fermentation. With metabolite-responsive transcriptional factors as basic tools, metabolic engineers are well positioned to engineer robust cell factories that achieve self-adaptation or autonomous control for both biotechnological and biomedical applications. In this review, we present promising dynamic control strategies that have been successfully applied to pathway optimization and chemical manufacturing. PMID- 29145022 TI - Valves in internal jugular vein: A reason of difficult central venous catheterization. PMID- 29145023 TI - Cardiac arrest following anaphylaxis induced by sugammadex in a regional hospital. PMID- 29145024 TI - Direct analysis of ethylene glycol in human serum on the basis of analyte adduct formation and liquid chromatography-tandem mass spectrometry. AB - The aim of this work was to develop a fast, cost-effective and time-saving liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method for the analysis of ethylene glycol (EG) in human serum. For these purposes, the formation/fragmentation of an EG adduct ion with sodium and sodium acetate was applied in the positive electrospray mode for signal detection. Adduct identification was performed with appropriate infusion experiments based on analyte solutions prepared in different concentrations. Corresponding analyte adduct ions and adduct ion fragments could be identified both for EG and the deuterated internal standard (EG-D4). Protein precipitation was used as sample preparation. The analysis of the supernatant was performed with a Luna 5MUm C18 (2) 100A, 150mm*2mm analytical column and a mobile phase consisting of 95% A (H2O/methanol=95/5, v/v) and 5% B (H2O/methanol=3/97, v/v), both with 10mmolL-1 ammonium acetate and 0.1% acetic acid. Method linearity was examined in the range of 100-4000MUg/mL and the calculated limit of detection/quantification was 35/98MUg/mL. However, on the basis of the signal to noise ratio, quantification was recommended at a limit of 300MUg/mL. Additionally, the examined precision, accuracy, stability, selectivity and matrix effect demonstrated that the method is a practicable alternative for EG quantification in human serum. In comparison to other methods based on liquid chromatography, the strategy presented made for the first time the EG analysis without analyte derivatisation possible. PMID- 29145025 TI - Coupling of on-column trypsin digestion-peptide mapping and principal component analysis for stability and biosimilarity assessment of recombinant human growth hormone. AB - Peptide mapping (PM) is a vital technique in biopharmaceutical industry. The fingerprint obtained helps to qualitatively confirm host stability as well as verify primary structure, purity and integrity of the target protein. Yet, in solution digestion followed by tandem mass spectrometry is not suitable as a routine quality control test. It is time consuming and requires sophisticated, expensive instruments and highly skilled operators. In an attempt to enhance the fuctionality of PM and extract multi-dimentional data about various critical quality attributes and comparability of biosimilars, coupling of PM generated using immobilized trypsin followed by HPLC-UV to principal component analysis (PCA) is proposed. Recombinant human growth hormone (rhGH); was selected as a model biopharmaceutical since it is available in the market from different manufacturers and its PM is a well-established pharmacopoeial test. Samples of different rhGH biosimilars as well as degraded samples: deamidated and oxidized were subjected to trypsin digestion followed by RP-HPLC-UV analysis. PCA of the entire chromatograms of test and reference samples was then conducted. Comparison of the scores of samples and investigation of the loadings plots clearly indicated the applicability of PM-PCA for: i) identity testing, ii) biosimilarity assessment and iii) stability evaluation. Hotelling's T2 and Q statistics were employed at 95% confidence level to measure the variation and to test the conformance of each sample to the PCA model, respectively. Coupling of PM to PCA provided a novel tool to identify peptide fragments responsible for variation between the test and reference samples as well as evaluation of the extent and relative significance of this variability. Transformation of conventional PM that is largely based on subjective visual comparison into an objective statiscally guided analysis framework should provide a simple and economic tool to help both manufacturers and regulatory authorities in quality and biosimilarity assessment of biopharmaceuticals. PMID- 29145026 TI - LC-MS/MS quantification of felinine metabolites in tissues, fluids, and excretions from the domestic cat (Felis catus). AB - Domestic cat urine contains large concentrations of the unusual amino acid, felinine (2-amino-7-hydroxy-5,5-dimethyl-4-thiaheptanoic acid). A felinine derivative, 3-mercapt-3-methylbutanol is a potential scent signal for letting other animals know that the scent owners are cats. 3-Methylbutanol-glutathione (MBG) is an upstream precursor of the biosynthetic pathway of felinine that may be produced in hepatocytes by conjugation of glutathione with isopentenyl pyrophosphate, an intermediate for cholesterol biosynthesis. However, little evidence exists to support the biosynthesis of MBG in the liver. This study examined the distribution of metabolites of the felinine biosynthetic pathway in multiple tissues, body fluids, and excretions of cats. MBG, the felinine precursor, 3-methylbutanol-cysteinylglycine (MBCG), felinine, and felinine N acetyl derivative were quantified by liquid chromatography-electron spray ionization-tandem mass spectrometry. All compounds were detected in cat serum. In males, MBG and MBCG contents were significantly higher than felinine and N acetylfelinine contents. MBG was detected in multiple tissues, including the salivary gland, heart, liver, spleen, gut, kidney, bladder, adipose tissue, and muscle. Sex differences in MBG levels were observed in the liver and other tissues. Felinine and N-acetylfelinine were also detected in those tissues. Furthermore, we detected all compounds in cat bile and fecal samples, indicating that felinine is excreted into the feces via bile from the liver. We conclude that MBG is synthesized in several tissues in a sex-dependent manner. These findings improve our understanding of felinine metabolism and function in cats. PMID- 29145027 TI - Differential gene expression in the intestine of sea cucumber (Apostichopus japonicus) under low and high salinity conditions. AB - Sea cucumber, Apostichopus japonicus is an important species for aquaculture, and its behavior and physiology can change in response to changing salinity conditions. For this reason, it is important to understand the molecular responses of A. japonicus when exposed to ambient changes in salinity. In this study, RNA-Seq provided a general overview of the gene expression profiles in the intestine of A. japonicus exposed to high salinity (SD40), normal salinity (SD30) and low salinity (SD20) environments. Screening for differentially expressed genes (DEGs) using the NOISeq method identified 109, 100, and 89 DEGs based on a fold change of >=2 and divergence probability >=0.8 according to the comparisons of SD20 vs. SD30, SD20 vs.SD40, and SD30 vs. SD40, respectively. Gene ontology analysis showed that the terms "metabolic process" and "catalytic activity" comprised the most enriched DEGs. These fell into the categories of "biological process" and "molecular function". While "cell" and "cell part" had the most enriched DEGs in the category of "cellular component". With these DEGs mapping to 2119, 159, and 160 pathways in the Kyoto Encyclopedia of Genes and Genomes database. Of these 51, 2, and 57 pathways were significantly enriched, respectively. The osmosis-specific DEGs identified in this study of A. japonicus will be important targets for further studies to understand the biochemical mechanisms involved with the adaption of sea cucumbers to changes in salinity. PMID- 29145028 TI - The complete mitochondrial genome of the alvinocaridid shrimp Shinkaicaris leurokolos (Decapoda, Caridea): Insight into the mitochondrial genetic basis of deep-sea hydrothermal vent adaptation in the shrimp. AB - Deep-sea hydrothermal vent is one of the most extreme environments on Earth with low oxygen and high levels of toxins. Decapod species from the family Alvinocarididae have colonized and successfully adapted to this extremely harsh environment. Mitochondria plays a vital role in oxygen usage and energy metabolism, thus it may be under selection in the adaptive evolution of the hydrothermal vent shrimps. In this study, the mitochondrial genome (mitogenome) of alvinocaridid shrimp Shinkaicaris leurokolos (Kikuchi & Hashimoto, 2000) was determined through Illumina sequencing. The mitogenome of S. leurokolos was 15,903bp in length, containing 13 protein-coding genes, 2 rRNAs, and 22 tRNAs. The gene order and orientation were identical to those of sequenced alvinocaridids. It has the longest concatenated sequences of protein-coding genes, tRNAs and shortest pooled rRNAs among the alvinocaridids. The control regions (CRs) of alvinocaridid were significantly longer (p<0.01) than those of the other caridaen. The alignment of the alvinocaridid CRs revealed two conserved sequence blocks (CSBs), and each of the CSBs included a noncanonical open reading frame (ORF), which may be involved in adjusting mitochondrial energy metabolism to adapt to the hydrothermal environment. Phylogenetic analysis supported that the deep-sea hydrothermal vent shrimps may have originated from those living in shallow area. Positive selection analysis reveals the evidence of adaptive change in the mitogenome of Alvinocarididae. Thirty potentially important adaptive residues were identified, which were located in atp6, cox1, cox3, cytb and nad1 5. This study explores the mitochondrial genetic basis of hydrothermal vent adaptation in alvinocaridid for the first time, and provides valuable clues regarding the adaptation. PMID- 29145029 TI - Captive gorillas' manual laterality: The impact of gestures, manipulators and interaction specificity. AB - Relationships between humans' manual laterality in non-communicative and communicative functions are still poorly understood. Recently, studies showed that chimpanzees' manual laterality is influenced by functional, interactional and individual factors and their mutual intertwinement. However, what about manual laterality in species living in stable social groups? We tackled this question by studying three groups of captive gorillas (N=35) and analysed their most frequent manual signals: three manipulators and 16 gesture types. Our multifactorial investigation showed that conspecific-directed gestures were overall more right-lateralized than conspecific-directed manipulators. Furthermore, it revealed a difference between conspecific- and human-directed gestural laterality for signallers living in one of the study groups. Our results support the hypothesis that gestural laterality is a relevant marker of language left-brain specialisation. We suggest that components of communication and of manipulation (not only of an object but also of a conspecific) do not share the same lateralised cerebral system in some primate species. PMID- 29145030 TI - The use of eConsults to improve access to specialty care in thrombosis medicine. AB - INTRODUCTION: Electronic consultations (eConsults) are asynchronous, consultative electronic-based communications that are aimed to improve efficient and timely access to specialist advice. Our study aim was to evaluate the use and impact of the Canadian Champlain BASETM (Building Access to Specialists through eConsultation) eConsult service in the specialty of thrombosis medicine. METHODS: We conducted a cross-sectional study that included descriptive statistics of provider and patient demographic information and consultative-specific data. The impact of eConsults on primary care provider (PCP) referral patterns and satisfaction was assessed using a mandatory close-out survey upon completion of each eConsult. RESULTS: There were 162 thrombosis eConsult cases completed between June 2012 and March 2016. The most common referral topics were for thrombophilia testing, management of superficial vein thrombosis, and the choice and duration of anticoagulation for venous thromboembolism. By completing an eConsult, PCPs reported 47.5% of face-to-face consultations were avoided, and 4.3% prompted a thrombosis referral that was not originally contemplated. Primary care providers' responses to a thrombosis eConsult service were overwhelmingly positive, which included appreciation for timely access for patients, expert guidance and providing additional educational opportunities. CONCLUSION: An eConsult service in thrombosis medicine improved timely access to specialist advice and potentially reduces the number of face-to-face consultations needed. Further research is needed to understand how a thrombosis eConsult service affects thrombosis clinic performance data and patient outcomes. PMID- 29145031 TI - Improved twin detection via tracking of individual Kikuchi band intensity of EBSD patterns. AB - Twin detection via EBSD can be particularly challenging due to the fine scale of certain twin types - for example, compression and double twins in Mg. Even when a grid of sufficient resolution is chosen to ensure scan points within the twins, the interaction volume of the electron beam often encapsulates a region that contains both the parent grain and the twin, confusing the twin identification process. The degradation of the EBSD pattern results in a lower image quality metric, which has long been used to imply potential twins. However, not all bands within the pattern are degraded equally. This paper exploits the fact that parent and twin lattices share common planes that lead to the quality of the associated bands not degrading; i.e. common planes that exist in both grains lead to bands of consistent intensity for scan points adjacent to twin boundaries. Hence, twin boundaries in a microstructure can be recognized, even when they are associated with thin twins. Proof of concept was performed on known twins in Inconel 600, Tantalum, and Magnesium AZ31. This method was then used to search for undetected twins in a Mg AZ31 structure, revealing nearly double the number of twins compared with those initially detected by standard procedures. PMID- 29145032 TI - Intravenous immunoglobulin improves glucose control and beta-cell function in human IAPP transgenic mice by attenuating islet inflammation and reducing IAPP oligomers. AB - Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by beta cell loss, insulin resistance, islet inflammation and amyloid deposits derived from islet amyloid polypeptide (IAPP). Reducing toxic IAPP oligomers and inhibiting islet inflammation may provide therapeutic benefit in treating T2DM. Intravenous immunoglobulin (IVIg) is an efficient anti-inflammatory and immunomodulatory agent for the treatment of several autoimmune or inflammatory neurological diseases. However, whether IVIg has therapeutic potential on T2DM remains unclear. In present study, we showed that IVIg treatment significantly improved glucose control and insulin sensitivity, and prevented beta-cell apoptosis by lowering toxic IAPP oligomer levels, attenuating islet inflammation and activating autophagy in human IAPP transgenic mouse model. These results suggest that IVIg is a promising therapeutic potential for T2DM treatment. PMID- 29145034 TI - Molecular insight into mutation-induced conformational change in metastasic bowel cancer BRAF kinase domain and its implications for selective inhibitor design. AB - Oncogenic BRAF V600E mutation confers constitutive activation for the kinase and is closely related to the pathogenesis of metastasic bowel cancer (MBC). Here, the V600E-induced conformational change in MBC BRAF kinase domain is characterized systematically at structural, energetic and dynamic levels. The mutation is observed to cause a conformational conversion of the kinase's activation loop from DFG-out to DFG-in, thus activating the kinase. Electrostatic force is primarily responsible for the conformational conversion and stabilization of DFG-in associated with the mutation. Molecular docking calculations are employed to analyze the binding mode difference of mutant selective inhibitors between the DFG-out and DFG-in conformations of BRAF kinase. It is revealed that the mutation can reshape inhibitor selectivity profile by altering kinase loop conformation. Several compounds are determined to have a high or moderate selectivity for mutant over wild-type kinase. The selectivity is primarily originated from hydrogen bond interactions of inhibitor ligands with mutant rather than wild type due to the conformational difference in kinase domain. PMID- 29145033 TI - Is chronic postsurgical pain surgery-induced? A study of persistent postoperative pain following breast reconstruction. AB - BACKGROUND: Chronic postsurgical pain (CPSP) is a reported risk for women undergoing breast reconstruction, but it remains unclear that such persistent pain is induced by reconstructive surgery. To address this concern, this prospective cohort study examined the prevalence of and risk factors associated with CPSP among women undergoing breast reconstruction. MATERIALS AND METHODS: Women (n = 1996) recruited for the Mastectomy Reconstruction Outcomes Consortium (MROC) Study were assessed preoperatively and at two-years postoperatively for relevant medical/.surgical variables, pain experience, body physical well-being, anxiety, depression, and reconstruction procedure type and characteristics. RESULTS: Nearly half of the entire sample reported some level of preoperative pain. At two years there were statistically significant but not clinically meaningful increases in both pain intensity and chest/upper body discomfort but a decrease in affective pain rating. Average clinical pain severity was strikingly similar for preoperative and postoperative assessments. Preoperative levels of pain, acute postoperative pain, and (marginally) level of depression held consistent relationship at two-year follow-up with all outcome measures. Autologous flap reconstruction was associated with more severe CPSP compared to TE/I reconstruction. Older age, higher BMI, bilateral reconstruction, and adjuvant radiation and chemotherapy were associated with CPSP and chest/upper body discomfort for at least one outcome measure at two years. CONCLUSIONS: The substantial rate of preoperative pain and comparable prevalence of preoperative and postoperative pain ratings suggest that persistent pain after breast reconstruction may not necessarily reflect surgery-induced pain. Future research will need to determine those factors that contribute to long-term pain following breast reconstruction. PMID- 29145035 TI - Controlled stabilization of anionic forms of the uracil derivatives: A DFT study. AB - Relative stabilities of the N1/N3/O5/O6 anions of 42 substituted uracils in gas phase and aqueous solutions have been theoretically studied using approximation IEFPCM (SMD) - TPSS/aug-cc-pVTZ. The specific solvation of uracil and its anions has been simulated with the first hydrate shell made up with 5 water molecules. The nonspecific solvation has been accounted in terms of the SMD model. We have found a series of relative stability under conditions of both specific and nonspecific hydration. The series is ranked according to the increase of the relative stability of the N3 anion. In gas phase, the N1 anion is significantly more stable than its N3 counterpart: the DeltaGgas values vary in the range from 19.54 (5OH6SN3U) to 83.14 (5NO26NH2U) kJ/mol that is caused by a more effective delocalization of the excess charge through the uracil framework in the N1 anion. The hydration pronouncedly diminishes DeltaG to the range from -0.02 (5OH6SN3U) to 38.16 (5Br6NO2U) kJ/mol due to the fact that the polar solvent is prone to stabilize more polar anionic states of uracils. Therefore, less polar uracil anions are more stable. We have defined the main factor influencing the N1/N3/O5/O6 distribution of anions, viz. the presence of the substituents in 5 and 6 positions of the pyrimidine ring. Herewith, the most favorable mechanism of the influence of 5-substituents has been previously defined as resonant whereas, as we found in this work, the inductive mechanism is more pronounced in the case of 6-substituents. PMID- 29145036 TI - Liver immunotolerance and hepatocellular carcinoma: Patho-physiological mechanisms and therapeutic perspectives. AB - At the moment of the diagnosis of hepatocellular carcinoma (HCC), 70% of patients have only access to palliative treatments, with very few therapeutic options. Liver immunology is very specific, and liver immunotolerance is particularly developed because of the constant and massive influx of antigens. Deregulation of hepatic immunotolerance is implicated in chronic liver diseases development and particularly in liver carcinogenesis. For these reasons, HCC may be an excellent candidate for anticancer immunotherapies such as immune checkpoint inhibitors targeting CTLA-4 and PD-L1/PD-1. Nonetheless, because of the specific immune environment of the liver and the frequent association of HCC with hepatocellular insufficiency, the safety and the efficacy of these new treatments have to be properly studied in this situation. Thus, multiple phase II and III studies are in progress studying immune checkpoint inhibitor monotherapies, combination of different immunotherapies or local strategies such as transarterial chemoembolization combined with immune checkpoint inhibitors. Currently, only the final results of the tremelimumab phase II and the Nivolumab phase I/II study (CheckMate-040) are available. The latter is promising but need to be confirmed by the ongoing phase III studies to confirm the place of immunotherapy in the treatment of HCC. With many new molecular targets and therapeutic combination, immunotherapy represents a new hope in treating HCC patients although serious evaluation is still needed to confirm its interest. PMID- 29145037 TI - Time to diagnosis and treatment for cancer patients in the Netherlands: Room for improvement? AB - BACKGROUND & AIM: Reducing the duration of the diagnostic cancer care pathway is intensively pursued. The aim of this study was to chart the diagnostic pathway for the five most common cancers in the Netherlands. METHODS: A retrospective cohort study using cancer patients' anonymised primary care data (free text and coded) linked to the Netherlands Cancer Registry. We determined the median duration of the following: 1. Primary care intervals (IPCs): the first cancer related general practitioner consultation to referral, 2. Referral intervals (IRs): referral to diagnosis, 3. Treatment intervals (ITs): diagnosis to treatment and the overarching intervals, 4. Diagnostic intervals (IDs): IPC and IR combined and 5. Health care intervals (IHCs): IPC, IR and IT combined. RESULTS: For 465, 309, 197, 237 and 149 patients diagnosed with breast-, colorectal-, lung-, prostate cancer and melanoma, respectively; median IPC, IR and ID durations were shortest for breast cancer and melanoma (ID duration 7 and 21 days, respectively), intermediate for lung- and colon cancer (ID duration 49 and 54 days) and the longest for prostate cancer (ID duration 137 days). For all cancers, the duration of intervals increased steeply for the 10-25% with longest durations. For colorectal cancer, increasing ID durations showed increasing proportions of time attributable to primary care (IPC). CONCLUSION: Approximately 10-25% of cancer patients show substantially long duration of diagnostic intervals. Reducing primary care delay seems particularly relevant for colorectal cancer. PMID- 29145038 TI - Precision medicine for patients with advanced biliary tract cancers: An effective strategy within the prospective MOSCATO-01 trial. AB - BACKGROUND: Recommended treatments of patients with advanced biliary tract cancer (aBTC) are limited to one chemotherapy doublet. Nevertheless, efficacy of treatment personalisation for aBTCs is supported by accumulating evidences but remains to be evaluated. PATIENTS AND METHODS: Patients with aBTCs included in the prospective clinical trial MOSCATO-01 were treated by at least one previous systemic treatment, had an ECOG performance status of 0-1, and at least one tumour site accessible to biopsy. Multiple high-throughput molecular analysis was performed on biopsies to drive the administration of molecular targeted agents (MTAs). RESULTS: From November 2011 to March 2016, 43 patients (4%) of the 1035 adult patients included in MOSCATO-01 had aBTCs with a majority of intrahepatic localisation (67%). Successful biopsy procedures and DNA extractions led to molecular portraits for 34 patients (79%). Orientation to an appropriate early clinical trial or accessible MTA(s) was possible for 23 of these patients (68%), and 18 (53%) have received matched MTA(s). Among them, the overall response rate was 33% and the disease control rate was 88%. A PFS >=6 months was observed in 37% and the PFS ratio was >1.3 for 50% of the patients. These patients had a lower risk for death as compared to the 20 patients not orientated to a matched MTA (HR, 0.29; 95% CI, 0.11-0.76; p = 0.008). CONCLUSIONS: Within the MOSCATO-01 trial, patients with aBTCs had the highest rate of orientation to matched MTAs and derived a clear clinical benefit. A broader evaluation of these findings may improve future treatments strategies for aBTCs. TRIAL REGISTRATION: NCT01566019. PMID- 29145040 TI - Pornography headache. AB - The headache associated with intercourse or masturbatory activity is a well recognized clinical entity but pornography headache is barely mentioned. We report a young man who suffered preorgasmic headache pertaining only to pornography of specific erotic contents but not to other sexual or nonsexual act. An antecedent activation of sexual arousal and vasoconstriction during pain were found. Finally, oral indomethacin favorably prevented the pain. Therefore, pornography headache is a distinguished headache disorder distinct from other sexual-related headache disorders. Sexual arousal-mediated cerebrovascular dysregulation consequence to visuoneural uncoupling in response to erotic stimulus is proposed. Pornography headache may be underestimated in population as pain-killer overuse may mask the actual incidence in real world. PMID- 29145039 TI - A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification. AB - PURPOSE: Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. METHODS: This was a phase I dose-escalation (3 + 3 design [50-740 mg/m2]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. RESULTS: In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m2, five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. CONCLUSION: The MTD of once-weekly SAR125844 was 570 mg/m2; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. CLINICAL TRIAL REGISTRATION NUMBER: NCT01391533. PMID- 29145041 TI - Transradial access for cerebrovascular angiography: Evaluation of palmar collateral circulation with hand angiography and its correlation with Allen test. AB - OBJECTIVES: Transradial cerebral angiography (TRCA) has been introduced as an alternative technique for the transfemoral access, and its use is becoming more common in the field. In this study, we retrospectively analyzed a group of patients who received TRCA, and investigated peri-procedural measurements indicating actual hand circulation, and studied their correlation with the Allen test. PATIENTS AND METHODS: A retrospective review of 168 patients whom underwent TRCA between 2015 July and 2016 July, were included in this study. Pre procedural Allen test and Doppler ultrasonography for the radial artery (RA) and ulnar artery (UA) were done. Plethysmography tests as well as pulse oximetry monitoring were done before and during the procedure and intra-procedural angiography of the forearm and hand was done for assessment of palmar circulation. RESULTS: Pre procedural UA diameters revealed statistically significant correlation with manual Allen test results (P <0.001, r=-0.381). The DUS RA diameters, however, did not correlate with any other pre-procedural measurements. The mean contrast filling time on forearm angiography was 3.33+/-1.97s, and it showed statistically significant correlation with the capillary filling time of Allen tests (P<0.001, r=0.389). CONCLUSION: Manual Allen test results correlated with angiographic capillary filling of the distal hand circulation and pre-procedural UA diameters. Our results suggest that Allen test sufficiently represent the collateral circulation status prior to TRCA. PMID- 29145042 TI - Relationship of T1 slope with loss of lordosis and surgical outcomes after laminoplasty for cervical ossification of the posterior longitudinal ligament. AB - OBJECTIVE: T1 slope (T1S) has emerged as a predictor of kyphotic alignment change after laminoplasty. Although it was reported that patients with cervical ossification of the posterior longitudinal ligament (OPLL) and higher T1S had more pronounced lordotic curvature before surgery and higher loss of cervical lordosis after surgery, few studies have attempted to correlate these findings with clinical outcomes. We aimed to investigate the relationship of T1S with loss of cervical lordosis and surgical outcomes after laminoplasty for cervical OPLL. PATIENTS AND METHODS: 35 consecutive patients (26 men and 9 women) with cervical OPLL who underwent double-door laminoplasty were followed for more than 12 months. Radiological and clinical measurements were performed to analyze the following parameters: pre and postoperative C2-C7 Cobb lordotic angle (LA), preoperative C2-C7 range of motion (ROM), loss of cervical lordosis, percentage of change in postoperative kyphosis, pre and postoperative C2-C7 sagittal vertical axis (SVA), change in C2-C7 SVA and occupying ratio of the OPLL, Japanese Orthopedic Association (JOA) score recovery rate, preoperative MRI grade. RESULTS: Patients were divided into 2 groups according to preoperative T1 slope, with the cutoff value being the average preoperative T1 slope. Preoperative C2-C7 Cobb LA (P=0.007) and loss of cervical lordosis (P=0.034) differed between the two groups. Preoperative C2-C7 Cobb LA (R=0.50, P=0.002) and loss of cervical lordosis (R=0.36, P=0.036) were significantly correlated to preoperative T1S. Multivariate linear regression analysis showed that the preoperative T1S was not related to JOA score recovery rate and the preoperative MRI grade (OR=-9.985, P=0.015) was only related to JOA score recovery rate. CONCLUSION: Although the degree of alignment compromise is correlated with the preoperative T1S, clinical outcomes demonstrate overall improvement after cervical laminoplasty with cervical OPLL, regardless of preoperative T1S. PMID- 29145043 TI - Diagnostic accuracy of magnetic resonance imaging in post-traumatic brachial plexus injuries: A systematic review. AB - Computed Tomographic Myelography (CTM) is a gold-standard imaging test for evaluating the brachial plexus and has been used for a long time. Another imaging test more recently used is Magnetic Resonance imaging (MRI), which is also part of the plexus evaluation. The purpose of this study was to determine the accuracy of MRI in diagnosing post-traumatic injuries of the brachial plexus. We conducted a Systematic Review with cross-sectional studies of diagnostic accuracy. Studies with populations presenting post-traumatic brachial plexus injury, over 16 years old, both genders, and examined by CT Myelography and MRI were evaluated. The trial resulted in three studies that covered the inclusion criteria. The sample consisted of 46 participants. The tool Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to evaluate the quality of the studies, and the software RevMan was used to identify the homogeneity of the studies that entered the analysis. The study was registered in PROSPERO under the number CRD42016041720. Studies showed moderate to high risk of bias, with low or very low quality of evidence due to the limitations of studies and differences in comparing the assessment groups. The heterogeneity of the studies made it impossible to create meta-analyzes. MRI has been an excellent test for assessing traumatic brachial plexus injuries in clinical practice; however, the quantitative analysis of studies identified a lack in methodological rigor. Future studies should focus on methodological rigor, providing more accurate assessments of modalities and their benefits. PMID- 29145044 TI - Image processing for precise three-dimensional registration and stitching of thick high-resolution laser-scanning microscopy image stacks. AB - The possible depth of imaging of laser-scanning microscopy is limited not only by the working distances of objective lenses but also by image degradation caused by attenuation and diffraction of light passing through the specimen. To tackle this problem, one can either flip the sample to record images from both sides of the specimen or consecutively cut off shallow parts of the sample after taking serial images of certain thickness. Multiple image substacks acquired in these ways should be combined afterwards to generate a single stack. However, subtle movements of samples during image acquisition cause mismatch not only in the translation along x-, y-, and z-axes and rotation around z-axis but also tilting around x- and y-axes, making it difficult to register the substacks precisely. In this work, we developed a novel approach called 2D-SIFT-in-3D-Space using Scale Invariant Feature Transform (SIFT) to achieve robust three-dimensional matching of image substacks. Our method registers the substacks by separately fixing translation and rotation along x-, y-, and z-axes, through extraction and matching of stable features across two-dimensional sections of the 3D stacks. To validate the quality of registration, we developed a simulator of laser-scanning microscopy images to generate a virtual stack in which noise levels and rotation angles are controlled with known parameters. We illustrate quantitatively the performance of our approach by registering an entire brain of Drosophila melanogaster consisting of 800 sections. Our approach is also demonstrated to be extendable to other types of data that share large dimensions and need of fine registration of multiple image substacks. This method is implemented in Java and distributed as ImageJ/Fiji plugin. The source code is available via Github (http://www.creatis.insa-lyon.fr/site7/fr/MicroTools). PMID- 29145045 TI - Realistic texture synthesis for point-based fruitage phenotype. AB - Although current 3D scanner technology can acquire textural images from a point model, visible seams in the image, inconvenient data acquisition and occupancy of a large space during use are points of concern for outdoor fruit models. In this paper, an SPSDW (simplification and perception based subdivision followed by down sampling weighted average) method is proposed to balance memory usage and texture synthesis quality using a crop fruit, such as apples, as a research subject for a point-based fruit model. First, the quadtree method is improved to make splitting more efficient, and a reasonable texton descriptor is defined to promote query efficiency. Then, the color perception feature is extracted from the image for all pixels. Next, an advanced sub-division scheme and down-sampling strategy are designed to optimize memory space. Finally, a weighted oversampling method is proposed for high-quality texture mixing. This experiment demonstrates that the SPSDW method preserves the mixed texture more realistically and smoothly and preserves color memory up to 94%, 84.7% and 85.7% better than the two-dimesional processing, truncating scalar quantitative and color vision model methods, respectively. PMID- 29145046 TI - Genetic and Clinical Characteristics of Phyllodes Tumors of the Breast. AB - PURPOSE: Phyllodes tumors (PTs) of the breast are rare, accounting for less than 1% of all breast tumors. Among PTs, malignant PTs (MPTs) have malignant characteristics and distant metastases occur in about 20% to 30% of MPTs. However, there is no effective treatment for MPTs with distant metastasis, resulting in an abject prognosis. We performed targeted deep sequencing on PTs to identify the associations between genetic alterations and clinical prognosis. METHODS: We performed targeted deep sequencing to evaluate the genetic characteristics of PTs and analyzed the relationships between clinical and genetic characteristics. RESULTS: A total of 17 PTs were collected between 2001 and 2012. Histologic review was performed by pathologists. The samples included three benign PTs, one borderline PT, and 13 MPTs. The most frequently detected genetic alteration occurred in the TERT promoter region (70.6%), followed by MED12 (64.7%). EGFR amplification and TP53 alteration were detected in four MPTs without genetic alterations in MED12 and TERT promoter regions. Genetic alterations of RARA and ZNF703 were repeatedly found in PTs with local recurrence, and genetic alterations of SETD2, BRCA2, and TSC1 were detected in PTs with distant metastasis. Especially, MPT harboring PTEN and RB1 copy number deletion showed rapid disease progression. CONCLUSIONS: In this study, we provide genetic characterization and potential therapeutic target for this rare, potentially lethal disease. Further large-scale comprehensive genetic study and functional validation are warranted. PMID- 29145047 TI - Effects of water and nitrogen addition on ecosystem respiration across three types of steppe: The role of plant and microbial biomass. AB - Evaluating the regional variation of ecosystem respiration (Reco) in its response to the changes of soil water and nitrogen (N) availability is crucial for fully understanding ecosystem carbon (C) exchange and its feedbacks to global changes. Here, we examined the responses of Reco, plant community aboveground biomass (AB), microbial biomass carbon (MBC) and soil moisture (SM) to water and N addition, using intact soil monoliths from three different temperate steppes along a precipitation gradient, including meadow steppe, typical steppe, and desert steppe in northern China. We found that the meadow steppe held the highest value of Reco. Water addition significantly enhanced Reco while N addition had no effect on Reco in all three ecosystems. The response of Reco in the typical steppe was more sensitive than the other two ecosystems. The changes of plant community AB exhibited a much stronger explanatory power than that of MBC for Reco in the typical steppe. In contrast, MBC was the dominant factor explaining the variation of Reco in the desert steppe and the meadow steppe. These findings contribute to our understanding of regional patterns of ecosystem C exchange under scenarios of global changes and highlight the importance of water availability in regulating ecosystem processes in temperate steppe grasslands. PMID- 29145048 TI - Development of a microscale land use regression model for predicting NO2 concentrations at a heavy trafficked suburban area in Auckland, NZ. AB - Land use regression (LUR) analysis has become a key method to explain air pollutant concentrations at unmeasured sites at city or country scales, but little is known about the applicability of LUR at microscales. We present a microscale LUR model developed for a heavy trafficked section of road in Auckland, New Zealand. We also test the within-city transferability of LUR models developed at different spatial scales (local scale and city scale). Nitrogen dioxide (NO2) was measured during summer at 40 sites and a LUR model was developed based on standard criteria. The results showed that LUR models are able to capture the microscale variability with the model explaining 66% of the variability in NO2 concentrations. Predictor variables identified at this scale were street width, distance to major road, presence of awnings and number of bus stops, with the latter three also being important determinants at the local scale. This highlights the importance of street and building configurations for individual exposure at the street level. However, within-city transferability was limited with the number of bus stops being the only significant predictor variable at all spatial scales and locations tested, indicating the strong influence of diesel emissions related to bus traffic. These findings show that air quality monitoring is necessary at a high spatial density within cities in capturing small-scale variability in NO2 concentrations at the street level and assessing individual exposure to traffic related air pollutants. PMID- 29145049 TI - Elements content in tree rings from Xi'an, China and environmental variations in the past 30years. AB - Using inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectroscopy (ICP-AES), the characteristics of chemical elements were analyzed in white poplar (Populus bonatii Levl.) and ailanthus (Ailanthus altissima (Mill.) Swingle) from three sites in the town of Xi'an, China. The results indicated that the concentration variations of Pb and Cd in tree rings were consistent with that of the environment where the trees were growing. P and Zn were translocated within tree rings to a certain degree, which led to an inaccurate pollution reconstruction. We also found that white poplar had a stronger absorptive capacity of Cd and Zn than ailanthus, which could make white poplar better as a species in environmental remediation. From this research we can see the great potential of tree rings for studying the history of different element pollution in the environment, showing that dendrochemical methods could be used as a powerful component in environmental monitoring programmes, to reconstruct past pollution history at the time when monitoring systems were not yet installed. PMID- 29145050 TI - Can farmers mitigate environmental impacts through combined production of food, fuel and feed? A consequential life cycle assessment of integrated mixed crop livestock system with a green biorefinery. AB - This study evaluates environmental impacts of an integrated mixed crop-livestock system with a green biorefinery (GBR). System integration included production of feed crops and green biomasses (Sys-I) to meet the demand of a livestock system (Sys-III) and to process green biomasses in a GBR system (Sys-II). Processing of grass-clover to produce feed protein was considered in Sys-II, particularly to substitute the imported soybean meal. Waste generated from the livestock and GBR systems were considered for the conversion to biomethane (Sys-IV). Digestate produced therefrom was assumed to be recirculated back to the farmers' field (Sys I). A consequential approach of Life Cycle Assessment (LCA) method was used to evaluate the environmental impacts of a combined production of suckler cow calves (SCC) and Pigs, calculated in terms of their live weight (LW). The functional unit (FU) was a basket of two products "1kgLW-SCC+1kgLW-Pigs", produced at the farm gate. Results obtained per FU were: 19.6kg CO2 eq for carbon footprint; 0.11kg PO4 eq for eutrophication potential, -129MJ eq for non-renewable energy use and -3.9 comparative toxicity units (CTUe) for potential freshwater ecotoxicity. Environmental impact, e.g. greenhouse gas (GHG) emission was primarily due to (i) N2O emission and diesel consumption within Sys-I, (ii) energy input to Sys-II, III and IV, and (iii) methane emission from Sys-III and Sys-IV. Specifically, integrating GBR with the mixed crop-livestock system contributed 4% of the GHG emissions, whilst its products credited 7% of the total impact. Synergies among the different sub-systems showed positive environmental gains for the selected main products. The main effects of the system integration were in the reductions of GHG emissions, fossil fuel consumption, eutrophication potential and freshwater ecotoxicity, compared to a conventional mixed crop livestock system, without the biogas conversion facility and the GBR. PMID- 29145051 TI - Towards stressor-specific macroinvertebrate indices: Which traits and taxonomic groups are associated with vulnerable and tolerant taxa? AB - Monitoring of macroinvertebrate communities is frequently used to define the ecological health status of rivers. Ideally, biomonitoring should also give an indication on the major stressors acting on the macroinvertebrate communities supporting the selection of appropriate management measures. However, most indices are affected by more than one stressor. Biological traits (e.g. size, generation time, reproduction) could potentially lead to more stressor-specific indices. However, such an approach has rarely been tested. In this study we classify 324 macroinvertebrate taxa as vulnerable (decreasing abundances) or tolerant (increasing abundances) along 21 environmental gradients (i.e. nutrients, major ions, oxygen and micropollutants) from 422 monitoring sites in Germany using Threshold Indicator Taxa Analysis (TITAN). Subsequently, we investigate which biological traits and taxonomic groups are associated with taxa classified as vulnerable or tolerant with regard to specific gradients. The response of most taxa towards different gradients was similar and especially high for correlated gradients. Traits associated with vulnerable taxa across most gradients included: larval aquatic life stages, isolated cemented eggs, reproductive cycle per year <1, scrapers, aerial and aquatic active dispersal and plastron respiration. Traits associated with tolerant taxa included: adult aquatic life stages, polyvoltinism, ovoviviparity or egg clutches in vegetation, food preference for dead animals or living microinvertebrates, substrate preference for macrophytes, microphytes, silt or mud and a body size >2-4cm. Our results question whether stressor-specific indices based on macroinvertebrate assemblages can be achieved using single traits, because we observed that similar taxa responded to different gradients and also similar traits were associated with vulnerable and tolerant taxa across a variety of water quality gradients. Future studies should examine whether combinations of traits focusing on specific taxonomic groups achieve higher stressor specificity. PMID- 29145052 TI - A comparison of personal exposure to air pollutants in different travel modes on national highways in India. AB - People often travel a long distance on highways to the nearest city for professional/business activities. However, relatively few publications on passenger exposure to pollutants on highways in India or elsewhere are available. The aim of this study was to examine the contribution of different travel modes to passengers' pollutant exposure for a long distance travel on a national highway in India. We measured PM2.5 and CO exposure levels of the passengers over 200km on a national highway using two portable air monitors, EVM-7 and EPAM-5000. Personal concentration exposures and per min-, per hour-, per trip- and round trip mass exposures for three travel modes were calculated for 9 trips. Association between pollutants and weather variables were evaluated using levels Spearman correlation. ANOVA was carried out to evaluate the influence of travel mode, the timing of trips, temperature and RH on personal exposures. On an average, PM2.5 personal concentration exposure levels were highest in the car (85.41+/-61.85MUgm-3), followed by the bus (75.08+/-55.39MUgm-3) and lowest in the car (ac) (54.43+/-34.09MUgm-3). In contrast, CO personal exposure was highest in the car (ac) (1.81+/-1.3ppm). Travel mode explained the highest variability for CO (18.1%), CO2 (9.9%), PM2.5 (1.2%) exposures. In-city mass exposures were higher than trip averages; PM2.5:1.21-1.22, 1.13-1.19 and 1.03-1.28 times; CO: 1.20-1.57, 1.37-2.10 and 1.76-2.22 times for bus, car and car (ac) respectively. Traveling by car (ac) results in the lowest PM2.5 exposures, although it exposes the passenger to high CO level. Avoiding national highways passing through cities can reduce up to 25% PM2.5 and 50% CO mass exposures. This information can be useful for increasing environmental awareness among the passengers and for framing better pollution control strategies on highways. PMID- 29145053 TI - Elucidating the urban levels, sources and health risks of polycyclic aromatic hydrocarbons (PAHs) in Pakistan: Implications for changing energy demand. AB - Due to the severe fuel crisis in terms of natural gas, a paradigm shift in fuel combustion (diesel, gasoline, and biomass) may increase the atmospheric emissions and associated health risks in Pakistan. Present study was aimed to investigate the concentration of fugitive PAHs in the environment (outdoor and indoor settings), associated probabilistic health risk assessment in the exposed population, and possible linkage between fuel consumption patterns and PAHs emissions in twin cities (Rawalpindi and Islamabad) of Pakistan. Results showed that the mean PAHs concentrations (air: 2390pgm-3; dust: 167ngg-1) in the indoor environment were higher than that of the outdoor environment (air: 2132pgm-3; dust: 90.0ngg-1). Further, the source apportionment PCA-MLR receptor model identified diesel and gasoline combustion as the primary PAHs sources in the urban and sub-urban settings. Estimated life cancer risk (LCR) potential via inhalation to indoor PAHs was higher with a probability of 2.0 cases per 10,000 inhabitants as compared to outdoor exposure. Incremental lifetime cancer risk (ILCR) model from exposure to dust bound PAHs showed risk in the order of ingestion>dermal>inhalation for various exposure pathways. Likewise, estimated daily intake (EDI) model reflects that PAHs in surface dust enter into the human body mainly through the respiratory system because EDI for breathing was reported higher than that of oral intake. Therefore, adoption of sustainable fuels is recommended to meet the energy requirements and to reduce PAHs emissions and related health risks in the twin cities of Pakistan. PMID- 29145054 TI - Associations between prenatal lead exposure and birth outcomes: Modification by sex and GSTM1/GSTT1 polymorphism. AB - Maternal lead exposure is associated with poor birth outcomes. However, modifying effects of polymorphism in glutathione S-transferases (GST) gene and infant sex remain unexplored. Our aim was to evaluate whether associations between prenatal lead and birth outcomes differed by maternal GST genes and infant sex. Prospective data of 782 mother-child pairs from Mothers and Children's Environmental Health (MOCEH) study were used. The genotyping of GST-mu 1 (GSTM1) and theta-1 (GSTT1) polymorphisms was carried out using polymerase chain reaction. Multivariable linear regression was used to examine whether the association between blood lead (BPb) level and birth outcomes (birthweight, length, and head circumference) varied by maternal GST genes and sex. We did not find a statistically significant association between prenatal BPb levels and birth outcomes; in stratified analyses, the association between higher BPb level during early pregnancy and lower birthweight (beta=-224 per square root increase in BPb; 95% confidence interval (CI): -426, -21; false discovery rate p=0.036) was significant in males of mothers with GSTM1 null. Results were similar for head circumference model (beta=-0.78 per square root increase in BPb; 95% CI: 1.69, 0.14, p=0.095), but the level of significance was borderline. Head circumference model showed a significant three-way interaction among BPb during early pregnancy, GSTM1, and sex (p=0.046). For combined analysis with GSTM1 and GSTT1, GSTM1 null and GSTT1 present group showed a significant inverse association of BPb with birthweight and head circumference in males. Our findings of the most evident effects of BPb on the reduced birthweight and head circumference in male born to the mother with GSTM1 null may suggest a biological interaction among lead, GST genes and sex in detoxification process during fetal development. PMID- 29145055 TI - Urban stormwater characterisation and nitrogen composition from lot-scale catchments - New management implications. AB - Stormwater runoff from urban areas has been shown to contain a variety of pollutants which are often linked to the specific land use of the catchment. This research program investigated the pollutant concentrations in stormwater runoff from several sites in South-east Queensland (SEQ), in Australia. The study sites are predominantly single development lots, under 7.5hectares (Ha) in area, with a single land-use classification that have been developed with stormwater treatment measures to manage pollutant loads as required by local regulations. The testing program also analysed the nitrogen composition in the catchment runoff samples (prior to treatment) during storm events and compared them to current Australian guidelines. The results to date (n=320) have shown pollutant concentrations to be significantly lower than those historically published as typical for Australian land uses (p<0.05). Ongoing application of out-dated influent values as part of development assessment processes could potentially provide inaccurate results, incorrectly sized and under-performing treatment measures. This current research also suggests that nitrogen in runoff from lot-scale, urban residential catchments has average nitrogen oxides (NOx) ~16% and ammonia ~9% as percentage of total nitrogen (TN). Total Kjeldahl nitrogen (TKN) forms on average ~84% of the total nitrogen concentration during events. Where it was previously recommended that to achieve water quality targets of 45% total nitrogen load reduction, treatment measures targeting NOx were required (e.g. Vegetated systems), this latest research indicates that solutions removing organic nitrogen also may be necessary, increasing the options available to designers. PMID- 29145056 TI - Environmental Life Cycle Assessment of marine sediment decontamination by citric acid enhanced-microwave heating. AB - The potential ability of microwave heating (MWH) for the remediation of marine sediments affected by severe hydrocarbon (HC) contamination was investigated. Decontamination effectiveness and environmental sustainability through a comparative Life Cycle Assessment (LCA) were addressed. Main results revealed that the application of a 650-W MWH treatment resulted in a rapid (15min) HC removal. A citric acid (CA) dose of 0.1M led to enhanced-HC removals of 76.9, 96.5 and 99.7% after 5, 10 and 15min of MW irradiation, respectively. The increase in CA dose to 0.2M resulted in a shorter successful remediation time of 10min. The exponential kinetic model adopted showed a good correlation with the experimental data with R2 values in the 0.913-0.987 range. The nature of the MW treatment was shown to differently influence the HC fraction concentration after the irradiation process. Achieved HC removals in such a short remediation time are hardly possible by other clean-up techniques, making the studied treatment a potential excellent choice. Removal mechanisms, which allowed the enhanced-MWH to operate as a highly effective multi-step technique (pure thermal desorption+chemical washing), undoubtedly represent a key factor in the whole remediation process. The LCA highlighted that the MW technology is the most environmentally sustainable alternative for sediment decontamination applications, with a total damage, which was 75.74% lower than that associated with the EK (0.0503pt). PMID- 29145057 TI - Bioerosive and bioprotective role of barnacles on rocky shores. AB - Bioerosion and bioprotection (bio-remodeling) is the action exerted by biota colonizing rocky shores. It represents an important component among processes responsible for shaping coastal landforms, and a clear evidence of interaction between the biosphere and the solid earth. Barnacles extensively colonize the midlittoral belt of rocky shores in the Mediterranean Basin. Previous research, mostly based on laboratory evidence, suggests that barnacles are bioprotectors, in that they protect the rock surface from different types of physical and chemical weathering. In this paper, we present the results of a field experiment carried out at different spatial scales at two study areas along the moderately energetic and microtidal coast of NW Italy. Barnacles were removed from the sandstone bedrock in replicated plots (manipulated plots) arranged according to a hierarchical spatial design. After four months rock hardness was tested on each plot with both Schmidt hammer and Equotip Piccolo devices, as well as on a corresponding number of control plots. Data were processed by means of a multifactorial analysis of variance (ANOVA). In control plots, rock hardness tested with Schmidt hammer exceeded that measured in previously manipulated plots. Testing with Equotip yielded the opposite results. This experimental evidence confirmed that barnacles play a bio-protective role in the midlittoral at sub-surficial level, while adding the key aspect that this effect is generalizable to spatial scales ranging from a few centimeters up to tens of kilometers. In addition, our results showed, for the first time, that at surface level they can simultaneously act as bioeroders, likely causing corrosion of the rock surface by fostering dissolution of the sandstone carbonate matrix. PMID- 29145058 TI - Occurrence, distribution, and ecological risks of phthalate esters in the seawater and sediment of Changjiang River Estuary and its adjacent area. AB - A total of 133 seawater samples and 17 sediment samples were collected from 81 sampling sites in the Changjiang River Estuary and its adjacent area and were analyzed for 16 phthalate esters (PAEs). The Sigma16 PAE concentrations in the seawater and sediment samples ranged from 180.3ng.L-1 to 3421ng.L-1 and from 0.48MUg.g-1 to 29.94MUg.g-1dry weight (dw), respectively, with mean values of 943.6ng.L-1 and 12.88MUg.g-1. The distribution of ?16PAE concentrations in the water column showed that PAE concentrations in the bottom samples were higher than those in the surface samples (except the transect C located inside the Changjiang River Estuary), with the maxima appearing in the bottom layer at the offshore stations. Among the 16 PAEs, di (2-ethylhexyl) phthalate (DEHP), diisobutyl phthalate (DiBP), and dibutyl phthalate (DnBP) dominated the PAEs, with 25.1%, 21.1%, and 18.9% of the Sigma16PAEs in seawater, respectively. The comparison of ?16PAEs and salinities in transects C and A6 suggested that the Changjiang River runoff was an important driving factor influencing the distribution of PAEs. DEHP concentrations in water samples and DEHP and DnBP concentrations in sediment samples exceeded the environmental risk levels (ERL), indicating their potential hazard to the ocean environment. PMID- 29145059 TI - Binding of naringin and naringenin with hen egg white lysozyme: A spectroscopic investigation and molecular docking study. AB - The interactions of naringenin (NG) and naringin (NR) with Hen Egg White Lysozyme (HEWL) in aqueous medium have been investigated using UV-vis spectroscopy, steady state fluorescence, circular dichroism (CD), Fourier Transform infrared spectroscopy (FT-IR) and molecular docking analyses. Both NG and NR can quench the intrinsic fluorescence of HEWL via static quenching mechanism. At 300K, the value of binding constant (Kb) of HEWL-NG complex (5.596+/-0.063*104M-1) was found to be greater than that of HEWL-NR complex (3.404+/-0.407*104M-1). The negative DeltaG degrees values in cases of both the complexes specify the spontaneous binding. The binding distance between the donor (HEWL) and acceptor (NG/NR) was estimated using the Forsters theory and the possibility of non radiative energy transfer from HEWL to NG/NR was observed. The presence of metal ions (Ca2+, Cu2+ and Fe2+) decreased the binding affinity of NG/NR towards HEWL. Synchronous fluorescence studies indicate the change in Trp micro-environment due to the incorporation of NG/NR into HEWL. CD and FT-IR studies indicated that the alpha-helicity of the HEWL was slightly enhanced due to ligand binding. NG and NR inhibited the enzymatic activity of HEWL and exhibited their affinity for the active site of HEWL. Molecular docking studies revealed that both NG and NR bind in the close vicinity of Trp 62 and Trp 63 residues which is vital for the catalytic activity. PMID- 29145060 TI - Familial cerebral cavernous malformation: Report of a novel KRIT1 mutation in a Portuguese family. AB - Cerebral cavernous malformations (CCMs) are vascular malformations which may occur in familial forms which have autosomal dominant inheritance. Mutations have been identified in three genes: KRIT1, MGC4607 and PDCD10. We have documented a novel mutation on KRIT1 gene, and the second to be reported in a Portuguese family. This mutation consists in a two nucleotide insertion (c.947_948insAC) within the exon 10, resulting in premature protein termination (p.Leu317Argfs*2). These findings will hopefully contribute to a better clinical, imaging and genetic characterisation of this disease, particularly while trying to identify the factors that influence its treatment and prognosis. PMID- 29145061 TI - Utility of electronic AKI alerts in intensive care: A national multicentre cohort study. AB - BACKGROUND: Electronic AKI alerts highlight changes in serum creatinine compared to the patient's own baseline. Our aim was to identify all AKI alerts and describe the relationship between electronic AKI alerts and outcome for AKI treated in the Intensive Care Unit (ICU) in a national multicentre cohort. METHODS: A prospective cohort study was undertaken between November 2013 and April 2016, collecting data on electronic AKI alerts issued. RESULTS: 10% of 47,090 incident AKI alerts were associated with ICU admission. 90-day mortality was 38.2%. Within the ICU cohort 48.8% alerted in ICU. 51.2% were transferred to ICU within 7days of the alert, of which 37.8% alerted in a hospital setting (HA AKI) and 62.2% in a community setting (CA-AKI). Mortality was higher in patients transferred to ICU following the alert compared to those who had an incident alert on the ICU (p<0.001), and was higher in HA-AKI (45.3%) compared to CA-AKI (39.5%) (35.0%, p=0.01). In the surviving patients, the proportion of patient recovering renal function following, was significantly higher in HA-AKI alerting (84.2%, p=0.004) and CA-AKI alerting patients (87.6%, p<0.001) compared to patients alerting on the ICU (78.3%). CONCLUSION: The study provides a nationwide characterisation of AKI in ICU highlighting the high incidence and its impact on patient outcome. The data also suggests that within the cohort of AKI patients treated in the ICU there are significant differences in the presentation and outcome between those patients that require transfer to the ICU after AKI is identified and those who develop AKI following ICU admission. Moreover, the study demonstrates that using AKI e-alerts provides a centralised resource which does not rely on clinical diagnosis of AKI or coding, resulting in a robust data set which can be used to define the incidence and outcome of AKI in the ICU setting. PMID- 29145062 TI - Differentiating multiple vs single lifetime suicide attempters with bipolar disorders: A retrospective study. AB - BACKGROUND: The risk of suicide in Bipolar Disorder (BD) has been estimated up to 20-30 times higher compared with the general population. Previous suicide attempts (SAs) represent a well-established risk factor for further attempts and for death by suicide in patients with psychiatric disorders. However, little is known about the socio-demographic and clinical profile of BD patients with a history of multiple SAs (MSAs). The present study sought to characterize BD patients with MSAs versus single suicide attempt (SSA) within a large Italian sample. METHODS: An original sample of 354 bipolar patients, recruited at the University Clinic and related community services at the Department of Psychiatry, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan (Italy), was screened for the presence of previous SAs (n=95). Socio-demographic and clinical variables were then compared between patients with multiple vs single lifetime suicide attempts. RESULTS: Bipolar patients with MSAs versus SSA had longer bipolar illness duration (26.9+/-12.6 vs 21.2+/-12.8years; p=0.05), and more frequently lived alone (38.5% vs 17.2%; p<0.05), had more than one psychiatric comorbidity (39.3% vs 17.5%; p=0.04), and utilized substance ingestion (e.g., overdose) (78.6% vs 47.2%, p=0.009), although the latter was the most common suicide attempt method in both groups. CONCLUSION: Present findings suggest different socio-demographic and clinical characteristics in bipolar patients with MSAs versus SSA. Further investigation is needed to confirm reported data. PMID- 29145063 TI - Prevalence, causes, resolution and consequences of bovine dystocia in Italy. AB - The aim of this study was to report prevalences and causes of dystocias in dairy and beef cattle, in primiparous and multiparous cows, as well as the mortality rate of calves and cows, obtained after 11 years of records across various farms in Italy. On a total of 14,575 records from dairy Italian Friesian cows, beef Romagnola and Marchigiana cows, a prevalence of 5.6% was observed, with a significant higher prevalence in primiparous (p < 0.0001), and dairy cows (p < 0.0001). Dystocias of fetal origin were higher than the ones of maternal origin (p < 0.0001). Dystocia management, performed with manual correction in 96% of the cases, was associated with the 25% of calf mortality and the 11% of maternal mortality. When the combined effects of attitude and parity were assessed in relation to each fetal or maternal dystocia cause, dystocia resolution method and on calf, cow and calf-and-cow mortality, results showed a stronger association of dairy primiparous and multiparous cows than beef cows to several dystocia causes and calf-and-cow mortality. Taken together the results from the present study highlighted, once more, the importance of a correct breeding herd management and genetic selection programmes, especially in dairy cows, as well as the prompt diagnosis and correction of difficult calvings, for the effective management of dystocias aimed to reduce calf mortality. PMID- 29145064 TI - Dog cloning with in vivo matured oocytes obtaining using serum estradiol levels for predicting time of ovulation. AB - Dog cloning using in vivo-matured oocytes has been carried out for a decade. To obtain mature oocytes, serum progesterone (P4) levels are used to evaluate ovulation. However, the accuracy of these methods is not sufficient. Thus, the aim of the present study was to verify the feasibility of serum estradiol (E2) on canine ovulation determination as assessed by the percentage of dogs yielding mature oocytes. In vivo-matured oocytes were utilized for canine somatic cell nuclear transfer (SCNT), and serum P4 and E2 levels were assessed to determine ovulation and oocyte maturation. Canine serum P4 and E2 concentrations during both pro-estrus and estrus were analyzed by electrochemiluminescence immunoassay. The percentage of dogs yielding mature oocytes using each of the two ovulation prediction methods were compared, and correlations between the percentage of each method and temperature were analyzed. Following evaluation, oocytes were collected surgically, and a significantly higher percentage (P < 0.05) of dogs yielding mature oocytes was observed using E2 (56.43%) for ovulation detection as compared with that using P4 (39.60%). The percentage of dogs yielding mature oocytes using P4 significantly lower (P < 0.05) than E2 in autumn (P4, 37.50% vs. E2, 52.00%) and winter (P4, 29.17% vs. E2, 59.09%). Using E2, the percentage was maintained at about 52.00-66.67% regardless of the season and temperature. Correlation analysis showed that the dynamic of percentage of dogs yielding mature oocyte using P4 was highly correlated with environmental temperature (RP4 = 0.862), whereas E2 was not affected by temperature (RE2 = 0.199). To determine whether serum E2 could be used for ovulation prediction for canine cloning, ovulation of 25 and 19 dogs (P < 0.05) were predicted using P4 or E2 methods, respectively and two puppies, one from each ovulation prediction method, were obtained after SCNT and embryo transfer. Thus, compared with the P4 method, E2 was an accurate and reliable method for canine cloning. PMID- 29145065 TI - Gestational differences in murine placenta: Glycolytic metabolism and pregnancy parameters. AB - The placenta is a complex and essential organ composed largely of fetal-derived cells, including several different trophoblast subtypes that work in unison to support nutrient transport to the fetus during pregnancy. Abnormal placental development can lead to pregnancy-associated disorders that often involve metabolic dysfunction. The scope of dysregulated metabolism during placental development may not be fully representative of the in vivo state in defined culture systems, such as cell lines or isolated primary cells. Thus, assessing metabolic function in intact placental tissue would provide a better assessment of placental metabolism. In this study, we describe a methodology for assaying glycolytic function in structurally-intact mouse placental tissue, ex vivo, without culturing or tissue dissociation, that more closely resembles the in vivo state. Additionally, we present data highlighting sex-dependent differences of two mouse strains (C57BL/6 and ICR) in the pre-hypertrophic (E14.5) and hypertrophic (E18.5) placenta. These data establish a foundation for investigation of metabolism throughout gestation and provides a comprehensive assessment of glycolytic function during placental development. PMID- 29145066 TI - Relationship between follicular dynamics and oocyte maturation during in vitro culture as a non-invasive sign of caprine oocyte meiotic competence. AB - The search for non-invasive signs of oocyte meiotic competence is very important for the development of in vitro follicle culture (IVFC) systems. The aims of the present study were: (1) to investigate the effect of in vitro maturation (IVM) of in vivo grown goat COCs, in group or individually, on oocyte chromatin configuration (Experiment 1), and (2) the influence of IVFC period (12 vs. 18 days) on the ability of the oocyte to resume meiosis immediately after IVFC (before in vitro maturation; IVM), or after IVM (Experiment 2). In experiment 1, in vivo grown cumulus-oocyte complexes (COCs) were submitted to IVM in groups (10 COCs/100 MUL-drop) or individually (1 COC/10 MUL-drop), and chromatin configuration was assessed. In experiment 2, isolated follicles were individually cultured for 12 or 18 days, and submitted to individual IVM afterwards. The following end points were evaluated: follicular growth and morphology, oocyte diameter, viability and chromatin configuration, as well as individual follicular estradiol production. Similar maturation rates were obtained between in vivo grown COCs matured individually and in groups (66.7% vs. 63.6%, respectively) (Experiment 1). Only after 18 days of IVFC, oocytes were able to grow during IVM, reaching a mean oocyte diameter of 119 MUm. Also, this treatment produced the highest rate of metaphase II oocytes (46.2% out of the total number of cultured follicles). Finally, it was observed that follicles with a daily growth rate >7.1 MUm/day (fast-growing) and that reached at least 600 MUm in diameter, were more likely (P < 0.05) to produce oocytes capable of attaining MII. In conclusion, caprine oocytes can be individually matured in vitro, as efficiently as in groups. This result was essential to pair in vitro follicle development and in vitro oocyte maturation with specific individual follicles. Using this approach, it was possible to establish non-invasive signs for the efficiency of IVFC based on follicle daily growth rate and diameter, and oocyte diameter: follicle daily growth >7 MUm, follicle diameter of at least 600 MUm, and oocyte diameter >=120 MUm. In addition, 18 days seems to be the most suitable culture time for caprine early antral follicles. PMID- 29145067 TI - Role of thalamic ventral posterolateral nucleus histamine H2 and opiate receptors in modulation of formalin-induced muscle pain in rats. AB - BACKGROUND: Histamine and opiate systems contribute to supraspinal processing of pain. In the present study, we investigated the effects of microinjection of histamine and agonists and antagonists of histamine H2 and opiate receptors into the thalamic ventral posterolateral nucleus on muscle pain in rats. METHODS: The thalamic ventral posterolateral nuclei were bilaterally implanted with two guide cannulas. Muscle pain was induced by intramuscular injection of a diluted formalin solution (2.5%, 50MUl) into the belly of gastrocnemius muscle, and pain related behaviors including paw licking duration and paw flinching number were recorded at five-min blocks for 60min. RESULTS: Formalin produced a biphasic pattern of pain-related behaviors. Ranitidine (a histamine H2 receptor antagonist) alone did not affect pain intensity, whereas it prevented the antinociceptive activities of histamine, dimaprit (a histamine H2 receptor agonist) and morphine (an opiate receptor agonist). Naloxone (an opiate receptor antagonist) alone increased pain, and inhibited histamine-, dimaprit-, and morphine-induced antinociception. Locomotor activity was not changed with these chemicals. CONCLUSIONS: Our results showed an interaction between histamine H2 and opiate receptors at the thalamic ventral posterolateral nucleus in modulation of muscle pain. PMID- 29145068 TI - Anorexigenic effects induced by RVD-hemopressin(alpha) administration. AB - BACKGROUND: Hemopressin, VD-hemopressin(alpha) and RVD-hemopressin(alpha) are hemoglobin alpha chain derived-peptides which have been found in mouse brain, and where they modulate cannabinoid (CB) receptor function. The nonapeptide hemopressin has been reported to inhibit feeding after both central and peripheral administration, possibly playing a role of antagonist/inverse agonist of CB1 receptors, and consequently blocking the orexigenic effects of endogenous cannabinoids. VD-hemopressin(alpha) and RVD- hemopressin(alpha), are N-terminal extended forms of hemopressin. VD-hemopressin(alpha) has CB1 agonist activity, and as such it has been shown to stimulate feeding. RVD-hemopressin(alpha) is reported to play a negative allosteric modulatory function on CB1 receptors, but there are no data on its possible effects on feeding and metabolic control. METHODS: We have studied, in rats, the effects of 14 daily intraperitoneal (ip) injections of RVD-hemopressin(alpha) (10nmol). RESULTS: We found that RVD hemopressin(alpha) treatment inhibited food intake while total body weight was not affected. The null effect on body weight despite diminished feeding could be related to decreased uncoupling protein 1 (UCP-1) gene expression in brown adipose tissue (BAT). We also investigated the underlying neuromodulatory effects of RVD-hemopressin(alpha) and found it to down regulate proopiomelanocortin (POMC) gene expression, together with norepinephrine (NE) levels, in the hypothalamus. CONCLUSIONS: In conclusion, RVD-hemopressin(alpha) administration has an anorectic effect, possibly related to inhibition of POMC and NE levels in the hypothalamus. Despite decreased food intake, body weight is not affected by RVD-hemopressin(alpha) treatment, possibly due to inhibition of UCP-1 gene expression in BAT. PMID- 29145069 TI - The SULTR gene family in maize (Zea mays L.): Gene cloning and expression analyses under sulfate starvation and abiotic stress. AB - Sulfur is an essential macronutrient required for plant growth, development and stress responses. The family of sulfate transporters (SULTRs) mediates the uptake and translocation of sulfate in higher plants. However, basic knowledge of the SULTR gene family in maize (Zea mays L.) is scarce. In this study, a genome-wide bioinformatic analysis of SULTR genes in maize was conducted, and the developmental expression patterns of the genes and their responses to sulfate starvation and abiotic stress were further investigated. The ZmSULTR family includes eight putative members in the maize genome and is clustered into four groups in the phylogenetic tree. These genes displayed differential expression patterns in various organs of maize. For example, expression of ZmSULTR1;1 and ZmSULTR4;1 was high in roots, and transcript levels of ZmSULTR3;1 and ZmSULTR3;3 were high in shoots. Expression of ZmSULTR1;2, ZmSULTR2;1, ZmSULTR3;3, and ZmSULTR4;1 was high in flowers. Also, these eight genes showed differential responses to sulfate deprivation in roots and shoots of maize seedlings. Transcript levels of ZmSULTR1;1, ZmSULTR1;2, and ZmSULTR3;4 were significantly increased in roots during 12-day-sulfate starvation stress, while ZmSULTR3;3 and ZmSULTR3;5 only showed an early response pattern in shoots. In addition, dynamic transcriptional changes determined via qPCR revealed differential expression profiles of these eight ZmSULTR genes in response to environmental stresses such as salt, drought, and heat stresses. Notably, all the genes, except for ZmSULTR3;3, were induced by drought and heat stresses. However, a few genes were induced by salt stress. Physiological determination showed that two important thiol-containing compounds, cysteine and glutathione, increased significantly under these abiotic stresses. The results suggest that members of the SULTR family might function in adaptations to sulfur deficiency stress and adverse growing environments. This study will lay a foundation for better understanding the functional diversity of the SULTR family and exploring genes of interest for genetic improvement of sulfur use efficiency in cereal crop plants. PMID- 29145070 TI - Arsenic forms and their combinations induce differences in phenolic accumulation in Ulmus laevis Pall. AB - Total phenolics and the profile of phenolic acids and flavonoids were investigated in the roots and leaves of Ulmus laevis cultured on the medium with inorganic and organic arsenic - As(III), As(V) and DMA(V) at 0.06mM and their equimolar combinations. Further, the accumulation of salicylic acid (free and glucoside-bound) and lipid oxidation were assayed following a three-month long experiment. As treatment caused elevated production of phenolics, which was higher in photosynthetic tissue than in roots for all As forms and their combinations, and their overall content was correlated with the accumulation of organic As in roots and As(III) in leaves. The accumulation of organic As strongly induced shikimate-derived protocatechiuc acid in roots. Contrary to this, shikimate-derived phenolics (protocatechuic, gallic acids and 4-HBA) were suppressed in leaves, while the accumulation of C6C3 acids (caffeic, p-coumaric and chlorogenic) was stimulated by As(V) application. Surprisingly, these acids were not detected in the leaves of As(III)-treated plants, and mutually applied As(III) and DMA(V) reduced their content. DMA(V) negatively influenced the level of salicylic acid and its storage mechanism and this effect correlated with elevated MDA content in leaves. Quercetin accumulation was observed in both organs (mainly leaves) of DMA(V)-treated plants thereby proving its function in defensive response of Ulmus laevis to organic forms of As. PMID- 29145071 TI - Proteomic analysis reveals that tomato interaction with plant growth promoting bacteria is highly determined by ethylene perception. AB - Feeding an increasing global population as well as reducing environmental impact of crops is the challenge for the sustainable intensification of agriculture. Plant-growth-promoting bacteria (PGPB) management could represent a suitable method but elucidation of their action mechanisms is essential for a proper and effective utilization. Furthermore, ethylene is involved in growth and response to environmental stimuli but little is known about the implication of ethylene perception in PGPB activity. The ethylene-insensitive tomato never ripe and its isogenic wild-type cv. Pearson lines inoculated with Bacillus megaterium or Enterobacter sp. C7 strains were grown until mature stage to analyze growth promotion, and bacterial inoculation effects on root proteomic profiles. Enterobacter C7 promoted growth in both plant genotypes, meanwhile Bacillus megaterium PGPB activity was only noticed in wt plants. Moreover, PGPB inoculation affected proteomic profile in a strain- and genotype-dependent manner modifying levels of stress-related and interaction proteins, and showing bacterial inoculation effects on antioxidant content and phosphorus acquisition capacity. Ethylene perception is essential for properly recognition of Bacillus megaterium and growth promotion mediated in part by increased levels of reduced glutathione. In contrast, Enterobacter C7 inoculation improves phosphorus nutrition keeping plants on growth independently of ethylene sensitivity. PMID- 29145072 TI - Pyridoxamine driven selective turn-off detection of picric acid using glutathione stabilized fluorescent copper nanoclusters and its applications with chemically modified cellulose strips. AB - The present work reports the interaction of various vitamin B6 cofactors with the red emitting glutathione stabilized copper nanoclusters (GSH-CuNCs). Addition of pyridoxamine (PM) resulted a new turn-on band at 410nm due to the possible adsorption over the surface of GSH-CuNCs. The nano-assembly PM-GSH-CuNCs was applied for the selective detection of nitro-aromatic compounds. Upon addition of picric acid (PA), the fluorescence of PM-GSH-CuNCs was selectively quenched at 410nm and ~ 625nm among the other tested nitro-aromatic compounds. With a linearity range from 9.9MUM to 43MUM, the concentration of PA can be detected down to 2.74MUM. The high selectivity exhibited by the nano-assembly allows to detect PA in real samples like tap water, river water and matchstick. Advantageously, the nano-assembly PM-GSH-CuNCs was chemically adsorbed over the cellulosic strips and applied for the naked-eye detection of PA down to 1MUM. PMID- 29145073 TI - Target-induced proximity ligation triggers recombinase polymerase amplification and transcription-mediated amplification to detect tumor-derived exosomes in nasopharyngeal carcinoma with high sensitivity. AB - Tumor-derived exosomes (TEXs) are extracellular vesicles that are continuously released into the blood by tumor cells and carry specific surface markers of the original tumor cells. Substantial evidence has implicated TEXs as attractive diagnostic markers for cancer. However, the detection of TEXs in blood at an early tumor stage is challenging due to their very low concentration. Here, we established a method called PLA-RPA-TMA assay that allows TEXs to be detected with high sensitivity and specificity. Based on two proximity ligation assay (PLA) probes that recognize a biomarker on a TEX, we generated a unique surrogate DNA signal for the specific biomarker, which was synchronously amplified twice by recombinase polymerase amplification (RPA) coupled with transcription-mediated amplification (TMA), and then the products of the RPA-TMA reaction were quantitatively detected using a gold nanoparticle-based colorimetric assay. We established proof-of-concept evidence for this approach using TEXs from nasopharyngeal carcinoma (NPC) cells, with a detection limit of 102 particles/mL, and reported the measurement of plasma Epstein-Barr virus latent membrane protein 1 (LPM1)-positive (LMP1+, accuracy: 0.956) and epidermal growth factor receptor (EGFR)-positive (EGFR+, accuracy: 0.906) TEXs as potent early diagnostic biomarkers for NPC. PMID- 29145074 TI - Ratiometric electrochemical assay for sensitive detecting microRNA based on dual amplification mechanism of duplex-specific nuclease and hybridization chain reaction. AB - We propose a ratiometric electrochemical assay for detecting microRNA (miRNA) on the basis of dual-amplification mechanism by using distinguishable electrochemical signals from thionine (Thi) and ferrocene (Fc). The thiol modified and ferrocene-labeled hairpin capture probes (CP) are first immobilized on an Au electrode via Au-S reaction. The target miRNA hybridizes with CP and unfolding the hairpin structure of CP to form miRNA-DNA duplexes. Then, kamchatka crab duplex specific nuclease (DSN) specifically cleaves the DNA in miRNA-DNA duplexes, leading to the release of miRNA and another cleaves cycle, meanwhile, numerous Fc leaves away from the electrode surface and leads to the signal-off of Fc. The residual fragment on electrode surface acts as a HCR primer to form dsDNA polymers through in situ HCR with the presence of the primer and two probes (HDNA and HDNA'), resulting in the capture of numerous DNA/Au NPs/Thi and the signal-on of Thi. The dual-amplification mechanism significantly amplifies the decrease of Fc signal and the increase of Thi signal for ratiometric readout (IThi/IFc), thus providing a sensitive method for the selective detection of miR-141 with a detection limit down to 11aM. The dual-signal ratiometric outputs have an intrinsic self-calibration to the effects from system, which is promising to be applied in biosensing and clinical diagnosis. PMID- 29145075 TI - Isolation and characterisation of an unexpected byproduct in the regioselective butane diacetal protection of alpha-methyl galactopyranoside. AB - The regioselective protection of both methyl galactopyranoside anomers at the 2 and 3-positions as the butane diacetal (BDA) is well known. Here we describe the formation of an unexpected byproduct, which mainly occurs when alpha-methyl galactopyranoside is reacted with 2,3-butanedione under BF3*OEt2 catalysis. The structure of the byproduct, which did not arise from anomerisation to the beta anomer or from BDA formation at the galactopyranoside 3,4-positions, was elucidated by NMR and X-ray crystallographic analysis, and proved to be the expected BDA protected galactopyranoside, but in which the stereochemistry of both its BDA acetal centres are inverted. Interestingly, the conformation of the resulting six-membered BDA ring was distorted to a skew boat conformation in order to maintain anomeric stabilisation. PMID- 29145076 TI - Veterans Group Exercise: A randomized pilot trial of an Integrative Exercise program for veterans with posttraumatic stress. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is prevalent among military veterans and is associated with significant negative health outcomes. However, stigma and other barriers to care prevent many veterans from pursuing traditional mental health treatment. We developed a group-based Integrative Exercise (IE) program combining aerobic and resistance exercise, which is familiar to veterans, with mindfulness-based practices suited to veterans with PTSD. This study aimed to evaluate the effects of IE on PTSD symptom severity and quality of life, as well as assess the feasibility and acceptability of IE. METHODS: Veterans (N = 47) were randomized to either IE or waitlist control (WL). Veterans in IE were asked to attend three 1-h group exercise sessions for 12 weeks. RESULTS: Compared with WL, veterans randomized to IE demonstrated a greater reduction in PTSD symptom severity (d = -.90), a greater improvement in psychological quality of life (d = .53) and a smaller relative improvement in physical quality of life (d = .30) Veterans' ratings of IE indicated high feasibility and acceptability. LIMITATIONS: The sample was relatively small and recruited from one site. The comparison condition was an inactive control. CONCLUSIONS: This initial study suggests that IE is an innovative approach to treating veterans with symptoms of PTSD that reduces symptoms of posttraumatic stress and improves psychological quality of life. This approach to recovery may expand the reach of PTSD treatment into non-traditional settings and to veterans who may prefer a familiar activity, such as exercise, over medication or psychotherapy. PMID- 29145077 TI - Stability of the diagnosis of seasonal affective disorder in a long-term prospective study. AB - BACKGROUND: Seasonal affective disorder (SAD) is mainly characterized by a seasonal pattern of depressive recurrences over the years. However, few studies have been conducted on the long-term course of patients with SAD, whose findings raised questions about the diagnosis stability over time. This study aimed to better characterize the diagnosis evolution, and determine prognosis markers. METHODS: An initial cohort of 225 outpatients diagnosed as having a SAD, was assessed at baseline (T1) for clinical symptoms and response to bright light therapy. One hundred and nineteen patients (53%) were interviewed 2-12 years after (T2). RESULTS: Of 119 patients reached at follow-up (T2), only 32 patients (27%) still fulfilled the DSM-IV criteria for a stable SAD (S-SAD). A large proportion (59%) of the follow up cohort was in remission and 14% still suffered from a non-seasonal mood disorder. Family history of depression, previous suicide attempt, carbohydrate craving and HAD-depression score at baseline were associated with a stable SAD (S-SAD) diagnosis at T2, the HAD-depression score being the only one still significantly predictive (p=0.025) of a later stable SAD, with a multivariate approach. Carbohydrate craving, a core symptom of SAD, showed a trend (p=0.100) to predict diagnosis stability. LIMITATIONS: Only 53% patients from the initial cohort were assessed at follow-up. CONCLUSIONS: Patients with eventual stable SAD show more subjective severity (higher HAD Depression score) and carbohydrate craving at baseline. A low predictive validity of diagnosis criteria suggests that SAD is a temporary expression of a mood disorder rather than a specific disorder. PMID- 29145078 TI - The efficacy of group metacognitive therapy for children (MCT-c) with generalized anxiety disorder: An open trial. AB - Metacognitive therapy is an effective treatment for anxiety disorders in adults. Studies have demonstrated that the underlying theoretical model is also supported in children. It has therefore been suggested that metacognitive therapy for children may be effective. Our study is an open trial of metacognitive therapy for children with generalized anxiety as their primary disorder. Therapy was provided in groups. Families were interviewed with the Anxiety Disorders Interview Schedule - child/parent versions. They reported on the child's anxiety levels using the Revised Childrens Anxiety and Depression Scale - child/parent versions. Children reported on metacognitive beliefs using the Metacognitions Questionnaire for Children - 30 item version. Fourty-four children aged 7-13 years (50% girls) were enrolled, and one family dropped out during treatment. Fifty percent of the children had received counseling or psychological treatment for their anxiety disorder previously. Following treatment, 86.4% of the children were free of their primary disorder and 72.7% were free of all anxiety disorders, the corresponding figures were 75% and 65.9% at 6-months follow-up. The effect sizes were large for all measures and clinically significant improvements were obtained for 70% of the children at posttest and 77% at follow-up. Our study suggests that metacognitive therapy for children with generalized anxiety disorder may be a highly promising treatment approach. PMID- 29145079 TI - Microbial transcript and metabolome analysis uncover discrepant metabolic pathways in autotrophic and mixotrophic anammox consortia. AB - The ability of anammox bacteria to utilize organic matter has drawn extensive attention. However, the metabolic discrepancies between autotrophic and mixotrophic anammox consortia need to be further explored. Here, microbial transcript and metabolomic analysis were conducted for the samples harvested in the reactors and batch assays to investigate the phenotype discrepancies and intrinsic causes in autotrophic and mixotrophic anammox consortia. Results showed that metabolically active community structures did not show significant difference between autotrophic and mixotrophic anammox consortia (C/N = 0.3). Changes in the metabolic state were the main cause for those discrepancies in virtue of the added acetate oxidized via the acetyl-CoA pathway by mixotrophic anammox bacteria. At C/N ratio of 0.3, anammox activity was obviously promoted compared to that in the autotrophic condition, due to higher levels of NADH and NAD+, as well as ATP consumption. Mixotrophic anammox consortia were found to yield more biomass, resulting from enhanced purine, pyrimidine, and putrescine synthetic pathways for regulating bacterial growth. Up-regulated amino sugar and nucleotide sugar metabolism pathways participating in regulating more extracellular polysaccharides secreted by mixotrophic anammox consortia. In adverse environment with higher COD concentration, more extracellular proteins were produced by anammox consortia to protect themselves and amino acids also accumulated in the cell. This study provides useful information to catch the optimal metabolism way of anammox consortia and accelerate anammox bacterial cultivation or reactor startup for wastewater treatment. PMID- 29145080 TI - Comparing the efficacy of solid and magic-echo refocusing sequences: Applications to 1H NMR echo spectroscopy of shale rock. AB - Quantitative evaluation of the solid and viscous components of unconventional shale rock, namely kerogen and bitumen, is important for understanding reservoir quality. Short transverse coherence times, due to strong 1H-1H dipolar interactions, motivates the application of solid state refocusing pulse sequences that allow for investigating components of the free-induction decay that are otherwise obscured by instrumental effects such as probe ringdown. This work reports on static, wide-line 1H spectroscopy of shale rock and their extracted components, which include kerogen and bitumen, by the application of solid echo and magic echo pulse sequences. We characterize the efficiency of these cycles as a function of the radio frequency power and inter-pulse spacing. Magic echos are shown to provide superior refocusing in comparison to solid echo based experiments, as can be understood from the truncation of the Magnus expansion and ability to also refocus any Iz Hamiltonians (e.g. static field inhomogeneity). We characterize the optimal echo spacing and RF power for two shale samples of different maturity, motivating routine core and cuttings analysis and applications. PMID- 29145081 TI - Elimination of chlorine-refractory carbamazepine by breakpoint chlorination: Reactive species and oxidation byproducts. AB - Breakpoint chlorination can be commonly observed in the chlorination of water treatments when ammonia is present. In this study, it was found that breakpoint chlorination can remarkably eliminate a ubiquitous and chlorine-refractory micropollutant, carbamazepine (CBZ), with the removal of 72% at neutral condition. At neutral pH, low CBZ elimination was observed at a chlorine/ammonia molar ratio (Cl/N) of 1.0 and higher CBZ elimination was observed as Cl/N ratio increased from 1.0 to 1.6 (breakpoint), indicating that CBZ elimination was closely related to the generation and decomposition of chloramines. The chloramines generation and decomposition rates were affected by the pH, so that the CBZ elimination rate was highest at pH 7.0 and lower in acidic and basic solutions (pH 5.5 and pH 9.5, respectively). The CBZ elimination at pH 7.0 was 72.4% after 10 min of breakpoint chlorination, while reaction times about 30 min and 60 min were required to achieve the same elimination at pH 5.5 and pH 9.5, respectively. Breakpoint chlorination of CBZ was strongly suppressed by radical scavenger tBuOH and moderately suppressed by N2 purging, the inhibiting ratios being 87.7% and 27.8% at breakpoint, respectively. Electron spin resonance experiments suggested that unidentified radicals were generated by breakpoint chlorination. The OH and unidentified radical species contributions to CBZ elimination were <23.7% and >76.3%, respectively, when a pseudo steady state breakpoint chlorination was performed in a microinjection system with nitrobenzene as OH probe. Although CBZ were efficiently eliminated, breakpoint chlorination of CBZ generated adsorbable organic chlorine. The cytotoxicity of the CBZ solution was therefore increased by breakpoint chlorination, suggesting that biological risk caused by the breakpoint chlorination of micropollutants should be taken into consideration. PMID- 29145082 TI - Insights into arsenic retention dynamics of Pleistocene aquifer sediments by in situ sorption experiments. AB - The migration of arsenic (As) enriched groundwater into Pleistocene aquifers as a consequence of extensive groundwater abstraction represents an increasing threat to the precious water resources in Asian delta regions. Pleistocene aquifer sediments are typically rich in FeIII-(hydr)oxides and are capable to adsorb high amounts of As. This results in a pronounced accumulation of As in Pleistocene aquifers, where high As groundwater infiltrates from adjacent Holocene aquifers. However, As retention by Pleistocene aquifers over long-term time scales remains largely unknown. We studied As sorption in situ by placing natural Pleistocene sediments and pure mineral phases directly inside groundwater monitoring wells at a study site near Hanoi (Vietnam). This in situ exposure allows for constant flushing of the samples with unaltered groundwater and the establishment of undisturbed sorption equilibria similar to those in local aquifer sediments, which is not readily attainable in traditional laboratory sorption experiments. The groundwaters in our experimental wells were characterized by different As concentrations (0.01-6.63 MUmol/L) and redox states, reaching from suboxic to anoxic conditions (Eh of +159 to -4 mV). Results show that adsorption is the dominant As retention mechanism, independent from the respective groundwater chemistry (i.e. concentrations of dissolved P, HCO3- and Si). Whilst most of the As sorbed within the first week, sorption further increased slowly but consistently by 6-189%, respectively, within six months. Hence, the As sorption behavior of Pleistocene aquifer sediments should be determined over longer periods to avoid an underestimation of the As sorption capacity. Accompanying desorption experiments revealed that about 51% of the sorbed As was remobilized within six months when exposed to low As groundwater. We therefore conclude that a considerable proportion of the As accumulated in the aquifer sediments is prone to remobilization once the As concentrations in migrating groundwater decline. Remobilization of As should be considered in local water management plans to avoid contamination of precious groundwater resources with this As legacy. PMID- 29145083 TI - Composition and functional group characterization of extracellular polymeric substances (EPS) in activated sludge: the impacts of polymerization degree of proteinaceous substrates. AB - Characteristics of extracellular polymeric substances (EPS) in activated sludge strongly depend on wastewater substrates. Proteinaceous substrates (ProS) present in heterogeneous polymeric form are intrinsic and important parts of wastewater substrates for microorganisms in activated sludge systems. However, correlations between ProS and characteristics of EPS are scarce. This study systematically explored the impacts of monomeric (Mono-), low polymeric (LoP-) and high polymeric (HiP-) ProS on compositions and functional groups of EPS in activated sludge. The results showed that the change of polymerization degree of ProS significantly altered the composition of EPS. Compared to EPSMono-ProS, the proportion of proteins in EPSLoP-ProS and EPSHiP-ProS increased by 12.8% and 27.7%, respectively, while that of polysaccharides decreased by 22.9% and 63.6%, respectively. Moreover, the proportion of humic compounds in EPSLoP-ProS and EPSHiP-ProS were ~6 and ~16-fold higher than that in EPSMono-ProS, respectively. The accumulation of humic compounds in EPS increased the unsaturation degree of EPS molecules, and thereby reduced the energy requirement for electrons transition of amide bonds and aromatic groups. Size exclusion chromatography (SEC) analyses detected more molecular clusters in EPSHiP-ProS, indicating more complex composition of EPS in HiP-ProS fed activated sludge. Spectroscopic characterization revealed the dominance of hydrocarbon, protein, polysaccharide and aromatic associated bonds in all three EPS. Nevertheless, with the increase of polymerization degree of ProS, the protein associated bonds (such as CONH, CO, NC, NH) increased, while the polysaccharide associated bonds (such as COC, COH, OCOH) decreased. This paper paves a path to understand the role of ProS in affecting the production and characteristics of EPS in biological wastewater treatment systems. PMID- 29145084 TI - Low voltage electric potential as a driving force to hinder biofouling in self supporting carbon nanotube membranes. AB - This study aimed at evaluating the contribution of low voltage electric field, both alternating (AC) and direct (DC) currents, on the prevention of bacterial attachment and cell inactivation to highly electrically conductive self supporting carbon nanotubes (CNT) membranes at conditions which encourage biofilm formation. A mutant strain of Pseudomonas putida S12 was used a model bacterium and either capacitive or resistive electrical circuits and two flow regimes, flow through and cross-flow filtration, were studied. Major emphasis was placed on AC due to its ability of repulsing and inactivating bacteria. AC voltage at 1.5 V, 1 kHz frequency and wave pulse above offset (+0.45) with 100Omega external resistance on the ground side prevented almost completely attachment of bacteria (>98.5%) with concomitant high inactivation (95.3 +/- 2.5%) in flow-through regime. AC resulted more effective than DC, both in terms of biofouling reduction compared to cathodic DC and in terms of cell inactivation compared to anodic DC. Although similar trends were observed, a net reduced extent of prevention of bacterial attachment and inactivation was observed in filtration as compared to flow-through regime, which is mainly attributed to the permeate drag force, also supported by theoretical calculations in DC in capacitive mode. Electrochemical impedance spectroscopy analysis suggests a pure resistor behavior in resistance mode compared to involvement of redox reactions in capacitance mode, as source for bacteria detachment and inactivation. Although further optimization is required, electrically polarized CNT membranes offer a viable antibiofouling strategy to hinder biofouling and simplify membrane care during filtration. PMID- 29145085 TI - Analysis of microplastics in water by micro-Raman spectroscopy: Release of plastic particles from different packaging into mineral water. AB - Microplastics are anthropogenic contaminants which have been found in oceans, lakes and rivers. Investigations focusing on drinking water are rare and studies have mainly been using micro-Fourier Transform Infrared Spectroscopy (MU-FT-IR). A major limitation of this technique is its inability to detect particles smaller than 20 MUm. However, micro-Raman spectroscopy is capable of detecting even smaller particle sizes. Therefore, we show that this technique, which was used in this study, is particularly useful in detecting microplastics in drinking water where particle sizes are in the low micrometer range. In our study, we compared the results from drinking water distributed in plastic bottles, glass bottles and beverage cartons. We tested the microplastic content of water from 22 different returnable and single-use plastic bottles, 3 beverage cartons and 9 glass bottles obtained from grocery stores in Germany. Small (-50-500 MUm) and very small (1-50 MUm) microplastic fragments were found in every type of water. Interestingly, almost 80% of all microplastic particles found had a particle size between 5 and 20 MUm and were therefore not detectable by the analytical techniques used in previous studies. The average microplastics content was 118 +/- 88 particles/l in returnable, but only 14 +/- 14 particles/l in single-use plastic bottles. The microplastics content in the beverage cartons was only 11 +/- 8 particles/l. Contrary to our assumptions we found high amounts of plastic particles in some of the glass bottled waters (range 0-253 particles/l, mean 50 +/- 52 particles/l). A statistically significant difference from the blank value (14 +/- 13) to the investigated packaging types could only be shown comparing to the returnable bottles (p < 0.05). Most of the particles in water from returnable plastic bottles were identified as consisting of polyester (primary polyethylene terephthalate PET, 84%) and polypropylene (PP; 7%). This is not surprising since the bottles are made of PET and the caps are made of PP. In water from single-use plastic bottles only a few micro-PET-particles have been found. In the water from beverage cartons and also from glass bottles, microplastic particles other than PET were found, for example polyethylene or polyolefins. This can be explained by the fact that beverage cartons are coated with polyethylene foils and caps are treated with lubricants. Therefore, these findings indicate that the packaging itself may release microparticles. The main fraction of the microplastic particles identified are of very small size with dimensions less than 20 MUm, which is not detectable with the MU-FT-IR technique used in previous studies. PMID- 29145086 TI - Active learning for classifying data streams with unknown number of classes. AB - The classification of data streams is an interesting but also a challenging problem. A data stream may grow infinitely making it impractical for storage prior to processing and classification. Due to its dynamic nature, the underlying distribution of the data stream may change over time resulting in the so-called concept drift or the possible emergence and fading of classes, known as concept evolution. In addition, acquiring labels of data samples in a stream is admittedly expensive if not infeasible at all. In this paper, we propose a novel stream-based active learning algorithm (SAL) which is capable of coping with both concept drift and concept evolution by adapting the classification model to the dynamic changes in the stream. SAL is the first AL algorithm in the literature to explicitly take account of these concepts. Moreover, using SAL, only labels of samples that are expected to reduce the expected future error are queried. This process is done while tackling the problem of sampling bias so that samples that induce the change (i.e., drifting samples or samples coming from new classes) are queried. To efficiently implement SAL, the paper proposes the application of non parametric Bayesian models allowing to cope with the lack of prior knowledge about the data stream. In particular, Dirichlet mixture models and the stick breaking process are adopted and adapted to meet the requirements of online learning. The empirical results obtained on real-world benchmarks demonstrate the superiority of SAL in terms of classification performance over the state-of-the art methods using average and average class accuracy. PMID- 29145087 TI - Retention performance of three widely used SPE sorbents for the extraction of perfluoroalkyl substances from seawater. AB - Some per- and polyfluoroalkyl substances (PFASs) have been detected ubiquitously in the environment. Owing to the polar character conferred by the presence of the carboxylic or sulfonic acid groups and their resistance to degradation, aquatic environments became their major reservoirs, including marine waters. The procedure of PFAS analysis in aqueous matrices consists usually of solid-phase extraction (SPE) followed by high-performance liquid chromatography coupled to tandem mass spectrometry. Moreover, passive sampling approach using various SPE sorbents may be applied. This study deals with the assessment of retention characteristics of a selected group of PFASs in marine water on three sorbent media widely used in SPE or passive sampling techniques. The influence of type of sorbent, matrix pH, salinity and eluent on the PFAS recovery from aquatic samples was investigated. The best overall extraction conditions were found to be at pH 8 and 50%/100% matrix seawater content using Oasis(r) HLB/StrataTM-X as SPE sorbents and methanol as eluent. The matrix properties found to be the most appropriate for extraction of investigated PFASs from aqueous samples (i.e., pH and salinity levels) match well the natural properties of marine and brackish waters. Acid-base behavior was found to be the main driver influencing the recovery of PFASs. These research findings can be used to optimize PFAS extraction conditions from aquatic samples and also to develop efficient extraction procedures for multiresidual analyses. PMID- 29145088 TI - Phosphorus recovery and leaching of trace elements from incinerated sewage sludge ash (ISSA). AB - Chemical extraction of phosphorus (P) from incinerated sewage sludge ash (ISSA) is adversely influenced by co-dissolution of metals and metalloids. This study investigated P recovery and leaching of Zn, Cu, Pb, As and Ni from ISSA using inorganic acids (sulphuric acid and nitric acid), organic acids (oxalic acid and citric acid), and chelating agents (ethylenediaminetetraacetic acid (EDTA) and ethylene diamine tetramethylene phosphonate (EDTMP)). The aim of this study was to optimize a leaching process to recover P-leachate with high purity for P fertilizer production. The results show that both organic and inorganic acids extract P-containing phases but organic acids leach more trace elements, particularly Cu, Zn, Pb and As. Sulphuric acid was the most efficient for P recovery and achieved 94% of total extraction under the optimal conditions, which were 2-h reaction with 0.2 mol/L H2SO4 at a liquid-to-solid ratio of 20:1. EDTA extracted only 20% of the available P, but the leachates were contaminated with high levels of trace elements under optimum conditions (3-h reaction with EDTA at 0.02 mol/L, pH 2, and liquid-to-solid ratio of 20:1). Therefore, EDTA was considered an appropriate pre-treatment agent for reducing the total metal/metalloid content in ISSA, which produced negligible changes in the structure of ISSA and reduced contamination during subsequent P extraction using sulphuric acid. PMID- 29145089 TI - Arsenic removal from As-hyperaccumulator Pteris vittata biomass: Coupling extraction with precipitation. AB - Proper disposal of As-hyperaccumulator Pteris vittata biomass (Chinese brake fern) enhances its application in phytoremediation. The goal of this study was to optimize As removal from P. vittata (PV) biomass by testing different particle sizes, extractants, extraction times and solid-to-liquid ratios. PV biomass was extracted using different extractants followed by different Mg-salts to recover soluble As via precipitation. Water-soluble As in PV biomass varied from 6.8% to 61% of total As depending on extraction time, with 99% of As being arsenate (AsV). Extraction with 2.1% HCl, 2.1% H3PO4, 1 M NaOH and 50% ethanol recovered 81, 78, 47 and 14% of As from PV biomass. A follow-up extraction using HCl recovered 27-32% with ethanol recovering only 5%. Though ethanol showed the lowest extractable As, residual As in the biomass was also the lowest. Among the extractants, 35% ethanol was the best to remove As from PV biomass. Approximately 90% As was removed from PV biomass using particle size <1 mm at solid:liquid ratio 1:50 and pH 6 for 2 h. Adding MgCl2 at As:Mg ratio of 1:400 with pH 9.5 was effective to precipitate soluble As, resulting in 98% removal. Effective removal of As from PV biomass prior to disposal helps make phytoremediation more feasible. PMID- 29145090 TI - Comparative study of dissolved organic matter generated from activated sludge during exposure to hypochlorite, hydrogen peroxide, acid and alkaline: Implications for on-line chemical cleaning of MBR. AB - Although on-line chemical cleaning has been extensively employed for maintaining the MBR permeability, little attention has been given to the negative impacts of such prevalent membrane cleaning practice. This study thus comparatively investigated the potential release of dissolved organic matter (DOM) from activated sludge upon the exposure to different kinds of frequently-used cleaning reagents, i.e. NaClO, H2O2, HCl and NaOH. It was found that NaClO at 50 and 80 mg L-1 triggered significant release of DOM, while NaOH strongly promoted soluble nitrogen release. However, the DOM generation induced by H2O2 in the range of 0 80 mg L-1 was nearly negligible. The combined analysis by EEM-PARAFAC and LC-OCD OND further revealed that NaClO-triggered DOM mainly originated from the breakdown of humic substances and other small humics with molecular weight (MW) less than 500 Da. In contrast, proteins and other biopolymers with higher MW highly contributed to DOM induced by NaOH. Most of DOM detected in this study belonged to low molecular weight (LMW) substances, which were not considered readily biodegradable or physically retainable by microfiltration membrane. It appears from this study that DOM generated from suspended activated sludge during membrane cleaning with different chemicals should be taken into serious consideration when water recycle and reuse are concerned. PMID- 29145091 TI - Discussion of "Occurrence, fate and environmental impact of linear alkylbenzene sulfonate in the Langat and Selangor River basins, Malaysia" by Nobumitsu Sakai, Junichi Shirasaka, Yasuto Matsui, Mohd Redzuam Ramli, Kousuke Yoshida, Mustafa Ali Mohd, Minoru Yoneda [Chemosphere 172 (2017) 234-241]. PMID- 29145092 TI - Ionic liquid solvent bar micro-extraction of CdCln(n-2)- species for ultra-trace Cd determination in seawater. AB - Water analysis of trace metals has been benefited by recent studies on sample preparation by liquid micro-extraction. However, there are still limitations for its application to seawater, such as the need of additives to preserve the sample or the availability of chemical extractants for the selective extraction from highly saline samples. In this work, a three phase solvent bar micro-extraction (3SBME) system containing the ionic liquid trioctylmethylammonium chloride (Aliquat(r) 336) has been used for isolation and pre-concentration of Cd from seawater samples, due to its ability for ionic exchange of CdCln(n-2)-. The system was optimized to work at the natural pH of seawater, and conditions for application to real samples were 0.18 M Aliquat(r) 336 dissolved in kerosene with 0.25 M dodecan-1-ol as organic solution, 1.5 M HNO3 as acceptor solution, 60 min extraction time, and 800 rpm stirring speed in the sample. Loss of organic solution into the sample during extraction was evaluated and revealed its dependence on stirring rate and extraction time. Under optimum conditions samples containing Cd 0.09-0.90 nM were pre-concentrated 65 times. GF-AAS was used for metal quantification with a limit of detection of 0.04 nM. Accuracy was successfully evaluated measuring Cd in a seawater certified reference material BCR-403. PMID- 29145093 TI - Proteomic profile and toxicity pathway analysis in zebrafish embryos exposed to bisphenol A and di-n-butyl phthalate at environmentally relevant levels. AB - Bisphenol A (BPA) and di-n-butyl phthalate (DBP) are well-known endocrine disrupting chemicals (EDCs) that have human health risks. Chronic exposure to BPA and DBP increases the occurrence of human disease. Despite the potential for exposure in embryonic development, the mechanism of action of BPA and DBP on vertebrate development and disease still remains unclear. In the present study, we identified proteins and protein networks that are perturbed by BPA and DBP during zebrafish (Danio rerio) development. Zebrafish embryos were exposed to environmentally relevant levels of BPA (10 MUg/L) and DBP (50 MUg/L) for 96 h. By iTRAQ labeling quantitative proteomics, a set of 26 and 41 differentially expressed proteins were identified in BPA- and DBP-treated zebrafish embryos, respectively. Integrated toxicity analysis predicted that these proteins function in common regulatory networks that are significantly associated with developmental and metabolic disorders. Exposure to low concentrations of BPA and DBP has potential health risks in zebrafish embryos. Our results also show that BPA and DBP significantly up-regulate the expression levels of multiple network proteins, providing valuable information about the molecular actions of BPA and DBP on the developmental systems. PMID- 29145094 TI - A mixture of five endocrine-disrupting chemicals modulates concentrations of bisphenol A and estradiol in mice. AB - Most people in developed countries are exposed to multiple endocrine-disrupting synthetic chemicals. We previously showed that a single dose of triclosan, tetrabromobisphenol A (TBBPA), butyl paraben, propyl paraben, or di(2-ethylhexyl) phthalate elevated concentrations of bisphenol A (BPA) in mice. Here we investigated whether concurrent exposure to lower doses of these five chemicals could modulate concentrations of bisphenol A (BPA) or the natural estrogen, 17beta-estradiol (E2). CF1 mice were injected subcutaneously with 0.1 or 0.5 mg of one chemical, or a 0.5 mg mixture containing 0.1 mg of each of all five chemicals, then given dietary 50 MUg kg-114C-BPA. The mixture elevated 14C-BPA concentrations in the lungs, muscle, uterus, ovaries, kidney, and blood serum of female mice. When administered alone, triclosan and TBBPA elevated 14C-BPA concentrations in the uterus, ovaries, and blood serum. In another experiment, CF1 mice were injected subcutaneously with the 0.5 mg mixture containing 0.1 mg of all five chemicals, then E2 was measured in urine 2-12 h later. The mixture elevated E2 at 8 h after injection in female mice. No treatments significantly altered concentrations of 14C-BPA or E2 in male mice. These data show that these endocrine-disrupting chemicals interact in vivo, magnifying one another's effects, consistent with inhibition of enzymes that are critical for estrogen metabolism. These findings highlight the importance of considering exposure to multiple chemicals when assessing health outcomes and determining regulatory exposure limits. PMID- 29145095 TI - Fear of food prospectively predicts drive for thinness in an eating disorder sample recently discharged from intensive treatment. AB - Fears of food are common in individuals with eating disorders and contribute to the high relapse rates. However, it is unknown how fears of food contribute to eating disorder symptoms across time, potentially contributing to an increased likelihood of relapse. Participants diagnosed with an eating disorder (N=168) who had recently completed intensive treatment were assessed after discharge and one month later regarding fear of food, eating disorder symptoms, anxiety sensitivity, and negative affect. Cross lagged path analysis was utilized to determine if fear of food predicted subsequent eating disorder symptoms one month later. Fear of food-specifically, anxiety about eating and feared concerns about eating-predicted drive for thinness, a core symptom domain of eating disorders. These relationships held while accounting for anxiety sensitivity and negative affect. There is a specific, direct relationship between anxiety about eating and feared concerns about eating and drive for thinness. Future research should test if interventions designed to target fear of food can decrease drive for thinness and thereby prevent relapse. PMID- 29145096 TI - Sulfaguanidine cocrystals: Synthesis, structural characterization and their antibacterial and hemolytic analysis. AB - Sulfaguanidine (SG), belongs to the class of sulfonamide drug used as an effective antibiotic. In the present work, using crystal engineering approach two novel cocrystals of SG were synthesized (SG-TBA and SG-PT) with thiobarbutaric acid (TBA) and 1,10-phenanthroline (PT), characterized by solid state techniques viz., powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and the crystal structures were determined by single crystal X-ray diffraction studies. A comparative antibacterial activity and hemolytic potential was done on SG drug, coformers and their cocrystals. The tested cocrystals formulations showed almost two fold higher antibacterial activity against the tested strains of bacteria Gram positive bacteria (S. mutans and E. faecalis) and Gram-negative bacteria (E. coli, K. pneumonia and E. clocae) over SG alone and their coformers. Cocrystal SG TBA showed better antibacterial activity and reduced hemolysis, thereby, reduced cytotoxicity than SG-PT. PMID- 29145097 TI - LC-ESI-MS/MS determination of defactinib, a novel FAK inhibitor in mice plasma and its application to a pharmacokinetic study in mice. AB - A sensitive, specific, selective and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of defactinib in mice plasma using 13C3,15N tofacitinib as an internal standard (I.S.). Sample preparation was accomplished through a liquid-liquid extraction process. Baseline chromatographic resolution of defactinib and the I.S. was achieved on an Atlantis dC18 column using an isocratic mobile phase comprising 0.2% formic acid in water and acetonitrile (25:75, v/v) delivered at a flow rate of 0.5mL/min. Defactinib and the I.S. eluted at ~1.59 and 0.99min, respectively. The total chromatographic run time was 2.50min. A linear response function was established in the concentration range of 0.13-106 ng/mL. Method validation was performed as per regulatory guidelines and the results met the acceptance criteria. The intra- and inter-day accuracy and precision were in the range of 5.57-13.3 and 8.63-12.1%, respectively. Defactinib was found to be stable under various stability conditions. This novel method has been applied to a pharmacokinetic study in mice. PMID- 29145098 TI - A novel, simplified strategy of relative quantification N-glycan: Quantitative glycomics using electrospray ionization mass spectrometry through the stable isotopic labeling by transglycosylation reaction of mutant enzyme Endo-M-N175Q. AB - The lack of a highly sensitive and simple method for the quantitative analysis of glycan has impeded the exploration of protein glycosylation patterns (glycomics), evaluation of antibody drug stability, and screening of disease glycan biomarkers. In this study, we describe a novel and simplified quantitative glycomics strategy. Quantitation by mutant enzyme reaction stable isotope labeling (QMERSIL) to label the N-glycans with either a nondeuterated (d0-) or deuterated (d8-) 4-(2,4-Dinitro-5-piperazin-1-yl-phenyl)-1,1-dimethyl-piperazin-1 ium (MPDPZ)-Boc-asparaginyl-N-acetyl-d-glucosamine (Boc-Asn-GlcNAc) acceptor of a positive charge structure through the glycosynthase (Endo-M-N175Q) transglycosylation reaction with mass spectrometry facilitates comparative glycomics. The sialylglycopeptide (SGP) of the complex type was used to demonstrate that QMERSIL facilitates the relative quantitation over a linear dynamic range (up to d0/d8=0.02:20) of 3 orders of magnitude. The area ratios of the N-glycan peaks from the QMERSIL method showed a good linearity (d0/d8, R2=0.9999; d8/d0, R2=0.9978). The reproducibility and accuracy assay precisions were all less than 6.12%, and the mean recoveries (%) of SGP spiked in the human plasma were 97.34%. Moreover, the QMERSIL using LC-MS/MS was evaluated with various molar ratios (1:1, 1:5, 5:1) of d0(d8)- MPDPZ-Boc-Asn-GlcNAc-labeled glycans from ribonuclease B, bovine fetuin, and ovalbumin. The ratios of the relative intensity between the isotopically MPDPZ-Boc-Asn-GlcNAc labeled N glycans were almost equal a close to the theoretical values (1:1, 1:5, 5:1). Finally, this method was used for the relative quantitative comparison of the N Linked oligosaccharides in human plasma. PMID- 29145099 TI - Degradation kinetics study of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) by a validated stability-indicating RP-HPLC method. AB - The chemical stability of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), a therapeutic agent for neutropenia, was investigated using a validated stability indicating reversed phase high-performance liquid chromatographic (RP-HPLC) method. The forced degradation of PLAG was carried out under the stress conditions of hydrolysis (alkaline, acidic and various pH buffers), oxidation, photolysis and heat. A simple, sensitive, specific, robust, precise and accurate RP-HPLC method was developed and validated for evaluating the degradation kinetics of PLAG. The chromatographic validation of various parameters, such as system suitability, detection limit, quantification limit, linearity, accuracy, precision, specificity, robustness and stability, was achieved. The method was validated for linearity, accuracy and precision over the concentration range of 0.7813-100MUg/mL (r2=0.9999). The proposed method provided excellent stability study of PLAG indicated by the resolution of degradation products from the drug. Degradation of PLAG provided first order kinetics under all experimental conditions. PLAG was catalysed more rapidly in alkaline and acidic conditions than in neutral conditions. PLAG was relatively stable in photolytic and oxidative conditions compared to hydrolysis and thermal conditions, although this drug was not also stable in these conditions. Exposed to high temperature, PLAG was more rapidly catalysed. The activation energy evaluated from the Arrhenius plot was about 110kJ/mol in the thermal conditions. Additionally, PLAG with a t1/2 of about 400h was very stable at room temperature. Therefore, PLAG was considerably influenced by alkaline and acidic hydrolysis, and thermal degradation. PMID- 29145100 TI - Environmental assessment of microwaves and the effect of European energy efficiency and waste management legislation. AB - More than 130 million microwaves are affected by European Union (EU) legislation which is aimed at reducing the consumption of electricity in the standby mode ('Standby Regulation') and at more sustainable management of end-of-life electrical and electronic waste ('WEEE Directive'). While legislation focuses on these two life cycle stages, there is little information on the environmental impacts of the entire life cycle of microwaves. To address this gap, this paper presents a comprehensive life cycle assessment of microwaves and assesses the environmental implications of the Standby Regulation and the WEEE Directive at the EU level. The impacts are first considered at the level of individual appliances and then at the EU level, with the aim of evaluating the potential environmental implications of the full implementation of the above two EU regulations by 2020. The effects of the electricity decarbonisation and the expected increase in the number of microwaves in use have also been considered. The results suggest that implementation of the EU regulation by 2020 will reduce the environmental impacts considered by 4%-9% compared to the current situation. The majority of these reductions is due to the Standby Regulation, with the contribution of the WEEE Directive being small (~0.3%). However, the expected decarbonisation of electricity will result in much higher reductions (6%-24%) for most impact categories. The results also show that the materials used to manufacture the microwaves, the manufacturing process and end-of-life disposal are environmental hot-spots for several impacts, including depletion of abiotic elements. Therefore, efforts to reduce the environmental impacts of a future electricity mix should be combined with the development of specific eco-design regulations for microwaves that stipulate optimisation of resource consumption. Possible future trends, such as shorter lifetimes and limited availability of some resources, make the development of such product regulations more critical. PMID- 29145101 TI - The distribution and trends of persistent organic pollutants and mercury in marine mammals from Canada's Eastern Arctic. AB - Arctic contaminant research in the marine environment has focused on organohalogen compounds and mercury mainly because they are bioaccumulative, persistent and toxic. This review summarizes and discusses the patterns and trends of persistent organic pollutants (POPs) and mercury in ringed seals (Pusa hispida) and polar bears (Ursus maritimus) in the Eastern Canadian Arctic relative to the rest of the Canadian Arctic. The review provides explanations for these trends and looks at the implications of climate-related changes on contaminants in these marine mammals in a region that has been reviewed little. Presently, the highest levels of total mercury (THg) and the legacy pesticide HCH in ringed seals and polar bears are found in the Western Canadian Arctic relative to other locations. Whereas, highest levels of some legacy contaminants, including ?PCBs, PCB 153, ?DDTs, p,p'-DDE, ?CHLs, ClBz are found in the east (i.e., Ungava Bay and Labrador) and in the Beaufort Sea relative to other locations. The highest levels of recent contaminants, including PBDEs and PFOS are found at lower latitudes. Feeding ecology (e.g., feeding at a higher trophic position) is shaping the elevated levels of THg and some legacy contaminants in the west compared to the east. Spatial and temporal trends for POPs and THg are underpinned by historical loadings of surface ocean reservoirs including the Western Arctic Ocean and the North Atlantic Ocean. Trends set up by the distribution of water masses across the Canadian Arctic Archipelago are then acted upon locally by on-going atmospheric deposition, which is the dominant contributor for more recent contaminants. Warming and continued decline in sea ice are likely to result in further shifts in food web structure, which are likely to increase contaminant burdens in marine mammals. Monitoring of seawater and a range of trophic levels would provide a better basis to inform communities about contaminants in traditionally harvested foods, allow us to understand the causes of contaminant trends in marine ecosystems, and to track environmental response to source controls instituted under international conventions. PMID- 29145102 TI - Remediation of a soil chronically contaminated with hydrocarbons through persulfate oxidation and bioremediation. AB - The impact of remediation combining chemical oxidation followed by biological treatment on soil matrix and microbial community was studied, of a chronically hydrocarbon contaminated soil sourced from a landfarming treatment. Oxidation by ammonium persulfate produced a significant elimination of polycyclic aromatic hydrocarbons (PAHs) and an increase in PAH bioavailability. Organic-matter oxidation mobilized nutrients from the soil matrix. The bacterial populations were affected negatively, with a marked diminution in the diversity indices. In this combined treatment with oxidation and bioremediation working in tandem, the aliphatic-hydrocarbon fractions were largely eliminated along with additional PAHs. The chemical and spectroscopic analyses indicated a change in soil nutrients. In spite of the high residual-sulfate concentration, a rapid recovery of the cultivable bacterial population and the establishment of a diverse and equitable microbial community were obtained. Pyrosequencing analysis demonstrated a marked succession throughout this twofold intervention in accordance with the chemical and biologic shifts observed. These remediation steps produced different effects on the soil physiology. Spectroscopic analysis became a useful tool for following and comparing those treatments, which involved acute changes in a matrix of such chronically hydrocarbon-contaminated soil. The combined treatment increased the elimination efficiency of both the aliphatic hydrocarbons and the PAHs at the expense of the mobilized organic matter, thus sustaining the recovery of the resilient populations throughout the treatment. The high-throughput-DNA sequencing techniques enabled the identification of the predominant populations that were associated with the changes observed during the treatments. PMID- 29145103 TI - Gold-chlorophyll a-hybrid nanoparticles and chlorophyll a/cetyltrimethylammonium chloride self-assembled-suprastructures as novel carriers for chlorophyll a delivery in water medium: Photoactivity and photostability. AB - The stability of Chlorophyll a in water during prolonged exposure, at room temperature, to a neon lamp has been investigated by means of UV-vis and fluorescence spectroscopies. In addition, the Chlorophyll a (photo)stability evaluation in presence of suitable carriers has been performed in order to investigate its reactivity under the same conditions, for possible and future applications in Antimicrobial Photodynamic Therapy. Cetyltrimethylammonium chloride was chosen to solubilize Chlorophyll a in water. While, cetyltrimethylammonium chloride-capped gold nanoparticles offer a great opportunity because combine the Chlorophyll a action, used as a photosensitizer in Antimicrobial Photodynamic Therapy, with gold nanoparticles effect used in photothermal therapy. Indeed, the latter ones have exhibited an interesting rise of temperature if irradiated with visible light. Overall, both examined systems, cetyltrimethylammonium chloride/Chlorophyll a and gold nanoparticles/Chlorophyll a, were able to induce the Reactive Oxygen Species formation fundamental for a potential application in Antimicrobial Photodynamic Therapy. PMID- 29145104 TI - Mentalizing impairment as a mediator between reported childhood abuse and outcome in nonaffective psychotic disorder. AB - Reported childhood abuse has been linked to the severity of clinical symptoms and social dysfunction in non-affective psychotic disorder. Impaired mentalizing ability may be one of the mechanisms accounting for this effect. This study examined whether impaired mentalizing mediates the effect of reported childhood abuse on positive symptoms, negative symptoms, and social dysfunction. Eighty seven patients with non-affective psychotic disorder were examined. Reported childhood abuse was measured using the Childhood Experience of Care and Abuse interview. Additionally, the Social Functioning Scale and the Positive and Negative Syndrome Scale were used. The Hinting Task was used to measure mentalizing impairment. Reported childhood abuse was significantly related to the severity of positive and negative symptoms, not to social dysfunction. Reported childhood abuse was also related to mentalizing impairment. Mentalizing impairment was related to negative symptoms, but not to positive symptoms or social dysfunction. Mentalizing impairment accounted for 40% of the association between reported childhood abuse and negative symptoms, indicating partial mediation. A sensitivity analysis revealed that the mediating effect was only observed in those who reported fairly severe childhood abuse. PMID- 29145105 TI - The steel pan sign of sigmoid volvulus-A case series. AB - INTRODUCTION: Signs in radiology are usually based on many common objects or patterns that are easily recognizable in everyday life. The objective behind this association is to aid in the understanding and diagnosis of the disease process. These signs can be seen in different imaging modalities such as plain radiograph and computed tomography. PRESENTATION OF CASE: 4 consecutive cases of sigmoid volvulus presented at our tertiary hospital between January 2016 and June 2017. 2 of these cases were managed surgically and others were managed conservatively. The CT scan and abdominal radiographs in these patients were reviewed with consultant radiologist, which bear resemblance to the percussion instrument known as the steel pan. DISCUSSION: The literature has described few radiological signs of sigmoid volvulus in the past. In the following case series, we would like to introduce the "Steel pan Sign", a novel radiological pattern which bears a close resemblance to the percussion instrument known as the steel pan. The Steel pan sign is easier to recognize on CT scan of the abdomen. However, in some cases it can be seen on plain X-Rays. CONCLUSION: The appearance of sigmoid volvulus on CT scans as well as on plain abdominal X-rays bears a significant resemblance to the pattern observed on the face of the Trinidadian steel pan, the recognition of which can aid in the diagnosis of this disease. PMID- 29145106 TI - Metachronous mediastinal lymph node metastasis from ascending colon cancer: A case report and literature review. AB - INTRODUCTION: Metachronous mediastinal lymph node metastasis without pulmonary metastasis is extremely rare in colorectal cancer, which makes the clinical diagnosis difficult and treatment strategy unclear. PRSENTATION OF CASE: A case was a 59-year-old man, who had undergone right hemicolectomy for ascending colon cancer 2 years and 8 months previously, presented with enlarged mediastinal lymph nodes. 18F-fluorodeoxyglucose (FDG) positron emission tomography revealed FDG was accumulated only into the mediastinal lymph nodes. Serum carcinoembryonic antigen (CEA) level was within the normal range. Six months later, the size and FDG uptake of the mediastinal lymph nodes had increased. We assumed a possibility that the mediastinal lymph nodes were metastasized from ascending colon cancer and so performed thoracoscopic-assisted resection of the mediastinal lymph nodes. Histopathological analysis revealed the resected lymph nodes were filled with moderately differentiated adenocarcinoma and a diagnosis of mediastinal lymph nodes metastasis from previously-resected ascending colon cancer was made. The patient was postoperatively followed for more than 1year and 8 months without any sign of recurrence. DISCUSSION: Only 7 cases of metachronous mediastinal lymph node metastasis from colorectal cancer, including our case, have been reported in the English literature. It is difficult to clinically diagnose mediastinal lymph node metastasis. CONCLUSION: We report a rare case of metachronous mediastinal lymph node metastasis from ascending colon cancer with literature review. If the mediastinal lymph nodes are enlarged after colorectal cancer resection, we need to make a treatment strategy as well as a diagnostic approach considering the possibility of mediastinal lymph node metastasis. PMID- 29145107 TI - Postoperative thoracic hemorrhage after right upper lobectomy with thoracic wall resection during rivaroxaban anticoagulant therapy for deep leg vein thrombosis: A case report. AB - INTRODUCTION: Postoperative pulmonary embolism (PE) is the one of the most important complications after thoracic surgery. This complicatin after the surgery is often treated by new anticoaglant drug, such as rivaroxaban, which dose not need to the monitoring of blood coaglation system. We experienced postoperative bleeding case during anticoaglant therapy using rivaroxaban. PRESENTATION OF CASE: The patient underwent a right upper lobectomy with lung and chest wall resection for lung cancer. On postoperative day (POD) 10, we started to use rivaroxaban to treat the deep vein thrombosis (DVT). Four days after starting the rivaroxaban treatment, severe surgical site hemorrhage occurred, which led to the need for the infusion of concentrated red cells (CRC). After stopping the rivaroxaban, the thoracic bleeding ceased. Because the event occurred so long after the surgery, and because the bleeding stopped after withdrawal of treatment, we believe that rivaroxaban induced the thoracic bleeding. CONCLUSION: Some reports in the field of orthopedics (Turpie et al., 2009) have noted that rivarxaban is effective to prevent postoperative DVT. However, there were few reports that invied the attention to postoperative bleeding be induced by rivarxaban. Thus, we describe this case in order to alert clinicians to the potential bleeding risks associated with the admistration of rivaroxaban postoperatively. PMID- 29145108 TI - Acute calcific tendinitis of the longus colli muscle masquerading as a retropharyngeal abscess: A case report and review of the literature. AB - INTRODUCTION: Acute calcific longus colli tendinitis, also known as retropharyngeal or acute calcific prevertebral tendinitis, is a reactive self limiting inflammatory response to acute or subacute deposition of amorphous calcium hydroxyapatite crystals in the tendons of the longus colli muscle, anterior to the C1-C2 disk space. CASE PRESENTATION: A 53-year-old man presented with a complaint of neck pain and odynophagia over a few days. Blood test findings showed mild leukocytosis and elevated C-reactive protein level. Computed tomography findings showed mild edematous prevertebral thickening involving the retropharyngeal space, predominantly on the left side, with no appreciable surrounding peripheral enhancement. A small amount of linear calcification/ossification involving the superior fibers of the left longus colli muscle, anterior to the C1 arch were also noted. DISCUSSION: The patient's presentation could be easily misdiagnosed as a retropharyngeal abscess. However, the presence of subtle findings on CT would lead to the correct diagnosis. The management of this condition is mainly with nonsteroidal anti-inflammatory drugs. CONCLUSION: This study presents the characteristic radiological features of retropharyngeal calcific tendinitis. These features are subtle and could be missed. Once an accurate diagnosis is made, treatment with nonsteroidal anti inflammatory drugs is indicated. The purpose of this case report is to highlight this rare condition's diagnosis and management. PMID- 29145109 TI - Cisplatin induced acute mesenteric ischaemia: A case report and review of the literature. AB - INTRODUCTION: Cisplatin is a platinum-based chemotherapeutic agent, widely used in cancer therapies for numerous solid tumours. It is becoming more recognised that a potentially life-threatening complication of cisplatin is accelerated arterial and venous thrombosis. PRESENTATION OF CASE: We describe a case of a 62year-old with no risk factors for vascular disease who presented with thromboembolic acute mesenteric ischaemia of the small bowel during treatment with cisplatin for head and neck cancer. DISCUSSION: We review the literature on the incidence and pathogenesis of cisplatin induced arterial thrombosis and discuss current treatment options of acute mesenteric ischaemia detailing our management of this case. CONCLUSION: Cisplatin increases the risk of arterial thrombosis and this case report details acute mesenteric ischaemia secondary to its use. We hope to raise clinician awareness of this sequelae which can occur even in patients in the absence of other identifiable risk factors. PMID- 29145110 TI - Traumatic separation of osseous segments in a double-layered patella. AB - INTRODUCTION: Double-layered patella is a rare intra-articular disorder associated with multiple epiphyseal dysplasia. PRESENTATION OF CASE: We present a case of a 40-year old man with acute pain in his left knee after a tackle during soccer play. DISCUSSION: Clinical examination and radiographs confirmed the diagnosis of a bilateral double-layered patella with traumatic separation of the osseous segments on the afflicted left side. Surgical management comprised of open arthrotomy and debridement of the bony interface. Stabilization was performed with tension cerclage, supported by a lag screw with excellent outcome at 12 months follow-up. CONCLUSION: It is possible that micromovement in a double layered patella can dispose to a traumatic coronal segment displacement. Osseous fusion of traumatic patellar segments can be achieved. PMID- 29145111 TI - A novel protein tyrosine phosphatase like phytase from Lactobacillus fermentum NKN51: Cloning, characterization and application in mineral release for food technology applications. AB - A novel protein tyrosine phosphatase like phytase (PTPLP), designated as PhyLf from probiotic bacterium Lactobacillus fermentum NKN51 was identified, cloned, expressed and characterized. The recombinant PhyLf showed specific activity of 174.5 U/mg. PhyLf exhibited strict specificity towards phytate and optimum temperature at 60 degrees C, pH 5.0 and ionic strength of 100 mM. Km and Kcat of PhyLf for phytate were 0.773 mM and 84.31 s-1, respectively. PhyLf exhibited high resistance against oxidative inactivation. PhyLf shares no homology, sans the active site with reported PTLPs, warranting classification as a new subclass. Dephytinization of durum wheat and finger millet under in vitro gastrointestinal conditions using PhyLf enhanced the bioaccessibility of mineral ions. Probiotic origin, phytate specificity, resistance to oxidative environment and gastric milieu coupled with ability to release micronutrients are unique properties of PhyLf which present a strong case for its use in ameliorating nutritional value of cereals and animal feed. PMID- 29145112 TI - Biochar assisted thermophilic co-digestion of food waste and waste activated sludge under high feedstock to seed sludge ratio in batch experiment. AB - Batch experiments were conducted using biochar (BC) to promote stable and efficient methane production from thermophilic co-digestion of food waste (FW) and waste activated sludge (WAS) at feedstock/seed sludge (F/S) ratios of 0.25, 0.75, 1.5, 2.25, and 3. The results showed that the presence of BC dramatically shortened the lag time of methane production and increased the methane production rate with increased organic loading. The higher buffer capacity and large specific surface area of BC promoted microorganism growth and adaption to VFAs accumulation. Additionally, the electron exchange in syntrophic oxidation of butyrate and acetate as intermediate products was significantly facilitated by BC possibly due to the selective succession of bacteria and methanogens which may have participated in direct interspecies electron transfer, in contrast with the control group with low-efficient electron ferried between syntrophic oxidizers and methanogens using hydrogen as the electron carrier. PMID- 29145113 TI - Denitrification behavior and microbial community spatial distribution inside woodchip-based solid-phase denitrification (W-SPD) bioreactor for nitrate contaminated water treatment. AB - The NO3- removal pathway and microorganisms change along with the height of an up flow W-SPD bioreactor was investigated in this study. Modeling and microbial community analysis were used to analyze the denitrification behavior in W-SPD bioreactor. The results showed that NO3- removal rate matched for zero-order (R2 > 0.97) and first-order (R2 > 0.94) combination Michaelis-Menten kinetics, whereas microbial reaction rate suited for modified logistic model (R2 > 0.99). The excellent denitrification performance (92.5%-96.4%) and microorganisms' quantity occurred in the middle of W-SPD bioreactor. Moreover, high-throughput sequencing analysis revealed that dominant denitrifiers, carbonaceous compound degrading bacteria and fermentative bacteria co-existed in W-SPD system, which was vital for efficiently sustainable NO3- removal. Hence, aerobic degradation, heterotrophic denitrification and dissimilatory nitrate reduction to ammonium (DNRA) occurred successively along the water direction in the bioreactor, offering reasonable references for W-SPD bioreactor study and application. PMID- 29145114 TI - Boosting Nannochloropsis oculata growth and lipid accumulation in a lab-scale open raceway pond characterized by improved light distributions employing built in planar waveguide modules. AB - Aiming at alleviating the adverse effect of poor light penetrability on microalgae growth, planar waveguide modules functioned as diluting and redistributing the intense incident light within microalgae culture more homogeneously were introduced into a lab-scale open raceway pond (ORP) for Nannochloropsis oculata cultivation. As compared to the conventional ORP, the illumination surface area to volume ratio and effective illuminated volume percentage in the proposed ORP were respectively improved by 5.53 times and 19.68 172.72%. Consequently, the superior light distribution characteristics in the proposed ORP contributed to 193.33% and 443.71% increase in biomass concentration and lipid yield relative to those obtained in conventional ORP, respectively. Subsequently, the maximum biomass concentration (2.31 g L-1) and lipid yield (1258.65 mg L-1) was obtained when the interval between adjacent planar waveguide modules was 18 mm. The biodiesel produced in PWM-ORPs showed better properties than conventional ORP due to higher MUFA and C18:1 components proportions. PMID- 29145115 TI - Effect of salinity on removal performance and activated sludge characteristics in sequencing batch reactors. AB - The removal performance, activated sludge characteristics and microbial community in sequencing batch reactors (SBRs) were studied at salinity ranging from 0 to 20 g/L. Results showed that salinity deteriorated the removal performance. Removal rate of ammonium (NH4+-N), total phosphorus (TP) and chemical oxygen demand (COD) were gradually dropped from 95.34%, 93.58% and 94.88% (0 g/L) to 62.98%, 55.64% and 55.78% (20 g/L), respectively. The removals of NH4+-N and TP were mainly influenced during aerobic phase. Besides, salinity increased the extracellular polymeric substances (EPS) content of activated sludge, decreased the content of protein (PN) and loosely bound extracellular polymeric substances (LB-EPS) which led to better settleability of activated sludge. Moreover, salinity inhibited the dehydrogenase activity (DHA) of activated sludge. Sequence analysis illustrated Zoogloea and Thioclava were predominant at 0 and 20 g/L salinity, respectively. The difference of microbial community under high salinity was likely caused by the variation of richness. PMID- 29145116 TI - Conversion of sweet potato waste to solid fuel via hydrothermal carbonization. AB - Hydrothermal carbonization (HTC) of sweet potato waste was performed to investigate the effect of process parameters including reaction temperature (180 300 degrees C) and residence time (0-120 min) on the characteristics of hydrochars. The results showed that the increase of reaction temperature and residence time both decreased the yield of hydrochars. With the increase of reaction temperature and residence time, the carbon content of hydrochars increased, while the hydrogen and oxygen contents decreased. The lower H/C and O/C ratios indicated that dehydration and decarboxylation reactions occurred during HTC. The occurrence of aromatization reaction was found in FTIR spectra. Thus, the fixed carbon content, higher heating value, and energy density of hydrochars increased. SEM analysis indicated that HTC developed rough surface with crack on the hydrochars. The thermogravimetric experiments displayed the increase trend in combustion ignition temperature, burnout temperature and activation energy as reaction temperature and time increase, which showed better combustion characteristics. PMID- 29145117 TI - Biodiesel production from microbial granules in sequencing batch reactor. AB - Effect of reaction variables of in situ transesterification on the biodiesel production, and the characteristic differences of biodiesel obtained from aerobic granular sludge (AG) and algae-bacteria granular consortia (AAG) were investigated. The results indicated that the effect of variables on the biodiesel yield decreased in the order of methanol quantity > catalyst concentration > reaction time, yet the parameters change will not significantly affect biodiesel properties. The maximum biodiesel yield of AAG was 66.21 +/- 1.08 mg/g SS, what is significant higher than that of AG (35.44 +/- 0.92 mg/g SS). Although methyl palmitate was the dominated composition of biodiesel obtained from both granules, poly-unsaturated fatty acid in the AAG showed a higher percentage (21.86%) than AG (1.2%) due to Scenedesmus addition. Further, microbial analysis confirmed that the composition of biodiesel obtained from microbial granules was also determined by bacterial community, and Xanthomonadaceae and Rhodobacteraceae were the dominant bacteria of AG and AAG, respectively. PMID- 29145118 TI - Long-term effects of combined divalent copper and tetracycline on the performance, microbial activity and community in a sequencing batch reactor. AB - The long-term effects of combined divalent copper (Cu(II)) and tetracycline (TC) on the performance, microbial activity and community in a sequencing batch reactor (SBR) were investigated. The addition of Cu(II), TC or mixed Cu(II)/TC caused the decrease of the organics and nitrogen removal efficiencies, and their decreased degrees were the lowest at the addition of mixed Cu(II)/TC. The increase of mixed Cu(II)/TC concentrations in the influent did not change the antagonistic effects between Cu(II) and TC on nitrifying and denitrifying activities. Nitrifiers had higher tolerances to Cu(II), TC and mixed Cu(II)/TC than denitrifiers. Compared to the addition of Cu(II) or TC alone, the microbial community richness was higher at the addition of mixed Cu(II)/TC, while the microbial community diversity was lower. The increased protein (PN) in extracellular polymeric substances (EPS) was a protective response of bacteria to Cu(II), TC and mixed Cu(II)/TC. PMID- 29145119 TI - Amine-functionalized magnetic bamboo-based activated carbon adsorptive removal of ciprofloxacin and norfloxacin: A batch and fixed-bed column study. AB - Amine-functionalized magnetic bamboo-based activated carbon (AFM-BAC) derived from bamboo products wastes were employed for effective adsorption of fluoroquinolone antibiotics ciprofloxacin (CIP) and norfloxacin (NOR) through batch processing. The effects of factors on the adsorption of both antibiotics were studied. The studies of various factors influencing the adsorption behavior indicated that the maximum adsorption capacities for two antibiotics adsorption were observed in weakly acidic condition and the adsorption amounts of two antibiotics increased with the increase of zwitterionic form, implying the importance of zwitterionic form, and the adsorption process is spontaneous and endothermic. The result of date indicated that adsorption of both two antibiotics onto the AFM-BAC better fits Langmuir isotherm model. The saturated magnetization of AFM-BAC reached 8.55 emu g-1. A fixed-bed column adsorption with a bench-scale was carried out. Desorption and regeneration experiments showed that the AFM-BAC for both antibiotics could remain above 80% after five consecutive recycling cycles. PMID- 29145120 TI - Enhanced nitrogen removal from piggery wastewater with high NH4+ and low COD/TN ratio in a novel upflow microaerobic biofilm reactor. AB - To enhance nutrient removal more cost-efficiently in microaerobic process treating piggery wastewater characterized by high ammonium (NH4+-N) and low chemical oxygen demand (COD) to total nitrogen (TN) ratio, a novel upflow microaerobic biofilm reactor (UMBR) was constructed and the efficiency in nutrient removal was evaluated with various influent COD/TN ratios and reflux ratios. The results showed that the biofilm on the carriers had increased the biomass in the UMBR and enhanced the enrichment of slow-growth-rate bacteria such as nitrifiers, denitrifiers and anammox bacteria. The packed bed allowed the microaerobic biofilm process perform well at a low reflux ratio of 35 with a NH4+ N and TN removal as high as 93.1% and 89.9%, respectively. Compared with the previously developed upflow microaerobic sludge reactor, the UMBR had not changed the dominant anammox approach to nitrogen removal, but was more cost-efficiently in treating organic wastewater with high NH4+-N and low COD/TN ratio. PMID- 29145121 TI - Role of acid/alkali-treatment in primary sludge anaerobic fermentation: Insights into microbial community structure, functional shifts and metabolic output by high-throughput sequencing. AB - This study aimed to investigate the effect of acid- or alkali-treatment on volatile fatty acids (VFAs) production and microbiological mechanism during primary sludge anaerobic fermentation. Seven fermentation experiments were conducted at different pH (3-12). Results showed that the optimal pH was 10 for accumulation of VFAs. High-throughput sequencing results indicated that acid and alkali treatment could inhibit Erysipelotrichaceae_UCG-004 and norank_p_Aminicenantes, instead of promoting Pseudomonas and Tissierella at acidic and alkaline condition, respectively. Besides, molecular ecological networks (MENs) analysis and multivariate canonical correspondence analysis (CCA) revealed that the microbial community interactions are significant different between acid and alkali treatment groups, and acetic acid was the most vital factor in the distinct bacterial community assemblages. Predictive functional profiling using marker gene sequences found that amino acid transport and metabolism was the most abundant metabolic type with 8.43-9.41%, and acid- and alkali-treatment did not benefit Stickland reaction. PMID- 29145122 TI - The myo-inositol/proton symporter IolT1 contributes to d-xylose uptake in Corynebacterium glutamicum. AB - Corynebacterium glutamicum has been engineered to utilize d-xylose as sole carbon and energy source. Recently, a C. glutamicum strain has been optimized for growth on defined medium containing d-xylose by laboratory evolution, but the mutation(s) attributing to the improved-growth phenotype could not be reliably identified. This study shows that loss of the transcriptional repressor IolR is responsible for the increased growth performance on defined d-xylose medium in one of the isolated mutants. Underlying reason is derepression of the gene for the glucose/myo-inositol permease IolT1 in the absence of IolR, which could be shown to also contribute to d-xylose uptake in C. glutamicum. IolR-regulation of iolT1 could be successfully repealed by rational engineering of an IolR-binding site in the iolT1-promoter. This minimally engineered C. glutamicum strain bearing only two nucleotide substitutions mimics the IolR loss-of-function phenotype and allows for a high growth rate on d-xylose-containing media (umax = 0.24 +/- 0.01 h-1). PMID- 29145123 TI - Continuous liquid fermentation of pretreated waste activated sludge for high rate volatile fatty acids production and online nutrients recovery. AB - Raw sludge was pretreated, and the separated sludge liquid was used as substrate in a continuous operated up-flow anaerobic sludge blanket reactor to produce volatile fatty acids (VFAs). The highest VFA productivity of continuous fermentation with sludge liquid at an organic loading rate (OLR) of 10.0 kg COD/m3/d was about 5.0-fold and 4.0-fold higher than batch and semi-continuous fermentation with pretreated sludge slurry, respectively. Moreover, the liquid fermentation with an OLR of 10.0 kg COD/m3/d consumed the least energy, which was about 10.57% and 12.12% of batch and semi-continuous sludge fermentation, respectively. When combined with online nitrogen and phosphorus recovery, VFA production further increased by 20.67% and struvite recovery efficiency reached 1.98 +/- 0.28 g/g PO43-. The process showed high VFA production, low energy consumption and good nutrients recovery by continuous liquid anaerobic fermentation, significantly increasing the economic potential of VFA production from waste activated sludge. PMID- 29145124 TI - Lignocellulosic biomass delignification using aqueous alcohol solutions with the catalysis of acidic ionic liquids: A comparison study of solvents. AB - The exploration of effective deconstruction of biomass complex structures and mild fractionation into individual components is a profound challenge for the development of biorefinery. Herein, a biomass fractionation process, via treating biomass in various aqueous alcohol solutions with the catalysis of acidic ionic liquids 1-butyl-3-methylimidazolium hydrogen sulfate, was demonstrated to fractionate coir and poplar into cellulose materials with a lignin content as low as 0.95% and lignin with a delignification rate of up to 98%. The participation of acidic ionic liquids into the solvent system greatly multiplied the biomass fractionation efficiency. The analysis on effects of the chemical structure and solubility parameter of alcohols on the delignification efficiency provided a rational and meaningful way to predict and screen solvent for the biomass fractionation process. Lignin in the present study exhibited similar structure with milled wood lignin, and comparable molecular and thermal properties with the conventional organosolv lignin. PMID- 29145125 TI - A closed-loop strategy for endoglucanase production using sugarcane bagasse liquefied by a home-made enzymatic cocktail. AB - Use of the same lignocellulosic biomass as feedstock for enzymes and ethanol production has been suggested as a lower cost option in future biorefineries. Here, we propose a closed-loop strategy to produce the cellulolytic enzymes required for biomass hydrolysis using sugarcane bagasse liquefied by a home-made enzymatic cocktail as carbon source and inducer. The fed-batch liquefaction conditions were firstly evaluated using commercial enzymes. Subsequently, the effects of different liquefied materials and solids loadings on endoglucanase production by Aspergillus niger cultivated in submerged fermentation were investigated. The liquefied bagasse produced using the home-made cocktail was more favorable for endoglucanase production, resulting in improvement up to 17%, compared to bagasse liquefied by commercial enzymes. The results indicated that liquefied bagasse produced by home-made enzymatic cocktail could provide a cost effective carbon source and inducer for cellulolytic enzyme production, and could contribute to closing loops within the biorefinery, thus reducing costs and minimizing waste. PMID- 29145126 TI - Pyrolysis/gasification of pine sawdust biomass briquettes under carbon dioxide atmosphere: Study on carbon dioxide reduction (utilization) and biochar briquettes physicochemical properties. AB - In this paper, the effects of temperature and CO2 content on CO2 reduction (utilization) efficiency and physicochemical properties of pyrolysis/gasification biochar briquettes were investigated. The CO2 reduction (utilization) efficiency (CRE) reached the peak value of 74.9% in a 10% CO2/90% N2 atmosphere at 600 degrees C. The crackings of hydroxyl, CC bonds, methyl and methylene groups of biochars briquette were enhanced by high temperature and CO2. The increase of CO2 concentration was beneficial for developing biochar microporosity, but not conductive to enhance higher heating value, volume density and durability of biochar briquette. To get a higher CRE and make feasible biochar briquettes are the primary goal for this work. Therefore, the optimal introduced CO2 to biomass ratio is calculated to be 135 g/kg for experiments done with 10% CO2 with N2 at 600 degrees C. PMID- 29145127 TI - Effect of lipid-free microalgal biomass and waste glycerol on growth and lipid production of Scenedesmus obliquus: Innovative waste recycling for extraordinary lipid production. AB - In the present work, a novel approach of using growth medium with different substitutions of lipid-free algal hydrolysate (LFAH, 0, 5, 10 and 15%) and/or waste glycerol (WG, 0, 5, 10 and 20 g L-1) for enhanced biodiesel production from Scenedesmus obliquus was studied. Combination of different concentrations of WG with 15% LFAH showed the maximum significant biomass productivity, which represented 27.4, 30.5 and 28.9% over the control at combined 5, 10 and 20 g L-1 WG, respectively. The combinations of different LFAH with 20 g L-1 WG showed the maximum significant lipid accumulation, where lipid productivity showed its maximum significant value of 59.66 mg L-1 d-1 using LFAH15-WG10. In addition, LFAH15-WG10 significantly enhanced total FAMEs yield by 21.2% over the control. Moreover, it reduced polyunsaturated fatty acids (PUFAs) ratio from 52.1% to 47.8% of total FAMEs, and increased monounsaturated fatty acids (MUFAs) ratio from 26.6% to 31.3% of total FAMEs. PMID- 29145128 TI - Microgravity simulation activates Cdc42 via Rap1GDS1 to promote vascular branch morphogenesis during vasculogenesis. AB - Gravity plays an important role in normal tissue maintenance. The ability of stem cells to repair tissue loss in space through regeneration and differentiation remains largely unknown. To investigate the impact of microgravity on blood vessel formation from pluripotent stem cells, we employed the embryoid body (EB) model for vasculogenesis and simulated microgravity by clinorotation. We first differentiated mouse embryonic stem cells into cystic EBs containing two germ layers and then analyzed vessel formation under clinorotation. We observed that endothelial cell differentiation was slightly reduced under clinorotation, whereas vascular branch morphogenesis was markedly enhanced. EB-derived endothelial cells migrated faster, displayed multiple cellular processes, and had higher Cdc42 and Rac1 activity when subjected to clinorotation. Genetic analysis and rescue experiments demonstrated that Cdc42 but not Rac1 is required for microgravity-induced vascular branch morphogenesis. Furthermore, affinity pull down assay and mass spectrometry identified Rap1GDS1 to be a Cdc42 guanine nucleotide exchange factor, which was upregulated by clinorotation. shRNA mediated knockdown of Rap1GDS1 selectively suppressed Cdc42 activation and inhibited both baseline and microgravity-induced vasculogenesis. This was rescued by ectopic expression of constitutively active Cdc42. Taken together, these results support the notion that simulated microgravity activates Cdc42 via Rap1GDS1 to promote vascular branch morphogenesis. PMID- 29145129 TI - High contamination in the areas surrounding abandoned mines and mining activities: An impact assessment of the Dilala, Luilu and Mpingiri Rivers, Democratic Republic of the Congo. AB - Abandoned mines and mining activities constitute important sources of toxic metals and Rare Earth Elements (REEs) affecting surrounding environmental compartments and biota. This study investigates the contamination degree and distribution of toxic metals and REEs in contrasting sediment, soil and plant samples surrounding rivers in the African copperbelt area characterized by the presence of numerous abandoned mines, artisanal and industrial mining activities. ICP-MS results highlighted the highest concentration of Cu, Co and Pb in sediments reaching values of 146,801, 18,434 and 899 mg kg-1, respectively. In soil, the values of 175,859, 21,134 and 1164 mg kg-1 were found for Cu, Co and Pb, respectively. These values are much higher than the sediment guidelines for the protection of aquatic life and international soil clean-up standards. Enrichment factor and geoaccumulation index results indicated important contribution of mining activities to the study sites pollution in addition to natural background. Highest metal accumulation in leaves of Phalaris arundinacea L., was observed, reaching values of 34,061, 5050 and 230 mg kg-1 for Cu, Co, and Pb, respectively. The ?REE concentration reached values of 2306, 733, 2796 mg kg 1 in sediment, soil and plant samples, respectively. The above results were combined with geographical information including satellite imagery, hydrography and mining concessions. Maps were produced to present the results in a comprehensive and compelling visual format. The results will be disseminated through an innovative mapping online platform to simplify access to data and to facilitate dialogue between stakeholders. PMID- 29145130 TI - Photophysical and photochemical insights into the photodegradation of sulfapyridine in water: A joint experimental and theoretical study. AB - For organic pollutants, photodegradation, as a major abiotic elimination process and of great importance to the environmental fate and risk, involves rather complicated physical and chemical processes of excited molecules. Herein, we systematically studied the photophysical and photochemical processes of a widely used antibiotic, namely sulfapyridine. By means of density functional theory (DFT) computations, we examined the rate constants and the competition of both photophysical and photochemical processes, elucidated the photochemical reaction mechanism, calculated reaction quantum yield (Phi) based on both photophysical and photochemical processes, and subsequently estimated the photodegradation rate constant. We further conducted photolysis experiments to measure the photodegradation rate constant of sulfapyridine. Our computations showed that sulfapyridine at the lowest excited singlet state (S1) mainly undergoes internal conversion to its ground state, and is difficult to transfer to the lowest excited triplet states (T1) via intersystem crossing (ISC) and emit fluorescence. In T1 state, compared with phosphorescence emission and ISC, chemical reaction is much easier to initiate. Encouragingly, the theoretically predicted photodegradation rate constant is close to the experimentally observed value, indicating that quantum chemistry computation is powerful enough to study photodegradation involving ultra-fast photophysical and photochemical processes. PMID- 29145131 TI - Removal of the precursors of N-nitrosodiethylamine (NDEA), an emerging disinfection byproduct, in drinking water treatment process and its toxicity to adult zebrafish (Danio rerio). AB - N-nitrosodiethylamine (NDEA) is one of the emerging nitrogenous disinfection byproducts with probable cytotoxicity, genotoxicity, and carcinogenesis. Its potential toxicological effects have received extensive attention but remain to be poorly understood. In this study, changes in NDEA precursors in drinking water treatment process were studied using the trial of its formation potential (FP), and the toxicity induced by NDEA to adult zebrafish was investigated. NDEA FP in the raw water of Taihu Lake ranged from 46.9 to 68.3 ng/L. The NDEA precursors were removed effectively by O3/BAC process. Hydrophilic fraction and low molecular-weight fraction (<1 kDa) had the highest NDEA FP. The toxicity results demonstrated that the acute lethal concentration of NDEA causing 50% mortality in 96 h (96-h LC50) was 210.4 mg/L, and NDEA was more likely to be accumulated in kidney, followed by liver and gill. NDEA induced oxidative stress and antioxidant defense to zebrafish metabolism system at concentrations over 5 MUg/L. After a 42 day exposure, a significant DNA damage was observed in zebrafish liver cells at NDEA concentrations beyond 500 MUg/L. This study investigated NDEA properties in both engineering prospective and toxicity evaluation, thus providing comprehensive information on its control in drinking water treatment process and its toxicity effect on zebrafish as a model animal. PMID- 29145132 TI - Effect of evaporative weathering and oil-sediment interactions on the fate and behavior of diluted bitumen in marine environments. Part 1. Spill-related properties, oil buoyancy, and oil-particulate aggregates characterization. AB - The fate and behavior of diluted bitumen spilled in marine conditions has recently become a topic of much interest, yet, only limited knowledge is available. One of the major issues of a diluted bitumen spill on water is whether the product will sink, especially when suspended sediment is present in the water column. This study demonstrated how weathering processes influenced the key spill related properties of a diluted bitumen product (Cold Lake Blend-Winter), and how interaction of diluted bitumen with sediment affected its tendency to float or sink in water. This study showed that the weathering states of the oils as well as the size of sediment are important factors influencing oil-sediment interactions and the tendency of the formed oil-particulate aggregates for buoyancy. When mixing with fine- and medium-sized sediments, the fresh to moderately weathered oils formed oil-particulate aggregates and sank in saltwater, while the very heavily-weathered oil formed discrete free-floating tarballs. PMID- 29145133 TI - Simultaneous treatment of dimethyl disulfide and hydrogen sulfide in an alkaline biotrickling filter. AB - Foul odors comprise generally a complex mixture of molecules, where reduced sulfur compounds play a key role due to their toxicity and low odor threshold. Previous reports on treating mixtures of sulfur compounds in single biofilters showed that hydrogen sulfide (H2S) interferes with the removal and degradation of other sulfur compounds. In this study, hydrogen sulfide (H2S) and dimethyl disulfide (DMDS) were fed to an alkaline biotrickling filter (ABTF) at pH 10, to evaluate the simultaneous removal of inorganic and organic sulfur compounds in a single, basic-pH system. The H2S-DMDS mixture was treated for more than 200 days, with a gas residence time of 40 s, attaining elimination capacities of 86 gDMDS m 3 h-1 and 17 gH2S m-3 h-1 and removal efficiencies close to 100%. Conversion of H2S and DMDS to sulfate was generally above 70%. Consumption of sulfide and formaldehyde was verified by respirometry, suggesting the coexistence of both methylotrophic and chemoautotrophic breakdown pathways by the immobilized alkaliphilic biomass. The molecular biology analysis showed that the long-term acclimation of the ABTF led to a great variety of bacteria, predominated by Thioalkalivibrio species, while fungal community was notoriously less diverse and dominated by Fusarium species. PMID- 29145134 TI - Comparative analyses of catalytic degradation of PCDD/Fs in the laboratory vs. industrial conditions. AB - This study investigates the efficiencies and mechanisms of the catalytic degradation of polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) first, in simulated laboratory conditions and then, in a commercial municipal solid waste incineration (MSWI) plant. Five commercially available V2O5-WO3/TiO2 (VWTi) catalysts were tested. The degradation efficiency of PCDD/Fs in the simulated flue gas ranged 22.8-91.7% and was generally higher than that in the MSWI flue gas of 8.0-85.4%. The degradation efficiency of PCDD/Fs in the real flue gas of the MSWI plant was largely hindered by the complex composition of the flue gas, which could not be completely reproduced in the simulated laboratory conditions. Furthermore, the degradation of the higher chlorinated PCDD/Fs was easier compared to the lower chlorinated ones in the presence of the VWTi catalysts, which was primarily driven by the tendency of the higher chlorinated PCDD/Fs to be adsorbed on the surface of the catalyst and further destructed due to their lower vapor pressure. In addition, powdered catalysts should be preferred over the honeycomb shaped ones as they exposed higher PCDD/Fs degradation efficiencies under equal reaction conditions. The chemical composition and a range of the relevant to the study properties of the catalysts, such as surface area, crystallinity, oxidation ability, and surface acidity, were analyzed. The study ultimately supports the identification of the preferred characteristics of the VWTi catalysts for the most efficient degradation of toxic PCDD/Fs and elucidates the corresponding deactivation reasons of the catalysts. PMID- 29145135 TI - Forced and long-term degradation assays of tenoxicam, piroxicam and meloxicam in river water. Degradation products and adsorption to sediment. AB - The fate of the pharmaceutical drugs tenoxicam, piroxicam and meloxicam in river water is evaluated here for first time. So, biological, photochemical and thermal degradation assays have been conducted to estimate their degradation rates and know their degradation products. Results indicated that the direct sunlight irradiation, without any protection, promoted a fast degradation of the oxicams while the chemical reactions in solution were less important. The biological degradation in water was negligible except for tenoxicam in whose case its influence was scarce. When the exposition of river water to sunlight was partially limited and kept under the natural day-night cycle, as occurs inside a body of water, tenoxicam, piroxicam and meloxicam (at 2 MUg L-1) were detected during a period of 15, 27 and 45 days, respectively. Residues were monitored by ultra-pressure liquid chromatography/quadrupole time-of-flight/mass spectrometry after solid-phase extraction and several degradation products were found (10 for tenoxicam, 9 for piroxicam and 7 for meloxicam) and monitored over time. Their structures were proposed from the molecular formulae and fragmentation observed in high-resolution tandem mass spectra; the nature of the transformation products found in the long-term resulted to be very variable for each oxicam. Furthermore, the degradation in presence of river sediment was also monitored over time, with some differences being noted; the adsorption coefficients of the compounds on sediment were calculated, meloxicam exhibited a higher sorption capacity. The ecotoxicity of the different compounds in aquatic ecosystems was predicted, too. PMID- 29145136 TI - Lead, cadmium and arsenic in human milk and their socio-demographic and lifestyle determinants in Lebanon. AB - INTRODUCTION: Exposure of newborns to toxic metals is of special interest due to their reported contamination in breast milk and potential harm. The aim of this study was to assess the occurrence and factors associated with lead, cadmium and arsenic contamination in breast milk collected from lactating mothers in Lebanon. METHODS: A total of 74 breast milk samples were collected from primaparas according to guidelines set by the World Health Organization. A survey was administered to determine the demographic and anthropometric characteristics of participating lactating mothers. Dietary habits were assessed using a semi quantitative food frequency questionnaire. The milk samples were analyzed for the presence of arsenic, cadmium and lead using microwave-assisted digestion and atomic absorption spectrophotometry. RESULTS: Arsenic contamination was found in 63.51% of breast milk samples (mean 2.36 +/- 1.95 MUg/L) whereas cadmium and lead were detected in 40.54% and 67.61% of samples respectively (means 0.87 +/- 1.18 MUg/L and 18.18 +/- 13.31 MUg/L). Regression analysis indicated that arsenic contamination was associated with cereal and fish intake (p = 0.013 and p = 0.042 respectively). Residence near cultivation activities (p = 0.008), smoking status before pregnancy (p = 0.046), potato consumption (p = 0.046) and education level (p = 0.041) were associated with lead contamination. Cadmium contamination was significantly associated with random smoke exposure (p = 0.002). CONCLUSION: Our study is the first in Lebanon to report toxic metal contamination in breast milk. Although estimated weekly infant intake of these metals from breast milk was found to be lower than the limit set by international guidelines, our results highlight the need for developing strategies to protect infants from exposure to these hazardous substances. PMID- 29145137 TI - Uncertainty in positive matrix factorization solutions for PAHs in surface sediments of the Yangtze River Estuary in different seasons. AB - To examine the variabilities of source contributions in the Yangtze River Estuary (YRE), the uncertainty based on the positive matrix factorization (PMF) was applied to the source apportionment of the 16 priority PAHs in 120 surface sediment samples from four seasons. Based on the signal-to-noise ratios, the PAHs categorized as "Bad" might drop out of the estimation of bootstrap. Next, the spatial variability of residuals was applied to determine which species with non normal curves should be excluded. The median values from the bootstrapped solutions were chosen as the best estimate of the true factor contributions, and the intervals from 5th to 95th percentile represent the variability in each sample factor contribution. Based on the results, the median factor contributions of wood grass combustion and coke plant emissions were highly correlated with the variability (R2 = 0.6797-0.9937) in every season. Meanwhile, the factor of coal and gasoline combustion had large variability with lower R2 values in every season, especially in summer (0.4784) and winter (0.2785). The coefficient of variation (CV) values based on the Bootstrap (BS) simulations were applied to indicate the uncertainties of PAHs in every factor of each season. Acy, NaP and BgP always showed higher CV values, which suggested higher uncertainties in the BS simulations, and the PAH with the lowest concentration among all PAHs usually became the species with higher uncertainties. PMID- 29145139 TI - Application and microbial ecology of psychrotrophs in domestic wastewater treatment at low temperature. AB - The feasibility of a bunch of screened psychrotrophs being applied to low temperature wastewater treatment was investigated. The screened psychrophillic strains are capable of growth at a broad temperature-range from 0 to 40 degrees C and exhibit a preferable TTC-dehydrogenase activity at low temperature (4-10 degrees C). Along the sharply fluctuant temperatures (25-4-25 degrees C), the screened psychrotrophs (compared with the indigenous mesophiles) demonstrate less fluctuations of COD removal and more rapid recovery after temperature shocks. COD removal of approximate 80% was recorded by single psychrotrophs (while only 10% by single mesophiles) at low temperature (4 degrees C). Soft polyurethane foam showed better performance for psychrotrophs immobilization, with the optimal filling rate of 30% (v/v) in the bioreactor. The observation shows that the immobilized psychrotrophs demonstrated a relatively high performance on both conventional and emerging organic contaminants removals at low temperature. In order to check the feasibility of the screened psychrotrophs in treating actual domestic wastewater, a pilot-scale ICABR bioreactor was operated firstly at low temperature (4 degrees C) and then at seasonal varying temperatures (0-30 degrees C) for one year, the influent COD of 150-600 mg L-1 was efficiently reduced to 40 +/- 18 mg L-1 under the conditions of an overall hydraulic retention time of 10 h. Furthermore, psychrotrophs performed stably as the predominant bacteria family during the whole operation. This study provides evidence that microbial intensification with psychrotrophs was a feasible strategy to improve the efficiency of conventional wastewater treatment process at low temperature. PMID- 29145138 TI - Exposure to selected limonene oxidation products: 4-OPA, IPOH, 4-AMCH induces oxidative stress and inflammation in human lung epithelial cell lines. AB - Limonene oxidation products (LOPs) have gained interest on their harmful health effects over time. Recently, studies have shown that the selected LOPs: 4 oxopentanal (4-OPA), 3-isopropenyl-6-oxo-heptanal (IPOH) and 4-acetyl-1 methylcyclohexene (4-AMCH) have sensory irritation effects in mice and inflammatory effects in human lung cells. This study was therefore undertaken to investigate the potential capacity of 4-OPA, IPOH and 4-AMCH to cause cell membrane damage, oxidative stress and inflammation in human bronchial (16HBE14o-) and alveolar (A549) epithelial cell lines. Overall results suggest that 4-OPA, IPOH have cytotoxic effects on human lung cells that might be mediated by ROS: the highest concentration applied of IPOH [500 MUM] enhanced ROS generation by 100-fold +/- 7.7 (A549) and 230-fold +/- 19.9 (16HBE14o-) compared to the baseline. 4-OPA [500 MUM] increased ROS levels by 1.4-fold +/- 0.3 (A549) and by 127-fold +/- 10.5 (16HBE14o-), while treatment with 4-AMCH [500 MUM] led to 0.9 fold +/- 0.2 (A549) and 49-fold +/- 12.8 (16HBE14o-) increase. IPOH [500 MUM] caused a decrease in the thiol-state balance (e.g. after 2 h, GSH:GSSG was reduced by 37% compared to the untreated 16HBE14o-cells). 4-OPA [500 MUM] decreased the GSH:GSSG by 1.3-fold change in A549 cells and 1.4-fold change in 16HBE14o-cells. No statistically significant decrease in the GSH:GSSG in A549 and 16HBE14o-cell lines was observed for 4-AMCH [500 MUM]. In addition, IPOH and 4 OPA [31.2 MUM] increased the amount of the inflammatory markers: RANTES, VEGF and EGF. On the other hand, 4-AMCH [31.2 MUM] did not show inflammatory effects in A549 or 16HBE14o-cells. The 4-OPA, IPOH and 4-AMCH treatment concentration and time-dependently induce oxidative stress and/or alteration of inflammatory markers on human bronchial and alveolar cell lines. PMID- 29145140 TI - Fluoxetine modulates the transcription of genes involved in serotonin, dopamine and adrenergic signalling in zebrafish embryos. AB - Neurotransmitters pathways in fish and mammals are phylogenetically conserved. Therefore, the environmental presence of psychopharmaceuticals, such as fluoxetine (FLU), are likely to interact with fish serotonergic, dopaminergic and adrenergic systems, affecting their response and associated biological functions. Hence, the present work aimed at evaluating the effects of FLU in the transcription of genes involved in serotonin, dopamine and adrenergic transporters and receptors signalling in early stages of Danio rerio development. Embryos (1 hpf) were exposed for 80 h to different concentrations of FLU (0.0015, 0.05, 0.1, 0.5 and 0.8 MUM) and mRNA levels of sert, 5-ht1a, 5-ht2c, dat, drd1b, drd2b, net, adra2a, adra2b, adra2c, vmat and mao were evaluated. A sensorimotor reflex assay was also performed demonstrating a significant decrease in tail reflex at 0.1 and 0.5 MUM. The transcription levels of serotonergic and dopaminergic transporters (sert and dat) and vmat were down-regulated at environmentally relevant concentration (0.0015 MUM). Receptors 5-ht2c, drd2b adra2b and adra2c mRNA levels also displayed a down regulation pattern after FLU exposure. In conclusion, this study demonstrated the interaction of FLU with the neurotransmission system at environmentally relevant concentrations by changing transcription patterns. Therefore, given the importance of these signalling pathways it is possible that their disruption can ultimately disturb the escape behaviour and biological functions in fish. Hence, evaluating the presence of this psychopharmaceutical in the aquatic environment should be implemented in future monitoring programmes. PMID- 29145141 TI - Characterizing pollutant emissions from mosquito repellents incenses and implications in risk assessment of human health. AB - Mosquito-repellent incense is one of the most popular products used for dispelling mosquitos during summer in China. It releases large amounts of particulate and gaseous pollutants which constitute a potential hazard to human health. We conducted chamber experiment to characterize major pollutants from three types of mosquito-repellent incenses, further assessed the size fractionated deposition in human respiratory system, and evaluated the indoor removing efficiency by fresh air. Results showed that the released pollutant concentrations were greater than permissible levels in regulations in GB3095 2012, as well as suggested by the World Health Organization (WHO). Formaldehyde accounted for 10-20% of the total amount of pollutants. Fine particles dominated in the total particulate concentrations. Geometric standard deviation (GSD) of particle number size distributions was in the range of 1.45-1.93. Count median diameter (CMD) ranged from 100 to 500 nm. Emission rates, burning rates and emission factors of both particulate and gaseous pollutants were compared and discussed. The deposition fractions in pulmonary airway from the disc solid types reached up to 52.7% of the total deposition, and the largest deposition appeared on juvenile group. Computational Fluid Dynamics (CFD) modellings indicated air conditioner on and windows closed was the worst case. The highest concentration was 180-200 times over the standard limit. PMID- 29145142 TI - Is ozonation environmentally benign for reverse osmosis concentrate treatment? Four-level analysis on toxicity reduction based on organic matter fractionation. AB - Ozonation is a promising option to treat reverse osmosis concentrate (ROC). However, a systematic understanding and assessment of ozonation on toxicity reduction is insufficient. In this study, ROC sampled from a typical industrial park wastewater treatment plant of China was fractionated into hydrophobic acid (HOA), hydrophobic base (HOB), hydrophobic neutral (HON), and hydrophilic fraction (HI). Systematic bioassays covering bacteria, algae, fish, and human cell lines were conducted to reveal the role of ozonation in toxicity variation of the four ROC fractions. HOA in the raw ROC exhibited the highest toxicity, followed by HON and HI. Ozonation significantly reduced total organic carbon (TOC) and UV254 values in HOA, HON, and HI and their toxicity except in HOB. Correlation analysis indicated that chemical data (TOC and UV254) of HOA and HON correlated well with their toxicities; however, poor correlations were observed for HOB and HI, suggesting that a battery of toxicity assays is necessary. This study indicates that TOC reduction during ozonation could not fully reflect the toxicity issue, and toxicity assessment is required in conjunction with the chemical data to evaluate the effectiveness of ozonation. PMID- 29145143 TI - Biodegradation of polystyrene wastes in yellow mealworms (larvae of Tenebrio molitor Linnaeus): Factors affecting biodegradation rates and the ability of polystyrene-fed larvae to complete their life cycle. AB - Commercial production of polystyrene (PS) -a persistent plastic that is not biodegradable at appreciable rates in most environments-has led to its accumulation as a major contaminant of land, rivers, lakes, and oceans. Recently, however, an environment was identified in which PS is susceptible to rapid biodegradation: the larval gut of Tenebrio molitor Linnaeus (yellow mealworms). In this study, we evaluate PS degradation capabilities of a previously untested strain of T. molitor and assess its survival and PS biodegradation rates for a range of conditions (two simulated food wastes, three temperatures, seven PS waste types). For larvae fed PS alone, the %PS removed in the short (12-15 h) residence time of the mealworm gut gradually increased for 2-3 weeks then stabilized at values up to 65%. Thirty two-day survival rates were >85% versus 54% for unfed larvae. For mealworms fed ~10% w/w PS and ~90% bran, an agricultural byproduct, rates of PS degradation at 25 degrees C nearly doubled compared to mealworms fed PS alone. Polymer residues in the frass showed evidence of partial depolymerization and oxidation. All of the tested PS wastes degraded, with the less dense foams degrading most rapidly. Mealworms fed bran and PS completed all life cycle stages (larvae, pupae, beetles, egg), and the second generation had favorable PS degradation, opening the door for selective breeding. PMID- 29145144 TI - Pyrethroid pesticide residues in the global environment: An overview. AB - Pyrethroids are synthetic organic insecticides with low mammalian toxicity that are widely used in both rural and urban areas worldwide. After entering the natural environment, pyrethroids circulate among the three phases of solid, liquid, and gas and enter organisms through food chains, resulting in substantial health risks. This review summarized the available studies on pyrethroid residues since 1986 in different media at the global scale and indicated that pyrethroids have been widely detected in a range of environments (including soils, water, sediments, and indoors) and in organisms. The concentrations and detection rates of agricultural pyrethroids, which always contain alpha-cyanogroup (alpha-CN), such as cypermethrin and fenvalerate, decline in the order of crops > sediments > soils > water. Urban pyrethroids (not contain alpha-CN), such as permethrin, have been detected at high levels in the indoor environment, and 3-phenoxybenzoic acid, a common pyrethroid metabolite in human urine, is frequently detected in the human body. Pyrethroid pesticides accumulate in sediments, which are a source of pyrethroid residues in aquatic products. PMID- 29145145 TI - Alleviation of ginsenoside Rg1 on hematopoietic homeostasis defects caused by lead-acetate. AB - The hematopoietic system is one of the potential targets of lead intoxication. Recognition of the lead-related deleterious outcomes promotes us to explore the potential therapeutic intervention. Here, we show that ginsenoside Rg1 (Rg1), extracted from the Chinese herb Panax ginseng, remarkably ameliorates the lead acetate-caused hematological index distortion as well as advanced hematopoietic stem cells (HSCs) aging and aging associated inflammation response. Specifically, Rg1 administration alleviated the increment of aging associated p53-p21-Rb signaling in aged HSCs induced by lead acetate. It also led a reduction of the lead acetate-induced increased inflammation level in blood plasma, which also partly contribute the aged HSCs rejuvenation. In conclusion, our results indicate that ginsenoside Rg1 therapeutically alleviated the essential blood deficits and advanced HSCs aging by lead acetate exposure, by which it could be viewed as a potential candidate for lead acetate-caused blood toxicity treatment. PMID- 29145146 TI - Evaluation of anti-urolithiatic and diuretic activities of watermelon (Citrullus lanatus) using in vivo and in vitro experiments. AB - Traditionally, Citrullus lanatus is known to have protective properties in kidney diseases and for having the ability to clear urine. Current study aims to validate the traditional uses of C. lanatus by evaluation of anti-urolithiatic and diuretic activities using in vivo and in vitro experiments. Male Wistar rats were used for in vivo anti-urolithiatic and diuretic activities. Supersaturated solution of calcium and oxalate was used for in vitro crystallization study. Hematoxylin & eosin staining was used for histopathological evaluation of kidney. In the in vivo rat model of urolithiasis, the pulp extract reduced calcium oxalate (CaOX) crystal count in both kidney and urine. The pulp extract also increased the urinary pH and output, and prevented the weight loss. Serum analysis showed elevation in creatinine clearance and reduction in urea and creatinine levels. Urinary analysis demonstrated that pulp extract restored altered phosphate, calcium, oxalate, and citrate levels. In the in vivo rat model of diuresis; the pulp extract produced diuresis, reduced serum chloride levels, and elevated urinary sodium and chloride levels. In the in vitro crystallization experiment, pulp extract inhibited the aggregation phase. Seed extract failed to show any convincing results. GC-MS analysis revealed the presence of steroids and alkanes as the major constituents of pulp extract, which might be responsible for anti-urolithiatic activity; however, further studies are required for isolation and identification of active constituents. Current study validated the traditional uses of watermelon and demonstrated that pulp extract possessed significant anti-urolithiatic and diuretic activities. PMID- 29145147 TI - Up-regulation of miR-299 suppressed the invasion and migration of HTR-8/SVneo trophoblast cells partly via targeting HDAC2 in pre-eclampsia. AB - Pre-eclampsia (PE), a pregnancy-associated disorder, is a major contributor to maternal mortality and morbidity worldwide. Recently, microRNAs (miRNAs) were found to be associated with the pathogenesis of PE. The present study investigated the function of miR-299 in HTR-8/SVneo trophoblast cells and explored its underlying mechanism in the pathogenesis of PE. The miR-299 and histone deacetylase 2 (HDAC2) mRNA expression levels were determined by quantitative real-time PCR. Transwell invasion and wound healing assays were used to measure cell invasive and migratory ability. Luciferase reporter assay was performed to confirm the downstream targets of miR-299. Western blot was performed to measure the protein expression of HDAC2. The expression level of miR 299 in placental tissues from pregnant women with severe PE was significantly higher than that from normal pregnant women. MiR-299 overexpression suppressed the invasion and migration of trophoblast cells; and knock-down of miR-299 promoted the invasion and migration of trophoblast cells. Bioinformatics prediction and luciferase reporter assay confirmed that miR-299 directly targeted the 3' untranslated region of HDAC2. The mRNA expression level of HDAC2 in placental tissues from pregnant women with severe PE was significantly lower than that from normal pregnant women, and was negatively correlated the expression level of miR-299 in placental tissues from pregnant women with severe PE. HDAC2 siRNA transfection suppressed the mRNA and protein expression levels of HDAC in trophoblast cells compared with control group, and HDAC2 siRNA transfection also suppressed the trophoblast cell invasion and migration compared with control group. Enforced expression of HDAC2 in trophoblast cells attenuated the inhibitory effects of miR-299 overexpression on cell invasion and migration. In summary, the results showed the up-regulation of miR-299 in the placental tissues from women with severe PE and miR-299 suppressed the invasion and migration of trophoblast cells partly via targeting HDAC2. PMID- 29145148 TI - Honokiol protects pancreatic beta cell against high glucose and intermittent hypoxia-induced injury by activating Nrf2/ARE pathway in vitro and in vivo. AB - Obstructive sleep apnea hypopnea syndrome (OSAHS) is associated with glucose intolerance, insulin resistance and type 2 diabetes mellitus (T2DM). Although several studies have revealed that intermittent hypoxia (IH) in OSAHS may further aggravate pancreatic beta cell damage and promote the evolution of type 2 diabetes (T2DM) by increasing oxidative stress, the underlying mechanisms are unclear. Honokiol, a potent radical scavenger, has been demonstrated to ameliorate oxidative stress in many cases. The present study aimed to explore the potential mechanism of IH and diabetes synergistically damage and destruct the pancreatic beta cell, examine the effects of honokiol on ameliorating pancreatic beta cell injury in this context and explore the mechanism of such effects. High glucose (HG) cultured INS-1 cells were exposed to 50 MUM of honokiol for 24, 48 and 72 h with or without IH intervention. T2DM rats were treated with honokiol and exposed to 80 s of IH followed by 160 s of normoxia for 8 weeks. The cell proliferation, apoptosis and oxidative stress were measured. Blood glucose, insulin, glucagon and HOMA-IR (Homeostasis model assessment -insulin resistence) were also detected, and the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were detected by immunofluorescence staining and western blotting. Honokiol can reduce oxidative stress, cytotoxicity and apoptosis in the INS-1 cells of rats receiving HG treatment or both HG and IH treatment. IH can further aggravate pancreas dysfunction, cause a marked elevation in fasting blood glucose, glucagon, HOMA-IR and oxidative stress levels in DM rats. In addition, honokiol can effectively activate the Nrf2/ARE pathway and reverse this pancreatic dysfunction in vivo and in vitro. These findings indicate that honokiol acts as a potent ROS scavenger via Nrf2/ARE pathway and effectively attenuates oxidative stress and improves pancreatic beta cell function of DM rats under IH treatment. PMID- 29145149 TI - SIRT2 decreases atherosclerotic plaque formation in low-density lipoprotein receptor-deficient mice by modulating macrophage polarization. AB - Compelling evidence has demonstrated that the M1 macrophage phenotype is central to atherosclerotic lesion development. SIRT2, an NAD+-dependent sirtuin deacetylase, is involved in modulating macrophage polarization. However, the role of SIRT2 in atherosclerotic progression remains unknown. Female LDL receptor knockout (LDLr-/-) mice were randomly divided into four groups for treatment with saline, empty lentivirus, lentivirus-SIRT2, or shRNA-SIRT2 for 4 weeks. Thereafter, the mice were fed an atherogenic high-fat diet (HFD) for another 8 weeks. Atherosclerotic plaques were assessed in the aortic sinus by morphometry, immunohistochemistry and immunofluorescence analyses. Aortic levels of macrophage polarization markers were analysed by Western blot and immunofluorescence analyses. We found that lentivirus-SIRT2-treated LDLr-/- mice had decreased plaque areas in the aortic sinus and developed a more stable plaque phenotype, as shown by decreased macrophage infiltration and apoptosis. In addition, treatment with lentivirus-SIRT2 significantly reduced the expression of iNOS (inducible nitric oxide synthase) and increased the levels of ARG-1 (arginase-1) in atheromas. These findings suggest that SIRT2 inhibited atherosclerotic plaque progression and enhanced plaque stability in LDLr-/- mice by inhibiting macrophage polarization towards the M1 phenotype. PMID- 29145150 TI - MicroRNA-146a knockdown suppresses the progression of ankylosing spondylitis by targeting dickkopf 1. AB - Ankylosing spondylitis (AS) seriously threatens healthy and life quality of patients, however, there is no extremely effective drug to cure the disease. Therefore, it is urgent to understand molecular basis in the progression of AS. MicroRNA-146a (miR-146a) has been demonstrated to be associated with the development of AS. However, its molecular mechanism has not been fully established. In this study, it is found that the expression levels of miR-146a and dickkopf 1 (DKK1) were respectively upregulated and downregulated in hip capsule tissues of AS patients. Moreover, a negative correlation was displayed between miR-146a and DKK1 expression. Functional analysis revealed that miR-146a inhibitor restrained cell proliferation and osteogenic potential as well as enhanced apoptosis in AS fibroblasts, while miR-146a overexpression enhanced proliferation and osteogenic potential of AS fibroblasts. Bioinformatics analysis, dual luciferase reporter assays, qRT-PCR and immunoblotting assays revealed that miR-146a inhibited DKK1 expression by directly targeting 3'UTR region of DKK1. Mechanism studies further revealed that loss of DKK1 partly reversed the effect of miR-146a inhibitor on cell proliferation, apoptosis and osteogenic potential in AS fibroblasts. Taken together, our finding revealed that miR-146a knockdown hindered AS progression partially by regulating target DKK1 expression, offering a potential therapy application for AS patients. PMID- 29145151 TI - Vildagliptin loaded triangular DNA nanospheres coated with eudragit for oral delivery and better glycemic control in type 2 diabetes mellitus. AB - Diabetes mellitus type 2 is a multidimensional disease associated with poor glycemic control through compromised sensitivity of pancreatic islet alpha and beta cells against glucose and dwindled secretion of insulin which is linked with the quantity of incretin hormones that are abridged by dipeptidyl peptidase-4 (DPP-4) in diseased condition. Vildagliptin (VG) inhibits DPP-4 therefore regulates the incretins that conversely maintains glycemic control. The safe reach and absorption of VG from intestine was dubious. Therefore we used Electrostatic Attraction Method to develop drug loaded DNA nanotechnology triangles coated by Eudragit (Eud) to make stable nanospheres of Vildagliptin (VG). We further analyzed the formulated nanospheres by AFM, XRD, DSC, SEM, TGA, ATR-FTIR and native PAGE. Additionally the efficacy of formulated nanospheres for drug release and glycemic control was assessed in Db/Db mouse. Our results showed that formulated nanospheres are smooth, spherical, stable and uniform in size ranging from 500 to 2000 nm with drug entrapment efficiency up to 95 +/- 2% and extended drug release up to 15 +/- 2 h. FTIR and DSC results confirmed the absence of VG-DNA-Eud interaction and XRD studies revealed a change in the crystalline status of the VG in nanospheres. Ex-vivo studies indicate that Eud DNA-VG nanospheres effectively bypasses the acidic pH of the stomach and enhances glycemic control in Db/Db mouse without any risk of pancreatitis or pancreatic cancer. To the best of our knowledge, this is the first study conclusively reporting that VG loaded DNA Nano-architects coated with Eudragit are stable, safe and may improve therapeutic outcomes after oral delivery. PMID- 29145152 TI - Possible role of Arthrospira platensis in reversing oxidative stress-mediated liver damage in rats exposed to lead. AB - Environmental pollutants, particularly metallic elements, mobilized and released into the environment, eventually accumulate in the food chain and thus pose a serious threat to human and animal health. In the present study, the role of Arthrospira (Spirulina platensis; SP) as a protector against oxidative stress mediated liver damage induced by an exposure to lead acetate (LA; as a metallic pollutant) was assessed. To achieve this aim, rats were orally administered with 300 mg/kg bw SP for 15 days, before and concurrently with an intraperitoneal injection of 50 mg/kg bw LA (6 injections throughout 15 days). As a result, co administration of SP with LA reduced the amount of lead that accumulated in both blood and liver tissue of the exposed rats and minimized the increased levels of lipid peroxidation, protein oxidation, DNA oxidative damage, and liver enzyme endpoints. In addition, because of SP administration, the levels of depleted biomarkers of antioxidant status and total antioxidant capacity in LA-exposed rats improved. Moreover, SP protected the liver tissue against the changes caused by LA exposure and also decreased the reactivity of HSP70 in the cytoplasm of hepatocytes. Collectively, our data suggest that SP has a potential use as a food supplement in the regions highly polluted with heavy metals such as lead. PMID- 29145153 TI - The pro-apoptosis effect of sinomenine in renal carcinoma via inducing autophagy through inactivating PI3K/AKT/mTOR pathway. AB - Renal cell carcinoma (RCC) is a heterogeneous histological disease and the most common kidney cancer. The mortality rate of RCC remains high despite the improved treatment. Sinomenine is an isoquinoline extracted from Chinese medicinal plant Sinomenium acutum, famous for its ability to suppress several cancer cell types. Our research aimed to explore the anti-cancer potential of sinomenine in RCC. Results showed that sinomenine reduced the viability by reducing sphere-forming ability and enhancing pro-apoptosis effect in ACHN cells in a dose dependent manner. The expression levels of proliferation/apoptosis markers further validated the result. In addition, sinomenine significantly regulated the level of autophagy-related proteins with decreased expression of p62, and increased Beclin1 and LC3 II/LC3 I. Furthermore, phosphatidylinositol-3 kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR), the negatively regulated cell autophagy signaling pathway, was inhibited by sinomenine with decreased membrane translocation of AKT in ACHN cell lines. All in all, our study demonstrated that sinomenine promoted apoptosis in RCC via enhancing autophagy through PI3K/AKT/mTOR pathway. PMID- 29145154 TI - A pipeline for proteome-scale identification and studies on hormone sensitive lipases in Mycobacterium tuberculosis. AB - Hormone sensitive lipases (HSLs) play an important role in the survival of M. tuberculosis during dormancy. They help in the utilization of fatty acids from stored lipids. The objective of the current study was to identify all HSLs from the proteome of M. tuberculosis H37Rv. We have developed a novel HSL identification pipeline, based on amino acid sequence homology, presence of conserved motifs and other sequence features deciphered from known HSL dataset. Through this pipeline, we identified 10 proteins as putative HSLs in M. tuberculosis. We have annotated a lipase LipT, as putative p-nitrobenzyl esterase and also identified a new motif "PGG" which is a possible characteristic motif of a subfamily of HSLs. PMID- 29145155 TI - Care and self-reported outcomes of care experienced by women with mental health problems in pregnancy: Findings from a national survey. AB - BACKGROUND: mental health problems in pregnancy and the postnatal period are relatively common and, in pregnancy, are associated with an increase in adverse outcome. It is recommended that all women are asked about their emotional and mental health and offered treatment if appropriate. OBJECTIVES: to describe the care received by women self-identifying with mental health problems in pregnancy, and to describe the effects of support, advice and treatment on outcomes in the postnatal period. DESIGN: this study used cross-sectional survey data collected in 2014 which described women's experience of maternity care. SETTING: England PARTICIPANTS: a random sample of women who had a live birth in January 2014. MEASUREMENTS: the questionnaire asked about sociodemographic characteristics, whether women were asked about emotional and mental health in pregnancy, support and treatment offered, about postnatal wellbeing, and questions relating to attachment to their baby. Descriptive statistics and logistic regression were used to examine the associations between mental health and outcomes taking account of sociodemographic characteristics. FINDINGS: the survey response rate was 47%. Women with antenatal mental health problems were significantly more worried at the prospect of labour and birth, had lower satisfaction with the experience of birth, worse postnatal mental health, and indications of poorer attachment to their baby. They received substantially more care than other women but they did not always view this positively. Support, advice and treatment for mental health problems had mixed effects. CONCLUSIONS: this study describes the significant additional care provided to women self-identifying with mental health problems in pregnancy, the mixed effects of support, advice and treatment, and the poor perception of staff interaction among women with mental health problems. IMPLICATIONS FOR PRACTICE: health care professionals may need additional training to effectively support women with mental health problems during the perinatal period. PMID- 29145156 TI - The potential of Ion Mobility Mass Spectrometry for high-throughput and high resolution lipidomics. AB - Lipids are a large and highly diverse family of biomolecules, which play essential structural, storage and signalling roles in cells and tissues. Although traditional mass spectrometry (MS) approaches used in lipidomics are highly sensitive and selective, lipid analysis remains challenging due to the chemical diversity of lipid structures, multiple isobaric species and incomplete separation using many forms of chromatography. Ion mobility (IM) separates ions in the gas phase based on their physicochemical properties. Addition of IM to the traditional lipidomic workflow both enhances separation of complex lipid mixtures, beneficial for lipid identification, and improves isomer resolution. Herein, we discuss the recent developments in IM-MS for lipidomics. PMID- 29145157 TI - BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis. AB - Autoimmune hepatitis is a chronic inflammatory disease in the liver with potential to the development of liver fibrosis. Recent evidences suggest that bone marrow derived mesenchymal stem cells (BMSCs) may exert its therapeutic activity through exosomes. Moreover, miR-223 is highly expressed in BMSCs and plays an important role in autoimmune diseases. Therefore, in this study, hepatoprotective role of BMSCs and miR-223 was investigated in both mice and hepatocytes. Liver antigen S100 was used to establish autoimmune hepatitis model in mice while LPS and ATP were used to establish cell injury model in hepatocyte. Before the experiments, BMSCs were infected with pre-miR-223 and transfected with miR-223 inhibitor respectively. Exosomes from bone marrow stem cells were isolated by ultracentrifugation. Liver injury was evaluated by serum levels of ALT and AST as well as liver histology. Inflammation and cell death were examined by inflammatory cytokines and lactase dehydrogenase respectively. Both BMSCs-exo and BMSCs-exomiR-223(+) significantly reversed either S100 or LPS/ATP induced injury in mice and hepatocytes. Meanwhile, the expressions of cytokines, NLRP3 and caspase-1 were also downregulated by BMSCs-exo and BMSCs-exomiR-223(+) at both protein and mRNA levels in mice and hepatocytes. Moreover, BMSCs-exomiR-223( ) reverses the effects of BMSCs-exo and BMSCs-exomiR-223(+) in mouse AIH and in hepatocytes. In conclusion, bone marrow stem cell derived exosomes can protect liver injury in an experimental model of autoimmune hepatitis and the mechanism could be related to exosomal miR-223 regulation of NLRP3 and caspase-1. PMID- 29145158 TI - Vibrio cholerae OmpU induces IL-8 expression in human intestinal epithelial cells. AB - Although Vibrio cholerae colonizes the small intestine and induces acute inflammatory responses, less is known about the molecular mechanisms of V. cholerae-induced inflammatory responses in the intestine. We recently reported that OmpU, one of the most abundant outer membrane proteins of V. cholerae, plays an important role in the innate immunity of the whole bacteria. In this study, we evaluated the role of OmpU in induction of IL-8, a representative chemokine that recruits various inflammatory immune cells, in the human intestinal epithelial cell (IEC) line, HT-29. Recombinant OmpU (rOmpU) of V. cholerae induced IL-8 expression at the mRNA and protein levels in a dose- and time-dependent manner. Interestingly, IL-8 was secreted through both apical and basolateral sides of the polarized HT-29 cells upon apical exposure to rOmpU but not upon basolateral exposure. rOmpU-induced IL-8 expression was inhibited by interference of lipid raft formation with nystatin, but not by blocking the formation of clathrin coated pits with chlorpromazine. In addition, rOmpU-induced IL-8 expression was mediated via ERK1/2 and p38 kinase pathways, but not via JNK signaling pathway. Finally, V. cholerae lacking ompU elicited decreased IL-8 expression and adherence to HT-29 cells compared to the parental strain. Collectively, these results suggest that V. cholerae OmpU might play an important role in intestinal inflammation by inducing IL-8 expression in human IECs. PMID- 29145159 TI - Potential link between m6A modification and systemic lupus erythematosus. AB - The field of m6A modification and epitranscriptomics has recently attracted much attention. More methods allowing for precise m6A site profiling and location are developed and crucial players of m6A modification machinery are increasingly identified. Although some challenges remain, m6A modification is found to modulate almost all aspects of RNA metabolism, such as splicing, stability, structure, translation, and export. Thus, m6A modification adds a new layer of post-transcriptional gene expression regulation, and it is implicated in T cell response to HIV infection, type I interferon production, and T cell differentiation and homeostasis. Moreover, evidence supporting its involvement in various human diseases including cancers is accumulating. Given the role of m6A modification in gene expression regulation and immune response, it invites the speculation that m6A modification may justify the pathogenesis of systemic lupus erythematosus (SLE) and take part in the initiation and progression of SLE. In this review, we introduce the widespread existence of m6A modification and briefly discuss components of m6A modification machinery in mammals. We mainly summarize the studies reporting the mechanisms of m6A modification in gene expression regulation through modulating pre-mRNA splicing, mRNA stability, RNA structure, translation, and pri-miRNA processing. Biological functions related to immune response of m6A modification and the implication of m6A modification in cancers are highlighted. In the end, we surmise the potential link between m6A modification and SLE. PMID- 29145160 TI - Larval development ratio test with the calanoid copepod Acartia tonsa as a new bioassay to assess marine sediment quality. AB - The copepod Acartia tonsa was used as a model species to assess marine sediment quality. Acute and chronic bioassays, such as larval development ratio (LDR) and different end-points were evaluated. As a pelagic species, A. tonsa is mainly exposed to water-soluble toxicants and bioassays are commonly performed in seawater. However, an interaction among A. tonsa eggs and the first larval stages with marine sediments might occur in shallow water environments. Here we tested two different LDR protocols by incubating A. tonsa eggs in elutriates and sediments coming from two areas located in Tuscany Region (Central Italy): Livorno harbour and Viareggio coast. The end-points analyzed were larval mortality (LM) and development inhibition (DI) expressed as the percentage of copepods that completed the metamorphosis from nauplius to copepodite. Aims of this study were: i) to verify the suitability of A. tonsa copepod for the bioassay with sediment and ii) to compare the sensitivity of A. tonsa exposed to different matrices, such as water and sediment. A preliminary acute test was also performed. Acute tests showed the highest toxicity of Livorno's samples (two out of three) compared to Viareggio samples, for which no effect was observed. On the contrary, LDR tests with sediments and elutriates revealed some toxic effects also for Viareggio's samples. Results were discussed with regards to the chemical characterization of the samples. Our results indicated that different end-points were affected in A. tonsa, depending on the matrices to which the copepods were exposed and on the test used. Bioassays with elutriates and sediments are suggested and LDR test could help decision-makers to identify a more appropriate management of dredging materials. PMID- 29145161 TI - CYP450 enzyme-specific enantioselective species-specific response for metalaxyl in in vitro hepatic cells. AB - Although enantioselective accumulation of chiral pesticide has been reported in organisms, the mechanisms remain unclear. In this study, the effects of chiral pesticide metalaxyl on CYP1A1, CYP1A2, CYP2B1, CYP2B2, CYP2E1 and CYP3A were investigated in human hepatoma HepG2, rat hepatic H4IIE, chicken hepatic LMH and grass carp hepatic L8824 cells. Moreover, the residual concentrations and enantiomeric ratios (ERs) of metalaxyl were also detected in the medium. The results showed the responses of these CYP450s to metalaxyl were enzyme-dependent and species-dependent in the four cells. CYP1A1, CYP1A2, and CYP2B1 were induced in HepG2 cells, CYP2A1 and CYP2B1 were induced in H4IIE cells, CYP1A1 and CYP2B1 were induced in LMH cells, and CYP2B1 was induced in L8824 cells. The enantioselective residual of metalaxyl was detected in the medium and found to be species-specific. HepG2, H4IIE and LMH cells were inclined to attenuate S metalaxyl and lead to decrease of ER of metalaxyl, while L8824 cells were inclined to remove R-metalaxyl and resulted in an inverse shift of ER. These findings suggest an enantioselective metabolism of metalaxyl in various species which is not only related with CYP450s and CYP450 enzyme-specific, but also species-specific. PMID- 29145162 TI - Biomonitoring-based exposure assessment of benzene, toluene, ethylbenzene and xylene among workers at petroleum distribution facilities. AB - Elevated emissions of volatile organic compounds, including benzene, toluene, ethylbenzene, and o, p, and m-xylenes (BTEX), are an occupational health concern at oil transfer stations. This exploratory study investigated personal exposure to BTEX through environmental air and urine samples collected from 50 male workers at a major oil distribution company in Iran. Airborne BTEX exposures were evaluated over 8h periods during work-shift by using personal passive samplers. Urinary BTEX levels were determined using solid-phase microextraction with gas chromatography mass spectrometry for separation and detection. Mean exposure to ambient concentrations of benzene differed by workers' job type: tanker loading workers (5390MUg/m3), tank-gauging workers (830MUg/m3), drivers (81.9MUg/m3), firefighters (71.2MUg/m3) and office workers (19.8MUg/m3). Exposure across job type was similarly stratified across all personal exposures to BTEX measured in air samples with maximum concentrations found for tanker loading workers. Average exposures concentrations of BTEX measured in urine were 11.83 ppb benzene, 1.87 ppb toluene, 0.43 ppb ethylebenzene, and 3.76 ppb xylene. Personal air exposure to benzene was found to be positively associated with benzene concentrations measured in urine; however, a relationship was not observed to the other BTEX compounds. Urinary exposure profiles are a potentially useful, noninvasive, and rapid method for assessing exposure to benzene in a developing and relatively remote production region. PMID- 29145163 TI - Spread of multidrug-resistant Escherichia coli harboring integron via swine farm waste water treatment plant. AB - Wastewater treatment plants (WWTPs) that release treated wastewater into the environment have emerged as a major threat to public health. In this study, we investigated Escherichia coli load and antibiotic-resistance profiles across different treatment processes at a swine farm WWTP. The frequency of the detection of class 1 and 2 integrons, and their association with antibiotic resistance, were also analyzed. Samples were obtained at each of five sampling sites that represented each processing step within the WWTP. The largest decrease in E. coli load was observed during the anaerobic digestion step (from 4.86 to 2.89log CFU/mL). Isolates resistant to beta-lactam antibiotics were efficiently removed after a series of treatment steps, whereas the proportions of isolates resistant to non-beta-lactam antibiotics and multidrug-resistant strains were maintained across treatments. The occurrence of integron-positive strains was not significantly different at the various sampling sites (43.4-70%; p>0.05). Of the class 1 integron-positive isolates, 17.9% harbored the integron-associated gene cassettes aadA2, aadA12, aadA22, and dfrA15. To the best of our knowledge, this is the first description of a class 1 integron containing the aadA12 gene cassette from a swine farm and the presence of a class 1 integron containing dfrA15 in E. coli. This suggests that novel antibiotic-resistance gene cassette arrays could be generated in swine farm WWTPs. Moreover, 75% of integron-positive strains were categorized as multidrug resistant, whereas only 15.4% of integron negative strains were multidrug resistant (p<0.05), indicating that integrons may be responsible for mediating resistance in WWTPs. With regard to the occurrence of multidrug-resistant, integron-positive E. coli recovered from the final effluent, our results highlighted the potential risks associated with wastewater discharge from swine farm WWTPs in terms of the spread of antibiotic-resistant bacteria to the aquatic environment. PMID- 29145164 TI - Long noncoding RNA HNF1A-AS1 indicates a poor prognosis of colorectal cancer and promotes carcinogenesis via activation of the Wnt/beta-catenin signaling pathway. AB - Long non-coding RNAs (lncRNAs) have been identified to play critical roles in tumorigenesis. LncRNA HNF1A-AS1 has been suggested to act as an oncogene and serves as a novel prognostic biomarker for various cancer. However, the biological role and clinical significance of lncRNA HNF1A-AS1 in colorectal cancer (CRC) have yet to be fully elusive. Therefore, the present study was designed to determine the expression of lncRNA HNF1A-AS1 in patients with CRC, the role of lncRNA HNF1A-AS1 in CRC cells, as well as the underlying regulatory mechanisms. Our results indicated that the expression of lncRNA HNF1A-AS1 was significantly upregulated in both CRC tumor tissues and CRC cell lines in comparison with adjacent non-tumor tissues and the human normal colonic epithelial cell line (HcoEpiC). The Kaplan-Meier survival analysis further suggested that high expression of lncRNA HNF1A-AS1 might be an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in patients with CRC. Moreover, the area under the receiver operating characteristic (ROC) curve for HNF1A-AS1 was up to 0.8714, implying that HNF1A-AS1 had diagnostic significance as it could discriminate tumor tissues from nontumorous tissues. In addition, silencing of lncRNA HNF1A-AS1 abrogated the proliferation of CRC cells by MTS assay and clonogenic assay, arrested cell cycle at G0/G1 stage and reduced the migration and invasion in CRC cells. Finally, we found that decreased expression of lncRNA HNF1A-AS1 suppressed the Wnt/beta-catenin signaling pathway activity by downregulating the expression of beta catenin,cyclinD1, and c-myc. In conclusion, these findings provide evidence that lncRNA HNF1A-AS1 may be considered as a new prognostic biomarker and therapeutic target in patients with CRC. PMID- 29145165 TI - Long non-coding RNA DLX6-AS1 aggravates hepatocellular carcinoma carcinogenesis by modulating miR-203a/MMP-2 pathway. AB - Long non-coding RNAs (lncRNAs) have been wildly verified to modulate multiple tumorigenesis, especially hepatocellular carcinoma (HCC). In present study, our team aims to investigate the role of lncRNA DLX6-AS1 in the HCC carcinogenesis. Results of early-stage experiments found that DLX6-AS1 expression level was up regulated in 60 cases of HCC tissue samples compared with adjacent normal tissue. Moreover, the aberrant overexpression of DLX6-AS1 indicated the poor prognosis of HCC patients. Loss-of-function experiments revealed that DLX6-AS1 knockdown inhibited the proliferation, migration and invasion of HCC cells in vitro, and decreased the tumor growth in vivo. Bioinformatics analysis predicted that miR 203a potentially targeted DLX6-AS1 3'-UTR, suggesting the interaction between miR 203a and DLX6-AS1. Furthermore, miR-203a also targeted MMP-2 mRNA 3'-UTR, which was validated by luciferase reporter assay. Taken together, our study discovered the oncogenic role of DLX6-AS1 in clinical specimens and cellular experiments, showing the potential DLX6-AS1/miR-203a/MMP-2 pathway. This results and findings provide a novel insight for HCC tumorigenesis. PMID- 29145166 TI - Revisiting interhemispheric imbalance in chronic stroke: A tDCS study. AB - OBJECTIVE: Chronic stroke patients with moderate-severe motor impairment may have an increased reliance on contralesional vs ipsilesional motor areas to control the paretic arm. We hypothesised that increasing contralesional excitability with anodal transcranial direct current stimulation (a-tDCS) would benefit motor performance in patients with moderate-severe impairment. METHODS: Ten patients with motor impairment at the chronic stage after stroke received a-tDCS, cathodal (c-tDCS) and sham with the target electrode over contralesional motor cortex (M1). Motor performance was quantified from the circularity and size of planar movements made with the paretic arm. Contralateral and ipsilateral corticospinal excitability was inferred using transcranial magnetic stimulation. Corticospinal tract integrity and basal GABA concentration were assessed with magnetic resonance imaging and spectroscopy. RESULTS: Anodal tDCS increased contralesional corticomotor excitability evident from motor evoked potentials in both wrist extensors (both P<0.043). Cathodal tDCS did not affect corticomotor excitability (P>0.37). The effect of tDCS on motor performance with the paretic limb was negatively associated with ipsilesional GABA concentration after c-tDCS (P=0.001). CONCLUSIONS: Further investigation of noninvasive brain stimulation protocols that facilitate contralesional M1 is warranted. SIGNIFICANCE: The inter hemispheric imbalance model of stroke recovery may not apply to patients with more severe impairment. PMID- 29145167 TI - Contraction response to muscle percussion: A reappraisal of the mechanism of this bedside test. AB - OBJECTIVE: To study whether the contraction evoked by muscle percussion stems from the excitation of the muscle or of the nerve and to discuss the changes of this response in neuromuscular disorders. METHODS: In 30 neurologically healthy patients undergoing surgery (for ear, nose, or throat problems unrelated to the study) under general anesthesia with propofol and sufentanil we measured with an electrogoniometer the maximal dorsiflexion of the ankle evoked by reflex hammer percussion of the tibialis anterior muscle before and under neuromuscular junction blockade with rocuronium bromide. In 3 additional healthy volunteers we searched for F-waves to disclose whether percussion excites axons within the muscle. RESULTS: Responses from 28 neurologically healthy patients (15 women) were analyzed after exclusion of 2 due to technical problems. Mean age (SD) was 28 (9) years. Maximal dorsiflexion of the ankle was not significantly modified by neuromuscular junction blockade (mean difference 0.01 mV [95%CI, -0.07 to 0.08], p=0.879). Muscle percussion evoked F-waves in the 3 healthy volunteers tested. CONCLUSIONS: Maximal contraction response to muscle percussion has a muscular rather than a neural origin. However, percussion also excites axons within the muscle. SIGNIFICANCE: These findings may provide clues to understand the changes observed in neuromuscular disorders. PMID- 29145168 TI - Frontal infraslow activity marks the motor spasms of anti-LGI1 encephalitis. AB - OBJECTIVE: The clinical and electrographic features of seizures in anti-LGI1 encephalitis are distinct from those seen in other autoimmune encephalitides or non-encephalitic epilepsies. One electroclinical phenomenon specific to the condition consists of lateralized motor spasms, known as faciobrachial dystonic seizures (FBDS). An electrodecremental pattern overriding a "DC shift" has been described as the EEG correlate of these spasms. We sought to further characterize this pre-spasm infraslow activity (ISA). METHODS: Continuous video-EEG recordings were acquired in four patients with anti-LGI1 encephalitis: each had frequent motor spasms/FBDS as well as frequent subclinical temporal lobe seizures (an independent indicator of anti-LGI1 encephalitis). RESULTS: In artifact-free recordings obtained using clinical amplifiers equipped with a low frequency analog filter of 0.07 Hz, ISA reliably preceded clinical onset of the motor spasms by ~1.2 s and preceded the electrodecremental pattern by ~700 ms. Pre spasm ISA was invariably recorded contralateral to FBDS, with a voltage topographic maximum over the mid frontal region. The pre-movement ISA differed from the Bereitschaftspotential in timing and topography and was an order of magnitude higher in amplitude. Sporadic FBDS that occurred in association with temporal lobe seizures were preceded by identical ISA. CONCLUSIONS: The motor spasms of anti-LGI1 encephalitis are preceded by frontal ISA. A paucity of data at the microscale level precludes mechanistic explanations at the macroscale level, or even determination of the relative contributions of neurons and glia in the generation of the ISA. SIGNIFICANCE: Although fundamental cellular mechanisms await elucidation, the pre-spasm ISA represents a singular and readily identifiable EEG response to this autoimmune brain disorder. PMID- 29145169 TI - A zinc Schiff base complex inhibits cancer progression both in vivo and in vitro by inducing apoptosis. AB - Cancer chemotherapy suffers from selectivity and undesired toxicity of the drugs. Since zinc is a biocompatible tracer element and cysteine derivatives are used in cancer chemoprevention, we intend to develop a complex of zinc and cysteine derivatives as potent, non-toxic anticancer agents. Herein, we synthesized and characterized cysteine based ligand, 2-[(2-Hydroxy-3-methoxy-benzylidene)-amino] 3-mercapto-propionic acid and its Zn-complex, which are found to be non-toxic towards normal human PBMC. Data also revealed that only Zn-complex exhibited remarkable apoptosis in drug-sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cancer cells as assessed by MTT, Cell cycle and AnnexinV binding assay. Moreover, Zn-complex altered ROS and GSH level of the respective cell lines. Finally, treatment of Zn-complex in Swiss albino mice did not show any systemic toxicity in preliminary trials in normal mice and remarkably increased the life-span of EAC bearing mice. In conclusion, the synthesized Zn-complex may be developed for efficacious, multidrug resistance reversal, non-toxic chemotherapeutic agents in future. PMID- 29145170 TI - Perioperative thrombocytopenia predicts poor outcome in patients undergoing transcatheter aortic valve implantation. AB - PURPOSE: To determine the time point at which thrombocytopenia after TAVI procedure is an indicator of the worst prognosis, with special consideration of perioperative platelet and coagulation activation as its potential causes. METHODS: Thirty two patients (mean age 78.5+/-7.9years, 62% females) qualified for TAVI procedure were prospectively evaluated. Platelet counts were assessed at baseline and for the next three postoperative (POD) days. Platelet activation was evaluated by P-selectin (PS, serum, ELISA) and platelet factor 4 (PF-4, CTAD plasma), and blood coagulation activation by prothrombin fragments 1+2 (F1+2, plasma, ELISA). Composite end point (CEP) including death and the need of cardiovascular rehospitalization was assessed after a mean of 14.1+/-6.7months. RESULTS: During the follow up period half of the patients reached CEP. Thrombocytopenia was more profound and frequent in patients with CEP as compared to those without (p<0.05). No differences regarding either the biomarkers of platelet (PS, PF-4) or coagulation (F1+F2) activation between the groups with and without CEP were found. Patients with moderate-to-severe thrombocytopenia at baseline had worse prognosis (log-rank test, p=0.0003). Based on the receiver operating characteristic curve analysis, the differences between platelet count on each postoperative day and the baseline count did not have any predictive value in CEP occurrence. CONCLUSIONS: Patients with thrombocytopenia following TAVI procedure have poor prognosis, however, the changes on the particular days are not more important than initial platelet count. Further studies are needed to evaluate platelet and blood coagulation activation as potential causes of thrombocytopenia and impaired prognosis related to it. PMID- 29145171 TI - Host target-based approaches against arboviral diseases. AB - In the 20th century, socioeconomic and environmental changes facilitated the reintroduction of mosquitoes in developing cities, resulting in the reinsertion of mosquito-borne viral diseases and the dispersal of their causative agents on a worldwide scale. Recurrent outbreaks of arboviral diseases are being reported, even in regions without a previous history of arboviral disease transmission. Of note, arboviral infections represented approximately 30% of all emerging vector borne diseases in the last decade. Therapeutic strategies against infectious viral diseases include the use of different classes of molecules that act directly on the pathogen and/or act by optimizing the host immune response. Drugs targeting the virus usually provide amelioration of symptoms by suppressing and controlling the infection. However, it is limited by the short-window of effectiveness, ineffectiveness against latent viruses, development of drug resistant mutants and toxic side effects. Disease may also be a consequence of an excessive, uncontrolled or misplaced inflammatory response, treatments that interfere in host immune response are interesting options and can be used isolated or in combination with virus-targeted therapies. The use of host targeted therapies requires specific knowledge regarding host immune patterns that may trigger dengue virus (DENV), chikungunya virus (CHIKV) or Zika virus (ZIKV) disease. PMID- 29145172 TI - Volatiles from Cinnamomum cassia buds. AB - While the chemical composition of leaf and stem bark essential oils of the Chinese cinnamon, Cinnamomum cassia (L.) J. Presl, has been well investigated, little is known about the volatilom of its buds, which appeared recently on German markets. Soxhlet extracts of the commercial samples were prepared, fractionated using silica gel and characterised by gas chromatography-flame ionisation detector (GC-FID) for semi-quantification, by gas chromatography-mass spectrometry (GC-MS) for identification and by GC-FID/olfactometry for sensory evaluation. Cinnamaldehyde was the most abundant compound with concentrations up to 40 mg/g sample. In total, 36 compounds were identified and 30 were semi quantified. The extracts contained mostly phenylpropanoids, mono- and sesquiterpene hydrocarbons and oxygenated derivatives. Because of the high abundance of cinnamaldehyde, the aldehyde fraction was removed from the extracts by adding hydrogen sulphite to improve both the detection of trace compounds and column chromatography. The aldehyde fraction was analysed by GC-MS separately. The highest flavour dilution factor of 316 was calculated for cinnamaldehyde. Other main sensory contributors were 2-phenylethanol and cinnamyl alcohol. This report provides the first GC-olfactometry data of a plant part of a Cinnamomum species. The strongly lignified C. cassia buds combine a high abundance of cinnamaldehyde with comparably low coumarin concentrations (<0.48 mg/g), and provide a large cinnamaldehyde depot for slow release applications. PMID- 29145173 TI - A new method for fast extraction and determination of chlorophylls in natural water. AB - Algae collection and chlorophyll extraction are two troublesome steps in the traditional methods used for the determination of chlorophyll concentration in natural water. A new method was established in this study for fast collection and extraction of chlorophyll. Based on our results, the optimum centrifugation condition for collecting algae was determined as: 5000 g for 15 min at 4 degrees C, and the optimum dilution ratio of dimethyl sulfoxide: 90% acetone was 1:4. The specific steps were as follows: the algae in water samples were collected by centrifugation at 5000 g at 4 degrees C for 15 min. The precipitated algae were suspended with 2 mL DMSO. Then the sample was transferred to a 15 mL centrifuge tube, and the tube was incubated at 65 degrees C for 1-2 h in the dark until the sample turned white. After cooling, the chlorophyll extract was diluted with 8 mL 90% acetone, before centrifugation at 5000 g for 5 min. The absorbance values of the supernatants at 750, 664, 647 and 630 nm were used for the calculation of chlorophyll concentrations by the trichromatic equations. This new method saved the filter cost, simplified the extraction process, improved the algae acquisition efficiency, and accelerated the chlorophyll extraction rate. PMID- 29145174 TI - Temperature dependent electron paramagnetic resonance study on magnetoelectric YCrO3. AB - We report temperature dependent electron paramagnetic resonance (EPR) studies on polycrystalline YCrO3 samples at X-band (9.46 GHz) in the temperature range of 120 K-298 K. The EPR spectra exhibit a single broad line across the whole temperature range, attributed to Cr3+ ions. The variation of EPR spectra parameters (line width, integrated intensity, and g-factor) as a function of temperature was analyzed to understand the nature of spin-dynamics in the paramagnetic region of YCrO3. A peak in the g-factor suggests the presence of a new phase within the paramagnetic state at an intermediate point of temperature T IP ~ 230 K, attributed to the onset of short range canted antiferromagnetic correlations in the material much above 140 K, Neel temperature (T N) of YCrO3. The EPR intensity increases with a decrease in temperature up to T N due to the renormalization of the magnetic moments arising from the appearance of canted antiferromagnetic correlations. Further, temperature dependent dielectric measurements also exhibit an anomaly at ~230 K suggesting the presence of magnetodielectric coupling in YCrO3, with a possibility towards a relatively high temperature magnetodielectric system. PMID- 29145175 TI - Antimicrobial Activity of Galangin and Its Effects on Murein Hydrolases of Vancomycin-Intermediate Staphylococcus aureus (VISA) Strain Mu50. AB - : Backgroud: Antibiotic treatment for infections caused by vancomycin intermediate Staphylococcus aureus (VISA) strains is challenging, and only a few effective and curative methods have been developed to combat these strains. This study aimed to investigate the antimicrobial activity of galangin against S. aureus and its effects on the murein hydrolases of VISA strain Mu50. This is the first report on these effects of galangin, and it may help to improve the treatment for VISA infections by demonstrating the effective use of galangin. METHODS: Firstly, the minimum inhibitory concentration (MIC) and growth curve were used to investigate the antimicrobial activity of galangin against S. aureus. Secondly, transmission electron microscopy (TEM) was used to observe morphological changes of VISA strain Mu50. Thirdly, Triton X-100-induced autolysis and cell wall hydrolysis assays were performed to determine the activities of the murein hydrolases of Mu50. Finally, fluorescence real-time quantitative PCR was used to investigate the expression of the murein hydrolase related Mu50 genes. RESULTS: The results indicated that the MIC of galangin was 32 MUg/mL against ATCC25293, N315, and Mu50, and galangin could significantly suppress the bacterial growth (p < 0.05) with concentrations of 4, 8 and 16 MUg/mL, compared with control group (0 MUg/mL). To explore the possible reasons of bacteriostatic effects of galangin, we observed morphological changes using TEM which showed that the division of Mu50 daughter cells treated with galangin was obviously inhibited. Considering the vital role of murein hydrolases in cellular division, assays were performed, and galangin markedly decreased Triton X-100-induced autolysis and cell wall hydrolysis. Galangin also significantly inhibited the expression of the murein hydrolase genes (atl, lytM, and lytN) and their regulatory genes (cidR, cidA, and cidB). CONCLUSIONS: Our findings indicated that galangin can effectively inhibit murein hydrolase activity as well as the growth of VISA strain Mu50. PMID- 29145177 TI - LncRna CPS1-IT1 Suppresses Cell Proliferation, Invasion and Metastasis in Colorectal Cancer. AB - BACKGROUND/AIMS: Increasing evidence demonstrates that long non-coding RNAs (lncRNAs) regulate diverse cellular processes and cancer progression. Whether lncRNAs play any functional role in colorectal carcinoma (CRC) remains largely unknown. The aim of this study was to investigate the role of lncRNA CPS1 intronic transcript 1 (CPS1-IT1) in CRC. METHODS: Expression of CPS1-IT1 was initially assessed in human CRC tissues and in a series of CRC cell lines. The correlations between CPS1-IT1 levels and survival outcomes were analyzed to elucidate the clinical significance of CPS1-IT1 in CRC. The underlying mechanisms of CPS1-IT1 in CRC were analyzed through in vitro and in vivo functional assays. RESULTS: Expression of CPS1-IT1 was significantly decreased in CRC tissues and cell lines, and patients with low CPS1-IT1 expression had poor survival outcomes. The results of in vitro assays revealed that CPS1-IT1 significantly reduced cell proliferation, migration and invasion capacities and accelerated cell apoptosis, thereby suppressing epithelial-mesenchymal transition (EMT). An in vivo animal model also demonstrated the tumor-suppressive role of CPS1-IT1. CONCLUSION: In this study, we found that CPS1-IT1 has a tumor-suppressive role in CRC. Our data suggest that CPS1-IT1 could be used as a new prognostic biomarker and therapeutic target for CRC. PMID- 29145178 TI - Minor Hemisphere Major Syndromes. AB - A right "minor hemisphere" does not exist as the right hemisphere is dominant for awareness (nosognosia), spatial attention, emotional regulation, facial and voice expressions, visual recognition, and topographical orientation. Without the right hemisphere, the world would be flat, deprived of general and spatial attentions, pointing preferentially to the right side of the space, lacking visual experiences and emotions, exhibiting diminished awareness of the self and environment. Clinical-related syndromes of the right hemisphere are unilateral spatial neglect, object and face visual agnosia, the anosognosia for hemiparesis and/or hemianopia, misidentification syndromes, mania, and other obsessions for the food and the body. Another key function of the right hemisphere is the modulation of the emotional processes of the linguistic communication (as prosody and facial expressions), and the tuning of some holistic aspects of language as the understanding of the abstract and figurative characters. The great mysteries of the right brain hemisphere concern the origin of the emotional nature of the human being, the way by which cognition interacts with perception and finally the human consciousness. Multidisciplinary researches in the domains of neurology, cognitive psychology, neuropsychiatry, functional neuroimaging, and neurophysiology will reveal in the future some of these mysteries. PMID- 29145176 TI - The Membrane Attack Complex/Perforin Superfamily. AB - The membrane attack complex/perforin (MACPF) superfamily consists of a diverse group of proteins involved in bacterial pathogenesis and sporulation as well as eukaryotic immunity, embryonic development, neural migration and fruiting body formation. The present work shows that the evolutionary relationships between the members of the superfamily, previously suggested by comparison of their tertiary structures, can also be supported by analyses of their primary structures. The superfamily includes the MACPF family (TC 1.C.39), the cholesterol-dependent cytolysin (CDC) family (TC 1.C.12.1 and 1.C.12.2) and the pleurotolysin pore forming (pleurotolysin B) family (TC 1.C.97.1), as revealed by expansion of each family by comparison against a large protein database, and by the comparisons of their hidden Markov models. Clustering analyses demonstrated grouping of the CDC homologues separately from the 12 MACPF subfamilies, which also grouped separately from the pleurotolysin B family. Members of the MACPF superfamily revealed a remarkably diverse range of proteins spanning eukaryotic, bacterial, and archaeal taxonomic domains, with notable variations in protein domain architectures. Our strategy should also be helpful in putting together other highly divergent protein families. PMID- 29145179 TI - Phantom Sensations, Supernumerary Phantom Limbs and Apotemnophilia: Three Body Representation Disorders. AB - Body representation disorders continue to be mysterious and involve the anatomical substrate that underlies the mental representation of the body. These disorders sit on the boundaries of neurological and psychiatric diseases. We present the main characteristics of 3 examples of body representation disorders: phantom sensations, supernumerary phantom limb, and apotemnophilia. The dysfunction of anatomical circuits that regulate body representation can sometimes have paradoxical features. In the case of phantom sensations, the patient feels the painful subjective sensation of the existence of the lost part of the body after amputation, surgery or trauma. In case of apotemnophilia, now named body integrity identity disorder, the subject wishes for the disappearance of the existing and normal limb, which can occasionally lead to self-amputation. More rarely, a brain-damaged patient with 4 existing limbs can report the existence of a supernumerary phantom limb. PMID- 29145180 TI - Misoplegia. AB - In 1974, Critchley described misoplegia as the phenomenon in which a hemiplegic patient develops a morbid dislike towards the offending immobile limbs. Patients with misoplegia may employ, but more commonly strike their paretic limbs not recognized as self. The pathophysiological mechanism is not well understood. The handful of cases of misoplegia described in the literature, frequently presented a right hemispheric damage. However, patients with chronic spinal cord injury may also present this symptomatology. Not only the modification of behavior by this organic injury, but also the patient reaction to disability and previous personality, may provoke the emergence of misoplegia, probably from other right hemispheric self-unawareness syndromes. No data exists related to treatment option, but we have to remember that the lack of awareness of the deficits in these patients makes the rehabilitation process difficult. Misoplegia is one of the passionate syndromes of the still "not-enough well-known" self-awareness syndromes of the right hemisphere, which shows how brain damage goes much further beyond neurological deficit. PMID- 29145181 TI - Pali and Echo Phenomena: Symptoms of Persistence and Perseveration. AB - Some neurological or psychiatric positive, productive symptoms are an abnormal persistence of a sensorial feeling or abnormal repetition of a motor, behavioral or cognitive process corresponding to a perseverative symptom. Palinopsia, palinacousis, and related sensorial symptoms have been described. Verbal and motor symptoms include echolalia, palilalia, echopraxia, and motor perseveration. Cognitive disorders induce perseverative behavior, perseverative thinking, including palipsychism, flashbulb memories, and reduplicative paramnesia (also known as "palimnesia") and many related perseverative symptoms. We propose a review of physiological phenomena and pathological symptoms involving these perseverative or repetitive characteristics and discuss the potential mechanisms and neural network involved in this productive semiology. PMID- 29145182 TI - Pathological Yawning, Laughing and Crying. AB - Yawning, laughing, and crying are normal physiological behaviors of humans in good health. As with all physiological behaviors, their deregulation can reveal disorders. Pathological yawning occurs in salvos of 10-20 successive yawns, and the number of yawns per day can exceed one hundred. After listing the functional etiologies, we will give the clinical keys for differentiating the most serious causes: iatrogenic, tumors, strokes, amyotrophic lateral sclerosis, and intracranial hypertension. Sudden, uncontrollable episodes of emotional display involving pathological laughing and crying (PLC) may be encountered in various neurological diseases: amyotrophic lateral sclerosis, multiple system atrophy (cerebellar), cerebrovascular disease, traumatic brain injuries, mass lesions in the cerebellopontine junction, and epilepsy. After describing the pathophysiology of PLC and the use of diagnostic scales for PLC, we will discuss the current treatments. PMID- 29145183 TI - Catastrophe Reaction and Emotionalism. AB - The catastrophic reaction (CR; a disruptive and uncontrolled behavior triggered by anger, irritability, and hostility) and emotionalism (a condition of uncontrolled crying or laughing) are disorders of the emotional regulation and expression, the prevalence of which is underestimated in neurology. Their occurrence is an additional factor of poor outcome for neurologic patients. Although they have been recognized and completely described in their clinical manifestations more than a century ago, many issues remain unsolved regarding their pathogenesis and the respective role of the brain damage and psychological factors. Thus, if pathological crying and laughing can be linked to one or more lesions within the corticospinal tracts, the emotional lability and CR have uncertain connections within specific functional brain systems and seem to be influenced by personality factors or depression and anxiety generated by coping with a serious neurological disease. These epistemological difficulties are also the consequence of some methodological limits of the questionnaires and scales, which diagnose these disorders and for which the cut-off values between the normal and pathological condition could be questioned. Thus, their assessment requires new psychophysical. The CR and emotionalism manifest in association with several different neurological disease (degenerative, vascular, inflammatory, epilepsy) and psychiatric conditions as psychosis, mania, and mood disorders. Across these different diseases, the findings of common patterns of lesion location, cognitive dysfunction, emotional changes, and behavioral responses to new paradigms might clarify the pathogenesis and orient the treatment. PMID- 29145184 TI - Addictive (Non-Drug) and Obsessive-Compulsive Symptoms after Focal Brain Lesions. AB - This chapter presents an overview of different addictive and obsessive-compulsive symptoms and their constellations due to focal brain lesions. In general, such symptoms are not systematically reported in the literature, and the knowledge about the networks involved is sometimes sparse. Finally, we present an original case with an unusual combination of kleptomania and hyper-religiosity. PMID- 29145185 TI - Hypersexuality in Neurological Disorders: From Disinhibition to Impulsivity. AB - Little is known about the neurological control of human sexual behavior. Investigating and measuring this behavior by using quantitative and objective methods is difficult. Insights from lesion studies contribute to analyze the effects of neurological disorders on human sexual behavior. In this chapter, we focus on frontal lobe lesions, brain injuries, epilepsia, dementia, and Parkinson disease to describe human sexual behavior disorders, in order to highlight cortical and subcortical brain regions and neural networks involved in human sexual behavior. PMID- 29145186 TI - The Kluver-Bucy Syndrome. AB - In 1937, Heinrich Kluver and Paul Bucy described a dramatic behavioral syndrome in monkeys after bilateral temporal lobectomy. The full Kluver-Bucy syndrome (KBS) - hyperorality, placidity, hypermetamorphosis, dietary changes, altered sexual behavior, and visual agnosia - is evident within 3 weeks following operation. Some KBS features (i.e., hyperorality, placidity, hypermetamorphosis) persist indefinitely, whereas others gradually resolve over several years. Kluver and Bucy were initially unaware of an earlier report of KBS by Sanger Brown and Edward Schafer in 1888. Human cases were recognized in the 1950s, as surgeons employed bilateral temporal lobectomies to treat seizures. Various attempts were made to localize the component features to specific areas of the temporal lobe, with mixed success. Bilateral ventral temporal ablations and bilateral temporal lobectomies produced marked impairment in visual discrimination, whereas lateral resections or unilateral lesions did not. Discrete bilateral lesions of the lateral amygdaloid nucleus produced a permanent "hypersexed state." By the 1970s, it was clear that the major symptoms of KBS are produced by destroying either the temporal neocortex or the amygdala bilaterally. KBS is now thought to be caused by disturbances of temporal portions of limbic networks that interface with multiple cortical and subcortical circuits to modulate emotional behavior and affect. The clinical features of KBS in man are similar to those in monkeys, but the full syndrome is rarely seen, probably because the anterior temporal lobe dysfunction is usually less severe than that following total temporal lobe ablation in monkeys. Human KBS does not occur in isolation, but is typically part of a complex behavioral syndrome that almost always includes amnesia and aphasia, and that may also include dementia and seizures. The treatment of KBS is difficult and often unsatisfactory. PMID- 29145187 TI - Diogenes Syndrome. AB - Diogenes syndrome (DS) is not a specific disease but a real neurobehavioral syndrome, characterized by severe domestic squalor, pathological hoarding, lack of insight into the condition, and no need for help. DS can be secondary when associated to psychosis or bipolar disorder, or primary when it occurs as a single entity, usually in the elderly. DS is a clinically complex transnosographic syndrome for which multidimensional approaches need to be considered: medical, psychiatric, neurological, social, scientific, and ethical. Known for more than 40 years mainly by geriatricians, psychiatrists, nurses or social workers and more recently by forensic specialists, the fine grained mechanisms of the syndrome are still incompletely understood. From a neurocognitive standpoint, frontal vulnerability certainly disrupts normal decision-making processes, explaining squalor, pathological hoarding, and lack of insight but we need to better understand the connection between the main symptoms and the neural underpinning of the full syndrome. We should definitely intervene earlier, before patients refuse any help, and when the syndrome is supposedly milder, to improve our clinical knowledge, follow patients prospectively, experiment hypothesis in laboratory settings, and launch randomized controlled trials for treatments. There is hope for future pharmacological and non pharmacological strategies to alleviate this socially disastrous condition. PMID- 29145188 TI - Brueghel Syndrome or Meige Syndrome? Two Sides of a Same Disease. AB - Different eponyms such as "Wood syndrome," Meige syndrome, "Brueghel syndrome," "Blepharospasm plus syndrome" have been used to describe segmental craniocervical dystonias. These facial and/or oromandibular movement disorders are characterized by muscle contractions and spasms involving eyes, facial region, and sometimes pharynx, jaw, floor of the mouth, and tongue. The pathophysiology of craniocervical dystonia is poorly understood, but abnormal plasticity and impaired inhibition are suspected. Injection of botulinum toxin appears to be the best therapeutic option for treating segmental craniocervical dystonia. The objective of this chapter is to depict the history of segmental craniocervical dystonia in order to delineate the phenotypic spectrum of the disorders and to distinguish this entity from other facial and/or oromandibular movement disorders. PMID- 29145189 TI - REM Sleep Behavior Disorder. AB - Rapid eye movement sleep behavior disorder (RBD) is a brain disorder, characterized by the dream enactment during rapid eye movement (REM) sleep due to a lack of physiologic muscle atonia and increased muscle twitching. Schenk was the first to describe this disorder in 1986; however, few authors reported in the 1970-1980s loss of physiological muscle atonia combined with dream enactment in the course of brainstem disorders and as a consequence of alcoholism and antidepressant treatment. RBD affects less than 1% of the adult population, but can be found in up to 25-50% of neurodegenerative disorders including Parkinson's disease, multisystem atrophy, and dementia with Lewy body. In the last decade, many studies provided evidence that RBD precedes parkinsonian motor signs by several years, suggesting that RBD should no longer be considered a complication but a part of the prodromal phase of these diseases. Etiologically, primary (idiopathic RBD) and several secondary forms in addition to neurodegeneration (related to focal brainstem damage, narcolepsy, autoimmune disorders, and drugs) are known. Pathophysiologically, brainstem and supratentorial mechanisms involving glutamatergic, glycinergic, and GABA-ergic neurotransmission have been implicated. Recently, an animal model of RBD has been described. Clinical features consist of characteristic nocturnal behaviors, but also daytime symptoms including excessive sleepiness and cognitive alterations. The diagnosis of RBD is made according to international diagnostic criteria, based on medical history, and video-polysomnographic features. Current treatment strategies include actions which ensure a safe sleep environment, the avoidance of triggering/exacerbating factors and if necessary pharmacological (mainly clonazepam and melatonin) and non-pharmacological (e.g., behavioral measures) interventions. Future research should clarify the exact sleep-wake characteristics of RBD (also beyond REM sleep) and their evolution over time, the contribution of brainstem but also supratentorial mechanisms to its pathophysiology, and the (early?) diagnostic and (causative?) treatment consequences of RBD in the context of neurodegeneration. PMID- 29145190 TI - Charles Bonnet Syndrome and Other Hallucinatory Phenomena. AB - Descriptions of hallucinatory phenomena have figured prominently since the beginning of recorded history. Jean Etienne Esquirol (1772-1840) is usually credited for having introduced the term in 1817, differentiating between hallucinations and illusions. Both are wrong perceptions, but in illusions, an external stimulus is always present whereas hallucinations are perceptions that occur in the absence of corresponding sensory stimuli. They occur in a variety of conditions but more often in the mentally ill, especially in schizophrenia where hallucinations, particularly auditory hallucinations represent for many, such as Henri Ey one of the cardinal features. This chapter, however, deals with visual hallucinations as found in individuals who are not necessarily mentally ill: the Charles Bonnet syndrome and autoscopy. PMID- 29145191 TI - Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species. AB - Reactive oxygen species (ROS) are produced by living cells as normal cellular metabolic byproduct. Under excessive stress conditions, cells will produce numerous ROS, and the living organisms eventually evolve series of response mechanisms to adapt to the ROS exposure as well as utilize it as the signaling molecules. ROS molecules would trigger oxidative stress in a feedback mechanism involving many biological processes, such as apoptosis, necrosis and autophagy. Growing evidences have suggested that ROS play a critical role as the signaling molecules throughout the entire cell death pathway. Overwhelming production of ROS can destroy organelles structure and bio-molecules, which lead to inflammatory response that is a known underpinning mechanism for the development of diabetes and cancer. Cytochrome P450 enzymes (CYP) are regarded as the markers of oxidative stress, can transform toxic metabolites into ROS, such as superoxide anion, hydrogen peroxide and hydroxyl radical which might cause injury of cells. Accordingly, cells have evolved a balanced system to neutralize the extra ROS, namely antioxidant systems that consist of enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidases (GPxs), thioredoxin (Trx) as well as the non-enzymatic antioxidants which collectively reduce oxidative state. Herein, we review the recent novel findings of cellular processes induced by ROS, and summarize the roles of cellular endogenous antioxidant systems as well as natural anti-oxidative compounds in several human diseases caused by ROS in order to illustrate the vital role of antioxidants in prevention against oxidative stress. PMID- 29145192 TI - Did the DSM-5 Improve the Traumatic Stressor Criterion?: Association of DSM-IV and DSM-5 Criterion A with Posttraumatic Stress Disorder Symptoms. AB - OBJECTIVE: A recent meta-analysis found that DSM-III- and DSM-IV-defined traumas were associated with only slightly higher posttraumatic stress disorder (PTSD) symptoms than nontraumatic stressors. The current study is the first to examine whether DSM-5-defined traumas were associated with higher levels of PTSD than DSM IV-defined traumas. Further, we examined theoretically relevant event characteristics to determine whether characteristics other than those outlined in the DSM could predict PTSD symptoms. METHOD: One hundred six women who had experienced a trauma or significant stressor completed questionnaires assessing PTSD, depression, impairment, and event characteristics. Events were rated for whether they qualified as DSM-IV and DSM-5 trauma. RESULTS: There were no significant differences between DSM-IV-defined traumas and stressors. For DSM-5, effect sizes were slightly larger but still nonsignificant (except for significantly higher hyperarousal following traumas vs. stressors). Self-reported fear for one's life significantly predicted PTSD symptoms. CONCLUSIONS: Our results indicate that the current DSM-5 definition of trauma, although a slight improvement from DSM-IV, is not highly predictive of who develops PTSD symptoms. Our study also indicates the importance of individual perception of life threat in the prediction of PTSD. PMID- 29145193 TI - Huaier Extract Inhibits Breast Cancer Progression Through a LncRNA-H19/MiR-675-5p Pathway. AB - BACKGROUND/AIMS: Increasing evidence indicates that Huaier extract has promising therapeutic effects against cancer. However, the mechanisms that underlie its anti-tumor effects remain unclear. In recent years, various studies have shown that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cancer development and progression. Here, we explored the role of lncRNAs in Huaier-induced tumor suppression. METHODS: Microarray profiling was performed to identify the candidate lncRNAs affected by Huaier extract. Quantitative realtime PCR (qPCR) was used to evaluate the transfection efficiency and the influence of Huaier extract on H19 expression. The effect of Huaier extract on the cell viability was examined by MTT. Moreover, the rates of apoptotic cells were detected using flow-cytometric analysis. Western blot analysis was applied to show the protein levels of CBL. RESULTS: Microarray data derived from Huaier treated breast cancer cells identified H19 as a potential target. Huaier extract reduced the expression of H19. The over-expression of H19 inhibited the cytotoxic effects of Huaier extract; in contrast, reduced H19 expression enhanced the function of Huaier extract. MiR-675-5p was identified as a mature product of H19. Moreover, Huaier extract reduced the miR-675-5p expression. Upregulating miR-675 5p reversed the inhibitory effects of Huaier extract, whereas downregulating miR 675-5p sensitized breast cancer cells to the effect of Huaier extract. In addition, Huaier extract increased the expression of CBL protein, a direct target of miR-675-5p. CONCLUSION: Collectively, the data demonstrate that Huaier extract reduces viability and induces apoptosis in breast cancer cells via H19-miR-675-5p CBL axis regulation. PMID- 29145194 TI - Deficiency of Functional Iron-Sulfur Domains in ABCE1 Inhibits the Proliferation and Migration of Lung Adenocarcinomas By Regulating the Biogenesis of Beta-Actin In Vitro. AB - BACKGROUND/AIMS: ATP-binding cassette transporter E1 (ABCE1), a unique ABC superfamily member that bears two Fe-S clusters, is essential for metastatic progression in lung cancer. Fe-S clusters within ABCE1 are crucial for ribosome dissociation and translation reinitiation; however, whether these clusters promote tumor proliferation and migration is unclear. METHODS: The interaction between ABCE1 and beta-actin was confirmed using GST pull-down. The lung adenocarcinoma (LUAD) cell line A549 was transduced with lentiviral packaging vectors overexpressing either wild-type ABCE1 or ABCE1 with Fe-S cluster deletions (DeltaABCE1). The role of Fe-S clusters in the viability and migration of cancer cells was evaluated using clonogenic, MTT, Transwell and wound healing assays. Cytoskeletal rearrangement was determined using immunofluorescent techniques. RESULTS: Fe-S clusters were the key domains in ABCE1 involved in binding to beta-actin. The proliferative and migratory capacity increased in cells overexpressing ABCE1. However, the absence of Fe-S clusters reversed these effects. A549 cells overexpressing ABCE1 exhibited irregular morphology and increased levels of cytoskeletal polymerization as indicated by the immunofluorescence images. In contrast, cells expressing the Fe-S cluster deletion mutant presented opposing effects. CONCLUSION: These results demonstrate the indispensable role of Fe-S clusters when ABCE1 participates in the proliferation and migration of LUADs by interacting with beta-actin. The Fe-S clusters of ABCE1 may be potential targets for the prevention of lung cancer metastasis. PMID- 29145195 TI - Contemporary Epidemiology of Transient Ischemic Attack in Dijon, France (2013 2015). AB - BACKGROUND: We aimed to evaluate the epidemiological features of transient ischemic attack (TIA). METHODS: All TIAs were prospectively collected in Dijon, France, using a population-based registry (2013-2015). TIAs were considered the first-ever in patients who had no previous cerebrovascular events (CVEs); otherwise they were considered recurrent TIAs. Annual incidence (first-ever TIAs) and attack rates (first-ever and recurrent TIAs) were calculated. RESULTS: Four hundred twenty TIAs were registered (255 first-ever and 165 recurrent TIAs, mean age: 74.1 +/- 15.7 years). The age-standardized incidence rate (to the 2013 European population) was 61 (95% CI 46-76) and the attack rate was 81 (95% CI 64 99) per 100,000/year. Patients with TIA as a recurrent event had a greater prevalence of risk factors and preventive treatments. However, one third of them were not receiving antithrombotic agents or antihypertensive treatments, and half were not treated with statins at the time of their recurrence. The mean ABCD2 score was 4.3 +/- 1.3, and 72% of patients had a high risk of recurrence (score >=4). In patients with available MRI (23%), an infarct lesion was seen in 15.5%. CONCLUSIONS: TIA is a frequent occurrence and a large proportion of patients have a high risk of recurrence, thus highlighting the need to establish dedicated emergency services to administer prompt secondary prevention. PMID- 29145196 TI - AQP2 Abundance is Regulated by the E3-Ligase CHIP Via HSP70. AB - BACKGROUND/AIMS: AQP2 expression is mainly controlled by vasopressin-dependent changes in protein abundance which is in turn regulated by AQP2 ubiquitylation and degradation, however the proteins involved in these processes are largely unknown. Here, we investigated the potential role of the CHIP E3 ligase in AQP2 regulation. METHODS: MCD4 cells and kidney slices were used to study the involvement of the E3 ligase CHIP on AQP2 protein abundance by cell homogenization and immunoprecipitation followed by immunoblotting. RESULTS: We found that AQP2 complexes with CHIP in renal tissue. Expression of CHIP increased proteasomal degradation of AQP2 and HSP70 abundance, a molecular signature of HSP90 inhibition. Increased HSP70 level, secondary to CHIP expression, promoted ERK signaling resulting in increased AQP2 phosphorylation at S261. Phosphorylation of AQP2 at S256 and T269 were instead downregulated. Next, we investigated HSP70 interaction with AQP2, which is important for endocytosis. Compared with AQP2-wt, HSP70 binding decreased in AQP2-S256D and AQP2-S256D S261D, while increased in AQP2-S256D-S261A. Surprisingly, expression of CHIP delUbox, displaying a loss of E3 ligase activity, still induced AQP2 degradation, indicating that CHIP does not ubiquitylate and degrade AQP2 itself. Conversely, the AQP2 half-life was increased upon the expression of CHIP-delTPR a domain which binds Hsc70/HSP70 and HSP90. HSP70 has been reported to bind other E3 ligases such as MDM2. Notably, we found that co-expression of CHIP and MDM2 increased AQP2 degradation, whereas co-expression of CHIP with MDM2-delRING, an inactive form of MDM2, impaired AQP2 degradation. CONCLUSION: Our findings indicate CHIP as a master regulator of AQP2 degradation via HSP70 that has dual functions: (1) as chaperone for AQP2 and (2) as an anchoring protein for MDM2 E3 ligase, which is likely to be involved in AQP2 degradation. PMID- 29145197 TI - Inflammatory and Angiogenic Factors Linked to Longitudinal Microvascular Changes in Hemodialysis Patients Irrespective of Treatment Dose Intensity. AB - BACKGROUND: Cardiovascular disease is a major contributor to the poor outcomes observed in hemodialysis. We investigated the relationship between hemodialysis intensity and vascular parameters in high-dose (HDHD; >12hrs/week) and Conventional (CHD; <=12hrs/week) hemodialysis intensity over a 6-month period. METHODS: We present the 6-month longitudinal analysis of a 2-year multicenter study investigating the effects of HDHD on cardiovascular parameters. We used pulse wave velocity, 24hr ambulatory blood pressure and sublingual dark field capillaroscopy measurements to assess macro- and microcirculation on 6-monthly basis. Pro-inflammatory and endothelial biomarkers were also measured at 6 monthly intervals. RESULTS: 47 participants (21 HDHD, 26 CHD) were studied. CHD were older (63.5+/-14.2 vs 53.7+/-12.6 yr; p=0.018), with shorter dialysis vintage (median 23 vs 61 months; p=0.001). There was considerable variability in the degree and direction of change of circulatory measurements over a 6-month period. Hemodialysis intensity (hrs/week) did not correlate to these changes, when adjusted for age, dialysis vintage and comorbidity. Higher levels of Interleukin (IL)-8 measured at baseline independently predicted an increase in the Perfused Boundary Region (5-25MUm) of the endothelial glycocalyx (p=0.010) whilst higher levels of soluble Flt-1 had a significant inverse effect (p=0.002) in an adjusted linear model. CONCLUSION: Hemodialysis intensity did not predict changes in either macro- or microvascular parameters. Inflammation mediated through the IL-8 pathway predicted microvascular injury while Flt-1, a potential marker of angiogenesis and endothelial repair, might have a significant protective role. Further understanding of these pathways will be necessary to improve dialysis outcomes. PMID- 29145198 TI - Heavy Alcohol Consumption Effects on Blood Pressure and on Kidney Structure Persist After Long-Term Withdrawal. AB - BACKGROUND/AIMS: Heavy ethanol consumption is a risk factor for hypertension and prompts organ damage. There is no information regarding the impact of long-term heavy ethanol consumption on kidney structure and function linking to their hypertensive effects nor the repercussions after withdrawal. METHODS: Rats were exposed to ethanol for 24 weeks and, afterwards, a group was assigned to withdrawal for 8 weeks. Blood pressure (BP) was measured and serum biochemical parameters were quantified. Glomerular volume density, areal density of glomerular tuft and renal corpuscles were determined. Angiotensin II type 1 receptor (AT1R) protein expression was evaluated. RESULTS: Twenty-four weeks of ethanol consumption causes atrophy of renal corpuscles and glomeruli and reduces the volume of glomeruli. Glomerular changes induced by ethanol consumption were still evident after withdrawal. Renal AT1R levels were increased in ethanol treated rats and returned to control levels during withdrawal. Ethanol consumption also induced an increase in BP, uric acid and albumin levels. Upon withdrawal, systolic and mean arterial pressures decreased, but were still higher than in controls rats. CONCLUSION: Ethanol consumption induces changes in glomerular morphology associated with increased BP and AT1R expression. Long-term withdrawal was inefficient to restore the structural integrity of renal corpuscles and in lowering systolic pressure. PMID- 29145199 TI - High Fracture Rates in Young Patients with Phenylketonuria. PMID- 29145200 TI - The Role of Copy Number Variants in Disorders of Sex Development. AB - Despite considerable research effort and significant advances in sequencing technologies, the majority of disorders of sex development (DSD) cases still lack a molecular genetic diagnosis. While coding variants have been discovered in known and candidate DSD genes, comparatively little is known about copy number variations (CNVs) affecting both coding and noncoding regions. Due to rapidly falling costs of whole genome sequencing, many more CNVs in individuals with DSD will be identified. These CNVs may explain a significant number of hitherto undiagnosed cases of DSD. In this review, we provide an overview of CNVs that are known to cause DSD and discuss approaches to identify and verify causative CNVs. PMID- 29145201 TI - Dietary Fructo-Oligosaccharides Attenuate Early Activation of CD4+ T Cells Which Produce both Th1 and Th2 Cytokines in the Intestinal Lymphoid Tissues of a Murine Food Allergy Model. AB - BACKGROUND: Fructo-oligosaccharides (FOS) are prebiotic agents with immunomodulatory effects involving improvement of the intestinal microbiota and metabolome. In this study, we investigated the cellular mechanisms through which FOS modulate intestinal antigen-specific CD4+ T cell responses in food allergy, using OVA23-3 mice. METHODS: OVA23-3 mice were fed an experimental diet containing either ovalbumin (OVA) or OVA and FOS for 1 week. Body weight and mucosal mast cell protease 1 in the serum were measured as the indicator of intestinal inflammation. Single-cell suspensions were prepared from intestinal and systemic lymphoid tissues for cellular analysis. Cytokine production was measured by ELISA. Activation markers and intracellular cytokines in CD4+ T cells were analyzed by flow cytometry. Activated CD4+ T cells were purified to examine cytokine production. RESULTS: Dietary intake of FOS provided moderate protection from the intestinal inflammation induced by the OVA-containing diet. FOS significantly reduced food allergy-induced Th2 cytokine responses in intestinal tissues but not in systemic tissues. FOS decreased OVA diet-induced IFN-gamma+IL 4+ double-positive CD4+ T cells and early-activated CD45RBhighCD69+CD4+ T cells in the mesenteric lymph nodes. Furthermore, we confirmed that these CD45RBhighCD69+CD4+ T cells are able to produce high levels of IFN-gamma and moderate level of IL-4, IL-10, and IL-13. CONCLUSIONS: Dietary intake of FOS during the development of food allergy attenuates the induction of intestinal Th2 cytokine responses by regulating early activation of naive CD4+ T cells, which produce both Th1 and Th2 cytokines. Our results suggest FOS might be a potential food agent for the prevention of food allergy by modulating oral sensitization to food antigens. PMID- 29145202 TI - Exploring the Association between Statin Use and the Risk of Parkinson's Disease: A Meta-Analysis of Observational Studies. AB - BACKGROUND: Parkinson's disease (PD) is a progressive disorder of the central nervous system. The prevalence of PD varies considerably by age group; it has a higher prevalence in patients aged 60 years and more. Several studies have shown that statin, a cholesterol-lowering medication, reduces the risk of developing PD, but evidence for this is so far inconclusive. The objective of this study is to evaluate the association between statin use and the risk of developing PD. METHODS: PubMed, EMBASE, and the bibliographies of articles were searched for studies published between January 1, 1990, and January 1, 2017, which reported on the association between statin use and PD. Articles were included if they (1) were published in English, (2) reported patients treated with statin, and the outcome of interest was PD, (3) provided OR/HR with 95% CI or sufficient information to calculate the 95% CI. All abstracts, full-text articles, and sources were reviewed, with duplicate data excluded. Summary relative risk (RRs) with 95% CI was pooled using a random-effects model. Subgroup and sensitivity analyses were also conducted. RESULTS: We selected 16 out of 529 unique abstracts for full-text review using our selection criteria, and 13 out of these 16 studies, comprising 4,877,059 persons, met all of our inclusion criteria. The overall pooled RR of PD was 0.70 (95% CI 0.58-0.84) with significant heterogeneity between estimates (I2 = 93.41%, p = 0.000) for the random-effects model. In subgroup analysis, the greater decreased risk was found in studies from Asia (RR 0.62 95% CI 0.51-0.76), whereas a moderate reduction was observed in studies from North America (RR 0.69 95% CI 0.47-1.00), but less reduction was observed in studies from Europe (RR 0.86 95% CI 0.80-0.92). Also, long-term statin use, simvastatin, and atorvastatin showed a higher rate of reduction with significance heterogeneity. CONCLUSION: Our results showed that statin use is significantly associated with a lower risk of developing PD. Physicians should consider statin drug therapy, monitor its outcomes, and empower their patients to improve their knowledge, therapeutic outcomes, and quality of life. However, preventive measures and their associated mechanisms must be further assessed and explored. PMID- 29145203 TI - Evaluation of Mental Disorders Using Proton Magnetic Resonance Spectroscopy in Dialysis and Predialysis Patients. AB - BACKGROUND/AIMS: Psychological complications are prevalent in patients with chronic kidney disease (CKD). This study aimed to investigate mental disorders in stage 4-5 CKD patients, to detect metabolite concentrations in the brain by proton magnetic resonance spectroscopy (1H-MRS) and to compare the effects of different dialysis therapies on mental disorders in end-stage renal disease (ESRD). METHODS: The sample population was made up of predialysis (13), hemodialysis (HD) (13), and peritoneal dialysis (PD) patients (12). We collected the baseline data of patients' age, sex, hemoglobin (Hb) and parathyroid hormone(PTH) levels. The predialysis patients served as the control group. The psychological status of the three groups was assessed using three psychological scales. 1H-MRS was used to evaluate the relative metabolite concentrations in the bilateral amygdala, hippocampus and unilateral anterior cingulated cortex (ACC). RESULTS: The psychological status was better in HD patients than in predialysis and PD patients. 1H-MRS alterations were predominantly found in the ACC. Choline containing compounds relative to creatine (Cho/Cr), myo-inositol relative to creatine (MI/Cr) and glutamate and glutamine relative to creatine (Glx/Cr) in the ACC were higher in HD patients. 1H-MRS results were correlated with the baseline data and the scores of psychological scales. CONCLUSIONS: CKD patients showed different types of mental disorders as well as metabolite disturbances in the brain. The metabolite concentrations correlated with the psychological status which was better in HD than in predialytic and PD patients. PMID- 29145204 TI - Comparing the Clinical Features and Outcomes of Acute Hepatitis E Viral Infections with Those of Acute Hepatitis A, B, and C Infections in Korea. AB - OBJECTIVES: This study investigated the etiology of acute viral hepatitis and compared the clinical features of hepatitis E virus (HEV) infections with those of other acute viral hepatitis infections in Korea. METHODS: This study included 2,357 consecutive patients who were diagnosed with acute hepatitis, based on acute illness with jaundice or elevated alanine aminotransferase levels (>100 IU/L), between January 2007 and January 2016. Acute viral infections were observed in 23 (19.8%) patients with HEV, 49 (42.2%) patients with hepatitis A virus, 28 (24.1%) patients with hepatitis B virus, and 16 (13.8%) patients with hepatitis C virus. RESULTS: The incidence of acute HEV infection was higher among older patients (median age: 49 years) and male patients (69.6%), and was associated with the consumption of undercooked or uncooked meat (43.5%). Half of the acute HEV infections involved underlying liver disease, such as alcoholic liver disease, chronic hepatitis B, common bile duct stones, and autoimmune hepatitis. Two HEV-infected patients were diagnosed with Guillain-Barre syndrome, although no patients developed fulminant hepatitis. CONCLUSION: Our findings indicate that HEV infection in Korea is frequently transmitted through the consumption of raw meat and may cause acute or chronic liver disease. PMID- 29145205 TI - Decline in Search Speed and Verbal Memory Over 26 Years of Midlife in a British Birth Cohort. AB - BACKGROUND: Cognitive capabilities change in later life, although their onset and rate of decline, and how they are shaped by lifetime socioeconomic position, childhood cognition and adult health status are all unclear. METHODS: From the Medical Research Council National Survey of Health and Development, we analysed 3,192 participants undergoing one or more cognitive assessments at ages 43, 53, 60-64 and 69. Linear mixed models described cognitive trajectories, adjusting for factors across the life course. RESULTS: For both search speed and verbal memory, better performance at age 43 (the intercept) was associated with higher paternal and own education, childhood cognition, and adult occupational class. For search speed, the trajectory was best described as a quadratic function (decline of 45.6 letters/5-years + 4.6 letters). Verbal memory showed a linear decline of 0.20 words/5-years between ages 43 and 60 and a steeper linear decline of 0.95 words/5 years between ages 60 and 69. Decline in verbal memory in the latter period was steeper in those with higher educational achievements at age 26 (additional 0.28 words/5-years for highest attainment). CONCLUSIONS: Decline in verbal memory and search speed across midlife is evident, though with different non-linear trajectories. By implication, pathways to cognitive impairment and dementia in older age may have their origins in this period. PMID- 29145206 TI - MicroRNA Expression Profiling of Pancreatic Cancer Cell Line L3.6p1 Following B7 H4 Knockdown. AB - BACKGROUND/AIMS: Co-stimulating molecule B7-H4 regulates T cell-mediated immune responses, participates in tumor immune escape, and promotes the proliferation and metastasis of pancreatic cancer cells. However, the specific mechanisms are unclear. MicroRNAs (miRNAs) participated in the pathogenesis and progression of cancer. METHODS: In this study, a microarray technique was used to screen B7-H4 related differentially expressed miRNAs in a pancreatic cancer cell line find those associated with pancreatic cancer. Using a miRCURYTM LNA Array approach, we compared the miRNA expression profiles of L3.6p1 pancreatic cancer cells transfected with B7-H4 siRNA for 72 h with those transfected with non-target siRNAs. RESULTS: B7-H4 siRNA significantly up-regulated 57 miRNAs and down regulated 14 miRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analysis of predicted miRNA targets showed that these genes were mainly involved in protein binding, pathways in cancer, mitogen activated protein kinase (MAPK) signaling pathway, and phosphatidylinositol 3 kinase-Akt (PI3K-Akt) signaling pathway. CONCLUSIONS: This is the first description of target genes of B7-H4, showing that miRNAs participate in the B7 H4 mediated regulation of oncogenicity and pathogenesis of pancreatic cancer. These results may help us better understand the role of B7-H4 in the progression of pancreatic cancer and its possible mechanisms. We also provide novel biomarkers for potential treatments of pancreatic cancer. PMID- 29145207 TI - Determinants, Prevalence, and Trajectory of Long-Term Post-Stroke Cognitive Impairment: Results from a 4-Year Follow-Up of the ARCOS-IV Study. AB - BACKGROUND: The long-term (>12 months) prevalence, predictors, and trajectory of post-stroke cognitive deficits are not well established, especially at a community level. This study investigated the longitudinal course and prevalence of cognitive impairment in an incidence cohort, identifying factors associated with declining cognition. METHODS: Two hundred fifty-seven participants (mean age = 67.93 +/- 13.59) of first-ever stroke survivors, completed cognitive assessments within 2 weeks post stroke, and/or 1, 6, 12, and 48-month. Multivariate linear and logistic models were used to identify baseline predictors (reported as OR with 95% CI) and trajectory of cognitive impairment. RESULTS: Cognitive functioning significantly declined by 2.8 points by 4 years post stroke. Eighty-four percent of stroke survivors had cognitive impairment indicative of post-stroke dementia (mean Montreal cognitive assessment = 20 +/- 4.7) at 4-year. There were significant as-sociations between progressive cognitive decline and the -following factors: male gender (OR 2.9, 95% CI 1.6 5.9, -p = 0.0171), coronary artery disease (OR 2.96, 95% CI 1.35-6.49, p = 0.0070), arrhythmia (OR 2.21, 95% CI 1.07-4.57, p = 0.0317), not in a relationship (OR 2.8, 95% CI 1.4-5.50, p < 0.0001), and not employed (OR 4.9, 95% CI 1.9-12.1, p < 0.0001). CONCLUSIONS: Cognitive deficits remain highly prevalent at 4-year post stroke. Early identification of those at higher risk of declining cognition is vital to target rehabilitation interventions at the acute stage and improve overall outcomes. PMID- 29145209 TI - Methodological Issues for Psychological Evaluation across the Lifespan of Individuals with a Difference/Disorder of Sex Development. AB - The aim of the current report is to provide guidance relevant to psychological evaluation for healthcare providers and researchers working in the field of disorders of sexual development (DSD). In doing so, we give careful consideration to methodological issues and limitations that may influence the utility of investigations. For example, rarity and heterogeneity of DSD conditions restrict sample sizes when conducting evaluations aimed at establishing condition-specific psychological outcomes. At the same time, the potential for stigmatization by virtue of conducting psychological evaluations is particularly high given the fundamental contribution of sex and gender to one's sense of self and integrity. This article will provide basic theory for psychological evaluation as well as give a review of specific measures that can be employed for clinical purposes depending on a variety of parameters, including life stage of the patient and goal(s) of the evaluation. Care providers and service users may benefit from guidance in coping with the difficulties inherent in having and/or treating DSD. The potential for identification with the patient with DSD is higher than in other domains of medicine because sexual and gender identities are fundamental to all humans and are continually evolving from a sociological perspective. PMID- 29145208 TI - Curcumin Delays Retinal Degeneration by Regulating Microglia Activation in the Retina of rd1 Mice. AB - BACKGROUND/AIMS: Retinitis pigmentosa (RP) is characterized by degeneration of photoreceptors, and there are currently no effective treatments for this disease. However, curcumin has shown neuroprotectant efficacy in a RP rat and swine model, and thus, may have neuroprotective effects in this disease. METHODS: Immunofluorescence staining, electroretinogram recordings, and behavioral tests were used to analyze the effects of curcumin and the underlying mechanism in retinal degeneration 1 (rd1) mice. RESULTS: The number of apoptotic cells in the retina of rd1 mice at postnatal day 14 significantly decreased with curcumin treatment and visual function was improved. The activation of microglia and secretion of chemokines and matrix metalloproteinases in the retina were inhibited by curcumin. These effects were also observed in a co-culture of BV2 microglial cells and retina-derived 661W cells. CONCLUSIONS: Curcumin delayed retinal degeneration by suppressing microglia activation in the retina of rd1 mice. Thus, it may be an effective treatment for neurodegenerative disorders such as RP. PMID- 29145210 TI - Diphthamide Biosynthesis 1 is a Novel Oncogene in Colorectal Cancer Cells and is Regulated by MiR-218-5p. AB - BACKGROUND/AIMS: This study focused on the oncogenic role of Diphthamide biosynthesis 1 (DPH1) in colorectal cancer (CRC) cells. METHODS: The expression of DPH1 was determined by quantitative RT-PCR analysis and western blotting in CRC tissues. The role of DPH1 in CRC cells was investigated via cell viability and invasion assays under the condition of DPH1 silencing or overexpression. Bioinformatics analysis and luciferase reporter analysis were used to identify the upstream microRNA which might regulate DPH1.The inverse correlation between the microRNA and DPH1 was also detected in CRC cells. RESULTS: We identified an unexpected role for DPH1 as an oncogene in CRC cells. The tumour-suppressive miR 218-5p regulates DPH1 directly and negatively. Loss of miR-218-5p drives the oncogenic role of DPH1 in CRC cells. CONCLUSION: The modulation of DPH1 by miR 218-5p may be an important regulatory axis during CRCtumourigenesis. PMID- 29145212 TI - Does Anaemia Have Major Public Health Importance in Children Aged 6-59 Months in the Duggina Fanigo District of Wolaita Zone, Southern Ethiopia? AB - BACKGROUND: Globally, a large number of children aged 6-59 months are affected by anaemia. In Ethiopia, like other developing countries, more than 40% of children under 5 years are affected by anaemia. Anaemia during infancy and childhood period is associated with poor health and impaired cognitive development, leading to reduced academic achievement and earning potential in their adult life. The aim of this research was to assess whether anaemia remained a major public health problem among children aged 6-59 months or not in Duggina Fanigo District of Wolaita Zone, South Ethiopia in 2016. METHODOLOGY: A community-based cross sectional study was conducted from February to March 2016, on 404 mothers with children aged 6-59 months who were selected through the systematic sampling method. Socio-demographic and other data on associated factors was collected using a pre-tested questionnaire. Capillary blood was taken from the fingertip of each child and hemoglobin was measured using Haemo-Cue digital photometer. All the necessary safety measures were taken during blood collection. Data analysis was made using SPSS version 21. Multivariable logistic regression analysis was used to assess the association of independent variables with outcome variables and to control the possible confounding factors. RESULT: The overall prevalence of anaemia was 51.4%. Anaemia was common among young children as compared to older children. After controlling the effect of confounding and adjusting for age, gender and altitude, explanatory variables like low dietary diversity (AOR = 3.24; 95% CI [1.68-6.23]), food insecurity (AOR = 3.63; 95% CI [2.18-6.04]), stunting (AOR = 2.60; 95% CI [1.56-4.35]), underweight (AOR = 2.46; 95% CI [1.29 4.67]) and fever within 2 weeks (AOR = 2.49; 95% CI [1.29-4.81]) prior to the survey were significantly associated with anaemia. In conclusion, the overall prevalence of anaemia among children aged 6-59 months has remained a major public health importance in the study area. Integrated efforts need to be prioritized to improve the health as well as the nutritional status of children aged 6-59 months through appropriate feeding practices in infants and children. PMID- 29145211 TI - Patient-Reported Outcome Results from the Open-Label Randomized Phase III SELECT BC Trial Evaluating First-Line S-1 Therapy for Metastatic Breast Cancer. AB - OBJECTIVE: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial. METHODS: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis. RESULTS: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness. CONCLUSION: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients. PMID- 29145213 TI - Depressed Immune Responses and Accelerated Splenic Apoptosis due to Experience of Food Deprivation and Inequality but not Unstable Social Status in Balb/c Mice. AB - OBJECTIVE(S): We aimed to show that the immune system is sensitive to the detrimental effects of inequality and social injustice, and splenic vulnerability to apoptosis may also increase. METHODS: In order of better determination of immune responses to chronic social stress, we implemented food deprivation, food intake inequality, and unstable social status (a change of cage-mate every 3 days) for a period of 14 days in 60 male Balb/c mice. At the end of this stress period, nitric oxide (NO) production by peritoneal adherent cells and the serum concentration of corticosterone were measured. Moreover, the viability of peritoneal adherent cells and spleen lymphocytes was evaluated by MTT assay. The terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was done to reveal the TUNEL-reactive apoptotic bodies in the spleen. RESULTS: Our results showed that food deprivation and inequality caused significant changes in the apoptosis of splenic cells in comparison with the control group (p < 0.05). Moreover, the vital activities of lymphocytes and peritoneal adherent cells, as well as NO production by the latter, increased significantly (p < 0.05). However, the experience of unstable social status did not cause a further increase in the viability of lymphocytes and peritoneal adherent cells, or NO production in animals that were food-deprived or experienced inequality. Serum concentration of corticosterone in all experimental groups, except for animals that experienced unstable social status only, significantly decreased versus the control group (p < 0.05). CONCLUSIONS: The results suggest that poverty and social inequality, but not unstable social status, affect immune responses and are likely involved in the induction of splenic apoptosis in mice. PMID- 29145215 TI - Comparison of Efficacy and Safety of Liraglutide 3.0 mg in Individuals with BMI above and below 35 kg/m2: A Post-hoc Analysis. AB - OBJECTIVE: To investigate whether the efficacy and safety of liraglutide 3.0 mg differed between two subgroups, BMI 27 to <35 and BMI >= 35 kg/m2, in individuals without and with type 2 diabetes (T2D). METHODS: A post-hoc analysis of two 56 week, randomized, double-blind, placebo-controlled trials (SCALE Obesity and Prediabetes; SCALE Diabetes). Subgroup differences in treatment effects of liraglutide 3.0 mg were evaluated by testing the interaction between treatment group and baseline BMI subgroup. RESULTS: Significantly greater weight loss (0-56 weeks) was observed with liraglutide 3.0 mg versus placebo in all patient groups while on treatment. There was no evidence that the weight-lowering effect of liraglutide 3.0 mg differed between BMI subgroups (interaction p > 0.05). Similarly, for most secondary endpoints significantly greater improvements were observed with liraglutide 3.0 mg versus placebo, with no indication treatment effects differing between subgroups. The safety profile of liraglutide 3.0 mg was broadly similar across BMI subgroups. CONCLUSION: This post-hoc analysis did not indicate any differences in the treatment effects, or safety profile, of liraglutide 3.0 mg for individuals with BMI 27 to <35 or >=35 kg/m2. Liraglutide 3.0 mg can therefore be considered for individuals with a BMI of >=35 as well as for those with a BMI of 27 to <35 kg/m2. PMID- 29145216 TI - Comparison of Warfarin use in terms of efficacy and safety in two different polyclinics. AB - OBJECTIVE: This study compared the efficacy and safety of warfarin in specialized international normalized ratio (INR) outpatient clinic (INR-C) and in general cardiology outpatient clinic (General-C). METHODS: Herein, 381 consecutive patients with a regular follow-up at INR-C (n=233) or General-C (n=148) for at least 1 year were retrospectively included. While INR-C patients were followed by a single experienced trained nurse, General-C patients were followed by a different cardiologist who worked in a rotational principle every month. During controls, demographic characteristics, INR levels, bleeding events, ischemic stroke, and transient ischemic attacks in the last 1 year were recorded. Primary endpoint was defined as the evaluation of the combined major bleeding and ischemic event, and secondary endpoint was defined as the evaluation of them separately. RESULTS: The mean age of the patients was 62+/-12.86 and 43.8% were male. Mean time in therapeutic range (TTR) level was statistically higher in INR C than that in General-C (68.8%+/-15.88 and 51.6%+/-23.04, respectively; p<0.001). Primary outcomes were significantly higher in General-C than that in INR-C [13.5% (20) and 6.4% (15); respectively, p=0.020]. Overall, major bleeding was observed in 25 patients (6.5%) and (2.6%) ischemic event was observed in 10 patients. In General-C patients, both major bleeding (8.8% vs. 5.2%; p=0.163) and the ischemic event (4.7% vs. 1.3%; p=0.051) were more, and no statistically significant differences were detected between the two clinics. CONCLUSION: The findings of our study demonstrate that patients followed in INR-C had higher TTR levels and lower bleeding and ischemic events rates that those followed in General-C. PMID- 29145217 TI - Association of female sex and heart rate with increased arterial stiffness in patients with type 2 diabetes mellitus. AB - OBJECTIVE: This study aimed to evaluate the factors associated with increased arterial stiffness (IAS) measured by pulse wave velocity (PWV) and its clinical implications in patients with type 2 diabetes mellitus (DM). METHODS: This was an observational, cross-sectional study. The ankle-brachial PWV was used to measure arterial stiffness, and 310 patients (mean age, 49+/-9 years; 180 men) with type 2 DM were divided into two groups according to the results of PWV: Group 1 (IAS; n=214) and Group 2 (normal arterial stiffness; n=96). RESULTS: Patients in Group 1 were predominantly females (48% vs. 28%, p=0.001) and showed higher blood pressure and faster heart rate (HR). The glomerular filtration rate was lower and the urine microalbumin level was higher in patients with IAS. In multiple regression analysis, female sex and faster HR were independently associated with IAS. In subgroup analysis among female patients, prior stroke was more common in patients with IAS, and faster HR and increased postprandial 2-h C-peptide level were independently associated with IAS. CONCLUSION: Female sex and faster HR were independently associated with IAS in patients with type 2 DM. In a subgroup analysis among female patients, prior stroke was more common in patients with IAS, and faster HR and elevated postprandial 2-h C-peptide level were found to be independently associated with IAS. PMID- 29145218 TI - Endovascular coil treatment of a coronary artery aneurysm related to polyarteritis nodosa. PMID- 29145219 TI - Simple electrocardiographic parameters predicting risk of hypertrophic cardiomyopathy: Too simple? PMID- 29145220 TI - Author's Reply. PMID- 29145221 TI - Who are the main actors of cardiac device follow-up? Analysis of the super follow up study. PMID- 29145222 TI - Author's Reply. PMID- 29145223 TI - Individualized intensified antiplatelet therapy based on platelet reactivity testing reduces the incidence of cardiovascular events in patients undergoing percutaneous coronary intervention. PMID- 29145224 TI - Author's Reply. PMID- 29145225 TI - Usefulness of left atrial speckle-tracking echocardiography in patients with atrial fibrillation. PMID- 29145226 TI - Author's Reply. PMID- 29145227 TI - Ganglionated plexi interactions with atrio-ventricular node and right vagus nerve. PMID- 29145228 TI - Author's Reply. PMID- 29145229 TI - Ibuprofen-induced Kounis syndrome with diffuse ST segment depression and atrial fibrillation. PMID- 29145230 TI - Who is Professor Ilhan Pasaoglu? PMID- 29145231 TI - Right atrial ball thrombus associated with atrial septal occluder device: A late complication of transcatheter atrial septal defect closure. PMID- 29145232 TI - Giant right coronary artery aneurysm mimicking sinus Valsalva aneurysm of the aorta. PMID- 29145234 TI - Scientific competition, impact factor, and Altmetrics. PMID- 29145233 TI - Prospective evaluation of the feasibility, safety, and efficacy of Cocoon Duct Occluder for transcatheter closure of large patent ductus arteriosus: A single center study with short- and medium-term follow-up results. AB - OBJECTIVE: To evaluate the feasibility, safety, and efficacy of a novel Cocoon Duct Occluder device for the transcatheter closure (TCC) of large patent ductus arteriosus (PDA). METHODS: In this prospective, non-randomized study, consecutive patients with large PDA (narrowest diameter: >=3.5/4.0 mm in symptomatic/asymptomatic patients, respectively), who underwent TCC with Cocoon Duct Occluder at our institute between November, 2012 and June, 2016 were examined. TCC was performed using the standard technique, and devices were antegradely delivered via 6-10F delivery sheaths. Device embolization, residual shunt, hemolysis, left pulmonary artery (LPA) stenosis, procedural and fluoroscopy time, and mortality were assessed. Patients were followed-up by transthoracic echocardiography with color Doppler imaging at 24 h (D1), 1 month (D30), and 6 months (D180) after implantation. RESULTS: A total of 57 patients (age: 11.7+/-2.8 years; weight: 22.3+/-3.5 kg) were enrolled. The mean narrowest diameter was 7.4+/-0.7 mm. The PDA closure was successfully performed in each patient. Fluoroscopy and procedural time was 6.7+/-3.2 min and 23.9+/-2.7 min, respectively. Postprocedural angiography revealed that 49 (85.9%) patients had immediate and complete closure, whereas 8 (14.1%) had residual shunt. Color Doppler imaging at D1 revealed complete closure in 52 (91.3%) patients. At D30, complete closure was reported in all patients and was maintained at D180. Hemolysis, embolization, obstruction of LPA or descending aorta, and death were not reported till D180. CONCLUSION: TCC using Cocoon Duct Occluder is feasible, safe, and effective in the management of patients with large PDA, with excellent results on short- and medium-term follow-up. PMID- 29145235 TI - Medicine and cardiology can have a high innovative potential in Turkey. PMID- 29145236 TI - Protection by nitrite against the ischemic effects induced by acute myocardial infarction in mice. AB - OBJECTIVE: This research was aimed to investigate the correct dose of nitrite that would act as a protection against the ischemic effects induced by acute myocardial infarction (AMI). METHODS: Mice were randomly divided into a sham operation group (sham), an AMI operation group (AMI), and a nitrite pretreatment+AMI operation group (N+AMI). Seven days before the AMI operation, mice in the N+AMI group were pretreated with sodium nitrite in drinking water. RESULTS: One week after the AMI operation, serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities in both AMI and N+AMI group were significantly higher than those in the sham group, but there were no significant differences between AMI and N+AMI mice. Contents of inducible nitric oxide synthase (iNOS) in the noninfarct area of the left ventricle in the N+AMI mice were significantly higher than those in the AMI mice, with no difference in the infarct area. Coagulation necrosis in the cardiomyocytes was observed in both AMI and N+AMI mice; however, it was less severe in the N+AMI mice. Western blot analyses showed that nitrite pretreatment resulted in up-regulation of antiapoptotic factors Bcl 2 and p21waf1/cip1 signal proteins, but down-regulation of the proapoptotic factor Bax signal protein. Furthermore, nitrite pretreatment also showed significant alleviation of AMI-induced signal protein expressions of inflammatory factors of NF-K B and oxidative factors of Hsp 70 and HO-1. CONCLUSION: These results suggest that nitrite show certain protective effects against the ischemic effects induced by AMI in mice, which might be attributed to the synthesis of NO induced by iNOS through up-regulation of antiapoptotic factors and down regulation of proapoptotic and inflammatory factors. PMID- 29145237 TI - The impact of the government health funding on prescribing behaviors in community health institutions in China. AB - Government health funding (GHF) is a cosmopolitan problem. It is especially conspicuous in China, where drug sales become a main source of medical institutions' incomes due to limited GHF. This is well known as China's "drug maintain medical institutions (DMMIs)" system which results directly in very high use of antibiotics, injections, and corticosteroids. However, few statistical data existed in China on the association between the GHF and the prevalence of inappropriate drug prescribing, despite widespread acknowledgment of its existence.A multistage sampling strategy was employed to select 442,100 prescriptions written between 2007 and 2011 by urban community health (CH) institutions and check the GHF in 36 key cities (districts) across China. This study examined the association between the GHF and the prevalence of inappropriate drug prescribing, which differs somewhat from previous studies.The data suggested that from 2007 to 2011, with the increase of GHF, prescribing behaviors (PB) gradually improved on the whole although doctors still prescribed a few more drugs than the recommendations from World Health Organization (WHO). This study found that there is significant negative association between GHF and main indicators of PB (correlation coefficients more than 0.5).The findings implied that government should further perfect the compensation mechanism to medical institutions for gradually weakening the compensation function of drug sales in medical institutions. PMID- 29145238 TI - Apatinib in refractory radiation-induced brain edema: A case report. AB - RATIONALE: Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which has observed to be effective and safe in refractory radiation-induced brain edema, like Avastin did. Till now, there is no case report after apatinib came in the market. PATIENT CONCERNS: Two patients who received brain radiotherapy developed clinical manifestations of brain edema, including dizziness, headache, limb activity disorder, and so on. DIAGNOSES: Two patients were both diagnosed as refractory radiation-induced brain edema. INTERVENTIONS: Two patients received apatinib (500 mg/day) for 2 and 4 weeks. OUTCOMES: Two patients got symptomatic improvements from apatinib in different degrees. Magnetic resonance imaging after apatinib treatments showed that compared with pre-treatment imaging, the perilesional edema reduced dramatically. However, the toxicity of apatinib was controllable and tolerable. LESSONS: Apatinib can obviously relieve the symptoms of refractory radiation-induced brain edema and improve the quality of life, which offers a new method for refractory radiation-induced brain edema in clinical practices. But that still warrants further investigation in the prospective study. PMID- 29145239 TI - Two case reports: Colorectal adenocarcinoma in children. AB - RATIONALE: Colorectal cancer in children is rare, with delayed diagnosis and advanced stage at presentation in high mortality. Early detection of colorectal cancer is, therefore, important for better prognosis. PATIENT CONCERNS: Thirteen year-old boy presented with symptoms of melena, vomiting, and abdominal pain for 6 months. 18-year-old girl was hospitalized due to the symptoms of hematochezia, and persistent abdominal pain for 6 months. They have no chronic disease or familial history of malignancy. DIAGNOSES: We encountered 2 teenagers diagnosed with colorectal cancer. INTERVENTIONS: Both patients had the same histological findings in postoperation colonic biopsy and underwent surgical resection. OUTCOMES: The boy fully recovered with only surgery, but the girl died, despite receiving adjuvant chemotherapy for the advanced stage of cancer. LESSONS: We recommend early and active evaluation, including a pediatric colonoscopy, in a child with suspected malignancy. PMID- 29145240 TI - Gastrointestinal stromal tumor (GIST) with liver metastases: An 18-year experience from the GIST cooperation group in North China. AB - Approximately 40% to 50% of gastrointestinal stromal tumor (GIST) patients will have recurrence or metastases after resection of the primary lesion, and the most common affected sites will be liver and peritoneum. Imatinib has been considered as the first-line therapy of metastatic GIST. Surgery for metastases is proposed when possible. Furthermore, there are controversies concerning hepatic resection and systemic tyrosin kinase inhibitors (TKIs). The therapeutic conditions and long-term outcome of GIST patients with liver metastases in northern China remain unknown.The clinical, pathological, and follow-up data of 144 GIST patients, who had liver metastases between June 1996 and June 2014 from 3 tertiary cancer centers in northern China, were reviewed.Thirty-two cases (22.2%) had hepatectomy with 23 (23/32, 71.9%) R0 resections and 9 (9/32, 28.1%) R1/R2 resections, respectively. Twenty-three patients were given imatinib postoperatively. Furthermore, 98 (68.1%) patients were given TKIs only to control disease progression, and sunitinib was considered after imatinib failure in 12 patients. The 1-, 3- and 5-year survival rate was 82%, 51%, and 24%, with a median overall survival of 48 months for all patients. Patients who had hepatic resection combined with TKIs had a tendency of improved outcome, and the median survival time was 89 months. This was in contrast to patients who received TKIs only, in which median survival time was 53 months. Patients who received imatinib plus sunitinib had a tendency of longer survival time, compared with patients who received imatinib only (not reached vs 50 months).TKIs combined with hepatic resection had a role in improving the outcome of GIST patients with liver metastases. PMID- 29145241 TI - The prognostic value of the serum neuron specific enolase and lactate dehydrogenase in small cell lung cancer patients receiving first-line platinum based chemotherapy. AB - The aim of this study was to investigate the associations of serum levels of neuron-specific enolase (NSE), pro-gastrin releasing peptide (ProGRP), and lactate dehydrogenase (LDH) with clinical response and survival in small cell lung cancer (SCLC) patients receiving first-line platinum-based chemotherapy.One hundred thirty-six patients with SCLC were recruited in this study. All the patients received first-line platinum-based chemotherapy. Clinical efficacy was assessed according to Response Evaluation Criteria in Solid Tumors v1.1 criteria. Serum samples were collected from SCLC patients before chemotherapy. NSE, ProGRP, and LDH levels were measured by commercial electrochemiluminescence immunoassay, enzyme-linked immune sorbent assay, and kinetic spectrophotometric method, respectively.Overall response rate was 71.3% with 97 patients who achieved complete response (CR) + partial response (PR). NSE and LDH level declined in patients who achieved CR + PR compared with patients in stable disease (SD) and progress disease (PD). Multivariate logistic regression analysis revealed that NSE > 50.324 ng/mL, stage ED, and distant metastases were independent risk factors for patients achieving CR + PR, and chemotherapy > 4 cycles was an independent protective factor in predicting CR + PR. Receiver operating characteristic (ROC) curves presented that expression of NSE, ProGRP, and LDH are of good predicting value for patients achieving CR + PR. Patients with a higher level of NSE and LDH presented worse progression-free survival and overall survival. In addition, multivariate Cox regression analysis showed that NSE level > 50.324 ng/mL and distant metastasis were independently correlated with worse OS.Serum NSE and LDH could be promising biomarkers for predicting therapy response and survival of SCLC patients receiving first-line platinum-based chemotherapy. PMID- 29145242 TI - The association of genetic variants in chemokine genes with the risk of psoriasis vulgaris in Chinese population: A case-control study. AB - This study aimed to investigate the influence of polymorphisms in chemokine genes, including MCP1, CCR2, and CCR5 with psoriasis vulgaris (PV) risk in a Chinese population.The genotyping of studied polymorphisms through polymerase chain reaction (PCR) and sequencing was conducted in 142 PV patients and 147 healthy controls. The genotype distribution of the polymorphisms in the control group was checked to determine whether it conformed to Hardy-Weinberg equilibrium (HWE). The genotype and allele frequencies were compared between PV patients and the healthy controls using Chi-square test. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated to assess the relative risk of PV related to genetic variants.CCR2 rs1799864 polymorphism was associated with significantly elevated risk of PV (AA+AG vs GG: OR = 1.62, 95% CI = 1.02-2.59; A vs G: OR = 1.48, 95% CI = 1.02-2.16). In the meanwhile, CCR5 rs1800024 polymorphism also exhibited significant differences in genotype and allele distribution (P < .05), demonstrating its promoting effect on the risk of PV under heterozygous model (OR = 1.73, 95% CI = 1.06-2.82), dominance model (OR = 1.83, 95% CI = 1.14-2.94), and allele model (OR = 1.68, 95% CI = 1.13-2.48).CCR2 rs1799864 and CCR5 rs1800024 polymorphisms may function as independent risk factors for PV in Chinese population. PMID- 29145243 TI - Obstructive internal hernia caused by mesodiverticular bands in children: Two case reports and a review of the literature. AB - INTRODUCTION: The mesodiverticular band (MDB) is an embryologic remnant of the vitelline circulation, which carries the arterial supply to the Meckel diverticulum. In the event of an error of involution, a patent or nonpatent arterial band persists and extends from the mesentery to the apex of the antimesenteric diverticulum. This creates a snare-like opening through which bowel loops may herniate and become obstructed. This report describes 2 rare cases of small bowel occlusion owing to an internal hernia caused by a MDB. CASES: Case 1 was a 5-year-old boy who presented to our Emergency Department with colicky abdominal pain diffused to all abdominal quadrants. He also had 5 episodes of emesis, the last with bilious vomiting. Case 2, a 12-year-old boy, presented to our Emergency Department complaining of colicky abdominal pain. He had 2 episodes of nonbilious emesis. On physical examination, both children showed distension and tenderness of the abdomen and abdominal x-ray and ultrasound confirmed an occlusive picture without an apparent etiology. In case 1, an urgent laparotomy was performed and the MDB was ligated and cut, whereas in case 2 diagnosis and excision were performed in laparotomy. In both patients, there was a positive clinical evolution. CONCLUSION: Although MDB causing internal hernia is very rare, it should be considered in patients with a clinical picture of small bowel obstruction. In these cases, early surgery is important to prevent strangulation and gangrene of the bowel and to avoid dramatic events. Moreover, laparoscopy seems a safe and effective technique in these patients, especially in children with mild abdominal distention without surgical or trauma history, highlighting that further studies on the value of laparoscopy for the treatment of small bowel obstruction in pediatric patients are urgently needed. PMID- 29145244 TI - Association between renin-angiotensin-aldosterone system blockade and future osteoporotic fracture risk in hypertensive population: A population-based cohort study in Taiwan. AB - Tissue renin-angiotensin-aldosterone system (RAAS) activation in sites of osteoporosis had been demonstrated in animal studies; however, the possibility of RAAS blockade to prevent future osteoporotic fracture had rarely been verified in clinical studies. We Used the Taiwan Longitudinal Health insurance database 2000 to 2008, the cohort study comprised patients age over 40 with a recorded new diagnosis of hypertension between January 1, 2000 to December 31, 2008, in addition, patients who had diagnosis of osteoporosis before the date of cohort enter were excluded. After the definite diagnosis of hypertension, each patient was followed until osteoporotic fracture happened or the end of 2008. The occurrence of osteoporotic fracture was evaluated in patients who either were or without taking RAAS blockade agents. Cox proportional hazard regressions were used to evaluate the osteoporotic fracture incidence after adjusting for known confounding factors. In total, 57,132 hypertensive patients comprised the study cohort. Our study results showed that the incidence of osteoporosis fracture in the whole cohort was significantly higher in the RAAS blockade non-user group than the user group. This phenomenon was observed in both sex and all age categories. Sensitivity analysis further showed the concordant lower osteoporosis fracture risk in patients with various RAAS blockers usage durations; the risk of osteoporosis fracture was the lowest in those drug use >365 days when compared with the non-user cohort. In conclusion, our study result demonstrated the lower future osteoporotic fracture risk in hypertensive subjects who received long term RAAS blocker treatment. PMID- 29145245 TI - Case reports about an overlooked cause of neck pain: calcific tendinitis of the longus colli: Case reports. AB - STUDY DESIGN: Case description. OBJECTIVE: Acute calcific tendinitis of the longus colli muscle is a rare clinical entity that causes severe neck pain. This entity is not well recognized due to its nonspecific presentation such as acute neck pain, neck stiffness, and odynophagia. The importance of this disease with a review of the literature is presented. SUMMARY OF BACKGROUND DATA: Acute calcific tendinitis of the longus colli muscle is an inflammatory condition caused by deposition of calcium hydroxyapatite in the superior oblique tendon fibers of the longus colli muscle. It can be misdiagnosed as other life-threatening conditions including retropharyngeal abscess, resulting in unnecessary medical or surgical interventions. METHODS: We retrospectively reviewed the clinical data, radiological features, and laboratory reports of 8 patients who were diagnosed with acute calcific tendinitis of the longus colli muscle and seen at our institution between April 2008 and March 2015 in this article. We describe the clinical presentation, diagnosis, and treatment of acute calcific tendinitis of the longus colli muscle. RESULTS: There were 5 men and 3 women who ranged in age from 41 to 49 years (mean age: 44.5 years). The associated symptoms included neck pain, stiffness, odynophagia, and headache. The duration of symptoms varied from 2 days to 1 week. All patients showed calcific deposition inferior to the anterior arch of the atlas, and prevertebral effusion extending from C1 to C4. All patients were treated with NSAIDs and immobilization with a cervical brace, and most patients showed complete resolution of symptoms within 1 week. CONCLUSION: We report 8 cases of acute calcific tendinitis of the longus colli, and describe the symptoms and radiological findings in detail. Awareness of this rare, benign, and self-limiting disease entity with characteristic radiologic findings is essential for early diagnosis and to avoid unnecessary medical and surgical interventions. PMID- 29145246 TI - Case report: Pentoxifylline treatment in microscopic colitis. AB - RATIONALE: Microscopic colitis is a common cause of diarrhea. Pentoxifylline, a xanthine derivative with anti-tumor necrosis factor-alpha properties, is prescribed for intermittent claudication and other disorders. Our goal was to evaluate the outcomes of patients with microscopic colitis treated with pentoxifylline. PATIENT CONCERNS: Nine patients with microscopic colitis (8 collagenous colitis and 1 lymphocytic colitis) seen at Mayo Clinic, Rochester, between January 1, 1997 and November 30, 2016, were included. The median age was 56.9 years (range 51.6-60.2), 8 were female (89%), and the median disease duration was 64.8 months (range 60-109). The indications for treatment were budesonide refractoriness in 7 patients, budesonide dependence in 1 patient, and budesonide intolerance in 1 patient. DIAGNOSES: A histological diagnosis of microscopic colitis was confirmed in all patients. INTERVENTIONS: Pentoxifylline 400 mg three times a day was used for a median of 3 months (range 2.5-8.3). OUTCOMES: Complete response occurred in 1 patient (11%) and partial response in 3 patients (33%). The patient who achieved complete response was treated with pentoxifylline due to budesonide intolerance, and completed 43 months of successful maintenance therapy. There were no adverse effects reported. LESSONS: The majority of budesonide-experienced patients with active microscopic colitis did not respond to pentoxifylline. However, it was well-tolerated, with 1 patient achieving long-term remission and one-third of the cohort having a partial response. Larger controlled studies are required to evaluate the efficacy of pentoxifylline and predictors of response in microscopic colitis. In particular, patients who are not budesonide-refractory may be more likely to respond. PMID- 29145247 TI - Comparison of chemoradiotherapy with and without brachytherapy as adjuvant therapy after radical surgery in early-stage cervical cancer with poor prognostic factors: An observational study. AB - This study aimed to determine whether the addition of intracavitary brachytherapy (ICBT) to chemoradiotherapy (CRT) improves outcome in patients with cervical cancer and poor prognostic factors. Patients with stage IB to IIA cervical cancer who had undergone radical hysterectomy and pelvic lymphadenectomy between August 2008 and December 2014 were retrospectively registered in this study. All patients received external beam radiation therapy (EBRT) + chemotherapy, and some patients additionally received ICBT. EBRT consisted of 45 to 50.4 Gy delivered to the standard pelvic field in 25 to 28 fractions. Chemotherapy consisted of 2 to 4 courses of weekly cisplatin-based treatment. ICBT was delivered in 1 to 3 insertions. Ninety-seven of 163 patients received CRT, and 66 patients additionally received ICBT. During a median follow-up period of 33 months, recurrence was detected in 38 patients. The 3-year locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) rates did not differ significantly between patients who did and did not receive ICBT. In subgroup analyses, fewer recurrences were seen in patients with at least 1 high-risk factor who received ICBT than in those who did not, with a significant (62%) reduction in the risk of progression or death (hazard ratio 0.384, 95% confidence interval 0.151-0.978, P = .045). The difference in OS between the CRT and CRT + ICBT subgroups was marginal (P = .064). The addition of ICBT to CRT after radical surgery significantly improves LRC and DFS rates in women with cervical cancer and at least 1 high-risk factor. PMID- 29145248 TI - Esophageal duplication cyst with hemivertebrae: A case report and literature review. AB - BACKGROUND: Esophageal duplication cysts (EDCs) are rare congenital anomalies that can be associated with symptomatic spinal abnormalities, but presentations due to EDC symptoms are rarely found in the presence of spinal abnormalities. CASE SUMMARY: A 6-month-old infant weighing approximately 5.0 kg presented with a 2-month pulmonary infection and more recent difficulty swallowing and nutritional intolerance that did not improve with medical treatment. Contrast-enhanced chest computed tomography showed a well-defined, mediastinal, homogeneous, low-density cystic mass of 11.9 * 5.5 * 5.1 cm, compressing the liver and bending the trachea forward. Hemivertebrae were present (T4 and T3). Diagnostic laparoscopy was performed, but was converted to open surgery. After ensuring that the cyst was not within the abdominal cavity, thoracotomy was performed, and the cyst was completely resected. Pathophysiological examination revealed an EDC. The patient recovered well, without symptoms 6 months later. CONCLUSIONS: Overall, noninvasive imaging and diagnostic procedures may not be sufficient to define the exact location of an EDC. Although hemivertebrae were present, they were asymptomatic and did not require treatment; only the EDC induced nonspecific symptoms that disappeared after surgery. PMID- 29145249 TI - Prospective associations between measures of gross and fine motor coordination in infants and objectively measured physical activity and sedentary behavior in childhood. AB - One important determinant of childhood physical activity and sedentary behavior may be that of motor development in infancy. The present analyses aimed to investigate whether gross and fine motor delays in infants were associated with objective and self-reported activity in childhood. Data were from the UK Millennium Cohort Study, a prospective cohort study, involving UK children born on or around the millennium (September 2000 and January 2002). When children were 9 months old, parents reported children's fine and gross motor-coordination, and at 7 years, sports club attendance and daily TV viewing time. Children's physical activity was measured using accelerometers at 7 years. Adjusted regression models were used to examine associations between delayed motor development and accelerometry measured moderate-to-vigorous physical activity and sedentary behavior, and parent-reported sport club attendance and TV viewing time. In this sample (n = 13,021), gross motor delay in infancy was associated with less time in moderate-to-vigorous physical activity (B -5.0 95% confidence interval [CI] 6.8, -3.2) and more time sedentary (B 13.5 95% CI 9.3, 17.8) in childhood. Gross and fine motor delays during infancy were associated with a reduced risk of having high attendance at sports clubs in childhood (both relative risk [RR] 0.7, 95% CI 0.6, 0.9). Fine motor delays, but not gross delays, were also associated with an increased risk of having high TV viewing time (RR 1.3 95% CI 1.0, 1.6). Findings from the present study suggest that delays in motor development in infancy are associated with physical activity and sedentary time in childhood. PMID- 29145250 TI - CONSORT-Independent prognostic value of asphericity of pretherapeutic F-18 FDG uptake by primary tumors in patients with breast cancer. AB - BACKGROUND: The aim of this study was to evaluate the prognostic implication of asphericity (ASP); spatial irregularity; of pretherapeutic F 2-deoxy-2-fluoro-D glucose (F FDG) tumor uptake in patients with invasive ductal carcinoma (IDC) of the breast. METHODS: One hundred thirty-one female IDC patients (mean age = 48.1 +/- 10.4 years), with pathological tumor size greater than 2 cm were retrospectively evaluated using F FDG positron emission tomography/computed tomography (PET/CT). ASP of F FDG distribution was calculated on the basis of the deviation of the tumor shape from spherical symmetry. Progression-free survival (PFS) was predicted on the basis of the univariate and multivariate analyses of the measured clinicopathologic factors and metabolic PET parameters [maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG)]. RESULTS: The PFS rate among the 131 patients was 90.1%. The mean follow-up time was 50 months for the entire study cohort and 26 months for the patients with recurrent disease. It is evident from the univariate analysis that N stage, hormonal receptor (Estrogen, ER/Progesterone, PR) status, MTV (<=4.2 mL), and ASP (<=15.1%) affected the PFS. Hazard ratios (HRs) estimated from the multivariate Cox regression analysis show that N stage (HR = 17.6), ASP (HR = 11.9), and hormonal receptor status (HR = 6.9) were independent prognostic factors in predicting PFS. In the subgroup of patients with lymph node metastasis, ASP (HR = 10.9) and hormonal receptor status (HR = 9.1) were independent prognostic factors for PFS. CONCLUSION: ASP of F FDG uptake is an independent predictor of outcome in IDC patients, and can be used for prognostic stratification. PMID- 29145251 TI - Renal osteodystrophy presenting as a metabolic superscan on F-18 FDG PET/CT: A case report. AB - RATIONALE: F-18 Fluoro Deoxyglucose positron emission tomography and computed tomography (F-18 FDG PET/CT) is a useful modality in the evaluation of patients with malignancies. Increased incidence of lympho-proliferative disorders has been reported in individuals with long-standing end-stage renal disorders treated with renal replacement therapy. PATIENT CONCERNS: A 30-year-old male on peritoneal dialysis on account of end-stage renal disease. He had acute rejection of an earlier transplanted renal allograft. He was referred for an F-18 FDG PET/CT based on a clinical suspicion of lymphoma on account of bilateral inguinal lymphadenopathy associated with bilateral pedal swelling. DIAGNOSIS: Renal osteodystrophy was diagnosed based on diffusely intense F-18 FDG uptake in the axial skeleton, focal uptake in the costochondrial junctions and linear cortical uptake in the appendicular skeleton. No findings suggestive of lymphoma was seen. INTERVENTIONS: A diagnosis of renal osteodystrophy with no evidence of a lymphoma prevented futile biopsy of inguinal lymphadenopathy. Patient continued with peritoneal dialysis with no further intervention OUTCOMES:: Regular follow-up of patient to monitor calcium, phosphate and parathyroid hormone levels. Treatment will be indicated when laboratory results as well as clinical signs and symptoms are suggestive. LESSON: Metabolic bone disorder such as is seen in renal osteodystrophy should be considered in the differential diagnoses in patients with diffusely increased bone uptake on F-18 FDG PET/CT scan. PMID- 29145252 TI - Identifications of potential therapeutic targets and drugs in angiotensin II induced hypertension. AB - This study aimed to identify the underlying therapeutic targets of angiotensin II (AngII)-induced hypertension, and screen the related drugs.The gene expression profiles of GSE93579 and GSE75815 were used to identify differentially expressed genes (DEGs) between AngII-induced hypertension and control samples based on meta analysis. These DEGs were analyzed using Gene-Ontology (GO) function and pathway enrichment methods. Subsequently, the weighed gene coexpression network analysis (WGCNA)-based meta-analysis was applied to determine transcriptional signature with DEGs. Additionally, the functions of the modules were analyzed based on the network, and miRNAs were identified. Finally, small molecule drugs correlation with DEGs was identified.In total, 346 upregulated DEGs (e.g., Rgs7 bp) and 360 downregulated DEGs (e.g., Ebf3) were identified between AngII and control samples. In addition, a total of 150 DEGs in the brown, red, and yellow modules with higher correlation coefficient according to WGCNA, were used to construct the coexpression network, including Rgs7 bp and Ebf3, etc. in brown modules. Besides, 3 modules were obtained after the functions of the modules analysis. Moreover, 5 miRNAs were integrated in modules, including miR-124A, miR-524, miR 493, miR-323, and miR-203. Finally, anisomycin was the highest correlation with DEGs.MiR-124a might be involved in the pathogenesis of hypertension via targeting Ebf3 and Rgs7 bp, which possibly represent a novel and effective strategy for treatment of hypertension. Anisomycin might be performed to reduce blood pressure by blocking MAPK signaling pathway. PMID- 29145253 TI - Anterior endoscopically assisted bone grafting for iatrogenic distraction of odontoid fracture after percutaneous anterior screw fixation: A case report. AB - RATIONALE: The complication of iatrogenic distraction of odontoid fracture after anterior screw fixation has not been reported in the literature. We treated the patient with endoscopically assisted bone grafting with good results. The new technique was not reported in the management of odontoid fracture or nonunion before. PATIENT CONCERNS: A 22-year-old man presented with neck pain after a motorcycle crash. The cervical spine radiograph and computed tomographic scan demonstrated the base of dens displaced 2 mm anteriorly. DIAGNOSES: Radiographic images showed a type II odontoid fracture. INTERVENTIONS: The patient was treated by percutaneous anterior screw fixation. The postoperative radiograph and CT demonstrated an iatrogenic distraction of the odontoid with a gap of 6 mm.The follow-up radiograph did not show any sign of bone union 1 month and a half later. A revision surgery was given by anterior endoscopically assisted bone grafting. The patient was encouraged to sit out of bed immediately after the surgery with the protection of a soft cervical collar for 3 months. OUTCOMES: No complications such as neural structures or vascular injuries were found. Bone union was achieved at the 1-year follow-up CT scans. Physical examination showed a full range of motion in the neck. LESSONS: We reported a case of iatrogenic odontoid distraction that was managed by anterior endoscopically assisted bone grafting. It is a technically feasible and minimally invasive procedure. PMID- 29145254 TI - Individualized prevention against hypertension based on Traditional Chinese Medicine Constitution Theory: A large community-based retrospective, STROBE compliant study among Chinese population. AB - Traditional Chinese Medicine Constitution (TCMC) theory states that individuals with a biased TCMC are more likely to suffer from specific diseases. However, little is known regarding the influence of TCMC on susceptibility to hypertension. The aim of this study is to examine the possible relationship between TCMC and hypertension. Retrospective evaluation and observation were performed using the STROBE guidelines checklist. A large community-based cross sectional study was conducted between 2009 and 2013 in Changsha, China. TCMC was assessed using a questionnaire that included 68 items. TCMC distributions and the associations of different TCMCs with hypertension risk were analyzed. In total, 144,439 subjects underwent evaluations of TCMC and blood pressure (BP). There were significant differences in the hypertension prevalence among the various TCMC groups (P < .01). An adjusted logistic regression model indicated that those with phlegm wetness, yin deficiency, blood stasis, or qi deficiency were more likely to have hypertension. Analysis of the clinical characteristics related to TCMC indicated that different TCMCs corresponded to different hypertension classifications using Western medicine criteria; for example, phlegm wetness with hypertension was similar to obesity-related hypertension. Our results suggest that phlegm wetness, yin deficiency, blood stasis, and qi deficiency have different effects on the prevalence of hypertension. More attention should be paid to TCMCs associated with susceptibility to hypertension, and corresponding preventive and therapeutic treatments should be developed according to different TCMCs. PMID- 29145255 TI - Functional polymorphism rs3783553 in the 3'-untranslated region of IL-1A increased the risk of ischemic stroke: A case-control study. AB - Accumulating evidence indicates interleukin-1 (IL-1) is a critical mediator of inflammatory responses in ischemic stroke (IS). The aim of this study was to investigate whether rs3783553 in the 3'-untranslated region of IL-1A was associated with the risk of IS. In this hospital-based case-control study, we genotyped the rs3783553 using polymerase chain reaction in 316 patients with IS and 332 age, sex, and ethnicity-matched controls. Plasma level of IL-1alpha was measured by enzyme-linked immunosorbent assay. The relative luciferase activities were measured by the Dual Luciferase assay system. The presence of ins/ins genotype was associated with higher odds ratios (ORs) of IS compared with del/del genotype (ins/ins vs del/del: adjusted OR 1.77, 95% confidence interval [CI] 1.06 2.98; recessive model: adjusted OR 1.69, 95% CI 1.06-2.70). The higher risk of IS was also observed in allele comparison (adjusted OR 1.29, 95% CI 1.00-1.65). Multivariate logistic regression analysis showed that age, hypertension, total cholesterol, triglyceride, low-density lipoprotein, and rs3783553ins/ins genotypes were independent risk factors for IS. Plasma level of IL-1alpha was higher among IS patients compared with controls (P = .03). Notably, IS patients with the TTCA/TTCA genotype had a higher level of IL-1alpha compared with those with the del/del genotype (P = .01). Luciferase reporter assay showed that the vector containing the TTCA del allele exhibited a reduced transcriptional activity in the presence of miR-122 and miR-378. These findings indicate that IL 1A rs3783553 ins/ins genotype may increase the susceptibility to IS, possibly by interrupting the binding site of miR-122 and miR-378. PMID- 29145256 TI - Morphologic features of the distal femur and tibia plateau in Southeastern Chinese population: A cross-sectional study. AB - Morphologic measurements of the femoral and tibial features of western population have been done in several studies, which provides the fundamental data for the design of total knee arthroplasty prosthesis used globally, including China. However, researches on anatomic and morphologic features of the knee in Chinese populations of both sexes have never been conducted. Our study was aimed at investigating the anatomic and morphologic features of the knees of the Southeastern Chinese population by magnetic resonance imaging (MRI) scans, so as to provide parameters for sex- and ethnic-specific implant designs in the future.A total of 245 knees from 244 Chinese adults (130 females and 114 males, aging from 18 to 89 years) who received knee MRI scan from November 2014 to October 2015 were recruited and analyzed. A set of linear and angular parameters, and 6 normalized ratios were measured and calculated on the distal femur and proximal tibia.The knee size was significantly different between sexes. Compared with women, men have larger (P < .01) medial-lateral (ML) and anterior-posterior (AP) dimensions in both distal femur and proximal tibia. Differences in femoral shape, represented by the femur surface ratio, between both sexes were also identified (1.23 +/- 0.07 vs 1.27 +/- 0.07, P < .01), whereas the ML/AP ratios of the tibia are similar between both sexes (1.44 +/- 0.07 vs 1.44 +/- 0.09, P = .97). We also found substantial difference in the morphology of femur and tibia plateau in Southeastern Chinese population compared with data obtained from western populations.Our study measured the anatomic and morphologic features of the knees in Southeastern Chinese population, and identified knee morphologic differences between both sexes, as well as western and Chinese population. Further clinical studies are needed to determine other essential parameters for the design of prosthesis to the Chinese populations. PMID- 29145257 TI - Clinical features of acute acquired comitant esotropia in the Chinese populations. AB - Acute acquired comitant esotropia (AACE) is an unusual presentation of esotropia that occurs after infancy. This study was aimed to study the clinical features and the differences between children and adult patients with AACE in the Chinese populations.This was a retrospective analysis of patients diagnosed with AACE over 4 years; 69 patients (25 females and 44 males) were identified. The patients were divided into 3 groups: < 10 year-old (n = 6, 8.7%), 10-18 year-old (n = 23, 33.3%), and >=18 year-old (n = 40, 58.0%). Patients underwent medical history, brain and orbital computed tomography, and ophthalmological and orthoptic examinations.The refractions of AACE patients varied among age groups: patients < 10 year-old had mild hypermetropia, while older children and adults showed moderate-to-high myopia (P < .001). The mean angles of esotropia were significantly larger in young children compared with older children and adults (P = .005). There was no significant difference in binocularity detected by either synoptophore or TNO stereoscopic testing among different disease durations. Stereopsis detected by synoptophore and TNO testing showed no significant difference at duration within half a year, but the stereopsis measured by TNO was significantly worse than that detected by synoptophore with extending disease duration (P < .05).AACE seems to occur mostly in older children and adults in the Chinese population. Younger children with AACE seem to demonstrate a common trait of mild hypermetropic refractive errors, while myopia can be seen in older children and adult patients. The duration from onset to treatment of esotropia does not affect the preoperative binocularity. PMID- 29145258 TI - Shift work, night work, and the risk of prostate cancer: A meta-analysis based on 9 cohort studies. AB - BACKGROUND: Epidemiology studies suggested that shift work or night work may be linked to prostate cancer (PCa); the relationship, however, remains controversy. METHODS: PubMed, ScienceDirect, and Embase (Ovid) databases were searched before (started from the building of the databases) February 4, 2017 for eligible cohort studies. We pooled the evidence included by a random- or fixed-effect model, according to the heterogeneity. A predefined subgroup analysis was conducted to see the potential discrepancy between groups. Sensitivity analysis was used to test whether our results were stale. RESULTS: Nine cohort studies were eligible for meta-analysis with 2,570,790 male subjects. Our meta-analysis showed that, under the fixed-effect model, the pooled relevant risk (RR) of PCa was 1.05 (95% confidence interval [CI]: 1.00, 1.11; P = .06; I = 24.00%) for men who had ever engaged in night shift work; and under the random-effect model, the pooled RR was 1.08 (0.99, 1.17; P = .08; I = 24.00%). Subgroup analysis showed the RR of PCa among males in western countries was 1.05 (95% CI: 0.99, 1.11; P = .09; I = 0.00%), while among Asian countries it was 2.45 (95% CI: 1.19, 5.04; P = .02; I = 0.00%); and the RR was 1.04 (95% CI: 0.95, 1.14; P = .40; I = 29.20%) for the high-quality group compared with 1.21 (95% CI: 1.03, 1.41; P = .02; I = 0.00%) for the moderate/low-quality group. Sensitivity analysis showed robust results. CONCLUSIONS: Based on the current evidence of cohort studies, we found no obvious association between night shift work and PCa. However, our subgroup analysis suggests that night shift work may increase the risk of PCa in Asian men. Some evidence of a small study effect was observed in this meta-analysis. PMID- 29145259 TI - Impulse oscillometry system as an alternative diagnostic method for chronic obstructive pulmonary disease. AB - : We aimed to compare impulse oscillation system (IOS) and traditional pulmonary function tests (PFTs) for the assessment of the severity of chronic obstructive pulmonary disease (COPD), and to assess the use of IOS parameters to identify patients who were forced expiratory volume in 1 second (FEV1)%pred < 50%.Patients with COPD (n = 215) were enrolled at the Ninth Hospital of Xi'an Affiliated Hospital of Xi'an Jiaotong University between October 2014 and September 2016. All patients were assessed by traditional PFT and IOS. Diagnostic performance of IOS parameters to determine indication for patients of FEV1%pred < 50% was assessed on receiver-operating characteristics (ROC) curve analysis.Out of 215 patients, 18, 83, 78, and 36 patients were classified as grade 1, 2, 3, and 4, respectively, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity grading. On Spearman correlation analysis, FEV1%pred, MMEF 75%-25%, and residual volume/total lung capacity (RV/TLC) correlated with total respiratory impedance (Z5)%pred, resistance at 5 Hz (R5)-resistance at 20 Hz (R20), R5-R20% R5, R5, R5%pred, frequency response (Fres), reactance area (Ax), and reactance at 5 Hz (X5). On ROC curve analysis, the area under the curve (AUC) of X5 absolute value, Fres, Ax, Z5%pred, R5-R20, and R5-R20% R5 were 0.748, 0.755, 0.760, 0.705, 0.715, and 0.735, respectively, for COPD patients who required inhalational glucocorticoid therapy.IOS parameters showed a good correlation with traditional pulmonary function parameters; reactance parameters showed a stronger correlation than that of the resistance parameters. IOS can be used as an alternative method for pulmonary function assessment in patients with COPD with FEV1%pred < 50% who need inhalational glucocorticoid therapy. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-OCH-14004904. PMID- 29145260 TI - Reversible severe fatty liver induced by capecitabine: A case report. AB - RATIONALE: Capecitabine (CAP) is a chemotherapeutic agent used to treat breast and gastrointestinal cancers. The most common adverse reactions of CAP primarily included gastrointestinal and dermatological effects. Whereas, the CAP-induced fatty liver had never been reported. PATIENT CONCERNS: In this study, a-69-year old female presented a history of hypertension with regulated blood pressure, whereas diabetes mellitus, hyperlipidemia, and hepatitis were excluded. No alcohol,tobacco, or other drugs use was declared. DIAGNOSES: She was diagnosed as infiltrating ductal carcinoma of left breast with the hepatic and pulmonary metastasis. The dihydropyrimidine dehydrogenase (DPD) deficiency is not involved. INTERVENTIONS: She received treatment with CAP that was administered orally at a dosage of 1500mg twice daily intermittently (2weeks on/1 week off). The treatment was well-tolerated any typical adverse reactions such as diarrhea, nausea, and hand-foot syndrome (HFS) were noted. The parameters of the functional liver, the total cholesterol, and triglyceride were in normal ranges before and after therapy. After 3 cycles of the treatment, computed tomography (CT) scan revealed signs of fatty liver. After a 10-cycle course, CAP was substituted with tamoxifen because of the further aggravation of fatty liver. OUTCOMES: Several months after withdrawal, the follow-up CT scans demonstrated significant improvement of fatty liver. LESSONS: We presented a case of breast cancer with severe fatty liver as a consequence of the administration of CAP that was not involved in DPD deficiency or CAP-associated hypertriglyceridemia; these potential adverse effects of therapy with CAP should be intensely investigated. PMID- 29145261 TI - Phyllodes tumors of the breast in 2 sisters: Case report and review of literature. AB - RATIONALE: Phyllodes tumors (PT) of the breast are rare neoplasm originating from fibroepithelial component. To our knowledge, our report is the first reported case of PT in 2 sisters. PATIENT CONCERNS: We presented 2 cases of PT of the breast involving in 2 sisters. On physical examination of the younger sister, a firm mass measuring approximately 3 cm in diameter was identified in upper inner quadrant of the right breast. Physical examination of the elder sister revealed a 3 cm lump in upper outer quadrant of the left breast. DIAGNOSES: Histopathology of the younger sister revealed a malignant PT. The elder sister was diagnosed with borderline PT. INTERVENTIONS: The younger sister with malignant PT underwent right mastectomy. The elder sister with borderline PT was scheduled for wide resection of the mass in the left breast. OUTCOMES: After a follow-up of 23 months, no local or distant recurrence was observed. LESSONS: Our cases indicate that genetic factor may contribute to the risk of PT of the breast. Markers such as p53 and Ki-67 may have some correlation with PT malignancy. PMID- 29145262 TI - Management of radiation-induced rectovesical fistula in a woman using ileum: A case report and review of the literature. AB - BACKGROUND: Radiation-induced rectovesical fistulas (RVFs) require the most demanding treatment. We presented a rare case of postradiation RVF in a woman repaired with ileum. CASE PRESENTATION: A 49-year-old women was referred to our department for fecaluria and dysuria after radiation for cervical cancer. The voiding cystourethrography demonstrated a large RVF. A segment of ileum was separated into 2 parts for the simultaneous reconstruction of bladder and rectum, which led to a permanently closed fistula. This approach is easily accessible via transabdominal approach, could be applied for large defect, and bladder augmentation could be performed simultaneously. CONCLUSION: The repair of an RVF using ileum appears feasible and represents an attractive alternative for the management of RVFs. PMID- 29145263 TI - LDL-cholesterol goal attainment under persistent lipid-lowering therapy in northeast China: Subgroup analysis of the dyslipidemia international study of China (DYSIS-China). AB - Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the efficacy of persistent treatment in a real-world setting may vary from regions. Routine lipid-lowering therapy in the region with a high prevalence of cardiovascular disease may lead to more failures of goal attainment. We therefore performed a study to observe different lipid-lowering strategies in northeast (NE) China with respect to low-density lipoprotein-cholesterol (LDL-C) reduction and goal attainments.A cross-sectional study (DYSIS-China) was conducted in 2012, involving 25,317 patients from 122 centers across China who were diagnosed with hyperlipidemia and treated with lipid-lowering therapy for at least 3 months. Of these patients, 4559 (18.0%) were assigned to the NE group according to their residential zones.Patients in the NE group tended to be younger, female, overweight, and had more comorbidities and higher blood lipid levels than those in the non-NE group (P < .001). The goal attainment for LDL-C in NE was lower than non-NE (45.3% vs 65.1%, P < .001), and especially lower in high (NE vs non NE, 38.5% vs 58.6%) and very high (NE vs non-NE, 22.6% vs 43.7%) risk patients. The proportion of high intensity statin was lower in NE than non-NE, and the proportion of combination therapy was similar (~2%). However, the goal attainment did not increase after administering higher dosages of statins in 2 groups. Logistic regression analysis identified diabetes mellitus (DM), coronary heart disease (CHD), cerebrovascular disease (CBD), being female, body mass index (BMI) >24 kg/m, drinking alcohol, smoking, and being residence in NE China as independent predictors of LDL-C attainment.Despite having received persistent lipid-lowering treatments, the current situation of dyslipidemia patients in NE China is unsatisfactory. The main treatment gap might be related to the choice of statin and effective combination therapy and the control of comorbidities and obesity, especially for high-risk patients. PMID- 29145264 TI - Influences of cardiac motion on computed tomography-guided biopsy of lung nodules located near the heart. AB - Computed tomography (CT)-guided lung biopsy of nodules located near the heart may be associated with potential complications. To understand the influences of cardiac motion on lung parenchyma during biopsy, we processed the cardiac phase images of coronary CT angiography (CCTA) and noticed shifts in mediastinum lung margin (MLM) at different zones.Thirty eight CCTA (27 men and 11 women) were retrospectively evaluated. Image processing was done with Fiji (an open source Java image processing program by Fiji contributors) using 10% to 90% phase images of CCTA; and tissue displacement (MLM shift) was shown on the resulting images.The participants were 58.29 +/- 9.87 years old; their height was 166.32 +/ 7.57 cm while their weight was 74.18 +/- 13.59 kg. The mean values of MLM shifts in Zones 1 to 9 ranged from 1.98 to 7.76 mm. Large MLM shifts were observed in the free wall of the left ventricle (LV). MLM shift of the upper free wall of the LV was 6.98 +/- 1.99 mm and that of the lower free wall of the LV was 7.76 +/- 3.26 mm. The largest MLM shift among all patients was 16.05 mm, found in the lower free wall of the LV. The age factor had a weak positive correlation with the wall of the pulmonary artery (r = 0.350, P = .031) and that of the right atrial appendage (r = 0.418, P = .009). In contrast, a weak negative correlation of age factor was observed with the lower free wall of the LV (r = -0.336, P = .039).In conclusion, we suggest that physicians observe caution when performing lung biopsy if the distance between the lung lesion and the MLM is 1 to 2 cm. CT guided lung biopsy should be avoided if the distance is <1 cm. Physicians should pay special attention to lung lesions near the LV. PMID- 29145265 TI - Corneal clarity measurements in healthy volunteers across different age groups: Observational study. AB - The aim of this study was to standardize and investigate the changes in corneal clarity with age. Densitometry software for the Oculus Pentacam was used to examine corneal clarity at different age groups.A total of 192 eyes from 97 healthy participants were included in this cohort comparative nonrandomized, cross-sectional study. An Oculus Pentcam was used to image the cornea of healthy participants grouped by age (between 10 and 70 years old). Data from the densitometry output have been used to determine clarity in concentric zones and different depths of the cornea.Corneal densitometry (CD) across all ages showed significant differences between groups when divided into the following layers: anterior, central, and posterior or divided into 0 to 2, 2 to 6, and 6 to 10 mm concentric zones (P < .05). The most striking decrease in clarity occurred with age in all 3 layers of the periphery (6-10 mm) (P < .05). In addition, we showed that the 10 to 19-year age group had lower clarity than the 20 to 30-age group (P < .05), and after 30 years, the cornea shows a steady progression of increased or decreased clarity.The values for CD, as well as for separate subdivisions based on layer and surface area, might provide a standard for use in further studies and clinical practice. This study established that relation between CD and age is differed when the cornea is divided into layers and zones. This study suggests that there are other factors that may play an essential role in corneal clarity as well as age. PMID- 29145266 TI - Catheter ablation of ventricular arrhythmia originating from isolated outflow tract diverticulum: Two case reports and literature review. AB - RATIONALE: Congenital ventricular diverticulum is a rare cardiac malformation with a prevalence of about 0.26% in unselected adult patients during other diagnostic procedures. Ventricular arrhythmia originating from outflow tract diverticulum is even rarer and its etiology, epidemiology and proper treatment still remain controversial. PATIENT CONCERNS: We present 2 cases of isolated outflow tract diverticulum incidentally revealed by cardiac angiography during catheter ablation for ventricular arrhythmia. The diverticulums in both cases were found to be the origins of the arrhythmia. DIAGNOSES: The 2 patients were both diagnosed with ventricular arrhythmia originating from the outflow tract diverticulum. INTERVENTIONS: Catheter ablation was successfully performed for case 1 while a conservative observation strategy was chosen for case 2. OUTCOMES: Case 1 has been asymptomatic and free of premature ventricular contractions (PVCs) and both patients have no cardiac event during observational follow-up for 12 months. LESSONS: For ventricular arrhythmia originating from outflow tract diverticulum, catheter ablation may be beneficial and choosing the mouth of the diverticulum or the outflow sites around as the ablation target may be reasonable. An observational follow-up strategy for the small and asymptomatic diverticulum may also be recommended. PMID- 29145267 TI - Osteoblastic bone metastases from neuroendocrine tumor (NET) of unknown origin detected by 18fluorocholine PET/CT and its comparison with 68gallium-DOTATOC PET/CT: Case report and review of the literature. AB - RATIONALE: Choline (CH) positron emission tomography (PET)/computed tomography (CT) with fluorine 18 (F) CH is increasingly used not only to evaluate patients with biochemically recurrent prostate cancer but also to assess metastatic lesions that are difficult or impossible to identify using more conventional modalities. Our experience with CH PET/CT has shown that it can also be used for many other malignancies. PRESENTING CONCERNS: A 71-year-old male with a neuroendocrine tumor (NET) of unknown origin showed osteoblastic bone metastases positive to F-CH PET. INTERVENTIONS: Diffuse bone and liver metastases were gallium-DOTATOC PET-positive with only mild uptake on FDG PET/CT. An increased prostate specific antigen (8 MUg/L) gave rise to a suspicion of concurrent prostate cancer and the patient underwent F-CH PET/CT which showed diffuse uptake in the bone. A CT-guided bone biopsy confirmed osteoblastic bone metastases from NET. OUTCOMES: Given the aggressiveness of the tumor, the patient underwent treatment with temozolomide from July 2015 to December 2015, maintaining stable disease. However, progression was documented in January 2016 and the patient was enrolled onto a phase II peptide receptor radionuclide therapy retreatment trial, which is currently ongoing. MAIN LESSON: Our study highlights that NETs should be taken into consideration in the differential diagnosis of osteoblastic bone metastases showing F-CH uptake. A prognostic role for this imaging technique can also be hypothesized. PMID- 29145268 TI - Seroconverting nonresponder of high-dose intramuscular HBV vaccine with intradermal HBV vaccine: A case report. AB - INTRODUCTION: Liver disease is a leading cause of death among human immunodeficiency virus (HIV)-infected patients in the United States. Patients with HIV and hepatitis B virus (HBV) coinfection have accelerated liver disease, higher rates of cirrhosis, and liver cancer, and markedly increased liver-related mortality. The CDC and US Advisory Committee on Immunization Practices recommend hepatitis B vaccination for all HIV-infected individuals. Unfortunately, HIV infected patients have a worse response rate after standard HBV vaccination. Intradermal (ID) vaccination continues to emerge as an important modality in such difficult to vaccinate individuals and should be considered whenever permissible. Herein, we report a case of a 46-year-old male with HIV who failed to mount an immune response to standard intramuscular vaccine, standard booster dose, and repeat high-dose booster vaccine but subsequently mounted an immune response to the ID vaccine which was sustained at 3 months postvaccination. CONCLUSION: ID vaccination continues to emerge as an important modality in difficult to vaccinate individuals and should be considered in all applicable cases. PMID- 29145269 TI - Multimodal ultrasonographic assessment of leiomyosarcoma of the femoral vein in a patient misdiagnosed as having deep vein thrombosis: A case report. AB - RATIONALE: Primary leiomyosarcoma (LMS) of the vein is a rare tumor that arises from the smooth muscle cells of the vessel wall and has an extremely poor prognosis. This tumor can occur in vessels such as the inferior vena cava, great saphenous vein, femoral vein, iliac vein, popliteal vein, and renal vein; the inferior vena cava is the most common site. LMS of the femoral vein can result in edema and pain in the lower extremity; therefore, it is not easy to be differentiated from deep vein thrombosis (DVT). Moreover, virtually no studies have described the ultrasonographic features of LMS of the vein in detail. PATIENT CONCERNS: We present a case of a 55-year-old woman with LMS of the left femoral vein that was misdiagnosed as having deep vein thrombosis (DVT) on initial ultrasonographic examination. The patient began to experience edema and pain in her left leg seven months previously. She was diagnosed as having DVT on initial ultrasonographic examination, but the DVT treatment that she had received for 7 months failed to improve the status of her left lower limb. DIAGNOSES: She subsequently underwent re-examination by means of a multimodal ultrasonographic imaging approach (regular B-mode imaging, color Doppler imaging, pulsed-wave Doppler imaging, contrast-enhanced ultrasonography), which confirmed a diagnosis of LMS. INTERVENTIONS: This patient was treated successfully with surgery. OUTCOMES: This case demonstrates that use of multiple ultrasonographic imaging techniques can be helpful to diagnose LMS accurately. Detection of vasculature in a dilated vein filled with a heterogeneous hypoechoic substance on ultrasonography is a sign of a tumor. LESSONS: The pitfall of misdiagnosing this tumor as DVT is a useful reminder. PMID- 29145270 TI - Study on the adverse effects following chemotherapy for breast cancer diagnosis during pregnancy: The first case report in China. AB - RATIONALE: Treatment of breast cancer during pregnancy (BCP) remains a challenge to physicians. Surgery and chemotherapy during pregnancy are widely used for the treatment of BCP. Herein, we reported 3 Chinese patients with BCP who underwent chemotherapy during pregnancy and were followed up for adverse effects. PATIENT CONCERNS: Three female patients (case 1, case 2, and case 3) of 37-, 32-, and 28 year-old with breast masses were enrolled. Case 1 had been pregnant for over 4 months, case 2 over 7 months, and case 3 for 7 months. Ultrasound findings revealed a mass in the left breast in cases 1 and 2 (30 mm * 26 mm * 23 mm and 34 mm * 16 mm * 40 mm), and case 3 had 2 masses in the outer upper quadrant of right breast (27 mm * 27 mm * 26 mm, 18 mm * 17 mm * 17 mm) and 2 fixed enlarged lymph nodes in the right axillary fossa, respectively. DIAGNOSES: All breast masses were diagnosed by core needle biopsy, and the result was infiltrating ductal carcinoma. INTERVENTIONS: Chemotherapy regimen administered during pregnancy was EwP (epirubicin 80 mg/m, d1 + paclitaxel 80 mg/m, d1, 8, 15, and cycled every 21 days). During pregnancy, case 1 received 5 cycles, case 2 received 1 cycle, and case 3 received 2 cycles. OUTCOMES: Case 2 patient experienced grade III bone marrow suppression once. Electrocardiogram (ECG) result of case 3 showed occasional occurrence of ventricular premature beats, with no complaint of discomfort. All 3 patients experienced uterine contractions, which caused preterm labor in case 2. Adverse events were nausea, hair loss, acid reflux, and constipation. Neonatal jaundice occurred in the premature infant (case 2), which was resolved by phototherapy. No relapse or metastasis was observed in the 3 cases and the infants are growing normally. LESSONS: Both patients and infants well tolerated the combination chemotherapy of epirubicin and paclitaxel during pregnancy. There were few drug toxicities and adverse effects. PMID- 29145271 TI - TUG1, SPRY4-IT1, and HULC as valuable prognostic biomarkers of survival in cancer: A PRISMA-compliant meta-analysis. AB - BACKGROUND: Long noncoding RNAs (LncRNAs) are involved in the development and progression of various cancers. Accumulating evidences indicated that expression of lncRNAs was related to the prognosis of tumors. METHODS: Here, 3 well-known lncRNAs associated with cancer were gathered to prove the potential role of lncRNAs as novel predictors of survival in human cancer. This meta-analysis collected all eligible studies about TUG1, SPRY4-IT1, and HULC and explored the relationship between lncRNAs expression and lymph node metastasis (LNM) or overall survival (OS). A comprehensive, computerized literature search was undertaken by using PubMed, EMBASE, Cochrane Library, and Web of Science (up to October 10, 2017). Strength of association between 3 lncRNAs and cancer prognosis was assessed by computing the hazard ratios (HR) with its corresponding 95% confidence interval (CI). According to the inclusion and exclusion criteria, respectively, 10, 9, and 7 studies of 3 lncRNAs were included in this meta analysis. RESULTS: In the current meta-analysis, it could be concluded that the expression of these 3 lncRNAs in tumor tissues is not a direct evidence of LNM. In general, there was a significant negative correlation between TUG1 levels and OS time (pooled HR 1.54, 95% CI 1.06-2.24), SPRY4-IT1 levels and OS time (pooled HR 2.12, 95% CI 1.58-2.86) and HULC levels and OS time (pooled HR 2.10, 95% CI 1.18-3.73). It could be revealed from the result that high level expression of these 3 lncRNAs might be correlated with a bad prognosis. CONCLUSIONS: In conclusion, the current meta-analysis demonstrated that TUG1, SPRY4-IT1, and HULC might serve as a moderate predictor of survival in human cancer. PMID- 29145272 TI - The efficiency of intravenous acetaminophen for pain control following total knee and hip arthroplasty: A systematic review and meta-analysis. AB - BACKGROUND: This meta-analysis aimed to evaluate the efficiency and safety of intravenous acetaminophen as an adjunct to multimodal analgesia for pain control after total joint arthroplasty (TJA). METHODS: PubMed, Embase, Web of science, Medline, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) and non-RCTs were included. Fixed/random effect model was used according to the heterogeneity tested by I statistic. Meta-analysis was performed using Stata 11.0 software. RESULTS: Four studies including 865 patients met the inclusion criteria. The present meta-analysis indicated that there were significant differences between groups in terms of pain scores at 24 hours (weighted mean difference [WMD] = -0.926, 95% confidence interval [CI]: -1.171 to -0.681, P = .000), 48 hours (WMD = -0.905, 95% CI: -1.198 to -0.612, P = .000), and 72 hours (WMD = -0.279, 95% CI: -0.538 to -0.021, P = .034). Significant differences were found regarding opioid consumption at 24 hours (WMD = -4.043, 95% CI: -5.041 to -3.046, P = .000), 48 hours (WMD = -5.665, 95% CI: -7.383 to 3.947, P = .000), and 72 hours (WMD = -6.338, 95% CI: -7.477 to -5.199, P = .000). CONCLUSION: Intravenous acetaminophen was efficacious for reducing postoperative pain and opioid consumption than the placebo following total joint arthroplasty. Due to the limited quality of the evidence currently available, more RCTs are needed. PMID- 29145273 TI - Diabetes mellitus and the risk of bladder cancer: A PRISMA-compliant meta analysis of cohort studies. AB - BACKGROUND: Epidemiologic studies have reported inconsistent results regarding the relationship between diabetes mellitus (DM) and the incidence of bladder cancer. This comprehensive systematic review and meta-analysis explored and evaluated this relationship in participants with different characteristics. METHODS: Studies indexed in the PubMed, Embase, and the Cochrane Library databases that compared bladder cancer incidence mortality between DM and non-DM participants were included in the present study. The relative risks (RRs) of a random-effects model were used to assess these associations. RESULTS: The final analysis included 21 cohort studies, involving a total of 13,505,643 participants. Overall, DM was associated with an increased risk of bladder cancer or cancer mortality when compared with non-DM participants (RR: 1.23; 95% confidence interval [CI]: 1.12-1.35; P < .001). Furthermore, DM had a harmful impact on subsequent bladder cancer risk in men compared with those without DM (RR: 1.23; 95% CI: 1.06-1.42; P = .005), whereas no significant relationship was observed between DM and bladder cancer in women (RR: 1.24; 95% CI: 0.95-1.61; P = .119). There was no significant gender difference for this relationship (ratio of RR: 0.99; 95% CI: 0.73-1.34; P = .958). In addition, cancer incidence (RR: 1.21; 95% CI: 1.09-1.35; P < .001) and cancer mortality (RR: 1.25; 1.17-1.35; P < .001) both increased in DM patients. Finally, smoking status and follow-up duration might also affect this relationship in men and women. CONCLUSIONS: The findings of this study indicated that DM was associated with elevated bladder cancer or cancer mortality risk, especially in men. This relationship in women requires further exploration. PMID- 29145274 TI - Diagnosis of fetal megacystis with chromosomal abnormality by 2D prenatal ultrasound: A case report. AB - RATIONALE: The pathogenesis of fetal megacystis is divided into obstructive and nonobstructive. Megacystis combined with chromosomal abnormalities is rare and most of the cases are nonobstructive. PATIENT CONCERNS: The fetus showed posterior urethral obstructive megacystis with features of bladder enlargement, "keyhole" feature, and thick bladder wall. DIAGNOSES: Here, we present a case of fetal megacystis diagnosed by ultrasound at pregnancy week 15+2 and with multisystem abnormalities. OUTCOMES: Moreover, the fetus showed edema, umbilical cord cyst, cardiac dysplasia, hook-shaped hand, and strephenopodia. These abnormalities strongly suggested chromosomal abnormalities. The fetus was diagnosed with trisomy 18 by amniocentesis. Posterior urethral obstructive megacystis was confirmed by pathology. LESSONS: In conclusion, this case suggests that in the presence of fetal megacystis and multisystem abnormalities, causes should be investigated and the possibility of chromosomal abnormalities should be considered in the presence of multisystem developmental abnormalities. PMID- 29145275 TI - Asymptomatic syringomyelia accompanied with metastatic cerebellar and spinal intramedullary lymphoma: A case report. AB - RATIONALE: Asympotamic syringomyelia accompanied with metastatic cerebellar and thoracic spinal intramedullary lymphoma is rare in clinical practice. If the intramedullary lymphoma is large enough, the patient will rapidly develop neurologic signs of spinal injury. The prognosis of this type of complication is always bad. PATIENT CONCERNS: Rapid and correct diagnosis and treatment is important for metastatic extranodal lymphoma with B cell of origin. DIAGNOSES: Syringomyelia accompanied with metastatic cerebellar and thoracic spinal intramedullary lymphoma. INTERVENTIONS: The patient was treated with a combination of systemic chemotherapy and focal radiotherapy and intrathecal therapy. OUTCOMES: Resolution of metastatic lymphoma was not continued after conservative medical management and the patient died finally due to multiple organ failure. LESSONS: Syringomyelia can develop due to the metastatic thoracic intramedullary lymphoma in patients with diffuse malignant large B cell lymphoma. Early and accurate diagnosis, anti-lymphoma treatment, and timely neurosurgical intervention may delay the development of the disease. PMID- 29145276 TI - Endovascular stenting of spontaneous isolated dissection of the superior mesenteric artery: A case report and literature review. AB - RATIONALE: Spontaneous isolated dissection of the superior mesenteric artery (SID SMA) is a rare arterial disease that is difficult to differentiate from other diseases because of lack of specific clinical manifestation and for which there is no available optimal management strategy. PATIENT CONCERNS: A 58-year-old male patient visited our emergency room with sudden onset of moderate-severe epigastric abdominal pain of uncertain cause. DIAGNOSES: Computed tomography scanning showed a characteristic "double lumen sign" of the superior mesenteric artery, and further computed tomography angiography findings revealed a dissected segment of the superior mesenteric artery. INTERVENTIONS: Conservative management was administered for 5 days, but the abdominal pain remained. Subsequently, an endovascular stent was placed in the affected superior mesenteric artery. Postoperative antiplatelet therapy was administered for 6 months. OUTCOMES: The abdominal pain was relieved. Six months later, a follow-up of computed tomography angiography showed that the stent placed had no interval narrowing. LESSONS: Based on our review and the illustration of this case, endovascular stenting may be a preferred rescue treatment in SID-SMA patients for whom initial conservative treatment fails. PMID- 29145277 TI - Tricho-hepato-enteric syndrome with novel SKIV2L gene mutations: A case report. AB - RATIONALE: Tricho-hepato-enteric syndrome (THES) is a rare disorder caused by mutations in the TTC37 or SKIV2L genes and characterized by chronic diarrhea, liver disease, hair abnormalities, and high mortality in early childhood due to severe infection or liver cirrhosis. PATIENT CONCERNS: The patient is the second child of three siblings born to non-consanguineous healthy Japanese parents. She had intrauterine growth retardation and was delivered at 33 weeks of gestation due to placental abruption. She presented with watery diarrhea, elevated levels of liver enzymes, multiple episodes of recurrent bacterial infection, and mild mental retardation. She had facial dysmorphism, including prominent forehead and hypertelorism, and had woolly hair without trichorrhexis nodosa. DIAGNOSIS: Clinical features led to consideration of THES. Novel compound heterozygous nonsense mutations, c.1420G>T (p.Q474*) and c.3262G>T (p.E1088*), in the SKIV2L gene were identified in the patient, and decreased levels of SKIV2L protein expression were revealed by flow cytometry and confirmed by western blot analysis using patient peripheral blood mononuclear cells (PBMCs). INTERVENTIONS: Total parenteral nutrition was required from day 30 to day 100. Trimethoprim sulfamethoxazole prophylaxis was started at the age of 7 years after multiple episodes of bacterial pneumonia and otitis media. OUTCOMES: Chronic diarrhea persisted for more than 10 years, but the symptoms gradually improved with age. At the age of 13 years, she started a normal diet in combination with oral nutritional supplementation and her height and weight were just below the 3rd percentile for healthy individuals. She developed secondary sex characteristics, and menarche occurred at the age of 12 years. Facial dysmorphism, including prominent forehead and hypertelorism, and woolly hair without trichorrhexis nodosa became noticeable as she matured. LESSONS: Physicians must be aware of THES when they encounter a patient with infantile diarrhea, hair abnormalities, immune deficiency, mental retardation, and liver disease. Moreover, flow cytometric detection of SKIV2L protein in PBMCs may facilitate early diagnosis. PMID- 29145278 TI - Safety of continuing aspirin therapy during spinal surgery: A systematic review and meta-analysis. AB - BACKGROUND: Questions whether to continue or discontinue aspirin administration in the perioperative period of spinal surgery has not been systematically evaluated. OBJECTIVE: The present systematic review is carried out to assess the impact of continuing aspirin administration on the bleeding and cardiovascular events in perispinal surgery period. METHODS: Studies were retrieved through MEDLINE, EMBASE, and Springer Link Databases (search terms, aspirin, continue or discontinue, and spinal fusion), bibliographies of the articles retrieved, and the authors' reference files. We included studies that enrolled patients who underwent spinal surgery who were anticoagulated with aspirin alone and that reported bleeding or cardiovascular events as an outcome. Study quality was assessed using a validated form. 95% confidence interval (95% CI) was pooled to give summary estimates of bleeding and cardiovascular risk. RESULTS: We identified 4 studies assessing bleeding risk associated with aspirin continuation or cardiovascular risk with aspirin discontinuation during spinal surgery. The continuation of aspirin will not increase the risk of blood loss during the spinal surgery (95% CI, -111.72 to -0.59; P = .05). Also, there was no observed increase in the operative time (95% CI, -33.29 to -3.89; P = .01) and postoperative blood transfusion (95% CI, 0.00-0.27; P = .05). But as for the cardiovascular risk without aspirin continuation and mean hospital length of stay with aspirin continuation, we did not get enough samples to make an accurate decision about their relations with aspirin. CONCLUSION: Patients undergoing spinal surgery with continued aspirin administration do not have an increased risk for bleeding. In addition, there is no observed increase in the operation time and postoperative blood transfusion. PMID- 29145279 TI - Osteosarcoma in the coracoid process that mimicked an osteochondroma: A case report. AB - RATIONALE: Osteosarcomas are the most common primary malignant bone tumors in children and young adults; these tumors often affect the metaphyses of long bones such as the proximal humerus, proximal tibia, and distal femur. In contrast, osteosarcoma of the coracoid process is extremely rare. PATIENT CONCERNS: Herein, we describe a case of osteosarcoma affecting the coracoid process in a 40-year old woman. The patient presented with shoulder pain, weakness, and an inability to raise her left arm. She had no previous record of shoulder injury and no significant family history. DIAGNOSES: Her C-reactive protein levels were normal, whereas her erythrocyte sedimentation rate and alkaline phosphatase levels were elevated. Imaging studies led to the initial diagnosis of osteochondroma. INTERVENTION: The patient underwent surgical resection. However, the postoperative pathological results revealed an osteosarcoma. The patient transferred to another hospital for subsequent treatment, and her outcome is unknown. LESSONS: A misdiagnosis or inadequate and/or delayed treatment for a coracoid process osteosarcoma could have grave consequences. Computed tomography and magnetic resonance imaging are essential for a diagnosis, and a biopsy can effectively confirm the diagnosis. Our findings suggest that considering only a single factor, or using incomplete information, can lead to an arbitrary diagnosis. PMID- 29145280 TI - Liver stiffness measurement and spleen diameter as predictors for the presence of esophageal varices in chronic hepatitis C patients. AB - Although it is an invasive and unpleasant procedure, esophagogastroduodenoscopy (EGD) is still the gold standard for esophageal varices (EV) detection. The aim of this study was to investigate liver stiffness measurement (LSM) and spleen diameter as simple noninvasive tools for EV prediction in chronic hepatitis C patients (CHC).A total of 123 Egyptian patients with CHC have been included and were classified based on screening EGD result into 2 groups; group A (without EV) and group B (with EV). Group (B) was subclassified according to EV grade into 4 subgroups: (B1, grade I), (B2, grade II), (B3, grade III), and (B4, grade IV). LSM was taken for each patient on the next day by an independent Fibroscan operator and correlated to the EGD result. Demographic, clinical, and biochemical data were recorded and analyzed using advanced data-mining computational technology.Mean LSM was 9.94 +/- 6 kPa for group A and 33.32 +/- 14 kPa for group B, whereas it was 21.22 +/- 3, 25.72 +/- 6, 33.82 +/- 8, and 46.1 +/- 15 kPa for subgroups B1, B2, B3, and B4, respectively. Mean spleen diameter was 11.09 +/- 1.7 cm for group A and 16.58 +/- 1.6 cm for group B. However, LSM >=17 kPa was the only independent factor for EV prediction; splenic longitudinal span >=15 cm was a complementary predictor when LSM was <17 kPa. The overall accuracy was 98.33 +/- 3.33, Mikro = 98.26%.LSM >=17 kPa and spleen diameter >=15 cm is a simple noninvasive algorithm that could be used for prediction of EV and discrimination among its different grades. PMID- 29145281 TI - Cup revision involving retention of a fixed but malpositioned acetabular component in patients with poor general conditions. AB - This study evaluated the surgical technique and outcomes of cup revision involving retention of a fixed but malpositioned acetabular component in patients with poor general conditions.Between 2007 and 2013, we performed cup revision on 12 hips while retaining a fixed (either cemented or uncemented) but malpositioned acetabular component. Indications for this technique were: malpositioned but fixed acetabular shell; sufficient space for the insertion of the prosthesis; and patients with poor general conditions. After intraoperative confirmation of shell stability, a replacement liner was oriented in a new plane. Clinical and imaging data were collected perioperatively and during follow-up for evaluation of surgical efficacy.No intraoperative complications were encountered. Mean operative duration was 70.4 minutes (range, 45-90 minutes) and mean estimated blood loss was 729 mL (range, 400-1200 mL). Mean follow-up duration was 5.1 years (range, 2.5-8.5 years). Average visual analog scale score decreased from (7.08 +/ 1.00) preoperatively to (1.42 +/- 0.67) at final follow-up (P < .05). Average Harris Hip Score improved from (14.7 +/- 6.58) preoperatively to (80.9 +/- 5.30) at final follow-up (P < .05). Anteversions and inclinations of new liners were (15.1 +/- 2.3) degrees and (46.4 +/- 3.9) degrees respectively. Postoperative radiographs showed no signs of prosthesis loosening, periprosthetic fractures, or dislocation compared with preoperatively.The short-term efficacy of cup revision with retention of a malpositioned but fixed acetabular component was satisfactory. PMID- 29145282 TI - Autosomal dominant polycystic kidney disease combined with hypertrophic cardiomyopathy: A case report. AB - INTRODUCTION: This report describes the novel sampling of autosomal dominant polycystic kidney disease (ADPKD) combined with hypertrophic cardiomyopathy (HCM). SYMPTOMS AND CLINICAL FINDINGS: A 48-year-old Chinese man presented with anasarca, hypourocrinia, gross hematuria, and weight gain by 10 kg subsequently developed acute kidney injury after struck by acute respiratory distress syndrome, really a threat to his heart. DIAGNOSES: Abdominal ultrasound revealed multiple small cysts in both kidneys, with the right kidney measuring 11.6 cm in length, and the left kidney measuring 11.5 cm in length, which supported ADPKD. Echocardiography showed left ventricular posterior wall thickness measuring 15.2 mm, interventricular septum measuring 17.2 mm, left atrial size 31.9 mm, ejection fraction measuring 69%, approving the diagnose of HCM. THERAPEUTICS INTERVENTIONS: Because of the failure treatment with tripterygium wilfordii and valsartan, the patient was administered with prednisone 1 mg/kg/day. Continuous renal replacement therapy was required to prevent heart and kidney from failure. OUTCOMES: The patient responded well and his renal function improved. CONCLUSION: This is the first reported case of ADPKD with HCM, with complete remission of acute kidney injury and preservation of cardiac function. Serial checks and measures should be considered for appropriate treatment of ADPKD patient who present with rapid decline of renal function. We present detailed analysis of the patient's disease course and review literature. Written informed consent was obtained from the patient for publication of this case report. It has been permitted by Committee on Ethics of Biomedicine, Second Military Medical University. PMID- 29145283 TI - The relationship between RASSF1A promoter methylation and thyroid carcinoma: A meta-analysis of 14 articles and a bioinformatics of 2 databases (PRISMA). AB - BACKGROUND: DNA promoter methylation can suppresses gene expression and shows an important role in the biological functions of Ras association domain family 1A (RASSF1A). Many studies have performed to elucidate the role of RASSF1A promoter methylation in thyroid carcinoma, while the results were conflicting and heterogeneous. Here, we analyzed the data of databases to determine the relationship between RASSF1A promoter methylation and thyroid carcinoma. METHODS: We used the data from 14 cancer-normal studies and Gene Expression Omnibus (GEO) database to analyze RASSF1A promoter methylation in thyroid carcinoma susceptibility. The data from the Cancer Genome Atlas project (TCGA) database was used to analyze the relationship between RASSF1A promoter methylation and thyroid carcinoma susceptibility, clinical characteristics, prognosis. Odds ratios were estimated for thyroid carcinoma susceptibility and hazard ratios were estimated for thyroid carcinoma prognosis. The heterogeneity between studies of meta analysis was explored using H, I values, and meta-regression. We adopted quality criteria to classify the studies of meta-analysis. Subgroup analyses were done for thyroid carcinoma susceptibility according to ethnicity, methods, and primers. RESULTS: Result of meta-analysis indicated that RASSF1A promoter methylation is associated with higher susceptibility to thyroid carcinoma with small heterogeneity. Similarly, the result from GEO database also showed that a significant association between RASSF1A gene promoter methylation and thyroid carcinoma susceptibility. For the results of TCGA database, we found that RASSF1A promoter methylation is associated with susceptibility and poor disease-free survival (DFS) of thyroid carcinoma. In addition, we also found a close association between RASSF1A promoter methylation and patient tumor stage and age, but not in patients of different genders. CONCLUSIONS: The methylation status of RASSF1A promoter is strongly associated with thyroid carcinoma susceptibility and DFS. The RASSF1A promoter methylation test can be applied in the clinical diagnosis of thyroid carcinoma. PMID- 29145284 TI - Effectiveness of bariatric surgical procedures: A systematic review and network meta-analysis of randomized controlled trials. AB - BACKGROUND: Bariatric surgery has proved to be an effective strategy in treating obesity. However, randomized controlled trials (RCTs) of 3 most common bariatric surgery procedures, Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and laparoscopic adjustable gastric band (LAGB), reported inconsistent results. We performed a systematic review and network meta-analysis to synthesize evidence of effectiveness of the 3 common bariatric procedures from relevant RCTs. METHODS: The present study was a systematic review and network meta-analysis of RCTs. All RCTs must meet the following criteria to be included in the analysis: patients with body mass index (BMI) >=30 kg/m, reported at least 1 outcome of interest, compared at least 2 of the 3 bariatric procedures, and had follow-ups of at least 1 year. Primary outcome was weight loss, expressed as differences in mean BMI reduction and percentage excess weight loss (%EWL) following 1 year after the surgery. Network meta-analysis was based on Bayesian framework with Markov Chain Monte Carlo simulation approach. RESULTS: Eleven RCTs that met the criteria were included in the review. Of 9 trials (n = 765), the differences in mean BMI reduction were -0.76 (95% CI: -3.1 to 1.6) for RYGB versus SG, -5.8 (95% CI: -9.2 to -2.4) for RYGB versus LAGB, and -5.0 (95% CI: -9.0 to -1.0) for SG versus LAGB. Eight RCTs (n = 656) reported percentage excess weight-loss (%EWL), the mean differences between RYGB and SG, RYGB and LAGB, and SG and LAGB were 3.8% (95% CI: -8.5% to 13.8%), -22.2% (95% CI: -34.7% to -6.5%), and -26.0% (95% CI: 40.6% to -6.4%), respectively. The meta-analysis indicated low heterogeneity between studies, and the node splitting analysis showed that the studies were consistent between direct and indirect comparisons (P > .05). CONCLUSION: The RYGB and SG yielded similar in weight-loss effect and both were superior to LAGB. Other factors such as complications and patient preference should be considered during surgical consultations. PMID- 29145285 TI - Degeneration of paramedian nuclei in the thalamus induces Holmes tremor in a case of artery of Percheron infarction. AB - RATIONALE: Holmes' tremor is an uncommon neurologic disorder following brain insults, and its pathogenesis is undefined. The interruption of the dento-rubro thalamic tract and secondary deterioration of the nigrostriatal pathway are both required to initiate Holmes' tremor. We used nuclear medicine imaging tools to analyze a patient with concurrent infarction in different zones of each side of the thalamus. Finding whether the paramedian nuclear groups of the thalamus were injured was a decisive element for developing Holmes' tremor. PATIENT CONCERNS: A 36-year-old woman was admitted to our department due to a bilateral paramedian thalamic infarction. Seven months after the stroke, a unilaterally involuntary trembling with irregularly wavering motions occurring in both her left hand and forearm. DIAGNOSIS: Based on the distinct features of the unilateral coarse tremor and the locations of the lesions on the magnetic resonance imaging (MRI), the patient was diagnosed with bilateral paramedian thalamic infarction complicated with a unilateral Holmes' tremor. INTERVENTIONS: The patient refused our recommendation of pharmacological treatment with levodopa and other dopamine agonists based on personal reasons and was only willing to accept physical and occupational training programs at our outpatient clinic. OUTCOMES: We utilized serial anatomic and functional neuroimaging of the brain to survey the neurologic deficit. A brain magnetic resonance imaging showed unequal recovery on each side of the thalamus. The residual lesion appeared larger in the right-side thalamus and had gathered in the paramedian area. A brain perfusion single-photon emission computed tomography (SPECT) revealed that the post-stroke hypometabolic changes were not only in the right-side thalamus but also in the right basal ganglion, which was anatomically intact. Furthermore, the brain Technetium-99m-labeled tropanes as a dopamine transporter imaging agents scan ( Tc-TRODAT-1) displayed a secondary reduction of dopamine transporters in the right nigrostriatal pathway which had resulted from the damage on the paramedian nuclear groups of the right side thalamus. LESSONS: Based on the functional images, we illustrated that a retrograde degeneration originating from the thalamic paramedian nuclear groups, and extending forward along the direct innervating fibers of the mesothalamic pathway, played an essential role towards initiating Holmes' tremor. PMID- 29145286 TI - Bilateral discoid medial meniscus associated with meniscal tears and hypoplasia of the medial femoral condyle: A case report. AB - RATIONALE: Bilateral discoid medial menisci is an extremely rare abnormality of the knee joint. The presence of a discoid medial meniscus has been associated with magnetic resonance imaging (MRI) and radiographic changes in the tibial region, such as cupping of the medial tibial plateau and tibial physis collapse. While discoid medial meniscal tears with hypoplasia of the femoral medial condyles have not been previously reported. Herein, we report a case of bilateral discoid medial menisci associated with meniscal tears and femoral bone changes. PATIENT CONCERNS: A 28-year-old man presented with left knee pain and restricted range of motion; the right knee was asymptomatic. DIAGNOSES: Based on radiographic and MRI findings, he was diagnosed with bilateral discoid medial meniscal tears. INTERVENTIONS: Partial meniscectomy and reshaping were performed for the torn discoid medial meniscus of the left knee only. OUTCOMES: MRI revealed short, flattened femoral medial condyles in the coronal and sagittal planes, and hypoplasia of the femoral medial condyles in the axial plane; these findings were confirmed arthroscopically in the left knee. The patient had a satisfactory results at the 12-month follow-up. LESSONS: This case indicates a potential link between discoid medial menisci and hypoplasia of the femoral medial condyle. We recommend preservation of the discoid medial meniscus in asymptomatic patients, while arthroscopic partial meniscectomy and reshaping is recommended in symptomatic patients. PMID- 29145287 TI - Transforaminal endoscopy in lumbar burst fracture: A case report. AB - RATIONALE: Lumbar burst fractures are frequent injury resulting from high-energy trauma, and the patients suffer from pain and the neurologic dysfunction. Although minimally invasive techniques have advanced rapidly, it was the first time to apply transforaminal endoscopic combined with percutaneous pedicle screw fixation to treatment of lumbar burst fractures. PATIENT CONCERNS: A 33-year-old man underwent Magerl type A3.1 burst fracture at L2 and compression fractures at L3 due to falling from a height with severe lower back pain, sensory loss, and atony of the right leg. DIAGNOSES: Burst fracture at L2, compression fractures at L3. INTERVENTIONS: The patient was presented to 1-stage operation of percutaneous pedicle screw fixation at L1, L2, L3, and L4 instead of delayed posterior open surgery. At 1 week after injury, the 2-stage operation with a percutaneous transforaminal endoscopic was undertaken for decompression. OUTCOMES: No matter the function of nerve and imaging findings, all got ideal recoveries in just 3 days after 2-stage operation. At the 3-month follow-up, there was no loss of sagittal plane alignment, and spinal cord compression was completely relieved. The patient regained near-full neurologic function postoperatively. LESSONS: A minimally invasive surgery (ie, transforaminal endoscopic combined with percutaneous pedicle screw fixation) for the treatment of Magerl type A3.1 burst fracture at lumbar was feasible. In addition, the key to the recovery of neurological function is the complete and effective decompression of spinal. PMID- 29145288 TI - Efficacy of cold application on pain during chest tube removal: a randomized controlled trial: A CONSORT-compliant article. AB - BACKGROUND: Use of analgesics is the most common method to alleviate the pain induced by chest tube removal (CTR), but patient response to medication can vary and may not be achieved complete relaxation. This study was to determine the effectiveness of cold application in combination with standard analgesic administration before CTR on CTR-induced pain. METHODS: A prospective, randomized, single-blind, sham-controlled study was conducted. In addition to the same routine care, subjects in the experimental group (n = 30) received cold application of 600-g ice packs 15 minutes before CTR, whereas subjects in the sham group (n = 30) received tap water packs. Numerical rating scale was used to measure pain intensity before, immediately after, and 10 minutes after CTR. RESULTS: The generalized linear estimating equation (GEE) model, adjusted for other factors, both the groups demonstrated a trend toward decreased pain during CTR over time (P < .001), but no significant differences between the 2 groups (P = .65), even stratifying by gender. If we fixed experimental group, women significant reduced pain score of 2.7 on immediately after CTR compared with before CTR (P < .0001) and reduced pain score of 2.05 on 10 minutes after CTR compared with before CTR (P < .0001). The sham group had no similar performance as the experimental group. In the male subgroup, both experimental and sham groups, men significantly reduced pain score on immediately after CTR and 10 minutes after CTR compared with before CTR (P < .0001). CONCLUSION: The results indicate that cold application is not more effective than sham treatment in decreasing pain during CTR, even among gender. Although statistically non significant, clinically important differences of decreased pain score were observed with cold application among women (Clinical Trial Registration: clinicaltrials.gov identifier NCT03307239). PMID- 29145289 TI - Mercury poisoning through intravenous administration: Two case reports with literature review. AB - RATIONALE: Metallic mercury poisoning through intravenous injection is rare, especially for a homicide attempt. Diagnosis and treatment of the disease are challenging. PATIENT CONCERNS: A 34-year-old male presented with pyrexia, chill, fatigue, body aches, and pain of the dorsal aspect of right foot. Another case is that of a 29-year-old male who committed suicide by injecting himself metallic mercury 15 g intravenously and presented with dizzy, dyspnea, fatigue, sweatiness, and waist soreness. DIAGNOSIS: The patient's condition in case 1 was deteriorated after initial treatment. Imaging studies revealed multiple high density spots throughout the body especially in the lungs. On further questioning, the patient's girlfriend acknowledged that she injected him about 40 g mercury intravenously 11 days ago. The diagnosis was then confirmed with a urinary mercury concentration of 4828 mg/L. INTERVENTIONS: Surgical excision, continuous blood purification, plasma exchange, alveolar lavage, and chelation were performed successively in case 1. Blood irrigation and chelation therapy were performed in case 2. OUTCOMES: The laboratory test results and organ function of the patient in case 1 gradually returned to normal. However, in case 2, the patient's dyspnea was getting worse and he finally died due to toxic encephalopathy and respiratory failure. LESSONS: Early diagnosis and appropriate treatment are critical for intravenous mercury poisoning. It should be concerned about the combined use of chelation agents and other treatments, such as surgical excision, hemodialysis and plasma exchange in clinical settings. PMID- 29145290 TI - Effective treatment of narcolepsy-like symptoms with high-frequency repetitive transcranial magnetic stimulation: A case report. AB - RATIONALE: Narcolepsy is a rare sleep disorder with disrupted sleep-architecture. Clinical management of narcolepsy lies dominantly on symptom-driven pharmacotherapy. The treatment role of repetitive transcranial magnetic stimulation (rTMS) for narcolepsy remains unexplored. PATIENT CONCERNS: In this paper, we present a case of a 14-year-old young girl with excessive daytime sleepiness (EDS), cataplexy and hypnagogic hallucinations. DIAGNOSES: After excluding other possible medical conditions, this patient was primarily diagnosed with narcolepsy. INTERVENTIONS: The patient received 25 sessions of high frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC). OUTCOMES: The symptoms of EDS and cataplexy significantly improved after rTMS treatment. Meanwhile, her score in the Epworth sleep scale (ESS) also remarkably decreased. LESSONS: This case indicates that rTMS may be selected as a safe and effective alternative strategy for treating narcolepsy-like symptoms. Well-designed researches are warranted in future investigations on this topic. PMID- 29145291 TI - Early enteral nutrition versus delayed enteral nutrition in acute pancreatitis: A PRISMA-compliant systematic review and meta-analysis. AB - BACKGROUND: Whether early enteral nutrition (EEN) administration is more beneficial than delayed enteral nutrition (DEN) for patients with acute pancreatitis remains controversial. METHODS: This meta-analysis aimed to pool all relevant articles to evaluate the effects of EEN within 48 hours versus DEN beyond 48 hours on the clinical outcomes of patients with acute pancreatitis. We searched PubMed, Scopus, Embase, and Web of Science for all relevant studies and extracted the data concerning basic characteristics, complications, and mortality. We calculated the pooled risk ratio (RR), weighted mean difference, and the corresponding 95% confidential interval (95% CI) using STATA 12.0. RESULTS: For complications, the pooled analysis showed that EEN was related to a reduced risk of multiple organ failure (RR = 0.67, 95% CI 0.46-0.99, P = .04), but not for necrotizing pancreatitis (RR = 0.95, 95% CI 0.81-1.12, P = .57). There was a tendency for decreased systemic inflammatory response syndrome in the EEN group, but the trend was not significant (RR = 0.85, 95% CI 0.71-1.02, P = .09). For mortality, no significant difference was found between the EEN and DEN groups (RR = 0.78, 95% CI 0.27-2.24, P = .64). CONCLUSION: EEN within 48 hours is superior to DEN beyond 48 hours for patients with acute pancreatitis; however, more studies are required to verify this conclusion. PMID- 29145292 TI - Recurrent spinal primitive neuroectodermal tumor with brain and bone metastases: A case report. AB - RATIONALE: Primary spinal primitive neuroectodermal tumor (PNET) is relatively rare in all age groups, and the prognosis in most cases of spinal PNETs appears to be poor, with a median patient survival of 1 to 2 years. We present a case with recurrent spinal PNET with brain and bone metastases that was successfully treated by multimodality treatment. PATIENT CONCERNS: A 14-year-old teenage girl had suffered from progressive left upper back pain with bilateral lower legs weakness and numbness for 1 year. After treatment, left neck mass was noted 3 years later. DIAGNOSES: Initially, magnetic resonance imaging (MRI) showed neurogenic tumor involving intradural extramedullary space of T5-T10. Pathology report showed PNET (World Health Organization grade IV) featuring lobules of neoplastic cells with round regular nuclei, high nucleus-to-cytoplasm ratio, and fibrillary cytoplasm. At the time of tumor recurrence, chest MRI then showed recurrent tumor at T2-T3 level of the epidural space with right neural foramina invasion. Brain MRI showed extensive bilateral calvarial metastases and leptomeningeal metastases in the right frontoparietal regions. Bone scan showed multiple bone metastases. INTERVENTIONS: T-spine tumor removal and adjuvant radiotherapy (RT) to T-spine tumor bed were performed in the initial treatment. After clinical tumor recurrence, tumor removal was done again. She then received chemotherapy followed by whole brain irradiation with hippocampal sparing with 35 gray in 20 fractions. OUTCOMES: After treatment, follow-up images showed that the disease was under control. There was no neurological sequela. She has survived more than 7 years from diagnosis and more than 4 years from recurrence to date. LESSONS: Multimodality treatments including operation, RT, and chemotherapy should be considered in the initial treatment planning, and salvage chemotherapy was useful in this case. PMID- 29145293 TI - Y-configuration stent combined with iodine-125 seeds strand for the treatment of hepatocellular carcinoma with tumor thrombosis in portal vein branches: A case report. AB - RATIONALE: Currently, the treatment of hepatocellular carcinoma (HCC) associated with portal vein tumor thrombosis (PVTT) is a challenge. Percutaneous puncture endovascular placement of iodine-125 (I) seeds strand and stent is reported to treat HCC with tumor thrombus effectively. However, it is proved to be only suitable for the main portal vein (MPV) thrombus. PATIENT CONCERNS: A 42-year-old male patient was referred to our institution after experiencing right upper abdominal distention without abdominal pain, nausea, or vomiting for 2 weeks. The patient had a history of hepatitis B virus infection over a 20 year period. DIAGNOSIS: After a full evaluation, the patient was diagnosed with primary HCC with a tumor thrombus in both main and branch portal veins. INTERVENTIONS: We used a Y-configuration stent combined with I seeds strand to treat the tumor thrombus in both main and branch portal veins. OUTCOMES: The patient's liver function and the stent patency period were improved. More importantly, the patient had an acceptable survival time. LESSONS: A Y-configuration stent makes it possible to treat tumor thrombosis in portal vein branches (PVBs). However, the long-term curative effects of Y-configuration stents need to be verified. PMID- 29145294 TI - Recurrent tracheoesophageal fistula in an adolescent without persistent symptoms: A case report. AB - RATIONALE: Congenital esophageal atresia (EA) and tracheoesophageal fistula (TEF) ininfants have been treated well with surgery. Approximately 10% of children displayed recurrent fistula. In the present case, we reported recurrent TEF in an adolescent as a complication of EA/TEF in infancy. PATIENT CONCERNS: An infant was diagnosed with gross type C congenital EA and TEF and subsequentlyunderwent repair in early infancy, with division of the TEF and primary esophageal anastomosis. Postoperative esophageal strictures developed and were relieved by bougienage of the esophagus partially. Then, the child had normal growth with mild symptoms, mainly choking when drinking water. At 11 years of age, the child developed fever and cough, and massive bronchiectasis in lobus inferior pulmonis sinister was found. DIAGNOSIS: Recurrent tracheoesophageal fistula. INTERVENTIONS: Division of the TEF and esophageal replacement with gastric tube was performed as treatment OUTCOMES:: The child recovered well. LESSONS: Recurrent tracheoesophageal fistula aftercongenital EA and TEF could be diagnosed in adolescence. Massive bronchiectasis might develop without apparent symptoms. PMID- 29145295 TI - Extrarenal teratoma with nephroblastoma in the retroperitoneum: Case report and literature review. AB - RATIONALE: Teratoma with nephroblastoma is a rare disease. The most common site at which teratoma with nephroblastoma occurs is the kidney. The mechanisms underlying the development of teratoma with nephroblastoma have not been fully elucidated. PATIENT CONCERNS: In the current report, we describe the clinical characteristics of a 3-year-old girl with a complaint of a painless abdominal mass in the upper right side of the body. Ultrasonography and computed tomography revealed a cystic-solid mass with a clear boundary. DIAGNOSIS: Surgical resection and a subsequent pathological examination confirmed that the mass contained teratoma tissues and renal blastemal components, which supports the diagnosis of teratoma with nephroblastoma. INTERVENTIONS: The patient underwent an exploratory laparotomy through a transverse abdominal incision. Complete resection of the mass was performed in this patient. OUTCOMES: The patient's postoperative course was uneventful and she was discharged on the 8th postoperative day. The girl had no complaints during the 2 years follow-up period. LESSONS: Teratoma with nephroblastoma is a rare entity that typically presents in childhood. Due to its rarity, no standardized criteria have been established for the categorization and treatment of these lesions. However, a complete excision of this tumor allows the diagnosis to be confirmed and lowers the risk of recurrence. PMID- 29145296 TI - Approach to the patient with pregnancy and lactation-associated osteoporosis: A case report and a review of the literature. AB - RATIONALE: Pregnancy and lactation-associated osteoporosis (PLO) is very rare, but it can cause severe vertebral compression fractures with disabling back pain. Although it is a rare, PLO must be kept in mind in the differential diagnosis in patients presenting with low back pain during or after pregnancy. PATIENT CONCERNS: A 23-year-old woman who suffered from lumbago and fractures in the vertebral column 1 month after delivery. DIAGNOSIS: Pregnancy and lactation associated osteoporosis. INTERVENTIONS: Combination therapy of calcium and vitamin D were used for treatment, as well as regular follow-up. OUTCOMES: The patient's back pain had decreased significantly, the bone metabolic index, bone mineral density (BMD) had improved and she did not experience any recurrence. LESSONS: Early diagnosis and treatment of calcium and vitamin D, as well as the efficacy of PLO intervention monitoring and evaluation are critical for the success of treatment. PMID- 29145297 TI - Therapeutic effect of neoadjuvant chemotherapy combined with curettage to treat distal femoral osteosarcoma: A case report. AB - RATIONALE: Osteosarcoma is the most common malignant bone tumor in children and adolescents. Metastasis occurs early, the mortality rate is high, and the tumor results in a tremendous physical, mental, and economic burden on patients. Therefore, the treatment of osteosarcoma has been important for orthopedic surgeons. However, treatment has always been a difficult problem globally. PATIENT CONCERN: We present the case of a 22-year-old girl with increasing local pain in the distal left thigh. DIAGNOSES: The patient was initially diagnosed as bone cancer according to computed tomography (CT) and X-ray imaging. And the patient was further diagnosed as osteosarcoma via to puncture biopsy of the left distal femur. INTERVENTIONS: Local arterial infusion chemotherapy, systemic intravenous chemotherapy, and curettage was conducted because of limb salvage program. OUTCOMES: The patient was doing well with no evidence of local or distant recurrence 7 years after the surgery. LESSONS: Our case indicated that limb osteosarcoma patients can undergo a limb salvage program of local arterial infusion chemotherapy, systemic intravenous chemotherapy, and curettage. PMID- 29145298 TI - Small cell lung cancer treated by radiofrequency ablation: A case report. AB - RATIONALE: The morbidity and mortality of small cell lung cancer (SCLC), an uncommon malignancy of the lung, remain high. Radiofrequency ablation (RFA) creates heat to destroy cancer cells and is usually used to treat non-SCLC, but not SCLC. PATIENT CONCERNS: An 85-year-old male presented with a 2-month history of a productive cough with white phlegm and a 2-day history of hemoptysis. Chest computed tomography revealed a mass in the right lower lobe. DIAGNOSES: An excision biopsy of the mass showed SCLC. INTERVENTIONS: We treated the tumor with RFA. OUTCOMES: At the 2-year follow-up examination, the efficacy of the RFA was evaluated as a partial response. LESSONS: RFA can improve the prognosis of SCLC and should be considered for its treatment. PMID- 29145299 TI - Prophylactic temporary abdominal aorta balloon occlusion in women with placenta previa accretism during late gestation. AB - BACKGROUND: To evaluate the clinical efficacy of prophylactic temporary balloon occlusion of the abdominal aorta in patients with placenta previa accretism during cesarean section. METHODS: Twenty-three consecutive patients, prenatally confirmed with placenta previa accretism were retrospectively analyzed in our center from August 2012 to October 2014. All 23 subjects underwent cesarean section with prophylactic balloon occlusion of the abdominal aorta. RESULTS: All of the 23 subjects experienced singleton pregnancies leading to the birth of live infants. Of these subjects, the following problems were diagnosed: placenta accrete (n = 10), placenta increte (n = 10), and placenta precrete (n = 3). Mean intraoperative hemorrhage was 1170.0 mL. Fifteen patients received red blood cell transfusion with a mean transfusion volume of 2.3 units. The incidence of hysterectomy was 21.74% (5/23) with blood loss ranging from 2000 to 5000 mL (mean 3360.0 mL). One complication encountered in this retrospective study was lower extremity arterial thrombosis. Eighteen patients were followed-up by telephone to 14 months following discharge, all babies were noted to be healthy. CONCLUSION: Prophylactic abdominal aorta balloon occlusion (ABO) was relatively safe in the treatment of patients with placenta previa accretism. This approach could represent a key aspect in a multidisciplinary algorithm in reducing hemorrhage in abnormal placentation. PMID- 29145300 TI - Cost-effectiveness analysis of neonatal screening of critical congenital heart defects in China. AB - BACKGROUND: Pulse oximetry screening is a highly accurate tool for the early detection of critical congenital heart disease (CCHD) in newborn infants. As the technique is simple, noninvasive, and inexpensive, it has potentially significant benefits for developing countries. The aim of this study is to provide information for future clinical and health policy decisions by assessing the cost effectiveness of CCHD screening in China. METHODS AND FINDINGS: We developed a cohort model to evaluate the cost-effectiveness of screening all Chinese newborns annually using 3 possible screening options compared to no intervention: pulse oximetry alone, clinical assessment alone, and pulse oximetry as an adjunct to clinical assessment. We calculated the incremental cost per averted disability adjusted life years (DALYs) in 2015 international dollars to measure cost effectiveness. One-way sensitivity analysis and multivariate probabilistic sensitivity analysis were performed to test the robustness of the model. Of the three screening options, we found that clinical assessment is the most cost effective strategy compared to no intervention with an incremental cost effectiveness ratio (ICER) of Int$5,728/DALY, while pulse oximetry plus clinical assessment with the highest ICER yielded the best health outcomes. Sensitivity analysis showed that when the treatment rate increased up to 57.5%, pulse oximetry plus clinical assessment showed the best expected values among the three screening options. CONCLUSION: In China, for neonatal screening for CCHD at the national level, clinical assessment was a very cost-effective preliminary choice and pulse oximetry plus clinical assessment was worth considering for the long term. Improvement in accessibility to treatment is crucial to expand the potential health benefits of screening. PMID- 29145301 TI - Sinonasal osteoblastomas in the middle turbinate: Two case reports. AB - RATIONALE: Sinonasal osteoblastoma is an extremely rare benign bone-forming tumor. PATIENT CONCERNS: We report 2 extremely rare cases of sinonasal osteoblastoma in the middle turbinate. DIAGNOSES: The preoperative diagnosis was osteoma in the middle turbinate. INTERVENTIONS: We performed endoscopic removal of the mass in the middle turbinate and frontal recess. OUTCOMES: Histological examination of biopsy specimens revealed osteoblastoma. LESSONS: Clinicians should consider osteoblastoma in the differential diagnosis of tumors arising in the nasal cavities. PMID- 29145302 TI - Burkitt lymphoma and cavernous sinus syndrome with breast uptake on 18F-FDG PET/CT: A case report. AB - RATIONALE: Burkitt lymphoma (BL) is a type of non-Hodgkin lymphoma that arises in the B-cells. Cavernous sinus involvement is rare, especially in adults. Here we report an unusual case of a 30-year-old HIV-positive woman with BL and cavernous sinus syndrome who also had intense bilateral breast uptake, related to menstrual cycle. Fluorine-18 2-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) has been found to be useful in the management of BL. PATIENT CONCERNS: A 30-year old female patient presented with a history of diplopia and headache. DIAGNOSES: Magnetic resonance imaging revealed a large cavernous sinus mass. A bone marrow biopsy was done and demonstrated extensive marrow infiltration by Burkitt lymphoma. Further investigation detected the Epstein-Barr virus in her cerebrospinal fluid using qualitative polymerase chain reaction. 18F-FDG PET/CT imaging done revealed a hypermetabolic cavernous sinus mass, conglomerates of enlarged pelvic and para-aortic lymph nodes as well as diffuse bone marrow uptake. Intense bilateral breast uptake was noted coinciding with the start of menses. INTERVENTIONS: She was started on chemotherapy with adjuvant radiotherapy. OUTCOMES: After her first cycle of chemotherapy, repeat 18F-FDG PET/CT imaging revealed a marked reduction in the metabolic activity and size of the cavernous sinus mass and conglomerates of lymph nodes. The bone marrow activity was still visualized but less intense compared to the staging PET/CT. LESSONS: A cavernous sinus mass will rarely be the primary lesion in Burkitt's Lymphoma. Our case demonstrates the role of 18F FDG PET/CT in the assessment of such cases to detect other primary areas of disease involvement. It is useful in accurate initial staging and monitoring of treatment response in patients with Burkitt's Lymphoma. PMID- 29145303 TI - Epicardial radiofrequency catheter ablation of Brugada syndrome with electrical storm during ventricular fibrillation: A case report. AB - RATIONALE: Brugada syndrome (BrS) is characterized by ST segment elevation at the J point >=2 mm in the right precordial electrocardiogram (ECG) leads, in the absence of structural heart disease, electrolyte disturbances, or ischemia. It is a well-described cause of sudden death in young patients, especially in the age of between 30 and 40 years old. Here, we reported an unusual case of electrical storm (ES) of ventricular fibrillation (VF) caused by BrS with complete right bundle-branch block (CRBBB) in a 75-year-old male patient. PATIENT CONCERNS: A 75 year-old male patient survived sudden cardiac death caused by a ventricular ES. He presented with the cove-shaped ST elevation of 2 mm in lead V1 with typical CRBBB and lacked structural cardiomyopathy and coronary heart disease. The patient suffered ventricular ES again, although the implantable cardioverter defibrillator(ICD) had implanted. DIAGNOSES: Brugada syndrome with complete right bundle-branch block. INTERVENTIONS: Implantable cardioverter defibrillator (ICD) implantation was performed. But this therapy could not prevent the recurrence of malignant arrhythmia. Finally, the ES was treated successfully using radiofrequency catheter ablation (RFCA) at the area of the free wall of the right ventricular outflow tract (RVOT) epicardium. OUTCOMES: During 7 months of follow up, the patient was asymptomatic and free of arrhythmic events. LESSONS: As far as we know, the patient is the oldest patient reported to have BrS. RFCA offers an alternative therapy for patients with BrS, especially when ICD shocks are encountered. PMID- 29145304 TI - Partially cystic thyroid nodules in ultrasound-guided fine needle aspiration: Prevalence of thyroid carcinoma and ultrasound features. AB - Partially cystic thyroid nodules (PCTNs) are common on ultrasound (US). However, there are insufficient data on the prevalence of thyroid carcinoma among such nodules. The purpose of this study was thus to evaluate the prevalence and differentiation of partially cystic thyroid cancers in US-guided fine needle aspiration (FNA).A total of 1342 consecutive patients with 1360 thyroid nodules underwent prospective US diagnosis and FNA biopsy. In total, 281 nodules (20.7%) were partially cystic lesions. The nodules were prospectively analyzed based on US features (ie, solid portion positions, shapes, margins, and microcalcifications) and US diagnosis (benign, suspicious, or malignant).Of the 281 partially cystic lesions, 22 nodules (8%) had inadequate FNA results, 14 nodules were diagnosed as malignant, 9 were suspicious for malignancy, and 236 were benign on FNA. Thirteen cancers were confirmed upon surgical histopathology examination or FNA, yielding a 4.6% rate of malignancy. Twelve of these cancers were papillary carcinomas, and 1 was an anaplastic carcinoma. The following individual sonographic characteristics had a statistically significant association with thyroid cancer: nodule composition (solid portion >=50%, P = .000), eccentric solid portion (P = .001), irregular nodule shape (P = .000), microcalcification (P = .000), and intranodular vascularity (P = .001). The sensitivity, specificity, and accuracy of the US-based diagnoses were 84.6%, 84.0%, and 84.0%, respectively.Fewer than 5% of the partially cystic nodules in this FNA series were malignant. Sonographic characteristics can be used to prioritize nodules for FNA biopsy. PMID- 29145305 TI - Prognostic significance of metabolic enzyme pyruvate kinase M2 in breast cancer: A meta-analysis. AB - BACKGROUNDS: Numerous studies have reported that aberrant pyruvate kinase M2 isoform (PKM2) expressed in cancer, indicating that PKM2 plays a critical role in tumor initiation and progression. Nevertheless, its prognostic value in breast cancer tumor is yet contentious. Therefore, we performed this meta-analysis to evaluate the prognostic significance of PKM2 in breast cancer. METHODS: Eligible relevant literatures were retrieved by searching PubMed, the Cochrane Library, Embase through December 2016. Articles that comparing different PKM2 expression levels in human breast cancer tissues and prognostic significance were included. Software RevMan 5.3 and STATA (Review Manager (RevMan): [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. STATA: StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP) were applied to analyze the outcomes. Pooled results were presented in hazardous ratios (HRs) of 5-year overall survival (OS), progression-free survival (PFS), and odds ratios (ORs) of clinicopathological features with 95% confidence intervals. RESULTS: Data from 6 involved studies with 895 patients were summarized. Breast cancer patients with high PKM2 had a worse OS (pooled HR = 1.65, 95% CI = 1.31-2.08, P < .001) and PFS (pooled HR = 2.49, 95% CI = 1.84-3.36, P < .00001). High PKM2 expression is related to lymph node metastasis (N1+N2+N3 vs N0, OR = 1.97, 95%CI = 1.39-2.80, P = .0001). The outcome stability was verified via sensitivity analysis. But elevated PKM2 expression was not correlated to tumor stage (T2+T3 vs T1, pooled OR = 0.80, 95% CI = 0.36-1.77, P = .58) and differential grade (G2+G3 vs G1, OR = 2.74, 95%CI = 0.76-9.84, P = .12). No publication bias was found in the included studies for OS (Begg test, P = .260; Egger test, P = .747). CONCLUSIONS: High PKM2 expression denotes worse OS and PFS in breast cancer patients, and correlate with the lymph node metastasis. However, there is no evidence for the impact of PKM2 expression on T stage and tumor differentiation. PMID- 29145306 TI - Dynamic noninvasive markers predict hepatocellular carcinoma in chronic hepatitis C patients without sustained virological response after interferon-based therapy: Prioritize who needs urgent direct-acting antiviral agents. AB - Some patients with hepatitis C virus (HCV) infections who fail to achieve sustained virological responses (SVRs) after interferon (IFN) therapy do not develop hepatocellular carcinoma (HCC). Risk stratification of these patients may help identify those who would benefit most from treatment with direct-acting antivirals (DAAs).A total of 552 HCV-infected patients with non-SVR status were enrolled. Laboratory data before and after IFN treatment were analyzed to determine the relationship of changes in serum markers with development of HCC during the 7-year study period.HCC developed in 93 patients. The risk factors for HCC were pre-existing liver cirrhosis, low hemoglobin level at baseline, low pretreatment platelet count, high post-treatment alpha-fetoprotein (AFP) level (>=15 ng/mL), and high post-treatment Fibrosis 4 (FIB4) index (>3.25). For patients without pre-existing cirrhosis, those with high post-treatment AFP level and FIB4 index had the highest risk of HCC (1 year: 6.7%; 3 years: 10.9%; 5 years: 29.7%), followed by those with high post-treatment AFP level and low post treatment FIB4 index (5 years: 25%), and those with low post-treatment AFP level and high post-treatment FIB4 index (1 year: 3.7%; 3 years: 5.2%; 5 years: 10.6%). The risk was even lower for patients with low post-treatment AFP level and FIB4 index (1 year: 0%; 3 years: 0.4%; 5 years: 2.5%). None of the patients with FIB4 indexes consistently below 1.45 developed HCC.The combined use of post-treatment AFP level and FIB4 index was useful for risk stratification of HCV-infected patients with non-SVR status after IFN therapy. These data may help clinicians to identify patients who most urgently need DAA treatment. PMID- 29145307 TI - Computed tomography-guided percutaneous cutting needle biopsy for small (<= 20 mm) lung nodules. AB - The goal of this study is to determine the feasibility, diagnostic accuracy, and risk factor of complications of computed tomography (CT)-guided percutaneous cutting needle biopsy (PCNB) for small lung nodules.From January 2014 to May 2015, 141 patients with small lung nodule were performed with CT-guided PCNB procedure. Data on technical success, diagnostic accuracy, and complication were collected and analyzed.Technical success of CT-guided PCNB for small lung nodules was 100%. A total of 141 nodules were punctured. The mean time of the procedure was 15.7 +/- 4.3 minutes. The PCNB results included malignancy (n = 79), suspected malignancy (n = 6), specific benign lesion (n = 8), nonspecific benign lesion (n = 47), and invalid diagnosis (n = 1). The final diagnosis of the 141 nodules included malignancy (n = 90), benign (n = 37), and nondiagnostic lesion (n = 14). The nondiagnostic nodules were not included for calculating the diagnostic accuracy. The sensitivity, specificity, and overall diagnostic accuracy of CT-guided PCNB for small lung nodule were 94.4% (85/90), 100% (37/37), and 96.1% (122/127), respectively. Pneumothorax and lung hemorrhage (>= grade 2) occurred in 17 (12.1%) and 22 (15.6%) patients, respectively. Based on the univariate and multivariate logistic analyses, the risk factors of pneumothorax included nonprone position (P = .019) and longer procedure time (P = .018). The independent risk factor of lung hemorrhage (>= grade 2) was deeper lesion distance from pleura along needle path (P = .024).This study demonstrates that CT-guided PCNB can provide a high diagnostic accuracy for small lung nodule with acceptable complications. PMID- 29145308 TI - Comparison of the Pentax AirwayScope and McGrath MAC videolaryngoscope for endotracheal intubation in patients with a normal airway. AB - Various videolaryngoscopes (VLs) have been developed to provide a better laryngeal view and facilitate difficult intubations. The goal of this study was to compare 2 VLs, the Pentax AWS and the McGrath VL, with respect to intubation time and ease of intubation.One hundred forty patients aged 19 to 65 years (American Society of Anesthesiologists classification I or II), who required tracheal intubation for elective surgery, were randomly assigned to 1 of the 2 groups: the Pentax AWS (n = 70) or the McGrath VL (n = 70). The primary outcome was time to intubation (TTI) measured by a blind observer. The intubation difficulty scale (IDS), percentage of glottic opening (POGO) scale, glottic grade, use of optimal external laryngeal manipulation (OELM), and ease of intubation were also recorded.The Pentax AWS provided a better laryngeal view than the McGrath VL with respect to the Cormack-Lehane (CL) glottic grade (1/2a/2b) (63/7/0 vs 43/24/3, P < .001) and the POGO scale (median [interquartile range, IQR]) (100 [100-100] vs 100 [80-100], P < .001). The IDS was significantly lower in the Pentax AWS group compared with the McGrath VL group (median [IQR]) (0 [0-0] vs 0 [0-1], P < .001). However, the TTI was similar in both the Pentax AWS and McGrath VL groups (median [IQR]) (30 [27-34] vs 32 [27-35] seconds, P = .440). OELM and ease of intubation were also similar between the 2 groups.The Pentax AWS offered a superior laryngeal view compared with the McGrath VL. There was no significant difference in either the intubation time or ease of intubation using these 2 devices in patients with normal airways. PMID- 29145309 TI - Short-term effects of sports taping on navicular height, navicular drop and peak plantar pressure in healthy elite athletes: A within-subject comparison. AB - Medial tibial stress syndrome (MTSS) is one of the most common exercise-induced leg pain. The navicular drop (ND) was identified as a risk factor for MTSS. This study aimed to evaluate the short-term effects of sports taping applied to the supporting lower leg during sitting, standing, walking, and jogging to restrict the ND in healthy elite athletes.Twenty-four healthy elite athletes without a history of exercise-induced pain or injuries in the lower limbs participated in this study (median age: 21.00 years; 1st--3rd quartiles; 19.25-22.00). The 4 taping conditions were used: rigid taping (RT), kinesiology taping (KT), placebo taping (PT), and non-taping (NT). The order of taping techniques was randomly assigned. Normalized navicular height (NH), ND, and normalized ND evaluated using 3-dimensional motion analysis, and normalized peak plantar pressure (PP) were compared in 4 taping conditions during sitting, standing, walking, and jogging.During sitting, the normalized NH of RT is higher than that of NT, KT, and PT (chi = 17.30, P = .001), while during jogging, the normalized NH of RT is higher than that of NT and PT (chi = 10.55, P = .014). The normalized peak PP of NT is higher than that of PT (chi = 8.871, P = .031) in the lateral midfoot region.This study showed the RT technique maintained NH during sitting and jogging, and the RT technique could be an effective preventive and treatment strategy for MTSS. PMID- 29145310 TI - Successful treatment with rivaroxaban of cerebral venous thrombosis and bone marrow necrosis induced by pegaspargase: A case report and literature review. AB - RATIONALE: Pegaspargase has been used in the treatment of acute lymphoblastic leukemia with promising results. However, it has also been associated with several potentially serious complications, including thrombosis. Pegaspargase induced cerebral venous thrombosis and bone marrow necrosis are very rare. PATIENT CONCERNS: A 50-year-old female developed headache, weakness of the right lower extremity, fever, and bone pain after chemotherapy including pegaspargase for the treatment of acute lymphoblastic leukemia. DIAGNOSES: Her imaging studies and bone marrow examinations were compatible with cerebral venous thrombosis and bone marrow necrosis. INTERVENTIONS: The patient received anticoagulation therapy with rivaroxaban. OUTCOMES: After treatment with rivaroxaban, she had a good outcome without major or minor bleeding. LESSONS: Clinicians should be aware of the very rare but possible induction of bone marrow necrosis during pegaspargase treatment when there is necrosis in other organs. Because of its greater safety and convenience, rivaroxaban gains popularity over traditional anticoagulant drugs. PMID- 29145311 TI - Pulmonary hypertension as a manifestation of mitochondrial disease: A case report and review of the literature. AB - BACKGROUND: Mitochondrial diseases are a group of multisystem heterogeneous diseases caused by pathologic dysfunction of the mitochondrial respiratory chain. A wide range of clinical expression has been described. However, pulmonary hypertension has rarely been described in association with mitochondrial disease until the past decade, and there is no currently recognized treatment for the pulmonary hypertension complicated with mitochondrial disorder. PATIENT CONCERNS: We reported the case of a 15-year-old boy who presented with shortness of breath and exercise limitation after a cold, and the diagnosis of pulmonary hypertension was confirmed by right heart catheter. Other examinations, such as blood tests, high- resolution chest computed tomography scan, and pulmonary function test, excluded other associated diseases as causes of pulmonary hypertension. DIAGNOSES AND OUTCOMES: The initial diagnosis was idiopathic pulmonary arterial hypertension and an injection of vasodilator (Treprostinil) was given. However, the dyspnea and fatigue subsequently got worsened. Tracing back his family history, together with the electromyography, nerve conduction studies, and the result of muscle biopsy, mitochondrial disease was confirmed. After treatment with vitamin E, vitamin B2, ATP, and coenzyme Q10, the patient's condition improved. CONCLUSION: Pulmonary hypertension should be considered as another potential manifestation of mitochondrial disease. Both mechanism and treatment for pulmonary hypertension complicated with mitochondrial disease are unclear. Further study is necessary. PMID- 29145312 TI - Bilateral femoral posterior neurocutaneous perforater flap successfully treating Fournier gangrene: A case report. AB - RATIONALE: Necrotizing fasciitis (NF), characterized by widespread fascial necrosis, is a rare disease in clinic. Fournier gangrene (FG) is a special type of NF involved of perineum and scrotum. To our knowledge, no article has reported on bilateral femoral posterior neurocutaneous perforater flap treating for FG. PATIENT CONCERNS: A 61-year-old Chinese male complained of perineal skin necrosis for 19 days. The patient received treatment in other hospital due to chronic bronchitis on April 15th and body temperature ranged from 38 to 39 degrees C. Then he received antiinfection therapy. Perianal cutaneous occurred mild necrosis on May 08th. And the necrosis generally deteriorated. He came to our hospital for treating necrosis in area of perineum and scrotum on May 28th. DIAGNOSES: He was diagnosed with FG and chronic bronchitis. INTERVENTIONS: The patient underwent debridement on June 2nd and received bilateral femoral posterior neurocutaneous perforater flap on June 29th. Besides, the patient was treated with whole-body nutrition support and antibiotic treatment. OUTCOMES: One week after the 2nd operation, the flap showed normal color. The result shows good outcome and no recurrence of the clinical symptoms occur till now. LESSONS: FG is rare. Bilateral femoral posterior neurocutaneous perforater flap is an effective procedure to treat FG. The outcome of combined therapy is satisfactory. PMID- 29145313 TI - The importance of family caregiving to achieving palliative care at home: a case report of end-of-life breast cancer in an area struck by the 2011 Fukushima nuclear crisis: A case report. AB - RATIONALE: The primary setting of palliative care has shifted from inpatient care to patients' residences. Family caregiving is essential for patients with life limiting illnesses to receive palliative care at home, however little information is available regarding potential interventions to achieve palliative homecare for those without sufficient support from family members in various settings, including disasters. PATIENT CONCERNS: In March 2011, Fukushima, Japan experienced an earthquake, tsunami and nuclear disaster. In August 2015, a 59 year-old Japanese female presented to our hospital, located 23 km north of Fukushima Daiichi Nuclear Power Plant, with a right breast ulcer. DIAGNOSES: The patient was diagnosed with stage IV breast cancer. INTERVENTIONS: The patient's general condition gradually worsened despite a one-year course of chemotherapy, and she became bedridden after a fall in October 2016. Although the patient wished to receive palliative homecare, this appeared challenging to achieve because she resided alone in a temporary housing shelter. Although she originally lived with her family in Odaka District, Fukushima, she relocated outside of the city following evacuation orders after the disaster. The evacuation orders for Odaka District were still in effect when she returned to the city alone in 2014. We contacted her sister who moved apart from her during the evacuation, and explained the necessity of family caregiving to enable her palliative homecare. OUTCOMES: The sister decided to move back to their original residence in Odaka District and live with the patient again. The patient successfully spent her end of-life period and died at home. LESSONS: Health care providers and community health workers may need to take a pro-active approach to communicating with family members to draw informal support to enable patients' end-of-life management according to their values and preferences. This is a lesson which may be applicable to broader healthcare settings beyond cancer, or disaster contexts, considering that population ageing and social isolation may continue to advance worldwide. PMID- 29145314 TI - Incidence of lower limb lymphedema after vulvar cancer: A systematic review and meta-analysis. AB - BACKGROUND: Lower limb lymphedema (LLL) is an important concern for patients with vulvar cancer. Studies of the incidence of vulvar cancer-related lymphedema and its risk factors have substantially increased in the new millennium. OBJECTIVES: This article is a meta-analysis that aimed to systematically evaluate the incidence of LLL and its risk factors related to vulvar cancer. DATA SOURCES: Data were collected from eligible studies from PubMed, ScienceDirect, and Web of Science. SYNTHESIS METHODS: Random effects models were used to calculate a pooled overall estimate of LLL incidence, and subgroup analyses were performed to assess the effects of different study designs, countries of study origin, diagnostic methods, and extent of lymph node surgery. Risk factors for lymphedema were also evaluated. RESULTS: Twenty-seven studies met the inclusion criteria for the assessment of lymphedema incidence with a pooled estimate of 28.8% [95% confidence interval (CI) 22.1-35.5]. The estimate was 16.7% (95% CI 9.7-23.7) when data were restricted to prospective cohort studies (7 studies). The incidence of LLL was increased by approximately 5-fold in women who underwent inguinofemoral lymph node dissection compared to those who underwent sentinel lymph node biopsy. The reported risk factors included wound infection, inguinofemoral lymphadenectomy, older age, body mass index (BMI), and radiation therapy. CONCLUSIONS: Approximately 3 in 10 women who survive vulvar cancer will develop lower limb lymphedema. More studies are needed to improve the understanding of its risk factors and to develop prevention and management strategies to alleviate this distressing disorder. PMID- 29145315 TI - Iodine-125 seed implantation for synchronous pancreatic metastases from hepatocellular carcinoma: A case report and literature review. AB - RATIONALE: The image-guided iodine-125 seed implantation has been widely used for a variety of tumors, including prostatic cancer, pulmonary cancer, hepatocellular carcinoma and pancreatic cancer. However, the clinical value of iodine-125 seed implantation for the treatment of pancreatic metastasis from hepatocellular carcinoma has not been reported. We presented the first case with ultrasound guided iodine-125 seed implantation for this disease. PATIENT CONCERNS: We presented the case of a 48-year-old man patient with primary hepatocellular carcinoma and pancreatic metastasis who was managed with ultrasound-guided iodine 125 seeds implantation. DIAGNOSES: She was diagnosed with synchronous pancreatic metastases from hepatocellular carcinoma. INTERVENTIONS: Puncture biopsy and ultrasound-guided iodine-125 seeds implantation. OUTCOMES: The hepatic and pancreatic tumors were obviously reduced after 15 months. Moreover, the liver function test was mildly abnormal in glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase. LESSONS: The image-guided iodine-125 seeds implantation was an important therapeutic approache to unresectable hepatocellular carcinoma with pancreatic metastasis. However, more related cases should be reported for further evaluating the value of the way. PMID- 29145316 TI - Application of ultrasound-guided C5 nerve root block using polydeoxyribonucleotide in traumatic C5 nerve root injury caused by fracture of the articular process of the cervical spine: A case report. AB - RATIONALE: Cervical nerve root injury is one of the complications of traumatic cervical spine fracture. Although one of the most effective treatments to reduce inflammation in nerve root injuries is the use of corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and NSAIDs can inhibit bone healing. So, when nerve injury accompanies bone fractures, corticosteroids and NSAIDs have limitations as therapeutic agents. However, polydeoxyribonucleotide (PDRN) may be useful in the treatment of neuropathy or musculoskeletal pain patients with contraindication of the use of corticosteroids because of its anti inflammatory effect, as revealed in previous studies. To the best of our knowledge, there has been no report of treatment of traumatic nerve root injury due to an articular process fracture with an ultrasound-guided cervical nerve root block (NRB) using PDRN. PATIENTS CONCERNS: A 54-year-old female patient with motor weakness of the left upper extremity and tingling sensation in the left neck and shoulder. DIAGNOSES:: traumatic C5 nerve root injury due to a fracture of the left articular process in the C4 spine. INTERVENTION: Ultrasound-guided C5 NRB using PDRN. OUTCOMES: Her motor weakness and sensory symptoms of the left upper extremity were significantly improved after treatment using an ultrasound guided C5 NRB using PDRN. LESSONS: Although it is impossible to draw a conclusion from a single case report, we suggest the ultrasound-guided NRB using PDRN could be a useful treatment for alleviating motor weakness and neuropathic pain caused by traumatic spinal nerve root injury in situations where corticosteroids cannot be used. PMID- 29145317 TI - Complete remission and long-term survival of a patient with melanoma metastases treated with high-dose fever-inducing Viscum album extract: A case report. AB - INTRODUCTION: Metastatic malignant cutaneous melanoma (MCM)-a highly immunogenic cancer-typically has a poor prognosis. Viscum album extracts (VAEs) have strong immune-stimulating, apoptogenic, and cytotoxic effects. CASE PRESENTATION: A 66 year-old MCM patient with newly diagnosed lymph node metastases opted for sole VAE treatment. VAEs were initially applied subcutaneously, and then later in exceptionally high, fever-inducing doses, both intravenously and intralesionally. The metastases shrunk over the following months, and after 2 years, all lesions had completely remitted (regional and hilar lymph nodes). The patient has been tumor free for 3.5 years at the time of publication (and for 5 years since initiation of intensified VAE treatment). Besides fever and flu-like symptoms, no side effects occurred. DISCUSSION: We presume that VAE triggered an increased release of tumor-associated antigens, enhanced immunologic recognition, and increased immune response against the tumor tissue and induced tumor remission. PMID- 29145318 TI - An unusual cause of fever of unknown origin with enlarged lymph nodes-relapsing polychondritis: A case report. AB - INTRODUCTION: Fever of unknown origin (FUO) is a common initial presentation leading to a diagnostic challenge. PATIENT CONCERNS: A 3-month history of moderate-to-high fever was reported in an otherwise healthy 54-year-old man. Enhanced computed tomography (CT) scans of his chest showed a remarkable progressive enlargement of bilateral cervical, supraclavicular, hilar, and mediastinal lymph nodes within 2 weeks. Bronchofibroscopy manifested obvious luminal stenosis with swelling, thick pale mucosa, and disappearing of structures of trachea cricoid cartilage, followed by a 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) with intense symmetric FDG uptake in larynx, tracheobronchial tree, and hilar, mediastinal, and axillary lymph nodes being demonstrated. DIAGNOSIS: A diagnosis of relapsing polychondritis (RP) was finally reached. INTERVENTIONS: The patient received methylprednisolone 40 mg daily with a gradual tapering in a 4-month follow-up. OUTCOMES: The patient experienced no relapse of fever and lymph nodes enlargement in the 4-month follow-up. LESSONS: Even though long-term fever with multiple lymphadenectasis usually lead to a diagnosis of lymphoma, the bronchoscopic features and evidence from 18F-FDG PET/CT in this case were much more approximate to RP, indicating an importance of a sensible differential diagnosis of RP in patients who present with nonspecific features such as FUO and lymph nodes enlargement. Keeping a high index of clinical suspicion in these patients can help recognize uncommon of RP and promote diagnosis and treatment. Our case highlights the significance of 18F-FDG PET/CT in helping reaching the diagnosis of RP in this condition. This report provides new data regarding the diagnostic difficulties of this rare type of autoimmune disease, and further investigations are needed as cases accumulate. PMID- 29145319 TI - Primary myelofibrosis and pregnancy outcomes after low molecular-weight heparin administration: A case report and literature review. AB - RATIONALE: Primary myelofibrosis is encountered with the myeloproliferative diseases and is the least prevalent among women of childbearing age. The prognosis is guided by pancytopenia, leukemic transformation and thrombosis which are the dominant complications. PATIENT CONCERNS: Data regarding protocol management during pregnancy in the context of myelofibrosis are insufficient. Fewer than ten cases have been described until now and half of this cases have resulted in fetal death due to placental infarction during the second and third trimesters. DIAGNOSES: We present the case of a 34-year-old pregnant woman diagnosed with Jak 2- negative primary myelofibrosis. Personal history did not include miscarriage or stillbirth. INTERVENTIONS: The patient was previously treated with anagrelide hydrochloride, which was interrupted at 6 weeks of gestation when the pregnancy was confirmed. It was replaced with Interferon-a 3 MU/day. Because of severe thrombocytosis, administration of aspirin 150 mg/day was recommended. OUTCOMES: The pregnancy was uneventful. The patient was hospitalized at 33 weeks of gestation because of moderate vaginal bleeding and high risk of preterm birth. After a specialized hematological investigation, the treatment with aspirin was replaced with low-molecular-weight heparin 0.6 ml per day. This combined treatment assisted in the natural tendency to lower platelet counts during pregnancy and resulted in stabilization of the hematological status. At 38 weeks of gestation the patient delivered a healthy baby boy via cesarean. He weight 2850 grams and his Apgar score was 9. Anticoagulant and interferon treatments were continued post-partum under hematologist surveillance. LESSONS: This case was rare and complex. Because it was related to pregnancy it required continuos collaboration and supervision between obstetrician and hematologist. PMID- 29145320 TI - Scapular metastasis of hepatocellular carcinoma presenting as acute bleeding and hematoma: A case report of safe and effective treatment. AB - RATIONALE: The occurrence of bleeding and hematoma from bone metastasis of hepatocellular carcinoma (HCC) is extremely rare. PATIENT CONCERNS: We present a case of scapular metastasis of HCC in a 69-year-old man who presented with acute bleeding and hematoma. DIAGNOSES: Chest computed tomography showed a large hematoma within the right pectoral muscle of the right upper chest and an exophytic metastatic mass in the right scapula with bony destruction, which caused the intramuscular hematoma. The final diagnosis was scapular metastasis of HCC presenting as acute bleeding and hematoma. INTERVENTIONS: Selective right subclavian angiography showed a hypervascular metastatic lesion in the right scapula. Subsequently, embolization of the tumoral feeding artery using a microcoil was performed and tumoral bleeding was stopped. OUTCOMES: The patient was discharged on hospital day 14 without any complications. LESSONS: Despite being extremely rare, the possibility of bleeding from bone metastasis of HCC needs to be considered. Transcatheter arterial embolization may be an effective means to treat bleeding from bone metastasis of HCC. PMID- 29145321 TI - Acupuncture and constraint-induced movement therapy for a patient with chronic stroke: One-year follow-up case report. AB - RATIONALE: Spasticity is a widespread problem in chronic stroke. To date, no study has reported the long-term (up to 1 year) outcomes of acupuncture in combination with constraint-induced movement therapy in patients with chronic stroke. This report describes the successful addition of acupuncture on spasticity and arm function in a patient with chronic stroke and arm paresis. PATIENT CONCERNS: At screening, the patient was unable to voluntarily extend her interphalangeal or metacarpophalangeal joints beyond the 10 degrees required for constraint-induced movement therapy. However, the BTX type A injection couldn't be used as she had ever suffered a severe allergic reaction in the injection of BTX type A for facial anti-wrinkle. DIAGNOSES: A 40-year-old female experienced arm paresis after an infarction in the right posterior limb of the internal capsule 2 years before the intervention. INTERVENTIONS: The BTX type A injection couldn't be used as she had ever suffered a severe allergic reaction in the injection of BTX type A for facial anti-wrinkle, so the patient received 1 hour of acupuncture as an alternative therapy before 5 hours of constraint-induced movement therapy for 12 weekdays. OUTCOMES: All outcome measures (Modified Ashworth Scale, Fugl-Meyer Assessment, Action Research Arm Test, Motor Activity Log) substantially improved over the 1-year period. Moreover, during the observation period, the patient's muscle tone and arm function did not worsen. LESSONS: As a result of a reduction in spasticity, a reduction of learned nonuse behaviors, or use-dependent plasticity after the combined therapy, the arm functions include volitional movements and coordination or speed of movements in the paretic arm have been improved. However, we can not rule out the possibility of an influence of the passage of time or the Hawthorne effect. The costs of the treatment of stroke may be reduced, if this combined therapy proved useful in future controlled studies. PMID- 29145322 TI - Ptosis as the only manifestation of diabetic superior division oculomotor nerve palsy: A case report. AB - RATIONALE: Diabetic oculomotor nerve palsies, also called ischemic third nerve palsies, are the most common etiologic subset of oculomotor nerve palsy in adults. Diabetic oculomotor nerve palsies typically present with ptosis and diplopia, but pupillary function is often spared. The oculomotor nerve separates into superior division and inferior division, with the superior division innervating the superior rectus and levator palpebrae superioris. The diabetic oculomotor nerve palsy may affect isolated superior or inferior division of the oculomotor nerve, but diplopia usually exists. PATIENT CONCERNS: A 56-year-old female was admitted to our hospital for acute onset right upper lid ptosis. The patient denied diplopia or other new focal neurologic symptoms. The neurological examination revealed ptosis of the right upper eyelid only, and other neurological examination revealed negative findings. DIAGNOSES: The diagnosis of diabetes-associated oculomotor nerve palsy was made, with acute ptosis as its only manifestation. INTERVENTIONS: We controlled her blood sugar aggressively with insulin. OUTCOMES: After the hyperglycemia improved, the right side ptosis recovered partially within one week. LESSONS: From this case, we suggest that when evaluating patients with acute onset ptosis as the only manifestation, diabetic-vasculopathic neuropathy should be considered. This case also implies that the most interior portion of the third cranial nerve may consist of nerve fibers mainly innervating the levator palpebrae superioris. PMID- 29145323 TI - The effectiveness of 2 consecutive intra-articular polydeoxyribonucleotide injections compared with intra-articular triamcinolone for hemiplegic shoulder pain: A STROBE-complaint retrospective study. AB - The aim of this study was to investigate the effects of intra-articular injection of polydeoxyribonucleotide (PDRN), compared with intraarticular triamcinolone (TA) injection, in subacute stroke patients with hemiplegic shoulder pain (HSP).Participants were subacute stroke patients with HSP who had undergone 2 consecutive intra-articular injections of TA or PDRN.Numeric rating scale (NRS) and passive range of motion (PROM) of hemiplegic shoulder were evaluated until 4 weeks after 2nd injection.In the results, there were significant improvements in all PROM measures 2 weeks after the second injection, compared with pre-injection results, in both groups (P < .05). In the PDRN group, however, none of the PROM measures were significantly improved at 3 and 4 weeks after the second injection, compared with pre-injection results (P >= .05). When comparing pre-injection results with those at 4 weeks after the second injection, all PROM and NRS measures in the TA group were more improved than in the PDRN group, but this was not statistically significant (P >= .05).In conclusion, considering the systemic side effects of steroids, especially among patients with diabetes or metabolic syndrome, PDRN seems to be a worthwhile treatment option for HSP, although PDRN does not seem to have an equivalent persistence effects when compared with TA. PMID- 29145324 TI - A rare case of Merkel cell carcinoma presenting as a giant intra-thoracic mass: A case report and review of the literature. AB - RATIONALE: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine-derived cutaneous cancer. Ectopic or single metastatic MCC located in thorax is extremely rare; meanwhile, its definite management has not been elucidated yet. PATIENT CONCERNS: A 64-year-old female patient with a giant mass located in her left thorax was presented for stuffy pain of left chest for 6 months and fever for half a month. She underwent radical resection of vulvar MCC 10 years ago. DIAGNOSES: Computed tomography (CT)-guided biopsy of the intrathoracic mass revealed a diagnosis of MCC, without synchronous urogenital lesions on pelvic CT images. INTERVENTIONS: This bulky tumor was completely resected via thoracotomy, along with the adjacent pulmonary lobe, pericardium, pleura, and diaphragm. OUTCOMES: The patient survived without local-regional recurrence or distant metastasis during the follow-up of 1 year up to now. LESSONS: Ectopic or single metastatic MCC should be considered in the differential diagnosis of intrathoracic tumors, especially in patients with a history of MCC. Besides, a timely surgery combined with chemotherapy is effective for this disease. PMID- 29145325 TI - Perforated appendicitis after colonoscopy: cause or coincidence?: A rare case report and literature review. AB - RATIONALE: Colonoscopy is a relatively safe and common procedure with low risks of complications, and acute appendicitis with perforation is an extremely rare complication of colonoscopy. The current study presents an unusual case of acute gangrenous appendicitis with perforation following a screening colonoscopy. PATIENT CONCERNS: A 73-year-old man presented to our emergency department with lower right abdominal pain 3 days after a routine screening colonoscopy. On physical examination the patient had signs of generalized peritonitis. Abdominal and pelvic computed tomography (CT) revealed the presence of multiple free gas in the right subphrenic space and abdominal cavity with exudate effusions in both sides of the paracolic sulci and the pelvic cavity, especially around the ascending colon and caecum. The CT scan also showed a dilated and inflamed appendix with fecaliths. DIAGNOSES: The patient was diagnosed with acute gangrenous appendicitis with perforation after colonoscopy. INTERVENTIONS: The patient underwent emergency exploratory laparotomy. Intraoperative findings revealed an inflamed gangrenous appendix with focal perforation and impacted fecaliths. The colon showed no evidence of perforation or other areas of concern and thus, a conclusive diagnosis was achieved. An appendectomy was performed and the abdominal cavity was rinsed and drained thoroughly. OUTCOMES: The postoperative course was uneventful. LESSONS: This study may increase clinical awareness with regard to perforated appendicitis after colonoscopy. Acute appendicitis should be included in the differential diagnosis of lower right abdominal pain following a colonoscopy, in addition to possible colonic injury. Furthermore, emergency surgery should be recommended for the typical signs of perforation with peritonitis and free pneumoperitoneum. Early recognition and prompt surgical treatment are critical, which can avoid severe outcomes and improve the prognosis. PMID- 29145326 TI - Should fraction flow reserve be considered an important decision-making tool to stratify patients with stable coronary artery disease for percutaneous coronary intervention?: A meta-analysis. AB - BACKGROUND: Nowadays, fraction flow reserve (FFR) is being discussed in every percutaneous coronary intervention (PCI) capable hospitals. Owing to recent development in the medical field, FFR-guided PCI should be able to find a place in Interventional Cardiology. At present, the importance of FFR to stratify patients who require PCI has seldom systematically been investigated. In this analysis, we aimed to compare the major adverse cardiac events (MACEs) mainly in patients with stable coronary artery disease (CAD) to whom PCI was recommended and deferred respectively based on the FFR value. METHODS: Electronic databases were searched for studies comparing FFR-recommended versus FFR-deferred coronary stenting. Long-term MACEs, mortality, and myocardial infarction (MI) were considered as the clinical endpoints in this analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and the analyses were carried out by the latest version of the RevMan software. RESULTS: A total number of 1753 patients (670 patients were revascularized, whereas 1083 patients were deferred from revascularization based on the FFR value) were analyzed. Current results showed MACEs and MI were significantly higher in the FFR-recommended PCI group with OR 1.34 (95% CI: 1.05-1.72; P = .02) and OR 1.73 (95% CI: 1.19-2.51; P = .004, I = 0%), respectively. However, mortality was similarly manifested with OR 1.23 (95% CI: 0.92-1.63; P = .16, I = 0%). CONCLUSION: Significantly higher MACEs were observed in patients to whom PCI was recommended compared to those patients who were deferred from undergoing PCI based on the FFR values. Therefore, FFR might indeed be an important decision-making procedural tool, which should be used to stratify stable CAD patients with an advanced disease and who are qualified candidates for PCI. Further research should confirm this hypothesis. PMID- 29145327 TI - Current practice and usual care of major cervical disorders in Korea: A cross sectional study of Korean health insurance review and assessment service national patient sample data. AB - Neck pain is a highly common condition and is the 4th major cause of years lived with disability. Previous literature has focused on the effect of specific treatments, and observations of actual practice are lacking to date. This study examined Korean health insurance review and assessment service (HIRA) claims data to the aim of assessing prevalence and comparing current medical practice and costs of cervical disorders in Korea.Current practice trends were determined through assessment of prevalence, total expenses, per-patient expense, average days in care, average days of visits, sociodemographic characteristics, distribution of medical costs, and frequency of treatment types of high frequency cervical disorders (cervical sprain/strain, cervical intervertebral disc displacement [IDD], and cervicalgia).Although the number of cervical IDD patients was few, total expenses, per-patient expense, average days in care, and average days of visits were highest. The proportion of women was higher than men in all 3 groups with highest prevalence in the >=50s middle-aged population for IDD compared to sprain/strain. Primary care settings were commonly used for ambulatory care, of which approximately 70% chose orthopedic specialist treatment. In analysis of medical expenditure distribution, costs of visit (consultation) (22%-34%) and physical therapy (14%-16%) were in the top 3 for all 3 disorders. Although heat and electrical therapies were the most frequently used physical therapies, traction use was high in the cervical IDD group. In nonnarcotics, aceclofenac and diclofenac were the most commonly used NSAIDs, and pethidine was their counterpart in narcotics.This study investigated practice trends and cost distribution of treatment regimens for major cervical disorders, providing current usage patterns to healthcare policy decision makers, and the detailed treatment reports are expected to be of use to clinicians and researchers in understanding current usual care. PMID- 29145328 TI - Endocarditis due to Abiotrophia defectiva, a biofilm-related infection associated with the presence of fixed braces: A case report. AB - RATIONALE: Endocarditis with Abiotrophia defectiva represents 4.3% to 6% of all streptococcal endocarditis. The article presents diagnosis issues and the complexity of the treatment. PATIENT CONCERNS: We present the case of a female white patient, aged 26 years, who developed infectious endocarditis caused by A defectiva, in the last trimester of pregnancy, a biofilm-related infection associated with the presence of fixed braces. DIAGNOSES: The diagnosis of infectious endocarditis was confirmed by the cardiac ultrasound examination that revealed a voluminous vegetation on the mitral valve, and acute mitral regurgitation caused by chordae tendinae rupture, and also by isolating Abiotrophia defectiva from two positive blood cultures. INTERVENTIONS: The decision to undergo surgical intervention was taken, and a mitral valve replacement was performed. Surgical intervention that was associated with board spectrum antibiotic therapy. OUTCOMES: A defectiva, remains a rare cause of infective endocarditis, with a reserved prognosis that is motivated by the extensive valvular lesions and the risk of embolism. LESSONS: The use of antibiotics administered in association, in the management of infective endocarditis, is mandatory. PMID- 29145329 TI - New onset of myasthenia gravis after intravesical Bacillus Calmette-Guerin: A case report and literature review. AB - RATIONALE: Recently, drug-related myasthenia gravis (MG) has received attention, because the number of reported cases involving MG associated with immune checkpoint inhibitors, a new immunotherapy, is increasing. We present a case involving the new onset of MG, in which the symptoms started shortly after intravesical Bacillus Calmette-Guerin (BCG) for bladder cancer. PATIENT CONCERNS: A 69-year-old male with bladder cancer developed ptosis and diplopia 4 days after the completion of a treatment regimen with intravesical BCG weekly for 6 weeks. DIAGNOSES: Ocular MG was confirmed by a positive serum anti-acetylcholine receptor antibody test. INTERVENTIONS: Treatment with high-dose methylprednisolone pulse therapy was given, after insufficient treatment with pyridostigmine bromide and 10 mg/d prednisolone. OUTCOMES: Symptoms resolved completely 12 days after high-dose methylprednisolone pulse therapy. LESSONS: Intravesical BCG could be listed as a novel drug that may induce a new onset of MG along with drugs such as D-penicillamine and immune checkpoint inhibitors. PMID- 29145330 TI - Pathologic femoral fracture due to tenofovir-induced Fanconi syndrome in patient with chronic hepatitis B: A case report. AB - RATIONALE: We report a case of a hepatitis B virus (HBV)-positive patient with preexisting bone disease who developed tenofovir-induced Fanconi syndrome and subsequently sustained pathologic fracture. To our best knowledge, this is the first report in the English literature about pathologic femoral fracture due to tenofovir-induced Fanconi syndrome in patient with chronic hepatitis B (CHB). The present report describes detailed our experience with the diagnosis of pathologic femoral fracture due to tenofovir-induced Fanconi syndrome and treatment. PATIENT CONCERNS: A 45-year-old man visited our hospital with pain in the right thigh region and gait disturbance which had started 3 months ago and worsened 1 week before admission. The patient was diagnosed with CHB in 2004. He was on lamivudine medication for 2 years. Medication for the patient was subsequently changed to adefovir in 2009 and tenofovir disoproxil fumarate (TDF) in 2013. He was on TDF since 2013. DIAGNOSIS: His hip joint magnetic resonance imaging (MRI) revealed hypointensity lesions and cortical bone destruction in fat-saturated MR image at the iliopsoas muscle attachment site of the lesser trochanter of both femur. On blood test showed 25-OH vitamin D level at 6.42 ng/mL (normal range, >20 ng/mL) and U-deoxypyridinoline level at 7.60 nM/mMcr (normal range, 2.30-5.40 nM mMcr). However, osteocalcin and parathyroid hormone levels were within normal range. Based on these findings, the present case was concluded as tenoforvir induced Fanconi syndrome. INTERVENTIONS: TDF treatment was discontinued. After cooperation with internal medicine department, in order to prevent further fractures of the right lesser trochanter, internal fixation was performed under spinal anesthesia using compression hip nails (APIS, TDM, Korea). OUTCOMES: Positive outcome by medication and operation demonstrates that his phosphorus and serum calcium levels were maintained within normal range and pain in the right thigh region was improved from visual analogue pain score (VAS) 7 before surgery to VAS 2 after surgery. LESSONS: Physicians need to regularly monitor bone metabolism in patients with take in tenofovir for early diagnosis before its progression to pathologic fractures. PMID- 29145331 TI - Severe hemodynamic instability after indocyanine green injection during off-pump coronary artery bypass grafting: A case report. AB - RATIONALE: The increasingly intraoperative use of indocyanine green (ICG) means that it is necessary to be aware of both its advantages and potential adverse effects. PATIENT CONCERNS: A 76-year-old woman developed symptoms of sudden severe hemodynamic instability while undergoing coronary artery bypass grafting with ICG injection to detect the patency of the graft. The main clinical manifestations were a sudden drop in blood pressure and increased heart rate. DIAGNOSES: Severe side effects or allergic reaction of ICG. INTERVENTIONS: Cardiopulmonary bypass (CPB) was established, and an intra-aortic balloon pump was implanted in the left femoral artery after intravenous epinephrine and manual cardiac compression failed. OUTCOMES: The patient was extubated and transferred to the general ward on the third postoperative day. LESSONS: Invasive blood pressure monitoring should be carried out in patients undergoing intraoperative ICG administration. Anesthetists should pay close attention to the patient's hemodynamic fluctuations, and effective emergency measures should be implemented immediately if severe hemodynamic instability occurs. PMID- 29145332 TI - Primary malignant melanoma of the lung: A case report and literature review. AB - RATIONALE: Primary malignant melanoma of the lung (PMML) is an extremely rare neoplasm with a dismal prognosis. The diagnosis of PMML is very difficult and is based on several clinical, radiological, and histopathological criteria. PATIENT CONCERNS: A 61-year-old women was admitted with a 2-month history of a productive cough and chest pain provoked by breathing and coughing. Computed tomography (CT) scans of the chest showed a large, solid tumor in the right middle lobe of the lung. Puncture biopsy of the right lung lesion was performed using B-ultrasound guidance, and immunohistochemical tests were performed. DIAGNOSES: The diagnosis of PMML was histopathologically confirmed by puncture biopsy with B-ultrasound guidance of the right lung lesion. INTERVENTIONS: The patient refused to receive surgery, adjuvant chemotherapy, or radiation therapy. OUTCOMES: The patient died 6 months after the diagnosis. LESSONS: The clinical manifestation and imaging features of PMML are not specific, and it does not differ from the more common primary bronchogenic carcinoma. In addition, it cannot be discriminated from other forms of primary melanoma according to its histology and immunohistochemistry. The treatment of choice is an aggressive surgical approach, combined with radiation therapy, chemotherapy, and immunotherapy. PMID- 29145333 TI - Risk factors and a simple model for predicting bile leakage after radical hepatectomy in patients with hepatic alveolar echinococcosis. AB - Postoperative bile leakage (BL) is a major complication of hepatic alveolar echinococcosis (HAE). The purpose of this study was to identify the risk factors for BL and to establish a simple scoring system for predicting BL.A total of 152 patients with HAE were included in the study between May 2004 and December 2016. The patient's baseline data, laboratory blood tests, imaging features, and surgical management were collected. Univariate and multivariate analyses were used to screen for factors to predict BL. The cutoff values for those factors and predictive value of a model were determined by receiver operative characteristic curve (ROC) analysis.BL was detected in 22 of the 152 patients. Univariate analyses showed significant differences in the lesion diameter, levels of lactate dehydrogenase (LDH), alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and direct bilirubin (DBIL), inferior vena cava invasion, surface area of hepatectomy, blood loss and history of percutaneous transhepatic cholangial drainage between patients with and without BL. On multivariate analyses, DBIL > 7.1 MUmol/L, LDH > 194 U/L, lesion diameter > 12 cm and a larger surface area of hepatectomy were independent predictors of BL. The resulting area under the ROC of the scoring model was 0.724 (95% CI, 0.646-0.793).The lesion diameter, DBIL, larger surface area of hepatectomy, and elevated LDH were the important factors affecting the occurrence of BL after surgery. The risk score model will help the clinician to assess BL before surgery. More studies are needed to confirm the scoring model and risk factors. PMID- 29145334 TI - Concurrent one-stage total knee and hip arthroplasty due to sequel of juvenile rheumatoid arthritis: A case report. AB - RATIONALE: Rheumatoid arthritis is a chronic systemic connective tissue disease. Total hip and knee arthroplasties are common major orthopaedic procedures worldwide. PATIENT CONCERNS: To date, no studies have presented 1-stage concurrent total hip arthroplasty (THA) and total knee arthroplasty (TKA) in patients with rheumatoid arthritis (RA). We reported a case which is, to our knowledge, the first description of both THA and TKA in a patient with RA simultaneously. DIAGNOSES: History of juvenile rheumatoid arthritis (JRA), deterioration of signs and symptoms in history and physical examinations and radiography were lead to making decision for her surgery. INTERVENTIONS: Concurrent total hip replacement and total knee arthroplasty were performed for patient. OUTCOMES: After more than a 2-year follow-up time, the patient showed excellent clinical function and remained satisfied with the surgical outcome. Multiple simultaneous total joint arthroplasty (TJA) is reviewed in this article. LESSONS: Joint arthroplasty surgeries can be performed in a simultaneous procedure to shorten disability and rehabilitation time with one anesthesia. PMID- 29145335 TI - Clavicle fracture associated with atlantoaxial rotatory displacement, type II in an 8-year-old girl: A case report. AB - RATIONALE: Fracture of the clavicle is a very common injury in children. However, association between clavicle fracture and atlantoaxial rotatory displacement is rarely observed. PATIENT CONCERNS: We present a case of an 8-year-old girl, who suffered a right clavicle fracture as a result of a sledge accident. Six weeks after figure of 8 casting for a right clavicle fracture, an 8-year-old girl was brought to the Pediatric Orthopedic Department due to torticollis. DIAGNOSES: Standard X-ray examination revealed nonunion of the clavicle without any clinical symptoms. Computed tomography (CT) examination was performed and subluxation of cervical vertebrae 1/cervical vertebrae 2 was detected. INTERVENTIONS: The use of Glisson's traction followed by a soft cervical collar resulted in the resolution of all the symptoms. Control CT and magnetic resonance imaging confirmed reduction. OUTCOMES: The patient fully recovered and currently is fully active. The neurological status of the child before and after procedure remained normal. LESSONS: Clavicle fracture rarely may be associated with atlantoaxial rotatory displacement. Therefore, careful examination including rotation of the neck is necessary to confirm that associations. Moreover, three-dimensional CT scan enables proper spine examination and provides correct diagnosis. As shown in available literature and as well in presented case report, none operative treatment is usually effective. PMID- 29145336 TI - Expression of hormone receptors in low-grade adenosquamous carcinoma of the breast: A case report. AB - RATIONALE: Low-grade adenosquamous carcinoma (LGASC) is a rare subtype of metaplastic breast carcinoma which is generally recognized as a characteristic subgroup of triple-negative breast cancers previously. However, in this study, we reported for the first time a case of LGASC with hormone receptors expression. PATIENT CONCERNS: Pathological analysis of breast tumor specimen obtained by a 42 year-old female patient was performed. Morphologically, it composed of glandular structures with scattered squamous differentiation accompanied by haphazard arrangement of spindle cell stroma. Immunohistochemically, all myoepithelial and squamous differentiation markers showed typical LGASC positive or negative staining pattern. Interestingly, we found that normally aberrant hormone receptors were reactivated in this case. To our knowledge, this is the first report of a hormone receptor-positive LGASC. Apart from this, in the extended resection sample, we found scattered squamous metaplasia and florid adenosquamous proliferation (ASP). Meanwhile, it was positive for CD44 variant isoforms (CD44v), which is a breast cancer stem cell (CSC) marker, and expressed in LGASC, squamous metaplasia, and ASP. DIAGNOSIS: LGASC with hormone receptors expression. INTERVENTIONS: The breast-extended local excision and axillary lymph node dissection were performed. OUTCOMES: The patient was free of local recurrence and distant metastasis 6 months after surgical resection. LESSONS: We herein report the first case of LGASC with immunoreactivity for hormone receptors, expanding its profile of immunophenotypes. CD44v may play an important role in the transition of LGASC precursor lesions into malignant processes, which may serve as a therapeutic target in LGASC. PMID- 29145337 TI - Partial resection and reconstruction of the sternum for treatment of metachronous sternal metastasis of thyroid carcinoma: A case report. AB - RATIONALE: Metachronous sternal metastasis of thyroid carcinoma was a rare disease. There was no consensus in the treatment for bone metastasis after the initial thyroid carcinoma surgery. PATIENT CONCERNS: A 53-year-old female patient was hospitalized due to recurrent dull chest pains, with a history of radical right side thyroid carcinoma 4 years ago. On examination, there was an irregular mass on the lower left half of the sternum. Computerized tomography scan showed sternal bone destruction with a soft tissue mass. DIAGNOSES: Metachronous sternal metastasis of thyroid carcinoma. INTERVENTIONS: Partial resection of the sternum and reconstruction with a titanium alloy mesh were performed. OUTCOMES: After a 3 year follow-up, the patient had no recurrence. LESSONS: Surgical resection may be a sufficient treatment for metachronous sternal metastasis of thyroid carcinoma. Biosynthesis material mesh is preferred to be used. PMID- 29145338 TI - Pancreatogenic choledocholithiasis in common bile duct stump after Roux-en-Y hepaticojejunostomy: A case report. AB - RATIONALE: Choledocholithiasis in common bile duct (CBD) stump after Roux-en-Y hepaticojejunostomy (RYHJ) is incredibly rare and its pathophysiology is poorly understood. PATIENT CONCERNS: A 79-year-old woman was admitted to our hospital with upper abdominal pain radiating through to the back in November 2016. DIAGNOSES: Abdominal computed tomography (CT) scan and magnetic resonance cholangiopancreatography (MRCP) revealed filling defects in CBD stump, chronic pancreatitis, and dilatation of CBD stump and main pancreatic duct (MPD). INTERVENTIONS: During the endoscopic retrograde cholangiopancreatography (ERCP), cannulation proceeded easily from MPD to CBD through a variant pancreatic duct, and then white crushed stones extracted from the CBD stump. Elemental analysis and infrared spectrophotometry demonstrated that the main constituent of the calculi was calcium carbonate. OUTCOMES: After a therapeutic ERCP, the patient's symptoms disappeared, and a 9-month follow-up indicated no remaining stones or lithiasis relapse. LESSONS: This type of choledocholithiasis in CBD stump after RYHJ has never been reported before. We nominated it as "pancreatogenic choledocholithiasis," and pancreatobiliary reflux caused by a variant pancreatic duct may be the main cause. PMID- 29145339 TI - Alveolar soft part sarcoma with multiple brain and lung metastases in pregnancy: A case report and literature review. AB - RATIONAL: Alveolar soft part sarcomas (ASPSs) with multiple brain metastases in pregnancy is a rare entity. PATIENT CONCERNS: We report our experience with a 19 year-old pregnant woman who presented with intermittent headaches and vomiting at 38 weeks gestation. DIAGNOSES: The patient was initially diagnosed as brain metastasis according to computed tomography and magnetic resonance imaging (MRI) imaging. INTERVENTIONS: Cesarean section and craniotomy (complete resection of both brain metastatic lesions) was performed sequentially. OUTCOMES: A healthy baby girl was delivered safely and no neonatal malformations were found. Histological analysis confirmed the diagnosis of ASPS. Follow-up MRI performed 10 months after surgery revealed no residual tumor or signs of recurrence. LESSONS: We report a case of ASPS with multiple brain and lung metastases in a pregnant woman. We recommend timely MRI examination for diagnosis and have discussed the approach to the treatment of pregnant women with brain metastasis. PMID- 29145340 TI - Open repair of intraoperative popliteal artery injury during total knee arthroplasty in a patient with severe hemophilia A: A case report and literature review. AB - RATIONALE: Arterial injuries during total knee arthroplasty (TKA) though rare may occur. Hemophilia may further challenge the management of such injury. PATIENT CONCERNS: A 48-year-old male patient with severe hemophilia type A and stiff knee arthropathy underwent bilateral TKAs. Left popliteal artery injury was detected at the end of the left TKA. DIAGNOSES: Urgent angiography confirmed the diagnosis of the left popliteal artery transection. INTERVENTIONS: With clotting factor VIII replacement treatment, open repair was performed by end-to-end vascular bypass with the autograft of the large saphenous vein. No anticoagulant and antiplatelet treatment was administered postoperatively. Doses of the factor VIII were decreased step by step postoperatively. OUTCOMES: Left lower limb was reperfused 4 hours after the onset of the ischemia. The patient recovered uneventfully. Postoperative Doppler examination showed the left popliteal artery remained patent. LESSONS: The hemophilia may endanger the patients to higher risk of arterial injury during TKA because of the severe deformity and fibrosis around knee joint. For the hemophilia patients, with rational coagulation factor replacement therapy, open repair with autograft was an effective revascularization procedure for artery injury. PMID- 29145341 TI - Primary malignant melanoma of the gallbladder with multiple metastases: A case report. AB - RATIONAL: Primary malignant melanoma of the gallbladder is an extremely rare tumor, with fewer than 40 cases reported in the literature worldwide. The majority of patients presented as a solitary lesion in the gallbladder. To our knowledge, only one case of primary malignant melanoma of the gallbladder with multiple metastases has been reported, which involved the stomach, duodenum, pancreas, jejunum and a mesenteric lymph node. PATIENT CONCERNS: We report a case of primary malignant melanoma of the gallbladder with metastases to the duodenal bulb, right adrenal and a celiac lymph node. DIAGNOSES: Primary malignant melanoma of the gallbladder with multiple metastases. INTERVENTIONS: Gastrojejunostomy, cholecystectomy, and biopsy of the three metastatic lesions were performed. Histopathologic examination revealed melanin pigments were within the tumor cells of the four lesions, however, junctional activity was noted only in the gallbladder, supporting that the gallbladder was the primary site. No pigmented lesions were detected on the skin or eyes. The postoperative recovery was uneventful, and subsequently, chemotherapy with paclitaxel and carboplatin was administered. OUTCOMES: The patient survived for 16 months due to tumor. progression. LESSONS: The current case was unique due to the adrenal involvement. For patients with multiple metastases of malignant melanoma, gallbladder origin should be considered in the differential diagnosis from cutaneous origin. PMID- 29145342 TI - Evaluation of anti-desmoglein-1 and anti-desmoglein-3 autoantibody titers in pemphigus patients at the time of the initial diagnosis and after clinical remission. AB - It has been suggested that anti-desmoglein autoantibody titers could be helpful in follow-up and therapeutic management of pemphigus patients. However, there is no consensus regarding the relationship between anti-desmoglein autoantibody titers and clinical activity of pemphigus.The aim of our study was to evaluate if clinical remission of pemphigus relates to the presence of anti-desmoglein autoantibodies.Thirty patients with pemphigus vulgaris and 7 patients with pemphigus foliaceous were included in the study. Assessment of autoantibody titers was carried out at the time of the initial diagnosis and after the clinical remission using an enzyme-linked immunosorbent assay-based assay.Our results indicate that pemphigus clinical remission did not necessarily imply a serological remission, and consequently it is necessary to establish if withdrawal of the immunosuppressive regimen in pemphigus should be based exclusively on the achievement of clinical remission or also on the serological findings. PMID- 29145343 TI - Anterior release and nonstructural bone grafting and posterior fixation for old lower cervical dislocations with locked facets. AB - Lower cervical dislocations are often missed at the time of initial injury for several reasons. The treatment of old facet dislocations of the lower cervical spine is difficult, and the optimal method has not been established. The objective of the present study was to evaluate the clinical outcomes of a surgical technique, anterior release, and nonstructural bone grafting combined with posterior fixation, for the treatment of old lower cervical dislocations with locked facets.This was a retrospective study of 17 patients (13 men and 4 women) with old facet dislocations, who underwent the same surgical treatment at our hospital between April 2010 and January 2016. The anterior procedure was conducted to remove the fusion mass and to achieve discectomy and morselized bone grafting. Subsequent posterior procedure included release, reduction, and posterior fusion. The neurologic status, clinical data (Japanese Orthopedic Association [JOA], Neck Disability Index [NDI], and Visual Analog Scale [VAS] scores), and radiographic information (local sagittal alignment and bone graft fusion) were recorded and evaluated pre and postoperatively.All patients achieved a nearly complete reduction intraoperatively. The mean operative time was 178 +/- 49 minutes. The mean blood loss was 174 +/- 73 mL. Each patient completed at least 12 months of follow-up. The mean follow-up duration was 32.6 +/- 18.5 months. The neurologic status according to the Frankel grade was significantly improved at the last follow-up. The JOA, NDI, and VAS scores all demonstrated significant improvements compared with the preoperative values (P < .05). The kyphosis angle of the dislocated segments was 10.5 +/- 5.9 degrees at preoperation, and was corrected to 5.9 +/- 4.3 degrees lordosis postoperatively. Anterior and posterior solid fusion was observed in all patients within 12 months of follow-up. Fat liquefaction and delayed healing of the posterior wound occurred in 1 patient. Cerebrospinal fluid leakage occurred in another patient. There was no neurologic deterioration and no procedure-related complications.Anterior release and nonstructural bone grafting combined with posterior fixation provides a safe and effective option for treating old lower cervical dislocations with locked facets. PMID- 29145344 TI - The relationship of lung cancer with menstrual and reproductive factors may be influenced by passive smoking, cooking oil fumes, and tea intake: A case-control study in Chinese women. AB - The aim of this study was to investigate the association of menstrual and reproductive factors with risk of lung cancer in women. Potential etiological clues related to lung cancer in women are identified to inform preventive strategies.Case-control study of 477 newly diagnosed women with lung cancer and 479 age-matched (+/-2 years) controls. Data on menstrual and reproductive factors and history of oral contraceptive use were obtained on personal interviews using a structured questionnaire. Risk factors were analyzed by unconditional logistic regression analysis.Maternal age >=25 years at first birth appeared to protect against female lung cancer [odds ratios (ORs): 0.511, 95% confidence interval (CI), 0.376-0.693]. Age at menopause > 50 years and use of contraceptives was associated with an increased risk of lung cancer in women (OR: 1.471, 95% CI, 1.021-2.119 and OR: 1.844, 95% CI: 1.111-3.061, respectively). Age >=13 years at menarche was associated with a decreased risk of lung adenocarcinoma (OR: 0.563, 95% CI, 0.317-0.997). There was significant heterogeneity in the levels of cooking oil fume (COF) exposure (Pheterogeneity = .015). Higher levels of exposure to passive smoking, COF, and lack of tea intake were associated with an increased risk of lung cancer.Menstrual and reproductive factors are considered to play a role in the development of lung cancer in women. Exposure to passive smoking, COF, and lack of tea intake appeared to significantly modify the relationship. PMID- 29145345 TI - The role of Sativex in robotic rehabilitation in individuals with multiple sclerosis: Rationale, study design, and methodology. AB - INTRODUCTION: Currently, none of the available multiple sclerosis (MS) disease modifying medications has been shown to stop or reverse gait disability. Recently, the nabiximols has been tested for the treatment of spasticity and walking impairment in MS. Nabiximols (trade name Sativex) is an oromucosal spray formulation containing 1:1 fixed ratio of delta-9-tetrahydrocannabinol and cannabidiol derived from cloned Cannabis sativa L. plant. METHOD AND ANALYSIS: A single-center, prospective, parallel design, single-blind trial will be conducted at the IRCCS Neurolesi "Bonino-Pulejo" (Italy) involving MS patients affected by spasticity and undergoing a Robotic Rehabilitation training. The aim of the study is to clarify the role of Sativex coupled to a robotic neurehabilitation training in MS patients in improving motor outcomes, by means of clinical, kinematic, and neurophysiological measures. Patients will be randomly divided in 2 groups: one taking only an oral antispastic drug and the other with Sativex in add-on. After 1 month, we will evaluate the response to Sativex (responder patients' amelioration >20% at MRS score) enrolling into the study the first 20 patients with a good response to Sativex, whereas other 20 no-responder individuals will continue their antispastic drug. All the 40 subjects, were divided into 2 groups (A: Sativex + Lokomat Training, and B: other antispastic+Lokomat Training), will perform a neurorobotic-assisted gait training (each session will last at least 45 minutes, 3 times per week, for a total of 20 sessions). All the patients will undergo a complete physical and neurological examination at baseline, at the end of the robotic training (T1), and 30 days after the end of the neurorehabilitation training (T2). PMID- 29145347 TI - Fingertip Winding Suture: Pull-out Suture Technique for Flexor Tendon Repair in Zone I. AB - Injuries to flexor tendons in zone I has always been challenging during repair. Over the time several techniques were developed and modified to achieve the highest repair strength and thus the best functional outcome. These techniques vary from pull-out sutures with internal and external fixation to the use of bone anchors. All techniques were accompanied with advantages and disadvantages as well as postoperative morbidities related to certain techniques. In the present technique we introduce a subperiosteal pull-out suturing technique. It is a simple, strong, and cost-effective method for repair of flexor tendon injuries in zone I or in the context of tendon grafting. PMID- 29145346 TI - Role of delayed-time-point imaging during abdominal and pelvic cancer screening using FDG-PET/CT in the general population. AB - Although delayed-time-point imaging is expected to improve the results of [F] fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT), how examinees will benefit from dual-time-point imaging versus initial time-point imaging alone, remains unclear. This study investigated the role of delayed-time-point imaging in improving the results of abdominal and pelvic cancer screening using FDG-PET/CT.This retrospective review included 3131 screening results (average subject age: 55.5 years, range: 40-88 years). First, 2 nuclear medicine physicians tentatively evaluated whole-body initial-time-point PET/CT scans. Subsequently, delayed-time-point imaging of the abdomen and pelvis was performed approximately 150 min after FDG injection, followed by re evaluation for necessary changes. All changed records were retrospectively reviewed and classified as either lesions that were found in initial-time-point images but were changed into negative by adding delayed scan or newly detected findings of suspected malignancy on delayed-time-point images; lesions suspected to be malignant were subjected to further pathologic review. Diagnostic performance according to sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated and compared between initial-time-point and dual-time-point imaging.Fifty-four records were changed after addition of the delayed-time-point imaging. Of the 105 suspected malignancies on initial-time-point images, 10 were changed into negative following the delayed scan. In addition, 44 lesions were newly detected as suspected malignancies on delayed-time-point images. Thirty-six lesions were proven to be pathologically malignant. Of these, 26 were detected on initial-time point images, and 8 lesions (gastrointestinal adenocarcinoma, 6; prostate adenocarcinoma, 2) were observed on delayed-time-point images. The sensitivity of dual-time-point imaging (58.6% [34/58]) was significantly higher than that of initial-time-point imaging only (44.8% [26/58]) (P = .005); however, specificity and accuracy of dual-time-point imaging (96.6% [2968/3073] and 95.9% [3002/3131], respectively) were significantly lower than those of initial-time-point imaging only (97.4% [2994/3073] and 96.5% [3020/3131], respectively) (P < .0001 and P = .013, respectively). There were no significant differences in PPV (initial-time point imaging: 24.8% [26/105], dual-time-point imaging: 24.5% [34/139]) and NPV (98.9% [2994/3026] and 99.2% [2968/3073], respectively).The inclusion of delayed PET/CT in screening examinations facilitated the detection of pathologically malignant lesions, particularly in the gastrointestinal tract, while also detecting benign and false-negative lesions. PMID- 29145348 TI - Magnusiomyces capitatus Peritonitis in a Child With Acute Lymphocytic Leukemia as a Breakthrough Infection During Caspofungin Therapy. AB - Magnusiomyces capitatus is an emerging opportunistic fungal pathogen particularly in immunocompromised patients. We report a case of a M. capitatus peritonitis in child with acute lymphocytic leukemia as a breakthrough infection during caspofungin therapy. The possibility of breakthrough infections caused by M. capitatus must be taken into consideration, particularly in immunosupressed patients being treated for systemic fungal infections by caspofungin. Although there are no defined breakpoints for susceptibility testing of M.capitatus, minimal inhibitory concentration results can be helpful for therapy. Antifungal treatment with amphotericin B lipid complex plus flucytosine can be effective against infections caused by M. capitatus. PMID- 29145349 TI - Current Status of Endoscopic Gallbladder Drainage. AB - The gold standard for treatment of acute cholecystitis is laparoscopic cholecystectomy. However, cholecystectomy is often not suitable for surgically unfit patients who are too frail due to various co-morbidities. As such, several less invasive endoscopic treatment modalities have been developed to control sepsis, either as a definitive treatment or as a temporizing modality until the patient is stable enough to undergo cholecystectomy at a later stage. Recent developments in endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) with endoscopic ultrasound EUS-specific stents having lumen-apposing properties have demonstrated potential as a definitive treatment modality. Furthermore, advanced gallbladder procedures can be performed using the stents as a portal. With similar effectiveness as percutaneous transhepatic cholecystostomy and lower rates of adverse events reported in some studies, EUS-GBD has opened exciting possibilities in becoming the next best alternative in treating acute cholecystitis in surgically unfit patients. The aim of this review article is to provide a summary of the various methods of gallbladder drainage GBD with particular focus on EUS-GBD and the many new prospects it allows. PMID- 29145350 TI - Ultrasonographic evaluation of complications related to transfemoral arterial procedures. AB - The transfemoral arterial approach is used to gain access for angiography, percutaneous coronary interventions, or various endovascular therapies. To decrease the risk of procedure-related vascular complications, it is recommended to puncture the common femoral artery in its middle segment. However, due to inadequate access or anatomical variability, various complications, including hematoma, pseudoaneurysm, arteriovenous fistula, thrombosis, or dissection, can occur after transfemoral arterial interventions. Duplex ultrasound has proven to be an excellent noninvasive modality that provides not only anatomic but also hemodynamic information, effectively detecting and differentiating various femoral puncture-related complications. Radiologists should be familiar with the characteristic sonographic findings of the entire spectrum of transfemoral puncture-related vascular complications for early detection and proper treatment. PMID- 29145352 TI - Erratum: Vol. 66, No. 42. PMID- 29145351 TI - Comparison of Treatment of Acute Unstable Distal Clavicle Fractures Using Anatomical Locking Plates with Versus without Additional Suture Anchor Fixation. AB - BACKGROUND Surgical managements were recommended for unstable distal clavicle fracture owing to the high incidence of nonunion. The present study compared the efficacy of anatomical locking plate with versus without additional suture anchor fixation for the treatment of unstable Neer type II distal clavicle fractures. MATERIAL AND METHODS Between January 2013 to January 2015, 28 consecutive patients with unstable Neer type II fractures were treated by using anatomical locking plate with or without additional suture anchor fixation. The patients were divided into anatomical locking plate group (group A) and anatomical locking plate combined with suture anchor group (group B) according to the surgical method. The operative-related parameters such as operation time, blood loss, length of hospitalization, union time, functional outcomes (Constant score, UCLA score and DASH score) and CC distance were compared. RESULTS The mean follow-up period of the 28 patients was 19.60 months (21.80 versus 18.39 months, respectively). No statistical differences in general and peri-operative parameters were found between 2 groups. The group B had significant higher Constant score than group A (P=0.004, 91.67 versus 83.10). While no statistical differences were reached in the UCLA score and DASH score between 2 groups (P=0.112 and 0.163, respectively). The group A had longer CC distance than group B (11.67 versus 8.94 mm), while no statistic difference was found (P=0.067). CONCLUSIONS For the treatment of acute unstable Neer type II distal clavicle fractures, both surgical methods could offer satisfactory outcome. However, anatomical locking plate combined with additional suture anchor fixation had a better functional and radiographic outcome than that without additional suture anchor fixation. PMID- 29145353 TI - CDC Grand Rounds: Improving Medication Adherence for Chronic Disease Management - Innovations and Opportunities. AB - Adherence to prescribed medications is associated with improved clinical outcomes for chronic disease management and reduced mortality from chronic conditions (1). Conversely, nonadherence is associated with higher rates of hospital admissions, suboptimal health outcomes, increased morbidity and mortality, and increased health care costs (2). In the United States, 3.8 billion prescriptions are written annually (3). Approximately one in five new prescriptions are never filled, and among those filled, approximately 50% are taken incorrectly, particularly with regard to timing, dosage, frequency, and duration (4). Whereas rates of nonadherence across the United States have remained relatively stable, direct health care costs associated with nonadherence have grown to approximately $100-$300 billion of U.S. health care dollars spent annually (5,6). Improving medication adherence is a public health priority and could reduce the economic and health burdens of many diseases and chronic conditions (7). PMID- 29145354 TI - Announcement: World Day of Remembrance for Road Traffic Victims - November 19, 2017. PMID- 29145355 TI - Disparities in State-Specific Adult Fruit and Vegetable Consumption - United States, 2015. AB - The 2015-2020 Dietary Guidelines for Americans recommend that Americans consume more fruits and vegetables as part of an overall dietary pattern to reduce the risk for diet-related chronic diseases such as cardiovascular disease, type 2 diabetes, some cancers, and obesity (1). Adults should consume 1.5-2.0 cup equivalents of fruits and 2.0-3.0 cups of vegetables per day.* Overall, few adults in each state met intake recommendations according to 2013 Behavioral Risk Factor Surveillance System (BRFSS) data; however, sociodemographic characteristics known to be associated with fruit and vegetable consumption were not examined (2). CDC used data from the 2015 BRFSS to update the 2013 report and to estimate the percentage of each state's population meeting intake recommendations by age, sex, race/ethnicity, and income-to-poverty ratio (IPR) for the 50 states and District of Columbia (DC). Overall, 12.2% of adults met fruit recommendations ranging from 7.3% in West Virginia to 15.5% in DC, and 9.3% met vegetable recommendations, ranging from 5.8% in West Virginia to 12.0% in Alaska. Intake was low across all socioeconomic groups. Overall, the prevalence of meeting the fruit intake recommendation was highest among women (15.1%), adults aged 31-50 years (13.8%), and Hispanics (15.7%); the prevalence of meeting the vegetable intake recommendation was highest among women (10.9%), adults aged >=51 years (10.9%), and persons in the highest income group (11.4%). Evidence based strategies that address barriers to fruit and vegetable consumption such as cost or limited availability could improve consumption and help prevent diet related chronic disease. PMID- 29145356 TI - QuickStats: Percentage* of Adults Aged 20-64 Years Whose Blood Cholesterol Was Checked by a Health Professional in the Past 12 Months,? by Race/EthnicityS - National Health Interview Survey, United States, 2011 and 2016. AB - The percentage of adults aged 20-64 years who had a blood cholesterol check by a health professional in the past 12 months increased from 56.0% in 2011 to 61.7% in 2016. From 2011 to 2016, there was an increase in the percentage of adults with a blood cholesterol check among Hispanic (49.0% to 56.7%), non-Hispanic white (56.8% to 62.5%), non-Hispanic black (60.8% to 65.6%), and non-Hispanic Asian (55.8% to 63.0%) persons. In both years, non-Hispanic black adults were more likely than non-Hispanic white adults to have had a blood cholesterol check, and Hispanic adults were the least likely to have had a blood cholesterol check. PMID- 29145357 TI - Global Routine Vaccination Coverage, 2016. AB - The Global Vaccine Action Plan 2011-2020 (GVAP) (1), endorsed by the World Health Assembly in 2012, calls on all countries to reach >=90% national coverage for all vaccines in the country's routine immunization schedule by 2020. CDC and the World Health Organization (WHO) evaluated the WHO and United Nations Children's Fund (UNICEF) global vaccination coverage estimates to describe changes in global and regional coverage as of 2016. Global coverage estimates for the third dose of diphtheria and tetanus toxoids and pertussis-containing vaccine (DTP3), the third dose of polio vaccine, and the first dose of measles-containing vaccine (MCV1) have ranged from 84% to 86% since 2010. The dropout rate (the proportion of children who started but did not complete a vaccination series), an indicator of immunization program performance, was estimated to be 5% in 2016 for the 3-dose DTP series, with dropout highest in the African Region (11%) and lowest in the Western Pacific Region (0.4%). During 2010-2016, estimated global coverage with the second MCV dose (MCV2) increased from 21% to 46% by the end of the second year of life and from 39% to 64% when older age groups (3-14 years) were included (2). Improvements in national immunization program performance are necessary to reach and sustain high vaccination coverage to increase protection from vaccine preventable diseases for all persons. PMID- 29145358 TI - Progress in Rubella and Congenital Rubella Syndrome Control and Elimination - Worldwide, 2000-2016. AB - Although rubella virus infection usually causes a mild fever and rash illness in children and adults, infection during pregnancy, especially during the first trimester, can result in miscarriage, fetal death, stillbirth, or infants with a constellation of congenital malformations known as congenital rubella syndrome (CRS) (1). Rubella is a leading vaccine-preventable cause of birth defects. Preventing these adverse pregnancy outcomes is the focus of rubella vaccination programs. In 2011, the World Health Organization (WHO) updated guidance on the preferred strategy for introduction of rubella-containing vaccine (RCV) into national immunization schedules and recommended an initial vaccination campaign, usually targeting children aged 9 months-14 years (1). The Global Vaccine Action Plan 2011-2020 (GVAP), endorsed by the World Health Assembly in 2012, includes goals to eliminate rubella in at least five of the six WHO regions by 2020 (2). This report updates a previous report (3) and summarizes global progress toward rubella and CRS control and elimination from 2000 to 2016. As of December 2016, 152 (78%) of 194 countries had introduced RCV into the national immunization schedule, representing an increase of 53 countries since 2000, including 20 countries that introduced RCV after 2012. PMID- 29145360 TI - Recommended. PMID- 29145361 TI - Let's Science That. PMID- 29145359 TI - Racial/Ethnic Health Disparities Among Rural Adults - United States, 2012-2015. AB - PROBLEM/CONDITION: Rural communities often have worse health outcomes, have less access to care, and are less diverse than urban communities. Much of the research on rural health disparities examines disparities between rural and urban communities, with fewer studies on disparities within rural communities. This report provides an overview of racial/ethnic health disparities for selected indicators in rural areas of the United States. REPORTING PERIOD: 2012-2015. DESCRIPTION OF SYSTEM: Self-reported data from the 2012-2015 Behavioral Risk Factor Surveillance System were pooled to evaluate racial/ethnic disparities in health, access to care, and health-related behaviors among rural residents in all 50 states and the District of Columbia. Using the National Center for Health Statistics 2013 Urban-Rural Classification Scheme for Counties to assess rurality, this analysis focused on adults living in noncore (rural) counties. RESULTS: Racial/ethnic minorities who lived in rural areas were younger (more often in the youngest age group) than non-Hispanic whites. Except for Asians and Native Hawaiians and other Pacific Islanders (combined in the analysis), more racial/ethnic minorities (compared with non-Hispanic whites) reported their health as fair or poor, that they had obesity, and that they were unable to see a physician in the past 12 months because of cost. All racial/ethnic minority populations were less likely than non-Hispanic whites to report having a personal health care provider. Non-Hispanic whites had the highest estimated prevalence of binge drinking in the past 30 days. INTERPRETATION: Although persons in rural communities often have worse health outcomes and less access to health care than those in urban communities, rural racial/ethnic minority populations have substantial health, access to care, and lifestyle challenges that can be overlooked when considering aggregated population data. This study revealed difficulties among non-Hispanic whites as well, primarily related to health related risk behaviors. Across each population, the challenges vary. PUBLIC HEALTH ACTION: Stratifying data by different demographics, using community health needs assessments, and adopting and implementing the National Culturally and Linguistically Appropriate Services Standards can help rural communities identify disparities and develop effective initiatives to eliminate them, which aligns with a Healthy People 2020 overarching goal: achieving health equity. PMID- 29145362 TI - I Feel Your Pain. PMID- 29145363 TI - Healthy See, Healthy Do. PMID- 29145364 TI - Could Genetic Engineering Save the Galapagos? PMID- 29145365 TI - Ice under Siege. PMID- 29145366 TI - 50, 100 &150 Years Ago. PMID- 29145368 TI - Wag the Lizard. PMID- 29145367 TI - DACA's Demise Is Bad for Our Health. PMID- 29145369 TI - Meet the Neighbors. PMID- 29145370 TI - Reprogram, Restore, Regenerate. PMID- 29145371 TI - The Digital-Subscription Dilemma. PMID- 29145372 TI - Top 10 Emerging Technologies of 2017. PMID- 29145373 TI - Quick Hits. PMID- 29145374 TI - Marijuana and the Teen Brain. PMID- 29145375 TI - Smoky Wine. PMID- 29145376 TI - Pluto Revealed. PMID- 29145377 TI - Dawn of Plate Tectonics. PMID- 29145378 TI - The Cloud Conundrum. PMID- 29145379 TI - How Captives Changed the World. PMID- 29145380 TI - Speaking in Clicks. PMID- 29145381 TI - Food High. PMID- 29145383 TI - Letters. PMID- 29145382 TI - Quantum Leaps. PMID- 29145384 TI - Outlawing War. PMID- 29145385 TI - Squirrels That Chunk. PMID- 29145386 TI - Solar Storm Doomsday? PMID- 29145387 TI - Beetle Resurrection. PMID- 29145388 TI - Correction: A Unifying Probabilistic View of Associative Learning. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1004567.]. PMID- 29145389 TI - The use of ambient humidity conditions to improve influenza forecast. AB - Laboratory and epidemiological evidence indicate that ambient humidity modulates the survival and transmission of influenza. Here we explore whether the inclusion of humidity forcing in mathematical models describing influenza transmission improves the accuracy of forecasts generated with those models. We generate retrospective forecasts for 95 cities over 10 seasons in the United States and assess both forecast accuracy and error. Overall, we find that humidity forcing improves forecast performance (at 1-4 lead weeks, 3.8% more peak week and 4.4% more peak intensity forecasts are accurate than with no forcing) and that forecasts generated using daily climatological humidity forcing generally outperform forecasts that utilize daily observed humidity forcing (4.4% and 2.6% respectively). These findings hold for predictions of outbreak peak intensity, peak timing, and incidence over 2- and 4-week horizons. The results indicate that use of climatological humidity forcing is warranted for current operational influenza forecast. PMID- 29145390 TI - Morphological and molecular characterization of Brazilian populations of Diatraea saccharalis (Fabricius, 1794) (Lepidoptera: Crambidae) and the evolutionary relationship among species of Diatraea Guilding. AB - The sugarcane borer or corn stalk borer, Diatraea Guilding is polyphagous insect pest of many important crops such as corn, sorghum and sugarcane. Losses arising from the attack of Diatraea species have been a serious problem, which may cause loss in sugarcane production around 0.25% in sugar, 0.20% in alcohol and 0.77% of body weight for every 1% infestation and up to 21% in corn production fields. In Brazil, the most commonly reported species are Diatraea saccharalis (Fabricius, 1794) and Diatraea impersonatella (Walker, 1863) (= D. flavipennella). However, multiple other species of Diatraea have been identified in Brazil according to the literature. Currently, little information exists on the presence of the other species causing injury to sugarcane and corn. The objectives of this study were to improve the accuracy of species assignment, evaluate the population genetic structure, and address many of the outstanding questions of systematics and evolution of Brazilian populations of D. saccharalis. To address these main questions, classical taxonomic methods were used, focused on morphological characterization of the reproductive organs, especially the male genitalia. In addition, genetic studies were performed using simple sequence repeats (SSR) and a fragment of cytochrome C oxidase subunit I (COI) gene. The data and findings from this research will contribute to the understanding of evolutionary aspects of insect pests in order to develop more effective and sustainable population management practices. PMID- 29145391 TI - Household food production is positively associated with dietary diversity and intake of nutrient-dense foods for older preschool children in poorer families: Results from a nationally-representative survey in Nepal. AB - BACKGROUND: Nutrition-sensitive interventions supporting enhanced household food production have potential to improve child dietary quality. However, heterogeneity in market access may cause systematic differences in program effectiveness depending on household wealth and child age. Identifying these effect modifiers can help development agencies specify and target their interventions. OBJECTIVE: This study investigates mediating effects of household wealth and child age on links between farm production and child diets, as measured by production and intake of nutrient-dense food groups. METHODS: Two rounds (2013 and 2014) of nationally representative survey data (n = 5,978 observations) were used to measure production and children's dietary intake, as well as a household wealth index and control variables, including breastfeeding. Novel steps used include measuring production diversity in terms of both species grown and food groups grown, as well as testing for mediating effects of family wealth and age of child. RESULTS: We find significant associations between child dietary diversity and agricultural diversity in terms of diversity of food groups and of species grown, especially for older children in poorer households, and particularly for fruits and vegetables, dairy and eggs. With each additional food group produced, log-odds of meeting minimum dietary diversity score (>=4) increase by 0.25 (p = 0.01) for children aged 24-59 months. For younger children aged 18-23 months there is a similar effect size but only in the poorest two quintiles of household wealth, and for infants 6-18 months we find no correlation between production and intake in most models. CONCLUSIONS: Child dietary intake is associated with the composition of farm production, most evident among older preschool children and in poorer households. To improve the nutrition of infants, other interventions are needed; and for relatively wealthier households, own farm production may displace market purchases, which could attenuate the impact of household production on child diets. PMID- 29145392 TI - Conservation of a microRNA cluster in parasitic nematodes and profiling of miRNAs in excretory-secretory products and microvesicles of Haemonchus contortus. AB - microRNAs are small non-coding RNAs that are important regulators of gene expression in a range of animals, including nematodes. We have analysed a cluster of four miRNAs from the pathogenic nematode species Haemonchus contortus that are closely linked in the genome. We find that the cluster is conserved only in clade V parasitic nematodes and in some ascarids, but not in other clade III species nor in clade V free-living nematodes. Members of the cluster are present in parasite excretory-secretory products and can be detected in the abomasum and draining lymph nodes of infected sheep, indicating their release in vitro and in vivo. As observed for other parasitic nematodes, H. contortus adult worms release extracellular vesicles (EV). Small RNA libraries were prepared from vesicle enriched and vesicle-depleted supernatants from both adult worms and L4 stage larvae. Comparison of the miRNA species in the different fractions indicated that specific miRNAs are packaged within vesicles, while others are more abundant in vesicle-depleted supernatant. Hierarchical clustering analysis indicated that the gut is the likely source of vesicle-associated miRNAs in the L4 stage, but not in the adult worm. These findings add to the growing body of work demonstrating that miRNAs released from parasitic helminths may play an important role in host parasite interactions. PMID- 29145393 TI - Estimating the probabilities of rare arrhythmic events in multiscale computational models of cardiac cells and tissue. AB - Ectopic heartbeats can trigger reentrant arrhythmias, leading to ventricular fibrillation and sudden cardiac death. Such events have been attributed to perturbed Ca2+ handling in cardiac myocytes leading to spontaneous Ca2+ release and delayed afterdepolarizations (DADs). However, the ways in which perturbation of specific molecular mechanisms alters the probability of ectopic beats is not understood. We present a multiscale model of cardiac tissue incorporating a biophysically detailed three-dimensional model of the ventricular myocyte. This model reproduces realistic Ca2+ waves and DADs driven by stochastic Ca2+ release channel (RyR) gating and is used to study mechanisms of DAD variability. In agreement with previous experimental and modeling studies, key factors influencing the distribution of DAD amplitude and timing include cytosolic and sarcoplasmic reticulum Ca2+ concentrations, inwardly rectifying potassium current (IK1) density, and gap junction conductance. The cardiac tissue model is used to investigate how random RyR gating gives rise to probabilistic triggered activity in a one-dimensional myocyte tissue model. A novel spatial-average filtering method for estimating the probability of extreme (i.e. rare, high-amplitude) stochastic events from a limited set of spontaneous Ca2+ release profiles is presented. These events occur when randomly organized clusters of cells exhibit synchronized, high amplitude Ca2+ release flux. It is shown how reduced IK1 density and gap junction coupling, as observed in heart failure, increase the probability of extreme DADs by multiple orders of magnitude. This method enables prediction of arrhythmia likelihood and its modulation by alterations of other cellular mechanisms. PMID- 29145395 TI - Positive valence music restores executive control over sustained attention. AB - Music sometimes improves performance in sustained attention tasks. But the type of music employed in previous investigations has varied considerably, which can account for equivocal results. Progress has been hampered by lack of a systematic database of music varying in key characteristics like tempo and valence. The aims of this study were to establish a database of popular music varying along the dimensions of tempo and valence and to examine the impact of music varying along these dimensions on restoring attentional resources following performance of a sustained attention to response task (SART) vigil. Sixty-nine participants rated popular musical selections that varied in valence and tempo to establish a database of four musical types: fast tempo positive valence, fast tempo negative valence, slow tempo positive valence, and slow tempo negative valence. A second group of 89 participants performed two blocks of the SART task interspersed with either no break or a rest break consisting of 1 of the 4 types of music or silence. Presenting positive valence music (particularly of slow tempo) during an intermission between two successive blocks of the SART significantly decreased miss rates relative to negative valence music or silence. Results support an attentional restoration theory of the impact of music on sustained attention, rather than arousal theory and demonstrate a means of restoring sustained attention. Further, the results establish the validity of a music database that will facilitate further investigations of the impact of music on performance. PMID- 29145394 TI - UNC-16/JIP3 regulates early events in synaptic vesicle protein trafficking via LRK-1/LRRK2 and AP complexes. AB - JIP3/UNC-16/dSYD is a MAPK-scaffolding protein with roles in protein trafficking. We show that it is present on the Golgi and is necessary for the polarized distribution of synaptic vesicle proteins (SVPs) and dendritic proteins in neurons. UNC-16 excludes Golgi enzymes from SVP transport carriers and facilitates inclusion of specific SVPs into the same transport carrier. The SVP trafficking roles of UNC-16 are mediated through LRK-1, whose localization to the Golgi is reduced in unc-16 animals. UNC-16, through LRK-1, also enables Golgi localization of the MU-subunit of the AP-1 complex. AP1 regulates the size but not the composition of SVP transport carriers. Additionally, UNC-16 and LRK-1 through the AP-3 complex regulates the composition but not the size of the SVP transport carrier. These early biogenesis steps are essential for dependence on the synaptic vesicle motor, UNC-104 for axonal transport. Our results show that UNC-16 and its downstream effectors, LRK-1 and the AP complexes function at the Golgi and/or post-Golgi compartments to control early steps of SV biogenesis. The UNC-16 dependent steps of exclusion, inclusion and motor recruitment are critical for polarized distribution of neuronal cargo. PMID- 29145396 TI - Detection of relapsing fever Borrelia spp., Bartonella spp. and Anaplasmataceae bacteria in argasid ticks in Algeria. AB - BACKGROUND: Argasid ticks (soft ticks) are blood-feeding arthropods that can parasitize rodents, birds, humans, livestock and companion animals. Ticks of the Ornithodoros genus are known to be vectors of relapsing fever borreliosis in humans. In Algeria, little is known about relapsing fever borreliosis and other bacterial pathogens transmitted by argasid ticks. METHODOLOGY/PRINCIPAL FINDINGS: Between May 2013 and October 2015, we investigated the presence of soft ticks in 20 rodent burrows, 10 yellow-legged gull (Larus michahellis) nests and animal shelters in six locations in two different bioclimatic zones in Algeria. Six species of argasid ticks were identified morphologically and through 16S rRNA gene sequencing. The presence and prevalence of Borrelia spp., Bartonella spp., Rickettsia spp. and Anaplasmataceae was assessed by qPCR template assays in each specimen. All qPCR-positive samples were confirmed by standard PCR, followed by sequencing the amplified fragments. Two Borrelia species were identified: Borrelia hispanica in Ornithodoros occidentalis in Mostaganem, and Borrelia cf. turicatae in Carios capensis in Algiers. One new Bartonella genotype and one new Anaplasmataceae genotype were also identified in Argas persicus. CONCLUSIONS: The present study highlights the presence of relapsing fever borreliosis agents, although this disease is rarely diagnosed in Algeria. Other bacteria of unknown pathogenicity detected in argasid ticks which may bite humans deserve further investigation. PMID- 29145397 TI - Post-kala-azar dermal leishmaniasis in the Indian subcontinent: A threat to the South-East Asia Region Kala-azar Elimination Programme. AB - BACKGROUND: The South-East Asia Region Kala-azar Elimination Programme (KAEP) is expected to enter the consolidation phase in 2017, which focuses on case detection, vector control, and identifying potential sources of infection. Post kala-azar dermal leishmaniasis (PKDL) is thought to play a role in the recurrence of visceral leishmaniasis (VL)/kala-azar outbreaks, and control of PKDL is among the priorities of the KAEP. METHODOLOGY AND PRINCIPAL FINDING: We reviewed the literature with regard to PKDL in Asia and interpreted the findings in relation to current intervention methods in the KAEP in order to make recommendations. There is a considerable knowledge gap regarding the pathophysiology of VL and PKDL, especially the underlying immune responses. Risk factors (of which previous VL treatments may be most important) are poorly understood and need to be better defined. The role of PKDL patients in transmission is largely unknown, and there is insufficient information about the importance of duration, distribution and severity of the rash, time of onset, and self-healing. Current intervention methods focus on active case detection and treatment of all PKDL cases with miltefosine while there is increasing drug resistance. The prevention of PKDL by improved VL treatment currently receives insufficient attention. CONCLUSION AND SIGNIFICANCE: PKDL is a heterogeneous and dynamic condition, and patients differ with regard to time of onset after VL, chronicity, and distribution and appearance of the rash, as well as immune responses (including tendency to self heal), all of which may vary over time. It is essential to fully describe the pathophysiology in order to make informed decisions on the most cost-effective approach. Emphasis should be on early detection of those who contribute to transmission and those who are in need of treatment, for whom short-course, effective, and safe drug regimens should be available. The prevention of PKDL should be emphasised by innovative and improved treatment for VL, which may include immunomodulation. PMID- 29145398 TI - Conservation demands safe gene drive. AB - Interest in developing gene drive systems to control invasive species is growing, with New Zealand reportedly considering the nascent technology as a way to locally eliminate the mammalian pests that threaten its unique flora and fauna. If gene drives successfully eradicated these invasive populations, many would rejoice, but what are the possible consequences? Here, we explore the risk of accidental spread posed by self-propagating gene drive technologies, highlight new gene drive designs that might achieve better outcomes, and explain why we need open and international discussions concerning a technology that could have global ramifications. PMID- 29145399 TI - Point mutation in D8C domain of Tamm-Horsfall protein/uromodulin in transgenic mice causes progressive renal damage and hyperuricemia. AB - Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys' thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance. Both the young and the old transgenic mice had significantly higher serum uric acid and its catabolic product, allantoin, than age-matched wild-type mice. This THP mutation apparently caused primary defects in TAL by compromising the luminal translocation and reabsorptive functions of NKCC2 and ROMK and secondary responses in proximal tubules by upregulating NHE3 and URAT1. Our results strongly suggest that the progressive worsening of kidney functions reflects the accumulation of the deleterious effects of the misfolded mutant THP and the compensatory responses. Transgenic mice recapitulating human THP/uromodulin-associated kidney diseases could be used to elucidate their pathogenesis and test novel therapeutic strategies. PMID- 29145400 TI - Zika virus: An updated review of competent or naturally infected mosquitoes. AB - Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) that recently caused outbreaks in the Americas. Over the past 60 years, this virus has been observed circulating among African, Asian, and Pacific Island populations, but little attention has been paid by the scientific community until the discovery that large-scale urban ZIKV outbreaks were associated with neurological complications such as microcephaly and several other neurological malformations in fetuses and newborns. This paper is a systematic review intended to list all mosquito species studied for ZIKV infection or for their vector competence. We discuss whether studies on ZIKV vectors have brought enough evidence to formally exclude other mosquitoes than Aedes species (and particularly Aedes aegypti) to be ZIKV vectors. From 1952 to August 15, 2017, ZIKV has been studied in 53 mosquito species, including 6 Anopheles, 26 Aedes, 11 Culex, 2 Lutzia, 3 Coquillettidia, 2 Mansonia, 2 Eretmapodites, and 1 Uranotaenia. Among those, ZIKV was isolated from 16 different Aedes species. The only species other than Aedes genus for which ZIKV was isolated were Anopheles coustani, Anopheles gambiae, Culex perfuscus, and Mansonia uniformis. Vector competence assays were performed on 22 different mosquito species, including 13 Aedes, 7 Culex, and 2 Anopheles species with, as a result, the discovery that A. aegypti and Aedes albopictus were competent for ZIKV, as well as some other Aedes species, and that there was a controversy surrounding Culex quinquefasciatus competence. Although Culex, Anopheles, and most of Aedes species were generally observed to be refractory to ZIKV infection, other potential vectors transmitting ZIKV should be explored. PMID- 29145401 TI - Anatomically-specific intratubular and interstitial biominerals in the human renal medullo-papillary complex. AB - Limited information exists on the anatomically-specific early stage events leading to clinically detectable mineral aggregates in the renal papilla. In this study, quantitative multiscale correlative maps of structural, elemental and biochemical properties of whole medullo-papillary complexes from human kidneys were developed. Correlative maps of properties specific to the uriniferous and vascular tubules using high-resolution X-ray computed tomography, scanning and transmission electron microscopy, energy dispersive X-ray spectroscopy, and immunolocalization of noncollagenous proteins (NCPs) along with their association with anatomy specific biominerals were obtained. Results illustrated that intratubular spherical aggregates primarily form at the proximal regions distant from the papillary tip while interstitial spherical and fibrillar aggregates are distally located near the papillary tip. Biominerals at the papillary tip were closely localized with 10 to 50 MUm diameter vasa recta immunolocalized for CD31 inside the medullo-papillary complex. Abundant NCPs known to regulate bone mineralization were localized within nanoparticles, forming early pathologic mineralized regions of the complex. Based on the physical association between vascular and urothelial tubules, results from light and electron microscopy techniques suggested that these NCPs could be delivered from vasculature to prompt calcification of the interstitial regions or they might be synthesized from local vascular smooth muscle cells after transdifferentiation into osteoblast-like phenotypes. In addition, results provided insights into the plausible temporal events that link the anatomically specific intratubular mineral aggregates with the interstitial biomineralization processes within the functional unit of the kidney. PMID- 29145402 TI - Specific effects of working memory training on the reading skills of Chinese children with developmental dyslexia. AB - Most research on working memory (WM) training for children with developmental dyslexia (DD) has focused on western alphabetical languages. Moreover, most of these studies used a combination of training tasks targeting a variety of WM components, making it difficult to determine whether WM training generates a general improvement in overall reading, or improves specific cognitive skills corresponding to the WM components that are targeted in training. We tested the general and specific effects of WM training on the reading skills of 45 Chinese children with DD, grades 3 to 5. In Experiment 1, the experimental group received a program targeting the verbal WM component; in Experiment 2, the experimental group was trained with a program targeting visuospatial WM. In both experiments the control group played a placebo video game. In Experiment 1, the experimental group outperformed the control group on the visual rhyming task, which is highly correlated with verbal WM. In Experiment 2, the experimental group outperformed the control group on the orthographic awareness test, which is highly correlated with visuospatial WM. Furthermore, in both Experiment 1 and Experiment 2, the experimental groups outperformed the control groups on the fast word naming test, which is highly related to both visuospatial WM and verbal WM. Results indicated that WM training improved specific reading-related cognitive skills that are highly correlated with the specific WM components that were the target of training. PMID- 29145403 TI - US Gulf Coast states: The rise of neglected tropical diseases in "flyover nation". PMID- 29145404 TI - Core Outcome Set-STAndards for Development: The COS-STAD recommendations. AB - BACKGROUND: The use of core outcome sets (COS) ensures that researchers measure and report those outcomes that are most likely to be relevant to users of their research. Several hundred COS projects have been systematically identified to date, but there has been no formal quality assessment of these studies. The Core Outcome Set-STAndards for Development (COS-STAD) project aimed to identify minimum standards for the design of a COS study agreed upon by an international group, while other specific guidance exists for the final reporting of COS development studies (Core Outcome Set-STAndards for Reporting [COS-STAR]). METHODS AND FINDINGS: An international group of experienced COS developers, methodologists, journal editors, potential users of COS (clinical trialists, systematic reviewers, and clinical guideline developers), and patient representatives produced the COS-STAD recommendations to help improve the quality of COS development and support the assessment of whether a COS had been developed using a reasonable approach. An open survey of experts generated an initial list of items, which was refined by a 2-round Delphi survey involving nearly 250 participants representing key stakeholder groups. Participants assigned importance ratings for each item using a 1-9 scale. Consensus that an item should be included in the set of minimum standards was defined as at least 70% of the voting participants from each stakeholder group providing a score between 7 and 9. The Delphi survey was followed by a consensus discussion with the study management group representing multiple stakeholder groups. COS-STAD contains 11 minimum standards that are the minimum design recommendations for all COS development projects. The recommendations focus on 3 key domains: the scope, the stakeholders, and the consensus process. CONCLUSIONS: The COS-STAD project has established 11 minimum standards to be followed by COS developers when planning their projects and by users when deciding whether a COS has been developed using reasonable methods. PMID- 29145405 TI - Drivers of house invasion by sylvatic Chagas disease vectors in the Amazon Cerrado transition: A multi-year, state-wide assessment of municipality aggregated surveillance data. AB - BACKGROUND: Insecticide spraying efficiently controls house infestation by triatomine bugs, the vectors of Trypanosoma cruzi. The strategy, however, is ineffective against sylvatic triatomines, which can transmit Chagas disease by invading (without colonizing) man-made structures. Despite growing awareness of the relevance of these transmission dynamics, the drivers of house invasion by sylvatic triatomines remain poorly understood. METHODS/FINDINGS: About 12,000 sylvatic triatomines were caught during routine surveillance in houses of Tocantins state, Brazil, in 2005-2013. Using negative binomial regression, information-theoretic model evaluation/averaging, and external model validation, we investigated the effects of regional (Amazon/Cerrado), landscape (preservation/disturbance), and climate covariates (temperature, rainfall) on the municipality-aggregated numbers of house-invading Rhodnius pictipes, R. robustus, R. neglectus, and Panstrongylus geniculatus. House invasion by R. pictipes and R. robustus was overall more frequent in the Amazon biome, tended to increase in municipalities with more well-preserved land, and decreased in rainier municipalities. Across species, invasion decreased with higher landscape disturbance levels and in hotter-day municipalities. Invasion by R. neglectus and P. geniculatus increased somewhat with more land at intermediate disturbance and peaked in average-rainfall municipalities. Temperature effects were more pronounced on P. geniculatus than on Rhodnius spp. CONCLUSIONS: We report widespread, frequent house invasion by sylvatic triatomines in the Amazon-Cerrado transition. Our analyses indicate that readily available environmental metrics may help predict the risk of contact between sylvatic triatomines and humans at coarse geographic scales, and hint at specific hypotheses about climate and deforestation effects on those vectors-with some taxon-specific responses and some seemingly general trends. Thus, our focal species appear to be quite sensitive to higher temperatures, and might be less common in more heavily disturbed than in better-preserved environments. This study illustrates, in sum, how entomological routine-surveillance data can be efficiently used for Chagas disease risk prediction and stratification when house-colonizing vectors are absent. PMID- 29145406 TI - The axis IL-10/claudin-10 is implicated in the modulation of aggressiveness of melanoma cells by B-1 lymphocytes. AB - B-1 lymphocytes are known to increase the metastatic potential of B16F10 melanoma cells via the extracellular signal-regulated kinase (ERK) pathway. Since IL-10 is associated with B-1 cells performance, we hypothesized that IL-10 could be implicated in the progression of melanoma. In the present work, we found that the C57BL/6 mice, inoculated with B16F10 cells that were co-cultivated with B-1 lymphocytes from IL-10 knockout mice, developed fewer metastatic nodules than the ones which were injected with the melanoma cells that were cultivated in the presence of wild-type B-1 cells. The impairment of metastatic potential of the B16F10 cells was correlated with low activation of the ERK signaling pathway, supporting the idea that the production of IL-10 by B-1 cells influences the behavior of the tumor. A microarray analysis of the B-1 lymphocytes revealed that IL-10 deficiency is associated with down-regulation of the genes that code for claudin-10, a protein that is involved in cell-to-cell contact and that has been linked to lung adenocarcinoma. In order to determine the impact of claudin-10 in the cross-talk between B-1 lymphocytes and the B16F10 tumor cells, we took advantage of small interfering RNA. The silencing of claudin-10 gene in B-1 lymphocytes inhibited activation of the ERK pathway and abrogated the B-1-induced aggressive behavior of the B16F10 cells. Thus, our findings suggest that the axis IL-10/claudin-10 is a promising target for the development of therapeutic agents against aggressive melanoma. PMID- 29145407 TI - Predicting mortality and hospitalization of older adults by the multimorbidity frailty index. AB - BACKGROUND: Existing operational definitions of frailty are personnel-costly and time-consuming, resulting in estimates with a small sample size that cannot be generalized to the population level. The objectives were to develop a multimorbidity frailty index using Taiwan's claim database, and to understand its ability to predict adverse event. METHODS: This is a retrospective cohort study. Subjects aged 65 to 100 years who have full National Health Insurance coverage in 2005 were included. We constructed the multimorbidity frailty index using cumulative deficit approach and categorized study population according to the multimorbidity frailty index quartiles: fit, mild frailty, moderate frailty and severe frailty. The multimorbidity frailty index included deficits from outpatient and inpatient diagnosis. Associations with all-cause mortality, unplanned hospitalization and intensive care unit admission were assessed using Kaplan-Meier curves and Cox regression analyses. RESULTS: The multimorbidity frailty index incorporated 32 deficits, with mean multimorbidity frailty index score of 0.052 (standard deviation = 0.060) among 86,133 subjects included. Compared to subjects in fit category, subjects with severe frailty were associated with a 5.0-fold (adjusted hazard ratio, aHR 4.97; 95% confidence interval, 95% CI 4.49-5.50) increased risk of death at 1 year after adjusting for age and gender. Subjects with moderate frailty or mild frailty was associated with 3.1- (adjusted HR 3.08; 95% CI 2.80-3.39) or 1.9- (adjusted HR 1.86; 95% CI 1.71-2.01) folds increased risk, respectively.4.49-5.50). The risk trend of unplanned hospitalization and intensive care unit admission is similar among the study population. Besides, the association between the frailty categories and all three outcomes was slightly stronger among women. CONCLUSION: The multimorbidity frailty index was highly associated with all-cause mortality, unplanned hospitalization and ICU admission. It could serve as an efficient tool for stratifying older adults into different risk groups for planning care management programs. PMID- 29145408 TI - Effect of pulse pressure on borehole stability during shear swirling flow vibration cementing. AB - The shear swirling flow vibration cementing (SSFVC) technique rotates the downhole eccentric cascade by circulating cementing fluid. It makes the casing eccentrically revolve at high speed around the borehole axis. It produces strong agitation action to the annulus fluid, makes it in the state of shear turbulent flow, and results in the formation of pulse pressure which affects the surrounding rock stress. This study was focused on 1) the calculation of the pulse pressure in an annular turbulent flow field based on the finite volume method, and 2) the analysis of the effect of pulse pressure on borehole stability. On the upside, the pulse pressure is conducive to enhancing the liquidity of the annulus fluid, reducing the fluid gel strength, and preventing the formation of fluid from channeling. But greater pulse pressure may cause lost circulation and even formation fracturing. Therefore, in order to ensure smooth cementing during SSFVC, the effect of pulse pressure should be considered when cementing design. PMID- 29145409 TI - Predictors of suicide ideation among older adults with bipolar disorder. AB - OBJECTIVES: Bipolar disorder (BD) carries the greatest risk of death by suicide of all psychiatric conditions as 25%-50% of those with BD will make one or more suicide attempt, and about 15% will intentionally end their lives. Among young adults with BD, substance misuse, medication non-adherence, age at onset, and comorbid psychiatric conditions each predict self-harm. It is currently unclear if these same factors or others predict suicide ideation among older adults with BD. METHODS: We recruited a global sample of 220 older adults with BD over 19 days using socio-demographically targeted, social media advertising and online data collection (Mean = 58.50, SD = 5.42; range 50 to 81 years). Path analyses allowed us to identify direct and indirect predictors of suicide ideation among older adults with BD. RESULTS: Cognitive failures (perception, memory, and motor function), depressive symptoms, alcohol misuse, and dissatisfaction with life as direct predictors of suicide ideation; duration of BD symptoms and medication non adherence emerged as indirect predictors. Of note, the significant impact of sleep on suicide ideation is indirect via depressive symptoms, cognitive failures, medication non-adherence and life dissatisfaction. CONCLUSIONS: As with young adults with BD, alcohol misuse and medication non-adherence emerged as significant predictors of suicide ideation. In addition, cognitive failures directly and indirectly predict suicide ideation in this sample of older adults with BD. Population aging and treatment efficacy are leading to ever growing numbers of older adults with BD. Both direct and indirect predictors of suicide ideation need to be considered in future BD research and treatment planning. PMID- 29145411 TI - One-shot exogenous interventions increase subsequent coordination in Denmark, Spain and Ghana. AB - Everyday, we are bombarded with periodic, exogenous appeals and instructions on how to behave. How do these appeals and instructions affect subsequent coordination? Using experimental methods, we investigate how a one-time exogenous instruction affects subsequent coordination among individuals in a lab. Participants play a minimum effort game repeated 5 times under fixed matching with a one-time behavioral instruction in either the first or second round. Since coordination behavior may vary across countries, we run experiments in Denmark, Spain and Ghana, and map cross-country rankings in coordination with known national measures of fractualization, uncertainty avoidance and long-term orientation. Our results show that exogenous interventions increase subsequent coordination, with earlier interventions yielding better coordination than later interventions. We also find that cross-country rankings in coordination map with published national measures of fractualization, uncertainty avoidance, and long term orientation. PMID- 29145410 TI - The influence of computer-based cognitive flexibility training on subjective cognitive well-being after stroke: A multi-center randomized controlled trial. AB - BACKGROUND: Stroke can result in cognitive complaints that can have a large impact on quality of life long after its occurrence. A number of computer-based training programs have been developed with the aim to improve cognitive functioning. Most studies investigating their efficacy used only objective outcome measures, whereas a reduction of subjective cognitive complaints may be equally important for improving quality of life. A few studies used subjective outcome measures but were inconclusive, partly due to methodological shortcomings such as lack of proper active and passive control groups. OBJECTIVE: The aim of the current study was to investigate whether computer-based cognitive flexibility training can improve subjective cognitive functioning and quality of life after stroke. METHODS: We performed a randomized controlled double blind trial (RCT). Adults (30-80 years old) who had a stroke 3 months to 5 years ago, were randomly assigned to either an intervention group (n = 38), an active control group (i.e., mock training; n = 35), or a waiting list control group (n = 24). The intervention and mock training consisted of 58 half-hour sessions within 12 weeks. The primary subjective outcome measures were cognitive functioning (Cognitive Failure Questionnaire), executive functioning (Dysexecutive Functioning Questionnaire), quality of life (Short Form Health Survey), instrumental activities of daily living (IADL; Lawton & Brody IADL scale), and participation in society (Utrecht Scale for Evaluation of Rehabilitation Participation). Secondary subjective outcome measures were recovery after stroke, depressive symptoms (Hospital Anxiety Depression Scale-depression subscale), fatigue (Checklist Individual Strength-Fatigue subscale), and subjective cognitive improvement (exit list). Finally, a proxy of the participant rated the training effects in subjective cognitive functioning, subjective executive functioning, and IADL. RESULTS AND CONCLUSIONS: All groups improved on the two measures of subjective cognitive functioning and subjective executive functioning, but not on the other measures. These cognitive and executive improvements remained stable 4 weeks after training completion. However, the intervention group did not improve more than the two control groups. This suggests that improvement was due to training-unspecific effects. The proxies did not report any improvements. We, therefore, conclude that the computer-based cognitive flexibility training did not improve subjective cognitive functioning or quality of life after stroke. PMID- 29145412 TI - Mapping and verification of grain shape QTLs based on an advanced backcross population in rice. AB - Grain shape is a key factor that influences both the appearance quality and grain yield of rice. To clarify the genetic basis of grain shape, an advanced backcross population was developed from the cross of a slender indica variety Jin23B and a round japonica variety QingGuAi, and a total of 10 quantitative trait loci (QTLs) for grain shape were detected over 2 years. Three QTLs, qGW1, qGS3 and qGS7 have large effects on grain shape and were detected in both years. To further validate their effects, the BC4F2 populations of the three QTLs were constructed. The alleles from QingGuAi of qGW1 and qGS7 both greatly increase grain width and the alleles from Jin23B of qGS3 greatly increase grain length. The allele variations of the three QTLs lead to the totally different grain shape of the two rice varieties. Our study provides insights into the genetic bases of grain shape and will promote the improvements of grain quality and yield in rice. PMID- 29145413 TI - Diffusion-based neuromodulation can eliminate catastrophic forgetting in simple neural networks. AB - A long-term goal of AI is to produce agents that can learn a diversity of skills throughout their lifetimes and continuously improve those skills via experience. A longstanding obstacle towards that goal is catastrophic forgetting, which is when learning new information erases previously learned information. Catastrophic forgetting occurs in artificial neural networks (ANNs), which have fueled most recent advances in AI. A recent paper proposed that catastrophic forgetting in ANNs can be reduced by promoting modularity, which can limit forgetting by isolating task information to specific clusters of nodes and connections (functional modules). While the prior work did show that modular ANNs suffered less from catastrophic forgetting, it was not able to produce ANNs that possessed task-specific functional modules, thereby leaving the main theory regarding modularity and forgetting untested. We introduce diffusion-based neuromodulation, which simulates the release of diffusing, neuromodulatory chemicals within an ANN that can modulate (i.e. up or down regulate) learning in a spatial region. On the simple diagnostic problem from the prior work, diffusion-based neuromodulation 1) induces task-specific learning in groups of nodes and connections (task-specific localized learning), which 2) produces functional modules for each subtask, and 3) yields higher performance by eliminating catastrophic forgetting. Overall, our results suggest that diffusion-based neuromodulation promotes task-specific localized learning and functional modularity, which can help solve the challenging, but important problem of catastrophic forgetting. PMID- 29145414 TI - Five-year survival and associated factors in women treated for cervical cancer at a reference hospital in the Brazilian Amazon. AB - Cervical cancer (CC) is the most common type of cancer in women and is the third leading cause of death in most developing countries, causing more than 288,000 deaths in women worldwide each year. The most favourable survival rate is in developed countries, since CC mortality has recently declined in those countries. The purpose of this study was to determine the survival rate and associated factors of CC patients at a reference hospital in the Amazon region. The patient sample included records of 339 patients with cervical cancer who had been hospitalized in Belem, Para, Brazil from January 2005 to December 2010; the socioeconomic and clinical data were collected between June and September 2016. A survival rate of approximately 84% was observed, and it was found that disease stage (p <0.01), metastasis (p <0.01) and readmission (p <0.01) had significant influences on patient outcome. The impact of these factors on the general survival rate was higher in the Amazon region compared with other regions of Brazil, and the primary survival factors were associated with earlier stages of the disease. However, more national studies are needed on this subject. Our findings may contribute to the development of regional strategies for the prevention of cervical cancer, a reduction in its incidence and mortality rate, an increase in survival time and an improvement in the quality of life of these women. PMID- 29145415 TI - Plant organ cultures as masked mycotoxin biofactories: Deciphering the fate of zearalenone in micropropagated durum wheat roots and leaves. AB - "Masked mycotoxins" senso strictu are conjugates of mycotoxins resulting from metabolic pathways activated by the interplay between pathogenic fungi and infected plants. Zearalenone, an estrogenic mycotoxin produced by Fusarium spp, was the first masked mycotoxin ever described in the literature, but its biotransformation has been studied to a lesser extent if compared to other compounds such as deoxynivalenol. We presented herein the first application of organ and tissue culture techniques to study the metabolic fate of zearalenone in durum wheat, using an untargeted HR-LCMS approach. A complete, quick absorption of zearalenone by uninfected plant organs was noticed, and its biotransformation into a large spectrum of phase I and phase II metabolites has been depicted. Therefore, wheat organ tissue cultures can be effectively used as a biocatalytic tool for the production of masked mycotoxins, as well as a replicable model for the investigation of the interplay between mycotoxins and wheat physiology. PMID- 29145416 TI - Two is better than one: The effects of strategic cooperation on intra- and inter brain connectivity by fNIRS. AB - Inter-brain synchronization during joint actions is a core question in social neuroscience, and the differential contribution of intra- and inter-brain functional connectivity has yet to be clarified along with the role of psychological variables such as perceived self-efficacy. The cognitive performance and the neural activation underlying the execution of joint actions were recorded by functional Near-Infrared imaging during a synchronicity game. An 8-channel array of optodes was positioned over the frontal and prefrontal regions. During the task, the dyads received reinforcing feedback that was experimentally manipulated to induce adoption of common strategies. Intra- and inter-brain connectivity indices were computed along with an inter-brain/intra brain connectivity index (ConIndex). Finally, correlation analyses were run to assess the relationship between behavioral and physiological levels. The results showed that the external feedback could modulate participant responses in both behavioral and neural components. After the reinforcing manipulation, there were faster response times and increased inter-brain connectivity, and ConIndex emerged primarily over the dorsolateral prefrontal cortex. Additionally, the presence of significant correlations between response times and inter-brain connectivity revealed that only the "two-players connection" may guarantee an efficient performance. The present study provides a significant contribution to the identification of intra- and inter-brain functional connectivity when social reinforcement is provided. PMID- 29145417 TI - Associations between medical cannabis and prescription opioid use in chronic pain patients: A preliminary cohort study. AB - BACKGROUND: Current levels and dangers of opioid use in the U.S. warrant the investigation of harm-reducing treatment alternatives. PURPOSE: A preliminary, historical, cohort study was used to examine the association between enrollment in the New Mexico Medical Cannabis Program (MCP) and opioid prescription use. METHODS: Thirty-seven habitual opioid using, chronic pain patients (mean age = 54 years; 54% male; 86% chronic back pain) enrolled in the MCP between 4/1/2010 and 10/3/2015 were compared to 29 non-enrolled patients (mean age = 60 years; 69% male; 100% chronic back pain). We used Prescription Monitoring Program opioid records over a 21 month period (first three months prior to enrollment for the MCP patients) to measure cessation (defined as the absence of opioid prescriptions activity during the last three months of observation) and reduction (calculated in average daily intravenous [IV] morphine dosages). MCP patient reported benefits and side effects of using cannabis one year after enrollment were also collected. RESULTS: By the end of the 21 month observation period, MCP enrollment was associated with 17.27 higher age- and gender-adjusted odds of ceasing opioid prescriptions (CI 1.89 to 157.36, p = 0.012), 5.12 higher odds of reducing daily prescription opioid dosages (CI 1.56 to 16.88, p = 0.007), and a 47 percentage point reduction in daily opioid dosages relative to a mean change of positive 10.4 percentage points in the comparison group (CI -90.68 to -3.59, p = 0.034). The monthly trend in opioid prescriptions over time was negative among MCP patients (-0.64mg IV morphine, CI -1.10 to -0.18, p = 0.008), but not statistically different from zero in the comparison group (0.18mg IV morphine, CI -0.02 to 0.39, p = 0.081). Survey responses indicated improvements in pain reduction, quality of life, social life, activity levels, and concentration, and few side effects from using cannabis one year after enrollment in the MCP (ps<0.001). CONCLUSIONS: The clinically and statistically significant evidence of an association between MCP enrollment and opioid prescription cessation and reductions and improved quality of life warrants further investigations on cannabis as a potential alternative to prescription opioids for treating chronic pain. PMID- 29145418 TI - Testosterone is protective against impaired glucose metabolism in male intrauterine growth-restricted offspring. AB - Placental insufficiency alters the intrauterine environment leading to increased risk for chronic disease including impaired glucose metabolism in low birth weight infants. Using a rat model of low birth weight, we previously reported that placental insufficiency induces a significant increase in circulating testosterone in male intrauterine growth-restricted offspring (mIUGR) in early adulthood that is lost by 12 months of age. Numerous studies indicate testosterone has a positive effect on glucose metabolism in men. Female growth restricted littermates exhibit glucose intolerance at 6 months of age. Thus, the aim of this paper was to determine whether mIUGR develop impaired glucose metabolism, and whether a decrease in elevated testosterone levels plays a role in its onset. Male growth-restricted offspring were studied at 6 and 12 months of age. No impairment in glucose tolerance was observed at 6 months of age when mIUGR exhibited a 2-fold higher testosterone level compared to age-matched control. Fasting blood glucose was significantly higher and glucose tolerance was impaired with a significant decrease in circulating testosterone in mIUGR at 12 compared with 6 months of age. Castration did not additionally impair fasting blood glucose or glucose tolerance in mIUGR at 12 months of age, but fasting blood glucose was significantly elevated in castrated controls. Restoration of elevated testosterone levels significantly reduced fasting blood glucose and improved glucose tolerance in mIUGR. Thus, our findings suggest that the endogenous increase in circulating testosterone in mIUGR is protective against impaired glucose homeostasis. PMID- 29145419 TI - Attitudes to mental illness among mental health professionals in Singapore and comparisons with the general population. AB - BACKGROUND: Similar to the general public, mental health professionals sometimes also have negative attitudes towards individuals with mental illness; which could ultimately affect the quality of care received by the patients. This study aims to explore attitudes to mental illness among mental health professionals in Singapore; make comparisons with the general population; and investigate the significant correlates. METHODS: A cross-sectional design was used. Eligible participants were recruited from the Institute of Mental Health, Singapore. Attitudes to mental illness among the mental health professionals were measured using an adapted 26-item Attitudes to Mental Illness questionnaire (AMI). An earlier study amongst the general population in Singapore had used the same tool; however, factor analysis suggested a 20-item, 4-factor structure (AMI-SG) was the best fit. This 4-factor structure was applied among the current sample of mental health professionals to allow comparisons between the professionals and the general population. Data were collected through an online survey tool 'Questionpro' from February to April 2016, and 379 participants were included in the current analysis. Attitudes to mental illness among these professionals were compared to those of the general population, which were captured as part of a national study conducted from March 2014 to April 2015. RESULTS: The 20-item, 4 factor structure AMI-SG derived from the general population was applicable among the mental health professionals in Singapore. Compared to the general population, mental health professionals had significantly more positive attitudes to mental illness; however their scores on 'social distancing' did not differ from the general population. Indian ethnicity was negatively associated with 'social distancing' and 'social restrictiveness' among the professionals; while higher education was negatively related to 'prejudice and misconception'. Compared to nurses, doctors showed significantly more positive attitudes on 'social restrictiveness' and 'prejudice and misconception'. Having family or close friends diagnosed with mental illness was negatively associated with 'social distancing' among the professionals. CONCLUSION: The AMI-SG is an effective tool to measure attitudes to mental illness among mental health professionals in Singapore. Although the professionals had significantly more positive attitudes to mental illness than the general public in Singapore, their attitudes on 'social distancing' resembled closely that of the general public. Professionals tended to have more negative attitudes if they were nurses, less educated, and of Chinese ethnicity. More studies are needed to explore the underlying reasons for the differences and to generalize these findings among mental health professionals elsewhere. PMID- 29145420 TI - Effects of increased levels of atmospheric CO2 and high temperatures on rice growth and quality. AB - The increased atmospheric temperatures resulting from the increased concentration of atmospheric carbon dioxide (CO2) have had a profound influence on global rice production. China serves as an important area for producing and consuming rice. Therefore, exploring the effects of the simultaneously rising levels of atmospheric CO2 and temperatures on rice growth and quality in the future is very important. The present study was designed to measure the most important aspects of variation for rice-related physiological, ecological and quality indices in different growing periods under a simultaneous increase of CO2 and temperature, through simulation experiments in climate-controlled growth chambers, with southern rice as the study object. The results indicated that the ecological indices, rice phenology, and leaf area would decrease under a simultaneous increase of CO2 and temperature. For the physiological indices, Malondialdehyde (MDA) levels increased significantly in the seedling period. However, it showed the trend of increase and subsequent decrease in the heading and filling periods. In addition, the decomposition of soluble protein (SP) and soluble sugar (SS) accelerated in filling period. The rice quality index of the Head Rice Rate showed the decreasing trend and subsequent increase, but the Chalky Rice Rate and Protein Content indices gradually decreased while the Gel Consistency gradually increased. PMID- 29145421 TI - Radiographic prediction of meningioma grade by semantic and radiomic features. AB - OBJECTIVES: The clinical management of meningioma is guided by tumor grade and biological behavior. Currently, the assessment of tumor grade follows surgical resection and histopathologic review. Reliable techniques for pre-operative determination of tumor grade may enhance clinical decision-making. METHODS: A total of 175 meningioma patients (103 low-grade and 72 high-grade) with pre operative contrast-enhanced T1-MRI were included. Fifteen radiomic (quantitative) and 10 semantic (qualitative) features were applied to quantify the imaging phenotype. Area under the curve (AUC) and odd ratios (OR) were computed with multiple-hypothesis correction. Random-forest classifiers were developed and validated on an independent dataset (n = 44). RESULTS: Twelve radiographic features (eight radiomic and four semantic) were significantly associated with meningioma grade. High-grade tumors exhibited necrosis/hemorrhage (ORsem = 6.6, AUCrad = 0.62-0.68), intratumoral heterogeneity (ORsem = 7.9, AUCrad = 0.65), non spherical shape (AUCrad = 0.61), and larger volumes (AUCrad = 0.69) compared to low-grade tumors. Radiomic and sematic classifiers could significantly predict meningioma grade (AUCsem = 0.76 and AUCrad = 0.78). Furthermore, combining them increased the classification power (AUCradio = 0.86). Clinical variables alone did not effectively predict tumor grade (AUCclin = 0.65) or show complementary value with imaging data (AUCcomb = 0.84). CONCLUSIONS: We found a strong association between imaging features of meningioma and histopathologic grade, with ready application to clinical management. Combining qualitative and quantitative radiographic features significantly improved classification power. PMID- 29145422 TI - Missense mutation at CLDN8 associated with a high plasma interferon gamma inducible protein 10 level in methadone-maintained patients with urine test positive for morphine. AB - We previously reported a high plasma chemokine interferon gamma-inducible protein 10 (IP-10) level and prolonged electrocardiography QT-interval in methadone maintenance treatment (MMT) patients with HIV or HCV infection. The purpose of this study was to evaluate the genetic association of high plasma IP-10 level in the MMT patients. The gene-based and pathway-based association analyses were conducted using a genome-wide association study dataset in 344 MMT patients for identifying genes and pathways associated with plasma IP-10 level. We found that plasma IP-10 level was significantly associated with a pathway in the tight junction (P = 1.01x10-5), where the claudin 8 (CLDN8) gene had the most significant association (P = 6.8x10-5). A functional single nucleotide polymorphism (SNP) rs686364 at exon 1 of CLDN8 showed strong association with plasma IP-10 levels, in the MMT subjects with positive urine test for morphine (dominant model, P = 0.00004). The minor allele type carriers had higher plasma IP-10 levels than the major allele type carriers. Our data support that the tight junction protein claudin 8 exon 1 is a predictor for the plasma levels of IP-10 in MMT patients with urine test positive for morphine. PMID- 29145423 TI - Examining the relationships between body image, eating attitudes, BMI, and physical activity in rural and urban South African young adult females using structural equation modeling. AB - The persistence of food insecurity, malnutrition, increasing adiposity, and decreasing physical activity, heightens the need to understand relationships between body image satisfaction, eating attitudes, BMI and physical activity levels in South Africa. Females aged 18-23 years were recruited from rural (n = 509) and urban (n = 510) settings. Body image satisfaction was measured using Stunkard's silhouettes, and the 26-item Eating Attitudes questionnaire (EAT-26) was used to evaluate participants' risk of disordered eating. Minutes per week of moderate to vigorous physical activity (MVPA) was assessed using the Global Physical Activity Questionnaire (GPAQ). Significant linear correlates were included in a series of regressions run separately for urban and rural participants. Structural equation modeling (SEM) was used to test the relationships between variables. Urban females were more likely to be overweight and obese than rural females (p = 0.02), and had a greater desire to be thinner (p = 0.02). In both groups, being overweight or obese was positively associated with a desire to be thinner (p<0.01), and negatively associated with a desire to be fatter (p<0.01). Having a disordered eating attitude was associated with body image dissatisfaction in the urban group (beta = 1.27, p<0.01, CI: 0.38; 2.16), but only with a desire to be fatter in the rural group (beta = 0.63, p = 0.04, CI: 0.03; 1.23). In the SEM model, body image dissatisfaction was associated with disordered eating (beta = 0.63), as well as higher MVPA participation (p<0.01). These factors were directly associated with a decreased risk of disordered eating attitude, and with a decreased desire to be thinner. Findings indicate a shift in both settings towards more Westernised ideals. Physical activity may provide a means to promote a healthy body image, while reducing the risk of disordered eating. Given the high prevalence of overweight and obesity in both rural and urban women, this study provides insights for future interventions aimed at decreasing adiposity in a healthy way. PMID- 29145424 TI - Levosimendan protects human hepatocytes from ischemia-reperfusion injury. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) is a major challenge in liver transplantation. The mitochondrial pathway plays a pivotal role in hepatic IRI. Levosimendan, a calcium channel sensitizer, was shown to attenuate apoptosis after IRI in animal livers. The aim of this study was to investigate the effect of levosimendan on apoptosis in human hepatocytes. METHODS: Primary human hepatocytes were either exposed to hypoxia or cultured under normoxic conditions. After the hypoxic phase, reoxygenation was implemented and cells were treated with different concentrations of levosimendan (10ng/ml, 100ng/ml, 1000ng/ml). The overall metabolic activity of the cells was measured using 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT), and aspartate aminotransferase (AST) levels were determined in order to quantify hepatic injury. Fluorescence activated cell sorting (FACS) analysis was applied to measure necrosis and apoptosis. Finally, Western blotting was performed to analyze apoptotic pathway proteins. RESULTS: Administration of levosimendan during reperfusion increases the metabolic activity of human hepatocytes and decreases AST levels. Moreover, apoptosis after IRI is reduced in treated vs. untreated hepatocytes, and levosimendan prevents down-regulation of the anti-apoptotic protein Bcl-2 as well as up-regulation of the pro-apoptotic protein BAX. CONCLUSION: The present study suggests a protective effect of levosimendan on human hepatocytes. Our findings suggest that treatment with levosimendan during reperfusion attenuates apoptosis of human hepatocytes by influencing BAX and Bcl-2 levels. PMID- 29145425 TI - Statistical analysis of co-occurrence patterns in microbial presence-absence datasets. AB - Drawing on a long history in macroecology, correlation analysis of microbiome datasets is becoming a common practice for identifying relationships or shared ecological niches among bacterial taxa. However, many of the statistical issues that plague such analyses in macroscale communities remain unresolved for microbial communities. Here, we discuss problems in the analysis of microbial species correlations based on presence-absence data. We focus on presence-absence data because this information is more readily obtainable from sequencing studies, especially for whole-genome sequencing, where abundance estimation is still in its infancy. First, we show how Pearson's correlation coefficient (r) and Jaccard's index (J)-two of the most common metrics for correlation analysis of presence-absence data-can contradict each other when applied to a typical microbiome dataset. In our dataset, for example, 14% of species-pairs predicted to be significantly correlated by r were not predicted to be significantly correlated using J, while 37.4% of species-pairs predicted to be significantly correlated by J were not predicted to be significantly correlated using r. Mismatch was particularly common among species-pairs with at least one rare species (<10% prevalence), explaining why r and J might differ more strongly in microbiome datasets, where there are large numbers of rare taxa. Indeed 74% of all species-pairs in our study had at least one rare species. Next, we show how Pearson's correlation coefficient can result in artificial inflation of positive taxon relationships and how this is a particular problem for microbiome studies. We then illustrate how Jaccard's index of similarity (J) can yield improvements over Pearson's correlation coefficient. However, the standard null model for Jaccard's index is flawed, and thus introduces its own set of spurious conclusions. We thus identify a better null model based on a hypergeometric distribution, which appropriately corrects for species prevalence. This model is available from recent statistics literature, and can be used for evaluating the significance of any value of an empirically observed Jaccard's index. The resulting simple, yet effective method for handling correlation analysis of microbial presence-absence datasets provides a robust means of testing and finding relationships and/or shared environmental responses among microbial taxa. PMID- 29145426 TI - Buserelin alleviates chloride transport defect in human cystic fibrosis nasal epithelial cells. AB - Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride (Cl-) channel regulated by protein kinases, phosphatases, divalent cations and by protein-protein interactions. Among protein protein interactions, we previously showed that Annexin A5 (AnxA5) binds to CFTR and is involved in the channel localization within membranes and in its Cl- channel function. The deletion of phenylalanine at position 508 (F508del) is the most common mutation in CF which leads to an altered protein (F508del-CFTR) folding with a nascent protein retained within the ER and is quickly degraded. We previously showed that AnxA5 binds to F508del-CFTR and that its increased expression due to a Gonadoliberin (GnRH) augments Cl- efflux in cells expressing F508del-CFTR. The aim of the present work was to use the GnRH analog buserelin which is already used in medicine. Human nasal epithelial cells from controls and CF patients (F508del/F508del) were treated with buserelin and we show here that the treatment alleviates Cl- channel defects in CF cells. Using proteomics we highlighted some proteins explaining this result. Finally, we propose that buserelin is a potential new pharmaceutical compound that can be used in CF and that bronchus can be targeted since we show here that they express GnRH-R. PMID- 29145427 TI - Do microplastic particles affect Daphnia magna at the morphological, life history and molecular level? AB - Microplastic particles are ubiquitous not only in marine but also in freshwater ecosystems. However, the impacts of microplastics, consisting of a large variety of synthetic polymers, on freshwater organisms remains poorly understood. We examined the effects of two polymer mixtures on the morphology, life history and on the molecular level of the waterflea Daphnia magna (three different clones). Microplastic particles of ~40 MUm were supplied at a low concentration (1% of the food particles) leading to an average of ~30 particles in the digestive tract which reflects a high microplastic contamination but still resembles a natural situation. Neither increased mortality nor changes on the morphological (body length, width and tail spine length) or reproductive parameters were observed for adult Daphnia. The analyses of juvenile Daphnia revealed a variety of small and rather subtle responses of morphological traits (body length, width and tail spine length). For adult Daphnia, alterations in expression of genes related to stress responses (i.e. HSP60, HSP70 & GST) as well as of other genes involved in body function and body composition (i.e. SERCA) were observed already 48h after exposure. We anticipate that the adverse effects of microplastic might be influenced by many additional factors like size, shape, type and even age of the particles and that the rather weak effects, as detected in a laboratory, may lead to reduced fitness in a natural multi-stressor environment. PMID- 29145428 TI - Abnormal brain white matter microstructure is associated with both pre hypertension and hypertension. AB - OBJECTIVES: To characterize effects of chronically elevated blood pressure on the brain, we tested for brain white matter microstructural differences associated with normotension, pre-hypertension and hypertension in recently available brain magnetic resonance imaging data from 4659 participants without known neurological or psychiatric disease (62.3+/-7.4 yrs, 47.0% male) in UK Biobank. METHODS: For assessment of white matter microstructure, we used measures derived from neurite orientation dispersion and density imaging (NODDI) including the intracellular volume fraction (an estimate of neurite density) and isotropic volume fraction (an index of the relative extra-cellular water diffusion). To estimate differences associated specifically with blood pressure, we applied propensity score matching based on age, sex, educational level, body mass index, and history of smoking, diabetes mellitus and cardiovascular disease to perform separate contrasts of non-hypertensive (normotensive or pre-hypertensive, N = 2332) and hypertensive (N = 2337) individuals and of normotensive (N = 741) and pre hypertensive (N = 1581) individuals (p<0.05 after Bonferroni correction). RESULTS: The brain white matter intracellular volume fraction was significantly lower, and isotropic volume fraction was higher in hypertensive relative to non hypertensive individuals (N = 1559, each). The white matter isotropic volume fraction also was higher in pre-hypertensive than in normotensive individuals (N = 694, each) in the right superior longitudinal fasciculus and the right superior thalamic radiation, where the lower intracellular volume fraction was observed in the hypertensives relative to the non-hypertensive group. SIGNIFICANCE: Pathological processes associated with chronically elevated blood pressure are associated with imaging differences suggesting chronic alterations of white matter axonal structure that may affect cognitive functions even with pre hypertension. PMID- 29145429 TI - Heritability of the morphology of optic nerve head and surrounding structures: The Healthy Twin Study. AB - BACKGROUND: Optic nerve head (ONH) and surrounding structures such as beta-zone peripapillary atrophy (PPA) are important structures in glaucomatous pathogenesis. Thus, for understanding genetic components in glaucoma pathogenesis, it is necessary to evaluate the heritability of ONH and surrounding structures. The present study investigated the genetic influences on ONH and surrounding structures such as beta-zone PPA and retinal vessels. METHODS: A total of 1,205 adult twins and their family members (362 monozygotic (MZ) twin subjects (181 pairs), 64 dizygotic (DZ) twin subjects (32 pairs), and 779 singletons from 261 families), were part of the Korean Healthy Twin Study. ONH parameters including the vertical cup-to-disc ratio, the presence, the area and the location of beta-zone PPA and the angular location of retinal vein were measured. The genetic influences on the structures were evaluated using variance component methods. RESULTS: The intraclass correlation coefficient (ICC) values of axial length were highest among the parameters. The ICCs of the area and location of PPA were similar to those of vertical cup-to-disc ratio. However, retinal vessel angular locations showed low ICC values even in MZ twins. After age and sex adjustment, for axial length, vertical cup-to-disc ratio, the presence, area and location of PPA, the estimated narrow-sense heritability was 0.85, 0.48, 0.76, 0.50 and 0.65 in the right eye and 0.84, 0.47, 0.72, 0.46 and 0.72 in the left eye, respectively. The estimated narrow-sense heritability of angular location of the superior and inferior vein was 0.17 and 0.12 in the right eye and 0.13 and 0.05 in the left eye, respectively. CONCLUSIONS: ONH and surrounding structures such as vertical cup-to-disc ratio and the presence, the area and the location of beta-zone PPA seemed to be determined by the substantial genetic influence, whereas the venous angular location did not. PMID- 29145430 TI - De novo sequencing and analysis of the transcriptome during the browning of fresh cut Luffa cylindrica 'Fusi-3' fruits. AB - Fresh-cut luffa (Luffa cylindrica) fruits commonly undergo browning. However, little is known about the molecular mechanisms regulating this process. We used the RNA-seq technique to analyze the transcriptomic changes occurring during the browning of fresh-cut fruits from luffa cultivar 'Fusi-3'. Over 90 million high quality reads were assembled into 58,073 Unigenes, and 60.86% of these were annotated based on sequences in four public databases. We detected 35,282 Unigenes with significant hits to sequences in the NCBInr database, and 24,427 Unigenes encoded proteins with sequences that were similar to those of known proteins in the Swiss-Prot database. Additionally, 20,546 and 13,021 Unigenes were similar to existing sequences in the Eukaryotic Orthologous Groups of proteins and Kyoto Encyclopedia of Genes and Genomes databases, respectively. Furthermore, 27,301 Unigenes were differentially expressed during the browning of fresh-cut luffa fruits (i.e., after 1-6 h). Moreover, 11 genes from five gene families (i.e., PPO, PAL, POD, CAT, and SOD) identified as potentially associated with enzymatic browning as well as four WRKY transcription factors were observed to be differentially regulated in fresh-cut luffa fruits. With the assistance of rapid amplification of cDNA ends technology, we obtained the full-length sequences of the 15 Unigenes. We also confirmed these Unigenes were expressed by quantitative real-time polymerase chain reaction analysis. This study provides a comprehensive transcriptome sequence resource, and may facilitate further studies aimed at identifying genes affecting luffa fruit browning for the exploitation of the underlying mechanism. PMID- 29145432 TI - Evaluating the intensity of fire at the Acheulian site of Gesher Benot Ya'aqov Spatial and thermoluminescence analyses. AB - This manuscript presents an attempt to evaluate the intensity of fire through spatial patterning and thermoluminescence methodology. Previous studies of Layer II-6 Level 2 at the Acheulian site of Gesher Benot Ya'aqov suggested that hominins differentiated their activities across space, including multiple activities around a hearth reconstructed on the basis of the distribution of burned flint artifacts. A transect of ~4 m was extended from the center of the reconstructed hearth of Level 2 to its periphery in order to examine the intensity of fire. Burned and unburned flint microartifacts were sampled along this transect. The results of earlier and current thermoluminescence (TL) analysis demonstrate a general agreement with the macroscopic determination of burning, indicating that the possibility of misinterpretation based on macroscopic observations is negligible. The TL signal from flint microartifacts close to the hearth's center shows unambiguous signs of strong heating, whereas with increasing distance from the hearth the TL signal can be interpreted as a result of decreasing temperatures and/or shorter durations of exposure to fire in addition to a decreasing number of flints showing fire damage. Our study shows that TL analysis can identify some variation in fire intensity, which allows a more precise classification of burned flint microartifacts with respect to their heating history. PMID- 29145431 TI - Effects of periodontitis on the development of asthma: The role of photodynamic therapy. AB - To evaluate whether periodontitis modulates lung inflammation in an experimental model of asthma as well as the photodynamic therapy (PDT) is associated with a reduction of lung inflammation. Seventy-two BALB/c male mice (~2 months) were randomly divided into 8 groups (n = 9): Basal, Periodontitis (P), P+PT, P+PT+PDT, Asthma (A), A+P, A+P+PT, and A+P+PT+PDT. Periodontitis was induced by using the ligature technique and asthma was induced by ovalbumin (OVA). PT was performed with curettes and PDT with methylene blue (0.005%), lambda = 660nm, with a radiant exposure of 318J/cm2. After 43 days, euthanasia was carried out prior to lung and mandible morphological analyzes. All of the manipulations of the animals were performed by only one operator. The total and differential cell counts and cytokines IL-4, IL-5, IL-10, IFN-gamma, TNF-alpha, IL-1beta, and IL-6 were evaluated in the bronchoalveolar lavage (BAL) and in the serum. Mucus and alkaline phosphatase were also quantified. Statistical analyzes were performed by a blinded statistician. One-way analysis of variance (ANOVA) was employed, followed by the Student-Newman-Keuls test. Periodontitis group (P) increased alkaline phosphatase and bone resorption (p<0.05), validating the experimental model of periodontitis. The A group and the P group increased the total amount of cells (p <0.05) in the BAL. However, in the A+P group, there was a decrease in these cells, except for in the A+P+PT+PDT group (p<0.05). The asthma group increased the Th2 cytokines and P group increased the Th1 cytokine profile, and A+P+PT+PDT group increased IL-10 cytokine. Mucus was increased for the A and P groups. In conclusion, periodontitis in the asthmatic mice reduced the inflammatory migrated cells in the BAL (eosinophils, lymphocytes, macrophages). In addition, it reduced the levels of the IL-4 and TNF-alpha cytokines, which was also accompanied by a decreased mucus production. After PDT treatment the total cell count increased however, this increase was not accompanied by a pro inflammatory cytokines release. Only in PDT group the anti-inflammatory IL-10 was increased. Further studies are needed to understand this mechanism of action. PMID- 29145433 TI - Maternal folic acid supplementation and dietary folate intake and congenital heart defects. AB - BACKGROUND: It has been reported that folic acid supplementation before and/or during pregnancy could reduce the risk of congenital heart defects (CHDs). However, the results from limited epidemiologic studies have been inconclusive. We investigated the associations between maternal folic acid supplementation, dietary folate intake, and the risk of CHDs. METHODS: A birth cohort study was conducted in 2010-2012 at the Gansu Provincial Maternity & Child Care Hospital in Lanzhou, China. After exclusion of stillbirths and multiple births, a total of 94 births were identified with congenital heart defects, and 9,993 births without any birth defects. Unconditional logistic regression was used to estimate the associations. RESULTS: Compared to non-users, folic acid supplement users before pregnancy had a reduced risk of overall CHDs (OR: 0.42, 95% CI: 0.21-0.86, Ptrend = 0.025) after adjusted for potential confounders. A protective effect was observed for certain subtypes of CHDs (OR: 0.37, 95% CI: 0.16-0.85 for malformation of great arteries; 0.26, 0.10-0.68 for malformation of cardiac septa; 0.34, 0.13-0.93 for Atrial septal defect). A similar protective effect was also seen for multiple CHDs (OR: 0.49, 95% CI: 0.26-0.93, Ptrend = 0.004). Compared with the middle quartiles of dietary folate intake, lower dietary folate intake (<149.88 MUg/day) during pregnancy were associated with increased risk of overall CHDs (OR: 1.63, 95% CI: 1.01-2.62) and patent ductus arteriosus (OR: 1.85, 95% CI: 1.03-3.32). Women who were non-user folic acid supplement and lower dietary folate intake have almost 2-fold increased CHDs risk in their offspring. CONCLUSIONS: Our study suggested that folic acid supplementation before pregnancy was associated with a reduced risk of CHDs, lower dietary folate intake during pregnancy was associated with increased risk. The observed associations varied by CHD subtypes. A synergistic effect of dietary folate intake and folic acid supplementation was also observed. PMID- 29145434 TI - Is the EuroSCORE II reliable to estimate operative mortality among octogenarians? AB - OBJECTIVES: Concerns have been raised about the predictive performance (PP) of the EuroSCORE I (ES I) to estimate operative mortality (OM) of patients aged >=80. The EuroSCORE II (ES II) has been described to have better PP of OM but external validations are scarce. Furthermore, the PP of ES II has not been investigated among the octogenarians. The goal of the study was to compare the PP of ES II and ES I among the overall population and patients >= 80. METHODS: The ES I and ES II were computed for 7161 consecutive patients who underwent major cardiac surgery in a 7-year period. Discrimination was assessed by using the c- index and calibration with the Hosmer-Lemeshow (HL) and calibration plot by comparing predicted and observed mortality. RESULTS: From the global cohort of 7161 patients, 832 (12%) were >=80. The mean values of ES I and ES II were 7.4+/ 9.4 and 5.2+/-9.1 respectively for the whole cohort, 6.3+/-8.6 and 4.7+/-8.5 for the patients <80, 15.1+/-11.8 and 8.5+/-11.0 for the patients >=80. The mortality was 9.38% (>=80) versus 5.18% (<80). The discriminatory power was good for the two algorithms among the whole population and the <80 but less satisfying among the >=80 (AUC 0.64 [0.58-0.71] for ES I and 0.67 [0.60-0.73] for the ES II without significant differences (p = 0.35) between the two scores. For the octogenarians, the ES II had a fair calibration until 10%-predicted values and over-predicted beyond. CONCLUSIONS: The ES II has a better PP than the ES I among patients <80. Its discrimination and calibration are less satisfying in patients >=80, showing an overestimation in the elderly at very high-surgical risk. Nevertheless, it shows an acceptable calibration until 10%- predicted mortality. PMID- 29145435 TI - Functional characterisation of filamentous actin probe expression in neuronal cells. AB - Genetically encoded filamentous actin probes, Lifeact, Utrophin and F-tractin, are used as tools to label the actin cytoskeleton. Recent evidence in several different cell types indicates that these probes can cause changes in filamentous actin dynamics, altering cell morphology and function. Although these probes are commonly used to visualise actin dynamics in neurons, their effects on axonal and dendritic morphology has not been systematically characterised. In this study, we quantitatively analysed the effect of Lifeact, Utrophin and F-tractin on neuronal morphogenesis in primary hippocampal neurons. Our data show that the expression of actin-tracking probes significantly impacts on axonal and dendrite growth these neurons. Lifeact-GFP expression, under the control of a pBABE promoter, caused a significant decrease in total axon length, while another Lifeact-GFP expression, under the control of a CAG promoter, decreased the length and complexity of dendritic trees. Utr261-EGFP resulted in increased dendritic branching but Utr230-EGFP only accumulated in cell soma, without labelling any neurites. Lifeact-7-mEGFP and F-tractin-EGFP in a pEGFP-C1 vector, under the control of a CMV promoter, caused only minor changes in neuronal morphology as detected by Sholl analysis. The results of this study demonstrate the effects that filamentous actin tracking probes can have on the axonal and dendritic compartments of neuronal cells and emphasise the care that must be taken when interpreting data from experiments using these probes. PMID- 29145436 TI - Scrambled eggs: Proteomic portraits and novel biomarkers of egg quality in zebrafish (Danio rerio). AB - Egg quality is a complex biological trait and a major determinant of reproductive fitness in all animals. This study delivered the first proteomic portraits of egg quality in zebrafish, a leading biomedical model for early development. Egg batches of good and poor quality, evidenced by embryo survival for 24 h, were sampled immediately after spawning and used to create pooled or replicated sample sets whose protein extracts were subjected to different levels of fractionation before liquid chromatography and tandem mass spectrometry. Obtained spectra were searched against a zebrafish proteome database and detected proteins were annotated, categorized and quantified based on normalized spectral counts. Manually curated and automated enrichment analyses revealed poor quality eggs to be deficient of proteins involved in protein synthesis and energy and lipid metabolism, and of some vitellogenin products and lectins, and to have a surfeit of proteins involved in endo-lysosomal activities, autophagy, and apoptosis, and of some oncogene products, lectins and egg envelope proteins. Results of pathway and network analyses suggest that this aberrant proteomic profile results from failure of oocytes giving rise to poor quality eggs to properly transit through final maturation, and implicated Wnt signaling in the etiology of this defect. Quantitative comparisons of abundant proteins in good versus poor quality eggs revealed 17 candidate egg quality markers. Thus, the zebrafish egg proteome is clearly linked to embryo developmental potential, a phenomenon that begs further investigation to elucidate the root causes of poor egg quality, presently a serious and intractable problem in livestock and human reproductive medicine. PMID- 29145437 TI - Assessment of the suitability of biodegradable rods for use in posterior lumbar fusion: An in-vitro biomechanical evaluation and finite element analysis. AB - Interbody fusion with posterior instrumentation is a common method for treating lumbar degenerative disc diseases. However, the high rigidity of the fusion construct may produce abnormal stresses at the adjacent segment and lead to adjacent segment degeneration (ASD). As such, biodegradable implants are becoming more popular for use in orthopaedic surgery. These implants offer sufficient stability for fusion but at a reduced stiffness. Tailored to degrade over a specific timeframe, biodegradable implants could potentially mitigate the drawbacks of conventional stiff constructs and reduce the loading on adjacent segments. Six finite element models were developed in this study to simulate a spine with and without fixators. The spinal fixators used both titanium rods and biodegradable rods. The models were subjected to axial loading and pure moments. The range of motion (ROM), disc stresses, and contact forces of facet joints at adjacent segments were recorded. A 3-point bending test was performed on the biodegradable rods and a dynamic bending test was performed on the spinal fixators according to ASTM F1717-11a. The finite element simulation showed that lumbar spinal fusion using biodegradable implants had a similar ROM at the fusion level as at adjacent levels. As the rods degraded over time, this produced a decrease in the contact force at adjacent facet joints, less stress in the adjacent disc and greater loading on the anterior bone graft region. The mechanical tests showed the initial average fatigue strength of the biodegradable rods was 145 N, but this decreased to 115N and 55N after 6 months and 12 months of soaking in solution. Also, both the spinal fixator with biodegradable rods and with titanium rods was strong enough to withstand 5,000,000 dynamic compression cycles under a 145 N axial load. The results of this study demonstrated that biodegradable rods may present more favourable clinical outcomes for lumbar fusion. These polymer rods could not only provide sufficient initial stability, but the loss in rigidity of the fixation construct over time gradually transfers loading to adjacent segments. PMID- 29145438 TI - Factors associated with patients' satisfaction in Brazilian dental primary health care. AB - OBJECTIVE: To assess factors associated with patients' satisfaction with the treatment by dentists in primary health care (PHC) in Brazil. MATERIALS AND METHODS: The dataset was part of a nationwide cross-sectional survey for evaluating PHC teams conducted by the Brazilian Ministry of Health. Patients from each of 16,202 oral health teams were interviewed. In addition to sociodemographic information, the questionnaire included information about patient experience domains: access and booking of dental appointments, bonding and accountability, welcoming of the patient, and their perception of dental facilities. STATISTICAL ANALYSIS: The dependent variable was the answer to the question 'From 0 to 10, how would you grade your satisfaction with treatment received from the dentist?' Negative binomial regression models were used to estimate the unadjusted and adjusted rate ratios and corresponding 95% confidence interval. RESULTS: The mean patient satisfaction was 9.4 (+/-2.3). Higher patient satisfaction with PHC was associated with lower education and the patient's perception of the clinic conditions. Moreover, higher satisfaction was associated with positive reception and hospitality, enough time for treatment, and instructions that met patients' needs. Lower satisfaction with PHC was associated with patients who have jobs compared to those who do not work. CONCLUSION: Patient satisfaction is increased with friendly and understanding PHC staff. Moreover, meeting patient expectations by taking time to understand the needs and giving the right instructions is associated with higher satisfaction. PMID- 29145439 TI - Impact of chronic and acute academic stress on lymphocyte subsets and monocyte function. AB - This study investigated the effects of a temporally confined naturalistic stressor (academic stress) on immune functions. Furthermore, moderating influences of a number of psychological variables were assessed. Five blood samples were obtained from 20 students during an observation period of 8 weeks, starting 4.5 weeks before an exam period up to 1 week following the last exam. The analysis of 45 immune parameters revealed several time-dependent changes attributable to examination stress. We observed a reduction in the absolute numbers of natural killer (NK) cells and monocytes in peripheral blood and a shift towards more immature and naive cells within NK and T cell populations. In addition, IL-6 and TNF-alpha production by LPS-stimulated monocytes was increased. Psychological variables were grouped by means of factor analyses into two factors. One factor, which was interpreted as an indication of chronic stress, moderated the relationships between academic stress and percentages of mature CD57+ NK cells. This chronic stress factor was also associated with an increase in memory and a decrease in naive CD8 T cells and increased serum levels of IL-17. The present study identifies important potential psychological mediators of stress-induced changes in specific immunological parameters. PMID- 29145440 TI - The relationship between shift work and mental health among electronics workers in South Korea: A cross-sectional study. AB - OBJECTIVE: To determine the relationship between shift work and mental health, particularly insomnia, depression, and suicidal ideation, among electronics production workers. METHODS: A survey was conducted with 14,226 workers from an electronics manufacturer in South Korea. After excluding 112 individuals with incomplete responses, 14,114 respondents were analyzed. As part of a larger project, we collected data on respondents' general characteristics, work-related characteristics, and health status; however, in this study, we focused on the data related to shift work and mental health. Insomnia, depression, and suicidal ideation were set as dependent variables and working schedule as set as the independent variable. We performed multiple logistic regression analysis with daytime workers as the reference group. The model was adjusted for age, gender, body mass index, workplace, educational level, and marital status with or without children under 6 years of age. RESULTS: Relative to daytime workers, shift workers had 2.35, 1.23, and 1.17 greater odds of insomnia, depression, and suicidal ideation, respectively. Within the shift worker group, we found that the odds of depression and suicidal ideation increased dramatically when respondents had insomnia. The ORs for depression and suicidal ideation were 4.899 and 7.934, respectively. CONCLUSIONS: Our findings suggest that shift work is related to an increased risk of mental health problems in production workers, and the sleep disturbance related with shift work is a central mechanism for this relationship. Since these results suggest that proactive management of sleep problems might attenuate their detrimental effects on shift worker's mental health. PMID- 29145441 TI - Distinct T and NK cell populations may serve as immune correlates of protection against symptomatic pandemic influenza A(H1N1) virus infection during pregnancy. AB - Maternal influenza infection during pregnancy is associated with increased risk of morbidity and mortality. However, the link between the anti-influenza immune responses and health-related risks during infection is not well understood. We have analyzed memory T and NK cell mediated immunity (CMI) responses in pandemic influenza A(H1N1)pdm09 (pdm09) virus infected non-vaccinated pregnant women participating in the Norwegian Influenza Pregnancy Cohort (NorFlu). The cohort includes information on immunization, self-reported health and disease status, and biological samples (plasma and PBMC). Infected cases (N = 75) were defined by having a serum hemagglutination inhibition (HI) titer > = 20 to influenza pdm09 virus at the time of delivery, while controls (N = 75) were randomly selected among non-infected pregnant women (HI titer <10). In ELISpot assays cases had higher frequencies of IFNgamma+ CD8+ T cells responding to pdm09 virus or conserved CD8 T cell-restricted influenza A virus epitopes, compared to controls. Within this T cell population, frequencies of CD95+ late effector (CD45RA+CCR7-) and naive (CD45RA+CCR7+) CD8+ memory T cells correlated inversely with self reported influenza illness (ILI) symptoms. ILI symptoms in infected women were also associated with lower numbers of poly-functional (IFNgamma+TNFalpha+, IL2+IFNgamma+, IL2+IFNgamma+TNFalpha+) CD4+ T cells and increased frequencies of IFNgamma+CD3-CD7+ NK cells compared to asymptomatic cases, or controls, after stimulation with the pdm09 virus. Taken together, virus specific and functionally distinct T and NK cell populations may serve as cellular immune correlates of clinical outcomes of pandemic influenza disease in pregnant women. Our results may provide information important for future universal influenza vaccine design. PMID- 29145442 TI - Downregulation of KCNMB4 expression and changes in BK channel subtype in hippocampal granule neurons following seizure activity. AB - A major challenge is to understand maladaptive changes in ion channels that sets neurons on a course towards epilepsy development. Voltage- and calcium-activated K+ (BK) channels contribute to early spike timing in neurons, and studies indicate that the BK channel plays a pathological role in increasing excitability early after a seizure. Here, we have investigated changes in BK channels and their accessory beta4 subunit (KCNMB4) in dentate gyrus (DG) granule neurons of the hippocampus, key neurons that regulate excitability of the hippocampus circuit. Two days after pilocarpine-induced seizures, we found that the predominant effect is a downregulation of the beta4 accessory subunit mRNA. Consistent with reduced expression, single channel recording and pharmacology indicate a switch in the subtype of channels expressed; from iberiotoxin resistant, type II BK channels (BK alpha/beta4) that have higher channel open probability and slow gating, to iberiotoxin-sensitive type I channels (BK alpha alone) with low open probability and faster gating. The switch to a majority of type I channel expression following seizure activity is correlated with a loss of BK channel function on spike threshold while maintaining the channel's contribution to increased early spike frequency. Using heterozygous beta4 knockout mice, we find reduced expression is sufficient to increase seizure sensitivity. We conclude that seizure-induced downregulation of KCNMB4 is an activity dependent mechanism that increases the excitability of DG neurons. These novel findings indicate that BK channel subtypes are not only defined by cell specific expression, but can also be plastic depending on the recent history of neuronal excitability. PMID- 29145443 TI - Lessons learned from continued TB outbreaks in a high school. AB - We investigated the aftereffects of confirmatory QuantiFERON testing (QFT) added to a positive tuberculin skin test (TST). We reviewed the pre and post course of sequential tuberculosis (TB) outbreaks in a high school where massive 43 active TB cases had been found within one year before delayed contact investigation. And we investigated the TB development in relation to initial TST and QFT during mean follow-up of 3.9 +/- 0.9 years. After delayed contact investigation for two subsequent TB outbreaks, 925 contacts were divided into the following 3 groups: TST- (n = 632), TST+/QFT+ (n = 24), TST+/QFT- (n = 258). QFT- was more prevalent than QFT+ in contacts with 10mm <= TST <15mm (158, 61.2%) compared with TST >=15mm (100, 38.8%) among the TST+ reactors (P < 0.001). Among the 258 TST+/QFT- subjects, 256 received no latent TB infection (LTBI) treatment, but 7 contacts developed TB during follow-up. Among these 7 patients, 4 had initial TST >=15mm and 3 had 10mm <= TST <15mm. In conclusion, the delayed contact investigation for LTBI in a high school resulted in continued TB developments. False-negative QFT performed late among the TST+ reactors should not be considered criteria for LTBI treatment. Additionally, the contacts only with TST >=15mm should be considered for LTBI treatment in congregate settings of intermediate-burden countries. PMID- 29145444 TI - Inhibition of the H3K9 methyltransferase G9A attenuates oncogenicity and activates the hypoxia signaling pathway. AB - Epigenetic mechanisms play important roles in the regulation of tumorigenesis, and hypoxia-induced epigenetic changes may be critical for the adaptation of cancer cells to the hypoxic microenvironment of solid tumors. Previously, we showed that loss-of-function of the hypoxia-regulated H3K9 methyltransferase G9A attenuates tumor growth. However, the mechanisms by which blockade of G9A leads to a tumor suppressive effect remain poorly understood. We show that G9A is highly expressed in breast cancer and is associated with poor patient prognosis, where it may function as a potent oncogenic driver. In agreement with this, G9A inhibition by the small molecule inhibitor, BIX-01294, leads to increased cell death and impaired cell migration, cell cycle and anchorage-independent growth. Interestingly, whole transcriptome analysis revealed that genes involved in diverse cancer cell functions become hypoxia-responsive upon G9A inhibition. This was accompanied by the upregulation of the hypoxia inducible factors HIF1alpha and HIF2alpha during BIX-01294 treatment even in normoxia that may facilitate the tumor suppressive effects of BIX-01294. HIF inhibition was able to reverse some of the transcriptional changes induced by BIX-01294 in hypoxia, indicating that the HIFs may be important drivers of these derepressed target genes. Therefore, we show that G9A is a key mediator of oncogenic processes in breast cancer cells and G9A inhibition by BIX-01294 can successfully attenuate oncogenicity even in hypoxia. PMID- 29145445 TI - A new approach by optical coherence tomography for elucidating biofilm formation by emergent Candida species. AB - The majority of microorganisms present a community lifestyle, establishing biofilm ecosystems. However, little is known about its formation in emergent Candida species involved in catheter-related infections. Thus, various techniques may be used in the biofilm detection to elucidate structure and clinical impact. In this context, we report the ability of emergent Candida species (Candida haemulonii, C. lusitaniae, C. pelliculosa, C.guilliermondii, C. famata and C. ciferrii) on developing well structured biofilms with cell viability and architecture, using optical coherence tomography (OCT). This new approach was compared with XTT analyses and Scanning Electron Microscopy (SEM). A positive correlation between oxidative activity (XTT) and OCT results (r = 0.8752, p < 0.0001) was observed. SEM images demonstrated cells attachment, multilayer and morphologic characteristics of the biofilm structure. C. lusitaniae was the emergent species which revealed the highest scattering extension length and oxidative metabolism when evaluated by OCT and XTT methods, respectively. Herein, information on C. ciferri biofilm structure were presented for the first time. The OCT results are independently among Candida strains and no species-specific pattern was observed. Our findings strongly contribute for clinical management based on the knowledge of pathogenicity mechanisms involving emergent yeasts. PMID- 29145446 TI - Large-scale climatic effects on traditional Hawaiian fishpond aquaculture. AB - Aquaculture accounts for almost one-half of global fish consumption. Understanding the regional impact of climate fluctuations on aquaculture production thus is critical for the sustainability of this crucial food resource. The objective of this work was to understand the role of climate fluctuations and climate change in subtropical coastal estuarine environments within the context of aquaculture practices in He'eia Fishpond, O'ahu Island, Hawai'i. To the best of our knowledge, this was the first study of climate effects on traditional aquaculture systems in the Hawaiian Islands. Data from adjacent weather stations were analyzed together with in situ water quality instrument deployments spanning a 12-year period (November 2004 -November 2016). We found correlations between two periods with extremely high fish mortality at He'eia Fishpond (May and October 2009) and slackening trade winds in the week preceding each mortality event, as well as surface water temperatures elevated 2-3 degrees C higher than the background periods (March-December 2009). We posit that the lack of trade wind-driven surface water mixing enhanced surface heating and stratification of the water column, leading to hypoxic conditions and stress on fish populations, which had limited ability to move within net pen enclosures. Elevated water temperature and interruption of trade winds previously have been linked to the onset of El Nino in Hawai'i. Our results provide empirical evidence regarding El Nino effects on the coastal ocean, which can inform resource management efforts about potential impact of climate variation on aquaculture production. Finally, we provide recommendations for reducing the impact of warming events on fishponds, as these events are predicted to increase in magnitude and frequency as a consequence of global warming. PMID- 29145447 TI - From bead to rod: Comparison of theories by measuring translational drag coefficients of micron-sized magnetic bead-chains in Stokes flow. AB - Frictional drag force on an object in Stokes flow follows a linear relationship with the velocity of translation and a translational drag coefficient. This drag coefficient is related to the size, shape, and orientation of the object. For rod like objects, analytical solutions of the drag coefficients have been proposed based on three rough approximations of the rod geometry, namely the bead model, ellipsoid model, and cylinder model. These theories all agree that translational drag coefficients of rod-like objects are functions of the rod length and aspect ratio, but differ among one another on the correction factor terms in the equations. By tracking the displacement of the particles through stationary fluids of calibrated viscosity in magnetic tweezers setup, we experimentally measured the drag coefficients of micron-sized beads and their bead-chain formations with chain length of 2 to 27. We verified our methodology with analytical solutions of dimers of two touching beads, and compared our measured drag coefficient values of rod-like objects with theoretical calculations. Our comparison reveals several analytical solutions that used more appropriate approximation and derived formulae that agree with our measurement better. PMID- 29145448 TI - Steps to achieve quantitative measurements of microRNA using two step droplet digital PCR. AB - Droplet digital PCR (ddPCR) is being advocated as a reference method to measure rare genomic targets. It has consistently been proven to be more sensitive and direct at discerning copy numbers of DNA than other quantitative methods. However, one of the largest obstacles to measuring microRNA (miRNA) using ddPCR is that reverse transcription efficiency depends upon the target, meaning small RNA nucleotide composition directly effects primer specificity in a manner that prevents traditional quantitation optimization strategies. Additionally, the use of reagents that are optimized for miRNA measurements using quantitative real time PCR (qRT-PCR) appear to either cause false positive or false negative detection of certain targets when used with traditional ddPCR quantification methods. False readings are often related to using inadequate enzymes, primers and probes. Given that two-step miRNA quantification using ddPCR relies solely on reverse transcription and uses proprietary reagents previously optimized only for qRT-PCR, these barriers are substantial. Therefore, here we outline essential controls, optimization techniques, and an efficacy model to improve the quality of ddPCR miRNA measurements. We have applied two-step principles used for miRNA qRT-PCR measurements and leveraged the use of synthetic miRNA targets to evaluate ddPCR following cDNA synthesis with four different commercial kits. We have identified inefficiencies and limitations as well as proposed ways to circumvent identified obstacles. Lastly, we show that we can apply these criteria to a model system to confidently quantify miRNA copy number. Our measurement technique is a novel way to quantify specific miRNA copy number in a single sample, without using standard curves for individual experiments. Our methodology can be used for validation and control measurements, as well as a diagnostic technique that allows scientists, technicians, clinicians, and regulators to base miRNA measures on a single unit of measurement rather than a ratio of values. PMID- 29145449 TI - Estimation of the proteomic cancer co-expression sub networks by using association estimators. AB - In this study, the association estimators, which have significant influences on the gene network inference methods and used for determining the molecular interactions, were examined within the co-expression network inference concept. By using the proteomic data from five different cancer types, the hub genes/proteins within the disease-associated gene-gene/protein-protein interaction sub networks were identified. Proteomic data from various cancer types is collected from The Cancer Proteome Atlas (TCPA). Correlation and mutual information (MI) based nine association estimators that are commonly used in the literature, were compared in this study. As the gold standard to measure the association estimators' performance, a multi-layer data integration platform on gene-disease associations (DisGeNET) and the Molecular Signatures Database (MSigDB) was used. Fisher's exact test was used to evaluate the performance of the association estimators by comparing the created co-expression networks with the disease-associated pathways. It was observed that the MI based estimators provided more successful results than the Pearson and Spearman correlation approaches, which are used in the estimation of biological networks in the weighted correlation network analysis (WGCNA) package. In correlation-based methods, the best average success rate for five cancer types was 60%, while in MI based methods the average success ratio was 71% for James-Stein Shrinkage (Shrink) and 64% for Schurmann-Grassberger (SG) association estimator, respectively. Moreover, the hub genes and the inferred sub networks are presented for the consideration of researchers and experimentalists. PMID- 29145450 TI - Enhanced expression of cell-surface B-cell receptor-associated protein 31 contributes to poor survival of non-small cell lung carcinoma cells. AB - B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum (ER) membrane protein which plays a role as a molecular chaperone for the newly synthesized transmembrane proteins. BAP31 is also an important apoptosis regulator for extrinsic apoptosis induction in the ER membrane. Recent studies have shown that BAP31 is also expressed on the surface of embryonic stem cells. However, the function of cell surface BAP31 (csBAP31) still remains unclarified. In an attempt to search for surface markers on tumorspheres, here, we generated monoclonal antibodies (MAbs) against the sphere cells from the non-small cell lung carcinoma cell (NSCLC) line A549. SP1-B7, one of the MAbs, recognized csBAP31 whose expression was further increased on A549 sphere cells, as compared with A549 adherent cells. To investigate the role of csBAP31 in A549 cells, A549 adherent and sphere cells were stained with annexin V, propidium iodide, and SP1 B7. Interestingly, annexin V-high cells showed increased expression of csBAP31 as compared with annexin V-low cells. Caspase-3/7 activity was also increased in csBAP31-high cells as compared with csBAP31-low cells, suggesting that csBAP31 high cells are more sensitive to apoptosis. To further demonstrate the survival of csBAP31-positive A549 cells, csBAP31-positive and -negative A549 cells were sorted and subjected to the clonogenic survival assay. The colony number of csBAP31-positive A549 cells was decreased by approximately 1.7-fold, as compared that of csBAP31-negative A549 cells, suggesting that csBAP31-positve cells are sensitive to cell death indeed. The results suggest that enhanced expression of csBAP31 contributes to poor survival of NSCLC cells. PMID- 29145451 TI - Stromal interaction molecule 1 haploinsufficiency causes maladaptive response to pressure overload. AB - Stromal interaction molecule 1 (STIM1), an endo/sarcoplasmic reticulum Ca2+ sensor, has been shown to control a Ca2+-dependent signal that promotes cardiac hypertrophy. However, whether STIM1 has adaptive role that helps to protect against cardiac overload stress remains unknown. We hypothesized that STIM1 deficiency causes a maladaptive response to pressure overload stress. We investigated STIM1 heterozygous KO (STIM1+/-) mice hearts, in which STIM1 protein levels decreased to 27% of wild-type (WT) with no compensatory increase in STIM2. Under stress-free conditions, no significant differences were observed in electrocardiographic and echocardiographic parameters or blood pressure between STIM1+/-and WT mice. However, when STIM1+/-mice were subjected to transverse aortic constriction (TAC), STIM1+/-mice had a higher mortality rate than WT mice. The TAC-induced increase in the heart weight to body weight ratio (mean mg/g +/- standard error of the mean) was significantly inhibited in STIM1+/-mice (WT sham, 4.12 +/- 0.14; WT TAC, 6.23 +/- 0.40; STIM1+/-sham, 4.53 +/- 0.16; STIM1+/-TAC, 4.63 +/- 0.08). Reverse transcription-polymerase chain reaction analysis of the left ventricles of TAC-treated STIM1+/-mice showed inhibited induction of cardiac fetal genes, including those encoding brain and atrial natriuretic proteins. Western blot analysis showed upregulated expression of transient receptor potential channel 1 (TRPC1) in TAC-treated WT mice, but suppressed expression in TAC-treated STIM1+/-mice. Taken together, the hearts of STIM1 haploinsufficient mice had a superficial resemblance to the WT phenotype under stress-free conditions; however, STIM1 haploinsufficient mice showed a maladaptive response to cardiac pressure overload. PMID- 29145452 TI - Behavioral, climatic, and environmental risk factors for Zika and Chikungunya virus infections in Rio de Janeiro, Brazil, 2015-16. AB - The burden of arboviruses in the Americas is high and may result in long-term sequelae with infants disabled by Zika virus infection (ZIKV) and arthritis caused by infection with Chikungunya virus (CHIKV). We aimed to identify environmental drivers of arbovirus epidemics to predict where the next epidemics will occur and prioritize municipalities for vector control and eventual vaccination. We screened sera and urine samples (n = 10,459) from residents of 48 municipalities in the state of Rio de Janeiro for CHIKV, dengue virus (DENV), and ZIKV by molecular PCR diagnostics. Further, we assessed the spatial pattern of arbovirus incidence at the municipal and neighborhood scales and the timing of epidemics and major rainfall events. Lab-confirmed cases included 1,717 infections with ZIKV (43.8%) and 2,170 with CHIKV (55.4%) and only 29 (<1%) with DENV. ZIKV incidence was greater in neighborhoods with little access to municipal water infrastructure (r = -0.47, p = 1.2x10-8). CHIKV incidence was weakly correlated with urbanization (r = 0.2, p = 0.02). Rains began in October 2015 and were followed one month later by the largest wave of ZIKV epidemic. ZIKV cases markedly declined in February 2016, which coincided with the start of a CHIKV outbreak. Rainfall predicted ZIKV and CHIKV with a lead time of 3 weeks each time. The association between rainfall and epidemics reflects vector ecology as the larval stages of Aedes aegypti require pools of water to develop. The temporal dynamics of ZIKV and CHIKV may be explained by the shorter incubation period of the viruses in the mosquito vector; 2 days for CHIKV versus 10 days for ZIKV. PMID- 29145453 TI - The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin. AB - BACKGROUND: Fibrosing diseases are a leading cause of morbidity and mortality worldwide and, therefore, there is a need for safe and effective antifibrotic therapies. Adenosine, generated extracellularly by the dephosphorylation of adenine nucleotides, ligates specific receptors which play a critical role in development of hepatic and dermal fibrosis. Results of recent clinical trials indicate that tenofovir, a widely used antiviral agent, reverses hepatic fibrosis/cirrhosis in patients with chronic hepatitis B infection. Belonging to the class of acyclic nucleoside phosphonates, tenofovir is an analogue of AMP. We tested the hypothesis that tenofovir has direct antifibrotic effects in vivo by interfering with adenosine pathways of fibrosis using two distinct models of adenosine and A2AR-mediated fibrosis. METHODS: Thioacetamide (100mg/kg IP) treated mice were treated with vehicle, or tenofovir (75mg/kg, SubQ) (n = 5-10). Bleomycin (0.25U, SubQ)-treated mice were treated with vehicle or tenofovir (75mg/kg, IP) (n = 5-10). Adenosine levels were determined by HPLC, and ATP release was quantitated as luciferase-dependent bioluminescence. Skin breaking strength was analysed and H&E and picrosirus red-stained slides were imaged. Pannexin-1expression was knocked down following retroviral-mediated expression of of Pannexin-1-specific or scrambled siRNA. RESULTS: Treatment of mice with tenofovir diminished adenosine release from the skin of bleomycin-treated mice and the liver of thioacetamide-treated mice, models of diffuse skin fibrosis and hepatic cirrhosis, respectively. More importantly, tenofovir treatment diminished skin and liver fibrosis in these models. Tenofovir diminished extracellular adenosine concentrations by inhibiting, in a dose-dependent fashion, cellular ATP release but not in cells lacking Pannexin-1. CONCLUSIONS: These studies suggest that tenofovir, a widely used antiviral agent, could be useful in the treatment of fibrosing diseases. PMID- 29145454 TI - Reduction of HIV-associated excess mortality by antiretroviral treatment among tuberculosis patients in Kenya. AB - BACKGROUND: Mortality from TB continues to be a global public health challenge. TB ranks alongside Human Immunodeficiency Virus (HIV) as the leading infectious causes of death globally. HIV is a major driver of TB related morbidity and mortality while TB is the leading cause of mortality among people living with HIV/AIDS. We sought to determine excess mortality associated with HIV and the effect of antiretroviral therapy on reducing mortality among tuberculosis patients in Kenya. METHODS: We conducted a retrospective analysis of Kenya national tuberculosis program data of patients enrolled from 2013 through 2014. We used direct standardization to obtain standardized mortality ratios for tuberculosis patients compared with the general population. We calculated the population attributable fraction of tuberculosis deaths due to HIV based on the standardized mortality ratio for deaths among TB patients with HIV compared to TB patients without HIV. We used Cox proportional hazards regression for assessing risk factors for mortality. RESULTS: Of 162,014 patients included in the analysis, 6% died. Mortality was 10.6 (95% CI: 10.4-10.8) times higher among TB patients than the general population; 42% of deaths were attributable to HIV infection. Patients with HIV who were not receiving ART had an over four-fold risk of death compared to patients without HIV (aHR = 4.2, 95% CI 3.9-4.6). In contrast, patients with HIV who were receiving ART had only 2.6 times the risk of death (aHR = 2.6, 95% CI 2.5-2.7). CONCLUSION: HIV was a significant contributor to TB-associated deaths in Kenya. Mortality among HIV-infected individuals was higher among those not on ART than those on ART. Early initiation of ART among HIV infected people (a "test and treat" approach) should further reduce TB associated deaths. PMID- 29145455 TI - Association of polymorphisms in heat shock protein 70 genes with the susceptibility to noise-induced hearing loss: A meta-analysis. AB - BACKGROUND: Several case-control studies reported the relationship between single nucleotide polymorphisms (SNPs) in HSP70 genes and noise-induced hearing loss (NIHL). However, their conclusions are conflicting. This meta-analysis aims to identify the association of HSP70 variants and NIHL susceptibility. METHOD: A systematical literature search was performed in PubMed, Web of Science, EMBASE, and Wanfang Chinese database. The pooled odds radio (OR), 95% confidence interval (CI) and p value were calculated in fixed- or random-effects model according to the I2 value in the heterogeneity test. RESULTS: Four articles containing five studies, including 633 cases and 926 controls, were included. Under the allele, homozygote and dominant model, the pooled ORs (95%CI, p-value) of rs1061581 were 1.32 (1.06-1.67, p = 0.019), 1.93 (1.10-3.36, p = 0.021) and 1.455 (1.408-2.019, p = 0.025), respectively. In addition, a significant association was found between rs2227956 in Caucasians and the NIHL susceptibility under all five genetic models. We did not discover evidence sufficient to prove the associations between the other three SNPs (rs1043618, rs2763979 and rs2075800) and the NIHL susceptibility. CONCLUSION: This meta-analysis indicated that the two HSP70 variants, rs1061581 and rs2227956, may serve as genetic susceptibility factors for NIHL. Larger scale studies are required to further update the results. PMID- 29145456 TI - Regulation of the bone marrow microenvironment by G-CSF: Effects of G-CSF on acute lymphoblastic leukaemia. AB - It has been suggested that disruption of the lymphoid niche by G-CSF may be of therapeutic benefit to patients with acute lymphoblastic leukaemia. We used a xenograft model to determine the effect of G-CSF on ALL progression in a minimal residual disease setting. Consistent with the effects on normal murine B cell progenitors, G-CSF slowed disease in the majority of ALL xenografts tested, suggesting that G-CSF may provide benefits beyond neutrophil recovery for ALL patients. However, two of eight xenografts demonstrated accelerated disease progression. G-CSF could be detrimental for these patients due to expansion of the malignant clone. PMID- 29145457 TI - Association between environmental noise and subjective symptoms related to cardiovascular diseases among elderly individuals in Japan. AB - Noise in housing environments may increase the risk of cardiovascular diseases (CVDs); however, the most significant sources of noise among elderly individuals remain poorly understood. A nationwide cross-sectional study comprised of 6,181 elderly people (age >= 65 years) was conducted using a web-based self-reported questionnaire in 2014. Questions pertaining to CVD-related subjective symptoms within the past year addressed symptoms of chest pain, disturbances in pulse, acute impaired tongue movement, limb paralysis, and foot pain or numbness during walking. Questions concerning noise included awakening during the night due to noise, automobile, neighborhood, construction, railway, and aircraft noise. The multivariable analyses revealed that all symptoms were significantly associated with awakening during the night due to noise. Automobile, construction, railway, and aircraft noise were significantly associated with more CVD-related symptoms at nighttime than at daytime. Our results suggest that noise at nighttime is an important risk factor for CVDs. Although several different sources of environmental noise, including automobile, neighborhood, construction, railway, and aircraft noise were found to be significantly associated with CVD-related symptoms, the strongest association was observed for construction noise, followed by neighborhood and automobile noise. The adjusted odds ratios (95% confidence intervals) for construction noise at nighttime were 1.12 (1.06-1.19) with disturbances in pulse, 1.21 (1.08-1.35) in acute impaired tongue movement, 1.25 (1.15-1.36) in limb paralysis, and 1.19 (1.12-1.28) in foot pain or numbness during walking. The associations with railway and aircraft noise were found to be weaker than those with automobile, neighborhood, and construction noise. Our study suggests that CVD-related symptoms may exhibit a greater association with construction, neighborhood, and automobile noise than with railway and aircraft noise. PMID- 29145458 TI - A model-guided symbolic execution approach for network protocol implementations and vulnerability detection. AB - Formal techniques have been devoted to analyzing whether network protocol specifications violate security policies; however, these methods cannot detect vulnerabilities in the implementations of the network protocols themselves. Symbolic execution can be used to analyze the paths of the network protocol implementations, but for stateful network protocols, it is difficult to reach the deep states of the protocol. This paper proposes a novel model-guided approach to detect vulnerabilities in network protocol implementations. Our method first abstracts a finite state machine (FSM) model, then utilizes the model to guide the symbolic execution. This approach achieves high coverage of both the code and the protocol states. The proposed method is implemented and applied to test numerous real-world network protocol implementations. The experimental results indicate that the proposed method is more effective than traditional fuzzing methods such as SPIKE at detecting vulnerabilities in the deep states of network protocol implementations. PMID- 29145459 TI - The construction of ventilation turrets in Atta vollenweideri leaf-cutting ants: Carbon dioxide levels in the nest tunnels, but not airflow or air humidity, influence turret structure. AB - Nest ventilation in the leaf-cutting ant Atta vollenweideri is driven via a wind induced mechanism. On their nests, workers construct small turrets that are expected to facilitate nest ventilation. We hypothesized that the construction and structural features of the turrets would depend on the colony's current demands for ventilation and thus might be influenced by the prevailing environmental conditions inside the nest. Therefore, we tested whether climate related parameters, namely airflow, air humidity and CO2 levels in the outflowing nest air influenced turret construction in Atta vollenweideri. In the laboratory, we simulated a semi-natural nest arrangement with fungus chambers, a central ventilation tunnel providing outflow of air and an aboveground building arena for turret construction. In independent series, different climatic conditions inside the ventilation tunnel were experimentally generated, and after 24 hours, several features of the built turret were quantified, i.e., mass, height, number and surface area (aperture) of turret openings. Turret mass and height were similar in all experiments even when no airflow was provided in the ventilation tunnel. However, elevated CO2 levels led to the construction of a turret with several minor openings and a larger total aperture. This effect was statistically significant at higher CO2 levels of 5% and 10% but not at 1% CO2. The construction of a turret with several minor openings did not depend on the strong differences in CO2 levels between the outflowing and the outside air, since workers also built permeated turrets even when the CO2 levels inside and outside were both similarly high. We propose that the construction of turrets with several openings and larger opening surface area might facilitate the removal of CO2 from the underground nest structure and could therefore be involved in the control of nest climate in leaf-cutting ants. PMID- 29145460 TI - TRAIL attenuates RANKL-mediated osteoblastic signalling in vascular cell mono culture and co-culture models. AB - BACKGROUND AND OBJECTIVES: Vascular calcification (VC) is a major risk factor for elevated cardiovascular morbidity/mortality. Underlying this process is osteoblastic signalling within the vessel wall involving complex and interlinked roles for receptor-activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). RANKL promotes vascular cell osteoblastic differentiation, whilst OPG acts as a neutralizing decoy receptor for RANKL (and TRAIL). With respect to TRAIL, much recent evidence points to a vasoprotective role for this ligand, albeit via unknown mechanisms. In order to shed more light on TRAILs vasoprotective role therefore, we employed in vitro cell models to test the hypothesis that TRAIL can counteract the RANKL-mediated signalling that occurs between the vascular cells that comprise the vessel wall. METHODS AND RESULTS: Human aortic endothelial and smooth muscle cell mono-cultures (HAECs, HASMCs) were treated with RANKL (0-25 ng/mL +/- 5 ng/mL TRAIL) for 72 hr. Furthermore, to better recapitulate the paracrine signalling that exists between endothelial and smooth muscle cells within the vessel wall, non-contact transwell HAEC:HASMC co cultures were also employed and involved RANKL treatment of HAECs (+/-TRAIL), subsequently followed by analysis of pro-calcific markers in the underlying subluminal HASMCs. RANKL elicited robust osteoblastic signalling across both mono and co-culture models (e.g. increased BMP-2, alkaline phosphatase/ALP, Runx2, and Sox9, in conjunction with decreased OPG). Importantly, several RANKL actions (e.g. increased BMP-2 release from mono-cultured HAECs or increased ALP/Sox9 levels in co-cultured HASMCs) could be strongly blocked by co-incubation with TRAIL. In summary, this paper clearly demonstrates that RANKL can elicit pro osteoblastic signalling in HAECs and HASMCs both directly and across paracrine signalling axes. Moreover, within these contexts we present clear evidence that TRAIL can block several key signalling actions of RANKL in vascular cells, providing further evidence of its vasoprotective potential. PMID- 29145461 TI - Climate change mitigation opportunities based on carbon footprint estimates of dietary patterns in Peru. AB - Food consumption accounts for an important proportion of the world GHG emissions per capita. Previous studies have delved into the nature of dietary patterns, showing that GHG reductions can be achieved in diets if certain foods are consumed rather than other, more GHG intensive products. For instance, vegetarian and low-meat diets have proved to be less carbon intensive than diets that are based on ruminant meat. These environmental patterns, increasingly analyzed in developed nations, are yet to be assessed in countries liked Peru where food purchase represents a relatively high percentage of the average household expenditure, ranging from 38% to 51% of the same. Therefore, food consumption can be identified as a potential way to reduce GHG emissions in Peru. However, the Peruvian government lacks a specific strategy to mitigate emissions in this sector, despite the recent ratification of the Paris Accord. In view of this, the main objective of this study is to analyze the environmental impacts of a set of 47 Peruvian food diet profiles, including geographical and socioeconomic scenarios. In order to do this, Life Cycle Assessment was used as the methodological framework to obtain the overall impacts of the components in the dietary patterns observed and primary data linked to the composition of diets were collected from the Peruvian National Institute for Statistics (INEI). Life cycle inventories for the different products that are part of the Peruvian diet were obtained from a set of previous scientific articles and reports regarding food production. Results were computed using the IPCC 2013 assessment method to estimate GHG emissions. Despite variations in GHG emissions from a geographical perspective, no significant differences were observed between cities located in the three Peruvian natural regions (i.e., coast, Andes and Amazon basin). In contrast, there appears to be a strong, positive correlation between GHG emissions and social expenditure or academic status. When compared to GHG emissions computed in the literature for developed nations, where the average caloric intake is substantially higher, diet-related emissions in Peru were in the low range. Our results could be used as a baseline for policy support to align nutritional and health policies in Peru with the need to reduce the environmental impacts linked to food production. PMID- 29145462 TI - Circulating soluble endoglin modifies the inflammatory response in mice. AB - Inflammation is associated with every health condition, and is an important component of many pathologies such as cardiovascular diseases. Circulating levels of soluble endoglin have been shown to be higher in the serum of patients with cardiovascular diseases with a significant inflammatory component. The aim of this study was to evaluate the implication of circulating soluble endoglin in the inflammatory response. For this purpose, a transgenic mouse expressing human soluble endoglin (sEng+) was employed, and three different inflammatory approaches were used to mimic inflammatory conditions in different tissues. This study shows that control sEng+ mice have a normal inflammatory state. The lung and kidney injury induced by the inflammatory agents was reduced in sEng+ mice, especially the intra-alveolar and kidney infiltrates, suggesting a possible reduction in inflammation induced by soluble endoglin. To deepen into this possible effect, the leukocyte number in the bronchoalveolar lavage and air pouch lavage was evaluated and a significant reduction of neutrophil infiltration in LPS-treated lungs and ischemic kidneys from sEng+ with respect to WT mice was observed. Additionally, the mechanisms through which soluble endoglin prevents inflammation were studied. We found that in sEng+ animals the increment of proinflammatory cytokines, TNFalpha, IL1beta and IL6, induced by the inflammatory stimulus was reduced. Soluble endoglin also prevents the augmented adhesion molecules, ICAM, VCAM and E-selectin induced by the inflammatory stimulus. In addition, vascular permeability increased by inflammatory agents was also reduced by soluble endoglin. These results suggest that soluble endoglin modulates inflammatory-related diseases and open new perspectives leading to the development of novel and targeted approaches for the prevention and treatment of cardiovascular diseases. PMID- 29145463 TI - The chicken or the egg? Exploring bi-directional associations between Newcastle disease vaccination and village chicken flock size in rural Tanzania. AB - Newcastle disease (ND) is a viral disease of poultry with global importance, responsible for the loss of a potential source of household nutrition and economic livelihood in many low-income food-deficit countries. Periodic outbreaks of this endemic disease result in high mortality amongst free-ranging chicken flocks and may serve as a disincentive for rural households to invest time or resources in poultry-keeping. Sustainable ND control can be achieved through vaccination using a thermotolerant vaccine administered via eyedrop by trained "community vaccinators". This article evaluates the uptake and outcomes of fee for-service ND vaccination programs in eight rural villages in the semi-arid central zone of Tanzania. It represents part of an interdisciplinary program seeking to address chronic undernutrition in children through improvements to existing poultry and crop systems. Newcastle disease vaccination uptake was found to vary substantially across communities and seasons, with a significantly higher level of vaccination amongst households participating in a longitudinal study of children's growth compared with non-participating households (p = 0.009). Two multivariable model analyses were used to explore associations between vaccination and chicken numbers, allowing for clustered data and socioeconomic and cultural variation amongst the population. Results demonstrated that both (a) households that undertook ND vaccination had a significantly larger chicken flock size in the period between that vaccination campaign and the next compared with those that did not vaccinate (p = 0.018); and (b) households with larger chicken flocks at the time of vaccination were significantly more likely to participate in vaccination programs (p < 0.001). Additionally, households vaccinating in all three vaccination campaigns held over 12 months were identified to have significantly larger chicken flocks at the end of this period (p < 0.001). Opportunities to understand causality and complexity through quantitative analyses are limited, and there is a role for qualitative approaches to explore decisions made by poultry-keeping households and the motivations, challenges and priorities of community vaccinators. Evidence of a bi-directional relationship, however, whereby vaccination leads to greater chicken numbers, and larger flocks are more likely to be vaccinated, offers useful insights into the efficacy of fee for-service animal health programs. This article concludes that attention should be focused on ways of supporting the participation of vulnerable households in ND vaccination campaigns, and encouraging regular vaccination throughout the year, as a pathway to strengthen food security, promote resilience and contribute to improved human nutrition. PMID- 29145464 TI - Cellular hnRNP A2/B1 interacts with the NP of influenza A virus and impacts viral replication. AB - The viral ribonucleoprotein (vRNP) of influenza A virus is formed by virion RNA (vRNA), viral polymerase complex, and nucleoprotein (NP). The NP plays an important role in facilitating the replication and stabilization of viral RNA. To explore host factors that may be involved in the regulation of viral replication through interactions with NP, we conducted an immunoprecipitation experiment followed by mass spectrometry to identify NP-associated cellular proteins. Here, we demonstrate that NP can interact and colocalize with heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 in mammalian cells and that the interaction may occur via direct binding to the glycine-rich domain (GRD) of hnRNP A2/B1. In addition, two residues in the tail loop of NP, F412 and R422, are required for the interaction of hnRNP A2/B1. Because the knockdown of hnRNP A2/B1 expression reduces viral RNP activity, hnRNP A2/B1 may act as a positive regulator in viral RNA synthesis of influenza A virus. More importantly, the findings in this research demonstrate that host proteins can regulate the replication of influenza A virus by interacting with NP. PMID- 29145465 TI - Hospital-associated methicillin-resistant Staphylococcus aureus: A cross sectional analysis of risk factors in South African tertiary public hospitals. AB - INTRODUCTION: Hospital-associated methicillin-resistant S. aureus (HA-MRSA) remains a significant cause of morbidity and mortality worldwide. We conducted a study to determine risk factors for HA-MRSA in order to inform control strategies in South Africa. METHODS: We used surveillance data collected from five tertiary hospitals in Gauteng and Western Cape provinces during 2014 for analysis. A case of HA-MRSA was defined as isolation of MRSA from a blood culture 48 hours after admission and/or if the patient was hospitalised in the six months prior to the current culture. Multivariable logistic regression modelling was used to determine risk factors for HA-MRSA. RESULTS: Of the 9971 patients with positive blood cultures, 7.7% (772) had S. aureus bacteraemia (SAB). The overall prevalence of MRSA among those with SAB was 30.9% (231/747; 95% confidence interval [CI] 27.6%- 34.3%). HA-MRSA infections accounted for 28.3% of patients with SAB (207/731; 95% CI 25.1%- 31.7%). Burns (adjusted odds ratio [aOR] 12.7; 95% CI 4.7-34.4), age <=1 month (aOR 8.7; 95% CI 3.0-24.6), residency at a long term care facility (aOR 5.2; 95% CI, 1.5-17.4), antibiotic use within two months of the current SAB episode (aOR 5.1; 95% CI 2.8-9.1), hospital stay of 13 days or more (aOR 2.8; 95% CI 1.3-5.6) and mechanical ventilation (aOR 2.2; 95% CI 1.07 4.6), were independent risk factors for HA-MRSA infection. CONCLUSION: The prevalence of MRSA remains high in South African tertiary public hospitals. Several identified risk factors of HA-MRSA infections should be considered when instituting infection and prevention strategies in public-sector hospitals, including intensifying the implementation of antimicrobial stewardship programmes. There is an urgent need to strengthen infection prevention and control in burn wards, neonatal wards, and intensive care units which house mechanically ventilated patients. PMID- 29145466 TI - Serum TSH levels as a predictor of malignancy in thyroid nodules: A prospective study. AB - BACKGROUND: The role of serum TSH concentrations as a predictor of malignancy of thyroid nodule remains unclear. OBJECTIVE: To prospectively evaluate the usefulness of serum TSH levels as a predictor of malignancy in thyroid nodules. METHODS: Patients with thyroid nodule(s) who underwent fine-needle aspiration biopsy under ultrasonographic guidance in a tertiary, university-based hospital were consecutively evaluated. Patients with known thyroid cancer and/or patients receiving thyroid medication were excluded. Serum TSH levels were measured by two differents methodologies, chemiluminescent (CLIA) and electrochemiluminscent immunoassay (ECLIA). Anatomopathological exam of tissue samples obtained at thyroidectomy was considered the gold standard for the diagnosis of thyroid cancer. RESULTS: A total of 615 patients participated in the study. The mean age was 55.9+/-14.7 years, and 544(88.5%) were female. The median TSH values were 1.48 and 1.55 MUU/mL, using CLIA and ECLIA, respectively. One-hundred-sixty patients underwent thyroidectomy and the final diagnoses were malignant in 47(29.4%) patients. TSH levels were higher in patients with malignant than in those with benign nodules in both TSH assays: 2.25 vs. 1.50; P = 0.04 (CLIA) and 2.33 vs. 1.27; P = 0.03 (ECLIA). Further analysis using binary logistic regression identified elevated TSH levels, a family history of thyroid cancer, the presence of microcalcifications, and solitary nodule on US as independent risk factors for malignancy in patients with thyroid nodules. Additional analyses using TSH levels as a categorical variable, defined by ROC curve analysis, showed that the risk of malignancy was approximately 3-fold higher in patients with TSH levels >=2.26 MUU/mL than in patients with lower TSH levels (P = 0.00). CONCLUSIONS: Higher serum TSH levels are associated with an increased risk of thyroid cancer in patients with thyroid nodules. Using TSH levels as an adjunctive diagnostic test for stratifying the risk of malignancy associated with a thyroid nodule may help on defining the best therapeutic approaches. PMID- 29145467 TI - Adenosine, lidocaine and Mg2+ (ALM) fluid therapy attenuates systemic inflammation, platelet dysfunction and coagulopathy after non-compressible truncal hemorrhage. AB - BACKGROUND: Systemic inflammation and coagulopathy are major drivers of injury progression following hemorrhagic trauma. Our aim was to examine the effect of small-volume 3% NaCl adenosine, lidocaine and Mg2+ (ALM) bolus and 0.9% NaCl/ALM 'drip' on inflammation and coagulation in a rat model of hemorrhagic shock. METHODS: Sprague-Dawley rats (429+/-4 g) were randomly assigned to: 1) shams, 2) no-treatment, 3) saline-controls, 4) ALM-therapy, and 5) Hextend(r). Hemorrhage was induced in anesthetized-ventilated animals by liver resection (60% left lateral lobe and 50% medial lobe). After 15 min, a bolus of 3% NaCl +/- ALM (0.7 ml/kg) was administered intravenously (Phase 1) followed 60 min later by 4 hour infusion of 0.9% NaCl +/- ALM (0.5 ml/kg/hour) with 1-hour monitoring (Phase 2). Plasma cytokines were measured on Magpix(r) and coagulation using Stago/Rotational Thromboelastometry. RESULTS: After Phase 1, saline-controls, no treatment and Hextend(r) groups showed significant falls in white and red cells, hemoglobin and hematocrit (up to 30%), whereas ALM animals had similar values to shams (9-15% losses). After Phase 2, these deficits in non-ALM groups were accompanied by profound systemic inflammation. In contrast, after Phase 1 ALM treated animals had undetectable plasma levels of IL-1alpha and IL-1beta, and IL 2, IL-6 and TNF-alpha were below baseline, and after Phase 2 they were less or similar to shams. Non-ALM groups (except shams) also lost their ability to aggregate platelets, had lower plasma fibrinogen levels, and were hypocoagulable. ALM-treated animals had 50-fold higher ADP-induced platelet aggregation, and 9.3 times higher collagen-induced aggregation compared to saline-controls, and had little or no coagulopathy with significantly higher fibrinogen shifting towards baseline. Hextend(r) had poor outcomes. CONCLUSIONS: Small-volume ALM bolus/drip mounted a frontline defense against non-compressible traumatic hemorrhage by defending immune cell numbers, suppressing systemic inflammation, improving platelet aggregation and correcting coagulopathy. Saline-controls were equivalent to no-treatment. Possible mechanisms of ALM's immune-bolstering effect are discussed. PMID- 29145468 TI - The effects of non-surgical periodontal treatment on glycemic control, oxidative stress balance and quality of life in patients with type 2 diabetes: A randomized clinical trial. AB - AIM: The purpose of this study was to investigate the effects of non-surgical periodontal treatment on hemoglobinA1c (HbA1c) levels, oxidative stress balance and quality of life (QOL) in patients with type 2 diabetes mellitus (T2DM) compared to no periodontal treatment (simple oral hygiene instructions only). METHODS: The design was a 6-month, single-masked, single center, randomized clinical trial. Patients had both T2DM and chronic periodontitis. Forty participants were enrolled between April 2014 and March 2016 at the Nephrology, Diabetology and Endocrinology Department of Okayama University Hospital. The periodontal treatment group (n = 20) received non-surgical periodontal therapy, including scaling and root planing plus oral hygiene instructions, and consecutive supportive periodontal therapy at 3 and 6 months. The control group (n = 17) received only oral hygiene instructions without treatment during the experimental period. The primary study outcome was the change in HbA1c levels from baseline to 3 months. Secondary outcomes included changes in oxidative stress balance (Oxidative-INDEX), the Diabetes Therapy-Related QOL and clinical periodontal parameters from baseline to 3 months and baseline to 6 months. RESULTS: Changes in HbA1c in the periodontal treatment group were not significantly different with those in the control group at 3 and 6 months. Systemic oxidative stress balance and QOL significantly improved in the periodontal treatment group compared to the control group at 3 months. In the subgroup analysis (moderately poor control of diabetes), the decrease in HbA1c levels in the periodontal treatment group was greater than that in the control group at 3 months but not significant. CONCLUSIONS: In T2DM patients, non surgical periodontal treatment improved systemic oxidative stress balance and QOL, but did not decrease HbA1c levels at 3 months follow-up. TRIAL REGISTRATION: Current Controlled Trials UMIN-ICDR UMIN 000013278 (Registered April 1, 2014). PMID- 29145470 TI - Active immunization in patients transplanted for hepatitis B virus related liver diseases: A prospective study. AB - INTRODUCTION: Prophylactic administration of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues (NAs) is the standard treatment for controlling hepatitis B virus (HBV) recurrence after liver transplantation (LT). Since lifelong use of HBIG is expensive and inconvenient and the antibodies level in anti-hepatitis B surface (HBs) is not sustainable and stable, an alternative strategy is to produce anti-HBs antibodies by active immunization. Our present study aimed to prospectively investigate the efficacy and safety of procedural HBV vaccination in transplanted patients. METHODS: Recipients who had undergone LT for hepatitis B related liver diseases more than one year before, with no evidence of HBV recurrence or rejection and normal liver function were enrolled. All subjects received the hepatitis B vaccine (40 MUg) by intramuscular injection at months 0, 1, 2, 6 and 12 after enrollment with continuous administration of NAs. The liver function and anti-HBs titers were measured before each vaccination and HBIG (400U) was administrated intramuscularly when anti-HBs titer was lower than 30 IU/L during the course. The results of routine blood tests, liver function, concentration of immunosuppressant, and HBV-DNA copies were monitored during the research. After completion of the vaccination procedure, recipients were regarded as responders if their anti-HBs greater than 30 IU/L were maintained for up to six months without using HBIG and vaccine. RESULTS: Twenty seven patients were enrolled in this study and the average anti-HBs titer before vaccination was 19.86+/-14.80 IU/L. The average anti-HBs titer of the nine responders at the end of the follow-up was 57.14+/-22.75 IU/L, giving an overall response rate of 33.3% (9/27). There were no reports of reactivation of HBV, rejection, severe anaphylaxis or other adverse events. Responders and non responders showed their significant difference in anti-HBs titers after the fourth vaccination (P<0.01). Moreover, the majority of non-responders (11/18, 63.64%) had high LY/EO rates (lymphocyte number/eosinophil number>15) while most responders (8/9, 88.89%) had low LY/EO rates at the beginning of vaccination (P = 0.019). CONCLUSIONS: Active immunization is an effective, cost-saving, and safe method for the prevention of HBV reactivation in patients transplanted for hepatitis B virus related liver diseases. The LY/EO rate may be a valuable indicator in selecting potential recipients for vaccination. PMID- 29145469 TI - Development of visual cortical function in infant macaques: A BOLD fMRI study. AB - Functional brain development is not well understood. In the visual system, neurophysiological studies in nonhuman primates show quite mature neuronal properties near birth although visual function is itself quite immature and continues to develop over many months or years after birth. Our goal was to assess the relative development of two main visual processing streams, dorsal and ventral, using BOLD fMRI in an attempt to understand the global mechanisms that support the maturation of visual behavior. Seven infant macaque monkeys (Macaca mulatta) were repeatedly scanned, while anesthetized, over an age range of 102 to 1431 days. Large rotating checkerboard stimuli induced BOLD activation in visual cortices at early ages. Additionally we used static and dynamic Glass pattern stimuli to probe BOLD responses in primary visual cortex and two extrastriate areas: V4 and MT-V5. The resulting activations were analyzed with standard GLM and multivoxel pattern analysis (MVPA) approaches. We analyzed three contrasts: Glass pattern present/absent, static/dynamic Glass pattern presentation, and structured/random Glass pattern form. For both GLM and MVPA approaches, robust coherent BOLD activation appeared relatively late in comparison to the maturation of known neuronal properties and the development of behavioral sensitivity to Glass patterns. Robust differential activity to Glass pattern present/absent and dynamic/static stimulus presentation appeared first in V1, followed by V4 and MT V5 at older ages; there was no reliable distinction between the two extrastriate areas. A similar pattern of results was obtained with the two analysis methods, although MVPA analysis showed reliable differential responses emerging at later ages than GLM. Although BOLD responses to large visual stimuli are detectable, our results with more refined stimuli indicate that global BOLD activity changes as behavioral performance matures. This reflects an hierarchical development of the visual pathways. Since fMRI BOLD reflects neural activity on a population level, our results indicate that, although individual neurons might be adult like, a longer maturation process takes place on a population level. PMID- 29145471 TI - Arbuscular mycorrhizal strategy for zinc mycoremediation and diminished translocation to shoots and grains in wheat. AB - Mycoremediation is an on-site remediation strategy, which employs fungi to degrade or sequester contaminants from the environment. The present work focused on the bioremediation of soils contaminated with zinc by the use of a native mycorrhizal fungi (AM) called Funneliformis geosporum (Nicol. & Gerd.) Walker & Schubetaler. Experiments were performed using Triticum aestivum L. cv. Gemmeza-10 at different concentrations of Zn (50, 100, 200 mg kg-1) and inoculated with or without F. geosporum. The results showed that the dry weight of mycorrhizal wheat increased at Zn stressed plants as compared to the non-Zn-stressed control plants. The concentrations of Zn also had an inhibitory effect on the yield of dry root and shoot of non-mycorrhizal wheat. The photosynthetic pigment fractions were significantly affected by Zn treatments and mycorrhizal inoculation, where in all treatments, the content of the photosynthetic pigment fractions decreased as the Zn concentration increased in the soil. However, the level of minerals of shoots, roots, and grains was greatly influenced by Zn-treatment and by inoculation with F. geosporum. Treatment with Zn in the soil increased Cu and Zn concentrations in the root, shoot and grains, however, other minerals (P, S, K, Ca and Fe) concentration was decreased. Inoculation of wheat with AM fungi significantly reduced the accumulation of Zn and depressed its translocation in shoots and grains of wheat. In conclusion, inoculation with a native F. geosporum improves yields of wheat under higher levels of Zn and is possible to be applied for the improvement of zinc contaminated soil. PMID- 29145472 TI - Replacing methyl bromide with a combination of 1,3-dichloropropene and metam sodium for cucumber production in China. AB - The combination of 1,3-dichloropropene (1,3-D) and metam sodium (MNa) is a potential resource to replace methyl bromide (MB) as a soil fumigant. The efficacy of 1,3-D+MNa as a crucial factor to limit soil-borne pests was evaluated in one laboratory experiment and two cucumber greenhouse studies conducted in commercial operations. Laboratory results revealed that 1,3-D and MNa (10+20 mg a.i. kg-1 soil) provided the best complementary control of the root-knot nematode, Fusarium oxysporum and two species of weed seeds. Greenhouse trials revealed that the blend of 1,3-D and MNa (10+20 g a.i. m-2) greatly inhibited the ability of Meloidogyne incognita to form root galls. In addition, the number of colony-forming units of F. oxysporum declined substantially after growth on media, resulting in higher fruit yields and greater economic benefits. The combined use of 1,3-D and MNa exhibited a higher control efficacy than when 1,3-D or MNa was utilized alone. The ability of this chemical combination to control soil-borne organisms did not differ significantly from the MB treatment and maintained high cucumber yields, enhancing the income of the farmers. Compared to the untreated control group, all the chemical treatments prominently improved the control of the pests. These results show that applying a combination of 1,3-D and MNa provides a promising alternative to MB that enables the sustained growth of cucumber production in China. PMID- 29145473 TI - Suppression and resolution of autoimmune arthritis by rhesus theta-defensin-1, an immunomodulatory macrocyclic peptide. AB - theta-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus theta-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA). Parenteral RTD-1 treatment of DA/OlaHsd rats with established pristane-induced arthritis (PIA) rapidly suppressed joint disease progression, restored limb mobility, and preserved normal joint architecture. RTD 1 significantly reduced joint IL-1beta levels compared with controls. RTD-1 dose dependently inhibited fibroblast-like synoviocyte (FLS) invasiveness and FLS IL-6 production. Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFalpha, and inhibited matrix metalloproteases, and cathepsin K. RTD-1 was non-toxic, non-immunogenic, and effective when administered as infrequently as once every five days. Thus theta-defensins, which are absent in humans, have potential as retroevolutionary biologics for the treatment of RA. PMID- 29145475 TI - Mapping three-dimensional surface deformation caused by the 2010 Haiti earthquake using advanced satellite radar interferometry. AB - Mapping three-dimensional (3D) surface deformation caused by an earthquake is very important for the environmental, cultural, economic and social sustainability of human beings. Synthetic aperture radar (SAR) systems made it possible to measure precise 3D deformations by combining SAR interferometry (InSAR) and multiple aperture interferometry (MAI). In this paper, we retrieve the 3D surface deformation field of the 2010 Haiti earthquake which occurred on January 12, 2010 by a magnitude 7.0 Mw by using the advanced interferometric technique that integrates InSAR and MAI data. The surface deformation has been observed by previous researchers using the InSAR and GPS method, but 3D deformation has not been measured yet due to low interferometric coherence. The combination of InSAR and MAI were applied to the ALOS PALSAR ascending and descending pairs, and were validated with the GPS in-situ measurements. The archived measurement accuracy was as little as 1.85, 5.49 and 3.08 cm in the east, north and up directions, respectively. This result indicates that the InSAR/MAI-derived 3D deformations are well matched with the GPS deformations. The 3D deformations are expected to allow us to improve estimation of the area affected by the 2010 Haiti earthquake. PMID- 29145474 TI - Long 3'UTR of Nurr1 mRNAs is targeted by miRNAs in mesencephalic dopamine neurons. AB - The development of mesencephalic dopamine neurons and their survival later in life requires the continuous presence of the transcription factor Nurr1 (NR4A2). Nurr1 belongs to the nuclear receptors superfamily. However, it is an orphan member that does not require a ligand to regulate the transcription of its target genes. Therefore, controlling the expression of Nurr1 is an important manner to control its function. Several reports have shown that microRNAs (miRNAs) regulate Nurr1 expression. However, Nurr1 has several splicing variants, posing the question what variants are subjected to miRNA regulation. In this work, we identified a long 3'UTR variant of rat Nurr1 mRNA. We used bioinformatics analysis to identify miRNAs with the potential to regulate Nurr1 expression. Reporter assays performed with the luciferase gene fused to the short (658 bp) or long (1,339 bp) 3'UTR of rat Nurr1 mRNAs, showed that miR-93, miR-204 and miR 302d selectively regulate the mRNA with the longest 3'UTR. We found that the longest variant of Nurr1 mRNA expresses in the rat mesencephalon as assessed by PCR. The transfection of rat mesencephalic neurons with mixed miR-93, miR-204 and miR-302d resulted in a significant reduction of Nurr1 protein levels. In conclusion, Nurr1 mRNA variant with the longest 3'UTR undergoes a specific regulation by miRNAs. It is discussed the importance of fine-tuning Nurr1 protein levels in mesencephalic dopamine neurons. PMID- 29145476 TI - An immunohistochemical identification key for cell types in adult mouse prostatic and urethral tissue sections. AB - Though many methods can be used to identify cell types contained in complex tissues, most require cell disaggregation and destroy information about where cells reside in relation to their microenvironment. Here, we describe a polytomous key for cell type identification in intact sections of adult mouse prostate and prostatic urethra. The key is organized as a decision tree and initiates with one round of immunostaining for nerve, epithelial, fibromuscular/hematolymphoid, or vascular associated cells. Cell identities are recursively eliminated by subsequent staining events until the remaining pool of potential cell types can be distinguished by direct comparison to other cells. We validated our identification key using wild type adult mouse prostate and urethra tissue sections and it currently resolves sixteen distinct cell populations which include three nerve fiber types as well as four epithelial, five fibromuscular/hematolymphoid, one nerve-associated, and three vascular-associated cell types. We demonstrate two uses of this novel identification methodology. We first used the identification key to characterize prostate stromal cell type changes in response to constitutive phosphatidylinositide-3-kinase activation in prostate epithelium. We then used the key to map cell lineages in a new reporter mouse strain driven by Wnt10aem1(cre/ERT2)Amc. The identification key facilitates rigorous and reproducible cell identification in prostate tissue sections and can be expanded to resolve additional cell types as new antibodies and other resources become available. PMID- 29145478 TI - Electrical impedance tomography: Amplitudes of cardiac related impedance changes in the lung are highly position dependent. AB - BACKGROUND: Electrical impedance tomography (EIT) is used on the thorax to measure impedance changes due to the presence of air and blood in the lung. This experimental study was performed to investigate the effect of posture on cardiac and respiratory related impedance changes. METHODS: EIT measurements were performed on 14 healthy subjects in left-, right lateral, prone, supine and upright positions. Simultaneously, tidal volume was recorded with an ultrasonic flowmeter. For image reconstruction, the classic Sheffield back-projection and three variants of the modern GREIT algorithm were applied with two different reference frames. Amplitudes of cardiac- and respiratory impedance changes were extracted and compared between the positions. RESULTS: We found significant differences in both cardiac and respiratory amplitudes between postures. Especially, supine and upright positions showed dramatic changes in amplitude. These differences between postures were unaffected by the change of reference frames in all reconstruction methods except of the classic Sheffield back projection. Possible sources that explain the observed posture dependency are discussed. CONCLUSION: Researchers and clinicians need to be aware of this phenomenon when comparing EIT amplitudes in different body positions. PMID- 29145477 TI - The abundance of health-associated bacteria is altered in PAH polluted soils Implications for health in urban areas? AB - Long-term exposure to polyaromatic hydrocarbons (PAHs) has been connected to chronic human health disorders. It is also well-known that i) PAH contamination alters soil bacterial communities, ii) human microbiome is associated with environmental microbiome, and iii) alteration in the abundance of members in several bacterial phyla is associated with adverse or beneficial human health effects. We hypothesized that soil pollution by PAHs altered soil bacterial communities that had known associations with human health. The rationale behind our study was to increase understanding and potentially facilitate reconsidering factors that lead to health disorders in areas characterized by PAH contamination. Large containers filled with either spruce forest soil, pine forest soil, peat, or glacial sand were left to incubate or contaminated with creosote. Biological degradation of PAHs was monitored using GC-MS, and the bacterial community composition was analyzed using 454 pyrosequencing. Proteobacteria had higher and Actinobacteria and Bacteroidetes had lower relative abundance in creosote contaminated soils than in non-contaminated soils. Earlier studies have demonstrated that an increase in the abundance of Proteobacteria and decreased abundance of the phyla Actinobacteria and Bacteroidetes are particularly associated with adverse health outcomes and immunological disorders. Therefore, we propose that pollution-induced shifts in natural soil bacterial community, like in PAH-polluted areas, can contribute to the prevalence of chronic diseases. We encourage studies that simultaneously address the classic "adverse toxin effect" paradigm and our novel "altered environmental microbiome" hypothesis. PMID- 29145479 TI - New analytical methodology for analysing S(IV) species at low pH solutions by one stage titration method (bichromatometry) with a clear colour change. Could potentially replace the state-of-art-method iodometry at low pH analysis due higher accuracy. AB - A new, faster and more reliable analytical methodology for S(IV) species analysis at low pH solutions by bichromatometry is proposed. For decades the state of the art methodology has been iodometry that is still well justified method for neutral solutions, thus at low pH media possess various side reactions increasing inaccuracy. In contrast, the new methodology has no side reactions at low pH media, requires only one titration step and provides a clear color change if S(IV) species are present in the solution. The method is validated using model solutions with known concentrations and applied to analyses of gaseous SO2 from purged solution in low pH media samples. The results indicate that bichromatometry can accurately analyze SO2 from liquid samples having pH even below 0 relevant to metallurgical industrial processes. PMID- 29145480 TI - Engineering the GH1 beta-glucosidase from Humicola insolens: Insights on the stimulation of activity by glucose and xylose. AB - The activity of the GH1 beta-glucosidase from Humicola insolens (Bglhi) against p nitrophenyl-beta-D-glucopyranoside (pNP-Glc) and cellobiose is enhanced 2-fold by glucose and/or xylose. Kinetic and transglycosylation data showed that hydrolysis is preferred in the absence of monosaccharides. Stimulation involves allosteric interactions, increased transglycosylation and competition of the substrate and monosaccharides for the -1 glycone and the +1/+2 aglycone binding sites. Protein directed evolution has been used to generate 6 mutants of Bglhi with altered stimulation patterns. All mutants contain one of three substitutions (N235S, D237V or H307Y) clustered around the +1/+2 aglycone binding sites. Two mutants with the H307Y substitution preferentially followed the transglycosylation route in the absence of xylose or glucose. The strong stimulation of their pNP glucosidase and cellobiase activities was accompanied by increased transglycosylation and higher monosaccharide tolerance. The D237V mutation favoured hydrolysis over transglycosylation and the pNP-glucosidase activity, but not the cellobiase activity, was stimulated by xylose. The substitution N235S abolished the preference for hydrolysis or transglycosylation; the cellobiase, but not the pNP-glucosidase activity of the mutants was strongly inhibited by xylose. Both the D237V and N235S mutations lowered tolerance to the monosaccharides. These results provide evidence that the fine modulation of the activity of Bglhi and mutants by glucose and/or xylose is regulated by the relative affinities of the glycone and aglycone binding sites for the substrate and the free monosaccharides. PMID- 29145481 TI - Amiloride-enhanced gene transfection of octa-arginine functionalized calcium phosphate nanoparticles. AB - Nanoparticles represent promising gene delivery systems in biomedicine to facilitate prolonged gene expression with low toxicity compared to viral vectors. Specifically, nanoparticles of calcium phosphate (nCaP), the main inorganic component of human bone, exhibit high biocompatibility and good biodegradability and have been reported to have high affinity for protein or DNA, having thus been used as gene transfer vectors. On the other hand, Octa-arginine (R8), which has a high permeability to cell membrane, has been reported to improve intracellular delivery systems. Here, we present an optimized method for nCaP-mediated gene delivery using an octa-arginine (R8)-functionalized nCaP vector containing a marker or functional gene construct. nCaP particle size was between 220-580 nm in diameter and all R8-functionalized nCaPs carried a positive charge. R8 concentration significantly improved nCaP transfection efficiency with high cell compatibility in human mesenchymal stem cells (hMSC) and human osteoblasts (hOB) in particular, suggesting nCaPs as a good option for non-viral vector gene delivery. Furthermore, pre-treatment with different endocytosis inhibitors identified that the endocytic pathway differed among cell lines and functionalized nanoparticles, with amiloride increasing transfection efficiency of R8-functionalized nCaPs in hMSC and hOB. PMID- 29145482 TI - Combination of ultrasound and rtPA enhances fibrinolysis in an In Vitro clot system. AB - BACKGROUND: Catheter-based lysis with recombinant tissue plasminogen activator (rtPA) is a well-established therapy for spontaneous intracerebral hemorrhage (ICH). The effectiveness of this therapy can be increased with ultrasound, but the optimal conditions are not yet clearly established. Using a novel in vitro system of blood clots previously developed by our group, we investigated various parameters of intralesional sonothrombolysis using an endosonography catheter in combination with rtPA. METHODS: Standardized human blood clots were equipped with a drainage catheter and weighed before and after 4 treatments: control (drainage only), rtPA only, ultrasound only and the combination of rtPA+ultrasound. The effectiveness of ultrasound was further analysed in terms of optimal frequency, duration and distance to the probe. Temperature and acoustic peak rarefaction pressure (APRP) were assessed to analyse potential adverse effects and quantify lysis. Histo-morphological analysis of the treated clots was performed by H&E staining and confocal laser scanning microscopy using fluorescent fibrinogen. RESULTS: The combined treatment rtPA+ultrasound achieved the highest lysis rates with a relative weight of 30.3%+/-5.5% (p<=0.0001) compared to all other groups. Similar results were observed when treating aged clots. Confocal fluorescent microscopy of the treated clots revealed a rarefied fibrin mesh without cavitations. No relevant temperature increase occurred (0.53+/-0.75 degrees C). The optimal insonation treatment time was 1 hour. APRP measurements showed a lysis threshold of 515.5+/-113.4 kPa. Application of 10 MHz achieved optimal lysis and lysis radius, while simultaneously proving to be the best frequency for morphologic imaging of the clot and surrounding tissue. CONCLUSIONS: These promising data provide the basis for an individualized minimal invasive ICH therapy by rtPA and sonothrombolysis independent of ICH age. PMID- 29145484 TI - Lifestyle intervention program in deprived obese adult patients and their non deprived counterparts. AB - INTRODUCTION: Although it is known that the prevalence of obesity is high in deprived patients, the link between deprivation and obesity, and the impact of deprivation on compliance and efficacy of a lifestyle intervention program are not known. MATERIALS AND METHODS: Deprivation was assessed in 40 patients (23 Females, mean+/-SD age: 49+/-17 years) from the diabetology department and 140 patients (101 Females, age: 50+/-15 years) from the nutrition department of Bordeaux University hospital. Eighty-seven patients suffering from obesity were evaluated before and after a tailored, multidisciplinary lifestyle intervention. Deprivation was assessed using EPICES scores. Deprivation was defined with an EPICES score > 30. RESULTS: Deprived patients suffering from obesity had significantly higher current (43.8 +/-8.4 versus 40.9 +/- 5.5 kg/m2, p = 0,02) and maximal BMI (46.1+/- 8.6 versus 42.3+/- 5.2 kg/m2, p = 0.002) compared to non deprived obese. Percentage of body weight loss was not different according to deprivation (4.74 +/- 0.75 versus 4.65 +/- 1.04%, p = 0.9). EPICES scores were not different according to adherence to lifestyle intervention program (20.5 +/- 8.5 versus 29.9 +/- 3.9 versus 29.0 +/-2.5, no follow up versus partial follow up versus total follow up, p = 0,58). CONCLUSION: Deprived patients suffering from obesity have a more serious disease than non-deprived patients. However, neither compliance to the lifestyle intervention program nor body weight loss differed between deprived patients with obesity and non-deprived ones. Deprivation should not be a limitation when enrolling patients with obesity in lifestyle intervention programs. PMID- 29145483 TI - Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease. AB - : Our understanding of mechanisms underlying progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease in humans remains limited. To define such mechanisms, we followed M. tuberculosis-infected adolescents longitudinally. Blood samples from forty-four adolescents who ultimately developed tuberculosis disease ("progressors") were compared with those from 106 matched controls, who remained healthy during two years of follow up. We performed longitudinal whole blood transcriptomic analyses by RNA sequencing and plasma proteome analyses using multiplexed slow off-rate modified DNA aptamers. Tuberculosis progression was associated with sequential modulation of immunological processes. Type I/II interferon signalling and complement cascade were elevated 18 months before tuberculosis disease diagnosis, while changes in myeloid inflammation, lymphoid, monocyte and neutrophil gene modules occurred more proximally to tuberculosis disease. Analysis of gene expression in purified T cells also revealed early suppression of Th17 responses in progressors, relative to M. tuberculosis-infected controls. This was confirmed in an independent adult cohort who received BCG re-vaccination; transcript expression of interferon response genes in blood prior to BCG administration was associated with suppression of IL-17 expression by BCG-specific CD4 T cells 3 weeks post-vaccination. Our findings provide a timeline to the different immunological stages of disease progression which comprise sequential inflammatory dynamics and immune alterations that precede disease manifestations and diagnosis of tuberculosis disease. These findings have important implications for developing diagnostics, vaccination and host-directed therapies for tuberculosis. TRIAL REGISTRATION: Clincialtrials.gov, NCT01119521. PMID- 29145485 TI - Adolescents' perception of parental feeding practices: Adaptation and validation of the Comprehensive Feeding Practices Questionnaire for Brazilian adolescents The CFPQ-Teen. AB - BACKGROUND: Parental feeding practices may play a key role in dietary habits and nutritional status of adolescents, but research from adolescents' point of view on this topic is scarce. OBJECTIVE: To adapt and validate an instrument of parental feeding practices as perceived by adolescents in a Brazilian setting. METHODS: The Comprehensive Feeding Practices Questionnaire was translated into Portuguese and adapted to be answered by adolescents (ages 12 to 18). Content analysis and FACE validity to assess cultural equivalence was undertaken by experts in the adolescent nutritional and psychological fields. Pilot study was evaluated in 23 adolescents. The final version was administered to 41 students to assess instrument reproducibility (Intraclass Correlation Coefficient). Internal consistency (Cronbach's Alpha) and construct validity (Confirmatory Factor Analysis) were assessed in a third sample of 307 adolescents. RESULTS: Experts and adolescents considered content validity as appropriate. In reproducibility analysis (Intraclass Correlation Coefficient), 10 of the 12 factors were above 0.7. The factors "teaching about nutrition" and "food as reward" obtained values of 0.60 and 0.68, respectively. The Cronbach's Alpha of the whole scale was 0.83 and alphas for subscales ranged from 0.52 to 0.85; the factors "teaching about nutrition" and "food as a reward" had the lowest values (0.52). After removing these two factors, the Confirmatory Factor Analysis indicated that the structural model was appropriate. The final scale was made up of 10 factors with 43 questions. CONCLUSIONS: The Comprehensive Feeding Practices Questionnaire-Teen demonstrates validity and reliability, and is a suitable tool to evaluate the perceptions of adolescents regarding parental feeding practices. PMID- 29145486 TI - Geography of current and future global mammal extinction risk. AB - Identifying which species are at greatest risk, what makes them vulnerable, and where they are distributed are central goals for conservation science. While knowledge of which factors influence extinction risk is increasingly available for some taxonomic groups, a deeper understanding of extinction correlates and the geography of risk remains lacking. Here, we develop a predictive random forest model using both geospatial and mammalian species' trait data to uncover the statistical and geographic distributions of extinction correlates. We also explore how this geography of risk may change under a rapidly warming climate. We found distinctive macroecological relationships between species-level risk and extinction correlates, including the intrinsic biological traits of geographic range size, body size and taxonomy, and extrinsic geographic settings such as seasonality, habitat type, land use and human population density. Each extinction correlate exhibited ranges of values that were especially associated with risk, and the importance of different risk factors was not geographically uniform across the globe. We also found that about 10% of mammals not currently recognized as at-risk have biological traits and occur in environments that predispose them towards extinction. Southeast Asia had the most actually and potentially threatened species, underscoring the urgent need for conservation in this region. Additionally, nearly 40% of currently threatened species were predicted to experience rapid climate change at 0.5 km/year or more. Biological and environmental correlates of mammalian extinction risk exhibit distinct statistical and geographic distributions. These results provide insight into species-level patterns and processes underlying geographic variation in extinction risk. They also offer guidance for future conservation research focused on specific geographic regions, or evaluating the degree to which species level patterns mirror spatial variation in the pressures faced by populations within the ranges of individual species. The added impacts from climate change may increase the susceptibility of at-risk species to extinction and expand the regions where mammals are most vulnerable globally. PMID- 29145487 TI - Defining external factors that determine neuronal survival, apoptosis and necrosis during excitotoxic injury using a high content screening imaging platform. AB - Cell death induced by excessive glutamate receptor overactivation, excitotoxicity, has been implicated in several acute and chronic neurological disorders. While numerous studies have demonstrated the contribution of biochemically and genetically activated cell death pathways in excitotoxic injury, the factors mediating passive, excitotoxic necrosis are less thoroughly investigated. To address this question, we developed a high content screening (HCS) based assay to collect high volumes of quantitative cellular imaging data and elucidated the effects of intrinsic and external factors on excitotoxic necrosis and apoptosis. The analysis workflow consisted of robust nuclei segmentation, tracking and a classification algorithm, which enabled automated analysis of large amounts of data to identify and quantify viable, apoptotic and necrotic neuronal populations. We show that mouse cerebellar granule neurons plated at low or high density underwent significantly increased necrosis compared to neurons seeded at medium density. Increased extracellular Ca2+ sensitized neurons to glutamate-induced excitotoxicity, but surprisingly potentiated cell death mainly through apoptosis. We also demonstrate that inhibition of various cell death signaling pathways (including inhibition of calpain, PARP and AMPK activation) primarily reduced excitotoxic apoptosis. Excitotoxic necrosis instead increased with low extracellular glucose availability. Our study is the first of its kind to establish and implement a HCS based assay to investigate the contribution of external and intrinsic factors to excitotoxic apoptosis and necrosis. PMID- 29145488 TI - Pseudoalteromonas piratica strain OCN003 is a coral pathogen that causes a switch from chronic to acute Montipora white syndrome in Montipora capitata. AB - Reports of mass coral mortality from disease have increased over the last two decades. Montipora white syndrome (MWS) is a tissue loss disease that has negatively impacted populations of the coral Montipora capitata in Kane'ohe Bay, Hawai'i. Two types of MWS have been documented; a progressive disease termed chronic MWS (cMWS), that can be caused by Vibrio owensii strain OCN002, and a comparatively faster disease termed acute MWS (aMWS), that can be caused by Vibrio coralliilyticus strain OCN008. M. capitata colonies exhibiting cMWS can spontaneously switch to aMWS in the field. In this study, a novel Pseudoalteromonas species, P. piratica strain OCN003, fulfilled Koch's postulates of disease causation as another etiological agent of aMWS. Additionally, OCN003 induced a switch from cMWS to aMWS on M. capitata in laboratory infection trials. A comparison of OCN003 and Vibrio coralliilyticus strain OCN008, showed that OCN003 was more effective at inducing the cMWS to aMWS switch in M. capitata than OCN008. This study is the first to demonstrate that similar disease signs on one coral species (aMWS on M. capitata) can be caused by multiple pathogens, and describes the first Pseudoalteromonas species that infects coral. PMID- 29145489 TI - Expert cognition in the production sequence of Acheulian cleavers at Gesher Benot Ya'aqov, Israel: A lithic and cognitive analysis. AB - Stone cleavers are one of the most distinctive components of the Acheulian toolkit. These tools were produced as part of a long and complex reduction sequence and they provide indications for planning and remarkable knapping skill. These aspects hold implications regarding the cognitive complexity and abilities of their makers and users. In this study we have analyzed a cleaver assemblage originating from the Acheulian site of Gesher Benot Ya'aqov, Israel, to provide a reconstruction of the chaine operatoire which structured their production. This reduction sequence was taken as the basis for a cognitive analysis which allowed us to draw conclusion regarding numerous behavioral and cognitive aspects of the GBY hominins. The results indicate that the cleavers production incorporated a highly specific sequence of decisions and actions which resulted in three distinct modes of cleavers modification. Furthermore, the decision to produce a cleaver must have been taken very early in the sequence, thus differentiating its production from that of handaxes. The substantial predetermination and the specific reduction sequence provide evidence that the Gesher Benot Ya'aqov hominins had a number of cognitive categories such as a general 'tool concept' and a more specific 'cleaver concept', setting them apart from earlier tool producing hominins and extant tool-using non-human primates. Furthermore, it appears that the Gesher Benot Ya'aqov lithic technology was governed by expert cognition, which is the kind of thinking typical of modern human experts in their various domains. Thus, the results provide direct indications that important components of modern cognition have been well established in the minds of the Gesher Benot Ya'aqov hominins. PMID- 29145490 TI - RNAi screen reveals a role of SPHK2 in dengue virus-mediated apoptosis in hepatic cell lines. AB - Hepatic dysfunction is a feature of dengue virus (DENV) infection. Hepatic biopsy specimens obtained from fatal cases of DENV infection show apoptosis, which relates to the pathogenesis of DENV infection. However, how DENV induced liver injury is not fully understood. In this study, we aim to identify the factors that influence cell death by employing an apoptosis-related siRNA library screening. Our results show the effect of 558 gene silencing on caspase 3 mediated apoptosis in DENV-infected Huh7 cells. The majority of genes that contributed to apoptosis were the apoptosis-related kinase enzymes. Tumor necrosis factor superfamily member 12 (TNFSF12), and sphingosine kinase 2 (SPHK2), were selected as the candidate genes to further validate their influences on DENV-induced apoptosis. Transfection of siRNA targeting SPHK2 but not TNFSF12 genes reduced apoptosis determined by Annexin V/PI staining. Knockdown of SPHK2 did not reduce caspase 8 activity; however, did significantly reduce caspase 9 activity, suggesting its involvement of SPHK2 in the intrinsic pathway of apoptosis. Treatment of ABC294649, an inhibitor of SPHK2, reduced the caspase 3 activity, suggesting the involvement of its kinase activity in apoptosis. Knockdown of SPHK2 significantly reduced caspase 3 activity not only in DENV-infected Huh7 cells but also in DENV-infected HepG2 cells. Our results were consistent across all of the four serotypes of DENV infection, which supports the pro-apoptotic role of SPHK2 in DENV-infected liver cells. PMID- 29145491 TI - The urine biomarker panel [IGFBP7]x[TIMP-2] (NephroCheck(r) parameter) does not correlate with IGFBP7 and TIMP-2 gene expression in urinary sediment. AB - BACKGROUND: Acute kidney injury (AKI) is frequently observed in serious infections, following nephrotoxic medication, surgery and trauma. Here we tested whether the detection of two recently identified biomarkers for AKI, Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) and Insulin-Like Growth Factor Binding Protein 7 (IGFBP7), depends on the expression of these proteins in cells of the urinary sediment. METHOD: We collected urine samples of 33 kidney transplant recipients and 14 non-transplanted patients who all had AKI (stages 1-3 according to KDIGO), and measured [IGFBP7]x[TIMP-2] using the NephroCheck(r) Astute1 40 TM meter. Concomitantly, we analyzed IGFBP7 and TIMP-2 mRNA expression by quantitative polymerase chain reaction (qPCR) from urinary sediment of the same patients, and correlated the results with [IGFBP7]x[TIMP-2] (protein), by linear regression analysis. We also determined the association between [IGFBP7]x[TIMP-2] and estimated glomerular filtration rate (eGFR), and between IGFBP7 and TIMP-2 mRNA expression and markers of inflammation. Light microscopy and confocal immunofluorescence served to illustrate changes in the urinary sediment over the time course of renal function improvement. RESULTS: Of the 47 analyzed AKI patients, 14 presented with ascending urinary tract infection. Serum creatinine (sCr), blood urea nitrogen (BUN) and eGFR in all patients were 3.9+/-2.28 mg/dL, 47.59+/-23.1 mg/dL and 22.88+/-16.0 mL/min/1.73m2, respectively, on average +/ standard deviation. [IGFBP7]x[TIMP-2] was 2.33+/-9.95 (ng/ml)2/1000, and did not associate with IGFBP7 and TIMP-2 gene expression (r = -0.0220, p = 0.4216; respectively r = 0.0972, p = 0.1909). [IGFBP7]x[TIMP-2] did not associate with eGFR; IGFBP7 and TIMP-2 mRNA expression. Improvement of renal function went along with disappearance of casts, decrease in aquaporin1 positive renal epithelial cells and leukocytes from the urinary sediment. CONCLUSION: The gene expression pattern of IGFBP7 and TIMP-2 from urinary sediment, which contains desquamated renal tubular epithelial cells, did not correlate with [IGFBP7]x[TIMP-2] protein, indicating that IGFBP7 and TIMP-2 measured in the NephroCheck(r) test originated predominantly from intact but stressed cells of the kidney itself. PMID- 29145492 TI - 3D multi-view convolutional neural networks for lung nodule classification. AB - The 3D convolutional neural network (CNN) is able to make full use of the spatial 3D context information of lung nodules, and the multi-view strategy has been shown to be useful for improving the performance of 2D CNN in classifying lung nodules. In this paper, we explore the classification of lung nodules using the 3D multi-view convolutional neural networks (MV-CNN) with both chain architecture and directed acyclic graph architecture, including 3D Inception and 3D Inception ResNet. All networks employ the multi-view-one-network strategy. We conduct a binary classification (benign and malignant) and a ternary classification (benign, primary malignant and metastatic malignant) on Computed Tomography (CT) images from Lung Image Database Consortium and Image Database Resource Initiative database (LIDC-IDRI). All results are obtained via 10-fold cross validation. As regards the MV-CNN with chain architecture, results show that the performance of 3D MV-CNN surpasses that of 2D MV-CNN by a significant margin. Finally, a 3D Inception network achieved an error rate of 4.59% for the binary classification and 7.70% for the ternary classification, both of which represent superior results for the corresponding task. We compare the multi-view-one-network strategy with the one-view-one-network strategy. The results reveal that the multi-view-one-network strategy can achieve a lower error rate than the one-view one-network strategy. PMID- 29145493 TI - Poxviruses: Slipping and sliding through transcription and translation. PMID- 29145494 TI - Global analysis of gene expression mediated by OX1 orexin receptor signaling in a hypothalamic cell line. AB - The orexins and their cognate G-protein coupled receptors have been widely studied due to their associations with various behaviors and cellular processes. However, the detailed downstream signaling cascades that mediate these effects are not completely understood. We report the generation of a neuronal model cell line that stably expresses the OX1 orexin receptor (OX1) and an RNA-Seq analysis of changes in gene expression seen upon receptor activation. Upon treatment with orexin, several families of related transcription factors are transcriptionally regulated, including the early growth response genes (Egr), the Kruppel-like factors (Klf), and the Nr4a subgroup of nuclear hormone receptors. Furthermore, some of the transcriptional effects observed have also been seen in data from in vivo sleep deprivation microarray studies, supporting the physiological relevance of the data set. Additionally, inhibition of one of the most highly regulated genes, serum and glucocorticoid-regulated kinase 1 (Sgk1), resulted in the diminished orexin-dependent induction of a subset of genes. These results provide new insight into the molecular signaling events that occur during OX1 signaling and support a role for orexin signaling in the stimulation of wakefulness during sleep deprivation studies. PMID- 29145495 TI - Regulatory mechanism of CCN2 production by serotonin (5-HT) via 5-HT2A and 5-HT2B receptors in chondrocytes. AB - Serotonin (5-hydroxytryptamine: 5-HT) is recognized as a neurotransmitter in the central nerve system and as a regulator of systemic blood pressure in the peripheral tissues. Recently, it was reported that 5-HT2 receptors (5-HT2Rs) were expressed in cartilage tissues lacking both vessels and neurons, suggesting possible novel functions of 5-HT during cartilage development and regeneration. Our previous data indicated that CCN family protein 2/connective tissue growth factor (CCN2/CTGF) plays a central role in cartilage development and regeneration. Therefore, the aim of this study was to investigate the effect of 5 HT on the production of CCN2 in chondrocytes. Firstly, we showed that the mRNAs of 5-HT2R subtypes 5-HT2AR and 5-HT2BR, were expressed in a human chondrocytic cell line, HCS-2/8; however, 5-HT2CR mRNA was not detected. In addition, exogenously added 5-HT did not affect the 5-HT2AR and 5-HT2BR expressions. Next, we demonstrated that CCN2 production was increased by treatment with a 5-HT2AR agonist and the combination of 5-HT and 5-HT2BR antagonist. In contrast, treatment with a 5-HT2BR agonist and the combination of 5-HT and 5-HT2AR antagonist decreased CCN2 production. Furthermore, we showed that phosphorylation of Akt and p38 MAPK were increased by treatment with 5-HT2AR agonist, and that phosphorylation of PKCepsilon, PKCzeta, ERK1/2 and JNK were increased by treatment with 5-HT2BR agonist. Finally, we found that 5-HT2AR was localized in the growth plate, whereas 5-HT2BR was localized in the articular cartilage. These findings suggest that 5-HT promotes CCN2 production through the 5-HT2AR in growth plates, and that it represses CCN2 production through the 5-HT2BR in articular cartilage for harmonized development of long bones. PMID- 29145496 TI - Insights into soybean transcriptome reconfiguration under hypoxic stress: Functional, regulatory, structural, and compositional characterization. AB - Soybean (Glycine max) is one of the major crops worldwide and flooding stress affects the production and expansion of cultivated areas. Oxygen is essential for mitochondrial aerobic respiration to supply the energy demand of plant cells. Because oxygen diffusion in water is 10,000 times lower than in air, partial (hypoxic) or total (anoxic) oxygen deficiency is important component of flooding. Even when oxygen is externally available, oxygen deficiency frequently occurs in bulky, dense or metabolically active tissues such as phloem, meristems, seeds, and fruits. In this study, we analyzed conserved and divergent root transcriptional responses between flood-tolerant Embrapa 45 and flood-sensitive BR 4 soybean cultivars under hypoxic stress conditions with RNA-seq. To understand how soybean genes evolve and respond to hypoxia, stable and differentially expressed genes were characterized structurally and compositionally comparing its mechanistic relationship. Between cultivars, Embrapa 45 showed less up- and more down-regulated genes, and stronger induction of phosphoglucomutase (Glyma05g34790), unknown protein related to N-terminal protein myristoylation (Glyma06g03430), protein suppressor of phyA-105 (Glyma06g37080), and fibrillin (Glyma10g32620). RNA-seq and qRT-PCR analysis of non-symbiotic hemoglobin (Glyma11g12980) indicated divergence in gene structure between cultivars. Transcriptional changes for genes in amino acids and derivative metabolic process suggest involvement of amino acids metabolism in tRNA modifications, translation accuracy/efficiency, and endoplasmic reticulum stress in both cultivars under hypoxia. Gene groups differed in promoter TATA box, ABREs (ABA-responsive elements), and CRT/DREs (C-repeat/dehydration responsive elements) frequency. Gene groups also differed in structure, composition, and codon usage, indicating biological significances. Additional data suggests that cis-acting ABRE elements can mediate gene expression independent of ABA in soybean roots under hypoxia. PMID- 29145497 TI - Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans. AB - Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (especially migraine), sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function. PMID- 29145499 TI - Clinical tool for disease phenotyping in granulomatous lung disease. AB - BACKGROUND: Exposure to beryllium may lead to granuloma formation and fibrosis in those who develop chronic beryllium disease (CBD). Although disease presentation varies from mild to severe, little is known about CBD phenotypes. This study characterized CBD disease phenotypes using longitudinal measures of lung function. METHODS: Using a case-only study of 207 CBD subjects, subject-specific trajectories over time were estimated from longitudinal pulmonary function and exercise-tolerance tests. To estimate linear combinations of the 30-year values that define underlying patterns of lung function, we conducted factor analysis. Cluster analysis was then performed on all the predicted lung function values at 30 years. These estimates were used to identify underlying features and subgroups of CBD. RESULTS: Two factors, or composite measures, explained nearly 70% of the co-variation among the tests; one factor represented pulmonary function in addition to oxygen consumption and workload during exercise, while the second factor represented exercise tests related to gas exchange. Factors were associated with granulomas on biopsy, exposure, steroid use and lung inflammation. Three clusters of patients (n = 53, n = 59 and, n = 95) were identified based on the collection of test values. Lower levels of each of the factor composite scores and cluster membership were associated with baseline characteristics of patients. CONCLUSIONS: Using factor analysis and cluster analysis, we identified disease phenotypes that were associated with baseline patient characteristics, suggesting that CBD is a heterogeneous disease with varying severity. These clinical tools may be used in future basic and clinical studies to help define the mechanisms and risk factors for disease severity. PMID- 29145500 TI - Estimation of stress distribution in ferromagnetic tensile specimens using low cost eddy current stress measurement system and BP neural network. AB - Estimation of the stress distribution in ferromagnetic components is very important for evaluating the working status of mechanical equipment and implementing preventive maintenance. Eddy current testing technology is a promising method in this field because of its advantages of safety, no need of coupling agent, etc. In order to reduce the cost of eddy current stress measurement system, and obtain the stress distribution in ferromagnetic materials without scanning, a low cost eddy current stress measurement system based on Archimedes spiral planar coil was established, and a method based on BP neural network to obtain the stress distribution using the stress of several discrete test points was proposed. To verify the performance of the developed test system and the validity of the proposed method, experiment was implemented using structural steel (Q235) specimens. Standard curves of sensors at each test point were achieved, the calibrated data were used to establish the BP neural network model for approximating the stress variation on the specimen surface, and the stress distribution curve of the specimen was obtained by interpolating with the established model. The results show that there is a good linear relationship between the change of signal modulus and the stress in most elastic range of the specimen, and the established system can detect the change in stress with a theoretical average sensitivity of -0.4228 mV/MPa. The obtained stress distribution curve is well consonant with the theoretical analysis result. At last, possible causes and improving methods of problems appeared in the results were discussed. This research has important significance for reducing the cost of eddy current stress measurement system, and advancing the engineering application of eddy current stress testing. PMID- 29145498 TI - Antigenicity of the 2015-2016 seasonal H1N1 human influenza virus HA and NA proteins. AB - Antigenic drift of the hemagglutinin (HA) and neuraminidase (NA) influenza virus proteins contributes to reduced vaccine efficacy. To analyze antigenic drift in human seasonal H1N1 viruses derived from the 2009 pandemic H1N1 virus (pH1N1-like viruses) accounts for the limited effectiveness (around 40%) of vaccination against pH1N1-like viruses during the 2015-2016 season, nasal washes/swabs collected from adult subjects in the Rochester, NY area, were used to sequence and isolate the circulating viruses. The HA and NA proteins from viruses circulating during the 2015-2016 season encoded eighteen and fourteen amino acid differences, respectively, when compared to A/California/04/2009, a strain circulating at the origin of the 2009 pandemic. The circulating strains belonged to subclade 6B.1, defined by HA amino acid substitutions S101N, S179N, and I233T. Hemagglutination-inhibiting (HAI) and HA-specific neutralizing serum antibody (Ab) titers from around 50% of pH1N1-like virus-infected subjects and immune ferrets were 2-4 fold lower for the 2015-2016 circulating strains compared to the vaccine strain. In addition, using a luminex-based mPlex HA assay, the binding of human sera from subjects infected with pH1N1-like viruses to the HA proteins from circulating and vaccine strains was not identical, strongly suggesting antigenic differences in the HA protein. Additionally, NA inhibition (NAI) Ab titers in human sera from pH1N1-like virus-infected subjects increased after the infection and there were measurable antigenic differences between the NA protein of circulating strains and the vaccine strain using both ferret and human antisera. Despite having been vaccinated, infected subjects exhibited low HAI Ab titers against the vaccine and circulating strains. This suggests that poor responses to the H1N1 component of the vaccine as well as antigenic differences in the HA and NA proteins of currently circulating pH1N1-like viruses could be contributing to risk of infection even after vaccination. PMID- 29145501 TI - A comparison of Indigenous and non-Indigenous survivors of sexual assault and their receipt of and satisfaction with specialized health care services. AB - In Canada, Indigenous women are more likely than non-Indigenous women to be survivors of sexual assault and experience sexual assaults that are more serious in terms of physical injury and other health-related consequences. Despite their related needs for care and support, there is a paucity of research to date that has examined their uptake of specialized acute health services post sexual assault. To address this gap, we explored the presentation, sociodemographic, assailant, assault, and service use characteristics of Indigenous women, as compared to non-Indigenous adult and adolescent women aged 12 and older presenting to 30 of 35 hospital-based sexual assault treatment centres in Ontario from 2009 to 2011, using bivariate analyses. Of the 948 women in our sample, 116 (12%) identified as being Indigenous. Indigenous survivors differed significantly from non-Indigenous survivors on many presentation, sociodemographic, and assault characteristics. For example, they were more likely to present to a hospital within 24 hours of being assaulted and a treatment centre serving a primarily rural population. They tended to be younger, were more likely to be living in an institutional setting, report community or group affiliations and government or community services as sources of social support, and be assaulted by a parent, guardian, or other relative. In terms of receipt of services, they were more likely to have undergone safety planning and to be referred to child protection or community agencies. They reported high levels of satisfaction with the services received, however, were less likely than non-Indigenous survivors to rate the overall care provided as excellent or good. On the whole, the results of our study suggest that Indigenous women value acute hospital-based sexual assault services. However, they experience sexual assaults in contexts different from non Indigenous survivors. It is important for health care providers to be attuned to this so that they can appropriately respond to their unique needs. PMID- 29145502 TI - Hi-fidelity discrimination of isomiRs using G-quadruplex gatekeepers. AB - Core microRNA (miRNA) sequences exist as populations of variants called isomiRs made up of different lengths and nucleotide compositions. In particular, the short sequences of miRNA make single-base isomiR mismatches very difficult to be discriminated. Non-specific hybridizations often arise when DNA probe-miRNA target hybridization is the primary, or initial, mode of detection. These errors then become exacerbated through subsequent amplification steps. Here, we present the design of DNA probes modified with poly-guanine (PG) tracts that were induced to form G-quadruplexes (G4) for hi-fidelity discrimination of miRNA core target sequence from single-base mismatched isomiRs. We demonstrate that, when compared to unmodified probes, this G4 'gate-keeping' function within the G4-modified probes enables more stringent hybridization of complementary core miRNA target transcripts while limiting non-specific hybridizations. This increased discriminatory power of the G4-modified probes over unmodified probes is maintained even after further reverse transcriptase extension of probe-target hybrids. Enzymatic extension also enhanced the clarity and sensitivity of readouts and allows different isomiRs to be distinguished from one another via the relative positions of the mismatches. PMID- 29145504 TI - Quantifying performance on an outdoor agility drill using foot-mounted inertial measurement units. AB - Running agility is required for many sports and other physical tasks that demand rapid changes in body direction. Quantifying agility skill remains a challenge because measuring rapid changes of direction and quantifying agility skill from those measurements are difficult to do in ways that replicate real task/game play situations. The objectives of this study were to define and to measure agility performance for a (five-cone) agility drill used within a military obstacle course using data harvested from two foot-mounted inertial measurement units (IMUs). Thirty-two recreational athletes ran an agility drill while wearing two IMUs secured to the tops of their athletic shoes. The recorded acceleration and angular rates yield estimates of the trajectories, velocities and accelerations of both feet as well as an estimate of the horizontal velocity of the body mass center. Four agility performance metrics were proposed and studied including: 1) agility drill time, 2) horizontal body speed, 3) foot trajectory turning radius, and 4) tangential body acceleration. Additionally, the average horizontal ground reaction during each footfall was estimated. We hypothesized that shorter agility drill performance time would be observed with small turning radii and large tangential acceleration ranges and body speeds. Kruskal-Wallis and mean rank post hoc statistical analyses revealed that shorter agility drill performance times were observed with smaller turning radii and larger tangential acceleration ranges and body speeds, as hypothesized. Moreover, measurements revealed the strategies that distinguish high versus low performers. Relative to low performers, high performers used sharper turns, larger changes in body speed (larger tangential acceleration ranges), and shorter duration footfalls that generated larger horizontal ground reactions during the turn phases. Overall, this study advances the use of foot-mounted IMUs to quantify agility performance in contextually-relevant settings (e.g., field of play, training facilities, obstacle courses, etc.). PMID- 29145503 TI - Zinc sulfate contributes to promote telomere length extension via increasing telomerase gene expression, telomerase activity and change in the TERT gene promoter CpG island methylation status of human adipose-derived mesenchymal stem cells. AB - The use of mesenchymal stem cells (MSCs) for cell therapy and regenerative medicine has received widespread attention over the past few years, but their application can be complicated by factors such as reduction in proliferation potential, the senescent tendency of the MSCs upon expansion and their age dependent decline in number and function. It was shown that all the mentioned features were accompanied by a reduction in telomerase activity and telomere shortening. Furthermore, the role of epigenetic changes in aging, especially changes in promoter methylation, was reported. In this study, MSCs were isolated from the adipose tissue with enzymatic digestion. In addition, immunocytochemistry staining and flow cytometric analysis were performed to investigate the cell-surface markers. In addition, alizarin red-S, sudan III, toluidine blue, and cresyl violet staining were performed to evaluate the multi lineage differentiation of hADSCs. In order to improve the effective application of MSCs, these cells were treated with 1.5 * 10-8 and 2.99 * 10-10 M of ZnSO4 for 48 hours. The length of the absolute telomere, human telomerase reverse transcriptase (hTERT) gene expression, telomerase activity, the investigation of methylation status of the hTERT gene promoter and the percentage of senescent cells were analyzed with quantitative real-time PCR, PCR-ELISA TRAP assay, methylation specific PCR (MSP), and beta-galactosidase (SA-beta-gal) staining, respectively. The results showed that the telomere length, the hTERT gene expression, and the telomerase activity had significantly increased. In addition, the percentage of senescent cells had significantly decreased and changes in the methylation status of the CpG islands in the hTERT promoter region under treatment with ZnSO4 were seen. In conclusion, it seems that ZnSO4 as a proper antioxidant could improve the aging-related features due to lengthening of the telomeres, increasing the telomerase gene expression, telomerase activity, decreasing aging, and changing the methylation status of hTERT promoter; it could potentially beneficial for enhancing the application of aged-MSCs. PMID- 29145505 TI - Spontaneous development of Epstein-Barr Virus associated human lymphomas in a prostate cancer xenograft program. AB - Prostate cancer research is hampered by the lack of in vivo preclinical models that accurately reflect patient tumour biology and the clinical heterogeneity of human prostate cancer. To overcome these limitations we propagated and characterised a new collection of patient-derived prostate cancer xenografts. Tumour fragments from 147 unsupervised, surgical prostate samples were implanted subcutaneously into immunodeficient Rag2-/-gammaC-/- mice within 24 hours of surgery. Histologic and molecular characterisation of xenografts was compared with patient characteristics, including androgen-deprivation therapy, and exome sequencing. Xenografts were established from 47 of 147 (32%) implanted primary prostate cancers. Only 14% passaged successfully resulting in 20 stable lines; derived from 20 independent patient samples. Surprisingly, only three of the 20 lines (15%) were confirmed as prostate cancer; one line comprised of mouse stroma, and 16 were verified as human donor-derived lymphoid neoplasms. PCR for Epstein-Barr Virus (EBV) nuclear antigen, together with exome sequencing revealed that the lymphomas were exclusively EBV-associated. Genomic analysis determined that 14 of the 16 EBV+ lines had unique monoclonal or oligoclonal immunoglobulin heavy chain gene rearrangements, confirming their B-cell origin. We conclude that the generation of xenografts from tumour fragments can commonly result in B-cell lymphoma from patients carrying latent EBV. We recommend routine screening, of primary outgrowths, for latent EBV to avoid this phenomenon. PMID- 29145507 TI - Light sensors for objective light measurement in ambulatory polysomnography. AB - Ambulatory polysomnography (PSG) does not commonly include an objective measure of light to determine the time of lights off (Loff), and thus cannot be used to calculate important indices such as sleep onset latency and sleep efficiency. This study examined the technical specifications and appropriateness of a prototype light sensor (LS) for use in ambulatory Compumedics Somte PSG.Two studies were conducted. The first examined the light measurement characteristics of the LS when used with a portable PSG device, specifically recording trace range, linearity, sensitivity, and stability. This involved the LS being exposed to varying incandescent and fluorescent light levels in a light controlled room. Secondly, the LS was trialled in 24 home and 12 hospital ambulatory PSGs to investigate whether light levels in home and hospital settings were within the recording range of the LS, and to quantify the typical light intensity reduction at the time of Loff. A preliminary exploration of clinical utility was also conducted. Linearity between LS voltage and lux was demonstrated, and the LS trace was stable over 14 hours of recording. The observed maximum voltage output of the LS/PSG device was 250 mV, corresponding to a maximum recording range of 350 lux and 523 lux for incandescent and fluorescent light respectively. At the time of Loff, light levels were within the recording range of the LS, and on average dropped by 72 lux (9-245) in the home and 76 lux (4-348) in the hospital setting. Results suggest that clinical utility was greatest in hospital settings where patients are less mobile. The LS was a simple and effective objective marker of light level in portable PSG, which can be used to identify Loff in ambulatory PSG. This allows measurement of additional sleep indices and support with clinical decisions. PMID- 29145506 TI - The PrpF protein of Shewanella oneidensis MR-1 catalyzes the isomerization of 2 methyl-cis-aconitate during the catabolism of propionate via the AcnD-dependent 2 methylcitric acid cycle. AB - The 2-methylcitric acid cycle (2-MCC) is a common route of propionate catabolism in microorganisms. In Salmonella enterica, the prpBCDE operon encodes most of the 2-MCC enzymes. In other organisms, e.g., Shewanella oneidensis MR-1, two genes, acnD and prpF replace prpD, which encodes 2-methylcitrate dehydratase. We showed that together, S. oneidensis AcnD and PrpF (SoAcnD, SoPrpF) compensated for the absence of PrpD in a S. enterica prpD strain. We also showed that SoAcnD had 2 methylcitrate dehydratase activity and that PrpF has aconitate isomerase activity. Here we report in vitro evidence that the product of the SoAcnD reaction is an isomer of 2-methyl-cis-aconitate (2-MCA], the product of the SePrpD reaction. We show that the SoPrpF protein isomerizes the product of the AcnD reaction into the PrpD product (2-MCA], a known substrate of the housekeeping aconitase (AcnB]. Given that SoPrpF is an isomerase, that SoAcnD is a dehydratase, and the results from in vivo and in vitro experiments reported here, it is likely that 4-methylaconitate is the product of the AcnD enzyme. Results from in vivo studies using a S. enterica prpD strain show that SoPrpF variants with substitutions of residues K73 or C107 failed to support growth with propionate as the sole source of carbon and energy. High-resolution (1.22 A) three-dimensional crystal structures of PrpFK73E in complex with trans-aconitate or malonate provide insights into the mechanism of catalysis of the wild-type protein. PMID- 29145508 TI - Irruptive mammal host populations shape tularemia epidemiology. PMID- 29145509 TI - Untargeted mass spectrometry discloses plasma solute levels poorly controlled by hemodialysis. AB - Many solutes have been reported to remain at higher plasma levels relative to normal than the standard index solute urea in hemodialysis patients. Untargeted mass spectrometry was employed to compare solute levels in plasma and plasma ultrafiltrate of hemodialysis patients and normal subjects. Quantitative assays were employed to check the accuracy of untargeted results for selected solutes and additional measurements were made in dialysate and urine to estimate solute clearances and production. Comparison of peak areas indicated that many solutes accumulated to high levels in hemodialysis patients, with average peak areas in plasma ultrafiltrate of dialysis patients being more than 100 times greater than those in normals for 123 features. Most of these mass spectrometric features were identified only by their mass values. Untargeted analysis correctly ranked the accumulation of 5 solutes which were quantitatively assayed but tended to overestimate its extent. Mathematical modeling showed that the elevation of plasma levels for these solutes could be accounted for by a low dialytic to native kidney clearance ratio and a high dialytic clearance relative to the volume of the accessible compartment. Numerous solutes accumulate to high levels in hemodialysis patients because dialysis does not replicate the clearance provided by the native kidney. Many of these solutes remain to be chemically identified and their pathogenic potential elucidated. PMID- 29145510 TI - Out-of-hospital cardiac arrests in Switzerland: Predictors for emergency department mortality in patients with ROSC or on-going CPR on admission to the emergency department. AB - BACKGROUND: One of the leading causes of death is out-of-hospital cardiac arrest (OHCA) with an in-hospital mortality of about 70%. To identify predictors for the high mortality of OHCA patients and especially for women, that are considered at high risk for in-hospital mortality, we evaluated one specific setting of in hospital treatment after OHCA: the emergency department (ED). METHODS: Retrospective analysis of consecutive ED admissions with OHCA at the Inselspital Bern, Switzerland from 1st June 2012 to 31th Mai 2015. Demographic, preclinical and ED medical data were compared for patient groups with return of circulation (ROSC) and on-going resuscitation (CPR) on admission, as well as for subgroups with and without ED mortality. Predictors for ED mortality were investigated using univariate analysis with logistic regression. RESULTS: In 354 patients (228 (64.4%) with ROSC; 126 (35.6%) with on-going CPR) we found an overall ED mortality of 28.5% (5.7% ROSC group; 69.8% on-going CPR group). Female gender (OR 7.053 (CI 95% 2.085; 24.853), p = 0.002) and greater age (OR 1.052 (95% CI 1.006 1.101), p = 0.029) were associated with ED mortality in the ROSC but not in the on-going CPR group. Ventricular fibrillation as initially monitored rhythm (OR 0.126 (95% CI 0.027-0.582), p = 0.008) and shorter CPR duration (OR 1.055 (95% CI 1.024;1.088), p = 0.001) were associated with ED survival in patients with ROSC but not in patients with on-going CPR on admission. In ROSC patients a higher lactate and lower pH were associated with mortality (pH: OR 0.009 (CI95% 0.000;0.420), p = 0.016; lactate: OR 1.183 (95% CI 1.037; 1.349), p = 0.013); similar in on-going CPR patients (pH 0.061 (95% CI 0.007, 0.558), p = 0.013, lactate: 1.146 (95% CI 1.041;1.261), p = 0.005). CONCLUSION: Patients with ROSC who died during ED care were predominantly women and older patients, as well as patients with non-shockable initial heart rhythm and long CPR durations. In patients with on-going CPR on admission, no clinical or demographic predictors for ED mortality were found. Higher lactate and lower pH were predictors in both OHCA groups. PMID- 29145511 TI - Crowdsourcing prior information to improve study design and data analysis. AB - Though Bayesian methods are being used more frequently, many still struggle with the best method for setting priors with novel measures or task environments. We propose a method for setting priors by eliciting continuous probability distributions from naive participants. This allows us to include any relevant information participants have for a given effect. Even when prior means are near zero, this method provides a principle way to estimate dispersion and produce shrinkage, reducing the occurrence of overestimated effect sizes. We demonstrate this method with a number of published studies and compare the effect of different prior estimation and aggregation methods. PMID- 29145512 TI - Impact of the surgical strategy on the incidence of C5 nerve root palsy in decompressive cervical surgery. AB - OBJECTIVE: Our aim was to identify the impact of different surgical strategies on the incidence of C5 palsy. BACKGROUND: Degenerative cervical spinal stenosis is a steadily increasing morbidity in the ageing population. Postoperative C5 nerve root palsy is a common complication with severe impact on the patients' quality of life. METHODS: We identified 1708 consecutive patients who underwent cervical decompression surgery due to degenerative changes. The incidence of C5 palsy and surgical parameters including type and level of surgery were recorded to identify predictors for C5 nerve palsy. RESULTS: The overall C5 palsy rate was 4.8%, with 18.3% of cases being bilateral. For ACDF alone the palsy rate was low (1.13%), compared to 14.0% of C5 palsy rate after corpectomy. The risk increased with extension of the procedures. Hybrid constructs with corpectomy plus ACDF at C3-6 showed significantly lower rates of C5 palsy (10.7%) than corpectomy of two vertebrae (p = 0.005). Multiple regression analysis identified corpectomy of C4 or C5 as a significant predictor. We observed a lower overall incidence for ventral (4.3%) compared to dorsal (10.9%) approaches (p<0.001). When imaging detected a postoperative shift of the spinal cord at index segment C4/5, palsy rate increased significantly (33.3% vs. 12.5%, p = 0.034). CONCLUSIONS: Extended surgical strategies, such as dorsal laminectomies, multilevel corpectomies and procedures with extensive spinal cord shift were shown to display a high risk of C5 palsy. The use of extended procedures should therefore be employed cautiously. Switching to combined surgical methods like ACDF plus corpectomy can reduce the rate of C5 palsy. PMID- 29145513 TI - Determinants for cardiovascular disease health check questionnaire: A validation study. AB - BACKGROUND: To improve individuals' participation in cardiovascular disease (CVD) screening, it is necessary to understand factors that influence their intention to undergo health checks. This study aimed to develop and validate an instrument that assess determinants that influence individuals' intention to undergo CVD health checks. METHODS: The concepts and items were developed based on findings from our prior exploratory qualitative study on factors influencing individuals' intention to undergo CVD health checks. Content validity of the questionnaire was assessed by a panel of six experts and the item-level content validity index (I CVI) was determined. After pretesting the questionnaire was pilot tested to check reliability of the items. Exploratory factor analysis was used to test for dimensionality using a sample of 240 participants. RESULTS: The finalized questionnaire consists of 36 items, covering nine concepts. The I-CVI for all items was satisfactory with values ranging from 0.83 to 1.00. The exploratory factor analysis showed that the number of factors extracted was consistent with the theoretical concepts. Correlations values between items ranged from 0.30 to 0.85 and all the factor loadings were more than 0.40, indicating satisfactory structural validity. All concepts showed good internal consistency, Cronbach's alpha values ranged 0.66-0.85. CONCLUSIONS: The determinants for CVD health check questionnaire has good content and structural validity, and its reliability was established. It can be used to assess determinants influencing individuals' intention to undergo CVD health checks. PMID- 29145514 TI - Why patients with THBD c.1611C>A (p.Cys537X) nonsense mutation have high levels of soluble thrombomodulin? AB - BACKGROUND: Recently our group has described a new autosomal dominant bleeding disorder characterized by very high plasma levels of soluble thrombomodulin (TM). The THBD c.1611C>A (p.Cys537X) mutation in heterozygous state was found in the propositus. This mutation leads to the synthesis of a truncated TM which has lost the last three amino-acids of the transmembrane domain and the cytoplasmic tail. OBJECTIVE: We investigated the mechanism responsible for TM shedding in endothelial cells with THBD c.1611C>A mutation. METHODS: Complementary DNA of TM wild type (TM-WT) was incorporated into a pcDNA3.1 vector for transient transfection in COS-1 cells. Mutagenesis was performed to create the c.1611C= 3 months, n = 244; continuous pain >= 3 months, n = 179) were compared. RESULTS: The refined two-factor model of the PVAQ fit best to the sample (chi2/degrees of freedom = 6.095; comparative fit index = 0.926; goodness of fit index = 0.928; root mean square error of approximation = 0.083; average variance extracted > 0.45; composite reliability and Cronbach's alpha > 0.85) and presented strong invariance in independent samples. Individuals with pain presented higher scores on PVAQ factors, and the highest scores were found among individuals with continuous pain. CONCLUSION: The Brazilian Portuguese version of the PVAQ was found to be adequate and reliable when applied to the sample. The methodologic considerations presented could improve research on pain vigilance and help clinicians assess PVAQ factors among patients. PMID- 29145524 TI - Tumor Necrosis Factor Alpha Signaling in Trigeminal Ganglion Contributes to Mechanical Hypersensitivity in Masseter Muscle During Temporomandibular Joint Inflammation. AB - AIMS: To determine the involvement of tumor necrosis factor alpha (TNFalpha) signaling in the trigeminal ganglion (TG) in the mechanical hypersensitivity of the masseter muscle during temporomandibular joint (TMJ) inflammation. METHODS: A total of 55 male Sprague-Dawley rats were used. Following injection of Complete Freund's Adjuvant into the TMJ, the mechanical sensitivities of the masseter muscle and the overlying facial skin were measured. Satellite glial cell (SGC) activation and TNFalpha expression in the TG were investigated immunohistochemically, and the effects of their inhibition on the mechanical hypersensitivity of the masseter muscle were also examined. Student t test or two way repeated-measures analysis of variance followed by Bonferroni multiple comparisons test were used for statistical analyses. P < .05 was considered to reflect statistical significance. RESULTS: Mechanical allodynia in the masseter muscle was induced without any inflammatory cell infiltration in the muscle after TMJ inflammation. SGC activation and an increased number of TNFalpha immunoreactive cells were induced in the TG following TMJ inflammation. Intra-TG administration of an inhibitor of SGC activity or of TNFalpha-neutralizing antibody depressed both the increased number of TG cells encircled by activated SGCs and the mechanical hypersensitivity of the masseter following TMJ inflammation. CONCLUSION: These findings suggest that persistent masseter hypersensitivity associated with TMJ inflammation was mediated by SGC-TG neuron interactions via TNFalpha signaling in the TG. PMID- 29145525 TI - Association Between Missing Posterior Teeth and Occurrence of Temporomandibular Joint Condylar Erosion: A Cone Beam Computed Tomography Study. AB - PURPOSE: To determine a possible association between asymptomatic temporomandibular joint (TMJ) condylar erosion and the number of missing posterior teeth and their location, as well as the number of dental quadrants with missing posterior teeth. MATERIALS AND METHODS: This case-control study involved 210 patients (male to female ratio = 98:112) aged 16-74 years, with 105 asymptomatic patients with TMJ condylar erosion and a control group of 105 patients without TMJ condylar erosion. Cone beam computed tomography images were evaluated to classify the severity of TMJ condylar erosion as grade 0 (absence of erosion), grade I (slight erosion), grade II (moderate erosion), or grade III (extensive erosion). RESULTS: The number of missing posterior teeth (mean +/- standard deviation [SD]; 2.7 +/- 2.4 vs 0.7 +/- 1.2) (P < .001), number of dental quadrants with missing posterior teeth (1.5 +/- 1.3 vs 0.6 +/- 0.9) (P < .001), and bilateral location of missing posterior teeth (41 +/- 39.0 vs 10 +/- 9.5) (P < .001) were all significantly higher in patients with erosion than in those without erosion. The condylar erosion grade was significantly associated with the number of missing posterior teeth (odds ratio [OR] = 1.24; P = .006), the number of dental quadrants with missing posterior teeth (OR = 1.36; P = .006), and the bilateral occurrence of missing posterior teeth (OR = 3.03; P = .002). CONCLUSION: The findings from this study suggest a possible association between TMJ condylar erosion grades and the number of missing posterior teeth, the number of quadrants with missing posterior teeth, and the bilateral occurrence of missing posterior teeth. PMID- 29145526 TI - Factors Affecting the Decision to Use Cemented or Screw-Retained Fixed Implant Supported Prostheses: A Critical Review. AB - PURPOSE: This review aimed to compile and enumerate all the factors described in the literature that may affect the decision to use either cemented or screw retained restorations and to determine the relative weights of each factor by type of retention and prosthesis. MATERIALS AND METHODS: The literature was reviewed, and the factors were classified as either determining (present in a clinical situation in which one of the retention mechanisms was clearly more suitable than the other) or conditioning (present in clinical situations in which one type of restoration was not clearly more advantageous than the other). RESULTS: Three determining factors (esthetic outcome, retention, and biologic risk) and five conditioning factors (passive fit, fracture strength, occlusal area, complications, and retrievability) were identified. CONCLUSION: Although there is not a clearly better alternative for all clinical situations, determining factors in certain scenarios can render one of the two approaches more recommendable. For esthetic reasons, when the implant angle cannot be corrected to conceal the access hole, cementation is more suitable; however, screw retention is the better option when the occlusal space is under 6 mm or margins cannot be located supra- or equigingivally. In the absence of determining factors, the decision should be based on conditioning factors, which carry different weights depending on the type of prosthesis. PMID- 29145527 TI - Evaluation of Operating Time and Patient Perception Using Conventional Impression Taking and Intraoral Scanning for Crown Manufacture: A Split-mouth, Randomized Clinical Study. AB - PURPOSE: To compare operating time and patient perception of conventional impression (CI) taking and intraoral scanning (IOS) for manufacture of a tooth supported crown. MATERIALS AND METHODS: A total of 19 patients needing indirect full-coverage restorations fitting the requirements for a split-mouth design were recruited. Each patient received two lithium disilicate crowns, one manufactured from CI taking and one from IOS. Both teeth were prepared following the manufacturers' recommendations. For both impression techniques, two retraction cords soaked in 15% ferric sulphate were used for tissue management. CIs were taken in a full-arch metallic tray using one-step, two-viscosity technique with polyvinyl siloxane silicone. The operating time for each step of the two impression methods was registered. Patient perception associated with each method was scored using a 100-mm visual analog scale (VAS), with 100 indicating maximum discomfort. RESULTS: Median total operating time for CI taking was 15:47 minutes (interquartile range [IQR] 15:18 to 17:30), and for IOS was 5:05 minutes (IQR 4:35 to 5:23). The median VAS score for patient perception was 73 (IQR 16 to 89) for CI taking and 6 (IQR 2 to 9) for IOS. The differences between the two groups were statistically significant (P < .05) for both parameters. CONCLUSION: IOS was less time consuming than CI taking, and patient perception was in favor of IOS. PMID- 29145528 TI - Auricular Prostheses Produced by Means of Conventional and Digital Workflows: A Clinical Report on Esthetic Outcomes. AB - The utilization of additive manufacturing (AM) technology for the production of auricular prostheses has been widely acknowledged. However, few studies and case history reports have evaluated the esthetic outcomes of AM prostheses compared to those of conventionally manufactured prostheses. In this case history report, three manufacturing approaches-conventional, indirect, and direct mold preparation-were assessed for their esthetic outcomes in the same patient. PMID- 29145529 TI - Volumetric Bone Measurement Around Dental Implants Using 3D Image Superimposition: A Methodological and Clinical Pilot Study. AB - PURPOSE: This study describes the development of a methodology for using three dimensional (3D) image superimposition to measure volumetric changes in bone level around dental implants in comparison with linear measures. MATERIALS AND METHODS: The sample was comprised of 46 dental implants of 6-mm length and 4.1-mm diameter placed in the posterior maxilla and posterior mandible in 20 patients. All implants received screw-retained single crowns. Radiographic images were taken using cone beam computed tomography (CBCT) and digital periapical radiography after implantation and after 12 and 24 months of functional loading (after crown installation). Tridimensional reconstructions of the bone perimeter closest to the implant were developed, superimposed, and volumetrically measured. Linear measures of bone levels were recorded in periapical radiography images. A multilevel regression model tested volumetric and linear bone loss. RESULTS: The mean peri-implant linear bone loss for the first and second years was 0.2 +/- 0.4 mm and 0.1 +/- 0.2 mm, respectively, and the mean volumetric bone loss for the first and second years was 7.2 +/- 6.1 mm3 and 6.4 +/- 7.8 mm3, respectively. It was estimated that an increase of 1 mm of linear bone loss was associated with a mean volumetric bone loss of approximately 14 mm3 (P < .001). CONCLUSION: The findings showed that linear and volumetric bone loss measures are related. Measuring volumetric bone changes around implants is possible provided that the CBCT images have proper contrast and sharpness, particularly around the implant outline. Improvements in image quality and in the filters for bone tissue detection would be important for this methodology to be made faster and used clinically. PMID- 29145535 TI - Atypical Microbial Isolates from Infected Diabetic Foot Ulcers: A Case Series from Greece. PMID- 29145536 TI - The Effects of Vitamin D Supplementation in Newly Diagnosed Type 1 Diabetes Patients: Systematic Review of Randomized Controlled Trials. AB - AIM: The aim of this study was to examine the effects of vitamin D supplementation in patients newly diagnosed with type 1 diabetes (T1D) assessed by insulin needs and changes in glycemic indices, as evidenced by randomized controlled trials (RCTs). METHODS: A total of 7 RCTs were retrieved from PubMed/Medline and EBSCO databases by MeSH term search, and were reviewed systematically. The RCTs included examined the effects of alphacalcidole (n = 2), cholecalciferol (n = 2), and calcitriol (n = 3) supplementation on changes in daily insulin dose (DID), fasting Cpeptide (FCP), stimulated C-peptide (SCP), and HbA1c. In total, 287 individuals, diagnosed with T1D within a period of 4 weeks to 1 year and aged between 5 to 38 years, were examined. RESULTS: Significant positive effects on DID, FCP, and SCP levels were observed after supplementation with alphacalcidole and cholecalciferol, whereas supplementation with calcitriol showed no effect. CONCLUSIONS: Vitamin D supplementation in the form of alphacalcidole and cholecalciferol appears to be beneficial in the treatment of T1D patients by attenuating the natural history of the disease. PMID- 29145537 TI - The Role of Iron in Type 1 Diabetes Etiology: A Systematic Review of New Evidence on a Long-Standing Mystery. AB - BACKGROUND: The incidence of type 1 diabetes (T1D) is rising, which might be due to the influence of environmental factors. Biological and epidemiological evidence has shown that excess iron is associated with beta-cell damage and impaired insulin secretion. AIM: In this review, our aim was to assess the association between iron and the risk of T1D. METHODS: A systematic literature search was performed in PubMed and EMBASE in July 2016. Studies investigating the effect of iron status/intake on the risk of developing T1D later were included, and study quality was evaluated. The results have been summarized in narrative form. RESULTS: From a total of 931 studies screened, we included 4 observational studies evaluating iron intake from drinking water or food during early life and the risk of T1D. The quality of the studies was moderate to high assessed via the nine-star Newcastle Ottawa Scale. One out of the four studies included in this review found estimates of dietary iron intake to be associated with risk of T1D development, whereas three studies found no such relationship for estimates of iron in drinking water. CONCLUSIONS: The limited number of studies included found dietary iron, but not iron in drinking water, to be associated with risk of T1D. Further studies are needed to clarify the association between iron and risk of T1D, especially studies including measurements of body iron status. PMID- 29145538 TI - Association Between Socioeconomic Determinants and the Metabolic Syndrome in the German Health Interview and Examination Survey for Adults (DEGS1) - A Mediation Analysis. AB - BACKGROUND: Metabolic syndrome and different socioeconomic characteristics including education and occupational status have been found to be associated in previous research. Nonetheless, theoretical models defining core variables and causal processes accounting for these associations are lacking. OBJECTIVES: The main objectives of the present investigation are (1) to present a theoretical model integrating physiological, biochemical, and psychosocial factors determining metabolic syndrome prevalence and (2) to corroborate the hypothesis that socioeconomic determinants are (partially) mediated by health-related behaviors, health risks, and dietary habits. METHODS: The research hypothesis is tested with cross-sectional data from the German Health Interview and Examination Survey for Adults (DEGS1) conducted from 2008 to 2011 (n = 7,987) by means of multivariate regression models which appropriately take into account the stochastic dependence of metabolic syndrome components. RESULTS: The results suggest that the metabolic syndrome is less frequent among individuals with a higher educational level and those who have a partner. These associations may point to protective effects of social support, self-efficacy, and other socio psychological constructs in relation to metabolic syndrome incidence. Furthermore, frequent consumption of wine, muesli, fruits, and raw vegetables are associated with lower prevalence rates of metabolic syndrome components. The associations of occupational status, income, and employment are partially mediated by health-related behavior, physiological and psychosocial factors, and dietary habits. Sensitivity analyses have suggested that even small changes in the distribution of potential risk and protective factors may reduce the prevalence of metabolic syndrome components. CONCLUSIONS: Healthrelated behavior (smoking, physical activity) and physiological and psychosocial factors mediate the association between socioeconomic characteristics and metabolic syndrome prevalence. However, metabolic syndrome components were much less frequent among individuals with a higher educational level, higher income and occupational status, and those having a life partner. PMID- 29145539 TI - Socioeconomic Deprivation, Household Education, and Employment are Associated With Increased Hospital Admissions and Poor Glycemic Control in Children With Type 1 Diabetes Mellitus. AB - BACKGROUND: Socioeconomic deprivation, obesity, and emotional discomfort are important determinants of health inequalities and poor glycemic control in children and young people with type 1 diabetes mellitus (T1D). OBJECTIVES: The aims of this study were to evaluate the incidence of hospital admissions of T1D children in relation to socioeconomic deprivation, and to determine the effects of social deprivation, body mass index (BMI), and patient-reported emotional well being on glycemic control. METHODS: All hospital admissions of T1D patients aged 1-18 years were identified during 2007 and 2012. Admission cause and glycemic control were related to social deprivation, BMI, and psychological, emotional well-being. Indices of Multiple Deprivation (IMD) 2010 were applied to the United Kingdom data. The associations were calculated using the Spearman's rank correlation coefficient. RESULTS: A significant correlation was found between hospital admission rates and overall deprivation scores (r = -0.18, p = 0.04). Patients living in deprived areas were more likely to selfpresent to the accident and emergency department (r = -0.24, p = 0.02). Poor glycemic control (n = 124) was significantly associated with lower levels of education (r = -0.22, p = 0.02) and unemployment (r = -0.19, p = 0.04). Significance was not reached for level of income (r = -0.16, p = 0.07) and overall deprivation (r = -0.17, p = 0.06). Glycemic control was not found to be associated with BMI, standard deviation scores (SDS), or emotional well-being. CONCLUSION: Early intervention and education from primary care and specialist diabetes teams within the community in deprived areas may be effective in reducing hospital admissions for diabetes related problems and improving glycemic control. PMID- 29145540 TI - Inverse Association of Peripheral Orexin-A with Insulin Resistance in Type 2 Diabetes Mellitus: A Randomized Clinical Trial. AB - AIMS: To investigate the association between serum orexin concentrations and insulin resistance/sensitivity in a sample of patients with type 2 diabetes mellitus, and to study the effects of anti-hyperglycemic treatment on orexin concentrations over three months. METHODS: This study was designed as a randomized, open-label, clinical trial. Before allocation, sixty medication naive, newly-diagnosed, type 2 diabetes patients underwent a 75 g oral glucose tolerance test (OGTT). Afterwards, using a randomized trial design (IRCT201102275917N1) patients were allocated to either the metformin (1000 mg daily) or pioglitazone (30 mg daily) arm, and were reexamined after three months. Serum insulin, plasma glucose, and orexin concentrations were measured at baseline, during OGTT, and after three months. RESULTS: Orexin concentrations significantly decreased after OGTT (0 vs. 120 min: 0.63 +/- 0.07 vs. 0.31 +/- 0.03 ng/ml, p < 0.001). Insulin resistance determined by homeostasis model assessment of insulin resistance (HOMA-IR) was significantly and negatively correlated with orexin (r = -0.301, p = 0.024). Furthermore, orexin concentrations were significantly and positively correlated with the insulin sensitivity index derived from OGTT (r = 0.326, p = 0.014). Three-month treatment with metformin and pioglitazone significantly improved insulin sensitivity and increased orexin concentrations by 26% (p = 0.025) and 14% (p = 0.076), respectively. Between-group analysis showed that changes in orexin concentrations with metformin and pioglitazone were not significantly different (p = 0.742). CONCLUSIONS: There was a negative association between peripheral orexin concentrations and insulin resistance in type 2 diabetes patients. Three-month anti-hyperglycemic treatment with proportionate doses of metformin or pioglitazone increased orexin concentrations via amelioration of insulin resistance and improvement of glycemic control. PMID- 29145542 TI - Gradually Worsening Pruritic Plaques. PMID- 29145541 TI - Variations in ADIPOR1 But Not ADIPOR2 are Associated With Hypertriglyceridemia and Diabetes in an Admixed Latin American Population. AB - BACKGROUND: Adiponectin is a hormone secreted by adipose tissue. It regulates glycolysis and lipolysis and is involved in the pathophysiology of diabetes and related disorders. Its activity is mainly mediated by the transmembrane receptors AdipoR1 and AdipoR2, which are encoded by ADIPOR1 (1q32.1) and ADIPOR2 (12p13.33) genes, respectively. In genetic association studies, single nucleotide polymorphisms (SNPs) in or near these genes have been associated with metabolic alterations. However, these relationships are still controversial. AIM: The aim of this work was to analyze possible associations between ADIPOR1/2 and diabetes and other metabolic disorders. METHODS: A genetic association study was carried out in an admixed Latin American population. A sample of 200 adults was analyzed. Clinical and serum-biochemical characteristics were measured to diagnose obesity, abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia, low HDLc, insulin resistance (HOMA-IR), and diabetes. Three SNPs were genotyped in ADIPOR1 (rs10494839, rs12733285, and rs2275737) and ADIPOR2 (rs11061937, rs11612383, and rs2286383). For the association analysis, an additive model was assessed through logistic regression. An admixture adjustment was performed using a Monte-Carlo Markov-Chain method, assuming a three-hybrid substructure (k = 3). RESULTS: Two SNPs in ADIPOR1 were associated with diabetes: rs10494839 (OR = 3.88, adjusted p < 0.03) and rs12733285 (OR = 4.72, adjusted p < 0.03). Additionally, rs10494839 was associated with hypertriglyceridemia (OR = 2.16, adjusted p < 0.01). None of the SNPs in ADIPOR2 were associated with metabolic disorders. CONCLUSIONS: ADIPOR1 was consistently associated with diabetes and hypertriglyceridemia. This association was maintained even after adjusting for genetic stratification. There were no significant associations involving ADIPOR2. PMID- 29145544 TI - Blast SMS Text Messaging to Facilitate Enrollment for Cleft Lip and Palate Surgery in Zimbabwe. PMID- 29145543 TI - Association of Ipilimumab With Safety and Antitumor Activity in Women With Metastatic or Recurrent Human Papillomavirus-Related Cervical Carcinoma. AB - Importance: Based on evidence of human papillomavirus (HPV)-induced immune evasion, immunotherapy may be an attractive strategy in cervical cancer. Ipilimumab is a fully humanized monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4 (CTLA-4), which acts to downregulate the T-cell immune response. Objective: To assess the safety and antitumor activity of ipilimumab in recurrent cervical cancer. Design, Setting, and Participants: A multicenter trial was designed for patients with metastatic cervical cancer (squamous cell carcinoma or adenocarcinoma) with measurable disease and progression after at least 1 line of platinum chemotherapy. A run-in safety cohort using ipilimumab, 3 mg/kg, every 21 days for 4 cycles in 6 patients was followed by a phase II cohort of ipilimumab, 10 mg/kg, every 21 days for 4 cycles and then 4 cycles of maintenance therapy every 12 weeks for patients demonstrating radiologic response or stabilization. Immune correlative studies were performed on peripheral blood before and after therapy on archival tissue and fresh tumor obtained prior to registration and 7 days after cycle 2. The study was conducted from December 3, 2012, to September 15, 2014. The data were analyzed from April 2016 to June 2016 and in July 2017. Main Outcomes and Measures: The primary end points were safety and objective response rate. Immune analyses were performed on blood and tumor tissue. Results: A total of 42 women (median age, 49 years; range, 23-78 years) were enrolled (29 [69%] squamous cell cervical cancer and 13 [31%] adenocarcinoma; 37 [93%] of 40 patients with tissue available for analysis had HPV-positive confirmation; there was no archival tissue for 2 women). Grade 3 toxic effects included diarrhea in 4 patients, 3 of whom had colitis. Of 34 patients evaluated for best response (Response Evaluation Criteria in Solid Tumors, version 1.1), 1 patient had partial response and 10 had stable disease. The median progression-free survival and overall survival were 2.5 months (95% CI, 2.1-3.2 months) and 8.5 months (95% CI, 3.6-not reached; 1 patient was still alive), respectively. Intratumoral pretreatment CD3, CD4, CD8, FoxP3, indoleamine 2,3-dioxygenase, and programmed cell death ligand 1 (PD-L1) expression was not predictive of benefit and did not significantly change with treatment. Multicolor flow cytometry on peripheral lymphocytes revealed a treatment-dependent increase of inducible T-cell costimulator, human leukocyte antigen-antigen D related, and PD-1 during initial treatment, which returned to baseline during maintenance. Conclusions and Relevance: Ipilimumab was tolerable in this population but did not show significant single-agent activity. Immune changes were induced by anti CTLA-4 therapy but did not correlate with clinical activity. Changes in these markers may guide further treatment strategies. PMID- 29145545 TI - Treatment of Alcohol-Induced Psychotic Disorder (Alcoholic Hallucinosis)-A Systematic Review. AB - Aims: To evaluate the effectiveness of evidence based treatments for alcohol induced psychotic disorder (AIPD) as described by ICD-10 and DSM-5, a condition that is distinct from schizophrenia and has a close relationship with alcohol withdrawal states. Method: Systematic review using PRISMA guidelines. Results: Of 6205 abstracts found, fifteen studies and ten case reports met criteria and were examined. Larger studies examined the use of first-generation antipsychotic drugs, reporting full or partial remission in most patients. Newer case reports report similar results using second generation antipsychotic drugs. Novel treatments, such as those acting on GABA receptors reported low numbers of patients in remission. Some large studies report the successful use of standard alcohol withdrawal treatments. Conclusion: The findings of our systematic review are inconclusive. There was significant heterogeneity between and within studies. Significant publication bias is likely. Randomized control trials of more carefully delineated samples would produce evidence of greater clinical utility, for example, on differential effectiveness of antipsychotics and optimal length of standard alcohol withdrawal treatments. AIPD patients who show poor treatment responses should be studied in greater depth. Short Summary: This systematic review of alcohol-induced psychotic disorder treatment found 15 studies and 10 case reports of relevance. Older studies of first-generation antipsychotics reported full or partial remission in most patients, as did newer studies with second-generation antipsychotics. Novel drugs reported low remission rates. Standard alcohol withdrawal treatments were successful. PMID- 29145546 TI - Congenital Fistulae of the Stapedial Footplate and Round Window Membrane: An Unusual Cause of Recurrent Meningitis. PMID- 29145547 TI - Association of First-in-Class Immune Checkpoint Inhibition and Targeted Therapy With Survival in Patients With Stage IV Melanoma. PMID- 29145548 TI - Supported Discharge Teams for older people in hospital acute care: a randomised controlled trial. AB - Background: Supported Discharge Teams aim to help with the transition from hospital to home, whilst reducing hospital length-of-stay. Despite their obvious attraction, the evidence remains mixed, ranging from strong support for disease specific interventions to less favourable results for generic services. Objective: To determine whether older people referred to a Supported Discharge Team have: (i) reduced length-of-stay in hospital; (ii) reduced risk of hospital readmission; and (iii) reduced healthcare costs. Methods: Randomised controlled trial with follow-up to 6 months; 103 older women and 80 men (n = 183) (mean age 79), in hospital, were randomised to receive either Supported Discharge Team or usual care. Home-based rehabilitation was delivered by trained Health Care Assistants up to four times a day, 7 days a week, under the guidance of registered nurses, allied health and geriatricians for up to 6 weeks. Results: Participants randomised to the Supported Discharge Team spent less time in hospital during the index admission (mean 15.7 days) in comparison to usual care (mean 21.6 days) (mean difference 5.9: 95% CI 0.6, 11.3 days: P = 0.03) and spent less time in hospital in the 6 months following discharge home. Supported discharge group costs were calculated at mean NZ$10,836 (SD NZ$12,087) compared to NZ$16,943 (SD NZ$22,303) in usual care. Conclusion: A Supported Discharge Team can provide an effective means of discharging older people home early from hospital and can make a cost-effective contribution to managing increasing demand for hospital beds. PMID- 29145550 TI - A Peripapillary Defect in a Woman With Myopia. PMID- 29145549 TI - Generational Differences in the 5-Year Incidence of Age-Related Macular Degeneration. AB - Importance: Whether a reported decline in the risk of developing age-related macular degeneration (AMD) continued for people born during the Baby Boom years (1946-1964) or later is unknown. These data are important to plan for ocular health care needs in the 21st century. Objectives: To determine whether the 5 year risk for AMD declined by generation and to identify factors that contributed to improvement in risk. Design, Setting, and Participants: Data came from the longitudinal cohort Beaver Dam Eye Study (March 1, 1988, through September 15, 1990, and March 1, 1993, through June 15, 1995) and the Beaver Dam Offspring Study (June 8, 2005, through August 4, 2008, and July 12, 2010, through March 21, 2013). These population-based studies examined residents of Beaver Dam, Wisconsin, aged 43 to 84 years in 1987 through 1988 and their adult offspring aged 21 to 84 years in 2005 through 2008. A total of 4819 participants were at risk for developing AMD based on fundus images obtained at baseline visits. Data were analyzed from February 18, 2016, through June 22, 2017, with additional analyses ending September 22, 2017. Main Outcomes and Measures: Fundus images were graded for AMD using the Wisconsin Age-related Maculopathy Grading System. The incidence of AMD was defined as the presence at the 5-year follow-up examination of pure geographic atrophy or exudative macular degeneration, any type of drusen with pigmentary abnormalities, or soft indistinct drusen without pigmentary abnormalities. Results: Among the 4819 participants, the mean (SD) baseline age of the cohort was 54 (11) years; 2117 were men (43.9%) and 2702 were women (56.1%). The 5-year age- and sex-adjusted incidence of AMD was 8.8% in the Greatest Generation (born during 1901-1924), 3.0% in the Silent Generation (born during 1925-1945), 1.0% in the Baby Boom Generation (born during 1946-1964), and 0.3% in Generation X (born during 1965-1984). Adjusting for age and sex, each generation was more than 60% less likely to develop AMD than the previous generation (relative risk, 0.34; 95% CI, 0.24-0.46). The generational association (relative risk, 0.40; 95% CI, 0.28 to 0.57) remained significant after adjusting for age, sex, smoking, educational attainment, exercise, levels of non-high density lipoprotein cholesterol and high-sensitivity C-reactive protein, and use of nonsteroidal anti-inflammatory drugs, statins, and multivitamins. Conclusions and Relevance: The 5-year risk for AMD declined by birth cohorts throughout the 20th century. Factors that explain this decline in risk are not known. However, this pattern is consistent with reported declines in risks for cardiovascular disease and dementia, suggesting that aging Baby Boomers may experience better retinal health at older ages than did previous generations. PMID- 29145551 TI - Age-Related Maculopathy-Degeneration by Generation. PMID- 29145552 TI - Association Between Perceived Barriers to Diabetes Self-management and Diabetic Retinopathy in Asian Patients With Type 2 Diabetes. AB - Importance: A patient's perceived barriers to diabetes self-management (DSM) may affect his or her risk of diabetic retinopathy (DR); however, few studies have examined this association. Objective: To examine the association between perceived barriers to DSM and the severity spectrum of DR in Asian patients with type 2 diabetes. Design, Setting, and Participants: A cross-sectional clinic based study, the Singapore Diabetes Management Project, was conducted from December 28, 2010, to March 20, 2013, at the Singapore National Eye Centre, a tertiary eye care institute. After excluding patients with type 1 diabetes and ungradable fundus images, 361 participants were included in the analyses. Statistical analysis was conducted from July 20 to September 8, 2017. Exposure: The degree of perceived barriers to DSM was assessed using a 23-item questionnaire comprising items about knowledge of DSM, access to care, and confidence in health care professionals. Rasch analysis was used to optimize the scale's psychometric properties, with lower scores indicating a higher degree of self-perceived barriers. Main Outcomes and Measures: Diabetic retinopathy was graded from 2-field retinal images into categories of no DR (Early Treatment Diabetic Retinopathy Study levels 10-15; n = 154), mild to moderate DR (levels 20 43; n = 112), and severe DR (levels >=53 and/or presence of clinically significant macular edema; n = 95) using the modified Airlie House classification system of DR. Multinomial logistic regression models were used to assess the association between perceived barriers and severity of DR in the worse-affected eye. Results: Among the 361 participants (105 women and 256 men; mean [SD] age, 57 [8] years), a greater magnitude of perceived barriers to DSM was independently associated with higher odds of having any DR (odds ratio, 1.32; 95% CI, 1.06 1.66), mild to moderate DR (odds ratio, 1.30; 95% CI, 1.01-1.68), and severe DR (odds ratio, 1.36; 95% CI, 1.03-1.79). This association was independent of diabetes control (hemoglobin A1c, blood pressure, and lipid levels), presenting visual acuity, and socioeconomic indicators. Conclusions and Relevance: These results suggest that greater perceived barriers to DSM are independently associated with severity of DR. Although longitudinal data are needed, these findings suggest that evidence-based interventions to reduce patient-, practitioner-, and system-related barriers to diabetes care may help reduce the risk of DR. PMID- 29145553 TI - Tumour boards in geriatric oncology. AB - Multidisciplinary tumour board is an integral part of cancer treatment planning. Although no definite survival benefits have yet been shown by mostly observational studies, other benefits of multidisciplinary tumour board have been identified. Traditionally the multidisciplinary tumour board involves participation of treating clinicians-medical, radiation and surgical oncologists. They tend to focus on the cancer alone. There is an increasing awareness that the treatment goal for cancer in older adults is not primarily on prolonging survival, with functional preservation and quality of life being particularly important for this population. The use of Comprehensive Geriatric Assessment and the input of the geriatrician in informing the oncologists regarding treatment decision have increasingly been shown to be beneficial. The integration of the geriatrician into the multidisciplinary tumour board should be urgently explored. PMID- 29145554 TI - Prevalence and Associations of Central-Peripheral Rivalry-Type Diplopia in Patients With Epiretinal Membrane. AB - Importance: The prevalence and clinical associations of patients with epiretinal membrane (ERM) who develop central-peripheral rivalry (CPR)-type diplopia are unknown. Objectives: To determine the prevalence of CPR-type diplopia in retinal disease clinic patients with ERM and to determine clinical findings associated with CPR-type diplopia. Design, Setting and Participants: A prospective cross sectional study of 31 patients with ERM from retinal disease clinics to determine the prevalence of CPR-type diplopia. A retrospective case cohort of 25 additional patients with ERM, selected from adult strabismus clinics, was added (total = 56) to determine clinical associations with CPR-type diplopia. All data were collected between June 2014 and November 2016; prospective cohort data were collected from June 2016 to November 2016. Main Outcomes and Measures: The presence of diplopia was determined by patient history and diplopia questionnaire responses. Visual acuity and ocular alignment were recorded. Metamorphopsia was documented qualitatively by evaluation of the door frame and Amsler grid and measured quantitatively using M-charts and D-charts. Aniseikonia was determined by subjective description and results of the Awaya new aniseikonia test. Retinal misregistration testing consisted of optotype-frame test and synoptophore; CPR type diplopia was defined as diplopia associated with evidence of retinal misregistration when other causes did not fully explain diplopia. Outcomes were as follows: prevalence of CPR-type diplopia in patients with ERM seen in retinal disease clinics, and whether or not clinical findings differed between patients with ERM and CPR-type diplopia vs patients with ERM without CPR-type diplopia. Results: Of the 31 patients with ERM seen in retinal disease clinics, 16 were women and 15 were men; the mean (SD) age was 69 (10) years. The prevalence of any diplopia was 23% (7 of 31; 95% CI, 10% to 41%), with CPR-type diplopia present in 16% (5 of 31; 95% CI, 5% to 34%). For analysis of associations, 12 of 56 patients (21%) had CPR-type diplopia and 37 (66%) had no diplopia. Seven of the 56 patients were excluded for other types of diplopia. Patients with CPR-type diplopia had better worse-eye visual acuity (mean difference, -0.23; 95% CI, 0.37 to -0.09 logMAR, P = .003), and more severe quantitative metamorphopsia (mean M-score difference 0.6; 95% CI, 0.05 to 1.1, P = .01) than patients without diplopia, but similar aniseikonia (Awaya new aniseikonia test; mean difference 0.6%; 95% CI, -2.9% to 4.0%, P = .33) and similar evidence of retinal misregistration (100% vs 73%; P = .09) by any test. Conclusions and Relevance: Our findings suggest that CPR-type diplopia is not uncommon in patients with ERM. On average, patients with CPR-type diplopia have better visual acuity and more metamorphopsia than those without CPR-type diplopia, but there is considerable individual variability. Aniseikonia and retinal misregistration are similar between patients with ERM associated with CPR-type diplopia and those without CPR type diplopia. Retinal misregistration with coexistent metamorphopsia appears necessary but is not sufficient for CPR-type diplopia. PMID- 29145555 TI - From Sgt. Pepper to Dreamachines: My Scientific Odyssey With William S. Burroughs. PMID- 29145556 TI - Combination Ipilimumab and Nivolumab for Metastatic Melanoma Associated With Ciliochoroidal Effusion and Exudative Retinal Detachment. PMID- 29145558 TI - Rethinking the Growth Pattern of Thyroid Cancer in Young Patients Based on the Fukushima Database. PMID- 29145557 TI - Comparative Analysis of the Growth Pattern of Thyroid Cancer in Young Patients Screened by Ultrasonography in Japan After a Nuclear Accident: The Fukushima Health Management Survey. AB - Importance: Thyroid cancer generally grows at a very slow rate in adults, and overdiagnosis is a global issue. However, the detection of early-stage thyroid cancer by screening is not well described in young patients. To prevent overdiagnosis, it is essential to understand the natural course of thyroid cancer growth detection by ultrasonography screening in young patients. Objective: To evaluate the natural progression of thyroid cancer in young patients. Design, Setting, and Participants: An observational study evaluated changes in the diameter of malignant or suspected malignant thyroid tumors on 2 occasions. Changes in malignant thyroid tumor diameter were estimated during the observation period between the screening and confirmatory examinations in the first-round thyroid ultrasonography examination of the Fukushima Health Management Survey in patients younger than 21 years after a nuclear accident at a power plant in Fukushima, Japan. In total, 116 patients cytologically diagnosed with or suspected to have thyroid cancer were classified into 3 groups based on a greater than 10% reduction, a change of -10% to +10% in diameter, and a greater than 10% increase in tumor diameter. The association between tumor growth rate and tumor diameter was analyzed. The study was conducted from March 1, 2016, to August 6, 2017. Main Outcomes and Measures: Tumor volume changes, the coefficient of growth of thyroid cancer in young patients, and the association between the observation period or tumor diameter and them. Results: Of 116 patients, 77 were female; the mean age was 16.9 years (median, 17.5 years). The mean observation period was 0.488 (range, 0.077-1.632) years. No significant differences in age, sex, tumor diameter, observation period, or serum levels of thyrotropin and thyroglobulin were observed among the groups. Whereas tumor volume changes were not linearly correlated with the observation period (Pearson R = 0.121; 95% CI, -0.062 to 0.297), the coefficient of growth was significantly and negatively correlated with the tumor diameter in the screening examination (Spearman rho = -0.183; 95% CI, -0.354 to -0.001), suggesting growth arrest after the initial proliferation phase. Conclusions and Relevance: Ultrasonography screening could reveal asymptomatic thyroid cancer that is falling into a growth arrest pattern in many young patients. Considering the long life expectancy, prevention of overdiagnosis necessitates careful long-term monitoring without immediate diagnosis for suspected noninvasive thyroid cancer. PMID- 29145559 TI - Prenatal Alcohol Exposure and Suspected Hearing Impairment Among Children: A Population-based Retrospective Cohort Study. AB - Aims: This study aimed to examine the association between prenatal alcohol exposure and hearing impairment among Japanese children using early childhood health check-up data. Methods: This retrospective cohort study used population based health check-up data for children who were born between April 2000 and March 2013 in Hofu city, Japan. Logistic regression models were used to evaluate the association between prenatal alcohol exposure and hearing impairment among children at the age of 36 months. The models were adjusted for mother's age, smoking habit, child sex, birth weight, birth order, history of otitis media and familial history of hearing impairment. Results: Among the 16,211 registered children, 10,680 children had maternal gestational information and underwent a health check-up at the age of 36 months. A total of 10,562 children were included in the analyses, which revealed that 640 children required a re-examination for hearing impairment, 157 children required a detailed examination for hearing impairment and 83 children were receiving treatment for hearing impairment at 36 months. Prenatal alcohol exposure was independently associated with suspected hearing impairment among children after adjusting for potential confounders. Conclusions: Our findings suggest that prenatal alcohol exposure may adversely affect the auditory system of children. Short Summary: Prenatal alcohol exposure was associated with suspected hearing impairment among children at 36 months, based on the findings of a population-based retrospective cohort study that used health check-up data from 10,562 Japanese children. PMID- 29145560 TI - Strategies to Achieve High-Value Oncology Care-A Beginning. PMID- 29145562 TI - Ulcerative Colitis Endoscopic Index of Severity is Feasible and Useful for Evaluation of Endoscopic Activity in Ulcerative Colitis Patients in a Real-life Setting. PMID- 29145561 TI - Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial. AB - Background: CD73 is an ecto-enzyme that promotes tumor immune escape through the production of immunosuppressive extracellular adenosine in the tumor microenvironment. Several CD73 inhibitors and adenosine receptor antagonists are being evaluated in phase I clinical trials. Patients and methods: Full-face sections from formalin-fixed paraffin-embedded primary breast tumors from 122 samples of triple-negative breast cancer (TNBC) from the BIG 02-98 adjuvant phase III clinical trial were included in our analysis. Using multiplex immunofluorescence and image analysis, we assessed CD73 protein expression on tumor cells, tumor-infiltrating leukocytes and stromal cells. We investigated the associations between CD73 protein expression with disease-free survival (DFS), overall survival (OS) and the extent of tumor immune infiltration. Results: Our results demonstrated that high levels of CD73 expression on epithelial tumor cells were significantly associated with reduced DFS, OS and negatively correlated with tumor immune infiltration (Spearman's R= -0.50, P < 0.0001). Patients with high levels of CD73 and low levels of tumor-infiltrating leukocytes had the worse clinical outcome. Conclusions: Taken together, our study provides further support that CD73 expression is associated with a poor prognosis and reduced anti-tumor immunity in human TNBC and that targeting CD73 could be a promising strategy to reprogram the tumor microenvironment in this BC subtype. PMID- 29145564 TI - Incorrect Percentages in the Abstract. PMID- 29145565 TI - Outcome prediction in patients with localized soft tissue sarcoma: which tool is the best? PMID- 29145566 TI - Vision Loss Associated With the Opioid Epidemic. PMID- 29145563 TI - Neuronal Dnmt1 Deficiency Attenuates Diet-Induced Obesity in Mice. AB - Aberrant neuronal DNA methylation patterns have been implicated in the promotion of obesity development; however, the role of neuronal DNA methyltransferases (Dnmts), enzymes that catalyze DNA methylation, in energy balance remains poorly understood. We investigated whether neuronal Dnmt1 regulates normal energy homeostasis and obesity development using a neuronal Dnmt1 knockout (ND1KO) mouse model, Dnmt1fl/fl Synapsin1Cre, which specifically deletes Dnmt1 in neurons. Neuronal Dnmt1 deficiency reduced adiposity in chow-fed mice and attenuated obesity in high-fat diet (HFD)-fed male mice. ND1KO male mice had reduced food intake and increased energy expenditure with the HFD. Furthermore, these mice had improved insulin sensitivity, as measured using an insulin tolerance test. The HFD-fed ND1KO mice had smaller fat pads and upregulation of thermogenic genes in brown adipose tissue. These data suggest that neuronal Dnmt1 plays an important role in regulating energy homeostasis. Notably, ND1KO male mice had elevated estrogen receptor-alpha (ERalpha) gene expression in the medial hypothalamus, which previously has been shown to control body weight. Immunohistochemistry experiments revealed that ERalpha protein expression was upregulated specifically in the dorsomedial region of the ventromedial hypothalamus, a region that might mediate the central effect of leptin. We conclude that neuronal Dnmt1 regulates energy homeostasis through pathways controlling food intake and energy expenditure. In addition, ERalpha expression in the dorsomedial region of the ventromedial hypothalamus might mediate these effects. PMID- 29145567 TI - Influence of Airflow Rate and Stimulus Concentration on Olfactory Event-Related Potentials (OERP) in Humans. AB - Although the association between odor concentration and olfactory event-related potential (OERP) has been studied, less is known about the influence of airflow on OERP. The aim of this study was to investigate the influence of airflow rate and stimulus concentration on OERP in humans. Electroencephalogram data were collected from young healthy volunteers (n = 17) in separate sessions where 2 phenylethanol (PEA) was delivered in the following conditions: 8 L/min 50% v/v, 8 L/min 30% v/v, 4 L/min 100% v/v, and 4 L/min 60%v/v. Odor concentrations are referred to the %v/v achieved with air dilution and was not measured in the nose. Odor intensity ratings were recorded immediately after stimulus presentation. Data recorded at 5 electrodes (Fz, Cz, Pz, C3, and C4) were pooled and analyzed using both time-domain averaging and single-trial time-frequency domain approaches. Higher airflow rate significantly increased intensity ratings (F = 10.98, P < 0.01), and improved the signal-to-noise-ratio (F = 5.42, P = 0.025). Results from time-frequency analysis showed higher concentration versus lower concentration increased brain oscillations in the slow frequency band (1-3 Hz) at 0-600 ms; while higher airflow rates versus lower airflow rate increased theta band oscillations (300-600 ms and 5-9 Hz) and decreased delta-band oscillations at 900-1500 ms after stimulus onset. In conclusion, compared to stimulus concentration, airflow rate was associated with improved OERP quality and more pronounced responses. The results suggest that intensity ratings and OERP are strongly related to the steepness of stimulus onset. High airflow rates are suggested for odor delivery in order to record OERP. PMID- 29145568 TI - Seasonal Influenza Vaccine Effectiveness in Preventing Laboratory-Confirmed Influenza in Primary Care in Israel, 2016-2017 Season: Insights Into Novel Age Specific Analysis. AB - Background: The 2016-2017 influenza season in Israel was dominated by the circulation of influenza A(H3N2). Influenza vaccine is recommended for the entire population in Israel aged >6 months. The inactivated influenza vaccine was chosen for use this season. Methods: We estimated the 2016-2017 end-of-season influenza vaccine effectiveness (VE) in preventing influenza-like illness due to influenza A(H3N2), using the test-negative design. Age-specific VE was estimated using a moving age window and weekly analysis. Results: During the 2016-2017 season, 1267 samples were collected; 467 (36.9%) were positive for influenza, with 97.9% A(H3N2), 0.2% A(H1N1)pdm09, and 1.9% B. A total of 1088 individuals were found eligible to be included in VE assessment. All vaccinated individuals included in the VE assessment received the inactivated influenza vaccine. Adjusted VE against influenza A(H3N2) was 29.0% (95% confidence interval [CI], 0.3%-49.5%). Age group specific adjusted VE was 69.2% (95% CI, 19.4%-88.3%) for children aged 5-17 years and 58.8% (95% CI, .8%-82.9%) for adults aged 45-64 years. Other age groups demonstrated lower VE estimates that were not statistically significant. Adjusted VE estimates using a moving window of 15 years and weekly VE analyses provided a more defined understanding of age-specific VE during the 2016-2017 season. Conclusions: Estimating VE using a moving age window as well as weekly VE analysis may provide more detailed information regarding the relationship between VE and age. PMID- 29145570 TI - Tooth wear and gingival recession in 210 orthodontically treated patients: a retrospective cohort study. AB - Aim: To assess the association between tooth wear (TW) and gingival recession (GR). Materials and Methods: Two hundred and ten orthodontically treated participants (100 males) were evaluated. GR and TW were rated independently by four raters on plaster models at four time points: before treatment (T1), mean age 13.8 years (SD = 3.7); after treatment (T2), mean age 16.7 years (SD = 3.9); 3 years after treatment (T3), mean age 19.7 years (SD = 4.2); and 7 years after treatment (T4), mean age 23.9 years (SD = 4.8). Univariable and mulitvariable random effects logistic regression analyses were performed with scores for GR as dependent variables and with TW, age, gender, dental segments (maxillary and mandibular anterior and posterior segments), time points, and Angle classification as independent variables. Method reliability was assessed with kappa statistics. Results: Mandibular incisors, mandibular and maxillary first premolars and maxillary first molars were most vulnerable to GR. The prevalence of GR increased during the observation period. At T1 20.5% participants had one or more recession sites, at T4 85.7 % of the participants had at least one GR. There was evidence of association between moderate/severe TW and GR-for a tooth with moderate/severe wear, the odds of recession were 23% higher compared to a tooth with no/mild wear (odds ratio 1.23; 95% CI: 1.08-1.40; P = 0.002). Age, dental segment, and time were also significant recession predictors, whereas gender was not. Conclusions: There is evidence that moderate/severe TW is associated with the presence of gingival recession. Clinical significance of this can be limited. PMID- 29145571 TI - Commentary on: Paradoxical Adipose Hypertrophy (PAH) After Cryolipolysis. PMID- 29145569 TI - Immune System: An Emerging Player in Mediating Effects of Endocrine Disruptors on Metabolic Health. AB - The incidence of metabolic disorders like type 2 diabetes and obesity continues to increase. In addition to the well-known contributors to these disorders, such as food intake and sedentary lifestyle, recent research in the exposure science discipline provides evidence that exposure to endocrine-disrupting chemicals like bisphenol A and phthalates via multiple routes (e.g., food, drink, skin contact) also contribute to the increased risk of metabolic disorders. Endocrine disrupting chemicals (EDCs) can disrupt any aspect of hormone action. It is becoming increasingly clear that EDCs not only affect endocrine function but also adversely affect immune system function. In this review, we focus on human, animal, and in vitro studies that demonstrate EDC exposure induces dysfunction of the immune system, which, in turn, has detrimental effects on metabolic health. These findings highlight how the immune system is emerging as a novel player by which EDCs may mediate their effects on metabolic health. We also discuss studies highlighting mechanisms by which EDCs affect the immune system. Finally, we consider that a better understanding of the immunomodulatory roles of EDCs will provide clues to enhance metabolic function and contribute toward the long-term goal of reducing the burden of environmentally induced diabetes and obesity. PMID- 29145572 TI - Differences in Clinical Course, Genetics, and the Microbiome Between Familial and Sporadic Inflammatory Bowel Diseases. AB - Background and Aim: Family history is the strongest risk factor for developing Crohn's disease [CD] or ulcerative colitis [UC]. We investigated whether the proximity of relationship with the affected relative and concordance for type of inflammatory bowel disease [IBD] modifies the effect of family history on phenotype and disease severity. Method: This cross-sectional study included patients with a confirmed diagnosis of IBD in a clinical registry. Family history of IBD was assessed by a questionnaire ascertaining presence of disease in a first-first-degree, second-second-degree or distant relative. Our primary outcomes were disease phenotype as per the Montreal classification and severity measured by need for immunomodulator, biologic, or surgical therapy. Genotyping was performed on the Immunochip and faecal samples were subjected to 16S rRNA microbiome sequencing. Results: Our study included 2136 patients with IBD [1197 CD, 939 UC]. Just under one-third [32%] of cases ere familial IBD [17% first degree, 21% second-degree]. Familial IBD was diagnosed at an earlier age, both in CD [26 vs 28 years, p = 0.0006] and UC [29 vs 32 years, p = 0.01]. Among CD patients, a positive family history for CD was associated with an increased risk for complicated disease in the presence of an affected family member (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.07-2.03). However, this effect was significant only for first-degree relatives [OR 1.82, 95% CI 1.19-2.78]. Conclusions: A family history of CD in first-degree relatives was associated with complicated CD. Family history discordant for type of IBD or in distant relatives did not influence disease phenotype or natural history. PMID- 29145574 TI - Rethinking Extended Adjuvant Antiestrogen Therapy to Increase Survivorship in Breast Cancer. PMID- 29145573 TI - Human papillomavirus (HPV) and somatic EGFR mutations are essential, mutually exclusive oncogenic mechanisms for inverted sinonasal papillomas and associated sinonasal squamous cell carcinomas. AB - Background: Inverted sinonasal (Schneiderian) papilloma (ISP) is a locally aggressive neoplasm often associated with sinonasal squamous cell carcinoma (SNSCC). While the etiology of ISP is not well understood, human papillomavirus (HPV) has been detected in a subset of cases. Our group recently identified activating somatic EGFR mutations in the majority of ISP and ISP-associated SNSCC. However, the relationship between EGFR mutations and HPV infection has not been explored. Patients and methods: We evaluated 58 ISP and 22 ISP-associated SNSCC (including 13 patients with matched ISP/SNSCC samples), as well as 14 SNSCC without clinical or pathologic evidence of an associated ISP. Formalin-fixed, paraffin-embedded samples were evaluated for EGFR mutations using Sanger sequencing and for HPV infection using GP5+/GP6+ PCR. HPV subtyping based on the L1 sequence was done for HPV positive cases including temporally distinct tumors for four patients. Clinicopathologic data including progression free survival was also analyzed. Results: All ISP and ISP-associated SNSCC demonstrated either an EGFR mutation or HPV infection. HPV and EGFR mutation were mutually exclusive in all cases of ISP-associated SNSCC and all but one ISP; this case was only weakly HPV positive, and analysis of a prior temporally distinct ISP specimen from this patient failed to show HPV infection, suggesting transient infection/incidental colonization. HPV subtypes in ISP and ISP-associated SNSCC were predominantly low risk, in contrast with SNSCC without ISP association, which showed frequent high risk HPV. All paired ISP and associated SNSCC samples demonstrated concordant HPV status and EGFR genotypes. ISP progression to SNSCC was significantly associated with the presence of HPV infection and the absence of an EGFR mutation (log-rank = 9.620, P = 0.002). Conclusions: Collectively our data show that EGFR mutations and HPV infection represent essential, alternative oncogenic mechanisms in ISP and ISP-associated SNSCC. PMID- 29145575 TI - Validity of the Somatic Symptom Disorder-B Criteria Scale (SSD-12) in primary care. AB - Aim: The Somatic Symptom Disorder-B Criteria Scale (SSD-12) assesses the psychological features of DSM-5 somatic symptom disorder. The purpose of the current study was to investigate the psychometric characteristics and validity of the 12-item instrument to demonstrate its suitability in primary care. Method: The study was designed as a cross-sectional survey set in five primary care practices from Munich, Germany (n = 501, 52.0% female, mean age 47 +/- 16 years). Item and scale characteristics, as well as measures of reliability and validity, were determined. Results: The SSD-12 has good item characteristics and excellent reliability (Cronbach's alpha = 0.92). Confirmatory factor analyses provided evidence to support a general factor model of the SSD-12 in primary care (comparative fit index > 0.98, Tucker-Lewis index > 0.98, root mean square error of approximation = 0.090, 90% confidence interval: 0.078-0.102). SSD-12 total sum score was significantly associated with somatic symptom burden (r = 0.48, P < 0.001), general anxiety (r = 0.54, P < 0.001) and depressive symptoms (r = 0.60, P < 0.001). At the group level, SSD-12 scores could differentiate between different patient groups (e.g. with and without chronic illness). Conclusions: The SSD-12 appears to be a reliable, valid and time-efficient self-report measure of the psychological characteristics related to the experience of somatic symptoms which is suitable for primary care. Future research should evaluate its responsiveness to treatment and feasibility as a screening tool in different clinical settings. PMID- 29145576 TI - Different Filling Patterns of the Choriocapillaris in Fluorescein and Indocyanine Green Angiography in Primate Eyes Under Elevated Intraocular Pressure. AB - Purpose: To investigate the hemodynamics of the choriocapillaris in primate eyes under elevated intraocular pressure. Methods: Indocyanine green angiography (ICGA) and fluorescein angiography (FA) were performed in two monkeys after elevation of the intraocular pressure (IOP) to 35 and 60 mm Hg. Results: ICGA and FA showed no perfusion delays in the choriocapillaris at 35 mm Hg. The slow dye filling at 60 mm Hg made it possible to observe the early phase angiography sequence. During ICGA, C-shaped precapillary arterioles multiplied in numbers and emerged in the posterior pole, forming the outer rim of the numerous mosaics or lobules. Dye subsequently infiltrated into the lobules. During FA, after numerous hyperfluorescent spots emerged in the posterior pole, each of the spots enlarged and became numerous mosaics with a dark outer rim. When the FA and ICGA images were superimposed, the C-shaped arterioles observed during the ICGA were shown to correspond to the outer dark rim of the mosaics seen during the FA. The earliest dye emergence was delayed during FA compared to ICGA, with 13 seconds elapsing in monkey 1 and 4 seconds in monkey 2. The horizontal diameter of the optic disc contained three to four mosaics in both monkeys. Conclusions: The choriocapillaris lobules appear to be supplied from peripheral arterioles, not central. After blood perfuses the lobules, it drains into the venules at the center. Mosaic or lobular patterns during FA may reflect extravasated fluorescein from the fenestrated choriocapillaris. PMID- 29145577 TI - Photodynamic Therapy Leads to Time-Dependent Regression of Pathologic Corneal (Lymph) Angiogenesis and Promotes High-Risk Corneal Allograft Survival. AB - Purpose: Pathologic corneal (lymph) angiogenesis is a known risk factor for immune-mediated allograft rejections after corneal transplantation. However, there is no established treatment to regress pre-existing pathological corneal blood and lymphatic vessels. This study assessed the possibility to regress both vessel types by photodynamic therapy (PDT) after intravenous (i.v.) verteporfin injection, the influence of timing of PDT after verteporfin injection, and the effect on graft survival in high-risk keratoplasty. Methods: BALB/c mice were used for suture-induced inflammatory corneal neovascularization to induce combined hem- and lymphangiogenesis. The treated group received PDT 3 minutes, 1 hour, and 24 hours after an i.v. verteporfin injection (control group: phosphate buffered saline). Corneal flatmounts were excised 3 days, 1 week, and 2 weeks after corneal PDT and stained with cluster of differentiation 31 (CD31) and lymphatic vessel endothelial hyaluronan receptor 1 antibodies (LYVE-1) to quantify hem- and lymphangiogenesis. Graft survival rates were compared between high-risk recipients with and without preoperative PDT. Results: Corneal blood vessels were significantly reduced when PDT was performed 3 minutes after i.v. verteporfin injection, whereas lymphatic vessels showed no significant difference. Both blood and lymphatic vessels were regressed when PDT was performed 1 hour or 24 hours after i.v. verteporfin application. Long-term allograft survival increased significantly in PDT-pretreated eyes when compared with controls. Conclusions: PDT after i.v. verteporfin injection can selectively regress pre-existing corneal blood vessels or both blood and lymphatic vessels depending on the timing of PDT after verteporfin injection. The pretreatment of recipients with PDT and i.v. verteporfin might be a promising new method to improve graft survival in high-risk eyes. PMID- 29145578 TI - The Changing Paradigm of Management of Liver Abscesses in Chronic Granulomatous Disease. AB - Background: Chronic granulomatous disease (CGD) is a rare genetic disorder causing recurrent infections. More than one-quarter of patients develop hepatic abscesses and liver dysfunction. Recent reports suggest that disease-modifying treatment with corticosteroids is effective for these abscesses. Comparison of corticosteroid therapy to traditional invasive treatments has not been performed. Methods: Records of 268 patients with CGD treated at the National Institutes of Health from 1980 to 2014 were reviewed. Patients with liver involvement and complete records were included. We recorded residual reactive oxygen intermediate (ROI) production by neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase germline mutation status, laboratory values, imaging characteristics, time to repeat hepatic interventions, and overall survival among 3 treatment cohorts: open liver surgery (OS), percutaneous liver-directed interventional radiology therapy (IR), and high-dose corticosteroid management (CM). Results: Eighty-eight of 268 patients with CGD suffered liver involvement. Twenty-six patients with a median follow-up of 15.5 years (8.5-32.9 years of follow-up) had complete records and underwent 100 standard interventions (42 IR and 58 OS). Eight patients received a treatment with high-dose corticosteroids only. There were no differences in NADPH genotype, size, or number of abscesses between patients treated with OS, IR, or CM. Time to repeat intervention was extended in OS compared with IR (18.8 vs 9.5 months, P = .04) and further increased in CM alone (median time to recurrence not met). Impaired macrophage and neutrophil function measured by ROI production correlated with shorter time to repeat intervention (r = 0.6, P = .0019). Conclusions: Treatment of CGD associated liver abscesses with corticosteroids was associated with fewer subsequent hepatic interventions and improved outcome compared to invasive treatments. PMID- 29145579 TI - Progesterone, the maternal immune system and the onset of parturition in the mouse. AB - The role of progesterone (P4) in the regulation of the local (uterine) and systemic innate immune system, myometrial expression of connexin 43 (Cx-43) and cyclooxygenase 2 (COX-2), and the onset of parturition was examined in (i) naive mice delivering at term; (ii) E16 mice treated with RU486 (P4-antagonist) to induce preterm parturition; and (iii) in mice treated with P4 to prevent term parturition. In naive mice, myometrial neutrophil and monocyte numbers peaked at E18 and declined with the onset of parturition. In contrast, circulating monocytes did not change and although neutrophils were increased with pregnancy, they did not change across gestation. The myometrial mRNA and protein levels of most chemokines/cytokines, Cx-43, and COX-2 increased with, but not before, parturition. With RU486-induced parturition, myometrial and systemic neutrophil numbers increased before and myometrial monocyte numbers increased with parturition only. Myometrial chemokine/cytokine mRNA abundance increased with parturition, but protein levels peaked earlier at between 4.5 and 9 h post-RU486. Cx-43, but not COX-2, mRNA expression and protein levels increased prior to the onset of parturition. In mice treated with P4, the gestation-linked increase in myometrial monocyte, but not neutrophil, numbers was prevented, and expression of Cx-43 and COX-2 was reduced. On E20 of P4 supplementation, myometrial chemokine/cytokine and leukocyte numbers, but not Cx-43 and COX-2 expression, increased. These data show that during pregnancy P4 controls myometrial monocyte infiltration, cytokine and prolabor factor synthesis via mRNA-dependent and independent mechanisms and, with prolonged P4 supplementation, P4 action is repressed resulting in increased myometrial inflammation. PMID- 29145580 TI - Effect of Botulinum Toxin A on Muscle Healing and its Implications in Aesthetic and Reconstructive Surgery. AB - Background: Muscle activity contributes to the enhancement of facial aging deformity, blepharospasm, cerebral palsy spasticity, trismus, torticollis, and other conditions. Myotomy of the involved muscles in order to reduce the deformity has variable success rates due to muscle healing and regeneration of activity. Objectives: The goal of this study was to investigate whether blocking striated muscle activity with Botulinum toxin (BtxA) during the healing time after myotomy alters the healing process and reduces long-term muscle activity. Methods: Eighteen Sprague Dawley rats where divided into 3 groups: group A (n = 7) underwent myotomy of their Latisimus Dorsi muscle; group B (n = 7) underwent myotomy and injection of BtxA into their severed muscle; group C (n = 4) injection of BtxA only. Muscle strength was tested periodically using a grip test. Results: Starting at week 16 and until the termination of study at week 22, group B (Myotomy + BtxA) showed significant reduction in muscle power compared to the two control groups. Conclusions: Addition of BtxA injection into a muscle immediately after myotomy may interfere with muscle healing and contribute to a more successful long-term result. PMID- 29145582 TI - Observed Pneumococcal Carriage Among Alaska Native Children Who Received Reduced Dose Schedules of 13-Valent Pneumococcal Conjugate Vaccine Between 2010 and 2012. PMID- 29145581 TI - Prospective Epidemiological Research Studies in Iran (the PERSIAN Cohort Study): Rationale, Objectives, and Design. AB - Noncommunicable diseases (NCDs) account for 76% of deaths in Iran, and this number is on the rise, in parallel with global rates. Many risk factors associated with NCDs are preventable; however, it is first necessary to conduct observational studies to identify relevant risk factors and the most appropriate approach to controlling them. Iran is a multiethnic country; therefore, in 2014 the Ministry of Health and Medical Education launched a nationwide cohort study Prospective Epidemiological Research Studies in Iran (PERSIAN)-in order to identify the most prevalent NCDs among Iran's ethnic groups and to investigate effective methods of prevention. The PERSIAN study consists of 4 population-based cohorts; the adult component (the PERSIAN Cohort Study), described in this article, is a prospective cohort study including 180,000 persons aged 35-70 years from 18 distinct areas of Iran. Upon joining the cohort, participants respond to interviewer-administered questionnaires. Blood, urine, hair, and nail samples are collected and stored. To ensure consistency, centrally purchased equipment is sent to all sites, and the same team trains all personnel. Routine visits and quality assurance/control measures are taken to ensure protocol adherence. Participants are followed for 15 years postenrollment. The PERSIAN study is currently in the enrollment phase; cohort profiles will soon emerge. PMID- 29145583 TI - Association Between the Severity of Diabetic Retinopathy and Falls in an Asian Population With Diabetes: The Singapore Epidemiology of Eye Diseases Study. AB - Importance: The presence and severity of diabetic retinopathy (DR) may contribute to the risk of falling in persons with diabetes, but evidence is currently equivocal. Objective: To investigate the associations of diabetes and DR severity with the likelihood of falls in a multiethnic Asian population. Design, Setting, and Participants: Cross-sectional post hoc analysis of the Singapore Epidemiology of Eye Diseases study, a population-based study of participants from 3 ethnic groups (3280 Malay, 3400 Indian, and 3353 Chinese individuals) conducted from 2004 to 2011. Of these participants, 552 had data missing on diabetes, falls history, or other covariates or had ungradable fundus photographs and were excluded, leaving 9481 participants. These 9481 underwent a standardized clinical examination and responded to an interviewer-administered questionnaire that collected clinical and sociodemographic information. Multivariable logistic regression models adjusted for confounding fall risk factors assessed the associations of falls with diabetes, DR, and DR severity. A trend analysis was conducted in participants with diabetes to assess if risk of falling was associated with DR severity. Data were analyzed from January 1 through April 30, 2017. Exposures: Diabetes was defined as a random glucose level of at least 200 mg/dL, hemoglobin A1c concentration of at least 6.5% of total hemoglobin, self reported use of diabetic medication, or history of physician-diagnosed diabetes. Severity of DR was graded as none, minimal, mild, moderate, and vision threatening (VT). Main Outcomes and Measures: A self-reported fall occurring in the previous 12 months, when the participant fell and landed on the ground. Results: Of the 9481 participants with a mean (SD) age of 58.7 (10.3) years (4781 women [50.4%]), 6612 (69.7%) had no diabetes and 2869 (30.3%) had diabetes, of whom 857 (29.9%) had DR in at least 1 eye. A history of falls was reported in 872 (13.2%) without diabetes, 328 (16.3%) with no DR, 44 (14.2%) with minimal DR, 54 (26.2%) with mild DR, 34 (27.2%) with moderate DR, and 43 (19.9%) with VTDR (P for trend < .001). In multivariable models, those with DR were more likely to have fallen (odds ratio [OR], 1.31; 95% CI, 1.07-1.60; P = .008) compared with those with no diabetes; no associations were found for participants without DR compared with those with no diabetes. In addition, compared with participants with diabetes but without DR, those with mild (OR, 1.81; 95% CI, 1.23-2.67; P = .003) and moderate (OR, 1.89; 95% CI, 1.16-3.07; P = .01) nonproliferative DR were more likely to have fallen. Having VTDR was not independently associated with a higher likelihood of falling. Conclusions and Relevance: The presence of mild to moderate nonproliferative DR was independently associated with an increased likelihood of falling in persons with diabetes compared with persons with diabetes but without DR. Management strategies for diabetes should incorporate fall education and prevention information, particularly in patients with early-stage DR. Longitudinal studies exploring the association between mild to moderate nonproliferative DR and falling will be required to confirm these findings. PMID- 29145587 TI - Paradoxical Adipose Hypertrophy (PAH) After Cryolipolysis. AB - Background: Cryolipolysis is a minimally invasive technique used to decrease local adipose tissue by thermal cooling. Paradoxical adipose hypertrophy (PAH) is a rare complication of cryolipolysis with important aesthetic consequences. Objectives: The objective of this study was to describe four cases of PAH after a cryolipolysis treatment. Methods: Between January 2014 and January 2017, all patients who had undergone a cryolipolysis treatment in a single center were reviewed. The device used was a CoolSculpting device and the same operator performed all the cryolipolysis treatments. We retrospectively included all patients who had a suspicion of PAH. Results: In our study, 398 patients underwent a session of cryolipolysis. Four patients presented with a voluminous painless swelling in the treated area, between 2 and 4 months after the cryolipolysis session. One patient was treated with liposuction. Histological analysis of the adipose tissue in this patient revealed a nonspecific panniculitis. The other three patients did not receive any additional treatment, and their symptoms stabilized after several months. Conclusions: Although cryolipolysis generally yields good results, it can be complicated with PAH, which tends to occur a few months after the cryolipolysis treatment. Patients should be informed of the possibility of developing this complication and encouraged to attend regular follow up for at least 6 months, so that this condition can be readily detected. Surgical treatment should be offered if there is no spontaneous improvement of the symptoms. Level of Evidence 5: PMID- 29145584 TI - Critical Lessons From High-Value Oncology Practices. AB - Importance: Cancer care is expensive. Cancer care provided by practice organizations varies in total spending incurred by patients and payers during treatment episodes and in quality of care, and this unnecessary variation contributes to the high cost. Objective: To use the variation in total spending and quality of care to assess oncology practice attributes distinguishing "high value" that may be tested and adopted by others to produce similar results. Design, Setting, and Participants: "Positive deviance" was used in this exploratory mixed-methods (quantitative and qualitative) analysis of interview results. To quantify value, oncology practices located near the US Pacific Northwest and Midwest with low mean insurer-allowed spending were identified. Among those, practices with high quality were selected. A team then conducted site visits to interview practice personnel from June 2, 2015, through October 3, 2015, and to probe for attributes of high-value care. A qualitative analysis of their interview results was performed, and a panel of experienced oncologists was convened to review attributes occurring uniquely or frequently in low-spending practices for their contribution to value improvement and ease of implementation. Four positive deviant (ie, low-spending) oncology practices and 3 oncology practices that ranked near the middle of the spending distribution were studied. Main Outcomes and Measures: Thematic saturation in a qualitative analysis of high value care attributes. Results: From the 7 oncology practices studied, 13 attributes within the following 5 themes emerged: treatment planning and goal setting, services supporting the patient journey, technical support and physical layout, care team organization and function, and external context. Five attributes (ie, conservative use of imaging, early discussion of treatment limitations and consequences, single point of contact, maximal use of registered nurses for interventions, and a multicomponent health care system) most sharply distinguished the high-value practice sites. The expert oncologist panel judged 3 attributes (ie, early and normalized palliative care, ambulatory rapid response, and early discussion of treatment limitations and consequences) to carry the highest immediate potential for lowering spending without compromising the quality of care. Conclusions and Relevance: Oncology practice attributes warranting further testing were identified that may lower total spending for high quality oncology care. PMID- 29145588 TI - The perspectives of pre-frail and frail older people on being advised about exercise: a qualitative study. AB - Background: Exercise is considered to be the most effective strategy to treat, prevent and delay frailty, a prevalent geriatric syndrome observed in clinical practice. Encouraging frail older people to take up exercise is crucial in the management of this condition. The study aimed to explore pre-frail and frail older peoples' perspectives in relation to being advised about exercise and their perceptions of the general practitioners' (GPs) role in promoting exercise for older people. Methods: Semi-structured interviews were conducted with 12 community-dwelling older (median age 83 years) participants screened pre-frail or frail using the FRAIL Screen. Their attitudes towards exercise, the advice received, their access to relevant information and their perceptions of the GP's role in promoting exercise were explored. Thematic analysis was conducted to analyse data. Results: The majority of participants had a positive attitude towards exercise, and many participants indicated a preference for being advised firstly by their GPs and then other healthcare professionals. Participants living in the community reported difficulties in accessing information on exercise and indicated that local governments and GP practices should promote exercise for older people more actively. Participants living in retirement villages, however, reported having access to relevant information and being encouraged to participate in exercise. Conclusion: This research identified a gap in current practice, demonstrating that GPs, healthcare providers and local governments should promote exercise for older people more actively. Convincing health professionals to encourage regular exercise among their older patients would provide an opportunity to avoid and manage frailty in this population. PMID- 29145589 TI - Featured Article: The ABCDs of Pain Management: A Double-Blind Randomized Controlled Trial Examining the Impact of a Brief Educational Video on Infants' and Toddlers' Pain Scores and Parent Soothing Behavior. AB - Objectives: To test the efficacy of a brief behavioral pain management strategy (The ABCDs of Needle Pain Management), delivered via video, on infants' and toddlers' pain scores and on parental soothing behavior. Methods: This was a double-blind, parallel trial design. Parent-child dyads (N = 128) were recruited before their child's 6-month (infant) or 18-month (toddler) vaccination in a pediatric clinic and randomly assigned to watch a 5-min treatment video or a placebo video. The primary outcome was the Modified Behavior Pain Scale (Taddio et al., Journal of Pain and Symptom Management, 10, pp. 456-463, 1995), coded during four epochs (Pain Reactivity, Pain Regulation 1 min, Pain Regulation 2 min, and Pain Regulation 3 min) after the last vaccination needle. Secondary analyses examined parental use of distraction, rocking, and physical comforting over this same time period. Results: Results demonstrated a treatment effect for toddlers (18-month-olds) for the Pain Regulation 1 (d = 0.84) and Pain Regulation 2 (d = 0.76) postvaccination scores. Secondary analyses found differences in parental rocking and physical comforting between treatment conditions and between age-groups (d's = 0.37-0.54). Conclusions: The ABCD pain management strategy delivered via video was an effective way to reduce toddler pain after vaccination and increase parental use of rocking and physical comforting. The treatment effect was not demonstrated with infants. PMID- 29145590 TI - Who uses foodbanks and why? Exploring the impact of financial strain and adverse life events on food insecurity. AB - Background: Rising use of foodbanks highlights food insecurity in the UK. Adverse life events (e.g. unemployment, benefit delays or sanctions) and financial strains are thought to be the drivers of foodbank use. This research aimed to explore who uses foodbanks, and factors associated with increased food insecurity. Methods: We surveyed those seeking help from front line crisis providers from foodbanks (N = 270) and a comparison group from Advice Centres (ACs) (N = 245) in relation to demographics, adverse life events, financial strain and household food security. Results: About 55.9% of foodbank users were women and the majority were in receipt of benefits (64.8%). Benefit delays (31.9%), changes (11.1%) and low income (19.6%) were the most common reasons given for referral. Compared to AC users, there were more foodbank users who were single men without children, unemployed, currently homeless, experiencing more financial strain and adverse life events (P = 0.001). Food insecurity was high in both populations, and more severe if they also reported financial strain and adverse life events. Conclusions: Benefit-related problems appear to be a key reason for foodbank referral. By comparison with other disadvantaged groups, foodbank users experienced more financial strain, adverse life events, both increased the severity of food insecurity. PMID- 29145591 TI - Asia Consensus Statement on NCCN Clinical Practice Guideline for bladder cancer. AB - The Asia Consensus Statement (ACS) on the NCCN Guideline (NCCN-ACS) for treatment of bladder cancer version 1.2016 is designed to provide documentation of modifications of the 'parent' NCCN Guideline: Bladder Cancer (Version 2.2015). When considering ethnic differences or differences in health regulatory environments between Western and Asian countries, a process of adaptation to match the circumstances is helpful for utilizing the guidelines. The NCCN-ACS for bladder cancer consist of 11 ACSs, focused on diagnosis, imaging, surgical treatment, adjuvant intravesical chemotherapy or immunotherapy, periopererative (neodjuvant or adjuvant) chemotherapy and radiation oncology including bladder preservation. This mini-review will briefly summarize the bladder cancer version 1.2016 of the NCCN-ACS. PMID- 29145592 TI - Soil bacterial community responses to altered precipitation and temperature regimes in an old field grassland are mediated by plants. AB - The structure and function of soil microbiomes often change in response to experimental climate manipulations, suggesting an important role in ecosystem feedbacks. However, it is difficult to know if microbes are responding directly to environmental changes or are more strongly impacted by plant responses. We investigated soil microbial responses to precipitation and temperature manipulations at the Boston-Area Climate Experiment in Massachusetts, USA, in both vegetated and bare plots to parse direct vs. plant-mediated responses to multi-factor climate change. We assessed the bacterial community in vegetated soils in 2009, two years after the experiment was initiated, and bacterial and fungal community in vegetated and bare soils in 2011. The bacterial community structure was significantly changed by the treatments in vegetated soils. However, such changes in the bacterial community across the treatments were absent in the 2011 bare soils. These results suggest that the bacterial communities in vegetated soils were structured via plant community shifts in response to the abiotic manipulations. Co-variation between bacterial community structure and temperature sensitivities and stoichiometry of potential enzyme activities in the 2011 vegetated soils suggested a link between bacterial community structure and ecosystem function. This study emphasizes the importance of plant-soil-microbial interactions in mediating responses to future climate change. PMID- 29145593 TI - Root respiratory burst oxidase homologue-dependent H2O2 production confers salt tolerance on a grafted cucumber by controlling Na+ exclusion and stomatal closure. AB - Plant salt tolerance can be improved by grafting onto salt-tolerant rootstocks. However, the underlying signaling mechanisms behind this phenomenon remain largely unknown. To address this issue, we used a range of physiological and molecular techniques to study responses of self-grafted and pumpkin-grafted cucumber plants exposed to 75 mM NaCl stress. Pumpkin grafting significantly increased the salt tolerance of cucumber plants, as revealed by higher plant dry weight, chlorophyll content and photochemical efficiency (Fv/Fm), and lower leaf Na+ content. Salinity stress resulted in a sharp increase in H2O2 production, reaching a peak 3 h after salt treatment in the pumpkin-grafted cucumber. This enhancement was accompanied by elevated relative expression of respiratory burst oxidase homologue (RBOH) genes RbohD and RbohF and a higher NADPH oxidase activity. However, this increase was much delayed in the self-grafted plants, and the difference between the two grafting combinations disappeared after 24 h. The decreased leaf Na+ content of pumpkin-grafted plants was achieved by higher Na+ exclusion in roots, which was driven by the Na+/H+ antiporter energized by the plasma membrane H+-ATPase, as evidenced by the higher plasma membrane H+-ATPase activity and higher transcript levels for PMA and SOS1. In addition, early stomatal closure was also observed in the pumpkin-grafted cucumber plants, reducing water loss and maintaining the plant's hydration status. When pumpkin grafted plants were pretreated with an NADPH oxidase inhibitor, diphenylene iodonium (DPI), the H2O2 level decreased significantly, to the level found in self-grafted plants, resulting in the loss of the salt tolerance. Inhibition of the NADPH oxidase-mediated H2O2 signaling in the root also abolished a rapid stomatal closure in the pumpkin-grafted plants. We concluded that the pumpkin grafted cucumber plants increase their salt tolerance via a mechanism involving the root-sourced respiratory burst oxidase homologue-dependent H2O2 production, which enhances Na+ exclusion from the root and promotes an early stomatal closure. PMID- 29145594 TI - Wellbeing of gay fathers with children born through surrogacy: a comparison with lesbian-mother families and heterosexual IVF parent families. AB - STUDY QUESTION: Are there differences in levels of parental wellbeing (parental stress, psychological adjustment and partner relationship satisfaction) between gay-father families with infants born through surrogacy, lesbian-mother families with infants born through donor insemination, and heterosexual-parent families with infants born through IVF? SUMMARY ANSWER: There were no differences in parental wellbeing. WHAT IS KNOWN ALREADY: The only other study of parental wellbeing in gay-father families formed through surrogacy (mean age children: 4 years old) found no difference in couple relationship satisfaction between these families and lesbian-mother families formed through donor insemination and heterosexual-parent families formed without assisted reproductive technologies. STUDY DESIGN, SIZE, DURATION: This cross-sectional study is part of an international research project involving 38 gay-father families, 61 lesbian mother families and 41 heterosexual-parent families with 4-month-olds. In each country (the UK, the Netherlands and France), participants were recruited through several sources, such as specialist lawyers with expertise in surrogacy (for the recruitment of gay fathers), lesbian and gay parenting support groups, fertility clinics (for the recruitment of lesbian and heterosexual parents), and/or online forums and magazines. PARTICIPANTS/MATERIALS, SETTING, METHODS: During a home visit when their infants were between 3.5 and 4.5 months old, participants completed standardized measures of parental stress, parental psychological adjustment (anxiety and depression) and partner relationship satisfaction. MAIN RESULTS AND THE ROLE OF CHANCE: All parents reported relatively low levels of parental stress, anxiety and depression, and were all relatively satisfied with their intimate relationships. After controlling for caregiver role (primary or secondary caregiver role), there were no significant family type differences in parental stress, P = 0.949, depression, P = 0.089, anxiety, P = 0.117, or relationship satisfaction, P = 0.354. LIMITATIONS, REASONS FOR CAUTION: The findings cannot be generalized to all first-time ART parents with infants because only families from relatively privileged backgrounds participated. WIDER IMPLICATIONS OF THE FINDINGS: Our findings may have implications for the development of policy and legislation in relation to these new family forms, as well as the regulation of surrogacy in the Netherlands and France. In addition, our findings might encourage professional organizations of obstetricians and gynecologists in these countries to recommend that requests for assisted reproduction should be considered regardless of the applicants' sexual orientation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported, under the auspices of the Open Research Area (Application BO 3973/1-1; Principal Investigator, Michael E Lamb), by grants from the UK Economic and Social Research Council (ESRC; Grant ES/K006150/1; Principal Investigator, Michael E. Lamb), The Netherlands Organisation for Scientific Research (NWO; Grant NWO 464-11-001, Principal Investigator, Henny W.M. Bos) and the French Agence Nationale de Recherche (ANR; Grant ANR-12-ORAR-00005-01, Principal Investigator, Olivier Vecho) whose support is gratefully acknowledged. There were no competing interests. PMID- 29145595 TI - Synchrony, Weather, and Cycles in Southern Pine Beetle (Coleoptera: Curculionidae). AB - Spatial synchrony and cycles are common features of forest insect pests, but are often studied as separate phenomenon. Using time series of timber damage caused by Dendroctonus frontalis Zimmermann (Coleoptera: Curculionidae) (southern pine beetle) in 10 states within the southern United States, this study examines synchrony in D. frontalis abundance, the synchronizing effects of temperature extremes, and the evidence for shared cycles among state populations. Cross correlation and cluster analyses are used to quantify synchrony across a range of geographic distances and to identify groups of states with synchronous dynamics. Similar techniques are used to quantify spatial synchrony in temperature extremes and to examine their relationship to D. frontalis fluctuations. Cross-wavelet analysis is then used to examine pairs of time series for shared cycles. These analyses suggest there is substantial synchrony among states in D. frontalis fluctuations, and there are regional groups of states with similar dynamics. Synchrony in D. frontalis fluctuations also appears related to spatial synchrony in summer and winter temperature extremes. The cross-wavelet results suggest that D. frontalis dynamics may differ among regions and are not stationary. Significant oscillations were present in some states over certain time intervals, suggesting an endogenous feedback mechanism. Management of D. frontalis outbreaks could potentially benefit from a multistate regional approach because populations are synchronous on this level. Extreme summer temperatures are likely to become the most important synchronizing agent due to climate change. PMID- 29145596 TI - A CRISPR/Cas9-based exploration into the elusive mechanism for lactate export in Saccharomyces cerevisiae. AB - CRISPR/Cas9-based genome editing allows rapid, simultaneous modification of multiple genetic loci in Saccharomyces cerevisiae. Here, this technique was used in a functional analysis study aimed at identifying the hitherto unknown mechanism of lactate export in this yeast. First, an S. cerevisiae strain was constructed with deletions in 25 genes encoding transport proteins, including the complete aqua(glycero)porin family and all known carboxylic acid transporters. The 25-deletion strain was then transformed with an expression cassette for Lactobacillus casei lactate dehydrogenase (LcLDH). In anaerobic, glucose-grown batch cultures this strain exhibited a lower specific growth rate (0.15 vs. 0.25 h-1) and biomass-specific lactate production rate (0.7 vs. 2.4 mmol g biomass-1 h 1) than an LcLDH-expressing reference strain. However, a comparison of the two strains in anaerobic glucose-limited chemostat cultures (dilution rate 0.10 h-1) showed identical lactate production rates. These results indicate that, although deletion of the 25 transporter genes affected the maximum specific growth rate, it did not impact lactate export rates when analysed at a fixed specific growth rate. The 25-deletion strain provides a first step towards a 'minimal transportome' yeast platform, which can be applied for functional analysis of specific (heterologous) transport proteins as well as for evaluation of metabolic engineering strategies. PMID- 29145597 TI - Laboratory Testing of a Cohort of Commercially Insured Users of HIV Preexposure Prophylaxis in the United States, 2011-2015. AB - To ensure the health and safety of persons taking antiretroviral medication as preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection, Centers for Disease Control and Prevention guidelines recommend initial and follow-up laboratory testing. We assessed the rates of recommended testing, using a commercial insurance claims database. Before taking PrEP, 45% of users were tested for HIV, 55% for syphilis, 43% for chlamydia/gonorrhea, and 38% for hepatitis B, and 31% had their creatinine level measured. By 6 months after PrEP initiation, 38% were tested for HIV, 49% for syphilis, and 39% for chlamydia/gonorrhea, and 37% had their creatinine level measured. Although laboratory testing was less frequent than recommended, testing rates increased over the study period. PMID- 29145599 TI - A Role for Thiopurine Metabolites in the Synergism Between Thiopurines and Infliximab in Inflammatory Bowel Disease. AB - Background: Interactions between principal cytotoxic thiopurine metabolites, that is 6-thioguanine nucleotides [6-TGN], and infliximab [IFX] and anti-IFX antibodies [Abs] may contribute to higher effectiveness of IFX-thiopurine combination therapy than monotherapies in inflammatory bowel disease. Methods: To examine if thiopurine metabolites influenced trough IFX and anti-IFX Abs, 89 patients previously assessed for anti-IFX Abs were included. To assess if IFX influenced thiopurine metabolites, eight patients who had responded to 12 weeks of intensified IFX at a constant thiopurine dosing were included. Results: In the first cohort, IFX-thiopurine combination therapy reduced anti-IFX Ab detection [8/40; 20%] as compared with IFX monotherapy [22/49; 45%], odds ratio [OR] 0.31 [0.12-0.80], p < 0.05. 6-TGN was significantly lower in anti-IFX Ab-positive patients (50 pmol/8 * 108 red blood cells [RBC] vs 105, p < 0.01). All anti-IFX Ab-positive patients had 6-TGN < 117 pmol/8 * 108 RBC (sensitivity 100% [63-100], specificity 47% [29-65], area under the curveROC = 0.82, p < 0.01). Trough IFX was similar between anti-IFX Ab-negative patients in IFX monotherapy and IFX thiopurine combination therapy [5.1 MUg/mL vs 4.9, p = 0.76]. 6-TGN and IFX did not correlate [rP = 0.04, p = 0.83; rS = 0.02, p = 0.89, respectively]. In the second cohort, trough IFX increased during IFX intensification [DeltaIFX median 6.5 MUg/mL, p = 0.02], but 6-TGN was stable [6-TGN at Weeks 0, 4, 8, 12: 90 pmol/8 * 108 RBC, 93, 101, 90; p > 0.05]. Methylated mercaptopurine metabolite associations were consistently negative. Conclusions: Superior effect of IFX thiopurine combination therapy over monotherapies partly relates to decrease in anti-IFX Abs, which associates with 6-TGN levels and has a lower therapeutic threshold than during thiopurine monotherapy. Additional benefit likely ascribes to synergy between different anti-inflammatory modes of action rather than direct drug interactions. PMID- 29145598 TI - Pubertal Escape From Estradiol Negative Feedback in Ewe Lambs Is Not Accounted for by Decreased ESR1 mRNA or Protein in Kisspeptin Neurons. AB - In this study, we investigated whether decreased sensitivity to estradiol negative feedback is associated with reduced estrogen receptor alpha (ESR1) expression in kisspeptin neurons as ewe lambs approach puberty. Lambs were ovariectomized and received no implant (OVX) or an implant containing estradiol (OVX+E). In the middle arcuate nucleus (mARC), ESR1 messenger RNA (mRNA) was greater in OVX than OVX+E lambs but did not differ elsewhere. Post hoc analysis of luteinizing hormone (LH) secretion from OVX+E lambs revealed three patterns of LH pulsatility: low [1 to 2 pulses per 12 hours; low frequency (LF), n = 3], moderate [6 to 7 pulses per 12 hours; moderate frequency (MF), n = 6], and high [>10 pulses per 12 hours; high frequency (HF), n = 5]. The percentage of kisspeptin neurons containing ESR1 mRNA in the preoptic area did not differ among HF, MF, or LF groups. However, the percentage of kisspeptin neurons containing ESR1 mRNA in the mARC was greater in HF (57%) than in MF (36%) or LF (27%) lambs and did not differ from OVX (50%) lambs. A higher percentage of kisspeptin neurons contained ESR1 protein in all regions of the arcuate nucleus (ARC) in OVX compared with OVX+E lambs. There were no differences in ESR1 protein among the HF, MF, or LF groups in the preoptic area or ARC. Contrary to our hypothesis, increases in LH pulsatility were associated with enhanced ESR1 mRNA abundance in kisspeptin neurons in the ARC, and absence of estradiol increased the percentage of kisspeptin neurons containing ESR1 protein in the ARC. Therefore, changes in the expression of ESR1, particularly in kisspeptin neurons in the ARC, do not explain the pubertal escape from estradiol negative feedback in ewe lambs. PMID- 29145600 TI - The influence of gender and household headship on voluntary health insurance: the case of North-West Cameroon. AB - Within the existing health financing literature, males are typically categorized as the household's decision-makers. While this view accurately reflects many local sociocultural realities, approximately a quarter of sub-Saharan African households are now headed by females. In light of various efforts to expand health insurance coverage in the region, it is necessary to examine whether the factors influencing voluntary health insurance enrolment are analogous across male- and female-headed households. This study sought to identify the gendered determinants of voluntary enrolment into a church-run micro health insurance scheme. A cross-sectional survey of 550 households was carried out in Bui and Donga-Mantung Divisions of North-West Cameroon in May 2016. A structured questionnaire was administered on health insurance membership, household attributes, headship characteristics and health-seeking behaviour. We assessed the influence of gender on the associations between health insurance enrolment and the explanatory variables using logistic regression. This study found that voluntary health insurance demand was influenced by involvement in social networks regardless of gender. However, in line with entrenched household roles, men's understanding of potential household health risks ultimately facilitated their enrolment decisions, while economically empowered women prioritised their direct knowledge of household health risks. Men's demand for health insurance was correlated primarily with their education level (OR = 2.238 [CI 1.228-2.552]), as well as with their socioeconomic status (OR = 2.207 [CI 1.173-4.153]), age (OR = 2.238 [CI 1.151-4.352]) and trust of the insurance provider (OR = 4.770 [CI 2.407 9.453]). Conversely, women's enrolment decision was primarily associated with their income levels (OR = 5.842 [CI 1.589-21.484]), as well as by the presence of children (OR = 3.734 [CI 1.228-11.348]). The influence of wealth on health insurance enrolment highlights the need for policymakers to subsidize health insurance schemes for vulnerable population groups. Further, it is imperative to develop sensitization campaigns that are simple and digestible to facilitate understanding of health insurance across all target groups. PMID- 29145601 TI - Identification and functional analysis of potential prophage-derived recombinases for genome editing in Lactobacillus casei. AB - Numerous lactic acid bacteria (LAB) bacteriophage genomes have been sequenced, while the functional genes are yet to be exploited. In this study, a lambda Red like recombinase operon LCABL_13040-50-60 was identified from a prophage PLE3 in Lactobacillus casei BL23 genome, and its recombination function was confirmed by the replacement of a 167-bp galK fragment with chloramphenicol-resistant gene (cat) in the L. casei BL23 genome. Further functional analysis showed that LCABL_13040 and LCABL_13060 were analogs to the host nuclease inhibitor (Redgamma) and 5?-3? exonuclease (Redalpha/RecE), respectively. After optimization of recombineering conditions, including induction, homology length, recovery time and double-strand DNA substrates quantity, the recombineering efficiency reached ~2.2 * 10-7. Subsequently, combining cre-lox technology, the optimal LCABL_13040-50-60 proteins could catalyze markerless deletion of a 167-bp galK fragment and insertion of the gfp gene as well as precision point mutation of rpoB gene in the L. casei BL23 genome, suggesting the LCABL_13040-50-60 operon encoded for three recombineering proteins. Moreover, with the assistance of Redgamma, the LCABL_13040-50-60 proteins also showed recombinase activity in six other L. casei strains, L. paracasei OY and L. plantarum WCSF1. All the results demonstrated that the prophage-associated recombinases LCABL_13040-50-60 have great potential to be used for genome editing in LAB. PMID- 29145602 TI - Genotype-based selection of treatment of patients with advanced colorectal cancer (SETICC): a pharmacogenetic-based randomized phase II trial. AB - Background: There has been little progress toward personalized therapy for patients with metastatic colorectal cancer (mCRC). TYMS-3' untranslated region (UTR) 6 bp ins/del and ERCC1-118C/T polymorphisms were previously reported to facilitate selecting patients for fluoropyrimidine-based treatment in combination with oxaliplatin as first-line therapy. We assessed the utility of these markers in selecting therapy for patients with mCRC. Patients and methods: This randomized, open-label phase II trial compared bevacizumab plus XELOX (control) versus treatment tailored according to TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T polymorphisms. Patients randomized to the experimental treatment received bevacizumab plus FUOX, FUIRI, XELIRI, or XELOX depending on their combination of favorable polymorphisms for FUOX treatment (TYMS-3'UTR ins/del or del/del; ERCC1 118T/T). Progression-free survival (PFS) was the primary end point. Results: Overall, 195 patients were randomized (control n = 65; experimental n = 130). The primary objective was not met: median PFS was 9.4 months in the control group and 10.1 months in the experimental group (P = 0.745). Median overall survival was similar in both groups (16.5 versus 19.1 months, respectively; P = 0.797). Patients in the experimental group had a significantly higher overall response rate (ORR; 65% versus 47% in the control group; P = 0.042) and R0 resection rate (86% versus 44%, respectively; P = 0.018). Neuropathy, hand-foot syndrome, thrombocytopenia, and dysesthesia were significantly less common in the experimental group. Conclusions: This study did not show survival benefits after treatment personalization based on polymorphisms in mCRC. However, the improved ORR and R0 resection rate and fewer disabling toxicities suggest that tailoring therapy by TYMS-3'UTR and ERCC1-118 polymorphisms warrants further investigation in patients with mCRC. ClinicalTrials.gov: NCT01071655. PMID- 29145603 TI - Accuracy of Next-Generation Sequencing for Molecular Diagnosis in Patients With Infantile Nystagmus Syndrome. AB - Importance: Infantile nystagmus syndrome (INS) is a group of disorders presenting with genetic and clinical heterogeneities that have challenged the genetic and clinical diagnoses of INS. Precise molecular diagnosis in early infancy may result in more accurate genetic counseling and improved patient management. Objective: To assess the accuracy of genomic data from next-generation sequencing (NGS) and phenotypic data to enhance the definitive diagnosis of INS. Design, Setting, and Participants: A single-center retrospective case series was conducted in 48 unrelated, consecutive patients with INS, with or without associated ocular or systemic conditions, who underwent genetic testing between June 1, 2015, and January 31, 2017. Next-generation sequencing analysis was performed using a target panel that included 113 genes associated with INS (n = 47) or a TruSight One sequencing panel that included 4813 genes associated with known human phenotypes (n = 1). Variants were filtered and prioritized by in depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Patients underwent a detailed ophthalmic examination, including electroretinography and optical coherence tomography, if feasible. Main Outcomes and Measures: Diagnostic yield of targeted NGS testing. Results: Among the 48 patients (21 female and 27 male; mean [SD] age at genetic testing, 9.2 [10.3] years), 8 had a family history of nystagmus and 40 were simplex. All patients were of a single ethnicity (Korean). Genetic variants that were highly likely to be causative were identified in 28 of the 48 patients, corresponding to a molecular diagnostic yield of 58.3% (95% CI, 44.4%-72.2%). FRMD7, GPR143, and PAX6 mutations appeared to be the major genetic causes of familial INS. A total of 10 patients (21%) were reclassified to a different diagnosis based on results of NGS testing, enabling accurate clinical management. Conclusions and Relevance: These findings suggest that NGS is an accurate diagnostic tool to differentiate causes of INS because diagnostic tests, such as electroretinography and optical coherence tomography, are not easily applicable in young infants. Accurate application of NGS using a standardized, stepwise, team-based approach in early childhood not only facilitated early molecular diagnosis but also led to improved personalized management in patients with INS. PMID- 29145604 TI - Commentary on: Incidence and Predictors of Venous Thromboembolism in Abdominoplasty. PMID- 29145605 TI - Corrigendum to: "Stereotype Threat Effects on Older Adults' Episodic and Working Memory: A Meta-Analysis". PMID- 29145607 TI - Phenology of the Dalmatian Toadflax Biological Control Agent Mecinus janthiniformis (Coleoptera: Curculionidae) in Utah. AB - The phenology of the stem-mining weevil Mecinus janthiniformis Tosevski and Caldara (Coleoptera: Curculionidae) as adults attacking Dalmatian toadflax, Linaria dalmatica (L.) Miller (Plantaginaceae), was studied in 2014-2015 at two low elevation sites in northern Utah. The seasonal pattern of adult weevil abundance on the host plant at the two sites was most similar between years when described by degree-day accumulation, versus calendar date. Repeated censusing over the growing season revealed that males appeared first and subsequently peaked in abundance on the host plant earlier than females did, such that the adult population was dominated by males early in the season and by females late in the season. Peak female abundance on the host plant occurred at the time when Dalmatian toadflax stems reached their maximum height and density and when they began flowering widely. Maximum toadflax stem heights and densities, and flowering activity, were markedly reduced in 2015 compared to 2014. In contrast to these host plant parameters that vary between years, degree-day accumulation can be used readily for timing collection and survey efforts for adult weevils and female adult weevils in particular. Use of degree-day accumulation can thereby facilitate implementation of redistribution and monitoring programs for M. janthiniformis as a biological control agent of Dalmatian toadflax. PMID- 29145606 TI - "Prokaryotic Pathway" Is Not Prokaryotic: Noncyanobacterial Origin of the Chloroplast Lipid Biosynthetic Pathway Revealed by Comprehensive Phylogenomic Analysis. AB - Lipid biosynthesis within the chloroplast, or more generally plastids, was conventionally called "prokaryotic pathway," which produces glycerolipids bearing C18 acids at the sn-1 position and C16 acids at the sn-2 position, as in cyanobacteria such as Anabaena and Synechocystis. This positional specificity is determined during the synthesis of phosphatidate, which is a precursor to diacylglycerol, the acceptor of galactose for the synthesis of galactolipids. The first acylation at sn-1 is catalyzed by glycerol-3-phosphate acyltransferase (GPAT or GPT), whereas the second acylation at sn-2 is performed by lysophosphatidate acyltransferase (LPAAT, AGPAT, or PlsC). Here we present comprehensive phylogenomic analysis of the origins of various acyltransferases involved in the synthesis of phosphatidate, as well as phosphatidate phosphatases in the chloroplasts. The results showed that the enzymes involved in the two steps of acylation in cyanobacteria and chloroplasts are entirely phylogenetically unrelated despite a previous report stating that the chloroplast LPAAT (ATS2) and cyanobacterial PlsC were sister groups. Phosphatidate phosphatases were separated into eukaryotic and prokaryotic clades, and the chloroplast enzymes were not of cyanobacterial origin, in contrast with another previous report. These results indicate that the lipid biosynthetic pathway in the chloroplasts or plastids did not originate from the cyanobacterial endosymbiont and is not "prokaryotic" in the context of endosymbiotic theory of plastid origin. This is another line of evidence for the discontinuity of plastids and cyanobacteria, which has been suggested in the glycolipid biosynthesis. PMID- 29145608 TI - MeDReaders: a database for transcription factors that bind to methylated DNA. AB - Understanding the molecular principles governing interactions between transcription factors (TFs) and DNA targets is one of the main subjects for transcriptional regulation. Recently, emerging evidence demonstrated that some TFs could bind to DNA motifs containing highly methylated CpGs both in vitro and in vivo. Identification of such TFs and elucidation of their physiological roles now become an important stepping-stone toward understanding the mechanisms underlying the methylation-mediated biological processes, which have crucial implications for human disease and disease development. Hence, we constructed a database, named as MeDReaders, to collect information about methylated DNA binding activities. A total of 731 TFs, which could bind to methylated DNA sequences, were manually curated in human and mouse studies reported in the literature. In silico approaches were applied to predict methylated and unmethylated motifs of 292 TFs by integrating whole genome bisulfite sequencing (WGBS) and ChIP-Seq datasets in six human cell lines and one mouse cell line extracted from ENCODE and GEO database. MeDReaders database will provide a comprehensive resource for further studies and aid related experiment designs. The database implemented unified access for users to most TFs involved in such methylation-associated binding actives. The website is available at http://medreader.org/. PMID- 29145609 TI - The Differential Effects of Human Immunodeficiency Virus and Hepatitis C Virus on Bone Microarchitecture and Fracture Risk. AB - Background: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected individuals have a significantly greater osteoporotic fracture risk than HIV monoinfected persons, despite the fact that HIV/HCV coinfection has not been associated with lower bone mineral density (BMD) than HIV or HCV alone. To evaluate if changes in bone microarchitecture, measured by trabecular bone score (TBS), could explain these differences, we performed a prospective, cross sectional cohort study of virologically suppressed HIV-infected subjects, untreated HCV-infected subjects, HIV/HCV-coinfected subjects, and uninfected controls. Methods: We enrolled 532 male subjects: 57 HIV/HCV coinfected, 174 HIV infected, 123 HCV infected, and 178 controls. We conducted analysis of covariance comparing BMD and TBS between groups, controlling for age, race, body mass index, and smoking. We used linear regression to evaluate predictors of BMD and TBS and evaluated the effects of severity of HCV infection and tenofovir disoproxil fumarate use. Results: Despite both infections being associated with decreased BMD, only HCV, but not HIV, was associated with lower TBS score. Also, HIV/HCV coinfected subjects had lower TBS scores than HIV-monoinfected, HCV-monoinfected, and uninfected subjects. Neither the use of TDF or HCV viremia nor the severity of HCV liver disease was associated with lower TBS. Conclusions: HCV infection is associated with microarchitectural changes at the lumbar spine as assessed by the low TBS score, suggesting that microstructural abnormalities underlie some of the higher fracture risk in HCV infection. TBS might improve fracture risk prediction in HCV infection. PMID- 29145610 TI - Transition to an Aquatic Habitat Permitted the Repeated Loss of the Pleiotropic KLK8 Gene in Mammals. AB - Kallikrein related peptidase 8 (KLK8; also called neuropsin) is a serine protease that plays distinct roles in the skin and hippocampus. In the skin, KLK8 influences keratinocyte proliferation and desquamation, and activates antimicrobial peptides in sweat. In the hippocampus, KLK8 affects memory acquisition. Here, we examined the evolution of KLK8 in mammals and discovered that, out of 70 placental mammals, KLK8 is exclusively lost in three independent fully-aquatic lineages, comprising dolphin, killer whale, minke whale, and manatee. In addition, while the sperm whale has an intact KLK8 reading frame, the gene evolves neutrally in this species. We suggest that the distinct functions of KLK8 likely became obsolete in the aquatic environment, leading to the subsequent loss of KLK8 in several fully-aquatic mammalian lineages. First, the cetacean and manatee skin lacks sweat glands as an adaptation to the aquatic environment, which likely made the epidermal function of KLK8 obsolete. Second, cetaceans and manatees exhibit a proportionally small hippocampus, which may have rendered the hippocampal functions of KLK8 obsolete. Together, our results shed light on the genomic changes that correlate with skin and neuroanatomical differences of aquatic mammals, and show that even pleiotropic genes can be lost during evolution if an environmental change nullifies the need for the different functions of such genes. PMID- 29145612 TI - Developmental and gut-related changes to microbiomes of the cultured juvenile spiny lobster Panulirus ornatus. AB - With recent technologies making it possible for commercial scale closed life cycle aquaculture production of spiny lobster (Panulirus ornatus) comes a strong impetus to further understand aspects of lobster health. The gut microbiome plays a crucial role in host health, affecting growth, digestion, immune responses and pathogen resistance. Herein we characterise and compare gut microbiomes across different developmental stages (6-7 days post-emergence [dpe], 52 dpe and 13 months post-emergence [mpe]) and gut regions (foregut, midgut and hindgut) of cultured P. ornatus juveniles. Gut samples were analysed using 16S rRNA next generation sequencing. Core gut microbiomes of P. ornatus comprised the phyla Tenericutes and Proteobacteria. Within class Gammaproteobacteria, families Pseudoalteromonadaceae and Vibrionaceae were dominant members across the majority of the gut microbiomes. Characterisation of bacterial communities from 13 mpe lobsters indicated that the hindgut microbiome was more diverse and compositionally dissimilar to the foregut and midgut. The bacterial composition of the hindgut was more similar among younger juveniles (6-7 dpe and 52 dpe) compared to 13 mpe lobsters. This is the first study to explore gut microbiomes of spiny lobster juveniles. We demonstrate that the composition of the gut microbiome was shaped by gut region, whereas the structure of the hindgut microbiome was influenced by developmental stage. PMID- 29145613 TI - Commentary on: Do Not Fear an Implant's Shape: A Single Surgeon's Experience of Over 1200 Round and Shaped Textured Implants in Primary Breast Augmentation. PMID- 29145611 TI - Identification of Novel Potentially Pleiotropic Variants Associated With Osteoporosis and Obesity Using the cFDR Method. AB - Context: Genome-wide association studies (GWASs) have been successful in identifying loci associated with osteoporosis and obesity. However, the findings explain only a small fraction of the total genetic variance. Objective: The aim of this study was to identify novel pleiotropic genes important in osteoporosis and obesity. Design and Setting: A pleiotropic conditional false discovery rate method was applied to three independent GWAS summary statistics of femoral neck bone mineral density, body mass index, and waist-to-hip ratio. Next, differential expression analysis was performed for the potentially pleiotropic genes, and weighted genes coexpression network analysis (WGCNA) was conducted to identify functional connections between the suggested pleiotropic genes and known osteoporosis/obesity genes using transcriptomic expression data sets in osteoporosis/obesity-related cells. Results: We identified seven potentially pleiotropic loci-rs3759579 (MARK3), rs2178950 (TRPS1), rs1473 (PUM1), rs9825174 (XXYLT1), rs2047937 (ZNF423), rs17277372 (DNM3), and rs335170 (PRDM6)-associated with osteoporosis and obesity. Of these loci, the PUM1 gene was differentially expressed in osteoporosis-related cells (B lymphocytes) and obesity-related cells (adipocytes). WGCNA showed that PUM1 positively interacted with several known osteoporosis genes (AKAP11, JAG1, and SPTBN1). ZNF423 was the highly connected intramodular hub gene and interconnected with 21 known osteoporosis-related genes, including JAG1, EN1, and FAM3C. Conclusions: Our study identified seven potentially pleiotropic genes associated with osteoporosis and obesity. The findings may provide new insights into a potential genetic determination and codetermination mechanism of osteoporosis and obesity. PMID- 29145614 TI - Asking the Right Questions With Animal Models: Methionine- and Choline-Deficient Model in Predicting Adverse Drug Reactions in Human NASH. AB - In the past few decades, great conceptual and technological advances have been made in the field of toxicology, but animal model-based research still remains one of the most widely used and readily available tools for furthering our current knowledge. However, animal models are not perfect in predicting all systemic toxicity in humans. Extrapolating animal data to accurately predict human toxicities remains a challenge, and researchers are obligated to question the appropriateness of their chosen animal model. This paper provides an assessment of the utility of the methionine- and choline-deficient (MCD) diet fed animal model in reflecting human nonalcoholic steatohepatitis (NASH) and the potential risks of adverse drug reactions and toxicities that are associated with the disease. As a commonly used NASH model, the MCD model fails to exhibit most metabolic abnormalities in a similar manner to the human disease. The MCD model, on the other hand, closely resembles human NASH histology and reflects signatures of drug transporter alterations in humans. Due to the nature of the MCD model, it should be avoided in studies of NASH pathogenesis, metabolic parameter evaluation, and biomarker identification. But it can be used to accurately predict altered drug disposition due to NASH-associated transporter alterations. PMID- 29145615 TI - iPTMnet: an integrated resource for protein post-translational modification network discovery. AB - Protein post-translational modifications (PTMs) play a pivotal role in numerous biological processes by modulating regulation of protein function. We have developed iPTMnet (http://proteininformationresource.org/iPTMnet) for PTM knowledge discovery, employing an integrative bioinformatics approach-combining text mining, data mining, and ontological representation to capture rich PTM information, including PTM enzyme-substrate-site relationships, PTM-specific protein-protein interactions (PPIs) and PTM conservation across species. iPTMnet encompasses data from (i) our PTM-focused text mining tools, RLIMS-P and eFIP, which extract phosphorylation information from full-scale mining of PubMed abstracts and full-length articles; (ii) a set of curated databases with experimentally observed PTMs; and iii) Protein Ontology that organizes proteins and PTM proteoforms, enabling their representation, annotation and comparison within and across species. Presently covering eight major PTM types (phosphorylation, ubiquitination, acetylation, methylation, glycosylation, S nitrosylation, sumoylation and myristoylation), iPTMnet knowledgebase contains more than 654 500 unique PTM sites in over 62 100 proteins, along with more than 1200 PTM enzymes and over 24 300 PTM enzyme-substrate-site relations. The website supports online search, browsing, retrieval and visual analysis for scientific queries. Several examples, including functional interpretation of phosphoproteomic data, demonstrate iPTMnet as a gateway for visual exploration and systematic analysis of PTM networks and conservation, thereby enabling PTM discovery and hypothesis generation. PMID- 29145617 TI - RADIOLOGICAL IMPACT OF SOME COMMON FOODS OF SOUTHERN PART OF WEST BENGAL, INDIA. AB - An appreciable portion of human exposure to natural radioactivity comes from food and drinking water. Gross alpha radioactivity has been measured in thirty one food items consumed almost every day by the people of southern part of West Bengal, India, by using the solid state nuclear track detector LR-115. The annual effective doses due to intake of alpha-emitting radionuclides through these food items have also been estimated, and the total average annual dose received by an adultthrough ingestion of these foodstuffs calculated, considering the food habit of the people of the region. The total average annual dose is below the 1 mSv y-1 limit proposed by WHO, and over half of this annual dose comes from consumption of cereals. PMID- 29145616 TI - Editor's Highlight: Variation in Methylmercury Metabolism and Elimination Status in Humans Following Fish Consumption. AB - Evaluating the potential for methylmercury (MeHg) toxicity relies on accurately predicting the mercury (Hg) body burden that results from eating fish. Hg body burden is directly determined by the slow elimination kinetics of MeHg in the human body (kel = 0.014 days-1 or t1/2 =50 days). Existing studies on MeHg half life in humans demonstrate a wide range values (t1/2 = 30 to >150 days) and has lead to uncertainty in the derivation of a regulatory standard for acceptable daily oral intake. The causes of variation in MeHg toxicokinetics in humans remain little explored. Here we characterize variation in human MeHg metabolism and elimination rate (kel) in 37 adult volunteers who consumed 3 fish meals. We determined MeHg elimination rates via longitudinal Hg analysis in single hairs using laser ablation inductively coupled plasma mass spectrometry. We also measured MeHg metabolism (biotransformation) via speciation of fecal Hg. We find an average kel = 0.0157 days-1 (t1/2 = 44 days) amongst a more than 2-fold variation in kel across the cohort (0.0248-0.0112 days-1; t1/2 = 28-62 days). Although MeHg biotransformation varied widely between individuals, it showed a positive association with elimination rates across the cohort. A more than 2-fold change in kel over a period of 2 years was seen in some individuals. In 2 individuals, who received antibiotic for unrelated health issues, elimination rate was seen to slow significantly. Associations of kel with age, body mass index, gender, and fish eating habits were not observed. We establish that a measure of methylmercury metabolism and eliminaiton status (MerMES) can reduce uncertainty in determining an individual's MeHg toxicokinetics subsequent to eating fish. PMID- 29145619 TI - Intranasal Immunization With an Attenuated pep27 Mutant Provides Protection From Influenza Virus and Secondary Pneumococcal Infections. AB - During influenza pandemics, secondary pneumococcal infections cause excessive mortality. However, the current 13-valent pneumococcal conjugate vaccine, PCV13, provides only limited protection against secondary infection. Therefore, a more effective pneumococcal vaccine is required to protect against secondary pneumococcal infections. Here, intranasal immunization with an attenuated pneumococcal pep27 mutant provides protection from influenza virus infection, and also from secondary pneumococcal challenge. These results indicate that mucosal immunity might be an effective way to reduce the morbidity and mortality due to secondary pneumococcal infections during influenza pandemics. PMID- 29145618 TI - The histone variant H2A.Z promotes initiation of meiotic recombination in fission yeast. AB - Meiotic recombination is initiated by programmed formation of DNA double strand breaks (DSBs), which are mainly formed at recombination hotspots. Meiotic DSBs require multiple proteins including the conserved protein Spo11 and its cofactors, and are influenced by chromatin structure. For example, local chromatin around hotspots directly impacts DSB formation. Moreover, DSB is proposed to occur in a higher-order chromatin architecture termed 'axis-loop', in which many loops protrude from cohesin-enriched axis. However, still much remains unknown about how meiotic DSBs are generated in chromatin. Here, we show that the conserved histone H2A variant H2A.Z promotes meiotic DSB formation in fission yeast. Detailed investigation revealed that H2A.Z is neither enriched around hotspots nor axis sites, and that transcript levels of DSB-promoting factors were maintained without H2A.Z. Moreover, H2A.Z appeared to be dispensable for chromatin binding of meiotic cohesin. Instead, in H2A.Z-lacking mutants, multiple proteins involved in DSB formation, such as the fission yeast Spo11 homolog and its regulators, were less associated with chromatin. Remarkably, nuclei were more compact in the absence of H2A.Z. Based on these, we propose that fission yeast H2A.Z promotes meiotic DSB formation partly through modulating chromosome architecture to enhance interaction between DSB-related proteins and cohesin loaded chromatin. PMID- 29145620 TI - Head and neck cancer in Hong Kong. AB - Head and neck cancer is a major cause of morbidity and mortality in Hong Kong. HNC is well-known for its heterogeneity in epidemiology, clinical behavior, clinic-pathological features and patient characteristics. Treatment strategies for this heterogeneous disease vary greatly in different parts of the world, depending on availability of resources, local expertise and experience. Extensive research in head and neck cancer, particularly nasopharyngeal carcinoma, has been conducted in Hong Kong in the past few decades. In this article, we will review the available local evidence and summarize common practice in management of head and neck cancer in Hong Kong. PMID- 29145621 TI - Methadone-Associated Hypoglycemia in Chronic Renal Failure Masquerading as an Insulinoma. PMID- 29145623 TI - Transition: Message from the Editor-in-Chief. PMID- 29145622 TI - Plant extracellular vesicles are incorporated by a fungal pathogen and inhibit its growth. AB - Extracellular vesicles (EV) are membrane particles released by cells into their environment and are considered to be key players in intercellular communication. EV are produced by all domains of life but limited knowledge about EV in plants is available, although their implication in plant defense has been suggested. We have characterized sunflower EV and tested whether they could interact with fungal cells. EV were isolated from extracellular fluids of seedlings and characterized by transmission electron microscopy and proteomic analysis. These nanovesicles appeared to be enriched in cell wall remodeling enzymes and defense proteins. Membrane-labeled EV were prepared and their uptake by the phytopathogenic fungus Sclerotinia sclerotiorum was verified. Functional tests further evaluated the ability of EV to affect fungal growth. Spores treated with plant EV showed growth inhibition, morphological changes, and cell death. Conclusive evidence on the existence of plant EV is presented and we demonstrate their ability to interact with and kill fungal cells. Our results introduce the concept of cell-to-cell communication through EV in plants. PMID- 29145624 TI - Green urine in the operating room: the 'Cloret Sign'. PMID- 29145625 TI - mSignatureDB: a database for deciphering mutational signatures in human cancers. AB - Cancer is a genetic disease caused by somatic mutations; however, the understanding of the causative biological processes generating these mutations is limited. A cancer genome bears the cumulative effects of mutational processes during tumor development. Deciphering mutational signatures in cancer is a new topic in cancer research. The Wellcome Trust Sanger Institute (WTSI) has categorized 30 reference signatures in the COSMIC database based on the analyses of ~10 000 sequencing datasets from TCGA and ICGC. Large cohorts and bioinformatics skills are required to perform the same analysis as WTSI. The quantification of known signatures in custom cohorts is not possible under the current framework of the COSMIC database, which motivates us to construct a database for mutational signatures in cancers and make such analyses more accessible to general researchers. mSignatureDB (http://tardis.cgu.edu.tw/msignaturedb) integrates R packages and in-house scripts to determine the contributions of the published signatures in 15 780 individual tumors from 73 TCGA/ICGC cancer projects, making comparison of signature patterns within and between projects become possible. mSignatureDB also allows users to perform signature analysis on their own datasets, quantifying contributions of signatures at sample resolution, which is a unique feature of mSignatureDB not available in other related databases. PMID- 29145626 TI - Twelve-Month Outcomes of a Group-Randomized Community Health Advocate-Led Smoking Cessation Intervention in Public Housing. AB - Background: Lower rates of smoking cessation are a major reason for the higher prevalence of smoking among socioeconomically disadvantaged adults. Because barriers to quitting are both more numerous and severe, socioeconomically disadvantaged smokers may benefit from more intensive intervention. We sought to determine whether a smoking cessation intervention delivered by public housing residents trained as Tobacco Treatment Advocates (TTAs) could increase utilization of cessation resources and increase abstinence. Methods: We conducted a group-randomized trial among Boston public housing residents who were interested in quitting smoking. Participants at control sites received standard cessation materials and a one-time visit from a TTA who provided basic counseling and information about cessation resources. Participants at intervention sites were eligible for multiple visits by a TTA who employed motivational interviewing, cessation counseling, and navigation to encourage smokers to utilize cessation treatment (Smokers' Quitline and clinic-based programs). Utilization and 7-day and 30-day point prevalence abstinence were assessed at 12 months. Self-reported abstinence was biochemically verified. Results: Intervention participants (n = 121) were more likely than control participants (n = 129) to both utilize treatment programs (adjusted odds ratio [aOR]: 2.15; 95% confidence interval [CI]: 0.93-4.91) and 7-day and 30-day point prevalence abstinence (aOR: 2.60 (1.72-3.94); 2.98 (1.56-5.68), respectively). Mediation analysis indicated that the higher level of utilization did not explain the intervention effect. Conclusions: An intervention delivered by peer health advocates was able to increase utilization of treatment programs and smoking abstinence among public housing residents. Future studies of similar types of interventions should identify the key mechanisms responsible for success. Implications: In order to narrow the large and growing socioeconomic disparity in smoking rates, more effective cessation interventions are needed for low-income smokers. Individual culturally-relevant coaching provided in smokers' residences may help overcome the heightened barriers to cessation experienced by this group of smokers. In this study among smokers residing in public housing, an intervention delivered by peer health advocates trained in motivational interviewing, basic smoking cessation skills, and client navigation significantly increased abstinence at 12 months. Future research should address whether these findings are replicable in other settings both within and outside of public housing. PMID- 29145627 TI - Bacterial communities associated with the ectoparasitic mites Varroa destructor and Tropilaelaps mercedesae of the honey bee (Apis mellifera). AB - Varroa and Tropilaelaps mites have been reported as serious ectoparasites of the honey bee (Apis mellifera). In this study, bacterial communities associated with Varroa destructor and Tropilaelaps mercedesae from northern Thailand were determined, using both culture-dependent and culture-independent approaches. Adult female mites were collected from apiaries in Chiang Mai and Lampang provinces. Culturable bacteria were isolated from individual mites. On average, we observed approximately 1340 and 1140 CFU/mite in Varroa and Tropilaelaps, respectively. All isolates were assigned to the genus Enterococcus. Six samples of genomic DNA from 30-50 mites were extracted and subjected to pyrosequencing of bacterial 16S rRNA amplicons. The resulting 81 717 sequences obtained from Varroa were grouped into 429 operational taxonomic units. The most abundant bacteria in Varroa mites belonged to the family Enterobacteriaceae, especially the genera Arsenophonus, Enterobacter and Proteus. For Tropilaelaps mites, 84 075 sequences were obtained and clustered into 166 operational taxonomic units, within which the family Enterococcaceae (particularly the genus Enterococcus) was predominant. Localization of bacteria in the mites using fluorescence in situ hybridization with two universal bacterial probes revealed that these bacteria were in the cecum of the mites. Taxon-specific Enterobacteriaceae and Arsenophonus probes also confirmed their localization in the cecum of Varroa. PMID- 29145628 TI - Friends, science and freedom-Can one ask for more. AB - The author describes her life in science, starting from 1945 in post II world war Warsaw to an enthusiastic and devoted member of the international yeast community, recalling her collaboration with laboratories from US through Australia to France and Germany where she met great scientists and great friends. PMID- 29145629 TI - The Reactome Pathway Knowledgebase. AB - The Reactome Knowledgebase (https://reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism, and other cellular processes as an ordered network of molecular transformations-an extended version of a classic metabolic map, in a single consistent data model. Reactome functions both as an archive of biological processes and as a tool for discovering unexpected functional relationships in data such as gene expression profiles or somatic mutation catalogues from tumor cells. To support the continued brisk growth in the size and complexity of Reactome, we have implemented a graph database, improved performance of data analysis tools, and designed new data structures and strategies to boost diagram viewer performance. To make our website more accessible to human users, we have improved pathway display and navigation by implementing interactive Enhanced High Level Diagrams (EHLDs) with an associated icon library, and subpathway highlighting and zooming, in a simplified and reorganized web site with adaptive design. To encourage re-use of our content, we have enabled export of pathway diagrams as 'PowerPoint' files. PMID- 29145630 TI - Yaf9 subunit of the NuA4 and SWR1 complexes targets histone H3K27ac through its YEATS domain. AB - Yaf9 is an integral part of the NuA4 acetyltransferase and the SWR1 chromatin remodeling complexes. Here, we show that Yaf9 associates with acetylated histone H3 with high preference for H3K27ac. The crystal structure of the Yaf9 YEATS domain bound to the H3K27ac peptide reveals that the sequence C-terminal to K27ac stabilizes the complex. The side chain of K27ac inserts between two aromatic residues, mutation of which abrogates the interaction in vitro and leads in vivo to phenotypes similar to YAF9 deletion, including loss of SWR1-dependent incorporation of variant histone H2A.Z. Our findings reveal the molecular basis for the recognition of H3K27ac by a YEATS reader and underscore the importance of this interaction in mediating Yaf9 function within the NuA4 and SWR1 complexes. PMID- 29145631 TI - Rifaximin Fails to Prevent Campylobacteriosis in the Human Challenge Model: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - Background: Campylobacter species are a leading cause of diarrheal disease globally with significant morbidity. Primary prevention efforts have yielded limited results. Rifaximin chemoprophylaxis decreases rates of travelers' diarrhea and may be suitable for high-risk persons. We assessed the efficacy of rifaximin in the controlled human infection model for Campylobacter jejuni. Methods: Twenty-eight subjects were admitted to an inpatient facility and randomized to a twice-daily dose of 550 mg rifaximin or placebo. The following day, subjects ingested 1.7 * 105 colony-forming units of C. jejuni strain CG8421. Subjects continued prophylaxis for 3 additional days, were followed for campylobacteriosis for 144 hours, and were subsequently treated with azithromycin and ciprofloxacin. Samples were collected to assess immunologic responses to CG8421. Results: There was no difference (P = 1.0) in the frequency of campylobacteriosis in those receiving rifaximin (86.7%) or placebo (84.6%). Additionally, there were no differences in the clinical signs and symptoms of C. jejuni infection to include abdominal pain/cramps (P = 1.0), nausea (P = 1.0), vomiting (P = .2), or fever (P = 1.0) across study groups. Immune responses to the CG8421 strain were comparable across treatment groups. Conclusions: Rifaximin did not prevent campylobacteriosis in this controlled human infection model. Given the morbidity associated with Campylobacter infection, primary prevention efforts remain a significant need. Clinical Trials Registration: NCT02280044. PMID- 29145632 TI - Clinical significance of CD13 and epithelial mesenchymal transition (EMT) markers in hepatocellular carcinoma. AB - Background & Aims: To improve prognosis in patients with hepatocellular carcinoma (HCC), the molecular mechanisms of tumor thrombus formation and metastasis must be clarified. The epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) play crucial roles in tumor invasion and metastasis. This study aimed to reveal the clinical significance of the expression of the functional CSC marker, CD13, and investigate the correlation between CD13 expression and two EMT markers, E-cadherin and vimentin. Methods: We acquired clinical samples from 86 patients with HCC that underwent radical liver resections. We performed immunohistochemistry to evaluate CD13, E-cadherin and vimentin expression. We investigated the relationships among protein expression levels, clinicopathological factors and prognosis. Results: Based on CD13 expression, patients were categorized into CD13high (n = 30, 34.9%) and CD13low (n = 56, 65.1%) groups. The mean tumor size was significantly larger in the CD13high group than in the CD13low group (P = 0.049). Compared with the CD13low group, the CD13high group showed significantly earlier recurrences and shorter survival times. In the multivariate analysis, CD13high was an independent prognostic factor for overall survival (hazard ratio, 1.98; P = 0.044). The disease-free survival time was shorter in the vimentin-positive group than that in the vimentin-negative group (P = 0.014). In an analysis of the relationship between CD13 and EMT, there was no significant correlation between CD13 and EMT markers. Conclusions: Our findings suggested that CD13 enrichment was correlated with early recurrences, and poor prognosis in patients with HCC and that vimentin was associated with early recurrences. CD13 represents a potential therapeutic target for HCC, because CSC regulation and EMT suppression are essential in cancer therapy. PMID- 29145633 TI - The initiation, propagation and dynamics of CRISPR-SpyCas9 R-loop complex. AB - CRISPR-Cas9 system has been widely used for efficient genome editing. Although the structures of Cas9 protein in complex with single-guided RNA (sgRNA) and target DNA have been resolved, the molecular details about the formation of Cas9 endonuclease R-loop structure remain elusive. Here we examine the DNA cleavage activities of Streptococcus pyogenes Cas9 (SpyCas9) and its mutants using various target sequences and study the conformational dynamics of R-loop structure during target binding using single-molecule fluorescence energy transfer (smFRET) technique. Our results show that Cas9-sgRNA complex divides the target DNA into several distinct domains: protospacer adjacent motif, linker, Seed, Middle and Tail. After seed pairing, the Cas9 transiently retains a semi-active conformation and induces the cleavage of either target or non-target strand. smFRET studies demonstrate that an intermediate state exists in prior to the formation of the fully stable R-loop complex. Kinetics analysis of this new intermediate state indicates that the lifetime of this state increases when the base-pairing length of guide-DNA hybrid duplex increases and reaches the maximum at the size of 18 bp. These data provide new insights into the process of R-loop formation and reveal the source of off-targeting in CRISPR/Cas9 system. PMID- 29145634 TI - Risk profiles for acute health events after incident atrial fibrillation in patients with end-stage renal disease on hemodialysis. AB - Background: Little is known about the cardiovascular risks of incident atrial fibrillation/flutter (AF) in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). Methods: We studied older US patients who newly initiated HD for ESRD (2006-11) and who had not previously been diagnosed with AF, stroke, myocardial infarction (MI) or hip fracture. We used Cox regression with AF as a time-varying covariate, adjusted for socio-demographic characteristics and comorbidities to estimate hazard ratios [HRs (95% confidence intervals)] for the events of ischemic stroke, MI and death. Hip fracture served as a negative control outcome. Results: We identified 85 377 older patients (mean age: 76.5 years) who initiated HD; of these, 14.3% were subsequently diagnosed with AF (14.9% thereof as primary diagnosis) and 49.8% died during follow-up. Incident AF was associated with nine times higher adjusted mortality during the first 30 days [9.2 (8.8-9.6)], 5-fold higher mortality between 31 and 90 days [4.6 (4.3-4.8)] and double the mortality beyond 90 days from first AF diagnosis [2.2 (2.1-2.3)]. Incident AF was similarly associated with higher adjusted risk of ischemic stroke: 2.1 (1.6-2.7) during the first 30 days, 2.5 (2.0-3.0) between 31 and 90 days and 1.5 (1.3-1.7) beyond 90 days. Similar findings were obtained for MI. However, the risk of hip fracture was only marginally increased following AF diagnosis [<=30 days: 1.1 (0.7-1.6); 31-90 days: 1.4 (1.0-1.8); >90 days: 1.2 (1.1-1.4)]. All associations were attenuated and the association with hip fracture was null when incident AF was defined by a primary diagnosis code. Conclusions: AF was strongly associated with increased risks of ischemic stroke, MI and death, with risks highest soon after AF diagnosis but extending beyond 90 days. PMID- 29145635 TI - tRex: A Web Portal for Exploration of tRNA-Derived Fragments in Arabidopsis thaliana. AB - tRNA-derived fragments (tRFs) constitute a new class of short regulatory RNAs that are a product of nascent or mature tRNA processing. tRF sequences have been identified in all domains of life; however, most published research pertains to human, yeast and some bacterial organisms. Despite growing interest in plant tRFs and accumulating evidence of their function in plant development and stress responses, no public, web-based repository dedicated to these molecules is currently available. Here, we introduce tRex (http://combio.pl/trex)-the first comprehensive data-driven online resource specifically dedicated to tRFs in the model plant Arabidopsis thaliana. The portal is based on verified Arabidopsis tRNA annotation and includes in-house-generated and publicly available small RNA sequencing experiments from various tissues, ecotypes, genotypes and stress conditions. The provided web-based tools are designed in a user-friendly manner and allow for seamless exploration of the data that are presented in the form of dynamic tables and cumulative coverage profiles. The tRex database is connected to external genomic and citation resources, which makes it a one-stop solution for Arabidopsis tRF-related research. PMID- 29145637 TI - Investigation and management of renal stone disease. PMID- 29145638 TI - Consequences of calorie restriction and calorie excess for the physiological parameters of the yeast Saccharomyces cerevisiae cells. AB - Glucose plays an important role in cell metabolism and has an impact on cellular physiology. Changes in glucose availability may strongly influence growth rate of the cell size, cell metabolism and the rate of generation of cellular by products, such as reactive oxygen species. The positive effect of low glucose concentration conditions-calorie restriction is observed in a wide range of species, including the Saccharomyces cerevisiae yeast, yet little is known about the effect of high glucose concentrations-calorie excess. Such analysis seems to be particularly important due to recently common problem of diabetes and obesity. The effect of glucose on morphological and physiological parameters of the yeast cell was conducted using genetic alteration (disruption of genes involved in glucose signalling) and calorie restriction and calorie excess conditions. The results show a significant relationship among extracellular glucose concentration, cell size and reactive oxygen species generation in yeast cells. Furthermore, the results obtained through the use of mutant strains with disorders in glucose signalling pathways suggest that the intracellular level of glucose is more important than its extracellular concentration. These data also suggest that the calorie excess as a factor, which has a significant impact on cell physiology, requires further comprehensive analyses. PMID- 29145636 TI - Localization and functional characterization of the p.Asn965Ser (N965S) ABCA4 variant in mice reveal pathogenic mechanisms underlying Stargardt macular degeneration. AB - ABCA4 is a member of the superfamily of ATP-binding cassette (ABC) proteins that transports N-retinylidene-phosphatidylethanolamine (N-Ret-PE) across outer segment disc membranes thereby facilitating the removal of potentially toxic retinoid compounds from photoreceptor cells. Mutations in the gene encoding ABCA4 are responsible for Stargardt disease (STGD1), an autosomal recessive retinal degenerative disease that causes severe vision loss. To define the molecular basis for STGD1 associated with the p.Asn965Ser (N965S) mutation in the Walker A motif of nucleotide binding domain 1 (NBD1), we generated a p.Asn965Ser knockin mouse and compared the subcellular localization and molecular properties of the disease variant with wild-type (WT) ABCA4. Here, we show that the p.Asn965Ser ABCA4 variant expresses at half the level of WT ABCA4, partially mislocalizes to the endoplasmic reticulum (ER) of photoreceptors, is devoid of N-Ret-PE activated ATPase activity, and causes an increase in autofluorescence and the bisretinoid A2E associated with lipofuscin deposits in retinal pigment epithelial cells as found in Stargardt patients and Abca4 knockout mice. We also show for the first time that a significant fraction of WT ABCA4 is retained in the inner segment of photoreceptors. On the basis of these studies we conclude that loss in substrate dependent ATPase activity and protein misfolding are mechanisms underlying STGD1 associated with the p.Asn965Ser mutation in ABCA4. Functional and molecular modeling studies further suggest that similar pathogenic mechanisms are responsible for Tangiers disease associated with the p.Asn935Ser (N935S) mutation in the NBD1 Walker A motif of ABCA1. PMID- 29145639 TI - ASSESSMENT OF INTAKE ACCORDING TO IDEAS GUIDANCE: CASE STUDY. AB - Estimation of radiation intake and internal dose can be carried out through direct or indirect measurements during routine or special monitoring program. In case of Iodine-131 contamination, direct measurements, such as thyroid counting, are fast and efficient to give quick results. Generally, the calculation method implements suitable values for known parameters whereas default values are used if no information is available. However, in view to avoid significant discrepancies, IDEAS guidelines put in route a comprehensive method to evaluate the monitoring data for one and different types of monitoring. This article deals with a case of internal contamination of a worker who inhaled aerosols containing 131I during the production of radiopharmaceuticals. The interpretation of data obtained was done by following IDEAS guidelines. PMID- 29145640 TI - Craving as a DSM-5 Symptom of Alcohol Use Disorder in Non-Treatment Seekers. AB - Aims: DSM-5 has added craving as a new criterion and changed the diagnostic structure of alcohol use disorder (AUD). Though craving has long been a target of intervention, less is known about the impact this addition will have on prevalence and factor structure of AUD, particularly in non-treatment seeker with alcohol problems. Methods: Non-treatment seeking individuals reporting alcohol related problems (N = 296) completed a structured clinical interview and the Penn Alcohol Craving Scale (PACS). PACS scores greater than 20 were considered to meet diagnostic criteria for the alcohol craving symptom. This study examined DSM-IV to DSM-5 diagnostic conversion and conducted an exploratory factor analysis to test the factor structure of the DSM-5 symptoms, including craving. Results: The mean PACS score was 13.1 and alcohol craving was strongly correlated with other measures of alcohol use. Using the proposed cut-off score of PACS > 20, 46 participants (16.2%) met criteria for alcohol craving. Craving loaded moderately (0.47) onto the retained DSM symptoms and produced a unidimensional factor structure. The majority of participants who met for a DSM-IV AUD also met for a DSM-5 AUD (98.8%). Conclusions: Craving prevalence using the PACS was relatively low compared to the remaining 10 DSM-5 symptoms, possibly due to the non treatment seeking nature of the sample. Conversion of DSM-IV to DSM-5 in this sample led to a small increase in overall AUD prevalence. Craving loaded well onto a single factor structure for AUD. PMID- 29145641 TI - Changes in global longitudinal strain and left ventricular ejection fraction during the first year after myocardial infarction: results from a large consecutive cohort. AB - Aims: To determine changes of global longitudinal strain (GLS) and their predictors in relation to classical echocardiographic parameters of left ventricular (LV) function, over 1 year, in consecutive patients with myocardial infarction (MI) and initially normal or impaired LV ejection fraction (EF). Methods and results: A total of 285 patients with MI prospectively included in the REBUS (RElevance of Biomarkers for future risk of thromb-oembolic events in UnSelected post-myocardial infarction patients) study underwent echocardiography within 72 h from admission and after 1 year. At baseline, 213 (74.7%) of MI patients had a normal EF (>=52% in men or >=54% in women), but in 70.4% of them, an impaired GLS ( >= -18.0%) was observed. During 1-year follow-up, in patients with normal EF at baseline, GLS improved from -15.8% to - 17.4% (10.1% relative change); EF decreased from 62.5% to 59.9% (4.0% relative change); indexed end diastolic volume, indexed end-systolic volume, and indexed stroke volume increased with 15.6%, 24.8%, and 10.0% of relative change, respectively (P < 0.001 for all the comparisons). In the whole cohort, initial impairment of LV function [by EF, wall motion score index (WMSI), or GLS], male gender, non smoking, and treatment with beta-blockers were the independent predictors of GLS improvement. In the group with initially impaired EF, over 1 year GLS improved from -11.9% to - 14.8% (24.4% relative change) and EF from 44.6% to 52.6% (18.2% relative change) (P < 0.001 for both). Improvement in GLS significantly correlated with EF increase in the group with impaired EF (r = -0.41, P = 0.001) but not in the patients with normal EF (r = -0.14, P = ns). Conclusions: Despite diveregent evolution of GLS compared with EF and ventricular volumes, one year after MI GLS significantly improved in patients with initially both normal and impaired EF. Initial impairment of LV function (by EF, WMSI, or GLS), male gender, non-smoking, and treatment with beta-blockers were independent predictors of GLS improvement. LV remodelling was present even in patients with normal EF at baseline and during follow-up, confirming limited functional assessment by EF alone. PMID- 29145642 TI - ARF2-ARF4 and ARF5 are Essential for Female and Male Gametophyte Development in Arabidopsis. AB - The plant hormone auxin plays critical roles in plant growth and development. Auxin response factors (ARFs) are a class of transcription factors which regulate auxin-mediated gene expression. While the functions of ARFs in sporophytic development have been well characterized, their functions specific to gametophytic development have not been studied extensively. In this study, Arabidopsis ARF genes were selectively down-regulated in gametophytes by misexpression of targeted microRNAs (amiRARF234, amiRARFMP and MIR167a) to silence AtARF2-AtAEF4, AtARF5, AtARF6 and AtARF8. Embryo sacs in amiRARF234- and amiRARFMP-expressing plants exhibited identity defects in cells at the micropylar pole, such as formation of two cells with egg cell-like morphology, concomitant with loss of synergid marker expression and seed abortion. The pollen grains of the transgenic plants were morphologically aberrant and unviable, and the inclusions and nuclei were lost in the abnormal pollen grains. However, plants misexpressing MIR167a showed no obvious abnormal phenotypes in the embryo sacs and pollen grains. Overall, these results provide evidence that AtARF2-AtARF4 and AtARF5 play significant roles in regulating both female and male gametophyte development in Arabidopsis. PMID- 29145643 TI - The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. AB - The MEROPS database (http://www.ebi.ac.uk/merops/) is an integrated source of information about peptidases, their substrates and inhibitors. The hierarchical classification is: protein-species, family, clan, with an identifier at each level. The MEROPS website moved to the EMBL-EBI in 2017, requiring refactoring of the code-base and services provided. The interface to sequence searching has changed and the MEROPS protein sequence libraries can be searched at the EMBL-EBI with HMMER, FastA and BLASTP. Cross-references have been established between MEROPS and the PANTHER database at both the family and protein-species level, which will help to improve curation and coverage between the resources. Because of the increasing size of the MEROPS sequence collection, in future only sequences of characterized proteins, and from completely sequenced genomes of organisms of evolutionary, medical or commercial significance will be added. As an example, peptidase homologues in four proteomes from the Asgard superphylum of Archaea have been identified and compared to other archaean, bacterial and eukaryote proteomes. This has given insights into the origins and evolution of peptidase families, including an expansion in the number of proteasome components in Asgard archaeotes and as organisms increase in complexity. Novel structures for proteasome complexes in archaea are postulated. PMID- 29145644 TI - Paf1 and Ctr9, core components of the PAF1 complex, maintain low levels of telomeric repeat containing RNA. AB - The conserved PAF1 complex (Cdc73, Paf1, Ctr9, Leo1 and Rtf1, in yeast), binds RNA pol II, and affects levels of many RNAs. Although PAF1 is a complex, there is evidence that different components perform different functions. In yeast, Cdc73, Paf1 and Ctr9 maintain normal telomerase RNA (TLC1) levels and affect telomere length. Here we report a new connection between the PAF1 complex and telomere biology. We show that Paf1 and Ctr9 maintain low telomere repeat containing RNA (TERRA) levels while Cdc73, Leo1 and Rtf1 have lesser effects. Analysis of double mutants shows that Paf1 and Ctr9 can affect TERRA independently of Sir4, Rat1, and Trf4, previously identified regulators of TERRA. The data suggest that Paf1 and Ctr9 maintain low TERRA levels by affecting both transcription and degradation and that short telomeres in cdc73Delta, paf1Delta and ctr9Delta mutants do not induce TERRA. These data establish the PAF1 complex as a new regulator of TERRA, and are consistent with the model in which Paf1 and Ctr9, the core components of the PAF1 complex, affect transcript levels and cell fitness by numerous mechanisms. PMID- 29145645 TI - Waddlia chondrophila, a Chlamydia-related bacterium, has a negative impact on human spermatozoa. AB - STUDY QUESTION: What is the impact of Waddlia chondrophila, an emerging Chlamydia related bacterium associated with miscarriage, on human spermatozoa? SUMMARY ANSWER: W. chondrophila had a negative impact on human spermatozoa (decrease in viability and mitochondrial membrane potential) and was not entirely removed from infected samples by density gradient centrifugation. WHAT IS KNOWN ALREADY: Bacterial infection or colonization might have a deleterious effect on male fertility. Waddlia chondrophila was previously associated with miscarriage, but its impact on male reproductive function has never been studied. STUDY DESIGN SIZE, DURATION: An in vitro model of human spermatozoa infection was used to assess the effects of W. chondrophila infection. Controls included Chlamydia trachomatis serovar D and latex beads with similar size to bacteria. PARTICIPANTS/MATERIALS, SETTING, METHODS: Purified motile spermatozoa were infected with W. chondrophila (multiplicity of infection of 1). Immunohistochemistry combined with confocal microscopy was used to evaluate how bacteria interact with spermatozoa. The impact on physiology was assessed by monitoring cell viability, mitochondrial membrane potential and DNA fragmentation. MAIN RESULTS AND THE ROLE OF CHANCE: Using super-resolution confocal microscopy, bacteria were localized on spermatozoa surface, as well as inside the cytoplasm. Compared to controls, W. chondrophila caused a 20% increase in mortality over 72 h of incubation (P < 0.05). Moreover, higher bacterial loads significantly reduced mitochondrial membrane potential. Bacteria present on spermatozoa surface were able to further infect a cell-monolayer, indicating that sperm might vector bacteria during sexual intercourse. LIMITATIONS REASONS FOR CAUTION: The main limitation of the study is the use of an in vitro model of infection, which might be too simplistic compared to an actual infection. An animal model of infection should be developed to better evaluate the in vivo impact of W. chondrophila. WIDER IMPLICATIONS OF THE FINDINGS: Intracellular bacteria, including C. trachomatis, Mycoplasma spp. and Ureaplasma spp., are associated with male infertility. Waddlia chondrophila might represent yet another member of this group, highlighting the need for more rigorous microbiological analysis during investigations for male infertility. STUDY FUNDING/COMPETING INTEREST(S): This work has been funded by the Department of Obstetrics and Gynecology, Lausanne University Hospital, Switzerland, and by the Swiss National Science Foundation (Grant nos. 310030-156169/1, 320030-169853/1 and 320030-169853/2 attributed to D.B.). D.B. is also supported by the 'Fondation Leenaards' through the 'Bourse pour la releve academique', by the 'Fondation Divesa' and by the 'Loterie Romande'. No conflicts of interest to declare. PMID- 29145646 TI - REVIEW OF DOSE-RATE EFFECTS IN THE THERMOLUMINESCENCE OF Lif:mg,ti (HARSHAW). AB - The literature describing the experimental investigations of possible dose-rate effects in the thermoluminescence (TL) of LiF:Mg,Ti (Harshaw) is reviewed. The total lack of glow curve analysis, coupled with inclusion of all or part of the high temperature TL and absence of parallel measurements of possible dose-rate effects in the irradiation stage severely limit the scientific and technical level of the experiments. In addition, the experimental procedures are far from sufficient to warrant any conclusion concerning the presence or absence of dose rate effects in the TL of LiF:Mg,Ti. This decision is contrary to the widely held belief that there are no dose-rate effects in the TL of LiF:Mg,Ti. In addition, the literature on dose-rate effects in the optical absorption (irradiation stage) of LiF is reviewed and is found contradictory. No dose-rate studies have been carried out on optical absorption in LiF:Mg,Ti. Kinetic simulations demonstrating the possibility, even likelihood, of dose-rate effects are also reviewed. Dose rate effects are shown to be likely due to competition between excitation and recombination in the irradiation stage. Some other possible mechanisms involving multiple charge carrier trapping are suggested. Further definitive experiments are sorely needed, but the interested researcher should beware, it is not an easy task. PMID- 29145647 TI - Trends and correlates of waterpipe use in the European Union: analysis of selected Eurobarometer surveys (2009-2017). AB - Introduction: To assess the trends and correlates of waterpipe use between 2009 and 2017 in the 28 European Union (EU) member states. Methods: We analysed data from wave 72.3 (2009, n=27,788); wave 77.1 (2012, n=26,751); wave 82.4 (2014, n=27,801); and wave 87.1 (2017, n=27,901) of the Eurobarometer survey. Representative samples of EU residents aged >=15 years were asked to report ever use of waterpipe. Regular waterpipe use, i.e. at least once a month was also assessed in 2017. Associations of ever and current use with sociodemographic factors were assessed with multi-level logistic regression. Results: The prevalence of ever waterpipe use in the EU increased from 11.6% in 2009 to 16.3% in 2014 before dropping to 12.9% in 2017, but there was wide variation between EU member states, ranging from 2.3% (Croatia, 2009) to 41.7% (Latvia, 2017). Regular waterpipe use was highest in Austria (3.6%), Latvia (2.5%) and Belgium (2.0%) in 2017. Respondents aged 15-24 years were 11.43 times more likely (95% Confidence Interval [CI]: 10.71-12.21) to have ever used waterpipe compared to those 55 years and older. Regular and ever waterpipe use were also more likely among current and former cigarette smokers. Males (adjusted Odds Ratio [aOR]=1.64; 95% CI: 1.58-1.70) and those living in urban areas (aOR=1.36; 95% CI: 1.30-1.42) were more likely to have ever used waterpipe. Conclusion: A substantial proportion of EU citizens, especially young men, have tried waterpipe. Regular use is relatively limited, but more systematic surveillance is required to monitor trends across the EU. Implications: Data on waterpipe use in the European Union (EU) are scarce. The prevalence of ever waterpipe use in the EU increased from 11.6% in 2009 to 16.3% in 2014 before dropping to 12.9% in 2017, with wide variation between EU member states. Males, those living in urban areas, younger respondents and current or former cigarette smokers were more likely to be ever or regular users of waterpipe. PMID- 29145648 TI - Relative Performance of HPV and Cytology Components of Cotesting in Cervical Screening. AB - Background: The main goal of cervical screening programs is to detect and treat precancer before cancer develops. Human papillomavirus (HPV) testing is more sensitive than cytology for detecting precancer. However, reports of rare HPV negative, cytology-positive cancers are motivating continued use of both tests (cotesting) despite increased testing costs. Methods: We quantified the detection of cervical precancer and cancer by cotesting compared with HPV testing alone at Kaiser Permanente Northern California (KPNC), where 1 208 710 women age 30 years and older have undergone triennial cervical cotesting since 2003. Screening histories preceding cervical cancers (n = 623) and precancers (n = 5369) were examined to assess the relative contribution of the cytology and HPV test components in identifying cases. The performances of HPV testing and cytology were compared using contingency table methods, general estimating equation models, and nonparametric statistics; all statistical tests were two-sided. Results: HPV testing identified more women subsequently diagnosed with cancer (P < .001) and precancer (P < .001) than cytology. HPV testing was statistically significantly more likely to be positive for cancer at any time point (P < .001), except within 12 months (P = .10). HPV-negative/cytology-positive results preceded only small fractions of cases of precancer (3.5%) and cancer (5.9%); these cancers were more likely to be regional or distant stage with squamous histopathology than other cases. Given the rarity of cancers among screened women, the contribution of cytology to screening translated to earlier detection of at most five cases per million women per year. Two-thirds (67.9%) of women found to have cancer during 10 years of follow-up at KPNC were detected by the first cotest performed. Conclusions: The added sensitivity of cotesting vs HPV alone for detection of treatable cancer affected extremely few women. PMID- 29145649 TI - Single-molecule compaction of megabase-long chromatin molecules by multivalent cations. AB - To gain insight into the conformational properties and compaction of megabase long chromatin molecules, we reconstituted chromatin from T4 phage DNA (165 kb) and recombinant human histone octamers (HO). The unimolecular compaction, induced by divalent Mg2+ or tetravalent spermine4+ cations, studied by single-molecule fluorescence microscopy (FM) and dynamic light scattering (DLS) techniques, resulted in the formation of 250-400 nm chromatin condensates. The compaction on this scale of DNA size is comparable to that of chromatin topologically associated domains (TAD) in vivo. Variation of HO loading revealed a number of unique features related to the efficiency of chromatin compaction by multivalent cations, the mechanism of compaction, and the character of partly compact chromatin structures. The observations may be relevant for how DNA accessibility in chromatin is maintained. Compaction of saturated chromatin, in turn, is accompanied by an intra-chain segregation at the level of single chromatin molecules, suggesting an intriguing scenario of selective activation/deactivation of DNA as a result of chromatin fiber heterogeneity due to the nucleosome positioning. We suggest that this chromatin, reconstituted on megabase-long DNA because of its large size, is a useful model of eukaryotic chromatin. PMID- 29145651 TI - Cracks in the Case against Epidural Steroids: Examining the Evidence for Vertebral Fracture Risk. PMID- 29145652 TI - Error in Byline. PMID- 29145650 TI - Loss of p300 and CBP disrupts histone acetylation at the mouse Sry promoter and causes XY gonadal sex reversal. AB - CREB-binding protein (CBP, CREBBP, KAT3A) and its closely related paralogue p300 (EP300, KAT3B), together termed p300/CBP, are histone/lysine acetyl-transferases that control gene expression by modifying chromatin-associated proteins. Here, we report roles for both of these chromatin-modifying enzymes in mouse sex determination, the process by which the embryonic gonad develops into a testis or an ovary. By targeting gene ablation to embryonic gonadal somatic cells using an inducible Cre line, we show that gonads lacking either gene exhibit major abnormalities of XY gonad development at 14.5 dpc, including partial sex reversal. Embryos lacking three out of four functional copies of p300/Cbp exhibit complete XY gonadal sex reversal and have greatly reduced expression of the key testis-determining genes Sry and Sox9. An analysis of histone acetylation at the Sry promoter in mutant gonads at 11.5 dpc shows a reduction in levels of the positive histone mark H3K27Ac. Our data suggest a role for CBP/p300 in testis determination mediated by control of histone acetylation at the Sry locus and reveal a novel element in the epigenetic control of Sry and mammalian sex determination. They also suggest possible novel causes of human disorders of sex development (DSD). PMID- 29145655 TI - Paternal Exposure to Environmental Chemical Stress Affects Male Offspring's Hepatic Mitochondria. AB - Preconceptional paternal exposures may affect offspring's health, which cannot be explained by mutations in germ cells, but by persistent changes in the regulation of gene expression. Therefore, we investigated whether pre-conceptional paternal exposure to benzo[a]pyrene (B[a]P) could alter the offspring's phenotype. Male C57BL/6 mice were exposed to B[a]P by gavage for 6 weeks, 3* per week, and were crossed with unexposed BALB-c females 6 weeks after the final exposure. The offspring was kept under normal feeding conditions and was sacrificed at 3 weeks of age. Analysis of the liver proteome by 2D-gel electrophoresis and mass spectrometry indicated that proteins involved in mitochondrial function were significantly downregulated in the offspring of exposed fathers. This down regulation of mitochondrial proteins was paralleled by a reduction in mitochondrial DNA copy number and reduced activity of citrate synthase and beta hydroxyacyl-CoA dehydrogenase, but in male offspring only. Surprisingly, analysis of hepatic mRNA expression revealed a male-specific up-regulation of the genes, whose proteins were downregulated, including Aldh2 and Ogg1. This discrepancy could be related to several selected microRNA (miRNA)'s that regulate the translation of these proteins; miRNA-122, miRNA-129-2-5p, and miRNA-1941 were upregulated in a gender-specific manner. Since mitochondria are thought to be a source of intracellular reactive oxygen species, we additionally assessed oxidatively-induced DNA damage. Both 8-hydroxy-deoxyguanosine and malondialdehyde dG adduct levels were significantly reduced in male offspring of exposed fathers. In conclusion, we show that paternal exposure to B[a]P can regulate mitochondrial metabolism in offspring, which may have profound implications for our understanding of health and disease risk inherited from fathers. PMID- 29145656 TI - Refining Operative Strategies for Optic Nerve Decompression: A Morphometric Analysis of Transcranial and Endoscopic Endonasal Techniques Using Clinical Parameters. AB - BACKGROUND: Various approaches can be considered for decompression of the intracanalicular optic nerve. Although clinical experience has been reported, no quantitative study has yet compared the extent of decompression achieved by an endoscopic endonasal versus transcranial approach. OBJECTIVE: Toward this aim, our morphometric analysis compared both approaches by quantifying the circumferential degree of optic canal decompression that is possible before any meningeal violation, which would result in cerebrospinal fluid (CSF) leak. METHODS: From 10 cadaver heads, 20 optic canals were sequentially decompressed using an endoscopic endonasal approach and pterional craniotomy with extradural clinoidectomy. Dissections ended before violation of the sphenoid sinus during the transcranial approach, and before intracranial transgression from the endonasal corridor. Based on our study criteria, decompressions were not maximal for either approach, but were maximal before violating the other compartment. Decompression achieved from each approach was quantified using CT scans for each stage. RESULTS: Greater circumferential bony optic canal decompression was obtained from transcranial (245.2 degrees ) than endonasal (114.8 degrees ) routes (P < .001). By endonasal perspective, the anatomical point where the optic nerve traverses intracranially was approximated by the medial border of the anterior ascending cavernous internal carotid artery. CONCLUSION: Our morphometric analysis comparing optic canal decompression for endonasal and transcranial corridors provides important guidance for this location. Ample visualization and wide exposure can be achieved via a transcranial approach with limited risk of CSF leak. A landmark, where the intracanalicular segment ends and optic nerve traverses intracranially, can mark the extent of decompression safely obtained before risking CSF leak. PMID- 29145657 TI - The utility of blood neuroendocrine gene transcript measurement in the diagnosis of bronchopulmonary neuroendocrine tumours and as a tool to evaluate surgical resection and disease progression. AB - OBJECTIVES: The management of bronchopulmonary neuroendocrine tumours (BPNETs) is difficult, since imaging, histology and biomarkers have a limited value in diagnosis, predicting outcome and defining therapeutic efficacy. We evaluated a NET multigene blood test (NETest) to diagnose BPNETs, assess disease status and evaluate surgical resection. METHODS: (i) Diagnostic cohort: BP carcinoids (n = 118)-typical carcinoid, n = 67 and atypical carcinoid, n = 51; other lung NEN (large-cell neuroendocrine carcinoma and small-cell lung carcinoma, n = 13); adenocarcinoma, (n = 26); squamous cell carcinoma (n = 23); controls (n = 90) and chronic obstructive pulmonary disease (n = 18). (ii) Surgical cohort, n = 28: BP carcinoids (n = 16: typical carcinoid 12; atypical carcinoid 4); large-cell neuroendocrine carcinoma, n = 3; lung adenocarcinoma, n = 8 and squamous cell carcinoma, n = 1. Blood sampling was performed presurgery and 30 days post surgery. Transcript levels measured by quantitative polymerase chain reaction were calculated as activity scores (0-100% scale: normal < 14%) and compared with chromogranin A (enzyme-linked immunosorbent assay; normal <109 ng/ml). RESULTS: NETest was significantly elevated in carcinoids (48.7 +/- 27%) versus controls (6 +/- 6%, P < 0.001) with metrics: sensitivity 93%, specificity 89%, positive predictive value 92% and negative predictive value 91%. NETest differentiated progressive disease (73 +/- 22%) from stable disease (36 +/- 19%, P < 0.001) and R0 resections (10 +/- 5%, P < 0.001, area under the curve: 0.98). Levels in chronic obstructive pulmonary disease and lung cancers were 18-24% while elevated in small-cell lung carcinoma/large-cell neuroendocrine carcinoma (59 +/- 10%). In BPNETs on postoperative Day 30, NETest decreased by 60% (P < 0.001). Chromogranin A was elevated in only 40% of carcinoids and not altered by surgery. CONCLUSIONS: Blood NET gene levels accurately identified BPNETs (100%) and differentiated these from controls, benign and malignant lung disease. Progressive disease could be identified and surgical resection verified. Chromogranin A had no clinical utility. Monitoring NET transcript levels in blood will facilitate management by detecting residual tumour and identifying progressive disease. PMID- 29145659 TI - The Population Health Research Institute. PMID- 29145660 TI - ACCA ESCel. PMID- 29145658 TI - Characterization of Detergent Insoluble Proteome in Chronic Traumatic Encephalopathy. AB - Quantitative proteomics of postmortem human brain can identify dysfunctional proteins that contribute to neurodegenerative disorders like Alzheimer disease (AD) and frontotemporal dementia. Similar studies in chronic traumatic encephalopathy (CTE) are limited, therefore we hypothesized that proteomic sequencing of CTE frontal cortex brain homogenates from varying CTE pathologic stages may provide important new insights into this disorder. Quantitative proteomics of control, CTE and AD brains was performed to characterize differentially expressed proteins, and we identified over 4000 proteins in CTE brains, including significant enrichment of the microtubule associated protein tau. We also found enrichment and pathologic aggregation of RNA processing factors as seen previously in AD, supporting the previously recognized overlap between AD and CTE. In addition to these similarities, we identified CTE-specific enrichment of proteins which increase with increasing severity of CTE pathology. NADPH dehydrogenase quinone 1 (NQO1) was one of the proteins which showed significant enrichment in CTE and also correlated with increasing CTE stage. NQO1 demonstrated neuropathologic correlation with hyperphosphorylated tau in glial cells, mainly astrocytes. These results demonstrate that quantitative proteomic analysis of CTE postmortem human brain can identify disease relevant findings and novel cellular pathways involved in CTE pathogenesis. PMID- 29145661 TI - David Conen MD MPH. PMID- 29145662 TI - Rare cardiovascular diseases. PMID- 29145663 TI - The EHJ Discussion Forum. PMID- 29145664 TI - Mice, vaccine, and human arteriosclerosis. PMID- 29145665 TI - Massimo Imazio MD FESC. PMID- 29145666 TI - Frontiers of Prevention: Pollution, Infection, Cognitive Function and Frailty. PMID- 29145667 TI - Planarians Customize Their Stem Cell Responses Following Genotoxic Stress as a Function of Exposure Time and Regenerative State. AB - Aiming to in vivo characterize the responses of pluripotent stem cells and regenerative tissues to carcinogenic stress, we employed the highly regenerative organism Schmidtea mediterranea. Its broad regenerative capacities are attributable to a large pool of pluripotent stem cells, which are considered key players in the lower vulnerability toward chemically induced carcinogenesis observed in regenerative organisms. Schmidtea mediterranea is, therefore, an ideal model to study pluripotent stem cell responses with stem cells residing in their natural environment. Including microenvironmental alterations is important, as the surrounding niche influences the onset of oncogenic events. Both short- (3 days) and long-term (17 days) exposures to the genotoxic carcinogen methyl methanesulfonate (50 uM) were evaluated during homeostasis and animal regeneration, two situations that render altered cellular niches. In both cases, MMS-induced DNA damage was observed, which provoked a decrease in proliferation on the short term. The outcome of DNA damage responses following long-term exposure differed between homeostatic and regenerating animals. During regeneration, DNA repair systems were more easily activated than in animals in homeostasis, where apoptosis was an important outcome. Knockdown experiments confirmed the importance of DNA repair systems during carcinogenic exposure in regenerating animals as knockdown of rad51 induced a stem cell-depleted phenotype, after regeneration was completed. PMID- 29145668 TI - Tamara K. Hervey, Calum Alasdair Young, and Louise E. Bishop (eds), Research Handbook on EU Health Law and Policy. PMID- 29145669 TI - Progress in Diagnostic Genetic Testing for Inherited Eye Disease. PMID- 29145670 TI - Sequential Firing Codes for Time in Rodent Medial Prefrontal Cortex. AB - A subset of hippocampal neurons, known as "time cells" fire sequentially for circumscribed periods of time within a delay interval. We investigated whether medial prefrontal cortex (mPFC) also contains time cells and whether their qualitative properties differ from those in the hippocampus and striatum. We studied the firing correlates of neurons in the rodent mPFC during a temporal discrimination task. On each trial, the animals waited for a few seconds in the stem of a T-maze. A subpopulation of units fired in a sequence consistently across trials for a circumscribed period during the delay interval. These sequentially activated time cells showed temporal accuracy that decreased as time passed as measured by both the width of their firing fields and the number of cells that fired at a particular part of the interval. The firing dynamics of the time cells was significantly better explained with the elapse of time than with the animals' position and velocity. The findings observed here in the mPFC are consistent with those previously reported in the hippocampus and striatum, suggesting that the sequentially activated time cells are not specific to these areas, but are part of a common representational motif across regions. PMID- 29145671 TI - Distinct Cerebellar Contributions to Cognitive-Perceptual Dynamics During Natural Viewing. AB - The crucial role of the cerebellum in motor learning and coordination is very well known. Considerable interest has recently shifted toward its contribution to nonmotor tasks, such as working memory, emotion, and language. However, the cognitive role and functional subdivisions of the cerebellum, particularly in dynamic, ecologically realistic contexts, are not yet established. By analyzing functional neuroimaging data acquired while participants viewed a short dramatic movie, we found that posterior and inferior cerebellar regions are reliably engaged in dynamic perceptual and affective processes with no explicit motor component. These cerebellar regions show significant relevance to visual salience and unexpected turning points of the movie. Our results demonstrate that distinct functional subdivisions of the cerebellum are robustly engaged in real-life cognitive processes, playing specific roles through a dynamic interaction with higher order regions in the cerebral cortex. PMID- 29145672 TI - Erratum to: "Helpfulness, Trust, and Safety of Neighborhoods: Social Capital, Household Income, and Self-Reported Health of Older Adults". PMID- 29145673 TI - Imaging Characteristics Predict Operative Difficulty Mobilizing the Sciatic Nerve for Proximal Hamstring Repair. AB - BACKGROUND: Repair of proximal hamstring avulsions requires mobilization of the sciatic nerve away from the tendon stump, which can be achieved with varying difficulty depending on the degree of scar formation and adherence. Predicting when a scarred, adherent, difficult-to-mobilize nerve will be encountered has been difficult. OBJECTIVE: To identify clinical and/or radiological factors predictive of a difficult intraoperative dissection of the sciatic nerve during proximal hamstring repair. METHODS: We retrospectively reviewed the medical records and preoperative magnetic resonance imaging of consecutive patients undergoing proximal hamstring repair. We compared the groups with and without a difficult sciatic nerve dissection. RESULTS: The total cohort consisted of 67 patients. Factors found to increase the likelihood of a difficult sciatic nerve dissection included complete conjoint tendon avulsion, higher maximal amount of tendon retraction, higher degree of imaging abnormality in the sciatic nerve, and higher degree of circumferential relationship of hematoma to the sciatic nerve. At a threshold of 23 for the Sciatic Nerve Dissection Score, the positive and negative predictive values were 53% and 88%, respectively. For the decision tree, the positive and negative predictive values were 75% and 87%, respectively. CONCLUSION: We have identified imaging factors associated with a scarred, adherent sciatic nerve that predict a difficult dissection during proximal hamstring repair. We have developed 2 novel methods-the Sciatic Nerve Dissection Score and a decision tree-that can be applied to predict the probability of a difficult sciatic nerve dissection at the time of surgical repair. PMID- 29145674 TI - ESGE-ESGENA technical specification for process validation and routine testing of endoscope reprocessing in washer-disinfectors according to EN ISO 15883, parts 1, 4, and ISO/TS 15883-5. AB - 1 Prerequisites. The clinical service provider should obtain confirmation from the endoscope washer-disinfector (EWD) manufacturer that all endoscopes intended to be used can be reprocessed in the EWD. 2 Installation qualification. This can be performed by different parties but national guidelines should define who has the responsibilities, taking into account legal requirements. 3 Operational qualification. This should include parametric tests to verify that the EWD is working according to its specifications. 4 Performance qualification. Testing of cleaning performance, microbiological testing of routinely used endoscopes, and the quality of the final rinse water should be considered in all local guidelines. The extent of these tests depends on local requirements. According to the results of type testing performed during EWD development, other parameters can be tested if local regulatory authorities accept this. Chemical residues on endoscope surfaces should be searched for, if acceptable test methods are available. 5 Routine inspections. National guidelines should consider both technical and performance criteria. Individual risk analyses performed in the validation and requalification processes are helpful for defining appropriate test frequencies for routine inspections. PMID- 29145675 TI - [Implementing the Cross-Disciplinary Subject Palliative Care - Lecture's Perspective]. AB - Introduction In 2009, palliative care was introduced as a mandatory subject in the undergraduate medical curriculum in Germany. Despite all efforts to integrate this subject into the curriculum, research suggests substantial differences and deficits in the quality of education between the medical schools. The aim of this research was to find out promoting as well as impedimental aspects of implementing palliative care in the medical training program. By this, a suitable framework in terms of content and structure for palliative care teaching should be extracted. Methods We performed guided interviews with 15 of the in total 36 lecturers responsible for the implementation of palliative care teaching at their respective medical schools. We focused on content, design and methods of implementation within the palliative care curriculum. Data was evaluated by content analysis according to Meuser and Nagel. Results We found that a lack of recognition of this subject within the medical faculties, coupled with entrenched structures of an already packed syllabus, were considered to be most relevant for the given heterogeneity in the implementation process. Deficits in personnel, financial and time resources also contributed to the perceived deficits. Faced with these difficulties, inner- and cross-faculty teamwork and support, extracurricular activities as well as external funds have proven to be important resources. Discussion To promote the implementation process, medical faculties need established palliative care structures that meet the interests and needs of the students more effectively. Analysis of structural needs (for instance, the amount of apprenticeships and teachings units) would be an important step to prove political claims. Moreover, the development of suitable and resource-saving teaching and assessment methods should be promoted. PMID- 29145676 TI - [Abnormal blood count - how to deal with an altered platelet and leukocytes count]. PMID- 29145677 TI - [88-Year-Old Patient with Known Dementia and Progressive Vigilance Reduction]. PMID- 29145678 TI - [Thrombocytosis and thrombocytopenia - background and clinical relevance]. AB - Due to the central role of platelets in hemostasis, the clinical relevance of quantitative changes in platelet counts (< 150 G/l or > 450 G/l) may be significant. Thrombopoesis (= production of platelets) occurs in the bone marrow, and the hormone thrombopoetin takes control on its regulation.In thrombocytosis, primary causes have to be distinguished from the far more common reactive (= secondary) reasons. The most important form of primary thrombocytosis occurs in myeloproliferative neoplasms especially in essential thrombocythemia (ET). Clinically, increased thrombophilia, microcirculatory disturbances as well as an increased hemorrhagic diathesis occur in patients with myeloproliferative neoplasms. According to the WHO diagnosis criteria 2016 standard diagnostic procedure in myeloproliferative neoplasms includes bone marrow biopsy and the detection of one of the acquired and typical MPN mutations in the JAK2, MPL or CALR gene.In contrast, patients with thrombocytopenia more often suffer from bleeding complications, however, in antiphospholipid syndrome or thrombotic microangiopathy (TMA) thrombotic events occur in spite of a low platelet count. Generally it makes sense to differentiate between pathological changes in thrombopoesis and the various causes of increased peripheral platelet turnover. Concerning differential diagnosis a careful anamnesis is very important in order to get hints like drugs associated with thrombocytopenia, signs of infection or autoimmune disorders. As an initial diagnostic approach we recommend examination of the blood smear in order to exclude pseudothrombocytopenia or disorderes like thrombotic microangiopathy, myelodysplasia or other hematological diseases. PMID- 29145679 TI - [Leukopenia - A Diagnostic Guideline for the Clinical Routine]. AB - Reasons for leukopenia can be numerous. To get close to the diagnosis it's always useful to check previous blood counts of the patient to get a feeling for the dynamic development of the leukopenia. Furthermore, it's important to check the red blood cell count and platelet count as well; a bi- or a pancytopenia usually implies an insufficient production in the bone marrow. Nevertheless, a manual counted peripheral blood smear is an essential step towards the right diagnosis in leukopenia: Beside cell counts of the single subgroups of leucocytes it also provides information on potential causes such as dysplasia.Leukopenia can be life threatening for the patient especially if the patient presents with an agranulocytosis and fever: In this case admission is mandatory and the patient has to be treated immediately with broad-spectrum antibiotics to reduce mortality. PMID- 29145681 TI - [Color- and Spectral-Doppler-Sonography: How to start an Examination - Step by Step]. PMID- 29145680 TI - [A Rare Differential Diagnosis of Chronic Cough]. AB - History and admission findings We report on a 62-year-old male patient with dry cough for 3 months, constitutional symptoms and elevated inflammatory markers. Investigations Despite extensive diagnostics no infectious, malignant or rheumatologic disease could be found. Bronchoscopy with bronchoalveolar lavage showed lymphocytosis. 18-FDG-PET/CT demonstrated increased metabolic activity of the aorta and its primary branches. Diagnosis, treatment and course We diagnosed large vessel vasculitis consistent to a subtype of giant cell arteritis (GCA) without cranial manifestation. Immunosuppressive therapy resulted in prompt resolution of symptoms and normalizing of inflammatory markers. Conclusions Elderly patients with unexplained fever, cough and constitutional symptoms should be investigated for GCA, even when classic symptoms are absent. Respiratory symptoms occur in about 4 % as initial and only presenting manifestation of GCA and in about 9 % along with classical symptoms.In cases with unclear focus of inflammation 18-FDG-PET/CT is becoming more and more important as a diagnostic tool. PMID- 29145682 TI - [Measles in Germany: An Epidemiological Analysis and First Measures for Containment]. AB - Measles are one of the most contagious diseases of mankind. Measles incidence has declined worldwide since the introduction of vaccinations. Due to low numbers of measles cases in countries with high vaccination rates the population is not aware of possible complications of measles any more. Measles elimination is an important goal set by all regions of the World Health Organization. However, it remains a challenge for Germany and other European countries. Because of a high proportion of susceptibles in specific population and age groups outbreaks take place in Germany every year after importation of the virus. More than 50 % of measles cases are 20 years and older. However, the highest incidences have been seen in two-year-olds since several years. In addition to epidemiological findings such as case numbers and risk groups, genotyping permits e. g. an assessment of the endemic circulation of viruses. Suspicion of a measles case should result in immediate and consistent measures. PMID- 29145683 TI - ? PMID- 29145684 TI - ? PMID- 29145685 TI - Relation between Monocyte to High-Density Lipoprotein Cholesterol Ratio and Presence and Severity of Erectile Dysfunction. AB - Previous studies have evidenced that inflammation and endothelial dysfunction have a crucial role in erectile dysfunction (ED). Increased monocyte count or activity and lower high-density lipoprotein cholesterol (HDL-C) levels have been associated with inflammation. The monocyte to HDL-C ratio (MHR) is a recently emerged indicator of inflammation. We aimed to investigate the relationship between MHR and ED. In this retrospective study, a total of 120 patients were enrolled, 60 of them having ED and 60 having a normal erectile function. The presence of ED was evaluated with the International Index of Erectile Function (IIEF-5). Patients with ED were compared with the control group for IIEF-5 and MHR. The mean ages of patients and controls were 55.6+/-5.53 and 56.42+/-6.63 years, respectively (p = 0.47). The risk factors for ED were similar between cases and controls. The total testosterone, glucose and creatinine levels did not differ between groups. While the HDL-C, LDL-C and triglyceride levels were similar between groups, the monocyte count (0.55+/-0.20 vs. 0.73+/-0.18, p < 0.0001) and MHR was significantly greater in patients with ED than in those without ED (1.31 vs. 1.77, p < 0.0001). MHR was significantly negatively correlated with IIEF-5 (p < 0.0001). To our knowledge, this is the first study that has shown a significant and independent association between elevated MHR and ED. PMID- 29145686 TI - [The use of partial nephrectomy in the treatment of patients with pT1/pT2 renal cell carcinoma: a trend analysis from a tertiary referral centre]. AB - INTRODUCTION: In patients with localised renal cell carcinoma, the only curative treatment option is surgical tumour excision. Current national and European guidelines recommend partial nephrectomy in the form of an open or minimally invasive procedure in case of small tumours. The aim of this study was to examine the use of radical (RN) or partial (PN) nephrectomy performed as open or minimally-invasive procedures in patients with pT1 /pT2 renal cell carcinoma at a tertiary referral centre. PATIENTS AND METHODS: This retrospective study included a total of 758 patients with localised renal cell carcinoma (pT1/pT2), who underwent PN or RN between 01/2008 and 10/2014. Nephrectomy was either performed as an open (OPN, ORN), laparoscopic (LPN, LRN) or robot-assisted laparoscopic (RAPN) procedure. RESULTS: Out of 758 patients, 439 (57.9 %) underwent PN performed as an LPN in n = 254 (57.9 %) and OPN in n = 185 (42.1 %). 319 patients (42.1 %) underwent RN performed as an LRN in n = 250 (78.4 %) and ORN in n = 69 (21.6 %). Between 2008 and 2014, there was a trend towards the use of PN, especially in patients with pT1a and pT1b. The majority of patients with pT2 underwent RN, performed as an LRN in 40 - 53.9 %. DISCUSSION: The results of this trend analysis from a tertiary referral centre demonstrate an increased use of PN and minimally-invasive procedures over time, as recommend by national and European guidelines. PMID- 29145687 TI - Foot Strike Patterns Differ Between Children and Adolescents Growing up Barefoot vs. Shod. AB - Effects of early and permanent footwear use are not well understood. The aim of this study was to investigate the effects of habituation to footwear on foot strike patterns of children and adolescents. Healthy habitually barefoot and shod participants (aged 6-18 years) from South Africa (n=288) and Germany (n=390) performed multiple 20-m jogging and running trials with and without shoes. Each foot strike was captured using a high-speed camera to determine a rearfoot or non rearfoot strike. The probability of a rearfoot strike in both cohorts and each age was analyzed by using a mixed-effects logistic regression adjusted for possible confounders. Habitually barefoot children showed a higher probability of using rearfoot strikes than habitually shod children (p<0.001). The probability was age-dependent and decreased in habitually barefoot children with age (ORbarefoot-jogging=0.82, 95% CI, 0.71 to 0.96, p=0.014; ORbarefoot-running=0.58, 95% CI, 0.50 to 0.67, p<0.001 and ORshod-running=0.68, 95% CI, 0.59 to 0.79, p<0.001). In habitually shod children, the probability increased significantly for shod jogging (OR=1.19, 95% CI, 1.05 to 1.35, p=0.006). To conclude, foot strike patterns of children are influenced by habituation to footwear. Younger habitually barefoot children show higher rates of rearfoot strikes for shod and barefoot running, and it converges in later adolescence. PMID- 29145688 TI - Is Primary Aldosteronism Still Largely Unrecognized? AB - Primary aldosteronism (PA) was first reported by Jerome W. Conn in 1954 when it was considered a rare disorder, only suspected in cases of hypertension and spontaneous hypokalemia. Over the last 30 years, with the wide application of the plasma aldosterone to plasma renin activity ratio as screening test, the clinical spectrum of PA has dramatically changed. Different studies displayed significant differences in term of patients investigated, diagnostic criteria and hormonal assays; however, large prospective studies with robust diagnostic criteria indicated that the prevalence of PA is around 6% of the general hypertensive population and 11% of the patients referred to hypertension centers. In light of these epidemiological studies, the Endocrine Society Guideline recommends the screening for PA of around 50% of patients with hypertension, and identifies the categories of patients at high risk for the disease. However, clinical data obtained from "real-life" show that the screening rate is much lower and PA remains an under-diagnosed and under-treated cause of secondary hypertension with an associated increased risk of cardio- and cerebrovascular mortality and morbidity. PMID- 29145689 TI - [Ultra-high-field MRI in the Chicken Embryo in Ovo - a Model for Experimental Ophthalmology]. AB - Ultra-high-field MRI (UHF-MRI) is an outstanding technique for non-invasive and non-destructive imaging of soft tissues and can provide versatile contrasts and high resolution in the um range. In vivo imaging of the embryonal chick eye with its filigree anatomical structures imposes these requirements. However, due to the short embryonal development cycle, chicken are a favourite animal model for embryonal research studies. Ultra-high-field MRI allows repeated and longitudinal in ovo investigations on the same embryo. In the present study, the limitations and opportunities of in ovo MR-imaging at 7 T were evaluated and the process of eye growth was described in detail. PMID- 29145690 TI - [Visual Analysis of Retinal OCT Data]. AB - Optical coherence tomography (OCT) enables noninvasive high-resolution 3D imaging of the human retina, and thus plays a fundamental role in ophthalmology. Via OCT examination, even subtle retinal changes can be captured, which occur in very early stages of different diseases (e.g., glaucoma, diabetes mellitus, or age related macular degeneration). Yet, analyzing the resulting data is challenging. Conventionally, OCT data are strongly aggregated via automated methods. While this reduces the amount of information to be analyzed, it also makes it difficult, if not impossible, to identify small and localized retinal changes. This might lead to wrong diagnoses, since these methods do not account for patient-specific characteristics. We address this problem by providing new and efficient visual-interactive methods. Particularly, we introduce dedicated visualizations that show different aspects of the data. In addition, we support patient-specific selections of relevant data regions. Selected regions are emphasized, or separately visualized to inspect retinal substructures in detail. By visually comparing the regions to reference data, even very small retinal changes can be detected. We demonstrate the utility of our approach by applying it to data of a study with pediatric patients suffering from diabetes mellitus type 1. Our results show that visual-interactive methods indeed help to analyze subtle retinal changes and, thus, support the diagnosis of diseases in an early stage. PMID- 29145691 TI - [Primary Intraocular Lymphoma: Relevance of Diagnostic Vitrectomy]. AB - Primary intraocular lymphomas are rare tumours that can be further subdivided into primary vitreoretinal and the even rarer primary uveal lymphoma. The incidence of primary vitreoretinal lymphoma (PVRL) has increased during the last few decades. Differential diagnostic distinction between lymphoma and posterior uveitis is often difficult, so that adequate diagnosis and treatment is often delayed. This is fatal, because PVRL is often associated with primary central nervous lymphoma. To confirm the diagnosis, prior treatment of cytological or histological detection of lymphoma cells is the gold standard. Therefore, a diagnostic vitrectomy should be performed with vitreous biopsy and sometimes transretinal biopsy. Cytokine analysis, as well as flow cytometry and molecular tests, are only additional methods that can be employed in case enough tumour material is available. After the diagnosis has been made, an interdisciplinary treatment concept must be developed by oncologists and ophthalmologists together. PMID- 29145692 TI - The Investigation on Resorcinarenes towards either Inhibiting or Promoting Insulin Fibrillation. AB - Different tail-engineered resorcinarenes have been examined for insulin fibrillation by experimental and computational studies. The resorcinarene showed a promising effect on the inhibition of insulin fibrillation, studied using a ThT assay, circular dichroism spectroscopy, and atomic force microscopy. Both the ThT assay and computational results indicate the tail from the resorcinarene has an impact on insulin fibrillation by either inhibition or promotion because of the resident position on insulin. These observations have significant biological implications in the design of drug molecules as well as the development of potential therapeutic strategies. PMID- 29145693 TI - Early erythropoiesis-stimulating agents in preterm or low birth weight infants. AB - BACKGROUND: Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES: To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions:To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives:Review authors performed subgroup analyses of low (<= 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (<= 5 mg/kg/d), and high (> 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs:To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance:To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives:To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. MAIN RESULTS: This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment.Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low.Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate.Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low.Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the ESA group (weighted mean difference (WMD) 8.22, 95% CI 6.52 to 9.92; I2 = 97% (high heterogeneity); 3 studies, 981 children). The quality of the evidence was low.The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced. Data show no significant difference in risk of stage >= 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI -0.02 to 0.04; I2 = 0% (no heterogeneity) for RR; I2 = 34% (low heterogeneity) for RD; 8 studies, 1283 infants). Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL). AUTHORS' CONCLUSIONS: Early administration of ESAs reduces the use of red blood cell (RBC) transfusions, the volume of RBCs transfused, and donor exposure after study entry. Small reductions are likely to be of limited clinical importance. Donor exposure probably is not avoided, given that all but one study included infants who had received RBC transfusions before trial entry. This update found no significant difference in the rate of ROP (stage >= 3) for studies that initiated EPO treatment at less than eight days of age, which has been a topic of concern in earlier versions of this review. Early EPO treatment significantly decreased rates of IVH, PVL, and NEC. Neurodevelopmental outcomes at 18 to 22 months and later varied in published studies. Ongoing research should evaluate current clinical practices that will limit donor exposure. Promising but conflicting results related to the neuro protective effect of early EPO require further study. Very different results from the two largest published trials and high heterogeneity in the analyses indicate that we should wait for the results of two ongoing large trials before drawing firm conclusions. Administration of EPO is not currently recommended because limited benefits have been identified to date. Use of darepoetin requires further study. PMID- 29145695 TI - Stealing Tregs' Identity (by Deleting NF-kappaB). PMID- 29145696 TI - Xenotransplantation: Time to Get Excited? PMID- 29145694 TI - Engineered and Natural Promoters and Chromatin-Modifying Elements for Recombinant Protein Expression in CHO Cells. AB - Promoters play a pivotal role in integrating and processing the signals related to transcription initiation. Strong natural viral promoters, such as hCMV or SV40E, have been routinely employed to achieve a high rate of gene expression in ubiquitously used Chinese hamster ovary (CHO) cells. However, viral promoters are susceptible to epigenetic silencing and lack precise regulation levers. This has paved the way to more sensible control elements: endogenous, inducible, and synthetic promoters. In this review we summarize and discuss the use of natural viral, mammalian, and endogenous promoters, as well as recent advances in synthetic promoters and inducible systems for protein expression in CHO cells. Not only the level of transcription, but its long-term stability is crucial for recombinant protein production. Epigenetic chromatin-modifying elements, such as ubiquitously acting chromatin opening elements (UCOEs), matrix attachment regions (MARs), insulators and stabilizing anti-repressors (STARs) significantly improve transcription levels over extended cultivation time and are also discussed here. This review provides up-to date information to facilitate the choice of a suitable promoter and adjacent chromatin-modifying elements to maximize transgene expression as well as ensure long-term expression stability in CHO cell culture. PMID- 29145697 TI - Acute liver failure in a pregnant patient. PMID- 29145698 TI - Illicit Drug Use, Illicit Drug Use Disorders, and Drug Overdose Deaths in Metropolitan and Nonmetropolitan Areas-United States. AB - PROBLEM/CONDITION: Drug overdoses are a leading cause of injury death in the United States, resulting in approximately 52,000 deaths in 2015. Understanding differences in illicit drug use, illicit drug use disorders, and overall drug overdose deaths in metropolitan and nonmetropolitan areas is important for informing public health programs, interventions, and policies. REPORTING PERIOD: Illicit drug use and drug use disorders during 2003-2014, and drug overdose deaths during 1999-2015. DESCRIPTION OF DATA: The National Survey of Drug Use and Health (NSDUH) collects information through face-to-face household interviews about the use of illicit drugs, alcohol, and tobacco among the U.S. noninstitutionalized civilian population aged >=12 years. Respondents include residents of households and noninstitutional group quarters (e.g., shelters, rooming houses, dormitories, migratory workers' camps, and halfway houses) and civilians living on military bases. NSDUH variables include sex, age, race/ethnicity, residence (metropolitan/nonmetropolitan), annual household income, self-reported drug use, and drug use disorders. National Vital Statistics System Mortality (NVSS-M) data for U.S. residents include information from death certificates filed in the 50 states and the District of Columbia. Cases were selected with an underlying cause of death based on the ICD-10 codes for drug overdoses (X40-X44, X60-X64, X85, and Y10-Y14). NVSS-M variables include decedent characteristics (sex, age, and race/ethnicity) and information on intent (unintentional, suicide, homicide, or undetermined), location of death (medical facility, in a home, or other [including nursing homes, hospices, unknown, and other locations]) and county of residence (metropolitan/nonmetropolitan). Metropolitan/nonmetropolitan status is assigned independently in each data system. NSDUH uses a three-category system: Core Based Statistical Area (CBSA) of >=1 million persons; CBSA of <1 million persons; and not a CBSA, which for simplicity were labeled large metropolitan, small metropolitan, and nonmetropolitan. Deaths from NVSS-M are categorized by the county of residence of the decedent using CDC's National Center for Health Statistics 2013 Urban-Rural Classification Scheme, collapsed into two categories (metropolitan and nonmetropolitan). RESULTS: Although both metropolitan and nonmetropolitan areas experienced significant increases from 2003-2005 to 2012-2014 in self-reported past-month use of illicit drugs, the prevalence was highest for the large metropolitan areas compared with small metropolitan or nonmetropolitan areas throughout the study period. Notably, past-month use of illicit drugs declined over the study period for the youngest respondents (aged 12-17 years). The prevalence of past-year illicit drug use disorders among persons using illicit drugs in the past year varied by metropolitan/nonmetropolitan status and changed over time. Across both metropolitan and nonmetropolitan areas, the prevalence of past-year illicit drug use disorders declined during 2003-2014. In 2015, approximately six times as many drug overdose deaths occurred in metropolitan areas than occurred in nonmetropolitan areas (metropolitan: 45,059; nonmetropolitan: 7,345). Drug overdose death rates (per 100,000 population) for metropolitan areas were higher than in nonmetropolitan areas in 1999 (6.4 versus 4.0), however, the rates converged in 2004, and by 2015, the nonmetropolitan rate (17.0) was slightly higher than the metropolitan rate (16.2). INTERPRETATION: Drug use and subsequent overdoses continue to be a critical and complicated public health challenge across metropolitan/nonmetropolitan areas. The decline in illicit drug use by youth and the lower prevalence of illicit drug use disorders in rural areas during 2012-2014 are encouraging signs. However, the increasing rate of drug overdose deaths in rural areas, which surpassed rates in urban areas, is cause for concern. PUBLIC HEALTH ACTIONS: Understanding the differences between metropolitan and nonmetropolitan areas in drug use, drug use disorders, and drug overdose deaths can help public health professionals to identify, monitor, and prioritize responses. Consideration of where persons live and where they die from overdose could enhance specific overdose prevention interventions, such as training on naloxone administration or rescue breathing. Educating prescribers on CDC's guideline for prescribing opioids for chronic pain (Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain United States, 2016. MMWR Recomm Rep 2016;66[No. RR-1]) and facilitating better access to medication-assisted treatment with methadone, buprenorphine, or naltrexone could benefit communities with high opioid use disorder rates. PMID- 29145699 TI - Focus on shared decision-making. PMID- 29145700 TI - Bridging the Gap Between Research and Practice. PMID- 29145701 TI - Editorial: Tumor Necrosis Factor Antagonists: Killing Two Birds With One Biologic Stone. PMID- 29145702 TI - Scorpion sting nephropathy: A case report. PMID- 29145703 TI - Zinc deficiency anaemia in haemodialysis patients: Often overlooked but a treatable cause of anaemia. PMID- 29145704 TI - Plasma exchange in the management of new onset multiple myeloma with cast nephropathy treated with bortezomib based chemotherapy. PMID- 29145705 TI - Review article: Critical Care Airway Management eLearning modules. AB - The Australasian College for Emergency Medicine (ACEM) has recently launched the Critical Care Airway Management eLearning modules to support emergency medicine trainees in developing their airway management skills in the ED. A team of emergency physicians and trainees worked collaboratively to develop the eLearning resources ensuring extensive stakeholder consultation. A comprehensive resource manual was written to provide learners with knowledge that underpins the modules. ACEM provided project coordination as well as administrative and technical team support to the production. Although specifically developed with early ACEM trainees in mind, it is envisaged the resources will be useful for all emergency clinicians. The project was funded by the Australian Commonwealth Department of Health. PMID- 29145706 TI - Expression of oestrogen receptors (GPER, ESR1, ESR2) in human ductuli efferentes and proximal epididymis. AB - Oestrogen targeting in the human genital ducts is still not well-known. In fact, to date, the localization of oestrogen receptors, ESR1 and ESR2, is controversial and the presence of the membrane oestrogen receptor GPER (G protein-coupled oestrogen receptor) is unexplored. This study has investigated the expression of GPER, ESR1, ESR2 in human ductuli efferentes and proximal caput epididymis by immunohistochemistry and Western blot analysis. Furthermore, the presence of PELP1 (proline-glutamic acid-leucine-rich protein 1), a co-regulator of the oestrogen receptors, was also evaluated. In ductuli efferentes, GPER and ESR1 were clearly localized in all epithelial cells, while ESR2 was evidenced only in ciliated cells. Conversely, the epithelial cells of proximal caput epididymis revealed moderate GPER immunoreactivity, the absence of ERS1 and the occasional presence of ESR2. Furthermore, PELP1 was observed in ciliated cells of ductuli efferentes and in principal cells of proximal caput epididymis. Therefore, this study firstly demonstrated the expression of GPER in human male genital ducts, revealing a new mediator of oestrogen action in these anatomical sites. ESR1 and ESR2 were differentially localized in the two genital tracts together with PELP1, but cell sites of ERs and their co-regulator were not homogeneous. So, a different regional/cellular association of GPER with the classical oestrogen receptors was highlighted, suggesting that oestrogen action could be mediated by GPER, ESR1, ESR2 in ductuli efferentes, while by GPER and, occasionally by ESR2, in proximal caput epididymis. This study suggests that the specific oestrogen mediated functions in human genital ducts might result from the different local interactions of oestrogens with oestrogen receptors and their co-regulators. PMID- 29145707 TI - Relationship between testosterone in serum, saliva and urine during treatment with intramuscular testosterone undecanoate in gender dysphoria and male hypogonadism. AB - Long-term testosterone replacement therapy is mainly monitored by trough levels of serum testosterone (S-T), while urinary testosterone (U-T) is used by forensic toxicology to evaluate testosterone doping. Testosterone in saliva (Sal-T) may provide additional information and simplify the sample collection. We aimed to investigate the relationships between testosterone measured in saliva, serum and urine during standard treatment with 1,000 mg testosterone undecanoate (TU) every 12th week during 1 year. This was an observational study. Males with primary and secondary hypogonadism (HG; n = 23), subjects with gender dysphoria (GD FtM; n = 15) and a healthy control group of men (n = 32) were investigated. Sal-T, S-T and U-T were measured before and after TU injections. Sal-T was determined with Salimetrics(r) enzyme immunoassay, S-T with Roche Elecsys(r) testosterone II assay and U-T by gas chromatography-mass spectrometry. Sal-T correlated significantly with S-T and calculated free testosterone in both controls and patients (HG men and GD FtM), while Sal-T to U-T showed weaker correlations. Trough values of Sal-T after 12 months were significantly higher in the GD FtM group (0.77 +/- 0.35 nmol/L) compared to HG men (0.53 +/- 0.22 nmol/L) and controls (0.46 +/- 0.15 nmol/L), while no differences between S-T and U-T trough values were found. Markedly elevated concentrations of salivary testosterone, 7 14 days after injection, were observed, especially in the GD FtM group. This study demonstrates that Sal-T might be a useful clinical tool to monitor long term testosterone replacement therapy and might give additional information in forensic cases. PMID- 29145708 TI - Managing non-serious low back pain in the emergency department: Time for a change? AB - Low back pain is a common condition seen in the ED. However, its management in this setting has received relatively little attention and there have been few efforts to develop strategies to improve emergency care of low back pain. In order to ensure that care is appropriately delivered for low back pain patients in the ED, emergency physicians must understand issues of providing low-value care and consider potential solutions to the problem. In this paper, we describe the usual emergency care provided for non-serious low back pain and present possible strategies for restructuring ED practice and approaches for changing physician and patient behaviour. A better understanding of how non-serious low back pain is currently being managed and discussion on how to provide evidence based care according to current guideline recommendations will help emergency physicians improve the value of care for these patients. PMID- 29145709 TI - Review: Defining a Unified Vascular Phenotype in Systemic Sclerosis. AB - Microcirculation impairment and related vasculopathy are hallmarks of systemic sclerosis (SSc). Digital ulceration is second only to Raynaud's phenomenon as a vascular complication occurring in patients with SSc. Digital ulcers are painful and generate disability. Furthermore, patients may develop recurrent digital ulcers, and it is reasonable to question whether the outcomes of such patients might be different from those of patients who are not affected. Recently, several registries have provided relevant information about digital ulcers. Male sex and severe skin disease appear to be the main associated factors observed in several registries. However, limitations of those studies are the differences in the definitions of digital ulcers and organ involvement. Few longitudinal studies are available, and the more robust data from the European League Against Rheumatism Scleroderma Trial and Research cohort suggested worse outcomes in patients with a history of digital ulcers but could not demonstrate that a history of digital ulcers can predict additional vascular complications such as pulmonary arterial hypertension, heart failure, or renal crisis. Nevertheless, the autopsy studies published many years ago and the more recent longitudinal biomarker studies support the concept of generalized vasculopathy and a potential association between various cardiovascular complications. It is expected that with the availability of several structured registries, identification of a vascular profile or vascular phenotype will be addressed using more robust data in the near future. PMID- 29145711 TI - Timing of antibiotics in the management of community-acquired sepsis: Can a randomised controlled trial of prehospital therapy provide answers? AB - Significant tension surrounds the application of antibiotics in suspected infection. Guidelines stress the importance of early empirical broad-spectrum therapy, with select observational data suggesting inferior outcomes when this is delayed. In contrast, microbiological resistance is an ever increasing global problem, with many advocating for a more restricted, culture-driven approach to antibiotic prescription. Controlled trial data are urgently needed, although many clinicians would find withholding of antibiotic therapy unethical. A trial of prehospital antibiotic administration (by paramedics) in patients with suspected sepsis would therefore provide crucial data, and go a long way to determining whether earlier empirical therapy does actually improve outcomes. PMID- 29145712 TI - Cartilage MicroRNA Dysregulation During the Onset and Progression of Mouse Osteoarthritis Is Independent of Aggrecanolysis and Overlaps With Candidates From End-Stage Human Disease. AB - OBJECTIVE: To identify candidate microRNAs (miRNAs) that potentially regulate the initiation and progression of osteoarthritis (OA). METHODS: OA was induced in 10 12-week-old male wild-type C57BL/6 mice and in mice resistant to aggrecanase cleavage (Acan p.374ALGS->374NVYS) by destabilization of the medial meniscus (DMM). Pathologic changes of OA were scored histologically. RNA from cartilage and subchondral bone was harvested in parallel by laser microdissection at 1 week and 6 weeks postsurgery. Global miRNA expression profiling was performed using Agilent microarrays and was validated by quantitative polymerase chain reaction analysis. RESULTS: Wild-type DMM mice had characteristic cartilage degeneration, subchondral bone sclerosis, and osteophyte formation. While no miRNA dysregulation was seen in subchondral bone, 139 miRNAs were differentially expressed in cartilage obtained at 1 and/or 6 weeks after OA initiation from wild type mice that underwent DMM. To prioritize OA candidates, dysregulated miRNAs with human orthologs were filtered, and paired miRNA/messenger RNA (mRNA) expression analysis was conducted to identify those with corresponding changes in mRNA target transcripts in the DMM mouse cartilage. An important cohort also overlapped with miRNAs identified in human end-stage OA. Comparisons of miRNA dysregulation in DMM mouse cartilage where aggrecan cleavage was genetically ablated demonstrated that all candidates were independent of aggrecan breakdown, earmarking these as important to the critical stages of OA initiation. Furthermore, functional enrichment analysis and data annotation revealed the responses to mechanical stimuli, apoptotic processes, and core extracellular matrix structural and regulatory factors to be potentially influenced by OA dysregulated miRNA/mRNA networks. CONCLUSION: Our comprehensive analyses identified high-priority miRNA candidates that have potential as biomarkers and therapeutic targets in human OA. PMID- 29145710 TI - Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis. AB - Sickle cell disease (SCD)-associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5. Adult male transgenic Berkeley sickle cell (Sickle) and wild-type (WT) mice were implanted with testosterone pellets, which release 1.2 MUg testosterone/day for 21 days, or vehicle. After 21 days, animals underwent erectile function assessment followed by collection of blood for serum testosterone measurements, penes for molecular analysis, and seminal vesicles as testosterone-responsive tissue. Serum testosterone levels were measured by radioimmunoassay; protein expressions of PDE5, alpha-smooth muscle actin, eNOS and nNOS, and phosphorylation of PDE5 at Ser-92, eNOS at Ser-1177, neuronal (n) NOS at Ser-1412, and Akt at Ser-473 were measured by Western blot in penile tissue. Testosterone treatment reversed downregulated serum testosterone levels and increased (p < 0.05) the weight of seminal vesicles in Sickle mice to levels comparable to that of WT mice, indicating restored testosterone levels in Sickle mice. Testosterone treatment reduced (p < 0.05) prolonged detumescence in Sickle mice and normalized downregulated P-PDE5 (Ser-92), PDE5, P-eNOS (Ser-1177), and P Akt (Ser-473) protein expressions in the Sickle mouse penis. Testosterone treatment did not affect P-nNOS (Ser-1412), eNOS, nNOS, or alpha-smooth muscle actin protein expressions in the Sickle mouse penis. In conclusion, in the mouse model of human SCD, increasing testosterone to eugonadal levels reduced priapic activity and reversed impaired Akt/eNOS activity and PDE5 protein expression in the penis. PMID- 29145713 TI - 18 F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis. AB - OBJECTIVE: To assess the clinical value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in a prospective cohort of patients with large vessel vasculitis (LVV) and comparator subjects. METHODS: Patients with Takayasu arteritis and giant cell arteritis were studied, along with a comparator group consisting of patients with hyperlipidemia, patients with diseases that mimic LVV, and healthy controls. Participants underwent clinical evaluation and FDG-PET imaging, and patients with LVV underwent serial imaging at 6-month intervals. We calculated sensitivity and specificity of FDG-PET interpretation for distinguishing patients with clinically active LVV from comparator subjects and from patients with disease in clinical remission. A qualitative summary score based on global arterial FDG uptake, the PET Vascular Activity Score (PETVAS), was used to study associations between activity on PET scan and clinical characteristics and to predict relapse. RESULTS: A total of 170 FDG-PET scans were performed in 115 participants (56 patients with LVV and 59 comparator subjects). FDG-PET distinguished patients with clinically active LVV from comparator subjects with a sensitivity of 85% (95% confidence interval [95% CI] 69, 94) and a specificity of 83% (95% CI 71, 91). FDG-PET scans were interpreted as active vasculitis in most patients with LVV in clinical remission (41 of 71 [58%]). Clinical disease activity status, disease duration, body mass index, and glucocorticoid use were independently associated with activity on PET scan. Among patients who underwent PET during clinical remission, future clinical relapse was more common in patients with a high PETVAS than in those with a low PETVAS (55% versus 11%; P = 0.03) over a median follow-up period of 15 months. CONCLUSION: FDG-PET provides information about vascular inflammation that is complementary to, and distinct from, clinical assessment in LVV. FDG-PET scan activity during clinical remission was associated with future clinical relapse. PMID- 29145714 TI - Clinical and biochemical correlates of male hypogonadism in type 2 diabetes. AB - The origin of hypogonadism, a condition including both symptoms and biochemical criteria of androgen deficiency, in type 2 diabetes is poorly known. In a cross sectional study of 267 unselected patients, we analyzed the potential correlation of several clinical and biochemical variables as well as chronic micro- and macrovascular diabetic complications with hypogonadism. Hypogonadism was present in 46 patients (17.2%) using a cutoff of total testosterone 10.4 nmol/L and in 31 (11.6%) with a cutoff of 8 nmol/L. Among these patients, hypogonadotropic hypogonadism was the most prevalent form (82.6%). Compared to eugonadal subjects, hypogonadal men had significantly lower glomerular filtration rate (67.1 +/- 23.4 vs. 78.4 +/- 24.6 mL/min/1.73 m2 , p = 0.005) and higher prevalence of chronic kidney disease (43.5% vs. 20.4%, p = 0.002), abnormal liver function tests (26.7% vs. 12%, p = 0.019), and psychiatric treatment (23.9% vs. 10.4%, p = 0.025). Total testosterone levels correlated inversely with age (R = -0.164, p = 0.007), fasting blood glucose (R = -0.127, p = 0.037), and triglycerides (R = -0.134, p = 0.029) and directly with glomerular filtration rate (R = 0.148, p = 0.015). Calculated free testosterone and bioavailable testosterone correlated directly with hemoglobin (R = 0.171, p = 0.015 and R = 0.234, p = 0.001, respectively). Multivariate logistic regression analysis, after adjusting for relevant confounding variables, showed that age >60 years (OR = 3.58, CI 95% = 1.48-8.69, p = 0.005), body mass index >27 kg/m2 (OR = 2.85, CI 95% = 1.14-7.11, p = 0.025), hypertriglyceridemia (OR = 2.16, CI 95% = 1.05-4.41, p = 0.035), glomerular filtration rate <60 mL/min/1.73 m2 (OR = 2.51, CI 95% = 1.19-5.29, p = 0.015), and abnormal liver function tests (OR = 3.57, CI 95% = 1.48-8.60, p = 0.005) were independently associated with male hypogonadism. Although older age, body mass index, and hypertriglyceridemia have been previously related to hypogonadism, our results describe that chronic kidney disease and abnormal liver function tests are independently correlated with hypogonadism in type 2 diabetic men. PMID- 29145715 TI - Effect of Social Support and Disclosure of Child Abuse on Adult Suicidal Ideation: Findings From a Population-Based Study. AB - Background: To examine the proportion of Canadian adults with a history of child abuse who disclosed the abuse to child protection services before age 16 years and identify the effect of social support and disclosure of child abuse on lifetime suicidal ideation. Methods: Data for this study came from the Statistics Canada 2012 Canadian Community Health Survey-Mental Health (N = 9,076). Binary logistic regression was conducted to identify the effect of social support and disclosure of child abuse on suicidal ideation while simultaneously adjusting for the effect of type of child abuse and demographic, socioeconomic, health, and mental health factors. Results: Of the 9,076 respondents who experienced at least one child abuse event, 21.5% reported ever experiencing suicidal ideation. Fewer than 6% of the respondents disclosed the abuse to someone from a child protection service before age 16 years. In the multivariate logistic regression model, respondents who disclosed the abuse to someone from child protection services were 1.37 times more likely to report lifetime suicidal ideation (95% CI, 1.10 1.71) than those who did not. Each additional unit increase in social support decreased the odds of lifetime suicidal ideation by a factor of 3% (95% CI, 0.95 0.98). Conclusions: Social support interventions that are effective in improving individuals' perception that support is available to them may help reduce suicidal ideation among those with a history of child abuse. PMID- 29145716 TI - Bupropion-Induced Dyskinesia in a Young Adult Patient With Bipolar Disorder. PMID- 29145717 TI - CTRP9 Regulates Growth, Differentiation, and Apoptosis in Human Keratinocytes through TGFbeta1-p38-Dependent Pathway. AB - Impairment of wound healing is a common problem in individuals with diabetes. Adiponectin, an adipocyte-derived cytokine, has many beneficial effects on metabolic disorders such as diabetes, obesity, hypertension, and dyslipidemia. C1q/TNF-Related Protein 9 (CTRP9), the closest paralog of adiponectin, has been reported to have beneficial effects on wound healing. In the current study, we demonstrate that CTRP9 regulates growth, differentiation, and apoptosis of HaCaT human keratinocytes. We found that CTRP9 augmented expression of transforming growth factor beta 1 (TGFbeta1) by transcription factor activator protein 1 (AP 1) binding activity and phosphorylation of p38 in a dose-dependent manner. Furthermore, siRNA-mediated suppression of TGFbeta1 reversed the increase in p38 phosphorylation induced by CTRP9. siRNA-mediated suppression of TGFbeta1 or p38 significantly abrogated the effects of CTRP9 on cell proliferation and differentiation while inducing apoptosis, implying that CTRP9 stimulates wound recovery through a TGFbeta1-dependent pathway in keratinocytes. Furthermore, intravenous injection of CTRP9 via tail vein suppressed mRNA expression of Ki67 and involucrin whereas it augmented TGFbeta1 mRNA expression and caspase 3 activity in skin of type 1 diabetes animal models. In conclusion, our results suggest that CTRP9 has suppressive effects on hyperkeratosis, providing a potentially effective therapeutic strategy for diabetic wounds. PMID- 29145718 TI - Lipopolysaccharide (LPS)-Induced Autophagy Is Responsible for Enhanced Osteoclastogenesis. AB - We hypothesized that inflammation affects number and activity of osteoclasts (OCs) via enhancing autophagy. Lipopolysaccharide (LPS) induced autophagy, osteoclastogenesis, and cytoplasmic reactive oxygen species (ROS) in bone marrow derived macrophages that were pre-stimulated with receptor activator of nuclear factor-kappaB ligand. An autophagy inhibitor, 3-methyladenine (3-MA) decreased LPS-induced OC formation and bone resorption, indicating that autophagy is responsible for increasing number and activity of OCs upon LPS stimulus. Knockdown of autophagy-related protein 7 attenuated the effect of LPS on OC specific genes, supporting a role of LPS as an autophagy inducer in OC. Removal of ROS decreased LPS-induced OC formation as well as autophagy. However, 3-MA did not affect LPS-induced ROS levels, suggesting that ROS act upstream of phosphatidylinositol-4,5-bisphosphate 3-kinase in LPS-induced autophagy. Our results suggest the possible use of autophagy inhibitors targeting OCs to reduce inflammatory bone loss. PMID- 29145719 TI - Maintained MPF Level after Oocyte Vitrification Improves Embryonic Development after IVF, but not after Somatic Cell Nuclear Transfer. AB - Levels of maturation-promoting factor (MPF) in oocytes decline after vitrification, and this decline has been suggested as one of the main causes of low developmental competence resulting from cryoinjury. Here, we evaluated MPF activity in vitrified mouse eggs following treatment with caffeine, a known stimulator of MPF activity, and/or the proteasome inhibitor MG132. Collected MII oocytes were vitrified and divided into four groups: untreated, 10 mM caffeine (CA), 10 MUM MG132 (MG), and 10 mM caffeine +10 MUM MG132 (CA+MG). After warming, the MPF activity of oocytes and their blastocyst formation and implantation rates in the CA, MG, and CA+MG groups were much higher than those in the untreated group. However, the cell numbers in blastocysts did not differ among groups. Analysis of the effectiveness of caffeine and MG132 for improving somatic cell nuclear transfer (SCNT) technology using cryopreserved eggs showed that supplementation did not improve the blastocyst formation rate of cloned mouse eggs. These results suggest that maintaining MPF activity after cryopreservation may have a positive effect on further embryonic development, but is unable to fully overcome cryoinjury. Thus, intrinsic factors governing the developmental potential that diminish during oocyte cryopreservation should be explored. PMID- 29145721 TI - Meta-analysis of day-of-week variation of acute aortic rupture or dissection. AB - BACKGROUND: We performed a meta-analysis to assess the presence of a day-of-week rhythmic variability of acute aortic rupture or dissection (AARD) onset. METHODS: Eligible studies were observational studies enrolling patients with AARD and reporting day-of-week variation of AARD. Study-specific estimates, i.e. day-of week incidence of AARD, were combined using the random-effects model. Chronobiological analysis was performed by applying a partial Fourier series to pooled day-of-week incidence by using the inverse-variance weighted least-squares method. RESULTS: We identified 9 eligible studies enrolling a total of 28,036 patients with AARD. Pooled incidence of AARD was 12.8% on Sunday, 15.9% on Monday, 14.8% on Tuesday, 15.1% on Wednesday, 14.7% on Thursday, 14.1% on Friday, and 12.1% on Saturday. Chronobiological analysis identified a significant (P = 0.0098) day-of-week in the occurrence of AARD with a peak on Monday and a nadir on Saturday. Pooled analysis demonstrated significantly more incidence on Monday than on Saturday (relative risk, 1.247; 95% confidence interval, 1.131 to 1.374; P = 0.012). CONCLUSIONS: Incidence of AARD was 12.8%, 15.9%, 14.8%, 15.1%, 14.7%, 14.1%, and 12.1%, on Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, and Saturday, respectively. A significant day-of-week pattern in the occurrence of AARD with a peak on Monday and a nadir on Saturday was identified with significantly more incidence on Monday than on Saturday. PMID- 29145722 TI - Outcomes of beating heart on pump utilizing a miniature bypass circuit versus off pump cardiac bypass at a Veterans Affairs Medical Center. AB - BACKGROUND: Off-pump coronary artery bypass grafting (OPCAB) helps reduce systemic inflammatory changes by maintaining native pulsatile flow. This analysis evaluates the outcomes of OPCAB at a Veterans Affairs Medical Center (VAMC) and evaluates the use of beating heart on-pump (BHOP) bypass grafting as an empiric therapy for high-risk patients. METHODS: We performed a retrospective analysis of 756 patients who underwent coronary bypass grafting between 2004-2015 at a single VAMC. This group was subdivided into BHOP (N.=60) versus OPCAB (N.=696). Analysis was performed using multivariate regression modeling with P=0.05 holding statistical significance. RESULTS: Both cohorts were predominantly male with an average age of 65 years and average Body Mass Index of 30 kg/m2. Individuals in the BHOP group were more likely to have COPD and resting ST depressions preoperatively. Operative time was longer and average number of conduits was higher for BHOP cases compared to OPCAB cases respectively. After controlling for differences between cohorts, multivariate regression analysis showed a protective effect of both BHOP (OR 0.325, P=0.035; OR 0.323, P=0.031) and two (OR 0.385, P<0.001; OR 0.539, P=0.018) and three (OR 0.154, P<0.001; OR 0.315, P<0.001) vessel revascularization on three and six-year mortality following revascularization. CONCLUSIONS: Postoperative survival following BHOP is superior to OPCAB when BHOP is used empirically with no difference in short-term mortality. Empiric use of BHOP should be considered for high risk coronary revascularization. PMID- 29145720 TI - Phospholipase D and Its Essential Role in Cancer. AB - The role of phospholipase D (PLD) in cancer development and management has been a major area of interest for researchers. The purpose of this mini-review is to explore PLD and its distinct role during chemotherapy including anti-apoptotic function. PLD is an enzyme that belongs to the phospholipase super family and is found in a broad range of organisms such as viruses, yeast, bacteria, animals, and plants. The function and activity of PLD are widely dependent on and regulated by neurotransmitters, hormones, small monomeric GTPases, and lipids. A growing body of research has shown that PLD activity is significantly increased in cancer tissues and cells, indicating that it plays a critical role in signal transduction, cell proliferation, and anti-apoptotic processes. In addition, recent studies show that PLD is a downstream transcriptional target of proteins that contribute to inflammation and carcinogenesis such as Sp1, NFkappaB, TCF4, ATF-2, NFATc2, and EWS-Fli. Thus, compounds that inhibit expression or activity of PLD in cells can be potentially useful in reducing inflammation and sensitizing resistant cancers during chemotherapy. PMID- 29145723 TI - Statin initiation and renal outcomes following isolated coronary artery bypass grafting: a meta-analysis. AB - INTRODUCTION: The effects of preoperative statin therapy (PST) on renal outcomes in patients with isolated coronary artery bypass grafting (CABG) are in controversial. This study aimed to assess the effects of preoperative statin use on postoperative renal outcomes in patients undergoing isolated CABG. EVIDENCE ACQUISITION: PubMed, EMBASE, and Cochrane Library were searched for studies published up to February 2017. Pooled odds ratio (OR) and its corresponding 95% confidence interval (95% CI) were calculated. Outcomes evaluated were occurrence of postoperative acute kidney injury (AKI)/failure, requirement of any postoperative renal replacement therapy (RRT) and change in serum creatinine (Scr) levels. We used random-effects model and calculated pooled effect estimate of outcome between statin and non-statin use groups. EVIDENCE SYNTHESIS: Eighteen studies consisting of 32,747 patients following CABG were included. PST was associated with a significant protective effect for perioperative renal dysfunction (OR 0.89; 95% CI: 0.82-0.97; P=0.01) and postoperative requirement for RRT (OR 0.54; 95% CI: 0.41-0.72; P=0.001) in patients undergoing CABG surgery. However, there were no effects of preoperative statin therapy on the risk of postoperative AKI and serum creatinine concentration. In the subgroup of patients after on-pump CABG surgery, PST significantly reduced the perioperative renal dysfunction and requirement for RRT (OR 0.69; 95% CI: 0.53-0.89; P=0.005, OR 0.51; 95% CI: 0.30-0.87; P=0.014, respectively). CONCLUSIONS: In patients undergoing isolated CABG, PST might be associated with lower risk of postoperative renal dysfunction and the requirement for RRT. However, PST may not reduce the risk of AKI. Future large well-designed randomized controlled trials are needed on this topic. PMID- 29145724 TI - Abdominal organ protection: distal perfusion during replacement of the ascending aorta and aortic arch. PMID- 29145725 TI - Effectiveness of 3D printed models in obtaining informed consent to complex aortic surgery. PMID- 29145726 TI - Developing a Continuous Bioprocessing Approach to Stromal Cell Manufacture. AB - To this day, the concept of continuous bioprocessing has been applied mostly to the manufacture of molecular biologics such as proteins, growth factors, and secondary metabolites with biopharmaceutical uses. The present work now sets to explore the potential application of continuous bioprocess methods to source large numbers of human adherent cells with potential therapeutic value. To this purpose, we developed a smart multifunctional surface coating capable of controlling the attachment, proliferation, and subsequent self-detachment of human corneal stromal cells. This system allowed the maintenance of cell cultures under steady-state growth conditions, where self-detaching cells were continuously replenished by the proliferation of those remaining attached. This facilitated a closed, continuous bioprocessing platform with recovery of approximately 1% of the total adherent cells per hour, a yield rate that was maintained for 1 month. Moreover, both attached and self-detached cells were shown to retain their original phenotype. Together, these results represent the proof-of-concept for a new high-throughput, high-standard, and low-cost biomanufacturing strategy with multiple potentials and important downstream applications. PMID- 29145727 TI - Directly Observing Micelle Fusion and Growth in Solution by Liquid-Cell Transmission Electron Microscopy. AB - Amphiphilic small molecules and polymers form commonplace nanoscale macromolecular compartments and bilayers, and as such are truly essential components in all cells and in many cellular processes. The nature of these architectures, including their formation, phase changes, and stimuli-response behaviors, is necessary for the most basic functions of life, and over the past half-century, these natural micellar structures have inspired a vast diversity of industrial products, from biomedicines to detergents, lubricants, and coatings. The importance of these materials and their ubiquity have made them the subject of intense investigation regarding their nanoscale dynamics with increasing interest in obtaining sufficient temporal and spatial resolution to directly observe nanoscale processes. However, the vast majority of experimental methods involve either bulk-averaging techniques including light, neutron, and X-ray scattering, or are static in nature including even the most advanced cryogenic transmission electron microscopy techniques. Here, we employ in situ liquid-cell transmission electron microscopy (LCTEM) to directly observe the evolution of individual amphiphilic block copolymer micellar nanoparticles in solution, in real time with nanometer spatial resolution. These observations, made on a proof of-concept bioconjugate polymer amphiphile, revealed growth and evolution occurring by unimer addition processes and by particle-particle collision-and fusion events. The experimental approach, combining direct LCTEM observation, quantitative analysis of LCTEM data, and correlated in silico simulations, provides a unique view of solvated soft matter nanoassemblies as they morph and evolve in time and space, enabling us to capture these phenomena in solution. PMID- 29145729 TI - Prof. Dr Fathi Saad (03.03.1944-16.08.2017). PMID- 29145728 TI - Understanding how emergency medicine physicians survive and thrive in rural practice: a theoretical model. AB - INTRODUCTION: The challenges facing emergency medicine (EM) services in Canada reflect the limitations of the entire healthcare system. The emergency department (ED) is uniquely situated in the healthcare system such that shortcomings in hospital- and community-based services are often first revealed there. This is especially true in rural settings, where there are additional site-specific barriers to the provision of EM care. Existing studies look at the factors that influence rural EM physicians in isolation. This study uses a qualitative approach and generates a theoretical model that describes the complex interplay between major factors that influence the experience of rural EM physicians. METHODS: Eight focus groups were conducted with 39 physicians from rural British Columbia, Canada. Semi-structured focus group protocols were designed to leverage the diversity of the focus groups, which included rural generalists, full-time EM practitioners, physicians from very small and remote communities, locums, international medical graduates, physicians new to practice, and physicians who no longer practice rural EM. Following the principles of grounded theory, interview probes were adjusted iteratively to reflect emerging findings. Transcripts were analysed to identify codes and major themes, which served as the basis for the theoretical model. RESULTS: The theoretical model reveals how the causal conditions (a lack of medical and human resources, and the isolation of rural communities due to topography, distance, and inclement weather) contribute to physicians' common experience of feeling fearful and under-supported at work. Two core phenomena emerge as important needs: supportive professional relationships, and healthcare system adaptability. Contextual factors such as remuneration and continuing medical education funding, and the intervening conditions of physicians' rural exposure during formative years, also have an effect. Physicians create innovative solutions to address the challenges that arise in the practice of rural EM. Ultimately, the ability to manage the pressures of rural EM leads physicians to either thrive in or leave rural EM practice. CONCLUSIONS: The theoretical model provides a more complex view of the realities of rural EM care than has been previously described. It identifies factors that enable and hinder rural EM physicians in their practice, and provides an understanding of the strategies they employ to navigate challenges. Some elements of the theoretical model have been previously identified. For example, existing work has found that many rural physicians experience fear and anxiety in their practice. The challenges posed by the variation in rural practice environments have also been previously identified as an important influence. Other elements of the theoretical model, and the common need for practitioners to creatively respond to barriers arising from the healthcare system's inability to respond to local needs, have not been previously identified. This work finds these factors to be a common experience for participants, and as such, more widespread recognition of the importance of these factors could lead to system improvements. Future research is needed to test the hypotheses proposed in this study and explore the generalizability of the findings. PMID- 29145730 TI - Screening and evaluation of antioxidant activity of some 1,2,4-triazolo[1,5 a]quinazoline derivatives. AB - AIM: The present study was carried out to assess a new series of triazoloquinazolines 1-40 for their antioxidant activities using 1,1-diphenyl-2 picryl hydrazyl radical scavenging, ferric reduction antioxidant power and reducing power capability assays. RESULTS: All triazoloquinazolines 1-40 exhibited antioxidant activity ranged from weak to moderate and high. The obtained findings revealed that the triazoloquinazolines 30, 36 and 38-40 have superiority among all compounds, demonstrating the highest capacity to deplete 1,1-diphenyl-2-picryl hydrazyl and free radicals, in relation to butylated hydroxyl toluene, as a synthetic antioxidant agent. CONCLUSION: Chemical modifications together with density functional theory study on the targets supplied us with some valuable clarifications about the required properties needed for the target compounds to be more active against free radicals. PMID- 29145731 TI - Decline of Physical Activity in Terminally Ill Patients Could Be Useful for Predicting Short-Term Survival. AB - BACKGROUND: Although it is recommended that all terminally ill patients receive advance care planning (ACP), this is occasionally challenging because of the difficulty in predicting survival. There are some indexes for predicting survival, but few are accurate, especially at the terminal stages of illness. METHODS: Twenty-two patients at the terminal stages of cancer were retrospectively analyzed. We assessed their physical activity and condition using activities of daily living (ADL) scores for 1 month before the death. The ADL scores included 7 items: walking, bathing, grooming, dressing, eating, transferring, and toileting. RESULTS: Survival time after the first decline of physical activity was calculated (median: 13 days, 95% confidence interval [95% CI]: 5.6-20.4 days). Survival time after the second (median: 5 days, 95% CI: 0 10.9 days), third (median: 5 days, 95% CI: 0-13.4 days), and fourth (median time: 1 day, 95% CI: not applicable due to small size) decline of physical activity was also calculated. CONCLUSION: Change in physical activity seems helpful for estimating survival time, especially at the end of life, and this index could be useful for coordinating final ACP. PMID- 29145732 TI - Nobel Prizes, Nudge Theory, and Public Health. PMID- 29145733 TI - Harnessing Novel Imaging Approaches to Guide HIV Prevention and Cure Discoveries A National Institutes of Health and Global HIV Vaccine Enterprise 2017 Meeting Report. AB - Advances in imaging technologies have greatly increased our understanding of cellular and molecular interactions in humans and their corresponding animal models of infectious diseases. In the HIV/SIV field, imaging has provided key insights into mucosal viral transmission, local and systemic virus spread, host virus dynamics, and chronic inflammation/immune activation and the resultant immunopathology. Recent developments in imaging applications are yielding physical, spatial, and temporal measurements to enhance insight into biological functions and disease processes, while retaining important cellular, microenvironmental, organ, and intact organism contextual details. Taking advantage of the latest advancements in imaging technologies may help answer important questions in the HIV field. The Global HIV Vaccine Enterprise in collaboration with the National Institutes of Health (NIH) sponsored a meeting on May 8 and 9, 2017 to provide a platform to review state-of-the-art imaging technologies and to foster multidisciplinary collaborations in HIV/AIDS research. The meeting covered applications of imaging in studies of early events and pathogenesis, reservoirs, and cure, as well as in vaccine development. In addition, presentations and discussions of imaging applications from non-HIV biomedical research areas were included. This report summarizes the presentations and discussions at the meeting. PMID- 29145734 TI - Two dopaminergic genes, DRD4 and SLC6A3, are associated with body mass index in a Colombian sample of young adults. AB - Obesity is becoming an epidemic in Latin American countries. Genetic analyses of endophenotypes for obesity, such as body mass index (BMI), are quite useful for research. In this study, we analysed two functional polymorphisms in the dopamine receptor 4 (DRD4) and dopamine transporter (SLC6A3) genes. A sample of 232 Colombian young subjects were recruited and evaluated for BMI. Two functional polymorphisms in the DRD4 and SLC6A3 and genes were genotyped by PCR and electrophoresis. A significant association was found between BMI and the polymorphisms in DRD4 and SLC6A3 genes. DRD4 4/4 genotype was associated with a lower mean BMI and SLC6A3 10/10 genotype was associated with a higher mean BMI. Our work provides additional novel findings about the association of dopaminergic genes with BMI in healthy young adults. In addition, our study is one the first analyses of candidate genes for BMI in Latin American samples. PMID- 29145735 TI - Evaluation of Performance of Laboratories and Manufacturers Within the Framework of the IFCC model for Quality Targets of HbA1c. AB - HbA1c is a key parameter in diabetes management. For years the test has been used exclusively for monitoring of long-term diabetic control. However, due to improvement of the performance, HbA1c is considered more and more for diagnosis and screening. With this new application, quality demands further increase. A task force of the International Federation of Clinical Chemistry and Laboratory Medicine developed a model to set and evaluate quality targets for HbA1c. The model is based on the concept of total error and takes into account the major sources of analytical errors in the medical laboratory: bias and imprecision. Performance criteria are derived from sigma-metrics and biological variation. This review shows 2 examples of the application of the model: at the level of single laboratories, and at the level of a group of laboratories. In the first example data of 125 individual laboratories of a recent external quality assessment program in the Netherlands are evaluated. Differences between laboratories as well as their relation to method principles are shown. The second example uses recent and 3-year-old data of the proficiency test of the College of American Pathologists. The differences in performance between 26 manufacturer related groups of laboratories are shown. Over time these differences are quite consistent although some manufacturers improved substantially either by better standardization or by replacing a test. The IFCC model serves all who are involved in HbA1c testing in the ongoing process of better performance and better patient care. PMID- 29145736 TI - Longitudinal study of the activities of daily living and quality of life in Japanese patients with fibrodysplasia ossificans progressiva. AB - PURPOSE: Fibrodysplasia ossificans progressiva is a rare congenital disorder that causes systemic heterotopic ossification, leading to systemic ankyloses and mobility losses. This study aimed to ascertain the natural history of fibrodysplasia ossificans progressiva. METHODS: In addition to the medical history questionnaire, patients aged 16 years and older were asked to complete activities of daily living and quality of life surveys using the Barthel Index, MOS 36-Item Short-Form Health Survey, and Health Assessment Questionnaire. The surveys were conducted over a 4-years period. RESULTS: Of the 15 participating patients, 13 reported swelling during the study period. The Barthel Index and Health Assessment Questionnaire surveys indicated a tendency for questionnaire items related to arm function to reflect early decreases in the activities of daily living. Decreases in activities of daily living functioning were closely related to decreases in the quality of life in physical function domains. Activities of daily living and quality of life were maintained at a similar level to baseline values over the study period (Barthel Index: p = 0.42, MOS 36-Item Short-Form Health Survey: p = 0.43, Health Assessment Questionnaire: p = 0.87). CONCLUSIONS: We obtained longitudinal information relating to natural history on fibrodysplasia ossificans progressiva patients. Implications for rehabilitation Fibrodysplasia ossificans progressiva is a rare congenital disease that causes heterotopic ossification of muscle tissue throughout the body, leading to systemic ankyloses and mobility losses. When the Barthel Index was high and the activities of daily living were relatively stable, the items on the Health Assessment Questionnaire that are related to arm function began to show impairment. Early focus on upper extremity function that includes the use of assistive devices during the period when a patient is still able to perform many activities of daily living is important. Although decreases in activities of daily living functioning were closely related to decreases in the quality of life in the physical function domains, the scores of the domains other than physical function were similar to the national standard score. PMID- 29145737 TI - Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. AB - This review describes trials evaluating the monoclonal antibody pembrolizumab (an immunotherapy that blocks the interaction between programmed death-1 and programmed death-ligand 1 and 2 [PD-L1/PD-L2]) as first-line therapy for advanced non-small-cell lung cancer (NSCLC). In the Phase III KEYNOTE-024 study, pembrolizumab monotherapy significantly improved progression-free survival (primary end point) and overall survival, and was associated with fewer adverse events compared with platinum-based chemotherapy in patients with NSCLC with PD L1 expression on >=50% of tumor cells. In cohort G of the Phase I/II KEYNOTE-021 study, pembrolizumab plus pemetrexed and carboplatin significantly improved objective response rate (primary end point) and progression-free survival versus pemetrexed and carboplatin alone, and had manageable toxicity in patients with nonsquamous NSCLC. These results have changed first-line management of advanced NSCLC. PMID- 29145738 TI - Development of a psychosocial group intervention for individuals with mild cognitive impairment (innovative practice). AB - A diagnosis of mild cognitive impairment is associated with an increase in anxiety and depression and a decrease in psychological well-being. Despite this, individuals with mild cognitive impairment may not receive the appropriate support needed to manage the emotional and practical elements of their diagnosis. A psychosocial group intervention based on the 'Recovery Model' was developed in order to meet these needs. Outcome data from a trial of this group intervention indicated it was successful in meeting its aims. PMID- 29145739 TI - The development of positive psychology outcome measures and their uses in dementia research: A systematic review. AB - Positive psychology is gaining credence within dementia research but currently there is a lack of outcome measures within this area developed specifically for people with dementia. Authors have begun adopting positive psychology measures developed with other populations but there is no consensus around which are more appropriate or psychometrically robust. A systematic search identified measures used between 1998 and 2017 and an appraisal of the development procedure was undertaken using standardised criteria enabling the awarding of scores based on reporting of psychometric information. Twelve measures within the constructs of identity, hope, religiosity/spirituality, life valuation, self-efficacy, community and wellbeing were identified as being used within 17 dementia studies. Development procedures were variable and scores on development criterion reflected this variability. Of the measures included, the Herth Hope Index, Systems of Belief Inventory and Psychological Wellbeing Scale appeared to be the most robustly developed and appropriate for people with dementia. PMID- 29145740 TI - Fair or square? Experiences of introducing a new method for assessing general work ability in a sickness insurance context. AB - PURPOSE: To study social validity and perceived fairness of a new method for assessing general work ability in a sickness insurance context. Assessments are based on self-reports, combined with examinations by physicians, and, if needed, occupational therapists, physiotherapists and/or psychologists. MATERIALS AND METHODS: Interviews with 36 insurance officials, 10 physicians, and 36 sick listed persons, which were analysed through a qualitative content analysis. RESULTS: Insurance officials and physicians considered the method useful and that it facilitated benefit decisions. The experiences of persons who had undergone the assessment differed, where the dialog with insurance officials seemed to have had an influence on experiences of the assessment and the decisions it led to. CONCLUSIONS: The perceived fairness and social validity of the assessment depended on how it was carried out; organisational conditions and priorities; communication skills; and decision outcomes. Professionals have an important pedagogical task in explaining the purpose and procedure of the assessment in order for the sick-listed to perceive it as fair rather than square, i.e., too standardised and not considering individual conditions. If the assessment could be used also for rehabilitative purposes, it could possibly be perceived as more acceptable also in cases where it leads to denied benefits. Implications for rehabilitation The perceived fairness of work ability assessments is dependent on procedures for the assessment, communication with the person, and the outcome. What is considered fair differs between assessing professionals and persons being assessed. Professionals may influence the perceptions of fairness through their way of communication. Assessments need to be coupled with rehabilitation measures in order to perceived as relevant and acceptable. PMID- 29145741 TI - A Cohort Approach to Real-Time Detection of Acute HIV Infections Among People Who Inject Drugs in St. Petersburg, Russia. AB - To detect acute HIV infections (AHIs) in real time among people who inject drugs (PWID) in St. Petersburg, Russia and to test the feasibility of this approach. Prospective cohort study. One hundred seronegative or acutely HIV-infected at screening PWID were enrolled and followed until the end of the 12-month pilot period. Each participant was evaluated, tested, and counseled for HIV monthly. Two HIV tests were used: HIV antibody and HIV RNA PCR. If diagnosed with AHI, participants were followed weekly for a month; then, monthly for 3 months; and then, quarterly for the duration of the follow-up period. HIV risk behavior was assessed at each study visit. Most enrolled PWID were 30-39 years old, male, completed high school or more, not employed full-time, heroin users, and frequently shared injection paraphernalia. AHI prevalence at screening was 1.8% [95% confidence interval (CI): 0.4, 5.5]. Three participants with AHI at enrollment represented 3% (95% CI: 0.6, 8.5) of the 100 participants who consented to enroll. Among the HIV-uninfected participants (n = 97), the AHI incidence over time was 9.3 per 100 person-years. Persons with AHI were more likely to report alcohol intoxication within the prior 30 days. This was the first study to detect AHI using a cohort approach. The approach proved to be feasible: recruitment, retention, AHI detection, and virological endpoints were successfully reached. A cost analysis in a real-world setting would be required to determine if this strategy could be brought to scale. The study revealed continued high HIV incidence rate among PWID in St. Petersburg, Russia and the importance of prevention and treatment programs for this group. PMID- 29145742 TI - Improving mechanical thrombectomy time metrics in the angiography suite: Stroke cart, parallel workflows, and conscious sedation. AB - Purpose Earlier reperfusion of large-vessel occlusion (LVO) stroke improves functional outcomes. We hypothesize that use of a stroke cart in the angiography suite, containing all commonly used procedural equipment in a mechanical thrombectomy, combined with parallel staff workflows, and use of conscious sedation when possible, improve mechanical thrombectomy time metrics. Methods We identified 47 consecutive LVO patients who underwent mechanical thrombectomy at our center, retrospectively and prospectively from implementation of these three workflow changes (19 pre- and 28 post-). For each patient, last known normal, NIHSS, angiography suite in-room time, type of anesthesia, groin puncture time, on-clot time, recanalization time, LVO location, number of passes, device(s) used, mTICI score, and outcome (mRS) were recorded. Between-group comparisons of time metrics and multivariate regression were performed. Results Stroke cart, parallel workflows, and primary use of conscious sedation decreased in-room time to groin puncture (-21.3 min, p < 0.0001), in-room to on-clot time (-24.1 min, p = 0.001), and in-room to reperfusion time (-29.5 min, p = 0.01). In a multivariate analysis, endotracheal intubation and general anesthesia were found to significantly increase in-room to on-clot time ( p = 0.01), in-room to reperfusion time ( p = 0.01), and groin puncture to on-clot time ( p = 0.05). The number of patients achieving a good outcome (mRS 0-2), however, did not significantly differ between the two groups (9/18 (47%) vs 14/28 (50%), p = 0.60). Conclusions Use of a stroke cart, parallel workflows by neurointerventionalists, technologists, and nursing staff, and use of conscious sedation may be useful to other institutions in efforts to improve procedural times. PMID- 29145743 TI - Novel avenues for drug discovery in diabetic kidney disease. AB - INTRODUCTION: Diabetic kidney disease (DKD) has emerged as major cause of morbidity and mortality. After progressing to renal failure, over 70% of DKD patients are dead with five years. New treatments to slow this progression are desperately needed. Areas covered: This review highlights the current treatment options for people with DKD with a particular focus on angiotensin pathway blockade and the potential use of sodium glucose linked transporter 2 (SGLT2) inhibitors. These treatments are associated with an initial decrease in glomerular filtration rate (GFR) and albuminuria; there is also attention on renal hyperfiltration as therapeutic target. Both clinical and preclinical testing are facilitated by leveraging albuminuria reduction as a dynamic biomarker of drug effect linked to renal failure. It is critical to ensure that animal models exhibit both albuminuria and progressive loss of renal function so drug effects can be established in both. Expert opinion: New pathways and potential drug targets are emerging from gene expression profiling of human kidney biopsies and genome wide association studies. By harmonizing animal experimentation endpoints with clinical outcomes, focusing on disease pathophysiology and incorporating novel gene expression and biomarker changes, therapeutics can be advanced into clinical testing with greater confidence. PMID- 29145745 TI - Recruitment of Underrepresented Minority Researchers into HIV Prevention Research: The HIV Prevention Trials Network Scholars Program. AB - Most U.S. investigators in the HIV Prevention Trials Network (HPTN) have been of majority race/ethnicity and sexual orientation. Research participants, in contrast, have been disproportionately from racial/ethnic minorities and men who have sex with men (MSM), reflecting the U.S. epidemic. We initiated and subsequently evaluated the HPTN Scholars Program that mentors early career investigators from underrepresented minority groups. Scholars were affiliated with the HPTN for 12-18 months, mentored by a senior researcher to analyze HPTN study data. Participation in scientific committees, trainings, protocol teams, and advisory groups was facilitated, followed by evaluative exit surveys. Twenty six trainees have produced 17 peer-reviewed articles to date. Research topics typically explored health disparities and HIV prevention among black and Hispanic MSM and at-risk black women. Most scholars (81% in the first five cohorts) continued HIV research after program completion. Alumni reported program-related career benefits and subsequent funding successes. Their feedback also suggested that we must improve the scholars' abilities to engage new research protocols that are developed within the network. Mentored engagement can nurture the professional development of young researchers from racial/ethnic and sexual minority communities. Minority scientists can benefit from training and mentoring within research consortia, whereas the network research benefits from perspectives of underrepresented minority scientists. PMID- 29145746 TI - Clinical efficacy and economic evaluation of online cognitive behavioral therapy for major depressive disorder: a systematic review and meta-analysis. AB - INTRODUCTION: Leading cause of disability worldwide, depression is the most prevalent mental disorder with growing societal costs. As mental health services demand often outweighs provision, accessible treatment options are needed. Our systematic review and meta-analysis evaluated the clinical efficacy and economic evidence for the use of online cognitive behavioral therapy (oCBT) as an accessible treatment solution for depression. Areas covered: Electronic databases were searched for controlled trials published between 2006 and 2016. Of the reviewed 3,324 studies, 29 met the criteria for inclusion in the efficacy meta analysis. The systematic review identified five oCBT economic evaluations. Therapist-supported oCBT was equivalent to face-to-face CBT at improving depressive symptoms and superior to treatment-as-usual, waitlist control, and attention control. Depression severity, number of sessions, or support did not affect efficacy. From a healthcare provider perspective, oCBT tended to show greater costs with greater benefits in the short term, relative to comparator treatments. Expert commentary: Although efficacious, further economic evidence is required to support the provision of oCBT as a cost-effective treatment for depression. Economic evaluations that incorporate a societal perspective will better account for direct and indirect treatment costs. Nevertheless, oCBT shows promise of effectively improving depressive symptoms, considering limited mental healthcare resources. PMID- 29145747 TI - Two novel families with hemiplegic migraine caused by recurrent SCN1A mutation p.F1499L. AB - Background Familial hemiplegic migraine type 3 is a monogenic subtype of migraine caused by missense mutations in the neuronal voltage-gated sodium channel gene SCN1A, with 10 different mutations reported so far. In two familial hemiplegic migraine type 3 families, partial cosegregation with a rare eye phenotype (elicited repetitive daily blindness) was previously reported. Methods Two novel familial hemiplegic migraine pedigrees were subjected to genetic analysis and detailed work-up of associated clinical features. Results In both pedigrees, we identified SCN1A mutation p.F1499L, which has been previously associated with familial hemiplegic migraine type 3 and elicited repetitive daily blindness. Both families displayed a pure familial hemiplegic migraine phenotype without evidence of an episodic eye phenotype. Conclusion Like a substantial proportion of other familial hemiplegic migraine type 3 mutations, p.F1499L affects the intracellular linker between domains III and IV of SCN1A, which seems to be a mutational hot spot. Our new data establish p.F1499L as a recurrent familial hemiplegic migraine type 3 mutation. Elicited repetitive daily blindness seems to be a rare phenomenon in familial hemiplegic migraine type 3, even in carriers of the same mutation. PMID- 29145748 TI - Application of hot melt extrusion for improving bioavailability of artemisinin a thermolabile drug. AB - Hot melt extrusion has been used to produce a solid dispersion of the thermolabile drug artemisinin. Formulation and process conditions were optimized prior to evaluation of dissolution and biopharmaceutical performance. Soluplus(r), a low Tg amphiphilic polymer especially designed for solid dispersions enabled melt extrusion at 110 degrees C although some drug-polymer incompatibility was observed. Addition of 5% citric acid as a pH modifier was found to suppress the degradation. The area under plasma concentration time curve (AUC0-24h) and peak plasma concentration (Cmax) were four times higher for the modified solid dispersion compared to that of pure artemisinin. PMID- 29145749 TI - First Experiences With a Wearable Multisensor Device in a Noninvasive Continuous Glucose Monitoring Study at Home, Part II: The Investigators' View. AB - BACKGROUND: Extensive past work showed that noninvasive continuous glucose monitoring with a wearable multisensor device worn on the upper arm provides useful information about glucose trends to improve diabetes therapy in controlled and semicontrolled conditions. METHOD: To test previous findings also in uncontrolled conditions, a long term at home study has been organized to collect multisensor and reference glucose data in a population of 20 type 1 diabetes subjects. A total of 1072 study days were collected and a fully on-line compatible algorithmic routine linking multisensor data to glucose applied to estimate glucose levels noninvasively. RESULTS: The algorithm used here calculates glucose values from sensor data and adds a constant obtained by a daily calibration. It provides point inaccuracy measured by a MARD of 35.4 mg/dL on test data. This is higher than current state-of-the-art minimally invasive devices, but still 86.9% of glucose rate points fall within the zone AR+BR. CONCLUSIONS: The multisensor device and the algorithmic routine used earlier in controlled conditions tracks glucose changes also in uncontrolled conditions, although with lower accuracy. The examination of learning curves suggests that obtaining more data would not improve the results. Therefore, further efforts would focus on the development of more complex algorithmic routines able to compensate for environmental and physiological confounders better. PMID- 29145750 TI - Feasibility of on-line temperature-based hyperthermia treatment planning to improve tumour temperatures during locoregional hyperthermia. AB - BACKGROUND: The effectiveness of hyperthermia is strongly dependent on the achieved tumour temperatures. Phased-array systems allow flexible power steering to realise good tumour heating while avoiding excessive heating in normal tissue, but the limited quantitative accuracy of pre-treatment planning complicates realising optimal tumour heating. On-line hyperthermia treatment planning could help to improve the heating quality. This paper demonstrates the feasibility of using on-line temperature-based treatment planning to improve the heating quality during hyperthermia in three patients. METHODS: Hyperthermia treatment planning was performed using the Plan2Heat software package combined with a dedicated graphical user interface for on-line application. Electric fields were pre calculated to allow instant update and visualisation of the predicted temperature distribution for user-selected phase-amplitude settings during treatment. On-line treatment planning using manual variation of system settings for the AMC-8 hyperthermia system was applied in one patient with a deep-seated pelvic melanoma metastasis and two cervical cancer patients. For a clinically relevant improvement the increase in average target temperature should be at least 0.2 degrees C. RESULTS: With the assistance of on-line treatment planning a substantial improvement in tumour temperatures was realised for all three patients. In the melanoma patient, the average measured target temperature increased from 38.30 degrees C to 39.15 degrees C (i.e. +0.85 degrees C). In the cervical cancer patients, the average measured target temperature increased from 41.30 degrees C to 42.05 degrees C (i.e. +0.75 degrees C) and from 41.70 degrees C to 42.80 degrees C (i.e. +1.1 degrees C), respectively. CONCLUSION: On-line temperature-based treatment planning is clinically feasible to improve tumour temperatures. A next, worthwhile step is automatic optimisation for a larger number of patients. PMID- 29145751 TI - Negative Symptoms and Reward Disturbances in Schizophrenia Before and After Antipsychotic Monotherapy. AB - BACKGROUND: Negative symptoms (NS) are a central part of the symptomatology of schizophrenia, which is highly correlated to the functional outcome. Disturbances of the brain reward system are suggested to be central in the pathogenesis of NS by decreasing motivation and hedonic experiences. In this study, we compared reward-related brain activity in patients improving and not improving in NS after treatment with amisulpride. METHODS: Thirty-nine antipsychotic-naive patients and 49 healthy controls completed functional magnetic resonance imaging with a modified monetary incentive delay task. Psychopathology of the patients was characterised with Positive and Negative Syndrome Scale (PANSS), and they were treated with individual doses of amisulpride (mean 271 mg) for 6 weeks, after which the examinations were repeated. RESULTS: Patients improved on positive, general, and total PANSS score after treatment ( P < .001). Fourteen patients had >=20% improvement of NS, whereas 25 patients improved <20%. At baseline, one-way analysis of variance showed group difference bilaterally in the caudate nucleus and in the right nucleus accumbens (all P < .002), which was caused by decreased reward anticipation activity in the nonimproving patients compared to healthy controls. There was a significant group * time interaction, with the healthy controls and the improvers decreasing and the nonimprovers increasing in reward anticipation activity after treatment, most pronounced in the left caudate nucleus ( P = .001). DISCUSSION: Patients improving in NS score had a less aberrant reward system at baseline, but reward related activity was reduced over time. Patients not improving in NS showed decreased striatal reward-activity at baseline, which improved over time. Whether this is associated with alteration in working memory and reward learning or with pronounced symptoms within specific domains of NS may be addressed in future studies. PMID- 29145752 TI - Association of Hormonal Contraception With Suicide Attempts and Suicides. AB - OBJECTIVE: The purpose of this study was to assess the relative risk of suicide attempt and suicide in users of hormonal contraception. METHOD: The authors assessed associations between hormonal contraceptive use and suicide attempt and suicide in a nationwide prospective cohort study of all women in Denmark who had no psychiatric diagnoses, antidepressant use, or hormonal contraceptive use before age 15 and who turned 15 during the study period, which extended from 1996 through 2013. Nationwide registers provided individually updated information about use of hormonal contraception, suicide attempt, suicide, and potential confounding variables. Psychiatric diagnoses or antidepressant use during the study period were considered potential mediators between hormonal contraceptive use and risk of suicide attempt. Adjusted hazard ratios for suicide attempt and suicide were estimated for users of hormonal contraception as compared with those who never used hormonal contraception. RESULTS: Among nearly half a million women followed on average for 8.3 years (3.9 million person-years) with a mean age of 21 years, 6,999 first suicide attempts and 71 suicides were identified. Compared with women who never used hormonal contraceptives, the relative risk among current and recent users was 1.97 (95% CI=1.85-2.10) for suicide attempt and 3.08 (95% CI=1.34-7.08) for suicide. Risk estimates for suicide attempt were 1.91 (95% CI=1.79-2.03) for oral combined products, 2.29 (95% CI=1.77-2.95) for oral progestin-only products, 2.58 (95% CI=2.06-3.22) for vaginal ring, and 3.28 (95% CI=2.08-5.16) for patch. The association between hormonal contraceptive use and a first suicide attempt peaked after 2 months of use. CONCLUSIONS: Use of hormonal contraception was positively associated with subsequent suicide attempt and suicide. Adolescent women experienced the highest relative risk. PMID- 29145755 TI - Defining, Recognizing, and Reporting Malnutrition. AB - Although malnutrition is a common health and social care problem, there is no universal agreement about its definition, prevalence, or method of identification and report. Fifteen definitions of malnutrition were critically examined to assess their variability. They ranged from descriptions of undernutrition alone to under- and overnutrition, with intakes ranging from dietary protein and energy alone to dietary and nondietary sources of all nutrients and energy. Definitions also varied from non-outcome based to those based on functional, physiological, and/or clinical outcomes. Some definitions relied on the pathways by which malnutrition develops, with one apparently requiring loss of fat-free mass. Also examined were nutrition screening tools, diversely developed for detection of malnutrition, management of malnutrition, and prediction of clinical outcomes or health care usage. Their intended use also varied from specific care settings (hospital, community, care homes) to all settings and from specific age groups to all age groups. With all these definitions and tools, there is considerable scope for confusion and misunderstanding. Therefore, to clarify the burden and significance of malnutrition, guidelines for documenting it in routine practice and reporting it in scientific literature are provided. PMID- 29145756 TI - Micronutrients and Natural Compounds Status and Their Effects on Wound Healing in the Diabetic Foot Ulcer. AB - The diabetic foot ulcer (DFU) is an invariably common complication of diabetes mellitus, it is also a significant cause of amputation as well as extended hospitalization. As most patients with DFU suffer from malnutrition, which has been related to improper metabolic micronutrients status, alterations can affect impaired wound healing process. Micronutrients and herbal remedies applications present a wide range of health advantages to patients with DFU. The purpose of this review is to provide current evidence on the potential effect of dietary supplementations such as vitamins A, C, D, E, magnesium, zinc, copper, iron, boron, and such naturally occurring compounds as Aloe vera, Naringin, and Radix Astragali (RA) and Radix Rehmanniae (RR) in the administration of lower extremity wounds, especially in DFU, and to present some insights for applications in the treatment of DFU patients in the future. PMID- 29145754 TI - Cortical and Subcortical Brain Morphometry Differences Between Patients With Autism Spectrum Disorder and Healthy Individuals Across the Lifespan: Results From the ENIGMA ASD Working Group. AB - OBJECTIVE: Neuroimaging studies show structural differences in both cortical and subcortical brain regions in children and adults with autism spectrum disorder (ASD) compared with healthy subjects. Findings are inconsistent, however, and it is unclear how differences develop across the lifespan. The authors investigated brain morphometry differences between individuals with ASD and healthy subjects, cross-sectionally across the lifespan, in a large multinational sample from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) ASD working group. METHOD: The sample comprised 1,571 patients with ASD and 1,651 healthy control subjects (age range, 2-64 years) from 49 participating sites. MRI scans were preprocessed at individual sites with a harmonized protocol based on a validated automated-segmentation software program. Mega-analyses were used to test for case control differences in subcortical volumes, cortical thickness, and surface area. Development of brain morphometry over the lifespan was modeled using a fractional polynomial approach. RESULTS: The case-control mega-analysis demonstrated that ASD was associated with smaller subcortical volumes of the pallidum, putamen, amygdala, and nucleus accumbens (effect sizes [Cohen's d], 0.13 to -0.13), as well as increased cortical thickness in the frontal cortex and decreased thickness in the temporal cortex (effect sizes, -0.21 to 0.20). Analyses of age effects indicate that the development of cortical thickness is altered in ASD, with the largest differences occurring around adolescence. No age-by-ASD interactions were observed in the subcortical partitions. CONCLUSIONS: The ENIGMA ASD working group provides the largest study of brain morphometry differences in ASD to date, using a well-established, validated, publicly available analysis pipeline. ASD patients showed altered morphometry in the cognitive and affective parts of the striatum, frontal cortex, and temporal cortex. Complex developmental trajectories were observed for the different regions, with a developmental peak around adolescence. These findings suggest an interplay in the abnormal development of the striatal, frontal, and temporal regions in ASD across the lifespan. PMID- 29145757 TI - Nutrition and Lower Extremity Ulcers: Causality and/or Treatment. AB - The association between malnutrition, impaired wound healing, and the presence of chronic wounds has been recognized for a long time. It is widely believed that the lack of adequate nutrition increases the risk of developing wounds which have a great likelihood of progressing to chronicity due to lack of appropriate healing responses. This risk is particularly high in the aging population. For the individual patient, as well as patient populations, the diagnosis of malnutrition has been in dispute; further, there is lack of agreement of when and how to intervene nutritionally in those with wounds or healing deficits. This article examines the relationship of nutritional status with the presence and clinical evolution of leg ulcers in humans, focusing on diabetic and venous leg ulcers; we will further review the effect of nutritional therapy on the outcome of these ulcers. PMID- 29145753 TI - The Neurodevelopmental Basis of Early Childhood Disruptive Behavior: Irritable and Callous Phenotypes as Exemplars. AB - The arrival of the Journal's 175th anniversary occurs at a time of recent advances in research, providing an ideal opportunity to present a neurodevelopmental roadmap for understanding, preventing, and treating psychiatric disorders. Such a roadmap is particularly relevant for early childhood-onset neurodevelopmental conditions, which emerge when experience dependent neuroplasticity is at its peak. Employing a novel developmental specification approach, this review places recent neurodevelopmental research on early childhood disruptive behavior within the historical context of the Journal. The authors highlight irritability and callous behavior as two core exemplars of early disruptive behavior. Both phenotypes can be reliably differentiated from normative variation as early as the first years of life. Both link to discrete pathophysiology: irritability with disruptions in prefrontal regulation of emotion, and callous behavior with abnormal fear processing. Each phenotype also possesses clinical and predictive utility. Based on a nomologic net of evidence, the authors conclude that early disruptive behavior is neurodevelopmental in nature and should be reclassified as an early-childhood-onset neurodevelopmental condition in DSM-5. Rapid translation from neurodevelopmental discovery to clinical application has transformative potential for psychiatric approaches of the millennium. [AJP at 175: Remembering Our Past As We Envision Our Future November 1938: Electroencephalographic Analyses of Behavior Problem Children Herbert Jasper and colleagues found that brain abnormalities revealed by EEG are a potential causal factor in childhood behavioral disorders. (Am J Psychiatry 1938; 95:641-658 )]. PMID- 29145758 TI - Higher Level of Chicken Consumption Associated With Less Severe Venous Disease. AB - The aim of this study was to investigate the impact of various food intake in patients with varicose veins. A cross-sectional study was conducted between December 2012 through November 2014. Patients at the outpatient department 101 at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand, who were older than > 18 years were invited to participate in this study. The severity of varicose veins was divided into 2 groups according to CEAP (clinical, etiological, anatomical, and pathophysiological) classification: mild type of venous disease (C0-C2) and severe type of venous disease (C3-C6). Patients were interviewed about their demographic data and frequency of meat consumption for varicose veins using Vein Consult Program (VCP). A total of 558 eligible outpatients were recruited for the study. Most patients were female (78.9%) and aged >50 years (47.1%). Seventeen out of 558 patients were diagnosed with high severity of venous disease (3.0%). Remarkably, significantly higher body weight (73.8 +/- 13.9 vs 58.4 +/- 11.2 kg, P = .000) and body mass index (28.8 +/- 4.4 vs 23.3 +/- 3.9 kg/m2, P = .000) was found in patients with severe types of venous disease compared with the mild group. Unexpectedly, only chicken intake demonstrated the different association with varicose veins ( P = .022). Patients with severe venous disease showed lower frequency of chicken consumption. The results suggested an association of chicken consumption with a reduced chance of developing varicose veins. PMID- 29145760 TI - Non-cirrhotic portal hypertension associated with multicentric Castleman's disease: a case report. PMID- 29145759 TI - Isolation and molecular characterization of a urease-negative Actinobacillus pleuropneumoniae mutant. AB - An atypical urease-negative mutant of Actinobacillus pleuropneumoniae serovar 2 was isolated in Japan. Nucleotide sequence analysis of the urease gene cluster revealed that the insertion of a short DNA sequence into the cbiM gene was responsible for the urease-negative activity of the mutant. Veterinary diagnostic laboratories should be watchful for the presence of aberrant urease-negative A. pleuropneumoniae isolates. PMID- 29145761 TI - Non-fluent speech following stroke is caused by impaired efference copy. AB - Efference copy is a cognitive mechanism argued to be critical for initiating and monitoring speech: however, the extent to which breakdown of efference copy mechanisms impact speech production is unclear. This study examined the best mechanistic predictors of non-fluent speech among 88 stroke survivors. Objective speech fluency measures were subjected to a principal component analysis (PCA). The primary PCA factor was then entered into a multiple stepwise linear regression analysis as the dependent variable, with a set of independent mechanistic variables. Participants' ability to mimic audio-visual speech ("speech entrainment response") was the best independent predictor of non-fluent speech. We suggest that this "speech entrainment" factor reflects integrity of internal monitoring (i.e., efference copy) of speech production, which affects speech initiation and maintenance. Results support models of normal speech production and suggest that therapy focused on speech initiation and maintenance may improve speech fluency for individuals with chronic non-fluent aphasia post stroke. PMID- 29145762 TI - A decade of sulphite control in Serbian meat industry and the effect of HACCP. AB - In total 7351 meat preparations and fresh processed meat products were analysed from 555 different Serbian meat producers over a 10-year period, 4.5 years before and 5.5 years after mandatory Hazard Analysis and Critical Control Points (HACCP) implementation. From the obtained results, it could be concluded that HACCP has contributed to a better alignment of practices with the legal provisions. The share of non-compliant samples dropped from 18.6% before HACCP to 8.3% after its mandatory implementation. Average sulphite concentrations for all categories of meat preparations and fresh processed meat products decreased by 43%, declining from 33.6 to 19.3 mg kg-1. Typical misuse and frequent abuse of sulphites was independent of a season. Application of HACCP principles in the Serbian meat industry raised awareness about the misuse of sulphites and contributed to a better control, minimising exposure to sulphites. PMID- 29145763 TI - The impact of students with left-behind experiences on childhood: The relationship between negative life events and depression among college students in China. AB - BACKGROUND: The number of left-behind children in rural China has increased dramatically over the last decade. It is reported that about 21.88% of child population with an estimated number of 61 million are left-behind children whose parents leave them to work in cities. We conducted a cross-sectional study to explore the impacts of left-behind experience (LBE) on college students' depression and other influencing factors. AIM: This study discusses the mediation effect of self-esteem together with psychological resilience on college students with depression and negative life events of left-behind. The study also discusses the regulation effect of LBE. METHODS: A total of 788 college students were selected from three universities in Sichuan and Chongqing (367 with LBEs, 421 without LBEs). Adolescent Self-Rating Life Events Check List (ASLEC), Self-Esteem Scale (SES), Resilience Scale of Chinese Adolescent (RSCA) and Self-Rating Depression Scale (SDS) were used to measure the negative life events, self esteem, psychological resilience and depression, respectively. Bootstrap program was used to test the mediation effect, and multiple-group analysis was used to examine the regulation effect for LBE. RESULTS: Scores of ASLEC for the college students with LBEs were higher than those without LBEs (8.59 +/- 3.57) vs (7.06 +/- 3.38), p < .001). The scores of LBE, ASLEC and SDS were positively correlated with the college students with LBEs ( r = .21 to .29, p < .01), while the scores of RSCA and SES were negatively correlated ( r = -.30 to -.59, p < .01). The mediation effect of college students' self-esteem and psychological resilience between negative life events and depression was significant (mediating effect = .08, .13, .07; p < .01). Thus, the college students' self-esteem and psychological resilience on negative life events had strong mediation effect on depression. The test of Bootstrap showed that the mediation effect of self-esteem and psychological resilience was significant (95% confidence interval (CI) = [0.04-0.76]). The LBE had regulation effect on college students' self-esteem and psychological resilience. (The constraint model fitting degree of variation is Deltachi2 = 2,120.68, Delta df = 8, p < .001.) The self-esteem and psychological resilience of college students with LBEs can be used to mediate the relation between negative life events and depression, whereas those without LBEs cannot. CONCLUSION: Self-esteem and psychological resilience fully mediates college students' negative life events and depression, which is regulated by their previous LBEs. PMID- 29145764 TI - Plasma corticosterone, epinephrine, and norepinephrine levels increase during administration of nitrous oxide in rats. AB - Nitrous oxide (N2O) is a gaseous drug with abuse potential. Despite its common clinical use, little is known about whether N2O administration activates the HPA axis and/or the sympathetic adrenomedullary system. The goal of this study was to determine whether 60% N2O alters plasma concentrations of corticosterone (CORT), epinephrine (EPI), and norepinephrine (NE) in male Long-Evans rats. A gas-tight swivel assembly in the lid of a gas administration chamber allowed the remote collection of blood samples from an indwelling jugular vein catheter at four time points: baseline and at 30, 60, and 120 min during a two-hour administration of 60% N2O. Relative to baseline, plasma CORT (n = 9) was significantly elevated at all three time-points during N2O inhalation (mixed model analysis, p = .001) and plasma EPI and NE levels were each significantly elevated (n = 8, p <= .001) at the 30 min assessment. EPI then declined and did not differ from baseline at the 60 and 120 min assessments (p > .05) whereas NE remained elevated (120 min, p = .001). Administration of 60% N2O increases circulating CORT, EPI, and NE, supporting N2O as a physiological stressor. An N2O-induced increase in CORT is consistent with the observation that addictive drugs typically activate the HPA axis causing increased plasma levels of glucocorticoids. Allostatic models of drug addiction typically involve stress systems and the possible role of stress hormones in N2O-induced allostatic dysregulation is discussed. PMID- 29145765 TI - Epidemiological and treatment-related factors contribute to improved outcome of oropharyngeal squamous cell carcinoma in Finland. AB - BACKGROUND: Treatment for oropharyngeal squamous cell carcinoma (OPSCC) has changed, as the proportion of human papilloma virus (HPV)-related disease has increased. We evaluated nationwide information on its management and outcome during the treatment paradigm change period. METHODS: We included all patients diagnosed and treated for OPSCC at the five Finnish university hospitals from 2000 to 2009. Patient records and pathology registries provided the clinicopathological data. p16 staining was performed on primary tumor samples of patients who had received treatment with curative intent. RESULTS: A total of 674 patients were diagnosed and treated for OPSCC and the incidence increased along the study period. Of the evaluable tumors 58.5% were p16-positive and the number of p16-positive tumors increased along the years. The treatment was given with curative intent for 600 patients and it was completed in 564. Of them, 47.9% underwent primary surgery and 52.1% received definitive oncological treatment. Also, the treatment protocol changed towards a more oncological approach. Among patients treated with curative intent the five-year overall, disease-specific and disease-free survival rates were 60.1, 71.5 and 57.0%. In multivariate analysis, p16-positivity seemed to relate to reduced disease mortality in lateral and anterior-wall disease. Depending on primary tumor localization, also sex, classes T3-4, presence of regional metastasis and radiotherapy modality had an association with disease mortality. CONCLUSION: The incidence of p16-positive OPSCC and delivery of definitive oncological treatment increased in Finland during the study period. An improved survival outcome compared with the previous nationwide investigation was observed in this subset of patients. PMID- 29145766 TI - Environmental samples make soiled bedding sentinels dispensable for hygienic monitoring of IVC-reared mouse colonies. AB - Accurate knowledge of the health status of experimental animals is pivotal to high scientific and ethical standards in biomedical research. Individually ventilated cages (IVCs) are becoming the predominant system for housing laboratory mice, as they prevent cage-to-cage infections. However, this feature constitutes a major drawback for hygienic monitoring of mouse colonies, as traditional screening programs build on reliable transmission of infectious agents from experimental animals to sentinel mice commonly tested as representatives for the mouse colonies. In recent years, the laboratory animal community has realized that sentinels are ineffectual for screening mouse colonies in IVC systems because infections are often not transmitted to sentinels and therefore remain undetected. Furthermore, sentinel monitoring results in high numbers of used animals. In contrast, environmental monitoring provides a more reliable approach to identify and exclude pathogens in rodent colonies. In recent studies we provided evidence that polymerase chain reaction analysis of exhaust air particles is superior to soiled bedding sentinels for different agents. In this study, we show that testing pooled environmental samples generates more meaningful information compared to soiled bedding sentinels during routine hygienic monitoring in different barriers. PMID- 29145767 TI - Addressing geographic confounding through spatial propensity scores: a study of racial disparities in diabetes. AB - Motivated by a study exploring differences in glycemic control between non Hispanic black and non-Hispanic white veterans with type 2 diabetes, we aim to address a type of confounding that arises in spatially referenced observational studies. Specifically, we develop a spatial doubly robust propensity score estimator to reduce bias associated with geographic confounding, which occurs when measured or unmeasured confounding factors vary by geographic location, leading to imbalanced group comparisons. We augment the doubly robust estimator with spatial random effects, which are assigned conditionally autoregressive priors to improve inferences by borrowing information across neighboring geographic regions. Through a series of simulations, we show that ignoring spatial variation results in increased absolute bias and mean squared error, while the spatial doubly robust estimator performs well under various levels of spatial heterogeneity and moderate sample sizes. In the motivating application, we construct three global estimates of the risk difference between race groups: an unadjusted estimate, a doubly robust estimate that adjusts only for patient level information, and a hierarchical spatial doubly robust estimate. Results indicate a gradual reduction in the risk difference at each stage, with the inclusion of spatial random effects providing a 20% reduction compared to an estimate that ignores spatial heterogeneity. Smoothed maps indicate poor glycemic control across Alabama and southern Georgia, areas comprising the so-called "stroke belt." These results suggest the need for community-specific interventions to target diabetes in geographic areas of greatest need. PMID- 29145768 TI - Robustness of crossover trials against subject drop-out - Examples of perpetually connected designs. AB - When performing a repeated measures experiment, such as a clinical trial, there is a risk of subject drop-out during the experiment. If one or more subjects leave the study prematurely, a situation could arise where the eventual design is disconnected, implying that very few treatment contrasts for both direct effects and carryover effects are estimable. This paper aims to identify experimental conditions where this problem with the eventual design can be avoided. It is shown that in the class of uniformly balanced repeated measurement designs consisting of two or more Latin squares, there are planned designs with the following useful property. Provided that all subjects have completed the first two periods of study, such a design will not be replaced by a disconnected eventual design due to drop-out, irrespective of the type of drop-out behaviour that may occur. Designs with this property are referred to as perpetually connected. These experimental conditions are identified and examined in the paper and an example of at least one perpetually connected uniformly balanced repeated measurement design is given in each case. The results improve upon previous contributions in the literature that have been confined largely to cases in which drop-out occurs only in the final periods of study. PMID- 29145769 TI - Exact statistical calculation of the uncertainty term in the decision limits of the GH-2000 score for growth hormone misuse (doping) detection. AB - The GH-2000 score has been developed as a powerful and unique technique for the detection of growth hormone misuse by sportsmen and women. The score depends upon the measurement of two growth hormone sensitive markers, insulin-like growth factor-I and the amino-terminal pro-peptide of type III collagen. It also includes a term to adjust for the age of the athlete. Decision limits for the GH 2000 score have been developed and are incorporated into the guidelines of the World Anti-Doping Agency. These decision limits are derived by setting a 1 in 10,000 false-positive rate rule. As these decision limits are estimated from samples of GH-2000 scores, they carry uncertainty. In previous work, this uncertainty has been addressed by establishing an upper 95% confidence interval for the true decision limits based on a normal approximation which has been shown to be appropriate if sample sizes are large (such as 1000 and above). Here, we show that these approximations, whether reasonable or not, can be entirely avoided by developing an upper 95% confidence interval for the true decision limits using an approach based upon the t-distribution. While there are considerable differences for smaller sample sizes, these become negligible when the sample size is large such as 1000 and above. PMID- 29145770 TI - Camptothecin prodrug nanomicelle based on a boronate ester-linked diblock copolymer as the carrier of doxorubicin with enhanced cellular uptake. AB - A novel pH-sensitive polymeric prodrug of camptothecin (CPT) by polymerizing gamma-camptothecin-glutamate N-carboxyanhydride (Glu (CPT)-NCA) on boronate ester linked poly (ethyleneglycol) (PEG) directly via the amine-initiated ring open polymerization (ROP) has been developed. The resulting amphiphilic prodrug (mPEG BC-PGluCPT) could self-assemble into nanoparticles and encapsulate doxorubicin (Dox) simultaneously in aqueous solution for dual-drug delivery. The formation of polymeric prodrug micelles (mPEG-BC@PGluCPT) was confirmed by the measurements of critical aggregation concentration (CAC), particle size, and morphology observations. The mPEG-BC@PGluCPT micelles were colloidally stable in solutions for two weeks. Polymeric prodrug micelles mPEG-BC@PGluCPT and Dox-loaded micelles mPEG-BC@PGluCPT?Dox showed sustained drug release profiles over 48 h. As expected, drug release was accelerated by the decreasement of pH value from 7.4 to 6.0, which demonstrated pH-dependent manner of drug release. Additionally, it was found that cellular uptake of mPEG-BC@PGluCPT?Dox micelles on HepG2 cells was higher than that on HL-7702 cells, especially in culture medium at pH 6.0. The enhanced cellular uptake of mPEG-BC@PGluCPT?Dox micelles under acidic condition on HepG2 cells resulted in the higher cytotoxicity of mPEG-BC@PGluCPT?Dox micelles at acidic pH than that at pH 7.4. PMID- 29145771 TI - Topical simvastatin gel as a novel therapeutic modality for palatal donor site wound healing following free gingival graft procedure. AB - OBJECTIVE: Autogenous soft-tissue grafting is a commonly used procedure nowadays in dentistry. However, the prolonged healing time needed for the donor site leads to increase the patient's pain and discomfort. Statin has been observed to be beneficial in reducing bacterial burden, improving epithelization and wound healing. The aim of this study was to evaluate intra-oral topical application of simvastatin/chitosan gel (10 mg/mL) over the palatal donor site following free gingival graft (FGG) procedure. MATERIAL AND METHODS: Subjects indicated for FGG procedure were divided into four groups. Group I: Simvastatin suspension (S), group II: simvastatin/chitosan gel (SC), group III: chitosan gel (C), group IV: petroleum gel (P). Treatment was applied three times/day for the following 7 days. Wound healing was evaluated at day 3, 7 and 14 post-surgery. A visual analogue scale (VAS) was used to measure the experienced discomfort at 1, 3, 5, 7 and 14 days. RESULTS: Statistical significant reduction in wound-healing scores was observed after 3 and 7 days for group II compared to other groups (p = .015). A significant reduction was also observed in VAS score for group II compared to other groups at day 1, 3, 5 and 7. CONCLUSION: Topical application of S/C gel could be used as a novel therapeutic modality that improved healing and reduced pain in the palatal donor site following FGG procedure. PMID- 29145772 TI - Do Primary Care Physicians Help the Bereaved With Their Suicide Losses: Loss Survivor Perceptions of Helpfulness From Physicians. AB - Several previous studies suggested that primary care physicians can provide important bereavement assistance to survivors of suicide, yet no study has investigated whether suicide-bereaved patients perceive their physicians as helpful. Contacting bereavement communities on social media, we collected online survey data from 146 bereaved respondents reporting suicides causing them severe emotional distress. Data analysis suggested that nearly half (48%) of the respondents encountered positive, help-offering responses from physicians, compared to 10% whose responses were deemed as negative. Analysis of our data suggested that loss survivors' perceptions of a physician's helping or reproachful responses were associated with differences in grief difficulties and mental health distress. PMID- 29145773 TI - Forced Use of the Paretic Leg Induced by a Constraint Force Applied to the Nonparetic Leg in Individuals Poststroke During Walking. AB - BACKGROUND: Individuals with stroke usually show reduced muscle activities of the paretic leg and asymmetrical gait pattern during walking. OBJECTIVE: To determine whether applying a resistance force to the nonparetic leg would enhance the muscle activities of the paretic leg and improve the symmetry of spatiotemporal gait parameters in individuals with poststroke hemiparesis. METHODS: Fifteen individuals with chronic poststroke hemiparesis participated in this study. A controlled resistance force was applied to the nonparetic leg using a customized cable-driven robotic system while subjects walked on a treadmill. Subjects completed 2 test sections with the resistance force applied at different phases of gait (ie, early and late swing phases) and different magnitudes (10%, 20%, and 30% of maximum voluntary contraction [MVC] of nonparetic leg hip flexors). Electromyographic (EMG) activity of the muscles of the paretic leg and spatiotemporal gait parameters were collected. RESULTS: Significant increases in integrated EMG of medial gastrocnemius, medial hamstrings, vastus medialis, and tibialis anterior of the paretic leg were observed when the resistance was applied during the early swing phase of the nonparetic leg, compared with baseline. Additionally, resistance with 30% of MVC induced the greatest level of muscle activity than that with 10% or 20% of MVC. The symmetry index of gait parameters also improved with resistance applied during the early swing phase. CONCLUSION: Applying a controlled resistance force to the nonparetic leg during early swing phase may induce forced use on the paretic leg and improve the spatiotemporal symmetry of gait in individuals with poststroke hemiparesis. PMID- 29145774 TI - Predicting the Risk of Opioid Use Disorder Based on Early Maladaptive Schemas. AB - Substance use is a globally devastating social problem. Early maladaptive schemas (EMSs) are inefficient mechanisms leading directly or indirectly to psychological distress. The current study aimed to assess the role of EMSs in predicting opioid use disorder. The cross-sectional study was conducted in 2013 in Bojnurd at northeast of Iran on 60 male opioid users who received Methadone Maintenance Treatment (MMT) and 60 control males. The opioid users were selected randomly from MMT clinics and control subjects were selected and matched with opioid users using demographic variables. The subjects completed the Young Schema Questionnaire-Short Form (YSQ-SF). Except for SS (self-sacrifice), EG (entitlement/grandiosity), US (unrelenting standards), and FA (Failure to Achieve), the mean of other maladaptive schemas in the opioid user group were significantly higher than that of the control group, adjusted for multiple comparisons. Multivariate analysis of variance (MANOVA) indicated significant differences in maladaptive schemas between the two groups. Logistic regression identified that Emotional Deprivation, Mistrust/Abuse, and Unrelenting Standards can predict opioid use. As a result, the risk of opioid-related disorders in people with higher YSQ-SF scores in these schemas is higher. The findings conclude that the existence of underlying EMS may constitute a vulnerability factor for developing opioid use disorders later on in life. Provided the vast amount of scientific literature in evidence-based treatments focusing on EMSs, maladaptive schemas and related core beliefs can be detected and treated in adolescence to prevent the enactment of the schema and psychological distress likely to induce opioid use. PMID- 29145775 TI - Factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). AB - Introduction To determine the factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Methodology All patients aged >18 years and having a fatty liver on abdominal ultrasound (US), presenting from January 2011 to January 2017, were included. A liver biopsy was performed on all the patients. Results Of 96 patients undergoing liver biopsy for non-alcoholic fatty liver disease (NAFLD), 76 (79.2%) were men. On liver US, diffuse fatty liver (DFL) was noted in 68 (70.8%) patients. Liver biopsy showed non-alcoholic steatohepatitis (NASH) in 78 (81.3%) patients. Factors associated with NASH were male gender, body mass index (BMI) > 27 kg/m2, DFL and raised alanine aminotransferase (ALT). A GULAB score (based on gender, US liver findings, lipid (fasting) levels, ALT level and BMI) of >=5 predicted NASH with 82.05% sensitivity. Factors associated with advanced fibrosis in NAFLD were age >40 years, diabetes mellitus, AST/ALT ratio > 1 and raised GGT. Conclusion NASH is common in patients with male gender, high BMI, DFL on liver US, raised ALT and GULAB score >=5. PMID- 29145776 TI - Role of computed tomography of abdomen in difficult to diagnose typhoid fever: a case series. AB - Background and Aim Diagnosis of typhoid is challenging when blood cultures fail to isolate Salmonella species. We report our experience with interpreting computed tomography (CT) abdomen findings in a case series of typhoid fever. Methods The case series consisted of patients who had a CT abdomen done as part of their investigations and a final diagnosis of typhoid fever. The CT films were reviewed and findings evaluated for distinctive features. Results During 2011 2017, 11 patients met the inclusion criteria. Indication for CT was pyrexia of unknown origin in the majority of patients. Review of CT films revealed mesenteric lymphadenopathy (100%), terminal ileum thickening (85%), hepatosplenomegaly (45%), retroperitoneal lymphadenopathy (18%) and ascites (9%). Conclusions Enhancing discrete mesenteric lymphadenopathy and terminal ileum thickening are non-specific findings noted in typhoid fever. Absence of matted necrotic nodes and peritoneal thickening rule out tuberculosis and raise suspicion of typhoid fever in endemic regions. PMID- 29145777 TI - A probability based method for selecting the optimal personalized treatment from multiple treatments. AB - In this work we propose a method for optimal treatment assignment based on individual covariate information for a patient. For the K treatment ([Formula: see text]) scenario, we compare quantities that are suitable surrogates to true conditional probabilities of outcome variable of each treatment dominating outcome variables for all other treatments conditional on patient specific scores constructed from patient-specific covariates. As opposed to methods based on conditional means, our method can be applied for a broad set of models and error structures. Furthermore, the proposed method has very desirable large sample properties. We suggest Single Index Models as appropriate models connecting outcome variables to covariates and our empirical investigations show that correct treatment assignments are highly accurate. The proposed method is also rather robust against departures from a Single Index Model structure. Furthermore, selection of a treatment using the proposed metric appears to incur no losses in terms of the average reward for cases when two treatments are close in terms of this metric. We also conduct a real data analysis to show the applicability of the proposed procedure. This analysis highlights possible gains both in terms of average response and survival time if one were to use the proposed method. PMID- 29145778 TI - An apparent case of brodifacoum toxicosis in a whelping dog. AB - A 7-y-old Weimaraner bitch was presented to emergency service after 3 h of active labor with no puppies produced. Hemoabdomen and hemothorax were present at the time of surgery; prothrombin time (PT) and activated partial thromboplastin time (aPTT) were both found to be within normal ranges. Surgical cesarean section was performed; 4 dead puppies and 5 live puppies were delivered. Because hemostasis was difficult to achieve, a hysterectomy was performed; however, the dog died as the operation was being completed. At autopsy, the pleural cavity contained 1.5 L of unclotted blood; the peritoneal cavity was relatively normal, and no obvious hemorrhage was associated with the surgical sites. All 4 dead fetuses were opened, and their pleural cavities were filled with unclotted blood. An anticoagulant screen was performed, and brodifacoum was identified in the liver of the bitch. This case is unusual in that the PT and aPTT were within reference intervals, but brodifacoum was present in sufficient amounts to potentially result in this dog bleeding to death, and also is suspected to have crossed the placenta and caused hemothorax and death in 4 of 9 puppies in utero. PMID- 29145779 TI - Quality and safety of maize (Zea mays L.) from Rondonia state storage units, Northern Brazil. AB - The quality and safety of maize (Zea mays L.) from different grain storage units (GSUs), located in the main producing region of Rondonia State, Northern Brazil, were evaluated. Maize grains (n = 76) stored in four GSUs were collected from July to November 2014 and evaluated for grain damages, humidity, fungi and fumonisins (FBs) content. The climate conditions data were also obtained from plant growing to storage periods. Regarding the moisture content and water activity (aw), these varied from 10.0% to 16.1% and 0.5 to 0.8, respectively. As expected, fungi spores were present in 94.8% of the samples, prevailing Fusarium genera, with a fungi colony maximum of 2.2 * 104 CFU g-1. Regarding FBs, 60.5% of the samples were contaminated, below Brazilian and United States maximum limits, but 9.2% had levels higher than the European legislation. PMID- 29145780 TI - Power and sample size for multivariate logistic modeling of unmatched case control studies. AB - Sample size calculations are needed to design and assess the feasibility of case control studies. Although such calculations are readily available for simple case control designs and univariate analyses, there is limited theory and software for multivariate unconditional logistic analysis of case-control data. Here we outline the theory needed to detect scalar exposure effects or scalar interactions while controlling for other covariates in logistic regression. Both analytical and simulation methods are presented, together with links to the corresponding software. PMID- 29145782 TI - Comprehensive Preclinical Postmortem Evaluation of Valvular Prosthesis. AB - Transcatheter prosthetic valves are heralding a new era in interventional cardiology and affording real therapeutic options to categories of patients currently medically disqualified, namely the elderly and higher risk individuals. An increasing variety of novel artificial valve designs and delivery systems are being tested preclinically. Cardiologists and surgeons are generally well equipped to assess deliverability and function; however, methods for pathological evaluation of animals enrolled in transcatheter valve implant testing are scant, often vague, and far from consensual. Through this manuscript, we present and discuss a comprehensive evaluation platform that is proving reliable, reproducible, effective, and applicable to most, if not all, types and locations of valvular prostheses. PMID- 29145781 TI - Analytical High-resolution Electron Microscopy Reveals Organ-specific Nanoceria Bioprocessing. AB - This is the first utilization of advanced analytical electron microscopy methods, including high-resolution transmission electron microscopy, high-angle annular dark field scanning transmission electron microscopy, electron energy loss spectroscopy, and energy-dispersive X-ray spectroscopy mapping to characterize the organ-specific bioprocessing of a relatively inert nanomaterial (nanoceria). Liver and spleen samples from rats given a single intravenous infusion of nanoceria were obtained after prolonged (90 days) in vivo exposure. These advanced analytical electron microscopy methods were applied to elucidate the organ-specific cellular and subcellular fate of nanoceria after its uptake. Nanoceria is bioprocessed differently in the spleen than in the liver. PMID- 29145783 TI - NTP/NIEHS Global Contributions to Toxicologic Pathology. AB - National Toxicology Program (NTP) pathologists are engaged in important initiatives that have significant global impact. These initiatives build on its leadership in pathology peer review and publications in the areas of toxicologic pathology, clinical pathology, and laboratory animal medicine. Over the past decade, NTP/National Institute of Environmental Health Sciences research initiatives have focused on cancer and noncancer hazard identification, with the goal of understanding cellular and molecular mechanisms of disease. New initiatives of significant global impact include the web-based nonneoplastic lesion atlas and an NTP partnership with international scientists to investigate molecular mechanisms at the whole genome level, which will be used to inform potential mechanisms of environmental exposures in human cancers. Also, we are dedicated to contributing to pathology and toxicology organizations through service on executive committees and editorial boards, participating in international projects and symposiums, and providing training for future leaders in toxicologic pathology. Herein, we provide highlights of our global contributions. PMID- 29145784 TI - Update on the Manuscript Peer Review Process. PMID- 29145785 TI - Adenosine deaminase activity in pig saliva: analytical validation of two spectrophotometric assays. AB - We validated 2 assays for the measurement of adenosine deaminase (ADA) activity in the saliva of pigs: the Giusti-Galanti manual method (ADA-GG) and a commercial automated assay (Diazyme Laboratories; ADA-D). Intra-assay coefficients of variation (CVs) were <7 and 9%, and interassay CVs were <12 and 5%, for ADA-GG and ADA-D, respectively. Accuracy was measured by 2 methods: recovery and linearity-under-dilution. Recovery was 82.4-106.8% for ADA-GG, and 92.8-107.9% for ADA-D. Serial dilutions showed R2 > 0.95 and 0.99 for ADA-GG and ADA-D, respectively. Linear regression between the methods gave R2 = 0.997 ( p < 0.0001), and a Bland-Altman plot showed a proportional bias of 112 IU/L (95% confidence interval of -99 to 322 IU/L) for ADA-D. No significant differences were observed between the results obtained by either method in saliva or serum. ADA activity was much higher in porcine saliva than in serum. Salivary ADA activity was significantly higher in lame pigs compared to healthy animals. However, serum ADA activity was significantly lower in lame pigs. PMID- 29145786 TI - Cephalexin susceptibility breakpoint for veterinary isolates: Clinical Laboratory Standards Institute revision. AB - The Clinical and Laboratory Standards Institute (CLSI) uses cephalothin as the class representative for testing veterinary isolates for susceptibility to other first-generation cephalosporins, including cephalexin. We examined replacing cephalothin with cephalexin because cephalexin is used more often clinically. Bacterial isolates were obtained from dogs and cats from a national surveillance program. CLSI testing methods were used to determine the MIC for 4 cephalosporins used in veterinary medicine. Cephalexin clinical breakpoints for canine isolates were established by using published pharmacokinetic data and Monte Carlo simulations to calculate the probability of target attainment (PTA). For 1,112 Staphylococcus pseudintermedius isolates, the mode, MIC50, and MIC90 were 1, 2, and 64 ug/mL, respectively, for cephalexin, and <=0.06, 0.12, and 2 ug/mL for cephalothin. Susceptibility of S. pseudintermedius from 2011 to 2014 did not change for the 4 cephalosporins tested. Only 4.3% of the penicillin-binding protein 2a-positive S. pseudintermedius isolates had MIC values <=2 ug/mL for cephalexin, but 66.3% of these isolates had MIC values <=2 ug/mL for cephalothin. There were also discrepancies between cephalexin and cephalothin for other bacteria tested, but the largest difference was for S. pseudintermedius, with a MIC difference of 4 doubling dilutions. Cephalexin interpretive categories (breakpoints) of <=2 MUg/mL (susceptible), 4 MUg/mL (intermediate), and >=8 MUg/mL (resistant) were established for isolates obtained from dogs. Cephalothin should not be used for susceptibility testing of cephalexin for veterinary bacterial pathogens, and canine-specific breakpoints should be used for testing susceptibility. Breakpoints determined using the methods described herein for the interpretive categories will be added to future CLSI tables to reflect this recommendation. PMID- 29145787 TI - Pneumocystosis in dogs: meta-analysis of 43 published cases including clinical signs, diagnostic procedures, and treatment. AB - We evaluated 43 published cases of dogs with confirmed Pneumocystis infection regarding the value of clinical parameters indicating the presence of the disease as well as tools for the detection of the pathogen. The assessed parameters included clinical signs, laboratory findings, results of thoracic radiography, autopsy, histopathology, methods for the detection of Pneumocystis, as well as medical therapy. Pneumocystosis was diagnosed most often in certain breeds (Cavalier King Charles Spaniel, Miniature Dachshund) with a predisposition for impaired immunity. The median age of the dogs was 1 y. Chronic therapy-resistant respiratory signs, such as tachypnea, dyspnea, and cough, along with leukocytosis, neutrophilia, and hypogammaglobulinemia, were the most frequently described clinical and clinicopathologic abnormalities. Pneumocystosis can be masked by coinfections with other respiratory pathogens, and the successful detection of Pneumocystis organisms is of major relevance. Several detection methods have been used in the past, but only a few provide reliable results. In 2017, the cytologic evaluation of Giemsa-stained bronchoalveolar lavage samples is generally used, even if sensitivity is only moderate. More reliable results can be achieved using special stains or sensitive molecular techniques. Fast and reliable detection of Pneumocystis is the essential basis for appropriate treatment and higher survival chances for dogs. PMID- 29145788 TI - Quality of life following treatment for PTSD: Comparison of videoconferencing and in-person modalities. AB - Introduction Quality of life (QOL) is significantly impaired among individuals with post-traumatic stress disorder (PTSD); however, few treatment outcome studies examine QOL following treatment. Furthermore, the use of videoconferencing to deliver evidence-based treatments for PTSD is increasing dramatically. Although videoconferencing has demonstrated non-inferiority to in person treatment modalities for improving PTSD symptom severity, no studies to date have directly compared QOL outcomes of an evidence-based intervention delivered via videoconferencing to one delivered in-person. Methods This study presents a secondary data analysis of two randomized controlled trials comparing cognitive processing therapy (CPT) delivered via videoconferencing or a traditional in-person modality. The Men's study delivered group CPT to 125 male veterans with PTSD, whereas the Women's study delivered individuals CPT to 126 female civilians and veterans. Multigroup latent growth curve models were used to model changes in QOL Inventory (QOLI) scores over time. Results There was no effect of treatment modality on changes in QOLI scores over time (modality effect on slope estimate = 0.004 (-0.60, 0.61) and on quadratic estimate = 0.001 (-0.18, 0.20); all ps > 0.33). Model fit was the same for both genders (Delta chi2 (2) = 2.28, p = 0.32) and for the gender * treatment modality interaction (Delta chi2 (2) = 2.87, p = 0.24). QOLI scores improved at post-treatment and three-month follow-up assessments, but declined at the six-month follow-up assessment. Discussion This secondary analysis extends the findings of the parent studies by establishing the efficacy of the videoconferencing platform in improving QOL. Clinical implications of findings are discussed. PMID- 29145789 TI - Helicobacter pylori controls NLRP3 expression by regulating hsa-miR-223-3p and IL 10 in cultured and primary human immune cells. AB - Inflammasome-mediated production of mature IL-1beta and IL-18 cytokines represents an important innate immune response against infecting pathogens. Helicobacter pylori, one of the most successful and persistent human pathogens, induces severe inflammation leading to gastritis and more serious gastric diseases. H. pylori modulates different immune responses for its survival and inflammasome signaling is manipulated by the cag pathogenicity island ( cagPAI), urease and VacA cytotoxin. Here we report that H. pylori regulates NLRP3 expression, an inflammasome forming regulator, in infected THP-1 monocytes. This response was independent of the major H. pylori pathogenicity-associated factors CagA, VacA, Cgt, FlaA and cagPAI. Two NLRP3 expression controlling factors, the NLRP3 mRNA targeting microRNA hsa-miR-223-3p and cytokine IL-10, were found to work in tandem for its regulation. H. pylori infection also induced copious amount of pro-IL-1beta in THP-1 monocytes/macrophages but secreted a very low amount of mature IL-1beta. Moreover, secreted IL-10 correlated with the down regulation of nigericin-induced NLRP3 inflammasome activation of LPS-primed THP-1 monocytes and human PBMCs from volunteers. However, H. pylori-treated PBMCs secreted significantly more mature IL-1beta throughout the infection period, which suggests a different mode of activation. Taken together, this study demonstrates targeting of inflammasome-forming NLRP3, an important innate immunity component, and crucial manipulation of pro- and anti-inflammatory cytokines in H. pylori infection. PMID- 29145790 TI - Innate immunity in cardiac myxomas and its pathological and clinical correlations. AB - Cardiac myxomas are the most common benign cardiac tumor. We investigated the immunohistochemical properties of 11 surgically excised cardiac myxomas, in order to analyze the correlation between macrophages and mast cell populations and clinical parameters. CD68+/CD163-/iNOS- (M0) cells represent the most abundant macrophage phenotype; however, CD68+/CD163+ cells (M2) were also frequent. CD68+/iNOS+ (M1) elements were rare. Mast cells, defined as a population of c-kit (CD117)+ and/or tryptase+ cells were also detected. Statistical analysis showed significant correlations between c-kit (CD117)+ and tryptase, CD68 and erythrocyte sedimentation rate (ESR), ESR and red blood cell count (RBC), and prothrombin time and platelet count. The inverse correlation between RBCs in peripheral blood and ESR suggested that anemia associated with chronic inflammatory disease is a noncasual event in patients suffering from cardiac myxoma. Mechanical hemolysis may be only a minor component of anemia, according to the lack of correlation between echographic surface and RBCs. Moreover, tumor size did not correlate with ESR, showing that inflammatory state may depend from both tumor cells population and inflammatory infiltrate. In the future, modulation of macrophage polarization in cardiac myxomas might represent important therapeutic target. PMID- 29145791 TI - Impact of novel N-aryl piperamide NO donors on NF-kappaB translocation in neuroinflammation: rational drug-designing synthesis and biological evaluation. AB - NO donor drugs showed a significant therapeutic effect in the treatment of many diseases, such as arteriopathies, various acute and chronic inflammatory conditions, and several degenerative diseases. NO-releasing anti-inflammatory drugs are the prototypes of a novel class of compounds, combining the pharmacological activities of anti-inflammatory and anti-nociceptive of drugs with those of NO, thus possessing potential therapeutic applications in a great variety of diseases. In this study, we designed and predicted biological activity by targeting cyclooxygenase type 2 (COX-2) and NF-kappaB subunits and pharmacological profiling along with toxicity predictions of various N-aryl piperamides linked via an ester bond to a spacer that is bound to a NO-releasing moiety (-ONO2). The result of absorption, distribution, metabolism and excretion and Docking studies indicated that among 51 designed molecules PA-3'K showed the best binding potential in both the substrate and inhibitory binding pocket of the COX-2 enzyme with affinity values of -9.33 and -5.12 for PDB ID 1CVU and 3LN1, respectively, thereby having the potential to be developed as a therapeutic agent. The results of cell viabilities indicated that PA-3'k possesses the best cell viability property with respect to its dose (17.33 ng/ml), with 67.76% and 67.93% viable cells for CHME3 and SVG cell lines, respectively. PMID- 29145792 TI - Evaluating feasibility and acceptability of a local psycho-educational intervention for pregnant women with common mental problems affected by armed conflict in Swat, Pakistan: A parallel randomized controlled feasibility trial. AB - BACKGROUND: The current research was conducted in the Swat valley, where widespread conflict and militancy had been experienced prior to the field activities. The aim of this trial was to evaluate the feasibility and acceptability of a locally developed psycho-educational intervention. METHODS: This mixed-methods study incorporated a quantitative and qualitative component. For the quantitative component, trial participants were identified from a cross sectional study conducted in the earlier phase of the research, with Self Reporting Questionnaire (SRQ) score of >=9. Participants with suicidal ideation, severe mental or medical illness, recently given birth or living with another woman with an SRQ score of 9 or above were excluded. Participants fulfilling eligibility were randomized on a 1:1 allocation ratio using simple randomization to the psycho-educational intervention or routine care arm. The intervention arm received two psycho-educational sessions at their homes delivered by local community health worker from the study area. The primary outcome was help-seeking for psychological distress, measured by a semi-structured interview by a researcher blind to the allocation status at 2 months post-intervention. Secondary outcomes include psychological distress and social support measured by SRQ and Multidimensional Scale of Perceived Social Support (MSPSS), respectively, at 2 months post-intervention. Intervention acceptability was explored through in depth interviews. RESULTS: Local community health workers with no mental health experience successfully delivered the psycho-educational sessions in the community. The uptake of intervention was good and the intervention was taken well by the families and the community health workers. The outcome evaluation was not powered; however, more women sought assistance for their distress from their community health workers in the intervention arm, compared to women in the control arm. CONCLUSION: This trial showed good acceptance and feasible delivery of a locally developed psycho-educational intervention through community health workers following conflict, giving way for further adaptation and evaluation. PMID- 29145793 TI - Portrayal of generalized anxiety disorder in YouTubeTM videos. AB - BACKGROUND: Individuals often search the Internet for information about their medical conditions, such as generalized anxiety disorder (GAD), a common mental health disorder. AIMS: To describe the content of the most popular videos on YouTubeTM related to GAD. METHODS: Videos with at least 50,000 views in October 2016 were coded for information regarding symptoms, treatments and causes for GAD. Associations of content with factors such as popularity and focus on a personal experience were examined. RESULTS: The search returned 95 videos, which had been collectively viewed 37,044,555 times. Most (65%) were uploaded by consumers and 56% were about a personal experience. The most common symptoms mentioned were worry or panic (72%) and social anxiety (46%). Many videos (63%) mentioned at least one treatment, but only 26% mentioned any cause of anxiety. Videos that focused on a personal experience were significantly less likely to mention other phobias ( p = .036), panic disorder ( p = .033) and sleep issues ( p = .016). CONCLUSION: The majority of the most popular videos on YouTube TM related to GAD were produced by consumers. Improved understanding about what information is available and popular online can assist mental health professionals in aiding their patients and in producing media that is likely to be viewed. PMID- 29145794 TI - Analysis of Bacterial and Fungal Nucleic Acid in Canine Sterile Granulomatous and Pyogranulomatous Dermatitis and Panniculitis. AB - Next generation sequencing (NGS) studies are revealing a diverse microbiota on the skin of dogs. The skin microbiota of canine sterile granulomatous and pyogranulomatous dermatitis (SGPD) has yet to be investigated using NGS techniques. NGS targeting the 16S rRNA and ITS-1 region of bacterial and fungal DNA, respectively, were used to investigate if bacterial and fungal DNA were associated with skin lesions in cases of canine SGPD. The study included 20 formalin-fixed paraffin-embedded (FFPE) skin samples and 12 fresh samples from SGPD-affected dogs, and 10 FFPE and 10 fresh samples from healthy dogs. DNA was extracted from deep dermis and panniculus, and microbial DNA was amplified using primers targeting the bacterial 16S rRNA V1-V3 and fungal ITS-1 regions. The amplified DNA was utilized for NGS on an Illumina MiSeq instrument. The sequences were processed using QIIME. No differences in fungal or bacterial alpha diversity were observed between the SGPD and control samples. Beta diversity analysis demonstrated differences in the bacterial communities between SGPD and control, but not in the fungal communities. Compared to controls, the family Erysipelotrichaceae and genus Staphylococcus were significantly more abundant in the SGPD FFPE samples, and genus Corynebacterium were more abundant in fresh samples. The bacteria found to be more abundant in SGPD are common inhabitants of skin surfaces, and likely secondary contaminants in SGPD cases. This study provides additional evidence that SGPD lesions are likely sterile. PMID- 29145795 TI - Use of Immunohistochemistry to Demonstrate In Vivo Expression of the Burkholderia mallei Virulence Factor BpaB During Experimental Glanders. AB - Burkholderia mallei causes the highly contagious and debilitating zoonosis glanders, which infects via inhalation or percutaneous inoculation and often culminates in life-threatening pneumonia and sepsis. In humans, glanders is difficult to diagnose and requires prolonged antibiotic therapy with low success rates. No vaccine exists to protect against B. mallei, and there is concern regarding its use as a bioweapon. The authors previously identified the protein BpaB as a potential target for devising therapies due to its role in adherence to host cells and the formation of biofilms in vitro and its contribution to pathogenicity in a mouse model of glanders. In the present study, the authors developed an immunostaining approach to probe tissues of experimentally infected animals and demonstrated that BpaB is produced exclusively in vivo by wild-type B. mallei in target organs from mice and marmosets. They detected the expression of BpaB by B. mallei both extracellularly and within macrophages, neutrophils, and epithelial cells in respiratory tissues (7/10 marmoset; 2/2 mouse). The authors also noted the intracellular expression of BpaB by B. mallei in macrophages in the regional lymph nodes of mice (2/2 tissues) and MALT of marmosets (4/5 tissues). It is interesting that B. mallei bacteria infecting distal organs did not express BpaB (2/2 mice; 3/3 marmosets), suggesting that the protein is not necessary for bacterial fitness in these anatomic locations. These findings underscore the value of BpaB as a target for developing medical countermeasures and provide insight into its role in pathogenesis. PMID- 29145797 TI - 14-3-3sigma Protein Expression in Canine Renal Cell Carcinomas. AB - 14-3-3sigma is a protein expressed in many epithelial tissues associated with essential cell functions, including cell-cycle control, apoptosis, and cytoskeletal integrity. There is a paucity of knowledge of the tumorigenesis of canine renal cell carcinomas (RCCs), and the histological origin of this tumor has not been established. This study analyzed the expression of 14-3-3sigma, Ki 67, cytokeratins, and vimentin in 40 canine RCCs. Aberrant expression of 14-3 3sigma was demonstrated in 15 (38%) cases and was associated with a significantly shorter survival time ( P < .002). In contrast to canine RCC, normal kidney did not express 14-3-3sigma. The Ki-67 proliferation index did not show utility as a prognostic factor. The distal convoluted tubular epithelium in normal kidneys coexpressed cytokeratins and vimentin, and thus maintenance of this coexpression pattern in canine RCC suggests that most tumors arise from the distal segment of the nephron. These results suggest that 14-3-3sigma is a potential negative prognostic factor and a possible therapeutic target. PMID- 29145798 TI - Experimental Transmission of Bovine Digital Dermatitis to Sheep: Development of an Infection Model. AB - Digital dermatitis is an infectious cause of lameness primarily affecting cattle but also described in sheep, goats, and wild elk. Digital dermatitis is a polymicrobial infection, involving several Treponema species and other anaerobic bacteria. Although the exact etiology has not been demonstrated, a number of bacterial, host, and environmental factors are thought to contribute to disease development. To study host-bacterial interactions, a reproducible laboratory model of infection is required. The objective of this study was to demonstrate key aspects of bovine digital dermatitis lesions in an easy-to-handle sheep model. Crossbred sheep were obtained from a flock free of hoof disease. Skin between the heel bulb and dewclaw was abraded before wrapping to emulate a moist, anaerobic environment. After 3 days, abraded areas were inoculated with macerated lesion material from active bovine digital dermatitis and remained wrapped. By 2 weeks postinoculation, experimentally inoculated feet developed erosive, erythematous lesions. At 4 weeks postinoculation, microscopic changes in the dermis and epidermis were consistent with those described for bovine digital dermatitis, including erosion, ulceration, hyperkeratosis, ballooning degeneration of keratinocytes, and the presence of neutrophilic infiltrates. Silver staining of lesion biopsy sections confirmed that spirochetes had penetrated the host epidermis. The model was then perpetuated by passaging lesion material from experimentally infected sheep into naive sheep. This model of bovine digital dermatitis will allow for future novel insights into pathogenic mechanisms of infection, as well as the development of improved diagnostic methods and therapeutics for all affected ruminants. PMID- 29145799 TI - Gangrenous dermatitis in chickens and turkeys. AB - Gangrenous dermatitis (GD) is a disease of chickens and turkeys that causes severe economic losses in the poultry industry worldwide. Clostridium septicum, Clostridium perfringens type A, and occasionally Clostridium sordellii are considered the main causes of GD, although Staphylococcus aureus and other aerobic bacteria may also be involved in some cases of the disease. GD has become one of the most significant diseases of commercial turkeys in the United States. Several infectious and/or environmental immunosuppressive factors can predispose to GD. Skin lesions are considered to be the main portal of entry of the microorganism(s) involved. GD is characterized by acute onset of mortality associated with gross skin and subcutaneous tissue lesions consisting of variable amounts of serosanguineous exudate together with emphysema and hemorrhages. The underlying skeletal muscle can also be involved. Ulceration of the epidermis may be also noticed in cases complicated with S. aureus. Microscopically, necrosis of the epidermis and dermis, and subcutaneous edema and emphysema are commonly observed. Gram-positive rods can be identified within the subcutis and skeletal muscles, usually associated with minimal inflammatory infiltrate. A presumptive diagnosis of GD can be made based on history, clinical signs, and gross anatomic and microscopic lesions. However, confirmation should be based on demonstration of the causative agents by culture, PCR, immunohistochemistry, and/or fluorescent antibody tests. PMID- 29145800 TI - Study approach and field work procedures of the MentDis_ICF65+ project on the prevalence of mental disorders in the older adult European population. AB - BACKGROUND: This study describes the study approach and field procedures of the MentDis_ICF65+ study, which aims to assess the prevalence of mental disorders in older adults. METHODS: An age-appropriate version of the Composite International Diagnostic Interview (CIDI65+) was developed and tested with regard to its feasibility and psychometric properties in a pre-test and pilot phase. In the cross-sectional survey an age-stratified, random sample of older adults (65-84 years) living in selected catchment areas of five European countries and Israel was recruited. RESULTS: N = 3142 participants (mean age 73.7 years, 50.7% female) took part in face-to-face interviews. The mean response rate was 20% and varied significantly between centres, age and gender groups. Sociodemographic differences between the study centres appeared for the place of birth, number of grandchildren, close significants, retirement and self-rated financial situation. The comparison of the MentDis_ICF65+ sample with the catchment area and country population of the study centres revealed significant differences, although most of these were numerically small. CONCLUSIONS: The study will generate new information on the prevalence of common mental disorders among older adults across Europe using an age-appropriate, standardized diagnostic instrument and a harmonized approach to sampling. Generalizability of the findings and a potentially limited representativeness are discussed. PMID- 29145801 TI - Comparative genomics of Coniophora olivacea reveals different patterns of genome expansion in Boletales. AB - BACKGROUND: Coniophora olivacea is a basidiomycete fungus belonging to the order Boletales that produces brown-rot decay on dead wood of conifers. The Boletales order comprises a diverse group of species including saprotrophs and ectomycorrhizal fungi that show important differences in genome size. RESULTS: In this study we report the 39.07-megabase (Mb) draft genome assembly and annotation of C. olivacea. A total of 14,928 genes were annotated, including 470 putatively secreted proteins enriched in functions involved in lignocellulose degradation. Using similarity clustering and protein structure prediction we identified a new family of 10 putative lytic polysaccharide monooxygenase genes. This family is conserved in basidiomycota and lacks of previous functional annotation. Further analyses showed that C. olivacea has a low repetitive genome, with 2.91% of repeats and a restrained content of transposable elements (TEs). The annotation of TEs in four related Boletales yielded important differences in repeat content, ranging from 3.94 to 41.17% of the genome size. The distribution of insertion ages of LTR-retrotransposons showed that differential expansions of these repetitive elements have shaped the genome architecture of Boletales over the last 60 million years. CONCLUSIONS: Coniophora olivacea has a small, compact genome that shows macrosynteny with Coniophora puteana. The functional annotation revealed the enzymatic signature of a canonical brown-rot. The annotation and comparative genomics of transposable elements uncovered their particular contraction in the Coniophora genera, highlighting their role in the differential genome expansions found in Boletales species. PMID- 29145802 TI - Effectiveness of current and future regimens for treating genotype 3 hepatitis C virus infection: a large-scale systematic review. AB - BACKGROUND: Six distinct genetic variants (genotypes 1 - 6) of hepatitis C virus (HCV) exist globally. Certain genotypes are more prevalent in particular countries or regions than in others but, globally, genotype 3 (GT3) is the second most common. Patients infected with HCV GT1, 2, 4, 5 or 6 recover to a greater extent, as measured by sustained virological response (SVR), following treatment with regimens based on direct-acting antivirals (DAAs) than after treatment with older regimens based on pegylated interferon (Peg-IFN). GT3, however, is regarded as being more difficult to treat as it is a relatively aggressive genotype, associated with greater liver damage and cancer risk; some subgroups of patients with GT3 infection are less responsive to current licensed DAA treatments. Newer DAAs have become available or are in development. METHODS: According to PRISMA guidance, we conducted a systematic review (and descriptive statistical analysis) of data in the public domain from relevant clinical trial or observational (real world) study publications within a 5-year period (February 2011 to May 2016) identified by PubMed, Medline In-Process, and Embase searches. This was supplemented with a search of five non-indexed literature sources, comprising annual conferences of the AASLD, APASL, CROI, EASL, and WHO, restricted to a 1 year period (April 2015 to May 2016). RESULTS: Of the all-oral regimens, the efficacy (SVR12 >= 90%) of sofosbuvir plus daclatasvir- and velpatasvir-based regimens in clinical trials supports and reinforces their recommendation by guidelines. Other promising regimens comprise grazoprevir + elbasvir + sofosbuvir, and ombitasvir + paritaprevir/ribavirin + sofosbuvir. Newer regimens incorporating pibrentasvir + glecaprevir or grazoprevir + ruzasvir + MK-3682 (uprifosbuvir), offer all-oral, ribavirin-free SVR12 rates consistently greater than 95%. Observational studies report slightly lower overall SVR rates but reflect corresponding clinical trial data in terms of treatments most likely to achieve good responses. CONCLUSIONS: On the basis of SVR12, we established that for treating GT3 infections (i) regimens incorporating newer DAAs are more effective than those comprising older DAAs, and (ii) ribavirin may be of less benefit in newer DAA regimens than in older DAA regimens. The analysis provides evidence that DAA regimens can replace Peg-IFN-based regimens for GT3 infection. PMID- 29145804 TI - A descriptive study of the health information needs of Kenyan women in the first 6 weeks postpartum. AB - BACKGROUND: A large number of maternal and neonatal deaths occur during birth and 48 h after birth. The benefits of postnatal care to the mother and newborn cannot be overemphasized as this is another opportunity where complications that might arise from pregnancy and childbirth can be treated, as well as the time to provide important information on maternal and newborn care after delivery. This study aimed to determine the information needs of mother-baby pairs in the first 6 weeks after birth. METHODS: An exploratory qualitative study using in-depth interviews at three points in time was conducted with 15 women who had their births at Moi Teaching and Referral Hospital, Kenya. The first interview was done within 48 h after birth followed by a telephone interview at 2 weeks and at 6 weeks after birth. Data were audio recorded and transcribed. Transcripts and field notes were analyzed using thematic content analysis and NVIVO 11 software. Ethical approval was obtained before commencement of studies and permission to conduct the study granted by the chief executive of the hospital. RESULTS: The only health needs that participants reported were unmet health information needs. Four major themes emerged from the study. 'Connecting with baby' centered on understanding and meeting baby's needs, monitoring growth and progress and protecting the baby. The second theme: "Birth as a unique encounter' is a blend of what was found to be new and a unique. The theme 'Regaining self' is a combination of managing self as a mother and handling discomfort related to birth. The final theme: 'Disconnected information' is a collection of unmet information needs, the need for clarity in information booklets and conflicting information by different providers. CONCLUSIONS: Participants used the hospital stay as an opportunity to receive more detailed information on how to take care of their babies both directly after birth and in the longer term. Participants had a range of unmet health information needs that extended beyond family planning and fertility. Needs extended to their own care and management of discomforts. The need for consistency in health information by different providers and updated printed material on postnatal care that includes sensitive information and allows opportunities for personalized information was highlighted. PMID- 29145803 TI - Unraveling the evolution and coevolution of small regulatory RNAs and coding genes in Listeria. AB - BACKGROUND: Small regulatory RNAs (sRNAs) are widely found in bacteria and play key roles in many important physiological and adaptation processes. Studying their evolution and screening for events of coevolution with other genomic features is a powerful way to better understand their origin and assess a common functional or adaptive relationship between them. However, evolution and coevolution of sRNAs with coding genes have been sparsely investigated in bacterial pathogens. RESULTS: We designed a robust and generic phylogenomics approach that detects correlated evolution between sRNAs and protein-coding genes using their observed and inferred patterns of presence-absence in a set of annotated genomes. We applied this approach on 79 complete genomes of the Listeria genus and identified fifty-two accessory sRNAs, of which most were present in the Listeria common ancestor and lost during Listeria evolution. We detected significant coevolution between 23 sRNA and 52 coding genes and inferred the Listeria sRNA-coding genes coevolution network. We characterized a main hub of 12 sRNAs that coevolved with genes encoding cell wall proteins and virulence factors. Among them, an sRNA specific to L. monocytogenes species, rli133, coevolved with genes involved either in pathogenicity or in interaction with host cells, possibly acting as a direct negative post-transcriptional regulation. CONCLUSIONS: Our approach allowed the identification of candidate sRNAs potentially involved in pathogenicity and host interaction, consistent with recent findings on known pathogenicity actors. We highlight four sRNAs coevolving with seven internalin genes, some of which being important virulence factors in Listeria. PMID- 29145805 TI - ANAT 2.0: reconstructing functional protein subnetworks. AB - BACKGROUND: ANAT is a graphical, Cytoscape-based tool for the inference of protein networks that underlie a process of interest. The ANAT tool allows the user to perform network reconstruction under several scenarios in a number of organisms including yeast and human. RESULTS: Here we report on a new version of the tool, ANAT 2.0, which introduces substantial code and database updates as well as several new network reconstruction algorithms that greatly extend the applicability of the tool to biological data sets. CONCLUSIONS: ANAT 2.0 is an up to-date network reconstruction tool that addresses several reconstruction challenges across multiple species. PMID- 29145806 TI - Computer and telephone delivered interventions to support caregivers of people with dementia: a systematic review of research output and quality. AB - BACKGROUND: To assess the scope, volume and quality of research on the acceptability, utilisation and effectiveness of telephone- and computer-delivered interventions for caregivers of people living with dementia. METHODS: Medline, EMBASE, CINAHL and Cochrane databases were searched (Jan 1990 - Dec 2016). Eligible papers were classified as data-based descriptive, measurement or intervention studies. Intervention studies were first categorised according to mode of delivery (e.g. telephone, computer); then assessed against the Effective Practice and Organisation of Care (EPOC) methodological criteria for research design. Impact on health-related outcomes; and the acceptability, feasibility and utilisation of interventions were also assessed. RESULTS: The number of publications increased by 13% each year (p < 0.001). Half were descriptive studies (n = 92, 50%) describing caregiver views on acceptability, access or utilization of technology. The remainder (n = 89, 48%) reported on interventions designed to improve caregiver outcomes. Only 34 met EPOC design criteria. Interventions were delivered via computer (n = 10), multiple modalities (n = 9) or telephone (n = 15). Interventions that incorporated various elements of psycho education, peer support, skills training and health assessments led to improvements in caregiver wellbeing. While largely acceptable, utilisation of computer-based interventions was variable, with use often decreasing over time. CONCLUSION: Interventions delivered via telephone and computer have the potential to augment existing dementia care. High-quality trials are required to make clear recommendations about the types of interventions that are most effective. Those that provide caregivers with: access to practical strategies to manage care of the person with dementia and their own wellbeing, advice and support from peers and/or clinicians; and that target the dyad should be explored. PMID- 29145807 TI - Durability of switch regimens based on rilpivirine or on integrase inhibitors, both in association with tenofovir and emtricitabine, in HIV-infected, virologically suppressed patients. AB - BACKGROUND: Switch strategies based on rilpivirine/tenofovir/emtricitabine or on an integrase inhibitor (InSTI) plus tenofovir/emtricitabine have never been compared in randomized clinical trials. The main aim of the study was to investigate the durability of these two switch regimens in virologically suppressed, HIV-infected patients. METHODS: Retrospective analysis of patients who started rilpivirine or an InSTI (both with tenofovir and emtricitabine) with <50 HIV-RNA copies/mL and had at least one HIV-RNA assessed while receiving the study regimen. Virological failure (VF) was defined as two consecutive measurements of HIV-RNA >50 copies/mL. Treatment failure (TF) was define as either VF or discontinuation of any drug of the regimen. Durability was assessed by the Kaplan-Meier method and compared by Log-rank test. Residual viremia was defined as any detectable HIV-RNA below 50 copies/mL, as assed by a real-time PCR assay. RESULTS: Six hundred seventy-five patients (466 switched to a rilpivirine , 209 switched to an InSTI-based regimen [18% dolutegravir, 39% raltegravir, 43% elvitegravir/cobicistat] were included in the analysis. The median (interquartile range, IQR) follow-up in the rilpivirine and in the InSTI group was 16.7 (8.8 22.2) and 10.4 (5.4-19.6) months. The 1-year cumulative probabilities (95%CI) of VF and TF were 0.97% (0.36%-2.62%) and 9.73% (7.21%-13.06%) in the rilpivirine group and 1.83% (0.57%-5.77%) and 8.75% (5.25%-14.4%) in the InSTI group, with no difference between groups (p = 0.328 and 0.209 for VF and TF). The proportion of time spent with residual viremia was comparable in the two groups (9% [IQR 0.5% 49%] and 17% [IQR 0.5%-50%] in the rilpivirine and in the InSTI group, p = 0.087). By the multivariable Cox regression model, TF was independently associated with being on therapy with a protease inhibitor vs. a non-nucleoside reverse transcriptase inhibitor at switch (AHR = 0.52; 95%CI = 0.31-0.90; p = 0.018), baseline total/HDL-cholesterol ratio (AHR = 1.19 per 0.5-units increments; 95%CI = 1.06-1.34; p = 0.004), baseline estimated glomerular filtration rate (AHR = 0.78 per 10-units increments; 95%CI = 0.67-0.90; p = 0.001) and baseline hemoglobin (AHR = 0.78 per 1-unit increments; 95%CI = 0.64 0.94; p = 0.009), but not with treatment group (rilpivirine vs. InSTI). CONCLUSIONS: In our clinical practice, the durability of the two regimens was comparable and both showed a very low probability of VF. PMID- 29145809 TI - Genome-wide characterization and expression profiling of PDI family gene reveals function as abiotic and biotic stress tolerance in Chinese cabbage (Brassica rapa ssp. pekinensis). AB - BACKGROUND: Protein disulfide isomerase (PDI) and PDI-like proteins contain thioredoxin domains that catalyze protein disulfide bond, inhibit aggregation of misfolded proteins, and function in isomerization during protein folding in endoplasmic reticulum and responses during abiotic stresses.Chinese cabbage is widely recognized as an economically important, nutritious vegetable, but its yield is severely hampered by various biotic and abiotic stresses. Because of, it is prime need to identify those genes whose are responsible for biotic and abiotic stress tolerance. PDI family genes are among of them. RESULTS: We have identified 32 PDI genes from the Br135K microarray dataset, NCBI and BRAD database, and in silico characterized their sequences. Expression profiling of those genes was performed using cDNA of plant samples imposed to abiotic stresses; cold, salt, drought and ABA (Abscisic Acid) and biotic stress; Fusarium oxysporum f. sp. conglutinans infection. The Chinese cabbage PDI genes were clustered in eleven groups in phylogeny. Among them, 15 PDI genes were ubiquitously expressed in various organs, while 24 PDI genes were up-regulated under salt and drought stress. By contrast, cold and ABA stress responsive gene number were ten and nine, respectively. In case of F. oxysporum f. sp. conglutinans infection 14 BrPDI genes were highly up-regulated. Interestingly, BrPDI1-1 gene was identified as putative candidate against abiotic (salt and drought) and biotic stresses, BrPDI5-2 gene for ABA stress, and BrPDI1-4, 6-1 and 9-2 were putative candidate genes for both cold and chilling injury stresses. CONCLUSIONS: Our findings help to elucidate the involvement of PDI genes in stress responses, and they lay the foundation for functional genomics in future studies and molecular breeding of Brassica rapa crops. The stress-responsive PDI genes could be potential resources for molecular breeding of Brassica crops resistant to biotic and abiotic stresses. PMID- 29145810 TI - Predictors of prenatal care satisfaction among pregnant women in American Samoa. AB - BACKGROUND: Pregnant women in American Samoa have a high risk of complications due to overweight and obesity. Prenatal care can mitigate the risk, however many women do not seek adequate care during pregnancy. Low utilization of prenatal care may stem from low levels of satisfaction with services offered. Our objective was to identify predictors of prenatal care satisfaction in American Samoa. METHODS: A structured survey was distributed to 165 pregnant women receiving prenatal care at the Lyndon B Johnson Tropical Medical Center, Pago Pago. Women self-reported demographic characteristics, pregnancy history, and satisfaction with prenatal care. Domains of satisfaction were extracted using principal components analysis. Scores were summed across each domain. Linear regression was used to examine associations between maternal characteristics and the summed scores within individual domains and for overall satisfaction. RESULT: Three domains of satisfaction were identified: satisfaction with clinic services, clinic accessibility, and physician interactions. Waiting >= 2 h to see the doctor negatively impacted satisfaction with clinic services, clinic accessibility, and overall satisfaction. Living > 20 min from the clinic was associated with lower clinic accessibility, physician interactions, and overall satisfaction. Women who were employed/on maternity leave had lower scores for physician interactions compared with unemployed women/students. Women who did not attend all their appointments had lower overall satisfaction scores. CONCLUSIONS: Satisfaction with clinic services, clinic accessibility and physician interactions are important contributors to prenatal care satisfaction. To improve patient satisfaction prenatal care clinics should focus on making it easier for women to reach clinics, improving waiting times, and increasing time with providers. PMID- 29145808 TI - Renal Association Clinical Practice Guideline on peritoneal dialysis in adults and children. AB - These guidelines cover all aspects of the care of patients who are treated with peritoneal dialysis. This includes equipment and resources, preparation for peritoneal dialysis, and adequacy of dialysis (both in terms of removing waste products and fluid), preventing and treating infections. There is also a section on diagnosis and treatment of encapsulating peritoneal sclerosis, a rare but serious complication of peritoneal dialysis where fibrotic (scar) tissue forms around the intestine. The guidelines include recommendations for infants and children, for whom peritoneal dialysis is recommended over haemodialysis.Immediately after the introduction there is a statement of all the recommendations. These recommendations are written in a language that we think should be understandable by many patients, relatives, carers and other interested people. Consequently we have not reworded or restated them in this lay summary. They are graded 1 or 2 depending on the strength of the recommendation by the authors, and A-D depending on the quality of the evidence that the recommendation is based on. PMID- 29145811 TI - Genome-wide analysis of the auxin/indoleacetic acid (Aux/IAA) gene family in allotetraploid rapeseed (Brassica napus L.). AB - BACKGROUND: Auxin/Indoleacetic acid (Aux/IAA) genes participate in the auxin signaling pathway and play key roles in plant growth and development. Although the Aux/IAA gene family has been identified in many plants, within allotetraploid Brassica napus little is known. RESULTS: In this study, a total of 119 Aux/IAA genes were found in the genome of B. napus. They were distributed non-randomly across all 19 chromosomes and other non-anchored random scaffolds, with a symmetric distribution in the A and C subgenomes. Evolutionary and comparative analysis revealed that 111 (94.1%) B. napus Aux/IAA genes were multiplied due to ancestral Brassica genome triplication and recent allotetraploidy from B. rapa and B. oleracea. Phylogenetic analysis indicated seven subgroups containing 29 orthologous gene sets and two Brassica-specific gene sets. Structures of genes and proteins varied across different genes but were conserved among homologous genes in B. napus. Furthermore, analysis of transcriptional profiles revealed that the expression patterns of Aux/IAA genes in B. napus were tissue dependent. Auxin-responsive elements tend to be distributed in the proximal region of promoters, and are significantly associated with early exogenous auxin up regulation. CONCLUSIONS: Members of the Aux/IAA gene family were identified and analyzed comprehensively in the allotetraploid B. napus genome. This analysis provides a deeper understanding of diversification of the Aux/IAA gene family and will facilitate further dissection of Aux/IAA gene function in B. napus. PMID- 29145812 TI - Successful percutaneous coronary intervention for an in-stent chronic total occlusion in a patient with dextrocardia: a case report. AB - BACKGROUND: Percutaneous coronary interventions of chronic total occlusion represent one of the most challengingissues in interventional cardiology. A Caucasian patient with dextrocardia presented with an in-stent chronic totaloccluded right coronary artery, a constellation which has not been described previously in the literature. CASE PRESENTATION: A 69-year-old man with pre-known situs inversus totalis and a long history of coronary arterydisease with multiple interventions and stent-implantations presented to our department suffering from episodes ofchest pain under exercise. A coronary angiogram showed a completely occluded right coronary artery in the area of adrug-eluting stent which had been implanted eight years before. We found collaterals from the left coronary arterysystem and signs of calcification, so the lesion was classified as chronic total occlusion and the recanalization using an antegrade wire escalation technique successfully performed. CONCLUSION: This is the first reported case of an in-stent chronic total occlusion in situs inversus with dextrocardia. Ourexperience in this case demonstrates the feasibility of recanalization of in stent chronic total occlusions even in the rare setting of this congenital cardiac malposition combined with severe coronary artery disease. PMID- 29145813 TI - Impact of a decision aid about stratified ovarian cancer risk-management on women's knowledge and intentions: a randomised online experimental survey study. AB - BACKGROUND: Risk stratification using genetic and other types of personal information could improve current best available approaches to ovarian cancer risk reduction, improving identification of women at increased risk of ovarian cancer and reducing unnecessary interventions for women at lower risk. Amounts of information given to women may influence key informed decision-related outcomes, e.g. knowledge. The primary aim of this study was to compare informed decision related outcomes between women given one of two versions (gist vs. extended) of a decision aid about stratified ovarian cancer risk-management. METHODS: This was an experimental survey study comparing the effects of brief (gist) information with lengthier, more detailed (extended) information on cognitions relevant to informed decision-making about participating in risk-stratified ovarian cancer screening. Women with no personal history of ovarian cancer were recruited through an online survey company and randomised to view the gist (n = 512) or extended (n = 519) version of a website-based decision aid and completed an online survey. Primary outcomes were knowledge and intentions. Secondary outcomes included attitudes (values) and decisional conflict. RESULTS: There were no significant differences between the gist and extended conditions in knowledge about ovarian cancer (time*group interaction: F = 0.20, p = 0.66) or intention to participate in ovarian cancer screening based on genetic risk assessment (t(1029) = 0.43, p = 0.67). There were also no between-groups differences in secondary outcomes. In the sample overall (n = 1031), knowledge about ovarian cancer increased from before to after exposure to the decision aid (from 5.71 to 6.77 out of a possible 10: t = 19.04, p < 0.001), and 74% of participants said that they would participate in ovarian cancer screening based on genetic risk assessment. CONCLUSIONS: No differences in knowledge or intentions were found between women who viewed the gist version and women who viewed the extended version of a decision aid about risk-stratified ovarian cancer screening. Knowledge increased for women in both decision aid groups. Further research is needed to determine the ideal volume and type of content for decision aids about stratified ovarian cancer risk-management. TRIAL REGISTRATIONS: This study was registered with the ISRCTN registry; registration number: ISRCTN48627877 . PMID- 29145814 TI - Elevated exhaled acetone concentration in stage C heart failure patients with diabetes mellitus. AB - BACKGROUND: Breath acetone is a noninvasive biomarker of heart failure; however, its significance in heart failure patients with diabetes mellitus has yet to be clarified. The objective of this study is to investigate whether exhaled acetone concentration is a noninvasive biomarker in heart failure patients with diabetes mellitus. METHODS: This study prospectively included 35 diabetic patients with stage C heart failure and 20 diabetic patients with or at risk of heart failure (stage A or B). Exhaled breath was collected after an overnight fast. RESULTS: The stage C group had significantly higher brain natriuretic peptide levels, larger left ventricular diameter, lower left ventricular ejection fraction, and more frequent use of beta-blocker, compared with the stage A or B group. The stage C group had higher exhaled acetone concentrations than the stage A or B group (p = 0.013). Exhaled acetone concentration was correlated with total ketone bodies (r = 0.588, p < 0.001) and brain natriuretic peptide (r = 0.415, p = 0.002). CONCLUSION: Stage C heart failure patients with diabetes mellitus have elevated exhaled acetone concentrations. Exhaled acetone concentration could be a noninvasive biomarker in heart failure patients with diabetes mellitus. PMID- 29145815 TI - Illness recognition and care seeking for maternal complications of pregnancy and birth in rural Amhara and Oromia Regional States of Ethiopia. AB - BACKGROUND: Ethiopia has made steady progress in improving maternal health over the decade, yet mortality remains high. The Maternal and Newborn Health in Ethiopia Partnership (MaNHEP) was a 3.5-year project aimed at developing a community-oriented model to improve maternal and newborn survival in rural Ethiopia. Two years after the project ended, we carried out a case study to explore illness recognition and care seeking for complications of pregnancy and childbirth in the project area. This paper describes the results of one component: illness narratives. METHODS: Sampling involved random selection of 12 health facilities from 6 MaNHEP project districts in Amhara and >Oromia regions, and purposive selection of cases from the facility catchment areas. The purposive sample included 17 cases of perceived excessive bleeding, 5 cases of maternal death from any cause, and witnesses to the illness events. Two-person teams facilitated the narrative interviews. Analysis included thematic content analysis of symptoms, causes, decision makers and decision-making, factors facilitating and impeding care seeking, and delineation of care-seeking steps. RESULTS: Most surviving mothers (and witnesses) perceived the symptoms and seriousness of excessive bleeding; a majority (53%) sought timely biomedical care. Three of five families of mothers who died from causes unrelated to bleeding failed to initially perceive symptoms as serious, yet all sought timely appropriate care once they did so. Many of these families took multiple steps to obtain care, leading to delays.. Health worker counseling and proximity to health services facilitated, while certain cultural norms, economic, geographic, and environmental constraints impeded care seeking. Surprisingly, poor quality of care at health facilities was not a barrier. CONCLUSION: Mothers and family caregivers are able to recognize and seek timely biomedical care for abnormal bleeding, and for less obvious symptoms of illness. These achievements can be reinforced through continued and focused health education and counseling, reduction of known barriers to care seeking, and improvements in the capacity of the health system to respond to maternal complications with high quality basic and comprehensive emergency obstetric care. PMID- 29145816 TI - Renal failure during chemotherapy: renal biopsy for assessing subacute nephrotoxicity of pemetrexed. AB - BACKGROUND: Pemetrexed, a multitargeted antifolate cytotoxic agent, is currently used primarily in combination with cisplatin for metastatic non-small cell lung cancer and for malignant mesothelioma. Acute renal toxicity of pemetrexed has been recently described with polychemotherapy, in which the individual responsibility of each drug is difficult to establish. Only one recent report documents renal involvement in long-term exposed patients. CASE PRESENTATION: We report on a case of rapidly progressive nephropathy leading to the cessation of platinum salts and the secondary interruption of pemetrexed and bevacizumab. Acute tubular necrosis shown on the renal biopsy could potentially be due to pemetrexed. Persistent severe renal failure after the resumption of all drugs led to new treatment lines with gemcitabine (while the glomerular filtration rate was below 30 ml/min/1.73m2), then followed by Taxol. CONCLUSIONS: The optimal strategy with regard to renal complications in cancer patients is not clear. Acute or chronic loss in renal function generally leads to a new treatment line, possibly impairing the overall success of the treatment. The use of chemotherapy in patients with a glomerular filtration rate below 30 ml/min/1.73m2 is usually associated with an increased risk of side effects when not contraindicated by renal elimination of the drug. PMID- 29145817 TI - Family context and individual situation of teens before, during and after pregnancy in Mexico City. AB - BACKGROUND: In the last 20 years, adolescent pregnancy has become one of the most critical problems affecting women in Latin America and the Caribbean. METHODS: This qualitative study was based on in-depth interviews with 29 teen mothers. All of the pregnant teens were from low- to lower-middle-class social strata in the Mexico City metropolitan area. The family (living with the girl) and the individual context of pregnant teens were analysed on the basis of data from at least three interviews: during pregnancy and at approximately 6 and 24 months following delivery. Additionally, six mothers, four fathers, and four partners of the pregnant girls of the group were interviewed. The information on the individual and family situation before, during and after the pregnancy was recorded and transcribed, then analysed in three phases, comprising pre-analysis, exploration and interpretation. RESULTS: The pregnant teens had a family background of teen pregnancy. The girls disclosed feelings of repression, loneliness and indifference to their parents, leading them to unprotected sexual relations without fear of pregnancy. After the pregnancy, communication improved between the girls and their parents, but became worse with their partner. Consequently, these teens returned to feeling as they did before getting pregnant. They stated that they would make their situation work for the sake of their child, and regretted dropping out of school and getting pregnant so young. Almost all said they were seeking love outside the family, which revealed a scenario of limited communication and unsatisfactory relations within the family. CONCLUSIONS: Understanding how communication works between parents and children is necessary to avoid teenage pregnancy, as well as early marriage or cohabitation, resulting in dropping out of school and financial constraints, which lead to great frustrations between the couple and affects the child. In addition, it is vitally important that adolescents be motivated in the family setting in order for them to continue their studies. There is also an urgent need to implement measures that compensate for educational inequality, as well as to strengthen strategies aimed at adolescent mothers and pregnant teens that encourage their school performance through the support of scholarship programs and day care centres. Many of the problems inherent in adolescence are related to the lack of affection and support, and in many cases are a reaction to authoritarian rules or limits established unilaterally by parents with little or no dialogue involved. PMID- 29145818 TI - Risk factors associated with the progression and metastases of hindgut neuroendocrine tumors: a retrospective study. AB - BACKGROUND: The worldwide incidence of neuroendocrine tumors (NETs) has increased remarkably, with the hindgut being the second most common site for such tumors. However, the mechanisms underlying progression and metastasis of hindgut NETs are unclear. A retrospective study was conducted to elucidate these mechanisms. METHODS: Clinicopathological data of cases of hindgut NET between April 1996 and September 2015 were analyzed, retrospectively. Patients with neuroendocrine carcinoma were excluded. Formalin-fixed paraffin-embedded tissues of hindgut NET cases were subjected to detailed morphometric and immunohistochemical analyses. Statistical analyses were performed using the non-parametric Mann-Whitney U test, Spearman's correlation coefficient, and chi-squared test. Multivariate logistic regression analysis was conducted as appropriate for the data set. RESULTS: Fifty six hindgut NET cases were considered. Microvessel density and lymphatic microvessel density were identified as significant risk factors for venous and lymphatic invasion. There was a positive correlation between microvessel density and the maximum tumor diameter. Multivariate logistic regression analysis revealed that the maximum tumor diameter alone was an independent predictor of lymph node metastasis, whereas lymphovascular invasion and MVD was not the predictor of lymph node metastasis. There were no significant correlations between the Ki-67 labeling index and any of the parameters evaluated including age, sex, the maximum tumor diameter, venous invasion, lymphatic invasion, microvessel density, lymphatic microvessel density, and lymph node metastasis. CONCLUSIONS: Angiogenic mechanisms may play important roles in the progression of hindgut NET. Otherwise, the maximum tumor diameter alone was an independent predictor of lymph node metastasis in hindgut NETs. Moreover, our study raises the question of whether the presence of lymphovascular invasion, in endoscopically obtained hindgut NET tissues, is an absolute indication for additional surgery or not. PMID- 29145819 TI - Recurrent tuberculosis in Finland 1995-2013: a clinical and epidemiological cohort study. AB - BACKGROUND: We investigated the epidemiology and prevalence of potential risk factors of tuberculosis (TB) recurrence in a population-based registry cohort of 8084 TB cases between 1995 and 2013. METHODS: An episode of recurrent TB was defined as a case re-registered in the National Infectious Disease Register at least 360 days from the date of the initial registration. A regression model was used to estimate risk factors for recurrence in the national cohort. To describe the presence of known risk factors for recurrence, patient records of the recurrent cases were reviewed for TB diagnosis confirmation, potential factors affecting the risk of recurrence, the treatment regimens given and the outcomes of the TB episodes preceding the recurrence. RESULTS: TB registry data included 84 patients, for whom more than 1 TB episode had been registered. After a careful clinical review, 50 recurrent TB cases (0.6%) were identified. The overall incidence of recurrence was 113 cases per 100,000 person-years over a median follow up of 6.1 years. For the first 2 years, the incidence of recurrence was over 200/100000. In multivariate analysis of the national cohort, younger age remained an independent risk factor at all time points, and male gender and pulmonary TB at 18 years of follow-up. Among the 50 recurrent cases, 35 patients (70%) had received adequate treatment for the first episode; in 12 cases (24%) the treating physician and in two cases (4%) the patient had discontinued treatment prematurely. In one case (2%) the treatment outcome could not be assessed. CONCLUSIONS: In Finland, the rate of recurrent TB was low despite no systematic directly observed therapy. The first 2 years after a TB episode had the highest risk for recurrence. Among the recurrent cases, the observed premature discontinuation of treatment in the first episode in nearly one fourth of the recurrent cases calls for improved training of the physicians. PMID- 29145820 TI - Demographic and need factors of early, delayed and no mental health care use in major depression: a prospective study. AB - BACKGROUND: Despite the availability of evidence based treatments, many people with major depression receive no or delayed professional treatment, which may put them at risk for adverse outcomes. The aim of this study was to examine which demographic and need factors distinguish early, delayed and no treatment use. METHODS: Data were obtained from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2). People with a diagnosis of major depression in the past 12 months were included (N = 434). Mental health care use was assessed during this same period and at follow up (three years later). Multinomial regression analysis was used to distinguish early, delayed and no mental health care users with respect to demographic and need factors. RESULTS: The majority of participants accessed treatment early (62%). Early treatment users were characterized by more severe and persistent symptoms and were more likely not to have a partner compared to no treatment users. The majority of those without treatment reached remission in three years (85%). Delayed treatment users were, compared to early users, characterized by relatively mild symptoms and a persistent or new major depressive disorder at follow up. CONCLUSIONS: Early access to treatment and the finding that need factors determine mental health care use among people with depression show that the filters along the pathway to treatment are not influenced by unfavorable determinants like education or age. PMID- 29145822 TI - Ultrasonographic parameters of the liver, spleen and kidneys among a cohort of school children in Sri Lanka. AB - BACKGROUND: Liver, spleen and kidney dimensions on ultrasonography vary with the age, weight and ethnicity. Reference standards of these parameters for normal Sri Lankan children are not available. Our aim was to establish normative data for longitudinal length of liver, spleen and kidneys in healthy children. METHOD: Three hundred fifty-seven children, 5-13 years of age were selected from two randomly selected schools in the Gampaha district in the western province of Sri Lanka. A questionnaire was administered to the parents after obtaining informed written consent. Participants were screened for risk factors for organomegaly and were examined by a trained officer. Children with a past history of infective, inflammatory, haematological, malignant, congestive, collagenous or congenital conditions that can affect the size of the organs were excluded as well as those with clinically evident malnutrition, anemia, lymphadenopathy or organomegaly. Ultrasonographic assessment was done using a high resolution real-time scanner with a 3.5 MHz convex transducer by a trained officer. Children with ultrasonographic abnormalities of organs were also excluded from the study and referred for further evaluation. RESULTS: The study comprised 332 children comprising 176 girls (53%). There was a significant difference in the longitudinal dimension of the liver between the two sexes with a higher value recorded among females (Mann Whitney U = 11,830.5, p = 0.037). Body weight was correlated with the dimensions of the liver, the spleen and the kidneys. On multiple regression analysis body weight significantly associated with all the organs. (p < 0.01) Percentile graphs for longitudinal length of liver, spleen, right and left kidneys were formed according to the body weight. CONCLUSION: The organ dimensions showed the highest correlation with body weight. We hope the normal ultrasonographic values of healthy Sri Lankan children will assist in interpretation of sonographic examinations in daily clinical practice. PMID- 29145821 TI - Exposure to a community-wide campaign is associated with physical activity and sedentary behavior among Hispanic adults on the Texas-Mexico border. AB - BACKGROUND: Despite evidence for the use of community-wide campaigns to promote physical activity, few evaluations of community-wide campaigns in Hispanic communities exist. This study assessed the associations of exposure to a community-wide campaign with physical activity and sedentary behavior among Hispanic adults living on the Texas-Mexico border. METHODS: The intervention, Tu Salud !Si Cuenta! (Your Health Matters!; TSSC), included a newsletter, community health worker discussion, TV and radio segments, which were conducted from 2005 to 2010. We matched an intervention (N = 399) and a control community (N = 400) on demographics and used a cross-sectional assessment in 2010 with randomly sampled adults from both communities. We collected exposure to the campaign, as well as physical activity and sedentary behavior with the International Physical Activity Questionnaire. We conducted bivariate analyses and multivariable logistic regression models to assess the association of TSSC exposure and its components with meeting moderate-to-vigorous intensity physical activity (MVPA) guidelines and exhibiting excessive sedentary behavior, controlling for covariates. RESULTS: As compared to the control community, the intervention community has 3 times the odds of meeting MVPA guidelines (Adjusted OR [AOR] = 3.01, 95% CI = 1.85-4.88, p < .05) and 2 times lower odds of excessive sedentary behavior ((AOR = 0.46, 95% CI = 0.30-0.70, p < .05). Exposure in the intervention group to any component was associated with five times the odds of meeting MVPA guidelines (AOR = 5.10, 95% CI 2.88-9.03, p < .001) and 3 times lower odds of excessive sedentary behavior (AOR = 0.32, 95% CI 0.17-0.60, p < .001), compared with those unexposed in the control community. Exposure to newsletters, CHW discussions and TV segments were associated with significantly lower odds of excessive sedentary behavior and higher odds of meeting MVPA guidelines. Exposure to radio segments was only associated with a significantly higher odds of meeting MVPA guidelines (AOR = 4.21, 95% CI = 1.17-15.09). CONCLUSIONS: This study provides some evidence of the association of community-wide campaigns and its components in Hispanic communities with higher levels of MVPA and lower levels of excessive sedentary behavior. TRIAL REGISTRATION NUMBER: NCT00788879 Date: November 11, 2008. PMID- 29145823 TI - dbMDEGA: a database for meta-analysis of differentially expressed genes in autism spectrum disorder. AB - BACKGROUND: Autism spectrum disorders (ASD) are hereditary, heterogeneous and biologically complex neurodevelopmental disorders. Individual studies on gene expression in ASD cannot provide clear consensus conclusions. Therefore, a systematic review to synthesize the current findings from brain tissues and a search tool to share the meta-analysis results are urgently needed. METHODS: Here, we conducted a meta-analysis of brain gene expression profiles in the current reported human ASD expression datasets (with 84 frozen male cortex samples, 17 female cortex samples, 32 cerebellum samples and 4 formalin fixed samples) and knock-out mouse ASD model expression datasets (with 80 collective brain samples). Then, we applied R language software and developed an interactive shared and updated database (dbMDEGA) displaying the results of meta-analysis of data from ASD studies regarding differentially expressed genes (DEGs) in the brain. RESULTS: This database, dbMDEGA ( https://dbmdega.shinyapps.io/dbMDEGA/ ), is a publicly available web-portal for manual annotation and visualization of DEGs in the brain from data from ASD studies. This database uniquely presents meta-analysis values and homologous forest plots of DEGs in brain tissues. Gene entries are annotated with meta-values, statistical values and forest plots of DEGs in brain samples. This database aims to provide searchable meta-analysis results based on the current reported brain gene expression datasets of ASD to help detect candidate genes underlying this disorder. CONCLUSION: This new analytical tool may provide valuable assistance in the discovery of DEGs and the elucidation of the molecular pathogenicity of ASD. This database model may be replicated to study other disorders. PMID- 29145824 TI - Observations on significant hemodynamic changes caused by a high concentration of epidurally administered ropivacaine: correlation and prediction study of stroke volume variation and central venous pressure in thoracic epidural anesthesia. AB - BACKGROUND: Thoracic epidural anesthesia (TEA) exacerbates hypotension due to peripheral vasodilator effects following the use of general anesthetics. This study aimed to compare the hemodynamic changes caused by three different concentrations of epidural ropivacaine and to evaluate the performance of the stroke-volume variation (SVV) and central venous pressure (CVP) during TEA with general anesthesia. METHODS: A total of 120 patients were administered 8 mL of ropivacaine solution via epidural injection, following randomization into one of three groups based on the concentration of ropivacaine in the study solution: 0.75%, 0.375%, or 0.2%. Hemodynamics were monitored for 30 min after loading. We analyzed the hemodynamic changes in the subgroups according to an age cutoff of 60 years. Receiver operating characteristic (ROC) analysis was performed to characterize the relationship of the SVV, CVP, and a 20% decrease in the mean arterial pressure (MAP) following TEA. RESULTS: Data from 109 patients were analyzed. MAP and systemic vascular resistance index were significantly decreased, and SVV was significantly increased after epidural loading only in the 0.75% ropivacaine group. There was a significant difference in hemodynamics between young and elderly subgroups in the 0.75% ropivacaine group. SVV showed a negative correlation with MAP, whereas CVP showed no correlation. The ROC analysis of SVV demonstrated a weak predictive ability of a 20% decrease in MAP at 10 min after the loading dose, with an area-under-the-curve of 0.687 and a 9.5% optimal cutoff value (sensitivity, 60.6%; specificity, 68.9%). CONCLUSIONS: A high concentration of ropivacaine through TEA caused a significant decrease in the systemic vascular resistance and blood pressure. More significant decreases were shown in the elderly patients. Though the change of SVV showed a negative correlation with hypotension and indicated functional hypovolemia after TEA, the predictability was limited. CLINICAL TRIALS REGISTRATION: Number: NCT01559285 , date: January 24, 2013. PMID- 29145825 TI - Assembling large genomes: analysis of the stick insect (Clitarchus hookeri) genome reveals a high repeat content and sex-biased genes associated with reproduction. AB - BACKGROUND: Stick insects (Phasmatodea) have a high incidence of parthenogenesis and other alternative reproductive strategies, yet the genetic basis of reproduction is poorly understood. Phasmatodea includes nearly 3000 species, yet only the genome of Timema cristinae has been published to date. Clitarchus hookeri is a geographical parthenogenetic stick insect distributed across New Zealand. Sexual reproduction dominates in northern habitats but is replaced by parthenogenesis in the south. Here, we present a de novo genome assembly of a female C. hookeri and use it to detect candidate genes associated with gamete production and development in females and males. We also explore the factors underlying large genome size in stick insects. RESULTS: The C. hookeri genome assembly was 4.2 Gb, similar to the flow cytometry estimate, making it the second largest insect genome sequenced and assembled to date. Like the large genome of Locusta migratoria, the genome of C. hookeri is also highly repetitive and the predicted gene models are much longer than those from most other sequenced insect genomes, largely due to longer introns. Miniature inverted repeat transposable elements (MITEs), absent in the much smaller T. cristinae genome, is the most abundant repeat type in the C. hookeri genome assembly. Mapping RNA-Seq reads from female and male gonadal transcriptomes onto the genome assembly resulted in the identification of 39,940 gene loci, 15.8% and 37.6% of which showed female biased and male-biased expression, respectively. The genes that were over expressed in females were mostly associated with molecular transportation, developmental process, oocyte growth and reproductive process; whereas, the male biased genes were enriched in rhythmic process, molecular transducer activity and synapse. Several genes involved in the juvenile hormone synthesis pathway were also identified. CONCLUSIONS: The evolution of large insect genomes such as L. migratoria and C. hookeri genomes is most likely due to the accumulation of repetitive regions and intron elongation. MITEs contributed significantly to the growth of C. hookeri genome size yet are surprisingly absent from the T. cristinae genome. Sex-biased genes identified from gonadal tissues, including genes involved in juvenile hormone synthesis, provide interesting candidates for the further study of flexible reproduction in stick insects. PMID- 29145826 TI - GPU-based detection of protein cavities using Gaussian surfaces. AB - BACKGROUND: Protein cavities play a key role in biomolecular recognition and function, particularly in protein-ligand interactions, as usual in drug discovery and design. Grid-based cavity detection methods aim at finding cavities as aggregates of grid nodes outside the molecule, under the condition that such cavities are bracketed by nodes on the molecule surface along a set of directions (not necessarily aligned with coordinate axes). Therefore, these methods are sensitive to scanning directions, a problem that we call cavity ground-and-walls ambiguity, i.e., they depend on the position and orientation of the protein in the discretized domain. Also, it is hard to distinguish grid nodes belonging to protein cavities amongst all those outside the protein, a problem that we call cavity ceiling ambiguity. RESULTS: We solve those two ambiguity problems using two implicit isosurfaces of the protein, the protein surface itself (called inner isosurface) that excludes all its interior nodes from any cavity, and the outer isosurface that excludes most of its exterior nodes from any cavity. Summing up, the cavities are formed from nodes located between these two isosurfaces. It is worth noting that these two surfaces do not need to be evaluated (i.e., sampled), triangulated, and rendered on the screen to find the cavities in between; their defining analytic functions are enough to determine which grid nodes are in the empty space between them. CONCLUSION: This article introduces a novel geometric algorithm to detect cavities on the protein surface that takes advantage of the real analytic functions describing two Gaussian surfaces of a given protein. PMID- 29145827 TI - Maternal iodine status during lactation and infant weight and length in Henan Province, China. AB - BACKGROUND: Infants are very sensitive to iodine deficiency. Breastfed infants are dependent on maternal iodine intake. The aim of this study was to evaluate the relationship between maternal iodine status during lactation and infant weight and length. METHODS: A cross-sectional survey was conducted to investigate maternal iodine status and infant anthropometric measures in Henan Province, China. Only exclusive breastfeeding mothers and their infants < 6 months of age (n = 747) were included in our final analysis. Urine samples were collected from all the mothers and infants. Infant weight and length were measured and converted into weight-for-age Z-score (WAZ) and height-for-age Z-score (HAZ) using the World Health Organization (WHO) AnthroPlus software. RESULTS: The median urinary iodine concentration (UIC) in lactating women was significant lower than that in their infants (177.4 vs 261.1 MUg/L, P < 0.001). A positive correlation was found between maternal and infant urinary iodine concentration (r = 0.203, P < 0.01). The mean HAZ and WAZ values were lowest in the infants whose mothers had UIC below 50 MUg/L (n = 41). Infant WAZ with maternal UIC below 50 MUg/L was significantly lower than those with maternal UIC of 50 MUg/L or above (P = 0.043). After adjusting for confounding factors, there were significant differences in infant WAZ between maternal UIC groups. CONCLUSIONS: The present study suggests that maternal iodine status during lactation may be related to their infant anthropometric index. Appropriate iodine intake of lactating women is beneficial for their infants. PMID- 29145828 TI - Long-term prognosis of patients with non-ST-segment elevation myocardial infarction according to coronary arteries atherosclerosis extent on coronary angiography: a historical cohort study. AB - BACKGROUND: Patients with non-ST-segment elevation myocardial infarction (NSTEMI) without obstructive coronary artery disease (CAD) are often managed differently than those with obstructive CAD, therefore we aimed in this study to examine the long-term prognosis of patients with NSTEMI according to the degree of CAD on coronary angiography (CAG). METHODS: We examined 8.889 consecutive patients admitted for first time NSTEMI during 2000-2011, to whom CAG was performed. Patients were classified by CAG into: 0-vessel disease (0VD), diffuse atherosclerosis (DA) (0% < stenosis <50%), 1-vessel disease (1VD), 2VD, and 3VD with stenosis >=50%. Follow-up period: 13 years (median 4.5). RESULTS: One-year mortality for NSTEMI patients with 0VD was 3.7%, DA 5.7%, 1VD 2.5%, 2VD 4.8%, and 3VD 11.5%. Non-diabetic 0VD patients had higher risk of mortality than 1VD patients (HR:1.59; 95% CI:1.21-2.02; P < 0.001), while those with diabetes mellitus (DM) had not significantly different risk. In addition 0VD group had higher risk of heart failure (HF) (HR 1.61; 95% CI: 1.39-1.88; P < 0.001), and lower risk of recurrent MI (HR:0.55; 95% CI:0.39-0.77; P < 0.001) compared with 1VD. For patients with DA; mortality and HF risks were higher than 1VD and not different than 2VD, while recurrent MI risk was not different than 1VD and lower than 2VD. Finally, the DA group had higher risk of mortality if they had DM, higher risk of recurrent MI, and not different risk of HF and stroke compared with the 0VD group patients. CONCLUSION: Patients with NSTEMI and non-obstructive CAD (both normal coronaries and diffuse atherosclerosis) have a comparable prognosis to patients with one- or two-vessel disease. Patients with diffuse atherosclerosis have worse prognosis than those with angiographically normal coronary arteries. PMID- 29145829 TI - Effect of a rare genetic variant of TM7SF4 gene on osteoclasts of patients with Paget's disease of bone. AB - BACKGROUND: Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) is involved in osteoclastogenesis with a key role in mononucleated osteoclasts fusion. We reported in patients with Paget's disease of bone (PDB) a rare variant (rs62620995) in the TM7SF4 gene, encoding for DC-STAMP, which changes a highly conserved amino acid, possibly damaging according to in silico predictions. This study aimed at determining the functional effects of this variant on osteoclast phenotype in PDB. METHODS: Fifty ml of peripheral blood were collected in pagetic patients carrier of this variant (n = 4) or not (n = 4) and healthy controls (n = 4). Monocytes were collected after Ficoll gradient and cultured in a medium containing RANKL (40 ng/ml) and hMCSF (25 ng/ml). At the end of the differentiation period, we assessed the osteoclast morphology and bone resorption abilities. We quantified gene expression of SQSTM1, DC-STAMP, OS9, CREB3, LAMP1, OC-STAMP, and NFATC1 genes from cell lysates. Proteins encoded by these genes were investigated by Western Blot. Statistical analyses relied on ANOVA followed by Tukey post-tests. RESULTS: After 21 days of differentiation, the mean number of nuclei per multinucleated cell was significantly higher in pagetic patients carrier of the variant than in healthy controls. Bone resorption abilities were not modified by the variant. qPCR and Western Blot analyses did not provide any differences, but DC-STAMP expression was higher in patients carrier of the variant than in patients non carrier. CONCLUSIONS: This TM7SF4 rare variant may have an impact on osteoclast morphology and on DC-STAMP expression during osteoclastogenesis. Further analyses are required to understand the role of this variant during osteoclastogenesis in PDB. PMID- 29145830 TI - Differences in vertebral morphology around the apical vertebrae between neuromuscular scoliosis and idiopathic scoliosis in skeletally immature patients: a three-dimensional morphometric analysis. AB - BACKGROUND: Recent morphological analyses of vertebrae in patients with scoliosis have revealed three-dimensional (3D) deformities in the vertebral bodies. However, it remains controversial whether these deformities are secondary changes caused by asymmetrical vertebral loading or primary changes caused by aberrant asymmetrical vertebral growth. Furthermore, the difference in vertebral morphology between scoliosis with different pathogeneses remains unclear. This study was aimed to investigate the difference in the coronal asymmetry of vertebral bodies between neuromuscular scoliosis (NS) in Duchenne muscular dystrophy (DMD) and idiopathic scoliosis (IS) using in vivo 3D analysis. METHODS: Twelve male skeletally immature patients with NS in DMD and 13 female skeletally immature patients with IS who underwent corrective fusion at our institution were included retrospectively. 3D bone models of the apical and adjacent upper and lower vertebrae in the major curve in the NS patients and in the main and compensatory curves in the IS patients were constructed using an image processing workstation. The heights of the concave and convex sides of the vertebral bodies were measured at the anterior, middle, and posterior and the concave-to-convex vertebral height ratios (VHR) were calculated. RESULTS: The mean VHRs (anterior/middle/posterior) for the main curve for IS (0.897 +/- 0.072/0.832 +/- 0.086/0.883 +/- 0.059) were significantly smaller than those for NS (0.970 +/- 0.048/0.934 +/- 0.081/0.958 +/- 0.043) in all three parts (p < 0.001). Those of the compensatory curve in IS (0.968 +/- 0.045/0.942 +/- 0.067/0.967 +/- 0.046) did not differ significantly from the NS values in any part. CONCLUSIONS: When compared to the wedging of the vertebral bodies around apical vertebrae in the major curve in NS, which was caused by asymmetric loading, the wedge deformities in both the main and compensatory curves in IS were more severe than would be expected. Our results indicated that morphometric characteristics of vertebral bodies differed according to the pathogenesis of scoliosis and that the pathology of the wedging of vertebral bodies in IS could not be a result only of asymmetric loading to the vertebral bodies. PMID- 29145831 TI - COPD online-rehabilitation versus conventional COPD rehabilitation - rationale and design for a multicenter randomized controlled trial study protocol (CORe trial). AB - BACKGROUND: Rehabilitation of patients with chronic obstructive pulmonary disease (COPD) is a key treatment in COPD. However, despite the existing evidence and a strong recommendation from lung associations worldwide, 50% of patients with COPD decline to participate in COPD rehabilitation program and 30-50% drop-out before completion. The main reasons are severe symptoms, inflexible accessibility and necessity for transportation. Currently there are no well-established and evident rehabilitation alternatives. Supervised online screen rehabilitation could be a useful approach to increase accessibility and compliance. The aim of this multicenter RCT study is to compare the potential benefits of a 10-week online COPD rehabilitation program (CORe) with conventional outpatient COPD rehabilitation (CCRe). METHODS: This study is a randomized assessor- and statistician blinded superiority multicenter trial with two parallel groups, employing 1:1 allocation to the intervention and the comparison group.On the basis of a sample size calculation, 134 patients with severe or very severe COPD and eligible to conventional hospital based outpatient COPD rehabilitation will be included and randomized from eight different hospitals. The CORe intervention group receives group supervised resistance- and endurance training and patient education, 60 min, three times/week for 10 weeks at home via online-screen. The CCRe comparison group receives group based supervised resistance- and endurance training and patient education, 90 min, two times/week for 10 weeks (two hospitals) or 12 weeks (six hospitals) in groups at the local hospital. The primary outcome is change in the 6-min walking distance after 10/12 weeks; the secondary outcomes are changes in 30 s sit-to-stand chair test, physical activity level, symptoms, anxiety and depression symptoms, disease specific and generic quality of life. Primary endpoint is 10/12 weeks from baseline, while secondary endpoints are 22, 36, 62 weeks from baseline assessments. DISCUSSION: The study will likely contribute to knowledge regarding COPD tele-rehabilitation and to which extent it is more feasible and thereby more efficient than conventional COPD rehabilitation in patients with severe and very severe COPD. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02667171 . Registration data: January 28th 2016. PMID- 29145832 TI - Upper urinary tract stone disease in patients with poor performance status: active stone removal or conservative management? AB - BACKGROUND: It remains controversial as to whether active stone removal should be performed in patients with poor performance status because of their short life expectancy and perioperative risks. Our objectives were to evaluate treatment outcomes of active stone removal in patients with poor performance status and to compare life prognosis with those managed conservatively. METHODS: We retrospectively reviewed 74 patients with Eastern Cooperative Oncology Group performance status 3 or 4 treated for upper urinary tract calculi at our four hospitals between January 2009 and March 2016. Patients were classified into either surgical treatment group or conservative management group based on the presence of active stone removal. Stone-free rate and perioperative complications in surgical treatment group were reviewed. In addition, we compared overall survival and stone-specific survival between the two groups. Cox proportional hazards analysis was performed to investigate predictors of overall survival and stone-specific survival. RESULTS: Fifty-two patients (70.3%) underwent active stone removal (surgical treatment group) by extracorporeal shock wave lithotripsy (n = 6), ureteroscopy (n = 39), percutaneous nephrolithotomy (n = 6) or nephrectomy (n = 1). The overall stone-free rate was 78.8% and perioperative complication was observed in nine patients (17.3%). Conservative treatment was undergone by 22 patients (29.7%) (conservative management group). Two-year overall survival rates in surgical treatment and conservative management groups were 88.0% and 38.4%, respectively (p < 0.01) and two-year stone-specific survival rates in the two groups were 100.0% and 61.3%, respectively (p < 0.01). On multivariate analysis, stone removal was not significant, but was considered a possible favorable predictor for overall survival (p = 0.07). Moreover, stone removal was the only independent predictor of stone-specific survival (p < 0.01). CONCLUSIONS: Active stone removal for patients with poor performance status could be performed safely and effectively. Compared to conservative management, surgical stone treatment achieved longer overall survival and stone-specific survival. PMID- 29145833 TI - Using root metaphors to analyze communication between nurses and patients: a qualitative study. AB - BACKGROUND: Metaphors in communication can serve to convey individuals' backgrounds, contexts, experiences, and worldviews. Metaphors used in a health care setting can help achieve consensual communication in professional-patient relationships. Patients use metaphors to describe symptoms, or how disease affects them. Health professionals draw on shared understanding of such metaphors to better comprehend and meet patient needs, and to communicate information that patients can more easily integrate into their lives. This study incorporated a theoretical framework based on four worldviews, each with an underlying foundational metaphor (root metaphor). The use of these root metaphors (formism, mechanism, contextualism, and organicism) can have an explanatory function and serve to impart new meanings, as each type of metaphor can lead to a particular interpretation. The study aimed to extract and discuss the root metaphors, with a view to analyzing the communication between health professionals and patients. METHODS: In a case study in Spain over a six-month period, we analyzed the content of recorded, transcribed interviews conducted by one nurse with 32 patients who had chronic illnesses. We inductively extracted five categories that emerged from the interviews: blood sugar, cholesterol, exercise, blood pressure, and diet. We then examined these categories from the standpoint of each of the four root metaphors using two approaches: A series (deductive) and an emergent (inductive) approach. RESULTS: The results show that the nurse tended to primarily use two worldviews: mechanism and formism. In contrast, patients tended to favor mechanism when discussing cholesterol, blood pressure, and blood sugar levels, whereas contextualism was predominant when the category was diet or exercise. CONCLUSIONS: This study adds to the existing literature on health professionals and patients' communication. It shows how the use of Pepper's root metaphors help to analyze the communication between the nurse and patients. Furthermore, it shows they are both using different root metaphors when they are talking about illness and treatments especially regarding blood sugar, cholesterol, exercise, blood pressure, and diet. Further qualitative and quantitative studies are needed to solidly these findings. PMID- 29145834 TI - Identification of outliers and positive deviants for healthcare improvement: looking for high performers in hypoglycemia safety in patients with diabetes. AB - BACKGROUND: The study objectives were to determine: (1) how statistical outliers exhibiting low rates of diabetes overtreatment performed on a reciprocal measure rates of diabetes undertreatment; and (2) the impact of different criteria on high performing outlier status. METHODS: The design was serial cross-sectional, using yearly Veterans Health Administration (VHA) administrative data (2009 2013). Our primary outcome measure was facility rate of HbA1c overtreatment of diabetes in patients at risk for hypoglycemia. Outlier status was assessed by using two approaches: calculating a facility outlier value within year, comparator group, and A1c threshold while incorporating at risk population sizes; and examining standardized model residuals across year and A1c threshold. Facilities with outlier values in the lowest decile for all years of data using more than one threshold and comparator or with time-averaged model residuals in the lowest decile for all A1c thresholds were considered high performing outliers. RESULTS: Using outlier values, three of the 27 high performers from 2009 were also identified in 2010-2013 and considered outliers. There was only modest overlap between facilities identified as top performers based on three thresholds: A1c < 6%, A1c < 6.5%, and A1c < 7%. There was little effect of facility complexity or regional Veterans Integrated Service Networks (VISNs) on outlier identification. Consistent high performing facilities for overtreatment had higher rates of undertreatment (A1c > 9%) than VA average in the population of patients at high risk for hypoglycemia. CONCLUSIONS: Statistical identification of positive deviants for diabetes overtreatment was dependent upon the specific measures and approaches used. Moreover, because two facilities may arrive at the same results via very different pathways, it is important to consider that a "best" practice may actually reflect a separate "worst" practice. PMID- 29145835 TI - Global health education in United States anesthesiology residency programs: a survey of resident opportunities and program director attitudes. AB - BACKGROUND: Interest in global health during postgraduate residency training is increasing across medical specialties, and multiple disciplines have categorized global health training opportunities in their arena. No such cataloging exists for anesthesiology residency programs. The aim of this study was to assess and characterize global health opportunities and the attitudes of program directors (PDs) in U.S. anesthesiology residency programs towards this training. METHODS: A cross-sectional 20-question survey on global health opportunities was distributed to 128 ACGME accredited anesthesiology residency program directors via email between October 2015 and January 2016. Descriptive statistics and exploratory inferential analyses were applied. Maximal nonresponse selection bias was estimated. RESULTS: The overall response rate was 44%. Of those who responded, 61% reported that their residency program had a global health elective, with a maximal bias estimate of 6.5%. 45% of program directors with no global health elective reported wanting to offer one. 77% of electives have articulated educational goals, but there is substantial heterogeneity in curricula offered. Program director attitudes regarding the value of global health programs differed significantly between those with and without existing programs. CONCLUSIONS: The proportion of U.S. anesthesiology residency programs offering global health electives is similar to that in other medical specialties. There is inconsistency in program structure, goals, curriculum, and funding. Attitudes of program directors differ between programs with and without electives, which may reflect bidirectional influence to be investigated further. Further studies are needed to codify curricula, assess effectiveness, and validate methodologies. PMID- 29145836 TI - Clinical utility of computed tomography Hounsfield characterization for percutaneous nephrolithotomy: a cross-sectional study. AB - BACKGROUND: Computed Tomography (CT) is considered the gold-standard for the pre operative evaluation of urolithiasis. However, no Hounsfield (HU) variable capable of differentiating stone types has been clearly identified. The aim of this study is to assess the predictive value of HU parameters on CT for determining stone composition and outcomes in percutaneous nephrolithotomy (PCNL). METHODS: Seventy seven consecutive cases of PCNL between 2011 and 2016 were divided into 4 groups: 40 (52%) calcium, 26 (34%) uric acid, 5 (6%) struvite and 6 (8%) cystine stones. All images were reviewed by a single urologist using abdomen/bone windows to evaluate: stone volume, core (HUC), periphery HU and their absolute difference. HU density (HUD) was defined as the ratio between mean HU and the stone's largest diameter. ROC curves assessed the predictive power of HU for determining stone composition/stone-free rate (SFR). RESULTS: No differences were found based on the viewing window (abdomen vs bone). Struvite stones had values halfway between hyperdense (calcium) and low-density (cystine/uric acid) calculi for all parameters except HUD, which was the lowest. All HU variables for medium-high density stones were greater than low-density stones (p < 0.001). HUC differentiated the two groups (cut-off 825 HU; specificity 90.6%, sensitivity 88.9%). HUD distinguished calcium from struvite (mean +/- SD 51 +/- 16 and 28 +/- 12 respectively; p = 0.02) with high sensitivity (82.5%) and specificity (80%) at a cut-off of 35 HU/mm. Multivariate analysis revealed HUD >= 38.5 HU/mm to be an independent predictor of SFR (OR = 3.1, p = 0.03). No relationship was found between HU values and complication rate. CONCLUSIONS: HU parameters help predict stone composition to select patients for oral chemolysis. HUD is an independent predictor of residual fragments after PCNL and may be fundamental to categorize it, driving the imaging choice at follow-up. PMID- 29145837 TI - Molecular network-based analysis of the mechanism of liver injury induced by volatile oils from Artemisiae argyi folium. AB - BACKGROUND: Volatile oils from Artemisiae argyi folium (VOAAF) is reported with hepatotoxicity, but the underlying mechanism is still unclear. METHODS: In the present study this molecular mechanism was explored with the Ingenuity Pathway Analysis (IPA). The chemical components of the VOAAF were searched in the database, and their target proteins were all identified in the PubChem, while drug-induced liver injury (DILI) genes were searched in the PubMed gene databases. The molecular network of protein targets for VOAAF and DILI genes was built with the IPA. The canonical pathways between the 2 networks were compared to decipher the molecular mechanisms of the liver injury induced by VOAAF. RESULTS: There were 159 target proteins for VOAAF and 338 genes related to DILI identified, which were further analyzed in the IPA. The canonical pathway comparison showed that VOAAF and DILI both worked on aryl hydrocarbon receptor (AHR), lipopolysaccharide (LPS)/interleukin 1 (IL-1) mediated inhibition of retinoid X receptor (RXR) function, pregnane X receptor (PXR)/RXR activation, xenobiotic metabolism, peroxisome proliferator-activated receptor (PPAR), hepatic cholestasis, farnesoid X receptor (FXR)/RXR activation, and glucocorticoid receptor. CONCLUSION: VOAAF-induced liver injury may be involved in many pathways in which the AHR signaling and LPS/IL-1 mediated inhibition of RXR function pathways could be the most vital. PMID- 29145838 TI - MRI characteristics for "phantom" scratching in canine syringomyelia. AB - BACKGROUND: A classic sign of canine syringomyelia (SM) is scratching towards one shoulder. Using magnetic resonance imaging (MRI) we investigate the spinal cord lesion relating to this phenomenon which has characteristics similar to fictive scratch secondary to spinal cord transection. Medical records were searched for Cavalier King Charles spaniels with a clinical and MRI diagnosis of symptomatic SM associated with Chiari-like malformation (CM). The cohort was divided into SM with phantom scratching (19 dogs) and SM but no phantom scratching (18 dogs). MRI files were anonymised, randomised and viewed in EFILM TM. For each transverse image, the maximum perpendicular dimensions of the syrinx in the dorsal spinal cord quadrants were determined. Visual assessment was made as to whether the syrinx extended to the superficial dorsal horn (SDH). RESULTS: We showed that phantom scratching appears associated with a large dorsolateral syrinx that extends to the SDH in the C3-C6 spinal cord segments (corresponding to C2-C5 vertebrae). Estimated dorsal quadrant syrinx sizes based on the perpendicular diameters were between 2.5 and 9.5 times larger in dogs with phantom scratching, with the largest mean difference p-value being 0.009. CONCLUSION: SM associated phantom scratching appears associated with MRI findings of a large syrinx extending into the mid cervical SDH. We hypothesise that damage in this region might influence the lumbosacral scratching central pattern generator (CPG). If a scratching SM affected dog does not have a large dorsolateral cervical syrinx with SDH involvement then alternative explanations for scratching should be investigated. PMID- 29145839 TI - Structural effects of intra-articular TGF-beta1 in moderate to advanced knee osteoarthritis: MRI-based assessment in a randomized controlled trial. AB - BACKGROUND: To determine effects of allogeneic human chondrocytes expressing TGF beta1 (TG-C) on structural progression of MRI features of knee osteoarthritis over a 1 year period. METHODS: This phase II randomized controlled trial of TG-C included patients with moderate to advanced osteoarthritis. Patients were randomized to receive an intraarticular 3:1 mixture of non-transduced allogeneic human chondrocytes and TG-C or placebo. 3 T MRI was acquired for all patients at baseline and follow-up (3, 6 and 12 months). MRIs were assessed using the WORMS system including cartilage damage, bone marrow lesions (BMLs), meniscal damage/extrusion, Hoffa-, effusion-synovitis, and osteophytes. Analyses were performed on a whole knee level, compartmental level, and subregional level. Binary logistic regression with Generalized Estimating Equation was used to compare risks of progression, adjusting for baseline age and gender. Mann - Whitney - Wilcoxon tests were used to assess differences for continuous variables. RESULTS: Fifty-seven Patients were included in the TG-C group and 29 in the placebo group. At 12 months, knees in the TG-C group showed less progression of cartilage damage compared to placebo on a whole knee level (34.6% vs. 47.9%; adjusted RR 0.7, 95%CI [0.5-1.1], p = 0.077). Less progression of Hoffa-synovitis and effusion-synovitis was observed in the TG-C group compared to placebo (9.6% vs. 21.1%, adjusted RR 0.5, 95%CI [0.2,1.2], p = 0.115). No statistically significant differences were seen for BMLs, meniscal damage and osteophytes. CONCLUSIONS: Intraarticular treatment with TG-C showed fewer patients in the treated group with progression in structural OA features and other MRI-defined inflammatory markers such as Hoffa-synovitis and effusion synovitis. However, no differences were observed in regard to progression of BMLs and meniscal damage, or hypertrophic osteophyte formation. TRIAL REGISTRATION: NCT01221441 .Registered 13th October, 2010. PMID- 29145840 TI - Blockade of nicotine sensitization by methanol extracts of Glycyrrhizae radix mediated via antagonism of accumbal oxidative stress. AB - BACKGROUND: We previously reported that a methanol extract of Glycyrrhizae radix (MEGR) blocked methamphetamine-induced locomotor sensitization and conditioned place preference in rats. In the present study, the effects of MEGR on repeated nicotine-induced locomotor sensitization and enhanced extracellular dopamine (DA) release in the nucleus accumbens (Nacc) were evaluated. METHODS: Male Sprague Dawley rats received repeated administrations of nicotine (0.4 mg/kg, subcutaneous) or saline twice a day for 7 d and were challenged with nicotine 4 d after the last daily dosing. During the 4-d withdrawal period, the rats were treated once a day with MEGR (60 or 180 mg/kg/d). Extracellular DA levels were measured by in vivo microdialysis, the malondialdehyde levels and the activities of superoxide dismutase and catalase in the Nacc were biochemically evaluated, and the expression of antioxidant proteins was confirmed by Western blot assays. All data were assessed with analysis of variance tests followed by post-hoc comparison tests and p values <0.05 were considered statistically significant. RESULTS: The expression of repeated nicotine-induced locomotor sensitization was dose-dependently attenuated by MEGR, and 180 mg/kg/d MEGR significantly inhibited augmented accumbal DA release induced by a direct local challenge of nicotine. Moreover, 180 mg/kg/d MEGR reversed increases in malondialdehyde production, decreases in superoxide dismutase and catalase activities, and the reduced expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1 in the nicotine-sensitized Nacc. CONCLUSIONS: These results suggest that MEGR inhibited nicotine-induced locomotion and dopaminergic sensitization via antioxidant action. PMID- 29145841 TI - Rehabilitation for cancer patients at Black Lion hospital, Addis Ababa, Ethiopia: a cross-sectional study. AB - BACKGROUND: In Ethiopia, there were greater than 2000 adult and 200 pediatric cancer patients annually in 2010, but the estimated number of cancer patients were increasing. Oncologic rehabilitation treatment may result in improved physical and mental impairment. There is a paucity of information about rehabilitation service utilization among cancer patients in Ethiopia. Hence, the purpose of this study was to assess the rehabilitation service for cancer patient and associated factors at Black Lion hospital, Addis Ababa, Ethiopia. METHODS: A hospital-based cross-sectional quantitative study was conducted from March to April 2014. Convenient sampling method was employed to recruit the study participants. Interviewer administered questionnaire was used to collect data. Data were entered into EPI data version 3.1 and exported to SPSS (16.0) software for analysis. Descriptive analysis, binary and multiple logistic regression were carried out. Significance association was interpreted using adjusted odds ratio at 95% confidence interval and p-value less than 0.05. RESULT: A sample of 423 patients aged 18 years and older were involved in the study. Breast cancer (25%), colorectal cancer (20.6%), cervical cancer (14.7%), lymphoma (7.7%), lung (7.2%), leukemia (5.4%), kidney (3.6%) and prostate cancer (2.6%) were the common forms of cancer diagnosed at cancer unit of the Black Lion Hospital. Twenty six percent of cancer patients received rehabilitation service at least once. The main rehabilitation services given were nutritional and psychological support. Unavailability of supplies, lack of professionals and cost of service were among the barriers to receiving rehabilitation services. CONCLUSION: Only a few cancer patients received cancer rehabilitation services. Increasing the knowledge of the professionals, stocking cancer units with necessary supplies, and other comprehensive programs are needed. PMID- 29145842 TI - Age-specific Plasmodium parasite profile in pre and post ITN intervention period at a highland site in western Kenya. AB - BACKGROUND: Monitoring and evaluation of entomological, parasitological and clinical data is an important component of malaria control as it is a measure of the success of the interventions. In many studies, clinical data has been used to monitor trends in malaria morbidity and mortality. This study was conducted to demonstrate age dependent prevalence of malaria in the pre- and post interventions period. METHODS: A series of cross-sectional malaria parasitological surveys were conducted in Iguhu, western Kenya. Participants were randomly selected school-aged children between 6 and 13 years. The study was conducted between June 2002-December 2003 and January 2012-February 2015. Sexual and asexual parasite prevalence and densities were determined using microscopy. Age-dependence in parasite infections was compared between 2002-2003 and 2012 2015. RESULTS: Plasmodium falciparum had the highest prevalence of 43.5 and 11.5% in the pre- and post-intervention periods. Plasmodium malariae had a prevalence of 2.3 and 0.2%, while Plasmodium ovale had a prevalence of 0.3 and 0.1% during the pre- and post-intervention period, respectively. There was a 73.7% reduction in prevalence of P. falciparum in the post-intervention compared to the pre intervention period. Plasmodium falciparum parasite density increased by 71.2% between pre- and post-intervention period from (geometric mean of) 554.4-949.2 parasites/ul. Geometric mean gametocytaemia in Iguhu was higher in the post intervention period (106.4 parasites/ul), when compared to the pre-intervention period (54.1 parasites/ul). Prevalence and density of P. falciparum showed a lower age-dependency during post-intervention period when compared to pre intervention period. CONCLUSION: The study provides evidence for reduction of malaria prevalence following the introduction of LLINs and ACT in western Kenya. Fewer people become infected but the few infected may be more infectious as suggested by higher gametocyte densities. The high parasite densities, which were not dependent on age, observed in the post intervention period imply that a more comprehensive integrated malaria management may be required to sustain the current interventions and hence reduce malaria transmission. PMID- 29145843 TI - Development of a CRISPR/Cas9 genome editing toolbox for Corynebacterium glutamicum. AB - BACKGROUND: Corynebacterium glutamicum is an important industrial workhorse and advanced genetic engineering tools are urgently demanded. Recently, the clustered regularly interspaced short palindromic repeats (CRISPR) and their CRISPR associated proteins (Cas) have revolutionized the field of genome engineering. The CRISPR/Cas9 system that utilizes NGG as protospacer adjacent motif (PAM) and has good targeting specificity can be developed into a powerful tool for efficient and precise genome editing of C. glutamicum. RESULTS: Herein, we developed a versatile CRISPR/Cas9 genome editing toolbox for C. glutamicum. Cas9 and gRNA expression cassettes were reconstituted to combat Cas9 toxicity and facilitate effective termination of gRNA transcription. Co-transformation of Cas9 and gRNA expression plasmids was exploited to overcome high-frequency mutation of cas9, allowing not only highly efficient gene deletion and insertion with plasmid borne editing templates (efficiencies up to 60.0 and 62.5%, respectively) but also simple and time-saving operation. Furthermore, CRISPR/Cas9-mediated ssDNA recombineering was developed to precisely introduce small modifications and single-nucleotide changes into the genome of C. glutamicum with efficiencies over 80.0%. Notably, double-locus editing was also achieved in C. glutamicum. This toolbox works well in several C. glutamicum strains including the widely-used strains ATCC 13032 and ATCC 13869. CONCLUSIONS: In this study, we developed a CRISPR/Cas9 toolbox that could facilitate markerless gene deletion, gene insertion, precise base editing, and double-locus editing in C. glutamicum. The CRISPR/Cas9 toolbox holds promise for accelerating the engineering of C. glutamicum and advancing its application in the production of biochemicals and biofuels. PMID- 29145844 TI - Development and evaluation of an interferon gamma assay for the diagnosis of tuberculosis in red deer experimentally infected with Mycobacterium bovis. AB - BACKGROUND: Red deer (Cervus elaphus) is regarded as an epidemiologically relevant host for Mycobacterium bovis (M. bovis) and closely related members of the Mycobacterium tuberculosis complex that cause animal tuberculosis (TB). The standard antemortem screening test for the detection of TB in deer is the intradermal tuberculin skin test, but the detection of interferon-gamma (IFNgamma) produced by white blood cells exposed to M. bovis antigens can be used as an alternative or supplemental assay in most TB eradication/control programs. This study aims to develop an in-house sandwich ELISA for deer IFNgamma, based on the cross-reactivity of the antibodies to both cervid and bovine IFNgamma, and to evaluate the potential of this assay to detect M. bovis-infected red deer in response to the in vitro stimulation of whole-blood cells with bovine purified protein derivative (bPPD), p22 protein complex derived from bPPD or using the specific tuberculous mycobacterial proteins ESAT-6/CFP-10, Rv3615c and Rv3020c. The positive control stimulant used in this study was pokeweed mitogen, which resulted in a consistent induction of IFNgamma in samples from red deer, thus allowing the interpretation of the assay. RESULTS: The percentage of animals correctly classified by this technique as M. bovis non-infected was 100%. The detection of infected animals as positive was high and ranged widely depending upon the antigen and the cut-off value applied, as well as the time after infection. Our findings indicate that this protocol may serve as a reliable assay for the antemortem diagnosis of TB from the initial stage of M. bovis-infection, and may also be adequately sensitive. CONCLUSIONS: The suggested optimal antigens and cut-off are bPPD, p22 and the combination of ESAT-6/CFP-10 and Rv3020c with a 0.05 Delta optical density, which yielded a up to 100% correct classification of TB positive and negatve red deer under our experimental conditions. This technique will aid in TB testing of farmed and translocated deer. Future studies should evaluate the ability of this IFNgamma assay to detect specific responses under field conditions. PMID- 29145845 TI - Network pharmacological mechanisms of Vernonia anthelmintica (L.) in the treatment of vitiligo: Isorhamnetin induction of melanogenesis via up-regulation of melanin-biosynthetic genes. AB - BACKGROUND: Vitiligo is a long-term skin disease characterized by the loss of pigment in the skin. The current therapeutic approaches are limited. Although the anti-vitiligo mechanisms of Vernonia anthelmintica (L.) remain ambiguous, the herb has been broadly used in Uyghur hospitals to treat vitiligo. The overall objective of the present study aims to identify the potential lead compounds from Vernonia anthelmintica (L.) in the treatment of vitiligo via an oral route as well as the melanogenic mechanisms in the systematic approaches in silico of admetSAR and substructure-drug-target network-based inference (SDTNBI). RESULTS: The results showed that the top 5 active compounds with a relatively higher bioavailability that interacted with 23 therapeutic targets were identified in Vernonia anthelmintica (L.) using admetSAR and SDTNBI methods. Among these compounds, Isorhamnetin and Kaempferide, which are methyl-flavonoids, performed 1st and 2nd. Isorhamnetin and Kaempferide significantly increased the expression of melanin-biosynthetic genes (MC1R, MITF, TYR, TYRP1 and DCT) and the tyrosinase activity in B16F10 cells. Isorhamnetin and Kaempferide significantly increased the mRNA-expression of melanin-biosynthetic genes (MC1R, MITF, TYR, TYRP1 and DCT), the protein level of MITF and the tyrosinase activity. Based on the SDTNBI method and experimental verification, Isorhamnetin and Kaempferide effectively increased melanogenesis by targeting the MC1R-MITF signaling pathway, MAPK signaling pathway, PPAR signaling pathway (PPARA, PPARD, PPARG), arachidonic acid metabolism pathway (ALOX12, ALOX15, CBR1) and serotonergic synapses (ALOX12, ALOX15) in the treatment of vitiligo from a network perspective. CONCLUSION: We identified the melanogenic activity of the methyl-flavonoids Isorhamnetin and Kaempferide, which were successfully predicted in a network pharmacological analysis of Vernonia anthelmintica (L.) by admetSAR and SDTNBI methods. PMID- 29145846 TI - Comparison of diagnostic methods for early interproximal caries detection with near-infrared light transillumination: an in vivo study. AB - BACKGROUND: Although numerous studies have used digital intraoral imaging, only a few studies have used photo-optical methods for the diagnosis of caries. Moreover, several limitations exist in terms of observers (experience and specialty) and the caries lesion itself. Hence, the aims of this study were to evaluate the diagnostic capability of near-infrared light transillumination (NILT) and PSP-Bitewing radiographs and to compare the interobserver and intraobserver differences in addition to observers' experience level to detect early interproximal caries lesions in vivo. METHODS: A total of 52 untreated posterior teeth with and without varying degrees of early interproximal carious lesions were included. Bitewing radiographs using digital phosphor plates (PSP Bitewing) and NILT were used to clarify the diagnosis. An oral and maxillofacial radiologist and a restorative dentistry consultant evaluated the images twice. A separate appointment for clinical validation and restoration was made. Kappa coefficients were calculated to assess both intraobserver and interobserver agreements for each evaluation method. Scores obtained from PSP-Bitewing and NILT were compared with the clinical validation via receiver operating characteristic (ROC) analysis. RESULTS: No significant differences were found between PSP Bitewing radiography and NILT for detecting early interproximal carious lesions with high average Az results. Both intraobserver and interobserver agreement values were relatively higher for NILT evaluation. The Az values increased at second evaluations for both caries detection methods. CONCLUSIONS: NILT examination has an appropriate sensitivity and diagnostic accuracy for detecting early interproximal caries lesions and can be considered as a method of choice for detecting caries without the use of ionizing radiation. PMID- 29145847 TI - A path analysis study of factors influencing hospital staff perceptions of quality of care factors associated with patient satisfaction and patient experience. AB - BACKGROUND: Hospital staff are interested in information on patient satisfaction and patient experience that can help them improve quality of care. Staff perceptions of quality of care have been identified as useful proxies when patient data are not available. This study explores the organizational factors and staff attitudes that influence staff perceptions of the quality of the care they provide in relation to patient satisfaction and patient experience. METHODS: Cross sectional survey completed by 258 staff of a large multi-campus, integrated metropolitan hospital in Australia. Structured equation modelling was used to analyse the data. RESULTS: Our data suggest that different perceived organizational factors and staff attitudes contribute to different pathways for patient satisfaction and patient experience indicators. Hospital staff in our sample were more likely to indicate they provided the care that would result in higher patient satisfaction if they felt empowered within a psychologically safe environment. Conversely their views on patient experience were related to their commitment towards their hospital. There was no relationship between the staff perceptions of patient satisfaction and the staff response to the friends and family test. CONCLUSIONS: This study provides empirical evidence that staff perceptions of the quality of care they provide that is seen to be related to patient satisfaction and patient experience are enacted through different pathways that reflect differing perceptions of organizational factors and workplace psychological attitudes. PMID- 29145848 TI - Pharmacological potential of Bidens pilosa L. and determination of bioactive compounds using UHPLC-QqQLIT-MS/MS and GC/MS. AB - BACKGROUND: Research of natural products from traditionally used medicinal plants to fight against the human ailments is fetching attention of researchers worldwide. Bidens pilosa Linn. var. Radiata (Asteraceae) is well known for its folkloric medicinal use against various diseases from many decades. Mizoram, North East India, has high plant diversity and the use of this plant as herbal medicine is deep rooted in the local tribes. The present study was executed to understand the pharmacological potential of B. pilosa leaves extract. METHODS: The antimicrobial potential was determined using agar well diffusion and broth microdilution method against bacterial and yeast pathogens. Cytotoxicity was evaluated using MTT and apoptotic DNA fragmentation assays. Further, the antioxidant ability of the extract was analysed using DPPH and ABTS free radical scavenging assay. Mosquitocidal activity was evaluated against third in-star larvae of C. quinquefasciatus using dose response and time response larvicidal bioassay. Additionally, the major phenolic and volatile compounds were determined using UHPLC-QqQLIT-MS/MS and GC/MS respectively. RESULTS: We found that the extract showed highest antimicrobial activity against E. coli (MIC 80 MUg/mL and IC50 110.04 MUg/mL) and showed significant cytotoxicity against human epidermoid carcinoma (KB-3-1) cells with IC50 values of 99.56 MUg/mL among the tested cancer cell lines. The IC50 values for scavenging DPPH and ABTS was 80.45 MUg/mL and 171.6 MUg/mL respectively. The extract also showed the high phenolics (72 MUg GAE/mg extract) and flavonoids (123.3 MUg Quercetin /mg extract). Lastly, five bioactive and six volatile compounds were detected using UHPLC-QqQLIT-MS/MS and GC-MS respectively which may be responsible for the plant's bioactivities. An anticancerous compound, Paclitaxel was detected and quantified for the first time from B. pilosa leaves extract, which further showed the anticancerous potential of the tested extract. CONCLUSION: On the basis of the present investigation, we propose that the leaf extract of B. pilosa might be a good candidate for the search of efficient environment friendly natural bioactive agent and pharmaceutically important compounds. PMID- 29145849 TI - Monitoring SO2emission trends and residents' perceived health risks from PGM smelting at Selous Metallurgical Complex in Zimbabwe. AB - BACKGROUND: Persistently high sulphur dioxide (SO2) emissions from platinum group metal (PGM) smelting pose a major threat to communities located around smelters. This paper examined SO2 emission trends, emission regulations and residents' perceived health risks from exposures to such emissions at Selous Metallurgical Complex (SMC) PGM smelting facility in Zimbabwe. METHODS: SO2 data from roof monitoring sites at the smelter furnace were aggregated into annual, quarterly and monthly emission trends from 2008 to 2015. The regulatory regime's ability to protect human health from SO2 pollution in communities located around the smelter was examined. Questionnaire responses to perceived health risks from SO2exposure from 40 purposively sampled residents were assessed. The relationships between SO2 emission trends and residents' self-reported health risks from exposure to SO2emissions were explored using STATA version 11. Descriptive statistics were used to illustrate SO2 emission trends and residents' self-reported health risks from exposure to SO2. RESULTS: Between 2008 and 2015, annual SO2emissions increased from 7951 to 2500 tonnes. Emissions exceeded the recommended standard limit of 50 mg/Nm3, presenting considerable adverse health risks to local residents. Concerns relating to inefficient environmental impact assessment (EIA) licensing system, poor monitoring and auditing by the environmental management agency, as well as non-deterring SO2emission exceedance penalties were identified as major drivers of emission increase. Thirty-two (80%) of the forty respondents perceived exposure to SO2 emissions as adverse and the cause of their illnesses, with coughing, nasal congestion and shortness of breath the most frequently self reported symptoms. CONCLUSION: A set of legally-binding SO2emission standards supported by stringent EIA licensing arrangements for smelting industries are suggested for development and enforcement to reduce the SO2emission problem. Community participation in SO2emissions monitoring is also proposed as a core part of sustainable environmental management in communities located around smelters. PMID- 29145851 TI - ALA/LA ameliorates glucose toxicity on HK-2 cells by attenuating oxidative stress and apoptosis through the ROS/p38/TGF-beta1 pathway. AB - BACKGROUND: Growing evidence indicates that oxidative stress (OS) plays a pivotal role in Diabetic nephropathy (DN). In a previous study we demonstrated that ALA/LA protected HK-2 cells against high glucose-induced cytotoxicity. So we aimed to establish the glucose injury model of HK-2 cells and investigate the beneficial effects of ALA/LA on high glucose-induced excessive production of TGF beta1 and the possible mechanisms mediating the effects. METHODS: The expression of OS markers in high glucose-induced HK-2 cells treated with ALA/LA., including the antioxidant enzymes and reactive oxygen species (ROS) production, as well as the apoptosis rate were assayed by ELISA and flow cytometry. The p38/transforming growth factor beta1 (TGF-beta1) signal pathway were measured by real-time RT-PCR and western blot. RESULTS: The modeling condition of glucose toxicity on HK-2 cells was at the glucose concentration of 40.9 mM. ALA/LA can significantly increase the activities of antioxidant enzymes and decrease ROS production stimulated by high glucose. The study also found that ALA/LA caused a decrease in the apoptosis rate and TGF-beta1 level of HK-2 cells under high glucose stress through the ROS/p38 pathway. CONCLUSIONS: ALA/LA exerts protective effects in vitro through inhibition of ROS generation, down regulation of the activation of the p38MAPK pathway and the expression of TGF-beta1 in HK-2 cells. PMID- 29145852 TI - A preliminary evaluation of influence of body mass index on in vitro fertilization outcome in non-obese endometriosis patients. AB - BACKGROUND/AIMS: Obese and overweight women experience a lower probability for pregnancy after IVF. However, despite the increasing prevalence of obesity, the large majority of infertile women are non-obese. One of the most common indications for IVF is endometriosis. Thought-provoking inverse correlation has been established between BMI and endometriosis. Lower BMI is a risk factor for development of endometriosis and a predictive factor for severe endometriosis. Since severe endometriosis carries lower reproductive chances, even after IVF, we preliminary tested a hypothesis that higher BMI among non-obese endometriosis patients improves IVF outcomes. METHODS: Preliminary retrospective observational cross-sectional study was performed in women with endometriosis as a sole infertility cause who underwent IVF. During analyzed period we performed 2782 IVF procedures. In order to achieve highly homogenous study sample and to eliminate almost all confound factors that could lead to bias, we implemented strict study criteria. The number of eligible subjects was 156 and they were divided into underweight, normal weight and overweight groups. Primary outcomes were number of retrieved oocytes, good quality oocytes, embryos, and the rates of biochemical, clinical and ongoing pregnancies. For group comparisons, we used parametric test, analysis of variance, and non-parametric tests (Kruskal-Wallis test, Chi-square test). Logistic regression and General linear model was used to assess correlation between BMI and dependent variables (outcome and stimulation duration) when adjusted for age. RESULTS: Endometriosis as a single infertility factor among IVF couples had prevalence of 5.61%. Underweight women accounted for 10.26%, normal weight 71.15% and overweight 18.59% of study population. Significant differences were not found in number of retrieved oocytes (p = 0.880), good quality oocytes (p = 0.476), obtained embryos (p = 0.706), and biochemical (p = 0.298), clinical (p = 0.770) and ongoing (p = 0.822) pregnancy rates between study groups. CONCLUSION: Although preliminary results do not support our hypothesis, increase in BMI did not adversely affect the outcome of IVF in non-obese endometriosis patients, which is in contrast to literature data as regards general population of infertile women undergoing IVF. Prospective studies with large number of patients with endometriosis or prospective case control studies should address these issues and provide more comprehensive counseling of infertile endometriosis patients regarding achievement of optimal BMI prior to IVF with the intention of achievement higher pregnancy rates. PMID- 29145853 TI - Molecular characterization of beta-lactamase genes in clinical isolates of carbapenem-resistant Acinetobacter baumannii. AB - BACKGROUND: Acinetobacter baumannii is a nosocomial pathogen which is establishing as a major cause of morbidity and mortality within the healthcare community. The success of this pathogen is largely due to its ability to rapidly gain resistance to antimicrobial therapies and its capability to persist in an abiotic environment through the production of a biofilm. Our tertiary-care hospital has showed high incidence of carbapenem-resistant Acinetobacter baumannii (CRAB) isolates. METHODS: In this study we explore both genotypic and phenotypic properties of 26 CRAB isolates: 16 isolates were collected from January 2010 to March 2011, and 10 were collected between February and May 2015. RESULTS: We determined that all 26 CRAB isolates possessed multiple beta lactamase genes, including genes from Groups A, C, and D. Specifically, 42% of the isolates possesses the potentially plasmid-borne genes of OXA-23-like or OXA 40-like beta-lactamase. The presence of mobile gene element integron cassettes and/or integrases in 88% of the isolates suggests a possible mechanism of dissemination of antibiotic resistance genes. Additionally, the location of insertion sequence (IS) ISAba1 in promotor region of of the OXA-51-like, ADC-7, and ampC genes was confirmed. Multilocus sequence typing (MLST) demonstrated that all 26 CRAB isolates were either sequence type (ST)-229 or ST-2. Interestingly, ST-2 went from being the minority CRAB strain in the 2010-2011 isolates to the predominant strain in the 2015 isolates (from 32 to 90%). We show that the ST-2 strains have an enhanced ability to produce biofilms in comparison to the ST-229 strains, and this fact has potentially led to more successful colonization of the clinical environment over time. CONCLUSIONS: This study provides a longitudinal genetic and phenotypic survey of two CRAB sequence types, and suggests how their differing phenotypes may interact with the selective pressures of a hospital setting effecting strain dominance over a 5-year period. PMID- 29145854 TI - Burnout in medical students: a systematic review of experiences in Chinese medical schools. AB - BACKGROUND: To identify the: extent to which medical students in China experience burnout; factors contributing to this; potential solutions to reduce and prevent burnout in this group; and the extent to which the experiences of Chinese students reflect the international literature. METHODS: Systematic review and narrative synthesis. Key words, synonyms and subject headings were used to search five electronic databases in addition to manual searching of relevant journals. Titles and abstracts of publications between 1st January 1989-31st July 2016 were screened by two reviewers and checked by a third. Full text articles were screened against the eligibility criteria. Data on design, methods and key findings were extracted and synthesised. RESULTS: Thirty-three studies were eligible and included in the review. Greater levels of burnout were generally identified in males, more senior medical students, and those who already experienced poorer psychological functioning. Few studies explored social or contextual factors influencing burnout, but those that did suggest that factors such as the degree of social support or the living environment surrounding a student may be a determinant of burnout. CONCLUSIONS: Greater understanding of the social and contextual determinants of burnout amongst medical students in China is essential towards identifying solutions to reduce and prevent burnout in this group. PMID- 29145855 TI - Generation of a platform strain for ionic liquid tolerance using adaptive laboratory evolution. AB - BACKGROUND: There is a need to replace petroleum-derived with sustainable feedstocks for chemical production. Certain biomass feedstocks can meet this need as abundant, diverse, and renewable resources. Specific ionic liquids (ILs) can play a role in this process as promising candidates for chemical pretreatment and deconstruction of plant-based biomass feedstocks as they efficiently release carbohydrates which can be fermented. However, the most efficient pretreatment ILs are highly toxic to biological systems, such as microbial fermentations, and hinder subsequent bioprocessing of fermentative sugars obtained from IL-treated biomass. METHODS: To generate strains capable of tolerating residual ILs present in treated feedstocks, a tolerance adaptive laboratory evolution (TALE) approach was developed and utilized to improve growth of two different Escherichia coli strains, DH1 and K-12 MG1655, in the presence of two different ionic liquids, 1 ethyl-3-methylimidazolium acetate ([C2C1Im][OAc]) and 1-butyl-3-methylimidazolium chloride ([C4C1Im]Cl). For multiple parallel replicate populations of E. coli, cells were repeatedly passed to select for improved fitness over the course of approximately 40 days. Clonal isolates were screened and the best performing isolates were subjected to whole genome sequencing. RESULTS: The most prevalent mutations in tolerant clones occurred in transport processes related to the functions of mdtJI, a multidrug efflux pump, and yhdP, an uncharacterized transporter. Additional mutations were enriched in processes such as transcriptional regulation and nucleotide biosynthesis. Finally, the best performing strains were compared to previously characterized tolerant strains and showed superior performance in tolerance of different IL and media combinations (i.e., cross tolerance) with robust growth at 8.5% (w/v) and detectable growth up to 11.9% (w/v) [C2C1Im][OAc]. CONCLUSION: The generated strains thus represent the best performing platform strains available for bioproduction utilizing IL treated renewable substrates, and the TALE method was highly successful in overcoming the general issue of substrate toxicity and has great promise for use in tolerance engineering. PMID- 29145856 TI - "Is it menopause or bipolar?": a qualitative study of the experience of menopause for women with bipolar disorder. AB - BACKGROUND: Menopause can be a time of change for women and may be marked by disturbances in mood. For women living with a mental illness, such as bipolar disorder, little is known about how they experience mood changes during menopause. This study aimed to explore how women with bipolar disorder constructed mood changes during menopause and how this impacted on treatment decisions. METHODS: Semi-structured interviews were undertaken with fifteen women who reported they had been diagnosed with bipolar disorder. Data was analysed using thematic analysis guided by a social constructionist framework. RESULTS: Themes identified included 'Constructions of mood change: menopause or bipolar disorder?',' Life events, bipolar disorder and menopause coming together'; 'Treatment choices for mood change during menopause'. CONCLUSIONS: The accounts suggested that women related to the experience of mood changes during menopause through the lens of their existing framework of bipolar disorder, with implications for understanding of self and treatment choices. PMID- 29145850 TI - Targeting protein quality control pathways in breast cancer. AB - The efficient production, folding, and secretion of proteins is critical for cancer cell survival. However, cancer cells thrive under stress conditions that damage proteins, so many cancer cells overexpress molecular chaperones that facilitate protein folding and target misfolded proteins for degradation via the ubiquitin-proteasome or autophagy pathway. Stress response pathway induction is also important for cancer cell survival. Indeed, validated targets for anti cancer treatments include molecular chaperones, components of the unfolded protein response, the ubiquitin-proteasome system, and autophagy. We will focus on links between breast cancer and these processes, as well as the development of drug resistance, relapse, and treatment. PMID- 29145857 TI - Treatment of Charcot Neuroarthropathy and osteomyelitis of the same foot: a retrospective cohort study. AB - BACKGROUND: We evaluated treatment of osteomyelitis in the foot in the presence of Charcot neuroarthropathy, a devastating condition with progressive degeneration and joint destruction. We hypothesized that there was a difference in (1) amputation rate, (2) amputation level, (3) duration of antibiotic therapy, and (4) duration of immobilization for treatment of osteomyelitis within versus outside the Charcot zone. METHODS: Forty patients (43 ft) diagnosed with Charcot neuroarthropathy and osteomyelitis of the same foot were retrospectively analyzed. Some patients were successfully treated for osteomyelitis at different sites on the same foot at different times, thus 60 cases of osteomyelitis were identified in 40 treated patients. Cases were divided according to osteomyelitis localization: Group 1 had osteomyelitis outside the active Charcot region; Group 2 had osteomyelitis within the active Charcot region. RESULTS: Male patients (n = 29; mean age 58.2, range 40.1 to 77.5 years) were younger than female patients (n = 11; mean age 70.4, range 51.4 to 87.5, p = 0.02 years). Amputation rate was 52% overall (26/40 patients; 26/43 ft): 63% of 30 Group 1 cases and 40% of 30 Group 2 cases (p = 0.09). Amputation level (p = 0.009), duration of antibiotic treatment (p = 0.045) and duration of immobilization (p = 0.01) differed significantly between the groups. CONCLUSIONS: Osteomyelitis within the Charcot region is associated with a higher level of amputation and longer durations of antibiotic therapy and immobilization. Osteomyelitis outside and within the Charcot affected region should be considered separately. If osteomyelitis occurs outside the active Charcot region, primary amputation may be preferred to internal resection. LEVEL OF EVIDENCE: Retrospective cohort chart review study. PMID- 29145858 TI - Cognitive appraisal of exposure to specific types of trauma - a study of gender differences. AB - BACKGROUND: The role of gender in posttraumatic cognitions has increasingly been approached. The current study comparatively evaluates posttraumatic cognitions in men and women exposed to specific nonsexual trauma (motor vehicle accidents, work - related accidents, burns). METHODS: Posttraumatic cognitions and posttraumatic stress symptoms were comparatively assessed in 53 men and 37 women treated in 3 Romanian primary care units after specific accidental trauma. Posttraumatic Cognitions Inventory (PTCI) was used to assess posttraumatic cognitions, and the Short Post-Traumatic Stress Disorder Rating Interview (SPRINT) was used to assess posttraumatic stress symptoms. RESULTS: Men with significant posttraumatic stress symptoms endorsed more negative cognitions than women. Men with posttraumatic disability more consistently endorsed some negative cognitions regarding instrumentality, strength and control than their female counterparts. Women and men without posttraumatic disability reported similarly low levels of negative posttraumatic cognitions. Time elapsed since trauma increased most negative cognitions in men. CONCLUSIONS: The intensity of PTSD symptoms and presence of posttraumatic disability influence negative cognitions after exposure to accidental trauma. Women experiencing clinically significant PTSD symptoms endorse more cognitions regarding instrumentality, strength and control than male counterparts. Women with permanent disability after trauma report less cognitions involving emotionality, dependence and low self - efficacy than male counterparts. In the absence of permanent posttraumatic disability, men and women endorse similar levels of negative cognitions after accidental trauma. With time elapsed since trauma, men perceive decreasing self - efficacy, problem - solving and emotional control, while women perceive decreasing interpersonal cooperation. Despite limitations (cross-sectional design, lack of normative data for PTCI to ascertain culturally - specific gendered cognitions), this study supports the gender - sensitive approach of accidental trauma, especially when its consequences are pervasive, disabling and increasingly burdensome. PMID- 29145860 TI - A new single-step protocol for rapid baculovirus-driven protein production in insect cells. AB - BACKGROUND: In the last three decades, the Baculovirus expression vector system (BEV) has evolved to one of the most widely used eukaryotic systems for heterologous protein expression including approved vaccines and therapies. Despite the significant improvements introduced during the past years, the BEV system still has major drawbacks, primarily the time required to generate recombinant virus and virus instability for certain target proteins. In this study we show that the conventional method to generate recombinant Baculovirus using a Tn7 transposition based system can be shortened to a single-step transfection-only procedure without further amplification. METHODS: In a first step we have adapted a recently published protocol that replaces the standard liposome-based transfection procedure of adherent insect cells by transfecting insect cells in suspension with a preformed DNA-PEI complex generating P0 virus. We have then expressed and purified six different target proteins, among them four intracellular and two secreted proteins, by infecting insect cells either with P0 or P1 virus. RESULTS: We demonstrate that transfection in suspension is as efficient as the standard protocol, but in addition allows generation of high amounts of P0 virus early in the process. To test if this P0 virus generated by bacmid transfection can be used directly for protein expression in either the screening or production process, we compared P0 versus amplified P1 virus mediated protein expression. We show that protein expression levels, purity and yield of the purified proteins are equally high for P0 and P1. CONCLUSION: The standard protocol for generating recombinant baculovirus comprises transfection of the bacmid followed by one or two subsequent virus amplification steps. In this study we show that Baculovirus generated by transfection-only is equally efficient in driving protein expression. This reduces the time from bacmid DNA to protein to eight days and reduces the risk of virus decay. In contrast to transient gene expression protocols, the required amount of DNA is minimal: 100 ug bacmid DNA is sufficient for a production scale of 10 L. PMID- 29145859 TI - Singapore's Anopheles sinensis Form A is susceptible to Plasmodium vivax isolates from the western Thailand-Myanmar border. AB - BACKGROUND: Singapore has been certified malaria-free by the World Health Organization since November 1982. However, sporadic autochthonous malaria outbreaks do occur. In one of the most recent outbreaks of vivax malaria, an entomological investigation identified Anopheles sinensis as the most probable vector. As metaphase karyotype studies divided An. sinensis into two forms, A and B, with different vector competence: the investigation of vector competence of An. sinensis found in Singapore was thus pursued using Plasmodium vivax field isolates from the Thailand-Myanmar border. METHODS: Adults and larvae An. sinensis were collected from Singapore from 14 different locations, using various trapping and collection methods between September 2013 and January 2016. Molecular identification of An. sinensis species were conducted by amplifying the ITS2 and CO1 region using PCR. Experimental infections of An. sinensis using blood from seven patients infected with P. vivax from the Thailand-Myanmar border were conducted with Anopheles cracens (An. dirus B) as control. RESULTS: Phylogenetic analysis showed that An. sinensis (F22, F2 and collected from outbreak areas) found in Singapore was entirely Form A, and closely related to An. sinensis Form A from Thailand. Artificial infection of these Singapore strain An. sinensis Form A resulted in the development of oocysts in four experiments, with the number of sporozoites produced by one An. sinensis ranging from 4301 to 14,538. CONCLUSIONS: Infection experiments showed that An. sinensis Form A from Singapore was susceptible to Thai-Myanmar P. vivax strain, suggesting a potential role as a malaria vector in Singapore. PMID- 29145861 TI - Hybrid de novo genome assembly and centromere characterization of the gray mouse lemur (Microcebus murinus). AB - BACKGROUND: The de novo assembly of repeat-rich mammalian genomes using only high throughput short read sequencing data typically results in highly fragmented genome assemblies that limit downstream applications. Here, we present an iterative approach to hybrid de novo genome assembly that incorporates datasets stemming from multiple genomic technologies and methods. We used this approach to improve the gray mouse lemur (Microcebus murinus) genome from early draft status to a near chromosome-scale assembly. METHODS: We used a combination of advanced genomic technologies to iteratively resolve conflicts and super-scaffold the M. murinus genome. RESULTS: We improved the M. murinus genome assembly to a scaffold N50 of 93.32 Mb. Whole genome alignments between our primary super-scaffolds and 23 human chromosomes revealed patterns that are congruent with historical comparative cytogenetic data, thus demonstrating the accuracy of our de novo scaffolding approach and allowing assignment of scaffolds to M. murinus chromosomes. Moreover, we utilized our independent datasets to discover and characterize sequences associated with centromeres across the mouse lemur genome. Quality assessment of the final assembly found 96% of mouse lemur canonical transcripts nearly complete, comparable to other published high-quality reference genome assemblies. CONCLUSIONS: We describe a new assembly of the gray mouse lemur (Microcebus murinus) genome with chromosome-scale scaffolds produced using a hybrid bioinformatic and sequencing approach. The approach is cost effective and produces superior results based on metrics of contiguity and completeness. Our results show that emerging genomic technologies can be used in combination to characterize centromeres of non-model species and to produce accurate de novo chromosome-scale genome assemblies of complex mammalian genomes. PMID- 29145862 TI - L161982 alleviates collagen-induced arthritis in mice by increasing Treg cells and down-regulating Interleukin-17 and monocyte-chemoattractant protein-1 levels. AB - BACKGROUND: To investigate the effects and potential mechanism of L161982 (a kind of EP4 antagonist) on the collagen-induced arthritis (CIA) mice model. METHODS: The CIA mice model were first established by immunizing with Chicken Type II Collagen on DBA/1 mice. The CIA groups were administered once a day for 2 weeks with either 5 mg/kg L161982 by intraperitoneal injections (IP), 200 U celecoxib by intragastrical injections, or 100 MUl PBS (IP). At the end of the study, total arthritis score and histopathologic examination were assessed to determine CIA severity. The plasma and tissue expressions of IL-17 and monocyte chemoattractant protein-1 (MCP-1) were detected by enzyme-linked immunosorbent assay (ELISA) and Immunohistochemical staining (IHC) respectively; The number of CD4+CD25+Foxp3+ regulatory T cells (Treg) determined as a proportion of total CD4+ cells in the lymph nodes and spleen. We also tested the proliferation of isolated Tregs and the ratio of Th17 polarization of Naive T cells under the treatment of L161982 by BrdU assay and flow cytometry respectively. RESULTS: CIA mice treated with L161982 showed reduced arthritis scores, joint swellings, cracked cartilage surface, and less hyperplasia in the connective tissue of the articular cavity. Plasma and tissue IL-17 and MCP-1 decreased, while the proportion of Treg cells is increased both in the spleen and lymph nodes of CIA mice. Otherwise, L161982 have no direct effect on Tregs proliferation; a decreased tendency of Th17 polarization in vitro were observed in L161982-treated naive T cells. CONCLUSION: Although less effective than Celecoxib, L161982 also resulted in a reduction of ankle joint inflammation in CIA mice. L161982 reduces the RA severity in CIA mice through inhibition of IL-17 and MCP-1, increasing Treg cells, and reducing inflammation. The mechanism of the reduction of IL-17 in plasma or tissue after administration of L161982 might be potentially derived from the suppression of CD4+ T cells differentiation into Th-17 cells. PMID- 29145863 TI - Assessing quality of maternity care in Hungary: expert validation and testing of the mother-centered prenatal care (MCPC) survey instrument. AB - BACKGROUND: Instruments to assess quality of maternity care in Central and Eastern European (CEE) region are scarce, despite reports of poor doctor-patient communication, non-evidence-based care, and informal cash payments. We validated and tested an online questionnaire to study maternity care experiences among Hungarian women. METHODS: Following literature review, we collated validated items and scales from two previous English-language surveys and adapted them to the Hungarian context. An expert panel assessed items for clarity and relevance on a 4-point ordinal scale. We calculated item-level Content Validation Index (CVI) scores. We designed 9 new items concerning informal cash payments, as well as 7 new "model of care" categories based on mode of payment. The final questionnaire (N = 111 items) was tested in two samples of Hungarian women, representative (N = 600) and convenience (N = 657). We conducted bivariate analysis and thematic analysis of open-ended responses. RESULTS: Experts rated pre-existing English-language items as clear and relevant to Hungarian women's maternity care experiences with an average CVI for included questions of 0.97. Significant differences emerged across the model of care categories in terms of informal payments, informed consent practices, and women's perceptions of autonomy. Thematic analysis (N = 1015) of women's responses identified 13 priority areas of the maternity care experience, 9 of which were addressed by the questionnaire. CONCLUSIONS: We developed and validated a comprehensive questionnaire that can be used to evaluate respectful maternity care, evidence based practice, and informal cash payments in CEE region and beyond. PMID- 29145864 TI - Intraductal tubulopapillary neoplasm (ITPN) of the pancreas associated with an invasive component: a case report with review of the literature. AB - BACKGROUND: Intraductal tubulopapillary neoplasm (ITPN) depicts a distinct entity in the subgroup of premalignant epithelial tumors of the pancreas. Although the histomorphological and immunophenotypical characterization of ITPN has been described by several authors in terms of report of case series in the past, the rarity of that tumor subtype and similarity to other entities still makes identification of ITPN a challenge for radiologists and pathologists. To date, little is known about tubulopapillary carcinoma that can evolve from ITPN. CASE PRESENTATION: In the present work, we analyze one case of ITPN associated with an invasive component and discuss the results involving the current literature. Collected patient data included medical history, clinical symptoms, laboratory tests, radiological imaging, reports of interventions and operation, and histopathological and immunohistochemical examinations. The patient initially presented with acute pancreatitis. A solid tumor obstructing the main pancreatic duct and sticking out of the papilla of Vater was detected and caught via endoscopic intervention. Histopathological examination of the specimen revealed mainly tubular growth pattern with back to back tubular glands. Immunohistochemically, the tumor was strongly positive for keratin 7 (CK7) and pankeratin AE1/AE3, and alpha 1 antichymotrypsin; negative for synaptophysin and chromogranin A, CDx2, CK20, S100, carcinoembryonic antigen (CEA), MUC 2, MUC5AC, and somatostatin; and in part positive for CA19-9. Extended pancreatoduodenectomy was performed, the final diagnosis was tubulopapillary carcinoma grown in an ITPN. CONCLUSION: The identification of an ITPN of the pancreas can be a challenging task. Endoscopic retrograde cholangiopancreaticography is an excellent tool to directly see and indirectly visualize the intraductal solid tumor and to take a biopsy for histopathological evaluation at the same time. Together with a thorough immunohistochemical workup, differential diagnoses can be ruled out quickly. To date, reports of ITPN are rare and little is known about the potential for malignant transformation and the prognosis of tubulopapillary carcinoma grown from an ITPN. Radical surgical resection following oncologic criteria is recommended; however, more data will be needed to assess an adequate treatment and follow-up standard. PMID- 29145865 TI - The endonuclease EEPD1 mediates synthetic lethality in RAD52-depleted BRCA1 mutant breast cancer cells. AB - BACKGROUND: Proper repair and restart of stressed replication forks requires intact homologous recombination (HR). HR at stressed replication forks can be initiated by the 5' endonuclease EEPD1, which cleaves the stalled replication fork. Inherited or acquired defects in HR, such as mutations in breast cancer susceptibility protein-1 (BRCA1) or BRCA2, predispose to cancer, including breast and ovarian cancers. In order for these HR-deficient tumor cells to proliferate, they become addicted to a bypass replication fork repair pathway mediated by radiation repair protein 52 (RAD52). Depleting RAD52 can cause synthetic lethality in BRCA1/2 mutant cancers by an unknown molecular mechanism. METHODS: We hypothesized that cleavage of stressed replication forks by EEPD1 generates a fork repair intermediate that is toxic when HR-deficient cells cannot complete repair with the RAD52 bypass pathway. To test this hypothesis, we applied cell survival assays, immunofluorescence staining, DNA fiber and western blot analyses to look at the correlation between cell survival and genome integrity in control, EEPD1, RAD52 and EEPD1/RAD52 co-depletion BRCA1-deficient breast cancer cells. RESULTS: Our data show that depletion of EEPD1 suppresses synthetic lethality, genome instability, mitotic catastrophe, and hypersensitivity to stress of replication of RAD52-depleted, BRCA1 mutant breast cancer cells. Without HR and the RAD52-dependent backup pathway, the BRCA1 mutant cancer cells depleted of EEPD1 skew to the alternative non-homologous end-joining DNA repair pathway for survival. CONCLUSION: This study indicates that the mechanism of synthetic lethality in RAD52-depleted BRCA1 mutant cancer cells depends on the endonuclease EEPD1. The data imply that EEPD1 cleavage of stressed replication forks may result in a toxic intermediate when replication fork repair cannot be completed. PMID- 29145866 TI - Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration. AB - BACKGROUND: Osteoinduction and subsequent bone formation rely on efficient mesenchymal stem cell (MSC) recruitment. It is also known that migration is induced by gradients of growth factors and cytokines. Degradation of Ca2+ containing biomaterials mimics the bone remodeling compartment producing a localized calcium-rich osteoinductive microenvironment. The aim of our study was to determine the effect of calcium sulfate (CaSO4) on MSC migration. In addition, to evaluate the influence of CaSO4 on MSC differentiation and the potential molecular mechanisms involved. METHODS: A circular calvarial bone defect (5 mm diameter) was created in the parietal bone of 35 Balb-C mice. We prepared and implanted a cell-free agarose/gelatin scaffold alone or in combination with different CaSO4 concentrations into the bone defects. After 7 weeks, we determined the new bone regenerated by micro-CT and histological analysis. In vitro, we evaluated the CaSO4 effects on MSC migration by both wound healing and agarose spot assays. Osteoblastic gene expression after BMP-2 and CaSO4 treatment was also evaluated by qPCR. RESULTS: CaSO4 increased MSC migration and bone formation in a concentration-dependent manner. Micro-CT analysis showed that the addition of CaSO4 significantly enhanced bone regeneration compared to the scaffold alone. The histological evaluation confirmed an increased number of endogenous cells recruited into the cell-free CaSO4-containing scaffolds. Furthermore, MSC migration in vitro and active AKT levels were attenuated when CaSO4 and BMP-2 were in combination. Addition of LY294002 and Wortmannin abrogated the CaSO4 effects on MSC migration. CONCLUSIONS: Specific CaSO4 concentrations induce bone regeneration of calvarial defects in part by acting on the host's undifferentiated MSCs and promoting their migration. Progenitor cell recruitment is followed by a gradual increment in osteoblast gene expression. Moreover, CaSO4 regulates BMP-2-induced MSC migration by differentially activating the PI3K/AKT pathway. Altogether, these results suggest that CaSO4 scaffolds could have potential applications for bone regeneration. PMID- 29145867 TI - Environmental variables associated with anopheline larvae distribution and abundance in Yanomami villages within unaltered areas of the Brazilian Amazon. AB - BACKGROUND: Many indigenous villages in the Amazon basin still suffer from a high malaria burden. Despite this health situation, there are few studies on the bionomics of anopheline larvae in such areas. This publication aims to identify the main larval habitats of the most abundant anopheline species and to assess their associations with some environmental factors. METHODS: We conducted a 19 month longitudinal study from January 2013 to July 2014, sampling anopheline larvae in two indigenous Yanomami communities, comprised of four villages each. All natural larval habitats were surveyed every two months with a 350 ml manual dipper, following a standardized larval sampling methodology. In a third study area, we conducted two field expeditions in 2013 followed by four systematic collections during the long dry season of 2014-2015. RESULTS: We identified 177 larval habitats in the three study areas, from which 9122 larvae belonging to 13 species were collected. Although species abundance differed between villages, An. oswaldoi (s.l.) was overall the most abundant species. Anopheles darlingi, An. oswaldoi (s.l.), An. triannulatus (s.s.) and An. mattogrossensis were primarily found in larval habitats that were partially or mostly sun-exposed. In contrast, An. costai-like and An. guarao-like mosquitoes were found in more shaded aquatic habitats. Anopheles darlingi was significantly associated with proximity to human habitations and larval habitats associated with river flood pulses and clear water. CONCLUSIONS: This study of anopheline larvae in the Brazilian Yanomami area detected high heterogeneities at micro-scale levels regarding species occurrence and densities. Sun exposure was a major modulator of anopheline occurrence, particularly for An. darlingi. Lakes associated with the rivers, and particularly oxbow lakes, were the main larval habitats for An. darlingi and other secondary malaria vectors. The results of this study will serve as a basis to plan larval source management activities in remote indigenous communities of the Amazon, particularly for those located within low-order river-floodplain systems. PMID- 29145868 TI - What happened in the 'Move for Well-being in School': a process evaluation of a cluster randomized physical activity intervention using the RE-AIM framework. AB - BACKGROUND: The aim of this study was to address the gap in the translation of research into practice through an extensive process evaluation of the Move for Well-being in School programme using the RE-AIM framework. The purpose was to gain insight into the extent by which the intervention was adopted and implemented as intended and to understand how educators observed its effectiveness and maintenance. METHODS: Public schools located in seven municipalities in Denmark were invited to enroll their 4th to 6th grade classes in the project. Of these, 24 school decided to participate in the project in the school-year 2015-16 and were randomly (cluster) allocated to either intervention or control group. A process survey was completed online by school personnel at the start, at midterm, and at the end of the school year. Additionally, informal interviews and observations were conducted throughout the year. RESULTS: At the 12 intervention schools, a total of 148 educators were involved in the implementation of the programme over the school-year. More than nine out of ten educators integrated brain breaks in their lessons and practically all the physical education teachers used the physical education lesson plans. The educators delivered on average 4.5 brain breaks per week and up to 90% of the physical education teachers used the project lesson plans for at least half of their classes. Half of the educators initiated new recess activities. A total of 78%, 85% and 90% of the educators believed that the implemented recess, brain break and physical education components 'to a high degree' or 'to some degree' promoted the pupils' well-being, respectively. CONCLUSIONS: This study shows that it is possible to design a school-based PA intervention that educators largely adopt and implement. Implementation of the PA elements was stable throughout the school year and data demonstrate that educators believed in the ability of the intervention to promote well-being among the pupils. Finally, the study show that a structured intervention consisting of competence development, set goals for new practices combined with specific materials, and ongoing support, effectively reached a vast majority of all teachers in the enrolled schools with a substantial impact. TRIAL REGISTRATION: Date of registration: retrospectively registered on 24 April 2015 at Current Controlled Trials (DOI 0.1186/ ISRCTN12496336 - named: "The role of physical activity in improving the well being of children and youth"). PMID- 29145869 TI - A mixed methods analysis of quality of life among late-life patients diagnosed with chronic illnesses. AB - BACKGROUND: Quality of life (QOL) is an important consideration for people living with advancing chronic conditions. Palliative care providers speak about how, despite physical decline in late life, many patients report growth and meaning in other domains. This mixed methods study uses QOL survey responses to explore domain trajectories and interview data to explore how patients with advancing chronic conditions experience distinct QOL domains. METHODS: The study sample includes 156 now-deceased participants who completed the FACIT-Pal quarterly, and 40 (10 now-deceased) participants who discussed QOL in an interview. Mean subscale scores were plotted over participants' last 18 months to reveal QOL trajectories. Interview data were analyzed to reveal how participants' experience, actions and cognitive processes influenced QOL scores. RESULTS: Physical and functional subscale ratings show gradual decline. Emotional QOL maintains with a small dip 2-3 months before death, and social QOL ratings improve in participants' final 3 months. Participants create and strengthen relationships that help them better manage health and receive instrumental and emotional support; seek activities in which they can find joy, meaning, and purpose; and support cognitions through which patients accept and communicate about illness, and emphasize positives. CONCLUSION: QOL domains exist in different trajectories. Despite physical and functional decline, participant ratings of emotional QOL maintain and ratings of social QOL improve at end of life. Understanding the processes through which participants countered declining QOL may help providers identify how to best support and promote improved QOL for patients during their final months. PMID- 29145870 TI - Bacillus anthracis gamma phage lysis among soil bacteria: an update on test specificity. AB - BACKGROUND: Bacillus anthracis, which causes anthrax in humans and animals, is enzootic in parts of the U.S. state of Texas where cases are typically reported in animals annually. The gamma phage lysis assay is a common diagnostic method for identification of B. anthracis and is based on the bacterium's susceptibility to lysis. This test has been shown to be 97% specific for B. anthracis, as a small number of strains of other Bacillus spp. are known to be susceptible. In this study, we evaluated the performance of a combination of B. anthracis diagnostic assays on 700 aerobic, spore-forming isolates recovered from soil collected in Texas. These assays include phenotypic descriptions, gamma phage susceptibility, and real-time polymerase chain reaction specific for B. anthracis. Gamma phage-susceptible isolates were also tested using cell wall and capsule direct fluorescent-antibody assays specific for B. anthracis. Gamma phage susceptible isolates that were ruled out as B. anthracis were identified by 16S rRNA gene sequencing. FINDINGS: We identified 29 gamma phage-susceptible isolates. One was confirmed as B. anthracis, while the other 28 isolates were ruled out for B. anthracis by the other diagnostic tests. Using 16S rRNA gene sequencing results, we identified these isolates as members of the B. cereus group, Bacillus sp. (not within B. cereus group), Lysinibacillus spp., and Solibacillus silvestris. Based on these results, we report a specificity of 96% for gamma phage lysis as a diagnostic test for B. anthracis, and identified susceptible isolates outside the Bacillus genus. CONCLUSIONS: In this study we found gamma phage susceptibility to be consistent with previously reported results. However, we identified non-B. anthracis environmental isolates (including isolates from genera other than Bacillus) that are susceptible to gamma phage lysis. To date, susceptibility to gamma phage lysis has not been reported in genera other than Bacillus. Though these isolates are not of clinical origin, description of unexpected positives is important, especially as new diagnostic assays for B. anthracis are being developed based on gamma phage lysis or gamma phage proteins. PMID- 29145871 TI - Challenges to implementing Gavi's health system strengthening support in Chad and Cameroon: results from a mixed-methods evaluation. AB - BACKGROUND: Since 2005, Gavi has provided health system strengthening (HSS) grants to address bottlenecks affecting immunization services. This study is the first to evaluate the Gavi HSS implementation process in either Cameroon or Chad, two countries with significant health system challenges and poor achievement on the child and maternal health Millennium Development Goals. METHODS: We triangulated quantitative and qualitative data including financial records, document review, field visit questionnaires, and key informant interviews (KII) with representatives from the Ministries of Health, Gavi, and other partners. We conducted a Root Cause Analysis of key implementation challenges, guided by the Consolidated Framework for Implementation Research. RESULTS: We conducted 124 field visits and 43 KIIs in Cameroon, and 57 field visits and 39 KIIs in Chad. Cameroon's and Chad's HSS programs were characterized by delayed disbursements, significant deviations from approved expenditures, and reprogramming of funds. Nearly a year after the programs were intended to be complete, many district and facility-level activities were only partially implemented and significant funds remained unabsorbed. Root causes of these challenges included unpredictable Gavi processes and disbursements, poor communication between the countries and Gavi, insufficient country planning without adequate technical assistance, lack of country staff and leadership, and weak country systems to manage finances and promote institutional memory. CONCLUSIONS: Though Chad and Cameroon both critically needed support to strengthen their weak health systems, serious challenges drastically limited implementation of their Gavi HSS programs. Implementation of future HSS programs in these and similar settings can be improved by transparent and reliable procedures and communication from Gavi, proposals that account for countries' programmatic capacity and the potential for delayed disbursements, implementation practices that foster learning and adaptation, and an early emphasis on developing managerial and other human resources. PMID- 29145872 TI - Correction to: A review of virulent Newcastle disease viruses in the United States and the role of wild birds in viral persistence and spread. AB - After publication of the article [1], it has been brought to our attention that Newcastle disease virus was incorrectly labeled as a Tier 1 USDA Select Agent. Newcastle disease virus is a USDA Select Agent but it is not a Tier 1 agent. PMID- 29145873 TI - Group physiotherapy compared to individual physiotherapy to treat urinary incontinence in aging women: study protocol for a randomized controlled trial. AB - BACKGROUND: Urinary incontinence (UI), one of the most prevalent health concerns confronting women aged over 60 years, affects up to 55% of older community dwelling women-20-25% with severe symptoms. Clinical practice guidelines recommend individualized pelvic floor muscle training (PFMT) as a first-line treatment for stress or mixed UI in women, although lack of human and financial resources limits delivery of this first-line treatment. Preliminary data suggest that group-based treatments may provide the answer. To date, no adequately powered trials have evaluated the effectiveness or cost-effectiveness of group compared to individual PFMT for UI in older women. Given demographic projections, high prevalence of UI in older women, costly barriers, and group PFMT promising results, there is a clear need to rigorously compare the short- and long-term effectiveness and cost-effectiveness of group vs individual PFMT. METHODS/DESIGN: The study is designed as a non-inferiority randomized controlled trial, conducted in two facilities (Montreal and Sherbrooke) in the Canadian province of Quebec. Participants include 364 ambulatory, community-dwelling women, aged 60 years and older, with stress or mixed UI. Randomly assigned participants will follow a 12 week PFMT, either in one-on-one sessions or as part of a group, under the supervision of a physiotherapist. Blinded assessments at baseline, immediately post intervention, and at one year will include the seven-day bladder diary, the 24-h pad test, symptoms and quality of life questionnaires, adherence and self efficacy questionnaire, pelvic floor muscle function, and cost assessments. Primary analysis will test our main hypothesis that group-based treatment is not inferior to individualized treatment with respect to the primary outcome: relative (%) reduction in the number of leakages. DISCUSSION: Should this study find that a group-based approach is not less effective than individual PFMT, and more cost-effective, this trial will impact positively continence-care accessibility and warrant a change in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02039830 . Registered on 12 December 2013; Study protocol version 2; 21 November 2013. PMID- 29145874 TI - Peripheral immune tolerance alleviates the intracranial lipopolysaccharide injection-induced neuroinflammation and protects the dopaminergic neurons from neuroinflammation-related neurotoxicity. AB - BACKGROUND: Neuroinflammation plays a critical role in the onset and development of neurodegeneration disorders such as Parkinson's disease. The immune activities of the central nervous system are profoundly affected by peripheral immune activities. Immune tolerance refers to the unresponsiveness of the immune system to continuous or repeated stimulation to avoid excessive inflammation and unnecessary by-stander injury in the face of continuous antigen threat. It has been proved that the immune tolerance could suppress the development of various peripheral inflammation-related diseases. However, the role of immune tolerance in neuroinflammation and neurodegenerative diseases was not clear. METHODS: Rats were injected with repeated low-dose lipopolysaccharide (LPS, 0.3 mg/kg) intraperitoneally for 4 days to induce peripheral immune tolerance. Neuroinflammation was produced using intracranial LPS (15 MUg) injection. Inflammation cytokines were measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Microglial activation were measured using immunostaining of Iba-1 and ED-1. Dopaminergic neuronal damage was evaluated using immunochemistry staining and stereological counting of TH-positive neurons. Behavioral impairment was evaluated using amphetamine-induced rotational behavioral assessment. RESULTS: Compared with the non-immune tolerated animals, pre-treatment of peripheral immune tolerance significantly decreased the production of inflammatory cytokines, suppressed the microglial activation, and increased the number of dopaminergic neuronal survival in the substantia nigra. CONCLUSIONS: Our results indicated that peripheral immune tolerance attenuated neuroinflammation and inhibited neuroinflammation-induced dopaminergic neuronal death. PMID- 29145875 TI - Re-visiting the detection of porcine cysticercosis based on full carcass dissections of naturally Taenia solium infected pigs. AB - BACKGROUND: Taenia solium is a neglected zoonotic parasite. The performances of existing tools for the diagnosis of porcine cysticercosis need further assessment, and their shortcomings call for alternatives. The objective of this study was to evaluate the performance of tongue palpation and circulating antigen detection for the detection of porcine cysticercosis in naturally infected pigs of slaughter age compared to full carcass dissections (considered the gold standard). Additionally, alternative postmortem dissection procedures were investigated. A total of 68 rural pigs of slaughter age randomly selected in the Eastern Province of Zambia were dissected. Dissections were conducted on full carcasses (or half carcass in case cysticerci were already detected in the first half), including all the organs. Total cysticercus counts, location and stages were recorded and collected cysticerci were identified morphologically and molecularly. All sera were analysed with the B158/B60 antigen detecting ELISA (Ag ELISA). RESULTS: Key findings were the high occurrence of T. solium infected pigs (56%) and the presence of T. solium cysticerci in the livers of 26% of infected animals. More than half of the infected carcasses contained viable cysticerci. Seven carcasses had T. hydatigena cysticerci (10%), out of which five carcasses were co-infected with T. hydatigena and T. solium; two carcasses (3%) had only T. hydatigena cysticerci. Compared to full carcass dissection, the specificity of the Ag-ELISA to detect infected carcasses was estimated at 67%, the sensitivity at 68%, increasing to 90% and 100% for the detection of carcasses with one or more viable cysticerci, and more than 10 viable cysts, respectively. Tongue palpation only detected 10% of the cases, half carcass dissection 84%. Selective dissection of the diaphragm, tongue and heart or masseters can be considered, with an estimated sensitivity of 71%, increasing to 86% in carcasses with more than 10 cysticerci. CONCLUSIONS: Depending on the aim of the diagnosis, a combination of Ag-ELISA and selective dissection, including investigating the presence of T. hydatigena, can be considered. Full carcass dissection should include the dissection of the liver, kidneys, spleen and lungs, and results should be interpreted carefully, as small cysticerci can easily be overlooked. PMID- 29145876 TI - Standing on slopes - how current microprocessor-controlled prosthetic feet support transtibial and transfemoral amputees in an everyday task. AB - BACKGROUND: Conventional prosthetic feet like energy storage and return feet provide only a limited range of ankle motion compared to human ones. In order to overcome the poor rotational adaptability, prosthetic manufacturers developed different prosthetic feet with an additional rotational joint and implemented active control in different states. It was the aim of the study to investigate to what extent these commercially available microprocessor-controlled prosthetic feet support a natural posture while standing on inclines and which concept is most beneficial for lower limb amputees. METHODS: Four unilateral transtibial and four unilateral transfemoral amputees participated in the study. Each of the subjects wore five different microprocessor-controlled prosthetic feet in addition to their everyday feet. The subjects were asked to stand on slopes of different inclinations (level ground, upward slope of 10 degrees , and downward slope of -10 degrees ). Vertical ground reaction forces, joint torques and joint angles in the sagittal plane were measured for both legs separately for the different situations and compared to a non-amputee reference group. RESULTS: Differences in the biomechanical parameters were observed between the different prosthetic feet and compared to the reference group for the investigated situations. They were most prominent while standing on a downward slope. For example, on the prosthetic side, the vertical ground reaction force is reduced by about 20%, and the torque about the knee acts to flex the joint for feet that are not capable of a full adaptation to the downward slope. In contrast, fully adaptable feet with an auto-adaptive dorsiflexion stop show no changes in vertical ground reaction forces and knee extending torques. CONCLUSIONS: A prosthetic foot that provides both, an auto-adaptive dorsiflexion stop and a sufficient range of motion for fully adapting to inclinations appears to be the key element in the prosthetic fitting for standing on inclinations in lower limb amputees. In such situations, this prosthetic concept appears superior to both, conventional feet with passive structures as well as feet that solely provide a sufficient range of motion. The results also indicate that both, transfemoral and transtibial amputees benefit from such a foot. PMID- 29145877 TI - Trajectory of instantaneous axis of rotation in fixed lumbar spine with instrumentation. AB - BACKGROUND: Several studies showed instantaneous axis of rotation (IAR) in the intact spine. However, there has been no report on the trajectory of the IAR of a damaged spine or that of a fixed spine with instrumentation. It is the aim of this study to investigate the trajectory of the IAR of the lumbar spine using the vertebra of deer. METHODS: Functional spinal units (L5-6) from five deer were evaluated with six-axis material testing machine. As specimen models, we prepared a normal model, a damaged model, and a pedicle screw (PS) model. We measured the IAR during bending in the coronal and sagittal planes and axial rotation. In the bending test, four directions were measured: anterior, posterior, right, and left. In the rotation test, two directions were measured: right and left. RESULTS: The IAR of the normal model during bending moved in the bending direction. The IAR of the damaged model during bending moved in the bending direction, but the magnitude of displacement was bigger compared to that of the normal model. In the PS model, the IAR during bending test hardly moved. During rotation test, the IAR of the normal model and PS model located in the spinal canal, but the IAR of the damaged model located in the posterior part of the vertebral body. CONCLUSIONS: In this study, the IAR of damaged model was scattering and that of PS model was concentrating. This suggests that higher mechanical load applied to the dura tube and nerve roots in the damaged model and less mechanical load applied to that in the PS model. PMID- 29145878 TI - Improving readiness for recruitment through simulated trial activation: the Adjuvant Steroids in Adults with Pandemic influenza (ASAP) trial. AB - BACKGROUND: Research in public health emergencies requires trials to be set up in readiness for activation at short notice and in anticipation of limited timelines for patient recruitment. We conducted a simulated activation of a hibernating pandemic influenza clinical trial in order to test trial processes and to determine the value of such simulation in maintaining trial readiness. METHODS: The simulation involved the Nottingham Clinical Trials Unit, one participating hospital, one manufacturing unit and the Investigational Medicinal Product (IMP) supplier. During the exercise, from 15 September 2015 to 2 December 2015, clinical staff at the participating site completed the trial training package, a volunteer acting as a patient was recruited to the study, 'dummy' IMP was prescribed and follow-up completed. RESULTS: Successful activation of the hibernating trial with patient recruitment within 4 weeks of 'arousal' as planned was demonstrated. A need for greater resilience in anticipation of staff absenteeism was identified, particularly in relation to key trial procedures where the potential for delay is high. A specific issue relating to the IMP Stock Control System was highlighted as a potential source of error that could compromise the randomisation sequence. The simulation exercise was well received by site investigators and increased their confidence in being able to meet the likely demands of the trial when activated. The estimated cost of the exercise was L1995; 90% of this being staff costs. CONCLUSIONS: Simulated activation is useful as a means to test, and prepare for, the rapid activation of 'hibernating' research studies. Whether simulation exercises can also help reduce waste in complex clinical trial research deserves further exploration. TRIAL REGISTRATION: EudraCT Number 2013-001051-12, ISRCTN72331452 . Registered on 6 March 2013. PMID- 29145879 TI - Allogeneic mesenchymal stem cell as induction therapy to prevent both delayed graft function and acute rejection in deceased donor renal transplantation: study protocol for a randomized controlled trial. AB - BACKGROUND: Using kidneys from deceased donors is an available strategy to meet the growing need of grafts. However, higher incidences of delayed graft function (DGF) and acute rejection exert adverse effects on graft outcomes. Since ischemia reperfusion injury (IRI) and ongoing process of immune response to grafts are the major causes of DGF and acute rejection, the optimal induction intervention should possess capacities of both repairing renal structure injury and suppressing immune response simultaneously. Mesenchymal stem cells (MSCs) with potent anti-inflammatory, regenerative and immune-modulatory properties are considered as a candidate to prevent both DGF and acute rejection in renal transplantation. Previous studies just focused on the safety of autologous MSCs on living-related donor renal transplants, and lack of concomitant controls and the sufficient sample size and source of MSCs. Here, we propose a prospective multicenter controlled study to assess the clinical value of allogeneic MSCs in preventing both DGF and acute rejection simultaneously as induction therapy in deceased-donor renal transplantation. METHODS/DESIGN: Renal allograft recipients (n = 100) will be recruited and divided into trial and control groups, and 50 patients in the trial group will be administered with a dose of 2 * 106 per kilogram human umbilical-cord-derived MSCs (UC-MSCs) via peripheral vein injection preoperatively, and a dose of 5 * 106 cells via renal arterial injection during surgery, with standard induction therapy. Incidences of postoperative DGF and biopsy-proved acute rejection (BPAR) will be recorded and analyzed. Additionally, other clinical parameters such as baseline demographics, graft and recipient survival and other severe postoperative complications, including complicated urinary tract infection, severe pneumonia, and severe bleeding, will be also assessed. DISCUSSION: This study will clarify the clinical value of UC-MSCs in preventing DGF and acute rejection simultaneously in deceased donor renal transplantation, and provide evidence as to whether allogeneic MSCs can be used as clinically feasible and safe induction therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02490020 . Registered on 29 June 2015. PMID- 29145880 TI - Anti-NF155 chronic inflammatory demyelinating polyradiculoneuropathy strongly associates to HLA-DRB15. AB - BACKGROUND: The aim of the research is to study the human leukocyte antigen (HLA) class II allele frequencies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) associated with anti-neurofascin 155 (NF155) antibodies. METHODS: Thirteen anti-NF155+ and 35 anti-NF155 negative (anti NF155neg) CIDP patients were included in a case-control study. The frequencies of the DRB1 HLA allele were analyzed in all patients while DQ frequencies were only studied in patients sharing the DRB1*15 allele. In silico HLA-peptide binding and NF155 antigenicity, predictions were performed to analyze overlap between presented peptides and antigenic regions. RESULTS: DRB1*15 alleles (DRB1*15:01 and DRB1*15:02) were present in 10 out of 13 anti-NF155+ CIDP patients and in only 5 out of 35 anti-NF155neg CIDP patients (77 vs 14%; OR = 20, CI = 4.035 to 99.13). DRB1*15 alleles appeared also in significantly higher proportions in anti NF155+ CIDP than in normal population (77 vs 17%; OR = 16.9, CI = 4.434 to 57.30). Seven anti-NF155+ CIDP patients (53%) and 5 anti-NF155neg CIDP patients had the DRB1*15:01 allele (OR = 7, p = 0.009), while 3 anti-NF155+ CIDP patients and none of the anti-NF155neg CIDP patients had the DRB1*15:02 allele (OR = 23.6, p = 0.016). In silico analysis of the NF155 peptides binding to DRB1*15 alleles showed significant overlap in the peptides presented by the 15:01 and 15:02 alleles, suggesting functional homology. CONCLUSIONS: DRB1*15 alleles are the first strong risk factor associated to a CIDP subset, providing additional evidence that anti-NF155+ CIDP patients constitute a differentiated disease within the CIDP syndrome. PMID- 29145881 TI - Multiple small hemorrhagic infarcts in cerebral air embolism: a case report. AB - BACKGROUND: Cerebral air embolism is a rare cause of cerebral infarction. In cerebral air embolism, T2 star-weighted imaging shows numerous spotty hypointense signals. Previous reports have suggested that these signals represent air in the brain and are gradually diminished and absorbed. We experienced two cases of cerebral air embolism, and in one of them, we conducted an autopsy. CASE PRESENTATION: Case 1 was a 76-year-old Japanese man with lung cancer and emphysema. A spasmodic cough induced massive cerebral and cardiac air embolisms and the patient died because of cerebral herniation. T2 star-weighted imaging of brain magnetic resonance imaging showed multiple spotty low signals. Brain autopsy showed numerous spotty hemorrhagic infarcts in the area of T2 star weighted imaging signals. Case 2 was an 85-year-old Japanese man with emphysema who suffered from acute stroke. Similar spotty T2 star-weighted imaging signals were observed and remained unchanged 2 months after the onset. CONCLUSIONS: These findings indicate that T2 star-weighted imaging in cerebral air embolism partially represents micro-hemorrhagic infarction caused by air bubbles that have migrated into the brain. PMID- 29145882 TI - What Goes Around: the process of building a community-based harm reduction research project. AB - BACKGROUND: Often, research takes place on underserved populations rather than with underserved populations. This approach can further isolate and stigmatize groups that are already made marginalized. What Goes Around is a community-based research project that was led by community members themselves (Peers). CASE PRESENTATION: This research aimed to implement a community-based research methodology grounded in the leadership and growing research capacity of community researchers and to investigate a topic which community members identified as important and meaningful. Chosen by community members, this project explored how safer sex and safer drug use information is shared informally among Peers. Seventeen community members actively engaged as both community researchers and research participants throughout all facets of the project: inception, implementation, analysis, and dissemination of results. Effective collaboration between community researchers, a community organization, and academics facilitated a research process in which community members actively guided the project from beginning to end. CONCLUSIONS: The methods used in What Goes Around demonstrated that it is not only possible, but advantageous, to draw from community members' involvement and direction in all stages of a community-based research project. This is particularly important when working with a historically underserved population. Purposeful and regular communication among collaborators, ongoing capacity building, and a commitment to respect the experience and expertise of community members were essential to the project's success. This project demonstrated that community members are highly invested in both informally sharing information about safer sex and safer drug use and taking leadership roles in directing research that prioritizes harm reduction in their communities. PMID- 29145883 TI - Self-reported actual and desired proportion of sitting, standing, walking and physically demanding tasks of office employees in the workplace setting: do they fit together? AB - OBJECTIVE: Occupational sitting time in white-collar workers represents a prominent contributor to overall daily sitting time, which is associated with various health risks. Workplace interventions intending to reduce sitting time during work typically focus on replacing sitting with standing. The aim was to investigate and compare actual and desired proportions of time spent sitting, standing, walking, and doing physically demanding tasks at work reported by desk based workers. Cross-sectional data were collected from German desk-based workers (n = 614; 53.3% men; 40.9 +/- 13.5 years). All were interviewed about their self reported actual and desired level of sitting, standing, walking and physically demanding tasks at work. RESULTS: Desk-based workers reported to sit 73.0%, stand 10.2%, walk 12.9% and do physically demanding tasks 3.9% of their working hours. However, the individuals desire to sit, stand, walk and do physically demand tasks significantly different [53.8% sit, 15.8% stand, 22.8% walk, physically demanding tasks (7.7%), p < 0.001]. The present data revealed greatest mismatch between the desk-based workers' actual and desired time for sitting and walking. Health promotion programs should offer not only options for more standing but also opportunities for more walking within the workplace setting to better match workers' desires. PMID- 29145884 TI - Systematic literature review of built environment effects on physical activity and active transport - an update and new findings on health equity. AB - BACKGROUND: Evidence is mounting to suggest a causal relationship between the built environment and people's physical activity behaviours, particularly active transport. The evidence base has been hindered to date by restricted consideration of cost and economic factors associated with built environment interventions, investigation of socioeconomic or ethnic differences in intervention effects, and an inability to isolate the effect of the built environment from other intervention types. The aims of this systematic review were to identify which environmental interventions increase physical activity in residents at the local level, and to build on the evidence base by considering intervention cost, and the differential effects of interventions by ethnicity and socioeconomic status. METHODS: A systematic database search was conducted in June 2015. Articles were eligible if they reported a quantitative empirical study (natural experiment or a prospective, retrospective, experimental, or longitudinal research) investigating the relationship between objectively measured built environment feature(s) and physical activity and/or travel behaviours in children or adults. Quality assessment was conducted and data on intervention cost and whether the effect of the built environment differed by ethnicity or socioeconomic status were extracted. RESULTS: Twenty-eight studies were included in the review. Findings showed a positive effect of walkability components, provision of quality parks and playgrounds, and installation of or improvements in active transport infrastructure on active transport, physical activity, and visits or use of settings. There was some indication that infrastructure improvements may predominantly benefit socioeconomically advantaged groups. Studies were commonly limited by selection bias and insufficient controlling for confounders. Heterogeneity in study design and reporting limited comparability across studies or any clear conclusions to be made regarding intervention cost. CONCLUSIONS: Improving neighbourhood walkability, quality of parks and playgrounds, and providing adequate active transport infrastructure is likely to generate positive impacts on activity in children and adults. The possibility that the benefits of infrastructure improvements may be inequitably distributed requires further investigation. Opportunities to improve the quality of evidence exist, including strategies to improve response rates and representativeness, use of valid and reliable measurement tools, cost-benefit analyses, and adequate controlling for confounders. PMID- 29145886 TI - Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans. AB - BACKGROUND: The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans. METHODS: Recently published musculoskeletal models of the mouse hindlimb and human lower limb were used to simulate muscle-tendon dynamics during mouse and human walking, a key daily activity. Muscle fiber length changes (fiber excursions) of 25 muscle homologs in the two species were calculated from these simulations and then compared. To understand potential causes of differences in fiber excursions in walking, joint excursions and muscle moment arms were also compared across one gait cycle. RESULTS: Most muscles (19 out of 25 muscles) of the mouse hindlimb had much smaller fiber excursions as compared to human lower limb muscles during walking. For these muscles, fiber excursions in mice were only 48 +/- 19% of those in humans. The differences in fiber excursion between the two species were primarily due to the reduced joint excursions and smaller muscle moment arms in mice as compared to humans. CONCLUSIONS: Since progressive neuromuscular diseases, such as Duchenne muscular dystrophy, are known to be accelerated by damage accumulated from active muscle lengthening, these results suggest that biomechanical differences in muscle function during walking between mice and humans may impede the translations of knowledge gained from mouse models to humans. This knowledge would add a fresh perspective on how pre-clinical studies on mice might be better designed to improve translation to human clinical trials. PMID- 29145885 TI - Future perspectives in melanoma research "Melanoma Bridge", Napoli, November 30th 3rd December 2016. AB - Major advances have been made in the treatment of cancer with targeted therapy and immunotherapy; several FDA-approved agents with associated improvement of 1 year survival rates became available for stage IV melanoma patients. Before 2010, the 1-year survival were quite low, at 30%; in 2011, the rise to nearly 50% in the setting of treatment with Ipilimumab, and rise to 70% with BRAF inhibitor monotherapy in 2013 was observed. Even more impressive are 1-year survival rates considering combination strategies with both targeted therapy and immunotherapy, now exceeding 80%. Can we improve response rates even further, and bring these therapies to more patients? In fact, despite these advances, responses are heterogeneous and are not always durable. There is a critical need to better understand who will benefit from therapy, as well as proper timing, sequence and combination of different therapeutic agents. How can we better understand responses to therapy and optimize treatment regimens? The key to better understanding therapy and to optimizing responses is with insights gained from responses to targeted therapy and immunotherapy through translational research in human samples. Combination therapies including chemotherapy, radiotherapy, targeted therapy, electrochemotherapy with immunotherapy agents such as Immune Checkpoint Blockers are under investigation but there is much room for improvement. Adoptive T cell therapy including tumor infiltrating lymphocytes and chimeric antigen receptor modified T cells therapy is also efficacious in metastatic melanoma and outcome enhancement seem likely by improved homing capacity of chemokine receptor transduced T cells. Tumor infiltrating lymphocytes therapy is also efficacious in metastatic melanoma and outcome enhancement seem likely by improved homing capacity of chemokine receptor transduced T cells. Understanding the mechanisms behind the development of acquired resistance and tests for biomarkers for treatment decisions are also under study and will offer new opportunities for more efficient combination therapies. Knowledge of immunologic features of the tumor microenvironment associated with response and resistance will improve the identification of patients who will derive the most benefit from monotherapy and might reveal additional immunologic determinants that could be targeted in combination with checkpoint blockade. The future of advanced melanoma needs to involve education and trials, biobanks with a focus on primary tumors, bioinformatics and empowerment of patients and clinicians. PMID- 29145887 TI - Postpartum infective endocarditis with Enterococcus faecalis in Japan: a case report. AB - BACKGROUND: The clinical characteristics of infective endocarditis include the presence of predisposing cardiac disease, a history of illegal drug use, and high morbidity in the elderly. Only a few cases of the disease after delivery have been reported in the literature. We describe here a first case of enterococcal postpartum infective endocarditis without underlying disease in Japan. CASE PRESENTATION: We report the case of a 31-year-old Japanese woman with postpartum infective endocarditis by Enterococcus faecalis. She had no significant medical history or any unusual social history. After emergency surgery for severe mitral regurgitation and antimicrobial treatment for 6 weeks, she was discharged from our hospital and is now being monitored at an out-patient clinic. CONCLUSIONS: We encountered a case of Enterococcus faecalis infective endocarditis that occurred in the native valve of a postpartum healthy woman. Although the pathogenesis of this case remains unclear, it could be due to bacteremia arising from the administration of prophylactic broad-spectrum antibiotics used for cesarean section. Previous use of cefotiam and urinary catheter insertion may be risk factors for nosocomial enterococcal bacteremia in this case. PMID- 29145888 TI - TGF-beta2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells' invasion. AB - BACKGROUND: Glioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-beta2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-beta2 and autophagy in glioma has been poorly understood. METHODS: U251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-beta2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models. RESULTS: Here we demonstrated that TGF-beta2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-beta2-induced autophagy. TGF-beta2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (?Psim). Autopaghy also initiated a feedback on TGF-beta2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-beta inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better "turn off" tumor growth. CONCLUSION: Our findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-beta2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells' invasion. PMID- 29145889 TI - Quality of life in children with infantile hemangioma: a case control study. AB - BACKGROUND: Infantile hemangioma (IH) is the most common vascular tumor in children. It is controversial whether IHs has effects on the quality of life (QOL) in patients of whom IH poses no threat or potential for complication. Thus, we conducted this study to evaluate the q QOL in patients with IH and find the predictors of poor QOL. METHODS: The PedsQL 4.0 Genetic Core Scales and the PedsQL family information form were administered to parents of children with IH and healthy children both younger than 2-year-old. The quality-of-life instrument for IH (IH-QOL) and the PedsQL 4.0 family impact module were administered to parents of children with IH. We compared the PedsQL 4.0 Genetic Core Scales (GCIS) scores of the two groups. Multiple step-wise regression analysis was used to determine factors that influenced QOL in children with IH and their parents. RESULTS: Except for physical symptom, we found no significant difference in GCIS between patient group and healthy group (P = 0.409). The internal reliability of IH-QOL was excellent with the Cronbach's alpha coefficient for summary scores being 0.76. Multiple step-wise regression analysis showed that the predictors of poor IH-QOL total scores were hemangioma size, location, and mother's education level. The predictors of poor FIM total scores were hemangioma location and father's education level. The predictors of poor GCIS total scores were children's age, hemangioma location and father's education level. CONCLUSION: The findings support the feasibility and reliability of the Chinese version of IH-QOL to evaluate the QOL in children with IH and their parents. Hemangioma size, location and education level of mother are important impact factors for QOL in children with IH and their parents. PMID- 29145890 TI - Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population. AB - BACKGROUND: Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. METHODS: An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. RESULTS: Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and Cmax showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The tmax of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed. CONCLUSIONS: Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The tmax of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. TRIAL REGISTRATION: This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017). PMID- 29145891 TI - The Inuit gut microbiome is dynamic over time and shaped by traditional foods. AB - BACKGROUND: The human gut microbiome represents a diverse microbial community that varies across individuals and populations, and is influenced by factors such as host genetics and lifestyle. Diet is a major force shaping the gut microbiome, and the effects of dietary choices on microbiome composition are well documented. However, it remains poorly known how natural temporal variation in diet can affect the microbiome. The traditional Inuit diet is primarily based on animal products, which are thought to vary seasonally according to prey availability. We previously investigated the Inuit gut microbiome sampled at a single time point, and found no detectable differences in overall microbiome community composition attributable to the traditional Inuit diet. RESULTS: To determine whether seasonal changes in the Inuit diet might induce more pronounced changes in the microbiome, we collected stool and toilet paper samples, and dietary information from Inuit volunteers living in Resolute Bay (Nunavut, Canada), and compared them to individuals of European descent living in Montreal (Quebec, Canada) consuming a typical Western diet. We sequenced the V4 region of the 16S rRNA gene to characterize microbiome diversity and composition, and compared samples collected with toilet paper or from stool. Our results show that these sampling methods provide similar, but non-identical portraits of the microbiome. Based on toilet paper samples, we found that much of the variation in microbiome community composition could be explained by individual identity (45-61% of variation explained, depending on the beta diversity metric used), with small but significant variation (3-5%) explained by sex or geography (Nunavut or Montreal). In contrast with our previous study at one time point, sampling over the course of a year revealed that diet explains 11% of variation in community composition across all participants, and 17% of variation specifically among Nunavut participants. However, we observed no clear seasonal shifts in the microbiomes of participants from either Nunavut or Montreal. Within-individual microbial diversity fluctuated more over time in Nunavut than in Montreal, consistent with a more variable and highly individualized diet in Nunavut. CONCLUSIONS: Together, these results shows that the traditional Inuit diet and lifestyle has an impact on the composition, diversity and stability of the Inuit gut microbiome, even if the seasonality of the diet is less pronounced than expected, perhaps due to an increasingly westernized diet. PMID- 29145893 TI - Normalization of the microbiota in patients after treatment for colonic lesions. AB - BACKGROUND: Colorectal cancer is a worldwide health problem. Despite growing evidence that members of the gut microbiota can drive tumorigenesis, little is known about what happens to it after treatment for an adenoma or carcinoma. This study tested the hypothesis that treatment for adenoma or carcinoma alters the abundance of bacterial populations associated with disease to those associated with a normal colon. We tested this hypothesis by sequencing the 16S rRNA genes in the feces of 67 individuals before and after treatment for adenoma (N = 22), advanced adenoma (N = 19), and carcinoma (N = 26). RESULTS: There were small changes to the bacterial community associated with adenoma or advanced adenoma and large changes associated with carcinoma. The communities from patients with carcinomas changed significantly more than those with adenoma following treatment (P value < 0.001). Although treatment was associated with intrapersonal changes, the change in the abundance of individual OTUs in response to treatment was not consistent within diagnosis groups (P value > 0.05). Because the distribution of OTUs across patients and diagnosis groups was irregular, we used the random forest machine learning algorithm to identify groups of OTUs that could be used to classify pre and post-treatment samples for each of the diagnosis groups. Although the adenoma and carcinoma models could reliably differentiate between the pre- and post-treatment samples (P value < 0.001), the advanced-adenoma model could not (P value = 0.61). Furthermore, there was little overlap between the OTUs that were indicative of each treatment. To determine whether individuals who underwent treatment were more likely to have OTUs associated with normal colons we used a larger cohort that contained individuals with normal colons and those with adenomas, advanced adenomas, and carcinomas. We again built random forest models and measured the change in the positive probability of having one of the three diagnoses to assess whether the post-treatment samples received the same classification as the pre-treatment samples. Samples from patients who had carcinomas changed toward a microbial milieu that resembles the normal colon after treatment (P value < 0.001). Finally, we were unable to detect any significant differences in the microbiota of individuals treated with surgery alone and those treated with chemotherapy or chemotherapy and radiation (P value > 0.05). CONCLUSIONS: By better understanding the response of the microbiota to treatment for adenomas and carcinomas, it is likely that biomarkers will eventually be validated that can be used to quantify the risk of recurrence and the likelihood of survival. Although it was difficult to identify significant differences between pre- and post-treatment samples from patients with adenoma and advanced adenoma, this was not the case for carcinomas. Not only were there large changes in pre- versus post-treatment samples for those with carcinoma, but also these changes were toward a more normal microbiota. PMID- 29145892 TI - Association between plasma phospholipid saturated fatty acids and metabolic markers of lipid, hepatic, inflammation and glycaemic pathways in eight European countries: a cross-sectional analysis in the EPIC-InterAct study. AB - BACKGROUND: Accumulating evidence suggests that individual circulating saturated fatty acids (SFAs) are heterogeneous in their associations with cardio-metabolic diseases, but evidence about associations of SFAs with metabolic markers of different pathogenic pathways is limited. We aimed to examine the associations between plasma phospholipid SFAs and the metabolic markers of lipid, hepatic, glycaemic and inflammation pathways. METHODS: We measured nine individual plasma phospholipid SFAs and derived three SFA groups (odd-chain: C15:0 + C17:0, even chain: C14:0 + C16:0 + C18:0, and very-long-chain: C20:0 + C22:0 + C23:0 + C24:0) in individuals from the subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study across eight European countries. Using linear regression in 15,919 subcohort members, adjusted for potential confounders and corrected for multiple testing, we examined cross sectional associations of SFAs with 13 metabolic markers. Multiplicative interactions of the three SFA groups with pre-specified factors, including body mass index (BMI) and alcohol consumption, were tested. RESULTS: Higher levels of odd-chain SFA group were associated with lower levels of major lipids (total cholesterol (TC), triglycerides, apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB)) and hepatic markers (alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT)). Higher even-chain SFA group levels were associated with higher levels of low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C) ratio, triglycerides, ApoB, ApoB/A1 ratio, ALT, AST, GGT and CRP, and lower levels of HDL-C and ApoA1. Very long-chain SFA group levels showed inverse associations with triglycerides, ApoA1 and GGT, and positive associations with TC, LDL-C, TC/HDL-C, ApoB and ApoB/A1. Associations were generally stronger at higher levels of BMI or alcohol consumption. CONCLUSIONS: Subtypes of SFAs are associated in a differential way with metabolic markers of lipid metabolism, liver function and chronic inflammation, suggesting that odd-chain SFAs are associated with lower metabolic risk and even-chain SFAs with adverse metabolic risk, whereas mixed findings were obtained for very-long-chain SFAs. The clinical and biochemical implications of these findings may vary by adiposity and alcohol intake. PMID- 29145894 TI - Inositol in the MAnaGemENt of abdominal aortic aneurysm (IMAGEN): study protocol for a randomised controlled trial. AB - BACKGROUND: An abdominal aortic aneurysm (AAA) is a focal dilation of the abdominal aorta and is associated with a risk of fatal rupture. Experimental studies suggest that myo-inositol may exert beneficial effects on AAAs through favourable changes to biological pathways implicated in AAA pathology. The aim of the Inositol in the MAnaGemENt of abdominal aortic aneurysm (IMAGEN) trial is to assess if myo-inositol will reduce AAA growth. METHODS/DESIGN: IMAGEN is a multi centre, prospective, parallel-group, randomised, double-blind, placebo-controlled trial. A total of 164 participants with an AAA measuring >= 30 mm will be randomised to either 2 g of myo-inositol or identical placebo twice daily for 12 months. The primary outcome measure will be AAA growth estimated by increase in total infrarenal aortic volume measured on computed tomographic scans. Secondary outcome measures will include AAA diameter assessed by computed tomography and ultrasound, AAA peak wall stress and peak wall rupture index, serum lipids, circulating AAA biomarkers, circulating RNAs and health-related quality of life. All analysis will be based on the intention-to-treat principle at the time of randomisation. All patients who meet the eligibility criteria, provide written informed consent and are enrolled in the study will be included in the primary analysis, regardless of adherence to dietary allocation. DISCUSSION: Currently, there is no known medical therapy to limit AAA progression. The IMAGEN trial will be the first randomised trial, to our knowledge, to assess the value of myo inositol in limiting AAA growth. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615001209583 . Registered on 6 November 2015. PMID- 29145895 TI - Comparative analysis of high-sensitivity cardiac troponin I and T for their association with coronary computed tomography-assessed calcium scoring represented by the Agatston score. AB - BACKGROUND: This study evaluates the association between high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) and coronary calcium concentration (CAC) detected by coronary computed tomography (CCT) and evaluated with the Agatston score in patients with suspected coronary artery disease (CAD). METHODS: Patients undergoing CCT during routine clinical care were enrolled prospectively. CCT was indicated for patients with a low to intermediate pretest probability for CAD. Within 24 h of CCT examination, peripheral blood samples were taken to measure cardiac biomarkers hs-cTnI and hs-cTnT. RESULTS: A total of 76 patients were enrolled including 38% without detectable CAC, 36% with an Agatston score from 1 to 100, 17% from 101 to 400, and 9% with values >= 400. hs-cTnI was increasing alongside Agatston score and was able to differentiate between different groups of Agatston scores. Both hs-cTn discriminated values greater than 100 (hs-cTnI, AUC = 0.663; p = 0.032; hs-cTnT, AUC = 0.650; p = 0.048). In univariate and multivariate logistic regression models, hs-cTnT and hs-cTnI were significantly associated with increased Agatston scores. Patients with hs-cTnT >= 0.02 ug/l and hs-cTnI >= 5.5 ng/l were more likely to reveal values >= 400 (hs-cTnT; OR = 13.4; 95% CI 1.545-116.233; p = 0.019; hs-cTnI; OR = 8.8; 95% CI 1.183-65.475; p = 0.034). CONCLUSION: The present study shows that the Agatston score was significantly correlated with hs cardiac troponins, both in univariable and multivariable linear regression models. Hs-cTnI is able to discriminate between different Agatston values. The present results might reveal potential cut-off values for hs cardiac troponins regarding different Agatston values. Trial registration Cardiovascular Imaging and Biomarker Analyses (CIBER), NCT03074253 https://clinicaltrials.gov/ct2/show/record/NCT03074253. PMID- 29145896 TI - Downregulation of MiR-31 stimulates expression of LATS2 via the hippo pathway and promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma. AB - BACKGROUND: Dysregulation of miRNAs is associated with cancer development by coordinately suppressing abundant target genes. Emerging evidence indicates that miR-31 plays a dual role in tumorigenicity. However, whether miR-31 plays as an oncogene in esophageal squamous cell carcinoma (ESCC) and the potential target molecules are still unclear. MiR-31 role in ESCC was investigated and an association of the target molecules with EMT was identified in the progression of ESCC. METHODS: Western blot assays and qRT-PCR was performed to detect the protein and mRNA levels. We investigated the role of miR-31 in the regulation of LATS2 expression in ESCC cell lines via functional assays both in vivo and in vitro. The luciferase reporter assays was conducted to confirm LATS2 is a potential target of miR-31. Immunohistochemistry was used to measure LATS2 and TAZ expression in normal and ESCC tissue. RESULTS: LATS2 is a component of the Hippo tumor-suppressive signaling pathway. Frequent loss of heterozygosity of LATS2 has been reported in esophageal cancer. We analyzed the reciprocal expression regulation of miR-31 and LATS2 and demonstrated that LATS2 expression was elevated by down-regulation of miR-31 at the post-transcriptional level in ESCC. Moreover, miR-31 significantly suppressed the luciferase activity of mRNA combined with the LATS2 3'-UTR, a key molecule in the Hippo pathway. Then, LATS2 consequently promoted the translocation of TAZ, which was examined using immunohistochemistry. Silencing of miR-31 significantly inhibited the cell proliferation, induced apoptosis and decreased the ability of migration/invasion in vitro. LATS2 impedes ESCC cell proliferation and invasion by suppressing miR 31, as well as mice xenograft model in vivo. Meanwhile, the nuclear localization of LATS2 constrained the phosphorylation of TAZ. Then, the expression level of TAZ was notably heightened with a high risk of recurrence compared to that observed in the low-risk patients, as well as, the higher expression associated with a poor survival. CONCLUSIONS: Our study demonstrated that overexpression of miR-31 undertook an oncogenic role in ESCC by repressing expression of LATS2 via the Hippo Pathway and activating epithelial-mesenchymal transition. LATS2 and TAZ could be potential novel molecular markers for predicting the risk of recurrence and prognosis of ESCC. PMID- 29145897 TI - It does matter where you come from: mothers' experiences of childbirth in midwife obstetric units, Tshwane, South Africa. AB - BACKGROUND: Health professionals are striving to improve respectful care for women, but they fall short in the domains of effective communication, respectful and dignified care and emotional support during labour. This study aimed to determine women's experiences of childbirth with a view to improving respectful clinical care practices in low-risk, midwife-led obstetric units in the Tshwane District Health District, South Africa. METHODS: A survey covering all midwife led units in the district was conducted among 653 new mothers. An anonymous questionnaire was administered to mothers returning for a three-days-to-six-weeks postnatal follow-up visit. Mothers were asked about their experiences regarding communication, labour, clinical care and respectful care during confinement. An ANCOVA was performed to identify the socio-demographic variables that significantly predicted disrespectful care. Six items representing the different areas of experience were used in the analysis. RESULTS: Age, language, educational level and length of residence in the district were significantly associated with disrespectful care (p <= 0.01). Overall, the following groups of mothers reported more negative care experiences during labour: women between the ages of 17 and 24 years; women with limited formal education; and women from another province or a neighbouring country. Items which attracted fewer positive responses from participants were the following: 46% of mothers had been welcomed by name on arrival; 47% had been asked to give consent to a physical examination; and 39% had been offered food or water during labour. With regard to items related to respectful care, 54% of mothers indicated that all staff members had spoken courteously to them, 48% said they had been treated with a lot of respect, and 55% were completely satisfied with their treatment. CONCLUSION: There is a need to improve respectful care through interventions that are integrated into routine care practices in labour wards. To stop the spiral of abusive obstetric care, the care provided should be culturally sensitive and should address equity for the most vulnerable and underserved groups. All levels of the health care system should employ respectful obstetric care practices, matched with support for midwives and improved clinical governance in maternity facilities. PMID- 29145899 TI - [Diagnosis of haemochromatosis]. AB - Interpretation of laboratory parameters in cases of haemochromatosis can be difficult. Here, we describe two patients with markedly elevated transferrin saturation and high ferritin levels. The first patient is a 51-year-old woman who had been complaining of fatigue, abdominal pain and arthritis for three years. Her liver enzymes were mildly elevated. Secondary causes of iron overload had been excluded. DNA investigation found a homozygous p.Cys282Tyr mutation in the HFE protein, consistent with hereditary haemochromatosis. The second patient is a 58-year-old man with general malaise and cholestatic liver injury. The p.Cys282Tyr and p.His63Asp mutations in the HFE protein could not be detected. Ultrasound of the liver revealed steatosis. The patient was a heavy drinker and a diagnosis of iron overload caused by alcoholic liver disease was made. Based on these case reports, we discuss the strategy to diagnose haemochromatosis and the background of associated laboratory tests. PMID- 29145900 TI - [A man with recurrent, episodic abdominal pain]. AB - A 56-year-old man with episodic abdominal pain was evaluated for acute left-side abdominal pain. CT scans showed an alternating location of the liver. This phenomenon, in which the liver is freely displaced along the transverse axis around the inferior vena cava, is called 'wandering liver'. PMID- 29145901 TI - [Food bolus obstruction of the oesophagus or ingestion of a foreign body; what should you do?] AB - A food bolus obstruction of the oesophagus and foreign body ingestion are frequently encountered in common clinical practice. There is currently no guideline in the Netherlands for management of these problems. We present two cases to illustrate how these can be managed in line with European and American guidelines. The first patient was a 36-year-old female with total obstruction of the oesophagus by a food bolus. Biopsies taken following endoscopic removal showed eosinophilic infiltration of the mucosa and a subsequent diagnosis of eosinophilic oesophagitis. Symptoms resolved following medical treatment. The second patient, a 23-year-old male with psychomotoric retardation, presented following ingestion of a steel fork. The patient had a previous history of three laparotomies because of ingestion of a foreign body. Endoscopic removal was not possible, and a fourth laparotomy was performed to remove the fork. Food bolus obstruction is a gastroenterological emergency that warrants swift endoscopic removal. In cases of ingestion of a foreign body, the characteristics of the object must be taken into account when determining timing of endoscopic removal. PMID- 29145898 TI - Making gametes from alternate sources of stem cells: past, present and future. AB - Infertile couples including cancer survivors stand to benefit from gametes differentiated from embryonic or induced pluripotent stem (ES/iPS) cells. It remains challenging to convert human ES/iPS cells into primordial germ-like cells (PGCLCs) en route to obtaining gametes. Considerable success was achieved in 2016 to obtain fertile offspring starting with mouse ES/iPS cells, however the specification of human ES/iPS cells into PGCLCs in vitro is still not achieved. Human ES cells will not yield patient-specific gametes unless and until hES cells are derived by somatic cell nuclear transfer (therapeutic cloning) whereas iPS cells retain the residual epigenetic memory of the somatic cells from which they are derived and also harbor genomic and mitochondrial DNA mutations. Thus, they may not be ideal starting material to produce autologus gametes, especially for aged couples. Pluripotent, very small embryonic-like stem cells (VSELs) have been reported in adult tissues including gonads, are relatively quiescent in nature, survive oncotherapy and can be detected in aged, non-functional gonads. Being developmentally equivalent to PGCs (natural precursors to gametes), VSELs spontaneously differentiate into gametes in vitro. It is also being understood that gonadal stem cells niche is compromised by oncotherapy and with age. Improving the gonadal somatic niche could regenerate non-functional gonads from endogenous VSELs to restore fertility. Niche cells (Sertoli/mesenchymal cells) can be directly transplanted and restore gonadal function by providing paracrine support to endogenous VSELs. This strategy has been successful in several mice studies already and resulted in live birth in a woman with pre-mature ovarian failure. PMID- 29145902 TI - [The 20-Year longitudinal trajectories of social functioning in individuals with psychotic disorders]. AB - OBJECTIVE: Social impairment is a long-recognized core feature of schizophrenia and is common in other psychotic disorders. Still, to date the long-term trajectories of social impairment in psychotic disorders have rarely been studied systematically. METHODS: Data came from the Suffolk County Mental Health Project, a 20-year prospective study of first-admission patients with psychotic disorders. A never-psychotic comparison group was also assessed. Latent class growth analysis was applied to longitudinal data on social functioning from 485 respondents with schizophrenia spectrum disorders and psychotic mood disorders, and associations of the empirically derived trajectories with premorbid social adjustment, diagnosis, and 20-year outcomes were examined. RESULTS: Four mostly stable trajectories of preserved (n = 82), moderately impaired (n = 148), severely impaired (n = 181), and profoundly impaired (n = 74) functioning best described the 20-year course of social functioning across diagnoses. The outcome in the group with preserved functioning did not differ from that of never psychotic individuals at 20 years, but the other groups functioned significantly worse. Differences among trajectories were already evident in childhood and adolescence. Poorer social functioning trajectories were strongly associated with other real-world outcomes at 20 years. Multiple trajectories were represented within each disorder. However, more participants with schizophrenia spectrum disorders had impaired trajectories, and more with mood disorders had better functioning trajectories. CONCLUSIONS: The results highlight substantial variability of social outcomes within diagnoses - albeit overall worse social outcomes in schizophrenia spectrum disorders - and show remarkably stable long term impairments in social functioning after illness onset across all diagnoses. PMID- 29145903 TI - ['Just Culture': legal potential and limits]. AB - In the context of patient safety, the concept of 'Just Culture' is of the utmost importance. Just Culture implies that quality systems in health care should focus on learning from incidents and errors rather than on blaming individuals; however, the basic assumptions of Just Culture cannot always be upheld in certain specific circumstances. This article focuses on the importance and the limits of Just Culture from a legal perspective. PMID- 29145904 TI - [An older man with a supraclavicular mass]. AB - An 80-year-old man, originally from Vietnam, was examined for a painful supraclavicular mass on the right side. Puncture and aspiration of the mass revealed purulent fluid. Examination of the aspirate showed acid-fast bacteria, consistent with tuberculous lymphadenitis. The patient was successfully treated with a 4-drug regimen. PMID- 29145905 TI - [A girl with a tumour on the thorax]. AB - A healthy 1-year old girl visits her general practitioner with a solitary dome shaped tumour on her thorax. The lesion is about one cm in diameter and is present since several months. Pathological research reveals a solitary giant molluscum contagiosum. This is a common viral disease of the childhood. In contrast to this case, mollusca contagiosa typically present as several small papules. PMID- 29145906 TI - [A rose is a rose is a rose]. AB - Over a century ago in 1913, the poet Gertrude Stein wrote these famous words: sometimes things are just what they are. There has been a recent debate centred around the question whether or not schizophrenia exists. Is there a brain disease that can be called schizophrenia? What difference does it make to patients how we define schizophrenia? This editorial explores said questions, concluding that there is still much to be done to improve the recovery of patients diagnosed with disorders of the schizophrenia spectrum. Regardless of these discussion items, the reality is that it will not significantly change the clinical reality. There remains a subset of patients with severe symptoms that limits their quality of life. Going forward, what should we do with the schizophrenia debate? The challenge is to focus on better understanding and treatment of these patients by all means and through various types of research. PMID- 29145907 TI - [Autosomal dominant polycystic kidney disease: should patients' young adult relatives be screened or not?] AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, with a global prevalence of 10 per 10,000. It is characterized by the formation of numerous cysts in both kidneys, and leads to renal function loss; the majority of patients will eventually need renal replacement therapy. It is possible to screen patients' presymptomatic family members from a young age, but this has not historically been recommended as until recently there were no treatment options. This year, the vasopressin V2 receptor antagonist tolvaptan was approved for prescription in ADPKD, to slow the rate of renal function decline. The availability of this new treatment option, along with other factors such as the possible use of IVF procedures with pre-implantation genetic diagnosis, imply that we have to rethink the issue of presymptomatic screening. Young adults at-risk should be screened, to give them the chance to opt for treatment. PMID- 29145908 TI - [Asymptomatic microscopic haematuria: usually not a problem]. AB - Asymptomatic microscopic haematuria is a common finding and can have many different causes. Only a small fraction of patients referred for microscopic haematuria have an underlying urological malignancy or serious nephrogenic disease. It is important that only those patients with microscopically confirmed microscopic haematuria are referred. Often no cause can be found even after thorough diagnostic work-up. The work-up of microscopic haematuria can include urethrocystoscopy, ultrasound, multi-phase CT and cytology. These procedures are not only costly, but can have associated health risks and may also cause patients anxiety and distress. There is no evidence to support the hypothesis that microscopic haematuria is the precursor of macroscopic haematuria, which is significantly more likely to have serious underlying causes. A diagnostic work-up should be initiated with caution. PMID- 29145909 TI - [A toddler with nightly vomiting and pain in the abdomen]. AB - A 4-year-old boy was referred to the emergency department with four days of nightly vomiting after ingestion of a marble. Abdominal X-ray showed the marble in the antrum of the stomach. The marble was successfully removed by endoscopy. X rays detect 86% of all glass objects and should therefore be considered as diagnostic option by ingestion of a marble. PMID- 29145910 TI - Brain activation during emotion regulation in women with premenstrual dysphoric disorder. AB - BACKGROUND: Difficulties in regulating emotions are linked to the core symptoms of premenstrual dysphoric disorder (PMDD). We therefore investigated the neural substrates of emotion-regulation problems in women with PMDD. METHODS: On the basis of self-evaluations over 2 months on the Daily Record of Severity of Problems, eligible participants were assigned to two groups: PMDD and control (18 per group). Functional magnetic resonance imaging (fMRI) and a well-validated task were used to assess brain function during emotion regulation. Participants were tested twice, once during the follicular (asymptomatic) and once in the late luteal (symptomatic) phase of the menstrual cycle. RESULTS: Women with PMDD gave higher ratings of negative affect in the luteal phase than in the follicular phase, and compared with healthy control participants during the luteal phase. A region-of-interest fMRI analysis indicated that during the late luteal phase, women with PMDD had hypoactivation in right dorsolateral prefrontal cortex (dlPFC) during all conditions of the emotion-regulation task, not only in the contrast that isolated emotion regulation. An exploratory whole-brain, voxel-wise analysis showed that women with PMDD had less activation in the precentral gyrus during the luteal phase than the follicular phase, and less activation in the postcentral gyrus compared with control participants. CONCLUSIONS: During the luteal phase of the menstrual cycle, women with PMDD experience difficulty regulating emotions. Hypoactivation in the right dlPFC may contribute to this problem, but may be related more generally to other affective symptoms of PMDD. Hypofunction in the right pre- and postcentral gyri warrants additional study. PMID- 29145912 TI - Facilitators and barriers to adaptive implementation of the Meeting Centers Support Program (MCSP) in three European countries; the process evaluation within the MEETINGDEM study. AB - : ABSTRACTBackground:In the MEETINGDEM project, the Meeting Centers Support Program (MCSP) was adaptively implemented and evaluated in three European countries: Italy, Poland, and the United Kingdom. The aim of this study was to investigate overall and country-specific facilitators and barriers to the implementation of MCSP in these European countries. METHODS: A qualitative multiple case study design was used. Based on the theoretical model of adaptive implementation, a checklist was composed of potential facilitators and barriers to the implementation of MCSP. This checklist was administered among stakeholders involved in the implementation of MCSP to trace the experienced facilitators and barriers. Twenty-eight checklists were completed. RESULTS: Main similarities between countries were related to the presence of suitable staff, management, and a project manager, and the fact that the MCSP is attuned to needs and wishes of people with dementia and informal caregivers. Main differences between countries were related to: communication with potential referrers, setting up an inter organizational collaboration network, receiving support of national organizations, having clear discharge criteria for the MCSP and continuous PR in the region. CONCLUSION: The results of this study provide insight into generic and country specific factors that can influence the implementation of MCSP in different European countries. This study informs further implementation and dissemination of MCSP in Europe and may also serve as an example for the dissemination and implementation of other effective psychosocial support interventions for people with dementia and their informal caregivers across and beyond Europe. PMID- 29145911 TI - Hepatitis E virus infection in North Italy: high seroprevalence in swine herds and increased risk for swine workers. AB - We determined the hepatitis E virus (HEV) seroprevalence and detection rate in commercial swine herds in Italy's utmost pig-rich area, and assessed HEV seropositivity risk in humans as a function of occupational exposure to pigs, diet, foreign travel, medical history and hunting activities. During 2011-2014, 2700 sera from 300 swine herds were tested for anti-HEV IgG. HEV RNA was searched in 959 faecal pools from HEV-seropositive herds and in liver/bile/muscle samples from 179 pigs from HEV-positive herds. A cohort study of HEV seropositivity in swine workers (n = 149) was also performed using two comparison groups of people unexposed to swine: omnivores (n = 121) and vegetarians/vegans (n = 115). Herd level seroprevalence was 75.6% and was highest in farrow-to-feeder herds (81.6%). Twenty-six out of 105 (24.8%) herds had HEV-positive faecal samples (25 HEV-3, one HEV-4). Only one bile sample tested positive. HEV seropositivity was 12.3% in swine workers, 0.9% in omnivores and 3.0% in vegetarians/vegans. Factors significantly associated with HEV seropositivity were occupational exposure to pigs, travel to Africa and increased swine workers' age. We concluded that HEV is widespread in Italian swine herds and HEV-4 circulation is alarming given its pathogenicity, with those occupationally exposed to pigs being at increased risk of HEV seropositivity. PMID- 29145913 TI - Goal Setting Deficits at 13 Years in Very Preterm Born Children. AB - OBJECTIVES: Preterm children demonstrate deficits in executive functions including inhibition, working memory, and cognitive flexibility; however, their goal setting abilities (planning, organization, strategic reasoning) remain unclear. This study compared goal setting abilities between very preterm (VP: <30 weeks/<1250 grams) and term born controls during late childhood. Additionally, early risk factors (neonatal brain abnormalities, medical complications, and sex) were examined in relationship to goal setting outcomes within the VP group. METHODS: Participants included 177 VP and 61 full-term born control children aged 13 years. Goal setting was assessed using several measures of planning, organization, and strategic reasoning. Parents also completed the Behavior Rating Inventory of Executive Function. Regression models were performed to compare groups, with secondary analyses adjusting for potential confounders (sex and social risk), and excluding children with major neurosensory impairment and/or IQ<70. Within the VP group, regression models were performed to examine the relationship between brain abnormalities, medical complications, and sex, on goal setting scores. RESULTS: The VP group demonstrated a clear pattern of impairment and inefficiency across goal setting measures, consistent with parental report, compared with their full-term born peers. Within the VP group, moderate/severe brain abnormalities on neonatal MRI predicted adverse goal setting outcomes at 13. CONCLUSIONS: Goal setting difficulties are a significant area of concern in VP children during late childhood. These difficulties are associated with neonatal brain abnormalities, and are likely to have functional consequences academically, socially and vocationally. (JINS, 2018, 24, 372-381). PMID- 29145914 TI - Development and initial validation of the Retrospective Indigenous Childhood Enrichment scale (RICE). AB - : ABSTRACTBackground:Years of education is the most commonly used proxy measure of cognitive reserve. Other forms of cognitive stimulation in childhood may provide similar protection against cognitive decline, particularly in Indigenous groups, where education may have been lacking in quality or quantity. The Retrospective Indigenous Childhood Enrichment (RICE) scale was developed to measure non-school-based activities and environmental stimulation during childhood that are likely to have enhanced cognitive reserve. The aim of the study was to assess the validity and reliability of the RICE scale with a group of older Aboriginal Australians. METHODS: 294 Aboriginal Australian people (60-92 years), living in urban or regional areas of NSW, completed the RICE scale as part of a longer face-to-face interview. Additional data was collected on their formal education, childhood environment, and childhood trauma (Study 1). Test retest, inter-method and inter-rater reliability were assessed in a convenience sample of a further 38 participants by re-administration of the RICE scale at two time points, approximately 14 days apart (M = 14.11, SD = 6.78) (Study 2). RESULTS: Factor analyses reduced the scale from 21 items to 18 and identified three factors: (1) Traditional, (2) Intellectual, and (3) Community. Higher scores on the RICE scale were related to higher years of formal education and lower scores on a childhood trauma questionnaire. The RICE scale had good internal consistency (Cronbach's alpha 0.79), and excellent test-retest reliability (ICC = 0.95, 95% CI 0.90-0.97) and inter-rater reliability (0.99, CI 95% 0.997-0.999). CONCLUSIONS: The RICE is, to our knowledge, the first standardized measure that assesses the level of childhood environmental stimulation in older Aboriginal Australians. This could provide an important supplementary measure, in addition to formal education, to investigate cognitive reserve and dementia risk in this population and enhance understanding of the links between childhood experiences and late-life cognitive decline. PMID- 29145915 TI - Keeping it simple: the grammatical properties of shared book reading. AB - The positive effects of shared book reading on vocabulary and reading development are well attested (e.g., Bus, van Ijzendoorn, & Pellegrini, 1995). However, the role of shared book reading in grammatical development remains unclear. In this study, we conducted a construction-based analysis of caregivers' child-directed speech during shared book reading and toy play and compared the grammatical profile of the child-directed speech generated during the two activities. The findings indicate that (a) the child-directed speech generated by shared book reading contains significantly more grammatically rich constructions than child directed speech generated by toy play, and (b) the grammatical profile of the book itself affects the grammatical profile of the child-directed speech generated by shared book reading. PMID- 29145916 TI - Monorchis lewisi n. sp. (Trematoda: Monorchiidae) from the surf bream, Acanthopagrus australis (Sparidae), in Moreton Bay, Australia. AB - We describe Monorchis lewisi n. sp. (Monorchiidae) from the surf bream, Acanthopagrus australis (Gunther, 1859) (Sparidae), in Moreton Bay, eastern Australia. The new species differs from most existing species of Monorchis Monticelli, 1893 in its possession of an elongate I-shaped excretory vesicle, and from other congeners in the relative configuration of the gut and suckers. Ovipusillus mayu Dove & Cribb, 1998 is re-reported from Gnathanodon speciosus (Forsskal, 1775) (Carangidae) from Moreton Bay. We report new second internal transcribed spacer (ITS2) and 28S rDNA sequence data for both species. Bayesian inference and Maximum Likelihood analyses of the 28S rDNA dataset suggest that existing subfamily and genus concepts within the family require substantial revision. PMID- 29145917 TI - Short-Term Effects of the Empathic Talk: The Role of Perceived Empathy, Interpersonal Dispositions, and Vagal Tone on Experiencing Depth. AB - The present study examines the immediate impact of empathic attitudes on the receiver, by comparing an empathic conversation (EC) with a neutral one (NC) on experiencing depth (EXP), perceived empathy and vagal tone. We also evaluate if empathy effects depend on personality dispositions relevant to interpersonal functioning. An experimental, counterbalanced, within-subject design was implemented wherein participants (n = 27, age M = 22.6, SD = 4.0, 52% females) talked about a personal, meaningful topic for 20 minutes under both the EC and NC conditions. At the group level, main results indicated that the EC was more effective than the NC in promoting increases in EXP over time (F(1, 25) = 21.04, p < .001, eta p 2 = .457) and perceived empathy in women (F(1, 25) = 9.42, p = .005, eta p 2 = .264). At the individual level, the NC particularly precluded EXP gains in people expressing a better interpersonal functioning (betas < -.46, ps < .05 for attachment security and empathy and beta = .38, p < .05 for aggression), and who also inhibited their vagal tone throughout this very condition (beta = .40, p = .024). We conclude that the empathic context has an immediate positive impact on healthy psychological variables, whereas a more impersonal setting would drive people away from this positive effect. Those results are discussed in the light of the role of interpersonal proximity (being empathic to another's experience and the lack of this attitude) in psychotherapy and healthy functioning. PMID- 29145918 TI - Baby sign but not spontaneous gesture predicts later vocabulary in children with Down Syndrome - CORRIGENDUM. PMID- 29145919 TI - Potentially inappropriate prescription of antidepressants in old people: characteristics, associated factors, and impact on mortality. AB - : ABSTRACTBackground:The increasing use of antidepressants (ADs) has raised concerns about their inappropriate use in old people. OBJECTIVE: To examine the prevalence of potentially inappropriate prescribing (PIP) of ADs, their associated factors, and their impact on mortality in a sample of old people in France. METHODS: The analysis used data from the SIPAF study, a cross-sectional study consisting of 2,350 people aged >= 70 years. Trained nurses interviewed participants at home between 2008 and 2010. Information was collected concerning socio-demographic and health characteristics, including medication use. The study population consisted of the 318 AD users from the SIPAF study (13.5%). PIP of ADs was defined according to national and international criteria. Factors associated with PIP of ADs were assessed using a multivariate logistic regression model. The influence of PIP of ADs on mortality was assessed using a Cox model (median follow-up 2.8 years). RESULTS: Among the SIPAF study, 71% of AD users were female and the mean age was 84 +/- 7 years. Selective serotonin reuptake inhibitors (SSRIs) were the most prescribed ADs (19.8%). We found PIP of ADs in 36.8% of the study population, mainly the co-prescription of diuretics with SSRIs (17.6%) and the prescription of tricyclics (12.9%). PIP of ADs was associated with polypharmacy (aOR5-9 drugs 2. 61, 95% CI 1.11-6.16 and aOR>=10 drugs 2.69, 95% CI 1.06-6.87) and comorbidity (aOR3-4 chronic diseases 2.59, 95%CI 1.04-6.44 and aOR>=5 chronic diseases 2.33, 95%CI 0.94-5.79), and increased the risk of mortality during follow-up (aHR 2.30, 95%CI 1.28-4.12). CONCLUSIONS: This study shows that more than one third of AD prescriptions may be inappropriate in old people. PIP of ADs was related to polypharmacy and comorbidity and increased mortality among AD users. PMID- 29145920 TI - Development of Spanish rhotics in Spanish-English bilingual children in the United States. AB - Rhotics, particularly the trill, are late acquired sounds in Spanish. Reports of Spanish-English bilingual preschoolers document age-appropriate articulations, but studies do not explore productions once exposure to English increases. This paper reports on the rhotic productions of a cross-sectional sample of 31 Spanish English bilingual children, ages 6;8 to 13;5. Children produced taps with high rates of accuracy across age groups; the trill did not reach 80% target production until age 11;3, later than reported for monolingual speakers. Increased English exposure is explored as a contributing factor, arguing a need for continued study of bilingual phonological development beyond the preschool years. PMID- 29145921 TI - Change in fear of falling in Parkinson's disease: a two-year prospective cohort study. AB - BACKGROUND: Fear of falling in Parkinson's disease (PD) has been suggested as predictor of future falling. The purpose of this study was to compare fear of falling score after two years of follow-up with those observed at baseline and to assess factors associated with change in fear of falling over time. METHODS: A total of 120 consecutive persons with PD were recruited and followed for two years. Fear of falling was assessed by using the 10-item Falls Efficacy Scale (FES). Occurrence of falling was registered during the first year of follow-up. RESULTS: After two years, the average FES score statistically significantly changed (p = 0.003) from 30.5 to 37.5 out of 100 (increase of 22.9%). We observed that median scores of all FES items, except for "Preparing a meal, not requiring carrying of heavy or hot objects" and "Personal grooming," significantly increased after two-year follow-up. After accounting for age, gender, PD duration, levodopa dosage, Hoehn and Yayhr stage, Unified Parkinson's Disease Rating Scale score three, depression, anxiety, and falling, we observed that sustaining greater number of falls in the first year of follow-up was associated with higher increase in FES score after two years (odds ratio 3.08, 95% confidence interval 1.30-4.87). CONCLUSION: After two years of follow-up, we observed a decrease in confidence at performing nearly all basic daily activities. Fall prevention programs should be prioritized in management of PD. PMID- 29145922 TI - Erdheim-Chester Disease and Palatal Tremor. PMID- 29145923 TI - CJEM Debate Series: #SocialMedia - Social media has created emergency medicine celebrities who now influence practice more than published evidence. PMID- 29145924 TI - Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis. AB - BACKGROUND: Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis (DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ. METHODS: We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB. This was a secondary analysis of a study designed to explore drug-drug interactions between BDQ and antiretrovirals. RESULTS: Of 46 participants, 30 were on concomitant CFZ when intensive PK sampling of BDQ was done. CFZ did not have a statistically significant effect on BDQ bioavailability (-9.1%, 90%CI -22.8 to +7.1; P = 0.19) or on BDQ and M2 clearance (+12.2%, 90%CI -13.7 to +38; P = 0.32). CONCLUSION: We did not find a statistically significant PK drug-drug interaction between BDQ and CFZ, but cannot exclude a potentially clinically relevant interaction due to the wide confidence intervals of the estimated interaction effects. PMID- 29145926 TI - Corrigendum to: Increased high molecular weight adiponectin, but decreased total adiponectin and kisspeptin, in central precocious puberty compared with aged matched prepubertal girls. AB - The aim of the present study was to compare serum leptin, kisspeptin, total adiponectin, high molecular weight (HMW) adiponectin and neuropeptide Y (NPY) levels between girls with central precocious puberty (CPP; n=26, 7-9.5 years old) and age-matched controls (n=29) including or excluding obese girls. Leptin and NPY levels were comparable between CPP and control girls. Kisspeptin levels were lower in the CPP than control group, and were positively correlated with oestrogen in the control group and with systolic and diastolic blood pressure in the CPP group. Kisspeptin levels were negatively correlated with FSH and LH in the CPP group. Total adiponectin levels were lower in CPP than control girls, and were negatively correlated with Tanner stage and body mass index, but positively correlated with the quantitative insulin sensitivity check index in the control group. HMW adiponectin was higher in the CPP than control group, and was positively correlated with Tanner stage and LH in all girls. Total adiponectin had a strong positive correlation with HMW adiponectin in the CPP group (r=0.915) compared with the control group (r=0.371). In conclusion, kisspeptin may be associated with increased oestrogen in prepubertal girls, but with increased blood pressure in girls with CPP. In girls entering puberty, HMW adiponectin was increased and associated with reproductive parameters. Based on these observations, HMW adiponectin probably plays an essential role in the initiation of puberty and is a candidate marker for the prediction of CPP. PMID- 29145927 TI - Corrigendum to: Hypoxia limits mouse follicle growth in vitro. AB - Ovarian follicle culture is useful for elucidation of factors involved in the regulation of follicular function. We examined the effects of gas phase oxygen concentration, an oil overlay, serum type and medium supplementation with FSH, insulin-transferrin-selenium (ITS) and I-ascorbic acid on cultured preantral mouse follicle growth in a spherical, non-attached follicle culture system. Follicle growth in 5% oxygen was significantly (P<0.01) inferior to growth in 20% oxygen in terms of follicle diameter. This was likely due to hypoxia, as evidenced by significantly (P<0.05) increased follicle secretion of vascular endothelial growth factor (VEGF), a marker of cell hypoxia. Follicular growth was not (P>0.05) affected by an oil overlay, ITS supplementation or serum type. Culture in medium with 5% mouse serum, 1 IU mL-1 FSH, 25 MUgmL-1 l-ascorbic acid and 20% oxygen without an oil overlay supported the growth of follicles to a maximum diameter of 380 MUm in 6 days. Compared with mature preovulatory mouse follicles in vivo that often have diameters >500 MUm within the same time frame, in vitro-grown follicles clearly exhibit limited growth. Thus, adequate oxygenation is an essential factor in the process of optimising follicle growth. PMID- 29145928 TI - Note of clarification: Potential risks to offspring of intrauterine exposure to maternal age-related obstetric complications. AB - Several hypotheses have been proposed to explain the negative effects of delayed motherhood on an offspring's morbidity later in life. However, these hypotheses are not supported by clinical and epidemiological evidence. Because advanced maternal age is associated with increased risk of obstetric complications, the aim of the present study was to ascertain whether the negative effects on offspring of intrauterine exposure to maternal age-related obstetric complications may explain the reported negative effects of delayed motherhood on offspring. To this end, a literature search was performed to identify relevant publications up to March 2016 on PubMed; references cited in relevant articles were also searched. There was a direct correlation between the risks to offspring conferred by intrauterine exposure to at least one of the obstetric complications present at the time of delivery in women aged >=35 years and the risks to offspring of delayed motherhood. This correlation was not observed when comparing the risks to offspring of delayed motherhood and the risks associated with maternal transmission of defective mitochondria, chromosomal anomalies or DNA double-strand breaks. Most of the effects on offspring of intrauterine exposure to maternal age-related obstetric complications may be induced by epigenetic DNA reprogramming during critical periods of embryo or fetal development. Women wanting to enrol in a fertility preservation program to offset age-related declines in fertility should be informed not only about their chances of pregnancy and the percentage of live births, but also about the risks to themselves and their prospective offspring of delaying motherhood. PMID- 29145929 TI - Ciprofloxacin does not Prolong the QTc Interval: A Clinical Study in ICU Patients and Review of the Literature. AB - PURPOSE: Ciprofloxacin may prolong the QT interval and increase the risk of Torsade de Pointes (TdP). Intravenous administration of ciprofloxacin in patients with additional risks may elevate the risk of QTc interval prolongation. We prospectively assessed whether intravenous ciprofloxacin prolongs the QT interval in patients with additional co-morbidities and risk factors. We also reviewed the literature on the QT prolonging effect or TdP inducing effect of ciprofloxacin. METHODS: ICU Patients who were treated with intravenous ciprofloxacin as part of their therapy were recruited. ECG was recorded within 60 min before start and in the last 30 min of 1 h infusion, or within 30 min after the end of ciprofloxacin infusion. QT interval was corrected for the heart rate using both Bazett's and Fridericia's formula. The changes were analyzed using the paired Student's t test. RESULTS: Ten patients were included in the study (average age 74-y, 6 males). The average baseline QTc interval corrected with Bazett's formula was 448 ms that was shortened during or after ciprofloxacin infusion by 3 ms and 2 ms based on Bazett's (p=0.67) and Fridericia's (p=0.68) formula, respectively. No observational study or cohort study thus far has shown that ciprofloxacin has a QT prolonging effect or increases the risk of TdP or (cardiovascular) mortality. Conclusion. Based on our results and the results of previous studies, it is unlikely that ciprofloxacin has a clinically relevant QT prolonging effect or an increased risk of TdP. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29145930 TI - Assessment of Predicted Rate and Associated Factors of Dabigatran-induced Bleeding Events in Malaysian Patients with Non-Valvular Atrial Fibrillation. AB - PURPOSE: To assess the predicted rate and the factors associated with bleeding events among patients with non-valvular atrial fibrillation (NVAF) receiving dabigatran therapy. METHODS: This retrospective cohort study includes adult patients of two tertiary hospitals in Malaysia. Potential study subjects were identified using pharmacy supply database or novel oral anticoagulant (NOAC) registry. Demographics, clinical data and laboratory test results were extracted from the medical records of the patients or electronic databases. The main outcome measure is the occurrence of a bleeding event. Bleeding events were classified into major bleeding, clinically relevant non-major bleeding, or minor bleeding, according to the International Society on Thrombosis and Haemostasis criteria. We consider clinically relevant non-major bleeding events or major bleeding events as clinically relevant bleeding events. An occurrence of any bleeding event was recorded from the initiation of NOAC therapy until the death of a patient, or the date of permanent discontinuation of NOAC use, or the last day of data collection. The predicted rate of dabigatran-induced bleeding events per 100 patient-years was estimated. RESULTS: During a median follow-up period of 18 months, 73 patients experienced 90 bleeding events. Among these patients, 25 including 4 fatal cases, experienced major bleeding events. The predicted rate per 100 patient-years of follow-up of any bleeding events was 9.0 [95% CI 6.9 to 11.1]; clinically relevant bleeding events 6.0 [95% CI 4.8 to 8.3], and major bleeding events 3.0 [95% CI 1.9 to 4.2]. The independent risk factor for clinically relevant bleeding events is prior bleeding. While prior bleeding or congestive heart failure is linked with major bleeding events. CONCLUSIONS: The predicted rate for dabigatran-induced major bleeding episodes is low but these adverse events carry a high fatality risk. Preventive measures should target older patients who have prior bleeding or congestive heart failure. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29145931 TI - In vitro and in silico Approaches to Study Cytochrome P450-Mediated Interactions. AB - In vitro and in silico models of drug metabolism are utilized regularly in the drug research and development as tools for assessing pharmacokinetic variability and drug-drug interaction risk. The use of in vitro and in silico predictive approaches offers advantages including guiding rational design of clinical drug drug interaction studies, minimization of human risk in the clinical trials, as well as cost and time savings due to lesser attrition during compound development process. This article gives a review of some of the current in vitro and in silico methods used to characterize cytochrome P450(CYP)-mediated drug metabolism for estimating pharmacokinetic variability and the magnitude of drug-drug interactions. Examples demonstrating the predictive applicability of specific in vitro and in silico approaches are described. Commonly encountered confounding factors and sources of bias and error in these approaches are presented. With the advent of technological advancement in high throughput screening and computer power, the in vitro and in silico methods are becoming more efficient and reliable and will continue to contribute to the process of drug discovery, development and ultimately safer and more effective pharmacotherapy. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29145932 TI - Lipid Emulsion, More Than Reversing Bupivacaine Cardiotoxicity: Potential Organ Protection. AB - Efforts to develop a treatment for bupivacaine cardiotoxicity led to the discovery that Intralipid, a popular brand of intravenous lipid emulsion, could be used not only as an effective treatment for anesthetic-induced cardiac arrest, but also as a means of reversing many other toxicities. Contradictory data exist regarding the mechanism of action of lipid emulsion, a combination of fatty acids traditionally used in parenteral nutrition. Some researchers attribute the effects to lipophilicity and the individual characteristics of the lipids, while other data demonstrate a direct empowering mechanism through cellular upstream and downstream pathways. Understanding the underlying mechanism of action of this safe source of calories may assist in the development of novel organ protective agents. In this review, some of the direct cardiac effects of lipid emulsion are briefly discussed. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29145933 TI - Quantitative Structure - Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs. AB - PURPOSE: Binding of drugs to plasma proteins is a common physiological occurrence which may have a profound effect on both pharmacokinetics and pharmacodynamics. The early prediction of plasma protein binding (PPB) of new drug candidates is an important step in drug development process. The present study is focused on the development of quantitative structure - pharmacokinetics relationship (QSPkR) for the negative logarithm of the free fraction of the drug in plasma (pfu) of basic drugs. METHODS: A dataset includes 220 basic drugs, which chemical structures are encoded by 176 descriptors. Genetic algorithm, stepwise regression and multiple linear regression are used for variable selection and model development. Predictive ability of the model is assessed by internal and external validation. Results. A simple, significant, interpretable and predictive QSPkR model is constructed for pfu of basic drugs. It is able to predict 59% of the drugs from an external validation set within the 2-fold error of the experimental values with squared correlation coefficient of prediction 0.532, geometric mean fold error (GMFE) 1.94 and mean absolute error (MAE) 0.17. CONCLUSIONS: PPB of basic drugs is favored by the lipophilicity, the presence of aromatic C-atoms (either non-substituted, or involved in bridged aromatic systems) and molecular volume. The fraction ionized as a base fB and the presence of quaternary C-atoms contribute negatively to PPB. A short checklist of criteria for high PPB is defined, and an empirical rule for distinguishing between low, high and very high plasma protein binders is proposed based. This rule allows correct classification of 69% of the very high binders, 71% of the high binders and 91% of the low binders in plasma. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29145934 TI - Economic Evaluations on Antimicrobial Stewardship Programme: A Systematic Review. AB - PURPOSE: To systematically review studies on cost-effectiveness of implementing Antimicrobial stewardship programmes (ASP) in the hospital setting. METHODS: A systematic literature search was performed using electronic databases, such as EMBASE, PubMed/Medline, CINAHL, NHS and CEA Registry from 2000 until 2017. The quality of each included study was assessed using Joanna Briggs Institute Critical Appraisal Checklist for Economic Evaluations and Consolidated Health Economic Evaluation Reporting Standards Statement checklist. RESULTS: Of the 313 papers retrieved, five papers were included in this review after assessment for eligibility. The majority of the studies were cost-effectiveness studies, comparing ASP to standard care. Four included economic studies were conducted from the provider (hospital) perspective while the other study was from payer (National Health System) perspective. The cost included for economic analysis were as following: personnel costs, warded cost, medical costs, procedure costs and other costs. CONCLUSIONS: All studies were generally well-conducted with relatively good quality of reporting. Implementing ASP in the hospital setting may be cost-effective. However, comprehensive cost-effectiveness data for ASP remain relatively scant, underlining the need for more prospective clinical and epidemiological studies to incorporate robust economic analyses into clinical decisions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29145935 TI - Effectiveness of Pharmacist-led Anticoagulation Management on Clinical Outcomes: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: We performed this systematic review and meta-analysis to confirm whether patients benefit more from pharmacist-led anticoagulation management than other models. METHODS: We searched PubMed, Embase, Cochrane Library and reference lists of yielded results conducted up to April 25, 2017. RCTs and observational cohort studies and case-control studies which compared the percentage of time within the target therapeutic range (TTR), the percentage of time within the expanded therapeutic range (TER), haemorrhage events, thrombosis events, mortality, patient satisfaction and/or medicine cost saving of pharmacist-led anticoagulation management with other models, and species were limited to humans. Two investigators evaluated methodology and extracted data from included studies independently. Data analysis were performed by STATA 12.0 software and quality of evidence assessment was performed by GRADEprofiler software. RESULTS: 8 RCTs and 9 observational cohort studies with 9919 patients were included eventually with high quality and no publication bias. In RCTs pooled results, TTR (p=0.548 moderate-quality), TER (p=0.285, moderate-quality), total haemorrhage events (p=0.140, low-quality), minor haemorrhage events (p=0.162, low-quality), major haemorrhage events (p=0.237, low-quality), thrombosis events (p=0.615, low quality) and mortality (p=0.876, low-quality) was not significant between two groups. In observational studies pooled results, TTR (p=0.000, low-quality) was significant higher in pharmacist-led management group and the risk of total haemorrhage events (p=0.000, moderate-quality), minor haemorrhage events (p=0.000, moderate-quality) and thrombosis events (p=0.000, moderate-quality) were significant lower in pharmacist-led management group. Patient satisfaction and medicine cost saving were descriptively reviewed. CONCLUSIONS: According to the grading of evidence, we concluded that the risk of total haemorrhage events, minor haemorrhage events and thrombosis events significantly decreased in pharmacist-led anticoagulation management group compared with other management models and no significant difference in TTR, TER, major haemorrhage events and mortality between two groups. Longer follow-up period RCT studies with large sample size should be done in the future to confirm effectiveness of pharmacist led anticoagulation management model. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29145936 TI - Biosimilars: State of Clinical and Regulatory Science. AB - On May 12, 2017, various issues and challenges associated with biologics were discussed during a session of the annual joint conference of Canadian Society for Pharmaceutical Sciences and Canadian Chapter of Controlled Release Society at Hyatt Regency Hotel, Montreal, QC, Canada. An update on the Canadian regulatory guidelines for biosimilars was given, followed by viewpoints expressed by regulatory, academic and industry scientists. Topics of discussion included: reference biologic drug, clinical considerations, immunogenicity, extrapolation and clarification of terminology, product monograph, international collaboration, switching and interchangeability, naming conventions, clinical and non-clinical evaluation, authorization of indications, statistical equivalence, the nor-switch study and biologics marketplace. PMID- 29145937 TI - Defending victims: What does it take to intervene in bullying and how is it rewarded by peers? AB - Defending is considered important in reducing bullying and victimization in schools. Yet, the prevalence of defending is quite low and there is little insight into aspects that explain why students intervene in bullying situations. The current study used a longitudinal design to simultaneously examine the antecedents and status outcomes of defending behavior. It was expected that affective and social-cognitive factors explain involvement in defending. Moreover, it was proposed that defending would be rewarded with popularity among peers, but only for defenders who were not victimized themselves. Unconflated multilevel path models were used and data came from students in grades 4-6 of Finnish elementary schools (N=4209 students from 210 classrooms and 38 schools; Mage 11.25; 50% boys). Affective empathy and students' self-efficacy beliefs were predictive of defending behavior over time, whereas cognitive empathy was not. Additionally, defenders increased their popularity among their peers. No substantial differences between victims and non-victims were found. This pattern of results suggests that, irrespective of victim status, specific children are more likely to defend in bullying situations and are rewarded with increased popularity. PMID- 29145938 TI - Teacher factors contributing to dosage of the KiVa anti-bullying program. AB - The KiVa Anti-Bullying Program (KiVa) seeks to meet the growing need for anti bullying programming through a school-based, teacher-led intervention for elementary school children. The goals of this study were to examine how intervention dosage impacts outcomes of KiVa and how teacher factors influence dosage. Participants included 74 teachers and 1409 4th- and 5th-grade students in nine elementary schools. Teachers and students completed data collection at the beginning and end of the school year, including measures of bullying and victimization, correlates of victimization (depression, anxiety, peer rejection, withdrawal, and school avoidance), intervention cognitions/emotions (anti bullying attitudes, and empathy toward victims), bystander behaviors, and teacher factors thought to relate to dosage (self-efficacy for teaching, professional burnout, perceived principal support, expected effectiveness of KiVa, perceived feasibility of KiVa). The dosage of KiVa delivered to classrooms was measured throughout the school year. Results highlight dosage as an important predictor of change in bullying, victimization, correlates of victimization, bystander behavior, and intervention cognitions/emotions. Of the teacher factors, professional burnout uniquely predicted intervention dosage. A comprehensive structural equation model linking professional burnout to dosage and then to child-level outcomes demonstrated good fit. Implications for intervention design and implementation are discussed. PMID- 29145939 TI - Effect of retention in elementary grades on dropping out of school early. AB - This study investigated the effect of grade retention in elementary school on dropping out of school by age 16. Participants were 538 (54% males) ethnically diverse, academically at-risk students recruited from Texas schools into a longitudinal study when they were in first grade (mean age=6.58). Propensity score weighting successfully equated the 171 retained students and the 367 continuously promoted students on 65 covariates assessed in grade 1. Fifty-one students dropped out of school by age 16 and 487 persisted. Retention (vs. promotion) led to an increased early dropout rate (odds ratio=1.68), even after controlling for 65 covariates associated with school achievement, retention, or both. Implications of findings for dropout prevention and grade retention policies are discussed. PMID- 29145940 TI - Happy classes make happy students: Classmates' well-being predicts individual student well-being. AB - Student well-being has mostly been studied as an individual phenomenon with little research investigating how the well-being of one's classmates could influence a student's well-being. The aim of the current study was to examine how the aggregate well-being of students who comprise a class could predict students' subsequent well-being (Time 2 well-being) after controlling for the effects of prior well-being (Time 1 well-being) as well as key demographic variables such as gender and age. Two studies among Filipino secondary school students were conducted. In Study 1, 788 students from 21 classes participated; in Study 2, 404 students from 10 classes participated. For Study 1, questionnaires assessing students' life satisfaction, positive affect and negative affect were administered twice seven months apart. For Study 2, the well-being questionnaires were administered twice, three months apart. Hierarchical linear modeling was used with level 1 (Time 1 individual well-being, gender, and age) and level 2 (class well-being) predictors. Results across the two studies provided converging lines of evidence: students who were in classes with higher levels of life satisfaction and positive affect were also more likely to have higher life satisfaction and positive affect at Time 2. The study indicated that the well being of a student partly depends on the well-being of their classmates providing evidence for the social contagion of well-being in the classroom context. PMID- 29145941 TI - An investigation of African American and European American students' perception of teaching behavior. AB - Teaching behaviors are associated with a range of student academic and mental health outcomes. Substantial academic, school disciplinary, and mental health disparities across African American and European American students suggest that diverse students may view and interpret teaching behaviors differently. The Teaching Behavior Questionnaire measures students' perceptions of teaching behaviors. The purpose of the current study was to examine the scale's factor structure among European American high school students using exploratory factor analysis and, subsequently, cross-validate using confirmatory factor analysis based on African American student data. Results supported reconceptualizing the scale according to a three-factor model in both groups. Implications related to the interpretation and use of scores are discussed. PMID- 29145942 TI - Teachers' dispositional mindfulness and the quality of their relationships with children in Head Start classrooms. AB - The quality of teachers' relationships with children is a key predictor of children's later social emotional competence and academic achievement. Interventions to increase mindfulness among teachers have focused primarily on the impacts on teachers' subjective well-being, but not on the quality of their relationships with children. Furthermore, none of these interventions have involved preschool teachers. To consider the potential of mindfulness-based interventions to improve the quality of teachers' relationships with preschool aged children, we examined data from an online survey of 1001 classroom teachers in 37 Pennsylvania Head Start Programs. Using path analysis we investigated the association between teachers' dispositional mindfulness and the quality of their relationships with children (conflict and closeness). We further examined whether this association was mediated by teacher depressive symptoms and moderated by perceived workplace stress. Higher levels of dispositional mindfulness among teachers were associated with higher quality relationships with children (less conflict and greater closeness). The association between greater dispositional mindfulness and less conflict was partially mediated by lower depressive symptoms, and the conditional direct effect of mindfulness on conflict was stronger when perceived workplace stress was lower. These findings suggest that preschool teachers who have higher levels of dispositional mindfulness may experience higher quality relationships with children in their classrooms. Interventions to increase levels of dispositional mindfulness among early childhood educators may improve their well-being along with the quality of their relationships with children, potentially impacting children's educational outcomes. The potential impacts of such interventions may be even stronger if structural and systemic changes are also made to reduce workplace stress. PMID- 29145943 TI - Possible economic benefits of full-grade acceleration. AB - Full-grade acceleration is an intervention in which students finish the K-12 curriculum at least one year early, usually due to early entrance to kindergarten, grade skipping, or early graduation from high school. Many studies have shown benefits during childhood for accelerated individuals, but few studies have examined outcomes of acceleration in adulthood. In this study data from five longitudinal datasets were combined to compare adult incomes of accelerated and non-accelerated subjects after controlling for five important childhood covariates. Results showed that accelerated adults earned 4.66% more per year (d=0.044). Income differences between accelerated and non-accelerated groups were larger for women than men. A conservative estimate is that there is a $72,000 lifetime earnings difference between accelerated and non-accelerated subjects, though this study cannot show a causal association between acceleration and increased income. PMID- 29145944 TI - Latent national subpopulations of early education classroom disengagement of children from underresourced families. AB - This research examined the latent developmental patterns for early classroom disengagement among children from some of the most underresourced families in the nation. Based on standardized teacher observations from the Head Start Impact Study, a nationally representative sample of children (N=1377) was assessed for manifestations of reticent/withdrawn and low energy behavior over four years spanning prekindergarten through first grade. For each form of disengagement, latent growth mixture modeling revealed three distinct subpopulations of change patterns featuring a dominant class associated with generally good classroom adjustment, a medial class that varied close to the population average over time, and a more extreme class (about 10% of the population) whose adjustment was relatively marginal and sometimes reached problematic levels. Whereas reticent/withdrawn behavior ordinarily subsided over time, low energy behavior increased. More extreme low energy behaviors tended to dissipate through schooling and extreme reticence/withdrawal became more accentuated, with both types associated with later academic and social problems. Attendant risk and protective factors are identified and mitigating assessment and prevention measures are discussed. PMID- 29145945 TI - Patterns of peer- and teacher-rated aggression, victimization, and prosocial behavior in an urban, predominantly African American preadolescent sample: Associations with peer-perceived characteristics. AB - This study investigated peer-perceived social/reputational correlates of patterns of aggression, victimization, and prosocial behavior. Participants were a predominantly African-American (i.e., 87%) sample of 320 fourth and fifth graders (45% male, Mean age=10.4years) attending six urban public elementary schools. Using latent profile analysis, profiles of peer-perceived and teacher-perceived aggressive, victimized, and prosocial youth were identified. These latent profiles were then compared on a range of peer-perceived social/reputational characteristics. Results indicated that teachers and peers identified similar profiles of normative and prosocial students. However, whereas peers distinguished between aggressive and victimized profiles, the teacher-identified victimized profile was also perceived as aggressive. Results also indicated that there was modest agreement between peers and teachers about who was involved in peer victimization. Findings underscore the importance of including both informants in efforts to identify youth involved in peer victimization. PMID- 29145946 TI - Predicting Subclinical Atherosclerosis in Low-Risk Individuals: Ideal Cardiovascular Health Score and Fuster-BEWAT Score. AB - BACKGROUND: The ideal cardiovascular health score (ICHS) is recommended for use in primary prevention. Simpler tools not requiring laboratory tests, such as the Fuster-BEWAT (blood pressure [B], exercise [E], weight [W], alimentation [A], and tobacco [T]) score (FBS), are also available. OBJECTIVES: The purpose of this study was to compare the effectiveness of ICHS and FBS in predicting the presence and extent of subclinical atherosclerosis. METHODS: A total of 3,983 participants 40 to 54 years of age were enrolled in the PESA (Progression of Early Subclinical Atherosclerosis) cohort. Subclinical atherosclerosis was measured in right and left carotids, abdominal aorta, right and left iliofemoral arteries, and coronary arteries. Subjects were classified as having poor, intermediate, or ideal cardiovascular health based on the number of favorable ICHS or FBS. RESULTS: With poor ICHS and FBS as references, individuals with ideal ICHS and FBS showed lower adjusted odds of having atherosclerotic plaques (ICHS odds ratio [OR]: 0.41; 95% confidence interval [CI]: 0.31 to 0.55 vs. FBS OR: 0.49; 95% CI: 0.36 to 0.66), coronary artery calcium (CACS) >=1 (CACS OR: 0.41; 95% CI: 0.28 to 0.60 vs. CACS OR: 0.53; 95% CI: 0.38 to 0.74), higher number of affected territories (OR: 0.32; 95% CI: 0.26 to 0.41 vs. OR: 0.39; 95% CI: 0.31 to 0.50), and higher CACS level (OR: 0.40; 95% CI: 0.28 to 0.58 vs. OR: 0.52; 95% CI: 0.38 to 0.72). Similar levels of significantly discriminating accuracy were found for ICHS and FBS with respect to the presence of plaques (C-statistic: 0.694; 95% CI: 0.678 to 0.711 vs. 0.692; 95% CI: 0.676 to 0.709, respectively) and for CACS >=1 (C-statistic: 0.782; 95% CI: 0.765 to 0.800 vs. 0.780; 95% CI: 0.762 to 0.798, respectively). CONCLUSIONS: Both scores predict the presence and extent of subclinical atherosclerosis with similar accuracy, highlighting the value of the FBS as a simpler and more affordable score for evaluating the risk of subclinical disease. PMID- 29145947 TI - Cardiovascular Health, Simplified. PMID- 29145949 TI - Change Is Not Always Good. PMID- 29145948 TI - Type of Atrial Fibrillation and Outcomes in Patients With Heart Failure and Reduced Ejection Fraction. AB - BACKGROUND: Atrial fibrillation (AF) is common in heart failure (HF), but the outcome by type of AF is largely unknown. OBJECTIVES: This study investigated outcomes related to type of AF (paroxysmal, persistent or permanent, or new onset) in 2 recent large trials in patients with HF with reduced ejection fraction. METHODS: The study analyzed patients in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) trials. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for outcomes related to AF type. RESULTS: Of 15,415 patients, 5,481 (35.6%) had a history of AF at randomization, and of these, 1,645 (30.0%) had paroxysmal AF. Compared with patients without AF, patients with paroxysmal AF at randomization had a higher risk of the primary composite endpoint of cardiovascular death or HF hospitalization (HR: 1.20; 95% confidence interval [CI]: 1.09 to 1.32; p < 0.001), HF hospitalization (HR: 1.34; 95% CI: 1.19 to 1.51; p < 0.001), and stroke (HR: 1.34; 95% CI: 1.02 to 1.76; p = 0.037), whereas the corresponding risks in patients with persistent or permanent AF were not elevated. Neither type of AF was associated with higher mortality. New onset AF was associated with the greatest risk of adverse outcomes: primary endpoint (HR: 2.21; 95% CI: 1.80 to 2.71), HF hospitalization (HR: 2.11; 95% CI: 1.58 to 2.81), stroke (HR: 2.20; 95% CI: 1.25 to 3.88), and all-cause mortality (HR: 2.26; 95% CI: 1.86 to 2.74), all p values < 0.001, compared with patients without AF. Anticoagulants were used less often in patients with paroxysmal (53%) and new onset (16%) AF than in patients with persistent or permanent AF (71%). CONCLUSIONS: Among HF patients with a history of AF, those with paroxysmal AF were at greater risk of HF hospitalization and stroke than were patients with persistent or permanent AF, underlining the importance of anticoagulant therapy. New onset AF was associated with increased risk of all outcomes. (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255) (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure [ATMOSPHERE]; NCT00853658). PMID- 29145951 TI - Combination Cell Therapy for Ischemic Cardiomyopathy: Is the Whole Greater Than Sum of Its Parts? PMID- 29145950 TI - A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration. AB - BACKGROUND: The combination of autologous mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) synergistically reduces scar size and improves cardiac function in ischemic cardiomyopathy. Whereas allogeneic (allo-)MSCs are immunoevasive, the capacity of CSCs to similarly elude the immune system remains controversial, potentially limiting the success of allogeneic cell combination therapy (ACCT). OBJECTIVES: This study sought to test the hypothesis that ACCT synergistically promotes cardiac regeneration without provoking immunologic reactions. METHODS: Gottingen swine with experimental ischemic cardiomyopathy were randomized to receive transendocardial injections of allo-MSCs + allo-CSCs (ACCT: 200 million MSCs/1 million CSCs, n = 7), 200 million allo-MSCs (n = 8), 1 million allo-CSCs (n = 4), or placebo (Plasma-Lyte A, n = 6). Swine were assessed by cardiac magnetic resonance imaging and pressure volume catheterization. Immune response was tested by histologic analyses. RESULTS: Both ACCT and allo-MSCs reduced scar size by -11.1 +/- 4.8% (p = 0.012) and -9.5 +/- 4.8% (p = 0.047), respectively. Only ACCT, but not MSCs or CSCs, prevented ongoing negative remodeling by offsetting increases in chamber volumes. Importantly, ACCT exerted the greatest effect on systolic function, improving the end-systolic pressure volume relation (+0.98 +/- 0.41 mm Hg/ml; p = 0.016). The ACCT group had more phospho-histone H3+ (a marker of mitosis) cardiomyocytes (p = 0.04), and noncardiomyocytes (p = 0.0002) than did the placebo group in some regions of the heart. Inflammatory sites in ACCT and MSC-treated swine contained immunotolerant CD3+/CD25+/FoxP3+ regulatory T cells (p < 0.0001). Histologic analysis showed absent to low-grade inflammatory infiltrates without cardiomyocyte necrosis. CONCLUSIONS: ACCT demonstrates synergistic effects to enhance cardiac regeneration and left ventricular functional recovery in a swine model of chronic ischemic cardiomyopathy without adverse immunologic reaction. Clinical translation to humans is warranted. PMID- 29145953 TI - Eat Nuts, Live Longer. PMID- 29145952 TI - Nut Consumption and Risk of Cardiovascular Disease. AB - BACKGROUND: The associations between specific types of nuts, specifically peanuts and walnuts, and cardiovascular disease remain unclear. OBJECTIVES: The authors sought to analyze the associations between the intake of total and specific types of nuts and cardiovascular disease, coronary heart disease, and stroke risk. METHODS: The authors included 76,364 women from the Nurses' Health Study (1980 to 2012), 92,946 women from the Nurses' Health Study II (1991 to 2013), and 41,526 men from the Health Professionals Follow-Up Study (1986 to 2012) who were free of cancer, heart disease, and stroke at baseline. Nut consumption was assessed using food frequency questionnaires at baseline and was updated every 4 years. RESULTS: During 5,063,439 person-years of follow-up, the authors documented 14,136 incident cardiovascular disease cases, including 8,390 coronary heart disease cases and 5,910 stroke cases. Total nut consumption was inversely associated with total cardiovascular disease and coronary heart disease after adjustment for cardiovascular risk factors. The pooled multivariable hazard ratios for cardiovascular disease and coronary heart disease among participants who consumed 1 serving of nuts (28 g) 5 or more times per week, compared with the reference category (never or almost never), were 0.86 (95% confidence interval: 0.79 to 0.93; p for trend = 0.0002) and 0.80 (95% confidence interval: 0.72 to 0.89; p for trend <0.001), respectively. Consumption of peanuts and tree nuts (2 or more times/week) and walnuts (1 or more times/week) was associated with a 13% to 19% lower risk of total cardiovascular disease and 15% to 23% lower risk of coronary heart disease. CONCLUSIONS: In 3 large prospective cohort studies, higher consumption of total and specific types of nuts was inversely associated with total cardiovascular disease and coronary heart disease. PMID- 29145956 TI - Myofilament Calcium-Buffering Dependent Action Potential Triangulation in Human Induced Pluripotent Stem Cell Model of Hypertrophic Cardiomyopathy. PMID- 29145957 TI - The Need to Define Treatment Goals for Protein-Losing Enteropathy in Fontan Care and Research. PMID- 29145958 TI - Reply: The Need to Define Treatment Goals for Protein-Losing Enteropathy in Fontan Care and Research. PMID- 29145959 TI - Influence of Diabetes on CABG Patency: Targeting Functional Status After CABG in Patients With DM. PMID- 29145954 TI - Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 1. AB - Modern cancer therapy has successfully cured many cancers and converted a terminal illness into a chronic disease. Because cancer patients often have coexisting heart diseases, expert advice from cardiologists will improve clinical outcome. In addition, cancer therapy can also cause myocardial damage, induce endothelial dysfunction, and alter cardiac conduction. Thus, it is important for practicing cardiologists to be knowledgeable about the diagnosis, prevention, and management of the cardiovascular complications of cancer therapy. In this first part of a 2-part review, we will review cancer therapy-induced cardiomyopathy and ischemia. This review is based on a MEDLINE search of published data, published clinical guidelines, and best practices in major cancer centers. With the number of cancer survivors expanding quickly, the time has come for cardiologists to work closely with cancer specialists to prevent and treat cancer therapy-induced cardiovascular complications. PMID- 29145955 TI - Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 2. AB - In this second part of a 2-part review, we will review cancer or cancer therapy associated systemic and pulmonary hypertension, QT prolongation, arrhythmias, pericardial disease, and radiation-induced cardiotoxicity. This review is based on a MEDLINE search of published data, published clinical guidelines, and best practices in major cancer centers. Newly developed targeted therapy can exert off target effects causing hypertension, thromboembolism, QT prolongation, and atrial fibrillation. Radiation therapy often accelerates atherosclerosis. Furthermore, radiation can damage the heart valves, the conduction system, and pericardium, which may take years to manifest clinically. Management of pericardial disease in cancer patients also posed clinical challenges. This review highlights the unique opportunity of caring for cancer patients with heart problems caused by cancer or cancer therapy. It is an invitation to action for cardiologists to become familiar with this emerging subspecialty. PMID- 29145960 TI - Absolute and relative stabilities for fracture fixation: the concept revisited. PMID- 29145961 TI - Vertical femoral neck fractures in young adults: a closed fixation strategy using a transverse cancellous lag screw. AB - Vertical femoral neck fractures (Pauwels type III classification) in young adults generally occur as a consequence of high-energy trauma and are frequently seen in association with multiple injuries. Considering the controversies regarding the optimal fixation for this fracture, our aim was to evaluate the clinical outcome of a closed fixation strategy for vertical femoral neck fractures in young adults using two parallel and one transverse cancellous lag screws. This was a single surgeon, prospective study including 20 young adults with average age of 38.75 years (range 18-59 years) with a high-energy Pauwels III femoral neck fracture. Closed reduction and internal fixation with three cancellous lag screws were performed. The first screw was inserted crosswise to avoid further shear forces. Second and third parallel screws were placed above the lesser trochanter and centrally on the greater trochanter, respectively. Clinical outcomes were assessed by comparing postoperative and final follow-up radiographs 24 months post-injury. Eleven patients had an isolated vertical femoral neck fracture. Of these, five had further femoral neck comminution. Nine patients had an associated ipsilateral femoral shaft fracture. All fractures were displaced at the time of the first radiological evaluation. Closed reduction quality was considered excellent or good in 15 patients. After 24 months, bone union was achieved in 16 cases. Osteonecrosis of the femoral head developed in association with two fractures, and a nonunion developed in association with two fractures. We conclude that vertical high-energy femoral neck fractures can be treated successfully with internal fixation with two parallel cancellous lag screws positioned above the lesser trochanter and a third screw inserted centrally on the greater trochanter at an angle perpendicular to the fracture line. PMID- 29145962 TI - Bone union with an in situ spacer after the first stage of the induced membrane technique. AB - INTRODUCTION: We report a case of an infected bone defect in the tibia in which the treatment was stopped in the first stage of the induced membrane technique. The polymethylmethacrylate (PMMA) spacer, retained in the bone defect, was encapsulated by the bone regeneration. CASE REPORT: A 37-year-old male patient with a 7-cm infected bone defect in the tibia was submitted to the first stage of the induced membrane technique with debridement and implantation of a PMMA spacer with antibiotics. The patient refused the second stage of the procedure and achieved bone union with the spacer in situ. There was no recurrence of infection at the 6-year follow-up. CONCLUSION: his is the first report of a case in which bone union was achieved with the spacer in situ after the first stage of the induced membrane technique. Keeping the spacer in the bone defect could be an option in some exceptional situations. PMID- 29145963 TI - Functional results and isokinetic muscle strength in patients with Fraser type I floating knee treated with internal fixation. AB - INTRODUCTION: According to Fraser's description, ipsilateral femoral and tibial diaphyseal fractures are characterised as type I floating knee and have a better prognosis than fractures with joint involvement (type II). There are few reports of functional and muscle strength in these patients. The objective of this study was to evaluate the functional and isokinetic muscle strength of patients with type I floating knee undergoing femoral and tibial internal fixation. METHODS: Patients with type I floating knee undergoing concomitant femoral and tibial internal fixation were invited for clinical evaluation. The parameters evaluated included the following: Karlstrom and Olerud score; Lysholm score; isokinetic thigh and hip muscle evaluation; knee range of motion; pain level; investigation of associated knee injuries by clinical evaluation and MRI; and types of complications. RESULTS: Twenty-one patients were included in the study; 11 of these were clinically evaluated, with a mean follow-up of 23.9 months. Six patients had an acceptable result according to the Karlstrom criteria, whereas eight patients had a poor result based on the Lysholm scale. The peak torque deficit was 61% for knee extensors, 37% for flexors and -9% for hip abductors. The mean pain level was 5.9. Three patients had a partial anterior cruciate ligament (ACL) injury; one patient had a posterior cruciate ligament (PCL) injury; and three patients had a meniscal injury. There were four cases of tibial or femoral nonunion at one year and two cases of chronic osteomyelitis. CONCLUSION: Patients with type I floating knee had unsatisfactory functional results, significant knee extensor and flexor muscle strength deficits and a significant rate of complications at the two-year follow-up. PMID- 29145964 TI - Does the position of the scapula in relation to the glenopolar angle change the preferred treatment of extra-articular fractures? AB - OBJECTIVE: To analyse the glenopolar angle (GPA) at different inclinations of the scapula using 3D CT, to test the hypothesis that the result could change the indication from conservative treatment to surgery. MATERIALS AND METHODS: Analysis of 30 3D CT images of patients' scapulae, measuring the GPA. The GPA was measured with scapulae at 0 degrees and at 20 degrees and 30 degrees of internal and external rotation. Angles were compared by age, sex and examiner for the different angles of rotation of the scapulae. RESULTS: The GPA of scapulae in rotation tended to be smaller than the GPA without rotation, and the larger the degree of rotation, the more the angle was underestimated. Additionally, for the same degree of rotation, internal rotation was associated with greater underestimation of the GPA than external rotation. Two different examiners achieved an excellent level of agreement between angle measurements. The GPA with the scapula at 0 degrees was significantly higher among elderly patients. The variation in GPA with the scapula in rotation (20 degrees and 30 degrees ) in relation to the GPA without rotation was significantly greater for female patients. CONCLUSIONS: As the rotation of the scapula was displaced from the scapula in the coronal position (GPA 0 degrees ), both in internal rotation and in external rotation, the GPA reduced. Therefore, rotational displacement may lead to an error in GPA measurement, resulting in incorrect indication of treatment. It is recommended that whenever possible, GPA measurements should be taken in neutral rotation, with the scapula in a neutral position at 0 degrees . PMID- 29145965 TI - Increased cytokine levels and histological changes in cartilage, synovial cells and synovial fluid after malleolar fractures. AB - BACKGROUND: Malleolar fractures are among the most common fractures in the human skeleton with a high risk of later development of post-traumatic osteoarthritis (OA). The acute ankle injury initiates a sequence of events potentially leading to progressive articular surface damage resulting from inflammatory changes in cartilage, synovial tissue and synovial fluid. We hypothesised that in the acute phase of ankle fracture, these changes occur at the same time in the different tissues. METHODS: Specimens of chondral tissue, synovial tissue and synovial fluid were collected from 16 patients with acute articular ankle fracture (study group). Additional samples were obtained from five male fresh cadavers within 12 hours of death (control group). Chondral tissue was assessed for cellularity, irregularities and chondrocyte disarray. Synovial tissue was assessed for synovitis, proteoglycans and collagen deposition. Synovial fluid was assessed for cytokines IL-2, IL-6, IL-10, IL-17, IFN-gamma and TGF-beta1. RESULTS: Chondral tissue showed discontinuity in the tidemark between cartilage and subchondral bone, chondrocyte disarray, increased cellularity (both at the cartilage surface and subchondral bone), articular surface irregularities and increased deposition of proteoglycans and collagen fibres. Synovial tissue showed a statistically significant difference between the study and control groups in the concentration per tissue area of both thin collagen fibres (p=0.0274) and thick collagen fibres (p<0.0001). Cytokine concentrations in synovial fluid samples were significantly higher in ankle fracture tissue compared with controls for IL-2 (p=0.0002), IL-6 (p<0.0001), IL-10 (p=0.002) and IL-17 (p<0.0001). No statistically significant differences were observed for IFN-gamma (p=0.06303) and TGF-beta1 (p=0.8832). CONCLUSION: We observed a pattern of simultaneous and interrelated pathological changes in cartilage, subchondral bone, synovial tissue and synovial fluid after acute malleolar fracture. As the observed inflammatory changes could lead to the development of OA, a more thorough knowledge of these early processes could be helpful to find strategies for prevention or delay of this common complication. PMID- 29145966 TI - Outcome evaluation of staged treatment for bicondylar tibial plateau fractures. AB - BACKGROUND: The universal accepted strategy for treating high-energy tibial plateau fractures remains a topic of ongoing debate. The challenge for the practicing orthopaedic trauma surgeon is to provide anatomical articular fracture reduction, with successfully managing the complex soft-tissue injury that is commonly present at patient admission. The primary aim of the actual study was to evaluate the results of a staged protocol for the treatment of high-energy bicondylar tibial plateau fractures. The secondary aim was to describe the technique used for the definitive fixation of this complex fracture pattern. METHODS: Thirty patients with unstable high-energy closed bicondylar tibial plateau fractures (17 Schatzker V and 13 Schatzker VI) were managed. There were 24 men (80%) and six women (20%). All of them were skeletally mature with their age ranging from 19 to 67 years (mean of 33.1+/-3.4 years). Treatment involved a two-stage procedure with appropriate emergency care, preoperative planning, and definitive fixation. Initial treatment, named 'damage control on complex articular fracture elements', consisted on temporary bridging external fixation. Definitive treatment was delayed in a mean of 10 days (ranging from seven to 13 days) and was performed when the soft-tissue conditioning demonstrated either complete or almost complete remission of the inflammatory reaction due to the 'first hit'. Conventional implants were used in the 30 patients. All patients were evaluated clinically and radiographically. RESULTS: Twenty-six (86.7%) patients had a moderate level of activity, three (10%) patients had a very light level of activity, and one (3.3%) patient was unable to have any kind of work activity and is currently supported by the Brazilian Welfare. Using the visual analog scale mean pain score was 30 (ranging from 10 to 60); even the patient with the workers' compensation had no severe pain. All patients except three have no difficulty with stairs, giving way, locking, swelling, and squatting, but were unable to run. Three (10%) patients had problems with stairs and could not bend the operated knee more than 90 degrees . One of them had a varus knee but no instability. Ninety percent of the patients were either very satisfied or somewhat satisfied with their outcome. The three dissatisfied patients suffered postoperative complications, most commonly wound infections. Four (13.4%) patients with former anatomical reduction had a residual articular step-off or diastasis of less than 3mm after fracture healing. All patients had no or mild arthrosis at the time of the last outpatient consultation. CONCLUSIONS: The two staged procedure presented herein showed to be an effective strategy for managing bycondilar tibial plateau fractures. The protocol used for these complex traumatic injuries follows very well defined steps, which means acute stabilization with a linear bridging external fixation, adequate soft tissue handling, preoperative planning, and definitive surgical fixation after seven to 14 days. The model presents a more biological approach to optimizing functional outcome with an acceptable complication rate and minimal risk of loss of reduction in these high-energy tibial plateau fractures. PMID- 29145967 TI - Bone intramedullary reaming grafts the fracture site with CD146+ skeletal progenitors and downmodulates the inflammatory environment. AB - INTRODUCTION: Femoral shaft fractures generally occur in young adults following a high-energy trauma and are prone to delayed union/non-union. Novel therapies to stimulate bone regeneration will have to mimic some of the aspects of the biology of fracture healing; however, which are these aspects is unclear. Locked intramedullary nailing is the current treatment of choice for the stabilisation of femur shaft fractures, and it is associated with accelerated healing and increased union rates. These benefits were partially attributed to the reaming procedure, which, regardless of significantly destroying the haematoma, stimulates the healing response. To better understand how reaming influences healing, we evaluated the viability of the nucleated cell fraction and the frequency of CD146+ skeletal progenitors, which contain multipotent cells, in the post-reaming haematoma. We also screened the concentrations of inflammatory mediators and growth factors in the fracture site after reaming compared with those in the original haematoma. METHODS: Pre- and post-reaming haematomas were percutaneously aspirated from the fracture site of 15 patients with closed femoral shaft fractures. Cellular viability and the percentage of CD146+ progenitors were analysed by flow cytometry. The concentrations of cytokines and growth factors were determined by ELISA. RESULTS: AnnexinV/Pi analysis showed that the viability of the total nucleated cell fraction was decreased in the post reaming haematoma. However, the procedure increased the percentage of CD146+ skeletal progenitors in the fracture site. Analysis of cytokines and growth factors in supernatants showed a decreased concentration of the inflammatory mediators IL-6, CCL-4, and MCP-1, along with an increase of anti-inflammatory IL 10, and the growth factors bFGF and PDGF-AB. CONCLUSION: These findings support the view that the positive effects of reaming on fracture healing might result from mechanically grafting the fracture site with a population of skeletal progenitors that contain multipotent cells; transitioning the signalling environment to a less inflammatory state, and enhancing the availability of specific osteogenic and angiogenic factors. A better understanding of the requisite stimuli for optimal bone repair, considering the disturbances made by orthopaedic treatments, will be determinant for the development of innovative treatments for bone repair. PMID- 29145968 TI - Effectiveness of a step-by-step oral recount before a practical simulation of fracture fixation. AB - OBJECTIVE: To evaluate the effectiveness of a step-by-step oral recount by residents before the final execution of a practical exercise simulating a surgical fixation of a radial diaphyseal fracture. MATERIAL AND METHODS: The study included 10 residents of orthopaedics and traumatology (four second- year and six first-year residents) divided into two groups with five residents each. All participants initially gathered in a room in which a video was presented demonstrating the practical exercise to be performed. One group (Group A) was referred directly to the practical exercise room. The other group (Group B) attended an extra session before the practical exercise, in which they were invited by instructors to recount all the steps that they would perform during the practical exercise. During this session, the instructors corrected the residents if any errors in the step-by-step recount were identified, and clarified questions from them. After this session, both Groups A and B gathered in a room in which they proceeded to the practical exercise, while being video recorded and evaluated using a 20-point checklist. RESULTS: Group A achieved a 57% accuracy, with results in this group ranging from 7 to 15 points out of a total of a possible 20 points. Group B achieved an 89% accuracy, with results in this group ranging from 15 to 20 points out of 20. CONCLUSION: An oral step-by step recount by the residents before the final execution of a practical simulation exercise of surgical fixation of a diaphyseal radial fracture improved the technique and reduced the execution time of the exercise. PMID- 29145969 TI - Late postoperative analysis of the tip-apex distance (TAD) in pertrochanteric fractures: is there an accommodation of the implant within the bone? AB - INTRODUCTION: This study measured the tip-apex distance (TAD) values in the immediate postoperative period and following weight-bearing and fracture impaction in patients undergoing osteosynthesis with dynamic hip screw and cephalomedullary nail. OBJECTIVE: To correlate the Baumgaertner index in the immediate postoperative period with values obtained after impaction of the fracture with the accommodation of the cephalic implant in the femoral head. PATIENTS AND METHODS: Radiographic TAD measurements were taken with AGFA-VIEW(r) of 82 patients with a mean age of 72 years with pertrochanteric fractures who were operated on and the fracture fixed with DHS- Synthes(r), TFN-Synthes(r), or Gamma Nail III-Stryker(r) in the immediate postoperative period, and following weight-bearing and fracture impaction (mean 3-8 weeks after surgery). RESULTS: The overall average TAD decreased from 20.3mm to 18.2mm. Regardless of the instability of the fracture, the age of the patient or the implant used, TAD decreased between the immediate postoperative period and following fracture impaction. CONCLUSION: The osteosynthesis of pertrochanteric fractures was associated with important accommodation of the cephalic implant in the femoral head with decreased TAD values after weight-bearing. PMID- 29145970 TI - Minimally invasive posteromedial percutaneous plate osteosynthesis for diaphyseal tibial fractures: technique description. AB - PURPOSE: The aim of this study was to evaluate the feasibility of performing minimally-invasive plate osteosynthesis (MIPO) in tibial fractures using two posteromedial incisions, and to measure the distance between the plate and neurovascular structures. MATERIALS AND METHODS: We performed nine dissections of specimens that were submitted to tibial MIPO with two posteromedial incisions. One locking compression plate (LCP) of 14 to 16 holes was inserted into the submuscular tunnel in a retrograde manner. Incisions were linked to evaluate the distance between neurovascular structures and the plate. RESULTS: During the proximal incision, a blunt dissection between semitendinosus and medial gastrocnemius tendons, as well as their lateral shift, helped to protect the main local neurovascular structures. In its distal portion, the submuscular plate tunnel insertion and its direction to the proximal incision prevented direct contact and possible damage to neurovascular structures. Moreover, we obtained successful results from a patient submitted to this procedure. CONCLUSION: Posteromedial MIPO represents a safe and attractive alternative for tibial fractures, particularly if there are damaged soft tissues in the anterior and medial side, or when access to intramedullary osteosynthesis is blocked. PMID- 29145973 TI - TAK-ing aim at chemoresistance: The emerging role of MAP3K7 as a target for cancer therapy. AB - Cellular drug resistance remains the main obstacle to the clinical efficacy of cancer chemotherapy. Alterations in key pathways regulating cell cycle checkpoints, apoptosis and Epithelial to Mesenchymal Transition (EMT), such as the Mitogen-activated protein kinase (MAPK) pathway, appear to be closely associated to cancer chemoresistance. Transforming growth factor-beta (TGF-beta)- activated kinase 1 (TAK1, also known as MAP3K7) is a serine/threonine kinase in the mitogen-activated protein kinase (MAP3K) family. It represents the cellular hub to which IL1, TGF-beta and Wnt signaling pathways converge. By regulating the phosphorylation status and activities of transcription factors including Activated Protein-1 (AP-1) and nuclear factor kappa-B (NF-kappaB), TAK1 mediates inflammatory and pro-survival responses. The interest towards the therapeutic targeting of TAK1 is due to its identification as one of the main mediators of both chemoresistance and EMT in several types of tumors, and as the possible target for a subset of treatment-refractory colon cancers exhibiting mutated KRAS or activated WNT pathways. For these reasons, many efforts have been made to design inhibitors of TAK1 kinase activity, which could be used to reverse TAK1 mediated chemoresistance. The activity of these inhibitors, in combination with the most commonly used chemotherapeutic drugs, has been tested in preclinical studies, proving the efficacy of TAK1 inhibition in reducing tumor growth and survival following chemotherapy administration. In the first part of this review, we describe the mechanisms underlying TAK1 regulation such as phosphorylation, ubiquitination and targeting by microRNAs. We then focus on the development of therapeutic small molecule inhibitors of TAK1 kinase activity, as well as preclinical studies supporting the role of TAK1 as a potential target for enhancing the response of tumors to anticancer therapies. PMID- 29145971 TI - Antimicrobial blue light inactivation of pathogenic microbes: State of the art. AB - As an innovative non-antibiotic approach, antimicrobial blue light in the spectrum of 400-470nm has demonstrated its intrinsic antimicrobial properties resulting from the presence of endogenous photosensitizing chromophores in pathogenic microbes and, subsequently, its promise as a counteracter of antibiotic resistance. Since we published our last review of antimicrobial blue light in 2012, there have been a substantial number of new studies reported in this area. Here we provide an updated overview of the findings from the new studies over the past 5 years, including the efficacy of antimicrobial blue light inactivation of different microbes, its mechanism of action, synergism of antimicrobial blue light with other angents, its effect on host cells and tissues, the potential development of resistance to antimicrobial blue light by microbes, and a novel interstitial delivery approach of antimicrobial blue light. The potential new applications of antimicrobial blue light are also discussed. PMID- 29145974 TI - Immunotherapy for triple-negative breast cancer: Existing challenges and exciting prospects. AB - Patients with breast tumors that do not express the estrogen receptor, the progesterone receptor, nor Her-2/neu are hence termed "triple negatives", and generally have a poor prognosis, with high rates of systemic recurrence and refractoriness to conventional therapy regardless of the choice of adjuvant treatment. Thus, more effective therapeutic options are sorely needed for triple negative breast cancer (TNBC), which occurs in approximately 20% of diagnosed breast cancers. In recent years, exploiting intrinsic mechanisms of the host immune system to eradicate cancer cells has achieved impressive success, and the advances in immunotherapy have yielded potential new therapeutic strategies for the treatment of this devastating subtype of breast cancer. It is anticipated that the responses initiated by immunotherapeutic interventions will explicitly target and annihilate tumor cells, while at the same time spare normal cells. Various immunotherapeutic approaches have been already developed and tested, which include the blockade of immune checkpoints using neutralizing or blocking antibodies, induction of cytotoxic T lymphocytes (CTLs), adoptive cell transfer based therapy, and modulation of the tumor microenvironment to enhance the activity of CTLs. One of the most important areas of breast cancer research today is understanding the immune features and profiles of TNBC and devising novel immune-modulatory strategies to tackling TNBC, a subtype of breast cancer notorious for its poor prognosis and its imperviousness to conventional treatments. On the optimal side, one can anticipate that novel, effective, and personalized immunotherapy for TNBC will soon achieve more success and impact clinical treatment of this disease which afflicts approximately 20% of patients with breast cancer. In the present review, we highlight the current progress and encouraging developments in cancer immunotherapy, with a goal to discuss the challenges and to provide future perspectives on how to exploit a variety of new immunotherapeutic approaches including checkpoint inhibitors and neoadjuvant immunotherapy for the treatment of patients with TNBC. PMID- 29145975 TI - In cancer, A-to-I RNA editing can be the driver, the passenger, or the mechanic. AB - In recent years, A-to-I RNA modifications performed by the Adenosine Deaminase Acting on RNA (ADAR) protein family were found to be expressed at altered levels in multiple human malignancies. A-to-I RNA editing changes adenosine to inosine on double stranded RNA, thereby changing transcript sequence and structure. Although A-to-I RNA editing have the potential to change essential mRNA transcripts, affecting their corresponding protein structures, most of the human editing sites identified to date reside in non-coding repetitive transcripts such as Alu elements. Therefore, the impact of the hypo- or hyper-editing found in specific cancers remains unknown. Moreover, it is yet unclear whether or not changes in RNA editing and ADAR expression levels facilitate or even drive cancer progression or are just a byproduct of other affected pathways. In both cases, however, the levels of RNA editing and ADAR enzymes can possibly be used as specific biomarkers, as their levels change differently in specific malignancies. More significantly, recent studies suggest that ADAR enzymes can be used to reverse the oncogenic process, suggesting a potential for gene therapies. This review focuses on new findings that suggest that RNA editing by ADARs can affect cancer progression and even formation. We also discuss new possibilities of using ADAR enzymes and RNA editing as cancer biomarkers, indicators of chemotherapeutic drug sensitivity, and even to be themselves potential therapeutic tools. PMID- 29145976 TI - Not only P-glycoprotein: Amplification of the ABCB1-containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins. AB - The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment. Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoprotein or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for example taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of published papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematological malignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo with anti-tumor agents such as paclitaxel and doxorubicin, increased ABCB1 copy number has been demonstrated, resulting from chromosomal amplification events at 7q11.2-21 locus, leading to marked P-glycoprotein overexpression, and multidrug resistance (MDR). Clearly however, additional mechanisms such as single nucleotide polymorphisms (SNPs) and epigenetic modifications have shown a role in the overexpression of ABCB1 and of other MDR efflux pumps. However, notwithstanding the design of 4 generations of ABCB1 inhibitors and the wealth of information on the biochemistry and substrate specificity of ABC transporters, translation of this vast knowledge from the bench to the bedside has proven to be unexpectedly difficult. Many studies show that upon repeated treatment schedules of cell cultures or tumors with taxenes and anthracyclines as well as other chemotherapeutic drugs, amplification, and/or overexpression of a series of genes genomically surrounding the ABCB1 locus, is observed. Consequently, altered levels of other proteins may contribute to the establishment of the MDR phenotype, and lead to poor clinical outcome. Thus, the genes contained in this ABCB1 amplicon including ABCB4, SRI, DBF4, TMEM243, and RUNDC3B are overexpressed in many cancers, and especially in MDR tumors, while TP53TG1 and DMTF1 are bona fide tumor suppressors. This review describes the role of these genes in cancer and especially in the acquisition of MDR, elucidates possible connections in transcriptional regulation (co-amplification/repression) of genes belonging to the same ABCB1 amplicon region, and delineates their novel emerging contributions to tumor biology and possible strategies to overcome cancer MDR. PMID- 29145977 TI - Outpatient Total Knee Arthroplasty: Are We There Yet? (Part 1). AB - Recent trends in total joint care have moved toward outpatient surgery. Total knee arthroplasty (TKA) remains a definitive management for end-stage osteoarthritis and has experienced increased utilization over the past several decades. The method by which surgeons conduct outpatient total knee procedures has yet to be fully elucidated as different institutions report different experiences from their pathways. This article will discuss current data and recommendations for implementing successful TKA and unicompartmental knee arthroplasty outpatient protocols. Specifically, this review will provide information regarding cost reduction, patient selection criteria, and preoperative medical optimization. PMID- 29145972 TI - Cancer Immunotherapy Getting Brainy: Visualizing the Distinctive CNS Metastatic Niche to Illuminate Therapeutic Resistance. AB - The advent of cancer immunotherapy (CIT) and its success in treating primary and metastatic cancer may offer substantially improved outcomes for patients. Despite recent advancements, many malignancies remain resistant to CIT, among which are brain metastases, a particularly virulent disease with no apparent cure. The immunologically unique niche of the brain has prompted compelling new questions in immuno-oncology such as the effects of tissue-specific differences in immune response, heterogeneity between primary tumors and distant metastases, and the role of spatiotemporal dynamics in shaping an effective anti-tumor immune response. Current methods to examine the immunobiology of metastases in the brain are constrained by tissue processing methods that limit spatial data collection, omit dynamic information, and cannot recapitulate the heterogeneity of the tumor microenvironment. In the current review, we describe how high-resolution, live imaging tools, particularly intravital microscopy (IVM), are instrumental in answering these questions. IVM of pre-clinical cancer models enables short- and long-term observations of critical immunobiology and metastatic growth phenomena to potentially generate revolutionary insights into the spatiotemporal dynamics of brain metastasis, interactions of CIT with immune elements therein, and influence of chemo- and radiotherapy. We describe the utility of IVM to study brain metastasis in mice by tracking the migration and growth of fluorescently labeled cells, including cancer cells and immune subsets, while monitoring the physical environment within optical windows using imaging dyes and other signal generation mechanisms to illuminate angiogenesis, hypoxia, and/or CIT drug expression within the metastatic niche. Our review summarizes the current knowledge regarding brain metastases and the immune milieu, presents the current status of CIT and its prospects in targeting brain metastases to circumvent therapeutic resistance, and proposes avenues to utilize IVM to study CIT drug delivery and therapeutic efficacy in preclinical models that will ultimately facilitate novel drug discovery and innovative combination therapies. PMID- 29145978 TI - Outpatient Management of Ankle Fractures. AB - Interest in outpatient orthopedic surgery has been fueled by provider desire to control costs and development of rapid recovery protocols. Open reduction and internal fixation (ORIF) is a commonly elected treatment strategy for ankle fracture that may be performed in an outpatient setting. Lessons on cost-savings of the outpatient model in orthopedics can be learned in total joint replacement and spine surgery. Moreover, in properly selected patients, outpatient ORIF has been shown to be comparably safe. Reasons for admission of the surgically managed patient with ankle fractures, including concern for surgical delay and additional social factors, warrant further investigation. PMID- 29145979 TI - Current Ultrasound Application in the Foot and Ankle. AB - This article is a comprehensive review of the current utilizations of ultrasound in the treatment of orthopedic conditions of the foot and ankle. It reviews the diagnostic and interventional applications to commonly encountered lower extremity ailments, including plantar fasciosis, tendinosis, and peripheral nerve disorders. It also outlines minimally invasive ultrasound-guided procedures and emerging therapies as alternatives to current treatments. These emerging therapies can be used to assist surgeons and provide options for patients needing intervention. Techniques such as hydrodissection, injection, aspiration, tenotomy, and fasciotomy are discussed, giving readers insight into different treatment modalities and options to help manage their patients. PMID- 29145980 TI - Total Hip Arthroplasty in the Outpatient Setting: What You Need to Know (Part 1). AB - The method by which surgeons conduct outpatient total hip arthroplasty (THA) procedures has yet to be fully standardized. Careful examination of components involved in the preoperative phase of outpatient hip arthroplasty procedures may lead to improved outcomes. This article will discuss methods for implementing successful outpatient THA protocols. Specifically it reviews information regarding patient selection criteria, preoperative education, and preoperative medical optimization. PMID- 29145982 TI - Impact of Outpatient Total Joint Replacement on Postoperative Outcomes. AB - Total joint arthroplasty (TJA) has demonstrated tremendous benefits to patients with osteoarthritis. Health care reform has influenced surgeons to optimize TJA care pathways as well as playing a role in the formation of outpatient TJA protocols. Understanding the outcomes of outpatient TJA is imperative to surgical predicate decision making. The aim of this review is to compare outcomes of outpatient TJA patients to standard-stay inpatients. Postoperative outcomes assessed include pain, complications, readmissions, reoperation, patient satisfaction, and cost. PMID- 29145981 TI - Total Hip Arthroplasty in the Outpatient Setting: What You Need to Know (Part 2). AB - The intra- and postoperative phases of outpatient total hip arthroplasty (THA) vary by institution and surgeon. An understanding of an evidence-based approach to enhancing the intra- and postoperative phases of the care continuum is warranted to offer high-value care to outpatient candidates. This article will discuss methods for implementing successful outpatient THA protocols. Specifically it reviews information regarding anesthesia and analgesia modalities, intraoperative considerations, and postoperative rehabilitation amenable to outpatient THA. PMID- 29145984 TI - Outpatient Pediatric Orthopedic Surgery. AB - Outpatient surgery refers to a surgical procedure that is performed without an overnight stay in a hospital. Outpatient surgery is associated with decreased individual and societal costs while achieving equivalent health outcomes and excellent patient satisfaction. Successful outpatient pediatric surgery is predicated on appropriate patient selection, adequate pain control, thorough preoperative education, and close clinical follow-up. Continuous research in quality, value, and patient safety are needed to ensure that this practice continues in as safe and efficient a manner as possible. PMID- 29145983 TI - The Role of Implant Removal in Orthopedic Trauma. AB - Although implant removal is common after orthopedic trauma, indications for removal remain controversial. There are few data in the literature to allow evidence-based decision-making. The risk of complications from implant removal must be weighed against the possible benefits and the likelihood of improving the patient's symptoms. PMID- 29145985 TI - Use of Wide-awake Local Anesthesia No Tourniquet in Hand and Wrist Surgery. AB - WALANT (wide-awake local anesthesia no tourniquet) appears to be a safe and effective anesthesia technique for many hand and wrist surgeries. Patient satisfaction is high because of the avoidance of preoperative testing and hospital admission. Postoperative recovery is rapid, and procedures can be done in outpatient settings, resulting in substantial savings in time and money. PMID- 29145986 TI - Hand Surgery in the Ambulatory Surgery Center. AB - Outpatient surgery, especially in free-standing ambulatory surgery centers (ASC), provides a safe, cost-effective option for a variety of surgical procedures and has become the preferred choice over inpatient and hospital-based outpatient surgery for most hand and wrist procedures. Complication rates after ASC hand surgery are low (0.2%-2.5%). Patient dissatisfaction with ASC surgery is primarily associated with postoperative nausea and vomiting and inadequate pain control. PMID- 29145987 TI - Outpatient Total Knee Arthroplasty: Are We There Yet? (Part 2). AB - The method by which surgeons conduct outpatient total knee procedures has yet to be fully elucidated. Literature demonstrates different experiences from various care protocols in place across the nation. This article reviews current recommendations for implementing successful total knee arthroplasty (TKA) and unicompartmental knee arthroplasty outpatient protocols. Specifically, information regarding anesthesia and analgesia modalities, perioperative care, operative technique, and postoperative care within outpatient TKA pathways is discussed. PMID- 29145988 TI - Outpatient Shoulder Arthroplasty. AB - Health care policy makers have placed increased attention on the cost of health care making outpatient joint arthroplasty an attractive alternative to routine hospital admission. Recent studies have shown outpatient shoulder arthroplasty is a safe and cost-effective alternative to inpatient shoulder arthroplasty. Proper patient selection, patient education, effective pain management strategies, and attention to intraoperative blood loss are keys in the success of outpatient shoulder arthroplasty. PMID- 29145989 TI - Pain Management Strategies in Shoulder Arthroplasty. AB - Pain control in total shoulder arthroplasty demands a multidisciplinary approach with collaboration between patients, surgeon, and anesthetist. A multimodal approach with preemptive medication, regional blockade, local anesthetics, and a combination of acetaminophen, nonsteroidal antiinflammatory drugs, tramadol, and gabapentinoids postoperatively leads to pain control and patient satisfaction. Assessment of patients' expectations constitutes a vital aspect of the preoperative patient evaluation. Educating and psychologically preparing patients reduces postoperative pain. Patients with anxiety and depression, preoperative narcotic use, and medical comorbidities are at an increased risk for suboptimal pain control. Minimizing narcotic use decreases opioid-related adverse effects and facilitates productive rehabilitation efforts. PMID- 29145991 TI - Outpatient Surgery. PMID- 29145990 TI - The Role of Superior Capsule Reconstruction in Rotator Cuff Tears. AB - Massive, irreparable rotator cuff disease is a challenging problem to treat, especially in the younger active patient. This condition allows the deltoid to generate anterosuperior translation and shoulder dysfunction. Ideally, this dysfunction may be improved with rotator cuff repair. However, in the setting of irreparable rotator cuff disease, normal function is challenging to restore. Superior capsule reconstruction theoretically improves function by recentering the humeral head and improving glenohumeral kinematics. This restoration of stability results in a stable fulcrum, and may allow the deltoid and remaining cuff can function more effectively. PMID- 29145992 TI - Translating scientific advances into disease-modifying therapies for Parkinson's Disease. PMID- 29145993 TI - An Absorbable Hydrogel Spray Reduces Postoperative Mediastinal Adhesions After Congenital Heart Surgery. AB - BACKGROUND: Adhesions encountered during reoperative cardiac surgery can prolong operative time and increase operative risk. The purpose of this clinical study was to investigate the antiadhesion property of a synthetic bioabsorbable polymer spray after cardiac reoperations in infants. METHODS: A prospective randomized double-blinded study was designed. Forty infants requiring staged cardiac operations were randomly allocated to a study group (n = 20) or a control group (n = 20). The appropriate volume of the polymer was sprayed onto the mediastinal surfaces before chest closure after the first surgical procedure in the study group. At reoperation, adhesions were evaluated by a blinded investigator following a 5-grade scoring system. Five predetermined anatomic areas were scored. Incision to extracorporeal circulation time was also analyzed. RESULTS: In all, 40 subjects were enrolled into the study. Four babies died before the second operation. Three others were missed for reevaluation. The control group (n = 16) had longer incision to extracorporeal circulation time (38 +/- 10 minutes) than the study group (n = 17; 23 +/- 6 minutes; p < 0.001). The control subjects had significantly more severe adhesions than the study group at all five mediastinal areas: (1) retrosternal (p < 0.001); (2) base of the heart (large vessels [p < 0.05]); (3) right side (p < 0.01); (4) left side (p < 0.02); and (5) diaphragmatic side of the mediastinum (p < 0.001). CONCLUSIONS: The use of synthetic bioabsorbable polymer sealant spray at the end of primary pediatric cardiac surgery reduces the intensity of mediastinal adhesions and the reentry time in infants undergoing repeat median sternotomy. PMID- 29145994 TI - Retinal vascular imaging in cardiovascular medicine: New tools for an old examination. PMID- 29145995 TI - PLGA-based monolithic filaments prepared by hot-melt extrusion: In-vitro comparative study. AB - To avoid frequent drug administration, PLGA-based monolithic filament-shaped implants were prepared. In this study, the effect of different formulation variables was studied, namely: type of PLGA (PLGA 502 and PLGA 503), type of drug (the lipophilic Prednisolone acetate, PA and the hydrophilic Propranolol Hydrochloride, PH) and drug loading (10 and 30% w/w). PLGA 503-based implants showed a lower water uptake, lower mass loss and erosion, slower drug release, and better mechanical properties and elasticity (P<0.05) compared to the corresponding PLGA 502-based implants. PH-loaded implants showed a faster swelling and degradation as well as drug release (P<0.05) compared to PA-loaded implants; the former attained almost complete drug release after about 18 days, while the latter attained it after about 30 days. All the implants followed a zero-order kinetic pattern suitable for a controlled drug release. Characterization was done using SEM and DSC. This study proved the potential tailoring of the properties of PLGA-implants, prepared by hot-melt extrusion (HME), based on some formulation variables. PMID- 29145996 TI - [Comparative profile of the use of filter needles in Quebec and France in healthcare facility]. AB - OBJECTIVES: The manipulation of drugs from glass ampules can generate particles when the ampule is broken. Several authors recommend the use of filter needle to withdraw the drug content. The main objective is to establish an inventory of the use of filter needles and the perception of pharmacists in Quebec and in France. METHODS: This is a cross-sectional descriptive study. A questionnaire was sent to all health facilities in Quebec (n=30) and a selection of hospitals in France (n=100). Respondents were asked to answer a questionnaire that included policies and procedures on the use of these medical devices and the conditions of their use at the pharmacy and in healthcare services. RESULTS: In total, 27 respondents from Quebec (response rate: 90%) and 41 respondents from France (response rate: 41%) participated in our survey. In Quebec, all exploitable questionnaires except one (42/43) used five micron filter needles at the pharmacy against 28% of utilisation in healthcare services. In France, this practice is nearly ignored. CONCLUSIONS: Action should be taken to decide on the use of filter needles including studies to confirm the consequences of the presence of these particles on an animal model, discussions with regulatory authorities to clarify the situation, incentives for manufacturers to use vials. PMID- 29145997 TI - Correlation of graft immune composition with outcomes after allogeneic stem cell transplantation: Moving towards a perfect transplant. AB - Allogeneic stem cell transplantation (allo-SCT) offers an important curative therapy for hematological malignancies and other diseases. A number of studies have demonstrated the association of immune compositions in allografts with outcomes after allo-SCT, which promote graft engineering to improve transplant prognosis. This review summarizes the advances in investigating the correlation of the graft immune compositions with transplant outcomes in different transplant modalities, focusing on the immune subsets likely to have the greatest impact on clinical outcomes. The progress made in graft engineering in order to design novel transplant protocols, to decrease graft-versus-host disease and relapse and to improve immune recovery is also discussed. It is our belief that an adoptive immune subset transfer to improve clinical outcomes might represent a future direction. PMID- 29145998 TI - Discussion of: "Impact of geriatric consultations on clinical outcomes of elderly trauma patients: A retrospective analysis". PMID- 29145999 TI - Discussion of: "Pretransfer CT scans are frequently performed, but rarely helpful in rural trauma systems". PMID- 29146000 TI - Discussion of: "Low-grade blunt hepatic injury and benefits of intensive care unit monitoring". PMID- 29146001 TI - What happens after a failed LIFT for anal fistula? AB - BACKGROUND: Ligation of the intersphincteric fistula tract (LIFT) was developed to treat transsphincteric anal fistulas. The aftermath of a failed LIFT has not been well documented. METHODS: Retrospective chart review of LIFT procedure for transsphincteric anal fistula between March 2012 and September 2016. RESULTS: 53 patients with LIFT procedure were identified, 20 (37.7%) had persistent fistula with median followup of 4 months. Following LIFT, recurrence of fistula was transsphincteric (75%) or intersphincteric (25%) (p = NS). Persistent transsphincteric fistulas after LIFT were treated with seton (71.4%) followed by advancement flap (20%) or fistulotomy (50%). Of the recurrent intersphincteric fistulas, 50% underwent seton placement followed by fistulotomy, or advancement flap. Of the patients who underwent surgery after failed LIFT, 50% have had resolution of the fistula; 31.7% are still undergoing treatment. CONCLUSION: Patients who underwent surgery after failed LIFT had 50% healing with placement of seton followed by fistulotomy or rectal advancement flap. PMID- 29146002 TI - Discussion of: "What happens after a failed LIFT for anal fistula?" PMID- 29146003 TI - Imaging features of rosette-forming glioneuronal tumours. AB - AIM: To describe the imaging features of rosette-forming glioneuronal tumours (RGNTs) to enable accurate diagnosis. MATERIALS AND METHODS: Image data and clinical findings for seven patients with histopathologically confirmed RGNTs were studied comprehensively. RESULTS: Six neoplasms were located near the midline and all were relatively well circumscribed. Most lesions were hypointense on T1-weighted images and hyperintense on T2-weighted images. Furthermore, five tumours were hypointense on diffusion-weighted imaging (DWI). On computed tomography (CT), the solid tumour portions showed hypo-attenuation compared with brain parenchyma. Obvious calcification was found in two cases, and hydrocephalus was seen in five. Cerebrospinal fluid (CSF) dissemination and multiple satellite lesions were not observed in these cases. Haemorrhage was found in one case. The "green bell pepper sign" was present in five cases on gadolinium-enhanced magnetic resonance imaging (MRI). Each of the patients accepted surgical treatment, and no recurrences occurred during follow-up. CONCLUSION: RGNTs are very rare mixed glioneuronal tumours and mostly affect young people. They are usually hypointense on T1-weighted images and DWI, hyperintense on T2-weighted images, and hypo-attenuated on CT images. The "green bell pepper sign" after gadolinium enhancement, intratumoural haemorrhage, CSF dissemination, and multiple satellite lesions provide additional clues to the correct diagnosis. A relatively well-demarcated tumour with these features and a midline location should raise suspicion of an RGNT. PMID- 29146004 TI - Comments on increased risk for complications following removal of hardware in patients with liver disease, pilon or pelvic fractures: A regression analysis. PMID- 29146006 TI - Expression of concern on 'The oldest hominin butchery in European mid-latitudes at the Jaramillo site of Untermassfeld (Thuringia, Germany)'. PMID- 29146005 TI - Bone marrow adipocytes in haematological malignancies. AB - Bone marrow adipocytes (BMAs) derived from mesenchymal stem cells (MSC) are an active and significant element of the bone marrow microenvironment. They are involved in metabolic functions, complex interactions with other stromal cells, and in the development and progression of tumours. Currently, there is little data regarding the role of BMAs in haematological malignancies. Due to this, we have attempted to characterise the BMAs in these malignancies in terms of quantity and morphology. Our study included 30 patients aged 22-76 with myelo- (n=17) and lymphoproliferative malignancies (n=13), both with and without bone marrow infiltration. Trepanobioptate was the evaluated material. The number and diameter of BMAs were measured, and the percentage of adipocytes (adipocyte fraction - AF), hematopoietic cells (hematopoietic fraction - HF) and trabecular bone (trabecular bone fraction - BF) was calculated. The obtained results were considered against the clinical parameters of age, sex, body weight, body surface area (BSA) and body mass index (BMI). We observed that as age increases, the number of BMA/mm2, the diameter of adipocytes and AF increase while BF and HF decrease. However, this relationship was not statistically significant. A significant correlation of BMA parameters was also not found in relation to weight, BMI and BSA, and the number and diameter of BMAs were comparable in both sexes. The trepanobioptate of infiltrated bone marrow showed a decreased number of BMA/mm2 compared to the trepanobioptate from bone marrow without infiltration (97.44+/-69.16 vs. 164.14+/-54.16; p=0.010) with a marked difference in men (69.75+/-65.26 vs. 180.33+/-60.40; p=0.007). These trepanobioptate also showed an increase in the number of BMA/mm2 with age (r=0.472; p=0.041), and with an increase of BMI, an increase in diameter of BMAs (r=0.625; p=0.007) and AF (r=0.546; p=0.023). The number and size of BMAs, as well as AF, BF and HF in patients with myeloproliferative malignancies did not differ significantly compared to patients with lymphoproliferative malignancies. PMID- 29146007 TI - [Psoriatic arthritis in France, from infants to the elderly: Findings from two cross-sectional, multicenter studies]. AB - BACKGROUND: Psoriatic arthritis affects 20-30% of patients with psoriasis. Few epidemiological data are available in France about its prevalence and its association with skin lesions and comorbidities. OBJECTIVES: To assess the epidemiological aspects and the risk factors for psoriatic arthritis in children and adults in France. METHODS: Two cross-sectional studies were conducted in France in children (chi-Psocar, 23 pediatric dermatology centers belonging to the SFDP, 1 year) and adults (Resopsocar, 29 dermatology centers belonging to GEM RESOPSO, 4 months) to study the link between psoriasis and cardiovascular and metabolic comorbidities. RESULTS: Three hundred and thirteen children (males: 47.6%; mean age: 9.4 yrs) and 1,954 adults (males: 56.0%; mean age: 48.5 yrs) with psoriasis were included, with 4.2% of the children and 21.0% of the adults presenting psoriatic arthritis. Prevalence increased with age: 2.2% of children, 14.2% of adolescents, and over 20% after 40 years. It decreased after the age of 70 years (19.4%). Regardless of age, arthritis was not associated with gender. In the children's group, rheumatism was associated with nail involvement (P=0.04) and disease severity (P=0.0004). Adult rheumatism was associated with generalized plaque psoriasis (P=0.002), disease severity (P<0.0001), and obesity (P<0.0001). Localized plaque psoriasis was less often associated with arthritis (P<0.05). CONCLUSIONS: These two cross-sectional studies conducted in 2267 patients in France yielded information on the prevalence of joint involvement from infants to elderly subjects. It is the first study conducted in a single population to provide data for the whole population. Prevalence gradually increases with age, without gender difference, before decreasing in old age. We confirm the association of nail involvement in the first years of life, and of obesity in adults. PMID- 29146008 TI - Heat and pregnancy-related emergencies: Risk of placental abruption during hot weather. AB - INTRODUCTION: Outdoor heat increases the risk of preterm birth and stillbirth, but the association with placental abruption has not been studied. Placental abruption is a medical emergency associated with major morbidity and mortality in pregnancy. We determined the relationship between ambient temperature and risk of placental abruption in warm seasons. MATERIAL AND METHODS: We performed a case crossover analysis of 17,172 women whose pregnancies were complicated by placental abruption in Quebec, Canada from May to October 1989-2012. The main exposure measure was the maximum temperature reached during the week before abruption. We computed odds ratios (OR) and 95% confidence intervals (CI) for the association of temperature with placental abruption, adjusted for humidity and public holidays. We assessed whether associations were stronger preterm or at term, or varied with maternal age, parity, comorbidity and socioeconomic status. RESULTS: Compared with 15 degrees C, a maximum weekly temperature of 30 degrees C was associated with 1.07 times the odds of abruption (95% CI 0.99-1.16). When the timing of abruption was examined, the associations were significantly stronger at term (OR 1.12, 95% CI 1.02-1.24) than preterm (OR 0.96, 95% CI 0.83-1.10). Relationships were more prominent at term for women who were younger than 35years old, nulliparous or socioeconomically disadvantaged, but did not vary with comorbidity. Associations were stronger within 1 and 5days of abruption. Temperature was not associated with preterm abruption regardless of maternal characteristics. CONCLUSIONS: Elevated temperatures in warm seasons may increase the risk of abruption in women whose pregnancies are near or at term. Pregnant women may be more sensitive to heat and should consider preventive measures such as air conditioning and hydration during hot weather. PMID- 29146009 TI - Timing of regular egg intake for prevention of egg allergy. PMID- 29146010 TI - Reply. PMID- 29146011 TI - Reply. PMID- 29146012 TI - A biomechanical cadaveric study comparing superior capsule reconstruction using fascia lata allograft with human dermal allograft for irreparable rotator cuff tear. AB - BACKGROUND: Biomechanical and clinical success of the superior capsule reconstruction (SCR) using fascia lata (FL) grafts has been reported. In the United States, human dermal (HD) allograft has been used successfully for SCRs; however, the biomechanical characteristics have not been reported. METHODS: Eight cadaveric shoulders were tested in 5 conditions: (1) intact; (2) irreparable supraspinatus tear; (3) SCR using FL allograft with anterior and posterior suturing; (4) SCR using HD allograft with anterior and posterior suturing; and (5) SCR using HD allograft with posterior suturing. Rotational range of motion, superior translation, glenohumeral joint force, and subacromial contact were measured at 0 degrees , 30 degrees , and 60 degrees of glenohumeral abduction in the scapular plane. Graft dimensions before and after testing were also recorded. Biomechanical parameters were compared using a repeated-measures analysis of variance with Tukey post hoc test, and graft dimensions were compared using a Student t-test (P < .05). RESULTS: Irreparable supraspinatus tear significantly increased superior translation, superior glenohumeral joint force, and subacromial contact pressure, which were completely restored with the SCR FL allografts. Both SCR HD allograft repairs partially restored superior translation and completely restored subacromial contact and superior glenohumeral joint force. The HD allografts significantly elongated by 15% during testing, whereas the FL allograft lengths were unchanged. CONCLUSIONS: Single-layered HD SCR allografts partially restored superior glenohumeral stability, whereas FL allograft SCR completely restored the superior glenohumeral stability. This may be due to the greater flexibility of the HD allograft, and the SCR procedure used was developed on the basis of FL grafts. PMID- 29146014 TI - [Confusion and weight loss]. PMID- 29146013 TI - [Chronic histiocytic intervillositis: Diagnosis and management]. AB - Chronic intervillositis is a rare condition, which is associated with severe obstetrical outcome and high recurrence rate. Obstetrical adverse events are intrauterine growth restriction, recurrent early miscarriages, intrauterine deaths and prematurity by placental insufficiency. The determination of the extension and the intensity of the chronic intervillositis are not currently standardized. High rates of recurrence have been described, but actually there is no reliable predictive biomarker. No treatment is currently validated, but the use of immunomodulatory drugs could be justified by the possible autoimmune or allo-immune origin. The treatment should be particularly discussed in patients with recurrent and severe obstetrical adverse events and in the presence of severe and massive histological lesions. PMID- 29146015 TI - Tablet-based sublingual immunotherapy for respiratory allergy. AB - Allergic respiratory disease represents a significant and expanding health problem worldwide. The gold standard of therapeutic intervention is still grucocorticosteroids, although they are not effective in all patients and may cause side effects. Allergen Immunotherapy has been administrated as subcutaneous injections for treatment of allergic rhinoconjunctivitis and asthma and has been practiced for the past century. Sublingual immunotherapy (SLIT) tablets are now available for grass- or ragweed-induced rhinoconjunctivitis and will be available in Spain for house dust mite (HDM)-induced rhinoconjunctivitis and asthma in the next months. In this review, new developments in the field of tablet-based SLIT for respiratory allergy are summarized, with special emphasis on HDM-induced allergic rhinitis and asthma. SLIT tablets are the best-documented immunotherapy products on the market and represent a more patient-friendly concept because they can be self-administrated at home. PMID- 29146016 TI - Evaluating the performance of the Minute Feedback System: A web-based feedback tool for medical students. AB - BACKGROUND: Medical students often report dissatisfaction with the feedback they receive on their clerkships. This study evaluates the performance of the Minute Feedback System (MFS), a web-based tool designed to facilitate medical student acquisition of same day written feedback from surgery residents and faculty. METHODS: System-generated data, targeted surveys, and end of clerkship questionnaires were used to evaluate MFS performance over a one-year period. RESULTS: 170 students made 3190 feedback requests and received 1978 responses (62% response rate). Students felt the system was easy to use (90%), provided useful feedback (74%), and allowed them to obtain more feedback than they would have in its absence (81%). Concerns were raised regarding the quality of electronic feedback and whether the data generated would be used for summative assessment. CONCLUSIONS: The MFS encourages same-day assessment and increases documented medical student feedback. Further development is required to improve feedback quality, response rates, and feedback application. PMID- 29146017 TI - The need for an epidural "window of opportunity" in pregnant women with a lumbar tattoo. AB - Pregnant women with lower back tattoos who wish to have an epidural placed during labour pose a dilemma to anesthesiologists. Clear guidelines have not been established. We reviewed the epidural risks in pregnant women with low back tattoos and have suggested precautionary measures to minimise them. Given the limited information available, and in the absence of a clear evidence-based medical contraindication, an epidural technique should not be excluded in those women with a lower back tattoo. PMID- 29146019 TI - Every-day coincidences and referential thinking: Differentiating normative experiences from symptoms in psychosis. PMID- 29146018 TI - Biological treatments in giant cell arteritis & Takayasu arteritis. AB - Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are the two main large vessel vasculitides. They share some similarities regarding their clinical, radiological and histological presentations but some pathogenic processes in GCA and TAK are activated differently, thus explaining their different sensitivity to biological therapies. The treatment of GCA and TAK essentially relies on glucocorticoids. However, thanks to major progress in our understanding of their pathogenesis, the role of biological therapies in the treatment of these two vasculitides is expanding, especially in relapsing or refractory diseases. In this review, the efficacy, the safety and the limits of the main biological therapies ever tested in GCA and TAK are discussed. Briefly, anti TNF-alpha agents appear to be effective in treating TAK but not GCA. Recent randomized placebo-controlled trials have reported on the efficacy and safety of abatacept and mostly tocilizumab in inducing and maintaining remission of GCA. Abatacept was not effective in TAK and robust data are still lacking to draw any conclusions concerning the use of tocilizumab in TAK. Furthermore, ustekinumab appears promising in relapsing/refractory GCA whereas rituximab has been reported to be effective in only a few cases of refractory TAK patients. If a biological therapy is indicated, and in light of the data discussed in this review, the first choice would be tocilizumab in GCA and anti-TNF-alpha agents (mainly infliximab) in TAK. PMID- 29146020 TI - Clinical and demographic predictors of continuing remission or relapse following discontinuation of antipsychotic medication after a first episode of psychosis. A systematic review. AB - BACKGROUND: Clinical guidelines recommend maintenance treatment with antipsychotic medication for one to two years following remission of symptoms after a first episode of psychosis. However, recent research has suggested that this may not be indicated. Consistent predictors of outcome would be beneficial to guide clinicians as to which individuals are likely to have a successful discontinuation. OBJECTIVES: This study reviews the literature with the aim of identifying demographic and clinical predictors of either relapse or continued remission in those with a first episode of psychosis following discontinuation of antipsychotic medication. METHODOLOGY: Data Sources: A systematic search of PubMed, CINAHL, and PsychInfo databases was performed. Eligibility Criteria: Cohort, case-control and clinical trials that were published in English, included participants with a first episode of psychosis, and examined clinical and demographic predictors of relapse or continued remission after antipsychotic discontinuation. RESULTS: Eleven studies fulfilled inclusion criteria. No positive findings were replicated across cohorts. Predictors of relapse: male sex, unemployment, prior psychiatric admission, premorbid adjustment, childhood isolation, premorbid functioning, schizoid-schizotypal traits, schizophrenia diagnosis, concomitant medication, and more severe negative symptoms. Some positive findings must be interpreted in the context of conflicting and replicated negative findings: sex, employment status, level of education, premorbid functioning, symptom severity, and schizophrenia diagnosis. Other replicated non-predictive findings: age, ethnicity, marital status, family history, disorganized thoughts, affective symptoms, cannabis abuse, clinical global impression, social integration, duration and dose of antipsychotic treatment, and compliance. CONCLUSION: No positive findings have been replicated across study cohorts. Non-predictive findings have been replicated. PMID- 29146021 TI - Symptom dimensions and subgroups in childhood-onset schizophrenia. AB - OBJECTIVE: This study investigated symptom dimensions and subgroups in the National Institute of Mental Health (NIMH) childhood-onset schizophrenia (COS) cohort and their similarities to adult-onset schizophrenia (AOS) literature. METHOD: Scores from the Scales for the Assessment of Positive and Negative Symptoms (SAPS & SANS) from 125 COS patients were assessed for fit with previously established symptom dimensions from AOS literature using confirmatory factor analysis (CFA). K-means cluster analysis of each individual's scores on the best fitting set of dimensions was used to form patient clusters, which were then compared using demographic and clinical data. RESULTS: CFA showed the SAPS & SANS data was well suited to a 2-dimension solution, including positive and negative dimensions, out of five well established models. Cluster analysis identified three patient groups characterized by different dimension scores: (1) low scores on both dimensions, (2) high negative, low positive scores, and (3) high scores on both dimensions. These groups had different Full scale IQ, Children's Global Assessment Scale (CGAS) scores, ages of onset, and prevalence of some co-morbid behavior disorders (all p<3.57E-03). CONCLUSION: Our analysis found distinct symptom-based subgroups within the NIMH COS cohort using an established AOS symptom structure. These findings confirm the heterogeneity of COS and were generally consistent with AOS literature. PMID- 29146022 TI - Performance of J-CTO and PROGRESS CTO Scores in Predicting Angiographic Success and Long-term Outcomes of Percutaneous Coronary Interventions for Chronic Total Occlusions. AB - Patient selection for and predicting clinical outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) remain challenging. We hypothesized that both J-CTO (Multicenter Chronic Total Occlusion Registry of Japan) and PROGRESS CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) scores will predict not only angiographic success but also long-term clinical outcomes of the patients who underwent PCI of CTO. Of 325 CTO PCIs performed at 2 Emory University hospitals from January 2012 to August 2015, 249 patients with complete baseline clinical, angiographic and follow-up data, were included in this analysis. Major adverse cardiovascular events (MACEs) consisted of a composite of death, myocardial infarction, and target vessel revascularization. Mean age was 63 +/- 11 years old and mean follow up was 19.8 +/- 13.1 months. Angiographic success rates increased from 74.5% in 2012 to 85.7% in 2015. Greater J-CTO and PROGRESS CTO scores were not only associated with lower likelihood of angiographic success but also higher rates of long-term MACE. Compared with the scores of 0 to 2, J-CTO and PROGRESS CTO scores of >=3 were associated with higher MACE. Multivariable analysis demonstrated that PROGRESS CTO scores of >=3, male sex, and peripheral vascular disease were independent predictors of MACE. In conclusion, J-CTO and PROGRESS CTO scores are useful in predicting procedural success. In addition, the PROGRESS CTO score, and to a lesser degree J-CTO score, have predictive value for long-term outcomes in patients who underwent CTO PCI. PMID- 29146023 TI - Longitudinal Associations of Pericardial and Intrathoracic Fat With Progression of Coronary Artery Calcium (from the Framingham Heart Study). AB - Cross-sectional studies have shown that pericardial fat is associated with atherosclerotic burden above and beyond generalized and central adiposity. Whether pericardial fat is longitudinally associated with coronary artery calcium (CAC) has not been firmly established. We examined the associations between cardiac ectopic fat including pericardial and intrathoracic fat with CAC progression and incidence in a community-based study setting. Study participants were from the Framingham Heart Study Offspring and Third Generation Cohorts who underwent multidetector computed tomography at 2 consecutive examinations (2002 to 2005 and 2008 to 2011) for the assessment of CAC. Multivariable-adjusted regression models were used to evaluate the associations between cardiac ectopic fat with CAC. Nonlinear associations were also examined. We included 1,732 participants (49.6% women, mean age 49.9 years). Of the 1,024 participants with a CAC score = 0 at baseline, 197 individuals developed a CAC score > 0 (19.2%) during 6.1 years of follow-up. The remaining 708 participants with a CAC score > 0 at baseline were eligible for CAC progression analysis. We identified nonlinear association between pericardial fat and CAC progression. Higher pericardial fat was associated with higher CAC progression only for those participants with pericardial fat higher than the median value (beta = 56.0, p = 0.04). Intrathoracic fat was linearly associated with CAC progression (beta = 23.0, p = 0.02). However, all of these associations did not persist after additional adjustment for body mass index, abdominal visceral adipose tissue, or waist circumference (all p >= 0.14). Neither pericardial nor intrathoracic fat were associated with CAC incidence (all p >= 0.33). Overall, both of the cardiac ectopic fat measures were longitudinally associated with CAC progression. PMID- 29146024 TI - Effect of Serum Albumin Concentration on Neurological Outcome After Out-of Hospital Cardiac Arrest (from the CRITICAL [Comprehensive Registry of Intensive Cares for OHCA Survival] Study in Osaka, Japan). AB - The aim of this study was to assess whether serum albumin concentration upon hospital arrival had prognostic indications on out-of-hospital cardiac arrest (OHCA). This prospective, multicenter observational study conducted in Osaka, Japan (the CRITICAL [Comprehensive Registry of Intensive Cares for OHCA Survival] study), enrolled all patients with consecutive OHCA transported to 14 participating institutions. We included adult patients aged >=18 years with nontraumatic OHCA who achieved return of spontaneous circulation and whose serum albumin concentration was available from July 2012 to December 2014. Based on the serum albumin concentration upon hospital arrival, patients were divided into quartiles (Q1 to Q4), namely, Q1 (<2.7 g/dl), Q2 (2.7 to 3.1 g/dl), Q3 (3.1 to 3.6 g/dl), and Q4 (>=3.6 g/dl). The primary outcome was 1-month survival with favorable neurological outcome (cerebral performance category scale 1 or 2). During the study period, a total of 1,269 patients with OHCA were eligible for our analyses. The highest proportion of favorable neurological outcome was 33.5% (109 of 325) in the Q4 group, followed by 13.2% (48 of 365), 5.0% (13 of 261), and 3.5% (11 of 318) in the Q3, Q2, and Q1 groups, respectively. In the multivariable logistic regression analysis, the proportion of favorable neurological outcome in the Q4 group was significantly higher, compared with that in the Q1 group (adjusted odds ratio 8.61; 95% confidence interval 4.28 to 17.33). The adjusted proportion of favorable neurological outcome increased in a stepwise manner across increasing quartiles (p for trend <0.001). Higher serum albumin concentration was significantly and independently associated with favorable neurological outcome in a dose-dependent manner. PMID- 29146025 TI - Pain and Its Control in Reptiles. AB - Reptiles have the anatomic and physiologic structures needed to detect and perceive pain. Reptiles are capable of demonstrating painful behaviors. Most of the available literature indicates pure MU-opioid receptor agonists are best to provide analgesia in reptiles. Multimodal analgesia should be practiced with every reptile patient when pain is anticipated. Further research is needed using different pain models to evaluate analgesic efficacy across reptile orders. PMID- 29146026 TI - Vaccination of Ferrets for Rabies and Distemper. AB - Companion ferrets need to be vaccinated against 2 viral diseases that cause neurologic illness: canine distemper and rabies. Although not common in ferrets, both viruses are fatal in ferrets and rabies virus is also fatal in humans. In this article, we provide a basic review of the 2 diseases, highlighting key neurologic concerns. We also review and update current vaccine concerns from a practitioner's perspective, including available vaccines, vaccine schedule recommendations, vaccine reactions, and risk assessment. Last, we mention the ferret and its use in cutting-edge vaccine development. PMID- 29146027 TI - Medication for Behavior Modification in Birds. AB - The use of behavior modifying drugs may be considered in birds with behavior problems, especially those refractory to behavior modification therapy and environmental management. To accomplish behavior change, a variety of drugs can be used, including psychoactive drugs, hormones, antihistamines, analgesics, and anticonvulsants. Because their prescription to birds is off-label, these drugs are considered appropriate only when a sound rationale can be provided for their use. This requires a (correct) behavioral diagnosis to be established. In addition, regular monitoring and follow-up are warranted to determine the efficacy of the treatment and evaluate the occurrence of potential adverse side effects. PMID- 29146028 TI - Functional and Anatomic Correlates of Neural Aging in Birds. AB - Avian species show variation in longevity, habitat, physiologic characteristics, and lifetime endocrine patterns. Lifetime reproductive and metabolic function vary. Much is known about the neurobiology of the song system in many altricial birds. Little is known about aging in neural systems in birds. Captive birds often survive beyond the age they would in the wild, providing an opportunity to gain an understanding of the physiologic and neural changes. This paper reviews the available information with the goal of capturing areas of potential investigation into gaps in our understanding of neural aging as reflected in physiologic, endocrine, and cognitive aging. PMID- 29146029 TI - Gut Brain Axis and Its Microbiota Regulation in Mammals and Birds. AB - This article provides a brief overview of the advances made in microbiota research in parrots and pet birds. It describes this complex ecosystem and the contribution of the intestinal microbiota to host health and disease, including the nervous system. PMID- 29146030 TI - Pain in Birds: The Anatomical and Physiological Basis. AB - This article reviews the current understanding of the anatomy and physiology of pain in birds, with consideration of some of its differences from mammalian pain. From transduction to transmission, modulation, projection, and perception, birds possess the neurologic components necessary to respond to painful stimuli and they likely perceive pain in a manner similar to mammals. This article also describes the current understating of opioid receptors, inflammatory mediators, and additional factors in the modulation of pain in avian species. PMID- 29146031 TI - Avian Ganglioneuritis in Clinical Practice. AB - Avian ganglioneuritis (AG) comprises one of the most intricate pathologies in avian medicine and is researched worldwide. Avian bornavirus (ABV) has been shown to be a causative agent of proventricular dilatation disease in birds. The avian Bornaviridae represent a genetically diverse group of viruses that are widely distributed in captive and wild populations around the world. ABV and other infective agents are implicated as a cause of the autoimmune pathology that leads to AG, similar to human Guillain Barre syndrome. Management of affected birds is beneficial and currently centered at reducing neurologic inflammation, managing secondary complications, and providing nutritional support. PMID- 29146032 TI - Clinical Signs, Diagnosis, and Treatment of Encephalitozoon cuniculi Infection in Rabbits. AB - Central vestibular dysfunction caused by Encephalitozoon cuniculi frequently mimics the condition of a peripheral disorder. A negative antibody titer rules out E cuniculi as the cause of present clinical signs. Cerebrospinal fluid analysis including polymerase chain reaction is considered an inappropriate diagnostic method for in vivo diagnosis of encephalitozoonosis. The usefulness of glucocorticoid anti-inflammatories in the treatment of encephalitozoonosis is called into question. Encouraging activity early in the course of disease and adding in therapeutic exercise may represent the most important part of therapy in rabbits with vestibular dysfunction associated with encephalitozoonosis. PMID- 29146033 TI - Analgesics in Small Mammals. AB - Managing pain effectively in any species is challenging, but small mammals present particular problems. Methods of pain assessment are still under development in these species, so the efficacy of analgesic therapy cannot be evaluated fully. Methods of assessing abdominal pain are established; however, applying these can be challenging. Alternative methods, using assessment of facial expression, may be more applicable to a range of painful procedures and across species. Multimodal and preventive analgesic strategies are most likely to be effective. Although data on analgesic dose rates are limited, sufficient information is available to enable analgesia to be provided safely. PMID- 29146034 TI - Preface. PMID- 29146035 TI - Renal outcomes with dipeptidyl peptidase-4 inhibitors. AB - Dipeptidyl peptidase-4 inhibitors (DPP-4is) are increasingly being used in the management of type 2 diabetes (T2D). The present review summarizes the current knowledge of the effects of DPP-4is on renal outcomes by analyzing the experimental preclinical data, the effects of DPP-4is on urinary albumin creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) from observational studies and clinical trials, and renal events (including kidney failure requiring renal replacement therapy) in recent large prospective cardiovascular outcome trials. Renal protection has been demonstrated in various animal models that have implicated different underlying mechanisms independent of glucose control, whereas prevention of new onset microalbuminuria and/or progression of albuminuria has been reported in some clinical studies, but with no significant effects on eGFR in most of them. The long-term clinical effects of DPP-4is on renal outcomes and the development of end-stage renal disease remain largely unknown and, thus, demand further investigations in prospective trials and long-term observational studies. In conclusion, despite promising results in animal models, data on surrogate biological markers of renal function and clinical renal outcomes remain rather scanty in patients with T2D, and mostly demonstrate the safety rather than true efficacy of DPP-4is. PMID- 29146036 TI - Long-term outcomes after infected mini-open rotator cuff repair: results of a 10 year review. AB - BACKGROUND: Infection after rotator cuff repair (RCR) is uncommon. There are few reports in the literature regarding the management and long-term results of patients in whom deep infection of the shoulder develops after RCR. The objective of this study was to assess the long-term clinical and radiologic outcomes of these patients. METHODS: We retrospectively reviewed a consecutive series of 764 patients after mini-open RCR in which 9 patients had postoperative infection. The demographic data, clinical and laboratory findings, risk factors, bacteriologic findings, and results of surgical management were analyzed. All patients underwent clinical and radiologic assessment at long-term follow-up of approximately 10 years after infection. RESULTS: The mean age of the patients was 56.2 years. The mean time to presentation for infection after RCR was 16 days. All patients had pain on presentation, and 6 patients had persistent discharge from their wounds with erythema. The most common organism was Staphylococcus aureus. At final follow-up at a mean of 11.62 years after surgery, the mean Simple Shoulder Test score was 10.5 and the mean Constant score was 70. The rotator cuff was intact in 5 of 7 patients. CONCLUSION: With appropriate treatment, eradication of infection can be achieved, and in appropriate cases, anchors can be retained. Reasonable long-term functional outcome scores can be achieved. PMID- 29146037 TI - Comparative effectiveness research methodology using secondary data: A starting user's guide. AB - BACKGROUND: The use of secondary data, such as claims or administrative data, in comparative effectiveness research has grown tremendously in recent years. PURPOSE: We believe that the current review can help investigators relying on secondary data to (1) gain insight into both the methodologies and statistical methods, (2) better understand the necessity of a rigorous planning before initiating a comparative effectiveness investigation, and (3) optimize the quality of their investigations. MAIN FINDINGS: Specifically, we review concepts of adjusted analyses and confounders, methods of propensity score analyses, and instrumental variable analyses, risk prediction models (logistic and time-to event), decision-curve analysis, as well as the interpretation of the P value and hypothesis testing. CONCLUSIONS: Overall, we hope that the current review article can help research investigators relying on secondary data to perform comparative effectiveness research better understand the necessity of a rigorous planning before study start, and gain better insight in the choice of statistical methods so as to optimize the quality of the research study. PMID- 29146038 TI - Microbiological monitoring of medical devices after cleaning, disinfection and sterilisation. AB - The use of reusable semi-critical devices has been extended in current medical practice for both diagnostic and therapeutic purposes. However, reuse of these instruments carries the risk of cross-transmission of microorganisms from one patient to another. The process of cleaning and disinfecting these devices is complex, long, expensive and very error-prone. This paper analyses the epidemiological aspects of infections associated with the reuse of semi-critical devices and the role of the Microbiology laboratory in monitoring the cleaning and disinfecting process through microbiological controls. The recommendations of different scientific societies on the relevance of such controls are reviewed and specific recommendations are proposed for the taking and processing of the samples, interpretation of the results and measures to be taken depending on the results obtained. PMID- 29146039 TI - Clinical features and outcomes of bacteraemia due to OXA-48-like carbapenemase producing Klebsiella pneumoniae in a tertiary hospital. AB - INTRODUCTION: Limited therapeutic options and high mortality make the management of OXA-48-like carbapenemase-producing Klebsiella pneumoniae (KPOXA-48) bacteraemia complicated. The aim of the study was to describe the clinical characteristics of KPOXA-48 bacteraemia between October 2013 and December 2016. MATERIAL AND METHODS: The variables to analyse were retrospectively collected from medical records. Carbapenemase production was confirmed by phenotypic and molecular methods. RESULTS: A total of 38 patients with bacteraemia were included, mainly classified as hospital-acquired (n=31). The majority of cases were secondary bacteraemia (n=26), most commonly arising from the urinary tract (n=11). All isolates presented a multidrug-resistant profile with the extended spectrum beta-lactamase CTX-M-15 and the carbapenemase OXA-48-like production. The crude mortality rate with adequate targeted antibiotic therapy was 0%, rising to 55% with inadequate treatment (p=0.0015). CONCLUSIONS: This study highlights the importance of identifying this resistance mechanism, the patient factors, type of bacteraemia and adequacy of antibiotic therapy in the outcome of bacteraemia. PMID- 29146040 TI - [Effectiveness, therapeutic maintenance and reasons for stopping tocilizumab (TCZ): A retrospective and monocentric study in 88 patients followed for rheumatoid arthritis (RA) at the Reims university hospital]. AB - OBJECTIVE: Study the therapeutic maintenance, efficacy and reasons for tocilizumab stop in daily practice. PATIENTS AND METHODS: A monocentric, retrospective study of patients treated for rheumatoid arthritis who received at least one TCZ infusion between January 2009 and December 2015. Therapeutic maintenance was evaluated using the Kaplan-Meier method. The efficacy of TCZ was measured by DAS28 and the EULAR response. Reasons for stopping and new treatment lines were also collected. RESULTS: Of the 88 patients (83% women and 17% men) who were included, the mean age was 54+/-12.5 years. There were 75% positive rheumatoid factors and 76% positive anti-CCP. The mean duration of the follow-up was 31 months. TCZ was used as monotherapy in 24 patients (27%). Before the introduction of TCZ, the mean DAS28 was 5.07+/-1.32. The EULAR response at 1 year in patients still under treatment (n=63) was obtained in 59 (93.7%) patients, 46 good responders and 13 moderate responders. Therapeutic maintenance was 82.9%, 72.5%, 68.7% and 57.2%, respectively, at 12, 24, 36 and 54 months. Twenty-eight patients (32%) followed TCZ, 10 for adverse events and 14 for ineffectiveness. Abatacept was the main new therapeutic line. CONCLUSION: The therapeutic maintenance of TCZ in common practice over a long period of follow-up is similar to pivotal studies. Efficacy data are reassuring in the long-term. PMID- 29146041 TI - Urinary retention associated with aripiprazole: Report of a new case and review of the literature. PMID- 29146042 TI - Outcomes of an online computerized cognitive behavioral treatment program for treating chinese patients with depression: A pilot study. AB - OBJECTIVE: This pilot study examined the feasibility, safety, and effectiveness of using an online computerized cognitive behavioral therapy (CBT) for treating Chinese patients with depression. METHODS: Seventy-five Chinese patients with depression in outpatient clinics were randomized into a 5-week intervention. The intervention group received the Chinese translated version of MoodGYM in addition to usual treatment, and the control group continued with usual treatment. Participants completed the 20-item Center for Epidemiologic Studies Depression Scale (CES-D) pre- and post-intervention. RESULTS: We conducted multivariate linear regression analyses to compare the change in CES-D scores for completers after the intervention. Seventy-eight percent (n=29) of participants in the intervention group and 84% (n=32) of patients in the control group completed the post-treatment assessments, and no serious adverse events were reported. Results indicated that while both groups significantly improved at post test, the intervention group improved significantly more than the control group (t(59)=2.37, p=0.02). CONCLUSION: Computerized CBT can be a cost-effective adjunct to medication treatment, particularly in areas with limited access to mental health services. The use of online computerized CBT has been found to be effective in many studies in Western countries, but has not been studied among Chinese outpatients. This study suggests that online computerized CBT is acceptable, and that MoodGYM is a feasible and efficacious augmentative treatment, specifically when used within an outpatient clinic population. With this small sample size we were able to demonstrate that the addition of MoodGYM to usual care improved treatment outcomes for outpatients with depression in China. PMID- 29146043 TI - Dose dependent hyponatremia caused by Vilazodone: A case report. PMID- 29146044 TI - Synthetic marijuana is no more marijuana. PMID- 29146045 TI - Amisulpride Induced Oropharyngeal Dyskinesia in a patient with Schizophrenia: A case report and review of literature. PMID- 29146046 TI - Influence of different smear layers on bond durability of self-etch adhesives. AB - OBJECTIVE: The purpose of this study was to determine the influence of different smear layers on enamel and dentin bond durability of various types of self-etch adhesives. METHODS: Two universal adhesives, Scotchbond Universal (SU) and Prime & Bond elect (PE); a conventional single-step self-etch adhesive, G-aenial Bond (GB); and two two-step self-etch adhesives, Optibond XTR (OX) and Clearfil SE Bond (SE) were used in this study. Shear bond strengths (SBS) and shear fatigue strengths (SFS) to human enamel and dentin were determined with different smear layer conditions. The prepared specimens were divided into three groups. The bonding surfaces were prepared by grinding with either (1) #180, (2) #600, or (3) #4000-SiC papers before making the bonded assemblies. For each group, 15 specimens were prepared for the SBS and 30 specimens for the SFS. RESULTS: The two-step self-etch adhesives showed significantly higher SFS values than the single-step self-etch adhesives, regardless of the smear layer condition or substrate. Although most of the tested adhesives showed no significant differences in enamel SFS values among the smear layer groups, SU, GB, and SE showed significantly lower SFS values in the #180 in dentin groups than the #600 and #4000 groups. CONCLUSION: The influence of different smear layer conditions on bond durability was adhesive dependent. Furthermore, the smear layers generated on different substrates also influenced the bond quality of the self etch adhesives. SIGNIFICANCE: Smear layer conditions of enamel and dentin influence the bond durability of universal adhesives and conventional single and two-step self-etch adhesives. PMID- 29146047 TI - Maternal Immune Activation Delays Excitatory-to-Inhibitory Gamma-Aminobutyric Acid Switch in Offspring. AB - BACKGROUND: The association between maternal infection and neurodevelopmental defects in progeny is well established, although the biological mechanisms and the pathogenic trajectories involved have not been defined. METHODS: Pregnant dams were injected intraperitoneally at gestational day 9 with polyinosinic:polycytidylic acid. Neuronal development was assessed by means of electrophysiological, optical, and biochemical analyses. RESULTS: Prenatal exposure to polyinosinic:polycytidylic acid causes an imbalanced expression of the Na+-K+-2Cl- cotransporter 1 and the K+-Cl- cotransporter 2 (KCC2). This results in delayed gamma-aminobutyric acid switch and higher susceptibility to seizures, which endures up to adulthood. Chromatin immunoprecipitation experiments reveal increased binding of the repressor factor RE1-silencing transcription (also known as neuron-restrictive silencer factor) to position 509 of the KCC2 promoter that leads to downregulation of KCC2 transcription in prenatally exposed offspring. Interleukin-1 receptor type I knockout mice, which display braked immune response and no brain cytokine elevation upon maternal immune activation, do not display KCC2/Na+-K+-2Cl- cotransporter 1 imbalance when implanted in a wild-type dam and prenatally exposed. Notably, pretreatment of pregnant dams with magnesium sulfate is sufficient to prevent the early inflammatory state and the delay in excitatory-to-inhibitory switch associated to maternal immune activation. CONCLUSIONS: We provide evidence that maternal immune activation hits a key neurodevelopmental process, the excitatory-to-inhibitory gamma-aminobutyric acid switch; defects in this switch have been unequivocally linked to diseases such as autism spectrum disorder or epilepsy. These data open the avenue for a safe pharmacological treatment that may prevent the neurodevelopmental defects caused by prenatal immune activation in a specific pregnancy time window. PMID- 29146048 TI - Cerebellar Volume in Autism: Literature Meta-analysis and Analysis of the Autism Brain Imaging Data Exchange Cohort. AB - BACKGROUND: The neuroanatomical bases of autism spectrum disorder remain largely unknown. Among the most widely discussed candidate endophenotypes, differences in cerebellar volume have been often reported as statistically significant. METHODS: We aimed at objectifying this possible alteration by performing a systematic meta analysis of the literature and an analysis of the ABIDE (Autism Brain Imaging Data Exchange) cohort. Our meta-analysis sought to determine a combined effect size of autism spectrum disorder diagnosis on different measures of the cerebellar anatomy as well as the effect of possible factors of variability across studies. We then analyzed the cerebellar volume of 328 patients and 353 control subjects from the ABIDE project. RESULTS: The meta-analysis of the literature suggested a weak but significant association between autism spectrum disorder diagnosis and increased cerebellar volume (p = .049, uncorrected), but the analysis of ABIDE did not show any relationship. The studies meta-analyzed were generally underpowered; however, the number of statistically significant findings was larger than expected. CONCLUSIONS: Although we could not provide a conclusive explanation for this excess of significant findings, our analyses would suggest publication bias as a possible reason. Finally, age, sex, and IQ were important sources of cerebellar volume variability, although independent of autism diagnosis. PMID- 29146049 TI - Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort. AB - TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFkappaB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13-1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts. PMID- 29146051 TI - Beta-catenin and p53 expression in topographic compartments of colorectal cancer and its prognostic value following surgery. AB - Colorectal cancer (CRC) is the third most prevalent neoplasm worldwide and the fourth cause of cancer-related death. From Vogelstein's initial model, new molecular knowledge has been incorporated which includes an elevated number of genetic mutations, many of them located in the Wnt pathway, which affect its principle effector: beta-catenin. Additionally, it is necessary to keep the heterogeneity of CRCs in mind, both in terms of morphology and biology. The aim of this work is to study the interaction between the Wnt molecular pathway, by means of immunoexpression of beta-catenin, in CRC and other molecular mechanisms, such as the p53 pathway, in order to determine the pattern - if one exists - of different immunohistochemical expression of beta-catenin and p53 in the superficial and deep tumor components, and lastly, to determine the impact of these markers on prognosis. Our cases showed an increasing gradient of beta catenin immunoexpression that parallels depth in the tumor, with a greater degree of nuclear immunoexpression in the deep compartment. We observe that in those cases with positivity for nuclear p53 and an absence of immunostaining of beta catenin show higher rates of survival, whereas one of the lowest rates was observed in patients who co-expressed p53 and beta-catenin. We conclude that a combined analysis of beta-catenin and p53 could have prognostic importance as markers for predicting the disease's progression and contribute to the identification of patients with a high risk of mortality. PMID- 29146052 TI - Phenotypic alterations in breast cancer associated with neoadjuvant chemotherapy: A comparison with baseline rates of change. AB - Several studies have documented phenotypic alterations in breast cancer associated with neoadjuvant chemotherapy [NACT], but many of these studies are limited by the fact that they did not account for the baseline rate of expected phenotypic change between biopsies and resections in the absence of NACT. Herein, we assess whether the NACT-associated rate of phenotypic change is significantly different than would be expected in a control population of patients that did not receive NACT. From a pathologic database, we documented the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2/neu) phenotypes of consecutive invasive breast carcinomas (n=826), as well as the subset in which at least one of these tests was assessed in both the biopsy and resection (n=340). We then compared the rates of phenotypic change in the patients that did (n=65) and did not (n=275) receive NACT. Respectively, 49.2% and 36% of the NACT and non-NACT groups showed a biopsy-to-resection change in status for at least one biomarker (p=0.0005). The NACT and non-NACT groups showed the following respective rates of a biopsy-to-resection change in phenotype: ER (9.2% vs 2.5%, p=0.02); PR (30.7% vs 8%, p=0.000006); Her2/neu-IHC (25% vs 22.3%, p=0.7), Her2/neu-FISH (7% vs 3%, p=0.6). The direction of change in the NACT group was positive in the biopsy to negative in the resection in >70% of cases for all markers. For ER and PR, there was no statistically significant difference between cases that showed a biopsy-to-excision change in phenotype and those that were more phenotypically stable regarding a wide array of clinicopathologic variables. The average percentage of ER/PR-immunoreactive tumor cells in the pre-NACT biopsies was significantly lower in the phenotypically altered cases as compared to the phenotypically stable cases. Our findings confirm that phenotypic alterations in breast cancer occur after NACT, and that these changes are more pronounced for hormone receptors (especially PR); Significant NACT-associated alterations were not apparent for HER2/neu. A distinct pathologic profile for cases displaying a phenotypic change within the NACT group was not demonstrable. The pre-NACT levels of ER and PR may affect the likelihood of a phenotypic change. These results highlight the need for repeat testing in residual tumors after NACT. PMID- 29146050 TI - Progranulin plasma levels predict the presence of GRN mutations in asymptomatic subjects and do not correlate with brain atrophy: results from the GENFI study. AB - We investigated whether progranulin plasma levels are predictors of the presence of progranulin gene (GRN) null mutations or of the development of symptoms in asymptomatic at risk members participating in the Genetic Frontotemporal Dementia Initiative, including 19 patients, 64 asymptomatic carriers, and 77 noncarriers. In addition, we evaluated a possible role of TMEM106B rs1990622 as a genetic modifier and correlated progranulin plasma levels and gray-matter atrophy. Plasma progranulin mean +/- SD plasma levels in patients and asymptomatic carriers were significantly decreased compared with noncarriers (30.5 +/- 13.0 and 27.7 +/- 7.5 versus 99.6 +/- 24.8 ng/mL, p < 0.00001). Considering the threshold of >61.55 ng/mL, the test had a sensitivity of 98.8% and a specificity of 97.5% in predicting the presence of a mutation, independent of symptoms. No correlations were found between progranulin plasma levels and age, years from average age at onset in each family, or TMEM106B rs1990622 genotype (p > 0.05). Plasma progranulin levels did not correlate with brain atrophy. Plasma progranulin levels predict the presence of GRN null mutations independent of proximity to symptoms and brain atrophy. PMID- 29146053 TI - Usefulness of a direct immunofluorescence in the diagnosis of plaque type oral lichen planus. PMID- 29146054 TI - Lymphocytic thrombophilic arteritis: A distinct inflammatory type I interferon and C5b-9 mediated subcutaneous endovasculitis. AB - BACKGROUND: Lymphocytic thrombophilic arteritis is a recently recognized subcuticular larger vessel vasculitis characterized by striking vascular luminal thrombosis. METHODS: The clinical features, histopathology and phenotypic profile of ten patients with lymphocytic thrombophilic arteritis were explored in an attempt to better define the entity from a clinical and pathophysiologic perspective. RESULTS: The patients were all female (mean age of 43) presenting with generally asymptomatic lower and upper extremity hyperpigmented macules. A consistent picture diagnostic of a connective tissue disease syndrome was not seen. The disease was not progressive although it was typically persistent. The morphology was characterized by a temporally heterogeneous subcutaneous arteritis targeting the endothelium and intima with changes ranging from incipient intimal expansion by hyaluronic acid to concentric intimal fibrin deposition to one of an end stage acellular intraluminal obliterative fibrous arteriopathy. The infiltrate was predominated by lymphocytes and histiocytes. The intimal elastic lamina was intact in most cases. All tested cases showed intimal and endothelial C5b-9 deposition, an upregulated type I interferon microenvironment and marked upregulation of the inducible interferon gamma 16 protein. CONCLUSIONS: Lymphocytic thrombophilic arteritis is a unique form of C5b-9 mediated arteritic endotheliopathy where the brunt of the changes involves the endothelium and intima and that is morphologically distinct from the transmural arteritis of benign cutaneous polyarteritis nodosa. PMID- 29146055 TI - IMP3 contributes to poor prognosis of patients with metaplastic breast carcinoma: A clinicopathological study. AB - Metaplastic breast carcinoma (MBC) is a rare type of tumor with heterogenous histological patterns. We investigated the immunohistochemical expression of IMP3, an oncofetal protein, in 31 MBC patients in association with histological subtypes and clinical outcomes. The cohort consisted of spindle cell carcinoma (SPC) (n=11), squamous cell carcinoma (SCC) (n=14), matrix-producing carcinoma (MPC) (n=4), carcinoma with osteocartilaginous elements (COC) (n=1), and low grade adenosquamous cell carcinoma (ASC) (n=1). IMP3 expression was identified in 7 cases of SPC (64%) and 6 patients of all the other subtypes (p=0.051). In comparison between IMP3 high (n=13) and low (n=18) groups, a large-sized tumor (>=4.0cm) was identified in 9 IMP3 high patients, and 14 IMP3 low patients had a small-sized tumor (p=0.01). High Ki67 positivity was detected in all of the IMP3 high patients and in 7 of the IMP3 low patients (p=0.002). During the follow-up period, 9 IMP3 high patients died, whereas 15 of the 18 IMP3 low patients remained alive (p=0.004). A univariate analysis revealed that IMP3 expression and tumor size were significantly associated with poor clinical outcomes (p=0.03 and <0.001, respectively). The IMP3 high group was likely to be associated with reduced overall survival compared to the IMP3 low group (p=0.06). These findings indicate that IMP3 may contribute to the aggressive behavior of MBC, and that this expression could potentially be a prognostic marker of MBC. PMID- 29146056 TI - Comparison of HER2 status determination methods in HER2 (2+) patients: Manual fluorescent in situ hybridization (FISH) vs. dual silver enhanced in situ hybridization (SISH). AB - HER2 amplification has been demonstrated in 15-25% of invasive breast carcinomas and can be assessed using immunohistochemical and in situ hybridization methods. Here, we compared the accuracy of dual SISH to manual FISH in HER2 (2+) breast carcinoma and evaluated the feasibility of dual SISH method in routine practice. Sixty HER2 (2+) consecutive tumor samples diagnosed between January 2009 and February 2013 were selected. Demographic, histological and immunohistochemical features and FISH results were recruited from patient records and compared to dual SISH results. Nine (15%) of the 60 tumor samples were excluded from statistical analysis due to lack of interpretable SISH signals. HER2 staining percentages by immunohistochemistry differed between 20 and 80%. HER2 amplification was shown in 7 (13.7%) and 8 (15.7%) patients by FISH and SISH, respectively. Very good agreement was observed between FISH and SISH methods (kappa value: 0.92). Significant correlation was found between HER2 staining percentage and FISH positivity, in contrast to SISH positivity (p=0.012 vs. p=0.069). Our results are consistent with previously reported literature, indicating SISH can be used to determine HER2 status. However, preanalytical and analytical problems may cause inadequate or uncountable signals, making interpretation impossible for the pathologist and highlighting the importance of standardization and quality control programs. PMID- 29146057 TI - Role of angiogenesis in colorectal carcinomas using VEGF and BCl2: An IHC study. PMID- 29146058 TI - Methylation-associated silencing of SFRP1 gene in high-grade serous ovarian carcinomas. AB - Wnt is a highly conserved signaling pathway responsible for tissue regeneration, maintenance and differentiation of stem cells in adults. Its aberrant activation through reduced expression of Wnt signaling pathway inhibitors, such as proteins from the SFRP family, is commonly seen in many tumors. In the present study we explored SFRP1 protein expression using immunohistochemistry in 11 low-grade serous ovarian carcinomas (LGSC), 42 high-grade serous ovarian carcinomas (HGSC), and 5 normal ovarian tissues (controls). SFRP1 gene methylation was analyzed by methylation-specific PCR in 8 LGSCs, 13 HGSCs and control samples. SFRP1 gene was unmethylated and SFRP1 protein expression was strong in normal ovaries (n=5). Although SFRP1 gene was unmethylated in almost all of the LGSC cases (7/8, 88%), SFRP1 protein expression was significantly lower than in normal ovaries (p<0.05). Seven out of 13 HGSCs (54%) showed SFRP1 gene hypermethylation and protein expression level was also significantly lower than in normal ovaries (p<0.001). Our preliminary data show loss of SFRP1 protein expression caused by the SFRP1 promoter hypermethylation in a subset of HGSCs. SFRP1 protein expression was also lost in LGSCs but different regulatory mechanisms may be involved. Further studies should elucidate the clinical and therapeutic relevance of the observed molecular alterations. PMID- 29146059 TI - Oral Lymphomatoid papulosis type C: A diagnostic pitfall, often confused with T cell lymphoma. AB - Eosinophilic ulcer of the oral mucosa (EUOM) is a rare, benign, self-resolving lymphoproliferative disorder, which typically presents with asymptomatic to mildly tender ulcers. Histological findings of EUOM are characterized by a polymorphic infiltrate with many eosinophils often extending into the underlying muscle. Although this entity is well documented within the dental literature, it is not well known to physicians. The pathogenesis of the condition is unclear, although reports dating back to 1997 suggest that at least a subset of EUOM represents CD30 positive lymphoproliferative disorder (CD30+ LPD). More specifically the original report and subsequent authors suggest that the patients fall on the spectrum of CD30+ LPD most reminiscent of Lymphomatoid papulosis (LyP) seen in the skin. This oral variant of LyP would be expected to have the same diverse morphologic spectrum as that seen in cutaneous LyP. We present five EUOM patients whose biopsies showed an atypical lymphocytic infiltrate most compatible with Type C LyP, a histologically unique subset of LyP, reminiscent of the biopsy findings encountered in the reported case by Ficarra and co-workers. (Ficarra, et al., 1997) In four of the five cases, the biopsies were interpreted by expert hematopathologists as an aggressive form of peripheral T cell lymphoma resulting in recommendations to administer systemic chemotherapy to four of the patients, the scheduling of one patient for induction therapy and transplantation before revision of the diagnosis, and administration of chemotherapy to one of the patients. The natural clinical course of spontaneous regression refuted the original diagnoses as a form of aggressive peripheral T cell lymphoma. Recognition of oral LyP is critical to avoid inadvertent exposure to potentially toxic chemotherapeutic regimens intended for the treatment of high grade lymphoma. PMID- 29146060 TI - Clinicopathologic correlation of programmed death ligand-1 expression in non small cell lung carcinomas: A report from India. AB - INTRODUCTION: Increased expression of Programmed death ligand-1 (PD-L1) on cancer cells and immune cells predict response to PD-1/PDL1 inhibitors. Data regarding frequency and pattern of PD-L1 expression in NSCLC from India is not available. OBJECTIVES: To analyse PD-L1 expression on tumour cells (TC) and immune cells (IC) and to correlate PD-L1 expression with baseline clinico-pathological characteristics, oncogenic drivers and outcome data. MATERIALS AND METHODS: PD-L1 expression on tumour cells and immune cells was analysed. RESULTS: Eighty-nine cases of resected NSCLC were included. Squamous cell carcinoma was more common than adenocarcinoma. IC were present in almost all cases. Immunopositivity for PD L1 in TC and IC was 27% and 18% respectively. PD-L1 immunopositivity in TC or IC did not correlate with age, sex, stage or mutation status however sarcomatoid carcinoma and solid predominant adenocarcinomas showed higher positivity rates. PD-L1 immunopositivity in ICs was found to correlate with better disease free survival. CONCLUSION: PD-L1 immunopositivity was seen in a quarter of NSCLC patients in India. PDL1 positivity on immune cells may be associated with better prognosis in resected NSCLC. However the prognostic value of PD-L1 and clinical response to check point inhibitors in Indian population need to be validated in larger studies. PMID- 29146061 TI - Sarcoid-like granulomas in renal cell carcinoma: The Houston Methodist Hospital experience. AB - Sarcoid-like (SL) granulomas have been previously described in association with malignant tumors. These granulomas appear to be tumor-related but are not indicative of systemic sarcoidosis, and hence are referred to as SL reactions. These SL reactions can be seen within the primary tumor, its vicinity, or in uninvolved sites such as the spleen, bone marrow, skin, and/or regional lymph nodes draining the tumor. It is a widely held view that SL granulomas are caused by soluble antigenic factors, shed by tumor cells or released due to tumor necrosis. SL reactions reported in Hodgkin lymphoma have been associated with a better prognosis. SL granulomas are thought to play an important role in the host's defenses against metastatic extension. SL granulomas have been reported in approximately 4.4% of carcinomas. Isolated cases of renal cell carcinoma (RCC) with SL granulomas have been reported with questionable prognostic significance. We identified 11 cases of RCCs with SL granulomas. Interestingly, all cases had abundant clear cell cytoplasm (10 clear cell RCC cases and 1 clear cell papillary RCC). We propose that this clear, abundant cytoplasm of the tumor cells with high content of glycogen and lipids may trigger granuloma formation akin to that seen in seminomas with SL granulomas. To date, this is the largest case series of RCCs with SL granulomas. PMID- 29146062 TI - Three cases of adrenocortical tumors mistaken for hepatocellular carcinomas/diagnostic pitfalls and differential diagnosis. AB - Adrenocortical adenomas and carcinomas in other parenchyma are extremely rare, with few cases reported and because of the rarity of these tumors, they occasionally cause problems during diagnosis. Adrenal cortical neoplasms in liver parenchyma can be present in 3 forms, including direct invasion or adhesion to liver parenchyma, tumors arising in adrenohepatic fusion tissue or in ectopic adrenal gland tissue. We report 3 cases of adrenal cortical tumors that were misdiagnosed as hepatocellular carcinoma in the preoperative state. The first case involved an adrenocortical adenoma arising in adrenohepatic fusion tissue. The remaining 2 cases involved an adrenocortical carcinoma and an adrenocortical oncocytoma arising in ectopic adrenal tissue in the liver. We describe the clinical presentations, gross, microscopic findings, immunohistochemical findings with respect to each case, with emphasis on differential diagnosis from hepatocellular carcinoma. PMID- 29146063 TI - The saga continues: How to set best PEEP in intra-abdominal hypertension? PMID- 29146064 TI - Reconstruction of preauricular soft tissue defects using a superiorly based rotation advancement scalp flap - A novel approach to the surgical treatment of preauricular sinuses. PMID- 29146065 TI - Post-thaw boar sperm motility is affected by prolonged storage of sperm in liquid nitrogen. A retrospective study. AB - Owing to the quick genetic turnover of the pig industry, most AI-boar sires live 2-3 yr, a period during which for 1-2 yr their semen is extended and used in liquid form for AI. Despite showing low cryosurvival, affecting fertility after AI, boar semen is frozen for easiness of transport overseas and reposition of valuable genetics. For the latter, semen is stored in liquid nitrogen (LN2, cryostorage) for many years, a controversial practice. Here we studied how length of cryostorage could affect sperm quality. Straws (0.5 mL) frozen using the same cryopreservation protocol at one specific location from AI- sires of proven fertility were stored in LN2 for up to 8 yr. Post-thaw sperm quality was evaluated after 2, 4 or 8 yr of cryostorage, always compared to early thawing (15 d after freezing). Sperm motility and kinematics were evaluated post-thaw using CASA and sperm viability was cytometrically evaluated using specific fluorophores. Sperm viability was not affected by length of cryostorage, but total and progressive sperm motility were lower (p < 0.01) in sperm samples cryostored for 4 or 8 yr compared to those thawed 15 d after freezing. Cryostorage time affected sperm kinetics, but with greater intensity in the samples cryostored for 4 yr (p < 0.001) than in those for 2 yr (p < 0.01). The fact that the major phenotypic characteristic of boar spermatozoa, motility, is constrained by time of cryostorage should be considered when building cryobanks of pig semen. Attention should be placed on the finding that >2 yr of cryostorage time can be particularly detrimental for the post-thaw motility of some sires, which might require increasing sperm numbers for AI. PMID- 29146066 TI - Immunological response induced by cryoablation against murine H22 hepatoma cell line in vivo. AB - OBJECTIVES: To describe immunological consequences induced by cryoablation against H22 cells in vivo. METHODS: Adult BALB/c mice underwent subcutaneous implantation of H22 cells. All of them were assigned into three groups randomly: group A (false surgery), group B (cryoablation) and group C (cryoablation plus Freund's adjuvant). Animals were sacrificed 1, 2 and 3 weeks after treatment. Serum IFN-gamma and IL-4, Th1/Th2 in spleens and cytotoxicity were detected. RESULTS: Compared with that of group A, (1) INF-gamma of group B was higher, but IL-4 was lower; cryoablation plus Freund's adjuvant enhanced these effects. (2) Th1/Th2 rose significantly in both group B and group C. (3) Strong cytolytic activity against H22 cells of group B and group C was found on day 7, 14 and 21. CONCLUSIONS: Our study showed a marked shift toward Th1 and IFN-gamma expression after cryoablation, with an immuno-stimulatory effect against murine H22 hepatoma Cell. PMID- 29146067 TI - Risky movies, risky behaviors, and ethnic identity among Black adolescents. AB - PURPOSE: To investigate how exposure to sex, alcohol and violent content in mainstream and Black-oriented movies relates to corresponding adolescent behavior among Black youth from the United States and whether those relationships are moderated by ethnic identity. METHODS: The present study uses survey data from an online sample of 1000 Black adolescents and content analysis ratings on top grossing 2014 films and 2013/2014 Black-oriented films. Content-specific exposure measures for alcohol, sexual activity, and violence were calculated from self reported exposure data and content analysis ratings. Regression analyses estimated the associations among exposures to risky health content in mainstream and Black-oriented films and adolescent behaviors as well as moderation by ethnic group identity. RESULTS: Black adolescents were mostly unaffected by exposure to risk portrayals in mainstream films, but exposure to risk in Black-oriented films was related to their behavior in all three domains. Strong group identity strengthened the relationship between exposure to sex in Black-oriented and mainstream films depending on the sexual outcome. CONCLUSION: The type of movie (i.e., mainstream or Black-oriented) through which Black adolescents are exposed to risky health portrayals is important for understanding its relationship to their behavior, and variations by ethnic identity were limited to sex content. Future research should identify the mechanisms through which risk content in Black-oriented films is associated with Black adolescents' risky behaviors to determine how media influence contributes to behavioral disparities among youth. PMID- 29146068 TI - Applying the reasoned action approach to understanding health protection and health risk behaviors. AB - RATIONALE: The Reasoned Action Approach (RAA) developed out of the Theory of Reasoned Action and Theory of Planned Behavior but has not yet been widely applied to understanding health behaviors. The present research employed the RAA in a prospective design to test predictions of intention and action for groups of protection and risk behaviors separately in the same sample. OBJECTIVE: To test the RAA for health protection and risk behaviors. METHOD: Measures of RAA components plus past behavior were taken in relation to eight protection and six risk behaviors in 385 adults. Self-reported behavior was assessed one month later. RESULTS: Multi-level modelling showed instrumental attitude, experiential attitude, descriptive norms, capacity and past behavior were significant positive predictors of intentions to engage in protection or risk behaviors. Injunctive norms were only significant predictors of intention in protection behaviors. Autonomy was a significant positive predictor of intentions in protection behaviors and a negative predictor in risk behaviors (the latter relationship became non-significant when controlling for past behavior). Multi-level modelling showed that intention, capacity, and past behavior were significant positive predictors of action for both protection and risk behaviors. Experiential attitude and descriptive norm were additional significant positive predictors of risk behaviors. CONCLUSION: The RAA has utility in predicting both protection and risk health behaviors although the power of predictors may vary across these types of health behavior. PMID- 29146069 TI - Solitary rectal ulcer in a patient with rectal prolapse. PMID- 29146070 TI - Acute appendicitis due to parasitosis. PMID- 29146071 TI - Comparison among the levels of patients' satisfaction according to the surgical technique used in breast reconstruction after mastectomy. AB - BACKGROUND: It has been proved that a breast reconstruction after a mastectomy has a great psycho-social impact on patients. For this reason, it is increasingly done in a greater percentage of cases. There are two major groups of reconstructive techniques: a reconstruction with implants and a reconstruction with autologous tissue of the patient. In order to make a more objective assessment of the results, it is important to know how satisfied these patients are with the results. Therefore, we performed a study using Q-BREAST, the aim of which is to analyze the satisfaction of mastectomized patients according to the different surgical reconstruction techniques. METHODS: A retrospective, descriptive and observational study of patients reconstructed in our service from 2008 to 2011 was carried out. Patient satisfaction levels were compared according to the surgical technique used in breast reconstruction using the Q-BREAST test, which was mailed to them. RESULTS: There are no statistical differences in the levels of satisfaction in terms of age, type of mastectomy done, coadjutant treatment or existence of complications. Higher levels of satisfaction are observed in patients reconstructed with autologous tissue versus implants (P=.028). CONCLUSIONS: Patients reconstructed with autologous tissue have higher levels of satisfaction than those reconstructed with implants. PMID- 29146072 TI - Amyloidosis of the colon and clinical features of intestinal obstruction. PMID- 29146073 TI - Robotic Assisted Transanal Polypectomies: Is There Any Indication? AB - OBJECTIVES: Robotic assisted transanal polipectomy may have advantages compared with the conventional transanal minimally invasive surgery technique. We evaluate the safety, feasibility and advantages of this technique. METHODS: Between February 2014 and October 2015, 9patients underwent robotic transanal polypectomy. We performed a retrospective study in which we analyse prospectively collected data regarding patient and tumor characteristics, perioperative outcomes, pathological report, morbidity and mortality. RESULTS: A total of 5 male and 4 female patients underwent robotic TAMIS. Lesions were 6,22cm from the anal verge. Mean size was 15,8cm2. All procedures were performed in the lithotomy position. Closure of the defect was performed in all cases. Mean blood loss was 39,8ml. Mean operative time was 71,9min. No severe postoperative complications or readmissions occured. Median hospital stay was 2,5 days. CONCLUSIONS: Robotic TAMIS is useful to treat complex rectal lesions. Our transanal platform allowed a wider range of movements of the robotic arms and to perform all procedures in the lithotomy position. PMID- 29146074 TI - Corrigendum to "Diagnostic utility of IDH1/2 mutations to distinguish dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma of bone" [Hum Pathol 2017;65:239-46]. PMID- 29146075 TI - Persistent organic pollutant emission via dust deposition throughout Pakistan: Spatial patterns, regional cycling and their implication for human health risks. AB - In the current study, Persistent Organic Pollutants (POPs) in outdoor dustfall was monitored for the first time along the Indus river system of Pakistan. Among the studied OCPs (ng/g, dry weight), DDTs (0.16-62) were the predominant contaminants identified in deposited dust followed by HCHs (0.1-10.2), HCB (0.09 7.4) and chlordanes (0.1-2.8). The indicative diagnostic ratio for DDTs and HCHs suggested recent emission of DDTs as well as historical emission of both chemicals in regions where they were used for crop protection and malarial control. The levels of ?31PCBs (ng/g, dry weight) in dust ranged from 0.95-125, and compositional profiles suggested arochlor-1248, -1254 commercial mixtures as source. A few exceptions were samples from urban areas that reflected the use of aroclor-1260, and-1262 and/or unintentional leakage from several industrial processes. The WHO05-TEQ values for dioxin-like PCBs (with major contributions of PCB-126) were found to be 0.07-34.5 (median; 1.87) pg TEQg-1dw for all the studied samples. Correlation analysis identified that DDTs, HCHs, HCB and PCBs were significantly associated (r=90; p<0.01) with dusts collected in proximity to urban centers with widespread anthropogenic activities in these areas. A few cases where high levels of POPs from remote mountain highlands were detected, point to the potential for long range transport of these chemicals. Human risk assessment analysis of contaminated dust showed that DDTs and PCBs are major constituent chemicals of concern with regard to the development of cancer in children, with ingestion being the main route of exposure of dust-borne DDTs (0.12-1.03*10-6) and PCBs (0.86-12.43*10-6). PMID- 29146076 TI - Short-term effects of prescribed burning on litterfall biomass in mixed stands of Pinus nigra and Pinus pinaster and pure stands of Pinus nigra in the Cuenca Mountains (Central-Eastern Spain). AB - Fire severity, defined as the magnitude of fire effects in an ecosystem, is a key factor to consider in planning management strategies for protecting forests against fire. Although prescribed burning has been used as a fuel reduction tool in forest ecosystems, it is quite limited in the Mediterranean region. Furthermore, little is known about how tree crowns are affected by prescribed underburning aimed at reducing fire severity in conifer stands. As part of an ongoing study to assess the effects of prescribed burning on the tree canopy, litterfall is currently being monitored in a network of experimental plots located in mixed (Pinus nigra and Pinus pinaster) and pure (P. nigra) conifer stands in the Cuenca Mountains (Castilla La Mancha, Spain). A total of 12 study plots (30m*30m) were established in a completely randomized experimental design to determine the effect of burning, with 2 treatments: no burning (control) and burning (i.e. with three replicate plots for each treatment and site). Burning was conducted in May 2016. In each plot, 8 litterfall collectors were installed at regular intervals, according to international protocols (ICP Forests), and all biomass falling into the collectors is being monitored monthly. The specific objective of this study is to assess how prescribed burning affects the rate of generation of foliar and non-foliar litterfall biomass due to the fire. In addition, the Leaf Area Index was estimated before burning and one year later to verify possible changes in the structure of the stands. This information could be used to help minimize the negative impacts of prescribed underburning on litterfall. To our knowledge, this study represents the first attempt to evaluate the effect of prescribed burning on litterfall biomass in Europe. PMID- 29146077 TI - Finite analytic method for modeling variably saturated flows. AB - This paper develops a finite analytic method (FAM) for solving the two dimensional Richards' equation. The FAM incorporates the analytic solution in local elements to formulate the algebraic representation of the partial differential equation of unsaturated flow so as to effectively control both numerical oscillation and dispersion. The FAM model is then verified using four examples, in which the numerical solutions are compared with analytical solutions, solutions from VSAFT2, and observational data from a field experiment. These numerical experiments show that the method is not only accurate but also efficient, when compared with other numerical methods. PMID- 29146078 TI - Bisphenol A distribution in serum, urine, placenta, breast milk, and umbilical cord serum in a birth panel of mother-neonate pairs. AB - Bisphenol A (BPA) exposure during the perinatal and postnatal periods increases the susceptibility to disease over the life cycle. However, information on the BPA delivered to fetuses or infants via the placenta and breastfeeding is limited. We determined the BPA exposure levels in various bodily fluids and tissues of pregnant women and described fetus and infant exposures to BPA based on associations and BPA ratios in mother-neonate paired samples. Maternal serum, urine, placenta, breast milk, cord serum, and neonatal urine samples were collected from 318 mother-neonate pairs at six university hospitals in Korea. BPA levels were detected using liquid chromatography tandem mass spectrometry. The ratios of the BPA levels in the other sample types to the levels in maternal serum were calculated. BPA was detected in 79.5-100% of the maternal and fetal samples. The median BPA concentration in the samples decreased in the order of neonatal urine (4.75ng/mL), maternal urine (2.86ng/mL), cord serum (1.71ng/mL), maternal serum (1.56ng/mL), breast milk (0.74ng/mL), and the placenta (0.53ng/g). We estimated the ratios of BPA levels in the other sample types to those in maternal serum. The median (95th percentile) cord serum-to-maternal serum ratio was 1.12 (15.2) for 160 mother-fetal pairs, in which BPA was detected in both samples. The placenta-, maternal urine-, neonatal urine-, and breast milk-to maternal serum ratios were 0.28 (5.31), 1.79 (29.9), 1.98 (28.2), and 0.51 (10.5), respectively. In addition, the median (95th percentile) cord serum-to placenta ratio was 4.03 (45.8), and the neonatal urine-to-cord serum ratio was 1.95 (25.6). The 95th percentile values were 14-20-fold greater than the medians. Urine contained the highest BPA concentrations, followed by serum, breast milk, and the placenta. The variations of BPA ratio show individual differences in the amounts of BPA delivered from mother to fetus. PMID- 29146079 TI - Occurrence of chlorinated volatile organic compounds (VOCs) in a sanitary sewer system: Implications for assessing vapor intrusion alternative pathways. AB - Sewer systems have been recently recognized as potentially important exposure pathways to consider during vapor intrusion assessments; however, this pathway has not been well-characterized and there is need for additional information about the occurrence of volatile organic compounds (VOCs) in sewer systems. This paper reports the results of sewer gas sampling conducted in a sanitary sewer over the years of 2014-2017. Sewer gas samples were collected and analyzed using several different techniques, including TO-15 (grab), TO-17 (passive), Radiello(r) (passive) and a novel continuous monitoring technique, the Autonomous Rugged Optical Multigas Analyzer (AROMA). The applicability of each of the different approaches used in this study is discussed in the context of investigating sanitary sewers as a vapor intrusion alternative pathway. The data confirmed that trichloroethylene (TCE) concentrations in sewer gas were detected adjacent to and extending hundreds of feet away from a previously defined vapor intrusion area, where TCE was a primary contaminant. TCE concentrations detected in sewer gas ranged from non-detect to 1600MUg/m3. Temporal variability was observed in TCE concentrations over timescales that ranged from minutes to months to years at discrete sampling locations. Spatial variability in sewer gas concentrations was also observed throughout the study area. Temporal and spatial variability may be caused by groundwater contamination sources in the study area, as well as sewer gas transport mechanisms. PMID- 29146080 TI - Zeroing in on endoscopic and histologic mucosal healing to reduce the risk of colorectal neoplasia in inflammatory bowel disease. PMID- 29146081 TI - Covered bridge over troubled strictures. PMID- 29146082 TI - Pancreatic function testing for the early diagnosis of chronic pancreatitis. PMID- 29146083 TI - ERCP: Time to take the lead off? PMID- 29146084 TI - PiCaSSO: a predictive score for endoscopic findings in ulcerative colitis that sounds like art but is all science. PMID- 29146085 TI - How to suction pancreatic juice from the duodenum: Endoscope, catheter, or cap assisted? PMID- 29146086 TI - Covered self-expanding metal stents: a promising therapy for difficult stone disease. PMID- 29146087 TI - Inadequate bowel preparation rates should be considered before screening colonoscopy is recommended. PMID- 29146088 TI - Response. PMID- 29146089 TI - ASGE guidelines for ERCP competence. PMID- 29146090 TI - Response. PMID- 29146091 TI - Choledocholithiasis: Should EUS replace MRCP in patients at intermediate risk? PMID- 29146092 TI - Ultrasonographic evaluation of changes in the muscle architecture of the gastrocnemius with botulinum toxin treatment for lower extremity spasticity in children with cerebral palsy. AB - BACKGROUND: Botulinum toxin A treatment involves injecting botulinum toxin A to relax muscle spasticity. Using ultrasonography, this study examined changes in the muscle architecture before and after treatment to evaluate the influence of botulinum toxin A injection on muscles. METHODS: The participants included 18 children (mean age, 6.2 years) with cerebral palsy who were treated with botulinum toxin A for lower extremity spasticity and 27 healthy children (mean age, 6.4 years) as a control group. In all cases, botulinum toxin A was injected into the gastrocnemius muscle. The muscle length, muscle width, and pennation angle (which indicates the degree of muscle fiber tone), were measured using B mode ultrasonography before and 12 weeks after injection. RESULTS: The muscle length and muscle width were shorter in the cerebral palsy group than in the control group. The pennation angle in the cerebral palsy group significantly decreased after injection from 28.2 +/- 3.6 degrees to 25.8 +/- 2.5 degrees in the resting position of the ankle and from 18.6 +/- 2.8 degrees to 15.9 +/- 1.7 degrees in the maximum dorsiflexion position of the ankle. In the control group, the pennation angle was 25.9 +/- 3.2 degrees in the resting position of the ankle and 15.1 +/- 2.5 degrees in the maximum dorsiflexion position of the ankle. The rate of increase of fascicle length during passive movement from the resting position of the ankle to the maximum dorsiflexion position was 143.9% in the cerebral palsy group, which was significantly less than the value of 157.7% in the control group. After botulinum toxin A treatment, the rate of increase of fascicle length in the cerebral palsy group increased to 155.1%. CONCLUSIONS: The decrease in the pennation angle after botulinum toxin A treatment is considered to be the result of a reduction of spasticity and subsequent structural changes in flaccid muscle fibers. PMID- 29146093 TI - Treatment status and radiographic features of patients with atypical femoral fractures. AB - BACKGROUND: The Japanese Orthopaedic Association (JOA) has been surveying approximately 3000 orthopedic surgery hospitals and clinics with inpatient facilities nationwide to collect information on atypical femoral fractures (AFFs) and patient characteristics since 2010. The present study aims to examine radiographic images and clarify the relationship between radiographic and patient characteristics of patients with AFF and treatment status. METHODS: The study involved 1996 facilities certified as clinical training sites by the JOA and 912 clinics with inpatient facilities affiliated with the Japanese Clinical Orthopaedic Association (JCOA). Additional clinical data collection and radiographic image review were performed in patients aged 35 years or older who met the American Society for Bone and Mineral Research (ASBMR) case definition for AFF and received treatment at participating facilities registered with JOA in 2013. Radiographic images were evaluated in accordance with the ASBMR case definition. RESULTS: Radiographic images of 304 fractures in 304 patients were collected. Among them, 230 fractures were determined to be AFFs. The fracture site was the proximal third in 70 AFFs (30.4%), middle third in 157 AFFs (68.3%), and distal third in 3 AFFs (1.3%). Among patients with AFFs, 173 (75.2%) were treated with bisphosphonates (BPs) and 45 patients (19.6%) were not (unknown in 12 patients). Duration of use was three years or longer in 103 patients (59.5%) and between one and three years in 24 patients (13.9%). Radiographic beaking was observed in 149 fractures (86.1%) in patients treated with BPs and 17 fractures (37.8%) in patients who were not treated with BPs (odds ratio 11.3, 95% CI 5.7 22.3). CONCLUSIONS: Radiographic beaking was observed more frequently in patients treated with BPs than in patients not treated with BPs. PMID- 29146094 TI - Is Balloon kyphoplasty a better treatment than percutaneous vertebroplasty for chronic obstructive pulmonary disease (COPD) patients with osteoporotic vertebral compression fractures (OVCFs)? AB - BACKGROUND: Although several studies reported that Balloon kyphoplasty (BK) or percutaneous vertebroplasty (PVP) could improve pulmonary functions, there is no study to compare the efficacy and safety of 2 procedures in COPD patients with osteoporotic vertebral compression fractures (OVCFs) and investigate the reason why they could improve pulmonary functions. METHOD: Two procedures, including BK and PVP were performed in 61 COPD patients with single-level OVCFS. VAS-score, ODI, pulmonary function and radiological parameters (Anterior vertebral body height ratio, posterior vertebral body height ratio and Local kyphotic angle) were evaluated preoperatively and 1 week, 3 months and 12 moths postoperatively, respectively. The operation time and cement leakage rate were also recorded. RESULT: The operation time was longer in BK than PVP (37.5 +/- 7.4 versus 27.6 +/ 6.2 min per vertebra). Both groups got an equally significant improvement in pain relief, functional result, pulmonary functions and demonstrated similar cement leakage rate (BK: 6.5%; PVP: 10%). Radiologically, BK is favored than PVP. A significant relationship between VAS and pulmonary functions except FEV1 was observed in first week postoperatively, while the ODI was related to MVV in first 3 months postoperatively. CONCLUSION: Both BK and PVP provided equally significant back pain relief and improvements of respiratory functions in patients affected by COPD with single level OVCFs. BK was favored in radiography, this improvement was not related to pain relief and improvement of pulmonary functions. Given much higher cost of BK, similar effectiveness and safety of BK and PVP, in COPD patients with OVCFs, PVP may be a better choice. PMID- 29146095 TI - A two-year study using cerebral gray matter volume to assess the response to fingolimod therapy in multiple sclerosis. AB - BACKGROUND: Cerebral gray matter (GM) atrophy has clinical relevance in multiple sclerosis (MS). Fingolimod has known efficacy on clinical and conventional MRI findings in MS; the effect on GM is unknown. OBJECTIVE: To explore fingolimod's treatment effect on cerebral GM atrophy over two years in patients with relapsing forms of MS. DESIGN/METHODS: Patients starting fingolimod [n=24, age (mean+/-SD) 41.2+/-11.6years, Expanded Disability Status Scale (EDSS) score 1.1+/-1.4; 58% women] were compared to untreated patients [n=29, age 45.7+/-8.4years, EDSS 1.0+/ 1.2; 93% women]. Baseline, one and two year MRI was applied to an SPM12 pipeline to assess brain parenchymal fraction (BPF) and cortical GM fraction (cGMF). T2 lesion volume (T2LV) and gadolinium-enhancing lesions were assessed. Change was modeled using a mixed effects linear regression with a random intercept and fixed effects for time, group, and the time-by-group interaction. The group slope difference was assessed using the interaction term. RESULTS: Over two years, cGMF remained stable in the fingolimod group (p>0.05), but decreased in the untreated group (p<0.001) (group difference p<0.001). BPF change did not differ between groups (all time-points p>0.05). T2LV increased over two years in the untreated group (p<0.001) but not in the fingolimod group (p>=0.44) (group difference p<0.001). CONCLUSION: These results suggest a treatment effect of fingolimod on cerebral GM atrophy in the first two years. GM atrophy is more sensitive to such effects than whole brain atrophy. However, due to the non-randomized, retrospective design, heterogeneous between-group characteristics, and small sample size, these results require confirmation in future studies. PMID- 29146097 TI - Descriptive study of current therapeutic practices, clinical reproductive findings and incidence of pregnancy loss in intensively managed thoroughbred mares. AB - Therapeutic practices in equine reproductive medicine have dramatically evolved over the last 20 years but current usage is not described. The aims of this study were to provide a description of medication use and clinical findings of reproductive examinations alongside measures of reproductive efficiency in thoroughbreds. A prospective cohort study was conducted in the 2013 and 2014 breeding seasons. Mare and stallion details, information on veterinary interventions and findings of reproductive ultrasound scans were collected using questionnaires and entered into a custom-designed Microsoft Access database. Descriptive summary statistics were derived directly from the database and using Microsoft Excel. Information was collected from 2246 pregnancies in 1754 mares from 29 stud farms. Ovulatory induction agents were used in 91.8% of cases, oestrus induction agents in 38.4% and covering therapies in 62.7%. Intrauterine antimicrobials were used in 49.6% of mares. Single pregnancies accounted for 83.9% of pregnancies, twins for 15.3% and triplets for 0.7%. The overall incidence of pregnancy loss between days 15-42 was 6.4% (95% CI 5.4%, 7.4%) and 1.6% (95% CI 1.1%, 2.1%) between days 43-65. A further 1.3% of pregnancies were lost by October and 4.5% by birth (including stillbirths). Eighty-three percent of all pregnancies resulted in a live foal. In conclusion, there has been a considerable increase in the use of reproductive therapeutics over the last 12 years. Nonetheless, incidence of pregnancy loss and live foal percentages remain essentially unchanged. Risk factor studies are required to determine if the substantial increase in therapeutic usage is conferring positive benefits. PMID- 29146096 TI - Ten-year review of isolated spontaneous mesenteric arterial dissections. AB - OBJECTIVE: Isolated spontaneous dissection of the superior mesenteric artery (SMA) and celiac artery (CA) remains a rare condition; however, it has been increasingly noted incidentally on diagnostic imaging. The purpose of this study was to examine the natural history and outcomes of patients presenting with isolated spontaneous mesenteric artery dissection (SMAD). We hypothesized that most SMADs can be treated nonoperatively. METHODS: This was a single-center retrospective review of patients presenting with the diagnosis of SMAD between 2006 and 2016. Data analysis included demographics, clinical data, radiologic review, treatment, and outcomes. RESULTS: A total of 77 patients were found to have CA dissection, SMA dissection, or both in the absence of aortic dissection diagnosed on computed tomography or magnetic resonance imaging. The average age was 56 years (range, 26-86 years), 80% were male, and 10 patients (13%) had underlying connective tissue disorders. The majority, 64%, presented with symptoms including abdominal pain, back pain, and chest pain; the remaining 36% were asymptomatic. Combined SMA and CA dissection was found in 14 (18%) patients; 33 (43%) presented with isolated CA dissection, and 30 (39%) presented with isolated SMA dissection. Only four patients required intervention. Mesenteric bypass was performed in two patients, and SMA endarterectomy with patch angioplasty was performed in one patient for signs of bowel ischemia. No patient required bowel resection. The two bypasses were anastomosed to a branch of the SMA, and complete lumen restoration was seen on long-term imaging follow-up. One patient underwent stent grafting of the CA and hepatic artery for aneurysmal degeneration 1 month after diagnosis. The remaining 73 patients were managed nonoperatively; 40 (52%) were treated with a short course of anticoagulation, 23 (30%) were treated with antiplatelet therapy, and 10 (13%) were treated with observation alone. No other late interventions or recurrences were noted during a mean follow-up of 21 months. CONCLUSIONS: Whereas isolated SMAD poses a risk of visceral ischemia, most patients presenting with this diagnosis can be treated nonoperatively with a short course of antiplatelet or anticoagulant therapy. Only a small number of patients require surgical revascularization for bowel ischemia. PMID- 29146098 TI - Characterization of polymorphism in the FSH receptor gene and its impact on some reproductive indices in dairy cows. AB - Follicle stimulating hormone (FSH) is released from the anterior pituitary gland and has an important role in female fertility. As FSH is a glycoprotein polypeptide hormone which cannot pass through the cell membrane, its influence on target cells must be mediated by the FSH receptor (FSHR). Accordingly, any kind of mutation in FSHR can affect reproduction in dairy cows. In this study, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used for recognition of a point mutation (A/G: position -278) located in the FSHR gene in Iranian dairy cows. The association was evaluated of this mutation with reproductive performance. Blood samples were collected from 79 cows in a dairy farm in Iran and genotyped based on this single nucleotide polymorphism (SNP). The 5'-flanking regions of FSHR gene were successfully amplified and produced a fragment of 211bp in all cases. Three different patterns were, however, produced following restriction digestion with FaqI enzyme. The molecular results showed the existence of three different genotypes of AA, AG and GG among examined cows. In this study percentages of genotypes were 51.9%, 43.2% and 4.9% for AA, AG and GG genotypes, respectively. Allele frequencies were 73.5% and 26.5% for A and G, respectively. Results indicate that cows lacking allele G had desirable fertility in which a greater percentage (53.7%) of cows lacking Allele G (AA) had services per conception (SPC) of <2 in the previous lactation; while a lesser percentage of cows with Allele G (28.9%) had SPC of <2 (P<0.05). There was no difference in the days non-pregnant (DNP) and calving to first service interval among cows with these genotypes (P>0.05). Calving to first service interval was 69.9 +/-12.3 in cows with Allele G and 74.73+/-13.9 in cows without Allele G (P>0.05). Percentage of cows with repeat breeder syndrome (SPC >3) was also 15.6% and 27.6% in cows without Allele G and with Allele G, respectively, but these values were not different (P>0.05). It can be concluded that the A to G mutation within the upstream region of FSHR gene (position -278) may affect some reproductive variables in Holstein dairy cows. PMID- 29146099 TI - Art, the visual imagination and neuroscience: The Chauvet Cave, Mona Lisa's smile and Michelangelo's terribilita. AB - This paper considers several types of imagination relevant to art historical enquiry. These are exemplified in artistic expressions ranging from palaeolithic paintings in the Chauvet Cave, to drawings, sculptures and buildings designed by Michelangelo and drawings and paintings by Leonardo, and are related to recent neuroscientific discoveries. From this it emerges that important types of imagination cannot be understood without an appreciation of the neural processes that underlie them and especially without an acknowledgement of the importance of neurochemistry. PMID- 29146100 TI - Emerging role of extracellular vesicles as a senescence-associated secretory phenotype: Insights into the pathophysiology of lung diseases. AB - Aging is a major risk factor for the development of chronic lung diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. A main aspect of aging is the impaired function of maintaining homeostasis in the organs and body, which is associated with cellular senescence. Cellular senescence is recognized as the state of irreversible cell cycle arrest in response to a variety of cellular stresses. Senescent cells are not simply cell cycle-arrested cells; they also affect bystander cells through the secretion of bioactive molecules, termed the senescence-associated secretory phenotype (SASP). Many studies strongly indicate that senescent cells in the lungs are associated with the pathogenesis of age-related lung diseases by releasing SASP factors. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are released from almost all cell types and are recognized as important mediators of intercellular communication. They have been shown to carry and transfer a wide variety of molecules, such as microRNAs, messenger RNAs, DNA, and proteins, which can contribute to physiological functions and the pathology of various diseases. Increasing evidence suggests that EVs secreted from senescent cells have unique characteristics and contribute to modulating the phenotype of recipient cells similar to SASP factors. Thus, the EVs secreted from senescent cells, namely, senescence-associated EVs, appear to be a novel SASP factor. In this review, we summarize the current knowledge linking senescence-associated EVs to the SASP factor and discuss the roles of these EVs in age-related lung diseases. PMID- 29146101 TI - Nutrition epidemiology of flavan-3-ols: The known unknowns. AB - Nutritional epidemiology has an important role, as it can provide long-term data from large populations and does not rely on surrogate markers for morbidity/mortality. Meaningful interpretation and applications of outcomes from epidemiological studies depend on the accurate assessment of dietary intake, which is currently mainly based on a combination of self-reporting and food composition data. Flavan-3-ols are a group of bioactives (non-essential dietary components with significant impact on health) that is a possible candidate for the development of dietary recommendations. The breadth of data available on their effect on health also provides the basis for investigating the suitability of the methods currently used in nutritional epidemiology to assess the health effects of bioactives. The outcomes of this assessment demonstrate that the limitations of currently used methods make it virtually impossible to estimate intake accurately from self-reported dietary data. This is due to the limitations of self-reporting, especially from food-frequency questionnaires, and the inability of currently used methods to deal with the high variability of food composition. Indeed, the estimated intake of flavan-3-ols, can only be interpreted as a marker of specific dietary patterns, but not as the actual intake amount. The interpretation of results from such studies are fraught with serious limitations, especially for establishing associations between intake and health and the development of dietary recommendations. Alternative assessment not affected by these limitations, such as biomarkers, are required to overcome these limitations. The development of nutritional biomarkers is therefore crucial to investigate the health effect of bioactives. PMID- 29146102 TI - Outcomes by molecular subtype after accelerated partial breast irradiation using single-entry catheters. AB - PURPOSE: Tumor biology is being recognized as an important indicator of prognosis and risk of locoregional recurrence. Here, we determine actuarial recurrence rates by approximated molecular subtype for women treated with single-entry catheter accelerated partial breast irradiation (sAPBI). METHODS AND MATERIALS: One thousand four hundred eighty-six women with invasive cancer having known ER, PR, and Her2 status and at least 1-year of followup were treated using MammoSite, Contura, or SAVI sAPBI from 2002 to 2014 at our institution. Actuarial recurrence rates were determined for the following four approximated molecular subtypes using the Kaplan-Meier method: luminal A (n = 1081), luminal B (n = 164), Her2 (n = 123), and triple-negative breast cancer (TNBC; n = 118). RESULTS: With a median followup time of 3.3 years (range 1-13.6 years), the 5-year in-breast tumor recurrence rate was 2.6% overall, 2.1% for luminal A, 1.5% for luminal B, 4.9% for Her2, and 5.4% for TNBC. Luminal A and B subtypes, as compared with the more aggressive Her2 and TNBC subtypes combined, demonstrated lower 5-year in-breast tumor recurrence (2.1% vs. 5.1%, p = 0.021). The 5-year regional nodal recurrence rate was 1.4% overall, 1.4% for luminal A, 0% for luminal B, 1% for Her2, and 4.2% for TNBC. The 5-year locoregional control is 97.3% for luminal breast cancers and 93.8% for the more aggressive Her2 and TNBC subtypes collectively. CONCLUSIONS: Luminal cancers demonstrated excellent 5-year locoregional control with sAPBI. Although caution should be used when treating patients with the more aggressive Her2 and TNBC subtypes, these subtypes have demonstrated higher LRR with mastectomy and whole-breast irradiation. Further randomized comparisons are needed to determine the optimal treatment for these higher risk patients. PMID- 29146103 TI - Assessment of the implant geometry in fractionated interstitial HDR breast brachytherapy using an electromagnetic tracking system. AB - PURPOSE: During the partial-breast treatment course by interstitial brachytherapy, electromagnetic tracking (EMT) was applied to measure the implant geometry. Implant-geometry variation, choice of reference data, and three registration methods were assessed. METHODS AND MATERIALS: The implant geometry was measured in 28 patients after catheter implantation (EMTbed), during CT imaging (EMTCT), and in each of up to n = 9 treatment fractions (EMTF(k), k = 1, 2,... n). EMTF(k) were registered to the planned implant reconstruction (CTplan) by using all dwell positions (DPs), the button centers, or three fiducial sensors on the patient's skin. Variation in implant geometry obtained from EMTF(k) was assessed for EMTbed, EMTCT, and CTplan. RESULTS: EMT was used to measure 3932 catheters. A duration of 6.5 +/- 1.7 min was needed for each implant measurement (mean, 17 catheters) plus setup of the EMT system. Data registration based on the DP deviated significantly lower than registration on button centers or fiducial sensors. Within a registration group, there was a <0.5-mm difference in the choice of reference data. Using CTplan as reference for registration, the mean residual distance of DPs on EMT-derived DPs was found at 2.1 +/- 1.6 mm (EMTbed), 1.3 +/- 0.9 mm (EMTCT), and 2.5 +/- 1.5 mm (EMTF(k)). CONCLUSIONS: EMT can assess the implant geometry in high-dose-rate interstitial brachytherapy breast treatments. EMTbed, EMTCT, and CTplan data can serve as reference for assessment of implant changes. PMID- 29146104 TI - An innovative approach to participatory health policy development in Bulgaria: The conception and first achievements of the Partnership for Health. AB - The Bulgarian Partnership for Health was established in 2015 as a new forum for health policy formulation and discussion. The Partnership presents a new approach of structured and sustained stakeholder involvement to overcome the lack of public participation in health policy development and implementation. Constituted as a permanent consultative body to the Council of Ministers, the Partnership engages a wide variety of stakeholders and professionals to shape and improve health policies. The shared governance of the Partnership between the Minister of Health and a patient organisation supports the elaboration of legislative acts based on the stakeholders' collaboration in priority areas. The governance and organisational structure of the Partnership assures capacity building, fast mobilisation of experts, continuity of stakeholder involvement, and increased responsibility in health policy development and implementation. This type of participatory approach may help reconcile initially opposing positions and foster reforms often impeded by political antagonism. Persisting challenges are a rather slow process of policy development and different perceptions of key concepts among the stakeholders. As policy-making in many countries in Eastern Europe suffers from political distrust, the Partnership's approach of involving experts and not only politicians - could provide inspiration also to other countries, which have struggled with inconsistency of health policies pursued by different governments. PMID- 29146105 TI - Content validation of behaviours and autonomic responses for the assessment of pain in critically ill adults with a brain injury. AB - BACKGROUND: The evidence shows that brain-injured patients express behaviours that are related to their level of consciousness (LOC), and different from other patients in the intensive care unit (ICU). Therefore, existing behavioural scales should be revised to enhance their content and validity for use in these patients. OBJECTIVES: The aim was to evaluate the content relevance of behaviours and autonomic responses for pain assessment of brain-injured ICU patients from the perspective of critical care clinicians. METHODS: A total of 77 clinicians from four adult neuroscience ICUs (three from Canada and one from the United States) participated in this descriptive study. A physician/nurse ratio of 21% (13/61) was reached in this quota sample, and three physiotherapists also participated. They completed a content validation questionnaire of 19 items rated on clarity and relevance based on the patient's LOC. Item Content Validity Index (I-CVI), and modified kappa (kappa*) were calculated. Values higher than 0.78 and 0.75 respectively were considered excellent. RESULTS: Regardless of the patient's LOC, brow lowering, grimacing, and trying to reach the pain site were rated as the most relevant behaviours by clinicians, with excellent values of I-CVI>0.78 and kappa*>0.75. Eyes tightly closed, moaning and verbal complaints of pain also obtained excellent values in altered LOC and conscious patients. Eye weeping obtained excellent values only in conscious patients. Other items showed fair (0.40-0.59) to good (0.60-0.74) values, while blinking and coughing showed poor values (<0.40) at various LOC. CONCLUSIONS: Facial expressions, movements towards the pain site, and vocalisation of pain were the most relevant pain-related behaviours rated by critical care clinicians. The relevance of some behaviours (e.g., moaning and verbal complaints of pain) varied across LOCs, thereby calling forth adaptations of behavioural pain scales to allow for interpretation in the context of a patient's LOC and ability to express specific behaviours. PMID- 29146107 TI - Cardiovascular anatomy in children with bidirectional Glenn anastomosis, regarding the transcatheter Fontan completion. AB - BACKGROUND: Transcatheter stent-secured completion of total cavopulmonary connection (TCPC) after surgical preparations during the Glenn anastomosis procedure has been reported, but complications from this approach have precluded its clinical acceptance. AIMS: To analyse cardiovascular morphology and dimensions in children with bidirectional Glenn anastomosis, regarding the optimal device design for transcatheter Fontan completion without special surgical "preconditionings". METHODS: We retrospectively analysed 60 thoracic computed tomography and magnetic resonance angiograms performed in patients with a median age of 4.1 years (range: 1.8-17.1 years). Additionally, we simulated TCPC completion using different intra-atrial stent-grafts in a three-dimensional model of the representative anatomy, and performed calculations to determine the optimal stent-graft dimensions, using measured distances. RESULTS: Two types of cardiovascular arrangement were identified: left atrium interposing between the right pulmonary artery (RPA) and inferior vena cava, with the right upper pulmonary vein (RUPV) orifice close to the intercaval axis (65%); and intercaval axis traversing only the right(-sided) atrial cavity, with the RUPV located posterior to the atrial wall (35%). In the total population, the shortest median RPA-to-atrial wall distance was 1.9mm (range: 0.6-13.8mm), while the mean intra atrial distance along the intercaval axis was 50.1+/-11.2mm. Regardless of the arrangement, 83% of all patients required a deviation of at least 5.9+/-2.4mm (range: 1.2-12.7mm) of the stent-graft centre at the RUPV level anteriorly to the intercaval axis to avoid covering or compressing this vein. Fixing the anterior deviation of the curved stent-graft centre at 10mm significantly decreased the range of bend angle per every given RUPV-RPA distance. CONCLUSIONS: For both types of cardiovascular arrangement, after conventional bidirectional Glenn anastomosis, the intra-atrial curved stent-graft seemed most suitable for achieving uncomplicated TCPC completion percutaneously without previous surgical "preconditionings" in the majority of children. Experimental study is necessary to validate this conclusion. PMID- 29146106 TI - The hydrophobic trap-the Achilles heel of RND efflux pumps. AB - Resistance-nodulation-division (RND) superfamily efflux pumps play a major role in multidrug resistance (MDR) of Gram-negative pathogens by extruding diverse classes of antibiotics from the cell. There has been considerable interest in developing efflux pump inhibitors (EPIs) of RND pumps as adjunctive therapies. The primary challenge in EPI discovery has been the highly hydrophobic, poly specific substrate binding site of the target. Recent findings have identified the hydrophobic trap, a narrow phenylalanine-lined groove in the substrate binding site, as the "Achilles heel" of the RND efflux pumps. In this review, we will examine the hydrophobic trap as an EPI target and two chemically distinct series of EPIs that bind there. PMID- 29146109 TI - Neuroactive steroids and metabolic axis. PMID- 29146108 TI - Pancreatectomy for pancreatic incidentaloma: What are the risks? AB - BACKGROUND: Pancreatic incidentalomas (PI) are nowadays common but the benefit risk balance of surgery remains difficult to determine. METHODS: Monocentric retrospective study of 881 pancreatectomies comparing resected PI with symptomatic lesion. Univariate and multivariate (MV) analyses were done to identify risk factors of malignancy in PI undergoing surgery. RESULTS: Overall, 32% of pancreatectomies were performed for PI. Median size of PI was 30 mm (vs 28 mm; p = 0.15) and 49% were cystic (vs 42%; p = 0.197). Resected PI were mostly located in distal pancreas (61% vs 34%; p < 0.001), less frequently malignant (49% vs 59%; p = 0.004). PNETs were more frequent in PI (50% vs 21%; p < 0.001). Distal pancreatectomy (36% vs 23%; p < 0.001) or parenchyma-sparing surgery (34% vs 13%; p < 0.001) were more frequently performed for PI. Overall mortality (1.1% vs 1.2%) and morbidity (70% vs 68%) were not significantly different between both groups. Severe morbidity was lower for PI (15% vs 22%; p = 0.007). In multivariate analysis, age>55 years (HR 6.14; p < 0.001), size >20 mm (HR:26.7; p < 0.001) and biliary dilatation (HR 29.9; p = 0.027) were independent risk factors of malignancy and, when associated, the likelihood of malignancy was above 90%. CONCLUSIONS: PI represent about 30% of indications for pancreatectomy and when resected after careful selection are malignant in 50% of cases. PMID- 29146110 TI - Exploring molecular mechanism of bone-forming capacity of Eurycoma longifolia: Evidence of enhanced expression of bone-related biomarkers. AB - BACKGROUND: Among the numerous well-documented medicinal herbs, Eurycoma longifolia (EL) has gained remarkable recognition due to its promising efficacy of stimulating bone formation in androgen-deficient osteoporosis. Though numerous animal studies have explored the bone-forming capacity of EL, the exact mechanism was yet to be explored. OBJECTIVES: The present study was aimed to investigate the mechanism of bone-forming capacity of EL using MC3T3-E1 as an in vitro osteoblastic model. MATERIALS AND METHODS: The cell differentiation capacity of EL was investigated by evaluating cell growth, alkaline phosphatase (ALP) activity, collagen deposition and mineralization. Taken together, time-mannered expression of bone-related mediators which include bone morphogenic protein-2 (BMP-2), ALP, runt-related transcription factor-2 (Runx-2), osteocalcin (OCN), type I collagen, osteopontin (OPN), transforming growth factor-beta1 (TGF-beta1) and androgen receptor (AR) were measured to comprehend bone-forming mechanism of EL. RESULTS: Results demonstrated a superior cell differentiation efficacy of EL (particularly at a dose of 25 MUg/mL) that was evidenced by dramatically increased cell growth, higher ALP activity, collagen deposition and mineralization compared to the testosterone. Results analysis of the bone-related protein biomarkers indicated that the expression of these mediators was well regulated in EL-treated cell cultures compared to the control groups. These findings revealed potential molecular mechanism of EL for the prevention and treatment of male osteoporosis. CONCLUSION: The resulting data suggested that EL exhibited superior efficacy in stimulating bone formation via up-regulating the expression of various mitogenic proteins and thus can be considered as a potential natural alternative therapy for the treatment of osteoporosis. PMID- 29146111 TI - MicroRNA expression patterns in human anterior cingulate and motor cortex: A study of dementia with Lewy bodies cases and controls. AB - OVERVIEW: MicroRNAs (miRNAs) have been implicated in neurodegenerative diseases including Parkinson's disease and Alzheimer's disease (AD). Here, we evaluated the expression of miRNAs in anterior cingulate (AC; Brodmann area [BA] 24) and primary motor (MO; BA 4) cortical tissue from aged human brains in the University of Kentucky AD Center autopsy cohort, with a focus on dementia with Lewy bodies (DLB). METHODS: RNA was isolated from gray matter of brain samples with pathology defined DLB, AD, AD + DLB, and low-pathology controls, with n = 52 cases initially included (n = 23 with DLB), all with low (<4 h) postmortem intervals. RNA was profiled using Exiqon miRNA microarrays. Quantitative PCR for post hoc replication was performed on separate cases (n = 6 controls) and included RNA isolated from gray matter of MO, AC, primary somatosensory (BA 3), and dorsolateral prefrontal (BA 9) cortical regions. RESULTS: The miRNA expression patterns differed substantially according to anatomic location: of the relatively highly-expressed miRNAs, 150/481 (31%) showed expression that was different between AC versus MO (at p < .05 following correction for multiple comparisons), most (79%) with higher expression in MO. A subset of these results were confirmed in qPCR validation focusing on miR-7, miR-153, miR-133b, miR-137, and miR-34a. No significant variation in miRNA expression was detected in association with either neuropathology or sex after correction for multiple comparisons. CONCLUSION: A subset of miRNAs (some previously associated with alpha-synucleinopathy and/or directly targeting alpha-synuclein mRNA) were differentially expressed in AC and MO, which may help explain why these brain regions show differences in vulnerability to Lewy body pathology. PMID- 29146112 TI - Different concentrations of docosahexanoic acid supplement during lactation result in different outcomes in preterm Sprague-Dawley rats. AB - PROPOSE: In this study, we evaluated the effects of different concentrations of docosahexanoic acid (DHA) supplement on preterm Sprague-Dawley rat pups, and in parallel, measured the phosphorylation activity of the mTOR pathway in the hippocampal CA1 area. METHODS: Preterm Sprague-Dawley rat pups were randomly assigned to experimental groups which included; a sufficient DHA group (100 mg/kg/day); an enriched DHA group (300 mg/kg/day); an excess DHA group (800 mg/kg/day); and a deficient DHA group (normal saline gavage 0.1 ml/10 g). Body weight (g) was measured at days 1/7/14/21/28/42, respectively. Spatial learning and memory were also tested using the Morris water maze at week 6 (day 42). Finally, activation of the mTOR signaling pathway in hippocampal CA1 area were evaluated by western blotting. RESULTS: Postnatal sufficient/enriched docosahexanoic acid supplement ameliorated body weight restriction, spatial learning and memory restriction, and decreased phosphorylation of AKT, mTOR, P70S6K1, and 4EBP1 in hippocampal CA1 area. Furthermore, excess docosahexanoic acid supplement impeded weight gain and spatial learning and memory, perturbed serum unsaturated fatty acid, and downregulated phosphorylation of AKT, mTOR, P70S6K1, and 4EBP1 in hippocampal CA1 area. CONCLUSION: Postnatal sufficient/enriched DHA supplement ameliorated growth and spatial learning and memory impairment and upregulated the mTOR pathway in preterm pups, although excessive DHA supplement did not have any beneficial effects. PMID- 29146113 TI - Editorial Comment. PMID- 29146114 TI - Author Reply. PMID- 29146115 TI - Use of a high-fidelity patient simulator for training 200 medical students in seizure management: A pilot study at the PRESAGE simulation center in Lille. PMID- 29146116 TI - Complications of dexamethasone prescribed for Streptococcus pneumoniae meningitis associated with cerebral vasculitis involving large- to medium-sized vessels. PMID- 29146117 TI - Implications of disturbances in circadian rhythms for cardiovascular health: A new frontier in free radical biology. AB - Cell autonomous circadian "clock" mechanisms are present in virtually every organ, and generate daily rhythms that are important for normal physiology. This is especially relevant to the cardiovascular system, for example the circadian mechanism orchestrates rhythms in heart rate, blood pressure, cardiac contractility, metabolism, gene and protein abundance over the 24-h day and night cycles. Conversely, disturbing circadian rhythms (e.g. via shift work, sleep disorders) increases cardiovascular disease risk, and exacerbates cardiac remodelling and worsens outcome. Notably, reactive oxygen species (ROS) are important contributors to heart disease, especially the pathophysiologic damage that occurs after myocardial infarction (MI, heart attack). However, little is known about how the circadian mechanism, or rhythm desynchrony, is involved in these key pathologic stress responses. This review summarizes the current knowledge on circadian rhythms in the cardiovascular system, and the implications of rhythm disturbances for cardiovascular health. Furthermore, we highlight how free radical biology coincides with the pathogenesis of myocardial repair and remodelling after MI, and indicate a role for the circadian system in the oxidative stress pathways in the heart and brain after MI. This fusion of circadian biology with cardiac oxidative stress pathways is novel, and offers enormous potential for improving our understanding and treatment of heart disease. PMID- 29146118 TI - Transcatheter mitral valve-in-valve implantation in patients with degenerated bio prostheses - Experience of a Centre in Mexico. PMID- 29146119 TI - An updated meta-analysis of pioglitazone exposure and bladder cancer and comparison to the drug's effect on cardiovascular disease and non-alcoholic steatohepatitis. AB - AIM: We performed a meta-analysis of epidemiological studies evaluating exposure to pioglitazone and the risk for bladder cancer and compared these results to the drug's effects on cardiovascular disease (CVD) and non-alcoholic steatohepatitis (NASH). METHODS: Pubmed and Embase were searched for cohort and case control studies for all years through 2016. RESULTS: Data from 17 papers were analyzed. In cohort studies, 822 of 357,888 pioglitazone-exposed patients (0.23%) developed bladder cancer while 7691 of 2,898,682 unexposed (0.26%) did. In case control studies, 3219 of 1,146,916 patients (0.28%) developed bladder cancer. A random effects model showed no significant association between ever vs never use or with cumulative doses of pioglitazone. However, there was a significant association with 1-2 years (HR = 1.28 [1.08-1.55]) and >2 years (HR = 1.42 [1.14-1.77]) of exposure. The numbers needed to treat for one additional case of bladder cancer ranged from 899 to 6380 while to benefit CVD and NASH, 4-256 and 2-12, respectively. CONCLUSIONS: Given the very small prevalence of bladder cancer in diabetic patients exposed (or not) to pioglitazone (<0.3%) and the much greater beneficial effects of the drug on CVD and NASH, the use of pioglitazone should be resurrected. PMID- 29146120 TI - Depressive symptoms and glycemic control in youth with type 2 diabetes participating in the TODAY clinical trial. AB - The relationship between depressive symptoms and glycemic control in youth with type 2 diabetes was assessed at baseline (n = 682), 6, and/or 24 months (n = 576). Neither baseline nor persistence of depressive symptoms was significantly associated with maintenance of glycemic control. Nevertheless, depressive symptoms were common, suggesting the importance of repeated screening. PMID- 29146121 TI - Treatment concentration of high-sensitivity C-reactive protein. PMID- 29146122 TI - Health and wellbeing of Indigenous adolescents in Australia: a systematic synthesis of population data. AB - BACKGROUND: Indigenous populations have high rates of disease and premature mortality. Most Indigenous communities are young, and adolescence (age 10-24 years) provides great opportunities for population health gain. However, the absence of a comprehensive account of Indigenous adolescents' health has been a barrier to effective policy. We aimed to report a national health profile for Indigenous adolescents in Australia. METHODS: We undertook a systematic synthesis of population data to report the health and wellbeing of Indigenous adolescents in Australia. A reporting framework for Indigenous adolescent health in Australia was defined to measure health outcomes, health risks, and sociocultural determinants. Available data (primary data from national surveys and administrative datasets, and available published data) were mapped against the defined reporting framework, and the quality graded, with the highest quality data selected to report a health profile for Indigenous adolescents. Comparison with non-Indigenous adolescents was made where possible, and estimates (disaggregated by age, sex, and remoteness) were reported as relative risks. A national advisory group (six Indigenous young people, three Indigenous adult community members, three researchers, three policy makers, and two service providers, all aged >=16 years) provided input about the reporting framework, interpretation of findings, and policy recommendations. FINDINGS: Data were available for 184 (79%) of 234 elements of the reporting framework. All-cause mortality for Indigenous adolescents (70 per 100 000) was more than twice that of non-Indigenous adolescents, with about 60% of deaths due to intentional self-harm and road traffic injury. 80% of all deaths among Indigenous adolescents were considered as potentially avoidable in the current health system. Communicable diseases (particularly sexually transmitted infections) were leading contributors to morbidity. Almost a third of Indigenous adolescents aged 18-24 years reported high levels of psychological distress (twice the non-Indigenous rate). There was an excess burden of mental disorders and substance use, alongside emerging type 2 diabetes and ischaemic heart disease. Additionally, there were excess intentional and unintentional injuries. Many aspects of this health profile differed markedly from that of non-Indigenous adolescents: rates of acute rheumatic fever, pneumococcal infection, gonorrhoea, and type 2 diabetes resulting in admission to hospital were ten times higher; rates of assault and childbirth in those aged 15 19 years were five times higher; whereas rates of eating disorders, melanoma and other skin cancers, and anaphylaxis were significantly lower. Risks for future ill-health were common; 43% of 15-24 year olds were current tobacco smokers and about 45% had high body mass (overweight or obese). Disadvantage across sociocultural health determinants also emerged, particularly around education. INTERPRETATION: Despite Australia's adolescents having one of the best health profiles globally, Indigenous adolescents have largely been left behind. Adequate responses will require intersectoral actions, including a health system responsive to the needs of Indigenous adolescents. Without a specific focus on adolescents, Australia will not redress Indigenous health inequalities. FUNDING: Australia's National Health and Medical Research Council, Sidney Myer Foundation, and the Murdoch Children's Research Institute. PMID- 29146123 TI - Planetary health: protecting human health on a rapidly changing planet. AB - The impact of human activities on our planet's natural systems has been intensifying rapidly in the past several decades, leading to disruption and transformation of most natural systems. These disruptions in the atmosphere, oceans, and across the terrestrial land surface are not only driving species to extinction, they pose serious threats to human health and wellbeing. Characterising and addressing these threats requires a paradigm shift. In a lecture delivered to the Academy of Medical Sciences on Nov 13, 2017, I describe the scale of human impacts on natural systems and the extensive associated health effects across nearly every dimension of human health. I highlight several overarching themes that emerge from planetary health and suggest advances in the way we train, reward, promote, and fund the generation of health scientists who will be tasked with breaking out of their disciplinary silos to address this urgent constellation of health threats. I propose that protecting the health of future generations requires taking better care of Earth's natural systems. PMID- 29146124 TI - Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. AB - BACKGROUND: Canakinumab, a monoclonal antibody targeting interleukin-1beta, reduces inflammation and cardiovascular event rates with no effect on lipid concentrations. However, it is uncertain which patient groups benefit the most from treatment and whether reductions in the inflammatory biomarker high sensitivity C-reactive protein (hsCRP) correlate with clinical benefits for individual patients. METHODS: The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) used computer-generated codes to randomly allocate 10 061 men and women with a history of myocardial infarction to placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. In a prespecified secondary analysis designed to address the relationship of hsCRP reduction to event reduction in CANTOS, we evaluated the effects of canakinumab on rates of major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality according to on-treatment concentrations of hsCRP. We used multivariable modelling to adjust for baseline factors associated with achieved hsCRP and multiple sensitivity analyses to address the magnitude of residual confounding. The median follow-up was 3.7 years. The trial is registered with ClinicalTrials.gov, number NCT01327846. FINDINGS: Baseline clinical characteristics did not define patient groups with greater or lesser cardiovascular benefits when treated with canakinumab. However, trial participants allocated to canakinumab who achieved hsCRP concentrations less than 2 mg/L had a 25% reduction in major adverse cardiovascular events (multivariable adjusted hazard ratio [HRadj]=0.75, 95% CI 0.66-0.85, p<0.0001), whereas no significant benefit was observed among those with on-treatment hsCRP concentrations of 2 mg/L or above (HRadj=0.90, 0.79-1.02, p=0.11). For those treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality (HRadj=0.69, 95% CI 0.56-0.85, p=0.0004) and all cause mortality (HRadj=0.69, 0.58-0.81, p<0.0001) were both reduced by 31%, whereas no significant reduction in these endpoints was observed among those treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or above. Similar differential effects were found in analyses of the trial prespecified secondary cardiovascular endpoint (which additionally included hospitalisation for unstable angina requiring unplanned revascularisation) and in sensitivity analyses alternatively based on median reductions in hsCRP, on 50% or greater reductions in hsCRP, on the median percent reduction in hsCRP, in dose-specific analyses, and in analyses using a causal inference approach to estimate the effect of treatment among individuals who would achieve a targeted hsCRP concentration. INTERPRETATION: The magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that lower is better for inflammation reduction with canakinumab. FUNDING: Novartis Pharmaceuticals. PMID- 29146126 TI - The role of T helper 25 cells in the immune response to Mycobacterium leprae. PMID- 29146125 TI - All-cause mortality in patients with basal and squamous cell carcinoma: A systematic review and meta-analysis. AB - BACKGROUND: There are varying reports of the association of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) with mortality. OBJECTIVE: To synthesize the available information on all-cause mortality after a diagnosis of BCC or SCC in the general population. METHODS: We searched PubMed (1966-present), Web of Science (1898-present), and Embase (1947-present) and hand-searched to identify additional records. All English articles that reported all-cause mortality in patients with BCC or SCC were eligible. We excluded case reports, case series, and studies in subpopulations of patients. Random effects model meta analyses were performed separately for BCC and SCC. RESULTS: The searches yielded 6538 articles, and 156 were assessed in a full-text review. Twelve studies met the inclusion criteria, and 4 were included in the meta-analysis (encompassing 464,230 patients with BCC and with 175,849 SCC), yielding summary relative mortalities of 0.92 (95% confidence interval, 0.83-1.02) in BCC and 1.25 (95% confidence interval, 1.17-1.32) in SCC. LIMITATIONS: Only a minority of studies controlled for comorbidities. There was significant heterogeneity in meta analysis (chi2P < .001, I2 > 98%), but studies of SCC were qualitatively concordant: all showed statistically significant increased relative mortality. CONCLUSIONS: We found that patients with SCC are at higher risk for death from any cause compared with the general population. PMID- 29146127 TI - Rituximab as first-line adjuvant therapy for pemphigus: Retrospective analysis of long-term outcomes at a single center. PMID- 29146128 TI - Validity and Accuracy of a Mobile Phone Application for the Assessment of Wounds in Recessive Dystrophic Epidermolysis Bullosa. PMID- 29146129 TI - Change over time in the rates of adverse events in patients receiving systemic therapy for psoriasis: A cohort study. PMID- 29146130 TI - Corrigendum to "Familial primary localized cutaneous amyloidosis in a Japanese family" [J. Dermatol. Sci. 83 (2016) 162-164]. PMID- 29146131 TI - Dysregulation of autophagy in melanocytes contributes to hypopigmented macules in tuberous sclerosis complex. AB - BACKGROUND: Tuberous sclerosis complex (TSC) gene mutations lead to constitutive activation of the mammalian target of rapamycin (mTOR) pathway, resulting in a broad range of symptoms. Hypopigmented macules are the earliest sign. Although we have already confirmed that topical rapamycin treatment (an mTOR inhibitor) protects patients with TSC against macular hypopigmentation, the pathogenesis of such lesions remains poorly understood. OBJECTIVE: Recently emerging evidence supports a role for autophagy in skin pigmentation. Herein, we investigated the impact of autophagic dysregulation on TSC-associated hypopigmentation. METHODS: Skin samples from 10 patients with TSC, each bearing characteristic hypopigmented macules, and 6 healthy donors were subjected to immunohistochemical and electron microscopic analyses. In addition, TSC2-knockdown (KD) was investigated in human epidermal melanocytes by melanin content examination, real-time PCR, western blotting analyses, and intracellular immunofluorescence staining. RESULTS: Activation of the mTOR signaling pathway decreased melanocytic pigmentation in hypopigmented macules of patients with TSC and in TSC2-KD melanocytes. In addition, LC3 expression (a marker of autophagy) and autophagosome counts increased, whereas, intracellular accumulation of autophagic degradative substrates (p62 and ubiquitinated proteins) was evident in TSC2-KD melanocytes. Furthermore, depigmentation in TSC2-KD melanocytes was accelerated by inhibiting autophagy (ATG7-KD or bafilomycin A1-pretreatment) and was completely reversed by induction of autophagy via mTOR-dependent (rapamycin) or mTOR-independent (SMER28) exposure. Finally, dysregulation of autophagy, marked by increased LC3 expression and accumulation of ubiquitinated proteins, was also observed in melanocytes of TSC-related hypopigmented macules. CONCLUSION: Our data demonstrate that melanocytes of patients with TSC display autophagic dysregulation, which thereby reduced pigmentation, serving as the basis for the hypomelanotic macules characteristic of TSC. PMID- 29146132 TI - Localization of collagen type 5 in the papillary dermis and its role in maintaining stem cell functions. PMID- 29146133 TI - Synthesis and bio-evaluation of indole-chalcone based benzopyrans as promising antiligase and antiproliferative agents. AB - DNA replication and repair are complex processes accomplished by the concerted action of a network of enzymes and proteins. DNA ligases play a crucial role in these processes by catalyzing the nick joining between DNA strands. As compared to normal cells, elevated levels of human DNA ligase I (hLigI) is reported in some cancers. We studied the inhibition of hLigI mediated DNA nick sealing activity followed by the antiproliferative activity of novel indole-chalcone based benzopyran compounds on cancer cells. One molecule called compound 27 showed a notable preference for inhibition of hLigI as compared to other ligases and showed enhanced cytotoxicity against colon cancer (DLD-1) cells as compared to normal cells. Mechanistic studies showed that compound 27 directly interacts with hLigI in a competitive manner and did not interact with the DNA substrate during ligation. This novel and potent hLigI inhibitor showed significant inhibition of both monolayer culture as well as 3D culture of DLD-1 cells that mimic solid tumor. It also affected the migration of DLD-1 cells indicating the potential anti-metastatic activity. This novel hLigI inhibitor could therefore serve as a promising lead for anticancer drug development. PMID- 29146134 TI - Novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(1,3,5-triazin-2 ylamino)guanidine derivatives: Inhibition of human carbonic anhydrase cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII, anticancer activity, and molecular modeling studies. AB - A series of novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(6 substituted-4-chloro-1,3,5-triazin-2-ylamino)guanidine derivatives 9-20 have been synthesized by substitution of chlorine atom at the 1,3,5-triazine ring in compounds 5-8 with 3- or 4-aminobenzenesulfonamide and 4 (aminomethyl)benzenesulfonamide hydrochloride. All the synthesized compounds were evaluated for their inhibitory activity toward hCA I, II, IX and XII as well as anticancer activity against HeLa, HCT-116 and MCF-7 human tumor cell lines. The investigated compounds showed weak inhibitory potency against the human CA I, while activity toward hCA II was differentiated and depended on structure of inhibitor (KI: 5.4-933.1 nM). Compounds containing the 4-sulfamoylphenyl moiety (9-12) exhibited the strongest inhibitory activity against hCA IX with KI values from 37.1 to 42.9 nM, as well as against hCA XII in range of 31-91.9 nM. The most promising compound 12 (KI = 41 nM) showed the highest selectivity toward hCA IX versus hCA I (hCA I/hCA IX = 18) and hCA II (hCA II/hCA IX = 4). Compound 12 displayed prominent cytotoxic effect selectively toward HeLa cancer cells (IC50 = 17 MUM) and did not exhibit toxicity to the non-cancerous HaCaT cells. In silico analysis suggested that despite the lack of a single binding pose, the selective affinity is conferred by specific interactions with an arginine moiety, as well as better-defined binding modes within the active site. PMID- 29146135 TI - Multivalent oleanolic acid human serum albumin conjugate as nonglycosylated neomucin for influenza virus capture and entry inhibition. AB - We report the synthesis of multivalent oleanolic acid (OA) protein conjugates as nonglycosylated neomucin mimic for the capture and entry inhibition of influenza viruses. Oleanolic acid derivatives bearing an amine-terminated linker were synthesized by esterification of carboxylic acid and further grafted onto the human serum albumin (HSA) via diethyl squarate method. The binding of hemagglutinin (HA) on the virion surface to the synthetic neomucin was evaluated by hemagglutination inhibition assay. The influenza virus capture ability of the PEGylated OA-HSA conjugate was further investigated by Dynamic Light Scattering (DLS), virus capture assay and Isothermal Titration Calorimeter (ITC) techniques. The pronounced agglutination of viral particles, the high capture efficiency and affinity constant indicate that this neoprotein is comparable to natural glycosylated mucin, suggesting that this material could potentially be used as anti-infective barriers to prevent virus from invading host cells. The study also rationalizes the feasibility of antiviral drug development based on OA or other antiviral small molecules conjugated protein strategies. PMID- 29146136 TI - Identification of highly potent BTK and JAK3 dual inhibitors with improved activity for the treatment of B-cell lymphoma. AB - The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors. Among these molecules, approximately two thirds displayed strong inhibitory capacity at less than 10 nM concentration, and four compounds (7e, 7g, 7m and 7n) could significantly inhibit the phosphorylation of BTK and JAK3 enzymes at concentrations lower than 1 nM. Additionally, these pyrimidine derivatives also exhibited enhanced activity to block the proliferation of B-cell lymphoma cells compared with the representative BTK inhibitor ibrutinib. In particular, two structure-specific compounds 7b and 7e displayed stronger activity than reference agents in cell-based evaluation, with IC50 values lower than 10 MUM. Further biological studies, including flow cytometric analysis, and a xenograft model for in vivo evaluation, also indicated their efficacy and low toxicity in the treatment of B-cell lymphoma. These findings provide a new insight for the development of novel anti-B-cell lymphoma drugs with multi-target actions. PMID- 29146137 TI - The Impact of Additives on the Phosphorus, Potassium, and Sodium Content of Commonly Consumed Meat, Poultry, and Fish Products Among Patients With Chronic Kidney Disease. AB - OBJECTIVE: Patients with chronic kidney disease (CKD) are advised to limit their dietary intake of phosphorus and potassium as hyperphosphatemia and hyperkalemia are both associated with an increased risk of mortality. There is uncertainty concerning the actual content of these minerals in the Canadian food supply, as phosphorus and potassium are increasingly being used as food additives. This study aimed to determine the impact of food additives on the chemically analyzed content of phosphorus, potassium, sodium, and protein in commonly consumed meat, poultry, and fish products (MPFs). DESIGN: Foods representing commonly consumed MPF identified by a food frequency questionnaire in dialysis patients were purchased from three major grocery store chains in Canada. MPF with and without phosphorus and potassium additives listed on their ingredient list (n = 76) as well as reference MPF that was additive free (n = 15) were chemically analyzed for phosphorus, potassium, sodium, and protein content according to Association of Analytical Community official methods. RESULTS: Phosphorus, potassium, and sodium additives were present on the ingredient list in 37%, 9%, and 72% of MPF, respectively. Among MPF categories that contained a phosphorus additive, phosphorus content was significantly (P < .05) higher in MPF with phosphorus additives versus MPF without phosphorus additives and MPF reference foods (median [min, max]): (270 [140, 500] mg/100 g) versus (200 [130, 510] mg/100 g) versus (210 [100, 260] mg/100 g), respectively. Among MPF categories containing a potassium additive, foods listing a potassium additive had significantly more (P < .05) potassium than foods that did not list potassium additives and reference foods (900 [750, 1100] mg/100 g) versus (325 [260, 470] mg/100 g) versus (420 [270, 450] mg/100 g). CONCLUSIONS: The use of additives in packaged MPF products as indicated by the ingredient list can significantly contribute to the dietary phosphorus and potassium loads in patients with CKD. Patients with CKD should be educated to avoid MPF foods listing phosphorus and/or potassium additives on the ingredient list, which may lead to improved dietary adherence. PMID- 29146138 TI - Development of Kidney Transplant Fibrosis Is Inversely Associated With Plasma Marine Fatty Acid Level. AB - OBJECTIVE(S): We assessed associations between plasma levels of polyunsaturated fatty acids (PUFAs) and degree of inflammation and interstitial fibrosis in transplanted kidneys. DESIGN: The design of the study was single center cohort study. SUBJECTS: A study population of 156 patients who received a kidney transplant at Oslo University Hospital during 2010. MAIN OUTCOME MEASURE: Kidney transplant biopsies were obtained at 2 months and 1 year after transplantation. Degree of inflammation and interstitial fibrosis in the cortex of transplanted kidneys were estimated semi-quantitatively. Plasma phospholipid fatty acids levels were measured in a stable phase 2 months posttransplant. We used multivariate linear regression to assess associations between plasma levels of PUFAs and degree of inflammation and interstitial fibrosis at 2 months and 1 year postoperatively and change in degree of interstitial fibrosis during the first year after transplantation, adjusting for inflammation and fibrosis risk factors. RESULTS: Higher plasma marine n-3 PUFA levels were associated with less development of interstitial fibrosis in the kidney transplant (unstandardized beta-coefficient -1.12, standardized beta-coefficient -0.18, P = .03) during the first year after transplantation. Plasma levels of alpha linoleic acid, linoleic acid, and arachidonic acid were not associated with development of interstitial fibrosis. No associations were found between plasma levels of PUFAs and inflammation inside fibrotic areas or outside fibrotic areas in the kidney transplant at neither 2 months nor 1 year postoperatively. Linolenic acid levels in plasma were positively associated with change in renal function during the first year after transplantation. CONCLUSION: The inverse association between plasma marine n-3 PUFA levels and development of interstitial fibrosis during the first year after kidney transplantation suggests that marine fatty acid consumption might halt progression of fibrosis. PMID- 29146140 TI - Patient Experiences of Dietary Management in Chronic Kidney Disease: A Focus Group Study. AB - OBJECTIVE: People with chronic kidney disease (CKD) contend with complex dietary recommendations. The challenge in practice is for clinicians to provide individualized support with the frequency and consistency required to sustain dietary changes. This study aimed to describe the experiences of patients with managing dietary recommendations, including their perspectives on the potential to use telehealth to support dietary management in CKD. DESIGN: Focus group study. SUBJECTS: Twenty-one adult patients with CKD (nondialysis) and 3 caregivers (total N = 24) purposively sampled to achieve diverse demographic and clinical characteristics, from two nephrology units in Queensland, Australia. METHODS: Five focus groups were conducted, audio recorded, and transcribed. Transcripts were analyzed using thematic analysis drawing on the principles of grounded theory. MAIN OUTCOME MEASURE: Themes aligned with the research question. RESULTS: We identified five themes: exasperating stagnancy (patronized by redundant advice, confused and unprepared for dietary change, inevitability of failure, and barriers to accessing dietetic services); supporting and sustaining change (receiving regular feedback, incremental and comprehendible modification, practical guidance on food, flexibility in monitoring schedule, and valuing peer advice); fostering ownership (seeking kidney diet information, enacting behavior change, making reminders, and tracking progress against targets); motivators and positive learning instruction (relying on reassurance, positive reinforcement, focusing on allowable foods, and involving family); threats and ambiguities of risk (sugar as the culprit, ubiquity of salt, illegible food labeling, avoiding processed foods, and questioning credibility of sources). CONCLUSIONS: Patients with CKD desire a preventative approach to CKD progression and maintaining their health, however, are stymied by dietary restrictions and a lack of reliable dietetic advice. Easy-to-use telehealth options have the potential to overcome the shortcomings in current health service delivery which may be limiting factors to providing these approaches. They provide patients with pragmatic tools, comprehensible and consistent information which fosters ownership and self monitoring. PMID- 29146139 TI - How to Prevent Renal Cachexia? A Clinical Randomized Pilot Study Testing Oral Supplemental Nutrition in Hemodialysis Patients With and Without Human Immunodeficiency Virus Infection. AB - OBJECTIVE: End-stage renal disease associates with catabolism and sarcopenia. Hypothetically, peroral supplemental nutrition over 6 months prevents catabolism in hemodialysis patients. DESIGN: Prospective randomized pilot study (ClinicalTrials.gov Identifier: NCT00687050). SUBJECTS: Twenty-three hemodialysis patients (15 males and 7 females) with or without human immunodeficiency virus (HIV) infection of 2 ambulatory hemodialysis centers. INTERVENTION: HIV-positive hemodialysis patients (n = 7, Group 1) were started on supplemental nutrition drinks (250 kcal/day), HIV-negative hemodialysis patients (n = 16, Group 2) were randomized to supplemental nutrition drinks (250 kcal/day) or received none. MAIN OUTCOME MEASURES: Body impedance analysis, anthropometric measures, magnetic resonance imaging results for mid-iliopsoas muscle cross-sectional area and laboratory parameters including albumin, cytokines at baseline, and at 6 months follow-up. RESULTS: Seven patients in Group 1 (mean age: 50.6 +/- 9.6 years) and 16 patients in Group 2 (mean age: 54.0 +/- 13.3 years) were recruited. Serum creatinine (Group 1: 6.4 +/- 3.0 mg/dL; Group 2: 10.7 +/- 2.5 mg/dL; P < .01), Body impedance analysis-derived phase angle alpha (Group 1: 5.1 +/- 1.2; Group 2: 6.9 +/- 1.6; P < .01), mid-arm circumference (Group 1: 26.1 +/- 1.3 cm; Group 2: 29.6 +/- 2.4 cm; P < .01) were less in Group 1 versus Group 2 patients at baseline suggesting that HIV-positive hemodialysis patients had a poorer nutritional status at baseline. At 6-month follow-up, mortality was higher in Group 1 patients (29%) than in Group 2 patients (6%). There was no significant treatment effect on nutritional status in survivors of Group 1 or in the supplemental nutrition arm of Group 2 when compared with baseline or to untreated controls. CONCLUSIONS: A new oral supplemental nutrition over 6 months had no treatment effect in surviving HIV-positive hemodialysis patients or in maintenance hemodialysis patients without HIV infection. The limitations of this study were small study size and unexpected high mortality among HIV-positive hemodialysis patients. PMID- 29146141 TI - The Myth of Water and Salt: From Aquaretics to Tenapanor. AB - The impact of water intake has been studied in several renal diseases. For example, increasing water intake is useful to prevent primary and secondary nephrolithiasis. In autosomal dominant polycystic kidney disease, arginine vasopressin (AVP) is involved in the progression of the disease, and water intake could play a therapeutic role by inhibiting the synthesis of AVP, but its efficacy is still controversial. Conversely, the use of aquaretics, which are antagonists of AVP V2 receptors, results in the reduction of the increase rate of total kidney volume with a slower decline of glomerular filtration rate. In chronic kidney disease, AVP contributes to glomerular hyperfiltration, arterial hypertension, and synthesis of renin, resulting in renal sclerosis. Increased water intake could reduce AVP activation determining a potential protective effect on the kidney, but its efficacy has not yet been clearly demonstrated. On the other side, sodium and potassium play an important role in the control of arterial blood pressure and are involved in the development and progression of chronic kidney disease. Reduction of sodium intake and increase of potassium intake determine a decrease of arterial blood pressure with a beneficial effect on the kidney; however, adherence to sodium restriction is very poor. Regarding this, sodium-hydrogen exchanger isoform 3 inhibitors may reduce sodium absorption in the gut. The most recent sodium-hydrogen exchanger isoform 3 inhibitor, known as tenapanor, reduces extracellular fluid volume, left ventricular hypertrophy, albuminuria, and blood pressure in experimental studies and increases fecal loss of sodium in humans. PMID- 29146142 TI - Visceral Adiposity Index as a Predictor of Chronic Kidney Disease in a Relatively Healthy Population in Taiwan. AB - OBJECTIVES: Abdominal obesity is an independent risk factor for cardiovascular disease and chronic kidney disease (CKD). Visceral adiposity index (VAI), a simple formula representing visceral adipose dysfunction, has already been proven to have a strong correlation with various cardiometabolic disorders. Limited studies are available regarding the relationship between VAI and renal function decline. Therefore, the purpose of this study was to evaluate the relationship between VAI and renal function and to estimate the risk of chronic kidney disease in a relatively healthy adult population in Taiwan. DESIGN: The design of the study is retrospective cross-sectional analysis. SUBJECTS: This study involved 23,570 subjects aged >=18 years who underwent annual heath checkups between January and December 2013. A multivariate logistic regression model was used to assess the relationship between VAI and CKD. Receiver-operating characteristic curve and Youden index were developed to determine the discrimination power of VAI for metabolic syndrome and CKD. INTERVENTION: None, observational study. MAIN OUTCOME MEASURE: The main outcome measure of this study was CKD. RESULTS: In our study, the adjusted odds ratio (OR) of abnormal VAI for CKD was 1.5 (95% confidence interval [CI], 1.08-2.08; P = .016) in all subjects. A higher VAI was superior in association with CKD in men than women (OR, 1.62; 95% CI, 1.13-2.32; P = .009 vs. OR, 1.28; 95% CI, 0.66-2.47; P = .469, respectively). The area under the curve for VAI was 0.694 (95% CI, 0.660-0.729; P < .001), and using a Youden index with a cut-off VAI value of 2.96 for CKD discrimination obtained a sensitivity of 67.7% and specificity of 65.1%. CONCLUSIONS: A higher VAI score was associated with increased risks of CKD. VAI would be an applicable tool for early detection of CKD in relatively healthy adults in Taiwan, especially men. PMID- 29146143 TI - Reported Mistreatment During the Surgery Clerkship Varies by Student Career Choice. AB - BACKGROUND: Student mistreatment is often a major concern during the surgery clerkship. We hypothesized that mistreatment is decreasing and that career choice may reflect perceived mistreatment. METHODS: We surveyed 2319 physicians about their surgery clerkships. Mistreatment reporting was correlated to physician specialty and medical school graduation year. RESULTS: The response rate was 18.9% (440/2319). Recent graduates reported less mistreatment than more senior graduates (24.3%-50%, p = 0.0198). General surgeons (3/31, 9%), neurologists (1/7, 14%), and subspecialty surgeons (8/35, 19%) reported the lowest mistreatment rates. Psychiatrists (9/16, 56%), internists (31/69, 45%), pathologists (5/13, 38%), and emergency physicians (5/14, 36%) reported the highest rates. The reported rate of mistreatment by nonsurgeons was higher than surgeons (30.4% versus 14.3%, p < 0.0046). Mistreatment included sexual harassment, verbal abuse, and lack of teaching. CONCLUSIONS: Mistreatment during surgery appears to be improving. Its perception varies by the field of training, indicating variable interpretations of what constitutes mistreatment. PMID- 29146144 TI - Drosophila adult muscle development and regeneration. AB - Myogenesis is a highly orchestrated, complex developmental process by which cell lineages that are mesodermal in origin generate differentiated multinucleate muscle cells as a final product. Considerable insight into the process of myogenesis has been obtained for the embryonic development of the larval muscles of Drosophila. More recently, the postembryonic development of the muscles of the adult fly has become a focus of experimental investigation of myogenesis since specific flight muscles of the fly manifest remarkable similarities to vertebrate muscles in their development and organization. In this review, we catalog some of the milestones in the study of myogenesis in the large adult-specific flight muscles of Drosophila. The identification of mesoderm-derived muscle stem cell lineages, the characterization of the symmetric and asymmetric divisions through which they produce adult-specific myoblasts, the multifaceted processes of myoblast fusion, and the unexpected discovery of quiescent satellite cells that can be activated by injury are discussed. Moreover, the finding that all of these processes incorporate a plethora of signaling interactions with other myogenic cells and with niche-like neighboring tissue is considered. Finally, we briefly point out possible future developments in the area of Drosophila myogenesis that may lead to of new avenues of genetic research into the roles of muscle stem cells in development, disease and aging. PMID- 29146145 TI - ADARs and editing: The role of A-to-I RNA modification in cancer progression. AB - Cancer arises when pathways that control cell functions such as proliferation and migration are dysregulated to such an extent that cells start to divide uncontrollably and eventually spread throughout the body, ultimately endangering the survival of an affected individual. It is well established that somatic mutations are important in cancer initiation and progression as well as in creation of tumor diversity. Now also modifications of the transcriptome are emerging as a significant force during the transition from normal cell to malignant tumor. Editing of adenosine (A) to inosine (I) in double-stranded RNA, catalyzed by adenosine deaminases acting on RNA (ADARs), is one dynamic modification that in a combinatorial manner can give rise to a very diverse transcriptome. Since the cell interprets inosine as guanosine (G), editing can result in non-synonymous codon changes in transcripts as well as yield alternative splicing, but also affect targeting and disrupt maturation of microRNA. ADAR editing is essential for survival in mammals but its dysregulation can lead to cancer. ADAR1 is for instance overexpressed in, e.g., lung cancer, liver cancer, esophageal cancer and chronic myoelogenous leukemia, which with few exceptions promotes cancer progression. In contrast, ADAR2 is lowly expressed in e.g. glioblastoma, where the lower levels of ADAR2 editing leads to malignant phenotypes. Altogether, RNA editing by the ADAR enzymes is a powerful regulatory mechanism during tumorigenesis. Depending on the cell type, cancer progression seems to mainly be induced by ADAR1 upregulation or ADAR2 downregulation, although in a few cases ADAR1 is instead downregulated. In this review, we discuss how aberrant editing of specific substrates contributes to malignancy. PMID- 29146146 TI - Herpes zoster in hospitalized adults: Practice gaps, new evidence, and remaining questions. AB - Herpes zoster can present many uncertainties for consulting dermatologists. We review the current guidelines and recent literature on important issues that arise in the care of hospitalized patients with herpes zoster, including infection control isolation practices, treatment courses for zoster and acute zoster-associated pain, and indications for long-term prophylaxis. We present the findings of an inpatient zoster management practices survey of the membership of the Society of Dermatology Hospitalists, an expert resource group of the American Academy of Dermatology, and discuss directions for future investigation and potential opportunities for management improvements in light of these collective data. PMID- 29146148 TI - Prevalence of the blaNDM gene among metallo-beta-lactamase-producing Gram negative isolates from western Nepal. PMID- 29146147 TI - Age-induced and photoinduced changes in gene expression profiles in facial skin of Caucasian females across 6 decades of age. AB - BACKGROUND: Intrinsic and extrinsic factors, including ultraviolet irradiation, lead to visible signs of skin aging. OBJECTIVE: We evaluated molecular changes occurring in photoexposed and photoprotected skin of white women 20 to 74 years of age, some of whom appeared substantially younger than their chronologic age. METHODS: Histologic and transcriptomics profiling were conducted on skin biopsy samples of photoexposed (face and dorsal forearm) or photoprotected (buttocks) body sites from 158 women. 23andMe genotyping determined genetic ancestry. RESULTS: Gene expression and ontologic analysis revealed progressive changes from the 20s to the 70s in pathways related to oxidative stress, energy metabolism, senescence, and epidermal barrier; these changes were accelerated in the 60s and 70s. The gene expression patterns from the subset of women who were younger appearing were similar to those in women who were actually younger. LIMITATIONS: Broader application of these findings (eg, across races and Fitzpatrick skin types) will require further studies. CONCLUSIONS: This study demonstrates a wide range of molecular processes in skin affected by aging, providing relevant targets for improving the condition of aging skin at different life stages and defining a molecular pattern of epidermal gene expression in women who appear younger than their chronologic age. PMID- 29146149 TI - Recent patterns in antibiotic use for children with group A streptococcal infections in Japan. AB - OBJECTIVES: Antibiotics are the most frequently prescribed medicines for children, however inappropriate antibiotic prescribing is prevalent. This study investigated recent trends in antibiotic use and factors associated with appropriate antibiotic selection among children with group A streptococcal infections in Japan. METHODS: Records of outpatients aged <18years with a diagnosis of group A streptococcal infection were obtained using the Japan Medical Data Center database. Prescription patterns for antibiotics were investigated and factors associated with penicillin use were evaluated using a multivariable log-binomial regression model. RESULTS: Overall, 5030 patients with a diagnosis of group A streptococcal infection were identified. The most commonly prescribed antibiotics were third-generation cephalosporins (53.3%), followed by penicillins (40.1%). In the multivariable log-binomial regression analysis, out of-hours visits were independently associated with penicillin prescriptions [prevalence ratio (PR)=1.10, 95% confidence interval (CI) 1.03-1.18], whereas clinical departments other than paediatrics and internal medicine were related to non-penicillin prescriptions (PR=0.57, 95% CI 0.46-0.71). CONCLUSIONS: Third generation cephalosporins were overprescribed for children with group A streptococcal infections. This investigation provides important information for promoting education for physicians and for constructing health policies for appropriate antibiotic prescription. PMID- 29146150 TI - The effect of cold acclimation on active ion transport in cricket ionoregulatory tissues. AB - Cold-acclimated insects defend ion and water transport function during cold exposure. We hypothesized that this is achieved via enhanced active transport. The Malpighian tubules and rectum are likely targets for such transport modifications, and recent transcriptomic studies indicate shifts in Na+-K+ ATPase (NKA) and V-ATPase expression in these tissues following cold acclimation. Here we quantify the effect of cold acclimation (one week at 12 degrees C) on active transport in the ionoregulatory organs of adult Gryllus pennsylvanicus field crickets. We compared primary urine production of warm- and cold-acclimated crickets in excised Malpighian tubules via Ramsay assay at a range of temperatures between 4 and 25 degrees C. We then compared NKA and V-ATPase activities in Malpighian tubule and rectal homogenates from warm- and cold acclimated crickets via NADH-linked photometric assays. Malpighian tubules of cold-acclimated crickets excreted fluid at lower rates at all temperatures compared to warm-acclimated crickets. This reduction in Malpighian tubule excretion rates may be attributed to increased NKA activity that we observed for cold-acclimated crickets, but V-ATPase activity was unchanged. Cold acclimation had no effect on rectal NKA activity at either 21 degrees C or 6 degrees C, and did not modify rectal V-ATPase activity. Our results suggest that an overall reduction, rather than enhancement of active transport in the Malpighian tubules allows crickets to maintain hemolymph water balance during cold exposure, and increased Malpighian tubule NKA activity may help to defend and/or re-establish ion homeostasis. PMID- 29146151 TI - A New Two Component Compression System Turning an Elastic Bandage into an Inelastic Compression Device: Interface Pressure, Stiffness, and Haemodynamic Effectiveness. AB - INTRODUCTION: Bandage application does not exert consistent compression pressure, leading to extremely variable compression when applied to patients. A new elastic bandage can exert a predefined pressure independently of healthcare providers and the size of the wrapped limb. The bandage system includes a series of non stretchable patches that when applied to the bandage make it stiff. The aim of this work was to assess, in an experimental setting, the venous ejection fraction (EF) from the lower leg and the tolerability of this new bandage in a group of patients affected by superficial venous incompetence. METHODS: EF was measured using strain gauge plethysmography under baseline conditions and the bandage was applied with a supine pressure of 20 and 30 mmHg, with and without the stiff patches, in 25 patients with severe venous reflux in the great saphenous vein. The interface pressure of the bandages was measured simultaneously in the medial gaiter area. RESULTS: All patients showed EF values that were significantly reduced compared with normal individuals. Elastic bandages with an average pressure of 20 and 30 mmHg in the supine position achieved a slight improvement in EF, and, after applying non-stretchable patches on the same bandage with similar resting pressure, EF was restored to its normal range (p < .001). Improvement in EF correlates with the pressure differences between standing and lying pressure and between muscle systole and diastole during exercise. CONCLUSION: This study confirms that inelastic is much more effective than elastic compression for improving impaired venous haemodynamics. The test material can be applied with a predetermined pressure, which considerably enhances the consistency of application, and it is easily transformed into an inelastic system just by applying stiff patches without any stretch and without significantly increasing the comfortable supine pressure. PMID- 29146152 TI - Improved antifungal activity of barley derived chitinase I gene that overexpress a 32kDa recombinant chitinase in Escherichia coli host. AB - Agricultural crops suffer many diseases, including fungal and bacterial infections, causing significant yield losses. The identification and characterisation of pathogenesis-related protein genes, such as chitinases, can lead to reduction in pathogen growth, thereby increasing tolerance against fungal pathogens. In the present study, the chitinase I gene was isolated from the genomic DNA of Barley (Hordeum vulgare L.) cultivar, Haider-93. The isolated DNA was used as template for the amplification of the ~935bp full-length chitinase I gene. Based on the sequence of the amplified gene fragment, class I barley chitinase shares 93% amino acid sequence homology with class II wheat chitinase. Interestingly, barley class I chitinase and class II chitinase do not share sequence homology. Furthermore, the amplified fragment was expressed in Escherichia coli Rosetta strain under the control of T7 promoter in pET 30a vector. Recombinant chitinase protein of 35kDa exhibited highest expression at 0.5mM concentration of IPTG. Expressed recombinant protein of 35kDa was purified to homogeneity with affinity chromatography. Following purification, a Western blot assay for recombinant chitinase protein measuring 35kDa was developed with His-tag specific antibodies. The purified recombinant chitinase protein was demonstrated to inhibit significantly the important phytopathogenic fungi Alternaria solani, Fusarium spp, Rhizoctonia solani and Verticillium dahliae compared to the control at concentrations of 80MUg and 200MUg. PMID- 29146154 TI - Biological effects of carbon ion beams with various LETs on budding yeast Saccharomyces cerevisiae. AB - It has been established that irradiation with higher linear energy transfer (LET) increases lethality and mutagenicity more than that with lower LET. However, the characteristics specific to carbon ion beam have not yet been elucidated. Yeast cells were irradiated with carbon ions with an LET of 13 or 50keV/MUm, and cell survival and mutation frequency were analyzed. The results, combined with our previous findings for ions with an LET of 107keV/MUm, demonstrated that, in conjunction with an increase in LET, cell survival decreased, while mutation frequency increased. This indicates that a carbon ion beam with a higher LET is more mutagenic than one with a lower LET. PMID- 29146153 TI - The stress kinase JNK regulates gap junction Cx43 gene expression and promotes atrial fibrillation in the aged heart. AB - BACKGROUND: The stress kinase c-jun N-terminal kinase (JNK) is critical in the pathogenesis of cardiac diseases associated with an increased incidence of atrial fibrillation (AF), the most common arrhythmia in the elderly. We recently discovered that JNK activation is linked to the loss of gap junction connexin43 (Cx43) and enhanced atrial arrhythmogenicity. However, direct evidence for JNK mediated impairment of intercellular coupling (cell-cell communication) in the intact aged atrium is lacking, as is evidence for whether and how JNK suppresses Cx43 in the aged human atrium. METHODS AND RESULTS: JNK activity in human atrial samples is correlated with both reduced Cx43 expression and increasing age. Using a unique technique of optical mapping space constant measurement, we found that impaired intercellular coupling and reduced Cx43 were linked to enhanced activation of JNK in intact aged rabbit atria. These JNK-associated alterations were further confirmed in naturally JNK activated aged mice and in cardiac specific inducible MKK7D (JNK upstream activator) young mice. Moreover, JNK inhibition, using either JNK specific inhibitors in aged wild-type (WT) mice and JNK activator anisomycin-treated young WT mice or JNK1/2 dominant-negative mice with genetically inhibited cardiac JNK activity, completely eliminated these functional abnormalities. Furthermore, we discovered for the first time that long term JNK activation downregulates Cx43 expression via c-jun suppressed transcriptional activity of the Cx43 gene promoter. CONCLUSION: Our results demonstrate that JNK is a critical regulator of Cx43 expression, and that augmented JNK activation in aged atria downregulates Cx43 to impair cell-cell communication and promote the development of AF. JNK inhibition may represent a promising therapeutic approach to prevent or treat AF in the elderly. PMID- 29146155 TI - A Comparison of Childbirth Costs for Adolescents and Adults From 2001 to 2010. AB - PURPOSE: Although teenage birth rates in America have fallen to a historic low of 26.2 births per 1,000 teenagers, the U.S. remains behind the rest of the industrialized world. Adolescent pregnancy is relatively well discussed in today's literature, with ever more detailed estimates constantly emerging to quantify the cost of children born to America's teenagers. This study, however, describes the financial cost of childbirth in the U.S. with a specific focus on understanding the impact of adolescent childbirth in comparison to that of adult women and of annual childbirth as a whole. METHODS: This retrospective cohort study used data from the 2001-2010 Healthcare Cost and Utilization Project Nationwide Inpatient Sample (HCUP-NIS), a uniform, multistate database containing information regarding approximately 8 million hospital inpatient stays per year of data. Data were analyzed involving payment type, length of stay, and aggregate cost of all childbirths to adolescent girls (under 18 years of age) and to adult women. RESULTS: This study found that Medicaid pays for the majority (70%) of births to adolescent girls, whereas private insurance pays for the majority (53%) of births to adult women. This was in contrast to the Medicaid coverage of 41% of all childbirths within the study time frame. Furthermore, the aggregate cost of childbirths to adolescent girls paid for by Medicaid was $670 million. CONCLUSIONS: Beyond their social impact, births to adolescent mothers place a financial burden on the national economy. Stronger efforts must be made to decrease adolescent childbirth. PMID- 29146156 TI - Latest guidelines for hypertension: adopt and adapt. PMID- 29146157 TI - Angiotensin-converting enzyme 2 activation ameliorates pulmonary endothelial dysfunction in rats with pulmonary arterial hypertension through mediating phosphorylation of endothelial nitric oxide synthase. AB - This study aims to investigate the effect of angiotensin-converting enzyme 2 (ACE2) activation on pulmonary endothelial function in the process of preventing pulmonary arterial hypertension (PAH) in rat models and to explore the underlying mechanisms. Specific pathogen free rats were randomly divided into five groups including control group, PAH group, PAH + Resorcinolnaphthalein (Res) group (ACE2 activation), PAH + Res + MLN4760 group (ACE2 inhibition), and PAH + Res + L-NAME group (endothelial nitric oxide synthase [eNOS] inhibition). Rat PAH model was constructed using combined left pneumonectomy with a single dose of monocrotaline injection 1 week after the surgery, and the rats were then given corresponding reagents. Hemodynamics, endothelial function, and pathologic changes were evaluated 3 weeks after monocrotaline injection. The concentration of nitric oxide (NO), expression of eNOS, and phosphorylation of eNOS at Ser1177 and Thr495 in the lung tissues from rats were also investigated.The Res-induced activation of ACE2 led to decreased mean pulmonary arterial pressure (mPAP) and pulmonary artery remodeling in the PAH + Res group comparing with the PAH rats (P < .05). In addition, the reduction in mPAP induced by acetylcholine (Ach) was augmented in PAH + Res group (P < .05), but this was not observed under the treatment with sodium nitroprusside (SNP) (P > .05). The ratio of decrease in mPAP caused by Ach to that caused by SNP (Ach/SNP) was also increased (P < .05) in ACE2-activated rats. However, the protective effects of ACE2 activation on PAH were counteracted by co-administration of MLN4760, an ACE2 antagonist (all P > .05). The mechanistic study showed that the concentration of NO in the lung tissues was downregulated in the PAH group but upregulated in the PAH + Res group (P < .05), whereas the NO concentration in the PAH + Res + MLN4760 group was not obviously different from that in the PAH group (P > .05). Regarding the factors regulating NO release, we found that the eNOS was upregulated in the PAH group, and Res did not affect the expression of eNOS. The phosphorylation of eNOS at Ser1177 was increased but at Thr495 was reduced after Res injection, when compared with the PAH group (P < .05). As expected, co-injection of MLN4760 eliminated these differences (P > .05). The reduction in mPAP induced by Ach was attenuated in the PAH + Res + L-NAME group compared with the PAH + Res group (P < .05), but this was not observed in rats treated with SNP (P > .05). The Ach/SNP ratio of decline in mPAP was also decreased in the PAH + Res + L-NAME group (P < .05). Activation of ACE2 had a protective role in the development of PAH via improving the function of pulmonary arterial endothelium. This effect was potentially mediated by promoted NO release as a consequence of increased phosphorylation of eNOS at Ser1177 and dephosphorylation of eNOS at Thr495. PMID- 29146158 TI - Plasma microRNA-155-5p is increased among patients with chronic kidney disease and nocturnal hypertension. AB - MicroRNAs play multiple roles in the regulation of blood pressure (BP). Nevertheless, to date, no study has assessed the association between microRNA plasma expression and BP control in chronic kidney disease (CKD) patients. Given this background, we evaluated the plasma expression of miR-155-5p, a translational inhibitor of angiotensin receptor type I, in CKD patients, to determine the association between miR-155-5p level and BP control. In this single center cross-sectional study, we analyzed the miR-155-5p concentration by quantitative reverse transcriptase polymerase chain reaction using the U6 snRNA as a reference gene and 24-hour ambulatory blood pressure monitoring in CKD patients (stage >=2) in relation to a control group of healthy age-matched and gender-matched individuals, with normal BP proven by the ambulatory blood pressure monitoring. We enrolled a total of 105 patients with CKD (stages 2-5, including 33 kidney renal transplant recipients), aged 59 +/- 14 years; 47% males and 26 healthy volunteers (aged 55 +/- 13, 50% male). Within the study group, a total of 36 patients (40%) presented with an average 24-hour systolic BP (SBP) >=130 mm Hg and 41 patients (45%) presented nocturnal hypertension (NHT; SBP >=120 mm Hg or diastolic BP >= 70 mm Hg). miRNA-155-5p was increased in plasma of CKD patients with median expression relative to control subjects equal to 2.92 (1.34-5.58). Interestingly, the plasma miRNA-155-5p expression was significantly higher in patients with NHT: 4.04 (2.92-10.8) versus 2.01 (1.21-3.07), P = .001 and its expression maintained an independent association with the average nocturnal SBP (coefficient B = 4.368, P = .047) by a multivariate regression analysis adjusted for confounders. The miR-155-5p was increased among CKD patients and further increased among subjects presenting with NHT. Further studies are warranted to determine the role of this non-coding RNA as a potential novel biomarker and therapeutic target in the non-dipping CKD individuals, characterized by increased cardiovascular risk. PMID- 29146159 TI - A patient with malignant pleural mesothelioma carrying BRAF V600E mutation responding to vemurafenib. PMID- 29146160 TI - Posterolateral Corner Injuries of the Knee at the National Football League Combine: An Imaging and Outcomes Analysis. AB - PURPOSE: (1) To determine the epidemiology, examination findings, imaging findings, and associated injuries of posterolateral corner (PLC) injuries in players participating in the National Football League (NFL) Combine and (2) to evaluate the impact of PLC injuries on performance compared with matched controls. METHODS: All PLC injuries identified at the NFL Combine between 2009 and 2015 were reviewed. The inclusion criteria were any player who had clinical findings or a previous surgical procedure consistent with a PLC injury and who participated in medical and performance testing at the NFL Combine. PLC injuries were identified by evaluating the side-to-side difference in lateral-compartment laxity with varus stress and reviewing magnetic resonance imaging studies. NFL performance outcomes (draft position and number of games played or started within the first 2 years) were compared with matched controls. RESULTS: Of the 2,285 players assessed at the NFL Combine, 16 (0.7%) were identified with a history of a grade II or III PLC tear and surgical management whereas 7 additional players (0.3%) had a PLC injury diagnosed on clinical examination, for 23 total PLC injuries (1%). On examination, 13 of 22 knees (59%) were shown to be stable; however, most of those managed surgically had significantly improved stability (13 of 15 stable) versus none of those managed nonsurgically (0 of 7 stable). Surgically managed PLC-injured athletes started significantly fewer games than controls (5.3 vs 10.5, P = .03); the mean draft position for players with surgically treated PLC injuries was 139.7 versus controls' mean draft position of 111.3. Of the 16 athletes treated operatively, 2 reported a PLC injury recurrence; both were managed nonoperatively. CONCLUSIONS: A small percentage of players at the NFL Combine had evidence of a previous PLC injury (1%), with 0.4% having residual varus asymmetry on clinical examination. A worse overall mean draft position for isolated PLC-injured athletes versus controls was found: 132.8 versus 111.3 (P = .02). It is recommended that the use of varus stress radiographs be considered for NFL Combine athletes to objectively determine their grade of injury. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29146161 TI - Intraoperative Workflow for All-Inside Anterior Cruciate Ligament Reconstruction: An In Vitro Biomechanical Evaluation of Preconditioning and Knot Tying. AB - PURPOSE: To evaluate and compare the effect of preconditioning according to intraoperative workflow on the elongation behavior of single-side and fully knotted all-inside anterior cruciate ligament (ACL) reconstruction configurations in a biomechanical in vitro study. METHODS: Four full construct all-inside ACL reconstruction groups (n = 8 per group) were tested using porcine tibias and bovine tendons. Groups included both an all-inside configuration with one- (group 1) and both-side knotted adjustable loop-length devices (group 2), without and with performing intraoperative preconditioning (group 1-intraoperative preconditioned [IPC], group 2-IPC). Adjustable loop-length devices for control groups were knotted according to test configurations. Intraoperative preconditioning specimens were further precycled for 10 times at 0.5 Hz and manually retensioned before knotting. All groups underwent dynamic cycling in position and force control mode each for 1,000 cycles at 0.75 Hz according to in vitro loading parameters replicating the in vivo ACL environment. Finally, a load to-failure test at 50 mm/min was performed. RESULTS: Intraoperative preconditioning increases initial graft tension for single- (242 +/- 22 N vs 174 +/- 13 N; P < .0001) and both-side knotted configurations (225 +/- 15 N vs 159 +/ 10 N; P < .0001) compared with controls and allows maintained graft tension at higher levels until reaching the end of position-controlled cyclic loading. Furthermore, dynamic elongation is reduced for one- (1.93 +/- 0.28 vs 0.76 +/- 0.12; P < .0001) and both-side knotted (1.84 +/- 0.20 vs 0.96 +/- 0.32; P < .0001) configurations by 61% and 47%, respectively. No intergroup (group 1 vs group 2 and group 1-IPC vs group 2-IPC) statistically significant differences could be found between one- and both-side knotted configurations. CONCLUSIONS: All-inside ACL reconstruction with preconditioning according to intraoperative workflow leads to a statistically significant improved mechanical behavior and may allow for optimizing initial graft tension and elongation for all-inside ACL reconstruction to reduce knee laxity. A single-side knotted configuration achieves similar stabilization strength to fully knotted constructs. CLINICAL RELEVANCE: Graft insertion until tunnel docking increases the intratunnel graft portion that may optimize graft incorporation. Eliminating a suture knot stack may improve intraoperative workflow and reduce postoperative knot irritation. PMID- 29146162 TI - Return to Play Criteria Following Surgical Stabilization for Traumatic Anterior Shoulder Instability: A Systematic Review. AB - PURPOSE: To identify and describe in the existing literature any criteria used for return to play following surgical stabilization for traumatic, anterior shoulder instability. METHODS: We performed a systematic review evaluating surgical stabilization for primary traumatic anterior shoulder instability in skeletally mature patients with a minimum of 1-year follow-up using Level I to IV studies in PubMed and EMBASE from January 1994 to January 2017. RESULTS: Fifty eight studies with at least 1 explicitly stated criterion for return to play were identified from a review of more than 5,100 published articles. Seven different categories of return to play criteria were identified, the most common of which were time from surgery (89.6%), strength (18.9%), and range of motion (13.8%). Pain, stability, proprioception, and postoperative radiographic evaluation were also used. As hypothesized, in 75.8% of the included studies (44/58), time was the only criterion explicitly used. The most commonly used time for return to play was 6 months. CONCLUSIONS: This systematic review identifies 7 criteria that have been used in the available literature to determine when patients are ready to return to play; however, consistent with our hypothesis, 75% of studies used time from surgery as the sole listed criterion, with the most commonly used time point of 6 months postoperative. All of these criteria can be used in future research to develop a comprehensive checklist of functional criteria in hopes of reducing recurrent injury. LEVEL OF EVIDENCE: Level IV, systematic review. PMID- 29146163 TI - A Comparative Biomechanical Study of Femoral Cortical Suspension Devices for Soft Tissue Anterior Cruciate Ligament Reconstruction: Adjustable-Length Loop Versus Fixed-Length Loop. AB - PURPOSE: To determine whether there are differences between adjustable-length loop and fixed-length loop devices in terms of the amount of displacement, temporal pattern of displacement, and ultimate failure load when tested using 4,500 cycles of sinusoidal loading with high loads (100-400 N). METHODS: Two cortical suspension devices with a fixed- or adjustable-length loop were tested. For our comparisons, a 20-mm fixed-length loop device and a fixed-length loop device with the same loop length were used. Comparisons between the devices used both a device-only model (DOM) and a device-bone-soft-tissue graft construct model (CM). RESULTS: In the DOM, the adjustable-length loop device showed weaker mechanical properties. Mean cumulative peak displacement was 1.91 mm for the adjustable-length loop device and 0.74 mm for the fixed-length loop device (P = .001). The displacement of the adjustable-length loop device increased between 1,000 and 4,500 cycles; in contrast, that of the fixed-length loop device reached a plateau. However, there was never displacement greater than 3 mm. In addition, the adjustable-length loop device showed a weaker ultimate failure load (925 N vs 1,410 N, P = .001). In the CM, the difference in cumulative peak displacement between the 2 groups decreased and did not reach statistical significance. The displacement of both devices showed a similar pattern. In addition, there was no difference in ultimate failure load between the 2 groups. CONCLUSIONS: There was no significant difference in terms of total displacement, temporal pattern of displacement, and ultimate failure load between the 2 devices in the CM, which is the more clinically relevant model. Furthermore, even in the DOM, the difference in total displacement was small and did not reach a clinically meaningful level. Therefore, both devices can be used effectively during anterior cruciate ligament reconstruction with soft-tissue graft. CLINICAL RELEVANCE: Both femoral cortical suspension devices with adjustable- and fixed-length loops can be used with similar mechanical properties during anterior cruciate ligament reconstruction. PMID- 29146164 TI - Magnetic Resonance Imaging Validation of Tibial Tubercle Transfer Distance in the Fulkerson Osteotomy: A Clinical and Cadaveric Study. AB - PURPOSE: To validate the medialization and anteriorization distances, and the osteotomy angle of anteromedialization tibial tubercle osteotomies using postoperative axial imaging. METHODS: From March 2004 to August 2015, 117 consecutive patients who underwent anteromedialization osteotomies of the tibial tubercle by a single surgeon were identified. Only patients with pre- and postoperative magnetic resonance imaging (MRI) studies were included. Using MRI multiplanar reformats, distances that the tibial tubercle was translated medially (medialization) and anteriorly (anteriorization) were measured. In addition, the osteotomy angle was measured on the postoperative MRI. The measured values were compared with intraoperative estimates. Tibial tubercle osteotomies were then performed on 3 cadaveric knee specimens and imaged with pre- and postprocedure MRIs to correlate intraoperative measurements with MRI findings. RESULTS: A total of 40 patients (41 knees) (34.2%) had both pre- and postoperative MRIs and were included. Compared with intraoperative assessment, MRI measured medialization values average 94.7% (standard deviation [SD] 37.7) of dictated values (P = .1). MRI measured anteriorization averaged less than half of dictated values (48.9%, SD 18.2%, P < .0001). MRI measured osteotomy angles averaged 67.2% of dictated values (SD 50.3%, P < .0001). The steepest osteotomy angle that could be performed without violating the posterior cortex and/or endangering the posterior neurovascular structures was 46.3 degrees . CONCLUSIONS: Surgeons often overestimate both the anteriorization distance and the osteotomy angle in anteromedialization tibial tubercle osteotomies. The steepest osteotomy angle is less than the 60 degrees described in the literature. Modifications should be considered when more anteriorization is desired with tubercle transfers. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29146165 TI - Preliminary Results of Arthroscopic Superior Capsule Reconstruction with Dermal Allograft. AB - PURPOSE: The purpose of this study was to evaluate the short-term outcomes of arthroscopic superior capsule reconstruction (SCR) with dermal allograft for the treatment of irreparable massive rotator cuff tears (MRCTs). METHODS: A multicenter study was performed on patients undergoing arthroscopic SCR for irreparable MRCTs. The minimum follow-up was 1 year. Range of motion and functional outcome according to visual analog scale (VAS) pain, American Shoulder and Elbow Surgeons (ASES) score, and subjective shoulder value (SSV) score were assessed preoperatively and at final follow-up. Radiographs were used to evaluate the acromiohumeral interval (AHI). RESULTS: Fifty-nine patients with a mean age of 62.0 years had a minimum follow-up of 1 year. Twenty-five patients (42.4%) had a prior rotator cuff repair. Forward flexion improved from 130 degrees preoperative to 158 degrees postoperative, and external rotation improved from 36 degrees to 45 degrees , respectively (P < .001). Compared with preoperative values, the VAS decreased from 5.8 to 1.7, the ASES score improved from 43.6 to 77.5, and the SSV score improved from 35.0 to 76.3 (P < .001). The AHI was 6.6 mm at baseline and improved to 7.6 mm at 2 weeks postoperatively but decreased to 6.7 mm at final follow-up. Based on postoperative magnetic resonance imaging, 45% (9 of 20) of the grafts demonstrated complete healing. Forty-six (74.6%) cases were considered a success. Eleven patients (18.6%) underwent a revision procedure including 7 reverse shoulder arthroplasties. CONCLUSIONS: Arthroscopic SCR using dermal allograft provides a successful outcome in approximately 70% of cases in an initial experience. The preliminary results are encouraging in this difficult to manage patient population, but precise indications are important and graft healing is low in our initial experience. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29146166 TI - Hip Dysplasia: Prevalence, Associated Findings, and Procedures From Large Multicenter Arthroscopy Study Group. AB - PURPOSE: To report observational findings of patients with acetabular dysplasia undergoing hip arthroscopy. METHODS: We performed a comparative case series of multicenter registry patients from January 2014 to April 2016 meeting the inclusion criteria of isolated hip arthroscopy, a documented lateral center-edge angle (LCEA), and completion of preoperative patient-reported outcome measures. A retrospective analysis compared range of motion, intra-articular pathology, and procedures of patients with dysplasia (LCEA <=25 degrees ) and patients without dysplasia (LCEA >25 degrees ). RESULTS: Of 1,053 patients meeting the inclusion criteria, 133 (13%) had dysplasia with a mean LCEA of 22.8 degrees (standard deviation, 2.4 degrees ) versus 34.6 degrees (standard deviation, 6.3 degrees ) for non-dysplasia patients. There were no statistically significant differences in preoperative modified Harris Hip Score, International Hip Outcome Tool-12 score, or visual analog scale score (pain). Cam deformity occurred in 80% of dysplasia patients. There was a significant difference in internal rotation between the dysplasia (21 degrees ) and non-dysplasia groups (16 degrees , P < .001). Mean internal rotation (33.5 degrees ; standard deviation, 15.6 degrees ) of the dysplastic subjects without cam morphology was greater than that of the dysplastic patients with cam morphology (18.5 degrees ; standard deviation, 11.6 degrees ; P < .001). Hypertrophic labra were found more commonly in dysplastic (33%) than non-dysplastic hips (11%, P < .001). Labral tears in patients with dysplasia were treated by repair (76%), reconstruction (13%), and selective debridement (11%); labral treatments were not significantly different between cohorts. The most common nonlabral procedures included femoroplasty (76%) and synovectomy (73%). There was no significant difference between the dysplasia and non-dysplasia groups regarding capsulotomy types and capsular closure rates (96% and 92%, respectively). CONCLUSIONS: Dysplasia, typically of borderline to mild severity, comprises a significant incidence of surgical cases (13%) by surgeons performing high-volume hip arthroscopy. Despite having similar preoperative pain and functional profiles to patients without dysplasia, dysplasia patients may have increased flexed-hip internal rotation. Commonly associated cam morphology significantly decreases internal rotation. Arthroscopic labral repair, femoroplasty, and closure of interportal capsulotomy are the most commonly performed procedures. LEVEL OF EVIDENCE: Level III, therapeutic comparative case series. PMID- 29146167 TI - Incidence and Return to Play After Biceps Tenodesis in Professional Baseball Players. AB - PURPOSE: To determine return to play (RTP) rates after biceps tenodesis (BT) in professional baseball players. METHODS: Major League Baseball has maintained a prospective database containing all major and minor league baseball players who have undergone shoulder surgery since 2010. All players who had undergone BT were included. Minimum follow-up was 24 months, and thus we included data from 2010 to 2013. Using this database we determined the incidence, demographics, prior surgery history, concomitant procedures, RTP rates, and time to RTP. RESULTS: Between 2010 and 2013, 17 professional baseball players underwent BT. Seventy-one percent of the 17 were pitchers, and 29% of the 17 were in the major league. Forty-seven percent of the 17 had a history of a prior shoulder surgery and 47% of the 17 underwent concomitant labral repair. For all players, RTP after BT was 35%, whereas RTP after BT without a concomitant reconstructive procedure was 44% in 10 +/- 6 months, and 25% for those who underwent both BT and a concomitant reconstructive procedure (P = .620). All players who RTP were able to return to at least 20 games at their preoperative level of play. Return to professional play was 80% among position players and 17% among pitchers (P = .028). For those pitchers who RTP, performance was not statistically changed. CONCLUSIONS: Professional baseball players who undergo BT have a 35% rate of return to their prior level of play. Whereas pitchers have only a 17% rate of RTP, position players have an 80% rate of RTP. Of those who returned, all returned to their prior level of play. The pitchers who returned had no significant change in performance statistics. LEVEL OF EVIDENCE: Level IV, therapeutic study, a case series. PMID- 29146168 TI - Bone Marrow-Derived Mesenchymal Stromal Cells Enhanced by Platelet-Rich Plasma Maintain Adhesion to Scaffolds in Arthroscopic Simulation. AB - PURPOSE: To assess the response of bone marrow-derived mesenchymal stromal cells (bMSCs) enhanced by platelet-rich plasma (PRP) in the setting of a normal human tendon (NHT), a demineralized bone matrix (DBM), and a fibrin scaffold (FS) with simulated arthroscopic mechanical washout stress. METHODS: Bone marrow was aspirated from the humeral head and concentrated. BMSCs were counted, plated, and grown to confluence. Cells were seeded onto 3 different scaffolds: (1) NHT, (2) DBM, and (3) FS. Each scaffold was treated with a combination of (+)/(-) PRP and (+)/(-) arthroscopic washout simulation. A period of 60 minutes was allotted before arthroscopic washout. Adhesion, proliferation, and differentiation assays were performed to assess cellular activity in each condition. RESULTS: Significant differences were seen in mesenchymal stromal cell adhesion, proliferation, and differentiation among the scaffolds. DBM and FS showed superior results to NHT for cell adhesion, proliferation, and differentiation. PRP significantly enhanced cellular adhesion, proliferation, and differentiation. Arthroscopic simulation did not significantly decrease bMSC adhesion. CONCLUSIONS: We found that the type of scaffold impacts bMSCs' behavior. Both scaffolds (DBM and FS) were superior to NHT. The use of an arthroscopic simulator did not significantly decrease the adhesion of bMSCs to the scaffolds nor did it decrease their biologic differentiation potential. In addition, PRP enhanced cellular adhesion, proliferation, and differentiation. CLINICAL RELEVANCE: Improved healing after tendon repair can lead to better clinical outcomes. BMSCs are attractive for enhancing healing given their accessibility and regenerative potential. Application of bMSCs using scaffolds as cell carriers relies on arthroscopic feasibility. PMID- 29146169 TI - Arthroscopy After Traumatic Hip Dislocation: A Systematic Review of Intra articular Findings, Correlation With Magnetic Resonance Imaging and Computed Tomography, Treatments, and Outcomes. AB - PURPOSE: To describe the literature concerning patient demographic characteristics and intra-articular injury seen at arthroscopy after traumatic hip dislocation, describe the reported computed tomography (CT) and magnetic resonance findings with arthroscopic correlation, and describe the reported arthroscopic treatments performed with complications and outcomes. METHODS: A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for assessment of arthroscopy after hip dislocation. Three databases were searched, and study screening and data abstraction were performed in duplicate. RESULTS: Thirty-one heterogeneous case series and case reports were included in the analysis from the initial search yielding 780 results, including reports of 151 patients who underwent arthroscopy after traumatic hip dislocation. A wide spectrum of intra articular injury was reported, with a high prevalence of labral tears, intra articular bodies, ligamentum teres injuries, and chondral damage. CT had a sensitivity of 87.3% for detecting intra-articular fragments; however, 43.3% of patients who had a preoperative CT scan with negative findings for intra articular fragments did show fragments at arthroscopy. Magnetic resonance had a sensitivity of 95.0% for detecting labral tears. There were no major complications directly attributed to arthroscopic surgery. A total of 75 of 151 patients were followed up for a median of 2 years after surgery, with osteoarthritis reported in 4.0% and avascular necrosis in 2.7%. CONCLUSIONS: In patients with traumatic hip dislocation, heterogeneously reported previously published cases show that arthroscopy reveals a broad spectrum of intra-articular damage amenable to arthroscopic intervention. CT is not sensitive in the detection of intra-articular bodies in all cases. Although no serious periprocedural adverse events were reported, only 49.7% of patients had reported follow-up data, and further prospective studies would be necessary to show the safety and efficacy of arthroscopy in comparison with conventional treatment algorithms of hip dislocation. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 29146170 TI - Identification of tagitinin C from Tithonia diversifolia as antitrypanosomal compound using bioactivity-guided fractionation. AB - Tithonia diversifolia (Asteraceae), is used as traditional medicine in tropical countries for the treatment of various diseases, including malaria. Although numerous studies have assessed the antimalarial properties, nothing is known about the effect of T. diversifolia extracts on trypanosomiasis. In this study extracts of T. diversifolia aerial parts were evaluated for their bioactivity against Trypanosoma brucei. The activity was studied against bloodstream forms of T. brucei (TC221), as well as against mammalian cells (BALB/3T3 mouse fibroblasts), as a counter-screen for toxicity. Both methanolic and aqueous extracts showed significant effects with IC50 values of 1.1 and 2.2MUg/mL against T. brucei (TC221) and 5.2 and 3.7MUg/mL against BALB/3T3 cells, respectively. A bioassay-guided fractionation on the methanolic extract yielded in identification of active fractions (F8 and F9) with IC50 values of 0.41 and 0.43MUg/mL, respectively, against T. brucei (TC221) and 1.4 and 1.5MUg/mL, respectively, against BALB/3T3 cells,. The phytochemical composition of the extracts and the purified fractions were investigated using HPLC-ESI-MS/MS and 1D and 2D NMR spectra showing the presence of sesquiterpene lactones that in turn were subjected to the isolation procedure. Tagitinin A and C were rather active but the latter presented a very strong inhibition on T. brucei (TC221) with an IC50 value of 0.0042MUg/mL. This activity was 4.5 times better than that of the reference drug suramin. The results of this study shed light on the antitrypanosomal effects of T. diversifolia extracts and highlighted tagitinin C as one of the possible responsible for this effect. Further structure activity relationships studies on tagitinins are needed to consider this sesquiterpenes as lead compounds for the development of new antitrypanosomal drugs. PMID- 29146171 TI - The Evidence is Out There; Let's Keep on Looking For It Re: The Evidence-Base Surrounding Lung Isolation is Often Wider Than Described. PMID- 29146172 TI - Placement of the Double-Lumen Endotracheal Tube: One Size Doesn't Fit All. PMID- 29146173 TI - Blocking inflammation: a new arsenal against atherosclerosis. PMID- 29146174 TI - Proteome-Level Analysis Indicates Global Mechanisms for Post-Translational Regulation of RRM Domains. AB - RRM, or RNA-recognition motif, domains are the largest class of single-stranded RNA binding domains in the human proteome and play important roles in RNA processing, splicing, export, stability, packaging, and degradation. Using a current database of post-translational modifications (PTMs), ProteomeScout, we found that RRM domains are also one of the most heavily modified domains in the human proteome. Here, we present two interesting findings about RRM domain modifications, found by mapping known PTMs onto RRM domain alignments and structures. First, we find significant overlap of ubiquitination and acetylation within RRM domains, suggesting the possibility for ubiquitination-acetylation crosstalk. Additionally, an analysis of quantitative study of ubiquitination changes in response to proteasome inhibition highlights the uniqueness of RRM domain ubiquitination - RRM domain ubiquitination decreases in response to proteasome inhibition, whereas the majority of sites increase. Second, we found conservation of tyrosine phosphorylation within the RNP1 and RNP2 consensus sequences, which coordinate RNA binding - suggesting a possible role for regulation of RNA binding by tyrosine kinase signaling. These observations suggest there are unique regulatory mechanisms of RRM function that have yet to be uncovered and that the RRM domain represents a model system for further studies on understanding PTM crosstalk. PMID- 29146175 TI - Autobiographical memory sources of threats in dreams. AB - Temporal sources of dream threats were examined through the paradigm of the Threat Simulation Theory. Two groups of young adults (18-24 years old), who did not experience severe threatening events in the year preceding their dream and reported a dream either with or without threats, were included. Participants (N = 119) kept a log of daily activities and a dream diary, indicating whether dream components referred to past experiences. The occurrence of oneiric threats correlated with the reporting of threats in the daily logs, their average severity, and the stress level experienced the day preceding the dream. The group whose dreams contained threats had significantly more references to temporal categories beyond one year than the group with dreams without threats. Our findings suggest that in the absence of recent highly negative emotional experiences, the threat simulation system selects memory traces of threatening events experienced in the past. PMID- 29146176 TI - Neosaxitoxin, a Paralytic Shellfish Poison toxin, effectively manages bucked shins pain, as a local long-acting pain blocker in an equine model. AB - Local anesthesia is an effective method to control pain. Neosaxitoxin is a phycotoxin whose molecular mechanism includes a reversible inhibition of voltage gated sodium channels at the axonal level, impeding nerve impulse propagation. The present study was designed to evaluate the clinical efficacy of Neosaxitoxin as a local long-acting pain blocker in horse bucked shins, and it was found to effectively control pain. While Neosaxitoxin and Gonyautoxin, another Paralytic Shellfish Poison (PSP) toxin, have been successfully used in humans as long lasting pain blockers, this finding marks the first time a PSP has been shown to have an established effect in veterinary medicine. PMID- 29146177 TI - Clostridium difficile and Clostridium sordellii toxins, proinflammatory versus anti-inflammatory response. AB - Clostridium difficile and Clostridium sordellii produce related potent toxins (C. difficile toxin A (TcdA) and toxin B (TcdB), C. sordellii lethal toxin (TcsL) and hemorrhagic toxin (TcsH)) which belong to the large clostridial glucosylating toxin (LCGT) family. TcsL is the main C. sordellii toxin as most of toxigenic C. sordellii strains only synthesize this toxin. Intestinal colonization by C. difficile subsequently to unbalanced microbiota is accompanied by release of toxins which induce local tissue destruction and severe inflammatory response. TcdA and TcdB inactivate Rho-GTPases. Notably inactivation of RhoA results in the stimulation of the pyrin/ASC inflammasome, which is one of the main signaling pathways used by these toxins to trigger the inflammatory response. In contrast, TcsL induces an anti-inflammatory effect, mainly by inactivating Ras proteins which results in blockage of the cell cycle and killing of immune cells. The absence or moderate local inflammatory response allows C. sordellii spreading in deep tissues, production of toxin which is released in the general circulation and causes a toxic shock syndrome. The toxin mechanisms of pro-versus anti inflammatory responses are discussed. PMID- 29146178 TI - Use of mathematical modelling to assess the impact of vaccines on antibiotic resistance. AB - Antibiotic resistance is a major global threat to the provision of safe and effective health care. To control antibiotic resistance, vaccines have been proposed as an essential intervention, complementing improvements in diagnostic testing, antibiotic stewardship, and drug pipelines. The decision to introduce or amend vaccination programmes is routinely based on mathematical modelling. However, few mathematical models address the impact of vaccination on antibiotic resistance. We reviewed the literature using PubMed to identify all studies that used an original mathematical model to quantify the impact of a vaccine on antibiotic resistance transmission within a human population. We reviewed the models from the resulting studies in the context of a new framework to elucidate the pathways through which vaccination might impact antibiotic resistance. We identified eight mathematical modelling studies; the state of the literature highlighted important gaps in our understanding. Notably, studies are limited in the range of pathways represented, their geographical scope, and the vaccine pathogen combinations assessed. Furthermore, to translate model predictions into public health decision making, more work is needed to understand how model structure and parameterisation affects model predictions and how to embed these predictions within economic frameworks. PMID- 29146179 TI - Soft palate reconstruction after radionecrosis: Combined anterolateral thigh adipofascial and nasoseptal flaps. AB - Although radiation-based treatment for nasopharyngeal cancer may achieve excellent long term oncologic results, late effects of therapy may lead to soft tissue radionecrosis and velopharyngeal insufficiency (VPI). Repair of these oro- and nasopharyngeal defects presents a complex reconstructive challenge. We present a case of a long-term survivor treated with chemoradiotherapy for nasopharyngeal cancer who developed progressive dysphagia, velopharyngeal insufficiency, and radionecrosis of the nasopharynx and soft palate, leading to tracheostomy and gastrostomy tube dependence. A staged reconstruction was performed, initially with a tubed nasoseptal flap for a creation of a mucosal lined nasopharyngeal port. An adipofascial anterolateral thigh free flap was subsequently performed for soft palate reconstruction. Within 2 months, the oropharyngeal reconstruction had remucosalized and she was decannulated, taking an oral diet. Her speech was intelligible and she had good nasal breathing without symptoms of velopharyngeal insufficiency. PMID- 29146180 TI - Chlorogenic acid attenuates diabetic retinopathy by reducing VEGF expression and inhibiting VEGF-mediated retinal neoangiogenesis. AB - Diabetic retinopathy (DR) is one of the most common and serious complications of diabetes mellitus (DM). This study aims to investigate the amelioration of chlorogenic acid (CGA) on proliferative DR (PDR) via focusing on inhibiting retinal neoangiogenesis. CGA reduced the increased cell proliferation, migration and tube formation induced by vascular endothelial growth factor (VEGF) in human retinal endothelial cells (HREC) and choroid-retinal endothelial RF/6A cells. CGA abrogated VEGF-induced the phosphorylation of VEGFR2 and its downstream mitogen activated extracellular regulated kinase (MEK1/2), extracellular regulated protein kinase (ERK1/2) and p38 kinase. CGA reduced high glucose (HG)-induced the activation of microglia BV-2 cells. CGA also reduced HG-induced the increased VEGF expression and hypoxia-inducible factor 1-alpha (HIF-1alpha) translocation into nucleus in BV2 cells. Retinal immunofluorescence staining with cluster of differentiation 31 (CD31) and retinal histopathological observation both demonstrated that CGA (1, 10mg/kg) decreased the increased retinal vessels in streptozotocin (STZ)-induced hyperglycemic mice. CGA reduced the elevated serum VEGF level and microglia activation in STZ-induced hyperglycemic mice. In conclusion, CGA inhibits retinal neoangiogenesis during the process of DR by abrogating HG-induced HIF-1alpha-mediated paracrine VEGF expression in microglia cells and inhibiting VEGF-induced angiogenesis in retinal endothelial cells. PMID- 29146181 TI - Proximity labeling of cis-ligands of CD22/Siglec-2 reveals stepwise alpha2,6 sialic acid-dependent and -independent interactions. AB - Lectins expressed on the cell surface are often bound and regulated by the membrane molecules containing the glycan ligands on the same cell (cis-ligands). However, molecular nature and function of cis-ligands are generally poorly understood partly because of weak interaction between lectins and glycan ligands. Cis-ligands are most extensively studied in CD22 (also known as Siglec-2), an inhibitory B lymphocyte receptor specifically recognizing alpha2,6 sialic acids. CD22, CD45 and IgM are suggested to be ligands of CD22. Here we labeled molecules in the proximity of CD22 in situ on B cell surface using biotin-tyramide. Molecules including CD22, CD45 and IgM were labeled in wild-type but not ST6GalI /- B cells that lack alpha2,6 sialic acids, indicating that these molecules associate with CD22 by lectin-glycan interaction, and are therefore cis-ligands. In ST6GalI-/- B cells, these cis-ligands are located in a slightly more distance from CD22. Thus, the lectin-glycan interaction recruits cis-ligands already located in the relative proximity of CD22 through non-lectin-glycan interaction to the close proximity. Moreover, cis-ligands are labeled in Cmah-/- B cells that lack Neu5Gc preferred by mouse CD22 as efficiently as in wild-type B cells, indicating that very low affinity lectin-glycan interaction is sufficient for recruiting cis-ligands, and can be detected by proximity labeling. Thus, proximity labeling with tyramide appears to be a useful method to identify cis ligands and to analyze their interaction with the lectins. PMID- 29146182 TI - Plakophilin3 increases desmosome assembly, size and stability by increasing expression of desmocollin2. AB - Previous reports show that the desmosomal plaque protein plakophilin3 (PKP3) is essential for desmosome formation. Here, we report that PKP3 over-expression decreases calcium dependency for de novo desmosome formation and makes existing cell-cell adhesion junctions more resilient in low calcium medium due to an increase in desmocollin2 expression. PKP3 overexpression increases the stability of other desmosomal proteins independently of the increase in DSC2 levels and regulates desmosome formation and stability by a multimodal mechanism affecting transcription, protein stability and cell border localization of desmosomal proteins. PMID- 29146183 TI - D Rhamnose beta-hederin inhibits migration and invasion of human breast cancer cell line MDA-MB-231. AB - Many natural products have been shown to have inhibitory effects on the metastatic process of various cancers including breast cancer. An active triterpenoid saponin D Rhamnose beta-hederin (DRbeta-H) from Clematis ganpiniana, has been known induce the apoptosis of breast cancer cells, but the effect of DRbeta-H on the metastasis of breast cancer cells is largely unknown. In this study, we demonstrated that a non-cytotoxic concentration of DRbeta-H markedly suppressed wound healing migration, migration through the chamber and invasion through the matrigel. In addition, DRbeta-H regulated expression of RNPC1, E cadherin proteins of MDA-MB-231 cells. Furthermore, RNPC1 knockdown decreased the DRbeta-H-induced up-regulation of RNPC1 and E-Cadherin in MDA-MB-231 cells. RNPC1 knockdown reduced the anti-metastasis activities of DRbeta-H, meaning that the up rugulation of RNPC1 by DRbeta-H is essential for its anti-metastatis activities. These results suggest that DRbeta-H might be a potential therapeutic candidate for the treatment of breast cancer metastasis. PMID- 29146184 TI - Glutamate production from ammonia via glutamate dehydrogenase 2 activity supports cancer cell proliferation under glutamine depletion. AB - Cancer cells rapidly consume glutamine as a carbon and nitrogen source to support proliferation, but the cell number continues to increase exponentially after glutamine is nearly depleted from the medium. In contrast, cell proliferation rates are strongly depressed when cells are cultured in glutamine-free medium. How cancer cells survive in response to nutrient limitation and cellular stress remains poorly understood. In addition, rapid glutamine catabolism yields ammonia, which is a potentially toxic metabolite that is secreted into the extracellular space. Here, we show that ammonia can be utilized for glutamate production, leading to cell proliferation under glutamine-depleted conditions. This proliferation requires glutamate dehydrogenase 2, which synthesizes glutamate from ammonia and alpha-ketoglutarate and is expressed in MCF7 and T47D cells. Our findings provide insight into how cancer cells survive under glutamine deprivation conditions and thus contribute to elucidating the mechanisms of tumor growth. PMID- 29146185 TI - Biomarker identification for statin sensitivity of cancer cell lines. AB - Statins are potent cholesterol reducing drugs that have been shown to reduce tumor cell proliferation in vitro and tumor growth in animal models. Moreover, retrospective human cohort studies demonstrated decreased cancer-specific mortality in patients taking statins. We previously implicated membrane E cadherin expression as both a marker and mechanism for resistance to atorvastatin mediated growth suppression of cancer cells; however, a transcriptome-profile based biomarker signature for statin sensitivity has not yet been reported. Here, we utilized transcriptome data from fourteen NCI-60 cancer cell lines and their statin dose-response data to produce gene expression signatures that identify statin sensitive and resistant cell lines. We experimentally confirmed the validity of the identified biomarker signature in an independent set of cell lines and extended this signature to generate a proposed statin-sensitive subset of tumors listed in the TCGA database. Finally, we predicted drugs that would synergize with statins and found several predicted combination therapies to be experimentally confirmed. The combined bioinformatics-experimental approach described here can be used to generate an initial biomarker signature for anticancer drug therapy. PMID- 29146186 TI - Human soluble thrombomodulin-induced blockade of peripheral HMGB1-dependent allodynia in mice requires both the lectin-like and EGF-like domains. AB - Thrombomodulin (TM), an endothelial protein with anti-coagulant activity, is composed of 5 domains, D1-D5. Recombinant human soluble TM (TMalpha) consisting of D1-D3, which is generated in CHO cells, suppresses inflammatory and nociceptive signals by inactivating high mobility group box 1 (HMGB1), one of damage-associated molecular patterns. TMalpha sequesters HMGB1 with the lectin like D1 and promotes its degradation by thrombin binding to the EGF-like D2. We prepared TM's D123, D1 and D2 by the protein expression system of yeast, and evaluated their effects on HMGB1 degradation in vitro and on the allodynia caused by HMGB1 in distinct redox forms in mice in vivo. TMalpha and TM's D123, but not D1, promoted the thrombin-dependent degradation of all-thiol (at-HMGB1) and disulfide HMGB1 (ds-HMGB1), an effect mimicked by TM's D2, though to a lesser extent. Intraplantar administration of TMalpha and TM's D123, but not D1, D2 or D1 plus D2, strongly prevented the mechanical allodynia caused by intraplantar at HMGB1, ds-HMGB1 or lipopolysaccharide in mice. Our data suggest that, apart from the role of D3, TMalpha and TM's D123 require both lectin-like D1 capable of sequestering HMGB1 and EGF-like D2 responsible for thrombin-dependent degradation of HMGB1, in abolishing the allodynia caused by exogenous or endogenous HMGB1. PMID- 29146187 TI - LOX-related collagen crosslink changes act as an initiator of bone fragility in a ZDF rats model. AB - Diabetes mellitus type 2 (DM2) results in bone abnormalities that manifest as increased bone fragility. Bone consists of two phases, the mineral phase and the matrix phase, and disorders in both are seen in DM2. However, the phase in which DM2 mediated bone fragility is initiated is still unknown. In this study, a male Zucker diabetic fatty (fa/fa) (ZDF) rat model was used to investigate the underlying mechanism initiating DM2 mediated bone fragility. The fracture surface morphology, pre- and post-yield bone mechanical behavior, insoluble collagen volume, lysyl oxidase family (LOX) enzyme levels and correlation analysis was performed to determine the relationship between insoluble collagen and post-yield behavior. Four weeks after the induction of diabetes, insoluble collagen was decreased in only the matrix phase in diabetic rats. Consistently, mechanical testing of the bone showed changes only in post-yield behavior. Diabetic rats also had decreased levels of enzymes involved in insoluble collagen formation (LOX and LOXL1 families). Correlation analysis demonstrated that insoluble collagen was a positive regressor of post-yield displacement (R = 0.894, P < 0.001) and post-yield energy (R = 0.918, P < 0.001). Together, these findings suggest that bone fragility in DM2 is initiated in the matrix phase and that the LOX family may play a critical part in the pathogenesis of DM2 mediated bone fragility. PMID- 29146188 TI - Old drug new tricks: Chlorhexidine acts as a potential allosteric inhibitor toward PAK1. AB - This paper describes the identification of chlorhexidine, an agent commonly used in clinical as a novel potential allosteric inhibitor of PAK1. In cellular assays, chlorhexidine showed a good inhibitory profile, and its inhibitory profile was even better than IPA-3, a well-known allosteric inhibitor. In pharmacology experiments, chlorhexidine successfully inhibited the relief of PAK1 dimer and inhibited the activation of PAK1. Our findings offer an insight for the new drug development of PAK1 inhibitor. We also provide a possible explanation for the phenomenon that the application of the chlorhexidine in peritoneal lavage inhibited the development of tumor. PMID- 29146189 TI - Oxidized low-density lipoprotein promotes osteoclast differentiation from CD68 positive mononuclear cells by regulating HMGB1 release. AB - Patients with ankylosing spondylitis (AS) have an increased risk for cardiovascular mortality. The circulating ox-LDL/LDL ratio is associated with subclinical atherosclerosis in patients with systemic lupus erythematosus. In this study, we found that the ox-LDL/LDL ratio was increased in AS patients. The levels of serum RANKL and HMGB1 were also elevated in AS patients, and the number of CD68+/RANK+ cells was increased in peripheral blood from AS patients. 0.03% ox LDL in LDL, similar to the ox-LDL/LDL ratio in peripheral blood from AS patients, promoted cytoplasmic translocation and release of HMGB1 as well as RANK expression. Further investigation evidenced that ox-LDL-induced EGR1 expression contributed to the cytoplasmic translocation of HMGB1 and CD68 assisted the secretion of HMGB1 from cytoplasm to extracellular matrix. Extracellular HMGB1 induced RANK expression in CD68+ mononuclear cells, forming osteoclast precursors that were differentiated to osteoclasts in response to RANKL. Taken together, these results suggested that the changes, including ox-LDL/LDL ratio, CD68+/RANK+ cells number, and the levels of RANKL and HMGB1 in AS patients, favored osteoclastogenesis. PMID- 29146190 TI - Newly developed selective immunoinactivation assay revealed reduction in adipose triglyceride lipase activity in peripheral leucocytes from patients with idiopathic triglyceride deposit cardiomyovasculopathy. AB - Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare and newly identified disease among patients requiring cardiac transplantation. TGCV is characterized by cardiomyocyte steatosis and triglyceride (TG)-deposit atherosclerosis, resulting from the abnormal intracellular metabolism of TG. TGCV is classified into primary and idiopathic types. Primary TGCV carries ultra-rare genetic mutations in the adipose triglyceride lipase (ATGL), a rate-liming enzyme that hydrolyzes intracellular TG in adipose and non-adipose tissues. Idiopathic TGCV, first identified among autopsied individuals with diabetes mellitus (DM) with severe heart diseases, shows no ATGL mutations and its causes and underlying mechanisms are still unknown. TGCV is difficult to diagnose in daily clinics, thereby demanding feasible diagnostic procedures. We aimed to develop an assay to measure ATGL activity using peripheral leucocytes. Human his6-ATGL was expressed in COS1 cells, purified to homogeneity, and used to raise a polyclonal antibody neutralizing TG-hydrolyzing activity of ATGL. We developed a selective immunoinactivation assay (SIIA) for the quantitation of ATGL activity in cell lysates of leucocytes by the antibody neutralizing ATGL activities. ATGL activity was measured in 13 idiopathic TGCV patients, with two patients with primary TGCV as the negative control. Healthy (non-DM) and DM controls without heart diseases were also subjected. The developed SIIA assay revealed significant reduction in ATGL activity in leucocytes from patients with idiopathic TGCV who did not carry ATGL mutations as compared with non-DM and DM controls. Thus, ATGL in leucocytes may be an important biomarker for the diagnosis of TGCV and our assay may provide insights into pathophysiology and elucidate the underlying mechanism of TGCV and related disorders. PMID- 29146191 TI - Automatic delineation of brain regions on MRI and PET images from the pig. AB - BACKGROUND: The increasing use of the pig as a research model in neuroimaging requires standardized processing tools. For example, extraction of regional dynamic time series from brain PET images requires parcellation procedures that benefit from being automated. COMPARISON WITH EXISTING METHODS: Manual inter modality spatial normalization to a MRI atlas is operator-dependent, time consuming, and can be inaccurate with lack of cortical radiotracer binding or skull uptake. NEW METHOD: A parcellated PET template that allows for automatic spatial normalization to PET images of any radiotracer. RESULTS: MRI and [11C]Cimbi-36 PET scans obtained in sixteen pigs made the basis for the atlas. The high resolution MRI scans allowed for creation of an accurately averaged MRI template. By aligning the within-subject PET scans to their MRI counterparts, an averaged PET template was created in the same space. We developed an automatic procedure for spatial normalization of the averaged PET template to new PET images and hereby facilitated transfer of the atlas regional parcellation. Evaluation of the automatic spatial normalization procedure found the median voxel displacement to be 0.22+/-0.08mm using the MRI template with individual MRI images and 0.92+/-0.26mm using the PET template with individual [11C]Cimbi-36 PET images. We tested the automatic procedure by assessing eleven PET radiotracers with different kinetics and spatial distributions by using perfusion-weighted images of early PET time frames. CONCLUSION: We here present an automatic procedure for accurate and reproducible spatial normalization and parcellation of pig PET images of any radiotracer with reasonable blood-brain barrier penetration. PMID- 29146192 TI - Calcium imaging method to visualize the spatial patterns of neural responses in the pygmy squid, Idiosepius paradoxus, central nervous system. AB - BACKGROUND: Cephalopods exhibit unique behaviors such as camouflage and tactile learning. The brain functions correlated to these behaviors have long been analyzed through behavioral observations of animals subject to surgical manipulation or electrical stimulation of brain lobes. However, physiological methods have rarely been introduced to investigate the functions of each individual lobe, though physiological work on giant axons and slices of the vertical lobe system of the cephalopods have provided deep insights into ion conductance of nerves and long-term synaptic plasticity. The lack of in vivo physiological work is partly due to difficulties in immobilizing the brain which is contained within the soft body and applying calcium indicators to the cephalopod central nervous system. NEW METHOD: We here present a calcium imaging method to visualize neural responses in the central nervous system of the smallest squid, Idiosepius paradoxus. RESULTS: We injected calcium indicator Cal 520 into the brachial lobes and revealed a spatiotemporal pattern of neural responses to the electrical stimulations of the axial nerve cord in the first arm. COMPARISON WITH EXISTING METHODS: We established a method to immobilize the central nervous system which is contained within the soft body and record the calcium responses from the intact central nervous system. CONCLUSIONS: Our method provides a novel approach to investigate the mechanisms of how the characteristic organization of the cephalopod brain functions to induce their unique behaviors. PMID- 29146193 TI - Detection of relationships among multi-modal brain imaging meta-features via information flow. AB - BACKGROUND: Neuroscientists and clinical researchers are awash in data from an ever-growing number of imaging and other bio-behavioral modalities. This flow of brain imaging data, taken under resting and various task conditions, combines with available cognitive measures, behavioral information, genetic data plus other potentially salient biomedical and environmental information to create a rich but diffuse data landscape. The conditions being studied with brain imaging data are often extremely complex and it is common for researchers to employ more than one imaging, behavioral or biological data modality (e.g., genetics) in their investigations. While the field has advanced significantly in its approach to multimodal data, the vast majority of studies still ignore joint information among two or more features or modalities. NEW METHOD: We propose an intuitive framework based on conditional probabilities for understanding information exchange between features in what we are calling a feature meta-space; that is, a space consisting of many individual featurae spaces. Features can have any dimension and can be drawn from any data source or modality. No a priori assumptions are made about the functional form (e.g., linear, polynomial, exponential) of captured inter-feature relationships. RESULTS: We demonstrate the framework's ability to identify relationships between disparate features of varying dimensionality by applying it to a large multi-site, multi-modal clinical dataset, balance between schizophrenia patients and controls. In our application it exposes both expected (previously observed) relationships, and novel relationships rarely considered investigated by clinical researchers. COMPARISON WITH EXISTING METHOD(S): To the best of our knowledge there is not presently a comparably efficient way to capture relationships of indeterminate functional form between features of arbitrary dimension and type. We are introducing this method as an initial foray into a space that remains relatively underpopulated. CONCLUSIONS: The framework we propose is powerful, intuitive and very efficiently provides a high-level overview of a massive data space. In our application it exposes both expected relationships and relationships very rarely considered worth investigating by clinical researchers. PMID- 29146194 TI - Association analyses of genetic variants in long non-coding RNA MALAT1 with breast cancer susceptibility and mRNA expression of MALAT1 in Chinese Han population. AB - The long non-coding RNA (lncRNA) Metastasis-associated lung adenocarcinoma transcript 1(MALAT1) has been implicated in breast cancer (BC). Polymorphisms in MALAT1 may play a vital role in the progress of breast cancer by its regulation function. However, potential genetic variants in MALAT1 affecting the development of BC is rarely explored. In our current molecular epidemiology study, all three tagging SNPs (rs3200401, rs619586 and rs7927113) in lncRNA MALAT1 were selected for genotyping in 487BCE patients and 489 cancer-free controls in Chinese Han population, and futher experiment of quantitative real-time (qRT) PCR was conducted to examine the relative expression of MALAT1. The results showed that individuals with genotype AG of rs619586 has a decreased risk of BC in codominant model (OR: 0.684, 95%CI: 0.478-0.979), dominant mode (OR: 0.675, 95%CI: 0.479 0.951) and over-dominant model (OR: 0.692, 95%CI: 0484-0.989). Also, qRT-PCR results revealed that the expression for MALAT1 with AG (0.827+/-0.490), GG (0.511+/-0.149) and AG+GG genotypes (0.743+/-0.447) of rs619586 was significantly lower than that with genotype AA (1.511+/-0.737). In addition, females with genotype CT of rs3200401 had a lower risk of BC in the codominant model (OR: 0.75, 95%CI: 0.559-1.007) and over-dominant model (OR: 0.741, 95%CI: 0.552 0.993). In summary, our results implied that the genetic variants of lncRNA MALAT1 were associated with the susceptibility of BC, and meaningful genetic alteration might affect the corresponding mRNA expression of lncRNA MALAT1. PMID- 29146195 TI - Author's Response. PMID- 29146196 TI - MRI-based determination of occlusal splint thickness for temporomandibular joint disk derangement: a randomized controlled clinical trial. AB - OBJECTIVE: This prospective study examined a method using magnetic resonance imaging (MRI) to assess the appropriate effective occlusal splint vertical thickness in the management of disk derangement. STUDY DESIGN: Patients were diagnosed as having internal disk displacement of the temporomandibular joint and were divided into 2 groups. Group I (disk displacement with reduction) was subdivided randomly into 2 subgroups: subgroup IA (control group) comprising patients treated with 3-mm-thick splints; and subgroup IB (study group) comprising patients treated with MRI-based splint thickness. Group II (disk displacement without reduction) was subdivided randomly into 2 subgroups: subgroup IIA (control group) comprising patients treated with 3-mm-thick splints; and subgroup IIB (study group) comprising patients treated with MRI-based splint thickness. The primary outcome variables were maximum voluntary mouth opening and visual analogue scale scores for pain. The secondary outcome variable was joint sound. The final sample was composed of 162 patients (Group I = 90 and Group II = 72). RESULTS: Statistical analysis showed significant improvement of the clinical outcomes in subgroups IB and IIB compared with that in subgroups IA and IIA. CONCLUSIONS: On the basis of MRI measurements and clinical outcome, the present study we recommend 4-mm and 6-mm vertical splint thickness for disk displacement with reduction and disk displacement without reduction, respectively, for 1 year. PMID- 29146197 TI - Illicit drug ketamine induces adverse effects from behavioral alterations and oxidative stress to p53-regulated apoptosis in medaka fish under environmentally relevant exposures. AB - With increasing problems of drug abuse worldwide, aquatic ecosystems are contaminated by human pharmaceuticals from the discharge of hospital or municipal effluent. However, ecotoxicity data and related toxic mechanism for neuroactive controlled or illicit drugs are still lacking, so assessing the associated hazardous risk is difficult. This study aims to investigate the behavioral changes, oxidative stress, gene expression and neurotoxic or apoptosis effect(s) in larvae of medaka fish (Oryzias latipes) with environmentally relevant exposures of ketamine (KET) solutions for 1-14 days. KET exposure at an environmentally relevant concentration (0.004 MUM) to 40 MUM conferred specific patterns in larval swimming behavior during 24 h. At 14 days, such exposure induced dose- and/or time-dependent alteration on reactive oxygen species induction, the activity of antioxidants catalase and superoxide dismutase, glutathione S-transferase and malondialdehyde contents in fish bodies. KET induced oxidative stress disrupted the expression of acetylcholinesterase and p53 regulated apoptosis pathways and increased caspase expression in medaka larvae. The toxic responses of medaka larvae, in terms of chemical effects, were qualitatively analogous to those of zebrafish and mammals. Our results implicate a toxicological impact of waterborne KET on fish development and human health, for potential ecological risks of directly releasing neuroactive drugs-containing wastewater into the aquatic environment. PMID- 29146198 TI - Bisphenol A alternatives bisphenol S and bisphenol F interfere with thyroid hormone signaling pathway in vitro and in vivo. AB - The wide use of the alternatives to bisphenol A (BPA) has raised concerns about their potential toxicities. Considering the disrupting activity of BPA on thyroid hormone (TH) signaling, we investigated whether bisphenol S (BPS) and bisphenol F (BPF), two leading alternatives, could interfere with TH signaling pathway using a series of assays in vitro and in vivo. In the fluorescence competitive binding assay, we found BPS and BPF, like BPA, bound to TH receptors (TRalpha and TRbeta), with the binding potencies an order of magnitude lower than BPA (BPA > BPF > BPS). Molecular docking data also show their binding potencies to TRs. In the coactivator recruitment assay, BPS and BPF recruited coactivator to TRbeta but not TRalpha, with weaker potencies than BPA. Correspondingly, agonistic actions of the three bisphenols in the absence or presence of T3 were observed in the TR-mediated reporter gene transcription assay. Also, all the three bisphenols induced TH-dependent GH3 cell proliferation, whereas BPA and BPF inhibited T3 induction in the presence of T3. As for in vivo assay, the three bisphenols like T3 induced TH-response gene transcription in Pelophylax nigromaculatus tadpoles, but in the presence of T3 altered T3-induced gene transcription in a biphasic concentration-response manner. These results for the first time demonstrate that BPS and BPF, like BPA, have potential to interfere with TH signaling pathway, i.e., they generally activate TH signaling in the absence of T3, but in the presence of TH, display agonistic or/and antagonistic actions under certain condition. Our study highlights the potential risks of BPS and BPF as BPA alternatives. PMID- 29146199 TI - Noise can affect acoustic communication and subsequent spawning success in fish. AB - There are substantial concerns that increasing levels of anthropogenic noise in the oceans may impact aquatic animals. Noise can affect animals physically, physiologically and behaviourally, but one of the most obvious effects is interference with acoustic communication. Acoustic communication often plays a crucial role in reproductive interactions and over 800 species of fish have been found to communicate acoustically. There is very little data on whether noise affects reproduction in aquatic animals, and none in relation to acoustic communication. In this study we tested the effect of continuous noise on courtship behaviour in two closely-related marine fishes: the two-spotted goby (Gobiusculus flavescens) and the painted goby (Pomatoschistus pictus) in aquarium experiments. Both species use visual and acoustic signals during courtship. In the two-spotted goby we used a repeated-measures design testing the same individuals in the noise and the control treatment, in alternating order. For the painted goby we allowed females to spawn, precluding a repeated-measures design, but permitting a test of the effect of noise on female spawning decisions. Males of both species reduced acoustic courtship, but only painted gobies also showed less visual courtship in the noise treatment compared to the control. Female painted gobies were less likely to spawn in the noise treatment. Thus, our results provide experimental evidence for negative effects of noise on acoustic communication and spawning success. Spawning is a crucial component of reproduction. Therefore, even though laboratory results should not be extrapolated directly to field populations, our results suggest that reproductive success may be sensitive to noise pollution, potentially reducing fitness. PMID- 29146200 TI - On-board measurements of particle and gaseous emissions from a large cargo vessel at different operating conditions. AB - This study investigated particle and gaseous emission factors from a large cargo vessel for her whole voyage including at berth, manoeuvring and cruising. Quantification of these factors assists in minimising the uncertainty in the current methods of exhaust gas emission factor estimation. Engine performance and emissions from the main marine engine were measured on-board while the ship was manoeuvring and cruising at sea. Emissions of an auxiliary engine working at 55% of maximum continuous rating (MCR) were measured when the ship was at actual harbour stopovers. Gaseous and particle emission factors in this study are presented in g kWh-1 or # kWh-1, and compared with previous studies. Results showed that the SO2 emission factor is higher than that of previous studies due to the high sulphur content of the fuel used. The particle number size distributions showed only one mode for different operating conditions of the ship, with a peak at around 40-50 nm, which was dominated by ultrafine particles. Emission factors of CO, HC, PM and PN observed during ship manoeuvring were much higher than that of those recorded at cruising condition. These findings highlight the importance of quantification and monitoring ship emissions in close proximity to port areas, as they can have the highest impact on population exposure. PMID- 29146201 TI - Arsenic speciation in environmental multimedia samples from the Youngsan River Estuary, Korea: A comparison between freshwater and saltwater. AB - Differences in the distribution, partitioning, and bioaccumulation characteristics of arsenicals between freshwater and saltwater systems remain poorly understood. To determine the characteristics of distribution and behavior of arsenicals, multimedia environmental samples including water, suspended particles, zooplankton, sediments, and porewater were collected from inner (five sites, freshwater) and outer (five sites, saltwater) regions of the estuary dike of the Youngsan River Estuary in South Korea (Nov., 2012). Six organic and inorganic forms of As were separated and measured using HPLC-ICP/MS equipped with an anion exchange column. Concentrations of arsenicals in water samples of the inner region (mean = 1.5 MUg As L-1) were significantly lower than in those of the outer region (mean = 5.2 MUg As L-1). Conversely, concentrations of As in suspended particles in the inner region (mean = 14 MUg As g-1) were much greater than in the outer region (mean = 5.7 MUg As g-1). The field-based distribution coefficient (Kd) for As depended strongly on salinity; relatively greater Kd values were found in freshwater compared with saltwater. The AsV was found to be the major form of As in all water and particle samples in both inner and outer regions. The zooplankton species were significantly distinguishable between the inner and outer regions; cladocerans were the most dominant species in freshwater and cyclopoida were predominantly found in saltwater. The As concentrations in zooplankton were shown to be particle-concentration dependent, suggesting that dietary exposure plays a substantial role in the bioaccumulation of As. Inorganic arsenicals, such as AsV and AsIII were the most dominant forms found in zooplankton. Partitioning behavior of As between porewater and sediments was similar to that in water-particle distributions. The results of the present study enhance the understanding of As biogeochemistry in river and estuarine environments. PMID- 29146202 TI - Effects of polystyrene microplastics on early stages of two marine invertebrates with different feeding strategies. AB - Nowadays, microplastics represent one of the main threats to marine ecosystems, being able to affect organisms at different stages of their life cycle and at different levels of the food web. Although the presence of plastic debris has been reported in different habitats and the ability to ingest it has been confirmed for different taxa, few studies have been performed to elucidate the effects on survival and development of marine animals. Thus, we explored the effects of different environmental concentrations of polystyrene microbeads on the early stages of two invertebrate species widespread in the Mediterranean shallow waters: the pelagic planktotrophic pluteus larvae of the sea urchin Paracentrotus lividus and the filter-feeding sessile juveniles of the ascidian Ciona robusta. We evaluated the effects on larvae and juvenile development and determined the efficiency of bead ingestion. The feeding stages of both species proved to be extremely efficient in ingesting microplastics. In the presence of microbeads, the metamorphosis of ascidian juveniles was slowed down and development of plutei altered. These results prompted the necessity to monitor the populations of coastal invertebrates since microplastics affect sensitive stages of life cycle and may have consequences on generation recruitment. PMID- 29146203 TI - Responses of reef building corals to microplastic exposure. AB - Pollution of marine environments with microplastic particles (i.e. plastic fragments <5 mm) has increased rapidly during the last decades. As these particles are mainly of terrestrial origin, coastal ecosystems such as coral reefs are particularly threatened. Recent studies revealed that microplastic ingestion can have adverse effects on marine invertebrates. However, little is known about its effects on small-polyp stony corals that are the main framework builders in coral reefs. The goal of this study is to characterise how different coral species I) respond to microplastic particles and whether the exposure might II) lead to health effects. Therefore, six small-polyp stony coral species belonging to the genera Acropora, Pocillopora, and Porites were exposed to microplastics (polyethylene, size 37-163 MUm, concentration ca. 4000 particles L 1) over four weeks, and responses and effects on health were documented. The study showed that the corals responded differentially to microplastics. Cleaning mechanisms (direct interaction, mucus production) but also feeding interactions (i.e. interaction with mesenterial filaments, ingestion, and egestion) were observed. Additionally, passive contact through overgrowth was documented. In five of the six studied species, negative effects on health (i.e. bleaching and tissue necrosis) were reported. We here provide preliminary knowledge about coral microplastic-interactions. The results call for further investigations of the effects of realistic microplastic concentrations on growth, reproduction, and survival of stony corals. This might lead to a better understanding of resilience capacities in coral reef ecosystems. PMID- 29146204 TI - Mercury exposure and short-term consequences on physiology and reproduction in Antarctic petrels. AB - Mercury (Hg) is a pervasive contaminant reaching Antarctic environments through atmospheric transport and deposition. Seabirds as meso to top predators can accumulate high quantities of Hg through diet. Reproduction is one of the most sensitive endpoints of Hg toxicity in marine birds. Yet, few studies have explored Hg exposure and effects in Antarctic seabirds, where increasing environmental perturbations challenge animal populations. This study focuses on the Antarctic petrel Thalassoica antarctica from Svarthamaren, Antarctica, where the world's largest breeding population is thought to be in decline. Hg and the stable isotopes of carbon (delta13C, proxy of feeding habitat) and nitrogen (delta15N, trophic position/diet) were measured in red blood cells from 266 individuals over two breeding years (2012-13, 2013-14). Our aims were to 1) quantify the influence of individual traits (size and sex) and feeding ecology (foraging location, delta13C and delta15N values) on Hg exposure, and 2) test the relationship between Hg concentrations with body condition and breeding output (hatching success and chick survival). Hg concentrations in Antarctic petrels (mean +/- SD, 0.84 +/- 0.25, min-max, 0.42-2.71 MUg g-1 dw) were relatively low when compared to other Antarctic seabirds. Hg concentrations increased significantly with delta15N values, indicating that individuals with a higher trophic level (i.e. feeding more on fish) had higher Hg exposure. By contrast, Hg exposure was not driven by feeding habitat (inferred from both foraging location and delta13C values), suggesting that Hg transfer to predators in Antarctic waters is relatively homogeneous over a large geographical scale. Hg concentrations were not related to body condition, hatching date and short-term breeding output. At present, Hg exposure is likely not of concern for this population. Nevertheless, further studies on other fitness parameters and long term breeding output are warranted because Hg can have long-term population-level effects without consequences on current breeding success. PMID- 29146205 TI - PAX3-FOXO1: Zooming in on an "undruggable" target. AB - Driver oncogenes are prime targets for therapy in tumors many of which, including leukemias and sarcomas, express recurrent fusion transcription factors. One specific example for such a cancer type is alveolar rhabdomyosarcoma, which is associated in the majority of cases with the fusion protein PAX3-FOXO1. Since fusion transcription factors are challenging targets for development of small molecule inhibitors, indirect inhibitory strategies for this type of oncogenes represent a more promising approach. One can envision strategies at different molecular levels including upstream modifiers and activators, epigenetic and transcriptional co-regulators, and downstream effector targets. In this review, we will discuss the current knowledge regarding potential therapeutic targets that might contribute to indirect interference with PAX3-FOXO1 activity in alveolar rhabdomyosarcoma at the different molecular levels and extrapolate these findings to fusion transcription factors in general. PMID- 29146206 TI - Using big data for non-communicable disease surveillance. PMID- 29146207 TI - Preface: Cytochrome P450. PMID- 29146209 TI - The Blood Brain Barrier and BRAF inhibitors: Implications for patients with melanoma brain metastases. PMID- 29146208 TI - Glaucoma-associated corneal endothelial cell damage: A review. AB - The corneal endothelium is critical in maintaining a healthy and clear cornea. Corneal endothelial cells have a significant reserve function, but preservation of these cells is paramount as they have limited regenerative capacity. Glaucoma is a prevalent disease, and damage to the corneal endothelium may be caused by the disease process itself as well as by its treatment. The mechanisms involved in glaucoma-associated damage to the corneal endothelium need further investigation. Understanding how glaucoma and glaucoma surgery impact the endothelium is important for protecting corneal clarity and visual acuity in all glaucoma patients, including those undergoing corneal transplant. We will discuss a range of identified factors that may impact corneal endothelial cell health in glaucoma, including intraocular pressure, glaucoma medications, surgical glaucoma management, mechanical forces, and alterations in the aqueous environment. PMID- 29146210 TI - Novel intracellular transport-refractory mutations in KCNH2 identified in patients with symptomatic long QT syndrome. AB - BACKGROUND: Missense mutations in KCNH2, a gene encoding the Kv11.1 channel, cause long QT syndrome (LQTS) type 2 primarily by disrupting the intracellular transport of Kv11.1 to the plasma membrane. The present study aimed to clarify the functional changes by two novel KCNH2 missense mutations. METHODS: We performed genetic screening of three unrelated symptomatic LQTS probands with family histories of cardiac symptoms. Chinese hamster ovary cells were transfected with wild-type (WT) and/or mutant KCNH2 plasmid and examined by patch clamp technique. Immunostaining and confocal microscopy were performed to evaluate the intracellular localization of WT and homozygous mutant Kv11.1 in human embryonic kidney cells. For the study of trafficking rescue, we used low temperature incubation (30 degrees C). We also examined pharmacological rescue of homozygous mutant Kv11.1 current in cells treated with E-4031 or dofetilide. RESULTS: We identified two novel KCNH2 missense mutations, G785D and T826I. Electrophysiological study showed that both mutant channels were nonfunctional in homozygous condition and reduced current densities by half in heterozygous condition compared with WT Kv11.1. Heterozygous Kv11.1-G785D produced a significant positive shift in activation and a significant negative shift in inactivation, whereas heterozygous Kv11.1-T826I caused no kinetic changes. Immunostaining revealed that both were transport-refractory mutations. Incubation at 30 degrees C rescued plasma membrane expression of Kv11.1-T826I but not G785D. We confirmed low-temperature-induced restoration of homozygous Kv11.1-T826I transport by functional current measurements. In contrast, incubation with E-4031 or dofetilide failed to produce measurable currents in both homozygous mutant channels. CONCLUSIONS: Two novel KCNH2 mutations disrupted the intracellular transport of Kv11.1. Low-temperature incubation rescued plasma membrane expression of Kv11.1-T826I but not G785D. Both mutations exerted loss-of-function effects on Kv11.1 and explained the phenotypes of the mutation carriers. PMID- 29146211 TI - Using parent- and self-reports to evaluate eating disturbances in young girls with Autism Spectrum Disorder. AB - BACKGROUND: Eating Disturbances (ED) often occur in Autism Spectrum Disorder (ASD) but most previous studies have relied on parent-reported data about males with ASD. Few studies have collected data from younger girls with ASD using self reports and parents' reports. AIMS: To compare self-reports and parents' reports of ED in a sample of 52 young girls with ASD, a standardised scale for ED was revised for use with younger girls with ASD. METHODS: Mothers of 52 girls with ASD aged from 6 to 17 years completed the Swedish Eating Assessment for Autism spectrum disorders (SWEAA) on their daughters; the girls also completed the SWEAA as a self-report. RESULTS: The prevalence of severe ED in the sample was low (about 11%). There were minimal significant differences between mothers' and daughters' SWEAA responses across most SWEAA subscales. Deletion of several of the original SWEAA items produced a scale that can be used as a self-report or a carer-report with young girls with ASD. CONCLUSION: The clinical assessment of ED via self- or parent reports is suggested as a pathway to identify girls with ASD who also exhibit ED so that adequate treatment planning can be developed for them. PMID- 29146212 TI - The current environmental levels of endocrine disruptors (mercury, cadmium, organochlorine pesticides and PCBs) in a Belgian adult population and their predictors of exposure. AB - A human biomonitoring study was carried out measuring the levels of endocrine disruptors in 252 participants (18-76 years old) recruited between February and May 2015 from the general population of Liege Province (Belgium). In this study, we reported the recent levels of cadmium and mercury in urine, some organochlorine pesticides and polychlorinated biphenyls (PCBs) in serum, and their relations to demographic characteristics, lifestyle behaviors and dietary habits. The median urinary levels of mercury and cadmium were 0.81MUg/l and <0.5MUg/l respectively. The mercury levels were higher in participants having at least 3 dental amalgams, and consuming sea fish more than once a week. Although our mercury levels in most participants were lower than some health-based guidelines, they were higher than in our neighboring countries where ban or restrictions on the dental amalgams use were implemented. Urinary cadmium levels in current smokers were significantly higher than former or never smokers, as well as non-smokers for passively exposed vs non-exposed ones. Median PCB-153 and -180 serum levels were 53.8 and 41.1ng/g lipid respectively, but PCB-138 was below the limit of quantification of 0.15MUg/l in 49% of the samples. Among the organochlorine pesticides, 4,4'-dichlorodiphenyldichloroethylene (4,4'-DDE), beta hexachlorohexane and hexachlorobenzene were positively detected respectively in 48%, 49% and 37% of the serum samples. Eventhough, a dramatic decrease in organochlorines levels was observed, at least 1 pesticide or PCB was detected in 96% of our population, and more than 50% of our samples were contaminated by 4 or more organochlorines. Age, body mass index, and breastfeeding duration were the most predictive determinants of pesticide or PCB serum concentrations, but not dietary habits. PMID- 29146213 TI - Contemporary and diverse approaches to perinatal ethics. PMID- 29146214 TI - [Treatments of steroid-dependent nephrotic syndrome in children]. AB - Primary nephrotic syndrome (NS) is the most common glomerular disease in children. It is characterized by massive proteinuria and hypoalbuminemia. It typically has a sudden onset and more than 70% of patients will experience at least one relapse. An immunological origin has long been postulated, although the precise molecular mechanisms underlying the disease remain debated. Steroids are the first-line therapy with cumulative dose and duration of initial treatment varying among countries. Steroid-sparing agents may be indicated in case of steroid-dependency or frequent relapses. However, no consensus exists regarding the different treatment options. These treatments are mostly suspensive and therefore, need to be prolonged for several months. Levamisole, an antihelminthic drug, also has an immunomodulatory function, and alone or in combination with steroids, it can decrease cumulative steroid dose and relapses. It is usually well tolerated, and its principal side effects are cytopenia and elevated liver enzymes. Mycophenolate mofetil is an immunosuppressive agent whose reported side effects are cytopenia and diarrhea. Calcineurin inhibitors (cyclosporine or tacrolimus) have long been used in steroid-dependent patients. Their major side effects are hirsutism, gum hypertrophy, and nephrotoxicity, leading to interstitial kidney fibrosis and chronic kidney disease. Cyclophosphamide is an efficient treatment but its gonadal toxicity is a major drawback to its use. More recent drugs such as rituximab are very effective but require hospitalization for the infusion and induce an increased risk of opportunistic infection, prolonged neutropenia, and anaphylaxis. In this review, we present the available treatments, their indications, and the side effects. PMID- 29146215 TI - [Acute methotrexate-related neurotoxicity and pseudo-stroke syndrome]. AB - Treatment of acute lymphoblastic leukemia requires high-dose systemic and/or intrathecal methotrexate to prevent and/or treat central nervous system disorders. Acute neurotoxicity of methotrexate, of unknown etiopathogenesis, is characterized by the polymorphism of clinical manifestations, responsible for a potentially harmful diagnostic delay in these immunosuppressed patients. We describe five episodes of transient acute leukoencephalopathy mimicking a stroke, reported in the literature as "pseudo-stroke syndrome". Neurologic symptoms occurred 3-10 days after IV or IT methotrexate and manifested as aphasia and alternating sensorimotor deficit. The fluctuating symptomatology regressed completely within a few days. Brain MRI, which is essential for diagnosis, demonstrated early white matter diffusion restriction in the affected cerebral area. These anomalies disappeared in one week, while hyperintense T2 FLAIR signals developed in the corresponding brain areas. The long-term progression of these pseudo-stroke patients was favorable, without any therapeutic modification. Nevertheless, the involvement of transient acute leukoencephalopathy episodes in the progressive onset of neuro-cognitive disorders is discussed. PMID- 29146216 TI - [NISCH syndrome, a rare cause of neonatal cholestasis: A case report]. AB - NISCH syndrome is a rare autosomal recessive disease. It is characterized by scalp hypotrichosis, scarring alopecia, ichthyosis, and neonatal sclerosing cholangitis. It is caused by mutations in the CLDN1 gene encoding the claudin-1 protein, which is located at tight junctions. Fifteen cases have been reported to date and three different mutations have been identified. We report on the case of a 2-year-old boy from a consanguineous Moroccan family, presenting with NISCH syndrome and carrying the so-called Moroccan homozygous mutation (c.200 201delTT). The patient presented with the characteristic symptoms of the syndrome and a favorable progression with normalization of hepatic analyses under symptomatic treatment (vitamin supplementation and ursodeoxycholic acid). The currently limited availability of clinical and therapeutic data does not allow accurate prediction of the course of the disease and short- and long-term prognosis. Moreover, substantial interindividual variability has been reported. Description of new cases will provide new insights into the understanding and the overall management of this syndrome, the course of which remains elusive. PMID- 29146217 TI - Bladder Herpes Infection in a Patient With Low-grade Non-Muscle-invasive Bladder Cancer. AB - Bladder herpes is a very uncommon event related to herpes simplex virus infection. We report a 69-year-old man with 4-year history of bladder cancer who presented with dysuria and urinary frequency. Cystoscopy showed erythematous lesion of the bladder mucosa that was biopsied and revealed multilobed nuclei with eosinophilic intranuclear inclusions, and presence of intracytoplasmic vacuoles that were suggestive of bladder involvement by herpes simplex virus. Different bladder disorders have been associated with herpes virus, but spontaneous resolution generally occurs in 1-2 months. PMID- 29146218 TI - Presentation and Diagnosis of Fournier Gangrene. AB - Necrotizing fasciitis is a severe type of necrotizing soft tissue infection involving the superficial fascia and subcutaneous tissues. Fournier gangrene, a type of necrotizing fasciitis, affects the genitalia or perineum. Although a rare health condition, Fournier gangrene can result in significant morbidity and unnecessary mortality following delay in diagnosis and management. We provide a review of relevant presenting features to aid diagnosis and allow timely surgical management of this serious infectious condition. PMID- 29146219 TI - Sexual Function in Couples With or Without Female Incontinent Partners: Correlates and Predictors. AB - OBJECTIVE: To evaluate the correlation between sexual function of couples with and without stress urinary incontinence (SUI) partners, and to identify predictors of poor sexual function. MATERIALS AND METHODS: A cross-sectional survey was conducted involving sexually active women with or without SUI aged at least 21 years old, and their respective partners. Both partners completed the Golombok Rust Inventory of Sexual Satisfaction (GRISS), a 28-item multidimensional measure with separate forms for male and female designed to assess sexual satisfaction of both partners. Spearman rank correlation coefficient was used to analyze bivariate association, whereas multiple regression analysis was used to identify predictors for overall sexual function as measured using GRISS score. RESULTS: Sixty-six couples with SUI partners and 95 couples with continent partners were recruited. Overall GRISS scores and thus sexual function of men and women were strongly correlated. The correlation coefficient was higher in couples with SUI partners (r = 0.702, P <.001) compared with couples with continent partners (r = 0.629, P <.001), indicating a stronger correlation in the sexual function of couples with SUI partners. In multivariate analysis, poorer sexual function (lower GRISS score) in women, increasing age, and less frequency of sexual intercourse were significant predictors of poorer overall GRISS score in couples (P <.001). CONCLUSION: Female sexual function is strongly correlated with male partners' sexual function, with a stronger correlation observed in couples with SUI partners. Poorer sexual function in women, increasing age, and less frequency of sexual intercourse are predictive of poorer sexual function in a couple. PMID- 29146220 TI - Autologous Chondrocyte Implantation for Talar Osteochondral Lesions: Comparison Between 5-Year Follow-Up Magnetic Resonance Imaging Findings and 7-Year Follow-Up Clinical Results. AB - Autologous chondrocyte implantation (ACI) is an established surgical procedure that has provided satisfactory results. The aim of the present study was to correlate the clinical outcomes of a series of 20 patients treated by ACI at a 7 year follow-up examination with the magnetic resonance imaging (MRI) T2-mapping 5 year follow-up findings. We evaluated 20 patients using the American Orthopaedic Foot and Ankle Society (AOFAS) score preoperatively and the established follow-up protocol until 87.2 +/- 14.5 months. MRI T2-mapping sequences were acquired at the 5-year follow-up examination. At the MRI examination (60 +/- 12 months), the mean AOFAS score improved from 58.7 +/- 15.7 to 83.9 +/- 18.4. At the final follow-up examination at 87.2 +/- 14.5 months, the AOFAS score was 90.9 +/- 12.7 (p = .0005). Those patients who experienced an improvement between 5 and 7 years after surgery had a significant greater percentage of T2-map value of 35 to 45 ms (hyaline cartilage) compared with those patients who did not improve (p = .038). MRI T2 mapping was shown to be a valuable tool capable of predicting reproducible clinical outcomes after ACI even 7 years after surgery. The quality of the regenerated tissue and the degree of defect filling became statistically significant to the clinical results at the final follow-up examination. PMID- 29146221 TI - Takedown of Ankle Arthrodesis With Insufficient Fibula: Surgical Technique and Intermediate-Term Follow-Up. AB - Conversion of ankle arthrodesis to total ankle arthroplasty has recently gained popularity. However, technical challenges are present when treating patients without a sufficient fibular buttress. We describe a technique for restoration of an adequate fibular buttress using an iliac crest bone graft or malleolar relocation. The results of 10 patients with an average follow-up period of 56 (range 24 to 123) months are presented. Of the 10 patients, 3 underwent tricortical iliac bone augmentation of the fibula, 4 underwent repositioning of the remnant fibula, and in 3, the in situ fibula was used. The average interval from fusion to takedown was 15.1 (range 5 to 35) years, and the average age at takedown was 52.8 (range 33 to 75) years. The average improvement in the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot scale and Buechel-Pappas scale scores was 35.8 (range 30 to 46) and 34 (range 25 to 42), respectively. Three patients underwent a total of 7 subsequent operations related to the ankle implant. Only 1 of the patients had any residual frontal plane deformity. None of the patients exhibited any component subsidence; however, 2 patients experienced asymptomatic lateral talar component overgrowth. The improvement in the clinical scores in this group of patients suggests that takedown of an ankle arthrodesis with an insufficient fibula is a viable option to improve function. Various techniques to restore the lateral buttress can be used even with complete absence of the distal fibula. PMID- 29146222 TI - Nursing Staff Distress Associated With Neuropsychiatric Symptoms in Young-Onset Dementia and Late-Onset Dementia. AB - OBJECTIVE: The aims of this study were (1) to investigate the relationship between different neuropsychiatric symptoms (NPS) and the level of distress experienced by nurses caring for residents with young-onset dementia (YOD) and (2) to compare these findings with those for nurses caring for residents with late-onset dementia (LOD). DESIGN/SETTING: This is a retrospective study conducted in Dutch long-term care facilities. Data were used from the Behavior and Evolution of Young-ONset Dementia studies (BEYOND) Parts I and II and the WAAL Behavior in Dementia-II (Waalbed-II) study. PARTICIPANTS: A total of 382 nursing home residents with YOD and 261 nursing home residents with LOD were included. MEASUREMENTS: The Neuropsychiatric Inventory, nursing home version, was used to assess nursing staff distress and the frequency (F) and severity (S) of NPS. Multilevel logistic regression analysis was used to investigate the relationships between nursing staff distress related to NPS and YOD and LOD care units, the F * S score per symptom, gender, dementia subtype, and dementia severity. RESULTS: Nurses working in YOD care units rated sleep and nighttime behavior disorders, delusions, and agitation/aggression most often as highly distressing and euphoria most often as not distressing. Multivariate analyses indicated that the frequency and severity of NPS were significantly associated with staff distress in all symptoms, except for apathy. Comparison of the 2 groups of nurses demonstrated that the odds for distress related to sleep and nighttime behavior disorders were higher for nurses in YOD care units than for nurses in LOD units. For both the YOD and LOD nurses, irritability in male residents had higher impact than similar behavior in female residents. CONCLUSION: This study provides important insight into distress related to individual NPS and the interaction with residents' characteristics. All NPS result in distress. The frequency and severity of the behavior is an important predictor. Sleep and nighttime behavior disorders are more likely to result in distress in YOD nurses than in LOD nurses. The amount of distress related to NPS emphasizes the urgent need for adequate management of NPS and the support of professional caregivers. PMID- 29146223 TI - Delivering Person-Centered Care: Important Preferences for Recipients of Long term Services and Supports. AB - OBJECTIVES: Although assessing individual consumer preferences are an important first step in providing person-centered care, the purpose of this study was to identify the top 10 shared preferences that are important to a majority of consumers receiving long-term services and supports. DESIGN: A cross-sectional survey design was used. SETTING AND PARTICIPANTS: Preference assessment interviews were conducted with 255 nursing home (NH) residents and 528 older adults receiving home and community-based services (HCBS). MEASUREMENTS: The Preferences for Everyday Living Inventory (PELI) was used to collect consumer preference information. Two versions of the PELI were used-the PELI-NH for NH residents and the PELI-HC for clients receiving HCBS and analysis focused on 41 shared items between the 2 versions. All respondents answered PELI questions independently and rated the importance of psychosocial preference items on a scale from not at all to a lot/very important. RESULTS: Ten preferences were shared as being important or very important by NH residents and older adults receiving HCBS. Most notably, more than 90% of respondents in each group rated "having regular contact with family" as an important priority. Having privacy, choices about what to eat, when to bathe, and activity options also were important preferences for a majority (77%-93%) in both settings. CONCLUSION: Providers seeking to incorporate preference-based care can utilize study results as a foundation to incorporating important preferences into the care delivery process at the organizational level across care settings. For example, assessing all consumers on this core set of 10 shared preferences can assist with relationship building, transitions in care, and quality improvement. However, preferences with aggregate low-rated levels of importance in this study should not be discredited or eliminated. It is important for providers to understand the unique preference inventory of each older adult, which can then be targeted toward meeting goals for preference fulfillment. This can aid in bringing preferences into practice to improve the quality of care and quality of life to best meet the psychosocial needs of each person. PMID- 29146224 TI - Joint Trajectories of Cognition and Frailty and Associated Burden of Patient Reported Outcomes. AB - OBJECTIVES: To evaluate joint trajectories of cognition and frailty and their association with the cumulative burden of patient-reported outcomes, including hospitalization, nursing home admission, and disability. DESIGN: Longitudinal study of 754 community-living persons aged 70 or older. PARTICIPANTS: 690 participants who had a baseline and at least one follow-up assessment of cognition and frailty between 1998 and 2009. MEASUREMENTS: Cognition was assessed using the Mini-Mental State Examination (MMSE). Frailty was defined by the 5 criteria for the Fried phenotype: muscle weakness, exhaustion, low physical activity, shrinking, and slow walking speed. A group-based, mixture modeling approach was used to fit the joint trajectories of cognition and frailty. The cumulative burden of hospitalization, nursing home admission, and disability over 141 months associated with the joint trajectories was evaluated using a series of generalized estimating equation Poisson models. RESULTS: Four joint trajectories were identified, including No cognitive frailty (27.8%), Slow cognitive decline and progressive frailty (45.5%), Rapid cognitive decline and progressive frailty (20.2%), and Cognitive frailty (6.5%). For each joint trajectory group, the interval-specific incidence density rates of all patient-reported outcomes tended to increase over time, with the exception of hospitalization for which the increasing trend was apparent only for the Slow cognitive decline and progressive frailty group. The No cognitive frailty group had the lowest cumulative burden of all patient-reported outcomes [eg, nursing home admissions, 7.5/1000 person months, 95% confidence interval (CI): 4.8-11.7], whereas the Cognitive frailty group had the highest cumulative burden (eg, nursing home admissions, 381.1/1000 person-months, 95% CI: 294.5-493.1), with the exception of hospitalization. Compared with the No cognitive frailty group, the 3 other joint trajectory groups all had significantly greater burden of the patient-reported outcomes. CONCLUSION: Community-living older persons exhibit distinct joint trajectories of cognition and frailty and experience an increasing burden of nursing home admission and disability as they age, with the greatest burden for those on a cognitive frailty trajectory. PMID- 29146225 TI - Response comparison of multiple myeloma and monoclonal gammopathy of undetermined significance to the same anti-myeloma therapy: a retrospective cohort study. AB - BACKGROUND: Multiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), which is usually only treated by a form of anti multiple myeloma therapy if it is causing substantial disease through deposition of secreted M proteins. However, studies comparing how MGUS and multiple myeloma plasma cell clones respond to these therapies are scarce. Biclonal gammopathy multiple myeloma is characterised by the coexistence of an active multiple myeloma clone and a benign MGUS clone, and thus provides a unique model to assess the responses of separate clones to the same anti-multiple myeloma therapy, in the same patient, at the same time. We aimed to identify how MGUS and multiple myeloma plasma cell clones responded to anti-multiple myeloma therapy in patients newly diagnosed with biclonal gammopathy multiple myeloma. METHODS: In this retrospective cohort study, we identified patients with biclonal gammopathy multiple myeloma by central laboratory analysis of 6399 newly diagnosed patients with multiple myeloma enrolled in three UK clinical trials (Myeloma IX, Myeloma XI, and TEAMM) between July 7, 2004, and June 2, 2015. In addition to the inclusion criteria of these trials, our study necessitated at trial entry the presence of two distinct M proteins in immunofixation electrophoresis. The primary endpoint was difference in response achieved with anti-multiple myeloma therapy on MGUS (which we defined as M2) and multiple myeloma (M1) clones overall, within patients, and between therapy types-with international therapy response criteria assessed with chi2 analyses. We analysed by intention to treat. FINDINGS: 44 patients with biclonal gammopathy multiple myeloma with IgG or IgA MGUS clones were subsequently identified from the three trials and then longitudinally monitored. 41 (93%) of M1 clones had a response to therapy (either complete response, very good partial response, partial response, or minor response) compared with only 28 (64%) of M2 clones (p=0.0010). For the 20 patients who received intensive therapy, there was no difference between the proportion of responding clones in M1 (19 [95%]) and M2 (15 [75%], p=0.13). However, for the 17 patients who received non-intensive therapy, 16 (94%) of M1 clones had a response compared with ten [59%] of M2 clones (p=0.031). When examining clones within the same patient, 30 (68%) of 44 individual patients had different levels of responses within the M1 and M2 clones. One patient exhibited M2 progression to myeloma and subsequently died. INTERPRETATION: These results show that, in patients with biclonal gammopathy multiple myeloma, anti-multiple myeloma therapies exert a greater depth of response against multiple myeloma plasma cell clones than MGUS plasma cell clones. Although some MGUS clones exhibited a complete response, many did not respond, which suggests that the underlying features that render multiple myeloma plasma cells susceptible to therapy are present in only some MGUS plasma cell clones. To determine MGUS clone susceptibly to therapy, future studies might seek to identify, with biclonal gammopathy multiple myeloma as an investigative model, the genetic and epigenetic alterations that affect whether MGUS plasma cell clones are responsive to anti multiple myeloma therapy. FUNDING: National Institute of Health Research, Medical Research Council, and Cancer Research UK. PMID- 29146226 TI - The N-terminal domains of Bacillus subtilis CopA do not form a stable complex in the absence of their inter-domain linker. AB - Copper-transporting P-type ATPases, which play important roles in trafficking Cu(I) across membranes for the biogenesis of copper proteins or for copper detoxification, contain a variable number of soluble metal-binding domains at their N-termini. It is increasingly apparent that these play an important role in regulating copper transport in a Cu(I)-responsive manner, but how they do this is unknown. CopA, a Cu(I)-transporter from Bacillus subtilis, contains two N terminal soluble domains that are closely packed, with inter-domain interactions at two principal regions. Here, we sought to determine the extent to which the domains interact in the absence of their inter-domain covalent linker, and how their Cu(I)-binding properties are affected. Studies of a 1:1 mixture of separate CopAa and CopAb domains showed that the domains do not form a stable complex, with only indirect evidence of a weak interaction between them. Their Cu(I) binding behaviour was distinct from that of the two domain protein and consistent with a lack of interaction between the domains. Cu(I)-mediated protein association was observed, but this occurred only between domains of the same type. Thus, the inter-domain covalent link between CopAa and CopAb is essential for inter-domain interactions and for Cu(I)-binding behaviour. PMID- 29146228 TI - Discussion. PMID- 29146227 TI - Bariatric surgery improves lipoprotein profile in morbidly obese patients by reducing LDL cholesterol, apoB, and SAA/PON1 ratio, increasing HDL cholesterol, but has no effect on cholesterol efflux capacity. AB - BACKGROUND: Bariatric surgery has been shown to reduce cardiovascular events and cause-specific mortality for coronary artery disease in obese patients. Lipoprotein biomarkers relating to low-density lipoprotein (LDL), high-density lipoprotein (HDL), their subfractions, and macrophage cholesterol efflux have all been hypothesized to be of value in cardiovascular risk assessment. OBJECTIVES: The objective of this study was to examine the effect of a lifestyle intervention followed by bariatric surgery on the lipid profile of morbidly obese patients. METHODS: Thirty-four morbidly obese patients were evaluated before and after lifestyle changes and then 1 year after bariatric surgery. They were compared with 17 lean subjects. Several lipoprotein metrics, serum amyloid A (SAA), serum paraoxonase-1 (PON1), and macrophage cholesterol efflux capacity (CEC) were assessed. RESULTS: Average weight loss after the lifestyle intervention was 10.5% and 1 year after bariatric surgery was 33.9%. The lifestyle intervention significantly decreased triglycerides (TGs; -28.7 mg/dL, P < .05), LDL cholesterol (LDL-C; -32.3 mg/dL, P < .0001), and apolipoprotein B (apoB; -62.9 MUg/mL, P < .001). Bariatric surgery further reduced TGs (-36.7 mg/dL, P < .05), increased HDL cholesterol (+12 mg/dL, P < .0001), and reductions in LDL-C and apoB were sustained. Bariatric surgery reduced large, buoyant LDL (P < .0001), but had no effect on the small, dense LDL. The large HDL subfractions increased (P < .0001), but there was no effect on the smaller HDL subfractions. The ratio for SAA/PON1 was reduced after the lifestyle intervention (P < .01) and further reduced after bariatric surgery (P < .0001). Neither the lifestyle intervention nor bariatric surgery had any effect on CEC. CONCLUSIONS: Lifestyle intervention followed by bariatric surgery in 34 morbidly obese patients showed favorable effects on TGs, LDL-C, and apoB. HDL cholesterol and apoA1 was increased, apoB/apoA1 ratio as well as SAA/PON1 ratio reduced, but bariatric surgery did not influence CEC. PMID- 29146229 TI - Evaluating the projected surgical impact of reclassifying noninvasive encapsulated follicular variant of papillary thyroid cancer as noninvasive follicular thyroid neoplasm with papillary-like nuclear features. AB - BACKGROUND: The reclassification of noninvasive encapsulated follicular variant of papillary thyroid cancer to noninvasive follicular thyroid neoplasm with papillary-like nuclear features will reduce nonefficacious and potentially harmful care. Reclassification is estimated in 18.6% of patients with papillary thyroid carcinoma; we aimed to quantify the implications of this change. METHODS: Pathology reports from April 2006 to April 2016 were reviewed to isolate cases that would have been designated as neoplasm with papillary-like nuclear features. Of the 1,335 cases of papillary thyroid carcinomas, 194 cases (14.5%) met criteria. Cases in which neoplasm with papillary-like nuclear features was found in combination with other thyroid malignancies (n = 25) and cases of prior thyroid lobectomy (n = 5) were excluded. Demographic, pathologic, treatment, and follow-up data were assessed for the remaining 164 potential neoplasm with papillary-like nuclear features cases. Logistic regression analysis was performed to evaluate association between fine-needle aspiration result and index procedure. RESULTS: Of the 164 patients with tumors who met neoplasm with papillary-like nuclear features criteria, fine-needle aspiration results were nondiagnostic (2%), benign (18%), atypia/follicular lesion of undetermined significance (26%), follicular neoplasm or suspicious for follicular neoplasm (20%), suspicious for malignancy (19%), malignant (6%), and not obtained (9%). Eighty-five (52%) patients underwent total thyroidectomy. A "suspicious for malignancy" fine-needle aspiration result was associated with undergoing total thyroidectomy versus thyroid lobectomy (P = .006). Thyroid lobectomy was the index procedure for 79 patients (48%); of these patients, 54% (n = 43, 3.2% of all patients with papillary thyroid carcinomas) underwent subsequent total thyroidectomy, and 24% received postoperative radioactive iodine treatment. There were no recurrences among the 125 patients with >3 months of follow-up. CONCLUSION: The reclassification of noninvasive encapsulated follicular variant of papillary thyroid cancer as neoplasm with papillary-like nuclear features will decrease nonefficacious treatment and reduce costs. However, the impact of this change with regard to extent of surgery was limited to 3.2% of patients with papillary thyroid carcinomas compared with the projected potential impact on 18.6%. PMID- 29146230 TI - Race, insurance status, and traumatic brain injury outcomes before and after enactment of the Affordable Care Act. AB - BACKGROUND: The Affordable Care Act aims to improve patient outcomes. Race/ethnicity and insurance status impact outcomes after traumatic brain injury. We sought to gauge the Affordable Care Act's effect on outcomes after traumatic brain injury, as graded by race/ethnicity and insurance status. METHODS: The National Trauma Data Bank was utilized to identify traumatic brain injury patients before and after the Affordable Care Act. Patient outcomes comprised of hospital duration of stay, in-hospital mortality, discharge to rehabilitation, and surgical procedures. Using regression analysis, we evaluated the impact of race/ethnicity and insurance status on traumatic brain injury outcomes, then compared them before and after the Affordable Care Act. RESULTS: Mortality decreased for blacks (odds ratio = 0.96 [confidence interval 0.83-1.10] to odds ratio = 0.79 [confidence interval = 0.70-0.89], and Hispanics (odds ratio = 1.03 [confidence interval = 0.90-1.17] to odds ratio = 0.79 [confidence interval = 0.70-0.89]). Mortality increased for the uninsured (odds ratio = 1.28 [confidence interval = 1.11-1.47] to odds ratio = 1.40 [confidence interval = 1.24-1.58]). Medicaid patients underwent decreased duration of stay, (coefficient = 2.75 [confidence interval = 2.49-3.02] to coefficient = 2.17, [confidence interval = 1.98-2.37]), discharge to rehabilitation (odds ratio = 1.15, [confidence interval = 1.04-1.26] to odds ratio = 0.95 [confidence interval = 0.87-1.03]), and surgical procedures (odds ratio = 1.28 [confidence interval = 1.13-1.45] to odds ratio = 1.18, [confidence interval = 1.07-1.30]), while mortality remained unchanged. CONCLUSION: After the Affordable Care Act traumatic brain injury mortality decreased for blacks and Hispanics, but increased for the uninsured. Decreasing trends in resource consumption were also evident, especially for Medicaid patients. These results may illustrate altered delivery of care. PMID- 29146231 TI - Is hungry bone syndrome a cause of postoperative hypocalcemia after total thyroidectomy in thyrotoxicosis? A prospective study with bone mineral density correlation. AB - BACKGROUND: Hungry bone syndrome is a well-established cause of postoperative hypocalcemia in thyrotoxicosis. To date, the incidence of hungry bone syndrome after total thyroidectomy is unclear. This prospective study examined the incidence of postthyroidectomy hungry bone syndrome and its correlation with preoperative bone mineral density. METHODS: Forty thyrotoxic subjects (Group A; age: mean +/- SD; 36.5 +/- 9.8 years) and 40 euthyroid controls with benign thyroid nodules (Group B) undergoing total thyroidectomy were evaluated for preoperative bone mineral density and serum calcium, magnesium, phosphorus, parathyroid hormone, alkaline phosphatase, and 25-Hydroxy Vitamin D serially. At least 3 parathyroid glands were preserved. RESULTS: Both groups were age and sex matched. Thyrotoxic subjects had higher postoperative hypocalcemia (82.5% vs controls 22.5%, 95% confidence interval 37.9 to 75.4), low preoperative bone mineral density and raised alkaline phosphatase (each, P = .001). Among thyrotoxic subjects experiencing hypocalcemia (n = 33), 39.4% (13/33) exhibited hungry bone syndrome (characterized by simultaneous fall in serum calcium, magnesium, and phosphorus), 18.1% (6/33) had hypoparathyroidism and 12% had hypomagnesemia. Hypocalcemic subjects exhibiting hungry bone syndrome displayed further decreased preoperative bone mineral density in the spine (0.875 +/- 0.138 vs 1.024 +/- 0.149 g/cm2, P = .004) and low serum magnesium 72-hour postsurgery (0.57 +/- 0.23 vs 0.88 +/- 0.25 mmol/L, P = .013) than those not exhibiting hungry bone syndrome. Postoperative serum calcium correlated with preoperative bone mineral density in the spine (P = .013). In group B subjects experiencing hypocalcemia (n = 9), none exhibited hungry bone syndrome but 77.78% (7/9) had hypoparathyroidism. All but one was eucalcemic after 6 months. CONCLUSION: Hungry bone syndrome occurs exclusively in thyrotoxic subjects and constitutes the major cause of postoperative hypocalcemia after total thyroidectomy. Vertebral osteoporosis and hypomagnesemia within 72 hours after total thyroidectomy is associated with the risk of hungry bone syndrome. PMID- 29146233 TI - Statin Use in Men and New Onset of Erectile Dysfunction: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Erectile dysfunction has been reported as an adverse effect of statin therapy. METHODS: We performed a meta-analysis of randomized trials and observational studies that compared statin users versus non-statin users and reported data regarding new onset of erectile dysfunction in men with established cardiovascular disease or cardiovascular disease risk factors. We used DerSimonian-Laird and Peto models to construct the summary estimates risk ratio. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the overall quality of evidence for new-onset erectile dysfunction. RESULTS: Three randomized trials and 3 observational studies were identified, with 69,448 men, of whom 24,661 were statin users. Statin use was not associated with an increased risk of new onset of erectile dysfunction by random effects model or fixed effect model (risk ratio 0.96; 95% confidence interval, 0.84-1.10; P = .58; and odds ratio 0.95; 95% confidence interval, 0.88-1.02; P = .20, respectively). This effect was similar in randomized trials and observational studies (Pinteraction = .86). Randomized trials provided a moderate quality of evidence, and observational studies provided a very low quality of evidence by the GRADE assessment. Random effects meta-regression analyses revealed no difference in treatment effect according to age or diabetes mellitus (P = .83 and P = .74, respectively). CONCLUSIONS: Among men with established cardiovascular disease or cardiovascular disease risk factors, statin use does not seem to be associated with a new onset of erectile dysfunction. Adequately powered and high-quality randomized trials are recommended to confirm these findings. PMID- 29146232 TI - Parathyroidectomy in patients with chronic kidney disease: Impacts of different techniques on the biochemical and clinical evolution of secondary hyperparathyroidism. AB - BACKGROUND: Parathyroidectomy (PTx) decreases the mortality rate of refractory secondary hyperparathyroidism (rSHP) due to chronic kidney disease. A consensus regarding which techniques of PTx are associated with better outcomes is not available. The aims of this study are to evaluate the clinical and laboratory evolution of 49 hemodialysis patients with rSHP who underwent PTx using different techniques. METHODS: Patients underwent subtotal PTx (sub-PTx) or total PTx with autotransplantation (AT) of 45 (PTx-AT45) or 90 parathyroid fragments (PTx-AT90) and were followed for 12 months. We analyzed the expression of proliferating cell nuclear antigen (PCNA), calcium-sensing receptor (CasR), vitamin D receptor (VDR), fibroblast growth factor receptor-1 (FGFR1), sodium-dependent phosphate cotransporter-1 (PIT1), and Klotho in parathyroid glands. RESULTS: Baseline median serum intact parathyroid hormone (iPTH) levels were 1,466 (1,087-2,125) pg/mL; vascular calcification scores correlated with serum iPTH (r = 0.529; P = .002) and serum phosphate levels (r = 0.389; P = .028); and Klotho expression was negatively correlated with serum phosphate levels (r = -0.4; P = .01). After 12 months, serum iPTH and alkaline phosphatase levels were significantly controlled in all groups, as was bone pain. The proportions of patients with serum iPTH levels within the ranges recommended by Kidney Disease: Improving Global Outcomes were similar among the treatment groups. During the hungry bone disease (HBS), patients received 3,786 g (1,412-7,580) of elemental calcium, and a trend toward a positive correlation between the cumulative calcium load at the end of follow up and VC score post-PTx was noted (r = 0.390; P = .06). Two cases evolved to clinically uncontrolled hyperparathyroidism in the sub-PTx group. The expression patterns of PCNA, VDR, CasR, PIT1, FGFR1, and Klotho in parathyroid glands did not correlate with serum systemic iPTH levels or the duration of HBS. CONCLUSIONS: All 3 operative techniques were effective at controlling rSHP, both in clinical and laboratory terms. Neither the quantity nor quality of parathyroid fragments influenced serum systemic iPTH and AT-iPTH levels. The cumulative calcium load appeared to correlate with the VC score and may have affected its progression. The effects of phosphate restriction on Klotho expression in human parathyroid glands and the subsequent decrease in FGF23 resistance must be addressed in further studies. PMID- 29146234 TI - Value of Patient-Directed Brain Magnetic Resonance Imaging Scan with a Diagnosis of Migraine. AB - BACKGROUND: The objective of this study was to determine whether a brain magnetic resonance imaging (MRI) scan in patients with a diagnosis of migraine, who insist on the performance of imaging, is of more benefit in detecting clinically significant unsuspected structural abnormalities than would be expected by chance. METHODS: This prospective, observational, single-center study was performed from January 1, 2010 to December 31, 2012 and included 100 subjects with a diagnosis of migraine and normal results on neurologic examination. A brain MRI scan was performed on all patients, solely at their request, to detect an unsuspected clinically significant structural lesion. RESULTS: Of the 100 patients, 86 were female, and the average age was 31.5 years. Forty-five patients experienced migraine without aura, 41 chronic migraine, and 14 migraine with aura. All of the patients had normal results on neurologic examination. The duration of headaches ranged from 4 months to 40 years. In all, 82 of the MRI scans showed normal results, and 17 revealed clinically insignificant abnormalities. One MRI in a patient with chronic migraine without aura revealed a meningioma that subsequently required surgery and radiation therapy. The 1% prevalence of tumor in this study was then compared with 2 large cohorts of MRI abnormalities in the general asymptomatic population, in which tumor was found in 35 out of 3000. Fisher's exact test was used to compare the prevalence of tumor in the study population with the combined cohorts, and there was no statistical difference between these rates (P > .99). CONCLUSIONS: Brain MRI obtained at the specific request of patients with a diagnosis of migraine in the presence of normal neurologic examination results has a yield that is equivalent to that of the general asymptomatic population. Patients do not seem to have more insight than the examining clinician with regard to detecting underlying structural abnormalities, and brain MRI should not performed as part of the routine evaluation of migraine without a clear clinical indication. PMID- 29146235 TI - Macrophages: Their role, activation and polarization in pulmonary diseases. AB - Macrophages, circulating in the blood or concatenated into different organs and tissues constitute the first barrier against any disease. They are foremost controllers of both innate and acquired immunity, healthy tissue homeostasis, vasculogenesis and congenital metabolism. Two hallmarks of macrophages are diversity and plasticity due to which they acquire a wobbling array of phenotypes. These phenotypes are appropriately synchronized responses to a variety of different stimuli from either the tissue microenvironment or - microbes or their products. Based on the phenotype, macrophages are classified into classically activated/(M1) and alternatively activated/(M2) which are further sub-categorized into M2a, M2b, M2c and M2d based upon gene expression profiles. Macrophage phenotype metamorphosis is the regulating factor in initiation, progression, and termination of numerous inflammatory diseases. Several transcriptional factors and other factors controlling gene expression such as miRNAs contribute to the transformation of macrophages at different points in different diseases. Understanding the mechanisms of macrophage polarization and modulation of their phenotypes to adjust to the micro environmental conditions might provide us a great prospective for designing novel therapeutic strategy. In view of the above, this review summarises the activation of macrophages, the factors intricated in activation along with benefaction of macrophage polarization in response to microbial infections, pulmonary toxicity, lung injury and other inflammatory diseases such as chronic obstructive pulmonary dysplasia (COPD), bronchopulmonary dysplasia (BPD), asthma and sepsis, along with the existing efforts to develop therapies targeting this facet of macrophage biology. PMID- 29146236 TI - Infectious bursal disease virus protein VP4 suppresses type I interferon expression via inhibiting K48-linked ubiquitylation of glucocorticoid-induced leucine zipper (GILZ). AB - Viruses have developed a variety of methods to evade host immune response. Our previous study showed that infectious bursal disease virus (IBDV) inhibited type I interferon production via interaction of VP4 with cellular glucocorticoid induced leucine zipper (GILZ) protein. However, the exact underlying molecular mechanism is still unclear. In this study, we found that IBDV VP4 suppressed GILZ degradation by inhibiting K48-linked ubiquitylation of GILZ. Furthermore, mutation of VP4 (R41G) abolished the inhibitory effect of VP4 on IFN-beta expression and GILZ ubiquitylation, indicating that the amino acid 41R of VP4 was required for the suppression of IFN-beta expression and GILZ ubiquitylation. Moreover, IBDV infection or VP4 expression markedly inhibited endogenous GILZ ubiquitylation. Thus, IBDV VP4 suppresses type I interferon expression by inhibiting K48-linked ubiquitylation of GILZ, revealing a new mechanism employed by IBDV to suppress host response. PMID- 29146237 TI - Parents' advice to healthcare professionals working with children who have spinal muscular atrophy. AB - AIM: To explore parents' advice to healthcare professionals working with children with spinal muscular atrophy (SMA). MATERIALS AND METHODS: This study derives from a Swedish nationwide survey and uses content analysis to make inferences from answers to an open-ended question concerning parent's advice to healthcare professionals. Of eligible parents who had a child born in Sweden between 2000 and 2010, diagnosed with SMA type 1 or 2, and for whom respiratory support was considered in the first year of life, 61 participated in the study (response rate: 87%). Of these, 51 parents answered the question about advice to healthcare professionals working with children with SMA. RESULTS: More than half of the advice from parents was related to professional-family relations. The second most frequent type of advice related to two aspects of knowledge about SMA: desire that healthcare professionals possess knowledge, and desire that they provide knowledge. The parents also had advice concerning support in daily life, both to the parents and to the affected child. Other pieces of advice were related to organization of care and the parents' desire to be involved in the child's care. CONCLUSIONS: Parents advised healthcare professionals to increase their disease specific knowledge, to treat the parents as experts on their child, and to treat the family with respect, particularly in situations where the child's case is used as an opportunity to improve healthcare professionals' competence. Increased practical support in daily life and a case coordinator is also among parents' advice to healthcare professionals. PMID- 29146240 TI - Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets. AB - Conventional immediate release dosage forms involve compressing the powder with a disintegrating agent that enables rapid disintegration and dissolution upon oral ingestion. Among 3D printing technologies, the fused deposition modelling (FDM) 3D printing technique has a considerable potential for patient-specific dosage forms. However, the use of FDM 3D printing in tablet manufacturing requires a large portion of polymer, which slows down drug release through erosion and diffusion mechanisms. In this study, we demonstrate for the first time the use of a novel design approach of caplets with perforated channels to accelerate drug release from 3D printed tablets. This strategy has been implemented using a caplet design with perforating channels of increasing width (0.2, 0.4, 0.6, 0.8 or 1.0mm) and variable length, and alignment (parallel or at right angle to tablet long axis). Hydrochlorothiazide (BCS class IV drug) was chosen as the model drug as enhanced dissolution rate is vital to guarantee oral bioavailability. The inclusion of channels exhibited an increase in the surface area/volume ratio, however, the release pattern was also influenced by the width and the length of the channel. A channel width was >=0.6mm deemed critical to meet the USP criteria of immediate release products. Shorter multiple channels (8.6mm) were more efficient at accelerating drug release than longer channels (18.2mm) despite having comparable surface area/mass ratio. This behaviour may be linked to the reduced flow resistance within the channels and the faster fragmentation during dissolution of these tablets. In conclusion, the width and length of the channel should be carefully considered in addition to surface area/mass when optimizing drug release from 3D printed designs. The incorporation of short channels can be adopted in the designs of dosage forms, implants or stents to enhance the release rate of eluting drug from polymer-rich structures. PMID- 29146239 TI - Innately activated TLR4 signal in the nucleus accumbens is sustained by CRF amplification loop and regulates impulsivity. AB - Cognitive impulsivity is a heritable trait believed to represent the behavior that defines the volition to initiate alcohol drinking. We have previously shown that a neuronal Toll-like receptor 4 (TLR4) signal located in the central amygdala (CeA) and ventral tegmental area (VTA) controls the initiation of binge drinking in alcohol-preferring P rats, and TLR4 expression is upregulated by alcohol-induced corticotropin-releasing factor (CRF) at these sites. However, the function of the TLR4 signal in the nucleus accumbens shell (NAc-shell), a site implicated in the control of reward, drug-seeking behavior and impulsivity and the contribution of other signal-associated genes, are still poorly understood. Here we report that P rats have an innately activated TLR4 signal in NAc-shell neurons that co-express the alpha2 GABAA receptor subunit and CRF prior to alcohol exposure. This signal is not present in non-alcohol drinking NP rats. The TLR4 signal is sustained by a CRF amplification loop, which includes TLR4 mediated CRF upregulation through PKA/CREB activation and CRF-mediated TLR4 upregulation through the CRF type 1 receptor (CRFR1) and the MAPK/ERK pathway. NAc-shell Infusion of a neurotropic, non-replicating herpes simplex virus vector for TLR4-specific small interfering RNA (pHSVsiTLR4) inhibits TLR4 expression and cognitive impulsivity, implicating the CRF-amplified TLR4 signal in impulsivity regulation. PMID- 29146238 TI - CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward. AB - The HIV-1 regulatory protein, trans-activator of transcription (Tat), interacts with opioids to potentiate neuroinflammation and neurodegeneration within the CNS. These effects may involve the C-C chemokine receptor type 5 (CCR5); however, the behavioral contribution of CCR5 on Tat/opioid interactions is not known. Using a transgenic murine model that expresses HIV-1 Tat protein in a GFAP regulated, doxycycline-inducible manner, we assessed morphine tolerance, dependence, and reward. To assess the influence of CCR5 on these effects, mice were pretreated with oral vehicle or the CCR5 antagonist, maraviroc, prior to morphine administration. We found that HIV-1 Tat expression significantly attenuated the antinociceptive potency of acute morphine (2-64 mg/kg, i.p.) in non-tolerant mice. Consistent with this, Tat attenuated withdrawal symptoms among morphine-tolerant mice. Pretreatment with maraviroc blocked the effects of Tat, reinstating morphine potency in non-tolerant mice and restoring withdrawal symptomology in morphine-tolerant mice. Twenty-four hours following morphine administration, HIV-1 Tat significantly potentiated (~3.5-fold) morphine conditioned place preference and maraviroc further potentiated these effects (~5.7-fold). Maraviroc exerted no measurable behavioral effects on its own. Protein array analyses revealed only minor changes to cytokine profiles when morphine was administered acutely or repeatedly; however, 24 h post morphine administration, the expression of several cytokines was greatly increased, including endogenous CCR5 chemokine ligands (CCL3, CCL4, and CCL5), as well as CCL2. Tat further elevated levels of several cytokines and maraviroc pretreatment attenuated these effects. These data demonstrate that CCR5 mediates key aspects of HIV-1 Tat-induced alterations in the antinociceptive potency and rewarding properties of opioids. PMID- 29146241 TI - Cardiac progenitor cells activated by mitochondrial delivery of resveratrol enhance the survival of a doxorubicin-induced cardiomyopathy mouse model via the mitochondrial activation of a damaged myocardium. AB - It has been reported that transplanting native cells would lack efficiency without producing artificial cell-tissue, due to the exaggerated oxidative stress in doxorubicin-induced cardiomyopathy. We attempted to activate cardiac progenitor cells (CPCs) by delivering resveratrol to mitochondria using a mitochondrial drug delivery system (MITO-Porter system). We first evaluated the viability of H9c2 cells (a cardio myoblast cell line) after doxorubicin treatment, where H9c2 cells were co-cultured with or without the mitochondria activated CPCs (referred to herein as MITO cell). We next evaluated the survival rate of doxorubicin treated mice, with or without the injection of MITO cells into the myocardium. Finally, we examined the molecular mechanism of the cell therapy by detecting oxidative stress and the induction of apoptosis in addition to quantification of the mRNA and protein levels about oxidative phosphorylation (OXPHOS). The MITO cell transplanted mice lived significantly longer than the conventional CPC transplanted ones. Oxidative stress and massive cell death were both significantly reduced in the MITO cell transplanted hearts, in which the expression levels of OXPHOS protein and gene were also higher than the control group. In doxorubicin-induced cardiomyopathy, the transplantation of MITO cells, which possess activated mitochondria, is more efficient compared to conventional CPC transplantation. PMID- 29146242 TI - Acid-activatable oxidative stress-inducing polysaccharide nanoparticles for anticancer therapy. AB - Drug delivery systems have been extensively developed to enhance the therapeutic efficacy of drugs by altering their pharmacokinetics and biodistribution. However, the use of high quantities of drug delivery systems can cause toxicity due to their poor metabolism and elimination. In this study, we developed polysaccharide-based drug delivery systems which exert potent therapeutic effects and could display synergistic therapeutic effects with drug payloads, leading to dose reduction. Cinnamaldehyde, a major component of cinnamon is known to induce anticancer activity by generating ROS (reactive oxygen species). We developed cinnamaldehyde-conjugated maltodextrin (CMD) as a polymeric prodrug of cinnamaldehyde and a drug carrier. Cinnamaldehyde was conjugated to the hydroxyl groups of maltodextrin via acid-cleavable acetal linkages, allowing facile formulation of nanoparticles and drug encapsulation. CMD nanoparticles induced acid-triggered ROS generation to induce apoptotic cell death. Camptothecin (CPT) was used as a model drug to investigate the potential of CMD nanoparticles as a drug carrier and also evaluate the synergistic anticancer effects with CMD nanoparticles. CPT-loaded CMD nanoparticles exhibited significantly higher anticancer activity than empty CMD nanoparticles and CPT alone in the study of mouse xenograft models, demonstrating the synergistic therapeutic effects of CMD with CPT. Taken together, we believe that CMD nanoparticles hold tremendous potential as a polymeric prodrug of cinnamaldehyde and a drug carrier in anticancer therapy. PMID- 29146243 TI - Current progress and challenges of nanoparticle-based therapeutics in pain management. AB - Pain is a widespread and growing health problem worldwide that exerts a considerable social and economic impact on both patients and healthcare systems and, therefore, on society in general. Although current treatment modalities include a wide variety of pharmacological and non-pharmacological approaches, due to the complexity of pain and individual differences in clinical response these options are not always effective in mitigating and relieving pain. In addition, some pain drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), local anesthetics and opioids show several unfavorable side effects. Therefore, current research advances in this medical field are based on the development of potential treatments to address many of the unmet needs and to overcome the existing limitations in pain management. Nanoparticle drug delivery systems present an exciting opportunity as alternative platforms to improve efficacy and safety of medications currently in use. Herein, we review a broad range of nanoparticle formulations (organic nanostructures and inorganic nanoparticles), which have been developed to encapsulate an array of painkillers, paying special attention to the key advantages that these systems offer, (compared to the use of the free drug), as well as to the more relevant results of preclinical studies in animal models. Additionally, we will briefly discuss the impact of some of these nanoformulations in clinical trials. PMID- 29146244 TI - Extending antigen release from particulate vaccines results in enhanced antitumor immune response. AB - Tumor-specific CD8+ cytotoxic T lymphocytes (CTLs) play a critical role in an anti-tumor immune response. However, vaccination intended to elicit a potent CD8+ T cell responses employing tumor-associated peptide antigens, are typically ineffective due to poor immunogenicity. Previously, we engineered a polyethylene glycol (PEG) hydrogel-based subunit vaccine for the delivery of an antigenic peptide and CpG (adjuvant) to elicit potent CTLs. In this study, we further examined the effect of antigen release kinetics on their induced immune responses. A CD8+ T cell epitope peptide from OVA (CSIINFEKL) and CpG were co conjugated to nanoparticles utilizing either a disulfide or a thioether linkage. Subsequent studies comparing peptide release rates as a function of linker, determined that the thioether linkage provided sustained release of peptide over 72h. Ability to control the release of peptide resulted in both higher and prolonged antigen presentation when compared to disulfide-linked peptide. Both NP vaccine formulations resulted in activation and maturation of bone marrow derived dendritic cells (BMDCs) and induced potent CD8+ T cell responses when compared to soluble antigen and soluble CpG. Immunization with either disulfide or thioether linked vaccine constructs effectively inhibited EG7-OVA tumor growth in mice, however only treatment with the thioether linked vaccine construct resulted in enhanced survival. PMID- 29146245 TI - Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells. AB - Cytosolic delivery remains a major bottleneck for siRNA therapeutics. To facilitate delivery, siRNAs are often enclosed in nanoparticles (NPs). However, upon endocytosis such NPs are mainly trafficked towards lysosomes. To avoid degradation, cytosolic release of siRNA should occur prior to fusion of endosomes with lysosomes, but current endosomal escape strategies remain inefficient. In contrast to this paradigm, we aim to exploit lysosomal accumulation by treating NP-transfected cells with low molecular weight drugs that release the siRNA from the lysosomes into the cytosol. We show that FDA-approved cationic amphiphilic drugs (CADs) significantly improved gene silencing by siRNA-loaded nanogels in cancer cells through simple sequential incubation. CADs induced lysosomal phospholipidosis, leading to transient lysosomal membrane permeabilization and improved siRNA release without cytotoxicity. Of note, the lysosomes could be applied as an intracellular depot for triggered siRNA release by multiple CAD treatments. PMID- 29146246 TI - Nanoparticle formulation improves doxorubicin efficacy by enhancing host antitumor immunity. AB - Strategies that enhance the host antitumor immune response promise to revolutionize cancer therapy. Optimally mobilizing the immune system will likely require a multi-pronged approach to overcome the resistance developed by tumors to therapy. Recently, it has become recognized that doxorubicin can contribute to re-establishing host antitumor immunity through the generation of immunogenic cell death. However, the potential for delivery strategies to further enhance the immunological effects of doxorubicin has not been adequately examined. We report herein that Chimeric Polypeptide Doxorubicin (CP-Dox), a nanoparticle formulation of doxorubicin, enhances antitumor immunity. Compared to free doxorubicin, a single intravenous (IV) administration of CP-Dox at the maximum tolerated dose increases the infiltration of leukocytes into the tumor, slowing tumor growth and preventing metastasis in poorly immunogenic 4T1 mammary carcinoma. We demonstrate that the full efficacy of CP-Dox is dependent on CD8+ T cells and IFN-gamma. CP dox treatment also repolarized intratumoral myeloid cells towards an antitumor phenotype. These findings demonstrate that a nanoparticle drug is distinct from the free drug in its ability to productively stimulate antitumor immunity. Our study strongly argues for the use of antitumor immunotherapies combined with nanoparticle-packaged chemotherapy. PMID- 29146247 TI - Distribution of apple and blackcurrant microbiota in Lithuania and the Czech Republic. AB - The microbial assemblies on the surface of plants correlate with specific climatic features, suggesting a direct link between environmental conditions and microbial inhabitation patterns. At the same time however, microbial communities demonstrate distinct profiles depending on the plant species and region of origin. In this study, we report Next Generation Sequencing-based metagenomic analysis of microbial communities associated with apple and blackcurrant fruits harvested from Lithuania and the Czech Republic. Differences in the taxonomic composition of eukaryotic and prokaryotic microorganisms were observed between plant types. Our results revealed limited geographic differentiation between the bacterial and fungal communities associated with apples. In contrast, blackcurrant berries harvested from different regions demonstrated high diversity in both bacterial and fungal microbiota structures. Among fungal and bacterial microorganisms, we identified both potentially beneficial (Cryptococcus, Hanseniaspora, Massilia, Rhodotorula, Sphingomonas) and phytopathogenic microorganisms (Cladosporium, Pantoea, Phoma, Pseudomonas, Septoria, Taphrina) indicating their important roles in ecological and evolutionary processes. PMID- 29146248 TI - Phosphatidylcholine absence affects the secretion of lipodepsipeptide phytoxins in Pseudomonas syringae pv. syringae van Hall CFCC 1336. AB - Pseudomonas syringae pv. syringae van Hall CFCC 1336 (Pss 1336) is the causal agent of bacterial disease of stone fruit trees, and also able to elicit hypersensitive response (HR) in non-host tobacco. It is known that this pathogen uses PCS-pathway to synthesize phosphatidylcholine (PC), and mutation of the pcs gene abolishes bacterial PC synthesis. Previous study also found that the 1336 pcs- mutant lacking PC in its membrane phospholipids was unable to secrete HrpZ harpin and elicit HR in non-host plants. In this study, we further analyzed virulence of lipodepsipeptide phytoxins of Pss 1336 wild type (pcs+), the 1336RM (pcs-/+) and the 1336 pcs- mutant, and found that the 1336 pcs- mutant was unable to cause necrosis of Chinese date fruits and inhibit fungal growth. HPLC analysis also showed that the 1336 pcs- mutant markedly reduced its secretion of lipodepsipeptide phytoxins. Analysis of semi-quantitative RT-PCR revealed that PC presence or absence did not affect gene expressions of SyrD, PseABC and PseEF efflux systems at transcriptional level. However, western blotting assays found that PseE and PseF present only in the cytoplasmic fractions but undetectable in the membrane extract of the 1336 pcs- mutant. PC absence obviously interrupted the translocation of two membrane-associated proteins PseE and PseF from cytoplasm to cell membranes to form an intact PseEF efflux system in bacterial membranes. Failure to form PseEF efflux system could be a major factor for less lipopeptide-phytoxin secretion. Our results demonstrate that PC in bacterial membrane phospholipids plays an important role in maintaining physiological functions of PseEF efflux system. PMID- 29146249 TI - Composition of lactic acid bacteria during spontaneous curly kale (Brassica oleracea var. sabellica) fermentation. AB - The present work is the first report on spontaneous fermentation of curly kale and characteristics of autochthonous lactic acid bacteria (LAB). Our results indicate that curly kale fermentation is the new possibility of the technological use of this vegetable. Bacteria representing ten different species were isolated from three phases of curly kale fermentation and identified by MALDI-TOF mass spectrometry and 16S rRNA gene sequencing. Among them, four species were identified as Lactobacillus spp. (Lb. plantarum 332, Lb. paraplantarum G2114, Lb. brevis R413, Lb. curvatus 154), two as Weissella spp. (W. hellenica 152, W. cibaria G44), two as Pediococcus spp. (P. pentosaceus 45AN, P. acidilactici 2211), one as Leuconostoc mesenteroides 153, and one as Lactococcus lactis 37BN. The functional properties of isolates, i.e. acid, NaCl and bile salt tolerance, enzyme activities, adhesion to hydrocarbons, and antibiotic resistance, were examined. Among the tested strains, Lb. plantarum 332, Lb. paraplantarum G2114, P. pentosaceus 2211, and Lb. brevis R413 exhibited the best hydrophobicity value and high tolerance to bile salts, NaCl, and low pH. PMID- 29146250 TI - Revitalization of plant growth promoting rhizobacteria for sustainable development in agriculture. AB - The progression of life in all forms is not only dependent on agricultural and food security but also on the soil characteristics. The dynamic nature of soil is a direct manifestation of soil microbes, bio-mineralization, and synergistic co evolution with plants. With the increase in world's population the demand for agriculture yield has increased tremendously and thereby leading to large scale production of chemical fertilizers. Since the use of fertilizers and pesticides in the agricultural fields have caused degradation of soil quality and fertility, thus the expansion of agricultural land with fertile soil is near impossible, hence researchers and scientists have sifted their attention for a safer and productive means of agricultural practices. Plant growth promoting rhizobacteria (PGPR) has been functioning as a co-evolution between plants and microbes showing antagonistic and synergistic interactions with microorganisms and the soil. Microbial revitalization using plant growth promoters had been achieved through direct and indirect approaches like bio-fertilization, invigorating root growth, rhizoremediation, disease resistance etc. Although, there are a wide variety of PGPR and its allies, their role and usages for sustainable agriculture remains controversial and restricted. There is also variability in the performance of PGPR that may be due to various environmental factors that might affect their growth and proliferation in the plants. These gaps and limitations can be addressed through use of modern approaches and techniques such as nano encapsulation and micro-encapsulation along with exploring multidisciplinary research that combines applications in biotechnology, nanotechnology, agro biotechnology, chemical engineering and material science and bringing together different ecological and functional biological approaches to provide new formulations and opportunities with immense potential. PMID- 29146251 TI - Differential protein-DNA contacts for activation and repression by ArgP, a LysR type (LTTR) transcriptional regulator in Escherichia coli. AB - ArgP is a LysR-type transcriptional regulator (LTTR) that operates with two effector molecules, lysine and arginine, to differentially regulate gene expression. Effector-free ArgP stimulates transcription of all investigated regulon members, except argO, whereas lysine abolishes this effect. Activation of argO, encoding an exporter for arginine and canavanine, is strictly dependent on arginine-bound ArgP. Lysine counteracts this effect and even though lysine-bound ArgP stimulates RNA polymerase recruitment at the argO promoter, the complex is non-productive. It is presently unclear what distinguishes argO from other ArgP targets and how binding of arginine and lysine translates in antagonistic effects on promoter activity. Here we generate high resolution contact maps of effector free and effector-bound ArgP-DNA interactions and identify the sequence 5'-CTTAT as the consensus recognition motif for ArgP binding. argO is the only operator at which ArgP binding overlaps the -35 promoter element and binding of arginine results in a repositioning of the promoter proximal bound ArgP-arg subunits. This effect was mimicked by the generation of a 10bp insertion mutant (ins-10) in the argO operator that renders its activation by ArgP arginine-independent. ArgP induced DNA bending of the argO operator by approximately 60 degrees was found to be effector independent. An ArgP:DNA binding stoichiometry of 4:1 indicates binding of four ArgP subunits even to DNA constructs that are truncated for one binding subsite (DeltaABS). These results provide insight into the molecular mechanisms of ArgP-mediated regulation and a molecular explanation for the unique arginine-dependence of argO activation that distinguishes this particular ArgP target from all others. PMID- 29146252 TI - The outer membrane protein OprF and the sigma factor SigX regulate antibiotic production in Pseudomonas fluorescens 2P24. AB - Pseudomonas fluorescens 2P24 produces 2,4-diacetylphloroglucinol (2,4-DAPG) as the major antibiotic compound that protects plants from soil-borne diseases. Expression of the 2,4-DAPG biosynthesis enzymes, which are encoded by the phlACBD locus, is under the control of a delicate regulatory network. In this study, we identified a novel role for the outer membrane protein gene oprF, in negatively regulating the 2,4-DAPG production by using random mini-Tn5 mutagentsis. A sigma factor gene sigX was located immediately upstream of the oprF gene and shown to be a positive regulator for oprF transcription and 2,4-DAPG production. Genetic analysis of an oprF and sigX double-mutant indicated that the 2,4-DAPG regulation by oprF was dependent on SigX. The sigX gene did not affect PhlA and PhlD expression, but positively regulated the level of malonyl-CoA, the substrate of 2,4-DAPG synthesis, by influencing the expression of acetyl-CoA carboxylases. Further investigations revealed that sigX transcription was induced under conditions of salt starvation or glycine addition. All these findings indicate that SigX is a novel regulator of substrate supplements for 2,4-DAPG production. PMID- 29146253 TI - Isolation and characterisation of theobromine-degrading filamentous fungi. AB - Strategies for achieving global food security include identification of alternative feedstock for use as animal feed, to contribute towards efforts at increasing livestock farming. The presence of theobromine in cocoa pod husks, a major agro-waste in cocoa-producing countries, hinders its utilisation for this purpose. Cheap treatment of cocoa pod husks to remove theobromine would allow largescale beneficial use of the millions of metric tonnes generated annually. The aim of this study was to isolate theobromine-degrading filamentous fungi that could serve as bioremediation agents for detheobromination of cocoa pod husks. Filamentous fungi were screened for ability to degrade theobromine. The most promising isolates were characterized with respect to optimal environmental conditions for theobromine degradation. Secretion of theobromine-degrading enzymes by the isolates was investigated. Theobromine degradation was monitored by HPLC. Of fourteen theobromine-degrading isolates collected and identified by rDNA 5.8S and ITS sequences, seven belonged to Aspergillus spp. and six were Talaromyces spp. Based on the extent of theobromine utilization, four isolates; Aspergillus niger, Talaromyces verruculosus and two Talaromyces marneffei, showed the best potential for use as bioagents for detheobromination. First-time evidence was found of the use of xanthine oxidase and theobromine oxidase in degradation of a methylxanthine by fungal isolates. Metabolism of theobromine involved initial demethylation at position 7 to form 3-methylxanthine, or initial oxidation at position 8 to form 3,7-dimethyuric acid. All four isolates degraded theobromine beyond uric acid. The data suggest that the four isolates can be applied to substrates, such as cocoa pod husks, for elimination of theobromine. PMID- 29146254 TI - Intertwined control of the cell cycle and nucleocytoplasmic transport by the cyclin-dependent kinase Pho85 and RanGTPase Gsp1 in Saccharomyces cerevisiae. AB - Deciphering the molecular mechanisms that connect cell cycle progression and nucleocytoplasmic transport is of particular interest: this intertwined relationship, once understood, may provide useful insight on the diseases resulting from the malfunction of these processes. In the present study we report on findings that indicate a biochemical connection between the cell cycle regulator CDK Pho85 and Ran-GTPase Gsp1, an essential nucleocytoplasmic transport component. When Gsp1 cannot be phosphorylated by Pho85, the cell cycle progression is impaired. Accordingly, a nonphosphorylatable version of Gsp1 abnormally localizes to the nucleus, which impairs the nuclear transport of molecules, including key components of cell cycle progression. Furthermore, our results suggest that the physical interaction of Gsp1 and the Kap95 karyopherin, essential to the release of nuclear cargoes, is altered. Altogether, the present findings point to the involvement of a biochemical mechanism in the interlocked regulation of the cell cycle and nuclear transport. PMID- 29146255 TI - Haemophilus parasuis CpxRA two-component system confers bacterial tolerance to environmental stresses and macrolide resistance. AB - Haemophilus parasuis is an opportunistic pathogen localized in the upper respiratory tracts of pigs, its infection begins from bacterial survival under complex conditions, like hyperosmosis, oxidative stress, phagocytosis, and sometimes antibiotics as well. The two-component signal transduction (TCST) system serves as a common stimulus-response mechanism that allows microbes to sense and respond to diverse environmental conditions via a series of phosphorylation reactions. In this study, we investigated the role of TCST system CpxRA in H. parasuis in response to different environmental stimuli by constructing the DeltacpxA and DeltacpxR single deletion mutants as well as the DeltacpxRA double deletion mutant from H. parasuis serotype 4 isolate JS0135. We demonstrated that H. parasuis TCST system CpxRA confers bacterial tolerance to stresses and bactericidal antibiotics. The CpxR was found to play essential roles in mediating oxidative stress, osmotic stresses and alkaline pH stress tolerance, as well as macrolide resistance (i.e. erythromycin), but the CpxA deletion did not decrease bacterial resistance to abovementioned stresses. Moreover, we found via RT-qPCR approach that HAPS_RS00160 and HAPS_RS09425, both encoding multidrug efflux pumps, were significantly decreased in erythromycin challenged DeltacpxR and DeltacpxRA mutants compared with wild-type strain JS0135. These findings characterize the role of the TCST system CpxRA in H. parasuis conferring stress response tolerance and bactericidal resistance, which will deepen our understanding of the pathogenic mechanism in H. parasuis. PMID- 29146256 TI - Isolation, purification, structural elucidation and antimicrobial activities of kocumarin, a novel antibiotic isolated from actinobacterium Kocuria marina CMG S2 associated with the brown seaweed Pelvetia canaliculata. AB - AIMS: Screening of seaweed-associated bacteria capable of producing antimicrobials. METHODS AND RESULTS: Fifteen microbial strains, associated to the brown seaweed Pelvetia canaliculata (Linnaeus) attached to the rocks of Sonmiani Beach (Karachi, Pakistan), were screened. Crude extract filtrates of CMG S2 strain grew on Zobell marine agar (ZMA) had the most remarkable antimicrobial activity. Based on its phenotypic aspects (e.g. Gram-positive, microccoid form), biochemical characteristics (e.g. halotolerance) and genetic analyses, CMG S2 is identified as a putatively new Kocuria marina type strain belonging to the actinobacteria's class and micrococcaceae family. Thereby, the nucleotide sequence analysis of its full-length 16S ribosomal ribonucleic acid (rRNA) gene (GenBank accession number EU073966.1) displayed highest identity (i.e. 99%) and score (2630) with K. marina KMM 3905. Phylogenic trees analysis using the neighbor-joining method showed closest evolutionary distance of CMG S2 with KMM 3905 strain and K. carniphila (DC2201) specie. Interestingly, a unique ultraviolet (UV)-bioactive compound was purified from CMG S2 crude extracts by flash silica gel column and thin-layer chromatography (TLC) techniques. Its chemical structure was unraveled as 4-[(Z)-2 phenyl ethenyl] benzoic acid (PEBA, later named kocumarin) by nuclear magnetic resonance (NMR) spectroscopy techniques. Importantly, kocumarin demonstrated prominent and rapid growth inhibition against all tested fungi and pathogenic bacteria including methicillin resistant Staphylococcus aureus (MRSA), with a minimal fungal inhibitory concentration (MFC) of 15-25MUg/mL and a minimal (bacterial) inhibitory concentration (MIC) of 10-15MUg/mL. SIGNIFICANCE AND IMPACT OF THE STUDY: Kocumarin represents a new promising natural antibiotic for in vivo and environmental applications. PMID- 29146257 TI - Klebsiella sp. confers enhanced tolerance to salinity and plant growth promotion in oat seedlings (Avena sativa). AB - Plant growth and yield is adversely affected by soil salinity. Salt tolerant plant growth-promoting rhizobacteria (PGPR) strain IG 3 was isolated from rhizosphere of wheat plants. The isolate IG 3 was able to grow in presence of NaCl ranging from 0 to 20% in Luria Bertani medium. The present study was planned to evaluate the role of inoculation of PGPR strain IG 3 and its efficacy in augmenting salt tolerance in oat (Avena sativa) under NaCl stress (100mM). The physiological parameter such as shoot length, root length, shoot dry weight, root dry weight and relative water content (RWC) were remarkably higher in IG 3 inoculated plants in comparison to un-inoculated plants under NaCl stress. Similarly, the biochemical parameters such as proline content, electrolyte leakage and malondialdehyde (MDA) content and activities of antioxidant enzymes were analyzed and found to be notably lesser in IG 3 inoculated oat plants in contrast to un-inoculated plants under salt stress. Inoculation of IG 3 strain to oat seedlings under salt stress positively modulated the expression profile of rbcL and WRKY1 genes. Root colonization of root surface and interior was demonstrated using scanning electron microscopy and tetrazolium staining, respectively. Due these outcomes, it could be implicated that inoculation of PGPR strain IG 3 enhanced plant growth under salt stress condition. This study demonstrates that PGPR play an imperative function in stimulating salt tolerance in plants and can be used as biofertilizer to enhance growth of crops in saline areas. PMID- 29146258 TI - Screening of tropically derived, multi-trait plant growth- promoting rhizobacteria and evaluation of corn and soybean colonization ability. AB - The present study assessed the plant growth-promoting (PGP) traits and diversity of culturable rhizobacteria associated with guarana (Paullinia cupana), a typical tropical plant. Ninety-six bacteria were isolated, subjected to biochemical tests, and identified by partial or total 16S rDNA sequencing. Proteobacteria and Firmicutes were the dominant rhizospheric phyla found, and Burkholderia and Bacillus were the most abundant genera. Thirteen strains exhibited the four PGP traits evaluated, and most of them belonged to the genus Burkholderia. Two multi trait PGP strains, RZ2MS9 (Bacillus sp.) and RZ2MS16 (Burkholderia ambifaria), expressively promoted corn and soybean growth under greenhouse conditions. Compared to the non-inoculated control, increases in corn root dry weight of 247.8 and 136.9% were obtained with RZ2MS9 and RZ2MS16 inoculation, respectively, at 60days after seeding. The dry weights of corn and soybean shoots were significantly higher than those of non-inoculated plants, showing increases of more than 47% for both strains and crops. However, soybean root dry weight did not increased after bacterial inoculation with either strain. The colonization behavior of RZ2MS16 was assessed using GFP-labeling combined with fluorescence microscopy and a cultivation-based approach for quantification. RZ2MS16:gfp was able to colonize the roots and shoots of corn and soybean, revealing an endophytic behavior. PMID- 29146259 TI - Characterization and assessment of two biocontrol bacteria against Pseudomonas syringae wilt in Solanum lycopersicum and its genetic responses. AB - Pseudomonas and Bacillus species are attractive due to their potential bio control application against plant bacterial pathogens. Pseudomonas aeruginosa strain D4 and Bacillus stratosphericus strain FW3 were isolated from mine tailings in South Korea. In these potent bacterial strains, we observed improved antagonistic activity against Pseudomonas syringae DC3000. These strains produced biocatalysts for plant growth promotion, and in vivo examination of Solanum lycopersicum included analysis of disease severity, ion leakage, chlorophyll content, and H2O2 detection. In addition, regulation of the defense genes pathogen-related protein 1a (PR1a) and phenylalanine ammonia lyase (PAL) was compared with treated plants and untreated control plants. The results suggest that these two bacterial strains provide protection against plant pathogens via direct and indirect modes of action and could be used as a bio-control agent. PMID- 29146260 TI - A novel Burkholderia ambifaria strain able to degrade the mycotoxin fusaric acid and to inhibit Fusarium spp. growth. AB - Fusaric acid (FA) is a fungal metabolite produced by several Fusarium species responsible for wilts and root rot diseases of a great variety of plants. Bacillus spp. and Pseudomonas spp. have been considered as promising biocontrol agents against phytopathogenic Fusarium spp., however it has been demonstrated that FA negatively affects growth and production of some antibiotics in these bacteria. Thus, the capability to degrade FA would be a desirable characteristic in bacterial biocontrol agents of Fusarium wilt. Taking this into account, bacteria isolated from the rhizosphere of barley were screened for their ability to use FA as sole carbon and energy source. One strain that fulfilled this requirement was identified according to sequence analysis of 16S rRNA, gyrB and recA genes as Burkholderia ambifaria. This strain, designated T16, was able to grow with FA as sole carbon, nitrogen and energy source and also showed the ability to detoxify FA in barley seedlings. This bacterium also exhibited higher growth rate, higher cell densities, longer survival, higher levels of indole-3 acetic acid (IAA) production, enhanced biofilm formation and increased resistance to different antibiotics when cultivated in Luria Bertani medium at pH 5.3 compared to pH 7.3. Furthermore, B. ambifaria T16 showed distinctive plant growth promoting features, such as siderophore production, phosphate-solubilization, 1 aminocyclopropane-1-carboxylate (ACC) deaminase activity, in vitro antagonism against Fusarium spp. and improvement of grain yield when inoculated to barley plants grown under greenhouse conditions. This strain might serve as a new source of metabolites or genes for the development of novel FA-detoxification systems. PMID- 29146261 TI - A comprehensive review of non-enterica subspecies of Salmonella enterica. AB - Salmonella is a major foodborne pathogen with a complex nomenclature. This genus is composed of two species, S. enterica and S. bongori. S. enterica is divided into six subspecies. S. enterica subspecies enterica is composed of more than 1500 serotypes with some of great importance, such as S. Typhimurium and S. Enteritidis. S. enterica subsp. enterica is responsible of more than 99% of human salmonellosis and therefore it is widely studied. However, the non-enterica subspecies of S. enterica have been little studied. These subspecies are considered to be related to cold-blooded animals and their pathogenicity is very limited. Phenotype and genotype information generated from different studies of non-enterica subspecies reveal poor ability to invade host cells and the absence or modification of important virulence factors. Also, the great majority of human infections due to non-enterica subspecies are related to a previous depressed immune system. Therefore, we propose to treat these subspecies only as opportunistic pathogens. For establish this premise, the present review evaluated, among other things, the genomic characteristics, prevalence, antimicrobial resistance and reported human cases of the non-enterica subspecies. PMID- 29146262 TI - Pathogenic Labyrinthula associated with Australian seagrasses: Considerations for seagrass wasting disease in the southern hemisphere. AB - Marine disease ecology is a growing field of research, particularly for host organisms negatively impacted by a changing climate and anthropogenic activities. A decrease in health and increase in susceptibility to disease has been hypothesised as the mechanism behind wide-spread seagrass die-offs related to wasting disease in the past. However, seagrass wasting disease and the causative pathogen, Labyrinthula, have been vastly understudied in the southern hemisphere. Our aim was to build on the current knowledge of Australian Labyrinthula descriptions and phylogeny, while also providing a first look at wasting disease ecology in Australia. Five seagrass species along a 750km stretch of coastline in southeastern Australia were sampled. The resulting 38 Labyrinthula isolates represented a diversity of morphotypes and five haplotypes of varying phylogenetic clade positions and virulence. The haplotypes clustered with previously-described phylogenetic clades containing isolates from Asia, USA and Europe. Pathogenicity tests confirmed, for the first time, the presence of at least two pathogenic haplotypes in Australia. While historically there have been no reports of wasting disease-related seagrass habitat loss, the presence of pathogenic Labyrinthula highlights the need for disease monitoring and research to understand seagrass wasting disease ecology in Australia. PMID- 29146263 TI - Transcription factors Atf1 and Sty1 promote stress tolerance under nitrosative stress in Schizosaccharomyces pombe. AB - Nitric Oxide (NO) and its associated reactive nitrogen species (RNS) produce nitrosative stress under various pathophysiological conditions in eukaryotes. The fission yeast Schizosaccharomyces pombe regulates stress response mainly through the Sty1-Atf1 MAP Kinase pathway. The present study deals with the role of transcription factor Atf1 and Sty1 in S. pombe under nitrosative stress. In this study, exposure to an NO donor resulted in S-phase slowdown with associated mitotic block in S. pombe. Deletion of sty1 and atf1 in S. pombe had differential growth sensitivity towards NO donor. Both Sty1 and Atf1 were involved in regulating mitotic slowdown in S. pombe under nitrosative stress. Experimental data obtained in this study reveals a novel role of Atf1 in initiating the replication slowdown in S. pombe under nitrosative stress. Both Sty1 and Atf1 were accumulated in the nucleus in S. pombe under nitrosative stress in a concentration and time dependent manner. Atf1 is also found to be nuclear delocalized under longer nitrosative stress. PMID- 29146264 TI - Combination of amplified rDNA restriction analysis and high-throughput sequencing revealed the negative effect of colistin sulfate on the diversity of soil microorganisms. AB - Colistin sulfate is widely used in both human and veterinary medicine. However, its effect on the microbial ecologyis unknown. In this study, we determined the effect of colistin sulfate on the diversity of soil microorganisms by amplified rDNA restriction analysis (ARDRA) and high-throughput sequencing.ARDRAshowed that the diversity of DNA from soil microorganisms was reduced after soil was treated with colistin sulfate, with the most dramatic reductionobserved after 35days of treatment. High-throughput sequencing showed that the Chao1 and abundance-based coverage estimators (ACE) were reduced in the soils treated with colistin sulfate for 35 dayscompared to those treated with colistin sulfate for 7days. Furthermore, Chao1 and ACE tended to be lower when higher concentration of colistin sulfate was used, suggesting that the microbial abundance is reduced by colistin sulfate in a dose-dependent manner. Shannon index showed that the diversity of soil microorganism was reduced upon treatment with colistin sulfate compared to the untreated control group. Following 7days of treatment, Bacillus, Clostridiumand Sphingomonas were sensitive to all the concentration of colistin sulfate used in this study. Following 35days of treatment, the abundance of Choroplast, Haliangium, Pseudomonas, Lactococcus, and Clostridium was significantly decreased. Our results demonstrated that colistin sulfate especially at high concentration (>=5mg/kg) could alter the population structure of microorganisms and consequently the microbial community function in soil. PMID- 29146265 TI - SawR a new regulator controlling pyomelanin synthesis in Pseudomonas aeruginosa. AB - Surface Acoustic Waves (SAW) were previously shown to inhibit biofilm formation, increase bacterial susceptibility to antibiotic treatment and alter the transcription pattern of Pseudomonas aeruginosa. Here we characterize one gene, sawR (PA3133), that is highly overexpressed when P. aeruginosa is exposed to SAW. SawR is a putative transcription factor belonging to the TetR regulator family. When overexpressed sawR causes numerous phenotypes, including the accumulation of a brown pigment which we identified as pyomelanin. In this study we describe how sawR regulates pyomelanin synthesis. We show that sawR down-regulates the expression levels of hmgA and this causes the accumulation of homogentisic acid which in turn undergoes oxidation and polymerization to pyomelanin. Using bioinformatics, we were able to identify a specific amino acid, arginine 23, which is found within the sawR DNA binding domain and is crucial for its regulatory activity. Our results indicate that sawR does not affect any other genes in the phenylalanine/tyrosine metabolic pathway and its repressive ability on hmgA is not mediated by the hmgA repressor PA2010 (i.e. hmgR). Taken together, our results shed light on the regulatory cascade controlling pyomelanin synthesis and uncover yet another unknown regulator involved in its regulation. PMID- 29146266 TI - Endophytism or saprophytism: Decoding the lifestyle transition of the generalist fungus Phomopsis liquidambari. AB - Filamentous ascomycete Phomopsis sp. are common inhabitants of natural ecosystems and, as saprophytes, are largely responsible for the destructive decay of litterfall, promoting the carbon and nitrogen cycles. Phomopsis liquidambari B3 can establish mutualistic symbiosis with a broad spectrum of crop plants. Colonizing dynamics observations and a growth promotion assay of rice and Arabidopsis thaliana revealed that the B3 colonization strategy is host-adapted and resulted in different growth promotions influenced by N availability. However, the biochemical mechanisms and underlying genetics of the saprophyte transition to an endophyte are poorly understood. Here, the transcriptome features of generalist P. liquidambari and highlighted gene sets involved in the lifestyle transition from saprophytism to endophytism were reported. Most notable were genes for translation, ribosome biogenesis and MAPK signaling, several of which were only up-regulated in endophytic B3. Coordinated up-regulation of genes encoding enzymes involved in phenylalanine, tyrosine and tryptophan biosynthesis were preceded by secondary metabolite induction, which was encountered with host defense. Quantitative PCR validates the reliability of RNA-seq. Dissection at the molecular level facilitated a deeper understanding of P. liquidambari adaptation to hosts and the complex natural environment to play a role in sustainable agriculture and carbon and nitrogen cycles. PMID- 29146267 TI - Indocyanine green tissue angiography affects anastomotic leakage after esophagectomy. A retrospective, case-control study. AB - PURPOSE: Optimal perfusion of the gastric conduit during esophagectomy is elementary for the anastomotic healing since poor perfusion has been associated with increased morbidity due to anastomotic leaks. Until recently surgical experience was the main tool to assess the perfusion of the anastomosis. We hypothesized that anastomoses located in the zone of optimal ICG perfusion of the gastric conduit ("optizone") have a reduced anastomotic leakage rate after esophagectomy. METHODS: Indocyanine green (ICG) fluorescence tissue angiography was used to evaluate the anastomotic perfusion in 35 patients undergoing esophagectomy with gastric conduit reconstruction. The transition point of the "optizone" to the malperfused area of the conduit was defined macroscopically and with the use of ICG angiography during the operation. The anastomosis was performed in the optizone whenever possible. The results of the ICG patients were retrospectively reviewed and compared with 55 patients previously operated without ICG angiography. RESULTS: The visual assessment of the conduit perfusion concurred with the ICG angiography in 27 cases. In 8 cases (22.8%) the ICG angiography deviated from the visual aspect. One case of anastomotic leakage was observed in the group of patients in which the anastomosis could be performed in the optizone (1/33; 3%) compared with 10 cases in the control group (18%; p = 0.04). In two cases we had to perform the anastomosis in an area of compromised ICG perfusion. Both patients developed an anastomotic leakage. CONCLUSIONS: ICG tissue angiography represents a feasible and reliable technical support in the evaluation of the anastomotic perfusion after esophagectomy. In this retrospective analysis we observed a significant decrease in anastomotic leakage rate when the anastomosis could be placed in the zone of good perfusion defined by ICG fluorescence. A prospective trial is needed in order to provide higher level evidence for the use of ICG fluorescence in reducing leakage rates after esophagectomy. PMID- 29146268 TI - Surgical Apgar Score predicts 30-day morbidity in elderly patients who undergo non-laparoscopic gynecologic surgery: A retrospective analysis. AB - INTRODUCTION: The aim of this study was to determine whether a preoperative health status index and intraoperative data could predict perioperative morbidity and mortality in women over the age of 65 years undergoing surgery for gynecologic disorders. METHODS: The medical records of 68 female patients who were >=65 years of age and who underwent surgery under general anesthesia in our institute from January 2014 to December 2015 were retrospectively reviewed. Preoperative data were extracted from a database and included comorbidities, American Society of Anesthesiologists physiological status classification, the Charlson Comorbidity Index, the Subjective Global Assessment 2011 revision, the subjects' risk of falling, body mass index, and age. The intraoperative factors investigated included the type of surgery and the Surgical Apgar Score (SAS). Major postoperative complications were defined as > Grade 3 based on the Clavien Dindo classification version 2.0. RESULTS: Of the 68 elderly gynecological patients, 6 (8.8%) developed serious Grade 3 or worse complications within 30 days of surgery. The only factor that significantly affected postoperative complications was the SAS, an index of the patient's intraoperative condition. The optimum cut-off SAS for the occurrence of complications was determined by the receiver operating characteristic curve to be <= 6 points; a score <=6 points predicted the development of postoperative complications with 66.7% sensitivity and 79.0% specificity. CONCLUSION: In this study, the SAS predicted the development of serious complications in elderly gynecological patients within 30 days of surgery more accurately than did other comorbidities, preoperative assessments, and type of surgery. PMID- 29146269 TI - Impact of obesity on postoperative complications after laparoscopic and open incisional hernia repair - A prospective cohort study. AB - BACKGROUND: Obese patients are often required to lose weight prior to incisional hernia repair as obesity is thought to increase postoperative complications and recurrence rates. The aim of this study was to determine the impact of BMI on the outcome after laparoscopic and open incisional hernia repair. MATERIALS AND METHODS: In a cohort study from May 2012 to August 2016, 178 patients underwent incisional hernia repair: 90 patients open SUBLAY and 88 patients laparoscopic intraperitoneal onlay mesh (IPOM). Patients' characteristics, hernia size and postoperative complications were prospectively recorded. Patients were divided into two groups according to their weight: non-obese (BMI < 30 kg/m2) and obese (BMI >= 30 kg/m2). In October 2016, eligible patients were assessed for recurrence. RESULTS: 109 patients (61%) were non-obese; 69 patients (39%) were obese. Morbidity rate was higher among obese patients without reaching statistical significance (35% versus 22%; p = 0.083). BMI had no impact on length of hospital stay. The mean duration of surgery was significantly longer for patients with a BMI >=30 kg/m2 (82 min versus 98 min; p = 0.026). Duration of surgery in particular was significantly longer for obese patients that underwent open SUBLAY repair (p = 0.001). 119 patients (67%) were available for follow-up. Recurrence rates also showed no significant difference between both groups (7% versus 8%, p = 0.856). CONCLUSION: Morbidity rate following incisional hernia repair is not significantly higher in obese than in non-obese patients. BMI has no significant impact on the recurrence rate. Laparoscopic IPOM could be beneficial for obese patients with regard to duration of surgery. PMID- 29146270 TI - Retrospective cohort study on Angio-Seal closure device safety and effectiveness in antegrade superficial femoral artery punctures: A comparison with antegrade common femoral artery punctures. AB - PURPOSE: This retrospective study evaluates the effectiveness and safety of the Angio-Seal closure device in superficial femoral artery (SFA) antegrade punctures compared to common femoral artery (CFA) antegrade punctures. METHODS: Over a period of 46 months from January 2012, consecutive patients who underwent antegrade CFA or SFA punctures using Angio-Seal as a closure device in a single centre were studied. Patients were identified by reading all the individual reports on our radiology system for all patients who underwent any angiographic examination during the study period, and their individual case notes were subsequently reviewed. A retrospective analysis of prospectively collected data on patients' demographics, type of intervention, clinical indication, Angio-Seal size, haemostasis status and complications was performed. RESULTS: Overall, 194 patients (mean (s.d.) age 74(12) years, 123(44%) males) underwent CFA or SFA antegrade punctures. A total of 228 (CFA group, n = 70, SFA group, n = 158) antegrade punctures were performed. Clinical characteristics of the two groups were comparable. Angio-Seal size 6F was deployed in 69(99%) antegrade CFA punctures and 155(98%) antegrade SFA punctures (P = 1.000). Haemostasis was achieved in 65(93%) antegrade CFA punctures compared to 156(99%) antegrade SFA punctures (P = 0.030). CONCLUSION: Angio-Seal closure device is safe and effective method of haemostasis both in antegrade SFA and CFA punctures with no significant complications or delayed discharge. PMID- 29146271 TI - Factors affecting the under-diagnosis of atypical ductal hyperplasia diagnosed by core needle biopsies - A 10-year retrospective study and review of the literature. AB - INTRODUCTION: Due to the possibility of underestimation, surgical excision is usually offered to patients with atypical ductal hyperplasia (ADH) diagnosed with core needle biopsy (CNB). Here we review the 10-year data of patients with ADH diagnosed by CNB, aiming to identify the factors associated with under-diagnosis. METHODS: Retrospective review of database from 1st Jan 2005 to 31st Dec 2014 was performed; patients with ADH diagnosed by CNB were identified. Diagnosis upgrade rate and its risk factors were evaluated. RESULTS: 104 patients were found to have ADH on CNB, 101 patients received excisional biopsy while 3 patients refused operation. 34 patients had ductal carcinoma in situ (DCIS) after excision, 6 had invasive ductal carcinoma, 1 had lobular carcinoma in situ and 1 had angiosarcoma. CNB under-diagnosed up to 41.6% of malignant lesions. Breast mass on presentation and suspicious mammograms (BIRADS >= 4) are associated with diagnosis upgrade (P = 0.0005, 0.0001). Literature review of 39 studies between 1997 and 2017 revealed 3125 excision procedures performed for ADH diagnosed by CNB, the pooled median diagnosis upgrade rate was 25% (Range 4-54%). CONCLUSION: We recommend excision in all patients with ADH diagnosed by CNB, especially in patients with suspicious mammographic features. PMID- 29146272 TI - Obstruction phenotype as a predictor of asthma severity and instability in children. AB - BACKGROUND: Small-airways instability resulting in premature airway closure has been recognized as a risk for asthma severity and poor control. Although spirometry has limited sensitivity for detecting small-airways dysfunction, a focus on the air-trapping component of obstruction might identify a risk factor for asthma instability. OBJECTIVE: We sought to use spirometric measurements to identify patterns of airway obstruction in children and define obstruction phenotypes that relate to asthma instability. METHODS: Prebronchodilation and postbronchodilation spirometric data were obtained from 560 children in the Asthma Phenotypes in the Inner City study. An air-trapping obstruction phenotype (A Trpg) was defined as a forced vital capacity (FVC) z score of less than -1.64 or an increase in FVC of 10% of predicted value or greater with bronchodilation. The airflow limitation phenotype (A Limit) had an FEV1/FVC z score of less than 1.64 but not A Trpg. The no airflow limitation or air-trapping criteria (None) phenotype had neither A Trpg nor A Limit. The 3 obstruction phenotypes were assessed as predictors of number of exacerbations, asthma severity, and airway lability. RESULTS: Patients with the A Trpg phenotype (14% of the cohort) had more exacerbations during the 12-month study compared with those with the A Limit (P < .03) and None (P < .001) phenotypes. Patients with the A Trpg phenotype also had the highest Composite Asthma Severity Index score, the highest asthma treatment step, the greatest variability in FEV1 over time, and the greatest sensitivity to methacholine challenge. CONCLUSIONS: A Trpg and A Limit patterns of obstruction, as defined by using routine spirometric measurements, can identify obstruction phenotypes that are indicators of risk for asthma severity and instability. PMID- 29146273 TI - Could substance P be an antiviral mediator and potential therapeutic target in the nose? PMID- 29146274 TI - Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices. AB - BACKGROUND: Angiotensin-neprilysin inhibition compared to angiotensin inhibition decreased sudden cardiac death in patients with reduced ejection fraction heart failure (rEFHF). The precise mechanism remains unclear. OBJECTIVE: The purpose of this study was to explore the effect of angiotensin-neprilysin inhibition on ventricular arrhythmias compared to angiotensin inhibition in rEFHF patients with an implantable cardioverter-defibrillator (ICD) and remote monitoring. METHODS: We prospectively included 120 patients with ICD and (1) New York Heart Association functional class >=II; (2) left ventricular ejection fraction <=40%; and (3) remote monitoring. For 9 months, patients received 100% angiotensin inhibition with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), beta-blockers, and mineraloid antagonist. Subsequently, ACEi or ARB was changed to sacubitril-valsartan in all patients, who were followed for 9 months. Appropriate shocks, nonsustained ventricular tachycardia (NSVT), premature ventricular contraction (PVC) burden, and biventricular pacing percentage were analyzed. RESULTS: Patients were an average age of 69 +/- 8 years and had mean left ventricular ejection fraction of 30.4% +/- 4% (82% ischemic). Use of beta-blockers (98%), mineraloid antagonist (97%) and antiarrhythmic drugs was similar before and after sacubitril-valsartan. Sacubitril-valsartan significantly decreased NSVT episodes (5.4 +/- 0.5 vs 15 +/- 1.7 in angiotensin inhibition; P <.002), sustained ventricular tachycardia, and appropriate ICD shocks (0.8% vs 6.7% in angiotensin inhibition; P <.02). PVCs per hour decreased after sacubitril-valsartan (33 +/- 12 vs 78 +/- 15 in angiotensin inhibition; P <.0003) and was associated with increased biventricular pacing percentage (from 95% +/- 6% to 98.8% +/- 1.3%; P <.02). CONCLUSION: Angiotensin-neprilysin inhibition decreased ventricular arrhythmias and appropriate ICD shocks in rEFHF patients under home monitoring compared to angiotensin inhibition. PMID- 29146275 TI - Beat-to-beat variations in activation-recovery interval derived from the right ventricular electrogram can monitor arrhythmic risk under anesthetic and awake conditions in the canine chronic atrioventricular block model. AB - BACKGROUND: In the chronic atrioventricular block (CAVB) dog model, beat-to-beat variation of repolarization in the left ventricle (LV) quantified as short-term variability of the left monophasic action potential duration (STVLVMAPD) increases abruptly upon challenge with a proarrhythmic drug. This increase occurs before the first ectopic beat (EB), specifically in subjects who demonstrate subsequent repetitive torsades de pointes arrhythmias (TdP). OBJECTIVE: The purpose of this study was to demonstrate that STV is feasible to monitor arrhythmic risk through use of the intracardiac electrogram (EGM) derived from the right ventricular (RV) lead from pacemakers or implantable cardioverter defibrillators. METHODS: In 30 anaesthetized, inducible (>=3 TdP) CAVB dogs, STV between LV and RV monophasic action potential duration (STVLVMAPD and STVRVMAPD) was compared. In prospectively enrolled CAVB dogs, STV of the activation-recovery interval (ARI) derived from the RV EGM (STVRVARI) was measured before and after a challenge with dofetilide under anesthesia (2a; n = 10) and cisapride under awake conditions (2b; n = 8). RESULTS: Both STVLVMAPD and STVRVMAPD increased before the first EB (1.29 +/- 0.58 ms to 3.05 +/- 1.70 ms and 1.11 +/- 0.53 ms to 2.18 +/- 1.43 ms, respectively; P = 0.001). STVRVARI increased from 2.82 +/- 0.33 ms to 3.77 +/- 0.69 ms (P = .001). Inducible subjects (4/8) showed an increase in STVRVARI from 2.65 +/- 0.55 ms to 3.45 +/- 0.33 ms (in the first hour; P = .02) and 4.20 +/- 1.33 ms (before the first EB; P = .04). CONCLUSION: Behavior of STV from the RV and LV is comparable. STVRVARI increases significantly before the occurrence of an arrhythmia in awake and anaesthetized conditions. This finding can be integrated into devices to monitor arrhythmic risk. PMID- 29146276 TI - Perioperative management of oral anticoagulation in patients undergoing implantation of subcutaneous implantable cardioverter-defibrillator. AB - BACKGROUND: The perioperative anticoagulation management during subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation is still evolving. OBJECTIVE: The purpose of this study was to assess whether it is safe to perform S-ICD implantation with uninterrupted warfarin. METHODS: This is a single-center retrospective review of patients undergoing S-ICD implantation between October 1, 2012 and June 30, 2017. One hundred thirty-seven patients underwent successful S ICD implantation during the study period. The most common indication for implantation was primary prevention of sudden cardiac death. In 24 (17.5%) patients, warfarin was continued without any interruption (warfarin group). In 113 (82.5%) patients, no warfarin was used in the perioperative period (nonwarfarin group). The incidence of clinically significant lateral pocket hematoma was compared in the 2 groups. RESULTS: The mean international normalized ratio was 1.83 +/- 0.47 in the warfarin group and 1.09 +/- 0.18 in the nonwarfarin group. A total of 8 patients developed a hematoma at the lateral pocket. No patient developed a hematoma at the parasternal pockets. Six patients (25%) in the warfarin group and 2 (1.5%) in the nonwarfarin group developed a significant lateral pocket hematoma (P = .001). The mean length of stay was longer in the warfarin group (1.23 +/- 0.46 days) than in the nonwarfarin group (1.02 +/- 0.18 days) (P = .0008). An international normalized ratio of >1.8 predicted the risk of hematoma. The concomitant use of dual antiplatelet therapy did not increase the risk of hematoma. None of the patients with a hematoma developed infection or required hematoma evacuation. CONCLUSION: Uninterrupted warfarin in the perioperative period during S-ICD implantation is associated with an increased risk of significant lateral pocket hematoma that results in prolonged hospital stay. PMID- 29146278 TI - What Factors Predict Fluid Responsiveness in Hemodynamically Unstable Patients? PMID- 29146279 TI - Which Compression-to-Ventilation Ratio Yields Better Cardiac Arrest Outcomes? PMID- 29146277 TI - Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation. AB - Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12 1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration. PMID- 29146280 TI - Evolutionary isolation and phylogenetic diversity loss under random extinction events. AB - The extinction of species at the present leads to the loss of 'phylogenetic diversity' (PD) from the evolutionary tree in which these species lie. Prior to extinction, the total PD present can be divided up among the species in various ways using measures of evolutionary isolation (such as 'fair proportion' and 'equal splits'). However, the loss of PD when certain combinations of species become extinct can be either larger or smaller than the cumulative loss of the isolation values associated with the extinct species. In this paper, we show that for trees generated under neutral evolutionary models, the loss of PD under a null model of random extinction at the present can be predicted from the loss of the cumulative isolation values, by applying a non-linear transformation that is independent of the tree. Moreover, the error in the prediction provably converges to zero as the size of the tree grows, with simulations showing good agreement even for moderate sized trees (n=64). PMID- 29146282 TI - [Measurement and estimation of glomerular filtration rate]. AB - Glomerular filtration rate is the best quantitative marker of renal function. It allows diagnosis and classification of severe chronic kidney disease into five stages. Theoretically, the measurement of glomerular filtration rate is based on the calculation of urinary clearance of exogenous substances such as chromium 51 labeled inulin or ethylenediaminetetraacetic acid ([51Cr]-EDTA). In practice, glomerular filtration rate is most often estimated from equations derived from plasma creatinine. This article reviews the range of methods used to measure or approximate glomerular filtration rate and attempts to describe recent developments in this area, including those related to plasma creatinine assay methods, creatinine and cystatin C concentration-derived estimations. Measurement of glomerular filtration rate by the clearance of exogenous tracers is also discussed. PMID- 29146281 TI - Nucleus accumbens core lesions induce sub-optimal choice and reduce sensitivity to magnitude and delay in impulsive choice tasks. AB - The nucleus accumbens core (NAc) has long been recognized as an important contributor to the computation of reward value that is critical for impulsive choice behavior. Impulsive choice refers to choosing a smaller-sooner (SS) over a larger-later (LL) reward when the LL is more optimal in terms of the rate of reward delivery. Two experiments examined the role of the NAc in impulsive choice and its component processes of delay and magnitude processing. Experiment 1 delivered an impulsive choice task with manipulations of LL reward magnitude, followed by a reward magnitude discrimination task. Experiment 2 tested impulsive choice under manipulations of LL delay, followed by temporal bisection and progressive interval tasks. NAc lesions, in comparison to sham control lesions, produced suboptimal preferences that resulted in lower reward earning rates, and led to reduced sensitivity to magnitude and delay within the impulsive choice task. The secondary tasks revealed intact reward magnitude and delay discrimination abilities, but the lesion rats persisted in responding more as the progressive interval increased during the session. The results suggest that the NAc is most critical for demonstrating good sensitivity to magnitude and delay, and adjusting behavior accordingly. Ultimately, the NAc lesions induced suboptimal choice behavior rather than simply promoting impulsive choice, suggesting that an intact NAc is necessary for optimal decision making. PMID- 29146283 TI - A computational framework for estimating statistical power and planning hypothesis-driven experiments involving one-dimensional biomechanical continua. AB - Statistical power assessment is an important component of hypothesis-driven research but until relatively recently (mid-1990s) no methods were available for assessing power in experiments involving continuum data and in particular those involving one-dimensional (1D) time series. The purpose of this study was to describe how continuum-level power analyses can be used to plan hypothesis-driven biomechanics experiments involving 1D data. In particular, we demonstrate how theory- and pilot-driven 1D effect modeling can be used for sample-size calculations for both single- and multi-subject experiments. For theory-driven power analysis we use the minimum jerk hypothesis and single-subject experiments involving straight-line, planar reaching. For pilot-driven power analysis we use a previously published knee kinematics dataset. Results show that powers on the order of 0.8 can be achieved with relatively small sample sizes, five and ten for within-subject minimum jerk analysis and between-subject knee kinematics, respectively. However, the appropriate sample size depends on a priori justifications of biomechanical meaning and effect size. The main advantage of the proposed technique is that it encourages a priori justification regarding the clinical and/or scientific meaning of particular 1D effects, thereby robustly structuring subsequent experimental inquiry. In short, it shifts focus from a search for significance to a search for non-rejectable hypotheses. PMID- 29146284 TI - Supervised learning techniques and their ability to classify a change of direction task strategy using kinematic and kinetic features. AB - This study examines the ability of commonly used supervised learning techniques to classify the execution of a maximum effort change of direction task into predefined movement pattern as well as the influence of fuzzy executions and the impact of selected features (e.g. peak knee flexion) towards classification accuracy. The experiment utilized kinematic and kinetic data from 323 male subjects with chronic athletic groin pain. All subjects undertook a biomechanical assessment and had been divided previously into 3 different movement strategies in an earlier paper. Examined supervised learning techniques were: a decision tree, an ensemble of decision trees, a discriminant analysis model, a naive Bayes classifier, a k-nearest-neighbour model, a multi-class model for support vector machines, a stepwise forward regression model, a neural network and a correlation approach. Performance (measured by comparing the predefined and classified movement pattern) was highest for the correlation approach (82% - CI 81-83%) and support vector machine (80% - CI 79-80%). The percentage of fuzzy observations within the data was between 16 and 25%. The most informative features for classification were: hip flexion and ankle rotation as well as ankle flexion moment, thorax [flexion and frontal sway], abduction angle in [hip and pelvis] and hip rotation. Findings of this study support the assumption that multiple patterns are used to execute a movement task and demonstrate that classification models can predict movement patterns with a high accuracy (~84%). PMID- 29146285 TI - Rapid Polymyxin NP test for the detection of polymyxin resistance mediated by the mcr-1/mcr-2 genes. AB - The Rapid Polymyxin NP test has been recently developed to rapidly detect polymyxin resistance in Enterobacteriaceae. Here we evaluated this test for detecting MCR-1/MCR-2-producing Enterobacteriaceae using a collection of 70 non redundant strains either recovered from the environment, animals, or humans. Sensitivity and specificity were found to be 100%. PMID- 29146286 TI - [Genital herpes and pregnancy: Epidemiology, clinical manifestations, prevention and screening. Guidelines for clinical practice from the French College of Gynecologists and Obstetrician (CNGOF)]. AB - OBJECTIVES: To analyze the consequences of genital herpes infections in pregnant women. METHODS: The PubMed database and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. RESULTS: The symptomatology of herpes genital rash is often atypical (NP2) and not different during pregnancy (Professional consensus). It is most often due to HSV2 (NP2). Seventy percent of pregnant patients have a history of infection with Herpes simplex virus, without reference to genital or labial localization, and this is in most cases type 1 (NP2). The prevalence of clinical herpes lesions at birth in the event of recurrence is about 16% compared with 36% in the case of initial infection (NP4). In HSV+ patients, asymptomatic herpetic excretion is 4 to 10%. The rate of excretion increases in HIV+ patients (20 to 30%) (NP2). The risk of HSV seroconversion during pregnancy is 1 to 5% (NP2), but can reach 20% in case of sero-discordant couple (NP2). Questioning is not always sufficient to determine the history of herpes infection of a patient and her partner (NP2) and the clinical examination is not always reliable (NP2). Herpetic hepatitis and encephalitis are rare and potentially severe (NP4). These diagnoses should be discussed during pregnancy and antiviral therapy should be started as soon as possible (Professional consensus). There is no established link between herpes infection and miscarriages (NP3). There appears to be an association between untreated herpes infection and premature delivery (NP3) but not in the case of treated infections (NP4). Herpetic fetopathies are exceptional (NP4). There is no argument for recommending specific prenatal diagnosis for herpes infection during pregnancy (Professional consensus). Condom use reduces the risk of initial infection in women who are not pregnant (NP3). There is no evidence to justify routine screening during pregnancy (Professional consensus). CONCLUSION: There is a strong discrepancy between the prevalence of herpetic excretion at the time of delivery and the scarcity of neonatal infections. There is a lack of data on the impact of herpes infections during pregnancy in France. Fetal and maternal consequences are potentially serious but rare. PMID- 29146287 TI - [Herpes and pregnancy: Guidelines for clinical practice - method and organization]. PMID- 29146288 TI - Unusual Iliac Crest Stress Fracture in a Marathoner: A Case Presentation. AB - : This case presentation describes a 50-year-old healthy woman who developed left sided hip pain while training for the Boston Marathon. Magnetic resonance imaging demonstrated a stress fracture of the left iliac body. This injury was unique in that it did not occur in the setting of low bone mineral density and it did not fall into the current published radiographic categorization based on location of injury. This case illustrates an uncommon and atypical bone stress injury in an endurance athlete. It should be considered in the differential diagnosis of runners presenting with hip or lumbopelvic pain. LEVEL OF EVIDENCE: V. PMID- 29146289 TI - Off-label treatments were not consistently better or worse than approved drug treatments in randomized trials. AB - OBJECTIVES: Off-label drug use is highly prevalent but controversial and often discouraged assuming generally inferior medical effects associated with off-label use. STUDY DESIGN AND SETTING: We searched PubMed, MEDLINE, PubMed Health, and the Cochrane Library up to May 2015 for systematic reviews including meta analyses of randomized clinical trials (RCTs) comparing off-label and approved drugs head-to-head in any population and on any medical outcome. We combined the comparative effects in meta-analyses providing summary odds ratios (sOR) for each treatment comparison and outcome, and then calculated an overall summary of the sOR across all comparisons (ssOR). RESULTS: We included 25 treatment comparisons with 153 RCTs and 24,592 patients. In six of 25 comparisons (24%), off-label drugs were significantly superior (five of 25) or inferior (one of 25) to approved treatments. There was substantial statistical heterogeneity across comparisons (I2 = 43%). Overall, off-label drugs were more favorable than approved treatments (ssOR 0.72; 95% CI = 0.54-0.95). Analyses of patient-relevant outcomes were similar (statistical significant differences in 24% (six of 25); ssOR 0.74; 95% CI = 0.56-0.98; I2 = 60%). Analyses of primary outcomes of the systematic reviews (n = 22 comparisons) indicated less heterogeneity and no statistically significant difference overall (ssOR 0.85; 95% CI = 0.67-1.06; I2 = 0%). CONCLUSION: Approval status does not reliably indicate which drugs are more favorable in situations with clinical trial evidence comparing off-label with approved use. Drug effectiveness assessments without considering off-label use may provide incomplete information. To ensure that patients receive the best available care, funding, policy, reimbursement, and treatment decisions should be evidence based considering the entire spectrum of available therapeutic choices. PMID- 29146290 TI - Sustained opioid antagonism modulates striatal sensitivity to baby schema in opioid use disorder. AB - BACKGROUND: Chronic opioid misuse is associated with reduced sensitivity to natural rewards and social motivation deficits that include impaired caregiving. The neurobiological mechanisms underlying these deficits and their response to treatment are not well understood. Baby schema (Kindchenschema) is a set of juvenile physical features, which is perceived as "cute" and triggers motivation for caregiving. Recent studies suggest that the "baby schema effect" is mediated by the brain "reward" network. We studied the impact of opioid antagonist treatment on the baby schema response in patients with opioid use disorder. METHODS: Forty-seven (24 F) recently detoxified patients with opioid use disorder underwent functional magnetic resonance imaging (fMRI) while viewing infant portraits that were parametrically manipulated for baby schema content and rating them for cuteness, at baseline and during treatment with the injectable extended release opioid antagonist naltrexone (XRNTX). The study was not placebo controlled. RESULTS: The behavioral effect of baby schema, indexed by "cuteness" ratings, was present and unaffected by XRNTX. The brain response to baby schema was absent at baseline, but present in the bilateral ventral striatum after two weeks of XRNTX treatment. The decline in self-reported craving for opioids was positively correlated with the brain fMRI response to baby schema in the bilateral ventral striatum. CONCLUSIONS: Opioid antagonist treatment modulated the brain reward system response to a marker of caregiving motivation in patients with opioid use disorder. Neural response to baby schema may offer a novel probe of social motivation and affiliative behaviors in this population. PMID- 29146291 TI - Development of MS Binding Assays targeting the binding site of MB327 at the nicotinic acetylcholine receptor. AB - The bispyridinium compound MB327 has been shown previously to have a positive pharmacological effect against poisoning with organophosphorous compounds (OPCs). The mechanism by which it exerts its therapeutic effect seems to be directly mediated by the nicotinic acetylcholine receptor (nAChR). In the present study, the development of mass spectrometry based binding assays (MS Binding Assays) for characterization of the binding site of MB327 at the nAChR from Torpedo californica is described. MS Binding Assays follow the principle of radioligand binding assays, but do not, in contrast to the latter, require a radiolabeled reporter ligand, as the readout is in this case based on mass spectrometric detection. For [2H6]MB327, a deuterated MB327 analogue employed as reporter ligand in the MS Binding Assays, an LC-ESI-MS/MS method was established allowing for its fast and reliable quantification in samples resulting from binding experiments. Using centrifugation for separation of non-bound [2H6]MB327 from target-bound [2H6]MB327 in saturation and autocompetition experiments (employing native MB327 as competitor) enabled reliable determination of specific binding. In this way, the affinities for [2H6]MB327 (Kd=15.5+/-0.9MUmolL-1) and for MB327 (Ki=18.3+/-2.6MUmolL-1) towards the nAChR could be determined for the first time. The almost exactly matching affinities for MB327 and [2H6]MB327 obtained in the MS Binding Assays are in agreement with potencies previously found in functional studies. In summary, our results demonstrate that the established MS Binding Assays represent a promising tool for affinity determination of test compounds towards the binding site of MB327 at the nAChR. PMID- 29146293 TI - Andrographolide - A promising therapeutic agent, negatively regulates glial cell derived neurodegeneration of prefrontal cortex, hippocampus and working memory impairment. AB - Over activation of glial cell derived innate immune factors induces neuro inflammation that results in neurodegenerative disease, like working memory impairment. In this study, we have investigated the role of andrographolide, a major constituent of Andrographis paniculata plant, in reduction of reactive glial cell derived working memory impairment. Real time PCR, Western bloting, flow cytometric and immunofluorescence studies demonstrated that andrographolide inhibited lipopolysaccharide (LPS)-induced overexpression of HMGB1, TLR4, NFkappaB, COX-2, iNOS, and release of inflammatory mediators in primary mix glial culture, adult mice prefrontal cortex and hippocampus region. Active microglial and reactive astrocytic makers were also downregulated after andrographolide treatment. Andrographolide suppressed overexpression of microglial MIP-1alpha, P2X7 receptor and its downstream signaling mediators including-inflammasome NLRP3, caspase1 and mature IL-1beta. Furthermore, in vivo maze studies suggested that andrographolide treatment reversed LPS-induced behavioural and working memory disturbances including regulation of expression of protein markers like PKC, p-CREB, amyloid beta, APP, p-tau, synapsin and PSD-95. Andrographolide, by lowering expression of pro apoptotic genes and enhancing the expression of anti apoptotic gene showed its anti-apoptotic nature that in turn reduces neurodegeneration. Morphology studies using Nissl and FJB staining also showed the neuroprotective effect of andrographolide in the prefrontal cortex region. The above studies indicated that andrographolide prevented neuroinflammation associated neurodegeneration and improved synaptic plasticity markers in cortical as well as hippocampal region which suggests that andrographolide could be a novel pharmacological countermeasure for the treatment of neuroinflammation and neurological disorders related to memory impairment. PMID- 29146294 TI - Distinct Effects of IL-6 Classic and Trans-Signaling in Bone Fracture Healing. AB - Bone healing is a complex process with closely linked phases of inflammation, regeneration, and remodeling. IL-6 may crucially regulate this process; however, the underlying mechanisms are unclear. IL-6 signals are transmitted via the transmembrane glycoprotein 130 by two distinct mechanisms: classic signaling using the membrane-anchored IL-6 receptor and trans-signaling using its soluble form. Herein, we investigated the hypothesis that IL-6 classic and trans signaling have different functions during bone healing. To investigate fracture healing, 12-week-old C57BL/6J mice underwent a femur osteotomy. To study the function of IL-6 during the inflammatory phase, either an anti-IL-6 antibody, which inhibits IL-6 classic and trans-signaling, or soluble glycoprotein 130 fusion protein, which selectively blocks trans-signaling, was injected after 30 minutes and 48 hours. To analyze IL-6 effects in the repair phase, compounds were injected from day 7 onwards. Global IL-6 inhibition in the early phase after fracture reduced systemic inflammation, the recruitment of immune cells, and bone regeneration, resulting in delayed fracture healing. Global IL-6 inhibition during the repair phase disturbed bone formation and remodeling. In contrast, inhibition of IL-6 trans-signaling exerted minor effects on the immune response and did not influence bone repair, suggesting that the classic pathway accounts for most of the effects observed after global IL-6 inhibition. Our results reveal that IL-6 classic signaling, but not IL-6 trans-signaling, is essential for bone repair. PMID- 29146292 TI - Identification of interfaces involved in weak interactions with application to F actin-aldolase rafts. AB - Macromolecular interactions occur with widely varying affinities. Strong interactions form well defined interfaces but weak interactions are more dynamic and variable. Weak interactions can collectively lead to large structures such as microvilli via cooperativity and are often the precursors of much stronger interactions, e.g. the initial actin-myosin interaction during muscle contraction. Electron tomography combined with subvolume alignment and classification is an ideal method for the study of weak interactions because a 3 D image is obtained for the individual interactions, which subsequently are characterized collectively. Here we describe a method to characterize heterogeneous F-actin-aldolase interactions in 2-D rafts using electron tomography. By forming separate averages of the two constituents and fitting an atomic structure to each average, together with the alignment information which relates the raw motif to the average, an atomic model of each crosslink is determined and a frequency map of contact residues is computed. The approach should be applicable to any large structure composed of constituents that interact weakly and heterogeneously. PMID- 29146295 TI - New markers for early detection of acute kidney injury after transcatheter aortic valve implantation. AB - BACKGROUND: Acute kidney injury (AKI) is a frequent complication after a transcatheter aortic valve implantation (TAVI). Biomarkers such as urinary G1 cell cycle arrest proteins (TIMP-2 and IGFBP7) and sonographic evaluation (Doppler Renal Resistive Index [RRI]) have been advocated to predict AKI at an early stage after a TAVI-procedure. The primary aim was to determine the predictive value of these markers to detect AKI after a TAVI-procedure at an early phase. PATIENTS AND METHODS: In a prospective observational study, 62 consecutive patients were scheduled for a TAVI. AKI was assessed based on the KDIGO criteria. Biomarkers and RRI were measured concomitantly before TAVI, at the first micturition post-implantation and the first micturition on the morning after the procedure. RESULTS: Twenty-two patients (35%) developed AKI. On the first day after the TAVI-procedure, urinary TIMP-2 and IGFBP7 concentrations increased significantly in patients who developed AKI (0.1, [interquartile] [0.1 0.35] to 0.40 [0.10-1.00] vs. 0.2 [0.1-0.5] to 0.10 [0.10-0.20], P=0.012) with an area under the receiver-operating characteristic curve of 0.71 [0.55-0.83]. Sensitivity was 0.57 and specificity was 0.83 for a cut-off value of 0.35. No significant increases in RRI were found in patients who developed AKI. CONCLUSIONS: Based on the current guidelines for the diagnosis of AKI, the urinary proteins TIMP-2 and IGFBP7 do not detect AKI at an early stage accurately in patients undergoing a TAVI-procedure. PMID- 29146296 TI - Anomalous origin of coronary arteries from the "wrong" sinus in athletes: Diagnosis and management strategies. AB - AIMS: Although anomalous origin of left (AOLCA) and right coronary artery (AORCA) from the wrong sinus may cause sudden death (SD) in athletes, early diagnosis and management of these anomalies are still challenging. We analysed clinical/instrumental profiles of athletes identified with AOLCA/AORCA focusing our attention on diagnosis, management and follow-up. METHODS AND RESULTS: We report 23 athletes (17 males, mean age 27+/-17yrs.), 6 with AOLCA and 17 with AORCA. Diagnosis was made by trans-thoracic echocardiography (TTE) in 21/23(91%). Symptoms were present only in 10(41%). Only 3 had an abnormal rest-ECG and 9(39%) an abnormal stress test ECG (3 ST-depression, 4 ventricular arrhythmias, 1 supraventricular arrhythmias, 1 rate-dependent left-bundle-branch-block). Anatomy of the anomalous coronary artery showed no significant correlation with clinical presentation, except for a tendency to higher occurrence of proximal hypoplasia in symptomatic athletes (83% vs 40%, p=0.09). All athletes were disqualified from competitive-sports and advised to avoid strenuous effort. Surgery was recommended to all athletes with AOLCA and 6 with AORCA, but only 6 underwent surgery. No major cardiac events or ischemic symptoms/signs occurred during a mean follow-up of 65+/-70months. CONCLUSIONS: Early diagnosis of AOLCA/AORCA in athletes is feasible by TTE. Typical symptoms/signs of myocardial ischemia are present only in one third of cases thus underlying the need of a high index of clinical suspicion to achieve the diagnosis. After exercise restriction, none had major cardiac events or ischemia symptoms/signs recurrence. There was no correlation between anatomical characteristics and clinical presentation with the possible exception of coronary hypoplasia. PMID- 29146297 TI - Pregnancy Intention and Contraceptive Use among Women by Class of Obesity: Results from the 2006-2010 and 2011-2013 National Survey of Family Growth. AB - OBJECTIVE: Conflicting research findings on the association of obesity and pregnancy intention may be due to their collective definition of obesity at a body mass index of 30 kg/m2 or greater. However, obese women with a BMI of 40 kg/m2 or greater may be both behaviorally and clinically different from obese women with a lower BMI. This study reexamines this relationship, stratifying by class of obesity; the study also explores variations in contraceptive use by class of obesity given their potential contribution to the incidence of unintended or unwanted pregnancy. METHODS: This study combined data from the 2006 through 2010 and 2011 through 2013 US National Survey of Family Growth. Pregnancy intention (intended, mistimed, unwanted) and current contraceptive use (no method, barrier, pill/patch/ring/injection, long-acting reversible contraceptive, sterilization) were compared across body mass index categories: normal (18.5-24.9 kg/m kg/m2), overweight (25.0-29.9), obese class 1 (30.0-34.9 kg/m2), class 2 (35.0-39.9 kg/m2), and class 3 (>=40 kg/m2, severe obesity). Weighted multinomial logistic regressions were refined to determine independent associations of body mass index class and pregnancy intention, as well as contraceptive method, controlling for demographic, socioeconomic, and reproductive factors. RESULTS: Body mass index data were available for 9,848 nonpregnant, sexually active women who reported not wanting to become pregnant. Women with class 3 obesity had significantly greater odds of mistimed (adjusted odd ratio [aOR], 1.67; 95% confidence interval [CI], 1.02-2.75) or unwanted (aOR, 1.96; 95% CI, 1.15-3.32) pregnancy compared with normal weight women. Women with class 2 or 3 obesity were more likely to not be using contraception (aOR, 1.53-1.62; 95% CI, 1.04-2.29). Although women with class 2 obesity were more likely to be using long-acting reversible contraceptive methods and sterilization over short-acting hormonal methods (aOR, 1.67; 95% CI, 1.08-2.57; aOR, 2.05; 95% CI,1.44-2.91), this association was not observed among women with class 3 obesity. CONCLUSIONS: Women with class 3 obesity are at greater risk of unintended pregnancy and are less likely to be using contraception than normal weight women. Whether these findings are related to patient and/or provider barriers that are not as visible among women with class 1 and class 2 obesity warrants further investigation. PMID- 29146298 TI - Dynamic and direct pathogen load surveillance to monitor disease progression and therapeutic efficacy in central nervous system infection using a novel semi quantitive sequencing platform. PMID- 29146300 TI - Eosinophils in COPD: are we nearly there yet? PMID- 29146299 TI - Functional connectivity during affective mentalizing in criminal offenders with psychotic disorders: Associations with clinical symptoms. AB - Psychotic disorders are associated with neurobehavioral impairments in mental state attribution (mentalizing). These impairments are most severe in psychotic patients with elevated symptom levels, particularly negative and cognitive symptoms. There have been few studies of functional connectivity related to mentalizing in psychotic disorders and associations with symptoms. We conducted a functional MRI study of affective mentalizing in individuals with psychotic disorders and varying symptom levels (positive, negative, cognitive). Participants were drawn from an adjudicated inpatient forensic psychiatric population (criminal offenders). Functional MRI scans were acquired using a 32 channel ultra-fast multiband imaging sequence. Mentalizing task performance and functional connectivity were assessed in psychotic criminal offenders (n = 46) and nonpsychotic offenders (n = 41). Temporal coherent brain networks were estimated with group independent component analysis (ICA). Relative to nonpsychotic offenders, psychotic offenders showed impaired task performance and reduced activation in a component comprising the dorsomedial prefrontal cortex, superior temporal gyrus, and ventrolateral prefrontal cortex. Positive and cognitive symptoms were inversely correlated with component activity and task performance. The results are discussed with reference to potential mechanisms underlying impaired social cognition in psychotic disorders and across symptom types. PMID- 29146302 TI - Mechanisms involved in bone resorption regulated by vitamin D. AB - Active forms of vitamin D enhance osteoclastogenesis in vitro and in vivo through the vitamin D receptor (VDR) in osteoblast-lineage cells consisting of osteoblasts and osteocytes. This pro-resorptive activity was evident basically with higher concentrations of active vitamin D than those expected in physiological conditions. Nevertheless, vitamin D compounds have been used in Japan for treating osteoporosis to increase bone mineral density (BMD). Of note, the increase in BMD by long-term treatment with pharmacological (=near physiological) doses of vitamin D compounds was caused by the suppression of bone resorption. Therefore, whether vitamin D expresses pro-resorptive or anti resorptive properties seems to be dependent on the treatment protocols. We established osteoblast lineage-specific and osteoclast-specific VDR conditional knockout (cKO) mice using Osterix-Cre transgenic mice and Cathepsin K-Cre knock in mice, respectively. According to our observation using these cKO mouse lines, neither VDR in osteoblast-lineage cells nor that in osteoclasts played important roles for osteoclastogenesis and bone resorption at homeostasis. However, using our cKO lines, we observed that VDR in osteoblast-lineage cells, but not osteoclasts, was involved in the anti-resorptive properties of pharmacological doses of vitamin D compounds in vivo. Two different osteoblast-lineage VDR cKO mouse lines were reported. One is a VDR cKO mouse line using alpha 1, type I collagen (Col1a1)-Cre transgenic mice (here we call Col1a1-VDR-cKO mice) and the other is that using dentin matrix protein 1 (Dmp1)-Cre transgenic mice (Dmp1-VDR cKO mice). Col1a1-VDR-cKO mice exhibited slightly increased bone mass due to lowered bone resorption. In contrast, Dmp1-VDR-cKO mice exhibited no difference in BMD in agreement with our results regarding Ob-VDR-cKO mice. Here we discuss contradictory results and multiple modes of actions of vitamin D in bone resorption in detail. (279 words). PMID- 29146303 TI - Comparison of intravesical (Cohen) and extravesical (Lich-Gregoir) ureteroneocystostomy in the treatment of unilateral primary vesicoureteric reflux in children. AB - INTRODUCTION: Various intravesical and extravesical techniques have been described for the surgical correction of vesicoureteral reflux (VUR). Among those techniques Cohen (intra-vesical) and Lich-Gregoir (extra-vesical) are the most commonly used ones. However, there are limited studies that compare those two surgical techniques in the literature. OBJECTIVE: In this study, we aim to compare the outcomes of the open intravesical and extravesical procedures for unilateral primary VUR in children. METHODS: We analyzed the records of 118 consecutive children with primary VUR who underwent open ureteral reimplantation surgery by single surgeon from January 2011 to October 2015 at our institution. Among them, intravesical reimplantation was group A, and extravesical reimplantation procedure was group B. We retrospectively analyzed the clinical data of both groups, including age, sex, preoperative reflux grade, presence of lower urinary tract symptoms (LUTS), operative time, postoperative complications and hospitalization period. Success of surgery was defined as the resolution of the VUR as determined by voiding cystourethrography 6 -12 months after surgery. All the parameters were statistically compared. RESULTS: A total of 58 patients were found eligible for the study. In 23 cases intravesical (group A) and in 35 cases extravesical (group B) procedure were performed. The operative time in group A was significantly higher than group B (110.3+/-16.9 and 87+/-29.8 min, respectively, p = 0.002). The mean hospital stay was also longer in group A (2.8+/-0.8 and 1.2+/-0.6 days, respectively, p = 0.007). The ureteral catheterization periods were 14.1+/-6.1 days for group A and there was no ureteral catheter placement in group B. The success rate of the two groups were comparable (100% vs 94.9%, p = 0.513). No intraoperative complications were detected in either group. The number of febrile urinary tract infections were similar between the groups after a mean follow up of 18.2 months (p = 0.746). DISCUSSION: Our results confirmed that both Cohen and Lich-Gregoir procedures had equivalent success and complication rates. Lich-Gregoir technique was found superior to Cohen technique in terms of hospital stay and operative time. Moreover, it avoids the necessity of urethral and ureteral stenting which probably might increase the comfort of the patients postoperatively. The main limitations of our study are unrecorded pain scores and amount of analgesics taken the after surgery and retrospective analysis of the data. CONCLUSION: Both the open intravesical and extravesical ureteroneocystostomy procedures are equally effective in the treatment of primary unilateral VUR. Any of the techniques can be opted by the surgeons depending on their surgical experience. PMID- 29146304 TI - Extensive evaluation of fastidious anaerobic bacteria recovery from the Copan eSwab(r) transport system. AB - Anaerobic infections are difficult to diagnose and treat, because of the often slow in vitro growth, the polymicrobial nature and the increasing antimicrobial resistance. Furthermore because of their fastidiousness, anaerobic bacteria often stay unrecognized in clinical practice. Clinical specimens potentially harboring these species require special handling to permit satisfactory recovery of these potential important pathogens. In a clinical setting, temporary storage and transportation to the laboratory are unavoidable before these specimens can be cultured. In the current study we expand the knowledge about the recovery of a wide range of clinically relevant anaerobic bacteria from an eSwab(r) container after different storage durations and temperatures. Our findings support the use of the eSwab(r) container as a relative short-term storage unit for anaerobic species. When stored at 2-4 degrees C immediately after inoculation, all anaerobic species (except for Clostridium clostridioforme) can be recovered from the liquid Amies medium until 1day post-specimen collection. Because most samples in the clinical setting are processed in this time span, the eSwab(r) container is sufficiently capable of retaining viability in daily routine. However; because of inevitable centralization of clinical laboratories, adequate storage of these specimens for an extended period of time will be essential in the future. Therefore in certain cases, when viability is desired for longer periods (>1day), storage of the containers at 2-4 degrees C is certainly advisable. PMID- 29146301 TI - Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort. AB - BACKGROUND: Increased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils. METHODS: We did a multicentre observational study analysing comprehensive baseline data from SPIROMICS in patients with COPD aged 40-80 years who had a smoking history of at least 20 pack-years, recruited from six clinical sites and additional subsites in the USA between Nov 12, 2010, and April 21, 2015. Inclusion criteria for this analysis were SPIROMICS baseline visit data with complete blood cell counts and, in a subset, acceptable sputum counts. We stratified patients on the basis of blood and sputum eosinophil concentrations and compared their demographic characteristics, as well as results from questionnaires, clinical assessments, and quantitative CT (QCT). We also analysed whether blood eosinophil concentrations reliably predicted sputum eosinophil concentrations. This study is registered with ClinicalTrials.gov (NCT01969344). FINDINGS: Of the 2737 patients recruited to SPIROMICS, 2499 patients were smokers and had available blood counts, and so were stratified by mean blood eosinophil count: 1262 patients with low (<200 cells per MUL) and 1237 with high (>=200 cells per MUL) blood eosinophil counts. 827 patients were eligible for stratification by mean sputum eosinophil percentage: 656 with low (<1.25%) and 171 with high (>=1.25%) sputum eosinophil percentages. The high sputum eosinophil group had significantly lower median FEV1 percentage predicted than the low sputum eosinophil group both before (65.7% [IQR 51.8-81.3] vs 75.7% [59.3-90.2], p<0.0001) and after (77.3% [63.1-88.5] vs 82.9% [67.8-95.9], p=0.001) bronchodilation. QCT density measures for emphysema and air trapping were significantly higher in the high sputum eosinophil group than the low sputum eosinophil group. Exacerbations requiring corticosteroids treatment were more common in the high versus low sputum eosinophil group (p=0.002). FEV1 percentage predicted was significantly different between low and high blood eosinophil groups, but differences were less than those observed between the sputum groups. The high blood eosinophil group had slightly increased airway wall thickness (0.02 mm difference, p=0.032), higher St George Respiratory Questionnaire symptom scores (p=0.037), and increased wheezing (p=0.018), but no evidence of an association with COPD exacerbations (p=0.35) or the other indices of COPD severity, such as emphysema measured by CT density, COPD assessment test scores, Body-mass index, airflow Obstruction, Dyspnea, and Exercise index, or Global Initiative for Chronic Obstructive Lung Disease stage. Blood eosinophil counts showed a weak but significant association with sputum eosinophil counts (receiver operating characteristic area under the curve of 0.64, p<0.0001), but with a high false-discovery rate of 72%. INTERPRETATION: In a large, well characterised cohort of former and current smoking patients with a broad range of COPD severity, high concentrations of sputum eosinophils were a better biomarker than high concentrations of blood eosinophils to identify a patient subgroup with more severe disease, more frequent exacerbations, and increased emphysema by QCT. Blood eosinophils alone were not a reliable biomarker for COPD severity or exacerbations, or for sputum eosinophils. Clinical trials targeting eosinophilic inflammation in COPD should consider assessing sputum eosinophils. FUNDING: National Institutes of Health, and National Heart, Lung, and Blood Institute. PMID- 29146305 TI - Validation of a liquid chromatography/tandem mass spectrometry method for the detection of aflatoxin B1 residues in broiler liver. AB - Aflatoxin B1 is a carcinogenic and mutagenic mycotoxin produced mainly by Aspergillus flavus and Aspergillus parasiticus. It is the predominant mycotoxin found in raw materials used for the manufacture of broiler feeds. The aim of the present study was to develop a new and optimized method for the detection and quantification of aflatoxin B1 (AFB1) residues in broiler liver using solid phase extraction (SPE) clean-up and liquid chromatography-electrospray ionization/tandem mass spectrometry (LC-ESI-MS/MS) detection. The method was validated for linearity, accuracy, precision, limit of detection (LOD) and limit of quantification (LOQ). The validation parameters indicated satisfactory linearity (r2>0.99), accuracy and precision (4.57% intra-day RSD; 14.65% inter day RSD) a very high recovery (99+/-13%) and high sensitivity achieved for AFB1 in animal samples (LOD=0.017 and LOQ=0.050ng/g). The method was effective for the detection and quantification of AFB1 residues in broiler liver and could also be potentially used for detecting AFB1 in other edible animal tissues after natural or experimental AFB1 exposure with high sensitivity and precision. PMID- 29146306 TI - Real-World Vision in Age-Related Macular Degeneration Patients Treated with Single Anti-VEGF Drug Type for 1 Year in the IRIS Registry. AB - PURPOSE: The purpose of this study is to compare real-world visual acuity (VA) in patients with neovascular age-related macular degeneration (nAMD) treated with a single anti-vascular endothelial growth factor (VEGF) drug monotherapy for 1 year from the American Academy of Ophthalmology (AAO) Intelligent Research in Sight (IRIS) Registry. DESIGN: Retrospective, nonrandomized, comparative study. PARTICIPANTS: IRIS Registry patients with nAMD who received bevacizumab, ranibizumab, or aflibercept only for 1 year between 2013-2016. METHODS: Participants were divided into 3 groups based on monotherapy type. Multivariate analysis of covariance models (ANCOVA) was constructed in a stepwise fashion. MAIN OUTCOME MEASURES: The logarithm of the minimum angle of resolution (logMAR) VA at 1 year and mean change in logMAR VA between baseline and 1 year were compared between drug types. RESULTS: Of 13 859 patients, 6723 received bevacizumab, 2749 received ranibizumab, and 4387 received aflibercept only for 1 year. A total of 84 828 injections were performed. The mean number of injections (standard deviation) at 1 year was higher in the ranibizumab (6.4 [+/-2.4]) and aflibercept groups (6.2 [+/-2.4]) compared to bevacizumab group (5.9 [+/-2.4]; P < 0.0001). In the age-adjusted model, both ranibizumab and aflibercept achieved better logMAR VA at 1 year compared with bevacizumab (0.50 [+/-0.49], 0.49 [+/ 0.44], 0.55 [+/-0.57]; P < 0.0001). However, this difference was not significant after multivariate adjustment (age, baseline VA, diabetes, posterior vitreous detachment, number of injections, race, insurance). There was no statistical difference in the age-adjusted or multivariate-adjusted mean logMAR VA change (standard deviation) at 1 year among treatment groups (-0.048 [0.44] bevacizumab, -0.053 [0.46] ranibizumab, -0.040 [0.39] aflibercept; P = 0.46). A higher percentage of patients achieved a >=3-line VA improvement at 1 year in the bevacizumab group (22.7%) compared with ranibizumab (20.1%; P = 0.0093) and aflibercept (17.8%; P < 0.0001). However, after multivariate adjustment, aflibercept exhibited a greater log odds of a >=3-line VA loss compared with bevacizumab only (1.25 log odds ratio; P < 0.0016). CONCLUSIONS: This study suggests that all 3 drugs improve VA similarly over 1 year of monotherapy. PMID- 29146307 TI - Long-Term Visual Outcomes and Safety Profile of 27-Gauge Pars Plana Vitrectomy for Posterior Segment Disease. AB - PURPOSE: To report longer-term outcomes of 27-gauge pars plana vitrectomy (PPV) in eyes with posterior segment disease. DESIGN: Multicenter, retrospective, interventional case series. PARTICIPANTS: A total of 390 eyes of 360 patients undergoing 27-gauge PPV for a vitreoretinal surgery indication. INTERVENTION: Three-port, transconjunctival, 27-gauge PPV. MAIN OUTCOME MEASURES: Change in visual acuity (VA) and occurrence of intraoperative and postoperative complications with a minimum follow-up of 365 days. RESULTS: Mean follow-up was 715+/-332 days (median, 514; range, 365-1440 days). Surgical indications included epiretinal membrane (ERM) (n = 121), vitreous floaters (n = 69), diabetic tractional retinal detachment (n = 49), vitreous hemorrhage (n = 40), full thickness macular hole (n = 33), recurrent proliferative vitreoretinopathy (PVR) related retinal detachment (n = 18), primary rhegmatogenous retinal detachment (RRD) (n = 17), silicone oil removal (n = 16), dislocated intraocular lens (n = 10), submacular hemorrhage (n = 7), endophthalmitis (n = 6), and retained lens material (n = 4). Mean logarithm of the minimum angle of resolution (logMAR) VA improved from 0.72+/-0.62 (20/105 Snellen equivalent) preoperatively to 0.40+/ 0.55 (20/50 Snellen equivalent) postoperatively (P < 0.001). No case required conversion to 23- or 25-gauge instrumentation. Postoperative complications included transient ocular hypertension in 44 eyes (11.3%), vitreous hemorrhage in 31 eyes (7.9%), and transient hypotony in 22 eyes (5.6%). Acute postoperative endophthalmitis occurred in 1 case (0.26%). Overall, 82 of 390 eyes (21.0%) underwent at least 1 additional intraocular surgery in the follow-up period, most commonly for cataract extraction (n = 40/82 eyes, 48.8%). Of the 18 eyes undergoing surgery for primary RRD, recurrent detachment due to PVR occurred in 2 eyes (11.1%). CONCLUSIONS: At a minimum follow-up of 1 year, 27-gauge PPV was well tolerated with low rates of postoperative complications across varied surgical indications, including primary and complex retinal detachment. PMID- 29146309 TI - StarD13 3'-untranslated region functions as a ceRNA for TP53INP1 in prohibiting migration and invasion of breast cancer cells by regulating miR-125b activity. AB - Competitive endogenous messenger RNA (ceRNA) affects transcription of other RNA molecules by competitively binding common microRNAs. Previous studies have shown that TP53INP1 functions as a suppressor in tumor metastasis. Our study elucidated StarD13 messenger RNA as a ceRNA in regulating migration and invasion of breast cancer cells. MicroRNA-125b was identified to induce metastasis of MCF-7 cells and bind with both StarD13 3'UTR and TP53INP1 3'UTR. Therefore, a ceRNA interaction between StarD13 and TP53INP1 mediated by competitively binding to miR 125b was indicated. Importantly, a microRNA-125b binding site at 4546-4560 nt on StarD13 was verified more vital for this ceRNA interaction. Indirectly regulation of SPARC in inducing metastasis of breast cancer cells by StarD13 via competitively binding with TP53INP1 was further confirmed. In conclusion, our findings demonstrate a ceRNA regulatory network which could give a better understanding of metastatic mechanisms of breast cancer. PMID- 29146310 TI - A review on moringa tree and vetiver grass - Potential biorefinery feedstocks. AB - Plants and derivatives have been explored for unlimited purposes by mankind, from crop cultivation for providing food and animal feed, to the use for cosmetics, therapeutics and energy. Moringa tree and vetiver grass features, capabilities and applications were explored through a literature review. The suitability of these plants for the bioenergy industry products is evidenced, namely for bioethanol, biogas and biodiesel, given the lignocellulosic biomass content of these plants and characteristics of moringa seed oil. In addition, moringa leaves and pods are an important source for food and animal feed industries due to their high nutrient value. Thus, the co-cultivation of moringa and vetiver could provide energy and food security, and contribute to more sustainable agricultural practices and for the development of rural areas. Policymakers, institutions and scientific community must engage to promote the cultivation of multipurpose crops to cope with energy and food industries competition for biomass. PMID- 29146308 TI - 'Molecular habituation' as a potential mechanism of gradual homeostatic loss with age. AB - The ability of reactive oxygen species (ROS) to cause molecular damage has meant that chronic oxidative stress has been mostly studied from the point of view of being a source of toxicity to the cell. However, the known duality of ROS molecules as both damaging agents and cellular redox signals implies another perspective in the study of sustained oxidative stress. This is a perspective of studying oxidative stress as a constitutive signal within the cell. In this work, we adopt a theoretical perspective as an exploratory and explanatory approach to examine how chronic oxidative stress can interfere with signal processing by redox signalling pathways in the cell. We report that constitutive signals can give rise to a 'molecular habituation' effect that can prime for a gradual loss of biological function. This is because a constitutive signal in the environment has the potential to reduce the responsiveness of a signalling pathway through the prolonged activation of negative regulators. Additionally, we demonstrate how this phenomenon is likely to occur in different signalling pathways exposed to persistent signals and furthermore at different levels of biological organisation. PMID- 29146311 TI - Microbial communities involved in biogas production exhibit high resilience to heat shocks. AB - We report here the impact of heat-shock treatments (55 and 70 degrees C) on the biogas production within the acidification stage of a two-stage reactor system for anaerobic digestion and biomethanation of grass. The microbiome proved both taxonomically and functionally very robust, since heat shocks caused minor community shifts compared to the controls, and biogas yield was not decreased. The strongest impact on the microbial profile was observed with a combination of heat shock and low pH. Since no transient reduction of microbial diversity occured after the shock, biogas keyplayers, but also potential pathogens, survived the treatment. All along the experiment, the heat-resistant bacterial profile consisted mainly of Firmicutes, Bacteroidetes and Proteobacteria. Bacteroides and Acholeplasma were reduced after heat shocks. An increase was observed for Aminobacterium. Our results prove the stability to thermal stresses of the microbial communities involved in acidification, and the resilience in biogas production irrespectively of the thermal treatment. PMID- 29146312 TI - ? PMID- 29146313 TI - Comparison between the Visual Analog Scale and the Numerical Rating Scale in the perception of esthetics and pain. AB - BACKGROUND: Pain is an unpleasant, emotional, and sensorial experience. Esthetics and pain express perceptions or sensations that are subjective and personal, but non-consensual, between professionals and patients. The Visual Analog Scale (VAS) and the Numerical Rating Scale (NRS) are simple methods to evaluate such subjective phenomena. OBJECTIVE: To verify whether a concordance exists between VAS and NS in the perception of esthetics and pain. MATERIAL AND METHODS: Regarding esthetics, an on-line questionnaire was prepared with extra- and intra oral images (adapted). The order of the scales was alternated between interwoven and sequential. Regarding perception of pain, respondents personally classified its intensity at the present moment, or over the past 30 days. RESULTS: A statistically significant concordance (P<0.001) - positive and moderate - was found between the scales, for the evaluation of both the extra- and intra-oral images, r=0.678 and 0.638, respectively. Regarding pain perception, taking formal education into account, no concordance was found between the two scales for participants who had "no formal education" (P>0.05). The concordance between the scales increased proportionally with the level of education. CONCLUSION: There was a concordance between the scales with regard to esthetical perception and the evaluation of pain. When assessing esthetics, the order in which the two scales are applied does not affect the concordance between them. However, the strength of the concordance is influenced. Esthetic perception is not influenced by the differences between the panels of evaluators. The concordance between the two scales, for the evaluation of pain, increases proportionally with the level of formal education. PMID- 29146314 TI - Interaction of wine mannoproteins and arabinogalactans with anthocyanins. AB - Wine polymeric material (WPM), which includes polysaccharides, proteins, and polyphenolic compounds, interacts with anthocyanins. To determine the contribution of polysaccharides in these interactions, the diffusion performance of anthocyanins along a dialysis membrane was determined in the presence and absence of isolated mannoproteins (MP) and arabinogalactans (AG) from WPM. Furthermore, to estimate the extent of the interaction between WPM and polyphenolic compounds, the activation energy (Ea) required for their diffusion in the presence of WPM was determined. AG, generally more abundant than MP in wine, interact in a greater extent with anthocyanins, showing their relevant contribution for WPM/anthocyanins interactions. The Ea for the diffusion of polyphenolic compounds in presence of WPM indicated the occurrence of interactions with relative weak to strong intensities (2.6-50.8kJ/mol). As not all polyphenolic compounds were able to be released from WPM, stronger interactions, possibly by covalent linkages, are involved, providing new insights on WPM/polyphenolic compounds relationships. PMID- 29146315 TI - Sensory, olfactometry and comprehensive two-dimensional gas chromatography analyses as appropriate tools to characterize the effects of vine management on wine aroma. AB - For the first time, the influence of different vine management was evaluated in relation to volatile profile and sensory perception through GC*GC/TOFMS, QDA, GC FID, GC/MS, and GC-O. GC*GC/TOFMS analyses and QDA have shown that a larger spacing between vine rows (2 rather than 1m), attachment of shoots upwards, and irrigation did not result in wine improvement. Conversely, wines elaborated with grapes from a vine with a lower bud load (20 per plant; sample M1) stood out among the other procedures, rendering the most promising wine aroma. GC*GC/TOFMS allowed identification of 220 compounds including 26 aroma active compounds also distinguished by GC-O. Among them, eight volatiles were important to differentiate M1 from other wines, and five out of those eight compounds could only be correctly identified and quantified after separation in second dimension. Higher levels of three volatiles may explain the relation of M1 wine with red and dry fruits. PMID- 29146316 TI - Comparative evaluation of three different ELISA assays and HPLC-ESI-ITMS/MS for the analysis of Nepsilon-carboxymethyl lysine in food samples. AB - Nepsilon-carboxymethyl-lysine (CML) is measured in food, but there is a controversy concerning the most convenient yet reliable method(s) for this task. This work compares three different ELISA assays and HPLC-ESI-ITMS/MS for the analysis of CML in several food items. The four methods showed the same decreasing order of CML concentration: beef, bacon>chicken > fish>dairy products>grain products>fruits/vegetables. HPLC-ESI-ITMS/MS results highly correlated with those obtained by ELISA performed with monoclonal CML-antibody (beta=0.98, p<0.0001) whereas My Bio Source(r) kit results were not correlated with those provided by Lamider(r). Small differences of CML concentrations in food items prepared by different culinary treatment were clearly distinguished by HPLC-ESI-ITMS/MS, but could not always be detected by ELISA. This work demonstrates a reasonable relationship between CM determined by ELISA and HPLC ESI-ITMS/MS and therefore supports the implementation of ELISA in food CML/AGEs screening. PMID- 29146317 TI - Characterization of binding interactions between selected phenylpropanoid glycosides and trypsin. AB - Phenylpropanoid glycosides (PPGs) are important bioactive polyphenolic compounds that are widely distributed in plants. In this paper, the inhibitory effects of four selected PPGs against trypsin were investigated. The interactions between these PPGs and trypsin were further investigated by multiple spectroscopic methods and molecular docking studies. The results showed that the binding of each of these PPGs to trypsin induced changes in the natural conformation of trypsin, which inhibited the enzyme in the following order: acteoside>syringalide A 3'-alpha-l-rhamnopyranoside>lipedoside A-I>osmanthuside B. The binding constant (Ka) values followed the same trend. The hydrogen bond force played an important role in the interaction between each PPG and trypsin. Interestingly, the binding affinity and inhibitory effect increased as the number of phenolic hydroxyl groups increased. In addition, the effect of the phenolic hydroxyl group on the A ring had a greater effect than one on the B ring. PMID- 29146318 TI - Aroma release in the oral cavity after wine intake is influenced by wine matrix composition. AB - The aim of this study has been to investigate if wine matrix composition might influence the interaction between odorants and oral mucosa in the oral cavity during a "wine intake-like" situation. Aroma released after exposing the oral cavity of three individuals to different wines (n=12) previously spiked with six target aromas was followed by an -in vivo intra-oral SPME approach. Results showed a significant effect of wine matrix composition on the intra-oral aroma release of certain odorants. Among the wine matrix parameters, phenolic compounds showed the largest impact. This effect was dependent on their chemical structure. Some phenolic acids (e.g. hippuric, caffeic) were associated to an increase in the intra-oral release of certain odorants (e.g. linalool, beta-ionone), while flavonoids showed the opposite effect, decreasing the intra-oral release of aliphatic esters (ethyl hexanoate). This work shows for the first time, the impact of wine composition on oral-mucosa interactions under physiological conditions. PMID- 29146319 TI - Developing a machine vision system for simultaneous prediction of freshness indicators based on tilapia (Oreochromis niloticus) pupil and gill color during storage at 4 degrees C. AB - The study assessed the feasibility of developing a machine vision system based on pupil and gill color changes in tilapia for simultaneous prediction of total volatile basic nitrogen (TVB-N), thiobarbituric acid (TBA) and total viable counts (TVC) during storage at 4 degrees C. The pupils and gills were chosen and color space conversion among RGB, HSI and L*a*b* color spaces was performed automatically by an image processing algorithm. Multiple regression models were established by correlating pupil and gill color parameters with TVB-N, TVC and TBA (R2=0.989-0.999). However, assessment of freshness based on gill color is destructive and time-consuming because gill cover must be removed before images are captured. Finally, visualization maps of spoilage based on pupil color were achieved using image algorithms. The results show that assessment of tilapia pupil color parameters using machine vision can be used as a low-cost, on-line method for predicting freshness during 4 degrees C storage. PMID- 29146320 TI - The functional properties of chitosan-glucose-asparagine Maillard reaction products and mitigation of acrylamide formation by chitosans. AB - This research aims to clarify the interactions that occur in a food model system consisting of glucose, asparagine and chitosans. Low molecular weight chitosan exerted a potent inhibitory effect (46.8%) on acrylamide and Maillard reaction products (MRPs) (>52.6%), respectively. Compared to a previous study conducted using the fructose system, the novel findings of this research demonstrate that the formation of acrylamide and Maillard reaction products was lower with glucose than with fructose when they were used as reducing sugars in food model systems. PMID- 29146321 TI - Energetic and electronic computation of the two-hydrogen atom donation process in catecholic and non-catecholic anthocyanidins. AB - Antioxidant activity of anthocyanidins is greatly affected by the 3-hydroxyl group and/or a catecholic moiety. The two-hydrogen atom donation process is frequently used to explain the high antioxidant activity of polyphenolic compounds leading to the formation of stable diketones e.g. 1,2-quinones. Thermodynamic parameters, HOMO and spin density were computed to identify the favoured path, either through the 3-hydroxyl group or through the catecholic moiety in a series of catecholic and non-catecholic 3-oxy- (and deoxy) anthocyanidins. DFT calculations showed that the donation process in non catecholic anthocyanidins depended on the substituents on ring B. Anthocyanidins with 3',5'-diOMe groups showed donation through 3,4'-OH or, otherwise, through 3,5-OH groups. Catecholic 3-oxyanthocyanidins, on the other hand, showed donation through the 3,4'-OH path rather than the catecholic path (4',3'-path). The 3,4' path was favoured by the formation of planar 3-radicals in the first step and the stabilization of 4'-radicals in the second step by H-bonding with the 3'-OH group. PMID- 29146322 TI - Evaluation of the non-aldehyde volatile compounds formed during deep-fat frying process. AB - To investigate the non-aldehyde volatile profile resulting from deep-fat frying, volatile compounds formed during the processes of heating soybean oil (SO), frying wheat dough (WD), and frying chicken breast meat (CBM) were comparatively studied. By using gas chromatography-mass spectrometry and internal standard method, alkanes, alkenes, alkynes, alcohols, ketones, nitrogen-containing volatiles (NCVs), and other volatiles were qualitatively and relatively quantitatively detected. NCVs were detected only in CBM-fried oil samples. Some volatiles (e.g. 2-pentylfuran and 2-pentylpyridine) were observed to increase in concentration, whereas others (e.g. 4-methyl-1,4-heptadiene and 7-methyl-3,4 octadiene) were observed to first increase and then decrease in concentration as the heating or frying time increased. Reduced quantity and concentrations of volatiles were observed in the food-fried oil samples which might be related to the intensified reactions induced by food components. The detection of some harmful volatiles in considerable concentrations indicated further attention might be paid to the safety of deep-fat frying. PMID- 29146323 TI - Development and validation of a screening and quantification method for simultaneous determination of seven fluorescent whitening agents in commercial flour using UPLC-MS/MS. AB - A sensitive UPLC-MS/MS method was established for the simultaneous determination of seven fluorescent whitening agents in flour matrix. Samples were ultrasonically extracted by trichloromethane-acetone. Then analytes were separated on a C18 column and detected by MS/MS. The developed method was validated in terms of the linearity, matrix effect, accuracy and precision. The method showed a good linearity (r>0.997) for all analytes in their respective concentration ranges. The LOQ for seven analytes were in the range of 2.5 25.0MUg/kg. The matrix effect was not significant and almost negligible. The average recoveries of seven analytes from the negative samples spiked at three different concentrations were in a range from 81.5% to 105%. The intra-day precision and inter-day precision were in the ranges of 2.9-9.0% and 6.7-11.2%. The developed method was successfully applied to analyze forty commercial flours and FWA184 was detected in three samples with the concentrations of 31-60ug/kg. PMID- 29146324 TI - Antioxidative, potentially anti-inflammatory, and antidiabetic properties, as well as oxidative stability and acceptability, of cakes supplemented with elicited basil. AB - The aim of the study was to investigate the effect of addition of basil elicited with jasmonic acid (JA) on the biological properties, oxidative stability, and sensory quality of cakes. Simulated gastrointestinal digestion was used for determination of bioavailability. The antioxidant, anti-inflammatory and antidiabetic potential of fortified cakes were significantly higher than those of the control cakes. The antioxidant activity of the tested cakes was increased after addition of basil, proportionally to the amount of the additive. Additionally, in some cases, better results were obtained using JA-elicited basil instead of the control basil. Basil addition inhibited fat peroxidation in the cakes, measured as the malondialdehyde content. Cakes supplemented with the control and elicited basil were characterized by satisfactory consumer acceptability. Based on the data obtained in the present study, it can be concluded that JA-elicited basil (especially elicited with 100uM jasmonic acid) can be recommended for food technologists. PMID- 29146325 TI - Study of human salivary proline-rich proteins interaction with food tannins. AB - In this work, saturation transfer difference-NMR, isothermal microcalorimetry and molecular dynamics simulations have been used to study the individual interactions between basic, glycosylated and acidic proline-rich proteins (bPRPS, gPRPs, aPRPs) and P-B peptide with some representative food tannins [procyanidin B2, procyanidin B2 3'-O-gallate (B2g) and procyanidin trimer (catechin-4-8 catechin-4-8-catechin)]. Results showed that P-B peptide was in general the salivary protein (SP) with higher affinity whereas aPRPs showed lower affinity to the studied procyanidins. Moreover, B2g was the procyanidin with higher affinity for all SP. Hydrophobic and hydrogen bonds were present in all interactions but the major driving force depended on the procyanidin-SP pair. Furthermore, proline clusters or residues in their vicinity were identified as the probable sites of proteins for interaction with procyanidins. For bPRP and aPRP a significant change to less extended conformations was observed, while P-B peptide did not display any structural rearrangement upon procyanidins binding. PMID- 29146327 TI - Effect of postharvest spray of apple polyphenols on the quality of fresh-cut red pitaya fruit during shelf life. AB - Fresh-cut (FC) red pitaya fruit were treated with 5ga.i.l-1 apple polyphenols (APP) and then stored at 20 degrees C for up to 4days to evaluate the effects on attributes. Results showed that FC pitaya fruit with APP treatment showed greater colour retention, delayed softening, reduced loss of soluble solids content, titratable acidity, betacyanin and total phenolics compared with untreated FC fruit. APP treatment also maintained antioxidant activity, as indicated by higher DPPH radical-scavenging activity and reducing power compared with untreated FC pitaya fruit. APP treatment strongly suppressed microbial growth, contributing to improvement of product safety. Because APP is a natural product, we propose that application of APP could be a convenient, safe and low-cost approach to maintain the quality and extend the shelf life of FC red pitaya fruit. PMID- 29146326 TI - Changes in molecular structure of chickpea starch during processing treatments: A thin layer chromatography study. AB - To detect the changes in molecular structure of chickpea starch during processing treatments, a thin layer chromatographic method for characterizing the molecular structure of chickpea starch was developed. With this method, the components in chickpea starch could be divided into amylopectin, small linear molecules and large linear molecules, and their contents could be determined. It was found that the degrees of polymerization of the large linear molecules and small linear molecules in chickpea enzyme-resistant starch were about 40 and below 15, respectively. Furthermore, the small linear molecules were more susceptible to alpha-amylase hydrolysis than the large linear molecules. The results suggested that the large linear molecules and small linear molecules in chickpea enzyme resistant starch might mainly originate from the amylose and amylopectin of native chickpea starch, respectively, based on the retrogradation properties of amylose and amylopectin and the enzymatic degradation behavior of the large linear molecules and small linear molecules. PMID- 29146328 TI - Fried potatoes: Impact of prolonged frying in monounsaturated oils. AB - Fresh potatoes were intermittently deep-fried up to recommended limits (175 degrees C, 8h/day, 28h) in extra-virgin olive oil (EVOO), peanut oil (PO) and canola oil (CO), and compared for diverse chemical components and sensorial attributes, aiming to quantify the impact of prolonged frying on potatoes nutrients, and the potential alterations resulting from the use of different monounsaturated-rich oils. Independently of oil type, its degradation promotes time-dependent losses of important potato nutrients, as vitamin C. Regarding the monounsaturated-rich oils tested, potatoes fried in CO had more equilibrated fatty acid profiles, but higher amounts of aldehydes derived from PUFA oxidation, while in EVOO were enriched with phenolic compounds. Acrylamide amounts were not affected by oil type or frying hours. Sensory degradation was gradually perceived by the panellists, except in PO. Prolonged frying should not be studied only on the basis of oil degradation because, even if within regulated limits, it induces loss of important food compounds. PMID- 29146329 TI - Effects of moisture content on mechanical properties, transparency, and thermal stability of yuba film. AB - Yuba is the skin formed at the surface during the heating of soymilk. The 3rd, 7th, and 11th films were evaluated for properties at different RH. At 39% RH, the 11th film had the lowest moisture, while the 3rd film had the highest moisture. However, at 75% RH, reverse moisture results were obtained. The tensile strengths of the 3rd and 11th films were highest at 15% moisture, whereas the tensile strength of the 7th film was highest at 25% moisture. Elongation of the 3rd (127%) and 11th (85%) films were highest at 25% moisture. The light transmittance of the films was low and opaque at 5% moisture. The films were transparent at 23% 28% moisture, but became opaque as the moisture increased. The films at 39% RH (DeltaH, 113-203J/g) had higher thermal stability than those at 87% RH (DeltaH, 315-493J/g). Moisture content markedly changed the yuba film properties. PMID- 29146330 TI - Assessment of the nitrogen fertilization effect on bioactive compounds of frozen fresh and dried samples of Stevia rebaudiana Bertoni. AB - The present study aims to assess the effect of different nitrogen (N) rates on the chemical composition and antioxidant properties of stevia frozen fresh and dried leaves, and to define the best growing conditions to maximize the levels of bioactive compounds. In general, processing affects more significantly the tocopherol and sugar contents than N fertilization. The most abundant sugars were xylose, arabinose + fructose and sucrose, presenting dried samples with higher contents than frozen fresh ones, while the latter better retained tocopherols than dry samples. Regarding phenolic compounds, greater levels were found in dried samples and in those fertilized with 25 kg N ha-1. Leaves from plants fertilized with 25 and 50 kg N ha-1 also evidenced higher antioxidant activity, which seemed to be influenced by the phenolic composition. In general, N fertilization provides an improvement in the chemical composition and bioactive potential of stevia leaves. PMID- 29146331 TI - Effects of controlled germination on selected physicochemical and functional properties of whole-wheat flour and enhanced gamma-aminobutyric acid accumulation by ultrasonication. AB - Using hard red spring (HRS), hard white (HW), and soft white (SW) wheat, this study examined how germination time affected the functionality of whole-wheat flour (WWF) and enhancement of gamma-aminobutyric acid (GABA) content through ultrasonication. The falling number values significantly decreased and the glucose content increased by 227-357% after 15h of controlled germination. The setback value of WWF paste decreased from 654 to 6cP (HW), 690 to 9cP (SW), and 698 to 7cP (HRS), respectively, showing significant decreases of starch retrogradation in an aqueous system. The gluten quality and dough mixing performance of WWF after 5-15h of controlled germination was enhanced since gluten is less weakened during the dough heating stage of Mixolab testing. After a 72h germination, the GABA content increased by 339% of the non-sprouting counterpart. Furthermore, the GABA content in the ultrasound-treated SW sample was 30.7% higher than that without ultrasound treatment. PMID- 29146332 TI - Micro-oxygenation does not eliminate hydrogen sulfide and mercaptans from wine; it simply shifts redox and complex-related equilibria to reversible oxidized species and complexed forms. AB - This work seeks to assess the effects of micro-oxygenation (MOX) on the present and potential levels of Volatile Sulfur Compounds (VSCs) of wine. With such purpose, three red wines with a tendency to develop sulfury off-odors were subjected to three different MOX conditions (4.4-20mg/L delivered at 0.05 or 0.2mg/L/day). Samples were further subjected to Accelerated Reductive aging (AR) and analyzed for free and Brine Releasable (BR) VSCs and redox potential. Although MOX induced strong decreases in the levels of all free VSCs, hardly affected the ability of the wine to release back hydrogen sulfide and other mercaptans during AR-aging. During aging BR-levels of MOX samples became in most cases similar or higher than non-oxygenated controls. BR-levels and the fractions free/BR follow characteristic sigmoid plots when represented versus redox potential suggesting that all changes are the result of reversible equilibria between free, metal-complexed and oxidized forms of VSCs. PMID- 29146333 TI - Comparative time-course of lipid and myofibrillar protein oxidation in different biphasic systems under hydroxyl radical stress. AB - This study aimed to investigate the relative reaction rate of protein and lipid oxidation in different biphasic model systems (linoleic acid; liposome; emulsion) containing myofibrillar protein (MFP at 1, 8 and 20 mg/mL) under hydroxyl radical stress. Protein oxidation markers exhibited significant changes in 2 h: reduced tryptophan fluorescence intensity, carbonyl formation, and extensive polymerization of myosin. In contrast, no detectable changes (P > .05) in lipid peroxide occurred within 2 h except for samples with 1 mg/mL MFP which showed an early TBARS formation. Of the three biphasic systems, the oxidative stability of lipids followed the order of emulsion > linoleic acid > liposome, indicating the steric role of proteins. In general, MFP was more susceptible to radicals than lipids, and a higher protein:lipid ratio was associated with a slower TBARS production and more rapid protein oxidation, suggesting a sacrificing role of MFP to protect lipids. PMID- 29146334 TI - Impact of fluorescent lighting on the browning potential of model wine solutions containing organic acids and iron. AB - Model wine solutions containing organic acids, individually or combined, and iron(III), were exposed to light from fluorescent lamps or stored in darkness for four hours. (-)-Epicatechin was then added, and the solutions incubated in darkness for 10days. Browning was monitored by UV-visible absorption spectrophotometry and UHPLC-DAD. The pre-irradiated solutions containing tartaric acid exhibited increased yellow/brown coloration compared to the dark controls mainly due to reaction of the tartaric acid photodegradation product glyoxylic acid with (-)-epicatechin to form xanthylium cation pigments. In these solutions, browning decreased as the concentrations of organic acids other than tartaric acid increased. Xanthylium cations were also detected in the pre-irradiated malic acid solution. However, in the malic acid, succinic acid, citric acid and lactic acid solutions, any coloration was mainly due to the production of dehydrodiepicatechin A, which was largely independent of prior light exposure, but strongly affected by the organic acid present. PMID- 29146335 TI - Antioxidant activity and sensory characteristics of Maillard reaction products derived from different peptide fractions of soybean meal hydrolysate. AB - Four peptide fractions PF1 (>5;kDa), PF2 (3-5;kDa), PF3 (1-3;kDa), PF4 (<1;kDa) were isolated from soybean hydrolysate using the ultrafiltration method. Then, d xylose and l-cysteine were reacted with specific peptide solution at 120; degrees C for 2;h, and the molecular weight distribution (MWD), pH, colour, browning intensity, DPPH radical-scavenging activity, free amino acids and sensory characteristics of corresponding Maillard reaction products (MRPF1, MRPF2, MRPF3 and MRPF4) were evaluated, respectively. Peptides with low molecular weight showed higher contribution to the changes of pH, colour and browning intensity during Maillard reaction. The DPPH radical-scavenging activity of PF4 was significantly improved after Maillard reaction. Aroma volatiles and PLSR analysis suggested MRPF3 had the best sensory characteristics with higher contents of umami amino acids and lower of bitter amino acids, therefore it could be deduced that the umami and meaty characteristics were correlated with the peptides of 1 3;kDa. PMID- 29146336 TI - Effect-directed analysis of ginger (Zingiber officinale) and its food products, and quantification of bioactive compounds via high-performance thin-layer chromatography and mass spectrometry. AB - Decision makers responsible for quality management along the food chain need to reflect on their analytical tools that should ensure quality of food and especially superfood. The "4ables" in target analysis (stable, extractable, separable, detectable) focusing on marker compounds do not cover all relevant information about the sample. On the example of ginger, a streamlined quantitative bioprofiling was developed for effect-directed analysis of 17 commercially available ginger and ginger-containing products via high-performance thin-layer chromatography (HPTLC-UV/Vis/FLD-bioassay). The samples were investigated concerning their active profile as radical scavengers, antimicrobials, estrogen-like activators and acetylcholinesterase/tyrosinase inhibitors. The [6]-gingerol and [6]-shogaol content of the different products ranged 0.2-7.4mg/g and 0.2-3.0mg/g, respectively. Further, multipotent compounds were discovered, characterized, and for example, assigned as [8]- and [10] gingerol via HPTLC-ESI-HRMS. The developed bioprofiling is a step forward to new analytical methods needed to inform on the true product quality influenced by cultivation, processing, and storage. PMID- 29146337 TI - Characterization, antioxidant and hypoglycemic activities of degraded polysaccharides from blackcurrant (Ribes nigrum L.) fruits. AB - In this study, the degradation of polysaccharides from blackcurrant (BCP) was investigated. Two low-molecular-weight polysaccharides (DBCP-1, DBCP-2) were obtained using Fe2+ with different concentrations of H2O2 solution. IR spectra showed DBCPs had obvious characteristic peaks of polysaccharides. GC analysis confirmed DBCPs were composed of the same monosaccharide units as BCP but with different molar ratios. NMR analysis indicated DBCPs and BCP had similar glycosidic linkage patterns. The surface area of fragmented structure in DBCPs was reduced compared to BCP, and they had no triple helix structure. The results of bioactivity assays indicated that DBCPs exhibited higher antioxidant, alpha amylase and alpha-glucosidase inhibitory activities than BCP, and the degraded polysaccharides with the lower molecular weight possessed higher bioactivities. These results suggested that Fe2+-H2O2 degradation did not change the main structure of polysaccharide and the degree of degradation could play a key role in the bioactivities of the polysaccharides. PMID- 29146338 TI - Analysis of changes in volatile constituents and expression of genes involved in terpenoid metabolism in oleocellosis peel. AB - Oleocellosis is a serious physiological disorder in citrus fruit that mainly results in appearance and quality deterioration. It has been well established that the occurrence of oleocellosis is highly correlated with the release of peel oil from citrus fruit, while there is little information on the dynamic changes in the content of the volatile constituents and the expression of genes involved in terpenoid metabolism during oleocellosis development. In the present research, large changes in the volatile profiles and gene expression in terpenoid metabolism were observed in oleocellosis peels compared to healthy ones. Among volatiles, the decreased contents of alpha-pinene, d-limonene, beta-myrcene, linalool, beta-caryophyllene, alpha-terpineol, nonanal, neryl acetate and (-) carvone played a major role in these changes. For gene expressions in terpenoid metabolism, the up-regulated genes aldehyde dehydrogenase (NAD+) (ALDH) and the down-regulated genes beta-caryophyllene synthase 1 (BCS1), alpha-terpineol synthase 2 (TES2) and myrcene synthase (MS) were the main differences in oleocellosis peels. PMID- 29146339 TI - Proteomic profiling of oxidized cysteine and methionine residues by hydroxyl radicals in myosin of pork. AB - In order to investigate the effects of hydroxyl radicals on the myosin of pork, with focus on reducible and non-reducible oxidation of specific cysteine and methionine residues, extracted myofibrillar protein from longissimus dorsi of pork was incubated with H2O2 for 24, 48 and 72h, respectively. The thiol contents and crosslinking of myofibrillar protein were analyzed after oxidation of the protein. Moreover, cysteine (labeled with N-ethylmaleimide (NEM) and iodoacetamide (IAM) before and after reduction, respectively) and methionine oxidation were detected by LC/MS using label-free quantitation. The result revealed that cysteine at head of myosin tended to form sulfinic and sulfonic acid, while the cysteine at coiled tail of myosin easily generated disulfide under same condition. Furthermore, it was also revealed that the methionine at the coiled tail of myosin was more easily oxidized than that of the head. PMID- 29146340 TI - Effect of the composition of extra virgin olive oils on the differentiation and antioxidant capacities of twelve monovarietals. AB - The effect of the composition of twelve varieties of extra virgin olive oils (EVOOs) on their differentiation based in agronomic criteria and on the antioxidant capacity was studied. Principal component analysis permitted an overview of the samples and their compositions, showing evidence of grouping and correlation between antioxidant capacity, oleuropein and ligstroside derivatives (OLD) and specific extinction at 270. Oleic and linoleic acids, 3,4-DHPEA-EA and p-HPEA-EDA (OLD), unsaturated/saturated ratio and induction time (IT) allowed the correct classification of samples according to year of harvest, ripening stage and variety. The antioxidant capacity of EVOOs was satisfactory predicted through a partial least square model based on DeltaK, hydroxytyrosol, pinoresinol, oleuropein derivate and IT. Validation of the model gave a correlation R>0.83 and an error of 7% for independent samples. This model could be a useful tool for the olive industry to highlight the nutritional quality of EVOOs and improve their marketing. PMID- 29146341 TI - Oxidation and nitrosation of meat proteins under gastro-intestinal conditions: Consequences in terms of nutritional and health values of meat. AB - The chemical changes (oxidation/nitrosation) of meat proteins during digestion lead to a decrease in their nutritional value. Moreover, oxidized and nitrosated amino acids are suspected to promote various human pathologies. To investigate the mechanisms and the kinetics of these endogenous protein modifications, we used a dynamic artificial digestive system (DIDGI(r)) that mimics the physicochemical conditions of digestion. The combined effect of meat cooking and endogenous addition of ascorbate and nitrite was evaluated on protein oxidation (by measuring carbonyl groups), protein nitrosation (by measuring nitrosamines), and proteolysis. Considerable carbonylation was observed in the digestive tract, especially under the acidic conditions of the stomach. Nitrosamines, caused by ammonia oxidation, were formed in conditions in which no nitrite was added, although the addition of nitrite in the model significantly increased their levels. Meat cooking and nitrite addition significantly decreased protein digestion. The interactions between all the changes affecting the proteins are discussed. PMID- 29146342 TI - Detection of coffee adulteration with soybean and corn by capillary electrophoresis-tandem mass spectrometry. AB - The detection of coffee adulteration with soybean and corn by capillary electrophoresis-tandem mass spectrometry was accomplished by evaluating the monosaccharides profile obtained after acid hydrolysis of the samples. The acid hydrolysis, using H2SO4 as a catalyst, increases the ionic strength of the sample impairing the electrophoretic separation. Therefore, Ba(OH)2 was used to both neutralize the medium and reduce the content of sulfate by precipitation of BaSO4. The best separation of nine determined monosaccharides (fucose, galactose, arabinose, glucose, rhamnose, xylose, mannose, fructose and ribose) plus inositol as internal standard was obtained in 500 mmol.L-1 triethylamine, pH 12.3. The monosaccharides are separated as anionic species at this pH. The proposed method is simple, fast (<12.0 min), present linear calibration curves (r2 = 0.995), and relative standard deviation for replicate injections lower than 5%. The LOQ for all monosaccharides was lower than 0.01 mmol.L-1, which is in accordance with the tolerable limits for coffee. Principal component analysis (PCA) was used to evaluate interrelationships between the monosaccharide profile and the coffee adulteration with different proportions of soybean and corn. Fucose, galactose, arabinose, glucose, sucrose, rhamnose, xylose, mannose, fructose, and ribose were quantified in packed roast-and-ground commercial coffee samples, and differences between adulterated and unadulterated coffees could be detected. PMID- 29146343 TI - Classification of white maize defects with multispectral imaging. AB - Multispectral imaging with object-wise multivariate image analysis was evaluated for its potential to grade whole white maize kernels. The types of defective materials regarded in grading legislation were divided into 13 classes, and were imaged with a multispectral imaging instrument spanning the UV, visible and NIR regions (19 wavelengths ranging from 375 to 970nm). Object-wise partial least squares discriminant analysis (PLS-DA) models were developed and validated with an independent data set. Results demonstrated good performance in distinguishing between sound maize and undesirable materials, with cross-validated coefficients of determination (Q2) and classification accuracies ranging from 0.35 to 0.99 and 83 to 100%, respectively. Wavelengths related to absorbance of green, yellow and orange colour indicated the presence of lycopene and anthocyanin (505, 525, 570 and 590 nm). NIR wavelengths 890, 940 nm (associated with fat) and 970 nm (associated with water) were generally identified as important features throughout the study. PMID- 29146344 TI - Lipid profiles in different parts of two species of scallops (Chlamys farreri and Patinopecten yessoensis). AB - Different classes of lipids and phospholipids (PL) as well as fatty acid (FA) compositions, and glycerophospholipid (GP) molecular species in edible parts (adductor muscles) and by-products (gonads and mantles) of scallops Patinopecten yessoensis and Chlamys farreri were characterized. The lipids contained high levels of polyunsaturated FA (PUFA) (20.44-58.81% of total FAs) and PL (54.99 78.26% of total lipids). Among PL, phosphatidylcholine (41.39-51.86 mol%) was dominant. More than 230 GP species belonging to glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoinositol, lysoglycerophosphocholine, lysoglycerophosphoethanolamine and lysoglycerophosphoinositol were characterized. Individual GP molecular species in different body parts of scallops were also partially quantified. Most of the dominant GP species contained PUFA, especially eicosapentaenoic acid (EPA, 20:5n 3) and docosahexaenoic acid (DHA, 22:6n-3). Considering the high level of PUFA enriched GP, edible parts and by-products (gonads and mantles) of scallops Patinopecten yessoensis and Chlamys farreri provide great potential as health promoting food for human consumption. PMID- 29146345 TI - Effect of high-pressure processing on colour, phytochemical contents and antioxidant activities of purple waxy corn (Zea mays L. var. ceratina) kernels. AB - High-pressure processing (HPP) at 250-700 MPa for 30-45 min affects the colour parameters, phytochemical contents and antioxidant activities of purple waxy corn kernels (p < 0.05). The higher pressure-level, the lower L*, a*, b*, C* and ho (p < 0.05). However, pressure-treated kernels at 700 MPa showed a similar colour profile to steam-treated kernels. HPP caused a loss in the total phenolic, flavonoid, and anthocyanin contents and antioxidant activities. The pressure treated kernels had a higher phytochemical content than the steam-treated kernels. The phytochemicals and antioxidant activities decreased as the pressure increased from 250 to 550 MPa, but the levels recovered at 700 MPa. The longer holding-time, the greater loss of the compounds and antioxidant activities (p < 0.05). Pressure treatment at 700 MPa yielded the highest total phenolic and anthocyanin contents (p < 0.05). Water-soluble compounds can leach from food materials due to cell rupture. Nevertheless, HPP is a potential process to preserve the phytochemicals in food. PMID- 29146346 TI - Enhanced functionality of pea-rice protein isolate blends through direct steam injection processing. AB - Direct steam injection (DSI) processing with pH adjustment was investigated to enhance the functionality of pea-rice protein isolate blends (PR). Protein slurries at concentration of 5%(w/w) of commercial pea and rice protein isolates in the ratio of 2:1(w/w) across a range of steam temperatures (66-107 degrees C) and pH values (2-11) were studied. After DSI treatment, the PR were freeze-dried to obtain the final dry protein powder. Based on protein solubility profiles, the optimal DSI processing conditions were 107 degrees C and pH 11. Available lysine was not reduced (P>0.05) in the blend. Solubility (from 3 to 41%, at pH 7), emulsifying activity index (from 5.9 to 52.5m2/g), foam stability (from 68.2 to 82.8%), and oil holding capacity (from 1.8 to 4.9g/g) values increased (P<0.05) compared to the untreated PR. DSI can modify the functionality of PR without affecting the essential amino acid composition. PMID- 29146347 TI - Effect of tea products on the in vitro enzymatic digestibility of starch. AB - The importance of postprandial hyperglycemia in the treatment of diabetes has been recognized recently. Tea products, such as tea polyphenols (TP), epigallocatechin gallate (EGCG), matcha, and instant tea, were chosen as constituents of tea-flour food, aimed at regulating the release of glucose from starchy foods in the postprandial period. Six starches were chosen for internal composition analysis and hydrolysis studies in vitro. Corn starch, wheat starch, and lily root flour appeared to have higher resistant starch content, slower digestion profiles, and lower kinetic constants, implying sustained release of glucose in the gastrointestinal tract. The effect of tea products on starch digestion was determined in order to get a desired formulation of dietary product for patients with hyperglycemia. Compared with macha and instant tea, TP and EGCG exerted greater inhibition of amylase and amyloglucosidase, especially for corn starch with 0.5% TP or 0.5% EGCG. PMID- 29146348 TI - Liquid-liquid microextraction of synthetic pigments in beverages using a hydrophobic deep eutectic solvent. AB - A method was developed for the determination of eight synthetic pigments in beverage samples by liquid-liquid microextraction followed by high performance liquid chromatography. Using hydrophobic deep eutectic solvent (DES) as the microextraction solvent, several key parameters were optimized, including the type and volume of the hydrophobic DES, pH value, vortex time and salt content. Detection limits were in the range 0.016-1.12 ng/mL, recoveries were in the range 74.5-102.5% and relative standard deviations were <5.4%. The method is simple, green and practical, and could be applied to the extraction and determination of synthetic pigments in beverages. PMID- 29146349 TI - Analysis of alternariol and alternariol monomethyl ether in foodstuffs by molecularly imprinted solid-phase extraction and ultra-high-performance liquid chromatography tandem mass spectrometry. AB - Molecularly imprinted porous polymer microspheres selective to Alternaria mycotoxins, alternariol (AOH) and alternariol monomethyl ether (AME), were synthesized and applied to the extraction of both mycotoxins in food samples. The polymer was prepared using 4-vinylpiridine (VIPY) and methacrylamide (MAM) as functional monomers, ethylene glycol dimethacrylate (EDMA) as cross-linker and 3,8,9-trihydroxy-6H-dibenzo[b,d]pyran-6-one (S2) as AOH surrogate template. A molecularly imprinted solid phase extraction (MISPE) method has been optimized for the selective isolation of the mycotoxins from aqueous samples coupled to HPLC with fluorescence (lambdaex=258nm; lambdaem=440nm) or MS/MS analysis. The MISPE method was validated by UPLC-MS/MS for the determination of AOH and AME in tomato juice and sesame oil based on the European Commission Decision 2002/657/EC. Method performance was satisfactory with recoveries from 92.5% to 106.2% and limits of quantification within the 1.1-2.8ugkg-1 range in both samples. PMID- 29146350 TI - Emerging approach for analytical characterization and geographical classification of Moroccan and French honeys by means of a voltammetric electronic tongue. AB - Moroccan and French honeys from different geographical areas were classified and characterized by applying a voltammetric electronic tongue (VE-tongue) coupled to analytical methods. The studied parameters include color intensity, free lactonic and total acidity, proteins, phenols, hydroxymethylfurfural content (HMF), sucrose, reducing and total sugars. The geographical classification of different honeys was developed through three-pattern recognition techniques: principal component analysis (PCA), support vector machines (SVMs) and hierarchical cluster analysis (HCA). Honey characterization was achieved by partial least squares modeling (PLS). All the PLS models developed were able to accurately estimate the correct values of the parameters analyzed using as input the voltammetric experimental data (i.e. r>0.9). This confirms the potential ability of the VE tongue for performing a rapid characterization of honeys via PLS in which an uncomplicated, cost-effective sample preparation process that does not require the use of additional chemicals is implemented. PMID- 29146351 TI - Impact of rapeseed press-cake on Maillard reaction in a cookie model system. AB - Rapeseed press-cake (RPC) is a byproduct of rapeseed oil production, rich in proteins and fiber. The aim of this study was to investigate the impact of cold pressed RPC, RPC fiber isolate and RPC alkaline extract on the formation of acrylamide and 5-hydroxymethylfufural (HMF) in cookies. Both compounds were influenced by the ingredients: the addition of RPC led to a significant dose dependent increase of HMF in the cookies and to an increase of acrylamide up to 66.9%. On the contrary, acrylamide concentration was reduced down to 39.6% in presence of the alkaline extract and down to 4.4% in the presence of the fiber extract. The Michael addition of free amino acids to acrylamide was further investigated by high-resolution mass spectrometry (HRMS) revealing that cysteine was the preferred nucleophile for acrylamide elimination. PMID- 29146352 TI - Anti-inflammatory properties of edible mushrooms: A review. AB - Mushrooms have been used extensively, owing to their nutritional and medicinal value, for thousands of years. Modern research confirms the therapeutic effect of traditionally used species. Inflammation is a natural response of the immune system to damaging factors, e.g. physical, chemical and pathogenic. Deficiencies of antioxidants, vitamins, and microelements, as well as physiological processes, such as aging, can affect the body's ability to resolve inflammation. Mushrooms are rich in anti-inflammatory components, such as polysaccharides, phenolic and indolic compounds, mycosteroids, fatty acids, carotenoids, vitamins, and biometals. Metabolites from mushrooms of the Basidiomycota taxon possess antioxidant, anticancer, and most significantly, anti-inflammatory properties. Recent reports indicate that edible mushroom extracts exhibit favourable therapeutic and health-promoting benefits, particularly in relation to diseases associated with inflammation. In all certainty, edible mushrooms can be referred to as a "superfood" and are recommended as a valuable constituent of the daily diet. PMID- 29146353 TI - Handheld NIR device: A non-targeted approach to assess authenticity of fish fillets and patties. AB - This study evaluates the reliability of a handheld NIR device in distinguishing fillets and patties of Atlantic cod (n = 80) from those of haddock (n = 90), in comparison with a FT-NIR benchtop spectrometer. The authentication issue was faced by Linear Discriminant Analysis (LDA) and Soft Independent Modelling of Class Analogy (SIMCA), pre-treating spectral data with different algorithms, and validating models both internally and externally. The best LDA models gave 100% correct classification in prediction. Sensitivity >65% and specificity >74% in prediction were calculated for the best SIMCA models. No significant differences (P > .05) were found between the two instruments by McNemar test. Thus, the work demonstrated that a handheld NIR device can be a simple, cost-effective, and reliable alternative to benchtop spectrometers in fish fillet and patty authentication. These important findings can help in improving commercial fraud fight, extending the possibility to authenticate fish species also in processed products. PMID- 29146354 TI - A novel calcium-binding peptide from Antarctic krill protein hydrolysates and identification of binding sites of calcium-peptide complex. AB - Trypsin was used for preparing peptides with high calcium-binding capacity from Antarctic krill. Hydroxyapatite chromatography (HAC), size-exclusion chromatography (SEC), and reversed phase high performance liquid chromatography (RP-HPLC) were used to capture and purify calcium-binding peptides. The peptide sequence was determined to be VLGYIQIR (N- to C-terminal, MW = 960.58 Da), using LTQ Orbitrap XL. According to the results of FTIR and mass spectrometry, chelating site of calcium ions may possibly involve the carbonal or amino groups of Gln, Ile and Arg residues. Molecular dynamic simulation showed the conformation of peptide was markedly varied, and the distance between calcium ion and Gln and Ile residues was changing all the time. However, the distance between calcium ion and carboxyl oxygen of arginine residues was not changed significantly from 2 ns to 100 ns. Identified peptide can be used as a novel calcium supplement. PMID- 29146355 TI - Gelatinized wheat starch influences crystallization behaviour and structure of roll-in shortenings in laminated bakery products. AB - One hydrogenated and one non-hydrogenated shortening were baked with isolated components of a croissant matrix, including crystalline wheat starch, gelatinized wheat starch, gluten, and formed gluten network. The impact of the matrix components on fat crystallization was analyzed for polymorphism using powder X ray diffraction, solid fat content by pulsed nuclear magnetic resonance and thermal behaviour by differential scanning calorimetry. When compared to results obtained from croissants prepared with the respective shortenings, samples containing gelatinized wheat starch displayed notably similar results: polymorphic conversion, from the beta' to beta form over storage, and visually broader peaks in the melting endotherms indicating a greater temperature was required to completely melt all of the fat. All other component mixtures behaved similar to the respective fats in bulk. The measured rate of crystallization was greater in samples containing gelatinized wheat starch, indicating that the gelatinized starch could act as a nucleation site to speed crystallization. PMID- 29146356 TI - Identification of cis/trans isomers of menaquinone-7 in food as exemplified by dietary supplements. AB - For the first time, the cis/trans isomer content of menaquinone-7 in food products has been identified and marked. A novel method of marking isomers of vitamin K2MK-7 in dietary supplements was developed and validated. Five different isomers of cis/trans vitamin K2MK-7 were identified. Identification of cis/trans isomers was performed by HRMS-QTOF, whereas their quantities were determined by using CAD and DAD detectors. In the majority of cases, the content of biologically active all trans vitamin K2MK-7 was below its declared content. The content of all trans K2MK-7 was in the range between 5.5 and 49 ug in pills. In one of the studied supplements, this vitamin was not found, regardless of the claim on the product label. The content of cis/trans isomers in certain dietary supplements exceeded the content of all trans K2MK-7 by up to 3.7 times. PMID- 29146357 TI - Effects of exogenous application of CPPU, NAA and GA4+7 on parthenocarpy and fruit quality in cucumber (Cucumis sativus L.). AB - In protected vegetable fields, plant growth regulators are often used to improve cucumber fruit growth. However, the effects of plant growth regulators on the appearance and nutritional quality of cucumber (Cucumis sativus L.) remain largely unknown. In the present study, 100 mg/L N-(2-chloro-4-pyridyl)-N' phenylurea (CPPU), naphthaleneacetic acid (NAA) or gibberellin A4+A7 (GA4+7) was applied to the female cucumber flowers 1 day before anthesis and at anthesis. The CPPU, NAA and GA4+7 treatments resulted in parthenocarpic fruits with similar weights, sizes and shapes as the pollinated fruits. NAA treatment did not affect the appearance and nutritional characteristics of cucumber at harvest and after storage. CPPU treatment increased the flesh firmness at harvest but decreased phenolic acid and vitamin C contents after storage. GA4+7 treatment decreased the flesh firmness but increased total flavonoids and protein content after storage. PMID- 29146358 TI - The effect of microwave roasting on bioactive compounds, antioxidant activity and fatty acid composition of apricot kernel and oils. AB - In this study, the effect of microwave (360W, 540W and 720W) oven roasting on oil yields, phenolic compounds, antioxidant activity, and fatty acid composition of some apricot kernel and oils was investigated. While total phenol contents of control group of apricot kernels change between 54.41mgGAE/100g (Sogancioglu) and 59.61mgGAE/100g (Hasanbey), total phenol contents of kernel samples roasted in 720W were determined between 27.41mgGAE/100g (Cataloglu) and 34.52mgGAE/100g (Sogancioglu). Roasting process in microwave at 720W caused the reduction of some phenolic compounds of apricot kernels. The gallic acid contents of control apricot kernels ranged between 7.23mg/100g (Kabaasi) and 11.23mg/100g (Cataloglu) whereas the gallic acid contents of kernels roasted in 540W changed between 15.35mg/100g (Sogancioglu) and 21.17mg/100g (Cataloglu). In addition, oleic acid contents of control group oils vary between 65.98% (Sogancioglu) and 71.86% (Hasanbey), the same fatty acid ranged from 63.48% (Sogancioglu) to 70.36% (Hasanbey). PMID- 29146359 TI - Determination of tryptophan derivatives in kynurenine pathway in fermented foods using liquid chromatography tandem mass spectrometry. AB - This study aimed to develop an analytical method for the determination of tryptophan and its derivatives in kynurenine pathway using tandem mass spectrometry in various fermented food products (bread, beer, red wine, white cheese, yoghurt, kefir and cocoa powder). The method entails an aqueous extraction and reversed phase chromatographic separation using pentafluorophenyl (PFP) column. It allowed quantitation of low ppb levels of tryptophan and its derivatives in different fermented food matrices. It was found that beer samples were found to contain kynurenine within the range of 28.7+/-0.7MUg/L and 86.3+/ 0.5MUg/L. Moreover, dairy products (yoghurt, white cheese and kefir) contained kynurenine ranging from 30.3 to 763.8MUg/kg d.w. Though bread samples analyzed did not contain kynurenic acid, beer and red wine samples as yeast-fermented foods were found to contain kynurenic acid. Among foods analyzed, cacao powder had the highest amounts of kynurenic acid (4486.2+/-165.6MUg/kgd.w), which is a neuroprotective compound. PMID- 29146360 TI - Behaviour of Trolox with macromolecule-bound antioxidants in aqueous medium: Inhibition of auto-regeneration mechanism. AB - This work aimed at investigating the behaviour of Trolox, vitamin E analogue, in presence of macromolecule-bound antioxidants in aqueous radical medium. Three main groups of macromolecule-bound antioxidants were assayed: dietary fiber (DF), protein and lipid-bound antioxidants, represented by whole wheat, soybean and olive oil products, respectively. Experimental studies were carried out in aqueous ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) radical medium. Trolox and macromolecule-bound antioxidants were added to radical separately and together in different concentrations. Antioxidant capacities were determined using QUENCHER procedure. pH of radical media was altered for DF and protein-bound antioxidant studies to examine its effect. Chemometric tools were used for experimental design and multivariate data analysis. Results revealed antagonistic interactions for Trolox with all macromolecule-bound antioxidants. The reason behind this antagonism was investigated through oxidation reactions of Trolox via mass spectrometry analysis. Consequently, a proof was obtained for inhibitory effect of bound-antioxidants on auto-regeneration reactions of Trolox. PMID- 29146361 TI - Rheological characterization of gum and starch nanoparticle blends. AB - Commercial interest on the application of starch nanoparticles (SNP) in food is rapidly growing. Since gums are commonly used in food processing for their texturizing functionality, it is important to understand the influence of SNP on gum rheology. lambda-Carrageenan and xanthan gum were selected in this study due to their wide range of applications in food systems. SNP isolated from waxy (0% amylose) and high amylose maize (71% amylose) were used. Binary blends consisting of 0.5% (w/v) gum and different concentrations of SNP were prepared and their flow behaviors evaluated using a rheometer. The starch source, concentration and thermal stability of the SNP influenced the viscosity and viscoelastic properties of the gum-SNP blends, in particular in the low elasticity lambda-carrageenan. The blends containing high concentrations of high amylose maize SNP, when compared to waxy SNP, showed higher viscoelastic stability at temperatures up to 90 degrees C, possibly due to their higher thermal stability. PMID- 29146362 TI - Ozone treatment for pesticide removal from carrots: Optimization by response surface methodology. AB - The present study aimed to optimize ozone (O3) treatments, as gas and dissolved in water, to remove difenoconazole and linuron in carrots. We employed a central composite design to study three variables governing the efficacy of treatments: O3 concentration, temperature and treatment time. The temperature did not influence the efficacy of treatments. The removal percentage of pesticides increases with increases in ozone concentration and the time of treatment. O3 application promoted the removal of more than 80% of pesticides when the roots were exposed for approximately 120min at 5 and 10mgL-1, respectively, in treatments with O3 as gas and dissolved in water. After storage, pesticide removal was higher than 98% for difenoconazole and 95% for linuron. The degradation products from the pesticides resulting from treatment were monitored, but none were found. This is the first report demonstrating the removal of difenoconazole and linuron from carrots by ozone. PMID- 29146363 TI - Vortex assisted deep eutectic solvent (DES)-emulsification liquid-liquid microextraction of trace curcumin in food and herbal tea samples. AB - We developed a new microextraction method for separation and preconcentration of curcumin using deep eutectic solvent known as green solvent. Deep eutectic solvent (DES) formed by mixing of choline chloride and phenol was used as an extraction solvent in microextraction study to extract the curcumin at pH 4.0. The curcumin concentration in enriched DES phase was analyzed by UV-Visible spectrophotometer. The effect of parameters such as pH, mol ratio of DES composition, volume of DES, volume of tetrahydrofuran (THF) and sample volume were examined. Interference effects of matrix components were investigated. The preconcentration factor was 12.5. The detection limit of method (n = 10) was 2.86 ug L-1 and the relative standard deviation (RSD, n = 8) was 1.8%. The method was successfully applied to determination of curcumin in food and herbal tea samples. The mean recoveries were between 96% and 102% and standard deviations were found in the range of 1-6%. PMID- 29146364 TI - Long-term stability of compression-molded soybean protein concentrate films stored under specific conditions. AB - Post-processing evolution of the functional properties of soybean protein concentrate (SPC) films, plasticized with varying levels of glycerol and processed by compression molding, was examined over a period of 90days. Films stored in the glassy state (25+/-2 degrees C and 65+/-2% relative humidity) lost glycerol and water over time, as determined by gas chromatography and the decline in moisture content. SPC films plasticized with 40-50% glycerol showed a time dependent increment of the elastic modulus and the tensile strength. In turn, the elongation, barrier properties, soluble mass and opacity of these films varied marginally with time. By contrast, films with 30% glycerol lost the most moisture and their elongation was reduced significantly, while water vapor permeability slightly increased with aging. The performance of aged films resulted from the balance between plasticizer and water loss, and the progressive replacement of unordered structures by intermolecular hydrogen bonded beta-sheets and aggregates. PMID- 29146365 TI - Sulfur free red wines through the use of grapevine shoots: Impact on the wine quality. AB - Following a preliminary study to determine the possibility of using a grapevine shoot extract (VIN) as a sustainable alternative to sulfur dioxide (SO2), in this study, the chromatic features, phenolic composition, and sensory analysis of wines treated with VIN at two concentrations were studied during storage in bottle for the first time. The highest differences were found in phenolic compounds after 12months of storage in bottle. The VIN wines had a low content of free anthocyanins and were high in vinyl-pyranoanthocyanins, and B-type vitisins. Consequently, they showed better chromatic characteristics. Moreover VIN, especially at high dose, preserved non-anthocyanin phenolic compounds better than SO2. However, at this high dose some organoleptic properties were affected. VIN, when used at a low dose, is able to preserve wine composition without loss of quality. PMID- 29146366 TI - Validation and theoretical justification of an LC-MS method for the animal species specific detection of gelatin. AB - Collagen is the most abundant protein family in mammals. Commercial edible gelatins are often produced from bovine and porcine skin and bone and consist mainly of partially hydrolyzed collagen type 1. The gelatin industry would benefit from a sensitive and reliable species detection method to unambiguously demonstrate species authenticity of their products. PCR and ELISA could in principle be used for this purpose. However, for gelatin, problems associated with false-positive and false-negative results, inconsistencies and low reactivity of commercially available kits have been observed with regard to ELISA and PCR methods. Therefore we developed a selective bottom-up LC-MS methodology for quantitative gelatin species determination with a lower limit of quantification of 0.05%. The present article describes the validation of this method, which was performed according to Good Laboratory Practice, and the theoretical justification for bovine and porcine target selection. The validated method can be used to determine the purity of gelatin batches with regard to bovine and porcine constituents. PMID- 29146367 TI - Corrigendum to "Interactions between polyphenols in thinned young apples and porcine pancreatic alpha-amylase: Inhibition, detailed kinetics and fluorescence quenching" [Food Chem. 208 (2016) 51-60]. PMID- 29146368 TI - Corrigendum to "Development of the method for identification of selected populations of torpedo scad, Megalaspis cordyla (Linnaeus, 1758), using microsatellite DNA analyses. CELFISH project - Part 4" [Food Chem. 221 (2017) 944 949]. PMID- 29146369 TI - Dose-dependent effects of rosmarinic acid on formation of oxidatively stressed myofibrillar protein emulsion gel at different NaCl concentrations. AB - The effects of rosmarinic acid (RA) (12, 60 and 300MUM/g protein) on the textural properties and stability of oxidized myofibrillar protein (MP) emulsion gels were investigated. A low dose (12uM/g) of RA significantly prevented the loss of thiol and epsilon-NH2 groups and the unfolding of the oxidized MP. However, a high dose of RA (300uM/g) covalently and non-covalently interacted with the MPs, which induced a significant loss of thiol and epsilon-NH2 groups and aggregation of the MPs, causing decreased solubility, resulting in a poor three-dimensional emulsion gel network, and hence, higher cooking loss and lower gel strength. Moreover, the emulsifying properties of the MP emulsion gel were jeopardized by 300uM/g RA. A high concentration of NaCl (0.6M) enhanced the interaction between RA and MPs, increasing deterioration of the internal structure and leading to extremely unstable emulsifying properties of the MP emulsion gel. PMID- 29146370 TI - Characterization of lipid oxidation process of beef during repeated freeze-thaw by electron spin resonance technology and Raman spectroscopy. AB - In this study, electron spin resonance (ESR) and Raman spectroscopy were applied to characterize lipid oxidation of beef during repeated freeze-thaw (RFT). Besides the conventional indexes including peroxide values (PV), thiobarbituric acid-reactive substances (TBARS) and acid values (AV) were evaluated, the radical and molecular structure changes were also measured by ESR and Raman spectroscopy. The results showed that PV, TBARS and AV were increased (P<0.05) after RFT. This suggested that lipid oxidation was occurred during RFT. With the increase of radical signal intensity, lower oxidation stability was presented by ESR. Raman intensity of nu(CC) stretching region (1655cm-1) was decreased during RFT. Furthermore, lower Raman intensity ratio of I1655/I1442, I1655/I1745 that determine total unsaturation was also observed. Significant correlations (p<0.01) were obtained among conventional methods, ESR and Raman spectroscopy. Our result has proved that ESR and Raman spectroscopy showed great potential in characterizing lipid oxidation process of beef during RFT. PMID- 29146371 TI - Comparison of the protective effect of black and white mulberry against ethyl carbamate-induced cytotoxicity and oxidative damage. AB - Increasing evidence indicates that crude extracts derived from mulberry confer protection against oxidative stress. However, the antioxidant capacity of mulberry extract among different cultivars remains elusive. The main objective of the present study was therefore to investigate the effect of black mulberry extract (BMB) and white mulberry extract (WMB) on ethyl carbamate (EC)-induced cytotoxicity and oxidative stress. This study showed that the contents of total phenolics, total flavonoids, total procyanidins, cyanidin-3-O-glucoside, cyanidin 3-O-rutinoside and pelargonidin-3-O-glucoside of BMB were higher than that of WMB. Moreover, our results showed that phenolics-abundant BMB was stronger than WMB in scavenging ABTS and DPPH free radicals. BMB was more effective in ameliorating EC-induced cytotoxicity by inhibiting excessive ROS generation, suppressing mitochondrial dysfunction and increasing GSH concentration in HepG2 cells than WMB. Taken together, our study revealed that BMB afforded better protection against EC-caused cytotoxicity than WMB. PMID- 29146372 TI - Interactions of cinnamaldehyde and its metabolite cinnamic acid with human serum albumin and interference of other food additives. AB - Considering the adverse effect of food additives on humans, thorough research of their physiological effects at the molecular level is important. The interactions of cinnamaldehyde (CNMA), a food perfume, and its major metabolite cinnamic acid (CA) with human serum albumin (HSA) were examined by multiple-spectroscopies. NMR analysis revealed CNMA and CA both bound to HSA, and STD-NMR experiments established CNMA and CA primarily interacted with site I and site II of HSA, respectively. The ligands caused strong quenching of HSA fluorescence through a static quenching mechanism, with hydrophobic and electrostatic interaction between CNMA/CA and HSA, respectively. UV-vis absorption and CD results showed ligands induced secondary structure changes of HSA. Binding configurations were proved by docking method. Furthermore, binding constants of CNMA/CA-HSA systems were influenced by the addition of four other food additives. These studies have increased our knowledge regarding the safety and biological action of CNMA and CA. PMID- 29146373 TI - Development and validation of a fallow deer (Dama dama)-specific TaqMan real-time PCR assay for the detection of food adulteration. AB - The aim of the present study was to develop a real-time PCR assay for the identification and quantification of fallow deer (Dama dama) in food to detect food adulteration. Despite high sequence homology among different deer species, a fallow deer-specific primer/probe system targeting a fragment of the nuclear MC1 R gene was designed. This primer/probe system did not amplify DNA from 19 other animals and 50 edible plant species. Moderate cross-reactivity was observed for sika deer, red deer, roe deer, reindeer and wild boar. The LOD and LOQ of the real-time PCR assay were 0.1% and 0.4%, respectively. To validate the assay, DNA mixtures, meat extract mixtures, meat mixtures and model game sausages were analyzed. Satisfactory quantitative results were obtained when the calibration mixture was similar to the analyzed sample in both the composition and concentration of the animal species of interest. PMID- 29146374 TI - Formation kinetics of furfuryl alcohol in a coffee model system. AB - The production of furfuryl alcohol from green coffee during roasting and the effect of multiple parameters on its formation were studied employing HPLC-DAD. Results show that coffee produces furfuryl alcohol in larger quantities (418ug/g) compared to other beans or seeds (up to 132ug/g) roasted under the same conditions. The kinetics of furfuryl alcohol production resemble those of other process contaminants (e.g., HMF, acrylamide) produced in coffee roasting, with temperature and time of roasting playing significant roles in quantities formed. Different coffee species yielded different amounts of furfuryl alcohol. The data point out that the amounts of furfuryl alcohol found in roasted coffee do not reflect the total amounts produced during roasting because great amounts of furfuryl alcohol (up to 57%) are evaporating and released to the atmosphere during roasting. Finally the effect of the moisture content on furfuryl alcohol formation was found to be of little impact. PMID- 29146375 TI - Investigating the optimum conditions for minimized 3-chloropropane-1,2-diol esters content and improved sensory attributes during savory beef flavor preparation. AB - In this study, the effects of enzymatic hydrolysis of tallow and addition of sodium chloride (NaCl) were evaluated on the formation of 3-monochloropropane-1,2 diol (3-MCPD) esters and sensory characteristic of beef flavors. The enzymatic hydrolysis condition had significant effects on 3-MCPD mono/di-esters formation during the beef flavor preparation. Considering the safety and sensory characteristics of beef flavors, the optimal enzymatic hydrolysis conditions were selected as: lipase concentration 75U/g tallow, tallow concentration 80% (w/v) and pH 7.0 at 47.5 degrees C for 9.5h. Using the optimal enzymatic hydrolysis conditions, no 3-MCPD monoesters were detected and 3-MCPD-diesters concentration was strongly dependent on NaCl concentration and its addition moment (before or after thermal reaction) at different temperatures. In conclusion, beef flavor was prepared using the optimal hydrolysis conditions and heated at 110 degrees C for 100min, then 10% NaCl was added when the system was cooled to 60 degrees C. PMID- 29146376 TI - Wronger than wrong: Graded mapping of the errors of an avatar in the performance monitoring system of the onlooker. AB - EEG studies show that observing errors in one's own or others' actions triggers specific electro-cortical signatures in the onlooker's brain, but whether the brain error-monitoring system operates according to graded or discrete rules is still largely unknown. To explore this issue, we combined immersive virtual reality with EEG recording in participants who observed an avatar reaching-to grasp a glass from a first-person perspective. The avatar could perform correct or erroneous actions. Erroneous grasps were defined as small or large depending on the magnitude of the trajectory deviation from the to-be-grasped glass. Results show that electro-cortical indices of error detection (indexed by ERN and mid-frontal theta oscillations), but not those of error awareness (indexed by error-Positivity), were gradually modulated by the magnitude of the observed errors. Moreover, the phase connectivity analysis revealed that enhancement of mid-frontal theta phase synchronization paralleled the magnitude of the observed error. Thus, theta oscillations represent an electro-cortical index of the degree of control exerted by mid-frontal regions whose activation depends on how much an observed action outcome results maladaptive for the onlooker. Our study provides novel neurophysiological evidence that the error monitoring system maps observed errors of different magnitude according to fine-grain, graded rather than all-or none rules. PMID- 29146377 TI - Cortical processing of pitch: Model-based encoding and decoding of auditory fMRI responses to real-life sounds. AB - Pitch is a perceptual attribute related to the fundamental frequency (or periodicity) of a sound. So far, the cortical processing of pitch has been investigated mostly using synthetic sounds. However, the complex harmonic structure of natural sounds may require different mechanisms for the extraction and analysis of pitch. This study investigated the neural representation of pitch in human auditory cortex using model-based encoding and decoding analyses of high field (7 T) functional magnetic resonance imaging (fMRI) data collected while participants listened to a wide range of real-life sounds. Specifically, we modeled the fMRI responses as a function of the sounds' perceived pitch height and salience (related to the fundamental frequency and the harmonic structure respectively), which we estimated with a computational algorithm of pitch extraction (de Cheveigne and Kawahara, 2002). First, using single-voxel fMRI encoding, we identified a pitch-coding region in the antero-lateral Heschl's gyrus (HG) and adjacent superior temporal gyrus (STG). In these regions, the pitch representation model combining height and salience predicted the fMRI responses comparatively better than other models of acoustic processing and, in the right hemisphere, better than pitch representations based on height/salience alone. Second, we assessed with model-based decoding that multi-voxel response patterns of the identified regions are more informative of perceived pitch than the remainder of the auditory cortex. Further multivariate analyses showed that complementing a multi-resolution spectro-temporal sound representation with pitch produces a small but significant improvement to the decoding of complex sounds from fMRI response patterns. In sum, this work extends model-based fMRI encoding and decoding methods - previously employed to examine the representation and processing of acoustic sound features in the human auditory system - to the representation and processing of a relevant perceptual attribute such as pitch. Taken together, the results of our model-based encoding and decoding analyses indicated that the pitch of complex real life sounds is extracted and processed in lateral HG/STG regions, at locations consistent with those indicated in several previous fMRI studies using synthetic sounds. Within these regions, pitch related sound representations reflect the modulatory combination of height and the salience of the pitch percept. PMID- 29146378 TI - Association of P wave duration index with atrial fibrillation recurrence after cryoballoon catheter ablation. AB - AIM: We aimed to investigate the relationship between the recurrence of AF and P wave duration index (PWDI) in patients with nonvalvular PAF. METHODS: We included 114 patients who underwent cryoballoon catheter ablation with the diagnosis of paroxysmal atrial fibrillation (PAF) (55 male, 59 female; mean age 55.5+/ 10,9years). PWDI was calculated by dividing the Pwd by the PR interval in DII lead of 12-lead ECG. Patients had regular follow-up visits with 12-lead ECG, medical history and clinical evaluation. 24h Holter ECG monitoring had been recorded at least 12months after ablation. RESULTS: AF recurrence was detected in 24 patients after 1year. Patients were divided into two groups according to the AF recurrence. All parameters were compared between the two groups. Age, DM, HT frequency, ACEI-ARB use, CHA2DS2VASc and HAS-BLED score, HsCRP, LA diameter, LA volume, LA volume index, Pwd and PWDI were related to AF recurrence. In binary logistic regression analysis, PWDI (OR=1.143, p=0.001) and HT (OR=0.194, p=0.020) were found to be independent parameters for predicting AF recurrence. Every 0,01 unit increase in PWDI was found to be associated with 14.3% increase in the risk of AF recurrence. The cut-off value of PWDI obtained by ROC curve analysis was 59,9 for prediction of AF recurrence (sensitivity: 75.0%, specificity: 69.0%). The area under the curve (AUC) was 0.760 (p<0.001). CONCLUSION: Increased PWDI may help to identify those patients in whom electrical remodeling has already occurred and who will get less benefit from cryoablation. PMID- 29146379 TI - LT adjuvant modulates epitope specificity and improves the efficacy of murine antibodies elicited by sublingual vaccination with the N-terminal domain of Streptococcus mutans P1. AB - In this study, we evaluated the immunogenicity, protective efficacy and peptide based immune signatures of antibodies raised in mice after sublingual immunization with a recombinant form of the P1 (aka AgI/II, PAc) adhesin (P139 512) of Streptococcus mutans, a major etiological agent of dental caries. Sublingual administration of P139-512 in combination with the mucosal adjuvant LTK4R (a derivative of heat-labile LT toxin) induced strong and long-lasting systemic and mucosal immune responses. Incorporation of the adjuvant resulted in an enhancement of the anti-adhesive and anti-colonization activity against S. mutans as evaluated both under in vitro and in vivo conditions. Incorporation of the adjuvant to the vaccine formulation also changed the epitope specificity of the induced antibodies as determined by immunological signatures of sera collected from vaccinated mice. Use of a peptide microarray library led to the identification of peptide targets recognized by antibodies in serum samples with enhanced anti-adhesive effects. Altogether, the results presented herein showed that the sublingual administration of a P1-based subunit vaccine represents a promising approach for the prevention of dental caries caused by S. mutans. In addition, the present study disclosed the role of adjuvants on the epitope specificity and functionality of antibodies raised by subunit vaccines. PMID- 29146380 TI - Inclusion of the value of herd immunity in economic evaluations of vaccines. A systematic review of methods used. AB - OBJECTIVE: The objectives of this review were to identify vaccine economic evaluations that include herd immunity and describe the methodological approaches used. METHODS: We used Kim and Goldie's search strategy from a systematic review (1976-2007) of modelling approaches used in vaccine economic evaluations and additionally searched PubMed/MEDLINE and Embase for 2007-2015. Studies were classified according to modelling approach used. Methods for estimating herd immunity effects were described, in particular for the static models. RESULTS: We identified 625 economic evaluations of vaccines against human-transmissible diseases from 1976 to 2015. Of these, 172 (28%) included herd immunity. While 4% of studies included herd immunity in 2001, 53% of those published in 2015 did this. Pneumococcal, human papilloma and rotavirus vaccines represented the majority of studies (63%) considering herd immunity. Ninety-five of the 172 studies utilised a static model, 59 applied a dynamic model, eight a hybrid model and ten did not clearly state which method was used. Relatively crude methods and assumptions were used in the majority of the static model studies. CONCLUSION: The proportion of economic evaluations using a dynamic model has increased in recent years. However, 55% of the included studies used a static model for estimating herd immunity. Values from a static model can only be considered reliable if high quality surveillance data are incorporated into the analysis. Without this, the results are questionable and they should only be included in sensitivity analysis. PMID- 29146381 TI - Impact of infant pneumococcal conjugate vaccination on community acquired pneumonia hospitalization in all ages in the Netherlands. AB - BACKGROUND: The long-term impact of pneumococcal conjugate vaccines on pneumonia hospitalizations in all age-groups varies between countries. In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV7) was implemented for newborns in 2006 and replaced by PCV10 in 2011. We assessed the impact of PCVs on community-acquired pneumonia (CAP) hospitalization rates in all age-groups. METHODS: A time series analysis using Poisson regression was performed on 155,994 CAP hospitalizations. Hospitalization rates were calculated using the total number of hospitalizations as denominator. The time trend in the pre-PCV period (1999-2006) was extrapolated to predict the hospitalization rate in the post-PCV period (2006-2014) if PCV had not been implemented. Rate ratios over time were calculated by comparing observed and predicted time trends. RESULTS: In children <5 years of age, the observed hospitalization rates during the post-PCV period were significantly lower than predicted if PCV had not been implemented (0-6 months: 0.62, 95% CI: 0.41-0.96; 6 months - 1 year: 0.67, 95% CI: 0.50-0.90; 2-4 years: 0.78, 95% CI: 0.61-0.97). In all other age-groups, rate ratios declined over time but did not reach statistical significance. CONCLUSIONS: After introduction of PCV, CAP hospitalizations declined in young children but no clear impact of PCV on CAP hospitalizations was seen in other age-groups. PMID- 29146382 TI - On the bias of estimates of influenza vaccine effectiveness from test-negative studies. AB - Estimates of the effectiveness of influenza vaccines are commonly obtained from a test-negative design (TND) study, where cases and controls are patients seeking care for an acute respiratory illness who test positive and negative, respectively, for influenza infection. Vaccine effectiveness (VE) estimates from TND studies are usually interpreted as vaccine effectiveness against medically attended influenza (MAI). However, it is also important to estimate VE against any influenza illness (symptomatic influenza (SI)) as individuals with SI are still a public health burden even if they do not seek medical care. We present a numerical method to evaluate the bias of TND-based estimates of influenza VE with respect to MAI and SI. We consider two sources of bias: (a) confounding bias due to a (possibly unobserved) covariate that is associated with both vaccination and the probability of the outcome of interest and (b) bias resulting from the effect of vaccination on the probability of seeking care. Our results indicate that (a) VE estimates may suffer from substantial confounding bias when a confounder has a different effect on the probabilities of influenza and non-influenza ARI, and (b) when vaccination reduces the probability of seeking care against influenza ARI, then estimates of VE against MAI may be unbiased while estimates of VE against SI may be have a substantial positive bias. PMID- 29146383 TI - Not Just Antibiotics: Is Cancer Chemotherapy Driving Antimicrobial Resistance? AB - The global spread of antibiotic-resistant pathogens threatens to increase the mortality of cancer patients significantly. We propose that chemotherapy contributes to the emergence of antibiotic-resistant bacteria within the gut and, in combination with antibiotics, drives pathogen overgrowth and translocation into the bloodstream. In our model, these processes are mediated by the effects of chemotherapy on bacterial mutagenesis and horizontal gene transfer, the disruption of commensal gut microbiology, and alterations to host physiology. Clinically, this model manifests as a cycle of recurrent sepsis, with each episode involving ever more resistant organisms and requiring increasingly broad spectrum antimicrobial therapy. Therapies that restore the gut microbiota following chemotherapy or antibiotics could provide a means to break this cycle of infection and treatment failure. PMID- 29146384 TI - Identification of candidate reference chemicals for in vitro steroidogenesis assays. AB - The Endocrine Disruptor Screening Program (EDSP) is transitioning from traditional testing methods to integrating ToxCast/Tox21 in vitro high-throughput screening assays for identifying chemicals with endocrine bioactivity. The ToxCast high-throughput H295R steroidogenesis assay may potentially replace the low-throughput assays currently used in the EDSP Tier 1 battery to detect chemicals that alter the synthesis of androgens and estrogens. Herein, we describe an approach for identifying in vitro candidate reference chemicals that affect the production of androgens and estrogens in models of steroidogenesis. Candidate reference chemicals were identified from a review of H295R and gonad derived in vitro assays used in methods validation and published in the scientific literature. A total of 29 chemicals affecting androgen and estrogen levels satisfied all criteria for positive reference chemicals, while an additional set of 21 and 15 chemicals partially fulfilled criteria for positive reference chemicals for androgens and estrogens, respectively. The identified chemicals included pesticides, pharmaceuticals, industrial and naturally occurring chemicals with the capability to increase or decrease the levels of the sex hormones in vitro. Additionally, 14 and 15 compounds were identified as potential negative reference chemicals for effects on androgens and estrogens, respectively. These candidate reference chemicals will be informative for performance-based validation of in vitro steroidogenesis models. PMID- 29146385 TI - Cross-cultural adaptation and implementation of Good Life with osteoarthritis in Denmark (GLA:DTM): group education and exercise for hip and knee osteoarthritis is feasible in Canada. AB - OBJECTIVE: Adapt and evaluate the feasibility of implementing Good Life with osteoArthritis in Denmark (GLA:DTM) in Canada for people with mild to severe hip/knee osteoarthritis. METHODS: Patients triaged to non-surgical management participated in two education sessions and 12 supervised, neuromuscular exercise classes. We used the RE-AIM implementation framework evaluating outcomes of Reach, Effectiveness/Efficacy, Adoption, Implementation and Maintenance. Patients completed surveys pre-program and at 3 months follow-up. Program fidelity was evaluated at four observations against a priori criteria. We conducted semi structured interviews with therapists post-program. RESULTS: 72 patients consented to participate, 59 started the program and one withdrew on physician advice. The remaining 58 provided follow-up data. Mean age was 67 years; 78% were female and 52% had body mass index (BMI) >25. The effect of the program was demonstrated: 40% improvement in pain with 59% achieving a clinically important improvement of >=2 points on the Numeric Pain Rating scale. Statistically significant improvement also occurred in the Hip disability/Knee injury and Osteoarthritis Outcome Score subscales. 24% reported increased physical activity. Program fidelity was demonstrated with all criteria met. Therapists emphasized that rolling recruitment allowed appropriate supervision and resulted in participants encouraging each other. 99% of participants indicated they benefitted from and were satisfied with the program and 90% reported using the knowledge daily. 52% were willing to pay >$250 Cdn for the program. CONCLUSION: GLA:DTM implementation was feasible in the Canadian context with results similar to those of >7,000 participants in Denmark. Implementation and evaluation of GLA:DTM Canada is now occurring nationally. PMID- 29146386 TI - The risk of symptomatic knee osteoarthritis after arthroscopic meniscus repair vs partial meniscectomy vs the general population. AB - OBJECTIVE: To compare consultation rate for knee osteoarthritis (OA) after meniscus repair, arthroscopic partial meniscectomy (APM), and in general population, respectively. METHOD: We identified patients aged 16-45 years having had meniscus surgery due to traumatic meniscus tear in 1998-2010 in southern Sweden by a healthcare register. Patients were followed from surgery until a diagnosis of knee OA, relocation, death, or December 31st, 2015. We studied the consultation rate for knee OA compared to the general population. RESULTS: We identified 2,487 patients diagnosed with traumatic meniscus tear (mean [SD] age 30.5 [8.6] years); 229 (9.2%) of them had had meniscus repair. The absolute risk of having consulted for knee OA during the study was 17% after APM, 10.0% after meniscus repair, and 2.3% in the general population. Hazard ratio (HR) (95% confidence interval (CI)) for knee OA after repair vs APM was: 0.74 (0.48, 1.15). Excluding cases with OA within 2 years post-surgery, yielded the HR of 0.51 (0.27, 0.96). The consultation rate for knee OA standardized to the general population was then 42 per 10,000 person-years (95% CI 12, 71) in the meniscus repair group, 118 per 10,000 person-years (95% CI 101, 135) after APM, and 20 per 10,000 person-years (95% CI 19.9, 20.1) in the general population. CONCLUSION: The point estimates suggests about 25-50% lower risk of consultation for knee OA after meniscus repair as compared to APM. However, the consultation rate for knee OA after repair was still at least two times higher as compared to the general population. PMID- 29146387 TI - Dilemmas in genetic counseling for low-penetrance neuro-susceptibility loci detected on prenatal chromosomal microarray analysis. AB - BACKGROUND: Chromosomal microarray analysis is standard of care in fetuses with malformations, detecting clinically significant copy number variants in 5-7% of cases over conventional karyotyping. However, it also detects variants of uncertain significance in 1.6-4.2% of the cases, some of which are low-penetrance neuro-susceptibility loci. The interpretation of these variants in pregnancy is particularly challenging because the significance is often unclear and the clinical implications may be difficult to predict. OBJECTIVE: The purpose of this study was to describe counseling dilemmas regarding low-penetrance neuro susceptibility loci that are detected by prenatal chromosomal microarray analysis. STUDY DESIGN: During the study period (January 2014 to December 2015), 700 prenatal chromosomal microarray analyses were performed. Cases were categorized as "indicated" (n=375) if there were abnormal sonographic findings or suggestive medical history and "patient choice" (n=325) in the presence of a structurally normal fetus with no other particular indication. The laboratory reported on copy number variants >=400 Kb in size in loci known to be associated with genetic syndromes and >=1 Mb in other areas of genome. Results were classified as gross aneuploidy, copy number variants, and normal. Copy number variants were categorized according to the American College of Medical Genetics standards and guidelines: pathogenic, variants of uncertain significance, or benign. Variants of uncertain significance were further subdivided into categories of likely pathogenic, variants of uncertain significance with no subclassification, and likely benign. Statistical analysis was performed with the use of Chi square test and Fisher's exact test to compare intergroup differences in incidence of the different result categories and demographic data. RESULTS: Patient choice cases became more prevalent with time (35.5% in the beginning of the study, compared with 48.4% at the end of the study period). Clinically significant copy number variants were found in 14 of 375 (3.7%) of indicated cases vs only 2 of 325 (0.6%) of patient choice cases (P=.009). All "likely benign" variants consisted of low-penetrance neuro-susceptibility loci. The incidence thereof was similar between the indicated and patient choice groups (3.7% vs 3.4%; P=.85). In the indicated group, some variants of uncertain significance may have contributed to the abnormal anatomic findings. Conversely, in the patient choice group, the finding of low-penetrance neuro-susceptibility loci was often unexpected and confounding for prospective parents. CONCLUSION: Prenatal chromosomal microarray analysis added clinically significant information in both groups. However, it also detected low-penetrance neuro-susceptibility loci in approximately 3.5% of the cases. This fact should be conveyed during pretest counseling to allow patients to make informed choices, particularly when chromosomal microarray is to be performed for patient choice. PMID- 29146388 TI - The Role of Pelvic Ultrasound in Preoperative Evaluation for Laparoscopic Myomectomy. AB - STUDY OBJECTIVE: To determine the accuracy of pelvic ultrasonography (US) in preoperative evaluation before laparoscopic myomectomy. DESIGN: A prospective cohort study (Canadian Task Force classification II-2). SETTING: A tertiary level referral center of minimally invasive gynecologic surgery, Sant'Orsola University Hospital, Bologna, Italy. PATIENTS: One hundred one of the 125 women undergoing laparoscopic myomectomy from September 2015 to May 2016 were included. INTERVENTIONS: Preoperative pelvic US was performed 2 weeks before surgery. MEASUREMENTS AND MAIN RESULTS: Among the 101 women enrolled in this study, preoperative US correctly identified the number of myomas in 73 patients (72.3%). A total of 208 myomas were preoperatively identified by US; 197 (94.7%) were surgically removed, and 11 (5.3%) were not visualized during laparoscopic myomectomy. The 11 undetected myomas were intramural (International Federation of Gynecology and Obstetrics [FIGO] type 3 and 4), with a mean diameter of 19.05 +/- 5.91 mm. The type, site, and location of the 197 myomas identified by US preoperatively and removed via laparoscopy were confirmed at surgery in 78.7% (155/197), 80.7% (159/197), and 84.3% (166/197) of the cases, respectively. Two hundred fifty-four total myomas were removed laparoscopically; 197 (77.6%) were preoperatively identified by US, and 57 (22.4%) were missed by US, having had a mean diameter of 13.51 +/- 7.84 mm and predominantly being the subserosal type (FIGO type 5, 6, and 7) (57.9%, p < .05). CONCLUSION: Pelvic US is a valuable tool in preoperative evaluation and should be systematically performed when planning laparoscopic myomectomy. PMID- 29146389 TI - Case of Psoas Abscess after Robotic-Assisted Laparoscopic Hysterectomy and Pelvic Lymphadenectomy. AB - Iliopsoas abscess (IPA) is a rare condition seen in a variety of specialties that presents with nonspecific complaints. Presented herein is the development of an IPA after robotic staging with sentinel lymphadenectomy for endometrial carcinoma. The patient was a 61-year-old woman with history of prolonged immunosuppressive therapy due to psoriasis. She presented with an IPA 8 weeks after a robotic-assisted laparoscopic hysterectomy, bilateral salpingo oophorectomy, and sentinel lymph node dissection. The patient was treated and cured with empiric antibiotics and drainage by interventional radiology. Although infrequent, one must keep IPA as a possible diagnosis in immunosuppressed patients who have undergone dissection of the retroperitoneal space during gynecologic surgery. PMID- 29146390 TI - Laparoendoscopic Single-Site Sentinel Lymph Node Detection in Endometrial Cancer. AB - STUDY OBJECTIVE: To demonstrate the feasibility of sentinel lymph node (SLN) biopsy using a laparoendoscopic single-site (LESS) approach in endometrial cancer (EC). DESIGN: A step-by-step video demonstration of the surgical procedure (Canadian Task Force Classification III). SETTING: The satisfaction of patients who undergo LESS hysterectomy is greater than that reported by patients who undergo multiport laparoscopic hysterectomy, owing to better cosmesis and reduced postoperative analgesic requirements [1]. SLN biopsy is associated with significantly lower estimated blood loss, shorter operation time, and less morbidity compared with systematic lymphadenectomy [2]. LESS surgery can be more feasible and safer with the use of SLN biopsy compared with complete lymphadenectomy in patients with early-stage EC. INTERVENTIONS: This 69-year-old woman with grade 2 endometrioid EC underwent SLN mapping followed by LESS SLN biopsy, total hysterectomy, and bilateral salpingo-oophorectomy. Before the umbilical incision was made, 1.25 mg/mL of indocyanine green was injected into the cervical stroma at the 3 o'clock and 9 o'clock positions to both deep and superficial levels. A 10-mm 30 degrees standard-length optical camera for near infrared fluorescence imaging was used. The total operative time was 75 minutes, and the estimated blood loss was 20 mL. SLNs were detected bilaterally between proximal parts of the external iliac arteries and veins. After SLN resection, total hysterectomy and bilateral salpingo-oophorectomy were performed. No postoperative complications occurred. The patient was discharged at 30 hours after surgery. In the final pathology, stage 1A G2 EC was detected. CONCLUSION: LESS SLN biopsy and TLH-BSO is a feasible procedure and sentinel lymph node concept may increase the use of LESS in EC. PMID- 29146393 TI - Cracking the Clinician Educator Code in Gastroenterology. PMID- 29146391 TI - Small-Diameter Hysteroscopic Metroplasty for a Septate Uterus after Open-Assisted Laparoscopic Radical Trachelectomy. AB - STUDY OBJECTIVE: To describe a 2-step fertility preservation technique for early stage cervical cancer of a patient with a complete septate uterus. DESIGN: A step by-step demonstration and explanation of the technique in a surgical video (Canadian Task Force classification III). SETTING: Center for cancer, a tertiary referral center. Institutional Review Board approval was not required for this kind of procedure. PATIENT: A 37-year-old woman. The patient provided informed consent to use images and videos of the procedure. INTERVENTIONS: Open-assisted laparoscopic radical trachelectomy (LRT) after metroplasty. MEASUREMENTS AND MAIN RESULTS: A 37-year-old woman presented with early-stage cervical cancer and a complete septate uterus. She desired fertility preservation. After careful counseling and in accordance with her wishes for fertility-sparing surgery, open assisted LRT after metroplasty were scheduled. First, LRT was successfully completed, and a cervical cerclage using permanent Ethibond sutures (Ethicon, Inc, Somerville, NJ) was doubly inserted around the level of the internal os with a Hegar size 8 dilator to maintain patency. At 6 months after this procedure, magnetic resonance imaging (MRI) revealed no sign of recurrence. Then, metroplasty without dilatation of the cervical os was performed using a small diameter (5.2-mm) resectoscope system (Karl Storz GmbH & Co. KG, Tuttlingen, Germany), scissor forceps, bipolar electrode, and normal saline. A hysteroscope was inserted without gripping the neocervix, and the septum was then resected with scissor forceps. The septum was cut from the cervical to the fundal side. Finally, an intrauterine device was placed in the uterine cavity to prevent adhesion in the uterine cavity. Three months later MRI confirmed normal development of the whole endometrium. No intraoperative or postoperative complications occurred. CONCLUSIONS: This 2-step fertility preservation technique with a small-diameter hysteroscopy presents an effective alternative to the traditional resectoscope technique. Further analyses with long-term follow-up are warranted to evaluate this surgical method. PMID- 29146394 TI - Is histological analysis of pilonidal sinus useful? Retrospective analysis of 731 resections. AB - The pilonidal sinus (SP) is a common pathology. The treatment is a surgical excision. Many surgeons continue to systematically send this SP in histological analysis. The objective of our retrospective study was to evaluate the interest of this systematic histological analysis. The retrospective analysis of patients undergoing surgery was performed between 1 January 2006 and 31 December 2014. The primary observation was the presence of a malignant disease on the surgical specimen. Secondary observations were the wound healing time and the rate of recurrence. Seven hundred and thirty-one patients were analyzed. There was no malignant lesion. For 323 patients, the histological analysis did not describe the resection margins. Two hundred and eighty five patients had complete resect on and 38 were incomplete. Twenty-four patients had recurrence (7%). There was no significant difference between those who had complete and incomplete resection. The healing time was 61 days. Our study raises the question about the value of systematic histological analysis of the PS specimen. PMID- 29146395 TI - Correlation between intraoperative proximal segment rotation and post-sagittal split ramus osteotomy relapse: a three-dimensional cone beam computed tomography study. AB - This study evaluated the effects of proximal segment rotation and the extent of mandibular setback on post-sagittal split ramus osteotomy (SSRO) relapse using three-dimensional (3D) analysis. Thirty-one patients diagnosed with a skeletal class III malocclusion who underwent SSRO alone were enrolled in this study. The movements of the mandibular condyles were assessed using cone beam computed tomography (CBCT) and a 3D imaging program at <=1 month before the operation (T0), 1 week after the operation (T1), and 6 months (T2) and 1year (T3) postoperative. Yaw and roll were increased at T1 as compared to T0. However, the proximal segments reverted to their original positions between T2 and T3. There was a positive correlation between the extent of the posterior movement of the mandible and relapse at 6 months and 1year postoperative. Although the proximal bone segments showed displacement in three dimensions at T1, they reverted to their original positions over time. In addition, although there was a positive correlation between the extent of the posterior movement of the mandible and the occurrence of post-surgical relapse at 6 months and 1year post-surgery, the rotation of the proximal bone segment during surgery had no relationship with postoperative relapse. PMID- 29146396 TI - Effect of implant loading protocols on failure and marginal bone loss with unsplinted two-implant-supported mandibular overdentures: systematic review and meta-analysis. AB - The aim of this study was to compare implant failure and radiographic bone level changes with different loading protocols for unsplinted two-implant-supported mandibular overdentures. An electronic search of two databases (PubMed, Cochrane Library) was performed, without language restriction, to identify randomized controlled trials (RCTs) comparing immediate or early versus conventional dental implant loading protocols for unsplinted two-implant-supported mandibular overdentures. Data were extracted independently by two reviewers. The Cochrane tool was used to assess the quality of included studies. A meta-analysis was performed. Eight RCTs were identified, seven of which were included; one trial was excluded because related outcomes were not measured. Four of the seven studies were considered to have a high risk of bias and three an unclear risk. Meta-analysis revealed no difference between immediate versus conventional or early versus conventional implant loading protocols regarding implant failure (risk difference (RD) -0.02, 95% confidence interval (CI) -0.13 to 0.10; RD 0.09, 95% CI -0.03 to 0.20) or marginal bone loss (mean difference (MD) 0.09, 95% CI 0.10 to 0.28; MD -0.05, 95% CI -0.12 to 0.02) for implants supporting mandibular overdentures. These findings should be interpreted with great caution given the serious numerical limitations of the studies included. PMID- 29146397 TI - Temporal evolution of the environmental performance of implementing selective collection in municipal waste management systems in developing countries: A Brazilian case study. AB - The aim of this study is to analyse the evolution of the municipal solid waste management system of Joao Pessoa (Brazil), which was one of the Brazilian pioneers cities in implementing door-to-door selective collection programmes, in order to analyse the effect of policy decisions adopted in last decade with regard to selective collection. To do it, this study focuses on analysing the evolution, from 2005 to 2015, of the environmental performance of the municipal solid waste management (MSWM) system implemented in different sorting units with selective collection programmes by applying the Life Cycle Assessment (LCA) methodology and using as a starting point data collected directly from the different stakeholders involved in the MSWM system. This article presents the temporal evolution of environmental indicators measuring the environmental performance of the MSWM system implemented in Joao Pessoa by sorting unit, for each stage of the life cycle of the waste (collection, classification, intermediate transports, recycling and landfilling), for each waste fraction and for each collection method (selective collection or mixed collection), with the aim of identifying the key aspects with the greatest environmental impact and their causes. Results show on one hand, that environmental behaviour of waste management in a door-to-door selective collection programme significantly improves the behaviour of the overall waste management system. Consequently, the potential to reduce the existing environmental impact based on citizens' increased participation in selective collection is evidenced, so the implementation of awareness-raising campaigns should be one of the main issues of the next policies on solid waste. On the other hand, increasing the amount of recyclable wastes collected selectively, implementing alternative methods for valorising the organic fraction (compost/biomethanization) and improving the efficiency of the transportation stage by means of optimizing vehicles or routes, are essential actions to reduce the overall net environmental impact generated by the MSWM system. PMID- 29146398 TI - Improving logistic efficiency of WEEE collection through dynamic scheduling using simulation modeling. AB - The complexity of collection systems for Waste from Electric and Electronic Equipment (WEEE) in the EU is increasing, due to the latest directive that sets new collection targets and modes. The high variability and the uncertainty of reverse flows require innovative logistic approaches. One recent option for increasing efficiency and responsiveness in waste collection services, boosted by new technological solutions for waste level monitoring, is to adopt a dynamic collection scheme, where the collection frequency is not established a priori (based on a fixed plan), but it is based on the actual filling levels of waste bins. This option can allow the service provider to plan the collection service following the actual demand, resulting in a more responsive service, while improving the logistic efficiency. This paper evaluates the implementation of dynamic scheduling schemes for the collection of WEEE. A hybrid simulation model has been developed in order to support researchers and practitioners in assessing quantitative impacts of adopting dynamic scheduling in WEEE collection. Three logistic alternatives (a fixed collection schedule scheme, a pure dynamic scheme and a mixed one) have been compared in a test case based on data of an Italian municipality; collection services for different types of WEEE (i.e. large appliances and small items) have been analyzed. Results show a promising performance of dynamic schedules compared to the fixed one, revealing, for the specific test case, how a mixed solution can combine the advantages of dynamic and fixed scheduling, gaining flexibility towards customer demand while improving truck resource utilization. PMID- 29146399 TI - Label-free discrimination analysis of de-differentiated vascular smooth muscle cells, mesenchymal stem cells and their vascular and osteogenic progeny using vibrational spectroscopy. AB - The accumulation of vascular smooth muscle (SMC)-like cells and stem cell-derived myogenic and osteogenic progeny contributes significantly to arteriosclerotic disease. This study established whether label-free vibrational spectroscopy can discriminate de-differentiated 'synthetic' SMCs from undifferentiated stem cells and their myogenic and osteogenic progeny in vitro, compared with conventional immunocytochemical and genetic analyses. TGF-beta1- and Jagged1-induced myogenic differentiation of CD44+ mesenchymal stem cells was confirmed in vitro by immunocytochemical analysis of specific SMC differentiation marker expression (alpha-actin, calponin and myosin heavy chain 11), an epigenetic histone mark (H3K4me2) at the myosin heavy chain 11 locus, promoter transactivation and mRNA transcript levels. Osteogenic differentiation was confirmed by alizarin red staining of calcium deposition. Fourier Transform Infrared (FTIR) maps facilitated initial screening and discrimination while Raman spectroscopy of individual cell nuclei revealed specific spectral signatures of each cell type in vitro, using Principal Components Analysis (PCA). PCA fed Linear Discriminant Analysis (LDA) enabled quantification of this discrimination and the sensitivity and specificity value was determined for all cell populations based on a leave one-out cross validation method and revealed that de-differentiated SMCs and stem cell derived myogenic progeny in culture shared the greatest similarity. FTIR and Raman spectroscopy discriminated undifferentiated stem cells from both their myogenic and osteogenic progeny. The ability to detect stem cell-derived myogenic progeny using label-free platforms in situ may facilitate interrogation of these important phenotypes during vascular disease progression. PMID- 29146400 TI - Extended adjuvant therapy in patients with HER2-positive breast cancer: some answers, even more questions. PMID- 29146402 TI - Rebuttal From Drs Bertolaccini and Solli. PMID- 29146403 TI - Rebuttal From Drs D'Andrilli and Rendina. PMID- 29146404 TI - COUNTERPOINT: Should Segmentectomy Rather Than Lobectomy Be the Operation of Choice for Early-Stage Non-small Cell Lung Cancer? No. PMID- 29146405 TI - POINT: Should Segmentectomy Rather Than Lobectomy Be the Operation of Choice for Early-Stage Non-small Cell Lung Cancer? Yes. PMID- 29146406 TI - Central nervous involvement by chronic lymphocytic leukaemia. AB - Inclusion of the central nervous system (CNS) in the course of chronic lymphocytic leukaemia (CLL) is rare. At the moment no risk factors or proven treatment methods are known. The disease is described both in its early phase and during its acceleration period, thus it has been suggested that there might be independent mechanisms influencing the development of this condition. As there are no unified diagnostic procedure algorithms each patient needs to be assessed individually. CLL can manifest mostly in elderly people, for whom a possibility of development of neurological disorders with their aetiology different from leukaemia, should also be taken into consideration. The thesis presents a group of seven patients with CLL with CNS infiltration. Patients with prolymphocytic leukaemia, Richter's transformation and the original location of leukemic infiltration within the eye socket constitute an especially interesting case. PMID- 29146407 TI - [Hemogram profile and interest of pre-donation hemoglobin measurement in blood donors in the northwest region of Morocco]. AB - BACKGROUND: Blood donation in Morocco and more particularly in the northwest region is carried out without prior determination of the pre-donation hemoglobin. In addition, we note the lack of scientific research that reports data on the red blood cells, leukocytes and platelet lines in donated blood at the regional or even national level. AIMS: To study hemogram profile in blood donors taken from the Northwest region of Morocco in order to provide decision makers of the National Center of Blood Transfusion and Hematology with valid scientific arguments to complete the criteria to donate whole blood, by the hemogram. METHODS: Prospective study, conducted in 15797 volunteer blood donors (BD) aged between 18 and 60 years, collected during mobile or fixed collections carried out by the Regional Blood Transfusion Center of Tangier and Tetouan from November 2014 to May 2016. The hemogram was performed using a Sysmex KX21N(r) and the analysis of the data was done by the software SPSS 20.0. RESULTS: According to the World Health Organization, anemia corresponds to a hemoglobin level less than 12g/dL in women and less than 13g/dL in men. We found that 14.5 % of women (n=1054) and 3.0 % of men (n=245) were anemic and anemia was hypochromic microcytic in 58,66 % of these BD. Analysis of the white line showed leucopenia in 2.05 % of BD and 807 cases of leukocytosis (5.27 % of BD). Platelet study showed thrombocytopenia in 3.97 % of BD and thrombocytosis in 151BD (0.99 % of cases). CONCLUSION: This study shows the interest of systematic pre-donation hemoglobin measurement and periodic realization of the hemogram among BD in the Northwest region of Morocco. PMID- 29146408 TI - Paroxetine blunts the corticosterone response to swim-induced stress and increases depressive-like behavior in a rat model of postpartum depression. AB - Perinatal depression (PND) affects 15% of women. During the perinatal period both stress- and gonadal hormones fluctuate widely. Putatively, these fluctuations are involved in PND disease mechanisms. The serotonin system is sensitive to such hormone fluctuations, and serotonin reuptake inhibitors (SSRIs) are used to treat PND, although treatment is suboptimal and it is not known at which peripartum time-point SSRI treatment may be most efficacious. In this study, we investigate the effect of the SSRI paroxetine (5mg/kgs.c.) on swim stress-induced corticosterone in a rat model of postpartum depression. In the rat model corticosterone (CORT; 40mg/kgs.c.) was administered in Sprague Dawley rats across postpartum day (PD)2 to PD14. Stress response was measured during the first exposure to the forced swim test (FST1), and depressive-like behavior was measured in both FST1 and FST2. We found that paroxetine completely blunted the swim stress-induced CORT response and increased depressive-like behavior in both FST1 and FST2. Our findings suggest that in the postpartum context, SSRIs compromise stress axis dynamics, which are needed for a healthy stress response. This is likely unfavorable for reversing depressive-like behavior and may provide a rationale for augmentation strategies beyond SSRIs alone to optimize the clinical management of PND. PMID- 29146409 TI - Safety and Effectiveness of Long-Term Treatment with Lurasidone in Older Adults with Bipolar Depression: Post-Hoc Analysis of a 6-Month, Open-Label Study. AB - OBJECTIVE: To evaluate the safety and effectiveness of 6 months of treatment with lurasidone in older adults with a diagnosis of bipolar I depression. DESIGN: Post hoc analysis of a multicenter, 6-month, open-label extension study. SETTING: Outpatient. PARTICIPANTS: Patients aged 55 to 75 years with a DSM-IV-TR diagnosis of bipolar I depression who had completed 6 weeks of double-blind, placebo controlled treatment with either lurasidone monotherapy (1 study) or adjunctive therapy with lithium or valproate (2 studies). INTERVENTION: Flexible doses of lurasidone, 20 to 120 mg/day, either as monotherapy, or adjunctive with lithium or valproate. MEASUREMENTS: Effectiveness was assessed using the Montgomery Asberg Depression Rating Scale (MADRS; change from open-label-baseline to month 6, observed case analysis). RESULTS: A total of 141 older adults entered the extension study (monotherapy, N = 55; 39%; adjunctive therapy, N = 86; 61%). At the end of 6 months of open-label treatment with lurasidone, as monotherapy or adjunctive therapy, minimal changes were observed in the older adult sample in mean weight (-1.0 kg and -0.4 kg, respectively); and median total cholesterol ( 2.0 mg/dL and +6.0 md/dL, respectively), triglycerides (+2.5 mg/dL and +6.0 mg/dL, respectively), and HbA1c (0.0% and -0.1%, respectively). Patients treated with 6 months of lurasidone showed a mean improvement on the MADRS in both the monotherapy (-6.2) and adjunctive therapy (-6.7) groups. CONCLUSIONS: Results of these post-hoc analyses found that up to 7.5 months of lurasidone treatment for bipolar depression in older adults was associated with minimal effects on weight and metabolic parameters, with low rates of switching to hypomania or mania, and was well tolerated. The antidepressant effectiveness of lurasidone in this age group was maintained over the 6-month treatment period. PMID- 29146410 TI - CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis. AB - OBJECTIVE: The cocaine- and amphetamine-regulated transcript (CART) codes for a pivotal neuropeptide important in the control of appetite and energy homeostasis. However, limited understanding exists for the defined effector sites underlying CART function, as discrepant effects of central CART administration have been reported. METHODS: By combining Cart-cre knock-in mice with a Cart adeno associated viral vector designed using the flip-excision switch (AAV-FLEX) technology, specific reintroduction or overexpression of CART selectively in CART neurons in the arcuate nucleus (Arc) and lateral hypothalamic area (LHA), respectively, was achieved. The effects on energy homeostasis control were investigated. RESULTS: Here we show that CART neuron-specific reintroduction of CART into the Arc and LHA leads to distinct effects on energy homeostasis control. Specifically, CART reintroduction into the Arc of otherwise CART deficient Cartcre/cre mice markedly decreased fat mass and body weight, whereas CART reintroduction into the LHA caused significant fat mass gain and lean mass loss, but overall unaltered body weight. The reduced adiposity in ArcCART;Cartcre/cre mice was associated with an increase in both energy expenditure and physical activity, along with significantly decreased Npy mRNA levels in the Arc but with no change in food consumption. Distinctively, the elevated fat mass in LHACART;Cartcre/cre mice was accompanied by diminished insulin responsiveness and glucose tolerance, greater spontaneous food intake, and reduced energy expenditure, which is consistent with the observed decrease of brown adipose tissue temperature. This is also in line with significantly reduced tyrosine hydroxylase (Th) and notably increased corticotropin-releasing hormone (Crh) mRNA expressions in the paraventricular nucleus (PVN). CONCLUSIONS: Taken together, these results identify catabolic and anabolic effects of CART in the Arc and LHA, respectively, demonstrating for the first time the distinct and region-specific functions of CART in controlling feeding and energy homeostasis. PMID- 29146411 TI - Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha. AB - BACKGROUND: Peroxisome proliferator-activated receptor alpha (PPARA) is a major regulator of fatty acid oxidation and severe hepatic steatosis occurs during acute fasting in Ppara-null mice. Thus, PPARA is considered an important mediator of the fasting response; however, its role in other fasting regiments such as every-other-day fasting (EODF) has not been investigated. METHODS: Mice were pre conditioned using either a diet containing the potent PPARA agonist Wy-14643 or an EODF regimen prior to acute fasting. Ppara-null mice were used to assess the contribution of PPARA activation during the metabolic response to EODF. Livers were collected for histological, biochemical, qRT-PCR, and Western blot analysis. RESULTS: Acute fasting activated PPARA and led to steatosis, whereas EODF protected against fasting-induced hepatic steatosis without affecting PPARA signaling. In contrast, pretreatment with Wy-14,643 did activate PPARA signaling but did not ameliorate acute fasting-induced steatosis and unexpectedly promoted liver injury. Ppara ablation exacerbated acute fasting-induced hypoglycemia, hepatic steatosis, and liver injury in mice, whereas these detrimental effects were absent in response to EODF, which promoted PPARA-independent fatty acid metabolism and normalized serum lipids. CONCLUSIONS: These findings indicate that PPARA activation prior to acute fasting cannot ameliorate fasting-induced hepatic steatosis, whereas EODF induced metabolic adaptations to protect against fasting induced steatosis without altering PPARA signaling. Therefore, PPARA activation does not mediate the metabolic adaptation to fasting, at least in preventing acute fasting-induced steatosis. PMID- 29146412 TI - Skeletal muscle overexpression of nicotinamide phosphoribosyl transferase in mice coupled with voluntary exercise augments exercise endurance. AB - OBJECTIVE: Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway that produces nicotinamide adenine dinucleotide (NAD+), an essential co-substrate regulating a myriad of signaling pathways. We produced a mouse that overexpressed NAMPT in skeletal muscle (NamptTg) and hypothesized that NamptTg mice would have increased oxidative capacity, endurance performance, and mitochondrial gene expression, and would be rescued from metabolic abnormalities that developed with high fat diet (HFD) feeding. METHODS: Insulin sensitivity (hyperinsulinemic-euglycemic clamp) was assessed in NamptTg and WT mice fed very high fat diet (VHFD, 60% by kcal) or chow diet (CD). The aerobic capacity (VO2max) and endurance performance of NamptTg and WT mice before and after 7 weeks of voluntary exercise training (running wheel in home cage) or sedentary conditions (no running wheel) were measured. Skeletal muscle mitochondrial gene expression was also measured in exercised and sedentary mice and in mice fed HFD (45% by kcal) or low fat diet (LFD, 10% by kcal). RESULTS: NAMPT enzyme activity in skeletal muscle was 7-fold higher in NamptTg mice versus WT mice. There was a concomitant 1.6-fold elevation of skeletal muscle NAD+. NamptTg mice fed VHFD were partially protected against body weight gain, but not against insulin resistance. Notably, voluntary exercise training elicited a 3 fold higher exercise endurance in NamptTg versus WT mice. Mitochondrial gene expression was higher in NamptTg mice compared to WT mice, especially when fed HFD. Mitochondrial gene expression was higher in exercised NamptTg mice than in sedentary WT mice. CONCLUSIONS: Our studies have unveiled a fascinating interaction between elevated NAMPT activity in skeletal muscle and voluntary exercise that was manifest as a striking improvement in exercise endurance. PMID- 29146413 TI - CT fluoroscopy-guided core needle biopsy of anterior mediastinal masses. AB - OBJECTIVE: To retrospectively evaluate the safety, diagnostic yield, and risk factors of diagnostic failure of computed tomography (CT) fluoroscopy-guided biopsies of anterior mediastinal masses. MATERIALS AND METHODS: Biopsy procedures and results of anterior mediastinal masses in 71 patients (32 women/39 men; mean [+/-standard deviation] age, 53.8+/-20.0years; range, 14-88years) were analyzed. Final diagnoses were based on surgical outcomes, imaging findings, or clinical follow-up findings. The biopsy results were compared with the final diagnosis, and the biopsy procedures grouped by pathologic findings into diagnostic success and failure groups. Multiple putative risk factors for diagnostic failure were then assessed. RESULTS: Seventy-one biopsies (71 masses; mean size, 67.5+/ 27.3mm; range 8.6-128.2mm) were analyzed. We identified 17 grade 1 and one grade 2 adverse events (25.4% overall) according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Sixty-nine biopsies (97.2%) provided samples fit for pathologic analysis. Diagnostic failure was found for eight (11.3%) masses; the 63 masses diagnosed successfully included thymic carcinoma (n=17), lung cancer (n=14), thymoma (n=12), malignant lymphoma (n=11), germ cell tumor (n=3), and others (n=6). Using a thinner needle (i.e., a 20-gauge needle) was the sole significant risk factor for diagnostic failure (P=0.039). CONCLUSION: CT fluoroscopy-guided biopsy of anterior mediastinal masses was safe and had a high diagnostic yield; however, using a thinner biopsy needle significantly increased the risk of a failed diagnosis. PMID- 29146414 TI - Predicting Chronic Climate-Driven Disturbances and Their Mitigation. AB - Society increasingly demands the stable provision of ecosystem resources to support our population. Resource risks from climate-driven disturbances, including drought, heat, insect outbreaks, and wildfire, are growing as a chronic state of disequilibrium results from increasing temperatures and a greater frequency of extreme events. This confluence of increased demand and risk may soon reach critical thresholds. We explain here why extreme chronic disequilibrium of ecosystem function is likely to increase dramatically across the globe, creating no-analog conditions that challenge adaptation. We also present novel mechanistic theory that combines models for disturbance mortality and metabolic scaling to link size-dependent plant mortality to changes in ecosystem stocks and fluxes. Efforts must anticipate and model chronic ecosystem disequilibrium to properly prepare for resilience planning. PMID- 29146415 TI - Response to reader's comments - The misleading electrocardiogram - Midventricular Takotsubo masquerading as anterior wall STEMI. PMID- 29146417 TI - Association between percutaneous hemodynamic support device and survival from cardiac arrest in the state of Michigan. AB - INTRODUCTION: The role of circulatory support in the post-cardiac arrest period remains controversial. Our objective was to investigate the association between treatment with a percutaneous hemodynamic support device and outcome after admission for cardiac arrest. METHODS: We performed a retrospective study of adult patients with admission diagnosis of cardiac arrest or ventricular fibrillation (VF) from the Michigan Inpatient Database, treated between July 1, 2010, and June 30, 2013. Patient demographics, clinical characteristics, treatments, and disposition were electronically abstracted based on ICD-9 codes at the hospital level. Mixed-effects logistic regression models were fit to test the effect of percutaneous hemodynamic support device defined as either percutaneous left ventricular assist device (pLVAD) or intra-aortic balloon pump (IABP) on survival. These models controlled for age, sex, VF, myocardial infarction (MI), and cardiogenic shock with hospital modeled as a random effect. RESULTS: A total of 103 hospitals contributed 4393 patients for analysis, predominately male (58.8%) with a mean age of 64.1years (SD 15.5). On univariate analysis, younger age, male sex, VF as the initial rhythm, acute MI, percutaneous coronary intervention, percutaneous hemodynamic support device, and absence of cardiogenic shock were associated with survival to discharge (each p<0.001). Mixed-effects logistic regressions revealed use of percutaneous hemodynamic support device was significantly associated with survival among all patients (OR 1.8 (1.28-2.54)), and especially in those with acute MI (OR 1.95 (1.31-2.93)) or cardiogenic shock (OR 1.96 (1.29-2.98)). CONCLUSION: Treatment with percutaneous hemodynamic support device in the post-arrest period may provide left ventricular support and improve outcome. PMID- 29146416 TI - Fulminant adrenergic myocarditis complicated by pulmonary edema, cardiogenic shock and cardiac arrest. AB - Adrenergic myocarditis is an uncommon presentation of pheochromocytoma and extremely rare cause of de novo acute heart failure (AHF). We present a case of a 31-year-old Caucasian woman with a history of hypertension and recurrent occipital headaches who was admitted to the emergency department due to severe de novo AHF presenting as pulmonary edema and cardiogenic shock. During the hospital admission the patient experienced asystolic cardiac arrest and was successfully resuscitated, intubated, and mechanically ventilated. Bedside transthoracic echocardiography revealed severe diffuse left ventricular hypokinesis with ejection fraction (LVEF) of 10%. Coronary angiography disclosed normal epicardial coronary arteries. The diagnosis of fulminant myocarditis was based on clinical, laboratory and imaging findings including cardiac magnetic resonance imaging (cMRI) Lake Louise criteria. STIR-cMRI sequences revealed myocardial edema in the lateral, inferior and posterior walls of the left ventricle, whereas T1-weighted early contrast-enhanced sequences showed myocardial hyperemia and capillary leak. An ultrasound and computed tomographic scan of the abdomen disclosed a solid, heterogeneous mass (3.6*3.2*2.8-cm) in the right suprarenal area. Urinary and plasma catecholamines and metanephrines were markedly elevated. A pheochromocytoma was suspected and laparoscopic resection of the tumor was performed after pharmacological preparation with phenoxybenzamine. The histopathological findings were consistent with pheochromocytoma. Follow-up cMRI showed complete reversal of myocardial edema and hyperemia. At 12-month follow up, the patient has remained asymptomatic and normotensive with no recurrence of cardiovascular symptoms. PMID- 29146418 TI - Diagnostic accuracy of the Extended Focused Abdominal Sonography for Trauma (E FAST) performed by emergency physicians compared to CT. AB - INTRODUCTION: The diagnostic accuracy of the FAST exam performed by EM residents were shown to be similar to radiology residents. However, in the last 2 decades, an extended-FAST (E-FAST) protocol including thoracic examination to exclude pneumo- and hemothorax was introduced. The accuracy of emergency physicians (EPs) while performing E-FAST is a less studied area, especially in Europe. The aim of this study was to compare the diagnostic accuracy of the E-FAST exam performed by EM residents with the results of CT scan as a gold standard. METHODS: This was a prospective, observational, diagnostic accuracy study conducted at the ED of a Level 1 Trauma Center. All consecutive adult multiple trauma patients were eligible, and any patient in whom thoraco-abdominal CT was ordered were recruited. Unstable and unavailable patients were excluded. E-FAST examination was performed by EPs as the index test, and CT examinations reported by a blinded academic radiology faculty was the gold standard. RESULTS: A total of 140 patients were recruited from eligible 144 patients. The final study population was 132 for abdominal and 130 for thorax examinations. In this study, AUC of E FAST was 0.71 for abdominal free fluid, 0.87 for pneumothorax and 1.00 for pleural effusion. The sensitivity was 42.9% and specificity was 98.4%. The +LR for abdominal free fluid was 26.8 and -LR was 0.58. CONCLUSION: E-FAST examination has an excellent specificity. However, the sensitivity of the test is not high enough to rule-out thoraco-abdominal injuries in trauma patients when performed by EPs. PMID- 29146401 TI - Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. AB - BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (>=20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or >=4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5.2 years (IQR 2.1-5.3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0.73, 95% CI 0.57-0.92, p=0.0083). The 5-year invasive disease-free survival was 90.2% (95% CI 88.3-91.8) in the neratinib group and 87.7% (85.7 89.4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events. FUNDING: Wyeth, Pfizer, and Puma Biotechnology. PMID- 29146419 TI - Syncope on presentation is a surrogate for submassive and massive acute pulmonary embolism. AB - INTRODUCTION: There are conflicting data regarding the prognostic value of syncope in patients with acute pulmonary embolism (APE). METHODS: We retrospectively reviewed data of 552 consecutive adults with computed tomography pulmonary angiogram-confirmed APE to determine the correlates and outcome of the occurrence of syncope at the time of presentation. RESULTS: Among 552 subjects with APE (mean age 54years, 47% men), syncope occurred in 12.3% (68/552). Compared with subjects without syncope, those with syncope were more likely to have admission systolic blood pressure<90mmHg (odds ratio (OR) 5.788, P<0.001), and an oxygen saturation<88% on room air (OR 5.560, P<0.001), right ventricular dilation (OR 2.480, P=0.006), right ventricular hypokinesis (OR 2.288, P=0.018), require mechanical ventilation for respiratory failure (OR 3.152, P=0.014), and more likely to receive systemic thrombolysis (OR 4.722, P=0.008). On multivariate analysis, syncope on presentation was an independent predictor of a massive APE (OR 2.454, 95% CI 1.109-5.525, P=0.03) after adjusting for patients' age, sex, requirement of antibiotics throughout hospitalization, peak serum creatinine, admission oxygen saturation<88% and admission heart rate>100bpm. There was no difference in mortality in cases with APE with or without syncope (P=0.412). CONCLUSION: Syncope at the onset of pulmonary embolization is a surrogate for submassive and massive APE but is not associated with higher in-hospital mortality. PMID- 29146420 TI - ECMO used successfully in a near fatal case of opioid-induced acute respiratory distress syndrome. AB - Acute Respiratory Distress Syndrome (ARDS) was first recognized during the 1960s. It is a distinct type of hypoxemic respiratory failure characterized by acute abnormality of both lungs. Extracorporeal membrane oxygenation (ECMO) is being increasingly used for patients with severe ARDS refractory to otherwise conventional management. A 29year old male arrived with Emergency Medical Services (EMS) status post presumed heroin overdose. He was administered Naloxone 2mg intravenously prior to arrival in the emergency department. The patient arrived in severe respiratory distress with a pulse oximetry level of 50% and was immediately intubated. The patient's pulse oximetry level remained in the seventies despite intubation and aggressive ventilator management. The Intensive Care Unit team in conjunction with cardiothoracic surgery initiated venovenous ECMO therapy in the emergency department itself. The patient was transferred to a tertiary center for venoarterial ECMO that was continued for 6 more days. After an extensive hospitalization, the patient was ultimately transferred to an acute medical rehabilitation center. With the current opioid crisis, emergency physicians and providers need to be aware that opioids can induce severe ARDS refractory to mechanical ventilation. ECMO as a treatment option can be used safely and successfully as described in this unique patient case report. PMID- 29146421 TI - Scene time interval in out-of-hospital cardiac arrest: It is time to measure time until patient contact. PMID- 29146422 TI - Numerical study of the effect of soft layer properties on bacterial electroporation. AB - We present a numerical model of electroporation in a gram-positive bacterium, which accounts for the presence of a negatively charged soft polyelectrolyte layer (which may include a periplasmic space, peptidoglycan layer, cilia, flagella, and other surface appendages) surrounding its plasma membrane. We model the ion transport within and outside the soft layer using the soft layer electrokinetics-based Poisson-Nernst-Planck formalism. Additionally, we model the electroporation dynamics on the plasma membrane using the pore nucleation-based electroporation formalism developed by Krassowska and Filev. We find that ion transport within the soft layer (surface conduction), which depends on the relative importance of the soft layer charged group concentration compared to the buffer concentration, significantly alters the transmembrane voltage across the plasma membrane and hence the pore characteristics. Our numerical simulations suggest that surface conduction significantly lowers the pore number in the plasma membrane. This observation is consistent with experimental studies that show that gram-positive bacteria, in general, have lower transformation efficiencies compared to gram-negative bacteria. Our studies highlight a strong dependence of bacterial electroporation on cell envelope properties and buffer conditions, which need to be taken into consideration when designing electroporation protocols. PMID- 29146423 TI - Comprehensive lipidomic analysis of human plasma using multidimensional liquid- and gas-phase separations: Two-dimensional liquid chromatography-mass spectrometry vs. liquid chromatography-trapped-ion-mobility-mass spectrometry. AB - Recent advancements in separation science have resulted in the commercialization of multidimensional separation systems that provide higher peak capacities and, hence, enable a more-detailed characterization of complex mixtures. In particular, two powerful analytical tools are increasingly used by analytical scientists, namely online comprehensive two-dimensional liquid chromatography (LC*LC, having a second-dimension separation in the liquid phase) and liquid chromatography-ion mobility-spectrometry (LC-IMS, second dimension separation in the gas phase). The goal of the current study was a general assessment of the liquid-chromatography-trapped-ion-mobility-mass spectrometry (LC-TIMS-MS) and comprehensive two-dimensional liquid chromatography-mass spectrometry (LC*LC-MS) platforms for untargeted lipid mapping in human plasma. For the first time trapped-ion-mobility spectrometry (TIMS) was employed for the separation of the major lipid classes and ion-mobility-derived collision-cross-section values were determined for a number of lipid standards. The general effects of a number of influencing parameters have been inspected and possible directions for improvements are discussed. We aimed to provide a general indication and practical guidelines for the analyst to choose an efficient multidimensional separation platform according to the particular requirements of the application. Analysis time, orthogonality, peak capacity, and an indicative measure for the resolving power are discussed as main characteristics for multidimensional separation systems. PMID- 29146424 TI - Graphene deposited onto aligned zinc oxide nanorods as an efficient coating for headspace solid-phase microextraction of gasoline fractions from oil samples. AB - The content of gasoline fraction in oil samples is not only an important indicator of oil quality, but also an indispensable fundamental data for oil refining and processing. Before its determination, efficient preconcentration and separation of gasoline fractions from complicated matrices is essential. In this work, a thin layer of graphene (G) was deposited onto oriented ZnO nanorods (ZNRs) as a SPME coating. By this approach, the surface area of G was greatly enhanced by the aligned ZNRs, and the surface polarity of ZNRs was changed from polar to less polar, which were both beneficial for the extraction of gasoline fractions. In addition, the ZNRs were well protected by the mechanically and chemically stable G, making the coating highly durable for use. With headspace SPME (HS-SPME) mode, the G/ZNRs coating can effectively extract gasoline fractions from various oil samples, whose extraction efficiency achieved 1.5-5.4 and 2.1-8.2 times higher than those of a G and commercial 7-MUm PDMS coating respectively. Coupled with GC-FID, the developed method is sensitive, simple, cost effective and easily accessible for the analysis of gasoline fractions. Moreover, the method is also feasible for the detection of gasoline markers in simulated oil-polluted water, which provides an option for the monitoring of oil spill accident. PMID- 29146426 TI - Determination of phthalic acid esters in water samples using core-shell poly(dopamine) magnetic nanoparticles and gas chromatography tandem mass spectrometry. AB - In this work, the first application of core-shell poly(dopamine) magnetic nanoparticles as sorbent for the extraction of a group of eleven phthalic acid esters of interest (i.e. diethyl phthalate (DEP), dipropyl phthalate (DPP), dibutyl phthalate (DBP), bis-isopentyl phthalate (DIPP), bis-n-pentyl phthalate (DNPP), benzylbutyl phthalate (BBP), dicyclohexyl phthalate (DCHP), di-(2 ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DNOP), diisononyl phthalate (DINP) and diisodecyl phthalate (DIDP)) and one adipate (bis (2-ethylhexyl) adipate, DEHA) from different water samples (Milli-Q, mineral, tap, pond and waste water) is proposed. Analysis were carried out by gas chromatography triple quadrupole tandem mass spectrometry. Parameters that affect the extraction performance were optimized following a step by step approach, being the optimum conditions the extraction of water at pH 6, with 60mg of sorbent and the elution with 6mL of dichloromethane. The methodology was validated for the five selected water samples using DBP-d4 as internal standard. Determination coefficients of matrix-matched calibration curves were above 0.9904 in all cases while relative recovery values ranged between 71 and 120%, with relative standard deviation values below 19%. The limits of quantification of the method ranged between 9 and 20ng/L. Matrix effects were found for most analytes and water samples. Real water samples were also analyzed, finding DEP and DBP at concentrations below 4.20 and 1.23MUg/L, respectively, in mineral, tap and waste water. DCHP, DEHP and BBP were also found in some of the samples at concentrations below the LOQs of the method. PMID- 29146425 TI - Unprecedented sensitivity of the planar yeast estrogen screen by using a spray-on technology. AB - The planar yeast estrogen screen (p-YES) can serve as a highly valuable and sensitive screening tool for the detection of estrogenic compounds in various sample matrices such as water and wastewater, personal care products and foodstuff. The method combines the separation of sample constituents by thin layer chromatography with the direct detection of estrogenic compounds on the surface of the HPTLC-plate. The previous protocol using the immersion of a normal phase silica HPTLC-plate in a cell suspension for bio-autography resulted in blurred signals due to the accelerated diffusion of compounds on the wet surface of the HPTLC-plate. Here, the application of the yeast cells by spraying on the surface of the HPTLC-plate is described as an alternative approach. The presented method for the hyphenation of normal phase thin layer chromatography with a yeast estrogen screen results in much sharper signals compared to reports in previous publications. Satisfying results were achieved using cultures with cell densities of 1000 FAU. Due to the reduced signal broadening, lower limits of quantification for estrogenic compounds were achieved (Estrone (E1)=2pg/zone, 17beta-estradiol (E2)=0.5pg/zone, 17alpha-ethinylestradiol (EE2)=0.5pg/zone and Estriol (E3)=20pg/zone). As demonstrated, it is possible to characterize profiles of estrogenic activity of wastewater samples with high quality and reproducibility. The improved sensitivity opens the stage for applications using native samples from waste- or even surface water directly applied on HPTLC-plates without the need for prior sample treatment by e.g. solid phase extraction. PMID- 29146427 TI - Applicability of retention modelling in hydrophilic-interaction liquid chromatography for algorithmic optimization programs with gradient-scanning techniques. AB - Computer-aided method-development programs require accurate models to describe retention and to make predictions based on a limited number of scouting gradients. The performance of five different retention models for hydrophilic interaction chromatography (HILIC) is assessed for a wide range of analytes. Gradient-elution equations are presented for each model, using Simpson's Rule to approximate the integral in case no exact solution exists. For most compound classes the adsorption model, i.e. a linear relation between the logarithm of the retention factor and the logarithm of the composition, is found to provide the most robust performance. Prediction accuracies depended on analyte class, with peptide retention being predicted least accurately, and on the stationary phase, with better results for a diol column than for an amide column. The two-parameter adsorption model is also attractive, because it can be used with good results using only two scanning gradients. This model is recommended as the first-choice model for describing and predicting HILIC retention data, because of its accuracy and linearity. Other models (linear solvent-strength model, mixed-mode model) should only be considered after validating their applicability in specific cases. PMID- 29146428 TI - Preparative fractionation of dextrin by polyethylene glycol: Effects of initial dextrin concentration and pH. AB - Polyethylene glycol (PEG) was further applied for fractionating dextrin prepared from cassava starch. The initial dextrin concentration and pH of the dextrin solutions were crucially considered in this study with the average molecular weight dispersity (DMa) as the index. The results showed that the initial dextrin concentration significantly affected the mass fraction and the molecular weight distribution of each dextrin fraction obtained from gradient PEG precipitation. However, the initial dextrin concentration, which ranged from 0.9% to 3.6%, did not affect the DMa of the dextrin fractions. Furthermore, the DMa of the fractions obtained at pHs 4.00, 4.96, 6.00, 6.92, 7.99, 8.96, and 9.91, was 1.364, 1.341, 1.305, 1.286, 1.273, 1.311, and 1.404, respectively, while the dispersity of the parent dextrin was 2.052. These results suggest that the preparative approach, gradient PEG precipitation, is applicable in acidic, neutral, and alkaline environments, and that a weakly alkaline environment is optimal for dextrin fractionation. PMID- 29146429 TI - Routine screening for Chlamydia trachomatis and Neisseria gonorrhoeae in first trimester abortion. AB - Currently no recommendation exists to collect genital culture for Chlamydia trachomatis and Neisseria gonorrhoeae at diagnosis of spontaneous abortion. A retrospective cross sectional study was performed to identify first trimester abortions with concurrent genital culture collection in an emergency room setting. The results were compared to most current 2015 Center for Disease Control (CDC) statistics. Among women aged 15-24 the rate of C. trachomatis was increased to 20.0% and greater than CDC rate of 6.7% (RR 2.97, p<0.0001). No positive screens for C. trachomatis were found above age 30 and the study rate of N. gonorrhoeae was not significantly elevated. Younger women presenting for miscarriage have high prevalence of C. trachomatis in comparison to 2015 CDC statistics. Routine genital culture could be recommended at diagnosis of first trimester spontaneous abortion. PMID- 29146430 TI - Soil Biodiversity Effects from Field to Fork. AB - Our knowledge of soil biodiversity in agriculture in general is currently increasing rapidly. However, almost all studies have stopped with the quantification of soil biodiversity effects on crops at harvest time, ignoring subsequent processes along the agrifood chain until food arrives on our plates. Here we develop a conceptual framework for the study of such postharvest effects. We present the main mechanisms (direct and indirect) via which soil biodiversity can influence crop quality aspects and give examples of how effects at harvest time may become attenuated through postharvest operations and how biodiversity may also affect some of these operations (i.e., storage) themselves. Future research with a broader focus has the potential to unveil how soil biodiversity may benefit from what ends up on our forks. PMID- 29146431 TI - Database Taxonomics as Key to Modern Plant Biology. AB - The advent of omic technologies opened new and multiple avenues to access higher levels of complexity. Taxonomy - discovering and naming biodiversity - has also entered a taxonomics epoch and serves as a tool not only to name biological diversity, but also to fully explore biological knowledge and to build bridges between disciplines. PMID- 29146432 TI - Predictors of Hospital Length of Stay and 30-Day Readmission in Cervical Spondylotic Myelopathy Patients: An Analysis of 3057 Patients Using the ACS-NSQIP Database. AB - BACKGROUND: Hospital length of stay (LOS), 30-day readmission rate, and other metrics are increasingly being used to evaluate quality of surgical care. The factors most relevant to cervical spondylotic myelopathy (CSM) are not yet established. OBJECTIVE: To identify perioperative factors associated with extended LOS and 30-day readmission following elective surgery for CSM. METHODS: Surgical CSM patients at institutions represented by the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) during 2010 2012 were included. Patients with fracture, 9 or more levels fused, or cancer were excluded. Extended LOS was defined as 75th percentile of the cohort. Univariate analysis and multivariate logistic regression identified predictors for extended LOS, 30-day readmission, and reoperation. Linear regression modeling was used to evaluate variables. RESULTS: Three thousand fifty-seven surgical CSM cases were isolated. Age (odds ratio [OR], 1.496), diabetes (OR, 1.691), American Society of Anesthesiologists (ASA) class (OR, 2.081), posterior surgical approach (OR, 2.695), and operative time (OR, 1.008) were all positive predictors (P < 0.05) for extended LOS (>=4 days). Thirty-two percent of the cohort (976 patients) had 30-day readmission data. Among these, 915 patients were not readmitted (93.8%), while 61 (6.2%) were readmitted. Diabetes (OR, 1.460) and ASA class (OR, 2.539) were significant positive predictors for hospital readmission. Age (OR, 0.918) was a negative predictor of re-operation in readmitted patients, and pulmonary comorbidities (OR, 4.584) were a positive predictor (P < 0.05). CONCLUSIONS: Patients with diabetes and higher ASA class were at increased risk for extended LOS and readmission within 30-days. Patients with increased operative time have greater risk for extended LOS. Preoperative pulmonary comorbidities increased reoperation risk, whereas increased age reduced the risk. Attention to these factors may benefit CSM patients. PMID- 29146433 TI - A Novel Technique for Cervical Facet Joint Hyperplasia-Spondylotic Radiculopathy by Laminar and Lateral Mass Screw Cofixations. AB - OBJECTIVE: We sought to describe the novel technique and report the outcomes of cervical spondylotic radiculopathy caused by facet joint hyperplasia treated with minimally invasive surgery by laminar and lateral mass screw cofixations. METHOD: In this retrospective study, patients with spondylotic radiculopathy caused by facet joint hyperplasia underwent this technique in our unit between January 2010 and June 2015. Hospital charts, magnetic resonance imaging studies, and follow-up records for all the patients were reviewed. Outcomes were assessed on the basis of neurologic status, magnetic resonance imaging, and visual analog scale for neck and radicular pain and by the short form-36 health survey questionnaire. RESULTS: Thirteen men and 5 women, aged 47-73 years (mean, 61.8 years), were included in this study. The follow-up time ranged from 19-50 months (mean, 32.4 months). The mean visual analog scale scores for radicular pain and neck pain, as well as the scores for all 8 domains of the short form-36 health survey questionnaire, showed significant improvements (P < 0.05). Cervical lordosis showed bending, whereas the height of the targeted disk segment showed no change (P > 0.05). Complications included 2 cases of neck pain that lasted for 3 months. CONCLUSION: Minimally invasive surgery by lamina and lateral mass screw cofixation is safe and effective for the treatment of cervical spondylotic radiculopathy caused by facet joint hyperplasia. In addition to sufficient decompression, this technique provides relative stability to the cervical spine. PMID- 29146434 TI - Cerebral Hyperperfusion Syndrome After Endovascular Reperfusion Therapy in a Patient with Acute Internal Carotid Artery and Middle Cerebral Artery Occlusions. AB - BACKGROUND: Cerebral hyperperfusion syndrome (CHS) is known to be a rare but devastating complication of carotid artery revascularization. Because patients with acute ischemic stroke due to acute major cerebral and/or cervical artery occlusion treated with endovascular reperfusion therapy may have impaired autoregulation in the cerebral vasculature, these patients may also develop CHS. Despite the growing number of endovascular reperfusion procedures for acute ischemic stroke, this complication has only rarely been reported. CASE DESCRIPTION: A 77-year-old man developed acute cerebral infarction as the result of occlusions of the right internal carotid artery and right middle cerebral artery. After systemic intravenous injection of recombinant tissue-type plasminogen activator, endovascular reperfusion therapy was initiated. The occluded arteries were successfully recanalized with thrombectomy by using a stent retriever for the middle cerebral artery and stent placement for the origin of the internal carotid artery. However, head computed tomography obtained 12 hours after treatment showed acute intracranial hemorrhage that did not involve the ischemic lesions. Under evaluation with transcranial near-infrared spectroscopy and single-photon emission computed tomography, the hemorrhage was considered to have been caused by CHS after reperfusion therapy. CONCLUSIONS: CHS may lead to unfavorable outcomes after reperfusion therapy for acute ischemic stroke. Recognizing clinical deterioration caused by CHS can be challenging in patients with neurologic disorders of acute ischemic stroke. Therefore, it is important to perform routine monitoring of regional cerebral oxygen saturation by using near-infrared spectroscopy, perform single-photon emission computed tomography promptly to evaluate cerebral blood flow, and maintain strict antihypertensive therapy to prevent CHS after reperfusion therapy. PMID- 29146435 TI - Epidemiology and Management of Spinal Trauma in Children and Adolescents <18 Years Old. AB - OBJECTIVE: This retrospective study reports the epidemiology, clinical aspects, and management of spinal trauma in children and adolescents. METHODS: Multicenter study of 215 cases of spinal trauma in individuals <18 years of age. All patients were submitted to preoperative and postoperative radiologic and clinical evaluation. The fractures were classified according to the AOSpine fracture classification. Neurological evaluation was performed using the Frankel scale at admission to hospital and at the last follow-up. RESULTS: Mean age was 14.7 (+/- 2.5) years and most of the patients were male (72.6%). Falls were responsible for 52.6% of the spinal trauma. Compression fracture was the most common type of fracture, observed in 48.4% of the cases. Most spinal fractures were located at the thoracic level (58.7%). Associated injuries were observed in 37.2% of the cases. The complication rates were 15.8%. Normal neurological examination was observed in 160 cases (74.4%) at the final follow-up. Neurological impairment was mostly observed due to shallow water diving, dislocation fractures types, and fractures located between the lower cervical spine and the thoracic spine. Surgical treatment was performed in 73.8% of the cases. Better neurological outcome was observed in fractures due to falls, fractures located in the upper cervical (C1-C2) and lower lumbar spine injuries (L3-L5). CONCLUSIONS: Surgical treatment is often necessary in children and adolescents after spinal trauma. Higher incidence of spinal cord injury was observed after shallow water diving, fractures located in the lower cervical spine and thoracic spine, and type B and C fractures. PMID- 29146436 TI - Rupture of Intraventricular Hydatid Cyst: Camalote Sign. AB - Only a few cases of intraventricular hydatid cysts have been described. The camalote or water lily sign is described when there is detachment of the endocyst membrane, resulting in a floating appearance like a water lily. This sign has been described most commonly in hepatic cysts. Here, we describe the camalote sign in an iatrogenically ruptured intraventricular hydatid cyst. Rupture of an intraventricular hydatid cyst poses the threat of widespread dissemination and is described in our case. PMID- 29146437 TI - Efficacy of Biomedical Glue Sling Technique Versus Traditional Technique for Microvascular Decompression for Hemifacial Spasm with Refractory Hypertension. AB - BACKGROUND: Microvascular decompression (MVD) is useful treatment for hemifacial spasm (HFS) with refractory hypertension (RHTN). The biomedical glue sling technique is a new method for MVD. In this study, we retrospectively compared the outcome of the biomedical glue sling technique with traditional technique in MVD for HFS with RHTN. METHODS: A retrospective study of HFS with RHTN treated by MVD was conducted between January 2010 and June 2016. Among 155 patients who underwent their first MVD at our institution, traditional technique was performed in 73 cases of patients and the biomedical glue sling technique was performed on 82 patients. RESULTS: At 3 days, 7 days, 1 month, 3 months, and 1 year after MVD surgery, in the traditional technique group the effective rates of MVD for HFS were 86.30%, 84.93%, 87.14%, 84.06%, and 83.33%. The effective rates for RHTN were 68.49%, 67.12%, 65.71%, 57.97%, and 57.58%. The incidence rates of complication were 5.48%, 5.48%, 4.29%, 2.90%, and 3.03%. In the biomedical glue sling technique group, the effective rates of MVD for HFS were 97.56%, 97.56%, 98.75%, 96.15%, and 94.59% (P < 0.05). The effective rates for RHTN were 85.37%, 82.93%, 81.25%, 79.49%, and 75.68% (P < 0.05). The incidence rates of complication were 6.10%, 6.10%, 5.00%, 3.85%, and 2.70% (P > 0.05). CONCLUSION: When HFS is associated with RHTN, the efficacy of the biomedical glue sling technique for MVD is higher than that of the traditional technique for both HFS and RHTN. PMID- 29146438 TI - Biomarkers for risk assessment in paracetamol hepatotoxicity. PMID- 29146440 TI - Clodronate: A Vesicular ATP Release Blocker. AB - Clodronate is a first-generation bisphosphonate used worldwide for antiresorptive therapy for osteoporosis. Although clodronate is analgesic in nature, its mechanism and efficacy were unknown for some time. Recently, clodronate was identified as a selective and potent inhibitor for vesicular nucleotide transporter (VNUT), a transporter responsible for vesicular storage of ATP. Clodronate inhibits vesicular ATP release from neurons and reduces chronic neuropathic and inflammatory pain following blockade of purinergic chemical transmission. Its effectiveness is stronger, faster acting, and longer lasting than that of existing drugs such as pregabalin. Thus, clodronate might be a promising drug for attenuating chronic neuropathic pain and opens a new field of drug discovery as a presynaptic blocker for purinergic chemical transmission. PMID- 29146439 TI - Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies. AB - BACKGROUND: Paracetamol overdose is common but patient stratification is suboptimal. We investigated the usefulness of new biomarkers that have either enhanced liver specificity (microRNA-122 [miR-122]) or provide mechanistic insights (keratin-18 [K18], high mobility group box-1 [HMGB1], and glutamate dehydrogenase [GLDH]). The use of these biomarkers could help stratify patients for their risk of liver injury at hospital presentation. METHODS: Using data from two prospective cohort studies, we assessed the potential for biomarkers to stratify patients who overdose with paracetamol. We completed two independent prospective studies: a derivation study (MAPP) in eight UK hospitals and a validation study (BIOPAR) in ten UK hospitals. Patients in both cohorts were adults (>=18 years in England, >=16 years in Scotland), were diagnosed with paracetamol overdose, and gave written informed consent. Patients who needed intravenous acetylcysteine treatment for paracetamol overdose had circulating biomarkers measured at hospital presentation. The primary endpoint was acute liver injury indicating need for continued acetylcysteine treatment beyond the standard course (alanine aminotransferase [ALT] activity >100 U/L). Receiver operating characteristic (ROC) curves, category-free net reclassification index (cfNRI), and integrated discrimination index (IDI) were applied to assess endpoint prediction. FINDINGS: Between June 2, 2010, and May 29, 2014, 1187 patients who required acetylcysteine treatment for paracetamol overdose were recruited (985 in the MAPP cohort; 202 in the BIOPAR cohort). In the derivation and validation cohorts, acute liver injury was predicted at hospital presentation by miR-122 (derivation cohort ROC-area under the curve [AUC] 0.97 [95% CI 0.95 0.98]), HMGB1 (0.95 [0.93-0.98]), and full-length K18 (0.95 [0.92-0.97]). Results were similar in the validation cohort (miR-122 AUC 0.97 [95% CI 0.95-0.99], HMGB1 0.98 [0.96-0.99], and full-length K18 0.93 [0.86-0.99]). A combined model of miR 122, HMGB1, and K18 predicted acute liver injury better than ALT alone (cfNRI 1.95 [95% CI 1.87-2.03], p<0.0001 in the MAPP cohort; 1.54 [1.08-2.00], p<0.0001 in the BIOPAR cohort). INTERPRETATION: Personalised treatment pathways could be developed by use of miR-122, HMGB1, and full-length K18 at hospital presentation for patient stratification. This prospective study supports their use for hepatic safety assessment of new medicines. FUNDING: Edinburgh and Lothians Health Foundation, UK Medical Research Council. PMID- 29146441 TI - Combining immunotherapies for the treatment of prostate cancer. AB - Sipuleucel-T, a therapeutic dendritic-cell vaccine, was Food and Drug Administration-approved for prostate cancer in 2010. No new immunotherapies for prostate cancer have been approved since. However, novel agents and combination approaches offer great promise for improving outcomes for prostate cancer patients. Here we review the latest developments in immunotherapy for prostate cancer. Sipuleucel-T has demonstrated a survival advantage of 4.1 months in metastatic castration-resistant prostate cancer. PSA-TRICOM (PROSTVAC), a prostate-specific antigen-targeted vaccine platform, showed evidence of clinical and immunologic efficacy in early-phase clinical trials, and results from a phase III trial in advanced disease are pending. While immune checkpoint inhibitors appear to have modest activity as monotherapy, preclinical and clinical data suggest that they may synergize with vaccines, poly [ADP-ribose] polymerase inhibitors, and other agents. Several clinical studies that combine these therapies are underway. Combining prostate cancer vaccines with immune checkpoint inhibitors has great potential for improving clinical outcomes in prostate cancer. Such combination approaches may create and then recruit tumor-specific T cells to tumor while also increasing their effector function. Other emerging agents may also enhance immune-mediated tumor destruction. PMID- 29146442 TI - ONDAM, T2A, PMSI, SROS, MIGAC, MERRI, SIGAPS & IF: Highly linked French financial medical acronyms.... PMID- 29146443 TI - Differential responses of a thioredoxin-like protein gene to Vibrio parahaemolyticus challenge in the noble scallop Chlamys nobilis with different total carotenoids content. AB - Being lack of specific immune system, both enzymes and non-enzymatic antioxidants play crucial roles in immune of invertebrates. In the present study, in order to investigate immune roles of enzyme (thioredoxin, TRX) and antioxidants (carotenoids), Golden scallops with golden shell and golden muscle rich in carotenoids content and Brown scallops with brown shell and white muscle less carotenoids content of the noble scallop Chlamys nobilis were challenged by Vibrio parahaemolyticus for 48 h. Firstly, a cDNA of TRX protein gene from the scallop (named as CnTRX) was cloned and characterized. The cDNA contains 1280 bp, consisting of a 5' -UTR of 99 bp, a long 3' -UTR of 860 bp and a 321 bp open reading frame (ORF) encoding 106 amino acids. Phylogenetic analysis showed that CnTRX had a closer evolution relationship with TRX from Chlamys farreri. CnTRX was ubiquitously expressed in all examined tissues including intestine, adductor, mantle, gonad, gill, kidney, hepatopancreas and hemolymph, and the highest expression level was detected in the hemolymph. Next, CnTRX transcripts were significantly up-regulated in V. parahaemolyticus group in comparison with PBS control group. Moreover, CnTRX transcripts were significantly higher in Golden scallops than that of Brown ones at 6 h, 12 h and 24 h with bacteria challenge (P < 0.05). The present result indicates that both CnTRX and carotenoids are important factors involved in the immune defense against bacteria challenge in the noble scallop. PMID- 29146444 TI - SNPs in the Toll1 receptor of Litopenaeus vannamei are associated with immune response. AB - Tolls and Toll-like receptors (TLRs) are important regulators in the innate immune system and their genetic variations usually affect the host's susceptibility/resistance to pathogen infections. In this study, we report on the single nucleotide polymorphisms (SNPs) of Toll1 in Litopenaeus vannamei (LvToll1) and how this is associated with immune response. PCR-DGGE analysis revealed genetic polymorphisms in LvToll1 at both the genomic DNA (gDNA) and cDNA levels. Using high-throughput sequencing, 223 SNPs were identified at the gDNA level, of which 145 were non-synonymous SNP (nsSNP), with 3 nsSNPs having frequency over 1%. On the other hand, 60 SNPs were identified at the cDNA level including 38 nsSNPs and 4 nsSNPs with frequency over 1%. Upon challenging shrimps with Streptococcus iniae, Vibrio parahaemolyticus and white spot syndrome virus (WSSV), LvToll1 was shown to generate 6, 4 and 4 novel bands, respectively when analyzed with PCR-DGGE. Sequencing analysis of these bands showed that they contained 6, 4 and 2 nsSNPs, respectively. Moreover, the nsSNP C1526T was detected in S. iniae-resistant but not in susceptible shrimps. Most significantly, the C1526T mutation could shorten the alpha-helix of the LRR domain and was predicted to affect the function of LvToll1, indicating that SNP C1526T might be associated with shrimp's resistance to pathogen infections. In sum, our findings here reveal that the genetic polymorphisms of Toll receptor are linked with the immune response to pathogen infections in L. vannamei. PMID- 29146445 TI - Interplay between daily rhythmic serum-mediated bacterial killing activity and immune defence factors in rainbow trout (Oncorhynchus mykiss). AB - Circadian rhythm is emerging as an important regulator of immune functions. However, there is a paucity of information on the influence of this biological phenomenon in the antimicrobial factors in teleost fish. This study investigated the dynamics and interplay of serum-mediated bacterial killing activity and immune defence factors throughout the light:dark (LD) cycle in rainbow trout (Oncorhynchus mykiss). The juvenile fish came from two different emergence time fractions (i.e., late and early) that were believed to exhibit behavioural and physiological differences. Serum collected during the day from fish (mean +/- SD: 39.8 +/- 6.3 g) reared under 14L:10D photoperiod demonstrated bactericidal activity against Flavobacterium psychrophilum, Yersinia ruckeri and Aeromonas salmonicida subsp. salmonicida of varying magnitude, but no significant differences between the emergence fractions were observed. A day-night comparison in the same batch of fish revealed time-of-day dependence in the bactericidal activity against F. psychrophilum and Y. ruckeri amongst emergence fractions. A group of fish (63.3 +/- 4.7 g) from each fraction was entrained to 12L:12D photoperiod for 21 days to investigate whether serum bactericidal activity exhibited daily rhythm. Serum-mediated bacterial killing activity against F. psychrophilum and Y. ruckeri displayed significant daily rhythm in both emergence fractions, where the peak of activity was identified during the light phase. Moreover, several serum defence factors manifested variations during the LD cycle, where anti-protease (ANTI) and myeloperoxidase (MPO) activities exhibited significant daily oscillation. However, there were no remarkable differences in the daily changes of serum factors amongst emergence fractions. Acrophase analysis revealed that the peaks of activity of alkaline phosphatase (only in late fraction), ANTI, lysozyme (only in early fraction) and MPO were identified during the light phase and corresponded with the period when serum-mediated bacterial killing activity was also at its highest. The daily dynamics of bactericidal activity and immune defence factors displayed positive correlation, particularly between MPO and, the two pathogens (i.e., F. pyschrophilum and Y. ruckeri). Taken together, the study revealed that serum-mediated bacterial killing activity and immune defence factors remarkably varied during the LD cycle in rainbow trout. In addition, the two emergence fractions displayed nearly comparable immunological profiles. PMID- 29146446 TI - Hericium caput-medusae (Bull.:Fr.) Pers. polysaccharide enhance innate immune response, immune-related genes expression and disease resistance against Aeromonas hydrophila in grass carp (Ctenopharyngodon idella). AB - The objective was to add 0, 400, 800 or 1200 mg/kg of Hericium caput-medusae polysaccharide (HCMP) to the basal diet of grass carp (Ctenopharyngodon idella) and determine effects on humoral innate immunity, expression of immune-related genes and disease resistance. Adding HCMP enhanced (P < 0.05) bactericidal activity at 1, 2 and 3 weeks and also lysozyme activity, complement C3, and SOD activity at 2 and 3 weeks. Supplementing 800 or 1200 mg/kg of HCMP for 2 or 3 weeks increased (P < 0.05) serum concentrations of total protein, albumin and globulin. Two immune-related genes (IL-1beta and TNF-alpha) were up-regulated (P < 0.05) in HCMP supplemented groups given 800 or 1200 mg/kg HCMP after 2 and 3 weeks of feeding. Expression of anti-inflammatory cytokine IL-10 was down regulated (P < 0.05) after receiving 800 or 1200 mg/kg HCMP for 2 or 3 weeks. Fish fed 800 mg/kg HCMP had maximal disease resistance against Aeromonas hydrophila (65.4%). In conclusion, HCMP enhanced immune response and expression of immune-related genes and increased disease resistance against Aeromonas hydrophila in grass carp, with greatest effects in fish given 800 mg/kg HCMP for 3 weeks. PMID- 29146447 TI - In the ovary of Ciona intestinalis (Type A), immune-related galectin and phenoloxidase genes are differentially expressed by the follicle accessory cells. AB - Riboprobes (in situ hybridization) and antibodies (immunohistochemistry), previously used to show the upregulation of Ciona intestinalis (Type A) galectins (CiLgals-a, CiLgals-b) and phenoloxidase (CinPO2) immune-related genes, were tested on histological sections of the ovary. The ovarian follicles are composed of oocytes encased by follicular cells (FCs) and test cells (TCs). Results show the transcription upregulation of both CiLgals and CinPO2 genes in the vitellogenic FCs, conversely distinct cytolocalization of the proteins are shown. At vitellogenic stage, the CiLgals are localized in the FCs, in the oocyte cytoplasm, and close to the germinal vesicle (GV), whereas the CinPO2 was never identified in the FCs. In a presumptive advanced phase and at the post vitellogenic stage the TCs appear to be labelled by the CinPO2 riboprobe, and the protein identified by the antibody suggesting an mRNA transcytosis process from FCs. At post-vitellogenic stage the CiLgals mainly enrich the GV nucleoplasm, whereas the CinPO2 is contained in TCs and in the ooplasm but never found in the GV. This finding sheds new light on a former paper in which TCs were reported to be the only CinPO2-producing cells in the ovarian follicle. Finally, CiLgals and CinPO2 genes transcription and proteins production seem to be associated with accessory cells during their differentiation from vitellogenic to post vitellogenic stage. The present findings promote further research on the early upregulation of immune-related genes, and the potential multifunctional role of the produced proteins. In addition further insight on the accessory cells involvement in ascidian oogenesis are reported. PMID- 29146448 TI - Sialic acid-binding lectins (SABLs) from Solen grandis function as PRRs ensuring immune recognition and bacterial clearance. AB - Sialic acid-binding lectins (SABLs) are ubiquitous ancient molecules with binding properties to N-acetyl or N-glycolyl carbohydrates, and play crucial roles in both adaptive and innate immune responses. In present study, recombinant protein and antibodies of two SABLs from mollusk Solen grandis (SgSABL-1 and SgSABL-2) were prepared to investigate their functions in innate immunity. The recombinant protein of SgSABL-1 (rSgSABL-1) could bind LPS, PGN and beta-glucan in vitro, while rSgSABL-2 could only bind PGN rather than LPS and beta-glucan. Be coincident with their PAMPs recognition properties, rSgSABL-1 displayed a broad agglutination spectrum towards gram-positive bacteria Micrococcus luteus, gram negative bacteria Listonella anguillarum and fungi Pichia pastoris, and rSgSABL-2 only showed remarkable agglutinative effect on M. luteus and L. anguillarum. More importantly, after PAMPs recognition, rSgSABL-1 and rSgSABL-2 enhanced phagocytosis as well as encapsulation ability of hemocytes in vitro, and the enhanced encapsulation could be blocked by specific antibodies. All these results indicated that SgSABL-1 and SgSABL-2 functioned as two compensative pattern recognition receptor (PRRs) with distinct recognition spectrum and involved in the innate immune response of S. grandis. PMID- 29146449 TI - An integrated metabolic consequence of Hepatospora eriocheir infection in the Chinese mitten crab Eriocheir sinensis. AB - Despite the economic and evolutionary importance of aquatic host-infecting microsporidian species, at present, limited information has been provided about the microsporidia-host interactions. This study focused on Hepatospora eriocheir, an emerging microsporidian pathogen for the Chinese mitten crab Eriocheir sinensis. Hypertrophy of hepatopancreas cells was a common feature of H. eriocheir infection. More importantly, mitochondria of the hepatopancreas were drawn around the H. eriocheir, most likely to aid the uptake of ATP directly from the host. To better understand the crab anti-microsporidian response, de novo transcriptome sequencing of the hepatopancreas tissue was furtherly proceeded. A total of 47.84 M and 57.21 M clean reads were generated from the hepatopancreas of H. eriocheir infected and control groups respectively. Based on homology searches, functional annotation with 6 databases (Nr, Swiss-Prot, KEGG, KOGs, Pfam and GO) for 88,168 unigenes was performed. 2619 genes were identified as differently up-regulated and 2541 genes as differently down-regulated. Prominent functional categories enriched with differentially expressed genes (DEGs) were "ATP binding", "mitochondrion and extracellular region", "oxygen transporter activity", "oxidoreductase activity", "alanine, aspartate and glutamate metabolism", "carbohydrate metabolic process", "starch and sucrose metabolism" and "fatty acid biosynthesis". These results confirmed a parasite external energy supply and an integrated metabolic stress. In addition, simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs) were also identified from the gene library. Taken together, these findings allow us to better understand the underlying mechanisms regulating interactions between H. eriocheir and the crab E. sinensis. PMID- 29146450 TI - Identification and expression of complement component C8alpha, C8beta and C8gamma gene in half-smooth tongue sole (Cynoglossus semilaevis) and C8alpha recombinant protein antibacterial activity analysis. AB - Complement component C8, which mediates membrane attack complex formation and bacterial lysis, plays important roles in the complement system. The cDNA sequences of the C8alpha, C8beta and C8gamma genes were cloned from half-smooth tongue sole (Cynoglossus semilaevis). Full-length cDNA of CsC8alpha (C8alpha of C. semilaevis), CsC8beta and CsC8gamma was 1990, 2219 and 886 bp, respectively, which contained open reading frames of 1797, 1749 and 666 bp, encoding 598, 582 and 221 amino acids, respectively. The deduced proteins of CsC8alpha, CsC8beta and CsC8gamma showed the closest amino acid similarity to C8alpha (73%) of Siniperca chuatsi, C8beta (76%) of Oryzias latipes and C8gamma (72%) of Takifugu rubripes, respectively. The highest expression level of CsC8alpha, CsC8beta and CsC8gamma among the 13 normal tissues was observed in liver tissue, followed by much lower levels in other tissues. After infection with Vibrio anguillarum, CsC8alpha, CsC8beta and CsC8gamma were significantly up-regulated in all of the detected tissues, including the intestine, liver, gill, head kidney, blood and spleen. Then, a recombinant expression plasmid was constructed, and the recombinant CsC8alpha protein was expressed in GS115 pichia pastoris yeast. Furthermore, to investigate the biological functions of recombinant CsC8alpha, an antibacterial assay was performed, and the results showed that recombinant CsC8alpha obviously inhibited growth of V. anguillarum, Edwardsiella tarda and Vibrio parahaemolyticus. Taken together, these results suggest that CsC8alpha, CsC8beta and CsC8gamma may play important roles in the immune defense of C. semilaevis. PMID- 29146451 TI - Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs. AB - OBJECTIVE: To evaluate the effect of rate of administration of propofol or alfaxalone on induction dose requirements and incidence of postinduction apnea (PIA) in dogs following premedication with methadone and dexmedetomidine. STUDY DESIGN: Prospective, randomized clinical trial. ANIMALS: Thirty-two healthy American Society of Anesthesiologists class I client-owned dogs (seven females, 25 males), aged between 5 and 54 months, weighing between 2.0 and 48.2 kg. METHODS: Dogs were premedicated intramuscularly with 0.5 mg kg-1 methadone and 5 MUg kg-1 dexmedetomidine. Thirty minutes after premedication, dogs were preoxygenated for 5 minutes before the induction agent was administered intravenously via a syringe driver until orotracheal intubation was achieved. Dogs were randomized to receive alfaxalone 0.5 mg kg-1 minute-1 (A-Slow), alfaxalone 2 mg kg-1 minute-1 (A-Fast), propofol 1 mg kg-1 minute-1 (P-Slow), or propofol 4 mg kg-1 minute-1 (P-Fast). Oxygen saturation of hemoglobin (SpO2), end tidal carbon dioxide and respiratory rate were monitored. If PIA (>=30 seconds without a breath) occurred, the time to the first spontaneous breath was measured. If SpO2 decreased below 90%, the experiment was stopped and manual ventilation initiated. RESULTS: The mean+/-standard deviation induction doses of alfaxalone and propofol were lower in the A-Slow [A-Slow 0.9+/-0.3 mg kg-1, A Fast 2.2+/-0.5 mg kg-1 (p<=0.001)] and P-Slow [P-Slow 1.8+/-0.6 mg kg-1, P-Fast 4.1+/-0.7 mg kg-1 (p<=0.001)] groups, respectively. The incidence of PIA was 25% for the A-Slow and P-Slow groups and 100% for the A-Fast and P-Fast groups (p = 0.007). CONCLUSIONS AND CLINICAL RELEVANCE: Both propofol and alfaxalone following methadone and dexmedetomidine premedication caused PIA. Induction dose requirement and incidence of PIA were affected by the rate of administration of both drugs. When possible, propofol and alfaxalone doses should be reduced and administered slowly to reduce PIA. PMID- 29146452 TI - Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors. AB - Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3 d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential. PMID- 29146453 TI - Cellular and biochemical parameters following autotomy and ablation-mediated cheliped loss in the Chinese mitten crab, Eriocheir sinensis. AB - In the pond culture of juvenile Eriocheir sinensis, various factors have frequently led to a high rate of autotomy and limb impairments. This study evaluated the differential effects of cheliped loss with autotomy and ablation on the short-term cellular and biochemical parameters of juvenile E. sinensis. In this study, compared with the crabs before treatment, the total hemocyte counts (THC), granulocyte counts (GC), hemocyte agglutination, phosphatase activity and glucose metabolism levels were significantly increased, while hyalinocyte counts (HC) and total antioxidant capacity (T-AOC) were significantly decreased within 3 h. However, the THC levels, hemocyte agglutination and hemocyte proliferation were significantly higher in the ablation group within 3 h compared to the autotomy group. Moreover, the changes of glucose metabolism and immune-related enzymes activities in ablation groups were later than autotomy groups. The bacterial challenge showed that the mortality rate of the ablation group was significantly higher than that of the autotomy group. Therefore, the observations in this study indicate that compared with the passive trauma response of ablation, autotomy is a congenital, efficient, and active trauma response mechanism, which is of great significance to the survival and growth of E. sinensis. PMID- 29146454 TI - Beyond immunity: The Imd pathway as a coordinator of host defense, organismal physiology and behavior. AB - The humoral arm of host defense in Drosophila relies on two evolutionarily conserved NFkappaB signaling cascades, the Toll and the immune deficiency (Imd) pathways. The Imd signaling pathway senses and neutralizes Gram-negative bacteria. Its activity is tightly adjusted, allowing the host to simultaneously prevent infection by pathogenic bacteria and tolerate beneficial gut microbiota. Over-activation of Imd signaling is detrimental at least in part by causing gut dysbiosis that further exacerbates intestinal pathologies. Furthermore, it is increasingly recognized that the Imd pathway or its components also play non immune roles. In this review, we summarize recent advances in Imd signal transduction, discuss the gut-microbiota interactions mediated by Imd signaling, and finally elaborate on its diverse physiological functions beyond immunity. Understanding the multifaceted physiological outputs of Imd activation will help integrate its immune role into the regulation of whole organismal physiology. PMID- 29146455 TI - Successful nonoperative management of uncomplicated appendicitis: predictors and outcomes. AB - BACKGROUND: Our objective was to identify predictors of successful nonoperative management (NOM) of uncomplicated appendicitis. We hypothesized that the absence of diabetes, absence of an appendicolith, short duration of symptoms, absence of systemic inflammation, and low modified Alvarado score would predict successful NOM. METHODS: We performed a retrospective cohort analysis of 81 consecutive patients who underwent NOM of uncomplicated appendicitis. Successful NOM was defined as resolution of appendicitis with antibiotics alone and no recurrent appendicitis within 180 days. Patients with successful NOM (n = 36) were compared with patients who failed NOM (n = 45). Multivariable logistic regression was used to identify predictors of successful NOM, expressed as odds ratios (ORs) with 95% confidence intervals. Model strength was assessed by calculating area under the receiver operating characteristic curve (AUC). RESULTS: Patient age (35 years), the American Society of Anesthesiologists class (2.0), and Charlson comorbidity index (0.0) were similar between groups. Independent predictors of successful NOM were duration of symptoms prior to admission >25 hours: OR 4.17 (1.42-12.24), maximum temperature within 6 hours of admission <37.3 degrees C: OR 8.07 (1.79 36.38), modified Alvarado score <4: OR 9.06 (1.26-64.93), and appendiceal diameter <13 mm: OR 17.55 (1.30-237.28); model AUC: 0.81 (0.72-0.90). CONCLUSIONS: Patients with a longer duration of symptoms prior to admission were more likely to have successful NOM. Other independent predictors of successful NOM included lower temperature, lower modified Alvarado score, and smaller appendiceal diameter. These findings provide a framework for clinical decision making and large-scale derivation and validation of a model to predict successful NOM of uncomplicated appendicitis. PMID- 29146457 TI - A novel index in the diagnosis of iNPH and its association with disproportionately enlarged subarachnoid space pathophysiology? PMID- 29146456 TI - Is more always better? How different 'doses' of exercise after incomplete spinal cord injury affects the membrane properties of deep dorsal horn interneurons. AB - Interneurons in the deep dorsal horn (DDH) of the spinal cord process somatosensory input, and form an important link between upper and lower motoneurons to subsequently shape motor output. Exercise training after SCI is known to improve functional motor recovery, but little is known about the mechanisms within spinal cord neurons that underlie these improvements. Here we investigate how the properties of DDH interneurons are affected by spinal cord injury (SCI) alone, and SCI in combination with different 'doses' of treadmill exercise training (3, 6, and 9wks). In an adult mouse hemisection model of SCI we used whole-cell patch-clamp electrophysiology to record intrinsic, AP firing and gain modulation properties from DDH interneurons in a horizontal spinal cord slice preparation. We find that neurons within two segments of the injury, both ipsi- and contralateral to the hemisection, are similarly affected by SCI and SCI plus exercise. The passive intrinsic membrane properties input resistance (Rin) and rheobase are sensitive to the effects of recovery time and exercise training after SCI thus altering DDH interneuron excitability. Conversely, select active membrane properties are largely unaffected by either SCI or exercise training. SCI itself causes a mismatch in the expression of voltage-gated subthreshold currents and AP discharge firing type. Over time after SCI, and especially with exercise training (9wks), this mismatched expression is exacerbated. Lastly, amplification properties (i.e. gain of frequency-current relationship) of DDH interneurons are altered by SCI alone and recover spontaneously with no clear effect of exercise training. These results suggest a larger 'dose' of exercise training (9wks) has a strong and selective effect on specific membrane properties, and on the output of interneurons in the vicinity of a SCI. These electrophysiological data provide new insights into the plasticity of DDH interneurons and the mechanisms by which exercise therapy after SCI can improve recovery. PMID- 29146459 TI - Factors influencing food choice of athletes at international competition events. AB - Although the nutrient requirements and dietary intake of athletes have been thoroughly investigated, little is known about the influences on their food choice, particularly prior to and during competition. This study sought to investigate factors that influence food selection of athletes at two similar international competition events: the Melbourne 2006 and Delhi 2010 Commonwealth Games. A secondary aim was to explore differences in these factors between at each event given the culturally diverse locations. A survey developed for this study was distributed to athletes in the village dining hall at both events. Athletes scored a selection of factors influencing food choice on a scale of 1 (not important) to 5 (very important). A total of 769 individuals completed the questionnaire in total, with 351 (46%) from Delhi and 418 (54%) from Melbourne. Overall, athletes rated nutrient composition (M = 4.22), stage of competition (M = 4.09), time of day (M = 4.02) and familiarity of the food (M = 4.07) higher than sensory properties (smell M = 3.88; visual appearance M = 3.22) when making a food selection. Visual appearance (p = 0.01), stage of competition (p < 0.001) and time of day (p = 0.01) had greater influence in Delhi than Melbourne. Overall, a significantly higher proportion of female athletes rated smell (p < 0.001) and familiar food (p < 0.001) as important compared to males. The stage of competition and nutrition composition was rated as very important by the greatest proportion of athletes from weight category sports (61.9%) and endurance sports (57.9%) respectively. The influence of the coach and team mates was less of an influence than other factors, but more so for athletes from Non-Western regions. Further investigation of the various determinants and motives for food section of athletes from a range of sports and cultures is warranted. PMID- 29146458 TI - Tap versus bottled water consumption: The influence of social norms, affect and image on consumer choice. AB - What drives consumers to choose bottled water instead of tap water where the latter is safe, accessible, costs far less, and in spite of its environmental impacts? This research investigates the influence of hitherto unexplored psychological drivers in an attempt to generate a more holistic understanding of the phenomenon, and strategies for designing more effective consumption reduction campaigns. Using data from an internet survey of Swiss and German respondents (N = 849) we investigated the role of, social norms, affect and image on water consumption. Results suggest that these psychological factors play a role in water consumption choice. Convenience was the only contextual predictor - the inconvenience of transporting bottled water has a negative effect on its consumption, and a positive effect on tap water consumption. Although concern about the effect of bottled water on the environment was not a significant predictor of tap water consumption, we found that for some people, a link exists between environmental concern and consumption choice. Ways through which consumers may be more effectively influenced towards environmentally-friendly consumption are discussed. PMID- 29146460 TI - The impact of price and nutrition labelling on sugary drink purchases: Results from an experimental marketplace study. AB - OBJECTIVE: To examine the effect of front-of-package (FOP) nutrition labelling and sugary drink taxation on consumer beverage purchases. METHODS: A total of 675 respondents aged 16 years and older participated in an experimental marketplace study using a 4 * 5 within-between group design. Participants were randomised to one of four labelling conditions (no label; star rating; high sugar symbol; health warning) and completed five within-subject purchase tasks. Beverage prices in each task corresponded to 'tax' conditions: 0%, 10%, 20%, 30% and a variable tax proportional to free sugar level. In each task, participants selected from 20 commercially available beverages; upon conclusion, one of five selections was randomly chosen for purchase. RESULTS: As price increased, participants were significantly less likely to select a sugary drink, and selected drinks with fewer calories and less free sugar (p < 0.001 for all). The overall effect of labelling was not statistically significant, although there was a trend for the 'high sugar' label to reduce the likelihood of selecting a sugary drink (p = 0.11) and encouraging participants to select drinks with less free sugar (p = 0.11). CONCLUSIONS: Increasing price was associated with reduced sugary drink purchases. Enhanced FOP labelling results highlight the need for further research to investigate their potential impact. The study adds empirical support for taxation to reduce sugary drink consumption. PMID- 29146461 TI - Resveratrol supports and alpha-naphthoflavone disrupts growth of human ovarian follicles in an in vitro tissue culture model. AB - Infertility is a global health problem with an estimated incidence of 15%. Exposure to chemicals is a potential causal factor, and there is a lack of studies examining the effects on female germ cells. Here, we have studied the impact of different aryl hydrocarbon receptor (AHR) modulators on human ovarian follicles using a human ovarian tissue culture model. Expression of AHR was analyzed in tissue samples, and effects of the selected ligands resveratrol (RSVL), 6-formylindolo(3,2-b)carbazole (FICZ), and alpha-naphthoflavone (aNF) on AHR transactivation studied in a granulosa cell tumor line. Cortical human ovarian tissue containing preantral follicles was exposed to the ligands or vehicle (dimethylsulfoxide, DMSO) for seven days in vitro. Follicle growth was assessed by counting and measuring follicles from serial tissue sections, cell death quantified using in situ Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assay, and steroid hormone production measured using a newly developed ultra-performance liquid chromatography method. AHR was expressed in all donated ovarian tissue samples. FICZ induced AHR transactivation in the granulosa cell line while aNF antagonised it. Compared to DMSO control, FICZ had no effect on follicles in culture, RSVL increased the proportion of growing follicles, and aNF increased cell death, disrupted growth of secondary follicles, increased testosterone, and reduced estradiol levels. We conclude that RSVL supports and aNF disrupts growth of human ovarian follicles in culture. We further conclude that the human ovarian tissue culture model is suitable for studying effects of chemicals on follicular biology. PMID- 29146462 TI - Individual serum bile acid profiling in rats aids in human risk assessment of drug-induced liver injury due to BSEP inhibition. AB - Drug-induced liver injury (DILI) has been the most frequent cause of post marketing drug withdrawals in the last 50years. The multifactorial nature of events that precede severe liver injury in human patients is difficult to model in rodents due to a variety of confounding or contributing factors that include disease state, concurrent medications, and translational species differences. In retrospective analyses, a consistent risk factor for DILI has been the inhibition of the Bile Salt Export Pump (BSEP). One compound known for potent BSEP inhibition and severe DILI is troglitazone. The purpose of the current study is to determine if serum profiling of 19 individual bile acids by liquid chromatography-mass spectrometry (LC/MS) can detect perturbations in bile acid homeostasis in rats after acute intravenous (IV) administration of vehicle or 5, 25, or 50mg/kg troglitazone. Minimal serum transaminase elevations (approximately two-fold) were observed with no evidence of microscopic liver injury. However, marked changes in individual serum bile acids occurred, with dose-dependent increases in the majority of the bile acids profiled. When compared to predose baseline values, tauromuricholic acid and taurocholic acid had the most robust increase in serum levels and dynamic range, with a maximum fold increase from baseline of 34-fold and 29-fold, respectively. Peak bile acid increases occurred within 2hours (h) after dosing and returned to baseline values before 24h. In conclusion, serum bile acid profiling can potentially identify a mechanistic risk of clinical DILI that could be poorly detected by traditional toxicity endpoints. PMID- 29146463 TI - Age dependent in vitro metabolism of bifenthrin in rat and human hepatic microsomes. AB - Bifenthrin, a pyrethroid insecticide, undergoes oxidative metabolism leading to the formation of 4'-hydroxy-bifenthrin (4'-OH-BIF) and hydrolysis leading to the formation of TFP acid in rat and human hepatic microsomes. In this study, age dependent metabolism of bifenthrin in rats and humans were determined via the rates of formation of 4'-OH-BIF and TFP acid following incubation of bifenthrin in juvenile and adult rat (PND 15 and PND 90) and human (<5years and >18years) liver microsomes. Furthermore, in vitro hepatic intrinsic clearance (CLint) of bifenthrin was determined by substrate consumption method in a separate experiment. The mean Vmax(+/-SD) for the formation of 4'-OH-BIF in juvenile rat hepatic microsomes was 25.0+/-1.5pmol/min/mg which was significantly lower (p<0.01) compared to that of adult rats (86.0+/-17.7pmol/min/mg). However, the mean Km values for juvenile (19.9+/-6.6MUM) and adult (23.9+/-0.4MUM) rat liver microsomes were similar. On the other hand, in juvenile human hepatic microsomes, Vmax for the formation of 4'-OH-BIF (73.9+/-7.5pmol/min/mg) was significantly higher (p<0.05) than that of adults (21.6+/-0.6pmol/min/mg) albeit similar Km values (10.5+/-2.8MUM and 8.9+/-0.6MUM) between the two age groups. The trends in the formation kinetics of TFP acid were similar to those of 4'-OH-BIF between the species and age groups, although the differences between juveniles and adults were less pronounced. The data also show that metabolism of bifenthrin occurs primarily via oxidative pathway with relatively lesser contribution (~30%) from hydrolytic pathway in both rat and human liver microsomes. The CLint values for bifenthrin, determined by monitoring the consumption of substrate, in juvenile and adult rat liver microsomes fortified with NADPH were 42.0+/-7.2 and 166.7+/ 20.5MUl/min/mg, respectively, and the corresponding values for human liver microsomes were 76.0+/-4.0 and 21.3+/-1.2MUl/min/mg, respectively. The data suggest a major species difference in the age dependent metabolism of bifenthrin. In human liver microsomes, bifenthrin is metabolized at a much higher rate in juveniles than in adults, while the opposite appears to be true in rat liver microsomes. PMID- 29146464 TI - Language control mechanisms differ for native languages: Neuromagnetic evidence from trilingual language switching. AB - How does the brain process and control languages that are learned at a different age, when proficiency in all these languages is high? Early acquired strong languages are likely to have higher baseline activation levels than later learned less-dominant languages. However, it is still largely unknown how the activation levels of these different languages are controlled, and how interference from an irrelevant language is prevented. In this magnetoencephalography (MEG) study on language switching during auditory perception, early Finnish-Swedish bilinguals (N = 18) who mastered English with high proficiency after childhood were presented with spoken words in each of the three languages, while performing a simple semantic categorisation task. Switches from the later learned English to either of the native languages resulted in increased neural activation in the superior temporal gyrus (STG) 400-600ms after word onset (N400m response), whereas such increase was not detected for switches from native languages to English or between the native languages. In an earlier time window of 350-450ms, English non-switch trials showed higher activation levels in the inferior frontal gyrus (IFG), pointing to ongoing inhibition of the native languages during the use of English. Taken together, these asymmetric switch costs suggest that native languages are suppressed during the use of a non-native language, despite the receptive nature of the language task. This effect seems to be driven mostly by age of acquisition or language exposure, rather than proficiency. Our results indicate that mechanisms of control between two native languages differ from those of a later learned language, as upbringing in an early bilingual environment has likely promoted automatiation of language control specifically for the native languages. PMID- 29146465 TI - More than blindsight: Case report of a child with extraordinary visual capacity following perinatal bilateral occipital lobe injury. AB - Injury to the primary visual cortex (V1, striate cortex) and the geniculostriate pathway in adults results in cortical blindness, abolishing conscious visual perception. Early studies by Larry Weiskrantz and colleagues demonstrated that some patients with an occipital-lobe injury exhibited a degree of unconscious vision and visually-guided behaviour within the blind field. A more recent focus has been the observed phenomenon whereby early-life injury to V1 often results in the preservation of visual perception in both monkeys and humans. These findings initiated a concerted effort on multiple fronts, including nonhuman primate studies, to uncover the neural substrate/s of the spared conscious vision. In both adult and early-life cases of V1 injury, evidence suggests the involvement of the Middle Temporal area (MT) of the extrastriate visual cortex, which is an integral component area of the dorsal stream and is also associated with visually guided behaviors. Because of the limited number of early-life V1 injury cases for humans, the outstanding question in the field is what secondary visual pathways are responsible for this extraordinary capacity? Here we report for the first time a case of a child (B.I.) who suffered a bilateral occipital-lobe injury in the first two weeks postnatally due to medium-chain acyl-Co-A dehydrogenase deficiency. At 6 years of age, B.I. underwent a battery of neurophysiological tests, as well as structural and diffusion MRI and ophthalmic examination at 7 years. Despite the extensive bilateral occipital cortical damage, B.I. has extensive conscious visual abilities, is not blind, and can use vision to navigate his environment. Furthermore, unlike blindsight patients, he can readily and consciously identify happy and neutral faces and colors, tasks associated with ventral stream processing. These findings suggest significant re-routing of visual information. To identify the putative visual pathway/s responsible for this ability, MRI tractography of secondary visual pathways connecting MT with the lateral geniculate nucleus (LGN) and the inferior pulvinar (PI) were analysed. Results revealed an increased PI-MT pathway in the left hemisphere, suggesting that this pulvinar relay could be the neural pathway affording the preserved visual capacity following an early-life lesion of V1. These findings corroborate anatomical evidence from monkeys showing an enhanced PI-MT pathway following an early-life lesion of V1, compared to adults. PMID- 29146466 TI - Causal mapping of emotion networks in the human brain: Framework and initial findings. AB - Emotions involve many cortical and subcortical regions, prominently including the amygdala. It remains unknown how these multiple network components interact, and it remains unknown how they cause the behavioral, autonomic, and experiential effects of emotions. Here we describe a framework for combining a novel technique, concurrent electrical stimulation with fMRI (es-fMRI), together with a novel analysis, inferring causal structure from fMRI data (causal discovery). We outline a research program for investigating human emotion with these new tools, and provide initial findings from two large resting-state datasets as well as case studies in neurosurgical patients with electrical stimulation of the amygdala. The overarching goal is to use causal discovery methods on fMRI data to infer causal graphical models of how brain regions interact, and then to further constrain these models with direct stimulation of specific brain regions and concurrent fMRI. We conclude by discussing limitations and future extensions. The approach could yield anatomical hypotheses about brain connectivity, motivate rational strategies for treating mood disorders with deep brain stimulation, and could be extended to animal studies that use combined optogenetic fMRI. PMID- 29146467 TI - Report of seizure induced by 10 Hz rTMS over M1. PMID- 29146469 TI - Percutaneous transcystic balloon dilation for common bile duct stone removal in high-surgical-risk patients with acute cholecystitis and co-existing choledocholithiasis. AB - BACKGROUND: Percutaneous procedures to treat common bile duct (CBD) stones typically require access via intrahepatic bile ducts. This study aimed to describe the outcomes of a percutaneous transcystic approach that expelled the CBD stones into the duodenum after percutaneous transcystic balloon dilation of the ampulla (PTCBDA) for high-risk patients who present with acute cholecystitis and CBD stones. METHODS: Patients diagnosed with acute cholecystitis and CBD stones who were deemed too high-risk for surgery or general anesthesia and were treated with PTCBDA and CBD stone removal between March 2010 and November 2015 were included for further analysis. Patients underwent emergency percutaneous transhepatic gallbladder drainage under ultrasound. Staged PTCBDA and CBD stone expulsion were performed. Outcomes evaluated included the success rate, causes of failure, and complications. RESULTS: Eighteen patients met the inclusion criteria. CBD stones were successfully expelled in 16 patients. A second procedure was performed in one patient because of residual stones. The procedure failed in two patients because their stones were large. One patient developed bile peritonitis and underwent percutaneous catheter drainage. DISCUSSION: Percutaneous transcystic anterograde expulsion of CBD stones may be a feasible and effective method for treating high-risk surgical patients with acute cholecystitis and co-existing CBD stones. PMID- 29146468 TI - tDCS changes in motor excitability are specific to orientation of current flow. AB - BACKGROUND: Measurements and models of current flow in the brain during transcranial Direct Current Stimulation (tDCS) indicate stimulation of regions in between electrodes. Moreover, the folded cortex results in local fluctuations in current flow intensity and direction, and animal studies suggest current flow direction relative to cortical columns determines response to tDCS. METHODS: Here we test this idea by using Transcranial Magnetic Stimulation Motor Evoked Potentials (TMS-MEP) to measure changes in corticospinal excitability following tDCS applied with electrodes aligned orthogonal (across) or parallel to M1 in the central sulcus. RESULTS: Current flow models predicted that the orthogonal electrode montage produces consistently oriented current across the hand region of M1 that flows along cortical columns, while the parallel electrode montage produces non-uniform current directions across the M1 cortical surface. We find that orthogonal, but not parallel, orientated tDCS modulates TMS-MEPs. We also show modulation is sensitive to the orientation of the TMS coil (PA or AP), which is thought to select different afferent pathways to M1. CONCLUSIONS: Our results are consistent with tDCS producing directionally specific neuromodulation in brain regions in-between electrodes, but shows nuanced changes in excitability that are presumably current direction relative to column and axon pathway specific. We suggest that the direction of current flow through cortical target regions should be considered for targeting and dose-control of tDCS. PMID- 29146470 TI - Combination of type II fatty acid biosynthesis enzymes and thiolases supports a functional beta-oxidation reversal. AB - An engineered reversal of the beta-oxidation cycle (r-BOX) and the fatty acid biosynthesis (FAB) pathway are promising biological platforms for advanced fuel and chemical production in part due to their iterative nature supporting the synthesis of various chain length products. While diverging in their carbon carbon elongation reaction mechanism, iterative operation of each pathway relies on common chemical conversions (reduction, dehydration, and reduction) differing only in the attached moiety (acyl carrier protein (ACP) in FAB vs Coenzyme A in r BOX). Given this similarity, we sought to determine whether FAB enzymes can be used in the context of r-BOX as a means of expanding available r-BOX components with a ubiquitous set of well characterized enzymes. Using enzymes from the type II FAB pathway (FabG, FabZ, and FabI) in conjunction with a thiolase catalyzing a non-decarboxylative condensation, we demonstrate that FAB enzymes support a functional r-BOX. Pathway operation with FAB enzymes was improved through computationally directed protein design to develop FabZ variants with amino acid substitutions designed to disrupt hydrogen bonding at the FabZ-ACP interface and introduce steric and electrostatic repulsion between the FabZ and ACP. FabZ with R126W and R121E substitutions resulted in improved carboxylic acid and alcohol production from one- and multiple-turn r-BOX compared to the wild-type enzyme. Furthermore, the ability for FAB enzymes to operate on functionalized intermediates was exploited to produce branched chain carboxylic acids through an r-BOX with functionalized priming. These results not only provide an expanded set of enzymes within the modular r-BOX pathway, but can also potentially expand the scope of products targeted through this pathway by operating with CoA intermediates containing various functional groups. PMID- 29146471 TI - Periodic acid-Schiff (PAS) reaction and plastination in whole body slices. A novel technique to identify fascial tissue structures. AB - Since collagen rich fascial tissue is often very delicate and difficult to discern on native tissue slices, we have developed a method for staining full body slices using the periodic acid-Schiff (PAS) reaction with subsequent plastination. Since the PAS reaction primarily stains carbohydrates, we could exploit the circumstance that different collagen types vary in carbohydrate content. Contrary to fasciae, tissues such as muscle, bone, nerves and blood vessels exhibit significantly less staining or remain unstained. We have validated the whole-body slice staining results in microscopic tissue slides which were stained with standard extracellular matrix stains such as Masson Goldner trichrome stain and van-Gieson stain. Furthermore, we have performed immunofluorescence imaging to confirm the presence of collagen in the stained tissue. We achieved very good staining and plastination results and were able to clearly identify even very thin fascia in transversal body slices. This technique may prove useful in advancing our knowledge on the complex topography of fascial structures. PMID- 29146472 TI - Discovery of the first low-shift positive allosteric modulators for the muscarinic M1 receptor. AB - Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and drug developers for the potential treatment of Alzheimer's disease or Schizophrenia. The precognitive potential of M1 activation has however not been clinically demonstrated as a result of side effects associated both with agonists and positive allosteric modulators (PAM's) of the M1-receptor. To avoid excessive activation of the M1-receptor we have designed a new screening format and developed the first low-shift positive allosteric modulators for the M1 receptor. Low-shift PAM's offer the potential of "use-dependent" attenuation of transmitter-signaling while avoiding pseudo-agonistic behavior in vivo as a common limitation of the so far described high-shift PAM's. With these novel M1 PAM's, the M1 receptor is potentially the first GPCR for which both, high- and low shift PAM's have become available. PMID- 29146473 TI - Estrogen levels, emotion regulation, and emotional symptoms of women with premenstrual dysphoric disorder: The moderating effect of estrogen receptor 1alpha polymorphism. AB - BACKGROUND: This study evaluated the association between estrogen levels, emotion regulation, depression, anxiety, and stress of women with premenstrual dysphoric disorder (PMDD). We also evaluated the moderating effect of estrogen receptor (ESR) alpha-Xbal polymorphism on the aforementioned association. METHODS: A total of 100 women were diagnosed with PMDD based on psychiatric interviews and a prospective investigation of 3 menstrual cycles. A total of 96 normal individuals were recruited as controls. Their estrogen levels, depression, anxiety, stress, and ESR alpha-Xbal polymorphism in both premenstrual and follicular phases were assessed, and these data were included in the final analysis. RESULTS: The PMDD group had high depression, anxiety, and stress and low emotional adjusting and tolerating in the premenstrual phase. Emotional adjustment was negatively associated with depression, anxiety and stress. No association was observed between PMDD and estrogen level. However, premenstrual estrogen level was negatively correlated with anxiety and stress in women with PMDD. The association was only significant in G carriers of ESR alpha-Xbal, as was the difference in premenstrual emotion regulation between the PMDD and control groups. CONCLUSIONS: The results demonstrate the association between estrogen and anxiety in PMDD, supporting the claim that women with PMDD differ in their responses to normal estrogen levels. Furthermore, this association and dysfunctional emotional regulation in PMDD existed only among the G carriers of ESR alpha-Xbal polymorphism. Future studies should investigate the effect of estrogen on brain functions involving emotional regulation in women with PMDD, stratified by ESR alpha-Xbal polymorphism. PMID- 29146474 TI - A systematic review and meta-analysis of deep brain stimulation in treatment resistant depression. AB - BACKGROUND: Deep brain stimulation (DBS) has been applied in treatment-resistant depression (TRD) as a putative intervention targeting different brain regions. However, the antidepressant effects of DBS for TRD in recent clinical trials remain controversial. METHODS: We searched Scopus, EMBASE, the Cochrane Library, PubMed, and PsycINFO for all published studies investigating the efficacy of DBS in TRD up to Feb 2017. Hamilton depression rating scale (HDRS) scores and Montgomery-Asberg depression rating scale (MARDS) scores were compared between baseline levels and those after DBS using the standardized mean difference (SMD) with 95% confidence intervals (CIs). The pooled response and remission rates were described using Risk Difference with 95% CIs. RESULTS: We identified 14 studies of DBS in TRD targeting the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS), medial forebrain bundle (MFB), and nucleus accumbens (NAcc). The overall effect sizes showed a significant reduction in HDRS after DBS stimulation in these four regions, with a standardized mean difference of -3.02 (95% CI=-4.28 to -1.77, p<0.00001) for SCG, -1.64 (95% CI=-2.80 to 0.49, p=0.005) for VC/VS, -2.43 (95% CI=-3.66 to -1.19, p=0.0001) for MFB, and 1.30 (95% CI=-2.16 to -0.44, p=0.003) for NAcc. DBS was effective, with high response rates at 1, 3, 6, and 12months. Some adverse events (AEs), especially some specific AEs related to targeting regions, occurred during the DBS treatment. CONCLUSIONS: DBS significantly alleviates depressive symptoms in TRD patients by targeting the SCG, VC/VS, MFB, and NAcc. Several adverse events might occur during DBS therapy, although it is uncertain whether some AEs can be linked to DBS treatment. Further confirmatory trials are required involving larger sample sizes. PMID- 29146475 TI - Electrical activity of sensory pathways in female and male geriatric Rhesus monkeys (Macaca mulatta), and its relation to oxidative stress. AB - Synapses loss during aging has been related to decreased neuronal excitability and reduced electrophysiological activity in the nervous system, as well as to increased brain damage. Those physiological and biochemical alterations have been related to the oxidative stress increase associated with old age. The main substrate of lipid peroxidation (LPX) in the central and peripheral nervous systems are the myelin sheaths, and their damage generates a delayed nerve conduction velocity. However, studies in which the neural conduction velocity is related to changes in the redox state are still lacking. Therefore, our aim was to correlate the sensory neural pathways delay in healthy geriatric Rhesus monkeys (Macaca mulatta) with the oxidative stress associated with physiological aging. Twenty-four monkeys were divided into four groups according to age and gender. Auditory, visual, and somatosensory evoked potentials were obtained. Superoxide dismutase, catalase, and glutathione peroxidase enzymatic activity, as well as LPX, were determined from blood samples. Our results showed significant differences between the older and younger age groups in all neural generators of the different sensory pathways evaluated, along with an increase in LPX and the antioxidant enzymatic activities. It suggests that, even though the enzymatic activity was found to be higher in older monkeys, probably as a compensatory effect, it was not enough to avoid LPX damage and the declined electric activity associated with age. PMID- 29146476 TI - Mutation screening of the GLIS3 gene in a cohort of 592 Chinese patients with congenital hypothyroidism. AB - OBJECTIVES: Defects in the human GLI-similar 3 (GLIS3) gene are reported to be a rare cause of congenital hypothyroidism (CH) and neonatal diabetes. The aim of this study was to examine the prevalence of GLIS3 mutation among CH patients in the Guangxi Zhuang Autonomous Region of China and to define the relationships between GLIS3 genotypes and clinical phenotypes. METHODS: Blood samples were collected from 592 patients with CH in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the GLIS3 gene with their exon-intron boundaries were screened by next-generation sequencing (NGS) and CNVplex(r). Chromosomal microarray analysis (CMA) was performed to detect the existence of the adjacent gene deletion. RESULTS: NGS and CNVplex(r) analysis of GLIS3 in 592 CH patients revealed two different variations in two individuals (2/592, 0.3%). Patient 1 was the paternal allele of 9p24.3p23 heterozygous deletion including the whole GLIS3 gene, and patient 2 was heterozygous for c.2159G>A (p.R720Q) GLIS3 variant combined with compound heterozygous DUOX2 mutations (p.R683L/p.L1343F). CONCLUSIONS: Our study indicated that the prevalence of GLIS3 variations was 0.3% among studied Chinese CH patients. Multiple variations in one or more CH associated genes can be found in one patient. We found a novel GLIS3 variation c.2159G>A (p.R720Q), thereby expanding the variation spectrum of the gene. PMID- 29146477 TI - A review of S100 protein family in lung cancer. AB - S100 protein family, representing 25 relatively small calcium binding proteins, has been reported to be involved in multiple stages of tumorigenesis and progression. These proteins are considered having potential value to be adopted as novel biomarkers in the detection and accurate prediction of many kinds of tumors, including lung cancer. As the one having the highest morbidity and mortality among all cancers, lung carcinoma is still occult for detection, especially at early stage. S100 proteins take participation in the lung neoplasia through playing intracellular and/or extracellular functions, therefore getting involved in a variety of biological processes such as differentiation, proliferation, and migration. A few members have also been testified to modulate TGF-beta/Smad-3 mediated transcriptional activity of target genes involved in tumor promotion. In addition to that, a number of proteins in this family have already been reported to experience an abnormal trend in lung cancer at cell, serum and tissue levels. Thus, S100 proteins may serve as effective biomarkers for suspected or already diagnosed lung cancer patients. In future, S100 protein family might be applied as therapeutic targets in clinical treatment of lung cancer. In this review, we firstly summed up the biological and clinical evidence connecting S100 proteins and lung cancer, which has not been summarized before. PMID- 29146478 TI - Diacylglycerols as biomarkers of sustained immune activation in Proteinopathies associated with dementia. AB - Cognitive decline is a devastating clinical condition, heavily correlated with age progression. In the cases of Alzheimer's disease, Parkinson's disease, and Lewy body disease, the common neuropathologies are proteinopathies and neuroinflammation. Herein, we review current lipidomics findings and conclude that brain and circulating diacylglycerols represent biomarkers of this ongoing sustained immune response, presumably involving microglia. We further hypothesize that a logical next step will be to evaluate biomarkers of immune activation in a cohort of patients with Mild Cognitive Impairment (MCI) and subsequently attempt to provide therapeutic intervention with anti-inflammatory therapy in MCI patients with immune activation. Although this is an urgent and theoretically safe therapeutic trial, it will likely necessitate government support. PMID- 29146479 TI - Visual outcome of penetrating keratoplasty, deep anterior lamellar keratoplasty and Descemet membrane endothelial keratoplasty. AB - PURPOSE: A single-center, cross-sectional study was designed to assess and compare objective and subjective quality of vision of patients intervened with penetrating keratoplasty (PK), deep anterior lamellar keratoplasty (DALK) and Descemet membrane endothelial keratoplasty (DMEK). METHODS: Forty-six patients previously intervened with PK (22 eyes), DALK (7 eyes) and DMEK (17 eyes) were recruited. Visual evaluation included spherical and cylindrical refraction, distance corrected visual acuity (DCVA), photopic contrast sensitivity (CS), optical quality, measured with the HD Analyzer (objective scattering index [OSI], MTF cut-off and Strehl ratio), and ocular and corneal aberrometry, measured with the KR-1W Wavefront Analyzer. RESULTS: Statistically significant between-group differences were found in age (p=0.006, DMEK patients were older) and time since surgery (p<0.001, longest time for PK patients). No statistically significant differences were found in DCVA between the techniques. Between-group differences were encountered in CS at 12 (p=0.007) and 18 (p<0.001) cycles per degree, with DMEK and DALK obtaining the best and worst outcomes, respectively. Differences in optical quality were found between the techniques (OSI, p=0.004; MTF cut-off, p=0.048; Strehl ratio p=0.022), with DMEK displaying the best outcomes. Highest and lowest values in ocular and corneal aberrations were for DALK and DMEK patients, respectively. Between-group differences were found in corneal astigmatism (p<0.001; -3.31+/-2.00 D in PK; -2.68+/-0.94 D in DALK; -1.09+/-0.62 D in DMEK). CONCLUSION: Overall, DMEK proved superior over PK and DALK in terms of quality of vision, with PK offering slightly better outcomes than DALK in most visual function parameters under evaluation. PMID- 29146480 TI - Neuroprotection by chotosan, a Kampo formula, against glutamate excitotoxicity involves the inhibition of GluN2B-, but not GluN2A-containing NMDA receptor mediated responses in primary cultured cortical neurons. AB - Chotosan (CTS), a traditional herbal formula called Kampo medicine, was shown to be effective in the treatment of vascular dementia in a clinical study, and exerted protective effects against transient cerebral ischemia-induced cognitive impairment in mice. In the present study, we investigated the neuroprotective effects of CTS using primary cultured rat cortical neurons. CTS (250-1000 MUg/mL) inhibited neuronal death induced by 100 MUM glutamate. This glutamate-induced neuronal death was blocked by a GluN2B-, but not GluN2A-containing NMDA receptor antagonist. Therefore, the neuroprotective effects of CTS were related to an inhibition of GluN2B-containing NMDA receptor-mediated responses. PMID- 29146481 TI - Central Obesity is the Key Component in the Association of Metabolic Syndrome With Left Ventricular Global Longitudinal Strain Impairment. AB - INTRODUCTION AND OBJECTIVES: Subclinical systolic dysfunction is one of the proposed mechanisms for increased cardiovascular risk associated with metabolic syndrome (MS). This study investigated the association between MS and impaired left ventricular global longitudinal strain (GLS) and the role of each MS criteria in this association. METHODS: We analyzed a random sample of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) after excluding participants with prevalent heart disease. RESULTS: Among the 1055 participants fulfilling the inclusion criteria (53% women; 52+/-9 years), 444 (42%) had MS. Those with MS had worse GLS (-18.0%+/-2.5%) than those without (-19.0%+/-2.4%; P<.0001). In multiple linear regression models, MS was associated with worse GLS after adjustment for various risk factors (GLS difference=0.86%; P <.0001), even after inclusion of body mass index. Adjusted PR for impaired GLS as assessed by 3 cutoffs (1, 1.5, and 2 standard deviations) were higher among participants with than without MS: GLS -16.1% (PR, 1.76; 95%CI, 1.30-2.39); GLS -14.8% (PR, 2.35; 95%CI, 1.45-3.81); and GLS -13.5% (PR, 2.07; 95%CI, 0.97-4.41). After inclusion of body mass index in the models, these associations were attenuated, suggesting that they may, at least in part, be mediated by obesity. In quantile regression analyses, elevated waist circumference was the only MS component found to be independently associated with GLS across the whole range of values. CONCLUSIONS: Metabolic syndrome is independently associated with impaired GLS. Among the MS criteria, central obesity best depicted the link between metabolic derangement and cardiac function. PMID- 29146482 TI - Impaired Left Atrial Strain as a Predictor of New-onset Atrial Fibrillation After Aortic Valve Replacement Independently of Left Atrial Size. AB - INTRODUCTION AND OBJECTIVES: Left atrial dysfunction in aortic stenosis may precede atrial enlargement and predict the occurrence of atrial fibrillation (AF). To test this hypothesis, we assessed left atrial function and determined its impact on the incidence of AF after aortic valve replacement. METHODS: A total of 149 severe aortic stenosis patients (74+/-8.6 years, 51% men) with no prior AF were assessed using speckle-tracking echocardiography. Left atrial function was evaluated using peak atrial longitudinal strain (PALS), peak atrial contraction strain (PACS), and phasic left atrial volumes. The occurrence of AF was monitored in 114 patients from surgery until hospital discharge. RESULTS: In multiple linear regression, PALS and PACS were inversely correlated with left atrial dilation, left ventricular hypertrophy, and diastolic function. Atrial fibrillation occurred in 36 patients within a median time of 3 days [interquartile range, 1-4] after aortic valve replacement. In multiple Cox regression, PALS and PACS were independently associated with the incidence of AF (HR, 0.946; 95%CI, 0.910-0.983; P=.005 and HR, 0.932; 95%CI, 0.883-0.984; P=.011, respectively), even after further adjustment for left atrial dimensions. Both reduced PALS and PACS were associated with the incidence of AF in patients with nondilated left atria (P value for the interaction of PALS with left atrial dimensions=.013). CONCLUSIONS: In severe aortic stenosis, left atrial dysfunction predicted the incidence of postoperative AF independently of left atrial dilation, suggesting that speckle-tracking echocardiography before surgery may help in risk stratification, particularly in patients with nondilated left atria. PMID- 29146483 TI - Why Should We Recommend Pneumococcal Vaccine in Patients With Chronic Heart Diseases? PMID- 29146484 TI - Association Between Ischemic and Bleeding Risk Scores and the Use of New P2Y12 Inhibitors in Patients With Acute Coronary Syndrome. AB - INTRODUCTION AND OBJECTIVES: Acute coronary syndrome (ACS) guidelines recommend the use of newer P2Y12 inhibitors (prasugrel and ticagrelor) over clopidogrel in patients with moderate-to-high ischemic risk, unless they have an increased bleeding risk. The aim of our study was to assess the GRACE risk score and the CRUSADE bleeding risk score relative to prescription of newer P2Y12 inhibitors at discharge in ACS patients. METHODS: Retrospective analysis of a multicenter ACS registry; 3515 consecutive patients were included. The association between risk scores and prescription of newer P2Y12 inhibitors was assessed by binary logistic regression analysis. RESULTS: A total of 1021 patients (29%) were treated with prasugrel or ticagrelor. On multivariate analyses, both GRACE (OR per 10 points, 0.89; 95%CI, 0.86-0.92; P < .001) and CRUSADE (OR per 10 points, 0.96; 95%CI, 0.94-0.98; P < .001) risk scores were inversely associated with the use of newer P2Y12 inhibitors. Moreover, other factors not included in these scores (revascularization approach, in-hospital stent thrombosis, major bleeding, and concomitant indication for anticoagulation therapy) also predicted the use of newer P2Y12 inhibitors. CONCLUSIONS: New P2Y12 inhibitors were more frequently prescribed among ACS patients with lower CRUSADE bleeding risk. However, an ischemic risk paradox was found, with higher use of these agents in patients with lower ischemic risk based on GRACE risk score estimates. These results underscore the importance of risk stratification to safely deliver optimal therapies. PMID- 29146486 TI - Rapidly growing, moderately differentiated HCC: A clinicopathological characteristic of HCC occurrence after IFN-free DAA therapy? PMID- 29146485 TI - In-frame Variants in FLNA Proximal Rod 1 Domain Associate With a Predominant Cardiac Valvular Phenotype. AB - INTRODUCTION AND OBJECTIVES: X-linked cardiac valvular dysplasia is a rare form of male-specific congenital heart defect mainly characterized by myxomatous degeneration of the atrioventricular valves with variable hemodynamic consequences. It is caused by genetic defects in FLNA-encoded filamin A, a widely expressed actin-binding protein that regulates cytoskeleton organization. Filamin A loss of function has also been associated with often concurring neurologic and connective tissue manifestations, with mutations in the first half of the Rod 1 domain apparently expressing the full cardiac phenotype. We contribute to previous genotype-phenotype correlations with a multidisciplinary approach in a newly-described family. METHODS: Cardiologic, dysmorphologic, and genetic evaluation of available members were complemented with transcriptional and X chromosome inactivation studies. RESULTS: A novel FLNA mutation c.1066-3C>G cosegregated with a male-expressed, apparently isolated, cardiac phenotype with no skewed X-inactivation pattern in female carriers. This variant was shown to result in an in-frame deletion of 8 amino acid residues near the N-terminal region of the protein. CONCLUSIONS: A nonimprinted, partial loss of function of filamin A proximal Rod 1 domain seems to be the pathogenetic mechanism of cardiac valvular dysplasia, with some cases occasionally expressing associated extracardiac manifestations. PMID- 29146487 TI - Mitochondria: A master regulator in macrophage and T cell immunity. AB - Orchestrating biological activities of immune cells through metabolic reprogramming reveals a new approach to harnessing immune responses. Increasing evidence reveals that the mitochondrion is a central regulator for modulating metabolic reprogramming and controlling immune cell activation and functions. In addition to supporting bioenergetic demands, the mitochondrion serves as a signaling platform through the generation of reactive oxygen species and metabolites of the tricarboxylic acid cycle to modulate signaling cascades controlling immune cell activation and immune responses. Herein, we discuss the mechanisms through which the mitochondrion acts as a master regulator to fine tune immune responses elicited by macrophages and T cells. PMID- 29146488 TI - Kinetics of parasite distribution after reinfection with genetically distinct strains of Toxoplasma gondii. AB - Recent data shows that prior infection by Toxoplasma gondii does not protect the host from subsequent reinfection even after the development of immunological memory. Although animal models for T. gondii reinfection were proposed after cases of natural human reinfection were described, little is known about the events that occur immediately after challenge. To further understand these events, BALB/c mice were chronically infected with D8 non-virulent strain (genotype ToxoDB#8 BrIII) and challenged with two different virulent strains: EGS (genotype ToxoDB #229) or CH3 strain (genotype ToxoDB #19). Primary infection protected animals from lethal challenge and morbidity was reduced. Reinfection was confirmed by PCR-RFLP, showing differences in the way the parasites spread in challenged animals. Parasites reached the lungs during early infection and a parasitism delay in the intestine was observed in D8+CH3 group. Parasites from challenge strains were not detected in the brain of D8+CH3 and in the intestine and brain of D8+EGS group. Previous infection with D8 strain of T. gondii protected against lethal challenges, but it did not prevent parasite spread to some organs. PMID- 29146489 TI - Exploring the Barriers to and Facilitators of Using Evidence-Based Drugs in the Secondary Prevention of Cardiovascular Diseases: Findings From a Multistakeholder, Qualitative Analysis. AB - BACKGROUND: Health-system barriers and facilitators associated with cardiovascular medication adherence have seldom been studied, particularly in low and middle-income countries where uptake rates are poorest. OBJECTIVES: This study sought to explore the major obstacles and facilitators to the use of evidence-supported medications for secondary prevention of cardiovascular disease using qualitative analysis in 2 diverse countries across multiple levels of their health care systems. METHODS: A qualitative descriptive study approach was implemented in Hamilton, Ontario, Canada, and Delhi, India. A purposeful sample (n = 69) of 23 patients, 10 physicians, 2 nurse practitioners, 5 Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homoeopathy physicians, 11 pharmacists, 3 nurses, 4 hospital administrators, 1 social worker, 3 nongovernmental organization workers, 2 pharmaceutical company representatives, and 5 policy makers participated in interviews in Hamilton, Ontario, Canada (n = 21), and Delhi, India (n = 48). All interviews were digitally recorded and transcribed followed by directed content analysis to summarize and categorize the interviews. RESULTS: Themes that emerged across the stakeholder groups included: medication counseling; monitoring adherence; medication availability; medication affordability and drug coverage; time restrictions; and task shifting. The depth of verbal medication counseling provided varied substantially between countries, with prescribers in India unable to convey relevant information about drug treatments due to time constraint and high patient load. Canadian patients reported drug affordability as a common issue and very few patients were familiar with government subsidized drug programs. In India, patients purchased medications out-of-pocket from private, community pharmacies to avoid long commutes, lost wages, and unavailability of medications from hospitals formularies. Task shifting medication-refilling and titration to nonphysician health workers was accepted and supported by physicians in Canada but not in India, where many of the physicians considered a high level of clinical expertise a precondition to carry out these tasks skillfully. CONCLUSIONS: Our findings reveal context-specific, health system factors that affect the patient's choice or ability to initiate and/or continue cardiovascular medication. Strategies to optimize cardiovascular drug use should be targeted and relevant to the health care system. PMID- 29146490 TI - Educational Inequalities in Cardiovascular Risk Factor and Blood Pressure Control in the Elderly: Comparison of MESA Cohort and Chilean NHS Survey Outcome Measures. AB - BACKGROUND: Social determinants differ between countries, which is not always considered when adapting health policies and interventions to face inequalities in noncommunicable diseases and their risk factors. OBJECTIVES: The study sought to analyze educational inequalities in controlled blood pressure (CBP), obesity, and smoking in study populations from Chile and the United States in 2 periods, both countries with large social inequalities. METHODS: The study used data from the first and fifth waves of the MESA (Multiethnic Study of Atherosclerosis) cohort, and the 2003 and 2009 to 2010 Chilean National Health Survey (CNHS) survey outcome measures. The study compared cardiovascular risk factors prevalence as well as relative index of inequality (RII) and slope index of inequality (SII) between the 2 samples. RESULTS: In the CNHS 67.9% and 52.6% of participants had below primary education in 2003 and 2009 to 2010, respectively, compared with 12.3% and 8.1% in the first and fifth waves of the MESA study, respectively. Smoking prevalence was higher and increased in the CNHS compared with the MESA study, concentrated in better-educated women in both years (RII: 0.34; 95% confidence interval [CI]: 0.17 to 0.68; and RII: 0.55; 95% CI: 0.34 to 0.89, respectively). In contrast, smoking decreased over time in the MESA study in all socioeconomic strata, although relative inequalities increased in both sexes (for women, RII: 2.32; 95% CI 1.36 to 3.97; for men, RII: 3.34; 95% CI 2.04 to 5.47). CBP prevalence in both periods was higher in the first and fifth waves of the MESA study (69.7% and 80.2%) compared with the 2003 and 2009 to 2010 CNHS samples (34.2% and 52.3%), but only for the MESA study RII, favoring the better educated, was it significant in both periods and sexes. Obesity inequalities for Chilean women decreased slightly between 2003 and 2009 as prevalence grew in the most educated (RII: 2.21 to 1.68; SII: 0.29 to 0.22, respectively); conversely, they increased for both sexes in the MESA study. CONCLUSIONS: The study findings confirm that patterns and trends in prevalence, and absolute and relative inequalities vary by country, suggesting that context and cultural issues matters. PMID- 29146492 TI - Improving infant CPR training at an academic medical center using a medical student-led program. PMID- 29146491 TI - Respiratory stress in mitochondrial electron transport chain complex mutants of Candida albicans activates Snf1 kinase response. AB - We have previously established that mitochondrial Complex I (CI) mutants of Candida albicans display reduced oxygen consumption, decreased ATP production, and increased reactive oxidant species (ROS) during cell growth. Using the Seahorse XF96 analyzer, the energetic phenotypes of Electron Transport Chain (ETC) complex mutants are further characterized in the current study. The underlying regulation of energetic changes in these mutants is determined in glucose and non-glucose conditions when compared to wild type (WT) cells. In parental cells, the rate of oxygen consumption remains constant for 2.5 h following the addition of glucose, oligomycin, and 2-DG, but glycolysis is highly active upon the addition of glucose. In comparison, over the same time period, electron transport complex mutants (CI, CIII and CIV) have heightened activities in both oxygen consumption and glycolysis upon glucose uptake. We refer to the response in these mutants as an "explosive respiration," which we believe is caused by low energy levels and increased production of reactive oxygen species (ROS). Accompanying this phenotype in mutants is a hyperphosphorylation of Snf1p which in Saccharomyces cerevisiae serves as an energetic stress response protein kinase for maintaining energy homeostasis. Compared to wild type cells, a 2.9- to 4.4-fold hyperphosphorylation of Snf1p is observed in all ETC mutants in the presence of glucose. However, the explosive respiration and hyperphosphorylation of Snf1 can be partially reduced by the replacement of glucose with either glycerol or oleic acid in a mutant-specific manner. Furthermore, Inhibitors of glutathione synthesis (BSO) or anti-oxidants (mito-TEMPO) likewise confirmed an increase of Sfn1 phosphorylation in WT or mutant due to increased levels of ROS. Our data establish the role of the C. albicans Snf1 as a surveyor of cell energy and ROS levels. We interpret the "explosive respiration" as a failed attempt by ETC mutants to restore energy and ROS homeostasis via Snf1 activation. An inherently high OCR baseline in WT C. albicans with a background level of Snf1 activation is a prerequisite for success in quickly fermenting glucose. PMID- 29146493 TI - Predicting ROSC in out-of-hospital cardiac arrest using expiratory carbon dioxide concentration: Is trend-detection instead of absolute threshold values the key? AB - AIM: Guidelines recommend detecting return of spontaneous circulation (ROSC) by a rising concentration of carbon dioxide in the exhalation air. As CO2 is influenced by numerous factors, no absolute cut-off values of CO2 to detect ROSC are agreed on so far. As trends in CO2 might be less affected by influencing factors, we investigated an approach which is based on detecting CO2-trends in real-time. METHODS: We conducted a retrospective case-control study on 169 CO2 time series from out of hospital cardiac arrests resuscitated by Muenster City Ambulance-Service, Germany. A recently developed statistical method for real-time trend-detection (SCARM) was applied to each time series. For each series, the percentage of time points with detected positive and negative trends was determined. RESULTS: ROSC time series had larger percentages of positive trends than No-ROSC time series (p=0.003). The median percentage of positive trends was 15% in the ROSC time series (IQR: 5% to 23%) and 7% in the No-ROSC time series (IQR: 3% to 14%). A receiver operating characteristic (ROC) analysis yielded an optimal threshold of 13% to differentiate between ROSC and No-ROSC cases with a specificity of 58.4% and sensitivity of 73.9%; the area under the curve was 63.5%. CONCLUSION: Patients with ROSC differed from patients without ROSC as to the percentage of detected CO2 trends, indicating the potential of our real-time trend-detection approach. Since the study was designed as a proof of principle and its calculated specificity and sensitivity are low, more research is required to implement CO2-trend-detection into clinical use. PMID- 29146494 TI - Sex-specific ultrasonic vocalization patterns and alcohol consumption in high alcohol-drinking (HAD-1) rats. AB - Ultrasonic vocalizations (USVs) have been established as an animal model of emotional status and are often utilized in drug abuse studies as motivational and emotional indices. Further USV functionality has been demonstrated in our recent work showing accurate identification of selectively-bred high versus low alcohol consuming male rats ascertained exclusively from 22 to 28kHz and 50-55kHz FM USV acoustic parameters. With the hypothesis that alcohol-sensitive sex differences could be revealed through USV acoustic parameters, the present study examined USVs and alcohol consumption in male and female selectively bred high-alcohol drinking (HAD-1) rats. For the current study, we examined USV data collected during a 12-week experiment in male and female HAD-1 rats. Experimental phases included Baseline (2weeks), 4-h EtOH Access (4weeks), 24-h EtOH Access (4weeks) and Abstinence (2weeks). Findings showed that both male and female HAD-1 rats spontaneously emitted a large number of 22-28kHz and 50-55kHz FM USVs and that females drank significantly more alcohol compared to males over the entire course of the experiment. Analyses of USV acoustic characteristics (i.e. mean frequency, duration, bandwidth and power) revealed distinct sex-specific phenotypes in both 50-55kHz FM and 22-28kHz USV transmission that were modulated by ethanol exposure. Moreover, by using a linear combination of these acoustic characteristics, we were able to develop binomial logistic regression models able to discriminate between male and female HAD-1 rats with high accuracy. Together these results highlight unique emotional phenotypes in male and female HAD-1 rats that are differentially modulated by alcohol experience. PMID- 29146495 TI - Polysaccharides from Citrus grandis L. Osbeck suppress inflammation and relieve chronic pharyngitis. AB - Chronic pharyngitis, a common inflammation of the pharyngeal mucosa, is often caused by bacteria, viruses, alcohol abuse, overuse of the voice and cigarettes. This study aimed to explore the effects of polysaccharides of Citrus grandis L. Osbeck (PCG) in relieving chronic pharyngitis and illustrate the underlying mechanisms. Polysaccharides were obtained from PCG by column chromatographic extraction. Six clinical symptom scores, such as the severity of itchy throat, hoarseness, pain, odynophagia, cough and otalgia were evaluated in chronic pharyngitis patients after the oral intake of PCG. The effects of polysaccharides on chronic pharyngitis were investigated in ammonia-stimulated rabbits through pathology analysis. The levels of inflammatory markers in the peripheral blood T cells were analyzed by ELISA. The total and phosphorylated levels of ERK1/2, JNK and p38 were assessed by Western blot. Protein amount of IKKalpha and p65, IKKalpha/beta activity and p65 activity were evaluated by Western blot and luciferase assay. The clinical studies presented that PCG significantly relieved the six symptoms of chronic pharyngitis patients. Pathology analysis of chronic pharyngitis animals showed that the PCG treatment groups showed a significant decrease in the number of pathologic cells and the reduction of pathologic cells was dose-dependent (p < 0.01). ELISA analysis showed that PCG significantly inhibited the alphaCD3-induced increase of IFN-gamma, IL-2 and IL-4 expression in a dose-dependent manner. Moreover, Western blot and luciferase assay suggested that the phosphorylation of IKKalpha/beta in peripheral blood T cells was inhibited by the administration of PCG. These results indicate that polysaccharides exhibit anti-inflammatory effects by inhibiting the phosphorylation of IKKs, subsequently suppressing the NF-kappaB pathway activation and decreasing the expression of inflammatory mediators. PMID- 29146496 TI - Euterpe oleracea pulp extract: Chemical analyses, antibiofilm activity against Staphylococcus aureus, cytotoxicity and interference on the activity of antimicrobial drugs. AB - Euterpe oleracea (Acai) fruit are widely consumed at the Brazilian Amazon region, and biological potentials such as immunomodulatory and antioxidant have been described for its extracts. However, its antimicrobial properties remain poorly investigated. Here, the antimicrobial and antibiofilm activities of the methanolic extract of an artisanally-manufactured acai pulp (MEAP) were evaluated against clinical isolates of Staphylococcus aureus. Besides, MEAP interference on the activity of antimicrobial drugs of clinical relevance was explored, and its cytotoxicity against hepatocellular carcinoma cells (HepG2) was investigated. Biochemical and physicochemical properties of the pulp were investigated, and the presence of polyphenols on the extract was confirmed. For the first time, we report that the methanolic extract of acai pulp is effective against planktonic cells and biofilms of S. aureus, and also decreased the proliferation of HepG2 cells. Statistically significant synergism was observed when the extract was combined to the tested antimicrobials except for erythromycin, and all biochemical and physicochemical parameters ranged within the accepted values established by the Brazilian legislation. Our data open doors for more studies on the antimicrobial activity of phytomolecules isolated from Euterpe oleracea extracts, and also for its combined use with antimicrobial drugs. PMID- 29146497 TI - Nocardiosis from 1888 to 2017. AB - The genus Nocardia is an aerobic bacterium, Gram-positive and catalase positive that is in Nocardiaceae family. This bacterium first described by Edmond Nocard in 1888 and is not in human commensal bacteria. To date, nocardiosis incidence is increasing due to increase population growth rate, increase in patients with immune disorder diseases and immunocompromised patients. We surveyed taxonomic position, isolation methods, phenotypic and molecular identification at the genus and species levels, antibiogram, treatment and epidemiology in the world from 1888 to 2017. PMID- 29146498 TI - Synthesis and characterization of silver nanoparticles using Gelidium amansii and its antimicrobial property against various pathogenic bacteria. AB - Microfouling is evolving at a fast rate causing augmented mortality rates and damage worldwide. Until now, several remedial measures have been exploited to overcome microfouling, amongst them nanoparticles play a superior role. Currently, green synthesized nanoparticles have been centered owing to its eco friendly, cost effectively and non-toxic nature which has also increased its industrial applications (biomedicine, food and textile). In the present research Silver Nanoparticles (Ag NPs) synthesized using marine red algae Gelidium amansii. The synthesized Ag NPs were characterized using UV-Vis Spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). Further the antibacterial potentials of Ag NPs were evaluated against pathogenic Gram positive (Staphylococcus aureus, Bacillus pumilus) and Gram negative bacterial (Escherichia coli, Pseudomonas aeruginosa, Vibrio parahaemolyticus, Aeromonas hydrophila) pathogens. Our findings suggest that Ag NPs synthesized using a green approach effectively reduce the bacterial growth by eliciting a bactericidal activity against the Gram Negative and Gram Positive biofilm forming pathogens. Thereby, Ag NPs synthesized using G. amansii could reflect as potential anti micro-fouling coatings for various biomedical and environmental applications. PMID- 29146499 TI - Antimicrobial resistance and virulence genes profiling of methicillin-resistant Staphylococcus aureus isolates in a burn center: A 5-year study. AB - Methicillin-resistant S. aureus (MRSA) has attracted more and more attention in recent years, especially in burn medical centers. Here we conducted a 5-year period study to evaluate the MRSA infection in our burn center. The staphylococcal chromosomal cassette mec (SCCmec) typing, antimicrobials susceptibility and virulence profiles were also performed among the MRSA isolates. Of the 259 S. aureus isolates, 239 (92.28%) isolates were identified as MRSA. A decreased trend of MRSA isolation rate over time was found (P = 0.0063). Majority of MRSA isolates in our center belonged to SCCmec type III (230/239, 96.23%). Antimicrobials susceptibility tests of the MRSA isolates revealed significantly decreased resistance to clindamycin (P = 0.0183), and increased resistance to chloramphenicol (P = 0.0020) and minocycline (P < 0.0001) over time. Trimethoprim/sulfamethoxazole, clindamycin, vancomycin, teicoplanin and linezolid were suggested to be good choice for MRSA infection in our center. Virulence factors profiling showed that most of MRSA isolates in our center carried the virulence factor pattern of cna-clfA-clfB-eno-fib-icaA-icaD-sea psmalpha-lukED-hlg-hlgv-hla-hld (214/239, 89.54%). In conclusion, our study suggests that MRSA infection is serious in our burn center, but presented decreased trend over time. Most of MRSA isolates in our center presented the same virulence factor profile. More attention should be attached to nosocomial infection in burn medical center. Antimicrobials susceptibility changing over time was observed. Antimicrobials susceptibility monitoring is necessary and helps to select appropriate drugs against MRSA infections. PMID- 29146500 TI - Motility, biofilm formation, apoptotic effect and virulence gene expression of atypical Salmonella Typhimurium outside and inside Caco-2 cells. AB - Disease outbreaks related to waterborne pathogen contamination throughout the world as well as challenges that lie ahead for addressing persistent infection are of renewed interest. In this research, we studied the effects of prolonged exposure of Salmonella enterica serovar Typhimurium to the cues encountered in the extracellular environment particularly in seawater microcosm on bacterial virulence and subsequent infection in Caco-2 cells. Our data show a significant difference in biofilm formation, swimming and swarming motilities between normal and stressed cells of S. Typhimurium under differing NaCl conditions (P < 0.05). Interestingly, adhesion, invasion and apoptotic activity to Caco-2 epithelial cells were determined during infection with normal and stressed Salmonella. Furthermore, we compared the expression of SPI-1 virulence genes (sopA, sopB, sopD, sopE2 and hilA) of normal and stressed S. Typhimurium in response to salt conditions encountered in the extracellular environment in LB broth and after epithelial cell exposure. The interest of the present study is due to the fact that to investigate the bacterial survival strategies during its movement from the natural surroundings to the host cell is fundamental to our understanding of the infection process during the host-pathogen interactions. PMID- 29146501 TI - Antibacterial activity and probiotic characterization of autochthonous Paenibacillus polymyxa isolated from Anabas testudineus (Bloch, 1792). AB - Microbial fish pathogens are prevalent in aquaculture. Control of bacterial fish pathogens is important and bio control of pathogenic bacteria is a novel field of study. The aim of this study was to evaluate the antagonistic activity of bacteria isolated from Anabas testudineus against potent fish pathogens. The cellular components/preparations and filtered cell free culture supernatants were effective against six fish pathogens. Altogether 110 strains were isolated from fish proximal and distal intestine, out of which 10 strains were selected through well diffusion method. From them a strain HGA4C having prominent antimicrobial activity was selected as candidate probiotic strain. The whole-cell product, heat killed whole-cell product and the filtered broth were exhibited bactericidal activity against the tested pathogens. Among them cell free culture supernatant showed maximum inhibition. In addition, isolated candidate probiotic bacterium was capable of producing extracellular enzymes important for the digestion of food ingredients and was effectively grown in fish mucus obtained from Oreochromis niloticus. The strain tolerated gradient of bile juice secreted by the host and effectively produced biofilm. Analysis of 16S rDNA sequence revealed that isolated strain HGA4C was Paenibacillus polymyxa (MF457398.1). Furthermore intraperitoneal injection of the bacterium did not induce any pathological anomalies or mortalities in Oreochromis niloticus and disclosed the safety of this bacterium as a candidate probiotic in aquaculture. PMID- 29146502 TI - Protracted motivational dopamine-related deficits following adolescence sugar overconsumption. AB - Adolescence represents a critical period characterized by major neurobiological changes. Chronic stimulation of the reward system during adolescence might constitute an important factor of vulnerability to pathological development. Increasing evidences suggest that adolescent overconsumption of sweet palatable foods impact reward-based processes. However, the neurobiological bases of these deficits remain poorly understood. Previous studies have demonstrated motivational deficits for palatable foods after sweet diet exposure during adolescence that might involve the dopamine (DA) system, a central actor in incentive processes. In the present study, the impact of adolescent sugar overconsumption on the sensitivity of the DA system was tested using pharmacological (Experiment 1) and receptor expression approaches (Experiment 2). Adolescent rats received free and continuous access to 5% sucrose solution from post-natal day 30-46. At adulthood, the functionality of the DA system in motivational processes was tested using systemic injections of specific DA receptors D1R or D2R agonists and antagonists during a motivation-dependent progressive ratio task (Experiment 1). Sucrose-exposed rats showed a lower motivation for saccharin and a decreased sensitivity to the effects of both D1R and D2R stimulation and blockade. In Experiment 2, Sucrose-exposed animals presented a lower expression of both D1R and D2R in the nucleus accumbens, a central brain region for incentive processes, but not in dorsal striatum or prefrontal cortex. These findings highlight the impact of sucrose overconsumption during adolescence on DA system that may support deficits in reward-related disorders. PMID- 29146503 TI - Methodology for controlled administration of smoked synthetic cannabinoids JWH 018 and JWH-073. AB - Synthetic cannabinoids (SCs) are a significant public health concern given their widespread use and severe effects associated with intoxication. However, there is a paucity of controlled human studies investigating the behavioral and physiological effects and pharmacokinetics of these compounds. Designing a reliable method to administer consistent, concentration-dependent synthetic cannabinoids is an integral component of controlled study of these compounds. Further, optimizing methods to assess the parent compounds and metabolites in plasma is critical in order to be able to establish their pharmacokinetics after administration. To develop a reliable method to administer smokable, concentration-dependent SCs, cigarettes were prepared with plant matter adulterated with increasing concentrations of the first generation cannabinoids found in SC products, JWH-018 and JWH-073. Cigarettes were assessed 1-6 months after preparation using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to determine compound stability over time and concentration consistency throughout the cigarettes. Optimal conditions to detect metabolites in human plasma as a function of storage temperature (-4 degrees C to -80 degrees C) and time (24 h - 1 month) were also determined. Analyses verified that the method utilized to develop SC cigarettes yielded consistent, concentration-dependent products within 25% of the expected concentrations. JWH 018, JWH-073 and metabolites in spiked plasma were stable under the time and temperature conditions; concentrations were within +/-20% of target values. These studies provide techniques and methods to conduct controlled investigations of the dose-dependent effects of first generation SCs to begin understanding risks associated with use. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' PMID- 29146506 TI - Silicone Metacarpophalangeal Arthroplasty for Osteoarthritis: Long-Term Results. AB - PURPOSE: To demonstrate that silicone metacarpophalangeal (MCP) arthroplasty provides excellent long-term outcomes with a low complication rate in osteoarthritis patients. METHODS: A consecutive cohort of 35 patients with osteoarthritis of 1 or more MCP joints undergoing anatomically neutral silicone MCP arthroplasty was followed over a 15-year period. Functional outcomes including strength and range of motion (ROM), as well as complications, were recorded. All patients were available for long-term assessment including radiographs and outcomes questionnaire. RESULTS: Average follow-up for the cohort of 35 patients (40 implants) was 8.3 years (range, 2-17 years). Average age was 58 years (range, 42-80 years) with 22 men and 13 women. In 31 patients, a single MCP joint was involved (middle finger, 20; index finger, 10; little finger, 1). The dominant hand was involved in 23 patients. Seven (of 14) patients had a concomitant RCL reconstruction of the index finger MCP joint; no other digit had a collateral ligament reconstruction. Average final visual analog scale pain score was 0.3 of 10. Average final active ROM arc was from 4 degrees (range, 0 degrees -20 degrees ) to 73 degrees (range, 50 degrees -90 degrees ) of flexion. One patient had a revision MCP arthroplasty for a 97% clinical survivorship. Radiographs demonstrated fractured implants in 5 of 40 (12.5%) implants, but none exhibited instability, pain, or ROM deterioration. Average Michigan Hand Outcomes Questionnaire score was 82 (of 100) at final follow-up. CONCLUSIONS: Silicone arthroplasty is effective in the treatment of primary MCP osteoarthritis. Implant survivorship is 97% (clinical) and 88% (radiographic) in long-term follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29146504 TI - Minocycline protects developing brain against ethanol-induced damage. AB - Fetal alcohol spectrum disorders (FASD) are caused by ethanol exposure during the pregnancy and is the leading cause of mental retardation. Ethanol exposure during the development results in the loss of neurons in the developing brain, which may underlie many neurobehavioral deficits associated with FASD. It is important to understand the mechanisms underlying ethanol-induced neuronal loss and develop appropriate therapeutic strategies. One of the potential mechanisms involves neuroimmune activation. Using a third trimester equivalent mouse model of ethanol exposure, we demonstrated that ethanol induced a wide-spread neuroapoptosis, microglial activation, and neuroinflammation in C57BL/6 mice. Minocycline is an antibiotic that inhibits microglial activation and alleviates neuroinflammation. We tested the hypothesis that minocycline may protect neurons ethanol-induced neuron death by inhibiting microglial activation and neuroinflammation. We showed that minocycline significantly inhibited ethanol-induced caspase-3 activation, microglial activation, and the expression of pro-inflammatory cytokines. In contrast, minocycline reversed ethanol inhibition of anti-inflammatory cytokines. Minocycline blocked ethanol-induced activation of GSK3beta, a key mediator of neuroinflammation and microglial activation in the developing brain. Consistent with the in vivo observations, minocycline inhibited ethanol-induced the expression of pro-inflammatory cytokines and activation of GSK3beta in a microglia cell line (SIM-9). GSK3beta inhibitor eliminated ethanol activation of pro-inflammatory cytokines in SIM-9 cells. Co-cultures of cortical neurons and SIM-9 microglia cells sensitized neurons to alcohol-induced neuronal death. Minocycline protected neurons against ethanol-induced neuronal death in neurons/microglia co-cultures. Together, these results suggest that minocycline may ameliorate ethanol neurotoxicity in the developing by alleviating GSK3beta mediated neuroinflammation. PMID- 29146507 TI - Impact of Osteoarthritis and Total Joint Arthroplasty on the Kinematics of the Trapeziometacarpal Joint: A Pilot Study. AB - PURPOSE: To quantify the effect of osteoarthritis (OA) and total trapeziometacarpal (TMC) joint replacement on thumb kinematics during the primary physiological motions of the thumb. METHODS: We included 4 female patients with stage III TMC OA. A computed tomography-based markerless method was used to quantify the 3-dimensional thumb kinematics in patients before and after TMC joint replacement surgery with the Arpe implant. RESULTS: Trapeziometacarpal OA led to a marked decrease of internal rotation and abduction of the first metacarpal (MC1) during thumb flexion and a decrease of MC1 adduction during thumb adduction. As a compensatory phenomenon, the trapezium displayed increased abduction. The absence of MC1 translation in the ball-and-socket implant seems to induce a decrease of MC1 adduction as well as a decrease of trapezium adduction during thumb adduction, compared with OA and healthy joints. Implant replacement displayed an unchanged MC1 flexion during thumb flexion and seemed to slightly increase MC1 axial rotation during thumb flexion and adduction. Abduction and adduction of the MC1 are limited and compensated by this somewhat increased axial rotation, allowing more efficient thumb opposition. CONCLUSIONS: The study highlights that advanced TMC OA mainly restricts the MC1 mobility. We also showed that, whereas total joint arthroplasty is able to restore thumb function, it cannot fully replicate the kinematics of the healthy TMC joint. CLINICAL RELEVANCE: The quantification of TMC joint kinematics in OA and implanted patients is essential to improve our understanding of TMC OA as well as to enhance the functionality of implant designs. PMID- 29146505 TI - Muscarinic receptor oligomerization. AB - G protein-coupled receptors (GPCRs) have been classically described as monomeric entities that function by binding in a 1:1 stoichiometric ratio to both ligand and downstream signalling proteins. However, in recent years, a growing number of studies has supported the hypothesis that these receptors can interact to form dimers and higher order oligomers although the molecular basis for these interactions, the overall quaternary arrangements and the functional importance of GPCR oligomerization remain topics of intense speculation. Muscarinic acetylcholine receptors belong to class A of the GPCR family. Each muscarinic receptor subtype has its own particular distribution throughout the central and peripheral nervous systems. In the central nervous system, muscarinic receptors regulate several sensory, cognitive, and motor functions while, in the peripheral nervous system, they are involved in the regulation of heart rate, stimulation of glandular secretion and smooth muscle contraction. Muscarinic acetylcholine receptors have long been used as a model for the study of GPCR structure and function and to address aspects of GPCR dimerization using a broad range of approaches. In this review, the prevailing knowledge regarding the quaternary arrangement for the various muscarinic acetylcholine receptors has been summarized by discussing work ranging from initial results obtained using more traditional biochemical approaches to those generated with more modern biophysical techniques. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'. PMID- 29146508 TI - Biomechanical Analysis of Palmar Midcarpal Instability and Treatment by Partial Wrist Arthrodesis. AB - PURPOSE: To create a biomechanical model of palmar midcarpal instability by selective ligament sectioning and to analyze treatment by simulated partial wrist arthrodesis. METHODS: Nine fresh-frozen cadaver arms were moved through 3 servohydraulic actuated motions and 2 passive wrist mobilizations. The dorsal radiocarpal, triquetrohamate, scaphocapitate, and scaphotrapeziotrapezoid ligaments were sectioned to replicate palmar midcarpal instability. Kinematic data for the scaphoid, lunate, and triquetrum were recorded before and after ligament sectioning and again after simulated triquetrohamate arthrodesis (TqHA) and radiolunate arthrodesis (RLA). RESULTS: Following ligament sectioning, the model we created for palmar midcarpal instability was characterized by significant increases in (1) lunate angular velocity, (2) lunate flexion extension, and (3) dorsal/volar motion of the capitate during dorsal/volar mobilizations. Simulated TqHA caused significantly more scaphoid flexion and less extension during the wrist radioulnar deviation motion. It also increased the amount of lunate and triquetral extension during wrist flexion-extension. Simulated RLA significantly reduced scaphoid flexion during both wrist radioulnar deviation and flexion-extension. CONCLUSIONS: Both simulated arthrodeses eliminate wrist clunking and may be of value in treating palmar midcarpal instability. However, simulated RLA reduces proximal row motion whereas simulated TqHA alters how the proximal row moves. Long-term clinical studies are needed to determine if these changes are detrimental. CLINICAL RELEVANCE: Palmar midcarpal instability is poorly understood, with most treatments based on pathomechanical assumptions. This study provides information that clinicians can use to design better treatment strategies for this unsolved condition. PMID- 29146509 TI - Isolated Coronal Shear Fracture of the Nonossified Humeral Trochlea in a 7-Year Old Patient. AB - Coronal shear fractures of the nonossified humeral trochlea are extremely rare in skeletally immature children. This fracture is difficult to diagnose accurately on routine radiographs. In addition, the mechanism of injury and appropriate treatment methods are unknown. We present the case of a 7-year-old boy who sustained an isolated coronal shear fracture of the nonossified humeral trochlea. Internal fixation of the fracture was performed with 2 K-wires. Two and a half years after surgery, the patient had pain-free active range of motion of the elbow from 0 degrees to 130 degrees with full forearm rotation and magnetic resonance imaging showed healing of the chondral fragment of the trochlea. Hand surgeons should be aware of the possibility of this rare fracture in skeletally immature children. Magnetic resonance imaging and arthrography are helpful in establishing the correct diagnosis. PMID- 29146510 TI - Relative Contributions of the Midcarpal and Radiocarpal Joints to Dart-Thrower's Motion at the Wrist. AB - PURPOSE: To identify the relative contributions of the radiocarpal (RC) and midcarpal (MC) joints to dart-thrower's motion (DTM) of the wrist. METHODS: Six cadaveric upper extremities were fixed to a custom-designed loading jig allowing for pure moment-rotation analysis in 24 different directions of wrist motion. Each specimen was tested in 3 states: intact, simulated radiocarpal fusion (sRCF) and simulated pancarpal fusion (sPCF). Moments of +/- 1.5 Nm were applied at each of 24 directions for each state and the resulting wrist rotation recorded. Data from each specimen were reduced to compute the range of motion (ROM) envelopes and the orientation of the ROM for the 3 different states. RESULTS: The ROM was significantly decreased in the sRCF and sPCF groups compared with the intact group in the directions of the pure extension, radial extension, ulnar flexion, and ulnar deviation. No significant difference in ROM was detected between the sRCF and sPCF groups in any direction. The ROM envelopes for the intact, sRCF, and sPCF groups were all oriented obliquely to the axis of pure wrist flexion extension near a path of ulnar flexion-radial extension, consistent with prior reports on DTM. CONCLUSIONS: Although both simulated fusion types decreased ROM compared with the intact wrist, the principal direction of wrist motion along the path of DTM was not significantly altered by simulated RCF or PCF. CLINICAL RELEVANCE: These findings suggest that the RC and MC joints can each contribute to a similar mechanical axis of motion located along the path of DTM when the other joint has been eliminated via fusion. Surgical options such as partial wrist fusions may maintain the native wrist's mechanical axis if either the RC or the MC joint is preserved, despite significant reduction in overall ROM. PMID- 29146511 TI - Surgical Management of Proximal Interphalangeal Joint Repetitive Stress Epiphyseal Fracture Nonunion in Elite Sport Climbers. AB - Repetitive stress fracture of the middle phalanx epiphysis is an injury specific to elite adolescent sport climbers. As sport climbing becomes increasingly popular in younger age groups, an increased number of these injuries have been reported in recent years. To date, treatment of these fractures has been nonsurgical, with strict rest and physiotherapy prescribed until fracture union. However, when these patients present in a delayed fashion with an established nonunion, nonsurgical treatment may fail, leading to disabling chronic pain and/or digital deformity in some cases. In this article, we present 2 cases of surgical treatment for finger middle phalanx repetitive stress epiphyseal fracture nonunion, using a percutaneous spot drilling epiphysiodesis technique. PMID- 29146512 TI - Neonatal tetanus in an African newborn. PMID- 29146513 TI - Seroprevalence and risk factors of Hepatitis E infection in Jordan's population: First report. AB - OBJECTIVES: Hepatitis E virus (HEV) is hyperendemic in many countries, but data on this virus are not available in Jordan. This study determined the seroprevalence, risk factors and zoonotic potential of HEV in a Jordanian population. METHODS: A total of 450 sera samples from 8 different governorates were tested for HEV-IgG. A pre-tested and validated questionnaire was used to collect risk factor data including animal interaction and environmental exposures. RESULTS: The overall seroprevalence was 30.9%. Eating undercooked meat was significantly associated with HEV seropositivity (OR=2.06, 95%CI 1.04-4.06) after controlling for age, gender, travel history and source of water. Age was also associated with HEV seropositivity; the youngest (<=14 years of age) and oldest age groups (60 and 80 years of age) had the highest prevalence (45.5% and 53.2%, respectively), compared to those between 20 to 29 years of age and 30 to 39 years of age (20.2 and 15.2%, respectively), although the small sample size among the youngest group tempers this association. There was evidence of a marginal association between owning camels and an increased odds of HEV seropositivity. Place of residence and source of drinking water were not associated with infection. CONCLUSION: This is the first study to report HEV seroprevalence in Jordan and shows that HEV exposure is high in Jordan. Surveillance for acute and chronic Hepatitis E is needed to estimate the frequency of the actual disease. PMID- 29146514 TI - Brucella related myocarditis. PMID- 29146515 TI - Family history of zoster and risk of developing herpes zoster. AB - BACKGROUND: Studies have investigated a possible association between family history of HZ and the occurrence of HZ. However, the results were inconclusive and susceptible to bias. We evaluated this association in an elderly population. METHODS: The matched case-control study conducted at Kaiser Permanente Southern California in 2012-2015 included 656 incident HZ patients >=60 whose skin lesion tested positive for varicella zoster virus by polymerase chain reaction. Half of the HZ patients were vaccinated with zoster vaccine as achieved by stratified sampling. The controls were randomly selected and 1:1 matched to the cases on sex, age (+/-1year), and zoster vaccination (+/-3 months of the case's vaccination date). Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Having any blood relative with a history of HZ was associated with a slightly increased risk of HZ (adjusted OR=1.37, 95% CI 1.05-1.79). The adjusted OR associated with having one and two categories of first-degree blood relatives with a history of HZ was 1.30 (95% CI: 0.97-1.73) and 2.53 (95% CI: 1.17-5.44), respectively. CONCLUSIONS: Our results suggested a weak association between the development of HZ and a positive family history of HZ among the elderly population. PMID- 29146516 TI - Response to "Worrisome high frequency of extended-spectrum beta-lactamase producing Escherichia coli in community-acquired urinary tract infections: a case control study; methodological issues". PMID- 29146517 TI - Nanomedicine safety in preclinical and clinical development: focus on idiosyncratic injection/infusion reactions. AB - Injection/infusion reactions to nanopharmaceuticals (and particulate drug carriers) are idiosyncratic and well documented. The molecular basis of nanoparticle-mediated injection reactions is debatable, with two hypotheses as front-runners. The first is complement-activation-related 'pseudoallergy', where a causal role for nanoparticle-mediated complement activation in injection/infusion reactions is considered. However, the second hypothesis (the rapid phagocytic response hypothesis) states a transitional link from robust clearance of nanoparticles (NPs) from the blood by strategically placed responsive macrophages to adverse hemodynamic and cardiopulmonary reactions, regardless of complement activation. Here, I critically examine and discuss these hypotheses. Current experimentally derived evidence appears to be more in support of the rapid phagocytic response hypothesis than of the 'pseudoallergy' hypothesis. PMID- 29146518 TI - Fixed-dose combinations: a potential means to boost drug development for selected drugs. PMID- 29146519 TI - Drug discovery tomorrow: how to Catapult ourselves into the future. PMID- 29146521 TI - HLA-DQ-Gluten Tetramer Blood Test Accurately Identifies Patients With and Without Celiac Disease in Absence of Gluten Consumption. AB - BACKGROUND & AIMS: Celiac disease is characterized by HLA-DQ2/8-restricted responses of CD4+ T cells to cereal gluten proteins. A diagnosis of celiac disease based on serologic and histologic evidence requires patients to be on gluten-containing diets. The growing number of individuals adhering to a gluten free diet (GFD) without exclusion of celiac disease complicates its detection. HLA-DQ-gluten tetramers can be used to detect gluten-specific T cells in blood of patients with celiac disease, even if they are on a GFD. We investigated whether an HLA-DQ-gluten tetramer-based assay accurately identifies patients with celiac disease. METHODS: We produced HLA-DQ-gluten tetramers and added them to peripheral blood mononuclear cells isolated from 143 HLA-DQ2.5+ subjects (62 subjects with celiac disease on a GFD, 19 subjects without celiac disease on a GFD [due to self-reported gluten sensitivity], 10 subjects with celiac disease on a gluten-containing diet, and 52 presumed healthy individuals [controls]). T cells that bound HLA-DQ-gluten tetramers were quantified by flow cytometry. Laboratory tests and flow cytometry gating analyses were performed by researchers blinded to sample type, except for samples from subjects with celiac disease on a gluten-containing diet. Test precision analyses were performed using samples from 10 subjects. RESULTS: For the HLA-DQ-gluten tetramer-based assay, we combined flow-cytometry variables in a multiple regression model that identified individuals with celiac disease on a GFD with an area under the receiver operating characteristic curve value of 0.96 (95% confidence interval [CI] 0.89 1.00) vs subjects without celiac disease on a GFD. The assay detected individuals with celiac disease on a gluten-containing diet vs controls with an area under the receiver operating characteristic curve value of 0.95 (95% CI 0.90-1.00). Optimized cutoff values identified subjects with celiac disease on a GFD with 97% sensitivity (95% CI 0.92-1.00) and 95% specificity (95% CI 0.84-1.00) vs subjects without celiac disease on a GFD. The values identified subjects with celiac disease on a gluten-containing diet with 100% sensitivity (95% CI 1.00-1.00]) and 90% specificity (95% CI 0.83-0.98) vs controls. In an analysis of 4 controls with positive results from the HLA-DQ-gluten tetramer test, 2 had unrecognized celiac disease and the remaining 2 had T cells that proliferated in response to gluten antigen in vitro. CONCLUSIONS: An HLA-DQ-gluten tetramer-based assays that detects gluten-reactive T cells identifies patients with and without celiac disease with a high level of accuracy, regardless of whether the individuals are on a GFD. This test would allow individuals with suspected celiac disease to avoid gluten challenge and duodenal biopsy, but requires validation in a larger study. Clinicaltrials.gov no: NCT02442219. PMID- 29146522 TI - Germline Genetic Features of Young Individuals With Colorectal Cancer. AB - BACKGROUND & AIMS: The incidence of colorectal cancer (CRC) in individuals younger than 50 years is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition. METHODS: We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing. For subjects with uninformative clinical evaluations, germline DNA samples were (re)sequenced using a research-based next-generation sequencing multigene panel. The primary outcome was identification of a pathogenic germline mutation associated with cancer predisposition. RESULTS: Of 430 young CRC cases, 111 (26%) had a first-degree relative with CRC. Forty-one of the subjects with CRC (10%) had tumors with histologic evidence for mismatch repair deficiency. Of 315 subjects who underwent clinical germline sequencing, 79 had mutations associated with a hereditary cancer syndrome and 21 had variants of uncertain significance. Fifty-six subjects had pathogenic variants associated with Lynch syndrome (25 with mutations in MSH2, 24 with mutations in MLH1, 5 with mutations in MSH6, and 2 with mutations in PMS2) and 10 subjects had pathogenic variants associated with familial adenomatous polyposis. Thirteen subjects had mutations in other cancer-associated genes (8 in MUTYH, 2 in SMAD4, 1 in BRCA1, 1 in TP53, and 1 in CHEK2), all identified through multigene panel tests. Among 117 patients with uninformative clinical evaluations, next-generation sequence analysis using a multigene panel detected actionable germline variants in 6 patients (5%). Only 43 of the 85 subjects with germline mutations associated with a hereditary cancer syndrome (51%) reported a CRC diagnosis in a first-degree relative. CONCLUSIONS: Approximately 1 in 5 individuals diagnosed with CRC at age younger than 50 years carries a germline mutation associated with cancer; nearly half of these do not have clinical histories typically associated with the identified syndrome. Germline testing with multigene cancer panels should be considered for all young patients with CRC. PMID- 29146524 TI - Undergraduate nutrition education of health professionals in Greek medical, dentistry, pharmacy, nursing and midwifery departments. PMID- 29146523 TI - Factors That Contribute to Differences in Survival of Black vs White Patients With Colorectal Cancer. AB - BACKGROUND & AIMS: Previous studies reported that black vs white disparities in survival among elderly patients with colorectal cancer (CRC) were because of differences in tumor characteristics (tumor stage, grade, nodal status, and comorbidity) rather than differences in treatment. We sought to determine the contribution of differences in insurance, comorbidities, tumor characteristics, and treatment receipt to disparities in black vs white patients with CRC 18-64 years old. METHODS: We used data from the National Cancer Database, a hospital based cancer registry database sponsored by the American College of Surgeons and the American Cancer Society, on non-Hispanic black (black) and non-Hispanic white (white) patients, 18-64 years old, diagnosed from 2004 through 2012 with single or first primary invasive stage I-IV CRC. Each black patient was matched, based on demographic, insurance, comorbidity, tumor, and treatment features, with 5 white patients, from partially overlapping subgroups, using propensity score and greedy matching algorithms. We used the Kaplan-Meier method to estimate 5-year survival and Cox proportional hazards models to generate hazard ratios. RESULTS: The absolute 5-year survival difference between black and white unmatched patients with CRC was 9.2% (57.3% for black patients vs 66.5% for white patients; P < .0001). The absolute difference in survival did not change after patient groups were matched for demographics, but decreased to 4.9% (47% relative decrease [4.3% of 9.2%]) when they were matched for insurance and to 2.3% when they were matched for tumor characteristics (26% relative decrease [2.4% of 9.2%]). Further matching by treatment did not reduce the difference in 5-year survival between black and white patients. In proportional hazards model, insurance and tumor characteristics matching accounted for the 54% and 27% excess risk of death in black patients, respectively. CONCLUSIONS: In an analysis of data from the National Cancer Database, we found that insurance coverage differences accounted for approximately one half of the disparity in survival rate of black vs white patients with CRC, 18-64 years old; tumor characteristics accounted for a quarter of the disparity. Affordable health insurance coverage for all populations could substantially reduce differences in survival times of black vs white patients with CRC. PMID- 29146525 TI - Maternal nutritional determinants of colostrum fatty acids in the EDEN mother child cohort. AB - BACKGROUND & AIMS: Programming of infant development and later health may depend on early-milk polyunsaturated fatty acids (PUFA) contents, that are very variable between women for reasons not well elucidated. Indeed, a high n-6/n-3 PUFA in milk was associated with higher adiposity, arterial pressure and lower psychomotor scores in childhood. We aimed to explore the respective contribution of several maternal and perinatal factors to the variability of linoleic (LA), alpha-linolenic (ALA), arachidonic (AA), and docosahexaenoic (DHA) acid levels in early milk. METHODS: Fatty acids of 934 colostrum samples from the EDEN mother child cohort were analyzed by gas chromatography. The dietary intakes during the last trimester of pregnancy were estimated using a quantitative food frequency questionnaire. Relationship between milk PUFA and dietary fatty acids, and other maternal or pregnancy variables were analyzed by multiple linear regression. RESULTS: The means (+/-SD) of colostrum LA, ALA, AA and DHA levels were, respectively, 9.85 +/- 1.85, 0.65 +/- 0.22, 0.86 +/- 0.16, and 0.64 +/- 0.19% of total fatty acids. Obese mothers colostrum contained the highest level of LA and AA and the lowest level of ALA and DHA. Colostrum LA, AA and DHA levels were higher in primiparous women. Mother's age was positively associated with colostrum AA and DHA. Dietary n-6 PUFA were associated with higher LA and lower DHA levels in colostrum, while dietary n-3 PUFA were related to higher LA and lower AA levels. Contrary to what was observed for DHA, AA level in colostrum was not related to its dietary intake. High dietary AA/DHA and total n-6/n-3 ratios were critical for the content of DHA in colostrum lipids. CONCLUSIONS: Our study brings new insights in the understanding of the main maternal factors involved in PUFA levels variability in early milk. These data are important to consider for dietary counseling for women prior to and during pregnancy. PMID- 29146520 TI - Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals. AB - BACKGROUND & AIMS: Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. METHODS: We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naive patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. RESULTS: RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. CONCLUSIONS: We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies. PMID- 29146526 TI - Application of the sum-peak method to activity standardizations of 152Eu sources in LNMRI (BR). AB - The sum-peak method, an absolute measurement technique that uses coincidence counting and gamma-ray spectrometry, was applied to activity standardization of 152Eu sources. The decay branch used was that of 152Sm, as it is almost entirely electron capture and exhibits X-rays with a high probability of coincidence with the 121.8keVgamma rays, as evidenced by the matrix technique used for complex decay schemes, a method for deriving counting rate equations describing coincidence summing of gamma and X-rays. The result was compared with the calibration performed by ionization chamber traceable to BIPM. The results presented uncertainty values of 0.50% (k = 1). PMID- 29146527 TI - Osthole attenuates right ventricular remodeling via decreased myocardial apoptosis and inflammation in monocrotaline-induced rats. AB - Osthole (Ost) is a coumarin that exhibits wide pharmacological effects in the cardiovascular system. However, whether Ost can inhibit apoptosis and inflammation in right ventricle (RV) cardiomyocytes and prevent RV remodeling is not clear. This study was designed to investigate the effect of Ost on RV remodeling and the underlying mechanism. By applying a monocrotaline (MCT) induced rat model, the effect of Ost on RV remodeling was investigated. Rats were given a single dose of MCT (50mg/kg) subcutaneously (s.c.) to establish the RV remodeling model, followed by treatment with 10 or 20mg/kg Ost via daily gavage for 28 days. The RV pressure was measured, and a histological analysis was performed. The results suggested that Ost remarkably decreased RV pressure and improved myocardial hypertrophy and mitochondrial swelling, vacuolization, and sarcoplasmic reticulum enlargement when compared with the model group. To further investigate the roles of apoptosis and inflammation in the effects of Ost on MCT induced RV remodeling, apoptosis-related factors and inflammatory-associated factors were examined by western blot. Ost was found to inhibit myocardial apoptosis and inflammation in the RV. Overall, the present results indicate that Ost suppresses the RV remodeling process induced by MCT in rats, which may be at least partially mediated through the reduction of myocardial apoptosis and inflammation. PMID- 29146528 TI - Hierarchical Bayesian models for the autonomic-based concealed information test. AB - The concealed information test (CIT) is a psychophysiological memory detection technique for examining whether an examinee recognizes crime-relevant information. In current statistical analysis practice, the autonomic responses are usually transformed into Z scores within individuals to remove inter- and intra-individual variability. However, this conventional procedure leads to overestimation of the effect size, specifically the standardized mean difference of the autonomic responses between the crime-relevant information and the crime irrelevant information. In this study, we attempted to resolve this problem by modeling inter- and intra-individual variability directly using hierarchical Bayesian modeling. Five models were constructed and applied to CIT data obtained from 167 participants. The validity of the CIT was confirmed using Bayesian estimates of the effect sizes, which are more accurate and interpretable than conventional effect sizes. Moreover, hierarchical Bayesian modeling provided information that is not available from the conventional statistical analysis procedure. PMID- 29146529 TI - Inhibitory effect of the extract of rhizome of Curcuma longa L in gelatinase activity and its effect on human skin. AB - Exposure to UV radiation to human skin up-regulates the synthesis of matrix metalloproteinase (MMP) family. Gelatinases are member of MMPs which have been suggested to play an important role in photoaging such as wrinkle formation. To inhibit gelatinase activity is regarded to be very important to keep healthy skin and to protect wrinkle formation. On the other hand, anti-photoaging agents are expected to be derived from natural resources, especially plants. Plant extracts having gelatinase-inhibitory effect that might be used as safe anti-photoaging ingredient were widely screened. An extract of rhizomes of Curcuma longa L. showed inhibitory effect of gelatinase activity. Curcuminoids and slight amount of compound, 6,11-dihydroxy-3-(4-hydroxy-3-mthoxyphenethyl)-7-[(E)-4-(4-hydroxy-3 methoxyphenyl)-2-oxo-3-butenyl]-10-methoxy-2-oxabicyclo[6.3.1.]dodeca 1(11),8(12),9-trien-5-yl (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate (curcuminoid D) were isolated as the gelatinase-inhibitory components from methanol extract of rhizomes. The structure of curcuminoid D was determined by means of spectral data including 1H- and 13C-NMR, and IR. Curcumin exerted the enhancing effect on deposition of basement membrane component at dermal-epidermal junction in skin equivalent model. Topical application of cream containing turmeric extract significantly improved facial skin elasticity and decreased the number of gelatinase-positive stratum corneum clusters in human facial skins. These results indicated that turmeric is an effective ingredient to improve skin condition and to prevent skin from photoaging by suppressing activation of gelatinase chronically caused by UV. PMID- 29146530 TI - Identification of the glucosamine kinase in the chitinolytic pathway of Thermococcus kodakarensis. AB - Although the chitinolytic pathway of the hyperthermophilic archaeon Thermococcus kodakarensis is well-studied, the genome does not contain genes homologous to previously identified glucosamine kinase genes. As some ADP-dependent glucokinases in the order Thermococcales exhibit phosphorylation activities for both glucose and glucosamine in vitro, the homolog in T. kodakarensis, encoded by TK1110, was selected as a candidate for the missing glucosamine kinase gene. The purified, recombinant TK1110 enzyme exhibited phosphorylation activities for not only glucose but also glucosamine and N-acetylglucosamine. Kinetic analysis indicated that activity towards glucosamine was as significant as that towards glucose. In order to determine the physiological role of TK1110 in the chitinolytic pathway of T. kodakarensis, a gene disruption strain of TK1110 was constructed. When grown in chitin-containing medium, the TK1110 disruption resulted in almost complete impairment in chitin degradation, and a complete loss of chitin-dependent H2 production. As H2 production is tightly linked to cell growth in T. kodakarensis, the present results strongly suggest that TK1110 functions as the glucosamine kinase responsible for the chitin degradation in T. kodakarensis. PMID- 29146531 TI - Specific oxygenation of plasma membrane phospholipids by Pseudomonas aeruginosa lipoxygenase induces structural and functional alterations in mammalian cells. AB - Pseudomonas aeruginosa is a gram-negative pathogen, which causes life-threatening infections in immunocompromized patients. These bacteria express a secreted lipoxygenase (PA-LOX), which oxygenates free arachidonic acid to 15S hydro(pero)xyeicosatetraenoic acid. It binds phospholipids at its active site and physically interacts with lipid vesicles. When incubated with red blood cells membrane lipids are oxidized and hemolysis is induced but the structures of the oxygenated membrane lipids have not been determined. Using a lipidomic approach, we analyzed the formation of oxidized phospholipids generated during the in vitro incubation of recombinant PA-LOX with human erythrocytes and cultured human lung epithelial cells. Precursor scanning of lipid extracts prepared from these cells followed by multiple reaction monitoring and MS/MS analysis revealed a complex mixture of oxidation products. For human red blood cells this mixture comprised forty different phosphatidylethanolamine and phosphatidylcholine species carrying oxidized fatty acid residues, such as hydroxy-octadecadienoic acids, hydroxy- and keto-eicosatetraenoic acid, hydroxy-docosahexaenoic acid as well as oxygenated derivatives of less frequently occurring polyenoic fatty acids. Similar oxygenation products were also detected when cultured lung epithelial cells were employed but here the amounts of oxygenated lipids were smaller and under identical experimental conditions we did not detect major signs of cell lysis. However, live imaging indicated an impaired capacity for trypan blue exclusion and an augmented mitosis rate. Taken together these data indicate that PA-LOX can oxidize the membrane lipids of eukaryotic cells and that the functional consequences of this reaction strongly depend on the cell type. PMID- 29146532 TI - Potential U.S. Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline. AB - BACKGROUND: The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults provides recommendations for the definition of hypertension, systolic and diastolic blood pressure (BP) thresholds for initiation of antihypertensive medication, and BP target goals. OBJECTIVES: This study sought to determine the prevalence of hypertension, implications of recommendations for antihypertensive medication, and prevalence of BP above the treatment goal among U.S. adults using criteria from the 2017 ACC/AHA guideline and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7). METHODS: The authors analyzed data from the 2011 to 2014 National Health and Nutrition Examination Survey (N = 9,623). BP was measured 3 times following a standardized protocol and averaged. Results were weighted to produce U.S. population estimates. RESULTS: According to the 2017 ACC/AHA and JNC7 guidelines, the crude prevalence of hypertension among U.S. adults was 45.6% (95% confidence interval [CI]: 43.6% to 47.6%) and 31.9% (95% CI: 30.1% to 33.7%), respectively, and antihypertensive medication was recommended for 36.2% (95% CI: 34.2% to 38.2%) and 34.3% (95% CI: 32.5% to 36.2%) of U.S. adults, respectively. Nonpharmacological intervention is advised for the 9.4% of U.S. adults with hypertension who are not recommended for antihypertensive medication according to the 2017 ACC/AHA guideline. Among U.S. adults taking antihypertensive medication, 53.4% (95% CI: 49.9% to 56.8%) and 39.0% (95% CI: 36.4% to 41.6%) had BP above the treatment goal according to the 2017 ACC/AHA and JNC7 guidelines, respectively. CONCLUSIONS: Compared with the JNC7 guideline, the 2017 ACC/AHA guideline results in a substantial increase in the prevalence of hypertension, a small increase in the percentage of U.S. adults recommended for antihypertensive medication, and more intensive BP lowering for many adults taking antihypertensive medication. PMID- 29146533 TI - 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. PMID- 29146534 TI - Systematic Review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. AB - OBJECTIVE: To review the literature systematically and perform meta-analyses to address these questions: 1) Is there evidence that self-measured blood pressure (BP) without other augmentation is superior to office-based measurement of BP for achieving better BP control or for preventing adverse clinical outcomes that are related to elevated BP? 2) What is the optimal target for BP lowering during antihypertensive therapy in adults? 3) In adults with hypertension, how do various antihypertensive drug classes differ in their benefits and harms compared with each other as first-line therapy? METHODS: Electronic literature searches were performed by Doctor Evidence, a global medical evidence software and services company, across PubMed and EMBASE from 1966 to 2015 using key words and relevant subject headings for randomized controlled trials that met eligibility criteria defined for each question. We performed analyses using traditional frequentist statistical and Bayesian approaches, including random-effects Bayesian network meta-analyses. RESULTS: Our results suggest that: 1) There is a modest but significant improvement in systolic BP in randomized controlled trials of self-measured BP versus usual care at 6 but not 12 months, and for selected patients and their providers self-measured BP may be a helpful adjunct to routine office care. 2) systolic BP lowering to a target of <130 mm Hg may reduce the risk of several important outcomes including risk of myocardial infarction, stroke, heart failure, and major cardiovascular events. No class of medications (i.e., angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium channel blockers, or beta blockers) was significantly better than thiazides and thiazide-like diuretics as a first-line therapy for any outcome. PMID- 29146535 TI - 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. PMID- 29146536 TI - ? PMID- 29146537 TI - Orodispersible films: Product transfer from lab-scale to continuous manufacturing. AB - Orodispersible films have been described as new beneficial dosage forms for special patient populations. Due to various production settings, different requirements on film formulations are required for non- continuous and continuous manufacturing. In this study, a continuous coating machine was qualified in regards of the process conditions for film compositions and their effects on the formed films. To investigate differences between both manufacturing processes, various film formulations of hydrochlorothiazide and hydroxypropylcellulose (HPC) or hydroxypropylmethycellulose (HPMC) as film formers were produced and the resulting films were characterized. The qualification of the continuously operating coating machine reveals no uniform heat distribution during drying. Coating solutions for continuous manufacturing should provide at least a dynamic viscosity of 1 Pa*s (wet film thickness of 500 MUm, velocity of 15.9 cm/min). HPC films contain higher residuals of ethanol or acetone in bench-scale than in continuous production mode. Continuous production lead to lower drug content of the films. All continuously produced films disintegrate within less than 30 s. There are observed significant effects of the production process on the film characteristics. When transferring film manufacturing from lab-scale to continuous mode, film compositions, processing conditions and suitable characterization methods have to be carefully selected and adopted. PMID- 29146538 TI - Rational design of polysorbate 80 stabilized human serum albumin nanoparticles tailored for high drug loading and entrapment of irinotecan. AB - Human serum albumin (HSA) nanoparticles are considered to be versatile carrier of anticancer agents in efficiently delivering the drug to the tumor site without causing any toxicity. The aim of the study was to develop stable HSA nanoparticles (NPs) of drug irinotecan (Iro) having slightly water solubility and moderate HSA binding. A novel strategy of employing a hydrophilic non-ionic surfactant polysorbate 80 which forms protein-polysorbate 80 complex with increased affinity and improvement in Iro-HSA binding has been used to maximize the loading and entrapment efficiency of Iro in HSA-NPs. Bespoke nanoparticles with entrapment efficiency (79.09%) and drug loading of 9.62% could be achieved with spherical shape and particle size of 77.38 nm, 0.290 polydispersity index and -23.7 mv Zeta potential. The drug entrapment in nanoparticles was confirmed by Differential Scanning Calorimeter, Fourier Transformation Infrared Spectroscopy and Fluorescence Spectroscopy. In vitro release of Iro from NPs showed biphasic-release with initial burst followed by prolonged release upto 24 h. The short-term stability investigation of nanodispersion showed no significant changes in physicochemical properties of NPs. Long-term studies on freeze dried Iro-HSA-NPs indicated good stability of NPs up to 12 months. This is the first report for efficient fabrication of Iro delivery system based on HSA nanoparticles. PMID- 29146539 TI - Hyaluronan-decorated liposomes as drug delivery systems for cutaneous administration. AB - The work aimed to evaluate the feasibility to design hyaluronic acid (HA) decorated flexible liposomes to enhance the skin penetration of nifedipine. Egg phosphatidylcholine (e-PC) based transfersomes (Tween 80) and transethosomes (ethanol) were prepared. HA was reacted with 1,2-dipalmitoyl-sn-glycero-3 phosphoethanolamine (HA-DPPE) and two molar ratios (0.5 and 3%) of conjugate with respect to e-PC were tested. The presence of HA significantly increased the packing order of the bilayer (as verified by differential scanning calorimetry), reducing both the encapsulation efficiency and the flexibility of the decorated liposomes in a dose-dependent manner. In fact, at the highest HA content the constant of deformability (K, N/mm) increased and the carriers remained on the skin surface after topical application. The stiffening effect of HA was counterbalanced by the addition of ethanol as fluidizing agent that allowed to maintain the highest HA concentration, meanwhile reducing the K value of the vesicles. HA-transethosomes allowed a suitable nifedipine permeation (J ~ 30 ng/cm2/h) and significantly improved the drug penetration, favouring the formation of a drug depot in the epidermis. These data suggest the potentialities of HA-transethosomes as drug delivery systems intended for the treatment of cutaneous pathologies and underline the importance of studying the effect of surface functionalization on carrier deformability to rationalize the design of such systems. PMID- 29146540 TI - Temperature-sensitive copolymer-coated fluorescent mesoporous silica nanoparticles as a reactive oxygen species activated drug delivery system. AB - In this study, a temperature and ROS-responsive drug delivery system ROSP@MSN based on mesoporous silica nanoparticles has been designed and synthesized by taking advantage of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate modified polymers (ROSP) as "nano-valve", which can respond selectively to cancer exclusive microenvironment and implement targeted drug release. Due to the superior temperature-sensitive properties of ROSP, ROSP@MSN could achieve cargo loading in cold water, and subsequently close the pore by raising temperature to obtain ROSP@MSN@DOX. Upon the stimulus of ROS, ROSP@MSN@DOX shows good release performance at physiological conditions. The cytotoxicity study demonstrates that the cell viability is about 80% after Hela cells are treated with ROSP@MSN at a concentration of 100 MUg/mL for 24 h, exhibiting the good biocompatibility of ROSP@MSN. Furthermore, after treated with ROSP@MSN@DOX at a concentration of 100 MUg/mL for 24 h, the viability of Hela cells is reduced to 40.5%; Control experiments demonstrate that, when Hela cells are pretreated with active oxygen scavenger, cell viability is about 65.3% due to the significant decrease of intracellular reactive oxygen species. Therefore, the therapeutic nanocarrier with effective encapsulation and release capacity in particular situation is a great candidate for the new drug delivery platform for targeted cancer therapy. PMID- 29146541 TI - Exploring gold nanoparticles interaction with mucins: A spectroscopic-based study. AB - The interaction between two mucin types (mucin from porcine stomach - PGM and mucin from bovine submaxillary glands - BSM) and gold nanoparticles (GNPs) of various size (5, 20 and 40 nm) and functionalization (with cysteamine or thioglycolic acid) was studied under physiological conditions, in order to investigate the affinity of the nanoparticles to the proteins. Different methods are employed to monitor the interactions: UV-vis and fluorescence spectroscopy, fluorescence lifetime, circular dichroism and transmission electron microscopy. These studies have shown the formation of a complex between GNPs and both PGM and BSM. This aspect could be of great importance for the use of gold nanoparticles for biomedical purposes in those diseases where qualitative and quantitative mucin anomalies play an essential role in mucus composition and rheology. PMID- 29146542 TI - Development of a mucoadhesive delivery system for control release of doxepin with application in vaginal pain relief associated with gynecological surgery. AB - The main purpose of this study was to develop a semisolid mucoadhesive formulation for the non-invasive vaginal administration of doxepin (DOX) for relief of pain derived from the scarring process after surgery. An orafix(r) platform loading DOX was tested for adequate stability, rheology and vaginal mucoadhesion capacity. The formulation exhibited appropriate pH and was microbiologically stable. The rheological studies confirmed its pseudoplastic and thixotropic nature with prevalence of the elastic behavior component over the viscous one. Appropriate syringeability and spreadability results were also confirmed. Different experiments showed adequate mucoadhesion capacity even in the presence of simulated vaginal fluid. Finally, DOX release, permeation and retention in vaginal mucosa studies were also accomplished with promising results. DOX release kinetics followed the modified Higuchi model and the permeation studies did not render such high values as to suggest potential systemic absorption which could lead to undesirable systemic side effects. Therefore, we can hypostatize that the proposed formulation may assist to fill in the therapeutic gap regarding pure pain relief at local level in vagina. PMID- 29146543 TI - Cardiac resynchronisation therapy optimisation of interventricular delay by the systolic dyssynchrony index: A comparative, randomised, 12-month follow-up study. AB - BACKGROUND: The aim of our study was to compare the effect of interventricular (VV) delay optimisation in CRT recipients on the basis of systolic dyssynchrony index (SDI) derived from the three-dimensional echocardiography (3DE) versus QRS width assessment on left ventricle volume reduction at the 12-month follow-up. METHODS: We included 63 patients with recently implanted CRT in this randomised, open-label trial. Patients were randomised to VV delay optimisation according to QRS complex width measurement in group 1 (n = 31) to obtain the narrowest QRS complex and SDI in group 2 (n = 32) to achieve its lowest possible value. We evaluated left ventricular end-systolic volume (LVESv), left ventricular ejection fraction (LVEF) and SDI by 3DE before CRT implantation and at a 12-month follow up in all the patients. We also obtained the New York Heart Association functional class, the 6-minute walk test, the quality of life questionnaire and the level of NT-proBNP. RESULTS: The number of volumetric responders was similar in both groups (17 vs. 20, P = 0.786). There were also no significant differences in the reduction of LVESv (-41 +/- 55 mL vs. - 61 +/- 51 mL, P = 0.111), improvement in LVEF (+10.1 +/- 10.6% vs. + 13.0 +/- 9.9%, P = 0.213) or differences in clinical outcomes between both groups at the 12-month follow-up. CONCLUSION: CRT optimisation of interventricular delay using SDI compared with QRS width assessment did not reveal any significant difference in terms of volumetric and clinical response at the 12-month follow-up. PMID- 29146544 TI - Pitfalls in coronary artery stenosis assessment in takotsubo syndrome: The role of microvascular dysfunction. PMID- 29146545 TI - Werner syndrome (WRN) gene variants and their association with altered function and age-associated diseases. AB - Werner syndrome (WS) is a heritable autosomal recessive human disorder characterized by the premature onset of several age-associated pathologies including cancer. The protein defective in WS patients, WRN, is encoded by a member of the human RECQ gene family that contains both a DNA exonuclease and a helicase domain. WRN has been shown to participate in several DNA metabolic pathways including DNA replication, recombination and repair, as well as telomere maintenance and transcription modulation. Here we review base pair-level genetic variation that has been documented in WRN, with an emphasis on non-synonymous coding single nucleotide polymorphisms (SNPs) and their associations with anthropomorphic features, longevity and disease risk. These associations have been challenging to identify, as many reported WRN SNP associations appear to be further conditioned upon ethnic, age, gender or other environmental co-variables. The WRN variant phenotypic associations identified to date are intriguing, and several are of clear clinical import. Consequently, it will be important to extend these initial associations and to identify the mechanisms and conditions under which specific WRN variants may compromise WRN function to drive cellular and organismal phenotypes as well as disease risk. PMID- 29146546 TI - Signaling via toll-like receptor 4 and CD40 in B cells plays a regulatory role in the pathogenesis of multiple sclerosis through interleukin-10 production. AB - BACKGROUND: B cells play an important role in the development of multiple sclerosis (MS), but can also exhibit regulatory functions through IL-10 production. Toll-like receptors (TLR) and CD40 signaling are likely to be involved in this process. OBJECTIVE: To investigate the ability of MS B cells to produce IL-10 in response to TLR stimulation in the presence or absence of CD40 co-stimulation. METHODS: Peripheral blood mononuclear cells obtained from 34 MS patients and 24 matched healthy participants (HS) were stimulated through either TLR4 or TLR9 alone, or together with CD40. Intracellular cytokine production was analyzed by flow cytometry. RESULTS: The frequency of IL-10-producing cells in total B cells after either TLR9 or CD40 stimulation was significantly lower in MS than HS, regardless of disease phase. The frequency of IL-10 producing B cells after TLR4 stimulation did not differ significantly between HS and MS, regardless of disease phase. TLR4 and CD40 co-stimulation synergistically increased the frequency of IL-10-producing but not pro-inflammatory cytokine-producing B cells at MS relapse. This effect was observed in both CD27- naive and CD27+ memory B cells. The frequency of IL-10-producing B cells following CD40 stimulation was significantly higher in interferon-beta responders than non-treated MS patients. Finally, we confirmed that the frequency of IL-10-producing B cells positively correlated with IL-10 production quantity by B cells using magnetic-isolated B cells. CONCLUSIONS: Cross-talk between TLR4 and CD40 signaling plays a crucial role in regulating IL-10 production by B cells during MS relapses, which may promote recovery from relapse. CD40 signaling in B cells is involved in the response to interferon-beta in MS. Collectively, TLR4 and CD40 signaling in B cells may provide a promising target for MS therapy. PMID- 29146547 TI - A gene module associated with dysregulated TCR signaling pathways in CD4+ T cell subsets in rheumatoid arthritis. AB - We analyzed the transcriptome of detailed CD4+ T cell subsets including them after abatacept treatment, and examined the difference among CD4+ T cell subsets and identified gene sets that are closely associated disease activity and abatacept treatment. Seven CD4+ T cell subsets (naive, Th1, Th17, Th1/17, nonTh1/17, Tfh and Treg) were sorted from PBMCs taken from 10 RA patients and 10 healthy controls, and three RA patients donated samples before and 6 months after abatacept treatment. Paired-end RNA sequencing was performed using HiSeq 2500. A total of 149 samples except for 12 outliers were analyzed. Overview of expression pattern of RA revealed that administration of abatacept exerts a large shift toward the expression pattern of HC. Most of differentially expressed gene (DEG) upregulated in RA (n = 1776) were downregulated with abatacept treatment (n = 1349). Inversely, most of DEG downregulated in RA (n = 1860) were upregulated with abatacept treatment (n = 1294). This DEG-based analysis revealed shared pathway changes in RA CD4+ T cell subsets. Knowledge-based pathway analysis revealed the upregulation of activation-related pathways in RA that was substantially ameliorated by abatacept. Weighted gene co-expression network analysis (WGCNA) evaluated CD4+ T cells collectively and identified a gene module that consisted of 227 genes and was correlated with DAS28-CRP (Spearman's rho = 0.46, p = 4 * 10-9) and abatacept administration (Spearman's rho = -0.91, p = 5 * 10-57). The most highly connected 30 genes of this module included ZAP70 and JAK3, and pathway analysis of this module revealed dysregulation of the TCR signaling pathway network, which was ameliorated by abatacept. PMID- 29146548 TI - First molecular characterisation of a Brazilian Burkholderia mallei strain isolated from a mule in 2016. AB - We present the first molecular characterisation based on MLVA and SNP analysis of a strain of Burkholderia mallei isolated from a mule found dead in Brazil in 2016. PMID- 29146549 TI - Risk assessment of infected children with Pseudomonas aeruginosa pneumonia by combining host and pathogen predictors. AB - The current criteria of pneumonia severity, which mainly depend on clinical manifestations and laboratory findings from blood routine tests and X-ray examination, are still of great significance in preliminary diagnosis. However, the utility of traditional severe pneumonia indexes (SPI) without considering high virulence and multidrug resistance of Pseudomonas aeruginosa has limitations. Thus, it is of great value to make a risk assessment, which can serve as a complementary option for incomplete clinical diagnosis. This study aims to determine risk factors related to severe pneumonia and to comprehensively evaluate the risk conditions of infected children with P. aeruginosa pneumonia. We collected the clinical information of 184 hospitalized children with P. aeruginosa pneumonia and measured pathogen data on virulence factors and drug resistance. The risk assessment matrix was formed from the significant host and pathogen predictors, and the risk score was determined by the clinical references and the optimal critical values (OCV) of the receiver operator characteristic (ROC) curves. There were 103 (56%) and 81 (44%) infected children diagnosed as mild and severe pneumonia by SPI, respectively. Seven risk factors were significantly associated with severe pneumonia, including body temperature, respiratory rate, C-reactive protein, elastase, exotoxin-A, exoenzyme-U and multidrug resistances. Among 184 infected children, the risk assessment matrix displayed 62 cases (34%) at high risk, 51 cases (28%) at medium risk, and 71 cases (38%) at low risk in terms of pneumonia severity. On the basis of the SPI preliminary diagnosis, the risk assessment prompted that 31% (32/103) mild patients would be faced with a poorer outcome and 23% (19/81) severe patients might get a better prognosis. Therefore, the well-established assessment indicates that the interplay between host response, antibiotic resistance, and virulence may modulate the severity of P. aeruginosa pneumonia in infected children. PMID- 29146550 TI - Temporal variations of fluctuating asymmetry in wing size and shape of Triatoma infestans populations from northwest Argentina. AB - Environmentally-induced developmental instability has frequently been assessed using fluctuating asymmetry (FA) methods. For Triatoma infestans, the major vector of Chagas disease, the combined effects of host-feeding sources and habitats affected wing developmental instability depending on sex in Figueroa villages, northwest Argentina. Here we investigated whether habitat, sex, season/year and insecticide applications affected wing developmental instability in T. infestans populations from Amama and other rural villages of northwest Argentina over a four-year period. We measured the occurrence and amount of wing size and shape FA in 423 adult triatomines collected in domiciles, goat corrals, pig corrals, storerooms and wood piles. Significant wing size and wing shape FA occurred in females and males from all habitats as determined by two-way mixed ANOVA and Procrustes ANOVA, respectively. For wing size and shape, the highest corrected indices of FA (FAI) for females occurred in wood piles, goat corrals and domiciles in late summer or early autumn, whereas for males, the largest FAIs consistently appeared in domiciles and storerooms. Wing size FAIs were significantly higher in recently infested goat corrals rather than in persistently infested goat corrals. The follow-up of four infested peridomestic sites showed that FA patterns were not stable over time or sites. Temporal variation of FA among habitats appears to be modified by the history of insecticide spraying, either through direct effects on insect development or through indirect effects related to flight dispersal and house invasion. Whether FA may provide another marker to identify the sources of reinfestant triatomines requires further investigation. PMID- 29146551 TI - Dual lumen microcatheters for complex percutaneous coronary interventions. AB - In some bifurcation anatomies side branch wiring can be difficult particularly when side branch is highly angulated. Furthermore a combination of bifurcations and chronic total occlusion can be a real challenge for interventional cardiologists. New devices have been produced to facilitate complex PCI and recently introduced dual lumen microcatheters can be really helpful in these scenarios. All these devices have both a rapid-exchange and an over-the-wire lumen. The rationale for dual lumen microcatheters is to preserve the highest number of side-branches. Nevertheless PCI should always aim to the most complete revascularization and to the lowest rate of side-branch loss. The purpose of this review is to describe current available dual lumen microcatheters, interventional scenarios in which their use may be helpful and basics of their proper use. PMID- 29146552 TI - Cardiogenic Shock Complicating Transcatheter Aortic Valve Replacement Due to Severe Para-Valvular Regurgitation. AB - We describe a challenging case of successful use of Impella CPTM to provide emergent left ventricular support following a circulatory collapse during transcatheter valve-in-valve implantation with a CoreValve Evolut R prosthesis. PMID- 29146553 TI - Impact of marital status on outcomes following ST-segment elevation myocardial infarction. AB - BACKGROUND: Mood disorders, depression, and loneliness are established risk factors for thrombotic occlusions. Social relationships in general, and marital status in particular may play a role in predicting cardiovascular outcomes and survival after ST-segment elevation myocardial infarction (STEMI), but the evidence is inconclusive especially in Asians. METHODS: The Korean patients presented with STEMI (n=980) constituted married (n=780); or widowed, divorced, or single (WDS, n=200) groups. After the matching for age, and gender, the groups were matched 1:1, with each group containing 172 patients. Clinical characteristics and STEMI prognosis such as major adverse cardiovascular events (MACE) and death at 1year, in married versus WDS patients were collected, and retrospectively analyzed. RESULTS: Overall, the total of 70 non-fatal MACE and 51 deaths occurred. At 1-year, the WDS patients exhibited significantly more MACE (44 vs.26; p=0.016), deaths (32 vs. 19; p=0.049) and shorter time to MACE occurrence (p=0.018), compared to the married patients. There were no differences in revascularization, cerebral infarction, cerebral bleeding, major bleeding, coronary artery bypass graft, early mortality and the overall survival between groups. CONCLUSION: Marital status may be linked to 1-year MACE including survival following STEMI, while being married may improve vascular outcomes compared to WDS in Korean patients. Further larger cohort or/and uniformed national registry studies are required to validate these data, and expand the evidence beyond East Asians. PMID- 29146554 TI - INGAP-PP effects on beta-cell mass and function are related to its positive effect on islet angiogenesis and VEGFA production. AB - Our aim was to determine whether islet angiogenesis and VEGFA production/release participate in the mechanism by which INGAP-PP enhances beta-cell function and mass. We used two models: a) in vivo (normal rats injected with INGAP-PP for 10 days) and b) in vitro (normal islets cultured for 4 days with INGAP-PP, VEGFA, Rapamycin, and the specific VEGF-Receptor inhibitor, SU5416). INGAP-PP administration enhanced insulin secretion, beta-cell mass, islet vascularization, and angiogenesis without affecting glucose homeostasis. Normal islets cultured with INGAP-PP and VEGFA increased insulin and VEGFA secretion while apoptosis decreased. INGAP-PP-induced effects were prevented by both Rapamycin and SU5416. INGAP-PP effects on beta-cell mass and function were significantly associated with a positive effect on islet angiogenesis and VEGFA production/release. VEGF-A possibly potentiates INGAP-PP effect through mTORC pathway. PMID- 29146556 TI - Shedding light on the role of cAMP in mammalian sperm physiology. AB - Mammalian fertilization relies on sperm finding the egg and penetrating the egg vestments. All steps in a sperm's lifetime crucially rely on changes in the second messenger cAMP (cyclic adenosine monophosphate). In recent years, it has become clear that signal transduction in sperm is not a continuum, but rather organized in subcellular domains, e.g. the sperm head and the sperm flagellum, with the latter being further separated into the midpiece, principal piece, and endpiece. To understand the underlying signaling pathways controlling sperm function in more detail, experimental approaches are needed that allow to study sperm signaling with spatial and temporal precision. Here, we will give a comprehensive overview on cAMP signaling in mammalian sperm, describing the molecular players involved in these pathways and the sperm functions that are controlled by cAMP. Furthermore, we will highlight recent advances in analyzing and manipulating sperm signaling with spatio-temporal precision using light. PMID- 29146557 TI - Quality of Life After Prostate Cancer Diagnosis: Data from the Pros-IT CNR. AB - Pros-IT CNR study provides a real-life report on changes in quality of life 6 mo after the diagnosis of prostate cancer. PMID- 29146558 TI - Role of His-His interaction in Ser474-His475-Tyr476 sequence of chondroitinase ABC I in the enzyme activity and stability. AB - Despite clinical importance of chondroitinase ABC I, its application has been limited due to thermal instability as reported in the literature. There are various approaches to improve thermal stability of enzymes, among them, His-His interactions are believed generally as an effective means. In the present study and for preparing a His-His interaction, various mutations in the sequence of Ser474-His475-Tyr476 at catalytic domain of the enzyme were performed using site directed mutagenesis method. The effect of these mutations on activity, stability and structural features of cABC I was assessed. The study showed that establishment of His475-His476 pair in cABC I, did not improve thermal stability of the enzyme and inactivated it. The study also revealed the existence a hydrogen bond network in the central domain of the enzyme with a specific role for tyrosine 476. In this network, replacement of His475 with Ala and Try476 with His and Ala, deactivated and destabilized the enzyme; confirming their importance in the enzyme catalysis and stability. Also, it was found that Tyr476 has some important role in substrate binding, an issue which should be more investigated. PMID- 29146559 TI - Development of poly (lactic acid) microspheres and their potential application in Pickering emulsions stabilization. AB - The aim of the present work was to study the feasibility of fabricating poly (lactic acid) (PLA) microspheres stabilized Pickering emulsions. For this purpose, the PLA microspheres were first prepared by oil-water emulsion solvent evaporation method. The effects of preparation conditions such as hydrophilic lipophilic balance (HLB) value, emulsifier concentration, oil-water ratio and preparation temperature were evaluated by using optical microscopy. Besides, orthogonal experiments were designed to investigate the influence of preparation parameters on average diameter and uniformity, include stirring time, stirring speed, and PLA and polyvinyl alcohol (PVA) concentrations. Based on the analysis of orthogonal experimental results, an optimal level of parameters was defined for the fabrication of PLA microspheres. Furthermore, these microspheres were applied to the stabilization of Pickering emulsions, and the optimal Pickering emulsion with uniform microstructure was obtained through the adjustment of PLA microspheres concentrations. This study opens up a promising way for producing PLA microspheres stabilized Pickering emulsions. PMID- 29146555 TI - Extranuclear signaling by sex steroid receptors and clinical implications in breast cancer. AB - Estrogen and progesterone play essential roles in the development and progression of breast cancer. Over 70% of breast cancers express estrogen receptors (ER) and progesterone receptors (PR), emphasizing the need for better understanding of ER and PR signaling. ER and PR are traditionally viewed as transcription factors that directly bind DNA to regulate gene networks. In addition to nuclear signaling, ER and PR mediate hormone-induced, rapid extranuclear signaling at the cell membrane or in the cytoplasm which triggers downstream signaling to regulate rapid or extended cellular responses. Specialized membrane and cytoplasmic proteins may also initiate hormone-induced extranuclear signaling. Rapid extranuclear signaling converges with its nuclear counterpart to amplify ER/PR transcription and specify gene regulatory networks. This review summarizes current understanding and updates on ER and PR extranuclear signaling. Further investigation of ER/PR extranuclear signaling may lead to development of novel targeted therapeutics for breast cancer management. PMID- 29146561 TI - Recurrent neural networks with specialized word embeddings for health-domain named-entity recognition. AB - BACKGROUND: Previous state-of-the-art systems on Drug Name Recognition (DNR) and Clinical Concept Extraction (CCE) have focused on a combination of text "feature engineering" and conventional machine learning algorithms such as conditional random fields and support vector machines. However, developing good features is inherently heavily time-consuming. Conversely, more modern machine learning approaches such as recurrent neural networks (RNNs) have proved capable of automatically learning effective features from either random assignments or automated word "embeddings". OBJECTIVES: (i) To create a highly accurate DNR and CCE system that avoids conventional, time-consuming feature engineering. (ii) To create richer, more specialized word embeddings by using health domain datasets such as MIMIC-III. (iii) To evaluate our systems over three contemporary datasets. METHODS: Two deep learning methods, namely the Bidirectional LSTM and the Bidirectional LSTM-CRF, are evaluated. A CRF model is set as the baseline to compare the deep learning systems to a traditional machine learning approach. The same features are used for all the models. RESULTS: We have obtained the best results with the Bidirectional LSTM-CRF model, which has outperformed all previously proposed systems. The specialized embeddings have helped to cover unusual words in DrugBank and MedLine, but not in the i2b2/VA dataset. CONCLUSIONS: We present a state-of-the-art system for DNR and CCE. Automated word embeddings has allowed us to avoid costly feature engineering and achieve higher accuracy. Nevertheless, the embeddings need to be retrained over datasets that are adequate for the domain, in order to adequately cover the domain-specific vocabulary. PMID- 29146560 TI - Changes in the degree of polymerization of wood celluloses during dilute acid hydrolysis and TEMPO-mediated oxidation: Formation mechanism of disordered regions along each cellulose microfibril. AB - Most commercially available plant celluloses, such as kraft pulps and cotton celluloses, have so-called leveling-off degrees of polymerization (LODPs) when subjected to dilute acid hydrolysis. The formation of LODPs is hypothesized to be caused by disordered regions that are present periodically along each cellulose microfibril in plant celluloses. Here, we prepared never-dried wood cellulose, and wood celluloses at different drying stages, and subjected them to dilute acid hydrolysis. The viscosity average degrees of polymerization (DPv) of the wood celluloses decreased in DPv with increasing dilute acid-hydrolysis times. However, the DPv values after 4h of acid hydrolysis differed from those of softwood bleached kraft pulp (SBKP), which showed typical patterns of LODPs. Thus, the disordered regions corresponding to LODPs that were observed for SBKP are probably not synthesized in the native wood. Instead, such disordered regions are formed secondarily or artificially during the isolation/purification and/or drying processes of plant cellulose fibers. The results of the dilute acid hydrolysis and the 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated oxidation of SBKP and softwood unbleached soda-anthraquinone pulp showed that the structures of disordered regions can be controlled via the preparation and drying conditions of wood cellulose used as starting materials. PMID- 29146563 TI - Characterization of the IPEC-J2 MDR1 (iP-gp) cell line as a tool for identification of P-gp substrates. AB - Recently, we transfected the porcine intestinal cell line IPEC-J2, with human P glycoprotein (P-gp, ABCB1). The resulting cell line, iP-gp, has a high expression of functional human P-gp in the apical membrane, and a low expression of nonhuman ATP-binding cassette (ABC) transporters. The aim of the present work was to investigate the usability of iP-gp cell line for determining transepithelial transport kinetics of the prototypical P-gp substrates digoxin and rhodamine 123. The cell line generated tight monolayers after 16days of culture, reflected by high transepithelial electrical resistance values (TEER>15,000Omega.cm2), immunocytochemistry and low fluxes of the paracellular flux marker [14C] mannitol. Monolayer integrity was not affected the common solvents dimethyl sulfoxide (DMSO), methanol and ethanol in concentrations up to 2% (v/v). Transepithelial fluxes of [3H]-labeled digoxin and rhodamine 123 were measured at varying donor concentrations, and kinetic parameters were estimated. Km and Vmax of P-gp mediated basolateral-to-apical (B-A) flux of rhodamine 123 were estimated to 332+/-124MUM and 111+/-16pmol.cm-2.min-1 (n=3, total N=6), respectively. Vmax and Km of digoxin B-A flux could not be estimated due to the low aqueous solubility of digoxin. The half maximal inhibitory concentrations (IC50) of the selective P-gp inhibitor, zosuquidar (LY-335979), were estimated to 0.05+/ 0.01MUM (n=3, total N=6) and 0.04+/-0.01MUM (n=3, total N=6) in transport experiments with digoxin and rhodamine 123 as substrates, respectively. Bidirectional fluxes of digoxin and rhodamine 123 were measured in transfected Madin Darby canine kidney cells (MDCK II MDR1) and compared with the fluxes obtained with the iP-gp cell monolayers. Efflux ratios were highest in the iP-gp cells, due to a tighter paracellular pathway. In conclusion, both digoxin and rhodamine 123 could be used to obtain IC50 values of inhibition, Ki values were only possible to obtain using rhodamine 123. The observed tightness, robustness towards solvents and the high efflux ratios confirmed that the iP-gp cell line may serve as a useful screening tool for investigations of substrate-P-gp interactions and modulation of P-gp function. PMID- 29146562 TI - Multi-method laboratory user evaluation of an actionable clinical performance information system: Implications for usability and patient safety. AB - INTRODUCTION: Electronic audit and feedback (e-A&F) systems are used worldwide for care quality improvement. They measure health professionals' performance against clinical guidelines, and some systems suggest improvement actions. However, little is known about optimal interface designs for e-A&F, in particular how to present suggested actions for improvement. We developed a novel theory informed system for primary care (the Performance Improvement plaN GeneratoR; PINGR) that covers the four principal interface components: clinical performance summaries; patient lists; detailed patient-level information; and suggested actions. As far as we are aware, this is the first report of an e-A&F system with all four interface components. OBJECTIVES: (1) Use a combination of quantitative and qualitative methods to evaluate the usability of PINGR with target end-users; (2) refine existing design recommendations for e-A&F systems; (3) determine the implications of these recommendations for patient safety. METHODS: We recruited seven primary care physicians to perform seven tasks with PINGR, during which we measured on-screen behaviour and eye movements. Participants subsequently completed usability questionnaires, and were interviewed in-depth. Data were integrated to: gain a more complete understanding of usability issues; enhance and explain each other's findings; and triangulate results to increase validity. RESULTS: Participants committed a median of 10 errors (range 8-21) when using PINGR's interface, and completed a median of five out of seven tasks (range 4-7). Errors violated six usability heuristics: clear response options; perceptual grouping and data relationships; representational formats; unambiguous description; visually distinct screens for confusable items; and workflow integration. Eye movement analysis revealed the integration of components largely supported effective user workflow, although the modular design of clinical performance summaries unnecessarily increased cognitive load. Interviews and questionnaires revealed PINGR is user-friendly, and that improved information prioritisation could further promote useful user action. CONCLUSIONS: Comparing our results with the wider usability literature we refine a previously published set of interface design recommendations for e-A&F. The implications for patient safety are significant regarding: user engagement; actionability; and information prioritisation. Our results also support adopting multi-method approaches in usability studies to maximise issue discovery and the credibility of findings. PMID- 29146564 TI - Breaking Health Insurance Knowledge Barriers Through Games: Pilot Test of Health Care America. AB - BACKGROUND: Having health insurance is associated with a number of beneficial health outcomes. However, previous research suggests that patients tend to avoid health insurance information and often misunderstand or lack knowledge about many health insurance terms. Health insurance knowledge is particularly low among young adults. OBJECTIVE: The purpose of this study was to design and test an interactive newsgame (newsgames are games that apply journalistic principles in their creation, for example, gathering stories to immerse the player in narratives) about health insurance. This game included entry-level information through scenarios and was designed through the collation of national news stories, local personal accounts, and health insurance company information. METHODS: A total of 72 (N=72) participants completed in-person, individual gaming sessions. Participants completed a survey before and after game play. RESULTS: Participants indicated a greater self-reported understanding of how to use health insurance from pre- (mean=3.38, SD=0.98) to postgame play (mean=3.76, SD=0.76); t71=-3.56, P=.001. For all health insurance terms, participants self-reported a greater understanding following game play. Finally, participants provided a greater number of correct definitions for terms after playing the game, (mean=3.91, SD=2.15) than they did before game play (mean=2.59, SD=1.68); t31= 3.61, P=.001. Significant differences from pre- to postgame play differed by health insurance term. CONCLUSIONS: A game is a practical solution to a difficult health issue-the game can be played anywhere, including on a mobile device, is interactive and will thus engage an apathetic audience, and is cost-efficient in its execution. PMID- 29146565 TI - Development and Usability Testing of a Computer-Tailored Decision Support Tool for Lung Cancer Screening: Study Protocol. AB - BACKGROUND: Awareness of lung cancer screening remains low in the screening eligible population, and when patients visit their clinician never having heard of lung cancer screening, engaging in shared decision making to arrive at an informed decision can be a challenge. Therefore, methods to effectively support both patients and clinicians to engage in these important discussions are essential. To facilitate shared decision making about lung cancer screening, effective methods to prepare patients to have these important discussions with their clinician are needed. OBJECTIVE: Our objective is to develop a computer tailored decision support tool that meets the certification criteria of the International Patient Decision Aid Standards instrument version 4.0 that will support shared decision making in lung cancer screening decisions. METHODS: Using a 3-phase process, we will develop and test a prototype of a computer-tailored decision support tool in a sample of lung cancer screening-eligible individuals. In phase I, we assembled a community advisory board comprising 10 screening eligible individuals to develop the prototype. In phase II, we recruited a sample of 13 screening-eligible individuals to test the prototype for usability, acceptability, and satisfaction. In phase III, we are conducting a pilot randomized controlled trial (RCT) with 60 screening-eligible participants who have never been screened for lung cancer. Outcomes tested include lung cancer and screening knowledge, lung cancer screening health beliefs (perceived risk, perceived benefits, perceived barriers, and self-efficacy), perception of being prepared to engage in a patient-clinician discussion about lung cancer screening, occurrence of a patient-clinician discussion about lung cancer screening, and stage of adoption for lung cancer screening. RESULTS: Phases I and II are complete. Phase III is underway. As of July 15, 2017, 60 participants have been enrolled into the study, and have completed the baseline survey, intervention, and first follow-up survey. We expect to have results by December 31, 2017 and to have data analysis completed by March 1, 2018. CONCLUSIONS: Results from usability testing indicate that the computer-tailored decision support tool is easy to use, is helpful, and provides a satisfactory experience for the user. At the conclusion of phase III (pilot RCT), we will have preliminary effect sizes to inform a future fully powered RCT on changes in (1) knowledge about lung cancer and screening, (2) perceived risk of lung cancer, (3) perceived benefits of lung cancer screening, (4) perceived barriers to lung cancer screening, (5) self efficacy for lung cancer screening, and (6) perceptions of being adequately prepared to engage in a discussion with their clinician about lung cancer screening. PMID- 29146566 TI - Improving Transition to Employment for Youth With Physical Disabilities: Protocol for a Peer Electronic Mentoring Intervention. AB - BACKGROUND: Although youth with disabilities have much to gain from employment readiness programs, they are often excluded from or have limited access to vocational programs. One encouraging approach to address gaps in vocational programming is through peer electronic mentoring (e-mentoring), which may facilitate a smoother transition to adulthood by offering support to enhance coping skills. Despite the increase in online communities, little is known about their impact on vocational mentoring for youth with physical disabilities and their parents. OBJECTIVE: The aim of this paper is to develop, implement, and assess the feasibility of an online peer mentor employment readiness intervention for youth with physical disabilities and their parents to improve their self determination, career maturity, and social support compared to controls. METHODS: A mixed-methods feasibility randomized controlled trial (RCT) design will be conducted to develop and assess the feasibility, acceptability, and initial efficacy of the "Empowering Youth Towards Employment" intervention. Youth (aged 15 to 25) with physical disabilities and their parents will be randomly assigned to a control or experimental group (4-week, interactive intervention, moderated by peer mentors). RESULTS: Data collection is in progress. Planned analyses include pre-post measures to determine the impact of the intervention on self determination, career maturity, and social support. A qualitative thematic analysis of the discussion forums will complement the surveys to better understand why certain outcomes may have occurred. CONCLUSIONS: Our intervention includes evidence-informed content and was co-created by a multi-disciplinary group of researchers and knowledge users. It has the potential for widespread implications as a cost-effective resource to supplement educational and vocational programming for youth with disabilities. TRIAL REGISTRATION: Clinicaltrials.gov NCT02522507; https://clinicaltrials.gov/ct2/show/NCT02522507 (Archived by WebCite at http://www.webcitation.org/6uD58Pvjc). PMID- 29146567 TI - Self-Guided Web-Based Interventions: Scoping Review on User Needs and the Potential of Embodied Conversational Agents to Address Them. AB - BACKGROUND: Web-based mental health interventions have evolved from innovative prototypes to evidence-based and clinically applied solutions for mental diseases such as depression and anxiety. Open-access, self-guided types of these solutions hold the promise of reaching and treating a large population at a reasonable cost. However, a considerable factor that currently hinders the effectiveness of these self-guided Web-based interventions is the high level of nonadherence. The absence of a human caregiver apparently has a negative effect on user adherence. It is unknown to what extent this human support can be handed over to the technology of the intervention to mitigate this negative effect. OBJECTIVE: The first objective of this paper was to explore what is known in literature about what support a user needs to stay motivated and engaged in an electronic health (eHealth) intervention that requires repeated use. The second objective was to explore the current potential of embodied conversational agents (ECAs) to provide this support. METHODS: This study reviews and interprets the available literature on (1) support within eHealth interventions that require repeated use and (2) the potential of ECAs by means of a scoping review. The rationale for choosing a scoping review is that the subject is broad, diverse, and largely unexplored. Themes for (1) and (2) were proposed based on grounded theory and mapped on each other to find relationships. RESULTS: The results of the first part of this study suggest the presence of user needs that largely remain implicit and unaddressed. These support needs can be categorized as task-related support and emotion related support. The results of the second part of this study suggest that ECAs are capable of engaging and motivating users of information technology applications in the domains of learning and behavioral change. Longitudinal studies must be conducted to determine under what circumstances ECAs can create and maintain a productive user relationship. Mapping the user needs on the ECAs' capabilities suggests that different kinds of ECAs may provide different solutions for improving the adherence levels. CONCLUSIONS: Autonomous ECAs that do not respond to a user's expressed emotion in real time but take on empathic roles may be sufficient to motivate users to some extent. It is unclear whether those types of ECAs are competent enough and create sufficient believability among users to address the user's deeper needs for support and empathy. Responsive ECAs may offer a better solution. However, at present, most of these ECAs have difficulties to assess a user's emotional state in real time during an open dialogue. By conducting future research with relationship theory-based ECAs, the added value of ECAs toward user needs can be better understood. PMID- 29146568 TI - Health-Seeking Influence Reflected by Online Health-Related Messages Received on Social Media: Cross-Sectional Survey. AB - BACKGROUND: Major social networking platforms, such as Facebook, WhatsApp, and Twitter, have become popular means through which people share health-related information, irrespective of whether messages disseminated through these channels are authentic. OBJECTIVE: This study aims to describe the demographic characteristics of patients that may demonstrate their attitudes toward medical information shared on social media networks. Second, we address how information found through social media affects the way people deal with their health. Third, we examine whether patients initiate or alter/discontinue their medications based on information derived from social media. METHODS: We conducted a cross-sectional survey between April and June 2015 on patients attending outpatient clinics at King Abdulaziz University, Jeddah, Saudi Arabia. Patients who used social media (Facebook, WhatsApp, and Twitter) were included. We designed a questionnaire with closed-ended and multiple-choice questions to assess the type of social media platforms patients used and whether information received on these platforms influenced their health care decisions. We used chi-square test to establish the relationship between categorical variables. RESULTS: Of the 442 patients who filled in the questionnaires, 401 used Facebook, WhatsApp, or Twitter. The majority of respondents (89.8%, 397/442) used WhatsApp, followed by Facebook (58.6%, 259/442) and Twitter (42.3%, 187/442). In most cases, respondents received health-related messages from WhatsApp and approximately 42.6% (171/401) reported ever stopping treatment as advised on a social media platform. A significantly higher proportion of patients without heart disease (P=.001) and obese persons (P=.01) checked the authenticity of information received on social media. Social media messages influenced decision making among patients without heart disease (P=.04). Respondents without heart disease (P=.001) and obese persons (P=.01) were more likely to discuss health-related information received on social media channels with a health care professional. A significant proportion of WhatsApp users reported that health-related information received on this platform influenced decisions regarding their family's health care (P=.001). Respondents' decisions regarding family health care were more likely to be influenced when they used two or all three types of platforms (P=.003). CONCLUSIONS: Health education in the digital era needs to be accurate, evidence based, and regulated. As technologies continue to evolve, we must be equipped to face the challenges it brings with it. PMID- 29146570 TI - Public spending cuts are linked to 120 000 excess deaths in England, study suggests. PMID- 29146571 TI - Using Schwartz Center Rounds to promote compassionate care in a children's hospital. PMID- 29146572 TI - Cognitive trajectories from infancy to early adulthood following birth before 26 weeks of gestation: a prospective, population-based cohort study. AB - OBJECTIVE: To determine the trajectory of cognitive test scores from infancy to adulthood in individuals born extremely preterm compared with term-born individuals. DESIGN: A prospective, population-based cohort study. SETTING: 276 maternity units in the UK and Ireland. PATIENTS: 315 surviving infants born less than 26 completed weeks of gestation recruited at birth in 1995 and 160 term-born classroom controls recruited at age 6. MAIN OUTCOME MEASURES: Bayley Scales of Infant Development-Second Edition (age 2.5); Kaufman Assessment Battery for Children (ages 6/11); Wechsler Abbreviated Scale of Intelligence-Second Edition (age 19). RESULTS: The mean cognitive scores of extremely preterm individuals over the period were on average 25.2 points below their term-born peers (95% CI 27.8 to -22.6) and remained significantly lower at every assessment. Cognitive trajectories in term-born boys and girls did not differ significantly, but the scores of extremely preterm boys were on average 8.8 points below those of extremely preterm girls (95% CI -13.6 to -4.0). Higher maternal education elevated scores in both groups by 3.2 points (95% CI 0.8 to 5.7). Within the extremely preterm group, moderate/severe neonatal brain injury (mean difference: 10.9, 95% CI -15.5 to -6.3) and gestational age less than 25 weeks (mean difference: -4.4, 95% CI -8.4 to -0.4) also had an adverse impact on cognitive function. CONCLUSIONS: There is no evidence that impaired cognitive function in extremely preterm individuals materially recovers or deteriorates from infancy through to 19 years. Cognitive test scores in infancy and early childhood reflect early adult outcomes. PMID- 29146573 TI - Prostanoid EP4 agonist L-902,688 activates PPARgamma and attenuates pulmonary arterial hypertension. AB - Prostacyclin agonists that bind the prostacyclin receptor (IP) to stimulate cAMP synthesis are effective vasodilators for the treatment of idiopathic pulmonary arterial hypertension (IPAH), but this signaling may occur through nuclear peroxisome proliferator-activated receptor-gamma (PPARgamma). There is evidence of scant IP and PPARgamma expression but stable prostanoid EP4 receptor (EP4) expression in IPAH patients. Both IP and EP4 functionally couple with stimulatory G protein (Gs), which activates signal transduction. We investigated the effect of an EP4-specific agonist on pulmonary arterial remodeling and its regulatory mechanisms in pulmonary arterial smooth muscle cells (PASMCs). Immunoblotting evealed IP, EP4, and PPARgamma expression in human pulmonary arterial hypertension (PAH) and monocrotaline (MCT)-induced PAH rat lung tissue. Isolated PASMCs from MCT-induced PAH rats (MCT-PASMCs) were treated with L-902,688, a selective EP4 agonist, to investigate the anti-vascular remodeling effect. Scant expression of IP and PPARgamma but stable expression of EP4 was observed in IPAH patient lung tissues and MCT-PASMCs. L-902,688 inhibited IP-insufficient MCT PASMC proliferation and migration by activating PPARgamma in a time- and dose dependent manner, but these effects were reversed by AH-23848 (an EP4 antagonist) and H-89 [a protein kinase A (PKA) inhibitor], highlighting the crucial role of PPARgamma in the activity of this EP4 agonist. L-902,688 attenuated pulmonary arterial remodeling in hypoxic PAH mice and MCT-induced PAH rats; therefore, we conclude that the selective EP4 agonist L-902,688 reverses vascular remodeling by activating PPARgamma. This study identified a novel EP4-PKA-PPARgamma pathway, and we propose EP4 as a potential therapeutic target for PAH. PMID- 29146574 TI - Mast cell-dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma. AB - Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated with the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2 dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. Mast cell deficient C57BL/6-KitW-sh (Wsh) mice engrafted with either wild-type (Wsh + MC WT) or ST2-deficient bone marrow-derived mast cells (Wsh + MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh + MC-ST2KO compared with Wsh + MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in bronchoalveolar lavage fluid (BALF) and lung, the aggravated AHR in Wsh + MC-ST2KO mice seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE2 levels in BALF. Due to the protective properties of PGE2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role, in the development of AHR. PMID- 29146569 TI - Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax. AB - Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL2 biology and facilitated the clinical development of venetoclax.Significance: Basic research into the pathways governing programmed cell death have paved the way for the discovery of apoptosis-inducing agents such as venetoclax, a BCL2 selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2-dependent tumor types have translated well into the clinic thus far and will likely continue to inform the clinical development of venetoclax and other BCL2 family inhibitors. Cancer Discov; 7(12); 1376-93. (c)2017 AACR. PMID- 29146576 TI - Accepting the challenge: maintaining AJP-Lung as the best place to publish basic and translational studies in lung biology and pathophysiology. AB - Rory E. Morty takes over from Sadis Matalon as Editor in Chief of the American Journal of Physiology-Lung Cellular and Molecular Physiology in January 2018. Here, key achievements and new and noteworthy additions to the editorial portfolio of the journal will be reviewed. Additionally, selected recent reports will be highlighted and used to illustrate how the broad spectrum of the journal's editorial content promotes methodological innovation and scientific advances in lung biology and pathophysiology. PMID- 29146575 TI - Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill Pseudomonas aeruginosa. AB - Cystic fibrosis (CF), the most common lethal genetic disease in Caucasians, is characterized by chronic bacterial lung infection and excessive inflammation, which lead to progressive loss of lung function and premature death. Although ivacaftor (VX-770) alone and ivacaftor in combination with lumacaftor (VX-809) improve lung function in CF patients with the Gly551Asp and del508Phe mutations, respectively, the effects of these drugs on the function of human CF macrophages are unknown. Thus studies were conducted to examine the effects of lumacaftor alone and lumacaftor in combination with ivacaftor (i.e., ORKAMBI) on the ability of human CF ( del508Phe/ del508Phe) monocyte-derived macrophages (MDMs) to phagocytose and kill Pseudomonas aeruginosa. Lumacaftor alone restored the ability of CF MDMs to phagocytose and kill P. aeruginosa to levels observed in MDMs obtained from non-CF (WT-CFTR) donors. This effect contrasts with the partial (~15%) correction of del508Phe Cl- secretion of airway epithelial cells by lumacaftor. Ivacaftor reduced the ability of lumacaftor to stimulate phagocytosis and killing of P. aeruginosa. Lumacaftor had no effect on P. aeruginosa-stimulated cytokine secretion by CF MDMs. Ivacaftor (5 uM) alone and ivacaftor in combination with lumacaftor reduced secretion of several proinflammatory cytokines. The clinical efficacy of ORKAMBI may be related in part to the ability of lumacaftor to stimulate phagocytosis and killing of P. aeruginosa by macrophages. PMID- 29146577 TI - A man with knee pain after a fall. PMID- 29146578 TI - Climate change: health effects and response in South Asia. PMID- 29146580 TI - Seven days in medicine: 8-14 November 2017. PMID- 29146579 TI - Diabetic foot. PMID- 29146581 TI - Long noncoding RNAs: emerging players in thyroid cancer pathogenesis. AB - Thyroid cancer continues to be the most common malignancy of endocrine glands. The incidence of thyroid cancer has risen significantly over the past 4 decades and has emerged as a major health issue. In recent years, significant progress has been achieved in our understanding of the molecular mechanisms of thyroid carcinogenesis, resulting in significant diagnostic, prognostic and therapeutic implications; yet, it has not reached a satisfactory level. Identifying novel molecular therapeutic targets and molecules for diagnosis and prognosis is expected to advance the overall management of this common malignancy. Long noncoding RNAs (lncRNAs) are implicated in the regulation of various key cellular genes involved in cell differentiation, proliferation, cell cycle, apoptosis, migration and invasion mainly through modulation of gene expression. Recent studies have established that lncRNAs are deregulated in thyroid cancer. In this review, we discuss extensively the tumor-suppressive (for example, LINC00271, MEG3, NAMA, PTCSC1/2/3, etc.) and oncogenic (for example, ANRIL, FAL1, H19, PVT1, etc.) roles of various lncRNAs and their possible disease associations implicated in thyroid carcinogenesis. We briefly summarize the strategies and mechanisms of lncRNA-targeting agents. We also describe the potential role of lncRNAs as prospective novel therapeutic targets, and diagnostic and prognostic markers in thyroid cancer. PMID- 29146582 TI - Elucidation of the Two H3K36me3 Histone Methyltransferases Set2 and Ash1 in Fusarium fujikuroi Unravels Their Different Chromosomal Targets and a Major Impact of Ash1 on Genome Stability. AB - In this work, we present a comprehensive analysis of the H3K36 histone methyltransferases Set2 and Ash1 in the filamentous ascomycete Fusarium fujikuroi In Saccharomyces cerevisiae, one single methyltransferase, Set2, confers all H3K36 methylation, while there are two members of the Set2 family in filamentous fungi, and even more H3K36 methyltransferases in higher eukaryotes. Whereas the yeast Set2 homolog has been analyzed in fungi previously, the second member of the Set2 family, designated Ash1, has not been described for any filamentous fungus. Western blot and ChIP-Seq analyses confirmed that F. fujikuroi Set2 and Ash1 are H3K36-specific histone methyltransferases that deposit H3K36me3 at specific loci: Set2 is most likely responsible for H3K36 methylation of euchromatic regions of the genome, while Ash1 methylates H3K36 at the subtelomeric regions (facultative heterochromatin) of all chromosomes, including the accessory chromosome XII. Our data indicate that H3K36me3 cannot be considered a hallmark of euchromatin in F. fujikuroi, and likely also other filamentous fungi, making them different to what is known about nuclear characteristics in yeast and higher eukaryotes. We suggest that the H3K36 methylation mark exerts specific functions when deposited at euchromatic or subtelomeric regions by Set2 or Ash1, respectively. We found an enhanced level of H3K27me3, an increased instability of subtelomeric regions and losses of the accessory chromosome XII over time in Deltaash1 mutants, indicating an involvement of Ash1 in DNA repair processes. Further phenotypic analyses revealed a role of H3K36 methylation in vegetative growth, sporulation, secondary metabolite biosynthesis, and virulence in F. fujikuroi. PMID- 29146583 TI - Comparison of ChIP-Seq Data and a Reference Motif Set for Human KRAB C2H2 Zinc Finger Proteins. AB - KRAB C2H2 zinc finger proteins (KZNFs) are the largest and most diverse family of human transcription factors, likely due to diversifying selection driven by novel endogenous retroelements (EREs), but the vast majority lack binding motifs or functional data. Two recent studies analyzed a majority of the human KZNFs using either ChIP-seq (60 proteins) or ChIP-exo (221 proteins) in the same cell type (HEK293). The ChIP-exo paper did not describe binding motifs, however. Thirty nine proteins are represented in both studies, enabling the systematic comparison of the data sets presented here. Typically, only a minority of peaks overlap, but the two studies nonetheless display significant similarity in ERE binding for 32/39, and yield highly similar DNA binding motifs for 23 and related motifs for 34 (MoSBAT similarity score >0.5 and >0.2, respectively). Thus, there is overall (albeit imperfect) agreement between the two studies. For the 242 proteins represented in at least one study, we selected a highest-confidence motif for each protein, utilizing several motif-derivation approaches, and evaluating motifs within and across data sets. Peaks for the majority (158) are enriched (96% with AUC >0.6 predicting peak vs. nonpeak) for a motif that is supported by the C2H2 "recognition code," consistent with intrinsic sequence specificity driving DNA binding in cells. An additional 63 yield motifs enriched in peaks, but not supported by the recognition code, which could reflect indirect binding. Altogether, these analyses validate both data sets, and provide a reference motif set with associated quality metrics. PMID- 29146586 TI - Correction: Acceptability of the Fitbit in behavioural activation therapy for depression: a qualitative study. PMID- 29146585 TI - Acute respiratory distress syndrome. PMID- 29146584 TI - MicroRNA Tissue Atlas of the Malaria Mosquito Anopheles gambiae. AB - Anopheles gambiae mosquitoes transmit the human malaria parasite Plasmodium falciparum, which causes the majority of fatal malaria cases worldwide. The hematophagous lifestyle defines mosquito reproductive biology and is exploited by P. falciparum for its own sexual reproduction and transmission. The two main phases of the mosquito reproductive cycle, previtellogenic (PV) and postblood meal (PBM), shape its capacity to transmit malaria. Transition between these phases is tightly coordinated to ensure homeostasis between mosquito tissues and successful reproduction. One layer of control is provided by microRNAs (miRNAs), well-known regulators of blood meal digestion and egg development in Aedes mosquitoes. Here, we report a global overview of tissue-specific miRNAs (miRNA) expression during the PV and PBM phases and identify miRNAs regulated during PV to PBM transition. The observed coordinated changes in the expression levels of a set of miRNAs in the energy-storing tissues suggest a role in the regulation of blood meal-induced metabolic changes. PMID- 29146588 TI - Cardiovascular Magnetic Resonance for Risk Stratification in Patients With ST Segment-Elevation Myocardial Infarction: A Novel Tool to Tailor Therapy or Emperor's New Clothes? PMID- 29146587 TI - Prognostic Stratification of Patients With ST-Segment-Elevation Myocardial Infarction (PROSPECT): A Cardiac Magnetic Resonance Study. AB - BACKGROUND: Cardiac magnetic resonance (CMR) is a robust tool to evaluate left ventricular ejection fraction (LVEF), myocardial salvage index, microvascular obstruction, and myocardial hemorrhage in patients with ST-segment-elevation myocardial infarction. We evaluated the additional prognostic benefit of a CMR score over standard prognostic stratification with global registry of acute coronary events (GRACE) score and transthoracic echocardiography LVEF measurement. METHODS AND RESULTS: Two hundred nine consecutive patients with ST segment-elevation myocardial infarction (age, 61.4+/-11.4 years; 162 men) underwent transthoracic echocardiography and CMR after succesful primary percutaneous coronary intervention. Major adverse cardiac events (MACE) were assessed at a mean follow-up of 2.5+/-1.2 years. MACE occurred in 24 (12%) patients who at baseline showed higher GRACE risk score (P<0.01), lower LVEF with both transthoracic echocardiography and CMR, lower myocardial salvage index, and higher per-patient myocardial hemorrhage and microvascular obstruction prevalence and amount as compared with patients without MACE (P<0.01). The best cut-off values of transthoracic echocardiography-LVEF, CMR-LVEF, myocardial salvage index, and microvascular obstruction to predict MACE were 46.7%, 37.5%, 0.4, and 2.6% of left ventricular mass, respectively. Accordingly, a weighted CMR score, including the following 4 variables (CMR-LVEF, myocardial salvage index, microvascular obstruction, and myocardial hemorrhage), with a maximum of 17 points was calculated and included in the multivariable analysis showing that only CMR score (hazard ratio, 1.867 per SD increase [1.311-2.658]; P<0.001) was independently associated with MACE with the highest net reclassification improvement as compared to GRACE score and transthoracic echocardiography-LVEF measurement. CONCLUSIONS: CMR score provides incremental prognostic stratification as compared with GRACE score and transthoracic echocardiography LVEF and may impact the management of patients with ST-segment-elevation myocardial infarction. PMID- 29146589 TI - Impact of increasing tobacco taxes on working-age adults: short-term health gain, health equity and cost savings. AB - OBJECTIVE: The health gains and cost savings from tobacco tax increase peak many decades into the future. Policy-makers may take a shorter-term perspective and be particularly interested in the health of working-age adults (given their role in economic productivity). Therefore, we estimated the impact of tobacco taxes in this population within a 10-year horizon. METHODS: As per previous modelling work, we used a multistate life table model with 16 tobacco-related diseases in parallel, parameterised with rich national data by sex, age and ethnicity. The intervention modelled was 10% annual increases in tobacco tax from 2011 to 2020 in the New Zealand population (n=4.4 million in 2011). The perspective was that of the health system, and the discount rate used was 3%. RESULTS: For this 10 year time horizon, the total health gain from the tobacco tax in discounted quality-adjusted life years (QALYs) in the 20-65 year age group (age at QALY accrual) was 180 QALYs or 1.6% of the lifetime QALYs gained in this age group (11 300 QALYs). Nevertheless, for this short time horizon: (1) cost savings in this group amounted to NZ$10.6 million (equivalent to US$7.1 million; 95% uncertainty interval: NZ$6.0 million to NZ$17.7 million); and (2) around two-thirds of the QALY gains for all ages occurred in the 20-65 year age group. Focusing on just the preretirement and postretirement ages, the QALY gains in each of the 60-64 and 65-69 year olds were 11.5% and 10.6%, respectively, of the 268 total QALYs gained for all age groups in 2011-2020. CONCLUSIONS: The majority of the health benefit over a 10-year horizon from increasing tobacco taxes is accrued in the working-age population (20-65 years). There remains a need for more work on the associated productivity benefits of such health gains. PMID- 29146591 TI - Retraction for Verbree et al., "Identification of Peptidoglycan Hydrolase Constructs with Synergistic Staphylolytic Activity in Cow's Milk". PMID- 29146590 TI - CaMKIIalpha Mediates the Effect of IL-17 To Promote Ongoing Spontaneous and Evoked Pain in Multiple Sclerosis. AB - Pain is a common and severe symptom in multiple sclerosis (MS), a chronic inflammatory and demyelinating disease of the CNS. The neurobiological mechanism underlying MS pain is poorly understood. In this study, we investigated the role of Ca2+/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) in driving chronic pain in MS using a mouse experimental autoimmune encephalomyelitis (EAE) model. We found that spinal CaMKIIalpha activity was enhanced in EAE, correlating with the development of ongoing spontaneous pain and evoked hypersensitivity to mechanical and thermal stimuli. Prophylactic or acute administration of KN93, a CaMKIIalpha inhibitor, significantly reduced the clinical scores of EAE and attenuated mechanical allodynia and thermal hyperalgesia in EAE. siRNA targeting CaMKIIalpha reversed established mechanical and thermal hypersensitivity in EAE mice. Furthermore, CaMKIIalphaT286A point mutation mice showed significantly reduced EAE clinical scores, an absence of evoked pain, and ongoing spontaneous pain when compared with littermate wild-type mice. We found that IL-17 is responsible for inducing but not maintaining mechanical and thermal hyperalgesia that is mediated by CaMKIIalpha signaling in EAE. Together, these data implicate a critical role of CaMKIIalpha as a cellular mechanism for pain and neuropathy in multiple sclerosis and IL-17 may act upstream of CaMKIIalpha in the generation of pain.SIGNIFICANCE STATEMENT Pain is highly prevalent in patients with multiple sclerosis (MS), significantly reducing patients' quality of life. Using the experimental autoimmune encephalomyelitis (EAE) model, we were able to study not only evoked hyperalgesia, but also for the first time to demonstrate spontaneous pain that is also experienced by patients. Our study identified a role of spinal CaMKIIalpha in promoting and maintaining persistent ongoing spontaneous pain and evoked hyperalgesia pain in EAE. We further demonstrated that IL-17 contributes to persistent pain in EAE and functions as an upstream regulator of CaMKIIalpha signaling. These data for the first time implicated CaMKIIalpha and IL-17 as critical regulators of persistent pain in EAE, which may ultimately offer new therapeutic targets for mitigating pain in multiple sclerosis. PMID- 29146592 TI - Correction for Borch-Pedersen et al., "The Cooperative and Interdependent Roles of GerA, GerK, and Ynd in Germination of Bacillus licheniformis Spores". PMID- 29146593 TI - Correction for Borch-Pedersen et al., "Effects of High Pressure on Bacillus licheniformis Spore Germination and Inactivation". PMID- 29146594 TI - Heterologous phosphorylation-induced formation of a stability lock permits regulation of inactive receptors by beta-arrestins. AB - beta-Arrestins are key regulators and signal transducers of G protein-coupled receptors (GPCRs). The interaction between receptors and beta-arrestins is generally believed to require both receptor activity and phosphorylation by GPCR kinases. In this study, we investigated whether beta-arrestins are able to bind second messenger kinase-phosphorylated, but inactive receptors as well. Because heterologous phosphorylation is a common phenomenon among GPCRs, this mode of beta-arrestin activation may represent a novel mechanism of signal transduction and receptor cross-talk. Here we demonstrate that activation of protein kinase C (PKC) by phorbol myristate acetate, Gq/11-coupled GPCR, or epidermal growth factor receptor stimulation promotes beta-arrestin2 recruitment to unliganded AT1 angiotensin receptor (AT1R). We found that this interaction depends on the stability lock, a structure responsible for the sustained binding between GPCRs and beta-arrestins, formed by phosphorylated serine-threonine clusters in the receptor's C terminus and two conserved phosphate-binding lysines in the beta arrestin2 N-domain. Using improved FlAsH-based serine-threonine clusters beta arrestin2 conformational biosensors, we also show that the stability lock not only stabilizes the receptor-beta-arrestin interaction, but also governs the structural rearrangements within beta-arrestins. Furthermore, we found that beta arrestin2 binds to PKC-phosphorylated AT1R in a distinct active conformation, which triggers MAPK recruitment and receptor internalization. Our results provide new insights into the activation of beta-arrestins and reveal their novel role in receptor cross-talk. PMID- 29146595 TI - The cartilage-specific lectin C-type lectin domain family 3 member A (CLEC3A) enhances tissue plasminogen activator-mediated plasminogen activation. AB - C-type lectin domain family 3 member A (CLEC3A) is a poorly characterized protein belonging to the superfamily of C-type lectins. Its closest homologue tetranectin binds to the kringle 4 domain of plasminogen and enhances its association with tissue plasminogen activator (tPA) thereby enhancing plasmin production, but whether CLEC3A contributes to plasminogen activation is unknown. Here, we recombinantly expressed murine and human full-length CLEC3As as well as truncated forms of CLEC3A in HEK-293 Epstein-Barr nuclear antigen (EBNA) cells. We analyzed the structure of recombinant CLEC3A by SDS-PAGE and immunoblot, glycan analysis, matrix-assisted laser desorption ionization time-of-flight mass spectrometry, size-exclusion chromatography, circular dichroism spectroscopy, and electron microscopy; compared the properties of the recombinant protein with those of CLEC3A extracted from cartilage; and investigated its tissue distribution and extracellular assembly by immunohistochemistry and immunofluorescence microscopy. We found that CLEC3A mainly occurs as a monomer, but also forms dimers and trimers, potentially via a coiled-coil alpha-helix. We also noted that CLEC3A can be modified with chondroitin/dermatan sulfate side chains and tends to oligomerize to form higher aggregates. We show that CLEC3A is present in resting, proliferating, and hypertrophic growth-plate cartilage and assembles into an extended extracellular network in cultures of rat chondrosarcoma cells. Further, we found that CLEC3A specifically binds to plasminogen and enhances tPA-mediated plasminogen activation. In summary, we have determined the structure, tissue distribution, and molecular function of the cartilage-specific lectin CLEC3A and show that CLEC3A binds to plasminogen and participates in tPA-mediated plasminogen activation. PMID- 29146596 TI - Structure and function of the Leptospira interrogans peroxide stress regulator (PerR), an atypical PerR devoid of a structural metal-binding site. AB - Peroxide sensing is essential for bacterial survival during aerobic metabolism and host infection. Peroxide stress regulators (PerRs) are homodimeric transcriptional repressors with each monomer typically containing both structural and regulatory metal-binding sites. PerR binding to gene promoters is controlled by the presence of iron in the regulatory site, and iron-catalyzed oxidation of PerR by H2O2 leads to the dissociation of PerR from DNA. In addition to a regulatory metal, most PerRs require a structural metal for proper dimeric assembly. We present here a structural and functional characterization of the PerR from the pathogenic spirochete Leptospira interrogans, a rare example of PerR lacking a structural metal-binding site. In vivo studies showed that the leptospiral PerR belongs to the peroxide stimulon in pathogenic species and is involved in controlling resistance to peroxide. Moreover, a perR mutant had decreased fitness in other host-related stress conditions, including at 37 degrees C or in the presence of superoxide anion. In vitro, leptospiral PerR could bind to the perR promoter region in a metal-dependent manner. The crystal structure of the leptospiral PerR revealed an asymmetric homodimer, with one monomer displaying complete regulatory metal coordination in the characteristic caliper-like DNA-binding conformation and the second monomer exhibiting disrupted regulatory metal coordination in an open non-DNA-binding conformation. This structure showed that leptospiral PerR assembles into a dimer in which a metal induced conformational switch can occur independently in the two monomers. Our study demonstrates that structural metal binding is not compulsory for PerR dimeric assembly and for regulating peroxide stress. PMID- 29146597 TI - Structure-guided engineering of the substrate specificity of a fungal beta glucuronidase toward triterpenoid saponins. AB - Glycoside hydrolases (GHs) have attracted special attention in research aimed at modifying natural products by partial removal of sugar moieties to manipulate their solubility and efficacy. However, these modifications are challenging to control because the low substrate specificity of most GHs often generates undesired by-products. We previously identified a GH2-type fungal beta glucuronidase from Aspergillus oryzae (PGUS) exhibiting promiscuous substrate specificity in hydrolysis of triterpenoid saponins. Here, we present the PGUS structure, representing the first structure of a fungal beta-glucuronidase, and that of an inactive PGUS mutant in complex with the native substrate glycyrrhetic acid 3-O-mono-beta-glucuronide (GAMG). PGUS displayed a homotetramer structure with each monomer comprising three distinct domains: a sugar-binding, an immunoglobulin-like beta-sandwich, and a TIM barrel domain. Two catalytic residues, Glu414 and Glu505, acted as acid/base and nucleophile, respectively. Structural and mutational analyses indicated that the GAMG glycan moiety is recognized by polar interactions with nine residues (Asp162, His332, Asp414, Tyr469, Tyr473, Asp505, Arg563, Asn567, and Lys569) and that the aglycone moiety is recognized by aromatic stacking and by a pi interaction with the four aromatic residues Tyr469, Phe470, Trp472, and Tyr473 Finally, structure-guided mutagenesis to precisely manipulate PGUS substrate specificity in the biotransformation of glycyrrhizin into GAMG revealed that two amino acids, Ala365 and Arg563, are critical for substrate specificity. Moreover, we obtained several mutants with dramatically improved GAMG yield (>95%). Structural analysis suggested that modulating the interaction of beta-glucuronidase simultaneously toward glycan and aglycone moieties is critical for tuning its substrate specificity toward triterpenoid saponins. PMID- 29146598 TI - Structural analyses unravel the molecular mechanism of cyclic di-GMP regulation of bacterial chemotaxis via a PilZ adaptor protein. AB - The bacterial second messenger cyclic di-GMP (c-di-GMP) has emerged as a prominent mediator of bacterial physiology, motility, and pathogenicity. c-di-GMP often regulates the function of its protein targets through a unique mechanism that involves a discrete PilZ adaptor protein. However, the molecular mechanism for PilZ protein-mediated protein regulation is unclear. Here, we present the structure of the PilZ adaptor protein MapZ cocrystallized in complex with c-di GMP and its protein target CheR1, a chemotaxis-regulating methyltransferase in Pseudomonas aeruginosa This cocrystal structure, together with the structure of free CheR1, revealed that the binding of c-di-GMP induces dramatic structural changes in MapZ that are crucial for CheR1 binding. Importantly, we found that restructuring and repositioning of two C-terminal helices enable MapZ to disrupt the CheR1 active site by dislodging a structural domain. The crystallographic observations are reinforced by protein-protein binding and single cell-based flagellar motor switching analyses. Our studies further suggest that the regulation of chemotaxis by c-di-GMP through MapZ orthologs/homologs is widespread in proteobacteria and that the use of allosterically regulated C terminal motifs could be a common mechanism for PilZ adaptor proteins. Together, the findings provide detailed structural insights into how c-di-GMP controls the activity of an enzyme target indirectly through a PilZ adaptor protein. PMID- 29146599 TI - Incretin-Based Therapies and the Short-term Risk of Pancreatic Cancer: Results From Two Retrospective Cohort Studies. AB - OBJECTIVE: Concerns have been raised about a possible increased risk of pancreatic cancer associated with incretin-based therapies. We examined the risk of pancreatic cancer among patients with diabetes prescribed incretin drugs. RESEARCH DESIGN AND METHODS: With the use of public health insurance databases of Belgium and the Lombardy Region, Italy, we created two retrospective cohorts that included adult patients who were first prescribed an incretin drug or another noninsulin antidiabetic drug (NIAD) from 1 July 2008 to 31 December 2013 in Belgium and from 1 January 2008 to 31 December 2012 in the Lombardy Region. The risk of pancreatic cancer was evaluated by multivariate-adjusted Cox models that included time-dependent variables. Adjusted hazard ratios (aHRs) from Belgium and Italy were pooled by using fixed-effects meta-analyses. RESULTS: The cohorts included 525,733 patients with diabetes treated with NIADs and 33,292 with incretin drugs. Results in both cohorts were similar. Eighty-five and 1,589 subjects who developed pancreatic cancer were registered among the incretin and NIAD new users, respectively, which represented an aHR of pancreatic cancer of 2.14 (95% CI 1.71-2.67) among those prescribed an incretin compared with an NIAD. The aHR with a drug use lag exposure of 6 months was 1.69 (1.24-2.32). The aHR decreased from 3.35 (2.32-4.84) in the first 3 months after the first incretin prescription to 2.12 (1.22-3.66) in months 3-5.9, 1.95 (1.20-3.16) in months 6 11.9, and 1.69 (1.12-2.55) after 12 months. Among those prescribed an NIAD, pancreatic cancer occurred mostly within the year after the first prescription. The risk of pancreatic cancer among patients subsequently prescribed insulin was 6.89 (6.05-7.85). CONCLUSIONS: The recent prescription of incretin therapy is associated with an increased risk of pancreatic cancer. The reason for such an increase is likely the consequence of an occult pancreatic cancer that provokes or aggravates diabetes. Studies are warranted for assessing the risk of pancreatic cancer associated with long-term use of incretin drugs. PMID- 29146600 TI - N-Glycan Profile and Kidney Disease in Type 1 Diabetes. AB - OBJECTIVE: Poorer glycemic control in type 1 diabetes may alter N-glycosylation patterns on circulating glycoproteins, and these alterations may be linked with diabetic kidney disease (DKD). We investigated associations between N-glycans and glycemic control and renal function in type 1 diabetes. RESEARCH DESIGN AND METHODS: Using serum samples from 818 adults who were considered to have extreme annual loss in estimated glomerular filtration rate (eGFR; i.e., slope) based on retrospective clinical records, from among 6,127 adults in the Scottish Diabetes Research Network Type 1 Bioresource Study, we measured total and IgG-specific N glycan profiles. This yielded a relative abundance of 39 total (GP) and 24 IgG (IGP) N-glycans. Linear regression models were used to investigate associations between N-glycan structures and HbA1c, albumin-to-creatinine ratio (ACR), and eGFR slope. Models were adjusted for age, sex, duration of type 1 diabetes, and total serum IgG. RESULTS: Higher HbA1c was associated with a lower relative abundance of simple biantennary N-glycans and a higher relative abundance of more complex structures with more branching, galactosylation, and sialylation (GP12, 26, 31, 32, and 34, and IGP19 and 23; all P < 3.79 * 10-4). Similar patterns were seen for ACR and greater mean annual loss of eGFR, which were also associated with fewer of the simpler N-glycans (all P < 3.79 * 10-4). CONCLUSIONS: Higher HbA1c in type 1 diabetes is associated with changes in the serum N-glycome that have elsewhere been shown to regulate the epidermal growth factor receptor and transforming growth factor-beta pathways that are implicated in DKD. Furthermore, N-glycans are associated with ACR and eGFR slope. These data suggest that the role of altered N-glycans in DKD warrants further investigation. PMID- 29146602 TI - Donor-specific and -nonspecific HLA antibodies and outcome post lung transplantation. AB - Donor-specific antibodies (DSAs) against human leukocyte antigen (HLA) are associated with chronic lung allograft dysfunction (CLAD) and mortality post lung transplantation, but data concerning prevalence, time of onset, persistence and effects on long-term outcome remain scarce.We assessed the association between HLA antibodies and CLAD-free and graft survival in a cohort of 362 patients. We stratified our analysis according to DSA status, persistence of antibodies and timing of antibodies (pre-transplant, early or late post-transplant).Within our cohort, 61 (17%) patients developed DSAs (mostly against HLA-DQ), which was associated with worse CLAD-free and graft survival (p<0.0001 and p=0.059, respectively). Persistent (hazard ratio (HR) 3.386, 95% CI 1.928-5.948; p<0.0001) as well as transient (HR 2.998, 95% CI 1.406-6.393; p=0.0045) DSAs were associated with shorter CLAD-free survival compared with patients without DSAs. Persistent DSAs (HR 3.071, 95% CI 1.632-5.778; p=0.0005) but not transient DSAs were negatively associated with graft survival compared with patients without DSAs, likely due to the higher incidence of restrictive CLAD. HLA non-DSAs and pre-transplant HLA antibodies had no effect on post-transplant outcome.We demonstrated an important difference in prognosis between persistent and transient DSAs. Moreover, the observed association between DSAs and restrictive CLAD suggests an overlap between antibody-mediated rejection and restrictive CLAD that needs further investigation. PMID- 29146603 TI - Tuberculosis patients with unknown HIV status in the Netherlands: analysing underreporting and lack of testing. PMID- 29146601 TI - Airway microbiota across age and disease spectrum in cystic fibrosis. AB - Our objectives were to characterise the microbiota in cystic fibrosis (CF) bronchoalveolar lavage fluid (BALF), and determine its relationship to inflammation and disease status.BALF from paediatric and adult CF patients and paediatric disease controls undergoing clinically indicated bronchoscopy was analysed for total bacterial load and for microbiota by 16S rDNA sequencing.We examined 191 BALF samples (146 CF and 45 disease controls) from 13 CF centres. In CF patients aged <2 years, nontraditional taxa (e.gStreptococcus, Prevotella and Veillonella) constituted ~50% of the microbiota, whereas in CF patients aged >=6 years, traditional CF taxa (e.gPseudomonas, Staphylococcus and Stenotrophomonas) predominated. Sequencing detected a dominant taxon not traditionally associated with CF (e.gStreptococcus or Prevotella) in 20% of CF BALF and identified bacteria in 24% of culture-negative BALF. Microbial diversity and relative abundance of Streptococcus, Prevotella and Veillonella were inversely associated with airway inflammation. Microbiota communities were distinct in CF compared with disease controls, but did not differ based on pulmonary exacerbation status in CF.The CF microbiota detected in BALF differs with age. In CF patients aged <2 years, Streptococcus predominates, whereas classic CF pathogens predominate in most older children and adults. PMID- 29146604 TI - The effect of treatment for sleep apnoea on determinants of blood pressure control. AB - Our aim was to assess the effect of continuous positive airway pressure (CPAP) on the nocturnal evolution of peripheral chemosensitivity, renin-angiotensin aldosterone system activity, sympathetic tone and endothelial biomarkers in obstructive sleep apnoea (OSA) patients with isolated nocturnal hypertension (INH) or day-night sustained hypertension (D-NSH).In a crossover randomised trial, 32 OSA patients newly diagnosed with hypertension and without antihypertensive treatment were randomly assigned to 12 weeks of CPAP or sham CPAP. Peripheral chemosensitivity was evaluated before and after sleep using the hypoxic withdrawal test (%DeltaVI).At baseline, D-NSH patients showed higher %DeltaVI before sleep and higher levels of aldosterone and diurnal catecholamines. CPAP only reduced the nocturnal increase of %DeltaVI in INH patients (6.9%, 95% CI 1.0-12.8%; p=0.026). CPAP-induced change from baseline in %DeltaVI after sleep was 7.5% (95% CI 2.6-12.2%, p=0.005) in the INH group and 5.7% (95% CI 2.2-9.3%, p=0.004) in the D-NSH group. In contrast, %DeltaVI before sleep only decreased with CPAP in the D-NSH patients (3.0%, 95% CI 0.5-5.6%; p=0.023).In conclusion, CPAP reduces the nocturnal increase of peripheral chemosensitivity experienced by INH patients and corrects the high daytime sensitivity of patients with D-NSH. Differences in response to CPAP between these patients can help better understand the mechanisms of perpetuation of hypertension in sleep apnoea. PMID- 29146605 TI - Cardiac safety of bedaquiline: a systematic and critical analysis of the evidence. PMID- 29146606 TI - Restricted magnetic resonance diffusion of lung consolidation is not specific for respiratory exacerbation. PMID- 29146607 TI - Proof of concept that most borderline Quantiferon results are true antigen specific responses. PMID- 29146608 TI - Closing the gap in surveillance of tuberculosis and HIV co-infection: a European perspective on the need for clinician-public health alliances. PMID- 29146609 TI - Inflammation, age and changing microbiology: the search for causation in the cystic fibrosis airways. PMID- 29146610 TI - Association Between Stroke Risk and Metformin Use in Hemodialysis Patients With Diabetes Mellitus: A Nested Case-Control Study. AB - BACKGROUND: Metformin use reduces the incidence and severity of stroke in patients with type 2 diabetes mellitus (DM). The benefits of metformin for stroke have not been examined in hemodialysis patients with DM. METHODS AND RESULTS: Using the National Health Insurance Research Database, we identified 17 760 patients with DM and new-onset hemodialysis between 2001 and 2013. Of these, 1898 patients hospitalized for either ischemic or hemorrhagic stroke were matched to 7592 control patients according to sex, age, and year of initial hemodialysis therapy by using incidence sampling. The association between metformin use and stroke risk was estimated using conditional logistic regression after adjustment for hemodialysis frequency, comorbidity, and prescribed medications. Metformin use was recorded before the date of stroke admission and the date of pseudostroke of the case and control patients, respectively. Results showed that hemodialysis patients with ischemic stroke were more likely to use metformin than the controls 1 year before the date of stroke admission (adjusted odds ratio: 1.64; 95% confidence interval, 1.32-2.04). The association was evident within 90 days before the index date (adjusted odds ratio: 1.81; 95% confidence interval, 1.27 2.60). The results were consistent with those of hemodialysis patients with hemorrhagic stroke. Metformin use remained a risk factor for stroke in patients treated with antihypertensive, sulfonylurea, and antiplatelet drugs. CONCLUSIONS: This nested case-control study is the first to show that metformin use is associated with stroke risk in hemodialysis patients with DM. We suggest that metformin should not be used by hemodialysis patients with DM. PMID- 29146611 TI - Smooth Muscle-Selective Nuclear Factor-kappaB Inhibition Reduces Phosphate Induced Arterial Medial Calcification in Mice With Chronic Kidney Disease. AB - BACKGROUND: Hyperphosphatemia is a major factor promoting the formation of arterial medial calcification in chronic kidney disease (CKD). However, arterial medial calcification begins to occur during the early stages of CKD, when hyperphosphatemia is not yet apparent. It is predicted that other factors also play a role. The aim of the present study was to determine the role of pro inflammatory nuclear factor-kappaB (NF-kappaB) signaling in smooth muscle cells (SMCs) for phosphate-induced arterial medial calcification in CKD mice. METHODS AND RESULTS: We first sought to establish a novel mouse model of CKD with arterial medial calcification. CKD was induced in DBA/2 mice by feeding them a low concentration of adenine, and these mice were fed a normal or high-phosphorus diet. Severe calcification was seen in CKD mice fed the high-phosphorus diet, while it was undetectable in CKD mice fed the normal phosphorus diet or control mice fed the high-phosphorus diet. Arterial medial calcification was accompanied by phenotypic switching of SMCs into osteogenic cells. Interestingly, NF-kappaB inhibitors, tempol and triptolide, both reduced arterial medial calcification in CKD mice fed the high-phosphorus diet. Moreover, formation of arterial medial calcification, as well as SMC phenotypic switching, was also markedly attenuated in transgenic mice, in which the NF-kappaB activity was inhibited selectively in SMCs. Mechanistic studies revealed that Kruppel-like factor 4 was involved in NF kappaB-induced SMC phenotypic switching and calcification. CONCLUSIONS: Results of the present studies suggest that the NF-kappaB signaling in SMCs plays an important role in high phosphate-induced arterial medial calcification in CKD. PMID- 29146612 TI - Derivation and Validation of a Geriatric-Sensitive Perioperative Cardiac Risk Index. AB - BACKGROUND: Surgical patients aged 65 and over face a higher risk of cardiac complications from noncardiac surgery. The Revised Cardiac Risk Index (RCRI) and the Gupta Myocardial Infarction or Cardiac Arrest (MICA) calculator are widely used to predict this risk, but they are not specifically designed to predict MICA in geriatric patients. Our hypothesis is that a new geriatric-sensitive index, derived from geriatric data, will capture this population's unique response to risk factors. METHODS AND RESULTS: The model was developed using the NSQIP (National Surgical Quality Improvement Program) 2013 geriatric cohort (N=584,931) (210,914 age >=65) and validated on the NSQIP 2012 geriatric cohort (N= 485,426) (172,905 age >=65). Least Angle Shrinkage and Selection Operator regression was used for initial variable selection. The Geriatric-Sensitive Cardiac Risk Index (GSCRI) was then evaluated in the 2012 data set. The area under the curve (AUC) was compared among the GSCRI, RCRI, and Gupta MICA in the 2012 data set. The GSCRI had an AUC of 0.76 in the validation cohort among geriatric patients. When the Gupta MICA was tested on geriatric patients in the validation cohort, a significant deterioration (~17%) was noted, as well as a significant underestimation of the risk. The GSCRI AUC of 0.76 in the geriatric subset was significantly greater (P<0.001) than those in the RCRI (AUC=0.63) or Gupta MICA (AUC=0.70) models, outperforming the RCRI and Gupta MICA models in geriatric patients by 13% and 6%, respectively, with a DeltaAUC and P-value of 0.13 (P<0.001), and 0.06 (P<0.001). CONCLUSIONS: The GSCRI is a significantly better predictor of cardiac risk in geriatric patients undergoing noncardiac surgery. PMID- 29146614 TI - Heart rate reduction improves biventricular function and interactions in experimental pulmonary hypertension. AB - The objective of the present study was to investigate mechanisms of heart rate (HR) reduction on biventricular function and interactions in experimental pulmonary arterial hypertension (PAH). We compared cardiac cycle mechanics and interventricular interactions in 15 sham, 8 monocrotaline-PAH, 9 PAH + carvedilol, and 8 PAH + ivabradine rats. We used echocardiography to assess biventricular function, timing of cardiac cycle events, and septal position in PAH rats and related HR reduction effects on biventricular function measured by echocardiography and conductance catheter. HR was 302 beats/min in PAH + carvedilol rats and 303 beats/min in PAH + ivabradine rats versus 359 beats/min in PAH rats ( P < 0.01). Sham rats showed temporal alignment between right ventricular (RV) and left ventricular (LV) events, whereas PAH rats showed increased biventricular isovolumic contraction times (ICTs), delayed RV peak radial motion, and impaired early relaxation. Temporal malalignment was associated with decreased tricuspid and mitral diastolic annular peak velocities (3.7 vs. 6.4 and 3.4 vs. 5.3 cm/s, respectively, P < 0.001), delayed and shortened biventricular filling, and reduced early diastolic LV filling velocity (0.56 vs. 0.81 cm/s, P < 0.01). LV eccentricity index was increased at systole (2.0 vs. 1.2, P < 0.001), early diastole (2.1 vs. 1.1, P < 0.001), and end diastole (1.6 vs. 1.1, P < 0.001) in PAH versus sham rats. HR reduction with carvedilol and ivabradine shortened biventricular ICTs and the time to biventricular peak radial motion, improved RV relaxation, and increased early diastolic LV filling through reduced interventricular interaction and improved timing. These improvements corresponded with enhanced hemodynamics (increased cardiac output, RV contractility, and diastolic relaxation). In conclusion, HR reduction by carvedilol and ivabradine improves biventricular filling and hemodynamics in experimental PAH through realignment of RV-LV cardiac cycle events and improved interventricular interactions. NEW & NOTEWORTHY Carvedilol improves biventricular function in experimental pulmonary arterial hypertension, but the mechanisms of heart rate reduction versus beta-blocker effect are inadequately defined. Here, we demonstrate that reducing heart rate using either carvedilol or ivabradine (hyperpolarization-activated current inhibitor without beta-blocker effect) improves right ventricular filling and biventricular hemodynamics through the realignment of right ventricular-left ventricular cardiac cycle events and improved interventricular interactions. PMID- 29146613 TI - Racial and Ethnic Differences in Trajectories of Hospitalization in US Men and Women With Heart Failure. AB - BACKGROUND: Prior studies have documented racial and ethnic disparities in hospitalization among patients with heart failure (HF). However, racial/ethnic differences in trajectories of hospitalization following the diagnosis of HF have not been well characterized. This study examined racial/ethnic differences in individual-level trajectories of hospitalization in older adults with diagnosed HF. METHODS AND RESULTS: Data from a nationally representative prospective cohort of US men and women aged 45 years and older were used to examine the number of hospitalizations reported every 24 months. Participants who were non-Hispanic white, non-Hispanic black, and Hispanic with a reported diagnosis of HF (n=3011) were followed from 1998 to 2014. Results showed a quadratic change in the number of reported hospitalizations following HF diagnosis, with an average of 2.36 (95% confidence interval [CI], 2.19-2.53; P<0.001) hospitalizations within 24 months that decreased by 0.35 (95% CI, -0.45 to -0.25; P<0.001) every 24 months and subsequently increased by 0.03 (95% CI, 0.02-0.05; P<0.001) thereafter. In men, there were no racial/ethnic differences in hospitalizations reported at the time of diagnosis; however, Hispanic men had significant declines in hospitalizations after diagnosis (Hispanic*time=-0.52; 95% CI, -0.99 to -0.05 [P=0.031]) followed by a sizeable increase in hospitalizations at later stages of disease (Hispanic*time2=0.06; 95% CI, 0.00-0.12 [P=0.047]). In women, hospitalizations were consistently high following their diagnosis and black women had significantly more hospitalizations throughout follow-up than white women (black=0.28; 95% CI, 0.00-0.55 [P=0.048]). Racial/ethnic disparities varied by geography and the differences remained significant after adjusting for multiple sociodemographic, psychosocial, behavioral, and physiological factors. CONCLUSIONS: There were significant racial/ethnic differences in trajectories of hospitalization following the diagnosis of HF in US men and women. Racial/ethnic disparities varied by place of residence and the differences persisted after adjustment for multiple risk factors. The findings have important implications that may be crucial to planning the immediate and long-term delivery of care in patients with HF to reduce potentially preventable hospitalizations. PMID- 29146615 TI - "Mighty-chondrial" DNA repair for mitigation of cardiac injury: focus on "A novel mtDNA repair fusion protein attenuates maladaptive remodeling and preserves cardiac function in heart failure". PMID- 29146616 TI - Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E. AB - : We previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2; human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti-ERBB2 therapeutic agents may be effective for ERBB2-mutant cancers. The familial lung cancer patient in one of the authors' institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib. We also encountered a patient with ampullary adenocarcinoma with ERBB2 G660D and S310F comutations in another institute of the authors', revealed by comprehensive genomic profiling. This patient was then treated with afatinib and also achieved transitory response. We also searched for ERBB2 transmembrane mutations in various types of cancers in PubMed, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) database. Besides our two cases, two patients with V659E mutations were found via PubMed. Three potential patients were found in TCGA. In addition, MSK-IMPACT allowed identification of three additional urothelial carcinomas with G660D mutations and two lung adenocarcinomas with V659E mutations. Our experience suggests that establishing a database of integrated information regarding the clinical genome and therapeutic outcome of patients with recurrent but less common mutations is essential to implement precision oncology. KEY POINTS: Rare but targetable mutations such as avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2; human epidermal growth factor receptor 2 [HER2]) transmembrane domain (TMD) mutations can be detected by comprehensive genomic profiling.Afatinib may be effective for patients with cancer with ERBB2 (HER2) TMD mutations.In order to implement precision oncology, it is important to establish a database of integrated information regarding the clinical genomes and therapeutic outcomes of patients with recurrent but less common mutations. PMID- 29146617 TI - Cure in Advanced Renal Cell Cancer: Is It an Achievable Goal? AB - BACKGROUND: Immunotherapy has historically been of interest in the management of metastatic renal cell cancer (mRCC) because of its relative chemoresistance and the reproducible but low incidence of spontaneous remission in metastatic disease. Recently, targeted immunotherapies in the form of checkpoint inhibitors have shown durable responses in approximately 20%-30% of patients with solid tumors, with a much more acceptable side-effect profile. Anti-programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 antibodies rely on the presence of host T cells in the tumor microenvironment to be stimulated in order to activate an antitumor response. The presence of tumor antigens augments this stimulation. This has led to further research into combination therapy with anti PD-1 inhibitors and radiotherapy, chemotherapy, or targeted therapy with the aim of increasing the response rate to these agents. MATERIALS AND METHODS: We describe three cases of patients with mRCC treated with anti-PD-1 antibody therapy in combination with targeted therapy (bevacizumab), anti-cytotoxic T lymphocyte antigen 4 therapy (ipilimumab), or radiotherapy. We perform a comprehensive literature review on combination immunotherapy and the scope for the future. RESULTS: Two patients had a complete clinical response within 3 months of commencing treatment. The third patient had a further significant response to radiotherapy outside the field of treatment after initial response to anti-PD-1 therapy, which lasted for over 12 months. CONCLUSION: We are now in the era of immunotherapy with promising results in select patients. However, the number of complete remissions with single agents are low. This report demonstrates the potential for combination therapy in mRCC to produce complete responses and improved survival rates. Whether these results equate to cure in a subset of patients requires longer follow-up. Further evaluation of dosing regimens, sequencing methods, and biomarkers to select patient population is required to advance this treatment strategy. IMPLICATIONS FOR PRACTICE: Multiple phase I-III studies exploring the benefit of combination immunotherapy are currently under way. Further research into predictive biomarkers to identify the cohort of patients who gain this benefit is pertinent. This case series demonstrates that the combination of immunotherapy with other treatments can lead to complete responses, even in patients with initially bulky disease. Combination therapy with immunotherapy seems to cause more durable responses in patients with metastatic renal cell cancer compared with monotherapy. Significantly longer follow-up is necessary to determine whether durable complete response confers a cure in a select group of patients. PMID- 29146619 TI - Urinary Neutrophil Gelatinase-Associated Lipocalin for the Diagnosis of Urinary Tract Infections. AB - OBJECTIVES: To determine the accuracy of the novel biomarker urinary neutrophil gelatinase-associated lipocalin (uNGAL) to diagnose urinary tract infections (UTIs) in febrile infants and young children. METHODS: Prospective cross sectional study of febrile infants <3 months ( >= 38.0 degrees C) and children 3 to 24 months (>= 39.0 degrees C) evaluated for UTIs. uNGAL levels, urinalysis, Gram-stain and culture were obtained. UTI was defined by colony counts. RESULTS: Of 260 patients, 35 (13.5%) had UTIs. Median uNGAL levels were 215.1 ng/mL (interquartile range: 100.3-917.8) and 4.4 ng/mL (interquartile range: 1.6-11.8) in the groups diagnosed with and without UTIs, respectively. The area under the receiver-operating characteristic curve for uNGAL was 0.978 (95% confidence interval [CI]: 0.948-1.000). At a threshold uNGAL level of 39.1 ng/mL, sensitivity was 97.1% (95% CI: 83.4-99.9) and specificity was 95.6% (95% CI: 91.7 97.7). uNGAL had higher sensitivity than the combination of leukocyte esterase (in trace or greater amounts) or nitrite (+) (97.1%, 95% CI: 83.4-99.9 vs 74.3%, 95% CI: 56.4-86.9), with similar specificity (95.6%, 95% CI: 91.7-97.7 vs 97.3%, 95% CI: 94.0-98.9). uNGAL had higher sensitivity than Gram-stain (97.1%, 95% CI: 83.4-99.9 vs 74.3%, 95%: CI: 56.4-86.9), with similar specificity (95.6%, 95% CI: 91.7-97.7 vs 100.0%, 95% CI: 97.9-100.0). CONCLUSIONS: uNGAL has substantial accuracy to identify those with and without UTIs in infants and young children. Further studies will need to confirm our findings and determine if uNGAL is a more cost-effective test than standard screening tests. PMID- 29146620 TI - Diagnosing Infection in a Neonate Using Whole-Body Screening Magnetic Resonance Imaging. AB - The location of invasive infections is difficult to detect in infants, in part due to their inability to localize signs and symptoms. However, identifying the location often significantly alters clinical management by extending the duration of antibiotic therapy or revealing a source requiring surgical intervention. Compared with commonly used first-line imaging techniques such as radiographs and ultrasounds, MRI has higher sensitivity for identifying invasive infections and allows for simultaneous evaluation of multiple foci. We present 2 cases in which whole-body screening MRI was used in neonates to identify invasive sources of infection, including one in which traditional modalities failed to detect multiple clinically significant sources. We posit that whole-body screening MRI merits consideration as a potential first-line imaging method when investigating invasive infections in infants. PMID- 29146618 TI - Management of Adverse Events Associated with Cabozantinib Therapy in Renal Cell Carcinoma. AB - : Cabozantinib was recently approved for the treatment of advanced renal cell carcinoma (RCC) after treatment with vascular endothelial growth factor (VEGF) targeted therapy. Cabozantinib is a multikinase inhibitor targeting VEGF receptor (VEGFR) 2, mesenchymal-epithelial transition receptor, and "anexelekto" receptor tyrosine kinase. A 60-mg daily dose led to improved overall survival and progression-free survival (PFS) versus everolimus in advanced RCC patients as a second- or later-line treatment in the METEOR trial. Improved PFS with cabozantinib versus sunitinib has also been demonstrated in the first-line setting in CABOSUN. However, cabozantinib, like other VEGFR inhibitors, is associated with toxicity that may affect the patient's quality of life. The most frequent adverse events (AEs) are diarrhea, fatigue, hypertension, hand-foot syndrome, weight loss, nausea, and stomatitis. This article summarizes the safety profile of cabozantinib in RCC patients and offers guidance for the management of these AEs. We discuss the underlying mechanisms of these AEs and, based on our experiences with cabozantinib and other multikinase inhibitors, we present approaches to manage toxicity. Prophylactic and therapeutic solutions are available to help with the management of toxicity associated with cabozantinib, and adequate interventions can ensure optimum adherence and maximize patient outcomes. IMPLICATIONS FOR PRACTICE: Cabozantinib leads to improved survival outcomes in renal cell carcinoma patients compared with everolimus. However, management of the adverse event profile is crucial to achieve optimum adherence and outcomes with the use of cabozantinib. This review aims to provide appropriate guidance that will minimize the impact of adverse events and help to maximize the utility of this agent in patients with advanced renal cell carcinoma. PMID- 29146621 TI - Effect of FDA Investigation on Opioid Prescribing to Children After Tonsillectomy/Adenoidectomy. AB - BACKGROUND: In August 2012, the Food and Drug Administration investigated the safety of codeine use by children after tonsillectomy and/or adenoidectomy, culminating in a black box warning in February 2013. The objective of this study was to evaluate the association between the investigation and opioid prescribing to children undergoing these surgeries. METHODS: We identified 362 992 privately insured children in the 2010-2015 Truven MarketScan Commercial Claims and Encounters database who underwent tonsillectomy and/or adenoidectomy. Using an interrupted time series design, we estimated level and slope changes in the proportion of children with >=1 prescription fills for codeine and >=1 fills for an alternative opioid, such as hydrocodone, within 7 days of surgery. RESULTS: The investigation was associated with a significant -13.3 (95% confidence interval: -14.5 to -12.1) percentage point level change in the proportion of children with >=1 prescription fills for codeine after tonsillectomy and/or adenoidectomy. Despite this drop, 5.1% of children had >=1 prescription fills for codeine in December 2015. The investigation was not associated with significant level changes in alternative opioid prescribing, although the proportion of children receiving alternative opioids increased during the study period because of other factors. CONCLUSIONS: The Food and Drug Administration investigation substantially decreased codeine prescribing to children after tonsillectomy and/or adenoidectomy. However, 1 in 20 children undergoing these surgeries were still prescribed codeine in December 2015 despite its well-documented safety and efficacy issues. PMID- 29146622 TI - Refusal of Treatment of Childhood Cancer: A Systematic Review. AB - CONTEXT: Refusal of treatment for childhood cancer engenders much discussion. No systematic study of this phenomenon exists in countries where access to treatment is readily available. OBJECTIVE: To identify and describe all published cases of treatment refusal for childhood cancer in the contemporary era. DATA SOURCES: We searched PubMed, Cumulative Index to Nursing and Allied Health Literature, Scopus, LexisNexis Academic, personal database, and secondary bibliographies. STUDY SELECTION: Eligible studies included at least 1 child <18 years of age and addressed refusal of medically recommended interventions intended to cure cancer. DATA EXTRACTION: Cases were analyzed with respect to key features, including demographics, rationale for refusal, legal action, and medical outcome; data were combined for multiple publications discussing the same case. RESULTS: Of 4342 unique publications identified, 579 were eligible after screening; 96 scholarly articles and 19 judicial opinions addressed 73 unique cases of treatment refusal. Most cases occurred in the United States. Rationales for refusal were broadly grouped into 4 categories. Fifty-one cases (70%) involved legal action at the time of refusal. Legal action did not reliably predict survival. : Publication bias and missing data, especially for cases without legal action, were limitations. CONCLUSIONS: We identified important gaps in the literature, including the significant variation in approaches and lack of consensus regarding the prognostic threshold necessary for compelling treatment and the absence of voices of children and adolescents who have received treatment over their families' objections. More research reporting effective strategies for working with families who refuse is needed. PMID- 29146623 TI - Variations in rotation of the aortic root and membranous septum with implications for transcatheter valve implantation. AB - OBJECTIVE: It is intuitive to suggest that knowledge of the variation in the anatomy of the aortic root may influence the outcomes of transcatheter implantation of the aortic valve (TAVI). We have now assessed such variation. METHODS: We used 26 specimens of normal hearts and 78 CT data sets of adults with a mean age of 64+/-15 years to measure the dimensions of the membranous septum and to assess any influence played by rotation of the aortic root, inferring the relationship to the atrioventricular conduction axis. RESULTS: The aortic root was positioned centrally in the majority of both cohorts, although with significant variability. For the cadaveric hearts, 14 roots were central (54%), 4 clockwise-rotated (15%) and 8 counterclockwise-rotated (31%). In the adult CT cohort, 44 were central (56%), 21 clockwise-rotated (27%) and 13 counterclockwise rotated (17%). A mean angle of 15.5 degrees was measured relative to the right fibrous trigone in the adult CT cohort, with a range of -32 degrees to 44.7 degrees . The dimensions of the membranous septum were independent of rotation. Fibrous continuity between the membranous septum and the right fibrous trigone increased with counterclockwise to clockwise rotation, implying variation in the relationship to the atrioventricular conduction axis. CONCLUSIONS: The central fibrous body is wider, providing greater fibrous support, in the setting of clockwise rotation of the aortic root. Individuals with this pattern may be more vulnerable to conduction damage following TAVI. Knowledge of such variation may prove invaluable for risk stratification. PMID- 29146624 TI - Recognition, assessment and management of the mechanical complications of acute myocardial infarction. PMID- 29146626 TI - Clinical outcomes in 1731 patients undergoing mitral valve surgery for rheumatic valve disease. AB - OBJECTIVE: Unlike degenerative mitral valve (MV) disease, the advantages of valve repair procedure over replacement have been debated in rheumatic MV disease. This study aims to evaluate the impact of procedural types on long-term outcomes through analyses on a large data set from an endemic area of rheumatic disease. METHODS: We evaluated 1731 consecutive patients (52.3+/-12.5 years; 1190 women) undergoing MV surgery for rheumatic MV disease between 1997 and 2015. Long-term survival and valve-related outcomes were compared between repair and replacement procedures. To adjust for selection bias, propensity score analyses were performed. RESULTS: Patients undergoing repair were younger and had more predominant mitral regurgitation than mechanical and bioprosthetic replacement groups (61.6% vs 15.6% vs 24.4%; P<0.001). During follow-up (130.9+/-27.7 months), 283 patients (16.3%) died and 256 patients (14.8%) experienced valve related complications. Propensity score matching yielded 188 pairs of repair and replacement patients that were well balanced for baseline covariates. In the matched cohort, there was no significant difference in the mortality risk between the repair and replacement groups (HR, 1.24; 95% CI 0.62 to 2.48). The risk of composite valve-related complications, however, was significantly lower in repair group (HR, 0.57; 95% CI 0.33 to 0.99) principally derived by a lower risk of haemorrhagic events (HR, 0.23; 95% CI 0.07 to 0.70). The incidence of reoperation was not significantly different between groups in the matched cohort (HR, 1.62; 95% CI 0.49 to 5.28). CONCLUSION: Valve repair in well-selected patients with severe rheumatic MV disease led to comparable survival, but superior valve related outcomes compared with valve replacement surgery. PMID- 29146625 TI - Cyanotic congenital heart disease following fertility treatments in the United States from 2011 to 2014. AB - OBJECTIVE: To examine the risk for cyanotic congenital heart diseases (CCHDs) among live births in the USA, resulting from various forms of infertility treatments. METHODS: This study is a cross-sectional analysis of live births in the USA from 2011 to 2014. Infertility treatments are categorised into two of the following groups on birth certificates: assisted reproductive technology (ART) fertility treatment (surgical egg removal; eg, in vitro fertilisation and gamete intrafallopian transfer) and non-ART fertility treatment (eg, medical treatment and intrauterine insemination). We compared the risk for CCHD in ART and non-ART fertility treatment groups with those infants whose mothers received no documented fertility treatment and were naturally conceived (NC). RESULTS: Among 14 242 267 live births from 2011 to 2014, a total of 101 494 live births were in the ART and 81 242 resulted from non-ART fertility treatments. CCHD prevalence in ART, non-ART and NC groups were 393/100 892 (0.39%), 210/80 884 (0.26%) and 10 749/14 020 749 (0.08%), respectively. As compared with naturally conceiving infants, risk for CCHD was significantly higher among infants born in ART (adjusted relative risk (aRR) 2.4, 95% CI 2.1 to 2.7) and non-ART fertility treatment groups (aRR 1.9, 95% CI 1.6 to 2.2). Absolute risk increase in CCHD due to ART and non-ART treatments were 0.03% and 0.02%, respectively. A similar pattern was observed when the analysis was restricted to twins, newborns with birth weights under 1500 g and gestational age of less than 32 weeks. CONCLUSIONS: Our findings suggest an increased risk for CCHD in infants conceived after all types of infertility treatment. PMID- 29146627 TI - Single-session versus staged procedures for elective multivessel percutaneous coronary intervention. AB - OBJECTIVES: To clarify the effect of single-session multivessel percutaneous coronary intervention (PCI) strategy relative to the staged multivessel strategy on clinical outcomes in patients with stable coronary artery disease (CAD) or non ST-elevation acute coronary syndrome. METHODS: In the Coronary REvascularisation Demonstrating Outcome Study in Kyoto PCI/coronary artery bypass grafting registry cohort-2, there were 2018 patients who underwent elective multivessel PCI. Primary outcome measure was composite of all-cause death, myocardial infarction and stroke at 5-year follow-up. RESULTS: Single-session multivessel PCI and staged multivessel PCI were performed in 707 patients (35.0%) and 1311 patients (65.0%), respectively. The cumulative 5-year incidence of and adjusted risk for the primary outcome measure were not significantly different between the single session and staged groups (26.7% vs 23.0%, p=0.45; HR 0.91, 95% CI 0.72 to 1.16, p=0.47). The 30-day incidence of all-cause death was significantly higher in the single-session group than in the staged group (1.1% vs 0.2%, p=0.009). However, the causes of death in 11 patients who died within 30 days were generally not related to the procedural complications, but related to the serious clinical status before PCI. For the subgroup analyses including age, gender, extent of CAD, severe chronic kidney disease and heart failure, there was no significant interaction between the subgroup factors and the effect of the single-session strategy relative to the staged strategy for the primary outcome measure. CONCLUSIONS: The single-session multivessel PCI strategy was associated with at least comparable 5-year clinical outcomes compared with the staged multivessel PCI, although the prevalence of the single-session strategy was low in the present study. PMID- 29146628 TI - Questions arising when NHS staff who refuse flu vaccine have to explain why. PMID- 29146629 TI - Erratum. Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging- and HFD Induced Obesity and Impairs the Feeding-Fasting Transition. Diabetes 2017;66:272 286. PMID- 29146630 TI - A Role for CXCR4 in Peritoneal and Hematogenous Ovarian Cancer Dissemination. AB - Epithelial ovarian cancer is characterized by a low recovery rate because the disease is typically diagnosed at an advanced stage, by which time most patients (80%) already exhibit disseminated neoplasia. The cytokine receptor CXCR4 has been implicated in the development of metastasis in various tumor types. Using a patient-derived tissue macroarray and mRNA expression analysis, we observed high CXCR4 levels in high-grade serous epithelial ovarian carcinomas, the most metastatic tumor, compared with those in endometrioid carcinomas. CXCR4 inhibition by treatment with the CXCR4 antagonist AMD3100 or by expression of shRNA anti-CXCR4 similarly inhibited angiogenesis in several models of ovarian carcinomas orthotopically grown in nude mice, but the effect on tumor growth was correlated with the levels of CXCR4 expression. Moreover, CXCR4 inhibition completely blocked dissemination and metastasis. This effect was associated with reduced levels of active Src, active ERKs, the inhibition of EMT transition, and block of hematogenous ovarian cancer dissemination decreasing circulating human tumoral cells (CTC). In tumors, CXCR4-expressing cells also had more mesenchymal characteristics. In conclusion, our results indicate that CXCR4 expression confers a proinvasive phenotype to ovarian carcinoma cells. Thus, anti-CXCR4 therapy is a possible agent for a complementary treatment of advanced disseminated epithelial high-grade serous ovarian cancer patients. Mol Cancer Ther; 17(2); 532-43. (c)2017 AACR. PMID- 29146631 TI - Frequency of 6-week follow-up appointment scheduling after intrauterine device insertion. AB - INTRODUCTION: Long-acting reversible contraception (LARC) is widely recommended to reduce unintended pregnancy in the USA. As intrauterine device (IUD) use increases, evaluating the role of post-insertion follow-up is important. METHODS: A retrospective patient record review was conducted to assess the follow-up experience of women who had an IUD placed at the University of Kansas Medical Center from 1 January to 30 June 2015. Data were collected on patient demographics, IUD placement, follow-up visit attendance, and outcomes in the 12 months following placement. The primary outcome of interest was the proportion of patients who attended a 6-week follow-up visit. Secondary outcomes included adverse events detected at the 6-week visit and IUD removal within a year of placement. RESULTS: Among 380 women who had an IUD inserted, physician documentation of a recommended 6-week follow-up visit was present in 91.3% of patient medical records. Two-thirds (66.6%) of patients receiving a recommendation returned for a follow-up visit. Of the 380 women who had an IUD placed, 66 (17.4%) had their IUD removed within 1 year of placement. Of those, 50 women attended the 6-week follow-up visit and 16 did not (19.8% vs 12.6%, p=0.08). Of the IUD removals, 14 occurred at the 6-week visit. After excluding IUD removals which occurred at the 6-week visit, attending a 6-week follow-up visit was not associated with IUD removal or retention (p=0.52). CONCLUSION: Despite recommendations to forgo the 6-week follow-up visit, visits were still common, with no demonstrated value added. PMID- 29146632 TI - The evolution of a 'one-stop' outpatient manual vacuum aspiration service for termination of pregnancy. PMID- 29146634 TI - Knowledge, attitudes and intention regarding mHealth in generation Y: evidence from a population based cross sectional study in Chakaria, Bangladesh. AB - BACKGROUND AND OBJECTIVES: mHealth offers a new opportunity to ensure access to qualified healthcare providers. Therefore, to better understand its potential in Bangladesh, it is important to understand how young people use mobile phones for healthcare. Here we examine the knowledge, attitudes and intentions to use mHealth services among young population. DESIGN: Population based cross sectional household survey. SETTING AND PARTICIPANTS: A total of 4909 respondents, aged 18 years and above, under the Chakaria Health and Demographic Surveillance System (HDSS) area, were interviewed during the period November 2012 to April 2013. METHODS: Participants younger than 30 years of age were defined as young (or generation Y). To examine the level of knowledge about and intention towards mHealth services in generation Y compared with their older counterparts, the percentage of the respective outcome measure from a 2*2 contingency table and adjusted odds ratio (aOR), which controls for potential confounders such as mobile ownership, sex, education, occupation and socioeconomic status, were estimated. The aOR was estimated using both the Cochran-Mantel-Haenszel approach and multivariable logistic regression models controlling for confounders. RESULTS: Generation Y had significantly greater access to mobile phones (50%vs40%) and better knowledge about its use for healthcare (37.8%vs27.5%;aOR 1.6 (95% CI1.3 to 2.0)). Furthermore, the level of knowledge about two existing mHealth services in generation Y was significantly higher compared with their older counterparts, with aOR values of 3.2 (95% CI 2.6 to 5.5) and 1.5 (95% CI 1.1 to 1.8), respectively. Similarly, generation Y showed significantly greater intention towards future use of mHealth services compared with their older counterparts (aOR 1.3 (95% CI 1.1 to 1.4)). The observed associations were not modified by sociodemographic factors. CONCLUSION: There is a greater potential for mHealth services in the future among young people compared with older age groups. However, given the low overall use of mHealth, appropriate policy measures need to be formulated to enhance availability, access, utilisation and effectiveness of mHealth services. PMID- 29146633 TI - Comparison of Outcomes of antibiotic Drugs and Appendectomy (CODA) trial: a protocol for the pragmatic randomised study of appendicitis treatment. AB - INTRODUCTION: Several European studies suggest that some patients with appendicitis can be treated safely with antibiotics. A portion of patients eventually undergo appendectomy within a year, with 10%-15% failing to respond in the initial period and a similar additional proportion with suspected recurrent episodes requiring appendectomy. Nearly all patients with appendicitis in the USA are still treated with surgery. A rigorous comparative effectiveness trial in the USA that is sufficiently large and pragmatic to incorporate usual variations in care and measures the patient experience is needed to determine whether antibiotics are as good as appendectomy. OBJECTIVES: The Comparing Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial for acute appendicitis aims to determine whether the antibiotic treatment strategy is non-inferior to appendectomy. METHODS/ANALYSIS: CODA is a randomised, pragmatic non-inferiority trial that aims to recruit 1552 English-speaking and Spanish-speaking adults with imaging-confirmed appendicitis. Participants are randomised to appendectomy or 10 days of antibiotics (including an option for complete outpatient therapy). A total of 500 patients who decline randomisation but consent to follow-up will be included in a parallel observational cohort. The primary analytic outcome is quality of life (measured by the EuroQol five dimension index) at 4 weeks. Clinical adverse events, rate of eventual appendectomy, decisional regret, return to work/school, work productivity and healthcare utilisation will be compared. Planned exploratory analyses will identify subpopulations that may have a differential risk of eventual appendectomy in the antibiotic treatment arm. ETHICS AND DISSEMINATION: This trial was approved by the University of Washington's Human Subjects Division. Results from this trial will be presented in international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02800785. PMID- 29146635 TI - Antibiotic use and bacterial complications following upper respiratory tract infections: a population-based study. AB - OBJECTIVES: To investigate if use of antibiotics was associated with bacterial complications following upper respiratory tract infections (URTIs). DESIGN: Ecological time-trend analysis and a prospective cohort study. SETTING: Primary, outpatient specialist and inpatient care in Stockholm County, Sweden. All analyses were based on administrative healthcare data on consultations, diagnoses and dispensed antibiotics from January 2006 to January 2016. MAIN OUTCOME MEASURES: Ecological time-trend analysis: 10-year trend analyses of the incidence of URTIs, bacterial infections/complications and respiratory antibiotic use. Prospective cohort study: Incidence of bacterial complications following URTIs in antibiotic-exposed and non-exposed patients. RESULTS: The utilisation of respiratory tract antibiotics decreased by 22% from 2006 to 2015, but no increased trend for mastoiditis (p=0.0933), peritonsillar abscess (p=0.0544), invasive group A streptococcal disease (p=0.3991), orbital abscess (p=0.9637), extradural and subdural abscesses (p=0.4790) and pansinusitis (p=0.3971) was observed. For meningitis and acute ethmoidal sinusitis, a decrease in the numbers of infections from 2006 to 2015 was observed (p=0.0038 and p=0.0003, respectively), and for retropharyngeal and parapharyngeal abscesses, an increase was observed (p=0.0214). Bacterial complications following URTIs were uncommon in both antibiotic-exposed (less than 1.5 per 10 000 episodes) and non-exposed patients (less than 1.3 per 10 000 episodes) with the exception of peritonsillar abscess after tonsillitis (risk per 10 000 tonsillitis episodes: 32.4 and 41.1 in patients with no antibiotic treatment and patients treated with antibiotics, respectively). CONCLUSIONS: Bacterial complications following URTIs are rare, and antibiotics may lack protective effect in preventing bacterial complications. Analyses of routinely collected administrative healthcare data can provide valuable information on the number of URTIs, antibiotic use and bacterial complications to patients, prescribers and policy-makers. PMID- 29146636 TI - Antenatal care services and its implications for vital and health outcomes of children: evidence from 193 surveys in 69 low-income and middle-income countries. AB - OBJECTIVES: Antenatal care (ANC) is an essential part of primary healthcare and its provision has expanded worldwide. There is limited evidence of large-scale cross-country studies on the impact of ANC offered to pregnant women on child health outcomes. We investigate the association of ANC in low-income and middle income countries with short- and long-term mortality and nutritional child outcomes. SETTING: We used nationally representative health and welfare data from 193 Demographic and Health Surveys conducted between 1990 and 2013 from 69 low income and middle-income countries for women of reproductive age (15-49 years), their children and their respective household. PARTICIPANTS: The analytical sample consisted of 752 635 observations for neonatal mortality, 574 675 observations for infant mortality, 400 426 observations for low birth weight, 501 484 observations for stunting and 512 424 observations for underweight. MAIN OUTCOMES AND MEASURES: Outcome variables are neonatal and infant mortality, low birth weight, stunting and underweight. RESULTS: At least one ANC visit was associated with a 1.04% points reduced probability of neonatal mortality and a 1.07% points lower probability of infant mortality. Having at least four ANC visits and having at least once seen a skilled provider reduced the probability by an additional 0.56% and 0.42% points, respectively. At least one ANC visit is associated with a 3.82% points reduced probability of giving birth to a low birth weight baby and a 4.11 and 3.26% points reduced stunting and underweight probability. Having at least four ANC visits and at least once seen a skilled provider reduced the probability by an additional 2.83%, 1.41% and 1.90% points, respectively. CONCLUSIONS: The currently existing and accessed ANC services in low-income and middle-income countries are directly associated with improved birth outcomes and longer-term reductions of child mortality and malnourishment. PMID- 29146637 TI - Unequal cluster sizes in stepped-wedge cluster randomised trials: a systematic review. AB - OBJECTIVES: To investigate the extent to which cluster sizes vary in stepped wedge cluster randomised trials (SW-CRT) and whether any variability is accounted for during the sample size calculation and analysis of these trials. SETTING: Any, not limited to healthcare settings. PARTICIPANTS: Any taking part in an SW CRT published up to March 2016. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is the variability in cluster sizes, measured by the coefficient of variation (CV) in cluster size. Secondary outcomes include the difference between the cluster sizes assumed during the sample size calculation and those observed during the trial, any reported variability in cluster sizes and whether the methods of sample size calculation and methods of analysis accounted for any variability in cluster sizes. RESULTS: Of the 101 included SW-CRTs, 48% mentioned that the included clusters were known to vary in size, yet only 13% of these accounted for this during the calculation of the sample size. However, 69% of the trials did use a method of analysis appropriate for when clusters vary in size. Full trial reports were available for 53 trials. The CV was calculated for 23 of these: the median CV was 0.41 (IQR: 0.22-0.52). Actual cluster sizes could be compared with those assumed during the sample size calculation for 14 (26%) of the trial reports; the cluster sizes were between 29% and 480% of that which had been assumed. CONCLUSIONS: Cluster sizes often vary in SW-CRTs. Reporting of SW CRTs also remains suboptimal. The effect of unequal cluster sizes on the statistical power of SW-CRTs needs further exploration and methods appropriate to studies with unequal cluster sizes need to be employed. PMID- 29146638 TI - Preventing type 2 diabetes: systematic review of studies of cost-effectiveness of lifestyle programmes and metformin, with and without screening, for pre-diabetes. AB - OBJECTIVE: Explore the cost-effectiveness of lifestyle interventions and metformin in reducing subsequent incidence of type 2 diabetes, both alone and in combination with a screening programme to identify high-risk individuals. DESIGN: Systematic review of economic evaluations. DATA SOURCES AND ELIGIBILITY CRITERIA: Database searches (Embase, Medline, PreMedline, NHS EED) and citation tracking identified economic evaluations of lifestyle interventions or metformin alone or in combination with screening programmes in people at high risk of developing diabetes. The International Society for Pharmaco-economics and Outcomes Research's Questionnaire to Assess Relevance and Credibility of Modelling Studies for Informing Healthcare Decision Making was used to assess study quality. RESULTS: 27 studies were included; all had evaluated lifestyle interventions and 12 also evaluated metformin. Primary studies exhibited considerable heterogeneity in definitions of pre-diabetes and intensity and duration of lifestyle programmes. Lifestyle programmes and metformin appeared to be cost effective in preventing diabetes in high-risk individuals (median incremental cost effectiveness ratios of L7490/quality-adjusted life-year (QALY) and L8428/QALY, respectively) but economic estimates varied widely between studies. Intervention only programmes were in general more cost effective than programmes that also included a screening component. The longer the period evaluated, the more cost effective interventions appeared. In the few studies that evaluated other economic considerations, budget impact of prevention programmes was moderate (0.13%-0.2% of total healthcare budget), financial payoffs were delayed (by 9-14 years) and impact on incident cases of diabetes was limited (0.1%-1.6% reduction). There was insufficient evidence to answer the question of (1) whether lifestyle programmes are more cost effective than metformin or (2) whether low intensity lifestyle interventions are more cost effective than the more intensive lifestyle programmes that were tested in trials. CONCLUSIONS: The economics of preventing diabetes are complex. There is some evidence that diabetes prevention programmes are cost effective, but the evidence base to date provides few clear answers regarding design of prevention programmes because of differences in denominator populations, definitions, interventions and modelling assumptions. PMID- 29146639 TI - Impact of informal caregiving on older adults' physical and mental health in low income and middle-income countries: a cross-sectional, secondary analysis based on the WHO's Study on global AGEing and adult health (SAGE). AB - OBJECTIVES: A high proportion of care stemming from chronic disease or disability in low-income and middle-income countries is provided by informal caregivers. The goal of this study was to determine the level of burden experienced by these caregivers, explore associated factors and assess whether caregivers' and non caregivers' health differed. DESIGN AND SETTING: This cross-sectional study was a secondary analysis of data on caregivers' burden, health and health risk factors in Ghana, India and the Russian Federation collected as part of the WHO's Study on global AGEing and adult health (SAGE) Wave 1. PARTICIPANTS: Caregivers in Ghana (n=143), India (n=490) and Russia (n=270) completed the measures. OUTCOME MEASURES: Factors associated (ie, demographics and caregiving profile variables) with burden were explored among caregivers. Then, quality of life (QOL), perceived stress, depression, self-rated health (SRH) and health risk factors were compared between caregivers and matched non-caregivers (1:2). RESULTS: The largest caregiving subgroups were spouses and adult children. Caregivers mostly cared for one person and provided financial, social/emotional and/or physical support, but received little support themselves. Burden level ranged from 17.37 to 20.03. Variables associated with burden were mostly country-specific; however, some commonality for wealth, type of care and caregiving duration was noted. Caregivers with a moderate or high level of burden reported lower QOL and higher perceived stress than those experiencing low burden. Caregivers reported lower QOL and SRH than non-caregivers. CONCLUSION: Given the lack of support received and consequences of the burden endured by caregivers, policy and programme initiatives are needed to ensure that caregivers in low- and middle-income countries can fulfil their role without compromising their own health. PMID- 29146640 TI - Lipid profiles and determinants of total cholesterol and hypercholesterolaemia among 25-74 year-old urban and rural citizens of the Yangon Region, Myanmar: a cross-sectional study. AB - OBJECTIVE: The first is to estimate the prevalence of dyslipidaemia (hypercholesterolaemia, hypertriglyceridaemia, high low-density lipoprotein (LDL) level and low high-density lipoprotein (HDL) level), as well as the mean levels of total cholesterol, triglyceride, LDL and HDL, in the urban and rural Yangon Region, Myanmar. The second is to investigate the association between urban-rural location and total cholesterol. DESIGN: Two cross-sectional studies using the WHO STEPS methodology. SETTING: Both the urban and rural areas of the Yangon Region, Myanmar. PARTICIPANTS: A total of 1370 men and women aged 25-74 years participated based on a multistage cluster sampling. Physically and mentally ill people, monks, nuns, soldiers and institutionalised people were excluded. RESULTS: Compared with rural counterparts, urban dwellers had a significantly higher age-standardised prevalence of hypercholesterolaemia (50.7% vs 41.6%; p=0.042) and a low HDL level (60.6% vs 44.4%; p=0.001). No urban-rural differences were found in the prevalence of hypertriglyceridaemia and high LDL. Men had a higher age-standardised prevalence of hypertriglyceridaemia than women (25.1% vs 14.8%; p<0.001), while the opposite pattern was found in the prevalence of a high LDL (11.3% vs 16.3%; p=0.018) and low HDL level (35.3% vs 70.1%; p<0.001).Compared with rural inhabitants, urban dwellers had higher age standardised mean levels of total cholesterol (5.31 mmol/L, SE: 0.044 vs 5.05 mmol/L, 0.068; p=0.009), triglyceride (1.65 mmol/L, 0.049 vs 1.38 mmol/L, 0.078; p=0.017), LDL (3.44 mmol/L, 0.019 vs 3.16 mmol/L, 0.058; p=0.001) and lower age standardised mean levels of HDL (1.11 mmol/L, 0.010 vs 1.25 mmol/L, 0.012; p<0.001). In linear regression, the total cholesterol was significantly associated with an urban location among men, but not among women. CONCLUSION: The mean level of total cholesterol and the prevalence of hypercholesterolaemia were alarmingly high in men and women in both the urban and rural areas of Yangon Region, Myanmar. Preventive measures to reduce cholesterol levels in the population are therefore needed. PMID- 29146641 TI - Menopausal hormone therapy and colorectal cancer: a linkage between nationwide registries in Norway. AB - OBJECTIVES: With the present study, we aimed to investigate the association between menopausal hormone therapy (HT) and risk of colorectal cancer (CRC). SETTING: Cohort study based on the linkage of Norwegian population-based registries. PARTICIPANTS: We selected 466822 Norwegian women, aged 55-79, alive and residing in Norway as of 1 January 2004, and we followed them from 2004 to 2008. Each woman contributed person-years at risk as non-user, current user and/or past HT user. OUTCOME MEASURES: The outcome of interest was adenocarcinoma of the colorectal tract, overall, by anatomic site and stage at diagnosis. Incidence rate ratios (RRs) with 95% CIs were estimated by Poisson regression and were used to evaluate the association between HT and CRC incidence. RESULTS: During the median follow-up of 4.8 years, 138 655 (30%) women received HT and 3799 (0.8%) incident CRCs occurred. Current, but not past, use of HT was associated with a lower risk of CRC (RR 0.88; 95% CI 0.80 to 0.98). RRs for localised, regionally advanced and metastatic CRC were 1.13 (95% CI 0.91 to 1.41), 0.81 (95% CI 0.70 to 0.94) and 0.79 (95% CI 0.62 to 1.00), respectively. RRs for current use of oestrogen therapy (ET) were 0.91 (95% CI 0.80 to 1.04) while RR for current use of combined oestrogen-progestin therapy (EPT) was 0.85 (95% CI 0.70 to 1.03), as compared with no use of HT. The same figures for ET and EPT in oral formulations were 0.83 (95% CI 0.68 to 1.03) and 0.86 (95% CI 0.71 to 1.05), respectively. CONCLUSIONS: In our nationwide cohort study, HT use lowered the risk of CRC, specifically the most advanced CRC. PMID- 29146642 TI - 'When it goes back to my normal I suppose': a qualitative study using online focus groups to explore perceptions of 'control' among people with eczema and parents of children with eczema in the UK. AB - OBJECTIVE: To inform the development of a core outcome set for eczema by engaging with people with eczema and parents of children with eczema to understand their experiences and understanding of the concept 'eczema control'. DESIGN: 37 participants took part in a total of six semi-structured online focus groups held in a typed chatroom with 5-7 participants per group. Three groups involved adults with eczema and three groups involved parents of children with eczema. Framework analysis was used for data analysis. SETTING: A community-based sample was recruited from across the UK via social media and email. PARTICIPANTS: 19 adults aged 17-61 years (15/19 female, 16/19 white) and 18 parents of children with eczema aged 9 months-17 years (9/18 female, 18/19 white). RESULTS: Four main themes were identified:(1) 'Commonalities and differences in the experiences of control': a reduction in symptoms such as itch and sleep loss characterised eczema control, but what level was acceptable differed across participants;(2) 'Eczema control goes beyond the skin': psychological factors, social factors, the constant scratching and the impact on everyday activities are a variety of ways an individual can be impacted;(3) 'Stepping up and down of treatment': participants' stepped-up treatment in response to loss of control, but several factors complicated this behaviour. Control needed to be maintained after stepped up treatment ended to be acceptable; and (4) 'How to measure control': self report was generally preferred to allow frequent measurements and to capture unobservable features. Although most thought their eczema needed to be measured frequently, many also felt that this was not always realistic or desirable. CONCLUSIONS: 'Eczema control' is a complex experience for people with eczema and parents of children with the condition. These experiences could have important implications on how long-term control should be measured in eczema clinical trials and clinical practice. PMID- 29146643 TI - Are IL18RAP gene polymorphisms associated with body mass regulation? A cross sectional study. AB - OBJECTIVES: To investigate the association between IL18RAP and body mass index (BMI) and obesity and to verify the effect of a polymorphism in the microRNA136 (MIR136) IL18RAP binding region. DESIGN: We analysed samples from two Spanish cross-sectional studies, VALCAR (Spanish Mediterranean coast) and Hortega (Spanish centre). These studies aimed at analysing cardiovascular risk and development of cardiovascular disease in the general population. Both populations correspond to regions with different characteristics. SETTING: Five IL18RAP single nucleotide polymorphisms were selected using the SYSNPs web tool and analysed by oligonucleotide ligation assay (SNPlex). For the MIR136 functional study, cells were transfected with plasmids containing different rs7559479 polymorphism alleles and analysed by luciferase reporter assays. PARTICIPANTS: 1970 individuals (Caucasian, both genders): VALCAR (468) and Hortega (1502). RESULTS: rs2293225, rs2272127 and rs7559479 showed the following associations: rs7559479 G allele correlated with a higher obesity risk (P=0.01; OR=1.82; 95% CI 1.15 to 2.87 for the VALCAR group; P=0.033; OR=1.35; 95% CI 1.03 to 1.79 for the Hortega population) and higher body mass index (BMI) values (P=0.0045; P=0.1 for VALCAR and Hortega, respectively); a significant association with obesity (P=0.0024, OR=1.44, 95% CI 1.14 to 1.82) and increased BMI values (P=0.008) was found when considering both populations together. rs2293225 T allele was associated with lower obesity risk (P=0.036; OR=0.60; 95% CI 0.35 to 0.96) and lower BMI values (P=0.0038; OR=1.41) while the rs2272127 G allele was associated with lower obesity risk (P=0.028; OR=0.66; 95% CI 0.44 to 0.97) only in the VALCAR population. A reporter assay showed that the presence of the A allele in rs7559479 was associated with increased MIR136 binding to IL18RAP. CONCLUSIONS: Our results suggest that polymorphisms in IL18RAP influence susceptibility to obesity. We demonstrated that the A allele in rs7559479 increases MIR136 binding, which regulates IL-18 system activity. PMID- 29146644 TI - A national cohort study evaluating infant and fetal mortality caused by birth defects in Korea. AB - OBJECTIVE: To analyse the prevalence of fetal and infant deaths due to birth defects in Korea and those trends according to maternal age. DESIGN: Retrospective national cohort study SETTING: Korean Vital Statistics database of the Korean Statistical Information Service, between 2009 and 2015. PARTICIPANTS: 2176 infant deaths and 4343 fetal deaths caused by birth defects, among 3 181 145 total live births and 43 385 fetal deaths during the study periods. METHODS: Infant and fetal mortality rates (IMRs and FMRs) by birth defects, from deaths caused by birth defects, were analysed. They were compared, according to maternal age groups: (I) '10-19 years'; (II) '20-29 years'; (III) '30-34 years'; (IV) '35 39 years'; and (V) '40-55 years'. MAIN OUTCOME MEASURES: IMRs and FMRs by birth defects and comparison according to maternal age group. RESULTS: IMRs and FMRs by birth defects were 6.84 per 10 000 live births and 13.47 per 10 000 total births. The most common causes of infant deaths and fetal deaths by birth defect were anomaly of the circulatory system (51.1%, IMR 3.5) and chromosomal abnormality (33.1%, FMR 4.46), respectively. Among groups by maternal age, FMRs by birth defects were significantly higher in groups I and V compared with group III (OR 6.59, 95% CI 3.49 to 12.43; and OR 3.46, 95% CI 1.77 to 6.78, respectively). IMR and FMR by nervous system anomaly were significantly higher in group I at 3.63 (OR 2.0, 95% CI 1.97 to 2.03) and 29.84 (OR 15.04, 95% CI 3.59 to 62.96) compared with 0.32 and 1.97 in group III. CONCLUSION: FMRs by birth defects were the highest in the extreme maternal age groups. Severe anomalies, except for chromosomal abnormality, were most prevalent in teenage pregnancies. PMID- 29146645 TI - Logistic regression analysis of factors influencing the effectiveness of intensive sound masking therapy in patients with tinnitus. AB - OBJECTIVES: To investigate factors influencing the effectiveness of intensive sound masking therapy on tinnitus using logistic regression analysis. DESIGN: The study used a retrospective cross-section analysis. PARTICIPANTS: 102 patients with tinnitus were recruited at the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, China. INTERVENTION: Intensive sound masking therapy was used as an intervention approach for patients with tinnitus. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants underwent audiological investigations and tinnitus pitch and loudness matching measurements, followed by intensive sound masking therapy. The Tinnitus Handicap Inventory (THI) was used as the outcome measure pre and post treatment. Multivariate logistic regression was performed to investigate the association of demographic and audiological factors with effective therapy. RESULTS: According to the THI score changes pre and post sound masking intervention, 51 participants were categorised into an effective group, the remaining 51 participants were placed in a non-effective group. Those in the effective group were significantly younger than those in the non-effective group (P=0.012). Significantly more participants had flat audiogram configurations in the effective group (P=0.04). Multivariable logistic regression analysis showed that age (OR=0.96, 95% CI 0.93 to 0.99, P=0.007), audiometric configuration (P=0.027) and THI score pre treatment (OR=1.04, 95% CI 1.02 to 1.07, P<0.001) were significantly associated with therapeutic effectiveness. Further analysis showed that patients with flat audiometric configurations were 5.45 times more likely to respond to intervention than those with high-frequency steeply sloping audiograms (OR=5.45, 95% CI 1.67 to 17.86, P=0.005). CONCLUSION: Audiometric configuration, age and THI scores appear to be predictive of the effectiveness of sound masking treatment. Gender, tinnitus characteristics and hearing threshold measures do not seem to be related to treatment effectiveness. A further randomised control study is needed to provide evidence of the effectiveness of prognostic factors in tinnitus interventions. PMID- 29146646 TI - Cross-sectional study of the financial cost of training to the surgical trainee in the UK and Ireland. AB - OBJECTIVES: Applications for surgical training have declined over the last decade, and anecdotally the costs of training at the expense of the surgical trainee are rising. We aimed to quantify the costs surgical trainees are expected to cover for postgraduate training. DESIGN: Prospective, cross-sectional, questionnaire-based study. SETTING/PARTICIPANTS: A non-mandatory online questionnaire for UK-based trainees was distributed nationally. A similar national questionnaire was distributed for Ireland, taking into account differences between the healthcare systems. Only fully completed responses were included. RESULTS: There were 848 and 58 fully completed responses from doctors based in the UK and Ireland, respectively. Medical students in the UK reported a significant increase in debt on graduation by 55% from L17 892 (2000-2004) to L27 655 (2010-2014) (p<0.01). 41% of specialty trainees in the UK indicated that some or all of their study budget was used to fund mandatory regional teaching. By the end of training, a surgical trainee in the UK spends on average L9105 on courses, L5411 on conferences and L4185 on exams, not covered by training budget. Irish trainees report similarly high costs. Most trainees undertake a higher degree during their postgraduate training. The cost of achieving the mandatory requirements for completion of training ranges between L20 000 and L26 000 (dependent on specialty), except oral and maxillofacial surgery, which is considerably higher (L71 431). CONCLUSIONS: Medical students are graduating with significantly larger debt than before. Surgical trainees achieve their educational requirements at substantial personal expenditure. To encourage graduates to pursue and remain in surgical training, urgent action is required to fund the mandatory requirements and annual training costs for completion of training and provide greater transparency to inform doctors of what their postgraduate training costs will be. This is necessary to increase diversity in surgery, reduce debt load and ensure surgery remains a popular career choice. PMID- 29146647 TI - Initial non-operative management of uncomplicated appendicitis in children: a protocol for a multicentre randomised controlled trial (APAC trial). AB - INTRODUCTION: Based on epidemiological, immunological and pathology data, the idea that appendicitis is not necessarily a progressive disease is gaining ground. Two types are distinguished: simple and complicated appendicitis. Non operative treatment (NOT) of children with simple appendicitis has been investigated in several small studies. So far, it is deemed safe. However, its effectiveness and effect on quality of life (QoL) have yet to be established in an adequately powered randomised trial. In this article, we provide the study protocol for the APAC (Antibiotics versus Primary Appendectomy in Children) trial. METHODS AND ANALYSIS: This multicentre, non-inferiority, randomised controlled trial randomises children aged 7-17 years with imaging-confirmed simple appendicitis between appendectomy and NOT. Patients are recruited in 15 hospitals. The intended sample size, based on the primary outcome, rate of complications and a non-inferiority margin of 5%, is 334 patients.NOT consists of intravenous antibiotics for 48-72 hours, daily blood tests and ultrasound follow up. If the patient meets the predefined discharge criteria, antibiotic treatment is continued orally at home. Primary outcome is the rate of complications at 1 year follow-up. An independent adjudication committee will assess all complications and their relation to the allocated treatment. Secondary outcomes include, but are not limited to, delayed appendectomies, QoL, pain and (in)direct costs.The primary outcome will be analysed both according to the intention-to treat principle and the per-protocol principle, and is presented with a one-sided 97.5% CI. We will use multiple logistic and linear regression for binary and continuous outcomes, respectively, to adjust for stratification factors. ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Ethics Review Committee of the Academic Medical Center, Amsterdam. Data monitoring is performed by an independent institute and a Data Safety Monitoring Board has been assigned. Results will be presented in peer-reviewed academic journals and at (international) conferences. TRIAL REGISTRATION NUMBER: NCT02848820; NTR5977; Pre results. PMID- 29146648 TI - Economic evaluation of an e-mental health intervention for patients with retinal exudative diseases who receive intraocular anti-VEGF injections (E-PsEYE): protocol for a randomised controlled trial. AB - INTRODUCTION: Because of the great potential of vascular endothelial growth factor inhibitors (anti-VEGF) for retinal exudative diseases, an increased number of patients receives this treatment. However, during this treatment, patients are subjected to frequent invasive intravitreal injections, and the effects on reversing the process of vision loss are uncertain, which may have negative consequences for patients' mental health. One in three patients experience at least mild symptoms of depression/anxiety. To support patients in dealing with these symptoms, an e-mental health intervention (called E-PsEYE) has been developed. E-PsEYE is based on cognitive-behavioural therapy (CBT) and contains nine modules. A stepped-care model with three steps will be used to deliver the intervention: (1) providing information and psychoeducation, (2) when symptoms of depression/anxiety persist, guided CBT is offered and supported by social workers from low vision rehabilitation services and (3) when symptoms still persist, patients are referred to their general practitioner. METHODS AND ANALYSIS: An economic evaluation from a healthcare and societal perspective will be conducted alongside a multicentre randomised controlled trial in two parallel groups to evaluate whether E-PsEYE is cost-effective in comparison with usual care. Participants (n=174) will be 50 years or older, have retinal exudative diseases, receive anti-VEGF treatment and have mild symptoms of depression/anxiety (assessed prior to randomisation). Main outcome measures are: depression (Patient Health Questionnaire-9), anxiety (Hospital Anxiety and Depression Scale-Anxiety) and quality-adjusted life-years (determined with the Health Utility Index-3 and the EuroQol-5 dimensions). Five measurements take place: at baseline and after 3, 6, 9 and 12 months. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the VU University Medical Centre Amsterdam. It will provide new and essential information on the cost-effectiveness of an innovative intervention for a vulnerable population. Outcomes will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION: http://www.trialregister.nl, identifier: NTR6337. PMID- 29146649 TI - What are older smokers' attitudes to quitting and how are they managed in primary care? An analysis of the cross-sectional English Smoking Toolkit Study. AB - OBJECTIVES: To investigate whether age is associated with access to smoking cessation services. DESIGN: Data from the Smoking Toolkit Study 2006-2015, a repeated multiwave cross-sectional household survey (n=181 157). SETTING: England. PARTICIPANTS: Past-year smokers who participated in any of the 102 waves stratified into age groups. OUTCOME MEASURES: Amount smoked and nicotine dependency, self-reported quit attempts and use of smoking cessation interventions. Self-report of whether the general practitioner (GP) raised the topic of smoking and made referrals for pharmacological support (prescription of nicotine replacement therapies (NRTs)) or other support (counselling or support groups). RESULTS: Older smokers (75+ years) were less likely to report that they were attempting to quit smoking or seek help from a GP, despite being less nicotine-dependent. GPs raised smoking as a topic equally across all age groups, but smokers aged 70+ were more likely not to be referred for NRT or other support (ORs relative to 16-54 years; 70-74 years 1.27, 95% CI 1.03 to 1.55; 75-79 years 1.87, 95% CI 1.43 to 2.44; 80+ years 3.16, 95% CI 2.20 to 4.55; p value for trend <0.001). CONCLUSIONS: Our findings suggest that there are potential missed opportunities in facilitating smoking cessation in older smokers. In this large population-based study, older smokers appeared less interested in quitting and were less likely to be offered support, despite being less addicted to nicotine than younger smokers. It is unclear whether this constitutes inequitable access to services or reflects informed choices by older smokers and their GPs. Future research is needed to understand why older smokers and GPs do not pursue smoking cessation. Service provision should consider how best to reduce these variations, and a stronger effectiveness evidence base is required to support commissioning for this older population so that, where appropriate, older smokers are not missing out on smoking cessation therapies and the health benefits of cessation at older ages. PMID- 29146650 TI - Benefits and risks of Iron interventions in children (BRISC): protocol for a three-arm parallel-group randomised controlled field trial in Bangladesh. AB - INTRODUCTION: Anaemia is a major global health problem affecting about 43% of preschool children globally and 60% of 6-24-month-old children in rural Bangladesh, half of which is attributed to iron deficiency (ID). Although WHO recommends universal supplementation with iron or home fortification with iron containing multiple micronutrient powders (MMPs) to children under 2 years, evidence for benefits of these interventions on childhood development (a key rationale for these interventions) and harms (especially infection) remains limited. This study aims to evaluate the impact of iron or MMPs supplementation compared with placebo on (a) children's development, (b) growth, (c) morbidity from infections and (d) haematological and iron indices. METHODS AND ANALYSIS: This study is a three-arm, blinded, double-dummy, parallel-group, placebo controlled superiority trial using stratified individual block randomisation. The trial will randomise 3300 children aged 8-9 months equally to arm 1: iron syrup (12.5 mg elemental iron), placebo MMPs; arm 2: MMPs (including 12.5 mg elemental iron), placebo syrup; and arm 3: placebo syrup, placebo MNPs. Children will receive interventions for 3 months based on WHO recommendations and then be followed up for 9 months post intervention. The primary outcome is cognitive composite score measured by Bayley III. Secondary outcomes include motor and language composite score by Bayley III, behaviour rating using selected items from Wolke's rating scales and BSID-II behaviour ratings, temperament, growth, haemoglobin, anaemia and iron status, and infectious morbidity. Outcomes will be measured at baseline, at the end of 3-month intervention and after 9 months postintervention follow-up. ETHICS AND DISSEMINATION: The trial has been approved by the Ethical Review Committee of icddr,b (Dhaka, Bangladesh) and the Melbourne Health Human Research Ethics Committee (Melbourne, Australia). Results of the study will be disseminated through scientific publications, presentations at international meetings and policy briefs to key stakeholders. TRIAL REGISTRATION NUMBER: ACTRN12617000660381;Pre-results. WHO UNIVERSAL TRIAL NUMBER: U1111-1196 1125. PMID- 29146651 TI - Prevalence of pregnancy-related pelvic girdle pain and associated factors in Australia: a cross-sectional study protocol. AB - INTRODUCTION: Pregnancy-related pelvic girdle pain (PPGP) is a common musculoskeletal disorder. Women with PPGP report difficulty performing everyday functional activities, such as standing and walking. However, the magnitude of the problem remains unknown in Australia. It is important to determine how many women are affected by this condition and the factors associated with PPGP as this will direct healthcare services to being able to better manage women during pregnancy. Thus, this study aims to determine the prevalence of PPGP and associated factors in a Western Sydney population. METHODS AND ANALYSIS: This study is a cross-sectional study to be conducted at a single hospital in Australia. Participants will be over 18 years of age, between 14 and 38 weeks gestation and recruited randomly from all pregnant women attending antenatal care. Participants will have anthropomorphic measures recorded, such as height and body weight, and be asked to complete questionnaires about their current pregnancy, sociodemographic information, ethnoculture, occupational factors and participation in functional activities. The classification of PPGP will be made as per the published guidelines and will include a physical examination. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Human Research Ethics Committees of Westmead Hospital, Sydney, and Western Sydney University, Sydney. Dissemination of results will be via journal articles and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12617000904370. PMID- 29146652 TI - Dynamic treatment selection and modification for personalised blood pressure therapy using a Markov decision process model: a cost-effectiveness analysis. AB - OBJECTIVE: Personalised medicine seeks to select and modify treatments based on individual patient characteristics and preferences. We sought to develop an automated strategy to select and modify blood pressure treatments, incorporating the likelihood that patients with different characteristics would benefit from different types of medications and dosages and the potential severity and impact of different side effects among patients with different characteristics. DESIGN, SETTING AND PARTICIPANTS: We developed a Markov decision process (MDP) model to incorporate meta-analytic data and estimate the optimal treatment for maximising discounted lifetime quality-adjusted life-years (QALYs) based on individual patient characteristics, incorporating medication adjustment choices when a patient incurs side effects. We compared the MDP to current US blood pressure treatment guidelines (the Eighth Joint National Committee, JNC8) and a variant of current guidelines that incorporates results of a major recent trial of intensive treatment (Intensive JNC8). We used a microsimulation model of patient demographics, cardiovascular disease risk factors and side effect probabilities, sampling from the National Health and Nutrition Examination Survey (2003-2014), to compare the expected population outcomes from adopting the MDP versus guideline-based strategies. MAIN OUTCOME MEASURES: Costs and QALYs for the MDP based treatment (MDPT), JNC8 and Intensive JNC8 strategies. RESULTS: Compared with the JNC8 guideline, the MDPT strategy would be cost-saving from a societal perspective with discounted savings of US$1187 per capita (95% CI 1178 to 1209) and an estimated discounted gain of 0.06 QALYs per capita (95% CI 0.04 to 0.08) among the US adult population. QALY gains would largely accrue from reductions in severe side effects associated with higher treatment doses later in life. The Intensive JNC8 strategy was dominated by the MDPT strategy. CONCLUSIONS: An MDP based approach can aid decision-making by incorporating meta-analytic evidence to personalise blood pressure treatment and improve overall population health compared with current blood pressure treatment guidelines. PMID- 29146653 TI - Identifying bioethical issues in biostatistical consulting: findings from a US national pilot survey of biostatisticians. AB - OBJECTIVES: The overall purposes of this first US national pilot study were to (1) test the feasibility of online administration of the Bioethical Issues in Biostatistical Consulting (BIBC) Questionnaire to a random sample of American Statistical Association (ASA) members; (2) determine the prevalence and relative severity of a broad array of bioethical violations requests that are presented to biostatisticians by investigators seeking biostatistical consultations; and (3) establish the sample size needed for a full-size phase II study. DESIGN: A descriptive survey as approved and endorsed by the ASA. PARTICIPANTS: Administered to a randomly drawn sample of 112 professional biostatisticians who were ASA members. PRIMARY AND SECONDARY OUTCOME MEASURES: The 18 bioethical violations were first ranked by perceived severity scores, then categorised into three perceived severity subcategories in order to identify seven 'top tier concern violations' and seven 'second tier concern violations'. RESULTS: Methodologically, this phase I pilot study demonstrated that the BIBC Questionnaire, as administered online to a random sample of ASA members, served to identify bioethical violations that occurred during biostatistical consultations, and provided data needed to establish the sample size needed for a full-scale phase II study. The No. 1 top tier concern was 'remove or alter some data records in order to better support the research hypothesis'. The No. 2 top tier concern was 'interpret the statistical findings based on expectation, not based on actual results'. In total, 14 of the 18 BIBC Questionnaire items, as judged by a combination of 'severity of violation' and 'frequency of occurrence over past 5 years', were rated by biostatisticians as 'top tier' or 'second tier' bioethical concerns. CONCLUSION: This pilot study gives clear evidence that researchers make requests of their biostatistical consultants that are not only rated as severe violations, but further that these requests occur quite frequently. PMID- 29146654 TI - Diagnostic and laboratory test ordering in Northern Portuguese Primary Health Care: a cross-sectional study. AB - OBJECTIVES: To characterise the test ordering pattern in Northern Portugal and to investigate the influence of context-related factors, analysing the test ordered at the level of geographical groups of family physicians and at the level of different healthcare organisations. DESIGN: Cross-sectional study. SETTING: Northern Primary Health Care, Portugal. PARTICIPANTS: Records about diagnostic and laboratory tests ordered from 2035 family physicians working at the Northern Regional Health Administration, who served approximately 3.5 million Portuguese patients, in 2014. OUTCOMES: To determine the 20 most ordered diagnostic and laboratory tests in the Northern Regional Health Administration; to identify the presence and extent of variations in the 20 most ordered diagnostic and laboratory tests between the Groups of Primary Care Centres and between health units; and to study factors that may explain these variations. RESULTS: The 20 most ordered diagnostic and laboratory tests almost entirely comprise laboratory tests and account for 70.9% of the total tests requested. We can trace a major pattern of test ordering for haemogram, glucose, lipid profile, creatinine and urinalysis. There was a significant difference (P<0.001) in test orders for all tests between Groups of Primary Care Centres and for all tests, except glycated haemoglobin (P=0.06), between health units. Generally, the Personalised Healthcare Units ordered more than Family Health Units. CONCLUSIONS: The results from this study show that the most commonly ordered tests in Portugal are laboratory tests, that there is a tendency for overtesting and that there is a large variability in diagnostic and laboratory test ordering in different geographical and organisational Portuguese primary care practices, suggesting that there may be considerable potential for the rationalisation of test ordering. The existence of Family Health Units seems to be a strong determinant in decreasing test ordering by Portuguese family physicians. Approaches to ensuring more rational testing are needed. PMID- 29146655 TI - Qualitative evaluation of a deferred consent process in paediatric emergency research: a PREDICT study. AB - BACKGROUND: A challenge of conducting research in critically ill children is that the therapeutic window for the intervention may be too short to seek informed consent prior to enrolment. In specific circumstances, most international ethical guidelines allow for children to be enrolled in research with informed consent obtained later, termed deferred consent (DC) or retrospective consent. There is a paucity of data on the attitudes of parents to this method of enrolment in paediatric emergency research. OBJECTIVES: To explore the attitudes of parents to the concept of DC and to expand the knowledge of the limitations to informed consent and DC in these situations. METHOD: Children presenting with uncomplicated febrile seizures or bronchiolitis were identified from three separate hospital emergency department databases. Parents were invited to participate in a semistructured telephone interview exploring themes of limitations of prospective informed consent, acceptability of the DC process and the most appropriate time to seek DC. Transcripts underwent inductive thematic analysis with intercoder agreement, using Nvivo 11 software. RESULTS: A total of 39 interviews were conducted. Participants comprehended the limitations of informed consent under emergency circumstances and were generally supportive of DC. However, they frequently confused concepts of clinical care and research, and support for participation was commonly linked to their belief of personal benefit. CONCLUSION: Participants acknowledged the requirement for alternatives to prospective informed consent in emergency research, and were supportive of the concept of DC. Our results suggest that current research practice seems to align with community expectations. PMID- 29146656 TI - Prevalence of diabetic retinopathy in children and young people living with diabetes: protocol for a systematic review. AB - INTRODUCTION: The frequency of diabetes mellitus in childhood is increasing. Thus, more children and young people are at risk of developing diabetic retinopathy and diabetes related visual impairment. However, there is no consensus on optimal screening strategies for the paediatric population reflecting the lack of clarity about the current burden of disease in this group. We aim to estimate the prevalence of diabetic retinopathy in children and young people living with types 1 or 2 diabetes, and to investigate potential sources of heterogeneity in this figure so as to inform screening strategies for this population. METHODS AND ANALYSIS: PubMed and EMBASE will be searched from 1995 to 2016 using the OvidSP platform with no language restriction. Additionally, manual review of the references lists of included articles will be conducted. Two investigators will independently screen titles and abstracts for potential eligibility. Studies which report prevalence of diabetic retinopathy among general populations of children and young people with types 1 or 2 diabetes will be included. Pooled prevalence estimates of diabetic retinopathy reported in studies with sample size greater than 200 participants will be calculated by the random effect model. Forest plots will be used to summarise individual and pooled estimates of the prevalence. Heterogeneity between studies will be assessed using the I2 statistic and explored through meta-regressions and subgroup analyses if the necessary data are available. ETHICS AND DISSEMINATION: Ethics approval is not required as this is a review of anonymised published data. We will report the findings of this systematic review in a peer-reviewed journal, and share it with the relevant professionals including health authorities through our Diabetic Eye disease in Childhood Study collaborative network. CLINICAL TRAIL REGISTRATION: PROSPERO (CRD42017067178). PMID- 29146657 TI - A randomised controlled trial of a duodenal-jejunal bypass sleeve device (EndoBarrier) compared with standard medical therapy for the management of obese subjects with type 2 diabetes mellitus. AB - INTRODUCTION: The prevalence of obesity and obesity-related diseases, including type 2 diabetes mellitus (T2DM), is increasing. Exclusion of the foregut, as occurs in Roux-en-Y gastric bypass, has a key role in the metabolic improvements that occur following bariatric surgery, which are independent of weight loss. Endoscopically placed duodenal-jejunal bypass sleeve devices, such as the EndoBarrier (GI Dynamics, Lexington, Massachusetts, USA), have been designed to create an impermeable barrier between chyme exiting the stomach and the mucosa of the duodenum and proximal jejunum. The non-surgical and reversible nature of these devices represents an attractive therapeutic option for patients with obesity and T2DM by potentially improving glycaemic control and reducing their weight. METHODS AND ANALYSIS: In this multicentre, randomised, controlled, non blinded trial, male and female patients aged 18-65 years with a body mass index 30-50 kg/m2 and inadequately controlled T2DM on oral antihyperglycaemic medications (glycosylated haemoglobin (HbA1c) 58-97 mmol/mol) will be randomised in a 1:1 ratio to receive either the EndoBarrier device (n=80) for 12 months or conventional medical therapy, diet and exercise (n=80). The primary outcome measure will be a reduction in HbA1c by 20% at 12 months. Secondary outcome measures will include percentage weight loss, change in cardiovascular risk factors and medications, quality of life, cost, quality-adjusted life years accrued and adverse events. Three additional subgroups will investigate the mechanisms behind the effect of the EndoBarrier device, looking at changes in gut hormones, metabolites, bile acids, microbiome, food hedonics and preferences, taste, brain reward system responses to food, eating and addictive behaviours, body fat content, insulin sensitivity, and intestinal tissue gene expression. TRIAL REGISTRATION NUMBER: ISRCTN30845205, ClinicalTrials.gov Identifier NCT02459561. PMID- 29146659 TI - Smoking and quit attempts during pregnancy and postpartum: a longitudinal UK cohort. AB - OBJECTIVES: Pregnancy motivates women to try stopping smoking, but little is known about timing of their quit attempts and how quitting intentions change during pregnancy and postpartum. Using longitudinal data, this study aimed to document women's smoking and quitting behaviour throughout pregnancy and after delivery. DESIGN: Longitudinal cohort survey with questionnaires at baseline (8 26 weeks' gestation), late pregnancy (34-36 weeks) and 3 months after delivery. SETTING: Two maternity hospitals in one National Health Service hospital trust, Nottingham, England. PARTICIPANTS: 850 pregnant women, aged 16 years or over, who were current smokers or had smoked in the 3 months before pregnancy, were recruited between August 2011 and August 2012. OUTCOME MEASURES: Self-reported smoking behaviour, quit attempts and quitting intentions. RESULTS: Smoking rates, adjusting for non-response at follow-up, were 57.4% (95% CI 54.1 to 60.7) at baseline, 59.1% (95% CI 54.9 to 63.4) in late pregnancy and 67.1% (95% CI 62.7 to 71.5) 3 months postpartum. At baseline, 272 of 488 current smokers had tried to quit since becoming pregnant (55.7%, 95% CI 51.3 to 60.1); 51.3% (95% CI 44.7 to 58.0) tried quitting between baseline and late pregnancy and 27.4% (95% CI 21.7 to 33.2) after childbirth. The percentage who intended to quit within the next month fell as pregnancy progressed, from 40.4% (95% CI 36.1 to 44.8) at baseline to 29.7% (95% CI 23.8 to 35.6) in late pregnancy and 14.2% (95% CI 10.0 to 18.3) postpartum. Postpartum relapse was lower among women who quit in the 3 months before pregnancy (17.8%, 95% CI 6.1 to 29.4) than those who stopped between baseline and late pregnancy (42.9%, 95% CI 24.6 to 61.3). CONCLUSIONS: Many pregnant smokers make quit attempts throughout pregnancy and postpartum, but intention to quit decreases over time; there is no evidence that smoking rates fall during gestation. PMID- 29146658 TI - Views of commissioners, managers and healthcare professionals on the NHS Health Check programme: a systematic review. AB - OBJECTIVE: To synthesise data concerning the views of commissioners, managers and healthcare professionals towards the National Health Service (NHS) Health Check programme in general and the challenges faced when implementing it in practice. DESIGN: A systematic review of surveys and interview studies with a descriptive analysis of quantitative data and thematic synthesis of qualitative data. DATA SOURCES: An electronic literature search of MEDLINE, Embase, Health Management Information Consortium, Cumulative Index of Nursing and Allied Health Literature, Global Health, PsycInfo, Web of Science, OpenGrey, the Cochrane Library, NHS Evidence, Google Scholar, Google, ClinicalTrials.gov and the International Standard Randomised Controlled Trial Number registry from 1 January 1996 to 9 November 2016 with no language restriction and manual screening of reference lists of all included papers. INCLUSION CRITERIA: Primary research reporting views of commissioners, managers or healthcare professionals on the NHS Health Check programme and its implementation in practice. RESULTS: Of 18 524 citations, 15 articles met the inclusion criteria. There was evidence from both quantitative and qualitative studies that some commissioners and general practice (GP) healthcare professionals were enthusiastic about the programme, whereas others raised concerns around inequality of uptake, the evidence base and cost effectiveness. In contrast, those working in pharmacies were all positive about programme benefits, citing opportunities for their business and staff. The main challenges to implementation were: difficulties with information technology and computer software, resistance to the programme from some GPs, the impact on workload and staffing, funding and training needs. Inadequate privacy was also a challenge in pharmacy and community settings, along with difficulty recruiting people eligible for Health Checks and poor public access to some venues. CONCLUSIONS: The success of the NHS Health Check Programme relies on engagement by those responsible for its commissioning, management and delivery. Recognising and addressing the challenges identified in this review, in particular the concerns of GPs, are important for the future of the programme. PMID- 29146660 TI - Changing physical activity behaviour for people with multiple sclerosis: protocol of a randomised controlled feasibility trial (iStep-MS). AB - INTRODUCTION: Although physical activity may reduce disease burden, fatigue and disability, and improve quality of life among people with multiple sclerosis (MS), many people with MS are physically inactive and spend significant time in sedentary behaviour. Behaviour change interventions may assist people with MS to increase physical activity and reduce sedentary behaviour. However, few studies have investigated their effectiveness using objective measures of physical activity, particularly in the long term. Further, interventions that have proven effective in the short term may not be feasible in clinical practice because of the large amount of support provided. The iStep-MS trial aims to determine the safety, feasibility and acceptability of a behaviour change intervention to increase physical activity and reduce sedentary behaviour among people with MS. METHODS AND ANALYSIS: Sixty people with MS will be randomised (1:1 ratio) to receive a 12-week intervention or usual care only. The intervention consists of four physical activity consultations with a physiotherapist supported by a handbook and pedometer. Outcomes assessed at baseline, 12 weeks and 9 months are physical activity (ActiGraph wGT3X-BT accelerometer), sedentary behaviour (activPAL3u), self-reported activity and sitting time, walking capability, fatigue, self-efficacy, participation, quality of life and health service use. The safety of the intervention will be determined by assessing change in pain and fatigue and the incidence of adverse events during the follow-up period. A parallel process evaluation will assess the feasibility and acceptability of the intervention through assessment of fidelity to the programme and semistructured interviews exploring participants' and therapists' experiences of the intervention. The feasibility of conducting an economic evaluation will be determined by collecting data on quality of life and resource use. ETHICS AND DISSEMINATION: Research ethics committee approval has been granted from Brunel University London. Results of the trial will be submitted for publication in journals and distributed to people with MS and physiotherapists. TRIAL REGISTRATION NUMBER: ISRCTN15343862 (doi 10.1186/ISRCTN15343862). Protocol version: 1.0; Pre-results. PMID- 29146661 TI - What is the relationship between physical activity and cardiovascular risk factors in stroke survivors post completion of rehabilitation? Protocol for a longitudinal study. AB - INTRODUCTION: Physical activity (PA) can modify cardiovascular and other health risks in people with stroke, but we know little about long-term PA in this group. This study aims to describe PA levels and investigate relationships between PA, cardiovascular risk factors, mobility and participant characteristics (eg, age, mood and fatigue) in the 2 years following rehabilitation discharge after first stroke. METHODS AND ANALYSIS: This is a longitudinal observational study with follow-up at 6, 12 and 24 months after rehabilitation discharge. Inclusion criteria are broad; excluding only those with previous stroke, palliative diagnosis, living more than 2 hours from the centre or admitted less than 5 days.The primary outcome of interest is duration of moderate to vigorous PA (min/day) measured by the Sensewear MF Armband (SWAB). Secondary outcomes include other PA measures measured with the SWAB; cardiovascular risk factors (eg, systolic blood pressure, fasting lipid profile and smoking status), mobility (10 m walk test), the Hospital Anxiety and Depression Scale and the Fatigue Severity Scale. All outcomes, except blood tests, are gathered at each time point.The target sample size is 77. We will explore associations between PA levels, cardiovascular risk factors, mobility and participant characteristics at baseline compared with 6, 12 and 24 months using random-effects regression modelling.The long-term PA of stroke survivors is largely unknown. We hope to identify factors that influence PA and cardiovascular risk in this population, which may help health professionals target the stroke survivors most at risk and implement appropriate treatment, preventative strategies and education. ETHICS AND DISSEMINATION: Approval was granted from Alfred Hospital and La Trobe University Research Ethics Committees. The study results will be disseminated in a number of ways including journal publication and international conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12613000196741. PMID- 29146662 TI - Comparative effectiveness of injectable penicillin versus a combination of penicillin and gentamicin in children with pneumonia characterised by indrawing in Kenya: a retrospective observational study. AB - OBJECTIVES: Kenyan guidelines for antibiotic treatment of pneumonia recommended treatment of pneumonia characterised by indrawing with injectable penicillin alone in inpatient settings until early 2016. At this point, they were revised becoming consistent with WHO guidance after results of a Kenyan trial provided further evidence of equivalence of oral amoxicillin and injectable penicillin. This change also made possible use of oral amoxicillin for outpatient treatment in this patient group. However, given non-trivial mortality in Kenyan children with indrawing pneumonia, it remained possible they would benefit from a broader spectrum antibiotic regimen. Therefore, we compared the effectiveness of injectable penicillin monotherapy with a regimen combining penicillin with gentamicin. SETTING: We used a large routine observational dataset that captures data on all admissions to 13 Kenyan county hospitals. PARTICIPANTS AND MEASURES: The analyses included children aged 2-59 months. Selection of study population was based on inclusion criteria typical of a prospective trial, primary analysis (experiment 1, n=4002), but we also explored more pragmatic inclusion criteria (experiment 2, n=6420) as part of a secondary analysis. To overcome the challenges associated with the non-random allocation of treatments and missing data, we used propensity score (PS) methods and multiple imputation to minimise bias. Further, we estimated mortality risk ratios using log binomial regression and conducted sensitivity analyses using an instrumental variable and PS trimming. RESULTS: The estimated risk of dying, in experiment 1, in those receiving penicillin plus gentamicin was 1.46 (0.85 to 2.43) compared with the penicillin monotherapy group. In experiment 2, the estimated risk was 1.04(0.76 to 1.40). CONCLUSION: There is no statistical difference in the treatment of indrawing pneumonia with either penicillin or penicillin plus gentamicin. By extension, it is unlikely that treatment with penicillin plus gentamicin would offer an advantage to treatment with oral amoxicillin. PMID- 29146663 TI - A Vision and Change Reform of Introductory Biology Shifts Faculty Perceptions and Use of Active Learning. AB - Increasing faculty use of active-learning (AL) pedagogies in college classrooms is a persistent challenge in biology education. A large research-intensive university implemented changes to its biology majors' two-course introductory sequence as outlined by the Vision and Change in Undergraduate Biology Education final report. One goal of the curricular reform was to integrate core biological concepts and competencies into the courses using AL pedagogical approaches. The purpose of this study was to observe the instructional practices used by faculty (N = 10) throughout the 3-year process of reform to determine whether the use of AL strategies (including student collaboration) increased, given that it can maximize student learning gains. Instructors participated in yearly interviews to track any change in their perceptions of AL instruction. Instructors increased their average use of AL by 12% (group AL by 8%) of total class time throughout the 3-year study. Interviews revealed that instructors shifted their definitions of AL and talked more about how to assess student learning over the 3 years of the project. Collaboration, feedback, and time may have been important factors in the reform, suggesting that small shifts over time can accumulate into real change in the classroom. PMID- 29146664 TI - The Effects of Practice-Based Training on Graduate Teaching Assistants' Classroom Practices. AB - Evidence-based teaching is a highly complex skill, requiring repeated cycles of deliberate practice and feedback to master. Despite existing well-characterized frameworks for practice-based training in K-12 teacher education, the major principles of these frameworks have not yet been transferred to instructor development in higher educational contexts, including training of graduate teaching assistants (GTAs). We sought to determine whether a practice-based training program could help GTAs learn and use evidence-based teaching methods in their classrooms. We implemented a weekly training program for introductory biology GTAs that included structured drills of techniques selected to enhance student practice, logic development, and accountability and reduce apprehension. These elements were selected based on their previous characterization as dimensions of active learning. GTAs received regular performance feedback based on classroom observations. To quantify use of target techniques and levels of student participation, we collected and coded 160 h of video footage. We investigated the relationship between frequency of GTA implementation of target techniques and student exam scores; however, we observed no significant relationship. Although GTAs adopted and used many of the target techniques with high frequency, techniques that enforced student participation were not stably adopted, and their use was unresponsive to formal feedback. We also found that techniques discussed in training, but not practiced, were not used at quantifiable frequencies, further supporting the importance of practice-based training for influencing instructional practices. PMID- 29146665 TI - The Relative Effect of Team-Based Learning on Motivation and Learning: A Self Determination Theory Perspective. AB - We investigate the effects of team-based learning (TBL) on motivation and learning in a quasi-experimental study. The study employs a self-determination theory perspective to investigate the motivational effects of implementing TBL in a physiotherapy course in higher education. We adopted a one-group pretest posttest design. The results show that the students' intrinsic motivation, identified regulation, perceived competence, and perceived autonomy support significantly increased going from lectures to TBL. The results further show that students' engagement and perceived learning significantly increased. Finally, students' amotivation decreased from pretest to posttest; however, students reported higher external regulation as a function of TBL. Path analysis shows that increases in intrinsic motivation, perceived competence, and external regulation positively predict increases in engagement, which in turn predict increases in perceived learning. We argue that the characteristics of TBL, as opposed to lectures, are likely to engage students and facilitate feelings of competence. TBL is an active-learning approach, as opposed to more passive learning in lectures, which might explain the increase in students' perception of teachers as autonomy supportive. In contrast, the greater demands TBL puts on students might account for the increase in external regulation. Limitations and practical implications of the results are discussed. PMID- 29146666 TI - Students in Fully Online Programs Report More Positive Attitudes toward Science Than Students in Traditional, In-Person Programs. AB - Following the growth of online, higher-education courses, academic institutions are now offering fully online degree programs. Yet it is not clear how students who enroll in fully online degree programs are similar to those students who enroll in in-person ("traditional") degree programs. Because previous work has shown students' attitudes toward science can affect their performance in a course, it is valuable to ask how attitudes toward science differ between these two populations. We studied students who completed a fully online astrobiology course. In an analysis of 451 student responses to the Classroom Undergraduate Research Experience survey, we found online program students began the course with a higher scientific sophistication and a higher sense of personal value of science than those in traditional programs. Precourse attitudes also showed some predictive power of course grades among online students, but not for traditional students. Given established relationships between feelings of personal value, intrinsic motivation, and, in turn, traits such as persistence, our results suggest that open-ended or exploration-based learning may be more engaging to online program students due to their pre-existing attitudes. The converse may also be true, that certain pre-existing attitudes among online program students are more detrimental than they are for traditional program students. PMID- 29146667 TI - Building Better Bridges into STEM: A Synthesis of 25 Years of Literature on STEM Summer Bridge Programs. AB - Summer bridge programs are designed to help transition students into the college learning environment. Increasingly, bridge programs are being developed in science, technology, engineering, and mathematics (STEM) disciplines because of the rigorous content and lower student persistence in college STEM compared with other disciplines. However, to our knowledge, a comprehensive review of STEM summer bridge programs does not exist. To provide a resource for bridge program developers, we conducted a systematic review of the literature on STEM summer bridge programs. We identified 46 published reports on 30 unique STEM bridge programs that have been published over the past 25 years. In this review, we report the goals of each bridge program and whether the program was successful in meeting these goals. We identify 14 distinct bridge program goals that can be organized into three categories: academic success goals, psychosocial goals, and department-level goals. Building on the findings of published bridge reports, we present a set of recommendations for STEM bridge programs in hopes of developing better bridges into college. PMID- 29146668 TI - Percutaneous Left Atrial Appendage Closure: Current Devices and Clinical Outcomes. AB - Chronic oral anticoagulation therapy is the standard therapy for preventing thromboembolic events in patients with atrial fibrillation. However, oral anticoagulation has been associated with an increased risk of bleeding events, and despite the improvements linked to the introduction of direct oral anticoagulants, more than one third of atrial fibrillation patients still remain untreated. Over the past decade, percutaneous left atrial appendage closure has emerged as a valid alternative to anticoagulation therapy for the prevention of stroke/systemic embolism in patients with atrial fibrillation. In this article, we provide an updated overview of current transcatheter left atrial appendage closure devices and review the results associated with left atrial appendage closure, focusing on procedural and late outcomes, and pointing to future directions. PMID- 29146669 TI - Relationships Between Baseline Q Waves, Time From Symptom Onset, and Clinical Outcomes in ST-Segment-Elevation Myocardial Infarction Patients: Insights From the Vital Heart Response Registry. AB - BACKGROUND: Using a comprehensive ST-segment-elevation myocardial infarction registry, we evaluated the relationships of baseline Q waves, time from symptom onset, and reperfusion strategy with in-hospital clinical outcomes. METHODS AND RESULTS: Consecutive ST-segment-elevation myocardial infarction patients from a defined health region were classified by the presence of baseline Q waves and additionally into primary percutaneous coronary intervention, fibrinolysis, or no reperfusion. ECGs were collected at baseline, after reperfusion, and analyzed for the presence of Q waves using Selvester criteria. Among 2290 ST-segment-elevation myocardial infarction patients, 36.9% had Q waves on their baseline ECG. Patients with Q waves were older (median age, 59 versus 57), were more often male (82.0% versus 75.4%), had higher heart rate (80 versus 72), had higher Global Registry of Acute Coronary Events risk score (129 versus 127), and were with longer time to reperfusion (42 minutes longer). They had higher composite end points (16.3% versus 10.0%), consistent across times from symptom onset to presentation (15.4% versus 9.9% <=3 hours; 18.5% versus 8.9% >3 to <=6 hours; 15.9% versus 11.3% >6 hours; Q and no Q, respectively). Baseline Q waves, but not time to reperfusion, were associated with an increased odds of the in-hospital composite end point of death, congestive heart failure, cardiogenic shock, and reinfarction (adjusted odds ratio, 1.65; 95% confidence interval, 1.18-2.30; P=0.003). Type of reperfusion did not modify the association of baseline Q waves and in-hospital outcomes (P interaction=0.918). CONCLUSIONS: The presence of baseline Q waves, rather than time to treatment, was significantly associated with adverse in hospital events in real-world patients, regardless of reperfusion strategy used. PMID- 29146670 TI - Three-Vessel Assessment of Coronary Microvascular Dysfunction in Patients With Clinical Suspicion of Ischemia: Prospective Observational Study With the Index of Microcirculatory Resistance. AB - BACKGROUND: Difficulty directly visualizing the coronary microvasculature as opposed to the epicardial coronary artery makes its assessment challenging. The goal of this study is to measure the index of microcirculatory resistance (IMR) in all 3 major coronary vessels to identify the clinical and angiographic predictors of an abnormal IMR. METHODS AND RESULTS: Ninety-three patients who underwent coronary physiological assessment in all 3 major coronary vessels were prospectively enrolled (59.8+/-9.4 years with 77.4% men). IMR was corrected using Yong's formula and coronary microvascular dysfunction (CMD) was defined using vessel-specific cutoffs. A global IMR was calculated as the sum of the IMR in all 3 major epicardial vessels. Angiographic epicardial disease severity was assessed with vessel-specific and overall SYNTAX score. Median IMR and fractional flow reserve was 17.2 (Q1-Q3: 13.3-22.9) and 0.92 (0.85-0.97). The majority of patients (59.1%) had no CMD, 23.7% had 1-vessel CMD, 14.0% had 2-vessel CMD, and 3.2% had 3-vessel CMD. CMD was observed at a similar rate in the territories supplied by all 3 major coronary vessels (left anterior descending coronary artery 28.0%, left circumflex artery 19.4%, and right coronary artery 23.7%; P=0.39). Fractional flow reserve had a weak, positive correlation with IMR (rho=0.16; P<0.01). The SYNTAX score had no significant correlation with IMR, both at a patient level (rho=-0.002; P=0.99) and a vessel-specific level (rho= 0.06; P=0.36). By multivariable ordinal logistic regression analysis, no variable was left as an independent predictor of an abnormal IMR. CONCLUSIONS: Clinical factors and epicardial coronary disease severity are not predictors of the extent of CMD. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01621438. PMID- 29146671 TI - Predictors and Long-Term Clinical Outcome of Longitudinal Stent Deformation: Insights From Pooled Analysis of Korean Multicenter Drug-Eluting Stent Cohort. AB - BACKGROUND: There are limited data on the frequency of and factors associated with quantitative coronary angiography (QCA)-defined longitudinal stent deformation (LSD) in various contemporary drug-eluting stents platforms. This study sought to evaluate the predictors of LSD and its long-term clinical implication. METHODS AND RESULTS: A patient-level pooled analysis was performed with 7350 lesions in 5871 patients treated with platinum-chromium-based everolimus-eluting stent (Promus Element), cobalt-chromium-based everolimus eluting stent (Promus/Xience V), or cobalt-chromium-based zotarolimus-eluting stent (Endeavor Resolute). QCA was performed to analyze differences of stent length between immediate post-deployment and final post-procedure. Independent factors associated with LSD were identified. Clinical outcomes at 3 years were compared between those with and without QCA-based LSD. The frequency of QCA-based LSD was 1.12% (82 cases). Nine of these cases were angiographically overt. Left main or ostial lesion, bifurcation treatment with provisional side branch stenting or ballooning, additional downstream intervention of a distal lesion, intravascular ultrasound use, and adjunctive post-dilatation were independently associated with QCA-based LSD. The type of stent was not associated with QCA based LSD. Rates of target lesion failure were nominally higher in lesions with QCA-based LSD than in those without (8.97% versus 5.88%; hazard ratio, 1.415; 95% confidence interval, 0.631-3.175; P=0.399). CONCLUSIONS: LSD is uncommon with contemporary drug-eluting stents, regardless of the type of stent platform. LSD is mainly associated with procedural factors, especially with additional downstream procedures which require the passage of devices through the stent. Careful manipulation of poststent imaging or procedural devices is required to prevent LSD. More data are needed to clarify the impact of LSD on clinical events. PMID- 29146673 TI - What Can We Do About Cardiogenic Shock? PMID- 29146672 TI - Culprit Vessel-Only Versus Multivessel Percutaneous Coronary Intervention in Patients With Cardiogenic Shock Complicating ST-Segment-Elevation Myocardial Infarction: A Collaborative Meta-Analysis. AB - BACKGROUND: The optimal revascularization strategy in patients with multivessel disease presenting with cardiogenic shock complicating ST-segment-elevation myocardial infarction remains unknown. METHODS AND RESULTS: Databases were searched from 1999 to October 2016. Studies comparing immediate/single-stage multivessel percutaneous coronary intervention (MV-PCI) versus culprit vessel only PCI (CO-PCI) in patients with multivessel disease, ST-segment-elevation myocardial infarction, and cardiogenic shock were included. Primary end point was short-term (in-hospital or 30 days) mortality. Secondary end points included long term mortality, cardiovascular death, reinfarction, and repeat revascularization. Safety end points were in-hospital stroke, renal failure, and major bleeding. The meta-analysis included 11 nonrandomized studies and 5850 patients (1157 MV-PCI and 4693 CO-PCI). There was no significant difference in short-term mortality with MV-PCI versus CO-PCI (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.81-1.43; P=0.61). Similarly, there were no significant differences in long-term mortality (OR, 0.84; 95% CI, 0.54-1.30; P=0.43), cardiovascular death (OR, 0.72; 95% CI, 0.42-1.23; P=0.23), reinfarction (OR, 1.65; 95% CI, 0.84-3.26; P=0.15), or repeat revascularization (OR, 1.13; 95% CI, 0.76-1.69; P=0.54) between the 2 groups. There was a nonsignificant trend toward higher in-hospital stroke (OR, 1.64; 95% CI, 0.98-2.72; P=0.06) and renal failure (OR, 1.30; 95% CI, 0.98-1.72; P=0.06), with no difference in major bleeding (OR, 1.47; 95% CI, 0.39-5.63; P=0.57) with MV-PCI when compared with CO-PCI. CONCLUSIONS: This meta-analysis of nonrandomized studies suggests that in patients with cardiogenic shock complicating ST-segment-elevation myocardial infarction, there may be no significant benefit with single-stage MV-PCI compared with CO-PCI. Given the limitations of observational data, randomized trials are needed to determine the role of MV-PCI in this setting. PMID- 29146674 TI - Needles in Our Technology Haystacks: Defining Efficacy Is Easy, Characterizing Complications Is the Challenge. PMID- 29146675 TI - Q Waves at Presentation in Patients With ST-Segment-Elevation Myocardial Infarction: An Underappreciated Marker of Risk. PMID- 29146676 TI - Epithelial immunity: priming defensive responses in the intestinal mucosa. AB - As the largest interface between the outside and internal milieu, the intestinal epithelium constitutes the first structural component facing potential luminal threats to homeostasis. This single-cell layer is the epicenter of a tightly regulated communication network between external and internal factors that converge to prime defensive responses aimed at limiting antigen penetration and the maintenance of intestinal barrier function. The defensive role developed by intestinal epithelial cells (IEC) relies largely on the variety of receptors they express at both extracellular (apical and basolateral) and intracellular compartments, and the capacity of IEC to communicate with immune and nervous systems. IEC recognize pathogen-associated molecules by innate receptors that promote the production of mucus, antimicrobial substances, and immune mediators. Epithelial cells are key to oral tolerance maintenance and also participate in adaptive immunity through the expression of immunoglobulin (Ig) receptors and by promoting local Ig class switch recombination. In IEC, different types of antigens can be sensed by multiple immune receptors that share signaling pathways to assure effective responses. Regulated defensive activity maintains intestinal homeostasis, whereas a breakdown in the control of epithelial immunity can increase the intestinal passage of luminal content and microbial invasion, leading to inflammation and tissue damage. In this review, we provide an updated overview of the type of immune receptors present in the human intestinal epithelium and the responses generated to promote effective barrier function and maintain mucosal homeostasis. PMID- 29146678 TI - Cross-organ sensitization between the colon and bladder: to pee or not to pee? AB - Chronic abdominal and pelvic pain are common debilitating clinical conditions experienced by millions of patients around the globe. The origin of such pain commonly arises from the intestine and bladder, which share common primary roles (the collection, storage, and expulsion of waste). These visceral organs are located in close proximity to one another and also share common innervation from spinal afferent pathways. Chronic abdominal pain, constipation, or diarrhea are primary symptoms for patients with irritable bowel syndrome or inflammatory bowel disease. Chronic pelvic pain and urinary urgency and frequency are primary symptoms experienced by patients with lower urinary tract disorders such as interstitial cystitis/painful bladder syndrome. It is becoming clear that these symptoms and clinical entities do not occur in isolation, with considerable overlap in symptom profiles across patient cohorts. Here we review recent clinical and experimental evidence documenting the existence of "cross-organ sensitization" between the colon and bladder. In such circumstances, colonic inflammation may result in profound changes to the sensory pathways innervating the bladder, resulting in severe bladder dysfunction. PMID- 29146677 TI - Functional role and therapeutic targeting of microRNAs in inflammatory bowel disease. AB - Inflammatory bowel diseases (IBD) are chronic inflammatory gastrointestinal diseases, primarily consisting of ulcerative colitis and Crohn's disease. The complex nature of the disease, as well as the limited therapeutic options characterized by low efficiency and major side effects, highlights the importance of developing novel strategies of therapeutic intervention in IBD. Susceptibility loci related to IBD are present only in a small percentage of IBD patients, implying that epigenetic modifications could influence the pathogenesis of the disease. MicroRNAs (miRNAs) are small noncoding RNAs that regulate multiple molecular pathways involved in IBD pathobiology. MiRNA inhibitors targeting the IBD-activated miRNAs could have therapeutic value for IBD patients. This review provides an overview of the recent advances in miRNA biology related to IBD pathogenesis and the pharmacological development of miRNA-based therapeutics. PMID- 29146679 TI - Undernutrition and severe acute malnutrition in children. PMID- 29146680 TI - The association between patient experience factors and likelihood of 30-day readmission: a prospective cohort study. AB - OBJECTIVE: Hospital care comprises nearly a third of US healthcare expenditures. Fifteen to 20 per cent of this spending is considered to be potentially preventable. Risk prediction models have suboptimal accuracy and typically exclude patient experience data. No studies have explored patient perceptions of the likelihood of readmission during index admission. Our objective was to examine associations between patient perceptions of care during index hospital admission and 30-day readmission. DESIGN: Prospective cohort study. SETTING: Two inpatient adult medicine units at Massachusetts General Hospital, Boston, Massachusetts. PARTICIPANTS: Eight hundred and forty-six patients admitted to study units between January 2012 and January 2016 who met eligibility criteria and consented to enrolment. MAIN OUTCOME: Odds of 30-day readmission. RESULTS: Of 1754 eligible participants, 846 (48%) were enrolled and 201 (23.8%) were readmitted within 30 days. Readmitted participants were less likely to have a high school diploma/GED (44.3% not readmitted vs 53.5% readmitted, P=0.02). In multivariable models adjusting for baseline differences, respondents who reported being 'very satisfied' with the care received during the index hospitalisation were less likely to be readmitted (adjusted OR 0.61, 95% CI 0.43 to 0.88, P=0.007). Participants reporting doctors 'always listened to them carefully' were less likely to be readmitted (adjusted OR 0.68, 95% CI 0.48 to 0.97, P=0.03). Participants reporting they were 'very likely' to be readmitted were not more likely to be readmitted (adjusted OR 1.35, 95% CI 0.83 to 2.19, P=0.22). CONCLUSION: Participants reporting high satisfaction and good provider communication were less likely to be readmitted. Rates of readmission were increased among participants stating they were very likely to be readmitted though this association was not statistically significant. Incorporating patient reported measures during index hospitalisations may improve readmission prediction. PMID- 29146681 TI - A qualitative study of patient involvement in medicines management after hospital discharge: an under-recognised source of systems resilience. AB - INTRODUCTION: There are risks to the safety of medicines management when patient care is transferred between healthcare organisations, for example, when a patient is discharged from hospital. Using the theoretical concept of resilience in healthcare, this study aimed to better understand the proactive role that patients can play in creating safer, resilient medicines management at a common transition of care. METHODS: Qualitative interviews with 60 cardiology patients 6 weeks after their discharge from 2 UK hospitals explored patients' experiences with their discharge medicines. Data were initially subjected to an inductive thematic analysis and a subsequent theory-guided deductive analysis. RESULTS: During interviews 23 patients described medicines management resilience strategies in two main themes: identifying system vulnerabilities; and establishing self-management strategies. Patients could anticipate problems in the system that supplied them with medicines and took specific actions to prevent them. They also identified when errors had occurred both before and after medicines had been supplied and took corrective action to avoid harm. Some reported how they had not foreseen problems or experienced patient safety incidents. Patients recounted how they ensured information about medicines changes was correctly communicated and acted upon, and described their strategies to enhance their own reliability in adherence and resource management. CONCLUSION: Patients experience the impact of vulnerabilities in the medicines management system across the secondary-primary care transition but many are able to enhance system resilience through developing strategies to reduce the risk of medicines errors occurring. Consequently, there are opportunities-with caveats-to elicit, develop and formalise patients' capabilities which would contribute to safer patient care and more effective medicines management. PMID- 29146682 TI - Magnitude of Soluble ST2 as a Novel Biomarker for Acute Aortic Dissection. AB - BACKGROUND: Misdiagnosis of acute aortic dissection (AAD) can lead to significant morbidity and death. Soluble ST2 (sST2) is a cardiovascular injury-related biomarker. The extent to which sST2 is elevated in AAD and whether sST2 can discriminate AAD from other causes of sudden-onset severe chest pain are unknown. METHODS: We measured plasma concentrations of sST2 (R&D Systems assay) in 1360 patients, including 1027 participants in the retrospective discovery set and 333 patients with initial suspicion of AAD enrolled in the prospective validation cohort. Measures of discrimination for differentiating AAD from other causes of chest pain were calculated. RESULTS: In the acute phase, sST2 levels were higher in patients with AAD than those with either acute myocardial infarction in the first case-control discovery set within 24 hours of symptom onset or with patients with pulmonary embolism in the second discovery set (medians of 129.2 ng/mL versus 14.7 with P<0.001 for AAD versus acute myocardial infarction and 88.6 versus 9.3 with P<0.001 for AAD versus pulmonary embolism). In the prospective validation set, sST2 was most elevated in patients with AAD (median [25th, 75th percentile]: 76.4 [49.6, 130.3]) and modestly elevated in acute myocardial infarction (25.0 [15.5, 37.2]), pulmonary embolism (14.9 [10.2, 30.1]), and angina patients (21.5 [13.1, 27.6], all P<0.001 versus AAD). The area under receiver operating characteristic curve for patients with AAD versus all control patients within 24 hours of presenting at the emergency department was 0.97 (0.95, 0.98) for sST2, 0.91 (0.88, 0.94) for D-dimer, and 0.50 (0.44, 0.56) for cardiac troponin I, respectively. At a cutoff level of 34.6 ng/mL, sST2 had a sensitivity of 99.1%, specificity of 84.9%, positive predictive value of 68.7%, negative predictive value of 99.7%, positive likelihood ratio of 6.6, and negative likelihood ratio of 0.01. CONCLUSIONS: Among patients with suspected aortic dissection in the emergency department, sST2 showed superior overall diagnostic performance to D-dimer or cardiac troponin I. Additional study is needed to determine whether sST2 might be a useful rule-out marker for AAD in the emergency room. PMID- 29146684 TI - Correction to "8-Aminoguanosine and 8-Aminoguanine Exert Diuretic, Natriuretic, Glucosuric, and Antihypertensive Activity". PMID- 29146683 TI - PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS). AB - BACKGROUND: Despite concerns about adverse neurocognitive events raised by prior trials, pharmacological PCSK9 (proprotein convertase subtilisin/kexin type-9) inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in lifelong exposure to lower levels of low-density lipoprotein cholesterol can provide information on the potential long-term effects of lower low-density lipoprotein cholesterol on neurocognitive impairment and decline. METHODS: We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among black REGARDS study (Reasons for Geographic and Racial Differences in Stroke) participants with (n=241) and without (n=10 454) C697X or Y142X LOF variants. Neurocognitive tests included the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery (Word List Learning, World List Delayed Recall, Semantic Animal Fluency) and Six-Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score >=1.5 SD below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments or, separately, a score <5 on any SIS assessment at baseline or during follow-up. Neurocognitive decline was assessed using standardized continuous scores on individual neurocognitive tests. RESULTS: The mean sample age was 64 years (SD, 9), 62% were women, and the prevalence of neurocognitive impairment at any assessment was 6.3% by CERAD and 15.4% by SIS definitions. Adjusted odds ratios for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% confidence interval [CI], 0.58-2.13) using the CERAD battery and 0.89 (95% CI, 0.61-1.30) using the SIS assessment. Standardized average differences in individual neurocognitive assessment scores over the 5.6-year (range, 0.1-9.1) study period ranged between 0.07 (95% CI, -0.06 to 0.20) and -0.07 (95% CI, -0.18 to 0.05) among participants with versus without PCSK9 LOF variants. Patterns of neurocognitive decline were similar between participants with and without PCSK9 LOF variants (all P>0.10). Odds ratios for neurocognitive impairment per 20 mg/dL low-density lipoprotein cholesterol decrements were 1.02 (95% CI, 0.96-1.08) and 0.99 (95% CI, 0.95-1.02) for the CERAD and SIS definitions of impairment, respectively. CONCLUSIONS: These results suggest that lifelong exposure to low PCSK9 levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks. PMID- 29146685 TI - Looking beyond macroventilatory parameters and rethinking ventilator-induced lung injury. PMID- 29146686 TI - Specific force of the vastus lateralis in adults with achondroplasia. AB - Achondroplasia is a clinical condition defined by shorter stature and disproportionate limb length. Force production in able-bodied individuals (controls) is proportional to muscle size, but given the disproportionate nature of achondroplasia, normalizing to anatomical cross-sectional area (ACSA) is inappropriate. The aim of this study was to assess specific force of the vastus lateralis (VL) in 10 adults with achondroplasia (22 +/- 3 yr) and 18 sex-matched controls (22 +/- 2 yr). Isometric torque (iMVCtau) of the dominant knee extensors (KE) and in vivo measures of VL muscle architecture, volume, activation, and patella tendon moment arm were used to calculate VL physiological CSA (PCSA), fascicle force, and specific force in both groups. Achondroplasic muscle volume was 53% smaller than controls (284 +/- 36 vs. 604 +/- 102 cm3, P < 0.001). KE iMVCtau was 63% lower in achondroplasia compared with controls (95 +/- 24 vs. 256 +/- 47 N?m, P < 0.001). Activation and moment arm length were similar between groups ( P > 0.05), but coactivation of bicep femoris of achondroplasic subjects was 70% more than controls (43 +/- 20 vs. 13 +/- 5%, P < 0.001). Achondroplasic subjects had 58% less PCSA (43 +/- 10 vs. 74.7 +/- 14 cm2, P < 0.001), 29% lower fascicle force (702 +/- 235 vs. 1704 +/- 303 N, P < 0.001), and 29% lower specific force than control subjects (17 +/- 6 vs. 24 +/- 6 N?cm-2, P = 0.012). The smaller VL specific force in achondroplasia may be attributed to infiltration of fat and connective tissue, rather than to any difference in myofilament function. NEW & NOTEWORTHY The novel observation of this study was the measurement of normalized force production in a group of individuals with disproportionate limb length-to-torso ratios. PMID- 29146687 TI - Exercise induces muscle fiber type switching via transient receptor potential melastatin 2-dependent Ca2+ signaling. AB - The aim of the present study was to examine whether transient receptor potential melastatin 2 (TRPM2) plays a role in muscle fiber-type transition during exercise. Mice were trained at a speed of 12 m/min at a slope of 0 degrees for 60 min for 5 consecutive days/wk for 4 wk. Exhaustion tests were performed on the treadmill (the speed was set at 6 m/min at a slope of 0 degrees and increased at a rate of 1 m/min every 6 min). Isolated primary skeletal muscle cells from TRPM2 knockout (KO) mice showed lower amplitudes of electrical stimuli (ES)-induced Ca2+ signals when compared with wild-type (WT) mice due to a defect in Ca2+ influx. Moreover, TRPM2-KO mice had a higher proportion of fast-twitch skeletal muscle fibers and a lower proportion of slow-twitch muscle fibers before exercise than WT mice. After exercise, the expression of slow-twitch skeletal muscle fibers was increased only in WT mice but not in TRPM2-KO mice. ES-induced nuclear translocation of the Ca2+-dependent transcription factor NFATc1 was significantly lower in TRPM2-KO mice than in WT mice. TRPM2-KO mice also showed decreased mitochondrial Ca2+ and membrane potential. Lactate levels were higher in the skeletal muscle cells of TRPM2-KO mice before and after ES compared with WT mice. Collectively, these data indicate that TRPM2-mediated Ca2+ signaling plays a critical role in the regulation of fiber-type switching and mitochondrial function in skeletal muscle. NEW & NOTEWORTHY TRPM2 has been shown to play an important role in a variety of cellular functions. However, the role of TRPM2 in skeletal muscle remains poorly understood. Here, we provide evidence that TRPM2 mediated Ca2+ signaling is required for training-induced improvement in skeletal muscle mitochondrial function and fiber type transition. PMID- 29146689 TI - Corrigendum: Cold-inducible RNA binding protein (CIRP) expression is modulated by alternative mRNAs. PMID- 29146688 TI - Cycling efficiency and energy cost of walking in young and older adults. AB - To determine whether age affects cycling efficiency and the energy cost of walking (Cw), 190 healthy adults, ages 18-81 yr, cycled on an ergometer at 50 W and walked on a treadmill at 1.34 m/s. Ventilation and gas exchange at rest and during exercise were used to calculate net Cw and net efficiency of cycling. Compared with the 18-40 yr age group (2.17 +/- 0.33 J.kg-1.m-1), net Cw was not different in the 60-64 yr (2.20 +/- 0.40 J.kg-1.m-1) and 65-69 yr (2.20 +/- 0.28 J.kg-1.m-1) age groups, but was significantly ( P < 0.03) higher in the >=70 yr (2.37 +/- 0.33 J.kg-1.m-1) age group. For subjects >60 yr, net Cw was significantly correlated with age ( R2 = 0.123; P = 0.002). Cycling net efficiency was not different between 18-40 yr (23.5 +/- 2.9%), 60-64 yr (24.5 +/- 3.6%), 65-69 yr (23.3 +/- 3.6%) and >=70 yr (24.7 +/- 2.7%) age groups. Repeat tests on a subset of subjects (walking, n = 43; cycling, n = 37) demonstrated high test-retest reliability [intraclass correlation coefficients (ICC), 0.74 0.86] for all energy outcome measures except cycling net energy expenditure (ICC = 0.54) and net efficiency (ICC = 0.50). Coefficients of variation for all variables ranged from 3.1 to 7.7%. Considerable individual variation in Cw and efficiency was evident, with a ~2-fold difference between the least and most economical/efficient subjects. We conclude that, between 18 and 81 yr, net Cw was only higher for ages >=70 yr, and that cycling net efficiency was not different across age groups. NEW & NOTEWORTHY This study illustrates that the higher energy cost of walking in older adults is only evident for ages >=70 yr. For older adults ages 60-69 yr, the energy cost of walking is similar to that of young adults. Cycling efficiency, by contrast, is not different across age groups. Considerable individual variation (~2-fold) in cycling efficiency and energy cost of walking is observed in young and older adults. PMID- 29146692 TI - Prediction of 90Y Radioembolization Outcome from Pretherapeutic Factors with Random Survival Forests. AB - Our objective was to predict the outcome of 90Y radioembolization in patients with intrahepatic tumors from pretherapeutic baseline parameters and to identify predictive variables using a machine-learning approach based on random survival forests. Methods: In this retrospective study, 366 patients with primary (n = 92) or secondary (n = 274) liver tumors who had received 90Y radioembolization were analyzed. A random survival forest was trained to predict individual risk from baseline values of cholinesterase, bilirubin, type of primary tumor, age at radioembolization, hepatic tumor burden, presence of extrahepatic disease, and sex. The predictive importance of each baseline parameter was determined using the minimal-depth concept, and the partial dependency of predicted risk on the continuous variables bilirubin level and cholinesterase level was determined. Results: Median overall survival was 11.4 mo (95% confidence interval, 9.7-14.2 mo), with 228 deaths occurring during the observation period. The random-survival forest analysis identified baseline cholinesterase and bilirubin as the most important variables (forest-averaged lowest minimal depth, 1.2 and 1.5, respectively), followed by the type of primary tumor (1.7), age (2.4), tumor burden (2.8), and presence of extrahepatic disease (3.5). Sex had the highest forest-averaged minimal depth (5.5), indicating little predictive value. Baseline bilirubin levels above 1.5 mg/dL were associated with a steep increase in predicted mortality. Similarly, cholinesterase levels below 7.5 U predicted a strong increase in mortality. The trained random survival forest achieved a concordance index of 0.657, with an SE of 0.02, comparable to the concordance index of 0.652 and SE of 0.02 for a previously published Cox proportional hazards model. Conclusion: Random survival forests are a simple and straightforward machine-learning approach for prediction of overall survival. The predictive performance of the trained model was similar to a previously published Cox regression model. The model has revealed a strong predictive value for baseline cholinesterase and bilirubin levels with a highly nonlinear influence for each parameter. PMID- 29146693 TI - Reply: Advantages and Limits of Targeted Radionuclide Therapy with Somatostatin Antagonists. PMID- 29146694 TI - Spatiotemporal Distribution of beta-Amyloid in Alzheimer Disease Is the Result of Heterogeneous Regional Carrying Capacities. AB - beta-amyloid (Abeta) accumulation in the brain is 1 of 2 pathologic hallmarks of Alzheimer disease (AD), and the spatial distribution of Abeta has been studied extensively ex vivo. Methods: We applied mathematical modeling to Abeta in vivo PET imaging data to investigate competing theories of Abeta spread in AD. Results: Our results provided evidence that Abeta accumulation starts in all brain regions simultaneously and that its spatiotemporal distribution is due to heterogeneous regional carrying capacities (regional maximum possible concentration of Abeta) for the aggregated protein rather than to longer-term spreading from seed regions. Conclusion: The in vivo spatiotemporal distribution of Abeta in AD can be mathematically modeled using a logistic growth model in which the Abeta carrying capacity is heterogeneous across the brain but the exponential growth rate and time of half maximal Abeta concentration are constant. PMID- 29146696 TI - Optimizing Strategies for Immune Checkpoint Imaging with Immuno-PET in Preclinical Study. PMID- 29146695 TI - First-in-Human Human Epidermal Growth Factor Receptor 2-Targeted Imaging Using 89Zr-Pertuzumab PET/CT: Dosimetry and Clinical Application in Patients with Breast Cancer. AB - In what we believe to be a first-in-human study, we evaluated the safety and dosimetry of 89Zr-pertuzumab PET/CT for human epidermal growth factor receptor 2 (HER2)-targeted imaging in patients with HER2-positive breast cancer. Methods: Patients with HER2-positive breast cancer and evidence of distant metastases were enrolled in an institutional review board-approved prospective clinical trial. Pertuzumab was conjugated with deferoxamine and radiolabeled with 89Zr. Patients underwent PET/CT with 74 MBq of 89Zr-pertuzumab in a total antibody mass of 20-50 mg of pertuzumab. PET/CT, whole-body probe counts, and blood drawing were performed over 8 d to assess pharmacokinetics, biodistribution, and dosimetry. PET/CT images were evaluated for the ability to visualize HER2-positive metastases. Results: Six patients with HER2-positive metastatic breast cancer were enrolled and administered 89Zr-pertuzumab. No toxicities occurred. Dosimetry estimates from OLINDA demonstrated that the organs receiving the highest doses (mean +/- SD) were the liver (1.75 +/- 0.21 mGy/MBq), the kidneys (1.27 +/- 0.28 mGy/MBq), and the heart wall (1.22 +/- 0.16 mGy/MBq), with an average effective dose of 0.54 +/- 0.07 mSv/MBq. PET/CT demonstrated optimal imaging 5-8 d after administration. 89Zr-pertuzumab was able to image multiple sites of malignancy and suggested that they were HER2-positive. In 2 patients with both known HER2 positive and HER2-negative primary breast cancers and brain metastases, 89Zr pertuzumab PET/CT suggested that the brain metastases were HER2-positive. In 1 of the 2 patients, subsequent resection of a brain metastasis proved HER2-positive disease, confirming that the 89Zr-pertuzumab avidity was a true-positive result for HER2-positive malignancy. Conclusion: This first-in-human study demonstrated safety, dosimetry, biodistribution, and successful HER2-targeted imaging with 89Zr-pertuzumab PET/CT. Potential clinical applications include assessment of the HER2 status of lesions that may not be accessible to biopsy and assessment of HER2 heterogeneity. PMID- 29146697 TI - Challenging Nuclear Cardiology Research: Stimulating Discovery, Validation, and Clinical Relevance. PMID- 29146698 TI - Characterization of Site-Specifically Conjugated Monomethyl Auristatin E- and Duocarmycin-Based Anti-PSMA Antibody-Drug Conjugates for Treatment of PSMA Expressing Tumors. AB - Prostate cancer (PCa) is the most common cancer in men worldwide. In general, PCa responds poorly to chemotherapy. Therefore, antibody-drug conjugates (ADCs) have been developed to specifically deliver highly cytotoxic drugs to the tumor. Because the prostate-specific membrane antigen (PSMA) is overexpressed in PCa, it represents a promising target for ADC-based therapies. The aim of this study was to evaluate the therapeutic efficacy of site-specifically conjugated duocarmycin- and monomethyl auristatin E (MMAE)-based anti-PSMA ADCs with drug-to-antibody ratios (DARs) of 2 and 4. Methods: The glycan group of the anti-PSMA antibody D2B was chemoenzymatically conjugated with duocarmycin or MMAE. Preservation of the immunoreactivity of the antibody on site-specific conjugation was investigated in vitro. Biodistribution and small-animal SPECT/CT imaging (18.5 +/- 2.6 MBq) with 25 MUg of 111In-labeled ADCs were performed on BALB/c nude mice with subcutaneous PSMA-positive LS174T-PSMA xenografts. Finally, the therapeutic efficacy of the 4 different ADCs was assessed in mice with LS174T-PSMA tumors. Results: The immunoreactivity of the anti-PSMA antibody was preserved on site-specific conjugation. Biodistribution revealed high tumor uptake of all agents. The highest tumor uptake was observed in mice administered with 111In-D2B-DAR2-MMAE, reaching 119.7 +/- 37.4 percentage injected dose per gram at 3 d after injection. Tumors of mice injected with 111In-D2B, 111In-D2B-DAR2-duocarmycin, 111In-D2B DAR4-duocarmycin, 111In-D2B-DAR2-MMAE, and 111In-D2B-DAR4-MMAE could clearly be visualized with small-animal SPECT/CT. In contrast to unconjugated D2B or vehicle, treatment with either of the MMAE-based ADCs, but not with a duocarmycin based ADC, significantly impaired tumor growth and prolonged median survival from 13 d (phosphate-buffered saline) to 20 and 29 d for DAR2 and DAR4 ADC, respectively. Tumor-doubling time increased from 3.5 +/- 0.5 d to 5.2 +/- 1.8 and 9.2 +/- 2.1 d after treatment with D2B-DAR2-MMAE and D2B-DAR4-MMAE, respectively. Conclusion: The site-specifically conjugated anti-PSMA ADCs D2B-DAR2-MMAE and D2B DAR4-MMAE efficiently targeted PSMA-expressing xenografts, effectively inhibited tumor growth of PSMA-expressing tumors, and significantly prolonged survival of mice. PMID- 29146699 TI - Association between Urine Ammonium and Urine TGF-beta1 in CKD. AB - BACKGROUND AND OBJECTIVES: Urinary ammonium excretion increases in response to nonvolatile acids to maintain normal systemic bicarbonate and pH. However, enhanced ammonia production promotes tubulointerstitial fibrosis in animal models. Therefore, a subset of individuals with CKD and normal bicarbonate may have acid-mediated kidney fibrosis that might be better linked with ammonium excretion than bicarbonate. We hypothesized that urine TGF-beta1, as an indicator of kidney fibrosis, would be more tightly linked with urine ammonium excretion than serum bicarbonate and other acid-base indicators. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We measured serum bicarbonate and urinary ammonium, titratable acids, pH, and TGF-beta1/creatinine in 144 persons with CKD. Multivariable-adjusted linear regression models determined the cross-sectional association between TGF-beta1/creatinine and serum bicarbonate, urine ammonium excretion, urine titratable acids excretion, and urine pH. RESULTS: Mean eGFR was 42 ml/min per 1.73 m2, mean age was 65 years old, 78% were men, and 62% had diabetes. Mean urinary TGF-beta1/creatinine was 102 (49) ng/g, mean ammonium excretion was 1.27 (0.72) mEq/h, mean titratable acids excretion was 1.14 (0.65) mEq/h, mean urine pH was 5.6 (0.5), and mean serum bicarbonate was 23 (3) mEq/L. After adjusting for eGFR, proteinuria, and other potential confounders, each SD increase of urine ammonium and urine pH was associated with a statistically significant 1.22-fold (95% confidence interval, 1.11 to 1.35) or 1.11-fold (95% confidence interval, 1.02 to 1.21) higher geometric mean urine TGF beta1/creatinine, respectively. Each SD increase of serum bicarbonate and urine titratable acids was associated with a nonsignificant 1.06-fold (95% confidence interval, 0.97 to 1.16) or 1.03-fold (95% confidence interval, 0.92 to 1.14) higher geometric mean urine TGF-beta1/creatinine, respectively. CONCLUSIONS: Urinary ammonium excretion but not serum bicarbonate is associated with higher urine TGF-beta1/creatinine. PMID- 29146701 TI - Mesangial C4d Deposits in Early IgA Nephropathy. AB - BACKGROUND AND OBJECTIVES: The prognostic value of mesangial C4d deposits in IgA nephropathy has been analyzed in patients with reduced GFR but has not been analyzed in those with normal kidney function. The main objective of the study was to analyze the prognostic value of C4d deposits and association with response to treatment in patients with IgA nephropathy and normal GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study included 190 patients with idiopathic IgA nephropathy diagnosed by kidney biopsy between 1988 and 2005. The patients had GFR>=80 ml/min per 1.73 m2 at the time of diagnosis, and they had a paraffin-embedded kidney biopsy with eight glomeruli available. RESULTS: In total, 170 (89%) and 20 (11%) patients were >18 and <18 years old, respectively; median (interquartile range) follow-up was 15 (12-22) years. Mesangial C4d deposit prevalence was 20% (38 of 190). At diagnosis, C4d-positive versus -negative patients had higher protein-to-creatinine ratio (median [interquartile range]: 1.94 g/g [0.9-3.1] versus 1.45 g/g [0.9-2.2]; P=0.04). During follow-up, C4d-positive patients showed a higher number of nephritic flares (median [range]: 1.4 [0-5] versus 0.9 [0-2]; P=0.04), had a higher protein to-creatinine ratio (median [interquartile range]: 1.32 g/g [0.7-1.7] versus 0.89 g/g [0.1-1.3]; P<0.01), were more prone to receive repeated treatment with corticosteroids (45% versus 24%; P<0.01), and showed a larger reduction in eGFR ( 1.6 versus -0.8 ml/min per 1.73 m2 per year; P=0.04). Furthermore, the presence of mesangial C4d deposits was an independent predictor of long-term kidney survival. CONCLUSIONS: C4d deposits may be one of the earliest poor prognostic variables available for patients with idiopathic IgA nephropathy and normal kidney function at the time of diagnosis. However, Cd4 deposits alone are not associated with the response to angiotensin blockers or corticosteroid treatment. PMID- 29146700 TI - Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies. AB - BACKGROUND AND OBJECTIVES: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5+/-6.1 years. RESULTS: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4+/-2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. CONCLUSIONS: Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes. PMID- 29146703 TI - A Perspective on Inherited Kidney Disease: Lessons for Practicing Nephrologists. PMID- 29146702 TI - Prevalence of Novel MAGED2 Mutations in Antenatal Bartter Syndrome. AB - BACKGROUND AND OBJECTIVES: Mutations in the MAGED2 gene, located on the X chromosome, have been recently detected in males with a transient form of antenatal Bartter syndrome or with idiopathic polyhydramnios. The aim of this study is to analyze the proportion of the population with mutations in this gene in a French cohort of patients with antenatal Bartter syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The French cohort of patients with antenatal Bartter syndrome encompasses 171 families. Mutations in genes responsible for types 1-4 have been detected in 75% of cases. In patients without identified genetic cause (n=42), transient antenatal Bartter syndrome was reported in 12 cases. We analyzed the MAGED2 gene in the entire cohort of negative cases by Sanger sequencing and retrospectively collected clinical data regarding pregnancy as well as the postnatal outcome for positive cases. RESULTS: We detected mutations in MAGED2 in 17 patients, including the 12 with transient antenatal Bartter syndrome, from 16 families. Fifteen different mutations were detected (one whole deletion, three frameshift, three splicing, three nonsense, two inframe deletions, and three missense); 13 of these mutations had not been previously described. Interestingly, two patients are females; in one of these patients our data are consistent with selective inactivation of chromosome X explaining the severity. The phenotypic presentation in our patients was variable and less severe than that of the originally described cases. CONCLUSIONS: MAGED2 mutations explained 9% of cases of antenatal Bartter syndrome in a French cohort, and accounted for 38% of patients without other characterized mutations and for 44% of male probands of negative cases. Our study confirmed previously published data and showed that females can be affected. As a result, this gene must be included in the screening of the most severe clinical form of Bartter syndrome. PMID- 29146705 TI - Complement C3 is a novel modulator of the anti-factor VIII immune response. AB - Development of neutralizing antibodies against therapeutic Factor VIII (FVIII) is the most serious complication of the treatment of hemophilia A. There is growing evidence to show the multifactorial origin of the anti-FVIII immune response, combining both genetic and environmental factors. While a role for the complement system on innate as well as adaptive immunity has been documented, the implication of complement activation on the onset of the anti-FVIII immune response is unknown. Here, using in vitro assays for FVIII endocytosis by human monocyte-derived dendritic cells and presentation to T cells, as well as in vivo complement depletion in FVIII-deficient mice, we show a novel role for complement C3 in enhancing the immune response against therapeutic FVIII. In vitro, complement C3 and its cleavage product C3b enhanced FVIII endocytosis by dendritic cells and presentation to a FVIII-specific CD4+ T-cell hybridoma. The C1 domain of FVIII had previously been shown to play an important role in FVIII endocytosis, and alanine substitutions of the K2092, F2093 and R2090 C1 residues drastically reduce FVIII uptake in vitro Interestingly, complement activation rescued the endocytosis of the FVIII C1 domain triple mutant. In a mouse model of severe hemophilia A, transient complement C3 depletion by humanized cobra venom factor, which does not generate anaphylatoxin C5a, significantly reduced the primary anti-FVIII immune response, but did not affect anti-FVIII recall immune responses. Taken together, our results suggest an important adjuvant role for the complement cascade in the initiation of the immune response to therapeutic FVIII. PMID- 29146706 TI - The clinical and laboratory evaluation of familial hemophagocytic lymphohistiocytosis and the importance of hepatic and spinal cord involvement: a single center experience. AB - Familial hemophagocytic lymphohistiocytosis is an autosomal recessive, life threatening condition characterized by defective immune response. A retrospective analysis was performed on 57 patients diagnosed with familial hemophagocytic lymphohistiocytosis at Hacettepe University Pediatric Hematology Department, Ankara, Turkey. Mutation analysis was performed on 37 patients, and of these: 11 had UNC13D, 10 had PRF1 and 3 had STX11 gene mutation. Of these patients, 44% were found to have central nervous system involvement on admission and spinal cord involvement was also seen in 5 patients. Remission was achieved in 24 patients with the treatment, in a median time of 76 days (min-max: 15-705 days). Time to remission was prolonged 3.1 times in patients with a ferritin level 1500 mg/dL or more. When patients were grouped according to age [Group 1 (<= 2 years), Group 2 (>2 years)]; patients in Group 1 had higher ferritin and aspartate aminotransferase levels but lower fibrinogen levels. The 5-year survival rate was also lower in Group 1. When patients in Group 1 were divided into two sub-groups according to hepatic involvement, the 5-year survival rate of patients who had hepatic involvement was significantly lower than those patients without hepatic involvement (0.7%, 27%, respectively) (P=0.002). The 5-year survival rate of patients who underwent hematopoietic stem cell transplantation was significantly higher than the patients who didn't (44%, 16%, respectively) (P=0.02). In conclusion, age two years and under, ferritin level above 1500 mg/dL, spinal cord or hepatic involvement should be considered as poor prognostic factors in familial hemophagocytic lymphohistiocytosis. PMID- 29146704 TI - Prospective Evaluation of Kidney Disease in Joubert Syndrome. AB - BACKGROUND AND OBJECTIVES: Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing. RESULTS: Patients were ages 0.6-36 years old (mean of 9.0+/-7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67, C5orf42, CC2D2A, CEP290, AHI1, and KIAA0586. Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (n=13) ranged from 6 to 24 years old (mean of 11.3+/-4.8 years old). CONCLUSIONS: Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in CEP290, TMEM67, and AHI1. Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease-like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype. PMID- 29146707 TI - Outcomes after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia harboring t(7;11)(p15;p15). PMID- 29146708 TI - Inflammatory molecule reduction with hydroxyurea therapy in children with sickle cell anemia. PMID- 29146709 TI - Alternatively spliced fibronectin extra domain A is required for hemangiogenic recovery upon bone marrow chemotherapy. PMID- 29146710 TI - JAK2, CALR, MPL and ASXL1 mutational status correlates with distinct histological features in Philadelphia chromosome-negative myeloproliferative neoplasms. PMID- 29146711 TI - Ethics, health policy, and Zika: From emergency to global epidemic? AB - Zika virus was recognised in 2016 as an important vector-borne cause of congenital malformations and Guillain-Barre syndrome, during a major epidemic in Latin America, centred in Northeastern Brazil. The WHO and Pan American Health Organisation (PAHO), with partner agencies, initiated a coordinated global response including public health intervention and urgent scientific research, as well as ethical analysis as a vital element of policy design. In this paper, we summarise the major ethical issues raised during the Zika epidemic, highlighting the PAHO ethics guidance and the role of ethics in emergency responses, before turning to ethical issues that are yet to be resolved. Zika raises traditional bioethical issues related to reproduction, prenatal diagnosis of serious malformations and unjust disparities in health outcomes. But the epidemic has also highlighted important issues of growing interest in public health ethics, such as the international spread of infectious disease; the central importance of reproductive healthcare in preventing maternal and neonatal morbidity and mortality; diagnostic and reporting biases; vector control and the links between vectors, climate change, and disparities in the global burden of disease. Finally, there are controversies regarding Zika vaccine research and eventual deployment. Zika virus was a neglected disease for over 50 years before the outbreak in Brazil. As it continues to spread, public health agencies should promote gender equity and disease control efforts in Latin America, while preparing for the possibility of a global epidemic. PMID- 29146712 TI - Golden opportunity, reasonable risk and personal responsibility for health. PMID- 29146713 TI - Autonomy, nudging and post-truth politics. AB - In his excellent essay, 'Nudges in a post-truth world', Neil Levy argues that 'nudges to reason', or nudges which aim to make us more receptive to evidence, are morally permissible. A strong argument against the moral permissibility of nudging is that nudges fail to respect the autonomy of the individuals affected by them. Levy argues that nudges to reason do respect individual autonomy, such that the standard autonomy objection fails against nudges to reason. In this paper, I argue that Levy fails to show that nudges to reason respect individual autonomy. PMID- 29146714 TI - Reasons, causes and identity. PMID- 29146715 TI - Convicted dermatologist is spared suspension in light of staff shortages. PMID- 29146716 TI - Dynamic Contrast-Enhanced MRI-Derived Intracellular Water Lifetime (tau i ): A Prognostic Marker for Patients with Head and Neck Squamous Cell Carcinomas. AB - BACKGROUND AND PURPOSE: Shutter-speed model analysis of dynamic contrast-enhanced MR imaging allows estimation of mean intracellular water molecule lifetime (a measure of cellular energy metabolism) and volume transfer constant (a measure of hemodynamics). The purpose of this study was to investigate the prognostic utility of pretreatment mean intracellular water molecule lifetime and volume transfer constant in predicting overall survival in patients with squamous cell carcinomas of the head and neck and to stratify p16-positive patients based upon survival outcome. MATERIALS AND METHODS: A cohort of 60 patients underwent dynamic contrast-enhanced MR imaging before treatment. Median, mean intracellular water molecule lifetime and volume transfer constant values from metastatic nodes were computed from each patient. Kaplan-Meier analyses were performed to associate mean intracellular water molecule lifetime and volume transfer constant and their combination with overall survival for the first 2 years, 5 years, and beyond (median duration, >7 years). RESULTS: By the last date of observation, 18 patients had died, and median follow-up for surviving patients (n = 42) was 8.32 years. Patients with high mean intracellular water molecule lifetime (4 deaths) had significantly (P = .01) prolonged overall survival by 5 years compared with those with low mean intracellular water molecule lifetime (13 deaths). Similarly, patients with high mean intracellular water molecule lifetime (4 deaths) had significantly (P = .006) longer overall survival at long-term duration than those with low mean intracellular water molecule lifetime (14 deaths). However, volume transfer constant was a significant predictor for only the 5-year follow-up period. There was some evidence (P < .10) to suggest that mean intracellular water molecule lifetime and volume transfer constant were associated with overall survival for the first 2 years. Patients with high mean intracellular water molecule lifetime and high volume transfer constant were associated with significantly (P < .01) longer overall survival compared with other groups for all follow-up periods. In addition, p16-positive patients with high mean intracellular water molecule lifetime and high volume transfer constant demonstrated a trend toward the longest overall survival. CONCLUSIONS: A combined analysis of mean intracellular water molecule lifetime and volume transfer constant provided the best model to predict overall survival in patients with squamous cell carcinomas of the head and neck. PMID- 29146717 TI - Bipolar Radiofrequency Ablation of Spinal Tumors: The Effect of the Posterior Vertebral Cortex Defect on Temperature Distribution in the Spinal Canal. PMID- 29146718 TI - Deep Brain Nuclei T1 Shortening after Gadobenate Dimeglumine in Children: Influence of Radiation and Chemotherapy. AB - BACKGROUND AND PURPOSE: Intrinsic T1-hyperintense signal has recently been reported in the deep gray nuclei on brain MR imaging after multiple doses of gadolinium-based contrast agents. Most reports have included adult patients and excluded those undergoing radiation or chemotherapy. We investigated whether T1 shortening is also observed in children and tried to determine whether radiochemotherapy is a risk factor for this phenomenon. MATERIALS AND METHODS: In this single-center retrospective study, we reviewed clinical charts and images of all patients 18 years of age or younger with >=4 gadobenate dimeglumine-enhanced MRIs for 6 years. Seventy-six children (mean age, 9.3 years; 60 unconfounded by treatment, 16 with radiochemotherapy) met the selection criteria (>4 MR imaging examinations; mean, 8). T1 signal intensity ratios for the dentate to pons and globus pallidus to thalamus were calculated and correlated with number of injections, time interval, and therapy. RESULTS: Among the 60 children without radiochemotherapy, only 2 had elevated T1 signal intensity ratios (n = 20 and 16 injections). Twelve of the 16 children with radiochemotherapy showed elevated signal intensity ratios. Statistical analysis demonstrated a significant signal intensity ratio change for the number of injections (P < .001) and amount of gadolinium (P = .008), but not for the interscan time interval (P = .35). There was a significant difference in the average signal intensity ratio change between those with and without radiochemotherapy (P < .001). Chart review revealed no new neurologic deficits in any patients, related to their underlying conditions and prior surgeries. CONCLUSIONS: Compared with published adult series, children show a similar pattern of T1 hyperintense signal changes of the dentate and globus pallidus after multiple gadobenate dimeglumine injections. The T1 signal changes in children may have a later onset but are accelerated by radiochemotherapy. PMID- 29146719 TI - Can Arterial Spin-Labeling with Multiple Postlabeling Delays Predict Cerebrovascular Reserve? AB - BACKGROUND AND PURPOSE: The effect of delayed transit time is the main source of error in the quantitative measurement of CBF in arterial spin-labeling. In the present study, we evaluated the usefulness of the transit time-corrected CBF and arterial transit time delay from multiple postlabeling delays arterial spin labeling compared with basal/acetazolamide stress technetium Tc99m hexamethylpropylene amineoxime (Tc99m-HMPAO) SPECT in predicting impairment in the cerebrovascular reserve. MATERIALS AND METHODS: Transit time-corrected CBF maps and arterial transit time maps were acquired in 30 consecutive patients with unilateral ICA or MCA steno-occlusive disease (severe stenosis or occlusion). Internal carotid artery territory-based ROIs were applied to both perfusion maps. Additionally, impairment in the cerebrovascular reserve was evaluated according to both qualitative and quantitative analyses of the ROIs on basal/acetazolamide stress Tc99m-HMPAO SPECT using a previously described method. The area under the receiver operating characteristic curve was used to evaluate the diagnostic accuracy of arterial spin-labeling in depicting impairment of the cerebrovascular reserve. The correlation between arterial spin-labeling and cerebrovascular reserve was evaluated. RESULTS: The affected hemisphere had a decreased transit time-corrected CBF and increased arterial transit time compared with the corresponding values of the contralateral normal hemisphere, which were statistically significant (P < .001). The percentage change of transit time corrected CBF and the percentage change of arterial transit time were independently differentiating variables (P < .001) for predicting cerebrovascular reserve impairment. The correlation coefficient between the arterial transit time and cerebrovascular reserve index ratio was -0.511. CONCLUSIONS: Our results demonstrate that the transit time-corrected CBF and arterial transit time based on arterial spin-labeling perfusion MR imaging can predict cerebrovascular reserve impairment. PMID- 29146720 TI - Role of MR Neurography for the Diagnosis of Peripheral Trigeminal Nerve Injuries in Patients with Prior Molar Tooth Extraction. AB - BACKGROUND AND PURPOSE: Clinical neurosensory testing is an imperfect reference standard to evaluate molar tooth extraction related peripheral trigeminal neuropathy. The purpose was to evaluate the diagnostic accuracy of MR neurography in this domain and correlation with neurosensory testing and surgery. MATERIALS AND METHODS: In this retrospective study, nerve caliber, T2 signal intensity ratio, and contrast-to-noise ratios were recorded by 2 observers using MR neurography for bilateral branches of the peripheral trigeminal nerve, the inferior alveolar and lingual nerves. Patient demographics and correlation of the MR neurography findings with the Sunderland classification of nerve injury and intraoperative findings of surgical patients were obtained. RESULTS: Among 42 patients, the mean +/- SD age for case and control patients were 35.8 +/- 10.2 years and 43.2 +/- 11.5 years, respectively, with male-to-female ratios of 1:1.4 and 1:5, respectively. Case subjects (peripheral trigeminal neuropathy or injury) had significantly larger differences in nerve thickness, T2 signal intensity ratio, and contrast-to-noise ratios than control patients for the inferior alveolar nerve and lingual nerve (P = .01 and .0001, .012 and .005, and .01 and .01, respectively). Receiver operating characteristic analysis showed a significant association among differences in nerve thickness, T2 signal intensity ratio, and contrast-to-noise ratios and nerve injury (area under the curve, 0.83 0.84 for the inferior alveolar nerve and 0.77-0.78 for the lingual nerve). Interobserver agreement was good for the inferior alveolar nerve (intraclass correlation coefficient, 0.70-0.79) and good to excellent for the lingual nerve (intraclass correlation coefficient, 0.75-0.85). MR neurography correlations with respect to clinical neurosensory testing and surgical classifications were moderate to good. Pearson correlation coefficients of 0.68 and 0.81 and kappa of 0.60 and 0.77 were observed for differences in nerve thickness. CONCLUSIONS: MR neurography can be reliably used for the diagnosis of injuries to the peripheral trigeminal nerve related to molar tooth extractions, with good to excellent correlation of imaging with clinical findings and surgical results. PMID- 29146721 TI - Development of a Function-Blocking Antibody Against Fibulin-3 as a Targeted Reagent for Glioblastoma. AB - Purpose: We sought a novel approach against glioblastomas (GBM) focused on targeting signaling molecules localized in the tumor extracellular matrix (ECM). We investigated fibulin-3, a glycoprotein that forms the ECM scaffold of GBMs and promotes tumor progression by driving Notch and NFkappaB signaling.Experimental Design: We used deletion constructs to identify a key signaling motif of fibulin 3. An mAb (mAb428.2) was generated against this epitope and extensively validated for specific detection of human fibulin-3. mAb428.2 was tested in cultures to measure its inhibitory effect on fibulin-3 signaling. Nude mice carrying subcutaneous and intracranial GBM xenografts were treated with the maximum achievable dose of mAb428.2 to measure target engagement and antitumor efficacy.Results: We identified a critical 23-amino acid sequence of fibulin-3 that activates its signaling mechanisms. mAb428.2 binds to that epitope with nanomolar affinity and blocks the ability of fibulin-3 to activate ADAM17, Notch, and NFkappaB signaling in GBM cells. mAb428.2 treatment of subcutaneous GBM xenografts inhibited fibulin-3, increased tumor cell apoptosis, and enhanced the infiltration of inflammatory macrophages. The antibody reduced tumor growth and extended survival of mice carrying GBMs as well as other fibulin-3-expressing tumors. Locally infused mAb428.2 showed efficacy against intracranial GBMs, increasing tumor apoptosis and reducing tumor invasion and vascularization, which are enhanced by fibulin-3.Conclusions: To our knowledge, this is the first rationally developed, function-blocking antibody against an ECM target in GBM. Our results offer a proof of principle for using "anti-ECM" strategies toward more efficient targeted therapies for malignant glioma. Clin Cancer Res; 24(4); 821-33. (c)2017 AACR. PMID- 29146722 TI - The NOTCH4-HEY1 Pathway Induces Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma. AB - Purpose: Recently, several comprehensive genomic analyses demonstrated NOTCH1 and NOTCH3 mutations in head and neck squamous cell carcinoma (HNSCC) in approximately 20% of cases. Similar to other types of cancers, these studies also indicate that the NOTCH pathway is closely related to HNSCC progression. However, the role of NOTCH4 in HNSCC is less well understood.Experimental Design: We analyzed NOTCH4 pathway and downstream gene expression in the TCGA data set. To explore the functional role of NOTCH4, we performed in vitro proliferation, cisplatin viability, apoptosis, and cell-cycle assays. We also compared the relationships among NOTCH4, HEY1, and epithelial-mesenchymal transition (EMT) related genes using the TCGA data set and in vitro assays.Results:HEY1 is specifically upregulated in HNSCC compared with normal tissues in the TCGA data set. NOTCH4 is more significantly related to HEY1 activation in HNSCC in comparison with other NOTCH receptors. NOTCH4 promotes cell proliferation, cisplatin resistance, inhibition of apoptosis, and cell-cycle dysregulation. Furthermore, NOTCH4 and HEY1 upregulation resulted in decreased E-cadherin expression and increased Vimentin, Fibronectin, TWIST1, and SOX2 expression. NOTCH4 and HEY1 expression was associated with an EMT phenotype as well as increased invasion and cell migration.Conclusions: In HNSCC, the NOTCH4-HEY1 pathway is specifically upregulated, induces proliferation and cisplatin resistance, and promotes EMT. Clin Cancer Res; 24(3); 619-33. (c)2017 AACR. PMID- 29146724 TI - Commentary: Nocturnal serum melatonin levels in sulfur mustard exposed patients with sleep disorders. PMID- 29146723 TI - Nocturnal serum melatonin levels in sulfur mustard exposed patients with sleep disorders. AB - BACKGROUND: Sulfur mustard (SM) exposure causes respiratory disorders, progressive deterioration in lung function and mortality in injured victims and poor sleep quality is one of the most common problems among SM-exposed patients. Since melatonin has a critical role in regulation of sleep and awareness, this study aimed to evaluate the serum melatonin levels in SM-injured subjects. METHODS: A total of 30 SM-exposed male patients and 10 controls was evaluated. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI); daytime sleepiness was measured by the Epworth Sleepiness Scale (ESS), and the risk of obstructive sleep apnoea was determined by the STOP-Bang questionnaire. Polysomnography (PSG) and pulmonary function tests (PFTs) were also available. Nocturnal serum melatonin levels were measured using an ELISA kit. RESULTS: The mean of PSQI, ESS and STOP-Bang scores in patients (11.76+/-3.56, 12.6+/-3.03 and 5.03+/-1.09, respectively) were significantly (p<0.01) higher than those in the controls (2.78+/-0.83, 4.69+/-1.15 and 1.18+/-0.82, respectively). PFTs also showed declined respiratory quality in SM-patients. There was a significant difference regarding the PSG results between patients and controls (p<0.01). The mean of nocturnal serum melatonin levels in patients (29.78+/-19.31 pg/mL) was significantly (p=0.005) lower than that in the controls (78.53+/-34.41 pg/mL). CONCLUSIONS: Reduced nocturnal serum melatonin and respiratory disorders can be the reasons for poor sleep quality among these patients. TRIAL REGISTRATION NUMBER: IRCT2015092924267N1, Pre-results. PMID- 29146725 TI - Rare cause of adrenal insufficiency. AB - A 72-year-old man presented with weight loss, night sweats and haemoptysis and was hypotensive. CT imaging showed rapidly enlarging bilateral adrenal masses, and he was found to have primary adrenal insufficiency. An adrenal gland biopsy revealed the rare diagnosis of primary adrenal lymphoma. This unique case highlights possible rare causes of adrenal masses and adrenal insufficiency, their investigation and management principles. PMID- 29146726 TI - Endovascular rescue treatment through stent positioning after surgical clipping of intracranial aneurysms complicated by parent artery obstruction. AB - During aneurysm clipping, ischemic complications may occur and require a rescue treatment, usually surgical. We present two such cases that required urgent rescue treatment, performed through an endovascular route. Our first case presented with a non-ruptured right posterior inferior cerebellar artery (PICA) aneurysm. After permanent clip positioning, occlusion of the PICA occurred. An unsuccessful attempt of clip repositioning was performed. We therefore positioned a stent obtaining complete flow restoration. Our second case was that of a ruptured giant left middle cerebral artery aneurysm with focal critical stenosis of the parent vessel, likely due to an underlying dissection. Initially, the aneurysm was secured through coiling. However, after permanent clip positioning, parent artery occlusion occurred. DSA showed occlusion of the parent artery downstream to the clip and persistence of the preaneurismatic stenosis. We achieved full recanalization through stent positioning. In both cases, there were no ischemic or hemorrhagic complications. PMID- 29146727 TI - Primary intraventricular haemorrhage due to rupture of giant varix of the basal vein of Rosenthal in a patient with long-standing direct CCF: angiographic features and treatment considerations. AB - Direct carotid cavernous fistulae (CCF) are often detected early and treated promptly resulting in a paucity of literature regarding its long-term evolution. We present a case of high flow post-traumatic direct CCF that was neglected for over 6 years and presented with a rare manifestation of primary intraventricular haemorrhage. Occlusions of the primary venous outlets likely resulted in engorgement of the deep venous system. The segmental anatomy of the shunting basal vein is critical to the clinical presentation and may range from basal ganglia or brainstem oedema/infarctions to uniquely, as in our case, isolated intraventricular haemorrhage secondary to variceal rupture. Treatment in such chronic cases requires a consideration of cerebral hyperperfusion syndrome necessitating deconstructive techniques with subsequent anticoagulation to avoid accelerated thrombosis of the venous varices. PMID- 29146728 TI - Source estimation of epileptic activity using eLORETA kurtosis analysis. AB - Exact low-resolution brain electromagnetic tomography (eLORETA) is a technique for three-dimensional representation of the distribution of sources of electrical activity in the brain. Kurtosis analysis allows for identification of spiky activity in the brain. To evaluate the reliability of eLORETA kurtosis analysis, the results of the analysis were compared with those of equivalent current dipole (ECD) and synthetic aperture magnetometry (SAM) kurtosis analysis of magnetoencephalography (MEG) data in a patient with epilepsy with elementary visual seizures in a 6-year follow-up.The results of electroencephalography (EEG) eLORETA kurtosis analysis indicative of a right superior temporal spike source partially overlapped with MEG ECD/SAM kurtosis results in all recordings, with a total overlapping at the end of the follow-up period. Overall findings suggest that eLORETA kurtosis analysis of EEG data may aid in the localisation of spike activity sources in patients with epilepsy. PMID- 29146729 TI - Keratoderma blennorrhagica. PMID- 29146730 TI - The swollen pinna. PMID- 29146732 TI - miR-539-5p inhibits experimental choroidal neovascularization by targeting CXCR7. AB - Stromal cell-derived factor-1 (SDF-1) has been previously confirmed to participate in the formation of choroidal neovascularization (CNV) via its receptor, CXC chemokine receptor (CXCR) 4; CXCR7 is a recently identified receptor for SDF-1. The molecular mechanisms and therapeutic value of CXCR7 in CNV remain undefined. In this study, experimental CNV was induced by laser photocoagulation in Brown-Norway pigmented rats, and aberrant CXCR7 overexpression was detected in the retinal pigment epithelial/choroid/sclera tissues of laser-injured eyes. Blockade of CXCR7 activation via CXCR7 knockdown or neutralizing Ab administration inhibited SDF-1-induced cell survival and the tubular formation of human retinal microvascular endothelial cells (HRMECs) in vitro and reduced CNV leakage and lesion size in vivo. By using microRNA array screening and bioinformatic analyses, we identified miR-539-5p as a regulator of CXCR7. Transfection of HRMECs and choroid-retinal endothelial (RF/6A) cells with the miR-539-5p mimic inhibited their survival and tube formation, whereas CXCR7 overexpression rescued the suppressive effect of miR-539-5p. The antiangiogenic activities of the miR-539-5p mimic were additionally demonstrated in vivo by intravitreal injection. ERK1/2 and AKT signaling downstream of CXCR7 is involved in the miR-539-5p regulation of endothelial cell behaviors. These findings suggest that the manipulation of miR-539-5p/CXCR7 levels may have important therapeutic implications in CNV-associated diseases.-Feng, Y., Wang, J., Yuan, Y., Zhang, X., Shen, M., Yuan, F. miR-539-5p inhibits experimental choroidal neovascularization by targeting CXCR7. PMID- 29146731 TI - Organic anion-transporting polypeptide 1B3 as a dual reporter gene for fluorescence and magnetic resonance imaging. AB - Reporter proteins have broad applications in visualizing molecular events at the cellular, tissue and whole-body levels. Transmembrane transporters recognizing specific molecular domains are of particular interest because they enable the migration of signal-source molecules from the extracellular space to the cytoplasm for subsequent application in multimodality imaging. Organic anion transporting polypeptides (OATPs) have demonstrated their MRI reporter efficacy. We further expanded their use as a dual-modality reporter in MRI and noninvasive in vivo imaging system (IVIS). We overexpressed OATP1B3 in the HT-1080 sarcoma cell line. Both Gd-EOB-DTPA, an MRI contrast agent, and indocyanine green (ICG), a near-infrared fluorescent dye that provides better deep-tissue detection because of its long wavelength, could be delivered to the intracellular space and imaged in a tumor-bearing nude mouse model. Our in vivo dual-imaging reporter system achieved high sensitivity in MRI and observation periods lasting as long as 96 h in IVIS. Because of the superior temporal and spatial resolutions and the clinical availability of both ICG and Gd-EOB-DTPA, this dual-imaging OATP1B3 system will find biomedical use in tumor biology, stem cell trafficking, and tissue engineering.-Wu, M.-R., Liu, H.-M., Lu, C.-W., Shen, W.-H., Lin, I.-J., Liao, L.-W., Huang, Y.-Y., Shieh, M.-J., Hsiao, J.-K. Organic anion-transporting polypeptide 1B3 as a dual reporter gene for fluorescence and magnetic resonance imaging. PMID- 29146733 TI - Effects of chronically increased VEGF-A on the aging heart. AB - Whether approaches to chronically increase VEGF-A in the heart may have beneficial effects and prevent the development of heart failure, in part by improving cardiac perfusion, or whether this increase could have detrimental effects on cardiac performance in the aging heart, has not been tested yet. In this study, a genetic mouse model with a chronic increase in VEGF-A in the heart is shown to have increased cardiac angiogenesis and develop cardiac hypertrophy with enhanced basal cardiac performance with age progression. However, in aged hearts, this increase in VEGF-A was associated with higher expression of fetal cardiac genes and reduced cardiac performance after beta-agonistic stress, features consistent with pathologic cardiac hypertrophy. Expression of Nod-like receptor protein (NLRP)-3 was increased in the hearts of the mice, and its genetic inactivation prevented increased fetal cardiac gene expression and partially rescued the impaired cardiac performance after beta-agonistic stimulation in aged hearts without reducing cardiac angiogenesis or hypertrophy. Thus, although a chronic increase in cardiac VEGF-A may improve cardiac perfusion, long-term upregulation of VEGF-A leads to reduced cardiac performance under stress, an effect that can be partially inhibited by NLRP3 inactivation. Targeting NLRP3 shifts the VEGF-A-induced cardiac hypertrophy from a pathologic toward a more physiologic hypertrophy.-Marneros, A. G. Effects of chronically increased VEGF-A on the aging heart. PMID- 29146735 TI - Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration. AB - DNA methylation is an epigenetic mechanism regulating gene expression. In this study, we observed that DNA methyltransferase 3a (Dnmt3a) expression is decreased after muscle atrophy. We made skeletal muscle-specific Dnmt3a-knockout (Dnmt3a KO) mice. The regeneration capacity after muscle injury was markedly decreased in Dnmt3a-KO mice. Diminished mRNA and protein expression of Dnmt3a were observed in skeletal muscles as well as in satellite cells, which are important for muscle regeneration, in Dnmt3a-KO mice. Dnmt3a-KO satellite cell showed smaller in size (length/area), suggesting suppressed myotube differentiation. Microarray analysis of satellite cells showed that expression of growth differentiation factor 5 (Gdf5) mRNA was markedly increased in Dnmt3a-KO mice. The DNA methylation level of the Gdf5 promoter was markedly decreased in Dnmt3a-KO satellite cells. In addition, DNA methylation inhibitor azacytidine treatment increased Gdf5 expression in wild-type satellite cells, suggesting Gdf5 expression is regulated by DNA methylation. Also, we observed increased inhibitor of differentiation (a target of Gdf5) mRNA expression in Dnmt3a-KO satellite cells. Thus, Dnmt3a appears to regulate satellite cell differentiation via DNA methylation. This mechanism may play a role in the decreased regeneration capacity during atrophy such as in aged sarcopenia.-Hatazawa, Y., Ono, Y., Hirose, Y., Kanai, S., Fujii, N. L., Machida, S., Nishino, I., Shimizu, T., Okano, M., Kamei, Y., Ogawa, Y. Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration. PMID- 29146734 TI - Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. AB - Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg- PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patient-derived xenografts [PDX; non-small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune engrafted NSG mice. Treatment with pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition in both CDX and PDX tumors in HuNSG but not in NSG mice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearing HuNSG mice may represent an important, new model for preclinical immunotherapy research.-Wang, M., Yao, L.-C., Cheng, M., Cai, D., Martinek, J., Pan, C.-X., Shi, W., Ma, A.-H., De Vere White, R. W., Airhart, S., Liu, E. T., Banchereau, J., Brehm, M. A., Greiner, D. L., Shultz, L. D., Palucka, K., Keck, J. G. Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy. PMID- 29146737 TI - Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study. AB - OBJECTIVES: To evaluate the prevalence and type of rheumatic immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs), as well as the correlation with tumour response. METHODS: This was a single centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs and tumour response was assessed on a regular basis. Patients who experienced musculoskeletal symptoms were referred to the department of rheumatology for clinical evaluation and management. RESULTS: From September 2015 to May 2017, 524 patients received ICIs and 35 were referred to the department of rheumatology (6.6%). All but one of the rheumatic irAEs occurred with anti-programmed cell death protein 1(PD-1)/PD-1 ligand 1(PD-L1) antibodies, with a median exposure time of 70 days. There were two distinct clinical presentations: (1) inflammatory arthritis (3.8%) mimicking either rheumatoid arthritis (n=7), polymyalgia rheumatica (n=11) or psoriatic arthritis (n=2) and (2) non-inflammatory musculoskeletal conditions (2.8%; n=15). One patient with rheumatoid arthritis was anti-cyclic citrullinated peptide (anti CCP) positive. Nineteen patients required glucocorticoids, and methotrexate was started in two patients. Non-inflammatory disorders were managed with non steroidal anti-inflammatory drugs, analgesics and/or physiotherapy. ICI treatment was pursued in all but one patient. Patients with rheumatic irAEs had a higher tumour response rate compared with patients without irAEs (85.7% vs 35.3%; P<0.0001). CONCLUSION: Since ICIs are used with increasing frequency, knowledge of rheumatic irAEs and their management is of major interest. All patients were responsive either to low-to-moderate doses of prednisone or symptomatic therapies and did not require ICI discontinuation. Furthermore, tumour response was significantly higher in patients who experienced rheumatic irAEs. PMID- 29146738 TI - Response to: 'Cardiovascular effects of hydroxychloroquine: a systematic review and meta-analysis' by Mathieu et al. PMID- 29146736 TI - Quantitative high-throughput screening identifies cytoprotective molecules that enhance SUMO conjugation via the inhibition of SUMO-specific protease (SENP)2. AB - The development of novel neuroprotective treatments for acute stroke has been fraught with failures, which supports the view of ischemic brain damage as a highly complex multifactorial process. Post-translational modifications such as small ubiquitin-like modifier (SUMO)ylation have emerged as critical molecular regulatory mechanisms in states of both homeostasis and ischemic stress, as evidenced by our previous work. Accordingly, the clinical significance of the selective control of the global SUMOylation process has become apparent in studies of ischemic pathobiology and pathophysiology. Herein, we describe a process capable of identifying and characterizing small molecules with the potential of targeting the SUMO system through inhibition of SUMO deconjugation in an effort to develop novel stroke therapies.-Bernstock, J. D., Ye, D., Smith, J. A., Lee, Y.-J., Gessler, F. A., Yasgar, A., Kouznetsova, J., Jadhav, A., Wang, Z., Pluchino, S., Zheng, W., Simeonov, A., Hallenbeck, J. M., Yang, W. Quantitative high-throughput screening identifies cytoprotective molecules that enhance SUMO-conjugation via the inhibition of SUMO-specific protease (SENP)2. PMID- 29146739 TI - Utility of PET/CT in the diagnosis of inflammatory rheumatic diseases: a systematic review and meta-analysis. PMID- 29146740 TI - Validation of the Psoriatic Arthritis Impact of Disease (PsAID) Questionnaire and its potential as a single-item outcome measure in clinical practice. AB - OBJECTIVES: The Psoriatic Arthritis Impact of Disease (PsAID) Questionnaire is a recently developed patient-reported outcome measure (PROM) of disease impact in psoriatic arthritis (PsA). We set out to assess the validity in an independent cohort of patients, estimate the minimally important difference for improvement and explore the potential of individual components of the PsAID in clinical practice. METHODS: Data were collected prospectively for a single-centre cohort of patients with PsA. Construct validity was assessed by Spearman correlation with other PROMs and reliability by intraclass correlation coefficient (ICC) at 1 week. Sensitivity to change at 3 months was determined by the standardised response mean (SRM) in those patients with active disease requiring a change in treatment. RESULTS: A total of 129 patients (mean +/-SD age 52.1+/-13.3, 57% women, disease duration 10.2+/-8 years) completed the baseline questionnaires and assessments. The mean baseline PsAID12 score was 3.92+/-2.26 with an ICC of 0.91 (95%CI 0.87 to 0.94). The SE of measurement was 0.51 and the minimal detectable change was 1.41. There was strong correlation (r>=0.70) with most of the PROMs studied and moderate correlation with clinical outcomes (r=0.40-0.57). The SRM of the PsAID12 was 0.74 (95%CI 0.45 to 0.97). There was strong correlation with individual PsAID items and their corresponding PROM questionnaires (r>=0.67). CONCLUSION: The PsAID is a reliable, feasible and discriminative measure in patients with PsA. The good responsiveness of the PsAID and strong correlation of individual items with other PROMS represent an opportunity to reduce questionnaire burden for patients in studies and clinical practice. PMID- 29146742 TI - Cardiovascular effects of hydroxychloroquine: a systematic review and meta analysis. PMID- 29146741 TI - Presence of monosodium urate crystal deposition by dual-energy CT in patients with gout treated with allopurinol. AB - OBJECTIVE: Dual-energy CT (DECT) detects and quantifies monosodium urate (MSU) crystal deposition with high precision. This DECT study assessed crystal deposition in patients with gout treated with stable-dose allopurinol, and investigated potential clinical determinants for crystal deposition. METHODS: Patients with gout treated with allopurinol >=300 mg daily for at least 3 months were prospectively recruited from the USA and New Zealand, using monitored enrolment to include approximately 25% patients with palpable tophi and approximately 50% with serum urate (sUA) levels <6.0 mg/dL (<357umol/L). MSU crystal deposition was measured in the hands/wrists, feet/ankles/Achilles and knees bilaterally. The presence and total volume of crystals were assessed by DECT and analysed according to sUA levels and gout characteristics. RESULTS: Among 152 patients receiving allopurinol >=300 mg/day for 5.1 years on average, 69.1% had crystal deposition on DECT, with a median total crystal volume of 0.16 cm3 (range: 0.01-19.53 cm3). The prevalence of crystal deposition ranged from 46.9% among patients with sUA <6.0 mg/dL and no palpable tophi to 90.0% among those with sUA >=6.0 mg/dL and tophi. Total volume of crystal deposition was positively associated with sUA >=6.0 mg/dL, gout flares within the past 3 months and tophi. Total volume of crystal deposition correlated positively with Patient Global Impression of Disease Activity scores. CONCLUSION: A substantial proportion of patients without palpable tophi have MSU crystal deposition, despite receiving allopurinol doses >=300 mg/day for a considerable duration. Patients with higher sUA and clinical features of severe disease have a higher frequency and greater volume of MSU crystal deposition. PMID- 29146743 TI - Testing treat-to-target outcomes with initial methotrexate monotherapy compared with initial tumour necrosis factor inhibitor (adalimumab) plus methotrexate in early rheumatoid arthritis. AB - OBJECTIVES: To compare responses in patients with early rheumatoid arthritis (RA) initially treated with the tumour necrosis factor inhibitor (TNFi) adalimumab+methotrexate (MTX) versus MTX monotherapy who may have continued receiving MTX or switched to adalimumab rescue therapy after inadequate response to MTX. METHODS: OPTIMA enrolled MTX-naive patients with active RA for <1 year. This post hoc analysis determined the proportion of patients, stratified by initial treatment, who achieved 28-joint modified Disease Activity Score based on C reactive protein <3.2, normal function and/or no radiographic progression at weeks 26, 52 and 78. RESULTS: Significantly greater proportions of patients initially treated with adalimumab+MTX (n=466) compared with MTX monotherapy (n=460) achieved good clinical (53% vs 30%), functional (45% vs 33%) and radiographic (87% vs 72%) outcomes at week 26. From weeks 26 to 78, adalimumab rescue patients achieved similar clinical and functional outcomes versus patients initially treated with adalimumab+MTX. However, significantly more patients initially treated with adalimumab+MTX had no radiographic progression at weeks 52 and 78 versus patients initially treated with MTX (both timepoints: 86% vs 72%). CONCLUSIONS: In early RA, starting with MTX monotherapy and adding TNFi after 26 weeks yields similar longer term clinical results as starting with TNFi+MTX combination therapy but allows a small but significant accrual of radiographic damage. PMID- 29146744 TI - Response to: 'Increased stroke incidence in systemic lupus erythematosus patients: risk factors or disease itself?' by Bruzzese and Zullo. PMID- 29146745 TI - Response to: 'Use of urate-lowering therapies is not associated with an increase in the risk of incident dementia in older adults' by Lee and Song. PMID- 29146746 TI - Response to: the value of 18(F)-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study. PMID- 29146748 TI - Stable Isotope Kinetic Study of ApoM (Apolipoprotein M). AB - OBJECTIVE: ApoM (apolipoprotein M) binds primarily to high-density lipoprotein before to be exchanged with apoB (apolipoprotein B)-containing lipoproteins. Low density lipoprotein (LDL) receptor-mediated clearance of apoB-containing particles could influence plasma apoM kinetics and decrease its antiatherogenic properties. In humans, we aimed to describe the interaction of apoM kinetics with other components of lipid metabolism to better define its potential benefit on atherosclerosis. APPROACH AND RESULTS: Fourteen male subjects received a primed infusion of 2H3-leucine for 14 hours, and analyses were performed by liquid chromatography-tandem mass spectrometry from the hourly plasma samples. Fractional catabolic rates and production rates within lipoproteins were calculated using compartmental models. ApoM was found not only in high-density lipoprotein (59%) and LDL (4%) but also in a non-lipoprotein-related compartment (37%). The apoM distribution was heterogeneous within LDL and non-lipoprotein related compartments according to plasma triglycerides (r=0.86; P<0.001). The relationships between sphingosine-1-phosphate and apoM were confirmed in all compartments (r range, 0.55-0.89; P<0.05). ApoM fractional catabolic rates and production rates were 0.16+/-0.07 pool/d and 0.14+/-0.06 mg/kg per day in high density lipoprotein and 0.56+/-0.10 pool/d and 0.03+/-0.01 mg/kg per day in LDL, respectively. Fractional catabolic rates of LDL-apoM and LDL-apoB100 were correlated (r=0.55; P=0.042). Significant correlations were found between triglycerides and production rates of LDL-apoM (r=0.73; P<0.004). CONCLUSIONS: In humans, LDL kinetics play a key role in apoM turnover. Plasma triglycerides act on both apoM and sphingosine-1-phosphate distributions between lipoproteins. These results confirmed that apoM could be bound to high-density lipoprotein after secretion and then quickly exchanged with a non-lipoprotein-related compartment and to LDL to be slowly catabolized. PMID- 29146747 TI - Transforming Growth Factor-beta1 Inhibits Pseudoaneurysm Formation After Aortic Patch Angioplasty. AB - OBJECTIVE: Pseudoaneurysms remain a significant complication after vascular procedures. We hypothesized that TGF-beta (transforming growth factor-beta) signaling plays a mechanistic role in the development of pseudoaneurysms. APPROACH AND RESULTS: Rat aortic pericardial patch angioplasty was associated with a high incidence (88%) of pseudoaneurysms at 30 days, with increased smad2 phosphorylation in small pseudoaneurysms but not in large pseudoaneurysms; TGF beta1 receptors were increased in small pseudoaneurysms and preserved in large pseudoaneurysms. Delivery of TGF-beta1 via nanoparticles covalently bonded to the patch stimulated smad2 phosphorylation both in vitro and in vivo and significantly decreased pseudoaneurysm formation (6.7%). Inhibition of TGF-beta1 signaling with SB431542 decreased smad2 phosphorylation both in vitro and in vivo and significantly induced pseudoaneurysm formation by day 7 (66.7%). CONCLUSIONS: Normal healing after aortic patch angioplasty is associated with increased TGF beta1 signaling, and recruitment of smad2 signaling may limit pseudoaneurysm formation; loss of TGF-beta1 signaling is associated with the formation of large pseudoaneurysms. Enhancement of TGF-beta1 signaling may be a potential mechanism to limit pseudoaneurysm formation after vascular intervention. PMID- 29146749 TI - Statins Promote Cardiac Infarct Healing by Modulating Endothelial Barrier Function Revealed by Contrast-Enhanced Magnetic Resonance Imaging. AB - OBJECTIVE: The endothelium has a crucial role in wound healing, acting as a barrier to control transit of leukocytes. Endothelial barrier function is impaired in atherosclerosis preceding myocardial infarction (MI). Besides lowering lipids, statins modulate endothelial function. Here, we noninvasively tested whether statins affect permeability at the inflammatory (day 3) and the reparative (day 7) phase of infarct healing post-MI using contrast-enhanced cardiac magnetic resonance imaging (MRI). APPROACH AND RESULTS: Noninvasive permeability mapping by MRI after MI in C57BL/6, atherosclerotic ApoE-/-, and statin-treated ApoE-/- mice was correlated to subsequent left ventricular outcome by structural and functional cardiac MRI. Ex vivo histology, flow cytometry, and quantitative polymerase chain reaction were performed on infarct regions. Increased vascular permeability at ApoE-/- infarcts was observed compared with C57BL/6 infarcts, predicting enhanced left ventricular dilation at day 21 post-MI by MRI volumetry. Statin treatment improved vascular barrier function at ApoE-/- infarcts, indicated by reduced permeability. The infarcted tissue of ApoE-/- mice 3 days post-MI displayed an unbalanced Vegfa(vascular endothelial growth factor A)/Angpt1 (angiopoetin-1) expression ratio (explaining leakage-prone vessels), associated with higher amounts of CD45+ leukocytes and inflammatory LY6Chi monocytes. Statins reversed the unbalanced Vegfa/Angpt1 expression, normalizing endothelial barrier function at the infarct and blocking the augmented recruitment of inflammatory leukocytes in statin-treated ApoE-/- mice. CONCLUSIONS: Statins lowered permeability and reduced the transit of unfavorable inflammatory leukocytes into the infarcted tissue, consequently improving left ventricular outcome. PMID- 29146750 TI - TRPM7 Kinase Controls Calcium Responses in Arterial Thrombosis and Stroke in Mice. AB - OBJECTIVE: TRPM7 (transient receptor potential cation channel, subfamily M, member 7) is a ubiquitously expressed bifunctional protein comprising a transient receptor potential channel segment linked to a cytosolic alpha-type serine/threonine protein kinase domain. TRPM7 forms a constitutively active Mg2+ and Ca2+ permeable channel, which regulates diverse cellular processes in both healthy and diseased conditions, but the physiological role of TRPM7 kinase remains largely unknown. APPROACH AND RESULTS: Here we show that point mutation in TRPM7 kinase domain deleting the kinase activity in mice (Trpm7R/R ) causes a marked signaling defect in platelets. Trpm7R/R platelets showed an impaired PIP2 (phosphatidylinositol-4,5-bisphosphate) metabolism and consequently reduced Ca2+ mobilization in response to stimulation of the major platelet receptors GPVI (glycoprotein VI), CLEC-2 (C-type lectin-like receptor), and PAR (protease activated receptor). Altered phosphorylation of Syk (spleen tyrosine kinase) and phospholipase C gamma2 and beta3 accounted for these global platelet activation defects. In addition, direct activation of STIM1 (stromal interaction molecule 1) with thapsigargin revealed a defective store-operated Ca2+ entry mechanism in the mutant platelets. These defects translated into an impaired platelet aggregate formation under flow and protection of the mice from arterial thrombosis and ischemic stroke in vivo. CONCLUSIONS: Our results identify TRPM7 kinase as a key modulator of phospholipase C signaling and store-operated Ca2+ entry in platelets. The protection of Trpm7R/R mice from acute ischemic disease without developing intracranial hemorrhage indicates that TRPM7 kinase might be a promising antithrombotic target. PMID- 29146751 TI - Exercise-based intervention for prevention of sports injuries (PEDro synthesis). PMID- 29146752 TI - Physical activity and cancer: an umbrella review of the literature including 22 major anatomical sites and 770 000 cancer cases. AB - OBJECTIVE: To provide an overview of the breadth and validity of claimed associations between physical activity and risk of developing or dying from cancer. DESIGN: Umbrella review. DATA SOURCES: We searched Medline, Embase, Cochrane Database and Web of Science. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Systematic reviews about physical activity and cancer incidence and cancer mortality in different body sites among general population. RESULTS: We included 19 reviews covering 22 cancer sites, 26 exposure-outcome pairs meta-analyses and 541 original studies. Physical activity was associated with lower risk of seven cancer sites (colon, breast, endometrial, lung, oesophageal, pancreas and meningioma). Only colon (a protective association with recreational physical activity) and breast cancer (a protective association with overall physical activity) were supported by strong evidence and highly suggestive evidence, respectively. Evidence from endometrial, lung, oesophageal, pancreas and meningioma presented hints of uncertainty and bias in the literature (eg, not reaching P values<10-6) showing large between-study heterogeneity and/or not demonstrating a definite direction for the effect when 95% prediction intervals were considered. Four of the 26 meta-analyses showed small study effects and 4 showed excess significance. CONCLUSION: Physical activity is associated with a lower risk of several cancers, but only colon and breast cancer associations were supported by strong or highly suggestive evidence, respectively. Evidence from other cancer sites was less consistent, presenting hints of uncertainty and/or bias. PMID- 29146754 TI - It is time to replace publish or perish with get visible or vanish: opportunities where digital and social media can reshape knowledge translation. PMID- 29146753 TI - Navigating the new landscape of apps: Overcoming the challenge of poor quality apps in sport and exercise medicine. PMID- 29146755 TI - Ocular findings in Loeys-Dietz syndrome. AB - BACKGROUND: Loeys-Dietz syndrome (LDS), an autosomal-dominant connective tissue disorder, is characterised by systemic manifestations including arterial aneurysm and craniofacial dysmorphologies. Although ocular involvement in LDS has been reported, detailed information on those manifestations is lacking. METHODS: Retrospective chart review of patients with diagnosed LDS and comparison with age matched control patients. RESULTS: Mean age was 37.8+/-14.6 years (patients with LDS) and 38.4+/-13.5 years (controls). Patients with LDS less frequently had iris transillumination, cataract and glaucoma compared with controls. Scleral and retinal vascular abnormalities were not found in any of the LDS eyes. Ectopia lentis was found in one patient with LDS. The eyes of patients with LDS tended to be more myopic (spherical equivalent, -2.47+/-2.70 dioptres (dpt) vs -1.30+/ 2.96dpt (controls); P=0.08) and longer (24.6+/-1.7mm vs 24.1+/-1.5mm (controls); P=0.10). Central corneal thickness was significantly reduced in LDS eyes (521+/ 48um vs 542+/-37um (controls); P=0.02). Corneal curvature (43.06+/-1.90dpt (LDS) versus 43.00+/-1.37dpt (controls); P=0.72) and interpupillary distance (65.0+/ 6.0mm (LDS) vs 64.3+/-4.8mm (controls); P=0.66) did not differ significantly between both groups. Visual acuity was similar between both groups (0.03+/ 0.09logarithm of the minimum angle of resolution (logMAR) for LDS eyes and 0.05+/ 0.17logMAR for control eyes, P=0.47). CONCLUSIONS: Ocular features of LDS include decreased central corneal thickness and mild myopia. Ectopia lentis may be slightly more common than in controls but appears less common than in Marfan syndrome. Hypertelorism, scleral and retinal vascular abnormalities were not features of LDS. PMID- 29146756 TI - Prevalence and factors associated with age-related macular degeneration in a southwestern island population of Japan: the Kumejima Study. AB - AIMS: To evaluate the prevalence of and factors associated with age-related macular degeneration (AMD) in a rural population of southwestern Japan. METHODS: This population-based cross-sectional study of all residents aged 40 years or older was conducted on the island of Kumejima, Okinawa, Japan. Of 4632 eligible residents, 3762 completed a comprehensive questionnaire and underwent ocular examination (participant rate, 81.2%). A non-mydriatic fundus photograph was used to grade AMD lesions according to the Wisconsin protocol. Prevalence of AMD was calculated and factors associated with AMD were identified by logistic regression. RESULTS: Of 3068 subjects with gradable photographs, 469 had early AMD and 4 had late AMD. Age-adjusted prevalence was 13.4% for any AMD, 13.3% for early AMD and 0.09% for late AMD. In multivariate analysis, any AMD was positively associated with age (OR 1.04 per year, 95% CI 1.03 to 1.05), male sex (OR 1.42, 95% CI 1.14 to 1.75) and history of cataract surgery (OR 1.35, 95% CI 1.00 to 1.82) and was negatively associated with longer axial length (OR 0.85 per millimetre, 95% CI 0.74 to 0.96). Early AMD similarly showed significant associations with these same factors. CONCLUSIONS: Prevalence of early or late AMD in a southwestern island population of Japan was 13.4% or 0.09%. Our data suggest relatively high prevalence for early AMD and low prevalence for late AMD in this sample of rural Japanese population. Significant factors associated with any or early AMD were mostly similar to that of previous studies. PMID- 29146758 TI - Non-aesthetic indications for periocular hyaluronic acid filler treatment: a review. AB - Dermal fillers have been in use for many years for aesthetic rejuvenation of the face. More recently, however, fillers have been increasingly used as an alternative to traditional surgical procedures for non-aesthetic indications. These indications include lagophthalmos, eyelid malpositions and orbital volume deficiency. The advantages of these filler injections are multiple: minimally invasive, repeatable, titratable and even reversible (depending on the product used). We review the current literature of functional uses of filler injections as mentioned above and evaluate the safety profile and efficacy of filler injections for this purpose. PMID- 29146757 TI - Is there consensus in defining childhood cerebral visual impairment? A systematic review of terminology and definitions. AB - The childhood condition of visual difficulties caused by brain damage, commonly termed cortical or cerebral visual impairment (CVI), is well established but has no internationally accepted definition. Clarification of its core features is required to advance research and clinical practice. This systematic review aimed to identify the definitions of childhood CVI in the original scientific literature to describe and critically appraise a consensual definition of the condition. MEDLINE, EMBASE, PsychINFO, CINAHL and AMED databases were searched in January 2017. Studies were included if they (1) were published original research, (2) contained a childhood CVI sample, (3) contained a definition of CVI and (4) described their CVI identification/diagnostic method. Thematic analysis identified concepts within definitions and narrative synthesis was conducted. Of 1150 articles, 51 met inclusion criteria. Definitions were subdivided according to detail (descriptive definition, description not reaching definition status and diagnostic/operationalising criteria). Three themes concerning visual deficits, eye health and brain integrity were identified (each containing subthemes) and analysed individually across definitions. The most common themes were 'visual impairment' (n=20), 'retrochiasmatic pathway damage'(n=13) and 'normal/near normal eye health' (n=15). The most consensual definition identified here may not be the best quality for advancing our understanding of CVI. We argue for the alternative definition: CVI is a verifiable visual dysfunction which cannot be attributed to disorders of the anterior visual pathways or any potentially co occurring ocular impairment. We propose reporting guidelines to permit comparison across studies and increase the evidence base for more reliable clinical assessment and diagnosis. PMID- 29146759 TI - Visual field indices and patterns of visual field deficits in mesopic and dark adapted two-colour fundus-controlled perimetry in macular diseases. AB - BACKGROUND/AIMS: To analyse the retest reliability of visual field indices and to describe patterns of visual field deficits in mesopic and dark-adapted two-colour fundus-controlled perimetry (FCP) in macular diseases. METHODS: Seventy-seven eyes (30 eyes with macular diseases and 47 normal eyes) underwent duplicate mesopic and dark-adapted two-colour FCP (Scotopic Macular Integrity Assessment, CenterVue). Non-weighted (mean defect, loss variance), variability-weighted (mean deviation, pattern standard deviation (PSD)) and graphical (cumulative defect (Bebie) curves) indices were computed. Reproducibility (coefficient of repeatability, CoR) of these indices was assessed. Cluster analysis was carried out to identify patterns of visual field deficits. RESULTS: The intrasession reproducibility was lower for the mean defect as compared with the mean deviation (CoR (dB) 2.67 vs 2.57 for mesopic, 1.71 vs 1.45 for dark-adapted cyan, 1.94 vs 1.87 for dark-adapted red testing) and lower for the square-root loss variance as compared with the PSD (CoR (dB) 1.48 vs 1.34, 0.77 vs 0.65, 1.23 vs 1.03). Hierarchical cluster analysis of the indices disclosed six patterns of visual field deficits (approximately unbiased P value>0.95) with varying degrees of global versus focal defect and rod versus cone dysfunction. These were also reflected by the cumulative defect curves. CONCLUSION: FCP with mesopic and dark adapted two-colour testing allows for reproducible assessment of different types of retinal sensitivity, whereby mean deviation and PSD exhibited the better retest reliability of the tested indices. Distinct patterns of retinal dysfunction can be identified using this setup, reflecting variable degrees of rod and cone dysfunction in different macular diseases. Dark-adapted two-colour FCP provides additional diagnostic information and allows for refined structure function correlation in macular diseases. PMID- 29146760 TI - Blepharitis as an early sign of metabolic syndrome: a nationwide population-based study. AB - BACKGROUND: To investigate the relationship between blepharitis and metabolic syndrome (MetS) by using the Longitudinal Health Insurance Database (LHID) of Taiwan. METHODS: This retrospective cohort study was conducted using data collected from the LHID for the period from 2009 to 2013. This study enrolled patients who received a diagnosis of blepharitis according to the International Classification of Diseases, Ninth Revision, diagnostic code. The exclusion criteria were legal blindness, eyeball removal, ocular tumours prior to the diagnosis of blepharitis, and patients diagnosed with blepharitis and initiated antibiotic treatment concurrently. An age-matched, gender-matched and disease matched population without blepharitis served as the control group. Multivariate analysis with a multiple Cox regression model was applied to analyse the data. RESULTS: In this study, a total of 10 093 patients with blepharitis were included in the study group, and another 40 372 participants without blepharitis were included in the control group. Conditional logistic regression revealed a higher cumulative probability of hyperlipidaemia and coronary arterial disease. After adjustment, patients with blepharitis had a higher probability of developing new MetS than controls. According to subgroup analysis, hyperlipidaemia and coronary artery diseases were significantly correlated with the prior development of blepharitis. However, hypertension and diabetes mellitus and insulin resistance showed no correlation with blepharitis. CONCLUSION: Blepharitis is significantly related to MetS and can serve as an early sign of MetS. Additional studies should examine the relationship between blepharitis and MetS in terms of severity. PMID- 29146761 TI - Comparison among adjuvant treatments for primary pterygium: a network meta analysis. AB - PURPOSE: Pterygium is a frequent ocular disease, where the major challenge is the high level of recurrence after its surgical removal. We performed a network meta analysis to identify, among several adjuvant treatments for primary pterygium, which is the best to prevent recurrence. METHODS: A search was conducted using PubMed, Scientific Electronic Library Online, Latin American and Caribbean Centre on Health Sciences and Cochrane Eyes and Vision Group Trials Register between 1993 and 2015 for randomisedclinical trials (RCTs) comparing adjuvant treatments following primary pterygium surgery. RESULTS: 24 RCTs that studied 1815 eyes of 1668 patients were included and allowed direct and indirect comparison among 14 interventions through network meta-analysis. The rank from the best to worse treatment to prevent recurrence is: conjunctival autograft + ciclosporin 0.05% eye drops, bare sclera + intraoperativemitomycin C (MMC) <0.02%, bare sclera + beta therapy (2500 cGy single dose), conjunctival autograft + beta therapy (1000 cGy single dose), bare sclera + MMC 0.02% eye drops, conjunctival autograft, bare sclera + intraoperative MMC >0.02%, bare sclera + ciclosporin 0.05% eye drops, bare sclera + intraoperative 5-fluorouracil 5%, amniotic membrane transplantation, bare sclera + intraoperative MMC 0.02%, conjunctival autograft + bevacizumab 0.05% eye drops, bare sclera + bevacizumab 0.05% eye drops and bare sclera alone. CONCLUSION: The best adjuvant treatment to prevent recurrence after primary pterygium surgery is the association of conjunctival autograft and ciclosporin 0.05% eye drops. Bare sclera technique alone should be discontinued since it is associated with high recurrence rates. PMID- 29146762 TI - Natural history of primary paediatric optic nerve sheath meningioma: case series and review. AB - PURPOSE: To study the natural history, clinical and radiological characteristics of primary paediatric optic nerve sheath meningioma (PPONSM). METHODS: Retrospective study of eight paediatric patients who were treated between 1994 and 2016 at the University Hospital Zurich, Switzerland and the Royal Adelaide Hospital, Australia. Clinical records and imaging studies were reviewed. RESULTS: The mean age at presentation was 11 years (range: 6-17 years). There were six female patients and two male patients. 2/8 patients had associated neurofibromatosis type 2. Patients were followed up for 71-297 months (mean 156+/ 70 months). 6/8 patients were observed through the course of their disease and 2/8 patients were treated with radiotherapy. 2/8 patients who were observed had minimal change in vision and did not experience tumour growth after long-term follow-up. CONCLUSIONS: This is the largest PPONSM case series with long-term data on patients treated conservatively. We highlight that a small subset of these tumours are indolent and can be managed using observation alone. PMID- 29146763 TI - Routine supplementary oxygen for the normoxic patient with suspected acute myocardial infarction is no longer warranted. PMID- 29146764 TI - What is a case study? PMID- 29146765 TI - Social media supremacy: a force of change paving the way for the next generation of healthcare and research. PMID- 29146767 TI - Pharmacists delivered 60% more flu vaccines through NHS scheme last winter, figures show. PMID- 29146766 TI - Lipid droplet biogenesis is spatially coordinated at ER-vacuole contacts under nutritional stress. AB - Eukaryotic cells store lipids in cytosolic organelles known as lipid droplets (LDs). Lipid droplet bud from the endoplasmic reticulum (ER), and may be harvested by the vacuole for energy during prolonged periods of starvation. How cells spatially coordinate LD production is poorly understood. Here, we demonstrate that yeast ER-vacuole contact sites (NVJs) physically expand in response to metabolic stress, and serve as sites for LD production. NVJ tether Mdm1 demarcates sites of LD budding, and interacts with fatty acyl-CoA synthases at the NVJ periphery. Artificially expanding the NVJ through over-expressing Mdm1 is sufficient to drive NVJ-associated LD production, whereas ablating the NVJ induces defects in fatty acid-to-triglyceride production. Collectively, our data suggest a tight metabolic link between nutritional stress and LD biogenesis that is spatially coordinated at ER-vacuole contact sites. PMID- 29146768 TI - Adhesive performance of tropical arboreal ants varies with substrate temperature. AB - The surface temperature of tree branches in the tropical rainforest canopy can reach up to 55 degrees C. Ants and other small cursorial organisms must maintain adequate attachment in this extreme microenvironment to forage effectively and avoid falling. Ant adhesion depends on liquid secretions that should become less viscous at high temperatures, causing ants to slip. However, tropical arboreal ants have high thermal tolerance and actively forage on hot canopy surfaces, suggesting that these ants can maintain adhesion on hot substrates. We measured tarsal pad shear adhesion of 580 workers (representing 11 species and four subfamilies) of tropical arboreal ants at temperatures spanning the range observed in the field (23-55 degrees C). Adhesive performance among species showed three general trends: (1) a linear decrease with increasing temperature, (2) a non-linear relationship with peak adhesive performance at ca. 30-40 degrees C, and (3) no relationship with temperature. The mechanism responsible for these large interspecific differences remains to be determined, but likely reflects variation in the composition of the secreted adhesive fluid. Understanding such differences will reveal the diverse ways that ants cope with highly variable, and often unpredictable, thermal conditions in the forest canopy. PMID- 29146769 TI - The interaction of path integration and terrestrial visual cues in navigating desert ants: what can we learn from path characteristics? AB - Ant foragers make use of multiple navigational cues to navigate through the world and the combination of innate navigational strategies and the learning of environmental information is the secret to their navigational success. We present here detailed information about the paths of Cataglyphis fortis desert ants navigating by an innate strategy, namely path integration. Firstly, we observed that the ants' walking speed decreases significantly along their homing paths, such that they slow down just before reaching the goal, and maintain a slower speed during subsequent search paths. Interestingly, this drop in walking speed is independent of absolute home-vector length and depends on the proportion of the home vector that has been completed. Secondly, we found that ants are influenced more strongly by novel or altered visual cues the further along the homing path they are. These results suggest that path integration modulates speed along the homing path in a way that might help ants search for, utilise or learn environmental information at important locations. Ants walk more slowly and sinuously when encountering novel or altered visual cues and occasionally stop and scan the world; this might indicate the re-learning of visual information. PMID- 29146770 TI - Environmental, population and life-stage plasticity in the visual system of Atlantic cod. AB - The visual system is for many fishes essential in guiding behaviors, such as foraging, predator avoidance and mate choice. The marine environment is characterized by large spatio-temporal fluctuations in light intensity and spectral composition. However, visual capabilities are restricted by both space limitations set by eye size and by the genomic content of light-absorbing opsin genes. The rich array of visual opsins in teleosts may be used differentially to tune vision towards specific needs during ontogeny and to changing light. Yet, to what extent visual plasticity is a pre-programmed developmental event, or is triggered by photic environment, is unclear. Our previous studies on Atlantic cod revealed an evolutionary genomic loss of UV-sensitive sws1 and red-sensitive lws opsin families, while blue-sensitive sws2 and green-sensitive rh2 opsins had duplicated. The current study has taken an opsin expression approach to characterize visual plasticity in cod towards different spectral light during the larval stage, to maturation and extreme seasonal changes in the Barents Sea. Our data suggest that opsin plasticity in cod larvae is controlled by developmental programme rather than immediate light environment. The lack of expressional changes during maturation suggests a less important role for visual modulation related to mate choice. Although no seasonal effects on visual opsins were detected in migratory Northeast Arctic cod, the expressed opsin subset differed from the more stationary Norwegian coastal cod described in previous studies. Interestingly, these data provide the first indications of a population difference in actively used visual opsins associated with cod ecotypes. PMID- 29146771 TI - Odor source localization in complex visual environments by fruit flies. AB - Flying insects routinely forage in complex and cluttered sensory environments. Their search for a food or a pheromone source typically begins with a whiff of odor, which triggers a flight response, eventually bringing the insect near the odor source. However, pinpointing the precise location of an odor source requires use of both visual and olfactory modalities, aided by odor plumes. Here, we investigated odor-tracking behavior in fruit flies (Drosophila melanogaster) presented with low- or high-contrast visual landmarks, either paired with or separate from an attractive odor cue. These experiments were conducted either in a gentle air stream which generated laminar odor plumes or in still air in which odor dissipates uniformly in all directions. Trajectories of flies revealed several novel features of their odor-tracking behavior in addition to those previously documented. First, in both moving and still air, odor-seeking flies rely on the co-occurrence of visual landmarks with olfactory cues to guide them to odorant objects. Second, flies abruptly decelerate upon encountering an odor plume, thereafter steering towards the nearest visual objects that had no inherent salience in the absence of odor. Thus, interception of an attractive odor increases their salience to nearby high-contrast visual landmarks. Third, flies adopt distinct odor-tracking strategies during flight in moving versus still air. Whereas they weave in and out of plumes towards an odor source in airflow, their approach is more incremental in still air. Both strategies are robust and flexible, and enable flies to reliably find odor sources under diverse visual and airflow environments. PMID- 29146774 TI - Split hand/foot malformation: a potential clue to underlying FGFR1 mutation in patients with isolated congenital hypogonadotropic hypogonadism. PMID- 29146772 TI - Cre-dependent Cas9-expressing pigs enable efficient in vivo genome editing. AB - Despite being time-consuming and costly, generating genome-edited pigs holds great promise for agricultural, biomedical, and pharmaceutical applications. To further facilitate genome editing in pigs, we report here establishment of a pig line with Cre-inducible Cas9 expression that allows a variety of ex vivo genome editing in fibroblast cells including single- and multigene modifications, chromosome rearrangements, and efficient in vivo genetic modifications. As a proof of principle, we were able to simultaneously inactivate five tumor suppressor genes (TP53, PTEN, APC, BRCA1, and BRCA2) and activate one oncogene (KRAS), achieved by delivering Cre recombinase and sgRNAs, which caused rapid lung tumor development. The efficient genome editing shown here demonstrates that these pigs can serve as a powerful tool for dissecting in vivo gene functions and biological processes in a temporal manner and for streamlining the production of genome-edited pigs for disease modeling. PMID- 29146773 TI - Glyoxal as an alternative fixative to formaldehyde in immunostaining and super resolution microscopy. AB - Paraformaldehyde (PFA) is the most commonly used fixative for immunostaining of cells, but has been associated with various problems, ranging from loss of antigenicity to changes in morphology during fixation. We show here that the small dialdehyde glyoxal can successfully replace PFA Despite being less toxic than PFA, and, as most aldehydes, likely usable as a fixative, glyoxal has not yet been systematically tried in modern fluorescence microscopy. Here, we tested and optimized glyoxal fixation and surprisingly found it to be more efficient than PFA-based protocols. Glyoxal acted faster than PFA, cross-linked proteins more effectively, and improved the preservation of cellular morphology. We validated glyoxal fixation in multiple laboratories against different PFA-based protocols and confirmed that it enabled better immunostainings for a majority of the targets. Our data therefore support that glyoxal can be a valuable alternative to PFA for immunostaining. PMID- 29146775 TI - Division Plane Orientation Defects Revealed by a Synthetic Double Mutant Phenotype. AB - TANGLED1 (TAN1) and AUXIN-INDUCED-IN-ROOTS9 (AIR9) are microtubule-binding proteins that localize to the division site in plants. Their function in Arabidopsis (Arabidopsis thaliana) remained unclear because neither tan1 nor air9 single mutants have a strong phenotype. We show that tan1 air9 double mutants have a synthetic phenotype consisting of short, twisted roots with disordered cortical microtubule arrays that are hypersensitive to a microtubule depolymerizing drug. The tan1 air9 double mutants have significant defects in division plane orientation due to failures in placing the new cell wall at the correct division site. Full-length TAN1 fused to yellow fluorescent protein, TAN1 YFP, and several deletion constructs were transformed into the double mutant to assess which regions of TAN1 are required for its function in root growth, root twisting, and division plane orientation. TAN1-YFP expressed in tan1 air9 significantly rescued the double mutant phenotype in all three respects. Interestingly, TAN1 missing the first 126 amino acids, TAN1-DeltaI-YFP, failed to rescue the double mutant phenotype, while TAN1 missing a conserved middle region, TAN1-DeltaII-YFP, significantly rescued the mutant phenotype in terms of root growth and division plane orientation but not root twisting. We use the tan1 air9 double mutant to discover new functions for TAN1 and AIR9 during phragmoplast guidance and root morphogenesis. PMID- 29146776 TI - Light Signaling-Dependent Regulation of Photoinhibition and Photoprotection in Tomato. AB - Photoreceptor-mediated light signaling plays a critical role in plant growth, development, and stress responses but its contribution to the spatial regulation of photoinhibition and photoprotection within the canopy remains unclear. Here, we show that low-red/far-red (L-R/FR) ratio light conditions significantly alleviate PSII and PSI photoinhibition in the shade leaves of tomato (Solanum lycopersicum) plants. This protection is accompanied by a phytochrome A-dependent induction of LONG HYPOCOTYL5 (HY5). HY5 binds to the promoter of ABA INSENSITIVE5 (ABI5), triggering RESPIRATORY BURST OXIDASE HOMOLOG1 (RBOH1)-dependent H2O2 production in the apoplast. Decreased levels of HY5, ABI5, and RBOH1 transcripts increased cold-induced photoinhibition and abolished L-R/FR-induced alleviation of photoinhibition. L-R/FR illumination induced nonphotochemical quenching (NPQ) of chlorophyll a fluorescence and increased the activities of Foyer-Halliwell Asada cycle enzymes and cyclic electron flux (CEF) around PSI. In contrast, decreased HY5, ABI5, and RBOH1 transcript levels abolished the positive effect of L-R/FR on photoprotection. Loss of PROTON GRADIENT REGULATION5-dependent CEF led to increased photoinhibition and attenuated L-R/FR-dependent NPQ. These data demonstrate that HY5 is an important hub in the cross talk between light and cold response pathways, integrating ABA and reactive oxygen species signaling, leading to the attenuation of photoinhibition by enhanced induction of photoprotection in shade leaves. PMID- 29146778 TI - Small vulnerable sets determine large network cascades in power grids. AB - The understanding of cascading failures in complex systems has been hindered by the lack of realistic large-scale modeling and analysis that can account for variable system conditions. Using the North American power grid, we identified, quantified, and analyzed the set of network components that are vulnerable to cascading failures under any out of multiple conditions. We show that the vulnerable set consists of a small but topologically central portion of the network and that large cascades are disproportionately more likely to be triggered by initial failures close to this set. These results elucidate aspects of the origins and causes of cascading failures relevant for grid design and operation and demonstrate vulnerability analysis methods that are applicable to a wider class of cascade-prone networks. PMID- 29146777 TI - Comment on "The extent of forest in dryland biomes". AB - Bastin et al (Reports, 12 May 2017, p. 635) infer forest as more globally extensive than previously estimated using tree cover data. However, their forest definition does not reflect ecosystem function or biotic composition. These structural and climatic definitions inflate forest estimates across the tropics and undermine conservation goals, leading to inappropriate management policies and practices in tropical grassy ecosystems. PMID- 29146779 TI - Erratum for the Report "Experimental measurement of binding energy, selectivity, and allostery using fluctuation theorems" by J. Camunas-Soler, A. Alemany, F. Ritort. PMID- 29146780 TI - Erratum for the Report "Biological fabrication of cellulose fibers with tailored properties" by F. Natalio, R. Fuchs, S. R. Cohen, G. Leitus, G. Fritz-Popovski, O. Paris, M. Kappl, H.-J. Butt. PMID- 29146782 TI - Beyond plastic waste. PMID- 29146781 TI - Self-assembling peptide semiconductors. AB - Semiconductors are central to the modern electronics and optics industries. Conventional semiconductive materials bear inherent limitations, especially in emerging fields such as interfacing with biological systems and bottom-up fabrication. A promising candidate for bioinspired and durable nanoscale semiconductors is the family of self-assembled nanostructures comprising short peptides. The highly ordered and directional intermolecular pi-pi interactions and hydrogen-bonding network allow the formation of quantum confined structures within the peptide self-assemblies, thus decreasing the band gaps of the superstructures into semiconductor regions. As a result of the diverse architectures and ease of modification of peptide self-assemblies, their semiconductivity can be readily tuned, doped, and functionalized. Therefore, this family of electroactive supramolecular materials may bridge the gap between the inorganic semiconductor world and biological systems. PMID- 29146784 TI - 'Biased' opioids could yield safer pain relief. PMID- 29146785 TI - 'David and Goliath' weather eyes set for launch. PMID- 29146786 TI - Livestock drove ancient Old World inequality. PMID- 29146787 TI - After failed rescue effort, rare porpoise in extreme peril. PMID- 29146788 TI - Autoimmune diseases surface after cancer treatment. PMID- 29146789 TI - Ancient Australian goes home. PMID- 29146790 TI - Oldest images of dogs show hunting, leashes. PMID- 29146791 TI - A change of mind. PMID- 29146792 TI - Curtailing cascading failures. PMID- 29146793 TI - Feeding frenzy for cancer cells. PMID- 29146794 TI - Evolution of neurovirulent Zika virus. PMID- 29146795 TI - Advancing dengue vaccine development. PMID- 29146796 TI - Skin color variation in Africa. PMID- 29146797 TI - The promise of plastics from plants. PMID- 29146798 TI - The future of plastics recycling. PMID- 29146799 TI - Designed to degrade. PMID- 29146800 TI - Racing for academic glory and patents: Lessons from CRISPR. PMID- 29146801 TI - Greenland: Build an economy on sand. PMID- 29146802 TI - Bluefin tuna science remains vague. PMID- 29146803 TI - Romanian ecosystems need EU protection. PMID- 29146804 TI - Response to Comment on "The extent of forest in dryland biomes". AB - Griffith et al do not question the quality of our analysis, but they question our results with respect to the definition of forest we employed. In our response, we explain why the differences we report result from a difference of technique and not of definition, and how anyone can adapt-as we did-our data set to any forest definition and tree cover threshold of interest. PMID- 29146806 TI - Full momentum- and energy-resolved spectral function of a 2D electronic system. AB - The single-particle spectral function measures the density of electronic states in a material as a function of both momentum and energy, providing central insights into strongly correlated electron phenomena. Here we demonstrate a high resolution method for measuring the full momentum- and energy-resolved electronic spectral function of a two-dimensional (2D) electronic system embedded in a semiconductor. The technique remains operational in the presence of large externally applied magnetic fields and functions even for electronic systems with zero electrical conductivity or with zero electron density. Using the technique on a prototypical 2D system, a GaAs quantum well, we uncover signatures of many body effects involving electron-phonon interactions, plasmons, polarons, and a phonon analog of the vacuum Rabi splitting in atomic systems. PMID- 29146805 TI - The structural basis of flagellin detection by NAIP5: A strategy to limit pathogen immune evasion. AB - Robust innate immune detection of rapidly evolving pathogens is critical for host defense. Nucleotide-binding domain leucine-rich repeat (NLR) proteins function as cytosolic innate immune sensors in plants and animals. However, the structural basis for ligand-induced NLR activation has so far remained unknown. NAIP5 (NLR family, apoptosis inhibitory protein 5) binds the bacterial protein flagellin and assembles with NLRC4 to form a multiprotein complex called an inflammasome. Here we report the cryo-electron microscopy structure of the assembled ~1.4-megadalton flagellin-NAIP5-NLRC4 inflammasome, revealing how a ligand activates an NLR. Six distinct NAIP5 domains contact multiple conserved regions of flagellin, prying NAIP5 into an open and active conformation. We show that innate immune recognition of multiple ligand surfaces is a generalizable strategy that limits pathogen evolution and immune escape. PMID- 29146807 TI - Tunable excitons in bilayer graphene. AB - Excitons, the bound states of an electron and a hole in a solid material, play a key role in the optical properties of insulators and semiconductors. Here, we report the observation of excitons in bilayer graphene (BLG) using photocurrent spectroscopy of high-quality BLG encapsulated in hexagonal boron nitride. We observed two prominent excitonic resonances with narrow line widths that are tunable from the mid-infrared to the terahertz range. These excitons obey optical selection rules distinct from those in conventional semiconductors and feature an electron pseudospin winding number of 2. An external magnetic field induces a large splitting of the valley excitons, corresponding to a g-factor of about 20. These findings open up opportunities to explore exciton physics with pseudospin texture in electrically tunable graphene systems. PMID- 29146809 TI - Compacted dimensions and singular plasmonic surfaces. AB - In advanced field theories, there can be more than four dimensions to space, the excess dimensions described as compacted and unobservable on everyday length scales. We report a simple model, unconnected to field theory, for a compacted dimension realized in a metallic metasurface periodically structured in the form of a grating comprising a series of singularities. An extra dimension of the grating is hidden, and the surface plasmon excitations, though localized at the surface, are characterized by three wave vectors rather than the two of typical two-dimensional metal grating. We propose an experimental realization in a doped graphene layer. PMID- 29146810 TI - Catalytic molten metals for the direct conversion of methane to hydrogen and separable carbon. AB - Metals that are active catalysts for methane (Ni, Pt, Pd), when dissolved in inactive low-melting temperature metals (In, Ga, Sn, Pb), produce stable molten metal alloy catalysts for pyrolysis of methane into hydrogen and carbon. All solid catalysts previously used for this reaction have been deactivated by carbon deposition. In the molten alloy system, the insoluble carbon floats to the surface where it can be skimmed off. A 27% Ni-73% Bi alloy achieved 95% methane conversion at 1065 degrees C in a 1.1-meter bubble column and produced pure hydrogen without CO2 or other by-products. Calculations show that the active metals in the molten alloys are atomically dispersed and negatively charged. There is a correlation between the amount of charge on the atoms and their catalytic activity. PMID- 29146811 TI - State-to-state chemistry for three-body recombination in an ultracold rubidium gas. AB - Experimental investigation of chemical reactions with full quantum state resolution for all reactants and products has been a long-term challenge. Here we prepare an ultracold few-body quantum state of reactants and demonstrate state-to state chemistry for the recombination of three spin-polarized ultracold rubidium (Rb) atoms to form a weakly bound Rb2 molecule. The measured product distribution covers about 90% of the final products, and we are able to discriminate between product states with a level splitting as small as 20 megahertz multiplied by Planck's constant. Furthermore, we formulate propensity rules for the distribution of products, and we develop a theoretical model that predicts many of our experimental observations. The scheme can readily be adapted to other species and opens a door to detailed investigations of inelastic or reactive processes. PMID- 29146808 TI - Extended gamma-ray sources around pulsars constrain the origin of the positron flux at Earth. AB - The unexpectedly high flux of cosmic-ray positrons detected at Earth may originate from nearby astrophysical sources, dark matter, or unknown processes of cosmic-ray secondary production. We report the detection, using the High-Altitude Water Cherenkov Observatory (HAWC), of extended tera-electron volt gamma-ray emission coincident with the locations of two nearby middle-aged pulsars (Geminga and PSR B0656+14). The HAWC observations demonstrate that these pulsars are indeed local sources of accelerated leptons, but the measured tera-electron volt emission profile constrains the diffusion of particles away from these sources to be much slower than previously assumed. We demonstrate that the leptons emitted by these objects are therefore unlikely to be the origin of the excess positrons, which may have a more exotic origin. PMID- 29146812 TI - Evolution of flower color pattern through selection on regulatory small RNAs. AB - Small RNAs (sRNAs) regulate genes in plants and animals. Here, we show that population-wide differences in color patterns in snapdragon flowers are caused by an inverted duplication that generates sRNAs. The complexity and size of the transcripts indicate that the duplication represents an intermediate on the pathway to microRNA evolution. The sRNAs repress a pigment biosynthesis gene, creating a yellow highlight at the site of pollinator entry. The inverted duplication exhibits steep clines in allele frequency in a natural hybrid zone, showing that the allele is under selection. Thus, regulatory interactions of evolutionarily recent sRNAs can be acted upon by selection and contribute to the evolution of phenotypic diversity. PMID- 29146813 TI - Structural basis of bacterial transcription activation. AB - In bacteria, the activation of gene transcription at many promoters is simple and only involves a single activator. The cyclic adenosine 3',5'-monophosphate receptor protein (CAP), a classic activator, is able to activate transcription independently through two different mechanisms. Understanding the class I mechanism requires an intact transcription activation complex (TAC) structure at a high resolution. Here we report a high-resolution cryo-electron microscopy structure of an intact Escherichia coli class I TAC containing a CAP dimer, a sigma70-RNA polymerase (RNAP) holoenzyme, a complete class I CAP-dependent promoter DNA, and a de novo synthesized RNA oligonucleotide. The structure shows how CAP wraps the upstream DNA and how the interactions recruit RNAP. Our study provides a structural basis for understanding how activators activate transcription through the class I recruitment mechanism. PMID- 29146815 TI - Science in 17 syllables. PMID- 29146816 TI - Miss Piggy on the catwalk again. PMID- 29146814 TI - Natural selection shaped the rise and fall of passenger pigeon genomic diversity. AB - The extinct passenger pigeon was once the most abundant bird in North America, and possibly the world. Although theory predicts that large populations will be more genetically diverse, passenger pigeon genetic diversity was surprisingly low. To investigate this disconnect, we analyzed 41 mitochondrial and 4 nuclear genomes from passenger pigeons and 2 genomes from band-tailed pigeons, which are passenger pigeons' closest living relatives. Passenger pigeons' large population size appears to have allowed for faster adaptive evolution and removal of harmful mutations, driving a huge loss in their neutral genetic diversity. These results demonstrate the effect that selection can have on a vertebrate genome and contradict results that suggested that population instability contributed to this species's surprisingly rapid extinction. PMID- 29146817 TI - Relapsed/refractory HL: FDG-PET is the trump card. PMID- 29146818 TI - Mutant RUNX1 and histone tales. PMID- 29146819 TI - Subphenotypes of sickle cell disease in Africa. PMID- 29146820 TI - Platelet CLEC-2: a molecule with 2 faces. PMID- 29146821 TI - Leukemic presentation of diffuse large B-cell lymphoma: an unusual pattern associated with splenic involvement. PMID- 29146823 TI - Diffuse large B-cell lymphoma in the elderly. PMID- 29146822 TI - Nasrallah R, Fast EM, Solaimani P, et al. Identification of novel regulators of developmental hematopoiesis using Endoglin regulatory elements as molecular probes. Blood. 2016;128(15):1928-1939. PMID- 29146824 TI - Doctors in India still carry out "two finger test" on rape victims. PMID- 29146825 TI - Toroidal plasmoid generation via extreme hydrodynamic shear. AB - Saint Elmo's fire and lightning are two known forms of naturally occurring atmospheric pressure plasmas. As a technology, nonthermal plasmas are induced from artificially created electromagnetic or electrostatic fields. Here we report the observation of arguably a unique case of a naturally formed such plasma, created in air at room temperature without external electromagnetic action, by impinging a high-speed microjet of deionized water on a dielectric solid surface. We demonstrate that tribo-electrification from extreme and focused hydrodynamic shear is the driving mechanism for the generation of energetic free electrons. Air ionization results in a plasma that, unlike the general family, is topologically well defined in the form of a coherent toroidal structure. Possibly confined through its self-induced electromagnetic field, this plasmoid is shown to emit strong luminescence and discrete-frequency radio waves. Our experimental study suggests the discovery of a unique platform to support experimentation in low-temperature plasma science. PMID- 29146827 TI - News Feature: The genuine problem of fake news. PMID- 29146828 TI - John Allcock and a brief history of Allcock's test. PMID- 29146826 TI - Social preferences of future physicians. AB - We measure the social preferences of a sample of US medical students and compare their preferences with those of the general population sampled in the American Life Panel (ALP). We also compare the medical students with a subsample of highly educated, wealthy ALP subjects as well as elite law school students and undergraduate students. We further associate the heterogeneity in social preferences within medical students to the tier ranking of their medical schools and their expected specialty choice. Our experimental design allows us to rigorously distinguish altruism from preferences regarding equality-efficiency tradeoffs and accurately measure both at the individual level rather than pooling data or assuming homogeneity across subjects. This is particularly informative, because the subjects in our sample display widely heterogeneous social preferences in terms of both their altruism and equality-efficiency tradeoffs. We find that medical students are substantially less altruistic and more efficiency focused than the average American. Furthermore, medical students attending the top-ranked medical schools are less altruistic than those attending lower-ranked schools. We further show that the social preferences of those attending top ranked medical schools are statistically indistinguishable from the preferences of a sample of elite law school students. The key limitation of this study is that our experimental measures of social preferences have not yet been externally validated against actual physician practice behaviors. Pending this future research, we probed the predictive validity of our experimental measures of social preferences by showing that the medical students choosing higher-paying medical specialties are less altruistic than those choosing lower-paying specialties. PMID- 29146829 TI - Is bridging therapy still required in stroke due to carotid artery terminus occlusions? AB - INTRODUCTION: Studies comparing endovascular stroke treatment using mechanical thrombectomy (MT) with or without prior IV tissue plasminogen activator (tPa) have included only 30% of internal carotid artery terminus occlusions (ICA-O), a known predictor of recanalization failure with IV tPa. OBJECTIVE: To carry out a retrospective multicenter analysis of prospectively collected data of consecutive patients to investigate the impact of intravenous thrombolysis on ICA-O by comparing patients treated with MT alone or bridging therapy (BT). MATERIAL AND METHODS: Patients with ICA-O treated with MT alone or BT were retrospectively examined and compared. Demographic data, vascular risk factors, treatment modalities, complications, technical and clinical outcomes were recorded. A propensity score (PS) analysis was used to compare modified Rankin Scale (mRS) score at 3 months and intracerebral hemorrhage (ICH) between groups. RESULTS: 141 consecutive patients (60% BT/40% MT) were included between January 2014 and June 2016. Baseline characteristics did not differ between the groups. There was no significant difference in the rate of Thrombolysis in Cerebral Infarction 2b/3, distal emboli, and median number of passes between the groups. There was a significant difference between BT and MT groups in the median time between imaging and groin puncture (median 97 min vs 75, p=0.007), the rate of ICH (44% vs 27%, p=0.05), but not for symptomatic ICH (18% vs 13%, p=0.49). With PS, there was a trend towards a higher rate of ICH (OR=2.3, 95% CI 0.9 to 5.9, p=0.09) in the BT group compared with the MT alone group, with no difference in mRS score <=2 at 3 months (OR=1.6, 95% CI 0.7 to 3.7, p=0.29). CONCLUSION: There was no significant difference in clinical outcomes between patients receiving bridging therapy versus direct thrombectomy. Bridging therapy delayed time to groin puncture and increased ICH rate. PMID- 29146830 TI - Mechanical thrombectomy performs similarly in real world practice: a 2016 nationwide study from the Czech Republic. AB - BACKGROUND: Randomized clinical trials have proven mechanical thrombectomy (MT) to be a highly effective and safe treatment in acute stroke. The purpose of this study was to compare neurothrombectomy data from the Czech Republic (CR) with data from the HERMES meta-analysis. METHODS: Available nationwide data for the CR from 2016 from the Safe Implementation of Treatments in Stroke-Thrombectomy (SITS TBY) registry for patients with terminal internal carotid artery (ICA) and/or middle cerebral artery (MCA) occlusions were compared with data from HERMES. CR and HERMES patients were comparable in age, sex, and baseline National Institutes of Health Stroke Scale scores. RESULTS: From a total of 1053 MTs performed in the CR, 845 (80%) were reported in the SITS-TBY. From these, 604 (72%) were included in this study. Occlusion locations were as follows (CR vs HERMES): ICA 22% versus 21% (P=0.16), M1 MCA 62% versus 69% (P=0.004), and M2 MCA 16% versus 8% (P<0.0001). Intravenous thrombolysis was given to 76% versus 83% of patients, respectively (P=0.003). Median onset to reperfusion times were comparable: 232 versus 285 min, respectively (P=0.66). A modified Thrombolysis in Cerebral Infarction score of 2b/3 was achieved in 74% (433/584) versus 71% (390/549) of patients, respectively (OR 1.17, 95% CI 0.90-1.5, P=0.24). There was no statistically significant difference in the percentage of parenchymalhematoma type 2 (OR 1.12, 95% CI 0.66-1.90, P=0.68). A modified Rankin Scale score of 0-2 at 3 months was achieved in 48% (184/268) versus 46% (291/633) of patients, respectively (OR 0.92, 95% CI 0.71-1.18, P=0.48). CONCLUSIONS: Data on efficacy, safety, and logistics of MT from the CR were similar to data from the HERMES collaboration. PMID- 29146831 TI - Stent-assisted coiling of cerebral aneurysms: a single-center clinical and angiographic analysis. AB - OBJECTIVE: This study retrospectively compared the clinical and angiographic outcomes of treating cerebral aneurysms with Neuroform (NEU), Enterprise (EP), and Low-profile Visualized Intraluminal Support (LVIS/LVIS Jr) stents. MATERIALS AND METHODS: We conducted a retrospective analysis of a procedural database. All aneurysm procedures using any of the three types of self-expanding nitinol stents (NEU, EP and LVIS/LVIS Jr) were included. Intra-procedure complications, post procedure complications, and angiographic results (Raymond-Roy grade scale, RRGS) were analyzed retrospectively. A multivariate logistic regression analysis was conducted to identify predictors of intra-procedure and post-procedure complications. RESULTS: Two hundred and forty-three aneurysms in 229 patients treated with stent-assisted coiling were included (NEU group: 109 aneurysms; EP group: 61 aneurysms; LVIS/LVIS Jr: 73 aneurysms). The LVIS/LVIS Jr group was associated with the lowest rate of initial complete occlusion (RRGS I: 47.9%; 35/73). Follow-up showed the proportion of RRGS I increased for all stent groups but was greatest in the LVIS/LVIS Jr group. Overall, 17 intra-procedural complications were seen in 229 patients (7.4%) and 15 post-procedural complications were found in 198 patients at follow-up (7.6%), with no differences between stent groups. Thrombotic events were the most common complications and occurred in 13 patients (13/229, 5.7%). CONCLUSIONS: All three types of stents used to treat cerebral aneurysms with unfavorable neck were safe and effective, providing suitable support for the coil mass. LVIS/LVIS Jr promotes better progressive aneurysm complete occlusion than the other two stents but seems to cause more common intra-procedural stent-related thrombotic events and fewer post procedural complications. PMID- 29146832 TI - He was brought in blue... with an LVAD. PMID- 29146833 TI - Draft Genome Sequences of Eight Streptogramin-Resistant Enterococcus Species Isolated from Animal and Environmental Sources in the United States. AB - Here, we present the draft genome sequences of eight streptogramin-resistant Enterococcus species isolated from animals and an environmental source in the United States from 2001 to 2004. Antimicrobial resistance genes were identified conferring resistance to the macrolide-lincosamide-streptogramins, aminoglycosides, tetracyclines, beta-lactams, and glycopeptides. PMID- 29146834 TI - Draft Genome Sequence of Carbapenemase-Producing Serratia marcescens Isolated from a Patient with Chronic Obstructive Pulmonary Disease. AB - The occurrence of multidrug-resistant Serratia marcescens strains producing metallo-beta-lactamases or extended-spectrum beta-lactamases represents a serious public health threat. Here, we report the draft genome sequence of a multidrug resistant carbapenemase-producing Serratia marcescens isolate recovered from the bronchoalveolar lavage specimen of a patient suffering from chronic obstructive pulmonary disease (COPD). PMID- 29146835 TI - Complete Genome Sequence of Bacillus cereus C1L, a Plant Growth-Promoting Rhizobacterium from the Rhizosphere of Formosa Lily in Taiwan. AB - Bacillus cereus C1L, a plant growth-promoting rhizobacterium, provides protection against fungal pathogens in monocot plants. To gain new insights into the biocontrol mechanisms used by this rhizobacterium, we determined the complete genome sequence of B. cereus C1L. One chromosome and three plasmids were identified with a total size of ~6.0 Mb. PMID- 29146836 TI - Complete Genome Sequences of BK Polyomavirus Strains from Two Patients with Urinary Tract Infection, Sequenced Using the Ion Torrent Platform. AB - BK polyomavirus is an important pathogen in kidney transplant patients. We report here two complete genome sequences, those of isolates CAMB-1035 and CAMB-1055, identified in two urine samples tested for urinary tract infection at a hospital in eastern England, United Kingdom. Variation and phylogenetic analyses indicate that both isolates belong to subtype Ib-1. PMID- 29146837 TI - Draft Genome Sequence of the Naturally Competent Bacillus simplex Strain WY10. AB - We sequenced a naturally competent bacterial isolate, WY10, cultured from a Wyoming soil sample. Sequence analysis revealed that WY10 is a novel strain of Bacillus simplex To our knowledge, WY10 is the first B. simplex strain to be characterized as naturally competent for DNA uptake by transformation. PMID- 29146838 TI - Retraction for Hong et al., "Whole-Genome De Novo Sequencing of the Lignin Degrading Wood Rot Fungus Phanerochaete chrysosporium (ATCC 20696)". PMID- 29146839 TI - Draft Genome Sequence of Myroides sp. N17-2, a Multidrug-Resistant Bacterium Isolated from Radiation-Polluted Soils. AB - We report here the 4.29-Mb draft genome sequence of Myroides sp. N17-2, a new bacterium isolated from radiation-polluted soils in Xinjiang, Uyghur Autonomous Region, China. The acquisition of its genome will provide valuable information to reveal the relationship between radiation and multidrug resistance. PMID- 29146840 TI - Draft Genome Sequence of the Mucoid Pseudomonas aeruginosa Clinical Isolate PA34. AB - Pseudomonas aeruginosa is a serious threat to patients suffering from cystic fibrosis. These organisms are exposed to a unique set of selective pressures within the lung. Here, we report the draft genome sequence of a mucoid P. aeruginosa clinical isolate obtained from a cystic fibrosis patient colonized with P. aeruginosa. PMID- 29146841 TI - Draft Whole-Genome Sequences of 18 Flavobacterium spp. AB - We report here the draft whole-genome sequences for 18 Flavobacterium species type strains that have historically been associated with fish gill disease. PMID- 29146843 TI - Complete Genome Sequences of Vibrio cholerae-Specific Bacteriophages 24 and X29. AB - The complete genomes of two Vibrio cholerae bacteriophages of potential interest for cholera bacteriophage (phage) therapy were sequenced and annotated. The genome size of phage 24 is 44,395 bp encoding 71 putative proteins, and that of phage X29 is 41,569 bp encoding 68 putative proteins. PMID- 29146844 TI - Complete Genome Sequence of Acetobacter tropicalis Oregon-R-modENCODE Strain BDGP1, an Acetic Acid Bacterium Found in the Drosophila melanogaster Gut. AB - Acetobacter tropicalis Oregon-R-modENCODE strain BDGP1 was isolated from Drosophila melanogaster for functional host-microbe interaction studies. The complete genome comprises a single chromosomal circle of 3,988,649 bp with a G+C content of 56% and a conjugative plasmid of 151,013 bp. PMID- 29146842 TI - Genome Sequences of 19 Novel Erwinia amylovora Bacteriophages. AB - Erwinia amylovora is the causal agent of fire blight, a devastating disease affecting some plants of the Rosaceae family. We isolated bacteriophages from samples collected from infected apple and pear trees along the Wasatch Front in Utah. We announce 19 high-quality complete genome sequences of E. amylovora bacteriophages. PMID- 29146845 TI - Draft Genome Sequences of 23 Salmonella enterica Strains Isolated from Cattle in Ibadan, Nigeria, Representing 21 Salmonella Serovars. AB - To provide a better understanding of the diversity of Salmonella enterica, we report the assembled genome sequences of 23 Salmonella enterica strains isolated from fecal samples of cattle in Nigeria comprising 21 different Salmonella serovars. PMID- 29146846 TI - High-Quality Draft Genome Sequence of "Candidatus Methanoperedens sp." Strain BLZ2, a Nitrate-Reducing Anaerobic Methane-Oxidizing Archaeon Enriched in an Anoxic Bioreactor. AB - The high-quality draft genome of "Candidatus Methanoperedens sp." strain BLZ2, a nitrate-reducing archaeon anaerobically oxidizing methane, is presented. The genome was obtained from an enrichment culture and measures 3.74 Mb. It harbors two nitrate reductase gene clusters, an ammonium-forming nitrite reductase, and the complete reverse methanogenesis pathway. Methane that escapes to the atmosphere acts as a potent greenhouse gas. Global methane emissions are mitigated by methanotrophs, which oxidize methane to CO2 "Candidatus Methanoperedens spp." are unique methanotrophic archaea that can perform nitrate dependent anaerobic oxidation of methane. A high-quality draft genome sequence of only 85 contigs from this archaeon is presented here. PMID- 29146847 TI - Complete Genome Sequence of a Psychrotolerant Denitrifying Bacterium, Janthinobacterium svalbardensis PAMC 27463. AB - We report here the complete genome sequence of Janthinobacterium svalbardensis PAMC 27463 isolated from a freshwater lake on Barton Peninsula on King George Island, Antarctica. The genome consists of a chromosome with 6,274,078 bp which contains 5,585 genes, including 121 RNA genes. PMID- 29146848 TI - Complete Mitochondrial Genome Sequence of the Human Neuroblastoma Cell Line 751 NA. AB - We report here for the first time the 16,566-bp mitochondrial genome sequence of the human neuroblastoma cell line 751-NA. The 13 protein-coding genes, 2 rRNAs, and 22 tRNAs are organized in a virtually identical fashion to a previously reported human mitochondrial genome, except that the 1,136-bp d-loop region is slightly variable between them. PMID- 29146849 TI - Draft Genome Sequence and Annotation of the Apicomplexan Parasite Besnoitia besnoiti. AB - The apicomplexan parasite Besnoitia besnoiti is the causative agent of bovine besnoitiosis that affects livestock, particularly cattle. The definitive host of B. besnoiti is unknown and its transmission only partially understood. Here, we report the first draft genome sequence, assembly, and annotation of this parasite. PMID- 29146850 TI - First Insight into the Genome Sequences of Two Linezolid-Resistant Nocardia farcinica Strains Isolated from Patients with Cystic Fibrosis. AB - The draft genome sequences of two Nocardia farcinica strains isolated from two patients with cystic fibrosis (CF), resistant to trimethoprim/sulfamethoxazole and linezolid, are reported here. The estimated genome sizes were 5.8 Mb with a 70.63% G+C content. Transposases from Tn916 were detected, but not 23S rRNA mutation (G2576T) related to linezolid resistance. PMID- 29146851 TI - Draft Whole-Genome Sequences of Periodontal Pathobionts Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia Contain Phase-Variable Restriction-Modification Systems. AB - Periodontal disease comprises mild to severe inflammatory host responses to oral bacteria that can cause destruction of the tooth-supporting tissue. We report genome sequences for 18 clinical isolates of Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia, Gram-negative obligate anaerobes that play a role in the periodontal disease process. PMID- 29146852 TI - Draft Genome Sequence of Agrobacterium tumefaciens Biovar 1 Strain 186, Isolated from Walnut. AB - Agrobacterium tumefaciens biovar 1 strain 186 was isolated from a walnut tree expressing crown gall symptoms. The draft genome sequence of this strain harbored genes for crown gall formation and will be useful for understanding its virulence on Paradox, the predominant hybrid rootstock used for the cultivation of English walnut in California. PMID- 29146854 TI - Complete Genomic Sequences of Two Salmonella enterica subsp. enterica Serogroup C2 (O:6,8) Strains from Central California. AB - Salmonella enterica subsp. enterica strains RM11060, serotype 6,8:d:-, and RM11065, serotype 6,8:-:e,n,z15, were isolated from environmental samples collected in central California in 2009. We report the complete genome sequences of these two strains. These genomic sequences are distinct and will provide additional data to our understanding of S. enterica genomics. PMID- 29146853 TI - Genome Sequences of Four Subcluster L2 Mycobacterium Phages, Finemlucis, Miley16, Wilder, and Zakai. AB - Four subcluster L2 mycobacteriophages, Finemlucis, Miley16, Wilder, and Zakai, that infect Mycobacterium smegmatis mc2155 were isolated. The four phages are closely related to each other and code for 12 to 14 tRNAs and 130 to 132 putative protein-coding genes, including tyrosine integrases, cro, immunity repressors, and excise genes involved in the establishment of lysogeny. PMID- 29146855 TI - Draft Genome Sequence of Entomopathogenic Brevibacillus laterosporus Strain Lak 1210, an Alkaliphilic Chitin Degrader. AB - We announce here the draft genome sequence of Brevibacillus laterosporus strain Lak 1210, isolated from mangrove soil. This alkaliphilic strain is an efficient chitin degrader and has the ability to control insects and inhibit phytopathogenic fungi. The assembly consists of 5,082,926 bp, with 4,321 protein coding sequences and a GC content of 41.15%. PMID- 29146856 TI - Complete Genome Sequence of Xanthomonas campestris pv. viticola Strain CCRMXCV 80 from Brazil. AB - Here, we report the complete 5.3-Mb genome sequence of Xanthomonas campestris pv. viticola (CCRMXCV 80), which causes grapevine (Vitis vinifera L.) bacterial canker. Genome data will improve our understanding of the strain's comparative genomics and epidemiology, and help to further define plant protection and quarantine procedures. PMID- 29146857 TI - Whole-Genome Sequence of Salmonella enterica subsp. enterica Serovar Typhimurium Strain UPM 260, Isolated from a Broiler Chicken in Perak, Malaysia. AB - Salmonella enterica subsp. enterica serovar Typhimurium is one of several well categorized Salmonella serotypes recognized globally. Here, we report the whole genome sequence of S Typhimurium strain UPM 260, isolated from a broiler chicken. PMID- 29146858 TI - Whole-Genome Shotgun Sequences of Three Multidrug-Resistant Mycobacterium tuberculosis Strains Isolated from Morocco. AB - Tuberculosis is a contagious disease that usually attacks the lungs but sometimes attacks other parts of the body, such as the kidneys, glands, and bones. It is an endemic and major public health problem in Morocco. Tuberculosis is transmitted through the airways via the inhalation of microdroplets containing Mycobacterium tuberculosis We present here the whole-genome shotgun sequences of three multidrug-resistant M. tuberculosis strains isolated from Morocco. PMID- 29146859 TI - Draft Genome Sequence of Saccharomycopsis fodiens CBS 8332, a Necrotrophic Mycoparasite with Biocontrol Potential. AB - Saccharomycopsis fodiens is an ascomycetous necrotrophic mycoparasite. Predator prey interaction leads to killing of the host cell by a penetration peg and utilization of cell content by the predator. Here, we report the 14.9-Mb S. fodiens draft genome sequence assembled into 9 large scaffolds and 13 minor scaffolds (<20 kb). PMID- 29146860 TI - Complete Genome Sequence of a Novel Nonnodulating Rhizobium Species Isolated from Agave americana L. Rhizosphere. AB - We report here the complete genome sequence of Rhizobium sp. strain ACO-34A, isolated from Agave americana L. rhizosphere. No common nod genes were found, but there were nif genes for nitrogen fixing. A low average nucleotide identity to reported species supports its designation as a novel Rhizobium species that has a complete ribosomal operon in a plasmid. PMID- 29146861 TI - Whole-Genome Sequence of Pantoea americana Strain VS1, an Extended-Spectrum beta Lactamase-Producing Epibiont Isolated from Magnolia grandiflora. AB - Pantoea americana strain VS1, an extended-spectrum beta-lactamase-producing epibiont, was isolated from Magnolia grandiflora in central Florida, USA. Here, we report the de novo whole-genome sequence of this strain, which consists of a total of 191 contigs spanning 5,412,831 bp, with a GC content of 57.3% and comprising 4,836 predicted coding sequences. PMID- 29146862 TI - Complete Genome Sequence of Faecalibacterium prausnitzii Isolated from the Gut of a Healthy Indian Adult. AB - Faecalibacterium prausnitzii is the most abundant (~4%) member of the phylum Firmicutes found in the colon of healthy humans. It is a strict anaerobe and plays an important role in intestinal homeostasis. Here, we report the complete genome sequence of F. prausnitzii strain Indica. PMID- 29146863 TI - Modeling search movements of an insect's front leg. AB - Beside locomotion, search movements are another important type of motor activity of insects. They are very often performed by the front legs of the animals. They consist of cyclic stereotypical leg movements that can be modified by sensory signals. The details of the local organization of these movements have however not yet been studied. In this paper, we, using an appropriate variant of our existing one-leg model, present a scheme of how these searching movements might be organized and performed on the level of local neuromuscular control networks. In the simulations with the model, we attempted to mimic the experimental results by Berg et al. (J. Exp. Biol. 216:1064-1074, 2013) in which an obstacle was put in the way of the search movements of the front leg for a very short while, and then the recovery to the usual search movements was observed and analyzed. Our simulation results suggest that the recruitment of the fast levator and depressor muscles play a crucial part in resuming the search movements after removal of the obstacle. The interplay between the levator and depressor, and the extensor and flexor local control networks can, according to the model, bring about a large variety of search movements upon removal of the obstacle. A number of these movements are comparable with those seen in the experiments. PMID- 29146865 TI - Echocardiographic changes with non-invasive ventilation and CPAP in obesity hypoventilation syndrome. AB - RATIONALE: Despite a significant association between obesity hypoventilation syndrome (OHS) and cardiac dysfunction, no randomised trials have assessed the impact of non-invasive ventilation (NIV) or CPAP on cardiac structure and function assessed by echocardiography. OBJECTIVES: We performed a secondary analysis of the data from the largest multicentre randomised controlled trial of OHS (Pickwick project, n=221) to determine the comparative efficacy of 2 months of NIV (n=71), CPAP (n=80) and lifestyle modification (control group, n=70) on structural and functional echocardiographic changes. METHODS: Conventional transthoracic two-dimensional and Doppler echocardiograms were obtained at baseline and after 2 months. Echocardiographers at each site were blinded to the treatment arms. Statistical analysis was performed using intention-to-treat analysis. RESULTS: At baseline, 55% of patients had pulmonary hypertension and 51% had evidence of left ventricular hypertrophy. Treatment with NIV, but not CPAP, lowered systolic pulmonary artery pressure (-3.4 mm Hg, 95% CI -5.3 to 1.5; adjusted P=0.025 vs control and P=0.033 vs CPAP). The degree of improvement in systolic pulmonary artery pressure was greater in patients treated with NIV who had pulmonary hypertension at baseline (-6.4 mm Hg, 95% CI -9 to -3.8). Only NIV therapy decreased left ventricular hypertrophy with a significant reduction in left ventricular mass index (-5.7 g/m2; 95% CI -11.0 to -4.4). After adjusted analysis, NIV was superior to control group in improving left ventricular mass index (P=0.015). Only treatment with NIV led to a significant improvement in 6 min walk distance (32 m; 95% CI 19 to 46). CONCLUSION: In patients with OHS, medium-term treatment with NIV is more effective than CPAP and lifestyle modification in improving pulmonary hypertension, left ventricular hypertrophy and functional outcomes. Long-term studies are needed to confirm these results. TRIAL REGISTRATION NUMBER: Pre-results, NCT01405976 (https://clinicaltrials.gov/). PMID- 29146866 TI - Higher altitude, bigger bulla. PMID- 29146864 TI - Acute hypoxia-reoxygenation and vascular oxygen sensing in the chicken embryo. AB - Fetal/perinatal hypoxia is one of the most common causes of perinatal morbidity and mortality and is frequently accompannied by vascular dysfunction. However, the mechanisms involved have not been fully delineated. We hypothesized that exposure to acute hypoxia-reoxygenation induces alterations in vascular O2 sensing/signaling as well as in endothelial function in the chicken embryo pulmonary artery (PA), mesenteric artery (MA), femoral artery (FA), and ductus arteriosus (DA). Noninternally pipped 19-day embryos were exposed to 10% O2 for 30 min followed by reoxygenation with 21% O2 or 80% O2 Another group was constantly maintained at 21% O2 or at 21% O2 for 30 min and then exposed to 80% O2 Following treatment, responses of isolated blood vessels to hypoxia as well as endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside and forskolin) relaxation were investigated in a wire myograph. Hypoxia increased venous blood lactate from 2.03 +/- 0.18 to 15.98 +/- 0.73 mmol/L (P < 0.001) and reduced hatchability to 0%. However, ex vivo hypoxic contraction of PA and MA, hypoxic relaxation of FA, and normoxic contraction of DA were not significantly different in any of the experimental groups. Relaxations induced by acetylcholine, sodium nitroprusside, and forskolin in PA, MA, FA, and DA rings were also similar in the four groups. In conclusion, exposure to acute hypoxia reoxygenation did not affect vascular oxygen sensing or reactivity in the chicken embryo. This suggests that direct effects of acute hypoxia-reoxygenation on vascular function does not play a role in the pathophysiology of hypoxic cardiovascular injury in the perinatal period. PMID- 29146867 TI - High prevalence of TB disease in contacts of adults with extrapulmonary TB. AB - UK guidelines no longer recommend routine screening of household contacts of adult patients with extrapulmonary TB (EPTB). From 27 March 2012 to 28 June 2016, we investigated the prevalence of active TB disease in household contacts of 1023 EPTB index cases in North West England, and compared estimates with: published new entrant migrant screening programme prevalence (~147/100 000 person-years); London-based contact screening data (700/100 000 contacts screened); and National Institute for Health and Care Excellence (NICE) new entrant TB screening thresholds (TB prevalence >40/100 000 people). Active TB disease prevalence in EPTB contacts was 440/100 000 contacts screened, similar to UK new entrant screening programmes, London EPTB contact prevalence and >10 times NICE's threshold for new entrant screening. The decision to no longer recommend routine screening of EPTB contacts should be re-evaluated and cost-effectiveness analyses of screening strategies for EPTB contacts should be performed. PMID- 29146868 TI - Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation. AB - Reversible detyrosination of alpha-tubulin is crucial to microtubule dynamics and functions, and defects have been implicated in cancer, brain disorganization, and cardiomyopathies. The identity of the tubulin tyrosine carboxypeptidase (TCP) responsible for detyrosination has remained unclear. We used chemical proteomics with a potent irreversible inhibitor to show that the major brain TCP is a complex of vasohibin-1 (VASH1) with the small vasohibin binding protein (SVBP). VASH1 and its homolog VASH2, when complexed with SVBP, exhibited robust and specific Tyr/Phe carboxypeptidase activity on microtubules. Knockdown of vasohibins or SVBP and/or inhibitor addition in cultured neurons reduced detyrosinated alpha-tubulin levels and caused severe differentiation defects. Furthermore, knockdown of vasohibins disrupted neuronal migration in developing mouse neocortex. Thus, vasohibin/SVBP complexes represent long-sought TCP enzymes. PMID- 29146869 TI - Vasohibins encode tubulin detyrosinating activity. AB - Tubulin is subjected to a number of posttranslational modifications to generate heterogeneous microtubules. The modifications include removal and ligation of the C-terminal tyrosine of ?-tubulin. The enzymes responsible for detyrosination, an activity first observed 40 years ago, have remained elusive. We applied a genetic screen in haploid human cells to find regulators of tubulin detyrosination. We identified SVBP, a peptide that regulates the abundance of vasohibins (VASH1 and VASH2). Vasohibins, but not SVBP alone, increased detyrosination of ?-tubulin, and purified vasohibins removed the C-terminal tyrosine of ?-tubulin. We found that vasohibins play a cell type-dependent role in detyrosination, although cells also contain an additional detyrosinating activity. Thus, vasohibins, hitherto studied as secreted angiogenesis regulators, constitute a long-sought missing link in the tubulin tyrosination cycle. PMID- 29146870 TI - Structure of the yeast spliceosomal postcatalytic P complex. AB - The spliceosome undergoes dramatic changes in a splicing cycle. Structures of B, Bact, C, C*, and intron lariat spliceosome complexes revealed mechanisms of 5' splice site (ss) recognition, branching, and intron release, but lacked information on 3'-ss recognition, exon ligation, and exon release. Here we report a cryo-electron microscopy structure of the postcatalytic P complex at 3.3 angstrom resolution, revealing that the 3' ss is mainly recognized through non Watson-Crick base pairing with the 5' ss and branch point. Furthermore, one or more unidentified proteins become stably associated with the P complex, securing the 3' exon and potentially regulating activity of the helicase Prp22. Prp22 binds nucleotides 15 to 21 in the 3' exon, enabling it to pull the intron-exon or ligated exons in a 3' to 5' direction to achieve 3'-ss proofreading or exon release, respectively. PMID- 29146871 TI - Postcatalytic spliceosome structure reveals mechanism of 3'-splice site selection. AB - Introns are removed from eukaryotic messenger RNA precursors by the spliceosome in two transesterification reactions-branching and exon ligation. The mechanism of 3'-splice site recognition during exon ligation has remained unclear. Here we present the 3.7-angstrom cryo-electron microscopy structure of the yeast P complex spliceosome immediately after exon ligation. The 3'-splice site AG dinucleotide is recognized through non-Watson-Crick pairing with the 5' splice site and the branch-point adenosine. After the branching reaction, protein factors work together to remodel the spliceosome and stabilize a conformation competent for 3'-splice site docking, thereby promoting exon ligation. The structure accounts for the strict conservation of the GU and AG dinucleotides at the 5' and 3' ends of introns and provides insight into the catalytic mechanism of exon ligation. PMID- 29146873 TI - Mobile Interventional Stroke Teams Lead to Faster Treatment Times for Thrombectomy in Large Vessel Occlusion. AB - BACKGROUND AND PURPOSE: Endovascular recanalization treatment for acute ischemic stroke is a complex, time-sensitive intervention. Trip-and-treat is an interhospital service delivery model that has not previously been evaluated in the literature and consists of a shared mobile interventional stroke team that travels to primary stroke centers to provide on-site interventional capability. We compared treatment times between the trip-and-treat model and the traditional drip-and-ship model. METHODS: We performed a retrospective analysis on 86 consecutive eligible patients with acute ischemic stroke secondary to large vessel occlusion who received endovascular treatment at 4 hospitals in Manhattan. Patients were divided into 2 cohorts: trip-and-treat (n=39) and drip-and-ship (n=47). The primary outcome was initial door-to-puncture time, defined as the time between arrival at any hospital and arterial puncture. We also recorded and analyzed the times of last known well, IV-tPA (intravenous tissue-type plasminogen activator) administration, transfer, and reperfusion. RESULTS: Mean initial door-to-puncture time was 143 minutes for trip-and-treat and 222 minutes for drip-and-ship (P<0.0001). Although there was a trend in longer puncture-to recanalization times for trip-and-treat (P=0.0887), initial door-to recanalization was nonetheless 79 minutes faster for trip-and-treat (P<0.0001). There was a trend in improved admission-to-discharge change in National Institutes of Health Stroke Scale for trip-and-treat compared with drip-and-ship (P=0.0704). CONCLUSIONS: Compared with drip-and-ship, the trip-and-treat model demonstrated shorter treatment times for endovascular therapy in our series. The trip-and-treat model offers a valid alternative to current interhospital stroke transfers in urban environments. PMID- 29146874 TI - Imaging Characteristics of Venous Parenchymal Abnormalities. AB - BACKGROUND AND PURPOSE: There are few published data on the patterns of parenchymal imaging abnormalities in a context of cerebral venous thrombosis (CVT). The objectives of the present study were to describe the patterns of parenchymal lesions associated with CVT and to determine the lesion sites. METHODS: We included 44 consecutively hospitalized patients with CVT and parenchymal lesions on magnetic resonance imaging. The diagnosis of CVT had been confirmed by magnetic resonance imaging/magnetic resonance venography. Magnetic resonance imaging patterns for CVT were retrospectively analyzed with regard to the lesion's type, shape, and site. RESULTS: The most frequent stroke subtype was hemorrhagic ischemia (in 56.8% of cases), followed by intracerebral hematoma (in 22.72% of cases) and nonhemorrhagic ischemia (in 20.45% of cases). Although there were no significant differences between these 3 groups with regard to the clinical and radiological characteristics, we observed a nonsignificant trend (P=0.08) toward a shorter time interval between hospital admission and magnetic resonance imaging for nonhemorrhagic stroke. The CVT parenchymal abnormalities were centered on 6 main foci and were related to the site of venous occlusion: (1) the inferior parietal lobule (n=20; 44.5%), associated mainly with occlusion of the transverse sinus (n=10) or pure cortical veins (n=10); (2) the inferior and posterior temporal regions (n=10; 22.75%), associated mainly with occlusion of the transverse sinus (n=9); (3) the parasagittal frontal region (n=6; 13.6%), associated mainly with occlusion of the superior sagittal sinus (n=4) or the transverse sinus (n=4); (4) the thalamus (n=5; 11.3%) associated with occlusion of the straight sinus (n=5); (5) the cerebellar hemisphere (n=2; 4.5%), associated in both cases with occlusion of the transverse sinus; and (6) the deep hemispheric regions (n=3; 6.8%), associated with occlusion of the superior sagittal sinus in all cases. CONCLUSIONS: Parenchymal lesions caused by CVT display specific anatomic patterns, which is mainly determined by the site of venous occlusion. PMID- 29146875 TI - Risk of Stroke in Patients With Short-Run Atrial Tachyarrhythmia. AB - BACKGROUND AND PURPOSE: The risk of stroke in patients with short-run atrial tachyarrhythmia (AT) remains unclear. This study aimed to investigate the relationship between short-run AT and the stroke and the use of the CHA2DS2-VASc score for the risk stratification. METHODS: From the registry of 24-hour Holter monitoring, 5342 subjects without known atrial fibrillation or stroke were enrolled. Short-run AT was defined as episodes of supraventricular ectopic beats <5 seconds. RESULTS: There were 1595 subjects (29.8%) with short-run AT. During the median follow-up period of 9.0 years, 494 subjects developed new-onset stroke. Patients with short-run AT had significantly higher stroke rates compared with patients without short-run AT (11.4% versus 8.3%; P<0.001). In patients with short-run AT, the number of strokes per 100 person-years for patients with CHA2DS2-VASc score of 0 and 1 were 0.23 and 0.67, respectively. However, the number of them for patients with CHA2DS2-VASc score of 2, 3, 4, and >=5 were 1.62, 1.89, 1.30, and 2.91, respectively. In patients with CHA2DS2-VASc score of 0 or 1, age (>61 years old) and burden of premature atrial contractions (>25 beats/d) independently predicted the risk of stroke. In subgroup analyses, short run AT patients were divided into 3 groups based on their CHA2DS2-VASc scores: low score (score of 0 [men] or 1 [women]; n=324), intermediate score (score of 1 [men] or 2 [women]; n=275), and high score (score of >=2 [men] or >=3 [women]; n=996). When compared with low score, intermediate and high scores were independent predictors for stroke (hazard ratio, 6.165; P<0.001 and hazard ratio, 8.577; P<0.001, respectively). CONCLUSIONS: Short-run AT increases the risk of stroke. Therefore, the CHA2DS2-VASc score could be used for the risk stratification. Age and burden of premature atrial contractions were independent predictors for stroke in patients with CHA2DS2-VASc score of 0 or 1. PMID- 29146876 TI - Organizational Update: World Health Organization. PMID- 29146872 TI - Holistic bioengineering: rewiring central metabolism for enhanced bioproduction. AB - What does it take to convert a living organism into a truly productive biofactory? Apart from optimizing biosynthesis pathways as standalone units, a successful bioengineering approach must bend the endogenous metabolic network of the host, and especially its central metabolism, to support the bioproduction process. In practice, this usually involves three complementary strategies which include tuning-down or abolishing competing metabolic pathways, increasing the availability of precursors of the desired biosynthesis pathway, and ensuring high availability of energetic resources such as ATP and NADPH. In this review, we explore these strategies, focusing on key metabolic pathways and processes, such as glycolysis, anaplerosis, the TCA (tricarboxylic acid) cycle, and NADPH production. We show that only a holistic approach for bioengineering - considering the metabolic network of the host organism as a whole, rather than focusing on the production pathway alone - can truly mold microorganisms into efficient biofactories. PMID- 29146877 TI - Stroke Physician Training in China. PMID- 29146878 TI - Reconsidering Neuroprotection in the Reperfusion Era. PMID- 29146879 TI - 2-Cl-MGV-1 Ameliorates Apoptosis in the Thalamus and Hippocampus and Cognitive Deficits After Cortical Infarct in Rats. AB - BACKGROUND AND PURPOSE: Focal cortical infarction causes neuronal apoptosis in the ipsilateral nonischemic thalamus and hippocampus, which is potentially associated with poststroke cognitive deficits. TSPO (translocator protein) is critical in regulating mitochondrial apoptosis pathways. We examined the effects of the novel TSPO ligand 2-(2-chlorophenyl) quinazolin-4-yl dimethylcarbamate (2 Cl-MGV-1) on poststroke cognitive deficits, neuronal mitochondrial apoptosis, and secondary damage in the ipsilateral thalamus and hippocampus after cortical infarction. METHODS: One hundred fourteen hypertensive rats underwent successful distal middle cerebral artery occlusion (n=76) or sham procedures (n=38). 2-Cl MGV-1 or dimethyl sulfoxide as vehicle was administrated 2 hours after distal middle cerebral artery occlusion and then for 6 or 13 days (n=19 per group). Spatial learning and memory were tested using the Morris water maze. Secondary degeneration and mitochondrial apoptosis in the thalamus and hippocampus were assessed using Nissl staining, immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling, JC-1 staining, and immunoblotting 7 and 14 days after surgery. RESULTS: Infarct volumes did not significantly differ between the vehicle and 2-Cl-MGV-1 groups. There were more neurons and fewer glia in the ipsilateral thalamus and hippocampus in the vehicle groups than in the sham operated group 7 and 14 days post-distal middle cerebral artery occlusion. 2-Cl MGV-1 significantly ameliorated spatial cognitive impairment and decreased neuronal death and glial activation when compared with vehicle treatment (P<0.05). The collapse of mitochondrial transmembrane potential and cytoplasmic release of apoptosis-inducing factors and cytochrome c was prevented within the thalamus. Caspase cleavage and the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling+ or Nissl atrophic cells were reduced within the thalamus and hippocampus. This was accompanied by upregulation of B-cell lymphoma 2 and downregulation of Bax (P<0.05). CONCLUSIONS: 2-Cl-MGV-1 reduces neuronal apoptosis via mitochondrial-dependent pathways and attenuates secondary damage in the nonischemic thalamus and hippocampus, potentially contributing to ameliorated cognitive deficits after cortical infarction. PMID- 29146880 TI - Optogenetic Inhibition of Striatal GABAergic Neuronal Activity Improves Outcomes After Ischemic Brain Injury. AB - BACKGROUND AND PURPOSE: Striatal GABAergic neuron is known as a key regulator in adult neurogenesis. However, the specific role of striatal GABAergic neuronal activity in the promotion of neurological recovery after ischemic stroke remains unknown. Here, we used optogenetic approach to investigate these effects and mechanism. METHODS: Laser stimulation was delivered via an implanted optical fiber to inhibit or activate the striatal GABAergic neurons in Gad2-Arch-GFP or Gad2-ChR2-tdTomato mice (n=80) 1 week after 60-minute transient middle cerebral artery occlusion. Neurological severity score, brain atrophy volume, microvessel density, and cell morphological changes were examined using immunohistochemistry. Gene expression and protein levels of related growth factors were further examined using real-time polymerase chain reaction and Western blotting. RESULTS: Inhibiting striatal GABAergic neuronal activity improved functional recovery, reduced brain atrophy volume, and prohibited cell death compared with the control (P<0.05). Microvessel density and bFGF (basic fibroblast growth factor) expression in the inhibition group were also increased (P<0.05). In contrast, activation of striatal GABAergic neurons resulted in adverse effects compared with the control (P<0.05). Using cocultures of GABAergic neurons, astrocytes, and endothelial cells, we further demonstrated that the photoinhibition of GABAergic neuronal activity could upregulate bFGF expression in endothelial cells, depending on the presence of astrocytes. The conditioned medium from the aforementioned photoinhibited 3-cell coculture system protected cells from oxygen glucose deprivation injury. CONCLUSIONS: After ischemic stroke, optogenetic inhibition of GABAergic neurons upregulated bFGF expression by endothelial cells and promoted neurobehavioral recovery, possibly orchestrated by astrocytes. Optogenetically inhibiting neuronal activity provides a novel approach to promote neurological recovery. PMID- 29146881 TI - beta-Adrenergic Signaling Impairs Antitumor CD8+ T-cell Responses to B-cell Lymphoma Immunotherapy. AB - beta-Adrenergic receptor (betaAR) signaling regulates many physiological processes, including immune system responses. There is growing evidence also for betaAR-induced modulation of cancer growth and metastasis. In the EMU-myc mouse model of B-cell lymphoma, we investigated the effects of chronically elevated betaAR signaling on lymphoma progression and antitumor immunity, as well as the impact on cancer immunotherapy. Chronic treatment with the nonselective beta agonist isoprenaline promoted lymphoma development in a manner dependent on signaling within the hematopoietic compartment. betaAR signaling significantly suppressed the proliferation, IFNgamma production, and cytolytic killing capacity of antigen-specific CD8+ T cells. This inhibited CD8+ T-cell responses to immune modulating antibodies, including anti-PD-1 and anti-4-1BB, resulting in less effective control of lymphoma. The inhibitory effects on CD8+ T cells occurred independently of changes to DC function and included direct suppression of CD8+ T cell stimulation. The suppressive effects of chronic betaAR signaling on antitumor effector cells was selective to T cells, as it did not perturb the innate lymphocyte response to an experimental NKT cell-targeting vaccine, in a setting where innate immune control is dependent on NKT cell and NK cell activation. These findings demonstrate that chronic betaAR signaling has an immunosuppressive effect on CD8+ T cells, which decreases the efficacy of CD8+ T cell-targeting immunotherapies. These findings identify betaAR signaling as a target for modulation during cancer immunotherapy that may increase therapeutic response and improve patient outcomes. Cancer Immunol Res; 6(1); 98-109. (c)2017 AACR. PMID- 29146882 TI - Physiological Srsf2 P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice. AB - Splicing factor mutations are characteristic of myelodysplastic syndromes (MDS) and related myeloid neoplasms and implicated in their pathogenesis, but their roles in the development of MDS have not been fully elucidated. In the present study, we investigated the consequence of mutant Srsf2 expression using newly generated Vav1-Cre-mediated conditional knockin mice. Mice carrying a heterozygous Srsf2 P95H mutation showed significantly reduced numbers of hematopoietic stem and progenitor cells (HSPCs) and differentiation defects both in the steady-state condition and transplantation settings. Srsf2-mutated hematopoietic stem cells (HSCs) showed impaired long-term reconstitution compared with control mice in competitive repopulation assays. Although the Srsf2 mutant mice did not develop MDS under the steady-state condition, when their stem cells were transplanted into lethally irradiated mice, the recipients developed anemia, leukopenia, and erythroid dysplasia, which suggests the role of replicative stress in the development of an MDS-like phenotype in Srsf2-mutated mice. RNA sequencing of the Srsf2-mutated HSPCs revealed a number of abnormal splicing events and differentially expressed genes, including several potential targets implicated in the pathogenesis of hematopoietic malignancies, such as Csf3r, Fyn, Gnas, Nsd1, Hnrnpa2b1, and Trp53bp1 Among the mutant Srsf2-associated splicing events, most commonly observed were the enhanced inclusion and/or exclusion of cassette exons, which were caused by the altered consensus motifs for the recognition of exonic splicing enhancers. Our findings suggest that the mutant Srsf2 leads to a compromised HSC function by causing abnormal RNA splicing and expression, contributing to the deregulated hematopoiesis that recapitulates the MDS phenotypes, possibly as a result of additional genetic and/or environmental insults. PMID- 29146884 TI - Computer graphics for the microscopist. PMID- 29146883 TI - A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. AB - Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented >=5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged <=2 years and 36.9% were >=18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling. PMID- 29146885 TI - Mammary phyllodes tumour: a 15-year multicentre clinical review. AB - AIMS: Phyllodes tumour (PT) is an uncommon fibroepithelial tumour of the breast. It has a spectrum of aggressiveness in biological behaviour with chance of local recurrence and, occasionally, metastasis. METHODS: A 15-year retrospective review from a multicentre database in Hong Kong was performed. RESULTS: Clinical and pathological records of 465 patients with 469 PTs between 1998 and 2014 were reviewed. Median age of occurrence was 44 years (range 12-86 years). 281 (59.9%) PTs were benign, 124 (26.4%) were borderline and 64 (13.6%) were malignant. About half of all PTs (239, 51.5%) were between 2 and 5 cm while another 186 (40.1%) were >5 cm in size. Most PT (84.6%) were radiologically benign. Breast-conserving surgery (BCS) was feasible in 384 (82%) patients, whereas 84 (18%) patients had mastectomy. Multivariate analysis found that positive surgical margin (P<0.001) and BCS (P<0.001) were the only significant risk factors for local recurrence, while large tumour size (P=0.008) and malignant PT histotype (P<0.001) were the only significant risk factors for metastasis. Long-term prognosis of benign and borderline PT was excellent. After median follow-up interval of 85 months (range 12-180 months), the disease-specific survival of benign, borderline and malignant PT were 99.6%, 100% and 90.6%, respectively. CONCLUSIONS: Local recurrence of PTs occurs irrespective of the tumour grade. Surgical margin is the only amendable factor to reduce the chance of recurrence. PMID- 29146886 TI - Cutaneous lymphoma. PMID- 29146888 TI - Halitosis in children with adenoid hypertrophy. AB - This paper attempts to identify the sources and evaluate the prevalence of halitosis in children with adenoid hypertrophy. The study included pediatric patients admitted for adenoidectomy due to obstructive symptoms. Patients with possibly other causes of halitosis, were excluded from the study. Halitosis was detected in 30 out of 136 children (22.1%). The effect of adenoid hypertrophy on halitosis was confirmed by the significant reduction in the organoleptic score rated according to the Rosenberg scale (on average by 2 degrees ) and the levels of volatile sulfur compounds (on average 84 ppb) post-adenoidectomy, as compared to pre-surgery results. In total, we reported a statistically significant decrease in the abovementioned values in 90% of patients with halitosis. It was found that in patients with halitosis, as compared to patients with no oral malodor, anaerobic bacteria and Staphylococcus aureus were more frequently observed in the adenoid tissue. Streptococcus oralis strains were more commonly reported in the material taken during adenoidectomy in children without oral malodor. PMID- 29146889 TI - Exhaled markers of antioxidant activity and oxidative stress in stable cystic fibrosis patients with moderate lung disease. AB - The sustained imbalance between oxidant and antioxidant species contributes to lung damage in patients with cystic fibrosis (CF). Glutathione (GSH) is an important component of the antioxidant defense in the airways epithelial lining fluid and its transportation out of the cells may be altered in CF. The aim of this study was to assess the oxidants/antioxidants balance in the airways of patients with CF. We measured the concentrations of GSH, the total antioxidant capacity and the concentration of 8-iso-prostaglandin F2alpha (8-isoprostane), a marker of oxidative stress, in the exhaled breath condensate of 17 non-smoking patients with CF, in stable phase, and in 17 age-matched healthy subjects. The levels of GSH and total antioxidant capacity in patients with CF were significantly lower than in healthy subjects (0.66 +/- 0.07 MUM versus 1.30 +/- 0.08 MUM, p < 0.001, respectively for GSH; 0.157 +/- 0.02 mM and 0.32 +/- 0.01 mM, p < 0.05, respectively for antioxidant capacity). The concentration of 8 isoprostane was higher in CF than in healthy controls (26.5 +/- 0.1 pg ml-1 versus 10.8 +/- 0.1 pg ml-1; p < 0.05). A low concentration of antioxidant agents, particularly glutathione, and increased levels of 8-isoprostane in the exhaled breath suggest an altered oxidizing environment in the airways of patients with CF. This altered redox environment in the epithelial liquid surface may contribute to progressive lung disease. PMID- 29146890 TI - Effectiveness of topical green tea against multidrug-resistant Staphylococcus aureus in cases of primary pyoderma: An open controlled trial. AB - Background: Antimicrobial activity of green tea against Staphylococcus aureus both in vitro and in vivo has been reported recently. Studies on clinical efficacy and safety of green tea as antibacterial agent against S. aureus in human cases are rare. Objectives: To evaluate the clinical effectiveness and safety of topical green tea on primary pyoderma caused by S. aureus. We also attempted to determine the minimum inhibitory concentration of green tea against S. aureus and methicillin-resistant S. aureus. Methods: Open label, prospective, placebo-controlled study included community-acquired primary pyoderma cases caused by S. aureus. Severity grading was done on a scale of 1-5. Green tea ointment 3% and placebo ointment were used. Cure was defined on the basis of negative culture and assessment of clinical improvement. Minimum inhibitory concentration was determined by agar dilution method. Data were analyzed using Statistical Package for Social Sciences (SPSS) software version 16. Results: Of the 372 patients, 250 received green tea and 122 received placebo. Multidrug resistant S. aureus was isolated in 89.1% in green tea group and 81.1% in placebo group, respectively. Methicillin-resistant S. aureus was isolated in 24 patients. Cure was seen in 86% in green tea group and 6.6% in placebo group which was statistically very significant. The number of days for comprehensive cure in green tea group was 9.2 +/- 6.4 days. All patients with methicillin-resistant S. aureus infection in the green tea group were cured. Minimum inhibitory concentration of green tea against S. aureus was 0.0265 +/- 0.008 MUg/ml and against methicillin-resistant S. aureus was 0.0205 +/- 0.003 MUg/ml. Limitations of the Study: Comparative trial was not conducted in the same patient with different lesions; children less than seven years were not considered as the school authorities did not permit for younger children to be included in the study and true randomization and blinding of investigators were not done. Conclusions: Green tea has a significant antibacterial effect against multidrug resistant S. aureus. Minimum inhibitory concentration of green tea is established and is promising in methicillin-resistant S. aureus infections. PMID- 29146887 TI - Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets. AB - Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras-Raf-MEK-ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors. PMID- 29146891 TI - Heart Transplantation and Risk of Cardiac Vasculopathy Development: What Factors Are Important? AB - BACKGROUND The aim of this study was to find the main risk factors for development of cardiac allograft vasculopathy (CAV), especially factors identified before the surgical procedure and factors related to the recipient profile and the medical history of the donor. MATERIAL AND METHODS There were 147 patients who had heart transplantation (HT) included in this study: mean age was 45.8+/-15.3 years. All study patients had coronary angiography after HT. Analyzed risk factors were: non-immunologic recipient risk factors (age of transplantation, smoking, hypertension, lipids, diabetes, obesity and weight gain after HT), immunologic recipient risk factors (acute cellular rejection (ACR), acute humoral rejection (AMR), cytomegalovirus (CMV) episodes), and donor-related risk factors (age, sex, catecholamine usage, ischemic time, compatibility of sex and blood groups, cause of death, cardiac arrest). RESULTS CAV was recognized in 48 patients (CAV group); mean age 53.6+/-13.6 years. There were 99 patients without CAV (nonCAV group); mean age 48.3+/-15.5 years. A univariate Cox analysis of the development of coronary disease showed statistical significance (p<0.05) for baseline high-density lipid (HDL), ACR, AMR, CMV, and donor age. Multivariate Cox regression model confirmed that only baseline HDL, episodes of ACR, donor age, and CMV infection are significant for the frequency of CAV after HT. CONCLUSIONS Older donor age is highly associated with CAV development. Older donor age and low level of HDL in heart recipients with the strongest influence of immunologic risk factors (ACR, CMV infection) were linked with development of CAV. PMID- 29146892 TI - Intermedin Ameliorates Atherosclerosis by Increasing Cholesterol Efflux Through the cAMP-PKA Pathway in Macrophage RAW264.7 Cell Line. AB - BACKGROUND The aim of this study was to explore the role of intermedin and its mechanism in cholesterol efflux of macrophage THP-1 and RAW264.7 cell lines in atherosclerosis (AS). MATERIAL AND METHODS ApoE-/- mice were fed with a high-fat diet, and the concentrations of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured. The lipidoses of the aortic sinus were analyzed by hematoxylin and eosin staining, and the cAMP level was detected by enzyme-linked immunosorbent assay (ELISA). The expressions of ATP-binding cassette transporter (ABCA1) were tested by real-time PCR and Western blot analysis. RESULTS IMD decreased serum TC and LDL-C, and increased serum HDL-C level in apoE-/- mice and attenuated AS plaque areas. In vitro, IMD increased intracellular cAMP concentration in a dose-dependent manner in THP-1 and RAW264.7 cell lines, which enhanced the expression of ABCA1 and increased cholesterol efflux rate. However, this effect was inhibited by PKAI in the RAW 264.7 cell line but not in the THP-1 cell line. CONCLUSIONS IMD can ameliorate the development of AS in ApoE-/- mice and regulate cholesterol balance in the RAW264.7 cell line through the cAMP-PKA pathway. PMID- 29146893 TI - Von Hippel-Lindau Disease With Multi-Organ Involvement: A Case Report and 8-Year Clinical Course With Follow-Up. AB - BACKGROUND Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome manifested by a spectrum of benign and malignant tumors. CASE REPORT The patient presented here was a 31-year-old female with unremarkable family history who presented initially complaining of intermittent abdominal pain. Abdominal CT scan revealed an inhomogeneous solid mass (13*9*7 cm) originating from the tail of the pancreas with splenic and gastric invasion as well as several pancreatic cysts. A nucleotide scan showed left adrenal involvement. The patient underwent tumor resection, splenectomy, partial gastrectomy, and left adrenalectomy. Histopathologic examination reported well-differentiated neuroendocrine carcinoma with low malignant potential of the tumor with splenic and adrenal involvement. Pancreatic cysts had benign component. Three years later, follow-up abdominal CT showed heterogeneously-enhanced solid nodules in both kidneys found to be renal cell carcinoma (RCC) on biopsy. At the same time, brain MRI showed cerebellar hemangioblastomas. Partial nephrectomy was done. Molecular genetic testing for demonstrated NM_000551.3:c.481C > T (p.R161* CGA>TGA), which has been reported previously in VHL disease. The next year, she developed peritonitis, which found to be the result of a perforated gastric ulcer. Histopathologic examination of the ulcer revealed neuroendocrine carcinoma. Then, the next year, a brain MRI revealed 4 solid and enhanced nodules in the cerebellum, suggesting multiple hemangioblastomas. Octreotide (Sandostatin(r) LAR) and everolimus (Afinitor(r)) were started for the patient. At the last visit, the patient was asymptomatic with acceptable condition. CONCLUSIONS Here, we present a young patient with pancreatic neuroendocrine tumor as the first presentation of VHL without a remarkable family history for VHL disease. The patient developed RCC, renal cysts, cardiomegaly, and brain hemangioblastomas during the 8-year follow-up. Regular follow-up with imaging (ultrasound, CT, MRI) are necessary to follow the previous lesions and detect any newly-developed VHL-associate tumors. PMID- 29146894 TI - Odd viscosity in chiral active fluids. AB - We study the hydrodynamics of fluids composed of self-spinning objects such as chiral grains or colloidal particles subject to torques. These chiral active fluids break both parity and time-reversal symmetries in their non-equilibrium steady states. As a result, the constitutive relations of chiral active media display a dissipationless linear-response coefficient called odd (or equivalently, Hall) viscosity. This odd viscosity does not lead to energy dissipation, but gives rise to a flow perpendicular to applied pressure. We show how odd viscosity arises from non-linear equations of hydrodynamics with rotational degrees of freedom, once linearized around a non-equilibrium steady state characterized by large spinning speeds. Next, we explore odd viscosity in compressible fluids and suggest how our findings can be tested in the context of shock propagation experiments. Finally, we show how odd viscosity in weakly compressible chiral active fluids can lead to density and pressure excess within vortex cores. PMID- 29146895 TI - Atomic-level molybdenum oxide nanorings with full-spectrum absorption and photoresponsive properties. AB - Superthin nanostructures, particularly with atomic-level thicknesses, typically display unique optical properties because of their exceptional light-matter interactions. Here, we report a facile strategy for the synthesis of sulfur-doped molybdenum oxide nanorings with an atomic-level size (thickness of 0.5 nm) and a tunable ring-in-ring architecture. These atomic-level nanorings displayed strong photo-absorption in both the visible and infrared-light ranges and acted as a photothermal agent. Under irradiation with an 808 nm laser with an intensity of 1 W/cm2, a composite of the nanorings embedded in polydimethylsiloxane showed an ultrafast photothermal effect, delivering a local temperature of up to 400 degrees C within 20 s, which to the best of our knowledge is the highest temperature by light irradiation reported to date. Meanwhile, the resulting nanorings were also employed as a photoinitiator to remotely induce a visible light shape memory response, self-healing, reshaping performance and reversible actuation of dynamic three-dimensional structures. This study demonstrates an advancement towards controlling atomic-level-sized nanostructures and achieving greatly enhanced optical performances for optoelectronics. PMID- 29146896 TI - Deterministic and robust room-temperature exchange coupling in monodomain multiferroic BiFeO3 heterostructures. AB - Exploiting multiferroic BiFeO3 thin films in spintronic devices requires deterministic and robust control of both internal magnetoelectric coupling in BiFeO3, as well as exchange coupling of its antiferromagnetic order to a ferromagnetic overlayer. Previous reports utilized approaches based on multi-step ferroelectric switching with multiple ferroelectric domains. Because domain walls can be responsible for fatigue, contain localized charges intrinsically or via defects, and present problems for device reproducibility and scaling, an alternative approach using a monodomain magnetoelectric state with single-step switching is desirable. Here we demonstrate room temperature, deterministic and robust, exchange coupling between monodomain BiFeO3 films and Co overlayer that is intrinsic (i.e., not dependent on domain walls). Direct coupling between BiFeO3 antiferromagnetic order and Co magnetization is observed, with ~ 90 degrees in-plane Co moment rotation upon single-step switching that is reproducible for hundreds of cycles. This has important consequences for practical, low power non-volatile magnetoelectric devices utilizing BiFeO3. PMID- 29146898 TI - Quantum suppression of antihydrogen formation in positronium-antiproton scattering. AB - The interaction of antiprotons with low-energy positronium atoms is a fundamental three-body problem whose significance is its utility for formation of antihydrogen. Particular importance resides in understanding processes involving excited positronium states. Until recently such studies were performed using classical techniques. However, they become inapplicable in the low-energy domain. Here we report the results of comprehensive quantum calculations, which include initial excited positronium states with principal quantum numbers up to n i = 5. Contrary to expectation from earlier work, there are only muted increases in the cross-sections for antihydrogen formation for n i > 3. We interpret this in terms of quantum suppression of the reaction at higher angular momenta. Furthermore, the cross-sections for elastic scattering are around two orders of magnitude higher, which we attribute to the degeneracy of the positronium states. We outline some experimental consequences of our results. PMID- 29146897 TI - GWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk. AB - Male pattern baldness (MPB) or androgenetic alopecia is one of the most common conditions affecting men, reaching a prevalence of ~50% by the age of 50; however, the known genes explain little of the heritability. Here, we present the results of a genome-wide association study including more than 70,000 men, identifying 71 independently replicated loci, of which 30 are novel. These loci explain 38% of the risk, suggesting that MPB is less genetically complex than other complex traits. We show that many of these loci contain genes that are relevant to the pathology and highlight pathways and functions underlying baldness. Finally, despite only showing genome-wide genetic correlation with height, pathway-specific genetic correlations are significant for traits including lifespan and cancer. Our study not only greatly increases the number of MPB loci, illuminating the genetic architecture, but also provides a new approach to disentangling the shared biological pathways underlying complex diseases. PMID- 29146899 TI - Alternative transcription start site selection in Mr-OPY2 controls lifestyle transitions in the fungus Metarhizium robertsii. AB - Metarhizium robertsii is a versatile fungus with saprophytic, plant symbiotic and insect pathogenic lifestyle options. Here we show that M. robertsii mediates the saprophyte-to-insect pathogen transition through modulation of the expression of a membrane protein, Mr-OPY2. Abundant Mr-OPY2 protein initiates appressorium formation, a prerequisite for infection, whereas reduced production of Mr-OPY2 elicits saprophytic growth and conidiation. The precise regulation of Mr-OPY2 protein production is achieved via alternative transcription start sites. During saprophytic growth, a single long transcript is produced with small upstream open reading frames in its 5' untranslated region. Increased production of Mr-OPY2 protein on host cuticle is achieved by expression of a transcript variant lacking a small upstream open reading frame that would otherwise inhibit translation of Mr-OPY2. RNA-seq and qRT-PCR analyses show that Mr-OPY2 is a negative regulator of a transcription factor that we demonstrate is necessary for appressorial formation. These findings provide insights into the mechanisms regulating fungal lifestyle transitions. PMID- 29146900 TI - The genomic landscape of pediatric myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDS) are uncommon in children and have a poor prognosis. In contrast to adult MDS, little is known about the genomic landscape of pediatric MDS. Here, we describe the somatic and germline changes of pediatric MDS using whole exome sequencing, targeted amplicon sequencing, and/or RNA sequencing of 46 pediatric primary MDS patients. Our data show that, in contrast to adult MDS, Ras/MAPK pathway mutations are common in pediatric MDS (45% of primary cohort), while mutations in RNA splicing genes are rare (2% of primary cohort). Surprisingly, germline variants in SAMD9 or SAMD9L were present in 17% of primary MDS patients, and these variants were routinely lost in the tumor cells by chromosomal deletions (e.g., monosomy 7) or copy number neutral loss of heterozygosity (CN-LOH). Our data confirm that adult and pediatric MDS are separate diseases with disparate mechanisms, and that SAMD9/SAMD9L mutations represent a new class of MDS predisposition. PMID- 29146901 TI - Genome-driven evolutionary game theory helps understand the rise of metabolic interdependencies in microbial communities. AB - Metabolite exchanges in microbial communities give rise to ecological interactions that govern ecosystem diversity and stability. It is unclear, however, how the rise of these interactions varies across metabolites and organisms. Here we address this question by integrating genome-scale models of metabolism with evolutionary game theory. Specifically, we use microbial fitness values estimated by metabolic models to infer evolutionarily stable interactions in multi-species microbial "games". We first validate our approach using a well characterized yeast cheater-cooperator system. We next perform over 80,000 in silico experiments to infer how metabolic interdependencies mediated by amino acid leakage in Escherichia coli vary across 189 amino acid pairs. While most pairs display shared patterns of inter-species interactions, multiple deviations are caused by pleiotropy and epistasis in metabolism. Furthermore, simulated invasion experiments reveal possible paths to obligate cross-feeding. Our study provides genomically driven insight into the rise of ecological interactions, with implications for microbiome research and synthetic ecology. PMID- 29146902 TI - Single molecule multiplexed nanopore protein screening in human serum using aptamer modified DNA carriers. AB - The capability to screen a range of proteins at the single-molecule level with enhanced selectivity in biological fluids has been in part a driving force in developing future diagnostic and therapeutic strategies. The combination of nanopore sensing and nucleic acid aptamer recognition comes close to this ideal due to the ease of multiplexing, without the need for expensive labelling methods or extensive sample pre-treatment. Here, we demonstrate a fully flexible, scalable and low-cost detection platform to sense multiple protein targets simultaneously by grafting specific sequences along the backbone of a double stranded DNA carrier. Protein bound to the aptamer produces unique ionic current signatures which facilitates accurate target recognition. This powerful approach allows us to differentiate individual protein sizes via characteristic changes in the sub-peak current. Furthermore, we show that by using DNA carriers it is possible to perform single-molecule screening in human serum at ultra-low protein concentrations. PMID- 29146903 TI - Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells. AB - Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention. PMID- 29146904 TI - Backward Cherenkov radiation emitted by polariton solitons in a microcavity wire. AB - Exciton-polaritons in semiconductor microcavities form a highly nonlinear platform to study a variety of effects interfacing optical, condensed matter, quantum and statistical physics. We show that the complex polariton patterns generated by picosecond pulses in microcavity wire waveguides can be understood as the Cherenkov radiation emitted by bright polariton solitons, which is enabled by the unique microcavity polariton dispersion, which has momentum intervals with positive and negative group velocities. Unlike in optical fibres and semiconductor waveguides, we observe that the microcavity wire Cherenkov radiation is predominantly emitted with negative group velocity and therefore propagates backwards relative to the propagation direction of the emitting soliton. We have developed a theory of the microcavity wire polariton solitons and of their Cherenkov radiation and conducted a series of experiments, where we have measured polariton-soliton pulse compression, pulse breaking and emission of the backward Cherenkov radiation. PMID- 29146905 TI - Pericytes regulate VEGF-induced endothelial sprouting through VEGFR1. AB - Pericytes adhere to the abluminal surface of endothelial tubules and are required for the formation of stable vascular networks. Defective endothelial cell pericyte interactions are frequently observed in diseases characterized by compromised vascular integrity such as diabetic retinopathy. Many functional properties of pericytes and their exact role in the regulation of angiogenic blood vessel growth remain elusive. Here we show that pericytes promote endothelial sprouting in the postnatal retinal vasculature. Using genetic and pharmacological approaches, we show that the expression of vascular endothelial growth factor receptor 1 (VEGFR1) by pericytes spatially restricts VEGF signalling. Angiogenic defects caused by pericyte depletion are phenocopied by intraocular injection of VEGF-A or pericyte-specific inactivation of the murine gene encoding VEGFR1. Our findings establish that pericytes promote endothelial sprouting, which results in the loss of side branches and the enlargement of vessels when pericyte function is impaired or lost. PMID- 29146906 TI - QTL mapping and molecular characterization of the classical D locus controlling seed and flower color in Linum usitatissimum (flax). AB - The flowers of flax (linseed) are blue-hued, ephemeral and self-pollinating, and the seeds are typically brown. A century-old interest in natural yellow seed variants and a historical model point to recessive alleles in B1, D and G loci being responsible, but the functional aspects had remained unknown. Here, we characterized the "D" locus by quantitative trait loci (QTL) mapping and identified a FLAVONOID 3'5' HYDROXYLASE (F3'5'H) gene therein. It does not belong to the F3'5'H clade, but resembles biochemically characterized F3'Hs (flavonoid 3' hydroxylase) but without F3'H activity. The genome lacks other F3'H or F3'H like genes. The apparent neo-functionalization from F3'H is associated with a Thr498 -> Ser498 substitution in a substrate recognition site (SRS). The yellow seed and white flower phenotypes of the classical d mutation was found to be due to one nucleotide deletion that would truncate the deduced product and remove three of the six potential SRS, negatively impacting delphinidin synthesis. Delphinidin is sporadic in angiosperms, and flax has no known pollination syndrome(s) with functional pollinator group(s) that are attracted to blue flowers, raising questions on the acquisition of F3'5'H. The appearance of d allele is suggestive of the beginning of the loss of F3'5'H in this species. PMID- 29146907 TI - Giant magnetic splitting inducing near-unity valley polarization in van der Waals heterostructures. AB - Monolayers of semiconducting transition metal dichalcogenides exhibit intriguing fundamental physics of strongly coupled spin and valley degrees of freedom for charge carriers. While the possibility of exploiting these properties for information processing stimulated concerted research activities towards the concept of valleytronics, maintaining control over spin-valley polarization proved challenging in individual monolayers. A promising alternative route explores type II band alignment in artificial van der Waals heterostructures. The resulting formation of interlayer excitons combines the advantages of long carrier lifetimes and spin-valley locking. Here, we demonstrate artificial design of a two-dimensional heterostructure enabling intervalley transitions that are not accessible in monolayer systems. The resulting giant effective g factor of 15 for interlayer excitons induces near-unity valley polarization via valley selective energetic splitting in high magnetic fields, even after nonselective excitation. Our results highlight the potential to deterministically engineer novel valley properties in van der Waals heterostructures using crystallographic alignment. PMID- 29146909 TI - Interference-like patterns of static magnetic fields imprinted into polymer/nanoparticle composites. AB - Interference of waves is important and used in many areas of science and technology but does not extend to static magnetic fields which lack the wave structure. On the other hand, magnetic fields can be spatially modulated using microstructured materials comprising magnetic and non-magnetic domains. Here, we show that when such spatial modulation is coupled to the dynamics of magnetic particles, it can give rise to interference-like patterns. These patterns are imprinted into thin polymer films by overlaying "stamps" presenting periodic arrays of magnetic and nonmagnetic regions. The structures that emerge from such a superposition are sensitive to any motions of the stamps, can depend on the history of these motions, can produce features significantly smaller than those in the stamps, and can be either planar or three-dimensional. PMID- 29146908 TI - LRPPRC-mediated folding of the mitochondrial transcriptome. AB - The expression of the compact mammalian mitochondrial genome requires transcription, RNA processing, translation and RNA decay, much like the more complex chromosomal systems, and here we use it as a model system to understand the fundamental aspects of gene expression. Here we combine RNase footprinting with PAR-CLIP at unprecedented depth to reveal the importance of RNA-protein interactions in dictating RNA folding within the mitochondrial transcriptome. We show that LRPPRC, in complex with its protein partner SLIRP, binds throughout the mitochondrial transcriptome, with a preference for mRNAs, and its loss affects the entire secondary structure and stability of the transcriptome. We demonstrate that the LRPPRC-SLIRP complex is a global RNA chaperone that stabilizes RNA structures to expose the required sites for translation, stabilization, and polyadenylation. Our findings reveal a general mechanism where extensive RNA protein interactions ensure that RNA is accessible for its biological functions. PMID- 29146910 TI - An unexpected protein interaction promotes drug resistance in leukemia. AB - The overall survival of patients with acute myeloid leukemia (AML) is poor and identification of new disease-related therapeutic targets remains a major goal for this disease. Here we show that expression of MPP1, a PDZ-domain-containing protein, highly correlated with ABCC4 in AML, is associated with worse overall survival in AML. Murine hematopoietic progenitor cells overexpressing MPP1 acquired the ability to serially replate in methylcellulose culture, a property crucially dependent upon ABCC4. The highly conserved PDZ-binding motif of ABCC4 is required for ABCC4 and MPP1 to form a protein complex, which increased ABCC4 membrane localization and retention, to enhance drug resistance. Specific disruption of this protein complex, either genetically or chemically, removed ABCC4 from the plasma membrane, increased drug sensitivity, and abrogated MPP1 dependent hematopoietic progenitor cell replating in methylcellulose. High throughput screening identified Antimycin A as a small molecule that disrupted the ABCC4-MPP1 protein complex and reversed drug resistance in AML cell lines and in primary patient AML cells. In all, targeting the ABCC4-MPP1 protein complex can lead to new therapies to improve treatment outcome of AML, a disease where the long-term prognosis is poor. PMID- 29146911 TI - Cytokinesis requires localized beta-actin filament production by an actin isoform specific nucleator. AB - Cytokinesis is initiated by the localized assembly of the contractile ring, a dynamic actomyosin structure that generates a membrane furrow between the segregating chromosomal masses to divide a cell into two. Here we show that the stabilization and organization of the cytokinetic furrow is specifically dependent on localized beta-actin filament assembly at the site of cytokinesis. beta-actin filaments are assembled directly at the furrow by an anillin-dependent pathway that enhances RhoA-dependent activation of the formin DIAPH3, an actin nucleator. DIAPH3 specifically generates homopolymeric filaments of beta-actin in vitro. By employing enhancers and activators, cells can achieve acute spatio temporal control over isoform-specific actin arrays that are required for distinct cellular functions. PMID- 29146914 TI - Cat-D: a targeted sequencing method for the simultaneous detection of small DNA mutations and large DNA deletions with flexible boundaries. AB - We developed a targeted DNA sequencing method that is capable of detecting a comprehensive panel of DNA mutations including small DNA mutations and large DNA deletions with unknown/flexible boundaries. The method directly identifies the large DNA deletions (Cat-D) without relying on sequencing coverage to make the genotype calls. We performed the method to simultaneously detect 10 small DNA mutations in beta-thalassemia and 2 large genomic deletions in alpha-thalassemia from 10 genomic DNA samples. Cat-D was performed on 8 genomic DNA samples in duplicate. The 18 Cat-D samples were combined in one sequencing run. In total, 216 genotype calls were made, and 215 of the genotype calls were accurate. No false negative genotype calls were made. One false positive genotype call was made on one target mutation in one experimental duplicate from a genomic DNA sample. In summary, Cat-D can be developed into a robust, high-throughput and cost-effective method suitable for population-based carrier screens. PMID- 29146912 TI - Structural insights into Legionella RidL-Vps29 retromer subunit interaction reveal displacement of the regulator TBC1D5. AB - Legionella pneumophila can cause Legionnaires' disease and replicates intracellularly in a distinct Legionella-containing vacuole (LCV). LCV formation is a complex process that involves a plethora of type IV-secreted effector proteins. The effector RidL binds the Vps29 retromer subunit, blocks retrograde vesicle trafficking, and promotes intracellular bacterial replication. Here, we reveal that the 29-kDa N-terminal domain of RidL (RidL2-281) adopts a "foot-like" fold comprising a protruding beta-hairpin at its "heel". The deletion of the beta hairpin, the exchange to Glu of Ile170 in the beta-hairpin, or Leu152 in Vps29 abolishes the interaction in eukaryotic cells and in vitro. RidL2-281 or RidL displace the Rab7 GTPase-activating protein (GAP) TBC1D5 from the retromer and LCVs, respectively, and TBC1D5 promotes the intracellular growth of L. pneumophila. Thus, the hydrophobic beta-hairpin of RidL is critical for binding of the L. pneumophila effector to the Vps29 retromer subunit and displacement of the regulator TBC1D5. PMID- 29146913 TI - Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins. AB - Macroautophagy can regulate cell signalling and tumorigenesis via elusive molecular mechanisms. We establish a RAS mutant cancer cell model where the autophagy gene ATG5 is dispensable in A549 cells in vitro, yet promotes tumorigenesis in mice. ATG5 represses transcriptional activation by the TGFbeta SMAD gene regulatory pathway. However, autophagy does not terminate cytosolic signal transduction by TGFbeta. Instead, we use proteomics to identify selective degradation of the signalling scaffold TRAF3. TRAF3 autophagy is driven by RAS and results in activation of the NF-kappaB family member RELB. We show that RELB represses TGFbeta target promoters independently of DNA binding at NF-kappaB recognition sequences, instead binding with SMAD family member(s) at SMAD response elements. Thus, autophagy antagonises TGFbeta gene expression. Finally, autophagy-deficient A549 cells regain tumorigenicity upon SMAD4 knockdown. Thus, at least in this setting, a physiologic function for autophagic regulation of gene expression is tumour growth. PMID- 29146915 TI - Transcriptional profiling provides new insights into the role of nitric oxide in enhancing Ganoderma oregonense resistance to heat stress. AB - Ganoderma is well known for its use in traditional Chinese medicine and is widely cultivated in China, Korea, and Japan. Increased temperatures associated with global warming are negatively influencing the growth and development of Ganoderma. Nitric oxide is reported to play an important role in alleviating fungal heat stress (HS). However, the transcriptional profiling of Ganoderma oregonense in response to HS, as well as the transcriptional response regulated by NO to cope with HS has not been reported. We used RNA-Seq technology to generate large-scale transcriptome data from G. oregonense mycelia subjected to HS (32 degrees C) and exposed to concentrations of exogenous NO. The results showed that heat shock proteins (HSPs), "probable stress-induced proteins", and unigenes involved in "D-amino-acid oxidase activity" and "oxidoreductase activity" were significantly up-regulated in G. oregonense subjected to HS (P < 0.05). The significantly up-regulated HSPs, "monooxygenases", "alcohol dehydrogenase", and "FAD/NAD(P)-binding domain-containing proteins" (P < 0.05) regulated by exogenous NO may play important roles in the enhanced HS tolerance of G. oregonense. These results provide insights into the transcriptional response of G. oregonense to HS and the mechanism by which NO enhances the HS tolerance of fungi at the gene expression level. PMID- 29146916 TI - Deposition of topological silicene, germanene and stanene on graphene-covered SiC substrates. AB - Growth of X-enes, such as silicene, germanene and stanene, requires passivated substrates to ensure the survival of their exotic properties. Using first principles methods, we study as-grown graphene on polar SiC surfaces as suitable substrates. Trilayer combinations with coincidence lattices with large hexagonal unit cells allow for strain-free group-IV monolayers. In contrast to the Si terminated SiC surface, van der Waals-bonded honeycomb X-ene/graphene bilayers on top of the C-terminated SiC substrate are stable. Folded band structures show Dirac cones of the overlayers with small gaps of about 0.1 eV in between. The topological invariants of the peeled-off X-ene/graphene bilayers indicate the presence of topological character and the existence of a quantum spin Hall phase. PMID- 29146917 TI - Flow behavior of N2 huff and puff process for enhanced oil recovery in tight oil reservoirs. AB - In the present work, the potential of N2 huff and puff process to enhance the recovery of tight oil reservoir was evaluated. N2 huff and puff experiments were performed in micromodels and cores to investigate the flow behaviors of different cycles. The results showed that, in the first cycle, N2 was dispersed in the oil, forming the foamy oil flow. In the second cycle, the dispersed gas bubbles gradually coalesced into the continuous gas phase. In the third cycle, N2 was produced in the form of continuous gas phase. The results from the coreflood tests showed that, the primary recovery was only 5.32%, while the recoveries for the three N2 huff and puff cycles were 15.1%, 8.53% and 3.22%, respectively.The recovery and the pressure gradient in the first cycle were high. With the increase of huff and puff cycles, and the oil recovery and the pressure gradient rapidly decreased. The oil recovery of N2 huff and puff has been found to increase as the N2 injection pressure and the soaking time increased. These results showed that, the properly designed and controlled N2 huff and puff process can lead to enhanced recovery of tight oil reservoirs. PMID- 29146918 TI - Systematic characterization of the effect of Ag@TiO2 nanoparticles on the performance of plasmonic dye-sensitized solar cells. AB - The use of plasmonic nanoparticles (NPs) in dye-sensitized solar cells (DSSCs) in an effort to enhance their power conversion efficiencies (PCEs) increases light absorbance of the cells but also affect their electron dynamics. This has contributed to the failure of plasmonic NPs to make the expected high impact of PCE enhancement. Herein, we investigated the wide range effects of plasmonic NPs on the performance of DSSCs, using extended characterization and a systematic approach. We prepared DSSCs using Ag@TiO2 NPs-doped TiO2 photoanodes. Using a wide range doping concentration, we obtained panchromatic enhancement effect with two optimal doping concentrations (0.1 and 1 wt. %).They enhanced PCE via mainly: a) optimal band alignment for efficient charge injection; and b) a balance of the negative and positive effects of plasmonic NPs on cell performance parameters (open circuit voltage, fill factor, charge transfer resistance against recombination, electron life time and charge collection efficiency); respectively. The PCE of the pristine sample increased from 4.66 to 4.88 and 5.00% via these 2 routes, respectively. The major cause of not obtaining very high PCE was charge recombination from high charge density. Thus, these observations might serve as invaluable guidance for the preparation of highly efficient plasmonic DSSCs. PMID- 29146919 TI - Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation. AB - The 'acidic patch' is a highly electronegative cleft on the histone H2A-H2B dimer in the nucleosome. It is a fundamental motif for protein binding and chromatin dynamics, but the cellular impact of targeting this potentially therapeutic site with exogenous molecules remains unclear. Here, we characterize a family of binuclear ruthenium compounds that selectively target the nucleosome acidic patch, generating intra-nucleosomal H2A-H2B cross-links as well as inter nucleosomal cross-links. In contrast to cisplatin or the progenitor RAPTA-C anticancer drugs, the binuclear agents neither arrest specific cell cycle phases nor elicit DNA damage response, but rather induce an irreversible, anomalous state of condensed chromatin that ultimately results in apoptosis. In vitro, the compounds induce misfolding of chromatin fibre and block the binding of the regulator of chromatin condensation 1 (RCC1) acidic patch-binding protein. This family of chromatin-modifying molecules has potential for applications in drug development and as tools for chromatin research. PMID- 29146920 TI - Andy's Algorithms: new automated digital image analysis pipelines for FIJI. AB - Quantification of cellular antigens and their interactions via antibody-based detection methods are widely used in scientific research. Accurate high throughput quantitation of these assays using general image analysis software can be time consuming and challenging, particularly when attempted by users with limited image processing and analysis knowledge. To overcome this, we have designed Andy's Algorithms, a series of automated image analysis pipelines for FIJI, that permits rapid, accurate and reproducible batch-processing of 3,3' diaminobenzidine (DAB) immunohistochemistry, proximity ligation assays (PLAs) and other common assays. Andy's Algorithms incorporates a step-by-step tutorial and optimization pipeline to make batch image analysis simple for the untrained user and adaptable across laboratories. Andy's algorithms provide a simpler, faster, standardized work flow compared to existing programs, while offering equivalent performance and additional features, in a free to use open-source application of FIJI. Andy's Algorithms are available at GitHub, publicly accessed at https://github.com/andlaw1841/Andy-s-Algorithm . PMID- 29146921 TI - Plastic deformation behaviour of single-crystalline martensite of Ti-Nb shape memory alloy. AB - beta-Ti alloys have attracted considerable attention as new biomedical shape memory alloys. Given the critical importance of the plastic deformation in the martensite phase for the shape memory effect and superelasticity, we investigated here the plastic deformation behaviour of a single crystal of alpha" (orthorhombic) martensite of Ti-27 mol%Nb shape memory alloy obtained by the stress-induced martensitic transformation of a single crystal of the parent beta phase. Four operative plastic deformation modes were observed, including two dislocation slips and two twinnings. To the best of our knowledge, two of these plastic deformation modes (one dislocation slip and one twinning) were discovered for the first time in this study. The identified slip and twinning systems in the martensite phase have corresponding slip and twinning systems in the parent beta phase with which they share many similarities. Therefore, we believe that the plastic deformation of the alpha" martensite is inherited from that of the parent beta phase. PMID- 29146923 TI - Incidence and mortality of kidney cancer: temporal patterns and global trends in 39 countries. AB - We tested the hypotheses that kidney cancer incidence was increasing globally whilst its mortality was reducing; and its incidence was positively correlated with country-specific socioeconomic development. The incidence and mortality figures of each country were projected to 2030. Data on age-standardized incidence/mortality rates were retrieved from the GLOBOCAN in 2012. Temporal patterns were examined for 39 countries from the Cancer Incidence in Five Continents volumes I-X and other national registries. We evaluated the correlation between the incidence/mortality rates and Human Development Index (HDI)/Gross Domestic Product (GDP]). The average annual percent change of its incidence and mortality in the most recent 10 years was obtained from joinpoint regression. The highest incidence rates were observed in Eastern Europe and North America, while its mortality rates were the highest in European countries. Incidence was positively correlated with HDI and GDP per capita. Many countries experienced incidence rise over the most recent 10 years, and a substantial reduction in mortality rates was observed for a significant number of countries, yet increases in mortality rates were observed in Eastern Europe. By 2030, Brazil and Ecuador may have the greatest rise in incidence both in men and women, which requires urgent need for planning healthcare resources. PMID- 29146922 TI - Molecular definition of multiple sites of antibody inhibition of malaria transmission-blocking vaccine antigen Pfs25. AB - The Plasmodium falciparum Pfs25 protein (Pfs25) is a leading malaria transmission blocking vaccine antigen. Pfs25 vaccination is intended to elicit antibodies that inhibit parasite development when ingested by Anopheles mosquitoes during blood meals. The Pfs25 three-dimensional structure has remained elusive, hampering a molecular understanding of its function and limiting immunogen design. We report six crystal structures of Pfs25 in complex with antibodies elicited by immunization via Pfs25 virus-like particles in human immunoglobulin loci transgenic mice. Our structural findings reveal the fine specificities associated with two distinct immunogenic sites on Pfs25. Importantly, one of these sites broadly overlaps with the epitope of the well-known 4B7 mouse antibody, which can be targeted simultaneously by antibodies that target a non-overlapping site to additively increase parasite inhibition. Our molecular characterization of inhibitory antibodies informs on the natural disposition of Pfs25 on the surface of ookinetes and provides the structural blueprints to design next-generation immunogens. PMID- 29146924 TI - Interpretation of dynamic tensile behavior by austenite stability in ferrite austenite duplex lightweight steels. AB - Phenomena occurring in duplex lightweight steels under dynamic loading are hardly investigated, although its understanding is essentially needed in applications of automotive steels. In this study, quasi-static and dynamic tensile properties of duplex lightweight steels were investigated by focusing on how TRIP and TWIP mechanisms were varied under the quasi-static and dynamic loading conditions. As the annealing temperature increased, the grain size and volume fraction of austenite increased, thereby gradually decreasing austenite stability. The strain hardening rate curves displayed a multiple-stage strain-hardening behavior, which was closely related with deformation mechanisms. Under the dynamic loading, the temperature rise due to adiabatic heating raised the austenite stability, which resulted in the reduction in the TRIP amount. Though the 950 degrees C-annealed specimen having the lowest austenite stability showed the very low ductility and strength under the quasi-static loading, it exhibited the tensile elongation up to 54% as well as high strain-hardening rate and tensile strength (1038 MPa) due to appropriate austenite stability under dynamic loading. Since dynamic properties of the present duplex lightweight steels show the excellent strength ductility combination as well as continuously high strain hardening, they can be sufficiently applied to automotive steel sheets demanded for stronger vehicle bodies and safety enhancement. PMID- 29146925 TI - To infinity and some glimpses of beyond. AB - When mathematical and computational dynamic models reach infinity in finite time, extending analysis and numerics beyond it becomes a notorious challenge. We suggest how, upon suitable transformations, it may become possible to go beyond infinity with the solution becoming again well behaved and the computations continuing normally. In our Ordinary Differential Equation examples the crossing of infinity occurs instantaneously. For Partial Differential Equations, the crossing of infinity may persist for finite time, necessitating the introduction of buffer zones, within which an appropriate transformation is adaptively identified. Along the path of our analysis, we present a regularization process via complexification and explore its impact on the dynamics; we also discuss a set of compactification transformations and their intuitive implications. This methodology could be useful toward a systematic approach to bypassing infinity and thus going beyond it in a broader range of evolution equation models. PMID- 29146926 TI - Correlations and forecast of death tolls in the Syrian conflict. AB - The Syrian armed conflict has been ongoing since 2011 and has already caused thousands of deaths. The analysis of death tolls helps to understand the dynamics of the conflict and to better allocate resources and aid to the affected areas. In this article, we use information on the daily number of deaths to study temporal and spatial correlations in the data, and exploit this information to forecast events of deaths. We found that the number of violent deaths per day in Syria varies more widely than that in England in which non-violent deaths dominate. We have identified strong positive auto-correlations in Syrian cities and non-trivial cross-correlations across some of them. The results indicate synchronization in the number of deaths at different times and locations, suggesting respectively that local attacks are followed by more attacks at subsequent days and that coordinated attacks may also take place across different locations. Thus the analysis of high temporal resolution data across multiple cities makes it possible to infer attack strategies, warn potential occurrence of future events, and hopefully avoid further deaths. PMID- 29146927 TI - Preparation and functional evaluation of collagen oligopeptide-rich hydrolysate from fish skin with the serine collagenolytic protease from Pseudoalteromonas sp. SM9913. AB - Although several serine collagenolytic proteases from bacteria were reported, none has been used to prepare bioactive collagen peptides. MCP-01 is the most abundant extracellular protease of deep-sea Pseudoalteromonas sp. SM9913 and is a serine collagenolytic protease with high efficiency on fish collagen hydrolysis. Here, we set up a pilot scale process to ferment SM9913 for extracellular protease production. With SM9913 extracellular protease as a tool, a process to prepare collagen oligopeptide-rich hydrolysate from codfish skin was set up, which was further scaled up to pilot (100 L) and plant (2000 L) levels with yields >66%. The hydrolysates from laboratory-, pilot- and plant-scales had quite similar quality, containing ~95% peptides with molecular weights lower than 3000 Da and approximately 60% lower than 1000 Da, in which collagen oilgopeptides account for approximately 95%. Bioactivity analyses showed that the hydrolysate had moisture-retention ability, antioxidant activity, and promoting effect on cell viability of human dermal fibroblasts. Safety evaluation showed that the hydrolysate was nontoxic and nonirritating to skin. Therefore, SM9913 extracellular protease is a good enzyme to prepare bioactive oligopeptides from fish skin. The results also suggest that the collagen oligopeptides-rich hydrolysate may have potentials in biomedical, functional food, pharmaceutical and cosmetic industries. PMID- 29146928 TI - Significant enhanced uranyl ions extraction efficiency with phosphoramidate functionalized ionic liquids via synergistic effect of coordination and hydrogen bond. AB - The influence of the linking group between the phosphoryl and bridging moieties in phosphoryl-containing task-specific ionic liquids (TSILs) on the extraction of uranyl ions was experimentally and theoretically investigated. A novel phosphoramidate-based TSIL with an amine group as the linking moiety resulted in a higher uranyl ion extraction efficiency compared with that of other phosphoryl based TSILs. A distribution ratio of 4999 +/- 51 can be achieved for uranyl ions. The uranyl ions (76.7 +/- 1.5%) were stripped from the loaded ionic liquid phase in a single stage using 0.05 M diethylenetriamine pentaacetic acid in a 1.0 M guanidine carbonate solution. The extraction stoichiometry of the uranyl ions was determined by a slope analysis of the extraction data. Furthermore, the fundamental nature of the interaction between the phosphoramidate-based TSIL and uranyl ions was theoretically studied for the first time. The theoretical calculations demonstrated that the synergistic effect of the complexation interaction and H-bond formation between the phosphoramidate-functional ionic liquid and uranyl nitrate led to the higher extraction efficiency. These results provide a basis for rational design, synthesis and potential applications of novel TSILs for uranyl extraction. PMID- 29146929 TI - Excavating hidden adsorption sites in metal-organic frameworks using rational defect engineering. AB - Metal-organic frameworks are known to contain defects within their crystalline structures. Successful engineering of these defects can lead to modifications in material properties that can potentially improve the performance of many existing frameworks. Herein, we report the high-throughput computational screening of a large experimental metal-organic framework database to identify 13 frameworks that show significantly improved methane storage capacities with linker vacancy defects. The candidates are first identified by focusing on structures with methane-inaccessible pores blocked away from the main adsorption channels. Then, organic linkers of the candidate structures are judiciously replaced with appropriate modulators to emulate the presence of linker vacancies, resulting in the integration and utilization of the previously inaccessible pores. Grand canonical Monte Carlo simulations of defective candidate frameworks show significant enhancements in methane storage capacities, highlighting that rational defect engineering can be an effective method to significantly improve the performance of the existing metal-organic frameworks. PMID- 29146930 TI - Previous crop and rotation history effects on maize seedling health and associated rhizosphere microbiome. AB - To evaluate crop rotation effects on maize seedling performance and its associated microbiome, maize plants were grown in the greenhouse in soils preceded by either maize, pea, soybean or sunflower. Soils originated from a replicated field experiment evaluating different four-year rotation combinations. In the greenhouse, a stressor was introduced by soil infestation with western corn rootworm (WCR) or Fusarium graminearum. Under non-infested conditions, maize seedlings grown in soils preceded by sunflower or pea had greater vigor. Stress with WCR or F. graminearum resulted in significant root damage. WCR root damage was equivalent for seedlings regardless of soil provenance; whereas F. graminearum root damage was significantly lower in maize grown in soils preceded by sunflower. Infestation with WCR affected specific microbial taxa (Acinetobacter, Smaragdicoccus, Aeromicrobium, Actinomucor). Similarly, F. graminearum affected fungal endophytes including Trichoderma and Endogone. In contrast to the biological stressors, rotation sequence had a greater effect on rhizosphere microbiome composition, with larger effects observed for fungi compared to bacteria. In particular, relative abundance of Glomeromycota was significantly higher in soils preceded by sunflower or maize. Defining the microbial players involved in crop rotational effects in maize will promote selection and adoption of favorable crop rotation sequences. PMID- 29146931 TI - A novel magnet-actuated droplet manipulation platform using a floating ferrofluid film. AB - In this paper, we propose a novel but versatile magnet-actuated platform for droplet manipulation, which uses a ferrofluid film floating on a liquid surface as magnetic actuator. In contrast to the traditional magnetic droplet manipulation, this platform can handle droplets without magnetically functionalizing them. Due to the immiscibility of the oil-based ferrofluid and water, the droplets desired to be manipulated can stably rest on the surface of the floating ferrofluid film (FFF) under the action of surface tension, thereby offering possibilities for magnetically-driven droplet manipulations. Such a floating, magnetically responsive liquid film not only offers an open surface for active 2D droplet manipulation, but also enables complex droplet manipulations in 3D space. Using FFF, we demonstrate a "full-space" droplet manipulation, including droplet transport/coalescence above FFF (i.e. in air), droplet transport/coalescence on FFF and droplet encapsulation/release under FFF (i.e. in liquid). Furthermore, we investigated the effects of the magnetic field intensity, the ferrofluid concentration, the droplet volume, and the FFF thickness on droplet kinematics. By finely tuning these operating conditions, the FFF strategy can enjoy more operational latitude than traditional droplet systems, thus allowing more versatile liquid handling. PMID- 29146932 TI - Activation of endogenous arginine vasopressin neurons inhibit food intake: by using a novel transgenic rat line with DREADDs system. AB - Various studies contributed to discover novel mechanisms of central arginine vasopressin (AVP) system responsible for the behaviour albeit endogenous vasopressin activation. We established a novel transgenic rat line which expresses both human muscarinic acetylcholine receptors (hM3Dq), of which ligand is clozapine-N-oxide (CNO), and mCherry fluorescence specifically in AVP neurons. The mCherry neurons that indicate the expression of the hM3Dq gene were observed in the suprachiasmatic (SCN), supraoptic (SON), and paraventricular nuclei (PVN). hM3Dq-mCherry fluorescence was localized mainly in the membrane of the neurons. The mCherry neurons were co-localized with AVP-like immunoreactive (LI) neurons, but not with oxytocin-LI neurons. The induction of Fos, which is the indicator for neuronal activity, was observed in approximately 90% of the AVP-LI neurons in the SON and PVN 90 min after intraperitoneal (i.p.) administration of CNO. Plasma AVP was significantly increased and food intake, water intake, and urine volume were significantly attenuated after i.p. administration of CNO. Although the detailed mechanism has unveiled, we demonstrated, for the first time, that activation of endogenous AVP neurons decreased food intake. This novel transgenic rat line may provide a revolutionary insight into the neuronal mechanism regarding central AVP system responsible for various kind of behaviours. PMID- 29146933 TI - Coupled Motion of Contact Line on Nanoscale Chemically Heterogeneous Surfaces for Improved Bubble Dynamics in Boiling. AB - We demonstrate that the contact line (CL) motion on energetically heterogeneous solid surfaces occurs in a coupled fashion as against the traditional staggered stick-slip motion. Introducing chemical inhomogeneities at nanoscale induces a local change in dynamic contact angles which manifests as a smooth and continuous motion of the CL. Nanoscale chemically inhomogeneous surfaces comprising of gold, palladium and nickel were generated on copper substrates to demonstrate the underlying CL dynamics. The spatial variations of chemical constituents were mapped using elemental display scanning electron microscope images. Further, the coupled and stick-slip motion was confirmed for a sliding water droplet on these surfaces, and then used in studying the pool boiling bubble dynamics of a single bubble from nucleation to departure. The coupled motion was seen to increase the CL velocity thereby increasing the contribution from transient conduction heat transfer. Consequently, a ~2X increase in the boiling critical heat flux (CHF) was observed. Enhancing the pool boiling performance by introducing nanoscale surface features is an attractive approach in many applications and this work provides a framework and understanding of the CL motion induced through the chemical inhomogeneity effects. PMID- 29146934 TI - A continuous 13.3-ka record of seismogenic dust events in lacustrine sediments in the eastern Tibetan Plateau. AB - Lacustrine sediments on the eastern Tibetan Plateau (TP) contain a wealth of information on local and regional tectonic activity. High-resolution grain-size and magnetic susceptibility measurements were conducted on the 23.4-m-thick Lixian lacustrine sedimentary sequence spanning from 19.3 to 6.0 ka, revealing 70 prehistoric seismic events on the eastern TP. The seismic events caused intermittent increases in source materials that endowed the samples of an individual event layer with a gradual fining trend along the C = M line on a C (one percentile)-M (median diameter) plot. Grain-size distribution and end-member modeling imply that dust particles of <20 MUm in size were transported primarily by long-term suspension, while medium to coarse silt and sand were transported primarily by short-term suspension, such as aeolian transport constrained by local topography. Provenance analysis based on U-Pb zircon ages indicates that dust particles generated by earthquakes at Lixian had no effect on dust deposition at Xinmocun and Diaolin, and vice versa. These prehistoric seismic events, revealed by variations in grain size and magnetic susceptibility, thus provide invaluable information on the long-term behavior of local seismic activity. PMID- 29146935 TI - Quantitative Evaluation of Nanosecond Pulsed Laser-Induced Photomodification of Plasmonic Gold Nanoparticles. AB - The rapid growth of gold nanoparticle applications in laser therapeutics and diagnostics has brought about the need for establishing innovative standardized test methods for evaluation of safety and performance of these technologies and related medical products. Furthermore, given the incomplete and inconsistent data on nanoparticle photomodification thresholds provided in the literature, further elucidation of processes that impact the safety and effectiveness of laser nanoparticle combination products is warranted. Therefore, we present a proof-of concept study on an analytical experimental test methodology including three approaches (transmission electron microscopy, dynamic light scattering, and spectrophotometry) for experimental evaluation of damage thresholds in nanosecond pulsed laser-irradiated gold nanospheres, and compared our results with a theoretical model and prior studies. This thorough evaluation of damage threshold was performed based on irradiation with a 532 nm nanosecond-pulsed laser over a range of nanoparticle diameters from 20 to 100 nm. Experimentally determined damage thresholds were compared to a theoretical heat transfer model of pulsed laser-irradiated nanoparticles and found to be in reasonably good agreement, although some significant discrepancies with prior experimental studies were found. This study and resultant dataset represent an important foundation for developing a standardized test methodology for determination of laser-induced nanoparticle damage thresholds. PMID- 29146936 TI - Hypomethylation of HOXA4 promoter is common in Silver-Russell syndrome and growth restriction and associates with stature in healthy children. AB - Silver-Russell syndrome (SRS) is a growth retardation syndrome in which loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy for chromosome 7 [UPD(7)mat] explain 20-60% and 10% of the syndrome, respectively. To search for a molecular cause for the remaining SRS cases, and to find a possible common epigenetic change, we studied DNA methylation pattern of more than 450 000 CpG sites in 44 SRS patients. Common to all three SRS subgroups, we found a hypomethylated region at the promoter region of HOXA4 in 55% of the patients. We then tested 39 patients with severe growth restriction of unknown etiology, and found hypomethylation of HOXA4 in 44% of the patients. Finally, we found that methylation at multiple CpG sites in the HOXA4 promoter region was associated with height in a cohort of 227 healthy children, suggesting that HOXA4 may play a role in regulating human growth by epigenetic mechanisms. PMID- 29146937 TI - TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes. AB - Lysosomal distribution is linked to the role of lysosomes in many cellular functions, including autophagosome degradation, cholesterol homeostasis, antigen presentation, and cell invasion. Alterations in lysosomal positioning contribute to different human pathologies, such as cancer, neurodegeneration, and lysosomal storage diseases. Here we report the identification of a novel mechanism of lysosomal trafficking regulation. We found that the lysosomal transmembrane protein TMEM55B recruits JIP4 to the lysosomal surface, inducing dynein-dependent transport of lysosomes toward the microtubules minus-end. TMEM55B overexpression causes lysosomes to collapse into the cell center, whereas depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery. TMEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress. TMEM55B or JIP4 depletion abolishes starvation-induced retrograde lysosomal transport and prevents autophagosome-lysosome fusion. Overall our data suggest that the TFEB/TMEM55B/JIP4 pathway coordinates lysosome movement in response to a variety of stress conditions. PMID- 29146939 TI - Optomechanical terahertz detection with single meta-atom resonator. AB - Most of the common technologies for detecting terahertz photons (>1 THz) at room temperature rely on slow thermal devices. The realization of fast and sensitive detectors in this frequency range is indeed a notoriously difficult task. Here we propose a novel device consisting of a subwavelength terahertz meta-atom resonator, which integrates a nanomechanical element and allows energy exchange between the mechanical motion and the electromagnetic degrees of freedom. An incident terahertz wave thus produces a nanomechanical signal that can be read out optically with high precision. We exploit this concept to demonstrate a terahertz detector that operates at room temperature with high sensitivity and a much higher frequency response compared to standard detectors. Beyond the technological issue of terahertz detection, our architecture opens up new perspectives for fundamental science of light-matter interaction at terahertz frequencies, combining optomechanical approaches with semiconductor quantum heterostructures. PMID- 29146938 TI - Computational Investigation of Homologous Recombination DNA Repair Deficiency in Sporadic Breast Cancer. AB - BRCAness has important implications in the management and treatment of patients with breast and ovarian cancer. In this study, we propose a computational framework to measure the BRCAness of breast and ovarian tumor samples based on their gene expression profiles. We define a characteristic profile for BRCAness by comparing gene expression differences between BRCA1/2 mutant familial tumors and sporadic breast cancer tumors while adjusting for relevant clinical factors. With this BRCAness profile, our framework calculates sample-specific BRCA scores, which indicates homologous recombination (HR)-mediated DNA repair pathway activity of samples. We found that in sporadic breast cancer high BRCAness score is associated with aberrant copy number of HR genes rather than somatic mutation and other genomic features. Moreover, we observed significant correlations of BRCA score with genome instability and neoadjuvant chemotherapy. More importantly, BRCA score provides significant prognostic value in both breast and ovarian cancers after considering established clinical variables. In summary, the inferred BRCAness from our framework can be used as a robust biomarker for the prediction of prognosis and treatment response in breast and ovarian cancers. PMID- 29146940 TI - Development and physiological effects of an artificial diet for Wolbachia infected Aedes aegypti. AB - The endosymbiotic bacterium Wolbachia spreads rapidly through populations of Aedes aegypti mosquitoes, and strongly inhibits infection with key human pathogens including the dengue and Zika viruses. Mosquito control programs aimed at limiting transmission of these viruses are ongoing in multiple countries, yet there is a dearth of mass rearing infrastructure specific to Wolbachia-infected mosquitoes. One example is the lack of a blood meal substitute, which accounts for the Wolbachia-specific physiological changes in infected mosquitoes, that allows the bacterium to spread, and block viral infections. To that end, we have developed a blood meal substitute specifically for mosquitoes infected with the wMel Wolbachia strain. This diet, ADM, contains milk protein, and infant formula, dissolved in a mixture of bovine red blood cells and Aedes physiological saline, with ATP as a phagostimulant. Feeding with ADM leads to high levels of viable egg production, but also does not affect key Wolbachia parameters including, bacterial density, cytoplasmic incompatibility, or resistance to infection with Zika virus. ADM represents an effective substitute for human blood, which could potentially be used for the mass rearing of wMel-infected A. aegypti, and could easily be optimized in the future to improve performance. PMID- 29146942 TI - Efficient near infrared light emitting electrochemical cell (NIR-LEEC) based on new binuclear ruthenium phenanthroimidazole exhibiting desired charge carrier dynamics. AB - Near-infrared light-emitting electrochemical cell (NIR-LEEC) has emerged as a new and promising lighting sourcewhich could serve as low-cost alternatives in NIR light-emitting sources which are typically expensive. LECs were also shown advantages such as light weight, simplicity and low operation voltages. However, only a few examples of NIR-LEEC are reported in which external quantum efficiency(EQE) of devices limited to 0.1%. Here, we report, efficient NIR-LEEC based of two novel binuclear ruthenium phenanthroimidzole complex which differ by employing the type of ancillary ligand including 2, 2'bipyridine (bpy) (B1) and 4, 4' dimethyl bpy (B2) that realize maximum EQE of 0.14 and 0.68% and extremely long excited state lifetimes of 220 and 374 ns for thin film were estimated, respectively, indicating that influences of substitution on ancillary ligand. Moreover, this substitution dramatically influences other electroluminescence metrics including decreasing turn on voltage from 4.5 to 3.1 V, increasing maximum luminance (Lmax) from 193to 742 cd.m-2 and increasing lifetime from 539 to 1104 second, which are the best value among the binuclear ruthenium polypyridyl complexes to date. PMID- 29146941 TI - Developmental excitatory-to-inhibitory GABA-polarity switch is disrupted in 22q11.2 deletion syndrome: a potential target for clinical therapeutics. AB - Individuals with 22q11.2 microdeletion syndrome (22q11.2 DS) show cognitive and behavioral dysfunctions, developmental delays in childhood and risk of developing schizophrenia and autism. Despite extensive previous studies in adult animal models, a possible embryonic root of this syndrome has not been determined. Here, in neurons from a 22q11.2 DS mouse model (Lgdel +/-), we found embryonic premature alterations in the neuronal chloride cotransporters indicated by dysregulated NKCC1 and KCC2 protein expression levels. We demonstrate with large scale spiking activity recordings a concurrent deregulation of the spontaneous network activity and homeostatic network plasticity. Additionally, Lgdel +/- networks at early development show abnormal neuritogenesis and void of synchronized spontaneous activity. Furthermore, parallel experiments on Dgcr8 +/- mouse cultures reveal a significant, yet not exclusive contribution of the dgcr8 gene to our phenotypes of Lgdel +/- networks. Finally, we show that application of bumetanide, an inhibitor of NKCC1, significantly decreases the hyper-excitable action of GABAA receptor signaling and restores network homeostatic plasticity in Lgdel +/- networks. Overall, by exploiting an on-a-chip 22q11.2 DS model, our results suggest a delayed GABA-switch in Lgdel +/- neurons, which may contribute to a delayed embryonic development. Prospectively, acting on the GABA-polarity switch offers a potential target for 22q11.2 DS therapeutic intervention. PMID- 29146943 TI - Cryopreservation of Human Mesenchymal Stem Cells in an Allogeneic Bioscaffold based on Platelet Rich Plasma and Synovial Fluid. AB - Transplantation of mesenchymal stem cells (MSCs) has emerged as an alternative strategy to treat knee osteoarthritis. In this context, MSCs derived from synovial fluid could provide higher chondrogenic and cartilage regeneration, presenting synovial fluid as an appropriate MSCs source. An allogeneic and biomimetic bioscaffold composed of Platelet Rich Plasma and synovial fluid that preserve and mimics the natural environment of MSCs isolated from knee has also been developed. We have optimized the cryopreservation of knee-isolated MSCs embedded within the aforementioned biomimetic scaffold, in order to create a reserve of young autologous embedded knee MSCs for future clinical applications. We have tested several cryoprotectant solutions combining dimethyl sulfoxide (DMSO), sucrose and human serum and quantifying the viability and functionality of the embedded MSCs after thawing. MSCs embedded in bioscaffolds cryopreserved with DMSO 10% or the combination of DMSO 10% and Sucrose 0,2 M displayed the best cell viabilities maintaining the multilineage differentiation potential of MSCs after thawing. In conclusion, embedded young MSCs within allogeneic biomimetic bioscaffold can be cryopreserved with the cryoprotectant solutions described in this work, allowing their future clinical use in patients with cartilage defects. PMID- 29146945 TI - Maraba virus-vectored cancer vaccines represent a safe and novel therapeutic option for cats. AB - Direct killing of malignant cells combined with induction of tumour-specific immune responses makes oncolytic vaccines attractive for cancer therapy. We previously developed a heterologous cancer immunization strategy that utilized a replication-defective adenovirus-vectored primary vaccine encoding a tumour antigen followed by boosting with a replication-competent Maraba virus expressing the same antigen. To assess the safety of oncolytic Maraba virus-based booster vaccines and inform the design of clinical trials, we conducted translational studies in cats, which have immune systems that are similar to people and spontaneously develop cancers of comparable types and etiologies. A dose of Maraba virus up to 2.5 * 1011 pfu per cat was well-tolerated, with adverse effects limited to mild, transient pyrexia, weight loss, neutropenia, lymphopenia and thrombocytopenia. Maraba viral genomes were present in some urine, stool and most plasma samples up to one week post-infection, but no infectious viruses were recovered. Post-mortem analysis showed one heart, one lung and all spleen samples contained Maraba virus genomes. No replication-competent viruses were recovered from any tissues. Post-mortem histopathological analyses revealed hyperplasia of lymphoid tissues, but no abnormal lesions were attributed to vaccination. This study demonstrated that Maraba virus-vectored cancer vaccines were well-tolerated and supports their use in treating cats. PMID- 29146944 TI - Structure of the transcription activator target Tra1 within the chromatin modifying complex SAGA. AB - The transcription co-activator complex SAGA is recruited to gene promoters by sequence-specific transcriptional activators and by chromatin modifications to promote pre-initiation complex formation. The yeast Tra1 subunit is the major target of acidic activators such as Gal4, VP16, or Gcn4 but little is known about its structural organization. The 430 kDa Tra1 subunit and its human homolog the transformation/transcription domain-associated protein TRRAP are members of the phosphatidyl 3-kinase-related kinase (PIKK) family. Here, we present the cryo-EM structure of the entire SAGA complex where the major target of activator binding, the 430 kDa Tra1 protein, is resolved with an average resolution of 5.7 A. The high content of alpha-helices in Tra1 enabled tracing of the majority of its main chain. Our results highlight the integration of Tra1 within the major epigenetic regulator SAGA. PMID- 29146946 TI - De novo Transcriptome Sequencing of MeJA-Induced Taraxacum koksaghyz Rodin to Identify Genes Related to Rubber Formation. AB - Increase in the consumption of natural rubber (NR) has necessitated the identification of alternative sources of NR. The quality of NR produced by Taraxacum koksaghyz Rodin (TKS) is comparable to that from Hevea brasiliensis (H.brasiliensis), and therefore, TKS is being considered as an alternative source of NR. Here, we sequenced the TKS root transcriptome after wild TKS seedlings were treated with methyl jasmonate (MeJA) for 0, 6, and 24 h. The clean reads generated for each experimental line were assembled into 127,833 unigenes. The Kyoto encyclopedia of genes and genomes pathway prediction suggested that methyl jasmonate regulated secondary metabolism in TKS. Differential expression analysis showed that the expression of HMGCR, FPPS, IDI, GGPPS, and REF/SRPP increased with methyl jasmonate treatment. Interestingly, differential expression analysis of the jasmonate (JA)-related transcription factors (TFs), indicated that certain genes encoding these transcription factors (namely, bHLH, MYB, AP2/EREBP, and WRKY) showed the same expression pattern in the lines treated for 6 h and 24 h. Moreover, HMGCR was up-regulated in the transgenic seedlings overexpressing DREB. We predicted that methyl jasmonate regulated secondary metabolism and affected rubber biosynthesis via the interaction of the JA-related TFs with genes associated with rubber biosynthesis in TKS. PMID- 29146947 TI - The semiquinone swing in the bifurcating electron transferring flavoprotein/butyryl-CoA dehydrogenase complex from Clostridium difficile. AB - The electron transferring flavoprotein/butyryl-CoA dehydrogenase (EtfAB/Bcd) catalyzes the reduction of one crotonyl-CoA and two ferredoxins by two NADH within a flavin-based electron-bifurcating process. Here we report on the X-ray structure of the Clostridium difficile (EtfAB/Bcd)4 complex in the dehydrogenase conducting D-state, alpha-FAD (bound to domain II of EtfA) and delta-FAD (bound to Bcd) being 8 A apart. Superimposing Acidaminococcus fermentans EtfAB onto C. difficile EtfAB/Bcd reveals a rotation of domain II of nearly 80 degrees . Further rotation by 10 degrees brings EtfAB into the bifurcating B-state, alpha FAD and beta-FAD (bound to EtfB) being 14 A apart. This dual binding mode of domain II, substantiated by mutational studies, resembles findings in non bifurcating EtfAB/acyl-CoA dehydrogenase complexes. In our proposed mechanism, NADH reduces beta-FAD, which bifurcates. One electron goes to ferredoxin and one to alpha-FAD, which swings over to reduce delta-FAD to the semiquinone. Repetition affords a second reduced ferredoxin and delta-FADH-, which reduces crotonyl-CoA. PMID- 29146948 TI - A rapid-response ultrasensitive biosensor for influenza virus detection using antibody modified boron-doped diamond. AB - According to the World Health Organization (WHO), almost 2 billion people each year are infected worldwide with flu-like pathogens including influenza. This is a contagious disease caused by viruses belonging to the family Orthomyxoviridae. Employee absenteeism caused by flu infection costs hundreds of millions of dollars every year. To successfully treat influenza virus infections, detection of the virus during the initial development phase of the infection is critical, when tens to hundreds of virus-associated molecules are present in the patient's pharynx. In this study, we describe a novel universal diamond biosensor, which enables the specific detection of the virus at ultralow concentrations, even before any clinical symptoms arise. A diamond electrode is surface-functionalized with polyclonal anti-M1 antibodies, which then serve to identify the universal biomarker for the influenza virus, M1 protein. The absorption of the M1 protein onto anti-M1 sites of the electrode change its electrochemical impedance spectra. We achieved a limit of detection of 1 fg/ml in saliva buffer for the M1 biomarker, which corresponds to 5-10 viruses per sample in 5 minutes. Furthermore, the universality of the assay was confirmed by analyzing different strains of influenza A virus. PMID- 29146949 TI - A Microfluidic Platform for the Characterisation of CNS Active Compounds. AB - New in vitro technologies that assess neuronal excitability and the derived synaptic activity within a controlled microenvironment would be beneficial for the characterisation of compounds proposed to affect central nervous system (CNS) function. Here, a microfluidic system with computer controlled compound perfusion is presented that offers a novel methodology for the pharmacological profiling of CNS acting compounds based on calcium imaging readouts. Using this system, multiple applications of the excitatory amino acid glutamate (10 nM-1 mM) elicited reproducible and reversible transient increases in intracellular calcium, allowing the generation of a concentration response curve. In addition, the system allows pharmacological investigations to be performed as evidenced by application of glutamatergic receptor antagonists, reversibly inhibiting glutamate-induced increases in intracellular calcium. Importantly, repeated glutamate applications elicited significant increases in the synaptically driven activation of the adjacent, environmentally isolated neuronal network. Therefore, the proposed new methodology will enable neuropharmacological analysis of CNS active compounds whilst simultaneously determining their effect on synaptic connectivity. PMID- 29146950 TI - Author Correction: Radiative recombination of confined electrons at the MgZnO/ZnO heterojunction interface. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29146951 TI - Alzheimer disease: Blood-derived Abeta induces AD pathology. PMID- 29146955 TI - Motor neuron disease: Positive trial results published for ground-breaking SMA therapies. PMID- 29146954 TI - Multiple sclerosis: Progressive multifocal leukoencephalopathy risk stratification. PMID- 29146952 TI - Migrainomics - identifying brain and genetic markers of migraine. AB - Migraine is one of the world's most prevalent and disabling disorders and imposes an enormous socioeconomic burden. The exact causes of migraine are unknown, and no recognizable diagnostic pathological changes have been identified. Specific identifiable markers of migraine would aid diagnosis and could provide insight into the pathogenesis of the condition, with the potential to direct development of new therapeutics. In the past few years, advances in neuroimaging and genetic studies have provided the most substantial progress towards the identification of markers. A growing number of brain imaging studies have provided important insights into the brain mechanisms that underlie migraine symptoms during and between migraine attacks. Similarly, large-scale genome-wide association studies have identified genetic variants associated with the common forms of migraine - migraine with aura and migraine without aura. In total, 44 independent single nucleotide polymorphism loci have been robustly associated with the risk of migraine and provide new evidence for the involvement of vascular mechanisms. Both imaging and genetics, therefore, have excellent potential as markers of migraine. In this Review, we provide a summary of results regarding current and potential neuroimaging and genetic markers of migraine, consider what conclusions can be drawn from these markers about migraine mechanisms and discuss the potential of combining imaging and genetics. PMID- 29146953 TI - Achievements and obstacles of remyelinating therapies in multiple sclerosis. AB - Remyelination in the CNS is the natural process of damage repair in demyelinating diseases such as multiple sclerosis (MS). However, remyelination becomes inadequate in many people with MS, which results in axonal degeneration and clinical disability. Enhancement of remyelination is a logical therapeutic goal; nevertheless, all currently licensed therapies for MS are immunomodulatory and do not support remyelination directly. Several molecular pathways have been identified as potential therapeutic targets to induce remyelination, and some of these have now been assessed in proof-of-concept clinical trials. However, trial design faces several obstacles: optimal clinical or paraclinical outcome measures to assess remyelination remain ill-defined, and identification of the ideal timing of therapy is also a crucial issue. In addition, realistic expectations are needed concerning the probable benefits of such therapies. Nevertheless, approaches that enhance remyelination are likely to be protective for axons and so could prevent long-term neurodegeneration. Future MS treatment paradigms, therefore, are likely to comprise a combinatorial approach that involves both immunomodulatory and regenerative treatments. PMID- 29146956 TI - Electrical analysis of c-Si/CGSe monolithic tandem solar cells by using a cell selective light absorption scheme. AB - A monolithic tandem solar cell consisting of crystalline Si (c-Si)/indium tin oxide (ITO)/CuGaSe2 (CGSe) was demonstrated by stacking a CGSe solar cell on a c Si/ITO solar cell to obtain a photovoltaic conversion efficiency of about 10%. Electrical analyses based on cell-selective light absorption were applied to individually characterize the photovoltaic performances of the top and bottom subcells. Illumination at a frequency that could be absorbed only by a targeted top or bottom subcell permitted measurement of the open-circuit voltage of the target subcell and the shunt resistance of the non-target subcell. The cell parameters measured from each subcell were very similar to those of the corresponding single cell, confirming the validity of the suggested method. In addition, separating the light absorption intensities at the top and bottom subcells made us measure the bias-dependent photocurrent for each subcell. The series resistance of a c-Si/ITO/CGSe cell subjected to bottom-cell limiting conditions was slightly large, implying that the tunnel junction was a little resistive or slightly beyond ohmic. This analysis demonstrated that aside from producing a slightly resistive tunnel junction, our fabrication processes were successful in monolithically integrating a CGSe cell onto a c-Si/ITO cell without degrading the performances of both cells. PMID- 29146957 TI - Frailty is an independent predictor of incident dementia: Evidence from the English Longitudinal Study of Ageing. AB - The aim of this study was to determine whether frailty in older adults is associated with the risk of subsequent dementia. A total of 8,722 older adults from the English Longitudinal Study of Ageing were followed-up every two years until they reported a diagnosis of dementia, died, or were right censored. Frailty was defined using a frailty index comprised of 47 health deficits. To test if cognitive function influences the relationship between frailty and incident dementia, the analyses were repeated according to lower or upper three quartiles of baseline cognitive function. Competing risks regression and Cox proportional hazard models were used to evaluate whether the degree of baseline frailty was associated with incident dementia. Compared with non-frail participants, pre-frail (HR: 1.51 95%CI [1.12-2.02]) and frail participants (HR: 1.73 95%CI [1.22-2.43]) had a higher risk of developing dementia, after adjustment for covariates. The association between frailty and incident dementia was significant for adults in the upper three quartiles of global cognitive function (HR: 3.48 95%CI [1.98-6.12]), but not for adults who were in the lowest quartile of cognitive function (HR: 1.13 95%CI [0.74-1.71]). Frailty should be monitored alongside cognitive functioning when assessing risk factors for dementia in older adults. PMID- 29146958 TI - Third Repeat Microvascular Reconstruction in Head and Neck Cancer Patients Aged 65 Years and Older: A Longitudinal and Sequential Analysis. AB - Performing a sequential third free flap for reconstruction of a head and neck defect after cancer resection can be challenging, and the problem is further compounded in elderly patients. The outcomes in this clinical scenario are currently unknown and this study aims to compare the results in elderly patients with younger patients in a high-volume microsurgical unit. A retrospective review of 126 consecutive patients who had undergone three sequential free flap reconstructions after head and neck cancer was performed. The patients were divided into two groups - older or younger than 65 years old (n = 105 and n = 21, respectively). Patient demographics, intraoperative and postoperative outcomes were noted and analyzed. The overall flap success in this patient cohort was 94.4% (7 flap losses in 126 patients). Cardiovascular complications were significantly more common in the older group (19% vs. 1.9%, p = 0.001). Delirium occurred more frequently in the older group compared with the younger group (23.8% vs. 6.7%, p = 0.023). There were no significant differences regarding surgical complications. With adequate planning, a sequential third free flap can be performed safely and successfully in patients who are more than 65 years of age. Particular attention to the perioperative morbidity in elderly patients is crucial for successful outcomes. PMID- 29146959 TI - Methanogenesis in oxygenated soils is a substantial fraction of wetland methane emissions. AB - The current paradigm, widely incorporated in soil biogeochemical models, is that microbial methanogenesis can only occur in anoxic habitats. In contrast, here we show clear geochemical and biological evidence for methane production in well oxygenated soils of a freshwater wetland. A comparison of oxic to anoxic soils reveal up to ten times greater methane production and nine times more methanogenesis activity in oxygenated soils. Metagenomic and metatranscriptomic sequencing recover the first near-complete genomes for a novel methanogen species, and show acetoclastic production from this organism was the dominant methanogenesis pathway in oxygenated soils. This organism, Candidatus Methanothrix paradoxum, is prevalent across methane emitting ecosystems, suggesting a global significance. Moreover, in this wetland, we estimate that up to 80% of methane fluxes could be attributed to methanogenesis in oxygenated soils. Together, our findings challenge a widely held assumption about methanogenesis, with significant ramifications for global methane estimates and Earth system modeling. PMID- 29146960 TI - Assessing species biomass contributions in microbial communities via metaproteomics. AB - Microbial community structure can be analyzed by quantifying cell numbers or by quantifying biomass for individual populations. Methods for quantifying cell numbers are already available (e.g., fluorescence in situ hybridization, 16-S rRNA gene amplicon sequencing), yet high-throughput methods for assessing community structure in terms of biomass are lacking. Here we present metaproteomics-based methods for assessing microbial community structure using protein abundance as a measure for biomass contributions of individual populations. We optimize the accuracy and sensitivity of the method using artificially assembled microbial communities and show that it is less prone to some of the biases found in sequencing-based methods. We apply the method to communities from two different environments, microbial mats from two alkaline soda lakes, and saliva from multiple individuals. We show that assessment of species biomass contributions adds an important dimension to the analysis of microbial community structure. PMID- 29146961 TI - Identification of host DEAD-box RNA helicases that regulate cellular tropism of oncolytic Myxoma virus in human cancer cells. AB - Myxoma virus (MYXV), a Leporipoxvirus, is being developed as an oncolytic virotherapeutic for the treatment of a variety of human cancers. MYXV tropism for human cancer cells is largely mediated by intracellular signaling networks that regulate viral replication or innate antiviral response pathways. Thus, MYXV is fully or partially permissive for the majority of human cancer cells that harbor defects in antiviral signaling, but a minority are nonpermissive because the virus infection aborts before its completion. To identify host factors relevant for MYXV tropism in human cancer cells, we performed a small interfering RNA (siRNA) library screen targeting the 58 human DEAD-box RNA helicases in two permissive human cancer cells (HeLa and A549), one semi-permissive (786-0), and one nonpermissive cell line (PANC-1). Five host RNA helicases (DDX3X, DDX5, DHX9, DHX37, DDX52) were inhibitory for optimal replication and thus classified as anti viral, while three other cellular RNA helicases (DHX29, DHX35, RIG-I) were identified as pro-viral or pro-cellular because knockdown consistently reduced MYXV replication and/or required metabolic functions of permissive cancer cells. These findings suggest that replication of MYXV, and likely all poxviruses, is dramatically regulated positively and negatively by multiple host DEAD-box RNA helicases. PMID- 29146962 TI - Microbial communities in the native habitats of Agaricus sinodeliciosus from Xinjiang Province revealed by amplicon sequencing. AB - Agaricus sinodeliciosus is an edible species described from China and has been successfully cultivated. However, no studies have yet reported the influence factors implicated in the process of fructification. To better know abiotic and biotic factors, physiochemical characteristics and microbial communities were investigated in five different soil samples collected in the native habitats of specimens from northern Xinjiang, southern Xinjiang, and Zhejiang Province, respectively. There are major differences in texture and morphology among different specimens of A. sinodeliciosus from Xinjiang Province. A. sinodeliciosus from southern Xinjiang was the largest. Concentrations of DOC and TN and C/N ratio are not the main reason for the differences. Microbial communities were analyzed to find out mushroom growth promoting microbes (MGPM), which may lead to the differences. Functional microbes were picked out and can be divided into two categories. Microbes in the first category may belong to MGPM. There may be symbiotic relationships between microbes in the second category and A. sinodeliciosus. Certain analyses of microbial communities support the hypothesis that interactions between microbes and mushrooms would be implicated in morphological variation of the collected mushrooms. Redundancy analysis results indicate that high DOC/NH4+-N ratio and NH4+-N concentration can improve the yield of A. sinodeliciosus. PMID- 29146963 TI - Chemical potential of quasi-equilibrium magnon gas driven by pure spin current. AB - Pure spin currents provide the possibility to control the magnetization state of conducting and insulating magnetic materials. They allow one to increase or reduce the density of magnons, and achieve coherent dynamic states of magnetization reminiscent of the Bose-Einstein condensation. However, until now there was no direct evidence that the state of the magnon gas subjected to spin current can be treated thermodynamically. Here, we show experimentally that the spin current generated by the spin-Hall effect drives the magnon gas into a quasi equilibrium state that can be described by the Bose-Einstein statistics. The magnon population function is characterized either by an increased effective chemical potential or by a reduced effective temperature, depending on the spin current polarization. In the former case, the chemical potential can closely approach, at large driving currents, the lowest-energy magnon state, indicating the possibility of spin current-driven Bose-Einstein condensation. PMID- 29146964 TI - Effects of waste sources on performance of anaerobic co-digestion of complex organic wastes: taking food waste as an example. AB - Few studies have addressed how to blend wastes for anaerobic co-digestion. This study investigated the effects of waste sources on anaerobic co-digestion (AcoD) performance, by varying the quality of food wastes (FWs) from six sources in Xi'an region, China that were individually co-digested with pre-treated corn straw and cattle manure. These effects were analysed in terms of their volatile solid (VS) ratios, C/N ratios, and the chemical composition of the FWs. The results indicated that the VS ratios were not suitable as a common mixture method because the VS ratios at which the best methane potentials occurred differed significantly among the six FW groups. The C/N ratios within a 17-24 range resulted in better methane potentials when the FWs were co-digested with other wastes. Synergistic effects were found among the carbohydrates, proteins, and lipids of the FWs; however, the optimum ratios of these components could not be determined. Thus, the C/N ratio is recommended as a mixture method when co digesting FWs with other organic wastes in selected region. PMID- 29146965 TI - Gpufit: An open-source toolkit for GPU-accelerated curve fitting. AB - We present a general purpose, open-source software library for estimation of non linear parameters by the Levenberg-Marquardt algorithm. The software, Gpufit, runs on a Graphics Processing Unit (GPU) and executes computations in parallel, resulting in a significant gain in performance. We measured a speed increase of up to 42 times when comparing Gpufit with an identical CPU-based algorithm, with no loss of precision or accuracy. Gpufit is designed such that it is easily incorporated into existing applications or adapted for new ones. Multiple software interfaces, including to C, Python, and Matlab, ensure that Gpufit is accessible from most programming environments. The full source code is published as an open source software repository, making its function transparent to the user and facilitating future improvements and extensions. As a demonstration, we used Gpufit to accelerate an existing scientific image analysis package, yielding significantly improved processing times for super-resolution fluorescence microscopy datasets. PMID- 29146966 TI - Revisiting the role of interleukin-8 in chronic lymphocytic leukemia. AB - The proliferation and survival of malignant B cells in chronic lymphocytic leukemia (CLL) depend on signals from the microenvironment in lymphoid tissues. Among a plethora of soluble factors, IL-8 has been considered one of the most relevant to support CLL B cell progression in an autocrine fashion, even though the expression of IL-8 receptors, CXCR1 and CXCR2, on leukemic B cells has not been reported. Here we show that circulating CLL B cells neither express CXCR1 or CXCR2 nor they respond to exogenous IL-8 when cultured in vitro alone or in the presence of monocytes/nurse-like cells. By intracellular staining and ELISA we show that highly purified CLL B cells do not produce IL-8 spontaneously or upon activation through the B cell receptor. By contrast, we found that a minor proportion (<0.5%) of contaminating monocytes in enriched suspensions of leukemic cells might be the actual source of IL-8 due to their strong capacity to release this cytokine. Altogether our results indicate that CLL B cells are not able to secrete or respond to IL-8 and highlight the importance of methodological details in in vitro experiments. PMID- 29146967 TI - Splenic glucocorticoid resistance following psychosocial stress requires physical injury. AB - Mice exposed to chronic subordinate colony housing (CSC) stress show glucocorticoid (GC) resistance of in vitro lipopolysaccharide (LPS)-stimulated splenocytes, increased anxiety and colitis. Similar effects were reported in wounded mice exposed to social disruption (SDR). Here we show that CSC exposure induced GC resistance in isolated and in vitro LPS-stimulated, but not unstimulated, splenocytes, and these effects were absent when CD11b+ splenocytes were depleted. Moreover, re-active coping behaviour during CSC correlated with the attacks and bites received by the resident, which in turn highly correlated with the dimension of splenic GC resistance, as with basal and LPS-induced in vitro splenocyte viability. Importantly, social stress promoted spleen cell activation, independent of bite wounds or CD11b+/CD11b- cell phenotype, whereas GC resistance was dependent on both bite wounds and the presence of CD11b+ cells. Together, our findings indicate that the mechanisms underlying splenic immune activation and GC resistance following social stress in male mice are paradigm independent and, to a large extent, dependent on wounding, which, in turn, is associated with a re-active coping style. PMID- 29146968 TI - Heterologous expression and characterization of a new lipase from Pseudomonas fluorescens Pf0-1 and used for biodiesel production. AB - As a kind of important biocatalysts, Pseudomonas lipases are commonly applied in various industrial fields. Pflip1, a new extracellular lipase gene from Pseudomonas. fluorescens Pf0-1, was first cloned and respectively expressed in Escherichia coli BL21(DE3) and Pichia pastoris KM71, the recombinant proteins Pflip1a and Pflip1b were later purified separately. Then Pflip1a was further characterized. The optimum pH of Pflip1a was 8.0 and its optimal temperature was 70 degrees C. After incubation at 70 degrees C for 12 h, Pflip1a could retain over 95% of its original activity. It showed the highest activity towards p nitrophenyl caprylate. Moreover, its activity was profoundly affected by metal ion, ionic surfactants and organic solvents. Furthermore, the two obtained recombinant lipases were immobilized on the magnetic nanoparticles for biodiesel preparation. The GC analysis showed that for the immobilized lipases Pflip1b and Pflip1a, the biodiesel yield within 24 h respectively attained 68.5% and 80.5% at 70 degrees C. The activities of the two immobilized lipases still remained 70% and 82% after 10 cycles of operations in non-solvent system. These characteristics and transesterification capacity of the recombinant protein indicated its great potential for organic synthesis, especially for biodiesel production. PMID- 29146969 TI - Thermal expansion of Pd-based metallic glasses by ab initio methods and high energy X-ray diffraction. AB - Metallic glasses are promising structural materials due to their unique properties. For structural applications and processing the coefficient of thermal expansion is an important design parameter. Here we demonstrate that predictions of the coefficient of thermal expansion for metallic glasses by density functional theory based ab initio calculations are efficient both with respect to time and resources. The coefficient of thermal expansion is predicted by an ab initio based method utilising the Debye-Gruneisen model for a Pd-based metallic glass, which exhibits a pronounced medium range order. The predictions are critically appraised by in situ synchrotron X-ray diffraction and excellent agreement is observed. Through this combined theoretical and experimental research strategy, we show the feasibility to predict the coefficient of thermal expansion from the ground state structure of a metallic glass until the onset of structural changes. Thereby, we provide a method to efficiently probe a potentially vast number of metallic glass alloying combinations regarding thermal expansion. PMID- 29146970 TI - Origin of the unusually strong and selective binding of vanadium by polyamidoximes in seawater. AB - Amidoxime-functionalized polymeric adsorbents are the current state-of-the-art materials for collecting uranium (U) from seawater. However, marine tests show that vanadium (V) is preferentially extracted over U and many other cations. Herein, we report a complementary and comprehensive investigation integrating ab initio simulations with thermochemical titrations and XAFS spectroscopy to understand the unusually strong and selective binding of V by polyamidoximes. While the open-chain amidoxime functionalities do not bind V, the cyclic imide dioxime group of the adsorbent forms a peculiar non-oxido V5+ complex, exhibiting the highest stability constant value ever observed for the V5+ species. XAFS analysis of adsorbents following deployment in environmental seawater confirms V binding solely by the imide-dioximes. Our fundamental findings offer not only guidance for future optimization of selectivity in amidoxime-based sorbent materials, but may also afford insight to understanding the extensive accumulation of V in some marine organisms. PMID- 29146971 TI - Skin hydration: interplay between molecular dynamics, structure and water uptake in the stratum corneum. AB - Hydration is a key aspect of the skin that influences its physical and mechanical properties. Here, we investigate the interplay between molecular and macroscopic properties of the outer skin layer - the stratum corneum (SC) and how this varies with hydration. It is shown that hydration leads to changes in the molecular arrangement of the peptides in the keratin filaments as well as dynamics of C-H bond reorientation of amino acids in the protruding terminals of keratin protein within the SC. The changes in molecular structure and dynamics occur at a threshold hydration corresponding to ca. 85% relative humidity (RH). The abrupt changes in SC molecular properties coincide with changes in SC macroscopic swelling properties as well as mechanical properties in the SC. The flexible terminals at the solid keratin filaments can be compared to flexible polymer brushes in colloidal systems, creating long-range repulsion and extensive swelling in water. We further show that the addition of urea to the SC at reduced RH leads to similar molecular and macroscopic responses as the increase in RH for SC without urea. The findings provide new molecular insights to deepen the understanding of how intermediate filament organization responds to changes in the surrounding environment. PMID- 29146972 TI - Specific Targeting of Melanotic Cells with Peptide Ligated Photosensitizers for Photodynamic Therapy. AB - A strategy combining covalent conjugation of photosensitizers to a peptide ligand directed to the melanocortin 1 (MC1) receptor with the application of sequential LED light dosage at near-IR wavelengths was developed to achieve specific cytotoxicity to melanocytes and melanoma (MEL) with minimal collateral damage to surrounding cells such as keratinocytes (KER). The specific killing of melanotic cells by targeted photodynamic therapy (PDT) described in this study holds promise as a potentially effective adjuvant therapeutic method to control benign skin hyperpigmentation or superficial melanotic malignancy such as Lentigo Maligna Melanoma (LMM). PMID- 29146973 TI - Graphene balls for lithium rechargeable batteries with fast charging and high volumetric energy densities. AB - Improving one property without sacrificing others is challenging for lithium-ion batteries due to the trade-off nature among key parameters. Here we report a chemical vapor deposition process to grow a graphene-silica assembly, called a graphene ball. Its hierarchical three-dimensional structure with the silicon oxide nanoparticle center allows even 1 wt% graphene ball to be uniformly coated onto a nickel-rich layered cathode via scalable Nobilta milling. The graphene ball coating improves cycle life and fast charging capability by suppressing detrimental side reactions and providing efficient conductive pathways. The graphene ball itself also serves as an anode material with a high specific capacity of 716.2 mAh g-1. A full-cell incorporating graphene balls increases the volumetric energy density by 27.6% compared to a control cell without graphene balls, showing the possibility of achieving 800 Wh L-1 in a commercial cell setting, along with a high cyclability of 78.6% capacity retention after 500 cycles at 5C and 60 degrees C. PMID- 29146974 TI - Human Cyclophilin B forms part of a multi-protein complex during erythrocyte invasion by Plasmodium falciparum. AB - Invasion of human erythrocytes by Plasmodium falciparum merozoites involves multiple interactions between host receptors and their merozoite ligands. Here we report human Cyclophilin B as a receptor for PfRhopH3 during merozoite invasion. Localization and binding studies show that Cyclophilin B is present on the erythrocytes and binds strongly to merozoites. We demonstrate that PfRhopH3 binds to the RBCs and their treatment with Cyclosporin A prevents merozoite invasion. We also show a multi-protein complex involving Cyclophilin B and Basigin, as well as PfRhopH3 and PfRh5 that aids the invasion. Furthermore, we report identification of a de novo peptide CDP3 that binds Cyclophilin B and blocks invasion by up to 80%. Collectively, our data provide evidence of compounded interactions between host receptors and merozoite surface proteins and paves the way for developing peptide and small-molecules that inhibit the protein-protein interactions, individually or in toto, leading to abrogation of the invasion process. PMID- 29146975 TI - Disturbance in Plasma Metabolic Profile in Different Types of Human Cytomegalovirus-Induced Liver Injury in Infants. AB - Human cytomegalovirus (HCMV) infection in infants is a global problem and the liver is a target organ of HCMV invasion. However, the mechanism by which HCMV causes different types of liver injury is unclear, and there are many difficulties in the differential diagnosis of HCMV infantile cholestatic hepatopathy (ICH) and extrahepatic biliary atresia (EHBA). We established a non targeted gas chromatography-mass spectrometry metabolomics method in conjunction with orthogonal partial least squares-discriminate analysis based on 127 plasma samples from healthy controls, and patients with HCMV infantile hepatitis, HCMV ICH, and HCMV EHBA to explore the metabolite profile of different types of HCMV induced liver injury. Twenty-nine metabolites related to multiple amino acid metabolism disorder, nitrogen metabolism and energy metabolism were identified. Carbamic acid, glutamate, L-aspartic acid, L-homoserine, and noradrenaline for HCMV ICH vs. HCMV EHBA were screened as potential biomarkers and showed excellent discriminant performance. These results not only revealed the potential pathogenesis of HCMV-induced liver injury, but also provided a feasible diagnostic tool for distinguishing EHBA from ICH. PMID- 29146976 TI - Association of a variant in the gene encoding for ERV1/ChemR23 with reduced inflammation in visceral adipose tissue from morbidly obese individuals. AB - Obesity comorbidities are closely associated with chronic low-grade adipose tissue inflammation. A number of SNPs associated with inflammation has been identified, underscoring the impact of genetic determinants on this process. Here, we screened SNPs in genes with pro-inflammatory (IL-1beta, IL-6, STAT3 and JAK2), anti-inflammatory (IL-10 and SOCS3) and pro-resolving (ERV1/ChemR23) properties in 101 obese and 99 non-obese individuals. Among the SNPs analyzed, we identified that individuals carrying a C allele in the rs1878022 polymorphism of the ERV1/ChemR23 gene, which encodes for the receptor of the pro-resolving mediator RvE1, had increased ERV1/ChemR23 protein expression and reduced levels of the inflammatory cytokine IL-6 in adipose tissue. Moreover, patients carrying the C allele in homozygosity had lower plasma levels of IL-6, IFN-alpha2, IL-15, IL-1ra, IL-10, GM-CSF, G-CSF and VEGF and enhanced leukocyte responsiveness to RvE1. C-carriers also exhibited decreased TAG to HDL ratio, a surrogate marker of insulin resistance and a predictor of incident fatty liver. Finally, we confirmed in vivo that the ERV1/ChemR23 receptor regulates systemic and tissue inflammation since mice lacking ERV1/ChemR23 expression showed increased IL-6 levels in adipose tissue and peritoneal macrophages. Together, our study identified an ERV1/ChemR23 variant that protects patients with obesity from excessive inflammatory burden. PMID- 29146977 TI - Hydrogen Adsorption on Nearly Zigzag-Edged Nanoribbons: A Density Functional Theory Study. AB - The realistic shapes of N doped graphene nanoribbons (GNRs) can be realized by considering nearly zigzag-edged (NZE) imperfections and pyridine defects (3NV). The paper focuses on NZE-GNRs with 3NV that is populated by Scandium abbreviated as Sc/NZE-3NVGNRs. Systematic calculations have clarified roles of the nano shapes of NZE-3NVGNRs in its formation, energetics, stability and electron states functionalized with Sc using density functional theory (DFT) formalisms. According to DFT calculations, the magnitude of the spin that is attributed to the rise of magnetic order is closely linked to the altered shape of the ribbon edges. Also, calculations show that the stability of Sc functionalization at the 3NV and NZE site is thermodynamically stable and is dictated by a strong binding energy (BE). The magnitude of the BE is enhanced when the zigzag edge is short or the ribbon width is narrow, suggesting a reduced clustering of Sc atoms over the Sc-doped NZE-3NVGNRs. Results also show that as the length of the zigzag edge in Sc/NZE-3NVGNRs increases it creates considerable distortion on the appearance of the structure. Finally, the Sc/NZE-3NVGNRs as a potential candidate for hydrogen storage was evaluated and it was found that it could adsorb multiple hydrogen molecules. PMID- 29146978 TI - Oxygen-rich microporous carbons with exceptional hydrogen storage capacity. AB - Porous carbons have been extensively investigated for hydrogen storage but, to date, appear to have an upper limit to their storage capacity. Here, in an effort to circumvent this upper limit, we explore the potential of oxygen-rich activated carbons. We describe cellulose acetate-derived carbons that combine high surface area (3800 m2 g-1) and pore volume (1.8 cm3 g-1) that arise almost entirely (>90%) from micropores, with an oxygen-rich nature. The carbons exhibit enhanced gravimetric hydrogen uptake (8.1 wt% total and 7.0 wt% excess) at -196 degrees C and 20 bar, rising to a total uptake of 8.9 wt% at 30 bar, and exceptional volumetric uptake of 44 g l-1 at 20 bar, and 48 g l-1 at 30 bar. At room temperature they store up to 0.8 wt% (excess) and 1.2 wt% (total) hydrogen at only 30 bar, and their isosteric heat of hydrogen adsorption is above 10 kJ mol 1. PMID- 29146979 TI - Thickness Dependent Parasitic Channel Formation at AlN/Si Interfaces. AB - The performance of GaN-on-Silicon electronic devices is severely degraded by the presence of a parasitic conduction pathway at the nitride-substrate interface which contributes to switching losses and lower breakdown voltages. The physical nature of such a parasitic channel and its properties are however, not well understood. We report on a pronounced thickness dependence of the parasitic channel formation at AlN/Si interfaces due to increased surface acceptor densities at the interface in silicon. The origin of these surface acceptors is analyzed using secondary ion mass spectroscopy measurements and traced to thermal acceptor formation due to Si-O-N complexes. Low-temperature (5 K) magneto resistance (MR) data reveals a transition from positive to negative MR with increasing AlN film thickness indicating the presence of an inversion layer of electrons which also contributes to parasitic channel formation but whose contribution is secondary at room temperatures. PMID- 29146981 TI - Fast-forwarding of Hamiltonians and exponentially precise measurements. AB - The time-energy uncertainty relation (TEUR) [Formula: see text] holds if the Hamiltonian is completely unknown, but can be violated otherwise; here we initiate a rigorous study describing when and to what extent such violations can occur. To this end, we propose a computational version of the TEUR (cTEUR), in which Deltat is replaced by the computational complexity of simulating the measurement. cTEUR violations are proved to occur if and only if the Hamiltonian can be fast forwarded (FF), namely, simulated for time t with complexity significantly smaller than t. Shor's algorithm provides an example of exponential cTEUR violations; we show that so do commuting local Hamiltonians and quadratic fermion Hamiltonians. A general FF method is ruled out, but finding further examples, as well as experimental demonstrations, are left for future work. We discuss possible connections to sensing and quantum gravity. This work initiates a rigorous theory of efficiency versus accuracy in energy measurements using computational complexity language. PMID- 29146980 TI - The energy cost of polypeptide knot formation and its folding consequences. AB - Knots are natural topologies of chains. Yet, little is known about spontaneous knot formation in a polypeptide chain-an event that can potentially impair its folding-and about the effect of a knot on the stability and folding kinetics of a protein. Here we used optical tweezers to show that the free energy cost to form a trefoil knot in the denatured state of a polypeptide chain of 120 residues is 5.8 +/- 1 kcal mol-1. Monte Carlo dynamics of random chains predict this value, indicating that the free energy cost of knot formation is of entropic origin. This cost is predicted to remain above 3 kcal mol-1 for denatured proteins as large as 900 residues. Therefore, we conclude that naturally knotted proteins cannot attain their knot randomly in the unfolded state but must pay the cost of knotting through contacts along their folding landscape. PMID- 29146982 TI - Photonic simulation of entanglement growth and engineering after a spin chain quench. AB - The time evolution of quantum many-body systems is one of the most important processes for benchmarking quantum simulators. The most curious feature of such dynamics is the growth of quantum entanglement to an amount proportional to the system size (volume law) even when interactions are local. This phenomenon has great ramifications for fundamental aspects, while its optimisation clearly has an impact on technology (e.g., for on-chip quantum networking). Here we use an integrated photonic chip with a circuit-based approach to simulate the dynamics of a spin chain and maximise the entanglement generation. The resulting entanglement is certified by constructing a second chip, which measures the entanglement between multiple distant pairs of simulated spins, as well as the block entanglement entropy. This is the first photonic simulation and optimisation of the extensive growth of entanglement in a spin chain, and opens up the use of photonic circuits for optimising quantum devices. PMID- 29146984 TI - Ocean forecasting of mesoscale features can deteriorate by increasing model resolution towards the submesoscale. AB - Submesoscale dynamics are ubiquitous in the ocean and important in the variability of physical, biological and chemical processes. Submesoscale resolving ocean models have been shown to improve representation of observed variability. We show through data assimilation experiments that a higher resolution submesoscale permitting system does not match the skill of a lower resolution eddy resolving system in forecasting the mesoscale circulation. Predictability of the submesoscale is inherently lower and there is an inverse cascade in the kinetic energy spectrum that lowers the predictability of the mesoscale. A benefit of the higher-resolution system is the ability to include information content from observations to produce an analysis that can at times compare more favourably with remotely sensed satellite imagery. The implication of this work is that in practice, higher-resolution systems will provide analyses with enhanced spatial detail but will be less skilful at predicting the evolution of the mesoscale features. PMID- 29146983 TI - Precise control of alloying sites of bimetallic nanoclusters via surface motif exchange reaction. AB - Precise control of alloying sites has long been a challenging pursuit, yet little has been achieved for the atomic-level manipulation of metallic nanomaterials. Here we describe utilization of a surface motif exchange (SME) reaction to selectively replace the surface motifs of parent [Ag44(SR)30]4- (SR = thiolate) nanoparticles (NPs), leading to bimetallic NPs with well-defined molecular formula and atomically-controlled alloying sites in protecting shell. A systematic mass (and tandem mass) spectrometry analysis suggests that the SME reaction is an atomically precise displacement of SR-Ag(I)-SR-protecting modules of Ag NPs by the incoming SR-Au(I)-SR modules, giving rise to a core-shell [Ag32@Au12(SR)30]4-. Theoretical calculation suggests that the thermodynamically less favorable core-shell Ag@Au nanostructure is kinetically stabilized by the intermediate Ag20 shell, preventing inward diffusion of the surface Au atoms. The delicate SME reaction opens a door to precisely control the alloying sites in the protecting shell of bimetallic NPs with broad utility. PMID- 29146985 TI - Drosophila muscles regulate the immune response against wasp infection via carbohydrate metabolism. AB - We recently found that JAK/STAT signaling in skeletal muscles is important for the immune response of Drosophila larvae against wasp infection, but it was not clear how muscles could affect the immune response. Here we show that insulin signaling is required in muscles, but not in fat body or hemocytes, during larval development for an efficient encapsulation response and for the formation of lamellocytes. This effect requires TOR signaling. We show that muscle tissue affects the immune response by acting as a master regulator of carbohydrate metabolism in the infected animal, via JAK/STAT and insulin signaling in the muscles, and that there is indirect positive feedback between JAK/STAT and insulin signaling in the muscles. Specifically, stimulation of JAK/STAT signaling in the muscles can rescue the deficient immune response when insulin signaling is suppressed. Our results shed new light on the interaction between metabolism, immunity, and tissue communication. PMID- 29146986 TI - Cascading predator effects in a Fijian coral reef ecosystem. AB - Coral reefs are among Earth's best-studied ecosystems, yet the degree to which large predators influence the ecology of coral reefs remains an open and contentious question. Recent studies indicate the consumptive effects of large reef predators are too diffuse to elicit trophic cascades. Here, we provide evidence that such predators can produce non-consumptive (fear) effects that flow through herbivores to shape the distribution of seaweed on a coral reef. This trophic cascade emerged because reef topography, tidal oscillations, and shark hunting behaviour interact to create predictable "hot spots" of fear on the reef where herbivores withhold feeding and seaweeds gain a spatial refuge. Thus, in risky habitats, sharks can exert strong ecological impacts even though they are trophic generalists that rarely feed. These findings contextualize the debate over whether predators influence coral reef structure and function and move us to ask not if, but under what specific conditions, they generate trophic cascades. PMID- 29146987 TI - Homocysteine in retinal artery occlusive disease: A meta-analysis of cohort studies. AB - Few studies have reported the relationship between retinal artery occlusion (RAO) and plasma homocysteine (Hcy) levels. Our goal was to evaluate the association between the plasma Hcy level and the risk of RAO disease. Several databases were searched for all published studies that involved Hcy and RAO. Six studies evaluated hyperhomocysteinemia (hHcy) in retinal artery occlusion patients and controls; the incidence of hHcy in patients with RAO was higher than the control and the pooled odds ratio (OR) was 6.64 (95% confidence interval (CI): 3.42, 12.89). Subgroup analyses showed that the ORs were 4.77 (95% CI: 2.69, 8.46) in Western countries, 22.19 (95% CI: 2.46, 200.37) in Asian countries, 9.70 (95% CI: 4.43, 21.20) in the age matched group, 11.41 (95% CI: 3.32, 39.18) in the sex matched group, 9.70 (95% CI: 4.37, 21.53) in the healthy control group, and 6.82 (95% CI: 4.19, 11.10) in the sample size >30. The mean plasma Hcy level from 5 case-control studies was higher than controls, and the weighted mean difference (WMD) was 6.54 (95% CI: 2.79, 10.29). Retinal artery occlusion is associated with elevated plasma Hcy levels. Our study results suggest that hHcy is probably an independent risk factor for RAO. PMID- 29146988 TI - Variations in nutrient and trace element composition of rice in an organic rice frog coculture system. AB - Introducing frogs into paddy fields can control pests and diseases, and organic farming can improve soil fertility and rice growth. The aim of this 2-year field study was compare the yield and elemental composition of rice between an organic farming system including frogs (ORF) and a conventional rice culture system (CR). The grain yields were almost the same in the ORF system and the CR system. The ORF significantly increased the contents of phosphorus (P), ion (Fe), zinc (Zn), molybdenum (Mo) and selenium (Se) in rice grain at one or both years. However, the ORF system decreased the calcium (Ca) content in grice grains, and increased the concentration of cadmium, which is potentially toxic. A principal components analysis showed the main impacts of ORF agro-ecosystem on the rice grain ionome was to increase the concentration of P and trace metal(loid)s. The results showed that the ORF system is an ecologically, friendly strategy to avoid excessive use of chemical fertilizers, herbicides and pesticides without decreasing yields, and to improve the nutritional status of rice by increasing the micronutrient contents. The potential risks of increasing Cd contents in rice grain should be addressed if this cultivation pattern is used in the long term. PMID- 29146989 TI - Pain dilates time perception. AB - We have all experienced that time seems stretched during unpleasant situations. While there is evidence of subjective time overestimation when perceiving external unpleasant stimuli, no study has measured the dilation of time when individuals experience an unpleasant situation in their own body. Here we measured the time dilation induced by a painful homeostatic deviance using temporal bisection task. We show that being in pain leads to an expansion of subjective time whereby a stronger increase in pain perception relative to non painful stimulation leads to a stronger time-estimate distortion. Neurophysiological studies suggest that time estimation and the perception of self might share a common neural substrate. We propose that, along with bodily arousal and attentional capture, the enhancement of self-awareness may be critical to support dilated subjective time when experiencing pain. As other homeostatic deviances, pain may induce a focus on ourselves contributing to the impression that "time stands still". PMID- 29146990 TI - How gluttonous cell aggregates clear substrates coated with microparticles. AB - We study the spreading of cell aggregates deposited on adhesive substrates decorated with microparticles (MPs). A cell monolayer expands around the aggregate. The cells on the periphery of the monolayer take up the MPs, clearing the substrate as they progress and forming an aureole of cells filled with MPs. We study the dynamics of spreading and determine the width of the aureole and the level of MP internalization in cells as a function of MP size, composition, and density. From the radius and width of the aureole, we quantify the volume fraction of MPs within the cell, which leads to an easy, fast, and inexpensive measurement of the cell - particle internalization. PMID- 29146991 TI - KLF5 promotes cervical cancer proliferation, migration and invasion in a manner partly dependent on TNFRSF11a expression. AB - Although the transcription factor Kruppel-like factor 5 (KLF5) plays important roles in both inflammation and cancer, the mechanism by which this factor promotes cervical carcinogenesis remains unclear. In this study, we demonstrated a potential role for tumour necrosis factor receptor superfamily member 11a (TNFRSF11a), the corresponding gene of which is a direct binding target of KLF5, in tumour cell proliferation and invasiveness. Coexpression of KLF5 and TNFRSF11a correlated significantly with tumorigenesis in cervical tissues (P < 0.05) and manipulation of KLF5 expression positively affected TNFRSF11a mRNA and protein expression. Functionally, KLF5 promoted cancer cell proliferation, migration and invasiveness in a manner dependent partly on TNFRSF11a expression. Moreover, in vivo functional TNFRSF11a-knockdown mouse studies revealed suppression of tumorigenicity and liver metastatic potential. Notably, tumour necrosis factor (TNF)-alpha induced KLF5 expression by activating the p38 signalling pathway and high KLF5 and TNFRSF11a expression increased the risk of death in patients with cervical squamous cell carcinoma. Our results demonstrate that KLF5 and TNFRSF11a promote cervical cancer cell proliferation, migration and invasiveness. PMID- 29146992 TI - Pre-pregnancy overweight or obesity and gestational diabetes as predictors of body composition in offspring twenty years later: evidence from two birth cohort studies. AB - BACKGROUND: Global prevalence of overweight/obesity and gestational diabetes (GDM) is increasing. In pregnant women both conditions affect offspring's later health. Overweight/obesity is a risk factor of GDM; to what extent maternal overweight/obesity explains long-term effects of GDM in offspring is unknown. OBJECTIVE: To evaluate effects of maternal pre-pregnancy overweight/obesity (body mass index (BMI) ?25 kg m-2) and GDM, occurring together or separately, on body composition among adult offspring. METHODS: Participants include 891 individuals aged 24.1 years (s.d. 1.4) from two longitudinal cohort studies (ESTER and AYLS). Adult offspring of normoglycemic mothers with overweight/obesity (ONOO, n=153), offspring of mothers with GDM (OGDM; n=191) and controls (n=547) underwent anthropometric measurements and bioimpedance analysis. Gestational diabetes mellitus was diagnosed by oral glucose tolerance test. Data were analyzed by linear regression models adjusted for confounders. RESULTS: Compared with controls, ONOO-participants showed higher BMI (men 1.64 kg m-2 (95% confidence interval 0.57, 2.72); women 1.41 kg m-2 (0.20, 2.63)) and fat percentage (men 2.70% (0.99, 4.41); women 2.98% (0.87, 5.09)) with larger waist circumferences (men 3.34 cm (0.68, 5.99); women 3.09 cm (0.35, 5.83)). Likewise, OGDM participants showed higher fat percentage (men 1.97% (0.32, 3.61); women 2.32% (0.24, 4.41)). Body mass index was non-significantly different between OGDM participants and controls (men 0.88 kg m-2 (-0.17, 1.92); women 0.82 kg m-2 ( 0.39, 2.04)). Also waist circumferences were larger (men 2.63 cm (-0.01, 5.28); women 3.39 cm (0.60, 6.18)); this difference was statistically significant in OGDM-women only. Differences in body composition measures were stronger among offspring of women with both GDM and overweight/obesity. For instance, fat mass was higher among OGDM-participants of overweight mothers (men 4.24 kg (1.36, 7.11) vs controls; women 5.22 kg (1.33, 9.11)) than OGDM participants of normal weight mothers (men 1.50 kg (-2.11, 5.11) higher vs controls; women 1.57 kg ( 3.27, 6.42)). CONCLUSIONS: Maternal pre-pregnancy overweight and GDM are associated with unhealthy body size and composition in offspring over 20 years later. Effects of maternal pre-pregnancy overweight appear more pronounced. PMID- 29146993 TI - Height associated variants demonstrate assortative mating in human populations. AB - Understanding human mating patterns, which can affect population genetic structure, is important for correctly modeling populations and performing genetic association studies. Prior studies of assortative mating in humans focused on trait similarity among spouses and relatives via phenotypic correlations. Limited research has quantified the genetic consequences of assortative mating. The degree to which the non-random mating influences genetic architecture remains unclear. Here, we studied genetic variants associated with human height to assess the degree of height-related assortative mating in European-American and African American populations. We compared the inbreeding coefficient estimated using known height associated variants with that calculated from frequency matched sets of random variants. We observed significantly higher inbreeding coefficients for the height associated variants than from frequency matched random variants (P < 0.05), demonstrating height-related assortative mating in both populations. PMID- 29146994 TI - Usefulness of the delta neutrophil index to predict 30-day mortality in patients with ST segment elevation myocardial infarction. AB - This study aimed to evaluate the association between the delta neutrophil index (DNI), which reflects immature granulocytes, and the severity of ST-elevation myocardial infarction (STEMI), as well as to determine the significance of the DNI as a prognostic marker for early mortality and other clinical outcomes in patients with STEMI who underwent reperfusion. This retrospective, observational cohort study was conducted using patients prospectively integrated in a critical pathway program for STEMI. We included 842 patients diagnosed with STEMI who underwent primary percutaneous coronary intervention (pPCI). Higher DNI values at time-I (within 2 h of pPCI; hazard ratio [HR], 1.075; 95% confidence interval [CI]: 1.046-1.108; p < 0.001) and time-24 (24 h after admission; HR, 1.066; 95% CI: 1.045-1.086; p < 0.001) were significant independent risk factors for 30-day mortality. Specifically, DNI values >2.5% at time-I (HR, 13.643; 95% CI: 8.13 22.897; p < 0.001) and > 2.9% at time-24 (HR, 12.752; 95% CI: 7.308-22.252; p < 0.001) associated with increased risks of 30-day mortality. In conclusion, an increased DNI value, which reflects the proportion of circulating immature granulocytes in the blood, was found to be an independent predictor of 30-day mortality and poor clinical outcomes in patients with acute STEMI post-pPCI. PMID- 29146995 TI - GABA concentrations in the anterior temporal lobe predict human semantic processing. AB - There is now considerable convergent evidence from multiple methodologies and clinical studies that the human anterior temporal lobe (ATL) is a semantic representational hub. However, the neurochemical nature of the ATL in the semantic processing remains unclear. The current study investigated the neurochemical mechanism underlying semantic processing in the ATL. We combined functional magnetic resonance imaging (fMRI) with resting-state magnetic resonance spectroscopy (MRS) to measure task-related blood-oxygen level-dependent (BOLD) signal changes during sematic processing and resting-state GABA concentrations in the ATL. Our combined fMRI and MRS investigation showed that the stronger ATL BOLD response induced by the semantic task, the lower GABA concentration in the same region. Moreover, individuals with higher GABA concentration in the ATL showed better semantic performance and stronger BOLD related fluctuations in the semantic network. Our data demonstrated that the resting-state GABA concentration predicts neural changes in the human ATL and task performance during semantic processing. Our findings indicate that individuals with higher GABA may have a more efficient semantic processing leading to better task performance and imply that GABAergic neurochemical processes are potentially crucial to the neurobiological contribution of the ATL to semantic cognition. PMID- 29146997 TI - A new method to measure mechanics and dynamic assembly of branched actin networks. AB - We measured mechanical properties and dynamic assembly of actin networks with a new method based on magnetic microscopic cylinders. Dense actin networks are grown from the cylinders' surfaces using the biochemical Arp2/3-machinery at play in the lamellipodium extension and other force-generating processes in the cell. Under a homogenous magnetic field the magnetic cylinders self-assemble into chains in which forces are attractive and depend on the intensity of the magnetic field. We show that these forces, from piconewtons to nanonewtons, are large enough to slow down the assembly of dense actin networks and controlled enough to access to their non linear mechanical responses. Deformations are measured with nanometer-resolution, well below the optical resolution. Self-assembly of the magnetic particles into chains simplifies experiments and allows for parallel measurements. The combination of accuracy and good throughput of measurements results in a method with high potential for cell and cytoskeleton mechanics. Using this method, we observed in particular a strong non linear mechanical behavior of dense branched actin networks at low forces that has not been reported previously. PMID- 29146996 TI - The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors. AB - CXCR3 plays important roles in angiogenesis, inflammation, and cancer. However, the precise mechanism of regulation and activity in tumors is not well known. We focused on CXCR3-A conformation and on the mechanisms controlling its activity and trafficking and investigated the role of CXCR3/LRP1 cross talk in tumor cell invasion. Here we report that agonist stimulation induces an anisotropic response with conformational changes of CXCR3-A along its longitudinal axis. CXCR3-A is internalized via clathrin-coated vesicles and recycled by retrograde trafficking. We demonstrate that CXCR3-A interacts with LRP1. Silencing of LRP1 leads to an increase in the magnitude of ligand-induced conformational change with CXCR3-A focalized at the cell membrane, leading to a sustained receptor activity and an increase in tumor cell migration. This was validated in patient-derived glioma cells and patient samples. Our study defines LRP1 as a regulator of CXCR3, which may have important consequences for tumor biology. PMID- 29146999 TI - Publisher Correction: 100 articles every ecologist should read. AB - This Article originally suggested that readers may be able to source PDF files of the papers analysed via a website that is involved in litigation over breach of copyright. This suggestion and the related URL have now been removed. PMID- 29146998 TI - Regulation of gene expression and RNA editing in Drosophila adapting to divergent microclimates. AB - Determining the mechanisms by which a species adapts to its environment is a key endeavor in the study of evolution. In particular, relatively little is known about how transcriptional processes are fine-tuned to adjust to different environmental conditions. Here we study Drosophila melanogaster from 'Evolution Canyon' in Israel, which consists of two opposing slopes with divergent microclimates. We identify several hundred differentially expressed genes and dozens of differentially edited sites between flies from each slope, correlate these changes with genetic differences, and use CRISPR mutagenesis to validate that an intronic SNP in prominin regulates its editing levels. We also demonstrate that while temperature affects editing levels at more sites than genetic differences, genetically regulated sites tend to be less affected by temperature. This work shows the extent to which gene expression and RNA editing differ between flies from different microclimates, and provides insights into the regulation responsible for these differences. PMID- 29147000 TI - Stable ICG-loaded upconversion nanoparticles: silica core/shell theranostic nanoplatform for dual-modal upconversion and photoacoustic imaging together with photothermal therapy. AB - We report here the design and multiple functions of a new hierarchical nanotheronostic platform consisting of an upconversion nanoparticle (UCNP) core: shell with an additional mesoporous silica (mSiO2) matrix load shell containing sealed, high concentration of ICG molecules. We demonstrate that this UCNP@mSiO2 ICG nanoplatform can perform the following multiple functions under NIR excitation at 800 nm: 1) Light harvesting by the UCNP shell containing Nd and subsequent energy transfer to Er in the Core to produce efficient green and red upconversion luminescence for optical imaging; 2) Efficient nonradiative relaxation and local heating produced by concentration quenching in aggregated ICG imbedded in the mesopourous silica shell to enable both photoacoustic imaging and photothermal therapy. Compared to pure ICG, sealing of mesoporous silica platforms prevents the leak-out and improves the stability of ICG by protecting from rapid hydrolysis. Under 800 nm laser excitation, we performed both optical and photoacoustic (PA) imaging in vitro and in vivo. Our results demonstrated that UCNP@mSiO2-ICG with sealed structures could be systemically delivered to brain vessels, with a long circulation time. In addition, these nanoplatforms were capable of producing strong hyperthermia efforts to kill cancer cells and hela cells under 800 nm laser irradiation. PMID- 29147001 TI - Quantum channels from reflections on moving mirrors. AB - Light reflection on a mirror can be thought as a simple physical effect. However if this happens when the mirror moves a rich scenario opens up. Here we aim at analyzing it from a quantum communication perspective. In particular, we study the kind of quantum channel that arises from (Gaussian) light reflection upon an accelerating mirror. Two competing mechanisms emerge in such a context, namely photons production by the mirror's motion and interference between modes. As consequence we find out a quantum amplifier channel and quantum lossy channel respectively below and above a threshold frequency (that depends on parameters determining mirror's acceleration). Exactly at the threshold frequency the channel behaves like a purely classical additive channel, while it becomes purely erasure for large frequencies. In addition the time behavior of the channel is analyzed by employing wave packets expansion of the light field. PMID- 29147003 TI - Real-time wash-free detection of unlabeled PNA-DNA hybridization using discrete FET sensor. AB - We demonstrate an electrochemical sensor for detection of unlabeled single stranded DNA using peptide nucleic acid (PNA) probes coupled to the field-effect transistor (FET) gate. The label-free detection relies on the intrinsic charge of the DNA backbone. Similar detection schemes have mainly concentrated on sensitivity improvement with an emphasis on new sensor structures. Our approach focuses on using an extended-gate that separates the FET and the sensing electrode yielding a simple and mass fabricable device. We used PNA probes for efficient hybridization in low salt conditions that is required to avoid the counter ion screening. As a result, significant part of the target DNA lies within the screening length of the sensor. With this, we achieved a wash-free detection where typical gate potential shifts are more than 70 mV with 1 uM target DNA. We routinely obtained a real-time, label- and wash-free specific detection of target DNA in nanomolar concentration with low-cost electronics and the responses were achieved within minutes after introducing targets to the solution. Furthermore, the results suggest that the sensor performance is limited by specificity rather than by sensitivity and using low-cost electronics does not limit the sensor performance in the presented sensor configuration. PMID- 29147002 TI - Capturing an initial intermediate during the P450nor enzymatic reaction using time-resolved XFEL crystallography and caged-substrate. AB - Time-resolved serial femtosecond crystallography using an X-ray free electron laser (XFEL) in conjunction with a photosensitive caged-compound offers a crystallographic method to track enzymatic reactions. Here we demonstrate the application of this method using fungal NO reductase, a heme-containing enzyme, at room temperature. Twenty milliseconds after caged-NO photolysis, we identify a NO-bound form of the enzyme, which is an initial intermediate with a slightly bent Fe-N-O coordination geometry at a resolution of 2.1 A. The NO geometry is compatible with those analyzed by XFEL-based cryo-crystallography and QM/MM calculations, indicating that we obtain an intact Fe3+-NO coordination structure that is free of X-ray radiation damage. The slightly bent NO geometry is appropriate to prevent immediate NO dissociation and thus accept H- from NADH. The combination of using XFEL and a caged-compound is a powerful tool for determining functional enzyme structures during catalytic reactions at the atomic level. PMID- 29147004 TI - Dose de-escalation to the normal larynx using conformal radiotherapy reduces toxicity while maintaining oncologic outcome for T1/T2 glottic cancer. AB - We evaluated the efficacy of dose de-escalation to the normal larynx using conformal radiotherapy (CRT) for T1/T2 glottic cancer. For conventional RT (2DRT, n = 38), the laryngeal box received a median equivalent dose in 2 Gy fractions (EQD2) of 66 Gy. For CRT (n = 42; 3D-CRT, 20; intensity-modulated RT, 22), clinical target volume (CTV)1 (gross tumor with a 3-mm margin) and CTV2 (laryngeal box) received median EQD2s of 66.6 Gy and 52.2 Gy, respectively. With a 71-month median follow-up, five-year local control and overall survival rates for 2DRT vs. CRT were 88.1% vs. 95.1% (p = 0.405) and 94.7% vs. 90.7% (p = 0.102), respectively. Grade 2 and 3 pharyngitis rates were 52.6% and 5.3% for 2DRT vs. 35.7% and 2.4% for CRT (p = 0.121). Grade 2 and 3 dermatitis rates were 42.1% and 2.6% for 2DRT vs. 35.7% and 0% for CRT (p = 0.013). The maximum phonation time increased from 12.1 +/- 7.1 to 14.0 +/- 6.6 seconds after 2DRT (p = 0.375) and from 12.0 +/- 5.5 to 13.8 +/- 10.1 seconds after CRT (p = 0.313). Fundamental frequency decreased from 150.6 +/- 40.3 to 121.9 +/- 30.2 Hz after 2DRT (p = 0.039) and from 138.5 +/- 31.9 to 126.1 +/- 23.7 Hz after CRT (p = 0.058). CRT can effectively de-escalate the normal larynx dose while maintaining oncologic outcome and voice quality. PMID- 29147005 TI - Binary phase masks for easy system alignment and basic aberration sensing with spatial light modulators in STED microscopy. AB - The use of binary phase patterns to improve the integration and optimization of spatial light modulators (SLM) in an imaging system, especially a confocal microscope, is proposed and demonstrated. The phase masks were designed to create point spread functions (PSF), which exhibit specific sensitivity to major disturbances in the optical system. This allows direct evaluation of misalignment and fundamental aberration modes by simple visual inspection of the focal intensity distribution or by monitoring the central intensity of the PSF. The use of proposed phase masks is investigated in mathematical modelling and experiment for the use in a stimulated emission depletion (STED) microscope applying wavefront shaping by a SLM. We demonstrate the applicability of these phase masks for modal wavefront sensing of low order aberration modes up to the third order of Zernike polynomials, utilizing the point detector of a confocal microscope in a 'guide star' approach. A lateral resolution of ~25 nm is shown in STED imaging of the confocal microscope retrofitted with a SLM and a STED laser and binary phase mask based system optimization. PMID- 29147006 TI - The influence of skin colour on the experience of ownership in the rubber hand illusion. AB - Racial prejudice is associated with a fundamental distinction between "us" and "them"-a distinction linked to the perceived overlap between representations of the self and others. Implicit prejudice has been shown to reduce the intensity of White individuals' hand ownership sensation as induced by the Rubber Hand Illusion (RHI) with dark rubber hands. However, evidence for this link to implicit prejudice comes from self-report questionnaire data regarding the RHI. As an alternative, we assessed the onset time of the RHI. We hypothesized that onset time of the RHI would be higher for the black compared to the white RH, acting as the mediator between implicit prejudice and magnitude of the RH illusion and proprioceptive drift. As expected, participants took longer to incorporate the black RH and presented lower RH illusion magnitude and a smaller proprioceptive drift for the black RH. Mediation analysis revealed a significant indirect effect of implicit racial bias on proprioceptive drift and magnitude of illusion through onset time to illusion only for the black RH. These findings further illuminate the connection between implicit prejudice and embodied perception, suggesting new perspectives on how implicit biases operate. PMID- 29147007 TI - Modulating cellular balance of Rps3 mono-ubiquitination by both Hel2 E3 ligase and Ubp3 deubiquitinase regulates protein quality control. AB - When a ribosome complex is stalled during the translation elongation process in eukaryotes, the mono-ubiquitination of Rps3 has recently been shown to be critical to ribosome quality control. We have discovered that the regulatory role of Rps3 mono-ubiquitination is controlled by a deubiquitinase. We also showed that an autophagic signal appears to be coupled to the mono-ubiquitination of Rps3p through the entrance of Ubp3p into the autophagosome in yeasts. The mono ubiquitination of the Rps3 protein is tightly modulated by reciprocal action between the Hel2p E3 ligase and the Ubp3p deubiquitinase in yeasts and the reciprocal action between the RNF123 E3 ligase and the USP10 deubiquitinase in mammalian cells. We also found that the Ubp3p/USP10 deubiquitinases critically modulate Hel2p/RNF123-mediated Rps3p mono-ubiquitination. In addition, we found that Hel2p/RNF123 and Ubp3p/USP10 appeared to be differently localized in the ribosome complex after ultraviolet irradiation. Together, our results support a model in which coordinated ubiquitination and deubiquitination activities can finely balance the level of regulatory Rps3p mono-ubiquitination in ribosome associated quality control and autophagy processes. PMID- 29147008 TI - The transcription factor Batf3 inhibits the differentiation of regulatory T cells in the periphery. AB - Naive CD4 T cells activated by antigen-presenting cells (APCs) undergo terminal differentiation in the periphery. Multiple mechanisms determine their fates, that is, whether they differentiate into conventional T (Tconv) cells or regulatory T (Treg) cells. The key event during Treg generation is expression of the transcription factor Foxp3, which is the lineage-determining regulator for Treg differentiation and function. Here we show that the transcription factor Batf3 acts as a fate-decision factor with respect to Tconv versus Tregs by restraining Treg differentiation. Batf3 was preferentially expressed in effector CD4 T cells but not in Treg cells, and ectopic expression of Batf3 inhibited Foxp3 induction. Batf3-deficient CD4 T cells favorably differentiated into Treg cells in vitro and in colonic lamina propria. Batf3 KO mice also showed enhanced Treg function in gut-associated immune disease models (for example, ovalbumin tolerance and inflammatory bowel disease models). Batf3 bound to the CNS1 region of the Foxp3 locus and reduced expression of the gene. Thus, Batf3 is a transcriptional suppressor of Treg differentiation. PMID- 29147009 TI - Mitochondrial UQCRB as a new molecular prognostic biomarker of human colorectal cancer. AB - Ubiquinol cytochrome c reductase binding protein (UQCRB) is important for mitochondrial complex III stability, electron transport, cellular oxygen sensing and angiogenesis. However, its potential as a prognostic marker in colorectal cancer (CRC) remains unclear. The aim of this study was to determine whether UQCRB can be used as a diagnostic molecular marker for CRC. The correlation between the expression of three genes (UQCRB, UQCRFS1 and MT-CYB) in the mitochondrial respiratory chain complex III and clinico-pathological features was determined. Compared to non-tumor tissues, UQCRB gene expression was upregulated in CRC tissues. Gene and protein expression of the genes were positively correlated. Copy number variation (CNV) differences in UQCRB were observed in CRC tissues (1.32-fold) compared to non-tumor tissues. The CNV of UQCRB in CRC tissues increased proportionally with gene expression and clinical stage. Single nucleotide polymorphisms in the 3'-untranslated region of UQCRB (rs7836698 and rs10504961) were investigated, and the rs7836698 polymorphism was associated with CRC clinical stage. DNA methylation of the UQCRB promoter revealed that most CRC patients had high methylation levels (12/15 patients) in CRC tissues compared to non-tumor tissues. UQCRB overexpression and CNV gain were correlated with specific CRC clinico-pathological features, indicating clinical significance as a prognostic predictor in CRC. Gene structural factors may be more important than gene transcription repression factors with respect to DNA methylation in UQCRB overexpression. Our results provide novel insights into the critical role of UQCRB in regulating CRC, supporting UQCRB as a new candidate for the development of diagnostics for CRC patients. PMID- 29147010 TI - Epithelial folliculin is involved in airway inflammation in workers exposed to toluene diisocyanate. AB - Toluene diisocyanate (TDI) exposure can directly activate and damage airway epithelium. Folliculin (FLCN) is a protein expressed by human airway epithelial cells (HAECs) to maintain airway epithelial integrity and survival. This study investigated the involvement of FLCN in the pathogenesis of TDI-induced occupational asthma (OA). Enzyme-linked immunosorbent assay was used to measure serum levels of FLCN in TDI-exposed subjects (93 TDI-OA patients and 119 asymptomatic exposed controls (AEC)), 200 non-occupational asthma (NOA) patients and 71 unexposed healthy normal controls (NCs). Significantly more subjects in the TDI-OA and AEC groups had high serum levels of FLCN compared to those in the NOA group (P=0.002 and P=0.001, respectively), all of which were higher than the NC group (all P<0.001). The serum level of FLCN was positively correlated with TDI exposure duration (r=0.251, P=0.027), but was negatively correlated with asthma duration of TDI-OA patients (r=-0.329, P=0.029). TDI-exposed subjects with high FLCN levels had higher serum levels of total IgE than those with lower levels. The effects of TDI exposure on FLCN production was investigated by treating HAECs (A549 cells) with TDI-human serum albumin conjugate, which showed increased expression and release of FLCN and interleukin-8 from HAECs. Co-culture with peripheral blood neutrophils also induced FLCN expression and release from HAECs. In conclusion, TDI exposure and TDI-induced neutrophil recruitment into the airways can activate and stimulate HAECs to produce FLCN, which could be involved in airway inflammation in workers exposed to TDI. PMID- 29147011 TI - Lower serum extracellular superoxide dismutase levels are associated with polyneuropathy in recent-onset diabetes. AB - Increased oxidative stress is implicated in the pathogenesis of experimental diabetic neuropathy, but translational evidence in recent-onset diabetes is scarce. We aimed to determine whether markers of systemic oxidative stress are associated with diabetic sensorimotor polyneuropathy (DSPN) in recent-onset diabetes. In this cross-sectional study, we measured serum concentrations of extracellular superoxide dismutase (SOD3), thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) in 107 type 1 and 215 type 2 diabetes patients from the German Diabetes Study baseline cohort and 37 glucose tolerant individuals (controls). DSPN was defined by electrophysiological and clinical criteria (Toronto Consensus, 2011). SOD3 and GSH concentrations were lower in individuals with type 1 and type 2 diabetes compared with concentrations in controls (P<0.0001). In contrast, the TBARS concentration was higher in participants with type 1 diabetes and type 2 diabetes compared with levels in controls (P<0.0001). In addition, the SOD3 concentration was higher in participants with type 1 diabetes compared to concentrations in those with type 2 diabetes (P<0.0001). A low SOD3 concentration was associated with DSPN in individuals with type 1 diabetes (beta=-0.306, P=0.002), type 2 diabetes (beta= 0.164, P=0.017), and in both groups combined (beta=-0.206, P=0.0003). Lower SOD3 concentrations were associated with decreased motor nerve conduction velocity (NCV) in men and, to a lesser degree, with reduced sensory NCV in women with diabetes. In conclusion, several biomarkers of oxidative stress are altered in recent-onset diabetes, with only a lower SOD3 concentration being linked to the presence of DSPN, suggesting a role for reduced extracellular antioxidative defense against superoxide in the early development of DSPN. PMID- 29147012 TI - Piperidylmethyloxychalcone improves immune-mediated acute liver failure via inhibiting TAK1 activity. AB - Mice deficient in the toll-like receptor (TLR) or the myeloid differentiation factor 88 (MyD88) are resistant to acute liver failure (ALF) with sudden death of hepatocytes. Chalcone derivatives from medicinal plants protect from hepatic damages including ALF, but their mechanisms remain to be clarified. Here, we focused on molecular basis of piperidylmethyloxychalcone (PMOC) in the treatment of TLR/MyD88-associated ALF. C57BL/6J mice were sensitized with D-galactosamine (GalN) and challenged with Escherichia coli lipopolysaccharide (LPS, TLR4 agonist) or oligodeoxynucleotide containing unmethylated CpG motif (CpG ODN, TLR9 agonist) for induction of ALF. Post treatment with PMOC sequentially ameliorated hepatic inflammation, apoptosis of hepatocytes, severe liver injury and shock mediated death in ALF-induced mice. As a mechanism, PMOC inhibited the catalytic activity of TGF-beta-activated kinase 1 (TAK1) in a competitive manner with respect to ATP, displaced fluorescent ATP probe from the complex with TAK1, and docked at the ATP-binding active site on the crystal structure of TAK1. Moreover, PMOC inhibited TAK1 auto-phosphorylation, which is an axis in the activating pathways of nuclear factor-kappaB (NF-kappaB) or activating protein 1 (AP1), in the liver with ALF in vivo or in primary liver cells stimulated with TLR agonists in vitro. PMOC consequently suppressed TAK1-inducible NF-kappaB or AP1 activity in the inflammatory injury, an early pathogenesis leading to ALF. The results suggested that PMOC could contribute to the treatment of TLR/MyD88-associated ALF with the ATP-binding site of TAK1 as a potential therapeutic target. PMID- 29147014 TI - Optimal percolation on multiplex networks. AB - Optimal percolation is the problem of finding the minimal set of nodes whose removal from a network fragments the system into non-extensive disconnected clusters. The solution to this problem is important for strategies of immunization in disease spreading, and influence maximization in opinion dynamics. Optimal percolation has received considerable attention in the context of isolated networks. However, its generalization to multiplex networks has not yet been considered. Here we show that approximating the solution of the optimal percolation problem on a multiplex network with solutions valid for single-layer networks extracted from the multiplex may have serious consequences in the characterization of the true robustness of the system. We reach this conclusion by extending many of the methods for finding approximate solutions of the optimal percolation problem from single-layer to multiplex networks, and performing a systematic analysis on synthetic and real-world multiplex networks. PMID- 29147013 TI - Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases. AB - Tissue fibrosis, characterized by excessive accumulation of aberrant extracellular matrix (ECM) produced by myofibroblasts, is a growing cause of mortality worldwide. Understanding the factors that induce myofibroblastic differentiation is paramount to prevent or reverse the fibrogenic process. Integrin-mediated interaction between the ECM and cytoskeleton promotes myofibroblast differentiation. In the present study, we explored the significance of integrin alpha 11 (ITGA11), the integrin alpha subunit that selectively binds to type I collagen during tissue fibrosis in the liver, lungs and kidneys. We showed that ITGA11 was co-localized with alpha-smooth muscle actin-positive myofibroblasts and was correlatively induced with increasing fibrogenesis in mouse models and human fibrotic organs. Furthermore, transcriptome and protein expression analysis revealed that ITGA11 knockdown in hepatic stellate cells (liver-specific myofibroblasts) markedly reduced transforming growth factor beta induced differentiation and fibrotic parameters. Moreover, ITGA11 knockdown dramatically altered the myofibroblast phenotype, as indicated by the loss of protrusions, attenuated adhesion and migration, and impaired contractility of collagen I matrices. Furthermore, we demonstrated that ITGA11 was regulated by the hedgehog signaling pathway, and inhibition of the hedgehog pathway reduced ITGA11 expression and fibrotic parameters in human hepatic stellate cells in vitro, in liver fibrosis mouse model in vivo and in human liver slices ex vivo. Therefore, we speculated that ITGA11 might be involved in fibrogenic signaling and might act downstream of the hedgehog signaling pathway. These findings highlight the significance of the ITGA11 receptor as a highly promising therapeutic target in organ fibrosis. PMID- 29147015 TI - Structure of FlgK reveals the divergence of the bacterial Hook-Filament Junction of Campylobacter. AB - Evolution of a nano-machine consisting of multiple parts, each with a specific function, is a complex process. A change in one part should eventually result in changes in other parts, if the overall function is to be conserved. In bacterial flagella, the filament and the hook have distinct functions and their respective proteins, FliC and FlgE, have different three-dimensional structures. The filament functions as a helical propeller and the hook as a flexible universal joint. Two proteins, FlgK and FlgL, assure a smooth connectivity between the hook and the filament. Here we show that, in Campylobacter, the 3D structure of FlgK differs from that of its orthologs in Salmonella and Burkholderia, whose structures have previously been solved. Docking the model of the FlgK junction onto the structure of the Campylobacter hook provides some clues about its divergence. These data suggest how evolutionary pressure to adapt to structural constraints, due to the structure of Campylobacter hook, causes divergence of one element of a supra-molecular complex in order to maintain the function of the entire flagellar assembly. PMID- 29147016 TI - Observation of dielectric universalities in albumin, cytochrome C and Shewanella oneidensis MR-1 extracellular matrix. AB - The electrodynamics of metals is well understood within the Drude conductivity model; properties of insulators and semiconductors are governed by a gap in the electronic states. But there is a great variety of disordered materials that do not fall in these categories and still respond to external field in an amazingly uniform manner. At radiofrequencies delocalized charges yield a frequency independent conductivity sigma 1(nu) whose magnitude exponentially decreases while cooling. With increasing frequency, dispersionless conductivity starts to reveal a power-law dependence sigma 1(nu)?nu s with s < 1 caused by hopping charge carriers. At low temperatures, such Universal Dielectric Response can cross over to another universal regime with nearly constant loss epsilon"?sigma1/nu = const. The powerful research potential based on such universalities is widely used in condensed matter physics. Here we study the broad-band (1-1012 Hz) dielectric response of Shewanella oneidensis MR-1 extracellular matrix, cytochrome C and serum albumin. Applying concepts of condensed matter physics, we identify transport mechanisms and a number of energy, time, frequency, spatial and temperature scales in these biological objects, which can provide us with deeper insight into the protein dynamics. PMID- 29147017 TI - Oxidation behavior of graphene-coated copper at intrinsic graphene defects of different origins. AB - The development of ultrathin barrier films is vital to the advanced semiconductor industry. Graphene appears to hold promise as a protective coating; however, the polycrystalline and defective nature of engineered graphene hinders its practical applications. Here, we investigate the oxidation behavior of graphene-coated Cu foils at intrinsic graphene defects of different origins. Macro-scale information regarding the spatial distribution and oxidation resistance of various graphene defects is readily obtained using optical and electron microscopies after the hot plate annealing. The controlled oxidation experiments reveal that the degree of structural deficiency is strongly dependent on the origins of the structural defects, the crystallographic orientations of the underlying Cu grains, the growth conditions of graphene, and the kinetics of the graphene growth. The obtained experimental and theoretical results show that oxygen radicals, decomposed from water molecules in ambient air, are effectively inverted at Stone Wales defects into the graphene/Cu interface with the assistance of facilitators. PMID- 29147018 TI - Enforced GFI1 expression impedes human and murine leukemic cell growth. AB - The differentiation of haematopoietic cells is regulated by a plethora of so called transcription factors (TFs). Mutations in genes encoding TFs or graded reduction in their expression levels can induce the development of various malignant diseases such as acute myeloid leukaemia (AML). Growth Factor Independence 1 (GFI1) is a transcriptional repressor with key roles in haematopoiesis, including regulating self-renewal of haematopoietic stem cells (HSCs) as well as myeloid and lymphoid differentiation. Analysis of AML patients and different AML mouse models with reduced GFI1 gene expression levels revealed a direct link between low GFI1 protein level and accelerated AML development and inferior prognosis. Here, we report that upregulated expression of GFI1 in several widely used leukemic cell lines inhibits their growth and decreases the ability to generate colonies in vitro. Similarly, elevated expression of GFI1 impedes the in vitro expansion of murine pre-leukemic cells. Using a humanized AML model, we demonstrate that upregulation of GFI1 expression leads to myeloid differentiation morphologically and immunophenotypically, increased level of apoptosis and reduction in number of cKit+ cells. These results suggest that increasing GFI1 level in leukemic cells with low GFI1 expression level could be a therapeutic approach. PMID- 29147019 TI - Identification and characterization of serine protease inhibitors in a parasitic wasp, Pteromalus puparum. AB - Serine protease inhibitors (SPIs) regulate protease-mediated activities by inactivating their cognate proteinases, and are involved in multiple physiological processes. SPIs have been extensively studied in vertebrates and invertebrates; however, little SPI information is available in parasitoids. Herein, we identified 57 SPI genes in total through the genome of a parasitoid wasp, Pteromalus puparum. Gene structure analyses revealed that these SPIs contain 7 SPI domains. Depending on their mode of action, these SPIs can be categorized into serpins, canonical inhibitors and alpha-2-macroglobulins (A2Ms). For serpins and canonical inhibitors, we predicted their putative inhibitory activities to trypsin/chymotrypsin/elastase-like enzymes based on the amino acids in cleaved reactive sites. Sequence alignment and phylogenetic tree indicated that some serpins similar to known functional inhibitory serpins may participate in immune responses. Transcriptome analysis also showed some canonical SPI genes displayed distinct expression patterns in the venom gland and this was confirmed by quantitative real-time PCR (qPCR) analysis, suggesting their specific physiological functions as venom proteins in suppressing host immune responses. The study provides valuable information to clarify the functions of SPIs in digestion, development, reproduction and innate immunity. PMID- 29147020 TI - Integrative taxonomy methods reveal high mealybug (Hemiptera: Pseudococcidae) diversity in southern Brazilian fruit crops. AB - The Serra Gaucha region is the most important temperate fruit-producing area in southern Brazil. Despite mealybugs (Hemiptera: Pseudococcidae) infesting several host plants in the region, there is a lack of information about the composition of species damaging different crops. A survey of mealybug species associated with commercial fruit crops (apple, persimmon, strawberry and grapes) was performed in Serra Gaucha between 2013 and 2015, using both morphology and DNA analyses for species identification. The most abundant species were Pseudococcus viburni (Signoret), found on all four host plant species, and Dysmicoccus brevipes (Cockerell), infesting persimmon, vines and weeds. The highest diversity of mealybug species was found on persimmon trees, hosting 20 different taxa, of which Anisococcus granarae Pacheco da Silva & Kaydan, D. brevipes, Pseudococcus sociabilis Hambleton and Ps. viburni were the most abundant. A total of nine species were recorded in vineyards. Planococcus ficus (Signoret) and Pseudococcus longispinus (Targioni Tozzetti) were observed causing damage to grapes for the first time. A single species, Ps. viburni, was found associated with apples, while both Ps. viburni and Ferrisia meridionalis Williams were found on strawberry. Four of the mealybug species found represent new records for Brazil. PMID- 29147021 TI - Genome-scale modeling and transcriptome analysis of Leuconostoc mesenteroides unravel the redox governed metabolic states in obligate heterofermentative lactic acid bacteria. AB - Obligate heterofermentative lactic acid bacteria (LAB) are well-known for their beneficial health effects in humans. To delineate the incompletely characterized metabolism that currently limits their exploitation, at systems-level, we developed a genome-scale metabolic model of the representative obligate heterofermenting LAB, Leuconostoc mesenteroides (iLME620). Constraint-based flux analysis was then used to simulate several qualitative and quantitative phenotypes of L. mesenteroides, thereby evaluating the model validity. With established predictive capabilities, we subsequently employed iLME620 to elucidate unique metabolic characteristics of L. mesenteroides, such as the limited ability to utilize amino acids as energy source, and to substantiate the role of malolactic fermentation (MLF) in the reduction of pH-homeostatic burden on F0F1-ATPase. We also reported new hypothesis on the MLF mechanism that could be explained via a substrate channelling-like phenomenon mainly influenced by intracellular redox state rather than the intermediary reactions. Model simulations further revealed possible proton-symporter dependent activity of the energy efficient glucose-phosphotransferase system in obligate heterofermentative LAB. Moreover, integrated transcriptomic analysis allowed us to hypothesize transcriptional regulatory bias affecting the intracellular redox state. The insights gained here about the low ATP-yielding metabolism of L. mesenteroides, dominantly controlled by the cellular redox state, could potentially aid strain design for probiotic and cell factory applications. PMID- 29147023 TI - Nitrogen-related intermediate band in P-rich GaNxPyAs1-x-y alloys. AB - The electronic band structure of phosphorus-rich GaNxPyAs1-x-y alloys (x ~ 0.025 and y >= 0.6) is studied experimentally using optical absorption, photomodulated transmission, contactless electroreflectance, and photoluminescence. It is shown that incorporation of a few percent of N atoms has a drastic effect on the electronic structure of the alloys. The change of the electronic band structure is very well described by the band anticrossing (BAC) model in which localized nitrogen states interact with the extended states of the conduction band of GaAsP host. The BAC interaction results in the formation of a narrow intermediate band (E- band in BAC model) with the minimum at the Gamma point of the Brillouin zone resulting in a change of the nature of the fundamental band gap from indirect to direct. The splitting of the conduction band by the BAC interaction is further confirmed by a direct observation of the optical transitions to the E+ band using contactless electroreflectance spectroscopy. PMID- 29147022 TI - Conventional CD4+ T cells present bacterial antigens to induce cytotoxic and memory CD8+ T cell responses. AB - Bacterial phagocytosis and antigen cross-presentation to activate CD8+ T cells are principal functions of professional antigen presenting cells. However, conventional CD4+ T cells also capture and kill bacteria from infected dendritic cells in a process termed transphagocytosis (also known as transinfection). Here, we show that transphagocytic T cells present bacterial antigens to naive CD8+ T cells, which proliferate and become cytotoxic in response. CD4+ T-cell-mediated antigen presentation also occurs in vivo in the course of infection, and induces the generation of central memory CD8+ T cells with low PD-1 expression. Moreover, transphagocytic CD4+ T cells induce protective anti-tumour immune responses by priming CD8+ T cells, highlighting the potential of CD4+ T cells as a tool for cancer immunotherapy. PMID- 29147024 TI - Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model. AB - Accumulating evidence suggests a key role of the gut-microbiota-brain axis in the antidepressant actions of certain compounds. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, showed rapid and sustained antidepressant effects in treatment-resistant depressed patients. In contrast, another NMDAR antagonist, lanicemine, did not exhibit antidepressant effects in such patients. (R) ketamine, the (R)-enantiomer of ketamine, has rapid-acting and long-lasting antidepressant effects in rodent models of depression. Here we compared the effects of (R)-ketamine and lanicemine on depression-like phenotype and the composition of the gut microbiota in susceptible mice after chronic social defeat stress (CSDS). In behavioral tests, (R)-ketamine showed antidepressant effects in the susceptible mice, whereas lanicemine did not. The 16S ribosomal RNA gene sequencing of feces demonstrated that (R)-ketamine, but not lanicemine, significantly attenuated the altered levels of Bacteroidales, Clostridiales and Ruminococcaceae in the susceptible mice after CSDS. At the genus level, (R) ketamine significantly attenuated the marked increase of Clostridium in the susceptible mice. In contrast, the effects of lanicemine were less potent than those of (R)-ketamine. This study suggests that the antidepressant effects of (R) ketamine might be partly mediated by the restoration of altered compositions of the gut microbiota in a CSDS model. PMID- 29147027 TI - Trapping/Pinning of colloidal microspheres over glass substrate using surface features. AB - Suspensions of micro/nano particles made of Polystyrene, Poly(methyl methacrylate), Silicon dioxide etc. have been a standard model system to understand colloidal physics. These systems have proved useful insights into phenomena such as self-assembly. Colloidal model systems are also extensively used to simulate many condensed matter phenomena such as dynamics in a quenched disordered system and glass transition. A precise control of particles using optical or holographic tweezers is essential for such studies. However, studies of collective phenomena such as jamming and flocking behaviour in a disordered space are limited due to the low throughput of the optical trapping techniques. In this article, we present a technique where we trap and pin polystyrene microspheres ~10 MUm over 'triangular crest' shaped microstructures in a microfluidic environment. Trapping/Pinning occurs due to the combined effect of hydrodynamic interaction and non-specific adhesion forces. This method allows trapping and pinning of microspheres in any arbitrary pattern with a high degree of spatial accuracy which can be useful in studying fundamentals of various collective phenomena as well as in applications such as bead detachment assay based biosensors. PMID- 29147028 TI - Cancer: Bispecific antibody directs T cells to solid tumours. PMID- 29147026 TI - Leveraging genome characteristics to improve gene discovery for putamen subcortical brain structure. AB - Discovering genetic variants associated with human brain structures is an on going effort. The ENIGMA consortium conducted genome-wide association studies (GWAS) with standard multi-study analytical methodology and identified several significant single nucleotide polymorphisms (SNPs). Here we employ a novel analytical approach that incorporates functional genome annotations (e.g., exon or 5'UTR), total linkage disequilibrium (LD) scores and heterozygosity to construct enrichment scores for improved identification of relevant SNPs. The method provides increased power to detect associated SNPs by estimating stratum specific false discovery rate (FDR), where strata are classified according to enrichment scores. Applying this approach to the GWAS summary statistics of putamen volume in the ENIGMA cohort, a total of 15 independent significant SNPs were identified (conditional FDR < 0.05). In contrast, 4 SNPs were found based on standard GWAS analysis (P < 5 * 10-8). These 11 novel loci include GATAD2B, ASCC3, DSCAML1, and HELZ, which are previously implicated in various neural related phenotypes. The current findings demonstrate the boost in power with the annotation-informed FDR method, and provide insight into the genetic architecture of the putamen. PMID- 29147025 TI - Sphingolipid metabolism in cancer signalling and therapy. AB - Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P-S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented. PMID- 29147029 TI - Sepsis: Stalking a new target. PMID- 29147030 TI - Eric Rubin. PMID- 29147031 TI - Metabolic disease: Ectopic olfactory receptor activation reverses obesity. PMID- 29147033 TI - Socratic Seminar with Data: A Strategy to Support Student Discourse and Understanding. AB - A Socratic seminar can be a powerful tool for increasing students' ability to analyze and interpret data. Most commonly used for text-based discussion, we found that using Socratic seminar to engage students with data contributes to student understanding by allowing them to reason through and process complex information as a group. This approach also provides teachers with insights about student misconceptions and understanding of concepts by listening to the student driven discussion. This article reports on Socratic seminar in the context of a high school type 2 diabetes curriculum that explores gene and environment interactions. A case study illustrates how Socratic seminar is applied in a classroom and how students engage with the process. General characteristics of Socratic seminar are discussed at the end of the article. PMID- 29147034 TI - Consumption Smoothing and Frequency of Benefit Payments of Cash Transfer Programs. PMID- 29147036 TI - Measuring arithmetic: A psychometric approach to understanding formatting effects and domain specificity. AB - Using multitrait, multimethod data, and confirmatory factor analysis, the current study examined the effects of arithmetic item formatting and the possibility that across formats, abilities other than arithmetic may contribute to children's answers. Measurement hypotheses were guided by several leading theories of arithmetic cognition. With a sample of 1314 3rd grade students (age M=103.24 months, SD=5.41 months), Abstract Code Theory, Encoding Complex Theory, Triple Code Theory, and the Exact versus Approximate Calculations Hypothesis were evaluated, using 11 measures of arithmetic with symbolic problem formats (e.g., Arabic numeral and language-based formats) and various problem demands (e.g., requiring both exact and approximate calculations). In general, results provided support for both Triple Code Theory and Encoding Complex Theory. As predicted by Triple Code Theory, arithmetic outcomes with language formatting, Arabic numeral formatting, and estimation demands (across formats) were related but distinct from one another. As predicted by Encoding Complex Theory, executive attention was a direct predictor of all arithmetic outcomes. Language was no longer a direct predictor of arithmetic outcomes when executive attention was accounted for in the model; however, a strong and enduring relationship between language and executive attention suggested that language may play a facilitative role in reasoning during numeric processing. These findings have important implications for assessing arithmetic in educational settings and suggest that in addition to arithmetic-focused interventions, interventions targeting executive attention, language, and/or the interplay between them (i.e., internal speech during problem solving) may be a promising avenues of mathematical problem-solving intervention. PMID- 29147032 TI - Emptying the stores: lysosomal diseases and therapeutic strategies. AB - Lysosomal storage disorders (LSDs) - designated as 'orphan' diseases - are inborn errors of metabolism caused by defects in genes that encode proteins involved in various aspects of lysosomal homeostasis. For many years, LSDs were viewed as unattractive targets for the development of therapies owing to their low prevalence. However, the development and success of the first commercial biologic therapy for an LSD - enzyme replacement therapy for type 1 Gaucher disease - coupled with regulatory incentives rapidly catalysed commercial interest in therapeutically targeting LSDs. Despite ongoing challenges, various therapeutic strategies for LSDs now exist, with many agents approved, undergoing clinical trials or in preclinical development. PMID- 29147035 TI - Dendrimers for Ocular Drug Delivery. AB - Existing methods of administering ocular drugs are limited in either their safety or efficiency. Nanomedicine therapies have the potential to address this deficiency by creating vehicles that can control drug biodistribution. Dendrimers are synthetic polymeric nanoparticles with a unique highly organized branching structure. In recent years, promising results using dendrimer vehicles to deliver ocular drugs through different routes of administration have been reported. In this review, we briefly summarize these results with emphasis on the dendrimer modifications used to target different ocular structures. PMID- 29147038 TI - Public health round-up. PMID- 29147039 TI - Communicating science-based messages on vaccines. AB - The public health response to false information about vaccines can sometimes backfire. A series of workshops aims to help public health officials in Europe meet the challenge. Tatum Anderson reports. PMID- 29147040 TI - Countries urged to take tough action to prevent NCDs. AB - Uruguay is hosting the WHO Global Conference on Noncommunicable Diseases (NCDs) this month, from 18-20 October. Tabare Vazquez, the President of Uruguay, tells the Bulletin of the World Health Organization about his country's efforts to prevent and fight NCDs and why countries should step up the global response. PMID- 29147041 TI - Using health-facility data to assess subnational coverage of maternal and child health indicators, Kenya. AB - Objective: To develop a systematic approach to obtain the best possible national and subnational statistics for maternal and child health coverage indicators from routine health-facility data. Methods: Our approach aimed to obtain improved numerators and denominators for calculating coverage at the subnational level from health-facility data. This involved assessing data quality and determining adjustment factors for incomplete reporting by facilities, then estimating local target populations based on interventions with near-universal coverage (first antenatal visit and first dose of pentavalent vaccine). We applied the method to Kenya at the county level, where routine electronic reporting by facilities is in place via the district health information software system. Findings: Reporting completeness for facility data were well above 80% in all 47 counties and the consistency of data over time was good. Coverage of the first dose of pentavalent vaccine, adjusted for facility reporting completeness, was used to obtain estimates of the county target populations for maternal and child health indicators. The country and national statistics for the four-year period 2012/13 to 2015/16 showed good consistency with results of the 2014 Kenya demographic and health survey. Our results indicated a stagnation of immunization coverage in almost all counties, a rapid increase of facility-based deliveries and caesarean sections and limited progress in antenatal care coverage. Conclusion: While surveys will continue to be necessary to provide population-based data, web-based information systems for health facility reporting provide an opportunity for more frequent, local monitoring of progress, in maternal and child health. PMID- 29147042 TI - Insecticide-treated nets and malaria prevalence, Papua New Guinea, 2008-2014. AB - Objective: To investigate changes in malaria prevalence in Papua New Guinea after the distribution of long-lasting Insecticide-treated nets, starting in 2004, and the introduction of artemisinin-based combination therapy in 2011. Methods: Two malaria surveys were conducted in 2010-2011 and 2013-2014. They included 77 and 92 randomly selected villages, respectively. In each village, all members of 30 randomly selected households gave blood samples and were assessed for malaria infection by light microscopy. In addition, data were obtained from a malaria survey performed in 2008-2009. Results: The prevalence of malaria below 1600 m in altitude decreased from 11.1% (95% confidence interval, CI: 8.5-14.3) in 2008 2009 to 5.1% (95% CI 3.6-7.4) in 2010-2011 and 0.9% (95% CI 0.6-1.5) in 2013 2014. Prevalence decreased with altitude. Plasmodium falciparum was more common than P. vivax overall, but not everywhere, and initially the prevalence of P. vivax infection decreased more slowly than P. falciparum infection. Malaria infections were clustered in households. In contrast to findings in 2008-2009, no significant association between net use and prevalence was found in the later two surveys. The prevalence of both fever and splenomegaly also decreased but their association with malaria infection became stronger. Conclusion: Large-scale insecticide-treated net distribution was associated with an unprecedented decline in malaria prevalence throughout Papua New Guinea, including epidemic-prone highland areas. The decline was accompanied by broader health benefits, such as decreased morbidity. Better clinical management of nonmalarial fever and research into residual malaria transmission are required. PMID- 29147044 TI - Effective, polyvalent, affordable antivenom needed to treat snakebite in Nepal. PMID- 29147043 TI - Postpartum depression in India: a systematic review and meta-analysis. AB - Objective: To provide an estimate of the burden of postpartum depression in Indian mothers and investigate some risk factors for the condition. Methods: We searched PubMed(r), Google Scholar and Embase(r) databases for articles published from year 2000 up to 31 March 2016 on the prevalence of postpartum depression in Indian mothers. The search used subject headings and keywords with no language restrictions. Quality was assessed via the Newcastle-Ottawa quality assessment scale. We performed the meta-analysis using a random effects model. Subgroup analysis and meta-regression was done for heterogeneity and the Egger test was used to assess publication bias. Findings: Thirty-eight studies involving 20 043 women were analysed. Studies had a high degree of heterogeneity (I2 = 96.8%) and there was evidence of publication bias (Egger bias = 2.58; 95% confidence interval, CI: 0.83-4.33). The overall pooled estimate of the prevalence of postpartum depression was 22% (95% CI: 19-25). The pooled prevalence was 19% (95% CI: 17-22) when excluding 8 studies reporting postpartum depression within 2 weeks of delivery. Small, but non-significant differences in pooled prevalence were found by mother's age, geographical location and study setting. Reported risk factors for postpartum depression included financial difficulties, presence of domestic violence, past history of psychiatric illness in mother, marital conflict, lack of support from husband and birth of a female baby. Conclusion: The review shows a high prevalence of postpartum depression in Indian mothers. More resources need to be allocated for capacity-building in maternal mental health care in India. PMID- 29147045 TI - Strategic procurement and international collaboration to improve access to medicines. PMID- 29147046 TI - Food supply, nutrition and trade policy: reversal of an import ban on turkey tails. PMID- 29147047 TI - Policy options for extending standardized tobacco packaging. PMID- 29147049 TI - Healthy ageing: moving forward. PMID- 29147050 TI - End-of-life care in low- and middle-income countries. PMID- 29147051 TI - Public health round-up. PMID- 29147053 TI - Interview with Yuji Kuroiwa: a novel approach to the ageing challenge. AB - Addressing the needs of Japan's rapidly ageing population is a major challenge for policy-makers. Yuji Kuroiwa tells Andreia Azevedo Soares why that challenge is an opportunity to boost wellbeing and growth. PMID- 29147052 TI - Supporting families to care for people with dementia. AB - The burden of care for people with dementia in low- and middle-income countries falls mainly on their families. Vijay Shankar Balakrishnan and Fiona Fleck report on some of the training and support that is available. PMID- 29147054 TI - Service readiness of health facilities in Bangladesh, Haiti, Kenya, Malawi, Namibia, Nepal, Rwanda, Senegal, Uganda and the United Republic of Tanzania. AB - Objective: To evaluate the service readiness of health facilities in Bangladesh, Haiti, Kenya, Malawi, Namibia, Nepal, Rwanda, Senegal, Uganda and the United Republic of Tanzania. Methods: Using existing data from service provision assessments of the health systems of the 10 study countries, we calculated a service readiness index for each of 8443 health facilities. This index represents the percentage availability of 50 items that the World Health Organization considers essential for providing health care. For our analysis we used 37-49 of the items on the list. We used linear regression to assess the independent explanatory power of four national and four facility-level characteristics on reported service readiness. Findings: The mean values for the service readiness index were 77% for the 636 hospitals and 52% for the 7807 health centres/clinics. Deficiencies in medications and diagnostic capacity were particularly common. The readiness index varied more between hospitals and health centres/clinics in the same country than between them. There was weak correlation between national factors related to health financing and the readiness index. Conclusion: Most health facilities in our study countries were insufficiently equipped to provide basic clinical care. If countries are to bolster health-system capacity towards achieving universal coverage, more attention needs to be given to within-country inequities. PMID- 29147055 TI - Assistive technologies for people with dementia: ethical considerations. AB - The sustainable development goals (SDGs) adopted by the United Nations in 2015 include a new target for global health: SDG 3 aims to "ensure healthy lives and promote well-being for all at all ages." Dementia care of good quality is particularly important given the projected increase in the number of people living with the condition. A range of assistive technologies have been proposed to support dementia care. However, the World Health Organization estimated in 2017 that only one in 10 of the 1 billion or more people globally who could benefit from these technologies in some way actually has access to them. For people living with dementia, there has been little analysis of whether assistive technologies will support their human rights in ways that are consistent with the United Nations Convention on the Rights of Persons with Disabilities. The aim of this paper is to examine the relevant provisions of the convention and consider their implications for the use of assistive technologies in dementia care. Assistive technologies can clearly play an important role in supporting social engagement, decision-making and advance planning by people living with dementia. However, concerns exist that some of these technologies also have the potential to restrict freedom of movement and intrude into privacy. In conclusion, an analysis of the implications of assistive technologies for human rights laws is needed to ensure that technologies are used in ways that support human rights and help meet the health-related SDG 3. PMID- 29147056 TI - Organizing integrated health-care services to meet older people's needs. AB - In most countries, a fundamental shift in the focus of clinical care for older people is needed. Instead of trying to manage numerous diseases and symptoms in a disjointed fashion, the emphasis should be on interventions that optimize older people's physical and mental capacities over their life course and that enable them to do the things they value. This, in turn, requires a change in the way services are organized: there should be more integration within the health system and between health and social services. Existing organizational structures do not have to merge; rather, a wide array of service providers must work together in a more coordinated fashion. The evidence suggests that integrated health and social care for older people contributes to better health outcomes at a cost equivalent to usual care, thereby giving a better return on investment than more familiar ways of working. Moreover, older people can participate in, and contribute to, society for longer. Integration at the level of clinical care is especially important: older people should undergo comprehensive assessments with the goal of optimizing functional ability and care plans should be shared among all providers. At the health system level, integrated care requires: (i) supportive policy, plans and regulatory frameworks; (ii) workforce development; (iii) investment in information and communication technologies; and (iv) the use of pooled budgets, bundled payments and contractual incentives. However, action can be taken at all levels of health care from front-line providers through to senior leaders - everyone has a role to play. PMID- 29147057 TI - Lessons learnt during 20 years of the Swedish strategic programme against antibiotic resistance. AB - Increasing use of antibiotics and rising levels of bacterial resistance to antibiotics are a challenge to global health and development. Successful initiatives for containing the problem need to be communicated and disseminated. In Sweden, a rapid spread of resistant pneumococci in the southern part of the country triggered the formation of the Swedish strategic programme against antibiotic resistance, also known as Strama, in 1995. The creation of the programme was an important starting point for long-term coordinated efforts to tackle antibiotic resistance in the country. This paper describes the main strategies of the programme: committed work at the local and national levels; monitoring of antibiotic use for informed decision-making; a national target for antibiotic prescriptions; surveillance of antibiotic resistance for local, national and global action; tracking resistance trends; infection control to limit spread of resistance; and communication to raise awareness for action and behavioural change. A key element for achieving long-term changes has been the bottom-up approach, including working closely with prescribers at the local level. The work described here and the lessons learnt could inform countries implementing their own national action plans against antibiotic resistance. PMID- 29147058 TI - Volunteer provision of long-term care for older people in Thailand and Costa Rica. AB - Problem: Demand for long-term care services for older people is increasing rapidly in low- and middle-income countries. Countries need to establish national long-term care systems that are sustainable and equitable. Approach: The Governments of Costa Rica and Thailand have implemented broadly comparable interventions to deploy volunteers in long-term home care. Both countries trained older volunteers from local communities to make home visits to impoverished and vulnerable older people and to facilitate access to health services and other social services. Local setting: Costa Rica and Thailand are upper-middle-income countries with strong traditions of community-based health services that they are now extending into long-term care for older people. Relevant changes: Between 2003 and 2013 Thailand's programme trained over 51 000 volunteers, reaching almost 800 000 older people. Between 2010 and 2016 Costa Rica established 50 community care networks, serving around 10 000 people and involving over 5000 volunteers. Despite some evidence of benefits to the physical and mental health of older people and greater uptake of other services, a large burden of unmet care needs and signs of a growth of unregulated private services still exist. Lessons learnt: There is scope for low- and middle-income countries to develop large-scale networks of community-based long-term care volunteers. The capacity of volunteers to enhance the quality of life of clients is affected by the local availability of care services. Volunteer care networks should be complemented by other initiatives, including training about health in later life for volunteers, and investment in community long-term care services. PMID- 29147059 TI - Tetanus in adult males, Bugando Medical Centre, United Republic of Tanzania. AB - Problem: In the United Republic of Tanzania, the incidence of non-neonatal circumcision-related tetanus is probably underreported. Approach: We analysed charts and extracted information on outcome and wound location for non-neonatal cases of tetanus admitted to the intensive care unit of Bugando Medical Centre between 2001 and 2016. Local setting: Bugando Medical Centre, which is one of four teaching referral hospitals in the United Republic of Tanzania, has a 13-bed intensive care unit that manages all admitted patients with tetanus. Within the United Republic of Tanzania, formal programmes of tetanus immunization are targeted at infants or women. Relevant changes: From our inpatient logs, we identified six patients with non-neonatal tetanus among male patients with a recent history of circumcision. Only one of these patients had been circumcised within a subnational programme of voluntary medical male circumcision. The other five had been circumcised outside of the programme - e.g. at small rural dispensaries or by a traditional provider with no formal medical training. The six patients were aged 11-55 years and five (83%) of them died in hospital - all of overwhelming sepsis. Lessons learnt: Within the Tanzanian programme of voluntary medical male circumcision, education on wound hygiene probably helps to reduce the incidence of non-neonatal circumcision-related tetanus. The corresponding incidence among the boys and men who are circumcised beyond this subnational programme is probably higher. The training of all circumcision providers in wound care and a vaccination programme to ensure that male Tanzanians receive tetanus immunization post-infancy are recommended. PMID- 29147060 TI - The need to monitor actions on the social determinants of health. PMID- 29147061 TI - Laws on filial support in four Asian countries. PMID- 29147062 TI - Equity and healthy ageing. PMID- 29147063 TI - Nativity, Race-Ethnicity, and Dual Diagnosis among US Adults. AB - Purpose: This study investigated disparities in dual diagnosis (comorbid substance-use and depressive/anxiety disorders) among US adults by nativity and racial-ethnic origin and socioeconomic, cultural, and psychosocial factors that may account for the observed disparities. Design/methodology: The study drew on data from two waves of the National Epidemiological Survey on Alcohol and Related Conditions. Racial-ethnic categories included African, Asian/Pacific Islander, European, Mexican, Puerto Rican, and other Hispanic/Latino. Substance-use and depressive/anxiety disorders were assessed per DSM-IV. A four-category measure of comorbidity was constructed: no substance-use or psychiatric disorder; substance use disorder only; depressive/anxiety disorder only; and, dual diagnosis. The data were analyzed using multinomial logistic regression. Findings: The prevalence of dual diagnosis was low but varied by nativity, with the highest rates among Europeans and Puerto-Ricans born in US states, and the lowest among Mexicans and Asians/Pacific Islanders. The nativity and racial-ethnic effects on likelihood of having dual diagnosis remained significant after all adjustments. Research limitations: The limitations included measures of immigrant status, race ethnicity, and stress and potential misdiagnosis of mental disorder among ethnic minorities. Practical and Social Implications: This new knowledge will help to guide public health and health care interventions addressing immigrant mental and behavioral health gaps. Originality/value: This study addressed the research gap in regard to the prevalence and correlates of dual diagnosis among immigrants and racial-ethnic minorities. The study used the most current and comprehensive data addressing psychiatric conditions among US adults and examined factors rarely captured in epidemiologic surveys (e.g., acculturation). PMID- 29147064 TI - LncRNA NEAT1 Regulates Cell Viability and Invasion in Esophageal Squamous Cell Carcinoma through the miR-129/CTBP2 Axis. AB - Background: Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) was reported to be aberrantly upregulated and promote esophageal squamous cell carcinoma (ESCC) cell progression. Nevertheless, the molecular mechanism of NEAT1 involved in the competing endogenous RNA (ceRNA) regulatory network in ESCC progression remains poorly defined. Methods: The expressions of NEAT1, miR-129, and C-terminal-binding protein 2 (CTBP2) in ESCC cells were examined by qRT-PCR. The effects of NEAT1 knockdown and miR-129 overexpression, or along with CTBP2 upregulation, on ESCC cell viability and invasion were explored by CCK-8 and transwell invasion assays, respectively. Luciferase reporter assay in combination with RIP was performed to confirm the interaction between NEAT1, miR-129, and CTBP2. Results: NEAT1 and CTBP2 were upregulated and miR-129 was downregulated in ESCC cells. Either NEAT1 knockdown or miR-129 overexpression suppressed ESCC cell viability and invasion. Moreover, NEAT1 functioned as an endogenous sponge to downregulate miR-129 by competitively binding to miR-129, thereby leading to the derepression of CTBP2, a target of miR-129. CTBP2 restoration overturned cell viability and invasion suppression mediated by NEAT1 knockdown or miR-129 overexpression. Conclusion: LncRNA NEAT1 regulated ESCC cell viability and invasion via the miR-129/CTBP2 axis, contributing to the better understanding of the molecular mechanism of ESCC pathogenesis and progression. PMID- 29147065 TI - Which eligible households get grants? Demographic correlates of receipt in South Africa. AB - Since Apartheid, the South African government transformed and expanded the social grants system to improve the well-being of its vulnerable populations. Despite increased efforts, a sub-section of the grant-eligible population is not reached. Too little is known about the factors that contribute to grant receipt, especially for the household as a whole. This paper examines the household and community characteristics associated with grant receipt among poor households in KwaZulu-Natal. We add to previous work by assessing grant receipt at the household level, examining receipt of the two major grants and analysing correlates in a multivariate framework. While associations with grant receipt are complex and varied, we find higher grant receipt (especially Child Support Grant) among more disadvantaged households. We also find that characteristics across multiple domains are needed to best distinguish household grant receipt. We discuss theoretical implications for models of grant receipt and practical implications for improving grants access. PMID- 29147066 TI - Dynamics of Stress Fibers Turnover in Contractile Cells. AB - Numerous experiments have shown that contractile cells like fibroblasts adapt their internal structure to their microenvironment by generating and orienting a network of stress fibers (SFs). This phenomenon has been modeled in previous studies with stability analysis through calculation of the fiber's potential or strain energy, where SFs are assigned a constant elasticity. Recent experiments have shown that the elasticity in SFs is rate dependent, resulting in a different stress fiber organization under constant or cyclic stretching. Here, a thermodynamical model that describes the anisotropic polymerization of the contractile units into SFs via the calculation of the mechanochemical potential of the two constituents is proposed. The stretch-dependent part of the SF potential is made of two terms that describe the passive and active behavior of the SF. In this paper, it is shown that the contributions of these two terms vary widely under constant or cyclic stretching as the SFs exhibit a rate-dependent elasticity and lead to two very different anisotropic SF organizations. It is further demonstrated that the substrate stiffness as well as its Poisson's ratio and anisotropy play a crucial role in the formation and organization of the SFs, consistent with what has been observed in various experiments. PMID- 29147067 TI - Aging and Predicting Inferences: A Diffusion Model Analysis. AB - In the domain of discourse processing, it has been claimed that older adults (60 90-year-olds) are less likely to encode and remember some kinds of information from texts than young adults. The experiment described here shows that they do make a particular kind of inference to the same extent that college-age adults do. The inferences examined were "predictive" inferences such as the inference that something bad would happen to the actress for the sentence "The director and cameraman were ready to shoot close-ups when suddenly the actress fell from the 14th story" (McKoon & Ratcliff, 1986). Participants read sentences like the actress one and then later they were asked to decide whether words that expressed an inference (e.g., "dead") had or had not appeared explicitly in a sentence. To directly compare older adults' performance to college-age adults' performance, we used a sequential sampling diffusion model (Ratcliff, 1978) to map response times and accuracy onto a single dimension of the strength with which an inference was encoded. On this dimension, there were no significant differences between the older and younger adults. PMID- 29147068 TI - The Italian Version of the Five-Word Test: A Simple Diagnostic Test for Dementia due to Alzheimer's Disease in Routine Clinical Practice. AB - Background: The five-word test (FWT) is a neuropsychological tool (derived from the Grober and Buschke paradigm), measuring hippocampal memory trace consolidation. The study aimed to validate the test for the Italian language and to verify its ability to discriminate patients affected by mild cognitive impairment and dementia due to Alzheimer's disease from healthy matches. Methods: 217 subjects (127 controls, 47 MCI due to AD, and 43 AD) underwent neuropsychological evaluation. The Spearman rank coefficient (rho) was used to assess the correlation between immediate (IRS), delayed (DRS), and total score (TRS) of the FWT and correspondent matches of a specific short story test, while receiving operator characteristic (ROC) curves were built to investigate the diagnostic accuracy of both. Results: Correlation between almost all the scores was significant in all the diagnostic subgroups; the ROC curves of the two tests were not statistically different. A TRS of the FWT with a cut-off of <=9/10 could accurately discriminate AD patients (sensitivity: 97%, specificity: 94%) and MCI due to AD (sensitivity: 76%, specificity: 68%) from control matches. Conclusion: FWT is a simple and valid test of hippocampal memory which appears recommendable in routine clinical practice. PMID- 29147069 TI - Expression Profiling of Long Noncoding RNA Splice Variants in Human Microvascular Endothelial Cells: Lipopolysaccharide Effects In Vitro. AB - Endothelial cell interactions with lipopolysaccharide (LPS) involve both activating and repressing signals resulting in pronounced alterations in their transcriptome and proteome. Noncoding RNAs are now appreciated as posttranscriptional and translational regulators of cellular signaling and responses, but their expression status and roles during endothelial interactions with LPS are not well understood. We report on the expression profile of long noncoding (lnc) RNAs of human microvascular endothelial cells in response to LPS. We have identified a total of 10,781 and 8310 lncRNA transcripts displaying either positive or negative regulation of expression, respectively, at 3 and 24 h posttreatment. A majority of LPS-induced lncRNAs are multiexonic and distributed across the genome as evidenced by their presence on all chromosomes. Present among these are a total of 44 lncRNAs with known regulatory functions, of which 41 multiexonic lncRNAs have multiple splice variants. We have further validated splice variant-specific expression of EGO (NONHSAT087634) and HOTAIRM1 (NONHSAT119666) at 3 h and significant upregulation of lnc-IL7R at 24 h. This study illustrates the genome-wide regulation of endothelial lncRNA splice variants in response to LPS and provides a foundation for further investigations of differentially expressed lncRNA transcripts in endothelial responses to LPS and pathophysiology of sepsis/septic shock. PMID- 29147071 TI - Exhaled Nitric Oxide Is Useful in Symptomatic Radioactive Pneumonia: A Retrospective Study. AB - The aim was to defect the exhaled nitric oxide (eNO) prediction value of symptomatic radioactive pneumonia (SRP). 64 cases of lung cancer or esophagus cancer, who had the primary radiotherapy (intensity-modulated radiation therapy), were included from 2015 June to 2016 January. During the following, the patients were divided: the symptomatic radiation pneumonia group (SRP, with the CTCAE v4.0 score > 2) and the asymptomatic radiation pneumonia group (ASRP, with CTCAE v4.0 score <= 1). All the patients were measured eNO before and at the end of thoracic radiotherapy and gain the posttherapy eNO value and the eNO ratio (posttherapy eNO value/pretherapy eNO value), then the predictive values of eNO toward SRP were measured using the receiver-operating characteristic (ROC). 17 cases were included in the SRP group and the other 47 were included in the ASRP group. The posttherapy eNO was 29.35 (19~60) bbp versus 20.646 (11~37) (P < 0.001), and the ratio was 1.669 (0.61~3.5) versus 0.920 (0.35~1.5) (P < 0.01) (symptomatic versus asymptomatic). ROC showed that the cutoff value of SRP was 19.5 bbp (posttherapy eNO, area under concentration-time curve (AUC) = 0.879) and 1.305 (eNO ratio, AUC = 0.774), which meant that posttherapy eNO and eNO ratio were useful in finding SRP. PMID- 29147070 TI - Evidences of a New Psychobiotic Formulation on Body Composition and Anxiety. AB - Background: Gut microbiota is implied in obesity, because of its ability to harvest energy from diet, and in the regulation of behavior. Given the link between gut microbiota, body composition, obesity, and anxiety, the aim of this study was to evaluate the effects of a new psychobiotic formulation. Methods: Eligible patients were randomly divided into three groups: psychobiotics oral suspension group (POSG); dietary treatment group (DTG); combined treatment group (CTG). All subjects underwent body composition and psychological profile evaluation. Results: Significant changes in body composition parameters in each group were relieved after all treatments. Hamilton anxiety rating scale (HAM-A) highlighted a significant reduction of the total score for all study population after treatments in POSG (p = 0.01) and CTG (p = 0.04). A reduction of HAM-A total score in anxious subjects in POSG or CTG and a significant reduction of positive subjects for HAM-A in POSG (p = 0.03) and in CDG (p = 0.01) were shown. Discussion: Three-week intake of selected POS represents a good approach to solve problems related to obesity and behavior disorders. However, new clinical trials need to be performed on a larger population and for a longer period of treatment before definitive conclusions can be made. This trial is registered with NCT01890070. PMID- 29147072 TI - Paradoxical Association of Postoperative Plasma Sphingosine-1-Phosphate with Breast Cancer Aggressiveness and Chemotherapy. AB - Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that has been shown to serve an important regulatory function in breast cancer progression. This study analyzes plasma S1P levels in breast cancer patients undergoing adjuvant therapy as compared to healthy control volunteers. 452 plasma S1P samples among 158 breast cancer patients, along with 20 healthy control volunteers, were analyzed. Mean S1P levels did not significantly differ between cancer patients and controls. Smoking was associated with higher S1P levels in cancer patients. Baseline S1P levels had weak inverse correlation with levels of the inflammatory mediator interleukin- (IL-) 17 and CCL-2 and positive correlation with tumor necrosis factor alpha (TNF-alpha). Midpoint S1P levels during adjuvant therapy were lower than baseline, with near return to baseline after completion, indicating a relationship between chemotherapy and circulating S1P. While stage of disease did not correlate with plasma S1P levels, they were lower among patients with Her2-enriched and triple-negative breast cancer as compared to luminal-type breast cancer. Plasma S1P levels are paradoxically suppressed in aggressive breast cancer and during adjuvant chemotherapy, which raises the possibility that postoperative plasma S1P levels do not reflect S1P secretion from resected breast cancer. PMID- 29147073 TI - Metformin Suppressed CXCL8 Expression and Cell Migration in HEK293/TLR4 Cell Line. AB - Chronic inflammation is associated with cancer. CXCL8 promotes tumor microenvironment construction through recruiting leukocytes and endothelial progenitor cells that are involved in angiogenesis. It also enhances tumor cell proliferation and migration. Metformin, type II diabetes medication, demonstrates anticancer properties via suppressing inflammation, tumor cell proliferation, angiogenesis, and metastasis. This study intended to address the role of metformin in regulation of CXCL8 expression and cell proliferation and migration. Our data indicated that metformin suppressed LPS-induced CXCL8 expression in a dose-dependent manner through inhibiting NF-kappaB, but not AP-1 and C/EBP, activities under the conditions we used. This inhibitory effect of metformin is achieved through dampening LPS-induced NF-kappaB nuclear translocation. Cell migration was inhibited by metformin under high dose (10 mM), but not cell proliferation. PMID- 29147075 TI - Pediatric ocular nanomedicines: Challenges and opportunities. AB - The eye is a highly complex, yet readily accessible organ within the human body. As such, the eye is an appealing candidate target for a vast array of drug therapies. Despite advances in ocular drug therapy research, the focus on pediatric ocular drug delivery continues to be highly underrepresented due to the limited number of degenerative ocular diseases with childhood onset. In this review, we explore more deeply the reasons underlying the disparity between ocular therapies available for children and for adults by highlighting diseases that most commonly afflict children (with focus on the anterior eye) and existing prognoses, recent developments in ocular drug delivery systems and nanomedicines for children, and barriers to use for pediatric patients. PMID- 29147074 TI - Increased Levels of sRAGE in Diabetic CKD-G5D Patients: A Potential Protective Mechanism against AGE-Related Upregulation of Fibroblast Growth Factor 23 and Inflammation. AB - Advanced glycation end products (AGEs) may induce cardiac remodeling in kidney disease by promoting fibroblast growth factor 23 (FGF-23) expression. Since AGEs are increased in diabetes mellitus (DM), our first aim was to evaluate the existence of any potential association between AGEs, FGF-23, inflammation, and increased cardiovascular risk in DM patients on dialysis (CKD-G5D). Secondarily, we explored the potential role of the soluble receptor for AGEs (sRAGE) as a marker of heart failure. Levels of glycated albumin (GA), sRAGE, c-terminal FGF 23 (cFGF-23), brain natriuretic peptide (BNP), and inflammatory mediators were compared between DM and non-DM CKD-G5D patients. The levels of sRAGE, cFGF-23, BNP, and proinflammatory markers were over the ranges of normality in both DM and non-DM groups. Only GA and sRAGE levels were increased in DM compared to non-DM patients. Plasma levels of sRAGE and CRP were the only independent predictors of BNP concentration. In conclusion, in DM CKD-G5D patients, sRAGE appeared to be a marker of cardiac remodeling. Indeed, its increase could be a potential protective mechanism against the increased risk of cardiovascular complications related to AGEs and inflammation. The causal relationship between sRAGE and cardiovascular risk in these patients needs to be further confirmed by mechanistic studies. PMID- 29147076 TI - Emotion Regulation Difficulties Moderate the Association Between Heavy Episodic Drinking and Dating Violence Perpetration Among College Men. AB - Because of high rates of heavy drinking and dating violence (psychological or physical aggression toward a dating partner) among college men, we examined whether emotion regulation difficulties moderated the association between heavy drinking and dating violence perpetration. One hundred and fifty-eight men were recruited from a large northwestern US university between April 2014 and August 2014. Participants completed an online survey that assessed their emotion regulation difficulties as well as their past year history of heavy episodic drinking (HED; consuming 5+ drinks in 2 hours) and dating violence perpetration. Generalized linear models revealed that the positive association between HED and dating violence perpetration was stronger for men with greater impulse control difficulties and for those who reported limited access to emotion regulation strategies. In addition to continued efforts to reduce heavy drinking among college men, interventions targeting emotion regulation difficulties should be incorporated into standard dating violence intervention and prevention efforts to further reduce the likelihood of dating violence perpetration in this population. PMID- 29147077 TI - Application of Breast Ultrasound Elastography to Differentiate Intracapsular Collection from Silicone-Induced Granuloma of Breast Implant Capsule Complementarily to Contrast-Enhanced Breast Magnetic Resonance Imaging. AB - Background: To determine whether there is correlation between magnetic resonance imaging (MRI) findings and breast elastography to differentiate seroma/hematoma from silicone-induced granuloma of breast implant capsule (SIGBIC). Methods: Prospective study of 99 patients with breast implants submitted to breast MRI during the period from February 1 to May 1, 2017. Patients who present MRI findings of seroma/hematoma or SIGBIC were submitted to a complementary ultrasound elastography study to evaluate the correlation of the results. The criteria adopted for the diagnosis of granuloma by MRI were heterogeneous hypersignal in the T2-weighted sequences, late contrast enhancement, and black drop sign. Lesions that did not enhance after the use of contrast were considered as seroma/hematoma. By elastography, the results were considered positive for granuloma when presented as hard lesions, whereas seroma/hematoma presented as soft lesions. Results: Of the 99 patients evaluated, 15 were included in the study. Of the 15 patients, 9 had solid intracapsular MRI masses, whereas 6 presented collections without contrast enhancement. The complementary elastography study showed correlation with MRI results in all cases of SIGBIC and seroma/hematoma, being elastography able to differentiate lesions from solid to cystic. Conclusions: Elastography of intracapsular masses in breast implants presented results compatible with those found by MRI to differentiate solid lesions from collections. PMID- 29147079 TI - Laboratory Evaluation of Residual Efficacy of Actellic 300 CS (Pirimiphos-Methyl) and K-Othrine WG 250 (Deltamethrin) on Different Indoor Surfaces. AB - The nature and type of local indoor resting wall surfaces to certain level influences the residual bio-efficacy of insecticides used in indoor residual spraying programs. Knockdown and mortality effects of an organophosphate Actellic 300 CS and pyrethroid K-Othrine WG 250 insecticides on the field-collected Culex quinquefasciatus were assessed bimonthly from July to November 2014, using World Health Organization (WHO) cones bioassay test. Knockdown and mortality rates were subjected to statistical analysis using chi2 and Student t tests. Result of the bioassay test on C quinquefasciatus showed that plywood surfaces had the best residual knockdown activity of Actellic 300 CS with knockdown rate above the WHO recommended threshold limit of >=95% for 30 days after treatment. This was followed by mud surface with knockdown rates >=95% threshold limit 15 days (97%) after treatment. The lowest knockdown rates of less than 95% were observed on cement surface throughout the assessment period. However, the knockdown rates of mosquitoes on deltamethrin WG 250-treated cement and plywood surfaces were 100% and >=95%, respectively, at 30 days after treatment. But the knockdown activity was below the recommended threshold limit on mud surface during the 17 weeks trial. Knockdown activities varied significantly (p < .05), and it is a function of exposure periods, different surfaces, and insecticide formulations. The 24 hour mortality rates of Actellic 300 CS and K-Othrine WG 250 at 120 days after treatment were 83.6% and 86.7%, and 80% and 83.3%, on plywood and cement surfaces, respectively. A maximum residual period of 75 and 45 days were recorded for Actellic 300 CS and K-Othrine WG 250, respectively, on mud surface. Both Actellic 300 CS and K-Othrine 250 WG were highly effective against Culex mosquito. The extended residual activity of p-methyl CS compared with deltamethrin WG 250 makes it a suitable alternative insecticide against pyrethroid-resistant mosquitoes in Southwest Nigeria. PMID- 29147080 TI - Effect of the Ginger Derivative, 6-Shogaol, on Ferritin Levels in Patients With Low to Intermediate-1-Risk Myelodysplastic Syndrome-A Small, Investigative Study. AB - Background: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal stem cell disorders characterized by dysplastic and ineffective hematopoiesis and peripheral cytopenias. Elevated serum ferritin (SF) is often observed in nontransfused, lower risk MDS. It has been reported that ineffective erythropoiesis enhances iron absorption in MDS through downregulation of hepcidin and its prohormones such that SF rises. Aim: To determine the effect of 6 shogaol, a dehydration derivative of ginger, known to have hepatoprotective and chemotherapeutic activity, on 6 early-stage, transfusion-independent patients with MDS, 3 of whom had raised levels of SF. Method: Six patients with MDS with low or intermediate-1 subtypes, as defined by the International Prognostic Scoring System (IPSS), were recruited into the study and were administered 1 gel capsule daily containing 20 mg ginger extract standardized for 20% 6-shogaol. Blood and urine samples were collected and various markers monitored at regular intervals. Results: 6-shogaol caused a decrease in SF levels in 3 of 6 patients with early MDS (50%) whose SF levels were elevated at the start of the study. Our findings suggest upregulation of hepcidin and its prohormones, possibly through an improvement in liver function. Discussion: In light of the encouraging results in this small, investigative study, we are planning a larger study to confirm the beneficial effect of 6-shogaol in patients with raised ferritin levels due to ineffective erythropoiesis. PMID- 29147081 TI - Skull Meningioma Associated with Intradural Cyst: A Case Report. AB - We present the first report of intraosseous meningioma accompanied by intradural cyst formation. A 76-year-old woman had previously undergone breast cancer treatment, so the preoperative diagnosis was metastatic breast cancer. This case reminds us that the possibility of meningioma should be kept in mind in patients with breast cancer, irrespective of neuroimaging findings. PMID- 29147082 TI - Impact of Pathology Review for Decision Therapy in Localized Prostate Cancer. AB - Background: The Gleason score is an essential tool in the decision to treat localized prostate cancer. However, experienced pathologists can classify Gleason score differently than do low-volume pathologists, and this may affect the treatment decision. This study sought to assess the impact of pathology review of external biopsy specimens from 23 men with a recent diagnosis of localized prostate cancer. Methods: All external biopsy specimens were reviewed at our pathology department. Data were retrospectively collected from scanned charts. Results: The median patient age was 63 years (range: 46-74 years). All patients had a Karnofsky performance score of 90% to 100%. The median prostate-specific antigen level was 23.6 ng/dL (range: 1.04-13.6 ng/dL). Among the 23 reviews, the Gleason score changed for 8 (35%) patients: 7 upgraded and 1 downgraded. The new Gleason score affected the treatment decision in 5 of 8 cases (62.5%). Conclusions: This study demonstrates the need for pathology review in patients with localized prostate cancer before treatment because Gleason score can change in more than one-third of patients and can affect treatment decision in almost two-thirds of recategorized patients. PMID- 29147078 TI - Long Noncoding RNAs as a Key Player in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is a major malignancy in the liver and has emerged as one of the main cancers in the world with a high mortality rate. However, the molecular mechanisms of HCC are still poorly understood. Long noncoding RNAs (lncRNAs) have recently come to the forefront as functional non-protein-coding RNAs that are involved in a variety of cellular processes ranging from maintaining the structural integrity of chromosomes to gene expression regulation in a spatiotemporal manner. Many recent studies have reported the involvement of lncRNAs in HCC which has led to a better understanding of the underlying molecular mechanisms operating in HCC. Long noncoding RNAs have been shown to regulate development and progression of HCC, and thus, lncRNAs have both diagnostic and therapeutic potentials. In this review, we present an overview of the lncRNAs involved in different stages of HCC and their potential in clinical applications which have been studied so far. PMID- 29147083 TI - Spinal Cord Stimulation in Failed Back Surgery Syndrome: Effects on Posture and Gait-A Preliminary 3D Biomechanical Study. AB - We studied 8 patients with spinal cord stimulation (SCS) devices which had been previously implanted to treat neuropathic chronic pain secondary to Failed Back Surgery Syndrome. The aim of our study was to investigate the effects of SCS on posture and gait by means of clinical scales (Short Form Health Survey-36, Visual Analogue Scale for pain, and Hamilton Depression Rating Scale) and instrumented evaluation with 3D Gait Analysis using a stereophotogrammetric system. The latter was performed with the SCS device turned both OFF and ON. We recorded gait and posture using the Davis protocol and also trunk movement during flexion-extension on the sagittal plane, lateral bending on the frontal plane, and rotation on the transversal plane. During and 30 minutes after the stimulation, not only the clinical scales but also spatial-temporal gait parameters and trunk movements improved significantly. Improvement was not shown under stimulation-OFF conditions. Our preliminary data suggest that SCS has the potential to improve posture and gait and to provide a window of pain-free opportunity to optimize rehabilitation interventions. PMID- 29147084 TI - Optimization of Replacing Pork Meat with Yellow Worm (Tenebrio molitor L.) for Frankfurters. AB - The effects of replacing pork meat with yellow mealworms on the physicochemical properties and sensory characteristics of frankfurters were investigated in this study. The control (50% pork ham), T1 (45% pork ham + 5% yellow mealworm), T2 (40% pork ham + 10% yellow mealworm), T3 (35% pork ham + 15% yellow mealworm), T4 (30% pork ham + 20% yellow mealworm), T5 (25% pork ham + 25% yellow mealworm), and T6 (20% pork ham + 30% yellow mealworm) were prepared, replacing lean pork meat with yellow mealworm. The moisture content, lightness, sarcoplasmic protein solubility, hardness, gumminess, chewiness, and apparent viscosity of frankfurters with yellow mealworm were lower than those of the control (p<0.05), whereas the content of protein and ash, pH, and yellowness of frankfurters with yellow mealworm were higher than those of the control (p<0.05). The fat content of frankfurters in T1 (p<0.05) was the highest, and the fat content of treatments decreased with increasing yellow mealworm concentrations (p<0.05). Frankfurters with increasing yellow mealworm concentrations had lower color, flavor, off flavor, and juiciness scores. The overall acceptability was not significantly different in the control, T1, and T2 (p>0.05). Thus, the results of this study showed that replacing lean pork meat with up to 10% yellow mealworm successfully maintained the quality of frankfurters at a level similar to that of the regular control frankfurters. PMID- 29147085 TI - A Comparison of the Essential Amino Acid Content and the Retention Rate by Chicken Part according to Different Cooking Methods. AB - This study set out to identify the changes in the nutrient contents during the chicken cooking process as basic data for the establishment of a national health nutrition policy. Samples were produced using 3 chicken parts (wing, breast, and leg) and 7 cooking methods (boiling, pancooking, pan-frying, deep-frying, steaming, roasting, and microwaving), and the essential amino acid contents, principal components, and retention rates were analyzed. Weight loss was observed in all chicken parts with all cooking methods. The protein and essential amino acid contents of the chicken samples differed significantly according to the part and the cooking method (p<0.01). The protein and essential amino acid contents (g/100 g) of raw and cooked chicken parts showed ranges of 16.81-32.36 and 0.44 2.45, respectively. The principal component analysis (PCA) clearly demonstrated that the cooking methods and chicken parts produced similar trends for the essential amino acid contents. The retention rates of the chicken parts varied with the cooking methods, yielding a minimum value of 83% for isoleucine in a roasted wing, 91% for protein in a steamed breast, and 77% for isoleucine and lysine in a roasted leg. Therefore, the protein and amino acid contents of the roasted breast were higher than those of the other cooked chicken parts. PMID- 29147086 TI - Edible Packaging Film Derived from Mechanically Deboned Chicken Meat Proteins: Effect of Transglutaminase on Physicochemical Properties. AB - In this study, effect of transglutaminase (TGase) addition on physical, water barrier, optical and mechanical properties of mechanically deboned chicken meat protein (MDCM-P) films was investigated. When TGase was added to the films, the thickness increased, but the solubility decreased. Films treated with TGase exhibited higher water vapor permeability than control film (p<0.05). When TGase concentration increased, the L* values of films decreased, but a* and b* values increased. All films showed very good barrier properties against UV light. The highest tensile strength was obtained in MDCM-P films containing 3% TGase (p<0.05). The elongation at break values increased with the TGase concentration increasing from 1 to 3%, but decreased at higher enzyme concentration (p<0.05). The addition of TGase altered molecular organization and intermolecular interaction in the film matrix. TGase treated films showed smoother and ordered surface structure and homogeneous and compact microstructure. The results indicated that TGase use can be an effective approach in improving the solubility and mechanical properties of MDCM-P films. PMID- 29147087 TI - Hydrolysate Preparation with High Content of 5-Hydroxytryptophan from Liquid Egg Protein and Its Sleep-Potentiating Activity. AB - Alcalase hydrolysis of liquid egg white was used to produce 5-hydroxytryptophan (HTP) under various conditions and investigate the sleep-potentiating activity of liquid egg white hydrolysate (LEH) on pentobarbital-induced sleep. Alcalase hydrolysis yielded the highest content of 5-HTP (13.50 MUg/mL), while neutrase hydrolysis showed the lowest 5-HTP content (5.23 MUg/mL). The liquid egg white to water ratio (1:1) was optimal for the production of 5-HTP with high amino nitrogen (A-N) content and degree of hydrolysis. The 5-HTP, amino-nitrogen, and degree of hydrolysis increased until 24 h of hydrolysis and slightly increased thereafter during hydrolysis with 2% and 5% enzyme addition. 5-HTP administration at doses of 6 and 9 mg/kg significantly increased sleep duration and decreased sleep latency time compared to that in the control (p<0.05). LEH (150 mg/mouse), which was equivalent to 5-HTP at 6 mg/kg, significantly decreased sleep latency time and increased sleep duration time compared to that in the control (p<0.05). Oral administration of LEH showed sleep-potentiating effects because of 5-HTP. The sleep-potentiating activity of LEH may have occurred through 5-HTP in our pentobarbital-induced sleep model. LEH may be a valuable alternative to sleep enhancement and may be used as a sleep-potentiating agent. PMID- 29147088 TI - Evaluation and Characterization of Milk-derived Microvescicle Isolated from Bovine Colostrum. AB - Extracellular microvesicles are membranous nano-sized cellular organelles secreted by a variety of cells under normal and pathological conditions and heterogeneous in size ranging from 30 nm to 1 MUm. They carry functional microRNAs that can influence immunity and development. For a particular application of microvesicles, choice of isolation method is particularly important; however, their isolation methods from colostrum in particular have not been described clearly. In this work, differential ultracentrifugation as a conventional method, ultracentrifugation with some modification such as additional precipitations, ultrafiltration, sucrose gradient separation and ExoQuickTM as a commercial reagent were compared. The goal was to compare mainly microvesicular total microRNA yield, distribution and purity among the methods then select the best isolation method for bovine colostrum microvesicles based largely on microRNA yield with the view of applying the vesicles in work where vesicular micro-RNA cargo is the target bioactive component. Highest yields for vesicular microRNA were obtained using conventional methods and among them, subsequent ultracentrifugation with 100,000 g and 135,000 g conventional method 2 was selected as it had the highest RNA to protein ratio indicating that it pelleted the least protein in relation to RNA an important factor for in vivo applications to assess microvesicle functionalities without risk of contaminating non-vesicular biomaterial. Microvesicles isolated using conventional method 2 were successfully internalized by cells in vitro showing their potential to deliver their cargo into cells in vitro and in vivo in case of functional studies. PMID- 29147089 TI - Multiple Regression Analysis to Estimate the Unit Price of Hanwoo (Bos taurus coreanae) Beef. AB - This study were estimated the contribution of carcass traits to unit price, to analyze the marbling score as a categorical variable rather than a numerical variable, and to develop an optimal model that also includes the holiday effect and the raising period. The data for this study were acquired from the Quality Evaluation of the Korea Institute for Animal Products, and consisted of the trading records of 1,613,699 heads at 12 wholesale markets from 2010 to 2014. The unit price of a cow was estimated from the following parameters: -52.50 Won/mm, 8.93 Won/cm2, 7.20 Won/kg, and -1.04 Won/day for backfat thickness, eye muscle area, carcass weight, and raising period, respectively. Parameters for the dummy variables of marbling scores varied from 0 to 8328.74 Won/kg, which means that each marbling score grade had a different price value. The unit price of a steer was estimated from the following parameters: -92.12 Won/mm, 20.22 Won/cm2, 1.30 Won/kg, and -1.72 Won/day for backfat thickness, eye muscle area, carcass weights, and raising period, respectively. Parameters for dummy variables of marbling scores varied from 0 to 7338.80 Won/kg, which means that the grades of each marbling score had different price values. The unit price of sales during traditional holidays was significantly higher (827.71 Won/kg for cows, and 645.15 Won/kg for steers) than during non-holidays.We conclude that the use of categorical values for marbling scores would be needed to evaluate the price of Hanwoo beef using multiple regression analysis based on carcass traits and environmental factors. PMID- 29147090 TI - Detection of Antibiotic Resistance and Resistance Genes in Enterococci Isolated from Sucuk, a Traditional Turkish Dry-Fermented Sausage. AB - The aim of this study was to isolate enterococci in Sucuk, a traditional Turkish dry-fermented sausage and to analyze isolates for their biodiversity, antibiotic resistance patterns and the presence of some antibiotic resistance genes. A total of 60 enterococci strains were isolated from 20 sucuk samples manufactured without using a starter culture and they were identified as E. faecium (73.3%), E. faecalis (11.7%), E. hirae (8.3%), E. durans (3.3%), E. mundtii (1.7%) and E. thailandicus (1.7%). Most of the strains were found resistant to rifampin (51.67%) followed by ciprofloxacin (38.33%), nitrofurantoin (33.33%) and erythromycin (21.67%). All strains were found susceptible to ampicillin. Only E. faecium FYE4 and FYE60 strains displayed susceptibility to all antibiotics. Other strains showed different resistance patterns to antibiotics. E. faecalis was found more resistant to antibiotics than other species. Most of the strains (61.7%) displayed resistance from between two and eight antibiotics. The ermB, ermC, gyrA, tetM, tetL and vanA genes were detected in some strains. A lack of correlation between genotypic and phenotypic analysis for some strains was detected. The results of this study indicated that Sucuk manufactured without using a starter culture is a reservoir of multiple antibiotic resistant enterococci. Consequently, Sucuk is a potential reservoir for the transmission of antibiotic resistance genes from animals to humans. PMID- 29147091 TI - Evaluation of the Digestibility of Korean Hanwoo Beef Cuts Using the in vitro Physicochemical Upper Gastrointestinal System. AB - The aim of this study was to investigate the digestibility of different Korean Hanwoo beef cuts using an in vitro digestion model, in vitro physicochemical upper gastrointestinal system (IPUGS). The four most commonly consumed cuts - tenderloin, sirloin, brisket and flank, and bottom round - were chosen for this study. Beef samples (75 g) were cooked and ingested into IPUGS, which was composed of mouth, esophagus, and stomach, thereby simulating the digestion conditions of humans. Digested samples were collected every 15 min for 4 h of simulation and their pH monitored. Samples were visualized under a scanning electron microscope (SEM) to examine changes in the smoothness of the surface after digestion. Analysis of the amino acid composition and molecular weight (MW) of peptides was performed using reverse-phase high performance liquid chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis, respectively. Following proteolysis by the gastric pepsin, beef proteins were digested into peptides. The amount of peptides with higher MW decreased over the course of digestion. SEM results revealed that the surface of the digested samples became visibly smoother. Total indispensable and dispensable amino acids were the highest for the bottom round cut prior to digestion simulation. However, the total amount of indispensable amino acids were maximum for the tenderloin cut after digestion. These results may provide guidelines for the elderly population to choose easily digestible meat cuts and products to improve their nutritional and health status. PMID- 29147092 TI - Meat Quality Traits of Pigs Finished on Food Waste. AB - Despite the benefits associated with the use of food waste (FW), there are mixed consumer perceptions regarding pork quality harvested from pigs fed FW. Twenty crossbred pigs were selected for the present study. Ten pigs were fed a conventional diet (control group), and the other 10 pigs were given a conventional diet and FW (FW group) during different growth stages. Meat quality in the FW group showed deteriorative qualities with higher lightness and yellowness synonymous to pale soft exudative meat. Drip loss in the experimental group was significantly higher than that in the control group (p<0.01). The contents of polyunsaturated fatty acids in the FW group were higher and those of saturated and monounsaturated fatty acids were lower than those in the control group. The contents of thiobarbituric acid were significantly different between the control and FW groups (p<0.05). There was also a significant difference between the control and FW groups in terms of off-flavor (p<0.05) after sensory evaluation. To conclude, the off-flavor noted, including other inferior pork quality traits, in the FW group implies that FW should not be used as swine feed. PMID- 29147093 TI - Impacts of Irradiation Sources on Quality Attributes of Low-salt Sausage during Refrigerated Storage. AB - This study was performed to investigate the impacts of irradiation sources on quality attributes of low-salt sausage during refrigerated storage. Control sausage was prepared with 1.5% sodium chloride (NaCl), whereas low-salt sausage was formulated with 0.75% NaCl (a 50% reduction; L-control). Sausage samples were vacuum-packaged, and low-sausages were irradiated with gamma-ray, electron-beam and X-ray at 5 kGy, respectively. The samples were stored at 4 degrees C for 28 d to determine changes in quality attributes. The pH of low-salt sausages was unaffected by irradiation at 5 kGy (p>0.05). Higher redness values were found at irradiated low-salt sausages compared to control (p<0.05). The hardness, gumminess and chewiness of control sausage were higher than those of low-salt sausages (p<0.05). However, there were no significant differences in the textural parameters between low-salt sausage treatments. The overall sensory acceptability score of irradiated/low-salt sausages were lower than L-control due to decreased scores for cooked meat flavor but increased radiolytic off-flavor (p<0.05). The initial 2-thiobarbituric acid-reactive substances (TBARS) values of irradiated/low-salt sausages were higher than control and L-control (p<0.05). However, the TBARS values of irradiated treatments were significantly lower than control at the end of storage. Irradiation could effectively inhibit the microorganism growth (total aerobic bacteria, coliforms, Enterobacteriaceae, and Pseudomonas spp.) in low-salt sausages (p<0.05). Therefore, our findings show that irradiation could be to improve microbial safety of low-salt sausages, and suggest that further studies should be necessary to reducing radiolytic off flavor of irradiated/low-salt sausages. PMID- 29147094 TI - Physicochemical Properties of Gelatin Extracted from Buffalo Hide Pretreated with Different Acids. AB - The acid pretreatment of collagen molecules disrupts their crosslinks and assists in the release of acid-soluble proteins, fats, and other components. Generally, to achieve optimum extraction efficiency, strong acids may be used at a lower acid concentration compared to weak acids. This study aimed to determine the yield and physicochemical properties of gelatins extracted from buffalo hides pretreated with different acids. Hides were extracted with hydrochloric, citric, and acetic acids at concentrations of 0.3, 0.6, 0.9, 1.2, and 1.5 M. A completely randomized design and the least significant difference test were used in the experimental design, and all measurements were performed in triplicate. The highest yield (29.17%) was obtained from pretreatment with 0.9 M HCl. The gel strength did not differ significantly (p>0.05) according to acid type (280.26 259.62 g Bloom), and the highest viscosity was obtained from the 0.6 M citric acid pretreatment. All the gelatins contained alpha- and beta-chain components and several degraded peptides (24-66 kDa). The color and Fourier-transform infrared spectrum of the gelatin extracted using 0.9 M HCl were similar to those of commercial bovine skin gelatin. In general, the physicochemical properties of the gelatin complied with the industry standard set by the Gelatin Manufacturers Institute of America, revealing that buffalo hide could serve as a potential alternative source of gelatin. PMID- 29147095 TI - Histochemical Characteristics in Relation to Meat Quality Traits of Eight Major Muscles from Hanwoo Steers. AB - The objective of this study was to determine the relationship between composition of muscle fiber types and meat quality traits of eight major muscles from Hanwoo steers. Longissimus lumborum (LL), psoas major (PM), semimembranosus (SM), semitendinosus (ST), gluteus medius (GM), triceps brachii (TB), rectus abdominis (RA) and superficialis flexor (SF) muscles were obtained from 9 Hanwoo steers and subjected to histochemical analysis. There were significant (p<0.05) differences in fiber number percentage (FNP) and fiber area percentage (FAP) of fiber types among these 8 major muscles. SF had the highest FNP of type I (55.9%), followed by PM (46.4%), TB (45.4%), RA (38.5%), LD (36.8%), GM (36.0%), SM (22.2%), and ST (18.8%). FAP of type IIB ranged from 9.9% in SF to 58.7% in ST. Meat quality traits, including fat content, myoglobin content, collagen content, CIE L* and a*, drip and cooking loss, sarcomere length and Warner-Bratzler shear force, were all significantly (p<0.05) different among these muscles. Due to such diversities among these 8 muscles, lack of correlations were found between fiber type composition and meat quality traits. These results suggest that correlation for each individual muscle should be used to improve meat quality and profitability of retail beef cuts. PMID- 29147096 TI - Meat Quality and Storage Characteristics of Pork Loin Marinated in Grape Pomace. AB - This study investigated the meat quality and storage characteristics of pork loin marinated in grape pomace powder during different storage periods. The experimental design included six treatments : pork loin containing only 100% water (Control, C); pork loin containing a combination of 20% grape pomace and 80% water (T1); pork loin containing a combination of 40% grape pomace and 60% water (T2); pork loin containing a combination of 0.5% grape pomace powder and 95.5% water (T3); pork loin containing a combination of 1.0% grape pomace powder and 99.0% water (T4); and pork loin containing a combination of 2.0% grape pomace powder and 98.0% water (T5). The pork loins aged by grape pomace and grape pomace powder showed decreased crude protein, crude fat, crude ash, pH, redness, and yellowness values; however, their moisture, lightness, and shear force increased significantly. During cold storage, marination with grape pomace and grape pomace powder reduced the 2-thiobarbituric acid value, volatile basic nitrogen value, and total microbial count in pork loin. Thus, marination with grape pomace and grape pomace powder improved the meat quality and storage characteristics, and could be used to improve storage stability of pork loin. PMID- 29147097 TI - Characterization of Paenibacillus sp. MBT213 Isolated from Raw Milk and Its Ability to Convert Ginsenoside Rb1 into Ginsenoside Rd from Panax ginseng. AB - This study was conducted to isolate and characterize Paenibacillus sp. MBT213 possessing beta-glucosidase activity from raw milk, and examine the enzymatic capacity on the hydrolysis of a major ginsenoside (Rb1). Strain MBT213 was found to have a high hydrolytic ability on ginsenoside Rb1 by Esculin Iron Agar test. 16S rDNA analysis revealed that MBT213 was Paenibacillu sp. Crude enzyme of MBT213 strain exhibited high conversion capacity on ginsenoside Rb1 into ginsenoside Rd proven by TLC and HPLC analyses. The API ZYM kit confirmed that Paenibacillu sp. MBT213 exerted higher beta-glucosidase and beta-galactosidase activity than other strains. Optimum pH and temperature for crude enzyme were found at 7.0 and 35 degrees C in hydrolysis of ginsenoside Rb1. After 10 d of optimal reaction conditions for the crude enzyme, ginsenoside Rb1 fully converted to ginsenoside Rd. Ginseng roots (20%) were fermented for 14 d, and analyzed by HPLC showed that amount of ginsenoside Rb1 significantly decreased, while that of ginsenoside Rd was significantly increased. The study confirmed that the beta glucosidase produced by Paenibacillus sp. MBT213 can hydrolyze the major ginsenoside Rb1 and convert to Rd during fermentation of the ginseng. The beta glucosidase activity of this novel Paenibacillus sp. MBT213 strain may be utilized in development of variety of health foods, dairy foods and pharmaceutical products. PMID- 29147099 TI - Changes in Quality Characteristics of Pork Patties Containing Antioxidative Fish Skin Peptide or Fish Skin Peptide-loaded Nanoliposomes during Refrigerated Storage. AB - Marine fish skin peptides (FSP) have been widely studied due to their antioxidant and antimicrobial properties. We aimed to use a natural antioxidant, FSP, to replacing synthetic preservatives in a pork patty model, which is safer for human body. Moreover, nano-liposome technology can be applied for masking the fishy smell and improving the stability of this peptide. Therefore, in this study, the effects of FSP and FSP-loaded liposomes (FSPL) on pork patty were evaluated through the tests of thiobarbituric acid reactive substances (TBARS), color, cooking loss, texture, volatile basic nitrogen (VBN), and the pH value, during 14 d of refrigerated (4 degrees C) storage. The results showed that all FSP-treated patties had lower TBARS values than control patties, which indicated an inhibitory effect of FSP on lipid oxidation. This effect in the patties depended on the FSP concentration. However, FSPL-treated patties showed significantly higher and undesirable TBARS values compared to the control, and this effect depended on the FSPL concentration. None of the physicochemical results showed remarkable changes except the pH and VBN values. Therefore, this study provides evidence that FSP has great potential to inhibit the lipid oxidation of pork patties and is capable of maintaining the quality and extending the shelf life. However, it is necessary to study the application of FSP treatments greater than 3% to improve the antioxidant effect on pork patties and search for other coating materials and technology to reduce the drawbacks of FSP. PMID- 29147098 TI - Purification and Anti-pathogenic Properties of Immunoglobulin Concentrates from Porcine Blood. AB - During slaughtering, animal blood is typically discarded, resulting in water pollution. However, this discarded blood has valuable components, such as immunoglobulin (Ig). Although several studies have been conducted to develop methods for effective recycling of slaughterhouse blood, they have not been commercially utilized in Korea. Here, we extracted an Ig-rich fraction from porcine blood that was then subjected to various in vitro tests, including pathogen growth inhibition, antigenic cross-reactivity, and anti-toxin activity. The porcine immunoglobulin concentrate (PIC) was effectively purified by eliminating other components, such as albumin, and consisted of approximately 63.2+/-2.9% IgG and 7.2+/-0.4% IgM on a protein basis. The results showed that it significantly suppressed the growth of pathogenic bacteria, and bound to all tested pathogens, including both gram-positive and gram-negative species, although the degree of activity differed according to strain. The PIC bound to two types of lipopolysaccharide (LPS) obtained from Escherichia coli O111:B4 and Salmonella enterica serotype typhimurium in a concentration-dependent manner. In addition, the PIC restored the proliferation activity of the lymphoblast K-562 cells when co-incubated with pathogenic LPS. These results confirm that the PIC prepared in this study is a potentially valuable functional food material or diet supplement as an alternative to antibiotics that can protect animals from pathogenic bacteria. PMID- 29147100 TI - Purification and Identification of a Natural Antioxidant Protein from Fertilized Eggs. AB - Fertilized hen eggs are rich in a variety of bioactive ingredients. In this study, we aimed to obtain an antioxidant protein from fertilized eggs and the radical scavenging abilities on 1, 1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl radical (*OH), superoxide anion (O2-*) were used to evaluate the antioxidant activity of the purified protein. During 20 d of incubation, the radical scavenging ability of protein extracted from fertilized eggs exhibited significantly differences and the protein on day 16 showed higher antioxidant capacity. Based on this, the antioxidant protein of the samples on day 16 were isolated for the follow-up study. With a molecular weight 43.22 kDa, the antioxidant protein was purified by Diethylaminoethyl cellulose -52 (DEAE-52) column and Sephadex G-100. The LC-MS analysis showed that the purified protein molecular weight was 43.22 kDa, named D2-S. The sequence of amino acids was highly similar to ovalbumin and the coverage reached to 84%. The purified protein showed a radical scavenging rate of 52.34+/-3.27% on DPPH and 63.49+/-0.25% on *OH, respectively. Furthermore, the C-terminal amino acid sequence was NAVLFFGRCVSP, which was consistent with the sequence of ovabumin. These results here indicated that purified protein may be a potential resource as a natural antioxidant. PMID- 29147101 TI - Characteristics of Kwark Cheese Supplemented with Bifidobacterium longum KACC 91563. AB - The effect of addition of the probiotic Bifidobacterium longum KACC 91563 on the chemical and sensory properties of Kwark cheese produced using CHN-11 as a cheese starter were investigated. The addition of B. longum KACC 91563 to Kwark cheese did not change the composition or pH value of the cheese, compared with control. B. longum KACC 91563 survived at a level of 7.58 Log CFU/g and did not have any negative effect on survival of the cheese starter. A sensory panel commented that the addition of B. longum KACC 91563 made Kwark cheese more desirable to consumers, and that the probiotic supplementation had no effect on perceived taste. Thus, B. longum KACC 91563 can be used for inclusion of probiotic bacteria in cheese. PMID- 29147102 TI - The Relationships between Muscle Fiber Characteristics, Intramuscular Fat Content, and Fatty Acid Compositions in M. longissimus lumborum of Hanwoo Steers. AB - The objective of this study was to investigate the relationship between muscle fiber characteristics, intramuscular fat (IMF) content, and fatty acids composition in longissimus lumborum (LL) muscle from Hanwoo steers. The LL muscles were obtained from four quality grades (QG) carcasses and subjected to histochemical analysis. There were significant (p<0.05) differences in fiber number percentage (FNP) and fiber area percentage (FAP) of muscle fiber types among muscles from four QGs. Both FNP and FAP of type I increased while those of type IIB decreased with increasing QG from QG 2 to QG 1++ (p<0.05). Also, with increasing QG, the saturated fatty acid (SFA) proportion decreased while monounsaturated fatty acid (MUFA) increased significantly (p<0.05). IMF content was positively correlated with both FNP and FAP of type I, but negatively correlated with those of type IIB. The proportions of SFA and MUFA were significantly (p<0.001) correlated with both type I and IIB composition. These results implied that muscle fiber type composition is an important factor influencing fatty acid composition in LL muscle of Hanwoo steer. PMID- 29147103 TI - Antibacterial Effects against Various Foodborne Pathogens and Sensory Properties of Yogurt Supplemented with Panax ginseng Marc Extract. AB - Panax ginseng marc is produced from fresh ginseng roots during processing and is generally treated as industrial waste. The primary aim of this study was to improve its utilization in the dairy industry as a potential high-value resource. Yogurt was prepared from 11% skim milk powder, 0.1% pectin, 10% sucrose, and ginseng marc ethanol extract (GME, 0.5% and 1.0%) in milk, and was inoculated with a 0.02% yogurt culture (Lactobacillus acidophilus, Bifidobacterium longum, and Streptococcus thermophilus). After fermentation at 40 degrees C for 6-8 h, the physicochemical properties of samples were analyzed by the AOAC, Kjeldahl, and Soxhlet methods. Sensory evaluation was performed based on consumer acceptability scores with a 7-point scale, and antimicrobial effects were measured by the agar plate method. The moisture, crude protein, crude fat, and ash contents of yogurt supplemented with 1% GME were 85.06+/-0.06%, 4.41+/-0.01%, 4.30+/-0.05%, and 0.81+/-0.03%, respectively, with no significant changes noted from those of yogurt without GME (control), except for an increase in the crude fat content. The sensory scores of color, flavor, texture, overall taste, and overall acceptance of yogurt supplemented with below 1% GME did not differ significantly (p<0.05) to those of the control yogurt. In addition, the growths of Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Escherichia coli, and Enterobacter sakazakii were inhibited during fermentation and storage. These results suggest that GME could be used in dairy products as a supplement and in the food industry as an antimicrobial material. PMID- 29147106 TI - Editorial. PMID- 29147104 TI - Predictors of Intraocular Pressure After Phacoemulsification in Primary Open Angle Glaucoma Eyes with Wide Versus Narrower Angles (An American Ophthalmological Society Thesis). AB - Purpose: To assess if narrower-angle status and anterior segment optical coherence tomography (AS-OCT) parameters can predict intraocular pressure (IOP) drop in primary open-angle glaucoma (POAG) patients after cataract surgery. Methods: This was a prospective case series of consecutive cataract surgery patients with POAG and no peripheral anterior synechiae (PAS) using a standardized postoperative management protocol. Preoperatively, patients underwent gonioscopy and AS-OCT. The same glaucoma medication regimen was resumed by 1 month. Potential predictors of IOP reduction included narrower-angle status by gonioscopy and angle-opening distance (AOD500) as well as other AS-OCT parameters. Mixed-effects regression adjusted for use of both eyes and other potential confounders. Results: We enrolled 66 eyes of 40 glaucoma patients. The IOP reduction at 1 year was 4.2+/-3 mm Hg (26%, P<.001) in the narrower-angle group vs 2.2+/-3 mm Hg (14%, P<.001) in the wide-angle group (P=.027 for difference), as classified by gonioscopy. By AOD500 classification, the narrower angle group had 3.4+/-3 mm Hg (21%, P<.001) reduction vs 2.5+/-3 mm Hg (16%, P<.001) in the wide-angle group (P=.031 for difference). When the entire cohort was assessed, iris thickness, iris area, and lens vault were correlated with increasing IOP reduction at 1 year (P<.05 for all). Conclusions: In POAG eyes, cataract surgery lowered IOP to a greater degree in the narrower-angle group than in the wide-angle group, and parameters relating to iris thickness and area, as well as lens vault, were correlated with IOP reduction. These findings can guide ophthalmologists in their selection of cataract surgery as a potential management option. PMID- 29147105 TI - Depletion of Stercobilin in Fecal Matter from a Mouse Model of Autism Spectrum Disorders. AB - Introduction: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders lacking a clinical biomarker for diagnosis. Emerging evidence shows that intestinal microflora from ASD subjects can be distinguished from controls, suggesting metabolite differences due to the action of intestinal microbes may provide a means for identifying potential biomarkers for ASD. Objectives: The aim of this study was to determine if quantitative differences in levels of stercobilin and stercobilinogen, metabolites produced by biological action of intestinal microflora, exist in the fecal matter between an ASD mouse model population and controls. Methods: Pairs of fecal samples were collected from two mouse groups, an ASD model group with Timothy syndrome 2 (TS2-NEO) and a gender matched control group. After centrifugation, supernatant was spiked with an 18O labeled stercobilin isotopomer and subjected to solid phase extraction for processing. Extracted samples were spotted on a stainless steel plate and subjected to matrix-assisted laser desorption and ionization mass spectrometry using dihydroxybenzoic acid as the matrix (n = 5). Peak areas for bilins and 18O stercobilin isotopomers were determined in each fecal sample. Results: A 40-45% depletion in stercobilin in TS2-NEO fecal samples compared with controls was observed with p < 0.05; a less dramatic depletion was observed for stercobilinogen. Conclusions: The results show that stercobilin depletion in feces is observed for an ASD mouse model vs. controls. This may help to explain recent observations of a less diverse microbiome in humans with ASD and may prove helpful in developing a clinical ASD biomarker. PMID- 29147107 TI - Debated agronomy: public discourse and the future of biotechnology policy in Ghana. AB - This paper examines the highly contested and ongoing biotechnology (Bt) policy making process in Ghana. We analyse media content on how Bt is viewed in the context of Ghana's parliamentary debate on the Plant Breeders Bill and within the broader public policy-making literature. This paper does not seek to take a position on Bt or the Bill, but to understand how policy actors influence the debate with political and scientific rhetoric in Ghana. The study reveals that in the midst of scientific uncertainties of Bt's potential for sustainable agriculture production and food security, policy decisions that encourage its future adoption are heavily influenced by health, scientific, economic, environmental and political factors dictated by different ideologies, values and norms. While locally pioneered plant breeding is visible and common in the Ghanaian food chain, plant breeding/GMOs/Bt from international corporations is strongly resisted by anti-GMO coalitions. Understanding the complex and messy nature of Bt policy-making is critical for future development of agricultural technology in Ghana and elsewhere. PMID- 29147108 TI - MUC1 Aptamer Targeted SERS Nanoprobes. AB - Recently, surface-enhanced Raman scattering (SERS) nanoprobes (NPs) have shown promise in the field of cancer imaging due to their unparalleled signal specificity and high sensitivity. Here we report the development of a DNA aptamer targeted SERS NP. Recently, aptamers are being investigated as a viable alternative to more traditional antibody targeting due to their low immunogenicity and low cost of production. We developed a strategy to functionalize SERS NPs with DNA aptamers, which target Mucin1 (MUC1) in human breast cancer (BC). Thorough in vitro characterization studies demonstrated excellent serum stability and specific binding of the targeted NPs to MUC1. In order to test their in vivo targeting capability, we co-injected MUC1-targeted SERS NPs, and as controls non-targeted and blocked MUC1-targeted SERS NPs in BC xenograft mouse models. A two-tumor mouse model with differential expression of MUC1 (MDA-MB-468 and MDA-MB-453) was used to control for active versus passive targeting in the same animals. The results showed that the targeted SERS NPs home to the tumors via active targeting of MUC1, with low levels of passive targeting. We expect this strategy to be an advantageous alternative to antibody-based targeting and useful for targeted imaging of tumor extent, progression, and therapeutic response. PMID- 29147110 TI - Colorectal Malignancy in a Prospective Irish Inflammatory Bowel Disease Population 15 Years Since Diagnosis: Comparison with the EC-IBD Cohort. AB - Background and Aim: As part of the EC-IBD prospective inception cohort study, we had unique opportunity to follow up our patients since diagnosis in the early 1990s. Patients and Methods: All patients from the greater Dublin area (n = 192) were followed up from inception between 1991 and 1993 until the 30 September 2009. Patients who developed malignancies were logged electronically with verification of the site and histology. Results: Of the initial 192 patients, 133 were included in the 15-year follow-up. Of those, 80 (60.2%) had UC and 53 (39.8%) had CD. There were 82 (61.7%) males and 51 (38.3%) females. Six patients had extraintestinal malignancy; however, there was no CRC related to IBD noted in our cohort. Four of the 6 identified cases had UC (64%) with a mean age of 54.25 years at the time of cancer diagnosis, whereas the two CD patients had a mean age of 51.5 years at the time of cancer diagnosis. Conclusion: CRC was not observed in our cohort. The six extraintestinal malignancies did not show significant relation to IBD. The high total colectomy rate (in the prebiological therapy era) may have contributed to low malignancy rate. PMID- 29147111 TI - Hereditary Colorectal Tumors: A Literature Review on MUTYH-Associated Polyposis. AB - MAP (MUTYH-associated polyposis) is a syndrome, described in 2002, which is associated with colorectal adenomas, with enhanced colorectal carcinogenesis. This review synthesizes the available literature on MAP and outlines its pathogenesis, association with colorectal tumorigenesis, screening, treatment, and the subtle differences between it and its close cousins-FAP and AFAP. The preponderance of data is collected using MAP guidelines. However, although AFAP and MAP appear similar, potentially important distinctions exist, warranting targeted diagnostic criteria and treatment approaches. We suggest that it may be prudent to screen for MAP earlier than in current clinical practice, as it has been shown that sequence variants are associated with more severe disease, presenting with an earlier onset of colorectal cancer. Finally, we issue a call to-action for much-needed further data to establish clear clinical and diagnostic criteria. PMID- 29147109 TI - Colorectal Cancer Blood-Based Biomarkers. AB - Mortality and morbidity associated with colorectal cancer (CRC) are increasing globally, partly due to lack of early detection of the disease. The screening is usually performed with colonoscopy, which is invasive and unpleasant, discouraging participation in the screening. As a source of noninvasive and easily accessible biomarkers, liquid biopsies are emerging. Blood-based biomarkers have the potential as diagnostic and prognostic tool in CRC. Early stage detection of CRC with high sensitivity and specificity would likely lead to higher participation in the screening test. It would also improve the prognosis of the disease and improve the recurrence risk. In this review, we summarize the potential biomarkers for early detection and monitoring of CRC. PMID- 29147112 TI - Do Changes in Welfare and Health Policy Affect Life Satisfaction of Older Citizens in Europe? AB - Objectives: Ageing of societies causes serious political concerns on well-being of old citizens and care for the (frail) old. These concerns increased with the economic crisis of 2008. In European countries policy measures were taken to deal with the consequences of this crisis. This study explores the possible effects of these measures on life satisfaction of older citizens. Methods: Life satisfaction was assessed through international surveys in 2007 and 2013 and changes in societal conditions, using eight indicators on demography, welfare, and health, are assessed in 31 European countries in 2006 and in 2014. Data are standardised and based on official, national surveys and statistics. Results: The former found that U-shape relationship between age and life satisfaction disappeared after the crisis. Negative changes in social protection and care arrangements, taken after the economic crisis, are related to low life satisfaction in old citizens. Conclusions: Various societal conditions deteriorated in 2014 as compared to 2006. Policy measures, taken due to the 2008 economic crisis, have changed societal conditions and affected life satisfaction of older citizens negatively. In countries with a rudimentary structure of health and welfare provisions old citizens could not cope with the imposed policy measures. PMID- 29147113 TI - Clinical Presentation, Management, and Outcomes of Primary Hyperparathyroidism during Pregnancy. AB - Background: Primary hyperparathyroidism (pHPT) in pregnancy is a rare event, but it poses a significant risk to mothers and fetuses. The optimal treatment strategy remains controversial. Methods: We present a consecutive series of twelve pregnant women with pHPT. Results: Twelve women were diagnosed with pHPT during pregnancy or in the postpartum period. Four of them presented no symptoms or mild symptoms. Four patients experienced serious complications, including hypercalcaemic crisis, acute pancreatitis, and eclampsia. Another four patients were identified postpartum as the result of neonatal convulsion with hypocalcaemia. Minimally invasive parathyroidectomy (MIP) under cervical plexus block was successfully performed in 11 of them during pregnancy or postpartum. The serum levels of ionized calcium and intact parathyroid hormone (iPTH) were much higher in patients with severe complications in this cohort than those in the group of patients with no symptoms or mild symptoms and patients who were diagnosed postpartum. Conclusions: MIP under cervical plexus block might be a safe and effective treatment for pregnant women with pHPT. Even though both conservative and surgical treatments are applicable for most mothers and fetuses with asymptomatic and mild hyperparathyroidism, serious complications may have catastrophic consequences for both. PMID- 29147114 TI - Antibiotic Resistant Bacterial Isolates from Captive Green Turtles and In Vitro Sensitivity to Bacteriophages. AB - This study aimed to test multidrug resistant isolates from hospitalised green turtles (Chelonia mydas) and their environment in North Queensland, Australia, for in vitro susceptibility to bacteriophages. Seventy-one Gram-negative bacteria were isolated from green turtle eye swabs and water samples. Broth microdilution tests were used to determine antibiotic susceptibility. All isolates were resistant to at least two antibiotics, with 24% being resistant to seven of the eight antibiotics. Highest resistance rates were detected to enrofloxacin (77%) and ampicillin (69.2%). More than 50% resistance was also found to amoxicillin/clavulanic acid (62.5%), ceftiofur (53.8%), and erythromycin (53.3%). All the enriched phage filtrate mixtures resulted in the lysis of one or more of the multidrug resistant bacteria, including Vibrio harveyi and V. parahaemolyticus. These results indicate that antibiotic resistance is common in Gram-negative bacteria isolated from hospitalised sea turtles and their marine environment in North Queensland, supporting global concern over the rapid evolution of multidrug resistant genes in the environment. Using virulent bacteriophages as antibiotic alternatives would not only be beneficial to turtle health but also prevent further addition of multidrug resistant genes to coastal waters. PMID- 29147115 TI - Effects of Aminoglycoside Antibiotics on Human Embryonic Stem Cell Viability during Differentiation In Vitro. AB - Human embryonic stem cells (hESCs) are being used extensively in array of studies to understand different mechanisms such as early human embryogenesis, drug toxicity testing, disease modeling, and cell replacement therapy. The protocols for the directed differentiation of hESCs towards specific cell types often require long-term cell cultures. To avoid bacterial contamination, these protocols include addition of antibiotics such as pen-strep and gentamicin. Although aminoglycosides, streptomycin, and gentamicin have been shown to cause cytotoxicity in various animal models, the effect of these antibiotics on hESCs is not clear. In this study, we found that antibiotics, pen-strep, and gentamicin did not affect hESC cell viability or expression of pluripotency markers. However, during directed differentiation towards neural and hepatic fate, significant cell death was noted through the activation of caspase cascade. Also, the expression of neural progenitor markers Pax6, Emx2, Otx2, and Pou3f2 was significantly reduced suggesting that gentamicin may adversely affect early embryonic neurogenesis whereas no effect was seen on the expression of endoderm or hepatic markers during differentiation. Our results suggest that the use of antibiotics in cell culture media for the maintenance and differentiation of hESCs needs thorough investigation before use to avoid erroneous results. PMID- 29147116 TI - Influence of Water, Sanitation, and Hygiene Practices on Common Infections among Under-Five Children in Longido and Monduli Districts of Arusha, Tanzania. AB - The study aimed at assessing water, sanitation, and hygiene practices and their influence on infectious diseases among under-five children in semipastoral communities of Arusha. The study was cross-sectional in design. Prevalence of infectious diseases among under-five children was derived from patients' attendance register. Mothers randomly sampled from households were interviewed using questionnaire. Information regarding child morbidity and sociodemographic and WASH characteristics was gathered. Hospital data revealed that 2/3 of under five patients visited the hospitals annually were suffering from infectious diseases. Mean percentage of diarrhea prevalence for years 2013-2015 in Longido was higher than the mean of the respective years prevalence in Monduli (p = 0.02). Households' survey showed that 15.5% of under-five children were suffering from diarrhea. Children who consumed foods kept in kibuyu (p < 0.001) or used unboiled cows' milk (p = 0.01) or were drinking surface water (p = 0.04) or born to uneducated mothers (p = 0.01) had increased risk of developing diarrhea compared to their counterparts. Storing complementary foods in kibuyu was strongly associated with diarrhea among under-five children. To address the problem, communities under study need to be motivated through health education on food hygiene, proper handling of food storage containers, and domestic water treatment at the household level. PMID- 29147117 TI - Colistin Resistance of Pseudomonas aeruginosa Isolated from Snakes in Taiwan. AB - This study included fifty-eight isolates of P. aeruginosa from the oral cavity of snakes that were recruited from clinical cases, captive and wild snakes. The minimum inhibitory concentrations (MICs) for the determination of susceptibility were identified by the broth microdilution method. Polymerase chain reaction (PCR) was employed to detect beta-lactamases genes. With regard to antipseudomonal antibiotics, the lowest nonsusceptible rates were in aztreonam (15%), piperacillin/tazobactam (12%), and amikacin (9%). The nonsusceptible rates were high in gentamicin (33%) and colistin (55%). Meanwhile, blaTEM presented in 100% of isolates where blaAmpC, blaOXA-1, and blaOXA-10 came at 94.8%, 89.7%, and 27.6%, respectively. Emergence of multidrug resistant (MDR) strains and colistin resistant strains highlights the potential breach of public health as P. aeruginosa could be transmitted through either direct contact or indirect dissemination through the environment. This study reports that the highly resistant P. aeruginosa from snakes' oral cavity were discovered for the very first time in Taiwan. PMID- 29147118 TI - The effects of public education through Short Message Service on the time from symptom onset to hospital arrival in patients with myocardial infarction: A field trial. AB - BACKGROUND: Patients' early hospital arrival is among the most important factors in minimizing the complications of myocardial infarction (MI). One of the measures which can reduce prehospital delay in these patients is public education. The aim of the present study was to investigate the effects of public education through Short Message Service (SMS) on the time from symptom onset to hospital arrival (or onset-to-door time) in patients with MI in Kashan, Iran. METHODS: This field trial was done on 131 patients with definite diagnosis of myocardial infarction. Intervention included sending an educational short message about the symptoms of MI and the necessity of referring to hospital immediately. Logistic regression analysis was performed to evaluate the predictors of the onset-to-door time. RESULTS: The results showed no significant difference in demographic characteristics, clinical variables and past medical history between the participants in the two groups. The onset-to-door time was significantly shorter in the intervention group than the control group (240.53 +/- 156.60 vs. 291.70 +/- 251.23, P= 0.003). Moreover, the onset-to-call time was significantly shorter in the intervention group than the control group (127.06 +/- 202.62 vs. 44.32 +/- 81.26, P = 0.002). The odds of arrival at hospital in the first 120 minutes after the onset of MI manifestations was 5.8 (2.04-16.8) times higher in the group that received the educational SMS. CONCLUSION: As both the onset-to door and onset-to-call times were shorter in the intervention group, it is suggested to use this method to raise the public awareness of MI symptoms and the need for early referral. PMID- 29147119 TI - Psychosocial factors predicting length of hospitalization in elderly individuals with diabetes in selected hospitals of Isfahan University of Medical Sciences, Isfahan, Iran, in 2015. AB - BACKGROUND: Currently, researchers seek to identify factors related to length of hospital stay in elderly in order to reduce burden on the health system. The importance of either physiological or psychological factors in determining health outcomes has been well stablished; however, the possible contribution of psychosocial factors particularly in elderly patients with diabetes is also of special importance. This study aimed to know what psychosocial variables predicts length of hospital stay in elderly patients with diabetes. METHODS: This was a cross-sectional, correlational study conducted on 150 elderly patients from July October 2015. Convenient sampling method was used to recruit the subjects. The data was collected by a three-part questionnaire consisted of demographic and health related characteristics, 21-item depression anxiety stress scale (DASS-21) and multidimensional scale of perceived social support (MSPSS). RESULTS: The mean +/- standard deviation of length of hospital stay was 15.6 +/- 7.7 days. Findings from multiple regression analysis showed that the models of predicting length of hospital stay in subgroups of both women (P = 0.001, F6,77 = 4.45) and men (P = 0.030, F6,71 = 2.43) were significant. The entered variables in subgroups of women and men accounted for 27% and 18% of total variance (R2) of the length of hospital stay, respectively. None of the psychosocial variables in women significantly predicted the lengths of hospital stay. However, one out of three predicting psychosocial variables (i.e. stress) in men significantly predicted the length of hospital stay (beta = 0.39, t = 2.1, P = 0.040). CONCLUSION: The results emphasized the importance of promoting social support of elderly patients with diabetes, particularly in patients who are women, have higher levels of stress, have higher period of disease and a history of hospitalization in the past 6 months in order to lower length of hospital stay and finally promote health status in elderly patients with diabetes. Further studies regarding the effect of each of these factors on health condition of elderly with diabetes are recommended. PMID- 29147120 TI - A comparative study of the effect of green tea and sour tea on blood pressure and lipid profile in healthy adult men. AB - BACKGROUND: Cardiovascular diseases (CVD) are a set of metabolic disorders affecting heart and blood vessels. Green tea and sour tea (Hibiscus sabdariffa L.) have attracted significant attention recently due to their high popularity, nutrient profile and therapeutic effects. The aim of the present study was to compare the effects of green tea and sour tea supplementation on blood pressure and lipid profile in healthy adult men. METHODS: This randomized, double-blind, placebo-controlled trial included 54 healthy adult men. The participants were randomly assigned to two intervention groups receiving 450 mg green tea or sour tea and one placebo group which consumed 450 mg placebo (maltodextrin) for 6 weeks. Blood pressure, lipid profile, dietary intake and physical activity were measured pre- and post-intervention and compared. RESULTS: After 6 weeks of intervention, sour tea supplementation led to a significant decrease in systolic blood pressure (SBP) compared with the placebo group. However, we faild to find any significant difference in SBP between green tea and control groups. Also, no significant changes were observed in diastolic blood pressure (DBP) and lipid profile between the three groups. In comparison with baseline, there was a significant increase in the mean level of serum high-density lipoprotein cholesterol (HDL-C) in green tea and sour tea groups. Also, the interventions resulted in significant decrease in the mean levels of serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and DBP in the sour tea group compared with the pre-intervention value. CONCLUSION: On the basis of our findings, sour tea supplementation led to decreased SBP in healthy men compared with the placebo, but there was no significant difference between their effects on DBP and lipid profile. PMID- 29147121 TI - Ambient air pollution and daily hospital admissions for cardiovascular diseases in Arak, Iran. AB - BACKGROUND: Outdoor air pollution has been considered as one of the most serious health concerns over the last decade. This study aimed to investigate the association between ambient air pollution and cardiovascular hospital admissions. METHODS: This investigation was carried out from January 1, 2010 to December 31, 2015, in the urban population of Arak, Iran. Daily records of concentrations of air pollutants including particulate matter less than 10 um (PM10), nitrogen dioxide (NO2), particulate matter less than 2.5 um (PM2.5), ozone (O3), carbon monoxide (CO), and sulfur dioxide (SO2) as well as the daily number of hospital admissions due to cardiovascular disease were inquired from the Arak Department of Environment and two major hospitals, respectively. Time-series regression analysis was used to evaluate the effect of the pollutants on cardiovascular hospital admissions with different lag structures, controlling for weather variables, seasonality and long-term time trends, and day of the week. RESULTS: Each 10 ug/m3 increase in PM10 and NO2 and 1 mg/m3 increase in CO concentrations at lag 0 (day) were significantly associated with an increase of 0.7% (P = 0.004), 3.3% (P = 0.006), and 9.4% (P < 0.001), respectively in overall cardiovascular hospital admissions. The elderly were more susceptible than those under 60 years to exposure to the pollutants (especially NO2) with regard to cardiovascular hospital admission. CONCLUSION: The results of this study showed that hospital admission for cardiovascular disease is partly related to the levels of ambient air pollutions in Arak. Susceptibility to air pollutants varies by age groups and sex. PMID- 29147123 TI - Acute necrotizing pancreatitis following coronary artery angiography: A case report. AB - BACKGROUND: Acute pancreatitis has different etiologies from biliary stone to metabolic disturbances. Coronary angiography is one of the newly understood etiologies. CASE REPORT: This paper is about a women suffering from acute pancreatitis after coronary angiography. CONCLUSION: Embolization of cholesterol crystals due to vessel wall trauma during coronary angiography as well as contrast medium are responsible for such side effect. PMID- 29147124 TI - The importance of electrocardiography parameters in healthy Iranian children. PMID- 29147122 TI - Use of lipid-lowering medicinal herbs during pregnancy: A systematic review on safety and dosage. AB - BACKGROUND: Hyperlipidemia is one of the important diseases in pregnancy that causes fetal abnormalities during pregnancy and after the birth. Unfortunately, the usual anti-fat drugs are associated with high morbidity in fetus and due to people's inclination towards taking herbs, it is required to identify side effects of medicinal herbs in pregnancy. The aim of this study was to present hypolipidemic herbs that would not any complications for mother and fetus. METHODS: In this review article, the major electronic databases such as EBSCO, Central Register of Controlled Trials (CENTRAL), China Network Knowledge Infrastructure (CNKI), Cochrane, Google scholar, MEDLINE, SciVerse, Scopus, and Web of Science were searched using the key words "herbal" and "hyperlipidemia", "herbal" and "pregnancy" matched by MeSH from their respective inceptions till September, 2016. Total of 1723 publications (145 review articles, 855 original research articles, and 723 abstracts) about the effect of herbals on hyperlipidemia and 682 publications (200 abstracts, 423 original research articles, and 59 review articles) about the effect of herbals in pregnancy were retrieved. At the end, a list of medicinal plants effective on hyperlipidemia alongside their effects on pregnancy was developed. Finally, the plants effective on hyperlipidemia and safe during pregnancy were determined and their dosage, complications, mechanism of action, and side effects were reported. RESULTS: A total of 110 effective herbs on hyperlipidemia were identified and complications of 95 plants in pregnancy were studied. At last, among the 55 selected plants effective on hyperlipidemia and examined for pregnancy, we reported 12 herbs with their dosage and special considerations that can be used to treat hyperlipidemia during pregnancy. CONCLUSION: Some medicinal plants can be used to treat hyperlipidemia during pregnancy without any significant side effects both on mother or fetus. PMID- 29147125 TI - Comparison of the prevalence of enteroviruses in blood samples of patients with and without unstable angina. AB - BACKGROUND: Although the role of enteroviruses has been proved in heart diseases, extensive information is not available on the association between enteroviruses and unstable angina. In the present study, the authors compared the prevalence of enteroviruses in patients with and without unstable angina. METHODS: Blood samples were taken from 51 patients with unstable angina and 55 patients without unstable angina or myocardial infarction that were admitted to Imam Reza and Ghaem hospitals (Mashhad, northeast of Iran). Reverse transcription polymerase chain reaction (RT-PCR) was performed using specific primers for the detection of the enteroviruses in blood samples of study subjects. RESULTS: Patients with and without unstable angina were similar in age with mean +/- standard deviation of 62.6 +/- 12.8 and 59.7 +/- 12.7 years, respectively (P = 0.243) and there were no differences in gender in these two groups (P = 0.174). Prevalence of the enteroviruses in patients with unstable angina was higher only in 66-80 years age group compared to the control group (patients without unstable angina, P = 0.032). There was a higher prevalence of enterovirus RNA positivity in the blood samples of women with unstable angina (75.9%) than those without unstable angina (41.7%, P = 0.011), however, no significant difference was observed in men (P = 0.983). CONCLUSION: Our data showed that enteroviral RNA positivity was higher in patients with unstable angina compared to those without unstable angina. However, the differences between the two groups were not statistically significant. PMID- 29147126 TI - Using rats as a research model to investigate the effect of human adenovirus 36 on weight gain. AB - BACKGROUND: Recent evidence has shown a positive correlation between obesity and viral infections with a particular emphasis on the human adenovirus-36 (Ad-36). Ad-36 is the first human virus that may increase adiposity in animals, and it is considered as a possible risk factor for obesity in humans; however, the results were not consistent across all the studies. The present study was conducted to examine the influence of Ad-36 infection on obesity in a rat model. METHODS: Eight-week-old male Wistar rats weighing 170-240 gram (g), were randomly divided into two groups, infection group (48 rats) and a control group (12 rats). The rats in the infection group were infected with human Ad-36. All rats were given free access to a normal chow diet and water. They were weighed weekly. RESULTS: The mean +/- standard deviation (SD) body weights were 229.0 +/- 25.9 g and 232.3 +/- 16.6 g in the infection and control groups, respectively at the time of infection. The mean +/- SD body weight of the infection group (304.0 +/- 39.0 g) was higher than the control group (301.0 +/- 36.5 g) at 12 weeks post-infection (P = 0.82). Although two groups had approximately same food intakes, the mean change in body weight was greater in the infection group than the control group (75.8 +/- 27.9 g vs. 70.8 +/- 24.5 g) but it was not significant (P = 0.57). CONCLUSION: We did not find a statistically significant association between weight gain and Ad-36 infection in the rat model. It seems that longer follow-up duration is needed to develop a significant weight gain in the infected rats. Rats can be used as a good animal model for further investigations about Ad-36 induced obesity, provided not to rely merely on weight measurements. Evaluating body composition or histopathological assessments are suggested. PMID- 29147127 TI - Association between ABO blood group and severity of coronary artery disease in unstable angina. AB - BACKGROUND: ABO blood groups are genetically transmitted through chromosome 9 at locus 9q34. It is supposed that there is a locus on 9p21, which has a role in developing coronary artery disease. METHODS: Our study population consisted of 309 patients with unstable angina admitted to the Ziaeian Hospital, Tehran, Iran, who underwent coronary angiography. The association between types of blood group (O and non-O) with the severity of coronary artery disease was investigated. RESULTS: Compared to the non-O groups, the O group had more severe coronary artery involvement (P = 0.004). CONCLUSION: Our study supports recent suggestions on the association between blood group and coronary artery disease. Further studies are needed to evaluate the effect of blood group on atherosclerosis. PMID- 29147128 TI - The effect of educational intervention on weight loss in adolescents with overweight and obesity: Application of the theory of planned behavior. AB - BACKGROUND: The increased prevalence of overweight and obesity in children and adolescents is associated with type 2 diabetes, hypertension, dyslipidemia, and cardiovascular diseases. The theory of planned behavior (TPB) efficiently explains the ability of perceived behavioral control and possibly attitude to enhance the motivations of the obese people to lose weight. Our aim was to investigate the effect of TPB-based education on weight loss in obese and overweight adolescents. METHODS: In an interventional study, simple random sampling was used to select 86 overweight and obese adolescents aged 13-18 years in the pediatric clinic at the Isfahan Cardiovascular Research Institute. Anthropometric measures and TPB constructs were collected using a researcher-made questionnaire. The questionnaires were filled out before and six weeks after the intervention. Participants received 5 sessions of training based on the constructs of the TPB. RESULTS: A significant increase was observed in the mean score for knowledge and TPB constructs (attitudes, subjective norms, perceived behavioral control, intention, and behavior) six weeks after the educational intervention (P < 0.001). Moreover, significant decrease in body mass index (P < 0.001), weight (P = 0.001), and waist circumference (P < 0.001) of adolescents were found after the educational intervention. CONCLUSION: The TPB-based interventions seem to be effective in losing weight in obese and overweight adolescents. This theory serves as a helpful theoretical framework for health related behaviors and can be an appropriate pattern to plan for educational interventions. PMID- 29147129 TI - The effect of exercise training on upregulation of molecular markers of bile acid metabolism in the liver of ovariectomized rats fed a cholesterol-rich diet. AB - BACKGROUND: Small heterodimer partner (SHP) is an important transcriptional factor involved in the regulation of glucose, lipid, and bile acid metabolism in the liver. SHP has been reported to be down-regulated in ovariectomized (Ovx) mice and up-regulated by estrogens suggesting a link between estrogens and SHP. The aim of the present study was to determine the effects of exercise training on SHP and key molecular markers of cholesterol and bile acid homeostasis in Ovx rats under cholesterol feeding. METHODS: Our main experimental group was composed of Ovx rats fed a high-cholesterol diet (Ovx-Chol) that was compared to a group of Ovx rats fed a standard diet (Ovx-SD) and a group of sham operated rats fed the cholesterol diet (Sham-Chol). These three groups of Ovx and sham rats were subdivided into either voluntary wheel running (Tr) or sedentary (Sed) groups for 5 weeks. The mRNA expression of all genes was measured by quantitative real-time polymerase chain reaction. RESULTS: Liver total cholesterol levels were not affected by exercise training in any of the experimental conditions. Cholesterol feeding in both sham and Ovx rats resulted in significantly higher hepatic cholesterol accumulation than in Ovx-SD (P < 0.001). Hepatic low density lipoprotein receptor (LDL-R) involved in cholesterol uptake from circulation was not influenced by training. A main effect of training was, however, found for transcripts of SHP and cholesterol 7 alpha-hydroxylase (CYP7A1, P < 0.050). CYP7A1 is the main gene involved in bile acid biosynthesis from cholesterol. CONCLUSION: These results suggest that voluntary wheel running modulates cholesterol metabolism in Ovx animals through up-regulation of SHP and bile acid formation. PMID- 29147130 TI - Mobile mass in the aortic arch: A case report. AB - BACKGROUND: The finding of a floating mass in the aortic arch is rare and the management remains controversial. CASE REPORT: We describe a 42-year-old woman with an embolic infarction in whom transesophageal echocardiography revealed a mobile mass in the aortic arch that was characterized as atherothrombi with an evidence of embolic infarction in the territory of the middle cerebral artery. Treatment with antiplatelet and anticoagulants failed to resolve the mass and is surgically resected. CONCLUSION: In conclusion, the presence of mobile aortic mass seems to carry a high embolic risk. The optimal treatment for mobile aortic arch atherothrombi remains to be elucidated. PMID- 29147131 TI - Transcriptional activity of tumor necrosis factor-alpha gene in peripheral blood mononuclear cells in patients with coronary slow flow. AB - BACKGROUND: Coronary slow flow (CSF), an angiographic phenomenon that is characterized by a delayed coronary blood flow in the absence of obstructive coronary artery stenosis, is known as a disorder of the coronary microcirculation. Inflammation has an important role in the vascular hemostasis and endothelial dysfunction especially regarding monocyte adhesion and infiltration. Pro-inflammatory cytokines released by inflammatory cells result in endothelial cell dysfunction and cardiovascular diseases. It has been demonstrated that tumor necrosis factor-alpha (TNF-alpha) mainly influences the vascular homeostasis and endothelial dysfunction. In the present enquiry the transcriptional activity of TNF-alpha gene in peripheral blood mononuclear cells (PBMCs) of patients with CSF was compared with healthy controls in order to further survey the role of TNF-alpha in pathophysiology of CSF. METHODS: The study was carried out on 30 patients with CSF and 30 matched healthy controls. To analysis gene expression of TNF-alpha, total mRNA was isolated from PBMCs. The quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was used to compare the transcriptional activity of TNF-alpha gene between patients with CSF and controls. RESULTS: The mean +/- standard error of mean of fold in CSF patients and controls were 0.20 +/- 0.04 and 1.38 +/- 0.27, respectively. The mRNA mean expressions of TNF-alpha (fold) were different in tested groups, which indicated a significant decrease in TNF-alpha in patients with CSF group (P = 0.0001). CONCLUSION: Expression of TNF-alpha was decreased in patients with CSF. Changes in TNF-alpha expression suggest a potential role for altered immune function in the pathophysiology of CSF. PMID- 29147132 TI - Numerical Investigation of Pulse Wave Propagation in Arteries Using Fluid Structure Interaction Capabilities. AB - The aim of this study is to present a reliable computational scheme to serve in pulse wave velocity (PWV) assessment in large arteries. Clinicians considered it as an indication of human blood vessels' stiffness. The simulation of PWV was conducted using a 3D elastic tube representing an artery. The constitutive material model specific for vascular applications was applied to the tube material. The fluid was defined with an equation of state representing the blood material. The onset of a velocity pulse was applied at the tube inlet to produce wave propagation. The Coupled Eulerian-Lagrangian (CEL) modeling technique with fluid structure interaction (FSI) was implemented. The scaling of sound speed and its effect on results and computing time is discussed and concluded that a value of 60 m/s was suitable for simulating vascular biomechanical problems. Two methods were used: foot-to-foot measurement of velocity waveforms and slope of the regression line of the wall radial deflection wave peaks throughout a contour plot. Both methods showed coincident results. Results were approximately 6% less than those calculated from the Moens-Korteweg equation. The proposed method was able to describe the increase in the stiffness of the walls of large human arteries via the PWV estimates. PMID- 29147133 TI - Allopurinol in combination with thiopurine induces mucosal healing and improves clinical and metabolic outcomes in IBD. AB - Background: Thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP) are common maintenance medications for inflammatory bowel disease (IBD). Excessive methylation via thiopurine methyltransferase (TPMT) frequently causes therapeutic failure. Allopurinol reduces excessive 6-methyl-mercaptopurine (6-MMP) while enhancing 6-thioguanine (6-TGN) levels. The aim of this study was to evaluate clinical, metabolic and endoscopic impact of allopurinol in combination with low dose thiopurine in IBD. Methods: Retrospective review of consecutive cases treated with allopurinol. Metabolites and their ratios (6-MMP/6-TGN) were compared pre- and post-allopurinol. Clinical and endoscopic remission were assessed. Results: Allopurinol (n = 66) reduced mean dose of AZA by 70% (p < 0.01). Baseline levels (SD) 6-TGN, 6-MMP and 6-MMP/6-TGN were 165 (64), 9388 (5234) and 59.8 (30.3), respectively. These values improved on allopurinol to 297 (102), 896 (1031) and 3.4 (4.0), respectively (p < 0.0001). Therapeutic 6-TGN level (>235) was achieved in 49/58 cases on allopurinol combination therapy, versus 9/58 monotherapy (p = 0.0001). Among the thiopurine failure group (40 patients), clinical remission or response was observed in 65% and 22% of patients, respectively. In the asymptomatic group with excessive 6-MMP, 11/14 achieved sustained remission on allopurinol. Repeat colonoscopy (n = 28) showed mostly endoscopic remission (67.9%) or improvement (17.8%). Few had unimproved lesions (14.3%). Importantly, 46% of cases had complete mucosal healing. Two patients had cancer on combination therapy (de novo pancreatic cancer and fatal recurrence of metastatic testicular cancer). Elevated transaminases were reduced on allopurinol (48.2 versus 6.9%) (p < 0.001); no change in leukopenic or infectious events occurred. Conclusion: Allopurinol in combination with low-dose thiopurine corrected excessive 6-MMP levels, resulting in clinical remission and mucosal healing in the majority of cases. The potential cancer risk of allopurinol and thiopurine combination therapy needs further research. PMID- 29147134 TI - The clinical course after glucocorticoid treatment in patients with inflammatory bowel disease is linked to suppression of the hypothalamic-pituitary-adrenal axis: a retrospective observational study. AB - Background: Adrenal insufficiency (AI) secondary to treatment with glucocorticoids (GCs) is common in patients with inflammatory bowel disease (IBD), but little is known about the relationship between AI and the clinical course in IBD. The aim of the study was to compare the clinical course in IBD patients with normal adrenal function versus patients with subnormal adrenal function. Methods: A retrospective observational study on 63 patients with IBD who had performed a low-dose short Synacthen test (LDSST) (1 MUg) immediately (1 7 days) after a standard course of GCs. A subnormal LDSST was defined as serum cortisol <550 nmol/L. Outcomes were time to next flare and fecal calprotectin levels. Results: Sixty-three percent (n = 40) of the IBD patients had a subnormal LDSST. Patients who were steroid-free (n = 41) after the LDSST were observed for 3 years. Patients with a peak serum cortisol <400 nmol/L immediately after GC treatment had significantly longer time until the next flare-up of their IBD and tended to use a lower cumulative prednisolone dose during the study period in comparison to the other subgroups. Fecal calprotectin levels were significantly lower in patients with a peak s-cortisol <550 nmol/L versus patients with peak s cortisol ?550 nmol/L (median 336 ug/g (IQR 521) versus 955 ug/g (IQR 1867); p = 0.012). Conclusions: GC-induced AI is common in patients with IBD and is associated with lower disease activity. This suggests a link between responsiveness to GC treatment and suppression of the hypothalamic-pituitary adrenal axis in IBD. PMID- 29147135 TI - Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation. AB - Background: Plecanatide, with the exception of a single amino acid replacement, is identical to human uroguanylin and is approved in the United States for adults with chronic idiopathic constipation (CIC). This double-blind, placebo controlled, phase III study evaluated the efficacy and safety of plecanatide versus placebo in CIC. Methods: Adults meeting modified Rome III CIC criteria were randomized to plecanatide 3 mg (n = 443), 6 mg (n = 449), or placebo (n = 445). Patients recorded bowel movement (BM) characteristics [including spontaneous BMs (SBMs) and complete SBMs (CSBMs)] and rated CIC symptoms in daily electronic diaries. The primary endpoint was the percentage of durable overall CSBM responders (weekly responders for ?9 of 12 treatment weeks, including ?3 of the last 4 weeks). Weekly responders had ?3 CSBMs/week and an increase of ?1 CSBM from baseline for the same week. Results: A significantly greater percentage of durable overall CSBM responders resulted with each plecanatide dose compared with placebo (3 mg = 20.1%; 6 mg = 20.0%; placebo = 12.8%; p = 0.004 each dose). Over the 12 weeks, plecanatide significantly improved stool consistency and stool frequency. Significant increases in mean weekly SBMs and CSBMs began in week 1 and were maintained through week 12 in plecanatide-treated patients. Adverse events were mostly mild/moderate, with diarrhea being the most common (3 mg = 3.2%; 6 mg = 4.5%; placebo = 1.3%). Conclusions: Plecanatide resulted in a significantly greater percentage of durable overall CSBM responders and improved stool frequency and secondary endpoints. Plecanatide was well tolerated; the most common AE, diarrhea, occurred in a small number of patients.[ClinicalTrials.gov identifier: NCT02122471]. PMID- 29147136 TI - Step-by-step strategy in the management of residual hepatolithiasis using post operative cholangioscopy. AB - Hepatolithiasis is the presence of calculi within the intrahepatic bile duct specifically located proximal to the confluence of the left and right hepatic ducts. The ultimate goal of hepatolithiasis treatment is the complete removal of the stone, the correction of the associated strictures and the prevention of recurrent cholangitis. Although hepatectomy could effectively achieve the above goals, it can be restricted by the risk of insufficient residual liver volume, and has a 15.6% rate of residual hepatolithiasis. With improvements in minimally invasive surgery, post-operative cholangioscopy (POC), provides an additional option for hepatolithiasis treatment with higher clearance rate and fewer severe complications. POC is very safe, and can be performed repeatedly until full patient benefit is achieved. During POC three main steps are accomplished: first, the analysis of the residual hepatolithiasis distribution indirectly by imaging methods or directly endoscopic observation; second, the establishment of the surgical pathway to relieve the strictures; and third, the removal of the stone by a combination of different techniques such as simple basket extraction, mechanical fragmentation, electrohydraulic lithotripsy or laser lithotripsy, among others. In summary, a step-by-step strategy of POC should be put forward to standardize the procedures, especially when dealing with complicated residual hepatolithiasis. This review briefly summarizes the classification, management and complications of hepatolithiasis during the POC process. PMID- 29147137 TI - Preventing disability in inflammatory bowel disease. AB - Disability is a common worldwide health challenge and it has been increasing over the past 3 decades. The treatment paradigm has changed dramatically in inflammatory bowel diseases (IBDs) from control of symptoms towards full control of disease (clinical and endoscopic remission) with the goal of preventing organ damage and disability. These aims are broadly similar to rheumatoid arthritis and multiple sclerosis. Since the 1990s, our attention has focused on quality of life in IBD, which is a subjective measure. However, as an objective end-point in clinical trials and population studies, measures of disability in IBD have been proposed. Disability is defined as '...any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner or within the range considered normal for a human being.' Recently, after 10 years of an international collaborative effort with the World Health Organization (WHO), a disability index was developed and validated. This index ideally would assist with the assessment of disease progression in IBD. In this review, we will provide the evidence to support the use of disability in IBD patients, including experience from rheumatoid arthritis and multiple sclerosis. New treatment strategies, and validation studies that have underpinned the interest and quantification of disability in IBD, will be discussed. PMID- 29147138 TI - An update on prucalopride in the treatment of chronic constipation. AB - Chronic constipation (CC) is a highly prevalent and often under-appreciated gastrointestinal disorder associated with significant impairment in quality of life. Symptoms of constipation are typically present for a number of years prior to a patient seeking help. Lifestyle modifications followed by, or coupled with, over-the-counter laxatives represent the initial treatment option; however, relief for many is limited and dissatisfaction rates for these approaches remain high. Over recent years, therefore, considerable effort has been exerted on the development of novel pharmacological approaches. Two major targets have emerged, motility and secretion. Research on the former led to the development of a number of prokinetic agents capable of stimulating colonic motility and, thus, accelerating colonic transit. Of these, earlier prototypes such as cisapride and tegaserod, though effective, were ultimately withdrawn due to cardiovascular adverse events due in part to receptor non-selectivity. Highly selective serotonergic receptor agonists have since emerged which appear to be equally effective in stimulating gut motility but are devoid of cardiac side effects. One such agent is prucalopride, which has now been approved for the management of chronic idiopathic constipation in several countries, but not in the United States. Multiple multicenter, randomized placebo-controlled clinical trials have demonstrated superiority for prucalopride compared to placebo in the short to medium term in relieving the major symptoms of constipation in both men and women across a broad spectrum of ages, ethnicities and geographic locations. To date, prucalopride has enjoyed a favorable safety profile and there have been no signals to suggest arrythmogenicity. Efficacy over longer periods of treatment remains to be confirmed. Evidence for efficacy in other forms of constipation, such as opioid-induced constipation and that related to Parkinson's disease is beginning to emerge; its status in the management of constipation-predominant irritable bowel syndrome or foregut motility disorders, such as gastroparesis, remains to be established. PMID- 29147140 TI - Measuring readiness for and satisfaction with a hand hygiene e-learning course among healthcare workers in a paediatric oncology centre in Guatemala City. AB - E-learning has been widely used in the infection control field and has been recommended for use in hand hygiene (HH) programs by the World Health Organization. Such strategies are effective and efficient for infection control, but factors such as learner readiness for this method should be determined to assure feasibility and suitability in low- to middle-income countries. We developed a tailored, e-learning, Spanish-language HH course based on the WHO guidelines for HH in healthcare settings for the pediatric cancer center in Guatemala City. We aimed to identify e-readiness factors that influenced HH course completion and evaluate HCWs' satisfaction. Pearson's chi-square test of independence was used to retrospectively compare e-readiness factors and course completion status (completed, non-completed, and never-started). We surveyed 194 HCWs for e-readiness; 116 HCWs self-enrolled in the HH course, and 55 responded to the satisfaction survey. Most e-readiness factors were statistically significant between course-completion groups. Moreover, students were significantly more likely to complete the course if they had a computer with an Internet connection (P=0.001) and self-reported comfort with using a computer several times a week (p=0.001) and communicating through online technologies (p=0.001). Previous online course experience was not a significant factor (p=0.819). E-readiness score averages varied among HCWs, and mean scores for all e-readiness factors were significantly higher among medical doctors than among nurses. Nearly all respondents to the satisfaction survey agreed that e-learning was as effective as the traditional teaching method. Evaluating HCWs' e-readiness is essential while integrating technologies into educational programs in low- to middle-income countries. PMID- 29147139 TI - Insights into the management of Wilson's disease. AB - Wilson's disease is a rare, inherited autosomal recessive disease of copper metabolism, in which the causative gene, ATP7B, results in absent or reduced function of the ATP7B transporter important for biliary excretion of copper and incorporation of copper into caeruloplasmin. Affected patients accumulate excessive copper within the liver, brain and other tissues. A disease mainly of children, adolescents and young adults; clinical features vary from the asymptomatic state to chronic liver disease, acute liver failure, and neuropsychiatric manifestations. Diagnosis requires a high index of suspicion and is based on a combination of clinical signs, biochemical tests, hepatic copper content assay and mutation analysis of the ATP7B gene; to date, there are more than 500 mutations of ATP7B in patients with Wilson's disease. Early recognition and treatment can result in an excellent prognosis whereas untreated disease is almost always fatal. Drug therapies include chelating agents, such as penicillamine or trientine, and zinc salts. Liver transplantation is curative correcting the underlying pathophysiology and is traditionally indicated in acute liver failure or end-stage liver disease refractory to medical therapy. This review provides an overview of various aspects of Wilson's disease including molecular basis of the disease, clinical features, diagnostic and management strategies with their current limitations. PMID- 29147141 TI - The Relationship Between Use of Social Network Sites, Online Social Support, and Well-Being: Results From a Six-Wave Longitudinal Study. AB - Existing work on the effects of social network sites (SNS) on well-being has often stressed that SNS can help people gain social support from their online networks, which positively affects their well-being. However, the majority of studies in this area have been cross-sectional in nature and/or relied on student samples. Using data from six waves of a longitudinal study with a representative sample of Dutch Internet users, we first examined whether users and nonusers of SNS differ in online social support and well-being (as indicated by life satisfaction and stress). In a second step, we investigated in more detail how SNS use - more specifically, asking for advice and the number of strong ties on these SNS - are related to online social support, stress, and satisfaction with life. Overall, our results provide no evidence for SNS use and online social support affecting either stress or life satisfaction. SNS users reported more online social support than nonusers did, but also higher levels of stress; the two groups did not differ in overall life satisfaction. With regard to the underlying processes, we found positive cross-sectional and longitudinal relationships between asking for advice on SNS and online social support, indicating that SNS can be an effective tool for receiving social support. However, online social support was not related to higher life satisfaction or reduced stress 6 months later; instead, it seems that SNS users with lower life satisfaction and/or higher stress seek more social support online by asking for advice on SNS. PMID- 29147142 TI - Analysis of functional brain connections for positive-negative emotions using phase locking value. AB - In this study, we investigate the brain networks during positive and negative emotions for different types of stimulus (audio only, video only and audio + video) in [Formula: see text], and [Formula: see text] bands in terms of phase locking value, a nonlinear method to study functional connectivity. Results show notable hemispheric lateralization as phase synchronization values between channels are significant and high in right hemisphere for all emotions. Left frontal electrodes are also found to have control over emotion in terms of functional connectivity. Besides significant inter-hemisphere phase locking values are observed between left and right frontal regions, specifically between left anterior frontal and right mid-frontal, inferior-frontal and anterior frontal regions; and also between left and right mid frontal regions. ANOVA analysis for stimulus types show that stimulus types are not separable for emotions having high valence. PLV values are significantly different only for negative emotions or neutral emotions between audio only/video only and audio only/audio + video stimuli. Finding no significant difference between video only and audio + video stimuli is interesting and might be interpreted as that video content is the most effective part of a stimulus. PMID- 29147143 TI - Analyzing text recognition from tactually evoked EEG. AB - Tactual exploration of objects produce specific patterns in the human brain and hence objects can be recognized by analyzing brain signals during tactile exploration. The present work aims at analyzing EEG signals online for recognition of embossed texts by tactual exploration. EEG signals are acquired from the parietal region over the somatosensory cortex of blindfolded healthy subjects while they tactually explored embossed texts, including symbols, numbers, and alphabets. Classifiers based on the principle of supervised learning are trained on the extracted EEG feature space, comprising three features, namely, adaptive autoregressive parameters, Hurst exponents, and power spectral density, to recognize the respective texts. The pre-trained classifiers are used to classify the EEG data to identify the texts online and the recognized text is displayed on the computer screen for communication. Online classifications of two, four, and six classes of embossed texts are achieved with overall average recognition rates of 76.62, 72.31, and 67.62% respectively and the computational time is less than 2 s in each case. The maximum information transfer rate and utility of the system performance over all experiments are 0.7187 and 2.0529 bits/s respectively. This work presents a study that shows the possibility to classify 3D letters using tactually evoked EEG. In future, it will help the BCI community to design stimuli for better tactile augmentation n also opens new directions of research to facilitate 3D letters for visually impaired persons. Further, 3D maps can be generated for aiding tactual BCI in teleoperation. PMID- 29147144 TI - Effects of spectral smearing of stimuli on the performance of auditory steady state response-based brain-computer interface. AB - There have been few reports that investigated the effects of the degree and pattern of a spectral smearing of stimuli due to deteriorated hearing ability on the performance of auditory brain-computer interface (BCI) systems. In this study, we assumed that such spectral smearing of stimuli may affect the performance of an auditory steady-state response (ASSR)-based BCI system and performed subjective experiments using 10 normal-hearing subjects to verify this assumption. We constructed smearing-reflected stimuli using an 8-channel vocoder with moderate and severe hearing loss setups and, using these stimuli, performed subjective concentration tests with three symmetric and six asymmetric smearing patterns while recording electroencephalogram signals. Then, 56 ratio features were calculated from the recorded signals, and the accuracies of the BCI selections were calculated and compared. Experimental results demonstrated that (1) applying smearing-reflected stimuli decreases the performance of an ASSR based auditory BCI system, and (2) such negative effects can be reduced by adjusting the feature settings of the BCI algorithm on the basis of results acquired a posteriori. These results imply that by fine-tuning the feature settings of the BCI algorithm according to the degree and pattern of hearing ability deterioration of the recipient, the clinical benefits of a BCI system can be improved. PMID- 29147145 TI - Long-range temporal correlations of broadband EEG oscillations for depressed subjects following different hemispheric cerebral infarction. AB - Abnormal long-range temporal correlation (LRTC) in EEG oscillation has been observed in several brain pathologies and mental disorders. This study examined the relationship between the LRTC of broadband EEG oscillation and depression following cerebral infarction with different hemispheric lesions to provide a novel insight into such depressive disorders. Resting EEGs of 16 channels in 18 depressed (9 left and 9 right lesions) and 21 non-depressed (11 left and 10 right lesions) subjects following cerebral infarction and 19 healthy control subjects were analysed by means of detrended fluctuation analysis, a quantitative measurement of LRTC. The difference among groups and the correlation between the severity of depression and LRTC in EEG oscillation were investigated by statistical analysis. The results showed that LRTC of broadband EEG oscillations in depressive subjects was still preserved but attenuated in right hemispheric lesion subjects especially in left pre-frontal and right inferior frontal and posterior temporal regions. Moreover, an association between the severity of psychiatric symptoms and the attenuation of the LRTC was found in frontal, central and temporal regions for stroke subjects with right lesions. A high discriminating ability of the LRTC in the frontal and central regions to distinguish depressive from non-depressive subjects suggested potential feasibility for LRTC as an assessment indicator for depression following right hemispheric cerebral infarction. Different performance of temporal correlation in depressed subjects following the two hemispheric lesions implied complex association between depression and stroke lesion location. PMID- 29147147 TI - Collective behavior of large-scale neural networks with GPU acceleration. AB - In this paper, the collective behaviors of a small-world neuronal network motivated by the anatomy of a mammalian cortex based on both Izhikevich model and Rulkov model are studied. The Izhikevich model can not only reproduce the rich behaviors of biological neurons but also has only two equations and one nonlinear term. Rulkov model is in the form of difference equations that generate a sequence of membrane potential samples in discrete moments of time to improve computational efficiency. These two models are suitable for the construction of large scale neural networks. By varying some key parameters, such as the connection probability and the number of nearest neighbor of each node, the coupled neurons will exhibit types of temporal and spatial characteristics. It is demonstrated that the implementation of GPU can achieve more and more acceleration than CPU with the increasing of neuron number and iterations. These two small-world network models and GPU acceleration give us a new opportunity to reproduce the real biological network containing a large number of neurons. PMID- 29147146 TI - Relationships between short and fast brain timescales. AB - Brain electric activity exhibits two important features: oscillations with different timescales, characterized by diverse functional and psychological outcomes, and a temporal power law distribution. In order to further investigate the relationships between low- and high- frequency spikes in the brain, we used a variant of the Borsuk-Ulam theorem which states that, when we assess the nervous activity as embedded in a sphere equipped with a fractal dimension, we achieve two antipodal points with similar features (the slow and fast, scale-free oscillations). We demonstrate that slow and fast nervous oscillations mirror each other over time via a sinusoid relationship and provide, through the Bloch theorem from solid-state physics, the possible equation which links the two timescale activities. We show that, based on topological findings, nervous activities occurring in micro-levels are projected to single activities at meso- and macro-levels. This means that brain functions assessed at the higher scale of the whole brain necessarily display a counterpart in the lower ones, and vice versa. Our topological approach makes it possible to assess brain functions both based on entropy, and in the general terms of particle trajectories taking place on donut-like manifolds. Condensed brain activities might give rise to ideas and concepts by combination of different functional and anatomical levels. Furthermore, cognitive phenomena, as well as social activity can be described by the laws of quantum mechanics; memories and decisions exhibit holographic organization. In physics, the term duality refers to a case where two seemingly different systems turn out to be equivalent. This topological duality holds for all the types of spatio-temporal brain activities, independent of their inter- and intra-level relationships, strength, magnitude and boundaries, allowing us to connect the physiological manifestations of consciousness to the electric activities of the brain. PMID- 29147148 TI - The effects of depression, anxiety and sleep disturbances on cognitive impairment in patients with chronic obstructive pulmonary disease. AB - The purpose of this study was to investigate the effects of depression, anxiety and sleep disturbances on cognitive functions in chronic obstructive pulmonary disease (COPD) patients. In this prospective case-control study, demographic data, smoking history, depression, anxiety, sleep quality and cognitive status of 48 COPD patients and 36 healthy volunteers aged 40-90 years were recorded. The Beck depression inventory (BDI), the Beck anxiety inventory (BAI), and Pittsburgh Sleep Quality Index (PSQI) were used to assess depression, anxiety and sleep quality, respectively in COPD patients. Cognitive performance was studied by the mini-mental state examination. The mean age of patients with COPD was 65.3 +/- 9.4 years, and disease duration was 9.6 +/- 7.8 years. Male sex ratio, smoking, BDI score, BAI score, total PSQI score, sleep latency, sleep duration, average use of sleep aids and sleep disturbances in patients with COPD were significantly higher than the control group (p < 0.05). When cognitive impairment was compared by age, FVC, FEV, FEV/FVC, PEF values and smoking, no statistically significant relationship was found (p > 0.05). A statistically significant relationship was established between cognitive impairment and severity of disease, presence of anxiety, presence of depression and sleep quality. In our study, we found that sleep disorders, depression and anxiety comorbid with COPD increased cognitive impairment as well as the severity of disease. We believe that this finding is important in terms of reducing the risk of cognitive impairment, preventing misdiagnosis and treatment of the aforementioned comorbid diseases. PMID- 29147149 TI - Endovascular Treatment of Infrarenal Isolated Abdominal Aortic Dissection with Application of the Kissing Stents Technique: A Case Report and Review of the Literature. AB - Isolated abdominal aortic dissection (IAAD) is a rare form of aortic dissection involving usually the infrarenal part of the abdominal aorta. A 45-year-old male presented with lumbar pain and claudication. Computed tomography angiography (CTA) revealed an infrarenal IAAD extending to the left external iliac artery (EIA), causing >=90% narrowing of the lumen. An endovascular approach was decided, with deployment of an aortic stent-graft and two balloon expandable stents in both common iliac arteries (IAs), applying the kissing stents technique. Post-surgical course was uneventful; 12 month follow-up showed excellent vessel patency. Endovascular therapy seems to be a feasible treatment option with promising long-term follow-up results. PMID- 29147150 TI - Localized Aortic Root Dissection with a Superior Mesenteric Artery Aneurysm. AB - In this study, the case of a 46-year-old female patient with localized aortic root dissection and a superior mesenteric artery (SMA) aneurysm is described. Computed tomographic angiography could not clearly delineate an intimal flap in the aortic root, but it detected SMA aneurysm, which implied the presence of a vulnerability of the aortic wall. Finally, transesophageal echocardiography (TEE) evidently showed the intimal flap localized in the aortic root. The present case suggests that TEE is of paramount importance for detecting localized aortic root dissection. In addition, a coexisting vascular lesion may be a clue to diagnose another vascular lesion. PMID- 29147151 TI - Percutaneous Direct Embolization for Pseudoaneurysm at the Gallbladder Fossa after Cholecystectomy. AB - Postoperative pseudoaneurysm at the gallbladder fossa is a rare complication of cholecystectomy. The typical clinical presentations of this condition are intraparenchymal or intraperitoneal hemorrhage or rupture into the gastrointestinal tract, and this may be life-threatening. For the treatment of pseudoaneurysms, percutaneous transarterial embolization is considered first line. We present a case of pseudoaneurysm at the gallbladder following cholecystectomy, which was successfully treated with echo-guided percutaneous transhepatic direct embolization using N-butyl cyanoacrylate, after the failure of transarterial embolization. PMID- 29147152 TI - Pulmonary Stenosis Caused by Ductus Arteriosus Aneurysm: A Case Report. AB - A 76-year-old woman with a 2-week history of dyspnea on exertion was admitted to our hospital. A computed tomography scan showed a 70-mm diameter aortic arch aneurysm containing a large thrombus that was compressing the pulmonary artery. Echocardiography showed severe pulmonary stenosis and no shunt flow. Operative findings revealed an aneurysmal thrombus protruding into the lumen of the pulmonary artery through a foramen. A ductus arteriosus aneurysm was diagnosed. After the thrombus removal, arch replacement and ductus closure with a prosthetic patch were performed. Histological examination showed that the thrombus had no vascular components. The patient's symptoms were relieved, and she was discharged. PMID- 29147153 TI - Successful Aortic Banding for Type IA Endoleak Due to Neck Dilatation after Endovascular Abdominal Aortic Aneurysm Repair: Case Report. AB - A 69-year-old man with a type IA endoleak that developed approximately 21 months after endovascular abdominal aortic aneurysm repair (EVAR) of a 46 mm diameter aneurysm was referred to our department. He had impaired renal function, Parkinson's disease, and previous cerebral infarction. Computed tomography angiography showed a type IA endoleak with neck dilatation and that the aneurysm had grown to 60 mm in diameter. We decided to perform aortic banding. The type IA endoleak disappeared after banding and the patient was discharged on postoperative day 10. Aortic banding may be effective for type IA endoleak after EVAR and less invasive for high-risk patients in particular. PMID- 29147154 TI - Successful Embolization Therapy through Reentry Tear in the Right Subclavian Artery for Treating Patent False Lumen in the Aortic Arch Formed after Type A Dissection Repair. AB - A 73-year-old woman had undergone hemiarch replacement with primary entry resection for treating acute type A dissection 6 years ago. Postoperative computed tomography (CT) showed a patent false lumen (FL) in the aortic arch and a reentry tear in the right subclavian artery. The remaining aortic arch enlarged, which resulted in formation of a 55-mm-diameter aneurysm. We performed reentry occlusion using embolization with glue and coil. The patient's clinical course after the procedure was uneventful, and subsequent CT showed that FL was thrombosed and had decreased in size. PMID- 29147155 TI - Endovascular Stent-Graft Repair of a Persistent Sciatic Artery Aneurysm. AB - Persistent sciatic artery (PSA) is a rare anomaly that may cause various symptoms, such as aneurysm, rupture, thromboembolism, and sciatica. Direct surgery can be performed to treat PSA aneurysm (PSAA), but is associated with complications; e.g., anatomical problems such as sciatic nerve injury. Herein we report a case of a 74-year-old woman with acute limb ischemia that developed from a distal embolism caused by a thrombus in the left PSAA; favorable results were obtained for her by treatment with a stent-graft after rapid anticoagulation therapy for limb salvage. PMID- 29147156 TI - Popliteal Artery Pseudoaneurysm Associated with Osteochondroma. AB - Osteochondroma is the most common benign bone tumor, which can sometimes cause vascular complications. Here we report two rare cases (a 48-year-old woman and a 28-year-old woman) presenting with pain and a pulsatile mass in the popliteal region. Computed tomography revealed pseudoaneurysm in the popliteal artery, which was closely associated with a protrusion of a femoral osteochondroma. Surgical repairs were performed, and the patients remained asymptomatic during follow-up. Therefore, considering the potential risk of vascular complications, close observation is mandatory in patients with femoral osteochondroma. PMID- 29147157 TI - Tuberculous Mycotic Aneurysm of Common Iliac Artery Secondary from Ureteric Tuberculosis: The First Case Report and Review of the Literature. AB - Extrapulmonary involvement of tuberculosis occurs in 10-40% of reported cases. However, tuberculous mycotic aneurysm is very rare. We report herein tuberculous mycotic aneurysm of left common iliac artery secondary from ureteric tuberculosis in a 63-year-old man who presented with left flank pain for 1 month, and review the literature of all reported cases of tuberculous aneurysm of iliac artery. PMID- 29147158 TI - Successful Hybrid Treatment of Stent-Graft Migration Caused by Type B Aortic Dissection after Endovascular Aortic Aneurysm Repair: A Case Report. AB - Herein, we report a rare case of type B aortic dissection that occurred after endovascular aortic aneurysm repair (EVAR). A 66-year-old man underwent successful EVAR for an abdominal aortic aneurysm (AAA). Computed tomography (CT) 2 years after EVAR showed a type B aortic dissection with stent-graft migration and AAA expansion. Juxtarenal aortic expansion precluded simple stent-graft placement. He underwent hepato-spleno-renal bypass followed by stent-graft placement just below the superior mesenteric artery. Postoperative CT showed no endoleaks. This case reconfirms the importance of regular follow-up after EVAR and illustrates the usefulness of a hybrid approach. PMID- 29147159 TI - ERRATUM. PMID- 29147160 TI - The 10th Korea-Japan Joint Meeting for Vascular Surgery. PMID- 29147161 TI - Is Conventional Open Repair for Abdominal Aortic Aneurysm Feasible in Nonagenarians? AB - Background: Although endovascular repair for abdominal aortic aneurysm has been found to be beneficial in very elderly patients, some patients have contraindications to this procedure. For nonagenarians, the results of open repair remain unclear. The purpose of this study was to compare the outcomes of open vs. endovascular repair for abdominal aortic aneurysm in nonagenarian patients. Methods and Results: Fourteen patients undergoing open surgical repair and 24 undergoing endovascular repair for abdominal aortic aneurysm were evaluated. There was no significant difference in early mortality between the open and endovascular groups (0% vs. 4.1%, p=0.16). The open repair group required much longer hospital stays (26.4 vs. 10.6 days, respectively, p=0.003). Finally, 12 patients (86%) undergoing open repair vs. 21 (88%) undergoing endovascular repair returned home (p=0.49). During a mean follow-up period of 23.4+/-23.5 months, cumulative estimated 1- and 3-year survival rates were 90.0% and 48.0%, respectively in the open repair group and 90.6% and 54.9%, respectively in the endovascular repair group (p=0.51). Conclusion: Although endovascular repair for abdominal aortic aneurysm was superior in terms of recovery, the results of conventional open repair were acceptable even in nonagenarian patients. Open repair remains an alternative for patients with contraindications to endovascular repair. PMID- 29147162 TI - High Preoperative Neutrophil-Lymphocyte Ratio (NLR) and Red Blood Cell Distribution Width (RDW) as Independent Predictors of Native Arteriovenous Fistula Failure. AB - Objective: To study the association between a high preoperative neutrophil lymphocyte ratio (NLR) and red cell distribution width (RDW) with arteriovenous fistula (AVF) failure, as well as to determine the cut-off values in a South Asian population. Materials and Methods: A total of 150 consecutive patients with a failed fistula who presented in the Department of Vascular Surgery between January 2014 and January 2016. Patients fulfilling the inclusion criteria were selected as defined as Case. They were compared with 150 patients who had matured fistulae (Control). Results: A significant difference was found between the Case and Control groups in mean preoperative NLR (3.3+/-0.5 versus 2.2+/-0.9, P value=0.011) and RDW (15.9+/-2.9 versus 13.6+/-1.1%, P value of 0.02), respectively. Multivariate analysis revealed that NLR (Odds Ratios (OR) 1.39; 95% Confidence Intervals (CI) 1.02 to 2.08; P<0.001) and RDW (OR 1.39; 95%CI 1.11 to 1.69; P<0.001) were strong independent predictors of AVF failure. A receiver operating characteristic curve analysis showed a cut-off value of 2.65 (specificity 80%, sensitivity 98%) and 15.1 (specificity 79%, sensitivity 98%) for NLR and RDW, respectively. Conclusion: Increased preoperative NLR and RDW were associated with a high rate of AVF failure in a South Asian population. PMID- 29147163 TI - Self-Care-Based Treatment Using Ordinary Elastic Bandages for Venous Leg Ulcers. AB - Objective: We aimed to study venous leg ulcer (VLU) healing and recurrence rates of VLU using a self-care-based treatment strategy. Methods: The study included 36 patients (43 legs) who visited our clinic between April 2009 and June 2015 because of non-healing VLUs and who had been treated by us for more than a year (until June 2016). Patients or their caregivers were first provided instructions for performing the "no-intentional-stretch" bandaging technique using ordinary elastic bandages. Wounds were cleansed with tepid water daily, and bandages were re-applied by patients or their caregivers; this was continued until VLUs were healed. Compression was discontinued after healing, but was restarted if persistent swelling and/or dermatitis was noticed on their legs. Results: The median ulcer size was 6.5 cm2 (range, 1-105 cm2). The median number of clinic visits until healing was six (range, 3-35). The 6- and 12-month healing rates were 67% and 86%, respectively. Twenty (44%) legs required compression therapy after VLU healing. The cumulative recurrence-free rate at 60 months was 86%. Conclusion: Reasonable healing and recurrence rates were achieved by applying a self-care-based VLU treatment strategy. PMID- 29147164 TI - A Series of 210 Peripheral Arterial Disease Below-Knee Amputations and Predictors for Subsequent Above-Knee Amputations. AB - Objective: To review patient characteristics and outcomes after peripheral arterial disease (PAD)-related below-knee amputation (BKA), and identify risk factors predicting subsequent above-knee amputation (AKA). Materials and Methods: A retrospective study of 210 BKAs between May 2008 and December 2015. Results: The mean age of the study population was 66 years. Most of the patients had cardiovascular comorbidities, and 33% had end-stage renal failure (ESRF); 89% were American Society of Anesthesiologists 3 or 4. Previous ipsilateral lower limb minor amputation was present in 49% and previous contralateral lower-limb major amputation was present in 20% patients. Limb salvage revascularization via angioplasty prior to BKA was performed in 73%, while 27% had extensive tissue loss that was not suitable for limb salvage. Postoperatively, 20% had BKA wound infection, with 3% requiring further surgical debridement, and 9% (19 patients) required subsequent AKA within 1 month. Overall survival analysis at 1-5 years was 75%, 66%, 64%, 59%, and 58%, respectively. Multivariate analysis showed ESRF (Odds Ratio [OR]=3.85; p=0.01) and preoperative non-ambulatory status (OR=5.58; p=0.01) to be independent risk factors in predicting for subsequent AKA. Conclusion: Patients with underlying ESRF or preoperative non-ambulatory status may benefit from direct AKA if major amputation is required. PMID- 29147165 TI - Outcomes of Popliteal-To-Distal Bypass Combined with Femoropopliteal Artery Endovascular Treatment for Critical Limb Ischemia. AB - Objective: The aim of this study was to evaluate outcomes of combined popliteal to-distal bypass and endovascular treatment (EVT) for femoropopliteal lesions in patients with critical limb ischemia (CLI). Patients and Methods: We reviewed data of 14 CLI patients who were treated by popliteal-to-distal bypass combined with femoropopliteal EVT. The femoropopliteal lesions included 3 TASC II-A, 8 TASC II-B, and 3TASC II-C but no TASC II-D, and balloon dilatation was performed in 9 cases and a stent was placed in 5 cases. The saphenous vein graft was used in all bypasses, and the target arteries were the dorsalis pedis artery in 12 cases and the posterior tibial artery in 2 cases. Results: At 12 and 24 months, primary patency rates were both 79%, primary assisted and secondary patency rates were both 93%, limb salvage rates were both 93%, and survival rates were 92% and 84%, respectively. Restenosis after femoropopliteal EVT occurred in 2 cases, and both were successfully revised by additional endovascular balloon dilatation. Conclusion: Combined popliteal-to-distal bypass and femoropopliteal EVT might be a useful therapeutic option for appropriately selected CLI patients. Intensive follow-up for endovascular treated lesions and vein graft is mandatory. PMID- 29147166 TI - A Cost-Utility Analysis of Endovascular Aneurysm Repair for Abdominal Aortic Aneurysm. AB - Objective: To assess medical economic adequacy of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA). Methods: Cost-utility analysis. A total of 21 patients with AAA treated at Ibaraki Prefectural Central Hospital in 2014 were divided into non-ruptured EVAR (Group E) and open surgery (OS) (Group O), and ruptured OS (Group R) groups, and hospital costs were aggregated with a medical accounting system. Mid-level hospital costs were estimated by a diagnosis procedure-combination analysis system. Incremental life years were extrapolated from the results of randomized controlled trials in the UK (EVAR Trial 1 and 2), a life table, and the Pancreas Cancer Registry in Japan. Quality-adjusted life years (QALY) were estimated under the assumption of a certain quality weight. Results: Incremental cost-effectiveness ratio (ICER) of EVAR compared with the OS was calculated to be 31.0 million yen/QALY, which is economically inadequate. ICER of EVAR compared with conservative treatment was inadequate in some subgroups of extremely old patients and in patients operated for far-advanced cancer. Conclusion: EVAR is inadequate with respect to medical economics as a substitute for OS for patients in whom both procedures are available. The indication for EVAR in patients ineligible for OS should be different from that for surgery in usual patients with AAA. (This is a translation of J Jpn Coll Angiol 2016; 56: 123-130.). PMID- 29147167 TI - Validation of the Risk Score of the Mortality and Lower Limb Loss Considering Ambulatory Status after Surgical Revascularization in Maintaining Patients with Dialysis. AB - Surgical revascularization is performed to preserve limb and to maintain functional status of patients with critical limb ischemia (CLI). The PREVENT III risk score helps to predict the postoperative course of CLI. However, this score is not available to estimate the risk of amputation or death properly in patients with hemodialysis (HD) and tissue loss (HD: 4 points, Tissue loss: 3 points), because they are classified as a high-risk group. Therefore, we investigated 213 patients with revascularized HD for CLI and proposed prognosis amputation or death for patients with HD risk score (PAD for HD risk score). PAD for HD risk score (non-ambulation: 3 points, ulcer/gangrene: 2 points, GNRI<92: 2 points, CRP>0.3 mg/dl: 1 point, Age>=75: 1 point) is more accurate for the prediction of amputation or death than the PREVENT III risk score (area under the curve [AUC]: 0.79 [95% confidence interval: CI: 0.71-0.87], p<0.01 vs. AUC: 0.63 [95%CI: 0.56 0.71]). The patients were stratified into three groups by total score in ascending order. The rate of 1-year amputation-free survival and independent ambulatory status were significantly different among three groups. PAD for HD risk score is useful for rehabilitation planning in patients with HD and CLI. (This is a translation of J Jpn Coll Angiol 2016; 56: 85-91.). PMID- 29147168 TI - Study of the Characteristics of Pulmonary Trunk in Pulmonary Hypertension Secondary to Left Heart Disease Using Pressure-Velocity Loops (PU-Loops). AB - Objectives: Although pulmonary hypertension (PH) caused by left heart disease (PH LHD) is more common in PH, little is known about its properties of pulmonary artery (PA) in PH-LHD. The purpose of this study was to measure pulmonary regional pulse wave velocity (PWV) and to quantify the magnitude of reflected waves in patients with PH-LHD by the analysis of the pressure-velocity loops (PU loop). Methods: High-fidelity PA pressure (Pm) and PA velocity (Vm) were measured in 11 subjects with PH-LHD (mean Pm>25 mmHg), 1 subject with atrial septal defect (ASD) without PH and 12 control subjects, using multisensor catheters. PWV was calculated as the slope of the initial part of the PU-loop in early systole. The similarity in the shapes of the pressure and flow velocity waveforms over one PU loop was quantified as the magnitude of reflected wave by calculating the standard error of the estimate (Sy/x) from linear regression analysis between Pm and corresponding Vm. PWV and Sy/x during a Valsalva maneuver (VM) were also assessed in nine control subjects. Results: The contour of PU-loop was so characteristic between control and PH-LHD. Max. PWV (349 cm/s) was recorded in PH LHD and min. PWV (111 cm/s) was recorded in ASD. VM increased Pm (12 [7-15] mmHg vs. 50 [18-110] mmHg; p=0.009) and PWV (200 [148-238] cm/s vs. 260 [192-306] cm/s; p=0.009) significantly without significant increase of Sy/x (19.6 [12.7 28.9]% vs. 28.2 [19.3-40.7]%; p=0.079). Although Sy/x was significantly higher in PH-LHD than in control and ASD (31.0 [14.3-36.3]% vs. 17.5 [8.4-28.9]%; p=0.009, ASD: 18.2%) , no significant difference was found in PWV between PH-LHD and control (269 [159-349] cm/s vs. 203 [154-289] cm/s; p=0.089). Conclusions: 1) The magnitude of wave reflection was elevated in PH-LHD significantly as compared with control and ASD. 2) Despite the significant increase in PA-PWV caused by abrupt elevation in Pm during VM in control, chronic elevation in Pm did not increase PA-PWV in PH-LHD significantly. It was hypothesized that the PA constituted a self-regulating system for maintaining the arterial stiffness stable against the chronic elevation in Pm in PH-LHD by a remodeling of increasing proximal pulmonary arterial crosssectional area gradually, which was compatible with the Moens-Korteweg equation. The PU-loop could provide a new simple and conventional method for assessing the pulmonary arterial properties, clinically. (This is a translation of J Jpn Coll Angiol 2016; 56: 45-53.). PMID- 29147169 TI - Uncomplicated Acute Type B Aortic Dissection: Selection Guidelines for TEVAR. AB - Traditionally, the surgical management of acute type B aortic dissections was reserved for patients with signs of malperfusion, rapid expansion, retrograde dissection or rupture. The adjunct of endovascular techniques has brought a paradigm shift, leaning towards preventing long term dissection complications. Multiple risk factors have been proposed to identify patients at risk for long term aortic complications. The patients, who are offered a prophylactic endovascular therapy for uncomplicated aortic dissection, should be selected carefully, and offered intervention by an experienced team in a high-volume center. (This is a review article based on the invited lecture of the 57th Annual Meeting of Japanese College of Angiology.). PMID- 29147170 TI - Clinical Assessment of Warfarin Therapy in Patients with Maintenance Dialysis Clinical Efficacy, Risks and Development of Calciphylaxis. AB - Recent years, multiple studies regarding clinical efficacy and risks of Warfarin therapy in dialysis patients have been reported, and not a few reports conclude that clinical advantage of Warfarin is questionable in dialysis patients. Conversely, its hemorrhagic risk might be a little more serious in dialysis patients comparing to non-dialysis patients. Basically, it is assumed that long term administration of Warfarin accelerates the development of vascular athelosclerosis because of the abolished anti-calcification effect of Gla-protein activation by decreased vitamin K activity. This assumption is recently confirmed by multiple reports, suggesting that the Warfarin administration might be worse harmful than ever expected in dialysis patients who are essentially considered to have higher risk of calcification comparing to non-dialysis patients. In addition, it is recently well considered that the Warfarin administration would be a risk factor to cause Warfarin skin necrosis or calciphylaxis, therapy resistant ulcerative skin lesions, which are considered to be highly related to the Warfarin-induced transient hypercoagulable state or acceleration of calcification. Therefore, it is considered that the indication of Warfarin administration to dialysis patients should be carefully assessed. (This is a translation of Jpn J Vasc Surg 2017; 26: 83-90.). PMID- 29147171 TI - Recent Progress of Bypass Surgery to the Dialysis-Dependent Patients with Critical Limb Ischemia. AB - According to expansion of dialysis-dependent population, more than half of patients with critical ischemic limbs are dialysis-dependent in Japan. Although patients with end-staged renal disease are well-known as poor life prognosis, well-managed dialysis patients in Japan can survive much longer compared to dialysis patients in the United States and Europe. Therefore, some dialysis patients can enjoy the long-term benefits of bypass surgery. To decide the indication of bypass surgery, patient's general condition, nutrition status, and vein availability are more important rather than arterial disease anatomy. Ultrasound guided nerve block anesthesia blocking both sciatic and femoral nerve is contributing greatly to quick postoperative recovery of high risk patients. Preoperative ultrasound examination also contribute to not only vein mapping but also find out the graftable segment of artery. The selection of distal target should be decided based on the degree of arterial disease (luminal surface as well as wall calcification), and arterial run-off. Several tips regarding anastomosis to heavily calcified artery have been established including how to create bloodless operative field without arterial clamps. Adequate wound management after bypass surgery is also important. Detection of deep infection such as osteomyelitis and the adequate treatment may avoid major amputation of salvageable limbs. In the era of endovascular treatment, the evidences guiding how to select dialysis patients suitable for bypass surgery are awaiting. (This is a translation of Jpn J Vasc Surg 2017; 26: 33-39.). PMID- 29147172 TI - Sentinel Lymph Node Biopsy in Breast Cancer. AB - The axillary lymph node status is the most reliable prognostic indicator of recurrence and overall survival in patients with breast cancer. The current standard surgical procedure for the management of invasive breast cancer is the complete removal of the cancer with total axillary clearance. However, recently, selective sentinel lymph node mapping and biopsy is gaining acceptance as a useful and accurate staging procedure, as it is minimally invasive. The sentinel lymph node is the first node into which a primary cancer drains, and is thus the first node to be involved by metastases. Patients whose sentinel nodes are negative for breast cancer metastases, can be spared a more extensive axillary lymph node dissection, with reduction in the postoperative morbidity. Sentinel node mapping is usually performed by intradermal or peritumoral injection of a combination of blue dye and radiotracer. Sentinel node examination is sometimes done intraoperatively, by imprint cytology and frozen sections, for an immediate assessment, to plan the extent of surgery at a single sitting. Permanent sections of the sentinel node are studied by serial sectioning, and immunohistochemistry for cytokeratin is done to detect micrometastases which are frequently missed on hematoxylin and eosin (H&E)-stained sections. The various aspects of sentinel node examination, and its role to decide further management in patients with ductal carcinoma-in-situ, and in other clinical settings, are discussed in this review. PMID- 29147173 TI - Targeting RhoC by Way of Ribozyme Trangene in Human Breast Cancer Cells and its Impact on Cancer Invasion. AB - Background: Cell motility and migration are known to be regulated by the Rho family of GTPases through their effects on the actin cytoskeleton. In breast cancer studies, RhoC has been identified as a highly specific marker in detecting tumors that developed metastases. This study aims to investigate the impact of targeting RhoC in human breast cancer cells by utilising ribozyme transgene technology and to assess its effect on cancer cell invasion. Methods: Retroviral hammerhead ribozyme transgenes, regulated by doxycycline, were designed to specifically target human RhoC mRNA. The breast cancer cell line MDA-MB-231 was transfected with either a retroviral RhoC transgene or a control retroviral transgene. Stably transfected cells were tested for their invasiveness and migratory properties in vitro. Results: In vitro testing of the invasiveness of wild type, plasmid control and the RhoC knockdown cells showed that MDA-MB 231DRHOC cells had significantly reduced invasiveness compared with MDA-MB-231WT (p < 0.038 RHOC2 knockdown cells; p < 0.006 RHOC3 knockdown cells) and MDA-MB 231pRevTRE control plasmid cells (p < 0.07 RHOC2 knockdown cells; p < 0.002 RHOC3 knockdown cells). An even greater reduction in invasiveness of the MDA-MB 231DRHOC cells compared with the MDA-MB-231WT cells was seen in response to hepatocyte growth factor (HGF/SF) (p < 0.009 RHOC1 knockdown; p = 0.004 RHOC2 knockdown; p = 0.00007 RHOC3 knockdown). The addition of doxycycline significantly improved the effectiveness of the ribozyme transgenes (p < 0.04 for all three Rho ribozymes), but did not improve the effectiveness of these knockdown cells when treated with HGF/SF (p > 0.1 for all three ribozymes). Conclusions: This data would indicate that targeting RhoC may be an effective way to reduce the invasive potential of human breast cancer cells. PMID- 29147174 TI - Synovial Sarcoma: A Clinicopathological and Radiological Study of 12 Cases Seen Over 18 Years. AB - Background: Synovial sarcoma is a rare malignant soft tissue tumor characterized by a poor outcome. We report herein our experience concerning synovial sarcoma and review its diagnosis, histology, treatment and prognosis. Methods: This is a retrospective review, from 1990 to 2007, of cases of synovial sarcoma diagnosed at the Department of Pathology, Farhat Hached hospital, Sousse, Tunisia. The clinical, radiological and pathological features as well as treatment modalities and patient's outcome were recorded. Results: From 1990 to 2007, 12 cases of synovial sarcoma have been diagnosed in our department. Patients' mean age at the time of diagnosis was 21 years. There was no sex predominance and the lower extremity was the most commonly involved. A painful tumefaction was the most common presenting symptom. The duration of symptoms ranged from 6 months to 6 years. Malignancy was suspected on radiological findings in only 2 cases. Ten patients underwent surgery, in association with adjuvant chemotherapy in 4 cases, one of whom underwent post-operative radiotherapy. Histological subtypes included monophasic synovial sarcoma in 8 cases, biphasic synovial sarcoma in 3 cases and poorly differentiated synovial sarcoma in one case. At the time of analysis, 6 patients were dead with an average follow-up of 18 months. Conclusions: Synovial sarcoma is a rare malignancy with a propensity for young adults and a poor prognosis. Its symptomatology is non-specific and it is characterized by histopathological diversity. Diagnosis can be suggested by radiology and definitive diagnosis is achieved after pathological analysis. PMID- 29147175 TI - Expression of Cyclooxygenase-1 and 2 in Epithelial Ovarian Cancer: A Clinicopathologic Study. AB - Background: To examine the rate and degree of expression of Cyclooxygenase-1 (COX 1) and Cyclooxygenase-2 (COX-2) in epithelial ovarian cancer (EOC) and associated with clinicopathological factors and survival. Methods: EOC patients being treated in our institute with available pathological tissue sections during 1996 2003 were identified. Immunohistochemical staining with antibody to COX-1 and COX 2 were studied. Degree of expression was categorized into low and high levels. The degrees of immunohistochemistry staining were associated with clinicopathological factors and overall survival. Results: A total of 107 patients were included in the study. Most of patients had stage 1 and 3, and the most common histology type was serous carcinoma. The expression rate of COX-1 and COX-2 was 83.2 % and 95.3 %, respectively. Non-mucinous tumor had significant higher level of expression of both COX-1 and COX-2. Except for a high level of expression of COX-2 in association with better response to chemotherapy, no significant association with other clinicopathologic factors were observed. Level of COX-1 or COX-2 expression did not associate with progression-free and overall survival. The combination of COX-1 and COX-2 level was analyzed and the combination of high COX-1 and low COX-2 level significant associated with short progression-free and overall survival. Conclusion: EOC in our study showed high rate of COX-1 and COX-2 expression, especially in non-mucinous tumors. High level of COX-2 associated with better response to chemotherapy. Neither COX-1 nor COX-2 expression showed association with survivals while combination of high COX-1 and low COX-2 level of expression was associated with poor progression-free and overall survivals. PMID- 29147176 TI - Results of Treatment of Squamous Cell Carcinoma of Maxillary Sinus: A 26-Year Experience. AB - Background: Five-year survival in squamous cell carcinoma of maxillary antrum is low. This article examines the results of various approaches to treatment as given in our hospital in past 26 years. Methods: From 1979 to 2005, 379 patients with squamous cell carcinoma of maxillary antrum managed with curative intent were studied. Twenty-eight patients had T2, 237 patients had T3, and 114 had T4 tumors. The N classification was N0 in 316 patients, N1 in 21 patients, N2a in 28 patients and N2b in 14 patients. Treatment to the primary site comprised of surgery (Sx) and radiation therapy (RT) in 284 patients, RT alone in 57 patients and chemotherapy (CTx) with radiotherapy in 38 patients. Results: There was a difference in survival between patients who underwent Sx with RT compared with patients who received RT alone or CTx with RT. The most common pattern of recurrence was in the primary site, 187 (49.3%) patients. Local control at 3 and 5 years was 71% and 63.8% respectively in Sx with RT, 31.6% and 28% respectively in RT, and 28.9% and 26% in CTx with RT group. Conclusions: The type of treatment to the primary site is an important determinant of survival and local control. Surgery with radiation is a better treatment option. PMID- 29147177 TI - Analysis of Survival Rates of Patients Diagnosed With Incipient Esophagic Cancer. AB - Background: Esophagic cancer incidence is extremely variable worldwide. Also, the global survival rate has not oscillated significantly since last decade. Most of the worse prognoses are found among patients with advanced stages. Despite that, around 10% of cases occur in patients with initial stage, which strongly associate these patients with unfavorable prognosis. We sought to analyze the impact of time free of disease and global survival rates of patients with initial stage of esophagic cancer. Methods: We studied 18 patients with initial stage of esophagic cancer (stage 0 and I), examined and treated at Hospital de Cancer de Barretos between 1990 and 2005. Results: The vast majority of patients were male (83.3%) with age up to 49 yarest old (77.8%), squamous cell carcinoma (SCC) (88.9%) and stage I (83.3%). Most of them were smoker (60.0%) and etilist (62.5%). There were 38.9% of the patients with comorbities like dysphagia and epigastralgia correlated to other pathological conditions. We found free disease rates of 100% and 82.5%, respectively for 12 and 36 months. The significant prognostic evidence was the age, epigastralgia symptoms and chemotherapy. From 18 patients, 6 passed away during the period of 36 months follow up due to cancer consequences. The probabilities of global survival were 76.7% and 64.4% after 12 and 36 months, respectively, and none of the analyzed variables influenced in theses rates. Conclusions: Our data ratifies those from previous reported. The global survival rates were worse than reported by literature, maybe in consequence of the poor clinical condition of many patients which limited the option for more aggressive therapy. PMID- 29147178 TI - In Situ and Invasive Ductal Carcinoma Within a Borderline Phyllodes Tumor. AB - A rare case of a borderline phyllodes tumor with simultaneous intraductal and infiltrating duct carcinoma is reported. The patient was a 52-year-old woman with a breast tumor detected by physical examination. A simple mastectomy was performed. The excised tumor had a macroscopic appearance of a phyllodes tumor. After histological examination, the diagnosis of ductal carcinoma within a borderline phyllodes tumor was made. Immunohistochemical staining revealed that the epithelial component was positive for Epithelial Membrane Antigen and cytokeratin. No metastasis was detected in the axillary lymph nodes and the patient didn't receive any adjuvant therapy. No recurrence or metastasis has been observed 38 months after the surgery. PMID- 29147179 TI - Synchronous Bilateral Benign Phyllodes Tumor of the Breast in a 32-year-old Woman. AB - Bilateral phyllodes tumors are distinctly uncommon. As some previous reports have described, most of them are malignant and asynchronous. We report a new case of bilateral synchronous phyllodes tumor in a 32-year-old women. Both tumors were classified as benign after large bilateral excision. No tumor recurrence was noted during the 10 months follow-up. PMID- 29147180 TI - Primary Subcutaneous Ewing Sarcoma Presented as Pseudo Aneurysmal Subcutaneous Tumor. AB - Background: Extraskeletal Ewing's sarcoma is a rare malignant tumor of mesenchymal origin, which is histologically similar to primary osseous Ewing's sarcoma. It has been well described in deep soft tissues. However, location in cutaneous or subcutaneous tissue has rarely been reported. Being seen principally in children, it can be seen, rarely, in old men. Case report: We present a case of subcutaneous Ewing sarcoma within the left shoulder of a 49-year-old man, without osseous involvement. Physical examination suggested a vascular tumor. Histologically, it was a small round cell tumor that marked strongly for CD99. The diagnosis of subcutaneous Ewing sarcoma was performed. Conclusion: Ewing sarcoma is a rare malignant small round cell tumor of the skin and subcutaneous tissue. It should be differentiated from other cutaneous neoplasms composed of small round cells. PMID- 29147181 TI - Acute Shoulder Monoarthritis in a Patient With Acute Myelomonocytic Leukemia With Novel Translocation t(5;13). AB - We present the case of a patient with acute myelomonocytic leukemia with trisomy 8 and novel translocation t(5;13). In addition to acute leukemia she had debilitating left shoulder arthritis due to granulocytic sarcoma formation in the joint space. Her shoulder pain did not improve during induction chemotherapy but she experienced rapid relief of symptoms with use of local radiation. Her leukemia was found to be primary refractory to chemotherapy and despite an attempt at salvage therapy she died 2 months after diagnosis. PMID- 29147183 TI - F-18-FDG and C-11-Choline Positron Emission Tomography in Human Esophago-Gastric Cancer: Prediction of Response to Therapy. AB - Background: To determine the utility of F-18-FDG and C-11-Choline uptake, in patients with esophageal and esophago-gastric junction tumors who are to undergo either neo-adjuvant or palliative chemotherapy, in predicting response (pathological and survival). Methods: Eighteen patients with biopsy proven cancer were recruited prospectively. Patients underwent PET imaging before and during the first cycle of chemotherapy (seven and 14 days) with both F-18-FDG and C-11 Choline. Tracer uptake was quantified using Standardized Uptake Values. Pathological tumor response was determined using the Mandard criteria. Cellular proliferation was determined using ki-67 immunohistochemistry. Relationships between tracer uptake and response, one-year survival and cellular proliferation were determined. Results: All 18 tumors were imaged by F-18-FDG PET compared to 16/18 with C-11-Choline. Change in uptake of either tracer did not correlate with pathological response. Pathological response did not influence survival (median survival, responders = 16.1 months; non-responders = 19.0 months, p = 0.978). There was no significant correlation of change in tracer uptake with survival. C 11-Choline tumor uptake did not correlate with cellular proliferation. Conclusion: F-18-FDG PET is superior for imaging of the primary tumor. Neither F 18-FDG nor C-11-Choline PET was able to predict response accurately. PMID- 29147182 TI - Tumors of the Pancreatic Body and Tail. AB - Tumors of the pancreatic body and tail are uncommon. They have a propensity to present late and often attain a large size with local invasion before they produce any clinical symptoms. The current review aims at comprehensively analysing these tumors with respect to their pathology, presentation, the investigation of these tumors, and finally the latest trends in their surgical and medical management. PMID- 29147184 TI - Sesamin Induces Human Leukemic Cell Apoptosis via Mitochondrial and Endoplasmic Reticulum Stress Pathways. AB - Background: Sesamin is a purified compounds extracted from the seeds of Sesamum orientale Linn., which contains antioxidant and anticancer activities. The objective of this study was to identify the mechanistic effect of sesamin on human leukemic HL-60, U937 and Molt-4 cell apoptosis. Methods: The cytotoxicity was performed by 3-(4,5-dimethyl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Reactive oxygen species was measured by employing 2', 7' dichlorodihydrofluorescein diacetate and flow cytometry. The mitochondrial transmembrane potential was determined by 3,3'-dihexyloxacarbocyanine iodide and flow cytometer. Caspase-3 and -8 activities were detected by using fluorogenic DEVD-AMC and IETD-AMC substrates, respectively. The protein expression of cytochrome c and GADD153, an endoplasmic reticulum (ER) stress protein, was illustrated by immunoblot. Results: Sesamin was cytotoxic to HL-60 > U937 > Molt 4 > PBMCs and caused the three cell lines to die with the morphology of apoptotic character, i.e., condensed nuclei and apoptotic bodies. It produced reactive oxygen species in all cell lines, with a decrease in mitochondrial transmembrane potential. The caspase-3 activity was increased in sesamin-induced HL-60 cell apoptosis whereas casase-8 activity did not alter. Cytochrome c release was not increased. The expression of GADD153 was increased time dependently, indicating the involvement of ER stress pathway in HL-60 cells. Conclusions: Sesamin-induced human leukemic cell apoptosis was via oxidative stress, the mitochondrial and ER stress pathways. PMID- 29147185 TI - Nutritional Status After Total Gastrectomy for Gastric Cancer. AB - Background: Gastric cancer is one of the most frequent causes of death secondary to cancer in the world. Surgery is the only potentially curative treatment but its clinical consequences are significant. The objective of this study is to evaluate the nutritional state of patients with a total gastrectomy secondary to gastric adenocarcinoma. Methods: We designed a descriptive study with a transversal cut in our institution. We included 22 patients which had a minimum evolution time of six months after total gastrectomy secondary to gastric cancer surgery was performed. Neither of them had metastasis. The nutritional analysis included only biochemical data. Descriptive statistics were used for statistical analysis. Results: Eight females and 14 males were included in the study. Median age was 57 years (34 - 69 years). The 74% of the patients were underweight and none of them was overweight. The average body mass index (BMI) was 16.88 kg/m2. Eleven patients suffered from mild anemia (10.5 - 12 g/dl) and 5 from moderate anemia (9 - 10.5 g/dl). Only two patients presented severe anemia (less than 9 g/dl). The 58% presented hypoproteinaemia and hypoalbuminaemia. The main post surgery complication was nausea (46%). Seventy-eight percent of the patients had loss of appetite. Twenty-one patients were able to walk without help and leave their homes. Conclusions: The incidence of anemia in these patients was very high. In most of the patients, albumin and proteins levels were affected too. So malnutrition was a relevant consequence of a total gastrectomy. PMID- 29147186 TI - Lymphoepithelial Carcinoma of the Nasal Cavity With EBV Infection in a North African Man. AB - We report the case of a 58-year-old Tunisian man who presented with a 2 months' history of left nasal obstruction and one episode of epistaxis. Nasal endoscopy revealed a polypoid mass of the left nasal septum. Magnetic resonance imaging showed a left nasal cavity tumor with erosion of the orbit. Diagnosis of nasal cavity lymphoepithelial carcinoma EBV positive was performed on biopsy. The patient was treated by chemotherapy and radiotherapy. No tumor recurrence has been reported with a follow-up of 12 months. PMID- 29147187 TI - Retroperitoneal Inflammatory Myofibroblastic Tumor: Case Report and Immunohistochemistry Study. AB - Inflammatory myofibroblastic tumors (IMT) are a rare clinicopathological entity of yet unknown etiology and those located retroperitoneally are even rarer. Clinical outcome is unpredictable and complete surgical resection of the tumor remains the principal treatment. We report the case of a 41-year old man presented with abdominal pain. An abdominal magnetic resonance imaging scan revealed a retroperitoneal tumor located between the pancreas, stomach small curvature and big vessels. A laparotomy with biopsy was performed because the tumor was not amenable to surgical resection. Histopathological examination concluded to an IMT with overexpression of protein p53. Epstein-Barr virus and Human Herpesvirus-8 investigation was negative. Postoperative outcome was unfavorable. PMID- 29147188 TI - Small Cell Carcinoma in the Mammary Gland: Primary or Metastatic? A Diagnostic Challenge. AB - Metastatic tumours to the mammary gland are relatively uncommon as compared to primary breast malignancies. Such lesions can pose diagnostic dilemmas for both the clinician and the pathologist because it is often difficult to categorize the tumour as primary or secondary and to determine the site of origin. We present the case of a thirty year old female who was diagnosed with small cell neuro endocrine carcinoma in the mammary gland, probably of pulmonary origin. The diagnostic challenges posed by such a case are highlighted. PMID- 29147189 TI - Intraperitoneal Alpha-Radioimmunotherapy of Advanced Ovarian Cancer in Nude Mice Using Different High Specific Activities. AB - Background: The aim of this study was to investigate the therapeutic efficacy of advanced ovarian cancer in mice, using alpha-radioimmunotherapy with different high specific activities. The study was performed using the monoclonal antibody (mAb) MX35 F(ab')2 labeled with the alpha-particle emitter 211At. Methods: Animals were intraperitoneally inoculated with >=1 * 107 cells of the ovarian cancer cell line NIH:OVCAR-3. Four weeks later 9 groups of animals were given 25, 50, or 400 kBq 211At-MX35 F(ab')2 with specific activities equal to 1/80, 1/500, or 1/1200 (211At atom/number of mAbs) for every activity level respectively (n = 10 in each group). As controls, animals were given PBS or unlabeled MX35 F(ab')2 in PBS (n = 10 in each group). Eight weeks after treatment the animals were sacrificed and the presence of macroscopic tumors was determined by meticulous ocular examination of the abdominal cavity. Cumulated activity and absorbed dose calculations on tumor cells and tumors were performed using in house developed program. Specimens for scanning electron-microscopy analysis were collected from the peritoneum at the time of dissection. Results: Summing over the different activity levels (25, 50, and 400 kBq 211At-MX35 F(ab')2) the number of animals with macroscopic tumors was 13, 17, and 22 (n = 30 for each group) for the specific activities equal to 1/80, 1/500, or 1/1200, respectively. Logistic regression analysis showed a significant trend that higher specific activity means less probability for macroscopic tumors (P = 0.02). Conclusions: Increasing the specific activity indicates a way to enhance the therapeutic outcome of advanced ovarian cancer, regarding macroscopic tumors. Further studies of the role of the specific activity are therefore justified. PMID- 29147190 TI - Correlation Between Anthropometric Measures and Biomarker Changes After Neoadjuvant Therapy With Tamoxifen or Anastrozole in Postmenopausal Women With Breast Cancer. AB - Background: Epidemiological studies have reported positive associations between anthropometric measures and risk for developing breast cancers that express hormone receptors and associated mortality. However, the impact of nutritional status on the molecular response to endocrine therapy has yet to be described. Methods: Body mass index (BMI), waist circumference (WC), hip circumference (HP), and waist-to-hip ratio (WHR) were measured in patients with invasive ductal carcinoma (IDC) before and after neoadjuvant treatment with either tamoxifen or anastrozole, and a possible correlation with prognostic factors, as estrogen receptor (ER), progesterone receptor (PgR), and proliferative index (Ki-67), was analyzed. Fifty-seven patients with palpable ER-positive IDC were randomized into three neoadjuvant treatment groups and received anastrozole or placebo or tamoxifen for twenty-one days. Biomarker status was obtained by comparing the immunohistochemical evaluation of samples collected before and after treatment, using the Allred scoring system. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS). Results and Conclusions: After treatment, the anastrozole group showed reduced ER and PgR expression (p < 0.05), and both the anastrozole and tamoxifen groups showed lower Ki-67 status. A significant reduction in PgR positivity (p < 0.05) was found in women with large WC and HC who were treated with anastrozole. Reduction in PgR positivity also tended to be associated with BMI (p = 0.09) in the anastrozole group. BMI, WC, HC and WHR correlated neither with biomarker levels in the tamoxifen and placebo groups nor with ER and Ki-67 status in the anastrozole group after primary endocrine treatment. PMID- 29147191 TI - Correlation Between Immunohistochemical Biomarkers Expression and Prognosis of Ovarian Carcinomas in Tunisian Patients. AB - Background: Ovarian cancer is the leading cause of death from gynaecological malignancies. Newer biological prognostic factors and predictors of response to therapy are needed. Our study was designed to evaluate the expression of p53, Bcl 2, Estrogen receptor (ER) and Progesterone receptor (PR) in ovarian carcinoma and to compare it with other prognostic parameters such as age, FIGO stage, size of residual tumor, histological type and grade. Methods: This is a retrospective study conducted in the department of pathology at Sfax University Hospital. Confirmed 57 cases of ovarian carcinoma were reviewed in the period between January 1995 and December 2006. We used immunohistochemistry to evaluate the expression of p53, Bcl-2, ER and PR receptors and Chi-Square and Student test to correlate immunohistochemical findings with some prognostic parameters of ovarian carcinoma. Results: The percentage of expression of p53, Bcl-2, ER and PR was 73,7; 47,4; 35,1 and 33,3 % respectively. p53 overexpression correlated with an advanced FIGO stage (p = 0,026) and presence of ascitis (p < 10-4). The expression of PR was associated with an early stage (FIGO I and II), a non serous histologic type and a low tumour grade (p = 0,045; 0,010 and 0,036 respectively). No correlation was found between Bcl-2 and ER and prognostic parameters. Survival analysis revealed that Bcl-2 status, FIGO stage, presence of ascites, peritoneal cytology, and residual disease were significant predictive factors of survival. Conclusion: p53 expression correlates with a worse prognosis in epithelial ovarian cancer, whereas Bcl-2 expression is related to a better outcome. For hormonal status, expression of PR is found to be an independent indicator of favourable prognosis. These results should be supported by more and larger studies. PMID- 29147192 TI - Phyllodes Tumors of the Breast: A Review of 26 Cases. AB - Background: Phyllodes tumors of the breast are rare and locally aggressive neoplasms. Our study aimed to report the experience of the Farhat Hached Hospital (Sousse, Tunisia) acquired during a 7-year period and to give an additional review of the available literature. Methods: The authors analyzed retrospectively clinical, radiological, histopathological and therapeutic features as well as outcome in a series of 26 cases diagnosed as phyllodes tumors of the breast at the Pathology Department of Farhat Hached Hospital, Sousse, Tunisia, from 2003 to 2009. The slides were reviewed in order to classify the tumors into benign, borderline and malignant on the basis of the criteria proposed by the World Health Organization. Results: All the cases occurred in women. The analysis of this series showed the following characteristics: mean age at diagnosis was 40 years (19 - 66), tumor size was 1.5 - 40 cm (mean: 7.8 cm); the chief complaint was a mammary mass; the right breast was affected in 14 cases, the upper outer quadrant was the most commonly involved site (42.3%); surgical treatment was used in all cases, 21 patients (80.8%) were treated conservatively (13 benign, 6 borderline, and 2 malignant) and 5 (19.2%) by radical surgery (1 borderline and 4 malignant); seven patients underwent post-operative radiotherapy; in 14/19 cases (73.7%), a good correlation was observed between intraoperative frozen section analysis and definitive histology; the tumor was classed as benign in 13 cases (50%), borderline in 7 cases (27%) and malignant in 6 cases (23%); follow-up data was available in 22 cases; the rate of recurrence was 23% (1 benign, 3 borderline, and 2 malignant) after a mean follow-up of 13.6 months; all the recurrent tumors were initially treated by lumpectomy and were close to margin at the initial pathologic examination; the treatment of recurrences consisted of simple mastectomy in 5 cases, and local excision in one case; three patients developed metastases, one of whom after recurrence; three patients have died. Conclusions: This is a substantial single institution experience of a rare tumor. Phyllodes tumors of the breast have an unpredictable outcome, thus a wide local excision, with an adequate margin of normal breast tissue, is the preferred initial therapy. PMID- 29147193 TI - Soft Tissue Metastases as the First Clinical Manifestation of Squamous Cell Carcinoma of the Esophagus: Case Report. AB - Soft tissue metastases are an uncommon presenting feature for primary solid tumours. This case highlights a rare presentation in which a soft tissue mass is the first clinical manifestation of a widespread disseminated malignancy of the esophagus. A 73-year-old woman presented with a soft swelling in the left upper quadrant of the abdomen arising from the anterior abdominal wall, suspicious of liposarcoma. Core biopsies revealed squamous carcinoma. Immunohistochemistry suggested the most likely diagnosis was that of metastatic carcinoma with a number of potential primary sites. Computed tomography scanning showed widespread metastatic disease, including lung, liver, kidney, omentum, subcutaneous and intramuscular lesions. The distal esophagus was noted to be circumferentially thickened. Finally, upper gastrointestinal endoscopy revealed carcinoma of the esophagus. The patient remains well awaiting esophageal stenting and palliative chemotherapy. In conclusion, it is important to be able to distinguish the origin of a soft-tissue swelling as the management will depend significantly on the histological type. Soft-tissue metastases are rarely encountered as a presenting sign of an occult cancer. Primary cancers that most commonly metastasise to soft tissues include those arising within the lung, colon and kidney. The most frequent histological diagnosis is adenocarcinoma. This case demonstrates the utility of biopsy in the investigation of soft tissue masses when the clinical presentation is unusual. PMID- 29147194 TI - A Case of Ovarian Clear Cell Carcinoma Simultaneously Producing Parathyroid Hormone-related Protein and Granulocyte Colony-Stimulating Factor. AB - We describe the first report of an ovarian clear cell carcinoma simultaneously producing parathyroid hormone-related protein (PTHrP) and granulocyte colony stimulating factor (G-CSF). A 64-year-old woman complained of general fatigue, loss of appetite, nausea, vomiting and constipation. The results of blood and biochemistry tests were white blood cell count of 21,060 /ml and calcium of 18.0 mg/dl, indicating an increase in the number of leukocytes and hypercalcemia. A computerized tomography scan showed a tumor in the lower abdomen with a maximum diameter of 16 cm and containing both cystic and solid parts. There was a remarkable elevation of the tumor marker CA 19-9, to 1611 IU/ml, and serum level of PTHrP was elevated to 25.9 pmol/ml. The PTH-intact level was 14 pg/ml, which was at the lower limit of the normal range. In addition, the G-CSF level was also elevated to 73 pg/ml (normal range: <38 pg/ml). Since hypercalcemia caused by tumor PTHrP production was suspected, and as this required elimination of the primary disease, extirpation of the tumor was carried out. Serum calcium levels promptly returned to 11.1 mg/ml on the first day following surgery, and PTHrP also dropped to its normal level on the same day. Histological and immunohistochemical examinations revealed that the tumor was clear cell adenocarcinoma which was partially positive for PTHrP and positive for G-CSF, indicating the tumor simultaneously producing PTHrP and G-CSF. PMID- 29147195 TI - Radiation Induced Leiomyosarcoma Three Decades After Treatment for Wilms' Tumor. AB - Wilms' tumor is one of the most common pediatric malignancies. Survival rates have increased dramatically over the last few decades. This increased survival means that there is an ever growing population of patients susceptible to the late effects of their initial therapy. Survivors of Wilms' tumor have a substantially higher rate of development of secondary neoplasms compared to general population. We report a case of metastatic radiation induced leiomyosarcoma thirty years after therapy for Wilms' tumor. This case highlights the need for minimizing the risk of late complications and for close surveillance to enable early detection of these complications. PMID- 29147196 TI - Metachronous Testicular Germ-cell Tumors: The Importance of a Long-Term Follow up. AB - Testicular germ cell tumors (TGCT) are the most common malignancy in young male adults. They can be bilateral, and occur as a synchronous or metachronous tumor. The authors intend to characterize the prevalence and outcome of metachronous TGCT in the last 12 years of experience at our center. Cancer data base of our center was reviewed in order to find the patients that had TGCT in the period between 1996 and 2008 and, among those, the patients that had a second malignancy in the contralateral testicle after at least 6 months apart. Risk factors, clinical presentation, histological characteristics, staging, therapy and outcome were considered. Two out of 79 patients had metachronous TGCT, representing 2.5% of the group. Both cases had a low stage malignancy at the time of the diagnosis of the first tumor, and the diagnosis of the second TGCT happened 7 and 12 years later. Both patients are still alive without evidence of residual disease, under androgen replacement therapy and with testicular bilateral prostheses. Sperm cryopreservation was done in one of the patients. Long-term surveillance for TGCT is needed due to the probability of a second malignancy after the first 5 years of normal follow up. Special consideration must be given to patients submitted to bilateral orchiectomy concerning sperm cryopreservation, androgen replacement therapy and testicular prostheses. PMID- 29147197 TI - Pure Small Cell Carcinoma of the Bladder: A Case Report. AB - Small cell carcinoma of the urinary bladder is an uncommon tumor that has been described in case reports or small series. We report a new case in a 67-year-old male who presented with gross hematuria and irritative symptoms. Cystoscopy revealed an extensive mass of the bladder and computed tomography scan showed an important thickening of the bladder wall. Diagnosis of small cell carcinoma was established after radical cystectomy and microscopic examination. The patient received pelvic hemostatic radiotherapy and platinium-based chemotherapy. Three months after the diagnosis, he developed bone, renal and adrenal metastases. PMID- 29147198 TI - Unusual Metastases in Renal Cell Carcinoma: A Single Institution Experience and Review of Literature. AB - Background: To report location and management of atypical metastases from renal cell carcinoma (RCC) in the Instituto Nacional de Ciencias Medicas e Investigacion Salvador Zubiran (INCMNSZ) in Mexico City. Methods: Between 1987 to 2009, 545 patients with RCC were retrospectively identified at the INCMNSZ. Patients with unusual metastases confirmed by histopathology were analyzed. Epidemiological, clinical, diagnosis, treatment and outcome data were reviewed. Results: Sixty patients developed 98 unusual metastases secondary to RCC. The group was comprised of 35 men (58.3%), with a median age of 60 years at diagnosis. Metachronous unusual metastases with primary renal cancer were observed in 37 individuals (61.7%). Median time from primary RCC diagnosis to the first unusual metastasis was 16.5 months. Median survival from diagnosis of the first unusual metastasis to death was 5.0 months (CI 95%: 2.8-7.2 months). Patients with an initial solitary metastatic lesion in an unusual site (28.3%) had a better survival compared to patients who primarily presented with multiple metastases, 17.0 (CI 95%: 6.1-27.9) Vs 3.0 months (CI 95%: 0.9-5.1), p = 0.001. Unusual metastasis resection (21 patients) improved survival, 25.0 (CI 95%: 5.1 44.9) Vs 3.0 months (CI 95%: 0.8-5.2), p < 0.0001. No survival difference was observed between localization of unsual metastases (p = 0.72). Conclusions: In patients with advanced RCC we suggest an individual diagnostic and surgical approach to achieve complete resection with disease-free margins, even in the presence of unusual metastatic sites, multifocality, or history of metastasectomy. These strategy might provide not only palliation for symptoms, but an opportunity for meaningful disease free and overall survival. PMID- 29147199 TI - Role of Radionuclide Therapy as Adjuvant to Palliative External Beam Radiotherapy for Painful Multiple Skeletal Metastasis. AB - Background: The aim of this study was to evaluate the palliative efficacy of localized external radiotherapy (RT) combined with systemic radionuclide (RN) therapy in patients who had multiple painful osseous metastases of different primary origins. Methods: Thirty-three patients initially local external radiotherapy was delivered to the most symptomatic region in all patients. Then they received either Re 186 HEDP or Sm 153 EDTMP. The performance status was assessed according to ECOG scale. Before treatment, at the end of the radiotherapy and after the four weeks of systemic radionuclide therapy, analgesic intake and pain status were recorded by the RTOG scoring system, and EORTC QLQ C30 (Version 3.0 Turkish) questionnaire was performed to evaluate the quality of life. Results: Improved performances of 33.3% for post radiation therapy and 50% for post radionuclide therapy in the ECOG scale were observed. Statistically significant correlations were found between the primary origins and decreased pain and analgesic intake (p < 0.05), but no differences were observed on the self assessment quality of life questionnaire. Conclusions: Both Re 186 HEDP, Sm 153 EDTMP are effective and safe in bone pain palliation as an adjuvant to local field radiation therapy of breast and prostate cancer patients, who also continued to receive chemotherapy and/or hormontherapy. PMID- 29147200 TI - Clinical and Pathological Response to Neoadjuvant Anthracycline Based Chemotherapy in women with breast cancer. AB - Background: Neoadjuvant chemotherapy has been used as a primary treatment for locally advanced or inflammatory breast cancer, and recently extended to operable breast cancer. The aim of this study was to evaluate the predictive value of different histologic factors in breast cancer treated with neoadjuvant anthracycline chemotherapy in Tunisian women. Methods: A total of 109 stage II and III breast cancer patients who received neoadjuvant anthracycline chemotherapy were enrolled in this study. Using pretreatment biopsy materials, histologic grade was recorded and immunohistochemical studies were performed for estrogen receptor, progesterone receptor and Her2neu. We analyzed the associations among this histologic factors and clinical and pathological complete response. Statistical analysis used is SEM logiciel. Results: The overall clinical response was 63% (clinical partial response in 49% of cases and clinical complete response in 14% of cases). The pCR was 7%; in univariate analysis, clinical response rate by each factors were as follows: 63% in ER-positive tumors, 84% in ER-negative (P = 0.2), 59% in PgR-positive, 62% in PgR-negative (P = 0.3), 64% in HER2-positive, 62% in HER2-negative (P = 0.6), 60% in tumors of low nuclear grade and 63% in ones of high nuclear grade (P = 0.9). Conclusions: Biological markers that reliably predict clinical and pathological response to primary systemic therapy may have considerable clinical potential. The future of neoadjuvant therapy lies in tailoring treatment to individual patients by identifying response predictors. PMID- 29147201 TI - Carboplatin Induced Fatal Autoimmune Hemolytic Anemia: First Reported Case. AB - Carboplatin is an alkylating anti-neoplastic drug used in various cancers especially ovarian cancer, germ cell tumors, endometrial cancer besides others. We present a case of acute autoimmune hemolytic anemia during Carboplatin infusion in a patient previously exposed to the drug, resulting in the death of the patient. Published reports of Carboplatin induced autoimmune hemolytic anemia suggest these are usually nonfatal and improve after discontinuation of the drug. Fatal autoimmune hemolysis from Carboplatin has not been reported to the best of our knowledge. A 77-year-old Caucasian lady with history of endometrial adenocarcinoma was receiving treatment with a combination of Carboplatin and Paclitaxel for recurrent adenocarcinoma presenting as a pelvic mass. She tolerated similar chemotherapy previously, except for mild side effects. During her fifth cycle of chemotherapy with Carboplatin, she suddenly collapsed in the infusion center. Despite aggressive treatment, she expired within seven hours. A direct Coomb's test was found to be positive. Carboplatin dependent antibody was also detected. She was felt to have had a Carboplatin-induced fatal hemolytic anemia. Acute autoimmune hemolytic anemia with Carboplatin is rare but could be a devastating complication. A sudden drop in hemoglobin during Carboplatin infusion should alert clinicians of this extremely fatal possibility. PMID- 29147202 TI - Renal Medullary Carcinoma is a Diagnosis Worth Considering: Case Report. AB - Medullary Renal Carcinoma is a rare, highly malignant neoplasm that originates in the renal medulla and typically affects young black patients with sickle cell trait. We report the case of a 17-year-old boy with a symptomatic left renal tumour. CT revealed that the mass originated from the kidney and was associated with a large para-aortic lymph node mass. Hemoglobin electrophoresis showed sickle cell trait and a needle biopsy confirmed the diagnosis of Renal Medullary Carcinoma. We discuss the obscurity and implications of such a diagnosis. It is essential that clinicians are aware of this diagnosis as any delay can be fatal in the outcome of this highly aggressive and extremely rare cancer. PMID- 29147203 TI - Peritoneal Malignant Psammomatous Mesothelioma. AB - Psammoma bodies (PBs) are observed most commonly in papillary thyroid carcinoma, meningioma, and papillary serous cystadenocarcinoma of the ovary. We report one case of peritoneal malignant mesothelioma (PMM) with massive deposition of PBs. A 72-years-old man presented with abdominal swelling and marked weight loss. Contrast enhanced computed tomography showed fluid diffuse in peritoneal recesses, thick septa with micronodules in the greater omentum and adjacent enhancement of the thickened peritoneum. The explorative laparoscopy showed diffuse minute parietal peritoneal nodules. The peritoneal biopsy revealed a superficial papillary growth of malignant epithelial-like cells with diffuse involvement of submesothelial tissues. Massive deposition of PBs was observed. Nuclear and cytoplasmic calretinin immunoreactivity was present in neoplastic cells along with membranous D2-40 and membranous/cytoplasmic cytokeratin 5 staining. The patient was treated with chemotherapy (gemcitabine, vinorelbine, cisplatin). PBs may represent an active biologic process ultimately leading to degeneration/death of tumor cells and retardation of growth of the neoplasm. It may also serve as a barrier against the spread of tumor. Psammomatous malignant mesothelioma may simulate serous psammocarcinoma of the peritoneum. The behavior of serous psammocarcinoma is more closely similar to borderline serous tumor than to serous carcinoma. Further studies are necessary to establish if massive deposition of PBs may define a new variant of psammomatous malignant mesothelioma with a favorable impact to the prognosis of usual psammomatous malignant mesothelioma, as well as in serous psammocarcinoma of the peritoneum. PMID- 29147204 TI - A Nasal Cavity Mucosal Melanoma Connected by Nasolacrimal Duct in a Patient with Multiple Co-morbidities: A Treatment Dilemma. AB - Nasal cavity is a rare site in melanoma and surgery plays important roles in its treatment. A mucosal melanoma penetrating through the nasolacriminal duct (NLD) into orbit in a patient with multiple co-morbidities poses some difficulties in its management. A 78 year-old man developed epiphora and ocular swelling in recent 1 week in his left eye. He had medical histories of hypertension, diabetes, chronic renal insufficiency and right middle cerebral artery infarction. Physical examination revealed left periorbital swelling, chemosis, lateral gaze impairment and a dark-colored mass in left nasal cavity. Mucosal melanoma was diagnosed by biopsy. Contrast enhanced T1-weighted MRI showed an enlarged hyperdense lesion in left nasal cavity which invades through the NLD and gets into left medial aspect of orbit with involvement of preseptal space and retrobulbar fat. The patient was treated with radiation therapy alone (450 cGY in 13 fractions) with partial response. Lung metastasis occurred 3 months later and the patient was alive with disease for 6 more months.Primary surgical resection has been the treatment of choice for mucosal melanoma. Radiotherapy in our patient was chosen for multiple co-morbidities. Neither local nor regional control was improved by this approach. Palliative chemotherapy in this situation could be the treatment of choice for patient's better quality of life. PMID- 29147205 TI - Twelve Years of Experience in the Management of Testicular Germ Cell Tumors at a Referral Center in Portugal. AB - Background: Testicular germ cell tumors (TGCT) are generally rare but quite frequent in young males. Guidelines are well established for their management. Methods: We present the first report from Portugal on clinical, histological, treatment modalities and outcomes of a population with TGCT. Data was retrospectively analyzed for the 1996 through 2008 period, applying a previous internally validated protocol. Results: Seventy nine patients with TGCT were identified, 40.5% had seminomatous and 59.5% nonseminomatous tumors. Incidence rates were higher among males in their twenties and thirties. Pain and swelling testis were the most common symptoms and microlithiasis was detected in 20.3% of patients. Lower stages were more frequent in seminomatous tumors. Orchiectomy was done in all patients and further therapy was performed by guidelines recommendations in 86.1% of them. Hematological toxicity was found in 44.3% of the population studied and free disease survival rates were at 88.6%. Conclusions: This retrospective study corroborates the European Western country trends concerning TGCT. Mortality was only seen in nonseminomatous TGCT group. Good risk and lower TGCT stages have no deaths reported. Public health campaigns should be undertaken to guide patients to seek medical advice earlier in the course of the disease. PMID- 29147206 TI - Antimetastatic Action of Pentoxifylline, a Methyl Xanthine Derivative, Through its Effect on PKC Mediated Integrin Transport in B16F10 Melanoma Cells. AB - Background: Integrins are adhesion molecules known to regulate cellular processes like adhesion, migration and proliferation. At the same time role of integrin in progress of cancer metastasis is well established, increased integrin expression is reported to be linked to high metastasis potential of cells. Pentoxifylline a methyl xanthine derivative is a potent antimetastatic agent. Studies on the mechanism of inhibition of lung homing of B16F10 melanoma cells by PTX shows that it can inhibit cell- Extracellular Matrix adhesion, cell surface integrin expression as well as Protein kinase C activity. Previous study from our laboratory have shown PTX treatment can selectively inhibit the cell surface expression of alpha5 integrin in B16F10 cells without affecting its total cellular protein levels. Numerous studies have documented that differences in surface expression and distribution of integrins affects metastasis. The purpose of present study is to observe the effect of PTX on cellular distribution/ redistribution of integrins and to study the underlying molecular mechanism of PTX action. Methods: Integrin internalization and transport was observed using immunofluorescence confocal microscopy. PKC activity was determined using MBP4-14 as a substrate. Immunoprecipitation and western blotting was used to show association between PKC and alpha5 integrin, cell adhesion assay was performed using fibronectin/fibrinogen as substrate. Results: Immunofluorescence studies showed that PTX treatment caused a redistribution of alpha5 integrins from the plasma membrane to a perinuclear compartment where it colocalized with Transferrin receptor and Rab-11 GTPase. Rate of integrin internalization and recycling showed that PTX inhibited the recycling of alpha5 integrins from perinuclear recycling endosomes. PTX is reported to affect kinases; here we showed that PTX inhibited total PKC activity. Association between alpha5beta1 integrin and PKC is studied using Immunoprecipitation which show that PTX affects alpha5beta1 integrin associated PKC activity without affecting the levels of PKC. Studying the effect of delay in integrin recycling on cell functionality showed that it affects spreading of cells on fibronectin/fibrinogen. Conclusions: Data in the present study shows that PTX interferes with PKC activity bringing about a change in integrin distribution, and there by affecting the functionality of the cell. And this may possibly serve as one of the mechanisms for antimetastatic action of PTX. PMID- 29147207 TI - Single Subcutaneous Nodule as Initial Presentation of Atypical Lung Carcinoid. AB - We report a 50-year-old woman whose atypical lung carcinoid presented as a single subcutaneous nodule. Biopsy of the nodule revealed neuroendocrine carcinoma likely from the lungs. Imaging studies revealed masses in lungs, pelvis and right axilla, and a seizure a few months later lead to discovery of brain metastasis. This case illustrates that an apparently innocuous subcutaneous nodule could be the initial presentation of an otherwise asymptomatic but widely metastatic atypical lung carcinoid. Physicians should be aware of signs of skin metastasis from lung malignancies and judiciously select patients with subcutaneous nodule for biopsy. PMID- 29147208 TI - Complete Radiographic Response to Zoledronic Acid Therapy in a Patient With Bony Metastatic Urothelial Carcinoma: A Case Report. AB - Zoledronic acid (ZA) is commonly used for the prevention of skeletal-related events (SREs) in patients with bony metastases. ZA is a bisphosphonate that inhibits osteoclasts, possibly through inhibition of proto-oncogenic Ras activity in osteoclasts by interfering with normal post-translational modifications of Ras. This would suggest that ZA could induce an objective tumor response in metastatic tumors in bone that harbor oncogenic Ras, as the oncogenic Ras in these tumors would require similar post-translational modifications. We recently cared for a patient with biopsy confirmed metastatic urothelial carcinoma who demonstrated a complete radiographic response to ZA. His tumor harbored an oncogenic K-Ras protein, supporting the possibility of interference with Ras activity as the mechanism for the radiographic complete response. PMID- 29147209 TI - Primary Leiomyosarcoma of the Male Breast. AB - We describe herein the third case of primary leiomyosarcoma of the breast in a 62 year-old man. Preoperative clinical examination and cytology findings indicated a leiomyosarcoma of the breast. A modified radical mastectomy was performed. Immunohistochemical analysis subsequently confirmed a diagnosis of leiomyosarcoma. After a follow-up period of 24 months, the patient is still in good health with no evidence of locoregional recurrence or distant metastasis. PMID- 29147210 TI - Sorafenib Improves Survival in Metastatic Hepatocellular Carcinoma: A Case Report. AB - Hepatocellular carcinoma (HCC) is a very common cancer. Curative treatments and local ones are well validated. Sorafenib, a multi-kinase receptor inhibitor was introduced in 2007 for advanced HCC in patients with preserved liver function. HCC is known to be resistant to systemic chemotherapy, and there are no validated therapies improving survival for metastatic disease. Herein, we report a case of a 45 years old woman with chronic hepatitis B infection submitted to a right hepatectomy in May 2001 for an hepatic tumor with more than 10 cm wide, confirmed as a HCC moderately differentiated. Three years later, a solitary pulmonary metastasis was documented and a metastectomy was done. In February 2009, the patient started on sorafenib 400 mg twice daily due to an inferior mediastinal metastasis with a vena cava thrombus associated. Computed tomography (CT) scan done 13 months after revealed a consistently mass reduction in more than 50% and a clinically well patient without important collateral effects. HCC is a highly vascularized tumor and sorafenib is known to inhibit both tumor angiogenesis and tumor cell survival. It is already approved for the treatment of advanced and metastatic renal cell cancer. In our case, the combination of two well done surgical procedures and the posterior use of sorafenib when a metastasis was found in an inaccessible surgical place with macroscopic vascular invasion, led to a long survival without important side effects. PMID- 29147211 TI - A Case of Metastatic Renal Cell Cancer Presenting as Jaundice. AB - Renal cell carcinoma is the second most common urological malignancy and it runs a highly variable clinical course. We describe a case of metastatic renal cell carcinoma in a 50-year-old lady with metastasis to the ampulla of Vater, clinically masquerading as cholelithiasis and biliary colic. The clinical, radiographic and endoscopic findings are presented. Ampullary metastases are rare, and prompt recognition and intervention are necessary before patient's performance status is compromised. PMID- 29147212 TI - Angiogenesis in Malignant Thyroid Tumors. AB - It is well known that radiation significantly impacts the morbidity of thyroid cancer and that is why Belarus has the highest incidence of the malignancy. Author describes statistical data, classification of angiogenesis, and typical pathological features of malignant thyroid diseases with regard to the vascular network. PMID- 29147213 TI - Topical Application of Hangeshashinto (TJ-14) in the Treatment of Chemotherapy Induced Oral Mucositis. AB - Background: The optimal treatment of chemotherapy-induced oral mucositis is not well established. A recent study showed that hangeshashinto (TJ-14) might be useful for periodontal disease via downregulating pro-inflammatory prostaglandins in the cyclooxygenase pathway in human. Our study aimed to determine whether TJ 14 is effective in the management of chemotherapy-induced oral mucositis. Methods: Fourteen patients afflicted with chemotherapy-induced oral mucositis during mFOLFOX6 or FOLFIRI treatment for metastasis of advanced colorectal cancer were randomly assigned to topical TJ-14 treatment thrice daily for 7 days. Patients prepared a 50 ml solution with 2.5 g of TJ-14 dissolved in tap water and rinsed their oral mucosa for more than 5 seconds and then expectorated it. TJ-14 was also topically applied with a cotton pellet on the mucosal lesions. The severity of oral mucositis was evaluated using the Common Terminology Criteria for Adverse Events version 4 before and after one-week TJ-14 treatment. Results: After the one-week topical treatment with TJ-14, thirteen of the fourteen patients (92.8 %) showed improvements in oral mucositis, with significantly decreased mean CTCAE grades (P = 0.0012). Compared to baseline, none of the patients' CTCAE grades worsened. The compliance of TJ-14-treatment was good and side effects from TJ-14 were not observed. Conclusions: Topical application of TJ 14 may have therapeutic effects in patients with chemotherapy-induced oral mucositis via downregulation of pro-inflammatory prostaglandins. A prospective, randomized, controlled, double-blind studies are necessary to confirm the findings of this open-label, pilot study. PMID- 29147214 TI - A Case-Control Study of TP53 R72P Polymorphism in the Breast Cancer Patients of Ethnic Kashmiri Population. AB - Background: TP53 R72P polymorphism has been proposed as a risk factor for breast cancer and is more likely to differ among different ethnic populations. We carried out the study to determine the role of R72P polymorphism in breast cancer patients of Kashmir, an ethnic population by PCR-RFLP. Methods: To evaluate the role of this polymorphism in our ethnic Kashmiri population, we devised our study to study its role in breast cancer patients and healthy controls. The contribution of TP53 R72P polymorphism in 130 breast cancer patients and 220 female healthy controls was assessed using a PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism). Results: We observed that women with PP genotype have increased risk for developing breast cancer. We found Pro/Pro genotype statistically significantly associated with dwelling, lymph node metastases, histopathological grade, and menopausal status. Pro/Pro genotype in cases and controls was observed and it was found that it is significantly associated with the breast cancer. Conclusions: Our findings suggest that TP53 R72P polymorphism is a risk factor in breast cancer. Furthermore, these results suggest Pro72 allele is associated with higher risk for breast cancer patients. Women with PP genotype have increased risk for developing breast cancer. PMID- 29147215 TI - Therapeutic Effect of Epigallocatechin-3-gallate (EGCG) and Silibinin on ATM Dynamics in Prostate Cancer Cell Line LNCaP. AB - Background: Epigallocatechin-3-gallate (EGCG) is a major ingredient of green tea (GT) and silibinin (SB), the active component of Silymarin presumably hold a potential to prevent pathogenomics. Prostate cancer exacerbation is triggered by fusion transcripts formed because of genomic instability induced by juxtapositioning of two genes. This chimeric transcript is implicated in androgen dependent and independent prostate cancer. Tremendous work is done on the characterization of the mediators involved in the disease refractoriness, yet no study has addressed clinical management of these prostate fusion transcripts impressively. Methods: An abolished ATM dynamics challenges integrity of DNA. In agreement with this assumption, ATM and DNA-PK were impaired in LNCaP cell line to confirm a tight interaction of these mediators with the expression profile of TMPRSS2-ERG. Abolished ATM enhanced the expression of the fusion transcript. Similarly blunting of DNA-PK downregulated the expression of the fusion transcript giving a notion that DNA-PK is involved in the chromosomal translocation. LNCaP cell lines were analyzed for the effect of EGCG and SB on the expression profile of TMPRSS2-ERG. Results: In this particular unprecedented study, treatment of the LNCaP cell line with EGCG and Silibilin recapitulated ATM expression and activity and downregulated the fusion transcript appearance. Conclusions: These results underscore the therapeutic effect of EGCG and SB in mitigating the exacerbation of the disease with reference to the fusion transcripts. PMID- 29147216 TI - Guillain-Barre Syndrome Associated with Gastric Cancer: Paraneoplastic Syndrome or Immunological Disorder? AB - Guillain-Barre syndrome is a rare clinical entity classified as an ascending muscle paralysis led by autonomic nervous dysfunction due to autoimmune damage of peripheral nerves. Paraneoplastic Guillain-Barre syndrome has been described in association with some kinds of tumors (B-cell Lymphoma and small cell lung cancer). We describe the case of a 74-year-old woman affected by gastric adenocarcinoma, treated with surgery and adjuvant chemotherapy, who developed simultaneously skin cancer relapse and severe Guillain-Barre syndrome. Although the timing of clinical presentation suggests a paraneoplastic origin, other interesting features were present in this patient such as familial and personal anamnesis for autoimmune disease, HCV infection, and neurotoxic chemotherapy. According to literature, we investigated different pathogenetic hypothesis. According to the poorness of data, further investigations are necessary to establish a relationship between Guillain-Barre syndrome and gastric cancer. PMID- 29147217 TI - Post-Irradiation Morphea in Breast Cancer: An Uncommon Differential Diagnosis to Keep in Mind. AB - Breast cancer is the most common cancer in women of developed countries. Early stage diagnosis is followed, in many cases, of conservative surgery and local radiotherapy. This treatment reduces loco-regional recurrences but may be accompanied by local complications. Morphea of the breast is an uncommon skin condition and has been described after radiotherapy. The inflammatory stage of morphea can commonly be mistaken for a local recurrence or inflammation. We report the case of a 51-year-old woman with breast cancer who underwent a conservative surgery with postoperative chemo and radiotherapy. She developed a sclerodermiform plaque with a biopsy that showed histopathological changes consistent with morphea. PMID- 29147218 TI - A Fatal Brain Stroke in Patient with Advanced Breast Cancer Treated with Bevacizumab: A Case Report. AB - Bevacizumab is a recombinant monoclonal antibody against vascular endothelial growth factor (VEGF) that is used to treat metastatic cancers of the colon, rectum, kidney, and breast. Its side effects include proteinuria, hypertension, gastrointestinal perforations, and arterial emboli. Although these toxic effects are more frequent in patients with atherosclerosis, their pathophysiology remains unresolved. We observed that patients treated with bevacizumab who developed hypertension had similar clinical presentations and biologic features, leading us to propose a unique mechanism for the vascular side effects of bevacizumab. We report a case of a woman treated for her metastatic breast cancer with first line chemotherapy with Paclitaxel plus bevacizumab who developed a brain stroke. PMID- 29147219 TI - Radiosensitivity and Capacity to Recover from Radiation-Induced Damage in Pimonidazole-Unlabeled Intratumor Quiescent Cells Depend on p53 Status. AB - Background: Using our method for selectively detecting the response of intratumor quiescent (Q) cells to irradiation, the Q cells was shown to have a much larger hypoxic fraction (HF) than total (= proliferating (P) + Q) tumor cell population irrespective of the p53 status of tumor cells. However, the size of the HF was clearly less than 100%, meaning the Q cell population was never fully hypoxic. Thus, the dependency of the radio-sensitivity and recovery capacity from radiation-induced damage on p53 status was investigated in pimonidazole-unlabeled oxygenated Q tumor cells. Methods: Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53), or with neo vector as a control (SAS/neo), were inoculated subcutaneously into left hind legs of Balb/cA nude mice. The tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor P cells. Tumors were irradiated with gamma-rays at a high dose-rate or a reduced dose-rate at 1 h after the administration of pimonidazole. The responses of Q and total cell populations were evaluated with the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of pimonidazole unlabeled tumor cell fractions was assessed with apoptosis frequency using immunofluorescence staining for pimonidazole. Results: The pimonidazole-unlabeled tumor cell fraction showed significantly enhanced radio-sensitivity compared with the whole tumor cell fraction more remarkably in Q cells and p53-mutated tumors than total cells and p53-wild type tumors, respectively. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay or a decrease in radiation dose rate, was more clearly observed in Q cells and p53-wild type tumors than total cells and p53-mutated type tumors, respectively. Concerning the whole tumor cell fraction, the Q cells showed significantly greater radio-resistance and recovery capacity from radiation induced damage than the total cells both in p53-wild and p53-mutated type tumors. Conclusions: The pimonidazole-unlabeled sub-fraction of the Q tumor cells, probably oxygenated, may be a critical target in the control of solid tumors, although its radio-sensitivity and recovery capacity from radiation-induced damage depend on p53 status of the tumor cell. PMID- 29147220 TI - Expression of HLA-I, CD8, and CD4 and Their Clinical Significance in Cervical Cancer. AB - Background: The local tissue immune status may play a role in the progression of cervical cancer. The aim of our study is to examine the expression of HLA-I, CD8 and CD4 in various cervical diseases and investigate their association with cervical cancer. Methods: We chose the tissues of cervical cancer, cervical intraepithelial neoplasia (CIN), chronic cervicitis and peri-cancer tissues, and then detected the expression of HLA-I, CD8 and CD4 using SP immunohistochemistry. The associations of the expression of HLA-I, CD8 and CD4 with the clinicopathologic profiles of the patients were analyzed. Results: The percentage of positive tissue staining of HLA class I antigen in cervical cancer, CIN, chronic cervicitis and peri-cancer tissues were 40%, 95%, 100.0% and 100.0%, respectively. And the percentage of CD8 in various tissues was 35%, 95%, 100% and 100.0%, respectively. The positive tissue staining percentage of CD4 in the tissues above was 45%, 80%, 100% and 100%, respectively. The percentage of positive tissue staining of HLA-I, CD8 and CD4 were significantly lower in tissues of cervical cancer when compared with other tissues (P < 0.01). No correlation between positive tissue staining of HLA-I, CD8, and CD4 and clinicopathologic profiles was observed (P > 0.05). A positive correlation was found between HLA-I and CD8 expression (Spearman's correlation rs = 0.913, P < 0.001). Conclusions: The expression of HLA-I, CD8 and CD4 are down-regulated or deleted in CIN and cervical cancer, and they may play important roles in the development and progression of CIN and cervical cancer. PMID- 29147221 TI - Evaluation of Serum Zinc Level Under Malignant Condition and its Possible Implication on Improving Cell-Mediated Immunity During Cancer Progression. AB - Background: Zinc is an essential trace element required for different biological functions in a living body. Evaluating its concentration and effect during malignancy is important not only to assess the disease activity but also to evaluate its role in some important biological activities like immunity. Methods: The experiments were carried out in transplanted, chemically induced and spontaneous tumors in mice. The serum zinc concentration (SZC) was determined under malignant condition and following treatment of solid tumor with anti-cancer agents. The importance of evaluating Cu/Zn ratio (CZR) was also determined. To evaluate its role in immune response during malignancy, studies were carried out on induced tumor bearing animals. Results: The results showed that SZC had an inverse correlation with the progression of the disease. It was significantly reduced in all forms of malignancy, more so in spontaneous and induced forms of the disease. Extensive studies done with the solid form of induced tumor, established the importance of estimating the concentration of Zn, in addition to that of copper, in assessing the disease activity following treatment with anti cancer agents. With regression of the tumor mass, there was a significant elevation in the SZC and depression in the serum copper concentration (SCC) compared to their levels prior to treatment. This was also reflected on the value of copper zinc ratio (CZR); with the onset of tumor regression, a significant reduction in CZR was noted in the tumor bearing animals compared to their untreated levels. As the state of 'regression' in the tumor mass was maintained for a considerable period of time following treatment with anti-cancer agents along with elevated zinc levels, we considered the role of zinc in controlling the tumor growth, indirectly. We observed that zinc is able to stimulate lymphocyte proliferation that may directly impact on the immune response of tumor bearing host. Conclusions: Zinc appears to play a role in tumor progression and regression and in stimulating lymphocyte proliferation. It is hypothesized that supplementing zinc to malignant subjects prior to and following therapeutic intervention with anti-cancer agents could help improve immune response of the host against existing tumor. PMID- 29147222 TI - Metastatic Colon Cancer to the Thyroid Gland in the Setting of Pathologically Diagnosed Papillary Thyroid Cancer: A Review and Report of a Case. AB - Colon carcinoma metastases to the thyroid are a rare phenomena. Here we report a case of multiple malignant neoplasms where an incidental diagnosis of colon cancer was made after pathologic evaluation of the thyroid specimen. PMID- 29147223 TI - Hepatocellular Carcinoma and High Grade Neuroendocrine Carcinoma: A Case Report and Review of the Literature. AB - We describe a rare hepatic collision tumor composed of a hepatocellular carcinoma and a high-grade neuroendocrine carcinoma. The patient, a 68-year-old man, underwent a partial hepatectomy because of a 4.0 cm mass. The tumor had two distinctive patterns. The majority of the tumor was a high-grade neuroendocrine carcinoma with features of a small cell carcinoma that was positive for chromogranin, synaptophysin, and cytokeratin 19 and negative for hepatocellular antigen and alpha-fetoprotein (AFP). The second component was a moderately differentiated hepatocellular carcinoma that was positive for hepatocellular antigen and AFP and negative for neuroendocrine markers. The two tumors were separated by fibrous bands. In areas where they collided, there was no transition or intermingling of cells between the two components, thus, it is different from the combined type of tumors. After removal of the tumor, the patient underwent four courses of chemotherappy which included etoposide and cisplatin with a follow-up period of 28 months. PMID- 29147224 TI - Increased Incidence of Tumors With the IKBKAP Gene Mutation? A Case Report and Review of the Literature. AB - An increased incidence of neoplasia was recently reported in patients with familial dysautonomia. This suggests that, in addition to its role in neuronal development, the IKBKAP gene may also influence DNA repair. Here we report the case of a 28-year-old male with familial dysautonomia who was found to have neoplastic lesions detected post mortem as incidental findings. This case indicates that the prevalence of tumorgenesis within this population may be underestimated. PMID- 29147225 TI - Functional Interference due to Pain Following Palliative Radiotherapy for Bone Metastases Among Patients in Their Last Three Months of Life. AB - Background: To compare the self-reported ratings of functional interference caused by pain between patients who did and did not respond to palliative radiotherapy for bone metastases during their last three months of life. Methods: A prospectively gathered Brief Pain Inventory (BPI) database compiled from patients receiving palliative radiotherapy for painful bone metastases was reviewed. Demographic and clinical data, pain response rates and self-reported ratings of functional interference caused by pain were analyzed for those patients who died within three months of beginning radiotherapy. Results: From 400 patients in the database, 83 died within 3 months of beginning radiotherapy. There were 54 male and 29 female patients. Their median age was 69 years and their median KPS was 70. The three most common primary cancers were lung (40%), gastrointestinal (16%) and breast (14%). For patients with available follow-up information the 1-month overall pain response rate was 78% and the 2-month rate was 83%, which include both complete and partial responses as defined by the International Bone Metastases Consensus. At 1 month, patients responding to treatment reported significantly less interference by pain on their general activity, walking ability, normal work, sleeping, and enjoyment of life than did patients not responding to treatment. Conclusions: Patients that responded to treatment reported less functional interference due to pain than did patients who did not respond. Despite being very near the end of life, patients responding to palliative radiotherapy for painful bone metastases may benefit from more than pain relief alone. PMID- 29147226 TI - Evaluation of Failure Patterns Using Trimodality in Non-Small Cell Lung Cancer. AB - Background: The effectiveness of trimodality therapy in NSCLC has been controversial. Methods: Ninety-two patients with stage III NSCLC were analyzed retrospectively based on treatment given. Overall survival (OS) and patterns of failure were examined in patients treated with chemoradiation alone (Group 1) versus neoadjuvant chemoradiation followed by surgical resection (Group 2). Results: OS for 2, 3, and 5 years in Group 1 and 2 were 19.7%, 15.7%, and 4.5% versus 56.4%, 40.4%, and 32.3% (P = 0.003), respectively. Median survival for Group 1 and 2 was 11.0 and 34.0 months, respectively (P = 0.003). The recurrence rate in Group 1 was 61.8% (47 of 76) with distant non-brain involvement (48.9%). In Group 2 it was 50.0% (8 of 16) with brain (50%) involvement. Conclusions: Patients with stage IIIA and, perhaps IIIB NSCLC with a high performance status should be considered for trimodality treatment. PMID- 29147227 TI - Quality of Life in Patients Treated with Palliative Radiotherapy for Advanced Lung Cancer and Lung Metastases. AB - Background: The purpose of this study was to investigate quality of life (QOL) in patients receiving palliative radiotherapy (RT) for advanced lung cancer/lung metastases using the EORTC QLQ-LC13 and the EORTC QLQ-C15-PAL questionnaires. Methods: Patients who received palliative RT for lung metastases or advanced lung cancer between November 2007 and October 2010 completed the EORTC QLQ-LC13 and the QLQ-C15-PAL at baseline prior to RT, 1, 2, 4, 8 and 12 weeks post-treatment. The Wilcoxon Signed Rank test was used to compare QOL scores between baseline and each follow-up period. Results: Thirty-one patients with advanced lung disease were included in this study; 61% of participants were male and 39% were female. The median age was 69 years (range 38 - 85), and median KPS and PPS scores at baseline were both 70 (range 30 - 90). All patients received radiotherapy to the lung. None of the QLQ-LC13 scores significantly improved or deteriorated at any follow-up. Of the QLQ-C15-PAL scales, fatigue, pain, insomnia and physical functioning significantly improved at their respective follow-ups. Conclusions: This was the first study to use the EORTC QLQ-LC13 in conjunction with the EORTC QLQ-C15-PAL questionnaires. Future studies should continue to incorporate quality of life assessment tools specific to disease characteristics in advanced cancer patients. PMID- 29147228 TI - Kikuchi Fujimoto Disease, a Worrisome Presentation With a Reassuring Outcome. AB - We describe the case of a 27-year-old male with painful lymphadenopathy involving multiple sites. An excisional lymph node biopsy established the diagnosis of Kikuchi-Fujimoto disease (KFD) and the patient improved with supportive care only and did not have further episodes. This is a case of a rare, benign lymphadenitis, of unknown etiology. The histopathology proved the benign character of the lymphadenopathy and made the diagnosis clear, despite the nonspecific character of the clinical presentation. It is important to recognize the clinical and histopathological aspects of KFD in order to avoid unnecessary and sometimes harmful treatment, such as chemotherapy, when this disease is confounded with lymphoma. PMID- 29147229 TI - Malignant Course of a Metastatic Melanoma During Pregnancy: A Case Report. AB - Cutaneous melanoma can metastasize to any organ, including brain and spinal cord. A 27-year-old lady, four months after conception presented with generalized seizures and was diagnosed to have subarachnoid hemorrhage. Further investigation did not reveal aneurysm. She underwent right ventriculo-peritoneal shunt for hydrocephalus and MTP for unprotected radiation from CT scan. Six weeks later she came to our institution with symptoms of dorsal compression. Imaging showed multiple intradural extramedullary spinal lesions at D3-D4, D8 and D10-D11. Surgical excision of the lesions was done and histopathology was consistent with metastatic deposits from malignant melanoma which was confirmed by immunohistochemistry studies also. Her conscious level deteriorated on the second postoperative day and CT scan showed multiple small tumor emboli with evidence of right temporal bleed and diffuse cerebral edema. In spite of aggressive treatment she could not be saved. This reported case concludes that pregnancy aggravates the clinical course of metastatic melanoma. PMID- 29147230 TI - Cervical Metastasis From Colorectal Cancer. AB - Metastatic carcinoma from colorectal cancer to the uterine cervix is rare. We report a case of metastatic carcinoma from a right colon cancer to the cervix with vaginal extension 3 years after primary treatment. Our report highlights the importance of immunohistochemical analysis to determine the origin of uterine cervix cancer in the event of adenocarcinoma in a patient with a history of colorectal cancer to adapt therapeutic strategy accordingly. PMID- 29147231 TI - Renal Inflammatory Myofibroblastic Tumor: A Case Report and Comprehensive Review of Literature. AB - Inflammatory myofibroblastic tumor (IMT) is a rare benign tumor found in various organs with a sparse number of cases reported in the kidney. We report a case of IMT in a 48-year-old male who underwent laparoscopic partial nephrectomy for a 2.4 cm renal mass suspicious for renal cell carcinoma. Pathologic findings revealed spindle shaped cells in a myxoid background with lymphoid aggregates consistent with inflammatory myofibroblastic tumor. PMID- 29147232 TI - Current Controversies on the Use of Magnetic Resonance Imaging in the Management of Breast Cancer. AB - The use of magnetic resonance imaging in the management of unselected female populations with early stage breast cancer has increased markedly over the past decade. Parallel to this trend many have observed an increased use of mastectomy over breast conservation due to concerns raised by the use of MRI. Similar concerns have led to the use of contra-lateral prophylactic mastectomy in patient populations not tested for potential genetic predisposition. These trends are difficult to understand as they divert from well established clinical paradigms which have been the result of widely accepted clinical research trials with more than three decades of clinical follow up. These trials have asserted that breast conserving surgery remains the accepted approach over mastectomy for the care of the patient with sporadic early stage breast cancer. PMID- 29147233 TI - A Review in Management of Testicular Cancer: Single Center Review. AB - Background: Testicular cancer is one of the few solid cancers that can be cured even when it is metastasized with overall survival rate of more than 90%. The aim of this study was to establish the age adjusted incidence of testicular cancer and to critically assess the management of testicular tumor. Methods: This is a quantitative retrospective study utilizing a review of clinical notes for patients who underwent testicular orchidectomy. The number of cancer cases, types of pathology and cancer staging were examined. Results: There is no substantial difference between the crude and the age-standardized incidence, moreover no difference from the reported crude incidence by the Scottish intercollegiate guidelines. We found 55.1% of seminoma, 14.28% of non-seminoma and 30.61% of combined (seminoma and non-seminoma), and stage I disease in 61.22% of cases, stage II in 36.73% of cases, and stage IV in 2.04% of cases. Most of the cancers were in the age group 20 - 50 with the majority (48.97%) in the age group 31 - 40. About 42.85% of cases were identified with high tumor markers; higher percentage of seminoma at stage II (40.74%). Conclusions: There is no substantial difference between the crude and the age-standardized incidence, moreover no difference from the reported crude incidence. Most of the cancers were in the age group 20 - 50 with the majority (48.97%) in the age group 31 - 40. Only 25% of seminomas had elevated tumor markers. Moreover, it is important to re-enforce strict adaptation to the IGCCCG prognostic factor-based classifications. PMID- 29147234 TI - Gender Difference in Symptom Presentations Among Patients With Bone Metastases in Gender-Specific and Gender-Neutral Primary Cancers. AB - Background: Studies have assessed gender differences on symptoms commonly experienced by cancer patients at various stages in their disease trajectory using heterogeneous cancer populations with different tumor types. The purpose of our study was to evaluate the effect of gender on symptoms among patients with bone metastases while controlling for gender-specific malignancies. Methods: A retrospective review of patients receiving palliative radiotherapy for bone metastases was conducted on patients that completed the Brief Pain Inventory (BPI) or Edmonton Symptom Assessment System (ESAS) questionnaires from 1999 - 2004. Baseline and follow-up BPI and ESAS symptom scores were compared between males and females, with and without controlling for gender-specific tumors. Results: A total of 900 patients completed baseline questionnaires: ESAS (n = 508) or BPI (n = 392). The most common tumor types were lung (26%), breast (25%) and prostate (24%). In all ESAS patients, females had significantly greater severity of tiredness, nausea, depression, anxiety and breathlessness. In the subgroup analysis when gender-specific primary cancers were removed (i.e., breast, prostate and gynecological), no significant differences in ESAS symptoms were found between genders. The BPI functional item of walking ability was significantly worse for females in both the overall and subgroup analyses. Females had worse symptoms at follow-up prior to the removal of gender-specific primaries in both ESAS and BPI. Conclusions: Gender-specific cancers may significantly bias gender studies of cancer-related symptoms when primary tumor type is not taken into account. Gender differences are best assessed in gender neutral primaries. PMID- 29147235 TI - Curcumin Induces Apoptosis in EJ Bladder Cancer Cells via Modulating C-Myc and PI3K/Akt Signaling Pathway. AB - Background: Cancer chemopreventive agent curcumin has been shown to possess cell growth inhibition and apoptosis induction properties in several types of cancer. However, the detailed molecular mechanisms of the compound remain far from clear in EJ bladder cancer cells. Methods: The effect of curcumin on EJ cell growth and apoptosis was detected by MTT assays and flow cytometry. The phosphorylation levels of PTEN, PDK1, Akt, GSK-3beta, c-Raf, and Bad and the expression levels of c-myc, Bax, Bcl-2, caspase-9, caspase-7, caspase-3, and PARP following curcumin administration were examined by immunoblots. Results: Curcumin suppressed the growth of EJ cells in a time and concentration dependent manner. Immunoblot showed that curcumin increased expression levels of c-myc and inhibited the activation of PI3K/Akt pathway in a time-dependent manner in EJ cells. Activation of PTEN, GSK-3beta, c-Raf, caspase-9, caspase-7, and caspase-3, cleavage of PARP, upregulation of Bad and Bax, and downregulation of Akt and Bcl-2 were also found in curcumin-treated EJ cells. Conclusions: These findings establish a mechanistic linkup or interaction between c-myc, Bax, Bad, Bcl-2, caspase cascades, PI3K/Akt pathway and curcumin- induced apoptosis of EJ cells, suggesting that c-myc and PI3K/Akt signaling pathway play important roles in curcumin-induced apoptosis of EJ bladder cancer cells. PMID- 29147236 TI - Analysis of Pain and Interference Patterns With Brief Pain Inventory in Patients With Bone Metastases: A Confirmatory Study. AB - Background: This study investigates the validity of the psychometric properties of the Brief Pain Inventory (BPI) in patients with bone metastases and determines if patients with lower body pain exhibit higher levels of activity interference than those with upper body pain. Methods: Three hundred and eighty-six patients treated, between May 2003 and June 2007, for painful bone metastases were included in this analysis, 336 patients with complete data were included in further analyses. Cronbach's Alpha, confirmatory factor analysis (CFA), and discriminant validity tests were performed to analyze the psychometric properties of the BPI. One-way analysis of variance was used to compare mean scores of BPI subscales (pain, activity, and affect) in patients with upper or lower bone metastases. Results: Internal consistency of two- and three-factor BPI analysis was high. In both cases, consistency was further improved when the sleep item was removed. CFA confirmed these results and showed that three-factor analysis was recommended. Patients with lower body metastases reporting moderate to severe pain exhibited greater levels of functional interference. A single fraction radiotherapy dose of 8 Gy was as effective as multi-fraction therapy where the predominant fractionation was 20 Gy in 5 fractions. Conclusions: Our data confirms the psychometric validation of the BPI and the recommendations to use three-factor analysis in patients with bone metastases. Patients exhibiting lower extremity pain should receive prompt pain interventions and functional aid. PMID- 29147237 TI - Hemophagocytic Lymphohistiocytosis in Association With Clostridium difficile Infection and Cutaneous T-Cell Lymphoma. AB - Hemophagocytic lymphohistiocytosis (HLH) or Macrophage Activation Syndrome (MAS) is a potentially life threatening disorder that presents with fever, suppressed blood cell counts, hepatosplenomegaly and multi-organ failure. HLH has been reported in association with genetic mutations, infections, autoimmune disorders, and various malignancies. However to the best of our knowledge, HLH in association with Clostridium difficile infection has never been reported. We present a case of HLH in a patient with Epstein-Barr virus (EBV) positive natural killer T (NKT) cell cutaneous lymphoma and active Clostridium difficile infection. A 35-year-old male with recently diagnosed EBV positive NKT cell lymphoma was admitted for Clostridium difficile associated diarrhea. During the course of hospitalization he gradually developed pancytopenia and multi-organ failure leading to death. Post-mortem examination confirmed the diagnosis of hemophagocytic lymphohistiocytosis. PMID- 29147238 TI - Intrathyroidal Parathyroid Carcinoma Presenting as Asymptomatic High Normal Serum Calcium and Slightly Elevated Intact Parathyroid Hormone: A Case Report and Review of Literature. AB - Parathyroid carcinoma is an uncommon endocrine malignancy and the probability of an intrathyroidal location is low. We report a case of intrathyroidal parathyroid carcinoma presenting as asymptomatic high normal serum calcium and slightly elevated intact parathyroid hormone (iPTH) making preoperative suspicion and diagnosis extremely difficult. PMID- 29147239 TI - Grade III Dermatitis in a Patient Treated With Paclitaxel and Radiotherapy: Case Report and Review of the Literature. AB - Taxanes, both paclitaxel and doxetaxel are the medication of the future in the management of solid tumors. In high risk breast cancer patients, the combination of concurrent paclitaxel and docetaxel chemotherapy with adjuvant radiotherapy is an attractive option to sequential treatment, with potential for enforcing both local and systemic control. This case report examines the tolerance of such treatment. A 54-year-old Greek woman without a relevant medical history, presented with clinical diagnosed breast cancer staged T4NxM0. Neo-adjuvant chemotherapy was initially administered, and paclitaxel was administered concurrently with radiotherapy in order to achieve local control. During the third cycle of paclitaxel the patient developed grade III dermatitis. The tumor showed a reduction in size by 70%, however, chronic cutaneous and subcutaneous changes have not been accessed. In conclusion, adjuvant breast cancer therapy with concurrent standard dose radiotherapy and paclitaxel (175 mg/m2) every three weeks, should be approached cautiously owing to paclitaxel induced dermatitis. PMID- 29147240 TI - Primary Breast Lymphoma: A Rare Clinical Entity. AB - Localized primary breast lymphoma is very rare. The typical clinical and radiographic presentation of isolated primary breast lymphoma mimics that of breast adenocarcinoma. Histologic diagnosis of primary breast lymphoma relies heavily on Hematoxylin and Eosin pathologic evaluation and immunohistochemical staining. Cytotoxic systemic chemotherapy is the primary treatment for this disease with the occasional need for adjuvant radiation therapy or surgical resection. This case report outlines the diagnosis and management of a patient with primary breast lymphoma. PMID- 29147241 TI - Biomarker for Cancer: A great Promise for Future. AB - Cancer is an uncontrolled growth of a cell due to failure in the cell growth signaling system. Cure of cancer is done only by the complete removal of cancerous cells from the body, the process may sound simple but its implementation is almost impossible. There are number of problems regarding its treatment such as its early detection. Science is progressing every second and so are our expectations. This review is about present scenario and future promises about the development of biomarkers. It is a big challenge whose completion will be beneficial in the early detection of cancer. As early detection is half victory in any disease, especially cancer, this kind of research will be advantageous in the field of cancer treatment. PMID- 29147242 TI - Kidney Cancer: Current Progress in Treatment. AB - Kidney cancer accounts for approximately 2% of all cancers worldwide, with renal cell carcinoma being the most widespread form. Worldwide, the occurrence and mortality rates are rising by 2-3% per decade. Cigarette smoking, obesity, acquired cystic kidney disease and inherited vulnerability are identified risk issues for kidney cancer. Immunotherapy confers a small but significant overall survival benefit in metastatic renal cell carcinoma but only for the minority of patients, i.e. the 20% with good predictive characteristics. Current developments in the molecular biology of renal cell carcinoma have recognized multiple pathways related with the progress of this cancer. Several strategies have been explored targeting these trails, with major clinical benefits shown in early studies. New agents including the small molecule targeted inhibitors like sunitinib, sorafenib and temsirolimus, and the monoclonal antibody bevacizumab have shown anti-tumour activity in randomised clinical trials and have become the standard of care for most patients. PMID- 29147243 TI - What QLQ-C15-PAL Symptoms Matter Most for Overall Quality of Life in Patients With Advanced Cancer? AB - Background: Few studies have evaluated the QLQ-C15-PAL health-related quality of life (QOL) questionnaire, an abbreviated version of the QLQ-C30 questionnaire that was designed specifically for patients with advanced cancer. The present study assessed whether certain symptoms or functional domains from the QLQ-C15 PAL predicted overall QOL when rated prior to palliative radiation treatment (RT). Patients and Methods: Patients attending an outpatient palliative radiotherapy clinic completed QLQ-C15-PAL questionnaires prior to palliative RT for bone, brain or lung disease. Pearson correlations were computed between the QLQ-C15-PAL functional/symptom scores and overall QOL scores. Multiple linear regressions were used to evaluate the relative importance of functional/symptom scales in association with overall QOL. Results: Data from 369 patients were analyzed. The QLQ-C15-PAL domains of physical and emotional functioning, pain, and appetite loss were significant predictors of overall QOL in these patients with advanced cancer. Appetite loss was the only significant independent predictor of overall QOL in the subgroup of patients with advanced lung cancer (n = 29). Both appetite loss and emotional functioning were independently predictive of overall QOL in patients with bone metastases (n = 190). In patients with brain metastases (n = 150), independent predictors of overall QOL included physical and emotional functioning as well as fatigue. Conclusion: The QLQ-C15-PAL domains of physical and emotional functioning, pain and appetite loss were significant predictors of overall QOL in this cohort of patients with advanced cancer. Different functional and symptom scales predicted overall QOL in patients with bone metastases, brain metastases or advanced lung cancer. PMID- 29147244 TI - Sarcomatoid Urothelial Carcinoma: A Single Cancer Center Experience. AB - Background: Sarcomatoid bladder cancer is a rare and aggressive variant of urothelial carcinoma. Methods: A retrospective review of our experience in managing patients with sarcomatoid bladder cancer (SRBC) between 1997 and 2011 was performed to better define the behavior and outcomes of this disease. Results: The median age of the patients was 63 years. All patients presented with high grade histology. Eighty-five percent of the patients presented with muscle invasive disease and fifty percent presented with stage IV carcinoma. Ten of 14 (71%) of patients underwent a cystectomy. Patients with SRBC was younger (P < 0.01), more commonly presented with higher grade histology (P < 0.01) and advanced stage disease (P < 0.01), in comparison with patients with Urothelial carcinoma (UC). At a median follow-up of 7 months (range 1.3 - 112), five (35.7%) patients have died in last follow-up. Two-year survival was 53.5%. Three patients with long term survival were reported. Conclusions: Sarcomatoid bladder cancer is associated with poor prognosis. Multimodality therapy may improve these patients outcome. PMID- 29147245 TI - Validation of a Predictive Model for Survival in Patients With Advanced Cancer: Secondary Analysis of RTOG 9714. AB - Background: The objective of this study was to validate a simple predictive model for survival of patients with advanced cancer. Methods: Previous studies with training and validation datasets developed a model predicting survival of patients referred for palliative radiotherapy using three readily available factors: primary cancer site, site of metastases and Karnofsky performance score (KPS). This predictive model was used in the current study, where each factor was assigned a value proportional to its prognostic weight and the sum of the weighted scores for each patient was survival prediction score (SPS). Patients were also classified according to their number of risk factors (NRF). Three risk groups were established. The Radiation Therapy and Oncology Group (RTOG) 9714 data was used to provide an additional external validation set comprised of patients treated among multiple institutions with appropriate statistical tests. Results: The RTOG external validation set comprised of 908 patients treated at 66 different radiation facilities from 1998 to 2002. The SPS method classified all patients into the low-risk group. Based on the NRF, two distinct risk groups with significantly different survival estimates were identified. The ability to predict survival was similar to that of the training and previous validation datasets for both the SPS and NRF methods. Conclusions: The three variable NRF model is preferred because of its relative simplicity. PMID- 29147246 TI - Giant Posterior Mediastinal Ancient Schwannoma Requiring Thoracoabdominal Resection: A Case Report and Literature Review. AB - Posterior mediastinal schwannomas are benign, slow growing nerve sheath tumors and rarely cause symptoms. We present a case of a 47-year-old man who presents with severe mid-back pain and dyspnea on exertion. Chest radiograph and computed topography revealed a large posterior mediastinum mass. Surgical resection required en bloc resection of a portion of the diaphragm, and wedge resection of the left lower lobe of the lung via left thoracoabdominal approach. Pathology was consistent with ancient schwannoma. This case is unique due to the location and size of the mass and the surgical approach required for complete resection. PMID- 29147247 TI - Paraneoplastic Necrotizing Myelopathy in a Patient With Newly Diagnosed Diffuse Large B Cell Lymphoma. AB - Paraneoplastic neurological disorders are rare but particularly devastating forms of paraneoplastic syndromes, in part due to the fact that the entity is not usually considered as the initial differentials of a cancer patient presenting with neurological symptoms. We report a case of paraneoplastic necrotizing myelopathy associated with Diffuse Large B-cell Lymphoma in an elderly Chinese lady. After extensive investigations, the diagnosis was confirmed on spinal cord biopsy which showed extensive necrotic tissue and absence of tumour or vascular involvement. PMID- 29147248 TI - Locally Advanced Cutaneous Squamous Cell Carcinoma: Two Case Reports of Dramatic Responses to Sequential Cisplatin, Docetaxel and Radiotherapy. AB - Systemic therapy for cutaneous squamous cell carcinoma is typically reserved for rare cases of metastatic disease or lesions which cannot be adequately managed with local therapies. The relevant published literature is comprised only of case series and reports. Herein the authors present two cases of neglected locally advanced cutaneous squamous cell carcinoma not initially amenable to local therapies, which achieved dramatic partial responses to palliative Cisplatin and Docetaxel, facilitating sequential palliative radiotherapy. These reports add to the limited literature supporting the use of platinum-based therapy in locally advanced and metastatic cutaneous squamous cell carcinoma. They are the first describing the use of Cisplatin and Docetaxel in this setting. PMID- 29147249 TI - Spontaneous Tumor Lysis Syndrome in Metastatic Melanoma. AB - Tumor lysis syndrome (TLS) complicating non-hematologic malignancy is infrequent and spontaneous TLS is a very rare occurrence in patients with solid tumors. We report a case of spontaneous TLS in a patient with metastatic melanoma. Clinicians should have awareness of the possibility of spontaneous TLS in patients with solid tumors and should recognize the clinical presentation and laboratory tests for its diagnosis. PMID- 29147250 TI - Primary Hepatic Neuroendocrine Tumor: What Do We Know Now? AB - Primary hepatic neuroendocrine tumors (PHNETs) are rear neoplasm. Diagnosis is an evolution, and requires a systematic clinical exclusion with histological confirmation. Treatment is surgical with excellent prognosis, and a long-term follow-up is required due to high tumor recurring rate. Knowledge from this species of tumor remains limited due to paucity of cases. This article elaborates the key features, diagnosis algorithm, current management, other treatment options and extensive review of literature on this rear tumor. PMID- 29147251 TI - Poor Accrual in Palliative Research Studies: An Update From the Rapid Response Radiotherapy Program. AB - Background: In June 2003, the Rapid Response Radiotherapy Program (RRRP) implemented changes to recruitment strategies in attempts to increase patient accrual to research studies. Such modifications included the use of a dedicated research assistant to screen for and identify eligible study patients, the introduction of more appropriate inclusion criteria, and the switch towards telephone interviews to minimize patient burden. The purpose of this study is to provide an update on patient accrual in the RRRP. Methods: All patients seen in the RRRP from January 2002 to December 2009 were recorded in a prospective database. Reasons for referral, eligibility for clinical trials, reasons for non accrual, and various demographics information were recorded. Descriptive statistics summarized findings. Results: A total of 4726 patient visits were recorded from January 1st, 2002 to December 31st, 2009. Prior to changes, the overall rate of accrual into research studies was 14.9% versus 48.1% after changes were implemented. Patients were not accrued onto studies mainly to due ineligibility according to study protocol. Other reasons such as language barrier (12.1%), physician objection (3.5%), patient declining participation (11.3%) and lack of a research assistant (9.3%) were cited. Conclusions: Changes in clinical structure and study design can significantly impact accrual patterns in palliative radiotherapy studies. Despite these changes however, the majority of patients are still not enrolled in studies. Therefore additional efforts need to be made to maximize patient accrual and minimize attrition. PMID- 29147252 TI - Comorbid Conditions in Patients With Metastatic Colorectal Cancer. AB - Background: Patients with metastatic colorectal cancer (mCRC) often have other medical conditions that may impact treatment decisions, prognoses and quality of care. We aimed to assess co-existing medical conditions in the mCRC patient population. This retrospective cohort study used linked medical and pharmacy claims data from two US-based Medstat MarketScan claims databases and identified patients with newly diagnosed mCRC between January 2005 and June 2008. Methods: Patient data were analyzed for comorbid conditions and medication use in the year prior to diagnosis of mCRC. Univariate analyses were conducted to compare the comorbid conditions between patients aged >= 65 and < 65 years old. In total, 12 648 patients aged >= 18 years were identified. The study was evenly populated by gender and age above and below 65, and most patients had a primary diagnosis of colon cancer (70.1%). Results: The most prevalent comorbidity was cardiovascular disease (CVD) (55.7% of patients) including hypertension (40.8%), cardiac dysrhythmia (14.2%), coronary artery disease (13.5%), congestive heart failure (7.2%) and arterial and venous thromboembolism (6.2% and 4.6%, respectively). Most comorbidities were significantly more prevalent in patients >= 65 years of age, particularly with respect to CVD (67.9% versus 42.5%, respectively; P < 0.0001). Additionally, nearly half (49.7%) of the patients received antihypertensive agents and many patients were prescribed more than one class of medications prior to mCRC diagnosis. Conclusions: Comorbid medical conditions, particularly CVDs, are common in patients with mCRC, which could increase the complexity of patient management. This should be a consideration integral to the selection of the most appropriate treatment for individual patients. PMID- 29147253 TI - Circulating Levels of Agouti-Related Peptide in Endometrial Cancer Survivors. AB - Background: Recently, it has been reported that central administration of agouti related peptide (AgRP) might have protective effect against cachexia development in tumor-bearing mice. In this study, we determined whether the disease-free endometrial cancer survivors present with different plasma AgRP levels than controls and whether there was an association with the duration of the disease free interval. Methods: The total of 53 endometrial cancer survivors was enrolled in the study along with 93 healthy control women of similar age. Fasting blood samples were obtained and AgRP plasma levels determined using ELISA-based methodology. Results: The AgRP plasma levels were significantly higher in the cases than in the controls; AgRP levels were the lowest in obese control women (77.4 +/- 19.8 pg/ml); on the contrary, the AgRP plasma levels were highest in non-obese cancer survivors (100.5 +/- 21.12 pg/ml). Moreover, we observed significant differences in AgRP levels between the endometrial cancer survivors and the control subjects [p (for comparison of the cases and the controls) = 0.002]. In the regression modeling, AgRP was significantly associated with the BMI as well as the case-control status, and the case-control differences in AgRP levels retained their statistical significance also after adjustment for BMI. Conclusions: Disease-free endometrial cancer survivors who did not develop cachexia during their treatment as well as post-treatment period present with significantly higher AgRP levels than the control population, independently on their BMI and menopausal status which could be indicative of the protective effect of circulating AgRP against cachexia development in endometrial cancer. PMID- 29147254 TI - Ultrasound-guided Central Venous Catheterization for Home Parenteral Nutrition and Hydratation in Advanced Incurable Cancer Patients: Results of A Prospective Observational Study. AB - Background: Most patients with advanced cancer are frequently malnourished and frequently they develop decreased oral fluid intake and dehidratation. Home parenteral nutrition (HPN) is an increasingly used therapy for patients with advanced cancer. A central venous access device is often an essential component allowing parenteral nutrition and hidratation. However central venous catheter (CVC) insertion represents a risk for pneumothorax or other mechanical complications. This study aimed to determine the reduction of risks related to central venous catheter positionement in the setting of cancer patients with palliative programm. Methods: Consecutive patients with a variety of cancer in advanced phase requiring palliative care who were undergoing placement of central venous catheter for parenteral nutrition or hydratation have been prospectively studied in a program of ultrasound-guided CVC placement. Four types of possible complications were defined:mechanical, thrombotic, infection and malfunctioning. After sterilization, local anesthesia is applied and a 7.5 MHZ puncturing US probe is placed in the supraclavicular site and a 16-gauge needle is advanced under real-time US guidance, into the last portion of internal jugular vein by experienced physicians. The Seldinger tecnique is used to place the catheter that is advanced into the superior vena cava until insertion to right atrium. Two hours after each procedure a chest X-ray and US scanning are carried out to confirm CVC position and rule out a pneumotorax. Results: From 30 October 2000 to 31 October 2008: 209 CVC insertional procedure were applied in 207 patients with cancer in the palliative phase only. There were 101 women and 106 men with a mean age of 67.68 year (range 22-86). A single needle puncture of the vein was performed on 206 of 209 procedures (98.6%), the technique was efficacious at the first attempt in 98.6% of cases, in 2 patients (0.96%) the CVC was positioned at the second attempt. The procedure failed only one case (0.44%). No cases of pneumothorax, of major bleeding or nerve punctured were reported. Symptomatic vein thrombosis developed in one patient (0.44%). Infection episodes were reported in two cases. Mean time for CVC permanence was 92.5+/-9.1 days (range 8 158). Conclusion: This study indicates that US-guided CVC insertion is a safe, cheap procedure for cancer patients in advanced phase and with palliative program, allowing parenteral nutrition and hydratation. PMID- 29147255 TI - "Short Course" of Nonpegylated Liposomal Doxorubicin Plus Paclitaxel and Trastuzumb as Primary Systemic Therapy for Operable and Locally-Advanced Breast Cancer: A Phase II Study (PacLiDox 07). AB - Background: Schedules with anthracyclines and taxanes are one of the best options for primary chemotherapy. The addition of trastuzumab showed an impressive percentage of pathological complete responses in Buzdar trial (66.7%). Recently, nonpegylated liposome-encapsulated doxorubicin (NLD) has been widely used in advanced breast cancer with high response rates (98.1 % in Cortes study). The aims of our study were to assess pathological responses and toxicity of NLD plus paclitaxel (and trastuzumab in patients with HER2 overexpression). Methods: Thirty patients entered the study: 9 locally advanced and 21 operable. Median age was 58.5 years (range: 31-73). 23 patients without HER2 overexpression (or FISH not amplified) were treated with NLD 50 mg/m2 every three weeks for 3 courses and weekly paclitaxel 80 mg/m2 for 8 courses. 7 patients with HER2 overexpression or FISH amplified were treated with the same schedules plus trastuzumab (Herceptin) 4 mg/kg for the first administration and 2 mg/kg for the following 7 weekly administrations. Results: Pathological complete response (pCR) was documented in 1 patient (treated with trastuzumab); no residual tumor (infiltrating or "in situ") on breast was documented in other 2 patients. Objective clinical responses were documented in 22 patients (73.3%): 8 complete, 10 partial and 4 "minimal" responses. 7 patients have shown stable and 1 progressive disease. Clinical response in patients with HER2 overexpression treated with trastuzumab was 100% (4 complete and 3 partial responses). Conservative surgery was performed in 8 (38%) and mastectomy in 13 (62%) out of 21 operable patients; however, 7 out of 14 responding patients with operable disease underwent quadrantectomy (50%). Main toxicity was neutropenia: febrile in 2 patients (7%) and gr. 3-4 in 13 (43%). Other grade 3 toxicities were as follows: vomiting in 1 patient, asthenia in 1 patient, joint symptom in 1 patient. 3 patients were withdrawn from the study. No episodes of left ventricular ejection fraction (LVEF) < 50% were recorded (with a median reduction of 8%). Conclusions: A "short course" of paclitaxel and NLD is active in terms of clinical response and conservative surgery for patients with potentially operable and locally advanced breast cancer; toxicity was manageable. High activity of the combination with trastuzumab has been confirmed. However, with this "short course" schedule, the result in term of clinical responses didn't turn into complete pathological responses. PMID- 29147256 TI - A Pilot Study of Chemoradiotherapy With Weekly Docetaxel for Thoracic Esophageal Carcinoma With T4 and/or M1 Lymph Node Metastasis. AB - Background: Patients with unresectable or inoperable esophageal carcinoma are usually treated with definitive chemoradiotherapy. The present standard regimen is radiation with concurrent chemotherapy with cisplatin and fluorouracil. However, significant toxicities have been observed. The efficacy and safety of concurrent chemoradiotherapy with weekly docetaxel for head-and-neck squamous cell carcinoma and non-small cell lung cancer have already been recognized. We conducted a pilot study of definitive chemoradiotherapy with weekly docetaxel for advanced esophageal carcinoma. Methods: Nine patients with advanced thoracic esophageal squamous cell carcinoma having a T4 tumor and/or distant lymph node metastasis (M1 LYM) were enrolled. Docetaxel was administered concurrently with 60 Gy of radiation by drip infusion at a dose of 10 mg/m2 for an hour once per week and 6 times in total. Results: All 9 patients completed the treatment schedule without any suspension. Grade 3 or higher hematological and biochemical toxicities did not occur. Two patients achieved complete response, and 4 achieved partial response. The response rate was 67%. The median survival time was 16.2 months and the 2-year survival rate was 38.9%. Conclusions: Concurrent chemoradiotherapy with weekly low dose docetaxel is a safe and effective treatment regimen for esophageal squamous cell carcinoma. We expect that this protocol of chemoradiotherapy may be one of the choices of treatment substituting the regimen with cisplatin and fluorouracil, particularly for the patients for whom chemotherapy with cisplatin and fluorouracil is considered inappropriate because of concomitant renal dysfunction or prior failure of systemic chemotherapy with cisplatin and fluorouracil. PMID- 29147257 TI - Agranulocytosis Associated With Spironolactone Therapy: A Case Report. AB - Herein, we report a case where agranulocytosis occurred after spironolactone administration. Patient presented with non-descript constitutional symptoms suggestive of a viral etiology associated to new onset agranulocytosis with neutrophilic maturation arrest on bone marrow biopsy. Patient's medical history included chronic liver disease as well as new onset acute renal insufficiency. Upon review of patient's medications, initiation of spironolactone was noted 4 weeks prior to admission. Few cases of agranulocytosis secondary to spironolactone have been reported in the literature, most of which were also in association with both renal insufficiency and chronic liver disease. Discontinuation of spironolactone resulted in normalization of granulocyte count within 3 weeks. As patients with chronic liver disease are frequently given spironolactone, we recommend monitoring blood counts 4 - 8 weeks following initiation of therapy to detect and treat this potentially life threatening complication. PMID- 29147258 TI - Clinical Improvement and Prolonged Survival With High Dose Intrathecal Methotrexate for Carcinomatous Meningitis Secondary to a Lung Adenocarcinoma. AB - Carcinomatous meningitis (CM) is a devastating complication of advanced cancers. No standard treatment is available for CM secondary to solid tumors. In particular, very few data have been published for CM related to lung adenocarcinoma. Herein we report the case of a 39-year old woman treated for a metastatic lung adenocarcinoma, without EGFR mutation, complicated by a CM. Intrathecal administrations of high dose methotrexate produced both a clinical improvement of symptoms related to CM and an unusually delayed survival. PMID- 29147259 TI - The Management Dilemma of Leiomyosarcoma of the Ovary. AB - Ovarian leiomyosarcomas (OLS) have a poor prognosis due to their late presentation and aggressive nature. This case illustrates that surgery alone can offer disease free survival in cases of early stage disease. PMID- 29147260 TI - Complete Remission of Advanced Gastric Cancer in Response to Chemotherapy With Docetaxel, Cisplatin and Capecitabine (dcx). AB - We describe the case of a 60 year-old man with advanced gastric cancer. The patient started chemotherapy with a combination of docetaxel, cisplatin and capecitabine. In a radiological assessment after the third treatment cycle, a significant reduction of adenopathies and gastric wall thickening was observed. Partial remission was maintained until the end of the chemotherapy (6 cycles). The follow-up evaluations indicated the radiological remission was maintained and that there was a reduction of gastric wall thickening and normalisation of remote lymph nodes. After 43 months since the final treatment cycle, the patient remains progression-free. PMID- 29147261 TI - Ovarian Clear Cell Carcinoma Presenting as Non-bacterial Thrombotic Endocarditis and Systemic Embolization. AB - Non-bacterial thrombotic endocarditis (NBTE) is a rare manifestation of cancer induced hypercoaguability. It most commonly occurs in association with mucin producing adenocarcinomas and has rarely been described with ovarian clear cell carcinoma (OCCC). We report a case of NBTE with multi-organ embolic infarcts occurring in a patient with early stage clear cell ovarian cancer. A 56 years old Caucasian female presented with leg pain, and left flank discomfort. Evaluation revealed multi-organ infarction, extensive deep vein thrombosis (DVT), and the incidental presence of an asymptomatic large ovarian mass with a laboratory picture consistent with disseminated intravascular coagulation (DIC). The diagnosis of NBTE was supported by echocardiogram and multiple negative bacteriological studies. She underwent surgical extirpation of an early stage OCCC and initiation of anticoagulation. Postoperatively, the patient's hypercoaguability promptly resolved with gradual resolution of vegetations. Subsequent recurrence of the malignancy was heralded by a return of the prothrombotic state. This case shows a rarely reported association between NBTE and OCCC. It illustrates how the clinical picture of NBTE can dominate the initial presentation of an early stage and otherwise asymptomatic malignancy. Late recognition can lead to significant morbidity and a rapidly fatal course. Recurrent thromboembolism may be the first indication of disease recurrence. PMID- 29147262 TI - Accuracy of Cytology Specimen and Needle Core Biopsies for Detection of KRAS Mutation in Non-Small Cell Carcinoma: Comparison With Resection Specimen. AB - Background: Recent studies have shown that KRAS mutations are negative predictors of benefit from both adjuvant chemotherapy and anti-EGFR directed therapies for non-small cell lung carcinoma (NSCLC). Needle core biopsy, cytology specimen and resected tissue have all been used for KRAS mutational analysis of malignant lung tumors. However, studies validating the correlation between needle core biopsy/cytology specimen and resected tissue, histologic reference standard for KRAS mutational analysis are lacking. We retrospectively compared the KRAS mutation detection on cytology specimen or needle core biopsy with corresponding resected malignant neoplasm of lung, the histologic reference standard for mutational analysis. Method: Twenty-seven samples including 8 cell blocks, 9 cytology smears and 10 needle core biopsies, and corresponding 22 resected malignant tumor of lung were correlated for KRAS mutational analysis. In cases where cell block material did not correspond with results on resected specimen, cytology smears of corresponding cases were microdissected for isolation of DNA. Results: The needle core biopsy specimens and the corresponding surgical resections showed 100% concordant results for KRAS mutational analysis. KRAS mutation was detected in 4 out of 8 cell blocks, compared to 7 out of 8 corresponding surgical resections. Low cellularity (2 cases) and failure to retrieve DNA (1case) resulted in lack of correlation in 3 cases with cell blocks. However, cytology smears in these 3 cases confirmed the KRAS mutation noted in corresponding surgical resections. Overall concordance between cytology smears and corresponding surgical resections was 89% (8 of 9 cases). KRAS mutation was detected in 1 of the 9 cytology smears and was lacking in corresponding surgically resection. Conclusion: Cytology specimen and needle core biopsies provide adequate material for KRAS mutational analysis. Excellent mutational analysis concordance between cytology specimen/needle core biopsies and resected tumor suggests that predictive marker based therapeutic decision need not shift to more invasive surgical procedures. PMID- 29147263 TI - Symptom Clusters in Cancer Patients With Bone Metastases: Subanalysis of Patients Reporting Exclusively Non-zero ESAS Scores. AB - Background: To identify symptom clusters in a subgroup of patients reporting exclusively non-zero Edmonton Symptom Assessment System (ESAS) scores at baseline, and to compare clusters with those identified in the total patient population. Secondary objective was to determine whether symptom clusters in patients with bone metastases vary when extracted using different statistical methods. Methods: An existing dataset compiled from bone metastases patients was used to identify a "non-zero" subgroup of patients reporting severity scores > 0 for all nine ESAS symptoms at baseline. Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA) and Exploratory Factor Analysis (EFA) were performed on the non-zero subgroup to derive symptom clusters at baseline and 1, 2, 4, 8 and 12 weeks following radiation treatment. Symptom clusters in the total patient sample at baseline were also derived using the three statistical methods. Results: At baseline, different symptom clusters were identified in the non-zero subgroup compared with the total patient population regardless of the statistical method utilized. When comparing clusters derived using different statistical methods, symptom cluster results varied depending on the method employed, with a few exceptions where analogous clusters were derived using two different statistical methods at a specific time point. A complete consensus between all three methods was never observed. Only two ESAS symptoms, anxiety and depression, consistently occurred in the same cluster across different methods and over time. Conclusion: Compiling data from all eligible consenting patients may not provide an accurate overview of clustering among all the symptoms included in the assessment tool. The quantity and composition of symptom clusters identified varied based on whether patients with zero symptom severity scores were included at baseline and which statistical method was utilized. PMID- 29147264 TI - Hypertonic Saline Attenuates the Pro-metastatic Effects of LPS by Reducing Tumor Cell Migration, Proliferation and MMP-9 Expression. AB - Background: Lipopolysaccharide (LPS) promotes tumor metastases. The aim of this study was to determine the ability of a hypertonic environment to attenuate the pro metastatic properties of LPS both in vitro, and in vivo. Methods: LPS stimulated, and unstimulated, 4T1 tumor cells were cultured in either an isotonic or hypertonic environment. The effect on invasion, migration, pro matellomatrixproteinase 9 (proMMP-9) expression, proliferation, and microscopic cell structure was assessed. Lung metastases were induced in C57 mice with systemic hypertonicity in unstimulated and stimulated mice. The metastatic burden was assessed by estimation of lung/body weight ratio, pleural nodules and clonogenic assay. Results: In vitro, a hypertonic environment reduced proMMP-9 expression (0.012 versus 1.16, P < 0.001) invasion (0.06 versus 0.119, P = 0.005), tumor cell proliferation (0.035 versus 0.041, P = 0.001), while inducing structural changes to tumor cells reducing overall cell volume. In vivo, the induction of transient systemic hypertonicity reduced metastatic burden as demonstrated by reduced lung nodules (4 versus 8, P = 0.004) and colonies on clonogenic assay (12 versus 43, P = 0.04). Conclusion: The in vitro exposure of tumor cells to a hypertonic environment reduces tumor cell migration and proliferation. Transient systemic hypertonicity can reduce the metastatic burden following intra-operative exposure to LPS in vivo. PMID- 29147265 TI - CD99/MIC2 Constitutes a Differentiation Antigen of a Human Osteoblast Cell Line. AB - Background: The histological origin of the Ewing's family of tumors (EFT) is still not clear. Since these small cell bone tumors may originate from osteogenic stem cells, the presence of the CD99/MIC2 antigen, known to be overexpressed in EFT, was studied in a human osteoblast cell line in response to differentiation inducers. Methods: The HBA-71 monoclonal antibody directed to the CD99/MIC2 antigen was used to stain a human osteoblast cell line as well as the two EFT cell lines KAL and EW-2 after pretreatment of the cells with the differentiation inducers calcitriol and the histone deacetylase (HDAC) inhibitors sodium butyrate (NaB), sodium phenylacetate (NaPA) as well as N, N'-hexamethylen-bis-acetamide (HMBA). Alkaline phosphatase (ALP) levels were determined as cellular differentiation marker. Results: Significant expression of the CD99/MIC2 antigen, yielding a molecular weight of 32 kD in Western blotting, was found in the human osteoblast cell line. Pretreatment of the osteoblasts with calcitriol and HMBA increased ALP content and suppressed the CD99/MIC2 antigen. Calcitriol had no major effect on CD99/MIC2 expression of both EFT cell lines, but HMBA enhanced ALP activity in KAL cells and downregulated CD99/MIC2. EW-2 cells exhibited reduced levels of both CD99/MIC2 and ALP. Conclusions: This study supports the role of CD99/MIC2 as differentiation antigen of osteoblasts and a Ewing's sarcoma cell line with neuroectodermal phenotype. Response to calcitriol is absent or low in the two EFT cell lines tested. PMID- 29147266 TI - Bilateral Successive Testicular Tumors With Different Cell Types. AB - We are presenting the case of a young man who had bilateral successive testicular tumors with different cell types. The time interval between the two tumors was about 6 years. This underlines the importance of recognising patients with germ cell tumors who are at risk of developing a second tumor and requires a long term follow up. PMID- 29147267 TI - Adrenocortical Carcinoma: Complete Surgical Resection After 18 Years. AB - Adrenal cortical carcinoma (ACC) is a rare neoplasm often associated with an aggressive biological behavior. Complete surgical resection is the mainstay of therapy for ACC and offers the best chance for prolonged disease-free survival. We present an unusual case of a long-standing adrenal mass, well documented over a period of at least 18 years, without the development of metastatic disease, and ultimately proven to represent ACC after successful surgical resection. Physicians should be aware that ACC can present with a wide spectrum of biological behavior, from very aggressive to more indolent disease. PMID- 29147268 TI - Should Internal Mammary Lymph Node Biopsy be A Routine Step in Recurrent Breast Cancer? Report of Three Cases With Negative Axilla and Positive Internal Mammary Node. AB - Lymph node status is the most important clinicopathological prognostic factor for breast cancer patients and in most breast units it reflects only the axillary lymph nodes. A second often overlooked basin consists of the internal mammary lymph nodes (IMLNs) whose evaluation is not done as a routine step during the staging process. We highlight the need to consider incorporation of IMLNs into a patient's staging by presenting three cases of recurrent breast cancer with negative axilla and positive IMLN, a finding which altered their final management. We suggest that biopsy of IMLN should be a routine step in recurrent breast cancer when axillary lymphatics are disrupted by previous surgery although further research is required to define the optimal management of node positive cases. PMID- 29147269 TI - Endometriosis in the Lumbar Plexus Mimicking a Nerve Sheath Tumor. AB - Endometriosis consists of ectopic endometrial tissue outside of the uterine cavity. It is typically benign. It may cause neurological symptoms if involving the central or peripheral nervous system. We present in this report a 46-year-old Caucasian female with progressively worsening lumbar pain with radiation to her left anterior thigh. MR imaging showed an enhancing mass in the L4 neural foramen, intrepreted as a nerve sheath tumor. At operation the nerve showed extrinsic and intrinsic abnormality, proven to be endometriosis. Postoperatively, the patient reported relief from her radiculopathy. We review the previous cases, discuss the pathogenesis and additional characteristics that highlight intraspinal endometriosis, although rare, should be considered as a potential cause of neurologic symptoms in women. Surgical resection is recommended in cases having severe or worsening neurologic symptoms or signs of cauda equina syndrome. Adjunctive treatment may be used in cases of residual or recurrent lesions. PMID- 29147270 TI - Pre-operative Embolization of Primary and Secondary Bone Tumours is Safe and Effective: a Retrospective Study. AB - Background: The surgical treatment of bone tumours can result in large peri operative blood loss, due to their large sizes and hypervascularity. Pre operative embolisation has been successfully used to downgrade vascularity, thus reducing peri-operative blood loss and its associated complications. Methods: Pre operative embolisation was successfully undertaken on twenty-six patients with a variety of primary and secondary bone tumours. Results: Mean blood loss was 796 mL and we experienced no complications. Conclusion: Pre-operative arterial embolisation of large, richly vascular bone tumours in anatomically difficult positions, is a safe and effective method of downstaging vascularity and reducing blood loss. PMID- 29147271 TI - New Considerations in the Design of Clinical Trials for Bone Metastases. AB - Palliative radiotherapy (RT) is prescribed to patients with bone metastases to alleviate symptoms and improve quality of life. The lack of consistent endpoints for such trials has made cross study comparison difficult and has led to contradictory conclusions. The International Bone Metastases Consensus Working Party was established to create a standard set of endpoints and recommendations for future clinical trials. Recommendations were included regarding eligibility criteria, pain assessments, follow-up assessments, timing, as well as radiation techniques. Suggestions were also made to facilitate the ease with which different studies could be compared as well as to encourage widespread consistency in certain aspects of trial design. Investigators conducting clinical trials in bone metastases should continue to adopt these recommendations to ensure consistent guidelines based on the most recent literature. PMID- 29147272 TI - Symptom Clusters in Patients With Bone Metastases: A Sub-Analysis of Patients Reporting Exclusively Non-Zero BPI Scores. AB - Background: The use of different statistical methods and inclusion criteria when deriving symptom clusters in cancer patients are contributing factors in cluster inconsistencies across studies. Primary objective was to extract symptom clusters in a subgroup of patients reporting non-zero Brief Pain Inventory (BPI) scores at baseline, and to compare clusters with those identified in the total patient sample. Methods: Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA) and Exploratory Factor Analysis (EFA) were performed on the non zero subgroup and total patient sample to identify symptom clusters at baseline and 1, 2 and 3 months following radiotherapy. Results: At baseline, different symptom clusters were derived from the non-zero subgroup and the total patient population. Only PCA identified identical clusters. Over time, clusters extracted using the three statistical methods varied, with a few exceptions where the same clusters were extracted using two different methods at a specific time point. A complete consensus between all three methods was not noted at any time. The BPI, which is a short assessment tool, may lead to the extraction of oversimplified clusters. In addition, since this study analyzed results in the non-zero subgroup, clusters derived may be reflective of patients with poorer prognosis as these patients experienced all symptoms. Conclusion: Analyzing data compiled from all eligible consenting patients may not provide clinically relevant clustering among all symptoms in the assessment tool. The composition of symptom clusters varied with the inclusion of patients with zero symptom severity scores and with the statistical method employed. PMID- 29147273 TI - Early Experiences of Image Guided Prostate and Pelvic Nodal Irradiation With Intensity Modulated Radiation Treatment in Localized Prostate Cancer. AB - Background: To present the early findings of a phase I clinical trial studying the use of intensity modulated radiation treatment (IMRT) to treat at risk pelvic and lower para-aortic lymph nodes in patients with high risk prostate cancer while escalating dose. Dose escalation was performed with a technique particularly aiming to limit the dose to surrounding critical structures. Methods: A total of 12 patients were treated with an IMRT plan that delivered 45 Gy to the pelvic lymph nodes, prostate and proximal seminal vesicles. This was followed by an image guided IMRT plan that delivered 9 Gy to the prostate and seminal vesicles and then an additional 21.6 Gy delivered to the prostate for a total dose of 75.6 Gy to the prostate. Gastrointestinal (GI) and genitourinary (GU) toxicity were recorded weekly throughout treatment and in follow up (range: 20 - 49 months). Results: At diagnosis, median age was 64, median PSA 15.5 (range: 5 - 103) and Gleason score ranged 7 - 9. The median dose to the bladder was 52 Gy, the median dose to the rectum was 53 Gy and the median dose to the small bowel was 26 Gy. During treatment, Grade 2 GU toxicity was noted in 3/12 (25%) patients and Grade 2 GI toxicity was noted in 2/12 patients (16%). At a median follow-up of 28 months, Grade 2 late GI toxicity was seen in 1/12 (8%) and late GU in 3/12 (25%) of patients. There were no acute or late grade 3 and 4 GU or GI toxicities. Conclusions: Our study shows the feasibility of using IMRT for pelvic and lower para-aortic nodal irradiation as the toxicities are low for the total dose that was delivered. This shows promise for reducing normal tissue doses, improving target control, and potentially allowing for additional dose escalation to the pelvic/lower para-aortic lymph nodes in our successive cohorts. PMID- 29147274 TI - Symptom Clusters Using the Edmonton Symptom Assessment System in Patients With Bone Metastases: A Reanalysis Comparing Different Statistical Methods. AB - Background: To determine whether symptom clusters in patients with bone metastases vary when extracted using three different statistical methods. To compare the temporal composition of symptom clusters in responders versus non responders to palliative radiation treatment. Methods: A previous dataset of 518 bone metastases patients who completed the Edmonton Symptom Assessment System (ESAS) was used in this study. Clusters derived using Principal Component Analysis (PCA) in our previous study were compared to symptom clusters extracted using Hierarchical Cluster Analysis (HCA) and Exploratory Factor Analysis (EFA). Clusters were derived at baseline, and 1, 2, 4, 8 and 12 weeks after radiation treatment. The patient sample was further divided into responders versus non responders to radiotherapy. The three statistical methods were performed to identify clusters in the subgroups at each time point. Results: A complete consensus between HCA, EFA and PCA for the number and composition of symptom clusters was not reached at any time point. Furthermore, little correlation in clusters was found between the three statistical methods despite the use of an identical data set. As expected, different symptom clusters were observed in the responders and non-responders with all three statistical methods. In addition, clusters varied at each time point within each subgroup. Depression and anxiety were consistently found in the same cluster. Conclusion: The quantity, composition, and occurrence of symptom clusters varied based on which statistical method was employed. The use of a common analytical method is necessary for consistency and comparison purposes in future symptom cluster research. PMID- 29147275 TI - Successful Retreatment With ADOC Chemotherapy in Relapsed Thymic Carcinoma: Experiences in Two Cases. AB - The optimal second-line chemotherapeutic regimen for thymic carcinoma remains uncertain and predictive factors for the response have not been identified. We encountered two cases of relapsed thymic carcinoma with recurrence 1.5 and 8 years after initial response to cisplatin/doxorubicin/vincristine/cyclophosphamide (ADOC) chemotherapy. Both cases were successfully retreated with ADOC. Our observations suggest that relapsed thymic carcinoma occurring a long treatment-free time from the initial response may be sensitive to the previous chemotherapy. We described two cases of relapsed thymic carcinoma successfully retreated with ADOC chemotherapy. Both patients had partial response to initial ADOC and long disease free times. PMID- 29147276 TI - Conservative Therapy in Two Cases of Non-Hodgkin Lymphoma of the Penis: Case Reports With Review of the Literature. AB - The malignant lymphomas rarely occur in the genito-urinary tract and particularly penis lymphomas are extremely uncommon. Frequently they do not have any specific symptoms and the diagnosis is delayed even in presence of a penis node. In our hospital we observed two patients affected by Non-Hodgkin Lymphoma (NHL), one of them with a primitive disease. Both cases were sexually active men who did not accept a radical surgery. A conservative polichemotherapy treatment by ciclophosphamide, vincristine and prednisone has been proposed and performed for both cases and a complete resolution of disease was demonstrated. At the same time we assessed the erectile function by the IIEF score, before and after treatments. PMID- 29147277 TI - Early and Complete Response of Bone Metastases, Documented by FDG-PET/CT Scan, in a Patient With NSCLC. AB - In this case report we describe the case of a patient with multiple bone metastases of NSCLC, adenocarcinoma with exon 21 point-mutation of EGFR, treated with gefitinib. After only 3 months, FDG-PET/CT scan showed a complete response of bone metastases and right hylar adenopathy. Implications for need of early use of FDG-PET/CT scan after gefitinib treatment are discussed. PMID- 29147278 TI - Small Cell Lung Cancer (SCLC) Presenting as Acute Pancreatitis: The Role of Hypercalcemia. AB - A 53-year-old smoker female presented to our hospital with abdominal pain secondary to acute pancreatitis. Severe hypercalcemia was felt to be the precipitating cause of pancreatitis. Her work up showed SCLC with bone marrow metastases as the only site of extra-thoracic metastases. We review the literature regarding hypercalcemia mechanisms in patients with SCLC. PMID- 29147279 TI - The Vascularised Groin Chamber: A Novel Model for Growing Primary Human Liposarcoma in Nude Mice. AB - Background: The preclinical development of anti-sarcoma drugs has been primarily based on the subcutaneous transplantation of xenografts. Transplant survival remains an obstacle of current models which has been attributed to the period of hypoxia after transplantation. We hypothesized that primary soft tissue sarcoma models with an intrinsic tissue engineered vascular supply would be easily reproducible. The aim of this study was to establish a model of primary human soft tissue sarcoma with an intrinsic vascular supply. Methods: Primary soft tissue sarcoma cells from resected human liposarcomas isolated and divided into tumour fragments were transplanted into a silicon chamber, placed around the superficial epigastric vessels in mice. Sarcoma xenograft samples were analysed histomorphologically (light/electron microscopy and immunohistochemistry). Results: All primary soft tissue sarcoma transplants engrafted, leading to solid tumours within 3 weeks. Histological and immunohistochemical staining confirmed the mouse xenografts as identical high grade liposarcomas compared to original tumour tissue. Conclusion: This study established a reproducible xenograft model of primary human liposarcoma. This animal model could be of high value for studying human soft tissue sarcomas and their therapy. PMID- 29147280 TI - Is There a Role of Double Reporting and CT Pelvis for Lung Cancer Staging? AB - Background: Lung cancer is the most common cancer in the world. Staging of lung cancer involves CT of chest and abdomen. Subsequently these are discussed in MDT and if required PET imaging is arranged. We have performed a study to assess double reporting of the initial staging CT would identify in field metastasis and hence decrease the use of PET. Methods: A refined search from the lung cancer database over 2 years of 980 patients was performed. Metastasis identified on PET (SUV > 2.5) was nominated as the gold standard, 219 patients had both PET and staging CT (chest and abdomen) with 38 patients having metastasis on both PET and CT. CT images were reviewed by two independent radiologist who were blinded to the report. Identified metastases were graded if identified. These were grade as 1- definite, 2- equivocal, 3- normal. Subsequently through a process of arbitration a combined decision about the in field metastasis was achieved. Results: There were 21 metastasis which were within the field of chest and abdomen (in field metastasis). Only a half of these were identified by blinded observers. Following an arbitration there was no significant improvement in the pick up rate. There were 19 out of field metastasis in 15 patients out of this cohort. Majority of these (72%) were in the bony pelvis which would have been reported if a CT pelvis was performed as a part of staging. We estimate that one would have to perform 10 CT pelvises to save one PET-CT. Conclusion: Double reading of staging scan would not identify all infield metastasis. The increased contrast in PET images makes it easy to spot metastases. Hence there is no role for double reporting of staging CT in lung cancer management. Inclusion of pelvis in staging of lung cancer may be effective and would improve the detection of out of field metastases hence decreasing the use of PET. PMID- 29147281 TI - Differing Serum Cea in Primary and Recurrent Rectal Cancer - A Reflection of Histology? AB - Background: Serum carcinoembryonic antigen (CEA) levels are not universally measured in colorectal cancers. CEA levels have been reported to be usually normal at time of primary rectal cancer diagnosis but elevated in recurrent disease. The aims of the study were to (1) compare serum CEA levels performed at time of primary and recurrent colorectal tumour diagnosis; and (2) to determine serum CEA levels in rectal cancers at primary diagnosis to analyse potential factors influencing differing CEA levels. Methods: A retrospective analysis of patients treated for colorectal cancers at Modbury Hospital, South Australia was performed. Each admission was reviewed within the electronic database. Serum CEA levels and tumour-related factors were determined in patients who underwent curative surgery for their primary tumour and developed tumour recurrence/metastases within the study period. Results: 438 patients were treated for colorectal cancer in the study period. In patients who underwent curative surgery and developed a recurrence, serum CEA was elevated in 20% patients at primary diagnosis and in 46.6% patients at recurrence. Only 1 of 30 patients with rectal cancer had an elevated CEA at diagnosis of primary tumour. Tumour relationship to the peritoneal reflection did not appear to play a role. Conclusions: In rectal cancers, serum CEA levels are often normal at the time of initial diagnosis. However, this should not preclude its use in post-operative surveillance. Serum CEA levels noted in primary rectal cancer appear unrelated to the relationship of the tumour to the peritoneal reflection. Stroma-related factors could possibly be involved and merit further investigation. PMID- 29147282 TI - Role of Reactive Oxygen Species and Nitric Oxide in Mediating Chemotherapeutic Drug Induced Bystander Response in Human Cancer Cells Exposed In-Vitro. AB - Background: The intention of cancer chemotherapy is to control the growth of cancer cells using chemical agents. However, the occurrence of second malignancies has raised concerns, leading to re-evaluation of the current strategy in use for chemotherapeutic agents. Although the mechanisms involved in second malignancy remain ambiguous, therapeutic-agent-induced non-DNA targeted effects like bystander response and genomic instability cannot be eliminated completely. Hence, Bleomycin (BLM) and Neocarzinostatin (NCS), chemotherapeutic drugs with a mode of action similar to ionizing radiation, were used to study the mechanism of bystander response in human cancer cells (A549, CCRF-CEM and HL-60) by employing co-culture methodology. Methods: Bystander effect was quantified using micronucleus (MN) assay and in-situ immunofluorescence(gammaH2AX assay).The role of reactive oxygen species (ROS) and nitric oxide (NO) in mediating the bystander response was explored by pre-treating bystander cells with dimethylsulphoxide (DMSO) and C-PTIO respectively. Results: Bystander response was observed only in CCRF-CEM and A549 cells (P < 0.001). A significant decrease in this response was observed with ROS scavenger, DMSO. Conclusion: This significant attenuation in the bystander response on treatment with DMSO, suggests that ROS has a more significant role in mediating the bystander response.Since the possibility of the ROS and NO in mediating these bystander effect was confirmed, mechanistic control of these signaling molecules could either reduce radiation damage and potential carcinogenicity of normal tissues (by reducing bystander signaling) or maximize cell sterilization during chemotherapy (by amplifying bystander responses in tumors). PMID- 29147283 TI - Occult Breast Cancer Presenting as Leptomeningeal Carcinomatosis. AB - Leptomeningeal carcinomatosis (LC) is a rare and devastating metastatic manifestation of both liquid and solid tumors consisting of dissemination of malignant cells with invasion into the meninges. Few options exist in most clinical situations, especially when LC is the presenting sign of occult malignancy. The prognosis is often poor with limited survival. Aims of palliation must be considered the primary goal for most patients. We report a case in which occult metastatic breast cancer presented with neurological symptoms from LC. We discuss diagnosing the primary malignancy when LC is the presenting manifestation as well as treatment, both palliative and cytoreductive. We also focus on those patients with breast cancer that are at highest risk of developing LC. PMID- 29147284 TI - Multiple Myeloma With Mixed Lytic and Blastic Bone Lesions With Lymphadenopathy: Rare Manifestation of a Common Disease-Case Presentation and Literature Review. AB - Multiple myeloma - a neoplastic proliferation of plasma cell is the second most common blood cancer. Multiple myeloma is characterized by neoplastic proliferation of the plasma cells. These cells infiltrate variety of organs. Infiltration by immature neoplastic cells and overproduction of monoclonal immunoglobulin chain is responsible for clinical manifestations of multiple myeloma. The most common clinical presentation of multiple myeloma is an asymptomatic person having anemia and elevated globulin in laboratory testing. Multiple myeloma is diagnosed by triad of > 10% marrow infiltration by plasma cells, serum/urine monoclonal protein and end organ damages. One of the common end organ damage is lytic bone lesions resulting from imbalance between osteolytic and osteoblastic activities. Lymphadenopathy and osteoblastic lesions are rare presentations of multiple myeloma - lymphadenopathy in 1% of cases with IgA subtype and osteoblastic lesions in IgE myeloma and lambda light chains. Osteoblastic multiple myeloma is a distinct entity from POEMS syndrome. IgG myeloma with kappa chain predominance is not described yet with osteoblastic lesions and lymphadenopathy. We present a rare case of IgG myeloma with kappa chain predominance that had both lymphadenopathy and osteoblastic lesions. PMID- 29147285 TI - Brain Metastasis From Prostate Adenocarcinoma: Case Report and Review of Literature. AB - It is rare for prostate carcinoma to metastasize to the central nervous system. It often represents a terminal event with death in one year frequently due to the advanced systemic disease. Starting by a case report, we also reviewed the relevant literature to focus on this uncommon entity from epidemiology to clinical manifestation and therapeutic strategies. In this article, a case of multiple brain prostate metastasis is reported and a review of relevant literature is also discussed. Treatments available for intracranial metastasis include neurosurgery, external beam radiation and hormonal manipulation. Surgery associated with whole brain radiotherapy seems to be effective in the control of brain lesions both relieving neurological symptoms and prolonging survival, even if prognosis remains dismal. From this case, we concluded that brain metastasis from prostate carcinoma is a rare, terminal event with death in one year frequently due to the advanced systemic disease. A better understanding of the biology of prostate carcinoma will help clarify the basis for its metastasis to the brain. PMID- 29147286 TI - Effusive-Constrictive Pericarditis Secondary to Primary Pericardial Lymphoma: A Case Report. AB - Few cases of primary cardiac lymphoma (PCL) are found in the literature. We report the case of an 85 year-old male who presented with cardiac tamponade and effusive-constrictive pericarditis secondary to primary cardiac lymphoma involving only the pericardium. There have been no prior published cases with these rare scenarios. PMID- 29147287 TI - Helicobacter Pylori Negative Extranodal Zone B Cell Lymphoma Presented as a Polypoid Gastric Mass: A Case Report. PMID- 29147288 TI - A Review of Novel Systemic Therapies and Brain Radiosurgery for Metastatic Melanoma. AB - Melanoma is a prevalent and particularly aggressive form of skin cancer. Although local disease can be treated well with excision, metastatic extracranial and intracranial disease can be very difficult to treat. Systemic therapies for melanoma have only recently led to statistically significant increases in overall survival with drugs such as Ipilimumab and Vemurafenib. Additionally, melanoma has been classically described as a relatively radio-resistant malignancy. Because of the potential radio-resistance, stereotactic radiosurgery has been widely utilized for intracranial brain metastases and clinical data has revealed excellent rates of local tumor control and tolerability with these highly focused radiation doses. PMID- 29147289 TI - Lung Cancer Screening for the Poor and Underserved: Should Routine Screening be Performed? AB - Background: Lung cancer is a leading cause of death in United States. A recent study using low dose CT scans for screening long term smokers for lung cancer has, for the first time, demonstrated reduction in mortality, although it is not a standard of care in the community yet. Method: We analyzed lung cancer data for stages 0 through 4 for 1,412 individuals from, a public hospital, Nassau University Medical Center (NUMC) with patients of lower income, two private hospitals, North Shore University Hospital (NSUH) and Long Island Jewish Hospital (LIJ), with patients of higher income, with average household income per year of 83,795 $, 152,777 $ and 93,234 $ respectively. Result: Significantly smaller percentages of patients were diagnosed with stages 0 and 1 lung cancer at NUMC (8.55%) versus either NSUH (36.18%, P < 0.001) or LIJ (35.70%, (P < 0.001). Conclusion: At this point there is evidence that Lung Cancer Screening reduces mortality in long term smokers, but there is debate over, if it should be made into a recommendation. In light of the above study we suggest, that screening for lower socioeconomic class, could be recommended, if not for general population. PMID- 29147290 TI - Evaluating the Usefulness of a Novel 10B-Carrier Conjugated With Cyclic RGD Peptide in Boron Neutron Capture Therapy. AB - Background: To evaluate the usefulness of a novel 10B-carrier conjugated with an integrin-binding cyclic RGD peptide (GPU-201) in boron neutron capture therapy (BNCT). Methods: GPU-201 was synthesized from integrin-binding Arg-Gly-Asp (RGD) consensus sequence of matrix proteins and a 10B cluster 1, 2-dicarba-closo dodecaborane-10B. Mercaptododecaborate-10B (BSH) dissolved in physiological saline and BSH and GPU-201 dissolved with cyclodextrin (CD) as a solubilizing and dispersing agent were intraperitoneally administered to SCC VII tumor-bearing mice. Then, the 10B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Meanwhile, tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with GPU-201, BSH-CD, or BSH. Immediately after reactor neutron beam or gamma-ray irradiation, during which intratumor 10B concentrations were kept at levels similar to each other, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. Results: The 10B from BSH was washed away rapidly in all these tissues and the retention of 10B from BSH-CD and GPU-201 was similar except in blood where the 10B concentration from GPU-201 was higher for longer. GPU-201 showed a significantly stronger radio-sensitizing effect under neutron beam irradiation on both total and Q cell populations than any other 10B carrier. Conclusion: A novel 10B-carrier conjugated with an integrin-binding RGD peptide (GPU-201) that sensitized tumor cells more markedly than conventional 10B carriers may be a promising candidate for use in BNCT. However, its toxicity needs to be tested further. PMID- 29147291 TI - The Role of Multi Detector Computed Tomographic Imaging Prior to Clinic Consultation in Patients Suspected to Have Lung Cancer. AB - Background: Scanning patients early in their diagnostic journey helps in differentiating benign from malignant aetiology. There is increasing pressure on diagnostic practices for rapid diagnoses and thereby early commencement of treatment in patients suspected to have lung cancer (LC). In our practice, multi detector computed tomography (MDCT) imaging is performed in selected patients referred to the LC service prior to them seeing a chest physician in the LC clinic. This study evaluates the role of such practice and reviews its potential impact on LC services. Methods: Prospective review of our practice from January 2007 to Apr 2007 was performed. Consecutive patients referred to the service with suspected LC were included. Chest radiograph (CXR) report and clinical information from general practitioners were reviewed and graded as high, medium or low risk for presence of LC. Patients with sufficient clinical and/or radiological concern underwent MDCT imaging prior to their clinic. Combined risk scores and modified risk scores were formulated and assessed against MDCT findings. Results: A total of 139 patients were referred to the service, 124 of these had pre-clinic MDCT. Fifty-three patients (43%) had malignancy, 39 (31%) had non-malignant significant abnormalities, 17 (14%) had other incidental findings and 15 (12%) were normal. Modified combined risk score was the best predictor of presence of cancer. Conclusion: Pre-clinic MDCT scanning in patients with suspected LC is feasible and has a promising role in the modern care of LC patients. It also empowers physicians with additional information at the primary consultation. PMID- 29147292 TI - A Case of Angiosarcoma Arising in Trunk of the Right Pulmonary Artery Clinically Simulating Pulmonary Thromboembolism. AB - Angiosarcoma arising in the pulmonary artery is extremely rare. We herein report a case of angiosarcoma arising in the pulmonary artery trunk of 71 year-old woman. This case was clinically diagnosed as pulmonary thromboembolism but angiosarcoma of the pulmonary artery should be considered as the differential diagnosis of unusual clinical manifestations of pulmonary thromboembolism because of the extremely poor prognosis of the lesion. PMID- 29147293 TI - Long Term Complete Remission in Advanced Gastric Adenocarcinoma With Docetaxel, Oxaliplatin and Capecitabine Combination Regimen. AB - Gastrointestinal tract cancers are highly lethal malignancies with early metastatic dissemination. Chemotherapy is therefore of crucial importance in advanced cancer for obtaining palliation of symptoms and improving survival. However, there is no universal standard chemotherapy regimen for the treatment of gastroesophageal cancer. Also, complete remission is an uncommon outcome in advanced gastroesophageal cancers treated with chemotherapy; and where encountered, the response is not sustained. We present a 65 year-old patient who presented with advanced gastric adenocarcinoma. She had histopathologically proven liver metastases. She was treated with chemotherapy comprising of six cycles of Docetaxel, Oxaliplatin and Capecitabine (DOX). She showed complete remission with disappearance of local as well as liver lesions, and achieved disease free status for 9 months. This is the first known sustained Complete Response in a case of advanced gastric carcinoma with DOX combination regimen. PMID- 29147294 TI - Meningioangiomatosis Without Neurofibromatosis Type 2. AB - Meningioangiomatosis (MA) is a rare, benign hamartomatous lesion found in cerebral cortex and leptomeninges. It occurs mostly in 5 - 15 year old children in form isolated or diffuse; the diffuse form may be associated with neurofibromatosis type 2 (NF2). The sporadic type in the adults is less common.The patient was a 37 year-old man with a long history of frontal headache. In suspected sinusitis, the patient underwent cerebral MRI that showed hypointense lesion in the right frontal lobe with heterogeneous contrast enhancement after gadolinium administration. There were no stigmata or family history of neurofibromatosis. A right pterional approach with a supraorbital craniotomy was performed. The lesion was removed with complete remission of the headache in the postoperative time. MA enters into differential diagnosis with several other diseases and a correct diagnosis is mandatory. The total surgical removal is the treatment of choice, and the prognosis after surgery is usually excellent for the absence of recurrence in sporadic cases. PMID- 29147295 TI - Germ Cell Tumor Located in Gastrointestinal System: A Report of Two Cases. AB - Germ cell tumors (GCTs) occur generally in the testes or ovaries. Extra-gonadal location of GCTs is very rare .Extra-gonadal GCTs usually arise from midline structures, the commonest sites being the retroperitoneal and mediastinum. Gastrointestinal germ cell tumors are very uncommon. The etiology, prognosis and clinical course of gastrointestinal GCTs are not well understood yet. Weherein present two GCTs cases who referred with gastrointestinal bleeding and obstruction these tumors originated from retroperitoneal site. In the light of the literature, the clinical and pathological findings of the cases are presented. Prominent features of our cases were being located in the gastrointestinal system, being at young ages, presenting with gastrointestinal bleeding and good outcome. PMID- 29147296 TI - Clinical Evidence: Metastases can Metastasize. AB - We report the unusual case of a 52-year-old female with known stable metastatic ovarian cancer presenting with a new, rapidly growing gastric metastasis, leading to surgical resection. Histologic assessment of the specimen revealed evidence of submucosal and intramuscular metastatic disease originating from a metastatic lesion and not from the primary tumor. This case represents one of an otherwise rarely documented clinical scenario that a metastatic focus can itself metastasize. PMID- 29147297 TI - Superior and Inferior Extension of Carotid Body Tumors. AB - Carotid body tumors typically arise at the level of the common carotid bifurcation where the carotid body exists. Superior and inferior extension beyond the carotid body may occur as well, especially if the tumor is long-standing. We herein describe a case of carotid body tumor in a patient who presented with a right-sided neck mass for 30 years. Computed tomography angiography (CTA) and B mode sonography with color-coded Doppler sonography showed a vascular tumor arising at the level of the right common carotid artery bifurcation with superior and inferior extension beyond the bifurcation. This report emphasizes the utility of computed tomography angiography (CTA) and B-mode sonography with color-coded Doppler sonography as non-invasive modalities in visualizing the extension of carotid body tumors. PMID- 29147298 TI - Detection of Skeletal Lesions by Whole Body Multidetector Computed Tomography in Multiple Myeloma has no Impact on Long-Term Outcomes Post Autologous Hematopoietic Cell Transplantation. AB - Background: Multiple myeloma (MM), a plasma cell malignancy, is the most common cancer to involve the skeleton. Skeletal related events such as pathologic fractures and lytic bone lesions have been associated with poor prognosis. Whole body multidetector computed tomography (WBCT) has been shown to be the most sensitive imaging modality in detecting small osteolytic lesions (< 5 mm) in the spine. The significance of lytic lesions detected only by CT is unknown as is their impact on overall survival of MM. The aim of this study was to evaluate the impact of lytic bone lesions seen only by WBCT on progression free survival (PFS) and overall survival (OS) in MM patients after hematopoietic cell transplantation (HCT). Methods: We evaluated 72 patients who had WBCT and conventional radiographic skeletal survey (CSS) after initial or salvage chemotherapy prior to HCT. Results: Forty-one patients (57%) had more findings on WBCT than CSS, 31 patients (43%) had no differences in the two imaging techniques, 9 patients had no bone lesions on either modality, and 5 patients had lesions only identified by WBCT and not on CSS. PFS and OS were similar in patients with lesions seen by CSS irrespective of whether additional lesions were noted by WBCT; similarly, in patients without lesions on CSS, OS and PFS were better than patients with lytic lesions, but detection of occult lesions by WBCT did not adversely affect PFS or OS. Conclusions: Our study shows that although WBCT is more sensitive in defining existing myelomatous bony disease in MM, these additional findings may not have any impact on PFS and OS of MM patients. Only patients without any bone lesions on conventional skeletal survey had significantly better PFS and OS. This suggests CSS remains the gold standard for evaluating myeloma bone disease. PMID- 29147299 TI - Serum Soluble Interleukin-2 Receptor is Increased in Malnourished and Immunosuppressed Patients With Gastric and Colorectal Cancer: Possible Influence of Myeloid-Derived Suppressor Cells. AB - Background: Soluble IL-2 receptor (sIL-2R) is the circulating form of a membrane receptor localized on lymphoid and some tumor cells; its biological function is not completely understood. Methods: Serum levels of sIL-2R in blood samples taken from 51 cancer patients (21 gastric and 30 colorectal) and 18 healthy volunteers were measured and found to be significantly higher in the patients. Results: Concentrations were significantly inversely correlated to nutritional parameters, including total protein and short turnover proteins such as prealbumin, retinol binding protein and transferrin, as well as to the stimulation index, which is a classical parameter of cell-mediated immunity. Concentrations were significantly positively correlated to neutrophil count and inversely to lymphocyte count. Significantly elevated levels of circulating myeloid-derived suppressor cells (MDSCs) were found in patients; this was significantly correlated to sIL-2R levels. Conclusions: Increased production of sIL-2R correlated with systemic inflammation, nutritional impairment and inhibition of cell-mediated immunity, and thus may be involved in immunological mechanisms inducing cancer cachexia. The same factors also appear to relate closely to induction of MDSCs. PMID- 29147300 TI - Clinical Characteristics of 130 Patients With Hepatocellular Carcinoma Followed at a Tertiary Hospital From Brazil. AB - Background: Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver that represents a serious public health problem all over the world, corresponding to the third cause of cancer death worldwide. The object was to present the clinical characteristics and follow-up of patients with HCC attended at the University Hospital of the Faculty of Medicine of Ribeirao Preto-USP (HCFMRP-USP), Ribeirao Preto, Sao Paulo, Brazil. Methods: Epidemiological and clinical data were revised from medical records. Results: A total of 130 patients participated in the study, 81.5% of them being males. Mean (+/- SD) age at the time of HCC diagnosis was 55.6 +/- 11.2 years. Cirrhosis was present in 89.2% of cases, with 53.4% of the patients being Child-Pugh A; chronic hepatitis B or C without cirrhosis was detected in 3.2%, non-alcoholic steatohepatitis (NASH) in 3.8%, and a normal liver in 3.8%. Orthotopic liver transplantation was performed in 26.2% of the subjects, 16.9% of the patients were submitted to surgical resection, and 6.2% to percutaneous ethanol infusion (PEI). Transarterial embolization and transarterial chemoembolization were performed in 9.2% of the patients. Systemic chemotherapy was applied to 4.6% of cases and 24.6% of the patients received symptomatic treatment. Conclusion: Thus, in the present series cirrhosis was the main risk factor for HCC, with 53.4% of the patients being Child-Pugh A. Liver transplantation or surgical resection of the tumor, potentially curative techniques, were possible in only 43.1% of cases. PMID- 29147301 TI - Low-Dose Aspirin Therapy Does not Increase the Severity of Acute Radiation Proctitis. AB - Background: Although anticoagulation therapy is commonly used in the prostate cancer population, there are only a few studies about the correlation between radiation proctitis and anticoagulation therapy. The purpose of the present study was to determine whether low-dose aspirin increases the severity of acute radiation proctitis in an experimental animal model. Methods: Wistar rats were used in the present study. The rats were administered either aspirin at doses of 5, 10, and 20 mg/kg, or saline, daily before and after irradiation. The rats were irradiated to the rectum as a single fraction of 25 Gy. The rectal mucosal changes of each rat were evaluated macroscopically and pathologically on the tenth day following irradiation. The findings of proctitis were graded from 0 to 4, and then were compared with regard to the status. Results: No apparent correlations were observed between the administration of aspirin and the severity of radiation proctitis in the macroscopic findings and in the morphological mucosal damage in the pathological examination. The proportion of rats with a severe degree of mucosal inflammation was 90.0%, 100.0%, 16.7% and 100.0% at 5 mg/kg, 10 mg/kg, and 20 mg/kg of aspirin, or saline, respectively. The rats receiving aspirin at the dose of 20 mg/kg showed significantly milder inflammation than the other groups (P < 0.05). Conclusions: In the present study, low-dose aspirin did not increase the severity of acute radiation proctitis. In addition, aspirin might decrease the severity of radiation-induced mucosal inflammation in the rectum. PMID- 29147302 TI - Metastatic Leiomyosarcoma to the Spine Complicated With Thrombocytopenia. AB - Uterine leiomyosarcomas do not frequently metastasize to the bone, and spinal column metastases are even less common. Surgery is the treatment of choice. Adjuvant radiation with or without chemotherapy depending on the extent of disease can be beneficial. We present the case of leiomyosarcoma metastasis to the spine with a previous history of known primary disease complicated by thrombocytopenia. Thrombocytopenia can present surgical challenges, but can also be present concurrently unrelated to the primary disease. A thorough evaluation is needed to rule out any underlying lymphoproliferative disorder or microangiopathic phenomenon. PMID- 29147303 TI - Atypical Presentation of Prostate Cancer and the Workup of an Adenocarcinoma of Unknown Primary. AB - Prostate Adenocarcinoma is one of the most commonly diagnosed cancers in the United States, with a prevalence of around 2.4 million. Patients with this disease commonly present with urinary frequency and hesitancy, nocturia, and dysuria secondary to tumor enlargement. We present the case of a 60-year-old man with multiple-site biopsy proven metastatic prostate cancer that presented with neither urological or bone related signs or symptoms. His findings were rather atypical; they included dyspnea, pancytopenia, nausea, and chills. We then detail how we narrowed our diagnosis through a systemic process of elimination, and review the general workup of an adenocarcinoma of unknown primary in a male patient. PMID- 29147304 TI - Hypercalcemia as a Presenting Clinical Manifestation of Adenocarcinoma of the Colon. AB - Hypercalcemia is rarely associated with colon cancer. It is related to overexpression of parathyroid hormone-related protein (PTH-rp) in malignant cells of the primary colon tumor and metastases. A 44 year old lady presented for evaluation of severe hypercalcemia (15.7 mg/dL) associated with abdominal pain, nausea and constipation. She was diagnosed with metastatic colon cancer involving the liver. Therapy for hypercalcemia consisted of intravenous bisphosphonate and saline hydration. Hypercalcemia remained resistant and refractory to treatment despite resection of the colon tumor. She died soon after admission to hospice. It is proposed that malignant cells of the primary colon tumor and distant metastases, in this patient, were the site of ectopic PTH-rp secretion resulting in hypercalcemia. This case illustrates the significance of recognizing hypercalcemia as a potential clue in detecting underlying colon cancer involving overproduction of PTH-rp. It also exemplifies the poor prognosis expected with this type of humoral hypercalcemia of malignancy and the difficulty encountered when trying to achieve normalization of calcium in this setting. PMID- 29147305 TI - Early Recognition of Immune Reconstitution Inflammatory Syndrome Leads to Avoidance of Endotracheal Intubation. AB - Immune reconstitution inflammatory syndrome occurs in patients with rapidly recovering immune systems in response to antigens (viable pathogens, nonviable pathogen debris, host antigens or tumor antigens). The acronym IRIS, Greek for spectrum of color, is often used for immune reconstitution inflammatory response syndrome and reflects the wide spectrum of clinical manifestations associated with this entity. This is a case report of an acute myelogenous leukemia patient with neutropenia after cytotoxic chemotherapy who developed severe dyspnea and new pulmonary infiltrates temporally associated with rapid neutrophil recovery. The incidence, pathogenesis, clinical presentation and therapy of IRIS will be discussed in this article. There should be an increased awareness of the many clinical manifestations of IRIS in hematologic malignancy patients with rapid neutrophil recovery after cytotoxic chemotherapy, in order to allow prompt institution of corticosteroids which could be life saving. PMID- 29147306 TI - Diffuse Large B-Cell Lymphoma at the Site of a Herpes Zoster Scar. AB - Herpes zoster, also known as shingles, occurs upon reactivation of a primary infection with varicella zoster virus (VZV). Risk factors for reactivation include stress, older age, and immunosuppression, all of which are associated with a decrease in host immunity. Common complications of herpes zoster include scarring and post-herpetic neuralgia (PHN). Cutaneous lesions such as granuloma annulare, lymphomas, and sarcoid granulomas have also been reported to potentially arise at the site of herpes zoster. Here, we report a case that to our knowledge is the first presentation of diffuse large B-cell lymphoma with its only cutaneous manifestation arising in a herpes zoster scar. Punch biopsy was performed on a nodule appearing in a dermatomal distribution within the herpes zoster scar. Histopathology revealed an atypical lymphoid infiltrate in the dermis that was determined to be CD20 positive B-cells. Immunostains for CD20, CD79a, and PAX-5 showed strong positive staining of the atypical cells, confirming B-cell origin and resulting in the diagnosis of lymphoma, large B-cell type. This case highlights the importance of raising clinical suspicion for a malignant process in patients who present with a changing or unresolving skin manifestation after infection with varicella zoster virus. PMID- 29147307 TI - Cancer Therapy: A Continuance of Health Burden. AB - Background: Cancer diagnosis coupled with emotional impact converge to create one of the most difficult physical and emotional periods of life. Cancer treatment causes plethora of short and long term complications which can be so debilitating that patient may interrupt treatment. Pretreatment oral assessment and supportive oral care during and after cancer therapy can increase quality of life and supportive care costs. Methods: Study was conducted on 189 patients (86: head and neck cancer cases, group I and 103: other than head and neck cancer cases, group II) receiving cancer therapy. Patients were subjected to clinical assessment and findings were recorded in specially designed proforma and complete oral (objective and subjective) and constitutional findings were recorded. Results: Among the patients undergoing chemotherapy in both groups, prevalence of oral findings was found to be highest with methotrexate whereas constitutional symptoms was found to be highest with doxyrubicin. Whereas in radiotherapy patients subjective and objective oral symptoms increased from 10th - 30th fractionated dose of radiations and then subsequently decreased and constitutional symptoms were found to be consistent in all fractionated dosages with lowest at 50th fraction. Under combined chemo and radiotherapy patients, constitutional symptoms were highest than the oral findings. Conclusions: Cancer therapy can greatly damage the normal tissues and diminish patients quality of life and often leads to serious clinical sequelae. Therefore, therapy induced damage should be anticipated and prevented whenever possible and managed early. PMID- 29147308 TI - Patients' and Health Care Providers' Evaluation of Quality of Life Issues in Advanced Cancer Using Functional Assessment of Chronic Illness Therapy - Palliative Care Module (FACIT-Pal) Scale. AB - Background: To examine the agreement of Health Care Providers (HCPs) and patients' evaluation of quality of life on the Functional Assessment of Chronic Illness therapy - Palliative care module (FACIT-Pal) scale. Methods: Sixty advanced cancer patients and fifty-six health care providers involved in their care at Sunnybrook Health Sciences Centre completed a modified version of the FACIT- Pal. In the survey, patients and HCPs indicated the 10 top issues affecting the quality of life of patients with advanced cancer most profoundly. The percentage of participants selecting each item as one of their 10 most relevant items was calculated in HCPs and patients. Results: There were differences in relative rankings of QOL issues among patients and HCPs. Among the top 10 items which were identified from both patients and HCPs, there were differences in the rankings. Patients ranked emotional support from family (40.9%) as most important followed by pain (38.6%), lack of energy (31.8%) and able to enjoy life (29.6%). HCPs ranked in the following order: pain (73.2%), lack of energy (63.4%), nausea (51.2%) and dyspnea (51.2%) whereas patients rated nausea at 18.2 % and dyspnea at 9.09%. Conclusion: There is a discrepancy between scores of patients and HCPs as they may prioritize differently. HCPs tended to put more emphasis on physical symptoms, whereas patients had emotional and global issues as priorities. PMID- 29147309 TI - Metastatic Cutaneous Squamous Cell Carcinoma to the Axilla: A Review of Patient Outcomes and Implications for Future Practice. AB - Background: Nodal metastasis from cutaneous SCC carries a high morbidity and mortality. Limited direct evidence is available as to the impact of radiotherapy on the outcome of patients with metastatic axillary SCC. The purpose of this study was to report on the outcomes of patients with metastatic cutaneous SCC to the axilla treated with radiotherapy. Methods: A retrospective review of patients treated with radiotherapy between 1993 and 2010 for metastatic cutaneous SCC to the axilla was undertaken at St George Hospital, Sydney. Results: Radiotherapy was administered to 36 patients, 30 with curative intent (4 definitive, 26 adjuvant) and 6 with palliative intent, 27/36 (75%) were male, 22/36 (61%) had a previous diagnosis of cutaneous SCC, and 1/36 (3%) was immunosuppressed. Mean age was 74.6 years. Mean radiotherapy dose (BEDGy10) was 61Gy10 (range 39-85 Gy10), 20/36 (56%) patients experienced recurrence, including 16 local failures and 4 isolated distant failures. Median survival for the curative and palliative groups was 3 years and 1 month, respectively. Relapse free survival (n = 36) at 2 and 5 years was 46% and 35%, respectively (curative 52% and 39%). Only 1 failure achieved complete salvage. Conclusion: Despite current best practice (surgery and radiotherapy), the predominant pattern of failure in these patients with metastatic axillary cSCC was locoregional. The difficulty in successfully salvaging patients after locoregional nodal relapse suggests a need for treatment intensification. PMID- 29147310 TI - Incidental Appendiceal Carcinoids: Is Surgery Affecting Their Incidence? AB - Background: There is lack of consensus on the incidence of appendiceal carcinoids in recent times. The influence of number of appendicectomies performed has been postulated to play a role in this. To determine the incidence and clinico pathological profile of appendiceal carcinoids in a cohort of patients undergoing emergency appendicectomies for clinically suspected acute appendicitis, and examine the influence of the trend (if any) of the number of appendicectomies performed on the overall incidence of appendiceal carcinoids. Methods: A retrospective analysis of patients diagnosed with appendiceal carcinoids following presentation with acute appendicitis to the Modbury hospital, South Australia from March 2007 to April 2011. The patient cohort was divided into Group 1 (March 2007 - March 2009) and group 2 (April 2009 - April 2011) to study the influence of time trends on incidence of appendiceal carcinoids. Statistical analyses were performed using the Statistical Product and Service Solutions, SPSS 14.0 for Windows. Results: Of 506 patients who underwent emergency appendicectomy for acute appendicitis, 8 patients (1.6%) were found to have appendiceal carcinoids. The median age was 23 years with 7 patients being female. There was no difference in the incidence of appendiceal carcinoids over the two time periods (P < 0.12). Conclusions: Appendiceal carcinoids were found in 1.6% of patients undergoing emergency appendicectomy for acute appendicitis. These tumors are found more commonly in young females with a predilection for the tip of the appendix. The perceived increased incidence appendiceal carcinoids appear to be unrelated to the increase in the number of appendicectomies being performed. PMID- 29147311 TI - Solitary Apical Lung Mass in a Patient With Cervical Cancer. AB - We present the case of a 40 years old female presenting with a solitary apical lung mass, associated Horner syndrome and evidence of medullary compression. Although she had a history of cervical cancer, a primary lung tumor was suspected. Tissue biopsy confirmed cervical cancer metastasis, highlighting the fact that although metastasis usually presents as multiple lung nodules, solitary lesions can be the presenting sign. PMID- 29147312 TI - Non-Hodgkin's Lymphoma as a Risk Factor for Persistent Chylothorax After Transhiatal Esophagectomy. AB - We report a case of an 82 years old female with Non-Hodgkin Lymphoma (NHL) in remission whom underwent a transhiatal esophagectomy (THE) for esophageal adenocarcinoma. The post-operative course was complicated by severe chylothorax requiring an additional thoracotomy for ligation of the thoracic duct. The influence of the patient's history of NHL on the development of such a severe chylothorax is under question. PMID- 29147313 TI - Hypertrophic Pulmonary Osteoarthropathy: A Case Report. AB - A 42-year-old male presented to the emergency department with difficulty breathing and body pain particularly in his bilateral lower extremities. A workup was done and he was diagnosed with sarcomatoid carcinoma of the lung. Bone scintigraphy was performed and hypertrophic pulmonary osteoarthropathy was diagnosed to be the source of the pain. PMID- 29147314 TI - Synchronous Duodenal Carcinoid and Adenocarcinoma of the Colon. AB - Carcinoid tumors are a histological subtype of well differentiated, low to intermediate grade, slow-growing neuroendocrine malignancies capable of secreting bioactive peptides, such as 5-hydroxytryptamine (5-HT, serotonin), chromogranin-A and chromogranin-C. Here we present a case of a duodenal carcinoid that simultaneously occurred with adenocarcinoma of the colon. A 59-year-old male with a past medical history of hepatitis C and hypertension presented complaining of worsening abdominal pain associated with 2 - 3 episodes per week of bright red blood per rectum for the past month. He also reported a 20 pounds weight loss in the last 6 months. Social history was significant for a 15 pack year history. Vitals on admission were within normal limits. Physical exam was significant for right upper quadrant tenderness without guarding, rebound, or organomegaly. Rectal exam revealed no blood or masses. Laboratory results showed iron deficiency anemia with hemoglobin of 9.6 K/mm3. Esophagogastroduodenoscopy revealed a 4 mm duodenal polyp. Colonoscopy was terminated early secondary to a large circumferential obstructing mass found in the descending colon. Immunohistochemistry of the duodenal biopsy was positive for synaptophysin and chromogranin-A; consistent with the diagnosis of stage I carcinoid tumor. Biopsy results of the colonic mass showed a stage I well-differentiated adenocarcinoma. The patient underwent a left colectomy and partial duodenectomy; he remains in remission after 2 year of close follow up. When the diagnosis of small bowel carcinoid is made, further screening for other primary neoplasms should be sought to prevent potential late stage diagnosis of synchronous malignancies. This is crucial because patients' demise usually result from the associate tumor and not the carcinoid component. Finally, we would like to raise clinician's awareness regarding the incidence of this entity since some of the studies suggest that it is more common than it was previously thought. PMID- 29147315 TI - Diagnostic Approach to a Patient With Paraneoplastic Neurological Syndrome. AB - Herein, we discussed a case of an otherwise healthy man who presented with progressive gait imbalance and ataxia, found to have small cell lung cancer. Based upon our clinical findings and laboratory data, a diagnosis of paraneoplastic cerebellar degeneration was made. Paraneoplastic neurological syndromes (PNS) are relatively rare but diverse and always should be considered in differentials. A diagnostic algorithm along with appropriate work up is discussed here. PMID- 29147316 TI - Health Care Professionals' Evaluation of Quality of Life Issues in Patients With Brain Metastases. AB - Background: The Functional Assessment of Cancer Therapy - Brain (FACT-Br) is a brain specific Quality of life (QOL) tool used for patients in the primary and metastatic cancer population. The purpose of this report is to evaluate the QOL issues health care professionals (HCPs) find most important when caring for brain metastases patients. Methods: HCPs were asked to rate whether each of the 23 FACT Br subscale items were relevant to patients or not. In the survey, HCPs indicated the 5 to 10 top issues affecting the QOL of patients with brain metastases. Demographic information such as gender, years of experience, and health care specialty were recorded. Results: A total of 46 HCPs participated in the study, 89% of HCPs ranked the need for help in caring for themselves as the most relevant item for patients with brain metastases. Other highly relevant items included the concern of getting headaches (81%) and weakness in arms or legs (78%). The lowest rated items included the ability to put thoughts together (8%), ability to write as they used to (11%) and also the ability to read as they used to (14%). Conclusion: It is very important to determine the issues that HCPs think are most important to patients in an attempt to harmonize these with those of patients. Future studies should compare the items that HCPs rate as most relevant to those that patients rate to ensure agreeability. PMID- 29147317 TI - Maintenance Chemotherapy Use for Advanced Non-Small Cell Lung Cancer in an Australian Cancer Centre. AB - Background: To investigate the rates of maintenance therapy in advanced non-small cell cancer, the reasons for not progressing to second line therapy at disease progression at our cancer centre and to use this data as a way to institute it into clinical practice in our cancer centre. Method: This study was approved by the ethics committee. The data was collected from a purpose built cancer unit database, patient and pharmacy records for all patients diagnosed with Stage 3 and 4 non-small cell lung cancer between 2005 - 2011. Demographic information was collected and subgroup analysis of mean overall survival was obtained. Reasons for not progressing to second line therapy were also analysed. Results: Of the 105 patients available for analysis, 44 achieved stable disease/partial response (SD/PR) post first cycle of which 42 were eligible for maintenance chemotherapy, 7 went onto receive maintenance with a mean overall survival (OS) of 18.26 months, 23 received second line with the highest OS of 28.19 months and 12 didn't receive either with the lowest OS of 11.52 months. The majority of these patients did not receive second line at disease progression because of being too unwell. Conclusion: Similar data on the progression to second line chemotherapy in this patient group was seen. Those that received second line chemotherapy had higher overall survival and thus maintenance therapy could be a means to allow patients to be fit enough to receive second line when they need it. PMID- 29147318 TI - Increasing Role of FDG-PET/CT in Detecting Bone Marrow Metastasis of Solid Tumors in Adults: An Analysis of Ten Patients. AB - Background: We aimed to test the hypothesis that whether FDG-PET/CT which was ordered for various purposes can predict suspected or particularly unsuspected bone marrow metastasis (BMM) from the complete blood count and therefore can change the management of these patients. Methods: In this retrospective study, the study sample consisted of 68 subsequent patients presented to our institution's pathology department with bone marrow metastases of solid tumors. PET/CT was found to have been ordered in 10 out of 68 patients (6.8%) for various purposes. All patients gave informed consent about the PET/CT examinations and bone marrow biopsies. Result: FDG-PET/CT was ordered in 10 out of 68 solid tumor patients with pathologically proven BMM. Of these 10 patients, 3 were female and 7 were male; mean age was 54.7 years. While FDG PET/CT showed bone and BMM in 4 of 10 patients (40%), the rest of the patients had BMM without bone involvement. Five patients (50%) who had probable bone marrow involvement on their FDG PET/CT scans had unsuspected complete blood counts with regard to BMM. Conclusion: PET/CT has the ability to detect a substantial number of metabolically active tumor cells in the bone marrow in all of our patients which we proved by bone marrow biopsies. We think that this cohort of patients with solid tumors is hypothesis-generating with regard to detecting early bone marrow metastases by FDG PET/CT. PMID- 29147319 TI - Quality of Life in Patients With Primary and Metastatic Brain Tumors in the Literature as Assessed by the FACT-Br. AB - Background: The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a quality of life (QOL) assessment tool that was originally developed for use in patients with primary brain tumors. However, the tool has also been used to assess QOL in patients with metastatic brain tumors. The purpose of this study is to compare the differences in QOL responses as assessed by the FACT-Br in patients with primary and metastatic brain neoplasms. Methods: A systematic literature search was conducted using the OvidSP platform in MEDLINE (1946 to July Week 2 2012) and EMBASE (1980 to 2012 Week 28). Articles in which the FACT Br was used as a QOL assessment for patients with malignant brain tumors (both primary and metastatic) were included in the study. The weighted means of FACT-Br subscale and overall scores were calculated for the studies. To compare these scores, weighted analysis of variance was conducted and PROC GLM was performed for the data. A P-value of < 0.05 was considered statistically significant. Results: A total of 23 studies (four in brain metastases, 18 in primary brain tumors and 1 in a mixed sample) using the FACT-Br for assessment of QOL were identified. Social and functional well-being were significantly better in patients with primary brain tumors (weighted mean score of 22.2 vs. 10.7, P = 0.0026, 16.9 vs. 6.2, P = 0.0025, respectively). No other scale of the FACT-Br was significantly different between the two groups and the performance status of patients included in both groups was similar. Conclusion: Patients with primary brain cancer seemed to have better social and functional well-being scores than those with metastatic brain tumors. Other QOL domains were similar between these two groups. However, the heterogeneity in the included studies and the low sample size of included samples in patients with metastatic brain tumors could have confounded our findings. PMID- 29147320 TI - Exposure to Temozolmide in the First Trimester of Pregnancy in a Young Woman With Glioblastoma Multiforme. AB - Literature on the outcome of pregnancy with first trimester exposure to Temozolomide is limited. We describe the case of a young woman with Glioblastoma Multiforme who was exposed to Temozolomide during her first trimester of pregnancy and subsequently delivered a healthy term newborn. At six months of age, the child remains healthy with no evidence of Temozolomide related effects. PMID- 29147321 TI - Suspected CNS Metastases of Askin's Tumor: Would You Irradiate the Neural Axis? AB - We present a case of a young-adult patient who was diagnosed with Askin's tumor, with central nervous system lesions suspected as metastases. The patient achieved complete response after chemotherapy, and the question of consolidation radiotherapy to the CNS is discussed. PMID- 29147322 TI - Testicular Mass: An Initial Sign of Squamous Cell Carcinoma of the Lung. AB - Metastatic carcinoma to the testis, excluding lymphoma and leukemia, is an extremely rare condition. The most frequent primary site is prostate cancer. These lesions present clinically either as the first sign of malignancy or more commonly as a complication during the course of known disease. We present the first case of a squamous cell carcinoma of the lung diagnosed with a testicular mass, which is very rarely seen in literature, to our knowledge. PMID- 29147323 TI - Clinicopathological Characteristics of Four Cases of Adrenal Myelolipomas: A Rare Surgical Entity. AB - Myelolipomas are unusual benign tumors or tumor-like lesions, composed of hematopoietic cells and mature adipose tissue. They usually are asymptomatic and behave as non-functioning, unilateral, small adrenal tumors often found incidentally on imaging studies. We report the clinicopathological characteristics of four cases of adrenal myelolipomas treated in our hospital, worth to mention because of their rarity and their significant size. Myelolipomas were first described by Gierke in 1905, and the term myelolipoma was coined by Oberling in 1929. The adrenal gland is the most common site, but myelolipomas are also rarely present in extra-adrenal sites, including the pelvis, mediastinum, retroperitoneum, and paravertebral region, as an isolated soft tissue mass. These tumors account for 2.6% of the primary adrenal masses with equal sex distribution and in our reviewed material of a decade they constitute about 5% in a series of surgically treated adrenals for various neoplastic processes of the adrenals. Although usually small in size, in our series a remarkable large size of the tumors examined was observed, ranging from 7 - 15 cm. Adrenal myelolipoma is often an "incidentaloma", since its diagnosis is frequently based on autoptic findings or made during surgical interventions and imaging procedures performed for other purposes, as happened in our cases. PMID- 29147324 TI - Preservation of Fertility in Female Cancer Patients Desiring Future Child Bearing; What is Available and What can be Offered. AB - The aim of this review is to present an overview of available methods for preservation of ovarian function and fertility in female cancer patients who desire to maintain their child-bearing capacity for future pregnancies. A Medline search was conducted. Published articles from American and European studies from 1976 to present were reviewed. The effect of cancer treatment on the ovary, as well as different methods of fertility preservation and their reproductive outcomes are presented. Pregnancy rates vary according to the type of primary malignancy, stage of disease, method of fertility preservation (for example, hormonal therapy, cryopreservation, fertility-sparing surgery), and other confounding factors such as the patient's age, reproductive capacity, status of partnership, and genetic disposition. The highest rates of successful pregnancy were observed with embryo cryopreservation. Today, higher cure rates and longer survival are a result of earlier cancer diagnosis and treatment. In conjunction with the advances in assisted reproduction, the preservation of ovarian function and fertility is a major part of multidisciplinary care that should be offered to any young female patient with cancer. Fertility preservation in young cancer patients raises a number of ethical issues particularly regarding standard versus experimental therapies, and long-term financial cost. PMID- 29147325 TI - Quality of Life in Patients with Advanced Cancer Using the Functional Assessment of Cancer Therapy-General Assessment Tool: A Literature Review. AB - Quality of life (QOL) has become an increasingly meaningful endpoint in advanced cancer research. Clinicians assess QOL to help them select appropriate treatment options and regimens. The present review aims to compare QOL scores of the Functional Assessment of Cancer Therapy-General Assessment Tool (FACT-G) in relation to clinical and socio-demographic features in patients with advanced cancer. A literature search in MEDLINE and EMBASE was conducted; a total of 33 studies encompassing 39 study arms were identified that reported FACT-G scores. Four statistically significant parameters were identified with respect to FACT-G scores: education, national per capita healthcare expenditures, admittance status and previous radiation therapy. A greater percentage of patients completing higher education programs were correlated to significantly better emotional well being and global QOL. Cohorts from countries with higher national per capita healthcare expenditures had better physical well-being, social/family well-being and improved relationships with their doctors. Patient samples comprised of purely outpatients had better levels of emotional well-being and global QOL when compared to samples with a mix of outpatients and inpatients. A greater percentage of patients previously receiving radiation therapy were correlated to a better relationship with doctor score. Although limitations of the present review exist, differences in QOL scores based on socio-demographic and clinical factors are observed; certain correlations described in the present work have been described previously in the literature while others have not. Future work aimed at either determining confounding parameters or cause and effect relationships is recommended. PMID- 29147326 TI - Cardiotoxicity After Anthracycline Treatment in Survivors of Adult Cancers: Monitoring by USCOM, Echocardiography and Serum Biomarkers. AB - Background: Anthracyclines are agents with a well known documented anti-tumoral activity. Cardiac side effects are the principal toxicity. Here we evaluate and monitor the onset of late anthracycline-induced cardiotoxicity with real-time CW Doppler ultrasound cardiac output monitoring (USCOM(r)) and echocardiography in combination with serum biomarkers. Methods: Fifty-two patients without cardiac disease who had received an anthracycline-based regimen for various cancer types were included in this study. Patients' hemodynamic parameters as stroke volume (SV USCOM (mL)) and ejection fraction (EF ECHOCARDIOGRAPHY (%)) were measured with USCOM and echocardiography and correlated to serum biomarkers (NT-pro-BNP and cTnT). Results: Eighteen patients (34.6%) developed cardiac disease (NYHA I III). An increasing cumulative anthracycline dose was associated with a decrease of the EF determined by echocardiography as well the SV by USCOM and with a higher NYHA class. Those patients who experienced cardiac disease showed a reduction of the EF and SV and increased serum biomarkers. Conclusions: Real-time CW-Doppler USCOM, is a fast and reliable method to monitor late hemodynamic changes as a symptom of anthracycline-induced cardiotoxicity comparable to the findings by echocardiography and serum biomarkers. PMID- 29147327 TI - Usefulness of Daily Fractionated Administration of Wortmannin Combined With gamma Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis. AB - Background: To evaluate the usefulness of fractionated administration of wortmannin combined with gamma-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. Methods: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received gamma-ray irradiation after wortmannin treatment through a single or 4 consecutive daily intraperitoneal administrations up to a total dose of 4 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Results: Wortmannin raised the sensitivity of Q cells more remarkably than the total cell population in both single and daily administrations. Daily administration of wortmannin elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases. Conclusion: Daily fractionated administration of wortmannin in combination with gamma-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential. PMID- 29147328 TI - Outcome Improvement in RPA I or II Patients With 1 or 2 Brain Metastases by Combined Surgery and Radiotherapy. AB - Background: To evaluate the role of surgery and postoperative radiotherapy in the management of brain metastases (BM): a retrospective analysis for overall survival (OS), local and brain control (LC and BC) of a series of 329 patients with recursive partitioning analysis (RPA) I or II with 1 or 2 BM in a single institution. Methods: Patients were treated either with combined surgical resection and whole brain radiation therapy (WBRT) in 104 cases (31.6%) or with WBRT alone in 225 cases (68.4%). Ninety-five patients (91.4%) who underwent surgery and WBRT and 147 (65.3%) who underwent WBRT alone benefited from a radiation boost to the metastatic site. Results: The median OS was higher for patients RPA I compared to RPA II: 21.3 and 5.9 months (P < 0.0001), as well as for the surgical group compared to the radiation group: 20.2 vs 5.3 months (P < 0.0001), respectively. After the multivariate analysis, the improved OS was significantly associated with control of primary tumor (P = 0.0002) after surgical resection and with type of primary tumor (P = 0.002), absence of extracranial metastases (ECM) (P = 0.006), and high Karnofsky performance status (90 - 100 vs 70 - 80) (P = 0.003) after radiotherapy alone. The 12-, 24- and 36 months LC rates were 91.1%, 91.1% and 83.9%, respectively, after surgical resection and 81.2%, 63.1% and 57.3%, respectively, after radiotherapy alone (P = 0.005). In a univariate analysis, improved LC for the surgical group was also associated with the absence of ECM (P = 0.01) and for the radiation group, with a radiation boost (P = 0.01). The BC rates at 12, 24 and 36 months were 73.2%, 66.9% and 56%, respectively, in the surgical group and 75.7%, 49.6% and 42.4%, respectively, in the radiation group (P = 0.2). In our univariate analysis, improved BC after surgical resection was associated with control of primary tumor (P = 0.02). For patients in the radiation group, gender (P = 0.03) and a radiation boost (P = 0.0003) were significant prognostic factors in a univariate analysis. In our multivariate analysis, only the radiation boost was significant (P = 0.001). Conclusions: Surgical resection followed by WBRT leads to a better outcome compared to WBRT alone for RPA I or II patients with 1 or 2 BM. PMID- 29147329 TI - Complete Response of Para-Aortic and Lateral Pelvic Lymph Node Recurrence of Rectal Cancer Treated to S-1 Monotherapy. AB - This report presents a case of para-aortic and lateral pelvic lymph node recurrence of rectal cancer that showed complete response to S-1 monotherapy. A 69-year-old man underwent low anterior resection for rectal cancer in 2007. Para aortic lymph and right lateral pelvic lymph node recurrence occurred in 2008. He received a fluorouracil/folinic acid plus oxaliplatin regimen; however, G4 neutropenia and G3 fatigue were experienced. We started S-1 monotherapy as a salvage treatment. Abdominal computed tomography did not reveal any para-aortic and lateral pelvic lymph nodes recurrence after 10 cycles of S-1 monotherapy. Hence, response in this case was classified as a complete response. No recurrence was noted 36 months after the complete response. S-1 monotherapy is likely to be effective in treating patients with metastatic colorectal cancer who do not respond to standard combination chemotherapy. PMID- 29147330 TI - Papillary Renal Cell Carcinoma Presented With Supraclavicular Lymph Node Metastasis Without Renal Primary Lesion. AB - Renal cell carcinoma is a rare cancer in Thailand. Most of the patients present in advanced metastatic stage with identifiable renal mass. In this case report, we presents a case of male patient who manifested with supraclavicular lymph node enlargement and CT scan of chest and abdomen showed multiple sites lymph node metastasis but there was no primary mass detected anywhere. The pathology of supraclavicular lymph node was papillary cell adenocarcinoma. The differential diagnoses were papillary thyroid cancer, gastrointestinal tract carcinoma such as pancreato-biliary cancer, non small cell lung cancer, and renal cancer. Immunohistochemistry result were negative for TTF-1, Thyroglobulin, CD7 and CD20 which ruled out non-small cell lung adenocarcinoma, thyroid cancer and gastrointestinal tract cancer respectively. CD10, Vimentin and RCC were all positive and all are specific for renal cell carcinoma. The diagnosis was renal cell carcinoma, papillary cell type. Sunitinib, a tyrosine kinase inhibitor, is the treatment of choice for renal cell carcinoma since it improves objective response rate and shows longer progression free survival than IFNalpha. PMID- 29147331 TI - Rectal Plasmablastic Lymphoma in HIV/AIDS: Two Cases. AB - Plasmablastic lymphoma is an aggressive variant of large B-cells lymphoma in which the infection by Human Immunodeficiency Virus and Epstein-Barr herpesvirus are involved. This recently denominated neoplasia has a special tropism through the oral cavity. However, its presence has been reported in the digestive tract, abdominal cavity and retroperitoneum. We describe two Human Immunodeficiency Virus infected patient cases with rectal presentation of PL in the HIV service of the Hospital Civil de Guadalajara. PMID- 29147332 TI - A Case of Complete Response to Letrozol Treatment in a Postmenopausal Woman With Breast Cancer Who has Progressed After Multiple Lines of Chemotherapy. AB - Approximately 60% of all breast cancers are endocrine dependent. Postmenopausal patients who have positive hormone receptor status are eligible for aromatase inhibitor treatment. Letrozole is a potent, selective, non-steroidal, third generation aromatase inhibitor which reduces oestrogen biosynthesis approximately 99% at the dose of 2.5 mg/day. We report a 54-years-old female patient diagnosed with grade 2 invasive ductal carcinoma of the breast. She received adjuvant chemotherapy, followed by 5 years of tamoxifen. After 8 years, recurrence appeared in lung, supraclavicular lymph nodes and brain. She had many cycles of cytotoxic chemotherapeutic agents, trastuzumab and lapatinib previously. After the progression (lung and brain), palliative therapy was thought due to very poor performance status of the patient. (ECOG: 3) Letrozole was added in the treatment and we obtained near-complete remission from her lung and brain metastasis with 2.5 mg/day dose of letrozole. This study might support successfully use of aromatase inhibitors in patients who has been previously treated with multiple lines of chemotherapy and had still progressive disease. PMID- 29147333 TI - Primary Testicular Diffuse Large B-Cell Lymphoma: A Case Report. AB - Testicular lymphoma was first reported by Malassez and Curling in 1866. Primary testicular lymphoma constitutes only 1-7% of all testicular neoplasms and less than 1% of all non Hodgkin lymphoma. We report the case of a 47-year-old man without a particular past medical history, who presented with a painful left testicular swelling that he has noticed for several weeks. Radiological findings consisted in multiple hypoechoic masses that corresponded in histological examination to a diffuse intratubular lymphomatous infiltration situated away from the spermatic cord, the epididymis, ductuli efferentes and rete testis. Immunohistochemical study showed positivity of MUM-1, Bcl-2 and B-cell marker (CD20) and TdT, CD 3, CD5, Bcl-1, CD10, Bcl-6 and Myeloperoksidaz were negative. Ki-67 proliferation index was 90% of neoplastic lenfoid infiltration. The patient underwent full staging for lymphoma by positron emission tomography, showing right superior paratrakeal, precarinal, subcarinal, left paraaortic and retrocrural and left iliac involvement lymph nodes also the right testis and of extra-testicular involvement by the skeleton sistem. The diagnosis of stage III primary testicular large B-cell lymphoma of germinal center B-cell-like group was made. The patient is now treated by chemotherapy. Primary testicular lymphoma is a rare tumor whose diagnosis is based on histological findings. There are non consensual etiological or predisposing factors. Treatment modalities consist in surgical excision, chemotherapy and radiation therapy but the accurate procedures are not standardized. Factors that have been linked to more favorable outcomes include younger patient age, localized disease, presence of sclerosis at pathologic analysis, smaller tumor size, lower histological tumor grade and lack of epididymal or spermatic cord involvement. PMID- 29147334 TI - An Update on the Quality of Life Measurements in Lung Cancer Patients Receiving Palliative Radiotherapy: A Literature Review. AB - To conduct a systematic review on validated instruments used to assess quality of life (QOL) in patients with either primary or metastatic lung neoplasms. A literature search was conducted through the Embase (1950 - 2012 week 30) and Medline (1946 - 2012 week 3 July) databases. All compiled studies utilized QOL or symptom palliation as a primary or secondary outcome for patients with advanced lung cancer. A total of 17 studies met our criteria. Four questionnaires were most commonly used: the EORTC QLQ-C-30, the EORTC QLQ-LC-13, the Rotterdam Symptom Check-list (RSCL), and the Hospital Anxiety and Depression Scale (HADS). The limited number of studies assessing QOL in patients with advanced lung cancer suggests that QOL is still an uncommon endpoint for this patient population. Nine of seventeen (53%) studies evaluated QOL in their cohorts and out of those nine, seven (77%) included the use of a lung-specific tool. In total there were eleven of seventeen (65%) studies that evaluated symptom palliation, indicating the relevance of symptom palliation as an endpoint in this population. It is encouraged that lung specific QOL questionnaires, such as the FACT-L and the EORTC QLQ LC-13, be used in tandem with general questionnaires, such as the FACT G and the EORTC QLQ C-30, in advanced lung cancer patients undergoing radiotherapy. Clinicians should also be advised to focus more on QOL assessment. PMID- 29147335 TI - Diagnostic Accuracy of Imaging Modalities in the Evaluation of Vascular Invasion in Pancreatic Adenocarcinoma: A Meta-Analysis. AB - Background: The extent of vascular invasion is a key factor determining the resectability of non-metastatic pancreatic adenocarcinoma. The purpose of this study is to determine the diagnostic accuracy of computed tomography (CT), endoscopic ultrasound (EUS), and magnetic resonance imaging (MRI) in the pre operative evaluation of vascular invasion in pancreatic adenocarcinoma, with surgery as the reference standard. Methods: A search of the MEDLINE database for relevant articles in the English language published between January 2000 and February 2009 was performed. From each study, 2 * 2 tables were obtained, and pooled sensitivity, specificity, positive likelihood ratios, negative likelihood ratios and diagnostic odds ratios were calculated for each modality, along with a summary receiver operating characteristics (SROC) curve. Results: 16 studies with a total of 797 patients who had surgical assessment of vascular invasion were included in the analysis. Several studies evaluated more than one imaging modality, allowing 24 datasets to be obtained in total. Sensitivity was highest for CT (0.73, 95% CI 0.67 - 0.79), followed by EUS (0.66, 95% CI 0.56 - 0.75) and MRI (0.63, 95% CI 0.48 - 0.77). The specificity for all three imaging modalities was comparable. The diagnostic odds ratios for CT, EUS and MRI were 45.9 (95% CI 18.0 - 117.4), 23.0 (95%CI 9.4 - 56.6), 23.9 (95% CI 5.4 - 105.1) respectively. Conclusion: CT was more accurate than EUS and MRI in the evaluation of vascular invasion in pancreatic adenocarcinoma and should be the first line investigation in pre-operative staging. PMID- 29147336 TI - Alpha-1 Antitrypsin Blood Levels as Indicator for the Efficacy of Cancer Treatment. AB - Background: Alpha-1 antitrypsin (alpha1-AT) is a member of the serine protease inhibitors (serpins) family. Liver cells are the major source of synthesis and secretion of (alpha1-AT) into the blood. Moreover, it has been demonstrated that alpha1-AT is expressed and secreted by many types of malignant cells. Studies have indicated that serum levels of (alpha1-AT) increase in a good number of malignant diseases. In addition, a significant correlation between serum levels and cancer stage has also been reported. In this work we aimed to test how alpha1 AT levels behave at the third week after treatment with chemotherapy. Methods: The alpha1-AT blood levels were measured using commercially available radial immunodiffusion kit (Kent Laboratory Inc, Bellinham, Washigton) following manufacturer instructions. Results: The alpha1-AT blood levels were significantly decreased after treatment compared with those before the treatment started. The mean difference (before - after) treatment was 127.82 and 137.37 mg/dL with 95% CI of difference 109.06 - 146.57 and 116.08 - 158.65 mg/dL in lung and prostate cancer respectively. When we compared these levels according to the stage of cancer, we found that the mean difference (before - after) treatment was also highly significant as indicated by P-value and the 95% CI of these differences. Conclusion: Obtained data strongly indicate the value of testing alpha1-AT blood levels as one of the important indicators for the efficacy of cancer treatment. PMID- 29147337 TI - The Relationship Between Prostate Cancer Aggressiveness and Glycemic Levels in Patients Submitted to Radical Prostatectomy. AB - Background: The relationship between hyperglycemia and prostate cancer remains controversial. According to current hypotheses, elevated serum glucose levels may lead to disease development or disease prevention. Our study examined the potential correlation between pre-operative glycemic levels of patients with prostate cancer and the grade of tumor aggressiveness. Method: We studied the case files of patients with a diagnosis of prostate cancer who had received putatively curative cancer surgery at the Urology Department of the Servidores do Estado Federal Hospital (RJ/Brazil). We transcribed information related to glycemia - collected up to 3 months before the surgery - and the histopathological grade of tumor aggressiveness (Gleason score) of the surgically removed prostates. Results: We analyzed 42 people who met the inclusion criteria. Based on Gleason scores, among the normoglycemic patients, we detected low, moderate, and highly aggressive neoplasias in 13%, 53%, and 36% of the cases, respectively. For the hyperglycemic group, these rates were 30%, 60%, and 10%, respectively. Normoglycemic patients had primary Gleason grade 3 in 40% of the cases and grade 4 in 60% of the cases. For the hyperglycemic patients, these rates were 90% and 10%, respectively (P < 0.05 vs. grade 3 group). Conclusion: Both Gleason score and primary Gleason grade were lower in hyperglycemic patients with prostate cancer than in normoglycemic patients, suggesting a "protective action" of hyperglycemic states. PMID- 29147338 TI - ALK+ Anaplastic Large Cell Lymphoma With Bladder Involvement Presenting as Fever of Unknown Origin: A Case Report and Literature Review. AB - Anaplastic large cell lymphoma (ALCL) is a rare malignant tumor normally originating in lymph nodes, though it can occur in extranodal sites. We report a 59-year-old man with anaplastic lymphoma kinase (ALK) positive ALCL involving the bladder diagnosed post-mortem who presented with fever of unknown origin. This is the seventh reported case of ALCL presenting as a bladder neoplasm. The patient presented to his primary care physician with a several day history of fever. An eventual computed tomography scan of the abdomen and pelvis showed widespread adenopathy in the pelvis and retroperitoneum. After a negative infectious investigation, the patient underwent exploratory laparotomy with excisional biopsy of periaortic lymph nodes. Pathology revealed reactive lymphocytes. Bone marrow biopsy also was negative for malignancy. The patient's fevers persisted, and he later exhibited dysuria and hematuria with evidence of bilateral hydronephrosis. Cystoscopy revealed an erythematous, diffusely friable bladder mucosa with inaccessible ureteral orifices, and biopsies were taken. The patient continued to deteriorate clinically because of associated macrophage activation syndrome, a close variant of hemophagocytic lymphohistiocytosis, and expired the following day. Autopsy was declined. Post-mortem pathology reports from cystoscopy revealed ALK+ ALCL of the bladder. PMID- 29147339 TI - Recurrent Adenocarcinoma of Colon Presenting as Duodenal Metastasis With Partial Gastric Outlet Obstruction: A Case Report With Review of Literature. AB - Colorectal cancer is one of the leading causes of cancer related deaths in western world. While most common site for metastasis for colon cancer is liver, lung, and the peritoneum, metastasis to various other organs such as brain, bones and thyroid has been reported. Metastatic lesions to the small bowel are more common than primary lesions and most common primary neoplasms that metastasize to the duodenum are lung cancer, renal cell carcinoma, breast cancer, and malignant melanoma. We report a very rare case of recurrent adenocarcinoma of colon metastasizing to duodenum after 2 years of curative resection of primary cancer. Surgical resection for curative intent as well as palliative management is recommended. PMID- 29147340 TI - Leiomyosarcoma of the Inferior Vena Cava - Radical Resection, Vascular Reconstruction and Challenges: A Case Report and Review of Relevant Literature. AB - Leiomyosarcomas of the inferior Vena Cava (IVC) are rare soft tissue sarcomas accounting for only 0.5% of all soft tissue sarcomas in adults with fewer than 300 cases reported. Extraluminal tumor growth along the adventitia of the IVC seems to be the common presentation. Intraluminal tumor growth is rare. The origin of the tumor is divided into three levels in relation to the hepatic and renal veins. The presentations and surgical modalities vary accordingly. Retroperitoneal tumors are often not diagnosed until the disease is at an advanced stage with large tumor growth and involvement of surrounding structures. This is partly because of the nonspecific clinical presentation as well as absence of early symptoms. Most patients present with abdominal or flank pain. Symptoms vary according to the dimensions of the tumor, growth pattern and localization of the tumor. Radical en bloc resection of the affected venous segment remains the only therapeutic option associated with prolonged survival. The goals of surgical management of these tumors include the achievement of local tumor control, maintenance of caval flow, and the prevention of recurrence. The involvement of renal or hepatic veins determines the strategy for vascular reconstruction. Reconstruction of the IVC is not always required, because gradual occlusion of the IVC allows the development of venous collaterals. However, when pararenal leiomyosarcoma of the IVC is present, reconstruction of the IVC and the renal vein is necessary to prevent transient or permanent renal dysfunction. Recent study has shown that radical surgery combined with adjuvant multimodal therapy has improved the cumulative survival rate. We report a case of IVC leiomyosarcoma in a young healthy woman along with details of its diagnostic workup and discussion of the surgical options and reconstruction of caval continuity. PMID- 29147341 TI - Skeletal Muscle Metastases in a Patient With Neuroendocrine Tumor. AB - Carcinoid tumors are rare but diverse group of malignancies that arise from neuroendocrine cells. Skeletal muscle metastasis is exceedingly rare and is associated with a poor prognosis. We report a case of carcinoid tumor of the ileocecal with skeletal muscle metastasis. We also review available case reports of carcinoid tumors metastasizing to the muscle. PMID- 29147342 TI - Pneumothorax as a Presenting Clinical Manifestation of Metastatic Prostate Cancer. AB - Pulmonary metastases are not encountered commonly in patients with prostate cancer. Pulmonary metastases with pneumothorax as a presenting clinical manifestation in newly diagnosed prostate cancer are very rare. Here, we present the case of an 82-year-old patient who was admitted to our center with a chief complaint of worsening dyspnea over the past few days. The chest X-ray and computed tomography (CT) showed left pneumothorax and bilateral lung opacities as well as generalized lymphadenopathy and diffuse bony metastases. After a series of workup including cervical lymph node biopsy with immunohistochemical staining, abdomen CT, serum prostate-specific antigen (PSA), and transrectal ultrasonography (TRUS), he was proved to have prostate cancer with multiple lung, bone and lymph node metastases. This case is reported because of the rarity for a prostate carcinoma presented clinically with an unusual pulmonary manifestation. PMID- 29147343 TI - Complete Radiologic Response of Bulky Cerebral Metastases From Newly Diagnosed HER2-Positive Breast Cancer to Upfront Trastuzumab-Based Chemotherapy. AB - The blood-brain barrier is traditionally regarded as an insurmountable obstacle to the effective drug therapy of brain metastases from solid tumors. Here we describe a striking case of complete radiologic response to chemotherapy, and propose that the critical success factors include the large tumor size, HER2 positivity, and concomitant use of trastuzumab. PMID- 29147344 TI - Principles and Innovations in Peritoneal Surface Malignancy Treatment. AB - Cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC) remains a controversial treatment for malignant disease of the peritoneal cavity. We review the scientific principles underscoring the rationale for CRS/HIPEC, recent innovations and ongoing controversies. Lack of level 1 data limits the understanding of the true benefit of CRS/HIPEC. PMID- 29147345 TI - Molecular Mechanism and Targeted Therapy Options of Triple-Negative (ER, PgR, HER 2/neu) Breast Cancer: Review. AB - Tripple negative breast cancer (TNBC) accounts for approximately 15% of breast cancers. It is defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER-2 Over expression. Expression of ER, PR and HER-2 plays an important role in therapeutic assessment of patients with breast cancer. TNBC is not one disease, but a family of diseases, some of which are highly aggressive with limited treatment options. Triple-negative breast cancers Patients are not benefiting from currently available receptor-targeted systemic therapy. At present, there is no single agent that targets triple-negative breast cancer. However, researchers are presently investigating large number of potential therapies that may eventually improve outcomes in these patients. In this review article, we discussed about tripple negative breast cancer, also the role of BRCA gene mutations and targeted therapeutic options available to triple negative breast cancer patients. PMID- 29147346 TI - Treatment of Active Mucositis With Caphosol (Calcium Phosphate): A Retrospective Case-Series. AB - Background: Mucositis is a common side effect due to chemo and/radiation therapy. Caphosol has been a proven preventive strategy against mucositis in randomized clinical trials. However, its efficacy to treat active mucositis in patients treated for solid tumors with chemotherapy is unknown. The objective was to evaluate the efficacy of Caphosol to treat mucositis by comparing the grade of mucositis before and after treatment and documenting the duration of treatment. Methods: A retrospective review was conducted on consecutive adult patients at London Regional Cancer Program (LRCP) who developed chemotherapy-induced oral mucositis and were then treated with Caphosol. This study was approved by ethics committee at University of Western Ontario. Results: A total of 21 patients, two males (one with cancer esophagus and another with lung cancer) and 19 females (all with breast cancer), with a median age of 59 years were evaluated. Grade 3 mucositis was present in 4 patients who completely resolved with Caphosol in an average of 4 days of treatment, without needing any hospitalization. Fifteen patients with grade 2 mucositis reverted back to grade 0 by using Caphosol for an average of 3.5 days. One patient with no effect had grade 1 mucositis dating prior to treatment with chemotherapy and remained as such. Another patient with no initial improvement had oral candidiasis and once treated with Fluconozole and Caphosol had a complete resolution. No obvious side effects were reported by patients related to the use of Caphosol. Conclusion: Our case series, for the first time, shows that Caphosol may be used as a potentially effective treatment in patients with solid tumor, who develop chemotherapy-induced mucositis. PMID- 29147348 TI - A Rare but Significant Cause of an Enlarging Neck Mass: A Case Report of Primary Thyroid Lymphoma. AB - Primary thyroid lymphoma is a rare form of non-Hodgkin's lymphoma that typically presents as a rapidly enlarging goiter in patients with a history of autoimmune thyroid disease. We present the evaluation, pitfalls in diagnosis, and treatment of a 49-year-old woman with diffuse large B-cell primary thyroid lymphoma presenting with airway obstruction. PMID- 29147347 TI - Nuclear Matrix Protein 22 in Voided Urine Cytology Efficacy in Risk Stratification for Carcinoma of Bladder. AB - Background: To investigate the nuclear matrix protein NMP22 in voided urine for detection of malignancy in patients with risk factors of symptoms of bladder cancer. Methods: January 2009 to December 2012, participants included 1,331 patients at elevated risk for bladder cancer due to factors such as history of smoking or symptoms including hematuria and dysuria, patients at risk for malignancy of the urinary tract provided a voided urine sample for analysis of NMP22 protein and cytology prior to cystoscopy. The diagnosis of bladder cancer, based on cystoscopy with biopsy, was accepted as the reference standard. The performance of the NMP22 test was compared with voided urine cytology as an aid to cancer detection. Testing for the NMP22 tumor marker was conducted in a blinded manner. Results: Bladder cancer was diagnosed in 79 patients. The NMP22 assay was positive in 44 of 79 patients with cancer (sensitivity, 55.7%, 95% confidence interval (CI), 44.1-66.7%), whereas cytology test results were positive in 12 of 76 patients (sensitivity, 15.8%; 95% CI, 7.6-24.0%). The specificity of the NMP22 assay was 85.7% (95% CI, 83.8-87.6%) compared with 99.2% (95% CI, 98 initial endoscopy, including 3 that were muscle invasive and 1 carcinoma in situ. Conclusion: The noninvasive point-of-care assay for elevated urinary NMP22 protein can increase the accuracy of cytoscopy, with test results available during the patient visit. PMID- 29147349 TI - Malignant Peripheral Nerve Sheath Tumors Masking as Ewing Sarcoma/Primitive Neuroectodermal Tumors. AB - Malignant peripheral nerve tumors, a small subset of soft tissue sarcomas, provide a unique diagnostic challenge. Although they may arise from peripheral nerves or from cells associated with nerve sheaths, malignant peripheral nerve tumors often present with diverse immunohistochemical features similar to those of other tumors. These features make MPNSTs difficult to diagnose and classify. We present a case of a 26-year-old female presenting with a rapidly growing soft tissue mass. The mass was excised and immunohistological staining suggested a Ewing's sarcoma/Primitive neuroectodermal tumor. Confirmational studies did not confirm this diagnosis and upon further review, the diagnosis was changed to a malignant peripheral nerve sheath tumor. We reviewed this case in the setting of the reported literature concerning MPNSTs with focus on the epidemiologic, diagnostic, and immunohistologic features that distinguish this tumor from other similar malignancies. PMID- 29147350 TI - A Rare Disease in Adult: Langerhans Cell Histiocytosis. AB - Langerhans cell histiocytosis is a rare histiocytic disorder and has been diagnosed in all age groups, but is most common in children. This disease is very rare in adults. We presented a patient who was 62 years old man diagnosed langerhans cell histiocytosis. PMID- 29147351 TI - Renal Medullary Carcinoma Masquerading as Bilateral Breast Carcinoma Category: Case Report. AB - Metastatic disease to the breast accounts for less than 1% of all breast carcinoma. Here we describe an unusual case of a 34-year-old black female with history of sickle cell trait who presented to her gynecologist with bilateral palpable breast masses. Based on initial workup including pathology results from biopsies of both breast masses, she was diagnosed with bilateral breast cancer. However further radiographic imaging revealed a large right kidney mass suspicious for primary renal neoplasm along with lung and bone lesions. This prompted re-review of the initial breast pathology. Sickled erythrocytes were identified and results of an additional immunohistochemical panel revealed positive expression of PAX 8, vimentin, Oct3/4, and loss of INI1, confirming the diagnosis of metastatic renal medullary carcinoma. We discuss the importance of considering renal medullary carcinoma in the differential diagnosis when evaluating young patients with sickle cell hemoglobinopathies who present with aggressive metastatic disease. PMID- 29147352 TI - Indolent Breast Lymphomas: A Case Series and Review of Literature. AB - Indolent breast lymphomas (IBL) are a rare form of extranodal lymphoma. There are very few reported cases of IBL presenting as a breast mass. We report two cases of IBL, a Marginal Zone Lymphoma (MZL) and a Small Lymphocytic Lymphoma (SLL), which were discovered on routine mammogram and later confirmed by biopsy and flow cytometery. Patient with MZL underwent chemotherapy and radiation therapy whereas patient with SLL was treated with chemotherapy alone. PMID- 29147353 TI - Clinical-Pathological Correlation of KRAS Mutation Status in Metastatic Colorectal Adenocarcinoma. AB - Background: KRAS gene mutations play an important role in the carcinogenesis of colorectal tumors. However, studies that have assessed the association between KRAS gene mutation status and disease characteristics report conflicting results. To assess KRAS gene status (mutated or wild-type) and its association with the clinical, epidemiological, and histopathological features of metastatic colorectal adenocarcinoma as well its association with clinical outcomes. Methods: Cross-sectional descriptive study in which clinical and histopathological data were collected from the medical records of 65 patients diagnosed with metastatic colorectal adenocarcinoma at the Clinical Oncology Service of the Teaching Hospital of the School of Medicine of Ribeirao Preto, University of Sao Paulo (Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo -HCFMRP-USP) between 2005 and 2012 and analyzed based on their KRAS gene status. Results: KRAS gene mutations were found in 49.2% of the tumors, and G/A (25.5%) and Gly12Asp (34.37%) were the most frequent mutations. Among the investigated clinical features (gender, ECOG (Eastern Cooperative Oncology Group), histology, degree of cell differentiation, lymph node ratio, primary tumor site, staging, presence of synchronous metastasis, lung metastasis, and liver metastasis), the association between age less than 65 years with KRAS mutation was statistically significant (P = 0.046). KRAS mutation status did not exhibit a significant correlation with the overall survival of the patients (P = 0.078); however, the cases with KRAS mutation exhibited shorter survival. In the multivariate analysis, synchronous metastasis (P = 0.03) and liver metastasis (P = 0.008) behaved as independent factors of poor prognosis relative to the overall survival of the patients. Conclusion: The KRAS mutation status did not exhibit prognostic value in the investigated sample. Among the older patients (> 65 years old), wild-type KRAS was more frequently observed compared to mutated KRAS. PMID- 29147354 TI - Female Body Mass Index and its Relationship With Triple Negative Breast Cancer and Ethnicity. AB - Background: Breast cancer in women is a relatively common malignancy in the western hemisphere and is perhaps one of the leading causes of mortality among females. We conducted a retrospect cohort study to investigate the association of body mass index (BMI) with triple negative breast cancer and ethnicity. Methods: Tumor Registry Database at the University of Florida, College of Medicine in Jacksonville was utilized for our cohort study. A total of 84 women with triple negative breast cancer, between 2004 and 2008 met our criteria and were selected for this study. For comparison, another 83 women with at least one hormone receptors positive breast cancer were randomly selected in the same time period. Chi-square testing was used to evaluate categorical variables, while the t-test analysis was used to analyze for the continuous variables. Results: Our data demonstrated that 27.4% of the triple negative group had BMI < 25 compared to the 14.5% of non-triple negative breast cancer, 73.6% of the triple negative group had BMI >= 25 compared to 86.5% in the non-triple negative group with a P-value of 0.245. In terms of ethnicity, triple negative breast cancer was found in 56% of African-American and 44% of Caucasian females. Non-triple negative breast cancer was found in 48.2% of African-Americans and 51.8% of Caucasians females with a P-value of 0.354. Conclusions: We were not able to show any statistically significant association of body mass index triple with triple negative breast cancer or ethnicity. While our findings are not in agreement with the research published earlier, we do submit that our retrospective cohort study has shortcomings, including the small sample size pooled from a single center, which greatly limits our ability to deduce any definitive conclusions. In light of these shortcomings, we recommend a future multicenter study with a larger sample size. PMID- 29147355 TI - Transient Plasmacytosis With Trisomy of Chromosome 8 in a Patient With Multiple Myeloma: A Case Report. AB - A 96-year-old woman with a 5-year history of multiple myeloma was admitted to our hospital because of increasing fatigue and fever. Bone marrow plasma cell analysis showed t(11;14), del(13q), and del(17p13). Her condition deteriorated, and she developed plasmacytosis resembling plasma cell leukemia. Chromosome analysis showed trisomy of chromosome 8 in the circulating plasma cells. The plasmacytosis resolved spontaneously without chemotherapy after about 5 weeks, and the trisomy became undetectable. The findings suggest that trisomy 8 might have contributed to the transient plasmacytosis, and that chromosome 8 carries genes associated with plasma cell proliferation, maturation, and apoptosis. PMID- 29147356 TI - Management of Metastatic Solid Pseudopapillary Cancer of the Pancreas: A Case Report. AB - Solid pseudopapillary tumors (SPT) of the pancreas are rare neoplasms predominantly found in females. The tumors are often histologically benign and patient outcomes are correspondingly favorable. This report presents the case of a 21-year-old woman who presented with metachronous metastatic SPT, and details the diagnosis and management of this patient. The patient underwent a distal pancreatectomy for resection of the primary neoplasm with negative margins. A surveillance ultrasound performed at 43 months post-operatively revealed new hepatic lesions; these lesions were surgically resected and pathologically demonstrated to be metastatic SPT of the pancreas. This case report demonstrates the potential for latent metastasis of resected SPT, imaging characteristics of metastatic disease, the need for surveillance of patients following resection of SPT of the pancreas and a review of relevant literature on SPT. PMID- 29147357 TI - Unusual Course of Splenic Marginal Zone Lymphoma. AB - A 53-year-old woman was diagnosed with splenic marginal zone lymphoma by pathological examination on left submandibular lymph node and bone marrow biopsies and markedly enlarged spleen. Four cycles of Rituximab chemotherapy were given. Seven months after finishing Rituximab chemotherapy, she developed left upper extremity swelling without evidence of deep venous thrombosis. Repeat PET/CT scan demonstrated multiple left axillary lymph nodes extending to left retroclavicular region and a new lymph node posterior to the left scapula. Biopsy of the lymph node demonstrated marginal zone lymhoma pattern with increased numbers of large cells, but not outright diffuse large B-cell lymphoma. Despite resuming rituximab, patient had persistent leukocytosis and severe anemia. Restaging PET/CT showed 3 new left anterior cervical lymph nodes and 1 new right axillary lymph node. Spleen has further enlarged. R-CHOP chemotherapy was started, which improved leukocytosis.After 4 cycles of R-CHOP, PET/CT showed new metabolic activity within right inguinal and abdominal lymph nodes. Patient was given one cycle of Bendamustine. She developed a possible "hematoma" in right medial elbow. However, MRI study revealed a subcutaneous deposit of the lymphoma. Patient needs consistently blood transfusion and she deteriorated quickly. Our patient had an aggressive course of splenic marginal zone lymphoma, not responding to four trials of chemotherapy although SMZL is well-known to be an indolent low grade lymphoma. This case report emphasizes the importance to individualize the treatment in SMZL patients and repeat bone marrow biopsy if the disease recurs. PMID- 29147358 TI - Excellent Response to Palliative Chemotherapy for Pleural Recurrence of Uterine Papillary Serous Carcinoma. AB - Uterine papillary serous carcinoma (UPSC) is an aggressive variant of endometrial cancer. Though the majority of women with UPSC have high risk of recurrence, recurrence limited only to the pleural space has not been previously reported. It is also unusual for it to occur as late as 10 years after the initial treatment as it is usually very aggressive. There is scant information in literature on response to treatment in these patients. A 65-year-old African-American woman was treated for FIGO stage IIA UPSC with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy with 32P catheter placement, followed by adjuvant external beam radiation. She relapsed 10 years later with right pleural effusion and pleural based nodules. Fluid cytology was consistent with UPSC. She was treated with 6 cycles of carboplatin and paclitaxel with excellent clinical and biochemical response. She continues to remain disease free 5 years later. To our knowledge, this is the first reported case of UPSC recurrence limited to pleura, and this is also the first reported case of UPSC recurrence without evidence of disease 5 years after palliative chemotherapy. PMID- 29147359 TI - Successful Use of Erlotinib in Treating Recurrent Thymic Carcinoma: A Case Report. AB - Thymic carcinomas are rare and aggressive tumors. Primary treatment for these tumors consists of surgical resection, followed by adjuvant radiation therapy or platinum based chemotherapy. Unfortunately these tumors often exhibit a high incidence of local recurrence and metastasis despite treatment. Of recent interest are new targeted therapies such as Tarceva(r) (erlotinib), an epidermal growth factor receptor (EGFR) inhibitor, for treatment of recurrent thymic carcinoma. Unfortunately recent literature has shown little success with its use, except for a few isolated case reports. Here we present a unique case of progressive disease despite 4 cycles of cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC) therapy, and subsequent treatment with 150mg erlotinib daily resulting in partial response at 6 months with tumor shrinking in size and resolution of many metastatic nodules. PMID- 29147360 TI - A Rare Case of Primary Gastric HIV-Associated Peripheral T-Cell Lymphoma: Relapsed Disease Treated With Pemetrexed. AB - We present a case of a patient with HIV/AIDS who presented with abdominal pain and melena and was found to have gastric peripheral T-cell lymphoma (PTCL). He was treated with 6 cycles of EPOCH with a complete response. Within 3 months, he had central nervous system (CNS) and soft-tissue relapse. He was subsequently treated with 3 cycles of intravenous pemetrexed and experienced a second complete response. To our knowledge, there are fewer than 100 reports of HIV-associated PTCL worldwide as of 2010, and among these cases involvement of the stomach as the primary site of extranodal disease is exceptionally rare. The disease carries a poor prognosis and current standard therapies highlight the importance of HIV/AIDS disease control and the need for more studies on therapies and the role of transplantation in refractory or relapsed HIV-associated PTCL. PMID- 29147362 TI - Distribution of Thyroid Cancer in the Eastern Part of Turkey 27 Years After the Chernobyl Accident. AB - Background: The Chernobyl accident caused widespread effects across Europe and huge areas where radiocontaminated. The effects of the Chernobyl accident on thyroid cancer have been investigated in most European countries. According to the data of the Turkish Atomic Energy Authority, the eastern part of the Black Sea region was the most radiocontaminated area in Turkey at the time of Chernobyl accident. We therefore aimed to examine the data of thyroid cancers at our center, Rize city which is located in the eastern Black Sea region. Methods: This retrospective study included the patients with histologically proven thyroid cancer at our center between January 2008 and May 2012. Pathologic examinations of thyroidectomy materials were reviewed. We evaluated patients' age, gender, size of the primary tumor (all sizes, < 1 cm, 1 - 2.9 cm, 3 - 3.9 cm and >= 4 cm), multicentricity, histologic subtypes of thyroid cancer, the presence of lymphatic, vascular, capsule and the extrathyroidal invasion. Results: Five hundred and forty-seven of the 3,556 patients were diagnosed with thyroid cancer. The mean age of the patients was 49.31 +/- 0.49 years. The histopathologic diagnosis of patients was papillary carcinoma in 533 (97.4%) and the tumor size was < 1 cm in 53.6% of the patients. The presence of multicentricity was detected in 47% of the patients. Conclusion: The portion of thyroid carcinomas in all thyroidectomies was 15.4% in our institution 27 years after the Chernobyl accident. PMID- 29147361 TI - Comparison of Neoadjuvant Intraarterial Chemotherapy Versus Concurrent Chemoradiotherapy in Patients With Stage IIIB Uterine Cervical Cancer. AB - Background: The purpose of this study was to compare the long-term survival of patients with stage IIIB squamous cell carcinoma of the cervix treated with neoadjuvant intraarterial chemotherapy (IA-NAC) versus those treated with concurrent chemoradiotherapy (CCRT). Methods: We retrospectively reviewed the clinical records of 38 patients with stage IIIB squamous cell carcinoma of the cervix admitted between January 1994 and December 1999 who received IA-NAC followed by abdominal radical hysterectomy (ARH) or radiotherapy (RT). IA-NAC consisted of bilateral infusion via the internal iliac artery of cisplatin, bleomycin and pirarubicin for 2-3 courses. A historical control group of 64 patients who underwent primary CCRT from January 2000 to September 2007 was used for comparison. Results: In the IA-NAC group, 12 patients (31.6%) with operable tumors underwent ARH, and the remaining 26 patients (68.4%) received RT. The response rates were 86.8% (12 complete response + 21 partial response) for IA-NAC and 98.4% (26 complete response + 37 partial response) for CCRT (P = 0.077), respectively. The 5-year overall survival and disease-free survival rates were 62.4 and 44.5% for IA-NAC and 51.1 and 46.9% for CCRT (P = 0.247 and 0.776), respectively. The 5-year overall survival and disease-free survival rates were 75.0 and 58.3% for the patients receiving IA-NAC followed by ARH, and 55.3 and 37.6% for the patients receiving IA-NAC followed by RT (P = 0.368 and 0.262), respectively. Conclusions: In the present study, IA-NAC followed by ARH or RT and primary CCRT showed similar survival rates for stage IIIB squamous cell carcinoma of the cervix. PMID- 29147363 TI - Surgical Staging of Early Stage Endometrial Cancer: Comparison Between Laparotomy and Laparoscopy. AB - Background: The aim of the present study was to compare the laparotomy (LT) and laparoscopy (LS) in patients who undergone surgical staging for early stage endometrium cancer. Methods: Retrospective data were collected and analyzed for amount of intraoperative bleeding, complication rates, total resected and laterality specific number of lymph nodes and duration of operation in patients operated with either LT or LS. Results: Seventy-nine stage I endometrium cancer patients were found to be eligible for the trial purposes: 58 (73.4%) treated by LT and 21 (26.6%) treated by LS. The number of lymph nodes was similar in LT (8.9 +/- 5.3) and LS (9.2 +/- 4.8) (P = 0.8). In LT group, there was no difference in the number of lymph nodes between the right and left sides (10 +/- 5.8 and 8.7 +/ 4.8 respectively, P = 0.19); in LS group, the number of lymph nodes resected from the right side was higher than the left side (9.8 +/- 5 and 7 +/- 3.5 respectively, P = 0.039). The amount of intraoperative bleeding and hospitalization period were significantly higher in LT group. Seventy-nine patients had a median follow-up of 30 months. The two groups were similar for disease-free survival (P = 0.46, log rank test). Conclusions: There was no significant difference between the two methods in terms of number of total resected lymph nodes. In early stage endometrial carcinoma, LS has provided adequate staging and similar survival rates with LT. PMID- 29147364 TI - TNBC vs. Non-TNBC: A Five-Year Retrospective Review of Differences in Mean Age, Family History, Smoking History and Stage at Diagnosis at an Inner City University Program. AB - Background: In recent years, breast cancer has been classified on the basis of estrogen or progesterone receptor (ER/PR) status and whether the human epidermal growth factor 2 receptor (HER2/neu) protein is overexpressed. Based on this system, breast cancer is broadly divided into the triple negative breast cancer (TNBC) and the non-TNBC subtypes. TNBC is a subtype of breast cancer, notable for its propensity to metastasize early and display a comparatively more aggressive course than its non-TNBC counterpart. Certain clinico-pathologic and demographic risk factors have been associated with breast cancer. In this study, we aim to compare mean age, ethnicity, family history, tobacco use and stage at presentation between TNBC and non-TNBC subtypes at our inner city university program. Methods: We reviewed data in our tumor registry between January 2000 and December 2005 with particular attention to mean age, race, family history, tobacco use and stage at presentation. We found a total of 445 patients with various subtypes of breast cancers. We included only those patients in whom the status of both ER/PR and the status of Her2/neu protein overexpression were recorded. Our strict selection criteria lead to an exclusion of about 103 patients. Out of the remaining 342 patients, 39 were TNBC and 303 were non-TNBC. Results: Mean age of onset for TNBC vs. non-TNBC patients was 59.87 +/- 15.67 years vs. 60.09 +/- 13.98 years respectively (P = 0.9272). In terms of ethnicity, TNBC vs. non-TNBC patients had the following racial backgrounds: black, 58.97% vs. 39.27%; white, 35.90% vs. 57.76%; Chinese, 2.56% vs. 0.99%; others, 2.57% vs. 1.98% respectively (P = 0.004, OR = 2.755). Comparisons with respect to a history of tobacco abuse for TNBC vs. non-TNBC patients revealed a positive smoking history in 20.51% vs. 27.72% whereas there was no former or current smoking history in 71.79% vs. 61.72% respectively (P = 0.4385). Comparison of family history of a breast cancer in TNBC vs. non-TNBC patients showed that positive family history of breast cancer was seen in 30.77% vs. 33.33%, no family history of cancer was seen in 51.28% vs. 51.82% and unknown 17.95% vs. 14.85% (P = 0.8384). Pathologic stage at the time of diagnosis for TNBC vs. non-TNBC patients was as follows: stage 0, 15.79% vs. 11.37% (P = 0.4332); stage 1, 34.21% vs. 30.98% (P = 0.6890); stage 2, 28.98% vs. 37.25% (P = 0.3205); stage 3, 18.42% vs. 17.25% (P = 0.0.8591); and stage 4, 3.63% vs. 3.14% (P = 0.8651). Analysis using Chi-square test revealed chi2 value of 0.855. Conclusion: Our results add to the growing body of evidence pertaining to the association of certain demographic and clinico-pathologic characteristics in women with breast cancer. We found that in our patient population, there is a significant ethnic predisposition for the two types of breast cancers that we studied. African Americans were more likely to have TNBC compared to the higher frequency of non-TNBC in white females. We did not find a significant difference in mean age, cigarette smoking, family history and stage at diagnosis between the TNBC and non-TNBC breast cancer patients. These findings are all consistent with the previously published research studies. PMID- 29147365 TI - A Case Report of Hepatocellular Carcinoma in a Non-cirrhotic Patient With Liver Iron Overload Associated With Myelodysplastic Syndrome. AB - Hereditary hemochromatosis (HH) is associated with an increased risk for hepatocellular carcinoma (HCC) occurring predominantly in patients with cirrhosis at the time of diagnosis. However, HCC in non-cirrhotic liver of patients with secondary hemochromatosis is rare. A 67-year-old man with a history of myelodysplastic syndrome (MDS) was found to have a liver tumor on abdominal computed tomography (CT). On the basis of findings of high levels of serum ferritin and transferrin saturation, and low intensity of liver parenchyma on magnetic resonance imaging (MRI), we made a diagnosis of hemochromatosis. Liver resection was performed and the specimen showed moderately differentiated hepatocellular carcinoma surrounded by non-cirrhotic liver parenchyma with intracellular iron deposition. Multicentric recurrence of liver tumor occurred 2 years after the surgery despite of deferoxamine therapy with well controlled ferritin level. We reported a case of hepatocellular carcinoma in a non-cirrhotic patient with liver iron overload secondary to MDS. It demonstrated the importance of early detection and initiation of treatment of iron overload in preventing HCC in MDS patients, even among Asian population. PMID- 29147366 TI - Metaplastic Breast Carcinoma in the Lungs: A Case Report. AB - Metaplastic carcinoma of the breast is a rare, aggressive form of cancer occurring in less than 1% of all breast cancers. Spindle cell carcinoma is a rare variant of the metaplastic carcinoma seen in less than 10% of such cases. The prognosis of spindle cell breast cancers is poor, hence aggressive treatment with surgery, chemotherapy and/or radiation is required. Here we report a case of a 62 year-old female with metastatic metaplastic breast cancer to the lungs. PMID- 29147367 TI - Sclerosing Epithelioid Fibrosarcoma of the Parietal Bone and Adjacent Meninges in an Adolescent: A Case Report. AB - Sclerosing epithelioid fibrosarcoma (SEF) is a rare and aggressive tumor for which no standardized treatment regimens are available. The occurrence of this tumor in children and adolescents has been rarely reported, especially in the head and neck region. Involvement of the neuraxis is reported only in a few patients. We report a case of a 13-year-old boy with SEF of the skull with intracranial extension. The tumor recurred after initial resection and rapidly spread to the brain parenchyma and the meninges with no response to surgery, chemotherapy and radiation therapy. PMID- 29147368 TI - High-Grade Primary Spindle Cell Sarcoma of the Prostate: A Case Report and Review of the Literature. AB - Evaluation of the primary spindle cell sarcoma prostate, which is seen extremely rare, is aimed. Literature search was made through a search in the MedLine database using PubMed and Scopus for the articles published between January 1988 and September 2013. Electronic search was limited to the following keywords: "spindle cell sarcoma", "primary prostate sarcoma". Primary prosatate sarcoma was reported as 100 patients in literature. High-grade primary spindle cell sarcoma of the prostate was encountered as 16 patients in literature. This patients was reported as the 17th case. It is a difficult cancer due to diagnosis and treatment because of the short average life expectancy, high potential of asymptomatic aggressive and metastatic. Histopatogenesis is not exactly known. In 50% of composed of patients who are previously diagnosed with prostate adenocarcinom. The case was reported as high-grade primary prosatate sarcoma at an early age. The case is different from other cases because of not being adenocarcinom component. PMID- 29147369 TI - The Role of Pretreatment Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio in the Diagnosis of Breast Cancer: Predicting Lymph Node Metastasis. PMID- 29147370 TI - Selective Pulmonary Artery Perfusion With Blood Flow Occlusion Delivers Concentrated Levels of Chemotherapy to Ipsilateral Hilar and Mediastinal Lymph Nodes. AB - Background: Although survival is historically low for patients presenting with N2 lung cancer, patients who respond to chemotherapy have up to a 30% chance for long term survival or cure. Selective pulmonary artery perfusion (SPAP) has been examined in several animal studies as a method for delivering chemotherapy in non small cell lung cancer; however, there is a paucity of data regarding the effect of SPAP on regional lymph nodes. Methods: Left SPAP was performed using gemcitabine on five swine and compared with standard central venous infusion in controls. Samples were taken from lung, kidney, liver, plasma, and lymph nodes. Tissue was measured for gemcitabine concentration using mass spectroscopy. Results: Left SPAP resulted in significantly higher gemcitabine concentration than standard infusion in hilar and mediastinal lymph nodes while plasma gemcitabine concentration was not significantly different. Conclusion: SPAP is a viable technique for concentrating a chemotherapeutic agent in the mediastinal and hilar lymph nodes. This could potentially increase the response to chemotherapy and render more patients to be surgical candidates who present with N2 disease. PMID- 29147371 TI - Age Influences Likelihood of Pancreatic Cancer Treatment, but not Outcome. AB - Background: Pancreatic cancer (PanCA) is predominantly diagnosed in elderly patients; nevertheless, a significant number of young patients are affected. We hypothesized more aggressive treatment of young PanCA patients would result in better overall survival (OS). Methods: A retrospective review of our institutional cancer database identified subjects for inclusion. Age 50 years was selected to stratify patients into age groups. Results: Of 309 PanCA patients, 54 (17%) were <= 50 years old. Exocrine cancer was the most common histology (90%). Patients <= 50 years old were more likely to have endocrine cancer (22% vs. 7%, P = 0.001). There was no difference in stage or curative intent surgery between age groups. Despite patients <= 50 years old receiving more chemotherapy (61% vs. 41%, P = 0.007) and radiotherapy (28% vs. 15%, P = 0.03), there was no difference in OS (24.1 months vs. 14.1 months, P = 0.08). When only exocrine cancers were considered, there was no difference between young and old patients regarding stage, grade, location or surgery. Exocrine cancer patients <= 50 years old received more chemotherapy (67% vs. 42%, P = 0.003) and radiation therapy (36% vs. 17%, P = 0.004), but there was no difference in OS. Conclusions: A substantial number of PanCA patients are <= 50 years old. Patients <= 50 years old received more treatment but did not have improved OS. Significant improvements in PanCA survival await development of new treatment strategies. PMID- 29147372 TI - Amplification of Genomic DNA for Decoy Receptor 3 Predicts Post-Resection Disease Recurrence in Breast Cancer Patients. AB - Background: Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, shows inhibitory effects on Fas-mediated apoptosis. Currently, data are lacking on the correlation between DcR3 and the recurrence of breast cancer. The authors examined DcR3 mRNA expression and genomic amplification in breast cancer, and investigated the effect of DcR3 gene amplification on prognosis of patients. Methods: A total of 95 patients formed the basis of the current retrospective study. DcR3 mRNA expression in breast cancer tissues was examined by RNase protection assay and in situ hybridization. DcR3 gene amplification was examined by quantitative polymerase chain reaction. The correlation between DcR3 gene amplification status and clinicopathological factors was examined and also the relationship between DcR3-Amp and relapse and survival. Results: The relative copy numbers of DcR3 genomic DNA correlated significantly with the levels of DcR3 mRNA expression (rho = 0.755, P = 0.0067). In addition, lymphatic invasion correlated significantly with DcR3 gene amplification (P = 0.012). However, there was no correlation between the remaining clinicopathological factors and DcR3 gene amplification. In the univariate analysis, the recurrence-free survival (RFS) rate of patients who were positive for DcR3 gene amplification was significantly lower than that of patients who were negative for DcR3 gene amplification (P = 0.0271). Multivariate analysis showed that DcR3 gene amplification (P = 0.028) and disease stage (P < 0.001) remained significant independent predictors of RFS. Conclusions: DcR3 gene amplification was significantly correlated with lymphatic invasion, and also DcR3 gene amplification predicts recurrence after resection, which may be an important prognostic factor in breast cancer patients. PMID- 29147373 TI - Advanced Thyroid Cancer Patients in Phase I Clinical Trials: Outcome Assessment and Literature Review. AB - Background: To describe the basic demographics, analyze the response and survival experience of advanced thyroid cancer subjects treated in Phase I clinical trials. We also reviewed early Phase studies using new targeted agents in thyroid cancer. Methods: We conducted a retrospective observational study in 32 advanced thyroid cancer patients who participated in 21 Phase I trials at our center between 2002 and 2012. Descriptive statistics and Kaplan Meier analyses were used to examine clinical outcomes and survival. Results: The median age of subjects was 57.5 years (range 21-81) at the time of study enrollment; more men (53.1%) than women were enrolled. A large number of study participants were Hispanic Americans. Nearly half (46.8%) of patients had ECOG performance status of zero, 53.1% were ECOG one and above. The most common histological subtypes were papillary (37.5%), medullary (28.1%), follicular (18.7) and anaplastic (15.6%). More than half of patients had >= 2 metastatic sites (62.6%). Of the 30 evaluable patients for tumor response, 2 confirmed partial responses (6.6%) were observed, whereas 17 patients had stable disease (SD) as best response. Among patients with stable disease, 10 patients (33.3%) achieved SD lasting >= 6 months. The median overall survival from the time of enrollment in a Phase I trial was 16.1 months. No treatment related death was observed among these patients treated with an investigational agent. Conclusion: Advanced thyroid cancer patients with no standard treatment options could participate in early Phase clinical trials of novel agents. PMID- 29147374 TI - A Case of Malignant Metastatic Pheochromocytoma After Eight Years of Primary Diagnosis. AB - We report a case of a 66-year-old female who presented to the hospital with abdominal discomfort for 3 months. Work-up revealed a 2.4 cm mass in the right adrenal gland. A laparoscopic resection of the adrenal mass was performed and the histopathology was consistent with a pheochromocytoma. Patient was under active surveillance for 8 years, until she developed local recurrence in the right adrenal bed. A right adrenal bed resection and right nephrectomy were performed. Although the tumor margins were positive, none of the sampled lymph nodes (0/6) were positive for metastasis. Patient refused any adjuvant therapy, and was discharged on surveillance from the hospital. A year later, patient was found to have metastatic disease involving her spine, iliac bones, bilateral hips and right dome of the diaphragm. Patient was offered a metaiodobenzylguanidine scan, and positive subsequent treatment with radioactive iodine was discussed with her. However, she denied any further intervention and was made hospice. PMID- 29147375 TI - Amylase-Producing Lung Cancer with a Positive Epidermal Growth Factor Receptor Mutation Treated With Gefitinib: A Case Report. AB - A 60-year-old woman was diagnosed with metastatic pulmonary adenocarcinoma (c stage IV) with an L858R point mutation in the gene encoding epidermal growth factor receptor (EGFR). Serum amylase levels were elevated (1,531 IU/L) with the salivary-type enzyme dominating. First-line chemotherapy using carboplatin plus paclitaxel reduced serum amylase levels, although second-line gefitinib eventually failed to control tumor growth and hyperamylasemia after 4.5 months of treatment. The cancer cells harbored a positive EGFR mutation and secreted amylase. The number of amylase-producing cancer cells and the immunochemical staining intensity for amylase were significantly reduced after gefitinib treatment. This was a rare case of a lung cancer that expressed amylase and harbored a positive EGFR mutation. PMID- 29147376 TI - Alveolar Soft Part Sarcoma of the Extremity: Case Report and Literature Review. AB - Alveolar soft part sarcoma (ASPS), a rare soft tissue sarcoma in children and adolescents, carries a poor prognosis. ASPS is an aggressive tumor of controversial histogenesis that, unlike other soft tissue sarcomas, tends to metastasize to the brain. A 9-year-old boy presented to our outpatient clinic in April 2009 with a chief complaint of a large painless mass in the left thigh whose size had increased significantly over the past 10 months. After staging the tumor, we performed open biopsy; the diagnosis was ASPS and he underwent wide local excision. In the course of 4-year follow-up by clinical and imaging studies, there was no evidence of early tumor recurrence or metastasis. Complete surgical resection is the treatment of choice in patients with ASPS. PMID- 29147377 TI - Rectal Carcinoma Case Causing Bicytopenia. AB - Although conditions leading to bicytopenia and pancytopenia secondary to infiltrative diseases of the bone marrow are seen, a profound anemia or hemorrhages are frequently observed in such cases. As bone marrow infiltrations may be associated with primary hematological diseases such as leukemia, lymphoma or myeloma, rarely they may also be associated with solid tumor metastases. Here we have presented a case of rectal carcinoma causing profound bicytopenia dependent on diffuse bone marrow involvement. PMID- 29147378 TI - Male Breast Cancer and Hyperestrogenemia: A Thirteen-Year Review. AB - Background: Male breast cancer (MBC) is a very rare malignancy and accounts for 0.1% of all male cancers. MBC has not been studied as extensively as its female counterpart. Certain clinical and pathological risk factors like smoking history, age at onset, family history of cancer, obesity, ethnicity, estrogen/progesterone receptor status and BRCA gene mutation status have all been studied well in the female breast cancer (FBC) patients and the clinical trial evidence from these studies is then extrapolated to treat and manage patients with MBC. One such area of interest is high levels of estrogen and its relationship with MBC. In our retrospect research study we aim to find an association between MBC and high levels of circulating estrogen at the time of diagnosis. Methods: A 13-year retrospective review of the male breast cases at University of Florida College of Medicine's Tumor Registry was conducted. Data regarding certain clinic pathological risk factors and MBC were collected and reviewed. Main surrogate indicators for elevated estrogen were examined, namely, low HDL (< 40 mg/dL), low albumin (< 4 g/dL) and high BMI (> 25). Presence of any one of these surrogates was seen as an indirect marker for high estrogen level. For cancer staging, the American Joint Committee on Cancer (AJCC) staging system was used. Stages 0-2 were grouped together as they are less extensive compared to stages 3-4 (also grouped together) which represent extensive disease. Univariate analysis was conducted using STATA 13 to do Fischer's exact test as cross-tables showed cell counts of five or less. The main comparison was that between extensive MBC (stages 3-4) and non-extensive breast cancer (stages 0-2). Results: Between January 2000 and November 2013, we found a total of 2,129 cases of breast cancer patients at our institute. Out of these 2,113 (99.24%) were female and 16 (0.75%) were men. Four MBC patients were excluded because their complete charts could not be found in the medical records department. Six (50%) patients had one indicator, four (33%) patients had two indicators and one (8.3%) patient had all three. Eleven (91.6%) patients had precursors suggestive of hyperestrogenemia. Only one (8.33%) patient did not have any surrogate marker indicator of high estrogen levels. Two (16%) were black and 10 (83.33%) were white. Mean age was 61.75. Five (41%) had a first degree relative with a malignancy. Laterality was nine (75%) in the left breast, three (35%) in right breast. Eight (66.6%) found a mass on physical exam. Five (41.6%) had a positive smoking history. One patient had no data in the chart. Remaining all 11 (91.6%) had non-TNBC. One patient did not have complete documentation. Five (41.6%) had mastectomy, six (50%) received RT, four (33.3%) received chemotherapy and another four received hormone therapy. In terms of stage, four (33.3%) had stage 4, two (16.6%) stage 3B, two (16.6%) stage 2B, two (16.6%) stage 2A, one (8.33%) had stage 1C and one had stage 0. HDL data were available in seven (58.3%) with mean of 37, albumin in 10 (83.3%) with mean of 3.61, BMI in 11 (91.66%) patients with a mean of 33.30. Within subgroups, two patients were black and 10 white. Both black patients had LE disease (stage 0-2). Of the white patients, four (40%) had limited disease while six (60%) had extensive breast cancer. Family history assumed a similar distribution as three (60%) of patients with negative family history for cancer had limited disease and two (40%) had extensive one, same numbers applied for family-history-positive population. Three (60%) of patients with limited disease smoker and two (40%) did not. As for laterality, a total of nine patients had left-sided breast cancer, of whom five had had limited disease and four fell into the extensive disease category. The hormonal status for most patients were HER/NEU negative (seven out of 10 patients, two patients did not have this information on file), ER positive (11 out of 12) and PR positive (8 out of 12). Estrogen status: Low HDL was seen in three out of seven patients, low albumin in four out of 10 and obese BMI in nine out of 11. Finally, 11 out of 12 patients had at least one indicator of high estrogen. No significant change in prevalence of these markers was seen when comparing patients with limited and extensive disease. Conclusion: None of the aforementioned variables assumed statistical significance between the two subgroups. Results, however, show that as a whole, 11 out of the 12 patients had at least one indicator of high estrogen. Our results point in the direction that elevated estrogen is probably associated with MBC. Further meta-analysis of similar studies can be helpful to explain the dynamics of this association. Our statistical analysis was limited due to the small sample size, which is due to the extreme rarity of the disease. PMID- 29147379 TI - Outcomes of Laser Conization for Cervical Intraepithelial Neoplasia 2-3 and Microinvasive Cervical Cancer. AB - Background: Currently, there is no standardized follow-up protocol for patients who undergo laser conization. Therefore, we retrospectively investigated the clinical outcomes of laser conization in patients with high-grade cervical intraepithelial neoplasia 2-3 (CIN 2-3) and microinvasive squamous cell carcinoma and assessed the risks of residual and recurrent lesions of the cervix uteri. Methods: The medical and pathological records of 91 patients with CIN 2, 580 with CIN 3 and 73 with microinvasive cervical cancer (MIC) who underwent laser conization between January 2000 and December 2011 were retrospectively reviewed. Results: Positive margins increased with the extent of disease and were observed in 5.5%, 8.9% and 16.4% patients with CIN 2, CIN 3 and MIC, respectively, while residual or recurrent disease was observed in 0%, 3.2% and 13.6% patients, respectively. Examination of specimens obtained through postconization biopsy or hysterectomy revealed that 1.5% and 20% patients with negative and positive margins, respectively, were diagnosed with residual or recurrent lesions. Among patients who were conservatively managed after conization, seven with CIN 3 exhibited residual or recurrent disease, as evidenced by abnormal cytological findings, within 2 years after conization. Conclusions: Continuous follow-up by cytology and colposcopy, particularly during the first 2 years after conization, can effectively detect early residual or recurrent disease in CIN 3 and MIC patients, regardless of their margin status. PMID- 29147380 TI - Concurrent Acute Monoblastic Leukemia and Multiple Myeloma in a 66-Year-Old Chemotherapy-Naive Woman. AB - Concurrent acute myeloid leukemia (AML) and multiple myeloma (MM) is rare, more so in chemotherapy-naive patients. Concurrent occurrence of these two malignancies portends poor prognosis. Although anthracycline-based AML regimen, allogeneic hematopoietic stem cell transplantation, tipifarnib and bortezomib have shown promising results in small number of patients, there is a lack of established therapy. We describe a case of concurrent AML and MM in a 66-year-old woman and review previously published literature. PMID- 29147381 TI - Neuroendocrine Differentiation of Prostate Cancer Metastases Evidenced "in Vivo" by 68Ga-DOTANOC PET/CT: Two Cases. AB - Prostate cancer is the second most commonly diagnosed neoplasm in men. This neoplasm has usually excellent prognosis, mostly consequent to the early diagnosis and the effective hormonal therapy. However, significant percentages of patients treated with total androgen blockade therapy, escape to treatment and evolve toward a more aggressive type of cancer. This clinical entity, named castration-resistant prostate cancer, has few and less effective therapeutic opportunities. Therefore, any additional information concerning possible biological targets to therapy is welcome. Here we describe two cases in which 68Ga-DOTANOC PET/CT evidenced the somatostatin receptor overexpression by prostate metastases. The presence of these receptors may support with a more strong evidence the possibility to administer somatostatin analogs as an adjuvant therapy. PMID- 29147382 TI - Leptomeningeal Relapse of Acute Promyelocytic Leukemia. AB - Extramedullary relapse (EMR) of acute promyelocytic leukemia (APL) is a rare entity, with predilection to involve the central nervous system (CNS). Risk factors include leukocytosis of > 10 * 109/L, bcr3 isoform, microgranular variant, age > 45 years and development of subarachnoid hemorrhage (SAH) during induction therapy. We report a case of APL who completed induction and consolidation therapy but subsequently relapsed with leptomeningeal involvement. Retrospectively, we identified several risk factors for EMR in our patient. Interestingly, the use of all-trans retinoic acid has recently been associated with higher risk of EMR possibly due to up-regulation of adhesion molecules on the surface of the leukemic cell, resulting in their passage through the endothelium to extramedullary tissues. However, data remain conflicting in that regard. Although universal CNS prophylaxis has been suggested, the low incidence of EMR among APL patients renders this strategy less attractive. Nonetheless, active surveillance and CNS prophylaxis may be considered in patients at high risk for EMR, particularly in those of SAH during induction therapy. Further research is needed to evaluate the effectiveness and safety of this strategy. PMID- 29147383 TI - Metastatic Medullary Thyroid Carcinoma and Cabozantinib: Case Series and Review of Literature. AB - Cabozantinib, a tyrosine kinase inhibitor, was approved by the US Food and Drug Administration in November 2012, for the treatment of metastatic medullary thyroid carcinoma. Although side effects typically include stomatitis, palmar plantar erythrodysesthesia syndrome, hypertension and diarrhea, most patients are able to tolerate the recommended dose of 140 mg daily. Surgical resection is the primary treatment for medullary thyroid carcinoma. Patients with metastatic disease, who are not candidates for surgery, are considered candidates for systemic therapy. However, systemic chemotherapy has a limited role in metastatic disease. Our paper highlights not only the malignant potential of a medullary thyroid carcinoma, but also the role of cabozantinib in patients with progressive metastatic disease. We report two cases of patients with progressive metastatic medullary thyroid carcinoma (involving lung, lymph nodes, liver, pancreas, brain and spine) who responded well to therapy with cabozantinib. PMID- 29147384 TI - Adrenal Ganglioneuroma Presenting As Left Renal Mass. AB - Ganglioneuromas (GNs) are benign tumors resulting from neural crest tissue. GNs contain mature ganglion cells and Schwann cells. GNs most commonly occur in the retroperitoneum and posterior mediastinum. GNs rarely occur in the adrenal gland. A 45-year-old asymptomatic patient presented with an incidental finding of left renal mass. A 10 cm mass lesion located in the upper pole of the left kidney and lymphadenopathy in renal hilus were detected. The patient underwent transperitoneal radical nephrectomy involving the removal of left adrenal gland. The immunohistochemical examination showed strong positive staining for S100, neuron-specific enolase, synaptophysin and chromogranin. The diagnosis of mature GN was established. GNs are among the rare diseases that should be considered in the evaluation of renal masses, particularly in the differential diagnosis of upper pole tumors of the kidneys. It can be confused with renal cell carcinomas. PMID- 29147385 TI - Cannonball Metastatic Lesions in a Young Male: A Case Report. AB - Testicular germ cell tumors are the most common malignancy among young men. These are highly chemo-sensitive tumors with high cure rates. More than 95% of patients with testicular cancer present with a painless testicular mass. Here we describe a rare initial presentation of testicular cancer in a previously asymptomatic 22 year-old male who presented with widespread metastatic cannonball lesions in his lungs. PMID- 29147387 TI - Application of Bayesian Approach in Cancer Clinical Trial. AB - The application of Bayesian approach in clinical trials becomes more useful over classical method. It is beneficial from design to analysis phase. The straight forward statement is possible to obtain through Bayesian about the drug treatment effect. Complex computational problems are simple to handle with Bayesian techniques. The technique is only feasible to performing presence of prior information of the data. The inference is possible to establish through posterior estimates. However, some limitations are present in this method. The objective of this work was to explore the several merits and demerits of Bayesian approach in cancer research. The review of the technique will be helpful for the clinical researcher involved in the oncology to explore the limitation and power of Bayesian techniques. PMID- 29147386 TI - Review of Cisplatin and Oxaliplatin in Current Immunogenic and Monoclonal Antibodies Perspective. AB - Platinum-based chemotherapy made a paradigm shift in the treatment of different cancers initially; however, the success of these agents may have reached the peak as researchers have tried different combination regimes in different trials without having major differences in the end results. New frontiers of research were opened up firstly with this discovery that conventional chemo-radiation therapy can induce immunological cell death by recruiting high-mobility group box 1 (HMGB1) protein which triggers the T cell immunity and secondly monoclonal antibodies agents which were regrettably not effective as "monotherapy"; however, the combination with conventional chemotherapy had demonstrated good results. Different monoclonal antibodies and conventional chemotherapeutic combination regimes are currently in use and researchers are trying different other combinations as well to glean the maximum benefits from them. Several strategies conferring resistance to platinum compounds have been identified, but there is still significant research required to achieve full understanding of these resistance mechanisms to overcome the ineffectiveness or toxicities of platinum compounds. It seems reasonable in the current perspective when conventional chemotherapeutic agents exhibited immunogenic cell death and they are currently in use with monoclonal antibodies to revisit the platinum agent's pharmacology. This may discover new basis for combination chemotherapy with monoclonal antibodies which may improve the current cancer treatments by opening new vistas for newer combination regimes with less toxicity and better efficacy. In this article we review the pharmacologies of both cisplatin and oxaliplatin in the drug development perspectives and explore the possible association of these drugs with monoclonal antibodies. PMID- 29147388 TI - Relationship of Gender and Smoking History in the Development of Hypothyroidism From Exposure to External Beam Radiation for Head and Neck Cancers. AB - Background: Patients with head and neck cancers (HNCs) are often treated with external beam radiation therapy (XRT). Unfortunately this therapy is not without its unintended consequences. One of these side effects includes the development of radiation-induced hypothyroidism. Our study is designed to pay special attention to variables like gender and smoking history and analyze their relationship with the development of hypothyroidism. Methods: Patients' charts were reviewed over a period of 13 years from January 1, 2000 to November 30, 2013 to gather information on patients who had previously received XRTs for HNCs. We used the Tumor Registry Database at the University of Florida, College of Medicine in Jacksonville for this retrospective review. Patient characteristics were examined including age, gender, race/ethnicity and smoking history. Special attention was paid to the development of hypothyroidism (thyroid stimulating hormones > 5.0 with appropriate decrease in free serum T4) levels after exposure to XRT for HNCs. Results were then analyzed using the univariate statistical analysis which was done using the SAS software using a 0.05 alpha level of significance expressed in terms of odds ratio (OR) with 95% confidence intervals (CIs). Results: We found a total of 1,116 patients in our database who have received XRTs for HNCs. Out of these 72 (6.45%) patients developed hypothyroidism. Out of 263 African American patients 20 (7.6%) had hypothyroidism, whereas 49 (6%) out of 819 white people had this outcome. As for gender 32 out of 341 females (9.4%) and 40 out of 775 males had hypothyroidism. Thirty-five out of 544 (6.4%) with no family history and 19 (2.4%) out of 205 (9.3%) with positive family history for cancer had the outcome too. Finally 43 (6.5%) out of 664 smokers and 17 (8.3%) out of 206 non-smokers were found to develop hypothyroid as well. Both groups were found to have homogenous average age at diagnosis. When the univariate analysis was conducted, the strongest predicting variable was gender as hypothyroid patients were 1.90 (95% CI 1.17 - 3.09) times more likely to be females, and these results were statistically significant with P value of 0.008. More patients tended to be African Americans with OR 1.21 (CI 0.822 - 1.78), had positive family history of cancer (negative family history had OR 0.67 (CI 0.38 - 1.21), and less likely to be smokers (OR 0.77 (0.43 - 1.38). However, race, family history of cancer and smoking history did not achieve any statistical significance as evident by the P values. Conclusion: In our patient population, females were more likely to develop radiation-induced hypothyroidism. PMID- 29147389 TI - Temozolomide and Reirradiation in Recurrent Grade II Brain Glioma. AB - Background: This phase II trial was designed to assess the response rate, survival benefits and toxicity profile of temozolomide, and brain reirradiation using conformal radiotherapy (CRT) for recurrent grade II brain glioma. Between February 2006 and June 2009, 18 patients with recurrent low grade glioma, and two with recurrent ependymoma were enrolled in the study. Patients had to show unequivocal evidence of tumor recurrence on gadolinium-enhanced magnetic resonance imaging after failing conventional radiotherapy for initial disease. Methods: Patients were treated by temozolomide at a dose of 200 mg/m2/day for chemonaive patients, and at a dose of 150 mg/m2/day for previously treated patients, for 4 - 5 cycles. Then, patients underwent reirradiation by CRT at a dose of 30 - 40 Gy by conventional fractionation. Results: All the 20 patients were treated with temozolomide and reirradiation. Two patients achieved complete remission, and six achieved partial remission, with an overall objective response rate of 40%. The mean overall survival (OS) was 16 months (range, 6 - 24 months). The median OS was 15.5 months. Additionally, treatment significantly improved quality of life. Treatment was tolerated well with mild grade 1, 2 hematological toxicities, and nausea/vomiting in 15% and 39% of cycles, respectively. Conclusions: Temozolomide and CRT had an anti-tumor activity in recurrent grade II brain glioma, and represented a good treatment hope for such patients. PMID- 29147390 TI - Isolated Recurrence of Diffuse Large B-Cell Lymphoma in Sciatic Nerve. AB - Sciatica is a common clinical presentation with a number of etiological factors. Many of them are innocuous like prolapsed intervertebral disc or peripheral compression in the sciatic nerve. Occasionally the cause could be of a more serious nature like a nerve sheath tumor or more infrequently, lymphomatosis. We describe recurrent lymphoma in a patient who had been in remission presented with sciatica as result of the involvement of the nerve with metastatic tumor. PMID- 29147391 TI - Precursor T-Cell Lymphoblastic Lymphoma Presenting as Cardiac Tamponade in a 25 Year-Old Male: A Case Report and Review of Literature. AB - Precursor T-cell lymphoblastic lymphoma (LBL) and T-cell acute lymphoblastic leukemia (ALL) are considered same disease with different clinical presentations. Clinically, a case is defined as lymphoma if there is a mass lesion in the mediastinum or elsewhere and < 25% blasts in the bone marrow. Whereas, bone marrow with > 25% blasts with or without mediastinal masses is classified as T cell ALL. Mediastinal masses caused by T-cell LBL can lead to complications such as superior vena cava syndrome, tracheal obstruction, pericardial effusion and tamponade. We report an unusual case of a 25-year-old male with no significant past medical history, who presented with clinical features of cardiac tamponade. Work-up revealed a massive pericardial effusion and a mass arising in the anterosuperior mediastinum. Patient underwent an emergent subxiphoid pericardial window and approximately 1 L of hemopericardium was drained. Histopathology (pericardial tissue) and flow cytometry on the pericardial fluid were compatible with a precursor T-cell LBL. Although pericardial involvement by lymphoma/leukemia is a very rare complication, cases have been reported with both lymphoma and acute/chronic leukemia. Our paper highlights cardiac tamponade as one of the life-threatening complications associated with a precursor T-cell LBL. PMID- 29147392 TI - Oligometastatic Large Cell Neuroendocrine Carcinoma of the Brain Without Radiologically Detected Primary. AB - A 60-year-old Polish male was admitted into our hospital with complaint of right sided lower extremity weakness. CT of head showed a left frontal 2.6 * 1.5 cm mass. Staging work-up did not show any other associated lesions in the chest or abdomen. Brain tumor was resected with histology consistent with large cell neuroendocrine carcinoma with most likely lung primary because of TTF-1 positivity. Following recovery from surgery, he had external beam radiation therapy to the brain and systemic chemotherapy with four cycles of cisplatin/etoposide. Patient is alive and doing well 6 months post diagnosis with no evidence of recurrence. PMID- 29147393 TI - Extraconal Orbital Soft Tissue Metastasis Secondary to Prostate Cancer: An Unusual Presentation. AB - Prostate cancer is mostly known to metastasize to the bony skeleton. Soft tissue metastasis involving visceral organs such as the liver, lung and brain are unusual and rare manifestations of this cancer. However, with better treatment modalities and increased survival, the incidence of these unusual presentations, seems to have risen in the last few years. Prostate cancer is rarely known to metastasize to the orbit. Although cases of bony metastasis involving the orbit have been reported, soft tissue metastasis involving the orbit is a very rare presentation. Most soft tissue metastasis to the orbit involves the uveal tract, with prostate cancer being the most common primary cancer to metastasize to the iris (uveal tract). Our paper highlights a case of extraconal orbital soft tissue metastasis secondary to prostate cancer, an extremely rare presentation. Patient was started on combined androgen blockade therapy. Three-month repeat MRI orbit showed that the extraconal orbital mass had decreased in size significantly. His clinical symptoms have resolved at the time of this report. To our knowledge, this is the first reported case of its kind. PMID- 29147394 TI - Primary Angiosarcoma of the Breast: A Case Report and Review of Literature. AB - Angiosarcoma of the breast (ASB) is a rare but aggressive tumor with very poor prognosis. It is important to recognize this tumor early and to distinguish between primary and secondary ASB. While mammograms frequently miss these lesions, ultrasound and MRI show promise as imaging modalities. In spite of characteristic features described on pathology, misdiagnosis is common, with over 35% tumors initially thought to be benign. We present the case of a 32-year-old woman with a history of bilateral reduction mammoplasty who presented with a non tender lump in her right breast. After repeated aspirations and biopsies, a diagnosis of primary ASB was made. She underwent bilateral simple mastectomies followed by adjuvant chemo-therapy and radiation. While surgery is the mainstay of treatment, roles of radiation and chemo-therapy are still evolving; we review the literature and discuss the decision pathways for diagnosis and management of this rare tumor. PMID- 29147395 TI - Pulmonary Embolism as an Initial Presentation of Adrenocortical Carcinoma. AB - Adrenocortical carcinomas (ACCs) are rare and often aggressive with more than 50% of the cases already in stage III-IV (ENSAT) at the time of diagnosis. Nearly 60% of ACCs present with hormone overproduction syndromes (Cushing's syndrome and/or virilization), while the rest present with abdominal mass or incidental finding. Aggressive surgical resection is the mainstay of treatment usually followed by adjuvant mitotane monotherapy. For the advanced stage, adjuvant radiotherapy and combined chemotherapy with mitotane therapy can be added for survival benefit. Here, we would like to report a case of stage III high-grade ACC without syndromes of hormone overproduction, initially presented with pulmonary embolism. It was rapidly progressive with metastases to lungs, peritoneum and bone despite aggressive surgery followed by adjuvant mitotane monotherapy. However, after palliative radiotherapy to thoraco-lumbar spine for spinal cord compression, and adding chemotherapy (six cycles of EDP: etoposide, doxorubicin, cisplatin) to mitotane, a significant partial remission was achieved. He has had 24 months of progression-free survival, and is currently on mitotane monotherapy with cortisol replacement. Discussion will support multimodality therapy for stage III high grade ACC with surgery immediately followed by adjuvant radiotherapy and combined chemotherapy with mitotane therapy to prevent local recurrence and distant metastases. PMID- 29147396 TI - Significance of Fractionated Administration of Thalidomide Combined With gamma Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis. AB - Background: The aim of this study was to evaluate the significance of fractionated administration of thalidomide combined with gamma-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. Methods: B16-BL6 melanoma tumor bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received gamma-ray irradiation after thalidomide treatment through a single or two consecutive daily intraperitoneal administrations up to a total dose of 400 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Results: Thalidomide raised the sensitivity of the total cell population more remarkably than Q cells in both single and daily administrations. Daily administration of thalidomide elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases. Conclusion: Daily fractionated administration of thalidomide in combination with gamma-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential. PMID- 29147397 TI - Liquid-Based Medium Used to Prepare Cytological Breast Nipple Fluid Improves the Quality of Cellular Samples Automatic Collection. AB - Background: Breast cancer is the second cause of death in women worldwide. The spontaneous breast nipple discharge may contain cells that can be analyzed for malignancy. Halo(r) Mamo Cyto Test (HMCT) was recently developed as an automated system indicated to aspirate cells from the breast ducts. The objective of this study was to standardize the methodology of sampling and sample preparation of nipple discharge obtained by the automated method Halo breast test and perform cytological evaluation in samples preserved in liquid medium (SurePathTM). Methods: We analyzed 564 nipple fluid samples, from women between 20 and 85 years old, without history of breast disease and neoplasia, no pregnancy, and without gynecologic medical history, collected by HMCT method and preserved in two different vials with solutions for transport. Results: From 306 nipple fluid samples from method 1, 199 (65%) were classified as unsatisfactory (class 0), 104 (34%) samples were classified as benign findings (class II), and three (1%) were classified as undetermined to neoplastic cells (class III). From 258 samples analyzed in method 2, 127 (49%) were classified as class 0, 124 (48%) were classified as class II, and seven (2%) were classified as class III. Conclusion: Our study suggests an improvement in the quality and quantity of cellular samples when the association of the two methodologies is performed, Halo breast test and the method in liquid medium. PMID- 29147398 TI - Exertional Chest Pain and Dyspnea From Hyperviscosity Syndrome Related to Marginal Zone Lymphoma. AB - Hyperviscosity syndrome is usually seen in Waldenstrom macroglobulinemia with the serum viscosity > 4 cP. It commonly manifests as skin or mucosal bleeding, visual abnormalities and neurological symptoms. We describe a case of a 65-year-old man, who presented with chronic exertional chest pain and dyspnea without other manifestation and had hyperviscosity syndrome related to marginal zone lymphoma (MZL) even with a marginally elevated plasma viscosity. The symptoms resolved after initiation of chemotherapy. This case illustrates that MZL can cause hyperviscosity syndrome, which can manifest with cardiopulmonary symptoms without other clinical features even at a marginally elevated plasma viscosity. Atypical cases of hyperviscosity syndrome can, thus, present diagnostic challenges and require a high index of suspicion. PMID- 29147399 TI - Modified Clagett Procedure Is Effective for Methicillin-Resistant Staphylococcus aureus Postpneumonectomy Empyema: A Case Report. AB - Postpneumonectomy empyema (PPE) with methicillin-resistant Staphylococcus aureus (MRSA) is a challenging problem because these germs have extensive virulence factors and mechanisms to escape from the host's immune system. The present case was successfully treated with accelerated repeated surgical debridement, vancomycin gauze packing and final obliteration of the postpneumonectomy space with latissimus myoplasty and vancomycin solution. PMID- 29147400 TI - Does Aromatase Inhibitors Cause Sjogren's Syndrome and Polyneuropathy? AB - Aromatase inhibitors (AIs) are the indispensible part of hormone-responsive breast cancer treatment. A potential relation between autoimmunity and AIs has been described before. Herein, we report a case of Sjogren's syndrome (SjS) and polyneuropathy which developed during treatment with anastrozole. A 70 years old female patient having a history of breast cancer was referred to our clinic with numbness in both legs for 1 year. She was receiving anastrazole since 2006. She was having sicca symptoms for 3 years. After laboratory evaluation, salivary gland biopsy and electroneuromyography, the patient was evaluated as SjS and polyneuropathy. Intravenous immunoglobulin treatment (400 mg/kg/day, 5 days, 6 months) was initiated. A potential pathogenic linkage between AI therapy and autoimmunity is mentioned. Only few cases of rheumatoid arthritis and SjS related with AIs have been reported. But, our case is the first in the literature having definite SjS and neuropathy in this setting. PMID- 29147401 TI - Another Case of Pulmonary Edema or May Be Not: An Unusual Presentation of Metastatic Melanoma. AB - Melanoma is a tumor of pigment producing cells melanocytes. Malignant melanoma is associated with a high morbidity and mortality because of its widespread and rapid metastasis. Melanoma commonly metastasizes to lung and secondary metastatic pulmonary melanoma is a well known entity. Metastatic melanoma can present with varied pattern of pulmonary involvement ranging from post obstructive pneumonia to atelectasis. However, lung involvement is not known to cause hypoxic respiratory failure. Here, we describe a rare case of metastatic melanoma presenting as an acute respiratory distress syndrome requiring mechanical ventilation. PMID- 29147402 TI - Immunohistochemical Analysis of Cyclooxygenase-2 in Non-Melanocytic Skin Cancer: Correlation With Morphological Subtype and Histologic Grade. AB - Background: Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are known as non-melanoma skin cancers (NMSCs), and they account for approximately 90% of all skin cancers. Cyclooxygenase-2 (COX-2) is expressed in NMSC and in premalignant cutaneous lesions (actinic keratosis). Methods: Immunohistochemistry was performed with COX-2 antibodies in skin biopsies (paraffin tissue archival blocks) from 28 cases with SCC and 33 cases with BCC. Results: COX-2 was immunostained in a total of 61 cases. There was no staining or weakly positive staining in 73.8% of the cases (45 cases), and there was moderate or strong positive staining in 26.3% of the cases (16 cases). COX-2 was expressed in 42.4% of the BCC cases and in 57.1% of the SCC cases. There was a significant relationship between positive COX-2 staining and SCC (P = 0.016). Conclusions: In this study, SCCs were significantly correlated with the expression of COX-2. In addition, COX-2 was more frequently expressed in SCC than in BCC. The largest diameters of the SCC were significantly correlated with the expression of COX-2. There were no significant associations between COX-2 staining and clinicopathologic features such as the ulceration of the tumor, its anatomic localization, patient gender, the histologic grade of the SCC and the morphological subtype of the BCC. PMID- 29147404 TI - A Retrospective Study of Efficacy and Safety of Albumin-Bound Paclitaxel in Metastatic Breast Cancer. AB - Background: Nab-paclitaxel is a novel nanoparticle, albumin-bound, solvent-free, taxane-based chemotherapy approved for the treatment of metastatic breast cancer (MBC). This study reports clinical benefit and toxicities experienced by women with MBC treated with nab-paclitaxel. Methods: Women with MBC treated with single agent nab-paclitaxel between January 2012 and March 2014 were included in this analysis. Retrospective data obtained included demographics, disease characteristics, prior chemotherapy, nab-paclitaxel treatment, toxicity and survival. Clinical benefit was defined as partial or complete response or stable disease (by clinical or radiologic evaluation, or both) at 6 months or more. Results: Overall response rates (complete or partial responses) were 43% (95% CI: 35.3 - 60.0) for all patients. Median time to disease progression was 26.6 weeks, and median survival was 63.6 weeks. No severe hypersensitivity reactions were reported despite the lack of premedication. Toxicities observed were typical of paclitaxel and included grade 3 sensory neuropathy (14.3%), grade 4 neutropenia (7.14%) and grade 4 febrile neutropenia (7.14%). Patients received a median of six treatment cycles; three patients had 25% dose reductions because of toxicities. Conclusions: Our clinical experience demonstrates that most women treated with nab-paclitaxel experienced some clinical benefit. Patients achieving clinical benefit lived significantly longer than those who did not. Nab paclitaxel was well tolerated, with the primary toxicity being mild sensory neuropathy. Nab-paclitaxel represents another treatment option, with a favorable toxicity profile, for women with MBC. PMID- 29147403 TI - Bacterial Spectrum, Isolation Sites and Susceptibility Patterns of Pathogens in Adult Febrile Neutropenic Cancer Patients at a Specialist Hospital in Saudi Arabia. AB - Background: Knowing local spectrum and sensitivity for bacterial isolates causing febrile neutropenia is important as starting an appropriate empirical antibiotic therapy is considered a medical emergency in these high-risk patients. Methods: A retrospective study of a total of 106 microbiologically febrile episodes in hospitalized adult neutropenic cancer patients, who were admitted from May 2009 to May 2013, at King Fahad Specialist Hospital, Dammam, Saudi Arabia, was conducted. Results: Among 106 microbiologically documented febrile neutropenic episodes, the majority of malignancies were solid tumors accounting for 53.8% (57/106) and hematological malignancies accounted for 46.23% (49/106). The most common malignancies were non-Hodgkin's lymphoma 19.81% (21/106) followed by acute myeloid leukemia 15.09% (16/106), then colorectal cancer 13.21% (14/106), pancreatic cancer and acute lymphoblastic leukemia accounting for 5.66% (6/106) each, multiple myeloma 4.72% (5/106), gall bladder cancer 3.77% (4/106), and lung cancer 2.83% (3/106). A total of 138 bacterial isolates were identified. The overall prevalence of gram-negative bacteria was 65.94% (91/138) and for gram positive bacteria was 34.06% (47/138). The most common bacterial isolation sites were blood 33.32% (46 isolates), urine 29.71% (41 isolates), wound 19.55% (27 isolates), body fluids 9.41% (13 isolates) and sputum 7.96% (11 isolates). The most predominant pathogens were Escherichia coli 30.43 (42/138), Klebsiella pneumonia 14.49% (20/138), Staphylococcus aureus 13.04% (18/138), Sptreptococcus spp. 7.25% (10/138), Pseudomonas spp. 7.25% (10/138), Enterococcus spp. 5.80% (8/138), Staphylococcus spp. 4.35% (6/138), Corynebacterium spp. 3.62% (5/138), Enterobacter spp. 3.62% (5/138), Acinobacter spp. 2.90% (4/138), Serratia marcescens 2.17% (3/138), Proteus mirabilis 1.45% (2). Aeromonas hydrophylia, Citrobacter freundii, Providencia stuartii, Sphingomonas paucimobilis and Stenotropomonas multipholia contributed to 0.72% with one isolate each. For gram negative Escherichia coli and Klebsiella pneumonia, the extended-spectrum beta lactamases producers (ESBLs) rates were 38% and 22.22% respectively. For Pseudomonas aerugenosa imipenem-cilastatin resistance rate was 18.84%. For gram positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA) rate was 28.62%. The vancomycin-resistant Enterococci (VRE) rate was 1.18%. Conclusion: Gram-negative bacteria were more prevalent as a cause of infection in adult cancer patients with febrile neutropenia at our institution, with Escherichia coli and Klebsiella pneumonia with high ESBLs rates being the most common pathogens. Blood stream infections followed by urinary tract infections were the most common sites of infection. The use of initial antibiotic therapy in febrile neutropenic episodes should be based on local bacterial spectrum and susceptibility/sensitivity patterns to prevent treatment failure with increased morbidity and mortality. PMID- 29147405 TI - Spontaneous Hepatic Rupture Associated With Epstein-Barr Virus Negative Aggressive Natural Killer Cell Leukemia. AB - Aggressive natural killer cell leukemia (ANKL) is a rare subtype of large granular lymphocyte (LGL) leukemia, which typically presents in young adults of Asian descent. It is an aggressive disease, characterized initially by fever, pancytopenia and hepatosplenomegaly, which rapidly progresses to organ failure and death over the course of months. Spontaneous hemorrhagic complications have been reported to occur in ANKL in a handful of case reports, including lethal intestinal and cerebral hemorrhage as well as splenic rupture. Here, we present a case of a 49-year-old man with Epstein-Barr virus (EBV)-negative ANKL who developed fatal spontaneous hepatic rupture approximately 4 months after initial diagnosis. To the best of our knowledge, this is first reported case of hepatic rupture associated with ANKL. PMID- 29147406 TI - Relapsing Episodes of Loss of Consciousness in a Patient With Hepatocellular Carcinoma. AB - Hypoglycemia is common in people with diabetes treated with insulin or oral medications such as sulphonylureas or other secretagogues, and constitutes a relatively rare paraneoplastic syndrome in patients with a variety of mesenchymal or epithelial tumors. In this case report we present a 51-year-old patient with metastatic hepatocellular carcinoma and persistent, severe, symptomatic hypoglycemia and we discuss management options and review the relevant medical literature. PMID- 29147407 TI - Primitive Neuroectodermal Tumor of the Vulva in an Adolescent Girl. AB - Extraskeletal primitive neuroectodermal tumor (PNET) is rare and that affecting the female genital tract is extremely rare. We report the case of a 17-year-old girl who presented with swelling of the clitorus. She underwent excision and histopathology was PNET. She received chemotherapy and radiation and achieved complete remission. However, she relapsed locally and systemically soon, progressed and died. PMID- 29147408 TI - Pazopanib-Induced Regression of Brain Metastasis After Whole Brain Palliative Radiotherapy in Metastatic Renal Cell Cancer Progressing on First-Line Sunitinib: A Case Report. AB - Pervious randomized studies have demonstrated survival benefit in favor of tyrosine kinase inhibitors (TKIs) compared to cytokines in metastatic clear cell renal cell carcinoma (RCC). However, the role of TKIs for treating brain metastasis from RCC remains unknown. Previous studies have reported possible activity of sunitinib and sorafenib in RCC patients with brain metastasis. We report on patient with metastatic RCC who responded to first-line sunitinib but then progressed with multiple brain metastasis, but with controlled extra-cranial metastatic disease. The patient was treated with whole-brain palliative radiotherapy followed by treatment schedule of pazopanib at standard dose of 800 mg/day which was associated with a response in brain metastasis. Subsequently, she was re-challenged at reduced dose of 600 mg/day and developed further response in metastatic brain lesions. She lived for more than 3 years from initial diagnosis of brain metastasis. This is the first case report of sequential TKI therapy for treating metastatic RCC with brain metastasis and supports the probable use of pazopanib as potent TKI for treating patients with cerebral metastasis. PMID- 29147409 TI - Synchronous Presentation of Cavernous Sinus Metastasis and Cervical Cancer: A Case Report and Review of Literature. AB - Uterine cervical cancers customarily spread by local extension to the adjacent viscera or through lymphatic embolization to the retroperitoneal lymph nodes. Distant hematogenous spread particularly to the brain is an uncommon and late event which heralds a poor prognosis. We report a case of uterine squamous cell carcinoma of the cervix with unusual simultaneous presentation of cavernous sinus metastasis and multiple brain metastases while reviewing the current literature on this clinical entity. PMID- 29147410 TI - Pemetrexed-Induced Interstitial Pneumonitis: A Case Study and Literature Review. AB - Pemetrexed is a new-generation antifolate drug, now widely used in patients with non-small cell lung cancer (NSCLC). We report a case of pemetrexed-induced interstitial pneumonitis, and review the literature of eight previously reported cases. As pemetrexed is now a widely used chemotherapeutic agent, it is important to be aware of rare adverse events related to its administration. PMID- 29147411 TI - Pulsed Erlotinib as Sole Treatment of Leptomeningeal Carcinomatosis: Can We Avoid the Use of Intrathecal Therapy? AB - Leptomeningeal carcinomatosis, a not uncommon complication of non-small cell lung cancer, is associated with poor prognosis, and median survival is reported in case series as weeks to months. The advent of targeted therapy may have positively impacted the prognosis of such patients recently. Standard approaches to treatment of leptomeningeal metastasis include intrathecal chemotherapy with or without cranial or craniospinal radiation and additional systemic therapy. We report a case of leptomeningeal metastasis in epidermal growth factor receptor overexpressing lung adenocarcinoma showing an excellent response with pulsed doses of erlotinib as the only therapy. PMID- 29147413 TI - The Role of Tracheostomy in Anaplastic Thyroid Carcinoma. AB - Even though management of thyroid cancer is generally standardized and has an overall excellent long-term outcome, anaplastic thyroid cancer (ATC) continues to be a major diagnostic and therapeutic challenge. ATC is an uncommon thyroid malignancy with a poor prognosis. American Thyroid Association guidelines acknowledge the complexity of airway management in these patients. We studied the literature with the aim of providing guidance in airway management in ATC. Tracheotomy can facilitate completion of palliative treatment in those patients with ATC and stridor. Given the short life expectancy of these patients, a balanced decision must be made regarding the role and timing of tracheotomy. PMID- 29147414 TI - Liver Metastases in Prostate Carcinoma Represent a Relatively Aggressive Subtype Refractory to Hormonal Therapy and Short-Duration Response to Docetaxel Monotherapy. AB - Background: We report a single institution's experience from a small series of patients suggesting that liver metastasis in metastatic castration-refractory prostate cancer (mCRPC) represents a relatively aggressive subtype that is refractory to hormonal manipulation treatment, including luteinizing hormone releasing hormone agonist (LA) and abiraterone (Ab) therapy, although docetaxel is briefly effective. Methods: Between 2007 and 2013, six patients with prostate cancer with liver metastases were analyzed. Biochemical response was defined as > 50% decrease in prostate-specific antigen (PSA) value. Results: Two patients who presented with liver metastases died in less than 3 months after LA therapy. Two out of three patients (one died while receiving chemotherapy) received Ab after chemotherapy did not show any response and died while on therapy. One patient who presented with lung metastases initially received LA therapy and progressed on it with liver metastases in < 6 months. Thus, five of six patients did not respond to hormone therapy including LA and Ab. Three patients who received docetaxel after LA therapy had more than 50% objective PSA response with a mean survival of 4 months. Conclusions: No literature addresses the response to hormone treatment in hepatic metastasis in prostate carcinoma. This small series suggests that liver metastases in prostate carcinoma represent a relatively aggressive subset against which hormonal therapy, including the LA and Ab, appears to be ineffective. Although our patients responded to docetaxel chemotherapy, their responses were of short duration. A further clinical trial involving more patients will be necessary to substantiate our findings. PMID- 29147412 TI - Prognostic Value of Molecular Markers and Implication for Molecular Targeted Therapies in Nasopharyngeal Carcinoma: An Update in an Era of New Targeted Molecules Development. AB - The aim of the study was to evaluate the prognostic significance of molecular biomarkers which could provide information for more accurate prognostication and development of novel therapeutic strategies for nasopharyngeal carcinoma (NPC). NPC is a unique malignant epithelial carcinoma of head and neck region, with an intimate association with the Epstein-Barr virus (EBV). Currently, the prediction of NPC prognosis is mainly based on the clinical TNM staging; however, NPC patients with the same clinical stage often present different clinical outcomes, suggesting that the TNM stage is insufficient to precisely predict the prognosis of this disease. In this review, we give an overview of the prognostic value of molecular markers in NPC and discuss potential strategies of targeted therapies for treatment of NPC. Molecular biomarkers, which play roles in abnormal proliferation signaling pathways (such as Wnt/beta-catenin pathway), intracellular mitogenic signal aberration (such as hypoxia-inducible factor (HIF) 1alpha), receptor-mediated aberrations (such as vascular endothelial growth factor (VEGF)), tumor suppressors (such as p16 and p27 activity), cell cycle aberrations (such as cyclin D1 and cyclin E), cell adhesion aberrations (such as E-cadherin), apoptosis dysregualtion (such as survivin) and centromere aberration (centromere protein H), are prognostic markers for NPC. Plasma EBV DNA concentrations and EBV-encoded latent membrane proteins are also prognostic markers for NPC. Implication of molecular targeted therapies in NPC was discussed. Such therapies could have potential in combination with different cytotoxic agents to combat and eradicate tumor cells. In order to further improve overall survival for patients with loco-regionally advanced NPC, the development of innovative strategies, including prognostic molecular markers and molecular targeted agents is needed. PMID- 29147415 TI - Thoracoscore and European Society Objective Score Fail to Predict Mortality in the UK. AB - Background: Thoracoscore and the European Society Objective Score (ESOS.01) are two scoring systems used in thoracic surgery to estimate operative mortality risk. We aimed to evaluate if these are valid tools for use in the UK population. Methods: A multi-center, prospective study was carried out on patients undergoing lung resection at six UK centers. Data were submitted electronically using our online data collection tool. Data were analyzed to determine the factors affecting mortality. A receiver operating characteristic analysis determined the ability of the thoracoscore and ESOS.01 to predict in-hospital mortality. Results: Data were complete for 2,245 patients. The observed in-hospital mortality was 31 patients (1.38%). Mean thoracoscore was 2.66 (SD +/- 3.21). Gender (P = 0.004, hazard ratio 4.786) and co-morbidity score (P = 0.005, hazard ratio 3.289) were identified as risk factors for mortality. A sub-analysis was performed using data from 1,912 patients with complete data for ESOS.01. In this group, mean thoracoscore was 2.55 (SD +/- 2.94), mean ESOS.01 was 2.11(SD +/- 1.41), and these were statistically significantly different (P < 0.0001). The observed in-hospital mortality was 28 patients (1.46%). The c-index for thoracoscore was 0.705, and for ESOS.01 was 0.739. Conclusions: Both thoracoscore and ESOS.01 overestimated mortality in the UK population. There is a continued need to develop an appropriate risk prediction system for the UK. PMID- 29147416 TI - Treatment Approaches in 102 Elderly Patients With Non-Small Cell Lung Cancer. AB - Background: The life expectancy and presence of co-morbidities cause reservations in treatment decisions for elderly patients with cancer. In this study, we retrospectively evaluated 102 patients who are considered as middle-old aged (aged 75 - 84) by gerontologists. Methods: Medical records of patients were reviewed. One hundred and two patients with a diagnosis of non-small cell lung cancer (NSCLC) whose follow-up ended with death between March 2006 and May 2013 were examined. Results: The median age at diagnosis was 77 (75 - 85) years. Thirty-three patients (67.6%) were over 80 years old. The number of patients with metastasis was 57 (55.8%). Forty-two (41.2%) patients had stage IIIA and IIIB disease. Fifteen of the metastatic patients (26.3%) were given chemotherapy, while 12 of the non-metastatic patients (26.6%) were given chemotherapy. Of the non-metastatic patients, 25 (55.6%) were treated with radiotherapy, and five (11.1%) were treated with chemotherapy. The median duration of follow-up was 4 (1 55) months. Progression-free survival (PFS) was 4 months in non-metastatic patients, and 3 months in metastatic patients. Overall survival (OS) was 4 months. OS rates for 1 and 2 years were 10% and 2%. Conclusion: Chemotherapy and radiotherapy may be administered even to patients of this age group. The beneficial effect of chemotherapy in patients with metastasis on OS is an important finding of our study. PMID- 29147417 TI - A Comparative Study of Piperacillin-Tazobactam With and Without Vancomycin as Empirical Therapy for Febrile Neutropenic Patients With Solid Tumor Malignancies. AB - Background: The objective of this study was to evaluate the outcomes, mortality and toxicity associated with piperacillin-tazobactam (PT) and the addition of vancomycin (VM) to the empirical treatment of febrile neutropenic cancer patients. Method: A retrospective study on adult febrile neutropenic patients who were admitted between September 2008 and May 2013 with solid tumor malignancies was conducted at King Fahad Specialist Hospital Dammam, Saudi Arabia. Results: Out of 86 febrile neutropenic patients, 60 patients were treated with PT group and 26 patients were with PT + VM group. The two groups were comparable in terms of outcome, mortality, nephrotoxicities and hepatotoxicities. The median duration of neutropenia in PT treatment group was 4 days (range 1 - 10) in the female and 7 days (range 1 - 13) in males while in PT + VM 6 days (range 1 - 5) in female and 7.5 days (range 1 - 6) in male with significance P = 0.007. There was no significant difference in terms of duration of fever and length of stay between the two treatment groups. There were no deaths reported during treatment in both groups. In PT, the microbial eradication was 27/40 (67.5%) patients (14/27 (51.9%) of female and 13/27 (48.1%) of male)), whereas it was 13/40 (32.5%) patients (9/13 (69.2%) of female and 4/13 (30.8%) of male)) in PT + VM group. Overall, there was no significant difference in terms of microbiological eradication between the two groups (OR: 1.22; 95% CI: 0.486 - 3.072; X2 stat: 0.182; P = 0.67). Response to therapy in clinically defined infections was higher 16/23 (69.56%) in PT treatment group than 7/23 (30.44%) in PT + VM group. But there was no significant difference between the two treatment groups in terms of clinically defined infections (OR: 1.013; 95% CI: 0.359 - 2.862; X2 stat: 0.001; P = 0.98). There was no significant difference in renal and liver functions between the two groups in terms of serum creatinine level and clearance, alkaline phosphate and alanine tranferase and gama glutamyl tranferase. The most commonly isolated organisms were Escherichais coli (eighteen isolates), Staphylococcus aureus (seven isolates), Streptococcus spp (six isolates) and Klebsiella pneumonia (four isolates). The overall success rate was similar in both treatment arms and treatment was well tolerated, with no severe adverse reactions reported. Conclusion: Although the addition of VM might provide an additional value for coverage of gram-positive pathogens. This study demonstrates that there was no significant difference in terms of response rate in both treatment groups, which could be due to the low local methicillin-resistant Staphylococcus aureus (MRSA) rates and other resistant gram-positive organisms at our institution, stressing the importance of local antibiograms in developing empirical neutropenic fever protocols. PMID- 29147418 TI - Serum Protein Pattern Could Predict the Therapeutic Effect of First-Line Pemetrexed/Cisplatin Chemotherapy in Patients With Lung Adenocarcinoma. AB - Background: In patients with advanced non-squamous non-small cell lung cancer (NSCLC), a pemetrexed/cisplatin (PP) regimen is considered as one of the preferred first-line treatments. However, only about half of the treated patients respond, and there is no clinically useful marker that can predict the response to the regimen. Methods: We established a potential pattern for the prediction of efficacy of first-line PP chemotherapy in patients with lung adenocarcinoma, by using artificial neural networks (ANNs) analysis of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) in this preliminary study. Results: The samples were randomly divided into training set and test set. From the test set, through cross-validation, the established protein pattern for PP separated the responders from the non-responders with a sensitivity of 95.8% and a specificity of 90.0%. Conclusion: It could be helpful for oncologists to select patients who could benefit from PP chemotherapy. PMID- 29147419 TI - Obstructive Jaundice as an Uncommon Manifestation of Metastatic Breast Cancer. AB - Invasive ductal carcinoma is the most common type of breast cancer and accounts for about 70-85% of all invasive breast carcinomas. It primarily metastasizes to the bone, lungs, regional lymph nodes, liver and brain. Most of breast cancer recurrence occurs within the first 5 years of diagnosis, particularly for ER negative disease. Gastrointestinal tract involvement is very rare and is detected in only 10% of all the cases, and it usually derives from lobular breast cancer rather than the much more common cell type of ductal breast cancer. Early diagnosis is very important because it enables prompt and adequate choice of treatment and improves patient's long-term prognosis. In this report we describe an unusual case of obstructive jaundice caused by metastases from invasive ductal breast cancer to the lymph nodes of the hepatoduodenal ligament with extramural compression of the distal common bile duct and tumor invasion to the lumen of the duct. Our goal is to emphasize possible diagnostic pitfalls and increase the clinical awareness and the importance of intensive follow-up in patients with breast cancer, even years after the initial diagnosis. PMID- 29147420 TI - A Rare Case of Metastasis of Small Cell Carcinoma of Cervix to Breast. AB - Extrapulmonary small cell carcinomas (SCCs) are rare and often have an aggressive natural course. A 42-year-old female presented to the hospital with vaginal bleeding and lower abdominal pain. She was eventually diagnosed with SCC of cervix by biopsy. She was treated with chemoradiation. However, on follow-up positron emission tomography (PET) scan, fluorodeoxyglucose (FDG) uptake was noted in bilateral breasts. Biopsy of these lesions was consistent with metastatic SCC. Breast is a very unusual site for metastasis of cervical SCC and only four cases have been reported in the medical literature to date. Our case highlights the importance of considering metastatic disease when evaluating breast mass in patients with history of SCC of cervix. PMID- 29147421 TI - Cutaneous Metastatic Adenocarcinoma of the Colon to the Scalp. AB - Cutaneous metastases from colorectal cancer are relatively uncommon presenting in fewer than 5% of patients but they are very important to recognize as they signify disseminated disease and poor prognosis. We describe a case a 62-year-old patient diagnosed with scalp metastasis during his systemic chemotherapy treatment for a colorectal carcinoma stage IVb who underwent excisional biopsy of the metastatic lesion. The identification of cutaneous metastases from colorectal cancer can radically alter therapeutic plans as they typically indicate a wide spread disease. Although they can be observed at any stage of malignancy, early recognition can lead to accurate and prompt diagnosis and timely treatment. PMID- 29147422 TI - Anorectal Melanoma: A Case Report and an Update of a Rare Malignancy. AB - Anal melanoma is an aggressive but rare malignancy. Patients commonly present with very advanced or even metastatic disease. Risk factors for anal melanoma are family history and an activating mutation of C-KIT. Surgical excision remains the mainstay of therapy. The presence of activating mutations of C-KIT has prompted use of C-KIT inhibitors such as imatinib and sunitini. Early diagnosis and treatment remain crucial. Abdominal perineal resection (APR) offers a higher rate of local control whereas wide local excision (WLE) can yield superior long-term survival. PMID- 29147423 TI - Overview of Recent Trends in the Management of Metastatic Anal Cancer. AB - Anal cancer is a relatively rare gastrointestinal tumor with roughly 7,000 new cases per year. Metastatic anal cancer as an initial presentation occurs in 10 20% of the patients. Treatment for localized disease is well established with concurrent chemoradiation (CCR) therapy as the standard of care; however, metastatic anal cancer remains a therapeutic challenge. National Comprehensive Cancer Network (NCCN) guidelines recommend systemic chemotherapy as the initial choice of treatment for metastatic anal disease. NCCN also recognizes the fact that there are limited data to influence the management of metastatic anal cancer but that some evidence suggests flouropyrimidine and cisplatin as the initial choice of treatment outside the setting of clinical trial. If the patient fails this regimen, options become limited with no strong level I evidence available to guide the treatment. We present two cases of metastatic anal cancer and discuss the potential treatment strategies after failing the initial systemic chemotherapy. PMID- 29147424 TI - Metformin and Cancer Treatment. PMID- 29147425 TI - Polymorphism T81C in H-RAS Oncogene Is Associated With Disease Progression in Imatinib (TKI) Treated Chronic Myeloid Leukemia Patients. AB - Background: Mammalian cells contain three functional RAS proto-oncogenes, known as H-RAS, K-RAS, and N-RAS, which encode small GTP-binding proteins in terms of p21rass. RAS genes have been elucidated as major participants in the development and progression of cancer. A single nucleotide polymorphism (SNP) at H-RAS cDNA position 81 T->C (rs12628) has been found to be associated with the risk of many human cancers like gastrointestinal, oral, colon, bladder and thyroid carcinomas. Therefore, we hypothesized that this polymorphisms in H-RAS could influence susceptibility to chronic myeloid leukemia as well, and we conducted this study to test the hypothesis in Indian population. Method: H-RAS polymorphism was studied in 100 chronic myeloid leukemia (CML) patients and 100 healthy controls by restriction fragmentation length polymorphism (RFLP-PCR). Associations between polymorphism and clinicopathological features of CML patients were investigated. Results: In CML patients, the TT, TC and CC genotype frequency was 38%, 61% and 1% respectively, compared to 92%, 8% and 0% in healthy controls respectively. Compared to TT genotype, CT was significantly associated with increased risk of CML (odds ratio (OR): 8.4, P < 0.00001). There was a statistically significant correlation of H-RAS polymorphism with phases (P < 0.0003), molecular response (P < 0.0001), hematological response (P < 0.04) and thrombocytopenia (P < 0.003). However, there was no correlation of this polymorphism found with other clinical parameters. Conclusion: H-RAS T81C polymorphism was found to be associated with CML risk and prognosis of CML. These results suggest that C heterozygosis may be considered a potential risk factor for CML development in the North Indian population. PMID- 29147426 TI - Active Monitoring of a Humeral Osteoblastoma in a 52-Year-Old Male: A Case Report. AB - An osteoblastoma is an uncommon benign but painful tumor, typically found on the axial skeleton or on long bones in the case of young patients. Some cases of humeral osteoblastomas have been described in literature but not in men older than 30. We report the case of a painless bone tumor on the humerus of a 52-year old patient. The CT scan shows a 30 mm hypodense lacunar formation, surrounded by thickened cortical bone resembling an osteoid osteoma. The anatomopathological and immunohistological analyses support the thesis of an osteoblastoma. A course of radiological monitoring without surgical resection was adopted. This unusual case introduces the possibility of carrying out a differential diagnosis with an osteosarcoma and raises the question of the treatment that should be adopted. PMID- 29147427 TI - The Risk of Misdiagnosing the Primary Site Responsible for Bone Metastases in Patients With Chronic Lymphocytic Leukemia and a Second Primary Carcinoma. AB - Chronic lymphocytic leukemia (CLL) is a common malignancy which may coexist with other primary cancers. CLL is rarely the cause of solitary bone lesions; such lesions in the context of CLL are believed to result from either Richter's transformation or metastasis from another primary malignancy. Renal cell carcinoma (RCC), on the other hand, is a malignancy which frequently metastasizes to bone and may cause an osteolytic solitary bone lesion. The origin of a solitary bone lesion in a patient with multiple potential primary malignancies has prognostic implications and affects treatment protocol, and as such must be diagnosed accurately. We describe a patient with CLL and a history of RCC who is found to have an incidental solitary bone lesion of the T11 vertebra. After two separate CT-guided biopsies revealed various lymphoid cell predominance and no evidence of RCC, treatment with low dose external beam radiation therapy (EBRT) was employed. Post-therapy MRI showed further propagation of the lesion. Surgical corpectomy was subsequently performed and postoperative pathology of the lesion was consistent with RCC. The patient was treated with bisphosphonates and a higher dose of EBRT. Our case illustrates the importance of surgical excisional biopsy for accurately diagnosing the primary source metastatic to the bone in a patient with CLL and another potential primary cancer. PMID- 29147428 TI - Langerhan Cell Histiocytosis: A Rare Disorder With a Rare Presentation. AB - Langerhans cell histiocytosis (LCH) is a rare disorder most commonly seen in Caucasians of Northern European decent, male, children. The most common presentation is osteolytic bone lesions. A 44-year-old native American presents with diffuse erythematous, scaling lesions. The patient also had pruritus and lymphadenopathy. These lesions were positive for S-100 and CD1a. The patient was started on chemotherapy which improved her symptoms immensely. This was a rare disease with a rare presentation. PMID- 29147429 TI - Primary Hepatic Non-Hodgkin's Lymphoma: An Enigma Beyond the Liver, a Case Report. AB - We have discussed a unique presentation of primary diffuse large cell B-cell non Hodgkin (DLBC NHL) hepatic lymphoma involving the porta hepatis and biliary confluence causing obstructive jaundice with contiguous soft tissue involvement of the right lobe of liver extending up to the right renal cortex. This appears to be the only case in literature where primary hepatic lymphoma has shown contiguous localized intra- and extrahepatic tumor infiltration. A 67-year-old gentleman presented with history of significant loss of appetite and weight in 2 months with associated progressive painless cholestatic jaundice. Physical evaluation revealed normal vitals with pallor, deep icterus, scratch marks over the abdomen, generalized muscle wasting, grade II clubbing and a palpable non tender liver with a globular, firm mass beneath the liver. He had a total serum bilirubin of 15.9 mg/dL and direct bilirubin of 9.24 mg/dL. His liver enzymes were moderately elevated with raised serum creatinine and dyselectrolytemia. Serology for enterohepatic viruses was negative. Contrast-enhanced magnetic resonance imaging (CEMRI) showed poorly enhancing multiple soft tissue masses in both lobes of liver with the largest mass involving, biliary confluence and porta hepatis causing right bile duct and portal vein encasement. The mass occupied the posterior right lobe and extended to the inferior surface of liver with contiguous invasion of the right renal upper pole cortex. The mass was associated with a retracted liver capsule in the involved segments and delayed enhancement, mimicking a cholangiocarcinoma. Tissue biopsy revealed hepatic DLBC type NHL and patient was subsequently treated with a CHOP-R (cyclophosphamide-doxorubicin vincristine-prednisolone/rituximab) regimen, on which he has shown non progressive disease at 1-year follow-up. DLBC NHL of the liver is a very rare tumor with propensity for isolated involvement of the liver and minimal extrahepatic spread. This case shows many interesting features such as obstructive jaundice for 2 months, porta hepatis involvement and tumor infiltration up to the right renal parenchyma. We have illustrated various imaging findings which should be considered when evaluating such a lesion to help differentiate it from cholangiocarcinoma. The literature is extensively reviewed. The case demonstrates relevant diagnostic parameters for physicians, radiologists and oncologists who are likely to encounter patients with tumor-induced obstructive jaundice in their daily practice. PMID- 29147430 TI - Denosumab Therapy for Refractory Hypercalcemia Secondary to Squamous Cell Carcinoma of Skin in Epidermolysis Bullosa. AB - Hypercalcemia secondary to malignancy is rare in children and the majority is caused by tumor-produced parathyroid hormone-related protein (PTHrP). We report a case of hypercalcemia refractory to bisphosphonate and corticosteroid therapy, but responsive to denosumab. A 17-year-old boy with epidermolysis bullosa (EB) and advanced squamous cell carcinoma (SCC) of the left leg was referred with severe hypercalcemia (serum calcium, 4.2 mmol/L). The serum parathyroid hormone (PTH) was 0.7 pmol/L (1.1 - 6.9 pmol/L). The hypercalcemia was initially managed with hyperhydration, prednisolone and pamidronate. Following two infusions of pamidronate (1 mg/kg/dose), serum calcium fell to 2.87 mmol/L. However the hypercalcemia relapsed within a week (serum calcium, 3.61 mmol/L) needing aggressive management with intravenous fluids, prednisolone and two further doses of pamidronate. The serum calcium fell to 2.58 mmol/L over the first 4 days, but rose to 3.39 mmol/L 3 days later. As the hypercalcemia was refractory to bisphosphonate treatment, a trial dose of subcutaneous denosumab (60 mg) was administered following which the calcium fell to 2.86 mmol/L within 24 h and normocalcemia was sustained 4 days later. We report a case of refractory hypercalcemia secondary to malignant SCC, which responded well to denosumab therapy. To our knowledge, this is the first case of hypercalcemia of malignancy in an adolescent managed with denosumab. PMID- 29147431 TI - What Can We Save for the First-Line Treatment of NSCLC in 2016? PMID- 29147432 TI - The Era of Multigene Panels Comes? The Clinical Utility of Oncotype DX and MammaPrint. AB - The AJCC Cancer Staging Manual, eighth edition published in late 2016, will become the new global guideline for cancer diagnosis and treatment from January 1, 2018. The new edition for the tumor staging system has numerous updates, including building up the prognostic stage group of tumors for the first time and adding a large number of non-anatomical factors into the prognostic evaluation. Oncotype DX and MammaPrint are two of the genomic predictors that will be part of routine clinical practice in the future. Numerous studies have proved the clinical utility of multigene panels in predicting clinical outcome and treatment response. Here we present our review of the studies on these multigene panels and their application to breast cancer. PMID- 29147433 TI - Does Obesity-Related Hemodilution of Carcinoembryonic Antigen Exist in Non-Small Cell Lung Cancer Patients? AB - Background: Previous investigations reported inverse relationship between prostate-specific antigen concentration and body mass index (BMI). These results have been explained by a hemodilution effect among obese men. However, the hemodilution of serum carcinoembryonic antigen (CEA) concentration in obese patients with non-small cell lung cancer (NSCLC) has not been ever reported. Methods: Consecutive 381 NSCLC patients were enrolled. A body surface area (BSA) based and a hematocrit (HCT)-based equations were applied for plasma volume (PV) estimation. The relationship between BMI and PV, serum CEA concentration and CEA amount, representing the total amount of CEA protein within the circulation, were examined. Results: Higher BMI was significantly associated with higher PV (P < 0.001). However, serum CEA concentration was not significantly associated with increasing BMI. Furthermore, there was no significant association between BMI and CEA amount. The 5-year survival rate of patients with a high serum CEA concentration was significantly lower than that of patients with a normal CEA. There was no difference in the prognostic significance of serum CEA concentration and CEA amount. Conclusions: We failed to find the association between BMI and CEA, suggesting no or small hemodilution effect of CEA in NSCLC patients. Furthermore, the measurement of the CEA amount could not provide any additional information. PMID- 29147434 TI - Acute Radiation-Induced Changes in Sprague-Dawley Rat Submandibular Glands: A Histomorphometric Analysis. AB - Background: Radiation-induced xerostomia is a distressing clinical condition that starts appearing from the initial stages of radiotherapy in head and neck cancer patients. Though submandibular glands contribute to maximum of the "resting salivary" secretions, most of the acute xerostomia experiments so far reported have been on animal parotid glands. Therefore, we assessed and quantified the histologic changes in submandibular glands of Sprague-Dawley (SD) rats using histomorphometry, 24 hours after radiation. Methods: Three SD rats were given single-dose radiation of 15 Gray from a gamma cobalt-60 irradiator. Same number of non-radiated animals was the controls. Animals were sacrificed at 24 hours followed by histopathology and histomorphometry of submandibular glands, where the mean values were analyzed by Student's t-test. Results: Irradiated submandibular glands showed highly significant reduction in acinar area (53%: 77.16+/-5.05% to 36.55+/-4.90%) and acinar size (87%: 3,447.53 +/- 461.03 mm2 to 428.25 +/- 75.22 mm2) with concomitant increase in inter-acinar space (3.46 +/- 0.67 mm to 10.08 +/- 0.60 mm). Acini nuclei displayed anisonucleosis, poikilonucleosis and pyknosis. "Serous acini" had marked morphologic changes, with fluid accumulation between cells, generalized cytoplasmic vacuolation and vascular congestion, while "mucous acini" largely retained cell architecture. Similarly, ductal cells and nuclei also did not show apparent differences. This demonstrated radiosensitivity variations among different submandibular gland cell types. Conclusion: Evaluation of acute submandibular acinar cell dysfunctions has helped in quantifying the histologic elements, which mainly contribute to the resting salivary secretions. Findings would aid in future research of radioprotector drugs, salivary glandular regeneration modalities and in devising prudent radiotherapy protocols to address radiation-induced xerostomia. PMID- 29147435 TI - Gliosarcoma in Young Adults: A Rare Variant of Glioblastoma. AB - Gliosarcoma is a rare central nervous system (CNS) malignancy. It is characterized by classical biphasic histological pattern with both glial and sarcomatous components, often seen in fifth and sixth decade of life. They are generally located in the supratentorial region. Due to its rarity, exact treatment recommendations are not available in literature. Since it is considered as a variant of glioblastoma multiforme (GBM), it is treated with surgery followed by adjuvant radiotherapy and temozolomide-based chemotherapy. We present a series of four cases of this rare malignancy that were treated at our institute. PMID- 29147436 TI - Repeated Multiple Neurofibromatosis Type 1 in the Right Lower Limb: A Case Report. AB - Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disease characterized by the presence of multiple neurofibromas. We encountered a unique case of NF1 that manifested as a recurrent soft tissue neurofibroma in the right lower limb that developed over a period of 16 years. The patient presented with a painless mass that was initially diagnosed as inflammatory changes via computed tomography and magnetic resonance imaging. However, the condition was subsequently diagnosed as an intraneural neurofibroma via pathological and immunohistochemical examination, which showed a focal to patchy lymphocytic chronic inflammatory infiltrate and several non-encapsulated masses with clear boundaries that were easily distinguishable from the adjacent neurofibroma. The mass relapsed three times over 3 years since it was discovered, for which the patient underwent comprehensive and complete local resection several times. Postoperative continuous follow-up confirmed that the patient recovered well. Early and complete surgical resection is an effective method for treating and preventing recurrent neurofibromas. However, because of the importance of pathologic examination in the diagnosis of such cases, this uncommon entity might be underreported in patients with NF1. PMID- 29147438 TI - A Retrospective Analysis of Clinical Utility of AJCC 8th Edition Cancer Staging System for Breast Cancer. AB - Background: The aim was to study the clinical utility of AJCC 8th edition prognostic stage system for patients with breast cancer. Methods: According to the AJCC 8th edition cancer staging system, a total of 784 patients with breast cancer diagnosed by Department of Breast Surgery in Peking University Shenzhen Hospital from January 2011 to June 2016 were analyzed in anatomic and prognostic stage. Results: Five hundred and five (64.4%) patients prognosis staging changed compared with anatomic stage. Among them, 63 (33.5%) patients were in stage I, 295 (73.8%) patients in stage II, and 128 (72.7%) patients in stage III according to anatomic stage, respectively. The distribution and variety of the anatomic and prognostic stage differ in intrinsic subtypes of breast cancer (P < 0.001). Conclusion: AJCC 8th edition cancer staging system is an important prognostic factor for disease outcome of breast cancer. PMID- 29147437 TI - The Effects of Anesthetics on Recurrence and Metastasis of Cancer, and Clinical Implications. AB - Surgical resection of the primary tumor may enhance the metastasis and recurrence of cancer. The reaction of patients to surgery includes changes of the immune system, the inflammatory system and the neuroendocrine system. In the perioperative period, anesthetics are used both for anesthesia and analgesia. There are several studies showing that the progression of cancer can be influenced by many kinds of anesthetics, although most of these studies are preclinical and thus have not yet influenced clinical recommendations. This review summarizes recent studies regarding the effects of anesthetics on metastasis and recurrence of cancer. PMID- 29147439 TI - Uterine Smooth Muscle Tumor of Uncertain Malignant Potential: Clinicopathologic Sonographic Characteristics, Follow-Up and Recurrence. AB - Background: Uterine smooth muscle tumor of uncertain malignant potential (STUMP) is rare tumor, and regarded as sub-classification in uterine smooth muscle tumors between benign and malignant criteria. In this study, we evaluated characteristics of cases with STUMP diagnosis in a 10-year period. Methods: We retrospectively evaluated medical records of patients with histopathological STUMP diagnosis in Istanbul Training and Research Hospital, a tertiary center. We analyzed preoperative demographic, clinical features and postoperative follow-up. Preoperative sonographic data were re-evaluated. Results: The mean age was 42 years. One patient was postmenopausal, and five patients were premenopausal. All of them had a complaint of meno-metrorrhagia. We re-evaluated preoperative sonographic images of patients, and defined 83.3% as well-defined margins, 66.7% hyperechoic, 100% heterogeneous, 66.7% non-cystic, 50% calcification and 66.7% acoustic shadowing. Pathologic features showed mean number of mitosis 8, mild atypia 66.7%, and necrosis 33.3%. In a 24-year-old unmarried female patient with myomectomy, we detected recurrance of tumor in sonographic and MRI studies after 11 months, and confirmed the diagnosis via tru-cut biopsy. There was no relevance between sonographic findings and atypia, necrosis and mitosis. The recurrence was not in relationship with mitosis, degree of atypia and necrosis. We found no relevance between tumor diameter and mitosis, atypia, necrosis and recurrence. Conclusions: STUMP is classified as an intermediate form, histopathologically so calling it benign or malignant for sure is not possible. Singulary, solidity, hyperechogenicity, heterogenecity and features of acoustic shadowing and margins can guide us to preoperative sonographic diagnosis. Recurrence/metastasis after many years from operation can be seen, and those patients should be followed long term. PMID- 29147440 TI - Rare Presentation of Adrenocortical Carcinoma in a 4-Month-Old Boy. AB - Adrenocortical carcinoma (ACC) is a rare malignancy and even rarer in infancy. Most of these tumors in pediatric age group are hormonally active and predominantly present with virilization. Cortisol hypersecretion presenting as Cushing syndrome is extremely rare and seen in older age groups. We report a 4 month-old infant who presented with linear growth arrest and excessive weight gain in early infancy, consequently diagnosed with ACC. On long-term follow-up for 7 years, he remained metastasis free following surgical resection and was not treated with chemotherapy. PMID- 29147441 TI - Intrahepatic Biliary Metastasis of Colonic Adenocarcinoma: A Case Report With Immunohistochemical Analysis. AB - Although intrabiliary metastasis of carcinoma in the liver is unusual, intraductal and/or intraepithelial spread of cancer cells along intrahepatic bile ducts is now well recognized as hepatic metastasis. However, several clinical and laboratory findings, including images, lead us to differentially diagnose from primary intrahepatic cholangiocarcinoma. We report here on a case of colonic adenocarcinoma that metastasized to the liver with spread along with the intrahepatic bile duct of S5/6 area. The patient was a 51-year-old man and clinically diagnosed liver metastasis of sigmoid colon cancer (tub2, pMP, ly1, v0, n0), which was diagnosed and treated by sigmoidectomy 7 years ago. The right hepatic lobectomy was performed in March 2016 and histopathological examination revealed that moderately differentiated adenocarcinoma proliferated along the epithelium of intrahepatic bile ducts. Immunohistochemistry (IHC) showed that cancer cells in the intrahepatic bile ducts were positive for CK20, CDX2, CK17 and CK19, but negative for CK7, MUC-5AC, MUC-2 and CA19-9. The findings were almost the same as those of the sigmoid colon cancer removed in July 2009. We finally diagnosed the liver tumor as intrahepatic biliary metastasis of sigmoid colon cancer. Patients with liver metastasis of cancer are hard to be detected biliary invasion and spread on diagnostic image examination. Knowledge of distinctive morphological and IHC features can help to accurately diagnose this rare intrahepatic biliary metastasis of colonic cancer in routine pathological diagnostic procedures. PMID- 29147442 TI - Metastatic Malignant Paraganglioma: A Case Report and Review of Literature. AB - Metastasis is a rare presentation of non-secretory paraganglioma. Consequently, there is no standard of care for the treatment of metastatic malignant paraganglioma. The most widely used chemotherapy regimen for non-resectable cases includes cyclophosphamide, vincristine, and dacarbazine (CVD). CVD has been previously studied with variable therapeutic response. However, yttrium-90 (Y90) radioembolization has not been previously studied in the treatment of hepatic metastasis in patients diagnosed with malignant paraganglioma. This case report follows the treatment of a patient with stage IV mediastinal paraganglioma with metastasis to the liver. Treatment consisted of the CVD chemotherapy regimen and Y90 radioembolization of the hepatic lesions. After 10 cycles of CVD, the tumor size has decreased from 6.0 * 8.8 to 5.5 * 3.0 * 3.4 cm on computed tomography scan. The prominent metastatic liver lesions responded after Y90 radioembolization of both the right and left hepatic arteries. The prominent right hepatic lobe lesion has decreased in size from 2.6 * 3.4 * 3.0 cm to 2.6 * 2.8 * 2.9 cm. The prominent left hepatic lobe lesion originally measuring 1.6 cm in diameter completely resolved on follow-up imaging studies. After completion of 12 cycles of chemotherapy, the most recent positron emission testing scan determined no evidence of disease regarding both the primary mass and the hepatic lesions. This study demonstrates the first case of combination chemotherapy and Y90 radioembolization with a complete response per response evaluation criteria in solid tumors criteria. The approaches toward diagnosis and treatment corresponding to this case of malignant metastatic paraganglioma are also reviewed in this study. PMID- 29147443 TI - 4-Nitroquinoline 1-Oxide-Induced Tongue and Esophagus Carcinogenesis in Obese and Diabetic TSOD Mice. AB - Background: Obesity and diabetes mellitus are associated with lifestyle-related carcinogenesis. They are also risk factors of esophageal adenocarcinoma, but there are only a few reports on association between obesity/diabetes and development of squamous cell carcinoma in the oral cavity and esophagus. In this study, we therefore aimed to determine whether obesity and diabetes affect oral and esophageal carcinogenesis using model mice of obesity and diabetes, the Tsumura Suzuki obese diabetes (TSOD) and Tsumura Suzuki non-obesity (TSNO) control mice, which were treated with 4-nitroquinoline 1-oxide (4-NQO) to produce tongue and esophageal carcinomas. Methods: We used 28 each of the male TSOD and TSNO mice of 8 weeks of age. They were divided into the 4-NQO-treated group (n = 20) and untreated group (n = 8). 4-NQO was administered to mice in drinking water at a dose level of 20 ppm for 8 weeks. The untreated group was given distilled water without 4-NQO. At 28 experimental weeks, histopathological examination was performed on all organs including tongue and esophagus. We performed analysis of histopathology of all organs which included buccal capsule (a tongue)/esophagus after an experiment start in 28 weeks. Fasting plasma glucose (FPG) and lipid parameters including total cholesterol (T-Cho), triglyceride (TG), high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol were measured and all these parameters were compared between the two genotypes. Also, mRNA expression of eight cytokines including interleukin (IL)-1beta, IL-6, IL-17, interferon (IFN)-gamma, keratinocyte-derived cytokine (KC), macrophage inflammatory protein (MIP)-1alpha, MIP-2, and tumor necrosis factor (TNF)-alpha in the esophageal mucosa was assayed. Results: 4-NQO treatment produced proliferative squamous cell lesions (dysplasia, papilloma and carcinoma) in the tongue and esophagus of both the TSOD and TSNO mice. The incidence and multiplicity of tongue tumors were 30% and 0.45 +/- 0.83 in the TSOD mice and 30% and 0.40 +/- 0.68 in the TSNO mice. The incidence and multiplicity of esophageal tumors were 70% and 2.25 +/- 2.29 in the TSOD mice and 30% and 0.60 +/- 1.14 (P < 0.01) in the TSNO mice. Conclusion: Our findings indicate that the obese and diabetic TSOD mice were susceptible to 4-NQO-induced esophageal carcinogenesis, suggesting risk factors of obese and diabetes for esophageal squamous cell carcinoma. Additionally, the TSOD mice were useful as esophagus carcinogenic model. Our study first reported that 4-NQO induced esophageal cancer in mice. PMID- 29147444 TI - Visceral Crisis Means Short Survival Among Patients With Luminal A Metastatic Breast Cancer: A Retrospective Cohort Study. AB - Background: Patients with visceral crisis from luminal metastatic breast cancer (mBC) are often treated with palliative chemotherapy. No studies have analyzed the aggressiveness of the care in visceral crisis from luminal mBC patients. The objective of this study was to assess practices in this setting in a university medical oncology department. Methods: This retrospective study included all patients who were managed for luminal mBC between January 2013 and April 2016. The analysis focused on the characteristics of the patients, the modalities of cancer treatment and delays between visceral crisis and death. Results: Thirty five patients pre-treated with two hormonal therapy lines were enrolled retrospectively. Worse performance status and a higher proportion of severe organ dysfunction for luminal mBC were observed among patients with visceral crisis. Sixty-five percent of patients received cytotoxic treatment. One cycle of chemotherapy was administrated in the majority of patients. Palliative care was performed in 35% of patients. Chemotherapy did not have any significant effect on patient outcome in the present study. The mean time between visceral crisis and death was 4.7 weeks (standard deviation = 1.9). Conclusion: Our study showed that visceral crisis in patients with luminal mBC is a complex problem. We need more comprehension of molecular pathogenesis to visceral crisis disease to propose efficacious treatments for these patients and to identify subgroup of patients who need chemotherapy followed by maintenance endocrine therapy. PMID- 29147445 TI - Role of Taxanes in Triple-Negative Breast Cancer: A Study From Tertiary Cancer Center in South India. AB - Background: Breast cancer is the most common female cancer seen globally. Triple negative breast cancer (TNBC) is a special subtype without any obvious target and optimum treatment remains challenging. The aim was to study the clinical, pathological profile and treatment outcome of TNBC patients. Methods: This was a retrospective observational study of TNBC patients diagnosed from January 2010 to June 2012 at a tertiary cancer center in South India. Patient's clinical and pathological characteristics were studied. The 5-year estimate of survival for non-metastatic TNBC was done using the Kaplan-Meier method. Results: Out of 804 patients of breast cancer, 237 were diagnosed as TNBC. The median age was 45 years and 58% were premenopausal. The 5-year disease-free survival (DFS) and overall survival (OS) for non-metastatic TNBC patients were 59% and 74%, respectively. The addition of a taxane to anthracycline-based regimen did not show a significant difference in DFS (P = 0.885) as well as OS (P = 0.856). Conclusion: The role of adding taxanes to anthracycline-based chemotherapy in adjuvant setting for TNBC remains controversial and larger prospective studies are warranted. PMID- 29147446 TI - Evaluation of Acute Toxicity and Early Clinical Outcome in Head and Neck Cancers Treated With Conventional Radiotherapy and Simultaneous Integrated Boost Arc Radiotherapy. AB - Background: Chemoradiotherapy plays an important role in management of locally advanced head and neck cancers. This retrospective analysis was done to evaluate and compare acute toxicity profiles and early clinical outcomes in patients treated with conventional and arc techniques. Methods: Fifty-five patients of head and neck cancers were evaluated. Thirty patients received conventional radiotherapy with 6 MV or cobalt 60 and 25 patients were treated with simultaneous integrated boost-volumetric modulated arc radiotherapy (SIB-VMAT) with dose prescription of 66 - 70 Gy. Concurrent chemotherapy was given as cisplatin injection at 40 mg/m2 weekly or 100 mg/m2 thrice weekly. Results: The incidence of grade 3-4 mucositis was 56% versus 83.3% with SIB-VMAT and conventional treatments (P = 0.026). The incidence of grade 2-3 xerostomia was 44% versus 80% (P = 0.006) in the two groups. Grade 2 dysphagia was seen in 40% versus 80% (P = 0.008) favoring the arc treatments. Seventeen patients undergoing arc treatment had complete response compared to 14 in the conventional group (P = 0.040). The median disease-free survival (median +/- standard error) was 16 months (11 +/- 1.987 months) in the conventional and arc groups (P = 0.073). Conclusion: SIB-VMAT shows a better toxicity profile and a trend towards better disease-free survival when compared to conventional radiotherapy in head and neck cancers. PMID- 29147447 TI - Rare Case of Spinal Cord Compression as Initial Presentation of Thymic Carcinoma. AB - Thymic carcinomas are rare aggressive cancers with limited clinical trial data. Its usual treatment is surgical resection with variable response to chemotherapy and radiation. It usually presents as anterior mediastinal mass with late sequela of metastases to the lymph nodes, pleura and bones. We present of thymic carcinoma with a rare initial presentation of vertebral metastases causing spinal cord compression. PMID- 29147448 TI - Lessons From Managing the Breast Malignant Adenomyoepithelioma and the Discussion on Treatment Strategy. AB - This study set out to investigate the clinical diagnosis and treatment strategies for malignant breast adenomyoepithelioma (AME), thus increasing the clinical knowledge on such disease. Two patients with malignant breast AME in Beijing Friendship Hospital were selected for study. Here we report the diagnosis and treatment processes in terms of the failure experience and lessons and relate our findings to those in the literature. Malignant breast AME is inclined to affect the areola area. It is recommended to conduct simple mastectomy combined with sentinel lymph node dissection due to the low sensitivity of the preoperative imaging diagnosis and difficulty in the pathological diagnosis. Malignant breast AME features strong invasiveness and vulnerability to recurrence and metastasis. Therefore, the operative schemes and clinical treatment strategies should be formulated based on the comprehensive analyses of the physical signs, imageological examinations and pathology. PMID- 29147449 TI - Prostatic Lymphoma Masquerading as Urinary Retention and Hematuria With Review of Literature. AB - Lymphomas of prostate are very rare tumors. They are not commonly considered in the clinical and histological differential diagnosis of prostatic enlargement. We report a case of a 49-year-old man who presented to emergency department with several weeks of difficulty in urination, for which he was being treated for benign prostate hyperplasia with no improvement. Computerized tomography scan showed lobulated mass originating from the superior aspect of the prostate with right inguinal lymph node involvement and no distant organ metastatic disease. Prostatic biopsy revealed diffuse large B-cell lymphoma. The patient achieved complete remission after six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy regimen. Lymphomas of the prostate should be considered in differential diagnosis of the patient presenting with obstructive lower urinary tract symptoms especially in patients with normal prostatic-specific antigen level and previous history of lymphoma in other sites. PMID- 29147450 TI - Effect of Tirapazamine, Metformin or Mild Hyperthermia on Recovery From Radiation Induced Damage in Pimonidazole-Unlabeled Quiescent Tumor Cells. AB - Background: The aim of the study was to examine the effect of tirapazamine (TPZ) on recovery from radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells compared with that of metformin (Met) or mild temperature hyperthermia (MTH). Methods: Proliferating (P) cells in EL4 tumors were labeled by continuous 5-bromo-2'-deoxyuridine (BrdU) administration. Tumors received gamma-rays at 1 h after pimonidazole administration followed by Met or TPZ treatment or MTH. Twenty-four hours later, the responses of Q and total (P + Q) cells and those of the pimonidazole-unlabeled cells were assessed with micronucleation and apoptosis frequencies using immunofluorescence staining for BrdU and apoptosis frequency using immunofluorescence staining for pimonidazole, respectively. Results: With gamma-rays only, the pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay, was more clearly observed in Q than total cells. Post-irradiation MTH or Met treatment more clearly repressed the decrease in radio-sensitivity in the Q than total cells. Post irradiation TPZ administration produced a large radio-sensitizing effect on both total and Q cells, especially on Q cells. In pimonidazole-unlabeled cell fractions in both total and Q cells, TPZ suppressed the reduction in sensitivity much more efficiently than MTH or Met without any radio-sensitizing effect. Conclusion: Post-irradiation TPZ administration has the potential to both suppress recovery from radiation-induced damage and enhance the radio-sensitivity both in total and Q tumor cells. Post-irradiation TPZ administration may be useful for controlling tumors. PMID- 29147451 TI - Metastatic Malignant Thymoma to the Abdomen: A SEER Database Review and Assessment of Treatment Strategies. AB - Background: Thymoma is a neoplasm occurring in 0.15 of 100,000 persons/year. Abdominal metastases are rare. We report the incidence of malignant thymoma (MT) and suggest imaging and treatment options for cases of abdominal metastasis. Methods: A National Cancer Institute's Surveillance, Epidemiology and End Results database review was conducted to identify MT cases, followed by a literature review examining cases of metastases to the abdomen. Incidence rates were calculated, and symptoms, treatments, size and location of tumors, disease-free interval (DFI), and survival time were recorded. Results: From 1973 to 2008, a total of 1,588 MT cases were identified (45.4 cases/year), which were extrapolated to 2,724 over 60 years. Incidence has risen from 17 cases in 1973 to 90 cases in 2008, with a larger incidence in males than females (0.23 vs. 0.17 per 100,000). There were 25 cases of abdominal metastasis (0.92%), 13 of which were asymptomatic. There was a wide variety of DFI and survival noted amongst the case reports. Multiple treatment modalities were used. Conclusions: The incidence of MT is on the rise with a male predominance. All patients should receive routine imaging to look for extrathoracic metastases as half will not have symptoms. All patients with abdominal metastases should be treated using a multimodal approach. PMID- 29147452 TI - The Effect of Aurora Kinase Inhibitor on Adhesion and Migration in Human Breast Cancer Cells and Clinical Implications. AB - Background: The Aurora kinase family is comprised of highly conserved serine/threonine protein kinases that are known to be crucial in the regulation of the cell cycle. Aberrant expression of Aurora kinases has been demonstrated in certain malignancies. We aimed to examine the expression of Aurora kinases in human breast cancer tissues and to investigate the cellular impact of Aurora kinases inhibitor on breast cancer cells. Methods: The expression of Aurora kinase A/B/C was individually examined in tumor specimens (n = 106) and normal tissues (n = 29) from breast cancer patients using quantitative real-time PCR (Q PCR) and immunohistochemistry. Cells were treated with the corresponding inhibitor, and then migration and adhesion were evaluated by electric cell impedance sensing assay. The proliferation of breast cancer cells treated with the inhibitor was examined using in vitro models. Results: High levels of Aurora kinase B and C were found in the tumor tissues from breast cancer patients, but low levels of Aurora kinase A were seen in normal tissues at the mRNA level and immunohistochemistry. The mRNA expression level of Aurora kinase B and C had a negative correlation with grade staging, staging and survival rate in breast cancer patients, whilst Aurora kinase A exhibited a converse expression. The inhibitor ZM447439 promoted adhesion of the human breast cancer cell line MDA-MB 231 and inhibited the migration of MCF-7 human breast cancer cells. Conclusion: Taken together, the expression of Aurora kinase B and C was down-regulated in breast tumor tissues but Aurora kinase A was not. Aurora kinase may have a key role in the progression and metastasis of breast cancer. PMID- 29147453 TI - CTLA-4 Genetic Variants (rs11571317 and rs3087243): Role in Susceptibility and Progression of Breast Cancer. AB - Background: Dysfunctional regulation at immune checkpoints may lead to escape of the tumor cells and gives a scope to set in the unresolved Breast cancer (BC). The major anti-tumor retort is cell-mediated response which involves T lymphocytes. CTLA-4 (Cytotoxic T lymphocyte associated protein-4) with immune suppressive function and tolerance is associated with various autoimmune diseases and cancers including BC. The present study deals with CTLA-4 gene selected polymorphisms (rs11571317 C/T and rs3087243G/A) to explore their relation with breast cancer susceptibility and progression in BC patients. Methods: For the present case-control study, we recruited a total of 570 women which include breast cancer patients and healthy control women from south India. Blood samples were collected, genomic DNA was isolated and genotyped by using PCR-RFLP method, and the data were analysed through suitable statistics. Results: We observed a significant association of rs11571317 with BC in our study group, where CC genotype showed a three-fold increased risk towards BC and CT genotype to be protective. In-silico analyses strengthened our observation revealing the abolition of SP1 binding site in the CTLA-4 promoter by the mutant allele T. The CTLA-4 rs3087243 polymorphism showed an association not with the susceptibility but towards the tumor progression, where GG genotype was coupled with reduced tumor growth (OR = 0.01) and GA (OR = 6.2), AA (OR = 3.4) with increased tumor growth. The T-G haplotype was found to confer protection against breast cancer risk while C-A (OR = 3.6) and T-A (OR = 15.8) haplotypes were associated with disease progression. In-silico analysis for rs3087243 revealed change in threshold values between reference and variant sequences. Conclusion: The study suggests varied roles of different polymorphisms of CTLA-4 in the aetiopathogenesis of BC. Understanding the mechanism may help in the CTLA-4 based immunotherapy for BC. PMID- 29147454 TI - Late Onset Chemo/Radiation Induced Tracheoesophageal Fistula in Squamous Cell Cancer of the Lung. AB - We report a 72-year-old male with past medical history of stage IV squamous lung cancer treated with radiation therapy and chemotherapy with gemcitabine/carboplatin. One year later, he presented with hemoptysis treated with another session of palliative radiotherapy. Two weeks later, patient developed aspiration pneumonia and further workup showed trachea-esophageal fistula documented by barium swallow. This case shows a rare complication of chemotherapy and radiation therapy on the setting of primary lung cancer. PMID- 29147455 TI - Community Residents' Beliefs About Neighborhood Corner Stores in 2 Latino Communities: Implications for Interventions to Improve the Food Environment. AB - We assessed community residents' perceptions of corner stores to better understand what facilitates and deters patronage at these food outlets. Data came from 978 household interviews in 2 Latino communities undergoing corner store interventions. Chi-square tests, an independent sample t test, and a multivariate logistic regression were conducted to assess the relationship between residents' perceptions about corner stores and their reported patronage at these food outlets. Residents reported that corner stores do not sell a variety of fruits and vegetables and are not places where one can get information about healthy eating. Convenience, cleanliness, positive customer service, availability of culturally appropriate items, and availability of quality fresh fruit increased the odds of store patronage. Simply providing healthy foods will not incentivize patrons to purchase them. Corner store interventions can be more effective if they address the characteristics that community residents prioritize. PMID- 29147456 TI - Prevalence of Sun Protection at Outdoor Recreation and Leisure Venues at Resorts in North America. AB - Background: Exposure to solar ultra violet radiation (UVR) is a primary risk factor for skin cancer. Vacationers often fail to protect themselves from harmful UVR. Purpose: The study assessed the sun protection practices of resort guests in various outdoor leisure and recreation venues during warm-weather seasons. Method: 41 North American resorts were enrolled in a quasi-experimental randomized controlled trial. Adult guests were observed (n=4091) and surveyed (n=3694) in a cross sectional sample. Data collection was conducted in recreation and leisure venues with outdoors commons/reception areas acting as the comparison condition. Results: The mean percent of vacationers at pools and beaches were more likely (p < 0.001) to wear sunscreen than in commons areas but less likely (p < 0.001) to wear cover-up clothing or use shade. In both samples, the combined sun protection scores were higher in commons areas compared to all venues except for outdoor dining (p < 0.001). Discussion: Sun safety was suboptimal in all venues and was potentially mitigated by venue type. Translation to Health Education Practice: Approaches are needed to encourage vacationers to practice comprehensive sun protection and to work with resorts to construct built environments that facilitate rather than act as barriers to sun safety. PMID- 29147458 TI - Erratum to "Nutritional and Lifestyle Interventions for Age-Related Macular Degeneration: A Review". AB - [This corrects the article DOI: 10.1155/2017/6469138.]. PMID- 29147457 TI - Oxidative Stress Delays Prometaphase/Metaphase of the First Cleavage in Mouse Zygotes via the MAD2L1-Mediated Spindle Assembly Checkpoint. AB - In zygotes, DNA damage delays the first cleavage to enable repair. Our previous study found that 0.03 mM hydrogen peroxide (H2O2) was the minimum concentration required for induction of oxidative DNA damage in mouse zygotes and that this represented the most similar situation to the clinical phenomenon. In this study, we quantified the cleavage rates of cells in blastocysts at different developmental stages, followed by immunofluorescence to detect activation of gamma-H2A histone family member X (a marker of DNA damage) in zygotes to confirm that oxidative DNA damage was induced in H2O2-treated zygotes. Monitoring H3S10P (phosphorylation of Ser10 on histone H3; a prometaphase/metaphase marker) levels at different hour postinsemination revealed that treatment of zygotes with 0.03 mM H2O2 resulted in a prometaphase/metaphase delay. Furthermore, immunofluorescence staining for mitotic arrest deficient 2-like 1 and the protein kinase TTK, components of the spindle assembly checkpoint (SAC), suggested that this delay possibly involved SAC activation. These studies of the relationships between oxidative stress and SAC can promote the success rate of in vitro fertilization. PMID- 29147459 TI - Erratum to "Impact of Yoga and Meditation on Cellular Aging in Apparently Healthy Individuals: A Prospective, Open-Label Single-Arm Exploratory Study". AB - [This corrects the article DOI: 10.1155/2017/7928981.]. PMID- 29147460 TI - Corrigendum to "Identification of Patients Affected by Mitral Valve Prolapse with Severe Regurgitation: A Multivariable Regression Model". AB - [This corrects the article DOI: 10.1155/2017/6838921.]. PMID- 29147462 TI - Oxygen-Sensing Nox4 Generates Genotoxic ROS to Induce Premature Senescence of Nucleus Pulposus Cells through MAPK and NF-kappaB Pathways. AB - Senescence is a crucial driver of intervertebral disc degeneration (IDD). Disc cells are exposed to high oxygen tension due to neovascularization in degenerative discs. However, the effect of oxygen tension on disc cell senescence was unknown. Herein, rat nucleus pulposus (NP) cells were cultured under 20% O2 or 1% O2. Consequently, ROS induced by 20% O2 caused DNA damage and then activated p53-p21-Rb and p16-Rb pathways via ERK signaling to induce NP cell senescence. It also induced catabolic and proinflammatory phenotype of NP cells via MAPK and NF-kappaB pathways. Furthermore, 20% O2 was found to upregulate Nox4 in NP cells. Small interfering RNA against Nox4 reduced ROS production induced by 20% O2 and consequently suppressed premature senescence of NP cells. On the contrary, NP cells overexpressing Nox4 produced more ROS and rapidly developed senescent signs. In consistent with the in vitro studies, the expression of Nox4, p21, and Rb was upregulated in rat degenerative discs. This study, for the first time, demonstrates that Nox4 is an oxygen-sensing enzyme and a main ROS source in NP cells. Nox4-dependent ROS are genotoxic and a potent trigger of NP cell senescence. Nox4 is a potential therapeutic target for disc cell senescence and IDD. PMID- 29147461 TI - The Role of Antioxidant Enzymes in the Ovaries. AB - Proper physiological function of the ovaries is very important for the entire female reproductive system and overall health. Reactive oxygen species (ROS) are generated as by-products during ovarian physiological metabolism, and antioxidants are indicated as factors that can maintain the balance between ROS production and clearance. A disturbance in this balance can induce pathological consequences in oocyte maturation, ovulation, fertilization, implantation, and embryo development, which can ultimately influence pregnancy outcomes. However, our understanding of the molecular and cellular mechanisms underlying these physiological and pathological processes is lacking. This article presents up-to date findings regarding the effects of antioxidants on the ovaries. An abundance of evidence has confirmed the various significant roles of these antioxidants in the ovaries. Some animal models are discussed in this review to demonstrate the harmful consequences that result from mutation or depletion of antioxidant genes or genes related to antioxidant synthesis. Disruption of antioxidant systems may lead to pathological consequences in women. Antioxidant supplementation is indicated as a possible strategy for treating reproductive disease and infertility by controlling oxidative stress (OS). To confirm this, further investigations are required and more antioxidant therapy in humans has to been performed. PMID- 29147463 TI - Acidic Polysaccharide from Angelica sinensis Reverses Anemia of Chronic Disease Involving the Suppression of Inflammatory Hepcidin and NF-kappaB Activation. AB - Anemia of chronic disease (ACD) is the second most prevalent anemia and frequently occurs in patients with acute or chronic immune activation. In the current study, we evaluated the therapeutic efficacy of Angelica sinensis polysaccharide (ASP) against ACD in rats and the potential mechanisms involved. The results showed that ASP inhibited inflammatory hepcidin in both HepG2 cells and ACD rats by blocking the IL-6/STAT3 and BMP/SMAD pathways. In ACD rats, the administration of ASP increased ferroportin expression, mobilized iron from the liver and spleen, increased serum iron levels, caused an elevation of serum EPO, and effectively relieved the anemia. Furthermore, ASP inhibited NF-kappaB p65 activation via the IkappaB kinases- (IKKs-) IkappaBalpha pathway, thereby reducing the secretion of interleukin-6 (IL-6) and TNF-alpha, which is known to inhibit erythropoiesis. Our findings indicate that ASP is a potential treatment option for patients suffering from ACD. PMID- 29147466 TI - Erratum to "Resveratrol Attenuates Copper-Induced Senescence by Improving Cellular Proteostasis". AB - [This corrects the article DOI: 10.1155/2017/3793817.]. PMID- 29147464 TI - Treatment of the Fluoroquinolone-Associated Disability: The Pathobiochemical Implications. AB - Long-term fluoroquinolone-associated disability (FQAD) after fluoroquinolone (FQ) antibiotic therapy appears in recent years as a significant medical and social problem, because patients suffer for many years after prescribed antimicrobial FQ treatment from tiredness, concentration problems, neuropathies, tendinopathies, and other symptoms. The knowledge about the molecular activity of FQs in the cells remains unclear in many details. The effective treatment of this chronic state remains difficult and not effective. The current paper reviews the pathobiochemical properties of FQs, hints the directions for further research, and reviews the research concerning the proposed treatment of patients. Based on the analysis of literature, the main directions of possible effective treatment of FQAD are proposed: (a) reduction of the oxidative stress, (b) restoring reduced mitochondrion potential DeltaPsim, PMID- 29147467 TI - Problematic communications during 2016 fellowship recruitment in internal medicine. AB - Some internal medicine residency program directors have expressed concerns that their third-year residents may have been subjected to inappropriate communication during the 2016 fellowship recruitment season. The authors sought to study applicants' interpersonal communication experiences with fellowship programs. Many respondents indicated that they had been asked questions that would constitute violations of the National Residency Matching Program (NRMP) Communications Code of Conduct agreement, including how they plan to rank specific programs. Moreover, female respondents were more likely to have been asked questions during interview experiences about other programs to which they applied, and about their family plans. Post-interview communication policies were not made clear to most applicants. These results suggest ongoing challenges for the internal medicine community to improve communication with applicants and uniform compliance with the NRMP communications code of conduct during the fellowship recruitment process. PMID- 29147465 TI - Myricetin Possesses Potential Protective Effects on Diabetic Cardiomyopathy through Inhibiting IkappaBalpha/NFkappaB and Enhancing Nrf2/HO-1. AB - Diabetic cardiomyopathy (DCM) is associated with a greater risk of mortality in patients with diabetes mellitus. Currently, no specific treatment has been suggested for DCM treatment. This study demonstrated that myricetin (M) attenuated DCM-associated cardiac injury in mice subjected to streptozotocin (SZT) and in neonatal rat cardiomyocytes (NRCM) challenged with high glucose. In vivo investigation demonstrated 6 months of M treatment (200 mg/kg/d) significantly alleviated cardiac hypertrophy, apoptosis, and interstitial fibrosis. Mechanically, M treatment significantly increased the activity of Nrf2/HO-1 pathway, strengthening antioxidative stress capacity evidenced by reversed activities of GPx and SOD, and decreased MDA production. M treatment also inhibited IkappaBalpha/NF-kappaB pathway, resulting in reduced secretion of inflammation cytokines including IL-1beta, TNF-alpha, and IL-6. Besides, the TGFbeta/Smad3 signaling was also blunted in DCM mice treated with M. These beneficial effects of M treatment protected cardiomyocytes from apoptosis as shown by decreased TUNEL-positive nucleus, c-caspase 3, and Bax. Similar effects of M treatment could be reproduced in NRCM treated with high glucose. Furthermore, through silencing Nrf2 in NRCM, we found that the regulation of IkappaBalpha/NFkappaB by M was independent on its function on Nrf2. Thus, we concluded that M possesses potential protective effects on DCM through inhibiting IkappaBalpha/NFkappaB and enhancing Nrf2/HO-1. PMID- 29147468 TI - Use of dictation as a tool to decrease documentation errors in electronic health records. AB - Background: Use of Electronic Health Records is increasing. Copy-and-paste function is frequently used with higher rates of documentation errors. Studies to determine the nature of such errors are needed.Objectives: Determination of the effect of implementing a dictation system for completing notes on the quality of clinical documentation. We hypothesized that implementation of the dictation system for note writing would decrease the rate of errors in the progress notes as well as decrease the rate of copying and pasting. Design/Methods: A prospective interventional study in inpatient medical service for six months' duration starting in July 2016. Resident physicians' charts were reviewed by the attending physician on a daily basis. This study was done in a community based hospital affiliated to a university program. Residents' physicians included Internal Medicine, Transitional year and Combined Internal Medicine Pediatrics residents. Charts reviewed for hospitalized patients. A total of 54 residents were offered a pre-intervention survey indicating their subjective use of copy/paste function. Response rate of 85.18%. Progress notes were reviewed on a daily basis for residents on their inpatient rotation. A total of 621 notes were reviewed. Results: Percentage of notes copied prior to the intervention was 92.73% which decreased to 49.71% post-intervention (RR of 0.54, 95% CI 0.48 0.60 Z statistic 11.005 with p-value <0.0001). Of the copied notes percentage of errors pre-intervention was 58% with no errors identified post-intervention (RR of 0.005, 95% CI 0.0003 0.0795 Z statistic 3.752 with p-value 0.0002). Most of the errors are from notes copied by the same author (85.8%). The most common documentation error was in the physical examination section. Conclusion: Implementing a dictation system eliminated documentation errors over our six months' study. Further studies are needed to check long effects of using such systems on documentation errors. PMID- 29147469 TI - Non-pharmacologic interventions to improve sleep of medicine inpatients: a controlled study. AB - Background: Sleep quality in hospitalized medicine patients is poor, with environmental factors among the most frequently cited reasons. Objective: We tested the efficacy of a non-pharmacologic intervention on the sleep quality of medicine inpatients. Design/Methods: A controlled study to evaluate our non pharmacologic multidisciplinary 'TUCK-in' protocol (which includes timed lights off periods, minimizing night-time noise, distribution of earplugs at bedtime, cued toileting before bedtime, and identification and reduction of modifiable interruptions) was deployed on two of five identical medicine wards. Randomization was at the level of the ward. The main outcome measure was self reported duration of night-time sleep within 48 hours prior to discharge. Additional outcome measures included the Verran-Snyder-Halpern (VSH) Sleep Score and inpatient sleep pharmaceutical use. Results: Self-reported duration of night time sleep (median 5.0 vs. 5.0 hours, p = 0.29) and daytime sleep (1.0 versus 0.5 hours, p = 0.43) did not differ between the 40 intervention patients and the 41 control patients (p = 0.13 on multivariate analysis). Cumulative VSH sleep disturbance (median 420 versus 359, p = 0.19), efficacy (median 169 versus 192, p = 0.29), or supplementation (median 97 versus 100, p = 0.51) scales were also not different between study arms. Conclusions: Although staff reported the protocol to be achievable and worthwhile, there were no significant differences in any of the outcomes between intervention and control patients.. PMID- 29147470 TI - Retrospective analysis of inferior vena cava collapsibility with point of care ultrasound and urine sodium and FENa in patients with early stage acute kidney injury. AB - Early stage acute kidney injury (AKI) is an independent risk factor for an increase in mortality. Accurate assessment of volume status is a major challenge during the early stages of acute renal injury. Determining volume status based on the history and physical exam lacks accuracy. Urine sodium and free excretion of sodium (FENa) provide objective evidence of intravascular volume status when interpreted carefully and is helpful to delineate prerenal from intrinsic renal failure. In recent years point of care ultrasound has been used to assess volume status. Our team conducted a retrospective chart review to assess the association of inferior vena cava collapsibility by point of care ultrasound (POCUS) and urine electrolytes (urine sodium, fractional excretion of sodium) during early stage AKI (Stage 1-2 of KDIGO guidelines). We reviewed 150 cases based on the provisional diagnosis. 36 patients met the criteria for further review. Using bivariate analysis, we found a strong association between >50% IVC collapsibility with FENa < 0.4% with an odds ratio 5.3 (CI 1.1-24.5, p = 0.04), and urine sodium <20 meq/dl with an odds ratio of 6.7 (Cl 1.5-30, p = 0.02). Subsequently, multivariate analysis and Spearman correlation showed an inverse relation between IVC collapsibility and fractional excretion of sodium FENa (beta = -0.4, p = 0.001) and (r = -0.44, p = 0.01). These findings suggest the role of POCUS and urinary markers in determining the intravascular volume status in AKI. POCUS is also valuable to assess volume status in cases of renal failure where urine studies are difficult to interpret. PMID- 29147471 TI - Experience with ceftaroline for treatment of methicillin-resistant Staphylococcus aureus pneumonia in a community hospital. AB - Background: Methicillin-resistant Staphylococcus aureus (MRSA) is an organism causing significant mortality and morbidity with nosocomial infections. Ceftaroline is a new cephalosporin antibiotic that has activity against MRSA. In the USA, this antibiotic has not been approved for use in pneumonia caused by MRSA. Objectives: To review the use of ceftaroline in MRSA pneumonia in a US hospital and evaluate its clinical success. Methods: A retrospective study was conducted in an urban community hospital assessing the use of ceftaroline for MRSA pneumonia. Results: The clinical success was comparable to the currently approved treatment for MRSA pneumonia. Conclusion: The results of our study showed a favorable result for the treatment of MRSA pneumonia. Well-designed studies need to be performed for further validation of these results. PMID- 29147472 TI - Recurrent dyspnea and wheezing- pulmonary function test and dynamic computed tomography may unfold the diagnosis of tracheobronchomalacia. AB - Tracheomalacia patients often present with nonspecific symptoms like cough, wheezing and dyspnea. Tracheomalacia diagnosis is usually attributed to alternative common conditions such as asthma or chronic obstructive lung disease. Certain maneuvers, like forced expiration, or recumbent position may elicit subtle signs of tracheomalacia. Ordering novel pulmonary function testing in sitting upright and supine positions may provide additional clues to suspect tracheomalacia, which can be confirmed by either dynamic chest tomography or bronchoscopy. PMID- 29147473 TI - Bioresorbable vascular scaffold versus metallic stent in percutaneous coronary intervention: results of the AIDA trial. AB - Drug-eluting stents have significantly improved the long-term outcomes of percutaneous coronary intervention (PCI) by decreasing the excessive growth of neointima. However, conventional stents have some limitations. PCI with a bioresorbable vascular scaffold (BVS) has emerged as an alternative since the presence of the prosthesis in the coronary artery is transient. A US Food and Drug Administration advisory panel of experts recommended approval of BVS based on the analysis of its risks and rewards in July 2016. In June 2017, the preliminary results of the Amsterdam Investigator-initiateD Absorb Strategy All comers (AIDA) trial were released. This randomized controlled trial compared an everolimus-eluting BVS with an everolimus-eluting metallic stent in the context of routine clinical practice. The preliminary results revealed no significant difference in target-vessel failure when BVS was compared with metallic stenting. However, during the 2 years of follow-up, BVS was associated with a higher rate of device thrombosis. This is seen as an important development in the trial. There are some concerns regarding stent thrombosis and the restoration of real vessel functionality in the long term. For these reasons, for now, metallic stents remain the treatment of choice for PCI. PMID- 29147474 TI - New onset of insomnia in hospitalized patients in general medical wards: incidence, causes, and resolution rate. AB - Background: Insomnia is common in hospitalized patients. However, no study has examined new onset of insomnia in patients without a prior history of insomnia. Objectives: Incidence of new onset of insomnia in inpatients, associated factors and resolution rate after 2 weeks. Method: This is a prospective observational study conducted at a community hospital. We used the Insomnia Severity Index questionnaire to screen for insomnia in all patients located in the general medical floors from day 3 to day 5 of their hospital stay. We excluded patients with a prior insomnia history. Results: Out of the 205 patients who met the inclusion criteria, 75 patients (36%) reported insomnia. Severe insomnia was present in 3% of patients. Difficulty in maintaining sleep is the most common symptom. Frequent staff disruptions due to blood draws and vital signs checks were reported by 68% as the cause of insomnia, followed by illness associated causes (64%) and sleep disruption due to noise and or brightness (23%). Patients with insomnia had more awakenings due to noise, brightness, and staff interruptions than those without insomnia (1.35 times vs. 0.9 times, p = 0.027). Patients with respiratory symptoms, cardiac monitoring, oxygen use, private rooms, and no sedative use did not have a higher insomnia risk. Patients with insomnia had significant lower satisfaction scores than patients without insomnia (4.53 vs. 4.05, p = 0.001) but did not have a different length of stay (6.18 vs. 6.19, p = 0.97). In 31% of patients with insomnia who were able to be contacted two weeks after discharge, 75% of them had insomnia resolution. Conclusion: New onset of insomnia occurred in 36% of hospitalized patients. Most common causes are staff disruption and disease symptoms. It was usually short-term and could decrease patients' satisfaction score. PMID- 29147475 TI - An extensive chronic aortic dissection presenting with acute embolic stroke. AB - Herein, we present a rare case of extensive chronic aortic dissection with extension to bilateral subclavian arteries, bilateral common carotid arteries, right internal carotid artery, bilateral proximal external iliac arteries and simultaneous presentation of acute embolic stroke and seizure. The rarity of this case presentation and the presence of neurological features necessitated a high index of clinical suspicion to reach the definitive diagnosis. This study also demonstrates a unique situation requiring correlation between chronic aortic dissection and multi-organ system dysfunction from chronic ischemia. PMID- 29147476 TI - Sudden cardiac arrest as a rare presentation of myxedema coma: case report. AB - Myxedema coma is a decompensated hypothyroidism which occurs due to long standing, undiagnosed, or untreated hypothyroidism. Untreated hypothyroidism is known to affect almost all organs including the heart. It is associated with a decrease in cardiac output, stroke volume due to decreased myocardial contractility, and an increase in systemic vascular resistance. It can cause cardiac arrhythmias and the most commonly seen conduction abnormalities are sinus bradycardia, heart block, ventricular tachycardia, and torsade de pointes. The authors report a case of an elderly man who presented with sudden cardiac arrest and myxedema coma and who was successfully revived. PMID- 29147477 TI - Vanishing vasculitis: a case of acute necrotic skin findings without pathologic features of vasculitis from adulterated cocaine. AB - While the usage of illicit drugs in itself carries significant health risks and associated toxicities, drugs that are adulterated to give them volume, alter their psychogenic properties, and make them cheaper to produce are to be considered even more dangerous. Cocaine is one of them, and it is now most commonly being adulterated with levamisole. We report a case of a 37-year-old female with the chief complaint of painful skin lesions and wounds on both of her upper and lower extremities for three weeks duration. She was tested positive for cocaine and had classical purpuric, ecchymotic, and necrotic patches on both ears, which are pathognomonic. She also had multiple wounds in extremities. The cocaine-levamisole related syndrome comprises a set of immunological abnormalities, out of which, ANCA positivity is the most important one. Our patient was ANCA positive. Regarding pathological findings in cocaine adulterated with levamisole syndrome, this can range from the classic finding of leukocytoclastic vasculitis of small vessels to occlusive vascular disease without true vasculitis. Our case's biopsy showed no vasculitis, and this is why it is important to highlight that cocaine can also cause a pseudo-vasculitic picture. The other possibility that we entertained was that of pyoderma gangrenosum as the skin finding in levamisole-contaminated cocaine, and the lesion was consistent in appearance. Recently, there have been a few case reports of pyoderma gangrenosum from adulterated cocaine with levamisole, where skin findings were consistent with pyoderma gangrenosum; however, serological findings rather favored levamisole vasculopathy or vasculitis. Therefore, we should familiarize ourselves with the multitude of pathological and skin findings that adulterated cocaine can cause and, finally, make ourselves aware that the classical pathological finding of vasculitis in such cases is not always seen. PMID- 29147478 TI - Abdominal pain with a twist: a rare presentation of acute gastric volvulus. AB - Acute gastric volvulus is a life threatening condition requiring early diagnosis and aggressive management. Diagnosis of gastric volvulus remains a challenge for clinicians due to variable, non-specific clinical presentation, which requires a high level of suspicion. It should be considered in patients presenting with chest pain and/or epigastric pain, especially in the elderly population. Endoscopic de-rotation could be initially attempted as a therapeutic modality especially in patients who cannot undergo surgery. However, surgery remains the main stay of treatment. Delay in diagnosis can lead to complications like mucosal ischemia, necrosis or perforation, shock, which substantially increase the morbidity and mortality. PMID- 29147479 TI - Isolated pulmonary valve endocarditis: truth or myth? AB - Pulmonary valve (PV) infective endocarditis (IE) is an extremely rare disease that involves normal as well as abnormal valves. This condition mostly occurs in patients with underlying predisposing factors. It could be missed if patients do not present with typical features of right-sided endocarditis or in the absence of classic risk factors. The case presented here did not have any known risk factors for IE until surgery and presented mainly with fever, weight loss, and musculoskeletal symptoms. PMID- 29147480 TI - A rare case of late onset saphenous vein graft spasm. AB - Spasm following coronary artery bypass graft surgery has been well established in arterial grafts, especially in grafts utilizing the internal mammary. Venous graft spasms are uncommon and are only observed in vein grafts during or soon after the coronary artery bypass surgery. It is exceedingly rare to see spasm of venous graft beyond one year of surgery. We report a 72-year-old female who had coronary artery bypass graft three years ago and presented with new onset chest pain for one month. The coronary angiogram revealed severe spasm of the proximal aspect of a patent saphenous venous graft which was relieved by intracoronary nitroglycerine. Patient was successfully managed using combination of anti spasmodic medications (nitrates and calcium channel blockers) leading to long term resolution of her anginal symptoms. PMID- 29147481 TI - Is precocious puberty linked to hypothalamic expression of arginine-phenylalanine amide-related peptide? AB - The up-regulation and down-regulation of gonadotropin-releasing hormone (GnRH) in central precocious puberty is not yet known. However, recent advances in neuroendocrinology have shown the controlling role of arginine-phenylalanine RF amide-related peptides (RFRPs) on GnRH secretion in different phenomenon of reproduction such as estrus cycle and pregnancy, but the exact role of RFRPs in puberty and its related pathologic condition, precocious puberty, is not clear yet. This paper hypothesizes that RFRP is a regulatory peptide of puberty and might prevent the precocious puberty. On the basis of previous studies on hormonal fluctuations at the time of puberty, RFRP might have a role on controlling of premature secretion of GnRH and avoiding central precocious puberty. PMID- 29147482 TI - Combined postconditioning with ischemia and cyclosporine-A restore oxidative stress and histopathological changes in reperfusion injury of diabetic myocardium. AB - Objectives: Chronic diabetes impedes cardioprotection in reperfusion injury and hence protecting the diabetic heart would have important outcomes. In this study, we evaluated whether combined postconditioning with ischemia and cyclosporine-A can restore oxidative stress and histopathological changes in reperfusion injury of the diabetic myocardium. Materials and Methods: Streptozocin-induced diabetic hearts and nondiabetic controls in eight subgroups (with or without receiving ischemic-postconditioning (IPostC), cyclosporine-A, an inhibitor of mitochondrial permeability transition, or both of them) suffered from 30 min regional ischemia followed by 45 min reperfusion on an isolated-heart Langendorff system. The levels of lactate dehydrogenase (LDH) in the coronary effluent, and the levels of oxidative stress markers including 8-isoprostane, superoxide dismutase (SOD), glutathione peroxidase (GPX), and total antioxidant capacity (TAC) in myocardial supernatant prepared from the ischemic zone were measured using specific kits, spectrophotometrically. Histopathological studies were performed -eosin staining method. Results: Administration of IPostC and cyclosporine-A (alone or together) in nondiabetic hearts potentially reduced the severity of histological changes and level of LDH release as compared with untreated-controls (P<0.05). of any procedures in diabetic hearts did not show significant cardioprotective effects (P>0.1). However, the combined postconditioning with ischemia and CsA exerted significant protective effects in diabetic hearts (P<0.05). Conclusion: By augmenting the protective effects of IPostC and CsA through their combined application, reperfusion injury and related oxidative stress are reduced in diabetic hearts similar to non-diabetics. PMID- 29147483 TI - Sonophotodynamic therapy mediated by liposomal zinc phthalocyanine in a colon carcinoma tumor model: Role of irradiating arrangement. AB - Objectives: Low penetration depth of light is the main defect of photodynamic therapy (PDT), which could be improved by sonodynamic therapy (SDT). In this study, a combination of PDT and SDT known as sonophotodynamic therapy (SPDT) was investigated using two reverse arrangements in CT26 tumor model. Materials and Methods: The liposomal zinc phthalocyanine was synthesized and characterized. It was then administered to CT26 tumor models as a sensitizer. The animal models were subjected to PDT, SDT, and the combined treatment in different groups. The doubling time for the survival of tumors and animals was considered as a measure to evaluate treatments efficacy. Results: In all treatment groups there was a significant decline in tumor volume 15 days after treatment compared to the main control group, but the optimum response was observed in the group receiving a combined treatment with the priority of PDT. 120 days after treatment, in the groups treated by PDT and SDT, the tumor shrank by 20%, while in the group receiving SPDT with PDT priority, 80% of tumors was recovered. No case of complete tumor progression was observed in SPDT group with SDT priority. This could be due to the pores created in cell membranes during ultrasound irradiation of the tumor, which removed the sensitizer molecules from the cells and reduced PDT efficacy in SPDT group with SDT priority. Conclusion: It seems that SPDT with PDT priority offers a more efficient alternative than each of PDT, SDT individually or SPDT with the reverse arrangement. PMID- 29147484 TI - Berberis integerrima ameliorates insulin resistance in high- fructose-fed insulin resistant rats. AB - Objectives: This study was aimed to investigate the effect of Berberis integerrima (B. integerrima) extract on insulin sensitivity in high-fructose-fed insulin-resistant rats. Materials and Methods: Experimental rats were randomly divided into two groups: the control group was fed a regular chow diet while other group fed with a high-fructose diet for 8 weeks. After the first six weeks, the animals were treated with B. integerrima extract or pioglitazone for two weeks. Insulin and adiponectin levels were measured by ELISA. Additionally, Insulin resistance was calculated using a Homeostasis Model Assessment of Insulin resistance (HOMA-IR). The plasma free fatty acid (FFA) profile was obtained by gas chromatography. PPARgamma and GLUT4 gene expression were assessed by real time polymerase chain reaction (PCR) and western-blotting. Results: Comparing the B. integerrima treated group with the control group, weight gain (P=0.009) and levels of insulin (P=0.001), blood glucose (P<0.0001), and HOMA-IR (P<0.0001) were significantly reduced. Additionally, the adiponectin concentration was significantly increased (P<0.0001). Among the FFA fractions, the mean concentration of palmitoleic acid and stearic acid in the B. integerrima group were significantly higher than the control group (P<0.0001 and P=0.005, respectively). However, there was no significant difference at the mRNA and protein level of GLUT4 and PPAR-gamma between B. integerrima treated group and control group. Conclusion: The study findings revealed that B. integerrima might be a protective candidate against Type 2 diabetes/insulin resistance through direct insulin-like effect and an increase in adiponectin levels. However, the mechanism of B. integerrima was independent of GLUT4 and PPARgamma. PMID- 29147485 TI - The effects of anti-Fas ribozyme on T lymphocyte apoptosis in mice model with chronic obstructive pulmonary disease. AB - Objectives: In this study, we aimed to investigate the effects of anti-Fas ribozyme on the apoptosis of T lymphocytes (T cells) in mice model with chronic obstructive pulmonary disease (COPD). Materials and Methods: Male 6-week-old C57BL/6 mice were used to establish the COPD model by exposure to cigarette smoke. The COPD mice were sacrificed for spleen dissection and T cell isolation. T cells were randomly divided into four groups (n=10 per group). Group A was used as the control. B, C, and D groups were transfected with empty lentivirus, anti Fas ribozyme, and an anti-Fas ribozyme mutant, respectively. The expression of Fas mRNA and protein in the T cells were evaluated using qPCR and Western blot, respectively. Flow cytometry was used to evaluate the apoptosis of CD4+ T cells and calculate the ratio of CD4+ to CD8+ T cells (CD4+/CD8+). Results: Anti-Fas ribozyme significantly inhibited the expression of Fas in the T cells of COPD mice. In addition, the number of apoptotic CD4+ T cells and CD4+/CD8+ of the C and D groups were significantly lower and higher than those of group A, respectively (P<0.05). The apoptotic CD4+ T cells and CD4+ CD8+ of the C group were significantly lower and higher than those of group D, respectively (P<0.05). Conclusion: Anti-Fas ribozyme significantly inhibited the expression of Fas, increased CD4+/CD8+, and inhibited the apoptosis of T cells in COPD mice. PMID- 29147486 TI - A novel medium-throughput biological assay system for HTLV-1 infectivity and drug discovery. AB - Objectives: Here, a reporter cell line containing two reporter vectors were developed, in order to monitor the Human T-Lymphotropic Virus type1(HTLV-1) infectivity and the cell viability simultaneously. Materials and Methods: The reporter cell line was constructed by stably transfected baby hamster's kidney cell line (BHK-21), with the genomes expressing two different reporters in separate plasmids. The first reporter gene is transactivated by the HTLV-1 tax protein, while the second reporter is continuously expressed when introduced into a mammalian cell. In order to show its functionality, the effect of the drug mix on HTLV-1 was assayed by this system and was compared to the results obtained by other methods. Results: HTLV-1 reporter cell line was found to produce high level of luciferase when co-cultured with MT-2 and Hut-102 cells but not with Jurkat cell. Moreover, the combination therapy against HTLV-1 can reduce luciferase expression of the cell when co-cultured with MT-2 and Hut-102 comparable to the ELISA (R=0.932, P-value =0.002). In addition, the results revealed the superiority of the present system over the molecular methods. Conclusion: The results demonstrated that the biological assay system is a beneficial tool for the medium-throughput anti-HTLV-1 drug screening and inhibitory effect. PMID- 29147487 TI - A study on the immune response induced by a DNA vaccine encoding Mtb32C-HBHA antigen of Mycobacterium tuberculosis. AB - Objectives: Tuberculosis (TB) has still remained a global health issue. One third of the world's population is infected with tuberculosis and the current BCG vaccine has low efficiency; hence, it is necessary to develop a new vaccine against TB. The aim of the current study was to evaluate the efficiency of a novel DNA vaccine encoding Mtb32C-HBHA antigen in inducing specific immune responses against Mycobacterium tuberculosis. Materials and Methods: A DNA plasmid vaccine expressing Mtb32C-HBHA fusion protein was constructed and its ability in protein expression was examined by RT-PCR and Western blot methods. Female BALB/c mice were vaccinated with 100 MUg of purified recombinant vector in an attempt to assess its immunogenicity and protective efficacy. Further, the cytokines, IFN-gamma, IL-12, IL-4, IL-10, and TGF-beta were assessed. Results: The levels of all the studied cytokines were significantly increased (P<0.05) compared with the control group. IFN-gamma production in the group receiving DNA vaccine plus BCG was increased compared with those receiving only DNA vaccine or BCG (P<0.001). Conclusion: The immunogenicity of the new chimeric DNA vaccine was confirmed alone and in combination with BCG. Based on the results of the current study, the constructed DNA vaccine induced the expression of Mtb32C-HBHA fusion protein efficiently in vitro. Furthermore, high levels of the specific cytokines were induced in mice. By using this DNA vaccine as a booster after BCG, higher amounts of IFN-gamma will be produced. PMID- 29147488 TI - The downregulation of ATG4B mediated by microRNA-34a/34c-5p suppresses rapamycin induced autophagy. AB - Objectives: Autophagy-related 4B (ATG4B) plays an important role in the process of autophagy induction. However, the molecular events that govern the expression of ATG4B in this process are not well known. Materials and Methods: Human ATG4B 3'-UTR region (1377 nt) containing miR-34a/miR-34c-5p binding site was amplified by PCR. Luciferase assay was used to assess the activity of reporter genes. Real time PCR was used to detect the levels of miR-34a and miR-34c-5p. Western blot was used toanalyze the protein levels of ATG4B, LC3 and p62. Results: Both miR 34a and miR-34c-5p could directly target the 3'-UTR of ATG4B mRNA at same site. Overexpression of either miR-34a or miR-34c-5p significantly down-regulated ATG4B at both mRNA and protein levels and this effect can be reversed by ATG4B overexpression. Moreover, Rapamycin-induced autophagy is accompanied with the upregulation of ATG4B and the downregulation of miR-34a/miR-34c-5p. Ectopic expression of either miR-34a or miR-34c-5p markedly suppressed rapamycin triggered autophagy. Conclusion: In the present study, we found that miR34/ATG4B signaling axis involves in rapamycin-triggered autophagy. This study may provide a new insight for understanding the mechanisms of ATG4B regulation and autophagy induction. PMID- 29147489 TI - The effect of platelet-rich plasma on human mesenchymal stem cell-induced bone regeneration of canine alveolar defects with calcium phosphate-based scaffolds. AB - Objectives: Autologous bone transplantation known as the "gold standard" to reconstruction of osseous defects has known disadvantages. This study was designed to explore the effects of hydroxy-apatite/tricalcium-phosphate (HA/TCP) and platelet-rich plasma (PRP) on the osteogenesis ability of human adipose derived mesenchymal stem cells (hAdMSCs) in vitro and in vivo. Materials and Methods: hAdMSCs were incubated with HA/TCP granules and/or PRP in vitro and then, cell proliferation and differentiation was assessed by MTT assay, AZR S staining and SEM examination. In vivo, four cylindrical defects were drilled in the mandibular bones of 5 mongrel dogs and divided randomly into the following groups: I-autologous crushed bone, II- no filling material, III- HA/TCP and PRP, IV- PRP-enriched hAdMSCs seeded on HA/TCP granules. Inserted hAdMSCs were labeled to trace their contribution to bone tissue regeneration. Finally, cell tracing and tissue regeneration were evaluated by immunohistochemistry and histomorphometry methods, respectively. Results: In vitro, co-incubation with HA/TCP granules significantly reduced proliferation and osteogenic differentiation ability of hAdMSCs; while PRP application promoted these capacities (P<0.05). In vivo, PRP-enriched hAdMSCs seeded on HA/TCP granules induced considerable bone formation in osseous defects (P<0.05). It was obviously shown that hAdMSCs were incorporated into the newly-formed bone. Conclusion: Based on this study, application of stem cells could offer a helpful therapeutic tool in bone tissue regeneration. Although inserted hAdMSCs were identifiable throughout the newly-formed bone tissue, their few number could be an indicator of indirect role of hAdMSCs in tissue regeneration. PMID- 29147490 TI - Hypolipidemic effects of total flavonoide extracted from the leaves of Actinidiakolomikta in rats fed a high-fat diet. AB - Objectives: This study was to investigate the antihyperlipidemic and antioxidant effect of total flavonoid extract from Actinidiakolomikta (TFAK) in hyperlipidemia induced by a high-fat diet. Materials and Methods: Male SD rats were randomly divided into 6 groups: normal group, model (hyperlipidemic diet) group, hyperlipedemic diet supplemented with TFAK (50, 100 and 200 mg/kg) and simvastatin (30 mg/kg) groups. The rats were administrated TFAK by oral for 28 days. Body weight, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), superoxide dismutase (SOD), catalase(CAT), glutathione peroxidase(GSH-Px) and malondialdehyde (MDA) were measured. The atherogenic index (AI) and coronary risk index (CRI) were calculated. The activity of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in hepatic tissue was examined. Histopathologic changes were also checked. Results: The levels of TC, TG and LDL-c were increased in model group. Compared to the model group, TFAK reduced significantly the body weight, TC, TG, LDL-c, AI, CRI and elevated the level of HDL-c. Moreover, the activity of SOD was elevated significantly, whereas the content of MDA decreased. The activity of HMG-CoA reductase was also decreased. Morphological evaluation found that rats in model group developed a severe steatosis, but the severity of liver steatosis was ameliorated in TFAK treated groups. The possible mechanism may be associated with decrease HMG-CoA reductase activity. Conclusion: Our results suggest that TFAK exerts strong antioxidant and lipid-lowering effects, prevents hepatic fatty deposition and regulates the HMG-CoA reductase. PMID- 29147491 TI - Augmented expression levels of lncRNAs ecCEBPA and UCA1 in gastric cancer tissues and their clinical significance. AB - Objectives: As the second cause of cancer death, gastric cancer (GC) is one of the eminent dilemmas all over the world, therefore investigating the molecular mechanisms involved in this cancer is pivotal. Unrestricted proliferation is one of the characteristics of cancerous cells, which is due to deficiency in cell regulatory systems. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of the epigenome. lncRNA extra coding CEBPA (ecCEBPA) is involved in DNA methylation. This lncRNA reduces CEBPA promoter methylation by interacting with DNA methyltransferase 1. lncRNA UCA1 (urothelial carcinoma-associated 1) elevates cell proliferation through the PI3K/Akt signaling pathway which has a critical role in cell growth and apoptosis. The aim of this study was to examine the expression of ecCEBPA and UCA1 genes in GC tissues as well as their clinical significance. Materials and Methods: Total RNA extraction, cDNA synthesis, and quantitative real-time PCR were performed for cells and 80 paired GC tissues. Furthermore, clinical relevance of UCA1 expression was investigated in TCGA cohort data. Results: Our results showed ecCEBPA and UCA1 over-expression in GC tissues. Furthermore, lncRNAs associations with clinicopathological features were demonstrated both in the current and TCGA cohort. Kaplan-Meier analysis indicated that patients with higher UCA1 expression had a worse overall survival in the case of pancreatic and lung adenocarcinomas but not other solid cancer types including GC. Conclusion: These data demonstrate UCA1 and ecCEBPA involvement in GC and suggest that these lncRNAs might be useful as diagnostic/ prognostic biomarkers in cancer. PMID- 29147492 TI - Alterations in adult hippocampal neurogenesis, aberrant protein s-nitrosylation, and associated spatial memory loss in streptozotocin-induced diabetes mellitus type 2 mice. AB - Objectives: Epidemiological and biochemical studies conducted over the past two decades have established a strong link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). However, the exact mechanisms through which aberrations in insulin signaling associated with T2DM contribute to cognitive decline are not yet known. Materials and Methods: In an effort to explore possible molecular links between T2DM and AD, the present study investigated the status of neurodegeneration, adult hippocampal neurogenesis, and nitrosative stress induced protein S-nitrosylation in streptozotocin (STZ) induced mice models of T2DM. Morris water maze task and subsequent histological and immunohistochemical assessment were conducted. Expression of neurogenesis markers (Ki67, DCX, and NeuN) and APP 770 was determined by qRT-PCR. Results: A significant decline in spatial learning and reference memory was observed with consequent neurodegeneration in brain cortex and hippocampus in the diabetic group as compared to the control group. A subsequent increase in expression of APP 770 was also observed in T2DM brain regions. Moreover, a significant decrease in transcriptional expression of Ki67, DCX, and NeuN was also evident in T2DM brain regions, which indicated possible aberrations in adult hippocampal neurogenesis in T2DM. Furthermore, an increased immunohistochemical signal for S nitrosylation was also observed in T2DM, which also suggested its potential contribution in T2DM associated neuronal deterioration. Conclusion: It is suggested that these identified aberrations in the diabetic brain may communally increase the susceptibility of developing AD in patients with T2DM. Further studies of the underlying molecular mechanisms may help to strategize a combination therapy for these debilitating disorders. PMID- 29147493 TI - The effect of the ovarian varicose vein on the DNA methylation in the rat's oocyte. AB - Objectives: We intended to determine whether the ovarian varicose which is one of the common etiologies of the pelvic congestion syndrome, has the ability to interfere with the DNA methylation reprogramming in the oocyte and thereby affect the oocyte quality or not. Materials and Methods: Varicose model was induced according to the Turner's method in the rats. Briefly, a 20-gauge needle was placed on the left renal vein and a thread was tied over both the needle and the renal vein medial to the insertion of the ovarian vein, and then the needle was removed. Evaluation of prooxidant-antioxidant balance (PAB) was assessed using specific kits and the expression level of the DNA methyltransferase genes Dnmt1, Dnmt3a and Dnmt3L was assessed by Real-time PCR. Immunofluorescent staining for 5 methylcytosine in the oocytes evaluated the global DNA methylation. Results: A significant PAB increase in the ovaries from varicose group was seen. Real-time PCR demonstrated a remarkable decrease in the expression of the Dnmt3a and Dnmt3L which are responsible for de novo DNA methylation in the oocytes. Immunofluorescent staining for 5-mC showed a reduction in the fluorescence intensity in the oocytes collected from the varicose group. Conclusion: Our findings from Real-time PCR and immunocytochemistry suggest that the epigenetic parameters in the oocyte could be affected by varicose induction and these epigenetic alteration has the potential to affect the oocyte quality. We suggest that the epigenetic changes could happen in the oocytes after the induction of ovarian varicose and lead to the oocyte quality reduction or even infertility. PMID- 29147494 TI - Renoprotective effect of crocin following liver ischemia/ reperfusion injury in Wistar rats. AB - Objectives: The objectives of the current study were to evaluate the effects of hepatic ischemia/reperfusion (IR) injury on the activity of antioxidant enzymes, biochemical factors, and histopathological changes in rat kidney, and to investigate the effect of crocin on IR-related changes. Materials and Methods: Thirty-two male Wistar rats were randomly allocated into four groups (n=8). They were sham-operated, IR, crocin pre-treatment, and crocin pretreatment+IR groups. Sham-operated and Crocin pre-treatment groups received normal saline (N/S, 2 ml/day) and crocin (200 mg/kg) for seven consecutive days intraperitoneally (IP), respectively, then rats underwent laparotomy, only. IR and crocin pretreatment+IR groups received N/S and crocin with the same dose, time, and route, respectively, then rats underwent partial (70%) ischemia for 45 min that was followed by reperfusion for 60 min. At the end of the experiment, kidney specimens were taken for histopathological and antioxidant evaluations and also blood samples were obtained for biochemical analysis. Results: The results of the present study showed that crocin pre-treatment significantly increased the activity of antioxidants, decreased the serum levels of liver enzymes and blood urea nitrogen following IR-induced hepatic injury. Crocin also ameliorated kidney's histopathological disturbance beyond IR-induced hepatic injury. Conclusion: Crocin as an antioxidant agent protected renal insult following liver IR injury by increasing the activity of antioxidant enzymes, reducing serum levels of liver enzymes, and improving histopathological changes. PMID- 29147495 TI - Standardized Cannabis sativa extract attenuates tau and stathmin gene expression in the melanoma cell line. AB - Objectives: Metastasis is the main cause of death in patients with melanoma. Cannabis-based medicines are effective adjunctive drugs in cancer patients. Tau and Stathmin proteins are the key proteins in cancer metastasis. Here we have investigated the effect of a standardized Cannabis sativa extract on cell migration and Tau and Stathmin gene expression in the melanoma cell line. Materials and Methods: In the treatment group, melanoma (B1617) was treated 48 hr with various concentrations of standardized C. sativa extract. Cells with no treatment were considered as the control group, then study was followed by Quantitative RT-Real Time PCR assay. Relative gene expression was calculated by the DeltaDeltact method. Migration assay was used to evaluate cancer metastasis. Results: Tau and stathmin gene expression was significantly decreased compared to the control group. Cell migration was also significantly reduced compared to controls. Conclusion: C. sativa decreased tau and stathmin gene expression and cancer metastasis. The results may have some clinical relevance for the use of cannabis-based medicines in patients with metastatic melanoma. PMID- 29147496 TI - Markov Chain-Based Acute Effect Estimation of Air Pollution on Elder Asthma Hospitalization. AB - Background: Asthma caused substantial economic and health care burden and is susceptible to air pollution. Particularly, when it comes to elder asthma patient (older than 65), the phenomenon is more significant. The aim of this study is to investigate the Markov-based acute effects of air pollution on elder asthma hospitalizations, in forms of transition probabilities. Methods: A retrospective, population-based study design was used to assess temporal patterns in hospitalizations for asthma in a region of Sichuan province, China. Approximately 12 million residents were covered during this period. Relative risk analysis and Markov chain model were employed on daily hospitalization state estimation. Results: Among PM2.5, PM10, NO2, and SO2, only SO2 was significant. When air pollution is severe, the transition probability from a low-admission state (previous day) to high-admission state (next day) is 35.46%, while it is 20.08% when air pollution is mild. In particular, for female-cold subgroup, the counterparts are 30.06% and 0.01%, respectively. Conclusions: SO2 was a significant risk factor for elder asthma hospitalization. When air pollution worsened, the transition probabilities from each state to high admission states increase dramatically. This phenomenon appeared more evidently, especially in female-cold subgroup (which is in cold season for female admissions). Based on our work, admission amount forecast, asthma intervention, and corresponding healthcare allocation can be done. PMID- 29147497 TI - Mechanism and performance of lithium-oxygen batteries - a perspective. AB - Rechargeable Li-O2 batteries have amongst the highest formal energy and could store significantly more energy than other rechargeable batteries in practice if at least a large part of their promise could be realized. Realization, however, still faces many challenges than can only be overcome by fundamental understanding of the processes taking place. Here, we review recent advances in understanding the chemistry of the Li-O2 cathode and provide a perspective on dominant research needs. We put particular emphasis on issues that are often grossly misunderstood: realistic performance metrics and their reporting as well as identifying reversibility and quantitative measures to do so. Parasitic reactions are the prime obstacle for reversible cell operation and have recently been identified to be predominantly caused by singlet oxygen and not by reduced oxygen species as thought before. We discuss the far reaching implications of this finding on electrolyte and cathode stability, electrocatalysis, and future research needs. PMID- 29147498 TI - Reduction rate as a quantitative knob for achieving deterministic synthesis of colloidal metal nanocrystals. AB - Despite the incredible developments made to the synthesis of colloidal metal nanocrystals, it is still challenging to produce them in a reproducible and predictable manner. This drawback can be attributed to the fact that the protocols continue to be built upon qualitative observations and empirical laws. Because of the vast number of intricately entangled experimental parameters in a synthesis, it is almost impossible to predict and control the outcome by knowingly alternating these parameters. In this Perspective article, we discuss the recent efforts in pushing nanocrystal synthesis towards a deterministic process based upon quantitative measurements. In particular, we focus on how the reduction rate of a salt precursor can be used as a quantitative knob for predicting and controlling the outcomes of both nucleation and growth. We begin with a brief introduction to the techniques that have been used to extract the kinetic information of a synthesis and then discuss how the reduction rate is correlated with the defect structure, shape/morphology, and elemental distribution of the resultant nanocrystals. We conclude by highlighting some of the recent advances related to in situ probing of nanocrystal synthesis, with an emphasis on the real-time, quantitative aspects with regard to both nucleation and growth. PMID- 29147499 TI - Nano/microvehicles for efficient delivery and (bio)sensing at the cellular level. AB - A perspective review of recent strategies involving the use of nano/microvehicles to address the key challenges associated with delivery and (bio)sensing at the cellular level is presented. The main types and characteristics of the different nano/microvehicles used for these cellular applications are discussed, including fabrication pathways, propulsion (catalytic, magnetic, acoustic or biological) and navigation strategies, and relevant parameters affecting their propulsion performance and sensing and delivery capabilities. Thereafter, selected applications are critically discussed. An emphasis is made on enhancing the extra and intra-cellular biosensing capabilities, fast cell internalization, rapid inter- or intra-cellular movement, efficient payload delivery and targeted on demand controlled release in order to greatly improve the monitoring and modulation of cellular processes. A critical discussion of selected breakthrough applications illustrates how these smart multifunctional nano/microdevices operate as nano/microcarriers and sensors at the intra- and extra-cellular levels. These advances allow both the real-time biosensing of relevant targets and processes even at a single cell level, and the delivery of different cargoes (drugs, functional proteins, oligonucleotides and cells) for therapeutics, gene silencing/transfection and assisted fertilization, while overcoming challenges faced by current affinity biosensors and delivery vehicles. Key challenges for the future and the envisioned opportunities and future perspectives of this remarkably exciting field are discussed. PMID- 29147500 TI - Pressure-induced dramatic changes in organic-inorganic halide perovskites. AB - Organic-inorganic halide perovskites have emerged as a promising family of functional materials for advanced photovoltaic and optoelectronic applications with high performances and low costs. Various chemical methods and processing approaches have been employed to modify the compositions, structures, morphologies, and electronic properties of hybrid perovskites. However, challenges still remain in terms of their stability, the use of environmentally unfriendly chemicals, and the lack of an insightful understanding into structure property relationships. Alternatively, pressure, a fundamental thermodynamic parameter that can significantly alter the atomic and electronic structures of functional materials, has been widely utilized to further our understanding of structure-property relationships, and also to enable emergent or enhanced properties of given materials. In this perspective, we describe the recent progress of high-pressure research on hybrid perovskites, particularly regarding pressure-induced novel phenomena and pressure-enhanced properties. We discuss the effect of pressure on structures and properties, their relationships and the underlying mechanisms. Finally, we give an outlook on future research avenues in which high pressure and related alternative methods such as chemical tailoring and interfacial engineering may lead to novel hybrid perovskites uniquely suited for high-performance energy applications. PMID- 29147501 TI - One-pot synthesis of hetero[6]rotaxane bearing three different kinds of macrocycle through a self-sorting process. AB - In this article, a six-component self-sorting process that involves three types of crown ether macrocycle and three types of cation guest molecule was carefully and thoroughly investigated. The six components include three kinds of crown ether, namely bis(p-phenylene-34-crown-10) (BPP34C10), dibenzo-24-crown-8 (DB24C8) and benzo-21-crown-7 (B21C7), and their corresponding cation guest molecules, namely a 4,4'-bipyridine dication (BPY2+) and dibenzylammonium (DBA) and benzylalkylammonium (BAA) ions, respectively. Based on this well-established highly selective six-component self-sorting process, a hetero[6]rotaxane bearing three different kinds of crown ether macrocycle was designed and successfully synthesized through a facile and efficient one-pot "click" stoppering strategy. Such work is proposed to be a significant advance in the construction of mechanically interlocked molecules with high structural complexity, as well as a good supplement in the areas of multi-component self-sorting and noncovalent self assembly. PMID- 29147503 TI - Hollowing out MOFs: hierarchical micro- and mesoporous MOFs with tailorable porosity via selective acid etching. AB - We report a new strategy for the synthesis of robust hierarchical micro- and mesoporous MOFs from water stable MOFs via a selective acid etching process. The process is controlled by the size-selective diffusion of acid molecules through the MOF windows. This method enables the fine-tuning of the porosity of hierarchical MOFs, allowing for the generation of well-defined mesopores with high mesopore volume. Because of the size-selective diffusion of acid molecules, the inherent crystallinity and external morphology of the resulting MOFs are well maintained after acid treatment. This novel strategy may provide an alternative route towards the synthesis of diverse hierarchical MOFs. PMID- 29147502 TI - Chemical space guided discovery of antimicrobial bridged bicyclic peptides against Pseudomonas aeruginosa and its biofilms. AB - Herein we report the discovery of antimicrobial bridged bicyclic peptides (AMBPs) active against Pseudomonas aeruginosa, a highly problematic Gram negative bacterium in the hospital environment. Two of these AMBPs show strong biofilm inhibition and dispersal activity and enhance the activity of polymyxin, currently a last resort antibiotic against which resistance is emerging. To discover our AMBPs we used the concept of chemical space, which is well known in the area of small molecule drug discovery, to define a small number of test compounds for synthesis and experimental evaluation. Our chemical space was calculated using 2DP, a new topological shape and pharmacophore fingerprint for peptides. This method provides a general strategy to search for bioactive peptides with unusual topologies and expand the structural diversity of peptide based drugs. PMID- 29147504 TI - Immuno-targeting of Staphylococcus aureus via surface remodeling complexes. AB - Agents with novel mechanisms of action are needed to complement traditional antibiotics. Towards these goals, we have exploited the surface-homing properties of vancomycin to tag the surface of Gram-positive pathogens with immune cell attractants in two unique modes. First, vancomycin was conjugated to the small molecule hapten 2,4-dinitrophenol (DNP) to promote bacterial opsonization. Second, we built on these results by improving the tagging specificity and mechanism of incorporation by coupling it to a sortase A substrate peptide. We demonstrated, for the first time, that the surface of Staphylococcus aureus (S. aureus) can be metabolically labeled in live Caenorhabditis elegans hosts. These constructs represent a class of promising narrow-spectrum agents that target S. aureus for opsonization and establish a new surface labeling modality in live host organisms, which should be a powerful tool in dissecting features of host pathogen interactions. PMID- 29147505 TI - Remote C-H insertion of vinyl cations leading to cyclopentenones. AB - We report a Lewis acid catalyzed reaction sequence involving a 1,2-shift and subsequent C-H insertion that gives monocyclic and fused bicyclic cyclopentenone products. This reaction sequence, which is initiated by treating beta-hydroxy alpha-diazo ketones with a Lewis acid, proceeds through vinyl cation intermediates that insert at non-activated gamma C-H bonds. This reaction represents an alternative strategy to exploit the diazo functional group in an intramolecular C-H insertion, and can provide products not accessible by transition metal catalyzed C-H insertions. This remote C-H activation process provides good yields of bicyclic cyclopentenone products that contain 7- and 8 membered rings, and monocyclic prostaglandin analogs. PMID- 29147506 TI - Pd-catalyzed asymmetric allylic alkylations via C-H activation of N-allyl imines with glycinates. AB - Herein is reported the first example of palladium-catalyzed asymmetric allylic alkylation (AAA) reactions involving 2-aza-pi-allyl palladium intermediates. The 2-aza-pi-allyl complex was generated via a novel mode of activation of N-allyl imines. Pd-catalyzed C(sp3)-H activation of N-allyl imines and subsequent nucleophilic attack by glycinates delivered vicinal diamino derivatives as the sole regioisomers with high levels of diastereo- and enantio-control in the presence of the chiral, bidentate (S,S)-Cy-DIOP ligand. This procedure is highly atom economical and could also be performed by a simple one-pot operation starting from aldehydes, allyl amines and glycinates under mild conditions. The products of this transformation could be converted into various useful derivatives, where the allyl substitution serves as a unique tool for differentiating the two amino moieties in the products. PMID- 29147507 TI - Gelation-driven selection in dynamic covalent C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 C/CN exchange. AB - Knoevenagel barbiturate derivatives bearing long alkyl chains were proven to form organogels in suitable solvents based on supramolecular interactions. Their reaction with imines allows for component exchange through CC/CN recombination. The effect of various parameters (solvents, chain length, and temperature) on the CC/CN exchange reaction has been studied. Mixing Knoevenagel compound K and imine I-16 in a 1 : 1 ratio generated a constitutional dynamic library containing the four constituents K, I-16, K'-16, and I'. The reversible exchange reaction was monitored by 1H-NMR, showing marked changes in the fractions of the four constituents on sol-gel interconversion as a function of temperature. The library composition changed from statistical distribution of the four constituents in the sol state to selective amplification of the gel forming K'-16 constituent together with that of its agonist I'. The process amounts to self-organization driven component selection in a constitutional dynamic organogel system undergoing gelation. This process displays up-regulation of the gel-forming constituent by component redistribution through reversible covalent connections. PMID- 29147508 TI - Chiral nanoprobes for targeting and long-term imaging of the Golgi apparatus. AB - The Golgi apparatus is an essential subcellular organelle. Targeting and monitoring the Golgi change at the single-cell level over a long time scale are critical but are challenges that have not yet been tackled. Inspired by the precise Golgi positioning ability of galactosyltransferase and protein kinase D, due to their cysteine residues, we developed a method for long-term Golgi imaging. Fluorescent molecules, carbon quantum dots (CQDs) and silica nanoparticles could target the Golgi when they are modified with l-cysteine. l Cysteine-rich chiral carbon quantum dots (LC-CQDs), which have the benefits of a high Golgi specificity from l-cysteine and excellent photostability and biocompatibility from the CQDs, are proven to be highly suitable for long-term in situ imaging of the Golgi. Investigation of the mechanism showed that free thiol groups and the l-type stereo configuration of LC-CQDs are essential for specific targeting of the Golgi. With the aid of the as-prepared LC-CQDs, the dynamic changes of the Golgi in the early stage of viral infection were visualized. The Golgi targeting and imaging strategy used in this work is beneficial for Golgi targeted drug delivery and early diagnosis and therapy of Golgi diseases. PMID- 29147509 TI - Composition-driven Cu-speciation and reducibility in Cu-CHA zeolite catalysts: a multivariate XAS/FTIR approach to complexity. AB - The small pore Cu-CHA zeolite is attracting increasing attention as a versatile platform to design novel single-site catalysts for deNO x applications and for the direct conversion of methane to methanol. Understanding at the atomic scale how the catalyst composition influences the Cu-species formed during thermal activation is a key step to unveil the relevant composition-activity relationships. Herein, we explore by in situ XAS the impact of Cu-CHA catalyst composition on temperature-dependent Cu-speciation and reducibility. Advanced multivariate analysis of in situ XANES in combination with DFT-assisted simulation of XANES spectra and multi-component EXAFS fits as well as in situ FTIR spectroscopy of adsorbed N2 allow us to obtain unprecedented quantitative structural information on the complex dynamics during the speciation of Cu-sites inside the framework of the CHA zeolite. PMID- 29147510 TI - Formation and ligand-based reductive chemistry of bridged bis-alkylidene scandium(iii) complexes. AB - The chemistry of rare-earth carbene and alkylidene complexes including their synthesis, structure and reaction is a challenging issue because of their high reactivity (or instability) and the lack of synthetic methods. In this work, we report the first synthesis of the bridged bis-alkylidene complexes which feature a 2-butene-1,1,4,4-tetraanion and four Sc-C(sp3) bonds by the reaction of 1,4 dilithio-1,3-butadienes with ScCl3. This reaction proceeds via two key intermediates: an isolable scandacyclopentadiene and a proposed scandacyclopropene. The scandacyclopentadiene undergoes beta,beta'-C-C bond cleavage to generate the scandacyclopropene, which then dimerizes to afford the bridged bis-alkylidene complex via a cooperative double metathesis reaction. Reaction chemistry study of the bridged bis-alkylidene complex reveals their ligand-based reduction reactivity towards different oxidants such as hexachloroethane, disulfide and cyclooctatetraene. PMID- 29147511 TI - Cytotoxic (salen)ruthenium(iii) anticancer complexes exhibit different modes of cell death directed by axial ligands. AB - Two novel series of (salen)ruthenium(iii) complexes bearing guanidine and amidine axial ligands were synthesized, characterized, and evaluated for anticancer activity. In vitro cytotoxicity tests demonstrate that these complexes are cytotoxic against various cancer cell lines and the leading complexes have remarkable cancer-cell selectivity. A detailed study of the guanidine complex 7 and the amidine complex 13 reveals two distinguished modes of action. Complex 7 weakly binds to DNA and induces DNA damage, cell cycle arrest, and typical apoptosis pathways in MCF-7 cells. In contrast, complex 13 induces paraptosis like cell death hallmarked by massive vacuole formation, mitochondrial swelling, and ER stress, resulting in significant cytotoxicity against human breast cancer cells. Our results provide an extraordinary example of tuning the mechanism of action of (salen)ruthenium(iii) anticancer complexes by modifying the structure of the axial ligands. PMID- 29147512 TI - On the performance of a photosystem II reaction centre-based photocell. AB - The photosystem II reaction centre is the photosynthetic complex responsible for oxygen production on Earth. Its water splitting function is particularly favoured by the formation of a stable charge separated state via a pathway that starts at an accessory chlorophyll. Here we envision a photovoltaic device that places one of these complexes between electrodes and investigate how the mean current and its fluctuations depend on the microscopic interactions underlying charge separation in the pathway considered. Our results indicate that coupling to well resolved vibrational modes does not necessarily offer an advantage in terms of power output but can lead to photo-currents with suppressed noise levels characterizing a multi-step ordered transport process. Besides giving insight into the suitability of these complexes for molecular-scale photovoltaics, our work suggests a new possible biological function for the vibrational environment of photosynthetic reaction centres, namely, to reduce the intrinsic current noise for regulatory processes. PMID- 29147513 TI - Sortase-mediated chemical protein synthesis reveals the bidentate binding of bisphosphorylated p62 with K63 diubiquitin. AB - Phosphorylation of S403 or S407 of the autophagic receptor protein p62 has recently been discovered to enhance the binding of p62 with ubiquitinated protein substrates to upregulate selective autophagy. To elucidate the molecular mechanism of how phosphorylation regulates the recruitment of ubiquitinated proteins, we report the first chemical synthesis of homogeneously phosphorylated p62, which enables the setting up of accurate in vitro systems for biochemical studies. Our synthesis employs the technology of sortase A-mediated protein hydrazide ligation, which successfully affords three types of phosphorylated p62 at the multi-milligram scale. Quantitative biochemical measurements show that the binding affinity of S403/S407-bisphosphorylated p62 to K63 diubiquitin is significantly higher than that of mono-phosphorylated p62. This finding suggests that phosphorylated S403 and S407 sites should bind to different epitopes on the ubiquitin chain. Furthermore, glutamate mutation is found to give a significantly impaired binding affinity, implying the necessity of using chemically synthesized phosphorylated p62 for the biochemical study of selective autophagy. PMID- 29147514 TI - alpha-Perfluoroalkyl-beta-alkynylation of alkenes via radical alkynyl migration. AB - Transition metal-free radical alpha-perfluoroalkylation with concomitant beta alkynylation of unactivated alkenes is presented. These cascades proceed via electron-catalysis and comprise a radical 1,4- or 1,5-alkynyl migration from tertiary propargylic alcoholates to secondary or tertiary C-radicals as the key step. Alkynyl migration leads to a ketyl radical anion that sustains the chain as a single electron transfer reducing reagent. PMID- 29147515 TI - Stereochemistry and biological activity of chlorinated lipids: a study of danicalipin A and selected diastereomers. AB - The syntheses of (+)-16-epi- and (+)-11,15-di-epi-danicalipin A (2 and 3) are reported. The conformations of the parent diols 5 and 6 as well as the corresponding disulfates 2 and 3 were determined on the basis of J-based configuration analysis and supported by calculations. The impact of configuration on membrane permeability in Gram-negative bacteria and mammalian cell lines was assessed as well as cytotoxicity. Although diastereomer 2 showed similar behavior to natural (+)-danicalipin A (1), strikingly, the more flexible C11,C15-epimer 3 had no effect on permeability and proved equally or more toxic towards multiple cell lines. PMID- 29147516 TI - A new route to N-aromatic heterocycles from the hydrogenation of diesters in the presence of anilines. AB - The hydrogenation of dicarboxylic acids and their esters in the presence of anilines provides a new synthesis of heterocycles. [Ru(acac)3] and 1,1,1 tris(diphenylphosphinomethyl)ethane (triphos) gave good to excellent yields of the cyclic amines at 220 degrees C. When aqueous ammonia was used with dimethyl 1,6-hexadienoic acid, epsilon-caprolactam was obtained in good yield. A side reaction involving alkylation of the amine by methanol was suppressed by using diesters derived from longer chain and branched alcohols. Hydrogenation of optically pure diesters (dimethyl (R)-2-methylbutanedioate and dimethyl (S)-2 methylbutanedioate) with aniline afforded racemic 3-methyl-1-phenylpyrrolidine in 78% yield. PMID- 29147517 TI - Ketones as directing groups in photocatalytic sp3 C-H fluorination. AB - The ubiquitous ketone carbonyl group generally deactivates substrates toward radical-based fluorinations, especially sites closest to it. Herein, ketones are used instead to direct aliphatic fluorination using Selectfluor, catalytic benzil, and visible light. Selective beta- and gamma-fluorination are demonstrated on rigid mono-, di-, tri-, and tetracyclic (steroidal) substrates employing both cyclic and exocyclic aliphatic ketones as directing groups. PMID- 29147518 TI - Machine learning molecular dynamics for the simulation of infrared spectra. AB - Machine learning has emerged as an invaluable tool in many research areas. In the present work, we harness this power to predict highly accurate molecular infrared spectra with unprecedented computational efficiency. To account for vibrational anharmonic and dynamical effects - typically neglected by conventional quantum chemistry approaches - we base our machine learning strategy on ab initio molecular dynamics simulations. While these simulations are usually extremely time consuming even for small molecules, we overcome these limitations by leveraging the power of a variety of machine learning techniques, not only accelerating simulations by several orders of magnitude, but also greatly extending the size of systems that can be treated. To this end, we develop a molecular dipole moment model based on environment dependent neural network charges and combine it with the neural network potential approach of Behler and Parrinello. Contrary to the prevalent big data philosophy, we are able to obtain very accurate machine learning models for the prediction of infrared spectra based on only a few hundreds of electronic structure reference points. This is made possible through the use of molecular forces during neural network potential training and the introduction of a fully automated sampling scheme. We demonstrate the power of our machine learning approach by applying it to model the infrared spectra of a methanol molecule, n-alkanes containing up to 200 atoms and the protonated alanine tripeptide, which at the same time represents the first application of machine learning techniques to simulate the dynamics of a peptide. In all of these case studies we find an excellent agreement between the infrared spectra predicted via machine learning models and the respective theoretical and experimental spectra. PMID- 29147519 TI - Multi-functional bis(alkynyl)gold(iii) N?C complexes with distinct mechanochromic luminescence and electroluminescence properties. AB - A new class of donor-acceptor type luminescent bis(alkynyl)gold(iii) N?C complexes has been synthesized and characterized. These gold(iii) complexes not only exhibit high photoluminescence quantum yields of up to 0.81, but also interesting mechanochromic luminescence behaviors that are reversible. Upon grinding, a dramatic luminescence color change from green to red can be observed in solid samples of the gold(iii) complexes, and the mechanochromic luminescence can be readily tuned via a judicious selection of substituents on the pyridine ring. In addition, solution-processable OLEDs based on this class of complexes with EQE values of up to 4.0% have been realized, representing the first demonstration of bis(alkynyl)gold(iii) N?C complexes as emissive materials in solution-processable OLEDs. PMID- 29147521 TI - Formal aromaticity transfer for palladium-catalyzed coupling between phenols and pyrrolidines/indolines. AB - We herein describe a palladium-catalyzed formal aromaticity transfer coupling reaction between phenols and pyrrolidines or indolines to generate the corresponding N-cyclohexyl pyrroles or indoles. In this transformation, the aromaticity of phenols is formally passed on to the pyrrolidine or indoline units. Substituted phenols thus can serve as latent cyclohexyl equivalents for the fast construction of various N-cyclohexyl pyrroles and indoles. PMID- 29147520 TI - Enhancing charge mobilities in organic semiconductors by selective fluorination: a design approach based on a quantum mechanical perspective. AB - Selective fluorination of organic semiconducting molecules is proposed as a means to achieving enhanced hole mobility. Naphthalene is examined here as a root molecular system with fluorination performed at various sites. Our quantum chemical calculations show that selective fluorination can enhance attractive intermolecular interactions while reducing charge trapping. Those observations suggest a design principle whereby fluorination is utilized for achieving high charge mobilities in the crystalline form. The utility of this design principle is demonstrated through an application to perylene, which is an important building block of organic semiconducting materials. We also show that a quantum mechanical perspective of nuclear degrees of freedom is crucial for a reliable description of charge transport. PMID- 29147522 TI - Impact of the structures of macrocyclic Michael acceptors on covalent proteasome inhibition. AB - Molecules that have a reactive functional group within a macrocycle represent a class of covalent inhibitor. The relationship between reactivity and affinity for the target is cooperative and complicated. An understanding and characterization of this class of inhibitor are vital for the development of covalent inhibitors as drug candidates. Herein, we describe a systematic analysis of structure activity relationships using a series of syringolin analogues, which are irreversible covalent inhibitors of proteasomes. We investigate the detailed mechanistic effects of the macrocycles on affinity and reaction rate. PMID- 29147523 TI - A unified view to Bronsted acidity scales: do we need solvated protons? AB - The most comprehensive solvent acidity scale spanning 28 orders of magnitude of acidity was measured in the low-polarity solvent 1,2-dichloroethane (DCE). Its experimental core is linked to the unified acidity scale (pHabs) in an unprecedented and generalized approach only based on experimental values. This enables future measurements of acid strengths and acidity adjustments in low polarity solvents. The scale was cross-validated computationally. The purely experimental and computational data agree very well. The DCE scale includes 87 buffer systems with values between -13.0 and +15.4, i.e. similar to water at hypothetical and extreme pH values of -13.0 to +15.4. Unusually, such high acidities in DCE are not realized via solvated protons, but rather through strongly acidic molecules able to directly donate their proton, even to weak bases dissolved in the solution. Thus, in all examined cases, not a single solvated proton is present in one liter of DCE. PMID- 29147524 TI - Manipulation of cytokine secretion in human dendritic cells using glycopolymers with picomolar affinity for DC-SIGN. AB - The human C-type lectin DC-SIGN (CD209) is a significant receptor on the surface of dendritic cells (DCs) - crucial components of host defense that bridge the innate and adaptive immune systems. A range of linear glycopolymers, constructed via controlled radical polymerization techniques have been shown to interact with DC-SIGN with affinities in the physiologically active range. However, these first generation glycopolymers possess limited structural definition and their effects on DCs were not known. Here we report the development of star-shaped mannose glycopolymers with the aim of targeting the clustered domain arrangement of DC SIGN and these were shown to bind with picomolar affinity. Increased secretion of IL-10 with simultaneous decrease in secreted IL-12p70 occurred in activated DCs incubated with star-shaped glycopolymers - a cytokine secretion pattern characteristic of wound-healing tissue environments. Incorporating stellar architecture into glycopolymer design could be key to developing selective and very high-affinity therapeutic materials with distinct immunomodulatory and tissue repair potential. PMID- 29147525 TI - Multi-component hybrid hydrogels - understanding the extent of orthogonal assembly and its impact on controlled release. AB - This paper reports self-assembled multi-component hybrid hydrogels including a range of nanoscale systems and characterizes the extent to which each component maintains its own unique functionality, demonstrating that multi-functionality can be achieved by simply mixing carefully-chosen constituents. Specifically, the individual components are: (i) pH-activated low-molecular-weight gelator (LMWG) 1,3;2,4-dibenzylidenesorbitol-4',4''-dicarboxylic acid (DBS-COOH), (ii) thermally activated polymer gelator (PG) agarose, (iii) anionic biopolymer heparin, and (iv) cationic self-assembled multivalent (SAMul) micelles capable of binding heparin. The LMWG still self-assembles in the presence of PG agarose, is slightly modified on the nanoscale by heparin, but is totally disrupted by the micelles. However, if the SAMul micelles are bound to heparin, DBS-COOH self-assembly is largely unaffected. The LMWG endows hybrid materials with pH-responsive behavior, while the PG provides mechanical robustness. The rate of heparin release can be controlled through network density and composition, with the LMWG and PG behaving differently in this regard, while the presence of the heparin binder completely inhibits heparin release through complexation. This study demonstrates that a multi-component approach can yield exquisite control over self-assembled materials. We reason that controlling orthogonality in such systems will underpin further development of controlled release systems with biomedical applications. PMID- 29147527 TI - Mechanistic analysis of a copper-catalyzed C-H oxidative cyclization of carboxylic acids. AB - We recently reported that carboxylic acids can be oxidized to lactone products by potassium persulfate and catalytic copper acetate. Here, we unravel the mechanism for this C-H functionalization reaction using desorption electrospray ionization, online electrospray ionization, and tandem mass spectrometry. Our findings suggest that electron transfer from a transient benzylic radical intermediate reduces Cu(ii) to Cu(i), which is then re-oxidized to Cu(ii) in the catalytic cycle. The resulting benzylic carbocation is trapped by the pendant carboxylate group to give the lactone product. Formation of the putative benzylic carbocation is supported by Hammett analysis. The proposed mechanism for this copper catalyzed oxidative cyclization process differs from earlier reports of analogous reactions, which posit a substrate carboxylate radical as the reactive oxidant. PMID- 29147526 TI - A ratiometric fluorescent probe for imaging and quantifying anti-apoptotic effects of GSH under temperature stress. AB - Hypothermia and hyperthermia are cell stressed states resulting from environmental temperature changes, which can abnormally decrease intracellular glutathione (GSH) concentrations and induce apoptosis. As the most abundant intracellular non-protein biothiol, GSH can protect cells from apoptosis. Considering the important roles of GSH in the anti-apoptotic process in cells and in vivo, we strive to develop a powerful chemical tool for the direct detection of GSH concentration changes under temperature stress. Herein, we report a ratiometric fluorescent probe (CyO-Dise) based on a selenium-sulfur exchange reaction for the qualitative and quantitative detection of GSH concentration fluctuations in cells and in vivo. The probe has been successfully used to assess the changes of GSH levels in HepG2 and HL-7702 cells using the stimulations of hypothermia and hyperthermia. In terms of the anti-apoptotic effect of GSH under hypothermic and hyperthermic conditions, human normal liver HL-7702 cells have stronger abilities to fight against temperature stress than human liver carcinoma HepG2 cells. Hypothermia and hyperthermia can also improve the drug resistance of cis-dichlorodiamineplatinum(ii) (DDP)-resistant HepG2/DDP cells. The CyO-Dise probe has been employed to image GSH concentration changes in HepG2 and HepG2/DDP xenografts on nude mice. With the adjuvant therapy effects of hypothermia and hyperthermia, the chemotherapy drug DDP exhibits good ability for the treatment of HepG2 and HepG2/DDP xenografts. The above applications make our probe a potential new candidate for the accurate diagnosis of cancer and efficacy evaluation of treatment. PMID- 29147528 TI - Room temperature C(sp2)-H oxidative chlorination via photoredox catalysis. AB - Photoredox catalysis has been developed to achieve oxidative C-H chlorination of aromatic compounds using NaCl as the chlorine source and Na2S2O8 as the oxidant. The reactions occur at room temperature and exhibit exclusive selectivity for C(sp2)-H bonds over C(sp3)-H bonds. The method has been used for the chlorination of a diverse set of substrates, including the expedited synthesis of key intermediates to bioactive compounds and a drug. PMID- 29147529 TI - Ratiometric photoacoustic imaging of endoplasmic reticulum polarity in injured liver tissues of diabetic mice. AB - As one of the complications of diabetes, liver injury results in significant hazards. Therefore, accurately diagnosing diabetes-induced liver injury beforehand is crucial for the warning and treatment of hepatic diseases. Diabetes induced liver injury can cause changes in the microstructure and morphology of liver tissue, leading to changes in the hydrophilic and hydrophobic domains in the endoplasmic reticulum (ER), which is closely associated with changes in cellular ER polarity. So, differences in the ER polarity can indicate the degree of diabetes-induced liver injury. Herein, we develop a new fluorescent and photoacoustic dual-mode probe, ER-P, for detection of the ER polarity of liver tissue in normal and diabetic mice. Upon excitation with a 633 nm laser, ER-P showed increasing fluorescence intensity at 800 nm accompanying a decline in the polarity. Due to its polarity-sensitivity, ER-P was utilized for confocal fluorescence imaging in live cells, and the results demonstrate that ER-P can exclusively accumulate in the ER and indicate an increase in the polarity during ER stress. Importantly, ER-P displayed different absorbance intensities at 700 nm and 800 nm in different polarity environments because of intramolecular charge transfer. The photoacoustic intensity ratios between 700 nm and 800 nm will enable quantification of polarity to be achieved. The ratiometric photoacoustic imaging data demonstrate that the polarity of the liver tissue of diabetic mice is higher than that of the liver tissue of normal mice. Meanwhile, after treatment with the antidiabetic drug metformin, diabetic mice exhibit a reduced polarity environment in their liver tissue. The proposed study may serve as a new approach for the early diagnosis and therapeutic evaluation of diabetes-induced liver injury. PMID- 29147530 TI - Programmed serial stereochemical relay and its application in the synthesis of morphinans. AB - Herein we report a rationally designed, serial point-to-axial and axial-to-point stereoinduction and its integration into multi-step and target-oriented organic synthesis. In this proof-of-concept study, the configurational stability of several carefully designed atropisomeric intermediates and the fidelity of their unconventional stereoinductions were systematically investigated. The highly functionalized prepared synthetic intermediate was further applied in a novel chemical method to access the morphinans and it is potentially applicable to other structurally related alkaloids. PMID- 29147532 TI - Copper-catalyzed cyanothiolation to incorporate a sulfur-substituted quaternary carbon center. AB - Sulfur-containing nitriles have important research value in the life sciences due to their diverse biological activities resulting from the sulfur and cyano functional groups. Herein, a copper-catalyzed cyanothiolation of N tosylhydrazones with thiocyanates to generate alpha-arylthioalkanenitriles bearing sulfur-substituted quaternary carbon center atoms has been described. This novel protocol involves the procedure of copper carbene species promoting S CN bond cleavage and C-CN/C-S bond reconstruction to introduce both sulfur and cyano groups onto a single carbon center. This cyanothiolation reaction will greatly enhance the synthetic utility of carbenoid species as new entries for the construction of diverse heteroatom-containing nitriles via cyanofunctionalization of metal-carbene species. PMID- 29147531 TI - Catalysis of a 1,3-dipolar reaction by distorted DNA incorporating a heterobimetallic platinum(ii) and copper(ii) complex. AB - A novel catalytic system based on covalently modified DNA is described. This catalyst promotes 1,3-dipolar reactions between azomethine ylides and maleimides. The catalytic system is based on the distortion of the double helix of DNA by means of the formation of Pt(ii) adducts with guanine units. This distortion, similar to that generated in the interaction of DNA with platinum chemotherapeutic drugs, generates active sites that can accommodate N-metallated azomethine ylides. The proposed reaction mechanism, based on QM(DFT)/MM calculations, is compatible with thermally allowed concerted (but asynchronous) [pi4s + pi2s] mechanisms leading to the exclusive formation of racemic endo cycloadducts. PMID- 29147533 TI - What is the fundamental ion-specific series for anions and cations? Ion specificity in standard partial molar volumes of electrolytes and electrostriction in water and non-aqueous solvents. AB - The importance of electrolyte solutions cannot be overstated. Beyond the ionic strength of electrolyte solutions the specific nature of the ions present is vital in controlling a host of properties. Therefore ion specificity is fundamentally important in physical chemistry, engineering and biology. The observation that the strengths of the effect of ions often follows well established series suggests that a single predictive and quantitative description of specific-ion effects covering a wide range of systems is possible. Such a theory would revolutionise applications of physical chemistry from polymer precipitation to drug design. Current approaches to understanding specific-ion effects involve consideration of the ions themselves, the solvent and relevant interfaces and the interactions between them. Here we investigate the specific ion effects trends of standard partial molar volumes and electrostrictive volumes of electrolytes in water and eleven non-aqueous solvents. We choose these measures as they relate to bulk properties at infinite dilution, therefore they are the simplest electrolyte systems. This is done to test the hypothesis that the ions alone exhibit a specific-ion effect series that is independent of the solvent and unrelated to surface properties. The specific-ion effects trends of standard partial molar volumes and normalised electrostrictive volumes examined in this work show a fundamental ion-specific series that is reproduced across the solvents, which is the Hofmeister series for anions and the reverse lyotropic series for cations, supporting the hypothesis. This outcome is important in demonstrating that ion specificity is observed at infinite dilution and demonstrates that the complexity observed in the manifestation of specific-ion effects in a very wide range of systems is due to perturbations of solvent, surfaces and concentration on the underlying fundamental series. This knowledge will guide a general understanding of specific-ion effects and assist in the development of a quantitative predictive theory of ion specificity. PMID- 29147534 TI - Nucleophilic addition and substitution at coordinatively saturated boron by facile 1,2-hydrogen shuttling onto a carbene donor. AB - The reaction of [(cAACMe)BH3] (cAACMe = 1-(2,6-iPr2C6H3)-3,3,5,5 tetramethylpyrrolidin-2-ylidene) with a range of organolithium compounds led to the exclusive formation of the corresponding (dihydro)organoborates, Li+[(cAACMeH)BH2R]- (R = sp3-, sp2-, or sp-hybridised organic substituent), by migration of one boron-bound hydrogen atom to the adjacent carbene carbon of the cAAC ligand. A subsequent deprotonation/salt metathesis reaction with Me3SiCl or spontaneous LiH elimination yielded the neutral cAAC-supported mono(organo)boranes, [(cAACMe)BH2R]. Similarly the reaction of [(cAACMe)BH3] with a neutral donor base L resulted in adduct formation by shuttling one boron-bound hydrogen to the cAAC ligand, to generate [(cAACMeH)BH2L], either irreversibly (L = cAACMe) or reversibly (L = pyridine). Variable-temperature NMR data and DFT calculations on [(cAACMeH)BH2(cAACMe)] show that the hydrogen on the former carbene carbon atom exchanges rapidly with the boron-bound hydrides. PMID- 29147535 TI - A platform for high-throughput screening of DNA-encoded catalyst libraries in organic solvents. AB - We have developed a novel high-throughput screening platform for the discovery of small-molecules catalysts for bond-forming reactions. The method employs an in vitro selection for bond-formation using amphiphilic DNA-encoded small molecules charged with reaction substrate, which enables selections to be conducted in a variety of organic or aqueous solvents. Using the amine-catalysed aldol reaction as a catalytic model and high-throughput DNA sequencing as a selection read-out, we demonstrate the 1200-fold enrichment of a known aldol catalyst from a library of 16.7-million uncompetitive library members. PMID- 29147536 TI - A complementary pair of enantioselective switchable organocatalysts. AB - A pair of enantioselective switchable bifunctional catalysts are shown to promote a range of conjugate addition reactions in up to 95 : 5 e.r. and 95% conversion. Each catalyst can be switched OFF using conditions that switch the other catalyst ON. Catalyst ON : OFF ratios of up to 98 : 2 and 1 : 99 were achieved, with a ratio of reaction rates of up to 16 : 1 between the ON and OFF states, maintained over complete ON-OFF-ON and OFF-ON-OFF cycles. However, simultaneous operation of the catalyst pair in the same reaction vessel, which in principle could allow product handedness to be switched by simple E-Z isomerisation of the catalyst pair, was unsuccessful. In this first generation complementary pair of enantioselective switchable organocatalysts, the OFF state of one catalyst inhibits the ON state of the other. PMID- 29147537 TI - Fluorinated molecular beacons as functional DNA nanomolecules for cellular imaging. AB - Molecular beacons (MBs) are simple, but practical, fluorescent nanoprobes widely used to detect small molecules, nucleic acids and proteins. However, some challenges still remain when MBs are employed in complex biological environments, such as instability and non-target interference. To meet such challenges, we have designed and synthesized fluorinated molecular beacons (FMBs) as functional DNA nanomolecules for cellular imaging, in which the stem sequence is simply composed of artificial nucleotides with 3,5-bis(trifluoromethyl)benzene (F) as the surrogate base of natural A, T, C and G bases. The introduction of F base into MBs significantly increases their hydrophobicity, and the stem is formed by the assembly of self-complementary base F nucleotides through hydrophobic interactions. Fluorescence studies revealed that FMBs confer improved stability over conventional MBs. To demonstrate the application of FMBs for cellular imaging, we constructed an FMB to detect mRNA in MCF-7 cells, and the FMB was proven to be a practical nanoprobe for cellular imaging of mRNA. PMID- 29147538 TI - Scaling behaviour and rate-determining steps in filamentous self-assembly. AB - The formation of filaments from naturally occurring protein molecules is a process at the core of a range of functional and aberrant biological phenomena, such as the assembly of the cytoskeleton or the appearance of aggregates in Alzheimer's disease. The macroscopic behaviour associated with such processes is remarkably diverse, ranging from simple nucleated growth to highly cooperative processes with a well-defined lagtime. Thus, conventionally, different molecular mechanisms have been used to explain the self-assembly of different proteins. Here we show that this range of behaviour can be quantitatively captured by a single unifying Petri net that describes filamentous growth in terms of aggregate number and aggregate mass concentrations. By considering general features associated with a particular network connectivity, we are able to establish directly the rate-determining steps of the overall aggregation reaction from the system's scaling behaviour. We illustrate the power of this framework on a range of different experimental and simulated aggregating systems. The approach is general and will be applicable to any future extensions of the reaction network of filamentous self-assembly. PMID- 29147539 TI - Reversible control of cell membrane receptor function using DNA nano-spring multivalent ligands. AB - Chemically functionalized and nanostructured materials, which mimic the features of the natural extracellular matrix, provide a tool to organize cell surface receptors into nanoscale clusters and manipulate cell functions. However, the existing materials are mainly based on static structures. Herein, we developed a DNA based structure-switchable and multivalent material that acts as a 'nano spring', enabling reversible control of membrane receptor function at the cell surface. This 'nano-spring' can be easily synthesized by rolling circle amplification and finely tuned by changing the circular template design. Using this 'nano-spring' to interact with cells, we have demonstrated that the movement of the DNA nanostructure is sufficient to direct a cell morphology change from the normal morphology to having numerous cell protrusions and affect the mRNA expression level of integrin related genes. This DNA nano-spring structure can be a competitive material for actively manipulating cell receptor function and may help us to understand the role of receptor mediated signalling cascades. PMID- 29147540 TI - Catalyst-controlled polycondensation of glycerol with diacyl chlorides: linear polyesters from a trifunctional monomer. AB - Diarylborinic acids catalyze the formation of linear polyesters from glycerol, a trifunctional, carbohydrate-based monomer. The selective activation of 1,2-diols over isolated alcohols by the organoboron catalyst results in polymers that are essentially free of branching or cross-linking and possess a high fraction of 1,3 enchained glycerol units, as assessed by 1H and 13C NMR spectroscopy. The ability to generate well-defined polyester architectures from glycerol is significant in light of the numerous applications of such macromolecules, particularly in the biomedical area. Isomerization, post-polymerization functionalization and controlled cross-linking reactions of the obtained linear poly(glycerol esters) are demonstrated. PMID- 29147541 TI - Dearomatization of electron poor six-membered N-heterocycles through [3 + 2] annulation with aminocyclopropanes. AB - Many abundant and highly bioactive natural alkaloids contain an indolizidine skeleton. A simple, high yielding method to synthesize this scaffold from N heterocycles was developed. A wide range of pyridines, quinolines and isoquinolines reacted with donor-acceptor (DA)-aminocyclopropanes via an ytterbium(iii) catalyzed [3 + 2] annulation reaction to give tetrahydroindolizine derivatives. The products were obtained with high diastereoselectivities (dr > 20 : 1) as anti-isomers. Additionally, the formed aminals could be easily converted into secondary and tertiary amines through iminium formation followed by reduction or nucleophile addition. This transformation constitutes the first example of dearomatization of electron-poor six-membered heterocycles via [3 + 2] annulation with DA cyclopropanes. PMID- 29147542 TI - Photocatalytic oxidation of benzene to phenol using dioxygen as an oxygen source and water as an electron source in the presence of a cobalt catalyst. AB - Photocatalytic hydroxylation of benzene to phenol by dioxygen (O2) occurs under visible light irradiation of an O2-saturated acetonitrile solution containing [RuII(Me2phen)3]2+ as a photocatalyst, [CoIII(Cp*)(bpy)(H2O)]2+ as an efficient catalyst for both the water oxidation and benzene hydroxylation reactions, and water as an electron source in the presence of Sc(NO3)3. The present study reports the first example of photocatalytic hydroxylation of benzene with O2 and H2O, both of which are the most green reagents, under visible light irradiation to afford a high turnover number (e.g., >500). Mechanistic studies revealed that the photocatalytic reduction of O2 to H2O2 is the rate-determining step, followed by efficient catalytic hydroxylation of benzene to phenol with H2O2, paving a new way for the photocatalytic oxygenation of substrates by O2 and water. PMID- 29147543 TI - Combining the catalytic enantioselective reaction of visible-light-generated radicals with a by-product utilization system. AB - We report an unusual reaction design in which a chiral bis-cyclometalated rhodium(iii) complex enables the stereocontrolled chemistry of photo-generated carbon-centered radicals and at the same time catalyzes an enantioselective sulfonyl radical addition to an alkene. Specifically, employing inexpensive and readily available Hantzsch esters as the photoredox mediator, Rh-coordinated prochiral radicals generated by a selective photoinduced single electron reduction are trapped by allyl sulfones in a highly stereocontrolled fashion, providing radical allylation products with up to 97% ee. The hereby formed fragmented sulfonyl radicals are utilized via an enantioselective radical addition to form chiral sulfones, which minimizes waste generation. PMID- 29147544 TI - Synthesis of azasilacyclopentenes and silanols via Huisgen cycloaddition initiated C-H bond insertion cascades. AB - An unusual transition metal-free cascade reaction of alkynyl carbonazidates was discovered to form azasilacyclopentenes. Mild thermolysis afforded the products via a series of cyclizations, rearrangements, and an alpha-silyl C-H bond insertion (rather than the more common Wolff rearrangement, 1,2-shift, or beta silyl C-H insertion) to form silacyclopropanes. A mechanistic proposal for the sequence was informed by control experiments and the characterization of reaction intermediates. The substrate scope and post-cascade transformations were also explored. PMID- 29147545 TI - Protein labeling for live cell fluorescence microscopy with a highly photostable renewable signal. AB - We present protein-PAINT - the implementation of the general principles of PAINT (Point Accumulation for Imaging in Nanoscale Topography) for live-cell protein labeling. Our method employs the specific binding of cell-permeable fluorogenic dyes to genetically encoded protein tags. We engineered three mutants of the bacterial lipocalin Blc that possess different affinities to a fluorogenic dye and exhibit a strong increase in fluorescence intensity upon binding. This allows for rapid labeling and washout of intracellular targets on a time scale from seconds to a few minutes. We demonstrate an order of magnitude higher photostability of the fluorescence signal in comparison with spectrally similar fluorescent proteins. Protein-PAINT ensures prolonged super-resolution fluorescence microscopy of living cells in both single molecule detection and stimulated emission depletion regimes. PMID- 29147546 TI - Origins of high catalyst loading in copper(i)-catalysed Ullmann-Goldberg C-N coupling reactions. AB - A mechanistic investigation of Ullmann-Goldberg reactions using soluble and partially soluble bases led to the identification of various pathways for catalyst deactivation through (i) product inhibition with amine products, (ii) by product inhibition with inorganic halide salts, and (iii) ligand exchange by soluble carboxylate bases. The reactions using partially soluble inorganic bases showed variable induction periods, which are responsible for the reproducibility issues in these reactions. Surprisingly, more finely milled Cs2CO3 resulted in a longer induction period due to the higher concentration of the deprotonated amine/amide, leading to suppressed catalytic activity. These results have significant implications on future ligand development for the Ullmann-Goldberg reaction and on the solid form of the inorganic base as an important variable with mechanistic ramifications in many catalytic reactions. PMID- 29147547 TI - Multi-dimensional charge transport in supramolecular helical foldamer assemblies. AB - Aromatic foldamers are bioinspired architectures whose potential use in materials remains largely unexplored. Here we report our investigation of vertical and horizontal charge transport over long distances in helical oligo quinolinecarboxamide foldamers organized as single monolayers on Au or SiO2. Conductive atomic force microscopy showed that vertical conductivity is efficient and that it displays a low attenuation with foldamer length (0.06 A-1). In contrast, horizontal charge transport is found to be negligible, demonstrating the strong anisotropy of foldamer monolayers. Kinetic Monte Carlo calculations were used to probe the mechanism of charge transport in these helical molecules and revealed the presence of intramolecular through-space charge transfer integrals approaching those found in pentacene and rubrene crystals, in line with experimental results. Kinetic Monte Carlo simulations of charge hopping along the foldamer chain evidence the strong contribution of multiple 1D and 3D pathways in these architectures and their dependence on conformational order. These findings show that helical foldamer architectures may provide a route for achieving charge transport over long distance by combining multiple charge transport pathways. PMID- 29147548 TI - Automaticity in Stimulus-Parity Synaesthesia. AB - Automaticity is a defining characteristic of synaesthesia. Here, we assess for automaticity in stimulus-parity synaesthesia; a subtype that has been documented only 3 times in the literature. Synaesthete R experiences many (nonnumerical) stimuli as being odd or even. She described a toy shape-sorter, which paired odd shapes with even colour slots (and vice versa) and relayed difficulties with the incongruency created by this simple toy. Inspired by this anecdote, we devised a computerised task in which Synaesthete R (and 10 control participants) indicated the location of a target shape, which was presented on a coloured bar. Synaesthete R (but not control participants) was faster to report the location of target shapes presented on colours of congruent synaesthetic parity, relative to target shapes presented on colours of incongruent synaesthetic parity. These results constitute the first objective demonstration as to the automatic nature of associations in stimulus-parity synaesthesia. PMID- 29147549 TI - Redox-sensitive reversible self-assembly of amino acid-naphthalene diimide conjugates. AB - Peptide and low molecular weight amino acid-based materials that self-assemble in response to environmental triggers are highly desirable candidates in forming functional materials with tunable biophysical properties. In this paper, we explore redox-sensitive self-assembly of cationic phenylalanine derivatives conjugated to naphthalene diimide (NDI). Self-assembly of the cationic Phe-NDI conjugates into nanofibrils was induced in aqueous solvent at high ionic strength. Under reducing conditions, these self-assembled Phe-NDI conjugate fibrils underwent a morphological change to non-fibril aggregates. Upon reoxidation, the initially observed fibrils were reformed. The study herein provides an interesting strategy to effect reversible switching of the structure of supramolecular materials that can be applied to the development of sophisticated stimulus-responsive materials. PMID- 29147550 TI - Self-assembly of nucleopeptides to interact with DNAs. AB - As a novel class of biomaterials, nucleopeptides, via the conjugation of nucleobases and peptides, usually self-assemble to form nanofibres driven mainly by hydrogen bonds. Containing nucleobase(s), nucleopeptides have a unique property-interacting with nucleic acids. Here we report the design and characterization of nucleopeptides that self-assemble in water and are able to interact with single-stranded DNAs (ssDNAs). Containing nucleobases on their side chains, these nucleopeptides bind with the ssDNAs, and the ssDNAs reciprocally affect the self-assembly of nucleopeptides. In addition, the interactions between nucleopeptides and ssDNAs also decrease their proteolytic resistance against proteinase K, which further demonstrates the binding with ssDNAs. The nucleopeptides also interact with plasmid DNA and deliver hairpin DNA into cells. This work illustrates a new and rational approach to create soft biomaterials by the integration of nucleobases and peptides to bind with DNA, which may lead to the development of nucleopeptides for controlling DNA in cells. PMID- 29147551 TI - Development of proteolytically stable N-methylated peptide inhibitors of aggregation of the amylin peptide implicated in type 2 diabetes. AB - Islet amyloid polypeptide, also known as amylin, is the main component of the amyloid deposits present in approximately 90% of people with type 2 diabetes mellitus (T2DM). In this disease, amylin aggregates into multimeric beta-pleated sheet structures which cause damage to pancreatic islet beta-cells. Inhibitors of early-stage amylin aggregation could therefore provide a disease-modifying treatment for T2DM. In this study, overlapping peptides were designed to target the 'binding' region (RLANFLVHSS, residues 11-20) of human amylin, and their effects on amyloid fibril formation were determined by thioflavin-T assay. The first generation peptides showed less than 50% inhibition of aggregation, but a second generation peptide (H2N-RGANFLVHGR-CONH2) showed strong inhibitory effects on amylin aggregation, and this was confirmed by negative stain electron microscopy. Cytotoxicity studies revealed that this peptide protected human pancreatic 1.4E7 (ECACC 10070102) insulin-secreting cells from the toxic effects of human amylin. Unlike the retro-inverso version of this peptide, which stimulated aggregation, two N-methylated peptides (H2N-RGAmNFmLVmHGR-CONH2 and H2N-RGANmFLmVHmR-CONH2) gave very clear dose-dependent inhibition of fibril formation. These two peptides were also stable against a range of different proteolytic enzymes, and in human plasma. These N-methylated peptides could provide a novel treatment for slowing progression of T2DM. PMID- 29147552 TI - Peptide-based ambidextrous bifunctional gelator: applications in oil spill recovery and removal of toxic organic dyes for waste water management. AB - A low molecular weight peptide-based ambidextrous gelator molecule has been discovered for efficient control of water pollution. The gelator molecules can gel various organic solvents with diverse polarity, e.g. n-hexane, n-octane, petroleum ether, petrol, diesel, aromatic solvents like chlorobenzene, toluene, benzene, o-xylene and even aqueous phosphate buffer of pH 7.5. These gels have been thoroughly characterized using various techniques including field emission scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray powder diffraction analysis, small angle X-ray scattering and rheological experiments. Interestingly, hydrogel obtained from the gelator molecule has been found to absorb toxic organic dyes (both cationic and anionic dyes) from dye contaminated water. The gelator molecule can be reused for several cycles, indicating its possible future use in waste water management. Moreover, this gelator can selectively gel petrol, diesel, pump oil from an oil-water mixture in the presence of a carrier solvent, ethyl acetate, suggesting its efficient application for oil spill recovery. These results indicate that the peptide-based ambidextrous gelator produces soft materials (gels) with dual function: (i) removal of toxic organic dyes in waste water treatment and (ii) oil spill recovery. PMID- 29147553 TI - Crafting of functional biomaterials by directed molecular self-assembly of triple helical peptide building blocks. AB - Collagen is the most abundant extracellular matrix protein in the body and has widespread use in biomedical research, as well as in clinics. In addition to difficulties in the production of recombinant collagen due to its high non natural imino acid content, animal-derived collagen imposes several major drawbacks-variability in composition, immunogenicity, pathogenicity and difficulty in sequence modification-that may limit its use in the practical scenario. However, in recent years, scientists have shifted their attention towards developing synthetic collagen-like materials from simple collagen model triple helical peptides to eliminate the potential drawbacks. For this purpose, it is highly desirable to develop programmable self-assembling strategies that will initiate the hierarchical self-assembly of short peptides into large-scale macromolecular assemblies with recommendable bioactivity. Herein, we tried to elaborate our understanding related to the strategies that have been adopted by few research groups to trigger self-assembly in the triple helical peptide system producing fascinating supramolecular structures. We have also touched upon the major epitopes within collagen that can be incorporated into collagen mimetic peptides for promoting bioactivity. PMID- 29147554 TI - Geometrical frustration as a potential design principle for peptide-based assemblies. AB - Two-dimensional peptide and protein assemblies have been the focus of increased scientific research as they display significant potential for the creation of functional nanomaterials. Soluble subunits derived from a variety of protein motifs have been demonstrated to self-assemble into structurally defined nanosheets under environmentally benign conditions in which the components often retain their native structure and function. These types of two-dimensional assemblies may have an advantage for nanofabrication in that their extended planar shapes can be more straightforwardly incorporated into the current formats of nanoscale devices. However, significant challenges remain in the fabrication of these materials, particularly in devising methods to control the size, shape and internal structure of the resultant materials. Geometrical frustration may be envisioned as a possible mechanism to exert control over these structural parameters through rational design. While this objective has yet to be realized in practice, we discuss in this article the potential role of geometrical frustration as a principle to rationalize unusual self-assembly behaviour in several examples of two-dimensional peptide assemblies. PMID- 29147556 TI - Mechanism of biosurfactant adsorption to oil/water interfaces from millisecond scale tensiometry measurements. AB - Many biological molecules are by their nature amphiphilic and have the ability to act as surfactants, stabilizing interfaces between aqueous and immiscible oil phases. In this paper, we explore the adsorption kinetics of surfactin, a naturally occurring cyclic lipopeptide, at hexadecane/water interfaces and compare and contrast its adsorption behaviour with that of synthetic alkyl benzene sulfonate isomers, through direct measurements of changes in interfacial tension upon surfactant adsorption. We access millisecond time resolution in kinetic measurements by making use of droplet microfluidics to probe the interfacial tension of hexadecane droplets dispersed in a continuous water phase through monitoring their deformation when the droplets are exposed to shear flows in a microfluidic channel with regular corrugations. Our results reveal that surfactin rapidly adsorbs to the interface, thus the interfacial tension equilibrates within 300 ms, while the synthetic surfactants used undergo adsorption processes at an approximately one order of magnitude longer timescale. The approach presented may provide opportunities for understanding and modulating the adsorption mechanism of amphiphiles on a variety of interfaces in the context of life sciences and industrial applications. PMID- 29147555 TI - What can machine learning do for antimicrobial peptides, and what can antimicrobial peptides do for machine learning? AB - Antimicrobial peptides (AMPs) are a diverse class of well-studied membrane permeating peptides with important functions in innate host defense. In this short review, we provide a historical overview of AMPs, summarize previous applications of machine learning to AMPs, and discuss the results of our studies in the context of the latest AMP literature. Much work has been recently done in leveraging computational tools to design new AMP candidates with high therapeutic efficacies for drug-resistant infections. We show that machine learning on AMPs can be used to identify essential physico-chemical determinants of AMP functionality, and identify and design peptide sequences to generate membrane curvature. In a broader scope, we discuss the implications of our findings for the discovery of membrane-active peptides in general, and uncovering membrane activity in new and existing peptide taxonomies. PMID- 29147557 TI - The diversity and utility of amyloid fibrils formed by short amyloidogenic peptides. AB - Amyloidogenic peptides are well known for their involvement in diseases such as type 2 diabetes and Alzheimer's disease. However, more recently, amyloid fibrils have been shown to provide scaffolding and protection as functional materials in a range of organisms from bacteria to humans. These roles highlight the incredible tensile strength of the cross-beta amyloid architecture. Many amino acid sequences are able to self-assemble to form amyloid with a cross-beta core. Here we describe our recent advances in understanding how sequence contributes to amyloidogenicity and structure. For example, we describe penta- and hexapeptides that assemble to form different morphologies; a 12mer peptide that forms fibrous crystals; and an eight-residue peptide originating from alpha-synuclein that has the ability to form nanotubes. This work provides a wide range of peptides that may be exploited as fibrous bionanomaterials. These fibrils provide a scaffold upon which functional groups may be added, or templated assembly may be performed. PMID- 29147558 TI - Discovery and design of self-assembling peptides. AB - Peptides are ubiquitous in nature and useful in many fields, from agriculture as pesticides, in medicine as antibacterial and antifungal drugs founded in the innate immune systems, to medicinal chemistry as hormones. However, the concept of peptides as materials was not recognized until 1990 when a self-assembling peptide as a repeating segment in a yeast protein was serendipitously discovered. Peptide materials are so called because they have bona fide materials property and are made from simple amino acids with well-ordered nanostructures under physiological conditions. These structures include well-ordered nanofibres, nanotubes and nanovesicles. These peptide materials have been used for: (i) three dimensional tissue cell cultures of primary cells and stem cells, (ii) three dimensional tissue printing, (iii) sustained releases of small molecules, growth factors, monoclonal antibody and siRNA, (iv) accelerated wound healing in reparative and regenerative medicine as well as tissue engineering, (v) used to stabilize membrane proteins including difficult G-protein coupled receptors and photosystem I for designing nanobiodevices, (vi) a few self-assembling peptides have been used in human clinical trials for accelerated wound healings in surgical uses and (vii) in human clinical trials for siRNA delivery for treatment of cancers. It is likely that these self-assembling peptides will open doors for more and more diverse uses. The field of self-assembling peptides is growing in a number of directions in areas of materials, synthetic biology, and clinical medicine and beyond. PMID- 29147560 TI - Correction to 'Why an extended evolutionary synthesis is necessary'. AB - [This corrects the article DOI: 10.1098/rsfs.2017.0015.]. PMID- 29147561 TI - Synthesis and reactivity of a 4His enzyme model complex. AB - A new iron(II) complex has been prepared and characterized. [Fe(TrIm)4(OTf)2] (1, TrIm = 1-Tritylimidazole). The solid state structure of 1 has been determined by X-ray crystallography. Compound 1 crystallizes in triclinic space group P1, with a = 13.342(7) A, b = 13.5131(7) A and c = 13.7025(7) A. The iron center resides in distorted octahedral geometry coordinated to four equatorial imidazole groups and two axial triflate oxygens groups. The complex is high spin between 20 K and 300 K as indicated by variable field variable temperature magnetic measurements. A fit of the magnetic data yielded g = 2.24 and D = -0.80 cm-1. A large HOMO-LUMO gap energy (3.89 eV) exists for 1 indicating high stability. Addition of H2O2 or t BuOOH to 1 results in formation of an oxygenated intermediate which upon decomposition results in oxidation of the trityl substituent on the imidazole ligand. PMID- 29147562 TI - Cognitive computing and eScience in health and life science research: artificial intelligence and obesity intervention programs. AB - Objective: To present research models based on artificial intelligence and discuss the concept of cognitive computing and eScience as disruptive factors in health and life science research methodologies. Methods: The paper identifies big data as a catalyst to innovation and the development of artificial intelligence, presents a framework for computer-supported human problem solving and describes a transformation of research support models. This framework includes traditional computer support; federated cognition using machine learning and cognitive agents to augment human intelligence; and a semi-autonomous/autonomous cognitive model, based on deep machine learning, which supports eScience. Results: The paper provides a forward view of the impact of artificial intelligence on our human computer support and research methods in health and life science research. Conclusions: By augmenting or amplifying human task performance with artificial intelligence, cognitive computing and eScience research models are discussed as novel and innovative systems for developing more effective adaptive obesity intervention programs. PMID- 29147563 TI - A novel microaneurysms detection approach based on convolutional neural networks with reinforcement sample learning algorithm. AB - Microaneurysms (MAs) are known as early signs of diabetic-retinopathy which are called red lesions in color fundus images. Detection of MAs in fundus images needs highly skilled physicians or eye angiography. Eye angiography is an invasive and expensive procedure. Therefore, an automatic detection system to identify the MAs locations in fundus images is in demand. In this paper, we proposed a system to detect the MAs in colored fundus images. The proposed method composed of three stages. In the first stage, a series of pre-processing steps are used to make the input images more convenient for MAs detection. To this end, green channel decomposition, Gaussian filtering, median filtering, back ground determination, and subtraction operations are applied to input colored fundus images. After pre-processing, a candidate MAs extraction procedure is applied to detect potential regions. A five-stepped procedure is adopted to get the potential MA locations. Finally, deep convolutional neural network (DCNN) with reinforcement sample learning strategy is used to train the proposed system. The DCNN is trained with color image patches which are collected from ground-truth MA locations and non-MA locations. We conducted extensive experiments on ROC dataset to evaluate of our proposal. The results are encouraging. PMID- 29147559 TI - Factors affecting the physical stability (aggregation) of peptide therapeutics. AB - The number of biological therapeutic agents in the clinic and development pipeline has increased dramatically over the last decade and the number will undoubtedly continue to increase in the coming years. Despite this fact, there are considerable challenges in the development, production and formulation of such biologics particularly with respect to their physical stabilities. There are many cases where self-association to form either amorphous aggregates or highly structured fibrillar species limits their use. Here, we review the numerous factors that influence the physical stability of peptides including both intrinsic and external factors, wherever possible illustrating these with examples that are of therapeutic interest. The effects of sequence, concentration, pH, net charge, excipients, chemical degradation and modification, surfaces and interfaces, and impurities are all discussed. In addition, the effects of physical parameters such as pressure, temperature, agitation and lyophilization are described. We provide an overview of the structures of aggregates formed, as well as our current knowledge of the mechanisms for their formation. PMID- 29147564 TI - A review of orexin's unprecedented potential as a novel, highly-specific treatment for various localized and metastatic cancers. AB - A systematic review was conducted to categorize the types of cancerous tissues that express orexin receptors and also to examine the effect of in vitro administration of orexin A or B to corresponding cell samples. Comprehensive literature analyses of primary experimental studies were performed. The results of the review included an increased frequency of orexin receptor expression in many colon and prostate cancer tissues and an upward trend of pro-apoptotic activity in these aggressive cell types. PMID- 29147565 TI - Operating room central serous chorioretinopathy. AB - Objectives: The operating room is a place of surgical intervention with its accompanying bodily and cognitive strain on the performers. Stress in the operating room may lead to the onset of central serous chorioretinopathy as reported hereby in a retina surgeon and is labeled as operating room central serous chorioretinopathy. Methods: The same operator performed the optical coherence tomography scans on one retina surgeon. A masked observer estimated the maximal height of the subretinal fluid. Results: Central serous chorioretinopathy recurred four times over a 1-year period 1 -2 days after a stressful day in the operating room, especially when cases were done under topical or subtenon anesthesia for cataract surgery, vitreous surgery or combined surgeries with complex ocular and medical problems and inability for anesthesia team to intervene. Stress management allowed resolution of subretinal fluid between 3 and 4 weeks. Adopting this strategy, no further attacks were documented by optical coherence tomography for 5 years. Conclusions: (1) This is one of a few optical coherence tomography documentation of resolution of central serous chorioretinopathy within 3-4 weeks of its occurrence and its recurrence induced by stress in the operating room; (2) Unassisted topical anesthesia required in patients with complex medical and ocular problems causes more cognitive stress than when surgery is carried under assisted local or general anesthesia (partly due to unexpected ocular or bodily movements); and (3) the available evidence suggests that those overcommitted surgeons (type A personality) may very well be most susceptible to burnout and central serous chorioretinopathy. PMID- 29147566 TI - Diagnosis of stenosis within the popliteal-femoral venous segment upon clinical presentation with a venous ulcer and subsequent successful treatment with venoplasty. AB - This case study reports the diagnosis and treatment of a lower limb venous ulcer with abnormal underlying venous pathology. One male patient presented with bilateral varicose veins and a right lower limb ulcer. Upon investigation, full leg duplex ultrasonography revealed total incompetence of the great saphenous vein in the left leg. In the right leg, duplex ultrasonography showed proximal incompetence of the small saphenous vein, and dilation of the anterior accessory saphenous vein, which remained competent. Incidentally, two venous collaterals connected onto the distal region of both these segments, emerging from a scarred, atrophic popliteal-femoral segment. An interventional radiologist performed venoplasty to this popliteal-femoral venous segment. Intervention was successful and 10 weeks post procedure ulceration healed. Popliteal-femoral venous stenosis may be associated with venous ulceration in some cases and may be successfully treated with balloon venoplasty intervention. PMID- 29147567 TI - Leriche syndrome: The inferior mesenteric artery saves the lower extremity. AB - Leriche syndrome presents as a triad of claudication, erectile dysfunction, and decreased distal pulses. This syndrome is a well-recognized entity in the current literature; however, our case report illustrates that even with a severe ostial lesion of the inferior mesenteric artery, the vessel was able to provide perfusion to bilateral lower extremities. The patient presented with symptoms of progressive pain in his right leg that limited his physical activity and he also complained of paresthesia, pallor, and cold skin with black discoloration of his toes bilaterally. Diagnostic testing confirmed Leriche syndrome and he successfully underwent surgical revascularization. PMID- 29147568 TI - Environmental influences on the skin microbiome of humans and cattle in rural Madagascar. AB - Background and objectives: The skin harbors a dynamic community of microorganisms, where contact with humans, other animals and the environment can alter microbial communities. Most research on the human skin microbiome features Western populations living in hygienic conditions, yet these populations have vastly different patterns of environmental contact than the majority of people on Earth, including those living in developing countries. Methodology: We studied skin microbial communities of humans and cattle (zebu) in rural Madagascar to investigate how zebu ownership affects microbial composition of the human skin, and to characterize non-Western human and zebu skin communities more generally. A portion of the 16S rRNA gene was sequenced from samples of zebu backs and human ankles, forearms, hands and armpits. Analyses were conducted in QIIME, R and LEfSe. Results: Human and zebu samples varied in microbial community composition, yet we did not find evidence for a shared microbial signature between an individual and his zebu. Microbial communities differed across human body sites, with ankles reflecting increased diversity and greater similarity to samples from zebu, likely due to extensive shared contact with soil by humans and zebu. Conclusions and implications: Cattle ownership had, at best, weak effects on the human skin microbiome. We suggest that components of human biology and lifestyles override the microbial signature of close contact with zebu, including genetic factors and human-human interaction, irrespective of zebu ownership. Understanding ecological drivers of microbial communities will help determine ways that microbial transfer and community composition change as populations adopt Western lifestyles, and could provide insights into zoonotic disease transmission. PMID- 29147569 TI - Growth hormone insensitivity: Mexican case report. AB - : Herein, we present a 14-year-old patient with short stature (134 cm) referred from Paediatrics to our department for complementary evaluation since growth hormone (GH) treatment failed to show any improvement. He was born premature and small for gestational age. Genital examination classified the patient as Tanner I II with small penis and testicular size for his age. Biochemical analyses revealed normal GH levels with low serum insulin-like growth factor-1 (IGF-1). Molecular diagnosis confirmed several mutations in IGF1R and IGFALS, and so he was diagnosed with Laron Syndrome or GH insensibility and treated with IGF-1 substitutive therapy. Learning points: Evaluation of the GH/IGF-1 axis when short stature does not respond to conservative treatment must be included in the ordinary practice.Laron Syndrome real incidence should be calculated once undiagnosed cases arise, as treatment, due to lack of market, is unaffordable.Even when adulthood is reached, and no longitudinal growth can be achieved, still IGF-1 treatment in Laron Syndrome patients should be pursued as metabolic and protective derangements could arise. PMID- 29147570 TI - Management of an acute catecholamine-induced cardiomyopathy and circulatory collapse: a multidisciplinary approach. AB - : A phaeochromocytoma (PC) is a rare, catecholamine-secreting neuroendocrine tumour arising from the adrenal medulla. Presenting symptoms of this rare tumour are highly variable but life-threatening multiorgan dysfunction can occur secondary to catecholamine-induced hypertension or hypotension and subsequent cardiovascular collapse. High levels of circulating catecholamines can induce an acute stress cardiomyopathy, also known as Takotsubo cardiomyopathy. Recent studies have focused on early diagnosis and estimation of the prevalence of acute stress cardiomyopathy in patients with PC, but very little is reported about management of these complex cases. Here, we report the case of a 38-year-old lady who presented with an acute Takotsubo or stress cardiomyopathy and catecholamine crisis, caused by an occult left-sided 5 cm PC. The initial presenting crisis manifested with symptoms of severe headache and abdominal pain, triggered by a respiratory tract infection. On admission to hospital, the patient rapidly deteriorated, developing respiratory failure, cardiogenic shock and subsequent cardiovascular collapse due to further exacerbation of the catecholamine crisis caused by a combination of opiates and intravenous corticosteroid. An echocardiogram revealed left ventricular apical hypokinesia and ballooning, with an estimated left ventricular ejection fraction of 10-15%. Herein, we outline the early stabilisation period, preoperative optimisation and intraoperative management, providing anecdotal guidance for the management of this rare life threatening complication of PC. Learning points: A diagnosis of phaeochromocytoma should be considered in patients presenting with acute cardiomyopathy or cardiogenic shock without a clear ischaemic or valvular aetiology.Catecholamine crisis is a life-threatening medical emergency that requires cross-disciplinary expertise and management to ensure the best clinical outcome.After initial resuscitation, treatment of acute catecholamine-induced stress cardiomyopathy requires careful introduction of alpha-blockade followed by beta-blockade if necessary to manage beta-receptor-mediated tachycardia.Prolonged alpha-adrenergic receptor stimulation by high levels of circulating catecholamines precipitates arterial vasoconstriction and intravascular volume contraction, which can further exacerbate hypotension. Invasive pressure monitoring can aid management of intravascular volume in these complex patients. PMID- 29147571 TI - A surprising treatment response in a patient with rare isolated growth hormone deficiency, type IB. AB - : Isolated Growth Hormone Deficiency (IGHD) is a rare cause of short stature, treated with the standard regimen of subcutaneous synthetic growth hormone (GH). Patients typically achieve a maximum height velocity in the first year of treatment, which then tapers shortly after treatment is stopped. We report a case of a 9-year-old male who presented with short stature (<3rd percentile for age and race). Basal hormone levels showed undetectable serum IGF1. Skeletal wrist age was consistent with chronologic age. Cranial MRI revealed no masses or lesions. Provocative arginine-GH stimulation testing demonstrated a peak GH level of 1.4 ng/mL. Confirmatory genetic testing revealed a rare autosomal recessive single-nucleotide polymorphism (SNP) with mutational frequency of 2%. GH supplementation was started and pursued for 2 years, producing dramatically increased height velocity. This velocity persisted linearly through adolescence, several years after treatment had been discontinued. Final adult height was >95th percentile for age and race. In conclusion, this is a case of primary hypopituitarism with differential diagnosis of IGHD vs Idiopathic Short Stature vs Constitutional Growth Delay. This case supports two objectives: Firstly, it highlights the importance of confirmatory genetic testing in patients with suspected, though diagnostically uncertain, IGHD. Secondly, it demonstrates a novel secondary growth pattern with implications for better understanding the tremendous variability of GH treatment response. Learning points: GHD is a common cause of growth retardation, and IGHD is a specific subtype of GHD in which patients present solely with short stature.The standard treatment for IGHD is subcutaneous synthetic GH until mid-parental height is reached, with peak height velocity attained in the 1st year of treatment in the vast majority of patients.Genetic testing should be strongly considered in cases of diagnostic uncertainty prior to initiating treatment.Future investigations of GH treatment response that stratify by gene and specific mutation will help guide treatment decisions.Response to treatment in patients with IGHD is variable, with some patients demonstrating little to no response, while others are 'super responders.' PMID- 29147572 TI - Association of Neutrophil-to-Lymphocyte Ratio With Inflammation and Erythropoietin Resistance in Chronic Dialysis Patients. AB - Background: Neutrophil-to-lymphocyte ratio (NLR) was widely studied as a prognostic marker in various medical and surgical specialties, but its significance in nephrology is not yet established. Objective: We evaluated its accuracy as an inflammation biomarker in a dialysis population. Design setting: Single-center retrospective study. Patients: The records of all 550 patients who were treated with hemodialysis (HD) or peritoneal dialysis (PD) from September 2008 to March 2011 were included. Measurements: NLR was calculated from the monthly complete blood count. Methods: Association between NLR and markers of inflammation (C-reactive protein [CRP], serum albumin, and erythropoietin resistance index [ERI]) was measured using Spearman coefficient. Results: In total, 120 patients were eligible for the correlation analyses. We found a positive correlation between NLR and CRP (all patients: r = 0.45, P < .001; HD: r = 0.47, P < .001; PD: r = 0.48, P = .13). NLR and albumin were inversely correlated (r = -0.51, P < .001). Finally, high NLR was associated with a nonsignificant increased ERI, but we have not demonstrated a direct correlation. Limitations: CRP and albumin are not measured routinely and were ordered for a specific clinical reason leading to an indication bias. Also, no relationship with clinical outcome was established. Conclusions: NLR seems to be a good inflammatory biomarker in dialysis in addition to being easily available. However, controlled studies should be conducted to properly assess and validate NLR levels that would be clinically significant and relevant, as well as its prognostic significance and utility in a clinical setting. PMID- 29147573 TI - Risk factors for exertional rhabdomyolysis with renal stress. AB - Background: Exercise-induced rhabdomyolysis denotes the exertional damage of myocytes with leakage of sarcoplasmic content into the circulation. The purpose of this study was to determine important risk factors for the development of exertional rhabdomyolysis in a temperate climate and to study the renal effects of myoglobinuria. Methods: A cluster of eight military recruits was admitted to hospital due to exertional rhabdomyolysis with myoglobinuria. The patients were treated according to current guidelines with isotonic saline and alkalinisation of the urine. The eight patients were compared with a randomly selected control group of 26 healthy fellow recruits. All subjects responded to a standardised questionnaire. Results: There were little differences in baseline characteristics between patients and controls. In the present study, exercise intensity, duration and type were all significant determinants of exertional rhabdomyolysis in univariate models. However, in a multivariate model, high exercise intensity on day -1 was the only significant predictor of rhabdomyolysis (p=0.02). All patients had a stable serum creatinine and cystatin C. There was a significant increase in serum neutrophil gelatinase-associated lipocalin (NGAL) in the patients, suggesting renal stress. Conclusions: Sustained maximal intensity exercise is a crucial risk factor for rhabdomyolysis with gross pigmenturia. Elevated serum NGAL concentrations indicate the presence of renal stress. It appears to be possible to quantify the risk of rhabdomyolysis by means of a simple questionnaire. In the future, this may be used as a tool to prevent rhabdomyolysis. PMID- 29147574 TI - Generational comparisons (F1 versus F3) of vinclozolin induced epigenetic transgenerational inheritance of sperm differential DNA methylation regions (epimutations) using MeDIP-Seq. AB - Environmentally induced epigenetic transgenerational inheritance of disease and phenotypic variation has been shown to involve DNA methylation alterations in the germline (e.g. sperm). These differential DNA methylation regions (DMRs) are termed epimutations and in part transmit the transgenerational phenotypes. The agricultural fungicide vinclozolin exposure of a gestating female rat has previously been shown to promote transgenerational disease and epimutations in F3 generation (great-grand-offspring) animals. The current study was designed to investigate the actions of direct fetal exposure on the F1 generation rat sperm DMRs compared to the F3 transgenerational sperm DMRs. A protocol involving methylated DNA immunoprecipitation (MeDIP) followed by next-generation sequencing (Seq) was used in the current study. Bioinformatics analysis of the MeDIP-Seq data was developed and several different variations in the bioinformatic analysis were evaluated. Observations indicate needs to be considered. Interestingly, the F1 generation DMRs were found to be fewer in number and for the most part distinct from the F3 generation epimutations. Observations suggest the direct exposure induced F1 generation sperm DMRs appear to promote in subsequent generations alterations in the germ cell developmental programming that leads to the distinct epimutations in the F3 generation. This may help explain the differences in disease and phenotypes between the direct exposure F1 generation and transgenerational F3 generation. Observations demonstrate a distinction between the direct exposure versus transgenerational epigenetic programming induced by environmental exposures and provide insights into the molecular mechanisms involved in the epigenetic transgenerational inheritance phenomenon. PMID- 29147575 TI - Cell death and cell lysis are separable events during pyroptosis. AB - Although much insight has been gained into the mechanisms by which activation of the inflammasome can trigger pyroptosis in mammalian cells, the precise kinetics of the end stages of pyroptosis have not been well characterized. Using time lapse fluorescent imaging to analyze the kinetics of pyroptosis in individual murine macrophages, we observed distinct stages of cell death and cell lysis. Our data demonstrate that cell membrane permeability resulting from gasdermin D pore formation is coincident with the cessation of cell movement, loss of mitochondrial activity, and cell swelling, events that can be uncoupled from cell lysis. We propose a model of pyroptosis in which cell death can occur independently of cell lysis. The uncoupling of cell death from cell lysis may allow for better control of cytosolic contents upon activation of the inflammasome. PMID- 29147576 TI - Erlotinib intercalating pemetrexed/cisplatin versus erlotinib alone in Chinese patients with brain metastases from lung adenocarcinoma: a prospective, non randomised, concurrent controlled trial (NCT01578668). AB - Objective: Erlotinib has a synergistic effect with pemetrexed for treating non squamous non-small-cell lung cancer. We investigated the efficacy and safety of erlotinib (E) in combination with pemetrexed/cisplatin (E-P) in Chinese patients with lung adenocarcinoma with brain metastases. Design: Patients who were erlotinib-naive or pemetrexed-naive were assigned in parallel to receive either E or E-P. The primary endpoint was the intracranial overall response rate (ORRi). Results: Sixty-nine patients with lung adenocarcinoma with brain metastases received E (n=35) or E-P (n=34) from January 2012 to November 2014. Demographics and patient characteristics were well balanced between the two groups, including epidermal growth factor receptor (EGFR) status, sex, age, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, brain metastases and number of prior treatments. ORRi in the E-P arm was superior to that in the E arm (79% vs 48%, p=0.008). Compared with E as the first-line treatment, E-P was associated with better intracranial progression-free survival (PFSi, median: 9 vs 2 months, p=0.027) and systemic PFS (median: 8 vs 2 months, p=0.006). The most frequent E related adverse events were higher in the combination arm. No new safety signals were detected. The side effects were tolerable, and there were no drug-related deaths. Conclusion: Our study suggests that the E-P combination may be effective in Chinese patients with lung adenocarcinoma with brain metastases, with improved PFS in treatment-naive patients. Toxicities are tolerable, and there are more E related side effects. PMID- 29147577 TI - Nivolumab for NSCLC in Japanese patients: similar benefits, but beware of pneumonitis. PMID- 29147578 TI - Modelling historical changes in the force-of-infection of Chagas disease to inform control and elimination programmes: application in Colombia. AB - Background: WHO's 2020 milestones for Chagas disease include having all endemic Latin American countries certified with no intradomiciliary Trypanosoma cruzi transmission, and infected patients under care. Evaluating the variation in historical exposure to infection is crucial for assessing progress and for understanding the priorities to achieve these milestones. Methods: Focusing on Colombia, all the available age-structured serological surveys (undertaken between 1995 and 2014) were searched and compiled. A total of 109 serosurveys were found, comprising 83 742 individuals from rural (indigenous and non indigenous) and urban settings in 14 (out of 32) administrative units (departments). Estimates of the force-of-infection (FoI) were obtained by fitting and comparing three catalytic models using Bayesian methods to reconstruct temporal and spatial patterns over the course of three decades (between 1984 and 2014). Results: Significant downward changes in the FoI were identified over the course of the three decades, and in some specific locations the predicted current seroprevalence in children aged 0-5 years is <1%. However, pronounced heterogeneity exists within departments, especially between indigenous, rural and urban settings, with the former exhibiting the highest FoI (up to 66 new infections/1000 people susceptible/year). The FoI in most of the indigenous settings remain unchanged during the three decades investigated. Current prevalence in adults in these 15 departments varies between 10% and 90% depending on the dynamics of historical exposure. Conclusions: Assessing progress towards the control of Chagas disease requires quantifying the impact of historical exposure on current age-specific prevalence at subnational level. In Colombia, despite the evident progress, there is a marked heterogeneity indicating that in some areas the vector control interventions have not been effective, hindering the possibility of achieving interruption by 2020. A substantial burden of chronic cases remains even in locations where serological criteria for transmission interruption may have been achieved, therefore still demanding diagnosis and treatment interventions. PMID- 29147579 TI - autoimage: Multiple Heat Maps for Projected Coordinates. AB - Heat maps are commonly used to display the spatial distribution of a response observed on a two-dimensional grid. The autoimage package provides convenient functions for constructing multiple heat maps in unified, seamless way, particularly when working with projected coordinates. The autoimage package natively supports: 1. automatic inclusion of a color scale with the plotted image, 2. construction of heat maps for responses observed on regular or irregular grids, as well as non-gridded data, 3. construction of a matrix of heat maps with a common color scale, 4. construction of a matrix of heat maps with individual color scales, 5. projecting coordinates before plotting, 6. easily adding geographic borders, points, and other features to the heat maps. After comparing the autoimage package's capabilities for constructing heat maps to those of existing tools, a carefully selected set of examples is used to highlight the capabilities of the autoimage package. PMID- 29147580 TI - Molecular Age-Related Changes in the Anterior Segment of the Eye. AB - Purpose: To examine the current knowledge about the age-related processes in the anterior segment of the eye at a biological, clinical, and molecular level. Methods: We reviewed the available published literature that addresses the aging process of the anterior segment of the eye and its associated molecular and physiological events. We performed a search on PubMed, CINAHL, and Embase using the MeSH terms "eye," "anterior segment," and "age." We generated searches to account for synonyms of these keywords and MESH headings as follows: (1) "Eye" AND "ageing process" OR "anterior segment ageing" and (2) "Anterior segment" AND "ageing process" OR "anterior segment" AND "molecular changes" AND "age." Results. Among the principal causes of age-dependent alterations in the anterior segment of the eye, we found the mutation of the TGF-beta gene and loss of autophagy in addition to oxidative stress, which contributes to the pathogenesis of degenerative diseases. Conclusions: In this review, we summarize the current knowledge regarding some of the molecular mechanisms related to aging in the anterior segment of the eye. We also introduce and propose potential roles of autophagy, an important mechanism responsible for maintaining homeostasis and proteostasis under stress conditions in the anterior segment during aging. PMID- 29147582 TI - Assessment of Weight Management Practices among Adults in the United Arab Emirates. AB - With a rise in global incidence of overweight and obesity, the number of patients seeking weight management (WM) advice is likely to increase. Our aim was to explore the prevalence of WM practices and investigate association of WM goals with sociodemographic variables and practices among United Arab Emirates (UAE) adults. An exploratory, cross-sectional research was conducted on 1275 adult males and females, residing in UAE. A structured questionnaire was administered. WM goals to lose/maintain/gain weight were reported in 88.3% participants. WM goals were significantly associated with age, sex, marital status, education, current body weight perception, and medical condition. Out of 21 selected WM practices, popular strategies included increasing physical activity (52.9%), eating less fat (51.1%), consuming fewer calories (43.3%), joining gym (27.5%), skipping meals (26.1%), and consuming natural herbs and teas (20.7%). Visiting dietitian (12.3%) ranked ninth in the order of preference. Males focused on physical activity, gyms, and wellness centers and females on calories counting, dietitian visits, meals replacement, skipping meals, and natural herbs/teas. Married adults reported eating less fat (54.3% versus 47.3%, p = 0.020); singles opted calories counting, gyms, and meals replacement. Frequent referral sources were friends (37.8%) and Internet (32.1%). Most UAE adults had WM goals that were associated with sociodemographic variables and WM practices. Awareness about the ill-effects of unhealthy WM practices and importance of dietitian's consultation are imperative. PMID- 29147583 TI - Patterns of Progression in Metastatic Estrogen Receptor Positive Breast Cancer: An Argument for Local Therapy. AB - Purpose: Despite advances in endocrine therapy (ET), metastatic estrogen receptor positive breast cancer (BrCA) remains incurable. Though the mechanisms of resistance to ET have been studied extensively, the anatomic pattern of disease progression remains poorly characterized. The purpose of this study was to characterize the pattern of progression for patients receiving ET for metastatic BrCA. Methods: The records of 108 patients with metastatic BrCA who progressed on ET were reviewed. Progression was characterized as follows: diffuse progression, progression in greater than 3 sites; oligoprogression, progression in fewer than 3 sites with prior diffuse metastases; and oligometastatic disease with progression, progression in 3 or fewer sites with prior limited metastases. Results: Seventy-four patients (69%) displayed only diffuse disease progression. Conversely, 23 patients (21%) displayed oligoprogression and 11 patients (10%) displayed oligometastases with progression at least once in their disease course. Further analysis of the patients with oligoprogression suggested that in 14 patients the sites of progression would have been amenable to local therapy. Conclusion: Oligoprogressive disease occurs in a significant subset of patients with metastatic BrCA treated with ET. These patients with oligoprogressive disease may be eligible for local therapy, potentially obviating the need to change of systemic therapy. PMID- 29147581 TI - Review of and Updates on Hypertension in Obstructive Sleep Apnea. AB - Obstructive sleep apnea (OSA) is a prevalent sleep disorder as is hypertension (HTN) in the 21st century with the rising incidence of obesity. Numerous studies have shown a strong association of OSA with cardiovascular morbidity and mortality. There is overwhelming evidence supporting the relationship between OSA and hypertension (HTN). The pathophysiology of HTN in OSA is complex and dependent on various factors such as sympathetic tone, renin-angiotensin aldosterone system, endothelial dysfunction, and altered baroreceptor reflexes. The treatment of OSA is multifactorial ranging from CPAP to oral appliances to lifestyle modifications to antihypertensive drugs. OSA and HTN both need prompt diagnosis and treatment to help address the growing cardiovascular morbidity and mortality due to these two entities. PMID- 29147584 TI - IL-33 Acts to Express Schaffer Collateral/CA1 LTP and Regulate Learning and Memory by Targeting MyD88. AB - Interleukin-33 (IL-33) is recognized to transmit a signal through a heterodimeric receptor complex ST2/interleukin-1 receptor accessory protein (IL-1RAcP) bearing activation of myeloid differentiation factor 88 (MyD88). High-frequency stimulation to the Schaffer collateral induced long-term potentiation (LTP) in the CA1 region of hippocampal slices from wild-type control mice. Schaffer collateral/CA1 LTP in IL-33-deficient mice was significantly suppressed, which was neutralized by application with IL-33. Similar suppression of the LTP was found with MyD88-deficient mice but not with ST2-deficient mice. In the water maze test, the acquisition latency in IL-33-deficient and MyD88-deficient mice was significantly prolonged as compared with that in wild-type control mice. Moreover, the retention latency in MyD88-deficient mice was markedly prolonged. In contrast, the acquisition and retention latencies in ST2-deficient mice were not affected. Taken together, these results show that IL-33 acts to express Schaffer collateral/CA1 LTP relevant to spatial learning and memory in a MyD88 dependent manner and that the LTP might be expressed through an IL-1R1/IL-1RAcP MyD88 pathway in the absence of ST2. PMID- 29147585 TI - Acute Exercise and Neurocognitive Development in Preadolescents and Young Adults: An ERP Study. AB - The purpose of this study was to examine the effect of a single bout of exercise on neurocognitive function in preadolescent children and young adults by determining the modulatory role of age and the neuroelectrical mechanism(s) underlying the association between acute exercise and executive function. Twenty preadolescents and 20 young adults completed the Stroop test, and neuroelectrical activity was recorded during two treatment sessions performed in a counterbalanced order. Exercise treatments involved moderate intensity aerobic exercise for 20 min as the main exercise and two 5 min periods of warm-up and cool-down. The control treatment participants read for a similar duration of time. Acute exercise improved participant reaction times on the Stroop test, regardless of Stroop congruency, and greater beneficial effects were observed in young adults compared to those in preadolescents. The P3 amplitudes increased after acute exercise in preadolescents and young adults, but acute exercise induced lower conflict sustained potential (conflict SP) amplitudes in preadolescent children. Based on these findings, age influences the beneficial effect of acute exercise on cognitive performance in general. Furthermore, the event-related brain potential differences attributed to acute exercise provide a potential clue to the mechanisms that differentiate the effects of acute exercise on individuals from preadolescence to young adulthood. PMID- 29147587 TI - Dexmedetomidine as Part of a Multimodal Analgesic Treatment Regimen for Opioid Induced Hyperalgesia in a Patient with Significant Opioid Tolerance. AB - Acute postoperative pain in patients with opioid tolerance creates a significant management challenge for anesthesiologists and pain medicine physicians. A multimodal approach is key; however other factors can complicate management such as opioid induced hyperalgesia. We present the case of a patient on large amounts of intrathecal opioids for chronic pain syndrome with opioid induced hyperalgesia after an exploratory laparotomy. Dexmedetomidine was utilized successfully as part of a controlled multimodal analgesic plan and should be a consideration for opioid tolerant patients experiencing opioid induced hyperalgesia. PMID- 29147586 TI - Corticospinal Plasticity in Bilateral Primary Motor Cortices Induced by Paired Associative Stimulation to the Dominant Hemisphere Does Not Differ between Young and Older Adults. AB - Older adults have been shown to exhibit a reduction in the lateralization of neural activity. Although neuroplasticity induced by noninvasive brain stimulation has been reported to be attenuated in the targeted motor cortex of older adults, it remains possible that the plasticity effects may instead manifest in a more distributed (bilateral) network. Furthermore, attention, which modulates neuroplasticity in young adults, may influence these effects. To address these questions, plasticity was induced in young (19-32 years) and older (65-78 years) adults using transcranial magnetic stimulation (TMS) paired with peripheral nerve stimulation. The plasticity effects induced by this paired associative stimulation (PAS) protocol in the targeted and nontargeted hemispheres were probed using TMS-induced motor-evoked potentials (MEPs) recorded from the abductor pollicis brevis (APB) muscle of each hand. PAS-induced effects were highly variable across individuals, with only half of the participants in each group demonstrating the expected increase in MEP amplitude. Contrary to predictions, however, PAS-induced corticospinal plasticity manifests predominately in the targeted hemisphere for both young and older adults. Attention to the target hand did not enhance corticospinal plasticity. The results suggest that plasticity does not manifest differently across bilateral corticospinal pathways between young and older adults. PMID- 29147588 TI - Diagnostic Challenge: A Report of Two Adult-Onset Still's Disease Cases. AB - This study reports two adult-onset Still's disease (AOSD) cases that met both Yamaguchi's and Fautrel's criteria and that presented with notable clinical manifestations. One case presented with atypical dermographism-like rash with an extremely high ferritin level. The other case presented with typical salmon-pink maculopapular rash but had atypical positive rheumatoid factor. This suggests that although negative rheumatoid factor is one of the criteria used for the diagnosis of AOSD, a positive rheumatoid factor result does not exclude AOSD. Beside a classic rash, characterized by transient salmon-pink maculopapular rash, we also find atypical dermographism-like rash. These findings remind us that there exist various types of rash from AOSD. PMID- 29147589 TI - gammadelta T-Cell Acute Lymphoblastic Leukemia/Lymphoma: Discussion of Two Pediatric Cases and Its Distinction from Other Mature gammadelta T-Cell Malignancies. AB - Gamma delta (gammadelta) T-cell antigen receptor (TCR) expression and its related T-cell differentiation are not commonly reported in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Here we report two pediatric T-ALL cases and present their clinical features, histology, immunophenotypes, cytogenetics, and molecular diagnostic findings. The first patient is a two-year-old girl with leukocytosis, circulating lymphoblasts, and a cryptic insertion of a short-arm segment at 10p12 into the long-arm segment of 11q23 resulting in an MLL and AF10 fusion transcript, which may be the first reported in gammadelta T-ALL. She responded to the chemotherapy protocol poorly and had persistent diseases. Following an allogeneic bone marrow transplant, she went into remission. The second patient is an eleven-year-old boy with a normal white cell count, circulating blasts, and a normal karyotype, but without any immature cellular markers by flow cytometric analysis. He responded to the chemotherapy well and achieved a complete remission. These cases demonstrate the diverse phenotypic, cytogenetic, and molecular aspects of gammadelta T-ALL. Early T-precursor- (ETP-) ALL and their differential diagnosis from other mature gammadelta T-cell leukemia/lymphomas are also discussed. PMID- 29147590 TI - Paroxysmal Nocturnal Hemoglobinuria in Pregnancy: A Dilemma in Treatment and Thromboprophylaxis. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a hematologic disorder characterized by an acquired somatic mutation in the phosphatidylinositol glycan class A gene which leads to a higher risk for increased venous and arterial thrombosis. Current treatment for PNH includes eculizumab. Pregnant patients who have PNH have higher risk for thrombosis and hemorrhage with both pregnancy and their underlying PNH. Treatment frequently poses conundrum. The safety and efficacy of eculizumab during pregnancy and breast feeding have not been extensively studied and contraception has been recommended due to potential for teratogenicity. We present a case of a patient who was safely on both eculizumab and modest prophylactic anticoagulation for 6 weeks post-partum. PMID- 29147591 TI - Upper Limb Deep Vein Thrombosis in Patient with Hemophilia A and Heterozygosity for Prothrombin G20210A: A Case Report and Review of the Literature. AB - Deep vein thrombosis (DVT) is a rare disease in patients with hemophilia A. We report a case of 22-year-old male with severe hemophilia A who presented to the emergency room with 5-day history of right arm pain that was attributed initially to bleeding event. In the absence of external signs of bleeding or hematoma and normal hemoglobin level, we suspected an underlying DVT. Doppler ultrasonography of the right upper limb revealed thrombosis of the subclavian vein and this was confirmed by CT venography. The d-dimer level was normal and investigations for prothrombotic state revealed heterozygosity for prothrombin G20210A mutation. Treatment with factor VIII and low molecular weight heparin led to successful resolution and marked improvement of his clinical condition. PMID- 29147592 TI - Unusual Presentation of a Small-Cell Variant of Anaplastic Large-Cell Lymphoma Case: When a Septic Picture Is Not Sepsis. AB - We report a case of a small-cell variant of anaplastic large-cell lymphoma, with an unusual clinical presentation mimicking sepsis and a fulminant clinic course, in a 48-year-old Caucasian female. In this report, we discuss the diagnostic challenge, histopathologic features, and unique cytogenetic features of this case, in order to raise awareness of this rare presentation and emphasize the importance of meticulous peripheral smear examination and early bone marrow evaluation. PMID- 29147593 TI - Rapidly Progressive Disseminated Sporotrichosis as the First Presentation of HIV Infection in a Patient with a Very Low CD4 Cell Count. AB - Sporotrichosis is a human and animal disease caused by species of the Sporothrix schenckii complex. It is classically acquired through traumatic inoculation of fungal elements. Most frequently, sporotrichosis presents as a fixed cutaneous or as a lymphocutaneous form. A much smaller number of cases occur as cutaneous disseminated and disseminated forms. These cases require immediate diagnosis and management to reduce morbidity and mortality. We present the case of a 34-year old male patient in whom the first presentation of HIV infection was a rapidly progressive sporotrichosis with multiple cutaneous lesions, a high fungal burden in tissues, and pulmonary involvement. He had an extremely low CD4 cell count (06/mm3). Treatment with amphotericin B deoxycholate led to complete clinical resolution. Sporotrichosis remains a neglected opportunistic infection among HIV infected patients in Rio de Janeiro state, Brazil, and awareness of this potentially fatal infection is of utmost importance if treatment is not to be delayed and if potentially devastating complications are to be avoided. PMID- 29147594 TI - Lactobacillus gasseri Causing Bilateral Empyema. AB - Lactobacilli are common commensal bacteria found in the gastrointestinal and genitourinary tract. Although they are usually thought to be nonpathogenic, there have been several cases that demonstrate severe infections caused by these microorganisms. This is a case of a 49-year-old male with previously undiagnosed type two diabetes mellitus who presented with a 3-month history of cough and was found to have right sided Lactobacillus gasseri empyema for which he underwent video-assisted thoracoscopic surgery (VATS) with chest tube placement. He subsequently developed a left sided pleural empyema for which the aspiration also grew out L. gasseri. The patient made a complete recovery and was seen for four months in follow-up after his initial presentation. PMID- 29147595 TI - Synchronous Ganglioneuroma and Schwannoma Mistaken for Carotid Body Tumor. AB - Ganglioneuromas are a very rare benign neural tumor, commonly derived from the ganglia of the sympathetic system, and are composed of mature Schwann cells, ganglion cells, and nerve fibres. They may arise anywhere from the base of the skull to the pelvis along the paravertebral sympathetic plexus. We report a rare case of synchronous ganglioneuroma and schwannoma, mistaken for carotid body tumor. The coexistence of these two entities in head and neck region is very rare. PMID- 29147596 TI - Carotidynia: A Rare Diagnosis for Unilateral Neck Pain Revealed by Cross Sectional Imaging. AB - Idiopathic carotidynia (IC) is a rare and poorly understood syndrome consisting of unilateral neck pain, tenderness, and increased pulsations over the affected carotid bifurcation. A growing body of evidence supports the hypothesis that IC is a distinct clinicopathologic entity with characteristic imaging features. We report the case of a 34-year-old Caucasian male presenting with intense unilateral neck pain in the emergency setting. Computed tomography and ultrasonography revealed fusiform eccentric thickening of the ipsilateral carotid bifurcation without vessel narrowing. Contrast-enhanced magnetic resonance imaging depicted major perivascular enhancement without evidence of dissection. Further imaging and laboratory work-up excluded vasculitis. The diagnosis of IC was made. The patient was treated with nonsteroidal anti-inflammatory drugs and symptoms and imaging findings disappeared within a few weeks. Cross-sectional imaging allows not only ruling out IC mimickers but also making the correct diagnosis of this rare condition, in particular, as the clinical presentation of IC is often nonspecific. PMID- 29147597 TI - Psychometric Evaluation of the Parkinson's Disease Activities of Daily Living Scale. AB - Objective: To evaluate a set of psychometric properties (i.e., data completeness, targeting, and external construct validity) of the Parkinson's disease Activities of Daily Living Scale (PADLS) in people with Parkinson's disease (PD). Specific attention was paid to the association between PADLS and PD severity, according to the Hoehn & Yahr (H&Y) staging. Methods: The sample included 251 persons with PD (mean age 70 [SD 9] years). Data collection comprised a self-administered postal survey, structured interviews, and clinical assessments at home visits. Results: Data completeness was 99.6% and the mean PADLS score was 2.1. Floor and ceiling effects were 22% and 2%, respectively. PADLS scores were more strongly associated (rs > 0.5) with perceived functional independence, ADL dependency, walking difficulties, and self-rated PD severity than with variables such as PD duration and cognitive function (rs < 0.5). PADLS scores differed across H&Y stages (Kruskal-Wallis test, p < 0.001). Those in H&Y stages IV-V had more ADL disability than those in stage III (Mann-Whitney U test, p < 0.001), whereas there were no significant differences between the other stages. Conclusion: PADLS revealed excellent data completeness, acceptable targeting, and external construct validity. It seems to be well suited as a rough estimate of ADL disability in people with PD. PMID- 29147598 TI - DBS Programming: An Evolving Approach for Patients with Parkinson's Disease. AB - Deep brain stimulation (DBS) surgery is a well-established therapy for control of motor symptoms in Parkinson's disease. Despite an appropriate targeting and an accurate placement of DBS lead, a thorough and efficient programming is critical for a successful clinical outcome. DBS programming is a time consuming and laborious manual process. The current approach involves use of general guidelines involving determination of the lead type, electrode configuration, impedance check, and battery check. However there are no validated and well-established programming protocols. In this review, we will discuss the current practice and the recent advances in DBS programming including the use of interleaving, fractionated current, directional steering of current, and the use of novel DBS pulses. These technological improvements are focused on achieving a more efficient control of clinical symptoms with the least possible side effects. Other promising advances include the introduction of computer guided programming which will likely impact the efficiency of programming for the clinicians and the possibility of remote Internet based programming which will improve access to DBS care for the patients. PMID- 29147599 TI - Prevalence of Dog Erythrocyte Antigen 1 in 7,414 Dogs in Italy. AB - The study aim was to establish the prevalence of DEA 1, the most immunogenic and clinically important blood group in canine blood transfusion, in 7,414 dogs from Italy. The potential sensitization risk following a first transfusion and the acute reaction risk following a second transfusion given without a cross-matching and blood typing test were also calculated. Dogs tested were purebred (4,798) and mongrel (2,616); 38.8% were DEA 1 negative and 61.2% were DEA 1 positive. High prevalence for DEA 1 positive blood type was found in Ariegeois and English Setter, whereas German Shepherd and Boxer had higher DEA 1 negative blood type. Breeds with blood type never reported before included French Brittany Spaniel and Pug showing a high prevalence of DEA 1 positive type, while French Bulldog and West Highland White Terrier were more often DEA 1 negative. Just 48.8% of purebred and 13.9% of mongrel dogs were considered as prospective blood donors based upon their blood type. Most of the breeds had a sensitization risk of 20.0 25.0%. Rottweiler and Ariegeois had less risk of sensitization (9.4 and 4.2%) and the minor risk of an acute transfusional reaction (0.9-0.2%). The prevalence of DEA 1 positive and negative dogs in Italy agrees with most of the data already reported in the literature. PMID- 29147600 TI - Osteoglophonic Dysplasia: Phenotypic and Radiological Clues. AB - Osteoglophonic dysplasia (OD) is an extremely rare, skeletal dysplasia with an autosomal dominant mode of inheritance. Rhizomelic dwarfism, craniosynostosis, impacted teeth, hypodontia or anodontia, and multiple nonossifying bone lesions are the salient features of this condition. We report a 14-year-old girl with clinical and radiological features consistent with OD. She presented with disproportionate short stature, craniosynostosis, a prominent supraorbital ridge, delayed teeth eruption, hypodontia, and multiple nonossifying bone lesions in the femur, tibia, and fibula. She had hypophosphatemia, which is a known association in this dysplasia. She also had advanced bone age, which is an unreported feature of this dysplasia. This condition is caused by activating mutations in FGFR1 . A missense mutation was detected in the FGFR1 , NM_001174067 ( FGFR1 _v001):c.1115G > A [p.(Cys372Tyr)] confirming the diagnosis; this is the first mutation-proven case to be reported from India. PMID- 29147601 TI - Tumor-infiltrating gammadeltaT cells predict prognosis and adjuvant chemotherapeutic benefit in patients with gastric cancer. AB - Purpose : Tumor-infiltrating gammadeltaT cells (gammadeltaTILs) have different prognostic value and functions among various cancers. The aim of the present study was to evaluate the effect of gammadeltaTILs in gastric cancer. Patients and methods : A discovery set (n = 190) and a validation set (n = 273) were involved in this study. Patients with TNM II and III disease were used to predict response to 5-fluorouracil (5-FU)-based adjuvant chemotherapy (ACT) in both sets. gammadeltaTILs were defined as intense (gammadeltaT cells>= 5/HPF) versus nonintense (gammadeltaT cells<5/HPF). Kaplan-Meier curve was plotted to analysis survival. Hazard ratio (HR) and 95%CI associated with gammadeltaTILs were evaluated by multivariable Cox models. Findings : The prognostic value of gammadeltaTILs in the discovery set (HR, 0.193; 95%CI, 0.097-0.383; P<0.001) was confirmed in the validation set (HR, 0.442; 95%CI, 0.251-0.779; P = 0.005) for overall survival (OS). Patients whose tumors with gammadeltaT cells>= 5/HPF could benefit from ACT, with a reduced risk of compromised survival compared with those with gammadeltaT cells<5/HPF (HR, 0.086; 95%CI, 0.023-0.327; P<0.001 in discovery set; and HR, 0.077; 95%CI, 0.023-0.256; P<0.001 in validation set). Conclusion : The present study shows that intense gammadeltaT cells infiltration is an independent prognostic factor in patients with gastric cancer and is predictive of a survival benefit from adjuvant chemotherapy in patients with TNM II and III disease. PMID- 29147602 TI - GDNF secreted by nerves enhances PD-L1 expression via JAK2-STAT1 signaling activation in HNSCC. AB - Programmed death ligand 1 (PD-L1) functions as a key immune inhibitory factor by binding with its receptor, programmed death 1 (PD-1), to induce immune cell dysfunction and escape of the immune system. However, the mechanisms of PD-L1 expression under growth factor stimulation are not well characterized. Here, we demonstrate a novel role for glial cell line-derived neurotrophic factor (GDNF) in upregulating PD-L1 expression in head and neck squamous cell carcinoma (HNSCC). The expression and correlation of PD-L1, GDNF and perineural invasion (PNI) status were evaluated by bioinformatics analysis of TCGA database and IHC assays from 145 HNSCC patients. PD-L1 expression was investigated by flow cytometry, Western blot and real-time PCR analyses in HNSCC cells after GNDF incubation. The cell signaling pathways activated by GDNF were analyzed with an antibody array and blocked by specific signaling inhibitors in cancer cell lines. PD-L1 expression was significantly higher in cancer cells that exhibited PNI in the HNSCC specimens, and elevated PD-L1 expression was significantly correlated with GDNF levels. GDNF not only enhanced cancer cell PNI in a co-culture of dorsal root ganglions and cancer cells but also had a potent role in inducing PD L1 expression through the JAK2-STAT1 signaling pathway. Moreover, a JAK2 inhibitor attenuated GDNF-induced PD-L1 and enhanced tumor cell susceptibility to NK cell killing. Our findings provide clinically novel evidence that nerve derived GDNF can increase PD-L1 levels in cancer cells around the perineural niche and that regulatory signaling is critical for cancer cell escape from immune surveillance in the nerve-cancer microenvironment. PMID- 29147603 TI - Age, estrogen, and immune response in breast adenocarcinoma and adjacent normal tissue. AB - Chronic inflammation promotes breast tumor growth and invasion by accelerating angiogenesis and tissue remodeling in the tumor microenvironment. There is a complex relationship between inflammation and estrogen, which drives the growth of 70 percent of breast tumors. While low levels of estrogen exposure stimulate macrophages and other inflammatory cell populations, very high levels are immune suppressive. Breast tumor incidence is increased by obesity and age, which interact to influence inflammatory cell populations in normal breast tissue. To characterize the impact of these factors on tumors and the tumor microenvironment, we measured gene expression in 195 breast adenocarcinomas and matched adjacent normal breast tissue samples collected at Akershus University Hospital (AHUS). Age and Body Mass Index (BMI) were independently associated with inflammation in adjacent normal tissue but not tumors. Estrogen Receptor (ER) negative tumors had elevated macrophage expression compared with matched normal tissue, but ER-positive tumors showed an unexpected decrease in macrophage expression. We found an inverse relationship between the increase in tumor estrogen pathway expression compared with adjacent normal tissue and tumor macrophage score. We validated this finding in 126 breast tumor-normal pairs from the previously published METABRIC cohort. We developed a novel statistic, the Rewiring Coefficient, to quantify the rewiring of gene co-expression networks at the level of individual genes. Differential correlation analysis demonstrated distinct pathways were rewired during tumorigenesis. Our data support an immune suppressive effect of high doses of estrogen signaling in breast tumor microenvironment, suggesting that this effect contributes to the greater presence of prognostic and therapeutically relevant immune cells in ER-negative tumors. PMID- 29147604 TI - TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer. AB - The anti-tumor immune response has been shown to be of great prognostic importance in colorectal cancer (CRC) and so has the tumors ability for immune evasion. Our aim of this study was to investigate tumor factors that influence immunity. We used a gene expression array to search for potential mechanisms of tumor immune escape. One candidate gene identified was TAP1, involved in antigen presentation by MHC class I. TAP1 protein expression was evaluated by immunohistochemistry in 436 CRC patients of the Colorectal Cancer in Umea Study cohort. We found a significant association between a downregulated expression of TAP1 and low infiltration of various subtypes of lymphocytes as well as macrophages. A downregulated expression of TAP1 was further found to be independent of molecular characteristics, suggesting TAP1 down-regulation to reach beyond the well described highly immunogenic MSI CRCs. A low expression of TAP1 was also significantly associated with poor prognosis in patients with CRC, a result that stayed significant in tumor front of early stage tumors (stage I II) through multivariable analyses. Furthermore, we found that TAP1 expression was inversely correlated with methylation at sites in close proximity to the promoter region. In summary, our results show down-regulation of TAP1 to be a general mechanism of tumor immune escape in CRC and a poor prognostic factor in stage I-II CRC patients. We also suggest that methylation of the TAP1 gene may be a putative mechanism for TAP1 downregulation. PMID- 29147605 TI - EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer. AB - Patients with EGFR mutations showed unfavorable response to programmed cell death 1 (PD-1) blockade immunotherapy in non-small cell lung cancer (NSCLC). Yet the underlying association between EGFR mutation and immune resistance remains largely unclear. We performed an integrated analysis of PD-ligand 1(PD-L1)/CD8 expression and mutation profile based on the repository database and resected early-stage NSCLC in Guangdong Lung Cancer Institute (GLCI). Meanwhile, 2 pool analyses were set to clarify the correlation between EGFR mutation and PD-L1 expression, and the association of EGFR status with response to anti-PD-1/L1 therapy. Pool-analysis of 15 public studies suggested that patients with EGFR mutations had decreased PD-L1 expression (odds ratio: 1.79, 95% CI: 1.10-2.93; P = 0.02). Analysis of The Cancer Genome Atlas (TCGA) and the GCLI cohort confirmed the inverse correlation between EGFR mutation and PD-L1 expression. Furthermore, patients with EGFR mutation showed a lack of T-cell infiltration and shrinking proportion of PD-L1+/CD8+ TIL (P = 0.034). Importantly, patients with EGFR mutations, especially the sensitive subtype, showed a significantly decreased mutation burden, based on analysis of the discovery and validation sets. Finally, a pool-analysis of 4 randomized control trials confirmed that patients with EGFR mutation did not benefit from PD-1/L1 inhibitors (Hazard ratio [HR] = 1.09, P = 0.51) while patients with EGFR wild-type did (HR = 0.73, P < 0.00001). This study provided evidence of a correlation between EGFR mutations and an uninflamed tumor microenvironment with immunological tolerance and weak immunogenicity, which caused an inferior response to PD-1 blockade in NSCLCs. PMID- 29147606 TI - Temporal and spatial heterogeneity of programmed cell death 1-Ligand 1 expression in malignant mesothelioma. AB - Background: Programmed Cell Death 1-Ligand 1 (PD-L1) and Programmed Death Protein 1 (PD-1) blocking antibodies are promising immunotherapies for malignancies. We have previously shown PD-L1 expression in 40% of malignant mesothelioma (MM); however, the temporal and spatial heterogeneity of its expression has not been thoroughly studied. We compared PD-L1 expression between paired primary and metastatic MM. Design: Pathology files (1995-2016) were searched for MM with tissue from multiple sites and/or time points. PD-L1 (clone SP263) expression was reviewed by 2 authors. Mesothelioma cell lines (H2461, One 58, EM-MESO) were cultured with or without vinorelbine or pemetrexed. Following incubation, PD-L1 expression (clone MIH1) was analyzed by flow cytometry. Results: 64 patients (53 men, median age, 64 years) with epithelioid (N = 50), biphasic (N = 11) or sarcomatoid (N = 2) MM or well differentiated papillary mesothelioma (N = 1) (pleural, n = 56; peritoneal, n = 8) were included. Patients had a subsequent specimen from the primary site (n = 48), from a metastasis (n = 6), or both (n = 10). Reviewers agreed on PD-L1 expression in 133 of 151 (88%) specimens. There was agreement of PD-L1 expression between paired primary lesions obtained at separate time points in 47 of 58 (81%) and between paired primary and metastatic lesions in 11 of 16 (69%) cases. A significant increase in PD-L1 expression was observed in all 3 MM cell lines (p < 0.003 each) following exposure to vinorelbine but not to pemetrexed. Conclusion: Overall there is good agreement in PD-L1 expression between paired MM lesions; however, the 19-31% of cases with discordant PD-L1 expression, and the dynamics of PD-L1 expression may limit its use as a predictive biomarker for therapy. PMID- 29147607 TI - Immune signature profiling identified predictive and prognostic factors for esophageal squamous cell carcinoma. AB - Understanding interactions between tumor and the host immune system holds great promise to uncover biomarkers for targeted therapies and clinical outcomes. However, systematical analysis of immune signatures in esophageal squamous cell carcinoma (ESCC) remains largely unstudied. In this study, immune signatures containing 708 immune related genes were curated from mRNA microarray data with tumor and paired normal tissues from 119 ESCC patients. Differential expression and survival analysis were performed with validations from Human Protein Atlas and an independent cohort of 110 ESCC patients by immunohistochemistry staining. We identified a total of 186 significantly dysregulated genes in ESCC, including downregulated genes SPINK5, IL1RN and upregulated genes SPP1 and PLAU, which were further confirmed in Human Protein Atlas data. Moreover, nine immune related genes (ABL1, ATF2, ATG5, C6, CD38, HMGB1, ICOSLG, IL12RB2 and PLAU) were significantly associated with patients' overall survival, among which, prognostic model was built including three independent factors ABL1, CD38 and ICOSLG. Validation by immunohistochemistry staining suggested that combination with tumor infiltrated CD4+ and CD8+ T lymphocytes would yield higher performance in distinguishing cases as high or low risk of unfavorable prognosis. In summary, we profiled the immune status in ESCC and established predictive and prognostic factors for ESCC, which could reflect immune disorders within tumor microenvironments and independently distinguish patients with a high risk of reduced survival, providing novel predictive and therapeutic targets for ESCC patients in the future. PMID- 29147608 TI - The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis. AB - Background - The presence of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment is associated with an improved prognosis and a better response to therapy in different types of cancer. In this systematic review and meta analysis, we investigated the prognostic value of T cells in head and neck squamous cell carcinoma (HNSCC). Methods - In a systematic review, Pubmed and Embase were searched for publications that investigated the prognostic value of T cells in HNSCC. A meta-analysis was performed including all studies assessing the association between CD3+, CD4+, CD8+, and FoxP3+ TILs and overall survival (OS), disease-free survival (DFS), or locoregional control (LRC). Results - A pooled analysis indicated a favorable, prognostic role for CD3+ TILs (HR 0.64 (95%CI 0.47-0.85) for OS, HR 0.63 (95%CI 0.49-0.82) for DFS) and CD8+ TILs (HR 0.67 (95%CI 0.58-0.79) for OS, HR 0.50 (95%CI 0.37-0.68) for DFS, and HR 0.82 (95%CI 0.70-0.96) for LRC) in the clinical outcome of HNSCC. FoxP3+ TILs were also associated with better OS (HR 0.80 (95%CI 0.70-0.92)). Conclusion - This systematic review and meta-analysis confirmed the favorable, prognostic role of CD3+ and CD8+ T cell infiltration in HNSCC patients and found an association between FoxP3+ TILs and improved overall survival. Future studies using homogeneous patient cohorts with regard to tumor subsite, stage and treatment are necessary to provide more insight in the predictive value of TILs in HNSCC. PMID- 29147609 TI - Tumor Immunology meets...Immunology: Modified cancer cells as professional APC for priming naive tumor-specific CD4+ T cells. AB - Although recent therapeutic approaches have revitalized the enthusiasm of the immunological way to combat cancer, still the comprehension of immunity against tumors is largely incomplete. Due to their specific function, CD8+ T cells with cytolytic activity (CTL) have attracted the attention of most investigators because CTL are considered the main effectors against tumor cells. Nevertheless, CTL activity and persistence is largely dependent on the action of CD4+ T helper cells (TH). Thus establishment of tumor-specific TH cell response is key to the optimal response against cancer. Here we describe emerging new strategies to increase the TH cell recognition of tumor antigens. In particular, we review recent data indicating that tumor cells themselves can act as surrogate antigen presenting cells for triggering TH response and how these findings can help in constructing immunotherapeutic protocols for anti-cancer vaccine development. PMID- 29147610 TI - Host immune response index in gastric cancer identified by comprehensive analyses of tumor immunity. AB - Tumor infiltrating lymphocytes (TIL) in Epstein-Barr virus (EBV) associated/microsatellite-unstable (MSI) gastric carcinomas (GC) constitute immune-active principal cellular components of tumor microenvironment and contribute to better prognosis. With the remarkable success of cancer immunotherapies, there is an urgent need for a comprehensive understanding of tumor-immune interactions in patients with GC in the context of host immune response. To identify GC subtype-specific immune response gene set, we tested differentially expressed genes for MSI and EBV+ GC subtypes in randomly selected test set (n = 278) in merged ACRG-SMC microarray and TCGA RNA sequencing data set. We identified Host ImmunE Response index (HIERI) consisting of 29 immune genes classifying GC patients into robust 3 groups with prognostic significance. Immune-high cluster 1 was enriched with PD-L1High/EBV+/MSI/TILHigh with the best clinical outcome while immune-low cluster 3 displayed worst outcome and exemplified with PD-L1Low/EBV-/MSS. The results were validated in the same cohort (n = 279) and independent cohort (n = 181) with RNA from formalin-fixed paraffin embedded (FFPE) tissue. Unexpectedly, nearly half of GC in cluster 1 were EBV /MSS and 10% of cluster 3 GC were EBV+/MSI GC patients, suggesting that in addition to EBV+/MSI GC subtypes, EBV-/MSS subtype also constitutes almost half of high immune cluster and would be a good candidate for immune checkpoint inhibitor therapy. In contrary, almost 10% of EBV+/MSI GC patients may not respond to immune checkpoint inhibitor therapy. Thus, our HIERI gene signature demonstrates the potential to subclassify tumor immunity levels, predict prognosis and help immunotherapeutic decisions. PMID- 29147611 TI - Chloroquine supplementation increases the cytotoxic effect of curcumin against Her2/neu overexpressing breast cancer cells in vitro and in vivo in nude mice while counteracts it in immune competent mice. AB - Autophagy is usually a pro-survival mechanism in cancer cells, especially in the course of chemotherapy, thus autophagy inhibition may enhance the chemotherapy mediated anti-cancer effect. However, since autophagy is strongly involved in the immunogenicity of cell death by promoting ATP release, its inhibition may reduce the immune response against tumors, negatively influencing the overall outcome of chemotherapy. In this study, we evaluated the in vitro and in vivo anti-cancer effect of curcumin (CUR) against Her2/neu overexpressing breast cancer cells (TUBO) in the presence or in the absence of the autophagy inhibitor chloroquine (CQ). We found that TUBO cell death induced by CUR was increased in vitro by CQ and slightly in vivo in nude mice. Conversely, CQ counteracted the Cur cytotoxic effect in immune competent mice, as demonstrated by the lack of in vivo tumor regression and the reduction of overall mice survival as compared with CUR treated mice. Immunohistochemistry analysis revealed the presence of a remarkable FoxP3 T cell infiltrate within the tumors in CUR/CQ treated mice and a reduction of T cytotoxic cells, as compared with single CUR treatment. These findings suggest that autophagy is important to elicit anti-tumor immune response and that autophagy inhibition by CQ reduces such response also by recruiting T regulatory (Treg) cells in the tumor microenvironment that may be pro-tumorigenic and might counteract CUR-mediated anti-cancer effects. PMID- 29147612 TI - Low-dose post-transplant cyclophosphamide can mitigate GVHD and enhance the G CSF/ATG induced GVHD protective activity and improve haploidentical transplant outcomes. AB - Use of high-dose, post-transplant cyclophosphamide (PTCy) results in low rates of graft-versus-host-disease (GVHD) and favorable immune reconstitution, although with higher rates of relapse and somewhat high rates of graft failure. We hypothesized that permissible dose reduction of PTCy might be feasible. The current study attempts to establish a murine model and focus on regulatory T cells (Tregs) to clarify the immunological mechanisms for GVHD prevention by low dose PTCy. In addition, a prospective, clinical cohort study in haploidentical, T cell replete transplantation is initiated to support the rational. We found that acute GVHD could be alleviated by low-dose PTCy and could be further mitigated after the combined use of low-dose PTCy and antithymocyte globulin (ATG) in mice. Flow-cytometric analyses in mice showed that low-dose PTCy could increase the number of Tregs and the effect on Tregs is significantly prominent with the combined use of low-dose PTCy and ATG. In the clinical cohort study, the cumulative incidence of grades II-IV acute GVHD in combined treatment cohort with low-dose PTCy and ATG/granulocyte colony-stimulating factor (G-CSF) (17%; 95% CI, 5-29%) was significantly lower than both that in matched-pair cohort (33%; 95% CI, 25-41%; P = 0.04) and that in historical cohort (56%; 95% CI, 42-70%; P < 0.001). In-vivo immune reconstitution analysis showed that low-dose PTCy could facilitate suppressive Tregs reconstitution. In conclusion, low-dose PTCy is sufficient for GVHD abrogation under lymphopenic situation and can enhance the protective effect of ATG/G-CSF on GVHD. Intensified conditioning followed by low dose PTCy might be a feasible option for patients undergoing haploidentical transplantation. PMID- 29147613 TI - CD103+ cells at the forefront of anticancer immunity. PMID- 29147614 TI - Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy. AB - Although promising, the clinical benefit provided by dendritic cell (DC)-based vaccines is still limited and the choice of the optimal antigen formulation is still an unresolved issue. We have developed a new DC-based vaccination protocol for aggressive and/or refractory lymphomas which combines the unique features of interferon-conditioned DC (IFN-DC) with highly immunogenic tumor cell lysates (TCL) obtained from lymphoma cells undergoing immunogenic cell death. We show that treatment of mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) cell lines with 9-cis-retinoic acid and IFNalpha (RA/IFNalpha) induces early membrane exposure of Calreticulin, HSP70 and 90 together with CD47 down regulation and enhanced HMGB1 secretion. Consistently, RA/IFNalpha-treated apoptotic cells and -TCLs were more efficiently phagocytosed by DCs compared to controls. Notably, cytotoxic T cells (CTLs) generated with autologous DCs pulsed with RA/IFNalpha-TCLs more efficiently recognized and specifically lysed MCL or DLBCL cells or targets loaded with several HLA-A*0201 cyclin D1 or HLA-B*0801 survivin epitopes. These cultures also showed an expansion of Th1 and Th17 cells and an increased Th17/Treg ratio. Moreover, DCs loaded with RA/IFNalpha-TCLs showed enhanced functional maturation and activation. NOD/SCID mice reconstituted with human peripheral blood lymphocytes and vaccinated with autologous RA/IFNalpha-TCL loaded-IFN-DCs showed lymphoma-specific T-cell responses and a significant decrease in tumor growth with respect to mice treated with IFN-DC unpulsed or loaded with untreated TCLs. This study demonstrates the feasibility and efficacy of the use of RA/IFNalpha to generate a highly immunogenic TCL as a suitable tumor antigen formulation for the development of effective anticancer DC based vaccines. PMID- 29147615 TI - Tumor-associated neutrophils induce apoptosis of non-activated CD8 T-cells in a TNFalpha and NO-dependent mechanism, promoting a tumor-supportive environment. AB - The role of neutrophils in tumor progression has become in recent years a subject of growing interest. Tumor-associated neutrophils (TANs), which constitute an important portion of the tumor microenvironment, promote immunosuppression in advanced tumors by modulating the proliferation, activation and recruitment of a variety of immune cell types. Studies which investigated the consequences of manipulating TAN polarization suggest that the impact of these neutrophils on tumor progression is considerably mediated by and dependent on the presence of CD8 T-cells. It has been previously shown that granulocytic myeloid regulatory cells, i.e. TANs and granulocytic myeloid-derived suppressor cells (G-MDSCs) are capable of suppressing CD8 T-cell proliferation and affect their activation. In the current study, we find that in addition, TANs isolated from different models of murine cancer promote immunosuppression by strongly inducing CD8 T-cell apoptosis. We demonstrate that the TNFalpha pathway in TANs is critical for the induction of apoptosis, and that the mechanism through which apoptosis is induced involves the production of NO, but not ROS. In the absence of pre-activation, TANs are capable of activating CD8 T-cells, but specifically induce the apoptosis of non-activated CD8+CD69- cells. Despite this contradictive effect on T-cell function, we show in vivo that TANs suppress the anti-tumor effect of CD8 T-cells and abolish their ability to delay tumor growth. Our results add another important layer on the understanding of the possible mechanisms by which TANs regulate the anti-tumor immune response mediated by CD8 T-cells, therefore promoting a tumor-supportive environment. PMID- 29147616 TI - mRNA Expression levels of genes involved in antitumor immunity: Identification of a 3-gene signature associated with prognosis of muscle-invasive bladder cancer. AB - Immunotherapy for bladder cancer has given promising results. Here we aimed to evaluate the possible involvement and prognostic value of 33 genes involved in the immune response during bladder carcinogenesis. Expression levels were assessed by quantitative real-time RT-PCR in normal and tumor human bladder samples. Immunohistochemistry was performed to evaluate the protein expression of 2 genes and relation of the mRNA and protein levels was analyzed. Tumors were obtained from 154 patients (83 with muscle-invasive bladder cancer [MIBC] and 71 non-MIBC [NMIBC]) who underwent transurethral bladder resection or radical cystectomy between 2002 and 2006. All patients signed an informed consent. Results of molecular analyses were coupled with survival analyses. Overall, 25 genes (75.8%) were significantly overexpressed in MIBC and 15 (45.5%) were deregulated in NMIBC as compared with normal tissue. On multivariate analysis, risk of NMIBC recurrence was increased with high FOXP3/CD8 ratio and overexpression of OX40L (p = 0.016 and p = 0.0039, respectively). In MIBC, a molecular signature of 3 genes (OX40L, CD8 and TIGIT) was significantly associated with prognosis in terms of recurrence-free and overall survival (p = 0.0007 and p = 0.007). RT-PCR findings were confirmed by immunohistochemistry for CD8 and FOXP3, with high association between mRNA and protein levels. Finally, risk of recurrence of non-muscle-invasive bladder cancer was increased with high FOXP3/CD8 ratio and OX40L overexpression. We identified a 3 gene molecular signature associated with prognosis of muscle-invasive bladder cancer. These results confirm the useful role of immune checkpoints in bladder carcinogenesis and suggest targets for therapy. PMID- 29147617 TI - Phase I trial of anti-GD2 monoclonal antibody hu3F8 plus GM-CSF: Impact of body weight, immunogenicity and anti-GD2 response on pharmacokinetics and survival. AB - Fifty-seven stage 4 patients with refractory/relapsed neuroblastoma were enrolled in a phase I trial (Clinicaltrials.gov NCT01757626) using humanized anti-GD2 monoclonal antibody hu3F8 in combination with granulocyte-macrophage colony stimulating factor. The influence of body weight and human anti-human antibody (HAHA) on the pharmacokinetics (PK) of hu3F8, and the effect of de novo anti-GD2 response on patient outcome were explored. Serum samples before hu3F8 infusion, and serially up to day 12 during treatment cycle #1, and at 5 min after each hu3F8 infusion for all subsequent cycles were collected. PK was analyzed using non-compartmental modeling. Immunogenicity was assayed by HAHA response, and vaccination effect by induced host anti-GD2 response measured periodically until disease progression or last followup. Progression-free and overall survival was estimated by the Kaplan-Meier method. Despite dosing being based on body weight, smaller patients had consistently lower area-under-the-curve and faster clearance over the 15 dose levels (0.9 to 9.6 mg/kg per treatment cycle) in this trial. Positive HAHA, defined by the upper limit of normal, when measured within 10 days from the last hu3F8 dose received, was associated with significantly lower serum hu3F8. Despite prior sensitization to other anti-GD2 antibody, e.g. mouse 3F8 or ch14.18, 75% of the patients never developed HAHA response even after getting more treatment cycles. Hu3F8 induced a de novo anti-GD2 response in patients, which was prognostic of progression-free survival. We conclude that hu3F8 had low immunogenicity. During treatment, positive HAHA and low body weight affected PK adversely, whereas induced anti-GD2 response was an outcome predictor. PMID- 29147618 TI - Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: Relationship with the hypoxic response, immune evasion and malignant behavior. AB - The hypoxic response underlies the pathogenesis and malignant behavior of PCC/PGL. Regulation of PD-1 receptor-ligand signaling, a therapeutically actionable driver of the anti-tumor immune response, is a hypoxic-driven trait across malignancies. We evaluated the prognostic role of PD ligands in association with biomarkers of hypoxia and angiogenesis in patients with PCC/PGL. Tissue microarrays sections including consecutive cases diagnosed between 1983 2011 were stained for PD-L1 and 2, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A). We explored the biologic significance of PD ligands expression using gene set enrichment analysis (GSEA) on The Cancer Genome Atlas (TCGA) for PCC/PGL (n = 184). In total, 100 patients, 10% malignant, 64% PCC, 29% familial with median tumor size of 4.7 cm (range 1-14) were included. Median follow-up was 4.7 y. We found PD-L1 expression in 18% of PCC/PGL, which was independent of adverse pathological features including capsular (CI), vascular invasion (VI), necrosis (N) and expression of biomarkers of hypoxia. PD-L2 expression (16%) strongly correlated with CI, VI, N and malignant behavior (p < 0.05) and was associated with stronger Hif-1a and CaIX immunolabeling (p < 0.01). PD-L2 was predictive of shorter survival (162 versus 309 months, HR 3.1 95%CI 1.1-9.2, p = 0.02). GSEA on TGCA samples confirmed enrichment of transcripts involved in hypoxia and anti-cancer immunity. We report for the first time PD ligands expression in PCC/PGL with a distinctive prognostic, clinico-pathologic and immuno-biologic role. These findings support a potential therapeutic role for PD-1/PD-L1 targeted checkpoint inhibitors in these tumors. KEY MESSAGE The molecular mechanisms underlying immune evasion in malignant phaeochromocytomas and paragangliomas (PCC/PGL) are poorly understood. This study demonstrates for the first time a distinctive immune-biologic and prognostic role of programmed death ligands 1 and 2 (PD-L1, PD-L2), two actionable drivers of the anti-cancer immune response. RNA-sequencing of tumor tissues reveals enrichment of transcripts relating to hypoxia and immune exhaustion to explain the adverse clinical course observed in PD-L2 overexpressing tumors. These findings provide a rationale for the development of anti PD-1 therapies in malignant PCC/PGL. PMID- 29147619 TI - The JAK2V617F and CALR exon 9 mutations are shared immunogenic neoantigens in hematological malignancy. AB - Approximately 90% of patients with the hematological malignancies termed the chronic myeloproliferative neoplasms harbor either the JAK2V617F-mutation or CALR exon 9 mutation. Both of these are recognized by T-cells, which make the mutations ideal targets for cancer immune therapy as they are shared antigens. PMID- 29147620 TI - Blinatumomab bridges the gap between leukemia and immunity. PMID- 29147622 TI - Factors released by the tumor far microenvironment are decisive for pancreatic adenocarcinoma development and progression. AB - The REG3beta protein was identified more than 2 decades ago, but its role in PDAC development was only recently reported. In Pancreatic Ductal Adenocarcinoma (PDAC), REG3beta protein is expressed and released by the far microenvironment, which is situated out of the tumor, at the periphery of the tumor mass, and is part of the healthy peri-tumoral region. This compartment is completely unrelated to the classical microenvironment that corresponds to the intra-tumoral stoma. Clinically relevant, the far microenvironment, and the factors released by it, could be novel and original therapeutic targets for treating patients with a PDAC. In this way we recently demonstrated that REG3beta is an essential soluble factor necessary for PDAC development which is able to stimulate several simultaneous pro-tumoral mechanisms. We also find that secreted REG3beta boosts interactions between epithelial cells and immune cells by activating the CXCL12/CXCR4 signaling cascade, which facilitates tumor escape through evasion of immune surveillance, and promotes metastasis. In addition, REG3beta interfere the intercellular communication inside the tumor mediated by extracellular vesicles, resulting in relevant changes in macrophage phenotype or tumor cell migration. Therefore, we are proposing to call as near microenvironment to the classical microenvironment that is constituted by fibroblasts, inflammatory cells and fibers and located into the tumor, and as far microenvironment, which is constituted by the parenchymal non transformed cells located at the periphery of the tumor mass. PMID- 29147621 TI - In-depth immunophenotyping of patients with glioblastoma multiforme: Impact of steroid treatment. AB - Despite aggressive treatment regimens based on surgery and radiochemotherapy, the prognosis of patients with grade IV glioblastoma multiforme (GBM) remains extremely poor, calling for alternative options such as immunotherapy. Immunological mechanisms including the Natural Killer Group 2 member D (NKG2D) receptor-ligand system play an important role in tumor immune surveillance and targeting the NKG2D system might be beneficial. However, before considering any kind of immunotherapy, a precise characterization of the immune system is important, particularly in GBM patients where conventional therapies with impact on the immune system are frequently co-administered. Here we performed an in depth immunophenotyping of GBM patients and age-matched healthy controls and analyzed NKG2D ligand expression on primary GBM cells ex vivo. We report that GBM patients have a compromised innate immune system irrespective of steroid (dexamethasone) medication. However, dexamethasone drastically reduced the number of immune cells in the blood of GBM patients. Moreover, higher counts of immune cells influenced by dexamethasone like CD45+ lymphocytes and non-Vdelta2 gammadelta T cells were associated with better overall survival. Higher levels of NKG2D ligands on primary GBM tumor cells were observed in patients who received radiochemotherapy, pointing towards increased immunogenic potential of GBM cells following standard radiochemotherapy. This study sheds light on how steroids and radiochemotherapy affect immune cell parameters of GBM patients, a pre-requisite for the development of new therapeutic strategies targeting the immune system in these patients. PMID- 29147623 TI - Tissue-resident memory T cells play a key role in the efficacy of cancer vaccines. AB - Resident memory CD8+T cells (TRM) usually defined by the CD103 marker represent a new subset of long-lived memory T cells that remain in the tissues. We directly demonstrate their specific role in cancer vaccine-induced tumor regression. In human, they also seem to play a major role in tumor immunosurveillance. PMID- 29147624 TI - High CXC chemokine receptor 1 level represents an independent negative prognosticator in non-metastatic clear-cell renal cell carcinoma patients. AB - CXC chemokine receptor 1 (CXCR1) signaling has been shown as an essential molecular nexus regarding cancer cell proliferation, tumor inflammation, and angiogenesis in clear cell renal cell carcinoma (ccRCC). The aim of this study was to investigate the prognostic significance of CXCR1 in patients with non metastatic ccRCC. Data from 446 consecutive non-metastatic ccRCC patients, operated between 2003 and 2008 at a single institution, were evaluated retrospectively. The cohort was split into a training set (n = 223) and a validation set (n = 223). CXCR1 expression was assessed by immunohistochemistry staining and its association with clinicopathologic features and prognosis were evaluated. High CXCR1 epithelial expression presented prognostic value, and indicated poor overall survival (OS) (P = 0.010 and P = 0.015, respectively) and recurrence-free survival (P = 0.011 and P = 0.019, respectively) in the training and validation sets. The incorporation of CXCR1 into the T stage and SSIGN score would help to refine individual risk stratification. Multivariate analysis identified increased epithelial CXCR1 was statistically significantly associated with a poor outcome for OS (HR [95% CI] 1.808 [1.184-2.761]; P = 0.006) and RFS (HR [95% CI] 1.570 [1.076-2.290]; P = 0.019) in all non-metastatic ccRCC patients. Predictive nomograms were generated with identified independent prognosticators to assess patient overall survival and recurrence-free survival at 3, 5 and 10 y. Furthermore, high CXCR1 expression were correlated with elevated infiltrated neutrophils and enriched MMP family gene expression. To conclude, high CXCR1 level within epithelial area represented a potential independent negative prognostic factor regarding OS and RFS in non-metastatic ccRCC patients after nephrectomy. PMID- 29147625 TI - A transcriptomic insight into the impacts of mast cells in lung, breast, and colon cancers. AB - To date, the exact impact of mast cells in tumor microenvironment is still controversial because of inconsistency in observations regarding the relationship between mast cell infiltrates and cancer development and prognosis. The discrepancies in previous studies have motivated us to examine the roles of mast cells in cancer pathology from different perspectives. Here, we investigated the impact of mast cells on transcriptomic profiles in the tissue microenvironment. Mice carrying the W-sh mutation in c-kit (KitW-sh ) are deficient in mast cell production and were used to assess the influence of mast cells on gene expression. By examining the transcriptomic profile among wild-type mice, KitW-sh mice, and KitW-sh mice with mast cell engraftment, we identified a list of "mast cell-dependent genes," which are enriched for cancer-related pathways. Utilizing whole-genome gene expression data from both mouse models and human cancer patients, we demonstrated that the expression profile of the mast cell-dependent genes differs between tumor and normal tissues from lung, breast, and colon, respectively. Mast cell infiltration is potentially increased in tumors compared with normal tissues, suggesting that mast cells might participate in tumor development. Accordingly, a prognostic molecular signature was developed based on the mast cell-dependent genes, which predicted recurrence-free survival for human patients with lung, breast, and colon cancers, respectively. Our study provides a novel transcriptomic insight into the impact of mast cells in the tumor microenvironment, though further experimental investigation is needed to validate the exact role of individual mast cell-dependent genes in different cancers. PMID- 29147626 TI - Functional T cells targeting tumor-associated antigens are predictive for recurrence-free survival of patients with radically operated non-small cell lung cancer. AB - In this prospective study, we examined postoperative follow-up and preoperative IFN-gamma T cell responses against 14 non-small cell lung cancer (NSCLC) associated antigens in the blood of 51 patients with NSCLC, 7 patients with benign pulmonary tumors, and 10 tumor-free patients by enzyme-linked immunospot assay. The phenotype and function of T cells specific for tumor-associated antigens (TAAs) in the blood or tumor tissue of 9 NSCLC patients were characterized in detail using TNF-alpha, IL-2, and IFN-gamma cytokine capture assays. We found that circulating TAA-specific T cells were significantly enriched in NSCLC compared with tumor-free patients. The most frequently recognized TAAs were Aurora kinase A, HER2/neu, NY-ESO-1, and p53. TNF-alpha was the most abundant cytokine secreted by TAA-specific T cells in the blood as well as by in situ-activated tumor-infiltrating lymphocytes, most of which were effector memory cells. The absence of TAA-reactive T cells identified patients at higher risk of tumor recurrence, irrespective of tumor stage (OR = 8.76, 95% CI: 1.57-34.79, p = 0.008). We conclude that pre-existing TAA-reactive circulating T cells are a strong independent prognostic factor for recurrence-free survival. These data may help discriminating high-risk from low-risk patients, improving prognostication, and redirecting adjuvant therapy. Our findings suggest the therapeutic relevance of Aurora kinase A, HER2/neu, NY-ESO-1, and p53 as targets for immunotherapy. This study is registered on Clinicaltrials.gov with trial identification number: NCT02515760. PMID- 29147627 TI - STAT1 gene deficient mice develop accelerated breast cancer growth and metastasis which is reduced by IL-17 blockade. AB - Signal transducer and activator of transcription 1 (STAT1) mediates interferon gamma signaling which activates the expression of various genes related to apoptosis, inflammation, cell cycle and angiogenesis. Several experimental and clinical studies have investigated the role of STAT1 in primary tumor growth in breast cancer; however, its role in tumor metastasis remains to be determined. To determine the role of STAT1 in breast cancer metastasis, we analyzed growth and metastasis in WT or STAT1-/- mice orthotopically implanted with metastatic 4T1.2 cells. Primary tumor development was faster in STAT1-/- mice and these mice developed significantly bigger primary tumors and displayed more lung metastasis compared with WT counterparts. STAT1-/- mice showed elevated Ly6G+CD11b+ granulocytic MDSC infiltration in their primary tumors and spleens with concomitant upregulation of Mmp9 and Cxcl1 expression in tumors compared with WT counterparts. Blockade of IL-17A in primary tumor-bearing STAT1-/- mice suppressed accumulation of Ly6G+CD11b+ cells and markedly reduced lung metastasis. These data show that STAT1 is an important suppressor of primary breast tumor growth and metastasis. Importantly, we found anti-IL-17 treatment can rescue STAT1 deficient animals from developing exacerbated metastasis to the lungs which could be important for immunotherapies for immunocompromised breast cancer patients. PMID- 29147630 TI - Sulforaphane from Broccoli Reduces Symptoms of Autism: A Follow-up Case Series from a Randomized Double-blind Study. AB - Introduction: Autism spectrum disorder (ASD) affects 1 in 68 children, is characterized by impaired social interaction and communication as well as restricted or repetitive behaviors, and varies widely with respect to its causes and presentations. There are no validated pharmacologic treatments for the core symptoms of ASD. The social, medical, and economic burdens of ASD on families and caregivers are profound. We recently showed in a small clinical trial that sulforaphane (SF) from broccoli sprouts could significantly reduce the behavioral symptoms of ASD. Methods: After we completed the intervention phase of the original trial (2011-2013), many caregivers used over-the-counter dietary SF supplements in order to attempt to maintain improvements similar to those noted during the intervention. We periodically followed the progress of study participants through the summer of 2016. Results: Families of 16 of the 26 subjects who received SF as part of the original study responded to requests for further information. Of these subjects, 6 did not continue taking SF supplements after the study. Nine of the 16 subjects are still taking an SF supplement and a 10th planned to. We present the edited testimonials of their caregivers in this case series. Conclusions: Many parents and caregivers articulated the positive effects of SF, both during the intervention phase and in the ensuing 3 years reported herein. These observations may contribute to understanding ASD and to treatments that may alleviate some of its symptoms. Diet- and supplement-based therapies deserve careful consideration for their potential to provide vital clinical as well as biochemical information about ASD. PMID- 29147631 TI - Automated Whole Brain Tractography Affects Preoperative Surgical Decision Making. AB - Surgery in and around eloquent brain structures poses a technical challenge when the goal of surgery is maximal safe resection. Magnetic resonance imaging (MRI) has revolutionized the diagnosis and treatment of neurological disorders, but tractography still remains limited in terms of utility because of the requisite manual labor and time required combined with the high risk of bias and inaccuracy. Automated whole brain tractography (AWBT) has simplified this workflow, overcoming historical barriers, and allowing for integration into modern neuronavigation. However, current literature showing the usefulness of this new technology is limited. In this study, we aimed to illustrate the utility of AWBT during cranial surgery and its ability to affect presurgical and intraoperative clinical decision making. We performed a retrospective chart review of cases that underwent AWBT for one year from July 2016 to July 2017. All patients underwent conventional anatomic MRI with and without contrast sequences, in addition to diffusion tensor imaging (DTI) on a 3 Tesla MRI scanner (Ingenia 3.0T, Philips, Amsterdam NL). Post-hoc AWBT processing was performed on a separate workstation. Patients were subsequently grouped into those that had undergone either language or motor mapping and those that did not. We compared both sets of patients to see any differences in patient age, sex, laterality of surgery, depth of resection from cortical surface, and smallest distance between the lesion and adjacent eloquent white matter tracts. We identified illustrative cases which demonstrated the ability of AWBT to affect surgical decision making. In this single-center series, we identified 73 total patients who underwent AWBT for intracranial surgery, of which 28 patients underwent either speech or language mapping. When comparing mapping to non-mapping patients, we found no difference with respect to age, gender, laterality of surgery, or whether the surgery was a revision. The distance between the lesion and eloquent white matter tracts demonstrated a statistically significant difference between mapping and non-mapping patients, namely in the corticospinal tract (p < 0.0001), the superior longitudinal fasciculus (p < 0.0001), and the arcuate fasciculus (p < 0.004). Patients who underwent mapping were at equal risk for having a postoperative deficit (p = 0.772) but had an improved chance of recovery (p = 0.041) after surgery. We believe this phenomenon is related to increased awareness and avoidance of functional tissue during surgery, which occurs due to the combination of preoperatively identifying white matter tracts with AWBT and intraoperatively testing margins with mapping. We provide two illustrative cases that show the impact of AWBT on patient outcomes. In conclusion, AWBT is relatively simple to perform and provides vital information for surgeons about eloquent white matter tracts that can be used to help improve patient outcomes. PMID- 29147632 TI - Acute Renal Failure with Overdose of Labetalol: Special Considerations in Management. AB - We report a case of acute renal failure in a patient with labetalol overdose, discuss the possible pathogenesis, and highlight special considerations in the management of labetalol overdose as compared with other beta-blocking agent overdoses. PMID- 29147633 TI - A Unique Case of Carotid Splaying by a Cervical Vagal Neurofibroma and the Role of Neuroradiology in Surgical Management. AB - Carotid splaying, also known as the Lyre sign, is a widening of the carotid bifurcation due to the displacement of the internal carotid artery and the external carotid artery just distal to the point of divergence. This phenomenon is classically exhibited by highly vascularized carotid body tumors and, in rare cases, by cervical sympathetic chain schwannomas. Demonstration of the Lyre sign by a cervical vagal neurofibroma, however, is a unique occurrence that has not been previously documented in the literature. Neurofibromas are slow growing, poorly vascularized soft tissue masses and are a hallmark of the autosomal dominant genetic disorder, neurofibromatosis type 1 (NF-1). While targeted genetic therapies are evolving, management is currently dependent on a case-by case resection of tumors with specific indications for chemo and radiation therapy. These resections rely on magnetic resonance imaging (MRI) to visualize tumor location and infiltration, but even in the setting of an established NF-1 diagnosis, additional imaging can be beneficial in ruling out more precarious tumors and optimizing surgical outcomes. In this case, a 25-year-old female with known NF-1 presented with an enlarging cervical mass that demonstrated splaying of the left internal and external carotid arteries on MRI. Due to the typical association of the Lyre sign with carotid body tumors, magnetic resonance angiography (MRA) was crucial in guiding surgical decision making. Carotid body tumors are highly vascularized, may compress carotid branches, and carry a high risk of intraoperative bleeding. They are best visualized with MRA, which assesses carotid splaying and patency, and demonstrates vascular blushing within the tumor. This patient's MRA demonstrated the Lyre sign, patency of all carotid vessels, and a lack of vascularity within the mass, thus lowering suspicion for a carotid body tumor. Intraoperative use of imaging results facilitated a successful resection of a soft tissue tumor with minimal blood loss and no complications. Postoperative histologic examination confirmed a neurofibroma and definitively ruled out a carotid body tumor. This case highlights the importance of utilizing MRA whenever carotid splaying is seen on MRI and supports the consideration of neurofibromas in the differential for this finding. PMID- 29147628 TI - Trial Watch: Adoptively transferred cells for anticancer immunotherapy. AB - Immunotherapies aimed at strengthening immune effector responses against malignant cells are growing at exponential rates. Alongside, the impressive benefits obtained by patients with advanced melanoma who received adoptively transferred tumor-infiltrating lymphocytes (TILs) have encouraged the scientific community to pursue adoptive cell transfer (ACT)-based immunotherapy. ACT involves autologous or allogenic effector lymphocytes that are generally obtained from the peripheral blood or resected tumors, expanded and activated ex vivo, and administered to lymphodepleted patients. ACT may be optionally associated with chemo- and/or immunotherapeutics, with the overall aim of enhancing the proliferation, persistence and functionality of infused cells, as well as to ensure their evolution in an immunological permissive local and systemic microenvironment. In addition, isolated lymphocytes can be genetically engineered to endow them with the ability to target a specific tumor-associated antigen (TAA), to increase their lifespan, and/or to reduce their potential toxicity. The infusion of chimeric antigen receptor (CAR)-expressing cytotoxic T lymphocytes redirected against CD19 has shown promising clinical efficacy in patients with B cell malignancies. Accordingly, the US Food and Drug Administration (FDA) has recently granted 'breakthrough therapy' designation to a CAR-based T-cell therapy (CTL019) for patients with B-cell malignancies. Considerable efforts are now being devoted to the development of efficient ACT-based immunotherapies for non hematological neoplasms. In this Trial Watch, we summarize recent clinical advances on the use of ACT for oncological indications. PMID- 29147634 TI - Intracranial Ischemic Infarct Due to Blunt Force Trauma in a High School Football Player. AB - Ischemic stroke is an uncommon cause of death among teenagers and young adults; however, the etiologies differ when compared to ischemic strokes in older individuals. Large-vessel atherosclerosis and small-vessel disease causing ischemic stroke are rare for the teenage population, while cervicocerebral arterial dissections account for up to 20% of ischemic strokes. Here, we present the case of a 16-year-old male who developed internal carotid artery dissection (ICAD) after a head injury and subsequently developed ischemic stroke and seizures. PMID- 29147635 TI - Global and Targeted Pathway Impact of Gliomas on White Matter Integrity Based on Lobar Localization. AB - Primary brain tumors comprise 28% of all tumors and 80% of malignant tumors. Pathophysiology of high-grade gliomas includes significant distortion of white matter architecture, necrosis, the breakdown of the blood brain barrier, and increased intracranial pressure. Diffusion tensor imaging (DTI), a diffusion weighted imaging technique, can be used to assess white matter architecture. Use of DTI as a non-invasive pathophysiological tool to analyze glioma impact on white matter microstructure has yet to be fully explored. Preliminary assessment of DTI tractography was done as a measure of intracranial tumor impact on white matter architecture. Specifically, we addressed three questions: 1) whether glioma differentially affects local white matter structure compared to metastasis, 2) whether glioma affects tract integrity of major white matter bundles, 3) whether glioma lobe localization affects tract integrity of different white matter bundles. In this study, we retrospectively investigated preoperative DTI scans from 24 patients undergoing tumor resection. Fiber tractography was estimated using a deterministic fiber tracking algorithm in DSI (diffusion spectrum imaging) Studio. The automatic anatomical labeling (AAL) atlas was used to define the left and right (L/R) hemisphere regions of interest (ROI). In addition, the John Hopkins University (JHU) White Matter Atlas was used to auto segment major white matter bundle ROIs. For all tracts derived from ROI seed targets, we computed the following parameters: tract number, tract length, fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD). The DTI tractography analysis revealed that white matter integrity in the hemisphere ipsilateral to intracranial tumor was significantly compromised compared to the control contralateral hemisphere. No differences were observed between high vs low-grade gliomas, however, gliomas induced significantly greater white matter degradation than metastases. In addition, targeted analysis of major white matter bundles important for sensory/motor function (i.e., corticospinal tract and superior longitudinal fasciculus) revealed tract-parameter specific susceptibility due to the presence of the tumor. Finally, major tract bundles were differentially affected based on lobar localization of the glioma. These DTI-based tractographic analyses complement findings from gross histopathological examination of glioma impact on neural tissue. Global and focal white matter architecture, ipsilateral to glioma, shows higher rates of degradation or edema - based on DTI tractographic metrics - in comparison to normal brain or metastases. Gliomas, which arise in the parietal lobe, also have a higher negative impact (potentially due to increased edema) on white matter integrity of the superior longitudinal fasciculus(SLF) than those which arise in the frontal lobe. Future studies will focus on using preoperative and postoperative tractography to predict functional deficits following resective surgery. PMID- 29147629 TI - Trial watch: Immune checkpoint blockers for cancer therapy. AB - Immune checkpoint blockers (ICBs) are literally revolutionizing the clinical management of an ever more diversified panel of oncological indications. Although considerable attention persists around the inhibition of cytotoxic T lymphocyte associated protein 4 (CTLA4) and programmed cell death 1 (PDCD1, best known as PD 1) signaling, several other co-inhibitory T-cell receptors are being evaluated as potential targets for the development of novel ICBs. Moreover, substantial efforts are being devoted to the identification of biomarkers that reliably predict the likelihood of each patient to obtain clinical benefits from ICBs in the absence of severe toxicity. Tailoring the delivery of specific ICBs or combinations thereof to selected patient populations in the context of precision medicine programs constitutes indeed a major objective of the future of ICB-based immunotherapy. Here, we discuss recent preclinical and clinical advances on the development of ICBs for oncological indications. PMID- 29147636 TI - Drug-Induced Lupus Erythematosus Associated with Antiretroviral Therapy in a Patient with Human Immunodeficiency Virus: A Case Report. AB - Antiretroviral medications are the mainstay of human immunodeficiency virus (HIV) therapy and some have been in use for over 20 years. To date, there have been no reported cases of antiretroviral therapy (ART) induced drug-induced lupus erythematosus (DILE). We present a case of a 35-year-old woman who received a combination of emtricitabine, rilpivirine, and tenofovir disoproxil fumarate for HIV treatment. Three years later, she developed an extensive rash and polyarthralgia in her extremities with laboratory findings significant for positive antinuclear antibody (ANA), anti-double stranded deoxyribonucleic acid (DNA) antibody (anti-dsDNA), and anti-histone antibody titers. Her systemic symptoms and rash improved with ART discontinuation. She was later restarted on her original ART due to difficulty in tolerating a different combination therapy. A few months after restarting ART, she developed new dermatologic symptoms, worsening arthralgias, tenderness of the metacarpophalangeal and proximal interphalangeal joints of the hand, and an increase in anti-dsDNA titers to 286 IU/ml. ART was then discontinued, which led to complete resolution of her symptoms and her anti-dsDNA decreased significantly. She had no further recurrence of symptoms. Awareness of the possibility of ART-induced DILE in the right clinical setting would prompt early recognition and management of this condition. PMID- 29147637 TI - Subtotal Resection of a Thalamic Glioblastoma Multiforme through Transsylvian Approach. AB - Glioblastoma multiforme (GBM) is a malignant brain tumor with an ominous prognosis. The standard treatment includes maximal safe resection plus adjuvant therapy. Thalamic GBMs, however, are unfavorable for microsurgical removal because of deep location and proximity to critical structures. We present a patient presenting with progressive hemiparesis and decreased consciousness with a large thalamic GBM who underwent subtotal resection through a transsylvian approach. His clinical and neurologic condition improved after surgery and he survived nine months after surgery. This may propose that in selected cases, more aggressive microsurgery for debulking of tumors might have some impact in the final outcome.. PMID- 29147638 TI - A Sensitive and Rapid Method for Detecting Formaldehyde in Brain Tissues. AB - The existing methods for detecting formaldehyde (FA) in brain samples are expensive and require sophisticated experimental procedures. Here, we established a highly sensitive and selective spectrophotometric method, which is based on a reaction in which FA reacts with colorless reagent 4-amino-3-penten-2-one (Fluoral-P) to produce a yellow compound, 3,5-diacetyl-1,4-dihydrolutidine (DDL), which can be detected by a spectrophotometer at 420 nm at room temperature. The sensitive response time point was found to be at the first hour, and the optimal pH of derivative reaction was pH 6.0. The limit of detection (LOD) and the limits of quantization (LOQ) for detecting FA were 0.5 MUM and 2.5 MUM, respectively. Using this method, an abnormally high level of FA was detected in both the brains of FA-injected mice and autopsy hippocampus tissues from patients with Alzheimer's disease. This finding suggests that the modified Fluoral-P method is effective for measuring levels of FA in the brains. PMID- 29147639 TI - Australian adults' behaviours, knowledge and perceptions of risk factors for heart disease: A cross-sectional study. AB - This research aimed to determine Australian adults' perceptions of risk factors for heart disease, self-reported behaviours relating to modifiable risk factors, and knowledge of leading causes of death. This study reports on HeartWatch survey data collected between January 2015 and December 2015 in a sample of Australian adults. The setting of the research was Australian communities, with all states and territories represented in the final sample. Participants were Australian adults aged 30-59 years (n = 8425), and were representative of the wider Australian population based on key demographic and health characteristics. Half of the sample overall correctly identified heart disease as the biggest underlying cause of death of males, and 26% for women. For risk factors for heart disease, respondents most frequently reported; poor diet (58.2%, 95%CI 57.0 59.1), physical inactivity (49.0%, 95%CI 47.9-50.1) and smoking (38.7%, 95%CI 37.7-39.8). A low proportion (< 10%) recognised underlying clinical risk factors for heart disease including high blood pressure (6.3%, 95%CI 5.8-6.8) and dyslipidaemia (9.8%, 95%CI 9.2-10.5). This study revealed broad misconceptions with regard to the leading cause of death and risk factors for heart disease among Australian men and women. Overall the lack of understanding in all groups suggests the need for a comprehensive national campaign reaching schools and the broad adult population. The health system alone cannot achieve national and international targets for disease prevention without understanding and engagement in the general community. PMID- 29147640 TI - Robinsoniella peoriensis infection related to right femoral hardware. AB - Discovered in swine manure relatively recently, Robsinoniella peoriensis is a gram-positive anaerobic bacilli that has been reported to cause human infections. Its antimicrobial susceptibility, epidemiology and overall pathogenicity are still not fully understood. We report a case of a hardware related soft tissue infection in the right femur caused by Robinsoneilla peoriensis following an open reduction internal fixation in a 67 year old immunocompetent woman. The patient was successfully treated with six weeks of ertapenem. PMID- 29147642 TI - Recurrent Cystoisospora belli in a patient with HTLV-1 infection. PMID- 29147641 TI - Severity of acute Zika virus infection: A prospective emergency room surveillance study during the 2015-2016 outbreak in Suriname. AB - Acute Zika virus (ZIKV) infection is usually mild and self-limiting. Earlier, we reported three cases of fatal acute ZIKV infection in patients without typical signs of ZIKV, but rather with criteria of systemic inflammation response syndrome (SIRS). To follow up these observations, we prospectively included patients at the emergency room with temperature instability and suspected to have acute ZIKV infection, SIRS, or both. A total of 102 patients were included of whom N = 21 (21%) were suspected of acute ZIKV infection, N = 56 (55%) of acute ZIKV infection with SIRS criteria, and N = 25 (24%) of SIRS alone. ZIKV-PCR was positive in N = 21 (20%) patients. Eight (38%) ZIKV-positive patients needed admission to the hospital of whom four (50%) presented with SIRS alone. One ZIKV positive patient had vascular co-morbidity and died following shock and severe coagulopathy. We confirm the hypothesis that acute ZIKV infection can present atypical and severely with systemic inflammation and have lethal course particularly amongst patients with significant prior disease. PMID- 29147643 TI - Renal vein tumor thrombus from metastatic anal gland adenocarcinoma. AB - A 62-year-old female with a history of anal gland adenocarcinoma presents with metastatic disease to the kidney with renal vein tumor thrombus extending into the inferior vena cava (IVC). Metastatic disease to the kidney with renal vein tumor thrombus is extremely rare with only several cases described in the literature. We present the first reported case of metastatic anal gland adenocarcinoma to the kidney with renal vein tumor thrombus. PMID- 29147644 TI - How are lung cancer risk perceptions and cigarette smoking related?-testing an accuracy hypothesis. AB - Background: Subjective risk perception is an important theoretical construct in the field of cancer prevention and control. Although the relationship between subjective risk perception and health behaviors has been widely studied in many health contexts, the causalities and associations between the risk perception of developing lung cancer and cigarette smoking have been inconsistently reported among studies. Such inconsistency may be from discrepancies between study designs (cross-sectional versus longitudinal designs) and the three hypotheses (i.e., the behavior motivation hypothesis, the risk reappraisals hypothesis, and the accuracy hypothesis) testing different underlying associations between risk perception and cigarette-smoking behaviors. To clarify this issue, as an initial step, we examined the association between absolute and relative risk perceptions of developing lung cancer and cigarette-smoking behaviors among a large, national representative sample of 1,680 U.S. adults by testing an accuracy hypothesis (i.e., people who smoke accurately perceived a higher risk of developing lung cancer). Methods: Data from the U.S. Health Information National Trends Survey (HINTS) were analyzed using logistic regression and multivariate linear regression to examine the associations between risk perception and cigarette smoking behaviors among 1,680 U.S. adults. Results: Findings from this cross sectional survey suggest that absolute and relative risk perceptions were positively and significantly correlated with having smoked >100 cigarettes during lifetime and the frequency of cigarette smoking. Only absolute risk perception was significantly associated with the number of cigarettes smoked per day among current smokers. Conclusions: Because both absolute and relative risk perceptions are positively related to most cigarette-smoking behaviors, this study supports the accuracy hypothesis. Moreover, absolute risk perception might be a more sensitive measurement than relative risk perception for perceived lung cancer risk. Longitudinal research is needed in the future to investigate other types of risk perception-risk behavior hypotheses-the behavior motivation and the risk reappraisals hypotheses-among nationally representative samples to further examine the causations between risk perception of obtaining lung cancer and smoking behaviors. PMID- 29147645 TI - Real-world cure rates for hepatitis C virus treatments that include simeprevir and/or sofosbuvir are comparable to clinical trial results. AB - AIM: To assess the real-world effectiveness and cost of simeprevir (SMV), and/or sofosbuvir (SOF)-based therapy for chronic hepatitis C virus (HCV) infection. METHODS: The real-world performance of patients treated with SMV/SOF +/- ribavirin (RBV), SOF/RBV, and SOF/RBV with pegylated-interferon (PEG) were analyzed in a consecutive series of 508 patients with chronic HCV infection treated at a single academic medical center. Patients with genotypes 1 through 4 were included. Rates of sustained virological response - the absence of a detectable serum HCV RNA 12 wk after the end of treatment [sustained virological response (SVR) 12] - were calculated on an intention-to-treat basis. Costs were calculated from the payer's perspective using Medicare/Medicaid fees and Redbook Wholesale Acquisition Costs. Patient-related factors associated with SVR12 were identified using multivariable logistic regression. RESULTS: SVR12 rates were as follows: 86% (95%CI: 80%-91%) among 178 patients on SMV/SOF +/- RBV; 62% (95%CI: 55%-68%) among 234 patients on SOF/RBV; and 78% (95%CI: 68%-86%) among 96 patients on SOF/PEG/RBV. Mean costs-per-SVR12 were $174442 (standard deviation: +/- $18588) for SMV/SOF +/- RBV; $223003 (+/- $77946) for SOF/RBV; and $126496 (+/- $31052) for SOF/PEG/RBV. Among patients on SMV/SOF +/- RBV, SVR12 was less likely in patients previously treated with a protease inhibitor [odds ratio (OR): 0.20, 95%CI: 0.06-0.56]. Higher bilirubin (OR: 0.47, 95%CI: 0.30-0.69) reduced the likelihood of SVR12 among patients on SOF/RBV, while FIB-4 score >= 3.25 reduced the likelihood of SVR12 (OR: 0.18, 95%CI: 0.05-0.59) among those on SOF/PEG/RBV. CONCLUSION: SVR12 rates for SMV and/or SOF-based regimens in a diverse real-world population are comparable to those in clinical trials. Treatment failure accounts for 27% of costs. PMID- 29147646 TI - Creation and pilot testing of cases for case-based learning: A pedagogical approach for pathology cancer diagnosis. AB - Background: Case-based learning (CBL) is an established pedagogical active learning method used in various disciplines and defined based on the field of study and type of case. The utility of CBL for teaching specific aspects of cancer diagnosis to practising pathologists has not been previously studied in sub-Saharan Africa. Objectives: We aimed to pilot test standardised cancer cases on a group of practising pathologists in sub-Saharan Africa to evaluate case content, clarity of questions and delivery of content. Methods: Expert faculty created cases for the four most commonly diagnosed cancers. The format included mini-cases and bullet cases which were all open-ended. The questions dealt with interpretation of clinical information, gross specimen examination, morphologic characteristics of tumours, ancillary testing, reporting and appropriate communication to clinicians. Results: Cases on breast, cervical, prostate and colorectal cancers were tested on seven practising pathologists. Each case took an average of 45-90 min to complete.Questions that were particularly challenging to testers were on: Specimens they should have been but for some reason were not exposed to in routine practice.Ancillary testing and appropriate tumour staging.New knowledge gained included tumour grading and assessment of radial margins. Revisions to cases were made based on testers' feedback, which included rewording of questions to reduce ambiguity and adding of tables to clarify concepts. Conclusion: Cases were created for CBL in Kenya, but these are applicable elsewhere in Africa and beyond to teach cancer diagnosis. The pilot testing of cases prepared faculty for the actual CBL course and feedback provided by the testers assisted in improving the questions and impact on day-to-day practice. PMID- 29147647 TI - Serum Albumin Is Independently Associated with Persistent Organ Failure in Acute Pancreatitis. AB - Background and Aims: To investigate the association between serum albumin levels within 24 hrs of patient admission and the development of persistent organ failure in acute pancreatitis. Methods: A total of 700 patients with acute pancreatitis were enrolled. Multivariate logistic regression and subgroup analysis determined whether decreased albumin was independently associated with persistent organ failure and mortality. The diagnostic performance of serum albumin was evaluated by the area under Receiver Operating Characteristic (ROC) curves. Results: As levels of serum albumin decrease, the risk of persistent organ failure significantly increases (Ptrend < 0.001). The incidence of organ failure was 3.5%, 10.6%, and 41.6% in patients with normal albumin and mild and severe hypoalbuminaemia, respectively. Decreased albumin levels were also proportionally associated with prolonged hospital stay (Ptrend < 0.001) and the risk of death (Ptrend < 0.001). Multivariate analysis suggested that biliary etiology, chronic concomitant diseases, hematocrit, blood urea nitrogen, and the serum albumin level were independently associated with persistent organ failure. Blood urea nitrogen and the serum albumin level were also independently associated with mortality. The area under ROC curves of albumin for predicting organ failure and mortality were 0.78 and 0.87, respectively. Conclusion: A low serum albumin is independently associated with an increased risk of developing of persistent organ failure and death in acute pancreatitis. It may also be useful for the prediction of the severity of acute pancreatitis. PMID- 29147649 TI - Knockdown of SIRT1 Suppresses Bladder Cancer Cell Proliferation and Migration and Induces Cell Cycle Arrest and Antioxidant Response through FOXO3a-Mediated Pathways. AB - Bladder cancer (BCa) is one of the most common tumors, but its underlying mechanism has not been fully clarified. Our transcriptome analysis suggested a close link of Sirtuins, Peroxisome Proliferator-Activated Receptor (PPAR), cell cycle regulation, reactive oxygen species (ROS) metabolism, and Forkhead Box Class O (FOXO) signaling pathway in BCa. SIRT1 is a key member of Sirtuins, playing important roles in aging and energy metabolism, which has been reported to be involved in various metabolic diseases and tumors. We observed that SIRT1 was upregulated in BCa tissues at both mRNA and protein levels. By establishing a SIRT1-knockdown BCa cell model, our results suggested that proliferation and viability were suppressed. Moreover, migration rate was inhibited as well, possibly via reduction of epithelial-mesenchymal transition (EMT). In addition, cell cycle arrest was significantly induced, consisting with strongly decreased proteins involved (CDK2/4/6). Furthermore, ROS production was slightly reduced, accompanied by increasing of antioxidant enzymes and total/acetylated FOXO3a. Consistently with our Path-net analysis, we observed no significant alteration of apoptosis in the SIRT1-knockdown BCa cells. Taken together, our results suggested that SIRT1 deficiency in BCa cells could suppress cell viability by activating antioxidant response and inducing cell cycle arrest possibly via FOXO3a-related pathways. PMID- 29147648 TI - Molecular Crosstalking among Noncoding RNAs: A New Network Layer of Genome Regulation in Cancer. AB - Over the past few years, noncoding RNAs (ncRNAs) have been extensively studied because of the significant biological roles that they play in regulation of cellular mechanisms. ncRNAs are associated to higher eukaryotes complexity; accordingly, their dysfunction results in pathological phenotypes, including cancer. To date, most research efforts have been mainly focused on how ncRNAs could modulate the expression of protein-coding genes in pathological phenotypes. However, recent evidence has shown the existence of an unexpected interplay among ncRNAs that strongly influences cancer development and progression. ncRNAs can interact with and regulate each other through various molecular mechanisms generating a complex network including different species of RNAs (e.g., mRNAs, miRNAs, lncRNAs, and circRNAs). Such a hidden network of RNA-RNA competitive interactions pervades and modulates the physiological functioning of canonical protein-coding pathways involved in proliferation, differentiation, and metastasis in cancer. Moreover, the pivotal role of ncRNAs as keystones of network structural integrity makes them very attractive and promising targets for innovative RNA-based therapeutics. In this review we will discuss: (1) the current knowledge on complex crosstalk among ncRNAs, with a special focus on cancer; and (2) the main issues and criticisms concerning ncRNAs targeting in therapeutics. PMID- 29147650 TI - Mitochondria Associated MicroRNA Expression Profiling of Heart Failure. AB - Heart failure (HF) is associated with mitochondrial dysfunction and energy metabolism impairment. MicroRNAs are implicated in the development of heart failure. However, the mitochondria enriched microRNA during heart failure remains elusive. Here, we generated a pressure overload-induced early and late stage heart failure model at 4 weeks and 8 weeks following transverse aortic constriction (TAC) in mice. We found that expression of mitochondrion protein COX4 was highly enriched in isolated mitochondria from cardiac tissues while GAPDH could hardly be detected. Furthermore, small RNA sequencing for mitochondria RNAs from failing hearts was performed. It was found that 69 microRNAs were upregulated and 2 were downregulated in early heart failure, while 16 microRNAs were upregulated and 6 were downregulated in late heart failure. 15 microRNA candidates were measured in both mitochondria and total cardiac tissues of heart failure by real-time PCR. MiR-696, miR-532, miR-690, and miR-345-3p were enriched in mitochondria from the failing heart at early stage. Bioinformatics analysis showed that mitochondria enriched microRNAs in HF were associated with energy metabolism and oxidative stress pathway. For the first time, we demonstrated microRNAs were enriched in mitochondria during heart failure, which established a link between microRNA and mitochondrion in heart failure. PMID- 29147651 TI - Prevalence and Relevance of Pruritus in Pregnancy. AB - Pregnant women are at greater risk to suffer from chronic pruritus, but data on this symptom in this group is very limited. The aim of this study was to investigate the prevalence, clinical characteristics, and the importance of pruritus in pregnant women. A total of 292 consecutive pregnant women at the 33.0 +/- 6.1 weeks of gestation (WoG) were recruited into this prospective, cross sectional study. All patients underwent thorough anamnesis and detailed physical examination with the special emphasis on pruritus. Pruritus was assessed according to Visual Analogue Scale (VAS). Quality of life was measured with the Dermatology Life Quality Index (DLQI). The point prevalence of pruritus was 20.2% (n = 59), while pruritus prevalence during the entire pregnancy was 38.0% (n = 111). Pruritus started on average at the 27.2 +/- 7.6 WoG; it was significantly more common among women in third trimester. The mean VAS was 4.8 (+/-2.4) points. The DLQI scoring significantly correlated with VAS (r = 0.52, p < 0.001). Based on the results of our study about one-third of women suffer from pruritus during pregnancy. Many of them find it a very distressing and disturbing symptom. PMID- 29147652 TI - Identification of Potent Chloride Intracellular Channel Protein 1 Inhibitors from Traditional Chinese Medicine through Structure-Based Virtual Screening and Molecular Dynamics Analysis. AB - Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score. Then, 30 potent hits were achieved from the top 500 TCM compounds using cluster and ligand-protein interaction analysis. Finally, MD simulation was employed to validate the stability of interactions between each hit and CLIC1 protein from docking simulation, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis was used to refine the virtual hits. Six TCM compounds with top MM-GBSA scores and ideal-binding models were confirmed as the final hits. Our study provides information about the interaction between TCM compounds and CLIC1 protein, which may be helpful for further experimental investigations. In addition, the top 6 natural products structural scaffolds could serve as building blocks in designing drug-like molecules for CLIC1 inhibition. PMID- 29147653 TI - Health Status and the Demand for Healthcare among the Elderly in the Rural Quoc Oai District of Hanoi in Vietnam. AB - Background: Vietnam is experiencing an unprecedented demographic transition. Its proportion of elderly people is growing rapidly. Objective: This study explored the health status and health-related quality of life (HRQoL) of rural elderly Vietnamese and assessed their needs for healthcare services. Design: This study used a survey with stratified proportion sampling and quota assignment. In 2016, data was collected from 713 people in the rural Quoc-Oai district of Hanoi aged 60 or older. Results: The mean age of the respondents was 70.9. Both self-rated health status and functional status decreased with age. Women reported more functional limitations than men. Musculoskeletal disorders were the most frequently reported chronic diseases, followed by hypertension, gastrointestinal diseases, and cardiovascular diseases. Age, self-rated health status, BMIs, and the number of noncommunicable diseases (NCDs) were found to be significant determinants of HRQoL, after controlling for socioeconomic effects. More than half the respondents requested more healthcare information, particularly on disease management. Conclusions: Vietnam's healthcare system is being challenged to make health services easily accessible and meet the growing needs for chronic illness management, risk reduction, promoting healthy lifestyles, and improving the aging population's quality of life. PMID- 29147654 TI - Susceptibility of In Vitro Melanoma Skin Cancer to Photoactivated Hypericin versus Aluminium(III) Phthalocyanine Chloride Tetrasulphonate. AB - The sensitivity of human melanoma cells to photoactivated Hypericin (Hyp) compared to aluminium(III) phthalocyanine chloride tetrasulphonate (AlPcS4Cl) is reported in this study. Melanoma cells (A375 cell line) were treated with various concentrations of Hyp or AlPcS4Cl alone, for 1, 4, and 24 hrs; varying doses of laser irradiation alone (594 or 682 nm); or optimal concentrations of PSs combined with laser irradiation. Changes in cell morphology, viability, membrane integrity, and proliferation after treatment of cells were determined using inverted microscopy, Trypan blue cell exclusion, Lactate Dehydrogenase (LDH) membrane integrity, and adenosine triphosphate (ATP) cell proliferation assay, respectively. More than 60% of cell survival was observed when cells were treated with 2.5 MUM of Hyp or AlPcS4Cl alone at all incubation times or with 5 J/cm2 of 594 or 682 nm laser alone. Combination of PSs and respective lasers leads to a statistically significant incubation time-dependent decrease in survival of cells. Flow cytometry using the FITC Annexin V/PI apoptosis kit demonstrated that cell death induced after Hyp-PDT is via early and late apoptosis whereas early apoptosis was the main mechanism observed with AlPcS4Cl-PDT. Hyp-PDT compared to AlPcS4Cl-PDT is indicated to be a more effective cancer cell death inducer in melanoma cells. PMID- 29147655 TI - Magnetic Resonance Colonography May Predict the Need for Bowel Resection in Colorectal Endometriosis. AB - Purpose: To define if MRI findings in patients with deep pelvic endometriosis (DPE) may be predictive for the need of bowel resection. Material and Methods: A retrospective survey of 196 pelvic MRIs of women who received laparoscopic procedures for DPE was carried out. A pelvic MRI was performed in all patients: it consisted in T2w-TSE sequences in axial, sagittal, and coronal planes and T1w and THRIVE sequences in the axial plane; the exam was completed by MR Colonography. Intestinal lesions were measured in short and long axis and the degree of stenosis was established. A multivariate logistic regression was used to identify the predictors of intestinal resection. Results: 57/196 patients received an intestinal resection. Multivariate logistic regression demonstrated a predictive value of short axis (Odds-Ratio = 2.29, p = 0.011) and stenosis (Odds Ratio = 1.20, p = 0.003). ROC analysis showed that a cut-off value of 11 mm for the short axis and 30% for the stenosis may correctly classify, respectively, 96,94% (sensitivity 92,9% and specificity 98,56%) and 97,96% (sensitivity 94,74% and specificity 99,3%) of the cases. Conclusion: The presence of an endometriotic rectal nodule > 11 mm in short axis causing a stenosis > 30% in pelvic MRI reliably predicts the need of a rectal resection. PMID- 29147656 TI - Polysaccharides from Trichosanthes Fructus via Ultrasound-Assisted Enzymatic Extraction Using Response Surface Methodology. AB - An efficient procedure for ultrasound-assisted enzymatic extraction of crude polysaccharides from Trichosanthes Fructus (crude TFP) using response surface methodology (RSM) was developed. The Box-Behnken design was applied to optimize the effects of pH (X1), enzyme amount (X2), extraction temperature (X3), and liquid-to-solid ratio (X4) on the extraction. The statistical analysis indicated that the independent variables (X4, X2, and X3), the quadratic coefficients (X12, X22, X32, and X42), and the interaction coefficient (X1X3) had significant impact on the yield of crude TFP. The optimal conditions were determined as follows: pH 4.5, enzyme amount 5000 u/g, extraction temperature 45 degrees C, and liquid-to solid ratio 30 ml/g. The experimental yield of crude TFP was 6.58%, which was very close to the predicted yield of 6.71%. TFPI was then purified and characterized with Sephadex G-100 column, UV-Vis, GPC, and FT-IR. The average molecular weight of TFPI was calculated to be 1.49 * 105 Da. TFPI exhibited strong reducing power and possessed not only remarkable scavenging activities against ABTS*+ and DPPH radicals, but also high antitumor activities in C4-2, DU145, and PC3 cells. The results suggest that Trichosanthes Fructus and TFPI could be a novel potent natural medicine with antioxidant and antitumor activities. PMID- 29147657 TI - Morphometric Analysis and Classification of the Cross-Sectional Shape of the C2 Lamina. AB - A thorough understanding of the morphology of the lamina of the second cervical vertebra (C2) is important for safe C2 translaminar screw placement. Although anatomical characteristics of the C2 lamina have been widely documented, individual differences in morphology have not been addressed. The aim of this study was to morphometrically analyze the cross-sectional shape of the C2 lamina and classify the shape to describe individual differences. Morphometric analysis was conducted on 145 three-dimensional C2 models based on computerized tomography images from Korean adult cadavers. Several parameters were measured on a cross section image of the lamina model. Based on numerical criteria, all of the C2 lamina's cross-sectional shapes could be categorized into three distinctive morphological types: pyriform, ellipse, and obpyriform shapes. We confirmed that most Koreans can accommodate C2 translaminar screw placement with a lower limit of the 95% confidence interval of thickness measured at 6.26 mm. Morphometric analysis suggested that the obpyriform-shaped lamina (4.48%) is likely to require screw trajectory adjustment to avoid cortical breakout of the screw. Our results will enhance current anatomical understanding of the C2 lamina and thus facilitate safer C2 translaminar screw placement. PMID- 29147658 TI - Corrigendum to "Chitosan Prevents Gentamicin-Induced Nephrotoxicity via a Carbonyl Stress-Dependent Pathway". AB - [This corrects the article DOI: 10.1155/2015/675714.]. PMID- 29147659 TI - Retracted: Study of Effect of Salvianolic Acid B on Motor Function Recovery in Rats with Spinal Cord Injury. AB - [This retracts the article DOI: 10.1155/2014/931850.]. PMID- 29147660 TI - Analytical Validation of a New Enzymatic and Automatable Method for d-Xylose Measurement in Human Urine Samples. AB - Hypolactasia, or intestinal lactase deficiency, affects more than half of the world population. Currently, xylose quantification in urine after gaxilose oral administration for the noninvasive diagnosis of hypolactasia is performed with the hand-operated nonautomatable phloroglucinol reaction. This work demonstrates that a new enzymatic xylose quantification method, based on the activity of xylose dehydrogenase from Caulobacter crescentus, represents an excellent alternative to the manual phloroglucinol reaction. The new method is automatable and facilitates the use of the gaxilose test for hypolactasia diagnosis in the clinical practice. The analytical validation of the new technique was performed in three different autoanalyzers, using buffer or urine samples spiked with different xylose concentrations. For the comparison between the phloroglucinol and the enzymatic assays, 224 urine samples of patients to whom the gaxilose test had been prescribed were assayed by both methods. A mean bias of -16.08 mg of xylose was observed when comparing the results obtained by both techniques. After adjusting the cut-off of the enzymatic method to 19.18 mg of xylose, the Kappa coefficient was found to be 0.9531, indicating an excellent level of agreement between both analytical procedures. This new assay represents the first automatable enzymatic technique validated for xylose quantification in urine. PMID- 29147661 TI - An EEG Tool for Monitoring Patient Engagement during Stroke Rehabilitation: A Feasibility Study. AB - Objective: Patient engagement is of major significance in neural rehabilitation. We developed a real-time EEG marker for attention, the Brain Engagement Index (BEI). In this work we investigate the relation between the BEI and temporary functional change during a rehabilitation session. Methods: First part: 13 unimpaired controls underwent BEI monitoring during motor exercise of varying levels of difficulty. Second part: 18 subacute stroke patients underwent standard motor rehabilitation with and without use of real-time BEI feedback regarding their level of engagement. Single-session temporary functional changes were evaluated based on videos taken before and after training on a given task. Two assessors, blinded to feedback use, assessed the change following single-session treatments. Results: First part: a relation between difficulty of exercise and BEI was identified. Second part: temporary functional change was associated with BEI level regardless of the use of feedback. Conclusions: This study provides preliminary evidence that when BEI is higher, the temporary functional change induced by the treatment session is better. Further work is required to expand this preliminary study and to evaluate whether such temporary functional change can be harnessed to improve clinical outcome. Clinical Trial Registration: Registered with clinicaltrials.gov, unique identifier: NCT02603718 (retrospectively registered 10/14/2015). PMID- 29147662 TI - Effectiveness of a Lytic Phage SRG1 against Vancomycin-Resistant Enterococcus faecalis in Compost and Soil. AB - Nosocomial infections caused by vancomycin-resistant Enterococcus have become a major problem. Bacteriophage therapy is proposed as a potential alternative therapy. Bacteriophages are viruses that infect bacteria and are ubiquitous in nature. Lytic bacteriophage was isolated from sewage water that infects VREF, the causative agent of endocarditis, bacteraemia, and urinary tract infections (UTIs). The phage produced clear plaques with unique clear morphology and well defined boundaries. TEM results of phage revealed it to be 108 +/- 0.2 nm long and 90 +/- 0.5 nm wide. The characterization of bacteriophage revealed that infection process of phage was calcium and magnesium dependent and phage titers were highest under optimum conditions for VREF, with an optimal temperature range of 37-50 degrees C. The maximum growth was observed at 37 degrees C, hence having 100% viability. The latent period for phage was small with a burst size of 512 viral particles per bacterial cell. The phage was tested against various clinical strains and results proved it to be host specific. It can be used as a potential therapeutic agent for VREF infections. The phage efficiently eradicated VREF inoculated in cattle compost, poultry compost, and a soil sample which makes it a potential agent for clearing compost and soil sample. PMID- 29147663 TI - Can the Weight of an External Breast Prosthesis Influence Trunk Biomechanics during Functional Movement in Postmastectomy Women? AB - Introduction: Recent papers indicate that one-side mastectomy can produce deleterious effects on the posture and musculoskeletal system. This study was conducted to better understand the underlying mechanisms involved in trunk motion in external prosthesis users. Objective: The aim was to evaluate the changes in surface electromyographic (SEMG) activity of the erector spinae muscles (ES) in postmastectomy women with and without breast prostheses during functional body movement tests. Methods: In 51 one-side postmastectomy women the SEMG muscle activity of bilateral ES was measured during symmetrical and asymmetrical dynamic activities in a counterbalanced manner with different weights of the breast prosthesis. Range-of-motion measurements were taken for forward bending, backward bending, lateral bending, and rotation. Results: The mean level of the ES activity in the lumbar region was not affected by the weight of the external breast prosthesis during most of the functional body tests (P > 0.05). The activity of ES during functional body tests with and without different external breast prostheses did not differ between the two sides of the trunk (mastectomy and nonmastectomy) for most of the movement tests (P > 0.05). Conclusion: The lumbar ES activity during functional tests is not associated with the weight of the external breast prosthesis in postmastectomy women. PMID- 29147665 TI - Corrigendum to "Optimal Hemoglobin A1c Levels for Screening of Diabetes and Prediabetes in the Japanese Population". AB - [This corrects the article DOI: 10.1155/2015/932057.]. PMID- 29147664 TI - Reduced Inspiratory Muscle Strength in Patients with Type 2 Diabetes Mellitus and Obstructive Sleep Apnoea. AB - Background: Obstructive sleep apnoea (OSA) is related to type 2 diabetes (T2DM), and it may be associated with reduced inspiratory muscle strength (IMS). The aim of this study was to investigate the IMS in patients with T2DM, with or without OSA. Methods: Patients with T2DM with OSA (n = 33) and without OSA (n = 28) were included. The maximum IMS was tested using the POWERbreathe KH2 device. Reference IMS values were data calculated using an algorithm based on general populations and adjusted for age and gender. Results: There was no difference in IMS between the OSA group (median (range) 77 (35-124) cmH2O) and the non-OSA group (84 (33 122) cmH2O) (p = 0.97). The IMS values were reduced in the OSA group compared with the reference values (92.9 (62.3-100.0) cmH2O) (p = 0.030), whereas the non OSA group did not have reduced IMS. When the IMS values of all T2DM patients were compared with reference values, the IMS values were 79 (33-124) cmH2O and 93.8 (62.3-102.4) cmH2O, respectively (p = 0.017). Conclusion: No difference in IMS between patients with T2DM with or without OSA was found. However, patients with T2DM and OSA had reduced IMS compared with age- and gender-matched references whereas the non-OSA group did not have reduced IMS. PMID- 29147667 TI - Metastasectomy of Solitary Adrenal Metastasis From Small Cell Lung Cancer. AB - Most extensive-stage small cell lung cancers have disseminated disease at diagnosis, and solitary adrenal metastasis from small cell lung cancer is rare. We report the case of a 51-year-old man with extensive-stage small cell lung cancer with solitary right adrenal metastasis (T2N0M1), who was cured with resection of primary tumor, chemotherapy (cisplatin, etoposide), adrenalectomy, consolidative thoracic radiotherapy, and prophylactic cranial irradiation. He remained cancer free, 7.5 years since diagnosis. For small cell lung cancer with solitary adrenal gland metastasis, metastasectomy combined with chemotherapy and radiotherapy can be curative and enable long-term survival. This treatment approach should be further studied, and similar cases should be reported. PMID- 29147666 TI - Sympathetic Denervation Accelerates Wound Contraction but Inhibits Reepithelialization and Pericyte Proliferation in Diabetic Mice. AB - Previous studies focused on the effects of sympathetic denervation with 6 hydroxydopamine (6-OHDA) on nondiabetic wounds, but the effects of 6-OHDA on diabetic wounds have not been previously reported. In this study, treated mice received intraperitoneal 6-OHDA, and control mice received intraperitoneal injections of normal saline. Full-thickness wounds were established on the backs of mice. The wounds were sectioned (four mice per group) for analysis at 2, 5, 7, 10, 14, 17, and 21 days after injury. The wound areas in the control group were larger than those in the treatment group. Histological scores for epidermal and dermal regeneration were reduced in the 6-OHDA-treated group on day 21. The mast cells (MCs) in each field decreased after sympathectomy on days 17 and 21. The expression levels of norepinephrine, epidermal growth factor (EGF), interleukin-1 beta, NG2 proteoglycan, and desmin in the treatment group were less than those in the control group. In conclusion, 6-OHDA delays reepithelialization during wound healing in diabetic mice by decreasing EGF, but increases wound contraction by reducing IL-1beta levels and the number of MCs. Besides, 6-OHDA led to reduced pericyte proliferation in diabetic wounds, which might explain the vascular dysfunction after sympathetic nerve loss in diabetic wounds. PMID- 29147668 TI - Do Magnetic Resonance Imaging Characteristics of Full-Thickness Rotator Cuff Tears Correlate With Sleep Disturbance? AB - Background: Many patients with rotator cuff tears suffer from nocturnal shoulder pain, resulting in sleep disturbance. Purpose: To determine whether rotator cuff tear size correlated with sleep disturbance in patients with full-thickness rotator cuff tears. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patients with a diagnosis of unilateral full-thickness rotator cuff tears (diagnosed via magnetic resonance imaging [MRI]) completed the Pittsburgh Sleep Quality Index (PSQI), a visual analog scale (VAS) quantifying their shoulder pain, and the American Shoulder and Elbow Surgeons (ASES) questionnaire. Shoulder MRI scans were analyzed for anterior-posterior tear size (mm), tendon retraction (mm), Goutallier grade (0-4), number of tendons involved (1-4), muscle atrophy (none, mild, moderate, or severe), and humeral head rise (present or absent). Bivariate correlations were calculated between the MRI characteristics and baseline survey results. Results: A total of 209 patients with unilateral full-thickness rotator cuff tears were included in this study: 112 (54%) female and 97 (46%) male (mean age, 64.1 years). On average, shoulder pain had been present for 24 months. The mean PSQI score was 9.8, and the mean VAS score was 5.0. No significant correlations were found between any of the rotator cuff tear characteristics and sleep quality. Only tendon retraction had a significant correlation with pain. Conclusion: Although rotator cuff tears are frequently associated with nocturnal pain and sleep disruption, this study demonstrated that morphological characteristics of full-thickness rotator cuff tears, such as size and tendon retraction, do not correlate with sleep disturbance and have little to no correlation with pain levels. PMID- 29147669 TI - Cervical Intervertebral Disc Degeneration and Low Cervical Extension Independently Associated With a History of Stinger Syndrome. AB - Background: Stinger syndrome frequently occurs in athletes who compete in collision sports. Sharp pain and impairment of neck motion are major symptoms. Cervical intervertebral disc degeneration (CIDD) is also frequently observed in those who compete in collision sports. Purpose/Hypothesis: To investigate whether CIDD and neck functionality are related to a history of stinger syndrome. The hypothesis was that a significant relationship exists between CIDD and neck motion and a history of stinger syndrome in Japanese collegiate football players. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 49 male Japanese collegiate football players (mean age, 20.0 +/- 1.1 years; mean athletic experience, 3.8 +/- 2.3 years; mean height, 172.3 +/- 4.8 cm; mean weight, 83.1 +/- 12.2 kg) were subdivided into athletes with stinger syndrome (stinger group) and those without (control group). Stinger syndrome was confirmed based on a questionnaire and interview. CIDD was assessed by using T2-weighted magnetic resonance imaging. Range of motion (ROM) and isometric muscle strength were measured for neck function testing. Results: Thirty-nine percent (19/49) of athletes had at least 1 episode of stinger syndrome. The prevalence of CIDD was significantly higher in the stinger group (68%) than in the control group (30%) (P < .01). A statistically significant difference in cervical extension ROM was found between the stinger group (50.9 degrees +/- 11.1 degrees ) and the control group (60.2 degrees +/- 11.4 degrees ) (P < .01). Logistic regression analysis showed that CIDD and low cervical extension were independently associated with a history of stinger syndrome. Conclusion: Study results suggest that stinger syndrome is associated with CIDD and low cervical extension in collegiate football players. PMID- 29147670 TI - Isokinetic Extension Strength Is Associated With Single-Leg Vertical Jump Height. AB - Background: Isokinetic strength testing is an important tool in the evaluation of the physical capacities of athletes as well as for decision making regarding return to sports after anterior cruciate ligament (ACL) reconstruction in both athletes and the lay population. However, isokinetic testing is time consuming and requires special testing equipment. Hypothesis: A single-jump test, regardless of leg dominance, may provide information regarding knee extension strength through the use of correlation analysis of jump height and peak torque of isokinetic muscle strength. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 169 patients who underwent ACL reconstruction were included in this study. Isokinetic testing was performed on the injured and noninjured legs. Additionally, a single-leg countermovement jump was performed to assess jump height using a jump accelerometer sensor. Extension strength values were used to assess the association between isokinetic muscle strength and jump height. Results: The sample consisted of 60 female (mean age, 20.8 +/- 8.3 years; mean weight, 61.7 +/- 6.5 kg; mean height, 167.7 +/- 5.3 cm) and 109 male (mean age, 23.2 +/- 7.7 years; mean weight, 74.6 +/- 10.2 kg; mean height, 179.9 +/- 6.9 cm) patients. Bivariate correlation analysis showed an association (r = 0.56, P < .001) between jump height and isokinetic extension strength on the noninvolved side as well as an association (r = 0.52, P < .001) for the involved side. Regression analysis showed that in addition to jump height (beta = 0.49, P < .001), sex (beta = -0.17, P = .008) and body mass index (beta = 0.37, P < .001) affected isokinetic strength. The final model explained 51.1% of the variance in isokinetic muscle strength, with jump height having the strongest impact (beta = 0.49, P < .001) and explaining 31.5% of the variance. Conclusion: Initial analysis showed a strong association between isokinetic strength and jump height. The study population encompassed various backgrounds, skill levels, and activity profiles, which might have affected the outcome. Even after controlling for age and sex, isokinetic strength was still moderately associated with jump height. Therefore, the jump technique and type of sport should be considered in future research. PMID- 29147671 TI - Distal 22q11.2 Microduplication: Case Report and Review of the Literature. AB - Distal chromosome 22q11.2 microduplications are associated with a wide range of phenotypes and unclear pathogenicity. The authors report on a 3-year-old girl with global developmental delay harboring a de novo 1.24 Mb distal chromosome 22q11.2 microduplication and a paternally inherited 0.25 Mb chromosome 4p14 microduplication. The authors review clinical features of 30 reported cases of distal 22q11.2 duplications. Common features include developmental delay (93%), neuropsychiatric features (26%), and nonspecific facial dysmorphisms (74%). In 70% of cases, the distal 22q11.2 duplications were inherited, and the majority of the carrier parents were phenotypically normal. Furthermore, 30% of probands carried an additional copy number variant. Review of the phenotype in individuals carrying microduplications involving similar low copy repeats (LCR) failed to establish any clear genotype-phenotype correlations. Distal 22q11.2 duplications represent a major challenge for genetic counseling and prediction of clinical consequences. Our report suggests a pathogenic role of distal 22q11.2 duplications and supports a "multiple hit" hypothesis underlying its variable expressivity and phenotypic severity. PMID- 29147672 TI - Calcium signaling and transcription: elongation, DoGs, and eRNAs. AB - The calcium ion (Ca2+) is a key intracellular signaling molecule with far reaching effects on many cellular processes. One of the most important such Ca2+ regulated processes is transcription. A body of literature describes the effect of Ca2+ signaling on transcription initiation as occurring mainly through activation of gene-specific transcription factors by Ca2+-induced signaling cascades. However, the reach of Ca2+ extends far beyond the first step of transcription. In fact, Ca2+ can regulate all phases of transcription, with additional effects on transcription-associated events such as alternative splicing. Importantly, Ca2+ signaling mediates reduced transcription termination in response to certain stress conditions. This reduction allows readthrough transcription, generating a highly inducible and diverse class of downstream of gene containing transcripts (DoGs) that we have recently described. PMID- 29147673 TI - The regulation of snail: on the ubiquitin edge. AB - Metastasis accounts for a majority of cancer death. One key feature during metastasis is epithelial-mesenchymal transition (EMT), which is regulated by transcription factors such as Snail and Twist. In non-malignant cells, Snail has a short half-life and is degraded via ubiquitination, but its stability is increased in cancer cell. However, the mechanism by which Snail escapes ubiquitination and degradation remains unknown. Recently, we found that Dub3 is a deubiquinase of Snail. Most importantly, we determined that Dub3 responded to extracellular signals such as IL-6, and that the resultant signaling prevented Snail degradation, and promoted cancer growth, invasion, and migration. In this highlight, we present a concise picture of how the transcription factor Snail is regulated by ubiquitination in cancer cells, the role of Dub3 in this process, and its potential use as a treatment target. PMID- 29147674 TI - Pediatric Otogenic Sigmoid Sinus Thrombosis: Case Report and Literature Reappraisal. AB - The purpose of this study was to review our experience with a single case of mastoiditis associated with sigmoid sinus thrombosis and increased intracranial pressure, and to review the experience of others through prior publications. We reviewed a case of a 6-year-old boy with an acute otitis media and mastoiditis, with associated ipsilateral sigmoid sinus and contralateral distal transverse sinus thrombosis. Based on the literature and our own experience, we conclude that most children with dural sinus thrombosis from acute otitis media and mastoiditis, in the setting of increased intracranial pressure, attain a good neurological outcome with a conservative neurosurgical approach. The mainstay of treatment seems to be appropriate antibiotic coverage and anticoagulation. Surgeries such as external ventricular drain, serial lumbar punctures, intracranial pressure monitor, and endovascular thrombectomy are reserved for patients with neurological deterioration despite maximal medical treatment. PMID- 29147675 TI - Newborn Screening for Sickle Cell Disease in St. Vincent and the Grenadines: Results of a Pilot Newborn Screening Program. AB - Objective: To pilot a newborn screening program for sickle cell disease (SCD) in St. Vincent and the Grenadines using a novel partnership method to determine the feasibility of a universal newborn screening program in this country. Methods: A prospective study of mothers and their newborns was conducted between January 1, 2015, and November 1, 2015, at the country's main hospital. Mothers of infants born at this hospital were offered screening for SCD for their infants. If accepted, the newborn's heel-stick blood specimen was obtained and mailed to the South Carolina Department of Health and Environmental Control Newborn Screening Laboratory for testing. Samples were analyzed for variant hemoglobins using standard laboratory techniques and results were communicated to local physicians. Feasibility was determined by a benchmark of having >50% of SCD patients receive the diagnosis and initiate disease-specific care by 3 months of age. Descriptive statistics were completed using SAS 9.4. Results: There were 1147 newborn infants screened for SCD. Of these, 123 (10.7%) had results indicative of sickle trait and 3 patients (0.3%) were diagnosed with SCD: 1 with HbSS and 2 with HbSC. All 3 patients with SCD received treatment before 3 months of age. Conclusions: A newborn screening program is feasible in this population when partnered with an established newborn screening laboratory. PMID- 29147676 TI - Characteristics of Very Young Hispanic Children Referred for Obesity Management. AB - Information on risks associated with obesity during infancy specific to Hispanic children is scarce. This retrospective medical record review describes characteristics and parenting practices of Hispanic children age <2 years referred for obesity care at a tertiary hospital over a 6-year period. Data on 29 Hispanic children collected from parent-completed assessment forms and clinician documentation were analyzed. Children were of mean age 16.2 +/- 4.9 months; body mass index z scores ranged from 1.5 to 9.4 (mean 4.5 +/- 1.7); 45% were male; 97% received public insurance; 38% were breastfed >=6 months; and 93% had a parent who was overweight or obese. Parenting practices included bottle feeding in bed (50%), regularly drinking sweetened beverages (33%), >=2 hours of screen time (60%), and having a TV in child's bedroom (55%). Better understanding of factors that contribute to the development of rapid weight gain of Hispanic children can inform future clinical and public health interventions. PMID- 29147677 TI - Antimicrobial Resistance Profiles of Bacteria Isolated from the Nasal Cavity of Camels in Samburu, Nakuru, and Isiolo Counties of Kenya. AB - This study was designed to determine antimicrobial resistance profiles of bacteria isolated from the nasal cavity of healthy camels. A total of 255 nasal samples (swabs) were collected in Isiolo, Samburu, and Nakuru counties, Kenya, from which 404 bacterial isolates belonging to various genera and species were recovered. The bacterial isolates included Bacillus (39.60%), coagulase-negative Staphylococcus (29.95%), Streptococcus species other than Streptococcus agalactiae (25.74%), coagulase-positive Staphylococcus (3.96%), and Streptococcus agalactiae (0.74%). Isolates were most susceptible to Gentamicin (95.8%), followed by Tetracycline (90.5%), Kanamycin and Chloramphenicol (each at 85.3%), Sulphamethoxazole (84.2%), Co-trimoxazole (82.1%), Ampicillin (78.9%), and finally Streptomycin (76.8%). This translated to low resistance levels. Multidrug resistance was also reported in 30.5% of the isolates tested. Even though the antibiotic resistance demonstrated in this study is low, the observation is significant, since the few resistant normal flora could be harboring resistance genes which can be transferred to pathogenic bacteria within the animal, to other animals' bacteria and, most seriously, to human pathogens. PMID- 29147679 TI - Dense fluidized granular media in microgravity. AB - Handling and transport of granular media are inevitably governed by the settling of particles. Settling into a dense state is one of the defining characteristics of granular media, among dissipation and absence of thermal agitation. Hence, settling complicates the adaptation of microscopic theories from atomic, molecular, or colloidal media to granular media. It is desirable to provide experiments in which selectively one of the granular characteristics is tuned to test suitable adaptation of a theory. Here we show that gas fluidization of granular media in microgravity is a suitable approach to achieve steady states closer to thermally agitated systems free of settling. We use diffusing-wave spectroscopy to compare the spatial homogeneity and the microscopic dynamics of gas-fluidized granular media on the ground and in drop tower flights with increasing packing densities up to full arrest. The gas fluidization on the ground leads to inhomogeneous states as known from fluidized beds, and partial arrest occurs at packing fractions lower than the full arrested packing. The granular medium in microgravity in contrast attains a homogeneous state with complete mobilization even close to full arrest. Fluidized granular media thus can be studied in microgravity with dynamics and packing fractions not achievable on the ground. PMID- 29147678 TI - A Haplotype Associated with Enhanced Mineralocorticoid Receptor Expression Facilitates the Stress-Induced Shift from "Cognitive" to "Habit" Learning. AB - Stress induces a shift from hippocampus-dependent "cognitive" toward dorsal striatum-dependent "habit" memory. However, not all individuals are susceptible to this shift under stress. Based on pharmacological studies indicating a critical role of the mineralocorticoid receptor (MR) in the stress-induced bias toward dorsal striatal learning, we hypothesized that MR gene variants contribute to these individual differences. In two experiments, healthy participants were genotyped, exposed to a stressor or control manipulation and performed a learning task that can be solved using hippocampal or dorsal striatal systems, while electroencephalography (EEG; Experiment I) or functional magnetic resonance imaging (fMRI; Experiment II) measurements were taken. Stress led to a shift from hippocampal to dorsal striatal learning which was more pronounced in homo- and heterozygous carriers of a six single nucleotide polymorphisms (SNPs)-comprising haplotype containing the alleles of two MR SNPs associated with increased MR expression and transactivational activity (MR-2G/C C [rs2070951], MR-I180V A [rs5522]). This stress-induced shift toward habit memory was paralleled by an increased feedback-related negativity (FRN), which may reflect striatal processing, and increased caudate activation. Carriers of the MR haplotype showed a reduced P3a, an event-related potential thought to indicate cognitive processing, and reduced hippocampal activity after stress. Moreover, stress resulted in reduced amygdala-hippocampus connectivity and the decrease in amygdala connectivity to the parahippocampal cortex was particularly pronounced in MR haplotype carriers. Our findings indicate that genetic variants associated with enhanced MR expression facilitate a stress-induced shift from hippocampal toward dorsal striatal learning, most likely via impaired hippocampal processing and reduced amygdala-hippocampus cross talk, allowing the dorsal striatum to guide behavior under stress. PMID- 29147680 TI - Coculture of meniscus cells and mesenchymal stem cells in simulated microgravity. AB - Simulated microgravity has been shown to enhance cartilaginous matrix formation by chondrocytes and chondrogenesis of mesenchymal stem cells (MSCs). Similarly, coculture of primary chondrocytes with MSCs has been shown as a strategy to simultaneously retain the differentiated phenotype of chondrocytes and enhance cartilaginous matrix formation. In this study, we investigated the effect of simulated microgravity on cocultures of primary human meniscus cells and adipose derived MSCs. We used biochemical, qPCR, and immunofluorescence assays to conduct our investigation. Simulated microgravity significantly enhanced cartilaginous matrix formation in cocultures of primary meniscus cells and adipose-derived MSCs. The enhancement was accompanied by increased hypertrophic differentiation markers, COL10A1 and MMP-13, and suppression of hypertrophic differentiation inhibitor, gremlin 1 (GREM1). PMID- 29147681 TI - Crimped Nanofibrous Biomaterials Mimic Microstructure and Mechanics of Native Tissue and Alter Strain Transfer to Cells. AB - To fully recapitulate tissue microstructure and mechanics, fiber crimping must exist within biomaterials used for tendon/ligament engineering. Existing crimped nanofibrous scaffolds produced via electrospinning are dense materials that prevent cellular infiltration into the scaffold interior. In this study, we used a sacrificial fiber population to increase the scaffold porosity and evaluated the effect on fiber crimping. We found that increasing scaffold porosity increased fiber crimping and ensured that the fibers properly uncrimped as the scaffolds were stretched by minimizing fiber-fiber interactions. Constitutive modeling demonstrated that the fiber uncrimping produced a nonlinear mechanical behavior similar to that of native tendon and ligament. Interestingly, fiber crimping altered strain transmission to the nuclei of cells seeded on the scaffolds, which may account for previously observed changes in gene expression. These crimped biomaterials are useful for developing functional fiber-reinforced tissues and for studying the effects of altered fiber crimping due to damage or degeneration. PMID- 29147682 TI - Synthesis and Application of Injectable Bioorthogonal Dendrimer Hydrogels for Local Drug Delivery. AB - We developed novel dendrimer hydrogels (DH)s on the basis of bioorthogonal chemistry, in which polyamidoamine (PAMAM) dendrimer generation 4.0 (G4) functionalized with strained alkyne dibenzocyclooctyne (DBCO) via PEG spacer (Mn = 2,000 g/mol) underwent strain-promoted azide-alkyne cycloaddition (SPAAC) with polyethylene glycol bisazide (PEG-BA) (Mn= 20,000 g/mol) to generate a dendrimer PEG cross-linked network. This platform offers a high degree of functionality and modularity. A wide range of structural parameters including dendrimer generation, degree of PEGylation, loading density of clickable DBCO groups, PEG-BA chain length as well as the ratio of clickable dendrimer to PEG-BA and their concentrations can be readily manipulated to tune chemical and physical properties of DHs. We used this platform to prepare an injectable liquid DH. This bioorthogonal DH exhibited high cytocompatibility and enabled sustained release of the anticancer drug 5-fluorouracil (5-FU). Following intratumoral injection, the DH/5-FU formulation significantly suppressed tumor growth and improved survival of HN12 tumor-bearing mice by promoting tumor cell death as well as by reducing tumor cell proliferation and angiogenesis. PMID- 29147683 TI - Impact of an Individualized Physical Activity Intervention on Improving Mental Health Outcomes in Family Caregivers of Persons with Dementia: A Randomized Controlled Trial. AB - Purpose: This study examined secondary benefits of an individualized physical activity intervention on improving dementia family caregivers' subjective burden, depressive symptoms and positive affect. Design and Methods: A community-based randomized controlled trial (RCT) was implemented with family caregivers of persons with dementia (N = 211) who received the Enhanced Physical Activity Intervention (EPAI: treatment intervention, n = 106) or the Caregiver Skill Building Intervention (CSBI: control intervention, n = 105). Interventions were delivered over 12 months, including a baseline home visit and regularly spaced telephone calls. Data were collected in person at baseline, 6 and 12-months; and telephonically at 3 and 9-months. The EPAI integrated physical activity and caregiving content while the CSBI focused only on caregiving content. Descriptive, bivariate and intention-to-treat analyses using generalized estimating equations (GEE) were performed to examine secondary benefits of the EPAI on family caregiver burden, depressive symptoms and positive affect. Results: Compared to caregivers in the CSBI group, caregivers in the EPAI significantly increased their overall and total moderate physical activity and showed a positive interaction between the intervention and time for positive affect at both six (p = 0.01) and 12-months (p = 0.03). The EPAI was significantly associated with improving burden at 3 months (p = 0.03) but had no significant effect on depressive symptoms. Implications: Caregiver involvement in an individualized physical activity intervention was associated with increased overall and total moderate physical activity and improved positive affect from baseline to 12 months. Improved positive affect may help caregivers to feel better about themselves and their situation, and better enable them to continue providing care for their family member for a longer time at lower risk to their own mental health. PMID- 29147684 TI - c.207C>G mutation in sepiapterin reductase causes autosomal dominant dopa responsive dystonia. AB - Objective: To elucidate the genetic cause of an Egyptian family with dopa responsive dystonia (DRD), a childhood-onset dystonia, responding therapeutically to levodopa, which is caused by mutations in various genes. Methods: Rare variants in all coding exons of GCH1 were excluded by Sanger sequencing. Exome sequencing was applied for 1 unaffected and 2 affected family members. To investigate the functional consequences of detected genetic variants, urinary sepiapterin concentrations were determined by high-performance liquid chromatography. Results: A heterozygous rare nonsynonymous variant in exon 1 of sepiapterin reductase (SPR, c.207C>G, p.Asp69Glu) was found in all affected family members. Urinary concentrations of sepiapterin were above the standard of normal controls in most SPR mutation carriers, suggesting functional biochemical consequences of the mutation. Variant filtering of all genes involved in the tetrahydrobiopterin pathway, required for levodopa synthesis, revealed an additional common variant in dihydrofolate reductase (DHFR, rs70991108). The presence of both variants was significantly stronger associated with the biochemical abnormality and the clinical disease state as opposed to 1 variant only. Conclusions: The rare SPR mutation can cause autosomal dominant DRD with incomplete penetrance. The common DHFR variant might have synergistic effects on production of tetrahydrobiopterin and levodopa, thereby increasing penetrance. PMID- 29147685 TI - Stimuli-Responsive Delivery of Therapeutics for Diabetes Treatment. AB - Diabetic therapeutics, including insulin and glucagon-like peptide 1 (GLP-1), are essential for diabetic patients to regulate blood glucose levels. However, conventional treatments that are based on subcutaneous injections are often associated with poor glucose control and a lack of patient compliance. In this review, we focus on the different stimuli-responsive systems to deliver therapeutics for diabetes treatment to improve patient comfort and prevent complications. Specifically, the pH-responsive systems for oral drug delivery are introduced first. Then, the closed-loop glucose-responsive systems are summarized based on different glucose-responsive moieties, including glucose oxidase (GOx), glucose binding protein (GBP), and phenylboronic acid (PBA). Finally, the on demand delivery systems activated by external remote triggers are also discussed. We conclude by discussing advantages and limitations of current strategies, as well as future opportunities and challenges in this area. PMID- 29147686 TI - Lipoprotein(a) Associated Molecules are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis. AB - The LPA gene is the only monogenetic risk factor for calcific aortic valve stenosis (CAVS). Oxidized phospholipids (OxPL) and lysophosphatidic acid generated by autotaxin (ATX) from OxPL are pro-inflammatory. Aortic valve leaflets were categorized pathologically from Both ATX-apoB and ATX-apo(a) were measureable in plasma. Lp(a), autotaxin, OxPL and MDA epitopes progressively increased in immunostaining (p<0.001 for all). Six species of OxPL and LysoPA were identified following extraction from valve leaflets. The presence of a constellation of pathologically-linked, Lp(a)-associated molecules in plasma and in aortic valve leaflets of patients with CAVS suggest that Lp(a) is a key etiological factor in CAVS. PMID- 29147687 TI - Multi-modal Registration Improves Group Discrimination in Pediatric Traumatic Brain Injury. AB - Traumatic brain injury (TBI) can disrupt the white matter (WM) integrity in the brain, leading to functional and cognitive disruptions that may persist for years. There is considerable heterogeneity within the patient group, which complicates group analyses. Here we present improvements to a tract identification workflow, automated multi-atlas tract extraction (autoMATE), evaluating the effects of improved registration. Use of study-specific template improved group classification accuracy over the standard workflow. The addition of a multi-modal registration that includes information from diffusion weighted imaging (DWI), T1-weighted, and Fluid-Attenuated Inversion Recovery (FLAIR) further improved classification accuracy. We also examined whether particular tracts contribute more to group classification than others. Parts of the corpus callosum contributed most, and there were unexpected asymmetries between bilateral tracts. PMID- 29147688 TI - A Continuous Model of Cortical Connectivity. AB - We present a continuous model for structural brain connectivity based on the Poisson point process. The model treats each stream-line curve in a tractography as an observed event in connectome space, here a product space of cortical white matter boundaries. We approximate the model parameter via kernel density estimation. To deal with the heavy computational burden, we develop a fast parameter estimation method by pre-computing associated Legendre products of the data, leveraging properties of the spherical heat kernel. We show how our approach can be used to assess the quality of cortical parcellations with respect to connectivty. We further present empirical results that suggest the "discrete" connectomes derived from our model have substantially higher test-retest reliability compared to standard methods. PMID- 29147689 TI - A theoretical prediction on the shear-induced phase transformation of TKX-50. AB - Dihydroxylammonium 5,5'-bistetrazole-1,1'-diolate (TKX-50) is a new and attractive energetic material that outperforms numerous common explosives because of its excellent properties and performance, and is thus a promising candidate to replace some of them. Nevertheless, knowledge of its physico-chemical properties, in particular, the underlying mechanism for it undergoing external stimuli for complete decay still remains poor. In the present study, we ascertain a preferred slip system of (010)/[101] and a shear-induced phase transition of TKX-50 with the aid of theoretical calculations. In other words, a new phase of TKX-50, gamma TKX-50, is observed to be formed by shearing TKX-50 along a slip system of (010)/[101] or (010)/[101[combining macron]] with a space group of P21/a, elevated energy of 9.4 kcal mol-1 and a unit cell expanded 4%, relative to the original TKX-50. Moreover, gamma-TKX-50 can most readily be formed by shearing TKX-50 along (010)/[101] with a lowest energy barrier of 18.6 kcal mol-1, which is much below that for TKX-50 decay. The predicted elastic constants of gamma-TKX 50 verify its mechanical stability with decreased mechanical anisotropy relative to the original TKX-50. In addition, we find that, after phase transition, the hydrogen bonding is weakened, while the electrostatic repulsion of Hdelta+Hdelta+ increases, which disfavors the proton transfer from NH3OH+ to C2O2N82- to facilitate the thermal decay of TKX-50. This suggests that the shear-induced transition from TKX-50 to gamma-TKX-50 can enhance thermal stability by elevating the energy barrier for proton transfer, potentially contributing to the low mechanical sensitivity of TKX-50. Hopefully, this study would enrich the insight into the underlying mechanism of TKX-50 against external thermal-mechanical stimuli. Moreover, in combination with the newly found heat-induced phase, the shear-induced phase observed in the present study and the original one, there are at least three phases for TKX-50. PMID- 29147690 TI - Physiological pH-dependent gelation for 3D printing based on the phase separation of gelatin and oxidized dextran. AB - An extrudable hydrogel with a tunable gelation time under physiological pH ranges based on the phase separation of gelatin and oxidized dextran was demonstrated. We envision that the easy handing properties of this hydrogel combined with thermosensitive physical gelation and postponed chemical reinforcing will provide a platform for 3D bioprinting applications. PMID- 29147691 TI - A meta-selective-C-H alkenylation of phenol-derivatives employing a traceless organosilicon template. AB - A traceless organosilicon template-directed meta-selective-C-H alkenylation of phenols was realized with good yields and high selectivities. The template was readily removable through F--promoted O-Si cleavage under extremely mild conditions or recyclable through a p-TSA catalyzed process. The product was successfully applied in the preparation of a series of meta-alkenylated aromatic compounds. PMID- 29147692 TI - Topological transformation of a trefoil knot into a [2]catenane. AB - Topological transformation of a zinc-templated trefoil knot, Zn-TK, into a zinc templated [2]catenane, Zn-[2]C, was studied. The net reaction 2 Zn-TK->3 Zn-[2]C was accomplished in 89% yield by heating a solution of Zn-TK in D2O. Kinetic investigation by 1H NMR spectroscopy and high resolution mass spectrometry revealed that the mechanism is complex, involving a large pool of intermediates that form after imine bond cleavage. Bromide ions, which can occupy the central cavity of Zn-TK, inhibited the reaction. Two similar transformations were also studied, one of a cadmium-containing trefoil knot, Cd-TK, into a cadmium containing catenane, Cd-[2]C, and the other of Cd-TK into Zn-[2]C. The latter transformation could be achieved in one step at high temperature or in two steps via transmetallation to form Zn-TK at room temperature followed by topological conversion of Zn-TK to Zn-[2]C at high temperature. PMID- 29147693 TI - Using evaporation to control capillary instabilities in micro-systems. AB - The instabilities of fluid interfaces represent both a limitation and an opportunity for the fabrication of small-scale devices. Just as non-uniform capillary pressures can destroy micro-electrical mechanical systems (MEMS), so they can guide the assembly of novel solid and fluid structures. In many such applications the interface appears during an evaporation process and is therefore only present temporarily. It is commonly assumed that this evaporation simply guides the interface through a sequence of equilibrium configurations, and that the rate of evaporation only sets the timescale of this sequence. Here, we use Lattice-Boltzmann simulations and a theoretical analysis to show that, in fact, the rate of evaporation can be a factor in determining the onset and form of dynamical capillary instabilities. Our results shed light on the role of evaporation in previous experiments, and open the possibility of exploiting diffusive mass transfer to directly control capillary flows in MEMS applications. PMID- 29147695 TI - Synthesis of an ethyleneimine/tetrahedral DNA nanostructure complex and its potential application as a multi-functional delivery vehicle. AB - Nowadays, DNA nanostructures are extensively researched for their biocompatibility, editable functionality, and structural stability. Tetrahedral DNA nanostructures (TDNs), widely known for their membrane permeability, are regarded as potential candidates for drug delivery. However, the stability and membrane permeability of TDNs call for further enhancement if in vivo usage is ascribed. To overcome the drawbacks of TDNs, ethylene imine (PEI, 25 kDa, branched)-a classic cationic polymer in the field of gene delivery-was applied. Via a facile one-pot synthesis method, a PEI/TDNs complex was formed. Subsequently, a DNase protection assay, a cytotoxicity assay, endocytosis-related experiments, and lysosome staining were performed to examine the potential of PEI/TDNs as a delivery vehicle. The combination of PEI and TDNs not only overcame the drawbacks of each substance but also retained their individual merits. Traditionally, drug-delivery vehicles that enable enhanced cell entry and lysosome escape are often compromised by their toxicity and poor multifunctionality. We believe this novel PEI/TDNs complex with enhanced systemic stability, biocompatibility, cell-entry ability, and lysosome-escape ability and unsurpassed editable functionality could be a powerful tool as a multi-functional delivery vehicle in targeted drug delivery, in vivo imaging, and other related fields. PMID- 29147694 TI - Emerging investigator series: the effect of wildfire on streamwater mercury and organic carbon in a forested watershed in the southeastern United States. AB - Wildfires alter forested ecosystems, which include large stores of mercury (Hg) and organic carbon, two compounds that are closely linked in vegetation, soils, and streamwater. Studies have shown that wildfires release elevated levels of mercury to the atmosphere which can be locally redeposited and leave charred organic material (vegetation and litter) on the soil surface. Both can contribute to the elevated mobilization of Hg into lakes and streams. However, no studies have conducted a detailed examination of hydrological transport of Hg following a wildfire. This study investigates the coupled transport of mercury and carbon at Twomile Run, a headwater stream located in the forested mountains of Shenandoah National Park, in the year following a low-severity wildfire. Weekly baseflow samples and bi-hourly high-flow storm samples were analyzed for dissolved and particulate mercury (HgD and HgP, respectively), dissolved organic carbon (DOC), UV absorbance at 254 nm (UV254, surrogate for DOC quantity and character), and total suspended solids (TSS), and were compared with identical measurements taken from a nearby unburned watershed. For all flow conditions sampled at the burned site (which did not include the 2 months following the fire), streamwater HgD and DOC concentrations, and corresponding UV254, were similar to the unburned system. TSS concentrations varied between sites but overall differences were relatively small in magnitude and likely attributable to site differences rather than fire effects. Notably, the HgP per unit of TSS at the burned site was an order of magnitude higher than the unburned site (2.66 and 0.13 ng HgP per mg TSS, respectively) for 8 months following the fire, resulting in elevated HgP concentrations for the range of flow conditions, after which there was a rapid return to non-disturbed conditions. Streamwater total Hg fluxes roughly doubled (0.55 to 1.04 MUg m-2 yr-1) as a consequence of the fire, indicating that in addition to changing atmospheric and terrestrial Hg cycling, fires can rapidly and significantly alter the streamwater Hg which has implication for downstream ecosystems. These findings are particularly relevant as the occurrence and severity of wildfires are expected to increase in the mid-latitudes in response to climate change. PMID- 29147696 TI - A biocatalytic cascade for the amination of unfunctionalised cycloalkanes. AB - Here we describe a one-pot, three-enzyme, cascade involving a cytochrome P450 monooxygenase, an alcohol dehydrogenase and a reductive aminase for the synthesis of secondary amines from cycloalkanes. Amine product concentrations of up to 19.6 mM were achieved. The preparative scale amination of cyclohexane was also demonstrated with a space-time yield of 2 g L-1 d-1. PMID- 29147697 TI - Role of spin-orbit interaction on the nonlinear optical response of CsPbCO3F using DFT. AB - We explore the effect of spin-orbit interaction (SOI) on the electronic and optical properties of CsPbCO3F using the full potential linear augmented plane wave method with the density functional theory (DFT) approach. CsPbCO3F is known for its high powder second harmonic generation (SHG) coefficient (13.4 times (d36 = 0.39 pm V-1) that of KH2PO4 (KDP)). Calculations are done for many exchange correlation (XC) potentials. After the inclusion of SOI, the calculated Tran Blaha modified Becke-Johnson (TB-mBJ) band gap of 5.58 eV reduces to 4.45 eV in agreement with the experimental value. This is due to the splitting of Pb p states. Importantly, the occurrence of a band gap along the H-A direction (indirect) transforms to the H-H (direct) high symmetry points/direction in the first Brillouin zone. We noticed a large anisotropy in the calculated complex dielectric function, absorption, and refractive index spectra. The calculated static birefringence of 0.1049 and 0.1057 (with SOI) is found to be higher than that of the other carbonate fluorides. From the Born effective charge (BEC) analysis we notice that the Cs atom shows a negative contribution to birefringence whereas Pb, C, and F atoms show a positive contribution. In addition, we have also calculated the nonlinear optical chi(-2omega;omega,omega) dispersion of a CsPbCO3F single crystal. We found that d11 = d12 = 4.35 pm V-1 at 1064 nm, which is 11.2 times higher than d36 of KDP. The origin of the highly nonlinear optical susceptibility dispersion of CsPbCO3F is explained. Overall, our results are in agreement with experiments and it is obvious from the present study that CsPbCO3F is a direct band gap, large second harmonic generation, and good phase matchable NLO crystal in the ultraviolet region. PMID- 29147698 TI - Molecular spin qudits for quantum algorithms. AB - Presently, one of the most ambitious technological goals is the development of devices working under the laws of quantum mechanics. One prominent target is the quantum computer, which would allow the processing of information at quantum level for purposes not achievable with even the most powerful computer resources. The large-scale implementation of quantum information would be a game changer for current technology, because it would allow unprecedented parallelised computation and secure encryption based on the principles of quantum superposition and entanglement. Currently, there are several physical platforms racing to achieve the level of performance required for the quantum hardware to step into the realm of practical quantum information applications. Several materials have been proposed to fulfil this task, ranging from quantum dots, Bose-Einstein condensates, spin impurities, superconducting circuits, molecules, amongst others. Magnetic molecules are among the list of promising building blocks, due to (i) their intrinsic monodispersity, (ii) discrete energy levels (iii) the possibility of chemical quantum state engineering, and (iv) their multilevel characteristics that lead to Qudits, where the dimension of the Hilbert space is d > 2. Herein we review how a molecular nuclear spin qudit, (d = 4), known as TbPc2, gathers all the necessary requirements to perform as a molecular hardware platform with a first generation of molecular devices enabling even quantum algorithm operations. PMID- 29147699 TI - Strain relaxation and ambipolar electrical transport in GaAs/InSb core-shell nanowires. AB - The growth, crystal structure, strain relaxation and room temperature transport characteristics of GaAs/InSb core-shell nanowires grown using molecular beam epitaxy are investigated. Due to the large lattice mismatch between GaAs and InSb of 14%, a transition from island-based to layer-like growth occurs during the formation of the shell. High resolution transmission electron microscopy in combination with geometric phase analyses as well as X-ray diffraction with synchrotron radiation are used to investigate the strain relaxation and prove the existence of different dislocations relaxing the strain on zinc blende and wurtzite core-shell nanowire segments. While on the wurtzite phase only Frank partial dislocations are found, the strain on the zinc blende phase is relaxed by dislocations with perfect, Shockley partial and Frank partial dislocations. Even for ultrathin shells of about 2 nm thickness, the strain caused by the high lattice mismatch between GaAs and InSb is relaxed almost completely. Transfer characteristics of the core-shell nanowires show an ambipolar conductance behavior whose strength strongly depends on the dimensions of the nanowires. The interpretation is given based on an electronic band profile which is calculated for completely relaxed core/shell structures. The peculiarities of the band alignment in this situation implies simultaneously occupied electron and hole channels in the InSb shell. The ambipolar behavior is then explained by the change of carrier concentration in both channels by the gate voltage. PMID- 29147700 TI - Brown rice and retrograded brown rice alleviate inflammatory response in dextran sulfate sodium (DSS)-induced colitis mice. AB - The present study was aimed to investigate the impacts of brown rice (BR) and retrograded brown rice (R-BR) consumption on colonic health and gut microbiota in dextran sulfate sodium (DSS) induced colitis mice. Thirty two female C57Bl/6Mlac mice were fed with modified AIN 93G diets by replacing cornstarch in the original composition with white rice (WR), BR and R-BR powder. The mice were divided into 4 groups and fed with the following experimental diets for 4 weeks: (1) negative control (WR: diet with WR), (2) positive control (DSS_WR: DSS and diet with WR), (3) DSS_BR: DSS and diet with BR, and (4) DSS_R-BR: DSS and diet with R-BR. BR and R-BR had a greater content of fat, dietary fiber, GABA, gamma-oryzanol, gamma tocotrienol, ferulic acid and p-coumaric acid than WR (p < 0.05). No significant difference in the level of these bioactive compounds was noted between BR and R BR. Nevertheless, R-BR had a 1.8 fold resistant starch (RS) content of BR (p < 0.05). The DSS_BR and DSS_R-BR groups showed a lower ratio of colonic weight to length, and a lower content of iNOS, COX-2, MPO, IL-6 and INF-gamma in colonic homogenates than the DSS_WR group. However, the DSS treated mice fed with the R BR diet had significantly milder histopathological inflammatory injury and lower colonic iNOS expression than the DSS_BR and DSS_WR groups. The percentage of mesenteric regulatory T cells significantly increased in the DSS_R-BR group compared to that in the DSS_WR group. The DSS treated mice fed with the R-BR diet showed a significant increase in cecal bacterial diversity and abundance of genera Prevotella, Ruminococcus, Dorea, Coprococcus and Dehalobacterium but a significant decrease in pathogenic bacteria including Bacteroides and Enterococcus compared to the DSS_WR group. Thus, the present data indicate that BR and R-BR ameliorate colonic inflammation in experimental colitis induced by DSS in mice by suppressing inflammatory mediators and modulating regulatory T cell responses as well as bacterial diversity in the cecum. PMID- 29147707 TI - Highlights from the Faraday Discussion: Bio-resources: Feeding a Sustainable Chemical Industry, 19-21 June 2017, London, UK. PMID- 29147706 TI - Amine assisted top-down delamination of the two-dimensional metal-organic framework Cu2(bdc)2. AB - A chemically assisted top-down method for the synthesis of MOF-nanoplates was developed applying amine based delamination agents. Applied on a well described model structure, the layered MOF Cu2(bdc)2(DMF)2 (bdc - 1,4 benzenedicarboxylate), two different strategies of amine assisted delamination turned out to be successful to obtain nanoplates. Particles with thicknesses of around 70 nm were obtained by direct delamination of crystals using octylamine. The surfactant (polyvinylpyrrolidone) assisted synthesis combined with a post synthetic amine delamination step enabled a further reduction of the thickness of the MOF nanoplates down to 4-14 nm. PMID- 29147708 TI - Advanced sensing, imaging, and therapy nanoplatforms based on Nd3+-doped nanoparticle composites exhibiting upconversion induced by 808 nm near-infrared light. AB - Malignant tumors are currently the leading cause of death worldwide, followed by cardiovascular and cerebrovascular diseases. Although various methods, such as blood examination, tissue biopsy, and radiography, for tumor detection, exist, these techniques still require further refinement. Researchers have recently explored the use of novel adjuvant methods, specifically luminescence imaging detection, for the detection of tumors. The light-triggered approach is less invasive and induces fewer side effects than traditional detection methods. This paper highlights recent advances in the design, property tuning, and applications of nanoparticles that exhibit upconversion under 808 nm excitation. When doped with neodymium ions, upconverted nanoparticles gain the ability to absorb 808 nm light. The advantageous unique features of 808 nm light include deep tissue penetration and limited thermal side effects. The 808 nm-excited upconverted nanoparticles exhibit superior potential for use in biosensing, bioimaging, therapy, and three-dimensional display. Thus, innovative theranostic nanoplatforms can be developed by incorporating 808 nm-excited upconverted nanoparticles with phototherapy agents. Such a composite technique is expected to possess the individual advantages of each material. PMID- 29147709 TI - Four one-dimensional lanthanide-phenylacetate polymers exhibiting luminescence and magnetic cooling/spin-glass behavior. AB - Four isostructural lanthanide coordination polymers with a phenylacetate (PAA-) ligand, [Ln(PAA)3(H2O)]n (Ln = Eu (1); Gd (2); Tb (3); Dy (4)), were synthesized under hydrothermal conditions. Complexes 1-4 display a one-dimensional (1D) wave chain structure bridged by the carboxylate of the PAA- ligand, which was generated via the in situ decarboxylation of phenylmalonic acid. Magnetic studies suggest the presence of ferromagnetic LnLn coupling in the 1D chain of 1-4. Meanwhile, 2 has a significant cryogenic magnetocaloric effect with the maximum DeltaSm of 26.73 at 3 K and 7 T, and 3 and 4 show interesting spin-glass behavior, which is rarely reported for Ln-containing complexes. Additionally, the solid-state photophysical properties of 1 and 3 display strong characteristic Eu3+ and Tb3+ photoluminescence emission in the visible region, indicating that Eu- and Tb-based luminescence are sensitized by the effective energy transfer from the ligand to the metal centers. PMID- 29147710 TI - Step-by-step build-up of covalent poly(ethylene oxide) nanogel films. AB - Hydrogels based on poly(ethylene glycol) (PEG) are commonly used for studies related to cell fate and tissue engineering. Here we present a new covalent layer by-layer build-up process leading to PEG coatings of nanometer size called "nanogel films". Compared to macroscopic hydrogels, such nanogels should provide a fine control over the structure and the thickness of the coating. Alternated deposition of bifunctional and tetra functional PEG molecules reacting through thiol/maleimide click chemistry is evaluated by quartz crystal microbalance. We first study parameters influencing the build-up process of such coatings and demonstrate the importance of (i) the nature of the first deposited layer, (ii) the PEG concentrations and (iii) the length of the PEG chains that appears to be the most significant parameter influencing film growth. The build-up process can be extended to a large variety of substrates like SiO2 or polymers by using an appropriate anchoring layer. Covalent functionalization of these nanogel films by proteins or enzymes is suited by modifying the biomolecules with thiol or maleimide groups and immobilizing them during the build-up process. Activity of the embedded enzymes can be maintained. Moreover ligands like biotin can be incorporated into the film and recognition by streptavidin can be modulated by playing with the number of PEG layers covering biotin. Compared to well-known PEG hydrogels, these new coatings are promising as they allow to (i) build thin nanometric coatings, (ii) finely control the amount of deposited PEG and (iii) organize the position of the embedded biomolecules inside the film layers. PMID- 29147711 TI - Distinct room-temperature dielectric transition in a perchlorate-based organic inorganic hybrid perovskite. AB - The organic-inorganic hybrid perovskite (H2hpz)[K(ClO4)3] (H2hpz = diprotonated homopiperazine) exhibits a distinct room-temperature dielectric transition. The dielectric switching at 303 K is associated with an order-disorder transition of the polar guest cation confined in the cage, corresponding to a dynamic change between motional and frozen states. PMID- 29147713 TI - Variation of the bone forming ability with the physicochemical properties of calcium phosphate bone substitutes. AB - Because of their bioactive properties and chemical similarity to the inorganic component of bone, calcium phosphate (CaP) materials are widely used for bone regeneration. Six commercially available CaP bone substitutes (Bio-Oss, Actifuse, Bi-Ostetic, MBCP, Vitoss and chronOs) as well as two tricalcium phosphate (TCP) ceramics with either a micron-scale (TCP-B) or submicron-scale (TCP-S) surface structure are characterized and their bone forming potential is evaluated in a canine ectopic implantation model. After 12 weeks of implantation in the paraspinal muscle of four beagles, sporadic bone (0.1 +/- 0.1%) is observed in two Actifuse implants (2/4), limited bone (2.1 +/- 1.4%) in four MBCP implants (4/4) and abundant bone (21.6 +/- 4.5%) is formed in all TCP-S implants (4/4). Bone is not observed in any of the Bio-Oss, Bi-Ostetic, Vitoss, chronOs and TCP-B implants (0/4). When correlating the bone forming potential with the physicochemical properties of each material, we observe that the physical characteristics (e.g. grain size and micropore size at the submicron scale) might be the dominant trigger of material directed bone formation via specific mechanotransduction, instead of protein adsorption, surface mineralization and calcium ion release. PMID- 29147712 TI - A biocompatible betaine-functionalized polycation for coacervation. AB - The aqueous nature of complex coacervates provides a biologically-relevant context for various therapeutic applications. In this sense, biological applications demand a corresponding level of biocompatibility from the polyelectrolytes that participate in complex coacervation. Continued development with naturally-occurring polyelectrolytes such as heparin and chitosan underscore such aims. Herein, we design a synthetic polycation, in which betaine is conjugated to a biodegradable polyester backbone. Betaine is a naturally occurring methylated amino acid that is ubiquitously present in human plasma. Inspired by its vast range of benefits - including but not limited to anti inflammation, anti-cancer, anti-bacterial, anti-oxidant, protein stabilization, and cardiovascular health - we aim to impart additional functionality to a polycation for eventual use in a complex coacervate with heparin. We report on its in vitro and in vivo biocompatibility, in vitro and in vivo effect on angiogenesis, in vitro effect on microbial growth, and ability to form complex coacervates with heparin. PMID- 29147714 TI - Stable Na plating/stripping electrochemistry realized by a 3D Cu current collector with thin nanowires. AB - Current collectors have a significant role in Na plating and stripping. Here we demonstrate that a three-dimensional (3D) Cu current collector with thin nanowires (<40 nm) can significantly promote the electrochemical deposition stability of Na via tuning a Na metal plating model, therefore contributing to a high efficiency, long lifespan, and low overpotential during electrode/battery cycling. PMID- 29147715 TI - The impact of ultraviolet B (UV-B) radiation in combination with different temperatures in the early life stage of zebrafish (Danio rerio). AB - Ultraviolet B (UV-B) radiation is an environmental stressor with detrimental effects on many aquatic organisms including fish. In addition, UV-B exposure combined with other environmental factors could have even more negative effects. The purpose of this study was to investigate the effect of UV-B radiation exposure on zebrafish embryos/larvae in terms of survival, developmental toxicity and the mRNA levels of the genes related to oxidative stress and innate immune response at different temperatures (24 degrees C, 28 degrees C and 30 degrees C). Zebrafish embryos were exposed to 3.3 W m-2 UV-B radiation and/or 24 degrees C, 28 degrees C (for the control) and 30 degrees C temperatures between 4 and 96 h post-fertilization. The mortality, hatching rate, malformations and heartbeat rate were evaluated. The results demonstrated that UV-B exposure or different temperatures (24 degrees C and 30 degrees C) induced developmental toxicity, including delayed hatching, increased the occurrence of malformations, and reduced the heartbeat rate and survival. The combined exposure to UV-B and different temperatures (24 degrees C and 30 degrees C) resulted in greater adverse effects on embryonic development. Furthermore, RT-PCR results showed that the mRNA levels of superoxide dismutase 1 (sod1), catalase 1 (cat1), heat shock protein 70 (hsp70), interleukin-1 beta (il-1beta) and tumor necrosis factor alpha (tnfalpha) genes were significantly up-regulated in all of the treatment groups. These results revealed that the interaction between UV-B and temperature impaired the development of zebrafish embryos and disrupted their metabolism. PMID- 29147716 TI - Complex coacervation of Mg(ii) phospho-polymethacrylate, a synthetic analog of sandcastle worm adhesive phosphoproteins. AB - The highly phosphorylated Pc3 proteins, major components of the sandcastle worm adhesive, are sequestered with Mg as spherical sub-granules within heterogeneous secretory granules in adhesive gland cells. The phase behavior of a synthetic phospho-polymethacrylate analog of the Pc3 phosphoproteins, in the presense of Mg(ii), was characterized to determine whether it is chemically possible for the natural adhesive components to be packaged and stored as liquid complex coacervates. Of several multivalent metal salts tested, only MgCl induced complex coacervation of the phospho-copolymer. Complex coacervates formed at Mg/P ratios from 0.5-8, and in [NaCl]s from 0-3 M. At low temperature and pH, the complex coacervates were clear and homogeneous. At higher temperatures and pH, the coacervate phases were translucent. The elastic and viscous moduli initially decreased as temperature increased, but then increased significantly near the temperature boundary between clear and translucent forms. A mechanism is proposed in which relatively weak, ionic strength-independent, outer shell crossbridging of -PO32- sidechains by Mg[H2O]62+ complex ions is responsible for the clear homogeneous lower viscosity coacervate form. At higher temperature and pH, displacement of inner shell H2O molecules by phosphate O- ligands creates stronger crossbridges, additional dehydration, and more viscous coacervates. The results demonstrate that Pc3 phosphoproteins can exist as condensed phospho/Mg(ii) complex coacervates under conditions expected in the adhesive glands of sandcastle worms in their natural environment. Considering the common regulatory role of phosphorylation and the intracellular abundance of Mg2+ it is possible that soft bridging of phosphate groups by Mg[H2O]n2+ may promote other regulated cellular liquid liquid phase separation phenomena. PMID- 29147717 TI - The role of hierarchical design and morphology in the mechanical response of diatom-inspired structures via simulation. AB - Diatoms are microscopic algae with intricate shell morphologies and features ranging from the nanometer to the micrometer scale, which have been proposed as templates for drug delivery carriers, optical devices, and metamaterials design. Several studies have found that diatom shells show unique mechanical properties such as high specific strength and resilience. One hypothesis is that these properties stem from the structural arrangement of the material at the nanometer and micrometer length scales, challenging the concept between what constitutes a "material" versus a "structure". In this work, we have conducted a systematic simulation-prototyping study to shed light on the mechanics of diatom-inspired hierarchical microstructures. The Finite Element Method (FEM) was used to replicate three-dimensional diatom shells under compressive forces. The intricate hierarchical shell structure of the Coscinodiscus sp. diatom frustule observed in nature was reproduced in detail. Simulation parameters were selected to reproduce compression experiments, with a force distributed on the surface of the diatom shell. A frustule diameter of 50 MUm was used with pore diameters ranging from 0.25 to 1.2 MUm across different layers. A "unit cell" FEM model was also created to focus on the basic structural element of a diatom frustule. Both of these models were used to elucidate the relation between morphology and mechanical response. Additionally, select designs were prototyped using 3D Direct Laser Writing (DLW) lithography to evaluate the feasibility of manufacturing diatom inspired devices at the micro-scale. Distinct correlations between pore size in each frustule layer, or pore shape in the basal layers, and the mechanical response of the diatom shell were established in this study. The 3D-DLW prototypes exhibit a similar level of intricate morphological traits observed in real diatoms, opening the possibility of a simulation-based process for the design and fabrication of diatom-inspired microdevices. This research helps explain how morphology features are central to the mechanical performance of hierarchically arranged structures and biomaterials in general, and it represents a step toward the manufacture of emerging metamaterials and microarchitectures. PMID- 29147718 TI - A novel homobimetallic nickel complex for the asymmetric direct Mannich reaction of imines: a practical method on a multi-gram scale. AB - A novel dinuclear Ni complex has been developed for the direct Mannich reaction of malonates with N-tosyl aryl imines with a low catalyst loading (0.1-0.05 mol%) on a preparative scale (5-50 mmol). The structure of the active species was verified via control experiments, ESI-HRMS, and DFT calculations. PMID- 29147719 TI - Crystal chemistry and magnetic properties of the solid solutions Ca14-xRExMnBi11 (RE = La-Nd, Sm, and Gd-Ho; x ~ 0.6-0.8). AB - The new solid solutions Ca14-xRExMnBi11 (RE = La-Nd, Sm, and Gd-Ho; x ~ 0.6-0.8) were prepared by using a Pb-flux technique and structurally characterized by single-crystal X-ray diffraction. All synthesized materials crystallize in the tetragonal Ca14AlSb11 structure type (space group: I41/acd, Pearson index: tI208). The magnetic responses of all the members of the series were investigated, and for all REs in this study, except for Sm, a ferromagnetic ordering was observed at TC = 35-44 K. The Sm-containing sample shows a ferromagnetic-like transition at 40 K and enters a long-range antiferromagnetic state below 17 K. The magnetic behavior of Ca14-xRExMnBi11 differs from that of the isostructural Ca14-xRExMnSb11 series, emphasizing the importance of the weak magnetic interactions in complex crystal structures. PMID- 29147720 TI - Anticoagulation in atrial fibrillation : Current evidence and guideline recommendations. AB - Atrial fibrillation (AF) is the most frequently encountered sustained arrhythmia with a prevalence of 0.5-10%, depending predominantly on age. The arrhythmia is associated with significant morbidity and mortality, mainly due to thromboembolic events including stroke and systemic embolisms. These complications can be effectively prevented with anticoagulation therapy either with vitamin K antagonists (VKA) or with non-vitamin K antagonists (NOAC). VKA therapy is effective in preventing strokes but these medications are difficult to use, are associated with significant bleeding risk, and have pharmacokinetic/dynamic properties that make their use cumbersome. NOACs-either factor II or factor Xa inhibitors-have been developed over the past two decades and have been tested against VKA in large randomized controlled trials. This trial evidence was complemented more recently by increasing real-world data comprising several 100,000 patients. Finally, NOACs have been examined for their use in specific clinical situations, for example, in patients undergoing cardioversion, catheter ablation, or coronary interventions. In all of these clinical scenarios, NOACs have been similarly effective or-in many instances-even superior to treatment with VKA. Recent guidelines, therefore, recommend NOAC therapy for stroke prevention in AF as first-line therapy. PMID- 29147721 TI - Osteomimicry: How the Seed Grows in the Soil. AB - Metastasis is defined as a very inefficient process, since less than 0.01% of cancer cells injected into the circulation will engraft in a distant organ, where they must acquire the ability to survive and proliferate inside a "foreign" environment. In bone metastases, the interaction with the host organ is much more favoured if tumour cells gain "osteomimicry", that is the ability to resemble a resident bone cell (i.e. the osteoblast), thus intruding in the physiology of the bone. This is accomplished by the expression of osteoblast markers (e.g. alkaline phosphatase) and the production of bone matrix proteins and paracrine factors which deregulate the physiology of bone, fuelling the so-called "vicious cycle". The main challenge of researchers is therefore to identify the genetic profile determining the osteotropism of tumour cells, which would eventually lead to bone colonisation. This could likely provide the answer to a quite intriguing question, that is why some cancers, such as prostate and breast, have a specific predilection to metastasise to the bone. Therefore, it is important to completely address the molecular mechanisms underlying this aspect of bone oncology, identifying relevant pathways, the targeting of which could make any type of bone metastasis curable or avoidable. PMID- 29147722 TI - [Dengue fever : Symptoms, epidemiology, entomology, pathogen diagnosis and prevention]. AB - Dengue infections are among the most frequent causes of febrile disease in tropical climates. Infections are caused by a flavivirus transmitted by the Aedes mosquito. Aedes aegypti mosquitos are the main transmitters of Dengue viruses. Since these insects are both diurnal and container breeders, particular prevention and control measures are required. Symptom severity varies and can range from a mild, flu-like clinical picture to severe hemorrhage and shock. The most common symptoms experienced by travelers include fever, muscular pain, headaches and skin rash. Depending on the stage of infection, either rapid point of-care tests or-during the viraemic phase-direct molecular detection of pathogens can be used as diagnostic methods. Serological diagnosis is challenging in terms of interpretation due to serological cross reactions with other flaviviruses. PMID- 29147723 TI - Desorption kinetics of organic chemicals from albumin. AB - When present in blood, most chemicals tend to bind to the plasma protein albumin. For distribution into surrounding tissues, desorption from albumin is necessary, because only the unbound form of a chemical is assumed to be able to cross cell membranes. For metabolism of chemicals, the liver is a particularly important organ. One potentially limiting step for hepatic uptake of the chemicals is desorption from albumin, because blood passes the human liver within seconds. Desorption kinetics from albumin can thus be an important parameter for our pharmacokinetic and toxicokinetic understanding of chemicals. This work presents a dataset of measured desorption rate constants and reveals a possibility for their prediction. Additionally, the obtained extraction profiles directly indicate physiological relevance of desorption kinetics, because desorption of the test chemicals is still incomplete after time frames comparable to the residence time of blood in the liver. PMID- 29147725 TI - [Stigma - risk factor and consequence of suicidal behavior : Implications for suicide prevention]. AB - Mental illness, previous suicidal behavior and loss of a relative by suicide are strong risk factors for suicidality. Both mental illness and suicide are stigmatized, which is a burden for those affected and potentially contributes to suicidality among stigmatized individuals. Many consequences of stigma, e. g. social isolation, low self-esteem and hopelessness, are well-known predictors of suicidality. Interventions to reduce stigmatization might therefore be an important component of successful suicide prevention. This paper discusses the currently available knowledge regarding this hypothesis. Many studies confirmed the association between the stigmatization of mental illness and suicidality and there is initial evidence for the influence of suicide stigma and suicidality. Nevertheless, the effectiveness of anti-stigma interventions to reduce suicidality and prevent suicide has not yet been tested. Reducing stigma among members of the general population and mental health care professionals as well as programs to support individuals in coping with stigmatization could be important components of successful suicide prevention. PMID- 29147724 TI - GLABROUS (CmGL) encodes a HD-ZIP IV transcription factor playing roles in multicellular trichome initiation in melon. AB - KEY MESSAGE: Map-based cloning identified CmGL that encodes a HD-ZIP type IV transcription factor that controls multicellular trichome initiation in melon. Trichomes are small hairs covering the aerial parts of plants that originate from the epidermal cells, which can protect plants against the damage by insects and pathogens. The regulatory pathway of unicellular trichomes has been well studied in the model plant Arabidopsis. Little is known about the genetic control and regulation of trichome development in melon (Cucumis melo L.) which has multicellular trichomes. In this study, we identified a melon mutant, cmgl, which showed completely glabrous on all aerial organs. A bulked segregant analysis was conducted to identify polymorphic markers for linkage analysis in a population with 256 F2 plants, which allowed to locate the cmgl locus in melon chromosome VIII. Next-generation sequencing-aided marker discovery and fine mapping in a large population with 1536 F2 plants narrowed the candidate gene region to 12 kb that harbored only one candidate gene for cmgl, which encoded a class IV homeodomain-associated leucine zipper transcription factor. Four SNPs in the coding region of the CmGL gene were identified between the two parental lines; a single base substitution from C to A resulted in a premature termination codon and a truncated protein in the cmgl. The SNP was converted into a dCAPS marker, which showed co-segregation in the F2 population and 564 melon accessions. Result of this study will be helpful for better understanding of genetic control of trichome development in melon and marker-assisted selection in developing new cultivars. PMID- 29147726 TI - [Radiculomyelopathy in schistosomiasis]. AB - The increasing migration of people from their homeland in far distant regions to Europe in the last few years has strongly influenced the rise of previously rarely seen diseases. They not only originate from the respective homeland but also from the transit countries during the migration process. We report the case of a 27-year-old male migrant from Eritrea, who after months of flight as a refugee travelling through various African countries, presented at our hospital with a progressive, painful radiculopathy. Whole spine magnetic resonance imaging (MRI) showed a focus located in the myelon, extending from T11 to the medullary conus. The differential diagnostic clarification ultimately revealed an infection with Schistosoma mansoni. After guideline-conform treatment with praziquantel for 3 days and additional administration of corticosteroids for 3 months, a slow regression of the findings and improvement of the symptoms could be shown clinically and by MRI. This case study shows the importance of taking the medical history and that a closer look at the potential exposure in the homeland and transit countries should be of great benefit in reaching the diagnosis, especially in patients with a migration background. PMID- 29147727 TI - [Percutaneous coronary interventions in infarct-related shock and multivessel disease : Only treat the infarct-related vessel or treat all relevant coronary stenoses?] PMID- 29147728 TI - [Immediate extubation or terminal weaning in ventilated intensive care patients after therapeutic goal change]. PMID- 29147729 TI - Regulation of human research with LSD in the United States (1949-1987). AB - Human research with hallucinogens such as lysergic acid diethylamide (LSD) has been ongoing in the USA since 1949. During the 1960s, LSD was investigated for a variety of psychiatric indications, including the following: as an aid in treatment of schizophrenia; as a means of creating a "model psychosis"; as a direct antidepressant; and as an adjunct to psychotherapy. Studies with all drugs, including LSD, have always been conducted under federal regulatory controls, including the 1938 Food Drug and Cosmetic Act (FDCA; which ensured the safety of drugs) and the 1962 Kefauver-Harris Amendments to the FDCA (which described appropriate scientific methodology and ensured drug efficacy). This paper details how the 1962 Amendments introduced numerous safety and efficacy requirements that must be in satisfied during clinical drug research-and how human studies conducted with LSD in the 1960s struggled with their fulfillment. Information is provided from Senate hearings, case law, and interviews with key investigators. Examples are also drawn from scientific papers and symposia published during and since that period, with a focus on information from clinical studies conducted with LSD by psychiatrist Albert Kurland at the Spring Grove State Hospital, near Baltimore, MD. While Kurland largely conformed with these new regulations, other investigators often fell short of complying with scientific standards and federal requirements. Thus, the human hallucinogen studies of the 1960s are best understood as providing pilot data on safety and efficacy, as well as testable hypotheses for current hallucinogen studies conducted under modern scientific and regulatory standards. PMID- 29147730 TI - On the skilled plantar flexor motor action and unique electromyographic activity of ballet dancers. AB - The study aimed to compare the ability of dance and non-dance subjects to perform fine control of a simple heel-raising/lowering movement, and to determine if there are any differences in motor unit activity in the primary plantar flexor muscles during the movement. Subjects were instructed to accurately track a sinusoidal trace with a heel-raising and lowering movement at four controlled frequencies (1, 0.5, 0.25, and 0.125 Hz). The ankle joint angle was used to characterize movement errors from the target. Surface electromyography was recorded from the soleus and medial gastrocnemius muscles. One trial including five sinusoidal traces was divided into two phases: an up phase and a down phase. To characterize motor unit activity of the plantar flexor muscles, a wavelet transform was applied to electromyographic signals recorded in each phase. For both phases, errors in movement accuracy were lower in dancers than in controls (8.7 +/- 4.6 vs. 11.5 +/- 6.8%, P < 0.05) regardless of the frequency of the sinusoidal wave traced. During the down phase, peak power of soleus electromyographic signals at ~ 10 Hz was statistically larger in control subjects than in dancers (10.4 +/- 0.7 vs. 6.3 +/- 0.4% total power, P < 0.05). These results indicate that dancers have a higher degree of motor skill in a heel raise tracking task and exhibit adaptations in the motor unit activity during skilled dynamic movements. PMID- 29147731 TI - The influence of cervical movement on eye stabilization reflexes: a randomized trial. AB - To investigate the influence of the amount of cervical movement on the cervico ocular reflex (COR) and vestibulo-ocular reflex (VOR) in healthy individuals. Eye stabilization reflexes, especially the COR, are changed in neck pain patients. In healthy humans, the strength of the VOR and the COR are inversely related. In a cross-over trial the amplitude of the COR and VOR (measured with a rotational chair with eye tracking device) and the active cervical range of motion (CROM) was measured in 20 healthy participants (mean age 24.7). The parameters were tested before and after two different interventions (hyperkinesia: 20 min of extensive active neck movement; and hypokinesia: 60 min of wearing a stiff neck collar). In an additional replication experiment the effect of prolonged (120 min) hypokinesia on the eye reflexes were tested in 11 individuals. The COR did not change after 60 min of hypokinesia, but did increase after prolonged hypokinesia (median change 0.220; IQR 0.168, p = 0.017). The VOR increased after 60 min of hypokinesia (median change 0.155, IQR 0.26, p = 0.003), but this increase was gone after 120 min of hypokinesia. Both reflexes were unaffected by cervical hyperkinesia. Diminished neck movements influences both the COR and VOR, although on a different time scale. However, increased neck movements do not affect the reflexes. These findings suggest that diminished neck movements could cause the increased COR in patients with neck complaints. PMID- 29147732 TI - [Incontinence]. PMID- 29147733 TI - [Inhibitors of the androgen receptor N-terminal domain : Therapies targeting the Achilles' heel of various androgen receptor molecules in advanced prostate cancer]. AB - Although prostate cancer responds well to primary endocrine therapies, tumor progression with castration resistant tumor cells almost invariably occurs within a few years. Unfortunately, some CRPC patients do not respond to second-line therapies with abiraterone or enzalutamide. Moreover, patients who initially responded well to second-line hormone therapy develop resistance to abiraterone and/or enzalutamide within a short period of time. Besides an increase of intracellular androgen receptor (AR) levels, the predominant resistance mechanisms include AR aberrations (point mutations, AR splice variants) occurring predominantly at the androgen or ligand binding domain of the AR. The following review delineates recent progress in the development of AR inhibitors that do not depend on androgen binding and represent a putative third generation of AR inhibitors. PMID- 29147735 TI - Reduction of Metallic Artifacts of the Post-treatment Intracranial Aneurysms: Effects of Single Energy Metal Artifact Reduction Algorithm. AB - PURPOSE: This study evaluated the quality of computed tomography (CT) and CT angiography images generated using the single-energy metal artifact reduction (SEMAR) algorithm during perfusion examination in patients who had undergone reconstruction with neurosurgical clipping or endovascular coiling for treatment of aneurysms. METHODS: A total of 55 patients with implanted intracranial clips or coils (24 men and 31 women; mean age 60.15 +/- 15.86 years) underwent perfusion studies evaluated by CT and CT angiography with a 320-row CT scanner. Images were reconstructed with either the SEMAR algorithm combined with iterative reconstruction (SEMAR group), or by iterative reconstruction only (non-SEMAR group control). The SEMAR and control images were compared for artifacts (index and maximum diameter), image quality, cerebral perfusion parameters, noise (images with the worst artifacts), and contrast-to-noise ratio. The metallic artifacts were visually evaluated by two radiologists using a four-point scale in a double-blinded manner. RESULTS: The noise, artifact diameter, and artifact index of the SEMAR images were significantly lower than that of the control images, and the subjective image quality score and contrast-to-noise ratio were significantly higher (P < 0.01, all). The cerebral perfusion parameters of the SEMAR and control images were comparable (i. e. blood flow, blood volume, and mean transit time). CONCLUSION: For imaging intracranial metallic implants, the SEMAR algorithm produced images with significantly fewer artifacts than the iterative reconstruction alone, with no statistical changes in perfusion parameters. Thus, SEMAR reconstruction can be instrumental in improving CT image quality and may ultimately improve the detection of postoperative complications and patient prognosis. PMID- 29147736 TI - Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and not Always Lactate Elevation. PMID- 29147737 TI - Genetic dissection of early-season cold tolerance in sorghum: genome-wide association studies for seedling emergence and survival under field and controlled environment conditions. AB - KEY MESSAGE: A QTL on sorghum chromosome SBI-06 putatively improves field emergence under low-temperature conditions. Low temperatures decisively limit seedling emergence and vigor during early growth of sorghum and, thus, strongly impair geographical expansion. To broaden sorghum cultivation to temperate regions, the establishment of cold-tolerant genotypes is a prioritized breeding goal. The present study aims at the quantification of seedling emergence and survival under chilling temperatures and the detection of marker-trait associations controlling temperature-related seedling establishment. A diversity set consisting of 194 biomass sorghum lines was subjected to extensive phenotyping comprising field trials and controlled environment experiments. The final emergence percentage (FEP) under field conditions was significantly reduced under cold stress. Broad-sense heritability was h 2 = 0.87 for FEP in the field and h 2 = 0.93 for seedling survival rate (SR) under controlled conditions. Correlations between FEP in the field and under controlled conditions were low; higher correlations were observed between field FEP and SR in controlled environments. Genome-wide association studies (GWAS) were conducted using 44,515 single nucleotide polymorphisms (SNPs) and revealed eight regions with suggestive marker-trait associations for FEP and SR on chromosomes SBI-01, -02, -03, -06, 09, and -10 (p < 5.7 * 10-5) and a significant association on SBI-06 for field FEP (p < 2.9 * 10-6). Although not significant under controlled conditions, SR of genotypes carrying the minor allele on the field FEP quantitative trait loci (QTL) on SBI-06 was on average 13.1% higher, while FEP under controlled conditions was on average 9.7% higher with a linearly decreasing effect with increasing temperatures (R 2 = 0.82). Promising candidate genes putatively conferring seedling cold tolerance were identified. PMID- 29147738 TI - Novel and effective synthesis protocol of AgNPs functionalized using L-cysteine as a potential drug carrier. AB - In this study, the protocol of a single-step L-cysteine functionalized silver nanoparticle synthesis was described. Particle size distribution was determined. The crystallinity and chemical properties were investigated using XRD, HR-TEM, and XPS methods. Acute toxicity and irritant properties of obtained nanoparticles were studied using mice and rats as an animal model. The results showed that thanks to the applied protocol, it was possible to synthesize silver nanoparticles with narrow particle size distribution. Moreover, the concentration of final product was extremely high in comparison to other known methods. These nanoparticles showed neither irritant properties nor acute toxicity. PMID- 29147739 TI - Effects of Coking Wastewater on the Growth of Five Wetland Plant Species. AB - In order to investigate the effect of wetland plants in the treatment of coking wastewater, Oenanthe javanica (Blume) DC (OC), Artemisia selengensis Turcz. ex Bess. (AB), Echinochloa crusgalli (L.) Beauv. (EB), Brasenia schreberi J.F.Gmel. (BG), and Lythrum salicaria L. (LL) were used to remove ammonia-nitrogen and chemical oxygen demand (COD) from coking wastewater. Results showed high concentrations (> 30%, diluted by deionized water) of coking wastewater caused decreased photosynthetic rate, transpiration rate, and relative growth rate in all studied plants. OC, BG, and LL showed higher adaptability than AB and EB. Wastewater concentrations < 30% resulted in less affected growth of OC, BG, and LL; However, AB and EB were suppressed when coking wastewater concentrations were > 15%. High concentrations of coking wastewater generated oxidative stress which resulted in increased malondialdehyde and proline contents and inhibition of superoxide dismutase. OC, BG, and LL were considered tolerable species in purifying coking wastewater (concentrations < 30%). PMID- 29147740 TI - Geo-Spatial Characterization of Soil Mercury and Arsenic at a High-Altitude Bolivian Gold Mine. AB - Soil mercury concentrations at a typical small-scale mine site in the Bolivian Andes were elevated (28-737 mg/kg or ppm) in localized areas where mercury amalgams were either formed or vaporized to release gold, but was not detectable beyond approximately 10 m from its sources. Arsenic was measurable, exceeding known background levels throughout the mine site (77-137,022 ppm), and was also measurable through the local village of Ingenio (36-1803 ppm). Although arsenic levels were high at all surveyed locations, its spatial pattern followed mercury, being highest where mercury was high. PMID- 29147741 TI - Achilles tendon elastic properties remain decreased in long term after rupture. AB - PURPOSE: Rupture of the Achilles tendon results in inferior scar tissue formation. Elastography allows a feasible in vivo investigation of biomechanical properties of the Achilles tendon. The purpose of this study is to investigate the biomechanical properties of healed Achilles tendons in the long term. MATERIALS AND METHODS: Patients who suffered from Achilles tendon rupture were recruited for an elastographic evaluation. Unilateral Achilles tendon ruptures were included and scanned in the mid-substance and calcaneal insertion at least 2 years after rupture using shear wave elastography. Results were compared to patients' contralateral non-injured Achilles tendons and additionally to a healthy population. Descriptive statistics, reliability analysis, and correlation analysis with clinical scores were performed. RESULTS: Forty-one patients were included in the study with a mean follow-up-time of 74 +/- 30; [26-138] months after rupture. Significant differences were identified in shear wave elastography in the mid-substance of healed tendons (shear wave velocity 1.2 +/-1.5 m/s) compared to both control groups [2.5 +/-1.5 m/s (p < 0.01) and 2.8 +/-1.6 m/s (p < 0.0001) contralateral and healthy population, respectively]. There was no correlation between the measurements and the clinical outcome. CONCLUSIONS: This study shows that the healed Achilles tendon after rupture has inferior elastic properties even after a long-term healing phase. Differences in elastic properties after rupture mainly originate from the mid-substance of the Achilles tendon, in which most of the ruptures occur. Elastographic results do not correspond with subjective perception. Clinically, sonoelastographical measurements of biomechanical properties can be useful to provide objective insights in tendon recovery. PMID- 29147742 TI - Varus tibial alignment is associated with greater tibial baseplate migration at 10 years following total knee arthroplasty. AB - PURPOSE: To examine implant migration and articular behavior of primary total knee arthroplasty (TKA) at 10 years after index surgery and correlate to implant alignment. METHODS: Thirty-five patients underwent a cemented posterior stabilized total knee arthroplasty with a surgical objective of neutral alignment and were enrolled in a long-term radiostereometric analysis (RSA) study. At 10 years after surgery, patients were analyzed for implant migration using RSA as well as radiographic assessment of articular behavior at four positions of knee flexion. Implant position and alignment was measured on full-length radiographs. Patient demographics and reported outcomes were also collected. RESULTS: No difference between patient demographics or patient-reported outcomes were found. When categorized into neutral and varus groupings, no difference in migration was present. If alignment was considered as a continuous variable, there was no correlation between overall leg alignment and migration, however, migration increased with an increasing varus tibial alignment. Although contact location did not differ between neutral and varus groups through a range of motion, condylar liftoff was much more common in the varus group, of which all were lateral liftoff. CONCLUSIONS: Increased tibial varus results in increased implant migration. Overall varus limb alignment is correlated with isolated lateral compartment liftoff, and liftoff occurs more commonly than in neutral aligned knees. The increased migration and liftoff raise concerns about the longevity of malaligned total knee replacements. If a goal of overall varus limb alignment is desired for TKA, the tibia should remain neutral. LEVEL OF EVIDENCE: Level III. PMID- 29147744 TI - Consistency in patient-reported outcome measures after total knee arthroplasty using patient-specific instrumentation: a 5-year follow-up of 200 consecutive cases. AB - PURPOSE: The purpose of this study was to evaluate the 5-year follow-up results of the first 200 total knee arthroplasties (TKA) performed by one high-volume surgeon, using patient-specific information (PSI). To date, there has been no other research into the mid-term follow-up of TKA performed using PSI. MATERIALS AND METHODS: A total of 184 consecutive patients (200 TKA) were evaluated. Outcome measures included implant survival rate, adverse events, and the following patient-reported outcome measures (PROMs); Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Oxford Knee Score (OKS), Pain Visual Analogue Score (VAS) and EuroQol-5D Score (EQ-5D). RESULTS: Revision surgery was performed for late secondary prosthetic joint infection (n = 1, total revision), aseptic loosening (n = 1, tibial component revision), instability (n = 1, isolated polyethylene insert exchange), and polyethylene insert breakage (n = 1, isolated polyethylene insert exchange). Other adverse events were as follows: debridement, antibiotics and implant retention for early prosthetic joint infection (n = 1), surgical debridement for haemarthrosis (n = 1), superficial wound infection (n = 2), thromboembolic events (n = 2), compartment syndrome (n = 1), and nerve injury (n = 2). All median outcome scores for patient reported outcome measures at 5 years improved significantly compared with the preoperative values (p <= 0.05). Median outcome scores were not significantly different between 1- and 5-year moments of follow-up, except for a significant decrease of EQ-VAS (p <= 0.05) between these two follow-up moments. CONCLUSION: PROMs are consistent for 5-year follow-up of TKA using PSI. After 5 years of follow-up, revision surgery for any reason occurred in four patients (2%). LEVEL OF EVIDENCE: III. PMID- 29147743 TI - Low implant migration of the SIGMA(r) medial unicompartmental knee arthroplasty. AB - PURPOSE: The purpose of this study was to evaluate implant migration of the fixed bearing Sigma(r) medial unicompartmental knee arthroplasty (UKA). UKA is a regularly used treatment for patients with medial osteoarthritis (OA) of the knee. UKA has a higher revision rate than total knee arthroplasty. Implant migration can be used as a predictor of implant loosening. METHODS: A prospective radiostereometric cohort study was performed. Forty-five patients with medial OA of the knee were included and received a cemented Sigma(r) UKA. The patients were followed for 24 months with radiostereometric analysis (RSA) and clinical outcome scores (Oxford knee score). Clinical precision was based on double determinations taken at 4 and 12 months. Tibial implants were classified as stable (difference in MTPM < 0.2 mm between 1 2 and 24 months) or as continuously migrating (difference in MTPM > 0.2 mm between 12 and 24 months). RESULTS: No significant differences in migration were found for the femoral component. For the tibial component, a difference of 0.05 mm was shown for translation on the x-axis between 4 months and 12 (p < 0.01) and between 4 months and 24 months (p < 0.01). A difference of - 0.23 to - 0.50 degrees was shown for rotation around the x axis (p < 0.01) and a difference of - 0.11 degrees was shown for rotation around the z-axis between 4 and 12 months (p = 0.02). These differences in migration over time were small and fall within the clinical precision of the measurements. Tibial components were divided into a stable group (N = 26) and a continuously migrating group (N = 11), which showed a significant difference in maximal total point motion (MTPM) (p < 0.01). The Oxford knee score improved significantly from poor before surgery (23.2) to good at follow-up (37.5-40.9). CONCLUSIONS: The Sigma(r) UKA showed low implant migration and good clinical outcomes, suggesting that the Sigma UKA can be used in clinical practice. However, continuous migration was found in 30% of our patients which could indicate a risk of later revision surgery in this group. LEVEL OF EVIDENCE: II. PMID- 29147745 TI - Steroid hormone profiling in human breast adipose tissue using semi-automated purification and highly sensitive determination of estrogens by GC-APCI-MS/MS. AB - Body mass index is a known breast cancer risk factor due to, among other mechanisms, adipose-derived hormones. We developed a method for steroid hormone profiling in adipose tissue to evaluate healthy tissue around the tumor and define new biomarkers for cancer development. A semi-automated sample preparation method based on gel permeation chromatography and subsequent derivatization with trimethylsilyl (TMS) is presented. Progestagens and androgens were determined by GC-EI-MS/MS (LOQ 0.5 to 10 ng/g lipids). For estrogen measurement, a highly sensitive GC-APCI-MS/MS method was developed to reach the required lower limits of detection (0.05 to 0.1 ng/g lipids in matrix, 100-200 fg on column for pure standards). The combination of the two methods allows the screening of 27 androgens and progestagens and 4 estrogens from a single sample. Good accuracies and repeatabilities were achieved for each compound class at their respective limit of detection. The method was applied to determine steroid hormone profiles in adipose tissue of 51 patients, collected both at proximity and distant to the tumor. Out of the 31 tested steroid hormones, 14 compounds were detected in human samples. Pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone (DHEA), and androstendione accounted together for 80% of the observed steroid hormone profiles, whereas the estrogens accounted for only 1%. These profiles did not differ based on sampling location, except for beta-estradiol; steroid hormone conversions from androgens to estrogens that potentially take place in adipose or tumoral tissue might not be detectable due a factor 100 difference in concentration of for example DHEA and beta-estradiol. Graphical Abstract Schematic overview of the determination of steroid hormones and metabolites in adipose tissue in proximity and distal to the tumor. PMID- 29147746 TI - Multianalyte, high-throughput liquid chromatography tandem mass spectrometry method for the sensitive determination of fungicides and insecticides in wine. AB - Evidence of pesticide transfer from grapes to wine, added to differences in the national regulations regarding the number and the maximum concentration of these species in wine, demands analytical procedures suitable for their routine control in this foodstuff. In this research, solid-phase extraction (SPE) and ultra performance liquid chromatography (UPLC), with tandem mass spectrometry (MS/MS) detection, are combined to obtain a sensitive and rapid procedure to determine 50 pesticides in red and white wines. Efficiency and selectivity of sample preparation are correlated with the type of sorbent, the elution solvent, and the physicochemical properties of pesticides. SPE of 2-mL wine samples followed by direct injection of the extract in the UPLC-MS/MS system provides quantification limits (LOQs) below 1 ng mL-1 for 48 out of 50 compounds, linear responses up to 200 ng mL-1, and acceptable accuracy, employing quantification against solvent based standards, for 45 species. A total analysis time of 10 min, including compounds separation and re-equilibration of the UPLC column, was achieved. The developed methodology was applied to 25 wines (20 conventional and 5 ecological), produced in 7 different countries. Out of 27 pesticides quantified in these wines, 12 displayed occurrence frequencies above 24%; moreover, all wines, except one of the ecological ones, contained residues from at least one pesticide. PMID- 29147747 TI - Isomers of tris(chloropropyl) phosphate (TCPP) in technical mixtures and environmental samples. AB - Tris(chloropropyl) phosphate (TCPP) is an environmentally abundant organophosphate ester (OPE). TCPP is comprised of four isomers with seven possible structures, eight CAS numbers, and even more common names. A review of 54 studies reporting one or more TCPP isomers confirmed that the most abundant and most often reported TCPP isomer was tris(2-chloro-1-methylethyl) phosphate, also known as tris(chloroisopropyl) phosphate (TCiPP, referred to hereafter as TCPP1). Full-scan gas chromatography-mass spectrometry (GC-MS) was used to identify the other three isomers numbered here according to their elution order on a non-polar GC column (DB-5): bis(2-chloro-1-methylethyl) (2-chloropropyl) phosphate (TCPP2), bis(2-chloropropyl)(2-chloro-1-methylethyl) phosphate (TCPP3), and tris(2-chloropropyl) phosphate (TCPP4). GC with a flame ionization detector (FID) was used to identify the relative abundances of the isomers in commercially available standards with unknown isomer composition. In technical TCPP, TCPP1-4 isomers averaged 71 +/- 1, 26 +/- 0.4, 3 +/- 0.5, and 0.1 +/- 0.02%, respectively. When these percent masses are incorporated into GC-MS quantification, response factors (RFs) for TCPP1 and TCPP2 are significantly different from TCPP3 and TCPP4, indicating that the multiple RF approach is more accurate than the commonly employed single RF method. Samples from urban streams and wastewater treatment plant (WWTP) effluent from Toronto, Canada, had isomeric ratios of TCPP1/2 that were not significantly different from a technical mixture whereas rain had a significantly different ratio indicating enrichment in the more volatile TCPP1 isomer. Reporting TCPP isomers can provide insight into sources, transport, and fate of TCPP in the environment. Graphical Abstract ?. PMID- 29147748 TI - Graphene quantum dots-terbium ions as novel sensitive and selective time-resolved luminescent probes. AB - We propose an alternative approach for the development of analytical methods based on terbium-sensitized luminescence (TSL). TSL is based on the complexation between Tb(III) ions and fluorescent organic compounds that have appropriate functional groups to complex with Tb(III). We report the use of graphene quantum dot (GQDs) nanoparticles to improve the sensitivity and selectivity of TSL detection. GQDs can react with terbium ions through the carboxylic groups present in their structure. These Tb(III)-GQD complexes, formed in situ in aqueous solution, can be used as time-resolved luminescent probes. Ascorbic acid was selected as a target analyte to demonstrate the suitability of the proposed method. The selectivity of the TSL method was highly improved for most of the interferences tested. Under the optimum conditions [Tb(III) concentration 5 * 10 4 mol L-1, GQD concentration 4 mg L-1], a minimum 100% increase in selectivity was observed for several vitamins and common cations that may be present in the samples to be analyzed. In addition, the analytical signal showed a 30% enhancement with the use of GQDs compared with the use of merely Tb(III) ions, with a detection limit of 0.12 MUg mL-1. The repeatability and intermediate precision were lower than 3% and 5%, respectively. From the results obtained, the implementation of GQDs in TSL can lead to the development of novel time-resolved luminescent probes with high analytical potential. Graphical abstract Quenching of Tb(III)-graphene quantum dot (GQD) luminescence by ascorbic acid (AA). TBL terbium-sensitized luminescence. PMID- 29147749 TI - Correction to: Characterization of trabecular bone microstructure in premenopausal women with distal radius fractures. AB - Owing to an oversight by the corresponding author, the name of the third author of this article was rendered wrongly. His correct name is Kempland C. Walley. PMID- 29147750 TI - The association between childhood fractures and adolescence bone outcomes: a population-based study, the Tromso Study, Fit Futures. AB - : Childhood fracture may predict persistent skeletal fragility, but it may also reflect high physical activity which is beneficial to bone development. We observe a difference in the relationship between previous fracture and bone outcome across physical activity level and sex. Further elaboration on this variation is needed. PURPOSE: Childhood fracture may be an early marker of skeletal fragility, or increased levels of physical activity (PA), which are beneficial for bone mineral accrual. This study investigated the association between a previous history of childhood fracture and adolescent bone mineral outcomes by various PA levels. METHODS: We recruited 469 girls and 492 boys aged 15-18 years to this study. We assessed PA levels by questionnaire and measured areal bone mineral density (aBMD) and bone mineral content (BMC) using dual energy X-ray absorptiometry (DXA) at arm, femoral neck (FN), total hip (TH), and total body (TB) and calculated bone mineral apparent density (BMAD, g/cm3). Fractures from birth to time of DXA measurements were retrospectively recorded. We analyzed differences among participants with and without fractures using independent sample t test. Multiple linear regression was used to examine the association between fractures and aBMD and BMC measurements according to adolescent PA. RESULTS: Girls with and without a previous history of fracture had similar BMC, aBMD, and BMAD at all sites. In multiple regression analyses stratified by physical activity intensity (PAi), there was a significant negative association between fracture and aBMD-TH and BMC-FN yet only in girls reporting low PAi. There was a significant negative association between forearm fractures, BMAD-FN, and BMAD-arm among vigorously active boys. CONCLUSION: Our findings indicate a negative association between childhood fractures and aBMD/BMC in adolescent girls reporting low PAi. In boys, such an association appears only in vigorously active participants with a history of forearm fractures. PMID- 29147751 TI - Interpretation of milk research results. PMID- 29147752 TI - Interpretation of milk research results: response to comments by Michaelsson and Byberg. PMID- 29147753 TI - Defective WNT signaling associates with bone marrow fibrosis-a cross-sectional cohort study in a family with WNT1 osteoporosis. AB - : This study explores bone marrow function in patients with defective WNT1 signaling. Bone marrow samples showed increased reticulin and altered granulopoiesis while overall hematopoiesis was normal. Findings did not associate with severity of osteoporosis. These observations provide new insight into the role of WNT signaling in bone marrow homeostasis. INTRODUCTION: WNT signaling regulates bone homeostasis and survival and self-renewal of hematopoietic stem cells. Aberrant activation may lead to osteoporosis and bone marrow pathology. We aimed to explore bone marrow findings in a large family with early-onset osteoporosis due to a heterozygous WNT1 mutation. METHODS: We analyzed peripheral blood samples, and bone marrow aspirates and biopsies from 10 subjects with WNT1 mutation p.C218G. One subject was previously diagnosed with idiopathic myelofibrosis and others had no previously diagnosed hematologic disorders. The findings were correlated with the skeletal phenotype, as evaluated by number of peripheral and spinal fractures and bone mineral density. RESULTS: Peripheral blood samples showed no abnormalities in cell counts, morphology or distributions but mild increase in platelet count. Bone marrow aspirates (from 8/10 subjects) showed mild decrease in bone marrow iron storages in 6 and variation in cell distributions in 5 subjects. Bone marrow biopsies (from 6/10 subjects) showed increased bone marrow reticulin (grade MF-2 in the myelofibrosis subject and grade MF-1 in 4 others), and an increase in overall, and a shift towards early phase, granulopoiesis. The bone marrow findings did not associate with the severity of skeletal phenotype. CONCLUSIONS: Defective WNT signaling associates with a mild increase in bone marrow reticulin and may predispose to myelofibrosis, while overall hematopoiesis and peripheral blood values are unaltered in individuals with a WNT1 mutation. In this family with WNT1 osteoporosis, bone marrow findings were not related to the severity of osteoporosis. PMID- 29147754 TI - Vaginal ultrasound for imaging of a urinary bladder mass and treatment of a large leiomyoma of the urinary bladder in pregnancy. PMID- 29147755 TI - Repair of a vesicouterine fistula following cesarean section. AB - INTRODUCTION AND HYPOTHESIS: Vesicouterine fistula is a rare complication of cesarean section. The aim of this video is to present a case report and to provide a tutorial on the surgical technique of delayed transvaginal repair of a high vesicouterine fistula that developed after cesarean section with manual removal of a morbidly adherent placenta. METHODS: A 43-year-old woman was referred to our unit for continuous urinary leakage 3 months after undergoing a cesarean section with manual removal of a morbidly adherent placenta. A vesicouterine fistula starting from the posterior bladder wall was identified. The surgical repair consisted of a transvaginal layered repair as shown in the video. RESULTS: No surgical complications were observed postoperatively. Two months after surgery the fistula had not recurred and the patient reported no urinary leakage. CONCLUSIONS: Transvaginal layered primary repair of vesicouterine fistula was shown to be a safe and effective procedure for restoring continence. The vaginal route can be particularly attractive for urogynecological surgeons. PMID- 29147756 TI - Locus and gene-based GWAS meta-analysis identifies new diabetic nephropathy genes. AB - Objective Assimilation of SNPs Interacting in Synchrony (OASIS) is a locus-based clustering algorithm recently described that can potentially address false positives and negatives in genome-wide association studies (GWAS) of complex disorders. Diabetic nephropathy (DN) is incompletely understood due to a paucity of genes identified despite several GWAS. OASIS was applied to three DN dbGAP GWAS datasets (4725 subjects; 1.06 million SNPs). OASIS identified 19 DN genes which were verified using single variant replication in a standard association study and gene-based analysis using GATES. CARS and FRMD3 were confirmed as DN genes, and five known diabetes-associated genes, viz. NLRP3, INPPL1, PIK3C2G, NRXN3, and TBC1D4, not previously identified using these datasets were discovered. Furthermore, three additional novel DN genes were found which replicated in two sets of analysis, viz. NTN1, EBF2, and DNAH11. Hence, composite analysis with OASIS, gene-based, and single variant association testing can be universally applied to existing GWAS datasets for the identification of new genes. PMID- 29147757 TI - Prospective evaluation of CO2 laser-assisted sclerectomy surgery (CLASS) with Mitomycin C. AB - PURPOSE: Our purpose was to evaluate the clinical safety and efficacy of CO2 laser-assisted sclerectomy surgery (CLASS) with Mitomycin C (MMC) in open angle glaucoma (OAG). METHODS: This was a prospective, uncontrolled, interventional case series. All subjects underwent CLASS procedure by a single surgeon. After the dissection of a partial thickness scleral flap, topical MMC 0.2 mg/ml was applied to the sclera and the conjunctiva for 3 min. The CO2 laser with a beam manipulating system was used to ablate the scleral tissue and expose the Schlemm's canal area. Primary outcomes: intraocular pressure (IOP) change, number of IOP-lowering medicaments change. Adverse events were evaluated as secondary outcomes. RESULTS: Twenty-one eyes of 21 patients underwent the CLASS procedure. Thirteen were primary OAG (62%), two normal pressure glaucoma (10%), three exfoliative glaucoma (14%) and three others secondary OAG. With a mean (SD) follow-up of 15.3 (5.9) months, the IOP changed from 25.4 (6.7) mmHg at baseline to 10.9 (3.4) mmHg al the last visit. Mean reduction of IOP was -14.5 mmHg (95% CI, -17.7 to -11.2, P < 0.001). The median (IQR) number of IOP-lowering medication decreased from 3 (3-3) at baseline to 1 (0-1) at the last visit (P < 0.001). Visual acuity did not change significantly. Adverse events: five eyes (24%) developed iris adhesion to the filtration area that was successfully managed with office-based procedures. In one case (5%), CLASS was converted to trabeculectomy due to intraoperative perforation of the ablated area. There was one case of hypotony maculopathy successfully treated with placement of additional transconjunctival scleral flap sutures. CONCLUSIONS: The CLASS procedure with MMC is clinically safe and effective maintaining a large reduction in IOP and in the number of IOP-lowering medications with a mean follow-up of 15 months. Iris adhesion at the filtrating area warrants further evaluation and possibly reflects the surgeon's learning curve. PMID- 29147758 TI - A systematic review assessing non-pharmacological conservative treatment studies for people with non-inflammatory multi-joint pain: clinical outcomes and research design considerations. AB - To systematically review the evidence to determine the clinical outcomes and the important methodological quality features of interventional studies on adults with non-inflammatory multi-joint pain (MJP). Systematic search of published and unpublished literature using the databases: AMED, CINAHL, MEDLINE, EMBASE, psycINFO, SPORTDiscus, PEDro, OpenGrey, the EU Clinical Trials Register, World Health Organization International Clinical Trial Registry Platform, ClinicalTrials.gov and the ISRCTN registry (search: inception to 19th October 2017). All papers reporting the clinical outcomes of non-pharmacological interventions for people with non-inflammatory MJP were included. Studies were critically appraised using the Downs and Black Critical Appraisal and the TIDieR reporting checklists. Data were analysed using a Best Evidence Synthesis approach. From 3824 citations, four papers satisfied the eligibility criteria. Three studies reported outcomes from multidisciplinary rehabilitation programmes and one study reported the findings of a spa therapy intervention. All interventions significantly improved pain, function and quality of life in the short-term. There was limited reporting of measures for absenteeism, presenteeism and psychosocial outcomes. The evidence was 'weak', and due to a lack of controlled trials, there is limited evidence to ascertain treatment effectiveness. Design consideration for future trials surround improved reporting of participant characteristics, interventions and the standardisation of core outcome measures. There is insufficient high-quality trial data to determine the effectiveness of treatments for non-inflammatory MJP. Given the significant health burden which this condition presents on both individuals and wider society, developing and testing interventions and accurately reporting these, should be a research priority. Registration PROSPERO (CRD42013005888). PMID- 29147760 TI - Nasal packing and trans-septal suturing after septoplasty. PMID- 29147759 TI - Patterns and predictors of recurrence after open radical cystectomy for bladder cancer: a comprehensive review of the literature. AB - PURPOSE: To review the currently available literature reporting the patterns of recurrence and their predictive factors after open radical cystectomy (RC) for bladder cancer. METHODS: A review of the literature was performed using the MEDLINE, Scopus and Web of Sciences databases from January 1997 to May 2017. The PRISMA guidelines were followed for the conduct of the study. RESULTS: Local recurrence rate ranges between 30 and 54%. Distant recurrence is not often standardized and is reported in up to 50% of cases. The overall 5-year recurrence free survival rates from 58 to 81%. The mean follow-up of studies included in the analysis ranged from 18 to 350 months. Details on the most important demographic and epidemiological, clinical, histologic and pathologic predictors of recurrence after radical cystectomy are provided through an evidence-based approach. The impact of the extension of lymph node dissection on recurrence after RC is investigated. CONCLUSIONS: A correct prognostic assessment is essential for patients undergoing radical cystectomy for bladder cancer, thereby potentially improving their oncologic outcomes. PMID- 29147761 TI - Single-leg spica provides adequate stability after open reduction in developmental dysplasia of the hip. AB - INTRODUCTION: The late detection of developmental dysplasia of the hip (DDH) will remain a major concern in some parts of the world until effective screening programs become available. With late diagnosis comes the need for open surgical reduction. Surgery is invariably followed by a period of immobilisation in a spica cast to prevent postoperative displacement. The goal of this study is to evaluate the effect of double-leg spica as compared to single-leg spica, on the risk of displacement after unilateral open reduction of the hip. MATERIALS AND METHODS: This was a retrospective review of DDH patients from 2012 to 2016 and younger than 4 years of age, who had unilateral anterior open reduction. Patients who had one of the following were excluded: neuromuscular diagnosis, the addition of K-wire, and simultaneous bilateral open reductions. Demographic data were collected along with related clinical and radiographic variables. A total of 128 patients (162 hips) met the inclusion criteria; 93 were in the double-leg spica group, and 69 were in the single-leg spica group. RESULTS: The mean age was 25.4 +/- 8.1 months and the mean follow-up was 18.6 +/- 11.6 months. Baseline characteristics were balanced between the two groups. There were three events of redislocation in the double-leg spica group as compared to one redislocation in the single-leg spica group. The difference did not reach statistical significance (p = 0.637, risk ratio 1.317, CI 0.736-2.356). The difference in subsequent disruption of Shenton's line and hip migration of more than 29% was (p = 0.395, risk ratio 1.411, CI 0.892-2.234) and (p = 0.087, risk ratio 0.67, CI 0.417 1.078), respectively. Three patients had a greenstick distal femur fracture after double-leg spica and one after single-leg spica. CONCLUSION: These data suggest that including the contralateral hip in the cast after open reduction is not essential as it does not seem to improve stability. PMID- 29147762 TI - Phenotypic Effects and Inhibition of Botrydial Biosynthesis Induced by Different Plant-Based Elicitors in Botrytis cinerea. AB - Botrytis cinerea is considered a model organism for the study of plant-pathogen interaction showing great genetic diversity and a high degree of morphological variability depending on environmental conditions. The use of new compounds and plant-based elicitors may trigger the expression of different B. cinerea genes, providing new sources of virulence factors. This work is focused on elucidating the phenotypic effect in B. cinerea of different carbon sources such as glucose, cellulose and tomato cell walls (TCW). Production of botrydial and dihydrobotrydial toxins was evaluated using thin-layer chromatography (TLC), proton nuclear magnetic resonance spectroscopy (1H-NMR) and mass spectrometry (UPLC-HRESIMS). Expression of the toxin biosynthesis gene BcBOT2 was followed using RT-qPCR. Results show an inhibition of the toxin biosynthesis pathway when TCW are present as a sole carbon source, suggesting that the toxin is only produced when rich molecules, like glucose, are available for fungal metabolism. That suggests a connection between gene expression of virulence factors and environmental conditions, where the silent genes can be induced by different culture conditions. PMID- 29147765 TI - Congestive hepatopathy. AB - Passive hepatic congestion may result from a variety of distinct cardiovascular conditions. Injury to the liver caused by congestion is often asymptomatic and may not be recognized clinically. Diagnosis of congestive hepatopathy is important as it has the potential to cause complications including hepatic fibrosis and development of benign and malignant liver masses. This review will summarize the pathophysiologic mechanisms of congestive hepatopathy and provide both description and examples of its multimodality imaging findings. Examples of alternative disease which may have a similar imaging appearance will be provided. Knowledge regarding the characteristic imaging findings of congestive hepatopathy will allow for its accurate identification. Reviewing both the benefits and limitations of imaging performed to evaluate congestive hepatopathy and its complications will help to avoid pitfalls and enable recommendation of appropriate next steps in diagnostic evaluation. PMID- 29147763 TI - Frailty in end-stage hip or knee osteoarthritis: validation of the Groningen Frailty Indicator (GFI) questionnaire. AB - Frailty is highly prevalent in the elderly, increasing the risk of poor health outcomes. The Groningen Frailty Indicator (GFI) is a 15-item validated questionnaire for the elderly. Its value in patients with end-stage hip or knee osteoarthritis (OA) has not yet been determined. This study assesses the validity of the GFI in this patient group. End-stage hip or knee OA patients completed the GFI (range 0-15, >= 4 = frail) before arthroplasty surgery. Convergent validity was determined by Spearman-rank correlation between the SF-12 physical (PCS) and mental (MCS) component scores and the physical and mental GFI-domains, respectively. Discriminant validity was assessed by means of overall GFI-score and the pain-domain of the Hip/Knee Osteoarthritis Outcome Score (HOOS/KOOS). Altogether 3275 patients were included of whom 2957 (90.3%) completed the GFI. Mean GFI-scores were 2.78 (2.41) and 2.28 (1.99) in hip and knee OA-patients, respectively, with 570 (35.9%) of hip and 344 (24.1%) of knee patients considered frail. The convergent validity was moderate to strong (physical domain R = - 0.4, mental domain R = - 0.6) and discriminant validity low (R HOOS/KOOS-pain domain = - 0.2), confirming the validity of the GFI-questionnaire in this population. With 90% of participants completing the GFI, it is a feasible and valid questionnaire to assess frailty in end-stage hip and knee OA-patients. One-third (33.3%) of the patients undergoing hip arthroplasty and a quarter (24.1%) of those undergoing knee arthroplasty are frail. Whether this is associated with worse outcomes and can thus be used as a pre-operative predictor needs to be explored. PMID- 29147764 TI - Prospective evaluation of 18F-FACBC PET/CT and PET/MRI versus multiparametric MRI in intermediate- to high-risk prostate cancer patients (FLUCIPRO trial). AB - PURPOSE: The purpose of this study was to evaluate 18F-FACBC PET/CT, PET/MRI, and multiparametric MRI (mpMRI) in detection of primary prostate cancer (PCa). METHODS: Twenty-six men with histologically confirmed PCa underwent PET/CT immediately after injection of 369 +/- 10 MBq 18F-FACBC (fluciclovine) followed by PET/MRI started 55 +/- 7 min from injection. Maximum standardized uptake values (SUVmax) were measured for both hybrid PET acquisitions. A separate mpMRI was acquired within a week of the PET scans. Logan plots were used to calculate volume of distribution (VT). The presence of PCa was estimated in 12 regions with radical prostatectomy findings as ground truth. For each imaging modality, area under the curve (AUC) for detection of PCa was determined to predict diagnostic performance. The clinical trial registration number is NCT02002455. RESULTS: In the visual analysis, 164/312 (53%) regions contained PCa, and 41 tumor foci were identified. PET/CT demonstrated the highest sensitivity at 87% while its specificity was low at 56%. The AUC of both PET/MRI and mpMRI significantly (p < 0.01) outperformed that of PET/CT while no differences were detected between PET/MRI and mpMRI. SUVmax and VT of Gleason score (GS) >3 + 4 tumors were significantly (p < 0.05) higher than those for GS 3 + 3 and benign hyperplasia. A total of 442 lymph nodes were evaluable for staging, and PET/CT and PET/MRI demonstrated true-positive findings in only 1/7 patients with metastatic lymph nodes. CONCLUSIONS: Quantitative 18F-FACBC imaging significantly correlated with GS but failed to outperform MRI in lesion detection. 18F-FACBC may assist in targeted biopsies in the setting of hybrid imaging with MRI. PMID- 29147766 TI - Pictorial essay: imaging findings following Y90 radiation segmentectomy for hepatocellular carcinoma. AB - Transarterial radioembolization is a novel therapy that has gained rapid clinical acceptance for the treatment of hepatocellular carcinoma (HCC). Segmental radioembolization [also termed radiation segmentectomy (RS)] is a technique that can deliver high doses (> 190 Gy) of radiation selectively to the hepatic segment(s) containing the tumor. The aim of this comprehensive review is to provide an illustrative summary of the most relevant imaging findings encountered after radiation segmentectomy. A 62-patient cohort of Child-Pugh A patients with solitary HCC < 5 cm in size was identified. A comprehensive retrospective imaging review was done by interventional radiology staff at our institution. Important imaging findings were reported and illustrated in a descriptive account. For the purposes of completeness, specific patients outside our initial cohort with unique educational imaging features that also underwent segmentectomy were included in this pictorial essay. This review shows that response assessment after RS requires a learning curve with common drawbacks that can lead to false positive interpretations and secondary unnecessary treatments. It is important to recognize that treatment responses and pathological changes both are time dependent. Findings such as benign geographical enhancement and initial benign pathological enhancement can easily be misinterpreted. Capsular retraction and segmental atrophy are some other examples of unique post-RS response that are not seen in any other treatment. PMID- 29147767 TI - Mechanism of accommodation assessed by change in precisely registered ocular images associated with concurrent change in auto-refraction. AB - PURPOSE: Our purpose was to determine the changes in anterior chamber depth (ACD) and central lens thickness (CLT) during pharmacologically induced accommodation. METHODS: Following pupillary dilation with phenylephrine 10%, baseline auto refractions and swept-source optical coherence tomographic biometric images (Zeiss IOLMaster 700) were obtained from the right eyes of 25 subjects aged 19 to 24 years. Pilocarpine 4% and phenylephrine 10% were then instilled into these right eyes. One hour later, auto-refractions and biometric imaging were repeated. Only data from eight of 25 subjects met the following stringent criteria to be included in the study analysis: pre and post-pilocarpine biometric foveal images were registerable, the images of the corneal centers were shifted by <=100 MUm, pupils >5 mm and the pharmacologically induced refractive change was >= -7 diopters. RESULTS: The mean auto-refractive accommodative change for the eight included subjects was -12.45 diopters (+/- 3.45 diopters). The mean change in CLT was 81 MUm (+/- 54 MUm) and the mean change in ACD was -145 MUm (+/- 86 MUm). Superimposition of the registered pre and post-pilocarpine biometric images of the sagittal sections of the whole eye from each subject demonstrated that the position of the whole lens did not shift either anteriorly, posteriorly or vertically during pharmacologically induced accommodation. CONCLUSIONS: A small increase in lens thickness was associated with a large change in accommodative amplitude and no significant change in lens position as predicted by the Schachar theory. PMID- 29147768 TI - Non-invasive methods for estimating mPAP in COPD using cardiovascular magnetic resonance imaging. AB - PURPOSE: Pulmonary hypertension (PH) is associated with a poor outcome in chronic obstructive pulmonary disease (COPD) and is diagnosed invasively. We aimed to assess the diagnostic accuracy and prognostic value of non-invasive cardiovascular magnetic resonance (CMR) models. METHODS: Patients with COPD and suspected PH, who underwent CMR and right heart catheter (RHC) were identified. Three candidate models were assessed: 1, CMR-RV model, based on right ventricular (RV) mass and interventricular septal angle; 2, CMR PA/RV includes RV mass, septal angle and pulmonary artery (PA) measurements; 3, the Alpha index, based on RV ejection fraction and PA size. RESULTS: Of 102 COPD patients, 87 had PH. The CMR-PA/RV model had the strongest diagnostic accuracy (sensitivity 92%, specificity 80%, positive predictive value 96% and negative predictive value 63%, AUC 0.93, p<0.0001). Splitting RHC-mPAP, CMR-RV and CMR-PA/RV models by 35mmHg gave a significant difference in survival, with log-rank chi-squared 5.03, 5.47 and 7.10. RV mass and PA relative area change were the independent predictors of mortality at multivariate Cox regression (p=0.002 and 0.030). CONCLUSION: CMR provides diagnostic and prognostic information in PH-COPD. The CMR-PA/RV model is useful for diagnosis, the RV mass index and PA relative area change are useful to assess prognosis. KEY POINTS: * Pulmonary hypertension is a marker of poor outcome in COPD. * MRI can predict invasively measured mean pulmonary artery pressure. * Cardiac MRI allows for estimation of survival in COPD. * Cardiac MRI may be useful for follow up or future trials. * MRI is potentially useful to assess pulmonary hypertension in patients with COPD. PMID- 29147769 TI - Skin barrier and microbiome in acne. AB - Acne is an immune-mediated chronic inflammatory disease. Although several factors are involved in its pathophysiology, this process is not completely understood. Androgen hormone activity increases sebum production inside the pilosebaceous follicle, adjusting the environment for the development of Propionibacterium acnes which triggers inflammation. Knowing how others factors such as the skin barrier and microbiome are involved in acne, can help in understanding more about the disease and may help to conduct a better treatment. PMID- 29147770 TI - [Infantile hemangioma of the eyelid]. AB - Hemangiomas are one of the most common vascular tumors in infancy. In most cases no therapy is necessary and spontaneous regression is observed; however, if they arise in the periocular region, immediate action is required as rapid growth frequently leads to obstruction of the visual field with the risk of developing amblyopia and orbital suppression up to permanent disfigurement and stigmatization of those affected. Novel pharmaceutical treatment options led to a significant paradigm shift in the treatment of pediatric hemangiomas. PMID- 29147771 TI - Maximum striking velocities in strikes with steel rods-the influence of rod length, rod mass and volunteer parameters. AB - In blunt force trauma to the head caused by attacks with blunt instruments, contact forces can be estimated based on the conservation of momentum if impact velocities are known. The aims of this work were to measure maximum striking velocities and to examine the influence of rod parameters such as rod mass and length as well as volunteer parameters such as sex, age, body height, body mass, body mass index and the average amount of physical exercise. Steel rods with masses of 500, 1000 and 1500 g as well as lengths of 40, 65 and 90 cm were exemplarily tested as blunt instruments. Twenty-nine men and 22 women participated in this study. Each volunteer performed several vertical strikes with the steel rods onto a passive immobile target. Maximum striking velocities were measured by means of a Qualisys motion capture system using high-speed cameras and infrared light. Male volunteers achieved maximum striking velocities between 14.0 and 35.5 m/s whereas female volunteers achieved values between 10.4 and 28.3 m/s. Results show that maximum striking velocities increased with smaller rod masses and less consistently with higher rod lengths. Statistically significant influences were found in the volunteers' sex and average amount of physical exercise. PMID- 29147772 TI - Correction to: A comparison of isomaltulose versus maltodextrin ingestion during soccer-specific exercise. AB - The article "A comparison of isomaltulose versus maltodextrin ingestion during soccer-specific exercise", written by "Emma J. Stevenson, Anthony Watson, Stephan Theis, Anja Holz,.Liam D. Harper, Mark Russell", was originally published Online First without open access. After publication in volume [117], issue [11], page. PMID- 29147773 TI - Extraperitoneal sigmoidostomy: a surgical approach with less complications and better functions for abdominoperineal resection of rectal cancer. AB - OBJECTIVE: The aim of this study is to explore the safety and function of extraperitoneal sigmoidostomy for patients with rectal cancer who underwent abdominoperineal resection. METHODS: We systematically reviewed records of patients with rectal cancer who underwent abdominoperineal resection and extraperitoneal or intraperitoneal sigmoidostomy from January 2010 to December 2014 at our department. They were grouped into the extraperitoneal (group A) and intraperitoneal sigmoidostomy (group B) groups. Clinical data were collected and statistically analyzed. RESULTS: A total of 231 consecutive cases were included: 108 cases in group A and 123 in group B. Patient demographics were similar in both groups. Group A was associated with less time for sigmoidostomy (19.6 +/- 2.8 vs. 27.0 +/- 4.5 min, p < 0.001), shorter postoperative hospitalization (6.4 +/- 1.3 vs. 6.9 +/- 1.6 days, p = 0.036), less incidence of stoma-related complications (p = 0.002) and less possibility of re-operation related to stomal complications (p = 0.037). Functions of stoma including stimulation of excrement, stimulating time for excrement, frequency of excrement, self-controlled ability of excrement, and regularity of excrement were all better than those in group B patients (p < 0.001, < 0.001, 0.018, 0.004, and 0.001, respectively). Patients in group A had less psychological problems including anxiety (p = 0.008), depression (p = 0.045), and impaired social interaction (p = 0.010). CONCLUSIONS: Extraperitoneal sigmoidostomy is associated with shorter operative duration and postoperative hospitalization and has fewer complications and better outcome for abdominoperineal resection of rectal cancer, and patients also had less psychological problems. PMID- 29147774 TI - Assessment of Mediastinal Lymph Node Size in Pneumococcal Pneumonia with Bacteremia. AB - INTRODUCTION: The significance of mediastinal lymphadenopathy in bacterial pneumonia is unclear. METHODS: We performed a retrospective analysis of mediastinal lymph node size determined by chest CT in patients with bacteremic pneumococcal pneumonia. All patients who had positive blood cultures for streptococcus pneumonia over an 11-year period and had a chest CT scan (index CT) within 2 weeks of the positive blood culture were included in the study. Two thoracic radiologists and one pulmonologist independently examined the index CT plus any chest CT scans performed prior (pre-CT) or after (post-CT) the bacteremic episode. RESULTS: The study cohort of 49 patients was 57% male, 65% White, with mean age of 53 (SD = 20) years. Mediastinal lymphadenopathy was detected in 25/49 (51%) of the cases. The mean size of the largest mediastinal lymph node in short axis was 0.99 (SD = 0.71), ranging from 0.0 to 2.05 cm. There was no correlation noted between the number of lobes involved with pneumonia, and the size of the largest mediastinal lymph node (p = 0.33) or the number of pathologically enlarged mediastinal lymph nodes (p = 0.08). There was a statistically significant increase in the mean size of the largest lymph node between the pre-CT and index-CT group (p = 0.02), and decrease between the index CT group and the post-CT (p = 0.03). CONCLUSION: Pneumococcal pneumonia with bacteremia is associated with mild mediastinal lymph node enlargement. The presence of marked mediastinal lymphadenopathy (short axis LN size > 2 cm) should not be assumed from pneumococcal pneumonia. PMID- 29147775 TI - DFT/TDDFT computational study of the structural, electronic and optical properties of rhodium (III) and iridium (III) complexes based on tris-picolinate bidentate ligands. AB - The electronic structures and spectroscopic properties of two complexes [M(pic)3] (M = Ir, Rh) containing picolinate as bidentate ligands have been calculated by means density functional theory (DFT) and time-dependent DFT/TD-DFT using three hybrid functionals B3LYP, PBE0 and mPW1PW91. The PBE0 and mPW1PW91 functionals, which have the same HF exchange fraction (25%), give similar results and do not differ drastically from B3LYP results. Calculated geometric parameters of the complexes are in good agreement with the available experimental data. The UV absorptions observed in acetonitrile were assigned on the basis of singlet state transitions. The most intense band observed in the UV-C region corresponds to ligand-to-ligand charge transfer states (LLCT) in both complexes. The theoretical spectrum of the rhodium complex is characterized by a large degree of mixing between metal-to-ligand-charge-transfer (MLCT), LLCT and metal centered (MC) states in the UV-A region. The presence of low-lying excited states with MC character affects the absorption spectrum under spin-orbit coupling (SOC) effects and play important roles in the photochemical properties. Graphical abstract Frontier molecular orbital diagram of mer-M(pic)3 (M=Ir, Rh). PMID- 29147776 TI - [Pain therapy in obstetrics]. AB - Labor pains can be stronger than pain caused by fractures and as a result of fear and stress can even have a negative effect on the course of parturition. A proportion of 75% of all women in labor use one or more supportive forms of analgesia to relieve labor pains. The procedures used range from supportive non pharmacological measures, single intramuscular or intravenous analgesics and a prolonged inhalative analgesia up to highly efficient neuraxial blocks. Non pharmacological interventions are considered to be generally safe but poorly effective. In contrast, pharmacological and invasive interventions are proven to be effective for analgesia but associated with potential side effects. PMID- 29147777 TI - How I do it - selective amygdalohippocampectomy via a navigated temporobasal approach, when veins forbid elevation of the temporal lobe. AB - BACKGROUND: Selective amygdalohippocampectomy is an effective treatment option for mesial temporal lobe epilepsy associated with hippocampal sclerosis. METHODS: To describe and emphasize potential pitfalls during selective amygdalohippocampectomy via a modified navigated temporobasal approach, in cases, where temporal basal veins hinder the required elevation of the temporal lobe. CONCLUSIONS: Selective amygdalohippocampectomy via navigated temporobasal approach is a safe procedure that can reduce the rate of visual field deficits by avoiding damage of optic radiation. The option of a small subpial corticotomy of the inferior temporal gyrus allows sufficient elevation of the temporal lobe in cases with difficult basal venous anatomy. PMID- 29147778 TI - Genome-wide investigation of transcription factors provides insights into transcriptional regulation in Plutella xylostella. AB - Transcription factors (TFs), which play a vital role in regulating gene expression, are prevalent in all organisms and characterization of them may provide important clues for understanding regulation in vivo. The present study reports a genome-wide investigation of TFs in the diamondback moth, Plutella xylostella (L.), a worldwide pest of crucifers. A total of 940 TFs distributed among 133 families were identified. Phylogenetic analysis of insect species showed that some of these families were found to have expanded during the evolution of P. xylostella or Lepidoptera. RNA-seq analysis showed that some of the TF families, such as zinc fingers, homeobox, bZIP, bHLH, and MADF_DNA_bdg genes, were highly expressed in certain tissues including midgut, salivary glands, fat body, and hemocytes, with an obvious sex-biased expression pattern. In addition, a number of TFs showed significant differences in expression between insecticide susceptible and resistant strains, suggesting that these TFs play a role in regulating genes related to insecticide resistance. Finally, we identified an expansion of the HOX cluster in Lepidoptera, which might be related to Lepidoptera-specific evolution. Knockout of this cluster using CRISPR/Cas9 showed that the egg cannot hatch, indicating that this cluster may be related to egg development and maturation. This is the first comprehensive study on identifying and characterizing TFs in P. xylostella. Our results suggest that some TF families are expanded in the P. xylostella genome, and these TFs may have important biological roles in growth, development, sexual dimorphism, and resistance to insecticides. The present work provides a solid foundation for understanding regulation via TFs in P. xylostella and insights into the evolution of the P. xylostella genome. PMID- 29147779 TI - The role of ants in north temperate grasslands: a review. AB - Historic and current land-use changes have altered the landscape for grassland biota, with over 90% of grasslands and savannas converted to agriculture or some other use in north temperate regions. Reintegrating grasslands into agricultural landscapes can increase biodiversity while also providing valuable ecosystem services. In contrast to their well-known importance in tropical and subtropical ecosystems, the role of ants in temperate grasslands is often underappreciated. As consumers and ecosystem engineers, ants in temperate grasslands influence invertebrate, plant, and soil microbial diversity and potentially alter grassland productivity. As common and numerically dominant invertebrates in grasslands, ants can also serve as important indicator species to monitor conservation and management practices. Drawing on examples largely from mesic, north temperate studies, and from other temperate regions where necessary, we review the roles of ants as consumers and ecosystem engineers in grasslands. We also identify five avenues for future research to improve our understanding of the roles of ants in grasslands. This includes identifying how grassland fragmentation may influence ant community assembly, quantifying how ant communities impact ecosystem functions and soil processes, and understanding how ant communities and their associated interactions are impacted by climate change. In synthesizing the role of ants in temperate grasslands and identifying knowledge gaps, we hope this and future work will help inform how land managers maximize grassland conservation value while increasing multiple ecosystem services and minimizing disservices. PMID- 29147780 TI - The effect of removing numerically dominant, non-native honey bees on seed set of a native plant. AB - Pollination services are compromised by habitat destruction, land-use intensification, pesticides, and introduced species. How pollination services respond to such stressors depends on the capacity of pollinator assemblages to function in the face of environmental disruption. Here, we quantify how pollination services provided to a native plant change upon removal of the non native, western honey bee (Apis mellifera)-a numerically dominant floral visitor in the native bee-rich ecosystems of southern California. We focus on services provided to clustered tarweed (Deinandra fasciculata), a native, annual forb that benefits from outcross pollination. Across five different study sites in coastal San Diego County, tarweed flowers attracted 70 insect taxa, approximately half of which were native bees, but non-native honey bees were always the most abundant floral visitor at each site. To test the ability of the native insect fauna to provide pollination services, we performed Apis removals within experimental 0.25 m2 plots containing approximately 20 tarweed plants and compared visitation and seed set between plants in removal and paired control plots (n = 16 pairs). Even though 92% of observed floral visits to control plots were from honey bees, Apis removal reduced seed production by only 14% relative to plants in control plots. These results indicate that native insect assemblages can contribute important pollination services even in ecosystems numerically dominated by introduced pollinators. PMID- 29147781 TI - A DFT study of a set of natural dyes for organic electronics. AB - We systematically investigate, at density functional theory level, the electronic properties of a set of ten carotenoid molecules with different conjugation length. Ground state geometries were fully optimized using both B3LYP and its long-range corrected version, i.e., the CAM-B3LYP functional. The time-dependent DFT approach (TD-DFT) was also performed for the calculation of the excited states of the optimized geometries and the results were compared to the experimental ones, when available. Our findings indicate a dependence of the transition vertical energies, oscillator strengths, and transition dipole moments on the extension of conjugation, as expected. We also investigate the impact of the intra-molecular vibrations on the absorption spectrum by means of the Franck Condon (FC) and nuclear ensemble (NE) approach to spectra simulation. Our simulations suggest that the Franck-Condon approximation may not be suitable to appropriately characterize the vibronic progression of these molecules, whereas the NE approach provides a contribution that vary from negligible to meaningful depending on which molecule and energy region is under analysis. PMID- 29147782 TI - Common functional variants of the glutamatergic system in Autism spectrum disorder with high and low intellectual abilities. AB - The genetic architecture underlying Autism spectrum disorder (ASD) has been suggested to differ between individuals with lower (IQ <= 70; LIQ) and higher intellectual abilities (IQ > 70; HIQ). Among the identified pathomechanisms, the glutamatergic signalling pathway is of specific interest in ASD. We investigated 187 common functional variants of this neurotransmitter system for association with ASD and with symptom severity in two independent samples, a German (German ALL: N = 583 families) and the Autism Genome Project cohort (AGP-ALL: N = 2001 families), split into HIQ, and LIQ subgroups. We did not identify any association withstanding correction for multiple testing. However, we report a replicated nominal significant under-transmission (OR < 0.79, p < 0.04) of the AKAP13 rs745191-T allele in both LIQ cohorts, but not in the much larger HIQ cohorts. At the phenotypic level, we nominally replicated associations of CAMK2A-rs2241694 with non-verbal communication in both combined LIQ and HIQ ASD cohorts. Variants PLD1-rs2124147 and ADCY1-rs2461127 were nominally associated with impaired non verbal abilities and AKAP2-rs3739456 with repetitive behaviour in both LIQ cohorts. All four LIQ-associated genes are involved in G-protein coupled signal transduction, a downstream pathway of metabotropic glutamate receptor activation. We conclude that functional common variants of glutamatergic genes do not have a strong impact on ASD, but seem to moderately affect ASD risk and phenotypic expression. Since most of our nominally replicated hits were identified in the LIQ cohort, further investigation of the glutamatergic system in this subpopulation might be warranted. PMID- 29147783 TI - New virus of the family Flaviviridae detected in lumpfish (Cyclopterus lumpus). AB - In this study, we determined the complete coding sequence of a putative new member of the family Flaviviridae, named "Cyclopterus lumpus virus" (CLuV), which is associated with a serious disease in lumpfish (Cyclopterus lumpus). The virus was present in all tissues tested, but pathology was primarily observed in the liver and kidneys. CLuV shows low but distinct similarity to the unassigned Tamana bat virus (TABV). Unlike other known members of the family Flaviviridae, translation of the entire CLuV polyprotein is dependent on a - 1 ribosomal frameshift in the NS2A region. PMID- 29147784 TI - Molecular characterization of faba bean necrotic yellows viruses in Tunisia. AB - Faba bean necrotic yellows virus (FBNYV) (genus Nanovirus; family Nanoviridae) has a genome comprising eight individually encapsidated circular single-stranded DNA components. It has frequently been found infecting faba bean (Vicia faba L.) and chickpea (Cicer arietinum L.) in association with satellite molecules (alphasatellites). Genome sequences of FBNYV from Azerbaijan, Egypt, Iran, Morocco, Spain and Syria have been determined previously and we now report the first five genome sequences of FBNYV and associated alphasatellites from faba bean sampled in Tunisia. In addition, we have determined the genome sequences of two additional FBNYV isolates from chickpea plants sampled in Syria and Iran. All individual FBNYV genome component sequences that were determined here share > 84% nucleotide sequence identity with FBNYV sequences available in public databases, with the DNA-M component displaying the highest degree of diversity. As with other studied nanoviruses, recombination and genome component reassortment occurs frequently both between FBNYV genomes and between genomes of nanoviruses belonging to other species. PMID- 29147785 TI - QT interval and dispersion in drug-free anorexia nervosa adolescents: a case control study. AB - Long QT values have been reported in patients with anorexia nervosa of the restricting type (ANr) potentially increasing the risk of fatal arrhythmia, especially if psychotropic drug treatment is required. Nevertheless, the previous studies on this topic are biased by drug exposure, long disease durations, and small sample sizes. This study is aimed at assessing QTc and QTcd values in ANr adolescents with recent onset and drug free, as compared to subjects affected by psychiatric disorders other than ANr. We evaluated QTc and its dispersion (QTcd) in a population of 77 drug-free ANr female adolescents and compared to an equal number of healthy controls (H-CTRL) and pathological controls (P-CTRL, mixed psychiatric disorders). The QT determination was performed on a standard simultaneous 12-lead ECG in blind by a single experienced investigator. QTc was calculated by the Bazett's formula and QTcd was determined as the difference between the maximum and minimum QTc intervals in different leads. Only for ANr patients, clinico-demographic data, hormones, and electrolytes were obtained. QTc was slightly reduced in ANr patients (27.7 ms, < 10%, p < 0.0003) vs. controls, while QTcd was increased in P-CTRL (30%, p < 0.0003). Heart rate was significantly lower in ANr patients vs. controls (25%; p < 0.003). Tyroid hormones and serum potassium showed weak although significant positive correlations with QTc in ANr patients. QTcd displayed a weak negative correlation with the BMI percentile (r = - 0.262, p = 0.03). We reject the hypothesis that QTc and QTcd are increased in drug-free ANr adolescents with a relatively short disease duration. Further studies are needed to understand if the previously reported increase might be related to other associated chronic disorders, such as hormonal or electrolyte imbalance. PMID- 29147786 TI - Risk Factors for Development of Ectopic Atrial Tachycardia in Post-operative Congenital Heart Disease. AB - Ectopic atrial tachycardia (EAT) is common in surgically repaired congenital heart disease (CHD) and carries the potential for significant hemodynamic compromise. Our objective was to determine the incidence, and risk factors of EAT after CHD surgery. Prospective study of patients that underwent surgery for CHD from February to October 2016 was performed. Demographic, perioperative and electrophysiologic data were collected. Sustained EAT (> 30 s) was documented by telemetry or electrocardiogram and confirmed by a pediatric electrophysiologist. All patients were followed through index hospitalization. During the study period, 17/204 (8%) of patients developed EAT with median time-to-event of 14 days. 15/17 (88%) received anti-arrhythmic therapy for sustained EAT. By univariate analysis, younger age (5 vs. 284 days, P < .001), lower weight (3.2 vs. 7.5 kg, P < .001), single ventricle physiology (P = .05), longer cardiopulmonary bypass time (176 vs. 94 min, P < .001), need for delayed sternal closure (P < .001), and higher STAT category (P < .001) were associated with EAT. Incidence among single ventricle patients was 7/44 (16%), and of those 7/13 (54%) were < 30 days of age. Multivariable Cox regression analysis confirmed age at surgery < 30 days (hazard ratio = 11.7, P = .002) and use of milrinone (hazard ratio = 4.4, P = .007) as independent predictors of EAT. Post-operative EAT is frequent following surgery for CHD especially in neonates. Further study is warranted, specifically in the single ventricle population, given the high potential risk for arrhythmia-induced hemodynamic compromise in this vulnerable population. PMID- 29147788 TI - Dissociated pulmonary vein activity after cryoballoon ablation and radiofrequency ablation for atrial fibrillation: a propensity score-matched analysis. AB - Cryoballoons (CBs) have proven to be effective for achieving pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF). Dissociated PV activity (DPVA) after successful radiofrequency PVI is sometimes observed inside the PV and has been found to prove the achievement of electrical disconnection from the left atrium. However, little is known about the incidence or characteristics of DPVA after CB-PVI. The aim of this study was to compare the incidence and characteristics of DPVA in patients undergoing CB and radiofrequency (RF) ablation for AF. Two hundred and ninety-four propensity score matched patients from 440 consecutive patients who underwent initial catheter ablation for paroxysmal AF were included in the present study (CB-PVI 147, RF-PVI 147). DPVA was more frequently observed after CB-PVI than after RF-PVI (32 vs. 19% of the PVs, P < 0.001), especially in the left superior PV (52 vs. 29%, P < 0.001) and left inferior PV (22 vs. 7%, P < 0.001). The AF-free rate after the initial ablation in the patients with and without DPVA was similar in both the CB (P = 0.23) and RF (P = 0.39) groups. During repeat ablation procedures for recurrent AF, PV reconnection was similarly observed in PVs with and without DPVA during the initial procedure, both in the CB (30 vs. 44%, P = 0.29) and RF (65 vs. 58%, P = 0.41) groups. DPVA was more frequently observed after CB-PVI than after RF-PVI. The presence of DPVA was not related to the ablation outcome or chronic PV reconnection following CB-PVI. PMID- 29147789 TI - Erythrocyte Nuclear Abnormalities in Astyanax lacustris in Response to Landscape Characteristics in Two Neotropical Streams. AB - The objective of this research was to evaluate land use and occupation in the landscape surrounding two neotropical streams of the Upper Parana River in Brazil and to investigate if the water from these streams induces erythrocyte nuclear abnormalities in Astyanax lacustris. We observed that the areas surrounding the streams are predominantly used for agricultural purposes (73.46% of the total area), followed by buildings (15.21%). Only 8.78% of the area consisted of forest fragments. We observed higher frequencies of micronuclei in erythrocytes of A. lacustris exposed to water from impacted sites (IMP) compared with less impacted sites and the negative control (NC) (p < 0.05). Analysis of nuclear alterations in A. lacrustis erythrocytes showed significant differences in the frequency of notched nuclei and nuclear pyknosis only between the NC and the IMP sites (p < 0.05). Our results indicate that water from the most impacted sites of the microbasin can induce mutagenic and genotoxic effects in A. lacustris. PMID- 29147787 TI - A lower eicosapentaenoic acid/arachidonic acid ratio is associated with in hospital fatal arrhythmic events in patients with acute myocardial infarction: a J-MINUET substudy. AB - The ratio of serum eicosapentaenoic acid (EPA) to arachidonic acid (AA) is significantly associated with long-term clinical outcomes in patients with acute myocardial infarction (AMI). However, it has not been conclusively demonstrated that higher serum EPA/AA ratio fares better clinical outcomes in the early phase of AMI. The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry conducted in 28 Japanese medical institutions between July 2012 and March 2014. We enrolled 3,283 consecutive AMI patients who were admitted to participating institutions within 48 h of symptom onset. A serum EPA/AA ratio was available for 629 of these patients. The endpoints were in-hospital mortality and major adverse cardiac events (MACE), defined as a composite of all cause death, cardiac failure, ventricular tachycardia (VT) and/or ventricular fibrillation (VF) and bleeding during hospitalization. Although similar rates of in-hospital mortality, cardiac failure, bleeding, and MACE were found in the lower serum EPA/AA group and higher serum EPA/AA group, the incidence of VT/VF during hospitalization was significantly higher in the low ratio group (p = 0.008). Receiver operating characteristic curve analysis showed that an EPA/AA ratio < 0.35 could predict the incidence of VT/VF with 100% sensitivity and 64.0% specificity. A lower serum EPA/AA ratio was associated with a higher frequency of fatal arrhythmic events in the early phase of AMI. PMID- 29147790 TI - [Etomidate for intravenous induction of anaesthesia]. AB - The pharmacological and historical knowledge about the currently available intravenous induction hypnotics form the basis for the daily work of anesthetists. Side effects of using hypnotic induction agents must be anticipated and adequately treated. Decades of experience with using intravenous induction hypnotics have led to theoretical requirements for an ideal narcotic agent with a best possible side effect profile. In the absence of this optimal hypnotic induction agent, a careful selection of one or a combination of narcotic drugs is necessary to meet the needs of the respective risk constellation of the patient. While propofol enjoyed increasing frequency of use over the last three decades and is currently regarded as the gold standard in numerous clinics, thiopental is a noteworthy alternative apart from its elimination kinetics. Furthermore, substances with favorable hemodynamic profiles are available with etomidate and ketamine. Midazolam as a short-acting benzodiazepine rounds off the spectrum. PMID- 29147791 TI - Completed sequence and corrected annotation of the genome of maize Iranian mosaic virus. AB - Maize Iranian mosaic virus (MIMV) is a negative-sense single-stranded RNA virus that is classified in the genus Nucleorhabdovirus, family Rhabdoviridae. The MIMV genome contains six open reading frames (ORFs) that encode in 3? to 5? order the nucleocapsid protein (N), phosphoprotein (P), putative movement protein (P3), matrix protein (M), glycoprotein (G) and RNA-dependent RNA polymerase (L). In this study, we determined the first complete genome sequence of MIMV using Illumina RNA-Seq and 3'/5' RACE. MIMV genome ('Fars' isolate) is 12,426 nucleotides in length. Unexpectedly, the predicted N gene ORF of this isolate and of four other Iranian isolates is 143 nucleotides shorter than that of the MIMV coding-complete reference isolate 'Shiraz 1' (Genbank NC_011542), possibly due to a minor error in the previous sequence. Genetic variability among the N, P, P3 and G ORFs of Iranian MIMV isolates was limited, but highest in the G gene ORF. Phylogenetic analysis of complete nucleorhabdovirus genomes demonstrated a close evolutionary relationship between MIMV, maize mosaic virus and taro vein chlorosis virus. PMID- 29147792 TI - Characterization of a novel single-stranded RNA mycovirus related to invertebrate viruses from the plant pathogen Verticillium dahliae. AB - Fungal viruses, also known as mycoviruses, are widespread in all major groups of fungi. Mycoviruses from plant pathogens can reduce the virulence of their host fungus and have therefore potential as biological control agents. This has spurred the identification of novel mycoviruses in plant pathogens, research which is greatly contributing to our understanding of these organisms. In this work, we report the characterization of a novel monopartite mycovirus from Verticillium dahliae, the main causal agent of Verticillium wilt. This novel mycovirus, which we termed Verticillium dahliae RNA virus 1 (VdRV1), was identified in three different isolates of V. dahliae collected in olive growing areas of the Guadalquivir valley, southern Spain. We determined that the VdRV1 genome is a positive (+) single-stranded (ss) RNA, 2631 nucleotides in length, containing two open reading frames. VdRV1 showed few similarities with known mycoviruses, only with a group of unassigned (+) ssRNA mycoviruses which are related to plant viruses classified within the family Tombusviridae. However, phylogenetic analysis revealed that VdRV1 and the unassigned (+) ssRNA mycoviruses have a closer relationship with recently reported invertebrate viruses. This result indicates that as more viral sequences become available, the relationships of mycoviruses with viruses from other hosts should be reexamined. Additionally, the work supports the hypothesis of a heterogeneous origin for mycoviruses. PMID- 29147793 TI - Pharmacophoric characteristics of dengue virus NS2B/NS3pro inhibitors: a systematic review of the most promising compounds. AB - Dengue virus (DENV) infection can lead to a wide range of clinical manifestations, including fatal hemorrhagic complications. There is a need to find effective pharmacotherapies to treat this disease due to the lack of specific immunotherapies and antiviral drugs. That said, the DENV NS2B/NS3pro protease complex is essential in both the viral multiplication cycle and in disease pathogenesis, and is considered a promising target for new antiviral therapies. Here, we performed a systematic review to evaluate the pharmacophoric characteristics of promising compounds against NS2B/NS3pro reported in the past 10 years. Online searches in the PUBMED/MEDLINE and SCOPUS databases resulted in 165 articles. Eight studies, which evaluated 3,384,268 molecules exhibiting protease inhibition activity, were included in this review. These studies evaluated anti-dengue activity in vitro and the IC50 and EC50 values were provided. Most compounds exhibited non-competitive inhibition. Cytotoxicity was evaluated in BHK-21, Vero, and LLC-MK2 cells, and the CC50 values obtained ranged from < 1.0 to 780.5 uM. Several groups were associated with biological activity against dengue, including nitro, catechol, halogen and ammonium quaternaries. Thus, these groups seem to be potential pharmacophores that can be further investigated to treat dengue infections. PMID- 29147794 TI - Action control in task switching: do action effects modulate N - 2 repetition costs in task switching? AB - Ideomotor theory posits that actions are controlled by the anticipation of their effects. In line with this theoretical framework, response-contingent action effects have been shown to influence performance in choice-reaction time tasks, both in single-task and task-switching context. Using a task-switching paradigm, the present study investigated whether task-contingent action effects influenced N - 2 repetition costs in task switching. N - 2 repetition costs are thought to be related to task-switch costs, and reflect inhibitory control in task switching. It was expected that task-contingent action effects reduce between task interference, leading to reduced N - 2 repetition costs. An experimental group (N = 24) performed eight blocks of trials with task-contingent action effects, followed by one block with non-contingent action effects; a control group (N = 24) performed nine blocks of trials with non-contingent action effects. In line with our expectations, a three-way interaction of group, block, and task sequence was obtained, indicating differential data patterns for the two groups: In error rates, the group who had received contingent action effects throughout blocks 1-8 showed larger N - 2 repetition costs in the random block 9 than in block 8, whereas the control group showed a reversed data pattern. The RT data pattern was in the same direction, although no significant three-way interaction was obtained. Taken together, we tentatively conclude that task contingent action effects reduce task inhibition in task switching, and we outline directions for future research on the role of action effects in multitasking performance. PMID- 29147795 TI - Preoperative pregabalin has no effect on intraoperative neurophysiological monitoring in adolescents undergoing posterior spinal fusion for spinal deformities: a double-blind, randomized, placebo-controlled clinical trial. AB - PURPOSE: This study was designed to evaluate the effect of preoperative pregabalin on intraoperative neurophysiological monitoring in adolescents undergoing surgery for spinal deformities. METHODS: Thirty-one adolescents undergoing posterior spinal fusion were randomized to receive preoperatively either pregabalin 2 mg/kg twice daily or placebo. The ability to make reliable intraoperative neurophysiological measurements, transcranial motor (MEPs) and sensory evoked potentials (SSEP) was evaluated. RESULTS: Two patients (pregabalin group) did not fulfil the inclusion criteria and one patient's (placebo group) spinal monitoring was technically incomplete and these were excluded from the final data. In the rest, spinal cord monitoring was successful. Anaesthesia prolonged the latency of MEPs and increased the threshold current of MEP. The current required to elicit MEPs did not differ between the study groups. There were no statistically significant differences between the study groups regarding the latency of bilateral SSEP (N32 and P37) and MEP latencies at any time point. CONCLUSIONS: Preoperative pregabalin does not interfere spinal cord monitoring in adolescents undergoing posterior spinal fusion. LEVEL OF EVIDENCE: I. PMID- 29147796 TI - Answer to the Letter to the Editor of A. Malhotra concerning "The utility of magnetic resonance imaging in addition to computed tomography scans in the evaluation of cervical spine injuries: a study of obtunded blunt trauma patients" by B. P. H. Lau, et al. (Eur Spine J [2017]; doi:10.1007/s00586-017-5317-y). PMID- 29147797 TI - Is it appropriate to measure age-related lumbar disc degeneration on the mid sagittal MR image? A quantitative image study. AB - PURPOSE: Even though phenotypes of disc degeneration vary on different sagittal magnetic resonance images (MRI), measurements typically are acquired on the mid sagittal MRI. This study investigated the appropriateness of using the mid sagittal MRI to measure various phenotypes of age-related disc degeneration. METHODS: Lumbar spine MRIs of 66 subjects (mean age 50.3 years, standard deviation 16.5 years, range 22-84 years) were studied. An image analysis program Spine Explorer was used to obtain quantitative measurements for disc height, bulging, and signal on para- and mid-sagittal T2-weighted MRIs. Measurements on para- and mid-sagittal MRIs and their associations with age were compared. RESULTS: Measurements of disc height, signal, and posterior disc bulging acquired on the mid-sagittal MRI were greater than those on the para-sagittal MRIs. Disc height measurements were not linearly associated with age. Greater age was correlated with greater anterior (r = 0.45, P < 0.001) and posterior (r = 0.33, P < 0.01) bulging on para-sagittal MRIs, but not posterior disc bulging on the mid sagittal MRI (r = - 0.10, P > 0.05). Disc signal intensity measurements on the mid-sagittal MRI had stronger correlations with age than those on para-sagittal MRIs. Mean and standard deviation of disc signal intensity acquired on the mid sagittal MRI had the strongest correlations with age among all measures of disc degeneration studied (r = - 0.50, - 0.67, respectively, P < 0.001 for both). CONCLUSIONS: Disc signal measurements acquired on the mid-sagittal MRI were reliable and had strong correlations with age and thus can be used as an appropriate measure of disc degeneration. Disc bulging had better be measured on para-sagittal MRIs. Although severe disc narrowing clearly is a sign of severe disc degeneration, disc height was not linearly associated with age. PMID- 29147799 TI - The use of fibrin glue to stabilize geometry of free-flaps vascular pedicle. PMID- 29147798 TI - The reassuring potential of spinal imaging results: development and testing of a brief, psycho-education intervention for patients attending secondary care. AB - PURPOSE: To develop and test a standardised method of interpreting spinal imaging findings in a manner designed to reassure patients with low back pain and promote engagement in an active recovery. METHODS: A five-phase development and testing process involved collaborative working party contributions, informal and formal appraisal of the intervention content by clinicians and consumers, a two-stage online evaluation of the take-home patient resource, and onsite testing. RESULTS: A total of 12 health professionals and 77 consumers were included in formal evaluative processes at various stages of the development and testing process. Consumers assessed the revised iteration of the take-home resource to be clearer and easier to understand than the original version. We integrated all feedback and evaluation outcomes to develop the final intervention content, which was approved by experienced clinicians and considered safe. We devised a framework to guide delivery of the low-cost clinical intervention and a 10-15-min timeframe was demonstrated to be realistic. CONCLUSIONS: We have developed, modified, and tested a pragmatic framework for a brief, psychoeducational intervention. We have established face validity and acceptability from key stakeholders and engaged clinicians and are ready to proceed with a pilot feasibility trial. PMID- 29147800 TI - The Pediatric Heart Failure Workforce: An International, Multicenter Survey. AB - Our objective was to understand the scope of pediatric heart failure (HF) and the current staffing environment of HF programs. An online survey was distributed to members of the Pediatric Heart Transplant Study and the Pediatric Council of the International Society for Heart and Lung Transplantation. All participants received the primary 23-question survey. Additionally, HF program directors received a 32-question supplemental survey. Of 235 invitations sent, there were 69 (29%) primary surveys and 34 program director surveys completed (24 U.S. programs, 9 outside non-U.S., and one non-specified location). A formal HF program was reported by 88% of directors. There were 150 [IQR 50-200] outpatients/institution and 40% [25-50] of patients had congenital heart disease. Inpatient HF census was 3 [2-4] patients. Most programs (70%) used a consulting service model to provide HF specialty care, while only 10 (30%) utilized an inpatient HF service. Inpatient HF service programs had a higher daily inpatient census versus consult service model programs (4 [3-7] vs. 2 [1-4], respectively; p = 0.022) and had a higher number of full-time equivalents dedicated to HF (5.5 [2-7] vs. 2.5 [1-4], respectively; p = 0.024). Only 47% of programs report a general fellowship rotation devoted to HF. Advanced practice providers (APP) were utilized in 15 programs, nurse coordinators in 2, and both in 3. Most HF programs are formalized, utilize APP, and have inadequate HF staffing to utilize a separate inpatient HF service. Exposure of general pediatric cardiology fellows to HF care is variable between institutions. PMID- 29147801 TI - Correction to: Peripheral markers of autophagy in polyglutamine diseases. AB - Dr. Peluso's given name and family name were initially interchanged inadvertently. The correct names have been corrected above. The original article was corrected. PMID- 29147802 TI - Executive summary of the 12th HHT international scientific conference. AB - Hereditary hemorrhagic telangiectasia is an autosomal dominant trait affecting approximately 1 in 5000 people. A pathogenic DNA sequence variant in the ENG, ACVRL1 or SMAD4 genes, can be found in the majority of patients. The 12th International Scientific HHT Conference was held on June 8-11, 2017 in Dubrovnik, Croatia to present and discuss the latest scientific achievements, and was attended by over 200 scientific and clinical researchers. In total 174 abstracts were accepted of which 58 were selected for oral presentations. This article covers the basic science and clinical talks, and discussions from three theme based workshops. We focus on significant emergent themes and unanswered questions. Understanding these topics and answering these questions will help to define the future of HHT research and therapeutics, and ultimately bring us closer to a cure. PMID- 29147803 TI - Secondary resistance to tolvaptan in two patients with SIAD due to small cell lung cancer. PMID- 29147804 TI - In reply. PMID- 29147805 TI - Can clinical practice indicator relating to long-acting benzodiazepine use in the elderly be easily generated in a hospital setting? AB - BACKGROUND: To improve the appropriate use of long-acting benzodiazepine (la.bzd) prescriptions in the elderly, the Haute Autorite de Sante (HAS) has developed clinical practice indicators (CPI). The alert indicator (AI) evaluates the prevalence of la.bzd prescription among older people. The mastering indicator (MI) corresponds to the prevalence of elderly with a justified, i.e., appropriate, la.bzd prescription among all the elderly with la.bzd prescriptions. OBJECTIVE: The objective of this study was to test the feasibility of routine generation of CPI regarding la.bzd prescriptions among the elderly in the hospital setting. DESIGN: This was a retrospective study. SETTING: The study was conducted in two university hospitals located in Paris. SUBJECT: Eligible cases were patients aged 65 years and older who were hospitalized in acute care units from January to June 2014. METHOD: The AI calculation was based on information extracted from medical databases from these hospitals. The appropriateness of la.bzd prescription was assessed by a physician and a pharmacist and was based on review of computerized patient records and prescriptions, using an ad hoc algorithm. The MI was then calculated. Variation in the level of indicators was explored according to the characteristics of patients and of their hospitalization using chi2 test. Factors associated with a potentially inappropriate prescription (PIP) of la.bzd were studied using univariate and multivariate logistic regression. RESULT: Among the 4167 patients included in the study, 362 had la.bzd prescriptions, i.e., the AI was 9%. Prescriptions were found to be appropriate for 83 patients, i.e., the MI was 23% and PIP was 77%. The MI varied between 13 and 31% according to characteristics of patients and of hospitalization. In multivariate analysis, factors associated with PIP were age, number of comorbidities, type of care unit, and concurrent prescription of a neuroleptic or hypnotic. CONCLUSION: Generation of the AI was routinely possible but only for acute care units with computerized prescriptions, corresponding to 78% of patients. Production of the MI has required medical record review for all patients with a la.bzd prescription and cannot be automated. However, difficulties in generating the MI have identified areas for significant improvement. Moreover, strategies to improve the care of older people with a la.bzd prescription could be targeted using characteristics of patients and of hospitalization associated with PIP. The future deployment of a single electronic medical record in all care departments would make it easier to mine the data and make possible automated production of CPI. PMID- 29147806 TI - Depression, Loneliness, and Sexual Risk-Taking Among HIV-Negative/Unknown Men Who Have Sex with Men in China. AB - Research conducted among men who have sex with men (MSM) in high-income countries has demonstrated that negative mental health is one of the significant drivers of HIV infection, and few studies have examined the status of mental health among MSM in China. We sought to describe depression and loneliness and identify their correlates among Chinese MSM. A cross-sectional study was conducted among HIV negative or unknown status MSM in 2014. Time-location sampling and online convenience sampling methods were employed. Depression was measured via a short version of CES-D (CES-D 10). Loneliness was measured from a single item in CES-D 10. Multivariable logistic regressions were conducted to identify independent correlates of depression and loneliness. A total of 507 individuals participated in the study. Of them, 26.8 and 35.5% reported moderate-to-severe symptoms of depression and feeling lonely, respectively. Depressed participants were more likely to have a sense of hopelessness for the future (AOR 3.20, 95% CI 1.90, 5.20) and report higher levels of internalized homophobia (AOR 2.32, 95% CI 1.47, 3.67). Participants who reported feeling lonely were more likely to have had condomless receptive anal intercourse in the past 6 months (AOR 1.67, 95% CI 1.08, 2.58) and feel hopeless for the future (AOR 2.40, 95% CI 1.60, 3.70). MSM in China have significant rates of depression and loneliness. HIV prevention efforts should address the mental health needs of Chinese MSM such as providing safe environments for social support and role models. PMID- 29147807 TI - Distinct diversity patterns of Planctomycetes associated with the freshwater macrophyte Nuphar lutea (L.) Smith. AB - Members of the phylum Planctomycetes were originally described as freshwater bacteria. Most recent studies, however, address planctomycete diversity in other environments colonized by these microorganisms, including marine and terrestrial ecosystems. This study was initiated in order to revisit the specific patterns of planctomycete diversity in freshwater habitats using cultivation-independent approaches. The specific focus was made on planctomycetes associated with Nuphar lutea (L.) Smith, an emergent macrophyte with floating leaves, which is widespread in the Holarctic. As revealed by Illumina pair-end sequencing of 16S rRNA gene fragments, the bacterial assemblages colonizing floating leaf blades of waterlilies sampled from two different boreal lakes displayed similar composition but were distinct from the planktonic bacterial communities. 16S rRNA gene fragments from the Planctomycetes comprised 0.1-1 and 1-2.2% of total 16S rRNA gene reads retrieved from water samples and plant leaves, respectively. Planktonic planctomycetes were mostly affiliated with the class Planctomycetaceae (77-97%), while members of the Phycisphaerae were less abundant (3-22%). The relative proportion of the latter group, however, increased by 13-45% on leaves of N. lutea. The Phycisphaera-related group WD2101, Pirellula-like planctomycetes, as well as Gemmata, Zavarzinella and Planctopirus species were the most abundant groups of planctomycetes associated with plant leaves, which may suggest their involvement in the degradation of plant-derived organic matter. PMID- 29147808 TI - Maribacter marinus sp. nov. isolated from a deep-sea seamount. AB - A Gram-stain negative, rod-shaped, aerobic strain, designated YC973T, was isolated from a seamount near the Yap Trench in the tropical western Pacific. Phylogenetic analysis based on its 16S rRNA gene sequence showed that strain YC973T is related to the genus Maribacter and has high 16S rRNA gene sequence similarity to Maribacter orientalis KMM 3947T (97.6%). The predominant cellular fatty acids were iso-C15:0, iso-C15:1 G and an unidentified fatty acid of equivalent chain-length 13.565. The polar lipid profile contained phosphatidylethanolamine and five unidentified lipids. The genomic DNA G+C content of strain YC973T was 36.1 mol%. On the basis of the evidence presented in this study, strain YC973T represents a novel species of the genus Maribacter, for which we propose the name Maribacter marinus sp. nov. (type strain YC973T = KACC 19025T = CGMCC 1.16328T). PMID- 29147809 TI - Application of actuator-driven pulsed water jet for coronary artery bypass grafting: assessment in a swine model. AB - Actuator-driven pulsed water-jet (ADPJ) dissection is an emerging surgical method for dissecting tissue without heat and mechanical injury to vessels. We elucidated the mechanical properties of the piezo ADPJ and evaluated its usefulness and safety in coronary artery bypass grafting procedures. The relationship between the input voltage (10-100 V) and peak pressure of the pulsed water jet was evaluated. The tissue strengths of swine internal thoracic and coronary arteries and the surrounding tissues were measured to assure tissue selective dissection. Internal thoracic arteries were harvested by conventional electric cautery and the water jet in four swine, and eight coronary arteries surrounded by myocardium were attempted to be exposed with the water jet. The dissected specimens were histologically evaluated. The peak pressure of the pulsed water jet was positively correlated with the input voltage (R 2 = 0.9984, P < 0.001). The breaking strengths of the target vessels (internal thoracic and coronary arteries) and the surrounding tissues were significantly different (P = 0.002 and P < 0.001, respectively). Histologic examination revealed that internal thoracic arteries were isolated with less heat damage using the pulsed water jet (P = 0.002) compared with electric cautery, and coronary arteries also were dissected without apparent histologic damage. ADPJ has the possibility of assuring tissue selectivity among the internal thoracic and coronary arteries. The results also indicated that the use of ADPJ may enhance safe procedures to harvest grafts during coronary artery bypass grafting. PMID- 29147810 TI - Acceptability of a Tenofovir Disoproxil Fumarate Vaginal Ring for HIV Prevention Among Women in New York City. AB - Vaginal rings for pre-exposure prophylaxis are a female-initiated HIV prevention method that does not require daily or coitally-dependent dosing. As part of a randomized placebo-controlled trial of a tenofovir disoproxil fumarate intravaginal ring, we assessed product acceptability through in-depth interviews with 18 women during and after 14 days of continuous use. Women reported that the ring was comfortable with few side effects, regardless of experimental arm. However, interest in future use by this cohort was modest for several reasons including: low self-perceived HIV risk; concern that use implied promiscuity; potential for interference with relationship formation and trust; concern for interference with menstruation and cleanliness; and worries about partners' acceptability and sexual pleasure. Potential issues were raised with duration of use prior to ring exchange. Future studies should continue to identify and address individual and relationship factors that influence acceptability, early in the product development process. PMID- 29147811 TI - C-terminal region of human p53 attenuates buffalo p53 N-terminal-specific transactivation of p21 promoter by modulating tetramerization of the protein. AB - Here, we have studied in p53 null H1299 lung carcinoma cells, the dominant negative effect of human p53 (h-p53) on buffalo p53 (b-p53) induced nuclear transactivation-dependent function. Recently, we have isolated and cloned the full-length cDNA of buffalo p53. Buffalo and human p53 proteins exhibit a high degree of structural and functional similarities. In transiently transfected H1299 cell line b-p53 appeared to be more sensitive to Mdm2-mediated degradation as compared to h-p53, although its ability to transactivate p21 promoter was stronger than that of the human counterpart. This higher transactivation ability of b-p53 was lost in the presence of h-p53 suggesting, a dominant-negative effect of h-p53 on b-p53's transactivation of p21 promoter. Both human and buffalo p53 proteins could hetero-oligomerize but the b-p53 could tetramerize much faster than the h-p53. A chimeric cDNA construct of human p53 was made where the 1-260 bp N-terminus was replaced with buffalo p53 counterpart and expressed in H1299 cell line. The tetramerization ability of the chimeric p53 protein was comparable to that of h-p53. Properties of b-p53 like stronger p21 transactivation and super sensitivity to Mdm2 mediated degradation were lacking in the chimeric protein. Thus, it is suggested that faster ability of tetramerization as well as higher transactivation property of buffalo p53 is determined by the interplay of N- and C-terminal domains through macromolecular interactions. PMID- 29147812 TI - Geissoschizine synthase controls flux in the formation of monoterpenoid indole alkaloids in a Catharanthus roseus mutant. AB - MAIN CONCLUSION: A Catharanthus roseus mutant accumulates high levels of ajmalicine at the expense of catharanthine and vindoline. The altered chemistry depends on increased expression and biochemical activities of strictosidine beta glucosidase and ajmalicine synthase activities and reduced expression and biochemical activity of geissoschizine synthase. The Madagascar periwinkle [Catharanthus roseus (L.) G. Don] is a commercially important horticultural flower species and is a valuable source for several monoterpenoid indole alkaloids (MIAs), such as the powerful antihypertensive drug ajmalicine and the antineoplastic agents, vinblastine and vincristine. While biosynthesis of the common MIA precursor strictosidine and its reactive aglycones has been elucidated, the branch point steps leading to the formation of different classes of MIAs remain poorly characterized. Screening of 3600 ethyl methyl sulfonate mutagenized C. roseus plants using a simple thin-layer chromatography screen yielded a mutant (M2-0754) accumulating high levels of ajmalicine together with significantly lower levels of catharanthine and vindoline. Comparative bioinformatic analyses, virus-induced gene silencing, and biochemical characterization identified geissoschizine synthase, the gateway enzyme that controls flux for the formation of iboga and aspidosperma MIAs. The reduction of geissoschizine synthase transcripts in this high ajmalicine mutant, together with increased transcripts and enzyme activities of strictosidine beta-glucosidase and of heteroyohimbine synthase, explains the preferential formation of ajmalicine in the mutant instead of catharanthine and vindoline that accumulates in the wild type parent. Reciprocal crosses established that that the high ajmalicine phenotype is inherited as a Mendelian recessive trait. PMID- 29147813 TI - Noninvasive induction of angiogenesis in tissues by external suction: sequential optimization for use in reconstructive surgery. AB - In reconstructive surgery, tissues are routinely transferred to repair a defect caused by trauma, cancer, chronic diseases, or congenital malformations; surgical transfer intrinsically impairs metabolic supply to tissues placing a risk of ischemia-related complications such as necrosis, impaired healing, or infection. Pre-surgical induction of angiogenesis in tissues (preconditioning) can limit postsurgical ischemic complications and improve outcomes, but very few preconditioning strategies have successfully been translated to clinical practice due to the invasiveness of most proposed approaches, their suboptimal effects, and their challenging regulatory approval. We optimized a method that adopts noninvasive external suction to precondition tissues through the induction of hypoxia-mediated angiogenesis. Using a sequential approach in a rodent model, we determined the parameters of application (frequency, suction levels, duration, and interfaces) that fine-tune the balance of enhanced angiogenesis, attenuation of hypoxic tissue damage, and length of treatment. The optimized repeated short intermittent applications of intermediate suction induced a 1.7-fold increase in tissue vascular density after only 5 days of treatment (p < 0.05); foam interfaces showed the same effectiveness and caused less complications. In a second separate experiment, our model showed that the optimized technique significantly improves survival of transferred tissues. Here we demonstrate that noninvasive external suction can successfully, safely, and promptly enhance vascularity of soft tissues: these translational principles can help design effective preconditioning strategies, transform best clinical practice in surgery, and improve patient outcomes. PMID- 29147814 TI - Health care service utilization of documented and undocumented hired farmworkers in the U.S. AB - This article analyzes issues related to U.S. hired farmworkers' utilization of health care services and their specific choices among health care provider and health bill payment method options. Using data from the National Agricultural Workers Surveys for the years 2000-2012, this article employs propensity score matching and probit estimation techniques to examine the health care utilization of hired farmworkers. This study's results indicate that undocumented hired farmworkers are 10.7 and 3% less likely to use U.S. and foreign health care, respectively, compared to documented farmworkers. Health insurance is found to significantly increase hired farmworkers' use of U.S. health care by 22.3%. Notably, compared to their documented working peers, undocumented workers are much less likely to patronize private clinics. They are even less likely to rely on migrant health centers even when these providers are their most viable sources of health care service. PMID- 29147815 TI - ATP-binding cassette transporters limit the brain penetration of Wee1 inhibitors. AB - Introduction Wee1 is an important kinase involved in the G2 cell cycle checkpoint and frequently upregulated in intracranial neoplasms such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG). Two small molecules are available that target Wee1, AZD1775 and PD0166285, and clinical trials with AZD1775 have already been started. Since GBM and DIPG are highly invasive brain tumors, they are at least to some extent protected by the blood-brain barrier (BBB) and its ATP-binding cassette (ABC) efflux transporters. Methods We have here conducted a comprehensive set of in vitro and in vivo experiments to determine to what extent two dominant efflux transporters in the BBB, P-gp (ABCB1) and BCRP (ABCG2), exhibit affinity towards AZD1775 and PD0166285 and restrict their brain penetration. Results Using these studies, we demonstrate that AZD1775 is efficiently transported by both P-gp and BCRP, whereas PD0166285 is only a substrate of P-gp. Nonetheless, the brain penetration of both compounds was severely restricted in vivo, as indicated by a 5-fold (PD0166285) and 25-fold (AZD1775) lower brain-plasma ratio in wild type mice compared to Abcb1a/b;Abcg2-/ mice. Conclusion The brain penetration of these Wee1 inhibitors is severely limited by ABC transporters, which may compromise their clinical efficacy against intracranial neoplasms such as DIPG and GBM. PMID- 29147816 TI - Development of pseudoaneurysm in cesarean section scar pregnancy: a case report and literature review. AB - Cesarean scar pregnancy (CSP) is a rare type of ectopic pregnancy. It is becoming more common, but it can lead to uterine rupture and severe hemorrhage. Here, we report a case of a 37-year-old woman with CSP complicated with pseudoaneurysm. The pseudoaneurysm emerged following focal injection of methotrexate (MTX) and potassium chloride with systemic MTX treatment. Due to a risk of sudden bleeding, uterine artery embolization (UAE) was recommended, but the patient hoped to avoid this if possible. Because the serum human chorionic gonadotropin level and the gestational sac were still persistent, dilation and curettage were performed with interventional radiologists on standby. Severe hemorrhage occurred and continued during the procedure, which necessitated emergent UAE. We reviewed six CSP case reports with vascular abnormalities, and all of them necessitated UAE, surgical excision, or hysterectomy. In the case of CSP combined with pseudoaneurysm, treatment should be planned carefully considering the risk of massive hemorrhage. PMID- 29147817 TI - Only "efficient" emotional stimuli affect the content of working memory during free-recollection from natural scenes. AB - Emotional events are thought to have privileged access to attention and memory, consuming resources needed to encode competing emotionally neutral stimuli. However, it is not clear whether this detrimental effect is automatic or depends on the successful maintenance of the specific emotional object within working memory. Here, participants viewed everyday scenes including an emotional object among other neutral objects followed by a free-recollection task. Results showed that emotional objects-irrespective of their perceptual saliency-were recollected more often than neutral objects. The probability of being recollected increased as a function of the arousal of the emotional objects, specifically for negative objects. Successful recollection of emotional objects (positive or negative) from a scene reduced the overall number of recollected neutral objects from the same scene. This indicates that only emotional stimuli that are efficient in grabbing (and then consuming) available attentional resources play a crucial role during the encoding of competing information, with a subsequent bias in the recollection of neutral representations. PMID- 29147818 TI - Inhalation Biopharmaceutics: Progress Towards Comprehending the Fate of Inhaled Medicines. AB - ?. PMID- 29147819 TI - A note from Patrick J. Cozzone, MAGMA Editor-in-Chief. PMID- 29147820 TI - Cue-Signal-Response Analysis in 3D Chondrocyte Scaffolds with Anabolic Stimuli. AB - Articular cartilage is an avascular connective tissue responsible for bearing loads. Cell signaling plays a central role in cartilage homeostasis and tissue engineering by directing chondrocytes to synthesize/degrade the extracellular matrix or promote inflammatory responses. The aim of this paper was to investigate anabolic, catabolic and inflammatory pathways of well-known and underreported anabolic stimuli in 3D chondrocyte cultures and connect them to diverse cartilage responses including matrix regeneration and cell communication. A cue-signal-response experiment was performed in chondrocytes embedded in alginate scaffolds subjected to a 9-day treatment with 7 anabolic cues. At the signaling level diverse pathways were measured whereas at the response level glycosaminoglycan (GAG) synthesis and cytokine releases were monitored. A significant increase of GAG was observed for each stimulus and well known anabolic phosphoproteins were activated. In addition, WNK1, an underreported protein of chondrocyte signaling, was uncovered. At the extracellular level, inflammatory and regulating cytokines were measured and DEFB1 and CXCL10 were identified as novel contributors to chondrocyte responses, both closely linked to TLR signaling and inflammation. Finally, two new pro-growth factors with an inflammatory potential, Cadherin-11 and MGP were observed. Interestingly, well known anabolic stimuli yielded inflammatory responses which pinpoints to the pleiotropic roles of individual stimuli. PMID- 29147821 TI - Large-scale monitoring of effects of clothianidin-dressed oilseed rape seeds on pollinating insects in Northern Germany: justification of study design and statistical analysis. PMID- 29147822 TI - Psychiatric Sequelae of Concussions. AB - PURPOSE OF REVIEW: The purpose of this study was to review the frequency, risk factors, phenomenology, and course of prolonged recovery from concussion and of psychiatric sequelae in pediatric populations. RECENT FINDINGS: Youth with prolonged recovery from concussions have higher initial symptoms, a history of multiple and/or recent concussions, and a tendency to somatization. Depression, post-traumatic stress disorder, behavioral disorders, and perhaps, suicidal behavior disorder are more common as both short- and longer-term sequelae of concussions. The weight of evidence supports a graduated return to function as compared to prolonged rest, which may actually impede recovery. For those with prolonged recovery, cognitive behavior therapy aimed at education about concussions, improving coping, problem-solving, sleep hygiene, and dealing with anxiety and depression provided in a collaborative care model is superior to usual care. Concussed youth have an increased risk of psychiatric symptoms and sleep disturbance that can be prevented or treated with proper management. PMID- 29147823 TI - Primary peri-implant oral intra-epithelial neoplasia/carcinoma in situ: a case report considering risk factors for carcinogenesis. AB - BACKGROUND: Major risk factors for oral squamous cell carcinoma (SCC) are tobacco smoking, a betel quid chewing habit, and heavy alcohol consumption. However, around 15% of oral SCCs cannot be explained by these risk factors. Although oral SCC associated with dental implants is quite rare, there has been a recent gradual accumulation of reports about it. Here, we report a case of primary peri implant oral intra-epithelial neoplasia/carcinoma in situ (OIN/CIS) in a woman without the major risk factors for oral SCC. CASE PRESENTATION: A 65-year-old woman was referred to our clinic with a tumor in the right lower gingiva. She had no history of tobacco smoking and only drank socially. Ten years previously, mandibular right posterior teeth had been replaced with an implant-supported porcelain-fused-to-metal restoration in a dental clinic. About 7 years later, she noticed swelling on the lingual side of the gingiva around the implant-supported restoration, and was eventually referred to our clinic with the suspicion of a neoplasia around the dental implant. The upper part of the implant body was exposed on the implant corresponding to the first molar of the right side of the mandible; this was associated with painless, elastic soft, and relatively well circumscribed gingival swelling on the lingual site. A panoramic radiograph showed slight vertical bone resorption around the implants. An incisional biopsy was conducted under the suspicion of neoplasia. Pathological microscopic examination of the biopsy specimen revealed thickened squamous epithelia with slight nuclear atypism and disorders of the epithelial rete pegs. Immunohistochemical findings showed positive staining for keratin 17 and a negative staining mosaic pattern for keratin 13. High p53, p63, and Ki-67 reactivity was also observed. From these findings, OIN/CIS of the gingiva was pathologically diagnosed, and a wide local excision with rim resection of the mandible, including the implants, was performed. The pathological findings for the resected specimen were same as those for the biopsy specimen. After 1 year of follow-up, there was no evidence of recurrence. CONCLUSION: In this case, prolonged peri-implant mucositis or peri-implantitis may have been a plausible risk factor for carcinogenesis. PMID- 29147824 TI - An integrated QSAR modeling approach to explore the structure-property and selectivity relationships of N-benzoyl-L-biphenylalanines as integrin antagonists. AB - Integrins [Formula: see text] and [Formula: see text] are important targets to treat different inflammatory diseases, such as multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, atherosclerosis, and asthma. Despite being valuable targets, only a few work has been reported to date regarding molecular modeling studies on these integrins. Not only that, none of these reports addressed the selectivity issue between integrins [Formula: see text] and [Formula: see text]. Therefore, a major challenge regarding the design and discovery of selective integrin antagonists remains. In this study, a series of 142 N-benzoyl-L-biphenylalanines having both integrin [Formula: see text] and [Formula: see text] inhibitory activities were considered for a variety of QSAR approaches including regression and classification-based 2D-QSARs, Hologram QSARs, 3D-QSAR CoMFA and CoMSIA studies to identify the structural requirements of these integrin antagonists. All these QSAR models were statistically validated and subsequently correlated with each other to get a detailed understanding of the activity and selectivity profiles of these molecules. PMID- 29147825 TI - Ice Squeezing Induced Multicolor Fluorescence Emissions from Polyacrylamide Cryogels. AB - Being short of conventional chromophores, polyacrylamide is generally not regarded as a fluorescent material. Exactly the polymerization of dilute solutions of acrylamide and N,N'-methylenebisacrylamide led to thick liquids at 60 degrees C, showing no fluorescence. Things changed when the phase transition of water was involved. The squeezing effect of ice crystals not only created polymeric solids (cryogels) at - 20 degrees C, but also endowed them unexpected fluorescence emissions. The macroporous cryogels are mainly blue fluorescent polymers. However yellow and red fluorescence were also achieved by changing the ingredient ratios. A series of instrumental detections revealed that the multicolor fluorescence were based on exquisite amido stacking induced from ice squeezing. If people make good use of the squeezing effect of the heaven-sent molecule to manipulate the interactions of monomer functionalities, cryogenic polymerization can be a promising method to produce diverse polymeric materials. PMID- 29147826 TI - Medium-term adoption trends for laparoscopic, robotic and transanal total mesorectal excision (TaTME) techniques. PMID- 29147827 TI - Sinoscopic treatment of persistent perineal sinus. PMID- 29147828 TI - A Reliable Spectral Method to Reaction-Diffusion Equations in Entrapped-Cell Photobioreactor Packed with Gel Granules Using Chebyshev Wavelets. AB - A mathematical model of a reaction-diffusion within an entrapped-cell photobioreactor packed with gel granules containing immobilized photosynthetic bacterial cells is discussed. A theoretical model is based on a system of coupled nonlinear reaction-diffusion equations. In this research work, we have developed an efficient wavelet-based spectral approach for solving the proposed model. Analytical expressions for the concentration of substrate and product are established for all values of reaction-diffusion parameters using second kind Chebyshev wavelet method. The analytical results were also compared with Homotopy perturbation method (HPM) and Adomian decomposition method (ADM). Satisfactory agreement with ADM and HPM solutions is observed. Moreover, the use of Chebyshev wavelets is found to be simple, reliable, efficient, and computationally attractive. PMID- 29147829 TI - Cardiovascular disease in the literature: A selection of recent original research papers. PMID- 29147830 TI - Asymptomatic adult intrapericardial diaphragmatic hernia detected on cardiac SPECT CT. AB - An 83-year-old man underwent exercise stress test with single photon emission computed tomography (SPECT) myocardial perfusion imaging for new electrocardiogram (EKG) changes. The stress EKG did not show any significant changes. Myocardial perfusion imaging with SPECT demonstrated an inferior wall defect and extracardiac uptake of nuclear tracer. Simultaneous cardiac computed tomography performed for attenuation correction showed presence of intrapericardial hepatic tissue in an anterior diaphragmatic hernia. The herniated tissue was noted to influence the perfusion image and cause the defect. To date, this is a unique finding based on review of literature. PMID- 29147832 TI - Wh-Questions, Universal Statements and Free Choice Inferences in Child Mandarin. AB - This study investigated 5-year-old Mandarin-speaking children's comprehension of wh-questions, universal statements and free choice inferences. Previous research has found that Mandarin-speaking children assign a universal interpretation to sentences with a wh-word (e.g., shei 'who') followed by the adverbial quantifier dou 'all' (Zhou in Appl Psycholinguist 36:411-435, 2013). Children also compute free choice inferences in sentences that contain a modal verb in addition to a wh word and dou (Zhou, in: Nakayama, Su, Huang (eds.) Studies in Chinese and Japanese language acquisition: in honour of Stephen Crain. John Benjamins Publishing Company, Amsterdam, pp 223-235, 2017). The present study used a Question-Statement Task to assess children's interpretation of sentences containing shei + dou, both with and without the modal verb beiyunxu 'was allowed to', as well as the contrast between sentences with shei + dou, which are statements for adults, versus ones with dou + shei, which are wh-questions for adults. The 5-year-old Mandarin-speaking child participants exhibited adult-like linguistic knowledge of the semantics and pragmatics of wh-words, the adverbial quantifier dou, and the deontic modal verb beiyunxu. PMID- 29147831 TI - Plants of Brazilian restingas with tripanocide activity against Trypanosoma cruzi strains. AB - Chagas disease is caused by the Trypanosoma cruzi affecting millions of people, and widespread throughout Latin America. This disease exhibits a problematic chemotherapy. Benznidazole, which is the drug currently used as standard treatment, lamentably evokes several adverse reactions. Among other options, natural products have been tested to discover a novel therapeutic drug for this disease. A lot of plants from the Brazilian flora did not contain studies about their biological effects. Restinga de Jurubatiba from Brazil is a sandbank ecosystem poorly studied in relation to plant biological activity. Thus, three plant species from Restinga de Jurubatiba were tested against in vitro antiprotozoal activity. Among six extracts obtained from leaves and stem parts and 2 essential oils derived from leave parts, only 3 extracts inhibited epimastigote proliferation. Substances present in the extracts with activity were isolated (quercetin, myricetin, and ursolic acid), and evaluated in relation to antiprotozoal activity against epimastigote Y and Dm28 Trypanosoma cruzi strains. All isolated substances were effective to reduce protozoal proliferation. Essentially, quercetin and myricetin did not cause mammalian cell toxicity. In summary, myricetin and quercetin molecule can be used as a scaffold to develop new effective drugs against Chagas's disease. PMID- 29147833 TI - The Processing Costs of Presupposition Accommodation. AB - The present study investigates the processing of presupposition accommodation. In particular, it concerns the processing costs and the time-course of accommodation as compared to presupposition satisfaction. Data collected in a self-paced word by-word reading times experiment support three results. First, independently on the presupposition trigger in use, accommodation is costlier than satisfaction. Second, presupposition accommodation takes places immediately just as the trigger becomes available and proceeds incrementally during the sentence processing. Third, accommodated information is harder to be recalled. The results offer evidence for the on-line processing of presuppositions and, consistently with the traditional semantic framework, support the idea that, presuppositions are semantic properties encoded in the lexical meaning of the presupposition triggers. PMID- 29147835 TI - Automatic localization of the left ventricular blood pool centroid in short axis cardiac cine MR images. AB - In this paper, we develop and validate an open source, fully automatic algorithm to localize the left ventricular (LV) blood pool centroid in short axis cardiac cine MR images, enabling follow-on automated LV segmentation algorithms. The algorithm comprises four steps: (i) quantify motion to determine an initial region of interest surrounding the heart, (ii) identify potential 2D objects of interest using an intensity-based segmentation, (iii) assess contraction/expansion, circularity, and proximity to lung tissue to score all objects of interest in terms of their likelihood of constituting part of the LV, and (iv) aggregate the objects into connected groups and construct the final LV blood pool volume and centroid. This algorithm was tested against 1140 datasets from the Kaggle Second Annual Data Science Bowl, as well as 45 datasets from the STACOM 2009 Cardiac MR Left Ventricle Segmentation Challenge. Correct LV localization was confirmed in 97.3% of the datasets. The mean absolute error between the gold standard and localization centroids was 2.8 to 4.7 mm, or 12 to 22% of the average endocardial radius. Graphical abstract Fully automated localization of the left ventricular blood pool in short axis cardiac cine MR images. PMID- 29147836 TI - Effects of saffron and its constituents, crocin-1, crocin-2, and crocetin on alpha-synuclein fibrils. AB - Saffron, the stigma of Crocus sativus Linne (Iridaceae family), has been known to inhibit aggregation of beta-amyloid, a nerve tissue protein. alpha-Synuclein (alphaS) is a 140-amino acid protein found abundantly in various regions of the brain. Its abnormal aggregation and accumulation in nerve tissue are said to cause neurodegenerative diseases such as Parkinson's disease, Lewy body dementia, and multiple-system atrophy. This study (part of this study was presented at the 137th Annual Meeting of the Pharmaceutical Society of Japan) examined the effects of saffron, its constituents (crocin-1, crocin-2, crocetin, and safranal), and crocetin structural analogs (hexadecanedioic acid, norbixin, and trans, trans muconic acid) on alphaS aggregation, and alphaS fibril dissociation. Saffron dose dependently inhibited alphaS aggregation and dissociated alphaS fibrils by thioflavin T fluorescence assay. These effects were observed by transmission electron microscopy, which showed reduced and shortened alphaS fibrils. Crocin-1, crocin-2, and crocetin showed anti-aggregation and fibril dissociation effects, with crocetin being the most potent. The effects of norbixin were weaker than those of crocetin, and the other crocetin structural analogs showed no effects. These results show that saffron and its constituents (crocin-1, crocin-2, and crocetin) can be effective in preventing and treating diseases caused by abnormal alphaS aggregation. PMID- 29147837 TI - Development of SAAP3D force field and the application to replica-exchange Monte Carlo simulation for chignolin and C-peptide. AB - Single amino acid potential (SAAP) would be a prominent factor to determine peptide conformations. To prove this hypothesis, we previously developed SAAP force field for molecular simulation of polypeptides. In this study, the force field was renovated to SAAP3D force field by applying more accurate three dimensional main-chain parameters, instead of the original two-dimensional ones, for the amino acids having a long side-chain. To demonstrate effectiveness of the SAAP3D force field, replica-exchange Monte Carlo (REMC) simulation was performed for two benchmark short peptides, chignolin (H-GYDPETGTWG-OH) and C-peptide (CHO AETAAAKFLRAHA-NH2). For chignolin, REMC/SAAP3D simulation correctly produced native beta-turn structures, whose minimal all-atom root-mean-square deviation value measured from the native NMR structure (except for H) was 1.2 A, at 300 K in implicit water, along with misfolded beta-hairpin structures with unpacked aromatic side chains of Tyr2 and Trp9. Similar results were obtained for chignolin analog [G1Y,G10Y], which folded more tightly to the native beta-turn structure than chignolin did. For C-peptide, on the other hand, the alpha-helix content was larger than the beta content on average, suggesting a significant helix-forming propensity. When the imidazole side chain of His12 was protonated (i.e., [His12Hip]), the alpha content became larger. These observations as well as the representative structures obtained by clustering analysis were in reasonable agreement not only with the structures of C-peptide that were determined in this study by NMR in 30% CD3CD in H2O at 298 K but also with the experimental and theoretical behaviors having been reported for protonated C peptide. Thus, accuracy of the SAAP force field was improved by applying three dimensional main-chain parameters, supporting prominent importance of SAAP for peptide conformations. PMID- 29147838 TI - The Reactive-Proactive Aggression Questionnaire: Measurement Invariance and Reliability Among a School Sample of Portuguese Youths. AB - Aggression is an important risk factor for various forms of problem behaviors in adolescence, and research has often distinguished between reactive and proactive forms of aggression. The aim of the present study was to compare the psychometric properties (i.e., structural invariance, internal consistency, and criterion validity) of the Reactive-Proactive Aggression Questionnaire (RPQ) between males and females among a mixed-gender school sample of 782 Portuguese youth (M = 15.87 years, SD = 1.72). Confirmatory factor analysis revealed that a two-factor first order structure obtained the best fit and cross-gender measurement invariance was demonstrated after excluding item 21. The Portuguese version of the RPQ demonstrated generally adequate psychometric properties of internal consistency measured by Cronbach's alpha and omega coefficient, convergent validity, discriminant validity, criterion-related validity, and known-groups validity. Findings are discussed in terms of the use of the RPQ with male and female youths. PMID- 29147839 TI - Screening Accuracy of the Brief Infant Toddler Social-Emotional Assessment to Identify Autism Spectrum Disorder in Toddlers Born at Less Than 30 Weeks' Gestation. AB - Despite the higher prevalence of autism spectrum disorder (ASD) in children born preterm, valid screening tools for use in preterm populations are lacking. We aimed to evaluate the screening accuracy of the Brief Infant Toddler Social Emotional Assessment (BITSEA) and to compare it to the Pervasive Developmental Disorders Screening Test-II, Stage 2, Developmental Clinic Screener (PDDST-II DCS) in identifying ASD diagnosis in toddlers born at < 30 weeks' gestation. Caregivers (94% mothers) of 555 children completed questionnaires (BITSEA, PDDST II-DCS, socio-demographics) when the children (58% male) were 18-36 months. Medical charts were abstracted 3.5 years later and showed that 4% (n = 24) of children had an ASD diagnosis. BITSEA competence (sensitivity = .74; specificity = .76) and ASD (sensitivity = .70; specificity = .73) subscales demonstrated better accuracy in identifying ASD compared to the recommended PDDST-II-DCS cut score (sensitivity = .73; specificity = .64), specifically as it related to specificity. Additional studies are needed in other preterm populations to replicate these findings. PMID- 29147840 TI - Medulloblastoma in adults : A retrospective single institution analysis. AB - PURPOSE: Adult medulloblastoma is a rare disease treated according to the current pediatric treatment guidelines. This retrospective analysis investigated the clinical outcomes and prognostic factors of adult medulloblastoma patients, who received multimodal therapy at our institution. METHODS: Treatment charts of all patients over the age of 15 years of age with de novo medulloblastoma, who had been treated at our institution between 2001 and 2014, were retrospectively analyzed. Patients' demographic parameters, initial symptoms, treatment modalities, toxicities, and survival outcomes were investigated. RESULTS: In all, 21 patients with a median age of 30.2 years were identified. The most frequent histologies were desmoplastic and classic, and the most common molecular subtype was sonic hedgehog (SHH). After tumor resection, all patients received craniospinal irradiation (median dose 35.2 Gy) and a boost to the posterior fossa (median dose 19.8 Gy). Simultaneous chemotherapy with vincristine was given to 20 patients and sequential chemotherapy to 15 patients. The most common side effects were hematological toxicities. Median overall survival (OS) has not been reached after a median follow-up of 92 months. Estimated 5- and 10-year OS was 89 and 80%, respectively. Estimated 5- and 10-year progression-free survival (PFS) was 89 and 81%, respectively. In univariate analysis, a shorter interval between tumor resection and end of irradiation was significantly associated with improved OS and PFS, anaplastic histology with worse OS and PFS. CONCLUSIONS: The combined modality treatment showed a good outcome in adults with medulloblastoma. Treatment time was revealed to be prognostic and should be kept as short as possible. PMID- 29147841 TI - Radiotherapy for extramedullary leukaemic manifestation (Chloroma). AB - PURPOSE: Extramedullary leukaemic disease (EMD, synonym chloroma) is a rare solid manifestation of myeloid leukaemia for which the value of radiotherapy (RT) as a treatment strategy remains controversial. The aim of this study is to analyse the effectiveness of various RT doses for EMD in the modern treatment era. MATERIALS AND METHODS: Between January 2000 and June 2016, 20 patients with total of 45 lesions underwent RT for EMD at our institution. RESULTS: With a median radiation dose of 26 Gy (range 4-42 Gy), local remission could be achieved in 91% of patients (complete remission rate: 71%). The median duration of local control (DOLC) was 17 months (95% confidence interval [CI] 0.5-33) and the median overall survival (OS) after chloroma onset was 24 months (95% CI 11-38). No noticeable difference between high- and low-dose regimens has been observed (74% versus 68%; P = 0.5). In the multivariate analysis, only Eastern Cooperative Oncology Group (ECOG) score and bone marrow state during RT have proven to be determinant for durable local control and OS. CONCLUSIONS: Low-dose RT (<=26 Gy) achieves good local control compared to high-dose regimes. Bone marrow state during RT and ECOG score during RT may play a crucial role, influencing both DOLC and OS. PMID- 29147842 TI - Tetrandrine Alleviates Nociception in a Rat Model of Migraine via Suppressing S100B and p-ERK Activation in Satellite Glial Cells of the Trigeminal Ganglia. AB - Sensitization and activation of the trigeminal ganglia have been implicated in the pathology of migraine. Satellite glial cells (SGCs), a specialized type of glial cells that ensheathe trigeminal neurons, may be critical for peripheral nociceptive sensitization. Tetrandrine (TET), an alkaloid extracted from a traditional Chinese herb, exerts an inhibitory effect on glial activation in vitro and has been used in various neurologic diseases. The current study investigated the effect of TET on nitroglycerin (NTG)-induced trigeminal sensitization and examined potential signaling pathways related to SGC activation in the model of migraine. We measured trigeminal nociceptive thresholds using electronic von Frey rigid tips before and after NTG injection in control rats and rats pretreated with TET, while expression and subcellular location of the inflammatory mediators S100B and activated phosphorylation extracellular signal regulated kinase (p-ERK) were measured using real-time quantitative polymerase chain reaction, Western blotting, and double immunofluorescence staining. Pretreatment with TET caused a dose-dependent reversal of the trigeminal nociceptive hypersensitivity induced by NTG. In addition, TET pretreatment blocked the activation of S100B and p-ERK in trigeminal ganglion SGCs of NTG treated rats. Reduced p-ERK activity can suppress the inflammation that leads to hyperexcitability of trigeminal ganglion neurons. Administration of TET may therefore be a safe and effective therapeutic treatment for the hyperalgesic symptoms of migraine. PMID- 29147843 TI - Iron and infection. AB - Iron is an essential trace metal for nearly all infectious microorganisms, and host defense mechanisms target this dependence to deprive microbes of iron. This review highlights mechanisms that are activated during infections to restrict iron on mucosal surfaces, in plasma and extracellular fluid, and within macrophages. Iron overload disorders, such as hereditary hemochromatosis or beta thalassemia, interfere with iron-restrictive host responses, and thereby cause increased susceptibility to infections with microbes that can exploit this vulnerability. Anemia of inflammation (formerly known as anemia of chronic diseases) is an "off-target" effect of host defense wherein inflammatory cytokines shorten erythrocyte lifespan by activating macrophages, prioritize leukocyte production in the marrow, and induce hepcidin to increase plasma transferrin saturation and the concentration of non-transferrin-bound iron. PMID- 29147845 TI - [Reconstruction of the examination of the laryngeal carcinoma of Emperor Frederick III by Rudolf Virchow]. AB - Rudolf Virchow is one of the founders of modern pathology, and many of his ideas on inflammatory and neoplastic diseases are still valid today. Even for Virchow, determination of malignancy was not always easy. As an example, the laryngeal disease of Crown Prince Frederick William, the later Emperor Frederick III, is presented.The clinical findings at the beginning of the disease were suggestive of a carcinoma, though an inflammatory lesion was also discussed. Several attempts were made to remove the lesion bioptically, but local recurrences occurred and the first tissue samples were not examined histopathologically. Since laryngeal tumour operations had a high mortality at that time, histopathologic examinations were made in order to decide for or against an operation. The samples taken after pre-treatment did not meet Virchow's criteria for determining a carcinoma. Contrary to the present concept of a carcinoma in situ-carcinoma sequence, Virchow's concept was based on the assumption that carcinomas are not derived from the epithelium, but arise from a mesenchymal epithelial transformation from the connective tissue. The clinical suspicion of a laryngeal carcinoma was confirmed only shortly before the patient's death and later by a post-mortem examination.The question repeatedly asked is whether Virchow should have diagnosed a carcinoma at the beginning of the disease. The answer has been the same for more than a hundred years: the clinician is dissatisfied with the histopathological diagnosis, so the pathologist is to blame. PMID- 29147846 TI - HCG administration after endogenous LH rise negatively influences pregnancy rate in modified natural cycle for frozen-thawed euploid blastocyst transfer: a pilot study. AB - PURPOSE: The aim of the present study was to evaluate whether in a modified natural cycle (modified-NC) for a frozen-thawed single euploid blastocyst transfer, a critical LH value, above which human chorionic gonadotropin (hCG) administration should be avoided, may be defined. METHODS: One hundred and sixty seven patients underwent modified natural cycle in order to transfer a single frozen-thawed euploid blastocyst. All embryos were obtained by intracytoplasmic sperm injection and were biopsied at the blastocyst stage and analyzed by means of array comparative genomic hybridization (aCGH). Ovulation was induced using 10.000 IU hCG when the mean follicle diameter was at least of 17 mm, independently from LH values. The primary end points were the hCG-positive test and clinical pregnancy. The interim analysis showed that LH value >= 13 mIU/ml on the day of hCG injection may negatively influence the clinical results, suggesting that in this condition, it should be advisable waiting for spontaneous ovulation. RESULTS: Among patients who received hCG for ovulation induction, the hCG-positive test and clinical pregnancy rates in modified-NC were significantly lower in cycles with LH >= 13 mIU/ml in respect to those with LH < 13 mIU/ml (45.4 vs 73.3 and 36.4 vs 65.9%, in LH >= 13 and LH < 13 groups, respectively). In patients with LH value >= 13 mIU/ml, hCG administration led to significantly lower rates of hCG-positive test (45.4 vs 74.5% in hCG administration and spontaneous ovulation groups, respectively) and clinical pregnancy (36.4 vs 64.7% in hCG administration and spontaneous ovulation groups, respectively). The baseline patient characteristics were comparable in all groups. CONCLUSIONS: The findings of this study highlight that LH elevation >= 13 mIU/ml prior to hCG administration may negatively affect clinical pregnancy rates in modified-NC for single euploid blastocyst transfer. The LH determination should be routinely performed during follicular monitoring. In the presence of LH level >= 13 mIU/ml, hCG administration should be avoided, and the embryo transfer should be planned only after spontaneous follicular rupture. PMID- 29147847 TI - R-hyper-CVAD versus R-CHOP/cytarabine with high-dose therapy and autologous haematopoietic stem cell support in fit patients with mantle cell lymphoma: 20 years of single-center experience. AB - Standard of care for untreated mantle cell lymphoma (MCL) is still debated. At the University Hospital Zurich, advanced MCL in physically fit patients is treated either with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone induction followed by consolidating high-dose chemotherapy and autologous stem cell support (R-CHOP/HD-ASCT), or with rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate-cytarabine (R-hyper-CVAD/MTX-AraC) without consolidating HD-ASCT upon physicians' and patients' choice. We retrospectively analysed the outcome and therapy tolerance in patients with MCL treated with R-CHOP/HD-ASCT or R-hyper-CVAD/MTX-AraC at the University Hospital Zurich between January 1996 and January 2016. Forty-three patients were included; 29 patients received R-CHOP/HD-ASCT and 14 patients R-hyper-CVAD/MTX-AraC. Mean age at diagnosis was 54.4 years (range 38-68 years). Thirty-five patients (81.4%) completed the entire first-line therapy (n = 24 in the R-CHOP/HD-ASCT group, n = 11 in the R-hyper-CVAD group). Of those, all patients responded and 97% achieved a complete remission (CR). With a mean follow-up of 5.7 years 10-year progression free survival (PFS) for all patients was 32% and overall survival (OS) was 76%, with no difference between the two therapy groups. Complication-induced hospitalisation rate, haematological toxicity and economic burden were significantly higher in the R-hyper-CVAD therapy group. In contrast, quality of life and global health state were better in the R-hyper-CVAD therapy group. Both first-line therapies showed similar outcome with a median OS longer than 10 years. Due to significantly lower haematological toxicity and lower economic burden, we recommend R-CHOP/HD-ASCT as first-line therapy in fit adult patients with advanced MCL. PMID- 29147849 TI - Heterogeneity of passive elastic properties within the quadriceps femoris muscle tendon unit. AB - PURPOSE: The purpose of this study was to compare regional elastic properties between anterior and posterior regions of the patellar tendon, and individual quadriceps muscles, over a range of knee flexion angles. METHODS: An isokinetic dynamometer passively positioned the non-dominant knee of 19 young, healthy participants, at 25 degrees , 40 degrees , 55 degrees , 70 degrees and 85 degrees flexion. Shear wave velocity (SWV, an index of tissue elasticity) was measured using ultrasound shear wave elastography in a relaxed (passive) state, confirmed by electromyography. RESULTS: SWV of the patellar tendon and quadriceps muscles increased with knee flexion (longer muscle-tendon unit; P < 0.001). Within the proximal third of the patellar tendon, SWV was lower in the posterior than anterior region at 70 degrees (P = 0.002) and 85 degrees (P < 0.001), but not at 25 degrees , 40 degrees or 55 degrees (region-by-angle interaction, P = 0.007). No differences were found between anterior and posterior regions within the middle third of the patellar tendon (P = 0.332). For the quadriceps muscles, a significant muscle-by-angle (P < 0.001) interaction was also observed. SWV of VL was greater than VM at 55 degrees (P = 0.005), 70 degrees (P = 0.001) and 85 degrees (P < 0.001), but not at 25 degrees or 40 degrees . SWV of RF was lower than VL at all angles (all P < 0.002) and lower than VM at 55 degrees , 70 degrees and 85 degrees (all P < 0.002). CONCLUSIONS: Passive knee flexion at and beyond 70 degrees was associated with non-uniform elastic properties within the proximal patellar tendon and between individual quadriceps muscles. To what extent this heterogeneity of passive elastic properties contributes to injury remains unknown. PMID- 29147848 TI - Simultaneous point-of-care detection of anemia and sickle cell disease in Tanzania: the RAPID study. AB - Both anemia and sickle cell disease (SCD) are highly prevalent across sub-Saharan Africa, and limited resources exist to diagnose these conditions quickly and accurately. The development of simple, inexpensive, and accurate point-of-care (POC) assays represents an important advance for global hematology, one that could facilitate timely and life-saving medical interventions. In this prospective study, Robust Assays for Point-of-care Identification of Disease (RAPID), we simultaneously evaluated a POC immunoassay (Sickle SCANTM) to diagnose SCD and a first-generation POC color-based assay to detect anemia. Performed at Bugando Medical Center in Mwanza, Tanzania, RAPID tested 752 participants (age 1 day to 20 years) in four busy clinical locations. With minimally trained medical staff, the SCD POC assay diagnosed SCD with 98.1% sensitivity and 91.1% specificity. The hemoglobin POC assay had 83.2% sensitivity and 74.5% specificity for detection of severe anemia (Hb <= 7 g/dL). Interobserver agreement was excellent for both POC assays (r = 0.95-0.96). Results for the hemoglobin POC assay have informed the second-generation assay design to be more suitable for low-resource settings. RAPID provides practical feasibility data regarding two novel POC assays for the diagnosis of anemia and SCD in real-world field evaluations and documents the utility and potential impact of these POC assays for sub-Saharan Africa. PMID- 29147850 TI - The tear cytokine profile in patients with active Graves' orbitopathy. AB - PURPOSE: The primary aim of this study is to isolate cytokines specific for active Graves' orbitopathy (GO) in the tears of affected patients. The secondary aim is to identify other cytokines of interest and to look at the profile of their levels over time. METHODS: This is a prospective pilot study conducted at the Singapore National Eye Centre. A total of 10 patients with active GO and 10 patients from each of 3 control groups were recruited. The 3 control groups were the following: age-matched normal female patients, patients with GO who were clinically inactive and patients with bilateral viral conjunctivitis. Tears from patients from the control groups were collected on a single visit. For patients with active GO, tears were collected on presentation, at 6 months, 12 months and 18 months. RESULTS: Of all the cytokines examined, only IL-7 yielded a difference when the concentration in patients with active GO was compared with concentrations in all the control groups. This difference was most significant at the 18-month follow-up visit. CONCLUSIONS: Low concentrations of IL-7 in tears exhibit specificity for active GO in patients nearly 2 years from the clinical onset of activity. Although using IL-7 in tears as a biomarker for disease activity may be limited due to its late manifestation, targeting immune restitution using IL-7 may have disease modifying effects. PMID- 29147852 TI - Enhanced Peptide Detection Toward Single-Neuron Proteomics by Reversed-Phase Fractionation Capillary Electrophoresis Mass Spectrometry. AB - The ability to detect peptides and proteins in single cells is vital for understanding cell heterogeneity in the nervous system. Capillary electrophoresis (CE) nanoelectrospray ionization (nanoESI) provides high-resolution mass spectrometry (HRMS) with trace-level sensitivity, but compressed separation during CE challenges protein identification by tandem HRMS with limited MS/MS duty cycle. Here, we supplemented ultrasensitive CE-nanoESI-HRMS with reversed phase (RP) fractionation to enhance identifications from protein digest amounts that approximate to a few mammalian neurons. An ~1 to 20 MUg neuronal protein digest was fractionated on a RP column (ZipTip), and 1 ng to 500 pg of peptides were analyzed by a custom-built CE-HRMS system. Compared with the control (no fractionation), RP fractionation improved CE separation (theoretical plates ~274,000 versus 412,000 maximum, resp.), which enhanced detection sensitivity (2.5-fold higher signal-to-noise ratio), minimized co-isolation spectral interferences during MS/MS, and increased the temporal rate of peptide identification by up to ~57%. From 1 ng of protein digest (<5 neurons), CE with RP fractionation identified 737 protein groups (1,753 peptides), or ~480 protein groups (~1,650 peptides) on average per analysis. The approach was scalable to 500 pg of protein digest (~a single neuron), identifying 225 protein groups (623 peptides) in technical triplicates, or 141 protein groups on average per analysis. Among identified proteins, 101 proteins were products of genes that are known to be transcriptionally active in single neurons during early development of the brain, including those involved in synaptic transmission and plasticity and cytoskeletal organization. Graphical abstract ?. PMID- 29147851 TI - Bijective codon transformations show genetic code symmetries centered on cytosine's coding properties. AB - Homology of some RNAs with template DNA requires systematic exchanges between nucleotides. Such exchanges produce 'swinger' RNA along 23 bijective transformations (nine symmetric, X <-> Y; and 14 asymmetric, X -> Y -> Z -> X, for example A <-> C and A -> C -> G -> A, respectively). Here, analyses compare amino acids coded by swinger-transformed codons to those coded by untransformed codons, defining coding invariance after transformations. Swinger transformations cluster according to coding invariance in four groups characterized by transformations into cytosine (C = C, T -> C, A -> C, and G -> C). C's central mutational coding role shows that swinger transformations constrained genetic code genesis. Coding invariance post-transformations correlate positively/negatively with mitochondrial swinger transcription/lepidosaurian body temperature. Presumably, low/high temperatures stabilize/revert rare swinger polymerization modes, producing long swinger sequences/point mutations, respectively. Coding invariance after swinger transformations might compensate effects of swinger polymerizations in species with low body temperatures. Hypothetically, swinger transcription increased coding potential of RNA self replicating protolife systems under heating/cooling cycles. PMID- 29147853 TI - Biospecimen donation among black and white breast cancer survivors: opportunities to promote precision medicine. AB - PURPOSE: Advances in precision medicine (PM) have potential to reduce and/or eliminate breast cancer disparities in both treatment and survivorship. However, compared to white Americans, black Americans are often underrepresented in genetic research. This report assessed factors that influence receipt of buccal cells via saliva kits. METHODS: This prospective study recruited women with confirmed hormonal-positive (HR+) breast cancer (BC). A standardized telephone survey collected sociodemographic, socio-cultural (e.g., religiosity), and healthcare process factors. Clinical information was abstracted from medical records. After the baseline survey, return postage-paid envelopes and mouthwash collection kits were mailed. Univariate and adjusted logistic regression models estimated the probability of biospecimen donation. RESULTS: Seventy percent of the sample provided buccal cells which were of good quality. No differences were noted by race or other demographic factors. In the multivariable logistic model, time spent with providers (OR 1.61 per 1-point increase; 95% CI 1.242, 2.088) and religiosity (OR 0.957 per 1-point increase; 95% CI 0.931, 0.984) remained associated with biospecimen provision. Women with lower-stage cancer (vs. higher stage III+) were more likely to donate biospecimens (p < 0.05). CONCLUSIONS: Cancer care experiences predicted specimen donation. Understanding the contextual reasons for lower receipt among women with higher religiosity scores and higher stage warrants further examination. IMPLICATIONS FOR CANCER SURVIVORS: PM is relevant to cancer survivors because of its potential to inform targeted therapies, understand disease resistance, and aide in prediction of toxicity and/or recurrence. Future efforts to launch precision medicine trials with BC survivors may benefit from engaging medical oncologists and/or leveraging patient provider encounters for trial participation. PMID- 29147854 TI - NOLAN: a randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim. AB - PURPOSE: Mild-to-moderate bone pain is a commonly reported adverse event (AE) associated with pegfilgrastim. We evaluated the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on pegfilgrastim-associated bone pain. METHODS: In this open-label study (NCT01712009), women >= 18 years of age with newly diagnosed stage I-III breast cancer and an ECOG performance status <= 2 who were planning >= 4 cycles of adjuvant or neoadjuvant chemotherapy with pegfilgrastim support starting in cycle 1 were randomized 1:1:1 to receive naproxen, loratadine, or no treatment to prevent pegfilgrastim-associated bone pain. The primary endpoint was all-grade bone pain in cycle 1 from AE reporting. Secondary endpoints included bone pain in cycles 2-4 and across all cycles from AE reporting and patient-reported bone pain by cycle and across all cycles. RESULTS: Six hundred patients were enrolled. Most patients (83.0%) were white, and mean (SD) age was 54.2 (11.1) years. The percentage of patients with all grade bone pain in cycle 1 from AE reporting in the naproxen, loratadine, and no prophylaxis groups was 40.3, 42.5, and 46.6%, respectively; differences between the treatment groups were not statistically significant. Maximum, mean, and area under the curve for patient-reported bone pain were consistently lower in the naproxen and loratadine groups than in the no prophylaxis group; some of these differences were significant. Loratadine was associated with fewer treatment related AEs and discontinuations than naproxen. CONCLUSIONS: Given its tolerability, its ease of administration, and its potential benefit, treatment with loratadine should be considered to help prevent bone pain in patients receiving chemotherapy and pegfilgrastim. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ; NCT01712009. PMID- 29147855 TI - Phase II study of palonosetron, aprepitant and dexamethasone to prevent nausea and vomiting induced by multiple-day emetogenic chemotherapy. AB - PURPOSE: This study aimed to determine the antiemetic efficacy and safety of palonosetron, aprepitant and dexamethasone in patients with testicular germ cell tumours (TGCTs) receiving 5-day cisplatin-based combination chemotherapy. METHODS: In this open-label, single-arm, single-centre study, the antiemetic therapy consisted of palonosetron 0.75 mg on day 1, aprepitant 125 mg on day 1 and 80 mg on days 2-7 and dexamethasone 6.6 mg on days 1-7. The primary endpoint was complete response (CR; no vomiting/retching or rescue medication) in the overall period (0-240 h), and secondary endpoints included complete protection (CP; defined as CR and no more than mild nausea) and total control (TC; defined as CR and no nausea). The incidence and severity of nausea were assessed on the basis of the Common Terminology Criteria for Adverse Events v4.0 and a subjective rating scale completed by patients. RESULTS: Twenty-five patients were enrolled and evaluated for safety, and 24 patients were evaluated for efficacy. CR was achieved in 62.5% of patients (95% confidence interval [CI] = 40.6-81.2, p = 0.043) in the overall period. CP and TC were achieved in 62.5% (95% CI = 40.6 81.2) and 25.0% of patients (95% CI = 9.8-46.7), respectively, in the overall period. The primary adverse drug reaction was hiccups (48.0%). The events were expected, and none was grade 3 or 4. CONCLUSIONS: The examined combination antiemetic therapy was effective and well-tolerated in patients with TGCTs receiving 5-day cisplatin-based combination chemotherapy. PMID- 29147856 TI - ? PMID- 29147857 TI - [Quality standards for epidemiologic cohort studies : An evaluated catalogue of requirements for the conduct and preparation of cohort studies]. AB - BACKGROUND: Cohort studies are a longitudinal observational study type. They are firmly established within epidemiology to assess the course of diseases and risk factors. Yet, standards to describe and evaluate quality characteristics of cohort studies need further development. OBJECTIVE: Within the TMF ("Technologie- und Methodenplattform fur die vernetzte medizinische Forschung e. V.") project "Quality management standards in cohort studies", a catalogue of requirements was compiled and evaluated, focusing on the preparation and conduct of epidemiologic cohort studies. MATERIALS AND METHODS: The catalogue of requirements was established based on a consensus process between representatives of seven German epidemiologic cohort studies. For this purpose, a set of expert meetings (telephone, face-to-face, web-based) was conducted and the importance of each element of the catalogue was assessed as well as its implementation. RESULTS: A catalogue of requirements with 138 requirements was consented. It is structured into ten sections: 1. Study documentation; 2. Selection of instruments; 3. Study implementation, 4. Organizational structure; 5. Qualification and certification; 6. Participant recruitment; 7. Preparation, conduct and follow-up processing of examinations; 8. Study logistics and maintenance, 9. Data capture and data management; 10. Reporting and monitoring. In total, 41 elements were categorized as being essential, 91 as important, and 6 as less important. CONCLUSION: The catalogue of requirements provides a guideline to improve the preparation and operation of cohort studies. The evaluation of the importance and degree of implementation of requirements depended on the study design. With adaptations, the catalogue might be transferable to other study types. PMID- 29147858 TI - Community Interventions to Increase Stroke Preparedness and Acute Stroke Treatment Rates. AB - PURPOSE OF REVIEW: Acute stroke treatments reduce the risk of post-stroke disability. These treatments, tissue plasminogen activator (tPA) and intra arterial treatment, are highly time-dependent; thus, one of the main barriers to treatment is pre-hospital delay. Stroke preparedness is defined as the ability to recognize stroke symptoms and the intent to activate emergency medical services (EMS). This review describes types of acute stroke treatment and preparedness interventions, including recent mass media interventions to increase acute stroke treatment rates, and adult and youth community interventions to increase stroke preparedness. RECENT FINDINGS: The mass media campaigns show mixed results regarding acute stroke treatment rates, possibly attributed to the various media platforms utilized and resources available. The adult and youth community interventions reveal an overall increase in stroke symptom recognition and behavioral intent to call EMS. However, most of these community interventions were not grounded in health behavior theory, and they were tested in single group, pre-post test study designs that assessed behavioral rather than clinical outcomes. The delivery of stroke preparedness information by youth to adults, for example via home assignments, is a promising and innovative approach to stroke preparedness. Mass media and community interventions show promise to increase stroke preparedness and acute stroke treatment rates. The development of health behavior theory-based interventions that are tested via scientifically rigorous study designs are needed to prioritize which interventions should be disseminated to culturally and socially similar communities. PMID- 29147859 TI - Initial psycho-oncological counselling in neuro-oncology: analysis of topics and needs of brain tumour patients. AB - Diagnosis of a brain tumour is associated with a tremendous disruption of emotional, physical and social well-being. Due to the complexity of the disease and the affection of the central organ, the brain, brain tumour patients differ from other cancer patients. The purpose of this study was to evaluate the concerns and burdens presented by brain tumour patients during their initial psycho-oncological consultation. We performed a retrospective analysis of 53 patients with the diagnosis of either benign or malignant brain tumour, seeking counsel by a neurosurgeon specialised in psycho-oncology. We performed a thematic analysis of the interviews at first consultation identifying themes and patterns and created thematic categories. The main concerns of the patients presented during the first consultations were psychological problems, reported by 40 patients (75.5%). Death and dying was mentioned by more than half of the patients (n = 30, 56.6%). In addition, 62.3% of the patients (n = 33) asked for information regarding the medical treatment and diagnosis. With our study, we created greater awareness of the psychological needs of brain tumour patients in order to define treatment strategies for this important aspect of disease. We showed that there is a need for patients to talk about death even during the initial consultation. Psycho-oncologist in a neuro-oncological setting should be prepared for topics like that and should have a neurosurgical background or collaborate with members of the surgical team in order to provide the patients with medical details and to better understand the impact of the disease. PMID- 29147860 TI - 18F-FDG PET/CT in primary brain lymphoma. AB - The actual role of 18F-FDG PET/CT in evaluating primary brain lymphoma is still an open issue. Brain lymphoma usually show elevated 18F-FDG uptake, often higher than other brain tumors or inflammatory processes, but the metabolic behavior of this lymphoma is not still understood. Our aim was to investigate the particular metabolic behavior of this lymphoma. Forty six patients (21 female, 25 male) with histologically-confirmed brain lymphoma who underwent 18F-FDG PET/CT from vertex to the mid-thigh for initial staging were retrospectively evaluated. The PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value (SUVmax), lesion-to-liver SUVmax ratio, lesion-to-blood pool SUVmax ratio and the tumor to normal brain uptake ratio (T/N ratio) and compared with epidemiological (age, sex, HIV infection) and morphological (tumor size, MRI appearance) characteristics. Thirty-eight patients (83%) had positive 18F-FDG PET/CT (average SUVmax was 15.6 +/- 9.2; lesion-to-liver SUVmax ratio 5.8 +/- 2.8; lesion-to-blood pool SUVmax ratio 7.1 +/- 3.8, T/N ratio 3.1 +/- 1.7) at the corresponding brain lesion; the remaining 8 (17%) were not 18F-FDG avid. 18F FDG avidity was significantly associated with morphological appearance and tumor size and not correlated with other features. 18F-FDG PET/CT detected extracranial disease in two cases (4%) with negative bone marrow biopsies and CT. In conclusion, brain lymphomas are 18F-FDG avid in 83% of cases showing high 18F-FDG uptake and 18F-FDG avidity is correlated with tumor size and morphological appearance of the lesion. PET/CT helped to recognize extracranial disease in two patients. PMID- 29147861 TI - Eosinophilia in a peritoneal dialysis patient: Questions. PMID- 29147862 TI - Eosinophilia in a peritoneal dialysis patient: Answers. AB - Icodextrin is a starch-derived glucose polymer used in peritoneal dialysis dialysate to treat volume overload by increasing ultrafiltration in patients with end-stage renal disease. Reported adverse reactions to icodextrin are mild and rare and mainly consist of skin rash that resolves spontaneously after discontinuation of treatment. We describe a young patient with extreme eosinophilia that appeared with the use of icodextrin, disappeared after its discontinuation, and reappeared after a rechallenge with the drug. The eosinophilia was not associated with peritonitis, was asymptomatic, and fully resolved after discontinuation of the drug. Severe eosinophilia can potentially cause tissue damage in several organs, which would indicate that blood eosinophil count is recommended in routine complete blood counts while icodextrin peritoneal dialysis is being administered. PMID- 29147863 TI - Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma. AB - The aim of this study was to determine the clinicopathological significance of programmed cell death ligand 1 (PD-L1) expression in glioblastoma (GBM). In a retrospective cohort of 115 consecutive patients with GBM, PD-L1 expression was determined using immunohistochemistry (IHC). Membranous and fibrillary PD-L1 staining of any intensity in > 5% neoplastic cells and tumour infiltrating immune cells (TIIs) was considered positive staining. In addition, isocitrate dehydrogenase-1 (IDH-1) (R132H) expression and cluster of differentiation 3 (CD3) positive T-cell infiltration were investigated using IHC. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation assay and fluorescence in situ hybridization (FISH) for the assessment of 1p/19q deletion were performed. Expression of PD-L1 in tumour cells and TIIs was found in 37 (32.2%) and 6 (5.2%) patients, respectively. Kaplan-Meier analysis indicated that PD-L1 expression in tumour cells was significantly associated with poor overall survival (OS) (P = 0.017), though multivariate Cox analysis did not confirm this association (hazard ratio 1.204; P = 0.615). PD-L1 expression in TIIs did not correlate with the patient prognosis (P = 0.545). In addition, MGMT methylation and IDH-1 (R132H) expression were associated with a better prognosis (P < 0.001 and P = 0.024, respectively). The expression of PD-L1 was associated with CD3-positive T-cell infiltration (P < 0.001), and IDH-1 wild type status (P = 0.008). A deeper insight into PD-L1 expression could help to ensure the success of future immunotherapy in GBM. Our study suggested that PD-L1 target therapy might be beneficial for PD-L1-expressing GBM patients with a poor prognosis. PMID- 29147864 TI - Impact of WHO 2016 update of brain tumor classification, molecular markers and clinical outcomes in pleomorphic xanthoastrocytoma. AB - We present outcomes of pleomorphic xanthoastrocytoma (PXA) and correlate the impact of clinical, pathologic and molecular markers. Between 2006 and 2016, 37 patients with histologically verified PXA form the study cohort. All underwent maximal safe resection; those who had good resection and young age were observed. Adjuvant radiotherapy was given in patients with some atypical features such as high MIB-1 index (> 5%), residual disease or at recurrence. Patients with anaplastic PXA were administered adjuvant radiotherapy and systemic therapy. Median age at diagnosis was 20 years (range 4-45). At median follow-up of 33 months, 3-year and 5-year overall survival (OS) was 80.2 and 74% respectively. Patients who underwent GTR (23 cases, 62%) had significantly better 3-year PFS of 85.6% compared to 32.3% (p = 0.001) achieved with STR (13 cases, 35%). PFS was significantly superior in PXA grade II as compared to anaplastic PXA group (3 year estimates 80.2 vs. 32%; p = 0.007). 13 out of 27 patients where BRAFV600E testing was successful showed a mutation (48%). 3-year PFS and OS survival in BRAFV600E mutated patients was 51.9 and 76.9% compared to 73 and 75% in BRAFV600E non-mutated patients, respectively. No patient had IDH1 mutation. This data may provide valuable insights and act as a benchmark for future studies. PMID- 29147865 TI - Changes of gut microbiota structure and morphology in weaned piglets treated with fresh fermented soybean meal. AB - This study investigated the effects of dietary fresh fermented soybean meal (FSM) on the intestinal microbiota and metabolites, bacterial enzyme activity and intestinal morphology of weaning piglets. A total of 64 weaned piglets were randomly allocated into two treatments. A corn-soybean-based diet was used as the control and other treatment was fed the same basal diet containing 15% fresh FSM. The feeding trial lasted for 21 days. Bacterial community structure and diversity in the cecum and colon were assessed using pyrosequencing-based analysis. The results showed that the phylum level, Firmicutes, Bacteroidetes, Proteobacteria and Tenericutes were dominant in the cecum or colon. Gut Firmicutes increased, while Bacteroidetes and Proteobacteria decreased in the fresh FSM-fed piglets. At the genus level, the relative abundances of butyrate-producing bacteria, Lactobacillus and Prevotella were higher in both cecum and colon of fresh FSM fed piglets. Meanwhile, fresh FSM could promote the development of intestinal morphological and reduce the incidence of diarrhea. The results indicated that fresh FSM might change intestinal function by influencing intestinal microenvironment. PMID- 29147866 TI - A Review of Onychomycosis Due to Aspergillus Species. AB - Aspergillus spp. are emerging causative agents of non-dermatophyte mould onychomycosis (NDMO). New Aspergillus spp. have recently been described to cause nail infections. The following criteria are required to diagnose onychomycosis due to Aspergillus spp.: (1) positive direct microscopy and (2) repeated culture or molecular detection of Aspergillus spp., provided no dermatophyte was isolated. A review of 42 epidemiological studies showed that onychomycosis due to Aspergillus spp. varies between < 1 and 35% of all cases of onychomycosis in the general population and higher among diabetic populations accounting for up to 71% and the elderly; it is very uncommon among children and adolescence. Aspergillus spp. constitutes 7.7-100% of the proportion of NDMO. The toenails are involved 25 times more frequently than fingernails. A. flavus, A. terreus and A. niger are the most common aetiologic species; other rare and emerging species described include A. tubingensis, A. sydowii, A. alliaceus, A. candidus, A. versicolor, A. unguis, A. persii, A. sclerotiorum, A. uvarum, A. melleus, A. tamarii and A. nomius. The clinical presentation of onychomycosis due to Aspergillus spp. is non specific but commonly distal-lateral pattern of onychomycosis. A negative culture with a positive KOH may point to a NDM including Aspergillus spp., as the causative agent of onychomycosis. Treatment consists of systemic therapy with terbinafine or itraconazole. PMID- 29147868 TI - Hydrogen peroxide (H2O2): a review of its use in surgery. AB - Hydrogen peroxide has been used in medicine for more than 100 years. It is known in surgery as a highly useful irrigation solution by virtue of both its hemostatic and its antimicrobial effects. Due to its possible negative effect on wound healing and its cytotoxic effect in higher concentrations, there are concerns about the safety of its use. The objective of this paper is to review the safety and beneficial effects of hydrogen peroxide. PMID- 29147869 TI - Hematological adverse effects in breast cancer patients treated with cyclin dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis. AB - BACKGROUND: The introduction of specific cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly improved progression-free survival in hormone receptor positive metastatic breast cancer. CDK 4/6 inhibitors induce cell cycle arrest via liberating the tumor suppressor retinoblastoma protein from CDK4/6 inhibitory effect. Preliminary studies suggested an increase in the hematological toxicities which might affect the quality of life in such palliative setting. METHODS: We searched PubMed, ASCO, ESMO and San Antonio meeting databases for randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors with safety data provided on the incidence of hematological adverse effects. RESULTS: Our search identified 1012 citations that were screened for relevance. Thirty-six studies were found to be potentially eligible. After excluding the ineligible studies, six studies were deemed to be eligible for meta-analysis. The risk ratio (RR) was 11.31 [95% confidence interval (CI) 8.06-15.87; p < 0.0001] for all grade leucopenia, 14.86 (95% CI 11.37-19.41; p < 0.0001) for all-grade neutropenia, 9.04 (95% CI 3.78-21.63; p < 0.0001) for all-grade thrombocytopenia and 3.57 (95% CI 2.65-4.81; p < 0.0001) for all-grade anemia. The RR for grade 3/4 leucopenia was 33.86 (95% CI 14.59-78.57; p < 0.0001), for grade 3/4 neutropenia was 44.00 (95% CI 24.72-78.33; p < 0.0001), for grade 3/4 thrombocytopenia was 5.70 (95% CI 2.03-16.01; p = 0.001) and for grade 3/4 anemia was 2.80 (95% CI 1.45-5.41; p = 0.002). There was no significant increase in the RR of febrile neutropenia with RR of 3.29 (95% CI 0.93-11.57; p = 0.06). CONCLUSION: Our analysis provides evidence that the use of CDK 4/6 inhibitors is associated with an increased risk of all-grade and high-grade hematological adverse events, which seems to be a class-effect, but not of febrile neutropenia compared with hormonal therapy alone. PMID- 29147870 TI - Changes in body composition and muscle attenuation during taxane-based chemotherapy in patients with metastatic breast cancer. AB - PURPOSE: Body composition parameters including low muscle mass, muscle attenuation (which reflects muscle quality) and adipose tissue measurements have emerged as prognostic factors in cancer patients. However, knowledge regarding the possibility of excessive muscle loss during specific systemic therapies is unknown. We describe the changes in body composition and muscle attenuation (MA) during taxane- and anthracycline-based regimens and its association with overall survival (OS) in metastatic breast cancer patients. METHODS: The lumbar skeletal muscle index (LSMI) was used as marker of muscle mass. LSMI, MA, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and intramuscular adipose tissue (IMAT) were measured before and after first-line treatment with paclitaxel (n = 73) or 5-fluorouracil-doxorubicin-cyclophosphamide (FAC) (n = 25) using CT images. Determinants of the change of LSMI and MA were analyzed using multiple linear regression. OS was assessed using Cox proportional hazard models. RESULTS: MA significantly decreased during paclitaxel treatment (- 0.9 HU, p = 0.03). LSMI (p = 0.40), SAT (p = 0.75), VAT (p = 0.84) and IMAT (p = 0.10) remained stable. No significant alterations in body composition parameters during FAC-treatment were observed. Previous (neo-)adjuvant chemotherapy contributed to larger loss of MA during the current treatment. Body composition changes during chemotherapy were not associated with OS. CONCLUSIONS: MA decreased during treatment with paclitaxel, while muscle mass was stable. Body composition changes are not associated with survival in the absence of progressive disease. PMID- 29147867 TI - Population Structure of Candida parapsilosis: No Genetic Difference Between French and Uruguayan Isolates Using Microsatellite Length Polymorphism. AB - Candida parapsilosis is a human commensal yeast, frequently involved in infection worldwide and especially in neonates. It is the second species responsible for bloodstream infections in Uruguay and the third species in France. We were interested in knowing whether the population structure of isolates responsible for candidemia in France and in Uruguay was different. Genotyping methods based on microsatellite length polymorphism (MLP) have been described and are especially used for investigation of local outbreaks. We therefore determined the genotypes of 159 C. parapsilosis isolates recovered from 122 patients (84 French patients from 43 hospitals and 38 Uruguayan patients from 10 hospitals) using three microsatellites markers previously described. Our results confirmed that C. parapsilosis population has a high genetic diversity, clonal inheritance and that majority of patients were infected by a single isolate. But we described recurrent infections due to related or unrelated genotypes resulting from isolates harboring loss or gain of heterozygosity. We also described three cases of coinfections due to unrelated genotypes. We did not uncover geographic specificity but observed two linked genotypes that seem to be associated with voriconazole resistance. Finally, among eight isolates involved in grouped cases, the genotypes were similar in six cases supporting the hypothesis of inter patient transmission. These results confirmed the usefulness of performing MLP genotyping analysis for grouped cases of C. parapsilosis isolates in order to reinforce preventive hygiene measures. PMID- 29147871 TI - An Optimized and Feasible Preparation Technique for the Industrial Production of Hydrogel Patches. AB - For hydrogel patches, the laboratory tests could not fully reveal the existing problems of full scale of industrial production, and there are few studies about the preparation technique for the industrial manufacturing process of hydrogel patches. So, the purpose of this work was to elucidate the effects of mainly technological operation and its parameters on the performance of hydrogel patches at the industrial-scale production. The results revealed the following: (1) the aqueous phase was obtained by polyvinylpyrrolidone (PVP) along with tartaric acid dissolved in purified water, then feeding this into a vacuum mixer as a whole in one batch, thus extended the crosslinking reaction time of hydrogel paste (matrix) and allowed the operation of coating/cutting-off to be carried out easily, and there was no permeation of backing layer; (2) the gel strength of the hydrogel patches increased with the increase of working temperature, however, once the temperature exceeded 35 +/- 2 degrees C, the hydrogel paste would lose water severely and the resultant physical crosslinking structure which has lower gel/cohesive strength would easily bring gelatinization/residues during application; (3) the relative humidity (RH) of the standing-workshop was dynamically controlled (namely at 35 +/- 2 degrees C, keeping the RH at 55 +/- 5% for 4 days, then 65 +/- 5% for 2 days), which would make patches with satisfactory characteristics such as better flexibility, higher adhesive force, smooth flat matrix surface, and without gelatinization/residues and warped edge during the using process; (4) the aging of the packaged hydrogel patches was very sensitive to storage temperature, higher temperature, higher gel strength and lower adhesiveness. The storage temperature of 10 +/- 2 degrees C could effectively prevent matrix aging and adhesion losing, which would also facilitate the expiration date of patches extended obviously. In conclusion, this work provides an optimized and feasible preparation technique for the industrial production of the hydrogel patches and establishes the hydrogel patches as a novel carrier for transdermal drug delivery. PMID- 29147872 TI - Fluidized Bed Hot-Melt Granulation as a Tool to Improve Curcuminoid Solubility. AB - Curcumin is the main bioactive component of Curcuma longa L. and has recently aroused growing interest from the scientific community. Unfortunately, the medicinal properties attributed to curcuminoids are impaired by their low oral bioavailability or low solubility in aqueous solutions. Many strategies have been studied to improve curcumin solubility; however, the preparation of granules using hydrophilic materials has never been attempted. The aim of this work was to develop curcumin granules by fluidized bed hot-melt granulation using the hydrophilic carrier Gelucire(r) 50:13. A two-level factorial design was used to verify the influence of Gelucire(r) 50:13 and lactose contents found in the granules on their size, morphology, bulk and tapped densities, flow, moisture content, and water activity. The granules obtained were also evaluated by differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction, and infrared spectrometry. The curcumin solubility and dissolution rates in water were determined by liquid chromatography. The best formulation provides an increase of curcumin solubility of 4642-fold and 3.8-fold compared to the physical mixture. The dissolution tests showed a maximum drug release from granules after 45 min of 70% at pH 1.2 and 80% at pH 5.8 and 7.4, while for non granulated curcumin, the release was below 20% in all pH. The solid-state characterization and solubility measurement showed good stability of granules over 9 months. The results attest that the fluidized bed hot-melt granulation with hydrophilic binders is an attractive and promising alternative to obtain solid forms of curcumin with enhanced bioavailability. PMID- 29147873 TI - Comparison of the adjuvanticity of two adjuvant formulations containing de-O acylated lipooligosaccharide on Japanese encephalitis vaccine in mice. AB - Adjuvants are essential vaccine components used to enhance, accelerate, and/or prolong adaptive immunity against specific vaccine antigens. In this study, we compared the adjuvanticity of two adjuvant formulations containing de-O-acylated lipooligosaccharide (dLOS), a toll-like receptor 4 agonist, on the Japanese encephalitis (JE) vaccine in mice. Mice were immunized once or twice at a two week interval with inactivated JE vaccine in the absence or presence of adjuvant. We found that both the alum- and the liposome-based formulation induced significantly faster and higher serum IgG antibody responses as compared with the non-adjuvanted vaccine after either one or two immunizations. The antibody titers of the mouse immune sera correlated with 50% plaque reduction neutralization test (PRNT50) antibody titers. In addition, the dLOS/liposome formulation was more effective in inducing a Th1-type immune response than the dLOS/alum formulation, as suggested by a strong antigen-specific interferon (IFN)-gamma response. Based on these results, we suggest that both alum- and liposome-based adjuvant formulations containing dLOS may be used for the development of JE vaccines with improved immunogenicity. PMID- 29147874 TI - Obituary Bernhard Brenner. PMID- 29147875 TI - Evaluation of NfsA-like nitroreductases from Neisseria meningitidis and Bartonella henselae for enzyme-prodrug therapy, targeted cellular ablation, and dinitrotoluene bioremediation. AB - OBJECTIVES: To characterize the activities of two candidate nitroreductases, Neisseria meningitidis NfsA (NfsA_Nm) and Bartonella henselae (PnbA_Bh), with the nitro-prodrugs, CB1954 and metronidazole, and the environmental pollutants 2,4- and 2,6-dinitrotoluene. RESULTS: NfsA_Nm and PnbA_Bh were evaluated in Escherichia coli over-expression assays and as His6-tagged proteins in vitro. With the anti-cancer prodrug CB1954, both enzymes were more effective than the canonical O2-insensitive nitroreductase E. coli NfsB (NfsB_Ec), NfsA_Nm exhibiting comparable levels of activity to the leading nitroreductase candidate E. coli NfsA (NfsA_Ec). NfsA_Nm is also the first NfsA-family nitroreductase shown to produce a substantial proportion of 4-hydroxylamine end-product. NfsA_Nm and PnbA_Bh were again more efficient than NfsB_Ec at aerobic activation of metronidazole to a cytotoxic form, with NfsA_Nm appearing a promising candidate for improving zebrafish-targeted cell ablation models. NfsA_Nm was also more active than either NfsA_Ec or NfsB_Ec with 2,4- or 2,6-dinitrotoluene substrates, whereas PnbA_Bh was relatively inefficient with either substrate. CONCLUSIONS: NfsA_Nm is a promising new nitroreductase candidate for several diverse biotechnological applications. PMID- 29147876 TI - Objective Differences in Colonoscopy Technique Between Trainee and Expert Endoscopists Using the Colonoscopy Force Monitor. AB - BACKGROUND: Learning to perform colonoscopy safely and effectively is central to gastroenterology fellowship programs. The application of force to the colonoscope is an important part of colonoscopy technique. AIMS: We compared force application during colonoscopy between novice and expert endoscopists using a novel device to determine differences in colonoscopy technique. METHODS: This is an observational cohort study designed to compare force application during colonoscopy between novice and experienced trainees, made up of gastroenterology fellows from two training programs, and expert endoscopists from both academic and private practice settings. RESULTS: Force recordings were obtained for 257 colonoscopies by 37 endoscopists, 21 of whom were trainees. Experts used higher average forward forces during insertion compared to all trainees and significantly less clockwise torque compared to novice trainees. CONCLUSIONS: We present significant, objective differences in colonoscopy technique between novice trainees, experienced trainees, and expert endoscopists. These findings suggest that the colonoscopy force monitor is an objective tool for measuring proficiency in colonoscopy. Furthermore, the device may be used as a teaching tool in training and continued medical education programs. PMID- 29147877 TI - Efficacy and Safety of Fully Covered Self-Expanding Metal Stents for Malignant Esophageal Obstruction. AB - BACKGROUND: Malignant dysphagia can result in poor nutritional status with severe weight loss. Rapid relief from dysphagia can be achieved with esophageal self expanding metal stents (SEMSs), a minimally invasive method. In this study, we evaluated the usefulness of SEMSs for malignant dysphagia. METHODS: Between 2012 and 2015, 119 patients with malignant dysphagia underwent esophageal SEMS insertion with endoscopic assistance. Their demographics and clinical outcomes were collected. Factors associated with stent-related complications and patient survival were evaluated. All data were retrospectively analyzed. RESULTS: The mean age of the 119 patients was 64.9 +/- 11.6 years, and 25 (21%) were female. Seventy-five patients (63.0%) had squamous carcinoma, majority of which were located in the lower thoracic esophagus (n = 42), followed by middle thoracic esophagus (n = 19) and upper esophagus (n = 10). Eighty patients (67.2%) underwent SEMS insertion at diagnosis. Technical and clinical success rates were 99.2 and 89.9%, respectively. Complications occurred in 47 patients (39.5%); the most common complication was migration (36.3%), followed by pain and obstruction. The median stent patency time was 145 days (95% confidence interval 55.19-234.81 days). Gastric cancer (odds ratio 3.51, 95% confidence interval 1.21-10.15; p = 0.021) and a 20-mm-wide stent (odds ratio 2.922, 95% confidence interval 1.237 6.904; p = 0.015) were risk factors for complications. CONCLUSIONS: SEMSs are effective in palliation of malignant dysphagia. However, stent-related complications should be borne in mind, particularly in patients with gastric cancer with esophageal invasion and with larger width stents. PMID- 29147878 TI - Knowledge Gaps in the Management of Postoperative Crohn's Disease: A US National Survey. AB - BACKGROUND: Postoperative recurrence (POR) of Crohn's disease (CD) is common. Guidelines on POR management have recently been issued, but clinical practice may vary. AIMS: To examine the current clinical practice of POR management in the USA METHODS: A web-based survey was sent to all members of the American Gastroenterological Association and the American College of Gastroenterology. The survey consisted of multiple-choice questions with clinical scenarios to assess how participants manage POR. RESULTS: A total of 189 responses were received from practices in 34 states. 44% of participants were from academic settings. The median number of CD patients seen each month was 20-30 patients per participant. The majority of participants considered smoking, prior intestinal surgery, penetrating disease, perianal fistula, early disease onset, and long extent of disease as high-risk factors for POR. To diagnose and grade endoscopic recurrence, 57% of participants used an endoscopic scoring system; 86% defined clinical recurrence using a combination of symptoms and endoscopic findings; and 79% of participants routinely performed colonoscopy after surgery. In high-risk patients, 65% offered medical prophylaxis-most often biologics and/or immunomodulators-immediately after surgery, while 34% offered medical prophylaxis regardless of the patient's risk of POR. 64% of participants never stopped medical prophylaxis once initiated. CONCLUSIONS: Most gastroenterologists routinely perform colonoscopy to guide POR management. The majority of these providers continue medical prophylaxis indefinitely regardless of subsequent endoscopic findings. Further research is needed to determine the risks and benefits of continuing versus deescalating therapy in patients with potentially surgically induced remission. PMID- 29147879 TI - Increased Risk for Colon Polyps in Patients with Reflux Disease. AB - BACKGROUND: Previous studies have found an increased risk for colonic neoplasm in patients with Barrett's esophagus. It is unknown whether such risk applies similarly to other types of gastroesophageal reflux disease (GERD). AIMS: To test whether GERD represents a risk factor for the occurrence of colon polyps. METHODS: The Miraca Life Sciences Database is a large national electronic repository of histopathologic records of patients distributed throughout the entire USA. A case-control study evaluated whether presence of (1) Barrett's metaplasia, (2) erosive esophagitis on endoscopy or histologic signs of reflux esophagitis, (3) clinical diagnosis of GERD, (4) any type of GERD affected the occurrence hyperplastic polyps (HP), sessile serrated adenomas/polyps (SSA/P), or tubular adenomas (TA) among 228,506 subjects undergoing bidirectional endoscopy. Multivariate logistic regression analyses were used to calculate odds ratios and their 95% confidence intervals for the risk of HP, TA or SSA/P associated with various types of GERD and adjusted for age, sex, and presence of H. pylori. RESULTS: The analysis revealed positive associations between GERD and all types of colon polyps. These associations applied similarly to HP (1.47, 1.44-1.50), TA (1.30, 1.27-1.32), and SSA/P (1.52, 1.46-1.58). They also applied to different forms of GERD, showing a trend toward stronger associations, that is higher odds ratios, with Barrett's metaplasia or erosive esophagitis than clinical diagnosis of GERD. CONCLUSION: All types of GERD represent a risk factor for the occurrence of different colon polyps, such as HP, TA, or SSA/P. PMID- 29147880 TI - Targeted Physician Education and Standardizing Documentation Improves Documented Reporting with Inflammatory Bowel Disease Quality Measures in a Large Academic and Private Practice. AB - BACKGROUND: Prior studies have shown poor compliance with quality measures for IBD at academic and private practices. We sought to provide focused interventions to improve compliance and documentation with the IBD measures. METHODS: Two centers, academic practice (AP) and private practice (PP), initially reviewed their compliance with eight established IBD quality measures in consecutive charts. A multi-faceted intervention was developed to improve awareness and documentation of these measures. The initial data and the quality measures were reviewed at a group meeting. Following this, a handout summarizing the measures was placed in each exam room. The AP added a new screen to the EHR that summarized the relevant IBD history, while the PP added a new template that was filled out and imported into the charts. Three months after this intervention, charts were reviewed for compliance with the measures. RESULTS: The intervention cohort consisted of 768 patients (AP = 569/PP = 199) compared to the initial cohort of 566 patients (AP = 367/PP = 199). Improvement was seen throughout all measures compared to the initial cohort. The AP reported compliance with all relevant measures in 21% and the PP in 60% compared to 7 and 10% in the initial cohort. PP had >= 75% compliance with every measure, of which only assessment for bone loss and pneumococcal vaccination was under 80%. In contrast, the AP compliance ranged from 35 to 100% with assessment for bone loss, influenza, and pneumococcal vaccination scoring lowest. CONCLUSION: Our study demonstrates that focused low-cost interventions can significantly improve compliance with IBD quality measures in different practice settings. PMID- 29147881 TI - Childhood Cancer and Brain Tumor Late Effects: Relationships with Family Burden and Survivor Psychological Outcomes. AB - This study examines illness-specific family burden as a mediator of the association between late effects of childhood cancer and survivors' emotional and behavioral outcomes. Childhood cancer survivors (n = 65; ages 10-17) two or more years off-treatment completed measures assessing internalizing and PTSD symptoms. Parents reported on illness-specific family burden, late effects severity, and survivor internalizing/externalizing problems. Providers documented the number of late effects. Illness-specific family burden was correlated with provider reported late effects (r = .29, p < .05) and parent report of severe late effects (r = .56, p < .01). Results supported an indirect effect of illness-specific family burden on number of late effects and parent-reported survivor internalizing problems, p < .05. Indirect effects were not found in models predicting PTSD and externalizing problems. Illness-specific family burden is an important intervention target for reducing internalizing problems in childhood cancer survivors with late effects. PMID- 29147882 TI - Growth-inhibition patterns and transfer-factor profiles in arsenic-stressed rice (Oryza sativa L.). AB - Arsenic (As) accumulation in rice owing to uptake from the soil is a critical human health issue. Here, we studied the chemical properties of As-treated soils, growth inhibition patterns of As-stressed rice plants, changes in the As content of soil and soil solutions, and the relationship between As accumulation and As transfer factor from the soil to the rice organs. Rice plants were cultivated in a greenhouse under four concentrations of As: 0 (control), 25, 50, and 75 mg kg 1. A significant positive correlation was found between available P2O5 and exchangeable K and between As concentration and available P2O5 or exchangeable K. The As concentration for 50% shoot growth inhibition was 50 mg kg-1. As levels in roots and shoots were positively correlated with the growth stages of rice. The transfer factor (TF)root/soil increased with As concentration at the tillering stage but decreased at the heading stage. TFroot/soil and TFshoot/soil were higher at the heading stage than at the tillering stage. As accumulation in the 25 mg kg-1 treatment was higher during the heading stage, whereas no difference was found at the tillering stage. As accumulation was related to plant biomass and soil As concentration. We found that As accumulation was greater at As concentrations that allowed for plant growth and development. Thus, species specific threshold concentrations must be determined based on As phytotoxicity for the phytoremediation of As-contaminated soils. Hence, developing practical approaches for managing safe crop production in farmlands with an As contamination of 25 mg kg-1 or less is necessary. PMID- 29147883 TI - Clinical and radiological diagnosis of gallstone ileus: a mini review. AB - Gallstone ileus is a rare cause of bowel obstruction, which mainly affects the elderly population. The associated mortality is estimated to be up to 30%. The presentation of gallstone ileus is notoriously non-specific, and this often contributes to the delay in diagnosis. The diagnosis of gallstone ileus relies on a radiological approach, and herein we discuss the benefits and drawbacks of the use of different modalities of radiological imaging: plain abdominal films, computed tomography, magnetic resonance imaging, and ultrasound scanning. Based on our case experience and review of the literature, the authors conclude that although an effective first-line tool, plain abdominal films are not adequate for diagnosing gallstone ileus. In fact, the gold standard in an acutely unwell patient is computed tomography. PMID- 29147884 TI - Ocular flutter following Zika virus infection. AB - Zika virus (ZIKV) is an emerging flavivirus which has been linked to a number of neurologic manifestations such as Guillain-Barre syndrome (GBS), transverse myelitis, and meningo-encephalitis. Ophthalmologic manifestations are increasingly being reported; however, ocular dyskinesias have not been described in this context to date. Herein, we report a case of a 22-year-old female who presented with ocular flutter and associated Guillain-Barre syndrome following acute ZIKV infection. We speculate that although such symptoms may have originated from a direct viral insult, a post-infectious autoimmune mechanism may not be excluded. Physicians should include ZIKV as well as other flaviviruses in their diagnostic workup for all patients with ocular flutter/opsoclonus, after excluding other non-infectious causes of central nervous system pathology. To the best of our knowledge, this is the first report on the association of ocular flutter, GBS, and ZIKV infection. PMID- 29147885 TI - Proceedings of the 2017 ISEV symposium on "HIV, NeuroHIV, drug abuse, & EVs". AB - Despite the success of combination antiretroviral therapy (cART), there is increased prevalence of HIV-associated neurocognitive disorders (HAND) in HIV-1 infected individuals on cART, which poses a major health care challenge. Adding further complexity to this long-term antiretroviral use is the comorbidity with drugs of abuse such as morphine, cocaine, and methamphetamine, which can in turn, exacerbate neurologic and cognitive deficits associated with HAND. Furthermore, HIV proteins, such as the transactivator of transcription (Tat) and the envelope protein (gp120), as well as antiretrovirals themselves can also contribute to the progression of neurodegeneration underlying HAND. In the field of NeuroHIV and drug addiction, EVs hold the potential to serve as biomarkers of cognitive dysfunction, targets of therapy, and as vehicles for therapeutic delivery of agents that can ameliorate disease pathogenesis. Based on the success of a previous Satellite Symposium in 2015 at the ISEV meeting in Washington, experts again expanded on their latest research findings in the field, shedding light on the emerging trends in the field of Extracellular Vesicle (EV) biology in NeuroHIV and drug abuse. The satellite symposium sought to align experts in the fields of NeuroHIV and drug abuse to share their latest insights on the role of EVs in regulating neuroinflammation, neurodegeneration, peripheral immune response, and HIV latency in HIV-infected individuals with or without the comorbidity of drug abuse. PMID- 29147886 TI - Peromyscus leucopus mouse brain transcriptome response to Powassan virus infection. AB - Powassan virus (POWV) is a tick-borne Flavivirus responsible for life-threatening encephalitis in North America and some regions of Russia. The ticks that have been reported to transmit the virus belong to the Ixodes species, and they feed on small-to-medium-sized mammals, such as Peromyscus leucopus mice, skunks, and woodchucks. We previously developed a P. leucopus mouse model of POWV infection, and the model is characterized by a lack of clinical signs of disease following intraperitoneal or intracranial inoculation. However, intracranial inoculation results in mild subclinical encephalitis from 5 days post infection (dpi), but the encephalitis resolves by 28 dpi. We used RNA sequencing to profile the P. leucopus mouse brain transcriptome at different time points after intracranial challenge with POWV. At 24 h post infection, 42 genes were significantly differentially expressed and the number peaked to 232 at 7 dpi before declining to 31 at 28 dpi. Using Ingenuity Pathway Analysis, we determined that the genes that were significantly expressed from 1 to 15 dpi were mainly associated with interferon signaling. As a result, many interferon-stimulated genes (ISGs) were upregulated. Some of the ISGs include an array of TRIMs (genes encoding tripartite motif proteins). These results will be useful for the identification of POWV restriction factors. PMID- 29147887 TI - A preliminary prediction model for potentially guiding patient choices between breast conserving surgery and mastectomy in early breast cancer patients; a Dutch experience. AB - PURPOSE: To guide early stage breast cancer patients to choose between breast conserving surgery (BCS) and mastectomy (MST) considering the predicted cosmetic result and quality of life (QoL). METHODS: A decision model was built to compare QoL after BCS and MST. Treatment could result in BCS with good cosmesis, BCS with poor cosmesis, MST only, and MST with breast reconstruction. QoL for these treatment outcomes were obtained from a previous study and the literature and translated into EuroQoL-5D derived utilities. Chance of good cosmesis after BCS was predicted based on tumor location and tumor/breast volume ratio. The decision model determined whether the expected QoL was superior after BCS or MST based on chance of good cosmesis. RESULTS: The mean utility for the treatments such as BCS with good cosmesis, BCS with poor cosmesis, MST only, and MST with breast reconstruction were 0.908, 0.843, 0.859, and 0.876, respectively. BCS resulted in superior QoL compared to MST in patients with a chance of good cosmesis above 36%. This 36% threshold is reached in case the tumor is located in the upper lateral, lower lateral, upper medial, lower medial, and central quadrant of the breast with a tumor/breast volume ratio below 21.6, 4.1, 15.1, 3.2, and 14.7, respectively. CONCLUSIONS: BCS results in superior QoL in patients with tumors in the upper breast quadrants or centrally and a tumor/breast volume ratio below 15. MST results in superior QoL in patients with tumors in the lower breast quadrants and a tumor/breast volume ratio above 4. PMID- 29147888 TI - A study of parental presence/absence technique for child dental behaviour management. AB - AIM: To examine the effectiveness of parental presence/absence (PPA) technique on the dental behaviour management of children. MATERIALS AND METHODS: This randomised control study recruited 61 child dental patients with uncooperative behaviour (Frankl 1 or 2) managed with AAPD-endorsed non-pharmacological techniques at a post-graduate university clinic. PPA was only used in the test group (31 children). Using a mini video-tape device, recording commenced at the onset of uncooperative behaviour and this was later rated, minute by minute, by a blinded experienced paediatric dentist. STATISTICAL ANALYSIS: Data were analysed with SPSS v.13.0. The Kolmogorov-Smirnov test was used for normality analysis. The Mann-Whitney U-test and Log Rank analysis were also performed. RESULTS: The mean point in time, after behavioural problems commenced that PPA or alternatives were applied was 1.82 +/- 1.04 min. Behaviour improvement (technique success) was shown by 65.6% of all children. There was no statistically significant difference between the study and control groups in age, gender, mean Frankl score, in Frankl score 2 min before/after technique application or regarding the time point at which the technique was first applied. Behaviour improvement was seen in 17 patients (54.8%) in the PPA group and in 23 patients (76.7%) in the control group. CONCLUSION: PPA applied to various dental sessions as a behaviour management technique showed no advantage over other basic, non-pharmacological techniques. PMID- 29147889 TI - Association of IL-10 Gene Polymorphism (-819C > T, -592C > A and -1082G > A) with Preterm Birth. AB - OBJECTIVE: To analyze the association of IL-10 gene and its polymorphisms with preterm birth (PTB). METHODS: Five hundred and fifty nine women with term birth and 559 with preterm birth were recruited from Lucknow, India. Genetic association analysis was conducted between cases and controls. Subjects recruited as cases were women (aged between 18-40 y) with singleton delivery before 37 wk of gestation and controls were with delivery after or on 37 wk. The genotyping was performed for rs1800871, rs1800872 and rs1800896 for assessing the allelic distribution, haplotypic association and linkage disequilibrium analysis. IL 10mRNA levels were evaluated by real time quantitative polymerase chain reaction (PCR) method. RESULTS: The risk of PTB was found significant in women carrying IL 10 (-1082) GA genotype [OR=1.72(1.7-2.5), p=0.006]. The haplotypic analysis of studied polymorphisms for rs1800871, rs1800872 and rs1800896 depicted the association of ATA (p=0.02) and ATC (p=0.01) haplotypes with PTB. The IL-10 mRNA levels were significantly lower in cases (p=0.05). CONCLUSIONS: IL-10 marks a protective impact in the inflammatory pathway of PTB. PMID- 29147890 TI - Food Allergy in Children: An Overview. AB - The estimated prevalence of food allergy amongst children in the west is around 6 8% but there is paucity of data in the Indian population. There is a complex interplay of environmental influences and genetic factors in the immuno pathogenesis and manifestations of food allergy. A reliable thorough clinical history, combined with positive skin prick tests or food-specific IgE, is essential for a more precise diagnosis of food allergy. Currently there is no cure for food allergy. The management of food allergy usually includes strict avoidance, patient education and provision of emergency medication (adrenaline autoinjectors). Emerging therapies based on evolving research are focused on a more active approach to management which includes early introduction of potentially allergenic foods, anticipatory testing and desensitisation to food allergens. Lack of food labelling policy and non availability of adrenaline auto injectors is a huge limiting factor for effective management of food allergy among children in India. The present review focuses on IgE mediated food allergy. PMID- 29147891 TI - Long-term presence of angiotensin II type 1 receptor autoantibody reduces aldosterone production by triggering Ca2+ overload in H295R cells. AB - Preeclamptic women are reported to have inadequate plasma volume expansion coupled with a suppressed secretion of aldosterone; however, the specific mechanism of preeclampsia remains unclear. We demonstrated that the presence of long-term angiotensin II type 1 receptor autoantibody (AT1-AA) reduces aldosterone production by triggering a Ca2+ overload in H295R cells. AT1-AA was discovered in preeclamptic women and reported to activate AT1R, and consequently elevate intracellular Ca2+. We found that AT1-AA significantly prolonged the time of intracellular Ca2+ elevation. Besides promoting aldosterone production as a second messenger, Ca2+ overload shows a cytotoxic effect. Our data reveals that long-term presence of AT1-AA triggered a Ca2+ overload and consequent impairment of aldosterone production, which could be prevented by a PKC inhibitor, Go 6983, or a calcium channel inhibitor, nifedipine. These findings have clinical significance because AT1R blockers are not recommended for treatment of preeclampsia due to their potential harm to the fetus. Our findings also emphasize a potential clinical benefit of immunoadsorption or neutralization of AT1-AA in preeclamptic women. PMID- 29147892 TI - Reply, Letter to the Editor. PMID- 29147893 TI - High Elective Surgery Cancellation Rate in Malawi Primarily Due to Infrastructural Limitations. AB - BACKGROUND: The provision of safe and timely surgical care is essential to global health care. Low- and middle-income countries have a disproportionate share of the global surgical disease burden and struggle to provide care with the given resources. Surgery cancellation worldwide occurs for many reasons, which are likely to differ between high-income and low-income settings. We sought to evaluate the proportion of elective surgery that is cancelled and the associated reasons for cancellation at a tertiary hospital in Malawi. METHODS: This was a retrospective review of a database maintained by the Department of Anesthesiology at Kamuzu Central Hospital in Lilongwe, Malawi. Data were available from August 2011 to January 2015 and included weekday records for the number of scheduled surgeries, the number of cancelled surgeries, and the reasons for cancellation. Descriptive statistics were performed. RESULTS: Of 10,730 scheduled surgeries, 4740 (44.2%) were cancelled. The most common reason for cancellation was infrastructural limitations (84.8%), including equipment shortages (50.9%) and time constraints (33.3%). Provider limitations accounted for 16.5% of cancellations, most often due to shortages of anaesthesia providers. Preoperative medical conditions contributed to 26.3% of cancellations. CONCLUSION: This study demonstrates a high case cancellation rate at a tertiary hospital in Malawi, attributable primarily to infrastructural limitations. These data provide evidence that investments in medical infrastructure and prevention of workforce brain drain are critical to surgical services in this region. PMID- 29147894 TI - Chest X-ray Prior to Thyroidectomy: Is It Really Needed? AB - BACKGROUND: Chest X-ray (CXR) prior to thyroid surgery continues to be routinely obtained at some institutions despite the lack of evidence for its utility. This study aimed to determine the utility of preoperative CXR in patients undergoing thyroidectomy at a single institution. METHODS: In total, 594 thyroidectomy patients were included in the study. Demographics, CXR findings, anesthesia records and pathologic data were assessed. We investigated whether difficult intubation or cancer stage correlated with the presence of CXR abnormalities. RESULTS: Of the total cohort, 83% had a preoperative CXR and 67% had cancer on surgical pathology. In total, 56% had at least one CXR abnormality, the most frequent being skeletal abnormalities (25%), followed by tracheal deviation (16%). Of 78 patients (15.8%) with tracheal deviation on CXR, only 5% had a difficult intubation. Tracheal deviation was more commonly seen in non-cancer cases compared to cancer cases (27 vs. 12%, p < 0.001). CXR impacted management in 4%. Among patients with cancer, a higher T-stage (>2) was associated with higher rate of tracheal deviation compared to T1 (17 vs. 8%, p < 0.001). While patients with non-metastatic cancer (n = 277) compared to metastatic cancer patients had a higher proportion of any abnormality on CXR (57 vs. 44%, p = 0.045), there was no significant difference for tracheal deviation, skeletal abnormalities or lung nodules. Of patients with nodules on CXR (n = 29), only 14% were found to have metastatic disease. CONCLUSION: The utility of preoperative CXR in patients undergoing thyroidectomy is very limited. In the climate of value based care, routine use of this modality may be redundant and should only be ordered if clinically indicated. PMID- 29147895 TI - Routine Virtual Ileostomy Following Restorative Proctocolectomy for Familial Adenomatous Polyposis. AB - BACKGROUND: Anastomotic leakage (AL) is the most feared complication in colorectal surgery. A diverting ileostomy is routinely used to prevent or reduce morbidity and mortality following AL. However, a diverting ileostomy cannot prevent AL. Besides, diverting ileostomy might be associated with relevant complications. Herein, we introduce the virtual ileostomy as an alternative to diverting ileostomy in patients undergoing restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for familial adenomatous polyposis (FAP). MATERIALS AND METHODS: The results of eight patients, five females and three males with a median age of 19.5 +/- 6.0 years (range 16.0-31.0 years), undergoing restorative proctocolectomy with IPAA and virtual ileostomy for FAP are presented. RESULTS: All cases were laparoscopically managed. The virtual ileostomy was released between postoperative day 7 and 9. No AL was registered. Postoperative recovery was uneventful in all cases. CONCLUSION: A diverting ileostomy was prevented via the use of virtual ileostomy in all cases. Thus, virtual ileostomy is a good alternative to diverting ileostomy in patients undergoing restorative proctocolectomy with IPAA for FAP. PMID- 29147896 TI - Genetic Diagnosis before Surgery has an Impact on Surgical Decision in BRCA Mutation Carriers with Breast Cancer. AB - BACKGROUND: The first aim of our study was to evaluate surgical decision-making by BRCA mutation carriers with breast cancer based on the timing of knowledge of their BRCA mutation status. The second aim was to evaluate breast cancer outcome following surgical treatment. METHODS: This was a retrospective study of 164 patients diagnosed with invasive breast cancer, tested for BRCA mutation, and treated with primary surgery between 2004 and 2015 at Samsung Medical Center in Seoul, Korea. We reviewed types of surgery and timing of the BRCA test result. We compared surgical decision- making of BRCA carriers with breast cancer based on the timing of knowledge of their BRCA mutation status. RESULTS: Only 15 (9.1%) patients knew their BRCA test results before their surgery, and 149 (90.9%) knew the results after surgery. In patients with unilateral cancer, there was a significant difference between groups whose BRCA mutation status known before surgery and groups whose BRCA status unknown before surgery regarding the choice of surgery (p = 0.017). No significant difference was observed across surgery types of risk of ipsilateral breast tumor recurrence (p = 0.765) and contralateral breast cancer (p = 0.69). CONCLUSION: Genetic diagnosis before surgery has an impact on surgical decision choosing unilateral mastectomy or bilateral mastectomy in BRCA mutation carriers with breast cancer. Knowledge about BRCA mutation status after initial surgery led to additional surgeries for patients with BCS. Thus, providing genetic counseling and genetic testing before surgical choice and developing treatment strategies for patients with a high risk of breast cancer are important. PMID- 29147898 TI - "Don't Mind the Gap!" Reflections on Improvement Science as a Paradigm. AB - Responding to this issue's invitation to bring new disciplinary insights to the field of improvement science, this article takes as its starting point one of the field's guiding metaphors: the imperative to "mind the gap". Drawing on insights from anthropology, history, and philosophy, the article reflects on the origins and implications of this metaphoric imperative, and suggests some ways in which it might be in tension with the means and ends of improvement. If the industrial origins of improvement science in the twentieth century inform a metaphor of gaps, chasms, and spaces of misalignment as invariably imperfect and potentially dangerous, and therefore requiring bridging or closure, other currents that feed the discipline of improvement science suggest the potential value and uses of spaces of openness and ambiguity. These currents include the science of complex adaptive systems, and certain precepts of philosophical pragmatism acknowledged to inform improvement science. Going a step further, I reflect on whether or not these two contrasting approaches within improvement science should be treated as incommensurable paradigms, and what each approach tells us about the very possibility of accommodating seemingly irreconcilable or incommensurable approaches within improvement science. PMID- 29147897 TI - Vacuum-Assisted Wound Closure with Mesh-Mediated Fascial Traction Achieves Better Outcomes than Vacuum-Assisted Wound Closure Alone: A Comparative Study. AB - BACKGROUND: Open abdomen (OA) permits the application of damage control surgery principles when abdominal trauma, sepsis, severe acute peritonitis and abdominal compartmental syndrome (ACS) occur. METHODS: Non-traumatic patients treated with OA between January 2010 and December 2015 were identified in a prospective database, and the data collected were retrospectively reviewed. Patients' records were collected from charts and the surgical and intensive care unit (ICU) registries. The Acosta "modified" technique was used to achieve fascial closure in vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM) patients. Sex, age, simplified acute physiology score II (SAPS II), abdominal compartmental syndrome (ACS), cardiovascular disease (CVD) and surgical technique performed were evaluated in a multivariate analysis for mortality and fascial closure prediction. RESULTS: Ninety-six patients with a median age of 69 (40-78) years were included in the study. Sixty-nine patients (72%) underwent VAWCM. Forty-one patients (68%) achieved primary fascia closure: two patients (5%) were treated with VAWC (37 median days) versus 39 patients (95%) who were treated with VAWCM (10 median days) (p = 0.0003). Forty-eight patients underwent OA treatment due to ACS, and 24 patients (50%) survived compared to 36 patients (75%) from the "other reasons" group (p = 0.01). The ACS group required longer mechanical ventilator support (p = 0.006), length of stay in hospital (p = 0.005) and in ICU (p = 0.04) and had higher SAPS II scores (p = 0.0002). CONCLUSIONS: The survival rate was 62%. ACS (p = 0.01), SAPS II (p = 0.004), sex (p = 0.01), pre-existing CVD (p = 0.0007) and surgical technique (VAWC vs VAWCM) (p = 0.0009) were determined to be predictors of mortality. Primary fascial closure was obtained in 68% of cases. VAWCM was found to grant higher survival and primary fascial closure rate. PMID- 29147899 TI - Introduction/Overview. AB - The DJ-1 gene is an oncogene and also causative gene for a familial form of Parkinson disease. Although exits of cancer and neurodegenerative diseases, including Parkinson disease, are completely opposite, there are some common points of view between both diseases, including growth and death signaling pathways, and oxidative stresses affect the onset and pathogenesis of both cancer and neurodegenerative diseases. DJ-1 has versatile functions and plays a role in protection against oxidative stress. Inactivation and/or excess activation of DJ 1 functions, therefore, leads to onsets of oxidative stress-related diseases such as type 2 diabetes and male infertility in addition to cancer and neurodegenerative diseases, and studies about DJ-1 will give rise to the common mechanism among these diseases. Furthermore, secreted DJ-1 levels in serum and DJ 1-binding compounds will be a diagnostic biomarker and therapeutic drug for neurodegenerative diseases, respectively. PMID- 29147900 TI - Structural Biology of the DJ-1 Superfamily. AB - The DJ-1 (also called the DJ-1/PfpI, ThiJ/PfpI, or DJ-1/ThiJ/PfpI) superfamily is a structural and functional diverse group of proteins that are present in most organisms. Many of these proteins remain poorly characterized at the biochemical level, but include some known chaperones, proteases, and various stress response proteins that remain mechanistically mysterious. This chapter outlines what is known from a structural perspective about the cellular and biochemical functions of many of these proteins from distinct clades of the superfamily in several organisms. In humans, DJ-1 appears to function primarily as a redox-responsive protein that may act as a sensor for imbalances in cellular redox state. Because mutations in human DJ-1 cause certain types of heritable Parkinson's disease, the role of oxidative posttranslational modifications and pathogenic mutations in human DJ-1 is emphasized in the latter sections of this chapter. PMID- 29147901 TI - Expression of DJ-1 in Neurodegenerative Disorders. AB - In 2003, autosomal recessive loss-of-function mutations were identified in PARK7 gene that caused early-onset Parkinson's disease (PD). The PARK7 gene encodes a conserved protein termed DJ-1. DJ-1 is a ubiquitous protein, and within the brain, it is present in the nucleus and cytoplasm of both neuronal and glial cells. DJ-1 is a multifunctional protein, and numerous studies have ascribed various roles, including antioxidative properties, chaperone function, protease activities, mitochondrial functions and regulation of transcription to the protein. The DJ-1 protein undergoes oxidation and post-translational modifications that are important for its function. Not only is DJ-1 linked to familial PD, but it is also associated with the pathogenic mechanisms of sporadic PD and other neurodegenerative disorders where oxidative stress is implicated. In this chapter we provide an overview on the expression of DJ-1 mRNA and protein in different neurodegenerative disorders and discuss some of its main functions together with DJ-1's potential for neuroprotection. PMID- 29147902 TI - Expression of DJ-1 in Cancer Cells: Its Correlation with Clinical Significance. AB - Upregulation of DJ-1 mRNA is commonly observed in various human cancers such as ductal carcinoma of the breast, non-small cell carcinoma of the lung, pancreatic duct adenocarcinoma, urinary transitional cell carcinoma, and gynecologic carcinoma. At the protein level, intensity and intracellular localization of DJ-1 expression is varied, and the DJ-1 protein regulates cancer progression, clinical aggressiveness, differentiation, cancer cell morphology, and drug sensitivity. Thus, DJ-1 plays a critical role in cancer. Although DJ-1 has an important role within cancer cells, cancer cells secrete DJ-1 outside the cells. DJ-1 may serve as a tumor marker that can be detected from an early stage in the blood, secretory fluids, ascites, or pleural effusion. PMID- 29147903 TI - Role of DJ-1 in Fertilization. AB - Neither a sperm nor an egg can develop into an individual alone. Only when the sperm and egg bind and fuse, which is known as fertilization, can they acquire the ability of developing into new individuals. DJ-1 was reported to be involved in the process of fertilization. PMID- 29147904 TI - The Multifaceted Roles of DJ-1 as an Antioxidant. AB - The DJ-1 protein was originally linked with Parkinson's disease and is now known to have antioxidant functions. The protein has three redox-sensitive cysteine residues, which are involved in its dimerisation and functional properties. A mildly oxidised form of DJ-1 is the most active form and protects cells from oxidative stress conditions. DJ-1 functions as an antioxidant through a variety of mechanisms, including a weak direct antioxidant activity by scavenging reactive oxygen species. DJ-1 also regulates a number of signalling pathways, including the inhibition of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis under oxidative stress conditions. Other proteins regulated by DJ-1 include enzymes, chaperones, the 20S proteasome and transcription factors, including Nrf2. Once activated by oxidative stress, Nrf2 upregulates antioxidant gene expression including members of the thioredoxin and glutathione pathways, which in turn mediate an antioxidant protective function. Crosstalk between DJ-1 and both the thioredoxin and glutathione systems has also been identified. Thioredoxin reduces a cysteine residue on DJ-1 to modulate its activity, while glutaredoxin1 de-glutathionylates DJ-1, preventing degradation of DJ-1 and resulting in its accumulation. DJ-1 also regulates the activity of glutamate cysteine ligase, which is the rate-limiting step for glutathione synthesis. These antioxidant functions of DJ-1 are key to its role in protecting neurons from oxidative stress and are hypothesised to protect the brain from the development of neurodegenerative diseases such as Parkinson's disease (PD) and to protect cardiac tissues from ischaemic-reperfusion injury. However, DJ-1, as an antioxidant, also protects cancer cells from undergoing oxidative stress-induced apoptosis. PMID- 29147905 TI - Transcriptional Regulation of DJ-1. AB - DJ-1 is an oncogene and also a causative gene for familial Parkinson's disease. DJ-1 has various functions, and the oxidative status of a cysteine residue at position 106 (C106) is crucial for determination of the activation level of DJ 1.DJ-1 binds to many proteins, including various transcription factors, and acts as a coactivator or corepressor for regulating their target genes without direct binding to DNA, thereby affecting various cell functions. DJ-1-regulating transcription factors and their modified proteins are the androgen receptor and its regulatory proteins, p53; polypyrimidine tract-binding protein-associated splicing factor (PSF); Keap1, an inhibitor for nuclear factor erythroid2-related factor 2 (Nrf2); sterol regulatory element-binding protein (SREBP); Ras responsive element-binding protein (RREB1); signal transducer and activator of transcription 1 (STAT1); and Nurr1. Considering oxidative stress response and dopamine synthesis, the regulation of Nrf2, p53, and PSF by DJ-1 is especially important. In addition, SREBP1 and RREB1 functions that are positively regulated by DJ-1 may participate in the onset and pathogenesis of metabolic syndrome.DJ-1 is expressed ubiquitously with high levels in the testis and brain and moderate levels in other tissues. Furthermore, DJ-1 is translocated from the cytoplasm to nucleus during the cell cycle after mitogen stimulation, suggesting that DJ-1 has a growth-related function. In this review, we describe how DJ-1 regulates cell growth/death and dopamine synthesis by targeting various transcription factors. PMID- 29147907 TI - Protein Repair from Glycation by Glyoxals by the DJ-1 Family Maillard Deglycases. AB - DJ-1 and its prokaryotic homologs, Hsp31, YhbO and YajL from Escherichia coli and PfpI from Pyrococcus furiosus, repair proteins from glycation by glyoxals (R-CO CHO), which constitute their major glycating agents. Glycation is a non-enzymatic covalent reaction discovered by Louis Camille Maillard in 1912, between reactive carbonyls (reducing sugars and glyoxals) and amino acids (cysteine, arginine and lysine), which inactivates proteins. By degrading Maillard adducts formed between carbonyls and thiols or amino groups, the DJ-1 family Maillard deglycases prevent the formation of the so-called advanced glycation end products (AGEs) that arise from Maillard adducts after dehydrations, oxidations and rearrangements. Since glycation is involved in ageing, cancer, atherosclerosis and cataracts, as well as post-diabetic, neurovegetatives and renal and autoimmune diseases, the DJ-1 deglycases are likely to play an important role in preventing these diseases. These deglycases, especially those from thermophilic organisms, may also be used to prevent the formation of dietary AGEs during food processing, sterilization and storage. They also prevent acrylamide formation in food, likely by degrading the asparagine/glyoxal Maillard adducts responsible for its formation. Since Maillard adducts are the substrates of the DJ-1 family deglycases, we propose renaming them Maillard deglycases. PMID- 29147908 TI - DJ-1 as a Biomarker of Parkinson's Disease. AB - Parkinson's disease is a progressive, age-related, neurodegenerative disorder, and oxidative stress is an important mediator in its pathogenesis. DJ-1 has been identified as a causative gene of a familial form of Parkinson's disease, PARK7, and plays a significant role in antioxidative defense, protecting cells from oxidative stress. A cysteine residue of DJ-1 at position 106 (Cys-106) is preferentially oxidized under oxidative stress. This reactive Cys-106 plays a critical role in the biological function of DJ-1, which could act as a sensor of oxidative stress by regulating antioxidative defense depending on Cys-106 oxidation. Thus, the levels of Cys-106-oxidized DJ-1 (oxDJ-1) could be a possible biomarker of oxidative stress. This chapter focuses on the properties of DJ-1 and oxDJ-1 levels as a biomarker of Parkinson's disease. In particular, the usability of these biomarkers to prevent and treat this neurodegenerative disease is discussed. Further, this section deals with the importance of identifying a biomarker of early-phase Parkinson's disease. Finally, this chapter summarizes the features of oxDJ-1 levels in the brain and blood as a biomarker candidate for early-phase Parkinson's disease based on our results using oxDJ-1-specific antibodies. PMID- 29147909 TI - The Role of the Antioxidant Protein DJ-1 in Type 2 Diabetes Mellitus. AB - Type 2 diabetes mellitus (T2DM) is a worldwide escalating health disorder resulting from insulin resistance and functional loss of insulin-producing beta cells that finally cause chronically elevated blood glucose concentrations. Here we review the role of ubiquitously expressed antioxidant protein DJ-1 in the pathogenesis of T2DM. In beta cells, DJ-1 protects against oxidative stress, endoplasmic reticulum stress, and streptozotocin- and cytokine-induced stress and preserves beta cell viability and insulin secretion. In skeletal muscle, DJ-1 controls energy metabolism and efficient fuel utilization, whereas in adipose tissue a role in adipogenesis and obesity-induced inflammation has been reported. This suggests that DJ-1 plays multiple roles in many cell types under metabolically challenging conditions as seen in obesity, insulin resistance, and T2DM. PMID- 29147906 TI - Regulation of Signal Transduction by DJ-1. AB - The ability of DJ-1 to modulate signal transduction has significant effects on how the cell regulates normal processes such as growth, senescence, apoptosis, and autophagy to adapt to changing environmental stimuli and stresses. Perturbations of DJ-1 levels or function can disrupt the equilibrium of homeostatic signaling networks and set off cascades that play a role in the pathogenesis of conditions such as cancer and Parkinson's disease.DJ-1 plays a major role in various pathways. It mediates cell survival and proliferation by activating the extracellular signal-regulated kinase (ERK1/2) pathway and the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. It attenuates cell death signaling by inhibiting apoptosis signal-regulating kinase 1 (ASK1) activation as well as by inhibiting mitogen-activated protein kinase kinase kinase 1 (MEKK1/MAP3K1) activation of downstream apoptotic cascades. It also modulates autophagy through the ERK, Akt, or the JNK/Beclin1 pathways. In addition, DJ-1 regulates the transcription of genes essential for male reproductive function, such as spermatogenesis, by relaying nuclear receptor androgen receptor (AR) signaling. In this chapter, we summarize the ways that DJ-1 regulates these pathways, focusing on how its role in signal transduction contributes to cellular homeostasis and the pathologic states that result from dysregulation. PMID- 29147910 TI - Therapeutic Activities of DJ-1 and Its Binding Compounds Against Neurodegenerative Diseases. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway. Loss-of-function mutations in the gene encoding PARK7/DJ-1 were identified in familial PD. Wild-type DJ-1 acts as an oxidative stress sensor in neural cells. Previously, we identified binding compounds of DJ-1, including UCP0045037/compound A, UCP0054278/compound B, and compound-23 (comp-23), by in silico virtual screening. These compounds prevented oxidative stress-induced dopaminergic neuronal death and restored locomotion defects in animal models of PD. In addition, these binding partners reduced infarct size in cerebral ischemia in rats. The neuroprotective effects of these compounds are lost in DJ-1 knockdown cells and DJ-1-knockout animal. These results suggest that these compounds interact with endogenous DJ-1 and then produce antioxidant and neuroprotective responses in both animal models for PD and cerebral ischemia in rats. This raises the possibility that interaction partners of DJ-1, such as UCP0045037, UCP0054278, and comp-23, may represent a novel dopaminergic neuroprotective drug for the treatment of PD. PMID- 29147911 TI - DJ-1 as a Therapeutic Target Against Cancer. AB - DJ-1 is a gene involved in various cellular processes, including transcriptional regulation, oxidative stress response, fertilization, mitochondrial regulation, inflammatory and fibrogenic niche formation, and glycation damage prevention. Although a disease-associated genetic study within the past decade has demonstrated that the mutation of DJ-1 is associated with autosomal early-onset Parkinson's disease, increasing evidence suggests that DJ-1 also plays a critical role in tumor development and progression. In this review, we provide an overview of current knowledge concerning the role and the mechanism of DJ-1 in cancer and also discuss the possibility of DJ-1 as a therapeutic target against cancer. PMID- 29147912 TI - Tracheal agenesis: optimization of computed tomography diagnosis by airway ventilation. AB - Tracheal agenesis is a rare and often lethal congenital defect that leads to airway emergency at birth. Computed tomography (CT) is the modality of choice to evaluate anomalous tracheal anatomy. The absence of spontaneous aeration of the tracheobronchial tree in children with tracheal agenesis makes CT interpretation difficult. We describe a procedure of airway management applied in two newborns with suspected tracheal agenesis. Correct airway management was performed immediately prior to CT examination by airway ventilation, with bag-valve mask alone in one case, and attached to an endotracheal tube placed into the esophagus in the other case. The images allowed for classification of tracheal agenesis. Computed tomography with appropriate airway ventilation is fundamental for the diagnosis of tracheal agenesis. PMID- 29147914 TI - Novice chimpanzees cooperate successfully in the presence of experts, but may have limited understanding of the task. AB - Despite many observations of cooperation in nature, laboratory studies often fail to find careful coordination between individuals who are solving a cooperative task. Further, individuals tested are often naive to cooperative tasks and there has been little exploration of partnerships with mixed expertise. In the current study, we examined acquisition of a cooperative pulling task in a group with both expert (N = 4) and novice (N = 11) chimpanzees (Pan troglodytes). We used five measures of competence and understanding: (1) success at the task, (2) latency to succeed, (3) efficiency, (4) uncoordinated pulling, and (5) pulling when a partner was present versus absent. We found that novices showed evidence of trial and error learning and developed competence over time, whereas the behavior of experts did not change throughout the course of the study. In addition to looking at patterns over time, we compared the performance of novices in this mixed expertise group to an earlier study of novices in a group of all-novices. Novices in the mixed-expertise group pulled the same overall amount but for shorter periods of time, leading to higher pulling rates than individuals in the all novice group. Taken together, these results suggest that learning in the presence of experts led to rapid and frequent success, although not necessarily careful coordination. PMID- 29147913 TI - Expression of TLR7, TLR9, JAK2, and STAT3 genes in peripheral blood mononuclear cells from patients with systemic sclerosis. AB - Systemic sclerosis (SSc) is a rare, chronic, multisystem autoimmune disease clinically characterized by progressive fibrosis of the skin and internal organs. The basic mechanism appears to involve endothelial cell injury, overproduction of extracellular matrix proteins, and aberrant immune activation. So far, there have been a few attempts to find genetic biomarkers for monitoring disease activity or for correlation with certain symptoms. In order to reveal reliable biomarkers, we analyzed the expression of four genes representing three important signaling pathways, TLR7, TLR9, and JAK2-STAT3. Using RT-qPCR technique, we analyzed the expression of TLR7, TLR9, JAK2, and STAT3 genes in peripheral blood mononuclear cells of 50 SSc patients and 13 healthy individuals. We detected significant upregulation of TLR7 gene expression in a group of SSc patients compared to non SSc group. Receiver operating characteristic (ROC) analysis showed that TLR7 expression efficiently discriminates SSc cases from healthy individuals. High TLR7 expression positively correlated with the late form of disease, active SSc, and the presence of digital ulcers. Decreased levels of TLR9 and JAK2 mRNA were found in the patient's cohort in comparison to non-SSc individuals, but showed no correlation with specific clinical outcomes. The expression level of the STAT3 gene did not differ between the analyzed groups. This is the first study on the expression of TLR7, TLR9, and STAT3 genes in SSc patients. Our results show that TLR7, TLR9, and JAK2 genes are potential biomarkers for SSc. The results obtained in this study could contribute to better classification, monitoring, and outcome prediction of patients with SSc based on genetics. PMID- 29147915 TI - Use of enzyme-linked immunosorbent assay to screen for aflatoxins, ochratoxin A, and deoxynivalenol in dry pet foods. AB - The objective of this study was to perform a market survey on dry pet foods using enzyme-linked immunosorbent assay (ELISA) to detect total aflatoxins (AFs), ochratoxin A (OTA), and deoxynivalenol (DON). Pet food products (n = 58) marketed for dogs, cats, birds, and rabbits were tested in duplicate with ELISA, and results above the limit of quantitation were confirmed using liquid chromatography tandem mass spectrometry (LC-MS/MS). OTA was detected in one product (rabbit food) and AFs were detected in two products (one dog treat and one bird treat). In contrast, DON was detected in the majority (74%) of products tested. Bird and rabbit products were the most affected by DON, with levels above 0.5 MUg/g in 50 and 80% of samples, respectively. One rabbit sample tested positive for both OTA and DON. Overall, the findings of this study revealed a low incidence of AFs and OTA in commercial pet food. Although DON was detected in numerous products, the levels were well below those associated with acute toxic effects. PMID- 29147916 TI - Integrative Analysis of Proteomics Data to Obtain Clinically Relevant Markers. AB - The analysis of proteomics data can be significantly challenging. Beyond the technical challenges of accurately identifying and quantifying peptides, identifying the most biologically coherent set of biomarkers can be a particularly daunting step. In this chapter, we will review a series of methods implemented in the software AltAnalyze that can be used to normalize proteomics peptide counts, identify a minimal set of the most distinguishing morbidity associated biomarkers, and connect up these results to known pathways and interacting protein and regulatory networks. Here, we will apply this workflow to two examples that highlight different benefits of an integrated analysis workflow: (1) urine proteomics samples from patients with distinct kidney transplantation morbidities and (2) sudden infant death syndrome. By the end of this chapter, the reader should be able to apply a similar workflow to their own datasets to identify biologically significant protein markers and relevant networks. PMID- 29147918 TI - Aortic arch aneurysm surgery: what is the gold standard temperature in the absence of randomized data? AB - In the absence randomized data for assessing the best and optimal temperature for managing open aortic arch surgery patients, cerebral protection method is still performed through hypothermic circulatory arrest with or without the use of adjuncts. A recent consensus has emerged setting to define the temperature levels. In an attempt, this was aimed to establish a solid ground for future trials in aortic arch surgery. This article reviews the current literature and the evidences behind using different temperature methods and their outcomes in patients undergoing open aortic arch surgery. PMID- 29147917 TI - Recommendations for perioperative management of lung cancer patients with comorbidities. AB - OBJECTIVES: To improve surgical outcomes, clinicians must provide optimal perioperative care for comorbidities identified as significant factors in risk models for patients undergoing lung cancer surgery. METHODS: We reviewed trends in perioperative care for idiopathic pulmonary fibrosis, cardiovascular diseases, and end-stage renal diseases in patients undergoing lung cancer surgery, as large clinical databases indicate that these comorbidities are significant risk factors for lung cancer surgery. Articles identified by keyword searches were included in the analysis. RESULTS: Significant predictive factors for acute exacerbation of idiopathic pulmonary fibrosis were identified. However, no effective perioperative care was identified for prevention of acute exacerbation of interstitial pneumonia. The timing of coronary revascularization and antithrombotic management for cardiovascular diseases are subjects of ongoing research, and acid-base balance is essential in the management of hemodialysis patients with end-stage renal diseases. CONCLUSIONS: To improve surgical outcomes for lung cancer patients, future studies should continue to study optimal perioperative management of comorbidities. PMID- 29147919 TI - Alterations to Swallowing Physiology as the Result of Effortful Swallowing in Healthy Seniors. AB - A significant proportion of healthy seniors report difficulty swallowing, thought to result from age-related decline in muscle bulk/function. Effortful Swallowing (ES) is used both as a compensatory maneuver to improve pharyngeal propulsion/clearance and has been proposed as an exercise to improve pharyngeal strength. This study sought to quantify the immediate kinematic, temporal, and functional changes during an ES maneuver to quantify its exercise potential to combat age-related changes in swallowing. Videofluoroscopy data were collected from 44 healthy seniors (21 male) over 65 years old (mean = 76.9, SD = 7.1). Each participant swallowed six 5 ml boluses of Varibar nectar-thick liquids: three with regular effort and three using ES. Individual swallows (n = 260) were measured on pharyngeal constriction, pharyngeal shortening, laryngeal closure duration, hyoid movement duration, UES opening duration, stage transition duration, pharyngeal transit time, pharyngeal response duration, Normalized Residue Ratio Scale (NRRS), and the Penetration-Aspiration Scale (PAS). Non parametric Wilcoxon Rank Sum for repeated measures tested the effect of ES on each outcome. Exact p-values were calculated based on permutation methods, individual p values < 0.008 was deemed to be significant. The ES maneuver significantly prolonged all temporal variables. While we found no significant differences for pharyngeal constriction, significantly less (i.e., worse) pharyngeal shortening was observed in ES condition compared with regular effort swallows. Further, significantly worse pyriform sinus residue (NRRSv) was observed in the ES condition. No differences between ES and regular effort swallows were noted for pharyngeal constriction, NRRSv or PAS. We speculate that these negative manifestations of worse kinematics (less pharyngeal shortening) and function (increase in NRRSp) may be the result of forced volitional manipulation of swallowing in the ES condition in an otherwise normal elderly swallow. PMID- 29147920 TI - Dysphagia in Multiple Sclerosis: Evaluation and Validation of the DYMUS Questionnaire. AB - OBJECTIVE: The 10-item Dysphagia in Multiple Sclerosis (DYMUS) questionnaire is a self-administered tool used to identify swallowing problems in adults with MS. The questionnaire was not validated against other existing questionnaires to assess its convergent validity. Moreover, its test-retest reliability was not measured previously. Therefore, the purpose of this study was to assess the factor analysis, internal consistency and test-retest reliability of the DYMUS, as well as its convergent validity against an established and validated questionnaire, the EAT-10. METHOD: English-speaking adults with MS in New South Wales, Australia who were seen for routine medical check-ups were invited to complete two questionnaires across two phases. One hundred participants completed phase 1, while 55 completed phase 2. Statistical analyses were performed to investigate the psychometric properties of the DYMUS questionnaire. RESULTS: Internal consistency (Cronbach's Alpha) reduced the DYMUS questionnaire from ten to five items. The shortened version of the DYMUS showed high internal consistency (alpha = 0.904). It also showed satisfactory reproducibility, and adequate correlation with the 10-item Eating Assessment Tool (EAT-10). CONCLUSION: Evaluation of the DYMUS resulted in a shortened version of the questionnaire with five questions related to dysphagia. This shortened version is considered an easy and useful tool in identifying patients with MS-related dysphagia. PMID- 29147921 TI - Correction to: Sub-anesthetic Xenon Increases Erythropoietin Levels in Humans: A Randomized Controlled Trial. AB - Page 1764, Column 2, 'Acknowledgements' section: The first sentence, which previously read. PMID- 29147922 TI - The Effect of Head-to-Head Competition on Behavioural Thermoregulation, Thermophysiological Strain and Performance During Exercise in the Heat. AB - BACKGROUND: It has been suggested that pacing is a thermoregulatory behaviour. We investigated the effect of competition on pacing, performance and thermophysiological strain during exercise in the heat and the psychological factors mediating competition effects. METHOD: Eighteen males (maximum oxygen uptake [V O 2max] 3.69 [0.44] L min-1) undertook a preliminary 20-km cool (wet bulb globe temperature [WBGT] 12 degrees C) cycling time trial (TT) and three experimental 20-km trials (balanced order): (i) cool TT (CoolSolo); (ii) hot (WBGT 26 degrees C) TT (HotSolo); (iii) hot head-to-head competition (HotH2H). During TTs, an avatar of the participant's performance was visible. During HotH2H, participants believed they were competing against another participant, but the competitor's avatar replicated their own preliminary (cool) TT. RESULTS: TTs (min:sec [SD]) slowed with increased ambient temperature [CoolSolo 35:31 (2:11) versus HotSolo 36:10 (2:26); p = 0.011]. This effect was negated by competition; performances were not different between HotH2H [35:17 (1:52)] and CoolSolo (p = 0.160) and were quicker in HotH2H versus HotSolo (p = 0.001). End exercise rectal temperature, mean body temperature and physiological strain index were (p < 0.05) higher in HotH2H than either solo condition. Despite faster performance and greater thermophysiological strain, rating of perceived exertion (RPE), thermal comfort and sensation, and perceptual strain index were not different between HotH2H and HotSolo. The difference in end-exercise rectal temperature between HotH2H and HotSolo was related to pre-exercise anticipatory heart rate response (r = 0.608, p = 0.010) and participants' propensity for deliberate risk-taking (B = 0.12, p < 0.001), whereas self-reported resilience predicted change in performance times between HotH2H versus HotSolo (B = - 9.40, p = 0.010). CONCLUSION: Competition changes the relationship between perceived and actual thermophysiological state, altering behavioural thermoregulation and increasing thermophysiological strain; this could increase heat-illness risk. Psychophysiological and psychological measures may identify susceptible individuals. PMID- 29147924 TI - Monoclonal gammopathy of renal significance presenting as monotypic plasma cell interstitial nephritis in two patients with Sjogren's syndrome. PMID- 29147923 TI - Anti-aminoacyl-tRNA synthetase-related myositis and dermatomyositis: clues for differential diagnosis on muscle biopsy. AB - Anti-synthetase syndrome is an autoimmune disease characterized by autoantibodies toward amino acyl-tRNA synthetases (ARS), anti-Jo 1 being the most commonly detected. Muscle damage develops in up to 90% of ARS-positive patients, characterized by a necrotizing myositis restricted to the perifascicular region. This topographic distribution of muscle damage may lead to a misdiagnosis of dermatomyositis (DM) at muscle biopsy. We compared morphological, immunohistochemical, and histoenzymatic features of muscle from ARS-positive patients (n = 11) with those of DM (n = 7) providing clues for their differential diagnosis. In addition, we evaluated markers of mitochondrial damage to provide a further distinction between these two entities. Necrosis occurred in the majority of ARS patients, mainly located in the perifascicular region. It was often limited to small foci of fibers, always associated with myocyte regeneration. This last often overwhelmed necrosis, representing occasionally the main finding. In DM, necrosis/regeneration was scarce while the peculiar feature was a diffuse atrophy of perifascicular fibers. These last showed decreased cytochrome c oxidase (COX) stain and mitochondrial DNA depletion, consistent with mitochondrial dysfunction. In contrast to DM, ARS displayed scattered COX deficient fibers, not restricted to the perifascicular region. This feature occurred in up to 91% of patients, being prominent only in two. PMID- 29147925 TI - Confusion Over Differences in Registration and Randomization Criteria for the LORIS (Low-Risk DCIS) Trial: A Reply. PMID- 29147926 TI - Response to "Complications in DIEP Flap Breast Reconstruction after Mastectomy for Breast Cancer: A Prospective Cohort Study Comparing Unilateral and Bilateral Reconstructions". PMID- 29147927 TI - Treatment Patterns and Outcomes for Patients with Adrenocortical Carcinoma Associated with Hospital Case Volume in the United States. PMID- 29147928 TI - Surgical Management of Early-Stage Esophageal Adenocarcinoma Based on Lymph Node Metastasis Risk. AB - BACKGROUND: In early-stage esophageal adenocarcinoma (EAC), esophagectomy improves staging but also increases mortality compared with endoscopic resection. Our objective was to quantify esophagectomy mortality and lymph node metastasis (LNM) risk in early-stage EAC to improve surgical treatment allocation. METHODS: We identified National Cancer Database (2004-2014) patients with nonmetastatic, Tis, T1a, or T1b EAC who had primary surgical resection and microscopic examination of at least 15 lymph nodes. Univariate and multivariable logistic regression identified predictors of LNM. Cox regression identified predictors of death. The Kaplan-Meier method predicted overall survival (OS). RESULTS: In 782 patients, LNM rates were: all patients 13.8%, Tis 0%, T1a 3.6%, T1b 23.4%. Independent predictors of LNM were submucosal invasion, lymphovascular invasion (LVI), decreasing differentiation, and tumor size >= 2 cm (P < 0.05). For T1a tumors with poor differentiation or size >= 2 cm, LNM rates were 10.2 and 6.7%, respectively; 90-day mortality was 3.1%. The LNM rate in well differentiated T1b tumors < 2 cm was 4.2%; 90-day mortality was 6.0%. Estimated 5-year OS was 80.2% versus 64.4% (T1a vs. T1b). LNM increased risk of death for T1a (hazard ratio [HR] 8.52, 95% confidence interval [CI] 3.13-23.22, P < 0.001) and T1b tumors (HR 2.52, 95% CI 1.59-4.00, P < 0.001). CONCLUSIONS: In T1a EAC with poor differentiation or size >= 2 cm, esophagectomy should be considered, whereas in T1b EAC with low-risk features (well-differentiated T1b EAC < 2 cm without LVI), endoscopic resection may be sufficient. Treatment guidelines for early-stage EAC should include all high-risk tumor features for LNM and stage-specific esophagectomy mortality. PMID- 29147929 TI - Primary Locoregional Treatment in Metastatic Breast Cancer: A Reply. PMID- 29147931 TI - Horses for Courses: Moving India towards Universal Health Coverage through Targeted Policy Design. AB - The debate on how India's health system should move towards universal health coverage was (meant to be) put to rest by the recent National Health Policy 2017. However, the new policy is silent about tackling bottlenecks mentioned in the said policy proposal. It aims to provide universal access to free primary care by strengthening the public system, and to secondary and tertiary care through strategic purchasing from the private sector, to overcome deficiencies in public provisioning in the short run. Yet, in doing so, it ignores critical factors needed to replicate successful models of public healthcare delivery from certain states that it hopes to emulate. The policy also overestimates the capacity of the public sector and downplays the challenges observed in purchasing secondary care. Drawing from literature in policy design, we emphasize that primary, secondary and tertiary care have distinct characteristics, and their provision requires separate approaches or policy tools depending on the context. Public provisioning, contract purchasing and insurance mechanisms are different policy tools that have to be matched with the context and characteristics of the policy arena. Given the current challenges of India's health system, we argue that tertiary care services are most suitable for insurance-based purchasing, while the public sector should concentrate on building the required capacities to dominate the provisioning of secondary care and fill gaps in primary care delivery, for India to achieve its universal coverage ambitions. PMID- 29147930 TI - SNP association study in PMS2-associated Lynch syndrome. AB - Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2-3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5-4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in PMS2 carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients. PMID- 29147932 TI - Girls (and Boys) Just Want to Have Fun: A Mixed-Methods Examination of the Role of Gender in Youth Mentoring Relationship Duration and Quality. AB - This prospective, mixed-methods study examined the role of gender in youth mentoring relationship duration and quality. Participants were 67 gender-matched pairs of adult mentors and youth participating in community-based mentoring programs as well as the youths' guardians. Mentors and youth completed surveys and qualitative interviews at multiple time points. At baseline, male youth reported stronger relationships with their guardians. Analysis of the survey data from the 3-month follow-up revealed that male mentors and youth reported stronger mentoring relationship quality. Male matches were more likely to last at least 1 year. Further, male youth whose matches lasted at least 1 year reported better relationships with their guardians at baseline and reported stronger mentoring relationships after 3 months, compared to both females whose matches lasted greater than a year, and females whose matches lasted less than 1 year. Examinations of the qualitative interviews from a sub-sample of matched pairs (n = 29) showed that male and female youth and male mentors held similar expectations for the relationship, mainly to engage in fun activities, while female mentors were more often looking for a close relationship to develop quickly, which resulted in a disconnect between female mentees' and female mentors' expectations. Findings highlight the importance of developmentally appropriate relationships for youth and suggest that mentoring programs may be able facilitate longer, more effective matches for girls by tempering female mentors' expectations for how close and quickly those relationships will develop. PMID- 29147933 TI - Aerobic bacteriological studies on the respiratory tracts of apparently healthy and pneumonic camels (Camelus dromedaries) in selected districts of Afar Region, Ethiopia. AB - A cross-sectional study was conducted to isolate and identify bacterial species from the respiratory tract of apparently healthy and pneumonic camels in Asayita and Dubti woredas in the Afar Region, Ethiopia. From a total of 74 lung tissue and 74 tracheal swab samples Staphylococcus aureus, 16.3%, Streptococcus equi subsp. equi, 13.0%, and Pasteurella multocida, 10.9%, were dominant isolates from pneumonic lungs; Escherichia coli, 12.7%, Proteus species, 10.9%, and Klebsiella pneumoniae, 9.1%, were the majority in the normal lungs. The majority of the isolates colonized both anatomical sites investigated. There was a statistically significant association between the health status of the camels as well as the anatomical site studied with the isolation rates of the major respiratory pathogens (p < 0.05). Furthermore, the isolates were susceptible to norfloxacin, streptomycin, and gentamicin but resistant to ampicillin and tetracycline on in vitro test. Further studies on the pathogenicity of the major isolates are recommended. PMID- 29147934 TI - An outbreak of poisoning by Kalanchoe blossfeldiana in cattle in northeastern Brazil. AB - In the world, Kalanchoe species are primarily ornamentals and houseplants, but some have escaped cultivation and can be found in the field. In Latin America, there are no reports of spontaneous poisoning by Kalanchoe species in animals. This study aimed to describe the epidemiological, clinical, and pathological aspects of an outbreak of poisoning by Kalanchoe blossfeldiana in cattle in the semiarid region of Pernambuco, Brazil. Epidemiological and clinical data were obtained from the owner and veterinarian during technical visits. Prunings of this plant were disposed of in a pasture with a shortness of forage. Seventeen cattle had clinical signs, and thirteen died 4-5 days after the first clinical signs were observed. Clinical signs and gross and histological lesions include gastrointestinal, cardiovascular, and neuromuscular disorders. Kalanchoe spp. contain cardiotoxic glycosides, and the clinical signs and lesions in cattle of this outbreak were consistent with poisoning by plants that contain these toxins. PMID- 29147935 TI - Nucleotide and octapeptide-repeat variations of the prion protein coding gene (PRNP) in Anatolian, Murrah, and crossbred water buffaloes. AB - Resistance to bovine spongiform encephalopathy (BSE) that is significantly associated with insertion/deletion (indel) polymorphisms at two loci (putative promoter and intron 1) on the prion protein gene (PRNP) in cattle has been well documented. Studies suggest that the insertion alleles are related to BSE resistance. Until recently, BSE has never been reported in water buffaloes (unlike cattle). Previous studies have demonstrated that the PRNP gene in water buffalo consists mostly of insertion alleles at both loci; nevertheless, whether or not water buffaloes are genetically resistant to BSE and the role of indel polymorphisms in their resistance status is not clear. We examined the coding region of PRNP to determine the nucleotide and octapeptide-repeat (octarepeats) variations of Anatolian, Murrah and Murrah * Anatolian (M * A) water buffaloes. Three synonymous single nucleotide polymorphisms (SNP) at positions 126, 234, and 285, and a non-synonymous SNP at position 322 (G108S) were detected. Triplet G/A/T base substitutions were observed at position 126 and two additional genotypes, T/A and T/G, at this position were determined. We also found six octarepeats that indicated the presence of the wild-type PRNP6 allele in the coding region. To the best of our knowledge, this is the first report of the T/A and T/G genotypes in water buffaloes. PMID- 29147937 TI - [SharedIt - A special service for our authors and subscribers to Der Schmerz]. PMID- 29147936 TI - Effect of breeding method and season on pregnancy rate and embryonic and fetal losses in lactating Nili-Ravi buffaloes. AB - The aim of this study was to determine the effect of breeding method and season on pregnancy rate and cumulative embryonic and fetal losses in Nili-Ravi buffalo. Estrus detection was performed twice a day by teaser buffalo bull for 1 hour each. A 2 * 2 factorial design was used to address the breeding method and season. Buffaloes (n = 130) exhibiting estrus were randomly assigned to be bred either in peak breeding season (PBS; n = 80) or low breeding season (LBS; n = 50). Within each season, buffaloes were divided to receive either natural service (NS; n = 65) or artificial insemination (AI; n = 65). NS buffaloes, in estrus, were allowed to remain with the bull until mating. AI was achieved, using frozen thawed semen of bull of known fertility. PBS comprised of September to December and LBS were from May to July. Serial ultrasonography was performed on days 30, 45, 60, and 90 after breeding (day 0) to monitor pregnancy rate and embryonic and fetal losses. The pregnancy rate on day 30 after breeding was higher in NS as compared to AI group (63 vs. 43%; P < 0.05) during PBS while it did not differ (48 vs. 32%; P > 0.05) in LBS. The cumulative embryonic and fetal losses between days 31 and 90 were significantly lower in PBS than LBS (33 vs. 60%; P < 0.05), ignoring breeding method. Pregnancy rates were better with NS in PBS, and cumulative embryonic fetal losses were higher in LBS in Nili-Ravi buffalo. PMID- 29147938 TI - [Application of a new pain balm based on TCM]. AB - In the context of an unsuccessful treatment over several years of existing knee pain after various sports injuries, a young, healthy female patient was treated with a novel pain balm based on traditional Chinese medicine. This resulted in a significant improvement in the stimulation and pain conditions without any recognizable local and systemic side effects. PMID- 29147939 TI - Reply to Letter to the Editor: Bariatric Surgery and Endoluminal Procedures: IFSO Worldwide Survey 2014. PMID- 29147940 TI - Interaction of proteins with ionic liquid, alcohol and DMSO and in situ generation of gold nano-clusters in a cell. AB - In this review, we give a brief overview on how the interaction of proteins with ionic liquids, alcohols and dimethyl sulfoxide (DMSO) influences the stability, conformational dynamics and function of proteins/enzymes. We present experimental results obtained from fluorescence correlation spectroscopy on the effect of ionic liquid or alcohol or DMSO on the size (more precisely, the diffusion constant) and conformational dynamics of lysozyme, cytochrome c and human serum albumin in aqueous solution. The interaction of ionic liquid with biomolecules (e.g. protein, DNA etc.) has emerged as a current frontier. We demonstrate that ionic liquids are excellent stabilizers of protein and DNA and, in some cases, cause refolding of a protein already denatured by chemical denaturing agents. We show that in ethanol-water binary mixture, proteins undergo non-monotonic changes in size and dynamics with increasing ethanol content. We also discuss the effect of water-DMSO mixture on the stability of proteins. We demonstrate how large scale molecular dynamics simulations have revealed the molecular origin of this observed phenomenon and provide a microscopic picture of the immediate environment of the biomolecules. Finally, we describe how favorable interactions of ionic liquids may be utilized for in situ generation of fluorescent gold nano clusters for imaging a live cell. PMID- 29147941 TI - Artificial bio-nanomachines based on protein needles derived from bacteriophage T4. AB - Bacteriophage T4 is a natural bio-nanomachine which achieves efficient infection of host cells via cooperative motion of specific three-dimensional protein architectures. The relationships between the protein structures and their dynamic functions have recently been clarified. In this review we summarize the design principles for fabrication of nanomachines using the component proteins of bacteriophage T4 based on these recent advances. We focus on the protein needle known as gp5, which is located at the center of the baseplate at the end of the contractile tail of bacteriophage T4. This protein needle plays a critical role in directly puncturing host cells, and analysis has revealed that it contains a common motif used for cell puncture in other known injection systems, such as T6SS. Our artificial needle based on the beta-helical domain of gp5 retains the ability to penetrate cells and can be engineered to deliver various cargos into living cells. Thus, the unique components of bacteriophage T4 and other natural nanomachines have great potential for use as molecular scaffolds in efforts to fabricate new bio-nanomachines. PMID- 29147943 TI - Unusual appearance of a cardiac mass. PMID- 29147944 TI - Relationship between MIDAS, depression, anxiety and alexithymia in migraine patients. AB - The co-existence of psychiatric comorbidities with migraine is well known; however, the relationship between alexithymia and migraine has not been persuasively shown yet. The aim of the study was to assess the relationships between migraine-related disability, depression, anxiety and alexithymia. One hundred and forty-five migraine patients (33.18 +/- 8.6; 111 females, 34 males), and 50 control subjects (29.06 +/- 7.6; 34 females, 16 males) were prospectively enrolled for the study. The participants completed a demographic data form and Migraine Disability Assessment Scale, Beck Depression Inventory, Beck Anxiety Inventory and Toronto Alexithymia Score-20 (TAS-20). All migraine patients were more depressive (p = 0.01) and anxious (p = 0.001) than the healthy subjects. TAS 20 scores of the migraine sufferers and the control group did not indicate alexithymia. The migraine-related disability of all migraine patients was severe (27.84 +/- 29.22). Depression and anxiety scores in the migraine patients were highly correlated with each other and TAS-20 (r = 0.485, p = 0.001) and all its subscales in turn: difficulty in identifying (r = 0.435, p < 0.001) and describing feelings (r = 0.451, p = 0.001) and externally oriented thinking (r = 0.302, p = 0.001). Moreover, logistic regression analysis revealed that depression and anxiety predicted alexithymia. Our findings showed a complex relationship between migraine, depression, anxiety and alexithymia. On the other hand, alexithymia apparently was not directly connected to migraine, but its presence could be predicted in migraine patients because of co-morbid depression and anxiety. PMID- 29147942 TI - Randomized controlled trials of simulation-based interventions in Emergency Medicine: a methodological review. AB - The number of trials assessing Simulation-Based Medical Education (SBME) interventions has rapidly expanded. Many studies show that potential flaws in design, conduct and reporting of randomized controlled trials (RCTs) can bias their results. We conducted a methodological review of RCTs assessing a SBME in Emergency Medicine (EM) and examined their methodological characteristics. We searched MEDLINE via PubMed for RCT that assessed a simulation intervention in EM, published in 6 general and internal medicine and in the top 10 EM journals. The Cochrane Collaboration risk of Bias tool was used to assess risk of bias, intervention reporting was evaluated based on the "template for intervention description and replication" checklist, and methodological quality was evaluated by the Medical Education Research Study Quality Instrument. Reports selection and data extraction was done by 2 independents researchers. From 1394 RCTs screened, 68 trials assessed a SBME intervention. They represent one quarter of our sample. Cardiopulmonary resuscitation (CPR) is the most frequent topic (81%). Random sequence generation and allocation concealment were performed correctly in 66 and 49% of trials. Blinding of participants and assessors was performed correctly in 19 and 68%. Risk of attrition bias was low in three-quarters of the studies (n = 51). Risk of selective reporting bias was unclear in nearly all studies. The mean MERQSI score was of 13.4/18.4% of the reports provided a description allowing the intervention replication. Trials assessing simulation represent one quarter of RCTs in EM. Their quality remains unclear, and reproducing the interventions appears challenging due to reporting issues. PMID- 29147946 TI - A case report of the first application of culture epithelial autograft (JACE(r)) for giant congenital melanocytic nevus after its approval in Japan. AB - In Japan, the JACE(r) cultured epidermal autograft (CEA) was approved and covered by public healthcare insurance for use in the treatment of giant congenital melanocytic nevus (GCMN) in 2016. We herein report the results of the application of JACE(r) after curettage and Q-switched ruby laser therapy. The current patient was the first patient with GCMN to be treated with JACE(r) since its approval. A 3-month-old girl had a hairy GCMN of 9.5 cm in diameter from her cheek to her temple on the left side of her face. We first performed curettage of the nevus on the temple and applied irradiation using a Q-switched ruby laser; however, erosion relapsed at 2 months after first surgery. After preparing JACE(r), we performed curettage a second time at 7 months with irradiation of a Q-switched ruby laser and the application of the CEA. The CEA took successfully and the wound was completely epithelized at 1 week after grafting. Re-pigmentation is an important issue that remains to be solved; however, overcoming this would allow for a deeper abrasion or more intense laser irradiation to be performed in cases in which CEA will be subsequently applied. PMID- 29147947 TI - Biocompatibility of vertically aligned multi-walled carbon nanotube scaffolds for human breast cancer cell line MDA-MB-231. AB - The aim of the current study was to determine whether the MWCNT-based scaffold has a suitable structure for cell growth and provides a biocompatible environment for human MDA-MB-231 cell lines. MWCNT-based nanostructured scaffolds were produced by plasma-enhanced chemical vapor deposition (PECVD) technique. MDA-MB 231 cells were seeded on MWCNTs-textured silicon scaffolds and on pristine silicon surfaces. After 1 week of culturing, the scaffolds were prepared for SEM analysis and immunocytochemical staining was performed for the two groups (MWCNT scaffold and pristine silicon surface), using MMP-2, MMP-9, PI3K, AKT and NF kappaB primary antibodies. SEM analyses showed that the MDA-MB-231 cells better adhered to the MWCNT-based nanostructured scaffold than the pristine silicon surface. Immunohistochemical activity of the MDA-MB-231 cells on both materials has similar staining with anti-AKT MMP-2, MMP-9 and NF-kappaB primary antibodies. Therefore, the results of the present study suggest that the MWCNT-based scaffolds enhanced cell adhesion to the scaffold and exhibited more biomimetic properties and physiological adaptation with the potential to be used for in vitro metastasis studies of BrCa cell lines. PMID- 29147948 TI - Adherence to Mediterranean diet and subjective cognitive function in men. AB - Benefits of a Mediterranean diet for cognition have been suggested, but epidemiologic studies have been relatively small and of limited duration. To prospectively assess the association between long-term adherence to a Mediterranean dietary pattern and self-reported subjective cognitive function (SCF). Prospective observational study. The Health Professionals' Follow-up Study, a prospective cohort of 51,529 men, 40-75 years of age when enrolled in 1986, of whom 27,842 were included in the primary analysis. Mediterranean diet (MD) score, computed from the mean of five food frequency questionnaires, assessed every 4 years from 1986 to 2002. Self-reported SCF assessed by a 6-item questionnaire in 2008 and 2012, and validated by association with genetic variants in apolipoprotein-4. Using the average of 2008 and 2012 SCF scores, 38.0% of men were considered to have moderate memory scores and 7.3% were considered to have poor scores. In a multivariate model, compared with men having a MD score in the lowest quintile, those in the highest quintile had a 36% lower odds of a poor SCF score (odds ratio 0.64, 95% CI 0.55-0.75; P, trend < 0.001) and a 24% lower odds of a moderate SCF score (OR 0.76, 95% CI 0.70-0.83; P, trend < 0.001). Both remote and more recent diet contributed to this relation. Associations were only slightly weaker using baseline dietary data and a lag of 22 years. Long-term adherence to the Mediterranean diet pattern was strongly related to lower subjective cognitive function. These findings provide further evidence that a healthy dietary pattern may prevent or delay cognitive decline. PMID- 29147949 TI - Physical activity across adulthood and subjective cognitive function in older men. AB - Low subjective cognitive function (SCF), which is associated with APOE4 genotype, adversely impacts quality of life and has predicted clinical dementia. We examined whether physical activity during early adulthood or mid-to-late life is associated with late-life SCF. We followed 28,481 US male health professionals aged 40-75 years who reported their physical activity in 1986 and biennially thereafter. SCF was reported in 2008 and 2012. The SCF score was averaged for the 2008 and 2012 assessments and categorized as "good", "moderate", and "poor". Men in the highest versus lowest quintile of mid-to-late life physical activity in 1986 had 38% lower odds of poor versus good SCF score (multivariable-adjusted odds ratio (OR) 0.62; 95% CI 0.53, 0.72; P for trend < 0.0001). Being physically active in early adulthood was also associated with a 23% lower odds of poor SCF, independent of later activity, and being active both in early and mid-to-late adulthood was associated with a 48% lower odds of poor SCF score compared with those who were always sedentary (OR 0.52; 95% CI 0.38, 0.71). Our results suggest that being physically active during early adulthood and mid-to-late life independently contribute to prevention of poor subjective cognitive function in late-life. PMID- 29147950 TI - Mental Health Consultation Among Ontario's Immigrant Populations. AB - To determine the prevalence rates and characteristics of past-year mental health consultation for Ontario's adult (18 + years old) immigrant populations. The Canadian Community Health Survey (CCHS) 2012 was used to calculate the prevalence rates of past-year mental health consultation by service provider type. Characteristics associated with mental health consultation were determined by carrying out multivariable logistic regression analysis on merged CCHS 2008-2012 data. Adult immigrant populations in Ontario (n = 3995) had lower estimated prevalence rates of past-year mental health consultation across all service provider types compared to Canadian-born populations (n = 14,644). Amongst those who reported past-year mental health consultation, 57.89% of Ontario immigrants contacted their primary care physician, which was significantly higher than the proportion who consulted their family doctor from Canadian-born populations (45.31%). The factors of gender, age, racial/ethnic background, education level, working status, food insecurity status, self-perceived health status, smoking status, alcohol drinking status, years since immigration, and age at time of immigration were significantly associated with past-year mental health consultation for immigrant populations. Ontario's adult immigrant populations most commonly consult their family doctor for mental health care. Potential exists for expanding the mental health care role of primary care physicians as well as efforts to increase accessibility of specialized mental health services. Integrated, coordinated care where primary care physicians, specialized mental health professionals, social workers, and community educators, etc. working together in a sort of "one-stop-shop" may be the most effective way to mitigate gaps in the mental health care system. In order to effectively tailor mental health policy, programming, and promotion to suit the needs of immigrant populations initiatives that focus on the connection between physical and mental health and migration variables such as length of stay in Canada, years since immigration, and other important migration variables (beyond the scope of the CCHS which require further study) need to be developed. Examination of the social determinants of mental health is critical to understand how we can best serve the mental health needs of Ontario's immigrant populations. PMID- 29147951 TI - Satisfaction with Mental Health Navigation Services: Piloting an Evaluation with a New Scale. AB - As mental health navigation services continue to be implemented, the need for valid and reliable tools to assess the quality of these services increases. While case managers target individuals with severe mental illness and aim to reduce burden and cost, and increase independence, navigation services target all individuals with a range of mental health and/or substance use issues, with the aim of reducing barriers to treatment and coordinating individualized care. The current study evaluated satisfaction with a navigation service using a new 22 item questionnaire, the Navigation Satisfaction Tool (NAVSAT). Forty clients completed a web-based version of the NAVSAT to evaluate satisfaction with a family mental health navigation service in Toronto, Canada. Descriptive statistics on the sample and range of treatments/services are provided. The NAVSAT has excellent reliability (Cronbach's alpha = 0.96) and face validity. Satisfaction with the following navigation-level factors were the best predictors of overall satisfaction with navigation; the navigator's ability to recommend the appropriate treatment (beta = 0.116, p = .05), intake procedures (beta = 0.364, p = .005), and the principal contact's satisfaction with his/her frequency of contact with the navigator (beta = 0.602, p = .001). Satisfaction with the following provider-level factors were the best predictors of overall satisfaction with the referred service; the referred service's ability to improve the youth's well being (beta = 0.684, p < .001), and the referred service's ability to listen and understand the family's concerns (beta = 0.356, p = .001). The NAVSAT appears to be a reliable tool for measuring satisfaction in the current sample. If these findings are replicated in a larger population serving youth and young adults in transition, the NAVSAT may prove to be a helpful guide for program evaluation and development for navigation and treatment services for this population. PMID- 29147952 TI - Gemigliptin, a novel dipeptidyl peptidase-IV inhibitor, exerts a synergistic cytotoxicity with the histone deacetylase inhibitor PXD101 in thyroid carcinoma cells. AB - PURPOSE: The influence of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the histone deacetylase inhibitor PXD101 on survival of thyroid carcinoma cells was investigated. METHODS: SW1736, TPC-1, 8505C and BCPAP human thyroid carcinoma cells were used. To assess cell survival, cell viability, the percentage of viable cells and dead cells, cytotoxic activity, ATP levels and FACS analysis were measured. To validate the impact of gemigliptin combined with PXD101, the interactions were estimated by obtaining combination index in cells treated with two agents. RESULTS: In cells treated with gemigliptin or PXD101, cell viability, the percentage of viable cells and ATP levels were reduced, and the percentage of dead cells and cytotoxic activity were elevated. In cells treated with both gemigliptin and PXD101, compared with PXD101 alone, cell death was augmented, and all of the combination index values were lower than 1.0, suggesting the synergism between gemigliptin and PXD101. The percentage of apoptotic cells, and the protein levels of Bcl2 and cleaved poly (ADP-ribose) polymerase were elevated, and the protein levels of xIAP and survivin were reduced. The protein levels of phospho-Akt and phospho-AMPK were elevated, and cell migration was reduced. CONCLUSIONS: Our results demonstrate that gemigliptin induces cytotoxicity in thyroid carcinoma cells. Moreover, gemigliptin has a synergistic activity with PXD101 in the induction of cell death through involvement of Bcl2 family proteins, xIAP and survivin as well as mediation of Akt and AMPK in thyroid carcinoma cells. PMID- 29147953 TI - Impact of perfluorochemicals on human health and reproduction: a male's perspective. AB - Perfluoroalkyl compounds (PFCs) are a class of organic molecules used in industry and consumer products. PFCs are non-biodegradable and bioaccumulate in the environment and for these reasons they have been a major subject of research regarding their toxicity, environmental fate, and sources of human exposure, since they have been shown to induce severe health consequences, such as neonatal mortality, neurotoxicity and immunotoxicity. The aim of this review is to explore the existing knowledge of the interplay between PFCs exposure and human health, with a focus on male reproductive health, given the emerging gender differences in PFCs clearance and their interaction with sex hormones receptors. A comprehensive PUBMED search was performed using relevant key terms for PFCs and male fertility. Different degrees of evidence suggest an impairment of semen parameters and sex hormones in relation to PFCs exposure. These preliminary results point towards a sex-dependent pharmacodynamics and clearance, with males having a much higher tendency to accumulation. Moreover, because of the widespread environmental occurrence of these chemicals, along with their ability to cross the placental barrier, exposure of the foetus to these compounds is inevitable. This is of concern because foetal development of the male reproductive organs may be disturbed by exposure to exogenous factors. These findings clearly suggest an antiandrogenic potential of PFCs and a link between endocrine disruptors and disorders of male health. PMID- 29147954 TI - A fully automatic end-to-end method for content-based image retrieval of CT scans with similar liver lesion annotations. AB - PURPOSE: The goal of medical content-based image retrieval (M-CBIR) is to assist radiologists in the decision-making process by retrieving medical cases similar to a given image. One of the key interests of radiologists is lesions and their annotations, since the patient treatment depends on the lesion diagnosis. Therefore, a key feature of M-CBIR systems is the retrieval of scans with the most similar lesion annotations. To be of value, M-CBIR systems should be fully automatic to handle large case databases. METHODS: We present a fully automatic end-to-end method for the retrieval of CT scans with similar liver lesion annotations. The input is a database of abdominal CT scans labeled with liver lesions, a query CT scan, and optionally one radiologist-specified lesion annotation of interest. The output is an ordered list of the database CT scans with the most similar liver lesion annotations. The method starts by automatically segmenting the liver in the scan. It then extracts a histogram based features vector from the segmented region, learns the features' relative importance, and ranks the database scans according to the relative importance measure. The main advantages of our method are that it fully automates the end-to end querying process, that it uses simple and efficient techniques that are scalable to large datasets, and that it produces quality retrieval results using an unannotated CT scan. RESULTS: Our experimental results on 9 CT queries on a dataset of 41 volumetric CT scans from the 2014 Image CLEF Liver Annotation Task yield an average retrieval accuracy (Normalized Discounted Cumulative Gain index) of 0.77 and 0.84 without/with annotation, respectively. CONCLUSIONS: Fully automatic end-to-end retrieval of similar cases based on image information alone, rather that on disease diagnosis, may help radiologists to better diagnose liver lesions. PMID- 29147955 TI - Kidney transplantation in Romania: two transplant centers experience. AB - PURPOSE: Kidney graft survival rates improved from decade to decade, but data about factors that affect patient and graft survival remain challenging and even controversial. METHODS: We analyzed retrospectively data from kidney transplanted patients followed in two Romanian transplant centers (Iasi and Bucharest)-new programmes specifically developed after 1989 to cover transplantation requirements for two-thirds of Romania. We used a composite survival outcome defined as 50% reduction in estimated glomerular filtration rate (eGFR), return to dialysis or death. Survival analysis was performed using uni- and multivariable Cox regression with baseline and time-updated covariates. RESULTS: From the entire cohort of 365 patients, 243 had the outcome of interest. In the univariable Cox survival analysis, age, hemoglobin, eGFR, cholesterol, AST and transplant center were associated with the outcome. The multivariable Cox analysis reveals that only cholesterol (HR 0.97, 95% CI 0.94-0.99 per 10 mg/dL increase) and transplant center (HR 3.64, 95% CI 2.67-4.97) remain associated. For the time-updated Cox survival analysis we found that eGFR (HR 0.91, 95% CI 0.87-0.96 per 10 ml/min/1.73 m2 increase) and cholesterol are associated with the outcome in the univariable analysis and only eGFR and transplant center in the multivariable Cox survival analysis. CONCLUSIONS: Our study reports data from two distinct transplant centers from a developing country. Our results are similar to the current literature data, but also reveal that the approach of a center to the transplantation management is an independent factor associated with graft survival. PMID- 29147956 TI - Endogenous sex hormones and memory performance in middle-aged Greek women with subjective memory complaints. AB - The changing hormonal milieu during the menopausal transition may contribute to the development of memory disorders. We aimed to assess the association of sex hormones with memory function in a sample of Greek middle-aged women. This pilot study included 44 women with subjective memory complaints. Memory performance was evaluated using the Hopkins Verbal Learning Test (HVLT), the Brief Visuospatial Memory test (BVMT), and the verbal digits backwards test (VSPAN), to assess verbal, visuospatial, and working memory performance, respectively. Menopausal symptoms were assessed using the Green Climacteric Scale. VSPAN backwards scores were positively associated with log-transformed free androgen index (logFAI), in models adjusted for age, education, log-transformed free estrogen index (logFEI), hypertension, and the intensity of menopausal symptoms. BVMT total scores were predicted by logFAI (b-coefficient = 0.424, p value = 0.002), education, and combined climacteric symptomatology, in a model adjusted for age, logFEI, and hypertension. Women with circulating estradiol above the median value of 10 pg/mL had better total HTLV total scores compared to women with estradiol values below the median (HTLV total scores, estradiol <= 10 pg/mL vs. > 10 pg/mL: 24.2 +/- 3.6 vs. 30.0 +/- 7.9, p value = 0.007 unadjusted). This association was affected by education and remained independent of menopausal symptoms and testosterone levels, education, and hypertension (model R 2 = 22.3%; b-coefficient = 0.318, p value = 0.024). Endogenous total estradiol is associated with verbal episodic memory, while logFAI is associated with working memory performance and visuospatial episodic memory in this sample of postmenopausal women. These associations were not influenced by age, education, or menopausal symptoms. Larger studies are necessary to evaluate the significance of our findings. PMID- 29147957 TI - Mobilization of endothelial progenitor cell in patients with acute ischemic stroke. AB - Endothelial progenitor cells (EPCs) have important effect in tissue repair in ischemic organs. The present study was conducted to demonstrate the mobilization of EPCs and its possible mechanism after acute ischemic stroke (AIS). A total of 148 individuals were examined, including 106 patients with ischemic stroke and 42 healthy controls. Seventy-one patients with imaging-confirmed AIS were examined at days 1, 7, 14, and 21 after stroke onset. Circulating EPCs were quantified by flow cytometry using CD133 and KDR surface markers. Serum stromal cell-derived factor-1 (SDF-1) concentrations were determined by enzyme-linked immunosorbent assay. Patients with AIS had significantly lower EPC level than that in the controls (0.022 +/- 0.013 vs 0.051 +/- 0.020; p < 0.01). This difference did not remain significant after adjusting for risk factors at multivariate analysis. Blood pressure, triglyceride, low-density lipoprotein (LDL), and fasting blood sugar were inversely correlated with EPC levels (p < 0.01). Systolic blood pressure and LDL remained independent predictors of baseline EPC levels. The number of circulating EPCs increased on day 7 after AIS, reached a peak on day 14, and decreased on day 21. The concentration of SDF-1 had similar changes. The increment of EPCs was correlated with the infarct volume (r = 0.708; p = 0.006) and SDF-1 concentration on day 14 (r = 0.714; p < 0.001). Baseline EPC level in patients with AIS reflects the cumulative vascular endothelial damage. EPCs could be mobilized into peripheral circulation in response to stroke stress. This mobilization was associated with the increased expression of SDF-1. PMID- 29147958 TI - Ginsenoside Rg1 Decreases Oxidative Stress and Down-Regulates Akt/mTOR Signalling to Attenuate Cognitive Impairment in Mice and Senescence of Neural Stem Cells Induced by D-Galactose. AB - Adult hippocampal neurogenesis plays a pivotal role in learning and memory. The suppression of hippocampal neurogenesis induced by an increase of oxidative stress is closely related to cognitive impairment. Neural stem cells which persist in the adult vertebrate brain keep up the production of neurons over the lifespan. The balance between pro-oxidants and anti-oxidants is important for function and surviving of neural stem cells. Ginsenoside Rg1 is one of the most active components of Panax ginseng, and many studies suggest that ginsenosides have antioxidant properties. This research explored the effects and underlying mechanisms of ginsenoside Rg1 on protecting neural stem cells (NSCs) from oxidative stress. The sub-acute ageing of C57BL/6 mice was induced by subcutaneous injection of D-gal (120 mg kg-1 day-1) for 42 day. On the 14th day of D-gal injection, the mice were treated with ginsenoside Rg1 (20 mg kg-1 day-1, intraperitoneally) or normal saline for 28 days. The study monitored the effects of Rg1 on proliferation, senescence-associated and oxidative stress biomarkers, and Akt/mTOR signalling pathway in NSCs. Compared with the D-gal group, Rg1 improved cognitive impairment induced by D-galactose in mice by attenuating senescence of neural stem cells. Rg1 also decreased the level of oxidative stress, with increased the activity of superoxide dismutase and glutathione peroxidase in vivo and in vitro. Rg1 furthermore reduced the phosphorylation levels of protein kinase B (Akt) and the mechanistic target of rapamycin (mTOR) and down-regulated the levels of downstream p53, p16, p21 and Rb in D-gal treated NSCs. The results suggested that the protective effect of ginsenoside Rg1 on attenuating cognitive impairment in mice and senescence of NSCs induced by D-gal might be related to the reduction of oxidative stress and the down-regulation of Akt/mTOR signaling pathway. PMID- 29147959 TI - Port site hernia after laparoscopic sleeve gastrectomy: a retrospective cohort study of 352 patients. AB - Port site hernia (PSH) following laparoscopic procedures is a rare but serious complication. The aim of this study was to evaluate the rate of PSH after laparoscopic sleeve gastrectomy (LSG), and the efficacy of closure of the port site as a means of preventing PSH. A retrospective analysis was performed on 386 patients who underwent LSG between December 2009 and January 2015. 352 (91.2%) of the patient were followed up for at least 24 months. In the first 206 patients, the fascial layers of the trocar incisions were not closed, while in the next 146 cases, routine closure of the trocar sites was performed. The patients were reviewed in relation to demographics, comorbidities, complications, percentage of excess weight loss, and rates of PSH. The total cohort consisted of 220 female and 132 male patients with a mean age of 36.2 +/- 12.3 years. Demographic data, initial BMI, and comorbidities were similar for the patients in both groups. The closure of the fascia was caused by the prolonged duration of the operation with no significant difference. The unclosed fascial defects were associated with a significantly increased incidence of PSH (1.3 vs. 3.9%, p < 0.05). All of the patients who experienced PSH had at least one comorbidity, and no complication was noted in the fascial closure cases. It was found that the rate of PSH after LSG is not as low as previously thought, and that routine closure of fascial defects at port sites may result in a decreased PSH rate. PMID- 29147960 TI - On the interplay of visuospatial and audiotemporal dominance: Evidence from a multimodal kappa effect. AB - When participants judge multimodal audiovisual stimuli, the auditory information strongly dominates temporal judgments, whereas the visual information dominates spatial judgments. However, temporal judgments are not independent of spatial features. For example, in the kappa effect, the time interval between two marker stimuli appears longer when they originate from spatially distant sources rather than from the same source. We investigated the kappa effect for auditory markers presented with accompanying irrelevant visual stimuli. The spatial sources of the markers were varied such that they were either congruent or incongruent across modalities. In two experiments, we demonstrated that the spatial layout of the visual stimuli affected perceived auditory interval duration. This effect occurred although the visual stimuli were designated to be task-irrelevant for the duration reproduction task in Experiment 1, and even when the visual stimuli did not contain sufficient temporal information to perform a two-interval comparison task in Experiment 2. We conclude that the visual and auditory marker stimuli were integrated into a combined multisensory percept containing temporal as well as task-irrelevant spatial aspects of the stimulation. Through this multisensory integration process, visuospatial information affected even temporal judgments, which are typically dominated by the auditory modality. PMID- 29147961 TI - Spatiotemporal competition and task-relevance shape the spatial distribution of emotional interference during rapid visual processing: Evidence from gaze contingent eye-tracking. AB - People's ability to perceive rapidly presented targets can be disrupted both by voluntary encoding of a preceding target and by spontaneous attention to salient distractors. Distinctions between these sources of interference can be found when people search for a target in multiple rapid streams instead of a single stream: voluntary encoding of a preceding target often elicits subsequent perceptual lapses across the visual field, whereas spontaneous attention to emotionally salient distractors appears to elicit a spatially localized lapse, giving rise to a theoretical account suggesting that emotional distractors and subsequent targets compete spatiotemporally during rapid serial visual processing. We used gaze-contingent eye-tracking to probe the roles of spatiotemporal competition and memory encoding on the spatial distribution of interference caused by emotional distractors, while also ruling out the role of eye-gaze in driving differences in spatial distribution. Spontaneous target perception impairments caused by emotional distractors were localized to the distractor location regardless of where participants fixated. But when emotional distractors were task-relevant, perceptual lapses occurred across both streams while remaining strongest at the distractor location. These results suggest that spatiotemporal competition and memory encoding reflect a dual-route impact of emotional stimuli on target perception during rapid visual processing. PMID- 29147962 TI - Retrospective review of ceftriaxone versus levofloxacin for treatment of E. coli urinary tract infections. AB - Background Urinary tract infections (UTIs) are among the most common bacterial infections. Options for initial treatment of pyelonephritis or UTI requiring hospitalization include levofloxacin (LVF) or extended-spectrum cephalosporins. Globally, uropathogenic Escherichia coli resistance rates to fluoroquinolones have increased in recent years. Objective To compare clinical outcomes of patients receiving ceftriaxone (CTX) to those who received LVF empirically for the treatment of E. coli UTI. Setting 433-bed community hospital in Lexington, KY. Methods Retrospective, single center, cohort study of adults with a urine culture positive for E. coli who received either IV LVF or CTX empirically for the treatment of UTI. Main outcome measure The primary outcome was hospital length of stay. Secondary outcomes include time to susceptible therapy (TsT), hospital cost, and susceptibility to empiric therapy. Results There was no statistically significant difference in LOS or hospital cost. Subgroup analysis compared patients that received concordant CTX treatment and patients that received discordant LVF treatment. Patients that received concordant CTX treatment had a nonsignificant shorter median LOS (4.16 vs. 6.34 days). Median hospital cost was lower ($4345 vs. $8462, p = 0.004) and median TsT was shorter (5.83 vs. 64.46 h, p < 0.001) in the concordant CTX group. Conclusion Choice of empiric antibiotic therapy should be based on local antibiogram data. For patients with UTI requiring hospitalization, CTX seems to be an effective empiric therapy for most patients. More data is required to examine the effectiveness of local and source specific antibiograms on clinical outcomes when guiding treatment of patients with UTI. PMID- 29147963 TI - Inappropriate anticholinergic drugs prescriptions in older patients: analysing a hospital database. AB - Background Although many anticholinergics are inappropriate in older patients, the prescription of these drugs in a hospital setting has not been extensively studied. Objective To describe prescriptions of anticholinergic drugs in terms of frequency, at risk situations and constipation in hospitalized, older adults. Setting Using a database from a French general hospital (period 2009-2013), we extracted information on 14,090 hospital stays by patients aged 75 and over. Methods Anticholinergic drug prescriptions were automatically detected, with a focus on prescriptions in three well-known at-risk situations: falls, dementia, and benign prostatic hyperplasia. Cases of constipation that might have been causally related to the administration of anticholinergic drugs were screened for and reviewed. Main outcome measure Prescriptions with a high associated risk of anticholinergic related adverse reactions. Results Administration of an anticholinergic drug was detected in 1412 (10.0%) of the hospital stays by older patients. At-risk situations were identified in 413 (36.5%) of these stays: 137 (9.7%) for falls, 243 (17.2%) for dementia, and 114 (8.1%) for benign prostatic hyperplasia; 78 (18.9%) of these 413 stays featured a combination of two or three at-risk situations. Cases of constipation induced by anticholinergic drug administration were identified in 188 (13.3%) patient stays by using validated adjudication rules for adverse drug reactions: 85 and 103 cases were respectively evaluated as "possible" or "probable" adverse drug reactions. Conclusions Anticholinergic drugs prescription was found in 10.0% of hospitalized, older patients. More than one third of these prescriptions occurred in at-risk situations and more than one in ten prescriptions induced constipation. PMID- 29147964 TI - Diabetes care in Qatar: a survey of pharmacists' activities, attitudes and knowledge. AB - Background Diabetes mellitus is recognized as a major public health issue and is one of the top ten causes of death in Qatar. Objective To describe the activities, and attitudes of Qatar pharmacists toward diabetes, to measure their diabetes knowledge and to assess their perceived barriers for diabetes care. Setting Community and ambulatory pharmacies in Qatar. Method Study objectives were addressed in a cross sectional survey of community and ambulatory pharmacists in Qatar. A phone call explaining the study was made to all community and ambulatory pharmacists in Qatar. Consenting pharmacists anonymously completed the survey either online or as paper. Main outcome measure Diabetes related activities, knowledge, attitudes and perceived barriers. Results Over 7 months, 126 surveys were collected (28% response rate). The majority of pharmacists always or often counselled patients on the appropriate time to take each medication and on medication side effects (90%, n = 100/111 and 73%, n = 81/111 respectively). Yet around 50% always or often provided education on the importance of screening for nephropathy (n = 59/112) and retinopathy (n = 58/109). In addition, 41% always or often provided education about the importance of immunization (n = 45/111) and 45% always or often provided therapy recommendations to physicians (n = 49/111). Using Diabetes Attitude Scale-3, most respondents had positive attitudes toward the need for special training, psychosocial impact of diabetes, and patient autonomy. Around 25% (n = 32/126) scored less than 6 out of 10 on the diabetes related knowledge test. The top three barriers for providing diabetes services were lack of time (53%, n = 67/126) shortage of personnel (42%, n = 53/126) and lack of private counseling area (42%, n = 53/126). Conclusion Qatar pharmacists mainly provide basic services for diabetic patients. They have an average diabetes related knowledge. Yet overall, they have positive attitudes toward diabetes, which is a vital component of any successful diabetes care service. PMID- 29147965 TI - Primary squamous cell carcinoma of the breast in association with Zuska's disease. AB - Breast cancer is the most common malignancy in women in the UK with well-defined algorithms of management in place in the western world. Squamous cell carcinoma of the breast is a rare entity and as such knowledge about the pathophysiology, treatment and prognosis are still uncertain. The report describes an unusual case of squamous cell carcinoma arising in an area of Zuska's disease of the breast. It illustrates the heterogeneity of the imaging findings with review of the literature. Decisions on management should be taken on an individual basis with full discussion in the multidisciplinary team meetings where all facets of the case are considered. PMID- 29147966 TI - Polyamine concentration is increased in thoracic ascending aorta of patients with bicuspid aortic valve. AB - Polyamines are cationic molecules synthesized via a highly regulated pathway, obtained from the diet or produced by the gut microbiota. They are involved in general molecular and cellular phenomena that play a role also in vascular disease. Bicuspid aortic valve (BAV) is a congenital malformation associated to a greater risk of thoracic ascending aorta (TAA) aneurysm, whose pathogenesis is not yet well understood. We focused on differential analysis of key members of polyamine pathway and on polyamine concentration in non-dilated TAA samples from patients with either stenotic tricuspid aortic valve (TAV) or BAV (diameter <= 45 mm), vs. normal aortas from organ donors, with the aim of revealing a potential involvement of polyamines in early aortopathy. Changes of gene expression in TAA samples were evaluated by RT-PCR. Changes of ornithine decarboxylase 1 (ODC1), a key enzyme in polyamine formation, and cationic amino acid transporter 1 (SLC7A1/CAT-1) expression were analyzed also by Western blot. ODC1 subcellular localization was assessed by immunohistochemistry. Polyamine concentration in TAA samples was evaluated by HPLC. BAV TAA samples showed an increased concentration of putrescine and spermidine vs. TAV and donor samples, together with a decreased mRNA level of polyamine anabolic enzymes and of the putative polyamine transporter SLC7A1/CAT-1. The catabolic enzyme spermidine/spermine N1 acetyltransferase 1 showed a significant mRNA increase in TAV samples only, together with a decreased concentration of spermine. The decreased expression of SLC7A1/CAT-1 and ODC1 mRNAs in BAV corresponded to increased or unchanged expression of the respective proteins. ODC was located mainly in smooth muscle cell (SMC) nucleus in TAV and donor samples, while it was present also in SMC cytoplasm in BAV samples, suggesting its activation. In conclusion, BAV, but not TAV non-dilated samples show increased polyamine concentration, accompanied by the activation of a regulatory negative feedback mechanism. PMID- 29147967 TI - Association of Inflammatory Bowel Disease with Arthritis: Evidence from In Silico Gene Expression Patterns and Network Topological Analysis. AB - Inflammatory bowel disease (IBD) is an idiopathic prolonged ailment accountable for inflammatory conditions of the intestine. Moreover, arthritis is responsible for joints' stiffness and painful inflammation. IBD shows certain articular extra intestinal manifestations associating IBD with arthritis. IBD associated arthritis is found to be linked with ankylosing spondylitis (AS). The present study insights for the potential and putative drug targets and biomarkers of IBD associated with arthritis using in silico approaches. Microarray data analysis of datasets involving IBD affected and AS affected vs controls were done to explore the differentially expressed genes (DEGs). In majority of the datasets, the common DEGs found were sterile alpha motif domain containing 9 like (SAMD9L), inhibin beta A subunit (INHBA), transmembrane protein 45A (TMEM45A) and transmembrane and tetratricopeptide repeat containing 1 (TMTC1). The common functions and pathways found between the DEGs were control of macromolecule metabolism process, control of metabolic process, control of primary metabolic process, and control of protein metabolic process, cell differentiation, organ development, single-organism development process, multicellular organism development process, development of system, single-multicellular organism development process, developmental process, development of anatomical structure, multicellular organismal development process, control of biological process, cell proliferation, hematopoietic progenitor cell differentiation and immune system process. TMTC1 and INBHA were found to be more biologically significant genes according to the topological properties of the network. This study also suggests that TMTC1, INBHA, TMEM45A and SAMD9L DEGs and their accompanying pathways might have the potential to be exploited as drug targets and biomarkers in the diagnosis and/or treatment of IBD linked arthritis and warrants for further experimental validation. PMID- 29147968 TI - Effects of fasting on the activities and mRNA expression levels of lipoprotein lipase (LPL), hormone-sensitive lipase (HSL) and fatty acid synthetase (FAS) in spotted seabass Lateolabrax maculatus. AB - To investigate the effects of fasting on lipid metabolism in spotted seabass muscle and liver tissues, we analyzed mRNA levels and enzyme activities of lipoprotein lipase (LPL), hormone-sensitive lipase (HSL) and fatty acid synthetase (FAS), and the relationship among fat content, mRNA level, and enzyme activity during fasting of 35 days. The results showed that expressions of all the three genes were ubiquitous. During the fasting experiment, the hepatosomatic index (HSI) and fat content of muscle and liver tissues significantly decreased before 5 days of fasting (P < 0.05). mRNA levels of LPL increased significantly after 5 days of fasting in liver and 7 days in muscle. Abundance of HSL transcripts increased significantly after 14 days of fasting in both muscle and liver. The activities of LPL and HSL presented a trend that increased firstly, decreased subsequently, and then raised again with the prolonged fasting experiment (P < 0.05). However, activities and mRNA levels of FAS decreased significantly after 1 day of fasting in both muscle and liver. Moreover, activities and mRNA levels of FAS showed a moderate correlation in muscle. These results suggested that FAS had a sooner response to fasting than LPL and HSL in both muscle and liver tissues. LPL and HSL played important roles in lipolysis mainly by increasing enzyme activities in the early stage of fasting and mRNA levels in the later stage of fasting in both muscle and liver. Our results also provided useful information on regulating muscle fat content by fasting. PMID- 29147969 TI - Effect of dietary phospholipid levels on growth, lipid metabolism, and antioxidative status of juvenile hybrid snakehead (Channa argus*Channa maculata). AB - The study was conducted to evaluate the effect of dietary phospholipids (PLs) on growth, lipid metabolism, and antioxidative status of hybrid snakehead (Channa argus * Channa maculata). Five isonitrogenous and isolipidic diets with graded levels of PLs (8.5, 19.3, 30.7, 41.5, and 50.8 g kg-1) were fed to triplicate groups of juveniles (initial body weight 12.6 +/- 0.23 g) for 8 weeks. Results showed that dietary PL supplementation significantly improved growth of juveniles. The final body weight (FBW) and specific growth rate (SGR) significantly increased with dietary PLs increasing from 8.5 to 41.5 g kg-1 (P < 0.05). Fish fed with the diet containing 8.5 g kg-1 PLs showed higher feed conversion ratio (FCR) compared to the other treatments (P < 0.05). Survival rate (SR) was not affected by dietary PL levels (P > 0.05). Liver lipid contents, serum triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) contents significantly decreased with the increasing levels of dietary PLs (P < 0.05). However, serum total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) contents and HDL-C/TC and HDL-C/LDL-C value significantly increased with increasing dietary PL levels (P < 0.05). The catalase (CAT), superoxide dismutase (SOD), and carnitine palmitoyl transferase I (CPT-1) activities in the liver significantly increased with incremental dietary PL level (P < 0.05), while the liver malondialdehyde (MDA) contents and fatty acid synthase (FAS) activity significantly reduced (P < 0.05). No significant difference was observed in the glutathione peroxidase (GPx) activity among dietary treatments (P > 0.05).These results confirmed that dietary PL supplementation has beneficial effects on growth performance and antioxidant capacity of juvenile hybrid snakehead. Dietary PLs might reduce lipid deposition in the liver of juvenile hybrid snakehead. PMID- 29147970 TI - Effect of different salinities on gene expression and activity of digestive enzymes in the thick-lipped grey mullet (Chelon labrosus). AB - The effects of different environmental salinities (0, 12, 40, and 55 ppt) on pepsinogen 2 (pga2), trypsinogen 2 (try2), chymotrypsinogen (ctr), and pancreatic alpha-amylase (amy2a) gene expression, and on the total activities of their corresponding enzymes, were assessed in Chelon labrosus juveniles, after their corresponding full-complementary DNA sequences were cloned. Furthermore, the quantitative effect of different salinities on the hydrolysis of feed protein by fish digestive enzymes was evaluated using an in vitro system. Relative pga2 expression levels were significantly higher in animals maintained at 12 ppt, while a significantly higher gene expression level for ctr and try2 was observed at 40 ppt. amy2a gene expression showed its maximum level at 40 ppt and the lowest at 55 ppt. A significant reduction in the activity of amylase with the increase in salinity was observed, whereas the maximum activity for alkaline proteases was observed in individuals maintained at 40 ppt. A negative effect of high salinity on the action of proteases was confirmed by the in vitro assay, indicating a decreased efficiency in the digestive function in C. labrosus when maintained at high environmental salinities. Nevertheless, individuals can live under different environmental salinities, even though gene expression is different and the enzymatic activities are not maintained at the highest studied salinity. Therefore, compensatory mechanisms should be in place. Results are discussed on the light of the importance as a new species for aquaculture. PMID- 29147971 TI - [Antiplatelet or anticoagulative strategies after surgical/interventional valve treatment]. AB - At the end of August 2017 the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) published new joint guidelines for the treatment of valvular heart disease. These guidelines incorporate the scientific progress since the last version of the guidelines published in 2012. This article reviews current guideline recommendations for antiplatelet and anticoagulative therapy after surgical/interventional treatment of the aortic and mitral valves and discusses the underlying scientific evidence. PMID- 29147972 TI - Plasma osteopontin levels in patients with dilated and hypertrophic cardiomyopathy. AB - BACKGROUND: Osteopontin (OPN) is an extracellular matrix glycoprotein that plays a role in a variety of cellular activities associated with inflammatory and fibrotic responses. Increased OPN levels in myocardium and plasma have been demonstrated in patients with dilated cardiomyopathy (DCM). However, nothing is known about OPN levels in patients with hypertrophic cardiomyopathy (HCM). Therefore, the aim of our study was to compare plasma OPN levels in patients with these two most common cardiomyopathies. PATIENTS AND METHODS: We examined plasma OPN as well as creatinine, C-reactive protein (CRP), brain-type natriuretic peptide (BNP), and troponin I levels in 64 patients with DCM, 43 patients with HCM, and 75 control subjects. Transthoracic echocardiography was also performed on all cardiomyopathy patients. RESULTS: Plasma OPN levels were significantly elevated in patients with DCM compared with HCM patients (95 +/- 43 vs. 57 +/- 21 ng/ml; p < 0.001) and control subjects (54 +/- 19 ng/ml; p < 0.001); however, there was no difference between HCM patients and control subjects. New York Heart Association (NYHA) class III or IV disease was more frequently present in DCM patients than in HCM subjects (44 % vs. 2 %, p < 0.0001). In multivariate analysis, BNP and CRP levels together with NYHA class were found to be significant predictors of plasma OPN levels in DCM patients (p = 0.002, p = 0.029, and p < 0.001 for BNP, CRP, and NYHA, respectively). CONCLUSION: Plasma OPN levels were associated with overall heart failure severity rather than with specific cardiomyopathy subtype in patients suffering from DCM or HCM, respectively. PMID- 29147973 TI - Co-Variation of Bacterial and Fungal Communities in Different Sorghum Cultivars and Growth Stages is Soil Dependent. AB - Rhizosphere microbial community composition can be influenced by different biotic and abiotic factors. We investigated the composition and co-variation of rhizosphere bacterial and fungal communities from two sorghum genotypes (BRS330 and SRN-39) in three different plant growth stages (emergence of the second leaf, (day10), vegetative to reproductive differentiation point (day 35), and at the last visible emerged leaf (day 50)) in two different soil types, Clue field (CF) and Vredepeel (VD). We observed that either bacterial or fungal community had its composition stronger influenced by soil followed by plant growth stage and cultivar. However, the influence of plant growth stage was higher on fungal community composition than on the bacterial community composition. Furthermore, we showed that sorghum rhizosphere bacterial and fungal communities can affect each other's composition and structure. The decrease in relative abundance of the fungus genus Gibberella over plant growth stages was followed by decrease of the bacterial families Oxalobacteracea and Sphingobacteriacea. Although cultivar effect was not the major responsible for bacterial and fungal community composition, cultivar SRN-39 showed to promote a stronger co-variance between bacterial and fungal communities. PMID- 29147974 TI - Genotype-related variations in proinflammatory and regulatory cytokine levels in treated and treatment-naive HCV-infected patients. AB - Hepatitis C virus (HCV) modulates immune-related inflammatory responses to induce milder reactions leading to virus persistence. In this regard, the present study aimed to investigate the link between the HCV genotypes and the proinflammatory and regulatory cytokine levels. Ninety patients with hepatitis C infection (68 treatment-naive and 22 treated patients) and 76 healthy blood donors were studied. The serum levels of IFN-gamma, IL-10, IL-17A, and IL-21 were measured by ELISA in the patients and healthy controls. IL-10, IL-17A, and IL-21 levels were significantly higher in HCV patients than in the healthy controls. The same cytokines were also higher in genotype 3a-infected patients compared with genotype 1a-infected patients. Interestingly, in treated patients, lower serum levels of IL-17A and IL-21 were detected in G3a-infected individuals, but not in those infected with G1a. G3a viral load displayed a significant correlation with IL-21 and IL-17A levels. In addition, G1a viral load correlated with IL-10 levels. In G3a-infected patients, a significant association was found between IL 17A serum levels and ALT. We found differences in IL-21 and IL-17A serum levels among HCV-infected patients which were genotype dependent. Since Th17-associated cytokines are associated with the progression of liver disease in HCV patients, IL-17A and IL-21 can be used as important biological markers for evaluating the immunopathogenesis of chronic hepatitis. Our results suggest that HCV G3a along with immune responses such as cytokines in HCV patients should be taken into account when interpreting clinical data and IFN-based therapeutic response. PMID- 29147975 TI - Batrachochytrium salamandrivorans and the Risk of a Second Amphibian Pandemic. AB - Amphibians are experiencing devastating population declines globally. A major driver is chytridiomycosis, an emerging infectious disease caused by the fungal pathogens Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal). Bd was described in 1999 and has been linked with declines since the 1970s, while Bsal is a more recently discovered pathogen that was described in 2013. It is hypothesized that Bsal originated in Asia and spread via international trade to Europe, where it has been linked to salamander die offs. Trade in live amphibians thus represents a significant threat to global biodiversity in amphibians. We review the current state of knowledge regarding Bsal and describe the risk of Bsal spread. We discuss regional responses to Bsal and barriers that impede a rapid, coordinated global effort. The discovery of a second deadly emerging chytrid fungal pathogen in amphibians poses an opportunity for scientists, conservationists, and governments to improve global biosecurity and further protect humans and wildlife from a growing number of emerging infectious diseases. PMID- 29147976 TI - Evaluation of microbial consortia and chemical changes in spontaneous maize bran fermentation. AB - Sustainable exploitation of agro-industrial by-products has attracted great interest in cereal bran valorization. In this research, a polyphasic approach has been carried out to characterize maize bran at microbiological and chemical level during a sourdough like fermentation process, in order to enhance its technological and nutritional properties. Autochthonous microbiota was isolated at different refreshment steps and subjected to identification and molecular characterization. Fermentation was characterized by a rapid increase in lactic acid bacteria and yeasts, with a co-dominance, at the initial stage, of Weissella spp., Pediococcus spp. and Wickerhamomyces anomalus. At the end of the fermentation, a natural selection was produced, with the prevalence of Lactobacillus plantarum, Lactobacillus brevis and Kazachstania unispora. This is the first time that a specific association between LAB and yeasts is reported, during the maize bran fermentation process. Enzymatic activities related to this microbial consortium promoted a "destructuration" of the fiber fraction, an increase in soluble dietary fiber and a reduction of phytic acid content. Our data also evidenced a noticeable increment in ferulic acid. The results obtained indicate that fermentation processes represent an efficient biotechnological approach to increase nutritional and functional potential of maize bran. Moreover, the characterization of microbiota involved in natural fermentation process will allow the selection of specific biotypes, with appropriate metabolic and enzymatic activities, to conduct "tailored" fermentation processes and improve brans or whole-meal flours from both nutritional and technological points of view. PMID- 29147977 TI - Are Isomeric Alkenes Used in Species Recognition among Neo-Tropical Stingless Bees (Melipona Spp). AB - Our understanding of the role of cuticular hydrocarbons (CHC) in recognition is based largely on temperate ant species and honey bees. The stingless bees remain relatively poorly studied, despite being the largest group of eusocial bees, comprising more than 400 species in some 60 genera. The Meliponini and Apini diverged between 80-130 Myr B.P. so the evolutionary trajectories that shaped the chemical communication systems in ants, honeybees and stingless bees may be very different. The aim of this study was to study if a unique species CHC signal existed in Neotropical stingless bees, as has been shown for many temperate species, and what compounds are involved. This was achieved by collecting CHC data from 24 colonies belonging to six species of Melipona from North-Eastern Brazil and comparing the results with previously published CHC studies on Melipona. We found that each of the eleven Melipona species studied so far each produced a unique species CHC signal based around their alkene isomer production. A remarkable number of alkene isomers, up to 25 in M. asilvai, indicated the diversification of alkene positional isomers among the stingless bees. The only other group to have really diversified in alkene isomer production are the primitively eusocial Bumblebees (Bombus spp), which are the sister group of the stingless bees. Furthermore, among the eleven Neotropical Melipona species we could detect no effect of the environment on the proportion of alkane production as has been suggested for some other species. PMID- 29147979 TI - Disappearing Lump-an Unusual Presentation of Large Metastatic Small Bowel Malignant Melanoma. PMID- 29147978 TI - Predictors of Client Satisfaction with Outpatient Mental Health Clinic Services in Italy and New York. AB - The aim of this cross-sectional study was to assess factors associated with client satisfaction in two mental health outpatient settings in Italy and the US. Sociodemographic and clinical variables, hope, and personality characteristics were evaluated in 18-65-year-old patients who had been receiving services for at least 2 months in one of two outpatient clinics, in Italy and the US. Patients were administered: the Healthy Days Core Module, the Kessler Screening Scale for Psychological Distress, the Verona Service Satisfaction Survey, the Client Satisfaction Inventory, the Health Service OutPatient Experience questionnaire, the Herth Hope Index, and the NEO Five-Factor Inventory-3. Bivariate tests for differences between the two samples were conducted, a Satisfaction Composite z score was computed, and a stepwise, backward elimination, multiple linear regression model-including the variables that were significantly associated with Satisfaction Composite Score in bivariate tests-was built. From July 1, 2015 to April 30, 2016, 184 patients (121 in Foligno, 63 in New York City) were enrolled in the study. Predictors of client satisfaction included: receiving services in New York City, being older, having lower educational attainment, having inner positive readiness and expectancy as well as interconnectedness with self and others, and high scores on the agreeableness personality domain. Interestingly, diagnosis and treatment characteristics did not influence satisfaction. Client satisfaction with outpatient mental health services is mainly influenced by sociodemographic characteristics and personality factors more than clinical variables or patterns of care. These findings could have implications regarding trends toward value-based payment models. PMID- 29147980 TI - A long-term comparative assessment of human health risk to leachate-contaminated groundwater from heavy metal with different liner systems. AB - The handling and management of municipal solid waste (MSW) are major challenges for solid waste management in developing countries. Open dumping is still the most common waste disposal method in India. However, landfilling also causes various environmental, social, and human health impacts. The generation of heavily polluted leachate is a major concern to public health. Engineered barrier systems (EBSs) are commonly used to restrict potentially harmful wastes by preventing the leachate percolation to groundwater and overflow to surface water bodies. The EBSs are made of natural (e.g., soil, clay) and/or synthetic materials such as polymeric materials (e.g., geomembranes, geosynthetic clay liners) by arranging them in layers. Various studies have estimated the human health risk from leachate-contaminated groundwater. However, no studies have been reported to compare the human health risks, particularly due to the leachate contamination with different liner systems. The present study endeavors to quantify the human health risk to contamination from MSW landfill leachate using multiple simulations for various EBSs. To quantify the variation in health risks to groundwater consumption to the child and adult populations, the Turbhe landfill of Navi Mumbai in India has been selected. The leachate and groundwater samples were collected continuously throughout January-September in 2015 from the landfill site, and heavy metal concentrations were analyzed using an inductively coupled plasma system. The LandSim 2.5 Model, a landfill simulator, was used to simulate the landfill activities for various time slices, and non-carcinogenic human health risk was determined for selected heavy metals. Further, the uncertainties associated with multiple input parameters in the health risk model were quantified under a Monte Carlo simulation framework. PMID- 29147982 TI - Opportunity mapping of natural flood management measures: a case study from the headwaters of the Warwickshire-Avon. AB - The use of natural flood management (NFM) measures to address severe flooding received considerable public attention during December 2015-January 2016 storms. Within the Warwickshire-Avon Catchment, UK, high arable and improved grassland land cover with small, isolated communities at risk, lead to the exploration of novel techniques that use farmland high up in flood-prone catchments to hold water and reduce outflow discharge. This paper will discuss the methodology used to identify areas in the Warwickshire-Avon, which could be used to install NFM measures to attenuate the storm peak and provide wider ecosystem services, principally addressing total phosphate and sediment entering the receiving watercourse. This involved constructing a GIS database of catchment geomorphological characteristics whilst simultaneously engaging with those significant stakeholders of farmers and landowners to capture local input and produce a model for applied NFM for future projects looking to explore the role of working with natural processes (WwNP) for flood risk reduction within the agricultural environment. The advantages, disadvantages and key lessons learnt are also presented in this paper, to recognise the benefits and limitations of communities and catchments exploring such methods for flood risk management (FRM). PMID- 29147981 TI - Low atrazine dosages reduce sperm quality of Calomys laucha mice. AB - Reproductive effects caused by the exposure to environmentally relevant dosages of atrazine on wild animals are poorly understood. This study evaluated the effects of three dosages of atrazine on sperm parameters of adult Calomys laucha males. Adult mice were orally exposed to dosages of 0 (water and vehicle control), 0.1, 1, and 10 mg/kg of animal weight for a 21-day period. Following exposure, analyses were performed to determine sperm motility parameters, plasma membrane integrity and fluidity, mitochondrial functionality, acrosome integrity, DNA damage, lipid peroxidation, and production of reactive oxygen species (ROS) in the sperm samples. Total and progressive motility were reduced in all dosages in comparison to control groups. Membrane integrity and mitochondrial functionality of sperm were reduced in all dosages, and the sperm membrane fluidity increased in the higher dosages of atrazine (1 and 10 mg/kg), in comparison with the vehicle control. A decrease in the acrosome integrity was noted at 10 mg/kg of atrazine, compared to the control groups. The integrity of DNA, ROS generation, and lipid peroxidation of sperm showed no significant differences when compared with the control groups. These results suggest that exposure to low dosages of atrazine can affect sperm parameters of Calomys laucha and therefore reduce the reproductive capacity of wild rodent species. PMID- 29147983 TI - Dynamics of microbial biomass and community composition after short-term water status change in Chinese paddy soils. AB - Paddy soil experiences repeated anaerobic and aerobic changes during rice growth, the dramatic dynamics of soil water status accompanied by changes in redox condition and O2 availability. However, the effect of rapid water status change on soil microbial biomass and community composition is not well explored. Here, we present a comprehensive study focusing on the short-term water status change in 13 Chinese paddy soils. In order to gain a reliable way to determine soil microbial biomass carbon (MBC) in flooded or water-saturated soils, we also evaluated two different procedures (nitrogen bubbled and 100 degrees C water bath) to remove chloroform in extracts during the fumigation process. Compared to non-flooded paddy soils, the flooded paddy soils tended to have a lower microbial biomass, and this was much clearer using adenosine 5'-triphosphate (ATP) and phospholipid fatty acid (PLFA) analysis compared to biomass measured by the fumigation method. Fungal biomass, which was indicated by both ergosterol and the PLFA 18:2omega6,9c, also decreased after short-term flooding. Changes in soil microbial community composition (determined by PLFA biomarkers) were observed after short-term flooding, but the extent varied between soils. This study indicates that the dynamics of short-term water status altered the soil microbial biomass (ATP, MBC, and total PLFA) and community composition. Finally, our results suggested that liquid fumigation combined with the nitrogen-bubbled method is the best choice for analyzing MBC concentrations in water-saturated soils. PMID- 29147984 TI - Removal of fluoroquinolone from aqueous solution using graphene oxide: experimental and computational elucidation. AB - The environmental risks of antibiotics have attracted increasing research attention due to their prevalence and persistence in the aquatic environment. In this study, oxygen functionalized graphene, namely, graphene oxide (GO), was synthesized by modified Hummer's and Offeman's method and used as potential effective absorbent for the removal of fluoroquinolones (FQs), i.e., ciprofloxacin (CIP), norfloxacin (NOR), and ofloxacin (OFL), from aqueous solution. The as-synthesized GO was characterized by Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction (XRD), thermogravimetric analysis (TGA), and high-resolution transmission electron microscopy (HRTEM). Out of various factors that were taken to consideration while studying the adsorption process, it was found that pH of antibiotic solution is more crucial than the other experimental parameters such as initial antibiotic concentration, contact time, and adsorbent dosage and has significant impact on FQ adsorption via the GO adsorbent. The maximum removal of FQ was observed at pH 7 for CIP and NOR, while adsorption was maximum at pH 4 for OFL. Experimental data best fitted to the pseudo-second-order model as compared to the pseudo-first-order kinetic adsorption model. Best fitting of the equilibrium experimental data to Langmuir isotherm compared to Freundlich isotherm models established that FQ adsorbs over the GO in monolayer manner. Density functional theory (DFT) calculations performed at B3LYP/6-31G(d) level of theory in order to elucidate the thermodynamic feasibility of adsorption process and nature of interactions of antibiotic molecules with the GO adsorbent. Graphical abstract ?. PMID- 29147985 TI - Deciphering the growth, organic acid exudations, and ionic homeostasis of Amaranthus viridis L. and Portulaca oleracea L. under lead chloride stress. AB - Lead (Pb) stress adversely affects in planta nutrient homeostasis and metabolism when present at elevated concentration in the surrounding media. The present study was aimed at investigation of organic acid exudations, elemental contents, growth, and lipid peroxidation in two wild plants (Amaranthus viridis L. and Portulaca oleracea L.), exhibiting differential root to shoot Pb translocation, under Pb stress. Plants were placed in soil spiked with lead chloride (PbCl2) concentrations of 0, 15, 30, 45, or 60 mg Pb/kg soil, in rhizoboxes supplied with nylon nets around the roots. The plant mucilage taken from root surfaces, mirroring the rhizospheric solution, was analyzed for various organic acids. Lead stress resulted in a release of basified root exudates from both plants. Exudates of P. oleracea roots showed a higher pH. In both plants, the pH rising effect was diminished at the highest Pb treatment level. The exudation of citric acid, glutamic acid (in both plants), and fumaric acid (in P. oleracea only) was significantly increased with applied Pb levels. In both plant species, root and shoot Pb contents increased while nutrients (Ca, Mg, and K) decreased with increasing Pb treatment levels, predominantly in A. viridis. At 60 mg Pb/kg soil, shoot Na content of A. viridis was significantly higher as compared to untreated control. Higher Pb treatment levels decreased plant fresh and dry masses as well as the quantity of photosynthetic pigments due to enhanced levels of plant H2O2 and thiobarbituric acid reactive substances in both species. Photosynthetic, growth, and oxidative stress parameters were grouped into three distinct dendrogram sections depending on their similarities under Pb stress. A positive correlation was identified between Pb contents of studied plants and secretion of different organic acids. It is concluded that Pb stress significantly impaired the growth of A. viridis and P. oleracea as a result of nutritional ion imbalance, and the response was cultivar-specific and dependent on exogenous applied Pb levels. Differential lipid oxidation, uptake of nutrients (Ca, Mg, and K) and exudation of citric acid, fumaric acid, and glutamic acid could serve as suitable physiological indicators for adaptations of P. oleracea to Pb enriched environment. The findings may help in devising strategies for Pb stabilization to soil colloids. PMID- 29147986 TI - Leachability and potential ecotoxic impact of trifluralin-impregnated mulch. AB - The leachability, potential ecotoxicity, and photolysis of trifluralin impregnated mulch, a popular retail consumer gardening product, were investigated under environmentally realistic conditions. Leachability of trifluralin from impregnated mulch was low (< 1% of total extractable compound) and in the range of reported values for agricultural soils. No trifluralin transformation products were detected in mulch leachate. Yeast-based estrogenicity and androgenicity screens indicated that aqueous trifluralin is not estrogenic but is moderately androgenic at concentrations ~ 1e - 5 M. Impregnated mulch leachate was not hormonally active, even at undiluted concentrations, but it did exert nonspecific toxicity at dilutions of ~ 1:10. Photolysis of trifluralin was investigated in acetonitrile and water and on mulch surfaces. Degradation on mulch surfaces was diffusion-limited; it was ~ 17 times slower than in aqueous solution, but faster than has been reported on kaolinite. An array of trifluralin transformation products was identified, but in no case did they exceed 10% of the parent compound. Using industry-recommended application guidelines, it is estimated that as much as 1400 MUg/m2 of trifluralin may leach from impregnated mulch upon the first rainfall. However, provided that consumers are aware that such mulch products contain trifluralin and are properly educated about its use, the potential for direct ecotoxic impact is likely to be small. PMID- 29147987 TI - Dynamics of natural revegetation of hydrocarbon-contaminated soil and remediation potential of indigenous plant species in the steppe zone of the southern Volga Uplands. AB - The result of monitoring of natural vegetation growing on oil-contaminated (2.0 75.6 g/kg) and uncontaminated (0.04-2.0 g/kg) soils of a petroleum refinery for a period of 13 years is presented. Floristic studies showed that the families Poaceae, Asteraceae, Fabaceae, and eventually Brassicaceae were predominant in the vegetation cover of both types of soils. Over time, the projective vegetation cover of the contaminated sites increased from 46 to 90%; the species diversity increased twofold: in the ecological-cenotic structure of the flora, the number of ruderal plant species decreased; and the number of steppe, i.e., zonal, plant species increased. Using 62 dominant plant species, we conducted a field study of plant characteristics such as resistance to oil pollution, the ability to enrich the rhizosphere soil with microorganisms and bioavailable mineral nitrogen, and reduction of the concentration of petroleum hydrocarbons. The results enable us to characterize the phytoremediation potential (PRP) of the native plants and identify species that, probably, played a key role in the natural restoration of oil-contaminated soils. Statistical analysis showed correlations between the PRP constituents, and the leading role of rhizosphere microorganisms in the rhizodegradation of petroleum hydrocarbons was proven. A conditional value of PRP was proposed which allowed the investigated plants to be ranked in 11 classes. The study of a large sample of plant species showed that some plants held promise for the use in reclamation of soils in arid steppe zone, and that other species can be used for the rehabilitation of saline soils and semideserts. PMID- 29147988 TI - Phytoextraction with Salix viminalis in a moderately to strongly contaminated area. AB - We tested the suitability of Salix viminalis for phytoextraction with the analysis of selected elements in soil, root, and leaf, and by visual tree condition assessment in an area with varying levels of contamination. Bioconcentration factor (BCF) and translocation factor (TF) were used to assess the phytoextraction potential of willows. The middle part of the study area was strongly contaminated, while the northern and southern parts were moderately contaminated. We found increasing element concentrations toward deeper layers. Mean concentrations of elements in roots were similar among the three parts, while in leaves the highest concentrations were found in the strongly contaminated part of the study area. Tree condition scores were the lowest in the strongly contaminated part of the study area, which was caused by Al, Ca, K, Mg, Ni, Sr, and Zn concentration. These elements induced leaf disease and leaf feeders. The highest BCF values were found for Cu, Fe, Mn, and Zn in root, and for Cd and Zn in leaves, indicating that S. viminalis had high accumulation potential of these elements. Furthermore, TF values were high for Cd, Mn, Sr, and Zn. Our results also demonstrated that soil element composition has major influence on the condition of S. viminalis individuals. Furthermore, visual condition assessment was found to be a useful tool to assess the phytoextraction potential of trees. PMID- 29147989 TI - Abatement of humic acid from aqueous solution using a carbonaceous conjugated microporous polymer derived from waste polystyrene. AB - Humic acid (HA) is a major constituent of natural organic matter (NOM) found in water systems. Although NOM generally does not have any known harmful effects to humans, it imparts repulsive organoleptic properties to water, reacts with disinfectants to produce toxic products, and interferes with the efficiency of water treatment processes. The removal of NOM and related compounds from water is therefore important to render water potable and suitable for other applications. In this work, a hitherto unreported carbonaceous conjugated microporous polymer (CCMP) prepared through the organic-polymeric-precursor-controlled carbonization of hypercrosslinked post-consumer waste polystyrene (WPS) was evaluated for its capacity to remove HA from synthetic wastewater. This advanced material retained the morphology of the precursor material, while its porosity and chemical integrity were significantly improved. The approach is an environmentally friendly way of handling WPS while at the same time remediating NOM-contaminated water. Overall, with a maximum adsorption capacity of 340 mg/g in batch experiments, and a maximum initial removal rate of 95.7% in column experiments, the results showed that CCMP can be used for the remediation of HA-contaminated water at high pH. PMID- 29147990 TI - Assessment of the Effect of Once Daily Nitisinone Therapy on 24-h Urinary Metadrenalines and 5-Hydroxyindole Acetic Acid Excretion in Patients with Alkaptonuria After 4 Weeks of Treatment. AB - BACKGROUND: One of the major metabolic consequences of using nitisinone to treat patients with alkaptonuria is that circulating tyrosine concentrations increase. As tyrosine is required for the biosynthesis of catecholamine neurotransmitters, it is possible that their metabolism is altered as a consequence. Herein we report the 24-h urinary excretion of normetadrenaline (NMA), metadrenaline (MA), 3-methoxytyramine (3-MT) (catecholamine metabolites) and 5-hydroxyindole acetic acid (5-HIAA, metabolite of serotonin) in a cohort of AKU patients before and after a 4-week treatment trial with nitisinone. MATERIALS AND METHODS: 24 h urinary excretions of NMA, MA, 3-MT and 5-HIAA were determined by liquid chromatography tandem mass spectrometry. Interassay coefficient of variation was <10% for all analytes measured, at all concentrations tested. RESULTS: Urine samples were assayed at baseline (pre-nitisinone, n = 36) and 4 weeks later; 7 received no nitisinone (4 male, mean age (+/-SD) 46.3 (16.4) years), and 29 received a daily dose of nitisinone [1 mg (n = 7, 6 male, mean age 45.9 (10.9) years), 2 mg (n = 8, 5 male, mean age 43.9 (13.7) years), 4 mg (n = 8, 5 male, mean age 47.3 (10.7) years) and 8 mg (n = 6, 4 male, mean age 53.8 (8.3) years)]. 3-MT concentrations increase significantly (p < 0.01, at all doses) following nitisinone therapy but not in a dose-dependent manner. NMA concentrations decreased (p < 0.05, at all doses) following nitisinone therapy at all doses. 5 HIAA concentrations decreased following nitisinone therapy and were significantly lower at a daily dose of 8 mg only (p < 0.05). CONCLUSIONS: This study shows that catecholamine and serotonin metabolism is altered by treatment with nitisinone. PMID- 29147991 TI - The Role of the Gut Microbiome in Multiple Sclerosis Risk and Progression: Towards Characterization of the "MS Microbiome". AB - Multiple sclerosis (MS) is the prototypic complex disease, in which both genes and the environment contribute to its pathogenesis. To date, > 200 independent loci across the genome have been associated with MS risk. However, these only explain a fraction of the total phenotypic variance, suggesting the possible presence of additional genetic factors, and, most likely, also environmental factors. New DNA sequencing technologies have enabled the sequencing of all kinds of microorganisms, including those living in and around humans (i.e., microbiomes). The study of bacterial populations inhabiting the gut is of particular interest in autoimmune diseases owing to their key role in shaping immune responses. In this review, we address the potential crosstalk between B cells and the gut microbiota, a relevant scenario in light of recently approved anti-B-cell therapies for MS. In addition, we review recent efforts to characterize the gut microbiome in patients with MS and discuss potential challenges and future opportunities. Finally, we describe the international MS microbiome study, a multicenter effort to study a large population of patients with MS and their healthy household partners to define the core MS microbiome, how it is shaped by disease-modifying therapies, and to explore potential therapeutic interventions. PMID- 29147992 TI - Monitoring the osseointegration process in porous Ti6Al4V implants produced by additive manufacturing: an experimental study in sheep. AB - BACKGROUND: This study investigated the design and osseointegration process of transitive porous implants that can be used in humans and all trabecular and compact bone structure animals. The aim was to find a way of forming a strong and durable tissue bond on the bone-implant interface. METHODS: Massive and transitive porous implants were produced on a direct metal laser sintering machine, surgically implanted into the skulls of sheep and kept in place for 12 weeks. At the end of the 12-week period, the Massive and porous implants removed from the sheep were investigated by scanning electron microscopy (SEM) to monitor the osseointegration process. RESULTS: In the literature, each study has selected standard sizes for pore diameter in the structures they use. However, none of these involved transitional porous structures. In this study, as opposed to standard pores, there were spherical or elliptical pores at the micro level, development channels and an inner region. Bone cells developed in the inner region. Transitive pores grown gradually in accordance with the natural structure of the bone were modeled in the inner region for cells to develop. Due to this structure, a strong and durable tissue bond could be formed at the bone-implant interface. CONCLUSIONS: Osseointegration processes of Massive vs. porous implants were compared. It was observed that cells were concentrated on the surface of Massive implants. Therefore, osseointegration between implant and bone was less than that of porous implants. In transitive porous implants, as opposed to Massive implants, an outer region was formed in the bone-implant interface that allowed tissue development. PMID- 29147993 TI - Preparation and characterization of gelatin/sericin/carboxymethyl chitosan medical tissue glue. AB - BACKGROUND: The development and application of medical glue has been continuously expanding and advancing. However, there are few glues that combine low-cost with excellent biocompatibility. METHODS: We have prepared a medical tissue glue using a gelatin (Gel), sericin (SS) and carboxymethyl chitosan (CMCS) blend solution, cross-linked with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). The combination's characteristics and microstructure morphology were observed by Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscope (SEM). Bond strength tests were used to measure the bond strength of the glue. To assay blood compatibility, a hemolytic test, dynamic coagulation test and platelet adherence test were also investigated. Further, the cellular behavior of L-929 and a systemic acute toxicity test on the Gel/SS/CMCS tissue glue were also investigated by MTT and H&E staining. RESULTS: Characterization analysis showed that there was stable binding between raw materials, forming an amide bond with homogeneous holes. The bond strength of the tissue glue reached 2.50 +/- 0.04 N in 10 minutes, slightly higher than the alpha-cyanoacrylate biological glue (2.25 +/- 0.05 N). Blood compatibility tests revealed that the glue had outstanding blood compatibility. Further, cytotoxicity test and systemic acute toxicity test both showed that the glue was without cytotoxicity and not toxic to the body. CONCLUSIONS: The Gel/SS/CMCS tissue glue we prepared at low cost had excellent biocompatibility and structural characteristics. It could be a better candidate for tissue engineering in biomedical applications applied in clinical practice to promote skin wound healing and to further reduce the formation of skin wound scars. PMID- 29147994 TI - Printability of papers recycled from toner and inkjet-printed papers after deinking and recycling processes. AB - BACKGROUND: In our contemporary world, while part of the fibers used in the paper industry is obtained from primary fibers such as wood and agricultural plants, the rest is obtained from secondary fibers from waste papers. To manufacture paper with high optical quality from fibers of recycled waste papers, these papers require deinking and bleaching of fibers at desired levels. High efficiency in removal of ink from paper mass during recycling, and hence deinkability, are especially crucial for the optical and printability quality of the ultimate manufactured paper. METHODS: In the present study, deinkability and printability performance of digitally printed paper with toner or inkjet ink were compared for the postrecycling product. To that end, opaque 80 g/m2 office paper was digitally printed under standard printing conditions with laser toner or inkjet ink; then these sheets of paper were deinked by a deinking process based on the INGEDE method 11 p. After the deinking operation, the optical properties of the obtained recycled handsheets were compared with unprinted (reference) paper. Then the recycled paper was printed on once again under the same conditions as before with inkjet and laser printers, to monitor and measure printing color change before and after recycling, and differences in color universe. RESULTS: Recycling and printing performances of water-based inkjet and toner-based laser printed paper were obtained. The outcomes for laser-printed recycled paper were better than those for inkjet-printed recycled paper. CONCLUSIONS: Compared for luminosity Y, brightness, CIE a* and CIE b* values, paper recycled from laser-printed paper exhibited higher value than paper recycled from inkjet-printed paper. PMID- 29147996 TI - Comments on a stripping method to remove stuck catheter and a plea to adopt large size hemodialysis catheters. PMID- 29147997 TI - Drug eluting balloon angioplasty for assisted maturation of failing fistulae. AB - OBJECTIVE: To present our experience of balloon-assisted maturation with drug eluting balloon dilation in patients with recurrent failing arteriovenous fistulae. CASE SERIES: Three patients (all males, mean age 71 years) with a complex history of failed attempts at native fistula creation underwent surgical creation of arteriovenous fistulae. Two patients had a two-stage brachio-brachial fistula and 1 had a brachio-cephalic fistula that also required subsequent elevation. After a few weeks of preserved patency with a thrill detected clinically, all patients had a gradual deterioration of flow manifested with loss of thrill and multiple severely stenotic lesions of neo-intimal hyperplasia seen on duplex ultrasound. All 3 non-maturing native arteriovenous fistulae had 1 or more angioplasties with regular balloons that were initially successful; however, they rapidly deteriorated with a loss of thrill and a recurrence of multiple stenosis. Drug-eluting balloon dilation was used subsequently as a last resort to save these failing fistulae. All procedures were successful with the preservation of patency and adequate fistula flow (>600 mL/min) during the follow-up period (4 8 months, mean 6 months), and all patients received successful dialysis with 2 needle cannulation of their fistulae. There were no adverse events during the study period. CONCLUSIONS: Drug-eluting balloon angioplasty was to salvage nonmaturing fistulae with durable results in complex patients where conventional treatment had previously failed. Drug-eluting balloons may provide a useful treatment option for patients prone to multiple access failures due accelerated neo-intimal hyperplasia. PMID- 29147998 TI - Hemodialysis tunneled-cuffed catheter-related atrial thrombus complicated with asymptomatic pulmonary emboli. PMID- 29147999 TI - Selective placement of autogenous arteriovenous fistulae in an over 80-year-old population. AB - INTRODUCTION: With improved life expectancy and quality of life, elderly patients constitute a progressively larger fraction of consumers utilising renal replacement therapy (RRT). Although substantial data exist for younger cohorts, minimal evidence exists for outcomes of arteriovenous fistula (AVF) and central catheters (CVC) placed in those patients over 80 years. We examined outcomes of primary AVF placement in this cohort to ascertain durability and benefits of AVF in the over 80-year-old population. METHODS: Retrospective analysis was undertaken of all autogenous AVFs and CVCs placed in patients aged over 80 years at Gold Coast University Hospital between March 2010 and February 2016. Prospectively collected demographic data, co-morbidities and operative factors were analysed. RESULTS: Sixty-five AVF and 12 CVC patients were identified. Mean age at intervention was 83.9 years and 76% of the patients were male. The majority of procedures were autogenous radio-cephalic AVF; median post-operative length of stay was 2 days. Cumulative AVF patient survival at 12 and 24 months was 82% and 72%, respectively. This was significantly better than survival rates of CVC patients, with 12-month survival of 45%. Primary patency at 6, 12 and 24 months was 58%, 39% and 31%. There were 113 follow-up procedures in 41 patients required to maintain patency. CONCLUSIONS: Although patency rates are inferior and re-intervention rates higher than in younger patients, AVF can be a durable option for RRT in selected elderly patients with improved mortality rates compared with CVC. Age alone should not preclude primary AVF placement. PMID- 29148000 TI - The feasibility and safety of PICCs accessed via the superficial femoral vein in patients with superior vena cava syndrome. AB - OBJECTIVE: To investigate the feasibility and safety of the peripherally inserted central catheters (PICCs) accessed via the superficial femoral vein in patients with superior vena cava syndrome (SVCS). METHODS: From October 2010 to December 2014, 221 cancer patients with SVCS in our center received real-time ultrasound guidance of the superficial femoral vein inserted central catheters (FICCs) at the mid-thigh. PICC insertion via upper extremity veins had also been investigated in 2604 cancer patients without SVCS as control. The average catheterization time, one-time puncture frequency, catheter duration and complications were compared between two groups. RESULTS: In the FICC group, the mean catheterization time was 31.60 +/- 0.15 minutes, one-time puncture frequency was 1.05 +/- 0.08, and catheter duration was 168.95 +/- 20.47 days. There was no significant difference compared with the upper extremity veins PICC group: 31.11 +/- 3.86 minutes, 1.03 +/- 0.30, and 173.58 +/- 39.81 days, respectively. The major complications included skin allergy to chlorhexidine gluconate (CHG) dressings, exudation, catheter-related infection, catheter occlusions, unplanned catheter withdrawal, venous thrombosis, mechanical phlebitis, and catheter malposition. It is interesting that a higher rate of catheter malposition was observed in the upper extremity veins PICC group than in the FICC group (2.15% vs. 0.00%). There were no significant differences in other complications between the two groups. CONCLUSIONS: Real-time ultrasound-guided PICCs accessed via the superficial femoral vein at the mid-thigh is a new modified technique with low complications, which can be a feasible and safe alternative venous access for patients with SVCS. PMID- 29148001 TI - An arterioarterial prosthetic graft as an alternative option for haemodialysis access: a systematic review. AB - INTRODUCTION: All arteriovenous fistula/grafts options should be exhausted before haemodialysis is carried out via central venous catheters (CVC). CVCs carry high morbidity and mortality risks and in some patients, the central veins could be exhausted. In these patients, an arterioarterial prosthetic loop (AAPL) or straight graft can be the only option for haemodialysis. A systematic review was thus carried out to look at the use of arterioarterial graft for haemodialysis, with regards to dialysis adequacy, complications, and patency rates. METHODS: An electronic search was performed using the EMBASE and MEDLINE databases from inception until June 2017. Study retrieval was conducted according to PRISMA guidelines. RESULTS: A total of eight studies published between 1976 and 2017 were identified for pooled analysis. The studies were retrospective cohort in design and reported data on 151 patients. Primary patency rate ranged from 67% 94.5% at six months to 54%-61% at 36 months, with secondary patency rates from 83%-93% at six months to 72%-87% at 36 months. All studies documented satisfactory haemodialysis. Although limited by the size of the cohort of patients studied, patients with end-to-side grafts did not suffer from distal ischaemia when the graft occluded unlike patients who had their graft sutured as end-to-end. CONCLUSIONS: This review highlights the potential benefit of arterioarterial grafts for dialysis as an alternative vascular access option. As a result, this review calls for registry-based multicentre study to evaluate this treatment arm as an alternative option when all AVF/AVG options are exhausted. PMID- 29148002 TI - Targeting zero catheter-related bloodstream infections in pediatric intensive care unit: a retrospective matched case-control study. AB - INTRODUCTION: The aim of this study was to evaluate the effectiveness and safety of a new three-component 'bundle' for insertion and management of centrally inserted central catheters (CICCs), designed to minimize catheter-related bloodstream infections (CRBSIs) in critically ill children. METHODS: Our 'bundle' has three components: insertion, management, and education. Insertion and management recommendations include: skin antisepsis with 2% chlorhexidine; maximal barrier precautions; ultrasound-guided venipuncture; tunneling of the catheter when a long indwelling time is expected; glue on the exit site; sutureless securement; use of transparent dressing; chlorhexidine sponge dressing on the 7th day; neutral displacement needle-free connectors. All CICCs were inserted by appropriately trained physicians proficient in a standardized simulation training program. RESULTS: We compared CRBSI rate per 1000 catheters days of CICCs inserted before adoption of our new bundle with that of CICCs inserted after implementation of the bundle. CICCs inserted after adoption of the bundle remained in place for a mean of 2.2 days longer than those inserted before. We found a drop in CRBSI rate to 10%, from 15 per 1000 catheters-days to 1.5. CONCLUSIONS: Our data suggest that a bundle aimed at minimizing CR-BSI in critically ill children should incorporate four practices: (1) ultrasound guidance, which minimizes contamination by reducing the number of attempts and possible break-down of aseptic technique; (2) tunneling the catheter to obtain exit site in the infra-clavicular area with reduced bacterial colonization; (3) glue, which seals and protects the exit site; (4) simulation-based education of the staff. PMID- 29148003 TI - Prevalence of medical adhesive-related skin injury at peripherally inserted central catheter insertion site in oncology patients. AB - INTRODUCTION: The aim of our study was to identify the prevalence and risk factors of medical adhesive-related skin injuries (MARSI) at peripherally inserted central catheters (PICC) insertion site in oncology patients. METHODS: A cross-sectional observational study lasting two weeks was carried out in four inpatient departments. Skin assessment data and photographs of skin were collected during PICC maintenance. Other related information came from medical records. The skin injuries were classified by dermatologists and PICC specialized nurses. MARSI prevalence was calculated and the associated factors were analyzed statistically. RESULTS: All 419 patients were included. The prevalence of total MARSI at PICC insertion site was 125, (29.83%), including mechanical skin injury (73, 17.42%), contact dermatitis (CD) (39, 9.31%), moisture-associated skin damage (11, 2.63%), folliculitis (2, 0.48%). Multivariate analysis identified two independent risk factors for MARSI including age >=50 y (p = 0.031, odds ratio [OR] = 4.521, 95% confidence interval [CI] [1.389, 20.620]) and hematologic malignancies (p = 0.000, OR = 2.514, 95% CI [1.590,3.97]. Oxaliplatin and arsenic trioxide infusion through PICC, history of skin allergies was associated with CD, with p = 0.020, OR = 3.492, 95% CI (1.220, 9.990); p = 0.003, OR = 4.565, 95% CI (1.661,12.547); p = 0.000, OR = 12.333, 95% CI (3.669, 41.454), respectively. CONCLUSIONS: MARSI at PICC insertion site is a frequent event among oncology patients. Epidemiological data and independent risk factors are presented in our study, which provide a basis for future study in this area. PMID- 29148004 TI - Cephalad dislocation of PICCs under different upper limb positions: influence of age, gender, BMI, number of lumens. AB - PURPOSE: To evaluate parameters that influence the amount of movement of peripherally inserted central catheter (PICC) tips regarding upper limb movement. METHODS: In a prospective 12-month observational study, 200 PICCs were implanted in 162 patients (mean age 56.8 +/- 15.2 years) by interventional radiologists into the basilic vein of the mid-aspect of the upper arm. Three PICC tip positions were documented with a chest x-ray: patient supine with an abducted (90 degrees ), an adducted arm, and in an upright position with an adducted arm. Multivariable analyses were performed, based on the three positions: body mass index (BMI), number of lumens, age, gender, side of the implantation, and brand. RESULTS: Up to 88% of the PICCs dislocated in a mean of 19 mm cephalad when the patient was positioned from a supine in an upright position. The greatest influence upon dislocation was the position change from supine to upright. The side of the implanted PICC (left vs. right) had no influence. CONCLUSIONS: Cephalad dislocations of mean 19 mm regularly occur in the upright position induced by gravity. This needs to be taken in account and the PICC should be safely positioned one vertebra lower in the superior vena cava superior with a last confirmation of the PICC placement in an upright position. PMID- 29148005 TI - Microsurgery for "wrist" arteriovenous fistula creation in children: a retrospective cohort study. AB - INTRODUCTION: Creating functional arteriovenous fistulae (AVF) at the wrist is challenging in paediatric patients because of the small calibre of the blood vessels. METHODS: We report our experience with AVF surgery in children younger than 15 years of age using microsurgical techniques. Twenty-five patients underwent AVF surgery between 2003 and 2015 (20 for haemodialysis, 4 for plasmapheresis and 1 for parenteral nutrition). Median (range) age was 9 (2-15) years and median weight was 24 (8-61) kg. RESULTS: The one-month occlusion rate was 8%. The primary and secondary patency rates at 1, 2, 3 years were: 60%, 49%, 42%, and 82%, 72%, 54%, respectively. The median (range) maturation time was 4.53 (0.5-11.2) months. We found no statistically significant effect of patient age, body weight, type of AVF and indication for AVF creation on the primary and secondary patency rates. CONCLUSIONS: Microsurgical AVF creation at the wrist can be performed with satisfactory results and should be the preferred technique in the paediatric population. PMID- 29148006 TI - Autogenous forearm loop arteriovenous fistula creation. AB - INTRODUCTION: Arteriovenous fistula is a lifeline for end-stage kidney disease patients on dialysis. The quality of the vein and artery to be used plays a crucial role in attaining a functioning, reliable and long-lasting arteriovenous fistula. The aim of the study is to present an alternative for haemodialysis access to preserve the upper arm vasculature for future use - the forearm loop arteriovenous fistula. METHODS: From October 2015 to September 2016, 202 patients with chronic kidney disease (CKD), stages 4 and 5, underwent arteriovenous fistula creation at the Universiti Sains Malaysia Hospital, Malaysia. Nine patients, with severe atherosclerosis of the distal artery, but with satisfactory veins, underwent forearm loop arteriovenous fistula creation. Maturation of the fistula was based on the classification by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI). RESULTS: All nine patients who underwent forearm loop arteriovenous fistula have had diabetes mellitus for more than 10 years. Only one fistula failed to mature within 6 weeks. Two arteriovenous fistulas thrombosed at 3 and 5 months, respectively, after the commencement of haemodialysis. However, the other six matured fistulas are still functioning well after a year of regular usage. CONCLUSIONS: Distal forearm arteries in diabetics may be severely atherosclerotic. Forearm loop arteriovenous fistula can be considered as the primary access for cases decided as inconvenient for fistula creation due to severe occlusive atherosclerotic disease of the forearm arteries; in order to preserve upper arm veins for future access procedures. PMID- 29148007 TI - How to treat arteriovenous graft infection: total versus partial graft excision. AB - INTRODUCTION: Arteriovenous graft (AVG) infection can result in life-threatening sepsis and loss of vascular access. A retrospective study was performed to establish an appropriate treatment strategy for AVG infection. METHODS: A total of 50 cases of AVG infection were treated between January 2005 and June 2016. The surgical methods used were total graft excision (TGE) (n = 34), or partial graft excision (PGE) with interposition graft (n = 16). RESULTS: Infection was noted at a puncture site (n = 22), a prior incision for surgery or endovascular therapy (n = 20), and abandoned (currently unused) grafts (n = 5). Infection occurred within 1 month after AVG creation (n = 1), or any intervention (n = 14), and more than 1 month after creation or intervention (n = 35). Simultaneous remote infection was identified in 7 patients, 2 of whom underwent an operation for infective endocarditis and spondylitis. After PGE, 5 patients (5/16, 31.2%) having recurrent infection were treated with further graft excision; however, no patient showed life-threatening complications. After TGE, a central venous catheter (CVC) was inserted and used for a median period of 90 days. Among 34 patients who underwent TGE, new vascular access was created in 18 patients at a median period of 2 months later, and 12 patients continued to use a CVC until last follow-up or death. CONCLUSIONS: PGE could be a treatment option for AVG infection to achieve both infection eradication and vascular access preservation in selected patients. Because of a higher risk of recurrent infection, sufficient surgical removal and careful postoperative management are warranted. PMID- 29148008 TI - Supervised preoperative forearm exercise to increase blood vessel diameter in patients requiring an arteriovenous access for hemodialysis: rationale and design of the PINCH trial. AB - BACKGROUND: Failure of maturation occurs in 30%-60% of arteriovenous fistula (AVF) creation for hemodialysis, with highest rates in distal radiocephalic fistulas. This is partly due to initial small blood vessel size with limited blood flow capacity. Forearm exercise has shown potential as stimulus for increasing blood vessel size in patients with end-stage renal disease (ESRD) and may promote maturation of AVFs in the upper limb when applied postoperatively. However, it is unknown if forearm exercise increases blood vessel size pre operatively, which may contribute to more distal AVF creation and raise success rates of AVF surgery. This study will investigate these issues. METHODS AND RESULTS: The PINCH trial (refers to 'pinching') is an investigator-initiated, multicenter, single-blinded, randomized controlled trial with 1:1 randomization to perform supervised forearm exercises compared to no exercise 6 weeks pre operatively before creation of an AVF. Forty patients receiving an AVF will be included. The main study endpoints are blood vessel diameter (cephalic or basilic vein and radial and ulnar artery), AVF surgical plan (radiocephalic or brachiobasilic/cephalic), and three-month (assisted) maturation rate. The burden of the performed forearm exercises will be evaluated using Kidney Disease Quality of Life (KDQOL-SF Dutch version 1.2) and exercise specific questionnaires. The PINCH trial is planned to start in November 2017. Enrollment is expected to be completed at the end of 2019. CONCLUSIONS: The PINCH study is the first trial to evaluate the effect of pre-operative, supervised forearm exercises on vein diameter and fistula maturation in hemodialysis patients. TRIAL REGISTRATION: NTR6382. PMID- 29148009 TI - Preoperative ultrasound for runoff-venous decompression of peripheral nerves for arteriovenous access-related pain in the upper limb. AB - INTRODUCTION: Arteriovenous access (AVA)-related pain treated successfully with runoff-venous decompression of the causative nerve, following ultrasound (US) assisted preoperative evaluation, has never been reported. CASE PRESENTATION: A 57-year-old man suffering from constant exhausting pains along the outflow cephalic vein of the radiocephalic arteriovenous fistula at the wrist and the antecubital fossa, was treated surgically after the diagnosis of AVA-related pain derived from cephalic vein compression on two peripheral cutaneous nerves, the superficial radial nerve (SRN) and the lateral antebrachial cutaneous nerve (LACN). TECHNIQUE: The SRN and LACN, which ran along and/or provided sensory innervation to the painful regions in the upper limb, were traced using ultrasonography in the short axis and proved to be compressed by and in contact with veins where the pain existed, at the wrist and the antecubital fossa. Once diagnostic US-guided blocks of both were performed and pain disappeared, they were identified as the causative nerves. The cephalic venous decompression surgeries that separated and transposed the veins away from the SRN and the LACN were performed sequentially under pneumatic tourniquet inflation to improve nerve visualization. RESULTS: The pains disappeared after the operations. An adequate length of the runoff cephalic vein was maintained for needle cannulations during hemodialysis. CONCLUSIONS: Outflow venous compression to the peripheral nerves may be a cause of AVA-related pain. US-guided assessments of the nerves may improve the safety and efficiency of venous decompression surgeries to treat AVA related pains. PMID- 29148011 TI - Dislocation of the end of the catheter due to pressure of the mass of soft tissue of the patient's breast. PMID- 29148010 TI - Experimental study on the chemico-physical interaction between a two-component cyanoacrylate glue and the material of PICCs. AB - INTRODUCTION: The use of cyanoacrylate glue as sealant on the exit site of peripherally inserted central catheters (PICCs) may offer some important clinical advantages. However, concerns exist about the potential interaction between cyanoacrylate and the material of the catheter itself. The aim of this study was to investigate the possibility of damage to the catheter secondary to a long-term contact with a two-component skin glue (N-butyl + octyl cyanoacrylate). METHODS: Twelve PICCs of different brands and types were selected (11 made of polyurethane and one made of silicon). PICCs were glued onto artificial skin pads, slightly wetted with Earle solution. The pads were kept in an egg incubator at 34 degrees C and 60% humidity, for up to twelve weeks. Possible signs of degradation were monitored by surface analyses and mechanical tests. Scanning electron microscopy observations, surface roughness measurements, pressure strength and uniaxial tests were performed. RESULTS: Samples were analyzed after 4, 8 and 12 weeks of contact with the glue. No chemical reaction between the glue and the material of the catheters was evident. The mechanical strength of PICCs was consistently within the ranges of ISO standards. An expected increase in the stiffness of the samples covered with glue was observed in uniaxial tests. The silicon catheter was weaker than the polyurethane catheters and was damaged while trying to remove it from the pad for tests. CONCLUSIONS: The long-term use of N-butyl + octyl cyanoacrylate glue on polyurethane PICCs is not expected to be associated to any damage to the catheter. PMID- 29148012 TI - Use of bovine carotid artery for buttonhole technique hemodialysis. AB - PURPOSE: Assess the feasibility of using a bovine carotid artery graft for buttonhole technique hemodialysis in patients who are not candidates for a native fistula. METHODS: Case reports used to demonstrate selection criteria and results for this approach. Criteria include: knowledgeable patient with prior dialysis experience, stable graft in place for 3 months minimum, not a candidate for a native fistula, and able to maintain close follow-up. RESULTS: Both grafts were based on axillary vessels and have been in place for a total of 64 months. They have been used for dialysis via buttonhole for a total of 40 months. There have been three procedures on these patients, post-buttonhole use (.87/year). There have been no infections. CONCLUSIONS: These patients were carefully selected based on desire, support, knowledge/experience and ability. Their success suggests that buttonhole technique for hemodialysis on a synthetic semi-biologic graft can be accomplished with morbidity and longevity similar to any graft using non-buttonhole needle access. PMID- 29148013 TI - VITOM(r) 3D system in surgeon microsurgical vascular training: our model and experience. PMID- 29148014 TI - Unfavorable clinical implications of peripheral blood CD44+ and CD54+ lymphocytes in patients with lung cancer undergoing chemotherapy. AB - BACKGROUND: There is an unmet need for identification of additional prognostic markers for lung cancer. The aim of this study was to identify novel clinical and immunological predictors of prognosis in lung cancer patients. METHODS: Lymphocyte subsets CD3+, CD4+, CD8+, CD4+/8+, CD25+, CD69+, CD44+ and CD54+ were quantified in peripheral blood using flow cytometry, for 203 newly diagnosed lung cancer patients and 120 healthy controls. RESULTS: The levels of CD3+, CD4+, CD8+, CD4+/CD8+ and CD69+ lymphocytes were significantly lower in patients with lung cancer compared with the healthy control group, while CD54+ and CD44+ lymphocytes were significantly higher. In stage III/IV patients with lymph node metastasis or distant metastasis, the levels of CD44+ and CD54+ lymphocytes were significantly increased compared with patients with stage I/II disease (p<0.05). The levels of CD44+ and CD54+ lymphocytes markedly reduced after chemotherapy, and follow-up analysis indicated that patients found without increase of CD44+ and CD54+ lymphocytes after chemotherapy had survival advantages. Independent predictors of survival in lung cancer patients included clinical stage (hazard ratio [HR] = 2.791; 95% confidence interval [95% CI], 1.42-3.54, p<0.001), CD44+ lymphocytes (HR = 1.282; 95% CI, 1.02-1.49, p = 0.002) and CD54+ lymphocytes (HR = 1.475; 95% CI, 1.22-1.73, p = 0.003). Elevated levels of CD44+ and CD54+ lymphocytes correlated with poor prognosis in lung cancer patients. CONCLUSIONS: Peripheral blood lymphocyte subsets in patients with lung cancer are different from those in healthy people, and circulating CD44+ and CD54+ lymphocytes seem to be a promising criterion to predict survival in lung cancer patients undergoing chemotherapy. PMID- 29148015 TI - Clinical performance and utility of a NNMT-based urine test for bladder cancer. AB - BACKGROUND: Bladder cancer (BC) represents the most common neoplasm of the urinary tract. Although cystoscopy and urine cytology represent the gold standard methods to monitor BC, both procedures have limitations. Therefore, the identification of reliable biomarkers for early and noninvasive detection of BC is urgently required. METHODS: In this study, we analyzed nicotinamide N methyltransferase (NNMT) expression in urine samples from 55 BC patients and 107 controls, using real-time polymerase chain reaction (PCR). Receiver operating characteristic (ROC) analysis was used to identify the best cutoff value to discriminate BC patients from healthy donors, and to evaluate the diagnostic accuracy of a urine-based NNMT test. RESULTS: The results demonstrated that urinary NNMT expression was significantly (p<0.05) higher in BC patients. Moreover, a significant (p<0.05) inverse correlation was found between NNMT expression and histological grade. The ROC analysis revealed that a DeltaCq of 13.3 was the best cutoff value, since it was associated with the highest combination of sensitivity and specificity. Moreover, the area under the curve (AUC) value was 0.913 (p<0.05), indicating the excellent diagnostic accuracy of a urine-based NNMT test. CONCLUSIONS: Our data indicate that NNMT is a promising biomarker that could be used to support the early and noninvasive diagnosis of BC. PMID- 29148016 TI - Association of XPG gene rs751402 polymorphism with gastric cancer risk: a meta analysis in the Chinese population. AB - BACKGROUND: Previous studies have revealed a conflicting relationship of xeroderma pigmentosum group G (XPG) gene polymorphism with gastric cancer (GC) risk. To our knowledge, this is the first meta-analysis to investigate the association between rs751402 mutation located on the XPG promoter region and GC risk. METHODS: We undertook a meta-analysis by identifying relevant articles from the PubMed, Web of Science and China National Knowledge Infrastructure (CNKI) databases on February 28, 2017. By pooling 9 eligible studies, 3,539 GC cases and 3,948 controls were included. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using the fixed-effects or random-effects model depending on the existence of heterogeneity across studies. The population attributable risk (PAR%) was estimated to better understand the public health risk. RESULTS: All included studies had been conducted in China. Significant associations were found between the XPG rs751402 polymorphism and the risk of GC (TT vs. CC: OR = 1.43, 95% CI, 1.11-1.84; CT vs. CC: OR = 1.15, 95% CI, 1.04 1.26; dominant model: OR = 1.17, 95% CI, 1.07-1.29; recessive model: OR = 1.30, 95% CI, 1.05-1.62; T vs. C: OR = 1.18, 95% CI, 1.06-1.32). The estimated PAR% was about 4.9%-8.8%. Funnel plots did not reveal any potential publication bias. The sensitivity analyses showed that the results were relatively robust. CONCLUSIONS: This meta-analysis indicates that the XPG rs751402 polymorphism may be a risk factor for GC in the Chinese population. PMID- 29148017 TI - Outcomes and mortality after hip fractures treated in Kazakhstan. AB - INTRODUCTION: Patients with hip fractures are usually treated operatively in Western Europe. However, in Mid-Asia different indications are used to decide whether this patient is suitable for operative treatment and those are related to specific traditions and rules in hospital. Thus, traditions and surgeon/patient fears seem to affect treatment choices in hip fractures and subsequent outcomes. The aim of our study was to investigate patients with hip fractures and compare outcome at 1-year follow-up in the operated and nonoperated patient groups. METHODS: All patients over 50 years old who sustained a hip fracture, between January 2014 and December 2014, were included. Patients were assessed preoperatively and at 1-year follow-up, using questionnaires from National Swedish Hip Fracture Register and quality of life (Euroqol EQ-5D). RESULTS: Out of 398 included patients, 299 were operated on and 99 were not. 344 patients remained for our analysis before the end of 1-year follow-up. 51 patients (65%) deceased in the nonoperated group as compared to 55 (21%) in the operated group, p<0.001. Out of 27 patients in the nonoperated group hip function was evaluated at 1-year follow-up, 11 (41%) were walking independently or using 1 stick, as compared to 192 (91%) in the operated group. CONCLUSIONS: We conclude that nonoperative treatment of hip fracture patients is associated with higher mortality and worse functional outcome as compared to those who were treated operatively. We therefore advocate operative treatment of the hip fracture in the vast majority of cases. PMID- 29148018 TI - Lightbulb technique for the treatment of osteonecrosis of the femoral head. AB - INTRODUCTION: The aim of this study was to report the clinical and radiological outcomes for 21 patients (28 hips) treated for osteonecrosis of the femoral head using the lightbulb technique, a nonvascularised bone grafting technique. METHODS: The study group included 14 men and 7 women, with a mean age of 33.2 (range 22-50) years, presenting with avascular necrosis of the femoral head of stage 4a or earlier, according to the Steinberg classification. Patients were treated using the nonvascularised lightbulb bone grafting technique. The primary clinical outcome was the Harris Hip Scores (HHS), while primary outcomes of treatment effectiveness and disease progression were based on radiographic evidence of disease progression and the need for total hip replacement. The rate of treatment success and failure was evaluated using the Kaplan-Meier survival analysis. RESULTS: The mean HHS increased from 52.66 to 74.33 after treatment, with excellent-to-good outcomes obtained in 21 (75%) of the cases. Fair-to-poor results were obtained in 7 (25%) of the cases, with total hip arthroplasty subsequently required in 5 of these cases. The radiological failure rate was 50% among cases treated in Steinberg stage 1 (1/2), 42% in stage 3 (5/12), and 100% in stage 4 (2/2). CONCLUSIONS: The lightbulb technique can provide a clinically acceptable rate of successful treatment of osteonecrosis of the femoral head when used in the early stages of the disease, prior to collapse of the femoral head. PMID- 29148019 TI - A prospective randomised comparison of 2 skin closure techniques in primary total hip arthroplasty surgery. AB - INTRODUCTION: As an essential step of total hip arthroplasty (THA), an effective and secure skin closure technique after primary THA is important. Metallic staples closure and subcuticular suture are the 2 common techniques for skin closure. However, which closure technique is the optimal skin-closure method remains unclear. The purpose of this prospective randomised clinical study was to compare the clinical outcomes and costs between staples and subcuticular suture techniques. METHODS: In this clinical study, 165 patients who underwent primary unilateral THA through a posterolateral approach from August 2014 to May 2015 were included. According to skin closure technique, the patients were randomised into staples group (interrupted suture with staples, 83 cases) and sutures group (running 4-0 absorbable subcuticular suture, 82 cases). The same operative and perioperative care were provided to all patients. The surgical site infections (SSIs) rate, closure time, time to dry wounds and postoperative hospital stay were recorded and compared. Besides, cosmetic results and patient's satisfaction were evaluated with Hollander wound evaluation score (HWES) and VAS score at postoperative 3 months follow-up respectively. Relative total costs were recorded as well. RESULTS: It was shown that no infections developed in sutures group, while 2 postoperative superficial infections (2.4%) occurred in the staples group. There was a statistically significant difference in the time to dry surgical incisions and postoperative hospital stay favoring sutures (4.8 vs. 5.0 days, p = 0.028; 6.0 vs. 12.0 days, p<0.001, respectively). The cutaneous incision closure using staples consumed significantly less time than that with subcuticular suture (24.7 vs. 357.7 seconds, p<0.001). Moreover, there was no significant difference in HWES and patient's satisfaction between the 2 groups. Finally, the application of subcuticular suture saved an average of $82.2 per case. CONCLUSIONS: Closure with running subcuticular suture is cheaper and appears to have a clinical advantage when compared with metallic staples skin closure in primary THA surgery. However, additional operating time may be incurred. PMID- 29148020 TI - Effect of different types of disinfection solution and aging on the hardness and colour stability of maxillofacial silicone elastomers. AB - INTRODUCTION: Understanding the effect of aging and different disinfecting agents on the physical properties of pigmented maxillofacial silicones may help eliminate the current uncertainty as to the best follow-up suggestions for the patients treated with silicone prostheses. METHODS: One hundred fifty specimens (14 * 2 mm) were evaluated for colour and 75 specimens (30 * 10 mm) for hardness (total, 225 specimens). Five specimens were used for hardness testing in each disinfecting solution while 10 silicone specimens were used for colour evaluation. The samples were separated into 5 groups and the initial hardness and colour evaluations were performed and placed in disinfectant solution (neutral soap, effervescent tablet, 0.2% chlorhexidine, 4% chlorhexidine, sodium hypochlorite). A second set of colour and hardness measurements was taken after 48 hours of disinfection and 1,008 hours of artificial aging in a QUV-accelerated weathering tester. Two-way and 1-way analysis of variance with Tukey tests and paired t-test were used for statistical analysis (alpha = 0.05). RESULTS: Before artificial aging, the hardness value of the red pigment group was found to be significantly lower than that of the brown pigment group. After aging, the lowest Shore A value was seen in the neutral soap group, while the highest was seen in the effervescent tablet. CONCLUSIONS: Based on the results of this study, chlorohexidine 0.2% was found to be most suitable agent for disinfection of the prostheses. Washing with neutral soap caused loss of pigment from the surface of the silicones. Sodium hypochlorite was found to have a colour-fading effect on silicone specimens. PMID- 29148022 TI - Hemodialysis versus peritoneal dialysis: an observational study in two international centers. AB - INTRODUCTION: Given that it is difficult to randomize end-stage renal disease (ESRD) patients to either hemodialysis (HD) or peritoneal dialysis (PD), differences between these renal replacement therapy (RRT) modalities are of major interest and remain controversial. METHODS: All data on maintenance dialysis patients during 2009 to 2013 in the Renji Hospital in Shanghai, China and in the San Bortolo Hospital in Vicenza, Italy were selected. Patients who changed their therapy from HD to PD or PD to HD during this study were excluded. RESULTS: 919 maintenance dialysis patients were included in the present study, including 509 patients on HD and 410 on PD. During the 5-year follow-up, mean arterial pressure (MAP) was higher in HD patients. The level of serum HCO3- was significantly better in PD patients than in HD patients. Phosphate was significantly higher in HD patients than in PD patients. With respect to lipid metabolism, triglyceride, total cholesterol and LDL were significantly higher in PD patients. Serum protein and albumin were higher in HD patients than in PD patients. Overall, 236 patients died (25.7%); 150 (16.3%) on HD and 86 (9.4%) on PD. The main cause of death in HD and PD patients was cerebral vascular disease and infection, respectively. After adjusting for dialysis vintage, the Kaplan-Meier patient survival was similar between HD and PD patients. CONCLUSIONS: Based on 5 years of data, we demonstrate that lipid metabolism and nutritional status were better in HD patients. However, blood pressure control, acid-base balance, phosphate (P) control were better in PD patients. The main cause of death in HD and PD was cerebral vascular disease and infection, respectively. Considering the dialysis vintage, the Kaplan-Meier patient survival was similar between HD and PD patients. PMID- 29148021 TI - Routine adoption of TIMP2 and IGFBP7 biomarkers in cardiac surgery for early identification of acute kidney injury. AB - BACKGROUND AND PURPOSE: Acute Kidney Injury (AKI) is a severe complication affecting many hospitalized patients after cardiac surgery, with negative impacts on short- and long-term clinical outcomes and on healthcare costs. Recently, clinical interest has been aimed at defining and classifying AKI, identifying risk factors and developing diagnostic strategies to identify patients at risk early on. Achieving an early and accurate diagnosis of AKI is a crucial issue, because prevention and timely detection may help to prevent negative clinical outcomes and avoid AKI-associated costs. In this retrospective study, we evaluate the NephroCheck Test as a diagnostic tool for early detection of AKI in a high risk population of patients undergoing cardiac surgery at the San Bortolo Hospital of Vicenza. METHODS: We assessed the ability of the NephroCheck Test to predict the probability of developing CSA-AKI (cardiac surgery-associated AKI) and evaluated its accuracy as a diagnostic test, by building a multivariate logistic regression model for CSA-AKI prediction. RESULTS: Based on our findings, when the results of the NephroCheck Test are included in a multivariate model its performance is substantially improved, as compared to the benchmark model, which only accounts for the other clinical factors. We also define a rule - in terms of a probability cut-off - for discriminating cases that are at higher risk of developing AKI of any stage versus those in which AKI is less likely. CONCLUSIONS: Our study has implications in clinical practice: when a Nephrocheck Test result is >0.3 ng/dL, an automated electronic alert prompts the physician to intervene by following a checklist of preventive measures. PMID- 29148023 TI - Fluid structure interaction model analysis of cerebrospinal fluid circulation in patients with continuous-flow left ventricular assist devices. AB - PURPOSE: The current 1-dimensional fluid structure interaction model (FSI) for understanding cerebrospinal fluid (CSF) circulation requires pulsatility as a precondition and has not been applied to patients with continuous-flow left ventricular assist devices (CF-LVAD) where pulsatility is chronically reduced. Our study aims to characterize the behavior of CSF pressure and flow in patients with CF-LVADs using a computational FSI model. METHODS: Utilizing the computational FSI model, CSF production in choroid plexuses of the 4 ventricles was specified as a boundary condition for the model. The other source of production from capillary ultrafiltrate spaces was accounted for by the mass conservation equation. The primary CSF absorption sites (i.e., arachnoid granulations) were treated as the outlet boundary conditions. We established a low pulse wave to represent patients with a CF-LVAD. RESULTS: From the model, low pulse conditions resulted in a reduction in CSF pressure amplitude and velocity though the overall flow rate was unchanged. CONCLUSIONS: The existing FSI model is not a suitable representation of CSF flow in CF-LVAD patients. More studies are needed to elucidate the role of pulsatility in CSF flow and the compensatory changes in CSF production and absorption that occur in patients with CF-LVADs in whom pulsatility is diminished. PMID- 29148024 TI - Blue Planet dialysis: novel water-sparing strategies for reducing dialysate flow. AB - INTRODUCTION: Hemodialysis (HD) is an expensive therapy in economic and in ecological terms, owing to a high carbon footprint and significant consumption of natural sources, especially water. Our aim was to review strategies to diminish waste of water in maintenance dialysis, exploring previously described water reuse trends and less known strategies for reducing the dialysate flow. METHODS: We conducted a systematic review of water-sparing strategies, including the reuse of reverse osmosis rejected water and the reduction of dialysate flux. We performed a search in Medline, Pubmed, Scielo, OVID and Biblioteca Redentor, using key words: Dialysate flow rate, Dialysate flux, and decrease; excluding: online, peritoneal, continuous, blood access, needle, hemodiafiltration, acute, pharmacokinetics, increase. We limited our search to adult humans or in vitro trials in English, Spanish, Italian and Portuguese, between January 1980 and June 2017. We found 816 trials. 37 articles were retrieved for review, and 11 articles were analyzed. RESULTS AND CONCLUSIONS: Conservation of water in chronic HD should be considered an important responsibility of healthcare practitioners all over the world. We present a wider usage of dialysate flow rates, considering that it would lead to significant water conservation without much compromise on dialysis efficacy in small patients. We believe that further investigation into the utility of reduced dialysate flux in different populations is needed to broaden our understanding of how we can use these techniques in order to significantly reduce water consumption during chronic HD while still ensuring optimum efficacy and efficiency of the therapy. PMID- 29148025 TI - A 3-day diary of dietary protein and calorie intake by serum phosphate concentration and binder use in hemodialysis patients. AB - INTRODUCTION: The use of phosphate binders to control hyperphosphatemia may allow diets less restricted in protein and calories for maintenance hemodialysis (MHD) patients. The study compared intakes of protein, calorie and phosphate among MHD patients with different serum phosphate concentrations, taking into account binder use. The hypothesis was that low serum phosphate would be associated with low intakes of protein and calories only in patients not on binders. METHODS: A cross-sectional study of 443 patients enrolled in the Prospective Study of the Prognosis of Chronic Hemodialysis Patients (PROHEMO) in Salvador, Brazil, with stratified sampling on serum phosphate: <=3.0 (n = 41), 3.5-5.5 (n = 328) and >=7.0 mg/dL (n = 74). A 3-day diet diary was used to determine dietary intakes. RESULTS: Approximately 49.0% confirmed binder use. Covariate-adjusted linear regression showed that associations between dietary intakes and serum phosphate were modified by the binder use. In patients not on binders, protein intake was >20% lower for serum phosphate <=3.0 mg/dL compared to higher concentrations. Also in those not on binders, calorie intake was >30% lower for serum phosphate <=3.0 mg/dL compared to >=7.0 mg/dL. Differences in dietary intakes by serum phosphate were virtually absent in patients on binders. CONCLUSIONS: The results are consistent with the hypothesis that low serum phosphate is associated with low protein and calorie intake only among MHD patients not on binders. This study supports recommendations to prevent hyperphosphatemia in MHD patients by adequate combination of binder use and selection of foods restricted in phosphors but not severely restricted in protein and calories. PMID- 29148026 TI - The influence of hemodialysis membrane permeability on serum procalcitonin values in patients on maintenance hemodialysis. AB - BACKGROUND: Procalcitonin (PCT) has emerged as a marker of infection and it could be useful for detection of systemic bacterial infections in patients with end stage renal disease (ESRD) undergoing hemodialysis (HD). The aim of this study was to assess the influence of HD membrane permeability to PCT serum levels in noninfected HD patients on maintenance HD. METHODS: In a prospective comparative study, we measured PCT serum levels and C reactive protein (CRP) before and after HD in 36 sessions (18 sessions of HD with low-flux = Group L; and 18 sessions with high flux membranes = Group H), in 18 chronic HD patients without history of infection. RESULTS: Sessions of HD by high-flux membranes (Group H) displayed median PCT values that were significantly decreased after dialysis (0.21 ng/mL [0.13-0.41] vs. 0.18 ng/mL [0.10-0.24], p <0.001) but median PCT significantly increased after HD sessions by low-flux membranes (Group L) (0.21 ng/mL [0.14 0.33] vs. 0.25 ng/mL [0.14-0.36]; p = 0.008). CRP values were significantly increased after HD in both groups. CRP correlated with PCT values only in group H before HD (r = 0.49; p = 0.36). CONCLUSIONS: PCT represents a useful diagnostic marker for systemic bacterial infection. However, there is a need for specific reference ranges to be developed in patients with renal failure undergoing HD; also, PCT serum levels must be interpreted according to the HD membrane permeability. PMID- 29148027 TI - Sequential tissue plasminogen activator, pneumatic displacement, and anti-VEGF treatment for submacular hemorrhage. AB - PURPOSE: To report the results of our sequential intravitreal (IV) tissue plasminogen activator (tPA), pneumatic displacement (PD), and IV anti-vascular endothelial growth factor (VEGF) treatment in patients with neovascular age related macular degeneration (nAMD)-related submacular hemorrhage (SMH). METHODS: A total of 16 eyes of 16 patients with SMH of less than 15 days duration were included in this retrospective pilot study. The tPA was applied on the day of diagnosis, and PD was performed the following day. Patients received 3 consecutive monthly IV injections of ranibizumab starting from 15 days after PD. During the follow-ups, additional ranibizumab treatment was performed if persistent macular or recurrent subretinal or intraretinal fluid hemorrhage was observed. RESULTS: The mean central retinal thickness was 489 +/- 92 MUm (311-621 MUm) at the time of diagnosis, 324 +/- 56 MUm (209-409 MUm) at the first month, 262 +/- 48 MUm (197-364 MUm) at 3 months, 248 +/- 40 MUm (190-334 MUm) at 6 months, and 253 +/- 41 MUm (192-356 MUm) at the last control (p<0.01). The mean best-corrected visual acuity was 2.08 +/- 0.79 logMAR (0.7-3.0 logMAR) at baseline, 1.41 +/- 0.70 logMAR (0.56-2.50 logMAR) at the first month, 1.21 +/- 0.66 logMAR (0.3-2.0 logMAR) at 3 months, 1.14 +/- 0.77 logMAR (0.2-2.50 logMAR) at 6 months, and 1.09 +/- 0.73 logMAR (0.3-2.50 logMAR) at the last follow-up (p<0.01). CONCLUSIONS: Sequential IV tPA, PD, and IV anti-VEGF treatments for SMH in patients with nAMD is effective. However, further studies are needed to establish the best treatment algorithm for SMH in patients with nAMD. PMID- 29148028 TI - Blindness and visual impairment in opera. AB - PURPOSE: The performing arts mirror the human condition. This study sought to analyze the reasons for inclusion of visually impaired characters in opera, the cause of the blindness or near blindness, and the dramatic purpose of the blindness in the storyline. METHODS: We reviewed operas from the 18th century to 2010 and included all characters with ocular problems. We classified the cause of each character's ocular problem (organic, nonorganic, and other) in relation to the thematic setting of the opera: biblical and mythical, blind beggars or blind musicians, historical (real or fictional characters), and contemporary or futuristic. RESULTS: Cases of blindness in 55 characters (2 as a choir) from 38 operas were detected over 3 centuries of repertoire: 11 had trauma-related visual impairment, 5 had congenital blindness, 18 had visual impairment of unknown cause, 9 had psychogenic or malingering blindness, and 12 were symbolic or miracle-related. One opera featured an ophthalmologist curing a patient. CONCLUSIONS: The research illustrates that visual impairment was frequently used as an artistic device to enhance the intent and situate an opera in its time. PMID- 29148029 TI - An unusual case of bilateral pigmented maculopathy and anterior segment dysgenesis. AB - PURPOSE: Pigmentary maculopathy can occur in the context of various inherited and acquired diseases. Anterior segment dysgenesis arises due to developmental anomalies and may be associated with systemic disease, as in Rieger syndrome. CASE REPORT: A 49-year-old woman presented with longstanding reduction in vision, evidence of anterior segment dysgenesis, and multiple discrete pigmented lesions throughout the macula bilaterally. Electroretinographic findings were consistent with severe macular dysfunction. Gene array analysis did not reveal any chromosomal imbalances or other specific abnormalities. CONCLUSIONS: This is a unique case of bilateral pigmentary maculopathy and anterior segment dysgenesis, with clinical findings that are not characteristic of previously reported disease. PMID- 29148030 TI - Incidence and quantitative analysis of dissociated optic nerve fiber layer appearance: real loss of retinal nerve fiber layer? AB - PURPOSE: To assess the association between appearance of dissociated optic nerve fiber layer (DONFL) after internal limiting membrane (ILM) peeling and changes in the macular nerve fiber layer (NFL) area by spectral-domain optical coherence tomography (SD-OCT). METHODS: This study included 132 consecutive patients who had successfully undergone vitrectomy with ILM peeling for idiopathic epiretinal membrane or macular holes and had been followed up for >=6 months. Two examiners evaluated macular 5-line raster horizontal SD-OCT images and categorized the patients on the basis of presence (group I) or absence (group II) of DONFL. The average macular NFL areas in both groups were measured using ImageJ at baseline and 1, 3, and 6 months after surgery. RESULTS: Among the 132 eyes of 132 patients, DONFL was noted in 42 (31.8%), 104 (78.8%), 106 (80.3%), and 106 (80.3%) eyes at 1, 3, and 6 months and at the last visit (12.8 +/- 6.5 months) after surgery. These layers appeared most commonly between 1 and 3 months after ILM peeling. There was no significant difference in average macular NFL area between groups I and II (3453.4 +/- 125.3 and 3513.0 +/- 100.2 pixels, respectively) at 6 months after surgery (p = 0.56). CONCLUSIONS: Appearance of DONFL increased between postoperative months 1 and 3. Moreover, there was no significant difference in average NFL in terms of DONFL. Thus, appearance of DONFL might represent macular NFL rearrangement and reorganization rather than true mechanical damage to the NFL after ILM peeling. PMID- 29148031 TI - Small incision lenticule extraction (SMILE) monovision for presbyopia correction. AB - PURPOSE: To evaluate the outcomes of myopic small incision lenticule extraction (SMILE) monovision in presbyopic patients. METHODS: This study included 49 presbyopic patients older than 45 years seeking surgical correction of myopia or myopic astigmatism who underwent bilateral SMILE with planned monovision in the SMILE Eyes Clinic Linz, Austria. Target refraction was plano for dominant (distance) eyes and ranged between -1.25 and -0.50 D for nondominant (near) eyes. Best-corrected distance visual acuity, uncorrected distance visual acuity (UDVA), uncorrected near visual acuity, as well as spectacle dependence were assessed after a mean postoperative period of 7.2 +/- 4.8 months. RESULTS: Mean age was 49 +/- 3 years and female to male ratio was 30:19. Distance eyes achieved a spherical equivalent correction of +/-0.50 D from target refraction in 80% of patients and 96% were within +/-1.0 D. Binocular UDVA of 20/20 or better was achieved by 90% of patients and all patients achieved 20/25 or better. The proportion of patients with a binocular UDVA of 20/20 or better who could read J2 or better amounted to 84%. Complete spectacle independence was achieved by 84% of patients and independence from reading glasses was achieved in 92% of cases. No patient requested refractive enhancement or monovision reversal. CONCLUSIONS: This first evaluation of SMILE monovision endorses the approach as a safe and effective option for the correction of presbyopia in myopic patients seeking refractive surgery. PMID- 29148032 TI - Secondary glaucoma in uveitis: comparison of the optic nerve head morphology among a nonmydriatic fundus camera, HRT, and SD-OCT. AB - PURPOSE: To assess the correlation between the disc damage likelihood scale (DDLS) objectively measured by a nonmydriatic fundus camera, confocal laser scanning ophthalmoscopy (HRT3), and spectral-domain optical coherence tomography (SD-OCT) in uveitic glaucoma. METHODS: A total of 59 patients with uveitic glaucoma (21 female, 38 male; mean age 56.8 +/- 18.7 years) were included in this prospective cross-sectional study. All patients were measured by the Kowa Nonmyd WX 3D camera (2D/3D nonmydriatic retinal camera, Kowa Company), the HRT3 (Heidelberg Engineering), and SD-OCT (Carl Zeiss Meditec) by one examiner on the same day. All 3 devices graded the optic disc topography. Statistical data were calculated using SPSS (v 20.0, SPSS). RESULTS: In patients showing borderline results in one of the modalities (n = 45), the DDLS showed a significant correlation with the retinal nerve fiber layer (p = 0.016), while Moorfields regression analysis (p = 0.550) and glaucoma probability score (p = 0.629) did not correlate significantly. The highest predictive power was demonstrated by the objectively measured DDLS (area under the receiver operating characteristic curve 0.445-0.588), compared to R. Burk (0.149-0.375) and F.S. Mikelberg (0.033-0.450) coefficients considering HRT and optical coherence tomography. CONCLUSIONS: In this study cohort, the objective DDLS showed the highest predictive power and thus is a reliable tool in diagnosing uveitic glaucoma. These 3 devices cannot be used interchangeably. As diagnosis and follow-ups are challenging in uveitis patients, the stereophotography is additionally a valuable tool. PMID- 29148033 TI - 4218T/C polymorphism associations with post-cesarean patient-controlled epidural fentanyl consumption and pain perception. AB - BACKGROUND: The utilization of intrathecal opioids is an efficacious component of post-cesarean section pain management. Given that growing evidence indicates that calcitonin gene-related peptide (CGRP) plays a key role in the development of peripheral sensitization and is associated with enhanced pain, we hypothesized that CGRP 4218T/C polymorphism is associated with the variability in fentanyl consumption for post-cesarean analgesia. METHODS: We recruited 548 patients who presented for elective cesarean delivery, and used polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method to analyze CGRP 4218T/C polymorphism. We examined the association of CGRP 4218T/C polymorphism and post-operative fentanyl consumption for analgesia as well as adverse reactions to fentanyl in those patients who received cesarean section surgeries. RESULTS: We found that the CGRP 4218T/C polymorphism has a significant effect on pain perception, analgesic requirement, and nausea and vomiting for the first 24 h after cesarean delivery in patients who received PCEA fentanyl. Individuals with the C/C genotype had more pain, required more PCEA fentanyl, and experienced a lower incidence of nausea and vomiting. CONCLUSION: These results indicated that patients with C/C genotype may have reduced sensitivity to fentanyl analgesia and/or increased pain perception, and were more willing to use PCEA fentanyl to manage their pain. PMID- 29148035 TI - Late age onset of amyotrophic lateral sclerosis is often not considered in elderly people. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing an upper and lower motor neuron loss. It is neurology textbook knowledge that the mean age of onset is about 60 years. However, recent investigations show an increasing incidence in older persons. We therefore evaluated whether ALS is potentially not considered in elderly people with ALS symptoms, respectively, not recognized. MATERIALS AND METHODS: We included retrospectively all patients with ALS diagnoses after work-up that were admitted to our neurological and geriatric departments from 2007 to 2010 and collected their clinical data. The diagnosis of ALS was based on the El Escorial criteria. Patients were grouped into three categories according to age (<50, between 50 and 70, >70), and differences in clinical and/ or biographical factors were investigated. RESULTS: We identified 35 patients (18 men and 17 women) with a median age at onset of 71.5 years (range: 36-87 years). When establishing the diagnosis, 51% were older than 70 years, 40% (14/35) between 50 and 70, and only 9% younger than 50. Only in 46 per cent of patients who were sent to our departments with ALS symptoms ALS was considered by the referring physician. CONCLUSION: Late age onset of ALS seems to be more common than formerly assumed and is presumably under-recognized in elderly patients. ALS needs to be considered as a differential diagnosis in older patients. Potential factors accounting for older people being underdiagnosed with ALS relate to frequent presentation with symptoms like dysphagia, frailty or general weakness for other reasons. PMID- 29148036 TI - Function and mechanism of the pyrin inflammasome. AB - Pyrin, encoded by the MEFV gene, is an intracellular pattern recognition receptor that assembles inflammasome complexes in response to pathogen infections. Mutations in the MEFV gene have been linked to autoinflammatory diseases such as familial Mediterranean fever (FMF) or pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Recent insights have now revealed how pyrin is activated during infection, providing a molecular basis for the understanding of such disease-causing mutations in pyrin. Interestingly, pyrin does not directly recognize molecular patterns (pathogen- or host-derived danger molecules), but rather responds to disturbances in cytoplasmic homeostasis caused by the infection. In the case of pyrin, these perturbations, recently defined as 'homeostasis-altering molecular processes' (HAMPs), are processes leading to the inactivation of the RhoA GTPase. This review attempts to combine early observation and findings with the most recent discoveries on how pyrin detects inactivation of RhoA to shed light on the function and mechanism of pyrin activation. PMID- 29148034 TI - Role of p62/SQSTM1 beyond autophagy: a lesson learned from drug-induced toxicity in vitro. AB - BACKGROUND AND PURPOSE: SQSTM1/p62 is a multifunctional, stress-induced, scaffold protein involved in multiple cellular processes including autophagic clearance, regulation of inflammatory responses and redox homeostasis. Its altered function has been associated with different human pathologies, such as neurodegenerative, metabolic and bone diseases (down-regulation), and cancerogenesis (up regulation). However, its role in the off-target effects of clinically used drugs is still not understood. EXPERIMENTAL APPROACH: We evaluated the expression of p62 in cultured Hep3B cells and their derived rho degrees cells (lacking mitochondria), along with markers of autophagy and mitochondrial dysfunction. The effects of efavirenz were compared with those of known pharmacological stressors, rotenone, thapsigargin and CCCP, and we also used transient silencing with siRNA and p62 overexpression. Western blotting, quantRT-PCR and fluorescence microscopy were used to assay these effects and their underlying mechanisms. KEY RESULTS: In Hep3B cells, efavirenz augmented p62 protein content, an effect not observed in the corresponding rho degrees cells. p62 up-regulation followed enhanced SQSTM1 expression mediated through the transcription factor CHOP/DDIT3, while other well known regulators (NF-kB and Nrf2) were not involved. Inhibition of autophagy with 3MA or with transient silencing of Atg5 did not affect SQSTM1 expression in efavirenz-treated cells while p62 overexpression ameliorated the deleterious effect of efavirenz on cell viability. CONCLUSION AND IMPLICATIONS: In our model, p62 exerted a specific, autophagy-independent role and protected against efavirenz-induced mitochondrial ROS generation and activation of the NLRP3 inflammasome. These findings add to the multifunctional nature of p62 and may help to understand the off-target effects of clinically useful drugs. PMID- 29148037 TI - Growth performance, fatty-acid composition, lipid deposition and hepatic-lipid metabolism-related gene expression in juvenile pond loach Misgurnus anguillicaudatus fed diets with different dietary soybean oil levels. AB - A 10 week feeding trial was conducted to evaluate the effects of different dietary soybean oil (SO) levels on growth performance, fatty-acid composition and lipid deposition in viscera, histology and histochemistry of liver, intestine and hepatic-lipid metabolism-related gene expressions in pond loach Misgurnus anguillicaudatus juveniles. Misgurnus anguillicaudatus (mean +/- s.d. mass 0.40 +/- 0.01 g) were fed five experimental diets containing SO at different concentrations: 0, 20, 32, 56 and 100% SO and a diet containing 100% fish oil (100% FO). The mass gains and specific growth rates of M. anguillicaudatus fed 20% SO and 100% FO diets were significantly higher than those of the other groups (P < 0.05). The lipid content of viscera and the amount of cytoplasmic vacuolation in the liver increased with incremental dietary SO level. Meanwhile, increasing dietary SO levels up-regulated the messenger (m)RNA levels of lipogenic genes (such as Delta6fad, scd, ppargamma, fas and srebp-1) and down regulated the mRNA levels of the lipolytic genes (such as pparalpha, cpt1, atgl and hsl) in the liver. The percentage of 20:4n-6 significantly (P < 0.05) increased with increasing dietary SO level, which might be correlated with the up regulation of the mRNA level of Delta6fad. The highest levels of dietary SO, however, had a negative effect on growth performance, lipid deposition of viscera and histology and histochemstry of liver and intestine. The increased lipid accumulation induced by incremental dietary SO level probably occurred through different strategies for lipid metabolism as a result of competition between lipolysis and lipogenesis and between export and import of lipids in this species. PMID- 29148038 TI - Visual field defect after ischemic stroke-impact on mortality. AB - OBJECTIVES: We aimed to investigate the impact of visual field defects (VFD) on mortality in ischemic stroke patients. MATERIALS AND METHODS: All patients with acute infarction and a clinically detected VFD from February 2006 to December 2013 in the NORSTROKE Registry (n = 506) were included and compared with ischemic stroke patients with normal visual fields (n = 2041). A record of patients who had died per ultimo April 2015 was obtained from the central registry at Haukeland University Hospital. RESULTS: Patients with VFD were significantly older (75.0 vs 69.8, P < .001) than patients with normal visual fields. The majority of patients with VFD was male, had higher cardiovascular morbidity prestroke, and were more likely to have shorter median time from symptom onset to admission (1.7 hours vs 2.7 hours, P < .001). Baseline National Institute of Health Stroke Scale (NIHSS) score was higher (12.7 vs 3.5, P < .001) as was modified Rankin Scale (mRS) score (3.5 vs 1.9, P < .001) and Barthel Index was lower (51.9 vs 84.8, P < .001) day 7. VFD was associated with increased mortality on Kaplan-Meier plots. Hazard ratio was significantly higher for patients with VFD after adjusting for age, sex, employment prior to infarction, married prior to infarction, institutionalization prior to infarction, prior myocardial infarction, atrial fibrillation, smoking, Barthel Index score and i.v. thrombolysis with Cox regression (hazard ratios [HR] 1.30, CI 1.07-1.56, P = .007). CONCLUSIONS: Having a visual field defect after ischemic stroke is independently associated with increased mortality. This should be addressed when selecting candidates for thrombolysis and in the rehabilitation process. PMID- 29148039 TI - 3D analysis of sexual dimorphism in size, shape and breathing kinematics of human lungs. AB - Sexual dimorphism in the human respiratory system has been previously reported at the skeletal (cranial and thoracic) level, but also at the pulmonary level. Regarding lungs, foregoing studies have yielded sex-related differences in pulmonary size as well as lung shape details, but different methodological approaches have led to discrepant results on differences in respiratory patterns between males and females. The purpose of this study is to analyse sexual dimorphism in human lungs during forced respiration using 3D geometric morphometrics. Eighty computed tomographies (19 males and 21 females) were taken in maximal forced inspiration (FI) and expiration (FE), and 415 (semi)landmarks were digitized on 80 virtual lung models for the 3D quantification of pulmonary size, shape and kinematic differences. We found that males showed larger lungs than females (P < 0.05), and significantly greater size and shape differences between FI and FE. Morphologically, males have pyramidal lung geometry, with greater lower lung width when comparing with the apices, in contrast to the prismatic lung shape and similar widths at upper and lower lungs of females. Multivariate regression analyses confirmed the effect of sex on lung size (36.26%; P < 0.05) and on lung shape (7.23%; P < 0.05), and yielded two kinematic vectors with a small but statistically significant angle between them (13.22 degrees ; P < 0.05) that confirms sex-related differences in the respiratory patterns. Our 3D approach shows sexual dimorphism in human lungs likely due to a greater diaphragmatic action in males and a predominant intercostal muscle action in females during breathing. These size and shape differences would lead to different respiratory patterns between sexes, whose physiological implications need to be studied in future research. PMID- 29148040 TI - The endocranial shape of Australopithecus africanus: surface analysis of the endocasts of Sts 5 and Sts 60. AB - Assessment of global endocranial morphology and regional neuroanatomical changes in early hominins is critical for the reconstruction of evolutionary trajectories of cerebral regions in the human lineage. Early evidence of cortical reorganization in specific local areas (e.g. visual cortex, inferior frontal gyrus) is perceptible in the non-human South African hominin fossil record. However, to date, little information is available regarding potential global changes in the early hominin brain. The introduction of non-invasive imaging techniques opens up new perspectives for the study of hominin brain evolution. In this context, our primary aim in this study is to explore the organization of the Australopithecus africanus endocasts, and highlight the nature and extent of the differences distinguishing A. africanus from the extant hominids at both local and global scales. By means of X-ray-based imaging techniques, we investigate two A. africanus specimens from Sterkfontein Member 4, catalogued as Sts 5 and Sts 60, respectively a complete cranium and a partial cranial endocast. Endocrania were virtually reconstructed and compared by using a landmark-free registration method based on smooth and invertible surface deformation. Both local and global information provided by our deformation-based approach are used to perform statistical analyses and topological mapping of inter-specific variation. Statistical analyses indicate that the endocranial shape of Sts 5 and Sts 60 approximates the Pan condition. Furthermore, our study reveals substantial differences with respect to the extant human condition, particularly in the parietal regions. Compared with Pan, the endocranial shape of the fossil specimens differs in the anterior part of the frontal gyri. PMID- 29148041 TI - FSCN1 predicts survival and is regulated by a PI3K-dependent mechanism in renal cell carcinoma. AB - While overexpression of FSCN1 is reported in several cancers, the prognostic significance of FSCN1 in renal cell carcinoma (RCC) and the molecular mechanisms involved remain largely unclear. We retrospectively enrolled 194 patients with non-metastatic clear-cell RCC undergoing nephrectomy in our center between 2008 and 2011. FSCN1 expression was assessed by immunohistochemical staining and its association with clinicopathologic features and survival were evaluated. Functional effects of a modulated FSCN1 expression were analyzed with regard to invasion in RCC cell lines and metastasis in vivo. Here, we reported that FSCN1 was up-regulated in RCC tissues compared to non-tumor tissues, and associated with poor overall survival and recurrence-free survival. Its expression was not associated with age, tumor size, and clinical TNM stage. The incorporation of FSCN1 into the T stage and histologic grade would help to refine individual risk stratification. Preclinical studies using multiple RCC cells and orthotopic xenografts mice model indicated that FSCN1 could promote RCC cell invasion in vitro, and metastasis in vivo. Mechanistically, overexpression of FSCN1 led to an up-regulation of MMP9 and N-Cadherin. Notably, treating RCC cells with PI3 K/AKT inhibitors or knockdown GSK-3beta decreased the expression of FSCN1, and then attenuated RCC invasion. Together, our results demonstrate that FSCN as an oncogene is a potential novel prognostic biomarker for RCC patients after nephrectomy, and can promote RCC metastasis. PMID- 29148042 TI - Comparative anatomy of zebrafish paired and median fin muscles: basis for functional, developmental, and macroevolutionary studies. AB - In the last decades, Danio rerio became one of the most used model organisms in various evo-devo studies devoted to the fin skeletal anatomy and fin-limb transition. Surprisingly, there is not even a single paper about the detailed anatomy of the adult muscles of the five fin types of this species. To facilitate more integrative developmental, functional, genetic, and evolutionary studies of the appendicular musculoskeletal system of the zebrafish and to provide a basis for further comparisons with other fishes and tetrapods, we describe here the identity, overall configuration, and attachments of appendicular muscles in a way that can be easily understood and implemented by non-anatomist researchers. We show that the muscle pattern of the caudal fin is very different from patterns seen in other fins but is very consistent within teleosts. Our observations support the idea of the developmental and evolutionary distinction of the caudal fin and point out that the musculature of the adult zebrafish pectoral and pelvic fins is in general very similar. Both paired fins have superficial and deep layers of abductors and adductors going to all/most rays plus the dorsal and ventral arrectors going only to the first ray. Nevertheless, we noted three major differences between the pelvic and pectoral fins of adult zebrafishes: (i) the pectoral girdle lacks a retractor muscle, which is present in the pelvic girdle - the retractor ischii; (ii) the protractor of the pelvic girdle is an appendicular/trunk muscle, while that of the pectoral girdle is a branchiomeric muscle; (iii) the first ray of the pectoral fin is moved by an additional arrector-3. The anal and dorsal fins consist of serially repeated units, each of which comprises one half-ray and three appendicular muscles (one erector, depressor, and inclinator) on each side of the body. The outermost rays are attachment points for the longitudinal protractor and retractor. Based on our results, we discuss whether the pectoral appendage might evolutionarily be closer to the head than to the pelvic appendage and whether the pelvic appendage might have been derived from the trunk/median fins. We discuss a hypothesis of paired fin origin that is a hybrid of the fin-fold and Gegenbaur's theories. Lastly, our data indicate that D. rerio is indeed an appropriate model organism for the appendicular musculature of teleosts in particular and, at least in the case of the paired fins, also of actinopterygians as a whole. PMID- 29148043 TI - New Hope for Sarcopenia. PMID- 29148045 TI - Reply to: New Hope for Sarcopenia. PMID- 29148044 TI - The incidence of bent dorsal fins in free-ranging cetaceans. AB - Laterally bent dorsal fins are rarely observed in free-ranging populations of cetaceans, contrary to captivity, where most killer whale Orcinus orca adult males have laterally collapsed fins. This topic has been poorly explored, and data/information on its occurrence and possible causes are limited. The present study: (i) undertakes a review of the available information on bent dorsal fins in free-ranging cetaceans, and updates it with new records, (ii) reports on the proportion of bent fins in different study populations, and (iii) discusses possible causes. An empirical approach based on bibliographic research and compilation of 52 new records collected worldwide resulted in a total of 17 species of cetaceans displaying bent dorsal fins. The species with the highest number of records (64%) and from most locations was O. orca. On average, individuals with bent dorsal fins represent < 1% of their populations, with the exception of false killer whales Pseudorca crassidens and O. orca. While line injuries associated with fisheries interactions may be the main cause for P. crassidens, and the vulnerability to health issues caused by the evolutionary enlargement of the fin may be the cause for O. orca adult males, factors contributing to this abnormality for other species are still unclear. The occurrence of bent dorsals could be influenced by a set of variables rather than by a single factor but, irrespective of the cause, it is suggested that it does not directly affect the animals' survivorship. While still rare in nature, this incident is more common (at least 101 known cases) and widespread (geographically and in species diversity) than hypothesized, and is not confined only to animals in captive environments. Investigation into the occurrence of bent fins may be an interesting avenue of research. PMID- 29148046 TI - Delirium and effect of circadian light in the intensive care unit: a retrospective cohort study. AB - BACKGROUND: Delirium is a serious condition often experienced by critically ill patients in intensive care units (ICUs). The role of circadian light for this condition is unclear. The aim of this study was to describe incidence of delirium, risk factors for delirium, and the association between delirium and circadian light for patients in the ICU. METHODS: This is a retrospective cohort study of all patients at a Danish ICU from 1 August 2015 to 31 January 2016. Exclusion criteria were heavy sedation, no Confusion Assessment Method for the ICU (CAM-ICU) scores, or inability to communicate in Danish. Delirium was defined as at least one positive CAM-ICU score or treatment with haloperidol. Three of nine beds at the ICU had a circadian light installation. Allocation to ICU beds with or without circadian light depended on availability at admission. Risk factors for development of delirium were analyzed by simple and multiple logistic regression. RESULTS: We included 183 patients in the study. The incidence of delirium was 28% (95% CI 22, 35). Allocation to beds with or without circadian lighting was not associated with delirium incidence (OR 1.14; 95% CI 0.55, 2.37; P = 0.73). We found that Simplified Acute Physiology Score II (SAPS II) (OR 1.03; 95% CI 1.01, 1.06; P = 0.002), and dexmedetomidine was associated with delirium (OR 4.14; 95% CI 1.72, 10.03; P = 0.002). CONCLUSION: In this population of patients admitted to an ICU during 6 months, the incidence of delirium was 28%. We did not find an association between circadian light and development of delirium. PMID- 29148047 TI - Plasma copeptin levels in patients with restless legs syndrome. AB - OBJECTIVES: Copeptin, the C-terminal fragment of antidiuretic hormone, is a new biomarker that has been found to be elevated in several disorders and could be related with prognosis. This study aimed to compare plasma copeptin levels in patients with restless legs syndrome (RLS) with healthy individuals and to investigate whether plasma copeptin levels were associated with the severity of disease. MATERIAL AND METHODS: 41 patients with primary RLS, who were followed in Bakirkoy Psychiatry and Neurology Research and Training Hospital and 41 age- and sex-matched healthy individuals were included into the study. RLS patients were divided into subgroups as mild-moderate, severe, and very severe according to the severity of symptoms. Sleep quality and excessive daytime sleepiness were determined according to Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale, respectively, and sleep quality scores were analyzed statistically among the groups divided according to disease severity. Copeptin levels in all the patients were compared to the controls. RLS subgroups were compared with each other to evaluate association between copeptin levels and disease severity. RESULTS: Plasma copeptin levels in RLS patients were significantly higher than controls (P < .001). However, there was no association between copeptin levels and disease severity. Excessive daytime sleepiness was found as 14.63% and low sleep quality as 68.29% in patients. CONCLUSIONS: Hypothalamic-pituitary-adrenal axis activation and sympathetic hyperactivity in RLS might be responsible for increased Antidiuretic hormone (ADH) and copeptin release. We think that copeptin might have a potential role in the pathogenesis of RLS and be a biomarker for this disease. PMID- 29148048 TI - Editorial Perspective: Whatever happened to temperament? AB - A recent editorial in this journal supported our need to be 'mindful of the field's strict adherence to the disease model of psychopathology, and wondered (not for the first time) whether our total allegiance to this model has obscured important information.' Dr. Burt pointed to studies in which normal behavioral style traits such as activity and resilience may have been significant factors in the outcome. These traits bear a close relationship to two of the nine normal temperament traits described by Chess and Thomas in their New York Longitudinal Study starting in 1956. Despite past acceptance, their important contribution to outcomes has been largely ignored for some time. However, lately there has been an unexpected revival of them. All nine of the NYLS traits have individually been shown to matter sometimes in mental health outcomes. It is not just activity and resilience or adaptability but all the rest: irregularity, inhibition, intensity, irritability, persistence, distractibility, and sensitivity. Should we not consider all normal temperamental predispositions as possible risk or protective factors in appraisals of behavioral outcomes and not just pathological nature and/or nurture contributions? PMID- 29148049 TI - Editorial: What is depression? AB - 'Depression is a common, debilitating, and potentially lethal disorder.' This is a standard opening to many a scientific paper on depression. And it is often followed by some very grim statistics. Over 300 million people in the world are estimated to live with depression, and the disorder is ranked by WHO as the single largest contributor to global disability. Most worryingly, adolescents with major depressive disorder are up to 30 times more likely to commit suicide. Yet, what exactly is depression? Do all 300 million depressed people in the world suffer from the same thing, with the same aetiology? Is depression one disorder that comes in different shades of severity or is it best thought of as heterogeneous mix of problems that we have given one common name to? And, more practically, should we be treating all depression in similar ways? PMID- 29148050 TI - The Pharmacokinetics of Morphine and Codeine in Human Plasma and Urine after Oral Administration of Qiangli Pipa Syrup. AB - Papaveris pericarpium, a natural source of morphine and codeine, is the principal active component in many antitussive traditional Chinese medicines. We herein report the first PK study of papaveris pericarpium in human plasma and urine following oral administration of single (15, 30, 60 mL) and multiple dose (15 mL) of Qiangli Pipa Syrup (MOR 0.1 mg/mL, COD 0.028 mg/mL) by monitoring morphine and codeine using a HPLC-MS/MS method. Their Tmax and t1/2 values are independent of dosages, while the AUC0-t linearly increased with higher dosages, indicating linear PK characteristics. AUC0-t increased obviously after multiple doses, indicating possible risk of accumulative toxicity. Urine studies suggested risks of positive opiate drug tests with a cutoff of 300 ng/mL, which lasted 6-14 h at different doses. These results provide important information for clinical safety, efficacy and rational drug use of Qiangli Pipa Syrup and also guide the related judicial expertise of its administration. PMID- 29148052 TI - Influence of the addition of soy product and wheat fiber on rheological, textural, and other quality characteristics of pizza. AB - : The effect of partial replacement of wheat flour with soy paste and wheat fiber on rheological, textural, physicochemical, and organoleptic characteristics of an enriched pizza base (E) was investigated in comparison with those of a control pizza base (C). New ingredients (e.g., enriched cooked ham, whey cheese, and tomato sauce realized using food industry by-products) were also used in E pizza topping to further increase its nutritional properties. Enriched dough was developed first at a laboratory level. Large and small deformation, moisture, leavening activity, and metabolic heat were tested. On the final product, produced at the industrial level, textural, color, sensory, and nutritional analyses were performed. Preliminary rheological analysis was essential to evaluate the suitability of the new pizza to be processed at industrial level. Both pizza dough samples showed a solid elastic-like behavior; however, the addition of soy and fiber increased moisture content of E pizza, due to the water binding ability of soy protein and to the effect of fibers that also decreased E dough elasticity. No differences in extensibility between the two samples were observed, whereas significantly lower values of resistance to extension and dough force were shown in sample E. These differences were likely due to the presence of soy that interfere with gluten formation and to the dietary fibers that interact with water. Ingredients used in E pizza improved its nutritional quality increasing dietary fibers and protein, and decreasing saturated fatty acids and cholesterol content, which contributed to decrease energy value, in terms of kilocalorie reduction. PRACTICAL APPLICATIONS: In this work, the effects of using new ingredients (e.g., soy paste, wheat fiber) on the rheological, textural, physicochemical, nutritional, and organoleptic characteristics of an enriched pizza type were investigated both at laboratory and industrial levels. The new pizza provides a product that combines solid technological performances, in terms of rheological properties and dough elasticity, with improved and balanced nutritional quality, thanks also to the ingredients used in the topping. Results demonstrate the possibility of obtaining new pizza products characterized by nutritional and sensorial properties tailored for different group of consumers. PMID- 29148051 TI - Mechanical parameters of the molecular motor myosin II determined in permeabilised fibres from slow and fast skeletal muscles of the rabbit. AB - KEY POINTS: The different performance of slow and fast muscles is mainly attributed to diversity of the myosin heavy chain (MHC) isoform expressed within them. In this study fast sarcomere-level mechanics has been applied to Ca2+ activated single permeabilised fibres isolated from soleus (containing the slow myosin isoform) and psoas (containing the fast myosin isoform) muscles of rabbit for a comparative definition of the mechano-kinetics of force generation by slow and fast myosin isoforms in situ. The stiffness and the force of the slow myosin isoform are three times smaller than those of the fast isoform, suggesting that the stiffness of the myosin motor is a determinant of the isoform-dependent functional diversity between skeletal muscles. These results open the question of the mechanism that can reconcile the reduced performance of the slow MHC with the higher efficiency of the slow muscle. ABSTRACT: The skeletal muscle exhibits large functional differences depending on the myosin heavy chain (MHC) isoform expressed in its molecular motor, myosin II. The differences in the mechanical features of force generation by myosin isoforms were investigated in situ by using fast sarcomere-level mechanical methods in permeabilised fibres (sarcomere length 2.4 MUm, temperature 12 degrees C, 4% dextran T-500) from slow (soleus, containing the MHC-1 isoform) and fast (psoas, containing the MHC-2X isoform) skeletal muscle of the rabbit. The stiffness of the half-sarcomere was determined at the plateau of Ca2+ -activated isometric contractions and in rigor and analysed with a model that accounted for the filament compliance to estimate the stiffness of the myosin motor (epsilon). epsilon was 0.56 +/- 0.04 and 1.70 +/- 0.37 pN nm-1 for the slow and fast isoform, respectively, while the average strain per attached motor (s0 ) was similar (~3.3 nm) in both isoforms. Consequently the force per motor (F0 = epsilons0 ) was three times smaller in the slow isoform than in the fast isoform (1.89 +/- 0.43 versus 5.35 +/- 1.51 pN). The fraction of actin-attached motors responsible for maximum isometric force at saturating Ca2+ (T0,4.5 ) was 0.47 +/- 0.09 in soleus fibres, 70% larger than that in psoas fibres (0.29 +/- 0.08), so that F0 in slow fibres was decreased by only 53%. The lower stiffness and force of the slow myosin isoform open the question of the molecular basis of the higher efficiency of slow muscle with respect to fast muscle. PMID- 29148053 TI - Effective inactivation of a wide range of viruses by pasteurization. AB - BACKGROUND: Careful selection and testing of plasma reduces the risk of blood borne viruses in the starting material for plasma-derived products. Furthermore, effective measures such as pasteurization at 60 degrees C for 10 hours have been implemented in the manufacturing process of therapeutic plasma proteins such as human albumin, coagulation factors, immunoglobulins, and enzyme inhibitors to inactivate blood-borne viruses of concern. A comprehensive compilation of the virus reduction capacity of pasteurization is presented including the effect of stabilizers used to protect the therapeutic protein from modifications during heat treatment. STUDY DESIGN AND METHODS: The virus inactivation kinetics of pasteurization for a broad range of viruses were evaluated in the relevant intermediates from more than 15 different plasma manufacturing processes. Studies were carried out under the routine manufacturing target variables, such as temperature and product-specific stabilizer composition. Additional studies were also performed under robustness conditions, that is, outside production specifications. RESULTS: The data demonstrate that pasteurization inactivates a wide range of enveloped and nonenveloped viruses of diverse physicochemical characteristics. After a maximum of 6 hours' incubation, no residual infectivity could be detected for the majority of enveloped viruses. Effective inactivation of a range of nonenveloped viruses, with the exception of nonhuman parvoviruses, was documented. CONCLUSION: Pasteurization is a very robust and reliable virus inactivation method with a broad effectiveness against known blood-borne pathogens and emerging or potentially emerging viruses. Pasteurization has proven itself to be a highly effective step, in combination with other complementary safety measures, toward assuring the virus safety of final product. PMID- 29148054 TI - Transcriptome analysis unravels an ethylene response factor involved in regulating fruit ripening in pear. AB - Ethylene response factor (ERF) has been widely studied in regulating fruit ripening in tomato, apple, banana and kiwifruit, but little is known in pear. In this study 1-methylcyclopropene (1-MCP) treatment, an inhibitor of ethylene perception, was conducted at approximately 30 days before harvest to delay fruit ripening in a climacteric white pear cultivar Yali. Transcriptome libraries were constructed and sequenced in pre-ripening, ripening, and 1-MCP treated fruits. Data analysis showed that 73 candidate genes related to fruit ripening were induced by 1-MCP, among which two were positively related, namely 1 aminocyclopropane-1-carboxyla oxidase and an ERF gene (designated as ACO54 and ERF24). Transient transformations in pear fruit revealed that over-expression of ACO54 enhance transcription level of ERF24 and most ripening-related genes. Meanwhile, over-expression of ERF24 raises expression level of ACO54 and partially ripening-related genes. Moreover, dual-luciferase and yeast-one-hybrid assays unravel an interaction between ERF24 and the ACO54 promoter. Therefore, the ERF24 could directly regulate ACO54 expression by binding to its promoter. These results suggested that the first identified ERF24 is involved in regulating fruit ripening in Chinese white pear. PMID- 29148055 TI - Theophylline: The forgotten antiarrhythmic drug... now for malignant early repolarization. PMID- 29148056 TI - The List Experiment for Measuring Abortion: What We Know and What We Need. AB - Measuring abortion incidence and prevalence is often difficult because of under reporting and other biases, complicated research designs, and other issues. Recently, family planning researchers have introduced a new method called the list experiment, adopted from political science and economics, to measure abortion. Three completed studies and at least four studies currently underway use this method to measure abortion in several countries. We discuss the lessons learned from completed studies, when the list experiment may and may not be appropriate, and open questions regarding the use of the list experiment for abortion research. This method has the potential to improve measures of abortion prevalence and incidence, which could translate to better-informed interventions to increase abortion access and reduce unmet need for family planning. Future research should further clarify the advantages and limitations of the list experiment for measuring abortion. PMID- 29148057 TI - Clinical patterns of Compositae dermatitis in Danish monosensitized patients. AB - BACKGROUND: Compositae dermatitis was originally described as airborne contact dermatitis. More recent studies have reported a wider clinical spectrum, but often in polysensitized patients. OBJECTIVE: To evaluate the clinical features of patients sensitized to Compositae only. PATIENTS/METHODS: Consecutive Compositae sensitive eczema patients, tested between 1990 and 2015, who, at the patch testing session diagnosing their Compositae allergy, were found to be sensitized only to the plant family, were included. RESULTS: Altogether, 529 of 13 139 patients tested (4.0%) were sensitized to Compositae, and 95 (18% of these) were monosensitized. The majority had hand eczema, and 39 (44%) had a vesicular volar pattern. Eighty-one patients were classified into one of three groups of similar size: localized eczema, eczema of exposed skin, and localized eczema turning into widespread eczema. CONCLUSIONS: The prevalence of Compositae sensitization is continuously high in consecutive eczema patients. Sensitization may occur at any age. Clinical features in monosensitized patients vary, but, with continuing exposure, the patients may develop more widespread dermatitis similar to classic Compositae dermatitis. Avoidance may clear the exogenous part, but not endogenous aetiological factors such as vesicular hand eczema or possible photosensitivity. Thorough clinical assessment and patient education are important in reducing the impact of Compositae contact allergy. PMID- 29148058 TI - Classification of consumer products under the EU CLP Regulation: what to consider when caring for contact dermatitis patients. AB - Possibly hazardous chemical substances and mixtures need to be clearly and correctly classified and labelled, in order for their hazards to be properly identified and communicated. As dermatologists may encounter cases of harm to patients induced by chemicals, such as chemical burns, and irritant and allergic contact dermatitis, it is essential for them to be aware of the EU CLP Regulation and its potential pitfalls. Manufacturers are required by CLP to classify their products according to the rules given in the CLP Regulation. The enforcement duty lies with the Member States and their competent authorities. Dangerous non-food consumer products have to be reported to the European Commission to be entered into the Rapid Alert System for Dangerous Non-food Products (RAPEX) notifications. The sheer complexity of the CLP Regulation and lack of awareness of its ramifications by companies, competent authorities, consumer associations and the public at large may prevent efficient enforcement actions. When dermatologists become aware of inappropriately labelled chemicals, they should inform the competent authorities. PMID- 29148059 TI - Theophylline as an adjunct to control malignant ventricular arrhythmia associated with early repolarization. AB - Early repolarization (ER) has been associated with an increased risk of sudden cardiac arrest. Interestingly, ventricular arrhythmias seem to be triggered by parasympathetic stimulation. In the present case report, we describe complete control of highly frequent malignant ventricular arrhythmias after adding theophylline to ineffective oral hydroquinidine and high-rate pacing in a patient suffering from malignant ER. We hypothesize that the theophylline-mediated enhanced beta-adrenergic stimulation could reduce the transmural myocardial voltage discrepancy by increasing the inward ICa,L current. PMID- 29148060 TI - Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling. AB - The amygdala is a key brain area regulating responses to stress and emotional stimuli, so improving our understanding of how it is regulated could offer novel strategies for treating disturbances in emotion regulation. As we review here, a growing body of evidence indicates that the gut microbiota may contribute to a range of amygdala-dependent brain functions from pain sensitivity to social behavior, emotion regulation, and therefore, psychiatric health. In addition, it appears that the microbiota is necessary for normal development of the amygdala at both the structural and functional levels. While further investigations are needed to elucidate the exact mechanisms of microbiota-to-amygdala communication, ultimately, this work raises the intriguing possibility that the gut microbiota may become a viable treatment target in disorders associated with amygdala dysregulation, including visceral pain, post-traumatic stress disorder, and beyond. Also see the video abstract here: https://youtu.be/O5gvxVJjX18. PMID- 29148061 TI - Endocannabinoids modulate Gq/11 protein-coupled receptor agonist-induced vasoconstriction via a negative feedback mechanism. AB - OBJECTIVES: The endocannabinoid (eCB) system centrally and peripherally regulates cardiovascular parameters, including blood pressure, in health and disease. The relationship between Gq/11 protein-coupled receptor activation, regulation of eCBs release (mainly 2-arachidonoylglycerol) and subsequent CB1 receptor activation was initially observed in the central nervous system. Here, we review the latest findings from systemic physiological studies which include for the first time data from pulmonary arteries. We present evidence for direct CB1 dependent cannabinoid ligand-induced vasorelaxation, vascular expression of eCBs along with their degradation enzymes, and indicate the location of the described interaction. KEY FINDINGS: Endocannabinoids (mainly 2-arachidonoylglycerol), acting via CB1 receptors, evoke vasodilatory effects and may modulate responses of vasoconstrictors for Gq/11 protein-coupled receptors including angiotensin II, thromboxane A2 , phenylephrine, noradrenaline in systemic or pulmonary arteries. However, the role of the endothelium in this interaction is not well-established, and the precise vascular location of eCB system components remains unclear, which contributes to discrepancies in the interpretation of results when describing the above-mentioned relationship. SUMMARY: Endocannabinoid's negative feedback is responsible for diminishing agonist-induced vasoconstriction, which may be clinically important in the treatment of arterial and pulmonary hypertension. Further research is required to establish the importance of the eCB system and its downstream signalling pathways. PMID- 29148062 TI - Flagellar incorporation of proteins follows at least two different routes in trypanosomes. AB - BACKGROUND INFORMATION: Eukaryotic cilia and flagella are sophisticated organelles composed of several hundreds of proteins that need to be incorporated at the right time and the right place during assembly. RESULTS: Two methods were used to investigate this process in the model protist Trypanosoma brucei: inducible expression of epitope-tagged labelled proteins and fluorescence recovery after photobleaching of fluorescent fusion proteins. This revealed that skeletal components of the radial spokes (RSP3), the central pair (PF16) and the outer dynein arms (DNAI1) are incorporated at the distal end of the growing flagellum. They display low or even no visible turnover in mature flagella, a finding further confirmed by monitoring a heavy chain of the outer dynein arm. In contrast, the membrane-associated protein arginine kinase 3 (AK3) showed rapid turnover in both growing and mature flagella, without particular polarity and independently of intraflagellar transport. CONCLUSION: These results demonstrate different modes of incorporation for structural and membrane-associated proteins in flagella. SIGNIFICANCE: The existence of two distinct modes for incorporation of proteins in growing flagella suggests the existence of different targeting machineries. Moreover, the absence of turnover of structural elements supports the view that the length of the mature flagellum in trypanosomes is not modified after assembly. PMID- 29148063 TI - Studies on the curcumin phospholipid complex solidified with Soluplus(r). AB - OBJECTIVES: With the purpose of developing a curcumin phospholipid complex (CPC) formulation with high performance, the CPC was prepared and solidified with Soluplus(r) in this study. METHODS: Soluplus(r) was used as a carrier to solidify CPC. The structures of the CPC and curcumin phospholipid complex - Soluplus(r) solidified powder (CSP) - were also characterized by differential scanning electron microscope, differential scanning calorimetry, Fourier transform infrared spectroscopy and X-ray diffractometer, and flowability, in-vitro dissolution and oral bioavailability were also investigated. KEY FINDINGS: All analysis indicated that curcumin was completely converted from crystalline to amorphous state in solidified powder. The angle of repose calculated in flowability study indicated a marked improvement from 'cannot be measured' to '37 degrees '. Meanwhile, the dissolution study showed that in phosphate buffer condition, the dissolution rate of CSP had released 76.34% in pH 6.8 and the 78.19% in pH 1.2. Furthermore, in pharmacokinetic study, significant (P < 0.01) improvement of AUC0-infinity value was observed between CPC and CSP groups, and the results showed that AUC0-infinity value was increased from 205.84 +/- 50.46 MUg h/ml to 330.47 MUg h/ml. CONCLUSIONS: A simple and convenient solidifying process was used in this study, and the data suggested that this process not only could improve the flowability and dissolution of phospholipid complex, but also increased the oral bioavailability of curcumin. PMID- 29148064 TI - A Validation Study of the Langley et al. (2017) Decision Tree Model for Sex Estimation. AB - Langley et al. (2017) developed a sex estimation decision tree utilizing two traditional cranial traits (glabella and mastoid) and a new trait: zygomatic extension. This study aimed to test the reliability of their zygomatic extension scoring method and validate their sex estimation method. Ordinal score data were collected from 281 male and female U.S. White and Black individuals. The five traditional cranial traits were collected from physical specimens, while zygomatic extension was scored from 3D cranial models. Intra- and interobserver analyses carried out on a subsample of 30 individuals indicate good agreement between zygomatic scores. The decision tree correctly sexed 71.5% of the sample, but a strong sex bias (94.2% correct for females, 49.3% correct for males) severely limits the utility of this method. The Walker (2008) and Stevenson et al. (2009) methods produced higher accuracy rates (80.8% and 82.6%, respectively), although these methods also produced sex and ancestry biases. PMID- 29148065 TI - Improvement in low upright baroreflex sensitivity is associated with positive clinical effect of orthostatic training. AB - AIM: To assess the clinical efficacy of orthostatic training (OT) and its effect on the autonomic activity. METHODS: OT was performed in 38 patients (13 males, age 36.4 +/- 15.2 years). Baroreflex sensitivity (BRS), heart rate variability, and quality of life (SF 36) were assessed before and after 6 months of OT. Patients with no recurrence of syncope and reduction of the presyncope number to one-third or less were classified as responders. RESULTS: Compliance to OT was low. Only 55% (38 from 69 patients) completed the training programme; 28 patients were responders (74%) and 10 patients were nonresponders. Before OT, BRS in upright position was lower in responders than in nonresponders (sitting: 8.05 +/- 3.94 ms/mm Hg vs 12.51 +/- 5.3 ms/mm Hg, P = 0.04, standing: 5.08 +/- 2.34 ms/mm Hg vs 7.54 +/- 2.16 ms/mm Hg, P = 0.02). After OT, BRS increased in responders (sitting: 8.05 +/- 3.94 ms/mm Hg to 9.31 +/- 4.49 ms/mm Hg, P = 0.05; standing: 5.08 +/- 2.34 ms/mm Hg to 5.96 +/- 2.38 ms/mm Hg, P = 0.03). No differences in supine BRS were observed. In responders, low frequency (LF) and high frequency (HF) power in sitting and standing positions significantly increased after OT (P < 0.05). In nonresponders, there was no significant rise in BRS, LF, and HF after OT. A significant increase in quality of life was noted in responders, but not in nonresponders. CONCLUSIONS: OT reduced symptoms in 74% patients who trained regularly. However, the compliance to training was low. Possible mechanism of OT is reconditioning effect on baroreceptor reactivity in upright position. PMID- 29148066 TI - Predicting the use of corporal punishment: Child aggression, parent religiosity, and the BDNF gene. AB - Corporal punishment (CP) has been associated with deleterious child outcomes, highlighting the importance of understanding its underpinnings. Although several factors have been linked with parents' CP use, genetic influences on CP have rarely been studied, and an integrative view examining the interplay between different predictors of CP is missing. We focused on the separate and joint effects of religiosity, child aggression, parent's gender, and a valine (Val) to methionine (Met) substitution in the brain-derived neurotrophic factor (BDNF) gene. Data came from a twin sample (51% male, aged 6.5 years). We used mothers' and fathers' self-reports of CP and religiosity, and the other parent's report on child aggression. Complete data were available for 244 mothers and their 466 children, and for 217 fathers and their 409 children. The random split method was employed to examine replicability. For mothers, only the effect of religiosity appeared to replicate. For fathers, several effects predicting CP use replicated in both samples: child aggression, child sex, religiosity, and a three-way (GxExE) interaction implicating fathers' BDNF genotype, child aggression and religiosity. Religious fathers who carried the Met allele and had an aggressive child used CP more frequently; in contrast, secular fathers' CP use was not affected by their BDNF genotype or child aggression. Results were also repeated longitudinally in a subsample with age 8-9 data. Findings highlight the utility of a bio-ecological approach for studying CP use by shedding light on pertinent gene-environment interaction processes. Possible implications for intervention and public policy are discussed. PMID- 29148067 TI - Should theophylline be added to the J wave syndrome therapeutic armamentarium? PMID- 29148068 TI - Gastrodin protects myocardial cells against hypoxia/reoxygenation injury in neonatal rats by inhibiting cell autophagy through the activation of mTOR signals in PI3K-Akt pathway. AB - OBJECTIVES: This study aimed to investigate the protective effect of gastrodin (GAS) on myocardial cells with hypoxia/reoxygenation (H/R) injury in neonatal rats and explore the underlying mechanism. METHODS: Myocardial cells were extracted from neonatal rats and divided into six groups: control, H/R, H/R + Low Concentration GAS, H/R + Middle-Concentration GAS, H/R + High-Concentration GAS and H/R + High-Concentration GAS + AKT Inhibitor groups. After 48-h treatment, cell viability, autophagosome quantity and the expression levels of LC3-II, p62, Akt, pAkt, mammalian target of rapamycin (mTOR) and uncoordinated 51-like kinase 1 (ULK1) in myocardial cells were made comparisons among each group. KEY FINDINGS: Gastrodin improved the proliferation activity of myocardial cells under H/R injury in a dose-dependent manner and inhibited the level of cell autophagy. However, when AKT inhibitor was added, the effect of GAS was partly inhibited (P < 0.05). Gene and protein expressions showed that GAS made no significant effect on the expression quantity of Akt and mTOR genes (P > 0.05) but could significantly promote the phosphorylation of Akt and mTOR (P < 0.05). GAS had significant inhibiting effect on the expression of ULK1 (P < 0.05). CONCLUSIONS: Gastrodin could protect against H/R injury of myocardial cells in neonatal rats by reducing the level of autophagy through the activation of mTOR signals in PI3K Akt pathway. PMID- 29148069 TI - Long-term oral exposure to safe dose of bisphenol A in association with high-fat diet stimulate the prostatic lesions in a rodent model for prostate cancer. AB - BACKGROUND: Studies have shown that exposure to environmental chemicals known as endocrine disruptors can cause permanent changes in genital organs, such as the prostate. Among these environmental chemicals stands out bisphenol A (BPA). Another factor associated with prostate changes is the consumption of a high-fat diet. Although the relationship between the consumption of a high-fat diet and an increased risk of prostate cancer is well established, the mechanisms that lead to the establishment of this disease are not completely understood, nor the simultaneous action of BPA and high-fat diet. METHODS: Adult gerbils (100 days old) were divided in four groups (n = 6 per group): Control (C): animals that received a control diet and filtered water; Diet (D): animals that received a high-fat diet and filtered water; BPA: animals that received a control diet and BPA - 50 ug kg-1 day-1 in drinking water; BPA + Diet (BPA + D): animals that received a high-fat diet + BPA - 50 ug kg-1 day-1 in drinking water. After the experimental period (6 months), the dorsolateral and ventral prostate lobes were removed, and analyzed by several methods. RESULTS: Histological analysis indicated premalignant and malignant lesions in both prostatic lobes. However, animals of the D, BPA, and BPA + D groups showed a higher incidence and larger number of prostatic lesions; inflammatory foci were also common. Markers to assess prostate lesions, such as increased activation of the DNA repair system (PCNA-positive cells), androgen receptor (AR), and number of basal cells, confirmed the histology. However, serum levels of testosterone did not change under the experimental conditions. CONCLUSIONS: The results indicated that the methodology used was effective in generating metabolic changes, which directly compromised prostatic homeostasis. Diet and BPA appear to modulate the activation of the AR pathway and thereby optimize tumor establishment in the gerbil prostate. PMID- 29148070 TI - Growth factors for diabetic foot ulcers: mixed treatment comparison analysis of randomized clinical trials. AB - AIMS: Topical growth factors accelerate wound healing in patients with diabetic foot ulcers (DFU). Due to the absence of head-to-head comparisons, we carried out Bayesian network meta-analysis to compare the efficacy and safety of growth factors. METHODS: Using an appropriate search strategy, randomized controlled trials on topical growth factors compared with standard of care in patients with DFU, were included. Proportion of patients with complete healing was the primary outcome. Odds ratio (95% confidence interval) was used as the effect estimate and random effects model was used for both direct and indirect comparisons. Markov Chain Monte Carlo simulation was used to obtain pooled estimates. Rankogram was generated based on surface under the cumulative ranking curve (SUCRA). RESULTS: A total of 26 studies with 2088 participants and 1018 events were included. The pooled estimates for recombinant epidermal growth factor (rhEGF), autologous platelet rich plasma (PRP), recombinant human platelet-derived growth factor (rhPDGF) were 5.72 [3.34, 10.37], 2.65 [1.60, 4.54] and 1.97 [1.54, 2.55] respectively. SUCRA for rhEGF was 0.95. Sensitivity analyses did not reveal significant changes from the pooled estimates and rankogram. No differences were observed in the overall risk of adverse events between the growth factors. However, the growth factors were observed to lower the risk of lower limb amputation compared to standard of care. CONCLUSION: To conclude, rhEGF, rhPDGF and autologous PRP significantly improved the healing rate when used as adjuvants to standard of care, of which rhEGF may perform better than other growth factors. The strength of most of the outcomes assessed was low and the findings may not be applicable for DFU with infection or osteomyelitis. The findings of this study needs to be considered with caution as the results might change with findings from head-to-head studies. PMID- 29148071 TI - Sonography of the Optic Nerve Sheath Diameter. PMID- 29148072 TI - Ultrastructure of endocrine pancreatic granules during pancreatic differentiation in the grass snake, Natrix natrix L. (Lepidosauria, Serpentes). AB - We used transmission electron microscopy to study the pancreatic main endocrine cell types in the embryos of the grass snake Natrix natrix L. with focus on the morphology of their secretory granules. The embryonic endocrine part of the pancreas in the grass snake contains four main types of cells (A, B, D, and PP), which is similar to other vertebrates. The B granules contained a moderately electron-dense crystalline-like core that was polygonal in shape and an electron dense outer zone. The A granules had a spherical electron-dense eccentrically located core and a moderately electron-dense outer zone. The D granules were filled with a moderately electron-dense non-homogeneous content. The PP granules had a spherical electron-dense core with an electron translucent outer zone. Within the main types of granules (A, B, D, PP), different morphological subtypes were recognized that indicated their maturity, which may be related to the different content of these granules during the process of maturation. The sequence of pancreatic endocrine cell differentiation in grass snake embryos differs from that in many vertebrates. In the grass snake embryos, the B and D cells differentiated earlier than A and PP cells. The different sequence of endocrine cell differentiation in snakes and other vertebrates has been related to phylogenetic position and nutrition during early developmental stages. PMID- 29148073 TI - Adaptation and validation of the VOICES (SF) questionnaire - for evaluation of end-of-life care in Sweden. AB - OBJECTIVES: Instruments for evaluating end-of-life care by voicing experiences of family members have previously been lacking in Sweden. The objective of this study was therefore to adapt and validate the VOICES (SF) questionnaire to evaluate quality of end-of-life care in Sweden. The VOICES (SF) [Views of Informal Carers - Evaluation of Services (Short form)] is a questionnaire about bereaved relatives' experiences of care in the last three months of life of a deceased family member. METHODS: This study was performed based on translation and back translation, cross-cultural adaptation and content validation through cognitive interviewing and feedback from professional experts. For the cognitive interviews, a purposeful sample of 35 bereaved family members was recruited from home care, hospital wards and nursing homes. The participants were 13 men and 22 women (age ranged between 20 and 90+, mean age 66), who were relatives of persons who died from life-limiting conditions. The bereaved family members' and the professional experts' concerns were summarised and analysed based on clarity, understanding, relevance, sensitivity and alternative response/wording. RESULTS: The main concerns emerging from the content validation related to the understanding and clarity of some of the questionnaire items', and a few concerns regarding the relevance of different response alternatives or items. Only two of the family members found it emotional to complete the questionnaire, and they still deemed completing it to be important and manageable. SIGNIFICANCE OF RESULTS: The VOICES (SF) can be considered as feasible in the Swedish context, provided that cultural adaptation has been achieved, that is translation alone is not enough. The Swedish version will be available for healthcare professionals to use for quality monitoring of the care provided over the last three months in life, and for research, it enables national and cross-national comparisons between different healthcare places and organisations. PMID- 29148074 TI - Salutogenic Healthy Ageing Programme Embracement (SHAPE) for senior-only households: A study protocol. AB - AIMS: To evaluate the effectiveness of a multi-dimensional community-based health promotion and risk prevention programme, named Salutogenic Healthy Ageing Programme Embracement (SHAPE) for senior-only households in Singapore. BACKGROUND: In view of ageing population and its significant impacts on economy, societal structure and policy-making, healthy ageing emerges as an important concept in maintaining health through the engagement of health-promoting behaviour and risk prevention actions in older people. DESIGN: A stratified randomized control trial with process evaluation is proposed. METHODOLOGY: The salutogenic model, which focuses on positive well-being and optimizing health outcomes, provides an underpinning theoretical framework for this study. SHAPE is a 12-week intervention programme comprising of both weekly group-based activity sessions and home visits. One hundred and fifty-four eligible participants will be stratified and randomly allocated to either the SHAPE intervention or the control group. Both outcome and process evaluation will be conducted. Outcome measures include sense of coherence, quality of life, health-promoting behaviours, self-efficacy and other health-related outcomes. These data will be collected at four time points: baseline, 3 months, 6 months and 12 months. Individual qualitative face-to-face interviews will be conducted for older people receiving SHAPE to explore their views on the programme. DISCUSSION: The use of salutogenic model breaks away from the negatively connoted conventional biomedical model and addresses optimization of positive health, providing an overall holistic approach to care of older people. The intervention SHAPE seeks to identify, equip and strengthen resources for senior-only households, encouraging the adaption of health-promoting and risk-preventing actions to achieve better health outcomes and higher quality of life. PMID- 29148075 TI - Job satisfaction, work environment and successful ageing: Determinants of delaying retirement among acute care nurses. AB - AIM: To determine the relationships between job satisfaction, work environment and successful ageing and how these factors relate to Registered Nurses' intent to retire. BACKGROUND: Although little studied, retention of older nurses by delaying early retirement, before age 65, is an important topic for research. Qualitative and quantitative studies have indicated that job satisfaction work environment and successful ageing are key motivators in acute care Registered Nurses retention and/or delaying retirement. This study was designed to provide information to administrators and policy makers about retaining older, experienced RNs longer and more productively. DESIGN: This was a correlational, descriptive, cross-sectional study. METHODS: An online survey of acute care Registered Nurses (N = 2,789) aged 40 years or older working in Florida was conducted from September - October 2013. Participants completed items related to job satisfaction, work environment, successful ageing and individual characteristics. Hypotheses derived from the modified Ellenbecker's Job Retention Model were tested using regression analysis. RESULTS: Job satisfaction scores were high. Highest satisfaction was with scheduling issues and co-workers; lowest with advancement opportunities. Successful ageing scores were also high with 81% reporting excellent or good health. Work environment explained 55% of the variance in job satisfaction. Years to retirement were significantly associated with successful ageing (p < .001), age (p < .001) and income (p < .010). CONCLUSIONS: This study provides quantitative evidence that environment and successful ageing are important areas that have an impact on job satisfaction and delay of retirement in older nurses and further studies in these areas are warranted to expand on this knowledge. PMID- 29148076 TI - Subjective cognitive complaints, psychosocial factors and nursing work function in nurses providing direct patient care. AB - AIMS: The aim of this study was to examine relationships among subjective cognitive complaints, psychosocial factors and nursing work function in nurses providing direct patient care. BACKGROUND: Cognitive functioning is a critical component for nurses in the assurance of error prevention, identification and correction when caring for patients. Negative changes in nurses' cognitive and psychosocial functioning can adversely affect nursing care and patient outcomes. DESIGN: A descriptive correlational design with stratified random sampling. METHOD: The sample included 96 nurses from the major geographic regions of the United States. Over 9 months in 2016-2017, data were collected using a web-based survey. Stepwise multiple linear regression analyses were used to examine relationships among subjective cognitive complaints, psychosocial factors and nursing work function. RESULTS: Overall, participants reported minimal work function impairment and low levels of subjective cognitive complaints, depression and stress. In multivariate analyses, depression was not associated with nurses' work function. However, perceived stress and subjective concerns about cognitive function were associated with greater impairment of work function. CONCLUSION: Nurses experiencing subjective cognitive complaints should be encouraged to address personal and environmental factors that are associated with their cognitive status. Additionally, stress reduction in nurses should be a high priority as a potential intervention to promote optimal functioning of nurses providing direct patient care. Healthcare institutions should integrate individual and institutional strategies to reduce factors contributing to workplace stress. PMID- 29148077 TI - Drug-related deaths in hospital inpatients: A retrospective cohort study. AB - AIMS: To determine the incidence of drug-related deaths (DRD) in a university hospital in 2015, to describe their characteristics, and to discover risk factors of DRD. METHODS: An analytic and retrospective cohort study. Patients with a death diagnosed predefined from a list of medical conditions potentially caused by drugs were the selected cases for further review. Causality assessment was evaluated by a local drug safety committee. RESULTS: Out of 1135 inpatient deaths, 73 DRD were included (six were hospital-acquired). The incidence of DRD of all hospital admissions was 0.34%, and the incidence of all deaths cases was 7%. Drugs were the cause of death in 38 patients (52%) and a contributive role in 35 (48%). The median age of DRD patients was 72 years (range 19-94) and 72.6% were men. The median hospital stay, Charlson score and number of drugs were 5 days, 2 points and seven drugs respectively. The most frequent DRD were cerebral haemorrhages and infections in drug-immunosuppressed patients (32, 43.8%, each group). The most frequently involved drugs were antineoplastics and glucocorticosteroids (40% and 18%), and antithrombotics (33%); drug-drug interactions were present in 44% DRD. Sex, age and number of drugs were risk factors of DRD. CONCLUSIONS: Adverse drug reactions were a significant cause of death in hospitalized patients, mainly haemorrhages and infections precipitated by drug-drug interactions. Risk factors for DRD were sex, age and number of drugs. Preventable DRD and measures to avoid them should be accurately assessed in further studies. PMID- 29148078 TI - Soluble TAM receptor tyrosine kinases in rheumatoid arthritis: correlation with disease activity and bone destruction. AB - The TAM receptor tyrosine kinases (TAM RTK) are a subfamily of receptor tyrosine kinases, the role of which in autoimmune diseases such as systemic lupus erythematosus has been well explored, while their functions in rheumatoid arthritis (RA) remain largely unknown. In this study, we investigated the role of soluble TAM receptor tyrosine kinases (sAxl/sMer/sTyro3) in patients with RA. A total of 306 RA patients, 100 osteoarthritis (OA) patients and 120 healthy controls (HCs) were enrolled into this study. The serum concentrations of sAxl/sMer/sTyro3 were measured by enzyme-linked immunosorbent assay (ELISA), then the associations between sAxl/sMer/sTyro3 levels and clinical features of RA patients were analysed. We also investigated whether sTyro3 could promote osteoclast differentiation in vitro in RA patients. The results showed that compared with healthy controls (HCs), sTyro3 levels in the serum of RA patients were elevated remarkably and sMer levels were decreased significantly, whereas there was no difference between HCs and RA patients on sAxl levels. The sTyro3 levels were correlated weakly but positively with white blood cells (WBC), immunoglobulin (Ig)M, rheumatoid factor (RF), swollen joint counts, tender joint counts, total sharp scores and joint erosion scores. Conversely, there were no significant correlations between sMer levels and the above indices. Moreover, RA patients with high disease activity also showed higher sTyro3 levels. In-vitro osteoclast differentiation assay showed further that tartrate-resistant acid phosphatase (TRAP)+ osteoclasts were increased significantly in the presence of sTyro3. Collectively, our study indicated that serum sTyro3 levels were elevated in RA patients and correlated positively with disease activity and bone destruction, which may serve as an important participant in RA pathogenesis. PMID- 29148079 TI - Insulinoma-associated 1: A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma). AB - Merkel cell carcinoma (MCC) is a rare, clinically aggressive, cutaneous neuroendocrine (NE) neoplasm. As a tumor with small, round, blue cells, the histologic differential diagnosis for MCC can include melanoma, metastatic small cell carcinoma (SCC), nodular hematopoietic tumors, basal cell carcinoma (BCC), atypical variants of squamous carcinoma and the uncommon occurrence of primary cutaneous Ewing sarcoma. In cases with atypical histology or without the classic immunophenotype, the diagnosis can be challenging. Ultimately, immunohistochemistry (IHC) is essential to the definitive diagnosis of MCC and in difficult cases, the diagnosis may hinge entirely on the immunophenotype of the tumor cells. Insulinoma-associated 1 (INSM1) is a transcription factor expressed in tissues undergoing terminal NE differentiation. As a nuclear protein tied to both differentiation and the cell cycle, INSM1 may offer additional utility in comparison to traditional, cytoplasmic markers of NE differentiation. PMID- 29148081 TI - Synthesis, antitumor activity evaluation, and DNA-binding study of coumarin-based agents. AB - A novel series of coumarin-thiadiazole heterocycle derivatives was synthesized by the nucleophilic substitution reaction. The synthesized compounds were structurally verified by IR, 1 H NMR, 13 C NMR, mass spectra, and elemental analyses. The antitumor activity of the synthesized compounds was evaluated through DNA binding assays and the 60-cell line panel according to the US NCI-DTP protocol or a selection of human tumor cell lines: breast cancer (MCF-7), liver cancer (HepG-2), and colorectal cancer (HCT-116). Most of the compounds had better DNA/ethidium bromide fluorescence quenching rather than methyl green displacement, suggesting superior DNA intercalation over DNA groove binding. Compounds 8 and 14b showed the best quenching effect with KSV = 4.27 * 105 M-1 . Moreover, the results for compounds 8, 4c, and 4e revealed a possible dual DNA binding mode with the intercalation to be superior, with KSV 4.27 * 105 , 3.96 * 105 , and 3.51 * 105 M-1 , respectively, compared to 42%, 45%, and 43% methyl green displacement, respectively. Out of the 60-cell line panel, the leukemia HL 60 cell line was the most susceptible to growth inhibition when treated with 14a, resulting in 61% growth, followed by the lung carcinoma cell line NCI-H522 showing 67% growth when treated with 9. Moreover, compound 10c had an IC50 value of 24.9 MUg/mL against the HepG-2 cell line. PMID- 29148080 TI - Genetic risk factors for perception of symptoms in GERD: an observational cohort study. AB - BACKGROUND: Genetic polymorphisms in G-protein beta-3 subunit (GNbeta3) and beta 2 adrenergic receptor (ADRB2) are associated with pain and gut hypersensitivity, which can overlap with gastroesophageal reflux disease (GERD). AIM: To evaluate relationships between single nucleotide polymorphisms (SNPs) within GNbeta3 and ADRB2 systems, and reflux symptom burden, GERD phenotypes from ambulatory reflux monitoring, and quality of life. METHODS: Symptomatic adults undergoing ambulatory reflux testing were recruited and phenotyped based on acid burden and symptom reflux association; major oesophageal motor disorders and prior foregut surgery were exclusions. A comparison asymptomatic control cohort was also identified. Subjects and controls completed questionnaires assessing symptom burden on visual analog scales, short-form health survey-36 (SF-36), and Beck Anxiety and Depression Inventories (BAI and BDI). Genotyping was performed from saliva samples; 6 SNPs selected from each of the two genes of interest were compared. RESULTS: Saliva from 151 study subjects (55.3 +/- 1.2 years, 63.6% F) and 60 control subjects (50.9 +/- 2.2 years, 66.7%) had sufficient genetic material for genotyping. Study subjects had higher symptom burden, worse total and physical health, and higher anxiety scores compared to controls (P <= .002). Tested SNPs within ADRB2 were similar between study subjects and controls (P > .09). Study subjects with recessive alleles in 3 GNbeta3 SNPs (Rs2301339, Rs5443, and Rs5446) had worse symptom severity (P = .011), worse mental health (P = .03), and higher depression scores (P = .005) despite no associations with GERD phenotypes or reflux metrics. CONCLUSIONS: Genetic variation within GNbeta3 predicts oesophageal symptom burden and affect, but not oesophageal acid burden or symptom association with reflux episodes. PMID- 29148082 TI - Insights into Flood-Coping Appraisals of Protection Motivation Theory: Empirical Evidence from Germany and France. AB - Protection motivation theory (PMT) has become a popular theory to explain the risk-reducing behavior of residents against natural hazards. PMT captures the two main cognitive processes that individuals undergo when faced with a threat, namely, threat appraisal and coping appraisal. The latter describes the evaluation of possible response measures that may reduce or avert the perceived threat. Although the coping appraisal component of PMT was found to be a better predictor of protective intentions and behavior, little is known about the factors that influence individuals' coping appraisals of natural hazards. More insight into flood-coping appraisals of PMT, therefore, are needed to better understand the decision-making process of individuals and to develop effective risk communication strategies. This study presents the results of two surveys among more than 1,600 flood-prone households in Germany and France. Five hypotheses were tested using multivariate statistics regarding factors related to flood-coping appraisals, which were derived from the PMT framework, related literature, and the literature on social vulnerability. We found that socioeconomic characteristics alone are not sufficient to explain flood-coping appraisals. Particularly, observational learning from the social environment, such as friends and neighbors, is positively related to flood-coping appraisals. This suggests that social norms and networks play an important role in flood preparedness decisions. Providing risk and coping information can also have a positive effect. Given the strong positive influence of the social environment on flood-coping appraisals, future research should investigate how risk communication can be enhanced by making use of the observed social norms and network effects. PMID- 29148083 TI - Macroscopic and microscopic analyses in flexor tendons of the tarsometatarso phalangeal joint of ostrich (Struthio camelus) foot with energy storage and shock absorption. AB - Flexor tendons function as energy storage and shock absorption structures in the tarsometatarso-phalangeal joint (TMTPJ) of ostrich feet during high-speed and heavy-load locomotion. In this study, mechanisms underlying the energy storage and shock absorption of three flexor tendons of the third toe were studied using histology and scanning electron microscopy (SEM). Macroscopic and microscopic structures of the flexor tendons in different positions of TMTPJ were analyzed. Histological slices showed collagen fiber bundles of all flexor tendons in the middle TMTPJ were arranged in a linear-type, but in the proximal and distal TMTPJ, a wavy-type arrangement was found in the tendon of the M. flexor digitorum longus and tendon of the M. flexor perforans et perforatus digiti III, while no regular-type was found in the tendon of the M. flexor perforatus digiti III. SEM showed that the collagen fiber bundles of flexor tendons were arranged in a hierarchically staggered way (horizontally linear-type and vertically linear type). Linear-type and wavy-type both existed in the proximal TMTPJ for the collagen fiber bundles of the tendon of the M. flexor perforatus digiti III, but only the linear-type was found in the distal TMTPJ. A number of fibrils were distributed among the collagen fiber bundles, which were likely effective in connection, force transmission and other functions. The morphology and arrangement of collagen fiber bundles were closely related to the tendon functions. We present interpretations of the biological functions in different positions and types of the tendons in the TMTPJ of the ostrich feet. PMID- 29148084 TI - Size, shape, and sex-dependent variation in force production by crayfish chelae. AB - The ability to generate large closing forces is important for many animals. Several studies have demonstrated that bite or pinching force capacity is usually related to the linear dimensions of the closing apparatus. However, relatively few studies have applied geometric morphometrics to examine the effects of size independent shape on force production, particularly in studies of crustacean pinching force. In this study, we utilized traditional and geometric morphometric techniques to compare the pinching force of Procambarus clarkii crayfish to their chela morphology. We found that males possessed larger chelae and pinched harder than females, but that their chela shape and size were weak predictors of strength. Female pinching force was significantly affected by both chela size and shape, with shape variation along the short axis of the claw contributing most to pinching force. We discuss our results in the context of reliable signaling of strength by males and females, and the different selective forces acting on chela shape in the two sexes. PMID- 29148085 TI - Built to bite? Differences in cranial morphology and bite performance between narrow- and broad-headed European glass eels. AB - The presence of two phenotypes in a single species is a widespread phenomenon, also observed in European eel (Anguilla anguilla). This dimorphism has been related to dietary differences in the subadult elver and yellow eel stages, with broad-heads generally feeding on harder and/or larger-bodied prey items than narrow-heads. Nevertheless, both broad- and narrow-headed phenotypes can already be found among glass eels, the stage preceding the elver eel stage. As these glass eels are considered nonfeeding, we investigate here to what degree the observed variation in head width is reflected in variation in the musculoskeletal feeding system, as well as whether this reflects the same variation observed in the older, dimorphic yellow eels. Additionally, we investigate whether musculoskeletal differences between broad- and narrow-headed glass eels have implications on their feeding performance and could thus impact prey preference when eels start feeding. Therefore, we compared the cranial musculoskeletal system of five broad- and narrow-headed glass eels using 3D-reconstructions and simulated the glass eel's bite force using the data of the muscle reconstructions. We found that the variation in the musculoskeletal system of glass eels indeed reflects that of the yellow eels. Broader heads were related to larger jaw muscles, responsible for mouth closure. Accordingly, broad-heads could generate higher bite forces than narrow-headed glass eels. In addition, broader heads were associated with higher coronoid processes and shorter hyomandibulae, beneficial for dealing with higher mechanical loadings and consequently, harder prey. We, thus, show that head width variation in glass eels is related to musculoskeletal differences which, in turn, can affect feeding performance. As such, differences in prey preference can already take place the moment the eels start feeding, potentially leading to the dimorphism observed in the elver and yellow eel stage. PMID- 29148086 TI - Novel gene fusion of PRCC-MITF defines a new member of MiT family translocation renal cell carcinoma: clinicopathological analysis and detection of the gene fusion by RNA sequencing and FISH. AB - AIMS: MITF, TFE3, TFEB and TFEC belong to the same microphthalmia-associated transcription factor family (MiT). Two transcription factors in this family have been identified in two unusual types of renal cell carcinoma (RCC): Xp11 translocation RCC harbouring TFE3 gene fusions and t(6;11) RCC harbouring a MALAT1-TFEB gene fusion. The 2016 World Health Organisation classification of renal neoplasia grouped these two neoplasms together under the category of MiT family translocation RCC. RCCs associated with the other two MiT family members, MITF and TFEC, have rarely been reported. Herein, we identify a case of MITF translocation RCC with the novel PRCC-MITF gene fusion by RNA sequencing. METHODS AND RESULTS: Histological examination of the present tumour showed typical features of MiT family translocation RCCs, overlapping with Xp11 translocation RCC and t(6;11) RCC. However, this tumour showed negative results in TFE3 and TFEB immunochemistry and split fluorescence in-situ hybridisation (FISH) assays. The other MiT family members, MITF and TFEC, were tested further immunochemically and also showed negative results. RNA sequencing and reverse transcription polymerase chain reaction confirmed the presence of a PRCC-MITF gene fusion: a fusion of PRCC exon 5 to MITF exon 4. We then developed FISH assays covering MITF break-apart probes and PRCC-MITF fusion probes to detect the MITF gene rearrangement. CONCLUSIONS: This study both proves the recurring existence of MITF translocation RCC and expands the genotype spectrum of MiT family translocation RCCs. PMID- 29148087 TI - An Agent-Based Model of Evolving Community Flood Risk. AB - Although individual behavior plays a major role in community flood risk, traditional flood risk models generally do not capture information on how community policies and individual decisions impact the evolution of flood risk over time. The purpose of this study is to improve the understanding of the temporal aspects of flood risk through a combined analysis of the behavioral, engineering, and physical hazard aspects of flood risk. Additionally, the study aims to develop a new modeling approach for integrating behavior, policy, flood hazards, and engineering interventions. An agent-based model (ABM) is used to analyze the influence of flood protection measures, individual behavior, and the occurrence of floods and near-miss flood events on community flood risk. The ABM focuses on the following decisions and behaviors: dissemination of flood management information, installation of community flood protection, elevation of household mechanical equipment, and elevation of homes. The approach is place based, with a case study area in Fargo, North Dakota, but is focused on generalizable insights. Generally, community mitigation results in reduced future damage, and individual action, including mitigation and movement into and out of high-risk areas, can have a significant influence on community flood risk. The results of this study provide useful insights into the interplay between individual and community actions and how it affects the evolution of flood risk. This study lends insight into priorities for future work, including the development of more in-depth behavioral and decision rules at the individual and community level. PMID- 29148088 TI - Effectiveness of an intensive intervention to improve lifestyles in people with intermediate cardiovascular risk (DATE study): Study protocol for a randomized controlled trial. AB - AIM: The aim of this study was to evaluate the effectiveness of an intensive intervention led by primary care nurses for lifestyle modification among people with intermediate cardiovascular risk. BACKGROUND: Cardiovascular diseases may be prevented by adopting healthy lifestyles. Interventions focused on populations at risk are more efficient than those aimed at the general population. More than 50 per cent of cardiovascular events occur in people with intermediate cardiovascular risk, but only a few studies have targeted this population. DESIGN: A randomized controlled trial approved in January 2017. METHODS: We will recruit 208 participants aged 35-74 years who have intermediate cardiovascular risk. They will be selected by consecutive sampling and will be randomized into a control group or intervention group. Individual standardized brief counselling on healthy lifestyles will be provided to both groups. Additionally, individuals from the intervention group will receive four weekly group sessions focusing on cardiovascular risk, healthy diet, moderation in alcohol consumption, daily physical activity, stress management and smoking cessation and two motivational follow-up calls. The primary outcome will be the lifestyle modification measured by total steps recorded by a pedometer, total score on the Mediterranean Diet Adherence Screener and percentage of current smokers. DISCUSSION: This study will allow us to investigate whether an intensive intervention based on a multifactorial group approach is more effective in lifestyle modification than individual standardized brief counseling among adults with intermediate cardiovascular risk. Our results could lead to the establishment of new strategies for cardiovascular risk management. PMID- 29148089 TI - Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms. AB - Acute myeloid leukemias secondary (sAML) to myeloproliferative neoplasms (MPN) have variable clinical courses and outcomes, but remain almost always fatal. Large cohorts of sAML to MPN are difficult to obtain and there is very little scientific literature or prospective trials for determining robust prognostic markers and efficient treatments. We analyzed event-free survival (EFS) and overall survival (OS) of 73 patients with MPN who progressed to sAML, based on their epidemiological characteristics, the preexisting MPN, the different treatments received, the different prognostic groups and the responses achieved according to the ELN, and their mutational status determined by next-generation DNA sequencing (NGS). For 24 patients, we were able to do a comparative NGS analysis at both MPN and sAML phase. After acute transformation EFS and OS were respectively of 2.9 months (range: 0-48.1) and 4.7 months (range: 0.1-58.8). No difference in EFS or OS regarding the previous MPN, the ELN2017 prognostic classification, the first-line therapy or the response was found. After univariate analysis, three genes, TP53, SRSF2 and TET2, impacted pejoratively sAML prognosis at sAML time. In multivariate analysis, TP53 (P = .0001), TET2 (P = .011) and SRSF2 (P = .018) remained independent prognostic factors. Time to sAML transformation was shorter in SRSF2-mutated patients (51.2 months, range: 14.7-98) than in SRSF2-unmutated patients (133.8 months, range: 12.6-411.2) (P < .001). Conventional clinical factors (age, karyotype, ELN2017 prognostic classification, treatments received, treatments response, Allo-SCT...) failed to predict the patients' outcome. Only the mutational status appeared relevant to predict patients' prognosis at sAML phase. PMID- 29148090 TI - Assessment of cumulative health risk in the World Trade Center general responder cohort. AB - BACKGROUND: Multiple comorbidities have been reported among rescue/recovery workers responding to the 9/11/2001 WTC disaster. In this study, we developed an index that quantifies the cumulative physiological burden of comorbidities and predicts life expectancy in this cohort. METHODS: A machine learning approach (gradient boosting) was used to model the relationship between mortality and several clinical parameters (laboratory test results, blood pressure, pulmonary function measures). This model was used to construct a risk index, which was validated by assessing its association with a number of health outcomes within the WTC general responder cohort. RESULTS: The risk index showed significant associations with mortality, self-assessed physical health, and onset of multiple chronic conditions, particularly COPD, hypertension, asthma, and sleep apnea. CONCLUSION: As an aggregate of several clinical parameters, this index serves as a cumulative measure of physiological dysregulation and could be utilized as a prognostic indicator of life expectancy and morbidity risk. PMID- 29148091 TI - Intrinsic Subtypes of Breast Cancers Initially Assessed as Probably Benign or of Low Suspicion on Ultrasonography Differ According to Tumor Size. AB - OBJECTIVES: To investigate whether the intrinsic subtypes of breast cancers initially assessed as American College of Radiology Breast Imaging and Reporting System (BI-RADS) category 3 or 4a differ according to tumor size. METHODS: A total of 444 breast cancers in 439 patients initially assessed as BI-RADS 3 or 4a through ultrasound-guided core needle biopsy were included. Tumors were classified by the size criterion of 10 mm or smaller or larger than 10 mm and categorized as the luminal type (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive and human epidermal growth factor receptor 2 [HER2] negative), HER2 type (HER2 positive regardless of ER or PR status), or triple-negative type (ER negative, PR negative, and HER2 negative). The relationships between tumor size and breast cancer intrinsic subtypes were analyzed. RESULTS: A total of 247 (55.6%) cancers were 10 mm or smaller, and 197 (44.4%) were larger than 10 mm. The luminal type was more frequently present in tumors of 10 mm or smaller (185 of 247 [74.9%]) than those larger than 10 mm (112 of 197 [56.9%]; P < .001). No significant difference was noted in the frequency of the HER2 type in tumors of 10 and mm smaller and those larger than 10 mm (27 of 247 [10.9%] versus 36 of 197 [18.3%]; P = .084). The triple-negative type was more frequently present in tumors larger than 10 mm than those of 10 mm or smaller (49 of /197 [24.9%] versus 35 of 247 [14.2%]; P = .012). CONCLUSIONS: Breast cancers assessed as BI-RADS category 3 or 4a had differing intrinsic subtypes according to tumor size, as the luminal type was more frequently present in tumors of 10 mm or smaller than those larger than 10 mm, whereas the triple negative type was more frequently present in tumors larger than 10 mm. PMID- 29148092 TI - An inductively coupled ultra-thin, flexible, and passive RF resonator for MRI marking and guiding purposes: Clinical feasibility. AB - PURPOSE: The purpose of this study is to develop a wireless, flexible, ultra thin, and passive radiofrequency-based MRI resonant fiducial marker, and to validate its feasibility in a phantom model and several body regions. METHODS: Standard microfabrication processing was used to fabricate the resonant marker. The proposed marker consists of two metal traces in the shape of a square with an edge length of 8 mm, with upper and lower traces connected to each other by a metalized via. A 3T MRI fiducial marking procedure was tested in phantom and ex vivo, and then the marker's performance was evaluated in an MRI experiment using humans. The radiofrequency safety was also tested using temperature sensors in the proximity of the resonator. RESULTS: A flexible resonator with a thickness of 115 MUm and a dimension of 8 * 8 mm was obtained. The experimental results in the phantom show that at low background flip angles (6-18 degrees ), the resonant marker enables precise and rapid visibility, with high marker-to-background contrast and signal-to-noise ratio improvement of greater than 10 in the vicinity of the marker. Temperature analysis showed a specific absorption ratio gain of 1.3. Clinical studies further showed a successful biopsy procedure using the fiducial marking functionality of our device. CONCLUSIONS: The ultra-thin and flexible structure of this wireless flexible radiofrequency resonant marker offers effective and safe MR visualization with high feasibility for anatomic marking and guiding at various regions of the body. Magn Reson Med 80:361-370, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29148093 TI - Keeping and breeding the rescued Sunda pangolins (Manis javanica) in captivity. AB - The Sunda pangolin (Manis javanica Desmarest, 1822) is a Critically Endangered species. Given that this species lacks effective policies for in situ conservation and prevention of poaching in the wild, ex situ conservation and a captive breeding program are urgently needed to save this species from extinction. However, techniques for the maintenance and captive breeding of pangolins have not been well developed. In June 2010, we established the Pangolin Research Base for Artificial Rescue and Conservation Breeding of South China Normal University (PRB-SCNU). To date, a total of 34 Sunda pangolin cubs have been born at PRB-SCNU, 26 of which were captive bred, indicating great progress in keeping and breeding the Sunda pangolin. The techniques for maintenance including housing, transitioning to an artificial diet, husbandry, and captive breeding-are described in this paper. The purpose of this manuscript is to share our successful experiences and techniques in the maintenance, management, and captive breeding of Sunda pangolins, and to provide guidance and a reference for the captive care and management of Sunda pangolins and other pangolin species. PMID- 29148094 TI - Acid-base alterations in ESRD and effects of hemodialysis. AB - Acid-base alterations in patients with kidney failure and on hemodialysis (HD) treatment contribute to (1) intradialytic hypercapnia and hypoxia, (2) hemodynamic instability and cardiac arrhythmia, (3) systemic inflammation, and (4) a number of associated electrolyte alterations including potentiating effects of hypokalemia, hypocalcemia and, chronically, soft-tissue and vascular calcification, imparting poor prognosis and mortality. This paper discusses acid base regulation and pathogenesis of dysregulation in patients with kidney failure. Major organ and systemic effects of acid-base perturbations with a specific focus on kidney failure patients on HD are emphasized, and potential mitigating strategies proposed. The high rate of HD-related complications, specifically those that can be accounted for by rapid and steep acid-base perturbations imposed by HD treatment, attests to the pressing need for investigations to establish a better dialysis regimen. PMID- 29148095 TI - Vascular complications after percutaneous mitral valve repair and venous access closure using suture or closure device. AB - OBJECTIVE: The aim of this study was to assess the impact of different access site closure strategies, suture or closure device (Proglide, Abbott Vascular), on vascular and bleeding complications after percutaneous mitral valve repair (MitraClip, Abbott Vascular). BACKGROUND: Considering the high-risk profile in patients receiving percutaneous mitral valve repair, complications related to the large 24 Fr access sheath and its relation to the closure technique have not been evaluated so far. METHODS AND RESULTS: Between 2009 and 2015, 277 consecutive high-risk patients with severe mitral valve regurgitation (MR) underwent percutaneous mitral valve repair at our institution using Z-suture (n = 150) or closure device (n = 127) to close the access-site. Duplex sonography was performed in all patients. The primary endpoint was access-site related complications according to the Valve Academic Research Consortium (VARC) criteria. Secondary outcomes were the incidence of bleeding complications and mortality. Access-site related VARC2 major and minor complications were comparable after closure with Z-suture or closure device (2,7% vs 3.1%, P = 0.81 and 15,3% vs 15.7%, P = 0.92). Three patients (2%) in the suture and four patients (3.1%) in the closure device group experienced unplanned endovascular intervention at the access site. Access-site related major bleeding was observed in 4 (2.7%) suture and 4 (3.1%) closure device treated patients (P = 0.81). No access site related mortality occurred. CONCLUSION: Both Z-suture and closure device use after percutaneous mitral valve repair are feasible and safe. However, there is no benefit of one strategy over the other according to VARC2 major and minor complications. PMID- 29148096 TI - Performance of the Dimension TAC assay and comparison of multiple platforms for the measurement of tacrolimus. AB - BACKGROUND: Therapeutic monitoring of tacrolimus is essential for reducing organ rejection and adverse effects. The measurement of tacrolimus in whole blood is taken by many automated platforms. We evaluated the analytical performance of the Dimension TAC assay, which is an upgraded reagent from the previous Dimension TACR assay. METHODS: The evaluations involved determination of precision, linearity, detection capability, and reagent lot-to-lot variability between three lot numbers. Correlation studies were conducted using the Dimension TACR assay, Architect, Elecsys assay, and MassTrak LC-MS/MS. RESULTS: The total coefficient of variation was below 10%. Acceptable linearity was observed in their respective reportable ranges. The limit of blank, limit of detection, and limit of quantification were 0.29, 0.47, and 0.81 ng/mL, respectively. Correlation analysis indicated that the Dimension TAC assay results were comparable to that of the Dimension TACR assay, Architect, and Elecsys results in liver and heart transplant patients. In kidney transplant patients, the Dimension TAC assay showed the poor correlation with Architect and Elecsys. The results from these assays were slightly higher than that of MassTrak. We found little lot-to-lot reagent variation among the reagents evaluated. CONCLUSION: The overall analytical performance of the Dimension TAC assay is acceptable for therapeutic monitoring in clinical practice. Our study that compared different platforms may provide some useful information regarding which test method to use. PMID- 29148097 TI - Ce3+ -Sensitized Tm3+ /Mn2+ -Doped NaYF4 Colloidal Nanocrystals: Intense Cool White Light from a Phosphor-Coated UV LED. AB - Colloidal NaYF4 :Ce3+ /Tm3+ /Mn2+ nanocrystals found to be an efficient single component phosphor to produce intense white light. The use of Mn2+ ions instead of green- and red-emitting Ln3+ ions is interesting as the later are expensive and less abundant. The single band blue emission of Tm3+ ions was combined with the broadband green-yellow emission of Mn2+ ions to produce strong white light emission using Ce3+ ions as excitation source. Interestingly, there is hardly any re-absorption of the blue emission by Mn2+ ions and the spectrum matches the commercial Ce3+ -doped yttrium aluminium garnet (YAG) phosphor coated over a blue LED. In addition, we have successfully incorporated the colloidal nanocrystals into a polymer matrix to make a nanocomposite as well as transparent films without altering the optical properties of the nanocrystals. The colloidal nanocomposite was coated over a UV LED to fabricate white LEDs. Finally, when the concentration of the dopant (Mn2+ ) ions was tuned the correlated color temperature (CCT) values varied between cool white light and daylight region. PMID- 29148098 TI - Absence or mislocalization of DNAH5 is a characteristic marker for motile ciliary abnormality in nasal polyps. AB - OBJECTIVE: Motile cilia impairment is a common condition in patients with chronically inflamed airways, such as is seen in nasal polyps (NPs). The mechanism underlying this pathogenic condition is complex and not fully understood. METHODS: We investigated the presence and localization of dynein axonemal heavy chain 5 (DNAH5) in motile cilia using immunofluorescence staining in paraffin-embedded nasal biopsies from NPs (n = 120) and inferior turbinate mucosa (n = 35) of healthy controls. We also performed single-cell staining on cytospin samples (NP = 5, control = 5). Three patterns of DNAH5 localization are defined, including pattern A (presence throughout the axoneme), pattern B (undetectable in the distal part of the axoneme), and pattern C (completely missing throughout the entire axoneme). We developed a semiquantitative scoring system for which 0 = (pattern A > 70%); 1 = (patterns A + B > 70%); and 2 = (pattern C >= 30%) in each high-power field (5 fields per sample). RESULTS: Based on our DNAH5 scoring system, the median (1st and 3rd quartile) score was 0.3 (0.2 and 0.4) for samples from controls, and 1.1 (0.6 and 1.6) for samples from NPs in paraffin specimens (P < 0.001). The DNAH5 score had a significant positive relationship with the Lund-Mackay computed tomography score (r = 0.329, P = 0.005) and was higher in patients with eosinophilic NPs (P = 0.006). For cytospin samples, the mean percentage of patterns A, B, and C were 74%, 14%, and 12% in controls, and 48%, 20%, and 32% in NPs, respectively. CONCLUSION: Our results suggest that the absence or mislocalization of DNAH5 from motile cilia is a common and potentially important pathological phenomenon in chronically inflamed airway epithelium. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E97-E104, 2018. PMID- 29148099 TI - Circulating PCSK9 is lowered acutely following surgery. AB - BACKGROUND: A decrease in serum low-density lipoprotein cholesterol (LDL-C) is well documented after acute stress. Plasma proprotein convertase subtilisin kexin 9 (PCSK9), which promotes degradation of low-density lipoprotein receptor (LDL-R) resulting in reduced plasma clearance of low-density lipoproteins (LDL) and an increase in serum LDL-C, would be predicted to decrease. Yet, a few studies have demonstrated an increase 1-8 days after acute stress. Our objective was to assess the earlier status of plasma PCSK9, within the first 24 hours of onset of stress. METHODS: We measured serum lipids and plasma PCSK9 in 39 patients before and soon after an elective surgical procedure (abdominal aortic aneurysm (AAA) repair). RESULTS: We observed an early decrease in PCSK9 following surgery, as well as a decrease in total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TG). CONCLUSION: Unlike other studies which showed an increase in PCSK9 after the onset of stress, our study detected a fall in PCSK9 following acute surgical stress. The observed difference is likely due to the earlier timing of PCSK9 measurement in our study. Further studies involving serial poststress measurements for several days are needed to determine whether PCSK9 behaves as an acute-phase reactant, whether it displays a biphasic response to acute stress, and whether changes in circulating PCSK9 are responsible for lipoprotein changes observed after surgical stress. (Clinical Trial Registration: ClinicalTrials.gov study ID NCT00493389). PMID- 29148100 TI - Changes in mothers' intended duration of breastfeeding from the prenatal to neonatal periods. AB - BACKGROUND: Although previous studies suggest that the intentions of mothers to breastfeed during pregnancy strongly predict actual breastfeeding practice, no studies have examined the changes in the intentions of mothers to breastfeed from the prenatal to neonatal periods. The purpose of this study was to examine changes in intended breastfeeding duration from the prenatal to neonatal periods, their association with actual duration, and predictors for shortened duration. METHODS: The Infant Feeding Practices Study II was a longitudinal study of mothers in the United States. Changes to intended breastfeeding duration were calculated as the difference from prenatal to neonatal reports (months); we compared this change to actual breastfeeding duration. By using multivariable logistic regression, we identified maternal characteristics associated with a shortened breastfeeding intention. RESULTS: Of 1780 women, 43.7% had no change to intended breastfeeding duration, 35.0% had a shorter intended duration, and 21.3% had a longer intended duration. Mothers with shortened intended duration also had shorter actual duration (P < .001). Women of Hispanic ethnicity, with a prepregnancy body mass index of >=30 kg/m2 , who were primiparous and who smoked prenatally had increased odds of shortening their breastfeeding intention from prenatal to neonatal reports. A maternal age of >=35 years was associated with decreased odds of shortened breastfeeding intention. CONCLUSION: Approximately one in three women shorten their intended breastfeeding duration during the early postpartum period, which negatively affects the actual duration of their breastfeeding. Women may need additional support during the early postpartum period to meet their prenatal breastfeeding intentions. PMID- 29148101 TI - Homeobox protein MSX-1 inhibits expression of bone morphogenetic protein 2, bone morphogenetic protein 4, and lymphoid enhancer-binding factor 1 via Wnt/beta catenin signaling to prevent differentiation of dental mesenchymal cells during the late bell stage. AB - Homeobox protein MSX-1 (hereafter referred to as MSX-1) is essential for early tooth-germ development. Tooth-germ development is arrested at bud stage in Msx1 knockout mice, which prompted us to study the functions of MSX-1 beyond this stage. Here, we investigated the roles of MSX-1 during late bell stage. Mesenchymal cells of the mandibular first molar were isolated from mice at embryonic day (E)17.5 and cultured in vitro. We determined the expression levels of beta-catenin, bone morphogenetic protein 2 (Bmp2), Bmp4, and lymphoid enhancer binding factor 1 (Lef1) after knockdown or overexpression of Msx1. Our findings suggest that knockdown of Msx1 promoted expression of Bmp2, Bmp4, and Lef1, resulting in elevated differentiation of odontoblasts, which was rescued by blocking the expression of these genes. In contrast, overexpression of Msx1 decreased the expression of Bmp2, Bmp4, and Lef1, leading to a reduction in odontoblast differentiation. The regulation of Bmp2, Bmp4, and Lef1 by Msx1 was mediated by the Wnt/beta-catenin signaling pathway. Additionally, knockdown of Msx1 impaired cell proliferation and slowed S-phase progression, while overexpression of Msx1 also impaired cell proliferation and prolonged G1-phase progression. We therefore conclude that MSX-1 maintains cell proliferation by regulating transition of cells from G1-phase to S-phase and prevents odontoblast differentiation by inhibiting expression of Bmp2, Bmp4, and Lef1 at the late bell stage via the Wnt/beta-catenin signaling pathway. PMID- 29148102 TI - Adaptive integrated parallel reception, excitation, and shimming (iPRES-A) with microelectromechanical systems switches. AB - PURPOSE: Integrated parallel reception, excitation, and shimming coil arrays with N shim loops per radio-frequency (RF) coil element (iPRES(N)) allow an RF current and N direct currents (DC) to flow in each coil element, enabling simultaneous reception/excitation and shimming of highly localized B0 inhomogeneities. The purpose of this work was to reduce the cost and complexity of this design by reducing the number of DC power supplies required by a factor N, while maintaining a high RF and shimming performance. METHODS: In the proposed design, termed adaptive iPRES(N) (iPRES(N)-A), each coil element only requires one DC power supply, but uses microelectromechanical systems switches to adaptively distribute the DC current into the appropriate shim loops to generate the desired magnetic field for B0 shimming. Proof-of-concept phantom experiments with an iPRES(2)-A coil and simulations in the human abdomen with an 8-channel iPRES(4)-A body coil array were performed to demonstrate the advantages of this innovative design. RESULTS: The iPRES(2)-A coil showed no loss in signal-to-noise ratio and provided a much more effective correction of highly localized B0 inhomogeneities and geometric distortions than an equivalent iPRES(1) coil (88.2% vs. 32.2% lower B0 root-mean-square error). The iPRES(4)-A coil array showed a comparable shimming performance as that of an equivalent iPRES(4) coil array (52.6% vs. 54.2% lower B0 root-mean-square error), while only requiring 8 instead of 32 power supplies. CONCLUSION: The iPRES(N)-A design retains the ability of the iPRES(N) design to shim highly localized B0 inhomogeneities, while drastically reducing its cost and complexity. Magn Reson Med 80:371-379, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29148103 TI - Extracytoplasmic function sigma factor sigmaD confers resistance to environmental stress by enhancing mycolate synthesis and modifying peptidoglycan structures in Corynebacterium glutamicum. AB - Mycolates are alpha-branched, beta-hydroxylated, long-chain fatty acid specifically synthesized in bacteria in the suborder Corynebacterineae of the phylum Actinobacteria. They form an outer membrane, which functions as a permeability barrier and confers pathogenic mycobacteria to resistance to antibiotics. Although the mycolate biosynthetic pathway has been intensively studied, knowledge of transcriptional regulation of genes involved in this pathway is limited. Here, we report that the extracytoplasmic function sigma factor sigmaD is a key regulator of the mycolate synthetic genes in Corynebacterium glutamicum in the suborder. Chromatin immunoprecipitation with microarray analysis detected sigmaD -binding regions in the genome, establishing a consensus promoter sequence for sigmaD recognition. The sigmaD regulon comprised acyl-CoA carboxylase subunits, acyl-AMP ligase, polyketide synthase and mycolyltransferases; they were involved in mycolate synthesis. Indeed, deletion or overexpression of sigD encoding sigmaD modified the extractable mycolate amount. Immediately downstream of sigD, rsdA encoded anti-sigmaD and was under the control of a sigmaD -dependent promoter. Another sigmaD regulon member, l,d transpeptidase, conferred lysozyme resistance. Thus, sigmaD modifies peptidoglycan cross-linking and enhances mycolate synthesis to provide resistance to environmental stress. PMID- 29148104 TI - Neuregulin-1 promotes remyelination and fosters a pro-regenerative inflammatory response in focal demyelinating lesions of the spinal cord. AB - Oligodendroglial cell death and demyelination are hallmarks of neurotrauma and multiple sclerosis that cause axonal damage and functional impairments. Remyelination remains a challenge as the ability of endogenous precursor cells for oligodendrocyte replacement is hindered in the unfavorable milieu of demyelinating conditions. Here, in a rat model of lysolecithin lysophosphatidyl choline (LPC)-induced focal demyelination, we report that Neuregulin-1 (Nrg-1), an important factor for oligodendrocytes and myelination, is dysregulated in demyelinating lesions and its bio-availability can promote oligodendrogenesis and remyelination. We delivered recombinant human Nrg-1beta1 (rhNrg-1beta1) intraspinally in the vicinity of LPC demyelinating lesion in a sustained manner using poly lactic-co-glycolic acid microcarriers. Availability of Nrg-1 promoted generation and maturation of new oligodendrocytes, and accelerated endogenous remyelination by both oligodendrocyte and Schwann cell populations in demyelinating foci. Importantly, Nrg-1 enhanced myelin thickness in newly remyelinated spinal cord axons. Our complementary in vitro studies also provided direct evidence that Nrg-1 significantly promotes maturation of new oligodendrocytes and facilitates their transition to a myelinating phenotype. Nrg 1 therapy remarkably attenuated the upregulated expression chondroitin sulfate proteoglycans (CSPGs) specific glycosaminoglycans in the extracellular matrix of demyelinating foci and promoted interleukin-10 (IL-10) production by immune cells. CSPGs and IL-10 are known to negatively and positively regulate remyelination, respectively. We found that Nrg-1 effects are mediated through ErbB2 and ErbB4 receptor activation. Our work provides novel evidence that dysregulated levels of Nrg-1 in demyelinating lesions of the spinal cord pose a challenge to endogenous remyelination, and appear to be an underlying cause of myelin thinning in newly remyelinated axons. PMID- 29148105 TI - Experiences of nurse case managers within a central discharge planning role of collaboration between physicians, patients and other healthcare professionals: A sociocultural qualitative study. AB - AIMS AND OBJECTIVES: To gain knowledge of nurse case managers' experiences within the German acute care context of collaboration with patients and physicians in a discharge planning role; further to learn about patients' assignment to the management of the nurse case managers; and explicitly to explore critical incidences of interactions between nurse case managers, patients and healthcare practitioner in discharge planning to understand the factor that contributes to effective collaboration. BACKGROUND AND PURPOSE: The defined role of nurse case managers in many contexts is a patient-centred responsibility for a central task of discharge management of patients with complex physical and social needs. Some studies have indicated that the general impact of the role reduces readmission rates. Given the necessity to work interprofessionally to achieve a safe discharge, little is known about how nurse case managers achieve this collaboratively. METHODS: A qualitative case study within a German teaching hospital of nurse case managers (N = 8). Data were collected through semi structured interviews prompted by a critical incident technique and rigorously analysed through the lenses of sociocultural theory. RESULTS: Consistent object being worked upon was a safe and effective discharge from hospital with a focus on patient advocacy. Significant themes were a self-value or recognition by others of professional expertise, reciprocal value on the capabilities of others thorough relational expertise and negotiation with patients and an identification of case trajectories. CONCLUSION: More continuity of nurse case managers' care and management, clarity of role and transparency to peers, physicians and other professionals would be beneficial in ensuring appropriate referral of complex patients to nurse case managers responsibility. RELEVANCE TO CLINICAL PRACTICE: Clearer role description and benefit realisation of the nurse case managers could be achieved by interventions that are interprofessional and focus on the tasks that matter from a collaborative perspective. This could lead to refinement of available indicators and policy developments. PMID- 29148106 TI - Epidemiology of donors and recipients: lessons from the SCANDAT database. AB - With the development of several 'vein-to-vein' databases, which capture data on the entire donor-recipient continuum and link this data to health outcomes, there has been an increasing number of studies investigating the health effects of all aspects of the practice of transfusion medicine. The Scandinavian Donations and Transfusions (SCANDAT) database is one of several such databases, which includes all electronically available data on blood donors, donations and transfusions since the late 1960s in Sweden and the early 1980s in Denmark. The SCANDAT database has been used to characterise disease occurrence among blood donors and transfused patients, as well as to investigate possible health effects of blood donations, aspects of transfusion care and possible transfusion transmission of disease. Recent publications include studies on recipient mortality associated with the storage lesion, studies on the effects of donor demographics on patient mortality and health effects of frequent blood donation. Although this research approach is clearly very powerful, the appropriate analysis of such real-world data is complex and requires close methodological attention. The purpose of this review is to present some of the research conducted within the SCANDAT collaboration. We hope more international collaboration may help improve our understanding of the important remaining questions about donor and recipient health. PMID- 29148107 TI - Pediatric drug information available at the time of new drug approvals: A cross sectional analysis. AB - PURPOSE: Greater than 50% of drugs lack pediatric labeling information, resulting in widespread "off-label" use in children. To increase pediatric prescribing information, the Pediatric Research Equity Act (PREA) was passed in 2003, requiring new drug applications to include pediatric assessments. We evaluated the study of new drugs in children since PREA was implemented. METHODS: We performed a cross-sectional analysis of new drug applications submitted to the FDA from December 2003 to July 2012, using publicly available documents at Drugs@FDA. We calculated the proportion of new drugs that included a pediatric assessment at the time of approval and at a final review performed in July 2016. RESULTS: We identified 92 new drugs requiring pediatric assessments. Only 20 (21.7%) had been fully studied in children at the time of approval, while 9 (9.8%) had been partially assessed, and 63 (68.5%) did not have pediatric data. Among drugs approved without pediatric assessments, 4.2% met FDA deferral deadlines and 34.9% eventually submitted pediatric data. At the time of our final review, allowing for a mean of 8.6 years since drug approval, 57.6% of new drugs had not been fully assessed in children. The mean time between approval in adults and availability of pediatric data for drugs approved without pediatric assessments was 6.5 years. CONCLUSIONS: These results represent a comprehensive evaluation of the study of new drugs in children and demonstrate that many drugs continue to be approved without pediatric data. Our findings serve to inform approaches to strengthen adherence to PREA requirements. PMID- 29148108 TI - Human pegivirus (HPgV) infection in sub-Saharan Africa-A call for a renewed research agenda. AB - The human pegivirus (HPgV)-formerly GB virus C-has a beneficial impact on HIV disease progression that has been described in multiple studies. Given the high prevalence of HIV in sub-Saharan Africa and the continuing need to suppress HIV replication, this review provides a comprehensive overview of the existing data on HPgV infection in sub-Saharan Africa, with a particular focus on studies of prevalence and the circulating HPgV genotypes. This review also highlights the need for additional studies of HPgV conducted on the African continent and proposes a research agenda for evaluation of HPgV. PMID- 29148109 TI - Notch Signaling Controls Transdifferentiation of Pulmonary Neuroendocrine Cells in Response to Lung Injury. AB - Production of an appropriate number of distinct cell types in precise locations during embryonic development is critical for proper tissue function. Homeostatic renewal or repair of damaged tissues in adults also requires cell expansion and transdifferentiation to replenish lost cells. However, the responses of diverse cell types to tissue injury are not fully elucidated. Moreover, the molecular mechanisms underlying transdifferentiation remain poorly understood. This knowledge is essential for harnessing the regenerative potential of individual cell types. This study investigated the fate of pulmonary neuroendocrine cells (PNECs) following lung damage to understand their plasticity and potential. PNECs are proposed to carry out diverse physiological functions in the lung and can also be the cells of origin of human small cell lung cancer. We found that Notch signaling is activated in proliferating PNECs in response to epithelial injury. Forced induction of high levels of Notch signaling in PNECs in conjunction with lung injury results in extensive proliferation and transdifferentiation of PNECs toward the fate of club cells, ciliated cells and goblet cells. Conversely, inactivating Notch signaling in PNECs abolishes their ability to switch cell fate following lung insult. We also established a connection between PNEC transdifferentiation and epigenetic modification mediated by the polycomb repressive complex 2 and inflammatory responses that involve the IL6-STAT3 pathway. These studies not only reveal a major pathway that controls PNEC fate change following lung injury but also provide tools to uncover the molecular basis of cell proliferation and fate determination in response to lung injury. Stem Cells 2018;36:377-391. PMID- 29148110 TI - Stress and ways of coping among nurse managers: An integrative review. AB - AIMS AND OBJECTIVES: To appraise and synthesise empirical studies examining sources of occupational stress and ways of coping utilised by nurse managers when dealing with stress. BACKGROUND: The Nurse Manager's role is challenging yet draining and stressful and has adverse consequences on an individual's overall health and well-being, patients' outcomes and organisational productivity. Considerable research has been carried out; however, an updated and broader perspective on this critical organisational issue has not been performed. DESIGN: An integrative review. METHODS: Five databases (Cumulative Index to Nursing and Allied Health Literature, SCOPUS, PubMed, PsychINFO and MEDLINE) were searched to identify relevant articles. Search terms and MeSH terms included: "charge nurse," "coping," "coping strategy," "coping style," "psychological adaptation," "psychological stress," "stressors," "nurse manager" and "unit manager." Twenty two articles were included in this review. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines. RESULTS: Four themes were identified: moderate stress levels, common sources of stress, ways of coping and the impact of nurses' characteristics on stress. CONCLUSIONS: Nurse managers experienced moderate levels of stress mainly from heavy workloads, lack of resources and financial responsibilities. Enhancing social support and promoting job control were seen as important in reducing work stress and its related consequences. Additional studies using a more rigorous method and a larger sample size preferably in multicultural settings would shed more light on this topic. RELEVANCE TO CLINICAL PRACTICE: Hospital and nurse administrators play an important role in promoting supportive structures for daily professional practice for nurse managers through staffing, organisational resources, support services, leadership and stress management training. PMID- 29148111 TI - Being overweight or obese as a risk factor for acute liver injury secondary to acute acetaminophen overdose. AB - PURPOSE: Increased incidences of hepatotoxicity have been observed in obese patients with acute acetaminophen overdose. We evaluate whether the status of being overweight or obese is associated with increase in the development of hepatotoxicity and acute liver injury (ALI) in patients with acute acetaminophen overdose. METHODS: This was a retrospective cohort study comparing the risk of hepatotoxicity and ALI between overweight or obese patients (body mass index [BMI] >= 25) and normal BMI patients (BMI <= 24.9) presenting with acute acetaminophen overdose at Siriraj Hospital during January 2004 to June 2012. All patients were treated with intravenous N-acetylcysteine. Psi parameters were calculated. High psi was defined as psi of >=5.0 mM-hour. Data were analyzed using multinomial logistic regressions, odds ratio (OR), stratified OR, and 95% confidence interval (CI). RESULTS: There were 197 patients who fulfilled the criteria for analysis, 35 (17.8%) were obese, 24 (12.2%) were overweight, and 138 (70%) were normal BMI cases. Hepatotoxicity and ALI developed in 25 (12.7%) and 40 (20.3%) cases, respectively. Multinomial logistic regression revealed that the overweight-obesity status and log10 (psi value) were significant risk factors of ALI, with OR (95% CI) of 2.68 (1.21-5.95) and 1.74 (1.27-2.38), respectively, while only log10 (psi) was a significant risk factor of hepatotoxicity with OR (95% CI) 378.51 (39.49-3627.99). From stratification, overweight-obesity had significant odds ratios for ALI in strata with low acetaminophen concentration, early initiation of N-acetylcysteine and low psi. CONCLUSION: We conclude that being overweight or obese is an independent risk factor of ALI in acute acetaminophen overdoses. PMID- 29148112 TI - Big data and data science in health care: What nurses and midwives need to know. PMID- 29148114 TI - On the character and production of 'active participation' in neuro rehabilitation: an Actor-Network perspective. AB - The importance of patients' active involvement in neuro-rehabilitation after acquired brain injury has been consistently emphasised in recent years. However, most approaches fail to show how 'active participation' is practically enacted, focusing on individualised explanations of patient choice and behaviours, or notions of inherent patient traits. Using actor-network theory (ANT) as a sensitising concept, we investigated neuro-rehabilitation practices, asking how participation is shaped through biological and socio-material specificities, how rights to knowledge and expertise are constructed, and how a body acclimatises and adjusts within an order of participation and transformation. We analysed video-recorded fieldwork extracts, examining the work of adjusting, testing and transforming; the construction of competence and incompetence; and material and social processes involved in the division of the body and its re-composition. Our findings show how an ANT-sensitised approach provides a critical understanding and context-specific characterisation of 'active participation', produced through the association of heterogeneous actors at any one time. Such specificity and the distribution of work suggest that efforts to account for optimum therapy 'dosages', and clinical attention to establishing individually-located levels of 'self-efficacy' or 'motivation' are misdirected. The performance of 'active participation', rather, should be re-imagined as a product of diverse, mutually attuned entities. A Virtual Abstract of this paper can be viewed at: https://www.youtube.com/channel/UC_979cmCmR9rLrKuD7z0ycA. PMID- 29148115 TI - The Actionability of Exome sequencing testing results. AB - Genomic tests such as exome sequencing have recently become an option for diagnosing patients. The tests allow clinical geneticists to sequence the majority of patients' disease causing genetic variants. As a new technology, exome sequencing confronts the question of what the benefit is of this increased genetic information. Against a narrow perspective of clinical utility that emphasises tangible improvements in a patient's disease management, professional organisations have argued that genomic sequencing should be considered beneficial if it helps families and society. Based on video-recorded observations of the return of exome sequencing results to parents of a child with disabilities in the clinic and in-depth interviews with these parents, we examine how genomic test results become actionable in the clinical encounter. We find that parents and clinicians marshal exome results beyond biomedical diagnostic and management goals to address questions about guilt for causing the disabilities and to secure access to disability-related services. We argue that genomic actionability rests on the interaction between the biological characteristics of genetic results and the predicaments facing parents of children with disabilities. PMID- 29148118 TI - Role of the combination of FA and T2* parameters as a new diagnostic method in therapeutic evaluation of parkinson's disease. AB - BACKGROUND: Simple diffusion delivery (SDD) has attained good effects with only tiny amounts of drugs. Fractional anisotropy (FA) and relaxation time T2* that indicate the integrity of fiber tracts and iron concentration within brain tissue were used to evaluate the therapeutic effect of SDD. PURPOSE: To evaluate therapeutic effect of SDD in the Parkinson's disease (PD) rat model with FA and T2* parameters. STUDY TYPE: Prospective case-control animal study. POPULATION: Thirty-two male Sprague Dawley rats (eight normal, eight PD, eight SDD, and eight subcutaneous injection rats). FIELD STRENGTH/SEQUENCE: Single-shot spin echo echo planar imaging and fast low-angle shot T2 WI sequences at 3.0T. ASSESSMENT: Parameters of FA and T2* on the treated side of the substantia nigra were measured to evaluate the therapeutic effect of SDD in a PD rat model. STATISTICAL TESTS: The effects of time on FA and T2* values were analyzed by repeated measurement tests. A one-way analysis of variance was conducted, followed by individual comparisons of the mean FA and T2* values at different timepoints. RESULTS: The FA values on the treated side of the substantia nigra in the SDD treatment group and subcutaneous injection treatment group were significantly higher at week 1 and lower at week 6 than that of the PD control group (SDD vs. PD, week 1, adjusted P = 0.012; subcutaneous vs. PD, week 1, adjusted P < 0.001; SDD vs. PD, week 6, adjusted P = 0.004; subcutaneous vs. PD, week 6, adjusted P = 0.024). The T2* parameter in the SDD treatment group and subcutaneous injection treatment group was significantly higher than that in the PD control group at week 6 (SDD vs. PD, adjusted P = 0.032; subcutaneous vs. PD, adjusted P < 0.001). DATA CONCLUSION: The combination of FA and T2* parameters can potentially serve as a new effective evaluation method of the therapeutic effect of SDD. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2017. PMID- 29148119 TI - The anatomy of the pediatric airway: Has our knowledge changed in 120 years? A review of historic and recent investigations of the anatomy of the pediatric larynx. AB - BACKGROUND: There is disagreement regarding the anatomy of the pediatric airway, particularly regarding the shape of the cricoid cartilage and the location of the narrowest portion of the larynx. AIMS: The aim of this review is to clarify the origin and the science behind these differing views. METHODS: We undertook a review of published literature, University Libraries, and authoritative textbooks with key search words and phrases. RESULTS: In vivo observations suggest that the narrowest portion of the airway is more proximal than the cricoid cartilage. However, in vitro studies of autopsy specimens measured with rods or calipers, confirm that the nondistensible and circular or near circular cricoid outlet is the narrowest level. These anatomic studies confirmed the classic "funnel" shape of the pediatric larynx. In vivo studies are potentially misleading as the aryepiglottic, vestibular, and true vocal folds are in constant motion with respiration. These studies also do not consider the effects of normal sleep, inhalation agents, and comorbidities such as adenoid or tonsil hypertrophy that cause some degree of pharyngeal collapse and alter the normal movement of the laryngeal tissues. Thus, the radiologic studies suggesting that the narrowest portion of the airway is not the cricoid cartilage may be the result of an artifact depending upon which phase of respiration was imaged. CONCLUSION: In vivo studies do not take into account the motion of the highly pliable laryngeal upper airway structures (aryepiglottic, vestibular, and vocal folds). Maximal abduction of these structures with tracheal tubes or bronchoscopes always demonstrates a larger opening of the glottis compared to the outlet of the cricoid ring. Injury to the larynx depends upon ease of tracheal tube or endoscope passage past the cricoid cartilage and not passage through the readily distensible more proximal structures. The infant larynx is funnel shaped with the narrowest portion the circular or near circular cricoid cartilage confirmed by multiple in vitro autopsy specimens carried out over the past century. PMID- 29148120 TI - Mapping brown adipose tissue based on fat water fraction provided by Z-spectral imaging. AB - BACKGROUND: Brown adipose tissue (BAT) has a great relevance in metabolic diseases and has been shown to be reduced in obesity and insulin resistance patients. Currently, Dixon MRI is used to calculate fat-water fraction (FWF) and differentiate BAT from white adipose tissue (WAT). However, it may fail in areas of phase wrapping and introduce fat-water swapping artifacts. PURPOSE: To investigate the capacity of the Z-spectrum imaging (ZSI) for the identification of BAT in vivo. STUDY TYPE: Retrospective study. SPECIMENS: WAT, BAT, and lean tissue from healthy mice. ANIMALS: Four C57BL/6 healthy mice. POPULATION: Five healthy volunteers. FIELD STRENGTH: 9.4T, 3T for volunteers. SEQUENCE: Z-Spectra data were fitted to a model with three Lorentzian peaks reflecting the direct saturation of tissue water (W) and methylene fat (F), and the magnetization transfer from the semi-solid tissues. The peak amplitudes of water and fat were used to map the FWF. The novel FWF metric was calibrated with an oil and water mixture phantom and validated in specimens, mice and human subjects. ASSESSMEMT: FWF distribution was compared with published works and values compared with Dixon's MRI results. STATISTICAL TESTS: Comparisons were performed by t-tests. RESULTS: ZSI clearly differentiated WAT, BAT, and lean tissues by having FWF = 1, 0.5, and 0, respectively. Calibration with oil mixture phantoms revealed a linear relationship between FWF and the actual fat fraction (R2 = 0.98). In vivo experiments in mice confirmed in vitro results by showing FWF = 0.6 in BAT. FWF maps of human subjects showed the same FWF distribution as Dixon's MRI (P > 0.05). ZSI is independent from B0 field inhomogeneity and fat-water swapping because both lipid and water frequency offsets are determined simultaneously during Z-spectral fitting. DATA CONCLUSION: ZSI can derive artifact-free FWF maps, which can be used to identify BAT distribution in vivo noninvasively. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1527 1533. PMID- 29148121 TI - Position Accuracy of Implant Analogs on 3D Printed Polymer versus Conventional Dental Stone Casts Measured Using a Coordinate Measuring Machine. AB - PURPOSE: To compare the accuracy of implant analog positions on complete edentulous maxillary casts made of either dental stone or additive manufactured polymers using a coordinate measuring machine (CMM). MATERIAL AND METHODS: A completely edentulous maxillary model of a patient with 7 implant analogs was obtained. From this model, two types of casts were duplicated, namely conventional dental stone (CDS) using a custom tray impression technique after splinting (N = 5) and polymer cast using additive manufacturing based on the STL file generated. Polymer casts (N = 20; n = 5 per group) were fabricated using 4 different additive manufacturing technologies (multijet printing-MJP1, direct light processing-DLP, stereolithography-SLA, multijet printing-MJP2). CMM was used to measure the correct position of each implant, and distortion was calculated for each system at x-, y-, and z-axes. Measurements were repeated 3 times per specimen in each axis yielding a total of 546 measurements. Data were analyzed using ANOVA, Sheffe tests, and Bonferroni correction (alpha = 0.05). RESULTS: Compared to CMM, the mean distortion (MUm) ranged from 22.7 to 74.9, 23.4 to 49.1, and 11.0 to 85.8 in the x-, y-, and z-axes, respectively. CDS method (x-axis: 37.1; z-axis: 27.62) showed a significant difference compared to DLP on the x-axis (22.7) (p = 0.037) and to MJP1 on the z-axis (11.0) (p = 0.003). Regardless of the cast system, x-axes showed more distortion (42.6) compared to y- (34.6) and z-axes (35.97). Among additive manufacturing technologies, MJP2 presented the highest (64.3 +/- 83.6), and MJP1 (21.57 +/- 16.3) and DLP (27.07 +/- 20.23) the lowest distortion, which was not significantly different from CDS (32.3 +/- 22.73) (p > 0.05). CONCLUSION: For the fabrication of the definitive casts for implant prostheses, one of the multijet printing systems and direct light processing additive manufacturing technologies showed similar results to conventional dental stone. CLINICAL SIGNIFICANCE: Conventional dental stone casts could be accurately duplicated using some of the additive manufacturing technologies tested. PMID- 29148122 TI - Altered frontal interhemispheric and fronto-limbic structural connectivity in unmedicated adults with obsessive-compulsive disorder. AB - BACKGROUND: Previous diffusion tensor imaging (DTI) studies of obsessive compulsive disorder (OCD) have primarily used voxel- or tract-based methods to assess white matter microstructure in medicated patients. This is the first probabilistic tractography study to assess the structural connectivity of all major white matter tracts in unmedicated adults with OCD without comorbid psychopathology. We hypothesized that OCD compared to healthy participants would show reduced integrity in frontal interhemispheric and fronto-limbic tracts. METHODS: DTI data from 29 unmedicated adults with OCD were compared to that of 27 matched healthy control (HC) participants. TRACULA was used to assess probabilistic tractography and compare groups in the average fractional anisotropy (FA) of 8 bilateral tracts plus forceps minor and major, and explore group differences in axial (AD), radial (RD), and mean (MD) diffusivities in tracts where FA differed across groups. RESULTS: Significantly less FA was detected in OCD compared to HC participants in forceps minor, interhemispheric fibers of the frontal cortex, and right uncinate fasciculus (UNC), association fibers connecting frontal and limbic regions (p's < .05). FA in forceps minor was inversely associated with symptom severity in the OCD participants. Exploratory analyses revealed less AD in right UNC was inversely associated with OCD symptoms. CONCLUSIONS: Structural connectivity of frontal interhemispheric and fronto-limbic circuits may be altered in unmedicated adults with OCD, especially those with the most severe symptoms. These findings suggest a microstructural basis for the abnormal function and reduced resting-state connectivity of frontal regions and fronto-limbic circuits in OCD. PMID- 29148123 TI - Donohue syndrome: A review of literature, case series, and anesthetic considerations. AB - BACKGROUND: Donohue syndrome is a rare autosomal recessive disorder of insulin resistance, causing a functional defect in insulin receptor function, and affecting the ability of the insulin to bind the receptor. Features include severe hyperinsulinism and fasting hypoglycemia, along with severe failure to thrive despite feeding. An accelerated fasting state results in muscle wasting, decreased subcutaneous fat, and an excess of thick skin. A reduced thoracic diameter is accentuated by increased abdominal distension, which impacts on respiratory reserve. Cardiac disease develops early in life, with progressive hypertrophic cardiomyopathy as a result of hyperinsulinism. Prognosis is poor with the majority of patients dying in infancy of sepsis. The aim of this review is to report our experience of providing anesthesia for patients with Donohue syndrome, and inform guidance for safe management of these children, based on a comprehensive literature review. METHODS: A literature search was carried out using PubMed, Medline, and the Cochrane Library, and using the MESH search terms detailed below. Patients were identified by formal request to the department of pediatric endocrinology at Great Ormond Street Hospital. Each patient's notes were searched manually and electronically for both clinical presentation and outcome, and anesthesia records. DISCUSSION: There is currently no published literature relating to anesthetic management of Donohue syndrome. We report a case series of 5 patients with Donohue syndrome who have presented to our institution. This small series of children with this complex disorder demonstrates a clearly increased risk of general anesthesia. Many of the risks relate to restrictive lung disease and abdominal distension which worsens with bag valve mask ventilation and limited respiratory reserve which leads to precipitous desaturation. During induction, a spontaneously breathing technique is recommended. If required, bag valve mask ventilation should be accompanied by constant gastric aspiration. Intubation is challenging, and a difficult airway plan, including a second experienced anesthetist and ENT support, should be in place. These children are predisposed to developing cardiomyopathy and therefore at risk of cardiovascular collapse under anesthesia. PMID- 29148124 TI - The safety of live attenuated influenza vaccine in children and adolescents 2 through 17 years of age: A Vaccine Safety Datalink study. AB - PURPOSE: To evaluate the safety of live attenuated influenza vaccine (LAIV) in children 2 through 17 years of age. METHODS: The study was conducted in 6 large integrated health care organizations participating in the Vaccine Safety Datalink (VSD). Trivalent LAIV safety was assessed in children who received LAIV between September 1, 2003 and March 31, 2013. Eighteen pre-specified adverse event groups were studied, including allergic, autoimmune, neurologic, respiratory, and infectious conditions. Incident rate ratios (IRRs) were calculated for each adverse event, using self-controlled case series analyses. For adverse events with a statistically significant increase in risk, or an IRR > 2.0 regardless of statistical significance, manual medical record review was performed to confirm case status. RESULTS: During the study period, 396 173 children received 590 018 doses of LAIV. For 13 adverse event groups, there was no significant increased risk of adverse events following LAIV. Five adverse event groups (anaphylaxis, syncope, Stevens-Johnson syndrome, adverse effect of drug, and respiratory failure) met criteria for manual medical record review. After review to confirm cases, 2 adverse event groups remained significantly associated with LAIV: anaphylaxis and syncope. One confirmed case of anaphylaxis was observed following LAIV, a rate of 1.7 per million LAIV doses. Five confirmed cases of syncope were observed, a rate of 8.5 per million doses. CONCLUSIONS: In a study of trivalent LAIV safety in a large cohort of children, few serious adverse events were detected. Anaphylaxis and syncope occurred following LAIV, although rarely. These data provide reassurance regarding continued LAIV use. PMID- 29148125 TI - Understanding the factors which promote registered nurses' intent to stay in emergency and critical care areas. AB - AIMS AND OBJECTIVE: To explore the influential factors and strategies that promote an experienced nurse's intent to stay in their emergency or critical care area. BACKGROUND: Turnover among registered nurses (herein referred to as nurses) working in specialty areas of practice can result in a range of negative outcomes. The retention of specialty nurses at the unit level has important implications for hospital and health systems. These implications include lost knowledge and experience which may in turn impact staff performance levels, patient outcomes, hiring, orientating, development of clinical competence and other aspects of organizational performance. DESIGN: This qualitative study used an interpretive descriptive design to understand nurses' perceptions of the current factors and strategies that promote them staying in emergency or critical care settings for two or more years. METHODS: Focus groups were conducted with 13 emergency and critical care nurses. Data analysis involved thematic analysis that evolved from codes to categories to themes. RESULTS: Four themes were identified: leadership, interprofessional relationships, job fit and practice environment. In addition, the ideas of feeling valued, respected and acknowledged were woven throughout. CONCLUSIONS: Factors often associated with nurse attrition such as burnout and job stresses were not emphasised by the respondents in our study as critical to their intent to stay in their area of practice. This study has highlighted positive aspects that motivate nurses to stay in their specialty areas. RELEVANCE TO CLINICAL PRACTICE: To ensure quality care for patients, retention of experienced emergency and critical care nurses is essential to maintaining specialty expertise in these practice settings. PMID- 29148126 TI - Risk stratification in acute heart failure. PMID- 29148127 TI - Iron deficiency and red cell indices in patients with heart failure. PMID- 29148128 TI - Step Ergometer Training Augmented With Functional Electrical Stimulation in Individuals With Chronic Spinal Cord Injury: A Feasibility Study. AB - Spinal cord injury (SCI) often results in loss of upright mobility and independence subsequently challenging rehabilitation practitioners for meaningful intervention strategies. The objective of this study was to evaluate the feasibility and potential impact on walking function of the stimulation and ergometer training protocol (STEP) in chronic SCI. Fourteen individuals with a chronic motor incomplete SCI (>1-year post injury) were enrolled in the study. The intervention consisted of a 12-week walking training program delivered three times per week from 20 up to 45 min in combination with 10 channels of FES on a step ergometer. Subsequent to this training, 30 min over ground walking training was performed. Ten out of the 14 participants completed the trial (71%). All participants who completed the intervention increased their walking speed by an average of 0.13 m/s (0.08) and walking endurance by an average of 117 ft (84 ft). For those who completed the trial, 50% demonstrated increases on the Walking Index for Spinal Cord Injury II by at least one level while 60% demonstrated an increase in lower extremity motor scores; all completing the Timed Up and Go Test at baseline demonstrated a reduction in time to complete during post-test evaluation. Recruitment objectives were attained. Overall retention was lower than anticipated with 29% withdrawing secondary to issues with lower extremity pain and exertional demands; however, no other adverse events occurred. Improvements in mobility outcomes generated by the STEP show promise in the context of feasibility and warrant further investigation to evaluate efficacy in comparison to other walking recovery interventions. The STEP was well-tolerated by participants who were >1 year and less than 10 years post SCI. Those completing the protocol exhibited improvements in commonly used SCI walking outcome measures. PMID- 29148129 TI - Development of Functional Electrical Stimulation Rowing: The Rowstim Series. AB - Potentially, functional electrical stimulation (FES)-assisted exercise may have an important therapeutic role in reducing comorbidities associated with spinal cord injury (SCI). Here, we present an overview of these secondary life threatening conditions, discuss the rationale behind the development of a hybrid exercise called FES rowing, and describe our experience in developing FES rowing technology. FES rowing and sculling are unique forms of adaptive rowing for those with SCI. The paralyzed leg musculature is activated by multiple channels of electrical pulses delivered via self-adhesive electrodes attached to the skin. The stimulated muscle contractions are synchronized with voluntary rowing movements of the upper limbs. A range of steady-state FES rowing exercise intensities have been demonstrated from 15.2 +/- 1.8 mL/kg/min in tetraplegia to 22.9 +/-7.1 mL/kg/min in paraplegia. We expect that such high levels may help some to achieve significant reductions in the risks to their health, particularly where a dose-response relationship exists as is the case for cardiovascular disease and Type II diabetes. Furthermore, preliminary results suggest that cyclical forces more than 1.5 times body weight are imposed on the leg long bones which may help to reduce the risk of fragility fractures. We have demonstrated the feasibility of FES rowing on land and water using adapted rowing technology that includes; a fixed stretcher indoor ergometer (adapted Concept 2, Model E), a floating stretcher indoor ergometer (adapted Concept 2 Dynamic), a turbine powered water rowing tank, a custom hydraulic sculling simulator and a single scull (adapted Alden 16). This has involved volunteers with paraplegia and tetraplegia with SCI ranging from C4 to T12 AIS A using at least 4-channels of surface electrical stimulation. FES rowers, with SCI, have competed alongside non SCI rowers over the Olympic distance of 2000 m at the British Indoor Rowing Championships in 2004, 2005, and 2006 and the World Indoor Rowing Championships in 2006 (CRASH-B's) in Boston, MA, USA. The best 2000 m FES rowing performance to date has been achieved by a 23-year-old male, Tom Aggar T12 AIS A, in 10 min 28 s. Moreover, two of our FES rowers with complete paraplegia have gone on to successfully compete in the Adaptive Rowing arms-only category (AM1x) at the World Rowing Championships and Paralympic Games. PMID- 29148130 TI - A Pseudo-One Compartment Model of Phosphorus Kinetics During Hemodialysis: Further Supporting Evidence. AB - A pseudo-one compartment model has been proposed to describe phosphorus kinetics during hemodialysis and the immediate post-dialysis period. This model assumes that phosphorus mobilization from tissues is proportional to the difference between the pre-dialysis serum concentration (a constant) and the instantaneous serum concentration. The current study is exploratory and evaluated the ability of a pseudo-one compartment model to describe the kinetics of phosphorus during two short hemodialysis treatments separated by a 60-min inter-treatment period without dialysis; the latter is the post-dialysis rebound period for the first short hemodialysis treatment. Serum was collected frequently during both hemodialysis treatments and the inter-treatment period to assess phosphorus kinetics in 21 chronic hemodialysis patients. Phosphorus mobilization clearance and pre-dialysis central distribution volume were previously estimated for each patient during the first hemodialysis treatment and the inter-treatment period. Assuming those kinetic parameters remained constant for each patient, serum phosphorus concentrations during the second treatment were used to estimate the driving force concentration (Cdf ) for phosphorus mobilization from tissues during the second treatment. Treatment time (117 +/- 14 [mean +/- standard deviation] vs. 117 +/- 14 min), dialyzer phosphorus clearance (151 +/- 25 vs. 140 +/- 32 mL/min), and net fluid removal (1.44 +/- 0.74 vs. 1.47 +/- 0.76 L) were similar during both short hemodialysis treatments. Measured phosphorus concentration at the start of the second hemodialysis treatment (3.3 +/- 0.9 mg/dL) was lower (P < 0.001) than at the start of the first treatment or Cpre (5.4 +/- 1.9 mg/dL). Calculated Cdf was 4.9 +/- 2.0 mg/dL, not significantly different from Cpre (P = 0.12). Cdf and Cpre were correlated (R = 0.72, P < 0.001). The results from this study demonstrate that the driving force concentration for phosphorus mobilization during hemodialysis is constant and not different from that pre-dialysis, providing further evidence supporting a fundamental assumption of the pseudo-one compartment model. PMID- 29148131 TI - Temporal and Spatial Variability of Surface Motor Activation Zones in Hemiplegic Patients During Functional Electrical Stimulation Therapy Sessions. AB - The goal of this study was to investigate surface motor activation zones and their temporal variability using an advanced multi-pad functional electrical stimulation system. With this system motor responses are elicited through concurrent activation of electrode matrix pads collectively termed "virtual electrodes" (VEs) with appropriate stimulation parameters. We observed VEs used to produce selective wrist, finger, and thumb extension movements in 20 therapy sessions of 12 hemiplegic stroke patients. The VEs which produce these three selective movements were created manually on the ergonomic multi-pad electrode by experienced clinicians based on visual inspection of the muscle responses. Individual results indicated that changes in VE configuration were required each session for all patients and that overlap in joint movements was evident between some VEs. However, by analyzing group data, we defined the probability distribution over the electrode surface for the three VEs of interest. Furthermore, through Bayesian logic we obtained preferred stimulation zones that are in accordance with our previously reported heuristically obtained results. We have also analyzed the number of active pads and stimulation amplitudes for these three VEs. Presented results provide a basis for an automated electrode calibration algorithm built on a priori knowledge or the starting point for manual selection of stimulation points. PMID- 29148132 TI - Functional Electrical Stimulation. PMID- 29148134 TI - In Vivo Validation of a Less Invasive Gastrostimulator. AB - Gastrointestinal stimulator implants have recently shown promising results in helping obese patients lose weight. However, to place the implant, the patient currently needs to undergo an invasive surgical procedure. We report a less invasive procedure to stimulate the stomach with a gastrostimulator. After attempting fully endoscopic implantation, we more recently focused on a single incision percutaneous procedure. In both cases, the challenges in electronic design of the implant are largely similar. This article covers the work achieved to meet these and details the in vivo validation of a gastrostimulator aimed to be endoscopically placed and anchored to the stomach. PMID- 29148135 TI - Cadence Tracking and Disturbance Rejection in Functional Electrical Stimulation Cycling for Paraplegic Subjects: A Case Study. AB - Functional electrical stimulation cycling has been proposed as an assistive technology with numerous health and fitness benefits for people with spinal cord injury, such as improvement in cardiovascular function, increase in muscular mass, and reduction of bone mass loss. However, some limitations, for example, lack of optimal control strategies that would delay fatigue, may still prevent this technology from achieving its full potential. In this work, we performed experiments on a person with complete spinal cord injury using a stationary tadpole trike when both cadence tracking and disturbance rejection were evaluated. In addition, two sets of experiments were conducted 6 months apart and considering activation of different muscles. The results showed that reference tracking is achieved above the cadence of 25 rpm with mean absolute errors between 1.9 and 10% when only quadriceps are activated. The disturbance test revealed that interferences may drop the cadence but do not interrupt a continuous movement if the cadence does not drop below 25 rpm, again when only quadriceps are activated. When other muscle groups were added, strong spasticity caused larger errors on reference tracking, but not when a disturbance was applied. In addition, spasticity caused the last experiments to result in less smooth cycling. PMID- 29148136 TI - Effects of Sensitive Electrical Stimulation-Based Somatosensory Cueing in Parkinson's Disease Gait and Freezing of Gait Assessment. AB - This study aims to investigate the effect of a somatosensory cueing on gait disorders in subjects with Parkinson's disease (PD). After having performed stepping in place and timed up and go assessing tasks, 13 participants with PD were equipped with an electrical stimulator and an inertial measurement unit (IMU) located under the lateral malleolus on the sagittal plane. Electrodes were positioned under the arch of the foot and electrical stimulation (ES) parameters (five 500 us/phase charge-balanced biphasic pulses delivered at 200 Hz, repeated four times at 10 Hz) adjusted to deliver a sensitive signal. Online IMU signal was processed in order to trigger ES at heel off detection. Starting from a quiet standing posture, subjects were asked to walk at their preferred speed on a path including 5 m straight line, u-turn, and walk around tasks. Three situations were considered: no stimulation baseline precondition (C0), ES condition (C1), and no stimulation baseline post-condition (C0bis), for eliminating a learning effect possibility. In ES condition (C1) the time to execute the different tasks was globally decreased in all the subjects (n = 13). Participants' results were then grouped regarding whether they experienced freezing of gait (FOG) or not during C0 no stimulation baseline precondition. In "freezer" subjects (n = 9), the time to complete the entire path was reduced by 19%. FOG episodes occurrence was decreased by 12% compared to baseline conditions. This preliminary work showed a positive global effect on gait and FOG in PD by a somatosensory cueing based on sensitive electrical stimulation. PMID- 29148137 TI - Brain-Computer Interfaces With Multi-Sensory Feedback for Stroke Rehabilitation: A Case Study. AB - Conventional therapies do not provide paralyzed patients with closed-loop sensorimotor integration for motor rehabilitation. This work presents the recoveriX system, a hardware and software platform that combines a motor imagery (MI)-based brain-computer interface (BCI), functional electrical stimulation (FES), and visual feedback technologies for a complete sensorimotor closed-loop therapy system for poststroke rehabilitation. The proposed system was tested on two chronic stroke patients in a clinical environment. The patients were instructed to imagine the movement of either the left or right hand in random order. During these two MI tasks, two types of feedback were provided: a bar extending to the left or right side of a monitor as visual feedback and passive hand opening stimulated from FES as proprioceptive feedback. Both types of feedback relied on the BCI classification result achieved using common spatial patterns and a linear discriminant analysis classifier. After 10 sessions of recoveriX training, one patient partially regained control of wrist extension in her paretic wrist and the other patient increased the range of middle finger movement by 1 cm. A controlled group study is planned with a new version of the recoveriX system, which will have several improvements. PMID- 29148138 TI - Artificial Walking Technologies to Improve Gait in Cerebral Palsy: Multichannel Neuromuscular Stimulation. AB - Cerebral palsy (CP) is the most common childhood motor disability and often results in debilitating walking abnormalities, such as flexed-knee and stiff-knee gait. Current medical and surgical treatments are only partially effective in improving gait abnormalities and may cause significant muscle weakness. However, emerging artificial walking technologies, such as step-initiated, multichannel neuromuscular electrical stimulation (NMES), can substantially improve gait patterns and promote muscle strength in children with spastic CP. NMES may also be applied to specific lumbar-sacral sensory roots to reduce spasticity. Development of tablet computer-based multichannel NMES can leverage lightweight, wearable wireless stimulators, advanced control design, and surface electrodes to activate lower-limb muscles. Musculoskeletal models have been used to characterize muscle contributions to unimpaired gait and identify high muscle demands, which can help guide multichannel NMES-assisted gait protocols. In addition, patient-specific NMES-assisted gait protocols based on 3D gait analysis can facilitate the appropriate activation of lower-limb muscles to achieve a more functional gait: stance-phase hip and knee extension and swing-phase sequence of hip and knee flexion followed by rapid knee extension. NMES-assisted gait treatment can be conducted as either clinic-based or home-based programs. Rigorous testing of multichannel NMES-assisted gait training protocols will determine optimal treatment dosage for future clinical trials. Evidence-based outcome evaluation using 3D kinematics or temporal-spatial gait parameters will help determine immediate neuroprosthetic effects and longer term neurotherapeutic effects of step-initiated, multichannel NMES-assisted gait in children with spastic CP. Multichannel NMES is a promising assistive technology to help children with spastic CP achieve a more upright, functional gait. PMID- 29148139 TI - Nitroglycerin: An unusual solution to intraoperative hypothermia in a 4-year-old burn patient. AB - We describe the case of a 4-year-old child undergoing extensive burn surgery with refractory intraoperative hypothermia. A low-dose nitroglycerin infusion was initiated to reverse vasoconstriction and improve heat absorption, after which the child's temperature steadily improved. In hypothermic burn patients, topical vasoconstrictors may hinder surface warming efforts. A vasodilator infusion may aid in warming the pediatric patient undergoing extensive excision and grafting. PMID- 29148140 TI - Haemodynamic effects of an acute vasodilator challenge in heart failure patients with reduced ejection fraction and different forms of post-capillary pulmonary hypertension. AB - AIMS: The most recent European guidelines have proposed new definitions of pulmonary hypertension (PH) in left heart disease, to better approach the characteristics required to reflect the presence of pulmonary vascular disease. The purpose of this study was to assess whether different haemodynamic definitions of post-capillary PH imply a different reversibility of PH in response to acute vasodilator administration in heart failure patients with reduced ejection fraction and PH (HFrEF-PH). METHODS AND RESULTS: Right heart catheterization and reversibility testing was performed in 156 HFrEF-PH patients. Patients were classified as combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH) vs. isolated post-capillary pulmonary hypertension (Ipc-PH) and on the basis of diastolic pulmonary gradient (DPG) >= 7 vs. < 7 mmHg or of transpulmonary gradient (TPG) >12 vs. <=12 mmHg. After vasodilator administration, Cpc-PH patients showed a greater per cent improvement in pulmonary vascular resistance (PVR), DPG and TPG as compared with Ipc-PH patients (all Pint < 0.001); only pulmonary compliance (PCa) improved less in Cpc-PH than in Ipc-PH patients (Pint = 0.007). However, despite vasodilatation, Cpc-PH patients remained in an unfavourable portion of the inverse hyperbolic relationship between PVR and PCa. The number of patients in whom PVR was reduced below 2.5 wood units was similar in Cpc-PH, DPG >=7 mmHg and TPG >12 mmHg groups (28.3, 26.7 and 18.9%, respectively). CONCLUSION: Although substantial improvements in PVR, DPG and TPG were observed in Cpc-PH patients after acute vasodilator administration, this response was associated with persistent abnormalities in the PVR vs. PCa relationship. The link between baseline right heart haemodynamics and pulmonary vascular disease remains elusive. PMID- 29148141 TI - The need for evaluating right ventricular adaptation and ventriculo-arterial coupling. PMID- 29148142 TI - Outcomes of primary percutaneous coronary intervention in acute myocardial infarction due to unprotected left main thrombosis: The Asia-Pacific Left Main ST Elevation Registry (ASTER). AB - INTRODUCTION: Prior studies of ULM STEMI have been confined to small cohorts. Recent registry data with larger patient cohorts have shown contrasting results. We aim to study the outcomes of patients with unprotected left main (ULM) ST elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI). METHODS: The Asia-pacific left main ST-Elevation Registry (ASTER) is a multicenter retrospective registry involving 4 sites in Singapore, South Korea, and the United States. The registry included patients presenting with STEMI due to an ULM coronary artery culprit lesion who underwent emergency PCI. The primary outcome was in-hospital mortality. Secondary outcomes included major adverse cardiovascular events. RESULTS: A total of 67 patients (mean age 64.2 +/- 12.8 years, 53 [79.1%] males) were included. The distal left main bifurcation was most commonly involved (85%, n = 57). Fifty one (76%) patients had TIMI 3 flow post-PCI. The in-hospital mortality rate was 47.8% (n = 32); 61% (n = 41) had cardiac failure, 4% (n = 3) had emergency coronary artery bypass grafting, 1% (n = 1) had a re-infarction, 3% (n = 2) had stroke and 55% (n = 37) had malignant ventricular arrhythmias. On multivariate analysis, predictors of in-hospital mortality included older age (odds ratio (OR) 1.085 (95% confidence interval (CI) 1.002-1.175), P = 0.044), diabetes mellitus (OR 10.882 (95%CI 11.074-110.287), P = 0.043) and absence of post-PCI TIMI 3 flow (OR 71.429 (95%CI 2.985-1000), P = 0.008). CONCLUSIONS: STEMI from culprit unprotected left main coronary artery stenosis is associated with significant mortality and morbidity. Emergency PCI provides an important treatment option in this high-risk group, but in-hospital mortality remains high. PMID- 29148143 TI - Leaf cell membrane stability-based mechanisms of zinc nutrition in mitigating salinity stress in rice. AB - Excess salt affects about 955 million ha of arable land worldwide, and 49% of agricultural land is Zn-deficient. Soil salinity and zinc deficiency can intensify plant abiotic stress. The mechanisms by which Zn can mitigate salinity effects on plant functions are not well understood. We conducted an experiment to determine how Zn and salinity effects on rice plant retention of Zn, K+ and the salt ion Na+ affect chlorophyll formation, leaf cell membrane stability and grain yield. We examined the mechanisms of Zn nutrition in mitigating salinity stress by examining plant physiology and nutrition. We used native Zn-deficient soils (control), four salinity (EC) and Zn treatments - Zn 10 mg.kg-1 (Zn10 ), EC 5 dS.m-1 (EC5 ), Zn10 +EC5 and Zn15 +EC5 , a coarse rice (KS-282) and a fine rice (Basmati-515) in the study. Our results showed that Zn alone (Zn10 ) significantly increased rice tolerance to salinity stress by promoting Zn/K+ retention, inhibiting plant Na+ uptake and enhancing leaf cell membrane stability and chlorophyll formation in both rice cultivars in native alkaline, Zn-deficient soils (P < 0.05). Further, under the salinity treatment (EC5 ), Zn inputs (10-15 mg.kg-1 ) could also significantly promote rice plant Zn/K+ retention and reduce plant Na+ uptake, and thus increased leaf cell membrane stability and grain yield. Coarse rice was more salinity-tolerant than fine rice, having significantly higher Zn/K+ nutrient retention. The mechanistic basis of Zn nutrition in mitigating salinity impacts was through promoting plant Zn/K+ uptake and inhibiting plant Na+ uptake, which could result in increased plant physiological vigour, leaf cell membrane stability and rice productivity. PMID- 29148144 TI - Systolic blood pressure and cardiovascular outcomes in heart failure with preserved ejection fraction: an analysis of the TOPCAT trial. AB - AIMS: Recent guidelines have advocated for stricter systolic blood pressure (SBP) control in heart failure with preserved ejection fraction (HFpEF), though data regarding the optimal SBP in HFpEF are sparse. METHODS AND RESULTS: We analysed participants from the Americas from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study with available baseline and 8-week visit SBP data (n = 1645). We related baseline SBP to several efficacy and safety outcomes. To determine whether blood pressure lowering was responsible for the potential beneficial effects of spironolactone observed in the Americas, we assessed the randomized treatment adjusting for baseline and change in 8-week SBP. The average age was 71.7 +/- 9.7 years, 50% were women, and 79% were White. Patients in the lowest baseline SBP quartile were less often female, more often White, had lower body mass index, lower baseline diastolic blood pressure and pulse pressure, and more often had atrial fibrillation. After multivariable adjustment, there was no relationship observed between baseline SBP quartiles and any outcome. Spironolactone reduced SBP by 4.4 +/- 0.6 mmHg compared with placebo (and consistently across baseline SBP quartiles). There was minimal change in the treatment effect for all outcomes after adjusting for baseline SBP and 8-week change in SBP. CONCLUSION: No relationship was observed between baseline SBP quartiles and outcomes in TOPCAT. The anti-hypertensive effects of spironolactone did not account for the potential benefit in cardiovascular outcomes in the Americas. PMID- 29148145 TI - Development of undergraduate gerodontology courses in Austria, Germany and Switzerland 2004-2014. AB - PURPOSE/OBJECTIVES: In view of the demographic shift, undergraduate dental students should be prepared for growing numbers of older people and their specific needs. The study examines changes in undergraduate dental teaching in Austria, Germany and Switzerland between 2004 and 2014. METHODS: Questionnaires were mailed in 2004, 2009 and 2014 to all deans and all department heads of Austrian (n = 4), German (n = 30) and Swiss (n = 4) dental schools. RESULTS: Response rates were 51% for deans and 47% for heads of department. Gerodontology was taught in 5 German universities, all 3 Swiss and 1 Austrian dental school. Aspects of gerodontology were included in traditional core subjects; however, in a large number of German (88%) and Austrian (50%) universities, dedicated lecture series and seminars are lacking. Changes over time indicate firmly established teaching in Switzerland, minor fluctuations in Austria and reduced dedicated teaching activities in Germany. CONCLUSIONS: Inclusion of gerodontology in the national syllabus is a decisive factor for the integration of the subject into undergraduate courses. The recommendations of the European College of Gerodontology (2009) regarding didactical and practical teaching should be implemented in the respective compulsory syllabus to prepare current undergraduate dental students for the challenges of tomorrow. PMID- 29148146 TI - Factors influencing nurse-assessed quality nursing care: A cross-sectional study in hospitals. AB - AIM: To propose a hypothesized theoretical model and apply it to examine the structural relationships among work environment, patient-to-nurse ratio, job satisfaction, burnout, intention to leave and quality nursing care. BACKGROUND: Improving quality nursing care is a first consideration in nursing management globally. A better understanding of factors influencing quality nursing care can help hospital administrators implement effective programmes to improve quality of services. Although certain bivariate correlations have been found between selected factors and quality nursing care in different study models, no studies have examined the relationships among work environment, patient-to-nurse ratio, job satisfaction, burnout, intention to leave and quality nursing care in a more comprehensive theoretical model. DESIGN: A cross-sectional survey. METHODS: The questionnaires were collected from 510 Chinese nurses in four Chinese tertiary hospitals in January 2015. The validity and internal consistency reliability of research instruments were evaluated. Structural equation modelling was used to test a theoretical model. RESULTS: The findings revealed that the data supported the theoretical model. Work environment had a large total effect size on quality nursing care. Burnout largely and directly influenced quality nursing care, which was followed by work environment and patient-to-nurse ratio. Job satisfaction indirectly affected quality nursing care through burnout. CONCLUSIONS: This study shows how work environment past burnout and job satisfaction influences quality nursing care. Apart from nurses' work conditions of work environment and patient to-nurse ratio, hospital administrators should pay more attention to nurse outcomes of job satisfaction and burnout when designing intervention programmes to improve quality nursing care. PMID- 29148147 TI - Altered N170 and mood symptoms in bipolar disorder: An electrophysiological study of configural face processing. AB - OBJECTIVES: Altered social behavior during mood episodes in bipolar disorder often has detrimental and long-lasting interpersonal consequences. Abnormal face processing may play a role in linking brain functions to clinical symptoms and behavior. This study aimed to understand configural face processing in bipolar disorder as a function of basic communicative attributes of the face and mood symptoms using event-related brain potentials (ERPs). METHODS: Forty-two participants with bipolar I disorder (BP) and 43 healthy controls (HC) viewed face stimuli varying in emotion (neutral or fearful), head orientation (forward or deviated), and gaze direction (direct or averted) while ERPs were recorded. Configural face processing was indexed by the N170 wave. RESULTS: BP participants had comparable overall N170 amplitude and peak latency to HC, although timing was more variable in the BP group. Abnormal N170 modulations by communicative face attributes were observed in BP: exaggerated sensitivity to emotion (fearful > neutral) in the left hemisphere, and reduced sensitivity to gaze-head incongruency (where N170 is normally larger in response to faces with incongruent than congruent gaze and head direction) in the right hemisphere. The former was not associated with mood symptoms, suggesting a heightened trait-like sensitivity to negative emotions. The latter was correlated with greater manic symptoms, indicating that an impaired perceptual sensitivity to faces with features signaling incongruent social attention may underlie social deficits observed during mania. CONCLUSIONS: These findings suggest a pathophysiological role of altered configural face processing in the phenomenology of bipolar disorder, and call for further investigations to evaluate its potential as a biomarker and treatment target. PMID- 29148149 TI - Tinkering at the margins. PMID- 29148148 TI - An integrative translational approach to study heart failure with preserved ejection fraction: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology. AB - As heart failure with preserved ejection fraction (HFpEF) rises to epidemic proportions, major steps in patient management and therapeutic development are badly needed. With the current position paper we seek to update our view on HFpEF as a highly complex systemic syndrome, from risk factors and mechanisms to long term clinical manifestations. We will revise recent advances in animal model development, experimental set-ups and basic and translational science approaches to HFpEF research, highlighting their drawbacks and advantages. Directions are provided for proper model selection as well as for integrative functional evaluation from the in vivo setting to in vitro cell function testing. Additionally, we address new research challenges that require integration of higher-order inter-organ and inter-cell communication to achieve a full systems biology perspective of HFpEF. PMID- 29148150 TI - Pressure-flow characteristics of breathing systems and their components for pediatric and adult patients. AB - BACKGROUND: Breathing circuits connect the ventilator to the patients' respiratory system. Breathing tubes, connectors, and sensors contribute to artificial airway resistance to a varying extent. We hypothesized that the flow dependent resistance is higher in pediatric breathing systems and their components compared to respective types for adults. AIMS: We aimed to characterize the resistance of representative breathing systems and their components used in pediatric patients (including devices for adults) by their nonlinear pressure-flow relationship. METHODS: We used a physical model to measure the flow-dependent pressure gradient (?P) across breathing tubes, breathing tube extensions, 90 degrees - and Y-connectors, flow- and carbon dioxide sensors, water traps and reusable, disposable and coaxial breathing systems for pediatric and for adult patients. ?P was analyzed for usual flow ranges and statistically compared at a representative flow rate of 300 mL?s-1 (?P300 ). RESULTS: ?P across pediatric devices always exceeded ?P across the corresponding devices for adult patients (all P < .001 [no 95% CI includes 0]). ?P300 across breathing system components for adults was always below 0.2 cmH2 O but reached up to 4.6 cmH2 O in a flow sensor for pediatric patients. ?P300 was considerably higher across the reusable compared to the disposable pediatric breathing systems (1.9 vs 0.3 cmH2 O, P < .001, [95% CI -1.59 to -1.56]). CONCLUSION: The resistances of pediatric breathing systems and their components result in pressure gradients exceeding those for adults several fold. Considering the resistance of individual components is crucial for composing a breathing system matching the patient's needs. Compensation of the additional resistance should be considered if a large composed resistance is unavoidable. PMID- 29148151 TI - Inflammation in cardiac amyloidosis: prognostic marker or therapeutic target? PMID- 29148152 TI - U-CH17P, -M and -S, a new cell culture system for tumor diversity and progression in chordoma. AB - Chordoma is a rare bone tumor with a known intrinsic heterogeneity. Here, we address this tumor heterogeneity in a new cell culture model for tumor diversity and progression in chordoma. The three cell lines U-CH17P, U-CH17M, and U-CH17S were established from a primary sacral chordoma and its derived metastases, a soft tissue and a skin metastasis, respectively. The lesions had divergent differentiation patterns which are conserved in the derived cell lines making them a suitable in vitro model for the analysis of tumorigenesis in chordoma. A common feature of the three cell lines is the expression of typical chordoma markers, such as Brachyury, vimentin, cytokeratins, EMA and S100 protein. A comparison of the genomic aberrations by array comparative genomic hybridization of the cell lines and the corresponding parental tumor tissues revealed that the precursor cells of U-CH17P, U-CH17M and U-CH17S were already present in the primary tumor. Therefore, we show that clonal diversity of this chordoma exists in the primary tumor and that not all of these subclones tend to metastasize. All cell lines had a CDKN2A loss. A comparison of the gene expression profiles of the cell lines revealed significant differences in the expression of several genes like MAGEC2 and SEMA6A known to be associated with the tendency to metastasize or proliferation and migration. Since the underlying mechanisms of tumor progression in chordoma are still largely unclear, the three U-CH17 cell lines are a suitable in vitro model for elucidating chordoma oncobiology. PMID- 29148153 TI - Clinical utility of cardiopulmonary exercise testing in patients with heart failure with preserved ejection fraction. PMID- 29148154 TI - Incident reporting behaviours following the Francis report: A cross-sectional survey. AB - RATIONALE, AIMS, AND OBJECTIVES: Previous studies have shown a lack of engagement in the reporting process. There is limited evidence about whether attitudes and behaviours of doctors in the UK towards incident reporting have changed following the events at Mid Staffordshire National Health Service Foundation Trust and the recommendations that followed. We conducted a relatively large survey of doctors, aiming to assess whether doctors recognised incidents and reported them accordingly, along with their behaviours towards reporting and their suggestions of how incident reporting may be improved. METHODS: A cross-sectional survey of doctors was undertaken in 11 hospitals in the north of England. The participants (n = 581) were invited to take part in an electronic questionnaire. Demographics were obtained, and engagement with the incident reporting process was assessed, including an estimate of the number of incidents which were witnessed but not actually reported. Factors which influenced reporting behaviours were recorded. Free-text comments were encouraged. A mixed method analysis of the responses was performed. RESULTS: Doctors do not appear to be engaging with the incident reporting process-in particular, junior doctors. The main reason given for not completing forms was not having enough time (38.2% of respondents), primarily due to the length and complexity of forms. Many doctors, 43.7%, witnessed more than 5 incidents, but only 13.3% of doctors submitted more than 5 reports. Free text comments revealed 4 themes which impact upon reporting behaviours: organisational issues, form structure, a culture of blame, and a lack of feedback. Several suggestions for improvement were made. CONCLUSIONS: Little has changed in the attitudes and behaviours of doctors. Improving incident reporting form structure to make it more user-friendly and improving feedback may engage doctors and lead to an improved safety culture. The way the medical profession reports serious and other incidents still needs to be improved. PMID- 29148155 TI - Identifying biomechanical gait parameters in adolescent boys with haemophilia using principal component analysis. AB - INTRODUCTION: Improvements in the medical management for those with haemophilia have resulted in improved clinical outcomes. However, current treatment regimens do not alleviate all joint haemarthroses with the potential for long-term joint deterioration remaining. The evaluation of functional activities such as gait, using standardized tools to monitor children with haemophilia is emerging. AIM: This study explored differences in sagittal plane biomechanics of walking in adolescent boys aged 11-18 years with haemophilia and an age-matched group of typically developing boys. METHODS: A motion capture system and 2 force platforms were used to collect sagittal plane kinematic, kinetic and temporal spatial data during level walking. Principal component analysis (PCA) was applied to kinematic and kinetic waveform variables. Group differences in temporal spatial and principal component scores for each kinematic and kinetic variable were evaluated using independent t tests. RESULTS: Significant alterations (P < .05) in temporal spatial and kinetic parameters were found in adolescent boys with haemophilia. Compared with typically developing adolescent boys, boys with haemophilia walked with reduced stance phase duration and altered pattern of external ankle joint moments during push off and the beginning of swing. CONCLUSION: The use of PCA rather than predetermined discriminatory variables provided additional insight into biomechanical alterations in adolescent boys with haemophilia, with adaptations occurring during terminal double support and early swing, affecting the ankle joint. This finding might be a key biomechanical marker that could be used to evaluate the joint function and the progression of early haemophilic arthropathy. PMID- 29148156 TI - Long-term outcomes for different surgical strategies to treat left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. AB - AIMS: Surgical intervention is used to treat dynamic left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy. This study assesses the effect of different surgical strategies on long-term mortality and morbidity. METHODS AND RESULTS: In total, 347 patients underwent surgical intervention for LVOTO (1988-2015). Group A (n = 272) underwent septal myectomy; Group B (n = 33), septal myectomy and mitral valve (MV) repair; Group C (n = 22), myectomy and MV replacement; and Group D (n = 20), MV replacement alone. Median follow-up was 5.2 years (interquartile range 1.9-7.9). The mean resting LVOT gradient improved post operatively from 71.9 +/- 39.6 mmHg to 13.4 +/- 18.5 mmHg (P < 0.05). Overall, 72.4% of patients improved by >1 New York Heart Association (NYHA) class; 58.9% of patients undergoing MV replacement alone did not improve their NYHA class. There were 5 perioperative deaths and 20 late deaths (>30 days). Survival rates at 1, 5 and 10 years respectively were 98.4, 96.9, 91.9% in Group A; 97.0, 92.4, 61.6% in Group B; 100.0, 100.0, 55.6% in Group C; and 94.7, 85.3, 85.3% in Group D (log-rank, P < 0.05). Long-term (>30 days) complications included atrial fibrillation (29.6%), transient ischaemic attack/stroke (2.4%) and heart failure hospitalisation (3.2%). There were 16 repeat surgical interventions at 3.0 years. CONCLUSION: Septal myectomy is a safe procedure resulting in symptomatic improvement in the majority of patients. The annual incidence of non-fatal disease-related complications after surgical treatment of LVOTO is relatively high. Patients who underwent MV replacements had poorer outcomes with less symptomatic benefit in spite of a similar reduction in LVOT gradients. PMID- 29148157 TI - New WS9326A Derivatives and One New Annimycin Derivative with Antimalarial Activity are Produced by Streptomyces asterosporus DSM 41452 and Its Mutant. AB - In this study, we report that Streptomyces asterosporus DSM 41452 is a producer of new molecules related to the nonribosomal cyclodepsipeptide WS9326A and the polyketide annimycin. S. asterosporus DSM 41452 is shown to produce six cyclodepsipeptides and peptides, WS9326A to G. Notably, the compounds WS9326F and WS9326G have not been described before. The genome of S. asterosporus DSM 41452 was sequenced, and a putative WS9326A gene cluster was identified. Gene-deletion experiments confirmed that this cluster was responsible for the biosynthesis of WS9326A to G. Additionally, a gene-deletion experiment demonstrated that sas16 encoding a cytochrome P450 monooxygenase was involved in the synthesis of the novel (E)-2,3-dehydrotyrosine residue found in WS9326A and its derivatives. An insertion mutation within the putative annimycin gene cluster led to the production of a new annimycin derivative, annimycin B, which exhibited modest inhibitory activity against Plasmodium falciparum. PMID- 29148158 TI - Long-term anesthetic protocol in rats: feasibility in electrophysiology studies in visual prosthesis. AB - Electrical stimulation of excitable cells provides therapeutic benefits for a variety of medical conditions, including restoration of partial vision to those blinded via some types of retinal degeneration. To improve visual percepts elicited by the current technology, researchers are conducting acute electrophysiology experiments, mainly in cats. However, the rat can provide a model of a range of retinal diseases and possesses a sufficiently large eye to be used in this field. This article presents a long-term anesthetic protocol to enable electrophysiology experiments to further the development of visual prostheses. Six Long-Evans rats (aged between 14 and 16 weeks) were included in this study. Surgical anesthesia was maintained for more than 15 h by combining constant intravenous infusion of ketamine (24.0-34.5 mg/kg/h), xylazine (0.9-1.2 mg/kg/h), and inhaled isoflurane in oxygen (<0.5%). Overall heart rate, respiratory rate, and body temperature remained between 187-233 beats/min, 45-58 breaths/min, and 36-38 degrees C, respectively. Neural responses to 200-ms light pulses were recorded from the superior colliculus using a 32-channel neural probe at the beginning and before termination of the experiment. Robust responses were recorded from distinct functional types of retinal pathways. In addition, a platinum electrode was implanted in the retrobulbar space. The retina was electrically stimulated, and the activation threshold was determined to be 5.24 +/- 0.24 MUC/cm2 . This protocol may be used not only in the field of visual prosthesis research, but in other research areas requiring longer term acute experiments. PMID- 29148159 TI - Re: Changes in anti-mullerian hormone levels as a biomarker for ovarian reserve after ultrasound-guided high-intensity focused ultrasound treatment of adenomyosis and uterine fibroid. PMID- 29148160 TI - Chronic parenting stress and mood reactivity: The role of sleep quality. AB - Sleep is a basic biological process supporting emotion regulation. The emotion regulation function of sleep may be particularly important in the context of chronic stress. To better understand how chronic stress and sleep interact to predict mood, 66 parents of children with autism completed daily diaries assessing parenting stress, negative mood, and sleep quality for 6 consecutive days. Hierarchical linear modelling revealed that daily negative mood was predicted by between-person differences in parenting stress and between-person differences in sleep efficiency. Further, between-person differences in sleep efficiency and within-person differences in sleep satisfaction moderated the impact of stress on mood. These data suggest that sleep disturbances may exacerbate the association between stress and mood in the context of chronic parenting stress. Further, high parenting stress appears to heighten the impact of transient sleep disturbances on mood. PMID- 29148161 TI - Piezoelectric versus conventional implant site preparation: A systematic review and meta-analysis. AB - BACKGROUND: The use of a piezoelectric device (PED) for implant site preparation (ISP) has been introduced to overcome the limitations of using conventional drills (CDs). With little and inconsistent information in the literature regarding their efficiency for preparing implant osteotomies, the objective of this systematic review was to compare the use of CDs to PEDs for ISP with regard to implant stability values, marginal bone level changes, operating time, and dental implant failure rate. METHODS: The systematic review was prepared according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The literature was searched for studies that assessed the use of CDs and PEDs for ISP. The Cochrane Collaboration risk of bias tool was used to evaluate the selected studies and meta-analyses were performed using statistical software. RESULTS: A total of 755 citations were identified. Of these, 4 studies with 178 implant osteotomies in 80 participants were included. The pooled estimates for the implant stability showed significant differences between the 2 surgical techniques in favor of PEDs at baseline, 8 and 12 weeks. A statistically significant difference in the operating time was also shown between the 2 techniques with more time required using PED. The differences in marginal bone level changes or implant failure rate were not statistically significant. CONCLUSIONS: With the limitations of this review in mind, PEDs appear to be a viable alternative to traditional drilling techniques for ISP. With the exception of prolonged operating time associated with the use of PEDs, both techniques were comparable in terms of the marginal bone level changes and the risk of implant failure. The favorable influence of the implant stability pattern related to the use of PEDs on the predictability of immediate and early loading protocols need to be confirmed in future studies. PMID- 29148162 TI - Re: Perinatal and maternal morbidity and mortality among term singletons following midcavity operative vaginal delivery versus caesarean delivery. PMID- 29148163 TI - Development and validation of a high-performance liquid chromatography method for determination of lisinopril in human plasma by magnetic solid-phase extraction and pre-column derivatization. AB - A sensitive, reliable and simple HPLC method was developed for the determination of lisinopril in human plasma. The method consists of extraction and clean-up steps based on magnetic solid-phase extraction and pre-column derivatization with a fluorescent reagent. The mobile phase consisted of a mixture of methanol-sodium dihydrogen phosphate (pH 3.0; 0.005 m; 75:25, v/v). The flow rate was set at 0.7 mL/min. Fluorescence detection was performed at 470nm excitation and 530nm emission wavelengths. Total chromatography run time was 5 min. The average extraction recovery of lisinopril and fluvoxamine (internal standard) was >=82.8%. The limits of detection and quantification were determined as 1 and 3 ng/mL respectively. The method exhibited a linear calibration line over the concentration range of 3-1000 ng/mL with coefficient of determination (r2 ) of >=0.98. The within-run and between-run precisions were satisfactory with values of CV of 1.8-12.8% (accuracy from 99.2 to 94.7%) and 2.4-13.7% (accuracy from 99.5 to 92.2%), respectively. These developments led to considerable improvement in method sensitivity and reliability. The method was validated according to the US Food and Drug Administration guidelines. Therefore, it can be considered as a suitable method for determination of lisinopril in plasma samples. PMID- 29148164 TI - Protein Profiling of Non-model Plant Cuminum cyminum by Gel-Based Proteomic Approach. AB - INTRODUCTION: Cumin (Cuminum cyminum), a popular spice has been widely used in traditional medicine to cure various ailments. Despite the existence of scientific literature about its pharmacological properties, no successful proteome profiling has yet been attempted. OBJECTIVE: To optimise extraction of cumin proteins and analyse its profile by shotgun proteomics, using one dimensional electrophoresis coupled with nano-ESI-LC-MS/MS. METHODOLOGY: As a first step, we have compared three extraction protocols for total proteins extraction from cumin. Extracted proteins were separated on one-dimensional gel and analysed by state-of-the-art linear ion trap (LTQ)-Orbitrap Velose and Q Exactive HF mass spectrometer. RESULTS: Evaluation of extraction method revealed significant differences in protein yield and proteome composition between the three extracts. LC-MS/MS allowed identification of several proteins with functional significance in various biological processes. CONCLUSION: This study provides identification of a large number of proteins and offers a molecular basis for future research on potential pharmacologically active cumin proteins. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29148165 TI - Dinitroaniline herbicide resistance in a multiple-resistant Lolium rigidum population. AB - BACKGROUND: The pre-emergence dinitroaniline herbicides (such as trifluralin and pendimethalin) are vital to Australian no-till farming systems. A Lolium rigidum population collected from the Western Australian grain belt with a 12-year trifluralin use history was characterised for resistance to dinitroaniline, acetyl CoA carboxylase (ACCase)- and acetolactate synthase (ALS)-inhibiting herbicides. Target-site resistance mechanisms were investigated. RESULTS: This L. rigidum population exhibited 32-fold resistance to trifluralin, as compared with the susceptible population. It also displayed 12- to 30-fold cross-resistance to other dinitroaniline herbicides (pendimethalin, ethalfluralin and oryzalin). In addition, this population showed multiple resistance to commonly used post emergence ACCase- and ALS-inhibiting herbicides. Two target-site alpha-tubulin gene mutations (Val-202-Phe and Thr-239-Ile) previously documented in other dinitroaniline-resistant weed species were identified, and some known target-site mutations in ACCase (Ile-1781-Leu, Asp-2078-Gly and Cys-2088-Arg) and ALS (Pro 197-Gln/Ser) were found in the same population. An agar-based Petri dish screening method was established for the rapid diagnosis of resistance to dinitroaniline herbicides. CONCLUSION: Evolution of target-site resistance to both pre- and post-emergence herbicides was confirmed in a single L. rigidum population. The alpha-tubulin mutations Val-202-Phe and Thr-239-Ile, documented here for the first time in L. rigidum, are likely to be responsible for dinitroaniline resistance in this population. Early detection of dinitroaniline herbicide resistance and integrated weed management strategies are needed to maintain the effectiveness of dinitroaniline herbicides. (c) 2017 Society of Chemical Industry. PMID- 29148166 TI - Author's reply re: Changes in anti-mullerian hormone levels as a biomarker for ovarian reserve after ultrasound-guided high-intensity focused ultrasound treatment of adenomyosis and uterine fibroid. PMID- 29148167 TI - Monitoring resistance of Cydia pomonella (L.) Spanish field populations to new chemical insecticides and the mechanisms involved. AB - BACKGROUND: Widespread resistance of Cydia pomonella to organophosphates was demonstrated in populations from the Spanish Ebro Valley area which showed high levels of enzymatic detoxification. To determine the efficacy of new insecticides, neonate larval bioassays were carried out on 20 field codling moth populations collected from three different Spanish apple production areas. Synergist bioassays were performed to determine the enzymatic mechanisms involved. RESULTS: The least active ingredients were methoxyfenozide, with 100% of the populations showing significantly lower mortality than the susceptible strain, and lambda-cyhalothrin, with very high resistance ratios (872.0 for the most resistant field population). Approximately 50% of the populations were resistant or tolerant to thiacloprid. By contrast, tebufenozide was very effective in all the field populations, as was chlorpyrifos-ethyl despite its widespread use during the last few years. Indoxacarb, spinosad and chlorantraniliprole also provided high efficacy, as did emamectin and spinetoram, which are not yet registered in Spain. CONCLUSION: The resistant Spanish codling moth populations can be controlled using new reduced-risk insecticides. The use of synergists showed the importance of the concentration applied and the difficulty of interpreting results in field populations that show multiple resistance to different active ingredients. (c) 2017 Society of Chemical Industry. PMID- 29148168 TI - Phenylbutazone induces equine glandular gastric disease without decreasing prostaglandin E2 concentrations. AB - In equids, phenylbutazone at high doses induces gastric disease, primarily in the glandular portion of the stomach. However, the mechanism of nonsteroidal anti inflammatory drug (NSAID)-induced gastric disease in horses has yet to be determined. While phenylbutazone-associated ulceration is often attributed to a decrease in basal gastric prostaglandins, this has not been demonstrated in the horse. Twelve horses were randomly assigned to treatment (n = 6; 4.4 mg/kg phenylbutazone PO in 20 ml molasses q 12 hr for 7 days) or placebo (n = 6; 20 ml molasses PO q 12 hr for 7 days) groups. Before treatment and 3 and 7 days after initiation of treatment, gastroscopy was performed and glandular gastric biopsies were collected and frozen at -80 degrees C. Glandular disease was assessed on a scale of 0-4. Prostaglandin E2 concentrations in biopsies were measured using a commercially available enzyme-linked immunosorbent assay. All phenylbutazone treated horses developed grade >=2 glandular disease. Prostaglandin concentrations increased over time (p = .0017), but there was no effect of treatment (p = .49). These findings indicate that despite induction of glandular disease grade >=2, phenylbutazone did not decrease basal glandular gastric prostaglandin E2 concentration. PMID- 29148169 TI - Antitumor and anti-metastatic mechanisms of Rhizoma paridis saponins in Lewis mice. AB - Lung cancer is one of the most common causes of death in the world. Rhizoma paridis saponins (RPS) have been found to show inhibition of pulmonary adenoma in previous research. However, the detailed mechanisms of RPS from a holistic view have not been established. In this study, Lewis pulmonary adenoma mice were successfully established to analyze the pathways involved in RPS intervening tumor formation and progression. As a result, RPS inhibited levels of cytokines or receptors such as VEGFD, VEGFR3, RAGE, IL6R, IL17BR, and CXCL16 which were regarded as the initiators induced tumor cell proliferation, adhesion, angiogenesis, and invasion. Meanwhile, RPS raised the content of SOD and CAT enzymes and thereby inhibited the aberrantly active NF-kappaB, and phosphorylation of PI3K/Akt and MAPK (including p38, Erk1/2, and JNK) signaling pathways. Soon after, RPS changed mRNA expression of nuclear factors containing NF-kappaB, HIF-1A, STAT3, and Jun, and consequentially suppressed the expression of angiogenesis, lymphangiogenesis, adhesion, inflammation, and invasion enzymes. In conclusion, this research provided a holistic view to understand the multi target antitumor mechanisms of RPS which promoted the application of RPS in the future. PMID- 29148170 TI - Community evolution increases plant productivity at low diversity. AB - Species extinctions from local communities negatively affect ecosystem functioning. Ecological mechanisms underlying these impacts are well studied, but the role of evolutionary processes is rarely assessed. Using a long-term field experiment, we tested whether natural selection in plant communities increased biodiversity effects on productivity. We re-assembled communities with 8-year co selection history adjacent to communities with identical species composition but no history of co-selection ('naive communities'). Monocultures, and in particular mixtures of two to four co-selected species, were more productive than their corresponding naive communities over 4 years in soils with or without co-selected microbial communities. At the highest diversity level of eight plant species, no such differences were observed. Our findings suggest that plant community evolution can lead to rapid increases in ecosystem functioning at low diversity but may take longer at high diversity. This effect was not modified by treatments simulating co-evolutionary processes between plants and soil organisms. PMID- 29148171 TI - Identification and expression profiling of Pht1 phosphate transporters in wheat in controlled environments and in the field. AB - Phosphorus (P) is an important macronutrient with critical functions in plants. Phosphate (Pi) transporters, which mediate Pi acquisition and Pi translocation within the plant, are key factors in Pi deficiency responses. However, their relevance for adaptation to long-term Pi limitation under agronomic conditions, particularly in wheat, remains unknown. Here, we describe the identification of the complete Pi transporter gene family (Pht1) in wheat (Triticum aestivum). Gene expression profiles were compared for hydroponic and field-grown plant tissues of wheat at multiple development stages. Cis-element analysis of selected Pht1 promoter regions was performed. A broad range of expression patterns of individual TaPht1 genes was observed in relation to tissue specificity and the nutrient supply in the soil or in liquid culture, as well as an influence of the experimental system. The expression patterns indicate the involvement of specific transporters in Pi uptake, and in Pi transport and remobilisation within the plant, at different growth developmental stages. Specifically, the influence of Pi nutrition indicates a complex regulatory pattern of TaPht1 gene transcript abundances as a response to low Pi availability in different culture systems, correlating with the existence of different cis-acting promoter elements. PMID- 29148172 TI - Quality of handwritten surgical operative notes from surgical trainees: a noteworthy issue. AB - BACKGROUND: Surgical operation notes are crucial for medical record keeping and information flow in continued patient care. In addition to inherent medical implications, the quality of operative notes also has important economic and medico-legal ramifications. Further, well-documented records can also be useful for audit purposes and propagation of research, facilitating the improvement of delivery of care to patients. We aimed to assess the quality of surgical operation notes written by junior doctors and trainees against a set standard, to ascertain whether these standards were met. METHOD: We undertook an audit of Urology and General Surgery operation notes handwritten by junior doctors and surgical trainees in a tertiary teaching hospital over a month period both in 2014 and 2015. Individual operative notes were assessed for quality based on parameters described by the Royal College of Surgeons of England guidelines. RESULTS: Based on the Royal College of Surgeons of England guidelines, a significant proportion of analysed surgical operative notes were incomplete, with information pertaining to the time of surgery, name of anaesthetist and deep vein thrombosis prophylaxis in particular being recorded less than 50% of the time (22.42, 36.36 and 43.03%, respectively).Overall, 80% compliance was achieved in 14/20 standards and 100% compliance was attained in only one standard. CONCLUSIONS: The quality of surgical operation notes written by junior doctors and trainees demonstrated significant deficiencies when compared against a set standard. There is a clear need to educate junior medical staff and to provide systems and ongoing education to improve quality. This would involve leadership from senior staff, ongoing audit and the development of systems that are part of the normal workflow to improve quality and compliance. PMID- 29148173 TI - Metformin protects against intestinal barrier dysfunction via AMPKalpha1 dependent inhibition of JNK signalling activation. AB - Disruption of the intestinal epithelial barrier, that involves the activation of C-Jun N-terminal kinase (JNK), contributes to initiate and accelerate inflammation in inflammatory bowel disease. Metformin has unexpected beneficial effects other than glucose-lowering effects. Here, we provided evidence that metformin can protect against intestinal barrier dysfunction in colitis. We showed that metformin alleviated dextran sodium sulphate (DSS)-induced decreases in transepithelial electrical resistance, FITC-dextran hyperpermeability, loss of the tight junction (TJ) proteins occludin and ZO-1 and bacterial translocation in Caco-2 cell monolayers or in colitis mice models. Metformin also improved TJ proteins expression in ulcerative colitis patients with type 2 diabetes mellitus. We found that metformin ameliorated the induction of colitis and reduced the levels of pro-inflammatory cytokines IL-6, TNF-a and IL-1beta. In addition, metformin suppressed DSS-induced JNK activation, an effect dependent on AMP activated protein kinase alpha1 (AMPKalpha1) activation. Consistent with this finding, metformin could not maintain the barrier function of AMPKalpha1-silenced cell monolayers after DSS administration. These findings highlight metformin protects against intestinal barrier dysfunction. The potential mechanism may involve in the inhibition of JNK activation via an AMPKalpha1-dependent signalling pathway. PMID- 29148174 TI - Prehospital transfusion of red cell concentrates in a paramedic-staffed helicopter emergency medical service. AB - OBJECTIVE: The optimal volume and type of intravenous fluid for the treatment of blood loss in the prehospital setting is controversial. The use of red cell concentrates (RCCs) may be associated with improved outcomes; however, the administration of blood products is limited to physicians in many jurisdictions. We sought to describe the characteristics of RCC transfusions in a paramedic staffed helicopter emergency medical system in Victoria, Australia. METHODS: We performed a retrospective analysis of all cases where paramedics consulted the responsible physician for approval of RCC transfusion between July 2011 and December 2015 in Victoria, Australia. Ambulance data was retrieved from electronic patient care records and hospital and outcome data was retrieved from a state-wide trauma registry. RESULTS: A total of 180 primary missions was identified where paramedics requested approval for transfusion of RCCs during the study period. A total of 150 patients received prehospital RCCs, of which 136 had suffered trauma. The majority of these patients were male (66.7%) and were involved in a car accident (62.5%). Most (97.4%) patients had an Injury Severity Score >=12. There were improvements in median systolic blood pressure (80 mmHg vs 94 mmHg, P < 0.001) and shock index (1.50 vs 1.23, P < 0.001) between time of consultation and arrival at hospital. Overall, mortality for trauma patients was 37.7%. There were no transfusion-related complications identified. CONCLUSION: Prehospital transfusion of RCC by paramedics is feasible. Future studies should compare the outcomes of patients receiving prehospital RCCs with outcomes for patients in which RCCs are administered in hospital. PMID- 29148175 TI - Treatment efficacy of a probiotic preparation for non-alcoholic steatohepatitis: A pilot trial. AB - OBJECTIVE: To evaluate the therapeutic effect of a probiotic cocktail containing Lactobacilli, Bifidobacteria and Streptococcus thermophilus on non-alcoholic steatohepatitis (NASH). METHODS: In this open-label trial, 75 patients with NASH fed a low-fat/low-calorie diet were randomly divided into the control group and experimental group, with the latter receiving the probiotic cocktail once daily for 12 weeks. RESULTS: All patients were diagnosed with fatty liver by ultrasound examination and had elevated levels of gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT), and slightly increased body mass index (BMI) and cholesterol levels. BMI and serum cholesterol were reduced by the low-fat/low calorie diet but ALT was not. However, the short-term (12-week) treatment with the probiotic cocktail caused a significant (by >20%) reduction of serum ALT compared with controls, indicating mitigation of inflammation. Accordingly, liver stiffness was decreased in the probiotic-treated group compared with the control group (P < 0.05). Moreover, a more significant decrease in the BMI and serum cholesterol was observed in the probiotic-treated group compared with control (P < 0.05). However, the reduction of GGT as a steatosis marker was insignificant. The composition of stool microbiota in probiotic-treated patients demonstrated a shift towards a normal pattern for all bacterial species examined. No adverse events were observed in any patient during the trial. CONCLUSION: Short-term treatment with the probiotic cocktail caused significant improvement of liver inflammation without adverse events and, thus, may represent a promising candidate therapeutic approach for NASH. PMID- 29148176 TI - Differential Proteomic Analysis Reveals Protein Networks and Pathways that May Contribute to Helicobacter pylori FKBP-Type PPIase-Associated Gastric Diseases. AB - PURPOSE: Though Helicobacter pylori (H. pylori) has been classified as class I carcinogen, key virulence factor generated by H. pylori that causes gastric cancer remains to be fully determined. Recently, we identified a gastric cancer associated H. pylori gene, peptidylprolyl isomerase-FK506 binding protein (PPIase FKBP), and showed that PPIase-FKBP was capable of inducing oncogenic transformation of gastric epithelial cells. But its mechanism was unclear. EXPERIMENTAL DESIGN: We carried out a comparative proteomic analysis of human gastric epithelial cells that either express PPIase-FKBP or green fluorescent protein using 2-DE and then MALDI-TOF-MS/MS. RESULTS: Our results identified 28 differentially expressed proteins induced by PPIase-FKBP. These proteins participate in some cellular biological processes, such as cell proliferation, cell apoptosis and DNA replication, mRNA splicing, and protein biosynthesis. Ingenuity Pathway Analysis categorized the 28 proteins into two molecular interaction networks, involved primarily in cancer and gastrointestinal diseases. CONCLUSIONS AND CLINICAL RELEVANCE: Our results provided insight on the protein interaction networks and signaling pathways that may contribute to PPIase-FKBP associated gastric diseases and may lead to a better understanding of the mechanisms indicating the oncogenic effects of H. pylori PPIase-FKBP. PMID- 29148177 TI - High concentrations of GTP induce conformational changes in the essential bacterial GTPase EngA and enhance its binding to the ribosome. AB - EngA is a conserved bacterial GTPase involved in ribosome biogenesis. While essential in bacteria, EngA does not have any human orthologue and can thus be an interesting target for new antibacterial compounds. EngA is the only known GTPase bearing two G domains, making unique its catalytic cycle and the induced modulation of its conformation and interaction with the ribosome. We have investigated nucleotide-induced conformational changes in EngA in order to unveil their role in ribosome binding. SAXS and limited proteolysis were used to probe EngA conformational changes, and revealed a change in protein structure and a distinct rate of proteolysis induced by GTP. Structure analysis showed that the conformation adopted in solution in the presence of GTP does not match any known EngA structure, while the SAXS data measured in the presence of GDP are in perfect agreement with two crystal structures (i.e. 2HGJ and 4DCU). Combination of mass spectrometry and N-terminal sequencing for the analysis of the fragmentation pattern upon proteolytic cleavage gave insights into which regions become more or less accessible in the different nucleotide-bound states. Interactions studies confirmed a stronger binding of EngA to the bacterial ribosome in the presence of GTP and suggest that the induced change in conformation of EngA plays a key role for ribosome binding. PMID- 29148178 TI - Training in molecular cytopathology testing. AB - Training in molecular cytopathology testing is essential in developing and maintaining skills in modern molecular technologies as they are introduced to a universal health care system such as extant in the UK and elsewhere. We review the system in place in Northern Ireland (NI) for molecular testing of solid tumours, as an example to train staff of all grades, including pathologists, clinical scientists, biomedical scientists and equivalent technical grades. We describe training of pathologists as part of the NI Deanery medical curriculum, the NI training programme for scientists and laboratory rotation for Biomedical Scientists. Collectively, the aims of our training are two-fold: to provide a means by which individuals may extend their experience and skills; and to provide and maintain a skilled workforce for service delivery. Through training and competency, we introduce new technologies and tests in response to personalised medicine therapies with a competent workforce. We advocate modifying programmes to suit individual needs for skill development, with formalised courses in pre analytical, analytical and postanalytical demands of modern molecular pathology. This is of particular relevance for cytopathology in small samples such those from formalin-fixed paraffin-embedded cell blocks. We finally introduce how university courses can augment training and develop a skilled workforce to benefit the delivery of services to our patients. PMID- 29148179 TI - Clinical implications of de Barsy syndrome. AB - BACKGROUND: De Barsy syndrome is a rare, autosomal recessive syndrome characterized by cutis laxa, progeroid appearance, ophthalmic opacification, skeletal malformations, growth delays, and intellectual disability. AIMS: The aim of this case series is to identify the anesthetic considerations in the clinical management of patients with de Barsy syndrome. METHODS: A retrospective case review from 1968 to 2016 was performed at a single tertiary medical center to identify patients with de Barsy syndrome who underwent anesthesia for diagnostic and surgical procedures. We collected and analyzed the perioperative records and following data: age, sex, American Society of Anesthesiologists physical status, relevant comorbidities, surgical procedures, anesthesia management, and observed complications. RESULTS: Three patients underwent 64 unique anesthetics for a diverse collection of diagnostic and surgical procedures. An array of anesthetics and techniques were successfully used. Observations of the perioperative period found 7 episodes of intraoperative hyperthermia (>38.3 degrees ), a single difficult airway requiring fiberoptic bronchoscopic-guided intubation, and repeatedly difficult intravenous access. CONCLUSION: This expanded case series suggests that providers caring for patients with de Barsy syndrome should be aware of potential challenges with airway management, vascular access, and temperature monitoring. PMID- 29148181 TI - Chloroplast-targeted antioxidant protein protects against necrotrophic fungal attack. PMID- 29148180 TI - DNA methylation in the central and efferent limbs of the chemoreflex requires carotid body neural activity. AB - KEY POINTS: The mechanisms underlying long-term (30 days) intermittent hypoxia (LT-IH)-evoked DNA methylation of anti-oxidant enzyme (AOE) gene repression in the carotid body (CB) reflex pathway were examined. LT-IH-treated rats showed increased reactive oxygen species (ROS) levels in the CB reflex pathway. Administration of a ROS scavenger or CB ablation blocked LT-IH-evoked DNA methylation and AOE gene repression in the central and efferent limbs of the CB reflex. LT-IH increased DNA methyltransferase (Dnmt) activity through upregulation of Dnmt1 and 3b proteins by ROS-dependent inactivation of glycogen synthase kinase 3beta (GSK3beta) by Akt. A pan-Akt inhibitor prevented LT-IH induced GSK3beta inactivation, elevated Dnmt protein expression and activity, AOE gene methylation, sympathetic activation and hypertension. ABSTRACT: Long-term exposure to intermittent hypoxia (LT-IH; 30 days), simulating blood O2 profiles during sleep apnoea, has been shown to repress anti-oxidant enzyme (AOE) gene expression by DNA methylation in the carotid body (CB) reflex pathway, resulting in persistent elevation of plasma catecholamine levels and blood pressure. The present study examined the mechanisms by which LT-IH induces DNA methylation. Adult rats exposed to LT-IH showed elevated reactive oxygen species (ROS) in the CB, nucleus tractus solitarius (nTS) and rostroventrolateral medulla (RVLM) and adrenal medulla (AM), which represent the central and efferent limbs of the CB reflex, respectively. ROS scavenger treatment during the first ten days of IH exposure prevented ROS accumulation, blocked DNA methylation, and normalized AOE gene expression, suggesting that ROS generated during the early stages of IH activate DNA methylation. CB ablation prevented the ROS accumulation, normalized AOE gene expression in the nTS, RVLM, and AM and blocked DNA methylation, suggesting that LT-IH-induced DNA methylation in the central and efferent limbs of the CB reflex is indirect and requires CB neural activity. LT-IH increased DNA methyl transferase (Dnmt) activity through upregulation of Dnmt1 and 3b protein expression due to ROS-dependent inactivation of glycogen synthase kinase 3beta (GSK3beta) by protein kinase B (Akt). Treating rats with the pan-Akt inhibitor GSK690693 blocked the induction of Dnmt activity, Dnmt protein expression, and DNA methylation, leading to normalization of AOE gene expression as well as plasma catecholamine levels and blood pressure. PMID- 29148182 TI - Reliability, validity and minimal detectable change of computerized respiratory sounds in patients with chronic obstructive pulmonary disease. AB - INTRODUCTION: Computerized respiratory sounds (CRS) are closely related to the movement of air within the tracheobronchial tree and are promising outcome measures in patients with chronic obstructive pulmonary disease (COPD). However, CRS measurement properties have been poorly tested. OBJECTIVE: The aim of this study was to assess the reliability, validity and the minimal detectable changes (MDC) of CRS in patients with stable COPD. METHODS: Fifty patients (36?, 67.26 +/ 9.31y, FEV1 49.52 +/- 19.67%predicted) were enrolled. CRS were recorded simultaneously at seven anatomic locations (trachea; right and left anterior, lateral and posterior chest). The number of crackles, wheeze occupation rate, median frequency (F50) and maximum intensity (Imax) were processed using validated algorithms. Within-day and between-days reliability, criterion and construct validity, validity to predict exacerbations and MDC were established. RESULTS: CRS presented moderate-to-excellent within-day reliability (ICC1,3 >= 0.51; P < .05) and moderate-to-good between-days reliability (ICC1,2 >= 0.47; P < .05) for most locations. Negligible-to-moderate correlations with FEV1 %predicted were found (-0.53 < rs < -0.28; P < .05), and the inspiratory number of crackles were the best discriminator between mild-to-moderate and severe-to very severe airflow limitations (area under the curve >0.78). CRS correlated poorly with patient-reported outcomes (rs < 0.48; P < .05) and did not predict exacerbations. Inspiratory number of crackles at posterior right chest, inspiratory F50 at trachea and anterior left chest and expiratory Imax at anterior right chest were simultaneously reliable and valid, and their MDC were 2.41, 55.27, 29.55 and 3.98, respectively. CONCLUSION: CRS are reliable and valid. Their use, integrated with other clinical and patient-reported measures, may fill the gap of assessing small airways and contribute toward a patient's comprehensive evaluation. PMID- 29148183 TI - Trends and predictors of appropriate complementary feeding practices in Nepal: An analysis of national household survey data collected between 2001 and 2014. AB - There is evidence that suboptimal complementary feeding contributes to poor child growth. However, little is known about time trends and determinants of complementary feeding in Nepal, where the prevalence of child undernutrition remains unacceptably high. The objective of the study was to examine the trends and predictors of suboptimal complementary feeding in Nepali children aged 6-23 months using nationally representative data collected from 2001 to 2014. Data from the 2001, 2006, and 2011 Nepal Demographic and Health Surveys and the 2014 Multiple Indicator Cluster Survey were used to estimate the prevalence, trends and predictors of four WHO-UNICEF complementary feeding indicators: timely introduction of complementary foods (INTRO), minimum meal frequency (MMF), minimum dietary diversity (MDD), and minimum acceptable diet (MAD). We used multilevel logistic regression models to identify independent factors associated with these indicators at the individual, household and community levels. In 2014, the weighted proportion of children meeting INTRO, MMF, MDD, and MAD criteria were 72%, 82%, 36% and 35%, respectively, with modest average annual rate of increase ranging from 1% to 2%. Increasing child age, maternal education, antenatal visits, and community-level access to health care services independently predicted increasing odds of achieving MMF, MDD, and MAD. Practices also varied by ecological zone and sociocultural group. Complementary feeding practices in Nepal have improved slowly in the past 15 years. Inequities in the risk of inappropriate complementary feeding are evident, calling for programme design and implementation to address poor feeding and malnutrition among the most vulnerable Nepali children. PMID- 29148185 TI - Eye for positive signs: A practical approach to childhood eye disease. PMID- 29148184 TI - Windsock in the heart. PMID- 29148186 TI - Undescended testis: What paediatricians need to know. AB - Undescended testis (UDT) occurs when something goes wrong with testicular descent from high in the abdominal cavity to the scrotum. Normal descent occurs in two steps, with the transabdominal phase controlled by a new testicular hormone, insulin-like hormone 3, and the inguinoscrotal phase controlled by androgens. The latter phase requires a complex process of migration from the inguinal abdominal wall to the scrotum and is commonly defective, leading to the high incidence (2 4%) of UDT at birth. The clinical examination of babies and infants aims to confirm the persistence of congenital UDT by 3-6 months, so surgery can be optimally timed at 6-12 months. For those boys who develop acquired UDT later in childhood, the 'ascending' testis often needs surgery between 5 years and 10 years, so all boys should be screened again for UDT at school entry. PMID- 29148187 TI - Lateral neck lumps: A systematic approach for the general paediatrician. AB - Lateral neck lumps are very common in children, and are largely benign in nature. The majority of lumps may be diagnosed on history and clinical examination alone, and further investigations are often not required. The most common pathologies in young children include reactive lymphadenopathy, lymphadenitis and atypical mycobacterial infections. A lateral neck lump is an uncommon presentation for malignancy and is largely restricted to older children and adolescents. The paediatric surgeon plays an important role in the assessment and management of lateral neck lumps, often in the form of reassurance to the patients and their carers. PMID- 29148188 TI - Acutely painful scrotum: Tips, traps, tricks and truths. PMID- 29148189 TI - Midline cervical swellings: What a paediatrician needs to know. AB - Midline cervical swellings are a heterogeneous group of conditions in children. Careful clinical examination will allow a diagnosis to be made in many instances and appropriate investigations to be performed before referral to surgical services. The approach to clinical examination, investigation and management of the most common conditions is described. PMID- 29148190 TI - Acute worsening of chronic abdominal pain and vomiting in an adolescent girl. PMID- 29148191 TI - Mitigating clinician and community concerns about children's flatfeet, intoeing gait, knock knees or bow legs. PMID- 29148192 TI - Acute worsening of chronic abdominal pain and vomiting in an adolescent girl. PMID- 29148193 TI - The treatment of pyloric stenosis: Evolution in practice. AB - Over the last hundred years, idiopathic hypertrophic pyloric stenosis has undergone an evolution in treatment, with subsequent improvements in outcome. Initially, it was treated by physicians with antispasmodics and various alternative feeding and resuscitation modalities. The evolution of surgical approaches led to a revolution in outcome, from almost certain death to complete cure. The progression of surgical and medical treatments is reviewed in this article until, ultimately, Ramstedt's pyloromyotomy is reached. This distilled operation has remained the gold-standard procedure for over a century. PMID- 29148194 TI - A newborn with a wrinkled abdominal wall. PMID- 29148195 TI - A newborn with abdominal distension. PMID- 29148196 TI - Umbilicus and its extensive clinical repertoire. AB - The umbilicus is involved in a wide range of abnormalities in infants and children. The most severe are evident at birth and include exomphalos (omphalocele) and gastroschisis, both of which can be life-threatening but are easy to diagnose. Exomphalos is often associated with other congenital abnormalities, whereas the associated problems in gastroschisis are largely confined to the gut. Infection of the umbilicus in the neonate presents as omphalitis. The causes of a moist umbilicus following separation of the umbilical stump are multiple, from the relatively minor umbilical granuloma or ectopic bowel mucosa to the more significant patent urachus that leaks urine. Patency of the entire vitello-intestinal (omphalomesenteric) tract allows air and faecal fluid to drain through the umbilicus. The clinical manifestations of persistence of the vitello-intestinal tract vary markedly according to which part remains: clinical presentations include melaena and anaemia, closed-loop bowel obstruction and Meckel diverticulitis. An umbilical hernia occurs when the umbilical cicatrix fails to close. On the other hand, the umbilicus has its uses, which range from being a route for intravenous access in the neonate to being a convenient point of access in laparoscopic surgery. PMID- 29148197 TI - Why surgery matters for paediatricians. PMID- 29148198 TI - Ear, nose and throat surgery: All you need to know about the surgical approach to the management of middle-ear effusions in Australian Indigenous and non Indigenous children. AB - Otitis media (OM) is a common condition in Australia. It represents a spectrum of diseases from otitis media with effusion (OME) to chronic suppurative otitis media. For all the OM diagnoses, Australian Indigenous children have higher rates of early onset, severe and persistent disease. OME is the most common form of OM and often occurs after an upper respiratory tract infection. It can be difficult to diagnose (and often goes unrecognised). Hearing loss is the most important complication. The middle-ear effusion impedes the movement of the tympanic membrane and causes a conductive hearing loss of around 25 dB. Around 20% will have a hearing loss exceeding 35 dB. Children with early onset, persistent, bilateral OME and hearing loss (or speech delay) are most likely to benefit from interventions. However, the impact of all the effective treatment options is modest. Giving advice about effective communication strategies for young children is always appropriate. The best evidence from randomised trials supports not using antihistamines and/or decongestants, considering a trial of antibiotics and referral for tympanostomy tubes. Despite the availability of evidence-based guidelines, giving advice about treatment is a challenge because recommendations vary according to condition, age, risk of complications and parental preference. While most children with OME can be effectively managed in primary care, we need to get children who meet the criteria for simple ear, nose and throat procedures that improve hearing on to ear, nose and throat surgery waiting lists. Long delays in hearing support may contribute to life-long social and economic disadvantage. PMID- 29148199 TI - Five lessons in uncomplicated appendicitis: Can we remove the surgery? AB - Appendicectomy has remained the treatment of choice for appendicitis for over a century and is the most commonly performed emergency operation in children. However, emerging evidence suggests that appendicectomy may not always be necessary in uncomplicated appendicitis, with early paediatric trials demonstrating that antibiotic-only therapy can be safe and effective. Further rigorously designed and appropriately powered studies are necessarily to establish the place of non-operative management of uncomplicated appendicitis in the future. PMID- 29148200 TI - Women in paediatric surgery. PMID- 29148201 TI - Current perspectives on the role of tonsillectomy. AB - Tonsillectomy is one of the most common paediatric surgical procedures performed in Australasia. The aim of this paper is to provide an up-to-date review of the indications for the procedure (and the evidence base for each of these indications), as well as describe the surgical technique and perioperative management and risks for a non-surgical audience. The primary indications for tonsillectomy are obstructive sleep apnoea (OSA) (where it is most commonly performed in association with adenoidectomy) and recurrent pharyngotonsillitis. There is now high-quality evidence that tonsillectomy improves objective measures of OSA on sleep studies, as well as quality of life and child behaviour. The impact of surgery on cognitive function is less well delineated. For recurrent pharyngotonsillitis, tonsillectomy has a modest impact on recurrent sore throat symptoms - clinicians should ensure an appropriate pre-operative observation period and adequately discuss the potential benefits with parents prior to surgery. Traditional approaches to tonsillectomy involve surgically dissecting the entire tonsil from the underlying pharyngeal muscle. Subtotal tonsillectomy (intracapsular tonsillectomy or tonsillotomy) is described for OSA and may reduce perioperative morbidity. Children younger than 3 years and those with moderate to severe OSA or significant comorbidities should be admitted for overnight observation. Simple analgesia is adequate for most patients postoperatively. Codeine is contraindicated due to reports of postoperative death due to respiratory suppression. Overall, tonsillectomy is a well-tolerated procedure, with pain and postoperative haemorrhage (2-4%) being the most common complications. Haemorrhage can be life threatening; however, the mortality rate remains very small at approximately 1:30 000. PMID- 29148202 TI - Common paediatric conditions of the lower limb. AB - Growing children are susceptible to a number of disorders to their lower extremities of varying degrees of severity. The diagnosis and management of these conditions can be challenging. With musculoskeletal symptoms being one of the leading reasons for visits to general practitioners, a working knowledge of the basics of these disorders can help in the appropriate diagnosis, treatment, counselling, and specialist referral. This review covers common disorders affecting the hip, the knee and the foot. The aim is to assist general practitioners in recognising developmental norms and differentiating physiological from pathological conditions and to identify when a specialist referral is necessary. PMID- 29148203 TI - The 'ins' and 'outs' of intussusception: Where best practice reduces the need for surgery. AB - Intussusception may be difficult to diagnose because the classical triad of symptoms is evident at the time of presentation in only about 20% of cases. This may lead to delays in making the correct diagnosis. The most common presenting features are colicky abdominal pain, vomiting, pallor, lethargy and listlessness. In recent years, the algorithms of management of intussusception have changed significantly: a routine plain abdominal X-ray has been replaced by ultrasonography, previously perceived contraindications to attempting an enema reduction no longer apply, gas has largely replaced barium for enema reduction, incomplete initial reduction is an indication for a delayed repeat enema if the child is stable clinically and partial reduction has been achieved, the indications for surgery have been tightened and laparoscopy affords an alternative surgical approach. This commentary expands on the rationale behind some of the recent advances in the management of children who present with suspected intussusception. PMID- 29148205 TI - Inhaled corticosteroids and the risks of low-energy fractures in patients with chronic airway diseases: A propensity score matched study. AB - BACKGROUND AND AIMS: Inhaled corticosteroids (ICSs) are crucial anti-inflammatory medications for chronic airway diseases. Studies investigating the relationship between ICSs and fractures in Asian populations are scant. We investigated whether ICSs increased the risk of low-energy fractures in patients with chronic airway diseases. METHODS: We used the Longitudinal Health Insurance Database to select patients aged 20 years and older with chronic airway diseases (asthma and COPD) between 2000 and 2011 as the base cohort. We identified ICS users and ICS non-users matched by propensity score method at 1:1 ratio. Cox proportional hazard regression models were used to calculate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for factors associated with the risk of fracture. RESULTS: A total of 1,182 ICS users and 1,182 controls were enrolled. After adjustment for age, gender, annual exacerbation number of acute respiratory events, comorbidity and medications, the risk of fracture was 1.10 for ICS users (aHR = 1.20; 95% CI = 1.10-1.31) compared with ICS non-users. The ICS users exhibited significantly 1.63-fold risk of hip fracture and 1.24-fold risk of ulna and radius fracture than did the ICS non-users. Patients with medium and high doses of ICS use were associated with significantly increased risks of fracture (aHR = 1.48, 95% CI = 1.25-1.76 for medium dose and aHR = 1.55, 95% CI = 1.39 1.72 for high dose) compared with those in ICS non-users. CONCLUSIONS: Patients with medium and high doses of ICS use are associated with an increased risk of fracture. PMID- 29148204 TI - Genome-wide and Phenome-wide Approaches to Understand Variable Drug Actions in Electronic Health Records. PMID- 29148206 TI - Comparison of valvar and right ventricular function following transcatheter and surgical pulmonary valve replacement. AB - OBJECTIVE: Trans-catheter (TC) pulmonary valve replacement (PVR) has become common practice for patients with right ventricular outflow tract obstruction (RVOTO) and/or pulmonic insufficiency (PI). Our aim was to compare PVR and right ventricular (RV) function of patients who received TC vs surgical PVR. DESIGN: Retrospective review of echocardiograms obtained at three time points: before, immediately after PVR, and most recent. PATIENTS: Sixty-two patients (median age 19 years, median follow-up 25 months) following TC (N = 32) or surgical (N = 30) PVR at Yale-New Haven Hospital were included. OUTCOME MEASURES: Pulmonary valve and right ventricular function before, immediately after, and most recently after PVR. RESULTS: At baseline, the TC group had predominant RVOTO (74% vs 10%, P < .001), and moderate-severe PI was less common (61% vs 100%, P < .001). Immediate post-procedural PVR function was good throughout. At last follow-up, the TC group had preserved valve function, but the surgical group did not (moderate RVOTO: 6% vs 41%, P < .001; >mild PI: 0% vs 24%, P = .003). Patients younger than 17 years at surgical PVR had the highest risk of developing PVR dysfunction, while PVR function in follow-up was similar in adults. Looking at RV size and function, both groups had a decline in RV size following PVR. However, while RV function remained stable in the TC group, there was a transient postoperative decline in the surgical group. CONCLUSIONS: TC PVR in patients age <17 years is associated with better PVR function in follow-up compared to surgical valves. There was a transient decline in RV function following surgical but not TC PVR. TC PVR should therefore be the first choice in children who are considered for PVR, whenever possible. PMID- 29148207 TI - Esthetic Evaluation of Implant-Supported Single Crowns: The Implant Restoration Esthetic Index and Patient Perception. AB - PURPOSE: To test the validity and reliability of a newly developed Implant Restoration Esthetic Index (IREI) and to compare esthetic outcomes reported by patients and professionals. MATERIALS AND METHODS: Ten graduate students and 10 prosthodontists assessed esthetic outcomes of 27 single-tooth implants with the IREI. Six peri-implant soft tissue parameters were measured using visual analog scales: mesial papilla presence, distal papilla presence, gingival trigone, soft tissue curvature, alveolar process deficiency, and soft tissue color and texture, as well as the six crown parameters: crown contour, crown position, crown labial convexity, crown characterization, crown color and translucency, and abutment visibility. The validity was tested based on Pearson's correlation. The internal consistency reliability was analyzed by Cronbach's alpha. Interclass correlation coefficients (ICC) were calculated to express the test-retest reliability and the inter-rater reliability. The correlations between patient and professional evaluations were analyzed by Pearson's correlation. RESULTS: The IREI demonstrated significant correlation (p < 0.05) to the pink esthetic score and white esthetic score (PES/WES). The internal consistency reliability showed a Cronbach's Alpha of 0.830. The test-retest reliability was excellent in both the graduate student group and the prosthodontist group, with ICCs of 0.961 and 0.952, respectively (p < 0.05). The inter-rater reliability was acceptable, with ICCs of 0.649 and 0.667, respectively (p < 0.05). Low correlation coefficients were found between patient and professional evaluations. CONCLUSIONS: The results of this study indicated that the IREI was considered a valid and reliable index involving sufficient parameters for professional esthetic evaluation of single tooth implant restorations. The patient-reported esthetic outcomes had poor or no significant correlation to professional-reported outcomes. PMID- 29148208 TI - Comparison of long-term outcome in anthracycline-related versus idiopathic dilated cardiomyopathy: a single centre experience. AB - AIMS: Cardiac dysfunction is a severe complication of anthracycline-containing anticancer therapy. The outcome of anthracycline-induced cardiomyopathy (AICM) compared with other non-ischaemic causes of heart failure (HF), such as idiopathic dilated cardiomyopathy (IDCM), is unresolved. The aim of this study was to compare the survival of AICM patients with an IDCM cohort followed at our centre from 1990 to 2016. METHODS AND RESULTS: We included 67 patients (67% female, 50 +/- 15 years) with AICM, defined as onset of otherwise unexplained left ventricular ejection fraction (LVEF) <=50% following anthracycline therapy, and 488 IDCM patients (28% female, 55 +/- 12 years). Patients were followed with constantly optimized HF therapy, for 7.6 +/- 5.5 and 8.1 +/- 5.5 years, respectively. In both cohorts, 25% of patients reached the combined endpoint of death/heart transplantation. Overall survival rates at 5 and 10 years were similar (AICM: 86% and 61%, IDCM: 88% and 75%; P = 0.61), and so was cardiovascular survival (AICM: 91% and 76%, IDCM: 91% and 80%; P = 0.373), also after 1:1 propensity matching (P = 0.27) and adjusting for age, LVEF and left ventricular size. A trend toward higher all-cause mortality was present in AICM patients [hazard ratio (HR) 1.67, 95% confidence interval (CI) 0.95-2.92, P = 0.076]. No differences were observed between AICM and IDCM with regard to pharmacological HF therapy, but AICM patients were less likely to receive devices (13% vs. 41.8% in IDCM, P < 0.001). CONCLUSION: Cardiovascular mortality in patients with AICM did not differ from that of a matched IDCM cohort, despite cancer-related morbidity and less prevalent use of devices. These data suggest that patients with AICM should be treated with appropriate guideline-directed medical therapies similar to other non-ischaemic dilated cardiomyopathies. PMID- 29148209 TI - Telocytes in the human sinoatrial node. AB - The sinoatrial node (SAN) is composed mostly of pacemaker, transitional and Purkinje-like cells. Pacemaker cells, especially in the centre of the SAN, are surrounded by dense fibrous tissue and do not have any contact with transitional cells. We hypothesize that the SAN contains telocytes that have contacts with pacemaker cells and contractile myocardium. Immunohistochemistry using antibodies against HCN4 and antibody combinations against CD34 and HCN4 was carried out on 12 specimens. Confocal laser scanning microscopy (CLSM) with two mixtures of primary antibodies, namely CD34/S100 and vimentin/S100, was performed in three cases. In two cases, CLSM was carried out with CD117 antibody. Specimens for electron microscopy and immunocytochemistry with HCN4 immunogold labelling were taken from another three patients. In our study, we found cells with the immunophenotype of telocytes in the SAN. There were twice as many of these cells in the centre of the SAN as in the periphery (20.3 +/- 4.8 versus 10.8 +/- 4.4 per high-power field). They had close contact with pacemaker cells and contractile cardiomyocytes and expressed HCN4. The ultrastructural characteristics of these cells are identical to those of telocytes observed earlier in other organs. Our study provides evidence that telocytes are present in the SAN. PMID- 29148210 TI - Factors associated with continued smoking after treatment of oral cavity cancer: An age and survival time-matched study. AB - AIMS: The aims of this study of people with oral cavity cancer were to compare the social support, depression, nicotine dependence, physical function and social emotional function of those who continued smoking with those who quit smoking, by matching age and survival time and to identify the predictors of continued smoking during the survival period. BACKGROUND: People who continue to smoke after cancer treatment may have an impact on treatment response and survival. DESIGN: A cross-sectional survey was conducted. METHODS: This study compared 92 people with oral cavity cancer who continued smoking with 92 people who quit smoking, with matching for age and survival time between January 2015 - November 2015. Conditional logistic regression analysis was used to compare the two groups. RESULTS: The quit smoking group had significantly more social support, less depression and greater social-emotional function than the continued smoking group. People who were unmarried, received surgery without reconstruction, had poor social support and had poor social-emotional function were more likely to continue smoking. CONCLUSIONS: People with oral cavity cancer were more likely to continue smoking after the treatment if they had low social support, depression, greater nicotine dependence and poor social-emotional function. Healthcare professionals should pay more attention to social support, psychological status and nicotine dependence of people who were treated for oral cavity cancer. PMID- 29148211 TI - Effect of Tetrahydrofuran on the Solubilization and Depolymerization of Cellulose in a Biphasic System. AB - The dissolution of cellulose from biomass is a crucial but complicated issue for maximizing the utilization of biomass resources to produce valuable chemicals, because of the extreme insolubility of cellulose. A biphasic NaCl-H2 O tetrahydrofuran (THF) system was studied, in which most of the pure microcrystalline cellulose (M-cellulose, 96.6 % conversion at 220 degrees C) and that contained in actual biomass were converted. Nearly half of the O6-H???O3 intermolecular hydrogen bonds could be broken by THF in the H2 O-THF co-solvent system, whereas the cleavage of O2-H???O6 intramolecular hydrogen bonds by H2 O was significantly inhibited. In the NaCl-H2 O-THF system, THF could significantly promote the effects of both H2 O and NaCl on the disruption of O2-H???O6 and O3 H???O5 intramolecular hydrogen bonds, respectively. In addition, THF could protect and transfer the cellulose-derived products to the organic phase by forming hydrogen bonds between the oxygen atom in THF and the hydrogen atom of C4 OH in the glucose or aldehyde group in 5-hydroxymethylfurfural (HMF), which can lead more NaCl to combine with the -OH of M-cellulose and further disrupt hydrogen bonding in M-cellulose, thereby improving the yield of small molecular weight products (especially HMF) and further promoting the dissolution of cellulose. As a cheap and reusable system, NaCl-H2 O-THF system may be a promising approach for the dissolution and further conversion of cellulose in lignocellulosic biomass without any enzymes, ionic liquids, or conventional catalysts. PMID- 29148212 TI - Flexible, Stretchable, and Transparent Planar Microsupercapacitors Based on 3D Porous Laser-Induced Graphene. AB - The graphene with 3D porous network structure is directly laser-induced on polyimide sheets at room temperature in ambient environment by an inexpensive and one-step method, then transferred to silicon rubber substrate to obtain highly stretchable, transparent, and flexible electrode of the all-solid-state planar microsupercapacitors. The electrochemical capacitance properties of the graphene electrodes are further enhanced by nitrogen doping and with conductive poly(3,4 ethylenedioxythiophene) coating. With excellent flexibility, stretchability, and capacitance properties, the planar microsupercapacitors present a great potential in fashionable and comfortable designs for wearable electronics. PMID- 29148213 TI - Dynamic expiratory CT: An effective non-invasive diagnostic exam for fragile children with suspected tracheo-bronchomalacia. AB - BACKGROUND: Tracheobronchomalacia, defined as variable collapse of the airways, has been recognized as an important cause of respiratory morbidity but still widely underdiagnosed. Bronchoscopy is still considered as the gold standard, but numerous limitations are known, especially for fragile sick children. Moreover, information on parenchymal lung disease cannot be described. There is a real need for a reliable, non-invasive test to help detection of airway and parenchymal malformations in children, specifically when bronchoscopy cannot be performed. METHODS AND RESULTS: 34 paediatric patients underwent cine multidector CT for ongoing respiratory symptoms and were included. All CT images were of good quality and sedation was never needed. Airway disease such as trachea broncomalacia with/without stenosis was described in 53% with the first being more frequent. Bronchomalacia alone was described in 10 patients and in 4 patients was associated with tracheomalacia. Moreover, CT allowed identification of parenchymal disease in 10 patients. Airways stenosis alone was detected in seven patients. The majority of patients (85%) underwent also bronchoscopy for clinical decision. The agreement between CT and bronchoscopy was explored. The two examinations did not agree only in two cases. CT dynamic showed an excellent sensitivity of 100% (81.47-100 %), a great specificity of 82% (48.22-97.72 %), NPV 100%, and PPV 90% (72-96.9 %). CONCLUSION: Dynamic CT results an effective and highly sensitive diagnostic exam for children with tracheo-bronchomalacia. CT is especially indicated for those small and fragile patients that cannot undergo an invasive investigation. Moreover, CT allows a detailed evaluation both of the airways and the lungs which is useful for the clinical management. PMID- 29148214 TI - Does cross-acclimation between drought and freezing stress persist over ecologically relevant time spans? A test using the grass Poa pratensis. AB - Despite evidence that prior exposure to drought can increase subsequent plant freezing tolerance, few studies have explored such interactions over ecologically relevant time spans. We examined the combined effects of drought and subsequent freezing on tiller growth and leaf sugar concentrations in the grass, Poa pratensis. We exposed tillers to no drought (-0.04 MPa), moderate drought (-0.19 MPa) or severe drought (-0.42 MPa) for 3 weeks in summer. Tillers were then frozen in autumn or spring at -5 degrees C (frost damage) or at 0 degrees C (control) for 3 days and harvested after a re-growth period. For shoot growth, there was a significant interaction between drought and autumn freezing, whereby the relative effect of freezing on growth was least for the plants previously exposed to severe drought; however, there was no significant interaction between drought and spring freezing. For root growth, there were no significant interactions between drought and freezing in either season. Leaf sugar concentrations increased significantly with drought intensity, but these effects dissipated within a month, prior to the onset of the autumn freezing treatment. Overall, our results suggest that interactions between prior drought and subsequent freezing in P. pratensis may be most relevant in the context of autumn freezing, and despite the important role of soluble sugars in increasing both drought and freezing tolerance in this species, the retention of these compounds after drought stress does not appear to explain the occurrence of drought-frost interactions at ecologically relevant time scales. PMID- 29148215 TI - The use of ultrasound for the estimation of muscle mass: one site fits most? PMID- 29148216 TI - Reproductive and neurobehavioral effects of maternal exposure to ethiprole in F1 generation mice. AB - BACKGROUND: Few published studies are reported for neurobehavioral toxicity of the phenylpyrazole insecticide ethiprole in mammals. This study was designed to evaluate the reproductive and neurobehavioral effects of maternal exposure to ethiprole in mice. METHODS: Ethiprole was given in the diet to provide levels of 0 (control), 0.0002, 0.001, and 0.005% during the gestation and lactation periods. Selected reproductive and neurobehavioral parameters were measured in the F1 generation. RESULTS: No adverse effect of ethiprole was observed in litter size, litter weight, or sex ratio at birth. The average body weight of male and female offspring was increased significantly in treatment groups at postnatal day (PND) 21. With respect to behavioral developmental parameters, the time of olfactory orientation on PND 14 of male offspring was accelerated significantly in the high-dose group. For movement activity of exploratory behavior of female offspring in the F1 generation, number of horizontal activities increased significantly in the high-dose group and the average speed declined significantly in all treatment groups. After weaning, the rearing time and the average time of rearing lengthened in a significant dose-related trend in adult males and females of the F1 generation. Spontaneous behavior examination indicated that total distance and rearing time increased in the high-dose group, and number of horizontal activities and movement time decreased in a significant dose-related trend through 120 min in the F1 -generation females. CONCLUSIONS: The high-dose level of ethiprole in the present study produced several adverse effects in neurobehavioral parameters after weaning without administration in mice. PMID- 29148217 TI - Factors contributing to managerial competence of first-line nurse managers: A systematic review. AB - AIMS: To determine the factors contributing to managerial competence of first line nurse managers. BACKGROUND: Understanding factors affecting managerial competence of nurse managers remains important to increase the performance of organizations; however, there is sparse research examining factors that influence managerial competence of first-line nurse managers. DESIGN: Systematic review. DATA SOURCES: The search strategy was conducted from April to July 2017 that included 6 electronic databases: Science Direct, PROQUEST Dissertations and Theses, MEDLINE, CINAHL, EMBASE, and Google Scholar for the years 2000 to 2017 with full text in English. Quantitative and qualitative research papers that examined relationships among managerial competence and antecedent factors were included. REVIEW METHODS: Quality assessment, data extractions, and analysis were completed on all included studies. Content analysis was used to categorize factors into themes. RESULTS: Eighteen influencing factors were examined and categorized into 3 themes-organizational factors, characteristics and personality traits of individual managers, and role factors. CONCLUSION: Findings suggest that managerial competence of first-line nurse managers is multifactorial. Further research is needed to develop strategies to develop managerial competence of first-line nurse managers. PMID- 29148218 TI - New solutions to reduce wrong route medication errors. AB - Wrong route medication errors due to tubing misconnections are potentially life threatening complications that have been made possible by the universal use of the Luer connector. The new International Organization of Standardization standards for small bore connectors, ISO 80369 series, have been developed to reduce the risk of these types of erroneous connections. Tubing connectors for different routes of clinical application will contain differently designed connectors that are physically incompatible. However, design and manufacturing standards have progressed slowly, and clinical roll-outs have been delayed, despite the implementation of California laws to promote their use. We are currently in a state of transition where new connectors for enteral and neuraxial use will be entering the clinical market in the next few years, and increasing use will identify additional patient safety concerns. PMID- 29148219 TI - Breaking free from vascular confinement: status and prospects for submicron ultrasound contrast agents. AB - The development of encapsulated microbubbles (~1-6 MUm) has expanded the utility of ultrasound from soft tissue anatomical imaging to not only functional intravascular imaging, but therapeutic interventions, with compelling studies of elicited biological effects. The large diameter of these bubbles has confined their utility to the vasculature, but converging interdisciplinary research pathways are giving rise to new submicron ultrasound contrast agents capable of extending their effects beyond the vascular compartment. This article reviews the status and prospects of exogenous agents including nanobubbles, echogenic liposomes, gas vesicles, cavitation seeds, and nanodroplets, and assesses outstanding criticisms preventing their advance. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Emerging Technologies. PMID- 29148221 TI - Meningeal and vestibulocochlear nerve enhancement in neuromyelitis optica. PMID- 29148222 TI - Intracranial elastance and idiopathic intracranial hypertension? PMID- 29148223 TI - Relative leucopenia and hemolytic anemia following infusion of immunoglobulin. PMID- 29148225 TI - On the generalizability of post-stroke proportional recovery. PMID- 29148224 TI - Functional freezing. PMID- 29148226 TI - Gerstmann-Straussler-Scheinker disease with PRNP P102L heterozygous mutation presenting as progressive myoclonus epilepsy. PMID- 29148227 TI - Age and ejection fraction modify the impact of atrial fibrillation on acute heart failure outcomes. PMID- 29148229 TI - Proteomics of Diabetes, Obesity, and Related Disorders. PMID- 29148228 TI - Evaluation of markers out of the steroid profile for the screening of testosterone misuse. Part I: Transdermal administration. AB - Although the introduction by the World Anti-Doping Agency (WADA) of the steroid module of the athlete biological passport (ABP) marked an important step forward in the screening of testosterone (T) misuse, it still remains one of the most difficult challenges in doping control analysis. The urinary determination of alternative markers has been recently reported as a promising tool for improving the screening of T oral administration. However, their evaluation for other, commonly used, administration routes is still required. The main goal of this study is the evaluation of the potential of 2 groups of metabolites (cysteinyl conjugated and glucuronoconjugated) after transdermal and intramuscular administration of T. Their suitability was evaluated in individuals with both low basal (L-T/E) and medium basal (M-T/E) values of T/E. In this Part I, we evaluated the urinary excretion profile of these 2 groups of T metabolites after the administration of 3 doses of T gel to 12 volunteers (6 L-T/E and 6 M-T/E) for 3 consecutive days. For this purpose, 9 different concentration ratios (5 cysteinyl conjugated and 4 glucuronoconjugated markers) were studied. Both, the intra-individual variability and the detection windows (DW) obtained by each ratio were evaluated. Cysteinyl conjugates showed a general low intra-individual variability and DWs that were shorter than any other tested marker. Despite the relatively large intra-individual variability, the DWs reached by glucuronoconjugates (2-3 days) were similar to those obtained by markers currently included in the ABP. Overall; this evaluation advises for the introduction of additional glucuronoconjugated markers in the screening of transdermal T administration. PMID- 29148230 TI - Personality traits such as neuroticism and disability predict psychological distress in medically unexplained symptoms: A three-year experience from a single centre. AB - BACKGROUND: People with medically unexplained symptoms (MUS) may have psychological co-morbidities. AIMS: Our objectives were to assess the rates and identify correlates of psychological distress in MUS. METHODS: A total of 171 subjects with MUS seeking treatment at a tertiary care facility were assessed over a 3-year period. Psychological distress was assessed using the Tamil version of General Health Questionnaire-12. Apart from socio-demographic factors, personality, coping, perceived social support and subjective disability were assessed using standard instruments. RESULTS: Ninety subjects (52.6%) endorsed symptoms of psychological distress. MUS subjects with psychological distress reported higher levels of neuroticism (p < 0.001), lower extraversion (p < 0.001), lower perceived social support (p = 0.002), higher disability (p < 0.001), lower problem focused engagement (p = 0.378) and higher emotion focused engagement (p = 0.009). In multivariate analysis, high neuroticism scores (odds ratio 1.579, 95% CI 1.108 to 2.251) and high disability (odds ratio 1.302, 95% CI 1.147 to 1.478) emerged as independent predictors of psychological distress in MUS. CONCLUSION: More than half of subjects with MUS have associated psychological distress. High levels of neuroticism and disability are potential markers of psychological distress in MUS. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29148231 TI - Employment status at time of first hospitalization for heart failure is associated with a higher risk of death and rehospitalization for heart failure. AB - AIMS: Employment status at time of first heart failure (HF) hospitalization may be an indicator of both self-perceived and objective health status. In this study, we examined the association between employment status and the risk of all cause mortality and recurrent HF hospitalization in a nationwide cohort of patients with HF. METHODS AND RESULTS: We identified all patients of working age (18-60 years) with a first HF hospitalization in the period 1997-2015 in Denmark, categorized according to whether or not they were part of the workforce at time of the index admission. The primary outcome was death from any cause and the secondary outcome was readmission for HF. Cumulative incidence curves, binomial regression and Cox regression models were used to assess outcomes. Of 25 571 patients with a first hospitalization for HF, 15 428 (60%) were part of the workforce at baseline. Patients in the workforce were significantly younger (53 vs. 55 years) more likely to be male (75% vs 64%) and less likely to have diabetes (13% vs 22%) and chronic obstructive pulmonary disease (5% vs 10%) (all P < 0.0001). Not being part of the workforce was associated with a significantly higher risk of death [hazard ratio (HR) 1.59; 95% confidence interval (CI) 1.50 1.68] and rehospitalization for HF (HR 1.09; 95% CI 1.05-1.14), in analyses adjusted for age, sex, co-morbidities, education level, calendar time, and duration of first HF hospitalization. CONCLUSION: Not being part of the workforce at time of first HF hospitalization was independently associated with increased mortality and recurrent HF hospitalization. PMID- 29148233 TI - Pd-Catalyzed beta-C(sp3 )-H Arylation of Propionic Acid and Related Aliphatic Acids. AB - A generally applicable Pd-catalyzed protocol for the beta-C(sp3 )-H arylation of propionic acid and related alpha-branched aliphatic acids is reported. Enabled by the use of N-acetyl-beta-alanine as ligand our protocol delivers a broad range of arylation products. Notably, the highly challenging substrate, propionic acid, which lacks any acceleration through the Thorpe-Ingold effect, can be employed as substrate with synthetically useful yields. Furthermore, the scalability and synthetic applicability of the protocol are demonstrated. PMID- 29148232 TI - Disulfiram combined with copper inhibits metastasis and epithelial-mesenchymal transition in hepatocellular carcinoma through the NF-kappaB and TGF-beta pathways. AB - Late-stage hepatocellular carcinoma (HCC) usually has a low survival rate because of the high risk of metastases and the lack of an effective cure. Disulfiram (DSF) has copper (Cu)-dependent anticancer properties in vitro and in vivo. The present work aims to explore the anti-metastasis effects and molecular mechanisms of DSF/Cu on HCC cells both in vitro and in vivo. The results showed that DSF inhibited the proliferation, migration and invasion of HCC cells. Cu improved the anti-metastatic activity of DSF, while Cu alone had no effect. Furthermore, DSF/Cu inhibited both NF-kappaB and TGF-beta signalling, including the nuclear translocation of NF-kappaB subunits and the expression of Smad4, leading to down regulation of Snail and Slug, which contributed to phenotype epithelial mesenchymal transition (EMT). Finally, DSF/Cu inhibited the lung metastasis of Hep3B cells not only in a subcutaneous tumour model but also in an orthotopic liver metastasis assay. These results indicated that DSF/Cu suppressed the metastasis and EMT of hepatic carcinoma through NF-kappaB and TGF-beta signalling. Our study indicates the potential of DSF/Cu for therapeutic use. PMID- 29148234 TI - Visible-Light-Mediated Metal-Free Hydrosilylation of Alkenes through Selective Hydrogen Atom Transfer for Si-H Activation. AB - Although there has been significant progress in the development of transition metal-catalyzed hydrosilylations of alkenes over the past several decades, metal free hydrosilylation is still rare and highly desirable. Herein, we report a convenient visible-light-driven metal-free hydrosilylation of both electron deficient and electron-rich alkenes that proceeds through selective hydrogen atom transfer for Si-H activation. The synergistic combination of the organophotoredox catalyst 4CzIPN with quinuclidin-3-yl acetate enabled the hydrosilylation of electron-deficient alkenes by selective Si-H activation while the hydrosilylation of electron-rich alkenes was achieved by merging photoredox and polarity-reversal catalysis. PMID- 29148235 TI - Assessment of interleukin-1beta, interleukin-6, and tumor necrosis factor-Alpha levels in the peri-implant sulcular fluid among waterpipe (narghile) smokers and never-smokers with peri-implantitis. AB - BACKGROUND: It is hypothesized that levels of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha are significantly higher in the peri-implant sulcular fluid (PISF) of waterpipe-smokers (WS) compared with never-smokers with peri-implantitis. PURPOSE: The aim of the present convenience sample case-control study was to compare the levels of IL-6, IL-1beta, and TNF-alpha in the PISF of WS and never-smokers with peri-implantitis. MATERIALS AND METHODS: Demographic data was collected using a questionnaire. Peri-implant probing depth (PPD) was measured and crestal bone loss (CBL) was measured on digital bitewing radiographs. PISF samples were collected using paper strips and the collected PISF volume was determined. levels of IL-6, IL-1beta, and TNF-alpha were measured using enzyme linked immunosorbent assay. Study sample-size was estimated and statistical analysis was performed. P values less than .05 were considered statistically significant. RESULTS: Sixty-six individuals (33 individuals in group-1 and 33 in group-2) were included. In groups 1 and 2, 41 and 44 implants, respectively were placed. The mean total PPD (P < .001) and peri-implant CBL (P < .001) was statistically significantly higher around implants affected by peri implantitis in group-1 compared with group-2. The PISF volume (P < .05) collected and levels of IL-1beta (P < .01), IL-6 (P < .01), and TNF-alpha (P < .01) were statistically significantly higher among individuals in group-1 compared with group-2. CONCLUSION: WS with peri-implantitis present increased expression of local proinflammatory cytokines in the PISF than never-smokers. PMID- 29148236 TI - Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synaptic dysfunction and accumulation of abnormal aggregates formed by amyloid beta peptides or phosphorylated tau proteins. Accumulating evidence suggests that alterations in the buffering capacity of the proteostasis network are a salient feature of AD. The endoplasmic reticulum (ER) is the main compartment involved in protein folding and secretion and is drastically affected in AD neurons. ER stress triggers the activation of the unfolded protein response (UPR), a signal transduction pathway that enforces adaptive programs to recover homeostasis or trigger apoptosis of irreversibly damaged cells. Experimental manipulation of specific UPR signaling modules in preclinical models of AD has revealed a key role of this pathway in regulating protein misfolding and neurodegeneration. Recent studies suggest that the UPR also influences synaptic plasticity and memory through ER stress-independent mechanisms. Consequently, targeting of the UPR in AD is emerging as an interesting therapeutic approach to modify the two pillars of AD, protein misfolding and synaptic failure. Here, we review the functional role of ER stress signaling in AD, discussing the complex involvement of the pathway in controlling neuronal survival, the amyloid cascade, neurodegeneration and synaptic function. Recent intervention efforts to target the UPR with pharmacological and gene therapy strategies are also discussed. PMID- 29148238 TI - Use of Resin-Based Provisional Material to Create the Posterior Palatal Seal in Complete Denture Definitive Impressions. AB - The purpose of this article was to present an alternative procedure using resin based provisional material to create the posterior palatal seal (PPS). This method offers more practicality in clinical routine and increased control for addition of material to create the PPS when compared to traditional techniques such as the use of impression wax. PMID- 29148237 TI - Supraclavicular flap repair in the free flap era. AB - BACKGROUND: Supraclavicular flap (SCF) repair is widely reported in head and neck surgery in select patients and defects. The authors' objective is to present our series of 30 patients who underwent SCF repair for varying defects and to review the scope and outcome of SCF repair in the literature. METHODS: The authors contributed primary evidence of 30 cases of SCF repair. Our outcomes are compared with those reported in the last 5 years' literature; 33 articles published between January 2012 and January 2017 that present original clinical experience of 528 SCFs. RESULTS: SCF is suitable for a wide variety of oral cavity, pharyngeal, skull base and cutaneous defects. Consistent with our experience, SCF is highly reliable even in previously irradiated or dissected necks, so long as the supraclavicular artery is intact. Our case series shows minor complications in 3/30 (10%) and flap loss in 1/30 (3.3%) cases. The literature reports a similar rate of complete flap failure of 3.4% and a slightly higher average minor complication rate of 24.6%. CONCLUSION: We add our experience of 30 cases of SCF repair to the international literature. We experienced a complication rate lower than the reported average, and maintain that the SCF is an excellent reconstructive option in patients with previously irradiated necks or comorbidities that affect microvasculature and anaesthetic resilience. PMID- 29148239 TI - Metabolic Signature of Microvesicles from Umbilical Cord Mesenchymal Stem Cells of Preterm and Term Infants. AB - PURPOSE: Microvesicles (MVs), 200-1000 nm bodies budding from the cell plasma membrane, are a promising source of biomarkers. This study aimed at comparing the proteome of MVs collected by ultracentrifugation from cultured Mesenchymal Stem Cells (MSCs) from Human Umbilical Cord of Preterm newborns (<34-weeks gestational age) in comparison to infants at Term (>=37 weeks). This discovery study was designed to establish the signature of prematurity. EXPERIMENTAL DESIGN: Orbitrap MS, statistical, bioinformatics and biochemical analyses were employed. RESULTS: A total of 3253 proteins were identified, 78.3% matching among Preterm and Term. Principal component dimensional analyses showed that the two proteomes cluster separately. Cytoscape analysis showed that the top gene signatures cluster around inflammation and oxidative metabolism. Both Preterm and Term MVs consumed oxygen, and express ATP synthase and cytochrome oxidase, but only Preterm MVs synthesized ATP. The gene signature of Preterm condition mainly clusters around inflammation and metabolism. CONCLUSION AND CLINICAL RELEVANCE: MVs from MSCs conduct aerobic metabolism similarly to exosomes from the same cells, with interesting differences related to their biogenesis and function. The clinical relevance of the study lays in the perspective to utilize MVs as promising sensor of the inflammatory and metabolic state of the preterm newborn, to help in preventing the complications of prematurity. PMID- 29148240 TI - What can intracoronary pressure measurements tell us about CFR? Now comes pb-CFR. AB - Pressure-bound (pb) coronary flow reserve (CFR) is a novel estimation of CFR, calculated from easily obtained baseline and hyperemic pressure assessment Validation of pb-CFR in previously reported lesions showed accuracy of 84% to CFR with sensitivity of 96% and specificity of 60% FFR >0.75 and low pb-CFR in DEFER was associated with increased angina and complications compared to high pb-CFR and this risk was not modified by elective revascularization. PMID- 29148241 TI - Peri-procedural myocardial infarction: Plaques and patients "at-risk". AB - Patients with acute coronary syndrome are at risk for peri-procedural myocardial infarction (PMI) Lipid-laden plaques with thinned disrupted fibrous caps are most prone to PMI PMI is associated with worse outcome over time, though whether such damaging events are causal or instead reflect patients prone to future instability from non-culprit vulnerable plaques requires further delineation. PMID- 29148242 TI - Infrapopliteal peripheral arterial disease and critical limb ischemia: The time has come for collaborative, streamlined diagnostic, and treatment paradigms. AB - The diagnosis, surveillance, and management of infrapopliteal critical limb ischemia remain inconsistent among clinicians. This study demonstrates that using an absolute ankle pressure of >73 mm Hg or an absolute toe pressure increase of 1 mm Hg or greater post endovascular intervention in patients with infrapopliteal critical limb ischemia may be predictive of a reduction in target limb revascularization, amputation, and death. This study highlights the need for vascular societies to come together to promote standardized screening, surveillance, and treatment paradigms for this complex population. PMID- 29148243 TI - Are new devices required to reduce contrast load in the cath lab, or is behavioral change sufficient? AB - A novel device that diverts a proportion of contrast injected by hand through the manifold can potentially reduce volume of contrast delivered to the patient by almost 50% to reduce risk of contrast-induced nephropathy. Another simple solution to reducing contrast volume is to limit the number of angiographic views and cine runs acquired. A conscious effort by the angiographer to limit the contrast volume to less than the eGFR should be considered. PMID- 29148244 TI - Real life experience with bioresorbable-polymer everolimus-eluting stents. Is this an answer in search of a question? AB - Stent thrombosis and clinically driven restenosis are rare in the era of newer generation DES. The Synergy bioresorbable polymer DES appears to be comparable to other durable polymer and other bioabsorbable polymer DES in terms of safety and efficacy at 1-year post implantation. Further long-term study is needed to determine the specific role of the Synergy stent and other DES with bioabsorbable polymers. PMID- 29148245 TI - A brain-heart team approach to PFO. PMID- 29148246 TI - Impact of Hospital Volume on Long-Term Neurological Outcome in Patients Undergoing Carotid Artery Stenting: A Nationwide Propensity Score-Matched Study. DOI: 10.1002/ccd.26989. PMID- 29148247 TI - Does the severity of left ventricular systolic dysfunction impact outcomes of Mitraclip therapy: How low is too low? AB - Percutaneous mitral valve repair for symptomatic severe mitral regurgitation has rapidly evolved as a viable therapeutic option for high-surgical risk patients. Both randomized clinical studies as well as real world registry data have demonstrated significant improvement in severity of MR and clinical outcomes. In carefully selected patients with severely reduced left ventricular systolic function and severe symptomatic MR, Mitraclip therapy seems to show promise. PMID- 29148248 TI - Recurrent coarctation of aorta after Norwood operation in single ventricle patients; the case of the missing ideal stent. AB - Recurrent coarctation postoperative Norwood is poorly tolerated in single ventricle patients. Although transcatheter balloon angioplasty is considered first line, it often leads to inadequate or non-durable relief of obstruction. Transcatheter stent implantation provides excellent relief of obstruction but necessitates staged redilation to account for somatic growth in children. Stent technology, delivery systems, and procedural techniques will need to evolve to obviate reported adverse events mainly due to patient size. PMID- 29148249 TI - Frailty in nonagenarians: A bridge too far? AB - There is no clear consensus about the definition of frailty and how to accurately measure it. There is accumulating evidence that frail old patients have worse outcomes after TAVR compared to non-frail patients. Further randomized research is needed to confirm those concerns and to standardize the role of frailty assessment in patient selection for TAVR. PMID- 29148250 TI - Ipsilateral shoulder pain in patients following lung resection in the decubitus position. AB - AIMS AND OBJECTIVES: To examine the frequency, influencing factors and clinical course of shoulder pain in patients following lung resection. BACKGROUND: Thoracoscopes have been introduced in the surgical treatment of lung cancer and allow for less invasive surgery with a minimal incision. However, decubitus position-related shoulder pain on the operated side has not yet been investigated. DESIGN: A longitudinal descriptive study. METHODS: Patients who underwent lung resection in the decubitus position. Patients were interviewed 2 days before surgery and once daily for 5 days after surgery. Interview items included background data, the concomitant use of epidural anaesthesia, operative duration, the presence of preoperative shoulder stiffness (excluding shoulder pain), type of surgery and site of operation. The intensity of pain was approximately 5 on an 11-point numerical rating scale. Descriptive statistics on patient backgrounds were obtained using SPSS Statistics 22 for Windows. RESULTS: Of the 74 patients who underwent lung resection in a decubitus position, 30 (40.5%) developed shoulder pain on the operated side. The highest rating occurred 1 day after surgery and decreased over time. The following two factors were found to influence shoulder pain on the operated side: operative duration (Z = -2.63; p = .01) and the presence of preoperative shoulder stiffness (excluding shoulder pain) (chi2 = 4.16; p = .04). CONCLUSIONS: This study demonstrated that approximately 40% of patients who underwent lung resection in the decubitus position developed shoulder pain. RELEVANCE TO CLINICAL PRACTICE: The presence of postoperative shoulder pain was related to both the duration of the operation and to the presence of preoperative shoulder stiffness. Although the shoulder pain resolves within 4 days, it causes the patient additional discomfort and distress. Therefore, further research is needed on positioning for thoracotomy in order to investigate ways to reduce or eliminate this complication of lung surgery. PMID- 29148251 TI - The enzymatic detoxification of the mycotoxin deoxynivalenol: identification of DepA from the DON epimerization pathway. AB - The biological detoxification of mycotoxins, including deoxynivalenol (DON), represents a very promising approach to address the challenging problem of cereal grain contamination. The recent discovery of Devosia mutans 17-2-E-8 (Devosia spp. 17-2-E-8), a bacterial isolate capable of transforming DON to the non-toxic stereoisomer 3-epi-deoxynivalenol, along with earlier reports of bacterial species capable of oxidizing DON to 3-keto-DON, has generated interest in the possible mechanism and enzyme(s) involved. An understanding of these details could pave the way for novel strategies to manage this widely present toxin. It was previously shown that DON epimerization proceeds through a two-step biocatalysis. Significantly, this report describes the identification of the first enzymatic step in this pathway. The enzyme, a dehydrogenase responsible for the selective oxidation of DON at the C3 position, was shown to readily convert DON to 3-keto-DON, a less toxic intermediate in the DON epimerization pathway. Furthermore, this study provides insights into the PQQ dependence of the enzyme. This enzyme may be part of a feasible strategy for DON mitigation within the near future. PMID- 29148252 TI - Sex hormone-binding globulin (SHBG) is a potential early diagnostic biomarker for gastric cancer. AB - The use of blood plasma biomarkers in gastric cancer (GC) management is limited due to a lack of reliable biomarkers. An LC-MS/MS assay and a bioinformatic analysis were performed to identify blood plasma biomarkers in a GC discovery cohort. The data obtained were verified and validated by western blotting and an ELISA in an independent study cohort. A label-free quantification analysis of the MS data using PEAKS7 software found that four plasma proteins of apolipoprotein C 1, gelsolin, sex hormone-binding globulin (SHBG), and complement component C4-A were significantly overexpressed in GC patients. A western blot assay of these plasma proteins showed that only SHBG was consistently overexpressed in the patient group. ELISA measurement of SHBG blood plasma levels confirmed that the patient group had significantly higher SHBG levels than the control group. SHBG levels in the patient group remained significantly higher after being stratified by gender, age, and disease stage. These findings show that LC-MS/MS is powerful and highly sensitive for plasma biomarker discovery, and SHBG could be a potential plasma biomarker for GC management. PMID- 29148253 TI - Quantification of vascular damage in acute kidney injury with fluorine magnetic resonance imaging and spectroscopy. AB - PURPOSE: To design a fluorine MRI/MR spectroscopy approach to quantify renal vascular damage after ischemia-reperfusion injury, and the therapeutic response to antithrombin nanoparticles (NPs) to protect kidney function. METHODS: A total of 53 rats underwent 45 min of bilateral renal artery occlusion and were treated at reperfusion with either plain perfluorocarbon NPs or NPs functionalized with a direct thrombin inhibitor (PPACK:phenyalanine-proline-arginine chloromethylketone). Three hours after reperfusion, kidneys underwent ex vivo fluorine MRI/MR spectroscopy at 4.7 T to quantify the extent and volume of trapped NPs, as an index of vascular damage and ischemia-reperfusion injury. Microscopic evaluation of structural damage and NP trapping in non-reperfused renal segments was performed. Serum creatinine was quantified serially over 7 days. RESULTS: The damaged renal cortico-medullary junction trapped a significant volume of NPs (P = 0.04), which correlated linearly (r = 0.64) with the severity of kidney injury 3 h after reperfusion. Despite global large vessel reperfusion, non-reperfusion in medullary peritubular capillaries was confirmed by MRI and microscopy, indicative of continuing hypoxia due to vascular compromise. Treatment of animals with PPACK NPs after acute kidney injury did not accelerate kidney functional recovery. CONCLUSIONS: Quantification of ischemia-reperfusion injury after acute kidney injury with fluorine MRI/MR spectroscopy of perfluorocarbon NPs objectively depicts the extent and severity of vascular injury and its linear relationship to renal dysfunction. The lack of kidney function improvement after early posttreatment thrombin inhibition confirms the rapid onset of ischemia-reperfusion injury as a consequence of vascular damage and non-reperfusion. The prolongation of medullary ischemia renders cortico medullary tubular structures susceptible to continued necrosis despite restoration of large vessel flow, which suggests limitations to acute interventions after acute kidney injury, designed to interdict renal tubular damage. Magn Reson Med 79:3144-3153, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29148254 TI - Connecting color with assembly in the fluorescent B-phycoerythrin protein complex. AB - Phycoerythrin is the major light-harvesting pigment protein in red algae and is nowadays widely used as a fluorescent probe in biotechnological applications such as flow cytometry and immunofluorescence microscopy. In addition, it has had substantial economic impact due to its potential as a natural food colorant. However, knowledge on the precise molecular composition of phycoerythrin is limited. Here, we use a combination of high-resolution native mass spectrometry (MS) and fluorescence spectroscopy to characterize the assembly properties of the B-phycoerythrin protein complex from Porphyridium cruentum. Our data highlight the stabilizing role of the gamma subunit in the intact B-phycoerythrin protein complex. In addition, by native MS we monitor B-phycoerythrin (dis)assembly intermediates, providing insight into which species contribute to B phycoerythrins color and the factors that give B-phycoerythrin its highly fluorescent properties. Together, the data provide significant insights into the structural properties of B-phycoerythrin which is beneficial for its use within the biotechnology industry. PMID- 29148255 TI - Heart transplantation and left ventricular assist systems. Not too early, not too late. PMID- 29148256 TI - Toward standardization of care: The feeding readiness assessment after congenital cardiac surgery. AB - BACKGROUND: Feeding practices after neonatal and congenital heart surgery are complicated and variable, which may be associated with prolonged hospitalization length of stay (LOS). Systematic assessment of feeding skills after cardiac surgery may earlier identify those likely to have protracted feeding difficulties, which may promote standardization of care. METHODS: Neonates and infants <=3 months old admitted for their first cardiac surgery were retrospectively identified during a 1-year period at a single center. A systematic feeding readiness assessment (FRA) was utilized to score infant feeding skills. FRA scores were assigned immediately prior to surgery and 1, 2, and 3 weeks after surgery. FRA scores were analyzed individually and in combination as predictors of gastrostomy tube (GT) placement prior to hospital discharge by logistic regression. RESULTS: Eighty-six patients met inclusion criteria and 69 patients had complete data to be included in the final model. The mean age of admit was five days and 51% were male. Forty-six percent had single ventricle physiology. Twenty-nine (42%) underwent GT placement. The model containing both immediate presurgical and 1-week postoperative FRA scores was of highest utility in predicting discharge with GT (intercept odds = 10.9, P = .0002; sensitivity 69%, specificity 93%, AUC 0.913). The false positive rate was 7.5%. CONCLUSIONS: In this analysis, systematic and standardized measurements of feeding readiness employed immediately before and one week after congenital cardiac surgery predicted need for GT placement prior to hospital discharge. The FRA score may be used to risk stratify patients based on likelihood of prolonged feeding difficulties, which may further improve standardization of care. PMID- 29148257 TI - Multiscale memory and bioelectric error correction in the cytoplasm-cytoskeleton membrane system. AB - A fundamental aspect of life is the modification of anatomy, physiology, and behavior in the face of changing conditions. This is especially illustrated by the adaptive regulation of growth and form that underlies the ability of most organisms-from single cells to complex large metazoa-to develop, remodel, and regenerate to specific anatomical patterns. What is the relationship of the genome and other cellular components to the robust computations that underlie this remarkable pattern homeostasis? Here we examine the role of constraints defined at the cellular level, especially endogenous bioelectricity, in generating and propagating biological information. We review evidence that the genome is only one of several multi-generational biological memories. Focusing on the cell membrane and cytoplasm, which is physically continuous across all of life in evolutionary timeframes, we characterize the environment as an interstitial space through which messages are passed via bioelectric and biochemical codes. We argue that biological memory is a fundamental phenomenon that cannot be understood at any one scale, and suggest that functional studies of information propagated in non-genomic cellular structures will not only strongly impact evolutionary developmental biology, but will also have implications for regenerative medicine and synthetic bioengineering. WIREs Syst Biol Med 2018, 10:e1410. doi: 10.1002/wsbm.1410 This article is categorized under: Developmental Biology > Stem Cell Biology and Regeneration Physiology > Physiology of Model Organisms Models of Systems Properties and Processes > Cellular Models. PMID- 29148259 TI - Vasovagal reactions in blood donors: risks, prevention and management. AB - This narrative review examines current research on risk factors, prevention methods and management strategies for vasovagal reactions (VVRs) that occur during or as a result of blood donation. VVRs are important to blood collection agencies (BCAs) as they negatively impact the number of completed collections, perceptions of the safety of blood donation and rates of donor return. There has been significant progress in understanding and preventing VVRs in blood donation in recent years, with a multitude of risk factors identified. This has resulted in many BCAs implementing evidence-based strategies, such as donor age and weight restrictions. However, the profile of our most vulnerable donors and features of the donation setting that may protect these donors from experiencing a VVR have not been identified. Furthermore, an increased number of trials of physiological and psychological prevention interventions to reduce both immediate and delayed VVRs have been reported. However, a lack of methodological consistency in operationalising interventions to reduce or prevent VVRs means that the identification of effective VVR prevention strategies remains a challenge for practitioners. Furthermore, research is still required to determine how to successfully implement prevention and management strategies into standard operating procedures within collection centres. Finally, research in the management and mitigation of the effect of VVRs is currently only suggestive of what should be done to care for the donor who reacts and how to empower those donors to return. Collectively, research into these aspects of VVRs will provide support to donors and BCAs and improve the safety of blood donation. PMID- 29148258 TI - Influence of medical insurance schemes and charity assistance projects on regular prophylaxis treatment of the boys with severe haemophilia A in China. AB - OBJECTIVE: To explore the influence of medical insurance policy and charity assistance projects on the uptake and discontinuation of regular prophylaxis treatment in Chinese severe haemophilia A children. METHODOLOGY: This retrospective study was conducted on children with severe haemophilia A, who received FVIII prophylaxis treatment at 12 haemophilia centres in China from 1 November 2007 to 31 May 2013. RESULTS: The average duration of prophylaxis treatment received by haemophilia children significantly increased from 16.7 weeks in 2008 to 32.8 weeks in 2012 (P < .001). The main reason for prophylaxis acceptance included dissatisfaction with previous "on-demand" regimens, availability of improved local medical insurance policies and patient/family awareness of haemophilia. The main reason for subsequent discontinuation of prophylaxis was economic instability. The upper limit of insurance was up to RMB 150 000/y (~USD: 22 000/y) for 80.1% of the insured patients and would be sufficient to cover the continuous low-dose prophylaxis regimen. However, for many patients the burden of out-of-pocket copayment cost represented a risk for poor adherence to regular prophylaxis. In about two third of the patients, the annual out-of-pocket copayment cost amounted to >50% of their average annual disposable income. Many patients therefore required assistance from the charity assistance projects, but nonadherence remained prevalent. CONCLUSION: Medical insurance policy and charity assistance projects helped haemophilia children to accept and continue prophylaxis regimens. It was the proportion of the out-of pocket copayment cost rather than the upper limit of insurance reimbursement that restricted long-term regular low-dose prophylaxis in China. PMID- 29148261 TI - Management of bilateral cataracts when general anaesthesia is required: same-day or different-day surgery? PMID- 29148260 TI - Peri-implant parameters and C-reactive protein levels among patients with different obesity levels. AB - BACKGROUND: It is hypothesized that peri-implant conditions are worse with increasing severity of obesity, because systemic low-grade inflammatory marker (C reactive protein [CRP]) is higher in severe form of obese individuals. PURPOSE: The aim of the cross-sectional retrospective study was to compare clinical and radiographic peri-implant inflammatory parameters in patients with different levels of obesity and correlate these parameters with CRP levels. MATERIALS AND METHODS: Eighty-four patients who participated in this study were divided into 4 groups: class I obese (group 1), class II obese (group 2), class III obese (group 3), and nonobese individuals (group 4) were included. Clinical (plaque index [PI], bleeding on probing [BOP], probing depth [PD]) and radiographic (marginal bone loss [MBL]) peri-implant parameters were recorded. Serum CRP were quantified using enzyme-linked immunosorbent assay (ELISA). Clinical peri-implant parameters and serum CRP concentrations were analyzed using 1-way analysis of variance. The Pearson correlation coefficient was used to analyze correlations of CRP levels with any of the clinical and radiographic parameters assessed. RESULTS: Peri implant PI, BOP, PD, and MBL were significantly higher in group-1, -2, and -3 patients as compared to nonobese individuals (P < .05). Peri-implant PI, BOP, PD, and MBL were significantly higher in obese patients of group-2 and group-3 as compared to obese patients in group-1 (P < .01). Mean PI, BOP, PD, and MBL were comparable between group-2 and group-3 patients (P > .05). A significant positive correlations were found between CRP levels and BOP (P = .0148) and PD (P = .0425); and significant negative correlation was found for MBL in group 3, respectively (P = .0212). CONCLUSION: Clinical and radiographic peri-implant inflammatory parameters and serum CRP were significantly high in patients with severe form of obesity. Serum CRP levels correlated with peri-implant bleeding in obese patients. These findings are preliminary and long-term controlled trials are recommended to support these outcomes. PMID- 29148263 TI - Continuing Professional Development. PMID- 29148262 TI - Is there still a place for short clinical case reports in modern mainstream medical publishing? PMID- 29148264 TI - Negative symptoms in first-episode psychosis: Clinical correlates and 1-year follow-up outcomes in London Early Intervention Services. AB - AIM: Negative symptoms (NS) have been associated with poor outcome and remain difficult to treat in patients with psychosis. This study examined the association of NS with clinical features at first presentation to mental health services for psychosis and with outcomes at 1-year follow-up. METHODS: Clinical data were utilized from five London Early Intervention Services (EIS) included in the MiData audit database. The sample comprised 484 first-episode psychosis patients with complete Positive and Negative Syndrome Scale data at baseline and 1-year follow-up. Multiple imputation (N = 50) was conducted to account for missing follow-up data. RESULTS: Baseline NS were associated with male gender (B = -1.63, P < .05), younger age at onset (B = -.15, P <. 05), a higher level of impairment on the Global Assessment of Functioning (disability) Scale at baseline (B = -.19, P <. 010), an absence of reported substance misuse prior to baseline assessment (B = -3.05, P <. 001) and unemployment at baseline (B = -.93, P <. 01). At 1-year follow-up, NS at presentation were associated with worse Global Assessment of Functioning Scale for symptom (B = -.28, P < .01) and disability (B = -.27, P <. 05) and with hospital admission (OR = 1.06, P < .01). CONCLUSIONS: Negative symptoms at presentation to EIS were associated with worse functioning at entry and poorer outcomes 1 year later. Future research is required to better understand the aetiology and trajectories of NS in early psychosis and propose novel targeted interventions. PMID- 29148265 TI - Resveratrol Ameliorates the Severity of Fibrogenesis in Mice with Experimental Chronic Pancreatitis. AB - SCOPE: Resveratrol is generally considered beneficial to health-span and longevity since this dietary stilbenoid has been scrutinized for its activating property on the "rescue gene" sirtuin-1 that promotes cellular survival under stress. In addition to its antiaging property, our previous in vitro studies revealed that resveratrol notably inhibits the production of extracellular matrix (ECM) proteins in pancreatic stellate cells (PSCs), the classic effector cells against pancreatic injury. OBJECTIVE: We aim to extrapolate resveratrol intervention to the management of fibrogenesis in mice with chronic pancreatitis. METHODS AND RESULTS: C57/BL6 mice are given repetitive injections of cerulein (50 MUg kg-1 h-1 ) for 6 weeks for the induction of chronic pancreatitis. We demonstrate that the oral administration of resveratrol (20 mg kg-1 d-1 ) effectively attenuated PSC activation, ECM deposition, fibrogenesis, and acinar atrophy in the pancreatitic parenchyma of cerulein-induced mice, as the damage index score was improved by 45.5%. The enhanced cell survival and preserved acinar integrity by resveratrol plausibly involves a perpetuated nuclear accumulation of Mist1 and a negative modulation of the Akt and p38 MAPK pathways. CONCLUSION: We suggest that resveratrol is potentially a nutraceutical for the mitigations of pancreatic fibrosis in chronic pancreatitis for which no effective therapeutic measure is currently available. PMID- 29148266 TI - NAD+ -Dependent Dehydrogenase PctP and Pyridoxal 5'-Phosphate Dependent Aminotransferase PctC Catalyze the First Postglycosylation Modification of the Sugar Intermediate in Pactamycin Biosynthesis. AB - The unique five-membered aminocyclitol core of the antitumor antibiotic pactamycin originates from d-glucose, so unprecedented enzymatic modifications of the sugar intermediate are involved in the biosynthesis. However, the order of the modification reactions remains elusive. Herein, we examined the timing of introduction of an amino group into certain sugar-derived intermediates by using recombinant enzymes that were encoded in the pactamycin biosynthesis gene cluster. We found that the NAD+ -dependent alcohol dehydrogenase PctP and pyridoxal 5'-phosphate dependent aminotransferase PctC converted N-acetyl-d glucosaminyl-3-aminoacetophonone into 3'-amino-3'-deoxy-N-acetyl-d-glucosaminyl-3 aminoacetophenone. Further, N-acetyl-d-glucosaminyl-3-aminophenyl-beta oxopropanoic acid ethyl ester was converted into the corresponding 3'-amino derivative. However, PctP did not oxidize most of the tested d-glucose derivatives, including UDP-GlcNAc. Thus, modification of the GlcNAc moiety in pactamycin biosynthesis appears to occur after the glycosylation of aniline derivatives. PMID- 29148267 TI - Detection of Teschovirus type 13 from two swine herds exhibiting nervous clinical signs in growing pigs. AB - Recently, the number of clinical reports of growing pigs showing neurological signs possibly related to viral infections has increased. The objective of this report was to describe two outbreaks of an atypical condition observed in 6- to 7 week-old pigs with a morbidity of 20% and a fatality rate of 60% in two unrelated farms of the same company. During the acute phase of the disease, fever, sudden death, neurological signs, ear necrosis and occasional corneal opacity were observed. Histopathological examination revealed interstitial pneumonia, lymphoid depletion and lymphocytic vasculitis in different organs and mild polioencephalomyelitis suggesting a potential viral infection. Possible aetiologies such as exogenous intoxications, salt intoxication, mineral deficiencies/intoxications (Se, Cu, Cd and Zn), oedema disease and mycotoxicosis were ruled out through the diagnostic process. No clinically relevant bacteria could be consistently isolated from affected animals, and the presence of the common swine viruses was ruled out by PCR or RT-PCR. Porcine Teschovirus serotype 13 was the only virus detected by RT-PCR within central nervous system (CNS) of acutely affected pigs. This is the first description of PTV serotype 13 within the CNS of clinically affected pigs. PMID- 29148268 TI - Development and validation of an ultrahigh performance liquid chromatography-high resolution tandem mass spectrometry quantification method for hypoglycin A and methylene cyclopropyl acetic acid carnitine in horse serum in cases of atypical myopathy. AB - Atypical myopathy (AM) is a fatal disease in horses presumably caused by hypoglycine A (HGA) from ingested maple seeds and its active metabolite methylene cyclopropyl acetic acid (MCPA). The aim of this study was the development and validation of a rapid and simple assay for HGA and MCPA-carnitine in horse serum and its application to authentic samples. Identification and quantification were carried out by ultra high performance liquid chromatography-high resolution tandem mass spectrometry (UHPLC-HRMS/MS) with full-scan/data-dependent MS/MS. Chromatographic separation was performed by isocratic elution on a hydrophilic interaction liquid chromatography (HILIC) column (100 x 2.1 mm, 1.7 MUm). Serum samples (250 MUL) were worked up by protein precipitation. The method was validated according to international guidelines with respect to selectivity, linearity, accuracy, precision, matrix effects, and recovery. The calibration range was from 100 to 2000 ng/mL for HGA and from 10 to 1000 ng/mL for MCPA carnitine. HGA and MCPA-carnitine showed acceptable accuracy and precision (bias 3.0% to 1.1%; RSD 9.2% to 12.4%). The limit of quantification (LOQ) was defined as the lowest calibrator and well below the lowest published serum concentrations in affected horses. Matrix effects ranged from -79% to +20% (RSD 4.2% to 14.4%), recoveries from 17.9% to 21.1% (RSD 2.3% to 10.8 %) for low and high quality control samples, respectively. Applicability was tested in 10 authentic AM cases. In all specimens, relevant amounts of HGA and MCPA-carnitine were found (570-2000 ng/mL; ~8.5-150 ng/mL, respectively). The developed assay allows reliable identification and quantification of HGA and MCPA-carnitine in horse serum and will be helpful to further study the association between HGA/MCPA and AM. PMID- 29148270 TI - A G3P[13] porcine group A rotavirus emerging in China is a reassortant and a natural recombinant in the VP4 gene. AB - Group A rotaviruses (RVAs) are a major cause of serious intestinal disease in piglets. In this study, a novel pig strain was identified in a stool sample from China. The strain was designated RVA/Pig/China/LNCY/2016/G3P[13] and had a G3 P[13]-I5-R1-C1-M1-A8-N1-T1-E1-H1 genome. The viral protein 7 (VP7) and non structural protein 4 (NSP4) genes of RVA/Pig/China/LNCY/2016/G3P[13] were closely related to cogent genes of human RVAs, suggesting that a reassortment between pig and human strains had occurred. Recombination analysis showed that RVA/Pig/China/LNCY/2016/G3P[13] is a natural recombinant strain between the P[23] and P[7] RVA strains, and crossover points for recombination were found at nucleotides (nt) 456 and 804 of the VP4 gene. Elucidating the biological characteristics of porcine rotavirus (PoRV) will be helpful for further analyses of the epidemic characteristics of this virus. The results of this study provide valuable information for RVA recombination and evolution and will facilitate future investigations into the molecular pathogenesis of RVAs. PMID- 29148269 TI - Salidroside attenuates neuroinflammation and improves functional recovery after spinal cord injury through microglia polarization regulation. AB - Spinal cord injury (SCI) is a severe neurological disease; however, few drugs have been proved to treat SCI effectively. Neuroinflammation is the major pathogenesis of SCI secondary injury and considered to be the therapeutic target of SCI. Salidroside (Sal) has been reported to exert anti-inflammatory effects in airway, adipose and myocardial tissue; however, the role of Sal in SCI therapeutics has not been clarified. In this study, we showed that Sal could improve the functional recovery of spinal cord in rats as revealed by increased BBB locomotor rating scale, angle of incline, and decreased cavity of spinal cord injury and apoptosis of neurons in vivo. Immunofluorescence double staining of microglia marker and M1/M2 marker demonstrated that Sal could suppress M1 microglia polarization and activate M2 microglia polarization in vivo. To verify how Sal exerts its effects on microglia polarization and neuron protection, we performed the mechanism study in vitro in microglia cell line BV-2 and neuron cell line PC12. The results showed that Sal prevents apoptosis of PC12 cells in coculture with LPS-induced M1 BV-2 microglia, also the inflammatory secretion phenotype of M1 BV-2 microglia was suppressed by Sal, and further studies demonstrated that autophagic flux regulation through AMPK/mTOR pathway was involved in Sal regulated microglia polarization after SCI. Overall, our study illustrated that Sal could promote spinal cord injury functional recovery in rats, and the mechanism may relate to its microglia polarization modulation through AMPK-/mTOR-mediated autophagic flux stimulation. PMID- 29148271 TI - High-refractive index of acrylate embedding resin clarifies mouse brain tissue. AB - Biological tissue transparency combined with light-sheet fluorescence microscopy is a useful method for studying the neural structure of biological tissues. The development of light-sheet fluorescence microscopy also promotes progress in biological tissue clearing methods. The current clarifying methods mostly use liquid reagent to denature protein or remove lipids first, to eliminate or reduce the scattering index or refractive index of the biological tissue. However, denaturing protein and removing lipids require complex procedures or an extended time period. Therefore, here we have developed acrylate resin with a high refractive index, which causes clearing of biological tissue directly after polymerization. This method can improve endogenous fluorescence retention by adjusting the pH value of the resin monomer. PMID- 29148272 TI - Adolf Friedrich Fercher: a pioneer of biomedical optics. AB - Adolf Friedrich Fercher, an outstanding pioneer of biomedical optics, passed away earlier this year. He was a brilliant and visionary researcher who pioneered various fields of biomedical optics, such as laser speckle flowgraphy, tissue interferometry, and optical coherence tomography (OCT). On the occasion of the 25th anniversary of OCT, this paper reviews and commemorates Fercher's pioneering work. PMID- 29148273 TI - Global routine vaccination coverage, 2016. PMID- 29148274 TI - Progress in rubella and congenital rubella syndrome control and elimination - worldwide, 2000-2016. PMID- 29148275 TI - Editorial for the Special Issue on Hypervalent Iodine Reagents. PMID- 29148276 TI - Correction to: Albury et al., RE: Six novel rare non-synonymous mutations for migraine without aura identified by exome sequencing. PMID- 29148277 TI - Care-ful definition of consent. AB - This proposal is an attempt to intervene in psychology's violent past and troubling present by calling for notions of "care-ful" practice, compelling us to recognize and celebrate the permeable, porous, and flexible boundaries between bodies and selves. With this heuristic of care, this article hopes to trouble the separation between rigor and relational responsibility, to trouble objectivism, to oust the illusion of cool rationality, and to offer an affective understanding of consent that refuses to deny sexuality in bodies oppressed with the label of intellectually disabled. PMID- 29148278 TI - 'Her choice of course': Negotiating legitimacy of 'choice' in abortion rights deliberations during the 'Repeal the Eighth' movement in Ireland. AB - Discourses of 'choice' are routinely involved in sexual and reproductive rights' advocacy. In this article, we offer a discursive psychological examination of how 'choice' is oriented to, in online deliberations on the ongoing movement for abortion rights in Ireland. Comment posters treated 'choice' as involving outcomes of and motives for choosing, in negotiating legitimacy of women's rights to choose. These accompanied alternative versions of women, either as independent or as intimately bound up with pregnancy/motherhood, which were flexibly used in negotiation legitimacy of women's rights to 'choice' in abortion practices. Choice advocacy is then situated in particular discursive practices. PMID- 29148280 TI - Anti-leucine-rich glioma-inactivated 1 encephalitis with manic symptoms as the initial manifestation. PMID- 29148279 TI - All Fiber-Coupled OH Planar Laser-Induced-Fluorescence (OH-PLIF)-Based Two Dimensional Thermometry. AB - Two-color, planar laser-induced fluorescence (PLIF)-based two-dimensional (2D) thermometry techniques for reacting flows, which are typically developed in the laboratory conditions, face a stiff challenge in their practical implementation in harsh environments such as combustion rigs. In addition to limited optical access, the critical experimental conditions (i.e., uncontrolled humidity, vibration, and large thermal gradients) often restrict sensitive laser system operation and cause difficulties maintaining beam-overlap. Thus, an all fiber coupled, two-color OH-PLIF system has been developed, employing two long optical fibers allowing isolation of the laser and signal-collection systems. Two OH excitation laser beams (~283 nm and ~286 nm) are delivered through a common 6 m long, 400 um core, deep ultraviolet (UV)-enhanced multimode fiber. The fluorescence signal (~310 nm) is collected by a 3 m long, UV-grade imaging fiber. Proof-of-principle temperature measurements are demonstrated in atmospheric pressure, near adiabatic, CH4/O2/N2 jet flames. The effects of the excitation pulse interval on fiber transmission are investigated. The proof-of-principle measurements show significant promise for thermometry in harsh environments such as gas turbine engine tests. PMID- 29148281 TI - Treatment patterns of biologics in US patients with ankylosing spondylitis: descriptive analyses from a claims database. AB - AIM: Examine treatment patterns among patients with active ankylosing spondylitis (AS) treated with a TNF inhibitor (TNFi). PATIENTS & METHODS: Patients with AS who initiated a TNFi between 1 January 2013, and 31 January 2015, were identified in the Optum Research Database. Outcomes included adherence, persistence, discontinuation and therapy modifications of the index TNFi during 12-month follow-up. RESULTS: Of the 426 patients included, 40.6% persisted on the index TNFi for >=12 months, 31.0% discontinued, 21.4% switched to a different TNFi, and 7.0% discontinued and then restarted. Of the 333 patients who persisted on their TNFi for >90 days, 44.7% received >=1 add-on medication. CONCLUSION: A high proportion of patients with AS switched, discontinued or modified their TNFi therapy. PMID- 29148282 TI - Macrocarpal C isolated from Eucalyptus globulus inhibits dipeptidyl peptidase 4 in an aggregated form. AB - Dipeptidyl peptidase 4 (DPP-4) inhibitors are used for the treatment of type-2 diabetes mellitus. Various synthetic inhibitors have been developed to date, and plants containing natural DPP-4 inhibitors have also been identified. Here, 13 plant samples were tested for their DPP-4 inhibitory activity. Macrocarpals A-C were isolated from Eucalyptus globulus through activity-guided fractionation and shown to be DPP-4 inhibitors. Of these, macrocarpal C showed the highest inhibitory activity, demonstrating an inhibition curve characterised by a pronounced increase in activity within a narrow concentration range. Evaluation of macrocarpal C solution by turbidity, nuclear magnetic resonance spectroscopy and mass spectrometry indicated its aggregation, which may explain the characteristics of the inhibition curve. These findings will be valuable for further study of potential small molecule DPP-4 inhibitors. PMID- 29148283 TI - Patient and provider perspectives on shared decision making: a systematic review of the peer-reviewed literature. AB - For comparative effectiveness research to be effective, patients and providers must collaborate in shared decision making (SDM) to make evidence-based clinical decisions that align with patient preferences. We conducted a systematic review to examine patient and provider attitudes toward and engagement in SDM in the USA. Searches in PubMed and PsycINFO identified 1585 articles published between July 2006 and December 2016, of which 290 were screened in for coding and analysis. We found that patients and providers have generally positive attitudes toward SDM, but actual engagement in SDM behavior is lagging. Translation of positive attitudes into behavior could be achieved through policies that support key SDM processes of sharing evidence, considering patient preferences and discussing the relative advantages of different clinical options. PMID- 29148285 TI - Characterization of Heat Diffusion Properties of Rubberized Two-Layer Systems Using Open Photoacoustic Cell Spectroscopy. AB - We applied the open photoacoustic cell method operating at high frequency as an efficient and highly precise tool for the measurement of thermal properties of rubberized two-layer systems. The heat-coupling between the two layers is treated using the analogy between thermal and electrical resistances widely used in heat transfer problems. The thermal resistance between the two layers is considered effective and the problem is decoupled for each layer. Measurements are performed in two-layer samples of aluminum foil coated with layers of rubberized paint with different thicknesses. Thermal diffusivity and thermal conductivity are determined for the paint. The results are retrieved from the thermal resistance model assuming the effective thermal diffusivity of the composite material. PMID- 29148286 TI - Composition- and Temperature-Resolved Raman Shift of Silicon. AB - We formulated the composition and temperature dependence of the Si and Si1-xGe x Raman shift from the perspectives of bond order-length-strength correlation and local bond average approach. It is verified that the Raman shift Deltaomega varies in the form of Deltaomega ? zE1/2/ d, with inclusion of bond length d and energy E changing with temperature and composition. Numerical reproduction of the thermally induced Si1-xGe x phonon softening indicates that bond thermal expansion and energy loss dictate the frequency redshift, which resulted in quantitative information on the bond energy and the reference frequencies from which the Raman shifts proceed. Observations not only gain deeper insight into the mechanism of the Raman shift but also demonstrate the revealing power of Raman technique for the bonding thermodynamics. PMID- 29148284 TI - Iodine-infused aeration for hull fouling prevention: a vessel-scale study. AB - Biofouling is a significant economic and ecological problem, causing reduced vessel performance and increases in fuel consumption and emissions. Previous research has shown iodine vapor (I2)-infused aeration to be an environmentally friendly method for deterring the settlement of fouling organisms. An aeration system was deployed on a vessel with hull sections coated with two types of antifoulant coatings, Intersleek(r) 1100 (fouling-release) and Interspeed(r) BRA 640 (ablative copper biocide), as well as an inert epoxy barrier coating, to assess the effectiveness of aeration in conjunction with common marine coatings. I2-infused aeration resulted in consistent reductions of 80-90% in hard fouling across all three coatings. Additionally, aeration reduced the soft fouling rate by 45-70% when used in conjunction with both Intersleek(r) and Interspeed(r) BRA versus those coatings alone. The results of this study highlight the contribution of I2-infused aeration as a standalone mechanism for fouling prevention or as a complement to traditional antifouling coatings. PMID- 29148287 TI - Does the Brief Observation of Social Communication Change help moving forward in measuring change in early autism intervention studies? AB - The field of early autism research is in dire need of outcome measures that adequately reflect subtle changes in core autistic behaviors. This article compares the ability of a newly developed measure, the Brief Observation of Social Communication Change (BOSCC), and the Autism Diagnostic Observation Schedule (ADOS) to detect changes in core symptoms of autism in 44 toddlers. The results provide encouraging evidence for the Brief Observation of Social Communication Change as a candidate outcome measure, as reflected in sufficient inter- and intra-rater reliability, independency from other child characteristics, and sensitivity to capture change. Although the Brief Observation of Social Communication Change did not evidently outperform the Autism Diagnostic Observation Schedule on any of these quality criteria, the instrument may be better able to capture subtle, individual changes in core autistic symptoms. The promising findings warrant further study of this new instrument. PMID- 29148288 TI - Cochlear volume as a predictive factor for residual-hearing preservation after conventional cochlear implantation. AB - OBJECTIVE: The preservation of residual hearing after conventional cochlear implantation (CI) is frequently observed when atraumatic soft surgery is adopted. The purpose of this study was to elucidate the predictive factors for residual hearing preservation after atraumatic CI. PATIENTS: This study included 46 patients who underwent CI based on an atraumatic technique using a standard length flexible electrode implant through a round window approach. MAIN OUTCOME MEASURE: Cochlear volume was measured using magnetic resonance imaging (MRI). Cochlear duct length (CDL) was taken as the length of the scala media measured using computed tomography (CT). The association between residual hearing preservation and cochlear volume/CDL was then examined. RESULT: Cochlear volume and CDL were significantly larger in patients with complete hearing preservation than in those with hearing loss. Multivariate logistic regression analysis revealed that cochlear volume was a significant predictive factor for residual hearing preservation. CONCLUSION: Residual hearing preservation after conventional CI was observed in patients with a larger cochlear volume and longer CDL. Cochlear volume could be a predictive factor for residual hearing preservation after conventional CI. PMID- 29148289 TI - Birth as Restorative. AB - A woman's past history of sexual trauma is inextricably woven into her pregnancy and birth experience. Two cases are presented by a practicing certified nurse midwife to demonstrate trauma-informed care in the childbearing setting. Providing trauma-informed care universally in the women's healthcare setting is imperative given not all women disclose their history. Empowering survivors may allow for a restorative birth, in which trust of one's own body can be regained. PMID- 29148290 TI - Single-centre experience with the Impella CP, 5.0 and RP in 109 consecutive patients with profound cardiogenic shock. AB - RATIONALE: Short-term mechanical circulatory support is increasingly used in the management of cardiogenic shock, but data from controlled studies are sparse. Thus, real-life data on complication rates and predictors of adverse outcome are important. OBJECTIVE: The objective of this study was to analyse the experience with Impella devices in the management of profound cardiogenic shock. METHODS AND RESULTS: A retrospective study of 109 consecutive patients with severe shock after myocardial infarction, acute heart failure, or cardiac surgery. Possible device-related complications were registered and predictors of death while on Impella support and within 180 days were identified. In 79 patients (72%) cardiogenic shock was caused by myocardial infarction, acute heart failure in 16 (15%) and post-cardiotomy shock in 14 patients (13%). Thirty-five patients (32%) were comatose after cardiac arrest and in seven, the Impella was placed during chest compression. Mean age was 62+/-12 years, mean arterial pressure was 57+/-13 mmHg, pH 7.19+/-0.17 and lactate 7.5+/-5.7 mmol/l (range 1.8-30.0 mmol/l) at placement. During Impella therapy, 26 patients (28%) died among patients with myocardial infarction or acute heart failure. Of data available prior to placement lactate (hazard ratio 1.14, 95% confidence interval 1.04-1.25, P=0.004) was the only predictor of death on support. During support, five patients (5%) developed leg ischaemia requiring intervention. Bleeding from the Impella insertion site was seen in 14 patients (13%). CONCLUSION: Impella treatment is feasible in profound cardiogenic shock at an acceptable rate of complications. Despite an aggressive approach to restore cardiac output, mortality was high. Besides the severity of lactic acidosis there were no strong predictors of early death. PMID- 29148291 TI - Effectiveness and safety of anti-ischemic trimetazidine in patients with stable angina pectoris and Type 2 diabetes. AB - : Aim & methods: This 6-month prospective, observational, noninterventional, open label clinical study assessed the effectiveness/safety of trimetazidine in 737 patients with stable angina pectoris and Type 2 diabetes mellitus (OGYI/51534 1/2014). RESULTS: Trimetazidine-based therapy was effective in stable coronary artery disease, with significant improvements from baseline (p < 0.05) in: number of angina attacks/week (2.9 +/- 2.4 vs 1.1 +/- 1.6), angina severity (Canadian Cardiovascular Society Classification 1.9 +/- 0.8 vs 1.2 +/- 0.8), exercise capacity (metabolic equivalents 6.1 +/- 1.7 vs 6.5 +/- 1.7), and exercise-induced myocardial ischemia (min 5.5 +/- 2.5 vs 6.5 +/- 2.6). DISCUSSION: Trimetazidine treatment significantly (p < 0.05) improved glucose metabolism, lowered HbA1c (7.1 +/- 1.1% vs 6.6 +/- 1.0%), glucose levels (7.7 +/- 2.1 mmol/l vs 6.9 +/- 1.6 mmol/l) and decreased arterial stiffness (pulse wave velocity 11.2 +/- 2.1 m/s vs 10.4 +/- 2.2 m/s). In most patients, the tolerability of trimetazidine was rated as excellent to good, with a low incidence of adverse events. PMID- 29148292 TI - Cholestatic liver injury as a side-effect of dabigatran and the use of coagulation tests in dabigatran intoxication and after reversal by idarucizumab in bleeding and sepsis. AB - Idarucizumab, an antidote specific for dabigatran, became available recently. Dabigatran is not associated with increased risk of hepatotoxicity in comparison with warfarin, but it is seen as a rare side-effect. Cases of cholestatic liver injury due to dabigatran have not been reported previously. We present a case of severe gastro-intestinal bleeding with underlying dabigatran intoxication in a patient with renal failure and the effect of reversal of dabigatran using idaruzicumab on coagulation assays. International normalized ratio (INR) and activated partial thromboplastin time (APTT) results were elevated in a setting of sepsis, possibly due to liver failure. INR and APTT can be elevated if sepsis is complicated by disseminated intravascular coagulation (DIC) or liver failure, making it challenging to determine dabigatrans contribution to their prolongation. A rebound effect after administration of idarucizumab and slow elimination of dabigatran due to reduced kidney function could be detected using the Hemoclot(r) diluted thrombin time (dTT) in this situation, in contrast to with non-dilutional assays. Before admission, cholestatic liver injury started shortly after initiation of dabigatran etexilate therapy. As no other cause was found, this liver injury was likely to be drug-induced. Bleeding cessated promptly after administration of idarucizumab in dabigatran intoxication. In conclusion, the anticoagulant effect of dabigatran can be measured by Hemoclot(r) dTT in sepsis and cholestatic liver injury was seen as a possible rare side effect of dabigatran treatment. PMID- 29148293 TI - Quantity of Movement as a Measure of Engagement for Dementia: The Influence of Motivational Disorders. AB - Engagement in activities is crucial to improve quality of life in dementia. Yet, its measurement relies exclusively on behavior observation and the influence that behavioral and psychological symptoms of dementia (BPSD) have on it is overlooked. This study investigated whether quantity of movement, gauged with a wrist-worn accelerometer, could be a sound measure of engagement and whether apathy and depression negatively affected engagement. Fourteen participants with dementia took part in 6 sessions of activities: 3 of cognitive games (eg, jigsaw puzzles) and 3 of robot play (Pleo). Results highlighted significant correlations between quantity of movement and observational scales of engagement and a strong negative influence of apathy and depression on engagement. Overall, these findings suggest that quantity of movement could be used as an ancillary measure of engagement and underline the need to profile people with dementia according to their concurrent BPSD to better understand their engagement in activities. PMID- 29148295 TI - Is naloxone the best antidote to reverse tramadol-induced neuro-respiratory toxicity in overdose? An experimental investigation in the rat. AB - CONTEXT: Since the banning of dextropropoxyphene from the market, overdoses, and fatalities attributed to tramadol, a WHO step-2 opioid analgesic, have increased markedly. Tramadol overdose results not only in central nervous system (CNS) depression attributed to its opioid properties but also in seizures, possibly related to non-opioidergic pathways, thus questioning the efficiency of naloxone to reverse tramadol-induced CNS toxicity. OBJECTIVE: To investigate the most efficient antidote to reverse tramadol-induced seizures and respiratory depression in overdose. MATERIALS AND METHODS: Sprague-Dawley rats overdosed with 75 mg/kg intraperitoneal (IP) tramadol were randomized into four groups to receive solvent (control group), diazepam (1.77 mg/kg IP), naloxone (2 mg/kg intravenous bolus followed by 4 mg/kg/h infusion), and diazepam/naloxone combination. Sedation depth, temperature, number of seizures, and intensity, whole-body plethysmography parameters and electroencephalography activity were measured. RESULTS: Naloxone reversed tramadol-induced respiratory depression (p < .05) but significantly increased seizures (p < .01) and prolonged their occurrence time. Diazepam abolished seizures but significantly deepened rat sedation (p < .05) without improving ventilation. Diazepam/naloxone combination completely abolished seizures, significantly improved rat ventilation by reducing inspiratory time (p < .05) but did not worsen sedation. None of these treatments significantly modified rat temperature. CONCLUSIONS: Diazepam/naloxone combination is the most efficient antidote to reverse tramadol-induced CNS toxicity in the rat. PMID- 29148296 TI - Board Walk - October 2016. PMID- 29148294 TI - Synthesis, physiochemical property and antimicrobial activity of novel quaternary ammonium salts. AB - Twenty-four novel 5-phenyl-1,3,4-oxadiazole-2-thiol (POT) analogues, benzo[d]oxazole-2-thiol, benzo[d]thiazole-2-thiol and 5-methyl-1,3,4-thiadiazole 2-thiol-substituted N,N-bis(2-hydroxyethyl) quaternary ammonium salts (QAS) (5a d, 6a-d, 7a-d, 10a-d, 13a-d, 16a-d) were prepared and characterised by FTIR, NMR and elemental analysis. Part of target compounds (5d, 6d, 7d, 10d, 13d, 16d) displayed potent antimicrobial effect against ten common pathogens (S. aureus, alpha-H-tococcus, beta-H-tococcus, E. coli, P. aeruginosa, Proteus vulgaris, Canidia Albicans, Cytospora mandshurica, Physalospora piricola, Aspergillus niger) and had relatively low cytotoxity against two human cell lines (HaCat and LO2). TEM and SEM images of E. coli and S. aureus morphologies treated with 7d showed that the antibacterial mechanism might be the QAS fixing on cell wall surfaces and puncturing to result in the release of bacterial cytoplasm. This study provides new information of QAS, which could be used to design novel antimicrobial agents applied in clinic or agriculture. PMID- 29148297 TI - Detection of pseudorabies virus by duplex droplet digital PCR assay. AB - Aujeszky's disease, caused by pseudorabies virus (PRV), has damaged the economy of the Chinese swine industry. A large number of PRV gene-deleted vaccines have been constructed based on deletion of the glycoprotein E ( gE) gene combined with other virulence-related gene deletions, such as thymidine kinase ( TK), whereas PRV wild-type strains contain an intact gE gene. We developed a sensitive duplex droplet digital PCR (ddPCR) assay to rapidly detect PRV wild-type isolates and gE gene-deleted viral vaccines. We compared this assay with a TaqMan real-time PCR (qPCR) using the same primers and probes. Both assays exhibited good linearity and repeatability; however, ddPCR maintained linearity at extremely low concentrations, whereas qPCR did not. Based on positive results for both gE and gB, the detection limit of ddPCR was found to be 4.75 copies/uL in contrast of 76 copies/uL for qPCR, showing that ddPCR provided a 16-fold improvement in sensitivity. In addition, no nonspecific amplification was shown in specificity testing, and the PRV wild-type was distinguished from a gE-deleted strain. The ddPCR was more sensitive when analyzing clinical serum samples. Thus, ddPCR may become an appropriate detection platform for PRV. PMID- 29148298 TI - Understanding patient requirements for technology systems that support pain management in palliative care services: A qualitative study. AB - Approaches to pain management using electronic systems are being developed for use in palliative care. This article explores palliative care patients' perspectives on managing and talking about pain, the role of technology in their lives and how technology could support pain management. Face-to-face interviews were used to understand patient needs and concerns to inform how electronic systems are developed. A total of 13 interviews took place with a convenience sample of community-based patients with advanced cancer receiving palliative care through a hospice. Data were analysed using framework analysis. Four meta-themes emerged: Technology could be part of my care; I'm trying to understand what is going on; My pain is ever-changing and difficult to control; and I'm selective about who to tell about pain. Patients described technology as peripheral to existing processes of care. To be relevant, systems may need to take account of the complexity of a patient's pain experience alongside existing relationships with health professionals. PMID- 29148299 TI - Treatment of leachate from municipal solid waste of Mostaganem district in Algeria: Decision support for advising a process treatment. AB - The aim of this work is to propose a plan for the choice of a suitable process for the treatment of a young leachate from municipal solid waste. Classical processes were applied: Fenton process, the coupling coagulation-Fenton process and the adsorption on powdered activated carbon (PAC). The study involves synthesised leachates from three types of wastes collected from sanitary landfill (SL): leachate of putrescible fraction (Lp), paper-cardboard (Lpc), sawdust (Ls) and the one of landfill (Lsl). The optimal operating conditions have been determined for the three processes: Fenton: [H2O2] = 6.8 g L-1 and [Fe2+] = 2.8 g L-1, coagulation: [Fe3+] = 0.3 g L-1 and adsorption: [PAC] = 60 g L-1. The three processes gave reduction rates of chemical oxygen demand ranging from 50% to 85% for Lp, 87% to 97% for Lpc and 61% to 87% for Ls. Whereas for Lsl, it was of 45%, 56% and 80% for the Fenton, coagulation-Fenton and adsorption processes, respectively. A modelling study was conducted to calculate the chemical oxygen demand of leachate produced during 25 years for different thicknesses of waste. This predicted value is used to advise for the process treatment to apply and to assess the environmental impacts in the long term. PMID- 29148300 TI - Corrigendum. PMID- 29148302 TI - Adoption of nanodiamonds as biomedical materials for bone repair. PMID- 29148303 TI - Orienting to guilty knowledge. AB - The Guilty Knowledge Test (GKT; Lykken, 1959) assesses whether suspects conceal information about a crime ( "guilty knowledge"). Previous studies have demonstrated larger physiological reactions to guilty knowledge compared to unknown information. In three experiments, we investigated whether guilty knowledge also demands attention. During an alleged polygraph examination, participants were presented with to-be-detected pictures ( "guilty knowledge"), nonsignificant, familiar pictures ( "mere knowledge"), and previously unseen pictures ( "neutral information") for 250 ms in a modified dot probe task. In all three experiments, probe responses were slower on guilty knowledge trials as compared to the neutral trials. Results are discussed in terms of an information processing view on orienting to guilty knowledge. PMID- 29148301 TI - Provider Connectedness to Other Providers Reduces Risk of Readmission After Hospitalization for Heart Failure. AB - Provider interactions other than explicit care coordination, which is challenging to measure, may influence practice and outcomes. We performed a network analysis using claims data from a commercial payor. Networks were identified based on provider pairs billing outpatient care for the same patient. We compared network variables among patients who had and did not have a 30-day readmission after hospitalization for heart failure. After adjusting for comorbidities, high median provider connectedness-normalized degree, which for each provider is the number of connections to other providers normalized to the number of providers in the region-was the network variable associated with reduced odds of readmission after heart failure hospitalization (odds ratio = 0.55; 95% confidence interval [0.35, 0.86]). We conclude that heart failure patients with high provider connectedness are less likely to require readmission. The structure and importance of provider relationships using claims data merits further study. PMID- 29148304 TI - Relations between emotions, display rules, social motives, and facial behaviour. AB - We report research on the relations between emotions, display rules, social motives, and facial behaviour. In Study 1 we used a questionnaire methodology to examine how respondents would react to a funny or a not funny joke told to them by a close friend or a stranger. We assessed display rules and motivations for smiling and/or laughing. Display rules and social motives (partly) mediated the relationship between the experimental manipulations and self-reported facial behaviour. Study 2 was a laboratory experiment in which funny or not funny jokes were told to participants by a male or female stranger. Consistent with hypotheses, hearing a funny joke evoked a stronger motivation to share positive affect by showing longer Duchenne smiling. Contrary to hypotheses, a not funny joke did not elicit greater prosocial motivation by showing longer "polite" smiling, although such a smiling pattern did occur. Rated funniness of the joke and the motivation to share positive affect mediated the relationship between the joke manipulation and facial behaviour. Path analysis was used to explore this mediating process in greater detail. PMID- 29148305 TI - Robust affective priming effects in a conditional pronunciation task: Evidence for the semantic representation of evaluative information. AB - Based on the hypothesis that information about the valence of words is encoded in a semantic system, we predicted that the match between the valence of a prime and the valence of a target word will influence the pronunciation of the target only if and to the extent that pronunciation is semantically mediated. In line with this prediction, we found affective priming effects (faster pronunciation when prime and target had the same valence than when they had a different valence) only when participants were instructed to read words but not nonwords (Experiment 1) or words that were not names of occupations (Experiment 2). Priming was not significant when participants were asked to read white but not red words (Experiment 1) or words that did not have a frame around them (Experiment 2). PMID- 29148306 TI - The face of wrath: The role of features and configurations in conveying social threat. AB - We examined the role of single features and feature configurations in the effect of schematic faces on rated threat. A total of 101 medical students rated their emotional impression of schematic facial stimuli using semantic differential scales (Activity, Negative Valence, and Potency). In different parts of the experiment, the ratings concerned single features, eyebrow-mouth configurations, or complete faces. Although eyebrows emerged as the overall most important feature, the effect of features was modulated by configuration. Simple configurations of eyebrows and mouth appeared to convey threat and nonthreat in a way highly similar to that of complete faces. In most cases, the configurations of eyebrows and mouth could significantly predict the effect of the complete faces. PMID- 29148307 TI - Defensive pessimism, self-esteem instability, and goal strivings. AB - Defensive pessimism (Norem & Cantor, 1986a) is conceived as an adaptive motivational strategy employed in academic contexts. The present research investigates some potentially deleterious correlates of the defensively pessimistic strategy. We examined the hypothesis that defensive pessimists would have a relatively high ratio of negative-to-positive academically relevant self thoughts, and these accessible thoughts would be related to high self-esteem instability. Mediational analyses generally supported this hypothesis. However, defensive pessimism-optimism differences in self-esteem seemed to partially account for the mediated effects. We also found support for the hypothesis that, relative to optimists, defensive pessimists would tend to be less oriented toward mastery goals and more oriented toward performance-avoidance achievement goals in academic settings. Results were discussed in terms of the processing correlates and adaptive trade-offs of defensive pessimism. PMID- 29148308 TI - Brief report Effects of spinal cord injuries on the subjective component of emotions. AB - Responses to a structured interview by 19 patients with spinal cord injuries (SCI) (7 women and 12 men) concerning their past (pre-injury) and present emotions were analysed and compared with responses by 19 SCI-free controls matched for sex, age, and education. In addition, subjects assessed the valence and arousal of 10 pleasant, 10 neutral, and 10 unpleasant pictures selected from the International Affective Picture System. The results indicate that there is no decrease in emotional experience among individuals with SCI compared with those without. For all the emotional scales (joy, love, sentimentalism, positive emotions as a whole, fear, anger, sadness, and negative emotions as a whole) the SCI group always showed either no change or an increase; this increase was significantly higher in SCI than in control subjects for sadness. No differences were observed between the two groups in the subjective assessment of the pictures. The implications of the results for the James versus Cannon controversy on the theory of emotions are discussed. PMID- 29148309 TI - Depression impairs the ability to ignore the emotional aspects of facial expressions: Evidence from the Garner task. AB - We assessed dysphoric and clinically distressed individuals' ability to ignore the emotional aspects of facial expressions using the Garner speeded classification task. Garner's paradigm tests the ability to selectively focus on a single relevant dimension while ignoring variations on other, irrelevant, ones. In the present task, the stimuli were faces of men and women expressing happy, angry, and neutral emotions. In Experiments 1 and 2, dysphoric and nondysphoric participants performed the Garner task, focusing on gender and ignoring emotion (Experiment 1) and focusing on emotion and ignoring gender (Experiment 2). Results suggest that dysphoric individuals exhibited more difficulty ignoring the emotional dimension of social stimuli even under specific instructions to do so than nondysphoric individuals. In Experiments 3 and 4, we replicated these results in clinically distressed and nondistressed individuals. The results of Experiment 3 further suggested that depression was more closely associated with the inability to selectively ignore emotion than was social anxiety. Experiment 4 confirmed that this failure of selective attention was specific to processing emotional, and not gender features. The implications of these findings for cognitive and interpersonal theories of depression are discussed. PMID- 29148310 TI - Biventricular Repair of Double Outlet Right Ventricle: Preoperative Echocardiography and Surgical Outcomes. AB - OBJECTIVE: To discuss the key anatomic features of double outlet right ventricle (DORV) assessed by preoperative echocardiography among patients treated with different types of biventricular repair. METHODS: Surgical and echocardiographic databases were queried to identify patients who had undergone biventricular repair for DORV and had adequate preoperative echocardiographic imaging. All patients underwent pre- and postoperative echocardiography and clinical evaluation following discharge. RESULTS: Two hundred sixty-two patients with DORV met the inclusion criteria of the study. The patients were divided into two groups-intraventricular tunnel repair (IVR) to the aorta (194 [74%] patients) or to the pulmonary artery with either concomitant arterial switch operation or double-root translocation (68 [26%] patients). Among 68 patients undergoing IVR to the pulmonary artery, 50 patients with transposition of the great arteries (TGA) type of DORV and 7 patients with remote ventricular septal defect (VSD) type underwent IVR plus arterial switch operation and 6 patients with TGA type and 5 patients with remote VSD type underwent IVR plus double-root translocation. There were three hospital deaths and one late death (overall operative mortality: 1.5%). CONCLUSION: Preoperative echocardiography provided crucial data to estimate the feasibility of intraventricular tunnel creation to either the aorta or the pulmonary artery and to guide the selection of either arterial switch or double-root translocation. Biventricular repair could be achieved with favorable outcomes in most patients with DORV. PMID- 29148311 TI - For which clinical rules do doctors want decision support, and why? A survey of Dutch general practitioners. AB - Despite the promise of decision support for improving care, alerts are often overridden or ignored. We evaluated Dutch general practitioners' intention to accept decision support in a proposed implementation based on clinical rules regarding care for elderly patients, and their reasons for wanting or not wanting support. We developed a survey based on literature and structured interviews and distributed it to all doctors who would receive support in the proposed implementation (n = 43), of which 65 percent responded. The survey consisted of six questions for each of 20 clinical rules. Despite concerns about interruption, doctors tended to choose more interruptive forms of support. Doctors wanted support when they felt the rule represented minimal care, perceived a need to improve care, and felt responsible for the action and that they might forget to perform the action; doctors declined support due to feeling that it was unnecessary and due to concerns about interruption. PMID- 29148312 TI - Experimental analysis of the process parameters affecting bone burring operations. AB - The experimental quantification of the process parameters associated with bone burring represents a desirable outcome both from the perspective of an optimized surgical procedure as well as that of a future implementation into the design of closed-loop controllers used in robot-assisted bone removal operations. Along these lines, the present study presents an experimental investigation of the effects that tool type, rotational speed of the tool, depth of cut, feed rate, cutting track overlap, and tool angle (to a total of 864 total unique combinations) have on bone temperature, tool vibration, and cutting forces associated with superficial bone removal operations. The experimental apparatus developed for this purpose allowed a concurrent measurement of bone temperature, tool vibration, and cutting forces as a function of various process parameter combinations. A fully balanced experimental design involving burring trials performed on a sawbone analog was carried out to establish process trends and subsets leading to local maximums and minimums in temperature and vibration were further investigated. Among the parameters tested, a spherical burr of 6 mm turning at 15,000 r/min and advancing at 2 mm/s with a 50% overlap between adjacent tool paths was found to yield both low temperatures at the bone/tool interface and minimal vibrations. This optimal set of parameters enables a versatile engagement between tool and bone without sacrificing the optimal process outcomes. PMID- 29148314 TI - Clinical decision support systems in hospital care using ubiquitous devices: Current issues and challenges. AB - Supporting clinicians in decision making using advanced technologies has been an active research area in biomedical engineering during the past years. Among a wide range of ubiquitous systems, smartphone applications have been increasingly developed in healthcare settings to help clinicians as well as patients. Today, many smartphone applications, from basic data analysis to advanced patient monitoring, are available to clinicians and patients. Such applications are now increasingly integrating into healthcare for clinical decision support, and therefore, concerns around accuracy, stability, and dependency of these applications are rising. In addition, lack of attention to the clinicians' acceptability, as well as the low impact on the medical professionals' decision making, are posing more serious issues on the acceptability of smartphone applications. This article reviews smartphone-based decision support applications, focusing on hospital care settings and their overall impact of these applications on the wider clinical workflow. Additionally, key challenges and barriers of the current ubiquitous device-based healthcare applications are identified. Finally, this article addresses current challenges, future directions, and the adoption of mobile healthcare applications. PMID- 29148313 TI - Facebook and Twitter vaccine sentiment in response to measles outbreaks. AB - Social media posts regarding measles vaccination were classified as pro vaccination, expressing vaccine hesitancy, uncertain, or irrelevant. Spearman correlations with Centers for Disease Control and Prevention-reported measles cases and differenced smoothed cumulative case counts over this period were reported (using time series bootstrap confidence intervals). A total of 58,078 Facebook posts and 82,993 tweets were identified from 4 January 2009 to 27 August 2016. Pro-vaccination posts were correlated with the US weekly reported cases (Facebook: Spearman correlation 0.22 (95% confidence interval: 0.09 to 0.34), Twitter: 0.21 (95% confidence interval: 0.06 to 0.34)). Vaccine-hesitant posts, however, were uncorrelated with measles cases in the United States (Facebook: 0.01 (95% confidence interval: -0.13 to 0.14), Twitter: 0.0011 (95% confidence interval: -0.12 to 0.12)). These findings may result from more consistent social media engagement by individuals expressing vaccine hesitancy, contrasted with media- or event-driven episodic interest on the part of individuals favoring current policy. PMID- 29148316 TI - Recognition dynamics of trinuclear copper cluster and associated histidine residues through conserved or semi-conserved water molecules in human Ceruloplasmin: The involvement of aspartic and glutamic acid gates. AB - Human Ceruloplasmin belongs to the family of multi-copper oxidases and it is involved in different physiological processes, copper ion transport, iron metabolism, iron homeostasis, and biogenic amine metabolism. MD-simulation studies have indicated the higher hydrophilic susceptibility of the trinuclear copper cluster in native CP compared to its oxygen bound form. The copper (T2/T3) atom Cu3047 of the cluster, which is close to T1 copper center Cu3052 (~13 A) has a higher affinity for water molecules compared to other copper centers. The water molecules of W3, W4, W5, W9, and W12 conserved water sites are coordinated to Cu3047, where W3, W9, and W12 centers are found to play some crucial role in the stabilization of native trinuclear copper cluster. The hydrogen bonding interaction of Asp169, Glu112, Asp995, and Glu1032 residues with the copper-bound conserved water molecules (W3, W4, W5, W10, and W11) in native CP is observed to be unique. The conformational flexibility of Asp169 and Glu112 and their association with the copper-bound water molecules, but the absence of such interaction in O2-bound simulated structure of the enzyme is indicating some plausible rational on the role of these acidic residues in the gating of O2 molecule in the native trinuclear Cu cluster of CP. The simulation results may shade some new light on the biochemistry/chemistry of CP, specially on the hydration dynamics of the trinuclear copper cluster. PMID- 29148315 TI - SUMOylation in brain ischemia: Patterns, targets, and translational implications. AB - Post-translational protein modification by small ubiquitin-like modifier (SUMO) regulates a myriad of homeostatic and stress responses. The SUMOylation pathway has been extensively studied in brain ischemia. Convincing evidence is now at hand to support the notion that a major increase in levels of SUMOylated proteins is capable of inducing tolerance to ischemic stress. Therefore, the SUMOylation pathway has emerged as a promising therapeutic target for neuroprotection in the face of brain ischemia. Despite this, it is prudent to acknowledge that there are many key questions still to be addressed in brain ischemia related to SUMOylation. Accordingly, herein, we provide a critical review of literature within the field to summarize current knowledge and in so doing highlight pertinent translational implications of the SUMOylation pathway in brain ischemia. PMID- 29148317 TI - Brainstem glioma: Prediction of histopathologic grade based on conventional MR imaging. AB - Objective The objective of this article is to investigate the association between specific MR imaging findings and histopathologic grading (low-grade vs. high grade) of brainstem gliomas (BSGs). Methods Sixty-two males and 34 females (mean (standard deviation, SD) age of 24.61 (17.20) years, range = 3 to 70 years) with histologically diagnosed BSG underwent conventional 1.5 T MR imaging, which included T1-weighted (T1W), T2W, and post-contrast T1W sequences. There were 39 children (mean age of 9.38 years) and 57 adults (mean age of 35 years). A binary logistic regression analysis was used to explore associations between MRI features and histopathological grade of the BSG. Results Binary logistic regression revealed that necrosis (adjusted odds ratio (OR) = 16.07; 95% confidence interval (CI) = 3.20 to 80.52; p = 0.001) and inhomogeneous contrast enhancement (adjusted OR = 8.04; 95% CI = 1.73 to 37.41; p = 0.008) as significant predictors of high-grade BSG. The equation (Nagelkerke R2 = 0.575) is Logit ( p high-grade BSG) = (2.77 * necrosis) + (2.08 * heterogeneous contrast enhancement) - 3.13. Sensitivity and specificity values were respectively 66.7% and 96.0% for necrosis and 85.7% and 65.9% for inhomogeneous contrast-enhancing lesions. In the pediatric age group, only inhomogeneous contrast enhancement (adjusted OR = 40; 95% CI = 3.95 to 445.73; p = 0.002) was a significant predictor for high-grade BSG. Conclusion Conventional MR imaging features such as necrosis and inhomogeneous contrast enhancement in adults and heterogeneous contrast enhancement in children suggest high-grade BSG. PMID- 29148318 TI - To What Extent Are State Scope of Practice Laws Related to Nurse Practitioners' Day-to-Day Practice Autonomy? AB - We explore the extent to which state scope of practice laws are related to nurse practitioners (NPs)' day-to-day practice autonomy. We found that NPs experienced greater day-to-day practice autonomy when they had prescriptive independence. Surprisingly, there were only small and largely insignificant differences in day to-day practice autonomy between NPs in fully restricted states and those in states with independent practice but restricted prescription authority. The scope of practice effects were strong for primary care NPs. We also found that the amount of variation in day-to-day practice autonomy within the scope of practice categories existed, which suggests that factors other than state scope of practice laws may influence NP practice as well. Removing barriers at all levels that potentially prevent NPs from practicing to the full extent of their education and training is critical not only to increase primary care capacity but also to make NPs more efficient and effective providers. PMID- 29148319 TI - Association Between Prescription Drug Insurance and Health Care Utilization Among Medicare Beneficiaries. AB - Medicare Part D was associated with reduced hospitalizations, yet little is known whether these effects varied across patients and how Part D was associated with length of stay and inpatient expenditures. We used Medicare claims and the Medicare Current Beneficiary Survey from 2002 to 2010 and an instrumental variables approach. Gaining drug insurance through Part D was associated with a statistically significant 8.0% reduction in likelihood of admission across conditions examined. Reductions were generally greater for younger, healthier, and male individuals. Across all conditions, mean length of stay decreased by 3.2% from a baseline of 5.1 days. Part D was associated with a 3.5% reduction in expenditures per admission, reflecting a decrease of $844 from a mean charge of $24,124 per admission prior to Part D. Thus, Part D was associated with statistically and clinically significant reductions in the probability of admission and length of stay for several common conditions. PMID- 29148320 TI - The Extraregulatory Effect of Nurse Practitioner Scope-of-Practice Laws on Physician Malpractice Rates. AB - Patients can hold physicians directly or vicariously liable for the malpractice of nurse practitioners under their supervision. Restrictive scope-of-practice laws governing nurse practitioners can ease patients' legal burdens in establishing physician liability. We analyze the effect of restrictive scope-of practice laws on the number of malpractice payments made on behalf of physicians between 1999 and 2012. Enacting less restrictive scope-of-practice laws decreases the number of payments made by physicians by as much as 31%, suggesting that restrictive scope-of-practice laws have a salient extraregulatory effect on physician malpractice rates. The effect of enacting less restrictive laws varies depending on the medical malpractice reforms that are in place, with the largest decrease in physician malpractice rates occurring in states that have enacted fewer malpractice reforms. Relaxing scope-of-practice laws could mitigate the adverse extraregulatory effect on physicians identified in this study and could also lead to improvements in access to care. PMID- 29148322 TI - The Health Care Job Engine: Where Do They Come From and What Do They Say About Our Future? AB - Health care has been cited as a job engine for the U.S. economy. This study used the Current Population Survey to examine the sector and occupation shifts that underlie this growth trend. Health care has had a cyclical relationship with retail trade, leisure and hospitality, education, and professional services. The entering workforce has been increasingly taking on low-skilled occupations. The exiting workforce has not been necessarily retiring or going back to school, but appeared to be leaving without a job, with potentially more child care duties, and with high rates of disability and poverty levels. This study also found that the number of workers staying in health care has been slowly declining over time. As the United States moves toward team-based care, more attention should be paid to the needs of the lower skilled workers to reduce turnover and ensure delivery of quality care. PMID- 29148321 TI - Impact of the Affordable Care Act's Dependent Coverage Expansion on the Health Care and Health Status of Young Adults: What Do We Know So Far? AB - The dependent coverage expansion (DCE), a component of the Affordable Care Act, required private health insurance policies that cover dependents to offer coverage for policyholders' children through age 25. This review summarizes peer reviewed research on the impact of the DCE on the chain of consequences through which it could affect public health. Specifically, we examine the impact of the DCE on insurance coverage, access to care, utilization of care, and health status. All studies find that the DCE increased insurance coverage, but evidence regarding downstream impacts is inconsistent. There is evidence that the DCE reduced high out-of-pocket expenditures and frequent emergency room visits and increased behavioral health treatment. Evidence regarding the impact of the DCE on health is sparse but suggestive of positive impacts on self-rated health and health behavior. Inferences regarding the public health impact of the DCE await studies with greater methodological diversity and longer follow-up periods. PMID- 29148323 TI - Impact of Postdischarge Follow-Up Care on Medicare Expenditures: Does Rural Make a Difference? AB - Reducing postdischarge Medicare expenditures is a key focus for hospitals. Early follow-up care is an important piece of this focus, but it is unclear whether there are rural-urban differences in the impact of follow-up care on Medicare expenditures. To assess this difference, we use the Medicare Current Beneficiary Survey, Cost and Use Files, 2000-2010. We conduct a retrospective analysis of 30 day postdischarge Medicare expenditures using two-stage residual inclusion with a quantile regression, where the receipt of 7-day follow-up care was the main independent variable. Postdischarge follow-up care increased the 25th percentile of 30-day expenditures, decreased the 75th percentile, and there were no rural urban differences. Partial effects show postdischarge follow-up care resulted in higher 30-day expenditures among low-cost rural beneficiaries. Ensuring early follow-up care for high-cost beneficiaries may be advantageous to both rural and urban providers in helping reduce postdischarge Medicare expenditures. PMID- 29148325 TI - Characteristics of High- and Low-Efficiency Hospitals. AB - We compared performance, operating characteristics, and market environments of low- and high-efficiency hospitals in the 37 states that supplied inpatient data to the Healthcare Cost and Utilization Project from 2006 to 2010. Hospital cost inefficiency estimates using stochastic frontier analysis were generated. Hospitals were then grouped into the 100 most- and 100 least-efficient hospitals for subsequent analysis. Compared with the least efficient hospitals, high efficiency hospitals tended to have lower average costs, higher labor productivity, and higher profit margins. The most efficient hospitals tended to be nonteaching, investor-owned, and members of multihospital systems. Hospitals in the high-efficiency group were located in areas with lower health maintenance organization penetration and less competition, and they had a higher share of Medicaid and Medicare admissions. Results of the analysis suggest there are opportunities for public policies to support improved efficiency in the hospital sector. PMID- 29148324 TI - The Impacts of Medicaid Expansion on Rural Low-Income Adults: Lessons From the Oregon Health Insurance Experiment. AB - Medicaid expansions through the Affordable Care Act began in January 2014, but we have little information about what is happening in rural areas where provider access and patient resources might be more limited. In 2008, Oregon held a lottery for restricted access to its Medicaid program for uninsured low-income adults not otherwise eligible for public coverage. The Oregon Health Insurance Experiment used this opportunity to conduct the first randomized controlled study of a public insurance expansion. This analysis builds off of previous work by comparing rural and urban survey outcomes and adds qualitative interviews with 86 rural study participants for context. We examine health care access and use, personal finances, and self-reported health. While urban and rural populations have unique demographic profiles, rural populations appear to have benefited from Medicaid as much as urban. Qualitative interviews revealed the distinctive challenges still facing low-income uninsured and newly insured rural populations. PMID- 29148326 TI - Understanding Professional Jurisdiction Changes in the Field of Anesthesiology. AB - We further our understanding of jurisdictional disputes between established professional groups through a 10-year longitudinal analysis of the differential adoption by U.S. states of policies expanding Certified Registered Nurse Anesthetists' (CRNAs) autonomy. In the United States, CRNAs are trained to deliver anesthetics to patients in the same way as physician anesthesiologists but have more restrictions in practice. Following a 2001 federal decision regarding Medicare reimbursement, states were permitted but not required to allow CRNAs to practice without physician supervision, potentially reducing health care costs. We show that higher levels of incumbent physician power makes it less likely that a state will change jurisdictional boundaries, while increasing relative power among challenging CRNAs and the past successes of other challenging health professionals increase the likelihood. State labor deficiency and proximity to other adopting states also positively influenced the expansion of CRNAs' autonomy. Implications for the professions and health services literature are discussed. PMID- 29148327 TI - Are Integrated Plan Providers Associated With Lower Premiums on the Health Insurance Marketplaces? AB - As the health insurance industry becomes more consolidated, hospitals and health systems have started to enter the insurance business. Insurers are also rapidly acquiring providers. Although these "vertically" integrated plan providers are small players in the insurance market, they are becoming more numerous. The health insurance marketplaces (HIMs) offer a unique setting to study integrated plan providers relative to other insurer types because the HIMs were designed to promote competition. In this descriptive study, the authors compared the premiums of the lowest priced silver plans of integrated plan providers with other insurer types on the 2015 and 2016 HIMs. Integrated plan providers were associated with modestly lower premiums relative to most other insurer types. This study provides early insights into premium competition on the HIMs. Examining integrated plan providers as a separate insurer type has important policy implications because they are a growing segment of the marketplaces and their pricing behavior may influence future premium trends. PMID- 29148328 TI - Medicare Part D Beneficiaries' Plan Switching Decisions and Information Processing. AB - Medicare Part D beneficiaries tend not to switch plans despite the government's efforts to engage beneficiaries in the plan switching process. Understanding current and alternative plan features is a necessary step to make informed plan switching decisions. This study explored beneficiaries' plan switching using a mixed-methods approach, with a focus on the concept of information processing. We found large variation in beneficiary comprehension of plan information among both switchers and nonswitchers. Knowledge about alternative plans was especially poor, with only about half of switchers and 2 in 10 nonswitchers being well informed about plans other than their current plan. We also found that helpers had a prominent role in plan decision making-nearly twice as many switchers as nonswitchers worked with helpers for their plan selection. Our study suggests that easier access to helpers as well as helpers' extensive involvement in the decision-making process promote informed plan switching decisions. PMID- 29148329 TI - The Implementation of Performance Management Systems in U.S. Physician Organizations. AB - Performance management systems (PMSYS) aid in improving the quality and efficiency of care, but little is known about factors that influence more robust PMSYS among physician organizations. Using a nationally representative survey of U.S. medical practices, we examined the extent to which organizational capabilities and external factors were associated with more developed PMSYS. Linear regression estimated the relative impact of these factors on PMSYS. On average, practices implemented a minority (32 points out of 100) of the PMSYS processes assessed. Practices evaluated ( p < .01) or financially incentivized by external entities ( p < .01), receiving data from health plans ( p < .01), participating in an accountable care organization ( p < .01), affiliating with an independent practice association and/or physician-hospital organization ( p < .01), and using health information technology ( p < .01) and chronic disease registries ( p < .01) to greater degrees had more robust PMSYS. PMSYS of medical practices are underdeveloped, although both external incentives and organizational capabilities may support PMSYS development. PMID- 29148330 TI - Risk Factors for Falls Among Older Adults Following Transition From Nursing Home to the Community. AB - This study analyzes the incidence of falls for older adults who transitioned from institutions to the community through the Connecticut Money Follows the Person demonstration program, identifying intrinsic and extrinsic fall risk factors for this population. This prospective cohort study analyzed data from 648 Money Follows the Person participants aged 65 years and older, using 6- and 12-month posttransition surveys. Of the 648 participants, 161 (25.2%) fell in the first 6 months after transition, while 156 (24.5%) fell between 6 and 12 months after transition. Unmet medical care needs, depressive symptoms, mistreatment, and previous falls significantly predicted falls. Given the vulnerability of this population and increased use of fall-related health services, fall prevention represents a critical element in posttransition care. Beyond previously identified risk factors, care providers should consider issues such as unmet medical care needs, depressive symptoms, and mistreatment in assessing fall risk. PMID- 29148331 TI - Financial Performance of Health Insurers: State-Run Versus Federal-Run Exchanges. AB - Many insurers incurred financial losses in individual markets for health insurance during 2014, the first year of Affordable Care Act mandated changes. This analysis looks at key financial ratios of insurers to compare profitability in 2014 and 2013, identify factors driving financial performance, and contrast the financial performance of health insurers operating in state-run exchanges versus the federal exchange. Overall, the median loss of sampled insurers was 3.9%, no greater than their loss in 2013. Reduced administrative costs offset increases in medical losses. Insurers performed better in states with state-run exchanges than insurers in states using the federal exchange in 2014. Medical loss ratios are the underlying driver more than administrative costs in the difference in performance between states with federal versus state-run exchanges. Policy makers looking to improve the financial performance of the individual market should focus on features that differentiate the markets associated with state-run versus federal exchanges. PMID- 29148332 TI - Medicare Advantage and Traditional Medicare Hospitalization Intensity and Readmissions. AB - Medicare Advantage plans have incentives and tools to optimize patient care. Therefore, Medicare Advantage hospitalizations may have lower cost and higher quality than similar traditional Medicare hospitalizations. We applied a coarsened matching approach to 2013 Healthcare Cost and Utilization Project hospital discharge data from 22 states to compare hospital cost, length of stay, and readmissions for Traditional Medicare and Medicare Advantage. We found that Medicare Advantage hospitalizations were substantially less expensive and shorter for mental health stays but costlier and longer for injury and surgical stays. We found little difference in the cost and length of medical stays and in readmission rates. One explanation is that Medicare Advantage plans use outpatient settings for many patients with behavioral health conditions and for injury and surgical patients with less complex health needs. Alternatively, the observed differences in behavioral health cost and length of stay may represent skimping on appropriate care. PMID- 29148333 TI - Geographic Variations in Physician Relationships Over Time: Implications for Care Coordination. AB - Care coordination may be more challenging when the specific physicians with whom primary care physicians (PCPs) are expected to coordinate care change over time. Using Medicare data on physician patient-sharing relationships and the Dartmouth Atlas, we explored the extent to which PCPs tend to share patients with other physicians over time. We found that 70.7% of ties between PCPs and other physicians that were present in 2012 persisted in 2013, and additional shared patients in 2012 increased the odds of being connected in 2013. Regions with higher persistent ties tended to have lower rates of emergency room visits, and regions where PCPs had more physician connections were more likely to have higher emergency room visits. The results point to potential opportunities and challenges faced by health care reforms that seek to improve coordination. PMID- 29148334 TI - Evidence of Pent-Up Demand for Care After Medicaid Expansion. AB - We compared new Medicaid enrollees with similar ongoing enrollees for evidence of pent-up demand using claims data following Minnesota's 2014 Medicaid expansion. We hypothesized that if new enrollees had pent-up demand, utilization would decline over time as testing and disease management plans are put in place. Consistent with pent-up demand among new enrollees, the probability of an office visit, a new patient office visit, and an emergency department visit declines over time for new enrollees relative to ongoing Medicaid enrollees. The pattern of utilization suggests that the newly insured are connecting with primary care after the 2014 Medicaid expansion and, unlike ongoing Medicaid enrollees; the newly insured have a declining reliance on the emergency department over time. PMID- 29148335 TI - Geographic Variation in Medicaid Acceptance Across Michigan Primary Care Practices in the Era of the Affordable Care Act. AB - Coverage and access have improved under the Affordable Care Act, yet it is unclear whether recent gains have reached those regions within states that were most in need of improved access to care. We examined geographic variation in Medicaid acceptance among Michigan primary care practices before and after Medicaid expansion in the state, using data from a simulated patient study of primary care practices. We used logistic regression analysis with time indicators to assess regional changes in Medicaid acceptance over time. Geographic regions with lower baseline (<50%) Medicaid acceptance had significant increases in Medicaid acceptance at 4 and 8 months post-expansion, while regions with higher baseline (>=50%) Medicaid acceptance did not experience significant changes in Medicaid acceptance. As state Medicaid expansions continue to be implemented across the country, policy makers should consider the local dynamics of incentives for provider participation in Medicaid. PMID- 29148337 TI - Hospital Compare and Hospital Choice: Public Reporting and Hospital Choice by Hip Replacement Patients in Texas. AB - The Centers for Medicare & Medicaid Services publicizes comparative performance data on Hospital Compare, a website maintained to support consumer decision making. Given the agency's goal, this study investigates the relationship between public reporting and hospital choices of hip replacement patients in Texas. Estimating individual-level valuations of provider characteristics allowing for heterogeneity across patients, we find consumer selections and hospitals' displayed performance vary together in time. Comparing associations involving public reporting with those associated with more readily observable hospital attributes, we conclude relationships coinciding with release of comparative performance data are modest, but not inconsequential. Our use of an empirical strategy novel for evaluation of public reporting has methodological implications, while the study's affirmative result is of potential interest to policy makers and administrators. PMID- 29148336 TI - Predictors of Medication Adherence in the Elderly: The Role of Mental Health. AB - The aging population routinely has comorbid conditions requiring complicated medication regimens, yet nonadherence can preclude optimal outcomes. This study explored the association of adherence in the elderly with demographic, socioeconomic, and disease burden measures. Data were from the fifth visit (2011 2013) for 6,538 participants in the Atherosclerosis Risk in Communities Study, conducted in four communities. The Morisky-Green-Levine Scale measured self reported adherence. Forty percent of respondents indicated some nonadherence, primarily due to poor memory. Logit regression showed, surprisingly, that persons with low reading ability were more likely to report being adherent. Better self reported physical or mental health both predicted better adherence, but the magnitude of the association was greater for mental than for physical health. Compared with persons with normal or severely impaired cognition, mild cognitive impairment was associated with lower adherence. Attention to mental health measures in clinical settings could provide opportunities for improving medication adherence. PMID- 29148339 TI - The Impact of IRS Tax Policy on Hospital Community Benefit Activities. AB - The Internal Revenue Service (IRS) recently introduced tax code revisions requiring stricter oversight of community benefit activities (CBAs) conducted by tax-exempt, not-for-profit hospitals. We examine the impact of this tax requirement on CBAs among these hospitals relative to for-profit and government hospitals that were not subject to the new policy. We employed a quasi experimental, difference-in-difference study design using a longitudinal observational approach and used secondary data collected by the American Hospital Association (years 2006-2010 including 20,538 hospital year observations). Findings show a significant increase in the reporting of 7 of the 13 CBAs among tax-exempt, not-for-profit hospitals compared with other hospitals after the policy change. Examples include partnering to conduct community health assessments ( b = 0.035, p = .002) and using capacity assessments to identify unmet community health needs ( b = 0.041, p = .001). Recent tax revisions are associated with increases in reported CBAs among tax-exempt, not-for-profit hospitals. As the debate continues regarding tax exemption status for not-for profit hospitals, policy makers should expand efforts for enhanced accountability. PMID- 29148338 TI - Comprehensive Support for Family Caregivers: Impact on Veteran Health Care Utilization and Costs. AB - This study aimed to examine the early impact of the Program of Comprehensive Assistance for Family Caregivers (PCAFC) on Veteran health care utilization and costs. A pre-post cohort design including a nonequivalent control group was used to understand how Veterans' use of Veteran Affairs health care and total health care costs changed in 6-month intervals up to 3 years after PCAFC enrollment. The control group was an inverse probability of treatment weighted sample of Veterans whose caregivers applied for, but were not accepted into, PCAFC. Veterans in PCAFC had similar acute care utilization postenrollment when compared with those in the control group, but significantly greater primary, specialty, and mental health outpatient care use at least 30, and up to 36, months postenrollment. Estimated total health care costs for PCAFC Veterans were $1,500 to $3,400 higher per 6-month interval than for control group Veterans. PCAFC may have increased Veterans' access to care. PMID- 29148340 TI - The Effects of Chains on the Measurement of Competition in the Nursing Home Industry. AB - Consistently accounting for more than 50% of the nursing homes in the United States, corporate chains have played an important role in the industry for several decades. However, few studies have explicitly considered the role of chains in measuring competition in nursing home markets. In this study, we use a newly developed database tracking common ownership over a period of nearly two decades to compare chain-adjusted and unadjusted measures of competition at the county and 25 km fixed-radius levels and explore how the differences would affect the assessment of local market structure. On average, the chain-adjusted Herfindahl-Hirschman Indexes (HHIs) are about 0.02 higher than the unadjusted HHIs. Each year, about 20% to 22% of the counties would appear more concentrated when recalculating HHIs accounting for common ownership. Evidence suggests that nursing home chains tend to focus more on expanding access to new markets within a state than to increasing market power within a smaller local market. PMID- 29148341 TI - The Affordable Care Act Appears to Have Narrowed Racial and Ethnic Disparities in Insurance Coverage and Access to Care Among Young Adults. AB - Prior to the Affordable Care Act, one in three young adults aged 19 to 25 years were uninsured, with substantial racial/ethnic disparities in coverage. We analyzed the separate and cumulative changes in racial/ethnic disparities in coverage and access to care among young adults after implementation of the Affordable Care Act's 2010 dependent coverage provision and 2014 Medicaid and Marketplace expansions. We find that the dependent coverage provision was associated with similar gains across racial/ethnic groups, but the 2014 expansion was associated with larger gains in coverage among Hispanics and Blacks relative to Whites. After the 2014 expansion, coverage increased by 11.0 and 10.1 percentage points among Hispanics and Blacks, respectively, compared with a 5.6 percentage point increase among Whites. The percentage with a usual source of care and a recent doctor's visit also increased more for Blacks relative to Whites. Increases in coverage were larger in Medicaid expansion compared with nonexpansion states for most racial/ethnic groups. PMID- 29148342 TI - Undiagnosed and Uncontrolled Chronic Conditions in China: Could Social Health Insurance Consolidation Make a Change? AB - Policy makers in China are considering consolidating the country's fragmented health insurance programs. This system consists of three components. The Urban Employee Basic Medical Insurance (UEBMI) covers formal employees, the New Cooperative Medical Scheme (NCMS) covers rural residents, and the Urban Resident Basic Medical Insurance (URBMI) covers urban residents. Consolidation could, in theory, create a more efficient health system that is better able to address noncommunicable diseases. Using national survey data during 2011 to 2013, I found that 44% to 76% cases of hypertension, diabetes, and dyslipidemia went undiagnosed among Chinese adults aged 45 and older. I found that the UEBMI enrollees had a greater number of health checks and 10% higher rates of diagnosis. Assuming that this level of efficiency would be possible under an integrated system, I conducted microsimulation analyses to project future benefits. Such consolidation could result in 46.2 million new diagnoses, and 30.0 million of these cases would be controlled. PMID- 29148343 TI - Lessons Learned From the Affordable Care Act: The Premium Subsidy Design May Promote Adverse Selection. AB - Since 2014, average premiums for health plans available in the Affordable Care Act marketplaces have increased. We examine how premium price changes affected the amount consumers pay after subsidies for the lowest-cost bronze and silver plans available by age in the federally facilitated exchanges. Between 2015 and 2016, benchmark plan premiums increased in 83.3% of counties. Overall, rising benchmark premiums were associated with lower average after-subsidy premiums for the lowest-cost bronze and silver plans for older subsidy-eligible adults, but with higher after-subsidy premiums for younger adults purchasing the same plans, regardless of income. With recent discussions to replace or overhaul the Affordable Care Act, it is critical that we learn from the successes and failures of the current policy. Our findings suggest that the subsidy design, which makes rising premiums costlier for younger adults looking to purchase an entry-level plan, may be contributing to adverse selection and instability in the marketplace. PMID- 29148344 TI - Moderating Effects of Patient Characteristics on the Impact of Financial Incentives. AB - While financial incentives to providers or patients are increasingly common as a quality improvement strategy, their impact on patient subgroups and health care disparities is unclear. To examine these patterns, we analyzed data from a randomized clinical trial of financial incentives to lower low-density lipoprotein (LDL) cholesterol levels in patients at risk for cardiovascular disease. Patients with higher baseline LDL experienced greater cholesterol reductions in the shared incentive arm (0.23 mg/dL per unit change in baseline LDL, 95% CI [-0.46, -0.00]) but were also less likely to have medication potency increases in the physician incentive arm ( OR = 0.98, 95% CI [0.97, 0.996]). Uninsured patients and those of race other than Black or White were less likely to have potency increases in the shared incentive arm ( OR = 0.15, 95% CI [0.03, 0.70] and OR = 0.09, 95% CI [0.01, 0.93], respectively). These findings suggest some differential response to incentives, particularly in the form of targeted medication changes. PMID- 29148345 TI - Exploring the Role of Executive Functioning Capacity in Patient Activation and Health Outcomes Among Medicaid Members With Multiple Comorbidities. AB - Patient activation, the perceived capacity to manage one's health, is positively associated with better health outcomes and lower costs. Underlying characteristics influencing patient activation are not completely understood leading to gaps in intervention strategies designed to improve patient activation. We suggest that variability in executive functioning influences patient activation and ultimately has an impact on health outcomes. To examine this hypothesis, 440 chronically ill Medicaid enrollees completed measures of executive functioning, patient activation, and health-related quality of life. Mediation analyses revealed that executive functioning: (a) directly affected patient activation and mental health-related quality of life, (b) indirectly affected mental health-related quality of life through patient activation, and (c) was unrelated to physical health-related quality of life. These data indicate that further study of the relationships among neurocognitive processes, patient activation, and health-related quality of life is needed and reinforces previous work demonstrating the association between patient activation and self-reported outcomes. PMID- 29148346 TI - Increasing the Use of Comparative Quality Information in Maternity Care: Results From a Randomized Controlled Trial. AB - This randomized controlled trial tested an intervention to increase uptake of hospital-level maternity care quality reports among 245 pregnant women in North Carolina (123 treatment; 122 control). The intervention included three enhancements to the quality report offered to the control: (a) biweekly text messages or e-mails directing women to the website, (b) videos and materials describing the relevance of quality measures to pregnant women's interests, and (c) tools to support discussions with clinicians. Compared with controls, intervention participants were significantly more likely to visit the website and report adopting behaviors to inform care, such as thinking through preferences, talking with their doctor, or creating a birth plan. Reports designed to put quality information into the larger context of what consumers want and need to know, along with targeted and timely communications, can increase consumer use of quality information and prompt them to talk with providers about care preferences and evidence-based practices. PMID- 29148347 TI - Consumer Health Insurance Shopping Behavior and Challenges: Lessons From Two State-Based Marketplaces. AB - Selecting a health plan in a health insurance exchange is a critical decision, yet consumers are known to face challenges with health plan choice. We surveyed new enrollees in two state-based exchanges in 2015 to investigate how a nonelderly, primarily low-income population chose their health plans and the implications of shopping behavior for early experiences in their plans. Financial considerations were most important to enrollees. Prior Medicaid enrollees and the uninsured were more likely to have multiple shopping challenges (e.g., difficulty identifying the best or most affordable plan, fair/poor experience, unmet need for help) than enrollees with prior employer coverage (42.9% vs. 32.5% vs. 16.4%, respectively, p < .01). Shopping challenges were associated with difficulty finding a doctor, understanding coverage, and getting questions answered. Assistance targeting enrollees who previously had Medicaid or lacked insurance could improve both shopping experiences and downstream outcomes in plans. PMID- 29148348 TI - Increasing Trends in the Use of Hospital Observation Services for Older Medicare Advantage and Privately Insured Patients. AB - Policy and financial pressures have driven up use of observation stays for patients in traditional Medicare and the Veterans' Affairs Healthcare System. Using claims data (2004-2014) from OptumLabsTM Data Warehouse, we examined whether people in private Medicare Advantage (MA) and commercial plans experienced similar changes. We found that use of observation increased rapidly for patients in MA plans-even though MA plans were not subject to the same pressures as government-run programs. In contrast, use of observation remained constant for people in commercial plans-except for enrollees 65 and older, for whom it increased somewhat. Privately insured patients returning to the hospital after an inpatient stay were increasingly likely to be placed under observation. Our results suggest that observation is rapidly replacing inpatient admissions and readmissions for many older patients in MA and commercial plans, while younger patients continue to be admitted as inpatients at relatively constant rates. PMID- 29148349 TI - Hospital Supply Expenses: An Important Ingredient in Health Services Research. AB - The purpose of this article is to shed light on hospital supply expenses, which form the second largest expense category after payroll and hold more promise for improving cost-efficiency compared to payroll. However, limited research has rigorously scrutinized this cost category, and it is rarely given specific consideration across cost-focused studies in health services publications. After reviewing previously cited estimates, we examine and independently validate supply expense data (collected by the American Hospital Association) for over 3,500 U.S. hospitals. We find supply expenses to make up 15% of total hospital expenses, on average, but as high as 30% or 40% in hospitals with a high case-mix index, such as surgery-intensive hospitals. Future research can use supply expense data to better understand hospital strategies that aim to manage costs, such as systemization, physician-hospital arrangements, and value-based purchasing. PMID- 29148350 TI - Economic Conditions and Drug and Opioid Overdose Deaths. AB - We examine the effects of state-level economic conditions including unemployment rates, median house price, median household income, insurance coverage, and annual and weekly work time on deaths on drug overdose deaths including from opioids and prescription opioids between 1999 and 2014. We employ difference-in differences estimation controlling for state and year fixed effects, state specific time trends, and demographic characteristics. Drug overdose deaths significantly declined with higher house prices, an effect driven by reduction in prescription-opioid mortality, by nearly 0.17 deaths per 100,000 (~4%) with a $10,000 increase in median house price. House price effects were more pronounced and only significant among males, non-Hispanic Whites, and individuals younger 45 years. Other economic indicators had insignificant effects. Our findings suggest that economic downturns that substantially reduce house prices such as the Great Recession can increase opioid-related deaths, suggesting that efforts to control access to such drugs should especially intensify during these periods. PMID- 29148351 TI - Opioid Prescribing by Nurse Practitioners in Medicare Part D: Impact of State Scope of Practice Legislation. AB - Many state legislatures restrict nurse practitioner (NP) scope of practice as a way of addressing patient safety concerns. The purpose of this study was to investigate the influence of state NP scope of practice laws on the prescription of oxycodone and hydrocodone containing medications by NP and MD/DO/PA prescribers to Medicare Part D beneficiaries. Using the Medicare Part D public use file, we analyzed oxycodone and hydrocodone containing prescriptions per Medicare Part D beneficiary by prescriber type, NP state scope of practice, and geographic variables. Our results demonstrate that the state scope of practice variable had the same effect, in identical direction and significance, on NP opioid prescribing patterns as it had on MD/DO/PA prescribers, a group to whom NP scope of practice laws do not apply. Thus, scope of practice in this study was not an exclusive predictor of NP practice and prescribing. PMID- 29148352 TI - Nursing Home Response to Nursing Home Compare: The Provider Perspective. AB - Nursing Home Compare (NHC) publishes composite quality ratings of nursing homes based on a five-star rating system, a system that has been subject to controversy about its validity. Using in-depth interviews, we assess the views of nursing home administrators and staff on NHC and unearth strategies used to improve ratings. Respondents revealed conflicting goals and strategies. Although nursing home managers monitor the ratings and expend effort to improve scores, competing goals of revenue maximization and avoidance of litigation often overshadow desire to score well on NHC. Some of the improvement strategies simply involve coding changes that have no effect on resident outcomes. Many respondents doubted the validity of the self-reported staffing data and stated that lack of risk adjustment biases ratings. Policy makers should consider nursing home incentives when refining the system, aiming to improve the validity of the self-reported domains to provide incentives for broader quality improvement. PMID- 29148353 TI - Uses of Population Health Rankings in Local Policy Contexts: A Multisite Case Study. AB - Population health rankings are a common strategy to spur evidence-informed health policy making, but little is known about their uses or impacts. The study aims were to (1) understand how and why the County Health Rankings (CH-Rankings) are used in local policy contexts, (2) identify factors that influence CH-Rankings utilization, and (3) explore potentially negative impacts of the CH-Rankings. Forty-four interviews were conducted with health organization officials and public policy makers in 15 purposively selected counties. The CH-Rankings were used instrumentally to inform internal planning decisions, conceptually to educate the public and policy makers about determinants of population health, and politically to advance organizational agendas. Factors related to organizational capacity, county political ideology, and county rank influenced if, how, and why the CH-Rankings were used. The CH-Rankings sometimes had the negative impacts of promoting potentially ineffective interventions in politically conservative counties and prompting negative media coverage in some counties with poor rank. PMID- 29148354 TI - Case Managers for High-Risk, High-Cost Patients as Agents and Street-Level Bureaucrats. AB - Case management programs often designate a nurse or social worker to take responsibility for guiding care when patients are expected to be expensive or risk a major decline. We hypothesized that though an intuitively appealing idea, careful program design and faithful implementation are essential if case management programs are to succeed. We employed two theory perspectives, principal-agent framework and street-level bureaucratic theory to describe the relationship between program designers (principals) and case managers (agents/street-level bureaucrats) to review 65 case management studies. Most programs were successful in limited program-specific process and outcome goals. But there was much less success in cost-saving or cost-effectiveness-the original and overarching goal of case management. Cost results might be improved if additional ideas of agency and street-level theory were adopted, specifically, incentives, as well as "green tape," clear rules, guidelines, and algorithms relating to resource allocation among patients. PMID- 29148355 TI - Vertical Integration of Hospitals and Physicians: Economic Theory and Empirical Evidence on Spending and Quality. AB - Hospital-physician vertical integration is on the rise. While increased efficiencies may be possible, emerging research raises concerns about anticompetitive behavior, spending increases, and uncertain effects on quality. In this review, we bring together several of the key theories of vertical integration that exist in the neoclassical and institutional economics literatures and apply these theories to the hospital-physician relationship. We also conduct a literature review of the effects of vertical integration on prices, spending, and quality in the growing body of evidence ( n = 15) to evaluate which of these frameworks have the strongest empirical support. We find some support for vertical foreclosure as a framework for explaining the observed results. We suggest a conceptual model and identify directions for future research. Based on our analysis, we conclude that vertical integration poses a threat to the affordability of health services and merits special attention from policymakers and antitrust authorities. PMID- 29148356 TI - Specialization as an Organizing Principle: The Case of Ambulatory Surgery Centers. AB - Ambulatory surgery centers (ASCs) recently have grown to become the dominant provider of specific surgical procedures in the United States. While the majority of ASCs focus primarily on a single specialty, many have diversified to offer a wide range of surgical specialties. We exploited a unique data set from Pennsylvania for the years 2004 to 2014 to conduct an empirical investigation of the relative cost of production in ASCs over varying degrees of specialization. We found that for the majority of ASCs, focus on a specialty was associated with lower facility costs. In addition, ASCs appeared to be capturing economies of scale over a broad range of service volume. In contrast to studies of cost efficiency in specialty hospitals, our results provide evidence that supports the focused factory model of production in the ASC sector. PMID- 29148357 TI - Cuts and the cutting edge: British science funding and the making of animal biotechnology in 1980s Edinburgh. AB - The Animal Breeding Research Organisation in Edinburgh (ABRO, founded in 1945) was a direct ancestor of the Roslin Institute, celebrated for the cloning of Dolly the sheep. After a period of sustained growth as an institute of the Agricultural Research Council (ARC), ABRO was to lose most of its funding in 1981. This decision has been absorbed into the narrative of the Thatcherite attack on science, but in this article I show that the choice to restructure ABRO pre-dated major government cuts to agricultural research, and stemmed from the ARC's wish to prioritize biotechnology in its portfolio. ABRO's management embraced this wish and campaigned against the cuts based on a promise of biotechnological innovation, shifting its focus from farm animal genetics to the production of recombinant pharmaceuticals in sheep milk. By tracing interaction between government policies, research council agendas and local strategies, I show how novel research programmes such as genetic modification could act as a lifeline for struggling institutions. PMID- 29148358 TI - All change...transcanal endoscopic ear surgery and house dust mite immunotherapy for allergic rhinitis. PMID- 29148359 TI - Albirhodobacter confluentis sp. nov., isolated from an estuary. AB - A Gram-stain-negative and strictly aerobic, moderately halophilic bacterium, designated strain S1-47T, was isolated from estuary sediment in South Korea. Cells were non-motile rods showing oxidase- and catalase-positive activities. Growth was observed at 10-30 degrees C (optimum, 25 degrees C), at pH 5.0-8.0 (optimum, pH 6.0-7.0) and in the presence of 0-6.0 % (w/v) NaCl (optimum, 2.0 %). Strain S1-47T contained summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c) and C16 : 0 as major cellular fatty acids and ubiquinone-10 as the sole isoprenoid quinone. Phosphatidylethanolamine, an unidentified aminolipid, an unidentified phospholipid and three unidentified lipids were detected as polar lipids. The G+C content of the genomic DNA was 69.3 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain S1-47T formed a tight phylogenetic lineage with Albirhodobacter marinus N9T. Strain S1-47T was most closely related to Albirhodobactermarinus N9T with a 99.4 % 16S rRNA gene sequence similarity. DNA DNA relatedness levels between strain S1-47T and the type strain of Albirhodobactermarinus were 49.8-52.2 %. Based on the phenotypic, chemotaxonomic and molecular features, strain S1-47T clearly represents a novel species of the genus Albirhodobacter, for which the name Albirhodobacter confluentis sp. nov. is proposed. The type strain is S1-47T (=KACC 18804T=JCM 31536T). PMID- 29148360 TI - Corynebacterium godavarianum sp. nov., isolated from the Godavari river, India. AB - A Gram-stain-positive, rod-shaped, non-motile bacterium, strain PRD07T, was isolated from Godavari river, India during the world's largest spiritual and religious mass bathing event 'Kumbh Mela'. Molecular analysis using 16S rRNA gene sequencing and phylogenetic analysis reveals the distinct phylogenetic positioning of strain PRD07T within the genus Corynebacterium. The strain demonstrated highest sequence similarity to Corynebacterium imitans DSM 44264T (97.9 %), Corynebacterium appendicis DSM 44531T (97.1 %) and <96.7 % with all other members of the genus Corynebacterium. The G+C content of PRD07T was 68.5 mol% (Tm) and the DNA-DNA hybridization depicts 61.09 % genomic relatedness with C. imitans DSM 44264T. Chemotaxonomic assessment of strain PRD07T suggested presence of C16 : 0 (31.6 %), C18 : 0 (3.5 %) and C18 : 1omega9c (58.6 %) as the major cellular fatty acids. The major polar lipids of strain PRD07T were phosphatidylglycerol, diphosphatidylglycerol and glycophospholipid. Differentiating molecular, phylogenetic and chemotaxonomic characteristics of strain PRD07T with its closest relatives necessitated the description of strain PRD07T as a novel species of genus Corynebacterium for which the name Corynebacteriumgodavarianum sp. nov., has been proposed. The type strain is PRD07T (=MCC 3388T=KCTC 39803T=LMG 29598T). PMID- 29148361 TI - Characterization of biofilm formation by Enterococcus faecalis isolates derived from urinary tract infections in China. AB - PURPOSE: This study explored the prevalence and characteristics of Enterococcus faecalis biofilm formation by urinary tract infection (UTI) isolates in order to identify virulence factors associated with biofilm formation. METHODOLOGY: A total of 113 E. faecalis isolates were collected from UTI patients in Shenzhen, China. The isolates were subjected to multilocus sequence typing based on housekeeping genes. Biofilms were detected by crystal violet staining and the expression levels of the E. faecalis genes were detected by quantitative real time PCR.Results/Key findings. The main sequence types (STs) were ST16 and ST179 with the ST16 isolates more likely to form strong biofilms than the ST179 isolates (P=0.008). Strong biofilm formation was more frequently detected in aggregation substance (agg)-positive (+) isolates than in negative (-) isolates (P=0.033). Biofilm formation was also more common in isolates containing enterococcal surface protein (esp), or cytolysin A (cylA)-positive (+) isolates than in isolates negative (-) for these virulence factors. Multivariate regression analysis indicated that cylA [odds ratio (OR), 7.143, P=0.012] was associated with weak biofilm formation, and that agg (OR, 4.471, P=0.004) was associated with strong biofilm formation. The expression of cylA was increased (8.75- to 23.05-fold) in weak biofilm, and the expression of agg was greatly elevated (11.99- to 439.10-fold) in strong biofilm isolates when compared to biofilm-negative isolates. CONCLUSION: ST16 classification was positively associated with strong biofilm formation in E. faecalis as was agg, while cylA was associated with weak biofilm formation. PMID- 29148362 TI - Pseudomonas floridensis sp. nov., a bacterial pathogen isolated from tomato. AB - An unusual fluorescent pseudomonad was isolated from tomato exhibiting leaf spot symptoms similar to bacterial speck. Strains were fluorescent, oxidase- and arginine-dihydrolase-negative, elicited a hypersensitive reaction on tobacco and produced a soft rot on potato slices. However, the strains produced an unusual yellow, mucoid growth on media containing 5 % sucrose that is not typical of levan. Based on multilocus sequence analysis using 16S rRNA, gap1, gltA, gyrB and rpoD, these strains formed a distinct phylogenetic group in the genus Pseudomonas and were most closely related to Pseudomonas viridiflava within the Pseudomonassyringae complex. Whole-genome comparisons, using average nucleotide identity based on blast, of representative strain GEV388T and publicly available genomes representing the genus Pseudomonas revealed phylogroup 7 P. viridiflava strain UASW0038 and P. viridiflava type strain ICMP 2848T as the closest relatives with 86.59 and 86.56 % nucleotide identity, respectively. In silico DNA DNA hybridization using the genome-to-genome distance calculation method estimated 31.1 % DNA relatedness between GEV388T and P. viridiflava ATCC 13223T, strongly suggesting the strains are representatives of different species. These results together with Biolog GEN III tests, fatty acid methyl ester profiles and phylogenetic analysis using 16S rRNA and multiple housekeeping gene sequences demonstrated that this group represents a novel species member of the genus Pseudomonas. The name Pseudomonas floridensis sp. nov. is proposed with GEV388T (=LMG 30013T=ATCC TSD-90T) as the type strain. PMID- 29148363 TI - Hymenobacter defluvii sp. nov., isolated from wastewater of an acidic water neutralization facility. AB - A non-motile, pink-coloured and rod-shaped bacterium, designated strain POA9T, was isolated from a wastewater treatment facility, Republic of Korea. Cells were Gram-reaction-negative, aerobic, catalase-positive and oxidase-negative. The major fatty acids were C16 : 1omega5c, iso-C15 : 0, summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c) and anteiso-C15 : 0. The strain contained MK-7 as the only isoprenoid quinone, phosphatidylethanolamine as the major polar lipid and sym-homospermidine as the major polyamine. The DNA G+C content was 57 mol%. A phylogenetic tree based on 16S rRNA gene sequences showed that strain POA9T forms a distinct evolutionary lineage within the radiation enclosing the members of the genus Hymenobacter, sharing the highest similarity with Hymenobacter actinosclerus CCUG 39621T (95.5 % sequence similarity) followed by Hymenobacterseoulensis 16F7GT (95.5 %), Hymenobactertibetensis XTM003T (95.4 %), Hymenobacterrutilus K2-33028T (95.4 %) and Hymenobacter psychrotolerans Tibet IIU11T (94.9 %). A number of phenotypic characteristics distinguished strain POA9T from the related members of the genus Hymenobacter. On the basis of the evidence presented in this study, a novel species, Hymenobacter defluvii sp. nov., is proposed for strain POA9T (=KCTC 52270T=JCM 31658T). PMID- 29148364 TI - Salibacterium lacus sp. nov., a halophilic, non-spore-forming bacterium isolated from sediment of a saline lake. AB - A novel halophilic bacterium, strain GSS13T, capable of growing at salinities of 8-28 % (w/v) NaCl (optimally at 24 %, w/v) was isolated from Yuncheng Saline Lake in China. GSS13T was Gram-stain-positive, strictly aerobic, rod-shaped, motile and a non-spore-former. Growth occurred at pH 5.5-8.5 (optimum pH 7.0) and at 10 45 degrees C (optimum 30 degrees C). On the basis of the results of 16S rRNA gene sequences phylogenetic analyses, GSS13T represents a member of the genus Salibacterium and is closely related to Salibacterium halotolerans S7T, Salibacterium qingdaonense CM1T and Salibacterium halochares MSS4T, with 16S rRNA gene sequence similarities of 98.7, 98.4 and 97.9 %, respectively. The results of DNA-DNA pairing studies revealed that GSS13T displayed 52, 43 and 48 % relatedness to S. halotolerans S7T, S. qingdaonense CM1T and S. halochares MSS4T, respectively. The polar lipids of GSS13 consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol unidentified glycolipids, an unidentified phospholipid and an unidentified lipid. The predominant isoprenoid quinone was MK-7, and the major fatty acids were anteiso-C17 : 0 (32.0 %) and anteiso C15 : 0 (26.4 %). The DNA G+C content of the type strain was 52.1 mol%. On the basis of phylogenetic, chemotaxonomic and phenotypic data, a novel species of the genus Salibacterium is proposed, with the name Salibacterium lacus sp. nov. The type strain is GSS13T (=KCTC 33792T=MCCC 1K00567T). PMID- 29148365 TI - Tenacibaculum insulae sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, aerobic, non-motile, non-spore-forming bacterial strain, designated JDTF-31T, was isolated from a tidal flat in Jindo, a South Korean island. Strain JDTF-31T grew optimally at 25 degrees C and in the presence of 2.0 % (w/v) NaCl. The neighbour-joining phylogenetic tree based on 16S rRNA gene sequences revealed that strain JDTF-31T fell within the cluster comprising the type strains of Tenacibaculum species, joining the type strain of Tenacibaculum soleae. The novel strain exhibited 16S rRNA gene sequence similarity values of 98.3, 97.8 and 97.1 % to the type strains of T. soleae, Tenacibaculum haliotisand Tenacibaculum ovolyticum, respectively, and of 94.2-96.8 % to the type strains of the other Tenacibaculum species. Strain JDTF-31T contained MK-6 as the predominant menaquinone and iso-C15 : 0 and iso-C15 : 0 3-OH as the major fatty acids. The major polar lipids of strain JDTF-31T were phosphatidylethanolamine, one unidentified lipid and one unidentified aminophospholipid. The DNA G+C content of strain JDTF-31T was 31.3 mol% and its DNA-DNA relatedness values with the type strains of T. soleae, T. haliotis and T. ovolyticum were 16-27 %. The differential phenotypic properties, together with its phylogenetic and genetic data, revealed that strain JDTF-31T is separated from other recognized species of the genus Tenacibaculum. On the basis of the data presented, strain JDTF-31T represents a novel species of the genus Tenacibaculum, for which the name Tenacibaculuminsulae sp. nov. is proposed. The type strain is JDTF-31T (=KCTC 52749T=NBRC 112783T). PMID- 29148366 TI - Involvement of the ytfK gene from the PhoB regulon in stationary-phase H2O2 stress tolerance in Escherichia coli. AB - The Escherichia coli PhoB-PhoR two-component system responds to phosphate starvation and induces the expression of many genes. Previous studies suggested that phosphate starvation induces oxidative stress, but the involvement of the PhoB regulon in oxidative stress tolerance has not been clarified. Here, we showed that ytfK, one of the PhoB regulon genes, is involved in cell tolerance to a redox-cycling drug, menadione, and H2O2 in stationary-phase cells. A ytfK deletion mutant was sensitive to H2O2 when the cells were grown anaerobically or micro-aerobically in the presence of nitrate. Genetic analysis suggested that the ytfK gene has a functional relationship with the oxyR and fur genes, among the oxyR regulon, at least, a catalase-encoding katG gene and peroxidase-encoding ahpCF genes. Overproduction of YtfK resulted in a KatG-dependent decrease of H2O2 concentration in the cell suspension, suggesting that katG is one of the targets of YtfK. Using a katG'-lacZ reporter fusion, we showed that YtfK enhances the transcription of katG although it was not clarified whether YtfK functions directly or not. We also showed that ytfK disruption results in reduced viability of stationary-phase cells under phosphate starvation. These results indicated that YtfK is involved in H2O2 tolerance by stimulating directly or indirectly the transcription of at least the catalase gene, and that this system plays an important role in cellular survival during phosphate starvation. PMID- 29148367 TI - Micromonospora phytophila sp. nov. and Micromonospora luteiviridis sp. nov., isolated as natural inhabitants of plant nodules. AB - Two actinobacterial isolates, strains SG15T and SGB14T, were recovered through a microbial diversity study of nitrogen fixing nodules from Pisum sativum plants collected in Salamanca (Spain). The taxonomic status of these isolates was determined using a polyphasic approach and both presented chemotaxonomic and morphological properties consistent with their classification in the genus Micromonospora. For strains SG15T and SGB14T, the highest 16S rRNA gene sequence similarities were observed with Micromonospora coxensis JCM 13248T (99.2 %) and Micromonospora purpureochromogenes DSM 43821T (99.4 %), respectively. However, strains SG15T and SGB14T were readily distinguished from their phylogenetic neighbours both genetically and phenotypically indicating that they represent two new Micromonospora species. The following names are proposed for these species: Micromonosporaphytophila sp. nov. type strain SG15T (=CECT 9369T; =DSM 105363T), and Micromonosporaluteiviridis sp. nov. type strain SGB14T (=CECT 9370T; =DSM 105362T). PMID- 29148368 TI - Lack of Secondary Transmission of Ebola Virus from Healthcare Worker to 238 Contacts, United Kingdom, December 2014. AB - In December 2014, Ebola virus disease (EVD) was diagnosed in a healthcare worker in the United Kingdom after the worker returned from an Ebola treatment center in Sierra Leone. The worker flew on 2 flights during the early stages of disease. Follow-up of 238 contacts showed no evidence of secondary transmission of Ebola virus. PMID- 29148369 TI - Newly Recognized Pediatric Cases of Typhus Group Rickettsiosis, Houston, Texas, USA. AB - An increase in typhus group rickettsiosis and an expanding geographic range occurred in Texas, USA, over a decade. Because this illness commonly affects children, we retrospectively examined medical records from 2008-2016 at a large Houston-area pediatric hospital and identified 36 cases. The earliest known cases were diagnosed in 2011. PMID- 29148370 TI - Phylogenetic Characterization of Crimean-Congo Hemorrhagic Fever Virus, Spain. AB - Two cases of Crimean-Congo hemorrhagic fever were reported in Spain during 2016. We obtained the virus from a patient sample and characterized its full genomic sequence. Phylogenetic analysis indicated that the virus corresponds to the African genotype III, which includes viruses previously found in West and South Africa. PMID- 29148371 TI - Diagnostic Accuracy of Parameters for Zika and Dengue Virus Infections, Singapore. AB - Singapore experienced its first documented Zika virus outbreak in 2016. We identified clinical and laboratory parameters that increase the probability for Zika or dengue virus infection. Early during the illness, combinations of key parameters obtained through clinical assessment and hematologic tests can help distinguish between these infections. PMID- 29148372 TI - Deaths among Wild Birds during Highly Pathogenic Avian Influenza A(H5N8) Virus Outbreak, the Netherlands. AB - During autumn-winter 2016-2017, highly pathogenic avian influenza A(H5N8) viruses caused mass die-offs among wild birds in the Netherlands. Among the ~13,600 birds reported dead, most were tufted ducks (Aythya fuligula) and Eurasian wigeons (Anas penelope). Recurrence of avian influenza outbreaks might alter wild bird population dynamics. PMID- 29148373 TI - Mycobacterium ulcerans DNA in Bandicoot Excreta in Buruli Ulcer-Endemic Area, Northern Queensland, Australia. AB - To identify potential reservoirs/vectors of Mycobacterium ulcerans in northern Queensland, Australia, we analyzed environmental samples collected from the Daintree River catchment area, to which Buruli ulcer is endemic, and adjacent coastal lowlands by species-specific PCR. We detected M. ulcerans DNA in soil, mosquitoes, and excreta of bandicoots, which are small terrestrial marsupials. PMID- 29148374 TI - Pathogenic Elizabethkingia miricola Infection in Cultured Black-Spotted Frogs, China, 2016. AB - Multiregional outbreaks of meningitis-like disease caused by Elizabethkingia miricola were confirmed in black-spotted frog farms in China in 2016. Whole genome sequencing revealed that this amphibian E. miricola strain is closely related to human clinical isolates. Our findings indicate that E. miricola can be epizootic and may pose a threat to humans. PMID- 29148375 TI - West Nile Virus Lineage 2 in Horses and Other Animals with Neurologic Disease, South Africa, 2008-2015. AB - During 2008-2015 in South Africa, we conducted West Nile virus surveillance in 1,407 animals with neurologic disease and identified mostly lineage 2 cases in horses (7.4%, 79/1,069), livestock (1.5%, 2/132), and wildlife (0.5%, 1/206); 35% were fatal. Geographic correlation of horse cases with seropositive veterinarians suggests disease in horses can predict risk in humans. PMID- 29148376 TI - Identification of Dermacentor reticulatus Ticks Carrying Rickettsia raoultii on Migrating Jackal, Denmark. AB - From a migrating golden jackal (Canis aureus), we retrieved 21 live male Dermacentor reticulatus ticks, a species not previously reported from wildlife in Denmark. We identified Rickettsia raoultii from 18 (86%) of the ticks. This bacterium is associated with scalp eschar and neck lymphadenopathy after tick bite syndrome among humans. PMID- 29148377 TI - Tick-Borne Encephalitis in Sheep, Romania. AB - Little is known about the occurrence of tick-borne encephalitis in Romania. Sheep are an infection source for humans and are useful sentinels for risk analysis. We demonstrate high antibody prevalence (15.02%) among sheep used as sentinels for this disease in 80% of the tested localities in 5 counties of northwestern Romania. PMID- 29148378 TI - Outbreak of Yellow Fever among Nonhuman Primates, Espirito Santo, Brazil, 2017. AB - In January 2017, a yellow fever outbreak occurred in Espirito Santo, Brazil, where human immunization coverage is low. Histologic, immunohistologic, and PCR examinations were performed for 22 deceased nonhuman New World primates; typical yellow fever features were found in 21. Diagnosis in nonhuman primates prompted early public health response. PMID- 29148379 TI - Characterization of Streptococcus pyogenes from Animal Clinical Specimens, Spain. AB - Streptococcus pyogenes appears to be almost exclusively restricted to humans, with few reports on isolation from animals. We provide a detailed characterization (emm typing, pulsed-field gel electrophoresis [PFGE], and multilocus sequence typing [MLST]) of 15 S. pyogenes isolates from animals associated with different clinical backgrounds. We also investigated erythromycin resistance mechanisms and phenotypes and virulence genes. We observed 2 emm types: emm12 (11 isolates) and emm77 (4 isolates). Similarly, we observed 2 genetic linages, sequence type (ST) 26 and ST63. Most isolates exhibited the M macrolide resistance phenotype and the mefA/ermB genotype. Isolates were grouped into 2 clones on the basis of emm-MLST-PFGE-virulence gene profile combinations: clone 1, characterized by the combined genotype emm12-ST36-pulsotype A-speG; and clone 2, characterized by the genotype emm77-ST63-pulsotype B-speC. Our results do not show conclusively that animals may represent a new reservoir of S. pyogenes but indicate the ability of human-derived S. pyogenes isolates to colonize and infect animals. PMID- 29148381 TI - Unexpected Infection with Armillifer Parasites. AB - Visceral pentastomiasis is usually found incidentally during surgery. We describe a case of visceral pentastomiasis discovered during inguinoscrotal hernia surgery for a man from Benin, Africa. Because surgical removal of nymphs is needed for symptomatic patients only, this patient's asymptomatic pentastomiasis was not treated and he recovered from surgery uneventfully. PMID- 29148380 TI - High Rate of MCR-1-Producing Escherichia coli and Klebsiella pneumoniae among Pigs, Portugal. AB - The mcr-1 (mobile colistin resistance 1) gene, which encodes phosphoethanolamine transferase, has been recently identified as a source of acquired resistance to polymyxins in Escherichia coli. Using the SuperPolymyxin selective medium, we prospectively screened 100 pigs at 2 farms in Portugal for polymyxin-resistant Enterobacteriaceae and recovered 98 plasmid-mediated MCR-1-producing isolates. Most isolates corresponded to nonclonally related E. coli belonging to many sequence types; we also found 2 Klebsiella pneumoniae sequence types. The mcr-1 gene was carried on IncHI2 or IncP plasmid backbones. Our finding of a high rate of MCR-1 producers on 2 pig farms in Portugal highlights the diffusion of that colistin-resistance determinant at the farm level. The fact that the pigs received colistin as metaphylaxis in their feed during the 6 weeks before sampling suggests selective pressure. PMID- 29148382 TI - High Abundance and Genetic Variability of Atypical Porcine Pestivirus in Pigs from Europe and Asia. AB - Atypical porcine pestivirus (APPV) was recently reported to be associated with neurologic disorders in newborn piglets. Investigations of 1,460 serum samples of apparently healthy pigs from different parts of Europe and Asia demonstrate a geographically wide distribution of genetically highly variable APPV and high APPV genome and antibody detection rates. PMID- 29148383 TI - Porcine Astrovirus Type 3 in Central Nervous System of Swine with Polioencephalomyelitis. AB - Using next-generation sequencing, we identified and genetically characterized a porcine astrovirus type 3 strain found in tissues from the central nervous system of 1 piglet and 3 sows with neurologic signs and nonsuppurative polioencephalomyelitis. Further studies are needed to understand the potential for cross-species transmission and clinical impact. PMID- 29148384 TI - Moku Virus in Invasive Asian Hornets, Belgium, 2016. AB - We report the detection of Moku virus in invasive Asian hornets (Vespa velutina nigrithorax) in Belgium. This constitutes an unexpected report of this iflavirus outside Hawaii, USA, where it was recently described in social wasps. Although virulence of Moku virus is unknown, its potential spread raises concern for European honeybee populations. PMID- 29148385 TI - Tool for Eliminating Dog-Mediated Human Rabies through Mass Dog Vaccination Campaigns. AB - The World Health Organization and collaborating agencies have set the goal of eliminating dog-mediated human rabies by 2030. Building on experience with rabies endemic countries, we constructed a user-friendly tool to help public health officials plan the resources needed to achieve this goal through mass vaccination of dogs. PMID- 29148386 TI - Human Case of Streptococcus suis Disease, Ontario, Canada. AB - We report a case of Streptococcus suis human disease in Ontario, Canada, caused by a serotype 2 strain genotypically similar to those commonly isolated from pigs in North America. Initially, the isolate was misidentified as a viridans group Streptococcus. Human S. suis infections may be underdiagnosed in North America. PMID- 29148387 TI - Incentives for Bushmeat Consumption and Importation among West African Immigrants, Minnesota, USA. AB - The knowledge, attitudes, and practices surrounding bushmeat consumption and importation in the United States are not well described. Focus groups of West African persons living in Minnesota, USA, found that perceived risks are low and unlikely to deter consumers. Incentives for importation and consumption were multifactorial in this community. PMID- 29148388 TI - Avian Influenza (H7N9) Viruses Co-circulating among Chickens, Southern China. AB - In April 2017, three avian influenza (H7N9) viruses were isolated from chickens in southern China. Each virus had different insertion points in the cleavage site of the hemagglutinin protein compared to the first identified H7N9 virus. We determined that these viruses were double or triple reassortant viruses. PMID- 29148389 TI - Angiostrongylus cantonensis DNA in Cerebrospinal Fluid of Persons with Eosinophilic Meningitis, Laos. AB - Definitive identification of Angiostrongylus cantonensis parasites from clinical specimens is difficult. As a result, regional epidemiology and burden are poorly characterized. To ascertain presence of this parasite in patients in Laos with eosinophilic meningitis, we performed quantitative PCRs on 36 cerebrospinal fluid samples; 4 positive samples confirmed the parasite's presence. PMID- 29148390 TI - Rabies and Distemper Outbreaks in Smallest Ethiopian Wolf Population. AB - Widespread deaths recently devastated the smallest known population of Ethiopian wolves. Of 7 carcasses found, all 3 tested were positive for rabies. Two wolves were subsequently vaccinated for rabies; 1 of these later died from canine distemper. Only 2 of a known population of 13 wolves survived. PMID- 29148392 TI - Acute Myopericarditis Associated with Tickborne Rickettsia sibirica mongolitimonae. AB - We report an unusual case of myopericarditis caused by Rickettsia sibirica mongolitimonae. Because of increasing reports of Rickettsia spp. as etiologic agents of acute myopericarditis and the ease and success with which it was treated in the patient reported here, rickettsial infection should be included in the differential diagnosis for myopericarditis. PMID- 29148391 TI - Outbreaks of Neuroinvasive Astrovirus Associated with Encephalomyelitis, Weakness, and Paralysis among Weaned Pigs, Hungary. AB - A large, highly prolific swine farm in Hungary had a 2-year history of neurologic disease among newly weaned (25- to 35-day-old) pigs, with clinical signs of posterior paraplegia and a high mortality rate. Affected pigs that were necropsied had encephalomyelitis and neural necrosis. Porcine astrovirus type 3 was identified by reverse transcription PCR and in situ hybridization in brain and spinal cord samples in 6 animals from this farm. Among tissues tested by quantitative RT-PCR, the highest viral loads were detected in brain stem and spinal cord. Similar porcine astrovirus type 3 was also detected in archived brain and spinal cord samples from another 2 geographically distant farms. Viral RNA was predominantly restricted to neurons, particularly in the brain stem, cerebellum (Purkinje cells), and cervical spinal cord. Astrovirus was generally undetectable in feces but present in respiratory samples, indicating a possible respiratory infection. Astrovirus could cause common, neuroinvasive epidemic disease. PMID- 29148393 TI - New Avian Hepadnavirus in Palaeognathous Bird, Germany. AB - In 2015, we identified an avian hepatitis B virus associated with hepatitis in a group of captive elegant-crested tinamous (Eudromia elegans) in Germany. The full length genome of this virus shares <76% sequence identity with other avihepadnaviruses. The virus may therefore be considered a new extant avian hepadnavirus. PMID- 29148394 TI - Enteropathogenic Escherichia coli O80:H2 in Young Calves with Diarrhea, Belgium. AB - Serogroup O80 was detected in 40% of 104 enteropathogenic Escherichia coli isolates from calves with diarrhea from 42 farms in Belgium during 2008-2015. These isolates harbored the eae-xi and fliCH2 genes, similar to the O80 attaching effacing Shigatoxigenic E. coli isolates found in humans in France. This strain might be emerging. PMID- 29148395 TI - Bourbon Virus in Field-Collected Ticks, Missouri, USA. AB - Bourbon virus (BRBV) was first isolated in 2014 from a resident of Bourbon County, Kansas, USA, who died of the infection. In 2015, an ill Payne County, Oklahoma, resident tested positive for antibodies to BRBV, before fully recovering. We retrospectively tested for BRBV in 39,096 ticks from northwestern Missouri, located 240 km from Bourbon County, Kansas. We detected BRBV in 3 pools of Amblyomma americanum (L.) ticks: 1 pool of male adults and 2 pools of nymphs. Detection of BRBV in A. americanum, a species that is aggressive, feeds on humans, and is abundant in Kansas and Oklahoma, supports the premise that A. americanum is a vector of BRBV to humans. BRBV has not been detected in nonhuman vertebrates, and its natural history remains largely unknown. PMID- 29148396 TI - Multiple Reassorted Viruses as Cause of Highly Pathogenic Avian Influenza A(H5N8) Virus Epidemic, the Netherlands, 2016. AB - In 2016, an epidemic of highly pathogenic avian influenza A virus subtype H5N8 in the Netherlands caused mass deaths among wild birds, and several commercial poultry farms and captive bird holdings were affected. We performed complete genome sequencing to study the relationship between the wild bird and poultry viruses. Phylogenetic analysis showed that the viruses are related to H5 clade 2.3.4.4 viruses detected in Russia in May 2016 but contained novel polymerase basic 2 and nucleoprotein gene segments and 2 different variants of the polymerase acidic segment. Molecular dating suggests that the reassortment events most likely occurred in wild birds in Russia or Mongolia. Furthermore, 2 genetically distinct H5N5 reassortant viruses were detected in wild birds in the Netherlands. Our study provides evidence for fast and continuing reassortment of H5 clade 2.3.4.4 viruses, which might lead to rapid changes in virus characteristics, such as pathogenicity, infectivity, transmission, and zoonotic potential. PMID- 29148397 TI - Evolutionary Context of Non-Sorbitol-Fermenting Shiga Toxin-Producing Escherichia coli O55:H7. AB - In July 2014, an outbreak of Shiga toxin-producing Escherichia coli (STEC) O55:H7 in England involved 31 patients, 13 (42%) of whom had hemolytic uremic syndrome. Isolates were sequenced, and the sequences were compared with publicly available sequences of E. coli O55:H7 and O157:H7. A core-genome phylogeny of the evolutionary history of the STEC O55:H7 outbreak strain revealed that the most parsimonious model was a progenitor enteropathogenic O55:H7 sorbitol-fermenting strain, lysogenized by a Shiga toxin (Stx) 2a-encoding phage, followed by loss of the ability to ferment sorbitol because of a non-sense mutation in srlA. The parallel, convergent evolutionary histories of STEC O157:H7 and STEC O55:H7 may indicate a common driver in the evolutionary process. Because emergence of STEC O157:H7 as a clinically significant pathogen was associated with acquisition of the Stx2a-encoding phage, the emergence of STEC O55:H7 harboring the stx2a gene is of public health concern. PMID- 29148398 TI - Investigation of Acute Flaccid Paralysis Reported with La Crosse Virus Infection, Ohio, USA, 2008-2014. AB - Infection with La Crosse virus can cause meningoencephalitis, but it is not known to cause acute flaccid paralysis (AFP). During 2008-2014, nine confirmed or probable La Crosse virus disease cases with possible AFP were reported in Ohio, USA. After an epidemiologic and clinical investigation, we determined no patients truly had AFP. PMID- 29148399 TI - Distribution of Usutu Virus in Germany and Its Effect on Breeding Bird Populations. AB - Usutu virus (USUV) is an emerging mosquitoborne flavivirus with an increasing number of reports from several countries in Europe, where USUV infection has caused high avian mortality rates. However, 20 years after the first observed outbreak of USUV in Europe, there is still no reliable assessment of the large scale impact of USUV outbreaks on bird populations. In this study, we identified the areas suitable for USUV circulation in Germany and analyzed the effects of USUV on breeding bird populations. We calculated the USUV-associated additional decline of common blackbird (Turdus merula) populations as 15.7% inside USUV suitable areas but found no significant effect for the other 14 common bird species investigated. Our results show that the emergence of USUV is a further threat for birds in Europe and that the large-scale impact on population levels, at least for common blackbirds, must be considered. PMID- 29148400 TI - Avian Influenza A(H7N2) Virus in Human Exposed to Sick Cats, New York, USA, 2016. AB - An outbreak of influenza A(H7N2) virus in cats in a shelter in New York, NY, USA, resulted in zoonotic transmission. Virus isolated from the infected human was closely related to virus isolated from a cat; both were related to low pathogenicity avian influenza A(H7N2) viruses detected in the United States during the early 2000s. PMID- 29148401 TI - Vitamin D and systemic lupus erythematous: a review of immunological and clinical aspects. AB - OBJECTIVES: To review the relationships between vitamin D status and systemic lupus erythematosus (SLE) concerning immunological, clinical aspects and possible effects of supplementation in disease modulation. METHODS: The literature was reviewed up to January 2017 for studies regarding the epidemiology, pathogenesis, immunological aspects, clinical implications and supplementation strategies. The focus was mainly on studies with implications on every day clinical practice. RESULTS: Vitamin D interacts with immune system mechanisms, therefore, it may be involved in the pathogenesis of autoimmune diseases. The literature is concordant on vitamin D insufficiency being endemic in SLE patients. Data on the correlation between SLE disease activity and circulating levels of vitamin D are controversial, as well as those related to the immunomodulatory effects of vitamin D supplementation. Novel areas of study are the relationship between constitutional symptoms and cognitive involvement of SLE and hypovitaminosis D, and the possible role of vitamin D in the formation of the atherosclerotic plaque, opening new avenues for the modulation of the cardiovascular risk. CONCLUSIONS: Future studies are needed to fully understand the relationship between hypovitaminosis D and different aspects of SLE. The most challenging topic will be to clarify supplementation strategies with vitamin D analogues that can be effective in modulating disease activity. PMID- 29148402 TI - Incidence and prevalence of axial spondyloarthritis: methodologic challenges and gaps in the literature. AB - OBJECTIVES: The incidence and prevalence of axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS) and non-radiographic (nr-)axSpA, have been investigated in multiple populations, though there is a paucity of population level data. Here, we identify population-based studies in AS and nr-axSpA, and describe the methodologic challenges in conducting these, outlining potential reasons for disparate incidence and prevalence estimates. METHODS: PubMed and Embase were searched for population-based studies providing incidence and prevalence rates, published in English from 1 Jan 2000-30 Jun 2015. Extracted information included incidence/prevalence rates, geographical population, study design, data source, case definition, age/gender, and classification criteria used. RESULTS: Of 2,148 articles identified, 19, from 15 countries, fulfilled eligibility criteria. Incidence rates per 100,000 patient-years were reported in 4 AS studies and varied from 0.4 (Iceland) to 15.0 (Canada). Reported AS prevalence rates per 100,000 persons also showed considerable variation (16 studies: 6.5 [Japan] to 540.0 [Turkey]). Only 3 axSpA and no nr-axSpA prevalence rates were reported. Considerable variation was seen in the methodology used to estimate incidence and prevalence rates, e.g. screening method, study design, and classification criteria. Although the prevalence of AS is known to vary by HLA B27 status, only 4 studies reported this genetic marker. CONCLUSIONS: There is an unmet need for future studies to use consistent methodology, capture all relevant information (including HLA-B27 positivity), and investigate under-reported populations (e.g. nr-axSpA; southern hemisphere countries) to estimate the population burden of axSpA. Future studies should aim to address data gaps to provide accurate incidence/prevalence estimates for the global axSpA population. PMID- 29148403 TI - Treatment patterns in rheumatoid arthritis after discontinuation of methotrexate: data from the Ontario Best Practices Research Initiative (OBRI). AB - OBJECTIVES: In active rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX), guidelines support adding or switching to another conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) and/or a biologic DMARD (bDMARD). The purpose of this analysis was to describe treatment practices in routine care and to evaluate determinants of regimen selection after MTX discontinuation. METHODS: Biologic-naive patients in the Ontario Best Practice Research Initiatives registry discontinuing MTX due to primary/secondary failure, adverse events, or patient/physician decision were included. RESULTS: Of 313 patients discontinuing MTX, 102 (32.6%) were on MTX monotherapy, 156 (49.8%) on double, and 55 (17.6%) on multiple csDMARDs. Patients on MTX monotherapy were older than patients on double or multiple csDMARDs (p=0.013), less likely to have joint erosions (p=0.009) and had lower patient global assessment (p=0.046) at MTX discontinuation. Post-MTX discontinuation, 169 (54.0%) transitioned to, or added new DMARD(s) (new csDMARD(s): 139 [44.4%]; bDMARD: 30 [9.6%]), and 144 (46.0%) opted for no new DMARD treatment. Patients on MTX monotherapy transitioning monotherapy, whereas patients on combination csDMARDs switched more to new csDMARDs and bDMARD combination therapy. Early RA (adjOR [95%CI]: 3.07 [1.40 6.72]) and treatment with multiple csDMARDs vs. MTX monotherapy (4.15 [1.35 12.8]) at MTX discontinuation were significant predictors of transitioning to or adding new csDMARD(s)/bDMARD treatment versus opting for no new DMARD treatment. CONCLUSIONS: Differences in subsequent treatment patterns exist between patients discontinuing MTX when used as monotherapy versus in combination with other csDMARDs where the former are more likely to use a subsequent monotherapy treatment. PMID- 29148404 TI - Other autoinflammatory disease genes in an FMF-prevalent population: a homozygous MVK mutation and a novel heterozygous TNFRSF1A mutation in two different Turkish families with clinical FMF. AB - OBJECTIVES: No MEFV mutations are detected in approximately 10% of the patients with clinical FMF in populations where the disease is highly prevalent. Causative mutations were searched in other genes in two such families with "MEFV negative clinical FMF". METHODS: Father and daughter of family A had attacks of fever, abdominal pain and AA amyloidosis. The two sibs of family B complained of febrile episodes with abdominal pain and arthritis. The patients were clinically investigated. Exome analysis in the daughter in family A and linkage analysis and candidate gene sequencing for the members of family B were performed. All patients were re-evaluated in the light of the genetic findings. RESULTS: In the daughter in family A, filtering of the exome file for variants in 25 autoimmune/inflammatory disease-related genes revealed two heterozygous missense variants in TNFRSF1A, novel p.Cys72Phe and frequent p.Arg121Gln. In family B, novel, homozygous missense p.Cys161Arg in MVK was identified. A clinical re evaluation of the patients revealed a phenotype consistent with FMF rather than TRAPS in family A and an overlap of FMF with HIDS in family B. CONCLUSIONS: In high risk populations of FMF a proportion of patients without MEFV mutations may carry causative mutations in other genes, and the clinical findings may not be fully consistent with the phenotype expected of the mutation identified but rather resemble FMF or an overlap syndrome. PMID- 29148405 TI - Autophagy inhibition in adult-onset Still's disease: still more space for hydroxychloroquine? PMID- 29148406 TI - High 3-year golimumab survival in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis: real world data from 328 patients. AB - OBJECTIVES: Our primary objective was to study the long-term survival on drug (SOD) of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) treated with golimumab (GLM) in real life settings. METHODS: This was a retrospective, observational study of all patients treated with GLM in 4 Academic Centres in Greece during a 4-year period (09/2010 06/2014). SOD was analysed using Kaplan-Meier survival analysis, while Cox regression analysis estimating hazard ratios (HRs) for different baseline variables associated with drug discontinuation was performed for each disease. RESULTS: 328 patients (RA: 166, PsA: 82, AS: 80) were included. The estimated SOD at 2 and 3 years was 68% and 62% overall and was better for AS (79% and 76%) compared to RA (69% and 60%, p=0.067) and PsA (58% and 53%, p=0.001) patients; no difference was noted between RA and PsA patients (p=0.204). There was no difference in SOD between biologic-naive and experienced nor between non-biologic co-treated or GLM monotherapy treated patients. Seropositivity (rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies) was associated with a lower risk for GLM discontinuation by multivariate analysis (HR=0.5, 95% CI=0.0.25-1.1, p=0.05) in RA patients. During 606 patient-years of follow-up, 11 (3.3%) patients discontinued GLM due to adverse events (AE), accounting for 11% of treatment discontinuations. The rates of serious AEs and serious infections were 2.3 and 1.0/100-patient-years, respectively. CONCLUSIONS: In this real-life study, GLM showed a high 3-year SOD in patients with inflammatory arthritides with a low rate of discontinuation due to AEs. PMID- 29148408 TI - Effects and safety of 99Tc-MDP in patients with refractory ankylosing spondylitis: a 2-stage (30-week follow-up) clinical trial. AB - OBJECTIVES: To evaluate the clinical efficacy and safety in patients with refractory ankylosing spondylitis (AS) initiating 99Tc-MDP therapy and explore the mechanisms. METHODS: Refractory AS patients were enrolled in the clinical trial and received 99Tc-MDP treatments for 3 or 5 courses according to ASAS improvement. Efficacy and safety evaluations were conducted during the follow-up. 37 cytokines were quantified by Luminex at baseline and week 30. p-values<0.05 were considered statistically significant. RESULTS: 51 refractory AS patients were included, with 20 healthy people serving as the control group. The patients were in an active disease state (mean (SD) ASDAS 3.66 (0.83), BASDAI 4.53 (1.92)), 42(82.35%) patients had syndesmophytes. Their cytokines were significantly higher than that in the control group. After 3 courses of 99Tc-MDP treatment, 32 (62.75%) patients achieved ASAS20 improvement, 24 (47.06%) patients achieved a clinically significant improvement (DeltaASDAS-CRP>=1.1). 27 patients entered the second stage to complete 5 courses of the treatment, all of whom achieved ASAS20 improvement, 18 (66.67%) patients achieved a clinically significant improvement. All clinical parameters including ASAS and ASDAS significantly improved as the treatment was continued. Cytokines also had significant down-regulation after the treatment, and the reductions had positive correlations with the improvements of disease activity. No serious adverse event was observed. CONCLUSIONS: This investigation confirmed the remarkable efficacy of 99Tc-MDP in a large number of refractory AS patients, and highlighted the mechanism by dramatic regulation on cytokines. 99Tc-MDP was safe in clinical application. PMID- 29148407 TI - Minor salivary gland fibrosis in Sjogren's syndrome is elevated, associated with focus score and not solely a consequence of aging. AB - OBJECTIVES: Evaluate the presence of minor salivary gland (SG) fibrosis in primary Sjogren's syndrome (pSS) as a function of disease pathology or a consequence of ageing. METHODS: Subjects with sicca symptoms attending a Sjogren's research clinic were classified by American European Consensus Group (AECG) criteria as either pSS or non-SS (nSS). Discovery (n=34 pSS, n=28 nSS) and replication (n=35 pSS, n=31 nSS) datasets were evaluated. Minor SG cross-sections from haematoxylin and eosin stained slides were imaged, digitally reconstructed and analysed for percent area fibrosis. Relationships between SG fibrosis, age, and clinical measures were evaluated using Spearman correlations. Association with SS was assessed by: ROC curve, Variable Selection Using Random Forests (VSURF) and uni- and bi-variate regression analyses. RESULTS: SS subjects had significantly more fibrotic tissue in their minor labial salivary glands (median 24.39%, range 5.12-51.67%) than nSS participants (median 16.7%, range 5.97 38.65%, p<0.0001); age did not differ between groups (average +/- SD pSS 50.2 +/ 13.9 years, nSS 53.8+/-12.4 years). In both the discovery and replication data sets, multiple regression models showed that the area of minor salivary gland fibrosis predicted pSS significantly better than age alone. Age-corrected linear regression revealed that the area of minor salivary gland fibrosis positively associated with vanBijsterveld score (p=0.042) and biopsy focus score (p=0.002). ROC curve and VSURF analyses ranked fibrosis as a significantly more important variable for subject discrimination than age. CONCLUSIONS: SG fibrosis is an element of pSS pathology that is related to focus score and is not solely attributable to age. PMID- 29148409 TI - A high and equal prevalence of the Q703K variant in NLRP3 patients with autoinflammatory symptoms and ethnically matched controls. AB - OBJECTIVES: Cryopyrin associated periodic syndromes (CAPS) comprise a spectrum of autoinflammatory disorders of varying severity caused by mutations in the NLRP3 gene. The NLRP3-Q703K allele has been reported both as a functional polymorphism and as a low penetrance mutation. METHODS: To describe the clinical phenotype of subjects with the Q703K allele and to report the frequency of this allele among patients with autoinflammatory symptoms and healthy controls. To this end, a cohort of 10 ethnically-matched controls per each Q703K-carrying patient, was composed. RESULTS: Ninety patients suspected of harboring a systemic autoinflammatory disease (SAID), exclusive of FMF, were referred to our center for genotyping between 2012 and 2015. Fourteen of them (15.5%) were found to carry the Q703K allele, compared to 22 of 130 (16.9%) healthy, ethnically matched controls. CONCLUSIONS: The similar carrier rate of the NLRP3-Q703K allele among patients with manifestations of a SAID and an ethnically matched control group suggest that this variant, does not determine the clinical phenotype. This reiterates the importance of testing a control group to avoid erroneously attributing a causative role to a gene polymorphism. PMID- 29148410 TI - Th17 gene expression in psoriatic arthritis synovial fluid and peripheral blood compared to osteoarthritis and cutaneous psoriasis. AB - OBJECTIVES: The IL-23/IL-17 axis is central to the pathogenesis of psoriatic arthritis (PsA). We aimed to identify Th17 signalling genes that are dysregulated in synovial fluid of PsA compared to osteoarthritis (OA) patients and to determine if differences in peripheral blood can distinguish PsA from psoriasis patients and controls. METHODS: Synovial fluid cells (SFCs) from 14 PsA and 9 OA patients were obtained and stored in TRIzol reagent. RNA was isolated by phenol chloroform extraction and purified with RNeasy miniprep kits. Total RNA was extracted from PAXgene whole blood from 20 PsA, 20 psoriasis without arthritis (PsC) and 11 controls. Quantitative RT-PCR arrays were used to profile expression of 84 genes related to the Th17 regulatory network. Fold change differences were compared by Mann-Whitney U-test with false discovery rate (FDR) correction (FDR<0.05). RESULTS: In PsA compared to OA SFCs, a total of 33 genes were up regulated and 27 genes were down-regulated. Signalling molecules (such as STAT3, FOXP3) were highly expressed in PsA SFCs, while cytokines (such as IL17F, IL6) were more predominant in OA SFCs after non-supervised hierarchal clustering. Nine genes (MMP3, CCL1, IL17C, CCL20, IL17F, IL3, CXCL5, IL6 and CX3CL1) had concordant expression in SFCs and in peripheral blood cells (PBCs) of PsA compared to PsC and/or controls. CONCLUSIONS: We identified expression differences in Th17 signalling genes in PsA compared to OA SFCs, with an elevation of signalling molecules and attenuation of cytokine expression in PsA. A subset of genes was concordant in PBCs; these may thus be potential biomarkers of PsA. PMID- 29148411 TI - Vitamin D status in spondyloarthritis: results of the ASAS-COMOSPA international study. AB - OBJECTIVES: Spondyloarthritis (SpA) encompasses both bone production and bone loss, and the latter is particularly linked to inflammation. Vitamin D deficiency has been associated with several inflammatory conditions (i.e. cardiovascular disease, rheumatoid arthritis), but it has been poorly evaluated in SpA patients. We aimed to a) describe the prevalence of vitamin D deficiency in SpA patients worldwide; b) compare SpA patients with and without vitamin D deficiency in terms of disease phenotype, activity severity and comorbidities. METHODS: This is an ancillary study of the ASAS-COMOSPA study initiative, an international cross sectional study of patients with SpA. Demographics, patients' phenotype, disease activity/severity measures and comorbidities were assessed. Serum 25 hydroxyvitamin D (25OHD) deficiency was defined as <20 ng/mL (<50 nmol/L). STATISTICAL ANALYSIS: a) prevalence of vitamin D deficiency; b) comparison of the disease presentation/activity/severity and comorbidities in the group of patients with and without vitamin D deficiency by bi-variable and multivariable analysis. RESULTS: Vitamin D deficiency was observed in 527(51.2%) of the 1030 patients with available data who were not receiving any supplementation. Vitamin D deficiency was independently associated with the presence of radiographic sacroiliitis (OR=2.1 [95%CI1.3; 3.3]) and a 25OHD measured in winter and spring (OR=1.88 [95%CI 1.2; 2.9]). No independent association between vitamin D deficiency and comorbidities was found. CONCLUSIONS: This study suggests that vitamin D deficiency is common in SpA worldwide and is associated with season but also with more severe forms of SpA. PMID- 29148412 TI - Psychological comorbidities associated with subclinical atherosclerosis in Greek patients with primary Sjogren's syndrome: a potential contribution of sleep impairment. AB - OBJECTIVES: Impaired sleep and psychological disorders are increasingly recognised as prevalent comorbidities in patients with primary Sjogren's syndrome (pSS), as well as important contributors of atherosclerosis in the general population. In the current study we sought to explore a potential role of psychological comorbidities in the pronounced atherosclerotic risk of pSS patients. METHODS: Fifty-nine pSS patients fulfilling the ACR/EULAR criteria completed specific validated questionnaires assessing fatigue, depression, anxiety and sleep disturbances. Clinical, laboratory and histopathological characteristics together with traditional risk factors for atherosclerosis were documented in all enrolled patients. Subclinical atherosclerosis defined either as carotid and/or femoral plaque formation or increased intima media thickness (IMT) levels were assessed by Doppler ultrasound. Univariate and multivariate analysis were performed. RESULTS: Plaque formation and high IMT levels were detected by ultrasound in 41(69.5%) out of the 59 pSS patients. In univariate analysis, age and higher triglyceride serum levels were associated with both plaque formation and high IMT levels. Hypertension was associated only with high IMT levels. While increased rates of both state anxiety and impaired sleep were detected in pSS patients with plaque formation in a univariate model, only impaired sleep proved to be independently associated with plaque formation among pSS patients (OR = 4.2, 95% CI =1.1-15.6, p=0.03). CONCLUSIONS: This is the first study showing impaired sleep to confer a significantly higher risk of subclinical atherosclerosis in patients with pSS. Clinicians should take psychological disturbances into account when trying to assess and manage the cardiovascular disease risk of pSS patients. PMID- 29148414 TI - More erronous statements about the use of frequentist statistical methods in medical research. PMID- 29148413 TI - Variable impacts of different remission states on health-related quality of life in rheumatoid arthritis. AB - OBJECTIVES: Targeting remission in rheumatoid arthritis (RA) improves health related quality of life (HRQoL) and disability. However, the impacts of different remission criteria and durations and their frequencies are uncertain. Our observational study assessed these factors. METHODS: We recruited RA patients with disease durations <10 years, stable suppressive therapies and stable disease activity scores for 28 joints using ESR (DAS28-ESR) <=3.2. Intermittent and sustained remisisons were classified using DAS28ESR, simple disease activity index (SDAI) and ACR/EULAR Boolean criteria. HRQoL, measured using SF-36, fatigue, EuroQol and health assessment questionnaire (HAQ) was compared using time-integrated areas under the curve (AUC). RESULTS: 104 patients were enrolled and followed for 12 months. DAS28-ESR remissions were intermittent in 42%, sustained in 47% and absent in 11%. Boolean remissions were intermittent in 38%, sustained in 10% and absent in 52%. Baseline remissions by all criteria significantly improved HAQ, Euroqol, SF36 and fatigue scores compared with low disease activity (LDAS); AUCs showed significant benefits for all HRQoLs persisted over 12-months. Boolean remissions achieved most benefits. Over time all remission states gave significantly better HRQoL scores than LDAS. Sustained DAS28ESR and SDAI remissions improved HRQoL more than intermittent remissions. Sustained and intermittent Boolean remissions gave similar improvements. Analysis of SF-36 domains showed even sustained Boolean remissions failed to optimise pain and fatigue. CONCLUSIONS: All remissions improve HRQoL but different criteria have variable impacts. Boolean remission had most impact but occurred least. There are trade-off between optimising individual impacts (Boolean remissions) and achieving maximal overall impacts (DAS28-ESR remissions). PMID- 29148416 TI - Reply to Dr. Boers' letter. PMID- 29148415 TI - Exacerbation of Behcet's syndrome and familial Mediterranean fever with menstruation. AB - OBECTIVES: Menstruation triggers several conditions such as migraine, recurrent aphthous stomatitis and acne vulgaris in healthy individuals. There is evidence that Behcet's syndrome (BS) and familial Mediterranean fever (FMF) may exacerbate during menstruation. The aim is to assess whether BS and FMF patients experience menstrual flares. METHODS: Females of reproductive age with BS and FMF seen consecutively at the outpatient clinic of Cerrahpasa Medical Faculty at Istanbul, as well as apparently healthy hospital workers were studied using a standardised questionnaire. BS patients were asked whether they experienced increased skin mucosa lesions during the menstrual period. A similar questionnaire assessing this time the frequency of abdominal pain, chest pain and fever attacks was given to the patients with FMF. The healthy controls received both questionnaires. RESULTS: A total of 200 BS patients, 240 FMF patients and 250 healthy controls were studied. The most commonly reported symptom among both BS patients (51%) and healthy controls (62%) was the acneiform lesion. At least 79% patients with FMF reported attacks with menstruation, notably abdominal pain which, majority thought, could be differentiated from dysmenorrhea. Additionally, 76% of healthy controls reported having abdominal pain consistent most probably with dysmenorrhea. CONCLUSIONS: This survey showed that, in 68% of the patients with BS at least one skin mucosa lesion was exacerbated with menstruation, this was most commonly acneiform lesion. Menstruation had a slightly stronger effect on FMF, triggering at least one symptom in 79%. The main limitation of the study was the self-reported assessment methodology. PMID- 29148417 TI - Recurrent pleural effusion is an important diagnostic clue to distinguish familial Mediterranean fever from Behcet's disease. PMID- 29148418 TI - Infliximab for uveitis of Behcet's syndrome: a trend for earlier initiation. AB - OBJECTIVES: The prognosis of uveitis in Behcet's syndrome (BS) has improved over decades. Whether this is related to the use of more aggressive management strategies is not known. METHODS: This is a retrospective study of BS patients who received infliximab (IFX) for refractory eye disease between 2003-2015. The patients were divided into two groups according to the date of onset of in IFX treatment as before and after 2013. We compared the two groups in terms of disease characteristics at the onset of IFX treatment and response to treatment. RESULTS: There were 43 patients in the old and 14 patients in the new group. The duration of uveitis and previous immunosuppressive treatment before the initiation of IFX were significantly shorter in the new group compared to the old group (p=0.043 and p=0.028, respectively). The baseline visual acuity (VA) at the initiation of IFX was better in the new group, but this was only significant for the left eye. Treatment with IFX was effective in both groups in preserving VA and this was more pronounced in the new group. Attack frequency under IFX was significantly lower in the new group (p<0.001). CONCLUSIONS: IFX seems to be initiated earlier and also in less severe cases during the course of BS uveitis than before. Despite the few numbers of patients and relatively short duration of follow-up, our results give a hint that this change has improved the outcome. PMID- 29148419 TI - Pure red aplasia induced by sodium valproate in a patient with Behcet's syndrome. PMID- 29148420 TI - The expression of mRNA for peptidylarginine deiminase type 2 and type 4 in bone marrow CD34+ cells in rheumatoid arthritis. AB - OBJECTIVES: Antibodies directed to citrullinated proteins are highly specific for rheumatoid arthritis (RA). Citrullination is catalyzed by peptidylarginine deiminase (PAD) enzymes. The current study examined the mRNA expression of PADI2 and PADI4 in bone marrow (BM) CD34+ cells from RA patients. METHODS: CD34+ cells were purified from BM samples obtained from 48 RA patients and from 30 osteoarthritis (OA) patients during joint operations via aspiration from the iliac crest. The expression of mRNAs for PADI2, PADI4 and Sp1 was examined by quantitative reverse transcription PCR. RESULTS: The expression of mRNA for PADI2 was significantly higher in RA BM CD34+ cells than OA BM CD34+ cells. The expression of mRNAs for PADI4 and Sp1 in RA BM CD34+ cells appeared to be increased compared to OA BM CD34+ cells, although it did not reach the statistical significance. The levels of mRNAs for PADI2, PADI4 and Sp1 were not correlated with serum C-reactive protein or with the administration of methotrexate or oral steroids. Finally, the level of PADI2 mRNA as well as that of PADI4 mRNA was significantly correlated with the level of Sp1 mRNA in RA BM CD34+ cells. CONCLUSIONS: These results indicate that the mRNA expression of PADI2, PADI4 and Sp1 is upregulated in RA BM CD34+ cells independently of the systemic inflammation or treatment regimen. Moreover, the data suggest that the enhanced mRNA expression of PADI2 and PADI4 in BM CD34+ cells might be a result of the enhanced expression of Sp1 gene in RA BM CD34+ cells. PMID- 29148421 TI - A validation study of the Simple Psoriatic Arthritis Screening (SiPAS) questionnaire to screen psoriasis patients for psoriatic arthritis. AB - OBJECTIVES: To validate in a multicentric cohort of patients a self-administered PsA screening tool, called Simple Psoriatic Arthritis Screening (SiPAS) questionnaire, to screen psoriasis patients for signs and symptoms of PsA. METHODS: The SiPAS questionnaire was validated in a multicentric Italian cohort of psoriasis patients referred to two rheumatological centres. RESULTS: A total of 202 psoriasis patients were screened with SiPAS in the validation study. Sixty two psoriasis patients (30.7%) were diagnosed with PsA. The five screening questions (1. Have you ever had a finger or a toe and/or another joint swollen and painful without any apparent reason?; 2. Occasionally, has an entire finger or toe become swollen, making it look like a 'sausage'?; 3. Do you wake up at night because of low back pain?; 4. Have you had pain in your heels?; 5. Has a doctor ever diagnosed you with psoriatic arthritis?) with a dichotomous response, demonstrated high sensitivity and specificity for predicting PsA. Likelihood ratios for individual parameters varied between 2.06 and 4.75. Using the Bayesian Analysis, the presence of three of five items answered as "yes" showed respectively a sensibility and a specificity of 79% and 87%, with a positive likelihood ratio of 6.14. CONCLUSIONS: The SiPAS questionnaire is able to quickly screen psoriasis patients for PsA. A SiPAS score >=3 is an indication for referral to a rheumatologist. The SiPAS needs further validation. PMID- 29148422 TI - Anti-adalimumab antibodies in juvenile idiopathic arthritis-related uveitis. AB - OBJECTIVES: To evaluate the association of adalimumab trough levels and anti adalimumab antibodies with activity of uveitis in juvenile idiopathic arthritis related uveitis. METHODS: This was a retrospective observational case series in a clinical setting at the Department of Ophthalmology, Helsinki University Hospital, Finland in 2014-2016. Thirty-one paediatric patients with chronic anterior juvenile idiopathic arthritis-related uveitis in 58 eyes and who had been on adalimumab >=6 months were eligible for the study. Uveitis activity during adalimumab treatment, adalimumab trough levels and anti-adalimumab antibody levels were recorded. RESULTS: Anti-adalimumab antibody levels >=12 AU /ml were detected in nine patients (29%). This level of anti-adalimumab antibodies was associated with a higher grade of uveitis (p<0.001), uveitis that was not in remission (p=0.001) and with lack of concomitant methotrexate therapy (p=0.043). In patients with anti-adalimumab antibody levels <12 AU/ml, higher serum trough levels did not associate with better control of uveitis (p=0.86). CONCLUSIONS: Adalimumab treatment might be better guided by monitoring anti adalimumab antibody formation in treating JIA-related uveitis. PMID- 29148423 TI - Non-invasive vascular biomarkers in patients with Behcet's disease: review of the data and future perspectives. AB - Vascular inflammation in small to large veins and arteries contributes substantially to mortality above that of the general population in Behcet's disease. Recent data verified also the presence of accelerated classical subclinical arterial damage (atheromatosis, arteriosclerosis, arterial hypertrophy) even in patients free of overt vascular complications, and may be complementary to that of vasculitis. Early detection of such vascular damage might provide helpful pathophysiological insight and potentially even guide treatment management. Herein, we review the existing literature for each one of the most widely applied non-invasive vascular biomarkers (assessing endothelial dysfunction, atheromatosis/hypertrophy, arteriosclerosis and central haemodynamic parameters) that are clinically used in primary cardiovascular prevention. We aim to: (i) identify early pathophysiological vascular pathways, complementary to vasculitis, in the development of vascular complications and (ii) identify gaps in knowledge and suggest future research topics. We identified evidence of proof of concept for some of the widely applied non-invasive vascular biomarkers (carotid plaques, pulse wave velocity, flow mediated dilatation). Yet, several steps in their clinical validation process are lacking. Extensive vascular phenotyping of a large prospective observational patient cohort with the application of these easy-to-use, low-cost, free of any adverse effect, non invasive methods should be performed in order to test their ability to provide clinically meaningful guidance regarding the prognosis and treatment of Behcet's disease. PMID- 29148424 TI - Effect of the metabolic syndrome on organ damage and mortality in patients with systemic lupus erythematosus: a longitudinal analysis. AB - OBJECTIVES: To study the effect of the metabolic syndrome (MetS) on organ damage and mortality in patients with SLE. METHODS: Consecutive patients who fulfilled >=4 ACR criteria for SLE were assessed for the MetS in October 2010. The MetS was defined by the updated joint consensus criteria, using the Asian criteria for central obesity. Longitudinal data on organ damage and mortality were retrieved. The association between MetS and new damage and mortality was studied by logistic regression. RESULTS: A total of 577 SLE patients were followed (93% women; age 41.2+/-13.4 years; SLE duration 9.3+/-7.2 years) and 85 (14.7%) patients qualified the MetS. After a follow-up of 66.3+/-1.8 month, new organ damage and vascular events developed in 128(22%) and 23(4.0%) patients, respectively. Thirty nine (6.8%) patients succumbed. Patients with the MetS, compared to those without, had significantly more SLICC damage score accrual (0.70+/-1.0 vs 0.26+/ 0.6; p<0.001), new vascular events (11% vs 2.8%; p=0.001), all-cause (14% vs 5.5%; p=0.003) and vascular (7.1% vs 0.2%; p<0.001) mortality. Logistic regression revealed that the MetS was significantly associated with new damage in the renal (OR 5.48[2.06-14.6]; p=0.001) and endocrine system (OR 38.0[4.50-321]; p=0.001), adjusted for age, sex, SLE duration, ever smoking, antiphospholipid antibodies and the new use of glucocorticoids or hydroxychloroquine since recruitment. Moreover, the presence of the MetS also significantly increased the risk of new vascular events (OR 3.38[1.31-8.74];p=0.01) and vascular mortality (OR 28.3[3.24-247]; p=0.002) after adjustment for the same covariates. CONCLUSION: In this longitudinal study, the MetS is significantly associated with new organ damage, vascular events and mortality in patients with SLE. PMID- 29148425 TI - Ex vivo inhibited cytokine profiling may explain inferior treatment response to golimumab after adalimumab failure in rheumatoid arthritis. AB - OBJECTIVES: Clinical data suggest that the response of rheumatoid arthritis patients to treatment with golimumab is much lower among those who switched from adalimumab than among those who switched from etanercept. To elucidate the mechanism behind this difference in response to sequential biologic treatment, we examined the effect of TNF inhibitors on ex vivo cytokine production profiling. METHODS: In a prospective cohort study, blood samples were obtained from patients before the start of a biologic. Peripheral blood mononuclear cells were pre incubated for 1 hour with the therapeutic in vivo concentration of adalimumab, etanercept or golimumab and stimulated for 24 hours with heat killed Candida albicans or Pam3Cys. Cytokine concentrations of IL-1beta, IL-6 and TNFalpha were determined by ELISA. RESULTS: Ex vivo cytokine profiling was performed in 71 patients. Golimumab, adalimumab and etanercept significantly (p<0.01) decreased Candida albicans-induced IL-1beta and IL-6 production and Pam3Cys-induced IL-6 production. In contrast to etanercept, golimumab and adalimumab decreased the concentration of TNFalpha below the detection limit. Absolute changes in cytokine levels after inhibition by golimumab or adalimumab were all significantly correlated (Spearman rank rs: 0.52-0.99, p<0.001). These correlations were much lower or non-significant between etanercept and either golimumab or adalimumab. CONCLUSIONS: High similarity between ex vivo inhibited cytokine profiling by golimumab and adalimumab, compared to etanercept, may explain the previously found inferior treatment response to golimumab after adalimumab failure. This suggests that patients who are non-responsive to adalimumab should preferably not switch to golimumab and vice versa. PMID- 29148427 TI - Urothelial Carcinoma of the Bladder in Pediatric Patient: Four Case Series and Review of the Literature AB - Background: Urothelial carcinoma of the bladder is a rare condition in children, and most cases in this age group are noninvasive and low-grade. However, no follow-up protocol has been defined for this patient group. The objective of this study was to draw attention to bladder tumors in children and focus on the current recommendations for postoperative follow-up along with a case study of four patients. Case Report: Four patients aged <18 years with urothelial carcinoma who were treated in our clinics between 2001 and 2015 were retrospectively evaluated. The results were compared with those of published pediatric case series in the literature. No abnormalities were found in the patients' physical examinations and laboratory analyses, except hematuria (microscopic or macroscopic). Ultrasonography was used in all the patients to detect lesions in the bladder. Surgical resections were performed endoscopically, except in one patient. Histopathological evaluations revealed low-grade superficial urothelial carcinoma. No recurrence or complication was observed for all patients. Conclusion: Although rarely encountered during childhood, urothelial carcinoma should be considered as a differential diagnosis in pediatric patients with hematuria. PMID- 29148426 TI - Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate. AB - Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here, we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique beta-strand structure distinct from the conventional amyloid beta-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation. PMID- 29148428 TI - 135La as an auger-electron emitter for targeted internal radiotherapy. AB - Introduction: 135La has favorable nuclear and chemical properties for Auger-based targeted internal radiotherapy. Here we present detailed investigations of the production, emissions, imaging characteristics, and dosimetry related to 135La therapy. Methods and Results: 135La was produced by 16.5 MeV proton irradiation of metallic natBa on a medical cyclotron, and was isolated and purified by trap-and-release on weak cation-exchange resin. The average production rate was 407 +/- 19 MBq/uA (saturation activity, n = 3), and the radionuclidic purity was 98% at 20 h post irradiation. Chemical separation recovered > 98 % of the 135La with an effective molar activity of 70 +/-20 GBq/umol. To better assess cellular and organ dosimetry of this nuclide, we have recalculated the X ray and Auger emission spectra using a Monte Carlo model accounting for effects of multiple vacancies during the Auger cascade. The generated Auger spectrum was used to recalculate cellular S-factors. Conclusion: 135La was produced with high specific activity, reactivity, radionuclidic purity, and yield. The emission spectrum and the dosimetry are favorable for internal radionuclide therapy. . PMID- 29148429 TI - Unconventional lithography for patterned nanomaterials. PMID- 29148431 TI - Comparative efficacy of hemorrhage control of a novel mesoporous bioactive glass versus two commercial hemostats. AB - Mesoporous bioactive glass containing 1% Ga2O3 (1%Ga-MBG) is attractive for hemorrhage control because of its surface chemistry which can promote blood clotting. The present study compares this proprietary inorganic coagulation accelerator with two commercial hemostats, CeloxTM (CX) and QuikClot Advanced Clotting Sponge PlusTM (ACS+). The results indicate that the number of adherent platelets were higher on the 1%Ga-MBG and CX surfaces than ACS+ whereas a greater contact activation was seen on 1%Ga-MBG and ACS+ surfaces than CX. 1%Ga-MBG not only resulted in larger platelet aggregates and more extensive platelet pseudopodia compared to CX and ACS+ but also significantly accelerated the intrinsic pathways of the clotting cascade. In vitro thrombin generation assays also showed that CX and ACS+ induced low levels of thrombin formation while 1%Ga MBG had significantly higher values. 1%Ga-MBG formed a larger red blood cell aggregate than both CX and ACS+. Direct exposure of 1%Ga-MBG to fibroblast cells increased cell viability after 3 days relative to CX and ACS+, inferring excellent cytocompatibility. The results of this study promote 1%Ga-MBG as a promising hemostat compared to the commercially available products as it possesses essential factors required for coagulation activation. PMID- 29148430 TI - Low-dose 4D cardiac imaging in small animals using dual source micro-CT. AB - Micro-CT is widely used in preclinical studies, generating substantial interest in extending its capabilities in functional imaging applications such as blood perfusion and cardiac function. However, imaging cardiac structure and function in mice is challenging due to their small size and rapid heart rate. To overcome these challenges, we propose and compare improvements on two strategies for cardiac gating in dual-source, preclinical micro-CT: fast prospective gating (PG) and uncorrelated retrospective gating (RG). These sampling strategies combined with a sophisticated iterative image reconstruction algorithm provide faster acquisitions and high image quality in low-dose 4D (i.e. 3D + Time) cardiac micro-CT. Fast PG is performed under continuous subject rotation which results in interleaved projection angles between cardiac phases. Thus, fast PG provides a well-sampled temporal average image for use as a prior in iterative reconstruction. Uncorrelated RG incorporates random delays during sampling to prevent correlations between heart rate and sampling rate. We have performed both simulations and animal studies to validate these new sampling protocols. Sampling times for 1000 projections using fast PG and RG were 2 and 3 min, respectively, and the total dose was 170 mGy each. Reconstructions were performed using a 4D iterative reconstruction technique based on the split Bregman method. To examine undersampling robustness, subsets of 500 and 250 projections were also used for reconstruction. Both sampling strategies in conjunction with our iterative reconstruction method are capable of resolving cardiac phases and provide high image quality. In general, for equal numbers of projections, fast PG shows fewer errors than RG and is more robust to undersampling. Our results indicate that only 1000-projection based reconstruction with fast PG satisfies a 5% error criterion in left ventricular volume estimation. These methods promise low-dose imaging with a wide range of preclinical applications in cardiac imaging. PMID- 29148432 TI - A singular value decomposition linear programming (SVDLP) optimization technique for circular cone based robotic radiotherapy. AB - With robot-controlled linac positioning, robotic radiotherapy systems such as CyberKnife significantly increase freedom of radiation beam placement, but also impose more challenges on treatment plan optimization. The resampling mechanism in the vendor-supplied treatment planning system (MultiPlan) cannot fully explore the increased beam direction search space. Besides, a sparse treatment plan (using fewer beams) is desired to improve treatment efficiency. This study proposes a singular value decomposition linear programming (SVDLP) optimization technique for circular collimator based robotic radiotherapy. The SVDLP approach initializes the input beams by simulating the process of covering the entire target volume with equivalent beam tapers. The requirements on dosimetry distribution are modeled as hard and soft constraints, and the sparsity of the treatment plan is achieved by compressive sensing. The proposed linear programming (LP) model optimizes beam weights by minimizing the deviation of soft constraints subject to hard constraints, with a constraint on the l 1 norm of the beam weight. A singular value decomposition (SVD) based acceleration technique was developed for the LP model. Based on the degeneracy of the influence matrix, the model is first compressed into lower dimension for optimization, and then back-projected to reconstruct the beam weight. After beam weight optimization, the number of beams is reduced by removing the beams with low weight, and optimizing the weights of the remaining beams using the same model. This beam reduction technique is further validated by a mixed integer programming (MIP) model. The SVDLP approach was tested on a lung case. The results demonstrate that the SVD acceleration technique speeds up the optimization by a factor of 4.8. Furthermore, the beam reduction achieves a similar plan quality to the globally optimal plan obtained by the MIP model, but is one to two orders of magnitude faster. Furthermore, the SVDLP approach is tested and compared with MultiPlan on three clinical cases of varying complexities. In general, the plans generated by the SVDLP achieve steeper dose gradient, better conformity and less damage to normal tissues. In conclusion, the SVDLP approach effectively improves the quality of treatment plan due to the use of the complete beam search space. This challenging optimization problem with the complete beam search space is effectively handled by the proposed SVD acceleration. PMID- 29148433 TI - A flow bioreactor system compatible with real-time two-photon fluorescence lifetime imaging microscopy. AB - Bioreactors are essential cell and tissue culture tools that allow the introduction of biophysical signals into in vitro cultures. One major limitation is the need to interrupt experiments and sacrifice samples at certain time points for analyses. To address this issue, we designed a bioreactor that combines high resolution contact-free imaging and continuous flow in a closed system that is compatible with various types of microscopes. The high throughput fluid flow bioreactor was combined with two-photon fluorescence lifetime imaging microscopy (2P-FLIM) and validated. The hydrodynamics of the bioreactor chamber were characterized using COMSOL. The simulation of shear stress indicated that the bioreactor system provides homogeneous and reproducible flow conditions. The designed bioreactor was used to investigate the effects of low shear stress on human umbilical vein endothelial cells (HUVECs). In a scratch assay, we observed decreased migration of HUVECs under shear stress conditions. Furthermore, metabolic activity shifts from glycolysis to oxidative phosphorylation-dependent mechanisms in HUVECs cultured under low shear stress conditions were detected using 2P-FLIM. Future applications for this bioreactor range from observing cell fate development in real-time to monitoring the environmental effects on cells or metabolic changes due to drug applications. PMID- 29148434 TI - The 'cutting away' of potential secondary electron tracks explains the effects of beam size and detector wall density in small-field photon dosimetry. AB - The well-known field-size dependent overresponse in small-field photon-beam dosimetry of solid-state detectors equipped with very thin sensitive volumes, such as the PTW microDiamond, cannot be caused by the photon and electron interactions within these sensitive layers because they are only a few micrometers thick. The alternative explanation is that their overresponse is caused by the combination of two effects, the modification of the secondary electron fluence profile (i) by a field size too small to warrant lateral secondary electron equilibrium and (ii) by the density-dependent electron ranges in the structural detector materials placed in front of or backing the sensitive layer. The present study aims at the numerical demonstration and visualization of this combined mechanism. The lateral fluence profiles of the secondary electrons hitting a 1 um thick scoring layer were Monte-Carlo simulated by modelling their generation and transport in the upstream or downstream adjacent layers of thickness 0.6 mm and densities from 0.0012 to 3 g cm-3, whose atomic composition was constantly kept water-like. The scoring layer/adjacent layer sandwich was placed in an infinite water phantom irradiated by circular 60Co, 6 MV and 15 MV photon beams with diameters from 3 to 40 mm. The interpretation starts from the ideal case of lateral secondary electron equilibrium, where the Fano theorem excludes any density effect. If the field size is then reduced, electron tracks potentially originating from source points outside the field border will then be numerically 'cut away'. This geometrical effect reduces the secondary electron fluence at the field center, but the magnitude of this reduction also varies with the density-dependent electron ranges in the adjacent layers. This combined mechanism, which strongly depends on the photon spectrum, explains the field size and material density effect on the response of detectors with very thin sensitive layers used in small-field photon-beam dosimetry. PMID- 29148435 TI - Methods for the analysis of complex fluorescence decays: sum of Becquerel functions versus sum of exponentials. AB - Ensemble fluorescence decays are usually analyzed with a sum of exponentials. However, broad continuous distributions of lifetimes, either unimodal or multimodal, occur in many situations. A simple and flexible fitting function for these cases that encompasses the exponential is the Becquerel function. In this work, the applicability of the Becquerel function for the analysis of complex decays of several kinds is tested. For this purpose, decays of mixtures of four different fluorescence standards (binary, ternary and quaternary mixtures) are measured and analyzed. For binary and ternary mixtures, the expected sum of narrow distributions is well recovered from the Becquerel functions analysis, if the correct number of components is used. For ternary mixtures, however, satisfactory fits are also obtained with a number of Becquerel functions smaller than the true number of fluorophores in the mixture, at the expense of broadening the lifetime distributions of the fictitious components. The quaternary mixture studied is well fitted with both a sum of three exponentials and a sum of two Becquerel functions, showing the inevitable loss of information when the number of components is large. Decays of a fluorophore in a heterogeneous environment, known to be represented by unimodal and broad continuous distributions (as previously obtained by the maximum entropy method), are also measured and analyzed. It is concluded that these distributions can be recovered by the Becquerel function method with an accuracy similar to that of the much more complex maximum entropy method. It is also shown that the polar (or phasor) plot is not always helpful for ascertaining the degree (and kind) of complexity of a fluorescence decay. PMID- 29148436 TI - Spectrofluorimetry with attomole sensitivity in photonic crystal fibres. AB - We report the use of photonic crystal fibres (PCF) as spectrofluorimetric systems in which sample solutions are excited within the microstructure of the fibre. The use of intra-fibre excitation has several advantages that combine to enable highly sensitive measurements of fluorescence spectra and lifetimes: long path lengths are achieved by the efficient guidance of the fundamental mode; sample volumes contained within the micron-scale structure are very small, only a few nanolitres per cm of path; collection and guidance of the emitted fluorescence is efficient and the fluorescence lifetime is unperturbed. Fluorophores in bulk solution can be studied in hollow core PCF, whereas the use of PCF with a suspended, solid core enables selective excitation of molecules in close proximity to the silica surface, through interaction with the evanescent field. We demonstrate the measurement of fluorescence spectra and fluorescence lifetimes in each of these excitation regimes and report the detection of attomole quantities of fluorescein. PMID- 29148437 TI - A two-channel detection method for autofluorescence correction and efficient on bead screening of one-bead one-compound combinatorial libraries using the COPAS fluorescence activated bead sorting system. AB - One-bead one-compound combinatorial library beads exhibit varying levels of autofluorescence after solid phase combinatorial synthesis. Very often this causes significant problems for automated on-bead screening using TentaGel beads and fluorescently labeled target proteins. Herein, we present a method to overcome this limitation when fluorescence activated bead sorting is used as the screening method. We have equipped the COPAS bead sorting instrument with a high speed profiling unit and developed a spectral autofluorescence correction method. The correction method is based on a simple algebraic operation using the fluorescence data from two detection channels and is applied on-the-fly in order to reliably identify hit beads by COPAS bead sorting. Our method provides a practical tool for the fast and efficient isolation of hit beads from one-bead one-compound library screens using either fluorescently labeled target proteins or biotinylated target proteins. This method makes hit bead identification easier and more reliable. It reduces false positives and eliminates the need for time consuming pre-sorting of library beads in order to remove autofluorescent beads. PMID- 29148438 TI - Initial stages of beta-amyloid Abeta1-40 and Abeta1-42 oligomerization observed using fluorescence decay and molecular dynamics analyses of tyrosine. AB - The development of Alzheimer's disease is associated with the aggregation of the beta-amyloid peptides Abeta1-40 and Abeta1-42. It is believed that the small oligomers formed during the early stages of the aggregation are neurotoxic and involved in the process of neurodegeneration. In this paper we use fluorescence decay measurements of beta-amyloid intrinsic fluorophore tyrosine (Tyr) and molecular dynamics (MD) simulations to study the early stages of oligomer formation for the Abeta1-40 and Abeta1-42 peptides in vitro. We demonstrate that the lifetime distributions of the amyloid fluorescence decay efficiently describe changes in the complex Tyr photophysics during the peptide aggregation and highlight the differences in aggregation performance of the two amyloids. Tyr fluorescence decay is found to be a more sensitive sensor of Abeta1-40 aggregation than Abeta1-42 aggregation. The MD simulation of the peptide aggregation is compared with the experimental data and supports a four-rotamer model of Tyr. PMID- 29148439 TI - Nanomorphology of polythiophene-fullerene bulk-heterojunction films investigated by structured illumination optical imaging and time-resolved confocal microscopy. AB - Structured illumination microscopy (SIM) and time-resolved confocal fluorescence microscopy are applied to investigate the nanomorphology of thin films comprising typical blends of the conjugated polymer, poly (3-hexylthiophene) (P3HT), and [6, 6]-phenyl C61-butyric acid methyl ester (PCBM), used for organic photovoltaic applications. SIM provides evidence for the presence of a thin emissive region around the crystalline regions of PCBM and at the tips of rod-like domains. The time-resolved measurements show that the emission surrounding the PCBM rods is longer lived than the bulk of the film. The two modes of microscopy provide complementary evidence indicating that electron-hole separation is inhibited between the polymer and the large PCBM-rich domains in these regions. We show here that structured illumination microscopy is a viable method of gaining additional information from these photovoltaic materials, despite their weak emission. PMID- 29148440 TI - Welcome to Methods and Applications in Fluorescence. AB - On behalf of the Editorial Board of Methods and Applications in Fluorescence and IOP Publishing we are delighted to invite you to read the first articles in our new journal. Methods and Applications in Fluorescence is forged out of the renowned MAF conference series of the same name and we fully expect the natural synergy between the two to provide the ideal platform for moving the field of fluorescence forward. Our aim is for this new journal to reflect the truly global and diverse impact fluorescence is having across many disciplines and help fluorescence achieve its full potential. Just as MAF is the leading conference in fluorescence we are confident of the high impact of this new journal. Methods and Applications in Fluorescence has a distinguished Editorial Board that is drawn from the MAF conference Permanent Steering Committee. Together with the Editorial Board and the rest of the community, the journal will closely track the very latest developments in fluorescence while delivering a fair and constructive review process. We are very pleased that this journal is backed by the Institute of Physics, one of the world's premier learned societies. IOP Publishing has a wealth of experience in science publishing that dates back to 1874. It is a not for-profit organization that publishes over 60 journals, many on multidisciplinary topics and many including seminal contributions from Nobel Laureates. Any funding surplus generated by IOP Publishing goes directly back into science through the Institute of Physics, thus helping to nurture science for future generations. We invite submissions as regular articles, review articles and technical notes within the scope of the journal, which includes all the major aspects of fluorescence. This covers both theory and experiment across spectroscopy, imaging, materials, labels, probes and sensors. The applications of fluorescence to emerging areas in bionanotechnology, nanotechnology and medicine are very much part of the vision for the journal. Methods and Applications in Fluorescence is a journal for the whole community, so do please join us in helping to give the field of fluorescence the standing it deserves by submitting your latest and most exciting work. The success of the journal depends on all of us in the field and we look forward to working with you on this exciting project. David Birch, Yves Mely and Otto S WolfbeisEditors in Chief. PMID- 29148441 TI - Rational design of fluorescent membrane probes for apoptosis based on 3 hydroxyflavone. AB - Environment-sensitive probes constitute powerful tools for monitoring changes in the physico-chemical properties of cell plasma membranes. Among these probes, 3 hydroxyflavone probes are of great interest due to their dual emission and ratiometric response. Here, three probes derived from the parent F2N12S were designed, characterized and applied to monitor the membrane changes occurring during apoptosis. These three probes were designed to orient the dye vertically in the membrane. They differ by the length of their alkyl chains (from 4 to 8 carbons), which were included to optimize their affinity to the lipid membranes. Among these three probes, the one with medium chain length (hexyl) showed the best affinity to model and cell membranes, while the one with the longest alkyl chains (octyl) did not efficiently stain the membranes, probably due to aggregation. The new probes were found to be more sensitive than F2N12S to both the lipid phase and surface charge in lipid vesicles and to loss of lipid order in cell plasma membranes after cholesterol extraction. The one with the shortest (butyl) chains was found to be the most sensitive to apoptosis, while the one with medium-length (hexyl) chains was the brightest. Interestingly, apoptosis induced by different agents led to similar spectroscopic effects to those produced by the loss of lipid order and change in the surface charge, confirming that apoptosis decreases the lipid order and increases the negative surface charge in the outer leaflet of cell membranes. In conclusion, these studies report the relationship between the probe structures and their sensitivity to lipid order, surface charge and apoptosis and propose new probes for membrane research. PMID- 29148442 TI - Azadioxatriangulenium: a long fluorescence lifetime fluorophore for large biomolecule binding assay. AB - Of the many optical bioassays available, sensing by fluorescence anisotropy has great advantages as it provides a sensitive, instrumentally simple, ratiometric method of detection. However, it is hampered by a severe limitation, as the emission lifetime of the label needs to be comparable to the correlation lifetime (tumbling time) of the biomolecule which is labelled. For proteins of moderate size this is on the order of 20-200 ns, which due to practical issues currently limits the choice of labels to the dansyl-type dyes and certain aromatic dyes. These have the significant drawback of UV/blue absorption and emission as well as an often significant solvent sensitivity. Here, we report the synthesis and characterization of a new fluorescent label for high molecular weight biomolecule assay based on the azadioxatriangulenium motif. The NHS ester of the long fluorescence lifetime, red-emitting fluorophore: azadioxatriangulenium (ADOTA NHS) was conjugated to anti-rabbit Immunoglobulin G (antiIgG). The long fluorescence lifetime was exploited to determine the correlation time of the high molecular weight antibody and its complex with rabbit Immunoglobulin G (IgG) with steady-state fluorescence anisotropy and time-resolved methods: solution phase immuno-assay was performed following either steady-state or time-resolved fluorescence anisotropy. By performing a variable temperature experiment it was determined that the binding of the ligand resulted in an increase in correlation time of more than 75%, and an increase in the steady-state anisotropy of 18%. The results show that the triangulenium class of dyes can be used in anisotropy assay to detect binding events involving biomolecules of far larger size than what is possible with most other red-emitting organic dyes. PMID- 29148443 TI - Nanoparticles and nanocomposites for fluorescence sensing and imaging. AB - The assortment of fluorescence reporters is changing dramatically. Traditionally explored intrinsic fluorescence of biological macromolecules and cellular pigments and of externally introduced organic dyes are presently in strong competition with new nanomaterials. Among them are conjugated polymers, semiconductor nanocrystals (quantum dots), up-converting nanocrystals, magic-size clusters of silver and gold, nanodiamonds and carbon dots. They demonstrate diverse photophysical behavior and allow one to obtain diverse information when used in analytical tools or when they form images in biological systems. Based on them, functional nanocomposites displaying a variety of useful features, thus extending dramatically the information content of output data, can be constructed. We describe their properties and compare them with those of small molecular emitters, such as organic dyes. With their aid, one can modulate over a wide range the wavelengths of excitation and emission, the lifetimes and anisotropies and design the systems with 'superenhancement' and 'superquenching'. Such unlimited possibilities are offered by combining different types of luminophores based on electronic conjugation, plasmonic effects or excited-state resonance energy transfer. This tutorial review provides a comparative analysis of the properties of new nanoscale materials and of their hybrid nanocomposites for applications in fluorescence sensing and imaging. PMID- 29148444 TI - Characteristics of distributed-type inorganic electroluminescence panels with comb-shaped electrodes. AB - We deposited comb electrodes with narrow gaps between the teeth on a glass substrate, thus realizing a high electric field intensity that cannot be achieved with conventional structures. Au electrodes are deposited to form a comb shape and then spin-coated with a phosphor layer obtained by mixing ZnS phosphor particles with resins in a certain ratio. An AC voltage was applied to the gaps between the teeth of the comb electrode to emit light, from which the luminance was measured for different electric field intensities. The luminance was not affected by the transmittance of the electrodes themselves when measured from the phosphor layer side. Therefore, it may be possible to produce a display that does not require transparent electrodes by using the phosphor layer side of a device with comb electrodes made of metals, such as Au, for the display. PMID- 29148445 TI - Ultra-small, highly stable, and membrane-impermeable fluorescent nanosensors for oxygen. AB - We report on the preparation of ultra-small fluorescent nanosensors for oxygen via a one-pot approach. The nanoparticles have a hydrophobic core capable of firmly hosting hydrophobic luminescent oxygen probes. Their surface is composed of a dense and long-chain poly(ethylene glycol) shell, which renders them cell membrane impermeable but yet highly sensitive to oxygen, and also highly stable in aqueous solutions and cell culture media. These features make them potentially suitable for sensing oxygen in extracellular fluids such as blood, interstitial and brain fluid, in (micro) bioreactors and micro- or nanoscale fluidic devices. Four kinds of nanosensors are presented, whose excitation spectra cover a wide spectral range (395-630 nm), thus matching many common laser lines, and with emission maxima ranging from 565 to 800 nm, thereby minimizing interference from background luminescence of biomatter. The unquenched lifetimes are on the order of 5.8-234 MUs, which-in turn-enables lifetime imaging and additional background separation via time-gated methods. PMID- 29148446 TI - Spectral phasor approach for fingerprinting of photo-activatable fluorescent proteins Dronpa, Kaede and KikGR. AB - The phasor global analysis algorithm is common for fluorescence lifetime applications, but has only been recently proposed for spectral analysis. Here the phasor representation and fingerprinting is exploited in its second harmonic to determine the number and spectra of photo-activated states as well as their conversion dynamics. We follow the sequence of photo-activation of proteins over time by rapidly collecting multiple spectral images. The phasor representation of the cumulative images provides easy identification of the spectral signatures of each photo-activatable protein. PMID- 29148448 TI - Methods and Applications in Fluorescence: Editorial Board Biographies. AB - The full text of this article is available in the PDF provided. PMID- 29148447 TI - Effect of acidic pH on flow cytometric detection of bacteria stained with SYBR Green I and their distinction from background. AB - Unspecific background caused by biotic or abiotic particles, cellular debris, or autofluorescence is a well-known interfering parameter when applying flow cytometry to the detection of microorganisms in combination with fluorescent dyes. We present here an attempt to suppress the background signal intensity and thus to improve the detection of microorganisms using the nucleic acid stain SYBR(r) Green I. It has been observed that the fluorescent signals from SYBR Green I are greatly reduced at acidic pH. When lowering the pH of pre-stained samples directly prior to flow cytometric analysis, we hypothesized that the signals from particles and cells with membrane damage might therefore be reduced. Signals from intact cells, temporarily maintaining a neutral cytosolic pH, should not be affected. We show here that this principle holds true for lowering background interference, whereas the signals of membrane-compromised dead cells are only affected weakly. Signals from intact live cells at low pH were mostly comparable to signals without acidification. Although this study was solely performed with SYBR(r) Green I, the principle of low pH flow cytometry (low pH FCM) might hold promise when analyzing complex matrices with an abundance of non cellular matter, especially when expanded to non-DNA binding dyes with a stronger pH dependence of fluorescence than SYBR Green I and a higher pKa value. PMID- 29148449 TI - Novel fluorescent carbonic nanomaterials for sensing and imaging. AB - Small brightly fluorescent carbon nanoparticles have emerged as a new class of materials important for sensing and imaging applications. We analyze comparatively the properties of nanodiamonds, graphene and graphene oxide 'dots', of modified carbon nanotubes and of diverse carbon nanoparticles known as 'C dots' obtained by different methods. The mechanisms of their light absorption and luminescence emission are still unresolved and the arguments are presented for their common origin. Regarding present and potential applications, we provide critical comparison with the other types of fluorescence reporters, such as organic dyes and semiconductor quantum dots. Their most prospective applications in sensing (based on the changes of intensity, FRET and lifetime) and in imaging technologies on the level of living cells and whole bodies are overviewed. The possibilities for design on their basis of multifunctional nanocomposites on a broader scale of theranostics are outlined. PMID- 29148450 TI - Celebrating our first year. AB - The full text of this article is available in the PDF provided. PMID- 29148451 TI - Ratiometric luminescence 2D in vivo imaging and monitoring of mouse skin oxygenation. AB - Tissue oxygenation plays a critical role in the pathogenesis of various diseases, but non-invasive, robust and user-friendly methods for its measurement in vivo still need to be established. Here, we are presenting an in vivo oxygen-detection system that uses ratiometric luminescence imaging (RLI) as a readout scheme to determine the skin oxygen tension of mouse hind footpads via side-by-side comparison with more established techniques including luminescence-lifetime imaging using planar sensor films and the polarographic electrode as the gold standard. We also demonstrate that this technology allows the detection of changes in mouse skin tissue oxygenation induced by subjecting mice to systemic hypoxia. The data demonstrate oxygen imaging based on RLI to be a most useful tool for reliably and easily analyzing and monitoring skin tissue oxygenation in vivo. This technology will advance our understanding of local regulation of skin tissue oxygenation in various disease conditions. PMID- 29148452 TI - Towards a spectrum-based bar code for identification of weakly fluorescent microparticles. AB - Spectrally resolved detection of fluorescent probes can be used to identify multiple labeled target molecules in an unknown mixture. We study how the spectral shape, the experimental noise, and the number of spectral detection channels affect the success of identification of weakly fluorescent beads on basis of their emission spectra. The proposed formalism allows to estimate the performance of the spectral identification procedure with a given set of spectral codes on the basis of the reference spectra only. We constructed a simple prism based setup for spectral detection and demonstrate that seven distinct but overlapping spectral codes realized by combining up to three fluorescent dyes bound to a single bead in a barcode-based manner can be reliably identified. The procedure allows correct identification even in the presence of known autofluorescence background stronger than the actual signal. PMID- 29148453 TI - Luminescent lanthanide reporters: new concepts for use in bioanalytical applications. AB - Lanthanides represent the chemical elements from lanthanum to lutetium. They intrinsically exhibit some very exciting photophysical properties, which can be further enhanced by incorporating the lanthanide ion into organic or inorganic sensitizing structures. A very popular approach is to conjugate the lanthanide ion to an organic chromophore structure forming lanthanide chelates. Another approach, which has quickly gained interest, is to incorporate the lanthanide ions into nanoparticle structures, thus attaining improved specific activity and a large surface area for biomolecule immobilization. Lanthanide-based reporters, when properly shielded from the quenching effects of water, usually express strong luminescence emission, multiple narrow emission lines covering a wide wavelength range, and exceptionally long excited state lifetimes enabling time gated luminescence detection. Because of these properties, lanthanide-based reporters have found widespread applications in various fields of life. This review focuses on the field of bioanalytical applications. Luminescent lanthanide reporters and assay formats utilizing these reporters pave the way for increasingly sensitive, simple, and easily automated bioanalytical applications. PMID- 29148454 TI - Mapping microscopic order in plant and mammalian cells and tissues: novel differential polarization attachment for new generation confocal microscopes (DP LSM). AB - Elucidation of the molecular architecture of complex, highly organized molecular macro-assemblies is an important, basic task for biology. Differential polarization (DP) measurements, such as linear (LD) and circular dichroism (CD) or the anisotropy of the fluorescence emission (r), which can be carried out in a dichrograph or spectrofluorimeter, respectively, carry unique, spatially averaged information about the molecular organization of the sample. For inhomogeneous samples-e.g. cells and tissues-measurements on macroscopic scale are not satisfactory, and in some cases not feasible, thus microscopic techniques must be applied. The microscopic DP-imaging technique, when based on confocal laser scanning microscope (LSM), allows the pixel by pixel mapping of anisotropy of a sample in 2D and 3D. The first DP-LSM configuration, which, in fluorescence mode, allowed confocal imaging of different DP quantities in real-time, without interfering with the 'conventional' imaging, was built on a Zeiss LSM410. It was demonstrated to be capable of determining non-confocally the linear birefringence (LB) or LD of a sample and, confocally, its FDLD (fluorescence detected LD), the degree of polarization (P) and the anisotropy of the fluorescence emission (r), following polarized and non-polarized excitation, respectively (Steinbach et al 2009 Acta Histochem.111 316-25). This DP-LSM configuration, however, cannot simply be adopted to new generation microscopes with considerably more compact structures. As shown here, for an Olympus FV500, we designed an easy-to-install DP attachment to determine LB, LD, FDLD and r, in new-generation confocal microscopes, which, in principle, can be complemented with a P-imaging unit, but specifically to the brand and type of LSM. PMID- 29148455 TI - Secondary emission influenced fluorescence decay of a homogeneous fluorophore solution. AB - An analytical expression is found allowing the calculation of the secondary emission influenced fluorescence decay of a homogeneous fluorophore solution. Before starting the calculation one has to know the shape of the primary fluorescence decay of the fluorophore and the value of the parameter kappa denoting the ratio of the secondary to primary steady-state fluorescence intensities. The method elaborated by Budo and Ketskemety is recommended for evaluation of the parameter kappa. The main importance of the obtained expression is that it can be used to recover parameters characterizing the fluorescence decay in the absence of secondary emission. The cases of monoexponential, biexponential and multiexponential primary fluorescence decays are discussed in detail. PMID- 29148456 TI - Energy transfer between a biological labelling dye and gold nanorods. AB - We have demonstrated energy transfer between a biological labelling dye (Alexa Fluor 405) and gold nanorods experimentally and theoretically. The fluorescence lifetime imaging microscopy and density matrix method are used to study a hybrid system of dye and nanorods under one- and two-photon excitations. Energy transfer between dye and nanorods via the dipole-dipole interaction is found to cause a decrease in the fluorescence lifetime change. Enhanced energy transfer from dye to nanorods is measured in the presence of an increased density of nanorods. This study has potential applications in fluorescence lifetime-based intra-cellular sensing of bio-analytes as well as nuclear targeting cancer therapy. PMID- 29148457 TI - Associated anisotropy decays of ethidium bromide interacting with DNA. AB - Ethidium Bromide (EB) is a commonly used dye in a deoxyribonucleic acid (DNA) study. Upon an intercalation, this dye significantly increases its brightness and fluorescence lifetime. In this report we have studied the time resolved fluorescence properties of EB existing simultaneously in free and DNA-bound forms in the solution. Fluorescence intensity decays were fitted globally to a double exponential model with lifetimes corresponding to free (1.6 ns) and bound (22 ns) forms, and molar fractions were determined for all used solutions. Anisotropy decays displayed characteristic time dependence with an initial rapid decline followed by recovery and slow decay. The short-lived fraction associated with free EB molecules decreases faster than long-lived fraction associated with EB bound to DNA. Consequently, contribution from fast rotation leads to initial rapid decay in anisotropy. On the other hand bound fraction, due to slow rotation helps recover anisotropy in time. This effect of associated anisotropy decays in systems such as EB free/EB-DNA is clearly visible in a wide range of concentrations, and should be taken into account in polarization assays and biomolecule dynamics studies. PMID- 29148458 TI - Imaging chemical extraction by polymer inclusion membranes using fluorescence microscopy. AB - Polymer inclusion membranes (PIMs) transport chemicals between bodies of liquid by simultaneously performing chemical extraction and back-extraction. The internal chemical and physical mechanisms by which this transport occurs are, however, poorly understood. Also, some PIMs, which are otherwise optimal for their task, age and lose function after only days, limiting their feasibility for industrial upscaling. Through the application of fluorescence imaging methods we are able for the first time to see where chemical extraction occurs in the membrane. Extraction of fluorescein from solution by PIMs demonstrates inhomogeneities that do not correlate to surface morphology. Fluorescence lifetime imaging demonstrates that regions of increased extraction have distinctly different fluorescence lifetimes to that of the surrounding PIM indicating localized chemical environments, and this is observed to change with membrane age. Fluorescence imaging is shown to allow probing and novel understanding of PIM internal chemical morphology. PMID- 29148459 TI - Generating multiple-pulse bursts for enhanced fluorescence detection. AB - The signal-to-background ratio is the limiting factor for fluorescence based detection, sensing, and imaging. A typical background signal will include direct scattering of excitation and Raman scattering of the sample as well as autofluorescence from the sample and additives. To improve the signal-to background ratio, fluorophores of high brightness and/or high concentration of the fluorophores need to be used. Most of the background is instantaneous and short-lived (picosecond to nanosecond time scale), and using long-lived fluorescence probes combined with time-gated detection allows for significant suppression of unwanted background. Unfortunately, this approach requires substantial sacrifice of the probe signal in order to sufficiently filter the background unless the fluorescence lifetime of the probe is very long. However, long lived probes like ruthenium bipyridyl have relatively low brightness compared to probes that have shorter, 10-30 ns fluorescence lifetimes.We recently presented an approach based on bursts of multiple pulses that allowed for high probe signal amplification using long-lived ruthenium based probe (Ru) and an 80 MHz repetition-rate laser excitation. Unfortunately, Ru represents an extreme case for probe lifetime, and a probe with a shorter lifetime of 20 ns will require excitation from a pulsed source with much higher repetition rate to significantly enhance its signal. Such high repetition rates are not possible to generate with most of today's available electronics. In this report we present new approaches to optimize and generate bursts of pulses with high repetition rate within the burst and no need for new or improved electronics. The high repetition rates originate from a low-repetition source and are highly tunable. We demonstrate that a burst of 2-10 pulses spaced 3 ns apart (corresponding to a 'burst repetition rate' of 330 MHz) allows for high signal enhancement of the 20 ns probe over the sub-nanosecond/nanosecond background. Such an approach can be applied for any sensing format, allowing much higher sensitivity for detection. Since the energy of a single pulse is spread over a few pulses in the burst, the fluorophore's photostability also improves. PMID- 29148460 TI - Dye-doped polystyrene-coated gold nanorods: towards wavelength tuneable SPASER. AB - We present the synthesis and photophysical study of a new type of fluorescent gold core-polystyrene shell nanoparticles fabricated by emulsion polymerization at neutral pH. The thickness of the PS shell can be controlled by varying the synthesis conditions. Decrease in the fluorescence intensity and lifetime of Rhodamine 800 (Rh800) were observed, indicating energy transfer from Rh800 to gold nanorods. This study suggests the possibility of exploiting dye-doped polystyrene shells as a gain medium to compensate for the energy loss of longitudinal surface plasmon resonance of gold nanorods and paving the way for eventually realizing a SPASER (surface plasmon amplification by stimulated emission of radiation) optical source of tuneable wavelength. PMID- 29148461 TI - Induced circularly polarized luminescence arising from anion or protein binding to racemic emissive lanthanide complexes. AB - A circularly polarized luminescence (CPL) spectrometer has been built and used to study the binding interaction of lactate and four different proteins with racemic EuIII and TbIII complexes in aqueous solution. Lactate binding gives rise to strong induced CPL spectra, and the observed emission dissymmetry factors vary linearly with enantiomeric composition. Particularly strong induced TbIII CPL also characterizes the binding interaction of alpha-1-acid glycoprotein with a dissociation constant, Kd, of 2.5 MUM. PMID- 29148462 TI - 13th Conference on Methods and Applications in Fluorescence-MAF-13. PMID- 29148463 TI - Chiroptical spectroscopic techniques based on fluorescence. AB - Among the various chiroptical spectroscopic methods circular dichroism (CD), optical rotatory dispersion (ORD), Raman optical activity (ROA), the methods based on fluorescence have so far played a marginal role. Fluorescence detected circular dichroism and circularly polarized luminescence (CPL) were both introduced many years ago with important, but not so frequent, applications. In particular, CPL, which requires specialist hardware, has been restricted by the limited number of users. Recent interest, which has increased in the field of material science particularly, where the emission properties are more attractive and important than the absorption ones, has motivated new application fields and may change the situation in the future. PMID- 29148464 TI - Metal ion influence on eumelanin fluorescence and structure. AB - Melanin has long been thought to have an unworkably weak and complex fluorescence, but here we study its intrinsic fluorescence in order to demonstrate how metal ions can be used to control the rate of formation, constituents and structure of eumelanin formed from the well-known laboratory auto-oxidation of 3,4-dihydroxy-L-phenylalanine (L-DOPA). The effect on eumelanin absorption and fluorescence of a range of solvated metal ions is reported including Cu, Zn, Ni, Na and K. Monovalent cations and Zn have little effect, but the effect of transition metal cations can be considerable. For example, at pH 10, copper ions are shown to accelerate the onset of eumelanin formation, but not the rate of formation once it commences, and simplify the usual complex structure and intrinsic fluorescence of eumelanin in a way that is consistent with an increased abundance of 5,5-dihydroxyindole-2-carboxylic acid (DHICA). The presence of a dominant 6 ns fluorescence decay time at 480 nm, when excited at 450 nm describes a distinct photophysical species, which we tentatively assign to small oligomers. Copper is well-known to normally quench fluorescence, but increasing amounts of copper surprisingly leads to an increase in the fluorescence decay time of eumelanin, while reducing the fluorescence intensity, suggesting copper modification of the excited state. Such results have bearing on diverse areas. The most accepted morphology for melanin is that of a graphite like sheet structure, and one which readily binds metal ions, an interaction that is thought to have an important, though as yet unclear bearing on several areas of medicine including neurology. There is also increasing interest in bio-mimicry by preparing and labelling sheet structures with metal ions for new electronic and photonic materials. PMID- 29148465 TI - New highly fluorescent pH indicator for ratiometric RGB imaging of pCO2. AB - A new diketo-pyrrolo-pyrrole (DPP) indicator dye for optical sensing of carbon dioxide is prepared via a simple one step synthesis from commercially available low cost 'Pigment Orange 73'. The pigment is modified via alkylation of one of the lactam nitrogens with a tert-butylbenzyl group. The indicator dye is highly soluble in organic solvents and in polymers and shows pH-dependent absorption (lambdamax 501 and 572 nm for the protonated and deprotonated forms, respectively) and emission spectra (lambdamax 524 and 605 nm for the protonated and deprotonated forms, respectively). Both the protonated and the deprotonated forms show high fluorescence quantum yields (Phiprot 0.86; Phideprot 0.66). Hence, colorimetric read-out and ratiometric fluorescence intensity measurements are possible. The emission of the two forms of the indicator excellently matches the response of the green and the red channels of an RGB camera. This enables imaging of carbon dioxide distribution with a simple and low cost optical set-up. The sensor based on the new DPP dye shows very high sensitivity and is particularly promising for monitoring atmospheric levels of carbon dioxide. PMID- 29148466 TI - Fluorescent sensors based on bacterial fusion proteins. AB - Fluorescence proteins are widely used as markers for biomedical and technological purposes. Therefore, the aim of this project was to create a fluorescent sensor, based in the green and cyan fluorescent protein, using bacterial S-layers proteins as scaffold for the fluorescent tag. We report the cloning, expression and purification of three S-layer fluorescent proteins: SgsE-EGFP, SgsE-ECFP and SgsE-13aa-ECFP, this last containing a 13-amino acid rigid linker. The pH dependence of the fluorescence intensity of the S-layer fusion proteins, monitored by fluorescence spectroscopy, showed that the ECFP tag was more stable than EGFP. Furthermore, the fluorescent fusion proteins were reassembled on silica particles modified with cationic and anionic polyelectrolytes. Zeta potential measurements confirmed the particle coatings and indicated their colloidal stability. Flow cytometry and fluorescence microscopy showed that the fluorescence of the fusion proteins was pH dependent and sensitive to the underlying polyelectrolyte coating. This might suggest that the fluorescent tag is not completely exposed to the bulk media as an independent moiety. Finally, it was found out that viscosity enhanced the fluorescence intensity of the three fluorescent S-layer proteins. PMID- 29148467 TI - Enhancing fluorescence by using pluronic block copolymers as carriers of monomeric porphycenes. AB - Porphycenes, structural isomers of porphyrins, usually exhibit strong fluorescence in organic solvents. However, in water they are practically insoluble or form only weakly emitting aggregates. We show that embedding porphycenes inside pluronic micelles in water solutions leads to the recovery of strong monomeric fluorescence, of which the decay times and quantum yields are similar to those observed for homogeneous solvents. One of the investigated porphycenes serves as a fluorescence sensor of the microenvironment viscosity, revealing that the viscosity inside pluronic micelles is quite high. Using confocal fluorescence microscopy, we obtained images of single pluronic micelles containing monomeric porphycene chromophores. PMID- 29148468 TI - Temperature dependence of the phosphorescence and of the thermally activated delayed fluorescence of 12C70 and 13C70 in amorphous polymer matrices. Is a second triplet involved? AB - The phosphorescence and thermally activated delayed fluorescence (TADF) lifetimes of 12C70 and 13C70 in two different glassy hydrocarbon polymers, one aliphatic (cyclic polyolefin) and one aromatic (polystyrene), were measured between -200 and 100 oC. The temperature dependence of the lifetimes is equally well described by a three-state mechanism (ground state, S0, and two excited states in thermal equilibrium, T1 and S1, the lifetime of T1 being temperature dependent) and by a four-state mechanism (ground state, S0, and three excited states in thermal equilibrium, T1, T2 and S1, all with temperature-independent lifetimes). The estimated S1-T1 and T2-T1 energy gaps (four-state mechanism) are in good agreement with spectroscopic measurements. These and the determined quantum yield of triplet formation, 0.997 +/- 0.001, are found to be essentially independent of the polymer matrix and of the isotopic composition of the fullerene. On the other hand, the lifetimes of both T1 and T2 (four-state mechanism) are weakly dependent on the polymer matrix but strongly vary with the fullerene isotopic composition, nearly doubling when going from 12C70 to 13C70. A parameter useful for the characterization of TADF, the on-set temperature T0, is also introduced. PMID- 29148469 TI - Phasor based analysis of FRET images recorded using spectrally resolved lifetime imaging. AB - The combined analysis of spectral and lifetime images has the potential to provide more accurate and more detailed information about Forster resonance energy transfer (FRET). We have developed a novel FRET analysis method to analyze images recorded by multispectral lifetime imaging. The new method is based on a phasor approach and facilitates the simultaneous analysis of decay kinetics of donor and acceptor molecules. The method is applicable to both molecules that exhibit a mono-exponential decay and a bi-exponential decay. As an example we show the possibility of extracting the energy transfer efficiency and the fraction of interacting molecules even in the presence of non-interacting molecules. The reliability of the method is investigated by comparing it with conventional FRET-FLIM analyses. We show that, with the same number of detected photons, the spectrally resolved phasor approach provides higher accuracy than other analysis methods; the confidence interval is improved and the FRET efficiency is closer to the real value. PMID- 29148470 TI - Exploiting fluorescence for multiplex immunoassays on protein microarrays. AB - Protein microarray technology is becoming the method of choice for identifying protein interaction partners, detecting specific proteins, carbohydrates and lipids, or for characterizing protein interactions and serum antibodies in a massively parallel manner. Availability of the well-established instrumentation of DNA arrays and development of new fluorescent detection instruments promoted the spread of this technique. Fluorescent detection has the advantage of high sensitivity, specificity, simplicity and wide dynamic range required by most measurements. Fluorescence through specifically designed probes and an increasing variety of detection modes offers an excellent tool for such microarray platforms. Measuring for example the level of antibodies, their isotypes and/or antigen specificity simultaneously can offer more complex and comprehensive information about the investigated biological phenomenon, especially if we take into consideration that hundreds of samples can be measured in a single assay. Not only body fluids, but also cell lysates, extracted cellular components, and intact living cells can be analyzed on protein arrays for monitoring functional responses to printed samples on the surface. As a rapidly evolving area, protein microarray technology offers a great bulk of information and new depth of knowledge. These are the features that endow protein arrays with wide applicability and robust sample analyzing capability. On the whole, protein arrays are emerging new tools not just in proteomics, but glycomics, lipidomics, and are also important for immunological research. In this review we attempt to summarize the technical aspects of planar fluorescent microarray technology along with the description of its main immunological applications. PMID- 29148471 TI - Quantitative measurement of fluorescence brightness of single molecules. AB - Single-molecule fluorescence spectroscopy and imaging probe many characteristics of the fluorescence from individual molecules like relative intensity, polarization, lifetime and spectrum. However, such an important and fundamental parameter as absolute fluorescence intensity (or in other words fluorescence brightness), which is proportional to the absorption cross section and fluorescence quantum yield, has not yet been sufficiently exploited in the field. One reason for that is the difficulty of absolute fluorescence brightness measurements. In the present work a detailed description of fluorescence brightness measurements of single molecules is given. We discuss several important factors like the power density and polarization of excitation light, the substrates and the local environment. It is shown that the fluorescence brightness of a single molecule indeed can be measured with sufficient accuracy and used as a powerful parameter for characterization of materials at single molecule/particle level. The brightness of a single object can give similar information as the fluorescence quantum yield that is crucial for understanding the photophysical properties for individual multi-chromophoric systems in inhomogeneous environments. PMID- 29148472 TI - Simple and versatile modifications allowing time gated spectral acquisition, imaging and lifetime profiling on conventional wide-field microscopes. AB - An inverted microscope has been adapted to allow time-gated imaging and spectroscopy to be carried out on samples containing responsive lanthanide probes. The adaptation employs readily available components, including a pulsed light source, time-gated camera, spectrometer and photon counting detector, allowing imaging, emission spectroscopy and lifetime measurements. Each component is controlled by a suite of software written in LabVIEW and is powered via conventional USB ports. PMID- 29148473 TI - Evidence of energy transfer from tryptophan to BSA/HSA protected gold nanoclusters. AB - This work reports on the chromophores interactions within protein-protected gold nanoclusters. We conducted spectroscopic studies of fluorescence emissions originated from gold nanoclusters and intrinsic tryptophan (Trp) in BSA or HSA proteins. Both steady state fluorescence and lifetime measurements showed a significant Forster Resonance Energy Transfer (FRET) from Trp to the gold nanocluster. Tryptophan lifetimes in the case of protein-protected gold nanoclusters are 2.6 ns and 2.3 ns for BSA and HSA Au clusters while 5.8 ns for native BSA and 5.6 for native HSA. The apparent distances from Trp to gold nanocluster emission center, we estimated as 24.75 A for BSA and 23.80 A for HSA. We also studied a potassium iodide (KI) quenching of protein-protected gold nanoclusters and compared with the quenching of BSA and HSA alone. The rates of Trp quenching were smaller in BSA-Au and HSA-Au nanoclusters than in the case of free proteins, which is consistent with shorter lifetime of quenched Trp(s) and lower accessibility for KI. While Trp residues were quenched by KI, the emissions originated from nanoclusters were practically unquenched. In summary, for BSA and HSA Au clusters, we found 55% and 59% energy transfer efficiency respectively from tryoptophan to gold clusters. We believe this interaction can be used to our advantage in terms of developing resonance energy transfer based sensing applications. PMID- 29148474 TI - Creating a high impact journal for research in fluorescence. PMID- 29148475 TI - Fluorescence kinetics of tryptophan in a heterogeneous environment. AB - The potentially highly informative, but complex fluorescence decay of amino acids in protein is not fully understood and presents a barrier to understanding. Here we have tested a new and general approach to describing experimentally measured the fluorescence decay in a heterogeneous macroscopic sample. The decay parameters carry information on the features of the kinetics induced by the environment's heterogeneity. Bayesian interference demonstrated that the model fits well to the fluorescence decay of tryptophan in human serum albumin (HSA). The approach has the potential to accelerate photophysical research of heterogeneous media and, specifically, to solve a critical outstanding problem in interpreting protein fluorescence, paving the way to further progress in biomedical research. PMID- 29148476 TI - Fluorescent probes and nanoparticles for intracellular sensing of pH values. AB - Intracellular pH regulates a number of cell metabolism processes and its sensing is thus of great importance for cell studies. Among various methods, fluorescent probes have been widely used for sensing intracellular pH values because of their high sensitivity and spatiotemporal resolution capability. In this article, the development of fluorescent probes with good practicability in sensing intracellular pH values and pH variation during 2009 - 2014 is reviewed. These fluorescence probes are divided into two kinds: small molecules and nanoparticles. Photophysical properties, advantages/disadvantages and applications of the two kinds of probes are discussed in detail. PMID- 29148477 TI - Phasor approaches simplify the analysis of tryptophan fluorescence data in protein denaturation studies. AB - The intrinsic fluorescence of tryptophan is frequently used to investigate the structure of proteins. The analysis of tryptophan fluorescence data is challenging: fluorescence (anisotropy) decays typically have multiple lifetime (correlation time) components and fluorescence spectra are broad and exhibit only minor shifts. In this work, we show that phasor approaches can substantially simplify tryptophan fluorescence analysis. To demonstrate this, we re-analyse previously recorded datasets of the denaturant (guanidinium hydrochloride, GuHCl) induced unfolding of a single-tryptophan-containing variant of apoflavodoxin from Azotobacter vinelandii. For three methods-(1) time-resolved fluorescence, (2) time-resolved fluorescence anisotropy and (3) steady-state fluorescence spectroscopy-we show that the phasor analysis can readily identify the presence of a folding intermediate. Moreover, the fractional contributions of protein states at various stages of unfolding and the values of the free energy difference of the unfolding process [Formula: see text] are obtained. The outcomes are compared to the global analysis results published previously. PMID- 29148478 TI - A joint Richardson-Lucy deconvolution algorithm for the reconstruction of multifocal structured illumination microscopy data. AB - We demonstrate the reconstruction of images obtained by multifocal structured illumination microscopy, MSIM, using a joint Richardson-Lucy, jRL-MSIM, deconvolution algorithm, which is based on an underlying widefield image formation model. The method is efficient in the suppression of out-of-focus light and greatly improves image contrast and resolution. Furthermore, it is particularly well suited for the processing of noise corrupted data. The principle is verified on simulated as well as experimental data and a comparison of the jRL-MSIM approach with the standard reconstruction procedure, which is based on image scanning microscopy, ISM, is made. Our algorithm is efficient and freely available in a user friendly software package. PMID- 29148479 TI - Correlative super-resolution imaging of RNA polymerase distribution and dynamics, bacterial membrane and chromosomal structure in Escherichia coli. AB - We demonstrate correlative super-resolution PALM, PAINT and dSTORM imaging of RNA polymerase, membrane and chromosomal DNA in fixed E. coli. This protocol allows the combination of precise structural information of the nucleoid (dSTORM) with quantitative super-resolution imaging (PALM) of interacting proteins. The spatial distribution and organization of RNA polymerase and DNA are visualized in bacterial cells grown at doubling times of 25 or 44 min. We observe that RNA polymerase is concentrated at the edge of the highly structured nucleoid during fast growth, whereas it is found more evenly distributed during medium-fast growth. In both conditions, the nucleoid shows densely packed areas which appear to be inaccessible to RNA polymerase. This finding is confirmed by live-cell tracking of RNA polymerase and subsequent imaging of the respective nucleoids using a protocol for fast fixation on-the-slide. PMID- 29148480 TI - fastSIM: a practical implementation of fast structured illumination microscopy. AB - A significant improvement in acquisition speed of structured illumination microscopy (SIM) opens a new field of applications to this already well established super-resolution method towards 3D scanning real-time imaging of living cells. We demonstrate a method of increased acquisition speed on a two beam SIM fluorescence microscope with a lateral resolution of ~100 nm at a maximum raw data acquisition rate of 162 frames per second (fps) with a region of interest of 16.5 * 16.5 um2, free of mechanically moving components. We use a programmable spatial light modulator (ferroelectric LCOS) which promises precise and rapid control of the excitation pattern in the sample plane. A passive Fourier filter and a segmented azimuthally patterned polarizer are used to perform structured illumination with maximum contrast. Furthermore, the free running mode in a modern sCMOS camera helps to achieve faster data acquisition. PMID- 29148481 TI - Rational design of enhanced photoresistance in a photoswitchable fluorescent protein. AB - Fluorescent proteins are particularly susceptible to photobleaching, the permanent loss of fluorescence emission resulting from photodestruction of the chromophore. In the case of Reversibly Switchable Fluorescent Proteins (RSFPs), which can be switched back and forth between a non-fluorescent and a fluorescent state, the achievable number of switching cycles is limited by photobleaching, a process known as photofatigue. Photofatigue has become a crucial limitation in a number of advanced applications based on repeated photoswitching of RSFPs, notably in the field of super-resolution fluorescence microscopy. Here, based on our previous structural investigation of photobleaching mechanisms in IrisFP, an RSFP also capable of green-to-red photoconversion, we present the rational design of a single-mutant IrisFP-M159A that displays considerably enhanced photostability. The results suggest that, under moderate illumination intensities, photobleaching of IrisFP-like Anthozoan fluorescent proteins such as EosFP, Dendra or Dronpa derivatives is mainly driven by an oxygen-dependent mechanism resulting in the irreversible sulfoxidation of methionine 159. The photofatigue decay profiles of IrisFP and its photoresistant mutant IrisFP-M159A were investigated in different experimental conditions, in vitro and in cellulo. Although the performance of the mutant was found to be always superior, the results showed switching behaviors strongly dependent on the nanoenvironment. Thus, in general, assessment of photostability and switching properties of RSFPs should be carried out in real experimental conditions. PMID- 29148482 TI - Tracking molecular dynamics without tracking: image correlation of photo activation microscopy. AB - Measuring protein dynamics in the plasma membrane can provide insights into the mechanisms of receptor signaling and other cellular functions. To quantify protein dynamics on the single molecule level over the entire cell surface, sophisticated approaches such as single particle tracking (SPT), photo-activation localization microscopy (PALM) and fluctuation-based analysis have been developed. However, analyzing molecular dynamics of fluorescent particles with intermittent excitation and low signal-to-noise ratio present at high densities has remained a challenge. We overcame this problem by applying spatio-temporal image correlation spectroscopy (STICS) analysis to photo-activated (PA) microscopy time series. In order to determine under which imaging conditions this approach is valid, we simulated PA images of diffusing particles in a homogeneous environment and varied photo-activation, reversible blinking and irreversible photo-bleaching rates. Further, we simulated data with high particle densities that populated mobile objects (such as adhesions and vesicles) that often interfere with STICS and fluctuation-based analysis. We demonstrated in experimental measurements that the diffusion coefficient of the epidermal growth factor receptor (EGFR) fused to PAGFP in live COS-7 cells can be determined in the plasma membrane and revealed differences in the time-dependent diffusion maps between wild-type and mutant Lck in activated T cells. In summary, we have developed a new analysis approach for live cell photo-activation microscopy data based on image correlation spectroscopy to quantify the spatio-temporal dynamics of single proteins. PMID- 29148483 TI - Spectroscopic investigation of interaction between bovine gamma globulin and gold nanoparticles. AB - The interaction of Citrate-capped gold nanoparticles (AuNPs) with Bovine gamma globulin (BGG) was studied using Fourier transform infrared (FTIR), UV-Visible and Fluorescence spectroscopy. FTIR has confirmed the conjugation of AuNPs and BGG. Fluorescence quenching of tryptophan has confirmed the strong interaction between BGG and AuNPs. UV-Visible and Fluorescence spectroscopy have investigated the extent of interaction by determining the binding constants. Binding constants evaluated from UV-Visible and Fluorescence data are in good agreement with each other. An independent class of binding site on BGG for AuNPs has been predicted, where AuNPs interact with a highly solvent accessible tryptophan residue. PMID- 29148484 TI - Is phase-mask alignment aberrating your STED microscope? AB - The performance of a stimulated emission depletion (STED) microscope depends critically upon the pupil plane phase mask that is used to shape the depletion focus. Misalignments of the mask create unwanted distortions of the depletion focus to the detriment of image quality. It is shown how the phase errors introduced by a misplaced mask are similar to coma aberrations. The effects are investigated analytically, through numerical modelling and experimental measurement. Strategies for the systematic alignment of the masks are discussed. PMID- 29148485 TI - Applying fluorescence lifetime imaging microscopy to evaluate the efficacy of anticancer drugs. AB - Fluorescence lifetime imaging microscopy was applied to evaluate the efficacy of anticancer drugs. A decrease in the fluorescence lifetime of the nucleus in apoptotic cancer cells stained by SYTO 13 dye was detected after treatment with antitumor antibiotics such as doxorubicin or epirubicin. It was confirmed that the change in fluorescence lifetime occurred earlier than morphological changes in the cells. We found that the fluorescence lifetime of the nucleus in the cells treated with epirubicin decreased more rapidly than that of the cells treated with doxorubicin. This implies that epirubicin was more efficacious than doxorubicin in the treatment of cancer cells. The change in fluorescence lifetime was, however, not indicated when the cells were treated with cyclophosphamide. The decrease in fluorescence lifetime was associated with the processes involving caspase activation and chromatin condensation. Therefore, this technique would provide useful information about apoptotic cells, particularly in the early stages. PMID- 29148486 TI - Determination of molecular stoichiometry without reference samples by analyzing fluorescence blinking with and without excitation synchronization. AB - Stoichiometry of molecular complexes plays a crucial role in biology. Moreover, for quantitative fluorescence studies, it is often useful to know the number of fluorophores labeled onto the molecules studied. In this work, we propose an approach to determine the number of independent fluorescence emitters on fluorescent molecules based on fluorescence blinking caused by photo-induced triplet state formation, photo-isomerization or charge transfer. The fluorescence blinking is measured under two different excitation regimes, on the same setup, and in one and the same sample. By comparing the fluorescence fluctuations under continuous excitation using Fluorescence Correlation Spectroscopy (FCS), when all the fluorophores are blinking independently of each other, with those occurring under square-pulsed excitation using Transient State (TRAST) spectroscopy, when all fluorophores are blinking in a synchronized manner, the number of fluorophores per molecule can be determined. No calibration sample is needed and the approach is independent of experimental conditions and of the specific environment of the molecules under study.The approach was experimentally validated by labeling double stranded DNA (dsDNA) with different concentrations of the intercalating dye YOYO-1 Iodide. The sample was then measured consecutively by TRAST and FCS and the number of fluorophores per molecule was calculated. The determined numbers were found to agree well with the number of fluorophores per dsDNA, as determined from FCS measurements using additional calibration samples. PMID- 29148487 TI - And yet they glow: thiazole based push-pull fluorophores containing nitro groups and the influence of regioisomerism. AB - Reported is a study on the influence of regioisomerism on the photophysical properties in 4-hydroxy-1,3-thiazole-based push-pull-chromophores/fluorophores to evaluate the molecular structure-property relationship as a basic foundation for future design strategies concerning this class of dyes. Surprisingly, the nitro groups used as acceptors do not act as a fluorescence quencher, instead the derivatives synthesized exhibit quantum yields of 37-40%. Two 4-ethoxy-1,3 thiazole derivatives which differ only in the positioning of their electron donating (methoxy) and electron withdrawing (nitro) groups have been synthesized and examined in terms of their photophysical properties, i.e. UV/Vis absorption and fluorescence emission spectra. Additionally, quantum chemical calculations have been performed to unravel the underlying fundamental transitions and to explain the experimental results. PMID- 29148488 TI - Investigation of the conformational flexibility of DGAT1 peptides using tryptophan fluorescence. AB - The conformational behavior of synthetic peptides corresponding to the putative binding sites of the diacylglycerol acyltransferase 1 enzyme (a polytopic integral membrane protein) was investigated using steady-state and time-resolved fluorescence spectroscopies. Three small linear peptides with 13, 15 and 22 amino acid residues, containing one, two and three Trp residues, respectively, were studied in aqueous solution, in the absence and presence of model membranes. The high flexibility and unordered conformation of the peptides in solution were confirmed by the low Trp polarization values, the high accessibility to water soluble quencher, and the fast rotational correlation times of the Trp residues. However, upon binding to the lipid systems, the Trp residues were incorporated within the acyl hydrophobic core and their lifetimes and rotational correlation times increased. Phasor plots were employed to analyze intensity decay of peptide lipid binding and provided a trajectory, in phasor space, that lies along a line connecting the points of the free and bound peptide. This trajectory was analyzed to determine the association constant of the peptide to the model membrane. PMID- 29148489 TI - Internalization mechanism of neuropeptide Y bound to its Y1 receptor investigated by high resolution microscopy. AB - The neuropeptide Y (NPY) plays numerous biological roles that are mediated by a family of G-protein-coupled receptors. Among the latter, the NPY Y1 subtype receptor undergoes a rapid desensitization following agonist exposure. This desensitization was suggested to result from a rapid clathrin-dependent internalization of Y1 and its recycling at the plasma membrane via sorting/early endosomes (SE/EE) and recycling endosomes (RE). Herein, to validate and quantitatively consolidate the mechanism of NPY internalization, we quantitatively investigated the NPY-induced internalization of the Y1 receptor by direct stochastic optical reconstruction microscopy (dSTORM), a super-resolution imaging technique that can resolve EE and SE, which are below the resolution limit of conventional optical microscopes. Using Cy5-labeled NPY, we could monitor with time the internalization and recycling of NPY on HEK293 cells stably expressing eGFP-labeled Y1 receptors. Furthermore, by discriminating the SE/EE from the larger RE by their sizes and monitoring these two populations as a function of time, we could firmly consolidate the kinetic model describing the internalization mechanism of the Y1 receptors as the basis for their rapid desensitization following agonist exposure. PMID- 29148490 TI - Dual color single particle tracking via nanobodies. AB - Single particle tracking is a powerful tool to investigate the function of biological molecules by following their motion in space. However, the simultaneous tracking of two different species of molecules is still difficult to realize without compromising the length or density of trajectories, the localization accuracy or the simplicity of the assay. Here, we demonstrate a simple dual color single particle tracking assay using small, bright, high affinity labeling via nanobodies of accessible targets with widely available instrumentation. We furthermore apply a ratiometric step-size analysis method to visualize differences in apparent membrane viscosity. PMID- 29148491 TI - A review of the analysis of complex time-resolved fluorescence anisotropy data. AB - Time-resolved fluorescence anisotropy measurements (TRAMs) are widely used to probe the dynamics of the various processes that can lead to the depolarisation of emission following photoselection by polarised excitation. The most commonly investigated of these emission depolarising phenomena is molecular rotational motion, but TRAMs are very useful for determining the kinetics of a host of other processes. In this paper we review several examples for which we have observed in our laboratories initially unexpectedly complex temporal behaviour of the time resolved fluorescence anisotropy signal from relatively 'simple' chemical systems. In certain circumstances the anisotropy (i) decays on timescales when superficially it might be thought it should remain constant, (ii) shows marked 'dip and rise' behaviour in its intensity, or (iii) can change sign as the anisotropy evolves in time. Fundamentally simple processes, including molecular rotational motion, energy migration and excited state photophysics, can cause such behaviour. PMID- 29148492 TI - Super-resolution fluorescent methods: where next for super-resolution? PMID- 29148493 TI - Chemical sensing and imaging based on photon upconverting nano- and microcrystals: a review. AB - The demand for photostable luminescent reporters that absorb and emit light in the red to near-infrared (NIR) spectral region continues in biomedical research and bioanalysis. In recent years, classical organic fluorophores have increasingly been displaced by luminescent nanoparticles. These consist of either polymer or silica based beads that are loaded with luminescent dyes, conjugated polymers, or inorganic nanomaterials such as semiconductor nanocrystals (quantum dots), colloidal clusters of silver and gold, or carbon dots. Among the inorganic materials, photon upconversion nanocrystals exhibit a high potential for application to bioimaging or biomolecular assays. They offer an exceptionally high photostability, can be excited in the NIR, and their anti-Stokes emission enables luminescence detection free of background and perturbing scatter effects even in complex biological samples. These lanthanide doped inorganic crystals have multiple emission lines that can be tuned by the selection of the dopants.This review article is focused on the applications of functionalized photon upconversion nanoparticles (UCNPs) to chemical sensing. This is a comparatively new field of research activity and mainly directed at the sensing and imaging of ubiquitous chemical analytes in biological samples, particularly in living cells. For this purpose, the particles have to be functionalized with suitable indicator dyes or recognition elements, as they do not show an intrinsic or specific luminescence response to most of these analytes (e.g. pH, oxygen, metal ions). We describe the strategies for the design of such responsive nanocomposites utilizing either luminescence resonance energy transfer or emission-reabsorption (inner filter effect) mechanisms and also highlight examples for their use either immobilized in sensor layers or directly as nanoprobes for intracellular sensing and imaging. PMID- 29148494 TI - SDmixer-a versatile software tool for spectral demixing of multicolor single molecule localization data. AB - Spectral demixing (SD) offers multicolor single molecule localization microscopy (SMLM) with low crosstalk and without the need to correct for registration errors. Here, we present SDmixer, a versatile, open-source software tool that enables any laboratory to perform rapid SD-based multicolor SMLM. A graphic user interface allows non-experts to process 2D or 3D data sets from any SML software and to reconstruct the super-resolved multicolor images with flexible output options. PMID- 29148495 TI - Intracellular probes for imaging oxygen concentration: how good are they? AB - In the last decade a number of cell-permeable phosphorescence based probes for imaging of (intra)cellular oxygen (icO2) have been described. These small molecule, supramolecular and nanoparticle structures, although allowing analysis of hypoxia, local gradients and fluctuations in O2, responses to stimulation and drug treatment at sub-cellular level with high spatial and temporal resolution, differ significantly in their operational performance and applicability to different cell and tissue models. Here we discuss and compare these probes with respect to their staining efficiency, brightness, photostability, toxicity, cell specificity, compatibility with different cell and tissue models, and analytical performance. Merits and limitations of particular probes are highlighted and strategies for development of new high-performance O2 imaging probes defined. Key application areas in hypoxia research, stem cells, cancer biology and tissue physiology are also discussed. PMID- 29148496 TI - Acid effect on excited Auramine-O molecular rotor relaxations in solution and adsorbed on insulin fibrils. AB - Steady-state and time-resolved UV-Vis spectroscopy techniques were employed to study the non-radiative process of Auramine-O (AuO). We focused our attention on the ultrafast nonradiative decay of Auramine-O in water and on the acid effect on Auramine-O spectroscopy. We found that weak acids like formic acid shorten the excited-state decay times of both the emission and the transient pump-probe spectra of Auramine-O. We found three time domains in the relaxation of the excited states back to the ground state. In mixtures of acetic and formic acids, the three decay times associated with the relaxation process are shorter in the presence of formic acid in Auramine-O solutions. We qualitatively explain the very large non-radiative rate in water and in formic-acetic acid mixtures by a protic nonradiative model proposed by Sobolewski and Domcke. The steady-state emission spectrum of AuO adsorbed on insulin fibrils consists of two bands assigned to protonated and deprotonated forms and the emission intensity increases by three orders of magnitude. We conclude that the nonradiative process prevails in the liquid state, whereas when AuO is adsorbed on fibrils the nonradiative rate is reduced by three orders of magnitude and thus enables a slow ESPT process to occur. PMID- 29148497 TI - Microfluidic platforms employing integrated fluorescent or luminescent chemical sensors: a review of methods, scope and applications. AB - Herein we critically review microfluidic platforms that contain integrated fluorescent or luminescent chemical sensor assemblies. These were employed in particular for miniaturized oxygen and pH sensing. Microchips with optical temperature sensing capability are also covered since these share many concepts and applications. Other analytes and derived parameters from the above analytes are found in some sensing approaches in microfluidics.After an introduction, the work is structured into three main chapters dealing with the fabrication and microintegration of these sensors, readout and detection strategies, and applications of these microsystems. The fabrication is discussed with a focus on soft lithography-based approaches in polydimethylsiloxane (PDMS) or PDMS and glass hybrid devices that form the majority of work so far. Alternative approaches, particularly using glass or quartz as the main chip material are also covered. Detection techniques employed to date are the subject of the next chapter, where simple intensity as well as lifetime- or wavelength-referenced schemes are presented and the utility of image-based sensing on the microscale is discussed.Lastly, exciting applications of these microfluidic chips are highlighted. Luminescent oxygen and pH sensing has been of particular interest in the field of microbioreactors but other areas are also of interest, particularly chemical reactors and electrophoresis. Optical temperature sensing is discussed and its use in fundamental studies as well as in enzyme reactors. Integrated microsystems with biosensing capabilities and some for monitoring of metal ions and other analytes are also presented. PMID- 29148498 TI - Spectral demixing avoids registration errors and reduces noise in multicolor localization-based super-resolution microscopy. AB - Multicolor single molecule localization-based super-resolution microscopy (SMLM) approaches are challenged by channel crosstalk and errors in multi-channel registration. We recently introduced a spectral demixing-based variant of direct stochastic optical reconstruction microscopy (SD-dSTORM) to perform multicolor SMLM with minimal color crosstalk. Here, we demonstrate that the spectral demixing procedure is inherently free of errors in multicolor registration and therefore does not require multicolor channel alignment. Furthermore, spectral demixing significantly reduces single molecule noise and is applicable to astigmatism-based 3D multicolor imaging achieving 25 nm lateral and 66 nm axial resolution on cellular nanostructures. PMID- 29148499 TI - Upconverting phosphors as an amplifier of a colorimetric signal in dry chemistry test strips for enzymatic measurement of glucose. AB - We describe the use of upconverting phosphors (UCPs) as an amplifier of the colorimetric signal in enzymatic dry chemistry test strips for the determination of glucose. The indicator compound used in the strips attenuated both the emission and excitation wavelengths of the upconverting phosphors, thus taking advantage of the nonlinear relationship between the excitation and emission of these particles. By monitoring the emission of the UCPs under 978 nm excitation, we were able to obtain significantly higher signal response (a steeper calibration curve) from the colorimetric assay compared to a reflectance measurement. The limit of detection of the developed method was 2.1-fold lower than the reflectance-based reference method. The new method was able to determine glucose from a sample of water in the range of 5.7 MUM to 22 mM, which covers the typical blood glucose range in newborns and adults. In low analyte concentrations we obtained up to 3-fold improvement in the slope of the assay calibration curve. This difference decreased with increasing analyte concentration and the effect was diminished by the highest glucose concentration. However, the analytical sensitivity (the ratio of slope and standard deviation) was practically identical between the two methods because of the higher deviation in the UCP emission signal. PMID- 29148500 TI - Imaging of oxygen in microreactors and microfluidic systems. AB - This review gives an overview on the state-of-the-art of oxygen imaging in microfluidics. Oxygen imaging using optical oxygen sensors based on luminescence is a versatile and powerful tool for obtaining profoundly space-resolved information of oxygen in microreactors and microfluidic systems. We briefly introduce the principle of oxygen imaging and present techniques of oxygen imaging applied in microreactors and microfluidic devices, including selection criteria and demands of sensing material and basic set-up for a 2D oxygen sensing system. A detailed review of oxygen imaging in microreactors and microfluidic systems is given on different applications in oxygen gradient monitoring, cell culturing, single-cell analysis and chemical reactions. Finally, we discuss challenges and trends of oxygen imaging in microfluidic systems. PMID- 29148501 TI - Azadioxatriangulenium: exploring the effect of a 20 ns fluorescence lifetime in fluorescence anisotropy measurements. AB - Azaoxatriangulenium (ADOTA) has been shown to be highly emissive despite a moderate molar absorption coefficient of the primary electronic transition. As a result, the fluorescence lifetime is ~20 ns, longer than all commonly used red fluorescent organic probes. The electronic transitions in ADOTA are highly polarised (r 0 = 0.38), which in combination with the long fluorescence lifetime extents the size-range of biomolecular weights that can be detected in fluorescence polarisation-based experiments. Here, the rotational dynamics of bovine serum albumin (BSA) are monitored with three different ADOTA derivatives, differing only in constitution of the reactive linker. A detailed study of the degree of labelling, the steady-state anisotropy, and the time-resolved anisotropy of the three different ADOTA-BSA conjugates are reported. The fluorescence quantum yields (phi fl) of the free dyes in PBS solution are determined to be ~55%, which is reduced to ~20% in the ADOTA-BSA conjugates. Despite the reduction in phi fl, a ~20 ns intensity averaged lifetime is maintained, allowing for the rotational dynamics of BSA to be monitored for up to 100 ns. Thus, ADOTA can be used in fluorescence polarisation assays to fill the gap between commonly used organic dyes and the long luminescence lifetime transition metal complexes. This allows for efficient steady-state fluorescence polarisation assays for detecting binding of analytes with molecular weights of up to 100 kDa. PMID- 29148502 TI - A journal in ascendancy. PMID- 29148503 TI - Highly surface functionalized carbon nano-onions for bright light bioimaging. AB - Carbon-based nanomaterials functionalized with fluorescent and water-soluble groups have emerged as platforms for biological imaging because of their low toxicity and ability to be internalized by cells. The development of imaging probes based on carbon nanomaterials for biomedical studies requires the understanding of their biological response as well as the efficient and safety exposition of the nanomaterial to the cell compartment where it is designed to operate. Here, we present a fluorescent probe based on surface functionalized carbon nano-onions (CNOs) for biological imaging. The modification of CNOs by chemical oxidation of the defects on the outer shell of these carbon nanoparticles results in an extensive surface functionalization with carboxyl groups. We have obtained fluorescently labelled CNOs by a reaction involving the amide bond formation between fluoresceinamine and the carboxylic acids groups on the surface of the CNOs. The functionalized CNOs display high emission properties and dispersability in water due to the presence of high surface coverage of carboxylic acid groups that translate in an efficient fluorescent probe for in vitro imaging of HeLa cells, without significant cytotoxicity. The resulting nanomaterial represents a promising platform for biological imaging applications due to the high dispersability in water, its efficient internalization by cancer cells and localization in specific cell compartments. PMID- 29148504 TI - Highly fluorescent copper nanoclusters as a probe for the determination of pH. AB - A simple, one-pot synthetic route was developed for the preparation of green emitting and pH-responsive Cu nanoclusters (NCs). The Cu NCs were obtained using cysteine (Cys) as both the reducing agent and the capping agent under alkaline conditions at room temperature. The Cu NCs were characterized using spectroscopic and microscopic techniques and exhibited excellent water solubility, ultrasmall size, good dispersion, bright fluorescence and good photostability. Moreover, the Cu NCs were stable even in a high ionic strength medium such as 1M NaCl. Interestingly, the Cys-Cu NCs showed an intrinsically reversible response toward pH change in the range 4-10, and thus can be utilized as an effective and reversible pH indicator. PMID- 29148505 TI - Bioorthogonal fluorescent labels: a review on combined forces. AB - This review ventures to summarize the latest developments in bioorthogonal fluorescent imaging labels with a special focus on bioimaging applications. We briefly summarize the most preferred means of bioorthogonal tagging schemes for the labeling of specific biomolecular structures. The review is structured by the type of the fluorescent labels that can address the problems that most commonly compromise fluorescent imaging techniques, i.e. the autofluorescence of biomolecules, the background fluorescence of unreacted reagents, and photobleaching. Thus, we present (i) far-red/near-infra-red emitting dyes, (ii) fluorogenic scaffolds, and (iii) nanoparticle-based signaling platforms. PMID- 29148506 TI - Advanced molecular (bio)probes-probes that are good, better, smarter. PMID- 29148507 TI - A two-color fluorogenic carbene complex for tagging olefins via metathesis reaction. AB - We describe a fluorogenic ruthenium (II) carbene complex in which the chromophore is directly connected to the metal center. The compound introduces a boron dipyrromethene (BODIPY) moiety into target double bonds by metathesis. Tagging of terminal double bonds is demonstrated on immobilized styrene units on a glass surface. We also show that two compounds with distinguishable fluorescence properties are formed in the model reaction with styrene. The outcome of the metathesis reaction is characterized by 19F-NMR, optical spectroscopy, and, finally, single-molecule trajectories. This labeling scheme, in our perception, is of particular interest in the fields of interfacial science and biorthogonal ligation in combination with super-resolution imaging. PMID- 29148508 TI - Bright and photostable cyanine-styryl chromophores with green and red fluorescence colour for DNA staining. AB - The synthesis and optical characterisation of a series of green- and red-emitting cyanine and cyanine-styryl dyes is presented that were developed based on the cyanine-indole-quinolinium and based on the thiazole red type structure. For the green emitting fluorophores the quinolinium part was replaced by a pyridinium group. The bridge to the indole group was attached either to the 2-position or to the 4-position of the pyridinium moiety. For the red-emitting dyes the connection to the indole moiety is at the 4-position of the quinolinium part. In each set of dyes a methyl group at the indole-NH and/or a phenyl group at the 2-position of the indole part were introduced to tune the optical properties and photostability. Additionally, two dyes were modified with a cyano group to tune the photophysical properties and to enhance the photostabilities. The developed dyes show good photostabilities and bright green or red fluorescence intensities in the presence of DNA. Thus, these dyes represent important and promising candidates for fluorescent molecular imaging of nucleic acids inside living cells. PMID- 29148509 TI - Fluorogen-based reporters for fluorescence imaging: a review. AB - Fluorescence bioimaging has recently jumped into a new area of spatiotemporal resolution and sensitivity thanks to synergistic advances in both optical physics and probe/biosensor design. This review focuses on the recent development of genetically encodable fluorescent reporters that bind endogenously present or exogenously applied fluorogenic chromophores (so-called fluorogens) and activate their fluorescence. We highlight the innovative engineering and design that gave rise to these new natural and synthetic fluorescent reporters, and describe some of the emerging applications in imaging and biosensing. PMID- 29148510 TI - A general synthetic route to isomerically pure functionalized rhodamine dyes. AB - A well-documented obstacle in the synthesis of functionalized rhodamine dyes is the generation of regioisomers which are difficult to separate. These isomers occur due to the use of unsymmetrical anhydride reagents, which possess two potential points of reactivity where condensation with meta-aminophenols can take place. In this report we describe a method which eliminates this problem by using phthalaldehydic acids as anhydride replacements. These reagents provide only one point of reactivity for the aminophenol, thus allowing direct access to single isomer tetramethylrhodamines and avoiding isomer generation altogether. A range of functionalities are shown to be tolerated at the 5- and 6-position of the dye compounds which are prepared in up to gram quantities using our method. The scope of the method is further demonstrated by the preparation of additional rhodamine family members Rhodamine B and X-Rhodamine. PMID- 29148511 TI - Intracellular FRET-based probes: a review. AB - Probes that exploit Forster resonance energy transfer (FRET) in their feedback mechanism are touted for their sensitivity, robustness, and low background, and thanks to the exceptional distance dependence of the energy transfer process, they provide a means of probing lengthscales well below the resolution of light. These attributes make FRET-based probes superbly suited to an intracellular environment, and recent developments in biofunctionalization and expansion of imaging capabilities have put them at the forefront of intracellular studies. Here, we present an overview of the engineering and execution of a variety of recent intracellular FRET probes, highlighting the diversity of this class of materials and the breadth of application they have found in the intracellular environment. PMID- 29148512 TI - Luminescent imaging with optical chemical sensors. PMID- 29148513 TI - Fluorescence cumulants analysis with non-ideal observation profiles. AB - One of the challenges of fluorescence fluctuation fpectroscopy (FFS) is an adequate approximation of a brightness profile. The key feature of fluorescence intensity distribution analysis (FIDA) is a polynomial approximation of a brightness profile. A broad range of brightness profile shapes can be well described by this approximation. A different approach consisting of the introduction of additional fitting parameters, defined as a relative difference between integrals of the actual brightness profile and its Gaussian approximation, is used in photon counting histogram (PCH) analysis. It is sufficient to introduce only one additional fitting parameter (first-order correction) to get an adequate fit to the experimental data in many practical applications. In the current study, we apply these approaches to the theory of time integrated fluorescence cumulants analysis. We demonstrate that developed corrections improve results of FFS analysis applied to simulated and experimental data. The use of different brightness profile approximations and normalizations in PCH and FIDA leads to different estimates of brightness and the number of molecules, even though they represent the same physical quantities. Based on the developed theory, we derive equations that relate brightness and the number of molecules in PCH and FIDA. PMID- 29148514 TI - Upconversion luminescent nanoparticles in physical sensing and in monitoring physical processes in biological samples. AB - The most frequently used strategy for sensing is based on the emission variation of a photoactive system and it can be classified as chemical or physical depending on its response to either a chemical or a physical stimulus. There are a large number of luminescent nanomaterials that respond to chemical species, but comparatively, with the exception of temperature sensing, to date there are few examples showing the capacity of photoactive nanosystems responsive to physical stimuli, such as magnetic and electric fields, high radiation energy, tension/pressure, viscosity, etc, and very few of them comprise upconversion nanoparticles (UCNPs). These nanomaterials consist of an inorganic matrix doped with rare earth (RE) ions and can be advantageously used in sensing due to their unique optical features: near-infrared excitation, anti-Stokes emission, multiplexed emissions that span over a broad range (i.e. from the UV to NIR region depending on the nature of the RE ions), narrow emission bands, long emission lifetimes, high photostability, and non-photoblinking, among others. In this review we focus on the advances in the application of the luminescence of UCNPs for sensing environmental physical changes and for tracking physical processes in living systems. PMID- 29148515 TI - Model-free methods to study membrane environmental probes: a comparison of the spectral phasor and generalized polarization approaches. AB - In this note, we present a discussion of the advantages and scope of model-free analysis methods applied to the popular solvatochromic probe LAURDAN, which is widely used as an environmental probe to study dynamics and structure in membranes. In particular, we compare and contrast the generalized polarization approach with the spectral phasor approach. To illustrate our points we utilize several model membrane systems containing pure lipid phases and, in some cases, cholesterol or surfactants. We demonstrate that the spectral phasor method offers definitive advantages in the case of complex systems. PMID- 29148516 TI - Using fluorescence for studies of biological membranes: a review. AB - Fluorescence techniques have become powerful and widely used tools for studies of biochemical and biophysical processes occurring in biological membranes. Various fluorescence methods have played and continue to play key roles in modern membrane science, so that there have been several focused reviews on this topic. Here, I present the progress and recent achievements in various fluorescence approaches commonly utilized in studies of biological membranes. Applications of numerous fluorescence methods have been reviewed, including single molecule detection, confocal scanning fluorescence microscopy and fluorescence lifetime imaging. I focus on the benefits and limitations of various fluorescence techniques and their combinations, as well as the available methods of in vivo studying. A separate section is dedicated to discussing and comparing different classes of fluorescent membrane probes and their applications to the study of biological membranes. The review should provide researchers from chemistry, biochemistry, and biophysics with the necessary background to identify a range of suitable fluorescence methods in order to successfully design and conduct experimental studies on model lipid bilayers and biological membranes. PMID- 29148517 TI - Azobenzene-caged sulforhodamine dyes: a novel class of 'turn-on' reactive probes for hypoxic tumor cell imaging. AB - New sulforhodamine-based fluorescent 'turn-on' probes have been developed for the direct imaging of cellular hypoxia. Rapid access to this novel class of water soluble 'azobenzene-caged' fluorophores was made possible through an easily implementable azo-coupling reaction between a fluorescent primary arylamine derived from a sulforhodamine 101 scaffold (named SR101-NaphtNH 2 ) and a tertiary aniline whose N-substituents are neutral, cationic, or zwitterionic. The detection mechanism is based on the bioreductive cleavage of the azo bond that restores strong far-red fluorescence (emission maximum at 625 nm) by regenerating the original sulforhodamine SR101-NaphtNH 2 . This valuable fluorogenic response was obtained for the three 'smart' probes studied in this work, as shown by an in vitro assay using rat liver microsomes placed under aerobic and then under hypoxic conditions. Most importantly, the probe namely SR101-NaphtNH 2 -Hyp-diMe was successfully applied for imaging the hypoxic status of tumor cells (A549 cells). PMID- 29148518 TI - Long-wavelength analyte-sensitive luminescent probes and optical (bio)sensors. AB - Long-wavelength luminescent probes and sensors become increasingly popular. They offer the advantage of lower levels of autofluorescence in most biological probes. Due to high penetration depth and low scattering of red and NIR light such probes potentially enable in vivo measurements in tissues and some of them have already reached a high level of reliability required for such applications. This review focuses on the recent progress in development and application of long wavelength analyte-sensitive probes which can operate both reversibly and irreversibly. Photophysical properties, sensing mechanisms, advantages and limitations of individual probes are discussed. PMID- 29148519 TI - Fluorescent dyes with large Stokes shifts for super-resolution optical microscopy of biological objects: a review. AB - The review deals with commercially available organic dyes possessing large Stokes shifts and their applications as fluorescent labels in optical microscopy based on stimulated emission depletion (STED). STED microscopy breaks Abbe's diffraction barrier and provides optical resolution beyond the diffraction limit. STED microscopy is non-invasive and requires photostable fluorescent markers attached to biomolecules or other objects of interest. Up to now, in most biology related STED experiments, bright and photoresistant dyes with small Stokes shifts of 20-40 nm were used. The rapid progress in STED microscopy showed that organic fluorophores possessing large Stokes shifts are indispensable in multi-color super-resolution techniques. The ultimate result of the imaging relies on the optimal combination of a dye, the bio-conjugation procedure and the performance of the optical microscope. Modern bioconjugation methods, basics of STED microscopy, as well as structures and spectral properties of the presently available fluorescent markers are reviewed and discussed. In particular, the spectral properties of the commercial dyes are tabulated and correlated with the available depletion wavelengths found in STED microscopes produced by LEICA Microsytems, Abberior Instruments and Picoquant GmbH. PMID- 29148521 TI - AUTHOR'S CORRECTION: Molecular epidemiology and antimicrobial susceptibility of AmpC- and/or extended-spectrum (ESBL) beta-lactamaseproducing Proteus spp. clinical isolates in Zenica-Doboj Canton, Bosnia and Herzegovina. AB - Volume 13, no. 2, p. 103-112, 2016. Page 103: The byline should appear as shown above. PMID- 29148520 TI - An in vitro prototype of a porcine biomimetic testis-like cell culture system: a novel tool for the study of reassembled Sertoli and Leydig cells. AB - At present, there is no reliable in vitro assembled prepubertal testis-like biomimetic organ culture system designed to assess the functional effects of human gonadotropins on Sertoli and Leydig cells. Spermatogenesis is regulated by endocrine, paracrine, and juxtacrine factors (testicular cross-talk), mainly orchestrated by gonadotropins such as luteinizing hormone (LH) and follicle stimulating hormone (FSH) that play a pivotal role by stimulating Leydig and Sertoli cells, respectively. The aim of our study was to set up an in vitro prepubertal porcine bioengineered construct as a new model for experimental studies on reassembled Sertoli and Leydig cells. We have evaluated Sertoli and Leydig cells obtained from 15- to 20-day-old neonatal pig testes in terms of purity and function. Subsequently, purified Sertoli and enriched Leydig cells were subjected to coincubation to obtain an in vitro prepubertal porcine testis like culture system. We performed enzyme-linked immunosorbent assay (ELISA) for anti-Mullerian hormone (AMH), inhibin B, and testosterone secretion in the medium, and Real-Time PCR analysis of AMH, inhibin B, FSH-r, aromatase, LHr, and 3beta-HSD mRNA expression levels. This in vitro testis-like system was highly responsive to the effects of human gonadotropins and testosterone. AMH mRNA expression and secretion declined, and inhibin-B increased, while FSH-receptor expression was downregulated upon FSH/LH exposure/treatment. Finally, the production of testosterone was increased selectively upon LH treatment. In summary, our proposed model could help to better determine the action of human gonadotropins on Sertoli and Leydig cells. The potential usefulness of the system for shedding light into male infertility-related issues is evident. PMID- 29148523 TI - Nephrotic syndrome and duplication of the inferior vena cava: a series of unfortunate events. PMID- 29148522 TI - A rare case of isolated streptococcal pulmonary valve endocarditis diagnosed with repeated echocardiography. PMID- 29148524 TI - Comparison of endothelial cell loss and complications following DMEK with the use of three different graft injectors. AB - PurposeTo compare endothelial cell loss and complications following Descemet membrane endothelial keratoplasty (DMEK) with use of three commercially available injectors.MethodsFrom 179 consecutive DMEK procedures, 66 cases with uncomplicated graft preparation and completed 12-month follow-up were included in this retrospective study. According to the injector used, 3 groups were formed: group 1 (D.O.R.C. injector, n=16), group 2 (Geuder injector, n=24), and group 3 (Pasteur laboratory pipette, n= 26). Endothelial cell density (ECD) and endothelial cell loss were evaluated preoperatively and at 3, 6 and 12 months postoperatively; surgery-related complications were recorded.ResultsDonor ECD was 2416+/-179 cells/mm2 (group 1), 2417+/-164 cells/mm2 (group 2), and 2478+/-234 cells/mm2 (group 3). At 12 months postoperatively ECD was 1473+/-403 cells/mm2 (group 1), 1379+/-317 cells/mm2 (group 2), and 1316+/-456 cells/mm2 (group 3) (P=0.533, ANOVA). Endothelial cell loss 12 months postoperatively was 39+/-15% (group 1), 43+/-13% (group 2), and 47+/-17% (group 3) (P=0.386, ANOVA). A single case of iris bleeding and reflux of the graft out of the anterior chamber (both in group 3) was noted. Partial graft detachment occurred in group 1 (n=1), group 2 (n=5), and group 3 (n=7) and rebubbling was performed in 6% (group 1), 17% (group 2), and 27% (group 3).ConclusionsTo our knowledge, this is the first clinical study assessing the safety of three different DMEK injectors. Group 1 (D.O.R.C injector) showed the least and group 3 (Pasteur laboratory pipette) the highest endothelial cell loss without reaching statistical significance at 12 months after surgery. Therefore, the graft injector may be chosen according to surgeon's preference. PMID- 29148525 TI - Differences in photoreceptor recovery among patients and between different parts of the posterior pole in Vogt-Koyanagi-Harada disease. AB - PurposeTo investigate the recovery of photoreceptors following the treatment in Vogt-Koyanagi-Harada (VKH) disease.Patients and methodsThis was a retrospective study. We enrolled 28 patients with VKH (56 eyes). The clinical and optical coherence tomography (OCT) findings were recorded for 12 months after treatment. The patterns of photoreceptor recovery on OCT were defined: pattern F group=Foveal photoreceptor recovery visible first; pattern E group=Extrafoveal photoreceptor recovery visible first; and pattern S group=Simultaneous foveal and extrafoveal photoreceptor recovery.ResultsPhotoreceptor recovery varied in different parts of the fundus among patients. Among the 56 eyes, the ellipsoid zone (EZ) recovery of 10 eyes and the interdigitation zone (IZ) recovery of 17 eyes belonged to pattern F group. In most eyes (46 eyes for EZ and 26 eyes for IZ), the recovery of these structures were pattern S. Only in 10 eyes, the recovery of IZ was pattern E. The different patterns of recovery correlated with how promptly the patients had been treated and with the anatomical and visual outcomes at 12 months. Patients in pattern F group were characterized by delayed treatment, delayed recovery of EZ or IZ, and a less favourable prognosis at 12 months relative to other patients, while those in pattern E group had the most prompt treatment and recovery as well as a more favourable outcome at 12 months.ConclusionsIn VKH patients with delayed treatment, foveal photoreceptors tended to recover more rapidly than photoreceptors in other regions. PMID- 29148526 TI - Collaborative research in ophthalmology: the way forward? PMID- 29148527 TI - A novel record for patients with neovascular age-related macular degeneration: providing information and a personal treatment record. PMID- 29148528 TI - Why the macula? AB - The regional susceptibility of the retina to diseases has been well known by clinicians for many years. It is surprising that the implications of these observations have not spawned major research efforts to characterise the structural and functional attributes of the outer retina in different regions of a foveate retina. Without such an effort, the understanding of the disease mechanisms in retinal dystrophies will remain limited and may hamper therapeutic efforts. That outer retinal disease is responsible for over 50% of blind registration in the western world underlines the importance of these considerations. PMID- 29148530 TI - Validation of VSLD questionnaire in patients with learning disabilities undergoing cataract surgery. PMID- 29148529 TI - Anterior segment ischemia: etiology, assessment, and management. AB - Anterior segment ischemia (ASI) is a potentially serious but rare complication of strabismus surgery. Among several risk factors, ASI occurs after strabismus surgery because of the nature of the anterior segment circulation. Disinsertion of rectus muscles leads to a decrease in the blood supply to the various anterior segment structures. We report a series of retrospective and prospective studies performed by our group focused on determining the risk of anterior segment ischemia following strabismus surgery, diagnosis, and modifications to surgical techniques to minimize the impact on anterior segment circulation. We found a significant decrease in postoperative anterior segment blood flow when operating vertical rectus muscles. Plication procedures preserve anterior segment circulation, and modifications to the technique allow the performance of adjustable sutures. Small adjustable selective procedures that spare the ciliary vessels have been demonstrated to be effective in patients with vertical and torsional diplopia. Ciliary sparing augmented adjustable transposition surgery decreases the risk of anterior segment ischemia while allowing management of potential post-operative alignment complications. Finally, ocular coherence tomography angiography is a valuable quantitative and qualitative technique to evaluate anterior segment ischemia. Strabismus surgeons should be aware of the risks of anterior segment ischemia when operating vertical rectus muscles. Modifications to standard surgical techniques allow surgeons to perform complex strabismus surgery in patients at risk for anterior segment ischemia. PMID- 29148531 TI - The Royal College of Ophthalmologists guidelines on serum eye drops for the treatment of severe ocular surface disease: executive summary. PMID- 29148532 TI - The Royal College of Ophthalmologists guidelines on serum eye drops for the treatment of severe ocular surface disease: full report. PMID- 29148533 TI - Identifying characteristic features of the retinal and choroidal vasculature in choroideremia using optical coherence tomography angiography. AB - : PurposeUsing optical coherence tomography angiography (OCTA) to investigate the area with flow in the superficial retinal vessel network (SVRN) and choriocapillaris (CC) layer among male subjects with choroideremia (CHM), female carriers, and normal controls to identify vascular changes.Patients and methodsImages of SRVN and CC layer were acquired in 9 affected males, 5 female carriers, and 14 age- and gender-matched controls using the Angiovue software of the RTVue XR Avanti.ResultsThe mean age was 33 years for affected male CHM patients (median 30 years), 46 years for female carriers (median 53 years), and 39 years for controls (median 38.5). Mean SRVN area+/-SD in subjects with CHM was 12.93+/-2.06 mm2, in carrier subjects 15.36+/-0.60 mm2, and in controls 15.30+/ 1.35 mm2 (P<0.01). The mean CC area+/-SD with flow was 6.97+/-5.26 mm2 in CHM subjects, 21.65+/-0.17 mm2 in carriers and 21.36+/-0.76 mm2 in controls (P<0.01). SRVN and CC area with flow showed a negative correlation in CHM subjects with the age (r=-0.86; P<0.003 and r=-0.77; P<0.01, respectively). CC area with flow had a positive correlation with SRVN (r=0.83, P<0.001). Overall, visual acuity had a negative correlation with SRVN and CC area with flow (r=-0.67, P<0.001 and r= 0.57, P<0.002, respectively). CONCLUSIONS: This is the first study to highlight changes in the SRVN in CHM subjects. OCTA detected a reduced area with flow in both retinal and choroidal circulations, and may be a useful tool for monitoring natural history and disease progression in forthcoming clinical trials. PMID- 29148534 TI - Genetic testing of complement and coagulation pathways in patients with severe hypertension and renal microangiopathy. AB - A diagnosis of thrombotic microangiopathy on kidney biopsy in a patient presenting with hypertensive emergency has historically elicited the diagnosis of malignant hypertension-associated thrombotic microangiopathy. Recent studies, however, have raised awareness that a number of these patients may actually represent atypical hemolytic uremic syndrome. To further investigate this premise, we performed next-generation sequencing to interrogate the coding regions of 29 complement and coagulation cascade genes associated with atypical hemolytic uremic syndrome in 100 non-elderly patients presenting with severe hypertension, renal failure and a kidney biopsy showing microangiopathic changes limited to the classic accelerated hypertension-associated lesion of arterial intimal edema ('mucoid intimal hyperplasia') in isolation and without accompanying glomerular microthrombi. No pathogenic or likely pathogenic variants were identified in any of the genes analyzed, although 13 patients had rare variants of uncertain significance predicted to be deleterious by all in-silico prediction methods utilized. Accordingly, this large patient cohort showed no definitive burden of disease secondary to genetic variants involving complement or coagulation pathways, which contrasts sharply with the high frequency of similar mutational events reported for atypical hemolytic uremic syndrome. Our results also inform recent data by suggesting that patients who present with severe or malignant hypertension and renal thrombotic microangiopathy may be at higher risk for atypical hemolytic uremic syndrome only if the biopsy shows more active disease that includes glomerular fibrin thrombi. PMID- 29148535 TI - The role of APC in WNT pathway activation in serrated neoplasia. AB - Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear beta-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of beta-catenin and truncating APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear beta-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P=0.0001). However, unlike the conventional pathway, truncating APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations common in conventional adenomas. PMID- 29148536 TI - Characterization of foreign materials in paraffin-embedded pathological specimens using in situ multi-elemental imaging with laser spectroscopy. AB - Pathologists typically encounter many disparate exogenous materials in clinical specimens during their routine histopathological examinations, especially within the skin, lymph nodes, and lungs. These foreign substances may be free extracellular deposits or induce several clinical abnormalities or histopathological patterns. However, pathologists almost never investigate or report the chemical nature of exogenous metals in clinical specimens due to a lack of convenient and available technologies. In this paper, a novel strategy based on laser-induced breakdown spectroscopy (LIBS) technology is evaluated for in situ multi-elemental tissue imaging. The improved procedures allow visualization of the presence of chemical elements contained within paraffin embedded specimens of medical interest with elemental images that are stackable with conventional histology images. We selected relevant medical situations for which the associated pathology reports were limited to the presence of lymphohistiocytic and inflammatory cells containing granules (a granuloma and a pseudolymphoma) or to lymph nodes or skin tissues containing pigments or foreign substances. Exogenous elements such as aluminum, titanium, copper, and tungsten were identified and localized within the tissues. The all-optical LIBS elemental imaging instrument that we developed is fully compatible with conventional optical microscopy used for pathology analysis. When combined with routine histopathological analysis, LIBS is a versatile technology that might help pathologists establish or confirm diagnoses for a wide range of medical applications, particularly when the nature of external agents present in tissues needs to be investigated. PMID- 29148537 TI - Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation. AB - Adenomatoid tumors are the most common neoplasm of the epididymis, and histologically similar adenomatoid tumors also commonly arise in the uterus and fallopian tube. To investigate the molecular pathogenesis of these tumors, we performed genomic profiling on a cohort of 31 adenomatoid tumors of the male and female genital tracts. We identified that all tumors harbored somatic missense mutations in the TRAF7 gene, which encodes an E3 ubiquitin ligase belonging to the family of tumor necrosis factor receptor-associated factors (TRAFs). These mutations all clustered into one of five recurrent hotspots within the WD40 repeat domains at the C-terminus of the protein. Functional studies in vitro revealed that expression of mutant but not wild-type TRAF7 led to increased phosphorylation of nuclear factor-kappa B (NF-kB) and increased expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation. Immunohistochemistry demonstrated robust L1CAM expression in adenomatoid tumors that was absent in normal mesothelial cells, malignant peritoneal mesotheliomas and multilocular peritoneal inclusion cysts. Together, these studies demonstrate that adenomatoid tumors of the male and female genital tract are genetically defined by TRAF7 mutation that drives aberrant NF-kB pathway activation. PMID- 29148538 TI - Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. AB - Approximately one-half of advanced (unresectable or metastatic) melanomas harbor a mutation in the BRAF gene, with V600E being the most common mutation. Targeted therapy with BRAF and MEK inhibitors is associated with significant long-term treatment benefit in patients with BRAF V600-mutated melanoma. Therefore, molecular testing for BRAF mutations is a priority in determining the course of therapy. A literature search was performed using MEDLINE/PubMed and scientific congress databases using the terms 'BRAF,' 'mutation,' and 'cancer/tumor.' These results were filtered to include manuscripts that focused on diagnostic tests for determining BRAF mutation status. Numerous BRAF testing methods were identified, including DNA-based companion diagnostic tests and DNA- and protein-based laboratory-developed tests. Herein we review the characteristics of each method and highlight the strengths and weaknesses that should be considered before use and when interpreting results for each patient. Molecular profiling has shown that mutation load increases with melanoma tumor progression and that unique patterns of genetic changes and evolutionary trajectories for different melanoma subtypes can occur. Discordance in the BRAF mutational status between primary and metastatic lesions, as well as intratumoral heterogeneity, is known to occur. Additionally, the development of acquired resistance to combination BRAF and MEK inhibitor therapy is still a formidable obstacle. Therefore, tumor heterogeneity and the development of acquired resistance have important implications for molecular testing and ultimately the treatment of patients with advanced-stage melanoma. Overall, this information may help community oncologists more accurately and effectively interpret results of diagnostic tests within the context of recent data characterizing melanoma tumor progression. PMID- 29148539 TI - Extrauterine high-grade serous carcinomas with bilateral adnexal involvement as the only two disease sites are clonal based on tp53 sequencing results: implications for biology, classification, and staging. AB - A previous multicenter study of 67 cases of Stage I/II tubo-ovarian high-grade serous carcinoma with complete tubal sampling identified 7 cases in which there were only two disease sites, comprising tumor involving opposite adnexa with no extra-adnexal involvement. This study aimed to determine whether such low-stage extrauterine high-grade serous carcinomas with only two sites of involvement, located on opposite adnexa, have identical or different TP53 mutations in order to investigate their clonal relationship. DNA extracted from both sites of involvement was subjected to TP53 sequencing (n=6) or sequencing of one site and mutation confirmation by droplet digital PCR for the other site (n=1). Of the 7 cases analyzed, 1 case had unilateral serous tubal intraepithelial carcinoma with contralateral ovarian high-grade serous carcinoma, 3 had tubal high-grade serous carcinomas (+/-serous tubal intraepithelial carcinoma) with contralateral ovarian high-grade serous carcinoma, 2 had bilateral ovarian high-grade serous carcinomas with normal tubes, and 1 had bilateral fallopian tube high-grade serous carcinoma with normal ovaries. All 7 cases showed identical TP53 mutations in tumor from both disease sites. Therefore, these rare cases of high-grade serous carcinoma confined to opposite adnexa all show clonal identity between the two sites of involvement, suggesting unifocal origin and metastasis rather than multifocal origin. Our results suggest that serous tubal intraepithelial carcinoma or adnexal high-grade serous carcinoma can metastasize to the contralateral adnexa without peritoneal involvement. Given the clonal relationship between the two sites, such cases should be considered stage II, with stage I reserved for cases with unilateral and unifocal adnexal involvement. Furthermore, serous tubal intraepithelial carcinoma without invasion should be taken to constitute a disease site for staging purposes. PMID- 29148540 TI - Single-cell heterogeneity in ductal carcinoma in situ of breast. AB - Heterogeneous patterns of mutations and RNA expression have been well documented in invasive cancers. However, technological challenges have limited the ability to study heterogeneity of protein expression. This is particularly true for pre invasive lesions such as ductal carcinoma in situ of the breast. Cell-level heterogeneity in ductal carcinoma in situ was analyzed in a single 5 MUm tissue section using a multiplexed immunofluorescence analysis of 11 disease-related markers (EGFR, HER2, HER4, S6, pmTOR, CD44v6, SLC7A5 and CD10, CD4, CD8 and CD20, plus pan-cytokeratin, pan-cadherin, DAPI, and Na+K+ATPase for cell segmentation). Expression was quantified at cell level using a single-cell segmentation algorithm. K-means clustering was used to determine co-expression patterns of epithelial cell markers and immune markers. We document for the first time the presence of epithelial cell heterogeneity within ducts, between ducts and between patients with ductal carcinoma in situ. There was moderate heterogeneity in a distribution of eight clusters within each duct (average Shannon index 0.76; range 0-1.61). Furthermore, within each patient, the average Shannon index across all ducts ranged from 0.33 to 1.02 (s.d. 0.09-0.38). As the distribution of clusters within ducts was uneven, the analysis of eight ducts might be sufficient to represent all the clusters ie within- and between-duct heterogeneity. The pattern of epithelial cell clustering was associated with the presence and type of immune infiltrates, indicating a complex interaction between the epithelial tumor and immune system for each patient. This analysis also provides the first evidence that simultaneous analysis of both the epithelial and immune/stromal components might be necessary to understand the complex milieu in ductal carcinoma in situ lesions. PMID- 29148542 TI - PRRT2-dependent dyskinesia: cerebellar, paroxysmal and persistent. AB - In an elegant publication in Cell Research, Tan and colleagues showed that ablation of PRRT2 in cerebellar granule cells is sufficient to induce paroxysmal kinesigenic dyskinesia. PRRT2 turns out to downregulate the presynaptic SNARE complex in granule cell axons, which in turn controls the activity patterns of Purkinje cells, the sole output of the cerebellar cortex. PMID- 29148543 TI - Endothelial-specific m6A modulates mouse hematopoietic stem and progenitor cell development via Notch signaling. PMID- 29148541 TI - Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia. AB - Aggressive NK-cell leukemia (ANKL) is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% (14/29) of ANKL patients, while the extracellular STAT3 stimulator IL10 was elevated by an average of 56-fold (P < 0.0001) in the plasma of all patients examined. Additional frequently mutated genes included TP53 (34%), TET2 (28%), CREBBP (21%) and MLL2 (21%). Patient NK leukemia cells showed prominent activation of STAT3 phosphorylation, MYC expression and transcriptional activities in multiple metabolic pathways. Functionally, STAT3 activation and MYC expression were critical for the proliferation and survival of ANKL cells. STAT signaling regulated the MYC transcription program, and both STAT signaling and MYC transcription were required to maintain the activation of nucleotide synthesis and glycolysis. Collectively, the JAK-STAT pathway represents a major target for genomic alterations and IL10 stimulation in ANKL. This newly discovered JAK/STAT-MYC-biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia. PMID- 29148544 TI - Reproductive endocrinology: Exposure to pesticide residues linked to adverse pregnancy outcomes. PMID- 29148545 TI - Cardiovascular endocrinology: Long-term safety of growth hormone. PMID- 29148547 TI - [Authors response (October 15, 2017) to the letter to the Editor concerning the paper "Factors affecting exposure level for medical staff during orthopedic procedures under fluoroscopic control"]. PMID- 29148546 TI - [Chronic kidney disease - The relevant information for an occupational physician]. AB - For a number of years chronic kidney disease (CKD) has been listed in the group of lifestyle diseases, such as obesity, diabetes, cardiovascular disease and hypertension. It is estimated that in Poland more than 4 million people may suffer from various stages of CKD. Chronic kidney disease may also be a consequence of all the other civilization diseases. At the same time it is worth noting that nephrological problems are increasingly being taken into account in modern medical certification. The aim of this work is, among other things, to improve safe access to the labor for patients with kidney diseases. In the legislation existing in our country since 2014 it is stated that chronic renal failure is a potential health contraindication to driving. Also in the annex to the Regulation of the Minister of Health dated 9 December 2015 on health conditions required for seafarers to work on a seagoing ship, it is said that ICD 10 codes (International Classification of Diseases) corresponding to acute and chronic renal failure (N17-N19) should be taken into account when qualifying employees to work at sea. Med Pr 2018;69(1):67-75. PMID- 29148548 TI - Acrylate-based materials for heart valve scaffold engineering. AB - Calcific aortic valve disease (CAVD) is the most frequent cardiac valve pathology. Its standard treatment consists of surgical replacement either with mechanical (metal made) or biological (animal tissue made) valve prostheses, both of which have glaring deficiencies. In the search for novel materials to manufacture artificial valve tissue, we have conducted a high-throughput screening with subsequent up-scaling to identify non-degradable polymer substrates that promote valve interstitial cells (VICs) adherence/growth and, at the same time, prevent their evolution toward a pro-calcific phenotype. Here, we provide evidence that one of the two identified 'hit' polymers, poly(methoxyethylmethacrylate-co-diethylaminoethylmethacrylate), provided robust VICs adhesion and maintained the healthy VICs phenotype without inducing pro osteogenic differentiation. This ability was also maintained when the polymer was used to coat a non-woven poly-caprolactone (PCL) scaffold using a novel solvent coating procedure, followed by bioreactor-assisted VICs seeding. Since we observed that VICs had an increased secretion of the elastin-maturing component MFAP4 in addition to other valve-specific extracellular matrix components, we conclude that valve implants constructed with this polyacrylate will drive the biological response of human valve-specific cells. PMID- 29148549 TI - Stanene based gas sensors: effect of spin-orbit coupling. AB - Density functional theory calculations are performed to investigate the gas sensing properties (NO, NO2, NH3 and N2O) of pure and doped (B@, N@, and B-N@) stanene. Dispersion corrected (DFT-D3) density functional calculations show that doping improves the interaction between stanene and gas molecules. The extent of interaction between the system and gas molecules is further studied through charge density difference (CDD), electrostatic potential (ESP) and Bader charge analysis. The electronic properties of pure stanene + gases are studied with and without the effect of spin-orbit coupling. Stanene + gas systems show the Rashba type of spin-splitting under spin-orbit coupling (SOC), which is very promising for spintronic applications. Interestingly, the doped systems (B@-, N@-, and B N@stanene) show higher selectivity and sensitivity toward gas molecules compared to pure stanene. Therefore, the B@-, N@-, and B-N@stanene systems are promising for semiconductor based gas sensors. PMID- 29148550 TI - Two-dimensional (2D) self-assembly of oligo(phenylene-ethynylene) molecules and their triangular platinum(ii) diimine complexes studied using STM. AB - In this investigation, the two-dimensional (2D) self-assembly nanostructures of a series of cyclic oligo(phenylene-ethynylene) (OPE) molecules (L1, L2-6 and L2-12) at the 1-phenyloctane/highly oriented pyrolytic graphite (HOPG) interface were thoroughly studied using scanning tunneling microscopy (STM). Comparative STM studies with their triangular Pt(ii) diimine complexes (C1, C2-6 and C2-12) were also carried out. Based on careful measurements on single molecule level STM images and density functional theory (DFT) calculations, the formation mechanisms of the nanoarrays formed were revealed. PMID- 29148551 TI - Tunable fluorescence behaviors of a supramolecular system based on a fluorene derivative and cucurbit[8]uril and its application for ATP sensing. AB - In this work, we developed a supramolecular fluorescent system based on host guest interactions between a fluorene derivative carrying two bispyridinium units (FPy) and cucurbit[8]uril (CB[8]). In aqueous solution, the system showed outstanding tunable emission properties. After being encapsulated into the rigid hydrophobic cavity of the CB[8] host, the fluorescence emission of fluorene had an obvious red-shift with enhanced quantum yield. Interestingly, the emission behavior of the FPy/CB[8] complex showed a two-step self-assembly process when the molar ratio of FPy to CB[8] changed from 1 : 1 to 1 : 2. Besides, the influence of several factors on the emission properties of the FPy/CB[8] complex was also investigated, like pH value, salt concentration, and temperature. Finally, the fluorescent FPy/CB[8] complexes displayed a good performance for detection of adenosine-5'-triphosphate (ATP), which can cause aggregation-induced quenching of the complexes via electrostatic attraction. PMID- 29148552 TI - Explaining the symmetry breaking observed in the endofullerenes H2@C60, HF@C60, and H2O@C60. AB - Symmetry breaking has been recently observed in the endofullerenes M@C60 (M = H2, HF, H2O), manifesting in the splittings of the three-fold degenerate ground states of the endohedral ortho-H2, ortho-H2O and the j = 1 level of HF. The nature of the interaction causing the symmetry breaking is established in this study. A fragment of the solid C60 is considered, comprised of the central C60 molecule surrounded by twelve nearest-neighbor (NN) C60 molecules. The fullerenes have either P (major) or H (minor) orientational orderings, and are assumed to be rigid with Ih symmetry. Only the central C60 is occupied by the guest molecule M, while the NN fullerenes are all empty. The key proposition of the study is that the electrostatic interactions between the charge densities on the NN C60 molecules and that on M inside the central C60 give rise to the symmetry breaking responsible for the measured level splittings. Using this model, the M@C60 level splittings of interest are calculated variationally and using perturbation theory, for both the P and H orientations. Those obtained for the dominant P orientation are in excellent agreement with the experimental results, with respect to the splitting magnitudes and patterns, for all three M@C60 systems considered, pointing strongly to the quadrupolar M-NN interactions as the main cause of the symmetry breaking. The level splittings calculated for the H orientation are about 30 times smaller than the ones in the P orientation. PMID- 29148553 TI - Rare earth metal-organic complexes constructed from hydroxyl and carboxyl modified arenesulfonate: syntheses, structure evolutions, and ultraviolet, visible and near-infrared luminescence. AB - The reaction of 2-hydroxyl-4-carboxylbenzenesulfonic acid (H3L) and rare earth (RE) metal nitrates together with two N-heterocyclic ligands gives rise to the formation of 38 complexes, namely, [La(H2L)2(ox)0.5(H2O)4]n.2nH2O (1-La) (ox = oxalate), [RE2(H2L)2 (ox)(H2O)12].2(H2L).8H2O (2-RE) (RE = Nd, Sm, Eu, Gd, Tb, Dy), [RE(SO4)(H2O)7].(H2L).3H2O (3-RE) (RE = Ho, Er, Tm, Yb, Lu and Y), [RE(L)(H2O)3]n.nH2O (4-RE) (RE = Er, Tm, Yb and Lu), [RE(L)(2,2'-bipy)(H2O)]n (5 RE) (RE = La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho and Y, 2,2'-bipy = 2,2'-bipyridine), [RE(L)(1,10-phen)(H2O)]n (6-RE) (RE = La, Pr, Nd, Sm, Eu, 1,10-phen = 1,10 phenanthroline), and [RE(L')(1,10-phen)2(H2O)]n (7-RE) (RE = Gd, Tb, Ho, Er, Yb and Lu, H3L' = 2-hydroxy-3-nitro-4-carboxybenzenesulfonic acid), which have been characterized by elemental analysis, IR, TG, PL, powder and single-crystal X-ray diffraction. Complexes 1-La, 2-RE and 3-RE present zigzag chain, di- and mono nuclear structures, in which H2L- acts as a counterion and monodentate and MU2 bridging monoanions. For the three species, light RE metal cations tend to induce the formation of oxalate while heavy RE metal cations tend to induce the formation of sulfate. Complexes 4-RE and 5-RE exhibit layer structures incorporating helical chains, in which the L3- trianion presents MU3 and MU4 coordination modes. Complexes 6-RE containing light RE metal cations show layer structures incorporating helical chains, while complexes 7-RE containing heavy RE metal cations have helical chain structures supported by the bridging of in situ generated L'3-. Remarkably, the in situ generated oxalates in 1-La and 2-RE, as well as the in situ generated L'3- in 7-RE, also play a crucial role in determining the structures of these complexes. Structure evolutions make these complexes present various luminescent emissions. Complexes 3-Tm, 3-Yb, 3-Lu, 3-Y and 4-Lu exhibit ultraviolet emissions from 354 to 370 nm. Complexes 1-La and 6 La present blue emissions at 442 and 463 nm. Complexes 2-Eu, 2-Tb, 5-Tb and 7-Tb exhibit characteristic red and green emissions while the complex 5-Y presents a green emission at 501 nm. Meanwhile, complexes 2-Nd, 3-Yb, 4-Yb, 5-Nd, 6-Nd, and 7-Yb show near-infrared (NIR) emissions. Moreover, 2-Eu, 2-Tb, 5-Tb, 7-Tb and 5-Y show longer luminescence lifetimes from 390.47 to 1211.57 MUs. PMID- 29148554 TI - Modelling direct DNA damage for gold nanoparticle enhanced proton therapy. AB - Gold nanoparticles have been proven as potential radiosensitizer when combined with protons. Initially the radiosensitization effect was attributed to the physical interactions of radiation with the gold and the production of secondary electrons that induce DNA damage. However, emerging data challenge this hypothesis, supporting the existence of alternative or supplementary radiosensitization mechanisms. In this work we incorporate a realistic cell model with detailed DNA geometry and a realistic gold nanoparticle biodistribution based on experimental data. The DNA single and double strand breaks, and damage complexity are counted under various scenarios of different gold nanoparticle size, biodistribution and concentration, and proton energy. The locality of the effect, i.e. the existence of higher damage at a location close to the gold distribution, is also addressed by investigating the DNA damage at a chromosomal territory. In all the cases we do not observe any significant increase in the single/double strand break yield or damage complexity in the presence of gold nanoparticles under proton irradiation; nor there is a locality to the effect. Our results show for the first time that the physical interactions of protons with the gold nanoparticles should not be considered directly responsible for the observed radiosensitization effect. The model used only accounts for DNA damage from direct interactions, whilst considering the indirect effect, and it is possible the radiosensitization effect to be due to other physical effects, although we consider that possibility unlikely. Our conclusion suggests that other mechanisms might have greater contribution to the radiosensitization effect and further investigation should be conducted. PMID- 29148555 TI - Enhanced electrochemical water oxidation: the impact of nanoclusters and nanocavities. AB - The structures of transition metal surfaces and metal oxides are commonly believed to have a significant effect on the catalytic reactions. Density functional theory calculations are therefore used in this study to investigate the oxygen evolution reaction (OER) over nanostructured, i.e. nanocluster and nanocavity, surfaces of hematite (Fe2O3). The calculated results demonstrate an optimum nanocluster size with respect to the OER overpotential. The presence of nanoclusters on the electrode is regarded as an attractive strategy for increasing the activity in photoelectrochemical water splitting. However, in this work, we found that the presence of a nanocavity is a more effective strategy for lowering the overpotential compared to nanoclusters. This finding of the nanocavity-favoured OER for hematite surfaces is verified by similar simulations of WO3 surfaces. PMID- 29148556 TI - CO2 adsorption on anatase TiO2(101) surfaces: a combination of UHV-FTIRS and first-principles studies. AB - The CO2 adsorption and dynamic behaviors on single crystal anatase TiO2(101) surfaces were investigated by UHV-FTIRS and first-principles calculations. The IRRAS results at 90 K show that the nu3(OCO) asymmetric stretching vibration of adsorbed CO2 exhibits band splitting at rather low CO2 coverage in p-polarized IR spectra for the IR beam incident along the [101[combining macron]] direction. Co adsorbed CO can prevent such band splitting. Ab initio molecular dynamics (AIMD) simulations revealed that the adsorbed CO2 at finite temperature does not keep a stationary adsorption state but keeps a certain swing motion: one end of the linear CO2 molecule binds to surface Ti5c sites and the other end swings within the (010) plane with a tilted angle distribution ranging from 10 degrees to 60 degrees relative to the [101[combining macron]] direction. By suggesting a statistical model, we confirmed that it is the swing motion that results in the band splitting phenomenon of CO2 vibration in IR spectra. The co-adsorbed CO decreases the swing angle distribution ranging from 10 degrees to 45 degrees through the intermolecular interaction between CO and CO2, leading to the disappearance of CO2 band splitting. PMID- 29148557 TI - Structural and thermodynamical properties of early human amylin oligomers using replica exchange molecular dynamics: mutation effect of three key residues F15, H18 and F23. AB - Human islet amyloid polypeptide (hIAPP) is a 37-residue polypeptide, considered to be the main component of the pancreatic islet amyloid associated with type 2 diabetes and is one of the most amyloidogenic polypeptides known. Although the structure of hIAPP fibrils has already been obtained, structures of early oligomers and the mechanism of beta-sheet formation remain poorly understood. Herein, we characterize the atomic structure and the thermodynamics of the 14-37 residue fragment of hIAPP wild-type and mutated dimers and trimers. More precisely, three key residues, F15, H18 and F23, thought to affect the aggregation process, are the focus of this numerical study using replica exchange molecular dynamics coupled with the OPEP coarse-grained protein force field. Our simulations show that the oligomerization process takes place through the formation of anti-parallel beta-sheets most probably between C-terminal regions. Two main characteristics are associated with the onset of the fibrillation process. First, the sequence matching between the central (20-29) and C-terminal (30-37) regions, at intra and inter-molecular levels, helps in stabilizing the secondary structure and facilitates intermolecular interactions. Second, hydrophobic residues I26 and L27 are likely to promote the capture of further oligomeric structures and thus facilitate fibril elongation. Histidine mutation should have a more pronounced effect in the N-terminal region while phenylalanine mutations do not seem to prevent amyloid formation since central/C-terminal interactions are conserved through other contacts. PMID- 29148558 TI - Ultrasound-propelled nanowire motors enhance asparaginase enzymatic activity against cancer cells. AB - Ultrasound-(US) propelled nanowires consisting of Au/Ni/Au/PEDOT-PPy-COOH segments are modified with asparaginase enzyme and applied as an effective anti cancer agent. After immobilization of asparaginase onto the surface of the nanowire motors, the enzyme displays enhanced thermal and pH stabilities, improved resistance towards protease, and higher affinity for the substrate. The fast motion of the motor-carrying asparaginase leads to greatly accelerated biocatalytic depletion of asparagine and hence to a significantly enhanced inhibition efficacy against El4 lymphoma cancer cells (92%) as compared to free enzyme counterpart (17%) and other control groups. Such enhanced enzymatic activity against cancer cells is attributed to the fast motion of the motors which facilitates the interaction between the enzyme and the cancer cells. While asparaginase and EL4 tumor cells are used as a model system in the present study for cancer cell inhibition, the same mechanism can be expanded to other types of enzymes and biomolecules for the corresponding biofunctions. PMID- 29148559 TI - Exploring the geometric, magnetic and electronic properties of Hofmann MOFs for drug delivery. AB - The geometric, magnetic, and electronic properties and the drug capturing abilities of Hofmann-type metal organic frameworks (MOFs) were examined using theoretical calculations. The detailed theoretical calculations predicted that the Hofmann sheet can have two different conformations, planar and twisted. The Ni-Co sheet was the most stable among the systems studied, whereas the Ni-Fe sheet was the least stable. All of the sheets were magnetic spin semiconductors, having Dirac-like and dispersionless bands, which give rise to a major spatial separation between the charge carriers upon excitation. After treatment with bidentate ligands, such as pyrazine and bipyridine, these sheets produce a three dimensional cage-like structure, which is efficient for capturing small drug molecules, e.g., fluorouracil and niacin. This study shows that the magnetic metal atom and ligand structure have a significant effect on the drug capturing abilities of these systems. Therefore, these systems may be a tunable host system for drug delivery. PMID- 29148560 TI - Complex formation of nickel(ii) with dimethyl sulfoxide, methanol, and acetonitrile in a TFSA--based ionic liquid of [C2mim][TFSA]. AB - The thermodynamics of complex formation of Ni2+ with molecular liquids (ML), dimethyl sulfoxide (DMSO), methanol (MeOH), and acetonitrile (AN) in the ionic liquid (IL) of 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide ([C2mim][TFSA]) has been elucidated using ultraviolet (UV)-visible spectroscopy. X-ray structural analyses for single crystals grown from Ni2+-[C2mim][TFSA]-DMSO and -AN solutions at high ML contents have shown that six DMSO oxygen or AN nitrogen atoms coordinate with Ni2+ to form octahedral structures of [Ni(dmso)6](TFSA)2 and [Ni(an)6](TFSA)2, respectively. This is the same in the case of the Co2+ complex of [Co(dmso)6](TFSA)2. UV-visible spectroscopic experiments have revealed that the TFSA- anions that initially combine with Ni2+ in the IL are replaced with ML molecules in the IL-ML systems in three steps with increasing ML content. The electron donicities of the three MLs are larger in the order of DMSO > MeOH > AN. However, the stability of each complex does not simply depend on this order; the stability is higher in the order of [Ni(dmso)n] > [Ni(an)n] > [Ni(meoh)n]. In other words, the stability of the MeOH complexes is lower than that of the AN ones, despite the higher electron donicity of MeOH. The reasons for the order of the complex stabilities have been interpreted on the molecular scale, according to the stepwise enthalpies and entropies determined, together with the strength of the hydrogen bonding between the MLs and the imidazolium ring and the formation of MeOH clusters in [C2mim][TFSA]. PMID- 29148562 TI - Recurrence of reported CDH23 mutations causing DFNB12 in a special cohort of South Indian hearing impaired assortative mating families - an evaluation. AB - Mutations in CDH23 are known to cause autosomal-recessive nonsyndromic hearing loss (DFNB12). Until now, there was only one study describing its frequency in Indian population. We screened for CDH23 mutations to identify prevalent and recurring mutations among South Indian assortative mating hearing-impaired individuals who were identified as non-DFNB1 (GJB2 and GJB6). Whole-exome sequencing was performed in individuals found to be heterozygous for CDH23 to determine whether there was a second pathogenic allele. In our study, 19 variants including 6 pathogenic missense mutations were identified. The allelic frequency of pathogenic mutations accounts to 4.7% in our cohort, which is higher than that reported previously; three mutations (c.429+4G>A, c.2968G>A, and c.5660C>T) reported in the previous Indian study were found to recur. DFNB12 was found to be the etiology in 3.4% of our cohort, with missense mutation c.2968G>A (p.Asp990Asn) being the most prevalent (2.6%). These results suggest a need to investigate the possibility for higher proportion of CDH23 mutations in the South Indian hearing-impaired population. PMID- 29148561 TI - The role of IL-23 receptor signaling in inflammation-mediated erosive autoimmune arthritis and bone remodeling. AB - The IL-23/Th17 axis has been implicated in the development of autoimmune diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). RA and PsA are heterogeneous diseases with substantial burden on patients. Increasing evidence suggests that the IL-23 signaling pathway may be involved in the development of autoimmunity and erosive joint damage. IL-23 can act either directly or indirectly on bone forming osteoblasts as well as on bone resorbing osteoclasts. As IL-23 regulates the activity of cells of the bone, it is conceivable that in addition to inflammation-mediated joint erosion, IL-23 may play a role in physiological bone remodeling. In this review, we focus on the role of IL-23 in autoimmune arthritis in patients and murine models, and provide an overview of IL-23 producing and responding cells in autoimmune arthritic joints. In addition, we discuss the role of IL-23 on bone forming osteoblasts and bone resorbing osteoclasts regarding inflammation-mediated joint damage and bone remodeling. At last, we briefly discuss the clinical implications of targeting this pathway for joint damage and systemic bone loss in autoimmune arthritis. PMID- 29148563 TI - Evaluation of the NZ guidelines for screening for persistent postpartum hyperglycaemia following gestational diabetes. AB - BACKGROUND: Recent New Zealand guidelines recommend annual glycated haemoglobin (HbA1c) measurements from three months postpartum, replacing the glucose tolerance test (GTT) at six weeks, to screen for persistent hyperglycaemia following gestational diabetes. Data suggest that this screening approach may miss cases of type 2 diabetes, but are they detected at subsequent screening and will screening rates improve? AIMS: Our aim was to evaluate the effectiveness of HbA1c monitoring in improving screening rates following gestational diabetes and in detecting postpartum hyperglycaemia. MATERIALS AND METHODS: During 2015 in Christchurch, all women with gestational diabetes were offered HbA1c and GTT measurements at three months postpartum and subsequent annual HbA1c measurements were recommended. Data from electronic hospital records were collected for a minimum 18 months postpartum. RESULTS: Of the cohort of 333 women, 218 (65%) completed both HbA1c and GTT at three months postpartum, 74 (22%) HbA1c only, 16 (5%) GTT only, 25 (8%) no screening; 184 (55%) had subsequent HbA1c tests. Diabetes was detected by GTT in five (2%) women and by HbA1c in only one out of five (20%); the disagreement between tests resolved in three out of four (75%) women with subsequent testing. Prediabetes was detected by GTT in 30 (14%) women; however, HbA1c only detected five out of 30 (17%) and subsequent HbA1c testing identified a further two out of 30 with prediabetes. CONCLUSIONS: HbA1c measurement at three months postpartum had a good uptake. However, most cases of diabetes were identified by subsequent HbA1c testing, the uptake of which was suboptimal. The importance of annual HbA1c monitoring following gestational diabetes needs greater emphasis. PMID- 29148564 TI - Differential processing in modality-specific Mauthner cell dendrites. AB - KEY POINTS: The present study examines dendritic integrative processes that occur in many central neurons but have been challenging to study in vivo in the vertebrate brain. The Mauthner cell of goldfish receives auditory and visual information via two separate dendrites, providing a privileged scenario for in vivo examination of dendritic integration. The results show differential attenuation properties in the Mauthner cell dendrites arising at least partly from differences in cable properties and the nonlinear behaviour of the respective dendritic membranes. In addition to distinct modality-dependent membrane specialization in neighbouring dendrites of the Mauthner cell, we report cross-modal dendritic interactions via backpropagating postsynaptic potentials. Broadly, the results of the present study provide an exceptional example for the processing power of single neurons. ABSTRACT: Animals process multimodal information for adaptive behavioural decisions. In fish, evasion of a diving bird that breaks the water surface depends on integrating visual and auditory stimuli with very different characteristics. How do neurons process such differential sensory inputs at the dendritic level? For that, we studied the Mauthner cells (M cells) in the goldfish startle circuit, which receive visual and auditory inputs via two separate dendrites, both accessible for in vivo recordings. We investigated whether electrophysiological membrane properties and dendrite morphology, studied in vivo, play a role in selective sensory processing in the M cell. The results obtained show that anatomical and electrophysiological differences between the dendrites combine to produce stronger attenuation of visually evoked postsynaptic potentials (PSPs) than to auditory evoked PSPs. Interestingly, our recordings showed also cross-modal dendritic interaction because auditory evoked PSPs invade the ventral dendrite (VD), as well as the opposite where visual PSPs invade the lateral dendrite (LD). However, these interactions were asymmetrical, with auditory PSPs being more prominent in the VD than visual PSPs in the LD. Modelling experiments imply that this asymmetry is caused by active conductances expressed in the proximal segments of the VD. The results obtained in the present study suggest modality-dependent membrane specialization in M-cell dendrites suited for processing stimuli of different time domains and, more broadly, provide a compelling example of information processing in single neurons. PMID- 29148565 TI - Tobacco cessation interventions for young people. AB - BACKGROUND: Most tobacco control programmes for adolescents are based around prevention of uptake, but teenage smoking is still common. It is unclear if interventions that are effective for adults can also help adolescents to quit. This is the update of a Cochrane Review first published in 2006. OBJECTIVES: To evaluate the effectiveness of strategies that help young people to stop smoking tobacco. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialized Register in June 2017. This includes reports for trials identified in CENTRAL, MEDLINE, Embase and PsyclNFO. SELECTION CRITERIA: We included individually and cluster-randomized controlled trials recruiting young people, aged under 20 years, who were regular tobacco smokers. We included any interventions for smoking cessation; these could include pharmacotherapy, psycho social interventions and complex programmes targeting families, schools or communities. We excluded programmes primarily aimed at prevention of uptake. The primary outcome was smoking status after at least six months' follow-up among those who smoked at baseline. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of candidate trials and extracted data. We evaluated included studies for risk of bias using standard Cochrane methodology and grouped them by intervention type and by the theoretical basis of the intervention. Where meta-analysis was appropriate, we estimated pooled risk ratios using a Mantel-Haenszel fixed-effect method, based on the quit rates at six months' follow-up. MAIN RESULTS: Forty-one trials involving more than 13,000 young people met our inclusion criteria (26 individually randomized controlled trials and 15 cluster-randomized trials). We judged the majority of studies to be at high or unclear risk of bias in at least one domain. Interventions were varied, with the majority adopting forms of individual or group counselling, with or without additional self-help materials to form complex interventions. Eight studies used primarily computer or messaging interventions, and four small studies used pharmacological interventions (nicotine patch or gum, or bupropion). There was evidence of an intervention effect for group counselling (9 studies, risk ratio (RR) 1.35, 95% confidence interval (CI) 1.03 to 1.77), but not for individual counselling (7 studies, RR 1.07, 95% CI 0.83 to 1.39), mixed delivery methods (8 studies, RR 1.26, 95% CI 0.95 to 1.66) or the computer or messaging interventions (pooled RRs between 0.79 and 1.18, 9 studies in total). There was no clear evidence for the effectiveness of pharmacological interventions, although confidence intervals were wide (nicotine replacement therapy 3 studies, RR 1.11, 95% CI 0.48 to 2.58; bupropion 1 study RR 1.49, 95% CI 0.55 to 4.02). No subgroup precluded the possibility of a clinically important effect. Studies of pharmacotherapies reported some adverse events considered related to study treatment, though most were mild, whereas no adverse events were reported in studies of behavioural interventions. Our certainty in the findings for all comparisons is low or very low, mainly because of the clinical heterogeneity of the interventions, imprecision in the effect size estimates, and issues with risk of bias. AUTHORS' CONCLUSIONS: There is limited evidence that either behavioural support or smoking cessation medication increases the proportion of young people that stop smoking in the long-term. Findings are most promising for group-based behavioural interventions, but evidence remains limited for all intervention types. There continues to be a need for well-designed, adequately powered, randomized controlled trials of interventions for this population of smokers. PMID- 29148567 TI - Silenced DMBT1 promotes nasal mucosa epithelial cell growth. AB - OBJECTIVE: The aim of this study was to investigate the role of the deleted in malignant brain tumors 1 (DMBT1) gene in the development of nasal polyps, as well as related mechanisms. METHODS: A stable human nasal mucosa epithelial cell (HNEpC) line with low expression of DMBT1 was generated. Three groups were established: a control group (HNEpCs without any treatment), a control short interference RNA (shRNA) group (HNEpCs transfected with an empty vector), and a DMBT1 shRNA group (HNEpCs with silenced DMBT1). Cell viability, apoptosis, and cell cycle distribution were measured after incubation. Expression of p53, signal transducer and activator of transcription 3 (STAT3), protein kinase B (AKT) and extracellular signal-regulated kinase1/2 (ERK1/2) was detected by western blotting. RESULTS: Compared with the control cell line, HNEpCs with silenced DMBT1 had increased viability and decreased apoptosis. Moreover, after DMBT1 silence, cell numbers were decreased significantly in the G1 phase and increased in the G2 and S phases. DMBT1 silence was associated with increased AKT expression and decreased p53 expression, but it did not alter expression of ERK1/2 or STAT3 (P > 0.05). Compared with the control cell line, HNEpCs transfected with an empty vector did not have altered cell viability, apoptosis, cell cycle distribution or expression of AKT, p53, ERK1/2, or STAT3 (P > 0.05). CONCLUSION: DMBT1 plays an important role in the growth and division of nasal epithelial cells. The possible mechanism might involve DMBT1 regulating the AKT p53 pathway to promote cell viability and reduce apoptosis of nasal epithelial cells. PMID- 29148568 TI - Intrathecal baclofen in dyskinetic cerebral palsy: effects on function and activity. AB - AIM: To investigate the effect of intrathecal baclofen (ITB) on function and activity in dyskinetic cerebral palsy (CP). METHOD: A retrospective cohort study of records from 25 children (15 males, 10 females; mean age 10y 11mo, SD 4y 9mo). Five were classified in Gross Motor Function Classification level IV and 20 in level V. Parents were interviewed about activities in daily life, sitting, communication, pain, sleep, and gross and fine motor function. Differences before and 1 year after ITB were graded as positive, no change, or negative. Assessments of dystonia (using the Barry-Albright Dystonia Scale) and muscle tone (Ashworth Scale) were made. Joint range of motion (ROM) was measured. RESULTS: Both dystonia and increased muscle tone, present in all participants before ITB, decreased after (p<0.001). Passive ROM was restricted, with no difference after. Parents reported improvements in activities in daily life (p<0.001), sitting (p<0.001), communication (p<0.001), and fine motor function (p=0.013), but no change in gross motor function. Before ITB, pain and disturbed sleep were reported. There was a reduction in pain (p=0.002) and sleep improved (p=0.004) after ITB. INTERPRETATION: After ITB in individuals with dyskinetic CP, improvements were found in sitting, communication, and fine motor skills. There was a reduction in dystonia and muscle tone, and pain and sleep improved. WHAT THIS PAPER ADDS: Intrathecal baclofen can affect specific aspects of functioning in dyskinetic cerebral palsy. Sitting, communication, and fine motor function improved. Dystonia and spasticity were reduced. Pain was reduced and sleep improved. PMID- 29148566 TI - Factors that influence the provision of intrapartum and postnatal care by skilled birth attendants in low- and middle-income countries: a qualitative evidence synthesis. AB - BACKGROUND: In many low- and middle-income countries women are encouraged to give birth in clinics and hospitals so that they can receive care from skilled birth attendants. A skilled birth attendant (SBA) is a health worker such as a midwife, doctor, or nurse who is trained to manage normal pregnancy and childbirth. (S)he is also trained to identify, manage, and refer any health problems that arise for mother and baby. The skills, attitudes and behaviour of SBAs, and the extent to which they work in an enabling working environment, impact on the quality of care provided. If any of these factors are missing, mothers and babies are likely to receive suboptimal care. OBJECTIVES: To explore the views, experiences, and behaviours of skilled birth attendants and those who support them; to identify factors that influence the delivery of intrapartum and postnatal care in low- and middle-income countries; and to explore the extent to which these factors were reflected in intervention studies. SEARCH METHODS: Our search strategies specified key and free text terms related to the perinatal period, and the health provider, and included methodological filters for qualitative evidence syntheses and for low- and middle-income countries. We searched MEDLINE, OvidSP (searched 21 November 2016), Embase, OvidSP (searched 28 November 2016), PsycINFO, OvidSP (searched 30 November 2016), POPLINE, K4Health (searched 30 November 2016), CINAHL, EBSCOhost (searched 30 November 2016), ProQuest Dissertations and Theses (searched 15 August 2013), Web of Science (searched 1 December 2016), World Health Organization Reproductive Health Library (searched 16 August 2013), and World Health Organization Global Health Library for WHO databases (searched 1 December 2016). SELECTION CRITERIA: We included qualitative studies that focused on the views, experiences, and behaviours of SBAs and those who work with them as part of the team. We included studies from all levels of health care in low- and middle-income countries. DATA COLLECTION AND ANALYSIS: One review author extracted data and assessed study quality, and another review author checked the data. We synthesised data using the best fit framework synthesis approach and assessed confidence in the evidence using the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach. We used a matrix approach to explore whether the factors identified by health workers in our synthesis as important for providing maternity care were reflected in the interventions evaluated in the studies in a related intervention review. MAIN RESULTS: We included 31 studies that explored the views and experiences of different types of SBAs, including doctors, midwives, nurses, auxiliary nurses and their managers. The included studies took place in Africa, Asia, and Latin America.Our synthesis pointed to a number of factors affecting SBAs' provision of quality care. The following factors were based on evidence assessed as of moderate to high confidence. Skilled birth attendants reported that they were not always given sufficient training during their education or after they had begun clinical work. Also, inadequate staffing of facilities could increase the workloads of skilled birth attendants, make it difficult to provide supervision and result in mothers being offered poorer care. In addition, SBAs did not always believe that their salaries and benefits reflected their tasks and responsibilities and the personal risks they undertook. Together with poor living and working conditions, these issues were seen to increase stress and to negatively affect family life. Some SBAs also felt that managers lacked capacity and skills, and felt unsupported when their workplace concerns were not addressed.Possible causes of staff shortages in facilities included problems with hiring and assigning health workers to facilities where they were needed; lack of funding; poor management and bureaucratic systems; and low salaries. Skilled birth attendants and their managers suggested factors that could help recruit, keep, and motivate health workers, and improve the quality of care; these included good-quality housing, allowances for extra work, paid vacations, continuing education, appropriate assessments of their work, and rewards.Skilled birth attendants' ability to provide quality care was also limited by a lack of equipment, supplies, and drugs; blood and the infrastructure to manage blood transfusions; electricity and water supplies; and adequate space and amenities on maternity wards. These factors were seen to reduce SBAs' morale, increase their workload and infection risk, and make them less efficient in their work. A lack of transport sometimes made it difficult for SBAs to refer women on to higher levels of care. In addition, women's negative perceptions of the health system could make them reluctant to accept referral.We identified some other factors that also may have affected the quality of care, which were based on findings assessed as of low or very low confidence. Poor teamwork and lack of trust and collaboration between health workers appeared to negatively influence care. In contrast, good collaboration and teamwork appeared to increase skilled birth attendants' motivation, their decision-making abilities, and the quality of care. Skilled birth attendants' workloads and staff shortages influenced their interactions with mothers. In addition, poor communication undermined trust between skilled birth attendants and mothers. AUTHORS' CONCLUSIONS: Many factors influence the care that SBAs are able to provide to mothers during childbirth. These include access to training and supervision; staff numbers and workloads; salaries and living conditions; and access to well-equipped, well-organised healthcare facilities with water, electricity, and transport. Other factors that may play a role include the existence of teamwork and of trust, collaboration, and communication between health workers and with mothers. Skilled birth attendants reported many problems tied to all of these factors. PMID- 29148569 TI - Exome sequence analysis and follow up genotyping implicates rare ULK1 variants to be involved in susceptibility to schizophrenia. AB - Schizophrenia (SCZ) is a severe, highly heritable psychiatric disorder. Elucidation of the genetic architecture of the disorder will facilitate greater understanding of the altered underlying neurobiological mechanisms. The aim of this study was to identify likely aetiological variants in subjects affected with SCZ. Exome sequence data from a SCZ cas-control sample from Sweden was analysed for likely aetiological variants using a weighted burden test. Suggestive evidence implicated the UNC-51-like kinase (ULK1) gene, and it was observed that four rare variants that were more common in the Swedish SCZ cases were also more common in UK10K SCZ cases, as compared to obesity cases. These three missense variants and one intronic variant were genotyped in the University College London cohort of 1304 SCZ cases and 1348 ethnically matched controls. All four variants were more common in the SCZ cases than controls and combining them produced a result significant at P = 0.02. The results presented here demonstrate the importance of following up exome sequencing studies using additional datasets. The roles of ULK1 in autophagy and mTOR signalling strengthen the case that these pathways may be important in the pathophysiology of SCZ. The findings reported here await independent replication. PMID- 29148571 TI - Panel Report, IPA Congress Buenos Aires 2017: Claustro-agoraphobia, Bertram Lewin, and the oral triad 6 April 2017. PMID- 29148570 TI - Robust optimization in IMPT using quadratic objective functions to account for the minimum MU constraint. AB - PURPOSE: Currently, in clinical practice of intensity-modulated proton therapy (IMPT), the influence of the minimum monitor unit (MU) constraint is taken into account through postprocessing after the optimization is completed. This may degrade the plan quality and plan robustness. This study aims to mitigate the impact of the minimum MU constraint directly during the plan robust optimization. METHODS AND MATERIALS: Cao et al. have demonstrated a two-stage method to account for the minimum MU constraint using linear programming without the impact of uncertainties considered. In this study, we took the minimum MU constraint into consideration using quadratic optimization and simultaneously had the impact of uncertainties considered using robust optimization. We evaluated our method using seven cancer patients with different machine settings. RESULT: The new method achieved better plan quality than the conventional method. The D95% of the clinical target volume (CTV) normalized to the prescription dose was (mean [min max]): (99.4% [99.2%-99.6%]) vs. (99.2% [98.6%-99.6%]). Plan robustness derived from these two methods was comparable. For all seven patients, the CTV dose volume histogram band gap (narrower band gap means more robust plans) at D95% normalized to the prescription dose was (mean [min-max]): (1.5% [0.5%-4.3%]) vs. (1.2% [0.6%-3.8%]). CONCLUSION: Our new method of incorporating the minimum MU constraint directly into the plan robust optimization can produce machine deliverable plans with better tumor coverage while maintaining high-plan robustness. PMID- 29148572 TI - Effects of tartary buckwheat polysaccharide combined with nisin edible coating on the storage quality of tilapia (Oreochromis niloticus) fillets. AB - BACKGROUND: To investigate the effect of tartary buckwheat polysaccharide (TBP) combined with nisin edible coatings on the preservation of tilapia (Oreochromis niloticus) fillets, fillets were dip treated with different concentrations of TBP (5, 10 and 15 g kg-1 ) combined with nisin and stored at 4 degrees C for 12 days. The pH values, thiobarbituric acid contents, total volatile base nitrogen (TVB-N) content, total viable count (TVC), surface colors, textures and sensory properties of the tilapia fillets at storage were all periodically investigated. RESULTS: TBP combined with nisin-treated groups significantly improved the bacteriological, physicochemical, and sensory characteristics of the tilapia fillets to a greater extent compared to the control group and presented better quality preservation effects than nisin coating alone. Based on the limits of the TVB-N, TVC and sensory scores, the shelf life of the control tilapia fillets was 4 days, whereas that for nisin with TBP-coated fillets was 8-10 days. CONCLUSION: Edible coatings made from TBP combined with nisin are suitable for maintaining qualities and enhancing the shelf lives of tilapia fillets stored at 4 degrees C. (c) 2017 Society of Chemical Industry. PMID- 29148574 TI - Effects of high temperatures and drought during anthesis and grain filling period on wheat processing quality and underlying gluten structural changes. AB - BACKGROUND: Climate changes do not only affect wheat yield, but also its quality. Information on this topic gathered so far is somewhat contradictory and insufficient. Climate changes also affect wheat indirectly through their influence on the ecosystem, including insects and fungi that affect wheat technological quality. The aim of this study was to examine trends in structural and technological changes of wheat quality under conditions typical of climate changes. With this in mind, three groups of wheat varieties with the same Glu score were examined in three production years, characterized by different production conditions. RESULTS: A production season characterized by climate change conditions results in lower activity of amylolytic enzymes. What is more, it results in lower content of gluten, higher gluten index value, its decrease after 1 h to 37 degrees C, lower number of free SH groups and higher content of free amino groups, which result in lower alveograph W, lower farinograph WA and higher extensograph dough resistance. CONCLUSION: Variability in wheat quality produced under different climatic conditions is mainly influenced by the production conditions, including their influence on ecosystem factors. The influence of wheat cultivar genetic predisposition is much less expressed. This indicates that differences among cultivars with different Glu-score might be diminished under the influence of altered production conditions, as a consequence of climate change. (c) 2017 Society of Chemical Industry. PMID- 29148573 TI - Phenotypic and genetic integration of personality and growth under competition in the sheepshead swordtail, Xiphophorus birchmanni. AB - Competition for resources including food, physical space, and potential mates is a fundamental ecological process shaping variation in individual phenotype and fitness. The evolution of competitive ability, in particular social dominance, depends on genetic (co)variation among traits causal (e.g., behavior) or consequent (e.g., growth) to competitive outcomes. If dominance is heritable, it will generate both direct and indirect genetic effects (IGE) on resource dependent traits. The latter are expected to impose evolutionary constraint because winners necessarily gain resources at the expense of losers. We varied competition in a population of sheepshead swordtails, Xiphophorus birchmanni, to investigate effects on behavior, size, growth, and survival. We then applied quantitative genetic analyses to determine (i) whether competition leads to phenotypic and/or genetic integration of behavior with life history and (ii) the potential for IGE to constrain life history evolution. Size, growth, and survival were reduced at high competition. Male dominance was repeatable and dominant individuals show higher growth and survival. Additive genetic contributions to phenotypic covariance were significant, with the G matrix largely recapitulating phenotypic relationships. Social dominance has a low but significant heritability and is strongly genetically correlated with size and growth. Assuming causal dependence of growth on dominance, hidden IGE will therefore reduce evolutionary potential. PMID- 29148575 TI - Effects of spot parameters in pencil beam scanning treatment planning. AB - BACKGROUND: Spot size sigma (in air at isocenter), interspot spacing d, and spot charge q influence dose delivery efficiency and plan quality in Intensity Modulated Proton Therapy (IMPT) treatment planning. The choice and range of parameters varies among different manufacturers. The goal of this work is to demonstrate the influence of the spot parameters on dose quality and delivery in IMPT treatment plans, to show their interdependence, and to make practitioners aware of the spot parameter values for a certain facility. Our study could help as a guideline to make the trade-off between treatment quality and time in existing PBS centers and in future systems. METHODS: We created plans for seven patients and a phantom, with different tumor sites and volumes, and compared the effect of small-, medium-, and large-spot widths (sigma = 2.5, 5, and 10 mm) and interspot distances (1sigma, 1.5sigma, and 1.75sigma) on dose, spot charge, and treatment time. Moreover, we quantified how postplanning charge threshold cuts affect plan quality and the total number of spots to deliver, for different spot widths and interspot distances. We show the effect of a minimum charge (or MU) cutoff value for a given proton delivery system. RESULTS: Spot size had a strong influence on dose: larger spots resulted in more protons delivered outside the target region. We observed dose differences of 2-13 Gy (RBE) between 2.5 mm and 10 mm spots, where the amount of extra dose was due to dose penumbra around the target region. Interspot distance had little influence on dose quality for our patient group. Both parameters strongly influence spot charge in the plans and thus the possible impact of postplanning charge threshold cuts. If such charge thresholds are not included in the treatment planning system (TPS), it is important that the practitioner validates that a given combination of lower charge threshold, interspot spacing, and spot size does not result in a plan degradation. Low average spot charge occurs for small spots, small interspot distances, many beam directions, and low fractional dose values. CONCLUSIONS: The choice of spot parameters values is a trade-off between accelerator and beam line design, plan quality, and treatment efficiency. We recommend the use of small spot sizes for better organ-at-risk sparing and lateral interspot distances of 1.5sigma to avoid long treatment times. We note that plan quality is influenced by the charge cutoff. Our results show that the charge cutoff can be sufficiently large (i.e., 106 protons) to accommodate limitations on beam delivery systems. It is, therefore, not necessary per se to include the charge cutoff in the treatment planning optimization such that Pareto navigation (e.g., as practiced at our institution) is not excluded and optimal plans can be obtained without, perhaps, a bias from the charge cutoff. We recommend that the impact of a minimum charge cut impact is carefully verified for the spot sizes and spot distances applied or that it is accommodated in the TPS. PMID- 29148576 TI - Free-breathing abdominal MRI improved by repeated k-t-subsampling and artifact minimization (ReKAM). AB - PURPOSE: We report an approach, termed Repeated k-t-subsampling and artifact minimization (ReKAM), for removing motion artifacts in free-breathing abdominal MRI. The method is particularly valuable for challenging patients who may not hold their breath for a long time or have irregular respiratory rate. METHODS: The ReKAM framework comprises one acquisition module and two reconstruction modules. A fast MRI sequence is used to repeatedly acquire multiple sets of k-t space data. Motion artifacts are then minimized by two reconstruction modules: (a) a bootstrapping module in k-t-space is used to identify a low-artifact image; (b) a constrained reconstruction module that integrates projection onto convex set (POCS) and multiplexed sensitivity encoding (MUSE), termed POCSMUSE, is applied to further remove residual artifact. The ReKAM framework is compatible with different pulse sequences, and generally applicable to irregular data sampling patterns in k-space. Free-breathing fast spin-echo MRI data, acquired from healthy volunteers and patients, were used to evaluate the developed ReKAM method. RESULTS: Experimental results show that the ReKAM technique can produce high-quality free-breathing images with the artifact levels comparable to that of breath-holding MRI. CONCLUSION: The ReKAM framework improves the quality of free breathing abdominal MRI data, and is compatible with various MRI pulse sequences. PMID- 29148577 TI - Mouse models to evaluate the role of estrogen receptor alpha in skeletal maintenance and adaptation. AB - Estrogen signaling and mechanical loading have individual and combined effects on skeletal maintenance and adaptation. Previous work investigating estrogen signaling both in vitro and in vivo using global estrogen receptor alpha (ERalpha) gene knockout mouse models has provided information regarding the role of ERalpha in regulating bone mass and adaptation to mechanical stimulation. However, these models have inherent limitations that confound interpretation of the data. Therefore, recent studies have focused on mice with targeted deletion of ERalpha from specific bone cells and their precursors. Cell stage, tissue type, and mouse sex all influence the effects of ERalpha gene deletion. Lack of ERalpha in osteoblast progenitor and precursor cells generally affects the periosteum of female and male mice. The absence of ERalpha in differentiated osteoblasts, osteocytes, and osteoclasts in mice generally resulted in reduced cancellous bone mass, with differing reports of the effect by animal sex and greater deficiencies in bone mass typically occurring in cancellous bone in female mice. Limited data exist for the role of bone cell-specific ERalpha in skeletal adaptation in vivo. Cell-specific ERalpha gene knockout mice provide an excellent platform for investigating the function of ERalpha in regulating skeletal phenotype and response to mechanical loading by sex and age. PMID- 29148578 TI - In order to function more fully as professionals and provide professional services, medical physicists should actively seek to be employed by physician groups rather than by facilities. PMID- 29148579 TI - A step-by-step review on patient-specific biomechanical finite element models for breast MRI to x-ray mammography registration. AB - Breast magnetic resonance imaging (MRI) and x-ray mammography are two image modalities widely used for the early detection and diagnosis of breast diseases in women. The combination of these modalities leads to a more accurate diagnosis and treatment of breast diseases. The aim of this paper is to review the registration between breast MRI and x-ray mammographic images using patient specific finite element-based biomechanical models. Specifically, a biomechanical model is obtained from the patient's MRI volume and is subsequently used to mimic the mammographic acquisition. Due to the different patient positioning and movement restrictions applied in each image modality, the finite element analysis provides a realistic physics-based approach to perform the breast deformation. In contrast with other reviews, we do not only expose the overall process of compression and registration but we also include main ideas, describe challenges, and provide an overview of the used software in each step of the process. Extracting an accurate description from the MR images and preserving the stability during the finite element analysis require an accurate knowledge about the algorithms used, as well as the software and underlying physics. The wide perspective offered makes the paper suitable not only for expert researchers but also for graduate students and clinicians. We also include several medical applications in the paper, with the aim to fill the gap between the engineering and clinical performance. PMID- 29148580 TI - Ultrasound-guided reduction of an incarcerated obturator hernia in an elderly patient. AB - Obturator hernia is a rare but clinically relevant cause of intestinal obstruction, usually found in elderly, thin, multiparous women. It is difficult to diagnose, leading to diagnostic delay with a high incidence of strangulation and a high mortality rate. Surgery is the only reported treatment. We report the case of an 86-year-old woman, in whom an early diagnosis of incarcerated obturator hernia was made with subsequent reduction by compression with an ultrasound transducer. When the risk of strangulation is presumed to be low, ultrasound-guided reduction of an obturator hernia is achievable and worth considering. PMID- 29148581 TI - Keeping the wheels of peer review turning. PMID- 29148583 TI - Study of the hooking behaviour of Lepeophtheirus salmonis (Kroyer, 1837) copepodids on Atlantic salmon, Salmo salar L., using a novel in vivo test system. AB - The screening of putative semiochemicals involved in the interaction between Lepeophtheirus salmonis copepodid and the Atlantic salmon could be used to develop methods to prevent infestation. A bioassay was designed to evaluate the attractiveness of Atlantic salmon for L. salmonis copepodids by counting the number of hooked parasites. A salmon was bathed in a tank with 60 copepodids during 45 min. The salmon was humanely killed and its body was scrubbed above a plastic bag. The content of the bag was filtered to count the number of hooked parasites. This procedure was tested at different water temperatures and for different body mass. The temperature significantly influenced the number of hooked copepodids (p < .05). Smolts presented significantly more hooked copepodids at a higher water temperature (24.6 at 13.8 degrees C) compared to smolts at a lower temperature (18.6 at 6.1 degrees C; p = .011). No correlation was found between the body mass and the number of hooked parasites (p = .65). This bioassay was used to successfully measure the attractiveness of Atlantic salmon for L. salmonis copepodids, making it an interesting tool to screen putative semiochemicals designed to prevent the infestation. PMID- 29148582 TI - Comparative pharmacokinetics study of orientin in rat plasma by UHPLC-MS/MS after intravenous administration of single orientin and Trollius chinensis Bunge extract. AB - Orientin showed a broad array of biological activities, and it is the major bioactive compound in the Trollius chinensis Bunge. The aim of this study was to investigate the comparative pharmacokinetics of orientin after intravenous administration of single orientin and T. chinensis Bunge extract. Sample preparation involved a simple one-step deproteinization procedure with acetonitrile. Chromatographic separation was achieved on a Waters BEH C18 column with a mobile phase consisting of acetonitrile and water containing 0.1% formic acid in an isocratic elution way. The detection was accomplished in multiple reaction monitoring mode with positive electrospray ionization. The pharmacokinetic properties of orientin were compared after intravenous administrations of pure orientin and T. chinensis Bunge extract to rats with approximately the same dosage of 10 mg/kg. The results of the study indicate that the pharmacokinetics of orientin in rat plasma show significant differences between two groups. This is useful for the clinical uses of therapeutic dosing of orientin and T. chinensis Bunge. PMID- 29148584 TI - Metabolic effects of p,p'-DDE on Atlantic salmon hepatocytes. AB - Decades after being banned in many countries, DDT and its metabolites are still considered major environmental hazards. The p,p'-DDE isomer, the DDT metabolite found in highest concentration in aquaculture feeds, is an endocrine disruptor with demonstrated ability to induce epigenetic effects. This study aimed at examining the impact of p,p'-DDE on Atlantic salmon. Primary hepatocytes were exposed to four concentrations of p,p'-DDE (0.1, 1, 10, 100 MUm) for 48 hours, and endpoints included cytotoxicity, global DNA methylation, targeted transcription and metabolomics profiling (100 MUm). p,p'-DDE was moderately cytotoxic at 100 MUm. No impact was seen on global DNA methylation. Vtg1 and esr1 transcription, markers of endocrine disruption, was most strongly induced at 10 MUm p,p'-DDE, while ar showed strongest response at 100 MUm. Metabolomics profiling showed that p,p'-DDE at 100 MUm most strongly affected carbohydrate metabolism, primary bile acid metabolism, leucine, isoleucine and valine metabolism, diacylglycerol and sphingolipid metabolism. Observed changes in lipid levels suggest that p,p'-DDE interferes with phospholipid membrane biosynthesis. Elevation of bile acid levels in p,p'-DDE-exposed hepatocytes indicates upregulation of synthesis of bile acids after cytochrome P450 activation. Pathway analysis showed that the superpathway of methionine degradation was the most significantly affected pathway by p,p'-DDE exposure, while endocrine system disorder topped the diseases and disorder ranking. In conclusion, this work predicts an endocrine response to p,p'-DDE exposure, and demonstrates how this legacy pesticide might interfere with mechanisms linked to DNA methylation in Atlantic salmon hepatocytes. PMID- 29148585 TI - Arsenite downregulates H3K4 trimethylation and H3K9 dimethylation during transformation of human bronchial epithelial cells. AB - Arsenic is an established human carcinogen but with weak mutagenic activity. The mechanisms of arsenic-induced carcinogenesis are not well understood. In the present study, we investigated the role of histone methylation in transformation of human bronchial epithelial (BEAS-2B) cells. After 16 weeks' exposure, cells were transformed by 0.1, 0.5 and 1 MUm arsenite. Global trimethylated H3K4 (H3K4me3) was decreased by 0.1 MUm arsenite at 12 weeks, and 0.5 and 1 MUm arsenite at 8, 12 and 16 weeks, which could be attributed to reduced histone methyltransferase activities, increased histone demethylase (HDM) activities as well as increased protein levels of H3K4 demethylase KDM5A. Global dimethylated H3K9 (H3K9me2) was also decreased after exposure to 0.5 MUm arsenite for 4, 8, 12 and 16 weeks and 1.0 MUm arsenite for 8 and 12 weeks, which was associated with an increase of HDM activities. Our findings indicated that arsenite decreased global H3K4me3 and H3K9me2 levels during cell transformation by modulating the enzymatic activities of histone methyltransferases and/or HDMs, and by upregulation of KDM5A protein levels for H3K4me3. PMID- 29148586 TI - A dynamic ultrasound simulation of a pulsating three-layered CCA for validation of two-dimensional wall motion and blood velocity estimation algorithms. AB - PURPOSE: A dynamic ultrasound simulation model for the common carotid artery (CCA) with three arterial layers for validation of two-dimensional wall motion and blood velocity estimation algorithms is proposed in the present study. This model describes layers with not only characteristics of echo distributions conforming to clinical ones but also varying thicknesses, axial, and radial displacements with pulsatile blood pressure during a cardiac cycle. METHODS: The modeling process is as follows: first, a geometrical model according with the clinical structure size of a CCA is built based on the preset layer thicknesses and the diameter of lumen. Second, a three-dimensional scatterer model is constructed by a mapping with a Hilbert space-filling curve from the one dimensional scatterer distribution with the position and amplitude following Gamma and Gaussian distributions, respectively. The characteristics of three layers and blood are depicted by smoothly adjusting the scatterer density, the scale, and shape parameters of the Gamma distribution as well as the mean and standard deviation of the Gaussian distribution. To obtain the values of parameters of scatterer distributions, including the shape parameter, density, and intensity, for arterial layers and blood, the envelope signals simulated from different configurations of scatterer distribution are compared with those from different kinds of tissue of CCAs in vivo through a statistic analysis. Finally, the dynamic scatterer model is realized based on the blood pressure, elasticity modulus of intima-media (IM) and adventitia, varying IM thickness, axial displacement of IM as well as blood flow velocity at central axis during a cardiac cycle. Then, the corresponding radiofrequency (RF) signals, envelope signals, and B-mode images of the pulsatile CCA are generated in a dynamic scanning mode using Field II platform. RESULTS: The three arterial layers, blood, and surrounding tissue in simulated B-mode ultrasound images are clearly legible. The results based on a statistical analysis for the envelope signals from 30 simulations indicate that the echo characteristics of blood, intima, media, and adventitia are in accordant with clinical ones. The maximum relative errors between the preset geometrical sizes and the measured ones from the simulated images for the diameter of the lumen and the thicknesses of the intima, media, and adventitia are 0.13%, 3.89%, 1.35%, and 0.06%, respectively. For the dynamic parameters, the variation in IM thickness, the radial displacements of lumen and adventitia as well as the axial displacement of IM and blood flow velocity are measured with the mean relative errors of 68.03%, 9.27%, 2.10%, 4.93%, and 17.34%, respectively. CONCLUSION: The simulated results present static sizes and dynamical variations according with preset values; echo distributions conforming to clinical versions. Therefore, the presented simulation model could be useful as a data source to evaluate the performance of studies on measurements of ultrasound-based tissue structures and dynamic parameters for the CCA layers. PMID- 29148587 TI - Experimental infection by Yersinia ruckeri O1 biotype 2 induces brain lesions and neurological signs in rainbow trout (Oncorhynchus mykiss). AB - Pathological manifestations in rainbow trout (Oncorhynchus mykiss) following experimental waterborne infection with Yersinia ruckeri serotype O1 biotype 2 (strain 07111224) were investigated. Rainbow trout were exposed to 8 * 107 CFU/ml of Y. ruckeri by bath for 6 hr, and mortality was then monitored for 22 days post-infection (dpi). Organs were sampled at 3 dpi and also from moribund fish showing signs of severe systemic infection such as bleeding, exophthalmia or erratic swimming behaviour. Y. ruckeri was observed in the meninges and diencephalon of the brain, and lamina propria of olfactory organ at 3 dpi. At 12 dpi, Y. ruckeri had spread throughout the brain including cranial connective tissues and ventricles and the infection was associated with haemorrhages and an infiltration with leucocytes. Y. ruckeri infection and associated with leucocyte infiltration were observed at 13 dpi. In conclusion, Y. ruckeri strain 07111224 causes encephalitis in the acute phase of infection, which could explain why Y. ruckeri-affected fish show exophthalmia and erratic swimming known as signs of ERM. PMID- 29148588 TI - Pleomorphic mastocytoma in an adult. AB - Cutaneous mastocytoma (CM) is a localized variant of mastocytosis, characterized by an over-accumulation of mast cells in the skin, without extra-cutaneous organ involvement. It is defined as the presence of up to 3 isolated mast-cell skin lesions and commonly develops in newborns and children. We report the case of a 35-year-old healthy Caucasian woman presenting with a 4-year history of a pruritic brown plaque on her left breast. Hematoxylin-eosin staining showed a dense dermal infiltrate of atypical mast cells extending to the subcutis. The cells presented a marked nuclear pleomorphism with bilobed and multilobed nuclei. Immunohistochemical studies revealed strongly expressed KIT (CD117) and CD25 proteins. Serum tryptase levels and bone marrow biopsy were normal. The diagnosis was a solitary cutaneous pleomorphic mastocytoma. This case can be added to 17 other cases of adult mastocytoma documented in the literature, although, unlike other reported cases, and as far as we are aware, this is the first case of pleomorphic mastocytoma in an adult. PMID- 29148589 TI - Determination of telbivudine in the plasma of chronic hepatitis B patients in long-term treatment by high-performance liquid chromatographic-tandem mass spectrometry. AB - Creatine kinase elevation is commonly reported in telbivudine-treated patients. However, little is known about the relationship between this adverse drug reaction and plasma concentration. In this study, a sensitive, rapid and safe quantitative bioanalytical method has been established by using LC-MS/MS for the determination of telbivudine in a clinical study of chronic hepatitis B patients. The assay was linear in a dynamic 10-10,000 ng/mL range (r2 > 0.999) and total analysis time was 6 min in this method. The validated method was applied to quantitatively determine plasma concentration in chronic hepatitis B patients during long-term telbivudine treatment. The results revealed that telbivudine concentration in the creatine kinase-elevated group (707.92-2788.78 ng/mL) was significantly higher than those with normal creatine kinase (412.63-1108.32 ng/mL). This method was adapted for therapeutic drug monitoring. PMID- 29148590 TI - Effects of bergenin on methylglyoxal-induced damage in osteoblastic MC3T3-E1 cells. AB - Bergenin is the main chemical constituent of plants in the genus Bergenia, which are used in traditional medicines. Methylglyoxal (MG), a highly reactive dicarbonyl compound, is the major precursor for forming advanced glycation end products (AGEs). Pretreating MC3T3-E1 cells with bergenin prevented MG-induced protein adduct formation. Bergenin inhibited the MG-induced soluble receptor for AGE (sRAGE), interleukin, reactive oxygen species and mitochondrial superoxide production. Additionally bergenin increased glyoxalase I activity, glutathione, heme oxygenase-1 and nuclear factor erythroid 2-related factor 2 levels in the presence of MG. Pretreatment with bergenin before MG exposure reduced MG-induced mitochondrial dysfunction by preventing mitochondrial membrane potential dissipation, loss of adenosine triphosphate and reduced adenosine monophosphate activated protein kinase. These results demonstrate that bergenin may prevent the development of diabetic osteopathy. PMID- 29148591 TI - Statistical modelling of sea lice count data from salmon farms in the Faroe Islands. AB - Fiskaaling regularly counts the number of sea lice in the attached development stages (chalimus, mobiles and adult) for the salmon farms in the Faroe Islands. A statistical model of the data is developed. In the model, the sea-lice infection is represented by the chalimus (or mobile) lice developing into adult lice and is used to simulate past and current levels of adult lice-including treatments-as well as to predict the adult sea lice level 1-2 months into the future. Time series of the chalimus and adult lice show cross-correlations that shift in time and grow in size with temperature. This implies in situ the temperature-dependent development times of about 56 down to 42 days and the inverted development times (growth rates) of 0.018 up to 0.024 lice/day at 8-10 degrees C. The temperature dependence DT=alpha1T+alpha2alpha3=17,840T+7.439-2.128is approximated byD1T=105.2 6.578T~49 days at the mean temperature 8.5 degrees C-similar to DchaT=100.6 6.507T~45 days from EWOS data. The observed development times at four sites for a year (2010-11) were 49, 50, 51 and 52 days, respectively. Finally, we estimate the sea lice production from fish farms to discuss approaches to control the sea lice epidemics-preferably by natural means. This study is useful for understanding sea lice levels and treatments, and for in situ analysis of the sea lice development times and growth rates. PMID- 29148592 TI - Use of oral anticoagulants in German nursing home residents: drug use patterns and predictors for treatment choice. AB - AIMS: Information on utilization of oral anticoagulants (OACs) in nursing homes is scarce. This study aimed to (i) describe OAC use in German nursing home residents, (ii) examine factors influencing whether treatment is initiated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) and (iii) assess which conditions predict switching to NOAC instead of continuing VKA. METHODS: Using claims data (2010-2014), we studied a cohort of new nursing home residents aged >=65 years receiving OAC. Further, OAC use in patients with atrial fibrillation (AF) was examined over the years. RESULTS: Overall, 16 804 patients (median age: 85 years, 75% female, 44% with renal disease) were included. The majority received phenprocoumon as first OAC (58.0%), followed by rivaroxaban (28.1%). Over the study period, NOAC use increased substantially. Initiating NOAC instead of VKA was predicted by a previous stroke (adjusted odds ratio: 1.76; 95% confidence interval: 1.49-2.08). In contrast, renal disease predicted VKA initiation (0.66; 0.59-0.75) as did the presence of a prosthetic heart valve. Switching from VKA to NOAC was predicted by a stroke (2.55; 2.00-3.24), bleeding events and a recent hospitalization. During 2010-2014, the proportion of AF patients with a CHADS2 score >=2 receiving OAC increased from 27% to 46%. CONCLUSIONS: NOACs are increasingly used in German nursing homes, both for initial anticoagulation but also in VKA pre-treated patients. Switching from VKA to NOAC was substantially influenced by aspects such as intended higher effectiveness and safety but probably also practicability due to less blood monitoring. PMID- 29148593 TI - First isolation of Vibrio tapetis and an atypical strain of Aeromonas salmonicida from skin ulcerations in common dab (Limanda limanda) in the North Sea. AB - Skin ulcerations rank amongst the most prevalent lesions affecting wild common dab (Limanda limanda) with an increase in prevalence of up to 3.5% in the Belgian part of the North Sea. A complex aetiology of these ulcerations is suspected, and many questions remain on the exact factors contributing to these lesions. To construct the aetiological spectrum of skin ulcerations in flatfish, a one-day monitoring campaign was undertaken in the North Sea. Fifteen fish presented with one or more ulcerations on the pigmented and/or non-pigmented side. Pathological features revealed various stages of ulcerations with loss of epidermal and dermal tissue, inflammatory infiltrates and degeneration of the myofibers bordering the ulceration, albeit in varying degrees. Upon bacteriological examination, pure cultures of Vibrio tapetis were retrieved in high numbers from five fish and of Aeromonas salmonicida in one fish. The V. tapetis isolates showed cross reactivity with the sera against the representative strain of serotype O2 originating form a carpet-shell clam (Ruditapes descussatus). Moreover, the A. salmonicida isolates displayed a previously undescribed vapA gene sequence (A layer type) with possible specificity towards common dab. Further research is necessary to pinpoint the exact role of these agents in the development of skin ulcerations in common dab. PMID- 29148594 TI - Metabolic study of paeoniflorin and total paeony glucosides from Paeoniae Radix Rubra in rats by high-performance liquid chromatography coupled with sequential mass spectrometry. AB - A clear understanding of the metabolism of Traditional Chinese Medicines is extremely important in their rational clinical application and effective material foundation research. A novel and reliable strategy was performed to find more metabolites of paeoniflorin, determine the metabolites of total paeony glucosides (TPG) by means of determining those metabolites of paeoniflorin, and compare the metabolism differences between paeoniflorin and TPG by intragastric administration. This strategy was characterized as follows. Firstly, the rats were divided into two groups (the paeoniflorin group and the TPG group) to find differences in metabolism mechanisms between paeoniflorin and TPG. Secondly, UPLC FT-ICR MS and UPLC-Q-TOF MS2 were applied to obtain accurate molecular weight and structural information, respectively. Thirdly, the metabolites were tentatively identified by a combination of data-processing methods including mass defect screening, characteristic neutral loss screening and product ion screening. Finally, a comparative study was employed in the metabolism of paeoniflorin and TPG. Based on the strategy, 18 metabolites of paeoniflorin (including four new compounds) and 11 metabolites of TPG (including two new compounds) were identified. In all of the identified metabolites of paeoniflorin, two metabolites in rat plasma, four metabolites in rat urine and six metabolites in rat feces were found for the first time after paeoniflorin administration. The results indicate that hydrolyzation of the ester bond and glucosidic band and conjugation with glucuronide were the major metabolic pathways of paeoniflorin. The metabolites of paeoniflorin and TPG in rat plasma, urine and feces have been detected for the first time after intragastric administration. The results may contribute to a better understanding of the metabolism mechanism and provide a scientific rationale for researching the material basis of paeoniflorin and TPG in vivo. PMID- 29148595 TI - Determination of cefoperazone and sulbactam in serum by HPLC-MS/MS: An adapted method for therapeutic drug monitoring in children. AB - A rapid, accurate and specific high-performance liquid chromatography-tandem mass spectrometry method has been validated for the simultaneous determination of cefoperazone and sulbactam in a small volume sample for children. A Shim-pack XR ODS C18 column with gradient elution of water (0.1% formic acid) and acetonitrile (0.1% formic acid) solution was used for separation at a flow rate of 0.3 mL/min. The calibration curves of two analytes in serum showed excellent linearity over the concentration ranges of 0.03-10 MUg/mL for cefoperazone, and 0.01-3 MUg/mL for sulbactam, respectively. This method involves simple sample preparation steps and was validated according to standard US Food and Drug Administration and European Medicines Agency guidelines in terms of selectivity, linearity, detection limits, matrix effects, accuracy, precision, recovery and stability. This assay can be easily implemented in clinical practice to determine concentrations of cefoperazone and sulbactam in children. PMID- 29148596 TI - Transition-Metal-Catalyzed Selective Cage B-H Functionalization of o-Carboranes. AB - Carboranes are a class of carbon-boron molecular clusters with unusual thermal and chemical stabilities. They have been proved as very useful building blocks in supramolecular design, optoelectronics, nanomaterials, boron neutron capture therapy agents and organometallic/coordination chemistry. Thus, the functionalization of o-carboranes has received growing interests. Over the past decades, most of the works in this area have been focused on cage carbon functionalization as the weakly acidic cage C-H proton can be readily deprotonated by strong bases. In sharp contrast, selective cage B-H activation/functionalization among chemically very similar ten B-H vertices is very challenging. Considering the differences in electron density of ten cage B-H bonds in o-carborane and the nature of transition metal complexes, we have tackled this selectivity issue by means of organometallic chemistry. Our strategy is as follows: using electron-rich transition metal catalysts for the functionalization of the most electron-deficient B(3,6)-H vertices (bonded to both cage CH vertices); using electron-deficient transition-metal catalysts for the functionalization of relatively electron-rich B(8,9,10,12)-H vertices (with no bonding to both cage CH vertices); and using the combination of directing groups and electrophilic transition metal catalysts for the functionalization of B(4,5,7,11)-H vertices (bonded to only one cage CH vertex). Successful applications of such a strategy result in the preparation of a large variety of cage B-functionalized carboranes in a regioselective and catalytic manner, which are inaccessible by other means. It is believed that as this field progresses, other cage B-functionalized carboranes are expected to be synthesized, and the results detailed in this concept article will further these efforts. PMID- 29148597 TI - Three-dimensional analysis of bone remodeling following ridge augmentation of compromised extraction sockets in periodontitis patients: A randomized controlled study. AB - OBJECTIVES: The aim of this study was to analyze linear and volumetric hard tissue changes in severely resorbed alveolar sockets after ridge augmentation procedure and to compare them with spontaneous healing using three-dimensional cone beam computed tomography (CBCT). MATERIAL AND METHODS: Thirty patients (mean age 53.2 +/- 6.3 years) requiring tooth extraction for advanced periodontitis were randomly allocated to test and control groups. The test sites were grafted using a collagenated bovine-derived bone (DBBM-C) covered with a collagen membrane, while control sites had spontaneous healing. Both groups healed by secondary intention. Linear and volumetric measurements were taken on superimposed CBCT images obtained after tooth extraction and 12 months later. RESULTS: Greater horizontal shrinkage, localized mainly in the crestal zone, was observed in the control group (4.92 +/- 2.45 mm) compared to the test group (2.60 +/- 1.24 mm). While both groups presented a rebuilding of the buccal wall, it was most pronounced in the grafted sockets (2.50 +/- 2.12 mm vs. 0.51 +/- 1.02 mm). A significant difference was also registered in the percentage of volume loss between grafted and non-grafted sites (9.14% vs. 35.16%, p-value <.0001). CONCLUSION: Alveolar sockets with extensive buccal bone deficiencies undergo significant three-dimensional volumetric alterations following natural healing. The immediate application of a slow-resorbing xenograft with a covering collagen membrane seems to be effective in improving alveolar ridge shape and dimensions, thus potentially reducing the need for adjunctive regenerative procedures at the time of implant placement. PMID- 29148598 TI - Job strain in nursing homes-Exploring the impact of leadership. AB - AIMS AND OBJECTIVES: To explore the association between nursing home managers' leadership, job strain and social support as perceived by direct care staff in nursing homes. BACKGROUND: It is well known that aged care staff experience high levels of job strain, and that aged care staff experiencing job strain are exposed to increased risk for adverse health effects. Leadership styles have been associated with job strain in the literature; however, the impact of perceived leadership on staff job strain and social support has not been clarified within nursing home contexts. DESIGN: This study had a cross-sectional design. METHODS: Participating staff (n = 3,605) completed surveys which included questions about staff characteristics, valid and reliable measures of nursing home managers' leadership, perceived job strain and social support. Statistical analyses of correlations and multiple regression analysis with interaction terms were conducted. RESULTS: Nursing home managers' leadership were significantly associated with lower level of job strain and higher level of social support among direct care staff. A multiple regression analysis including an interaction term indicated individual and joint effects of nursing home managers' leadership and social support on job strain. CONCLUSIONS: Nursing home managers' leadership and social support were both individually and in combination associated with staff perception of lesser job strain. Thus, nursing home managers' leadership are beneficial for the working situation and strain of staff. RELEVANCE TO CLINICAL PRACTICE: Promoting a supporting work environment through leadership is an important implication for nursing home managers as it can influence staff perception of job strain and social support within the unit. By providing leadership, offering support and strategies towards a healthy work environment, nursing home managers can buffer adverse health effects among staff. PMID- 29148599 TI - Hierarchical Porous Phenolic Resin and Its Supported Pd-Catalyst for Suzuki Miyaura Reactions in Water Medium. AB - The motivation of this work is to build micro and mesopores within phenolic resins to extend their applications to the heterogeneous catalysis field. For this purpose, porous hyper-cross-linked phenolic resin (PFN-P) with Brunauer Emmett-Teller (BET) surface area of 775 m2 g-1 is synthesized through one-step polycondensation from tri(4-formylphenyl)phosphine and 2,5-dihydroxy-1,4 benzoquinone, which simultaneously contains abundant hydroxyl and triphenylphosphine moieties in the network. The resultant palladium-coordinated Pd@PFN-P possesses hierarchical porous structure with pore sizes ranging from 1.3 to 42.6 nm. The good hydrophilicity and broad pore sizes are advantageous for the accessibility of reactants to the catalyzing sites in the water medium for Suzuki Miyaura reactions. As a result, high conversions for reactions between various aryl halides and phenylboronic acid are achieved under both oxygen-free and aerobic conditions. Moreover, the reaction conversions are almost unchanged after repeatedly using Pd@PFN-P for five times, showing promising potential for application in heterogeneous catalysis. PMID- 29148600 TI - New evidence for the recent divergence of Devil's Hole pupfish and the plausibility of elevated mutation rates in endangered taxa. AB - Saglam et al. recently argued that the Devil's Hole pupfish (Cyprinodon diabolis), a conservation icon with the smallest known species range, was isolated 60 kya based on a new genomic data set. If true, this would be a radically long timescale for any species to persist at population sizes <500 individuals, in contrast to conservation genetics theory. However, here we argue that their analyses and interpretation are inappropriate. They placed highly restrictive prior distributions on divergence times, which do not appropriately model the large uncertainty and result in removing nearly all uncertainty from their analyses, and chose among models by assuming that pupfishes exhibit human mutation rates. We reanalysed their data with their same methods, only using an informative prior for the plausible range of mutation rates observed across vertebrates, including an estimate of the genomewide mutation rate from a pedigree analysis of cichlid fishes. In fact, Saglam et al.'s phylogenetic data support much younger median divergence times for C. diabolis, ranging from 6.2 to 19.9 kya, overlapping with our previous phylogenetic divergence time estimates of 2.5-6.5 kya. There are many reasons to suspect an even younger age and higher mutation rate in C. diabolis, as we previously estimated, due to their high metabolism, small adult size, small population size and severe environmental stressors. In conclusion, our results highlight the need for measuring mutation rate in this fascinating species and suggest that the ages of endangered taxa present in small, isolated populations may frequently be overestimated. PMID- 29148601 TI - Convergent, incremental, and criterion-related validity of multi-informant assessments of adolescents' fears of negative and positive evaluation. AB - Adolescents who experience social anxiety tend to hold fears about negative evaluations (e.g., taunting) and may also hold fears about positive evaluations (e.g., praise from a teacher). The Brief Fear of Negative Evaluation (BFNE) scale and Fear of Positive Evaluation Scale (FPES) are 2 widely used measures of adults' evaluative concerns. Yet we know little about their psychometric properties when assessing adolescents. In a mixed clinical/community sample of 96 adolescents (66.7% female; M = 14.50 years, SD = 0.50; 63.3% African American), we examined both self-report and parent report versions of the BFNE and FPES. Adolescents and parents also provided reports about adolescents on survey measures of social anxiety and depressive symptoms. Adolescents participated in multiple social interactions in which they self-reported their state arousal before and during the tasks. Adolescent and parent BFNE and FPES reports distinguished adolescents who displayed elevated social anxiety from those who did not. Both informants' reports related to survey measures of adolescent social anxiety, when accounting for domains that commonly co-occur with social anxiety (i.e., depressive symptoms). Further, both the BFNE and FPES displayed incremental validity in relation to survey measures of adolescent social anxiety, relative to each other. However, only adolescents' BFNE and FPES reports predicted adolescents' self-reported arousal within social interactions, and only adolescents' FPES displayed incremental validity in predicting self-reported arousal, relative to their BFNE. Adolescent and parent BFNE and FPES reports display convergent validity and in some cases incremental and criterion-related validity. These findings have important implications for evidence-based assessments of adolescents' evaluative concerns. PMID- 29148602 TI - Nurses' professional stigma and attitudes towards postpartum women with severe mental illness. AB - AIMS AND OBJECTIVES: To examine professional stigma and attitudes of parenthood towards postpartum women with severe mental illness and the association between postpartum nurses' attitudes and nursing interventions that promote motherhood. BACKGROUND: Stigma and attitudes towards parenthood of women with severe mental illness may influence nurses' clinical practices. DESIGN: Cross-sectional, mixed methods. METHODS: The Stigma among Health Professionals towards People with Severe Mental Illness, Attitudes towards Parenthood among People with Severe Mental Illness and Nursing Interventions that Promote Becoming a Mother Questionnaires were used in the study, as well as qualitative analysis. RESULTS: Sixty-one postpartum nurses participated in the study. Increased stigma was associated with an increase in negative attitudes towards parenthood among people with severe mental illness, in general, and towards their parenthood skills, in particular. Postpartum nurses reported a decrease in nursing interventions and a therapeutic nurse-client relationship that fosters mother's empowerment. Themes that emerged from the qualitative analysis were postpartum nurse's perceptions of inadequacy, difficulty of postpartum nurses taking responsibility for managing women with severe mental illness and a paternalistic approach to these women, rather than empowerment, regarding infant care. CONCLUSION: Nurses providing care to postpartum women with severe mental illness and their infants may provide fewer routine postpartum interventions due to professional stigma and negative attitudes concerning parenting skills. Nurses should provide individualised, tailored care that allows women with severe mental illness to become a mother to the best of her ability. RELEVANCE TO CLINICAL PRACTICE: Not all women with severe mental illness are capable of caring for themselves and/or their baby. Nurses should provide individualised, tailored care that allows the women with severe mental illness to become a mother to the best of her ability. PMID- 29148603 TI - MCP2 activates NF-kappaB signaling pathway promoting the migration and invasion of ESCC cells. AB - MCP2, aliased CCL8, has been suggested to be implicated in the metastasis of cancer cells; however, no direct evidence has been established in esophageal squamous cell carcinoma (ESCC). In our present study, to investigate the role MCP2 played in the metastasis of ESCC cells; in vitro cell co-culture system was established. Wound-healing and Transwell assays were used to evaluate the migratory and invasive variation of ESCC cells before and after treatment with recombinant human MCP2. It was shown that MCP2 was able to activate the NF-kappaB signaling pathway inducing the epithelial-mesenchymal transition (EMT) and promoting the migration and invasion of ESCC cells in vitro. Our study provides an alternative working mechanism for M2 macrophage mediated the metastasis in tumor microenvironment in ESCC. PMID- 29148604 TI - Biomass-Derived N-doped Carbon Materials with Silica-Supported Ultrasmall ZnO Nanoparticles: Robust Catalysts for the Green Synthesis of Benzimidazoles. AB - Ultrasmall ZnO nanoparticles anchored on N-doped carbon materials with a silica support (ZnO/SiO2 -NC) were fabricated from chitosan and metal ions by using a one-pot self-assembly strategy and were successfully applied to the synthesis of 2-arylbenzimidazoles under mild conditions. These catalysts showed excellent stability and could be used six times without any loss of conversion and selectivity. The use of silica gel and the biomass chitosan as a source of hydrophilic N-doped carbon materials facilitated the uniform dispersion of the ZnO nanoparticles in methanol and therefore the contact of these nanoparticles with reactants, thus contributing to a high catalytic performance. TEM analysis showed that the ZnO nanoparticles were around 2.55 nm in diameter and uniformly distributed on the support surface. The binding behavior of ZnO and N-doped carbon materials affected the catalytic activity. Interestingly, temperature programmed NH3 desorption indicated that the interactions between ZnO and N-doped carbon materials might induce the presence of more acidic sites in these catalysts, thus resulting in enhanced activity and hence promoting this transformation. PMID- 29148605 TI - An overview: Rabbit hepatitis E virus (HEV) and rabbit providing an animal model for HEV study. AB - Hepatitis E virus (HEV) is a single-stranded, positive-sense RNA virus and the causative agent of hepatitis E. The virus belongs to genus Orthohepevirus in the family Hepeviridae, which contains 4 major genotypes closely relating to humans. Genotypes 1 and 2 only infect humans whereas genotypes 3 and 4 HEV are harbored in a wide range of animal species worldwide and are zoonotic to humans. Recently, a novel animal strain of HEV has been isolated in farmed rabbits in China, and subsequently more strains were discovered in the rabbit populations in at least 7 other countries. Due to high sequence similarity to genotype 3 HEV, rabbit HEV (rHEV) has been assigned to genotype 3. Experimental study showed that rHEV could infect non-human primate and human, which pose a direct threat to human. Further pathogenesis studies showed laboratory rabbits infected with rHEV and genotype 4 HEV could present similar signs of acute and chronic hepatitis E along with extra hepatic replication as observed in humans. High mortality and vertical transmission were reproduced in rHEV infected pregnant rabbits. Furthermore, rabbit model was also found suitable for evaluating HEV vaccine efficacy in order to manage zoonotic transmission. These data showed laboratory rabbits could serve as an alternative animal model for HEV study under the current circumstances that HEV propagation is limited in vitro. In general, this review aims at presenting comprehensive up-to-date information about rHEV strains and rabbit model for HEV studies. PMID- 29148606 TI - Severe subvalvular pulmonic stenosis due to a ball-shaped accessory tissue in an asymptomatic woman with congenitally corrected transposition of great arteries and mesocardia: A rare case report. AB - Congenitally corrected transposition of great arteries (CCTGA) is a rare anomaly described by atrioventricular and ventriculoarterial discordance. On the other hand, mesocardia that is extremely rare includes two relatively well-defined apexes defined by each ventricle with the major axis of the heart lies in the midline. We describe a rare case of an asymptomatic 20-year-old woman with mesocardia, CCTGA, and severe subvalvular pulmonic stenosis due to a ball-shaped accessory tissue in left ventricular outflow tract. PMID- 29148607 TI - The art of oral handovers: A participant observational study by undergraduate students in a hospital setting. AB - AIMS AND OBJECTIVES: To explore the conditions for oral handovers between shifts in a hospital setting, and how these impact patient safety and quality of care. BACKGROUND: Oral handovers transfer patient information and nursing responsibilities between shifts. Short written summaries of patients can complement an oral handover. How to find the balance between a standardised protocol for handovers and tailoring variations to specific patients and situations is debated in the literature. Oral handovers provide time for discussion, debriefing and problem solving, which can lead to increased team cohesiveness. DESIGN: This study used a participant observation design. METHOD: Fifty-two undergraduate nursing students conducted 1100 hr of participant observation in seven different units in a hospital in Western Norway from 2014 2015. Field notes were analysed using qualitative content analysis. RESULTS: Six themes emerged from the data: (i) content and structure of the handover, (ii) awareness of nurses' attitudes during oral handover, (iii) verbal and nonverbal communication, (iv) distractions, (v) relaying key information accurately, (vi) ensuring quality through oral handovers. CONCLUSION: Developing a familiar structure for oral handovers and minimising the use of abbreviations and unfamiliar medical terms promote clarity and understanding. Limiting disturbances during handovers helps nurses focus on the content of the report. Awareness of one's attitudes and the use of verbal and nonverbal communication can enhance the quality of a handover. Time allocated for an oral handover should allow for professional discussions and student supervision. Involving nurse leaders in promoting the quality of oral handovers can impact the quality of care. CLINICAL IMPLICATIONS: Oral handovers serve many purposes, such as the safe transfer of patient information between shifts and staff education and debriefing, which enhance team cohesiveness. PMID- 29148608 TI - Criteria to define interruption of transmission of human cytomegalovirus from organ donor to recipient. AB - In this review article, we consider results suggesting that transmission of human cytomegalovirus (HCMV) from a donor of a solid organ to an immunologically naive individual can be reduced. Two randomized controlled trials have been conducted recently, one of active immunization of recipients pretransplant and another of passive immunization with monoclonal antibodies specific for HCMV given at the time of transplant. Although the available data are encouraging-providing evidence of a reduction in the incidence of HCMV viraemia-they fall short of what would be required to prove definitively that transmission has been completely prevented. Here, we reflect on these studies and propose a set of 5 criteria, which, if satisfied in the future, could be taken as proof that active and/or passive immunization against HCMV effectively interrupts transmission of virus from the donor. We suggest that these criteria are considered when designing future randomized controlled trials. PMID- 29148609 TI - Fetal Brain Tutor 4us: an app for interactive multiplanar navigation through the normal fetal brain. PMID- 29148610 TI - Can Coordination-Driven Supramolecular Self-Assembly Reactions Be Conducted from Fully Aliphatic Linkers? AB - The reaction between a preassembled CuI bimetallic molecular clip with a short intermetallic distance and a series of fully aliphatic cyano-capped ditopic linkers with increasing lengths was investigated. It is shown that, depending on the length of the ditopic linkers, the rational design of unprecedented supramolecular compact metallacycles containing fully aliphatic walls is possible. The specific preorganized molecular arrangement of the molecular clip used favors stabilizing interlinker London dispersion interactions, which allow, as the length of the linkers increases, the selective formation of discrete compact metallacycles at the expense of 1D coordination polymers. The generalizability of this approach was demonstrated by the reaction of fully aliphatic cyano-capped linkers with two other types of preassembled CuI bimetallic molecular clips that also had short intermetallic distances. PMID- 29148611 TI - Biomechanical investigation of the modified Tardieu Scale in assessing knee extensor spasticity poststroke. AB - OBJECTIVE: The modified Tardieu Scale (MTS) is a clinical tool for the measurement of muscle spasticity. The present study aimed to investigate the relationship between the MTS and the slope of the work-velocity curve as a biomechanical measure in assessing knee extensor muscle spasticity in patients with stroke. METHODS: Thirty patients with stroke (22 female, 8 male; mean age 55.4 +/- 12.0 years) participated in this study. The knee extensor spasticity was assessed with the MTS. An isokinetic dynamometer was used to move the knee passively from full extension to 90 degrees flexion at speeds of 60 degrees /s, 120 degrees /s, 180 degrees /s, and 240 degrees /s to collect torque-angle data. The slope of the work-velocity curve was calculated using linear regression [J/( degrees /s)]. RESULTS: The mean of R2-R1 component of MTS was 19.73 (SD 29.85). The mean work significantly decreased as the speed increased (p < .001). The mean (SD) slope for the work-velocity curve was -0.83 (SD 0.73, range -2.6-0.3). There was no significant relationship between the R2 -R1 and the slope of work-velocity curve (r = 0.09, p = .62). CONCLUSIONS: The lack of significant relationship between the MTS and the slope of work-velocity curve may question the usefulness of the MTS as a valid measure of muscle spasticity after stroke. PMID- 29148612 TI - Mat-like telangiectasias. PMID- 29148613 TI - Ambrosia artemisiifolia as a potential resource for management of golden apple snails, Pomacea canaliculata (Lamarck). AB - BACKGROUND: Ambrosia artemisiifolia, an invasive weed in Europe and Asia, is highly toxic to the golden apple snail (GAS; Pomacea canaliculata) in laboratory tests. However, little is known about the chemical components of A. artemisiifolia associated with the molluscicidal activity or about its potential application for GAS control in rice fields. This study evaluated the molluscicidal activities of powders, methanol extracts, and individual compounds from A. artemisiifolia against GAS in rice fields and under laboratory conditions. RESULTS: Ambrosia artemisiifolia powders did not negatively affect the growth and development of rice but they reduced damage to rice caused by GAS. Extracts had moderate acute toxicity but potent chronic toxicity. The 24-h 50% lethal concentration (LC50 ) of the extracts against GAS was 194.0 mg L-1 , while the weights, lengths and widths of GAS were significantly affected by exposure to a sublethal concentration (100 mg/mL). Psilostachyin, psilostachyin B, and axillaxin were identified as the most active molluscicide components in the aerial parts of A. artemisiifolia, and the 24-h LC50 values of these purified compounds were 15.9, 27.0, and 97.0 mg/L, respectively. CONCLUSION: The results indicate that chemical compounds produced by A. artemisiifolia may be useful for population management of GAS in rice fields. (c) 2017 Society of Chemical Industry. PMID- 29148614 TI - Double Regioselective Asymmetric C-Allylation of Isoxazolinones: Iridium Catalyzed N-Allylation Followed by an Aza-Cope Rearrangement. AB - Isoxazolinones are biologically and synthetically interesting densely functionalized heterocycles, which for a long time were not accessible in enantioenriched form by asymmetric catalysis. Next to the deficit of enantioselective methods, the functionalization of isoxazolinones is often plagued by regioselectivity issues due to the competition of various nucleophilic centers within the heterocycles. We report the first regio- and enantioselective C-allylations of isoxazolinones. These occur with high regioselectivity in favor of the linear allylation products, although Ir phosphoramidite catalysts were used, which commonly results in branched isomers. Our studies suggest that this outcome is the result of a reaction cascade via an initial regio- and enantioselective N-allylation to provide a branched allyl intermediate, followed by a spontaneous [3,3]-rearrangement resulting in chirality transfer. PMID- 29148615 TI - Farmers' perspective on herbicide-resistant weeds and application of resistance management strategies: results from a German survey. AB - BACKGROUND: A herbicide resistance survey was conducted in Germany to determine farmers' awareness of herbicide resistance and experience with resistant weeds, the information sources on herbicide resistance used and the methods employed to confirm resistance. In addition, the application pattern and perception of resistance management strategies by farmers were assessed. RESULTS: The majority of farmers (88%) were aware of the presence of herbicide resistance cases in Germany and 64% and 50% of farmers reported that resistant weeds had been detected in their county and on their farm, respectively. Resistance management strategies were reported to be applied by 87% of the farmers and three clusters of different resistance management approaches used to minimize the evolution of resistant weed populations were identified and linked to farmers' perception of resistance and farm management characteristics. When asked about obstacles to adopting resistance management strategies, higher cost was the obstacle most cited by farmers, followed by weather and labour intensity/labour costs. CONCLUSION: Outcomes from this survey may help researchers and crop consultants to increase understanding of farmers' perception of herbicide resistance issues, to improve knowledge dissemination concerning herbicide resistance and to develop resistance management programmes with high agronomic practicability and acceptance by farmers. (c) 2017 Society of Chemical Industry. PMID- 29148616 TI - Corrigendum. PMID- 29148617 TI - Microfibers as Physiologically Relevant Platforms for Creation of 3D Cell Cultures. AB - Microfibers have received much attention due to their promise for creating flexible and highly relevant tissue models for use in biomedical applications such as 3D cell culture, tissue modeling, and clinical treatments. A generated tissue or implanted material should mimic the natural microenvironment in terms of structural and mechanical properties as well as cell adhesion, differentiation, and growth rate. Therefore, the mechanical and biological properties of the fibers are of importance. This paper briefly introduces common fiber fabrication approaches, provides examples of polymers used in biomedical applications, and then reviews the methods applied to modify the mechanical and biological properties of fibers fabricated using different approaches for creating a highly controlled microenvironment for cell culturing. It is shown that microfibers are a highly tunable and versatile tool with great promise for creating 3D cell cultures with specific properties. PMID- 29148618 TI - Interest in tanning beds and sunscreen in German-speaking countries. AB - BACKGROUND: The growing incidence of nearly all types of skin cancer can be attributed to increased exposure to natural or artificial ultraviolet (UV) radiation. However, there is a scarcity of statistical data on risk behavior or sunscreen use, which would be important for any prevention efforts. METHODS: Using the search engine Google(r) , we analyzed search patterns for the terms Solarium (tanning bed), Sonnencreme (sunscreen), and Sonnenschutz (sun protection) in Germany, Austria, and Switzerland between 2004 and 2016, and compared it to search patterns worldwide. For this purpose, "normalized search volumes" (NSVs) were calculated for the various search queries. The corresponding polynomial functions were then compared with each other over the course of time. RESULTS: Since 2001, there has been a marked worldwide decrease in the search queries for tanning bed, whereas those for sunscreen have steadily increased. In German-speaking countries, on the other hand, there have - for years - consistently been more search queries for tanning bed than for sunscreen. There is an annual periodicity of the queries, with the highest NSVs for tanning bed between March and May and those for sunscreen in the summer months around June. In Germany, the city-states of Hamburg and Berlin have particularly high NSVs for tanning bed. CONCLUSIONS: Compared to the rest of the world, German-speaking countries show a strikingly unfavorable search pattern. There is still great need for education and prevention with respect to sunscreen use and avoidance of artificial UV exposure. PMID- 29148619 TI - Molten Salt Assisted Self-Assembly: Synthesis of Mesoporous LiCoO2 and LiMn2 O4 Thin Films and Investigation of Electrocatalytic Water Oxidation Performance of Lithium Cobaltate. AB - Mesoporous thin films of transition metal lithiates (TML) belong to an important group of materials for the advancement of electrochemical systems. This study demonstrates a simple one pot method to synthesize the first examples of mesoporous LiCoO2 and LiMn2 O4 thin films. Molten salt assisted self-assembly can be used to establish an easy route to produce mesoporous TML thin films. The salts (LiNO3 and [Co(H2 O)6 ](NO3 )2 or [Mn(H2 O)4 ](NO3 )2 ) and two surfactants (10-lauryl ether and cethyltrimethylammonium bromide (CTAB) or cethyltrimethylammonium nitrate (CTAN)) form stable liquid crystalline mesophases. The charged surfactant is needed for the assembly of the necessary amount of salt in the hydrophilic domains of the mesophase, which produces stable metal lithiate pore-walls upon calcination. The films have a large pore size with a high surface area that can be increased up to 82 m2 g-1 . The method described can be adopted to synthesize other metal oxides and metal lithiates. The mesoporous thin films of LiCoO2 show promising performance as water oxidation catalysts under pH 7 and 14 conditions. The electrodes, prepared using CTAN as the cosurfactant, display the lowest overpotentials in the literature among other LiCoO2 systems, as low as 376 mV at 10 mA cm-2 and 282 mV at 1 mA cm-2 . PMID- 29148620 TI - Perceptions of adults with overweight/obesity and chronic musculoskeletal pain: An interpretative phenomenological analysis. AB - AIMS AND OBJECTIVES: To gain insight into the lived experience of adults with overweight/obesity and chronic musculoskeletal pain. Knowledge gained will inform healthcare professionals about the complexity of the weight-pain relationship and enable more effective engagement with this population. BACKGROUND: Quantitative studies show links between weight and pain. Adults with overweight/obesity are more likely to experience comorbidity; however, qualitative research describing the complexities of the relationship is limited. METHODS: A purposive sample of adults with overweight/obesity and chronic musculoskeletal pain participated in face-to-face interviews. Interviews were audio-recorded, transcribed verbatim and analysed using interpretive phenomenological analysis. RESULTS: Eighteen adults (16 female) aged 29-71, body mass index >=25-46, participated in this study. Three superordinate themes emerged: "pain as a motivator and barrier to weight loss"; "fear of weight causing more damage"; and "activity is positive." Pain motivates some individuals to lose weight while simultaneously inhibiting weight loss efforts. Participants' perception that extra pressure caused by their weight further damaged joints contributed to fear and catastrophising. Fear is often exacerbated by healthcare professionals' descriptions of musculoskeletal damage, or participants' perception of healthcare professionals' attitude towards people with overweight/obesity. Conversely, individuals acknowledged the benefits of increased activity. CONCLUSION: Adults with overweight/obesity and chronic musculoskeletal pain in this study identified a bidirectional relationship between their weight and pain that challenged their weight loss efforts. Overweight/obesity contributed to fear and catastrophising, which resulted in avoidance of exercise that would have assisted their weight loss. RELEVANCE TO CLINICAL PRACTICE: Healthcare professionals need to understand the complex relationship between weight and pain, and their patients' understanding of that relationship. Healthcare professionals should use therapeutic communication to reduce the fear of weight causing damage, and thus promote physical activities that will contribute to weight loss. It is also important to ensure that the language used with this patient group does not stigmatise individuals, or cause or exacerbate fear of normal movement. PMID- 29148621 TI - Guidelines for the use of flow cytometry. PMID- 29148622 TI - Upcoming events of interest. PMID- 29148623 TI - Dual Roles of Protein as a Template and a Sulfur Provider: A General Approach to Metal Sulfides for Efficient Photothermal Therapy of Cancer. AB - Fabrication of clinically translatable nanoparticles (NPs) as photothermal therapy (PTT) agents against cancer is becoming increasingly desirable, but still challenging, especially in facile and controllable synthesis of biocompatible NPs with high photothermal efficiency. A new strategy which uses protein as both a template and a sulfur provider is proposed for facile, cost-effective, and large scale construction of biocompatible metal sulfide NPs with controlled structure and high photothermal efficiency. Upon mixing proteins and metal ions under alkaline conditions, the metal ions can be rapidly coordinated via a biuret reaction like process. In the presence of alkali, the inert disulfide bonds of S rich proteins can be activated to react with metal ions and generate metal sulfide NPs under gentle conditions. As a template, the protein can confine and regulate the nucleation and growth of the metal sulfide NPs within the protein formed cavities. Thus, the obtained metal sulfides such as Ag2 S, Bi2 S3 , CdS, and CuS NPs are all with small size and coated with proteins, affording them biocompatible surfaces. As a model material, CuS NPs are evaluated as a PTT agent for cancer treatment. They exhibit high photothermal efficiency, high stability, water solubility, and good biocompatibility, making them an excellent PTT agent against tumors. This work paves a new avenue toward the synthesis of structure controlled and biocompatible metal sulfide NPs, which can find wide applications in biomedical fields. PMID- 29148624 TI - Critical consciousness-raising, popular education and liberation in community health nursing: Let's start the debate. PMID- 29148625 TI - Evaluation of anabolic steroid induced renal damage with sonography in bodybuilders. AB - BACKGROUND: The aim of this study was to investigate the effect of anabolic steroids on kidneys in bodybuilders. METHODS: Twenty-two bodybuilders were included in the study. Participants were divided into three groups according to the scheme of steroid usage: group 1 (N.=8, intramuscular 500 mg testosterone enanthate, intramuscular 400 mg nandrolone decanoate and oral 40 mg methandrostenolone for 12 weeks), group 2 (N.=7, intramuscular 500 mg testosterone enanthate, intramuscular 300 mg nandrolone decanoate and intramuscular 300 mg boldenone undecylenate for 16 weeks), and group 3 (N.=7, no steroid intake). Blood urea nitrogen (BUN), creatinine (Cr), urine micro-albumin and electrolyte levels were measured. Renal volume, cortical thickness and echogenicity were obtained in ultrasonographic scans. RESULTS: Renal volume, cortical thickness, echogenicity and protein intake value were significantly higher in group 2 than group 1 and 3. Plasma levels of BUN and Cr in group 2 were significantly higher than other groups (P?0.001). Urine microalbumin and electrolyte levels were normal in all groups. CONCLUSIONS: The results of this study indicate that high protein intake, steroid usage, particularly the schemes, including boldenone undecylenate increases cortical echogenicity, thickness of renal parenchyma and renal volume in bodybuilders. PMID- 29148626 TI - Effects of detraining on breathing pattern and ventilatory efficiency in young soccer players. AB - BACKGROUND: This study investigated the effects of detraining on breathing pattern. The aim of this study was to evaluate the effect of a sixweek detraining period on breathing patterns and ventilatory efficiency. METHODS: Fourteen young soccer players were evaluated at the end of a competitive season and after a sixweek detraining period. Assessment of respiratory efficiency was based on VE/VCO2 slope changes below 70% of exercise intensity. All participants underwent twice an incremental graded exercise test up to exhaustion. RESULTS: No differences in breathing frequency and inspiratory time/ total time ratio (Ti/Ttot) were found after detraining (p>.05). Differences in tidal volume (VT), VT/Ti quotient and VE were significant (p<.05) at between 40 to 100% of exercise intensity. The VE/VCO2 slope did not change (p>.05) during a postdetraining maximal incremental test. CONCLUSIONS: A sixweek detraining period causes changes in inspiratory flow but does not affect the inspiratory time/total respiratory cycle time ratio. The overall ventilatory efficiency of the respiratory system remains constant and is not affected by detraining. PMID- 29148627 TI - Assessment of endpoint criteria and perceived barriers during maximal cardiorespiratory fitness testing among pregnant women. AB - BACKGROUND: A plateau in volume of oxygen consumption (VO2) is the primary indicator for determining if an individual has reached their maximal aerobic capacity. However, secondary criteria can also be used to identify maximal effort (i.e. lactate level, rating of perceived exertion (RPE), percent of age-predicted maximal heart rate (HR) and respiratory exchange ratio (RER)). Age and gender specific secondary criteria have been developed for the general population, but no secondary criteria have been established for pregnant women. The primary purpose of this study was to analyze secondary endpoint criteria during VO2max testing among pregnant women. A secondary purpose was to identify emotional and physical barriers pregnant women have that may prevent them from reaching maximal effort. METHODS: 25 pregnant women (age= 30.0+/-3.6yrs; gestation age= 22.1+/ 1.4wks, pre-pregnancy BMI= 23.68+/-4.04kg/m2) participated. Each participant completed a Bruce protocol treadmill test and maximal HR, RER, lactate, and RPE were assessed and compared to standards. Barriers were assessed immediately post exercise via open-ended questions. RESULTS: The mean VO2max was 32.9+/ 8.8ml/kg/min. Mean RPEmax was 17.6+/-1.8 versus the standard of RPE>=17 (p=0.12). Percent of age-predicted HRmax was 88.0+/-6.8% versus the standard of 95% (p<0.001). Immediate post-exercise lactate was 6.8+/-2.4mM versus the standard of >= 8mM (p=0.03). Maximal RER was 1.2+/-0.2 versus the standard of RERmax >= 1.1 (p=0.08). CONCLUSIONS: Our data provide preliminary evidence that secondary criteria may need to be adjusted for pregnant women. Additionally, physical and emotional barriers may be enhanced by pregnancy (e.g. pain, discomfort, anxiety, health concerns), and may limit the performance of pregnant women during maximal exercise. PMID- 29148628 TI - Clinical significance of ST depression at exercise stress testing in competitive athletes: usefulness of coronary CT during screening. AB - BACKGROUND: Congenital coronary anomalies (CCAs) and coronary artery disease (CAD) arouse intense scientific and clinical interest in sports medicine and sports cardiology medical communities because of their potential to trigger sudden cardiac death (SCD) in athletes. Exercise stress testing represent the first instrumental assessment to evaluate electrocardiographic changes during effort. Coronary computed tomography angiography (CCTA) is an advanced accurate noninvasive imaging modality for excluding CAD and abnormalities of origin and course of coronary vessels. The aim of this study is to investigate with CCTA the clinical significance of ST depression suggestive for myocardial ischemia during exercise stress testing in athletes and to determine the prevalence of CAD and/or CCAs. METHODS: 65 consecutive athletes showing electrocardiographic findings positive or equivocal for myocardial ischemia on exercise stress testing during pre-participation screening were investigated with CCTA. RESULTS: Among 65 athletes investigated, 36 showed Myocardial Bridge (MB), 1 showed an anomalous coronary origin and 7 showed CAD. Among 36 athletes with MB, 4 were associated with mild coronary artery stenosis. Three athletes with CAD needed percutaneous transluminal coronary angioplasty or coronary artery bypass surgery. CONCLUSIONS: In competitive athletes even with excellent workload capacities, in absence of cardiomyopathy, the presence of ischaemic electrocardiographic abnormalities could be mainly determined by a coronary congenital or acquired pathology. In this population CCTA is an useful imaging modality of choice for the risk stratification and for the diagnostic process, to allow eligible athletes to compete and to follow up subjects requiring medical surveillance. PMID- 29148629 TI - Carbohydrate mouth rinse improves cycling performance carried out until the volitional exhaustion. AB - BACKGROUND: Carbohydrates (CHO) are among the most investigated nutritional ergogenic aids, and may be consumed in different forms, e.g., mouth rinse with carbohydrate solution (MRCS). In this sense, the aim of this study was to evaluate the impact of MRCS on the performance of physically active individuals undergoing a physical exercise session carried out until the volitional exhaustion. METHODS: This is a counter-balanced randomized study, with a double blind design. The sample consisted of twenty-one physically active healthy men with a mean (+/-SD) of age of 22.4 (+/-2.7) years old, 76.7 (+/-6.0) cm of height,12.1% (+/-3.7) of body fat mass, and 23.9 (+/-2.4) kg/m2 of body mass index. After familiarizing the participants with the protocol (cycle ergometer, with oral mouth rinse procedure) and assessing the maximal lactate steady state the cycling exercise was performed until the volitional exhaustion in the following conditions: without mouth rinse (CONTROL), PLACEBO and MRCS. RESULTS: Time to reach exhaustion was statistically different (p<0.0001) between conditions (CONTROL: 43,0 +/- 27,5 minutes; PLACEBO: 57,4 +/- 30,6 minutes; MRCS: 70,9 +/- 30,3 minutes). CONCLUSIONS: The administration of MRCS was shown to be effective in improving cycling performance, increasing the time to exhaustion until the volitional exhaustion. Thus, the use of methodology proposed by the present study may help coaches and practitioners improve the performance of physically active young adults. PMID- 29148630 TI - Men exhibit greater fatigue resistance than women in alternated bench press and leg press exercises. AB - BACKGROUND: The purpose of this study was to evaluate the influence of sex, exercise order, and rest interval on neuromuscular fatigue resistance for an alternated strength training sequence of bench press (BP) and leg press (LP) exercises. METHODS: Twelve women and 16 men, both recreationally trained, performed four sessions in a random order: 1) BP followed by LP with three minutes rest (BP+LP with rest), 2) LP followed by BP with three-minutes rest (LP+BP with rest), 3) BP followed by LP without rest interval (BP+LP no rest), and 4) LP followed by BP without rest interval (LP+BP no rest). Participants performed four sets with 100% of 10RM load to concentric failure with the goal of completing the maximum number of repetitions in both exercises. The fatigue index was analyzed from the first and last sets of each exercise bout. RESULTS: A main effect for sex showed that women exhibited 25.5% (p=0.001) and 24.5% (p=0.001) greater BP and LP fatigue than men respectively when performing 10RM. Men exhibited greater BP (p<0.0001; 34.1%) and LP (p<0.0001; 30.5%) fatigue resistance when a rest period was provided. Men did not show an exercise order effect for BP fatigue and exhibited greater (p=0.0003; 14.5%) LP fatigue resistance when BP was performed first. CONCLUSIONS: The present study demonstrated the greater fatigue resistance of men when performing 10RM BP and LP exercises. Since men tend to experience less fatigue with the second exercise in the exercise pairing, women's training programs should be adjusted to ensure they do not parallel men's resistance training programs. PMID- 29148631 TI - Retracted: Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via Induction of Cell Cycle Arrest and Apoptosis AB - Retraction: Retracted: Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via Induction of Cell Cycle Arrest and Apoptosis Asian Pacific Journal of Cancer Prevention has retracted the article titled "Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via Induction of Cell Cycle Arrest and Apoptosis"(1) for reason of similarity with a series of articles identified by Byrne and Labbe (2). Xue-Mei Wang, Jiu-Wei Cui1&, Wei Li , Lu Cai, Wei Song , Guan-Jun Wang 1. Xue-Mei Wang, Jiu-Wei Cui1&, Wei Li , Lu Cai, Wei Song , Guan-Jun Wang. Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via Induction of Cell Cycle Arrest and Apoptosis. Asian Pac J Cancer Prev. 2012;13(5):1823-7. 2. J. A. Byrne and C. Labbe, "Striking similarities between publications from China describing single gene knockdown experiments in human cancer cell lines," Scientometrics, vol. 110, no. 3, pp. 1471-1493, 2017. Authors did not respond to request for comment. PMID- 29148632 TI - BREAKS IN REPORTING OF RESEARCH RESULTS: WHERE DO WE GO FROM HERE? PMID- 29148633 TI - CLINICAL ASSESSMENT OF CARDIOVASCULAR DISEASE ASSOCIATED RISK FACTORS IN JIMMATOWN, SOUTHWEST ETHIOPIA; A COMMUNITY BASED CROSS - SECTIONAL STUDY. AB - Introduction: Cardiovascular disease has been identified as emerging epidemic in developing world and Sub-saharan Africa. The prevalence of risk factors associated with cardiovascular disease is not clearly established in our country. We conducted this study to determine the prevalence of cardiovascular disease associated risk factors in Jimma town. Methods: A cross-sectional study was conducted in sampled adults in Jimma town. Multi-stage sampling was used by combining simple random sampling to select kebeles of Jimma town and then systematic random sampling to select the house hold .An individual was selected with a lottery method if there were more than one adult in the house hold who fulfills inclusion criteria. Data were collected using the World Health Organization standardized structured questionnaire on cardiovascular risk assessment for developing countries. The study variables included anthropometric measurements, demographic information and behavioral risk factors. The data variables were computed using SPSS version 20. Results: Majority (70.9%) of the respondents have one or more of the seven cardiovascular disease risk factors assessed. Nearly one forth (23.8%) of the study participants were hypertensive, 6.2% were known diabetes and the prevalence of smoking was 11.8% among males 2% among females. The prevalence of overweight/obesity was 26.8 %. Conclusion: Majority were found to have at least one of the risk factors for cardiovascular disease. Hypertension and diabetes mellitus were the most common. Screening programs, health education and awareness creation are recommended to prevent the development of the disease. Large scale prospective study with laboratory data will help to further analyze and strengthen the results for policy makers. PMID- 29148634 TI - LABOR, DELIVERY AND POSTPARTUM COMPLICATIONS IN NULLIPAROUS WOMEN WITH FEMALE GENITAL MUTILATION ADMITTED TO KARAMARA HOSPITAL. AB - Objectives: To assess labor, delivery and postpartum complications in nulliparous women with FGM/C and evaluate the attitude of mothers towards elimination of FGM. Methods: A prospective hospital based study using structured questionnaire was conducted between January to March 2015 at Karamara hospital, Jijiga, Ethiopia. All nulliparous women admitted for labor and delivery were included. Data were collected regarding circumcision status, events of labor, delivery; postpartum and neonatal outcomes as well as attitude of mothers towards elimination of FGM/C. Results: Two hundred sixty four (92.0%) of the women had FGM/C with most (93.0%) undergoing Type III FGM. The mean age of the women was 22 yr. Failure to progress in 1st stage and prolonged 2nd stage of labor occurred in 165 (57.0%) and189 (65.6%) of the cases respectively. Caesarean section was performed in 17.0% and instrumental delivery in 23.0%. 64.5% required episiotomies, 83.3% had an anterior episiotomy, 29 % had perineal tears, 25.7%% experienced post-partum hemorrhage and 24% postpartum infection. Among the newborns, there were 6.4% perinatal deaths; 18.8 % low birth weight and 1.5% birth injuries. Almost all complications were more frequently seen in circumcised compared to non-circumcised women. Conclusions: The prevalence of FGM is high and it substantially increases the risk of many maternal complications. Health professionals should be aware of these complications and support/care of women with FGM should be integrated at all levels of reproductive health care provision. Capacity building of responsible health professional should be initiated in the area with intensification of FGM eradication activities. PMID- 29148635 TI - ADMISSION PATTERNS AND OUTCOMES IN THE MEDICAL INTENSIVE CARE UNIT OF ST. PAUL'S HOSPITAL MILLENNIUM MEDICAL COLLEGE, ADDIS ABABA, ETHIOPIA. AB - Background: Knowledge of the characteristics and outcomes of critically ill patients admitted to Medical Intensive Care Unit (MICU) helps with identification of priorities and the resources required to improve care. The objective of this study was to examine admission patterns and outcomes in MICU at St. Paul's Hospital Millennium Medical College. Materials: A retrospective review of 1256 patients' case notes who were admitted to the MICU at St. Paul's Hospital Millennium Medical College from 2007 to 2012 was carried out. The data was analyzed by SPSS version 18.0 to obtain descriptive and inferential measurements. P values < 0.05 were considered significant for all tests. Results: Among specific diagnoses, diabetic ketoacidosis; 187 (14.9%), was the leading cause of admission, followed by all Strokes; 103 (8.2%), and Unspecified Diseases of Circulatory System; 81 (6.4%). The overall mortality rate was 39 %. Strokes were the leading causes of death, accounting for 12.2% of total deaths. The deceased were older than the survivors by five mean age years, mean age (+/-SD) 41.9 (+/- 18.5) and 36.7 (+/- 17.4) years, respectively. Conclusions: Non- communicable will continue to be increasing proportion of ICU admissions in the study. The mortality in this study is also substantial, and reasons looks like late admissions and limited care in the facility. Improving the ICU infrastructure and staffing with skilled personnel might improve the quality of care. PMID- 29148636 TI - OUTCOME OF PREGNANCY WITH CLINICALLY VISIBLE/PALPABLE MYOMA AMONG WOMEN WHO UNDERGO CAESARIAN SECTION IN THREE TEACHING HOSPITALS, ADDIS ABABA, ETHIOPIA: A CROSS SECTIONAL STUDY. AB - Introduction: Myoma is the most common pelvic tumor and an enormous healthcare concern in women. Complications occur in approximately 10-40% of pregnancies with myomatous uterus. This study is conducted to determine the prevalence and obstetric outcome of grossly visible and/or palpable myoma among women who gave birth by caesarean section. Methods: A cross sectional study conducted in three teaching hospitals in Addis Ababa, Ethiopia. Data was collected using a pre tested questioner. Results: A total of 404 cases were included in the study. The prevalence of myoma was 15.3% (62/404). Only 9.7% (6/62) of the myoma cases were diagnosed preoperatively with ultrasound. The number of myoma per case ranged from 1-to-14 with mean number of 3 +/-2.7. The mean diameter of largest single myoma per case was 5.2cm +/- 3.4. The commonest location of myoma was subserous being the location in 58.1% (36/62). There was significant association between presence of myoma and age of the woman (P<0.05). The adjusted prevalence of myoma increases as women's age increases, and gestational age and birth weight decreases. In addition, the prevalence of myoma was about two times higher in low (<=6) first and fifth minute APGAR score groups with adjusted prevalences of 22.2% (Vs 14.1% in >=7 group) and 31.8% (Vs 14.4% in >=7 group) respectively. Conclusions: The prevalence of myoma during pregnancy in this study is higher than prior reports from similar setups. But, no statistically significant association was observed between the presence of myoma and maternal out come. PMID- 29148637 TI - PSYCHOACTIVE SUBSTANCE USE AMONG NIGERIAN COHORT WITH HIV/AIDS: FREQUENCY, TYPES AND DEMOGRAPHIC CORRELATES. AB - Introduction: There are good pointers from literature to the detrimental impacts of psychoactive substance use in HIV/AIDS patients. This study aimed at investigating the prevalence, types and demographic correlates of psychoactive substance use among people living with HIV/AIDS. Methods: The study participants consisted of 295 adults with HIV/AIDS and were interviewed with a designed questionnaire that consisted of two parts. The first part contained questions to elicit socio-demographic and treatment related information of the participants, while the second part focused on psychoactive substance use. Results: The mean (SD) age of participants was 37.6 (+/-8.6) years, and majority (61.0%) of them were made up of females. Most of the subjects were married, 181 (61.4%) and employed 174 (59.0%). Of the total participants, 64 (21.7%) reported use of a form of psychoactive substance, among which the largest proportion (19.3%) reported use of alcohol, 1.4% use cannabis while 1% admitted to use of nicotine. Following regression analyses, being male (Odds Ratio =2.38; 95% Confidence Interval: 95% CI = 1.26 - 4.49; p=0.008) and increasing educational attainment (Odds Ratio = 1.62; 95% CI: 1.07 - 2.45; p=0.02) correlated positively with psychoactive substance use, while being single (Odds Ratio = 0.59; 95% CI: 0.35 - 0.99; p=0.047) correlated negatively. Conclusion: Proactive and targeted intervention strategies against psychoactive substance use among people living with HIV/AIDS using what is known about vulnerability are implied. Further research on the complex relationship between HIV/AIDS and psychoactive substance use is indicated. PMID- 29148638 TI - FACTORS ASSOCIATED WITH TREATMENT OUTCOME OF PEDIATRIC CANCERPATIENTS ADMITTED WITH FEBRILE NEUTROPENIA IN TIKURANBESSA SPECIALIZED TEACHING HOSPITAL, ADDIS ABABA, ETHIOPIA. AB - Background: Cancer treatment is associated with variable degrees of myelosupression. Infection is often a life-threatening complication of chemotherapy-induced neutropenia, and it is also considered an oncologic emergency. Febrile neutropenia is a common, costly and potentially fatal complication in oncology. Objective: To assess factors affecting treatment outcome of cancer patients with chemotherapy induced febrile neutropenia. Method: We conducted a review of records of pediatric patients hospitalized and treated for chemotherapy-induced febrile neutropenia from January 1, 2013 to December 31, 2013 and met the selection criteria. Result: A total of 60 patients (36 males and 24 females) fulfilled the selection criteria. Twelve of them died while in hospital. The mean (SD) age of patients who died was 4.78 (+/-2.48) years and the mean (SD) hospital stay before death was 20.2 (+/-5.26) days. Ten children had hematologic malignancy and two had a solid tumor. Ten of the 12 patients had an absolute neutrophil count of less than 100/mm3 (p=0.008, OR=20.3) and a platelet count of less than 50,000/mm3. Six of the 10 children (10%) had sepsis. Patients with profound neutropenia, platelet count of less than 50,000 and sepsis were more likely to die (P=0.048, OR=7). Conclusion: The result of this study showed that absolute neutrophil count of less than 100/mm3, platelet count of less than 50,000/mm3 and a diagnosis of sepsis were factors affecting outcome patients with febrile neutropenia. Careful evaluation of these factors and assessing severity of patients' clinical condition at time of admission can be useful for triaging children with febrile neutropenia. PMID- 29148639 TI - INSTITUTIONAL DELIVERY SERVICES UTILIZATION BY WOMEN OF CHILDBEARING AGE IN SOUTH WEST SHOWA ZONE, OROMIA REGION. AB - Introduction: Institutional delivery is very low in Ethiopia, particularly in Oromia where less than one-third of antenatal care attendees utilize the services. This study assessed the magnitude of institutional delivery and associated factors in South West Showa Zone of Oromia. Methods: A cross-sectional community based study was conducted in 2010. A stratified cluster sampling technique used to select study districts, villages and households. Four hundred thirty childbearing women with at least one birth in the past 5 years preceding the survey were interviewed. Qualitative study method was employed to supplement the quantitative data. Data analyses were done using SPSS v15. Frequency tables and percentages were used to describe study population. Association of independent variables with outcome variable was measured using odds ratio with 95% confidence interval. Multivariate logistic regression analysis was run to control for confounding variables. Results: Eighty percent (344) respondents were from rural. Mean age of the women was 28.8 (+/-6.6). Most (70.5%) respondents and 39% of their husbands were uneducated. A quarter of them delivered at health institutions over five years preceding the survey. In a regression model with maternal age, residence, maternal and paternal education, all were significantly associated with use of institutional delivery services. Obstetric factors have also showed a statistically significant association. The qualitative findings revealed that trust in traditional birth attendants and health workers' negative attitude were among the reasons for not delivering at health institutions. Conclusion: Institutional delivery service utilization in the zone is affected by maternal and paternal education, ANC attendance and duration of labor. Traditional beliefs and health workers' negative attitude were among the identified barriers. Multiple interventions involving community, service providers and health system are recommended. PMID- 29148640 TI - SHORT-TERM OUTCOME OF OPERATED TRAUMATIC BRAIN INJURY PATIENTS FOR INTRACRANIAL HEMORRHAGE AT TIKUR ANBESSA SPECIALIZED TEACHING HOSPITAL (TASTH), ADDIS ABABA, ETHIOPIA. AB - Background: Traumatic brain injury is the leading cause of death and disability in people younger than 40 years of age worldwide. Objective: The study primarily aims at assessing the short-term outcome of patients operated for traumatic intracranial hemorrhage. Patients and Methods: This is a hospital based cross sectional study on patients with traumatic brain injury at Tikur Anbessa Specialized Teaching Hospital in Addis Ababa, Ethiopia, between February 2013 and February 2014. Standardized and structured questionnaire was used to collect sociodemographic data. All patients with traumatic brain injury operated following intracranial hemorrhage were included. Glasgow Coma Scale was used to determine the outcome. Difference in proportions was examined using Chi-square test. Results: The study reviewed 91 patients with traumatic brain injury. Their age ranged from 13 to 60 years with a mean (SD) of 32.3 (+/-12.1). Eighty-seven (95.6%) of the cases were males and 4(4.4%) females and 34(37.4%) of them cases had mild and 30(33%) had severe traumatic brain injury. Acute Epidural Hematoma was seen in 79(86.8%), Acute Subdural hematoma had the highest proportion, 4/11(36.4%), of deaths and it was also significantly associated with unfavorable Glasgow Outcoma Scale at 3 months (p=0.03). Overall, the proportion patients who died was 18.7% with older patients (>50 years) had a significantly higher proportion of death (p=0.01). Most of the patients had favorable Glasgow Outcoma Scale ,unfavorable was seen in 22/30 (73.3%) and 17/30 (56.7%) of patients with severe traumatic brain injury at 3 and 6 months, respectively. Conclusion: In conclusion, male predominance was substantially high. Acute Subdural hematoma and old patients had high death rates and unfavorable outcome. Overall the death rate was not different from global figures. PMID- 29148641 TI - Ganglioneuroma of the Neck: A case report. AB - Ganglioneuroma (GN) is benign tumor arising from sympathetic ganglion which commonly occurs at posterior mediastinum, retroperitoneum and adrenal gland. Rarely, it may also present in cervical region as slow growing painless neck mass. Here we present a 7 years old female child with 4 years duration of slow growing left lateral neck mass. After proper investigations the patient was prepared & taken to the operation room for complete excision of the mass. Post operation biopsy settled the definitive diagnosis as Ganglioneuroma. Thus ganglioneuroma should be considered in patients with neck mass. PMID- 29148642 TI - RARE CO-EXISTENCE OF CORONARY ANOMALIES: ANOMALY OF ORIGIN AND DISTRIBUTION TOGETHER WITH ANOMALY OF INTRINSIC CORONARY ARTERY ANOMALY. AB - We describe a 63 year old Romanian female patient admitted to our institution with complaints of typical anginaand a diagnosis of non ST-elevation myocardial infarction. Coronary arteriography unveiled anomalous origin ofa left circumflex coronary artery from the right coronary sinus of Valsalva near the right coronary ostium and ahyperdominant left anterior descending coronary artery giving off a posterior descending coronary artery withsmall distal-posterolateral left ventricular branch. The co-existence of a left circumflex coronary artery originatingectopically from the right sinus of Valsalva together with a posterior descending coronary artery originatingfrom the distal end of the anterior descending artery is important to keep in mind especially by those doing coronaryangiography in the cardiac catheterization laboratory. PMID- 29148643 TI - Present. PMID- 29148644 TI - Resin-Bonded Bridges - the Problem or the Solution? Part 1- Assessment and Design. AB - Resin-bonded bridges (RBBs) have an important role to play in the minimally invasive prosthodontic replacement of missing teeth. This treatment modality is perceived to have a high clinical failure rate by some practitioners, which may be associated with poorly planned and executed designs and adhesive techniques. This paper, the first part of a two-part series, discusses the important planning stages in the successful provision of RBBs, including assessment, appropriate abutment selection and design considerations. The second part of this series will focus on the clinical stages of RBB provision. Clinical relevance: This paper aims to provide the general dental practitioner with a guide to appropriate case selection and an overview of the planning stages involved for the provision of RBBs. PMID- 29148645 TI - Implant Dentistry in General Practice Part 2: Treatment Planning. AB - This paper, the second of a series of two, provides an introduction to treatment planning in implant dentistry for the general dental practitioner. Clinical relevance: Appropriate training has made implant placement and restoration a routine treatment option in general practice. PMID- 29148646 TI - Denture Stomatitis - A Clinical Update. AB - Denture stomatitis is a benign condition, usually asymptomatic, that can affect edentulous patients. Studies have reported a prevalence of denture stomatitis affecting over 75% of denture wearers and, whilst the aetiology may be multifactorial, Candida albicans has a strong association with the condition, along with denture trauma and poor denture hygiene being associated local risk factors. This paper describes the aetiology, diagnosis and treatment of denture stomatitis, with the aim of helping clinicians to provide appropriate management of this condition. Clinical relevance: Denture stomatitis can be a recurrent problem amongst denture wearers and is often asymptomatic to the patient. Dental practitioners should be able to identify and manage this condition. Clinical relevance: Denture stomatitis can be a recurrent problem amongst denture wearers and is often asymptomatic to the patient. Dental practitioners should be able to identify and manage this condition. PMID- 29148647 TI - Mouthwashes: Do They Work and Should We Use Them? Part 1: Antiplaque Efficacy of Mouthwashes. AB - This article will focus on the antiplaque efficacy of mouthwashes. An antiplaque agent inhibits the formation of plaque and also reduces gingivitis. There is good evidence that chlorhexidine digluconate, used in the correct concentrations, is the gold standard agent against which all others should be measured. It does, however, have some unwanted side-effects. One of the major problems for antiplaque mouthwashes is that they have a much reduced effect on established plaque within the oral environment. Although they can flow into the biofilm channels and kill bacteria in the superficial layers of dental plaque, they cannot penetrate the biomass and inhibit the pathogenic bacteria adjacent to the tooth surface and gingival margin. There is no evidence that they prevent the progression of periodontitis. Clinical relevance: The evidence supporting the use of 'over the counter' antiplaque mouthwashes is evaluated. This provides guidance for dentists and dental care professionals of when it is appropriate to recommend mouthwash use to their patients. PMID- 29148648 TI - A Mouthful of Anomalies. AB - Isolated bilateral macrodontia of the mandibular second premolars is a rare condition. We believe that the case reported here is the first in which isolated bilateral macrodontia of the mandibular second premolars presents with numerous dental anomalies affecting other teeth. A 14-year-old boy was referred to the Paediatric Dental Department of King's College Hospital with a partially erupted mandibular left second premolar. Clinical and radiographic examination subsequently revealed macrodontia of both mandibular second premolar teeth and multiple other dental anomalies. This report discusses the presentation and multidisciplinary management of this case. Clinical relevance: This case report describes an already rare condition made even more extraordinary owing to its presentation with multiple other dental anomalies. PMID- 29148649 TI - An Overview of the Surgical Correction of Dentofacial Deformity. AB - The correction of severe dentofacial discrepancies involving a combination of orthodontic and surgical therapies (termed 'orthognathic treatment') is commonplace. There is an abundance of evidence within this field but it is often inconsistent. This article is an evidence-based overview of such treatments and is aimed at the general dental practitioner. It will cover: the timing of treatment; the indications and risks associated with different surgical osteotomies; the magnitude of surgical movements that can be achieved with these procedures; and the importance of mandibular autorotation when planning treatment. Orthognathic treatment is considered to be the gold standard for comprehensive correction of severe dentofacial discrepancies. It is undertaken by a multidisciplinary team of clinicians involving, but not exclusive to, consultants in orthodontics and oral and maxillofacial surgery in secondary and tertiary medical centres throughout the United Kingdom. Clinical relevance: It is imperative that general dental practitioners have a good understanding of orthognathic treatment in order to recognize when such treatments are indicated, to inform the patient of possible treatment modalities and to be able to discuss associated risks in order to make appropriate referrals. Since treatment timing and magnitude of surgical movements have a profound effect on stability of the treatment result, these must be carefully considered by all clinicians involved in patient care to minimize relapse potential. PMID- 29148650 TI - Residual Effectiveness of Permethrin-Treated Clothing for Prevention of Mosquito Bites Under Simulated Conditions. AB - Biological hazards such as exposure to ticks and mosquitoes can affect health. Permethrin-treated clothing is available to the public. We don't currently understand, however, the effects of environmental factors such as fabric type, washing, sunlight, and temperature on permethrin content in treated clothing with respect to mosquito knockdown and mortality. We evaluated the extent to which fabric type (100% cotton denim jeans, 100% polyester work shirt, 35% cotton/65% polyester work shirt), light exposure (0 or 100%), temperature (18 degrees C, 32 degrees C), and number of washes (0, 3, 12, 36) affected mosquito knockdown 2 hours post-exposure, mosquito mortality 24 hours post-exposure, and permethrin content. All fabrics used in this study were treated with permethrin at a concentration of 125 ug/cm2. Denim fabric having no washes and no light exposure showed the highest amount of permethrin. Washing and light exposure significantly reduced the ability of permethrin-treated fabrics to induce mosquito knockdown and/or mortality under the simulated conditions used for this test. Temperatures tested did not affect permethrin content or mosquito knockdown and mortality. Long-lasting impregnation of uniforms protects against mosquito bites under simulated laboratory conditions. Employers and employees should consider the use of permethrin-impregnated clothing and uniforms in addition to daily repellent sprays. PMID- 29148652 TI - Mouth Cancer for Clinicians Part 12: Cancer Treatment (Chemotherapy and Targeted Therapy). AB - A MEDLINE search early in 2015 revealed more than 250,000 papers on head and neck cancer; over 100,000 on oral cancer; and over 60,000 on mouth cancer. Not all publications contain robust evidence. We endeavour to encapsulate the most important of the latest information and advances now employed in practice, in a form comprehensible to healthcare workers, patients and their carers. This series offers the primary care dental team in particular, an overview of the aetiopathogenesis, prevention, diagnosis and multidisciplinary care of mouth cancer, the functional and psychosocial implications, and minimization of the impact on the quality of life of patient and family. Clinical relevance: This article offers the dental team a brief overview of chemotherapy and targeted therapy. PMID- 29148651 TI - Spontaneous Osteonecrosis of the Maxilla. AB - In the past decade there has been a rise of osteonecrosis of the jaws (ONJ) predominately related to bisphosphonate therapy and osteoradionecrosis secondary to radiotherapy. However, osteonecrosis can occur in the absence of these agents. A case of idiopathic osteonecrosis of the maxilla is reported and the literature discussed. Clinical relevance: It is not always possible to make a definitive diagnosis. PMID- 29148653 TI - Novel Indices of Meterological Drivers of West Nile Virus in Ohio Culex Species Mosquitoes From 2002-2006. AB - Novel indices were developed representing estimated stages in the mosquito life cycle and its ecology, and informed with meteorological data. We used descriptive statistics to identify relationships between meteorological/ecological trends and peak infection rates (IRs), and mixed model linear regression to identify meteorological/ecological trends that were significantly associated with increases in mosquito IRs. Results showed increased mean weekly temperature as a significant driver of increased IRs between 2002 and 2006 during oviposition (the trapping week); the gonotrophic cycle; the egg, larvae, and pupae stage; the development of oviposition sites; and during the over-winter months preceding trapping. Decreases in weekly cumulative precipitation during the last half of the development of oviposition sites, and the egg, larvae, and pupae stage, were significantly associated with increases in IRs. Increased cumulative precipitation during the first half of the development of oviposition sites was significantly associated with increases in IRs. Decreases in the weekly Palmer Drought Index during the development of oviposition sites were significantly associated with increases in IRs. PMID- 29148654 TI - Effective Pain Management Strategies in Endodontic Therapy. AB - Pain management is the key to providing successful root canal therapy. All patients hope for a painless procedure and look forward to being free of their symptoms when treatment is complete. However, managing pain throughout endodontic therapy can be challenging and improving awareness of various analgesic techniques can make a significant difference to both patient and practitioner. This article should provide some insight into these methods and use current literature to discuss how they can be delivered in a clinical setting. By doing so, practitioners can utilize these techniques to make endodontic treatment a more comfortable procedure. Clinical relevance: This article aims to improve the reader's awareness of the various clinical, pharmacological and behavioural analgesic techniques that can be used to help control presenting symptoms, reduce iatrogenic-induced pain and manage post-operative discomfort in the endodontically compromised patient. PMID- 29148655 TI - Feframing Climate Change for Environmental Health. AB - Repeated warnings by the scientific community on the dire consequences of climate change through global warming to the ecology and sustenance of our planet have not been give appropriate attention by the U.S. public. Research has shown that climate change is responsible for catastrophic weather occurrences--such as floods, tornadoes, hurricanes, and heat waves--resulting in environmental and public health issues. The purpose of this report is to examine factors influencing public views on climate change. Theoretical and political perspectives are examined to unpack opinions held by the public in the U.S. on climate change. The Health Belief Model is used as an example to showcase the efficacy of an individual behavior change program in providing the synergy to understand climate change at the microlevel. The concept of reframing is discussed as a strategy to alter how the public views climate change. PMID- 29148656 TI - Letters to the editor PMID- 29148657 TI - A Comparison of Heat Wave Response Plans From an Aged Care Facility Perspective. AB - Heat waves result in significant excess mortality, particularly amongst elderly people. This article examines selected heat wave response plans at national, state/provincial, and municipal levels, with a particular focus on specific responses aimed at residents of aged care facilities. We sourced heat wave response plans from several countries that are experiencing a demographic transition that features a growing aging population. We collected a total of 23 heat wave response plans; most of those plans were from Australia, with only three plans each available from Canada and the UK, and only two available from the U.S. Key components found across the plans were analysis of temperature thresholds, heat stress prevention measures, and communication strategies. Only three heat wave response plans that were analyzed included specific guidance for aged care facilities. Projected increases in frequency and duration of heat waves in coming decades underline the need for governments to implement effective guidelines that include specific provisions for aged care facilities. PMID- 29148658 TI - Authors' response. PMID- 29148659 TI - EDTA - Factual disputes. PMID- 29148660 TI - Crumbine Award Winner Continues to Build Capacity. PMID- 29148661 TI - Authors' reply. PMID- 29148662 TI - A rare presentation of a primary diffuse large B-cell lymphoma of the oral cavity. PMID- 29148664 TI - Dental implications of novel oral anticoagulants. PMID- 29148665 TI - An interesting development. PMID- 29148666 TI - Clinical Challenges Q&A: Clinical Challenges Q&A 22. Red Mark on Face and Lip. PMID- 29148667 TI - Technique Tips: Technique Tips - The Natural Tooth Pontic: A Novel Approach. PMID- 29148668 TI - The commoditization of choice. PMID- 29148669 TI - The 'Uberization of orthodontics' - or how low can you go? PMID- 29148670 TI - Using the National Environmental Assessment Reporting System to Enhance Foodborne Illness Outbreak Investigations in New York City Restaurants. PMID- 29148671 TI - Resin-Bonded Bridges - the Problem or the Solution? Part 2: Practical Techniques. AB - This is the second part of this two-part series. The first paper discussed key aspects of case selection, planning and design of resin-bonded bridges (RBBs). This paper outlines the important clinical stages involved in the successful provision of RBBs, including communication with the dental laboratory, clinical protocols and management of the de-bonded RBB. Clinical relevance: This paper aims to provide the general dental practitioner with a practical guide to the successful provision of RBBs, highlighting common barriers to successful treatment and how these may be overcome. PMID- 29148672 TI - The Management of the Dilacerated Impacted Maxillary Central Incisor. AB - The clinical problem of how best to manage a dilacerated, impacted maxillary central incisor will only be encountered rarely. The treatment aim should be to achieve results that are indistinguishable from normal appearance in a way that is appropriate for the patient. This article discusses the incidence of dilacerations in maxillary incisors and describes the treatment approaches available - orthodontic alignment or surgical removal and management of the resulting space, considering orthodontic repositioning, autotransplantation and various prosthetic replacements. Treatment indications, advantages and disadvantages, restorative and surgical implications, as well as the evidence base relating to the various treatment modalities will be presented, along with clinical case examples. Clinical relevance: This paper discusses a problem that, if not managed appropriately, can lead to poor results for the patient. Even for practitioners who may not undertake the treatment mentioned, it will enable them to have more in-depth discussion with their patients should the situation arise. PMID- 29148673 TI - Mouthwashes: Do They Work and Should We Use Them? Part 2: Anticaries, Antihalitosis and Dry Mouth Relief Efficacy of Mouthwashes. AB - This article will review the anticaries, antihalitosis and dry mouth relief efficacy of mouthwashes. Fluoride mouthwashes may provide an additional benefit to toothpaste and gel in children with a high risk of dental caries, but toothpaste alone may be a more acceptable mode of delivery. There may be a beneficial effect of fluoride mouthwashes on caries levels in older adults, particularly those at higher risk of root caries. The available data of the antihalitosis effect of mouthwashes neither supports nor contra-indicates their use. The key area where a mouthwash may be of use in the treatment of patients with a dry mouth is through the anticaries effect of fluoride. Clinical relevance: The evidence supporting the use of anticaries, antihalitosis and dry mouth relief mouthwashes is evaluated. This provides guidance for dentists and dental care professionals of when it is appropriate to recommend the use of a mouthwash in these situations. PMID- 29148674 TI - Amyloidosis Presenting as Macroglossia and Restricted Tongue Movement. AB - Amyloidosis (AL) is a well recognized cause of macroglossia. A case of localized deposition of systemic amyloidosis secondary to multiple myeloma is reported in a 63-year-old female presenting with restricted tongue movement in the dental setting. Amyloidosis secondary to multiple myeloma is well documented in the literature, with amyloid deposits being found at various sites throughout the oral cavity and systemically. This case emphasizes the importance of a full oral soft tissue examination, including the need to examine mobility of the tissues, as it was the restricted movement of the tongue that ultimately alerted the clinician to the diagnosis. This report also highlights other dental implications of managing patients with multiple myeloma and amyloidosis. Clinical relevance: To provide an understanding of what multiple myeloma and amyloidosis are whilst, importantly, relating this to how these conditions can impact on routine dental treatment. PMID- 29148675 TI - A Case Series: The Orthodontic Management of Central Incisors with Horizontal Root Fractures. AB - This case series illustrates the successful orthodontic management of previously root-fractured central incisors. Orthodontic treatment was carried out to correct the underlying malocclusion, remove traumatic occlusal forces and to provide a suitable occlusion for future restorative treatment should the root-fractured teeth be lost in the future. Clinical relevance: Dental trauma occurs commonly; having affected 10% of orthodontic patients. All practitioners should be able to discuss the possibility of orthodontic treatment with patients who have had previous trauma to their front teeth. PMID- 29148676 TI - Managing the Unstable Mandibular Complete Denture - Tooth Placement and the Polished Surface. AB - Constructing satisfactory conventional mandibular complete dentures is often challenging in comparison to the upper counterpart partially due to differences in the anatomy of the denture-bearing area. This problem is exaggerated in the atrophic mandible, where supporting structures are frequently ill-defined and suboptimal in quality. Implant-retained prostheses offer well recognized benefits but are not always a feasible options, so conventional methods must be relied upon. The importance of impression quality and registration has been reviewed previously. This article aims to discuss the influence of tooth placement, the polished surfaces and the neutral zone on the success of lower dentures. Clinical relevance: This article highlights the importance that polished surface contouring and tooth prescription can have on the outcome of lower dentures. Techniques for assessing and recording the neutral zone are explained, along with alternative occlusal schemes. PMID- 29148677 TI - Mouth Cancer for Clinicians Part 13: Life After Mouth Cancer Treatment. AB - A MEDLINE search early in 2015 revealed more than 250,000 papers on head and neck cancer; over 100,000 on oral cancer; and over 60,000 on mouth cancer. Not all publications contain robust evidence. We endeavour to encapsulate the most important of the latest information and advances now employed in practice, in a form comprehensible to healthcare workers, patients and their carers. This series offers the primary care dental team, in particular, an overview of the aetiopathogenesis, prevention, diagnosis and multidisciplinary care of mouth cancer, the functional and psychosocial implications, and minimization of the impact on the quality of life of patient and family. Clinical relevance: This article offers the dental team an overview of prognostication, quality of life and oral and dental healthcare. PMID- 29148678 TI - DirecTalk: Musings From the 10th Floor: Connectivity Is Power. PMID- 29148679 TI - Human Factors and Ergonomics for the Dental Profession. AB - This paper proposes that the science of Human Factors and Ergonomics (HFE) is suitable for wide application in dental education, training and practice to improve safety, quality and efficiency. Three areas of interest are highlighted. First it is proposed that individual and team Non-Technical Skills (NTS), such as communication, leadership and stress management can improve error rates and efficiency of procedures. Secondly, in a physically and technically challenging environment, staff can benefit from ergonomic principles which examine design in supporting safe work. Finally, examination of organizational human factors can help anticipate stressors and plan for flexible responses to multiple, variable demands, and fluctuating resources. Clinical relevance: HFE is an evidence-based approach to reducing error rates and procedural complications, and avoiding problems associated with stress and fatigue. Improved teamwork and organizational planning and efficiency can impact directly on patient outcomes. PMID- 29148680 TI - Clinical Challenges Q&A 23. Lip Swelling. PMID- 29148681 TI - Technique Tips: Technique Tips - Removing a fractured root tip with a Hedstrom endodontic file. PMID- 29148682 TI - A tale of two sisters. PMID- 29148683 TI - Counterfeit and Non-Compliant Dental Devices: The Dangers and How to Mitigate Them. AB - The Medicines and Healthcare products Regulatory Agency (MHRA) is dealing with a growing number of counterfeit and non-compliant dental devices and instruments for sale to dental practices in the UK. This paper examines the extent of the issue, the dangers posed by the use of counterfeit and non-compliant products, discusses initiatives to address the problem and how the dental team can identify these products and mitigate the associated risks. Clinical relevance: To ensure that all members of the dental team are aware of the dangers posed by counterfeit and non-compliant dental devices and instruments and how to mitigate such risks. PMID- 29148684 TI - Tooth Decorations and Modifications - Current Trends and Clinical Implications. AB - Since earliest times, humans have felt the need to modify and beautify their bodies. Adornments in the form of tooth decorations have featured around the world for generations and continue to evolve. This paper describes current and forthcoming trends. It explores the use of tooth jewels, 'dental grills' and tooth tattoos which are not yet common in the UK, but are currently trending in the United States of America. This article reviews the literature and aims to describe the clinical effects each tooth decoration has on the dentition, along with appropriate management strategies. Owing to the lack of good quality studies, it is difficult to determine accurate effects on the dentition, but dental practitioners should focus on conservative and preventive management strategies. Clinical relevance: This paper describes modern day tooth decorations, explores the possible effects on oral health and suggests management strategies. PMID- 29148685 TI - Modern Endodontic Principles Part 7: The Restorative Interface. AB - The restoration of endodontically-treated teeth is a topic that has been extensively studied and yet remains controversial. The endodontically-treated tooth can be restored with a wide range of techniques of varying complexity. This article reviews the literature on this topic. Consideration is given to the ferrule and its importance in achieving success. Furthermore, consideration will be given to the use of endodontically-treated teeth as abutments for fixed and removable prostheses and the challenges this presents. Clinical recommendations are presented as guidelines to improve the predictability and outcome of treatment when restoring structurally compromised root-filled teeth. Clinical relevance: The prognosis of endodontically-treated teeth depends not only on the success of the endodontic treatment, but also on the type of reconstruction. PMID- 29148686 TI - Oral Cancer Red Flags - A Case of Misdiagnosis. AB - The clinical presentations of oral malignancy are diverse. This short article discusses a case of a late-presenting oral malignancy and signifies the importance of general dental and medical practitioners' knowledge in the diagnosis of oral malignancy. Clinical relevance: Oral malignancy is a life threatening diagnosis. The importance of a structured systematic approach in the diagnosis is discussed. PMID- 29148687 TI - Pain Part 9: Trigeminal Autonomic Cephalalgias. AB - The trigeminal autonomic cephalalgias are a group of rare, highly disabling, primary headache syndromes distinctly characterized by the unilaterality of their attacks and presence of cranial autonomic symptoms. Although pain is often localized to the peri-orbital and temporal regions, it is not uncommon for pain to radiate to tooth-bearing areas and mimic toothache or jaw pain. Hence, dental practitioners should be aware of these syndromes to enable appropriate referral and avoid unnecessary, and often irreversible, dental treatments. Many dentists will not have heard of these conditions but must remain vigilant, and ensure that they are not confused with trigeminal neuralgia, so that their patients are appropriately advised and referred. Clinical relevance: The dental practitioners may be the first line of healthcare providers consulted by these patients in the hope of obtaining pain relief. Lack of familiarity with an uncommon condition may lead to poor patient management. PMID- 29148688 TI - Spontaneous Oral Mucosal Bleeding Unmasking Undiagnosed Sarcoidosis: A Case Report. AB - Sarcoidosis is a multisystem, non-caseating, chronic, granulomatous disease affecting any organ. In the head and neck region, salivary glands and lymph nodes are most commonly involved. Oral manifestations are rare but these lesions, occasionally haemorrhagic, may be the first sign of systemic disease. It is important to recognize the oral manifestations of sarcoidosis and to be aware of potential secondary disease-driven processes, such as thrombocytopenia. The purpose of this paper is to present a previously undiagnosed case of sarcoidosis, initially presenting with oral manifestations, including mucosal bleeding, and to review the current literature on oral sarcoidosis. Clinical relevance: Oral lesions can be the first sign of undiagnosed systemic sarcoidosis. PMID- 29148689 TI - The Prosthodontic Pathway for Patients with Anomalies Affecting Tooth Structure. AB - There are a number of anomalies that affect the structure of the dental hard tissues which impact upon the form, function and aesthetics of the dentition. Understanding the challenges these conditions pose will enable dentists to manage the functional and aesthetic problems with restorative techniques better. This article will present cases that demonstrate the different conditions, the restorative challenges experienced and a variety of restorative treatments in the management of these conditions. Clinical relevance: Awareness of different anomalies affecting tooth structure that may present to the dental practitioner is necessary. Clinicians should appreciate the specific restorative challenges that may arise in treating such patients and the possible treatment options that may be available. PMID- 29148690 TI - Mouth Cancer for Clinicians Part 10: Cancer Treatment (Surgery). AB - A MEDLINE search early in 2015 revealed more than 250,000 papers on head and neck cancer; over 100,000 on oral cancer; and over 60,000 on mouth cancer. Not all publications contain robust evidence. We endeavour to encapsulate the most important of the latest information and advances now employed in practice, in a form comprehensible to healthcare workers, patients and their carers. This series offers the primary care dental team in particular, an overview of the aetiopathogenesis, prevention, diagnosis and multidisciplinary care of mouth cancer, the functional and psychosocial implications, and minimization of the impact on the quality of life of patient and family. Clinical relevance: This article offers the dental team an overview of surgery for the treatment of mouth cancer. PMID- 29148691 TI - Adult Dental Anxiety: Recent Assessment Approaches and Psychological Management in a Dental Practice Setting. AB - Dental anxiety of patients is a common feature of the everyday experience of dental practice. This article advocates the use of regular assessment of this psychological construct to assist in patient management. Various tools, such as the Modified Dental Anxiety Scale (MDAS), are available to monitor dental anxiety that are quick to complete and easy to interpret. Patient burden is low. A new mobile phone assessment system (DENTANX) is being developed for distribution. This application and other psychological interventions are being investigated to assist patients to receive dental care routinely. Clinical relevance: This article provides evidence and expert opinion on the worth of regular dental anxiety assessment in dental practice using structured tools, such as the Modified Dental Anxiety Scale, and consideration of psychological intervention development. PMID- 29148692 TI - Clinical Challenges Q&A 20. Polyp in the Upper Alveolar Mucosa. PMID- 29148693 TI - Technique Tips - A Predictable Method for Retrieval of Silver Cones Using Ultrasonics. PMID- 29148694 TI - Ambient Aqueous Synthesis of Ultrasmall Ni0.85Se Nanoparticles for Noninvasive Photoacoustic Imaging and Combined Photothermal-Chemotherapy of Cancer. AB - Large-size-induced long-term retention in the body has hampered the translational applications of many reported nanomedicines. Herein, we reported a multifunctional theranostic agent composed of ultrasmall poly(acrylic acid) functionalized Ni0.85Se nanoparticles (PAA-Ni0.85Se NPs), which were successfully obtained through a facile ambient aqueous precipitation strategy. Without exhibiting any noticeable toxicity, the as-prepared PAA-Ni0.85Se NPs (average diameter of 6.40 +/- 1.89 nm) showed considerable absorption in near-infrared (NIR) region and high photothermal conversion efficiency of 54.06%, which could induce remarkable photoacoustic signals for tumor imaging and heat for localized ablation of cancerous cells upon exposure to NIR light. Notably, the ultrasmall PAA-Ni0.85Se NPs, unlike conventional nanomaterials with larger sizes, showed reasonable body clearance within 8 h after intravenous injection. Furthermore, ascribed to protonation process of amino groups in DOX molecules and carboxyl groups in PAA molecules in an acidic microenvironment, the drug-loaded (doxorubicin hydrochloride, DOX.HCl) PAA-Ni0.85Se NPs (PAA-Ni0.85Se-DOX NPs) revealed promoted drug release at acidic pH, which could be useful for acidic tumor microenvironment responsive drug delivery. Evident from the results of cell killing assay in vitro and tumor treatment study in vivo, PAA-Ni0.85Se-DOX NPs exhibited evident synergistic effects on killing 4T1 breast cancer cells. Thus, this study presents a multifunctional theranostic agent composed of ultrasmall PAA-Ni0.85Se NPs for potential cancer treatment without long-term toxicity concerns. PMID- 29148695 TI - High-Thermal- and Air-Stability Cathode Material with Concentration-Gradient Buffer for Li-Ion Batteries. AB - Delivery of high capacity with high thermal and air stability is a great challenge in the development of Ni-rich layered cathodes for commercialized Li ion batteries (LIBs). Herein we present a surface concentration-gradient spherical particle with varying elemental composition from the outer end LiNi1/3Co1/3Mn1/3O2 (NCM) to the inner end LiNi0.8Co0.15Al0.05O2 (NCA). This cathode material with the merit of NCM concentration-gradient protective buffer and the inner NCA core shows high capacity retention of 99.8% after 200 cycles at 0.5 C. Furthermore, this cathode material exhibits much improved thermal and air stability compared with bare NCA. These results provide new insights into the structural design of high-performance cathodes with high energy density, long life span, and storage stability materials for LIBs in the future. PMID- 29148696 TI - Epidermal Penetration of Gold Nanoparticles and Its Underlying Mechanism Based on Human Reconstructed 3D Episkin Model. AB - Nanomaterials are widely used in diverse aspects, and their translocation behavior through the skin would be helpful in understanding the corresponding exposure risks. To reveal how surface functionalization of nanoparticles influences the skin penetration, three kinds of gold nanoparticles (GNPs) with negatively, neutrally, and positively charged surfaces, that is, cetyltrimethylammonium bromide-coated GNPs (CTAB@GNP), polyvinylpyrrolidone coated GNPs (PVP@GNP), and citrate-coated GNPs (Citrate@GNP), were studied using human reconstructed 3D Episkin model. The measurement of Au distribution in diverse layers of the Episkin model indicated that all three GNPs could penetrate through the epidermis, wherein CTAB@GNP with positive surface charges exhibited the highest efficiency in skin penetration. The upward osmosis of the medium proteins confirmed the occurrence of skin permeation induced by GNP treatment, and the lipid network in the stratum corneum was also altered as the consequence of GNP exposure. When compared to Citrate@GNP and PVP@GNP, CTAB@GNP significantly compromised the tight junction of keratinocytes, causing paracellular penetration of nanoparticles. The existence of cytoplasmic gold showed the transcytosis pathway through endocytosis and exocytosis processes was the main epidermic penetration behavior of the tested GNPs. The study on GNP penetration process through the 3D Episkin model has, on one hand, offered a promising approach to evaluate the translocation process of nanoparticles across the skin, and, on the other hand, provided mechanism explanation for diverse penetration behaviors of GNPs with different surface charges. The findings herein would be of great help in nanotechnology improvement and nanosafety evaluation. PMID- 29148697 TI - Synthesis of Hierarchical Sisal-Like V2O5 with Exposed Stable {001} Facets as Long Life Cathode Materials for Advanced Lithium-Ion Batteries. AB - Vanadium pentoxide (V2O5) is considered a promising cathode material for advanced lithium-ion batteries owing to its high specific capacity and low cost. However, the application of V2O5-based electrodes has been hindered because of their inferior conductivity, cycling stability, and power performance. Herein, hierarchical sisal-like V2O5 microstructures consisting of primary one dimensional (1D) nanobelts with [001] facets orientation growth and rich oxygen vacancies are synthesized through a facile hydrothermal process using polyoxyethylene-20-cetyl-ether as the surface control agent, followed by calcination. The primary 1D nanobelt shortens the transfer path of electrons and ions, and the stable {001} facets could reduce the side reaction at the interface of electrode/electrolyte, simultaneously. Moreover, the formation of low valence state vanadium would generate the oxygen vacancies to facilitate lithium-ion diffusion. As a result, the sisal-like V2O5 manifests excellent electrochemical performances, including high specific capacity (297 mA h g-1 at a current of 0.1 C) and robust cycling performance (capacity fading 0.06% per cycle). This work develops a controllable method to craft the hierarchical sisal-like V2O5 microstructures with excellent high rate and long-term cyclic stability. PMID- 29148699 TI - Controlling Ligand Spacing on Surface: Polyproline-Based Fluorous Microarray as a Tool in Spatial Specificity Analysis and Inhibitor Development for Carbohydrate Protein Interactions. AB - Multivalent carbohydrate-protein interactions are essential for many biological processes. Convenient characterization for multivalent binding property of proteins will aid the development of molecules to manipulate these processes. We exploited the polyproline helix II (PPII) structure as molecular scaffolds to adjust the distances between glycan ligand attachment sites at 9, 18, and 27 A on a peptide scaffold. Optimized fluorous groups were also introduced to the peptide scaffold for immobilization to the microarray surface through fluorous interaction to control the orientation of the helical scaffolds. Using lectin LecA and antibody 2G12 as model proteins, the binding preference to the 27 A glycopeptide scaffold, matched the distance of 26 A between its two galactose binding sites on LecA and 31 A spacing between oligomannose binding sites on 2G12, respectively. We further demonstrate this microarray system can aid the development of inhibitors by transforming the selected surface-bound scaffold into multivalent ligands in solution. This strategy can be extended to analyze proteins that lacking structural information to speed up the design of potent and selective multivalent ligands. PMID- 29148698 TI - Chelator-Free Conjugation of 99mTc and Gd3+ to PEGylated Nanographene Oxide for Dual-Modality SPECT/MR Imaging of Lymph Nodes. AB - PEGylated ultrasmall nanographene oxide (usNGO-PEG) has exhibited a great potential in nanotheranostics due to its newly discovered physicochemical properties derived from the rich functional groups and bonds. Herein, we developed a general, simple, and kitlike preparation approach for 99mTc- and Gd anchored NGO-PEG using a chelator-free strategy. In this strategy, [99mTcI(CO)3(OH2)3]+ (abbreviated to 99mTcI) and GdCl3 were mixed with usNGO-PEG to yield 99mTc- and Gd-usNGO-PEG via the synergistic coordination of N and O atoms from NGO and PEG with 99mTcI and Gd3+ without additional exogenous chelators. Under optimized conditions, the nanoprobes 99mTc- and Gd-usNGO-PEG were reliably prepared with high yields and good stability. Serial comparative experiments of the labeling yield, the measurements of -NH2 density and zeta potentials, and various characterizations including energy-dispersive X-ray analysis spectroscopy, X-ray photoelectron spectroscopy, and Fourier-transform infrared spectroscopy demonstrated that both usNGO and PEG synergistically provide the electron-donating atoms O and N to coordinate with 99mTcI and Gd to form stable nanocomplexes. Furthermore, both 99mTc- and Gd-usNGO-PEG exhibited excellent in vivo imaging of lymph nodes using single-photon emission computed tomography/computed tomography (SPECT/CT) and magnetic resonance (MR) imaging after local injection. Therefore, these results showed the successful establishment of 99mTc- and Gd-anchored usNGO-PEG using a chelator-free strategy and the potential of multimodality SPECT/CT and MR imaging of lymph nodes. PMID- 29148700 TI - Selective pH-Responsive Core-Sheath Nanofiber Membranes for Chem/Bio/Med Applications: Targeted Delivery of Functional Molecules. AB - Core-sheath fibers using different Eudragit materials were successfully produced, and their controlled multi-pH responses have been demonstrated. Core-sheath fibers made of Eudragit L 100 (EL100) core and Eudragit S 100 (ES100) sheath provide protection and/or controlled release of core material at pH 6 by adjusting the sheath thickness (controlled by the flow rate of source polymer solution). The thickest sheath (~250 nm) provides the least core release ~1.25%/h, while the thinnest sheath (~140 nm) provides much quicker release ~16.75%/h. Furthermore, switching core and sheath material dramatically altered the pH response. Core-sheath fibers made of ES100 core and EL100 sheath can provide a consistent core release rate, while the sheath release rate becomes higher as the sheath layer becomes thinner. For example, the thinnest sheath (~120 nm) provides a core and sheath release ratio of 1:2.5, while the thickest sheath (~200 nm) shows only a ratio of 1:1.7. All core-sheath Eudragit fibers show no noticeable release at pH 5, while they are completely dissolved at pH 7. Extremely high surface area in the porous network of the fiber membranes provides much faster (>30 times) response to external pH changes as compared to that of equivalent cast films. PMID- 29148701 TI - Metal-Organic Framework-Derived Metal Oxide Embedded in Nitrogen-Doped Graphene Network for High-Performance Lithium-Ion Batteries. AB - Metal-organic frameworks (MOFs) are hybrid inorganic-organic materials that can be used as effective precursors to prepare various functional nanomaterials for energy-related applications. Nevertheless, most MOF-derived metal oxides exhibit low electrical conductivity and mechanical strain. These characteristics limit their electrochemical performance and hamper their practical application. Herein, we report a rational strategy for enhancing the lithium storage performance of MOF-derived metal oxide. The hierarchically porous Co3O4@NGN is successfully prepared by embedding ZIF-67-derived Co3O4 particles in a nitrogen-doped graphene network (NGN). The high electrical conductivity and porous structure of the NGN accelerates the diffusion of electrolyte ions and buffers stress resulting from the volume changes of Co3O4. As an anode material, the Co3O4@NGN shows high capacity (1030 mA h g-1 at 100 mA g-1), outstanding rate performance (681 mA h g 1 at 1000 mA g-1), and good cycling stability (676 mA h g-1 at 1000 mA g-1 after 400 cycles). PMID- 29148702 TI - Influence of Particle Geometry on Gastrointestinal Transit and Absorption following Oral Administration. AB - Geometry has been considered as one of the important parameters in nanoparticle design because it affects cellular uptake, transport across the physiological barriers, and in vivo distribution. However, only a few studies have been conducted to elucidate the influence of nanoparticle geometry in their in vivo fate after oral administration. This article discloses the effect of nanoparticle shape on transport and absorption in gastrointestinal (GI) tract. Nanorods and nanospheres were prepared and labeled using fluorescence resonance energy transfer molecules to track the in vivo fate of intact nanoparticles accurately. Results demonstrated that nanorods had significantly longer retention time in GI tract compared with nanospheres. Furthermore, nanorods exhibited stronger ability of penetration into space of villi than nanospheres, which is the main reason of longer retention time. In addition, mesenteric lymph transported 1.75% nanorods within 10 h, which was more than that with nanospheres (0.98%). Fluorescent signals arising from nanoparticles were found in the kidney but not in the liver, lung, spleen, or blood, which could be ascribed to low absorption of intact nanoparticles. In conclusion, nanoparticle geometry influences in vivo fate after oral delivery and nanorods should be further investigated for designing oral delivery systems for therapeutic drugs, vaccines, or diagnostic materials. PMID- 29148703 TI - Bond-Energy-Driven, Low- or High-Angle-Grain-Boundary-Movement-Mediated Synthesis of Porous Se-Te for Use in Water-Splitting Reactions. AB - Herein, for the first time, we applied the metal-metal-bond-energy factor to the evolution of a porous Se-Te alloy. The porous Se-Te material has been prepared from the constituents' elemental states, through only a heating-cooling process in silicone oil without the use of any reagent, surfactant, or capping agent. Surprisingly, the reaction occurred at a much lower temperature (240 degrees C) than the mp (450 degrees C) of Te0. The reaction's nucleation and growth by means of varied bond energy have been clarified for the first time. A difference in the bond energies of a hetero metal-metal bond (Se-Te) and a homo metal-metal bond (Se-Se) directs nucleation and growth toward the fabrication of a porous structure, even from the constituents' elemental states, in which low-angle-grain boundary (LAGB) and high-angle-grain-boundary (HAGB) movements play governing roles. Proper band-gap alignment of Se and Te makes the alloy composite applicable to water-splitting reactions under Xe-arc-lamp illumination. PEC efficiency of Se-Te was found to be higher than those reported for Se and other composite materials. PMID- 29148704 TI - Electrospun Poly(3-hydroxybutyrate-co-4-hydroxybutyrate)/Graphene Oxide Scaffold: Enhanced Properties and Promoted in Vivo Bone Repair in Rats. AB - Bone tissue engineering emerges as an advantageous technique to achieve tissue regeneration. Its scaffolds must present excellent biomechanical properties, where bare polymers poorly perform. Development of new biomaterials with high osteogenic capacity is urgently pursued. In this study, an electrospun poly(3 hydroxybutyrate-co-4-hydroxybutyrate)/graphene oxide (P34HB/GO) nanofibrous scaffold is successfully fabricated and characterized. The effects of GO amount on scaffold morphology, biomechanical properties, and cellular behaviors are investigated. GO reduces the fiber diameter and enhances porosity, hydrophilicity, mechanical properties, cellular performance, and osteogenic differentiation of scaffolds. P34HB/GO triumphs over P34HB in in vivo bone regeneration in critical-sized calvarial defect of rats. We believe that this study is the first to evaluate the capability of in vivo bone repair of electrospun P34HB/GO scaffold. With facile fabrication process, favorable porous structures, enhanced biomechanical properties, and fast osteogenic capability, P34HB/GO scaffold holds practical potentials for bone tissue engineering application. PMID- 29148705 TI - Li+-Desolvation Dictating Lithium-Ion Battery's Low-Temperature Performances. AB - Lithium (Li) ion battery has penetrated almost every aspect of human life, from portable electronics, vehicles, to grids, and its operation stability in extreme environments is becoming increasingly important. Among these, subzero temperature presents a kinetic challenge to the electrochemical reactions required to deliver the stored energy. In this work, we attempted to identify the rate-determining process for Li+ migration under such low temperatures, so that an optimum electrolyte formulation could be designed to maximize the energy output. Substantial increase in the available capacities from graphite?LiNi0.80Co0.15Al0.05O2 chemistry down to -40 degrees C is achieved by reducing the solvent molecule that more tightly binds to Li+ and thus constitutes a high desolvation energy barrier. The fundamental understanding is applicable universally to a wide spectrum of electrochemical devices that have to operate in similar environments. PMID- 29148706 TI - Porous Carbon with Willow-Leaf-Shaped Pores for High-Performance Supercapacitors. AB - A novel kind of biomass-derived, high-oxygen-containing carbon material doped with nitrogen that has willow-leaf-shaped pores was synthesized. The obtained carbon material has an exotic hierarchical pore structure composed of bowl-shaped macropores, willow-leaf-shaped pores, and an abundance of micropores. This unique hierarchical porous structure provides an effective combination of high current densities and high capacitance because of a pseudocapacitive component that is afforded by the introduction of nitrogen and oxygen dopants. Our synthetic optimization allows further improvements in the performance of this hierarchical porous carbon (HPC) material by providing a high degree of control over the graphitization degree, specific surface area, and pore volume. As a result, a large specific surface area (1093 m2 g-1) and pore volume (0.8379 cm3 g-1) are obtained for HPC-650, which affords fast ion transport because of its short ion diffusion pathways. HPC-650 exhibits a high specific capacitance of 312 F g-1 at 1 A g-1, retaining 76.5% of its capacitance at 20 A g-1. Moreover, it delivers an energy density of 50.2 W h kg-1 at a power density of 1.19 kW kg-1, which is sufficient to power a yellow-light-emitting diode and operate a commercial scientific calculator. PMID- 29148707 TI - Versatile Supermolecular Inclusion Complex Based on Host-Guest Interaction for Targeted Gene Delivery. AB - A facile and targeted gene delivery system was prepared by conjugating beta cyclodextrin modified polyethylenimine (PEI-CD) and adamantyl peptide (AdGRGDS) based on host-guest interaction. With the rational design between PEI-CD and AdGRGDS, the PEI-CD/AdGRGDS gene delivery system showed excellent DNA binding capability and exhibited good ability to compact DNA into uniform spherical nanoparticles. In vitro luciferase assay showed that gene expression transfected by PEI-CD/AdGRGDS was stronger than that by PEI-CD in HeLa cells, whereas gene expression transfected by PEI-CD/AdGRGDS and PEI-CD was similar to each other in COS7 cells. Internalization of complexes was qualitatively studied using a confocal laser scanning microscope (CLSM) and quantitatively analyzed by flow cytometry, respectively, and targeting specificity was also evaluated by CLSM. Results of CLSM and flow cytometry indicated that PEI-CD/AdGRGDS had good targeting specificity to tumor cells with integrin alphavbeta3 overexpression. To further evaluate the targeting specificity and transfection efficiency in vivo, a rat model with murine hepatic carcinoma cell line H22 was used. PEI-CD/AdGRGDS showed stronger gene expression efficiency than PEI-CD via in vivo transfection of pORF-LacZ and pGL-3 plasmids after subcutaneous injection. Interestingly, PEI CD/AdGRGDS also showed high targeting specificity and transfection distribution to tumor xenograft after tail-vein injection. In vitro and in vivo assays highlighted the importance of GRGDS targeting specificity to tumor cells with integrin alphavbeta3 overexpression and demonstrated that the PEI-CD/AdGRGDS gene delivery system would have great potential for targeted tumor therapy. PMID- 29148708 TI - Magnetron Sputtering Deposition Cu@Onion-like N-C as High-Performance Electrocatalysts for Oxygen Reduction Reaction. AB - The idea of a core-shell structure can promote the utilization of nonprecious metallic catalysts by enhancing their activity and stability for the oxygen reduction reaction (ORR). Developing a low-cost, high-efficiency, and high reproducibility method for synthesizing core-shell-structured materials represents an urgent challenge. Here, we fabricate encapsulated Cu nanoparticles with nitrogen-doped onion-like graphite nanoshells (Cu@onion-like N-C) as an efficient ORR catalyst by magnetron sputtering, in which the graphite shells grow by an in situ self-assembly process activated by the surface-catalyzed behavior with Cu nanoparticles. The results show that the CuCN-650 degrees C catalyst achieves the optimized Cu@onion-like N-C structure with small-sized Cu nanoparticles and a few-layer nanoshells and exhibits excellent ORR electrocatalytic properties, including a half-wave potential and onset potential similar to those of commercial Pt/C, coupled with better stability and higher methanol tolerance than for commercial Pt/C in alkaline electrolytes. The internal Cu nanoparticles in the core-shell structure not only promote the formation of a high content of pyridinic N but also donate the electronic charges to outer N-doped C shells, and thus the synergistic effect between the encapsulated Cu nanoparticles and N-doped C shells is responsible for the excellent electrocatalytic activity for the ORR. PMID- 29148709 TI - NIR Emitting Nanoprobes Based on Cyclic RGD Motif Conjugated PbS Quantum Dots for Integrin-Targeted Optical Bioimaging. AB - Here, silica-coated PbS quantum dots (QDs) with photoluminescence emission properties in the near-infrared (NIR) region are proposed as potential effective single particle optical nanoprobes for future in vivo imaging of tumors. The dispersibility in aqueous medium of hydrophobic PbS QDs was accomplished by growing a silica shell on their surface by exploiting a base assisted water-in oil microemulsion method. The silica-coated PbS QDs were then conjugated with a specifically designed cyclic arginine-glycine-aspartic acid (cRGD) peptide that is able to specifically recognize alphavbeta3 integrins, which are overexpressed in angiogenic tumor-induced vasculatures and on some solid tumors, to achieve tumor-specific targeting. The cRGD peptide PbS silica-coated QDs were systematically characterized, at each step of their preparation, by means of complementary optical and structural techniques, demonstrating appropriate colloidal stability and the maintenance of their optical futures in aqueous solutions. The cellular uptake of cRGD peptide functionalized luminescent nanostructures in human melanoma cells, where overexpression of alphavbeta3 was observed, was assessed by means of confocal microscopy analysis and cytometric study. The selectivity of the cRGD peptide PbS silica-coated QDs for the alphavbeta3 integrin was established, consequently highlighting the significant potential of the developed NIR emitting nanostructures as optically traceable nanoprobes for future alphavbeta3 integrin receptor in vivo targeting in the NIR region. PMID- 29148710 TI - LipidQC: Method Validation Tool for Visual Comparison to SRM 1950 Using NIST Interlaboratory Comparison Exercise Lipid Consensus Mean Estimate Values. AB - As advances in analytical separation techniques, mass spectrometry instrumentation, and data processing platforms continue to spur growth in the lipidomics field, more structurally unique lipid species are detected and annotated. The lipidomics community is in need of benchmark reference values to assess the validity of various lipidomics workflows in providing accurate quantitative measurements across the diverse lipidome. LipidQC addresses the harmonization challenge in lipid quantitation by providing a semiautomated process, independent of analytical platform, for visual comparison of experimental results of National Institute of Standards and Technology Standard Reference Material (SRM) 1950, "Metabolites in Frozen Human Plasma", against benchmark consensus mean concentrations derived from the NIST Lipidomics Interlaboratory Comparison Exercise. PMID- 29148711 TI - Rational Manipulation of IrO2 Lattice Strain on alpha-MnO2 Nanorods as a Highly Efficient Water-Splitting Catalyst. AB - Developing more efficient and stable oxygen evolution reaction (OER) catalysts is critical for future energy conversion and storage technologies. We demonstrate that inducing a lattice strain in IrO2 crystal structure due to interface lattice mismatch enables an enhancement of the OER catalytic activity. The lattice strain is obtained by the direct growth of IrO2 nanoparticles on a specially exposed surface of alpha-MnO2 nanorods via a simple two-step hydrothermal synthesis. Interestingly, the prepared hydride OER activity increases with a lower IrO2 grown mass, which offers an opportunity to reduce the usage of precious iridium and ultimately obtains a specific mass activity of 3.7 times than that of IrO2 prepared under the same conditions and exhibits equivalent stability. The lattice mismatch in the underlying interface induces the formation of lattice strain in IrO2 rather than the charge transfer between the materials. The lattice strain changes are in good agreement with the order of the OER activity. Our experimental results indicate that using the special exposed surface substrates or tuning the supporting morphology structure can manipulate the catalyst materials lattice strain for the design of more efficient OER catalysts. PMID- 29148712 TI - Constructing Repairable Meta-Structures of Ultra-Broad-Band Electromagnetic Absorption from Three-Dimensional Printed Patterned Shells. AB - Ultra-broad-band electromagnetic absorption materials and structures are increasingly attractive for their critical role in competing with the advanced broad-band electromagnetic detection systems. Mechanically soft and weak wax based materials composites are known to be insufficient to serve in practical electromagnetic absorption applications. To break through such barriers, here we developed an innovative strategy to enable the wax-based composites to be robust and repairable meta-structures by employing a three-dimensional (3D) printed polymeric patterned shell. Because of the integrated merits from both the dielectric loss wax-based composites and mechanically robust 3D printed shells, the as-fabricated meta-structures enable bear mechanical collision and compression, coupled with ultra-broad-band absorption (7-40 and 75-110 GHz, reflection loss smaller than -10 dB) approaching state-of-the-art electromagnetic absorption materials. With the assistance of experiment and simulation methods, the design advantages and mechanism of employing such 3D printed shells for substantially promoting the electromagnetic absorption performance have been demonstrated. Therefore, such universal strategy that could be widely extended to other categories of wax-based composites highlights a smart stage on which high-performance practical multifunction meta-structures with ultra-broad-band electromagnetic absorption could be envisaged. PMID- 29148713 TI - Wireless Acoustic-Surface Actuators for Miniaturized Endoscopes. AB - Endoscopy enables minimally invasive procedures in many medical fields, such as urology. However, current endoscopes are normally cable-driven, which limits their dexterity and makes them hard to miniaturize. Indeed, current urological endoscopes have an outer diameter of about 3 mm and still only possess one bending degree-of-freedom. In this article, we report a novel wireless actuation mechanism that increases the dexterity and that permits the miniaturization of a urological endoscope. The novel actuator consists of thin active surfaces that can be readily attached to any device and are wirelessly powered by ultrasound. The surfaces consist of two-dimensional arrays of microbubbles, which oscillate under ultrasound excitation and thereby generate an acoustic streaming force. Bubbles of different sizes are addressed by their unique resonance frequency, thus multiple degrees-of-freedom can readily be incorporated. Two active miniaturized devices (with a side length of around 1 mm) are demonstrated: a miniaturized mechanical arm that realizes two degrees-of-freedom, and a flexible endoscope prototype equipped with a camera at the tip. With the flexible endoscope, an active endoscopic examination is successfully performed in a rabbit bladder. The results show the potential medical applicability of surface actuators wirelessly powered by ultrasound penetrating through biological tissues. PMID- 29148714 TI - Evaluating the Rate and Substrate Specificity of Laboratory Evolved XNA Polymerases. AB - Engineered polymerases that can copy genetic information between DNA and xeno nucleic acids (XNA) hold tremendous value as reagents in future biotechnology applications. However, current XNA polymerases function with inferior activity relative to their natural counterparts, indicating that current polymerase engineering efforts would benefit from new benchmarking assays. Here, we describe a highly parallel, low-cost method for measuring the average rate and substrate specificity of XNA polymerases in a standard qPCR instrument. Our approach, termed polymerase kinetic profiling (PKPro), involves monitoring XNA synthesis on a self-priming template using high-resolution melting (HRM) fluorescent dyes that intercalate into the growing duplex as the template strand is copied into XNA. Since changes in fluorescence are directly proportional to XNA synthesis, quantitative measurements are obtained by calibrating the fluorescent signal against chemically synthesized standards. Using PKPro, we discovered that XNA polymerases function with rates of ~1-80 nt/min and exhibit substrate specificities of ~0.1-5-fold for xNTP versus dNTP. Last, we show how PKPro could be used in a highly parallel screen by analyzing 288 different polymerase reaction conditions. On the basis of these results, we suggest that PKPro provides a powerful tool for evaluating the activity of XNA polymerases. PMID- 29148715 TI - Ultrafast Long-Range Charge Separation in Nonfullerene Organic Solar Cells. AB - Rapid, long-range charge separation in polymer-fullerene organic solar cells (OSCs) enables electrons and holes to move beyond their Coulomb capture radius and overcome geminate recombination. Understanding the nature of charge generation and recombination mechanisms in efficient, nonfullerene-acceptor-based OSCs are critical to further improve device performance. Here we report charge dynamics in an OSC using a perylene diimide (PDI) dimer acceptor. We use transient absorption spectroscopy to track the time evolution of electroabsorption caused by the dipolar electric field generated between electron hole pairs as they separate after ionization at the donor-acceptor interface. We show that charges separate rapidly (<1 ps) and that free charge carriers are generated very efficiently (~90% quantum yield). However, in the PDI-based OSC, external charge extraction is impaired by faster nongeminate decay to the ground state and to lower-lying triplet states. PMID- 29148716 TI - Rapid Quantification of 4,4'-Methylenedianiline by Surface-Enhanced Raman Spectroscopy. AB - Methylenedianiline (MDA) is a common industrial chemical with health and product safety concerns. Common analysis methods require many steps including extraction and derivatization ending in GC/MS or HPLC analysis, which minimize its use as an on-line or at-line technique. The procedure can take hours, prohibiting its use as a real-time decision-making tool as well as using valuable resources and laboratory space. The new method presented here has been validated for MDA quantification in industrial grease samples over the concentration range of 1-40 ppm 4,4'-MDA. We present comparative results to the currently accepted method with excellent fidelity. This analytical method using surface-enhanced Raman spectroscopy reduces sample preparation and analysis time by more than an hour while preserving method accuracy, specificity, and dynamic range. PMID- 29148717 TI - Raman Spectroscopy of Single Light-Absorbing Carbonaceous Particles Levitated in Air Using an Annular Laser Beam. AB - A laser trapping technique is a powerful means to investigate the physical and chemical properties of single aerosol particles in a noncontact manner. However, optical trapping of strongly light-absorbing particles such as black carbon or soot is quite difficult because the repulsive force caused by heat is orders of magnitude larger than the attractive force of radiation pressure. In this study, a laser trapping and Raman microspectroscopy system using an annular laser beam was constructed to achieve noncontact levitation of single light-absorbing particles in air. Single acetylene carbon black or candle soot particles were arbitrarily selected with a glass capillary connected to a three-axis oil hydraulic micromanipulator and introduced into a minute space surrounded by a repulsive force at the focal point of an objective lens. Using the developed system, we achieved optical levitation of micrometer-sized carbonaceous particles and observation of their Raman spectra in air. Furthermore, we demonstrated in situ observations of changes in the morphology and chemical composition of optically trapped carbonaceous particles in air, which were induced by heterogeneous oxidation reactions with ozone and hydroxyl radicals. PMID- 29148718 TI - Atomic-Layer Deposition of Single-Crystalline BeO Epitaxially Grown on GaN Substrates. AB - We have grown a single-crystal beryllium oxide (BeO) thin film on a gallium nitride (GaN) substrate by atomic-layer deposition (ALD) for the first time. BeO has a higher thermal conductivity, bandgap energy, and dielectric constant than SiO2. As an electrical insulator, diamond is the only material on earth whose thermal conductivity exceeds that of BeO. Despite these advantages, there is no chemical-vapor-deposition technique for BeO-thin-film deposition, and thus, it is not used in nanoscale-semiconductor-device processing. In this study, the BeO thin films grown on a GaN substrate with a single crystal showed excellent interface and thermal stability. Transmission electron microscopy showed clear diffraction patterns, and the Raman shifts associated with soft phonon modes verified the high thermal conductivity. The X-ray scan confirmed the out-of-plane single-crystal growth direction and the in-plane, 6-fold, symmetrical wurtzite structure. Single-crystalline BeO was grown on GaN despite the large lattice mismatch, which suggested a model that accommodated the strain of hexagonal-on hexagonal epitaxy with 5/6 and 6/7 domain matching. BeO has a good dielectric constant and good thermal conductivity, bandgap energy, and single-crystal characteristics, so it is suitable for the gate dielectric of power semiconductor devices. The capacitance-voltage (C-V) results of BeO on a GaN-metal-oxide semiconductor exhibited low frequency dispersion, hysteresis, and interface defect density. PMID- 29148719 TI - Effect of Antigen Retrieval Methods on Nonspecific Binding of Antibody-Metal Nanoparticle Conjugates on Formalin-Fixed Paraffin-Embedded Tissue. AB - Immunohistochemical analysis of formalin-fixed paraffin-embedded (FFPE) tissues provides important diagnostic and prognostic information in pathology. Metal nanoparticles (NPs) and, in particular, surface-enhanced Raman scattering (SERS) nanotags as a new class of labeling reagents are promising to be used for multiplexed protein profiling on tissue sections. However, nonspecific binding of NPs onto the tissue specimens greatly hampers their clinical applications. In this study, we found that the antigen retrieval method strongly influences the extent of nonspecific binding of the antibody-SERS NP conjugates to the tissue. Our SERS labels comprised ca. 70 nm Au nanostars coated with ethylene glycol modified Raman reporter molecules for hydrophilic stabilization and subsequent covalent bioconjugation to antibodies. We systematically investigated the influence of heat- and protease-induced epitope retrieval (HIER and PIER, respectively) on the immunostaining quality of prostate-specific antigen (PSA) on human prostate tissue sections. The best staining results were obtained with PIER. Pretreatment of the tissue sections by HIER led to selective but nonspecific adsorption of the antibody-Au nanostar conjugates onto epithelial cells, while enzymatic treatment within PIER did not. In addition to gold nanostars, also other types of metal NPs with different shapes and sizes (including ca. 20 nm quasi-spherical Au NPs and ca. 60 nm quasi-spherical Au/Ag nanoshells) as well as tissue sections from different organs (including prostate and breast) were tested; in each case the same tendency was observed, i.e., PIER yielded better results than HIER. Therefore, we recommend PIER for future NP based tissue immunostaining such as immuno-SERS microscopy. Alternatively, for antigens that can only be unmasked by heating, PEGylation of the NPs is recommended to avoid nonspecific binding. PMID- 29148721 TI - Ratiometric Fluorescence Sensing and Real-Time Detection of Water in Organic Solvents with One-Pot Synthesis of Ru@MIL-101(Al)-NH2. AB - Ratiometric fluorescence detection attracts much attention because of its decreased environmental influence and easy-to-differentiate color and intensity change. Herein, a guest-encapsulation metal-organic framework (MOF), Ru@MIL-NH2, is prepared with 2-aminoterephthalic acid, AlCl3, and Ru(bpy)32+ by a simple one pot method for ratiometric fluorescence sensing of water in organic solvents. The rational selection of the excitation wavelength provides dual emission at 465 and 615 nm from Ru@MIL-NH2 under a single excitation of 300 nm. High sensitivity, low detection limit (0.02% v/v), wide response range (0-100%), and fast response (less than 1 min) are obtained for ratiometric fluorescence sensing of water under single excitation with Ru@MIL-NH2 as the probe. Moreover, the result of water content is independent of the concentration of Ru@MIL-NH2 as the merit of ratiometric fluorescence detection. The response mechanism reveals that the protonation of the nitrogen atom of the MIL-NH2, the pi-conjugation system, and the stable fluorescence of Ru(bpy)32+ achieve the ratiometric fluorescence. The analysis of real spirit samples confirms the proposed method. A test strip is prepared with Ru@MIL-NH2 for convenient use. We believe that such turn-on ratiometric host-guest MOFs and the rational selection of excitation wavelength will offer guidance for ratiometric fluorescence detection with wide applications. PMID- 29148720 TI - Dual-Signal Readout Nanospheres for Rapid Point-of-Care Detection of Ebola Virus Glycoprotein. AB - Rapid detection of highly contagious pathogens is the key to increasing the probability of survival and reducing infection rates. We developed a sensitive and quantitative lateral flow assay for detection of Ebola virus (EBOV) glycoprotein with a novel multifunctional nanosphere (RNs@Au) as a reporter. Each RNs@Au contains hundreds of quantum dots and dozens of Au nanoparticles and can achieve enhanced dual-signal readout (fluorescence signal for quantitative detection and colorimetric signal for visual detection). Antibody (Ab) and streptavidin (SA) were simultaneously modified onto the RNs@Au to label the target and act as signal enhancer. After the target was labeled by the Ab-RNs@Au SA and captured on the test line, biotin-modified RNs@Au was used to amplify the dual signal by the reaction of SA with biotin. The assay enables naked-eye detection of 2 ng/mL glycoprotein within 20 min, and the quantitative detection limit is 0.18 ng/mL. Additionally, the assay has been successfully tested in field work for detecting EBOV in spiked urine, plasma, and tap water samples and is thus a promising candidate for early diagnosis of suspect infections in EBOV stricken areas. PMID- 29148722 TI - Acoustic Wave-Driven Functionalized Particles for Aptamer-Based Target Biomolecule Separation. AB - We developed a hybrid microfluidic device that utilized acoustic waves to drive functionalized microparticles inside a continuous flow microchannel and to separate particle-conjugated target proteins from a complex fluid. The acoustofluidic device is composed of an interdigitated transducer that produces high-frequency surface acoustic waves (SAW) and a polydimethylsiloxane (PDMS) microfluidic channel. The SAW interacted with the sample fluid inside the microchannel and deflected particles from their original streamlines to achieve separation. Streptavidin-functionalized polystyrene (PS) microparticles were used to capture aptamer (single-stranded DNA) labeled at one end with a biotin molecule. The free end of the customized aptamer15 (apt15), which was attached to the microparticles via streptavidin-biotin linkage to form the PS-apt15 conjugate, was used to capture the model target protein, thrombin (th), by binding at exosite I to form the PS-apt15-th complex. We demonstrated that the PS apt15 conjugate selectively captured thrombin molecules in a complex fluid. After the PS-apt15-th complex was formed, the sample fluid was pumped through a PDMS microchannel along with two buffer sheath flows that hydrodynamically focused the sample flow prior to SAW exposure for PS-apt15-th separation from the non-target proteins. We successfully separated thrombin from mCardinal2 and human serum using the proposed acoustofluidic device. PMID- 29148723 TI - DNA Microviscosity Characterization with Particle Diffusometry for Downstream DNA Detection Applications. AB - Analytical characterization of DNA microviscosity provides critical biophysical insights into nuclear crowding, nucleic acid based pharmaceutical development, and nucleic acid based biosensor device design. However, most viscosity characterization methods require large sample volumes and destructive testing. In contrast, particle diffusometry permits in situ analysis of DNA microviscosity with short measurement times (8 s) using small volumes (<3 MUL) which are compatible with DNA preparatory procedures. This unconventional biosensing approach involves measuring the change in sample viscosity using image processing and correlation-based algorithms. Particle diffusometry requires only a fluorescence microscope equipped with a charge-coupled device (CCD) camera and is a nondestructive measurement method. We use particle diffusometry to characterize the effect of DNA topology, length, and concentration on solution viscosity. In addition, we use particle diffusometry to detect the amplification of DNA from Staphylococcus aureus and Klebsiella pneumoniae, two pathogens commonly related to neonatal sepsis. Successful characterization of pathogen amplification with particle diffusometry provides a new opportunity to apply viscosity characterization toward downstream applications in nucleic acid based pathogen detection. PMID- 29148724 TI - Photooxidation of Aniline Derivatives Can Be Activated by Freezing Their Aqueous Solutions. AB - A combined experimental and computational approach was used to investigate the spectroscopic properties of three different aniline derivatives (aniline, N,N dimethylaniline, and N,N-diethylaniline) in aqueous solutions and at the air-ice interface in the temperature range of 243-298 K. The absorption and diffuse reflectance spectra of ice samples prepared by different techniques, such as slow or shock freezing of the aqueous solutions or vapor deposition on ice grains, exhibited unequivocal bathochromic shifts of 10-15 nm of the absorption maxima of anilines in frozen samples compared to those in liquid aqueous solutions. DFT and SCS-ADC(2) calculations showed that contaminant-contaminant and contaminant-ice interactions are responsible for these shifts. Finally, we demonstrate that irradiation of anilines in the presence of a hydrogen peroxide/O2 system by wavelengths that overlap only with the red-shifted absorption tails of anilines in frozen samples (while having a marginal overlap with their spectra in liquid solutions) can almost exclusively trigger a photochemical oxidation process. Mechanistic and environmental considerations are discussed. PMID- 29148725 TI - Chromophore Isomer Stabilization Is Critical to the Efficient Fluorescence of Cyan Fluorescent Proteins. AB - ECFP, the first usable cyan fluorescent protein (CFP), was obtained by adapting the tyrosine-based chromophore environment in green fluorescent protein to that of a tryptophan-based one. This first-generation CFP was superseded by the popular Cerulean, CyPet, and SCFP3A that were engineered by rational and random mutagenesis, yet the latter CFPs still exhibit suboptimal properties of pH sensitivity and reversible photobleaching behavior. These flaws were serendipitously corrected in the third-generation CFP mTurquoise and its successors without an obvious rationale. We show here that the evolution process had unexpectedly remodeled the chromophore environment in second-generation CFPs so they would accommodate a different isomer, whose formation is favored by acidic pH or light irradiation and which emits fluorescence much less efficiently. Our results illustrate how fluorescent protein engineering based solely on fluorescence efficiency optimization may affect other photophysical or physicochemical parameters and provide novel insights into the rational evolution of fluorescent proteins with a tryptophan-based chromophore. PMID- 29148726 TI - Novel Approach for 99mTc-Labeling of Red Blood Cells: Evaluation of 99mTc 4SAboroxime as a Blood Pool Imaging Agent. AB - Angiography with radiolabeled red blood cells (RBCs) plays an important role in diagnosis and prognosis in vascular diseases. Both in vitro and in vivo methods have been developed for 99mTc-labeling of RBCs. However, these methods are complicated and lack reproducibility. Therefore, it is highly desirable to develop an alternative method for routine 99mTc-labeling of RBCs. In this report, we present a novel approach for 99mTc-labeling of RBCs. We prepared a new 99mTc(III) radiotracer [99mTcCl(CDO)(CDOH)2B-4AS] (99mTc-4ASboroxime: 4AS-B(OH)2 = 4-aminosulfonylphenyl)boronic acid, and CDOH2 = cyclohexanedione dioxime) in >95% radiochemical purity. Imaging and biodistribution studies were performed in Sprague-Dawley (SD) rats. It was found that the blood radioactivity was ~6.0%ID/g (~90% injected dose for 200-225 g SD rats) for 99mTc-4ASboroxime with low uptake in the myocardium, kidneys, liver, lungs, and muscle, most likely due to lack of leakage of 99mTc-labeled RBCs from the intravascular space. The blood radioactivity was almost unchanged over the 2 h period, suggesting that the binding of 99mTc-4ASboroxime to blood components (cells, proteins, and plasma) is stable. The results from gamma-counting of the isolated blood components showed that 99mTc-4ASboroxime had >95% of blood radioactivity binding to RBCs, ~1% to albumin, and ~3% remaining free in blood plasma, demonstrating its RBC specificity. The results from imaging studies in SD rats indicated that 99mTc 4ASboroxime is predominantly distributed in the blood pool. Main blood vessels were well delineated in the head/neck and abdominal regions. This statement was further substantiated by the results from imaging studies in pigs. 99mTc 4ASboroxime is an excellent blood pool agent with the potential for diagnosis and prognosis of vascular diseases. PMID- 29148727 TI - Substrate-Assisted in Situ Confinement Pyrolysis of Zeolitic Imidazolate Frameworks to Nitrogen-Doped Hierarchical Porous Carbon Nanoframes with Superior Lithium Storage. AB - Porous carbons generated from the direct pyrolysis of metal organic frameworks (MOFs) have shown great potential as a kind of promising electrode material for lithium-ion batteries (LIBs). However, several common drawbacks, such as the inevitable structural damage during carbonization process and intrinsic micropore dominated feature of MOFs-derived products, largely impede the exposure of active sites and mass transfer, thus usually resulting in inferior electrochemical performances. In this work, an effective and controllable approach was reported to construct nitrogen-doped hierarchical porous carbon nanoframes (N-HPCFs) through in situ pyrolysis transformation of small-sized zeolitic imidazolate frameworks (ZIFs) that are in advance combined with a two-dimensional substrate templated from g-C3N4. Using this strategy, numerous ZIFs derived carbon nanoparticles appear to be well arranged on surfaces of a hollow carbon nanoplatelet produced by the adopted substrate after calcination, and the corresponding final product shows great improvements on both structural stability and pore distribution compared with that from direct pyrolysis of monodispersed ZIFs without the substrate. As expected, when used as the anode material for LIBs, the N-HPCFs electrode exhibits a high lithium storage capacity with good cycle stability (651 mAh g-1 after 400 cycles at the current density of 1 A g-1) and outstanding rate capability. Such enhanced electrochemical performances can be well ascribed to the stable frame structure as well as highly developed transport pathways for ions and electrons. So the synthetic strategy presented in this paper may pave a new way for the further application of ZIFs-based materials. PMID- 29148729 TI - Stressor Exposures Determine Risk: So, Why Do Fellow Scientists Continue To Focus on Superficial Microplastics Risk? PMID- 29148728 TI - Neutral Luminescent Metal-Organic Frameworks: Structural Diversification, Photophysical Properties, and Sensing Applications. AB - Utilizing flexible bis(tridentate)polypyridyl ligands, the two new luminescent 2D metal organic frameworks {Zn2(tpbn)(2,6-NDC)2}n (1) and {[Zn2(tphn)(2,6 NDC)2].4H2O}n (2), where tpbn = N,N',N",N'''-tetrakis(2-pyridylmethyl)-1,4 diaminobutane, tphn = N,N',N",N'''-tetrakis(2-pyridylmethyl)-1,6-diaminohexane, and 2,6-H2NDC = 2,6-naphthalenedicarboxylic acid, have been isolated in good yields under solvothermal conditions. Their solid-state molecular structures have been determined by single-crystal X-ray diffractometry. Both 1 and 2 have pentacoordinated Zn(II) centers with an N3O2 environment from three nitrogen atoms of the tpbn or tphn ligand and two carboxylate oxygen atoms from two different 2,6-NDC linkers. However, the binding modes of the tridentate part of polypyridyl ligands to the Zn(II) center are different in 1 and 2-meridional (tpbn) vs facial (tphn) due to an increase (1.5 times) in the methylene chain length. Thus, the binding mode of 2,6-NDC to the Zn(II) center differs: bis(monodentate) syn-anti in 1 and bis(monodentate) syn-syn in 2. This difference in binding modes of the components has a profound effect on the conformation of the six-membered ring (metal centers are considered as the vertices in it) within the 2D framework: honeycomb vs chair form for 1 and 2, respectively. In addition to further characterization by elemental analysis and UV-vis and FT-IR spectroscopy, their framework stabilities in water and thermal properties have been studied by powder X-ray diffraction and thermogravimetric analysis, respectively. On the basis of thermodiffractometry, 1 and 2 retain their crystallinity and overall structure up to 350 and 325 degrees C, respectively. Their luminescent properties have been utilized to demonstrate sensing of various solvents as well as nitro-aromatic compounds in water, which correlate well with their structural differences. Through the spectral overlap, lifetime measurements, and nature of the Stern-Volmer plots, the fluorescence quenching pathway for the nitro-analytes, particularly 2,4,6-trinitrophenol (TNP), is established for 1 and 2. Their recyclability and stability after sensing experiments are found to be excellent. PMID- 29148730 TI - Effect of Different Treatment Technologies on the Fate of Antibiotic Resistance Genes and Class 1 Integrons when Residual Municipal Wastewater Solids are Applied to Soil. AB - Residual wastewater solids are a significant reservoir of antibiotic resistance genes (ARGs). While treatment technologies can reduce ARG levels in residual wastewater solids, the effects of these technologies on ARGs in soil during subsequent land-application are unknown. In this study we investigated the use of numerous treatment technologies (air drying, aerobic digestion, mesophilic anaerobic digestion, thermophilic anaerobic digestion, pasteurization, and alkaline stabilization) on the fate of ARGs and class 1 integrons in wastewater solids-amended soil microcosms. Six ARGs [erm(B), qnrA, sul1, tet(A), tet(W), and tet(X)], the integrase gene of class 1 integrons (intI1), and 16S rRNA genes were quantified using quantitative polymerase chain reaction. The quantities of ARGs and intI1 decreased in all microcosms, but thermophilic anaerobic digestion, alkaline stabilization, and pasteurization led to the most extensive decay of ARGs and intI1, often to levels similar to that of the control microcosms to which no wastewater solids had been applied. In contrast, the rates by which ARGs and intI1 declined using the other treatment technologies were generally similar, typically varying by less than 2 fold. These results demonstrate that wastewater solids treatment technologies can be used to decrease the persistence of ARGs and intI1 during their subsequent application to soil. PMID- 29148731 TI - Conjugation of Transforming Growth Factor Beta to Antigen-Loaded Poly(lactide- co glycolide) Nanoparticles Enhances Efficiency of Antigen-Specific Tolerance. AB - Current strategies for treating autoimmunity involve the administration of broad acting immunosuppressive agents that impair healthy immunity. Intravenous (i.v.) administration of poly(lactide- co-glycolide) nanoparticles (NPs) containing disease-relevant antigens (Ag-NPs) have demonstrated antigen (Ag)-specific immune tolerance in models of autoimmunity. However, subcutaneous (s.c.) delivery of Ag NPs has not been effective. This investigation tested the hypothesis that codelivery of the immunomodulatory cytokine, transforming growth factor beta 1 (TGF-beta), on Ag-NPs would modulate the immune response to Ag-NPs and improve the efficiency of tolerance induction. TGF-beta was coupled to the surface of Ag NPs such that the loadings of Ag and TGF-beta were independently tunable. The particles demonstrated bioactive delivery of Ag and TGF-beta in vitro by reducing the inflammatory phenotype of bone marrow-derived dendritic cells and inducing regulatory T cells in a coculture system. Using an in vivo mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis, TGF-beta codelivery on Ag-NPs resulted in improved efficacy at lower doses by i.v. administration and significantly reduced disease severity by s.c. administration. This study demonstrates that the codelivery of immunomodulatory cytokines on Ag NPs may enhance the efficacy of Ag-specific tolerance therapies by programming Ag presenting cells for more efficient tolerance induction. PMID- 29148732 TI - Photocontrolled Release of Doxorubicin Conjugated through a Thioacetal Photocage in Folate-Targeted Nanodelivery Systems. AB - Despite their proven ability for precise and targeted release, nanoplatform systems for photocontrolled delivery often face formidable synthetic challenges, in part due to the paucity of advanced linker strategies. Here, we report on a novel linker strategy using a thioacetal ortho-nitrobenzaldehyde (TNB) cage, demonstrating its application for delivery of doxorubicin (Dox) in two nanoscale systems. This photocleavable linker, TNB(OH), which presents two identical arms, each terminated with a hydroxyl functionality, was prepared in a single step from 6-nitroveratraldehyde. TNB(OH) was used to cross-link Dox to a folate receptor (FAR)-targeting poly(amidoamine) dendrimer conjugate G5(FA)n=5.4(Dox)m=5.1, and also used to prepare an upconversion nanocrystal (UCN) conjugate, UCN PPIX@(Dox)(G5FA), a larger core/shell nanostructure. In this core/shell nanostructure, the UCN core emits UV and visible light luminescence upon near infrared (NIR) excitation, allowing for the photocleavage of the TNB linker as well as the photostimulation of protoporphyrin IX (PPIX) coupled as a cytotoxic photosensitizer. Drug-release experiments performed in aqueous solutions with long-wavelength ultraviolet A (UVA) light showed that Dox release occurred rapidly from its TNB linked form or from its dendrimer conjugated form with comparable decay kinetics. Cellular toxicity studies in FAR-overexpressing KB carcinoma cells demonstrated that each nanoconjugate lacked intrinsic cytotoxicity until exposed to UVA or NIR (980 nm) (for the UCN nanoconjugate), which resulted in induction of potent cytotoxicity. In summary, this new TNB strategy offers synthetic convenience in drug conjugation chemistry with the ability for the temporal control of drug activation at the delivery site. PMID- 29148733 TI - Fluorescence and Quenching Assessment (EEM-PARAFAC) of de Facto Potable Reuse in the Neuse River, North Carolina, United States. AB - The Neuse River, North Carolina, U.S., exemplifies a typical de facto potable reuse scenario, where drinking water sources are located downstream of treated wastewater effluent discharges. The study results imply that planned potable water reuse, whether in an indirect or direct potable reuse scenario, might provide better control over water quality than the status quo conditions. Using fluorescence excitation-emission matrix (EEM) measurements, anthropogenic influence of a wastewater treatment plant (WWTP) discharge was observed in samples near the location of drinking water treatment plant (WTP) intakes, eight or more miles downstream of the WWTP, implying that anthropogenic compounds were not fully removed or degraded by natural processes in this reach of the river. PARAllel FACtor (PARAFAC) analysis supported a two-component model of humic-like and nonhumic-like dissolved organic matter (DOM). A nonmodeled anthropogenic feature was also indicated. Significantly, the quenched fluorescence of humic like DOM (static and/or dynamic quenching) by nonhumic-like DOM-previously demonstrated for probe molecules but first reported here in a natural/anthropogenic-influenced system-offers exciting insight into studies of humic/nonhumic interactions with important implications for pollutant fate and transport, sensing applications, and water treatment. A molecular spectroscopic explanation for dual fluorescing peaks in amino acids and humic substances is postulated. PMID- 29148734 TI - Unraveling the Role of Structural Order in the Transformation of Electrical Conductivity in Ca2FeCoO6-delta, CaSrFeCoO6-delta, and Sr2FeCoO6-delta. AB - The ability to control the electrical conductivity of solid-state oxides using structural parameters has been demonstrated. A correlation has been established between the electrical conductivity and structural order in a series of oxygen deficient perovskites using X-ray and neutron diffraction, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and electrical conductivity studies at a wide temperature range, 25-800 degrees C. The crystal structure of CaSrFeCoO6-delta has been determined, and its stark contrast to Ca2FeCoO6-delta and Sr2FeCoO6-delta has been demonstrated. The Fe/Co distribution over tetrahedral and octahedral sites has been determined using neutron diffraction. There is a systematic increase in the structural order in progression from Sr2FeCoO6-delta (delta = 0.5) to CaSrFeCoO6 delta (delta = 0.8) and Ca2FeCoO6-delta (delta = 0.9) . The oxygen contents of these materials were determined using iodometric titration and TGA. At room temperature, there is an inverse correlation between the electrical conductivity and structural order. The ordered Ca2 and CaSr compounds are semiconductors, while the disordered Sr2 compund shows metallic behavior. The metallic nature of the Sr2 material persists up to 1073 K (800 degrees C), while the Ca2 and CaSr compounds undergo a semiconductor-to-metal transition above 500 and 300 degrees C, respectively, highlighting another important impact of the structural order. At high temperature, the CaSr compound has the highest conductivity compared to the Ca2 and Sr2 materials. There appears to be an optimum degree of structural order that leads to the highest conductivity at high temperature. Another consequence of the structural order is the observation of mixed ionic-electronic conductivity in CaSr and Ca2 compounds, as is evident from the hysteresis in the conductivity data obtained during heating and cooling cycles. The average ionic radius required for each structural transition was determined through the synthesis of 21 different materials by systematic variation of the Ca/Sr ratio. In addition, SEM and XPS were employed to gain insight into the crystallite morphology and oxidation states of transition metals, revealing an interesting redox process between Fe and Co. PMID- 29148735 TI - Stereoselective Stabilization of Polymeric Vitamin E Conjugate Micelles. AB - Vitamin E (alpha-tocopherol; TPGS) micelle is a robust nanocarrier in delivering hydrophobic active pharmaceutical ingredients, but it is suffering from poor stability that is essential in terms of pharmaceutical and biomedical applications. Taking advantage of the chirality of vitamin E, this work reports the stereoselective stabilization of polymer-vitamin E conjugate micelles. Vitamin E was covalently linked to multivalent methoxy poly(ethylene glycol)-co poly(glutamic acid), generating amphiphilic conjugates that could self-assemble into micelles. Eight types of micelles were produced via tailored combination of polymer backbone and side chain with different chirality. The particle size and critical micelle concentration analysis demonstrated a correlation between conjugate chirality and micelle stability. The most stable micelles were obtained when poly(glutamic acid) and vitamin E both are dextrorotatory, because of the high degree of alpha-helix revealed by both circular dichroism spectroscopy and molecular dynamics simulation. This phenomenon was further verified by the fluorescence resonance energy transfer (FRET) analysis in HepG2 cells. The current work not only provides a method to enhance the stability of vitamin E micelles, but also adds an additional facile tool in regulating the stability of polymer conjugate micelles without changing the conjugate composition. PMID- 29148736 TI - Formation of Metal-Cyanide Complexes in Deliquescent Airborne Particles: A New Possible Sink for HCN in Urban Environments. AB - Hydrogen cyanide is a ubiquitous gas in the atmosphere and a biomass burning tracer. Reactive gases can be adsorbed onto aerosol particles where they can promote heterogeneous chemistry. In the present study, we report for the first time on the measurement and speciation of cyanides in atmospheric aerosol. Filter samples were collected at an urban background site in the city center of Padua (Italy), extracted and analyzed with headspace gas chromatography and nitrogen phosphorus detection. The results showed that strongly bound cyanides were present in all aerosol samples at a concentration ranging between 0.3 and 6.5 ng/m3 in the PM2.5 fraction. The concentration of cyanides strongly correlates with concentration of total carbon and metals associated with combustion sources. The results obtained bring evidence that hydrogen cyanide can be adsorbed onto aerosol liquid water and can react with metal ions to form stable metal-cyanide complexes. PMID- 29148737 TI - Site-Specific One-to-One Click Coupling of Single Proteins to Individual Carbon Nanotubes: A Single-Molecule Approach. AB - We report the site-specific coupling of single proteins to individual carbon nanotubes (CNTs) in solution and with single-molecule control. Using an orthogonal Click reaction, Green Fluorescent Protein (GFP) was engineered to contain a genetically encoded azide group and then bound to CNT ends in different configurations: in close proximity or at longer distances from the GFP's functional center. Atomic force microscopy and fluorescence analysis in solution and on surfaces at the single-protein level confirmed the importance of bioengineering optimal protein attachment sites to achieve direct protein nanotube communication and bridging. PMID- 29148738 TI - Interfacial Electrochemistry in Liquids Probed with Photoemission Electron Microscopy. AB - Studies of the electrified solid-liquid interfaces are crucial for understanding biological and electrochemical systems. Until recently, use of photoemission electron microscopy (PEEM) for such purposes has been hampered by incompatibility of the liquid samples with ultrahigh vacuum environment of the electron optics and detector. Here we demonstrate that the use of ultrathin electron transparent graphene membranes, which can sustain large pressure differentials and act as a working electrode, makes it possible to probe electrochemical reactions in operando in liquid environments with PEEM. PMID- 29148739 TI - UV/Peracetic Acid for Degradation of Pharmaceuticals and Reactive Species Evaluation. AB - Peracetic acid (PAA) is a widely used disinfectant, and combined UV light with PAA (i.e., UV/PAA) can be a novel advanced oxidation process for elimination of water contaminants. This study is among the first to evaluate the photolysis of PAA under UV irradiation (254 nm) and degradation of pharmaceuticals by UV/PAA. PAA exhibited high quantum yields (Phi254 nm = 1.20 and 2.09 mol.Einstein-1 for the neutral (PAA0) and anionic (PAA-) species, respectively) and also showed scavenging effects on hydroxyl radicals (k*OH/PAA0 = (9.33 +/- 0.3) * 108 M-1.s-1 and k*OH/PAA- = (9.97 +/- 2.3) * 109 M-1.s-1). The pharmaceuticals were persistent with PAA alone but degraded rapidly by UV/PAA. The contributions of direct photolysis, hydroxyl radicals, and other radicals to pharmaceutical degradation under UV/PAA were systematically evaluated. Results revealed that *OH was the primary radical responsible for the degradation of carbamazepine and ibuprofen by UV/PAA, whereas CH3C(?O)O* and/or CH3C(?O)O2* contributed significantly to the degradation of naproxen and 2-naphthoxyacetic acid by UV/PAA in addition to *OH. The carbon-centered radicals generated from UV/PAA showed strong reactivity to oxidize certain naphthyl compounds. The new knowledge obtained in this study will facilitate further research and development of UV/PAA as a new degradation strategy for water contaminants. PMID- 29148741 TI - Controlling Association and Separation of Gold Nanoparticles with Computationally Designed Zinc-Coordinating Proteins. AB - Functionalization of nanoparticles with biopolymers has yielded a wide range of structured and responsive hybrid materials. DNA provides the ability to program length and recognition using complementary oligonucleotide sequences. Nature more often leverages the versatility of proteins, however, where structure, assembly, and recognition are more subtle to engineer. Herein, a protein was computationally designed to present multiple Zn2+ coordination sites and cooperatively self-associate to form an antiparallel helical homodimer. Each subunit was unstructured in the absence of Zn2+ or when the cation was sequestered with a chelating agent. When bound to the surface of gold nanoparticles via cysteine, the protein provided a reversible molecular linkage between particles. Nanoparticle association and changes in interparticle separation were monitored by redshifts in the surface plasmon resonance (SPR) band and by transmission electron microscopy (TEM). Titrations with Zn2+ revealed sigmoidal transitions at submicromolar concentrations. The metal-ion concentration required to trigger association varied with the loading of the proteins on the nanoparticles, the solution ionic strength, and the cation employed. Specifying the number of helical (heptad) repeat units conferred control over protein length and nanoparticle separation. Two different length proteins were designed via extension of the helical structure. TEM and extinction measurements revealed distributions of nanoparticle separations consistent with the expected protein structures. Nanoparticle association, interparticle separation, and SPR properties can be tuned using computationally designed proteins, where protein structure, folding, length, and response to molecular species such as Zn2+ can be engineered. PMID- 29148742 TI - Identification of the Peptide PyroQ-betaCasein194-209 as a Highly Specific and Sensitive Marker to Differentiate between Ultrahigh-Temperature Processed (UHT) Milk and Mildly Heated Milk. AB - In this study, a new approach was introduced to identify marker peptides that reflect the thermal treatment of commercial milk samples and differentiate ultrahigh-temperature processed (UHT) milk from mildly heated milk. Peptide profiles of training set samples, pasteurized (n = 20), extended shelf life (n = 29), and UHT (n = 29) milk, were recorded by MALDI-TOF-MS after StageTip microextraction. As marker candidates, 13 peptides were selected, and their cutoff levels were defined. The quality of the cutoff levels was then tested with a blind test set. Thus, the peptide m/z 1701.0, which was identified as pyroQ betacasein194-209, could ideally differentiate UHT milk from mildly heated milk with an accuracy of 100%. Due to its high reliability and sensitivity, this peptide may be applied in routine analysis to monitor thermal processing of milk. An additional heating experiment showed that the marker peptide candidates are formed during milk processing by endogenous enzymes and selective thermal cleavage. PMID- 29148743 TI - Rh(III)-Catalyzed Redox-Neutral Unsymmetrical C-H Alkylation and Amidation Reactions of N-Phenoxyacetamides. AB - A Rh(III)-catalyzed unsymmetrical C-H alkylation and amidation of N phenoxyacetamides with diazo compounds has been developed under mild and redox neutral conditions, producing dinitrogen as the only byproduct. The reaction represents the first example of one-step, unsymmetrical difunctionalization of two ortho-C-H bonds. Experimental and computational studies support that N phenoxyacetamides most likely undergo an initial ortho-C-H alkylation with diazo compounds via a Rh(III)-catalyzed C-H activation, and the resulting Rh(III) intermediate subsequently undergoes an intramolecular oxidative addition into the O-N bond to form a Rh(V) nitrenoid species that is protonated and further directed toward electrophilic addition to the second ortho position of the phenyl ring. This work might provide a new direction for unsymmetrical C-H difunctionalization reactions in an efficient manner. PMID- 29148740 TI - Effect of an Imposed Contact on Secondary Structure in the Denatured State of Yeast Iso-1-cytochrome c. AB - There is considerable evidence that long-range interactions stabilize residual protein structure under denaturing conditions. However, evaluation of the effect of a specific contact on structure in the denatured state has been difficult. Iso 1-cytochrome c variants with a Lys54 -> His mutation form a particularly stable His-heme loop in the denatured state, suggestive of loop-induced residual structure. We have used multidimensional nuclear magnetic resonance methods to assign 1H and 15N backbone amide and 13C backbone and side chain chemical shifts in the denatured state of iso-1-cytochrome c carrying the Lys54 -> His mutation in 3 and 6 M guanidine hydrochloride and at both pH 6.4, where the His54-heme loop is formed, and pH 3.6, where the His54-heme loop is broken. Using the secondary structure propensity score, with the 6 M guanidine hydrochloride chemical shift data as a random coil reference state for data collected in 3 M guanidine hydrochloride, we found residual helical structure in the denatured state for the 60s helix and the C-terminal helix, but not in the N-terminal helix in the presence or absence of the His54-heme loop. Non-native helical structure is observed in two regions that form Omega-loops in the native state. There is more residual helical structure in the C-terminal helix at pH 6.4 when the loop is formed. Loop formation also appears to stabilize helical structure near His54, consistent with induction of helical structure observed when His-heme bonds form in heme-peptide model systems. The results are discussed in the context of the folding mechanism of cytochrome c. PMID- 29148744 TI - The Fundamental Noninnocent Role of Water for the Hydrogenation of Nitrous Oxide by PNP Pincer Ru-based Catalysts. AB - The hydrogenation of nitrous oxide by PNP pincer ruthenium complexes supposes a promising way to functionalize a hazardous gas and reduce the greenhouse effect, generating dinitrogen and water. Here, by DFT calculations we describe not only the whole mechanism for such a green transformation but we unravel the fundamental role of water, without which the reaction could not go forward. Water assists mandatorily in the H transfer to generate the hydroxyl group together with the release of dinitrogen. PMID- 29148745 TI - Influence of Countercation Hydration Enthalpies on the Formation of Molecular Complexes: A Thorium-Nitrate Example. AB - The influence of countercations (An+) in directing the composition of monomeric metal-ligand (ML) complexes that precipitate from solution are often overlooked despite the wide usage of An+ in materials synthesis. Herein, we describe a correlation between the composition of ML complexes and A+ hydration enthalpies found for two related series of thorium (Th)-nitrate molecular compounds obtained by evaporating acidic aqueous Th-nitrate solutions in the presence of A+ counterions. Analyses of their chemical composition and solid-state structures demonstrate that A+ not only affects the overall solid-state packing of the Th nitrato complexes but also influences the composition of the Th-nitrato monomeric anions themselves. Trends in composition and structure are found to correlate with A+ hydration enthalpies, such that the A+ with smaller hydration enthalpies associate with less hydrated and more anionic Th-nitrato complexes. This perspective, broader than the general assumption of size and charge as the dominant influence of An+, opens a new avenue for the design and synthesis of targeted metal-ligand complexes. PMID- 29148746 TI - Keto-Enol Tautomerization Triggers an Electrophilic Aldehyde Deformylation Reaction by a Nonheme Manganese(III)-Peroxo Complex. AB - Oxygen atom transfer by high-valent enzymatic intermediates remains an enigma in chemical catalysis. In particular, manganese is an important first-row metal involved in key biochemical processes, including the biosynthesis of molecular oxygen (through the photosystem II complex) and biodegradation of toxic superoxide to hydrogen peroxide by superoxide dismutase. Biomimetic models of these biological systems have been developed to gain understanding on the structure and properties of short-lived intermediates but also with the aim to create environmentally benign oxidants. In this work, we report a combined spectroscopy, kinetics and computational study on aldehyde deformylation by two side-on manganese(III)-peroxo complexes with bispidine ligands. Both manganese(III)-peroxo complexes are characterized by UV-vis and mass spectrometry techniques, and their reactivity patterns with aldehydes was investigated. We find a novel mechanism for the reaction that is initiated by a hydrogen atom abstraction reaction, which enables a keto-enol tautomerization in the substrate. This is an essential step in the mechanism that makes an electrophilic attack on the olefin bond possible as the attack on the aldehyde carbonyl is too high in energy. Kinetics studies determine a large kinetic isotope effect for the replacement of the transferring hydrogen atom by deuterium, while replacing the transferring hydrogen atom by a methyl group makes the substrate inactive and hence confirm the hypothesized mechanism. Our new mechanism is confirmed with density functional theory modeling on the full mechanism and rationalized through valence bond and thermochemical cycles. Our unprecedented new mechanism may have relevance to biological and biomimetic chemistry processes in general and gives insight into the reactivity patterns of metal-peroxo and metal-hydroperoxo intermediates in general. PMID- 29148747 TI - Investigation of the Iron-Peroxo Complex in the Fenton Reaction: Kinetic Indication, Decay Kinetics, and Hydroxyl Radical Yields. AB - The Fenton reaction describes the reaction of Fe(II) with hydrogen peroxide. Several researchers proposed the formation of an intermediate iron-peroxo complex but experimental evidence for its existence is still missing. The present study investigates formation and lifetime of this intermediate at various conditions such as different Fe(II)-concentrations, absence vs presence of a hydroxyl radical scavenger (dimethyl sulfoxide, DMSO), and different pH values. Obtained results indicate that the iron-peroxo complex is formed under all experimental conditions. Based on these data, stability of the iron-peroxo complex could be examined. At pH 3 regardless of [Fe(II)]0 decay rates for the iron-peroxo complex of about 50 s-1 were determined in absence and presence of DMSO. Without DMSO and [Fe(II)]0 = 300 MUM variation of pH yielded decay rates of about 70 s-1 for pH 1 and 2 and of about 50 s-1 at pH 3 and 4. Hence, the iron-peroxo complex becomes more stable with increasing pH. Furthermore, pH-dependent hydroxyl radical yields were determined to investigate whether the increasing stability of the intermediate complex may indicate a different reaction of the iron-peroxo complex which might yield Fe(IV) instead of hydroxyl radical formation as suggested in literature. However, it was found that hydroxyl radicals were produced proportionally to the Fe(II)-concentration. PMID- 29148748 TI - Total Syntheses of (-)-Majucin and (-)-Jiadifenoxolane A, Complex Majucin-Type Illicium Sesquiterpenes. AB - We report the first chemical syntheses of both (-)-majucin and (-) jiadifenoxolane A via 10 net oxidations from the ubiquitous terpene (+)-cedrol. Additionally, this approach allows for access to other majucin-type sesquiterpenes, like (-)-jiadifenolide, (-)-jiadifenin, and (-)-(1R,10S)-2-oxo 3,4-dehydroxyneomajucin (ODNM) along the synthetic pathway. Site-selective aliphatic C(sp3)-H bond oxidation reactions serve as the cornerstone of this work which offers access to highly oxidized natural products from an abundant and renewable terpene feedstock. PMID- 29148749 TI - Glycosyl Cross-Coupling of Anomeric Nucleophiles: Scope, Mechanism, and Applications in the Synthesis of Aryl C-Glycosides. AB - Stereoselective manipulations at the C1 anomeric position of saccharides are one of the central goals of preparative carbohydrate chemistry. Historically, the majority of reactions forming a bond with anomeric carbon has focused on reactions of nucleophiles with saccharide donors equipped with a leaving group. Here, we describe a novel approach to stereoselective synthesis of C-aryl glycosides capitalizing on the highly stereospecific reaction of anomeric nucleophiles. First, methods for the preparation of anomeric stannanes have been developed and optimized to afford both anomers of common saccharides in high anomeric selectivities. We established that oligosaccharide stannanes could be prepared from monosaccharide stannanes via O-glycosylation with Schmidt-type donors, glycal epoxides, or under dehydrative conditions with C1 alcohols. Second, we identified a general set of catalytic conditions with Pd2(dba)3 (2.5 mol%) and a bulky ligand (JackiePhos, 10 mol%) controlling the beta-elimination pathway. We demonstrated that the glycosyl cross-coupling resulted in consistently high anomeric selectivities for both anomers with mono- and oligosaccharides, deoxysugars, saccharides with free hydroxyl groups, pyranose, and furanose substrates. The versatility of the glycosyl cross-coupling reaction was probed in the total synthesis of salmochelins (siderophores) and commercial anti-diabetic drugs (gliflozins). Combined experimental and computational studies revealed that the beta-elimination pathway is suppressed for biphenyl-type ligands due to the shielding of Pd(II) by sterically demanding JackiePhos, whereas smaller ligands, which allow for the formation of a Pd-F complex, predominantly result in a glycal product. Similar steric effects account for the diminished rates of cross-couplings of 1,2-cis C1-stannanes with aryl halides. DFT calculations also revealed that the transmetalation occurs via a cyclic transition state with retention of configuration at the anomeric position. Taken together, facile access to both anomers of various glycoside nucleophiles, a broad reaction scope, and uniformly high transfer of anomeric configuration make the glycosyl cross-coupling reaction a practical tool for the synthesis of bioactive natural products, drug candidates, allowing for late-stage glycodiversification studies with small molecules and biologics. PMID- 29148750 TI - Catalytic Cyclopropanation by Myoglobin Reconstituted with Iron Porphycene: Acceleration of Catalysis due to Rapid Formation of the Carbene Species. AB - Myoglobin reconstituted with iron porphycene catalyzes the cyclopropanation of styrene with ethyl diazoacetate. Compared to native myoglobin, the reconstituted protein significantly accelerates the catalytic reaction and the kcat/Km value is 26-fold enhanced. Mechanistic studies indicate that the reaction of the reconstituted protein with ethyl diazoacetate is 615-fold faster than that of native myoglobin. The metallocarbene species reacts with styrene with the apparent second-order kinetic constant of 28 mM-1 s-1 at 25 degrees C. Complementary theoretical studies support efficient carbene formation by the reconstituted protein that results from the strong ligand field of the porphycene and fewer intersystem crossing steps relative to the native protein. From these findings, the substitution of the cofactor with an appropriate metal complex serves as an effective way to generate a new biocatalyst. PMID- 29148751 TI - Correction to "Structure of Colloidal Quantum Dots from Dynamic Nuclear Polarization Surface Enhanced NMR Spectroscopy". PMID- 29148752 TI - Substituent Effects on the Reactivity of Cyclic Tertiary Sulfamidates. AB - The reactivity of cyclic tertiary sulfamidates derived from alpha-methylisoserine strongly depends on the substitution at the C and N termini. These substrates are one of the very few examples able to undergo nucleophilic ring opening at a quaternary carbon with complete inversion of the configuration, as demonstrated both experimentally and computationally. When the sulfonamide is unprotected, the characteristic ring-opening reaction is completely silenced, which explains that the majority of the ring-opening reactions reported in the literature invoke N alkyl or N-carbonyl-protected sulfamidates. Accumulation of negative charge at the NSO3 moiety in the transition state, especially when the sulfonamide NH is deprotonated, drastically raises the activation barrier for the nucleophilic attack. On the other hand, ester groups at the carboxylic position favor ring opening, whereas amides allow competition between the substitution and elimination pathways. Using pyridine as a nucleophilic probe, we have demonstrated both experimentally and computationally that a proper selection of the substitution scheme can enhance the synthetic scope of alpha-methylisoserine derived sulfamidates, switching off and on the nucleophilic ring-opening in a controlled manner. This is particularly convenient for hybrid alpha/beta-peptide synthesis, as demonstrated recently by our group. PMID- 29148753 TI - Kinetics of the Aqueous Phase Reactions of Atmospherically Relevant Monoterpene Epoxides. AB - Laboratory and field measurements have demonstrated that an isoprene-derived epoxide intermediate (IEPOX) is the origin of a wide range of chemical species found in ambient secondary organic aerosol (SOA). In order to explore the potential relevance of a similar mechanism for the formation of monoterpene derived SOA, nuclear magnetic resonance techniques were used to study kinetics and reaction products of the aqueous-phase reactions of several monoterpene epoxides: beta-pinene oxide, limonene oxide, and limonene dioxide. The present results, combined with a previous study of alpha-pinene oxide, indicate that all of these epoxides will react more quickly than IEPOX with aqueous atmospheric particles, even under low-acidity conditions. As for alpha-pinene oxide, the observed products can be mainly rationalized with a hydrolysis mechanism, and no long-lived organosulfate or nitrate species nor species that retain the beta pinene bicyclic carbon backbone are observed. As bicyclic ring-retaining organosulfate and nitrate species have been previously observed in monoterpene derived SOA, it appears that monoterpene-derived epoxides may not be as versatile as IEPOX in producing a range of SOA species, and other mechanisms are needed to rationalize organosulfate and nitrate formation. PMID- 29148754 TI - Eurycomalactone Inhibits Expression of Endothelial Adhesion Molecules at a Post Transcriptional Level. AB - The C-19 quassinoid eurycomalactone (1) has recently been shown to be a potent (IC50 = 0.5 MUM) NF-kappaB inhibitor in a luciferase reporter model. In this study, we show that 1 with similar potency inhibited the expression of the NF kappaB-dependent target genes ICAM-1, VCAM-1, and E-selectin in TNFalpha activated human endothelial cells (HUVECtert) by flow cytometry experiments. Surprisingly, 1 (2 MUM) did not inhibit TNFalpha-induced IKKalpha/beta or IkappaBalpha phosphorylation significantly. Also, the TNFalpha-induced degradation of IkappaBalpha remained unchanged in response to 1 (2 MUM). In addition, pretreatment of HUVECtert with 1 (2 MUM) had no statistically significant effect on TNFalpha-mediated nuclear translocation of the NF-kappaB subunit p65 (RelA). Quantitative RT-PCR revealed that 1 (0.5-5 MUM) exhibited diverse effects on the TNFalpha-induced transcription of ICAM-1, VCAM-1, and SELE genes since the mRNA level either remained unchanged (ICAM-1, E-selectin, and VCAM-1 at 0.5 MUM 1), was reduced (VCAM-1 at 5 MUM 1), or even increased (E selectin at 5 MUM 1). Finally, the time-dependent depletion of a short-lived protein (cyclin D1) as well as the measurement of de novo protein synthesis in the presence of 1 (2-5 MUM) suggested that 1 might act as a protein synthesis inhibitor rather than an inhibitor of early NF-kappaB signaling. PMID- 29148756 TI - Inhibitory Activities of Compounds from the Marine Actinomycete Williamsia sp. MCCC 1A11233 Variant on IgE-Mediated Mast Cells and Passive Cutaneous Anaphylaxis. AB - The compounds of the deep-sea-derived marine Williamsia sp. MCCC 1A11233 (CDMW) were isolated, which are secondary metabolites of the actinomycetes. In this study, seven kinds of CDMW were found to decrease degranulation and histamine release in immunoglobulin E (IgE)-mediated rat basophilic leukemia (RBL)-2H3 cells. The production of cytokines (tumor necrosis factor-alpha, interleukin-4) was inhibited by these CDMW in RBL-2H3 cells, and their chemical structures were established mainly based on detailed analysis of their NMR spectra. CDMW-3, CDMW 5, and CDMW-15 were further demonstrated to block mast cell-dependent passive cutaneous anaphylaxis in IgE-sensitized mice. Bone marrow mononuclear cells (BMMCs) were established to clarify the effect of CDMW-3, CDMW-5, and CDMW-15 on mast cells. The seven kinds of CDMW decreased the degranulation and histamine release of BMMCs. Furthermore, flow cytometry results indicated that CDMW-3, CDMW 5, and CDMW-15 increased the annexin+ cell population of BMMCs. In conclusion, CDMW-3, CDMW-5, and CDMW-15 have obvious antiallergic activity due to induction of the apoptosis of mast cells. PMID- 29148757 TI - Cross-Linked Artificial Enzyme Crystals as Heterogeneous Catalysts for Oxidation Reactions. AB - Designing systems that merge the advantages of heterogeneous catalysis, enzymology, and molecular catalysis represents the next major goal for sustainable chemistry. Cross-linked enzyme crystals display most of these essential assets (well-designed mesoporous support, protein selectivity, and molecular recognition of substrates). Nevertheless, a lack of reaction diversity, particularly in the field of oxidation, remains a constraint for their increased use in the field. Here, thanks to the design of cross-linked artificial nonheme iron oxygenase crystals, we filled this gap by developing biobased heterogeneous catalysts capable of oxidizing carbon-carbon double bonds. First, reductive O2 activation induces selective oxidative cleavage, revealing the indestructible character of the solid catalyst (at least 30 000 turnover numbers without any loss of activity). Second, the use of 2-electron oxidants allows selective and high-efficiency hydroxychlorination with thousands of turnover numbers. This new technology by far outperforms catalysis using the inorganic complexes alone, or even the artificial enzymes in solution. The combination of easy catalyst synthesis, the improvement of "omic" technologies, and automation of protein crystallization makes this strategy a real opportunity for the future of (bio)catalysis. PMID- 29148758 TI - Synthesis and Structure of Feet-to-Feet Connected Bisresorcinarenes. AB - Bisresorcinarenes 1a-d were obtained in excellent yields, and 1e was finally obtained in 50% yield. X-ray diffraction analysis showed that 1a and 1b adopted helical conformations, whereas the two resorcinarenes of 1c-e were in parallel orientations in which the clefts of the aliphatic chains entrapped one or two solvent molecules. The conformational study revealed that the helix interconversion between the (P)- and (M)-helical conformers depended on the length of the aliphatic chains. 1a had the largest energetic barrier to helix interconversion, while in 1b, its more flexible aliphatic chains lowered its energetic barriers. The P/M interconversion of 1a was coupled with the clockwise/anticlockwise interconversion of the interannular hydrogen bonding of the two resorcinarenes. The large negative entropic contributions indicate that the transition state is most likely more ordered than the ground states, suggesting that the transition state is most likely symmetric and is solvated by water molecules. Calculations at the M06-2X/6-31G(d,p) level revealed that the more stable (P)-conformation has clockwise interannular hydrogen bonding between the two resorcinarenes. PMID- 29148755 TI - Novel Antitubercular 6-Dialkylaminopyrimidine Carboxamides from Phenotypic Whole Cell High Throughput Screening of a SoftFocus Library: Structure-Activity Relationship and Target Identification Studies. AB - A BioFocus DPI SoftFocus library of ~35 000 compounds was screened against Mycobacterium tuberculosis (Mtb) in order to identify novel hits with antitubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc1 complex, disruption of cell-wall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization. Compounds from this series were active against clinical Mtb strains, while no cross-resistance to conventional antituberculosis drugs was observed. This suggested a novel mechanism of action, which was confirmed by chemoproteomic analysis leading to the identification of BCG_3193 and BCG_3827 as putative targets of the series with unknown function. Initial structure-activity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochemical properties. PMID- 29148759 TI - Exploring the Mechanism and Stereoselectivity in Chiral Cinchona-Catalyzed Heterodimerization of Ketenes. AB - Catalytic heterodimerization of ketenes can lead to important four-membered beta lactones. A recent asymmetric organocatalytic [2 + 2] cycloaddition between methylketene (MK) and methylphenylketene (MPK) in the presence of pseudoenantiomeric cinchona catalysts (trimethylsilylquinine (TMSQ) or methylquinidine (MeQd)) provided beta-lactones with high enantio- and diastereoselectivities. We employ DFT(M06-2X) computations to understand the mechanism and the origin of stereoselectivity in this ketene heterodimerization. The mechanism is found to involve the formation of an ammonium enolate first, by the action of the quinuclidine tertiary amine of the cinchona catalyst on MK. A stepwise pathway wherein the MK-cinchona enolate (enolate-A) adds to MPK in the selectivity-determining C-C bond formation step leading to the R-Z and S-Z product respectively with TMSQ and MeQd catalysts is predicted. The inclusion of LiClO4 is found to favor the C-C bond formation transition state to the S-E isomer in the case of MeQd and the R-E isomer with TMSQ catalysts. In the most preferred transition states, more effective C-H...pi (between the phenyl ring of the EPK and the catalyst) and C-H...O interactions (between the catalyst and LiClO4) are noticed than that in the higher energy analogues, underscoring the importance of noncovalent interactions in enantio- and diastereocontrol. PMID- 29148763 TI - Discovery of N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran 2-yl)-lH-pyrazole-5-carboxamide (GLPG1837), a Novel Potentiator Which Can Open Class III Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels to a High Extent. AB - Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described. PMID- 29148764 TI - Synthesis of Allylic Amines by Asymmetric Transfer Hydrogenation of alpha,beta Unsaturated N-(tert-Butylsulfinyl)imines. AB - Primary allylic amines with enantiomeric excesses from 97 to >99% were prepared by asymmetric transfer hydrogenation of alpha,beta-unsaturated N-(tert butylsulfinyl)ketimines followed by removal of the sulfinyl group. The effect caused by different substituents at the C?C bond and at the iminic carbon atom on the chemoselectivity of the reduction was studied. The desired enantiomer of the final allylic amine can be synthesized by choosing the sulfinyl group with the appropriate absolute configuration. PMID- 29148765 TI - One-Pot Synthesis of Polysubstituted Imidazoles via Sequential Staudinger/aza Wittig/Ag(I)-Catalyzed Cyclization/Isomerization. AB - A new one-pot preparation of polysubstituted imidazoles by a Staudinger/aza Wittig/Ag(I)-catalyzed cyclization/isomerization has been developed. The easily accessible propargylazide derivatives reacted with triphenylphosphine, isocyanates, and amines sequentially to produce the fully substituted imidazoles in good overall yields in the presence of catalytic amount of AgNO3/DMAP. PMID- 29148766 TI - Heterodimeric Diterpenoids Isolated from Euphorbia ebracteolata Roots and Their Inhibitory Effects on alpha-Glucosidase. AB - Two heterodimeric diterpenoids (1 and 2) comprising abietane lactone and nor rosane constituent units were isolated from Euphorbia ebracteolata roots. Compound 1 exhibited a moderate inhibitory effect on alpha-glucosidase (IC50 = 7.94 MUM), with a Ki value of 10.8 MUM. In silico molecular docking has been performed to investigate the inhibition mechanism. Compound 2 inhibited the acetyl transfer activity of Mycobacterium tuberculosis GlmU (IC50 = 41.85 MUM), which is a novel tuberculosis treatment target. PMID- 29148767 TI - Role of the Benzodioxole Group in the Interactions between the Natural Alkaloids Chelerythrine and Coptisine and the Human Telomeric G-Quadruplex DNA. A Multiapproach Investigation. AB - The binding properties toward the human telomeric G-quadruplex of the two natural alkaloids coptisine and chelerythrine were studied using spectroscopic techniques, molecular modeling, and X-ray diffraction analysis. The results were compared with reported data for the parent compounds berberine and sanguinarine. Spectroscopic studies showed modest, but different rearrangements of the DNA ligand complexes, which can be explained considering particular stereochemical features for these alkaloids, in spite of the similarity of their skeletons. In fact, the presence of a dioxolo moiety rather than the two methoxy functions improves the efficiency of coptisine and sanguinarine in comparison to berberine and chelerythrine, and the overall stability trend is sanguinarine > chelerythrine ~ coptisine > berberine. Accordingly, the X-ray diffraction analysis confirmed the involvement of the benzodioxolo groups in the coptisine/DNA binding by means of pi...pi, O...pi, and CH...O interactions. Similar information is provided by modeling studies, which, additionally, evidenced reasons for the quadruplex vs double-helix selectivity shown by these alkaloids. Thus, the analyses shed light on the key role of the benzodioxolo moieties in strengthening the interaction with the G4-folded human telomeric sequence and indicated the superior G4 stabilizing properties of the benzophenanthridine scaffold with respect to the protoberberine one and conversely the better G4 vs dsDNA selectivity profile of coptisine over the other alkaloids. PMID- 29148768 TI - Cyanopivaloyl Ester in the Automated Solid-Phase Synthesis of Oligorhamnans. AB - The development of effective protecting group chemistry is an important driving force behind the progress in the synthesis of complex oligosaccharides. Automated solid-phase synthesis is an attractive technique for the rapid assembly of oligosaccharides, built up of repetitive elements. The fact that (harsh) reagents are used in excess in multiple reaction cycles makes this technique extra demanding on the protecting groups used. Here, the synthesis of a set of oligorhamnan fragments is reported using the cyanopivaloyl (PivCN) ester to ensure effective neighboring group participation during the glycosylation events. The PivCN group combines the favorable characteristics of the parent pivaloyl (Piv) ester, stability, minimal migratory aptitude, minimal orthoester formation, while it can be cleaved under mild conditions. We show that the remote CN group in the PivCN renders the PivCN carbonyl more electropositive and thus susceptible to nucleophilic cleavage. This feature is built upon in the automated solid-phase assembly of the oligorhamnan fragments. Where the use of a Piv-protected building block failed because of incomplete cleavage, PivCN-protected synthons performed well and allowed the generation of oligorhamnans, up to 16 monosaccharides in length. PMID- 29148770 TI - Covalent Bonding in the Hydrogen Molecule. AB - This work addresses the continuing disagreement between two schools of thought concerning the mechanism of covalent bonding. According to Hellmann, Ruedenberg, and Kutzelnigg, covalent bonding is a quantum mechanical phenomenon whereby lowering of the kinetic energy associated with electron sharing, i.e., delocalization, is the key stabilization mechanism. The opposing view of Slater, Feynman, and Bader has maintained that the source of stabilization is electrostatic potential energy lowering due to electron density redistribution to binding regions between nuclei. Following our study of H2+ we present an analogous detailed study of H2 where bonding involves an electron pair with repulsion and correlation playing a significant role in its properties. We use a range of different computational approaches to study and reveal the relevant contributions to bonding as seen in the electron density and corresponding kinetic and potential energy distributions. The energetics associated with the more complex electronic structure of H2, when examined in detail, clearly agrees with the analysis of Ruedenberg; i.e., covalent bonding is due to a decrease in the interatomic kinetic energy resulting from electronic delocalization. Our results support the view that covalent bonding is a quantum dynamical phenomenon requiring a properly quantized kinetic energy to be used in its description. PMID- 29148769 TI - Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase. AB - Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compound 6, a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose. PMID- 29148771 TI - QM/MM Study of the Reaction Catalyzed by Alkyladenine DNA Glycosylase: Examination of the Substrate Specificity of a DNA Repair Enzyme. AB - Human alkyladenine DNA glycosylase (AAG) functions as part of the base excision repair pathway to excise structurally diverse oxidized and alkylated DNA purines. Specifically, AAG uses a water molecule activated by a general base and a nonspecific active site lined with aromatic residues to cleave the N-glycosidic bond. Despite broad substrate specificity, AAG does not target the natural purines (adenine (A) and guanine (G)). Using the ONIOM(QM:MM) methodology, we provide fundamental atomic level details of AAG bound to DNA-containing a neutral substrate (hypoxanthine (Hx)), a nonsubstrate (G), or a cationic substrate (7 methylguanine (7MeG)) and probe changes in the reaction pathway that occur when AAG targets different nucleotides. We reveal that subtle differences in protein DNA contacts upon binding different substrates within the flexible AAG active site can significantly affect the deglycosylation reaction. Notably, we predict that AAG excises Hx in a concerted mechanism that is facilitated through correct alignment of the (E125) general base due to hydrogen bonding with a neighboring aromatic amino acid (Y127). Hx departure is further stabilized by pi-pi interactions with aromatic amino acids and hydrogen bonds with active site water. Despite possessing a similar structure to Hx, G is not excised since the additional exocyclic amino group leads to misalignment of the general base due to disruption of the key E125-Y127 hydrogen bond, the catalytically unfavorable placement of water within the active site, and weakened pi-contacts between aromatic amino acids and the nucleobase. In contrast, cationic 7MeG does not occupy the same position within the AAG active site as G due to steric clashes with the additional N7 methyl group, which results in the correct alignment of the general base and permits nucleobase excision as observed for neutral Hx. Overall, our structural data rationalizes the observed substrate specificity of AAG and contributes to our fundamental understanding of enzymes with flexible active sites and broad substrate specificities. PMID- 29148772 TI - Electromechanical Properties of Ba(1-x)SrxTiO3 Perovskite Solid Solutions from First-Principles Calculations. AB - An enhancement of the piezoelectric properties of lead-free materials, which allow conversion of mechanical energy into electricity, is a task of great importance and interest. Results of first-principles calculations of piezoelectric/electromechanical properties of the Ba(1-x)SrxTiO3 (BSTO) ferroelectric solid solution with a perovskite structure are presented and discussed. Calculations are performed within the linear combination of atomic orbitals (LCAO) approximation and periodic-boundary conditions, using the advanced hybrid functionals of density functional theory (DFT). A supercell model allows the investigation of multiple chemical compositions x. In particular, three BSTO solid solutions with x = 0, 0.125, 0.25 are considered within the experimental stability domain of the ferroelectric tetragonal phase of the solid solution (x < 0.3). The configurational disorder with x = 0.25 composition is also investigated explicitly considering the seven possible atomic configurations corresponding to this composition. It is predicted that Sr-doping of BaTiO3 makes it mechanically harder and enhances its electromechanical/piezoelectric properties, which are important for relevant applications. PMID- 29148773 TI - In Situ Nondestructive Analysis of Kalanchoe pinnata Leaf Surface Structure by Polarization-Modulation Infrared Reflection-Absorption Spectroscopy. AB - The outermost surface of the leaves of land plants is covered with a lipid membrane called the cuticle that protects against various stress factors. Probing the molecular-level structure of the intact cuticle is highly desirable for understanding its multifunctional properties. We report the in situ characterization of the surface structure of Kalanchoe pinnata leaves using polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS). Without sample pretreatment, PM-IRRAS measures the IR spectra of the leaf cuticle of a potted K. pinnata plant. The peak position of the CH2-related modes shows that the cuticular waxes on the leaf surface are mainly crystalline, and the alkyl chains are highly packed in an all-trans zigzag conformation. The surface selection rule of PM-IRRAS revealed the average orientation of the cuticular molecules, as indicated by the positive and negative signals of the IR peaks. This unique property of PM-IRRAS revealed that the alkyl chains of the waxes and the main chains of polysaccharides are oriented almost perpendicular to the leaf surface. The nondestructive, background-free, and environmental gas-free nature of PM-IRRAS allows the structure and chemistry of the leaf cuticle to be studied directly in its native environment. PMID- 29148774 TI - Atmospheric Oxidation of Furan and Methyl-Substituted Furans Initiated by Hydroxyl Radicals. AB - The atmospheric oxidation mechanism of furan and methylfurans (MFs) initiated by OH radicals is studied using high-level quantum chemistry and kinetic calculations. The reaction starts mainly with OH addition to the C2/C5-position, forming highly chemically activated adduct radical R2*/R5*, which would either be stabilized by collision or promptly isomerize to R2B*/R5B* by breaking the C2 O/C5-O bond and then isomerize to other conformers of R2B/R5B by internal rotations. Under the atmospheric conditions, the ring-retaining radical R2/R5 would recombine with O2 and be converted to a 5-hydroxy-2-furanone compound and a compound containing epoxide, ester, and carbonyl functional groups, while the ring-opening radicals R2B/R5B would react with O2 and form unsaturated 1,4 dicarbonyl compounds. RRKM-ME calculations on the fate of R2*/R5* from the addition of OH and furans predict that the fractions of R2B/R5B formation, i.e., the molar yields of the corresponding dicarbonyl compounds, are 0.73, 0.43, 0.26, 0.07, and 0.28 for furan, 2-MF, 3-MF, 2,3-DMF, and 2,5-DMF, respectively, at 298 K and 760 Torr when using the RHF-UCCSD(T)-F12a/cc-pVDZ-F12 reaction energies and barrier heights. The predicted yields for dicarbonyl compounds agree reasonably with recent experimental measurements. Calculations here also suggest high yields of ring-retaining 5-hydroxy-2-furanone compounds, which might deserve further study. PMID- 29148775 TI - Gold-Catalyzed Synthesis of Substituted 3-Trifluoromethylpyrroles from Mesylated Amino Trifluoromethylpropargylic Alcohols. AB - A series of substituted 3-trifluoromethylpyrroles was obtained from trifluoromethylamino-ynol derivatives via a gold-catalyzed cyclization. Using fluorinated starting materials, after mesylation, allowed for the desired compounds to be obtained in good yields under mild conditions. PMID- 29148776 TI - Coagulation of Metals in Superfluid and Normal Liquid Helium. AB - The thermal emission study in this work has shown that coagulation of metals in liquid helium is accompanied by enormous local overheating of several thousand degrees. Direct experiments demonstrated, for the first time, that condensation of metals in superfluid helium occurs via the specific mechanism which is substantially faster than that in normal liquid helium. It has been stated that coagulation of metals in superfluid helium indeed occurs in two stages, a "hot" one of nanoparticles coalescence with the formation of molten nanospheres and the subsequent stage of their sticking together into nanowires. It turned out that if a laser ablation of metal targets immersed in superfluid helium was used for introducing a metal into liquid, the formation of nanowires occurs at distances of only about 1 mm from the laser focus. This leads to the presence of a considerable number of spherical inclusions in nanowires grown in such a way. PMID- 29148777 TI - Programmable RNA Binding Proteins for Imaging and Therapeutics. PMID- 29148778 TI - Ligand-Mediated Deposition of Noble Metals at Nanoparticle Plasmonic Hotspots. AB - We report the use of gold nanoparticle surface chemistry as a tool for site selective noble metal deposition onto colloidal gold nanoparticle substrates. Specifically, we demonstrate that partial passivation of the gold nanoparticle surface using thiolated ligands can induce a transition from linear palladium island deposition to growth of palladium selectively at plasmonic hotspots on the edges or vertices of the underlying particle substrate. Further, we demonstrate the broader applicability of this approach with respect to substrate morphology (e.g., prismatic and rod-shaped nanoparticles), secondary metal (e.g., palladium, gold, and platinum), and surface ligand (e.g., surfactant molecules and n alkanethiols). Taken together, these results demonstrate the important role of metal-ligand surface chemistry and ligand packing density on the resulting modes of multimetallic nanoparticle growth, and in particular, the ability to direct that growth to particle regions of impact such as plasmonic hotspots. PMID- 29148779 TI - Hydrogen Uptake on Coordinatively Unsaturated Metal Sites in VSB-5: Strong Binding Affinity Leading to High-Temperature D2/H2 Selectivity. AB - We examine the adsorption of hydrogen and deuterium into the nanoporous nickel phosphate, VSB-5. On the basis of gas sorption analysis, VSB-5 exhibits one of the highest measured H2 heats of adsorption (HOA) for hydrogen (16 kJ/mol) yet reported. This high HOA is consistent with an unusually large red shift in the Q(1) and Q(0) hydrogen vibrational modes as measured with in situ infrared spectroscopy. The HOA for D2 is measured to be 2 kJ/mol higher than that for H2. "Ideal adsorbed solution theory" analysis of H2 and D2 isotherms provides selectivities above 4 for deuterium at 140 K, suggesting that VSB-5 is a promising adsorbent for pressure-swing adsorption-type separations of hydrogen isotopes. PMID- 29148780 TI - Spectroscopic Study of the Interaction of Carboxyl-Modified Gold Nanoparticles with Liposomes of Different Chain Lengths and Controlled Drug Release by Layer-by Layer Technology. AB - In this article, we investigate the interactions of carboxyl-modified gold nanoparticles (AuC) with zwitterionic phospholipid liposomes of different chain lengths using a well-known membrane probe PRODAN by steady-state and time resolved spectroscopy. We use three zwitterionic lipids, namely, dipalmitoylphosphatidylcholine (DPPC), 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC), and 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), which are widely different in their phase transition temperatures to form liposome-AuC assemblies. The steady-state and time-resolved studies indicate that the AuC brings in stability toward liposomes by local gelation. We observe that the bound AuC detach from the surface of the liposomes under pH ~ 5 due to protonation of the carboxyl group, thus eliminating the electrostatic interaction between nanoparticles and head groups of liposomes. The detachment rate of AuC from the liposome-AuC assemblies is different for the aforementioned liposomes due to differences in their fluidity. We exploited the phenomena for the controlled release of a prominent anticancer drug Doxorubicin (DOX) under acidic conditions for different zwitterionic liposomes. The drug release rate was further optimized by coating of liposome-AuC assemblies with oppositely charged polymer (P), polydiallyldimethylammonium chloride, followed by a mixture of lipids L (DMPC:DMPG) and again with a polymer in a layer-by-layer fashion to obtain capsule-like structures. This system is highly stable for weeks, as confirmed by field-emission scanning electron microscopy (FE-SEM) and confocal laser scanning microscopy (CLSM) imaging, and inhibits premature release. The layer coating was confirmed by hydrodynamic size and zeta potential measurements of the systems. The capsules obtained are of immense importance as they can control release of the drug from the systems to a large extent. PMID- 29148781 TI - Compound Stability in Nanoparticles: The Effect of Solid Phase Fraction on Diffusion of Degradation Agents into Nanostructured Lipid Carriers. AB - The stability of active compounds encapsulated in nanoparticles depends on the resistance of the particles to diffusion of environmental degradation agents. In this paper, off-lattice Monte Carlo simulations are used to investigate a suspension of nanostructured lipid carriers (NLC) composed of interspaced liquid and solid lipid domains, immersed in a solution containing molecules representing oxidative or other degradation agents. The simulations examine the diffusion of the degradation agents into the nanoparticles as a function of nanoparticle size, solid domain fraction, and domain size. Two types of suspensions are studied: one (representing an infinitely dilute nanoparticle suspension) where the concentration of oxidative agents is constant in the solution around the particle and the other, finite system where diffusion into the nanoparticle causes depletion in the concentration of degradation agents in the surrounding solution. The total number of degradation agent molecules in the NLCs is found to decrease with the solid domain fraction, as may be expected. However, their concentration in the liquid domains is found to increase with the solid domain fraction. Since the degradation reaction depends on the concentration of the degradation agents, this suggests that compounds encapsulated in nanoparticles with high liquid content (such as emulsions) will degrade less and be more stable than those encapsulated in NLCs with high solid domain fraction, in agreement with previous experimental results. PMID- 29148782 TI - Effect of Side-Chain Branching on Enhancement of Ionic Conductivity and Capacity Retention of a Solid Copolymer Electrolyte Membrane. AB - Low current drain driven by the low ionic conductivity of a solid polymer electrolyte is one of the major obstacles of solid-state battery. In an effort to improve the ionic conductivity of a solid polymer electrolyte membrane (PEM), polyethylene glycol diacrylate (PEGDA) and monofunctional polyethylene glycol methyl ether acrylate (PEGMEA) were copolymerized via photopolymerization to afford a PEGDA network with dangling PEGMEA side chains. By attaching PEGMEA side branches to the PEGDA network backbone, the glass transition temperature (Tg) was found to decrease, which may be controlled by relative amounts of PEGMEA and PEGDA. Concurrently, the ionic conductivity of a co-PEM consisting of lithium bis(trifluoromethane)sulfonylimide (LiTFSI) salt and a succinonitrile plasticizer in the PEGMEA-co-PEGDA copolymer network was enhanced with increasing PEGMEA side branching. The relationship between the network Tg and ionic conductivity of the branched co-PEM was analyzed in the context of the Vogel-Tammann-Fulcher equation. The plasticized branched co-PEM network exhibited room-temperature ionic conductivity at a superionic conductor level of 10-3 S/cm. Of particular importance is the fact that excellent capacity retention at a high current rate (2 C) in charge/discharge cyclings of Li4Ti5O12/co-PEM/Li and LiFePO4/co-PEM/Li half-cells was achieved. This improved charge retention may be attributed to lower frictional surfaces of the electrodes afforded by side brushes, which probably alleviates formation of irreversible reaction byproducts at the electrode/electrolyte interface. PMID- 29148783 TI - In Situ Assembly of Nanoparticles into Hierarchical Beta Zeolite with Tailored Simple Organic Molecule. AB - A hierarchically structured beta zeolite with intercrystalline mesopores was successfully synthesized via in situ assembly of nanoparticles by employing a simple organic molecule N2-p-N2, tailored from polyquaternium surfactant, with no hydrophobic long chain. The generated samples were studied by using powder X-ray diffraction (XRD) and nitrogen adsorption/desorption isotherms. Computer simulation, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) technologies were also used. The characterized results show that the tailored template molecule N2-p-N2 without hydrophobic long-chain tail still can direct the zeolite crystallization, while the hydrophobic long-chain tail is not necessary during the mesoporous Beta zeolite formation. The catalytic performances of the sample were studied using alkylation of benzene with propene reaction to evaluate the relationship between the structure and property. The results apparently suggested an overall improved resistance against deactivation as compared to conventional beta zeolite in reactions. Furthermore, this tailored simple organic molecule strategy from dual-functional surfactant for making mesoporous zeolite would offer a new method of synthesizing other hierarchically structured zeolites. PMID- 29148784 TI - Multistage Transformation and Lattice Fluctuation at AgCl-Ag Interface. AB - Solid-state transformation between different materials is often accompanied by mechanical expansion and compression due to their volume change and structural evolution at interfaces. However, these two types of dynamics are usually difficult to monitor in the same time. In this work, we use in situ transmission electron microscopy to directly study the reduction transformation at the AgCl-Ag interface. Three stages of lattice fluctuations were identified and correlated to the structural evolution. During the steady state, a quasi-layered growth mode of Ag in both vertical and lateral directions were observed due to the confinement of AgCl lattices. The development of planar defects and depletion of AgCl are respectively associated with lattice compression and relaxation. Topography and structure of decomposing AgCl was further monitored by in situ scanning transmission electron microscopy. Silver species are suggested to originate from both the surface and the interior of AgCl, and be transported to the interface. Such mass transport may have enabled the steady state and lattice compression in this volume-shrinking transformation. PMID- 29148785 TI - Rapid Quantitative Measurements of Paramagnetic Relaxation Enhancements in Cu(II) Tagged Proteins by Proton-Detected Solid-State NMR Spectroscopy. AB - We demonstrate rapid quantitative measurements of site-resolved paramagnetic relaxation enhancements (PREs), which are a source of valuable structural restraints corresponding to electron-nucleus distances in the ~10-20 A regime, in solid-state nuclear magnetic resonance (NMR) spectra of proteins containing covalent Cu2+-binding tags. Specifically, using protein GB1 K28C-EDTA-Cu2+ mutant as a model, we show the determination of backbone amide 15N longitudinal and 1H transverse PREs within a few hours of experiment time based on proton-detected 2D or 3D correlation spectra recorded with magic-angle spinning frequencies >= ~ 60 kHz for samples containing ~10-50 nanomoles of 2H,13C,15N-labeled protein back exchanged in H2O. Additionally, we show that the electron relaxation time for the Cu2+ center, needed to convert PREs into distances, can be estimated directly from the experimental data. Altogether, these results are important for establishing solid-state NMR based on paramagnetic-tagging as a routine tool for structure determination of natively diamagnetic proteins. PMID- 29148786 TI - n-Alkanethiols Directly Grown on a Bare Si(111) Surface: From Disordered to Ordered Transition. AB - We observed the growth phase transition of n-alkanethiols (AT), CH3(CH2)n-1SH, n = 4-16, directly implanted on a bare Si(111) surface, forming an AT monolayer. These monolayers were characterized with static water-contact angle, high resolution X-ray photoelectron spectroscopy, near-edge X-ray fine-structure spectroscopy, and grazing-angle reflection absorption Fourier-transform infrared spectroscopy. The integrated spectral results indicated that the implanted n-AT molecules formed a self-oriented and densely packed monolayer through formation of an S-Si bond. With the number of carbons in the alkyl chain at six or more, namely beginning at hexanethiol, the molecular monolayer began to develop an orientation-ordered structure, which is clearly shorter than that for AT monolayers on Au and Ag. This result implies that, with a stronger molecule substrate interaction, an ordered molecular monolayer can form with a short chain. PMID- 29148787 TI - Acid-Base Properties of Xanthohumol: A Computational and Experimental Investigation. AB - UV-vis spectrophotometry has been applied to determine acid dissociation constants of the prenylated chalcone xanthohumol. The pKa values were compared with those derived from pH-metric titrations. The order of the deprotonation site in the xanthohumol molecule was estimated by quantum mechanical calculations as 2'-OH, 4'-OH, and 4-OH. Furthermore, the electronic and spectroscopic properties of xanthohumol have been investigated on the basis of the time-dependent density functional theory (TDDFT). The TDDFT method, combined with a hybrid exchange correlation functional using the B3LYP and CAM-B3LYP levels of theory in conjunction with the SMD solvation model, was used to optimize all geometries and predict the excitation energies of the neutral form and ionized species of the chalcone depending on pH value. The computed results were in good agreement with the experimental data. Consideration of the acid-base profile in conjunction with other molecular properties has a great importance and has the potential to be used to further improve the bioavailability of xanthohumol. PMID- 29148788 TI - Temperature-Dependent Empirical Parameters for Polarity in Choline Chloride Based Deep Eutectic Solvents. AB - Deep eutectic solvents have emerged as a promising and economically viable alternative to address our need for environmentally benign media. Efficient utilization of deep eutectic solvents in various fields will require adequate knowledge about their physicochemical properties. In this work, independent polarity scales pertaining to solvent polarizability, dipolarity, acidity and basicity have been determined for some commonly used deep eutectic solvents based on choline chloride. The three eutectic mixtures selected for the study include reline (1:2 mixture of choline chloride and urea), ethaline (1:2 mixture of choline chloride and ethylene glycol), and glyceline (1:2 mixture of choline chloride and glycerol). The variation of the probe response as a function of temperature revealed some interesting details about the polarity of neoteric solvents being investigated. Our observations indicate that while the polarity parameters for ethaline and glyceline are easily determined, the instability of probe molecules in reline poses a potential challenge for the determination of its polarity parameters. Attempts to correlate the empirical polarity parameters with solvatochromic response of Reichardt's dye (ETN parameter) also led to surprising observations. Use of alternative probes to measure the polarity in reline indicated that the polarity scales using different probes need to be normalized for DESs. The results emphasize the extent of applicability of currently employed polarity scales to determine the polarity of DES, the need to develop appropriate probe molecules, and the factors limiting our understanding of these extremely interesting class of solvents. PMID- 29148789 TI - Amphiphilic N-Heterocyclic Carbene-Stabilized Gold Nanoparticles and Their Self Assembly in Polar Solvents. AB - Soft matter-directed self-assembly of amphiphilic inorganic nanoparticles (NPs) has recently emerged as a promising approach to access NP ensembles with superior collective properties. While thiol-terminated molecules are primarily employed to tether the amphiphilic ligand to the metal, concerns remain regarding the stabilities of the resulting NPs and their corresponding aggregates. As an alternative, we report amphiphilic N-heterocyclic carbene (NHC)-functionalized gold nanoparticles (AuNPs). To accomplish this, an amphiphilic NHC-AuI complex based on an asymmetric triethylene glycol-/dodecyl-functionalized benzimidazole was first synthesized and used to prepare the corresponding stable amphiphilic NHC-decorated AuNPs. The resulting NPs were comprehensively characterized using both solution- and solid-state-based techniques such as proton nuclear magnetic resonance spectroscopy, dynamic light scattering, transmission electron microscopy, thermogravimetric analysis, and X-ray photoelectron spectroscopy. By optimizing the self-assembly behavior of these amphiphilic AuNPs in deionized water, ethanol, and their mixtures, we were able to fine-tune the plasmonic properties of the AuNPs in the wide range of 525-640 nm. Furthermore, when treated with thiols, the ensembles showed greater stability compared to their parent discrete AuNP counterparts at room temperature. PMID- 29148790 TI - Solid-State Dewetting of Gold Aggregates/Islands on TiO2 Nanorod Structures Grown by Oblique Angle Deposition. AB - A composite film made of a stable gold nanoparticle (NP) array with well controlled separation and size atop a TiO2 nanorod film was fabricated via the oblique angle deposition (OAD) technique. The fabrication of the NP array is based on controlled, Rayleigh-instability-induced, solid-state dewetting of as deposited gold aggregates on the TiO2 nanorods. It was found that the initial spacing between as-deposited gold aggregates along the vapor flux direction should be greater than the TiO2 interrod spacing created by 80 degrees OAD to control dewetting and produce NP arrays. A numerical investigation of the process was conducted using a phase-field modeling approach. Simulation results showed that coalescence between neighboring gold aggregates is likely to have caused the uncontrolled dewetting in the 80 degrees deposition, and this could be circumvented if the initial spacing between gold aggregates is larger than a critical value smin. We also found that TiO2 nanorod tips affect dewetting dynamics differently than planar TiO2. The topology of the tips can induce contact line pinning and an increase in the contact angle along the vapor flux direction to the supported gold aggregates. These two effects are beneficial for the fabrication of monodisperse NPs based on Rayleigh-instability-governed self assembly of materials, as they help to circumvent the undesired coalescence and facilitate the instability growth on the supported material. The findings uncover the application potential of OAD as a new method to fabricate structured films as template substrates to mediate dewetting. The reported composite films would have uses in optical coatings and photocatalytic systems, taking advantage of their ability to combine plasmonic nanostructures within a nanostructured dielectric film. PMID- 29148791 TI - Total Synthesis and Absolute Configuration of Raputindole A. AB - The first total synthesis of the bisindole alkaloid raputindole A from the rutaceous plant Raputia simulans is reported. The key step is a Au(I)-catalyzed cyclization that assembles the cyclopenta[f]indole tricycle from a 6-alkynylated indoline precursor. The isobutenyl side chain was installed by Suzuki-Miyaura cross-coupling, followed by a regioselective reduction employing LiDBB. Starting from 6-iodoindole, the sequence needs nine steps and provided (+/-)-raputindole A in 6.6% overall yield. The absolute configuration of the natural product (+) raputindole A was determined by quantum chemical calculation of the ECD spectrum. PMID- 29148792 TI - Proteomic Markers of Functional Sperm Population in Bovines: Comparison of Low- and High-Density Spermatozoa Following Cryopreservation. AB - Mammalian semen contains a heterogeneous population of sperm cells. This heterogeneity results from variability in the complex processes of cell differentiation in the testis, biochemical modifications undergone by spermatozoa during transit along the male reproductive tract, interactions with secretions from accessory sex glands at ejaculation, and, in the context of reproductive technologies, in the ability of ejaculated spermatozoa to resist damage associated with freeze-thaw procedures. When submitted to density gradient centrifugation, ejaculated spermatozoa distribute themselves into two distinct populations: a low-density population characterized by low motility parameters, and a high-density population with high motility characteristics. To understand the origin of ejaculated spermatozoa heterogeneity, cryopreserved semen samples from bulls used by the artificial insemination (A.I.) industry were submitted to Percoll gradient centrifugation. Proteins from low and high density spermatozoa were then extracted with sodium deoxycholate and submitted to proteomic analysis using iTRAQ (isobaric tag for relative and absolute quantitation) methodologies. Quantification of selected sperm proteins was confirmed by multiple reaction monitoring (MRM). Overall, 31 different proteins were more abundant in low density spermatozoa, while 80 different proteins were more abundant in the high density subpopulation. Proteins enriched in high-density spermatozoa were markers of sperm functionality such as the glycolytic process, binding to the egg zona pellucida, and motility. Low-density spermatozoa were not solely characterized by loss of proteins and their associated functions. Chaperonin-containing TCP1s and chaperones are hallmarks of the low-density subpopulation. iTRAQ analysis revealed that other proteins such as binder of sperm proteins, histone, GPX5, ELSPBP1, and clusterin are overexpressed in low-density spermatozoa suggesting that these proteins represent defects occurring at different steps during the sperm journey. These differences contribute to the sperm cell heterogeneity present in mammalian semen. PMID- 29148793 TI - Light and Magnetic Dual-Responsive Pickering Emulsion Micro-Reactors. AB - Emulsion droplets can serve as ideal compartments for reactions. In fact, in many cases, the chemical reactions are supposed to be triggered at a desired position and time without change of the system environment. Here, we present a type of light and magnetic dual-responsive Pickering emulsion microreactor by coadsorption of light-sensitive titania (TiO2) and super paramagnetic iron oxide (Fe3O4) nanoparticles at the oil-water interface of emulsion droplets. The droplets encapsulating different reactants in advance can be driven close to each other by an external magnetic field, and then the chemical reaction is triggered by UV illumination due to the contact of the isolated reactants as a result of droplet coalescence. An insight into the incorporation of hydrophobic TiO2 and hydrophilic Fe3O4 nanoparticles simultaneously at the emulsion interface is achieved. On the basis of that, an account is given of the coalescence mechanism of the Pickering emulsion microreactors. Our work not only provides a novel Pickering emulsion microreactor platform for triggering chemical reactions in a nonintrusive and well-controlled way but also opens a promising avenue to construct multifunctional Pickering emulsions by assembly of versatile building block nanoparticles at the interface of emulsion droplets. PMID- 29148794 TI - Preparation and Formation Process of Zn(II)-Coordinated Nanovesicles. AB - Mixing a glycylglycine lipid and zinc acetate has been reported to form novel supramolecular Zn(II)-coordinated nanovesicles in ethanol. In this study, we investigate in detail the formation of nanovesicles by using three lipids at different temperatures and discuss their formation process. The original lipids show extremely low solubilities and appear as plate structures in ethanol. Within a small window of lipid solubility, the formation of lipid-Zn(II) complexes occurs mainly on the solid surfaces of plate structures. Controlling of the lipid solubility by temperature affects the kinetics of complex formation and the subsequent transformation of the complexes into nanovesicles and nanotubes. An improved method of two-step control of temperature is developed for preparing all the three kinds of nanovesicles. We provide new insights into the formation process of nanovesicles based on several control experiments. A tetrahedral lipid cobalt(II) complex similarly produces nanovesicles, whereas an octahedral complex gives sheet structures. Mixing of zinc acetate with a beta-alanyl-beta-alanine lipid can only give sheet structures, which lack a polyglycine II hydrogen-bond network and induce no morphological changes. We conclude that the formation of the lipid-Zn(II) complexes on solid plate structures, tetrahedral geometry, and polyglycine II hydrogen-bond network in the complexes shall work cooperatively for the formation of Zn(II)-coordinated nanovesicles. PMID- 29148795 TI - Bromide-Mediated C-H Bond Functionalization: Intermolecular Annulation of Phenylethanone Derivatives with Alkynes for the Synthesis of 1-Naphthols. AB - Bromide-mediated intermolecular annulation of phenylethanone derivatives with alkynes has been developed, which allows for the regioselective formation of polysubstituted 1-naphthols. The usage of readily available bromine catalyst, broad substrate scope, and mild conditions make this protocol very practical. Mechanistic investigations reveal that the bromination of phenylethanone derivatives occurs to yield bromo-substituted intermediates, which react in situ with alkynes to furnish the desired 1-naphthols. PMID- 29148796 TI - Layer-By-Layer Self-Assembly of Polyelectrolytic Block Copolymer Worms on a Planar Substrate. AB - Cationic and anionic block copolymer worms are prepared by polymerization-induced self-assembly via reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion copolymerization of 2-hydroxypropyl methacrylate and glycidyl methacrylate (GlyMA), using a binary mixture of a nonionic poly(ethylene oxide) macromolecular RAFT agent and either a cationic poly([2 (methacryloyloxy)ethyl]trimethylammonium chloride) or an anionic poly(potassium 3 sulfopropyl methacrylate) macromolecular RAFT agent. In each case, covalent stabilization of the worm cores was achieved via reaction of the epoxide groups on the GlyMA repeat units with 3-mercaptopropyltriethoxysilane. Aqueous electrophoresis studies indicated a pH-independent mean zeta potential of +40 mV and -39 mV for the cationic and anionic copolymer worms, respectively. These worms are expected to mimic the rigid rod behavior of water-soluble polyelectrolyte chains in the absence of added salt. The kinetics of adsorption of the cationic worms onto a planar anionic silicon wafer was examined at pH 5 and was found to be extremely fast at 1.0 w/w % copolymer concentration in the absence of added salt. Scanning electron microscopy (SEM) analysis indicated that a relatively constant worm surface coverage of 16% was achieved at 20 degrees C for adsorption times ranging from just 2 s up to 2 min. Furthermore, the successive layer-by-layer deposition of cationic and anionic copolymer worms onto planar surfaces was investigated using SEM, ellipsometry, and surface zeta potential measurements. These techniques confirmed that the deposition of oppositely charged worms resulted in a monotonic increase in the mean layer thickness, with a concomitant surface charge reversal occurring on addition of each new worm layer. Unexpectedly, two distinct linear regimes were observed when plotting the mean layer thickness against the total number of adsorbed worm layers, with a steeper gradient (corresponding to thicker layers) being observed after the deposition of six worm layers. PMID- 29148797 TI - Nigegladines A-C, Three Thymoquinone Dimers from Nigella glandulifera. AB - Nigegladines A-C (1-3), three thymoquinone dimers, were isolated from the seeds of Nigella glandulifera. Racemic 1 possesses a unique tricyclo[5.4.0.12,6]dodecane carbon skeleton, and compounds 2 and 3 are two unusual diterpenoid alkaloids with indole cores. Their structures were determined by extensive spectroscopic analyses, and that of 1 was confirmed by single crystal X-ray diffraction. Both (+)-1 and (-)-1 exhibited significant protective effects against hypoxia/reoxygenation-induced H9c2 myocardial cell injury. PMID- 29148798 TI - Addition to "Molecular Origin and Self-Assembly of Fluorescent Carbon Nanodots in Polar Solvents". PMID- 29148799 TI - Uniaxial 2D Superlattice of Fe4 Molecular Magnets on Graphene. AB - We demonstrate that electrospray deposition enables the fabrication of highly periodic self-assembled arrays of Fe4H single molecule magnets on graphene/Ir(111). The energetic positions of molecular states are probed by means of scanning tunneling spectroscopy, showing pronounced long- and short-ranged spatial modulations, indicating the presence of both locally varying intermolecular as well as adsorption-site dependent molecule-substrate interactions. From the magnetic field dependence of the X-ray magnetic circular dichroism signal, we infer that the magnetic easy axis of each Fe4H molecule is oriented perpendicular to the sample surface and that after the deposition the value of the uniaxial anisotropy is identical to the one in bulk. Our findings therefore suggest that the observed interaction of the molecules with their surrounding does not modify the molecular magnetism, resulting in a two dimensional array of molecular magnets that retain their bulk magnetic properties. PMID- 29148800 TI - Size and Shape of Amyloid Fibrils Induced by Ganglioside Nanoclusters: Role of Sialyl Oligosaccharide in Fibril Formation. AB - Ganglioside-enriched microdomains in the presynaptic neuronal membrane play a key role in the initiation of amyloid beta-protein (Abeta) assembly related to Alzheimer's disease. We previously isolated lipids from a detergent-resistant membrane microdomain fraction of synaptosomes prepared from aged mouse brain and found that spherical Abeta assemblies were formed on Abeta-sensitive ganglioside nanoclusters (ASIGN) of reconstituted lipid bilayers in the synaptosomal fraction. In the present study, we investigated the role of oligosaccharides in Abeta fibril formation induced by ganglioside-containing mixed lipid membranes that mimic the features of ASIGN. Ganglioside nanoclusters were constructed as ternary mixed lipid bilayers composed of ganglioside (GM1, GM2, GM3, GD1a, or GT1b), sphingomyelin, and cholesterol, and their surface topography was visualized by atomic force microscopy. Abeta fibril formation on the nanocluster was strongly induced in the presence of 10 mol % ganglioside, and Abeta-sensitive features were observed at cholesterol contents of 35-55 mol %. GM1-, GD1a-, and GT1b-containing membranes induced longer fibrils than those containing GD1b and GM2, indicating that the terminal galactose of GM1 along with N-acetylneuraminic acid accelerates protofibril elongation. These results demonstrate that Abeta fibril formation is induced by ASIGN that are highly enriched ganglioside nanoclusters with a limited number of components and that the generation and elongation of Abeta protofibrils are regulated by the oligosaccharide structure of gangliosides. PMID- 29148801 TI - Neuropeptidomics of the Bed Bug Cimex lectularius. AB - The bed bug Cimex lectularius is a globally distributed human ectoparasite with fascinating biology. It has recently acquired resistance against a broad range of insecticides, causing a worldwide increase in bed bug infestations. The recent annotation of the bed bug genome revealed a full complement of neuropeptide and neuropeptide receptor genes in this species. With regard to the biology of C. lectularius, neuropeptide signaling is especially interesting because it regulates feeding, diuresis, digestion, as well as reproduction and also provides potential new targets for chemical control. To identify which neuropeptides are translated from the genome-predicted genes, we performed a comprehensive peptidomic analysis of the central nervous system of the bed bug. We identified in total 144 different peptides from 29 precursors, of which at least 67 likely present bioactive mature neuropeptides. C. lectularius corazonin and myosuppressin are unique and deviate considerably from the canonical insect consensus sequences. Several identified neuropeptides likely act as hormones, as evidenced by the occurrence of respective mass signals and immunoreactivity in neurohemal structures. Our data provide the most comprehensive peptidome of a Heteropteran species so far and in comparison suggest that a hematophageous life style does not require qualitative adaptations of the insect peptidome. PMID- 29148802 TI - pPB Peptide-Mediated siRNA-Loaded Stable Nucleic Acid Lipid Nanoparticles on Targeting Therapy of Hepatic Fibrosis. AB - Hepatic fibrosis is a necessary process in the development of liver diseases such as hepatic cirrhosis and its complications, which has become a serious threat to human health. Currently, antifibrotic drug treatment is ineffective, and one reason should be the lack of liver targeting ability. In this report, polypeptide pPB-modified stable nucleic acid lipid nanoparticles (pPB-SNALPs) were prepared to selectively deliver siRNAs against heat shock protein 47 to the liver for targeted therapy of hepatic fibrosis. First, siRNA sequences with high silencing efficiency were screened based on siRNA transfection efficacy. Then, pPB-SNALPs were prepared, which showed a narrow size distribution with a diameter in the range of 110-130 nm and a neutral z-potential of 0 mV. As evidenced by the in vitro and in vivo targeting study, compared with unmodified SNALP, pPB-SNALP showed increased uptake by LX-2 cells and primary hepatic stellate cells (HSC) of mice in vitro and showed increased liver distribution and HSC uptake in vivo. In addition, pPB-SNALP also exhibited an enhanced inhibitory effect on TAA-induced hepatic fibrosis mice with high gp46 mRNA expression in vivo. In summary, our results demonstrated that pPB-SNALP is an effective liver-targeted delivery system. This study could lay a good foundation for the targeted gene therapy of hepatic fibrosis. PMID- 29148803 TI - HsDHODH Microdomain-Membrane Interactions Influenced by the Lipid Composition. AB - Human dihydroorotate dehydrogenase (HsDHODH) enzyme has been studied as selective target for inhibitors to block the enzyme activity, intending to prevent proliferative diseases. The N-terminal microdomain seems to play an important role in the enzyme function. However, the molecular mechanism of action and dynamics of this region are not totally understood yet. This study analyzes the interaction and conformation in model membranes of HsDHODH microdomain using peptide analogues containing the paramagnetic amino acid TOAC at strategic positions. In buffer solution, the analogues presented a disordered conformation, but acquired a high content of alpha-helical structure in membrane mimetics, which was found to be lipid dependent. The microdomain peptide structure in micelles showed a very different peptide conformation when compared to the reported crystal structure, displaying a conformational flexibility of its helices, promoted by the connecting loop, which might be functionally relevant. Electron spin resonance in membrane compositions containing POPC, POPE, and cardiolipin showed that interaction of the analogues was enhanced by the presence of cardiolipin, indicating that the microdomain preferentially interacts with cardiolipin-containing membranes. Therefore, the great flexibility of the microdomain and the cardiolipin affinity should be considered in further studies aimed at finding new inhibitory compounds to fight proliferative diseases. PMID- 29148804 TI - A Nanobionic Light-Emitting Plant. AB - The engineering of living plants for visible light emission and sustainable illumination is compelling because plants possess independent energy generation and storage mechanisms and autonomous self-repair. Herein, we demonstrate a plant nanobionic approach that enables exceptional luminosity and lifetime utilizing four chemically interacting nanoparticles, including firefly luciferase conjugated silica (SNP-Luc), d-luciferin releasing poly(lactic-co-glycolic acid) (PLGA-LH2), coenzyme A functionalized chitosan (CS-CoA) and semiconductor nanocrystal phosphors for longer wavelength modulation. An in vitro kinetic model incorporating the release rates of the nanoparticles is developed to maximize the chemiluminescent lifetimes to exceed 21.5 h. In watercress (Nasturtium officinale) and other species, the nanoparticles circumvent limitations such as luciferin toxicity above 400 MUM and colocalization of enzymatic reactions near high adenosine triphosphate (ATP) production. Pressurized bath infusion of nanoparticles (PBIN) is introduced to deliver a mixture of nanoparticles to the entire living plant, well described using a nanofluidic mathematical model. We rationally design nanoparticle size and charge to control localization within distinct tissues compartments with 10 nm nanoparticles localizing within the leaf mesophyll and stomata guard cells, and those larger than 100 nm segregated in the leaf mesophyll. The results are mature watercress plants that emit greater than 1.44 * 1012 photons/sec or 50% of 1 MUW commercial luminescent diodes and modulate "off" and "on" states by chemical addition of dehydroluciferin and coenzyme A, respectively. We show that CdSe nanocrystals can shift the chemiluminescent emission to 760 nm enabling near-infrared (nIR) signaling. These results advance the viability of nanobionic plants as self-powered photonics, direct and indirect light sources. PMID- 29148805 TI - Near-Infrared Quantum Dot Emission Enhanced by Stabilized Self-Assembled J Aggregate Antennas. AB - Enhancing photoluminescent emission (PL) in the near-infrared-infrared (NIR-IR) spectral region has broad applications from solar energy conversion to biological imaging. We show that self-assembled molecular dye J-aggregates (light-harvesting nanotubes, LHNs) can increase the PL emission of NIR PbS quantum dots (QDs) in both liquid and solid media more than 8-fold, promoted primarily by a long-range antenna effect and efficient Forster resonance energy transfer (FRET) from donor to acceptor. To create this composite material and preserve the optical properties of the nanocrystals, we performed an in situ ligand substitution followed by a functionalization reaction using click-chemistry. This resulted in PbS QDs soluble in an aqueous environment compatible with the molecular J aggregates (LHNs). Theoretical and experimental results demonstrate that long range diffusive exciton transport in LHNs enables efficient energy transfer to low concentrations of QDs despite there being no direct binding between molecular donors and QD acceptors. This suggests a broad application space for mixed light harvesting and photophysically active nanocomposite materials based on self assembling molecular aggregates. PMID- 29148806 TI - Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). AB - The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC. PMID- 29148807 TI - Catholyte Formulations for High-Energy Li-S Batteries. AB - The sulfur electrode in LiS batteries suffers from rapid capacity loss and low efficiency due to the solubility of long chain polysulfides formed during discharge. Herein, we demonstrate the beneficial effect of original catholyte formulations containing redox active organyl disulfides (PhS2Ph) on the capacity utilization and retention as well as the efficiency in LiS batteries. Resulting from the chemical equilibria in the electrolyte between the sulfur/polysulfides (S8/Sx2-) and disulfide/thiolates (PhS2Ph/PhSx-), the polysulfide redox shuttle phenomenon is minimized due to the suppression of formation of soluble polysulfides (Sx2-, x > 4). Using the catholyte containing 0.4 M Ph2S2 as an additive in a standard base electrolyte (DOL/DME + LiTFSI/LiNO3), a stable capacity of 1050 mAh.g-1 is obtained under galvanostatic cycling at C/5 with a Coulombic efficiency of >99.5%. At 45 degrees C, it is shown that the formulated catholyte enables galvanostatic cycling at a high c-rate of 1C over 500 cycles with a capacity above 900 mAh.g-1 and a high energy efficiency of 82%. PMID- 29148808 TI - Detection of Short-Waved Spin Waves in Individual Microscopic Spin-Wave Waveguides Using the Inverse Spin Hall Effect. AB - The miniaturization of complementary metal-oxide-semiconductor (CMOS) devices becomes increasingly difficult due to fundamental limitations and the increase of leakage currents. Large research efforts are devoted to find alternative concepts that allow for a larger data-density and lower power consumption than conventional semiconductor approaches. Spin waves have been identified as a potential technology that can complement and outperform CMOS in complex logic applications, profiting from the fact that these waves enable wave computing on the nanoscale. The practical application of spin waves, however, requires the demonstration of scalable, CMOS compatible spin-wave detection schemes in material systems compatible with standard spintronics as well as semiconductor circuitry. Here, we report on the wave-vector independent detection of short waved spin waves with wavelengths down to 150 nm by the inverse spin Hall effect in spin-wave waveguides made from ultrathin Ta/Co8Fe72B20/MgO. These findings open up the path for miniaturized scalable interconnects between spin waves and CMOS and the use of ultrathin films made from standard spintronic materials in magnonics. PMID- 29148809 TI - Catalytic Enantioselective Intermolecular [5 + 2] Dipolar Cycloadditions of a 3 Hydroxy-4-pyrone-Derived Oxidopyrylium Ylide. AB - The first catalytic enantioselective [5 + 2] dipolar cycloaddition of a 3-hydroxy 4-pyrone-derived oxidopyrylium ylide is described. These studies leveraged the recently recognized ability of oxidopyrylium dimers to serve as the source of ylide, which was found to be key to increasing yields and achieving enantiomeric excesses up to 99%. General reaction conditions were identified for an array of alpha,beta-unsaturated aldehyde dipolarophiles. Reaction products possess four stereocenters, and subsequent reduction introduced a fifth contiguous stereocenter with total stereocontrol. PMID- 29148810 TI - Enhancement of Light Absorption in Silicon Nanowire Photovoltaic Devices with Dielectric and Metallic Grating Structures. AB - We report the enhancement of light absorption in Si nanowire photovoltaic devices with one-dimensional dielectric or metallic gratings that are fabricated by a damage-free, precisely aligning, polymer-assisted transfer method. Incorporation of a Si3N4 grating with a Si nanowire effectively enhances the photocurrents for transverse-electric polarized light. The wavelength at which a maximum photocurrent is generated is readily tuned by adjusting the grating pitch. Moreover, the electrical properties of the nanowire devices are preserved before and after transferring the Si3N4 gratings onto Si nanowires, ensuring that the quality of pristine nanowires is not degraded during the transfer. Furthermore, we demonstrate Si nanowire photovoltaic devices with Ag gratings using the same transfer method. Measurements on the fabricated devices reveal approximately 27.1% enhancement in light absorption compared to that of the same devices without the Ag gratings without any degradation of electrical properties. We believe that our polymer-assisted transfer method is not limited to the fabrication of grating-incorporated nanowire photovoltaic devices but can also be generically applied for the implementation of complex nanoscale structures toward the development of multifunctional optoelectronic devices. PMID- 29148811 TI - Continuous Pore-Spanning Lipid Bilayers on Silicon Oxide-Coated Porous Substrates. AB - A number of techniques has been developed and analyzed in recent years to generate pore-spanning membranes (PSMs). While quite a number of methods rely on nanoporous substrates, only a few use micrometer-sized pores to be able to individually resolve suspending membranes by means of fluorescence microscopy. To be able to produce PSMs on pores that are micrometer in size, an orthogonal functionalization strategy resulting in a hydrophilic surface is highly desirable. Here, we report on a method to prepare PSMs based on the evaporation of a thin layer of silicon monoxide on top of the porous substrate. PM-IRRAS experiments demonstrate that the final surface is composed of SiOx with 1 < x < 2. The hydrophilic surface turned out to be well suited to spread giant unilamellar vesicles forming PSMs. As the method does not rely on a gold coating as frequently used for orthogonal functionalization, fluorescence micrographs provide information not only from the freestanding membrane areas but also from the supported ones. The observation of the entire PSM area enabled us to observe phase-separation in these membranes on the freestanding and supported parts as well as protein binding and possible lipid reorganization of the membranes induced by binding of the protein Shiga toxin. PMID- 29148812 TI - Behavior of a Liquid Bridge between Nonparallel Hydrophobic Surfaces. AB - When a liquid bridge is formed between two nonparallel identical surfaces, it can move along the surfaces. Literature indicates that the direction of bridge movement is governed by the wettability of surfaces. When the surfaces are hydrophilic, the motion of the bridge is always toward the cusp (intersection of the plane of the two bounding surfaces). On the other hand, the movement is hitherto thought to be always pointing away from the cusp when the surfaces are hydrophobic. In this study, through experiments, numerical simulations, and analytical reasoning, we demonstrate that for hydrophobic surfaces, wettability is not the only factor determining the direction of the motion. A new geometrical parameter, i.e., confinement (cf), was defined as the ratio of the distance of the farthest contact point of the bridge to the cusp, and that of the closest contact point to the cusp. The direction of the motion depends on the amount of confinement (cf). When the distance between the surfaces is large (resulting in a small cf), the bridge tends to move toward the cusp through a pinning/depinning mechanism of contact lines. When the distance between the surfaces is small (large cf), the bridge tends to move away from the cusp. For a specific system, a maximum cf value (cfmax) exists. A sliding behavior (i.e., simultaneous advancing on the wider side and receding on the narrower side) can also be seen when a liquid bridge is compressed such that the cf exceeds the cfmax. Contact angle hysteresis (CAH) is identified as an underpinning phenomenon that together with cf fundamentally explains the movement of a trapped liquid between two hydrophobic surfaces. If there is no CAH, however, i.e., the case of ideal hydrophobic surfaces, the cf will be a constant; we show that the bridge slides toward the cusp when it is stretched, while it slides away from the cusp when it is compressed (note sliding motion is different from motion due to pinning/depinning mechanism of contact lines). As such, the displacement is only related to geometrical parameters such as the amount of compression (or stretching) and the dihedral angle between the surfaces. PMID- 29148813 TI - Stitching Oxindoles and Ynones in a Domino Process: Access to Spirooxindoles and Application to a Short Synthesis of Spindomycin B. AB - A general, transition-metal-free, one-pot, domino Michael-SNAr or AdNE substitution protocol was devised for spiroannulation of oxindoles with ortho bromoaryl ynones, beta-bromoalkenyl ynones, and beta-bromoalkenyl enones in a convenient and efficient manner. As an application, a short synthesis of tetracyclic alkaloid spindomycin B was accomplished. PMID- 29148814 TI - High-Yield Production of MoS2 and WS2 Quantum Sheets from Their Bulk Materials. AB - Mass production of two-dimensional quantum sheets (2D QSs) is highly desired to fully exploit their properties. Herein, we present a general strategy for the high-yield production of molybdenum disulfide (MoS2) and tungsten disulfide (WS2) QSs by a sequential combination of salt-assisted ball-milling and sonication assisted solvent exfoliation of their bulk materials. Such a strategy enables reproducible production of intrinsic and defect-free MoS2 and WS2 QSs with exceedingly high yields of 25.5 and 20.1 wt %, respectively. By precipitation redispersion treatment, the QSs can be redispersed in a wide range of solvents with redispersion concentration up to 20 mg/mL or even higher. Remarkable nonlinear absorption saturation is demonstrated in the QSs-poly(methyl methacrylate) (PMMA) hybrid thin film with loading content of merely 0.1 wt %. Our method provides an avenue toward mass production and full exploration of 2D QSs. PMID- 29148815 TI - Information-Theoretic Approaches to Atoms-in-Molecules: Hirshfeld Family of Partitioning Schemes. AB - Many population analysis methods are based on the precept that molecules should be built from fragments (typically atoms) that maximally resemble the isolated fragment. The resulting molecular building blocks are intuitive (because they maximally resemble well-understood systems) and transferable (because if two molecular fragments both resemble an isolated fragment, they necessarily resemble each other). Information theory is one way to measure the deviation between molecular fragments and their isolated counterparts, and it is a way that lends itself to interpretation. For example, one can analyze the relative importance of electron transfer and polarization of the fragments. We present key features, advantages, and disadvantages of the information-theoretic approach. We also codify existing information-theoretic partitioning methods in a way that clarifies the enormous freedom one has within the information-theoretic ansatz. PMID- 29148816 TI - Assessment of Antipiperacillin IgG Binding to Structurally Related Drug Protein Adducts. AB - The risk of developing hypersensitivity to alternative antibiotics is a concern for penicillin hypersensitive patients and healthcare providers. Herein we use piperacillin hypersensitivity as a model to explore the reactivity of drug specific IgG against alternative beta-lactam protein adducts. Mass spectrometry was used to show the drugs (amoxicillin, flucloxacillin, benzyl penicillin, aztreonam, and piperacillin) bind to similar lysine residues on the protein carrier bovine serum albumin. However, the hapten-specific IgG antibodies found in piperacillin hypersensitive patient plasma did not bind to other beta-lactam protein conjugates. These data outline the fine specificity of piperacillin specific IgG antibodies that circulate in patients with hypersensitivity. PMID- 29148817 TI - Specific Recognition of G-Quadruplexes Over Duplex-DNA by a Macromolecular NIR Two-Photon Fluorescent Probe. AB - The implication of guanine-rich DNA sequences in biologically important roles such as telomerase dysfunction and the regulation of gene expression has prompted the search for structure-specific G-quadruplex agents for targeted diagnostic and therapeutic applications. Herein, we report on a near-infrared (NIR) two-photon poly(cationic) anthracene-based macromolecule able to selectively target G quadruplexes (G4s) over genomic double-stranded DNA. In particular, the striking changes in its linear and third-order nonlinear optical properties, combined with the emergence of a strong induced electronic circular dichroism (ECD) signal upon binding to canonical and noncanonical DNA secondary structures allowed for a highly specific detection of several different G4s. Furthermore, through a detailed computational analysis we bring compelling evidence that our probe intercalation within G4s is a thermodynamically favored event, and we fully rationalize the spectroscopic evolution resulting from this complexation event by providing a reasonable explanation regarding the origin of the peculiar ECD effect that accompanies it. PMID- 29148818 TI - Dissociation Constants of Cytochrome P450 2C9/Cytochrome P450 Reductase Complexes in a Lipid Bilayer Membrane Depend on NADPH: A Single-Protein Tracking Study. AB - Cytochrome P450-reductase (CPR) is a versatile NADPH-dependent electron donor located in the cytoplasmic side of the endoplasmic reticulum. It is an electron transferase that is able to deliver electrons to a variety of membrane-bound oxidative partners, including the drug-metabolizing enzymes of the cytochrome P450s (P450). CPR is also stoichiometrically limited compared to its oxidative counterparts, and hypotheses have arisen about possible models that can overcome the stoichiometric imbalance, including quaternary organization of P450 and diffusion-limited models. Described here are results from a single-protein tracking study of fluorescently labeled CPR and cytochrome P450 2C9 (CYP2C9) molecules in which stochastic analysis was used to determine the dissociation constants of CPR/CYP2C9 complexes in a lipid bilayer membrane for the first time. Single-protein trajectories demonstrate the transient nature of these CPR-CYP2C9 interactions, and the measured Kd values are highly dependent on the redox state of CPR. It is shown that CPRox/CYP2C9 complexes have a much higher dissociation constant than CPR2-/CYP2C9 or CPR4-/CYP2C9 complexes, and a model is presented to account for these results. An Arrhenius analysis of diffusion constants was also carried out, demonstrating that the reduced forms of CPR and CYP2C9 interact differently with the biomimetic ER and may, in addition to protein conformational changes, contribute to the observed NADPH-dependent shift in Kd. Finally, it is also shown that the CPRox/CYP2C9 affinity depends on the nature of the ligand, being higher when a substrate is bound, compared to an inhibitor. PMID- 29148819 TI - Unveiling Structural Motions of a Highly Fluorescent Superphotoacid by Locking and Fluorinating the GFP Chromophore in Solution. AB - Superphotoacidity involves ultrafast proton motions implicated in numerous chemical and biological processes. We used conformational locking and strategic addition of electron-withdrawing substituents to synthesize a new GFP chromophore analogue: p-HO-3,5-diF-BDI:BF2 (diF). It is highly fluorescent and exhibits excited-state proton transfer (ESPT) in various solvents, placing it among the strongest photoacids. Tunable femtosecond stimulated Raman spectroscopy with unique resonance conditions and transient absorption are complementarily employed to elucidate the structural basis for superphotoacidity. We reveal a multistep ESPT reaction from diF to methanol with an initial proton dissociation on the ~600 fs time scale that forms a charge-separated state, stabilized by solvation, and followed by a diffusion-controlled proton transfer on the ~350 ps time scale. A ~1580 cm-1 phenolic ring motion is uncovered to accompany ESPT before 1 ps. This study provides a vivid movie of the photoinduced proton dissociation of a superphotoacid with bright fluorescence, effectively bridging fundamental mechanistic insights to precise control of macroscopic functions. PMID- 29148820 TI - A Functional Kinase Short Interfering Ribonucleic Acid Screen Using Protease Activated Receptor 2-Dependent Opening of Transient Receptor Potential Vanilloid 4. AB - Protease-activated receptor 2 (PAR2) is a proinflammatory G-protein coupled receptor (GPCR) that is activated by inflammatory proteases, and its activation initiates signaling pathways that modulate the nonselective cation channel transient receptor potential vanilloid-4 (TRPV4). PAR2-dependent opening of TRPV4 has been attributed to kinase activation, but the identity of the responsible enzymes is unknown. Deciphering the signaling pathways involved in the PAR2 dependent opening of TRPV4 may yield new targets for pain treatment. This study has identified specific kinases that are involved in opening TRPV4, using a selective screen of short interfering ribonucleic acid (siRNA) SMARTpools, which individually targeted all human kinases, in human embryonic kidney 293 (HEK293) cells that stably express inducible TRPV4. This screen is unique because it uses a real-time assay measuring intracellular calcium with Fura-2AM dye. From the primary screen, subsequent confirmation screen, and on-target messenger ribonucleic acid expression analysis, we identified two kinases as crucial to the PAR2-dependent opening of TRPV4 in HEK293 cells, mitogen-activated protein kinase 13 and with no lysine kinase 4. In conclusion, this study describes a powerful new application of siRNA knockdown to identity signaling molecules that are responsible for the PAR2-dependent opening of TRPV4, which will help elucidate this signaling process. PMID- 29148821 TI - The Effect of Prior Continuous Glucose Monitoring Use on Glycemic Outcomes in the Pivotal Trial of the MiniMedTM 670G Hybrid Closed-Loop System. AB - A 3-month pivotal trial using the MiniMedTM 670G hybrid closed-loop (HCL) system in adolescent and adult patients with type 1 diabetes (T1D), relative to a 2-week baseline run-in period, resulted in increased sensor glucose (SG) values in target range (71-180 mg/dL), reduced HbA1c levels, and no events of diabetic ketoacidosis or severe hypoglycemia ( Clinicaltrials.gov : NCT02463097). This brief report evaluated how prior continuous glucose monitoring (CGM) experience influenced glycemic outcomes, in the same pivotal trial. HbA1c levels and the percentage of SG values in low, high, and in-target ranges were analyzed from participants (n = 124) completing the Hybrid Closed-Loop Pivotal Trial in T1D. There were 78 individuals comprising the prior CGM group and 46 comprising the no prior CGM group. Compared to baseline, HbA1c was reduced from 7.4% +/- 0.9% to 6.9% +/- 0.7% for the prior CGM group and from 7.5% +/- 0.9% to 6.8% +/- 0.5% for the no prior CGM group. For those with prior CGM experience, the mean percentage of in-target SG values increased from 66.9% +/- 12.5% to 72.6% +/- 9.1%, and for those with no prior CGM experience it increased from 66.6% +/- 11.7% to 71.5% +/- 8.5%. Similar improvement in glucose values in the low and high ranges, relative to baseline, was observed for both groups. Resulting outcomes, from baseline to study end, did not differ between each group. These findings suggest that individuals without prior CGM experience, and those already using CGM, will benefit similarly with use of the FDA-approved MiniMed 670G HCL system therapy. PMID- 29148822 TI - The Long-Term Efficacy of a Galactagogue Containing Sylimarin-Phosphatidylserine and Galega on Milk Production of Mothers of Preterm Infants. AB - AIMS: To investigate the efficacy of a galactagogue, containing Sylimarin phosphatidylserine (SILITIDIL) and galega consumed in the first month after delivery by mothers of preterm infants, in maintaining milk production during the first 3-6 months after delivery. MATERIALS AND METHODS: Mothers of infants born at gestational age (GA) between 27 and 32 weeks, enrolled in our previous prospective, double-blind, randomized trial and randomly allocated to receive either the galactagogue (GG) or a placebo (PG), were asked about their milk production at 3 and 6 months after delivery. RESULTS: Of the 100 mothers involved in this study, 45 of GG and 44 of PG responded comprehensively to the questions asked. At the third month after delivery, exclusive human milk administration was reported by 22 mothers of GG and 12 mothers of PG (p < 0.05), whereas 29 mothers of GG and 18 mothers of PG were able to administer >50% of the amount of milk assumed. At the sixth month of life, only eight infants received exclusive human milk (six and two of GG and PG, respectively), and the data are not sufficient for a meaningful clinical evaluation. CONCLUSIONS: It is assumed that a galactagogue during the first month after delivery improves human milk administration to preterm neonates after discharge and for the first 3 months of life. PMID- 29148823 TI - Space Dust Collisions as a Planetary Escape Mechanism. AB - It is observed that hypervelocity space dust, which is continuously bombarding Earth, creates immense momentum flows in the atmosphere. Some of this fast space dust inevitably will interact with the atmospheric system, transferring energy and moving particles around, with various possible consequences. This paper examines, with supporting estimates, the possibility that by way of collisions the Earth-grazing component of space dust can facilitate planetary escape of atmospheric particles, whether they are atoms and molecules that form the atmosphere or larger-sized particles. An interesting outcome of this collision scenario is that a variety of particles that contain telltale signs of Earth's organic story, including microbial life and life-essential molecules, may be "afloat" in Earth's atmosphere. The present study assesses the capability of this space dust collision mechanism to propel some of these biological constituents into space. Key Words: Hypervelocity space dust-Collision-Planetary escape Atmospheric constituents-Microbial life. Astrobiology 17, 1274-1282. PMID- 29148824 TI - Biobanking of Fresh-Frozen Cancer Tissue: RNA Is Stable Independent of Tissue Type with Less Than 1 Hour of Cold Ischemia. AB - BACKGROUND: The effects of preanalytical variables in tissue processing and storage periods on RNA quality of tissues have been well documented in each type of cancer. However, few studies have been performed on a comparative assessment of the impacts across different cancer tissues, even though it is well known that RNase activity is highly variable in various tissue types and RNase-rich tissues have been found to yield low-quality RNA. METHODS: We investigated the impacts of cold ischemia times and long-term storage on RNA integrity in various types of cancer tissue, which had been fresh-frozen and collected at the Samsung Medical Center Biobank. RNA quality was also evaluated with regard to histopathological variables. We analyzed RNA integrity number (RIN) data, which had been obtained from our quality control (QC) processes over the last 7 years. Approximately 2% of samples were randomly selected and processed to measure RIN quarterly and after 6 years of storage for QC purposes. RESULTS: Fresh-frozen tumor tissues yielded high-quality RNA regardless of tumor type and histopathological features. Up to 1-hour cold ischemia times and up to 6-year storage times did not adversely influence RNA integrity. Only 3 samples showed RIN of <7 out of a total of 396 analyzed tumor tissues. CONCLUSIONS: Tissue quality was not adversely affected by long-term storage or limited variations of cold ischemia times. The low-quality samples could be correlated with the structural composition or intratumoral heterogeneity of tissues. The strict application of standardized protocols for tissue collection is the key for high-quality biobanking. PMID- 29148825 TI - On the Growth and Detectability of Land Plants on Habitable Planets around M Dwarfs. AB - One signature of life on Earth is the vegetation red edge (VRE) feature of land plants, a dramatic change of reflectivity at wavelength near 0.7 MUm. Potentially habitable planets around M dwarfs are tidally locked, which can limit the distribution of land plants. In this study, we used a biogeochemical model to investigate the distribution of land plants on potentially habitable planets around M dwarfs driven by climate data produced in a general circulation model (GCM). When considering the effects of clouds, the observation time needed for VRE detection on nearby p = 1 exoplanets around nearby M dwarfs is on the order of days using a 25 m2 telescope if a large continent faces Earth during observations. For p = 1.5 exoplanets, the detection time could be similar if land plants developed the capability to endure a dark/cold environment for extended periods of time and the continent configuration favors observations. Our analysis suggests that hypothetical exovegetation VRE features are easier to detect than Earth vegetation and that VRE detection is possible for nearby exoplanets even under cloudy conditions. Key Words: Vegetation red edge-Exoplanets-M dwarfs Biosignature detection. Astrobiology 17, 1219-1232. PMID- 29148826 TI - Engagement in the Overdose RIsk InfOrmatioN (ORION) e-Health Tool for Opioid Overdose Prevention and Self-Efficacy: A Preliminary Study. AB - Increasing awareness of, and information about, overdose risk is an appropriate approach in risk reduction. e-Health technology in substance use disorders is an opportunity to support behavioral changes related to public health concerns. The present study aimed to evaluate the short-term impact of an innovative e-health psychoeducational software, the Overdose RIsk InfOrmatioN (ORION) tool. The ORION programme provided relevant information to opioid-dependent individuals about the risk of suffering a drug overdose as a result of high risky and dysfunctional behaviors. Seven aggregate risk factors were identified through a systematic review and their outputs included in a risk estimation model. We recruited 194 opioid-dependent treatment-seeking individuals from the United Kingdom, Germany, Italy, and Denmark. All participants were given at study entry, and after their use of the software, the General Self-Efficacy (GSE) Scale. We found comparable pre- and post-ORION administration mean GSE scores (SD), 28.49 (5.50) and 28.32 (5.90), respectively (p = 0.297). However, there was an inverse correlation between the number of risk factors and reported levels of self-efficacy (p < 0.001). ORION was able to identify individuals who are most in need of reducing their modifiable risk factors with appropriate interventions. However, a one-shot e-health tool cannot influence complex domains such as self-efficacy unless this is used with other effective interventions. Nonetheless, the ORION tool is unique in its style and content of delivery, that is translating risks combination into a clear estimation, and will need further development such as (a) integration in smartphone-based e-health apps and (b) testing in other high-risk populations. PMID- 29148827 TI - For Video Games, Bad News Is Good News: News Reporting of Violent Video Game Studies. AB - News coverage of video game violence studies has been critiqued for focusing mainly on studies supporting negative effects and failing to report studies that did not find evidence for such effects. These concerns were tested in a sample of 68 published studies using child and adolescent samples. Contrary to our hypotheses, study effect size was not a predictor of either newspaper coverage or publication in journals with a high-impact factor. However, a relationship between poorer study quality and newspaper coverage approached significance. High impact journals were not found to publish studies with higher quality. Poorer quality studies, which tended to highlight negative findings, also received more citations in scholarly sources. Our findings suggest that negative effects of violent video games exposure in children and adolescents, rather than large effect size or high methodological quality, increase the likelihood of a study being cited in other academic publications and subsequently receiving news media coverage. PMID- 29148828 TI - Increased Cellular Aging by 3 Years of Age in Latino, Preschool Children Who Consume More Sugar-Sweetened Beverages: A Pilot Study. AB - BACKGROUND: Previous studies in adults and older children find that sugar sweetened beverage (SSB) consumption increases risk for obesity and cellular aging, as measured by leukocyte telomere length (LTL). METHODS: In a previously described, San Francisco-based Latino birth cohort, where telomere length was measured at birth, we evaluate the relationship between beverage consumption (including SSB and 100% fruit juice), obesity, and LTL at 2-3 years old, as well as change in LTL from birth. LTL (T/S Ratio) was measured in 61 children (mean 2.4 years +/-0.6 standard deviation). Multivariable linear regression models are used to ascertain beverage type and obesity as independent predictors of LTL and change in LTL. RESULTS: Mean telomere length was 1.58 +/- 0.20 (T/S Ratio) and mean yearly change was -0.08 +/- -0.09 (T/S Ratio). Predictors of shorter telomere length at age 2-3 included increased consumption of SSB (Beta Coeff = 0.009 95% CI [-0.02 to -0.0008]; p = 0.03). Telomere length at birth was the strongest predictor of rate of attrition from birth to 2-3 years of age and males tended to have more rapid attrition. CONCLUSION: Excessive SSB consumption impacts early childhood immune system health adversely, possibly before the development of obesity. PMID- 29148829 TI - Volumetric absorptive microsampling combined with impact-assisted extraction for hematocrit effect free assays. AB - AIM: Volumetric absorptive microsampling (VAMS) is a recent technology available for sampling and analyzing low blood volume. The present work describes the utilization of VAMS for the quantitation of naproxen and ritonavir in human blood using a novel bead-based impact-assisted extraction (IAE) procedure. RESULTS: Sampling volume accuracy of the VAMS device was independent of the blood hematocrit (HCT) level, however analyte recovery decreased with increasing HCT when extracted using ultrasonication. In contrast, IAE was unaffected by HCT, resulting in quantitative recovery for all levels evaluated. Precision and accuracy batches, as well as matrix effect evaluation, met acceptance criteria. CONCLUSION: The IAE procedure coupled with VAMS is immune to HCT biases affecting sampling volume and recovery. PMID- 29148830 TI - Age differences in the use of emotion regulation strategies derived from the process model of emotion regulation: a systematic review. AB - OBJECTIVES: This review examines differences in the use of emotion regulation (ER) strategies among younger and older adults. METHOD: A systematic review using search terms related to ageing and ER identified 23 relevant studies. Narrative synthesis was adopted to analyse the findings. RESULTS: Generally, greater use of situation selection and attentional deployment was identified among older adults, although these relationships were dependent on contextual/moderator variables. While older adults employed greater levels of situation modification in response to negative stimuli, there was considerable variation in age differences across specific situation modification subtypes. Available evidence pointed to an absence of age differences in the cognitive change strategy of cognitive reappraisal. The use of relatively less-cognitively demanding cognitive change subtypes (e.g. acceptance) was, under particular circumstances, greater among older adults. Findings regarding the response modulation strategy of expressive suppression were equivocal. CONCLUSION: Adult development is not characterised by straightforward shifts in preferences for use of different ER strategies. Moderator variables appear to be of central importance in shaping the emergence of age differences in ER. Systematically examining interactions of age with individual difference variables and situational factors in samples including oldest-old adults will be important for advancing knowledge regarding developmental differences in ER. PMID- 29148831 TI - Is Your Biobank Up to Standards? A Review of the National Canadian Tissue Repository Network Required Operational Practice Standards and the Controlled Documents of a Certified Biobank. AB - Ongoing quality management is an essential part of biobank operations and the creation of high quality biospecimen resources. Adhering to the standards of a national biobanking network is a way to reduce variability between individual biobank processes, resulting in cross biobank compatibility and more consistent support for health researchers. The Canadian Tissue Repository Network (CTRNet) implemented a set of required operational practices (ROPs) in 2011 and these serve as the standards and basis for the CTRNet biobank certification program. A review of these 13 ROPs covering 314 directives was conducted after 5 years to identify areas for revision and update, leading to changes to 7/314 directives (2.3%). A review of all internal controlled documents (including policies, standard operating procedures and guides, and forms for actions and processes) used by the BC Cancer Agency's Tumor Tissue Repository (BCCA-TTR) to conform to these ROPs was then conducted. Changes were made to 20/106 (19%) of BCCA-TTR documents. We conclude that a substantial fraction of internal controlled documents require updates at regular intervals to accommodate changes in best practices. Reviewing documentation is an essential aspect of keeping up to date with best practices and ensuring the quality of biospecimens and data managed by biobanks. PMID- 29148833 TI - Correction to: DNA Cell Biol 2017;36(10):813-821. DOI: 10.1089/dna.2017.3790. PMID- 29148834 TI - Respiratory phagocytes are implicated in enhanced colibacillosis in chickens co infected with influenza virus H9N2 and Escherichia coli. AB - 1. The aim of this study was to determine the most likely time interval after infection with influenza virus H9N2 for co-infection with Escherichia coli to cause colibacillosis, the importance of lung load of E. coli and the involvement of respiratory phagocytes. 2. Specific pathogen free chickens were inoculated intranasally with 106EID50 of influenza virus or uninfected. After specified time intervals, 107 CFU E. coli or phosphate-buffered saline was inoculated. The presence of lesions, the number of respiratory phagocytes in the respiratory lavage fluid and the E. coli load in the lung were determined after different time intervals. 3. Compared with the number of lesions in chickens receiving only E. coli inoculation, the number lesions in co-infected chickens were increased at 0- and 3-d time intervals, but reduced in the groups at 6- and 9-d intervals between co-infection. 4. At 1-3 d after E. coli inoculation, the number of lesions chickens was correlated with the number of respiratory phagocytes harvested and related to the E. coli load in the lungs at 5 d. 5. These results suggest that the lesions caused by E. coli in chickens were increased within a 0 3 d interval following H9N2 virus inoculation and that this effect is related to the number of respiratory phagocytes. PMID- 29148836 TI - Automatic Sex-Liking and Sex-Failure Associations in Men With Sexual Dysfunction. AB - Current models of sexual functioning imply an important role for both automatic and controlled appraisals. Accordingly, it can be hypothesized that erectile dysfunction may be due to the automatic activation of negative appraisals at the prospect of sexual intercourse. However, previous research showed that men with sexual dysfunction exhibited relatively strong automatic sex-positive instead of sex-negative associations. This study tested the robustness of this unexpected finding and, additionally, examined the hypothesis that perhaps more specific sex failure versus sex-success associations are relevant in explaining sexual dysfunction and distress. Male urological patients (N = 70), varying in level of sexual functioning and distress, performed two Single-Target Implicit Association Tests (ST-IATs) to assess automatic associations of visual erotic stimuli with attributes representing affective valence ("liking"; positive versus negative) and sexual success versus sexual failure. Consistent with the earlier findings, the lower the scores on sexual functioning, the stronger the automatic sex positive associations. This association was independent of explicit associations and most prominent in the younger age group. Automatic sex-positive and sex failure associations showed independent relationships with sexual distress. The relationship between sexual distress and sex-failure associations is consistent with the view that automatic associations with failure may contribute to sexual distress. PMID- 29148835 TI - 2017 White Paper on recent issues in bioanalysis: aren't BMV guidance/guidelines 'Scientific'? (Part 1 - LCMS: small molecules, peptides and small molecule biomarkers). AB - The 2017 11th Workshop on Recent Issues in Bioanalysis (11th WRIB) took place in Los Angeles/Universal City, California from 3 April 2017 to 7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis, Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS and ligand binding assay (LBA) approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for Small Molecules, Peptides and Small Molecule Biomarkers using LCMS. Part 2 (Biotherapeutics, Biomarkers and Immunogenicity Assays using Hybrid LBA/LCMS and Regulatory Agencies' Inputs) and Part 3 (LBA: Immunogenicity, Biomarkers and PK Assays) are published in volume 9 of Bioanalysis, issues 23 and 24 (2017), respectively. PMID- 29148837 TI - Prostitution Stigma and Its Effect on the Working Conditions, Personal Lives, and Health of Sex Workers. AB - Researchers have shown that stigma is a fundamental determinant of behavior, well being, and health for many marginalized groups, but sex workers are notably absent from their analyses. This article aims to fill the empirical research gap on sex workers by reviewing the mounting evidence of stigmatization attached to sex workers' occupation, often referred to as "prostitution" or "whore" stigma. We give special attention to its negative effect on the working conditions, personal lives, and health of sex workers. The article first draws attention to the problem of terminology related to the subject area and makes the case for consideration of prostitution stigmatization as a fundamental cause of social inequality. We then examined the sources of prostitution stigma at macro, meso, and micro levels. The third section focuses on tactics sex workers employ to manage, reframe, or resist occupational stigma. We conclude with a call for more comparative studies of stigma related to sex work to contribute to the general stigma literature, as well as social policy and law reform. PMID- 29148838 TI - Discordance between age- and size-based criteria of child passenger restraint appropriateness. AB - OBJECTIVES: In this study, we sought to accomplish the following objectives: to (1) calculate the percentage of children considered appropriately restrained across 8 criteria of increasing restrictiveness; (2) examine agreement between age- and size-based appropriateness criteria; (3) assess for changes in the percentage of children considered appropriately restrained by the 8 criteria between 2011 (shortly after updates to U.S. guidelines) and 2015. METHODS: Data from 2 cross-sectional surveys of 928 parents of children younger than 12 years old (n = 591 in 2011, n = 337 in 2015) were analyzed in 2017. Child age, weight, and height were measured at an emergency department visit and used to determine whether the parent-reported child passenger restraint was considered appropriate according to 8 criteria. Age-based criteria were derived from Michigan law and U.S. GUIDELINES: Weight, height, and size-based criteria were derived from typical restraints available in the United States in 2007 and 2011. The percentage appropriate restraint use was calculated for each criterion. The kappa statistic was used to measure agreement between criteria. Change in appropriateness from 2011 to 2015 was assessed with chi-square statistics. RESULTS: Percentage appropriate restraint use varied from a low of 19% for higher weight limits in 2011 to a high of 91% for Michigan law in 2015. Agreement between criteria was slight to moderate. The lowest kappa was for Michigan law and higher weight limits in 2011 (kappa = 0.06) and highest for U.S. guidelines and lower weight limits in 2011 (kappa = 0.60). Percentage appropriate restraint use was higher in 2015 than 2011 for the following criteria: U.S. guidelines (74 vs. 58%, P < .001), lower weight (57 vs. 47%, P = .005), higher weight (25 vs. 19%, P = .03), greater height (39 vs. 26%, P < .001), and greater size (42 vs. 30%, P = .001). CONCLUSIONS: The percentage of children considered to be using an appropriate restraint varied substantially across criteria. Aligning the definition of appropriate restraint use with current U.S. guidelines would increase consistency in reporting results from studies of child passenger safety in the United States. Potential explanations for the increased percentage of children considered appropriately restrained between 2011 and 2015 include adoption of the updated U.S. guidelines and the use of child passenger restraints with higher weight and height limits. PMID- 29148839 TI - Sexual Risk Behaviors and Perceptions of Men Who Go to Gay Sex Parties in New York City: Comparisons Between Three HIV Groups. AB - Men who have sex with men (MSM) who attend group-sex events often engage in risky sexual behaviors that contribute to the high human immunodeficiency virus (HIV) incidence among this population. We conducted an online survey with 211 New York City MSM who attended sex parties in the prior year and asked them to describe their behaviors and perceptions of risk. We compared responses from HIV-positive undetectable men (n = 36), HIV-negative men on pre-exposure prophylaxis (PrEP; n = 62), and HIV-negative men never on PrEP (n = 113). In bivariate analyses, undetectable and on-PrEP men had been to more sex parties in the prior six months, had more anal sex partners there, and had higher rates of sexually transmitted infection (STI) diagnoses than men never on PrEP. Although less than the other groups, 43% of the presumably HIV-negative men never on PrEP reported condomless anal sex at a party in the prior six months. About half of participants agreed that, at sex parties, they made assumptions about others' HIV status, that they sometimes took more risks than intended, and that the atmosphere of these events was conducive to risk taking. Most disagreed that there was discussion of HIV status at sex parties. Implications for sexual health interventions are discussed. PMID- 29148840 TI - Resveratrol Induces Mitochondrial Apoptosis and Inhibits Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma Cells. AB - OSCC is the most common malignant cancer of the head and neck. EMT is an essential cellular process critical to the morphogenesis and homeostasis of solid tissues. It is also involved in the initial stage of cancer metastasis and invasion in which cells lose epithelial characteristics. While cancer therapy protocols such as surgery, radiation, and chemotherapy are effective and useful, the drug tolerance and toxicity of OSCC patients remain a problem. Resveratrol is mainly produced in red grape skin and exhibits anti-oxidative, anti-inflammatory, anti-proliferative, and anti-cancer properties. This study was undertaken to investigate the underlying mechanisms giving rise to the induction of apoptosis by resveratrol in the human tongue squamous cell carcinoma cell line. Resveratrol treatment resulted in a time- and dose-dependent decrease in cell viability and increased the apoptotic cell ratio in CAL-27, SCC15, and SCC25 cells. Resveratrol treatment of CAL-27 cells showed that several lines of apoptotic manifestation and decreased cell migration, invasion, and EMT-inducing transcription factor. Taken together, our findings demonstrate the inhibitory effect of resveratrol in human OSCC cells via the mitochondrial pathway and that resveratrol is able to inhibit cell invasion and migration by inhibiting the EMT-inducing transcription factors. PMID- 29148841 TI - Promoting Transparent Reporting of Conflicts of Interests and Statistical Analyses at The Journal of Sex Research. PMID- 29148842 TI - Erratum. AB - Yao H, Lu H, Zhao H, et al. Open reduction assisted with an external fixator and internal fixation with calcaneal locking plate for intra-articular calcaneal fractures. Foot Ankle Int. 2017;38(10):1107-1114. (Original DOI: 10.1177/1071100717715908) The above article appeared with the incorrect corresponding author. The correct corresponding author is Huading Lu, PhD. The corrected corresponding author information is below: Corresponding Author: Huading Lu, PhD, Department of Orthopaedics, The Fifth Affiliated Hospital of Sun Yat-sen University, NO. 52 Meihuadong Road, Zhuhai 519000, China. Email: johnnie.lu@163.com. PMID- 29148843 TI - Erratum. PMID- 29148844 TI - Circadian phase, circadian period and chronotype are reproducible over months. AB - The timing of the circadian clock, circadian period and chronotype varies among individuals. To date, not much is known about how these parameters vary over time in an individual. We performed an analysis of the following five common circadian clock and chronotype measures: 1) the dim light melatonin onset (DLMO, a measure of circadian phase), 2) phase angle of entrainment (the phase the circadian clock assumes within the 24-h day, measured here as the interval between DLMO and bedtime/dark onset), 3) free-running circadian period (tau) from an ultradian forced desynchrony protocol (tau influences circadian phase and phase angle of entrainment), 4) mid-sleep on work-free days (MSF from the Munich ChronoType Questionnaire; MCTQ) and 5) the score from the Morningness-Eveningness Questionnaire (MEQ). The first three are objective physiological measures, and the last two are measures of chronotype obtained from questionnaires. These data were collected from 18 individuals (10 men, eight women, ages 21-44 years) who participated in two studies with identical protocols for the first 10 days. We show how much these circadian rhythm and chronotype measures changed from the first to the second study. The time between the two studies ranged from 9 months to almost 3 years, depending on the individual. Since the full experiment required living in the laboratory for 14 days, participants were unemployed, had part-time jobs or were freelance workers with flexible hours. Thus, they did not have many constraints on their sleep schedules before the studies. The DLMO was measured on the first night in the lab, after free-sleeping at home and also after sleeping in the lab on fixed 8-h sleep schedules (loosely tailored to their sleep times before entering the laboratory) for four nights. Graphs with lines of unity (when the value from the first study is identical to the value from the second study) showed how much each variable changed from the first to the second study. The DLMO did not change more than 2 h from the first to the second study, except for two participants whose sleep schedules changed the most between studies, a change in sleep times of 3 h. Phase angle did not change by more than 2 h regardless of changes in the sleep schedule. Circadian period did not change more than 0.2 h, except for one participant. MSF did not change more than 1 h, except for two participants. MEQ did not change more than 10 points and the categories (e.g. M-type) did not change. Pearson's correlations for the DLMO between the first and second studies increased after participants slept in the lab on their individually timed fixed 8-h sleep schedules for four nights. A longer time between the two studies did not increase the difference between any of the variables from the first to the second study. This analysis shows that the circadian clock and chronotype measures were fairly reproducible, even after many months between the two studies. PMID- 29148845 TI - Speech recovery and language plasticity can be facilitated by Sensori-Motor Fusion training in chronic non-fluent aphasia. A case report study. AB - The rehabilitation of speech disorders benefits from providing visual information which may improve speech motor plans in patients. We tested the proof of concept of a rehabilitation method (Sensori-Motor Fusion, SMF; Ultraspeech player) in one post-stroke patient presenting chronic non-fluent aphasia. SMF allows visualisation by the patient of target tongue and lips movements using high-speed ultrasound and video imaging. This can improve the patient's awareness of his/her own lingual and labial movements, which can, in turn, improve the representation of articulatory movements and increase the ability to coordinate and combine articulatory gestures. The auditory and oro-sensory feedback received by the patient as a result of his/her own pronunciation can be integrated with the target articulatory movements they watch. Thus, this method is founded on sensorimotor integration during speech. The SMF effect on this patient was assessed through qualitative comparison of language scores and quantitative analysis of acoustic parameters measured in a speech production task, before and after rehabilitation. We also investigated cerebral patterns of language reorganisation for rhyme detection and syllable repetition, to evaluate the influence of SMF on phonological-phonetic processes. Our results showed that SMF had a beneficial effect on this patient who qualitatively improved in naming, reading, word repetition and rhyme judgment tasks. Quantitative measurements of acoustic parameters indicate that the patient's production of vowels and syllables also improved. Compared with pre-SMF, the fMRI data in the post-SMF session revealed the activation of cerebral regions related to articulatory, auditory and somatosensory processes, which were expected to be recruited by SMF. We discuss neurocognitive and linguistic mechanisms which may explain speech improvement after SMF, as well as the advantages of using this speech rehabilitation method. PMID- 29148846 TI - Preparation and evaluation of curcumin-loaded self-assembled micelles. AB - OBJECTIVE: Curcumin being used to treat various chronic diseases while its poor bioavailability issue limited its wide clinical application as a therapeutic agent. The aim of this work was to prepare curcumin-loaded self-assembled micelles using soluplus and solutol(r)HS15 (SSCMs) to enhance curcumin's solubility and thus oral bioavailability. METHODS: Optimum formulation was investigated and the optimized ratio of drugs and excipients was obtained and the SSCMs were prepared via ethanol solvent evaporation method. The optimal SSCMs were characterized by transmission electron microscopy, drug content analysis including loading efficiency (LE%) and entrapment efficiency (EE%), and the cumulative amount of curcumin released from the micelles were all calculated using HPLC method. The in vitro cytotoxicity and the permeability of SSCMs were measured by Caco-2 cell monolayers and the oral bioavailability was evaluated by SD rats. KEY FINDINGS: The solubility of curcumin in self-assembled micelles was dramatically increased by 4200 times as compared to free curcumin. Caco-2 cells transport experiment exhibited that while soluplus and solutol(r)HS15 were self assembled into micelles, it could not only promote the permeability of curcumin across membrane for better absorption, but also could restrain the curcumin pumped outside due to the role of P-gp efflux mechanism of soluplus and solutol(r)HS15. Furthermore, the prepared SSCMs formulation was almost nontoxic and had safety performance on Caco-2 cells model. Moreover, curcumin's oral bioavailability of SSCMs formulation in SD rats had doubled than that of free curcumin. CONCLUSIONS: The prepared SSCMs were characterized by PS, PDI, LE%, EE% data analysis. After the soluplus and solutol(r)HS15 were self assembled into micelles, both the solubility and membrane permeability of curcumin were evaluated to have been enhanced, as well as the effect of efflux pump of curcumin was inhibited, hence to promote oral absorption and generate an increased bioavailability. PMID- 29148848 TI - Corrigendum. AB - Klemola T, Leppilahti J, Laine V, et al. Effect of first tarsometatarsal joint derotational arthrodesis on first ray dynamic stability compared to distal chevron osteotomy. Foot Ankle Int. 2017;38(8):847-854. (Original DOI: 10.1177/1071100717706153). PMID- 29148849 TI - Towards an overarching model for electronic medical-record systems, including problem-oriented, goal-oriented, and other approaches. AB - There is no consensus among health professionals on how to structure medical records to serve clinical decision-making. Three approaches co-exist (source oriented, problem-oriented, goal-oriented), each suiting a different subset of patients. In primary care, the problem-oriented approach is dominant, but for patients with multiple conditions (multimorbidity) the goal-oriented approach seems more appropriate. There is a need to combine different approaches in one medical-record system. In this article, we explain some misconceptions about 'problems' and 'goals' that hinder the way to consensus. When putting the approaches into historical perspective, it becomes evident that each relates to a different definition of health. Each approach has its specific merits that should be preserved even when health definitions change. Hence, we combine the merits of each approach into one overarching model, as to show the way to a new generation of electronic medical-record systems that can serve all patients. This model has three levels: a level of problems, diseases, and patient goals, a level of (shared) objectives, and a level of action plans and results. PMID- 29148850 TI - ATAD2 in cancer: a pharmacologically challenging but tractable target. AB - INTRODUCTION: ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2's bromodomain (BRD) may be a very challenging task. ATAD2's BRD has been predicted as a 'difficult to drug' or 'least druggable' target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding. Areas covered: In this review, after shedding light on the multifaceted roles of ATAD2 in normal physiology as well as in cancer-etiology, we discuss technical challenges rendered by ATAD2's BRD active site and the recent drug discovery efforts to find small molecule inhibitors against it. Expert opinion: The identification of a novel low-nanomolar semi-permeable chemical probe against ATAD2's BRD by recent drug discovery campaign has demonstrated it to be a pharmacologically tractable target. Nevertheless, the development of high quality bioavailable inhibitors against ATAD2 is still a pending task. Moreover, ATAD2 may also potentially be utilized as a promising target for future development of RNAi-based therapy to treat cancers. PMID- 29148851 TI - Airway geometry, airway flow, and particle measurement methods: implications on pulmonary drug delivery. AB - INTRODUCTION: The effectiveness of drug delivery to the lungs is inextricably linked to the fundamental interactions that occur between particles and flow in the extrathoracic airway. Research in this field requires time resolved in-vivo and in-vitro measurements of three separate, yet intricately linked parameters: i) airway flow, ii) airway geometry, and iii) drug particle characteristics. A number of recent significant developments have been made in the experimental diagnostic tools used to characterise these parameters. Areas covered: In this review paper, we summarize the key recent findings that have resulted from the implementation of laser and optical diagnostic tools towards characterization of airway flow, extrathoracic airway geometry and drug particle characteristics. These three areas are discussed together, enabling a critical review of the implications of recent experimental findings on likely future developments in drug delivery to the lungs. Expert opinion: Improvements in drug delivery systems will result through implementation of laser and optical based diagnostic methods that can spatially and temporally resolve particle and agglomerate shape, size and dynamic characteristics. Design of inhaler devices must be done in parallel to developing realistic in-vitro upper airway replicas that account for physiological differences between patient groups, as a function of respiratory disease severity. PMID- 29148852 TI - Sildenafil citrate improves the delivery and anticancer activity of doxorubicin formulations in a mouse model of breast cancer. AB - Sildenafil is an approved drug for the treatment of erectile dysfunction. The drug exerts its action through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. In this work, we tested whether the aforementioned effects of sildenafil on tumour vasculatures could result in an improvement of anticancer drug concentration in tumour tissues and hence improves its anticancer effect. Sildenafil when added to doxorubicin showed synergistic anticancer activity against 4T1 breast cancer cells in vitro. Adding 1, 30 and 100 MUM of Viagra to 1 MUM of doxorubicin resulted in 1.8-fold, 6.2 fold and 21-fold statistically significant increases in its cytotoxic effect, respectively. As a result, 4T1 tumour-bearing mice showed up to 2.7-fold increase in drug concentrations of the fluorescent Dye DiI and doxorubicin in tumour tissues, as well as their nanoformulations. Animals treated with the combinations of both Sildenafil citrate and doxorubicin showed a statistically significant 4.7 fold reduction in tumour size compared to doxorubicin alone. This work highlights the effect of Sildenafil on tumour vasculatures and provides a rational for further testing the combination on breast cancer patients. PMID- 29148847 TI - Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T cell leukemia and lymphomas. AB - INTRODUCTION: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools. PMID- 29148853 TI - Multi-stage subunit vaccines against Mycobacterium tuberculosis: an alternative to the BCG vaccine or a BCG-prime boost? AB - INTRODUCTION: More than two billion people are latently infected with Mycobacterium tuberculosis. Most tuberculosis (TB)-subunit vaccines currently in various stages of clinical trials are designed for prevention of active TB, but not to prevent reactivation of latent TB-infection. Thus, there is an urgent need for an effective multi-stage vaccine based on early-expressed and latently expressed antigens that prevents both acute and latent infections. Areas covered: Here, we reviewed the published pre-clinical and clinical studies of multi-stage subunit vaccines against TB, and the protective capacities of the vaccines were compared with BCG, either alone or in combination with different vaccine delivery systems/adjuvants. The results revealed that multi-stage subunit vaccines induced a wide variety of immune-responses to all forms of TB, including CD8 + T-cell mediated cytolytic and IFN-gamma responses comparable to those induced by the BCG. They could potentially be used as a booster vaccine to improve the efficacy of the BCG. Expert commentary: Multi-stage TB-vaccines could boost BCG-primed immunity, decrease bacterial loads and provide efficient protection against progressive TB-infection, especially in the latent phase. These types of vaccines administered before and after TB-infection can act as pre-exposure, post-exposure and even therapeutic vaccines. In the near future, these vaccines could provide a new generation of prime-vaccines or BCG prime-boosters. PMID- 29148854 TI - Comparative effectiveness of lipid-lowering treatments to reduce cardiovascular disease. AB - INTRODUCTION: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is a new treatment option for patients with hypercholesterolemia. The objective of this study was to systematically review the cost-effectiveness of lipid lowering agents. Areas covered: Based on Pubmed, Embase, and Cochrane Database of Systematic Reviews, we identified 29 relevant articles. Studies found statins were cost-effective compared with placebo or no treatment in general. Atorvastatin was reported to be cost-effective against simvastatin. In most cases, rosuvastatin was more cost-effective than atorvastatin or simvastatin. Additionally, ezetimibe was considered to be cost-effective compared with no treatment for statin intolerant patients. For patients not meeting treatment goals with their statins, switching to ezetimibe plus simvastatin was consistently reported cost-effective. The cost-effectiveness of ezetimibe plus a hybrid of a statin varied by the source of clinical data and cost of ezetimibe. Finally, the cost-effectiveness of PCSK9 inhibitor plus a statin against statin monotherapy was uncertain. The PCSK9 inhibitor plus a stain was cost-ineffective compared with ezetimibe plus a statin. Expert commentary: Drug costs and treatment efficacy were the key drivers of the cost-effectiveness results in prior analyses. Future evaluations are warranted to reflect the decreasing drug prices and the long-term treatment effects of PCSK9 inhibitors. PMID- 29148855 TI - Effects of virtual reality-based training with BTs-Nirvana on functional recovery in stroke patients: preliminary considerations. AB - AIM OF THE STUDY: Cognitive impairment occurs frequently in post-stroke patients. This study aimed to determine the effects of a virtual reality training (VRT) with BTs-Nirvana (BTsN) on the recovery of cognitive functions in stroke patients, using the Interactive-Semi-Immersive Program (I-SIP). MATERIALS AND METHODS: We enrolled 12 subjects (randomly divided into two groups: experimental group (EG); and control group (CG)), who attended the Laboratory of Robotic and Cognitive Rehabilitation of IRCCS Neurolesi of Messina from January to June 2016. The EG underwent a VRT with BTsN, whereas CG received a standard cognitive treatment. Both the groups underwent the same conventional physiotherapy program. Each treatment session lasted 45 minutes and was repeated three times a week for 8 weeks. All the patients were evaluated by a specific clinical-psychometric battery before (T0), immediately (T1), and one month (T2) after the end of the training. RESULTS: At T1, the EG presented a greater improvement in the trunk control test (p = 0.03), the Montreal Cognitive Assessment (p = 0.01), the selective attention assessment scores (p = 0.01), the verbal memory (p = 0.03), and the visuospatial and constructive abilities (p = 0.01), as compared to CG. Moreover, such amelioration persisted at T2 only in the EG. CONCLUSIONS: According to these preliminary data, VRT with I-SIP can be considered a useful complementary treatment to potentiate functional recovery, with regard to attention, visual-spatial deficits, and motor function in patients affected by stroke. PMID- 29148856 TI - Novel applications for serum procalcitonin testing in clinical practice. AB - INTRODUCTION: Procalcitonin has emerged as a reliable marker of acute bacterial infection in hospitalized patients and the assay has recently been incorporated into several clinical algorithms to reduce antimicrobial overuse, but its use in patients with end-organ dysfunction is controversial. Areas covered: In this review, the authors examine what is known about procalcitonin testing in patients with organ dysfunction, including those with end-stage renal disease, congestive heart failure, chronic obstructive pulmonary disease, and cirrhosis, and explore how the assay is now being used in the management of non-infectious diseases. Expert commentary: Procalcitonin holds tremendous promise to identify a diverse set of medical conditions beyond those associated with acute bacterial infection, including post-surgical anastomotic leaks, acute kidney injury, and complications after intracerebral hemorrhage. The authors review recent studies examining procalcitonin in these areas and explore how the assay might be used to guide diagnosis and prognosis of non-infectious diseases in the near future. PMID- 29148857 TI - Update on the role and therapeutic potential of polycomb repressive complexes in (biliary tract) cancer. PMID- 29148859 TI - The Landscape is Changing. PMID- 29148860 TI - The Role of Distal Minority Stress and Internalized Transnegativity in Suicidal Ideation and Nonsuicidal Self-Injury Among Transgender Adults. AB - Transgender people are at elevated risk for nonsuicidal self-injury (NSSI) and suicidal ideation compared to the general population. Transgender (trans) refers to a diverse group of people who experience incongruence between their gender identity and sex assigned at birth. The present study is guided by the minority stress model and the psychological mediation framework, which postulate that sexual minority groups experience elevated stress as a result of anti-minority prejudice, contributing to negative mental health outcomes. This study utilized these theories to investigate the role of internalized transnegativity internalization of negative societal attitudes about one's trans identity-in the relationships of distal trans stress to suicidal ideation and NSSI. A U.S. national sample of trans adults (N = 237) completed a battery of online measures. Structural equation modeling (SEM) was used to compare models with mediation and moderation effects. Results suggested that internalized transnegativity acts as both a mediator and a moderator in the relationship between distal trans stress and suicidal ideation. Log likelihood comparisons suggested moderation models had the superior fit for these data. Results suggest that clinical interventions should directly target individuals' internalized transnegativity as well as societal-level transnegativity. PMID- 29148858 TI - From bench to almost bedside: the long road to a licensed Ebola virus vaccine. AB - INTRODUCTION: The Ebola virus (EBOV) disease epidemic during 2014-16 in West Africa has accelerated the clinical development of several vaccine candidates that have demonstrated efficacy in the gold standard nonhuman primate (NHP) model, namely cynomolgus macaques. Areas covered: This review discusses the pre clinical research and if available, clinical evaluation of the currently available EBOV vaccine candidates, while emphasizing the translatability of pre clinical data generated in the NHP model to clinical data in humans. Expert opinion: Despite the existence of many successful EBOV vaccine candidates in the pre-clinical stages, only two platforms became the focus of Phase 2/3 efficacy trials in Liberia, Sierra Leone, and Guinea near the peak of the epidemic: the Vesicular stomatitis virus (VSV)-vectored vaccine and the chimpanzee adenovirus type 3 (ChAd3)-vectored vaccine. The results of three distinct clinical trials involving these candidates may soon pave the way for a licensed, safe and efficacious EBOV vaccine to help combat future epidemics. PMID- 29148861 TI - A New Approach for Determining Short-Term, Objective Prognostic Predictive Methods for Terminal Cancer Patients Based on the Change Point of Laboratory Test Values. AB - BACKGROUND: In terminal phase cancer, predicting a prognosis precisely plays an important role for patients and their families to live meaningful lives. However, there are no established short-term, objective prognostic predictive methods. OBJECTIVE: To develop simple, short-term, objective prognostic predictive methods through detecting a change point for laboratory test values. DESIGN: A retrospective chart review. SETTING/SUBJECTS: Subjects were cancer patients aged >=16 years and discharged dead from Osaka University Hospital in 2008. MEASUREMENTS: Using different laboratory test values, new prognostic predictive methods were determined based on either six laboratory test values (white blood cell [WBC], platelet [PLT], C-reactive protein, blood urea nitrogen [BUN], aspartate aminotransferase [AST], and lactase dehydrogenase [LDH]): the WPCBAL score, or five test values (WBC, PLT, BUN, AST, and LDH): the WPBAL score. Their utility, including sensitivity and specificity, was compared with that of Glasgow prognostic scores (GPSs). RESULTS: In total, 121 cancer patients were enrolled. WPCBAL and WPBAL scores showed higher sensitivity (0.88 and 0.91 vs. 0.68), specificity (0.79 and 0.70 vs. 0.53), negative predictive value (0.98 and 0.97 vs. 0.76), and a much larger relative risk (16.5 and 14.2 vs. 1.78) as prognostic predictors within two weeks of death than GPS as a prognostic predictor within three weeks of death. CONCLUSION: This is the first study that suggests that the objective prognostic predictive methods, through detecting the change point of laboratory test values, are useful for predicting short-term prognosis. The WPCBAL score and WPBAL score could objectively predict the remaining lifetime within two weeks of mortality. PMID- 29148862 TI - In this issue: Cancer immunity and immunotherapy. PMID- 29148865 TI - Metronomic therapy has low toxicity and is as effective as current standard treatment for recurrent high-risk neuroblastoma. AB - The metronomic therapy concept uses low doses of continuously applied chemotherapeutic, anti-angiogenetic, and immunomodulating drugs. Twenty patients with recurrent and 3 with refractory high-risk neuroblastoma were treated by the metronomic concept using celecoxib, cyclophosphamide, vinblastine, and etoposide for up to 24 months. The outcome was compared to 274 matched patients with a first recurrence from stage 4 neuroblastoma using the variables time from diagnosis to first recurrence, number of organs involved, and MYCN amplification. All were treated with dose-intensive conventional chemotherapy. The study patients experienced 1-3 recurrences and had 1-3 sites involved (osteomedullary, primary tumor, central nervous system, lymph nodes, liver, lungs) before the metronomic therapy started. Two patients in complete remission and three with active refractory disease following recurrence treatment were excluded from the outcome analysis. The curves for secondary event-free and overall survival demonstrated no significant differences. The toxicity was minimal except for >=3 grade thrombocytopenia and leukopenia (all heavily pretreated). The treatment was realized in an outpatient setting. The metronomic approach is similarly effective as standard treatment in recurrent high-risk neuroblastoma, has low toxicity, and is applicable in an outpatient setting. A prospective study including propranolol as a fifth drug is underway. PMID- 29148867 TI - Major Greenwood and clinical trials. PMID- 29148871 TI - A welcome return to lectures in JRSM. PMID- 29148864 TI - Morphologic Criteria of Lesion Activity in Neovascular Age-Related Macular Degeneration: A Consensus Article. AB - Intravitreal antivascular endothelial growth factor drugs represent the current standard of care for neovascular age-related macular degeneration (nAMD). Individualized treatment regimens aim at obtaining the same visual benefits of monthly injections with a reduced number of injections and follow-up visits, and, consequently, of treatment burden. The target of these strategies is to timely recognize lesion recurrence, even before visual deterioration. Early detection of lesion activity is critical to ensure that clinical outcomes are not compromised by inappropriate delays in treatment, but questions remain on how to effectively monitor the choroidal neovascularization (CNV) activity. To assess the persistence/recurrence of lesion activity in patients undergoing treatment for nAMD, an expert panel developed a decision algorithm based on the morphological features of CNV. After evaluating all current retinal imaging techniques, the panel identified optical coherent tomography as the most reliable tool to ascertain lesion activity when funduscopy is not obvious. PMID- 29148872 TI - Disease context and gene editing. PMID- 29148866 TI - Drugs of Abuse and Novel Psychoactive Substances at Outdoor Music Festivals in Colorado. AB - BACKGROUND: Drugs of abuse (DOA) are widely used in the United States and are ubiquitous at outdoor music festivals. Attendees at music festivals are at high risk for novel psychoactive substance (NPS) use, which is becoming more prevalent worldwide. No U.S. studies have employed an qualitative approach to investigate the etiologies of both traditional DOA and NPS use amongst music festival attendees. OBJECTIVES: The objective of this study was to improve understanding of the knowledge, attitudes, beliefs, and practices of festival attendees using NPS and DOA. METHODS: We conducted semi-structured interviews of 171 attendees during the Sonic Bloom and Arise music festivals in Colorado in 2015 and 2016. Discrete variables were summarized with descriptive statistics. The anonymous, multi-domain interview documented the knowledge, attitudes beliefs, and practices underlying DOA use, which were analyzed with qualitative methods. RESULTS: We enrolled 171 participants that endorsed DOA use at the festivals. Most were experienced DOA users, who perceived minimal risks associated with DOA and NPS use. Nearly all unanimously reported normalization of DOA at music festivals. Participants popularly cited empathogenic, entactogenic, and entheogenic effects of DOA as their primary motivations for use. NPS use was endorsed by 39.8% (n = 68) of respondents, all of whom identified as being experienced DOA users. CONCLUSIONS: This population of novel psychoactive substance users is primarily composed of experienced drug users that endorsed use because of low cost, minimal perceived risk, accessibility, and normalization of drug use at music festivals. PMID- 29148873 TI - Erratum. PMID- 29148874 TI - Managing population healthcare. PMID- 29148876 TI - Food Safety at Farmers' Markets: A Knowledge Synthesis of Published Research. AB - Farmers' markets are increasingly popular venues in North America for the sale of fresh produce and other foods. However, the nature of their operation can present possible food safety issues, challenges, and risks to consumers. A knowledge synthesis was conducted to identify, characterize, and summarize published research on the microbial food safety issues and implications associated with farmers' markets. A scoping review was conducted using the following steps: comprehensive search strategy, relevance screening of abstracts, and characterization of relevant articles. Two subsets of data were prioritized for more detailed systematic review (data extraction and risk-of-bias assessment) and meta-analysis: (i) studies comparing the microbial safety of foods from farmers' markets versus other sources and (ii) studies evaluating the use of food safety practices at farmers' markets. Overall, 83 relevant studies were identified. The majority of studies were published as journal articles (64%), used a cross sectional design (81%), and were conducted in the United States (78%). Most studies (39%; n = 32) investigated stakeholder, mostly consumer (n = 22), attitudes toward food safety at farmers' markets. Limited but heterogeneous evidence indicated a higher prevalence of Campylobacter and Salmonella in chicken meat from farmers' markets versus other retail sources, but there was no difference in the microbial contamination of fresh produce. Studies evaluating the use of food safety practices at farmers' markets identified some gaps; for example, the average prevalence of vendor hand washing was 4% (95% confidence interval: 0 to 11%; I2 = 27%; n = 5 studies). Twelve foodborne outbreaks and case reports were identified, resulting in a total of 411 illnesses, 38 hospitalizations, and two deaths from 1994 to 2016. Only five intervention studies were identified. Key knowledge gaps and areas warranting future research, training, and education are highlighted and discussed. PMID- 29148875 TI - Repurposing of Kinase Inhibitors as Broad-Spectrum Antiviral Drugs. AB - The high cost of drug development and the narrow spectrum of coverage typically provided by direct-acting antivirals limit the scalability of this antiviral approach. This review summarizes progress and challenges in the repurposing of approved kinase inhibitors as host-targeted broad-spectrum antiviral therapies. PMID- 29148877 TI - Characterization and Horizontal Transfer of Antimicrobial Resistance Genes and Integrons in Bacteria Isolated from Cooked Meat Products in China. AB - The aim of this study was to investigate antimicrobial resistance and the presence and transferability of corresponding resistance genes and integrons in bacteria isolated from cooked meat samples in the People's Republic of China. A total of 150 isolates (22 species belonging to 15 genera) were isolated from 49 samples. Resistance of these isolates to antimicrobials was commonly observed; 42.7, 36.0, and 25.3% of the isolates were resistant to tetracycline, streptomycin, and ampicillin, respectively. Multidrug resistance was observed in 41 (27.3%) of the isolates. Sixteen resistance genes, i.e., blaTEM-1 and blaCTX-M 14 (beta-lactams), aac(3)-IIa (gentamicin), strA and strB (streptomycin), qnrB and qnrS (fluoroquinolone), sul1, sul2, and sul3 (sulfamethoxazole), cat1 and cat2 (chloramphenicol), and tetM, tetA, tetS, and tetB (tetracycline), were found in 54 isolates. One isolate of Pseudomonas putida carried qnrB, and sequence analysis of the PCR product revealed 96% identity to qnrB2. The qnr genes were found coresiding and were cotransferred with bla genes in two isolates. Twelve isolates were positive for the class 1 integrase gene, and four isolates carried the class 2 integrase gene. However, no class 3 integrase gene was detected. One isolate of Proteus mirabilis carried dfrA32-ereA-aadA2, and this unusual array could be transferred to Escherichia coli. Nonclassic class 1 integrons lacking qacEDelta1 and sul1 genes were found in 2 of the 12 intI1-positive isolates. Our results revealed the presence of multidrug-resistant bacteria in cooked meats and the presence and transferability of resistance genes in some isolates, suggesting that cooked meat products may act as reservoirs of drug-resistant bacteria and may facilitate the spread of resistance genes. PMID- 29148878 TI - Molecular Characterization of Fluoroquinolone Resistance Mechanisms of Campylobacter Isolates from Duck Meats. AB - The purpose of this study was to identify the molecular basis of quinolone resistance of Campylobacter isolates recovered from duck meats. Sixty-one isolates from duck meat samples were studied using sequence analysis of the gyrA gene, and PCR assays were used to identify the presence of the CmeABC efflux pump and its restored sensitivity in the presence of efflux-pump inhibitors. High level resistance to nalidixic acid and ciprofloxacin was attributed to amino acid substitutions Thr-86-Ile in some isolates. The PCR assay confirmed the presence of the cmeB gene in 29 (47.5%) of the 61 Campylobacter isolates. Phenylalanine arginine beta-naphthylamide reduced the MICs of ciprofloxacin and nalidixic acid in 16 (55.2%) and 26 (89.7%) isolates, respectively. The Thr-86-Ile substitution in the gyrA was the primary contributor to the high-level quinolone resistance in Campylobacter isolates from duck meats. PMID- 29148879 TI - A Multicenter Investigation of Factors Influencing Women's Participation in Clinical Trials. AB - OBJECTIVE: To identify factors that influence women's participation in clinical research. METHODS: We administered a survey in outpatient and inpatient populations of Obstetrics and Gynecology facilities of six institutions located in four states. The survey included questions regarding any of the participant's past experiences in clinical research and the factors that would influence their participation in clinical research. Analyses included descriptive statistics and a Principal Component Analysis. RESULTS: The analysis included 3,773 respondents; 2,477 (68.1%) were pregnant. The majority of participants were Caucasian (1,453, 40.2%), followed by Hispanic (933, 25.8%), African American/black (744, 20.6%), other minorities (270, 7.5%), and multiracial (212, 5.9%). Ten potential motivating factors and 10 potential barriers were assessed. The greatest motivating factor was "how well research is explained" (mean = 2.87) while "risk of unknown side effects" was the greatest barrier (mean = 3.07) for women's participation in clinical trials. Among six helpful resources assessed, "material in my own language" was scored as the highest (mean = 2.8) in facilitating women's decision to participate. For "risk to the fetus/future fertility" as a barrier, pregnant women's score (mean = 3.25) was significantly higher than nonpregnant women's score (mean = 2.37). CONCLUSIONS: Overall, the risk of unknown side effects discourages women in general, and the risk to the fetus/future fertility discourages pregnant women the most from participating in clinical trials. However, explaining a study well and providing written material in the patients' own language may increase their willingness to participate. PMID- 29148880 TI - Does Aspirin Decrease Risk of Specific Breast Cancer Subtype in Women with Diabetes? PMID- 29148881 TI - Ultrarapid Influence of Buprenorphine on Major Depression in Opioid-Dependent Patients: A Double Blind, Randomized Clinical Trial. AB - OBJECTIVE: To examine the impact of different doses of buprenorphine on depression symptoms in opioid dependent inpatient over a three-day interval, using a randomized clinical trial design (RCT). DESIGN: Patients were randomized and assigned to three groups. PARTICIPANTS: Forty males who were admitted to an inpatient psychiatric unit and who fulfilled the DSM-5 criteria for both opioid dependence and major depressive disorder. INTERVENTION: Patients randomly received 32 mg, 64 mg, or 96 mg of buprenorphine as a single high dose. Out of 40 patients, 11 (27.5%) received 32 mg, 14 (35%) received 64 mg and 15 (37.5%) received 96 mg of buprenorphine. We conducted medical precautional measures, including cardiovascular and respiratory monitoring. MEASUREMENTS: Depression was measured by the Beck Depression Inventory (BDI). All patients completed the three day treatment duration. The results showed a significant reduction in depression symptoms within each of the three groups (p = 0.00), although there was no significant difference in depression outcome across the groups (p = 0.90). CONCLUSIONS: The results suggest that a single high dose of buprenorphine could provide a safe, simple and speedy means of depression improvement. A single high dose of buprenorphine can be used as medication that supplies a fast and maintained treatment for major depressive disorder in patients who are opioid dependent. Placebo-controlled trials of longer periods and larger sample sizes are needed to test ability and safety, as well as the physiological and psychological impact of extended exposure to this drug. PMID- 29148882 TI - Characterization of a Polymicrobial Dermal Infection in a Peninsular Pronghorn ( Antilocapra americana peninsularis) in Baja California, Mexico. AB - In situ conservation efforts are assisting the recovery of free-ranging populations of the endangered peninsular pronghorns ( Antilocapra americana peninsularis) at the Vizcaino Biosphere Reserve, Baja California Sur, Mexico. We detected a polymicrobial dermal infection. Etiologic agents were identified as a keratinophilic dermatomycete and opportunistic pathogenic bacteria. PMID- 29148883 TI - Gammaherpesvirus (Type 1 Ruminant Rhadinovirus) in Muskox ( Ovibos moschatus) in Greenland. AB - The world's native distribution of muskox ( Ovibos moschatus) is restricted to Canada and Greenland, and a muskox-specific gammaherpesvirus has been described from Canadian populations. We analyzed spleen samples from the Kangerlussuaq muskox population in Greenland and identified muskox gammaherpes by PCR and sequencing. PMID- 29148884 TI - EPIDEMIOLOGY OF SCHMALLENBERG VIRUS IN EUROPEAN BISON ( BISON BONASUS) IN POLAND. AB - Schmallenberg virus (SBV), an emerging arbovirus in Europe, is an important pathogen in domestic ruminants; however, its impact on free-ranging wild ruminants is not well studied. Three hundred and forty-seven serum samples collected between 2011 and 2016 from 302 European bison ( Bison bonasus) from 12 different sites in Poland were tested for the presence of SBV antibodies. In addition, 86 sera were collected between 2013 and 2016 from three species of cervids for testing for SBV antibodies. After the first detection of the virus in Poland in October 2012, the proportion of SBV-seropositive European bison reached 81% (95% confidence interval [CI]: 77.1-85.8%), whereas in cervids seroprevalence was 34% (95% CI: 23.5-43.9%). There was an increase in seroprevalence in European bison from 2012 to 2014. Biting midges ( Culicoides spp.), the primary vectors of SBV, were monitored entomologically for the identification of the biting midge populations and virologically for SBV infections in the Bialowieza Forest region, which contains the world's largest European bison population. We detected SBV by PCR in 3% of Culicoides pools from 2015. In addition, seven fetal brain samples from European bison or cervids were tested and were negative for SBV RNA. Our results indicate a high seroprevalence with reduced transmission of SBV in subsequent years in the European bison populations and lower seroprevalence in cervids. PMID- 29148885 TI - Self-clearance of Pestivirus in a Pyrenean Chamois ( Rupicapra pyrenaica) Population. AB - Understanding the dynamics of host-pathogen interaction is key to the management of epidemics. A pestivirus belonging to the border disease virus group 4 emerged around 2001 in Pyrenean chamois ( Rupicapra pyrenaica) in Spain and France. The virus had significant demographic impact in some populations, but it was less harmful and more endemic in other places. The determinants of these local variations are still unclear. Here, we documented empirical evidence of self clearance of the virus in a chamois population in France. This population has regularly been counted, and chamois were trapped and harvested each year, providing unique demographic and epidemiologic surveys of the population since 1984 and 1994, respectively. The virus was detected using direct (PCR) and indirect (antibody) testing. We showed that virus transmission declined in 2011 12 and likely ceased in 2013, leading to a decline in antibody prevalence since 2014. Self-clearance may be due to limited exchanges with other populations, decrease in population size after an epizootic, and herd immunity. The age structure of captured animals shifted to younger age classes after virus self clearance, suggesting a return to a colonizing population structure. The possible consequences of virus re-entry are discussed. This observation suggests that pestivirus dynamics occurs at the scale of the metapopulation of Pyrenean chamois. Local self-clearance and re-emergence may help explain the variation of virus dynamics at the local scale. PMID- 29148886 TI - AN EXPERIMENTAL STUDY OF THE EFFECTS OF CHEMICALLY DISPERSED OIL ON FEATHER STRUCTURE AND WATERPROOFING IN COMMON MURRES ( URIA AALGE). AB - Following an oil spill in the marine environment, chemical dispersants, which increase oil droplet formation and distribution into the water column, are assumed to provide a net benefit to seabirds by reducing the risk of exposure to oil on the water surface. However, few data are available regarding acute, external impacts of exposure to dispersed oil. We evaluated the effects of known concentrations of dispersant and crude oil in artificial seawater on live Common Murres ( Uria aalge). Waterproofing and microscopic feather geometry were evaluated over time and compared to pre-exposure values. Birds exposed to a high concentration of dispersant experienced an immediate, life-threatening loss of waterproofing and buoyancy, both of which resolved within 2 d. Birds exposed to oil, or a dispersant and oil mixture, experienced dose-dependent waterproofing impairment without resolution over 2 d. Alterations in feather geometry were observed in oil-exposed or dispersant- and oil-exposed birds and were associated with increased odds of waterproofing impairment compared to control birds. At a given contaminant concentration, there were no significant differences in waterproofing between oil-exposed and dispersant- and oil-exposed birds. We found that acute, external effects of oil and dispersed oil exposure are comparable and dose-dependent. Our results also indicate that a zero-risk assumption should not be used when seabirds are present within the dispersant application zone. PMID- 29148887 TI - WILD BIRDS AS A POTENTIAL SOURCE OF KNOWN AND NOVEL MULTILOCUS SEQUENCE TYPES OF ANTIBIOTIC-RESISTANT ENTEROCOCCUS FAECALIS. AB - We assessed the antibiotic resistance and genetic diversity of 27 Enterococcus faecalis isolates from 25 wild bird species in Poland. Resistance to lincomycin (100%) was most common followed by tetracycline (48%), erythromycin (44%), and ciprofloxacin (22%). High-level resistance to streptomycin and kanamycin was observed in 19% and 15% of isolates, respectively. One isolate (4%) exhibited low level resistance to penicillin and vancomycin, and all isolates were susceptible to gentamicin and chloramphenicol. Antibiotic resistance was linked to the tet(M), tet(L), erm(A), erm(B), msr(A/B), ant(6)-Ia, and aph(3')-IIIa genes. None of the tested van ( vanA, vanB, vanC1, vanC2/C3, vanD, vanE, vanG) genes were found in the vancomycin-resistant isolate. Based on pulsed-field gel electrophoresis and multilocus sequence typing analysis, the E. faecalis population from wild birds revealed high genetic diversity. All isolates were divided into 22 pulsotypes and 18 sequence types (STs), among which seven STs were newly assigned (ST748-ST753 and ST764). The most-prevalent STs were ST290 and ST374 followed by ST287 and ST34. The coexistence of strains assigned to the same STs in wild birds and in nonwildlife populations strongly indicated that many wild bird species could constitute a source of E. faecalis for infections in humans, pets, and farm animals. PMID- 29148888 TI - Tissue Residue Levels after Immobilization of Rocky Mountain Elk ( Cervus elaphus nelsoni) using a Combination of Nalbuphine, Medetomidine, and Azaperone Antagonized with Naltrexone, Atipamezole, and Tolazoline. AB - Previous studies demonstrated that nalbuphine, medetomidine, and azaperone (NalMed-A) can effectively immobilize adult elk ( Cervus elaphus nelsoni), and be antagonized using naltrexone and atipamezole, with or without tolazoline. To assess duration of tissue residues for this immobilization package, we immobilized 14 captive adult elk with NalMed-A, then euthanized animals and collected tissues 0, 3, 6, 14, 21, or 28 d later. Except for two animals euthanized immediately, all elk were recovered using naltrexone, atipamezole, and tolazoline. Tissue residues (>=0.01 parts per million) for the tranquilizers nalbuphine, medetomidine, and azaperone were detected in liver and muscle tissue samples from elk euthanized within 40 min postinjection (PI) and one animal that died 12-24 h PI, but not in tissues from any of the animals euthanized at 3, 6, 14, 21, or 28 d PI. Tissue residues for the antagonists naltrexone, atipamezole, and tolazoline were detected in liver and muscle of the animal that died 12-24 h PI. Only naltrexone was detected in liver from the two elk euthanized at day 3, and no antagonist residues were detected thereafter. PMID- 29148889 TI - Lack of Detection of Avian Influenza, Newcastle Disease, and West Nile Viruses in Wild Birds of Northeastern Brazil. AB - We tested 529 wild birds captured in northeastern Brazil for infection by avian influenza, Newcastle disease, and West Nile. Viruses were not detected by real time PCR with the exception of one Tropical Gnatcatcher ( Polioptila plumbea) positive for influenza virus, but this could not be confirmed by viral isolation or gene sequencing. PMID- 29148890 TI - Changes in the Use of Long-Acting Reversible Contraceptive Methods Among U.S. Nulliparous Women: Results from the 2006-2010, 2011-2013, and 2013-2015 National Survey of Family Growth. AB - OBJECTIVE: Nulliparous women in the United States have high rates of unintended pregnancy comparable with parous women. Long-acting reversible contraceptives (LARCs) are recommended as first-line contraceptive choices to reduce unintended pregnancy. However, use of LARCs among nulliparous women has been low. This study aims to examine changes in the prevalence of current LARC use among sexually experienced U.S. nulliparous women across the time period of 2006-2010, 2011 2013, and 2013-2015, and examine correlates of use. MATERIALS AND METHODS: Sexually experienced nulliparous women (15-44 years) from the 2006-2010, 2011 2013, and 2013-2015 rounds of the National Survey of Family Growth (N = 7463) were examined. Changes in the prevalence of current use of LARCs were examined and correlates of current LARC use were evaluated using multiple logistic regression. RESULTS: Increases in the prevalence of current LARC use from 2008 to 2012 (0.8% vs. 3.8%, p < 0.0001) and from 2012 to 2014 (3.8% vs. 5.7%, p = 0.09) were observed among sexually experienced nulliparous women. Significant increases were also observed across different subgroups of nulliparous women. Maternal age, education, future birth intention, sexual activity, and discontinuation of non LARC hormonal contraceptives due to dissatisfaction were significant correlates of current LARC use. CONCLUSION: Although current use of LARCs among sexually experienced U.S. nulliparous women shows an increasing trend, prevalence of use still remains low. There is the need to increase awareness of LARCs as an effective contraceptive choice for nulliparous women. PMID- 29148891 TI - Hyperventilation and breath-holding test with indocyanine green kinetics predicts cerebral hyperperfusion after carotid artery stenting. AB - Cerebral hyperperfusion syndrome (CHS) is a serious complication following carotid artery stenting (CAS), but definitive early prediction of CHS has not been established. Here, we evaluated whether indocyanine green kinetics and near infrared spectroscopy (ICG-NIRS) with hyperventilation (HV) and the breath holding (BH) test can predict hyperperfusion phenomenon after CAS. The blood flow index (BFI) ratio during HV and BH was prospectively monitored using ICG-NIRS in 66 patients scheduled to undergo CAS. Preoperative cerebrovascular reactivity (CVR) and the postoperative asymmetry index (AI) were also assessed with single photon emission computed tomography before and after CAS and the correlation with the BFI HV/rest ratio, BFI BH/rest ratio was evaluated. Twelve cases (18%) showed hyperperfusion phenomenon, and one (1.5%) showed CHS after CAS. A significant linear correlation was observed between the BFI HV/rest ratio, BFI BH/rest ratio, and preoperative CVR. A significant linear correlation was observed between the BFI HV/rest ratio and postoperative AI (r = 0.674, P < 0.0001). A BFI HV/rest ratio of 0.88 or more was the optimal cut-off point to predict hyperperfusion phenomenon according to receiver operating characteristic curve analyses. HV and BH test under ICG-NIRS is a useful tool for detection of hyperperfusion phenomenon in patients who underwent CAS. PMID- 29148892 TI - Impact of Prognostic Discussions on the Patient-Physician Relationship: Prospective Cohort Study. AB - Purpose Some research has suggested that discussion of prognosis can disrupt the patient-physician relationship. This study assessed whether physician discussion of prognosis is associated with detrimental changes in measures of the strength of the patient-physician relationship. Methods This was a longitudinal cohort study of 265 adult patients with advanced cancer who visited 38 oncologists within community- and hospital-based cancer clinics in Western New York and Northern California. Prognostic discussion was assessed by coding transcribed audio-recorded visits using the Prognostic and Treatment Choices (PTCC) scale and by patient survey at 3 months after the clinic visit. Changes in the strength of the patient-physician relationship were computed as differences in patient responses to The Human Connection and the Perceived Efficacy in Patient-Physician Interactions scales from baseline to 2 to 7 days and 3 months after the clinic visit. Results Prognostic discussion was not associated with a temporal decline in either measure. Indeed, a one-unit increase in PTCC during the audio-recorded visit was associated with improvement in The Human Connection scale at 2 to 7 days after the visit (parameter estimate, 0.10; 95% CI, -0.02 to 0.23) and 3 months after the visit (parameter estimate, 0.18; 95% CI, 0.02 to 0.35) relative to baseline. Standardized effect sizes (SES) associated with an increase of two standard deviations in the PTCC at each time point were consistent with small beneficial effects (SES, 0.14 [95% CI, -0.02 to 0.29] at 2 to 7 days; SES, 0.24 [95% CI, 0.02 to 0.45] at 3 months), and lower bounds of CIs indicated that substantial detrimental effects of prognostic discussion were unlikely. Conclusion Prognostic discussion is not intrinsically harmful to the patient physician relationship and may even strengthen the therapeutic alliance between patients and oncologists. PMID- 29148893 TI - Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000). AB - Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8 year rate of disease-free survival (+/- SE) was 89.2 +/- 1.3% and 92.3 +/- 1.2% ( P = .04); cumulative incidence of relapse, 8.7 +/- 1.2% and 6.4 +/- 1.1% ( P = .09); and overall survival, 96.1 +/- 0.8% and 98.0 +/- 0.6% ( P = .06). Patients with ETV6-RUNX1-positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 +/- 0.5% and 0.6 +/- 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response. PMID- 29148894 TI - Metabolic Profile in Patients with Mild Obstructive Sleep Apnea. AB - BACKGROUND: Mild obstructive sleep apnea (OSA) is a highly prevalent disorder in adults. However, it is not clear whether mild OSA has significant metabolic complications. This study examined the prevalence of metabolic syndrome (MS) in patients with mild OSA compared to control group. METHODS: Adults (18-65 years of age) of both genders with a body mass index (BMI) <=35 kg/m2 were included. The mild OSA group comprised of patients with an apnea-hypopnea index (AHI) score of >=5 but <=15 events/hr of sleep, independent of other symptoms. The control group (CG) comprised individuals with an AHI of <5 events/hr of sleep and an Epworth Sleepiness Scale score of <10. The following were used for both groups: two questionnaires on sleepiness, the maintenance of wakefulness test, and full-night polysomnography. Anthropometric measurements and fasting blood samples were obtained, including fasting glucose and insulin, total cholesterol and its subfractions [low-density lipoprotein, very low-density lipoprotein, and low density lipoprotein cholesterol (HDL-c)], triglycerides (TG), and the TG/HDL-c ratio. In addition, the quantitative insulin sensitivity check index and homeostasis model assessment indices were calculated. RESULTS: Thirty-two percent of mild OSA patients had MS, 43.5% of mild OSA patients had hypertension, 14% showed dyslipidemia, and 56% had prediabetes. The OSA group showed increased TG (CG: 90.0 +/- 51.9 vs. OSA: 140.3 +/- 78.2 mg/dL, P = 0.004), and TG/HDL-c (CG: 1.9 +/- 1.4 vs. OSA: 3.1 +/- 2.0, P = 0.05), independent of adjustments. Independent of obesity (BMI <30 kg/m2), there was a negative correlation between total cholesterol and TG with mean oxygen saturation, independent of obesity (BMI <30 kg/m2). CONCLUSIONS: Our findings showed dysregulation in lipid profiles after adjustments for confounders in the mild OSA group, and there was a correlation between these parameters and sleep hypoxemia. The TG/HDL-c ratio in particular was high, suggesting that it might be investigated as a marker of a detrimental metabolic profile in these patients. PMID- 29148895 TI - Characterization of Cefotaxime- and Ciprofloxacin-Resistant Commensal Escherichia coli Originating from Belgian Farm Animals Indicates High Antibiotic Resistance Transfer Rates. AB - Food-producing animals represent one of the sources of antibiotic resistant commensal bacteria. There is an increasing awareness that these bacteria might have the potential to transfer their resistance genes to other (pathogenic) bacteria. In this study, 50 commensal Escherichia coli strains originating from food-producing animals and resistant to the "highest priority, critically important antibiotics" cefotaxime and/or ciprofloxacin, were selected for further characterization. For each strain (i) an antibiogram, (ii) the phylogenetic group, (iii) plasmid replicon type, (iv) presence and identification of integrons, and (v) antibiotic resistance transfer ratios were determined. Forty five of these strains were resistant to 5 or more antibiotics, and 6 strains were resistant to 10 or more antibiotics. Resistance was most common to ampicillin (100%), sulfamethoxazole, ciprofloxacin (82%), trimethoprim, tetracycline (74%), cefotaxime, (70%) and ceftazidime (62%). Phylogenetic groups A (62%) and B1 (26%) were most common, followed by C (8%) and E (4%). In 43 strains, more than 1 replicon type was detected, with FII (88%), FIB (70%), and I1 (48%) being the most encountered types. Forty strains, positive for integrons, all harbored a class I integron and seven of them contained an additional class II integron. No class III integrons were detected. The antibiotic resistance transfer was assessed by liquid mating experiments. The transfer ratio, expressed as the number of transconjugants per recipient, was between 10-5 and 100 for cefotaxime resistance and between 10-7 and 10-1 for ciprofloxacin resistance. The results of the current study prove that commensal E. coli in food-production animals can be a source of multiple resistance genes and that these bacteria can easily spread their ciprofloxacin and cefotaxime resistance. PMID- 29148896 TI - Prooxidant-antioxidant balance, advanced oxidation protein products and lipid peroxidation in Serbian patients with Parkinson's disease. AB - BACKGROUND: Biomarkers of oxidative stress are relevant in the evaluation of the disease status and prooxidant-antioxidant balance, advanced oxidation protein products and lipid peroxidation products (malondialdehyde and 4-hydroxynonenal) are being extensively evaluated regarding their relationship with clinical presentation and disease severity. AIM OF THE STUDY: The aim of this study was to evaluate the levels of the above-mentioned parameters in plasma of 39 men and 17 women with Parkinson's disease, originated from the Republic of Serbia and their relation to clinicopathological characteristics (gender, age at examination, duration of the disease, and Hoehn and Yahr score) and oxidative status. RESULTS: The incidence of disease was 2:1 towards males. The investigated oxidative parameters were gender and Hoehn and Yahr related. Significant association of higher Hoehn and Yahr scores was observed for malondialdehyde (p = 0.01) and prooxidant-antioxidant balance (p = 0.02). Relation between oxidant-antioxidant status was further supported by observed positive correlation between 4 hydroxynonenal (p = 0.04) and prooxidant-antioxidant balance (p = 0.03). Finally, the multivariate analysis indicated that prooxidant-antioxidant balance and malondialdehyde were partially determined by gender (10.6% and 7.6%) and Hoehn and Yahr scores (13.6% and 18.8%), while Hoehn and Yahr scores contributed to the variance of advanced oxidation protein products with 13.2%. CONCLUSION: Our results indicate the higher level of oxidative stress (oxidant-antioxidant imbalance) and possible relation of several markers with gender and disease stage in patients with Parkinson's disease. The analyzed markers could be used to specify the severity of oxidative stress; however, their potential value should be analyzed in further studies. PMID- 29148897 TI - Oxidative stress response in SH-SY5Y cells exposed to short-term 1800 MHz radiofrequency radiation. AB - The exact mechanism that could explain the effects of radiofrequency (RF) radiation exposure at non-thermal level is still unknown. Increasing evidence suggests a possible involvement of reactive oxygen species (ROS) and development of oxidative stress. To test the proposed hypothesis, human neuroblastoma cells (SH-SY5Y) were exposed to 1800 MHz short-term RF exposure for 10, 30 and 60 minutes. Electric field strength within Gigahertz Transverse Electromagnetic cell (GTEM) was 30 V m-1 and specific absorption rate (SAR) was calculated to be 1.6 W kg-1. Cellular viability was measured by MTT assay and level of ROS was determined by fluorescent probe 2',7'-dichlorofluorescin diacetate. Concentrations of malondialdehyde and protein carbonyls were used to assess lipid and protein oxidative damage and antioxidant activity was evaluated by measuring concentrations of total glutathione (GSH). After radiation exposure, viability of irradiated cells remained within normal physiological values. Significantly higher ROS level was observed for every radiation exposure time. After 60 min of exposure, the applied radiation caused significant lipid and protein damage. The highest GSH concentration was detected after 10 minute-exposure. The results of our study showed enhanced susceptibility of SH-SY5Y cells for development of oxidative stress even after short-term RF exposure. PMID- 29148898 TI - Enhancement of invadopodia activity in glioma cells by sublethal doses of irradiation and temozolomide. AB - OBJECTIVE Glioblastoma is the most common primary central nervous system tumor in adults. These tumors are highly invasive and infiltrative and result in tumor recurrence as well as an extremely poor patient prognosis. The current standard of care involves surgery, radiotherapy, and chemotherapy. However, previous studies have suggested that glioblastoma cells that survive treatment are potentially more invasive. The goal of this study was to investigate whether this increased phenotype in surviving cells is facilitated by actin-rich, membrane based structures known as invadopodia. METHODS A number of commercially available cell lines and glioblastoma cell lines obtained from patients were initially screened for the protein expression levels of invadopodia regulators. Gelatin based zymography was also used to establish their secretory protease profile. The effects of radiation and temozolomide treatment on the glioblastoma cells were then investigated with cell viability, Western blotting, gelatin-based zymography, and invadopodia matrix degradation assays. RESULTS The authors' results show that the glioma cells used in this study express a number of invadopodia regulators, secrete MMP-2, and form functional matrix-degrading invadopodia. Cells that were treated with radiotherapy and temozolomide were observed to show an increase primarily in the activation of MMP-2. Importantly, this also resulted in a significant enhancement in the invadopodia-facilitated matrix-degrading ability of the cells, along with an increase in the percentage of cells with invadopodia after radiation and temozolomide treatment. CONCLUSIONS The data from this study suggest that the increased invasive phenotype that has been previously observed in glioma cells posttreatment is mediated by invadopodia. The authors propose that if the formation or activity of these structures can be disrupted, they could potentially serve as a viable target for developing novel adjuvant therapeutic strategies that can be used in conjunction with the current treatment protocols in combatting the invasive phenotype of this deadly disease. PMID- 29148899 TI - Patients with cranial dural arteriovenous fistulas may benefit from expanded hypercoagulability and cancer screening. AB - OBJECTIVE: Cranial dural arteriovenous fistulas (DAVFs) have been associated with dural sinus occlusion, and previous reports have suggested the association of hypercoagulability with some cases. But the prevalence of a hypercoagulable state has not been systematically analyzed in conjunction with laboratory markers and clinical manifestations, including history of thromboembolism or systemic malignancy. The authors hypothesize that laboratory or clinical evidence of a hypercoagulable state, including cancer, is commonly identifiable in consecutively identified patients with DAVFs, with implications for clinical management. METHODS: The retrospective cohort study included all patients older than 17 years with cranial DAVFs diagnosed at University of Chicago Medicine during a 6-year period, whose medical records and imaging results were reviewed for objective laboratory or clinical evidence of a hypercoagulable state, including malignancy. Each case was analyzed for implications on clinical management. Data were analyzed in relation to a systematic review of the literature on this association. RESULTS: Fifteen (88%) of 17 cases of DAVFs had laboratory (n = 8) or clinical evidence of a hypercoagulable state (thromboembolism [n = 8] or cancer [n = 6]). This hypercoagulability or cancer impacted clinical care in all 15 cases. CONCLUSIONS: An underlying hypercoagulable state manifested by laboratory testing or clinically, including cancer, is staggeringly common. It is important to recognize this association, along with its impact on the management of the DAVFs and systemic diseases. PMID- 29148900 TI - Combined interventional and surgical treatment of tandem middle cerebral artery embolus and internal carotid artery occlusion: case report. AB - Tandem internal carotid artery (ICA) origin occlusion and middle cerebral artery (MCA) thromboembolism is a life-threatening condition with poor neurological outcome. The authors report on a patient presenting with acute ischemic stroke from a tandem ICA and MCA occlusion with penumbra. Emergency MCA mechanical thrombectomy was performed through percutaneous cervical ICA access due to the inability to cross the cervical carotid occlusion. Emergency carotid endarterectomy to reperfuse the poorly collateralized hemisphere and repair the ICA access site was performed 2 hours after completion of tissue plasminogen activator (tPA) infusion. This case illustrates the shortest reported interval between tPA infusion and open surgical intervention for carotid revascularization, as well as the role of direct carotid artery access for mechanical thrombectomy. The authors also describe the use of a temporizing femoral artery-to-ICA shunt to maintain cerebral perfusion in the setting of ICA occlusion. PMID- 29148901 TI - Glaucoma in patients with shunt-treated normal pressure hydrocephalus. AB - OBJECTIVE: Changes in the pressure gradient between intraocular and intracranial compartments at the lamina cribrosa level are a possible explanation of normal tension glaucoma (NTG). Shunt-treated normal pressure hydrocephalus (NPH) is a model for testing whether the increase (time from disease onset to CSF shunt placement, i.e., "protection period") and decrease (time from shunt placement to observation, i.e., "exposure period") in intracranial pressure (ICP) are glaucoma protective or risk factors, respectively. The authors estimated the prevalence of NTG in patients with shunt-treated NPH and calculated the extent of optic nerve exposure to changes in the trans-lamina cribrosa gradient. METHODS: Data obtained in patients with NPH who had undergone ventriculoperitoneal (VP) shunt placement were analyzed. Patients with more than 6 months' follow-up, no pathologies associated with ICP changes or CSF dynamics disturbances, and no surgical or valve-related complications were scheduled for ophthalmic evaluation. RESULTS: Nine of 22 patients had NTG, which is about a 40-fold increase in rate compared with the rate in the general elderly population without hydrocephalus (p < 0.001). The median protection period was 12.0 months in patients with NTG and 18.0 months in those without NTG (p = 0.033). The median ICP decrease multiplied by duration of exposure in months was 76.0 mm Hg * months in the NTG group and 24.1 mm Hg * months in the no-NTG group (p = 0.048). The patients' median adjusted age (adjusted for "protection" and "exposure" times) was 85.1 years in the NTG group and 78.8 years in the no-NTG group (p = 0.001). CONCLUSIONS: A crucial risk factor for development of NTG in patients with shunt-treated NPH is the duration of optic nerve exposure to the lowering of ICP. Patients with NPH who are candidates for CSF shunting should be informed of the risk of incurring glaucoma. Longitudinal studies could provide estimates of tolerated times for a given ICP decrease. PMID- 29148902 TI - Microsurgical anatomy and approaches around the lateral recess with special reference to entry into the pons. AB - OBJECTIVE The lateral recess is a unique structure communicating between the ventricle and cistern, which is exposed when treating lesions involving the fourth ventricle and the brainstem with surgical approaches such as the transcerebellomedullary fissure approach. In this study, the authors examined the microsurgical anatomy around the lateral recess, including the fiber tracts, and analyzed their findings with respect to surgical exposure of the lateral recess and entry into the lower pons. METHODS Ten cadaveric heads were examined with microsurgical techniques, and 2 heads were examined with fiber dissection to clarify the anatomy between the lateral recess and adjacent structures. The lateral and medial routes directed to the lateral recess in the transcerebellomedullary fissure approach were demonstrated. A morphometric study was conducted in the 10 cadaveric heads (20 sides). RESULTS The lateral recess was classified into medullary and cisternal segments. The medial and lateral routes in the transcerebellomedullary fissure approach provided access to approximately 140o-150o of the posteroinferior circumference of the lateral recess. The floccular peduncle ran rostral to the lateral recess, and this region was considered to be a potential safe entry zone to the lower pons. By appropriately selecting either route, medial-to-lateral or lateral-to-medial entry axis is possible, and combining both routes provided wide exposure of the lower pons around the lateral recess. CONCLUSIONS The medial and lateral routes of the transcerebellomedullary fissure approach provided wide exposure of the lateral recess, and incision around the floccular peduncle is a potential new safe entry zone to the lower pons. PMID- 29148903 TI - An Onyx tunnel: reconstructive transvenous balloon-assisted Onyx embolization for dural arteriovenous fistula of the transverse-sigmoid sinus. AB - Transvenous embolization is an effective method for treating dural arteriovenous fistulas (DAVFs) of the transverse-sigmoid sinus (TSS). However, in cases of complicated DAVFs, it is difficult to preserve the patency of the dural sinus. The authors describe the technical details of a new reconstructive technique using transvenous balloon-assisted Onyx embolization as another treatment option in a patient with an extensive and complex DAVF of the left TSS. A microcatheter and compliant balloon catheter were navigated into the left internal jugular vein and placed at the distal end of the DAVF in the transverse sinus. The microcatheter was placed between the vessel wall of the TSS and the balloon. After the balloon was fully inflated, Onyx-18 was injected at the periphery of the balloon in a slow, controlled, progressive, stepwise manner; the balloon and microcatheter were simultaneously withdrawn toward the sigmoid sinus, with Onyx encompassing the entirety of the complex DAVF. The Onyx refluxed into multiple arterial feeders in a distal-to-proximal step-by-step manner, ultimately resulting in an Onyx tunnel. The final angiography study revealed complete obliteration of the DAVF and patency of the TSS. The Onyx tunnel, or reconstructive transvenous balloon-assisted Onyx embolization technique, may be an effective treatment option for large, complex DAVFs of the TSS. This technique may provide another option to facilitate the complete obliteration of the DAVF while preserving the functional sinus. PMID- 29148904 TI - Randomized controlled study comparing 2 surgical techniques for decompressive craniectomy: with watertight duraplasty and without watertight duraplasty. AB - OBJECTIVE: Decompressive craniectomy (DC) is a widely used procedure in neurosurgery; however, few studies focus on the best surgical technique for the procedure. The authors' objective was to conduct a prospective randomized controlled trial comparing 2 techniques for performing DC: with watertight duraplasty and without watertight duraplasty (rapid-closure DC). METHODS: The study population comprised patients ranging in age from 18 to 60 years who were admitted to the Neurotrauma Service of the Hospital da Restauracao with a clinical indication for unilateral decompressive craniectomy. Patients were randomized by numbered envelopes into 2 groups: with watertight duraplasty (control group) and without watertight duraplasty (test group). After unilateral DC was completed, watertight duraplasty was performed in the control group, while in the test group, no watertight duraplasty was performed and the exposed parenchyma was covered with Surgicel and the remaining dura mater. Patients were then monitored daily from the date of surgery until hospital discharge or death. The primary end point was the incidence of surgical complications (CSF leak, wound infection, brain abscess, or subgaleal fluid collections). The following were analyzed as secondary end points: clinical outcome (analyzed using the Glasgow Outcome Scale [GOS]), surgical time, and hospital costs. RESULTS: Fifty eight patients were enrolled, 29 in each group. Three patients were excluded, leaving 27 in the test group and 28 in the control group. There were no significant differences between groups regarding age, Glasgow Coma Scale score at the time of surgery, GOS score, and number of postoperative follow-up days. There were 9 surgical complications (5 in the control group and 4 in the test group), with no significant differences between the groups. The mean surgical time in the control group was 132 minutes, while in the test group the average surgical time was 101 minutes, a difference of 31 minutes (p = 0.001). The mean reduction in total cost was $420.00 USD (a 23.4% reduction) per procedure in the test group. CONCLUSIONS: Rapid-closure DC without watertight duraplasty is a safe procedure. It is not associated with a higher incidence of surgical complications (CSF leak, wound infection, brain abscess, or subgaleal fluid collections), and it decreased surgical time by 31 minutes on average. There was also a hospital cost reduction of $420.00 USD (23.4% reduction) per procedure. Clinical trial registration no.: NCT02594137 (clinicaltrials.gov). PMID- 29148905 TI - Serum glucose/potassium ratio as a clinical risk factor for aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: Aneurysmal subarachnoid hemorrhage (SAH) can result in poor outcomes, and biomarkers for predicting poor prognosis have not yet been established. The aim of this study was to clarify the significance of the serum glucose/potassium ratio for predicting the prognosis of aneurysmal SAH. METHODS: The authors retrospectively reviewed the records of 565 patients with aneurysmal SAH between 2006 and 2016. The patient group comprised 208 men and 357 women (mean age 61.5 years, range 10-95 years). A statistical analysis was conducted of the clinical and laboratory risk factors of poor outcome, including the serum glucose/potassium ratio. RESULTS: On estimation of the initial assessment using Hunt and Kosnik (H-K) grading, 233 patients (41.2%) were classified as the severe SAH group (H-K Grade IV or V). There were significant correlations between the severe SAH group and serum glucose/potassium ratio (p < 0.0001). Serum glucose/potassium ratio was elevated in an H-K grade-dependent manner (Spearman's r = 0.5374, p < 0.0001). With the estimation of the Glasgow Outcome Scale (GOS) score at discharge, 355 patients (62.8%) were classified as poor outcome (GOS score 1-3). The serum glucose/potassium ratio was elevated in a GOS score at discharge-dependent manner (Spearman's r = 0.4006, p < 0.0001), and was significantly elevated in the poor outcome group compared with the good outcome group (GOS score 4 or 5; p = 0.0245). There were significant correlations between poor outcome and serum glucose/potassium ratio (p < 0.0001), age (p < 0.0001), brain natriuretic peptide levels (p = 0.011), cerebral infarction due to vasospasm (p < 0.0001), and H-K grade (p < 0.0001). Multivariate logistic regression analyses showed significant correlations between poor outcome and serum glucose/potassium ratio (p = 0.009). CONCLUSIONS: In this study, the serum glucose/potassium ratio of patients with aneurysmal SAH at admission was significantly correlated with H-K grade and GOS score at discharge. Therefore, this ratio was useful for predicting prognosis of aneurysmal SAH, especially in severe cases. PMID- 29148906 TI - Research and Policy Change to Improve Healthcare and Elder Services for LGBT Older Adults. PMID- 29148907 TI - Impact of Patients' Expressed Wishes on Their Surrogate Decision Makers' Preferred Decision-Making Roles in Japan. AB - BACKGROUND: Home medical care (HMC) patients and their families are expected to prepare for end-of-life decision making. OBJECTIVE: We investigated the decision readiness of HMC patients and their family surrogates. DESIGN: Cross-sectional survey. SETTING/SUBJECTS: We collected data from dyads, consisting of a HMC patient aged 65 years or older and a family member of the patient, recruited at four Japanese primary care clinics from January 2016 to November 2016. MEASUREMENTS: Surrogates completed a questionnaire on their sociodemographic and health status and their decision readiness. Primary HMC physicians provided information on their patients. RESULTS: A total of 337 dyads were screened, and 159 were included. The mean age of patients and surrogates was 86 and 64 years, respectively, and 29% of patients were cognitively impaired. Only 1.9% of the patients left written advance directives, and 32% were entrusting all decision making to the doctor or their families. Regarding the surrogate's preferred decision-making role, 21.9% of the surrogates preferred doctors to assume decision-making responsibility. A multivariate analysis revealed that no discussion of care goals (odds ratio [OR] 2.88, 95% confidence interval [CI] 1.02 8.17) and patients having expressed their wishes verbally, including entrusting decision making to others (OR 2.51, 95% CI 1.07-5.89), were associated with surrogates' preference for doctors to have decision-making responsibility. CONCLUSIONS: Many patients preferred to entrust the end-of-life decisions to others rather than utilizing advance directives, which made surrogates more dependent on doctors for decision making. Qualified advance care planning is required to promote familial discussion and surrogates' decision readiness. PMID- 29148908 TI - Rethink radiotherapy - BIGART 2017. PMID- 29148909 TI - Inhibition of GABA transporters fails to afford significant protection following focal cerebral ischemia. AB - Brain ischemia triggers excitotoxicity and cell death, yet no neuroprotective drugs have made it to the clinic. While enhancing GABAergic signaling to counterbalance excitotoxicity has shown promise in animal models, clinical studies have failed. Blockade of GABA transporters (GATs) offers an indirect approach to increase GABA inhibition to lower the excitation threshold of neurons. Among the GATs, GAT1 is known to promote neuroprotection, while the protective role of the extrasynaptic transporters GAT3 and BGT1 is elusive. A focal lesion was induced in the motor cortex in two to four-month-old C57BL/6 J male mice by photothrombosis. The GAT1 inhibitor, tiagabine (1 and 10 mg/kg), the GAT2/3 inhibitor, ( S)-SNAP-5114 (5 and 30 mg/kg) and the GAT1/BGT1 inhibitor, EF 1502 (1 and 10 mg/kg) were given i.p. 1 and 6 h post-stroke to assess their impact on infarct volume and motor performance seven days post-stroke. One mg/kg tiagabine improved motor performance, while 10 mg/kg tiagabine, ( S)-SNAP-5114 and EF-1502 had no effect. None of the compounds affected infarct volume. Interestingly, treatment with tiagabine induced seizures and ( S)-SNAP-5114 led to increased mortality. Although we show that tiagabine can promote protection, our findings indicate that caution should be had when using GAT1 and GAT3 inhibitors for conditions of brain ischemia. PMID- 29148910 TI - Impact of Pelvic Pain and Endometriosis on Patient-Reported Outcomes and Experiences of Benign Hysterectomy: A Study from the Swedish National Register for Gynecological Surgery. AB - BACKGROUND: The study objective was to analyze and compare patient-reported experience measures (PREMs) and patient-reported outcome measures (PROMs) after hysterectomy in women with and without a preoperative complaint of pelvic pain associated with and without a confirmed diagnosis of endometriosis. METHODS: Retrospective nationwide register study. Data on 28,776 hysterectomies performed on benign indication between 2004 and 2016 were retrieved from the Swedish National Register for Gynecological Surgery. Multivariable logistic regression models were used to compare the PREMs and PROMs items. The results are presented as adjusted odds ratios (aORs) and 95% confidence intervals (CI). RESULTS: Regardless of the occurrence of pelvic pain preoperatively and a diagnosis of endometriosis, 1 year after surgery, the women were satisfied or very satisfied (>90%) with the hysterectomy, and their medical condition was improved or much improved (>95%). The women with a preoperative complaint of pelvic pain and endometriosis more often reported excessively short hospital stays (aOR 1.45, 95% CI 1.17-1.79), more severe complications after discharge (aOR 2.02, 95% CI 1.59 2.66) at the 8-week follow-up and at the 1-year follow-up (aOR 2.31, 95% CI 1.57 3.39), and more dissatisfaction with the operation (aOR 1.83, 95% CI 1.35-2.48) than preoperative pelvic pain-free women without endometriosis at the 1-year follow-up. CONCLUSIONS: The majority of the women were satisfied after their hysterectomy. The women with pelvic pain and endometriosis were at a higher risk of being dissatisfied. Pelvic pain per se seemed to be the main factor affecting the rating in the PREMs and PROMs, and the endometriosis was a significant contributing factor. PMID- 29148911 TI - Report from enhanced safety surveillance of two influenza vaccines (Vaxigrip and Intanza 15 MUg) in two European countries during influenza season 2016/17 and comparison with 2015/16 season. AB - Passive enhanced safety surveillance (ESS) was implemented in the United Kingdom and in the Republic of Ireland for Vaxigrip and Intanza 15 ug influenza vaccines during the 2016/17 influenza season. Lessons learned during 2015/16 ESS implementation were integrated and applied towards the current ESS. The primary objective was to estimate the reporting rates of suspected adverse reactions (ARs) occurring within 7 days of vaccination with Vaxigrip or Intanza 15 ug. For Vaxigrip (N = 962), 17 vaccinees (1.8%) reported 59 suspected ARs (6.1%) within 7 days of vaccination. For Intanza 15 ug (N = 1000), 21 vaccinees (2.1%) reported 101 (10.1%) suspected ARs within 7 days of vaccination. No obvious pattern in the type of suspected ARs or their frequency was observed for either vaccine. None of the frequencies of suspected ARs were above the 2015/16 ESS frequencies for Vaxigrip, whereas for Intanza 15 ug only one AR (oropharyngeal pain) crossed the historical threshold. There was no change in reactogenicity and data was consistent with the safety profiles of the two vaccines. The passive ESS experience gained from season to season will help to contribute to a sustainable safety surveillance system of seasonal influenza vaccines early in the season. PMID- 29148912 TI - Influence of Different Restoration Techniques on Fracture Resistance of Root filled Teeth: In Vitro Investigation. AB - OBJECTIVE: The purpose of this study was to determine the fracture strength of endodontically treated mandibular premolar teeth restored with composites and different reinforcement techniques. METHODS AND MATERIALS: Forty-eight freshly extracted human mandibular premolar teeth were randomly divided into four groups: group IN, group CR, group FRC, and group PRF. Group IN consisted of teeth with intact crowns and served as the control group. In the other three groups, endodontic treatment was performed and standard mesio-occluso-distal (MOD) cavities were prepared. Then cavities were restored with hybrid resin composite only, flowable composite and hybrid resin composite, and Ribbond, flowable composite and hybrid resin composite in groups CR, FRC and PRF, respectively. All of the teeth were subjected to fracture by means of a universal testing machine, and compressive force was applied with a modified stainless-steel ball at a crosshead speed at 0.5 mm/min. RESULTS: The highest values were observed in group IN, while the lowest values were determined in group CR. There was not any statistically significant difference between group CR and group FCR ( p>0.05). When groups CR, FCR, and PRF were compared, group PRF showed significantly better fracture strength than did groups CR and FCR ( p<0.05). It was determined that there was not any significant difference between group IN and group PRF ( p>0.05). CONCLUSIONS: Polyethylene ribbon fiber considerably increases the fracture strength of mandibular premolar teeth with MOD cavities restored with composite. PMID- 29148913 TI - Using Cross-Polarized Photography as a Guide for Selecting Resin Composite Shade. AB - The restoration of single discolored maxillary anterior teeth is still a difficult task, as not only shape and surface characterization play an important role in the success of the treatment, but the propagation of light throughout the restorative material does as well. In some cases, small changes in morphology, color, and brightness will be noticeable. These factors are sometimes very tricky, and shade guides alone are difficult to use for color selection. This article proposes a protocol of employing cross-polarization imaging for improving the accuracy of the shade selection of resin composites. The step-by-step technique is presented for the restoration of a single discolored tooth. PMID- 29148914 TI - Marginal Gap Formation in Approximal "Bulk Fill" Resin Composite Restorations After Artificial Ageing. AB - The aim of this in vitro study was to investigate the marginal gap formation of a packable "regular" resin composite (Filtek Supreme XTE [3M ESPE]) and two flowable "bulk fill" resin composites (Filtek Bulk Fill [3M ESPE] and SDR [DENTSPLY DeTrey]) along the approximal margins of Class II restorations. In each of 39 extracted human molars (n=13 per resin composite), mesial and distal Class II cavities were prepared, placing the gingival margins below the cemento-enamel junction. The cavities were restored with the adhesive system OptiBond FL (Kerr) and one of the three resin composites. After restoration, each molar was cut in half in the oro-vestibular direction between the two restorations, resulting in two specimens per molar. Polyvinylsiloxane impressions were taken and "baseline" replicas were produced. The specimens were then divided into two groups: At the beginning of each month over the course of six months' tap water storage (37 degrees C), one specimen per molar was subjected to mechanical toothbrushing, whereas the other was subjected to thermocycling. After artificial ageing, "final" replicas were produced. Baseline and final replicas were examined under the scanning electron microscope (SEM), and the SEM micrographs were used to determine the percentage of marginal gap formation in enamel or dentin. Paramarginal gaps were registered. The percentages of marginal gap formation were statistically analyzed with a nonparametric analysis of variance followed by Wilcoxon-Mann-Whitney tests and Wilcoxon signed rank tests, and all p-values were corrected with the Bonferroni-Holm adjustment for multiple testing (significance level: alpha=0.05). Paramarginal gaps were analyzed descriptively. In enamel, significantly lower marginal gap formation was found for Filtek Supreme XTE compared to Filtek Bulk Fill ( p=0.0052) and SDR ( p=0.0289), with no significant difference between Filtek Bulk Fill and SDR ( p=0.4072). In dentin, significantly lower marginal gap formation was found for SDR compared to Filtek Supreme XTE ( p<0.0001) and Filtek Bulk Fill ( p=0.0015), with no significant difference between Filtek Supreme XTE and Filtek Bulk Fill ( p=0.4919). Marginal gap formation in dentin was significantly lower than in enamel ( p<0.0001). The percentage of restorations with paramarginal gaps varied between 0% and 85%, and for all three resin composites the percentages were markedly higher after artificial ageing. The results from this study suggest that in terms of marginal gap formation in enamel, packable resin composites may be superior to flowable "bulk fill" resin composites, while in dentin some flowable "bulk fill" resin composites may be superior to packable ones. PMID- 29148915 TI - Frequency of Mutations in Quinolone Resistance-Determining Regions and Plasmid Mediated Quinolone Resistance in Shigella Isolates Recovered from Pediatric Patients in Tehran, Iran: An Overlooked Problem. AB - Fluoroquinolone (FQ) resistance in clinical isolates of Shigella species has been increasing reported in recent years. This study was carried out to find the mutations within the quinolone resistance-determining regions (QRDRs) and the prevalence of plasmid-mediated quinolone resistance (PMQR) determinants among the clinical isolates of Shigella sp. in Tehran, Iran. A total of 50 Shigella isolates were collected from five teaching therapeutic centers in Tehran, Iran and analyzed for antibiotic susceptibility over a period of 20 months from July 2015 to January 2017. The PCR and direct nucleotide sequencing were used for genetic alterations in the QRDRs. The PMQR genes were detected using PCR. The results revealed four types of mutations in the QRDR of gyrA: 20 (40%) had a S83L mutation, 1 (2%) had a S83A mutation, 2 (4%) had a D87G mutation, and 1 (2%) isolate had a D87Y mutation. Mutations were also found at codon N57D, D200N, and E210K in three isolates. Seven hospitalized children had qnrS determinants, and one isolates had the mutation S83A, while two isolates had double mutations at S83L and/or D87G (Ser83Leu and Asp-87Gly). The PMQR gene-positive isolates had the single replacement of serine with leucine. In hospitalized children, two isolates had two types of PMQR determinants (qnrS and qnrA) and (qnrS and qnrB) at once. The results of this study indicate that the emergence of strains with mutations in the QRDR regions and the capture of PMQR determinants in strains may lead to failure in therapy with FQ and the widespread emergence of strains with high-level FQ resistance. PMID- 29148916 TI - Time and spatial variability in the concentrations of selected metals in water and bottom sediments of Plawniowice and Dzierzno Male reservoirs (Poland). AB - The migration of metals and metalloids between bottom sediments and water and the other way round is a complex process. Understanding those mechanisms is essential for recognizing transformations taking place in water reservoir ecosystems. The objective behind the following study was to define time and spatial correlations in the changes in total concentrations of selected elements (Cr, Zn, Co, Mn, Cu, Ni, Pb, As, Ba, Sb, Sr and V) in waters and bottom sediments from two water reservoirs located in Upper Silesia (Poland), i.e., Plawniowice and Dzierzno Male. The research was carried out to demonstrate whether the bottom sediments deposited in the discussed reservoirs could pose an environmental threat due to the possible release of toxic metals and metalloids into the pelagic zone. The obtained results constitute material helping to describe the bioavailability of particular elements. They also expose the existing environmental threats for such water reservoirs and their users. PMID- 29148917 TI - Evaluation of antibacterial activity and toxic metal removal of chemically synthesized magnetic iron oxide titanium coated nanoparticles and application in bacterial treatment. AB - Co-precipitation method was used for preparation of two types of iron oxide nanoparticles coated by titanium dioxide according to divalent salts used. The average size of iron oxide nanoparticles coated by titanium dioxide measured by particle size analyzer, ranged approximately between 20 nm and 100 nm with mean particle size of 60 nm. Characterization of the prepared nanoparticles was done by X-ray diffraction analysis and scanning electron microscope indicating the sole existence of inverse cubic spinel phase of magnetic iron oxide nanoparticles. Further, the antibacterial activity of two prepared iron oxide nanoparticles was evaluated against four pathogenic bacteria where both preparations showed promising antibacterial activities against Gram positive and Gram negative strains which offers a potential application in pharmaceutical and biomedical industries. The antibacterial activity showed high reduction percent after 30 min by 150 MUg mL-1 of nanoparticles prepared. Also, high reduction percent was achieved for removal of iron and manganese ions from polluted water and good effect on decreasing chemical oxygen demand and biochemical oxygen demand concentrations with decreased percent of total nitrogen concentration. PMID- 29148919 TI - Bacterial flora analysis of coliforms in sewage, river water, and ground water using MALDI-TOF mass spectrometry. AB - The aim of this study was to rapidly and effectively analyze coliforms, which are the most fundamental indicators of water quality for fecal pollution, using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Coliform bacteria were isolated from municipal sewage, river water, and groundwater. For each sample, 100 isolates were determined by MALDI TOF MS. In addition, these same 100 isolates were also identified via 16S rRNA gene sequence analysis. Obtained MALDI-TOF MS data were compared with the 16S rRNA sequencing analysis, and the validity of MALDI-TOF MS for classification of coliform bacteria was examined. The concordance rate of bacterial identification for the 100 isolates obtained by MALDI-TOF MS analysis and 16S rRNA gene sequence analysis for sewage, river water, and ground water were 96%, 74%, and 62% at the genus level, respectively. Among the sewage, river water, and ground water samples, the coliform bacterial flora were distinct. The dominant genus of coliforms in sewage, river water, and groundwater were Klebsiella spp., Enterobacter spp., and Serratia spp., respectively. We determined that MALDI-TOF MS is a rapid and accurate tool that can be used to identify coliforms. Therefore, without using conventional 16S rRNA sequencing, it is possible to rapidly and effectively classify coliforms in water using MALDI-TOF MS. PMID- 29148921 TI - A Predictive Model for Readmissions Among Medicare Patients in a California Hospital. AB - Predictive models for hospital readmission rates are in high demand because of the Centers for Medicare & Medicaid Services (CMS) Hospital Readmission Reduction Program (HRRP). The LACE index is one of the most popular predictive tools among hospitals in the United States. The LACE index is a simple tool with 4 parameters: Length of stay, Acuity of admission, Comorbidity, and Emergency visits in the previous 6 months. The authors applied logistic regression to develop a predictive model for a medium-sized not-for-profit community hospital in California using patient-level data with more specific patient information (including 13 explanatory variables). Specifically, the logistic regression is applied to 2 populations: a general population including all patients and the specific group of patients targeted by the CMS penalty (characterized as ages 65 or older with select conditions). The 2 resulting logistic regression models have a higher sensitivity rate compared to the sensitivity of the LACE index. The C statistic values of the model applied to both populations demonstrate moderate levels of predictive power. The authors also build an economic model to demonstrate the potential financial impact of the use of the model for targeting high-risk patients in a sample hospital and demonstrate that, on balance, whether the hospital gains or loses from reducing readmissions depends on its margin and the extent of its readmission penalties. PMID- 29148922 TI - Feasibility and safety of using thoracic and lumbar cortical bone trajectory pedicle screws in spinal constructs in children: technical note. AB - Thoracic and lumbar cortical bone trajectory pedicle screws have been described in adult spine surgery. They have likewise been described in pediatric CT-based morphometric studies; however, clinical experience in the pediatric age group is limited. The authors here describe the use of cortical bone trajectory pedicle screws in posterior instrumented spinal fusions from the upper thoracic to the lumbar spine in 12 children. This dedicated study represents the initial use of cortical screws in pediatric spine surgery. The authors retrospectively reviewed the demographics and procedural data of patients who had undergone posterior instrumented fusion using thoracic, lumbar, and sacral cortical screws in children for the following indications: spondylolysis and/or spondylolisthesis (5 patients), unstable thoracolumbar spine trauma (3 patients), scoliosis (2 patients), and tumor (2 patients). Twelve pediatric patients, ranging in age from 11 to 18 years (mean 15.4 years), underwent posterior instrumented fusion. Seventy-six cortical bone trajectory pedicle screws were placed. There were 33 thoracic screws and 43 lumbar screws. Patients underwent surgery between April 29, 2015, and February 1, 2016. Seven (70%) of 10 patients with available imaging achieved a solid fusion, as assessed by CT. Mean follow-up time was 16.8 months (range 13-22 months). There were no intraoperative complications directly related to the cortical bone trajectory screws. One patient required hardware revision for caudal instrumentation failure and screw-head fracture at 3 months after surgery. Mean surgical time was 277 minutes (range 120-542 minutes). Nine of the 12 patients received either a 12- or 24-mg dose of recombinant human bone morphogenic protein 2. Average estimated blood loss was 283 ml (range 25-1100 ml). In our preliminary experience, the cortical bone trajectory pedicle screw technique seems to be a reasonable alternative to the traditional trajectory pedicle screw placement in children. Cortical screws seem to offer satisfactory clinical and radiographic outcomes, with a low complication profile. PMID- 29148923 TI - Ames and random amplified polymorphic DNA tests for the validation of the mutagenic and/or genotoxic potential of the drinking water disinfection by products chloroform and bromoform. AB - Chloroform and Bromoform are two abundant trihalomethanes found in Algerian drinking water. The investigation of the mutagenic hazard of these disinfection by-products was studied by Ames test as prokaryotic bioassay to show their mutagenic effects. For this, Salmonella typhimurium TA98 and TA100 strains were employed. Both chloroform and bromoform showed a direct mutagenic effect since the number of revertant colonies gradually increase in dose-dependent manner with all concentrations tested with the two bacterial strains and these were both in the absence and presence of S9 metabolic activation. The genotoxic hazard was also studied by random amplified polymorphic DNA test on the root cells of Allium cepa as eukaryotic bioassay. DNA extracted from the roots of the onion were incubated at different concentrations of chloroform and bromoform and then amplified by polymerase chain reaction. This was based on demonstrating a major effect of disappearance of bands compared to roots incubated in the negative control (distilled water). The results showed that these two compounds affected genomic DNA by breaks although by mutations. PMID- 29148924 TI - Influence of gestational diabetes on the activity of delta-aminolevulinate dehydratase and oxidative stress biomarkers. AB - OBJECTIVES: This study aimed to evaluate the activity of delta-aminolevulinate dehydratase (delta-ALA-D) and oxidative stress biomarkers in pregnant women with gestational diabetes mellitus (GDM), in order to demonstrate the involvement of oxidative stress in this condition, which presents pathophysiology still undetermined. METHODS: delta-ALA-D activity, lipid peroxidation estimated as the levels of thiobarbituric acid reactive substances (TBARS), protein (P-SH) and non protein thiol (NP-SH) content, catalase (CAT) activity and concentration of vitamin C (VIT C) in samples of pregnant women with GDM (n = 48) and in healthy pregnant women (n = 30), who constituted the control group. RESULTS: The delta ALA-D activity was significantly lower in pregnant women with GDM compared to controls, as well as levels of thiols, VIT C and CAT activity. Lipid peroxidation was higher in GDM group. DISCUSSION: The results suggest that the main factor for the increase in oxidative stress and reduced delta-ALA-D activity in diabetic pregnant women is gestational hyperglycemic environment, which changed the redox balance and interfered on mechanism of the delta-ALA-D activity in relation to normoglycemic pregnant women. PMID- 29148920 TI - The Unexpected Impact of Vaccines on Secondary Bacterial Infections Following Influenza. AB - Influenza virus infections remain a significant health burden worldwide, despite available vaccines. Factors that contribute to this include a lack of broad coverage by current vaccines and continual emergence of novel virus strains. Further complicating matters, when influenza viruses infect a host, severe infections can develop when bacterial pathogens invade. Secondary bacterial infections (SBIs) contribute to a significant proportion of influenza-related mortality, with Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus influenzae as major coinfecting pathogens. Vaccines against bacterial pathogens can reduce coinfection incidence and severity, but few vaccines are available and those that are, may have decreased efficacy in influenza virus-infected hosts. While some studies indicate a benefit of vaccine induced immunity in providing protection against SBIs, a comprehensive understanding is lacking. In this review, we discuss the current knowledge of viral and bacterial vaccine availability, the generation of protective immunity from these vaccines, and the effectiveness in limiting influenza-associated bacterial infections. PMID- 29148925 TI - Degradation of chlordecone and beta-hexachlorocyclohexane by photolysis, (photo )fenton oxidation and ozonation. AB - Intensive use of chlorinated pesticides from the 1960s to the 1990s has resulted in a diffuse contamination of soils and surface waters in the banana-producing areas of the French West Indies. The purpose of this research was, for the first time, to examine the degradation of two of these persistent pollutants - chlordecone (CLD) and beta-hexachlorocyclohexane (beta-HCH) in 1 mg L-1 synthetic aqueous solutions by means of photolysis, (photo-) Fenton oxidation and ozonation processes. Fenton oxidation is not efficient for CLD and yields less than 15% reduction of beta-HCH concentration in 5 h. Conversely, both molecules can be quantitatively converted under UV-Vis irradiation reaching 100% of degradation in 5 h, while combination with hydrogen peroxide and ferrous iron does not show any significant improvement except in high wavelength range (>280 nm). Ozonation exhibits comparable but lower degradation rates than UV processes. Preliminary identification of degradation products indicated that hydrochlordecone was formed during photo-Fenton oxidation of CLD, while for beta-HCH the major product peak exhibited C3H3Cl2 as most abundant fragment. PMID- 29148926 TI - Identification of Gene Candidates Associated with Huanglongbing Tolerance, Using 'Candidatus Liberibacter asiaticus' Flagellin 22 as a Proxy to Challenge Citrus. AB - The 22-amino acid (flg22) pathogen-associated molecular pattern from the flagellin of Xanthomonas citri subsp. citri has been shown to induce defense responses correlated with citrus canker resistance. Here, flg22 of 'Candidatus Liberibacter asiaticus', the putative causal agent of Huanglongbing (HLB), elicited differential defense responses that were weaker than those from Xcc flg22, between those of the HLB-tolerant mandarin cultivar Sun Chu Sha and susceptible grapefruit cultivar Duncan. Transcriptomics was used to compare the effect of CLas-flg22 and Xcc-flg22 between the citrus genotypes and identified 86 genes induced only by CLas-flg22 in the tolerant mandarin. Expression of 16 selected genes was validated, by reverse transcription-quantitative polymerase chain reaction, and was evaluated in citrus during 'Ca. L. asiaticus' infection. Differential expression of a number of genes occurred between tolerant and susceptible citrus infected with 'Ca. L. asiaticus', suggesting their involvement in HLB tolerance. In addition, several genes were similarly regulated by CLas flg22 and 'Ca. L. asiaticus' treatments, while others were oppositely regulated in the tolerant mandarin, suggesting similarity and interplay between CLas-flg22 and 'Ca. L. asiaticus'-triggered defenses. Genes identified are valuable in furthering the study of HLB tolerance mechanisms and, potentially, for screening for HLB-tolerant citrus using CLas-flg22 as a pathogen proxy. PMID- 29148927 TI - Flat Serrated Polyps at CT Colonography: Relevance, Appearance, and Optimizing Interpretation. AB - Serrated polyps are a recently recognized family of colonic polyps with subgroups that harbor future malignant potential. In the past, the significance of these lesions to the colorectal cancer carcinogenesis pathway was not recognized nor well understood. It is now known that serrated polyps account for approximately one-fourth of all sporadic colorectal cancers. The sessile serrated polyp (SSP) (also known as a sessile serrated adenoma [SSA]) is the main lesion of interest given its prevalence and subtle presentation. These lesions are often flat-only minimally raised from the colonic surface-and occur in the right colon. These lesions have been a likely common cause of screening failure at colonoscopy, although detection has improved with improved recognition over time. Although detection is difficult with image-based screening, serrated lesions can be detected at CT colonography. The prevalence in CT colonography screening populations mirrors the rates at colonoscopy for similar size categories. CT colonography allows identification of SSPs despite their minimally raised profile owing to the phenomenon of lesional contrast material coating. This contrast material coat aids in lesion detection by highlighting the subtle morphologic changes as well as increasing confidence that a true lesion exists despite a flat morphology. It is important to optimize contrast material coating with specific bowel preparations and other technical parameters. Radiologists should be aware of these technical and interpretation issues. Armed with this knowledge, radiologists should expect excellent results in detection of these subtle but important lesions. (c)RSNA, 2017. PMID- 29148928 TI - Spatiotemporal variations and relationship of PM and gaseous pollutants based on gray correlation analysis. AB - The present work characterizes the spatiotemporal variations of air pollution at four sites in Xi'an city. The investigations lasted for 1 year: January 1 through December 31, 2015. The concentrations of CO, NO2, O3, PM and SO2 were systematically monitored. The gray correlation analysis was used to correlate PM2.5 and gaseous pollutants. The formation mechanisms of sulfate and nitrate aerosols were discussed. Results clearly revealed severe air pollution by PM2.5, PM10 and NO2 at all four sites. Significant monthly variations were observed for PM2.5, PM10, SO2 and CO with the maximum values in December/January and minimum values in June/July. The O3 level showed an opposite trend. Spatially, high variations were observed for PM and some gaseous pollutants at individual sites. Gray correlation analysis revealed the significance of various major influencing factors on seasonal PM2.5 values at each site. In general, PM10, SO2 and NO2 affect the PM2.5 more than other pollutants. For a more efficient control of air pollution, a systematic spatial characterization of the seasonal variability of individual influencing factors is necessary. PMID- 29148929 TI - Web-Based Alcohol Intervention in First-Year College Students: Efficacy of Full Program Administration Prior to Second Semester. AB - BACKGROUND: Commercially available, web-based interventions for the prevention of alcohol use are being adopted for universal use with first-year college students, yet few have received empirical evaluation. OBJECTIVES: This randomized controlled trial investigated the effectiveness of a novel, commercially available, personalized web-based alcohol intervention, Alcohol-Wise (version 4.0, 3rd Millennium Classrooms), on multiple measures of alcohol consumption, alcohol consequences, alcohol expectancies, academic achievement, and adaptation to college in first-year students. METHOD: Participants received Alcohol-Wise either prior to first semester or were waitlisted and received the intervention second semester. As longitudinal effectiveness was of interest, follow-up surveys were conducted 10 weeks (n = 76) and 24 weeks (n = 64) following the web-based alcohol intervention. RESULTS: Completion of Alcohol-Wise had effects on academic achievement. Specifically, at the 24 week follow-up, academic achievement was higher in participants who received the intervention first semester of their freshman year as compared to the waitlist control. The incremental rise in heavy episodic drinking during the first semester of college was also reduced in waitlisted participants by Alcohol-Wise administration prior to second semester. Conclusion/Importance: Implications for the timing of web-based alcohol interventions to include administration prior to both first and second semesters of the freshman year are discussed. PMID- 29148930 TI - Use of Mixed-Oil Fat Emulsion to Improve Intestinal Failure-Associated Liver Disease in Long-Term Home Parenteral Nutrition: A Case Report. AB - Home parenteral nutrition (HPN) is a life-saving therapy for patients who are not able to use their gastrointestinal tract. There are a number of complications associated with HPN, including metabolic bone disease, intestinal failure associated liver disease (IFALD), and catheter-related bloodstream infections. We present a case of a 32-year-old HPN patient who initially developed biopsy-proven IFALD (total bilirubin, 2.4 mg/dL) while on long-term HPN. His HPN was initiated due to myopathic intestinal dysmotility and pseudo-obstruction when he was 15 years old. Because of his IFALD, the intravenous (IV) fat emulsion had been reduced and dextrose increased to >500 g/d in the HPN. Although the IFALD improved, he had signs of insulin resistance and struggled with numerous episodes of pancreatitis. His dextrose was decreased and insulin resistance improved, but he began losing weight. As his IV fat emulsion was gradually increased, IFALD worsened and he was switched to mixed-oil (MO) IV fat emulsion (30% soy, 30% medium-chain triglycerides, 25% olive oil, and 15% fish oil). His IFALD improved and total bilirubin normalized (0.4 mg/dL) when switched to the MO lipid. He has been on MO lipid for >8 months (current dose 70 g given 7 days per week) with no more episodes of pancreatitis, normal liver enzymes, and weight gain. PMID- 29148932 TI - Response to Second Letter by Lee et al. of 2016. PMID- 29148933 TI - Surgical strategies for the treatment of os odontoideum with atlantoaxial dislocation. AB - OBJECTIVE This study aimed to compare the clinical results of using posterior fixation and fusion with or without anterior decompression to treat os odontoideum with atlantoaxial dislocation. METHODS Twenty-five consecutive patients with os odontoideum were included in this study. Sixteen patients with reducible atlantoaxial dislocation were treated by single-level posterior fusion and stabilization; the other 9 were treated with posterior fusion and stabilization combined with transoral decompression. Pre- and postoperative CT scans and MR images were obtained. RESULTS Twenty-four patients were followed for 24-54 months (average 36.5 months). Postoperative CT scans indicated that all pedicle screws were placed satisfactorily except in 2 cases, in which the screws slightly penetrated the transverse foramen. Postoperative MR images demonstrated that sufficient decompression of the spinal cord was obtained in all patients. Complications included 1 case each of pedicle screw breakage, pharynx ulcer, and persistent pharynx discomfort. Statistical analysis of all cases revealed that mean Japanese Orthopaedic Association scores improved from a preoperative score of 10.2 (range 7-13) to a postoperative score of 15.6 (range 11-18). CONCLUSIONS Patients who have os odontoideum with a reducible atlantoaxial dislocation can be effectively treated with single-level posterior fusion and stabilization. Combined transoral decompression and posterior fusion and stabilization is recommended for those with irreducible atlantoaxial dislocation. PMID- 29148934 TI - Reconciling Competence and Consent in Opioid-Dependence Research: The Value of Vulnerability Rhetoric. PMID- 29148935 TI - The Idea of a "Standard View" of Informed Consent. PMID- 29148936 TI - On the Wrongness of Exploitation and the Voluntariness of Consent in Clinical Research on Opioid Assisted Treatment. PMID- 29148937 TI - Do Not Forget the Right to Withdraw! PMID- 29148939 TI - Functionalism, Formalism, and Undue Influence. PMID- 29148938 TI - Applicability of a Function-Based Approach to Informed Consent in International Settings. PMID- 29148940 TI - A Functional Approach to Assessing Consent for Biospecimen Research. PMID- 29148941 TI - Risk Environments and the Ethics of Reducing Drug-Related Harms. PMID- 29148942 TI - Attending to the Interrelatedness of the Functions of Consent. PMID- 29148944 TI - Competence and Inequity Are Both Important to the Ethics of Supervised Injectable Opioid Assisted Treatment. PMID- 29148945 TI - Changing the Conversation: A Critical Bioethics Response to the Opioid Crisis. PMID- 29148946 TI - Instrumentalist Analyses of the Functions of Health Ethics Concepts and Principles: Methodological Guideposts. PMID- 29148947 TI - Germline Genome Editing and the Functions of Consent. PMID- 29148948 TI - Collaborative Efforts With Opioid Users to Promote Competence and Voluntariness in Clinical Trials With Injectable Opioid Assisted Treatment. PMID- 29148949 TI - Does Consent Form Follow Function? PMID- 29148950 TI - Considering Consent to Research for Patients in Chronic Pain and With Mental Illnesses. PMID- 29148952 TI - Review of Patricia Illingworth and Wendy Parmet, The Health of Newcomers1. PMID- 29148951 TI - Reframing Consent for Clinical Research: A Function-Based Approach. AB - Although informed consent is important in clinical research, questions persist regarding when it is necessary, what it requires, and how it should be obtained. The standard view in research ethics is that the function of informed consent is to respect individual autonomy. However, consent processes are multidimensional and serve other ethical functions as well. These functions deserve particular attention when barriers to consent exist. We argue that consent serves seven ethically important and conceptually distinct functions. The first four functions pertain principally to individual participants: (1) providing transparency; (2) allowing control and authorization; (3) promoting concordance with participants' values; and (4) protecting and promoting welfare interests. Three other functions are systemic or policy focused: (5) promoting trust; (6) satisfying regulatory requirements; and (7) promoting integrity in research. Reframing consent around these functions can guide approaches to consent that are context sensitive and that maximize achievable goals. PMID- 29148953 TI - A Matter of Heart: Beyond Informed Consent. PMID- 29148954 TI - Our Life Depends on This Drug: Competence, Inequity, and Voluntary Consent in Clinical Trials on Supervised Injectable Opioid Assisted Treatment. AB - Supervised injectable opioid assisted treament (siOAT) prescribes injectable opioids to individuals for whom other forms of addiction treatment have been ineffective. In this article, we examine arguments that opioid-dependent people should be assumed incompetent to voluntarily consent to clinical research on siOAT unless proven otherwise. We agree that concerns about competence and voluntary consent deserve careful attention in this context. But we oppose framing the issue solely as a matter of the competence of opioid-dependent people and emphasize that it should be considered in the context of inequities in access to siOAT as a medical treatment. Consequently, we suggest that bioethics literature on nonexploitation, which focuses on clinical research in low-income countries, is helpful due to locating ethical issues within systemic social conditions. Finally, we consider the implications of our argument for the ethics of clinical research on siOAT. PMID- 29148955 TI - Experience of Tubo-Ovarian Abscess: A Retrospective Clinical Analysis of 318 Patients in a Single Tertiary Center in Middle Turkey. AB - BACKGROUND: The objective was to identify the clinical and laboratory parameters, ultrasonographic (USG) morphology, and to predict surgical treatment for patients with tubo-ovarian abscess (TOA). PATIENTS AND METHODS: Data for a total of 318 patients with a diagnosis of TOA between January 2005 and December 2016 were analyzed retrospectively at a referral center in Turkey. Patients requiring surgical treatment were compared with those who did not with respect to demographic characteristics and clinical, USG, and laboratory findings. RESULTS: Ninety-three (29.25%) patients whose medical treatment failed underwent surgical intervention and a minimally invasive drainage procedure. Menopausal status, diabetes mellitus, long-term intrauterine device use, fever at admission, bilateral and multi-cystic TOA, and TOA size are risk factors for surgical treatment. An abscess size of 6.5 cm was a significant indicator for surgical intervention (odds ratio = 16.632; 95% confidence interval 8.745-31.632; p < 0.05). The area under the curve (AUC = 0.868) in the receiver operating characteristic (ROC) curve analysis was found to be statistically significant for TOA size, with a threshold value of 6.5 cm. The recommended cutoff value for erythrocyte sedimentation rate (ESR) was 61.0 mm/h, and the cutoff point of the C reactive protein (CRP) level in the ROC analysis was found to be 24.5 mg/dL. There were no complications in the USG-guided drainage surgical treatment group. CONCLUSION: The TOA size, complex multi-cystic mass image, CRP, and ESR are useful indicators as to whether surgical treatment is required for the management of TOA. The USG-guided drainage was less invasive with fewer complications and should be the preferred surgical treatment. PMID- 29148956 TI - The Challenge of Emerging Viruses. PMID- 29148957 TI - Aerobic exercise training performed by parents reduces mice offspring adiposity. AB - The present study aimed to determine the effects of physical training performed by parents on mice offspring adiposity. Male and female parents underwent an aerobic training protocol for 7 weeks. The trained and sedentary parents were allowed to mate and the resultant offspring divided in: S (Offspring from Sedentary Parents), T (Offspring from Trained Parents), ST (Offspring from Sedentary Father and Trained Mother) and TS (Offspring from Trained Father and Sedentary Mother). After weaning, offspring was euthanized, blood collected and samples of mesenteric and inguinal fat pads used to isolate adipocytes for morphologic and histological analyses. Lee index, mesenteric fat pad, sum of visceral fat and total fat weight of female T was reduced in comparison to the other groups (p < 0.05). Periepididymal and sum of visceral fat in male T group was also reduced when compared to the other groups (p < 0.05). The diameter of mesenteric and inguinal adipocytes of T group was smaller compared to all groups comparisons for both sexes (p < 0.05). In summary, exercise training performed by parents reduced visceral offspring adiposity, the diameter of subcutaneous adipocytes and improved metabolic parameters associated to metabolic syndrome. PMID- 29148959 TI - Effect of Measuring gamma-Glutamyl Transpeptidase and Using Smoflipid in a Parenteral Nutrition Infusion in a Patient With Severe Malabsorption and Overlapping Primary Sclerosing Cholangitis and Ulcerative Colitis. AB - Studies discussing inflammation and oxidative stress state that these conditions are known contributors in the pathogenesis of cholestatic diseases and ulcerative colitis, and studies examining patients with liver disease have found decreased antioxidant status and significant elevation of lipid peroxides as compared with healthy subjects. One hypothesis in liver disease is that deficient antioxidant defense mechanisms may lead to excess oxygen free radical formation, which promotes deleterious processes in the liver. The role of oxidant agents in cells is complex and depends on the balance between oxidant and antioxidant particles, but there is 1 potential marker of oxidative stress that can be readily utilized for our patients who are receiving nutrition support: gamma-glutamyl transpeptidase (GGT). GGT is thought to induce oxidative stress in the artery wall in the presence of free iron and is likely an indicator of a depleted supply of glutathione, especially in the liver, which can lead to a cascade of problems related to increased oxidative stress. One could consider giving these patients liposomal glutathione or the components that make up glutathione, such as glycine, glutamine, and N-acetyl-cysteine, but unfortunately total parenteral nutrition (TPN) in the United States contains no cysteine or glutamine. Another possible way would be to give additional antioxidants, such as selenium and zinc, as well as vitamins A, C, and E. In this case report, I demonstrate the potential effect that switching from a straight omega-6 fatty acid solution to a blended fatty acid solution had on liver function tests, specifically GGT, for a 66-year old patient dependent on TPN for the prior 16 months. PMID- 29148958 TI - Human leptospirosis vaccines in China. AB - The present incidence of leptospirosis in China is significantly lower than past rates, although small localized outbreaks continue to occur in epidemic regions. Improvements in sanitation, as well as vaccination of high-risk populations, have played crucial roles in reducing the disease burden. Several types of human leptospirosis vaccines have been developed, including inactivated whole-cell, outer-envelope, and recombinant vaccines. Of these, only a multivalent inactivated leptospirosis vaccine is available in China, which was added to the Chinese Expanded Program on Immunization in 2007. However, this vaccine elicits serogroup-specific immunity, and serogroup epidemiology should continue to be monitored to enhance vaccine coverage and distribution. On the other hand, the efficiency of the inactivated vaccine should be further improved by optimizing the formulation, and by expanding the target population. More importantly, additional investments should be made to develop universal recombinant vaccines. PMID- 29148960 TI - How to do a systematic review. AB - High quality up-to-date systematic reviews are essential in order to help healthcare practitioners and researchers keep up-to-date with a large and rapidly growing body of evidence. Systematic reviews answer pre-defined research questions using explicit, reproducible methods to identify, critically appraise and combine results of primary research studies. Key stages in the production of systematic reviews include clarification of aims and methods in a protocol, finding relevant research, collecting data, assessing study quality, synthesizing evidence, and interpreting findings. Systematic reviews may address different types of questions, such as questions about effectiveness of interventions, diagnostic test accuracy, prognosis, prevalence or incidence of disease, accuracy of measurement instruments, or qualitative data. For all reviews, it is important to define criteria such as the population, intervention, comparison and outcomes, and to identify potential risks of bias. Reviews of the effect of rehabilitation interventions or reviews of data from observational studies, diagnostic test accuracy, or qualitative data may be more methodologically challenging than reviews of effectiveness of drugs for the prevention or treatment of stroke. Challenges in reviews of stroke rehabilitation can include poor definition of complex interventions, use of outcome measures that have not been validated, and poor generalizability of results. There may also be challenges with bias because the effects are dependent on the persons delivering the intervention, and because masking of participants and investigators may not be possible. There are a wide range of resources which can support the planning and completion of systematic reviews, and these should be considered when planning a systematic review relating to stroke. PMID- 29148961 TI - Corrigendum for "Benefits of stroke treatment delivered using a mobile stroke unit trial". AB - Benefits of stroke treatment delivered using a mobile stroke unit trial. International Journal of Stroke . 2017: 1-7. First Published 14 June 2017. DOI: 10.1177/1747493017711950 The authors would like to highlight to the readers the addition of the following text (in bold) to the funding statement. PMID- 29148962 TI - Design and implementation of observational studies to measure disease burden with a focus on stroke. AB - Observational epidemiological studies have the dual goals of measuring disease burden and assessing the association between exposures and outcomes. This report focuses on the first of these goals and provides an overview of design considerations of commonly used approaches, specifically community surveillance studies, cross-sectional studies, and longitudinal cohort studies. Each of these designs has strengths and weaknesses, with no study design being superior in all cases. Rather, these designs are complementary to achieve a better understanding of the burden of stroke. PMID- 29148963 TI - Clinical stroke research in resource limited settings: Tips and hints. AB - Background Most stroke research is conducted in high income countries, yet most stroke occurs in low- and middle-income countries. There is an urgent need to build stroke research capacity in low- and middle-income countries. Aims To review the global health literature on how to improve research capacity in low- and middle-income countries, provide additional data from the recently completed ATTEND Trial and provide examples from our own experience. Summary of review The main themes from our literature review were: manpower and workload, research training, research question and methodology and research funding. The literature and our own experience emphasized the importance of local stakeholders to ensure that the research was appropriate, that there were robust local ethics and regulatory processes, and research was conducted by trained personnel. Research training opportunities can be developed locally, or internationally, with many international schemes available to help support new researchers from low- and middle-income country settings. International collaboration can successfully leverage funding from high income countries that not only generate data for the local country, but also provide new data appropriate to high income countries. Conclusions Building stroke research capacity in low- and middle-income countries will be vital in improving global health given the huge burden of stroke in these countries. PMID- 29148964 TI - Twenty-Five Years of the Binary Power Law for Characterizing Heterogeneity of Disease Incidence. AB - Spatial pattern, an important epidemiological property of plant diseases, can be quantified at different scales using a range of methods. The spatial heterogeneity (or overdispersion) of disease incidence among sampling units is an especially important measure of small-scale pattern. As an alternative to Taylor's power law for the heterogeneity of counts with no upper bound, the binary power law (BPL) was proposed in 1992 as a model to represent the heterogeneity of disease incidence (number of plant units diseased out of n observed in each sampling unit, or the proportion diseased in each sampling unit). With the BPL, the log of the observed variance is a linear function of the log of the variance for a binomial (i.e., random) distribution. Over the last quarter century, the BPL has contributed to both theory and multiple applications in the study of heterogeneity of disease incidence. In this article, we discuss properties of the BPL and use it to develop a general conceptualization of the dynamics of spatial heterogeneity in epidemics; review the use of the BPL in empirical and theoretical studies; present a synthesis of parameter estimates from over 200 published BPL analyses from a wide range of diseases and crops; discuss model fitting methods, and applications in sampling, data analysis, and prediction; and make recommendations on reporting results to improve interpretation. In a review of the literature, the BPL provided a very good fit to heterogeneity data in most publications. Eighty percent of estimated slope (b) values from field studies were between 1.06 and 1.51, with b positively correlated with the BPL intercept parameter. Stochastic simulations show that the BPL is generally consistent with spatiotemporal epidemiological processes and holds whenever there is a positive correlation of disease status of individuals composing sampling units. PMID- 29148965 TI - Nonclinical Safety Assessment of Anti-Factor D: Key Strategies and Challenges for the Nonclinical Development of Intravitreal Biologics. AB - PURPOSE: The nonclinical toxicology program described here was designed to characterize the safety profile of anti-factor D (AFD; FCFD4514S, lampalizumab) to support intravitreal (ITV) administration in patients with geographic atrophy (GA). METHODS: The toxicity of AFD was assessed in a single-dose and 6-month repeat-dose study in monkeys at doses up to 10 mg/eye. Toxicity was assessed by clinical ophthalmic examinations, intraocular pressure measurements, ocular photography, electroretinography, fluorescein angiography, optical coherence tomography, and anatomic pathology. RESULTS: Systemic exposure to AFD generally increased with the increase in dose level. The increases in mean maximal concentration and area under the curve values were roughly dose proportional. No accumulation of AFD was observed following 10 doses, and drug exposures were not affected by anti-drug antibodies. AFD was locally and systemically well tolerated in monkeys following ITV doses of up to 10 mg/eye. Ocular effects associated with AFD were limited to transient, reversible, dose-related, aqueous cell responses and injection-related, mild, vitreal cell responses. In the 6-month repeat-dose study, 2 monkeys had a nonspecific immune response to AFD that resulted in severe ocular inflammation, attributed to administration of a heterologous (humanized) protein. CONCLUSIONS: The comprehensive toxicology program in monkeys described here was designed to evaluate the safety profile of AFD and to support multiple ITV injections in the clinic. Administration of a heterologous (humanized) protein presents a challenge, and immunogenicity in nonclinical species is not predictive of immunogenicity in humans. Taken together, the results of the nonclinical program described here support the use of AFD in patients with GA. PMID- 29148966 TI - Exploring the Healthcare Environment and Associations with Clinical Outcomes of People Living with HIV/AIDS. AB - Despite three decades of dramatic treatment breakthroughs in antiretroviral regimens, clinical outcomes for people living with HIV vary greatly. The HIV treatment cascade models the stages of care that people living with HIV go through toward the goal of viral suppression and demonstrates that <30% of those living with HIV/AIDS in the United States have met this goal. Although some research has focused on the ways that patient characteristics and patient provider relationships contribute to clinical adherence and treatment success, few studies to date have examined the ways that contextual factors of care and the healthcare environment contribute to patient outcomes. Here, we present qualitative findings from a mixed-methods study to describe contextual and healthcare environment factors in a Ryan White Part C clinic that are associated with patients' abilities to achieve viral suppression. We propose a modification of Andersen's Behavioral Model of Health Services Utilization, and its more recent adaptation developed by Ulett et al., to describe the ways that clinic, system, and provider factors merge to create a system of care in which more than 86% of the patient population is virally suppressed. PMID- 29148967 TI - Group B Streptococcus Infections Caused by Improper Sourcing and Handling of Fish for Raw Consumption, Singapore, 2015-2016. AB - We assessed microbial safety and quality of raw fish sold in Singapore during 2015-2016 to complement epidemiologic findings for an outbreak of infection with group B Streptococcus serotype III sequence type (ST) 283 associated with raw fish consumption. Fish-associated group B Streptococcus ST283 strains included strains nearly identical (0-2 single-nucleotide polymorphisms) with the human outbreak strain, as well as strains in another distinct ST283 clade (57-71 single nucleotide polymorphisms). Our investigations highlight the risk for contamination of freshwater fish (which are handled and distributed separately from saltwater fish sold as sashimi) and the need for improved hygienic handling of all fish for raw consumption. These results have led to updated policy and guidelines regarding the sale of ready-to-eat raw fish dishes in Singapore. PMID- 29148968 TI - Collecting Practice-level Data in a Changing Physician Office-based Ambulatory Care Environment: A Pilot Study Examining the Physician induction interview Component of the National Ambulatory Medical Care Survey. AB - Objective This report examines ways to improve National Ambulatory Medical Care Survey (NAMCS) data on practice and physician characteristics in multispecialty group practices. Methods From February to April 2013, the National Center for Health Statistics (NCHS) conducted a pilot study to observe the collection of the NAMCS physician interview information component in a large multispecialty group practice. Nine physicians were randomly sampled using standard NAMCS recruitment procedures; eight were eligible and agreed to participate. Using standard protocols, three field representatives conducted NAMCS physician induction interviews (PIIs) while trained ethnographers observed and audio recorded the interviews. Transcripts and field notes were analyzed to identify recurrent issues in the data collection process. Results The majority of the NAMCS items appeared to have been easily answered by the physician respondents. Among the items that appeared to be difficult to answer, three themes emerged: (a) physician respondents demonstrated an inconsistent understanding of "location" in responding to questions; (b) lack of familiarity with administrative matters made certain questions difficult for physicians to answer; and (c) certain primary care-oriented questions were not relevant to specialty care providers. Conclusions Some PII survey questions were challenging for physicians in a multispecialty practice setting. Improving the design and administration of NAMCS data collection is part of NCHS' continuous quality improvement process. PMID- 29148969 TI - The structure of the COPI coat determined within the cell. AB - COPI-coated vesicles mediate trafficking within the Golgi apparatus and from the Golgi to the endoplasmic reticulum. The structures of membrane protein coats, including COPI, have been extensively studied with in vitro reconstitution systems using purified components. Previously we have determined a complete structural model of the in vitro reconstituted COPI coat (Dodonova et al., 2017). Here, we applied cryo-focused ion beam milling, cryo-electron tomography and subtomogram averaging to determine the native structure of the COPI coat within vitrified Chlamydomonas reinhardtii cells. The native algal structure resembles the in vitro mammalian structure, but additionally reveals cargo bound beneath beta'-COP. We find that all coat components disassemble simultaneously and relatively rapidly after budding. Structural analysis in situ, maintaining Golgi topology, shows that vesicles change their size, membrane thickness, and cargo content as they progress from cis to trans, but the structure of the coat machinery remains constant. PMID- 29148970 TI - Autophagic cell death is dependent on lysosomal membrane permeability through Bax and Bak. AB - Cells deficient in the pro-death Bcl-2 family members Bax and Bak are known to be resistant to apoptotic cell death, and previous we have shown that these two effectors are also needed for mitochondrial-dependent cellular necrosis (Karch et al., 2013). Here we show that mouse embryonic fibroblasts deficient in Bax/Bak1 are resistant to the third major form of cell death associated with autophagy through a mechanism involving lysosome permeability. Indeed, specifically targeting Bax only to the lysosome restores autophagic cell death in Bax/Bak1 null cells. Moreover, a monomeric-only mutant form of Bax is sufficient to increase lysosomal membrane permeability and restore autophagic cell death in Bax/Bak1 double-deleted mouse embryonic fibroblasts. Finally, increasing lysosomal permeability through a lysomotropic detergent in cells devoid of Bax/Bak1 restores autophagic cell death, collectively indicting that Bax/Bak integrate all major forms of cell death through direct effects on membrane permeability of multiple intracellular organelles. PMID- 29148971 TI - Convergence of topological domain boundaries, insulators, and polytene interbands revealed by high-resolution mapping of chromatin contacts in the early Drosophila melanogaster embryo. AB - High-throughput assays of three-dimensional interactions of chromosomes have shed considerable light on the structure of animal chromatin. Despite this progress, the precise physical nature of observed structures and the forces that govern their establishment remain poorly understood. Here we present high resolution Hi C data from early Drosophila embryos. We demonstrate that boundaries between topological domains of various sizes map to DNA elements that resemble classical insulator elements: short genomic regions sensitive to DNase digestion that are strongly bound by known insulator proteins and are frequently located between divergent promoters. Further, we show a striking correspondence between these elements and the locations of mapped polytene interband regions. We believe it is likely this relationship between insulators, topological boundaries, and polytene interbands extends across the genome, and we therefore propose a model in which decompaction of boundary-insulator-interband regions drives the organization of interphase chromosomes by creating stable physical separation between adjacent domains. PMID- 29148972 TI - Rapid DNA replication origin licensing protects stem cell pluripotency. AB - Complete and robust human genome duplication requires loading minichromosome maintenance (MCM) helicase complexes at many DNA replication origins, an essential process termed origin licensing. Licensing is restricted to G1 phase of the cell cycle, but G1 length varies widely among cell types. Using quantitative single-cell analyses, we found that pluripotent stem cells with naturally short G1 phases load MCM much faster than their isogenic differentiated counterparts with long G1 phases. During the earliest stages of differentiation toward all lineages, MCM loading slows concurrently with G1 lengthening, revealing developmental control of MCM loading. In contrast, ectopic Cyclin E overproduction uncouples short G1 from fast MCM loading. Rapid licensing in stem cells is caused by accumulation of the MCM loading protein, Cdt1. Prematurely slowing MCM loading in pluripotent cells not only lengthens G1 but also accelerates differentiation. Thus, rapid origin licensing is an intrinsic characteristic of stem cells that contributes to pluripotency maintenance. PMID- 29148975 TI - Learning from losers. AB - Bacteria can overcome environmental challenges by killing nearby bacteria and incorporating their DNA. PMID- 29148974 TI - Revealing the distribution of transmembrane currents along the dendritic tree of a neuron from extracellular recordings. AB - Revealing the current source distribution along the neuronal membrane is a key step on the way to understanding neural computations; however, the experimental and theoretical tools to achieve sufficient spatiotemporal resolution for the estimation remain to be established. Here, we address this problem using extracellularly recorded potentials with arbitrarily distributed electrodes for a neuron of known morphology. We use simulations of models with varying complexity to validate the proposed method and to give recommendations for experimental applications. The method is applied to in vitro data from rat hippocampus. PMID- 29148973 TI - The somatically generated portion of T cell receptor CDR3alpha contributes to the MHC allele specificity of the T cell receptor. AB - Mature T cells bearing alphabeta T cell receptors react with foreign antigens bound to alleles of major histocompatibility complex proteins (MHC) that they were exposed to during their development in the thymus, a phenomenon known as positive selection. The structural basis for positive selection has long been debated. Here, using mice expressing one of two different T cell receptor beta chains and various MHC alleles, we show that positive selection-induced MHC bias of T cell receptors is affected both by the germline encoded elements of the T cell receptor alpha and beta chain and, surprisingly, dramatically affected by the non germ line encoded portions of CDR3 of the T cell receptor alpha chain. Thus, in addition to determining specificity for antigen, the non germline encoded elements of T cell receptors may help the proteins cope with the extremely polymorphic nature of major histocompatibility complex products within the species. PMID- 29148977 TI - The role of microRNAs in chronic respiratory disease: recent insights. AB - Chronic respiratory diseases encompass a group of diverse conditions affecting the airways, which all impair lung function over time. They include cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma, which together affect hundreds of millions of people worldwide. MicroRNAs (miRNAs), a class of small non-coding RNAs involved in post transcriptional gene repression, are now recognized as major regulators in the development and progression of chronic lung disease. Alterations in miRNA abundance occur in lung tissue, inflammatory cells, and freely circulating in blood and are thought to function both as drivers and modifiers of disease. Their importance in lung pathology has prompted the development of miRNA-based therapies and biomarker tools. Here, we review the current literature on miRNA expression and function in chronic respiratory disease and highlight further research that is needed to propel miRNA treatments for lung disorders towards the clinic. PMID- 29148976 TI - Small molecule Photoregulin3 prevents retinal degeneration in the RhoP23H mouse model of retinitis pigmentosa. AB - Regulation of rod gene expression has emerged as a potential therapeutic strategy to treat retinal degenerative diseases like retinitis pigmentosa (RP). We previously reported on a small molecule modulator of the rod transcription factor Nr2e3, Photoregulin1 (PR1), that regulates the expression of photoreceptor specific genes. Although PR1 slows the progression of retinal degeneration in models of RP in vitro, in vivo analyses were not possible with PR1. We now report a structurally unrelated compound, Photoregulin3 (PR3) that also inhibits rod photoreceptor gene expression, potentially though Nr2e3 modulation. To determine the effectiveness of PR3 as a potential therapy for RP, we treated RhoP23H mice with PR3 and assessed retinal structure and function. PR3-treated RhoP23H mice showed significant structural and functional photoreceptor rescue compared with vehicle-treated littermate control mice. These results provide further support that pharmacological modulation of rod gene expression provides a potential strategy for the treatment of RP. PMID- 29148978 TI - Antidiabetic and in vitro antioxidant effects of hydromethanol extract of Paullinia pinnata root bark in alloxan-induced diabetic rat. AB - Background The study evaluated phytochemical composition, antidiabetic, oral glucose tolerance test and in vitro antioxidant activities of hydromethanol extract of Paullinia pinnata root bark. Methods Cold maceration method was used in extract preparation and scavenging of 2,2-diphenyl-1-picrylhydrazyl radicals was used to evaluate antioxidant properties of the extract. Diabetes was induced with alloxan at the dose of 160 mg/kg. The antidiabetic activity of the extract was tested at doses of 50, 100 and 200 mg/kg, and glibenclamide was used as reference drug. Results Phytochemical analysis of the extract showed the presence of alkaloids, flavonoids, glycosides, tannins, saponins and terpenes/sterols. The extract produced a significant (p<0.05) time-dependent decrease in the fasting blood glucose (FBG) levels in the treated rats when compared with the distilled water treated rats, but did not produce dose-dependent effects. The extract 50, 100 and 200 mg/kg and glibenclamide (2 mg/kg) caused 83.62 %, 60.66 %, 47.77 % and 68.52 % reduction respectively in FBG at 6 h post-treatment while the distilled water (5 mL/kg) produced 8.12 % reduction in FBG at 6 h post treatment. The extract (50 mg/kg) and glibenclamide (2 mg/kg) produced a significant (p<0.05) oral glucose tolerance effect in both normoglycemic and diabetic rats. The extract produced concentration-dependent increase in antioxidant activity and had its optimum effect at 400 ug/mL concentration. Conclusions This study suggests that P. pinnata root bark has potent antidiabetic and antioxidant activities and also validates its use in folkloric medicine in the management of diabetes-related conditions. PMID- 29148979 TI - Role of caftaric acid in lead-associated nephrotoxicity in rats via antidiuretic, antioxidant and anti-apoptotic activities. AB - Background Lead is a toxic metal that is widely distributed in the environment where caftaric acid (CA) is the ester form of caffeic acid where CA is the major dietary polyphenol present in various foods and beverages. The aim of this study was to evaluate the effect of CA in lead acetate (LA)-associated nephrotoxicity through antidiuretic, antioxidant and anti-apoptotic activities. Methods Forty eight male albino rats divided into six equal groups; group 1 control injected intraperitoneally (ip) with saline (1 mL/kg of bw) over two weeks period, group 2 injected ip with CA (80 mg/kg of bw) over two weeks period, groups 3, 4, 5 and 6 injected ip with 100 MUmol/kg of bw LA over two weeks period where groups 4, 5 & 6 co-injected ip with 1-deamino-8-D-arginine vasopressin (dDAVP) drug (1 mg/kg of bw), CA (40 mg/kg of bw), and CA (80 mg/kg of bw), respectively. Results The results obtained revealed that LA induced a significant decrease in kidney weight and serum sodium, potassium and chloride, but caused a significant increase in urinary volume, urinary excretion of sodium, potassium and chloride, serum urea, creatinine and uric acid. The LA also caused a significant decrease in kidney superoxide dismutase, glutathione peroxidase and induced a significant decrease in glutathione level while caused an increase in lipid peroxidation level. In addition, LA caused a decrease in p53 expression while induced an increase in bcl 2 expression in the kidney tissues. Co-injection of CA to LA-treated group restored all the above parameters to approach the normal values. The results supported with histopathological examinations. Conclusions In conclusion, the effect of CA on LA-related nephrotoxicity was occurred through antidiuretic, antioxidant, anti-apoptotic activities where the effect of CA was dose dependent. PMID- 29148980 TI - "Just don't be creepy": A phenomenological study of the experiences of men in massage therapy. AB - Background Societal expectations around traditional binary gender roles result in some professions being considered "men's work" or "women's work". Massage therapy (MT) is one such profession that, despite being predominantly female, is joined by an increasing number of men with a desire to help others. Methods This descriptive phenomenological study asked male massage therapists in Ontario, Canada, about their experience of gender in their professional lives. Fourteen men shared their experiences of practice, which included discriminatory hiring and patient preferences for female practitioners. These issues resulted in difficulty establishing a clinical practice. To create a successful practice, men described the need for professionalism, clear communication, and a comfortable treatment environment. Results and conclusions Researchers should explore the impact of discrimination on men in MT, patient preferences based on the therapist's gender, and the role of education in perpetuating societal heterosexual norms. Finally, as with any shift in culture, all levels of organization must take action to remove discrimination and bias within the profession of MT. PMID- 29148983 TI - Densification of chlorine-doped continuous CNT sheet/polyvinylidene fluoride sandwich film and improvement of the mechanical and dielectric properties. AB - The compact structure of a chlorine-doped continuous CNT sheet/polyvinylidene fluoride (Cl-CNT sheet/PVDF) was successfully optimized by means of a hot-press treatment to improve the mechanical and dielectric properties with a high densification degree. Then, the densified Cl-CNT sheet/PVDF dielectric layer was inserted between two PVDF insulating layers to fabricate a sandwich composite. It was found that the dielectric and mechanical properties were effectively enhanced, with a dielectric permittivity of 40.4 (@102 Hz), a dielectric loss of 0.16 (@102 Hz), a tensile strength of 139 MPa, and a tensile modulus of 4.4 GPa under a hot-pressing pressure of 20 MPa. Furthermore, the densified Cl-CNT sheet/PVDF was used as an electrode in a multilayer sandwich composite film, and good performance was obtained. The improvement mechanism was discussed and the studied CNT composite and other dielectric composites were compared. It demonstrates great potential for applications in dielectric and electrode materials to achieve structural and functional integration. PMID- 29148981 TI - Walnut leaf extract acts as a fertility agent in male Wistar albino rats - A search for herbal male fertility enhancer. AB - Background Walnut leaf is one of the many medicinal plants used in folklore as male fertility enhancers. The present work was therefore undertaken with an aim to scientifically validate this claim. As such, we evaluated the effect of the aqueous extract from walnut leaves on biomolecules related to fertility in adult male rats and its mode of action as fertility-enhancing agent. Methods Twenty five rats were randomly divided into five groups of five animals each; Group 1 served as control and received normal (0.9%) saline only; Groups II, III, IV received 50, 500, 1,000 mg/kg body weight (BW) of T. conophorum leaf extract orally, while Group V served as standard and was given suspension of clomiphene citrate orally at the dose of 1.04 mg/kg/ml BW. The extract and drug were given daily and the experiment lasted for 21 consecutive days. Results The testicular biochemical parameters in treated groups showed significant (p<0.05) increase in lactate dehydrogenase activity activity, Glucose-6-phosphate dehydrogenase (G 6PDH) activity, glycogen content, 3beta and 17beta hydroxysteroid dehydrogenase activities and testicular and epididymal Zn and Se contents with a significant decrease in cholesterol content. A significant increase in testis weight and epididymis weight were also observed. Also, a significant (p<0.05) increase in the level of serum testosterone, luteinizing hormone (LH), follicle-stimulating hormone, sperm count, motility, viability and a decrease in sperm abnormality were observed in the various treated groups when compared with the control group. This increment was concentration dependent, while the extract at the highest concentration showed a more pronounced effect than the standard drug. Also, no sperm DNA fragmentation index was found in all the treatment groups. Photomicrographs from light and scanning electron microscopy showed large fenestrae of interstitial tissue, large fluid space and intact seminiferous epithelium layers fully packed with spermatogenic cells in treated groups than the control group. Conclusions The present study has demonstrated that Tetracarpidium conophorum leaf possesses fertility-enhancing property and have useful effects on spermatogenesis and sperm parameters in rats. PMID- 29148984 TI - Supercritical diethylamine facilitated loading of ultrafine Ru particles on few layer graphene for solvent-free hydrogenation of levulinic acid to gamma valerolactone. AB - We demonstrate a facile and versatile method to grow Ru particles uniformly on pristine few-layer graphene (FLG) in supercritical diethylamine. In particular, a large number of Ru subnanometer clusters less than 1.0 nm were observed. The particle size can be tuned by manipulating the loading content of Ru and controlling the reaction temperature. The resulting Ru/FLG showed remarkably high activity, selectivity, and reusability towards the hydrogenation of levulinic acid to gamma-valerolactone. This method is flexible, and can be extended to the synthesis of a variety of other ultrafine metal particles supported on FLG. PMID- 29148985 TI - Subtyping sub-Saharan esophageal squamous cell carcinoma by comprehensive molecular analysis. PMID- 29148986 TI - Aligning Intention and Effect: What Can We Learn From Family Members' Responses to Condolence Letters? PMID- 29148987 TI - Is A Hemoglobin Concentration As Low As 7 g/dL Adequate For All Critically Ill Patients With Sepsis? Legitimate Doubts Remain! PMID- 29148988 TI - Humidified High-Flow Nasal Cannula Oxygen-More Than Just Supplemental Oxygen. PMID- 29148989 TI - Chronic Critical Illness After Trauma: From Description to Treatment? PMID- 29148990 TI - Extracorporeal Life Support: What Should We Be Targeting? PMID- 29148991 TI - Missing Data and ICU Mortality Prediction: Gone But Not to Be Forgotten. PMID- 29148992 TI - A Qualitative Look at End-of-Life Care in the ICU. PMID- 29148993 TI - It Just Makes Sense. PMID- 29148995 TI - Microcirculation First!-Esmolol, a Candidate for the Next Term of Office. PMID- 29148996 TI - Could the Outcome of Septic Patients Be Improved by a Prehospital Emergency Medical Service With Physician on Scene? PMID- 29148994 TI - Critical Care Resources in Mainland China: When More May Not Always Be Better. PMID- 29148997 TI - Physicians' Variation in Care: The Practical Balance of Warranted Versus Unwarranted Variation. PMID- 29148998 TI - The authors reply. PMID- 29148999 TI - Gender Bias and Cardiopulmonary Rescue: The Context of No Context. PMID- 29149000 TI - The authors reply. PMID- 29149001 TI - Leadership in Medical Emergencies Is "Highly Teachable". PMID- 29149002 TI - The authors reply. PMID- 29149003 TI - Determinants of Ventilator Withdrawal Among Patients With Prolonged Mechanical Ventilation. PMID- 29149004 TI - The authors reply. PMID- 29149005 TI - Respiratory Muscle Weakness, a Major Contributor to Pediatric Extubation Failure: Does Low Serum Phosphorus Contribute to Muscle Weakness? PMID- 29149007 TI - Awake Bronchoscopic Intubation With a Noninvasive Positive Pressure Support in Critically Ill Patients. PMID- 29149006 TI - The authors reply. PMID- 29149008 TI - The authors reply. PMID- 29149010 TI - The author replies. PMID- 29149009 TI - First Recognition, Then Education. PMID- 29149011 TI - Quality: A Bridge From Guidelines to Practice. PMID- 29149012 TI - The author replies. PMID- 29149013 TI - Confounders Affecting the Prognosis in Patients With Acute Decompensated Heart Failure Who Underwent Extracorporeal Membrane Oxygenation. PMID- 29149014 TI - The authors reply. PMID- 29149015 TI - Potential Confounders of Procalcitonin-Guided Antibiotic Therapy for Sepsis. PMID- 29149016 TI - Oleanane-Type Saponins from the Roots of Ligulariopsis shichuana and Their alpha Glucosidase Inhibitory Activities. AB - Five new oleanane-type saponins, named ligushicosides A-E, and three known oleanane-type saponins were isolated from the roots of Ligulariopsis shichuana. Their structures were established by a combination of spectroscopic techniques, including 1D and 2D NMR and high resolution electrospray ionization mass spectroscopy (HR-ESI-MS). Furthermore, all isolates were evaluated for their yeast alpha-glucosidase inhibitory effects and exhibited potent inhibition against alpha-glucosidase, while compounds 1 and 2 showed excellent inhibitory activities. The 3-O-glycoside moiety in oleanane-type saponin is important for the alpha-glucosidase inhibitory effects. PMID- 29149017 TI - The Ms6 Mycolyl-Arabinogalactan Esterase LysB is Essential for an Efficient Mycobacteriophage-Induced Lysis. AB - All dsDNA phages encode two proteins involved in host lysis, an endolysin and a holin that target the peptidoglycan and cytoplasmic membrane, respectively. Bacteriophages that infect Gram-negative bacteria encode additional proteins, the spanins, involved in disruption of the outer membrane. Recently, a gene located in the lytic cassette was identified in the genomes of mycobacteriophages, which encodes a protein (LysB) with mycolyl-arabinogalactan esterase activity. Taking in consideration the complex mycobacterial cell envelope that mycobacteriophages encounter during their life cycle, it is valuable to evaluate the role of these proteins in lysis. In the present work, we constructed an Ms6 mutant defective on lysB and showed that Ms6 LysB has an important role in lysis. In the absence of LysB, lysis still occurs but the newly synthesized phage particles are deficiently released to the environment. Using cryo-electron microscopy and tomography to register the changes in the lysis phenotype, we show that at 150 min post-adsorption, mycobacteria cells are incompletely lysed and phage particles are retained inside the cell, while cells infected with Ms6wt are completely lysed. Our results confirm that Ms6 LysB is necessary for an efficient lysis of Mycobacterium smegmatis, acting, similarly to spanins, in the third step of the lysis process. PMID- 29149018 TI - Please Wait, Processing: A Selective Literature Review of the Neurological Understanding of Emotional Processing in ASD and Its Potential Contribution to Neuroeducation. AB - Autism spectrum disorder (ASD) and its corresponding conditions have been investigated from a multitude of perspectives resulting in varying understandings of its origin, its outplay, its prognosis, and potential methods of intervention and education for individuals with the disorder. One area that has contributed significantly to providing a different type of understanding is that of neuroscience, and specifically neuroimaging. This paper will offer a selective literature review of research that investigates the role of emotional processing in ASD, and how a deepening of this line of understanding can be used to inform more comprehensive educational practices. PMID- 29149019 TI - Incidence and Consequences of Near-Drowning-Related Pneumonia-A Descriptive Series from Martinique, French West Indies. AB - Drowning represents one major cause of accidental death. Near-drowning patients are exposed to aspiration that may result in pneumonia with life-threatening consequences. We designed this descriptive study to investigate the frequency, nature, and consequences of post-drowning pneumonia. One hundred and forty-four near-drowning patients (33 children and 111 adults) admitted during four years to the University Hospital of Martinique, French Indies, were included. Patients presented pre-hospital cardiac arrest (41%) and exhibited acute respiratory failure (54%), cardiovascular failure (27%), and lactic acidosis (75%) on admission. Empirical antibiotics, as decided by the physicians in charge, were administered in 85 patients (59%). Post-drowning early onset bacterial pneumonia was diagnosed as "possible" in 13 patients (9%) and "confirmed" in 22 patients (15%). Tracheal aspiration revealed the presence of polymorphous pharyngeal flora (59%) or one predominant bacteria species (41%) including Enterobacter aerogenes, Enterobacter cloacae, Staphylococcus aureus, Pseudomonas aeruginosa, Aeromonas hydrophilia, and Morganella morgani. Despite adequate supportive care, drowning resulted in 45 fatalities (31%). Early onset bacterial aspiration pneumonia (either possible or confirmed) did not significantly influence the risk of death. In conclusion, near-drowning-related bacterial aspiration pneumonia seems rare and does not influence the mortality rate. There is still a need for practice standardization to improve diagnosis of post-drowning pneumonia and near-drowning patient management. PMID- 29149022 TI - Pyogenic Brain Abscess Caused by Peptostreptococcus in a Patient with HIV-1 Infection. AB - In the setting of HIV, cerebral lesions are usually secondary to lymphoma and opportunistic infections; however, in patients with CD4 counts above 200 cells/uL, other pathologies such as pyogenic brain abscess could gain importance. The microbiology of pyogenic brain abscess has Staphylococcus and Streptococcus as the leading etiologic pathogens in immunocompetent individuals. Peptostreptococcus is also recognized as a common cause of brain abscess in this patient population. In HIV-infected individuals, there have been sporadic reports of Peptostreptococcus infections but none of brain abscess. We describe the case of a 43-years-old HIV-infected patient with a CD4 count of 350 cells/uL that developed a Peptostreptococcus brain abscess presumably from hematogenous spread of an odontogenic source. Treatment with stereotactic needle aspiration in two opportunities and four weeks of intravenous antibiotics led to a complete resolution of this infection. This case highlights the importance of a multidisciplinary approach for an effective treatment of pyogenic brain abscess in HIV-1 patients. PMID- 29149021 TI - Using Gamma and Quantile Regressions to Explore the Association between Job Strain and Adiposity in the ELSA-Brasil Study: Does Gender Matter? AB - This paper explores the association between job strain and adiposity, using two statistical analysis approaches and considering the role of gender. The research evaluated 11,960 active baseline participants (2008-2010) in the ELSA-Brasil study. Job strain was evaluated through a demand-control questionnaire, while body mass index (BMI) and waist circumference (WC) were evaluated in continuous form. The associations were estimated using gamma regression models with an identity link function. Quantile regression models were also estimated from the final set of co-variables established by gamma regression. The relationship that was found varied by analytical approach and gender. Among the women, no association was observed between job strain and adiposity in the fitted gamma models. In the quantile models, a pattern of increasing effects of high strain was observed at higher BMI and WC distribution quantiles. Among the men, high strain was associated with adiposity in the gamma regression models. However, when quantile regression was used, that association was found not to be homogeneous across outcome distributions. In addition, in the quantile models an association was observed between active jobs and BMI. Our results point to an association between job strain and adiposity, which follows a heterogeneous pattern. Modelling strategies can produce different results and should, accordingly, be used to complement one another. PMID- 29149020 TI - Role of Transforming Growth Factor beta in Uterine Fibroid Biology. AB - Uterine fibroids (UFs) are benign tumors of the female genital tract made of the smooth muscle of the uterus. UF growth depends mostly on the influence of the steroid hormones and selected growth factors. Transforming growth factor beta (TGF-betas) is a polypeptide that consists of three isoforms: TGF-beta1, TGF beta2, and TGF-beta3. At present, TGF-beta is considered to be one of the key factors in the pathophysiology of UFs. It plays a major role in cellular migration within the tumor, stimulates tumor growth, and enhances tumor metabolism. As a consequence of various dependencies, the synthesis and release of TGF-beta in a UF tumor is increased, which results in excessive extracellular matrix production and storage. High concentrations or overexpression of TGF-beta mediators may be responsible for clinically symptomatic UFs. The aim of this review was to check the available evidence for the influence of the TGF-beta family on UF biology. We conducted their search in PubMed of the National Library of Medicine with the use of the following selected keywords: "uterine fibroid", "leiomyoma", and "transforming growth factor beta". After reviewing the titles and abstracts, more than 115 full articles were evaluated. We focused on the TGF beta-related molecular aspects and their influence on the most common symptoms that are associated with UFs. Also, we described how the available data might implicate the current medical management of UFs. PMID- 29149023 TI - Antibiotic Susceptibility, Genetic Diversity, and the Presence of Toxin Producing Genes in Campylobacter Isolates from Poultry. AB - This study examined antibiotic susceptibility, genetic diversity, and characteristics of virulence genes in Campylobacter isolates from poultry. Chicken (n = 152) and duck (n = 154) samples were collected from 18 wet markets in Korea. Campylobacter spp. isolated from the carcasses were identified by PCR. The isolated colonies were analyzed for antibiotic susceptibility to chloramphenicol, amikacin, erythromycin, tetracycline, ciprofloxacin, nalidixic acid, and enrofloxacin. The isolates were also used to analyze genetic diversity using the DiversiLabTM system and were tested for the presence of cytolethal distending toxin (cdt) genes. Campylobacter spp. were isolated from 45 poultry samples out of 306 poultry samples (14.7%) and the average levels of Campylobacter contamination were 22.0 CFU/g and 366.1 CFU/g in chicken and duck samples, respectively. Moreover, more than 90% of the isolates showed resistance to nalidixic acid and ciprofloxacin. Genetic correlation analysis showed greater than 95% similarity between 84.4% of the isolates, and three cdt genes (cdtA, cdtB, and cdtC) were present in 71.1% of Campylobacter isolates. These results indicate that Campylobacter contamination should be decreased to prevent and treat Campylobacter foodborne illness. PMID- 29149024 TI - The Role of the Mammalian Prion Protein in the Control of Sleep. AB - Sleep disruption is a prevalent clinical feature in many neurodegenerative disorders, including human prion diseases where it can be the defining dysfunction, as in the case of the "eponymous" fatal familial insomnia, or an early-stage symptom as in certain types of Creutzfeldt-Jakob disease. It is important to establish the role of the cellular prion protein (PrPC), the key molecule involved in prion pathogenesis, within the sleep-wake system in order to understand fully the mechanisms underlying its contribution to both healthy circadian rhythmicity and sleep dysfunction during disease. Although severe disruption to the circadian rhythm and melatonin release is evident during the pathogenic phases of some prion diseases, untangling whether PrPC plays a role in circadian rhythmicity, as suggested in mice deficient for PrPC expression, is challenging given the lack of basic experimental research. We provide a short review of the small amount of direct literature focused on the role of PrPC in melatonin and circadian rhythm regulation, as well as suggesting mechanisms by which PrPC might exert influence upon noradrenergic and dopaminergic signaling and melatonin synthesis. Future research in this area should focus upon isolating the points of dysfunction within the retino-pineal pathway and further investigate PrPC mediation of pinealocyte GPCR activity. PMID- 29149025 TI - Fatty Acid Composition of Dried Fruits of Sclerocarya birrea, Diospyros blancoi and Landolphia kirkii. AB - Wild fruits are commonly consumed in the rural communities of South Africa. The information on their nutritionally important fatty acids is, however, limited. Three wild fruit species, Diospyros blancoi, Landolphia kirkii and Sclerocarya birrea from Limpopo Province were selected for evaluation of fatty acid content. Fatty acids composition of dried fruits of Diospyros blancoi (Db), Landolphia kirkii (Lk) and ripe and/or overripe Sclerocarya birrea (Sb) were evaluated by a gas chromatography-time of flight-mass spectrometer (GC-TOF-MS). Hexadecanoic acid (C16:0) was found in highest abundance in L. kirkii (57.73-73.55%), followed by S. birrea (55.92-71.31%) and D. blancoi (46.31-62.05%), respectively. Octadecanoic acid (C18:0) was of second highest abundance, with 24.71-100% in D. blancoi, L. kirkii (31.03-41.60%) and S. birrea (9.11-17.0%). The 9-octadecenoic acid (C18:1n-9) was the major unsaturated fatty acid in both S. birrea (5.33 18.82%), D. blancoi (8.22-8.92%), and L. kirkii (3.84-8.63%). The 9,-12 octadecadienoic acid (C18:2n-6) was the major unsaturated fatty acid in D. blancoi (22.34%). The 9,-12,-15-octadecatrienoic acid (C18:3n-3) was found in L. kirkii (3.51%) and S. birrea (2.79%). From the results, saturated fatty acids were the most dominant, whereas mono- and poly-unsaturated fatty acids were the minor constituents. Therefore, presence of nutritionally important essential fatty acids from S. birrea, D. blancoi and L. kirkii has been shown. PMID- 29149026 TI - Non-Catalytic Roles of the Topoisomerase IIalpha C-Terminal Domain. AB - DNA Topoisomerase IIalpha (Topo IIalpha) is a ubiquitous enzyme in eukaryotes that performs the strand passage reaction where a double helix of DNA is passed through a second double helix. This unique reaction is critical for numerous cellular processes. However, the enzyme also possesses a C-terminal domain (CTD) that is largely dispensable for the strand passage reaction but is nevertheless important for the fidelity of cell division. Recent studies have expanded our understanding of the roles of the Topo IIalpha CTD, in particular in mitotic mechanisms where the CTD is modified by Small Ubiquitin-like Modifier (SUMO), which in turn provides binding sites for key regulators of mitosis. PMID- 29149027 TI - Baccharis reticularia DC. and Limonene Nanoemulsions: Promising Larvicidal Agents for Aedes aegypti (Diptera: Culicidae) Control. AB - Baccharis reticularia DC. is a plant species from the Asteraceae family that is endemic to Brazil. Despite the great importance of Baccharis genus, no study has been carried out regarding either the phytochemical composition of B. reticularia or the evaluation of its larvicidal potential. Considering the intrinsic immiscibility of essential oils, this study shows larvicidal nanoemulsions containing the B. reticularia phytochemically characterized essential oil and its main constituent against Aedes aegypti. The major compound found was d-limonene (25.7%). The essential oil inhibited the acetylcholinesterase, one of the main targets of insecticides. The required hydrophile-lipophile balance of both nanoemulsions was 15.0. The mean droplet sizes were around 90.0 nm, and no major alterations were observed after 24 h of preparation for both formulations. After 48 h of treatment, the estimated LC50 values were 118.94 MUg mL-1 and 81.19 MUg mL-1 for B. reticularia essential oil and d-limonene nanoemulsions, respectively. Morphological alterations evidenced by scanning electron micrography were observed on the larvae treated with the d-limonene nanoemulsion. This paper demonstrated a simple and ecofriendly method for obtaining B. reticularia essential oil and d-limonene aqueous nanoemulsions by a non-heating and solvent free method, as promising alternatives for Aedes aegypti control. PMID- 29149028 TI - Changes of Cerebral and/or Peripheral Adenosine A1 Receptor and IGF-I Concentrations under Extended Sleep Duration in Rats. AB - Extended sleep improves sustained attention and reduces sleep pressure in humans. Downregulation of adenosine A1 receptor (A1R) and modulation of the neurotrophic factor insulin growth factor-1 (IGF-I) in brain structures controlling attentional capacities could be involved. In the frontal cortex and hippocampus of rats, we measured adenosine A1R and IGF-I protein concentrations after photoperiod-induced sleep extension. Two groups of twelve rats were adapted over 14 days to a habitual (CON) 12:12 light-dark (LD) schedule and an extended (EXT) 16:8 LD schedule. IGF-I content was also measured in plasma, liver, and skeletal muscle. In EXT, compared to CON rats, A1R content in the frontal cortex was significantly lower (p < 0.05), while IGF-I content was higher (p < 0.001), and no significant change was observed in the hippocampus. IGF-I content in plasma and muscle was higher (p < 0.001 and p < 0.01), while it was lower in liver (p < 0.001). The absolute weight and weight gain were higher in EXT rats (p < 0.01). These data suggest that 14 days under a 16:8 LD photoperiod respectively down- and upregulated cortical A1R and IGF-I levels. This photoperiod induced an anabolic profile with increased weight gain and circulating and muscular IGF-I levels. An extension of sleep duration might favor cerebral and peripheral anabolism, which may help attentional and physical capacities. PMID- 29149029 TI - Kappaphycus alvarezii as a Food Supplement Prevents Diet-Induced Metabolic Syndrome in Rats. AB - The red seaweed, Kappaphycus alvarezii, was evaluated for its potential to prevent signs of metabolic syndrome through use as a whole food supplement. Major biochemical components of dried Kappaphycus are carrageenan (soluble fiber ~34.6%) and salt (predominantly potassium (K) 20%) with a low overall energy content for whole seaweed. Eight to nine week old male Wistar rats were randomly divided into three groups and fed for 8 weeks on a corn starch diet, a high carbohydrate, high-fat (H) diet, alone or supplemented with a 5% (w/w) dried and milled Kappaphycus blended into the base diet. H-fed rats showed symptoms of metabolic syndrome including increased body weight, total fat mass, systolic blood pressure, left ventricular collagen deposition, plasma triglycerides, and plasma non-esterified fatty acids along with fatty liver. Relative to these obese rats, Kappaphycus-treated rats showed normalized body weight and adiposity, lower systolic blood pressure, improved heart and liver structure, and lower plasma lipids, even in presence of H diet. Kappaphycus modulated the balance between Firmicutes and Bacteroidetes in the gut, which could serve as the potential mechanism for improved metabolic variables; this was accompanied by no damage to the gut structure. Thus, whole Kappaphycus improved cardiovascular, liver, and metabolic parameters in obese rats. PMID- 29149030 TI - Using Next-Generation Sequencing to Detect Differential Expression Genes in Bradysia odoriphaga after Exposure to Insecticides. AB - Bradysia odoriphaga (Diptera: Sciaridae) is the most important pest of Chinese chive. Insecticides are used widely and frequently to control B. odoriphaga in China. However, the performance of the insecticides chlorpyrifos and clothianidin in controlling the Chinese chive maggot is quite different. Using next generation sequencing technology, different expression unigenes (DEUs) in B. odoriphaga were detected after treatment with chlorpyrifos and clothianidin for 6 and 48 h in comparison with control. The number of DEUs ranged between 703 and 1161 after insecticide treatment. In these DEUs, 370-863 unigenes can be classified into 41 46 categories of gene ontology (GO), and 354-658 DEUs can be mapped into 987-1623 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The expressions of DEUs related to insecticide-metabolism-related genes were analyzed. The cytochrome P450-like unigene group was the largest group in DEUs. Most glutathione S transferase-like unigenes were down-regulated and most sodium channel-like unigenes were up-regulated after insecticide treatment. Finally, 14 insecticide metabolism-related unigenes were chosen to confirm the relative expression in each treatment by quantitative Real Time Polymerase Chain Reaction (qRT-PCR). The results of qRT-PCR and RNA Sequencing (RNA-Seq) are fairly well-established. Our results demonstrate that a next-generation sequencing tool facilitates the identification of insecticide-metabolism-related genes and the illustration of the insecticide mechanisms of chlorpyrifos and clothianidin. PMID- 29149031 TI - Anti-Inflammatory and Antinociceptive Effects of Ethyl Acetate Fraction of an Edible Red Macroalgae Sarcodia ceylanica. AB - Research so far has only shown that edible red macroalgae, Sarcodia ceylanica has the ability to eliminate free radicals and anti-diabetic, anti-bacterial properties. This study was conducted both in vitro and in vivo on the ethyl acetate extract (PD1) of farmed red macroalgae in order to explore its anti inflammatory properties. In order to study the in vitro anti-inflammatory effects of PD1, we used lipopolysaccharide (LPS) to induce inflammatory responses in murine macrophages. For evaluating the potential in vivo anti-inflammatory and antinociceptive effects of PD1, we used carrageenan-induced rat paw edema to produce inflammatory pain. The in vitro results indicated that PD1 inhibited the LPS-induced pro-inflammatory protein, inducible nitric oxide synthase (iNOS) in macrophages. Oral PD1 can reduce carrageenan-induced paw edema and inflammatory nociception. PD1 can significantly inhibit carrageenan-induced leukocyte infiltration, as well as the protein expression of inflammatory mediators (iNOS, interleukin-1beta, and myeloperoxidase) in inflammatory tissue. The above results indicated that PD1 has great potential to be turned into a functional food or used in the development of new anti-inflammatory and antinociceptive agents. The results from this study are expected to help scientists in the continued development of Sarcodia ceylanica for other biomedical applications. PMID- 29149032 TI - Optimal Line and Tube Placement in Very Preterm Neonates: An Audit of Practice. AB - BACKGROUND: Placement of endotracheal tubes (ETTs) and umbilical catheters (UCs) is essential in very preterm infant care. The aim of this study was to assess the effect of an educational initiative to optimize correct placement of ETTs and UCs in very preterm infants. METHODS: A pre-post study design, evaluating optimal radiological position of ETTs and UCs in the first 72 h of life in infants <32 weeks gestational age (GA) was performed. Baseline data was obtained from a preceding 34-month period. The study intervention consisted of information from the pre-intervention audit, surface anatomy images of the newborn for optimal UC positioning, and weight-based calculations to estimate insertion depths for endotracheal intubation. A prospective evaluation of radiological placement of ETTs and UCs was then conducted over a 12-month period. RESULTS: During the study period, 211 infants had at least one of the three procedures performed. One hundred and fifty-seven infants were included in the pre-education group, and 54 in the post-education group. All three procedures were performed in 50.3% (79/157) in the pre-education group, and 55.6% (30/54) in the post-education group. There was no significant difference in accurate placement following the introduction of the educational sessions; depth of ETTs (50% vs. 47%), umbilical arterial catheter (UAC) (40% vs. 43%,), and umbilical venous catheter (UVC)(14% vs. 23%). CONCLUSION: Despite education of staff on methods for appropriate ETT, UVC and UAC insertion length, the rate of accurate initial insertion depth remained suboptimal. Newer methods of determining optimal position need to be evaluated. PMID- 29149034 TI - Multiferroic Hysteresis Loop. AB - Multiferroics, showing both ferroelectric and magnetic order, are promising candidates for future electronic devices. Especially, the fundamental understanding of ferroelectric switching is of key relevance for further improvements, which however is rarely reported in literature. On a prime example for a spin-driven multiferroic, LiCuVO4, we present an extensive study of the ferroelectric order and the switching behavior as functions of external electric and magnetic fields. From frequency-dependent polarization switching and using the Ishibashi-Orihara theory, we deduce the existence of ferroelectric domains and domain-walls. These have to be related to counterclockwise and clockwise spin spirals leading to the formation of multiferroic domains. A novel measurement multiferroic hysteresis loop-is established to analyze the electrical polarization simultaneously as a function of electrical and magnetic fields. This technique allows characterizing the complex coupling between ferroelectric and magnetic order in multiferroic LiCuVO4. PMID- 29149033 TI - Validity and Reproducibility of a Food Frequency Questionnaire for Dietary Factors Related to Colorectal Cancer. AB - Dietary factors play a major role in the development of colorectal cancer. This study evaluated the reproducibility and validity of a 109-food item Food Frequency Questionnaire (FFQ) to measure the consumption of foods and nutrients related to the development of colorectal cancer in a population aged >=50 years in Flanders, Belgium. A semi-quantitative FFQ was administered two times in a period of two weeks to evaluate reproducibility (FFQ1 and FFQ2). The validity of the FFQ was assessed by comparing FFQ1 against the 3-day diary method (3 DD). A total of 162 respondents (mean age 57.5 years) provided data for the FFQ, of whom 156 also participated in the validity assessment. Mean differences in the intake of foods and nutrients between FFQ1 and FFQ2 were, overall, small and statistically insignificant. However, a higher estimation was observed by FFQ1 as compared to the 3-DD method for the majority of food groups and nutrient intake in the validity assessment. A systematic mean difference (g/day) was observed for eight food groups in the Bland-Altman agreement test; the largest was for fruit intake. Regarding the nutrients, a systematic mean difference was observed in calcium, fat, and vitamin D intake. Overall, the reproducibility of the FFQ was good, and its validity could be satisfactory for estimating absolute food and nutrient intakes and ranking individuals according to high and low intake categories. PMID- 29149035 TI - WearETE: A Scalable Wearable E-Textile Triboelectric Energy Harvesting System for Human Motion Scavenging. AB - In this paper, we report the design, experimental validation and application of a scalable, wearable e-textile triboelectric energy harvesting (WearETE) system for scavenging energy from activities of daily living. The WearETE system features ultra-low-cost material and manufacturing methods, high accessibility, and high feasibility for powering wearable sensors and electronics. The foam and e-textile are used as the two active tribomaterials for energy harvester design with the consideration of flexibility and wearability. A calibration platform is also developed to quantify the input mechanical power and power efficiency. The performance of the WearETE system for human motion scavenging is validated and calibrated through experiments. The results show that the wearable triboelectric energy harvester can generate over 70 V output voltage which is capable of powering over 52 LEDs simultaneously with a 9 * 9 cm2 area. A larger version is able to lighten 190 LEDs during contact-separation process. The WearETE system can generate a maximum power of 4.8113 mW from hand clapping movements under the frequency of 4 Hz. The average power efficiency can be up to 24.94%. The output power harvested by the WearETE system during slow walking is 7.5248 uW. The results show the possibility of powering wearable electronics during human motion. PMID- 29149036 TI - Identification of the Caprine Keratin-Associated Protein 20-2 (KAP20-2) Gene and Its Effect on Cashmere Traits. AB - The gene encoding the high glycine/tyrosine keratin-associated protein 20-2 (KAP20-2) gene has been described in humans, but has not been identified in any livestock species. A search for similar sequences in the caprine genome using the human KAP20-2 gene (KRTAP20-2) revealed a homologous sequence on chromosome 1. Three different banding patterns representing distinct sequences (A-C) in Longdong cashmere goats were identified using polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) analysis. These sequences shared high sequence similarity with the human and mouse KRTAP20-2 sequences, suggesting that A-C are caprine variants of the human and mouse genes. Four single nucleotide polymorphisms (SNPs) were identified, and three of them were non synonymous. KRTAP20-2 was found to be expressed in secondary hair follicles, but not in heart, liver, lung, kidney, spleen, or longissimus dorsi muscle. The presence of A was associated with increased cashmere fibre weight, while the presence of B was associated with a decrease in cashmere fibre weight and curly fibre length. Goats with genotype AA had a higher cashmere fibre weight and a higher curly fibre length than those with genotypes AB or BB. These results indicate that caprine KRTAP20-2 variation may have value as a genetic marker for improving cashmere fibre weight. PMID- 29149037 TI - Development of Novel Polymorphic EST-SSR Markers in Bailinggu (Pleurotus tuoliensis) for Crossbreeding. AB - Identification of monokaryons and their mating types and discrimination of hybrid offspring are key steps for the crossbreeding of Pleurotus tuoliensis (Bailinggu). However, conventional crossbreeding methods are troublesome and time consuming. Using RNA-seq technology, we developed new expressed sequence tag simple sequence repeat (EST-SSR) markers for Bailinggu to easily and rapidly identify monokaryons and their mating types, genetic diversity and hybrid offspring. We identified 1110 potential EST-based SSR loci from a newly-sequenced Bailinggu transcriptome and then randomly selected 100 EST-SSRs for further validation. Results showed that 39, 43 and 34 novel EST-SSR markers successfully identified monokaryons from their parent dikaryons, differentiated two different mating types and discriminated F1 and F2 hybrid offspring, respectively. Furthermore, a total of 86 alleles were detected in 37 monokaryons using 18 highly informative EST-SSRs. The observed number of alleles per locus ranged from three to seven. Cluster analysis revealed that these monokaryons have a relatively high level of genetic diversity. Transfer rates of the EST-SSRs in the monokaryons of closely-related species Pleurotuseryngii var. ferulae and Pleurotus ostreatus were 72% and 64%, respectively. Therefore, our study provides new SSR markers and an efficient method to enhance the crossbreeding of Bailinggu and closely-related species. PMID- 29149038 TI - Adherence to Hunger Training over 6 Months and the Effect on Weight and Eating Behaviour: Secondary Analysis of a Randomised Controlled Trial. AB - Monitoring blood glucose prior to eating can teach individuals to eat only when truly hungry, but how adherence to 'hunger training' influences weight loss and eating behaviour is uncertain. This exploratory, secondary analysis from a larger randomized controlled trial examined five indices of adherence to 'hunger training', chosen a priori, to examine which adherence measure best predicted weight loss over 6 months. We subsequently explored how the best measure of adherence influenced eating behavior in terms of intuitive and emotional eating. Retention was 72% (n = 36/50) at 6 months. Frequency of hunger training booklet entry most strongly predicted weight loss, followed by frequency of blood glucose measurements. Participants who completed at least 60 days of booklet entry (of recommended 63 days) lost 6.8 kg (95% CI: 2.6, 11.0; p < 0.001) more weight than those who completed fewer days. They also had significantly higher intuitive eating scores than those who completed 30 days or less of booklet entry; a difference (95% CI) of 0.73 (0.12, 1.35) in body-food choice congruence and 0.79 (0.06, 1.51) for eating for physical rather than emotional reasons. Adherent participants also reported significantly lower scores for emotional eating of 0.70 (-1.13, -0.27). Following hunger training and focusing on simply recording ratings of hunger on a regular basis can produce clinically significant weight loss and clinically relevant improvements in eating behaviour. PMID- 29149039 TI - Growth of Anisotropic Gold Nanoparticle Assemblies via Liposome Fusion. AB - Anisotropic assembly of nanoparticles (NPs) has attracted extensive attention because of the potential applications in materials science, biology, and medicine. However, assembly control (e.g., the number of assembled NPs) has not been adequately studied. Here, the growth of anisotropic gold NP assemblies on a liposome surface is reported. Citrate-coated gold NPs adsorbed on liposome surfaces were assembled in one dimension at temperatures above the phase transition temperature of the lipid bilayer. Growth of the anisotropic assemblies depended on the heating time. Absorption spectroscopy and transmission electron microscopy revealed that the gradual growth was attributed to liposome fusion, which was strongly affected by the size of the gold NPs. This method enabled us to precisely control the number of NPs in each anisotropic assembly. These results will enable the fabrication of functional materials based on NP assemblies and enable investigations of cell functions and disease causality. PMID- 29149040 TI - A CoAP-Based Network Access Authentication Service for Low-Power Wide Area Networks: LO-CoAP-EAP. AB - The Internet-of-Things (IoT) landscape is expanding with new radio technologies. In addition to the Low-Rate Wireless Personal Area Network (LR-WPAN), the recent set of technologies conforming the so-called Low-Power Wide Area Networks (LP WAN) offers long-range communications, allowing one to send small pieces of information at a reduced energy cost, which promotes the creation of new IoT applications and services. However, LP-WAN technologies pose new challenges since they have strong limitations in the available bandwidth. In general, a first step prior to a smart object being able to gain access to the network is the process of network access authentication. It involves authentication, authorization and key management operations. This process is of vital importance for operators to control network resources. However, proposals for managing network access authentication in LP-WAN are tailored to the specifics of each technology, which could introduce interoperability problems in the future. In this sense, little effort has been put so far into providing a wireless-independent solution for network access authentication in the area of LP-WAN. To fill this gap, we propose a service named Low-Overhead CoAP-EAP (LO-CoAP-EAP), which is based on previous work designed for LR-WPAN. LO-CoAP-EAP integrates the use of Authentication, Authorization and Accounting (AAA) infrastructures and the Extensible Authentication Protocol (EAP) protocol. For this integration, we use the Constrained Application Protocol (CoAP) to design a network authentication service independent of the type of LP-WAN technology. LO-CoAP-EAP represents a trade-off between flexibility, wireless technology independence, scalability and performance in LP-WAN. PMID- 29149041 TI - The HMGA1 Pseudogene 7 Induces miR-483 and miR-675 Upregulation by Activating Egr1 through a ceRNA Mechanism. AB - Several studies have established that pseudogene mRNAs can work as competing endogenous RNAs and, when deregulated, play a key role in the onset of human neoplasias. Recently, we have isolated two HMGA1 pseudogenes, HMGA1P6 and HMGA1P7. These pseudogenes have a critical role in cancer progression, acting as micro RNA (miRNA) sponges for HMGA1 and other cancer-related genes. HMGA1 pseudogenes were found overexpressed in several human carcinomas, and their expression levels positively correlate with an advanced cancer stage and a poor prognosis. In order to investigate the molecular alterations following HMGA1 pseudogene 7 overexpression, we carried out miRNA sequencing analysis on HMGA1P7 overexpressing mouse embryonic fibroblasts. Intriguingly, the most upregulated miRNAs were miR-483 and miR-675 that have been described as key regulators in cancer progression. Here, we report that HMGA1P7 upregulates miR-483 and miR-675 through a competing endogenous RNA mechanism with Egr1, a transcriptional factor that positively regulates miR-483 and miR-675 expression. PMID- 29149043 TI - Local Homing Navigation Based on the Moment Model for Landmark Distribution and Features. AB - [-10]For local homing navigation, an agent is supposed to return home based on the surrounding environmental information. According to the snapshot model, the home snapshot and the current view are compared to determine the homing direction. In this paper, we propose a novel homing navigation method using the moment model. The suggested moment model also follows the snapshot theory to compare the home snapshot and the current view, but the moment model defines a moment of landmark inertia as the sum of the product of the feature of the landmark particle with the square of its distance. The method thus uses range values of landmarks in the surrounding view and the visual features. The center of the moment can be estimated as the reference point, which is the unique convergence point in the moment potential from any view. The homing vector can easily be extracted from the centers of the moment measured at the current position and the home location. The method effectively guides homing direction in real environments, as well as in the simulation environment. In this paper, we take a holistic approach to use all pixels in the panoramic image as landmarks and use the RGB color intensity for the visual features in the moment model in which a set of three moment functions is encoded to determine the homing vector. We also tested visual homing or the moment model with only visual features, but the suggested moment model with both the visual feature and the landmark distance shows superior performance. We demonstrate homing performance with various methods classified by the status of the feature, the distance and the coordinate alignment. PMID- 29149042 TI - Comparative Study of Biological Activities of Venom from Colubrid Snakes Rhabdophis tigrinus (Yamakagashi) and Rhabdophis lateralis. AB - Rhabdophis lateralis, a colubrid snake distributed throughout the continent of Asia, has recently undergone taxonomic revisions. Previously, Rhabdophis lateralis was classified as a subspecies of R. tigrinus (Yamakagashi) until 2012, when several genetic differences were discovered which classified this snake as its own species. To elucidate the toxicity of venom from this poorly studied colubrid, various biological activities were compared between the venom from the two snake species. The components of their venom were compared by the elution profiles of reversed-phase HPLC and SDS-PAGE, and gel filtrated fractions were tested for effects on blood coagulation. Proteolytic activities of these fractions were also assayed by using synthetic substrates, fibrinogen, and matrix proteins. Similar to the R. tigrinus venom, the higher molecular weight fraction of R. lateralis venom contained a prothrombin activator. Both prothrombin time (PT) and activated partial thromboplastin time (APTT) of human plasma were shortened by the addition of R. lateralis and R. tigrinus venom. The thrombin formation was estimated by the uses of SDS-PAGE and chromogenic substrates. These venom fractions also possessed very specific proteinase activity on human fibrinogen, but the substrates for matrix metalloproteinase, such as collagen and laminin, were not hydrolyzed. However, there were some notable differences in reactivity to synthetic substrates for matrix metalloproteinase, and R. tigrinus venom possessed relatively higher activity. Our chemical investigation indicates that the components included in both venoms resemble each other closely. However, the ratio of components and proteolytic activity of some ingredients are slightly different, indicating differences between two closely-related snakes. PMID- 29149044 TI - The Effect of Hock Injury Laterality and Lameness on Lying Behaviors and Lying Laterality in Holstein Dairy Cows. AB - Lactating dairy cattle divide their lying equally between their left side and their right side. However, discomfort, such as pregnancy and cannulation, can cause a cow to shift lying side preference. The objective of this study was to determine the effect of lameness and hock injuries on lying behaviors, particularly lying laterality, of lactating dairy cows. Cows from four commercial farms in eastern Croatia that had lying behavior data, health score data, and production records were used in the study. Health scores including hock injuries and locomotion were collected once per cow. Severely lame cows had greater daily lying time compared to sound cows and moderately lame cows. Overall, cows spent 51.3 +/- 1.2% of their daily lying time on the left side. Maximum hock score, locomotion score, hock injury laterality, or parity did not result in lying laterality differing from 50%. PMID- 29149045 TI - Self-Organizing Peer-To-Peer Middleware for Healthcare Monitoring in Real-Time. AB - As the number of elderly persons with chronic illnesses increases, a new public infrastructure for their care is becoming increasingly necessary. In particular, technologies that can monitoring bio-signals in real-time have been receiving significant attention. Currently, most healthcare monitoring services are implemented by wireless carrier through centralized servers. These services are vulnerable to data concentration because all data are sent to a remote server. To solve these problems, we propose self-organizing P2P middleware for healthcare monitoring that enables a real-time multi bio-signal streaming without any central server by connecting the caregiver and care recipient. To verify the performance of the proposed middleware, we evaluated the monitoring service matching time based on a monitoring request. We also confirmed that it is possible to provide an effective monitoring service by evaluating the connectivity between Peer-to-Peer and average jitter. PMID- 29149046 TI - Impact of a Single Oral Acute Dose of Aflatoxin B1 on Liver Function/Cytokines and the Lymphoproliferative Response in C57Bl/6 Mice. AB - Aflatoxin B1 (AFB1), a mycotoxin found in food and feed, exerts harmful effects on humans and animals. The liver is the earliest target of AFB1, and its effects have been evaluated in animal models exposed to acute or chronic doses. Considering the possibility of sporadic ingestion of AFB1-contaminated food, this study investigated the impact of a single oral dose of AFB1 on liver function/cytokines and the lymphoproliferative response in mice. C57BL/6 mice were treated with a single oral AFB1 dose (44, 442 or 663 MUg AFB1/kg of body weight) on the first day. Liver function (ALT, gamma-GT, and total protein), cytokines (IL-4, IFN-gamma, and IL-17), histopathology, and the spleen lymphoproliferative response to mitogens were evaluated on the 5th day. Although AFB1 did not produce any significant changes in the biochemical parameters, 663 MUg AFB1/kg-induced hepatic upregulation of IL-4 and IFN-gamma, along with liver tissue injury and suppression of the lymphoproliferative response to ConA (p < 0.05). In conclusion, a single oral dose of AFB1 exposure can induce liver tissue lesions, liver cytokine modulation, and immune suppression in C57BL/6 mice. PMID- 29149047 TI - New Insights into Phasmatodea Chromosomes. AB - Currently, approximately 3000 species of stick insects are known; however, chromosome numbers, which range between 21 and 88, are known for only a few of these insects. Also, centromere banding staining (C-banding) patterns were described for fewer than 10 species, and fluorescence in situ hybridization (FISH) was applied exclusively in two Leptynia species. Interestingly, 10-25% of stick insects (Phasmatodea) are obligatory or facultative parthenogenetic. As clonal and/or bisexual reproduction can affect chromosomal evolution, stick insect karyotypes need to be studied more intensely. Chromosome preparation from embryos of five Phasmatodea species (Medauroidea extradentata, Sungaya inexpectata, Sipyloidea sipylus, Phaenopharos khaoyaiensis, and Peruphasma schultei) from four families were studied here by C-banding and FISH applying ribosomal deoxyribonucleic acid (rDNA) and telomeric repeat probes. For three species, data on chromosome numbers and structure were obtained here for the first time, i.e., S. inexpectata, P. khaoyaiensis, and P. schultei. Large C positive regions enriched with rDNA were identified in all five studied, distantly related species. Some of these C-positive blocks were enriched for telomeric repeats, as well. Chromosomal evolution of stick insects is characterized by variations in chromosome numbers as well as transposition and amplification of repetitive DNA sequences. Here, the first steps were made towards identification of individual chromosomes in Phasmatodea. PMID- 29149048 TI - Quit Methods Used by American Smokers, 2013-2014. AB - : This report describes the quit methods used in the past 12 months by current and former smokers in the baseline Population Assessment of Tobacco and Health (PATH) Study during 2013-2014. Descriptive statistics were used to report the use of single and two or more quit methods; survey weights were used to compute population estimates. Logistic regression was used to estimate the association between past year former smokers and single quit method, including individual characteristics. RESULTS: Of 11,402 current smokers and 4919 former smokers, 4541 had tried and 839 had quit in the past 12 months. Unaided quit attempts were the most common; the number was almost as high as all single methods combined (n = 1797 and n = 1831 respectively). The most frequently used single method was help from friends and family (n = 676) followed by e-cigarettes (n = 587). Use of e cigarettes was the only method with higher odds of users being a former smoker than unaided attempts (OR = 1.42, 95% CI 1.12-1.81). Current use of e-cigarettes among current (34%) and former (54%) smokers was significantly higher than current use of nicotine replacement therapy (NRT). CONCLUSIONS: In 2013-2014 e cigarettes were used by American adult smokers as quit-smoking aids more frequently than NRT products or prescription drugs. PMID- 29149049 TI - Preparation of Solution Blown Polyamic Acid Nanofibers and Their Imidization into Polyimide Nanofiber Mats. AB - Solution blow spinning (SBS) is an innovative process for spinning micro/nanofibers. In this paper, polyamic acid (PAA) nanofibers were fabricated via a SBS apparatus and then imidized into polyimide (PI) nanofibers via thermal process. The morphology and diameter distributions of PAA nanofibers were determined by scanning electron microscope (SEM) and Image Tool software, the processing parameters, including PAA concentration, solution feeding rate, gas pressure, nozzle size, and receiving distance were investigated in details. The fourier transform infrared spectroscopy (FTIR) was used to characterize the chemical changes in the nanofibers after thermal imidization. The results showed that the solution concentration exhibited a notable correlation with spinnability, and the formation of bead defects in PAA nanofibers. Solution feeding rate, gas pressure, nozzle size, and receiving distance affected nanofiber production efficiency and diameter distribution. The average diameters of fibers produced ranged from 129.6 to 197.7 nm by varying SBS parameters. Precisely, PAA nanofibers with good morphology were obtained and the average diameter of nanofibers was 178.2 nm with optimum process parameter. After thermal imidization, the PI nanofibers exhibited obvious adhesion morphology among interconnected fibers, with an increased average diameter of 209.1 nm. The tensile strength of resultant PI nanofiber mat was 12.95 MPa. PMID- 29149050 TI - Combining a Disturbance Observer with Triple-Loop Control Based on MEMS Accelerometers for Line-of-Sight Stabilization. AB - In the CCD-based fine tracking optical system (FTOS), the whole disturbance suppression ability (DSA) is the product of the inner loop and outer position loop. Traditionally, high sampling fiber-optic gyroscopes (FOGs) are added to the platform to stabilize the line-of-sight (LOS). However, because of the FOGs' high cost and relatively big volume relative to the back narrow space of small rotating mirrors, we attempt in this work to utilize a cheaper and smaller micro electro-mechanical system (MEMS) accelerometer to build the inner loop, replacing the FOG. Unfortunately, since accelerometers are susceptible to the low-frequency noise, according to the classical way of using accelerometers, the crucial low frequency DSA of the system is insufficient. To solve this problem, in this paper, we propose an approach based on MEMS accelerometers combining disturbance observer (DOB) with triple-loop control (TLC) in which the composite velocity loop is built by acceleration integration and corrected by CCD. The DOB is firstly used to reform the platform, greatly improving the medium-frequency DSA. Then the composite velocity loop exchanges a part of medium-frequency performance for the low-frequency DSA. A detailed analysis and experiments verify the proposed method has a better DSA than the traditional way and could totally substitute FOG in the LOS stabilization. PMID- 29149052 TI - Flanking Variation Influences Rates of Stutter in Simple Repeats. AB - It has been posited that the longest uninterrupted stretch (LUS) of tandem repeats, as defined by the number of exactly matching repeating motif units, is a better predictor of rates of stutter than the parental allele length (PAL). While there are cases where this hypothesis is likely correct, such as the 9.3 allele in the TH01 locus, there can be situations where it may not apply as well. For example, the PAL may capture flanking indel variations while remaining insensitive to polymorphisms in the repeat, and these haplotypic changes may impact the stutter rate. To address this, rates of stutter were contrasted against the LUS as well as the PAL on different flanking haplotypic backgrounds. This study shows that rates of stutter can vary substantially depending on the flanking haplotype, and while there are cases where the LUS is a better predictor of stutter than the PAL, examples to the contrary are apparent in commonly assayed forensic markers. Further, flanking variation that is 7 bp from the repeat region can impact rates of stutter. These findings suggest that non proximal effects, such as DNA secondary structure, may be impacting the rates of stutter in common forensic short tandem repeat markers. PMID- 29149051 TI - Molecular Alliance of Lymantria dispar Multiple Nucleopolyhedrovirus and a Short Unmodified Antisense Oligonucleotide of Its Anti-Apoptotic IAP-3 Gene: A Novel Approach for Gypsy Moth Control. AB - Baculovirus IAP (inhibitor-of-apoptosis) genes originated by capture of host genes. Unmodified short antisense DNA oligonucleotides (oligoDNAs) from baculovirus IAP genes can down-regulate specific gene expression profiles in both baculovirus-free and baculovirus-infected insects. In this study, gypsy moth (Lymantria dispar) larvae infected with multiple nucleopolyhedrovirus (LdMNPV), and LdMNPV-free larvae, were treated with oligoDNA antisense to the RING (really interesting new gene) domain of the LdMNPV IAP-3 gene. The results with respect to insect mortality, biomass accumulation, histological studies, RT-PCR, and analysis of DNA apoptotic fragmentation suggest that oligoRING induced increased apoptotic processes in both LdMNPV-free and LdMNPV-infected insect cells, but were more pronounced in the latter. These data open up possibilities for promising new routes of insect pest control using antisense phosphodiester DNA oligonucleotides. PMID- 29149053 TI - Laser-Induced Breakdown Spectroscopy for Rapid Discrimination of Heavy-Metal Contaminated Seafood Tegillarca granosa. AB - Tegillarca granosa samples contaminated artificially by three kinds of toxic heavy metals including zinc (Zn), cadmium (Cd), and lead (Pb) were attempted to be distinguished using laser-induced breakdown spectroscopy (LIBS) technology and pattern recognition methods in this study. The measured spectra were firstly processed by a wavelet transform algorithm (WTA), then the generated characteristic information was subsequently expressed by an information gain algorithm (IGA). As a result, 30 variables obtained were used as input variables for three classifiers: partial least square discriminant analysis (PLS-DA), support vector machine (SVM), and random forest (RF), among which the RF model exhibited the best performance, with 93.3% discrimination accuracy among those classifiers. Besides, the extracted characteristic information was used to reconstruct the original spectra by inverse WTA, and the corresponding attribution of the reconstructed spectra was then discussed. This work indicates that the healthy shellfish samples of Tegillarca granosa could be distinguished from the toxic heavy-metal-contaminated ones by pattern recognition analysis combined with LIBS technology, which only requires minimal pretreatments. PMID- 29149054 TI - A Dual-Polymer Fiber Fizeau Interferometer for Simultaneous Measurement of Relative Humidity and Temperature. AB - This paper presents a novel design method in which a dual-polymer fiber Fizeau interferometer (DPFFI) is proposed for simultaneously measuring relative humidity (RH) and temperature (T). Since the polymer is intrinsically highly sensitive to both RH and T, the polymer fiber Fizeau interferometer (PFFI) exhibits cross sensitivity of RH and T. In general, it is difficult to demodulate the optical responses from both variations of RH and T using a single PFFI. If two PFFIs with different structures are combined, they will individually exhibit distinct sensitivity responses with respect to RH and T, respectively. The technical problem of analyzing multiple interferences of the optical spectra of the DPFFI and the individual sensitivity of RH and T to each PFFI is obtained using the fast Fourier transform (FFT). A mathematical method is applied to solve the simultaneous equations of the DPFFI, so that the two variables RH and T can be determined at the same time. Experimental results, indicating good sensitivity and accuracy, with small measurement errors (average errors of ~1.46 degrees C and ~1.48%, respectively), are shown, determining the feasibility, and verifying the effectiveness, of the proposed DPFFI sensor. PMID- 29149055 TI - Exploration for the Salinity Tolerance-Related Genes from Xero-Halophyte Atriplex canescens Exploiting Yeast Functional Screening System. AB - Plant productivity is limited by salinity stress, both in natural and agricultural systems. Identification of salt stress-related genes from halophyte can provide insights into mechanisms of salt stress tolerance in plants. Atriplex canescens is a xero-halophyte that exhibits optimum growth in the presence of 400 mM NaCl. A cDNA library derived from highly salt-treated A. canescens plants was constructed based on a yeast expression system. A total of 53 transgenic yeast clones expressing enhanced salt tolerance were selected from 105 transformants. Their plasmids were sequenced and the gene characteristics were annotated using a BLASTX search. Retransformation of yeast cells with the selected plasmids conferred salt tolerance to the resulting transformants. The expression patterns of 28 of these stress-related genes were further investigated in A. canescens leaves by quantitative reverse transcription-PCR. In this study, we provided a rapid and robust assay system for large-scale screening of genes for varied abiotic stress tolerance with high efficiency in A. canescens. PMID- 29149056 TI - Characterization of Ovine A3Z1 Restriction Properties against Small Ruminant Lentiviruses (SRLVs). AB - Intrinsic factors of the innate immune system include the apolipoprotein B editing enzyme catalytic polypeptide-like 3 (APOBEC3) protein family. APOBEC3 inhibits replication of different virus families by cytosine deamination of viral DNA and a not fully characterized cytosine deamination-independent mechanism. Sheep are susceptible to small ruminant lentivirus (SRLVs) infection and contain three APOBEC3 genes encoding four proteins (A3Z1, Z2, Z3 and Z2-Z3) with yet not deeply described antiviral properties. Using sheep blood monocytes and in vitro derived macrophages, we found that A3Z1 expression is associated with lower viral replication in this cellular type. A3Z1 transcripts may also contain spliced variants (A3Z1Tr) lacking the cytidine deaminase motif. A3Z1 exogenous expression in fully permissive fibroblast-like cells restricted SRLVs infection while A3Z1Tr allowed infection. A3Z1Tr was induced after SRLVs infection or stimulation of blood-derived macrophages with interferon gamma (IFN-gamma). Interaction between truncated isoform and native A3Z1 protein was detected as well as incorporation of both proteins into virions. A3Z1 and A3Z1Tr interacted with SRLVs Vif, but this interaction was not associated with degradative properties. Similar A3Z1 truncated isoforms were also present in human and monkey cells suggesting a conserved alternative splicing regulation in primates. A3Z1-mediated retroviral restriction could be constrained by different means, including gene expression and specific alternative splicing regulation, leading to truncated protein isoforms lacking a cytidine-deaminase motif. PMID- 29149057 TI - Effects of Surfactants on the Preparation of Nanocellulose-PLA Composites. AB - Thermoplastic composite materials containing wood fibers are gaining increasing interest in the manufacturing industry. One approach is to use nano- or micro size cellulosic fibrils as additives and to improve the mechanical properties obtainable with only small fibril loadings by exploiting the high aspect ratio and surface area of nanocellulose. In this study, we used four different wood cellulose-based materials in a thermoplastic polylactide (PLA) matrix: cellulose nanofibrils produced from softwood kraft pulp (CNF) and dissolving pulp (CNFSD), enzymatically prepared high-consistency nanocellulose (HefCel) and microcellulose (MC) together with long alkyl chain dispersion-improving agents. We observed increased impact strength with HefCel and MC addition of 5% and increased tensile strength with CNF addition of 3%. The addition of a reactive dispersion agent, epoxy-modified linseed oil, was found to be favorable in combination with HefCel and MC. PMID- 29149059 TI - A High-Performance Portable Transient Electro-Magnetic Sensor for Unexploded Ordnance Detection. AB - Portable transient electromagnetic (TEM) systems can be well adapted to various terrains, including mountainous, woodland, and other complex terrains. They are widely used for the detection of unexploded ordnance (UXO). As the core component of the portable TEM system, the sensor is constructed with a transmitting coil and a receiving coil. Based on the primary field of the transmitting coil and internal noise of the receiving coil, the design and testing of such a sensor is described in detail. Results indicate that the primary field of the transmitting coil depends on the diameter, mass, and power of the coil. A higher mass-power product and a larger diameter causes a stronger primary field. Reducing the number of turns and increasing the clamp voltage reduces the switch-off time of the transmitting current effectively. Increasing the cross-section of the wire reduces the power consumption, but greatly increases the coil's weight. The study of the receiving coil shows that the internal noise of the sensor is dominated by the thermal noise of the damping resistor. Reducing the bandwidth of the system and increasing the size of the coil reduces the internal noise effectively. The cross-sectional area and the distance between the sections of the coil have little effect on the internal noise. A less damped state can effectively reduce signal distortion. Finally, a portable TEM sensor with both a transmitting coil (constructed with a diameter, number of turns, and transmitting current of 0.5 m, 30, and 5 A, respectively) and a receiving coil (constructed with a length and resonant frequency of 5.6 cm and 50 kHz, respectively) was built. The agreement between experimental and calculated results confirms the theory used in the sensor design. The responses of an 82 mm mortar shell at different distances were measured and inverted by the differential evolution (DE) algorithm to verify system performance. Results show that the sensor designed in this study can not only detect the 82 mm mortar shell within 1.2 m effectively but also locate the target precisely. PMID- 29149061 TI - Mechanical, Corrosion and Biological Properties of Room-Temperature Sputtered Aluminum Nitride Films with Dissimilar Nanostructure. AB - Aluminum Nitride (AlN) has been long time being regarded as highly interesting material for developing sensing applications (including biosensors and implantable sensors). AlN, due to its appealing electronic properties, is envisaged lately to serve as a multi-functional biosensing platform. Although generally exploited for its intrinsic piezoelectricity, its surface morphology and mechanical performance (elastic modulus, hardness, wear, scratch and tensile resistance to delamination, adherence to the substrate), corrosion resistance and cytocompatibility are also essential features for high performance sustainable biosensor devices. However, information about AlN suitability for such applications is rather scarce or at best scattered and incomplete. Here, we aim to deliver a comprehensive evaluation of the morpho-structural, compositional, mechanical, electrochemical and biological properties of reactive radio-frequency magnetron sputtered AlN nanostructured thin films with various degrees of c-axis texturing, deposited at a low temperature (~50 degrees C) on Si (100) substrates. The inter-conditionality elicited between the base pressure level attained in the reactor chamber and crystalline quality of AlN films is highlighted. The potential suitability of nanostructured AlN (in form of thin films) for the realization of various type of sensors (with emphasis on bio sensors) is thoroughly probed, thus unveiling its advantages and limitations, as well as suggesting paths to safely exploit the remarkable prospects of this type of materials. PMID- 29149060 TI - Epigenetic Regulation of Viral Biological Processes. AB - It is increasingly clear that DNA viruses exploit cellular epigenetic processes to control their life cycles during infection. This review will address epigenetic regulation in members of the polyomaviruses, adenoviruses, human papillomaviruses, hepatitis B, and herpes viruses. For each type of virus, what is known about the roles of DNA methylation, histone modifications, nucleosome positioning, and regulatory RNA in epigenetic regulation of the virus infection will be discussed. The mechanisms used by certain viruses to dysregulate the host cell through manipulation of epigenetic processes and the role of cellular cofactors such as BRD4 that are known to be involved in epigenetic regulation of host cell pathways will also be covered. Specifically, this review will focus on the role of epigenetic regulation in maintaining viral episomes through the generation of chromatin, temporally controlling transcription from viral genes during the course of an infection, regulating latency and the switch to a lytic infection, and global dysregulation of cellular function. PMID- 29149058 TI - Neurotrophic and Neuroregenerative Effects of GH/IGF1. AB - INTRODUCTION: Human neurodegenerative diseases increase progressively with age and present a high social and economic burden. Growth hormone (GH) and insulin like growth factor-1 (IGF-1) are both growth factors exerting trophic effects on neuronal regeneration in the central nervous system (CNS) and peripheral nervous system (PNS). GH and IGF-1 stimulate protein synthesis in neurons, glia, oligodendrocytes, and Schwann cells, and favor neuronal survival, inhibiting apoptosis. This study aims to evaluate the effect of GH and IGF-1 on neurons, and their possible therapeutic clinical applications on neuron regeneration in human subjects. METHODS: In the literature, we searched the clinical trials and followed up studies in humans, which have evaluated the effect of GH/IGF-1 on CNS and PNS. The following keywords have been used: "GH/IGF-1" associated with "neuroregeneration", "amyotrophic lateral sclerosis", "Alzheimer disease", "Parkinson's disease", "brain", and "neuron". RESULTS: Of the retrieved articles, we found nine articles about the effect of GH in healthy patients who suffered from traumatic brain injury (TBI), and six studies (four using IGF-1 and two GH therapy) in patients with amyotrophic lateral sclerosis (ALS). The administration of GH in patients after TBI showed a significantly positive recovery of brain and mental function. Treatment with GH and IGF-1 therapy in ALS produced contradictory results. CONCLUSIONS: Although strong findings have shown the positive effects of GH/IGF-1 administration on neuroregeneration in animal models, a very limited number of clinical studies have been conducted in humans. GH/IGF-1 therapy had different effects in patients with TBI, evidencing a high recovery of neurons and clinical outcome, while in ALS patients, the results are contradictory. More complex clinical protocols are necessary to evaluate the effect of GH/IGF-1 efficacy in neurodegenerative diseases. It seems evident that GH and IGF-1 therapy favors the optimal recovery of neurons when a consistent residual activity is still present. Furthermore, the effect of GH/IGF-1 could be mediated by, or be overlapped with that of other hormones, such as estradiol and testosterone. PMID- 29149062 TI - Polyphenolics from Albizia harveyi Exhibit Antioxidant Activities and Counteract Oxidative Damage and Ultra-Structural Changes of Cryopreserved Bull Semen. AB - Albizia harveyi is a tropical deciduous tree, found across South and Eastern Africa and widely used in traditional medicine. The leaf extract ameliorated the damaging effects of the frozen-thawing process in cryopreserved bull semen. In a dose-dependent pattern, sperm motility, viability, and membrane integrity were improved compared to the untreated control. Furthermore, the extract increased the percentage of viable sperm cells and reduced the percentages of early apoptotic and apoptotic sperm cells as well as the damage in sperm ultra structure. These activities are in agreement with the robust antioxidant properties in vitro and in the seminal fluid as observed in the total antioxidant capacity and the lipid peroxidation parameter malondialdehyde. LC-MS yielded 35 compounds. The extract was dominated by quercetin-O-galloyl-hexoside and quercetin-O-pentoside, along with other flavonoid glycosides. The polyphenols are probably responsible for the observed activities. In conclusion, the current findings show that A. harveyi leaves are rich in bioactive polyphenols with functional properties, validating its traditional use. PMID- 29149063 TI - Estimating Stair Running Performance Using Inertial Sensors. AB - Stair running, both ascending and descending, is a challenging aerobic exercise that many athletes, recreational runners, and soldiers perform during training. Studying biomechanics of stair running over multiple steps has been limited by the practical challenges presented while using optical-based motion tracking systems. We propose using foot-mounted inertial measurement units (IMUs) as a solution as they enable unrestricted motion capture in any environment and without need for external references. In particular, this paper presents methods for estimating foot velocity and trajectory during stair running using foot mounted IMUs. Computational methods leverage the stationary periods occurring during the stance phase and known stair geometry to estimate foot orientation and trajectory, ultimately used to calculate stride metrics. These calculations, applied to human participant stair running data, reveal performance trends through timing, trajectory, energy, and force stride metrics. We present the results of our analysis of experimental data collected on eleven subjects. Overall, we determine that for either ascending or descending, the stance time is the strongest predictor of speed as shown by its high correlation with stride time. PMID- 29149064 TI - Who Participates in the Great ShakeOut? Why Audience Segmentation Is the Future of Disaster Preparedness Campaigns. AB - Background: In 2008, the Southern California Earthquake Center in collaboration with the U.S. Geological Survey Earthquake Hazards Program launched the first annual Great ShakeOut, the largest earthquake preparedness drill in the history of the United States. Materials and Methods: We collected online survey data from 2052 campaign registrants to assess how people participated, whether audience segments shared behavioral patterns, and whether these segments were associated with five social cognitive factors targeted by the ShakeOut campaign. Results: Participants clustered into four behavioral patterns. The Minimal cluster had low participation in all activities (range: 0-39% participation). The Basic Drill cluster only participated in the drop, cover and hold drill (100% participation). The Community-Oriented cluster, involved in the drill (100%) and other interpersonal activities including attending disaster planning meetings (74%), was positively associated with interpersonal communication (beta = 0.169), self efficacy (beta = 0.118), outcome efficacy (beta = 0.110), and knowledge about disaster preparedness (beta = 0.151). The Interactive and Games cluster, which participated in the drill (79%) and two online earthquake preparedness games (53% and 75%), was positively associated with all five social cognitive factors studied. Conclusions: Our results support audience segmentation approaches to engaging the public, which address the strengths and weaknesses of different segments. Offering games may help "gamers" gain competencies required to prepare for disasters. Targeting the highly active Community-Oriented cluster for leadership roles could help build community resilience by encouraging others to become more involved in disaster planning. We propose that the days of single, national education campaigns without local variation should end. PMID- 29149065 TI - Calcined Chitosan-Supported Layered Double Hydroxides: An Efficient and Recyclable Adsorbent for the Removal of Fluoride from an Aqueous Solution. AB - In this work, calcined chitosan-supported layered double hydroxides (CSLDO) were synthesized through a co-precipitation method that restrained the particles' aggregation of LDHs and exhibited huge specific surface areas, which can enhance the fluoride adsorption capacity. CSLDOs were characterized by physical and chemical methods and used for fluoride adsorption in an aqueous solution. The results indicated that the nanoparticles were constructed first and then assembled to form a porous and layered structure, and chitosan-supported layered double hydroxides (CSLDHs) calcined at 400 degrees C (CSLDO400) showed the highest specific surface area of 116.98 m2.g-1 and the largest pore volume of 0.411 cm3.g-1. CSLDO400 exhibited excellent adsorption performance at a wide pH range from 5 to 9 for fluoride. The adsorption kinetics indicated that the adsorption reached equilibrium after 120 min, and followed a pseudo-first-order model. It agreed well with the Langmuir isotherm with maximum adsorption amounts of 27.56 mg.g-1. The adsorption of fluoride ions was spontaneous and endothermic. Furthermore, CSLDO400 showed a high stability for fluoride removal; it could still achieve 68% removal for fluoride after repeating five times of adsorption desorption cycles. This study demonstrated that CSLDO400 is a promising functional material to remove fluoride from surface/ground water. PMID- 29149066 TI - Nanostructured MnO2 as Electrode Materials for Energy Storage. AB - Manganese dioxides, inorganic materials which have been used in industry for more than a century, now find great renewal of interest for storage and conversion of energy applications. In this review article, we report the properties of MnO2 nanomaterials with different morphologies. Techniques used for the synthesis, structural, physical properties, and electrochemical performances of periodic and aperiodic frameworks are discussed. The effect of the morphology of nanosized MnO2 particles on their fundamental features is evidenced. Applications as electrodes in lithium batteries and supercapacitors are examined. PMID- 29149068 TI - A New UPLC-MS/MS Method for the Characterization and Discrimination of Polysaccharides from Genus Ephedra Based on Enzymatic Digestions. AB - Ephedra sinica polysaccharides have been reported to possess important activities, so quality evaluation of polysaccharides from the genus Ephedra is urgent. In this study, enzymatic digestions were performed to establish multiple saccharide fingerprints by ultra-performance liquid chromatography with electrospray ionization triple quadrupole linear ion trap mass spectrometry (UPLC ESI-TQ-MS/MS) based on a multiple-reaction monitoring in negative mode. Under optimum UPLC-ESI--TQ-MS/MS conditions, excellent separation and quantification of 21 constituents were achieved within 20 min on a solid core column with a 1.6 MUm particle using pre-column derivatization with a PMP reagent. This method, coupled with enzymatic digestions and principal component analysis, has been successfully applied to characterize and discriminate Ephedra polysaccharides attributed to different species and plant parts. The results suggest that the proposed analytical strategy could achieve a quality evaluation of plant polysaccharides from traditional Chinese medicines. PMID- 29149069 TI - Temperature Uncertainty Analysis of Injection Mechanism Based on Kriging Modeling. AB - A kriging modeling method is proposed to conduct the temperature uncertainty analysis of an injection mechanism in squeeze casting. A mathematical model of temperature prediction with multi input and single output is employed to estimate the temperature spatiotemporal distributions of the injection mechanism. The kriging model applies different weights to the independent variables according to spatial location of sample points and their correlation, thus reducing the estimation variance. The predicted value of the kriging model is compared with the sample data at the corresponding position to investigate the influence of the temperature uncertainty of the injection mechanism on the injection process including friction. The results indicate that the significant error is observed at a few sample points in the early injection due to the impact of the uncertainty facts. The variance mean and standard deviation obtained by the model calibrated by experimental samples reduce largely in comparison to those obtained from the initial kriging model. This study indicates that model calibration produces more accurate prediction. PMID- 29149067 TI - The HMGB1/RAGE Pro-Inflammatory Axis in the Human Placenta: Modulating Effect of Low Molecular Weight Heparin. AB - We evaluated whether physiological and pre-eclamptic (PE) placentae, characterized by exacerbated inflammation, presented alterations in pro inflammatory High Mobility Group Box 1 (HMGB1) and its Receptor of Advanced Glycation End products (RAGE) expression. Moreover, we investigated, in physiological placental tissue, the ability of Low Molecular Weight Heparin (LMWH) to modify HMGB1 structural conformation thus inhibiting RAGE binding and HMGB1/RAGE axis inflammatory activity. HMGB1, RAGE, IL-6 and TNFalpha (HMGB1/RAGE targets) mRNA expression were assessed by Real Time PCR. HMGB1, RAGE protein levels were assessed by western blot assay. Physiological term placental explants were treated by 0.5 U LMWH for 24 or 48 h. HMGB1 and RAGE expression and association were evaluated in LMWH explants by RAGE immunoprecipitation followed by HMGB1 immunoblot. HMGB1 spatial localization was evaluated by immuofluorescent staining (IF). HMGB1 expression was increased in PE relative to physiological placentae while RAGE was unvaried. 24 h LMWH treatment significantly up-regulated HMGB1 expression but inhibited HMGB1/RAGE complex formation in physiological explants. RAGE expression decreased in treated relative to untreated explants at 48 h. IF showed HMGB1 localization in both cytoplasm and nucleus of mesenchymal and endothelial cells but not in the trophoblast. IL-6 and TNFalpha gene expression were significantly increased at 24 h relative to controls, while they were significantly down-regulated in 48 h vs. 24 h LMWH explants. Our data depicted a new molecular mechanism through which LMWH exerts its anti inflammatory effect on PE placentae, underlying the importance of HMGB1/RAGE axis in PE inflammatory response. PMID- 29149070 TI - Placement Stability, Cumulative Time in Care, and Permanency: Using Administrative Data from CPS to Track Placement Trajectories. AB - Objectives: The Quebec Youth Protection Act was amended in 2007. The main goal of this reform was to improve placement stability for children who are removed from their home for their protection. Among several legal provisions introduced was the establishment of maximum age-specific durations of out-of-home care, after which a plan must be established to provide stability for children placed in substitute care by finding permanent homes for them. The purpose of this study is (1) to examine trends in placement use and placement stability since the reform and (2) to document the current frequency of each type of placement setting, the cumulative time in care before the exit to permanency, and the sustainability of the permanency outcome. Methods: The study relies on 3 entry cohorts of all children investigated who received protection measures in the province of Quebec during 3 specific time frames before and after the reform (n = 9620, 8676, 8425). Cohorts were observed for a period varying from 3 to 4 years. Administrative data from all 16 child protection agencies were used to track placement trajectory indicators and to compare cohorts. Results: There has been a decrease in the proportion of children receiving protection measures who were placed in care since the reform, and placement in kinship care has become more frequent among children placed. Placement stability improved slightly after the reform. Overall, for infants, the most frequent type of permanency attained is adoption, while reunification is the option most often indicated for older children. Some children are at a greater risk of experiencing unstable placement trajectories: young children have a high rate of reunification breakdown, some wait a long time to be adopted, and adolescents are frequently removed from the substitute care setting where they were supposed to stay until the age of 18. Conclusions: The results suggest interesting avenues for policy makers and service providers to improve the stability of placement trajectories. Advantages and disadvantages of administrative data are discussed. PMID- 29149071 TI - Sleep and Dietary Patterns in Pregnancy: Findings from the GUSTO Cohort. AB - Evidence on the association between sleep, diet, and eating behaviors in pregnant women is lacking. We examine this in a cohort of apparently healthy pregnant women. At 26-28 weeks gestation, 497 participants completed the Pittsburgh Sleep Quality Index to assess sleep and a 24-h recall to assess dietary intake. Diet quality was assessed by the Healthy Eating Index for pregnant women in Singapore (HEI-SGP) score and previously derived dietary patterns (vegetables-fruit-rice, seafood-noodles, and pasta-cheese-meat pattern). Eating behaviors studied included the longest night-time fasting interval, frequency of consumption occasions, energy from discretionary foods, and nighttime eating. Adjusted means were estimated between poor/good quality and short/normal sleepers using linear regressions, including covariates. Good sleep quality versus poor sleep quality, was associated with better diet quality (mean HEI-SGP 54.6 vs. 52.0; p = 0.032), greater adherence to the vegetables-fruit-rice pattern (mean 0.03 vs. -0.15; p = 0.039), lesser adherence to the seafood-noodle pattern (mean -0.14 vs. 0.03; p = 0.024), and a trending lower calories from discretionary foods (mean 330.5 vs. 382.6 kcal; p = 0.073), after adjusting for covariates. After additional adjustment for anxiety, only sleep quality and the seafood-noodle pattern remained significantly associated (p = 0.018). Short sleep was not associated with any diet or eating behavior. In conclusion, good sleep quality is associated with a better diet quality and a greater adherence to the vegetable-fruit-rice pattern, but with lesser adherence to the seafood-noodle diets in pregnant women. PMID- 29149072 TI - Different Inhibitory Potencies of Oseltamivir Carboxylate, Zanamivir, and Several Tannins on Bacterial and Viral Neuraminidases as Assessed in a Cell-Free Fluorescence-Based Enzyme Inhibition Assay. AB - Neuraminidaseis a key enzyme in the life cycle of influenza viruses and is present in some bacterial pathogens. We here assess the inhibitory potency of plant tannins versus clinically used inhibitors on both a viral and a bacterial model neuraminidase by applying the 2'-(4-methylumbelliferyl)-alpha-d-N acetylneuraminic acid (MUNANA)-based activity assay. A range of flavan-3-ols, ellagitannins and chemically defined proanthocyanidin fractions was evaluated in comparison to oseltamivir carboxylate and zanamivir for their inhibitory activities against viral influenza A (H1N1) and bacterial Vibrio cholerae neuraminidase (VCNA). Compared to the positive controls, all tested polyphenols displayed a weak inhibition of the viral enzyme but similar or even higher potency on the bacterial neuraminidase. Structure-activity relationship analyses revealed the presence of galloyl groups and the hydroxylation pattern of the flavan skeleton to be crucial for inhibitory activity. The combination of zanamivir and EPs(r) 7630 (root extract of Pelargonium sidoides) showed synergistic inhibitory effects on the bacterial neuraminidase. Co-crystal structures of VCNA with oseltamivir carboxylate and zanamivir provided insight into bacterial versus viral enzyme-inhibitor interactions. The current data clearly indicate that inhibitor potency strongly depends on the biological origin of the enzyme and that results are not readily transferable. The therapeutic relevance of our findings is briefly discussed. PMID- 29149073 TI - Micronutrient Deficiencies among Breastfeeding Infants in Tanzania. AB - Infant mortality accounts for the majority of child deaths in Tanzania, and malnutrition is an important underlying cause. The objectives of this cross sectional study were to describe the micronutrient status of infants in Tanzania and assess predictors of infant micronutrient deficiency. We analyzed serum vitamin D, vitamin B12, folate, and ferritin levels from 446 infants at two weeks of age, 408 infants at three months of age, and 427 mothers three months post partum. We used log-Poisson regression to estimate relative risk of being deficient in vitamin D and vitamin B12 for infants in each age group. The prevalence of vitamin D and vitamin B12 deficiency decreased from 60% and 30% at two weeks to 9% and 13% at three months respectively. Yet, the prevalence of insufficiency at three months was 49% for vitamin D and 17% for vitamin B12. Predictors of infant vitamin D deficiency were low birthweight, urban residence, maternal education, and maternal vitamin D status. Maternal vitamin B12 status was the main predictor for infant vitamin B12 deficiency. The majority of infants had sufficient levels of folate or ferritin. Further research is necessary to examine the potential benefits of improving infants' nutritional status through vitamin D and B12 supplements. PMID- 29149074 TI - Central [CNS] and Peripheral [Gastric Tissue] Selective Monitoring of Somatostatin (SRIF) with Micro-Sensor and Voltammetry in Rats: Influence of Growth Factors (GH, EGF). AB - Somatostatin (SRIF) is widely distributed throughout the body, and regulates the endocrine system via interactions with various hormones, including the pituitary growth hormone, the thyroid stimulating hormone and the majority of the hormones of the gastrointestinal tract. SRIF is present in the central nervous system (CNS), where it affects rates of neurotransmission, and is also reported to be active in the intestinal tract, with evidence that stressed rats present a significant decrease in antral somatostatin-like immunoreactivity (SLI). Analysis of SRIF has mainly been carried out by means of radioimmunoassay methods. Here, we propose the use of an electrochemical method, such as voltammetry, applied with carbon-based sensors and, in particular, the combination of differential pulse voltammetry with treated carbon fiber micro electrodes (DPV-uCFE) to facilitate the analysis of such peptidergic electro active hormones in the rat striatum and gastric tissue; the effect of growth hormone (GH) and epidermal growth factor (EGF), in particular, upon the SRIF signal has been studied in such tissues. PMID- 29149075 TI - A Game Theoretic Approach for Balancing Energy Consumption in Clustered Wireless Sensor Networks. AB - Clustering is an effective topology control method in wireless sensor networks (WSNs), since it can enhance the network lifetime and scalability. To prolong the network lifetime in clustered WSNs, an efficient cluster head (CH) optimization policy is essential to distribute the energy among sensor nodes. Recently, game theory has been introduced to model clustering. Each sensor node is considered as a rational and selfish player which will play a clustering game with an equilibrium strategy. Then it decides whether to act as the CH according to this strategy for a tradeoff between providing required services and energy conservation. However, how to get the equilibrium strategy while maximizing the payoff of sensor nodes has rarely been addressed to date. In this paper, we present a game theoretic approach for balancing energy consumption in clustered WSNs. With our novel payoff function, realistic sensor behaviors can be captured well. The energy heterogeneity of nodes is considered by incorporating a penalty mechanism in the payoff function, so the nodes with more energy will compete for CHs more actively. We have obtained the Nash equilibrium (NE) strategy of the clustering game through convex optimization. Specifically, each sensor node can achieve its own maximal payoff when it makes the decision according to this strategy. Through plenty of simulations, our proposed game theoretic clustering is proved to have a good energy balancing performance and consequently the network lifetime is greatly enhanced. PMID- 29149076 TI - The Association between Food Addiction and Early Maladaptive Schemas in Overweight and Obese Women: A Preliminary Investigation. AB - In recent years, there has been a growing focus on early maladaptive schemas (EMSs) as core features associated with eating psychopathology. The aims of the present study were to assess in overweight and obese women: (i) the association between dysfunctional eating patterns (i.e., food addiction and binge eating) and EMSs, and (ii) the association between food addiction and EMSs after controlling for potential confounding variables (i.e., binge eating severity and psychopathology). Participants were 70 overweight and obese women seeking low energy-diet therapy. The patients were administered self-report measures investigating food addiction, binge eating, EMSs, anxiety symptoms, and depressive symptoms. Food addiction severity was strongly associated with all main schema domains. Binge eating severity was positively related to disconnection/rejection (r = 0.41; p < 0.01), impaired limits (r = 0.26; p < 0.05), and other-directedness domains (r = 0.27; p < 0.05). The disconnection/rejection schema was independently associated with food addiction severity, after controlling for the presence of other potential confounding variables (i.e., binge eating severity and psychopathology) suggesting that this domain may be a crucial factor for the development of food addiction. PMID- 29149077 TI - RNA Virus Evolution via a Quasispecies-Based Model Reveals a Drug Target with a High Barrier to Resistance. AB - The rapid occurrence of therapy-resistant mutant strains provides a challenge for anti-viral therapy. An ideal drug target would be a highly conserved molecular feature in the viral life cycle, such as the packaging signals in the genomes of RNA viruses that encode an instruction manual for their efficient assembly. The ubiquity of this assembly code in RNA viruses, including major human pathogens, suggests that it confers selective advantages. However, their impact on viral evolution cannot be assessed in current models of viral infection that lack molecular details of virus assembly. We introduce here a quasispecies-based model of a viral infection that incorporates structural and mechanistic knowledge of packaging signal function in assembly to construct a phenotype-fitness map, capturing the impact of this RNA code on assembly yield and efficiency. Details of viral replication and assembly inside an infected host cell are coupled with a population model of a viral infection, allowing the occurrence of therapy resistance to be assessed in response to drugs inhibiting packaging signal recognition. Stochastic simulations of viral quasispecies evolution in chronic HCV infection under drug action and/or immune clearance reveal that drugs targeting all RNA signals in the assembly code collectively have a high barrier to drug resistance, even though each packaging signal in isolation has a lower barrier than conventional drugs. This suggests that drugs targeting the RNA signals in the assembly code could be promising routes for exploitation in anti viral drug design. PMID- 29149078 TI - Comfort, Energy Efficiency and Adoption of Personal Cooling Systems in Warm Environments: A Field Experimental Study. AB - It is well known that personal cooling improves thermal comfort and save energy. This study aims to: (1) compare different personal cooling systems and (2) understand what influences users' willingness to adopt them. A series of experiments on several types of personal cooling systems, which included physical measurements, questionnaires and feedback, was conducted in a real office environment. The obtained results showed that personal cooling improved comfort of participants in warm environments. Then an improved index was proposed and used to compare different types of personal cooling systems in terms of comfort and energy efficiency simultaneously. According to the improved index, desk fans were highly energy-efficient, while the hybrid personal cooling (the combination of radiant cooling desk and desk fan) consumed more energy but showed advantages of extending the comfortable temperature range. Moreover, if personal cooling was free, most participants were willing to adopt it and the effectiveness was the main factor influencing their willingness, whereas if participants had to pay, they probably refused to adopt it due to the cost and the availability of conventional air conditioners. Thus, providing effective and free personal cooling systems should be regarded as a better way for its wider application. PMID- 29149080 TI - Novel Tactile Sensor Technology and Smart Tactile Sensing Systems: A Review. AB - During the last decades, smart tactile sensing systems based on different sensing techniques have been developed due to their high potential in industry and biomedical engineering. However, smart tactile sensing technologies and systems are still in their infancy, as many technological and system issues remain unresolved and require strong interdisciplinary efforts to address them. This paper provides an overview of smart tactile sensing systems, with a focus on signal processing technologies used to interpret the measured information from tactile sensors and/or sensors for other sensory modalities. The tactile sensing transduction and principles, fabrication and structures are also discussed with their merits and demerits. Finally, the challenges that tactile sensing technology needs to overcome are highlighted. PMID- 29149079 TI - Sphingosine 1-phosphate (S1P) signaling in glioblastoma multiforme-A systematic review. AB - The multifunctional sphingosine-1-phosphate (S1P) is a lipid signaling molecule and central regulator in the development of several cancer types. In recent years, intriguing information has become available regarding the role of S1P in the progression of Glioblastoma multiforme (GBM), the most aggressive and common brain tumor in adults. S1P modulates numerous cellular processes in GBM, such as oncogenesis, proliferation and survival, invasion, migration, metastasis and stem cell behavior. These processes are regulated via a family of five G-protein coupled S1P receptors (S1PR1-5) and may involve mainly unknown intracellular targets. Distinct expression patterns and multiple intracellular signaling pathways of each S1PR subtype enable S1P to exert its pleiotropic cellular actions. Several studies have demonstrated alterations in S1P levels, the involvement of S1PRs and S1P metabolizing enzymes in GBM pathophysiology. While the tumorigenic actions of S1P involve the activation of several kinases and transcription factors, the specific G-protein (Gi, Gq, and G12/13)-coupled signaling pathways and downstream mediated effects in GBM remain to be elucidated in detail. This review summarizes the recent findings concerning the role of S1P and its receptors in GBM. We further highlight the current insights into the signaling pathways considered fundamental for regulating the cellular processes in GMB and ultimately patient prognosis. PMID- 29149081 TI - 19F-NMR Diastereotopic Signals in Two N-CHF2 Derivatives of (4S,7R)-7,8,8 Trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole. AB - In this paper, we report the anisochrony of the fluorine atoms of a CHF2 group when linked to a pyrazole ring. The pyrazole is part of (4S,7R)-7,8,8-trimethyl 4,5,6,7-tetrahydro-4,7-methano-2H-indazole also known as (4S,7R)-campho[2,3 c]pyrazole, which has two stereogenic centers. Gauge-Independent Atomic Orbital (GIAO)/Becke, 3-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,f) calculated 19F chemical shifts of the minimum energy conformations satisfactorily agree with the experimental data. The energy differences between minima need to consider solvent effects (continuum model) to be satisfactorily reproduced. PMID- 29149082 TI - The Biological Properties of OGI Surfaces Positively Act on Osteogenic and Angiogenic Commitment of Mesenchymal Stem Cells. AB - Osteogenesis process displays a fundamental role during dental implant osteointegration. In the present work, we studied the influence of Osteon Growth Induction (OGI) surface properties on the angiogenic and osteogenic behaviors of Mesenchymal Stem cells (MSC). MSC derived from dental pulp and HUVEC (Human Umbilical Vein Endothelial Cells) were grown in on OGI titanium surfaces, and cell proliferation and DNA synthesis were evaluated by MTT [3-(4,5 dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide] test and DNA quantification. Gene expression has been performed in order to evaluate the presence of mRNA related to endothelial and osteogenesis markers. Moreover, morphological and biochemical analyses of osteogenesis commitments has been performed. On OGI surfaces, MSC and HUVEC are able to proliferate. Gene expression profiler confirms that MSC on OGI surfaces are able to express endothelial and osteogenic markers, and that these expression are higher compared the expression on control surfaces. In conclusion On OGI surfaces proliferation, expression and morphological analyses of angiogenesis-associated markers in MSC are promoted. This process induces an increasing on their osteogenesis commitment. PMID- 29149083 TI - Co-precipitation Synthesis and Optical Properties of Mn4+-doped Hexafluoroaluminate w-LED Phosphors. AB - Mn4+-activated hexafluoroaluminates are promising red-emitting phosphors for white light emitting diodes (w-LEDs). Here, we report the synthesis of Na3AlF6:Mn4+, K3AlF6:Mn4+ and K2NaAlF6:Mn4+ phosphors through a simple two-step co-precipitation method. Highly monodisperse large (~20 MUm) smoothed-octahedron shaped crystallites are obtained for K2NaAlF6:Mn4+. The large size, regular shape and small size distribution are favorable for application in w-LEDs. All Mn4+ doped hexafluoroaluminates show bright red Mn4+ luminescence under blue light excitation. We compare the optical properties of Na3AlF6:Mn4+, K3AlF6:Mn4+ and K2NaAlF6:Mn4+ at room temperature and 4 K. The luminescence measurements reveal that multiple Mn4+ sites exist in M3AlF6:Mn4+ (M = Na, K), which is explained by the charge compensation that is required for Mn4+ on Al3+ sites. Thermal cycling experiments show that the site distribution changes after annealing. Finally, we investigate thermal quenching and show that the luminescence quenching temperature is high, around 460-490 K, which makes these Mn4+-doped hexafluoroaluminates interesting red phosphors for w-LEDs. The new insights reported on the synthesis and optical properties of Mn4+ in the chemically and thermally stable hexafluoroaluminates can contribute to the optimization of red emitting Mn4+ phosphors for w-LEDs. PMID- 29149085 TI - The Design and Characterization of a Prototype Wideband Voltage Sensor Based on a Resistive Divider. AB - The most important advantage of voltage dividers over traditional voltage transformers is that voltage dividers do not have an iron core with non-linear hysteresis characteristics. The voltage dividers have a linear behavior with respect to over-voltages and a flat frequency response larger frequency range. The weak point of a voltage divider is the influence of external high-voltage (HV) and earth parts in its vicinity. Electrical fields arising from high voltages in neighboring phases and from ground conductors and structures are one of their main sources for systematic measurement errors. This paper describes a shielding voltage divider for a 24 kV medium voltage network insulated in SF6 composed of two resistive-capacitive dividers, one integrated within the other, achieving a flat frequency response up to 10 kHz for ratio error and up to 5 kHz for phase displacement error. The metal shielding improves its immunity against electric and magnetic fields. The characterization performed on the built-in voltage sensor shows an accuracy class of 0.2 for a frequency range from 20 Hz to 5 kHz and a class of 0.5 for 1 Hz up to 20 Hz. A low temperature effect is also achieved for operation conditions of MV power grids. PMID- 29149084 TI - Preparative Separation and Purification of Four Glycosides from Gentianae radix by High-Speed Counter-Current Chromatography and Comparison of Their Anti-NO Production Effects. AB - Secoiridoid and iridoid glycosides are the main active components of Gentianaeradix. In this work, one iridoid and three secoiridoid glycosides from Gentianaeradix have been purified by high-speed counter-current chromatography in two runs using different solvent systems. Ethyl acetate-n-butanol-water (2:1:3, v/v/v) was the optimum solvent system to purify ca. 4.36 mg of loganic acid, 3.05 mg of swertiamarin, and 35.66 mg of gentiopicroside with 98.1%, 97.2% and 98.6% purities, respectively, while 31.15 mg of trifloroside with 98.9% purity was separated using hexane-ethyl acetate-methanol-water (1:3:1:3, v/v/v/v). The structures of the glycosides were identified by mass spectrometry and NMR. After separation, the anti-nitric oxide production effects of the compounds on lipopolysaccharide-induced BV-2 murine microglial cells were also evaluated. All of the compounds inhibited the production of nitric oxide in lipopolysaccharide induced BV-2 cells with high cell viabilities in a concentration-dependent manner, which demonstrated that were able to be used as a nitric oxide inhibitor. PMID- 29149086 TI - Physiological Peculiarities of Lignin-Modifying Enzyme Production by the White Rot Basidiomycete Coriolopsis gallica Strain BCC 142. AB - Sixteen white-rot Basidiomycota isolates were screened for production of lignin modifying enzymes (LME) in glycerol- and mandarin peel-containing media. In the synthetic medium, Cerrena unicolor strains were the only high laccase (Lac) (3.2 9.4 U/mL) and manganese peroxidase (MnP) (0.56-1.64 U/mL) producers while one isolate Coriolopsis gallica was the only lignin peroxidase (LiP) (0.07 U/mL) producer. Addition of mandarin peels to the synthetic medium promoted Lac production either due to an increase in fungal biomass (Funalia trogii, Trametes hirsuta, and T. versicolor) or enhancement of enzyme production (C. unicolor, Merulius tremellosus, Phlebia radiata, Trametes ochracea). Mandarin peels favored enhanced MnP and LiP secretion by the majority of the tested fungi. The ability of LiP activity production by C. gallica, C. unicolor, F. trogii, T. ochracea, and T. zonatus in the medium containing mandarin-peels was reported for the first time. Several factors, such as supplementation of the nutrient medium with a variety of lignocellulosic materials, nitrogen source or surfactant (Tween 80, Triton X-100) significantly influenced production of LME by a novel strain of C. gallica. Moreover, C. gallica was found to be a promising LME producer with a potential for an easy scale up cultivation in a bioreactor and high enzyme yields (Lac-9.4 U/mL, MnP-0.31 U/mL, LiP-0.45 U/mL). PMID- 29149087 TI - Taxonomic Classification for Living Organisms Using Convolutional Neural Networks. AB - Taxonomic classification has a wide-range of applications such as finding out more about evolutionary history. Compared to the estimated number of organisms that nature harbors, humanity does not have a thorough comprehension of to which specific classes they belong. The classification of living organisms can be done in many machine learning techniques. However, in this study, this is performed using convolutional neural networks. Moreover, a DNA encoding technique is incorporated in the algorithm to increase performance and avoid misclassifications. The algorithm proposed outperformed the state of the art algorithms in terms of accuracy and sensitivity, which illustrates a high potential for using it in many other applications in genome analysis. PMID- 29149088 TI - Model-Based Heterogeneous Data Fusion for Reliable Force Estimation in Dynamic Structures under Uncertainties. AB - Direct measurements of external forces acting on a structure are infeasible in many cases. The Augmented Kalman Filter (AKF) has several attractive features that can be utilized to solve the inverse problem of identifying applied forces, as it requires the dynamic model and the measured responses of structure at only a few locations. But, the AKF intrinsically suffers from numerical instabilities when accelerations, which are the most common response measurements in structural dynamics, are the only measured responses. Although displacement measurements can be used to overcome the instability issue, the absolute displacement measurements are challenging and expensive for full-scale dynamic structures. In this paper, a reliable model-based data fusion approach to reconstruct dynamic forces applied to structures using heterogeneous structural measurements (i.e., strains and accelerations) in combination with AKF is investigated. The way of incorporating multi-sensor measurements in the AKF is formulated. Then the formulation is implemented and validated through numerical examples considering possible uncertainties in numerical modeling and sensor measurement. A planar truss example was chosen to clearly explain the formulation, while the method and formulation are applicable to other structures as well. PMID- 29149089 TI - MnSOD and Cyclin B1 Coordinate a Mito-Checkpoint during Cell Cycle Response to Oxidative Stress. AB - Communication between the nucleus and mitochondrion could coordinate many cellular processes. While the mechanisms regulating this communication are not completely understood, we hypothesize that cell cycle checkpoint proteins coordinate the cross-talk between nuclear and mitochondrial functions following oxidative stress. Human normal skin fibroblasts, representative of the G2-phase, were irradiated with 6 Gy of ionizing radiation and assayed for cyclin B1 translocation, mitochondrial function, reactive oxygen species (ROS) levels, and cytotoxicity. In un-irradiated controls, cyclin B1 was found primarily in the nucleus of G2-cells. However, following irradiation, cyclin B1 was excluded from the nucleus and translocated to the cytoplasm and mitochondria. These observations were confirmed further by performing transmission electron microscopy and cell fractionation assays. Cyclin B1 was absent in mitochondria isolated from un-irradiated G2-cells and present in irradiated G2-cells. Radiation-induced translocation of cyclin B1 from the nucleus to the mitochondrion preceded changes in the activities of mitochondrial proteins, that included decreases in the activities of aconitase and the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD), and increases in complex II activity. Changes in the activities of mito-proteins were followed by an increase in dihydroethidium (DHE) oxidation (indicative of increased superoxide levels) and loss of the mitochondrial membrane potential, events that preceded the restart of the stalled cell cycle and subsequently the loss in cell viability. Comparable results were also observed in un-irradiated control cells overexpressing mitochondria-targeted cyclin B1. These results indicate that MnSOD and cyclin B1 coordinate a cross-talk between nuclear and mitochondrial functions, to regulate a mito-checkpoint during the cell cycle response to oxidative stress. PMID- 29149090 TI - Computational Methods for Modeling Aptamers and Designing Riboswitches. AB - Riboswitches, which are located within certain noncoding RNA region perform functions as genetic "switches", regulating when and where genes are expressed in response to certain ligands. Understanding the numerous functions of riboswitches requires computation models to predict structures and structural changes of the aptamer domains. Although aptamers often form a complex structure, computational approaches, such as RNAComposer and Rosetta, have already been applied to model the tertiary (three-dimensional (3D)) structure for several aptamers. As structural changes in aptamers must be achieved within the certain time window for effective regulation, kinetics is another key point for understanding aptamer function in riboswitch-mediated gene regulation. The coarse-grained self organized polymer (SOP) model using Langevin dynamics simulation has been successfully developed to investigate folding kinetics of aptamers, while their co-transcriptional folding kinetics can be modeled by the helix-based computational method and BarMap approach. Based on the known aptamers, the web server Riboswitch Calculator and other theoretical methods provide a new tool to design synthetic riboswitches. This review will represent an overview of these computational methods for modeling structure and kinetics of riboswitch aptamers and for designing riboswitches. PMID- 29149091 TI - Social Environment and Hospitalisation after Release from Prison: A Prospective Cohort Study. AB - This study examined the association between remoteness and area disadvantage, and the rate of subsequent hospitalisation, in a cohort of adults released from prisons in Queensland. A baseline survey of 1267 adult prisoners within 6 weeks of expected release was prospectively linked with hospital, mortality and reincarceration records. Postcodes were used to assign remoteness and area disadvantage categories. Multivariate Andersen-Gill regression models were fitted to test for associations between remoteness, area disadvantage and hospitalisation after release from prison. Over a total of 3090.9 person-years of follow-up, the highest crude incidence rates were observed in areas characterised by remoteness and area disadvantage (crude incidence rate (IR) = 649; 95%CI: 526 791), followed by remoteness only (IR = 420; 95%CI: 349-501), severe area disadvantage only (IR = 403; 95%CI: 351-461), and neither of these factors (IR = 361; 95%CI: 336-388). Unadjusted analyses indicated that remoteness (hazard ratio (HR) = 1.32; 95%CI: 1.04-1.69; p = 0.024) was associated with increased risk of hospitalisation; however, this attenuated to the null after adjustment for covariate factors. The incidence of hospitalisation for those who live in remote or socio-economically disadvantaged areas is increased compared to their counterparts in more urban and less socio-economically disadvantaged areas. Experiencing both these factors together may compound the hospitalisation in the community. PMID- 29149093 TI - Evolutionarily Distant Streptophyta Respond Differently to Genotoxic Stress. AB - Research in algae usually focuses on the description and characterization of morpho-and phenotype as a result of adaptation to a particular habitat and its conditions. To better understand the evolution of lineages we characterized responses of filamentous streptophyte green algae of the genera Klebsormidium and Zygnema, and of a land plant-the moss Physcomitrellapatens-to genotoxic stress that might be relevant to their environment. We studied the induction and repair of DNA double strand breaks (DSBs) elicited by the radiomimetic drug bleomycin, DNA single strand breaks (SSB) as consequence of base modification by the alkylation agent methyl methanesulfonate (MMS) and of ultra violet (UV)-induced photo-dimers, because the mode of action of these three genotoxic agents is well understood. We show that the Klebsormidium and Physcomitrella are similarly sensitive to introduced DNA lesions and have similar rates of DSBs repair. In contrast, less DNA damage and higher repair rate of DSBs was detected in Zygnema, suggesting different mechanisms of maintaining genome integrity in response to genotoxic stress. Nevertheless, contrary to fewer detected lesions is Zygnema more sensitive to genotoxic treatment than Klebsormidium and Physcomitrella. PMID- 29149092 TI - Analysis of the Roles of the Arabidopsis nMAT2 and PMH2 Proteins Provided with New Insights into the Regulation of Group II Intron Splicing in Land-Plant Mitochondria. AB - Plant mitochondria are remarkable with respect to the presence of numerous group II introns which reside in many essential genes. The removal of the organellar introns from the coding genes they interrupt is essential for respiratory functions, and is facilitated by different enzymes that belong to a diverse set of protein families. These include maturases and RNA helicases related proteins that function in group II intron splicing in different organisms. Previous studies indicate a role for the nMAT2 maturase and the RNA helicase PMH2 in the maturation of different pre-RNAs in Arabidopsis mitochondria. However, the specific roles of these proteins in the splicing activity still need to be resolved. Using transcriptome analyses of Arabidopsis mitochondria, we show that nMAT2 and PMH2 function in the splicing of similar subsets of group II introns. Fractionation of native organellar extracts and pulldown experiments indicate that nMAT2 and PMH2 are associated together with their intron-RNA targets in large ribonucleoprotein particle in vivo. Moreover, the splicing efficiencies of the joint intron targets of nMAT2 and PMH2 are more strongly affected in a double nmat2/pmh2 mutant-line. These results are significant as they may imply that these proteins serve as components of a proto-spliceosomal complex in plant mitochondria. PMID- 29149094 TI - Genomic Analysis of Third Generation Cephalosporin Resistant Escherichia coli from Dairy Cow Manure. AB - The production of extended-spectrum beta-lactamases (ESBLs) conferring resistance to new derivatives of beta-lactams is a major public health threat if present in pathogenic Gram-negative bacteria. The objective of this study was to characterize ceftiofur (TIO)- or cefotaxime (FOX)-resistant Escherichia coli isolated from dairy cow manure. Twenty-four manure samples were collected from four farms and incubated under anaerobic conditions for 20 weeks at 4 degrees C or at 25 degrees C. A total of 37 TIO- or FOX-resistant E. coli were isolated from two of the four farms to determine their susceptibility to 14 antibiotics. Among the 37 resistant E. coli, 10 different serotypes were identified, with O8:H1 being the predominant serotype (n = 17). Five isolates belonged to each of serotypes O9:NM and O153:H42, respectively. All 37 cephalosporin resistant isolates were multi-resistant with the most prevalent resistance spectrum being amoxicillin-clavulanic acid-ampicillin-cefoxitin-ceftiofur-ceftriaxone chloramphenicol-streptomycin-sulfisoxazole-tetracycline-trimethoprim sulfamethoxazole. The genomes of 18 selected isolates were then sequenced and compared to 14 selected human pathogenic E. coli reference genomes obtained from public repositories using different bioinformatics approaches. As expected, all 18 sequenced isolates carried at least one beta-lactamase bla gene: TEM-1, TEM 81, CTX-M115, CTX-M15, OXA-1, or CMY-2. Several other antibiotic resistance genes (ARGs) and virulence determinants were detected in the sequenced isolates and all of them harbored antimicrobial resistance plasmids belonging to classic Inc groups. Our results confirm the presence of diverse ESBL producing E. coli isolates in dairy cow manure stored for a short period of time. Such manure might constitute a reservoir of resistance and virulence genes for other bacteria that share the same environment. PMID- 29149095 TI - Proton Nuclear Magnetic Resonance (1H-NMR)-Based Metabolomic Evaluation of Human Renal Allografts from Donations After Circulatory Death. AB - BACKGROUND Delayed graft function (DGF) is a common complication that impairs allograft function after kidney transplantation. However, the mechanism of DGF remains unclear. Nuclear magnetic resonance (NMR)-based analysis has been widely used in recent times to assess changes in metabolite levels. MATERIAL AND METHODS Samples of perfusate from allografts donated after circulatory death were collected prior to transplantation, during static cold storage. 1H-NMR-based metabolomics combined with the statistical methods, orthogonal partial least squares discriminant analysis (OPLS-DA), and principle-component analysis (PCA), were employed to test different levels of metabolites between the allografts that exhibited DGF and those that exhibited immediate graft function (IGF). RESULTS The study population consisted of 36 subjects, 11 with DGF and 25 with IGF. Of the 37 detected and identified metabolites, a-glucose and citrate were significantly elevated in the perfusate of DGF allografts, and taurine and betaine were significantly decreased. CONCLUSIONS 1H-NMR analysis of DGF and IGF perfusates revealed some significant differences in their metabolite profiles, which may help explain the mechanisms of kidney ischemia-reperfusion injury and DGF. PMID- 29149096 TI - [Fertility preservation in the oncology patient]. AB - In recent years, medical advances have substantially improved survival of cancer patients, generating growing concern about the quality of life of the survivors. Increased attention has been paid to reproductive problems after oncological treatments. International guidelines on fertility preservation in cancer patients require that healthcare teams discuss, as early as possible, the impact of cancer treatments on fertility and encourage access to fertility preservation techniques. The development of these techniques in women is a recent effort and many patients and health care providers are not familiar with their rapid expansion. This article discusses indications, results, and risks of the different options currently available. PMID- 29149097 TI - Acute coronary disease, prognosis and prevalence of risk factors in young adults. AB - Acute coronary disease is a rare entity in young people and is mostly related to atherosclerotic disease. However, other causes such as myocardial bridges, coronary artery dissection and antiphospholipid syndrome may be present. The prognosis of the disease in this group of patients is favorable; although women may have a higher morbidity because diagnosis and treatment can be delayed. The goal of this review is to update the knowledge about risk factors and prognosis of young patients with an acute coronary event compared to the older population. PMID- 29149098 TI - Early versus late surgical correction in congenital diaphragmatic hernia. AB - INTRODUCTION: The timing of surgical repair in patients with congenital diaphragmatic hernia has been a controversial topic over the years, and there is still no agreement as to whether immediate repair or late surgery with preoperative stabilization is preferable. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified four systematic reviews including 38 studies overall, of which two were randomized trials. We concluded it is not clear whether immediate surgical repair in congenital diaphragmatic hernia increases mortality or decreases hospitalization days compared to late repair because the certainty of evidence is very low. PMID- 29149099 TI - What are preprints? PMID- 29149100 TI - BCL-2 family proteins: changing partners in the dance towards death. AB - The BCL-2 family of proteins controls cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP) leading to the irreversible release of intermembrane space proteins, subsequent caspase activation and apoptosis. The affinities and relative abundance of the BCL-2 family proteins dictate the predominate interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins that regulate MOMP. We highlight the core mechanisms of BCL-2 family regulation of MOMP with an emphasis on how the interactions between the BCL-2 family proteins govern cell fate. We address the critical importance of both the concentration and affinities of BCL-2 family proteins and show how differences in either can greatly change the outcome. Further, we explain the importance of using full-length BCL-2 family proteins (versus truncated versions or peptides) to parse out the core mechanisms of MOMP regulation by the BCL-2 family. Finally, we discuss how post-translational modifications and differing intracellular localizations alter the mechanisms of apoptosis regulation by BCL-2 family proteins. Successful therapeutic intervention of MOMP regulation in human disease requires an understanding of the factors that mediate the major binding interactions between BCL-2 family proteins in cells. PMID- 29149102 TI - Recombinant immunotoxins targeting B-cell maturation antigen are cytotoxic to myeloma cell lines and myeloma cells from patients. PMID- 29149101 TI - How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? AB - The tumour suppressor gene TP53 is mutated in ~50% of human cancers. In addition to its function in tumour suppression, p53 also plays a major role in the response of malignant as well as nontransformed cells to many anticancer therapeutics, particularly those that cause DNA damage. P53 forms a homotetrameric transcription factor that is reported to directly regulate ~500 target genes, thereby controlling a broad range of cellular processes, including cell cycle arrest, cell senescence, DNA repair, metabolic adaptation and cell death. For a long time, induction of apoptotic death in nascent neoplastic cells was regarded as the principal mechanism by which p53 prevents tumour development. This concept has, however, recently been challenged by the findings that in striking contrast to Trp53-deficient mice, gene-targeted mice that lack the critical effectors of p53-induced apoptosis do not develop tumours spontaneously. Remarkably, even mice lacking all mediators critical for p53-induced apoptosis, G1/S boundary cell cycle arrest and cell senescence do not develop any tumours spontaneously. In this review we discuss current understanding of the mechanisms by which p53 induces cell death and how this affects p53-mediated tumour suppression and the response of malignant cells to anticancer therapy. PMID- 29149104 TI - Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in ALK-positive NSCLC. AB - BACKGROUND: We evaluated the cumulative incidence rate (CIR) of central nervous system (CNS) and non-CNS progression in alectinib-treated patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) to determine the extent to which alectinib may treat or control CNS disease. METHODS: Patients with crizotinib-pretreated locally advanced or metastatic disease received alectinib 600 mg orally twice daily in two phase II trials. All patients underwent baseline imaging and regular centrally reviewed scans. RESULTS: At 24 months, the CIR for CNS progression was lower in patients without vs with baseline CNS metastases (8.0 vs 43.9%). Patients with baseline CNS disease and prior radiotherapy had a higher CIR of CNS progression than radiotherapy-naive patients (50.5 vs 27.4%) and a lower CIR of non-CNS progression (25.8 vs 42.5%). Adverse events leading to withdrawal occurred in 5.9% and 6.7% of patients with and without baseline CNS metastases, respectively. CONCLUSIONS: This analysis indicates a potential role for alectinib in controlling and preventing CNS metastases. PMID- 29149103 TI - Human hepatocyte transplantation for liver disease: current status and future perspectives. AB - Liver transplantation is the accepted treatment for patients with acute liver failure and liver-based metabolic disorders. However, donor organ shortage and lifelong need for immunosuppression are the main limitations to liver transplantation. In addition, loss of the native liver as a target organ for future gene therapy for metabolic disorders limits the futuristic treatment options, resulting in the need for alternative therapeutic strategies. A potential alternative to liver transplantation is allogeneic hepatocyte transplantation. Over the last two decades, hepatocyte transplantation has made the transition from bench to bedside. Standardized techniques have been established for isolation, culture, and cryopreservation of human hepatocytes. Clinical hepatocyte transplantation safety and short-term efficacy have been proven; however, some major hurdles-mainly concerning shortage of donor organs, low cell engraftment, and lack of a long-lasting effect-need to be overcome to widen its clinical applications. Current research is aimed at addressing these problems, with the ultimate goal of increasing hepatocyte transplantation efficacy in clinical applications. PMID- 29149105 TI - LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity. AB - BACKGROUND: LGR5 serves as a co-receptor for Wnt/beta-catenin signalling and marks normal intestinal stem cells; however, its role in colorectal cancer (CRC) remains controversial. LGR5+ cells are known to exist outside the stem cell niche during CRC progression, and the requirement for epidermal growth factor (EGF) signalling within early adenomas remains to be fully elucidated. METHODS: Epidermal growth factor and gefitinib treatments were performed in EGF-responsive LGR5+ early adenoma RG/C2 cells. 2D growth assays were measured using an IncuCyte. LGR5 or MEK1/2 silencing studies were executed using siRNA and LGR5 expression was assessed by qRT-PCR and immunoblotting. Ki67 level and cell cycle status were analysed by flow cytometry. RESULTS: Epidermal growth factor suppresses expression of LGR5 at both the transcript and protein level in colorectal adenoma and carcinoma cells. Suppression of LGR5 reduces the survival of EGF-treated adenoma cells by increasing detached cell yield but also inducing a proliferative state, as evidenced by elevated Ki67 level and enhanced cell cycle progression. Repression of LGR5 further increases the sensitivity of adenoma cells to EGFR inhibition. CONCLUSIONS: LGR5 has an important role in the EGF-mediated survival and proliferation of early adenoma cells and could have clinical utility in predicting response of CRC patients to EGFR therapy. PMID- 29149106 TI - Reply to 'Comment on 'Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study''. PMID- 29149109 TI - Targeted therapies: Precision medicine for ATC - BRAF and MEK inhibition shows promise. PMID- 29149107 TI - Treponema denticola chymotrypsin-like proteinase may contribute to orodigestive carcinogenesis through immunomodulation. AB - BACKGROUND: Periodontal pathogens have been linked to oral and gastrointestinal (orodigestive) carcinogenesis. However, the exact mechanisms remain unknown. Treponema denticola (Td) is associated with severe periodontitis, a chronic inflammatory disease leading to tooth loss. The anaerobic spirochete Td is an invasive bacteria due to its major virulence factor chymotrypsin-like proteinase. Here we aimed to investigate the presence of Td chymotrypsin-like proteinase (Td CTLP) in major orodigestive tumours and to elucidate potential mechanisms for Td to contribute to carcinogenesis. METHODS: The presence of Td-CTLP within orodigestive tumour tissues was examined using immunohistochemistry. Oral, tonsillar, and oesophageal squamous cell carcinomas, alongside gastric, pancreatic, and colon adenocarcinomas were stained with a Td-CTLP-specific antibody. Gingival tissue from periodontitis patients served as positive controls. SDS-PAGE and immunoblot were used to analyse the immumodulatory activity of Td-CTLP in vitro. RESULTS: Td-CTLP was present in majority of orodigestive tumour samples. Td-CTLP was found to convert pro MMP-8 and -9 into their active forms. In addition, Td-CTLP was able to degrade the proteinase inhibitors TIMP-1, TIMP-2, and alpha-1-antichymotrypsin, as well as complement C1q. CONCLUSIONS: Because of its presence within tumours and regulatory activity on proteins critical for the regulation of tumour microenvironment and inflammation, the Td-CTLP may contribute to orodigestive carcinogenesis. PMID- 29149108 TI - Comment on 'Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study'. PMID- 29149110 TI - [Does Omega-3 supplementation after the age of 65 influence cognitive function? Results of a systematic review]. AB - BACKGROUND: The percentage of the older population is progressively increasing as are diseases associated with aging such as cognitive decline (CD) and dementia. Observational epidemiological studies suggest that diets rich in omega 3 polyunsaturated fatty acids (w3-PUFA) might reduce the risk of CD and dementia. The main objective was to assess whether there is sufficient scientific evidence about the relationship between w3-PUFA supplementation in patients aged 65 or older and cognitive performance. METHODS: We used the Pubmed data base to search for articles related to w3-PUFA and CD or dementia. Initially we identified 582 articles, after applying the eligibility criterion we included six studies in this systematic review. RESULTS: The studies included were heterogeneous regarding population, measurement of exposure and outcome. Therefore, it was not possible to conduct a quantitative analysis. Two studies found that w3-PUFA supplementation decreased the risk of Alzheimer and improved cognitive performance. Two studies found an improvement in only one of the domains of cognitive performance (visual analogical classification and verbal fluency) and another two did not find any evidence of protection. CONCLUSIONS: We found few studies to support or refute the evidence that w3-PUFA supplementation in patients aged 65 or older improves cognitive performance or prevents dementia. PMID- 29149111 TI - [Bilateral bronchopneumonia due to Rothia mucilaginosa]. AB - Rothia mucilaginosa (R. mucilaginosa), formerly named Stomatococcus mucilaginosus, is a facultatively anaerobic, encapsulated gram-positive coccus, which forms part of the normal oropharyngeal and is rarely considered to be a pathogen in immunocompetent patients, although it can produce, on rare occasions, serious infections like bacteremia, endocarditis and respiratory infections; such as pneumonia, pleural empyema or superinfection of bronchiectasis. We present the case of a 74-year-old male diagnosed with right basal pneumonia of torpid evolution with a poor initial response to different antibiotics, with clinical and radiological worsening and the appearance of bilateral bronchopneumonia with pseudonodular images. R. mucilaginosa in pure culture was isolated in three sputum cultures and in bronchial suction. The patient was finally treated with Linezolid with a good clinical response and normalisation of the thorax radiography, confirming the disappearance of R. mucilaginosa in subsequent sputum cultures. As there are few documented cases of pneumonia due to R. mucilaginosa, we believe that presenting this case will be of interest. PMID- 29149112 TI - [Quality of clinical practice guidelines on deterioration of skin integrity]. PMID- 29149113 TI - [Incidence of surgical site infection in colon surgery and antibiotic prophylaxis adequacy: prospective cohort study]. AB - BACKGROUND: Surgical site infection (SSI) has a considerable clinical and economic impact at the hospital level, so prevention and monitoring are considered a high priority. The objective of this study was to assess compliance with the protocol of antibiotic prophylaxis in colon surgery and the effect of its inadequacy for the incidence of SSI. METHODS: Prospective cohort study from July 2008 to July 2016. Compliance with antibiotic prophylaxis protocol and the causes of non-compliance were evaluated in colon surgery: duration and starting, choice, route of administration and dose of the antibiotic. The incidence of SSI was studied after a maximum incubation period of 30 days. Relative risk (RR) was used to evaluate the non-compliance causes of prophylaxis. RESULTS: The study included 771 patients. The cumulative incidence of SSI was 5.8% (n=45), of which 2/3 were superficial incisional infections. The most common cause of SSI was Escherichia coli (28%). Antibiotic prophylaxis was administered in 97.8% of patients, with an overall protocol compliance of 91.9%. The principle cause of non-compliance was the choice of antibiotic (58.2%). No relationship between the inadequacy of prophylaxis and incidence of surgical site infection was found (RR=0.5; CI95% 0.1-1.8). CONCLUSIONS: The overall adequacy rate to antibiotic prophylaxis protocol was high. No significant association between the adequacy of prophylaxis and incidence of surgical site infection in colon surgery was found. PMID- 29149114 TI - [Calls due to suicidal behaviour made to the prehospital, emergency department in Malaga: characteristics and associated factors]. AB - BACKGROUND: Suicidal behaviour (fatal and non-fatal) has become a serious public health problem in many countries. The aim of the study was to describe the differential characteristics of emergency calls due to suicidal behaviour made to the Emergency Coordinating Centre (CCUE) in the province of Malaga, in comparison with calls due to physical or psychiatric problems. METHODS: Retrospective observational study of the calls recorded in the database of the Public Company for Emergency Health during one year. Multivariate logistic regression analyses were carried out including age, gender and the following variables related with the demand: hours of the day, type of day (working days or bank holidays), months of the year and trimesters, number of resources mobilized and types of resolution. RESULTS: The analyses were carried out on 163,331 calls, of which 1,380 calls were due to suicidal behaviour (0.8%), 9,951 for psychiatric reasons (6.1%) and 152,000 for physical reasons (93%). The emergency calls for suicidal behaviour were mainly made by females, between 31-60 years, in the evening and at night, and required transfer to hospital and more than one mobilized resource. Calls due to completed suicide were more frequently made by older men. Calls due to suicidal tendencies predominated over those due to attempted or threatened suicide during the first trimester of the year, while the opposite was the case during the third trimester. CONCLUSIONS: The results indicated differential characteristics of suicide calls that are potentially relevant for prevention in spite of the limitations of the present study. PMID- 29149115 TI - [Emergency department doctors must get involved in organising the services]. PMID- 29149116 TI - Solving the problem of smoking in the Polish enterprises during 2003-2015. AB - OBJECTIVES: Tobacco smoking is a major organizational, economical, and public relations-related (PR-related) problem for the company. Moreover, it is an important health determinant of the working population. The paper reports the results of the research which analyzed the current state and the tobacco control activities' transformations undertaken by Polish employers between 2003 and 2015. MATERIAL AND METHODS: Data comes from the research performed in 2006, 2010 and 2015, involving random- selected representative samples of Polish enterprises, employing no fewer than 50 employees. The sampling pattern covered location and classification of activities (excluding public administration, national defense, social security, education, health care and social assistance sectors). Consecutive interviews were conducted with representatives of 611, 1002 and 1000 companies, respectively. RESULTS: The companies improved their compliance with the national regulations on smoking in the workplace. The strategy for limiting smoking in public places resulted in a steady increase in the number of companies (11%, 23%, 38%, respectively) that introduced smoking ban. Approximately in every second company, smoking was allowed only in the smoking room or outdoors. Voluntary activities (e.g., education and support for employees wishing to cease smoking) were very rarely undertaken by medium and large companies (several percent) and since 2010, when the law had become more restrictive, such tendency reinforced. Employers also were seldom interested in the prevalence of tobacco smoking among their personnel, its consequences for the company's functioning and the effectiveness of the implemented tobacco control measures. CONCLUSIONS: National anti-smoking policy caused that companies were more focused on smoking bans at the expense of education and support for those who wanted to cease smoking. Although this contributes to reducing secondary smoking in the workplace, the companies' potential to become a major agent for tobacco control policies is neglected while the downward trend of smoking in the Polish society has slowed down. Int J Occup Med Environ Health 2018;31(3):261-280. PMID- 29149117 TI - [Influence of titanium dioxide activated under visible light on survival of mold fungi]. AB - BACKGROUND: In public and residential buildings, fungi are usually found in the dust or growing on building materials medium such. It has been known that a number of their spores may contaminate the indoor environment and deteriorate air quality in accommodation spaces. Previously designed air cleaning systems do not guarantee a complete removal of agents harmful to humans and animals. Therefore, there is a great need to develop a new solution to remove molds from indoor air. In recent years, photocatalysis based on titanium dioxide (TiO2) has been proposed as an effective method for air pollutants removal. The aim of the study was to determine the effect of TiO2 activated under artificial sun light (UV-VIS - ultraviolet - visible spectroscopy) on survival of fungi Penicillium chrysogenum and Aspergillus niger. MATERIAL AND METHODS: The commercial P 25 (Aeroxide P 25, Evonik, Germany) and nitrogen modified titanium dioxide (N-TiO2) were used. The microbiological study was performed using Penicillium chrysogenum and Aspergillus niger fungi. The survival of fungi was determined on the basis of changes in their concentration. RESULTS: It was found that N-TiO2 has a stronger antifungal activity against P. chrysogenum and A. niger than P 25. For N-TiO2, the complete elimination of molds was possible after 3 h under artificial solar light activation. The minimal concentration of photocatalyst was 0.01 g*dm-3 (P. chrysogenum) and 0.1 g*dm-3 (A. niger). CONCLUSIONS: The nitrogen modification of titanium dioxide produced expected results and N TiO2 presented good antifungal activity. The findings of the presented investigation can lead to the development of air filter to be used for removal of harmful agents (including molds) from indoor environment. Med Pr 2018;69(1):59 65. PMID- 29149118 TI - Perceived Self-Efficacy: A Concept Analysis for Symptom Management in Patients With Cancer?. AB - BACKGROUND: Perceived self-efficacy (PSE) for symptom management plays a key role in outcomes for patients with cancer, such as quality of life, functional status, symptom distress, and healthcare use. Definition of the concept is necessary for use in research and to guide the development of interventions to facilitate PSE for symptom management in patients with cancer.?. OBJECTIVES: This analysis will describe the concept of PSE for symptom management in patients with cancer.?. METHODS: A database search was performed for related publications from 2006-2016. Landmark publications published prior to 2006 that informed the concept analysis were included.?. FINDINGS: Greater PSE for symptom management predicts improved performance outcomes, including functional health status, cognitive function, and disease status. Clarification of the concept of PSE for symptom management will accelerate the progress of self-management research and allow for comparison of research data and intervention development. PMID- 29149119 TI - Pain Management: Strategies for Screening and Monitoring Patients Receiving Chronic Opioid Therapy?. AB - The current state of pain management within the oncology setting, effectiveness of opioids for the relief of pain, and limited alternatives for chronic pain management have produced reliance on opioid medications with an inherent risk for aberrant behavior. Although standardization is lacking among prescribers who manage cancer-related pain, advanced practice RNs must act according to the available evidence that suggests assessing and monitoring for abuse and misuse. ?. PMID- 29149120 TI - Genomics Education: Knowledge of Nurses Across the Profession and Integration Into Practice. AB - BACKGROUND: Since the completion of the Human Genome Project in 2003, the implications of genetics and genomics for health and illness have become clearer. All nurses, at all levels and across all specialties, must have a basic understanding of genetics and genomics to provide appropriate care. ?. OBJECTIVES: This article provides an overview of the integration of genetics and genomics into nursing education, as well as continued barriers to nursing knowledge of genetics and genomics.?. METHODS: A literature review was conducted using CINAHL(r), PubMed, ProQuest, and Google Scholar. Databases were reviewed for literature published from January 1962 to November 2017.?. FINDINGS: Although genetic and genomic education has been integrated into undergraduate and graduate nursing curricula, a gap exists in this knowledge among student nurses, practicing nurses, and nursing faculty. PMID- 29149121 TI - Ethics and Genetics: Examining a Crossroads in Nursing Through a Case Study?. AB - BACKGROUND: The field of genetics and genomics is rapidly expanding, particularly in oncology. Genetics and genomics can lead to ethical concerns. Oncology nurses must balance the need for evidence-based oncology care with that of ethical care for patients and their family members. OBJECTIVES: The purpose of this article is to provide an overview of cancer genetics and ethics and their impact on oncology nurses, patients, and families. METHODS: A case study of familial adenomatous polyposis (FAP) is offered to illustrate the impact of a hereditary cancer syndrome on several generations of a family and ethical issues surrounding cancer genetics. In addition, a brief review of FAP, gene and tissue biobanking, and genome editing is provided.?. FINDINGS: Genetics, genomics, and pharmaco-genomics are ubiquitous in cancer diagnosis and management. Nurses must be knowledgeable about the ethical issues related to cancer genetics and oncology care to advocate for the needs of patients with cancer. Communication with and education of patients and their families before germline genetic testing may reduce the emergence of ethical dilemmas. PMID- 29149122 TI - Leukostasis: Management to Prevent Crisis in Acute Leukemia?. AB - BACKGROUND: Hyperleukocytosis, a peripheral white blood cell count greater than 100,000/mm3,is most commonly seen in patients with newly diagnosed or relapsed acute lymphoblastic leukemia and acute myeloid leukemia. Leukostasis is a reduction in blood flow related to hyperviscosity. Hyperleukocytosis, causing leukostasis, is an oncologic emergency and requires an exacting assessment and rapid response with appropriate intervention to prevent morbidity and mortality in the first week after diagnosis. OBJECTIVES: The objectives of this article are to equip oncology nurse to identify patients with hyperleukocytosis and to provide nursing interventions that will ensure safe, quality care. METHODS: A case study is used to demonstrate key concepts that are critical in early assessment, identification, and treatment of patients with leukostasis.?. FINDINGS: Oncology nurses well versed in the pathophysiology, clinical presentation, and management of leukostasis can make a significant contribution to the safe management of patients with cancer. PMID- 29149123 TI - Precision Medicine: Accelerating the Science to Revolutionize Cancer Care?. AB - BACKGROUND: Precision medicine in cancer care uses specific information about a person's tumor to help diagnose, plan treatment, prognosticate, and surveil throughout the cancer trajectory. Applications exist for cancer prevention, early detection, cancer treatment, and supportive care. Several national initiatives (e.g., National Cancer Moonshot Initiative) support these efforts to accelerate this science forward.?. OBJECTIVES: This article presents an overview of the way in which precision medicine is revolutionizing cancer care.?. METHODS: Definitions, historic perspectives, and specific examples are provided, which illustrate the use of precision medicine in cancer care.?. FINDINGS: Oncology nurses and other healthcare professionals have a responsibility to learn about the science and national initiatives supporting precision medicine, provide clear patient education messages for optimal understanding, and address challenges. PMID- 29149124 TI - How Do You Adapt Your Plans For a Nursing Career When the Unexpected Occurs. AB - I graduated nursing school seven months pregnant in November 2015. My plans were to take the NCLEX immediately, give birth, take three months to adjust, and begin my nursing career in a glamorous emergency department position by the spring.? Fast forward to January 2016. My family lost three members in a car accident and my daughter was born high-needs, requiring multiple hospitalizations. Although she and my family needed me, I was anxious about taking too much time off after nursing school, which could delay my career advancement.?. PMID- 29149125 TI - Survivorship Care Plans: Rural, Low-Income Breast Cancer Survivor Perspectives?. AB - BACKGROUND: Despite increasing implementation of survivorship care plans (SCPs), cancer survivors still experience unmet needs post-treatment. Rural, low-income survivors experience less planning for supportive care during treatment, which is difficult to overcome after patients complete treatment.?. OBJECTIVES: This pilot study explores post-?treatment survivorship care planning execution, perception, and needs among rural, low-income cancer survivors. ?. METHODS: A longitudinal, descriptive, qualitative design with semistructured interviews was used. ?. FINDINGS: Rural survivors' responses reflected lack of knowledge about post treatment care, including how to assess for cancer recurrence. Delivery of the SCP during the final treatment appointment was inadequate for knowledge retention. Individualized assessment of survivorship needs and education post treatment may improve long-term health outcomes for this population. PMID- 29149126 TI - Pharmacogenomics: Principles and Relevance to Oncology Nursing?. AB - BACKGROUND: Pharmacogenomics is the fastest growing field in precision medicine. Based on current use, oncology encompasses the largest share of the precision medicine market, necessitating that oncology nurses understand the principles of pharmacogenomics and how it affects clinical practice.?. OBJECTIVES: This article will define precision medicine and pharmacogenomics and will provide examples of pharmacogenomic tests, including those associated with tumor markers, and nursing implications.?. METHODS: Educational and clinical resources are supplied for oncology nurses to expand their pharmacogenomics expertise.?. FINDINGS: The knowledge surrounding precision medicine and pharmacogenomics will position oncology nurses to engage in current research, improve practice, and educate patients. As the focus of health care remains on reducing costs and improving morbidity and mortality, the reduction in adverse drug reactions will continue to be highlighted. Tailoring medications based on individual responses will not only help improve patient outcomes but also potentially affect the cost of health care as these genetic tests become a standard of care. PMID- 29149128 TI - Who We Are. AB - The holiday season may seem different this year with recent searing memories of individual and community heartbreak. For many, the holidays may be tough, and this season in particular may be very tough. Let's pause to take that in and remind ourselves of who we are: master clinicians who care for patients with cancer and their family members; caregiving instructors; and those prepared to answer the call, serving humanity. ?. PMID- 29149127 TI - Percutaneous Nephrostomy Infusion: Nursing Considerations for Treatment of Upper Urinary Tract Urothelial Carcinoma. AB - An intrarenal approach using a percutaneous nephrostomy tube is a novel method to deliver chemotherapy and biotherapy to patients with upper urinary tract urothelial carcinoma. A paucity of evidence exists regarding basic nursing implications for this unique treatment option. This column will provide suggested guidelines to administer intrarenal treatment via a percutanous nephrostomy tube.?. PMID- 29149129 TI - Oncology Nurse Generalist Competencies: Oncology Nursing Society's Initiative to Establish Best Practice. AB - BACKGROUND: A project team was formulated to create evidence-based oncology nurse generalist competencies (ONGCs) to establish best practices in competency development, including high-risk tasks, critical thinking criteria, and measurement of key areas for oncology nurses.?. OBJECTIVES: This article aims to describe the process and the development of ONGCs. ?. METHODS: This article explains how the ONGCs were accomplished, and includes outcomes and suggestions for use in clinical practice. ?. FINDINGS: Institutions can use the ONGCs to assess and develop competency programs, offer educational strategies to measure proficiency, and establish processes to foster a workplace committed to mentoring and teaching future oncology nurses. PMID- 29149130 TI - Errors in Genetic Testing: Common Causes and Strategies for Prevention. AB - Genetic testing for hereditary cancer syndromes is an integral component of oncology care. Various types of common errors that occur in the genetic testing process are presented in this article with actual clinical case examples and commentary. Genetic errors are expensive and may result in poor outcomes for the patient and his or her family. Oncology nurses need to be aware of potential sources of error and advocate for comprehensive genetic care.?. PMID- 29149131 TI - Genetics and Genomics: An Oncology Nurse's Journey in Practice. AB - BACKGROUND: Cancer genetics and genomics are now an integral component of oncology care. Genetics and genomics guide recommendations not only for cancer prevention and early detection, but also for cancer treatment. ?. OBJECTIVES: This article documents the personal experiences of an oncology nurse who has worked in cancer prevention and early detection since the 1990s and describes the many changes that have occurred in cancer-related genetic and genomic care during that time. ?. METHODS: This is a personal account of genetic practice in the past 30 years. ?. FINDINGS: Nurses can no longer ignore cancer genetics and genomics in oncology care. Some aspects of care have changed dramatically, including the number of genetic tests and potential uses for genomic information; however, some remain the same, particularly the human component of care. Patients and families need comprehensive education and support to understand the role that genetics and genomics play in cancer care. Oncology nurses are well suited to provide this care. PMID- 29149132 TI - Lifelong Impression: Remembering One of Our Own During the Holiday Season?. AB - In life, meeting someone who truly possesses the gift of teaching is a blessing. As an exceptional mentor and role model, this person will inspire us to be the best that we can be and make us want to be better human beings. As oncology nurses, we have the honor of caring for patients who have been devastated by the diagnosis of cancer. Establishing deep connections with some of these patients will enrich and give more meaning to our own lives. ?. PMID- 29149133 TI - Computer-Based Exercise Program: Effects of a 12-Week Intervention on Mood and Fatigue in Pediatric Patients With Cancer?. AB - BACKGROUND: Increasing rates of survival present a new set of physical and psychological challenges for children dealing with side effects during cancer treatment. Physical activity has been shown to be an effective strategy to reduce several side effects.?. OBJECTIVES: The purpose of this pilot study was to determine the benefits of a 12-week computer-based exercise intervention on perceived physical, motivational, and fatigue syndrome and psychological state.?. METHODS: Nine inpatient and outpatient pediatric patients with cancer participated in a 12-week intervention consisting of supervised computer-based exercise sessions. Participants completed measures assessing mood and fatigue pre and postintervention.?. FINDINGS: The intervention was feasible and provided preliminary evidence for the benefits on mood and fatigue in pediatric patients with cancer. The results promote the effectiveness of physical activity in pediatric oncology and call for continuing research in pediatric patients with cancer where sedentary behavior and the associated side effects are a growing concern. PMID- 29149134 TI - Financial Toxicity: Management as an Adverse Effect of Cancer Treatment?. AB - Along with many physical and emotional adverse effects associated with cancer therapy, attention has been directed to defining and identifying interventions to manage financial strain that can occur because of high medical payments and reduced income from employment interruption. Nurses can support patients and families by encouraging open communication during shared treatment decision making and throughout the cancer experience.?. PMID- 29149135 TI - Oncology Qualified Clinical Data Registry: A Patient-Centered, Symptom-Focused Framework to Guide Quality Improvement?. AB - The Oncology Nursing Society is the steward of seven patient-centered, symptom focused custom quality measures that have been codified into electronic format to facilitate extraction of data from the electronic health record. Because quality measurement is the cornerstone of the Quality Payment Program for providers in the pay-for-value framework, oncology nurses must be engaged in the quality measurement and improvement activities within their practice sites.?. PMID- 29149136 TI - MAPK Pathway-Targeted Therapies: Care and Management of Unique Toxicities in Patients With Advanced Melanoma?. AB - BACKGROUND: Agents targeting the MAPK pathway, including inhibitors of BRAF and MEK, have dramatically transformed the treatment landscape for patients with BRAF mutant metastatic melanoma. Although generally well tolerated, targeted agents were associated with unique toxicities.?. OBJECTIVES: This article aims to provide nurses with an overview of the key toxicities and associated management strategies of the characteristic adverse event (AE) profile associated with agents targeting the MAPK pathway.?. METHODS: Data from clinical trials evaluating vemurafenib, dabrafenib, trametinib, and cobimetinib were reviewed and summarized along with research on management of AEs identified in clinical trials.?. FINDINGS: The key AEs associated with these agents included pyrexia and cutaneous toxicities. Other notable AEs included arthralgias, ocular toxicities, and cardiac events. Because these agents are administered until progressive disease or unacceptable toxicity, nurses should be aware of management strategies to optimize treatment outcomes. PMID- 29149137 TI - Decision Aids: Assisting Patients With Multiple Myeloma and Caregivers With Treatment Decision Making ?. AB - A consolidated evaluation of resources on treatment decision aids (DAs) for multiple myeloma (MM) is lacking in the literature. This review identified 29 published DAs. Further analysis of these DAs revealed that the personal values and preferences of patients with MM are not well integrated into the development of these DAs, indicating the need for a more explicit shared decision-making model of MM care delivery. The development and testing of a web-based and individualized treatment DA will likely promote a shared decision-making process in clinical practice, improve patient satisfaction with treatment decisions, and decrease decisional regrets in patients newly diagnosed with MM.?. PMID- 29149138 TI - Complementary Health Approaches: Overcoming Barriers to Open Communication During Cancer Therapy?. AB - BACKGROUND: Complementary health approaches (CHAs) have been widely used by patients with cancer for many reasons. However, some patients choose not to disclose their use of CHAs to their nurses, fearing that this use will be viewed as unacceptable. Nurses may be uncomfortable talking about CHAs because of a lack of evidence-based research on the subject.?. OBJECTIVES: This article promotes ways in which nurses can overcome barriers to open communication about CHAs with patients during cancer therapy.?. METHODS: The literature related to CHAs and communication was reviewed.?. FINDINGS: To encourage open communication between nurses and patients regarding the use of CHAs, nurses need to be more knowledgeable about CHAs through training or by conducting research related to CHAs. PMID- 29149139 TI - Reversal of Growth of Utilization of Interventional Techniques in Managing Chronic Pain in Medicare Population Post Affordable Care Act. AB - BACKGROUND: Over the past 2 decades, the increase in the utilization of interventional techniques has been a cause for concern. Despite multiple regulations to reduce utilization of interventional techniques, growth patterns continued through 2009. A declining trend was observed in a previous evaluation; however, a comparative analysis of utilization patterns of interventional techniques has not been performed showing utilization before and after the enactment of the Affordable Care Act (ACA). OBJECTIVES: Our aim is to assess patterns of utilization and variables of interventional techniques in chronic pain management in the fee-for-service (FFS) Medicare population, with a comparative analysis of pre- and post-ACA. STUDY DESIGN: Utilization patterns and variables of interventional techniques were assessed from 2000 to 2009 and from 2009 to 2016 in the FFS Medicare population of the United States in managing chronic pain. METHODS: The master data from the Centers for Medicare & Medicaid Services (CMS) physician/supplier procedure summary from 2000 to 2016 was utilized to assess overall utilization and comparative utilization at various time periods. RESULTS: The analysis of Medicare data from 2000 to 2016 showed an overall decrease in utilization of interventional techniques 0.6% per year from 2009 to 2016, whereas from 2000 to 2009, there was an increase of 11.8% per year per 100,000 individuals of the Medicare population. In addition, the United States experienced an increase of 0.7% per year of population growth, 3.2% of those 65 years or older and a 3% annual increase in Medicare participation from 2009 to 2016. Further analysis also showed a 1.7% annual decrease in the rate of utilization of epidural and adhesiolysis procedures per 100,000 individuals of the Medicare population, with a 2.2% decrease for disc procedures and other types of nerve blocks, whereas there was an increase of 0.8% annually for facet joint interventions and sacroiliac joint blocks from 2009 to 2016. Epidural and adhesiolysis procedures showed an 8.9% annual increase, facet joint interventions and sacroiliac joint blocks showed a 17.6% increase, and disc procedures and other types of nerve blocks showed a 7.2% increase annually per 100,000 individuals of the Medicare population from 2000 to 2009. LIMITATIONS: The limitations of this assessment include lack of analysis of individual procedures. Additional limitations include lack of inclusion of patients from Medicare Advantage plans and lack of complete and accurate data for statewide utilization. CONCLUSION: From 2009 to 2016, interventional techniques decreased at an annual rate of 0.6% with an overall decrease of 3.9%, compared to an overall increase of 173.6% from 2000 to 2009 with an annual increase of 11.8%. An additional analysis of data with individual procedures is essential to gain further insights into utilization patterns. KEY WORDS: Interventional pain management, chronic spinal pain, interventional techniques, epidural injections, adhesiolysis, facet joint interventions, sacroiliac joint injections, disc procedures, other types of nerve blocks. PMID- 29149140 TI - Optimization of Postoperative Intravenous Patient-Controlled Analgesia with Opioid-Dexmedetomidine Combinations: An Updated Meta-Analysis with Trial Sequential Analysis of Randomized Controlled Trials. AB - BACKGROUND: It is still a challenge to optimize postoperative pain management. The effects of adding dexmedetomidine (DEX) to opioid-based postoperative intravenous patient-controlled analgesia (PCA) are not fully understood. OBJECTIVES: The aim of this study is to assess the efficacy and safety of opioid DEX combinations for postoperative PCA, and a trial sequential analysis (TSA) is utilized to evaluate the robustness of the current evidence. STUDY DESIGN: A systematic review and meta-analysis. SETTING: Randomized controlled trials that compared opioid-DEX combinations with opioid-only for PCA in adult surgical patients. METHODS: MEDLINE, EMBASE, and CENTRAL databases were searched for relevant articles. The main outcomes analyzed were postoperative pain intensity, opioid requirement, and opioid-related adverse events. The random-effects model was used to estimate mean differences (MDs) or relative risks (RRs) with 95% confidence intervals (CIs). A TSA was performed to test whether the evidence was reliable and significant. The quality of evidence for the main outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Eighteen studies involving 1,284 patients were included. The meta-analysis indicated that opioid-DEX combinations were associated with lower postoperative pain intensity (at rest: MD [24 hours] = -0.48, 95% CI [-0.75, -0.21], P = 0.0005), lower morphine-equivalent requirement (MD [0 - 24 hours] = -12.16 mg [-16.12, -8.21], P < 0.00001), and lower adverse events (nausea: RR = 0.66 [0.52, 0.83]; vomiting: RR = 0.65 [0.49, 0.87]; and pruritus: RR = 0.57 [0.40, 0.81]). For the above results, the TSA revealed that the cumulative Z-curve exceeded both the traditional boundary and the trial sequential monitoring boundary for benefit. DEX had no effect on the incidence of hypotension or bradycardia, which was also confirmed by the TSA. The GRADE level of evidence was high for postoperative nausea, moderate for pain intensity at rest at 24 hours postoperatively, morphine-equivalent requirement during 0 - 24 hours postoperatively, and postoperative vomiting, pruritus, and bradycardia, and low for postoperative hypotension. LIMITATIONS: The risk of introducing potentially significant heterogeneity exists, and this study did not evaluate the effects of DEX combined with opioids on long-term outcomes including chronic pain and patients' satisfaction after hospital discharge. CONCLUSIONS: Postoperative PCA strategies with opioid-DEX combinations decreased postoperative pain, opioid requirement, and opioid-related adverse events. DEX is a useful adjuvant to opioid-based PCA. KEY WORDS: Dexmedetomidine, pain, postoperative analgesia, opioid, patient-controlled. PMID- 29149141 TI - Music-Induced Analgesia in Chronic Pain Conditions: A Systematic Review and Meta Analysis. AB - BACKGROUND: Music is increasingly used as an adjuvant for the management of chronic pain (CP), as it is non-invasive, inexpensive, and patients usually report positive experiences with it. However, little is known about its clinical efficacy in chronic pain patients. OBJECTIVES: We aimed to determine the effect of music as an adjuvant for chronic pain, as well as to identify characteristics of music interventions associated with positive clinical outcomes. STUDY DESIGN: In this systematic review and meta-analysis, we investigated randomized controlled trials (RCTs) of adult patients that reported any type of music intervention for chronic pain, chosen by the researcher or patient, lasting for any duration. Searches were performed using PsycINFO, Scopus, and PubMed for RCTs published until the end of May 2016. The primary outcome was reduction in self reported pain using a standardized pain measurement instrument, reported post intervention. The secondary outcomes were: quality of life measures, depression, anxiety, and related measures. METHODS: The study was pre-registered with PROSPERO (CRD42016039837), and the meta-analysis was performed using RevMan 5.3 (The Nordic Cochrane Centre for The Cochrane Collaboration, Copenhagen, Denmark). We identified 768 titles and abstracts, and we included 14 RTCs that fulfilled our criteria. The sample size of the studies varied between 25 and 200 patients. RESULTS: We found that music reduced self-reported chronic pain and depressive symptoms. We also found that music had a greater effect when the patient chose the music, compared to when the researcher chose it. LIMITATIONS: The sample size of RCTs was small and sometimes with different outcome measures. There was high heterogeneity associated with pooled estimates. CONCLUSIONS: Our analysis suggests that music may be beneficial as an adjuvant for chronic pain patients, as it reduces self-reported pain and its common comorbidities. Importantly, the analgesic effect of music appears higher with self-chosen over researcher-chosen music. KEY WORDS: Pain, music, analgesia, music-induced analgesia, chronic pain, meta-analysis, systematic review, therapy. PMID- 29149142 TI - Mapping the Association between Vitamin D and Low Back Pain: A Systematic Review and Meta-Analysis of Observational Studies. AB - BACKGROUND: Low back pain (LBP) is the highest contributor to disability worldwide, with current intervention strategies only providing small to moderate analgesic effects. The use of vitamin D supplementation for LBP has gained interest due to its proposed anti-inflammatory and neuromodulatory properties. However, it is still unclear whether vitamin D levels differ between those with and without LBP or if vitamin D levels are associated with pain intensity. OBJECTIVES: We aim to investigate the association between vitamin D levels and LBP and to determine if vitamin D levels correlate with pain intensity in individuals with LBP. STUDY DESIGN: This study was conducted in accordance with the guidelines for performing a Meta-analysis and Systematic Review Of Observational Studies in Epidemiology (MOOSE). METHODS: We performed electronic database searches combined keywords relating to vitamin D and LBP in MEDLINE, CINAHL, EMBASE, AMED, WEB OF SCIENCE, and SCOPUS from the earliest record to March 2017. Studies were included if they reported any quantitative measure of vitamin D, such as serum 25-hydroxyvitamin D [25(OH)D], with adequate data in patients with and without LBP or adequate data on pain intensity in patients with LBP. No restriction on the type or duration of LBP, nor the age and gender of patients was applied. Two reviewers independently performed the selection of studies, extracted data, and assessed the methodological quality of the included studies using a modified 15-item Downs and Black checklist. RESULTS: After the removal of duplicates and the screening of titles and abstracts, 105 full texts were evaluated. There were 29 articles included in this systemic review (22 entered into a meta-analysis), including 19 cross-sectional studies, 9 case control studies, and one single-arm surgical trial where the pre-operative data were used in our analyses. The pooled results from 19 studies showed that individuals with LBP were more likely to have vitamin D deficiency (pooled OR = 1.60, 95% CI: 1.20 - 2.12, P = 0.001, n = 19), severe deficiency (pooled OR = 2.08, 95% CI: 1.19 - 3.64, P = 0.010, n = 7), and lower serum concentrations of 25(OH)D (weighted MD = 3.86, 95% CI: 0.20 - 7.52, P = 0.039, n = 12) compared to those without LBP (where "n" is the number of studies). The association between vitamin D deficiency (pooled OR = 1.83, 95% CI: 1.26 - 2.66, P = 0.002, n = 9) or serum 25(OH)D (weighted MD = 7.64, 95% CI: 4.02 - 11.26, P < 0.001, n = 4) and LBP was stronger for women but failed to be statistically significant for men (pooled OR = 1.06, 95% CI: 0.62 - 1.81, P = 0.213, n = 3). In addition, there were strong associations between vitamin D deficiency and LBP in patients < 60 years old (particularly women). We found minimal evidence to support an association between vitamin D levels and pain intensity in patients with LBP. LIMITATIONS: We were unable to investigate whether vitamin D deficiency increases the risk of developing LBP as there were no longitudinal studies included in this review. CONCLUSION: Vitamin D deficiency is associated with LBP, with stronger associations observed in younger women and those with severe levels of deficiency. The association between vitamin D levels and pain intensity is inconsistent. These results may guide the implementation of future studies on vitamin D supplementation for LBP. PROSPERO Registration No: CRD42016046874. KEY WORDS: Vitamin D, low back pain, deficiency, pain intensity, serum 25 hydroxyvitamin D, supplementation, cross-sectional study, case-control study. PMID- 29149143 TI - Efficacy of Magnesium Sulfate Added to Local Anesthetic in a Transversus Abdominis Plane Block for Analgesia Following Total Abdominal Hysterectomy: A Randomized Trial. AB - BACKGROUND: Major abdominal surgeries are associated with severe pain, which can affect respiratory and cardiac functions if insufficiently treated; this increases postoperative morbidity. OBJECTIVE: We aim at evaluating the efficacy of magnesium sulfate as an adjuvant to local anesthetic in an ultrasound-guided transversus abdominis plane (TAP) block for postoperative analgesia in total abdominal hysterectomy. STUDY DESIGN: A prospective, randomized, double-blinded clinical trial. SETTING: An academic medical center. METHODS: This study is registered at https://clinicaltrials.gov (no.: NCT02930707). This randomized, double-blinded clinical trial included 60 women undergoing total abdominal hysterectomy that were divided into 2 groups (30 patients per group). Group I received a TAP block with 20 mL per side of 0.25% bupivacaine plus 2 mL magnesium sulphate 10% (200 mg). Group II received a TAP block with 20 mL per side of 0.25% bupivacaine. Visual analog scale (VAS) scores, the time of the first analgesic request, total morphine consumption, and any side effects were assessed and recorded. RESULTS: The mean postoperative VAS score was significantly reduced in group I compared to group II in all of the time-points except after 10 hours. The mean time of the first request for rescue analgesia was significantly prolonged in group I (15.67 hrs.) compared to group II (7.33 hrs.) (P < 0.001), and the mean total morphine consumption, over the first 24 hours postoperatively, was significantly lower in group I (7.63 +/- 2.93 mg) than in group II (16.20 +/- 3.24 mg) (P < 0.001). No significant difference in side effects was observed. LIMITATIONS: Sample size. CONCLUSION: The addition of 200 mg of magnesium sulfate to bupivacaine in an ultrasound-guided TAP block significantly reduced postoperative opioid requirements, prolonged the duration of analgesia, and reduced the VAS score in patients who underwent abdominal hysterectomy, without significant side effects. KEY WORDS: Magnesium sulfate, TAP block, postoperative pain, total abdominal hysterectomy. PMID- 29149144 TI - The Efficacy of Preoperative Gabapentin in Spinal Surgery: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Pain management after spinal surgery has been studied for years. Gabapentin is a third-generation antiepileptic drug that selectively affects the nociceptive process and has been used for pain relief after surgery. However, the relationship between gabapentin and postoperative pain in spinal surgery is still controversial. OBJECTIVE: To assess the efficacy of the pre-emptive use of gabapentin in spinal surgery. STUDY DESIGN: A meta-analysis of randomized controlled studies. SETTING: The MEDLINE, EMBASE, ClinicalTrials.gov, and Web of Science databases were systematically searched. METHODS: This meta-analysis of randomized controlled trials (RCTs) was performed to compare the use of gabapentin with placebo in spinal surgery regarding to the following: the mean difference (MD) of postoperative opioid requirements, the changes of visual analog scale (VAS) scores in 2 groups, and the incidence rate of adverse effects. An electronic-based search of all related literatures was conducted, and only RCTs for spinal surgery were included. The MD of postoperative opioid requirements and VAS scores and the relative risk (RR) of the incidence rate of adverse effects in the gabapentin group versus the placebo group were extracted throughout the study. RESULTS: Ten trials, involving 827 patients, met the inclusion criteria and were included in this meta-analysis. The total morphine consumption was significantly lower over the first 24 hours postoperatively in the gabapentin group (P < 0.05). The VAS scores at 2, 4, 6, 12, and 24 hours were less in the gabapentin group (P < 0.05). The incidence rate of vomiting, pruritus, and urinary retention was significantly less in the gabapentin groups (RR = 0.53, 95% CI 0.32-0.86, P < 0.05; RR = 0.38, 95% CI 0.22-0.66, P < 0.05; RR = 0.57, 95% CI 0.34-0.98, P < 0.05, respectively). LIMITATIONS: All of the studies we screened were published online except for unpublished articles. Only 10 RCTs met our inclusion criteria, so the sample size was still relatively small. CONCLUSION: This meta-analysis suggests that the administration of gabapentin is effective in reducing postoperative opioid consumption, VAS scores, and some side effects after spinal surgery. KEY WORDS: Gabapentin, analgesia, spinal surgery, meta-analysis, randomized controlled trials, visual analog scale score, side effect. PMID- 29149145 TI - Endoscopic Epidural Laser Decompression Versus Transforaminal Epiduroscopic Laser Annuloplasty for Lumbar Disc Herniation: A Prospective, Randomized Trial. AB - BACKGROUND: Lumbar radicular pain often results from lumbar disc herniation, spinal stenosis, or degenerative spondylolisthesis. Minimally invasive disc decompression procedures, such as nucleo-annuloplasty or epiduroscopic neural decompression by laser, have been devised to treat such pain. OBJECTIVE: The short-term outcomes of disc decompression by endoscopic epidural laser decompression (EELD) or transforaminal epiduroscopic laser annuloplasty (TELA) were compared in patients with lumbar radicular pain due to disc herniation. STUDY DESIGN: A randomized, prospective trial. SETTING: The Department of Anesthesiology and Pain Medicine at Spine Health Wooridul Hospital in Daegu, Korea. METHODS: A total of 97 patients were enrolled in this study; 48 patients underwent EELD and 49 underwent TELA. The pain relief was evaluated at baseline and at 1, 3, and 6 months post-procedure via the numeric rating scale (NRS). The Oswestry Disability Index (ODI) was recorded at baseline and at the final follow up. Postoperative wound pain was assessed over a 24-hour period. Complications and side effects were also recorded, as were operative times (from local anesthetic infiltration at entry sites to suturing of skin). RESULTS: At post treatment months 1, 3, and 6 the mean pain scores of patients were significantly lower (relative to pre-treatment baseline) regardless of the procedure used. However, the mean pain scores did not differ significantly by procedure (EELD vs TELA). As well, the number of patients who obtained relief from their pain and needed analgesics was not statistically significant. The irrigation volume was significantly higher in the TELA group. Two patients undergoing TELA procedures experienced headache during the procedures; however, no serious complications such as bleeding, dural/neural injuries, or infection were recorded for either group. LIMITATION: The observed significant reductions in pain (from baseline) lacked secondary outcome substantiation and given the mid follow-up period, no long-term follow-up results were monitored. CONCLUSION: Both EELD and TELA provide similar outcomes and are reasonable treatment options for carefully selected patients with lower back or radicular pain. KEY WORDS: Epiduroscopy, laser, annuloplasty, disc, herniation, TELA. PMID- 29149146 TI - Dexamethasone and Dexmedetomidine as an Adjuvant to Intraarticular Bupivacaine for Postoperative Pain Relief in Knee Arthroscopic Surgery: A Randomized Trial. AB - BACKGROUND: Knee arthroscopy causes minimal trauma, however, good analgesia is required for early rehabilitation and return to normal life in the patients. OBJECTIVE: We aimed to compare the analgesic effects of intraarticular dexamethasone and dexmedetomidine added to bupivacaine with those of bupivacaine alone. STUDY DESIGN: This study uses a double-blind, randomized, controlled design with allocation concealment in a 3-armed parallel group format among patients undergoing arthroscopic meniscal surgery. SETTING: The study was conducted at Assiut University Hospital in Asyut, Egypt. The study duration was from July 2016 to February 2017. METHODS: After the ethics committee approval, 60 patients, with the American Society of Anesthesiologists (ASA) physical status of I or II, 20 - 50 years old, and scheduled for arthroscopic meniscal surgery were randomized in a double-blind manner to receive 18 mL intraarticular bupivacaine 0.25% with either dexamethasone 8 mg (group I), dexmedetomidine 1 ug/kg (group II), or 2 mL of normal saline (group III). The total volume of injectate used in each group was 20 mL. All of the patients received spinal anesthesia. Postoperatively, oral paracetamol 1000 mg was given every 8 hours, and oral tramadol 50 mg was administered, as needed, for rescue analgesia. The visual analog scale (VAS) pain scores, time to first analgesic request, and total dose of postoperative analgesics were recorded for 3 days postoperatively. RESULTS: The VAS scores were lower in groups I and II compared with group III. The time to the first analgesic was significantly shorter in group III compared with groups I and II (P = 0.001). The total dose of rescue paracetamol was higher in group III compared with groups I and II (P = 0.001). No need for tramadol rescue analgesia was recorded in any of the groups. No significant differences between groups I and II were noticed. LIMITATIONS: The limitations of this study include the lack of previous research to compare the effect of both intraarticular dexamethasone and dexmedetomidine added to bupivacaine for postoperative analgesia in arthroscopic knee surgery. Additionally, there was a short observation period for the detection of chondrotoxicity, if occurred. CONCLUSION: The addition of dexamethasone or dexmedetomidine to a solution of bupivacaine 0.25% provided better analgesia than using bupivacaine alone. CLINICAL TRIAL REGISTRATION: NCT02818985. KEY WORDS: Intraarticular, knee arthroscopy, bupivacaine, dexmedetomidine, dexamethasone, postoperative pain. PMID- 29149147 TI - Hypothalamic Pituitary Adrenocortical Axis Suppression following a Single Epidural Injection of Methylprednisolone Acetate. AB - BACKGROUND: Epidural injections (EIs) are the most commonly performed minimally invasive intervention in managing chronic low back pain (CLBP). There is inconsistency in data to accurately predict the degree of hypothalamic-piuitary adrenal (HPA) axis suppression in patients receiving exogenous steroid therapy, especially in the form of epidural steroid injections (ESIs). OBJECTIVE: We aim to quantify the degree and duration of HPA axis suppression after a single ESI of 80 mg methyl prednisolone acetate in patients with CLBP. STUDY DESIGN: A single open-label prospective study. SETTING: An operating room of a tertiary care hospital. METHODS: Patients with CLBP and unilateral radicular pain were included in this study. An ESI of 80 mg of methylprednisolone acetate was administered in each patient. Blood samples for cortisol and adrenocorticotropic hormone (ACTH) were collected before the ESI and on days 7, 14, and 28 after the ESI. The patients' pain levels were graded on the numeric rating scale (NRS) at baseline and on days 7, 14, 28, and 60 after the ESI in the pain clinic. RESULTS: A total of 30 patients were enrolled in this study. The median with interquartile range (IQR) serum cortisol level at baseline and on days 7, 14, and 28 after intervention were found to be 329.55 (208.49 - 399.48) nmol/L, 72.99 (52.95 - 119.82) nmol/L, 194.45 (73.88 - 292.52) nmol/L, and 302.56 (257.68 - 357.43) nmol/L, respectively. A significant discrease in the serum cortisol levels was observed on days 7 (P < 0.001) and 14 (P < 0.001). Twenty-six (87%), 13 (43%), and 2 (7%) patients had serum cortisol levels below normal (<170 nmol/L) on days 7, 14, and 28, respectively. HPA axis suppression was observed in all of the patients for a median (IQR) period of 14 days (range: 11-17 days). LIMITATIONS: This study was an unblinded observational study. The effect of a single ESI was studied and the sample collection of day 21 serum cortisol and ACTH were passed over. CONCLUSIONS: HPA axis function was suppressed after the ESI until day 14 and returned to the normal range by postoperative week 4. KEY WORDS: Epidural injections, steroids, HPA, suppression, cortisol, ACTH. PMID- 29149148 TI - Current Impact and Application of Abuse-Deterrent Opioid Formulations in Clinical Practice. AB - BACKGROUND: Abuse-deterrent formulations (ADFs) represent one novel strategy for curbing the potential of opioid abuse. OBJECTIVE: We aim to compare and contrast the characteristics and applications of current abuse-deterrent opioid products in clinical practice. METHODS: Literature searches were conducted in databases (Pubmed Medline, International Pharmaceutical Abstracts, Google Scholar) and official reports. Relevant data were screened and organized into: 1) epidemiology of opioid abuse, 2) mitigation strategies for reducing opioid abuse, 3) development of ADFs, and 4) clinical experience with these formulations. RESULTS: Increasing trends of opioid abuse and misuse have been reported globally. There are 5 types of abuse-deterrent opioid products: physical chemical barrier, combined agonist/antagonist, sequestered aversive agent, prodrug, and novel delivery system. The advantages and disadvantages of the 5 options are discussed in this review. A total of 9 products with abuse-deterrent labels have been approved by the Food and Drug Administration (FDA). The rates of abuse, diversion, and overdose deaths of these new products are also discussed. A framework for collecting in-time data on the efficacy, benefit and risk ratio, and cost-effectiveness of these new products is suggested to facilitate their optimal use. LIMITATIONS: The present review did not utilize systematic review standards or meta-analytic techniques, given the large heterogeneity of data and outcomes reviewed. CONCLUSIONS: ADFs provide an option for inhibiting the abuse or misuse of oral opioid products by hindering extraction of the active ingredient, preventing alternative routes of administration, or causing aversion. Their relatively high costs, uncertain insurance policies, and limited data on pharmacoeconomics warrant collaborative monitoring and assessment by government agencies, pharmaceutical manufacturers, and data analysis services to define their therapeutic role in the future. KEY WORDS: Opioid abuse, abuse-deterrent formulations, ADF, post-marketing, FDA guidance, cost impact, abuse liking, physician attitude, generic abuse-deterrent formulation, clinical application. PMID- 29149149 TI - Decreased Regional Grey Matter Volume in Women with Chronic Whiplash-Associated Disorders: Relationships with Cognitive Deficits and Disturbed Pain Processing. AB - BACKGROUND: Patients with chronic whiplash-associated disorders (CWAD) are characterized by pain of traumatic origin, cognitive deficits, and central sensitization (CS). Previous neuroimaging studies revealed altered grey matter volume (GMV) in mild traumatic brain injury patients and chronic pain conditions also characterized by CS. It can therefore be hypothesized that GMV alterations also play a role in the persistent complaints of CWAD. However, brain alterations remain poorly investigated in these patients. OBJECTIVES: This study examined regional GMV alterations in patients with CWAD compared to patients with non traumatic chronic idiopathic neck pain (CINP), who normally do not show CS at a group level, and healthy controls. Additionally, in both patient groups, relationships between regional GMV and measures of cognition as well as pain processing were assessed. STUDY DESIGN: A cross-sectional case-control study. SETTING: This study was performed at the Department of Rehabilitation Sciences and Physiotherapy of Ghent University in cooperation with the Ghent Institute for Functional and Metabolic Imaging. METHODS: Ninety-three women (28 healthy controls, 34 CINP patients, and 31 CWAD patients) were enrolled. First, T1 weighted magnetic resonance images (MRIs) were acquired to examine GMV alterations in the brain regions involved in processing cognition and pain. Next, cognitive performance, pain cognitions, and CS symptoms were assessed. Finally, hyperalgesia and conditioned pain modulation efficacy were examined. RESULTS: Regional GMV of the right lateral orbitofrontal cortex, left supramarginal cortex, and left posterior cingulate cortex was decreased in CWAD patients compared to healthy controls (P = 0.023; P = 0.012; P = 0.047, respectively). Additionally, GMV of the right superior parietal cortex and left posterior cingulate cortex was decreased in CWAD patients compared to CINP patients (P = 0.008; P = 0.035, respectively). Decreased regional GMV correlated with worse cognitive performance, higher maladapted pain cognitions, CS symptoms, and hyperalgesia in CWAD patients (rs = -0.515 to -0.657; P < 0.01). In CINP patients, decreased regional GMV correlated only with worse cognitive performance (rs = -0.499 to -0.619; P < 0.01), and no GMV differences compared with the controls could be revealed. LIMITATIONS: No conclusions about the causality of the observed relationships can be drawn. CONCLUSIONS: These results provide the first evidence for reduced GMV in cortical regions involved in processing cognition and pain in patients with CWAD. Accordingly, it is recommended that therapy approaches for CWAD patients should address the brain and take into account neuroplasticity of the central nervous system (CNS). KEY WORDS: Whiplash injuries, neck pain, magnetic resonance imaging, grey matter, cognitive dysfunction, pain catastrophizing, central sensitization. PMID- 29149150 TI - The Hopeless Case? Palliative Cryoablation and Cementoplasty Procedures for Palliation of Large Pelvic Bone Metastases. AB - BACKGROUND: Metastases to the bone are common in cancer patients, and it has been estimated that up to 50% of patients with pelvic bone metastases will not achieve adequate pain control with medications alone. This has led to a paradigm shift over recent years towards the use and development of minimally invasive image guided treatment options for palliation of bony metastases. Despite these developments, large metastatic lesions are still often considered to be "hopeless cases" that would garner little to no benefit from image-guided intervention. This study is the first large series to describe the novel use of combination percutaneous cryoablation and cementoplasty for palliation of such large metastases to the pelvis. OBJECTIVES: We aim to evaluate the efficacy and safety of image-guided percutaneous cryoablation and cementoplasty for palliation of large pelvic bone metastases. STUDY DESIGN: This retrospective analysis was approved by our institutional review board. This study was conducted from January 2013 to December 2016, where consecutive patients referred for pain management of large pelvic bone metastases underwent combination percutaneous cryoablation and cementoplasty. SETTING: This study took place at a tertiary care center after patients were referred following formal review from a multidisciplinary conference, which was comprised of interventional radiologists, pain management and palliative care physicians, radiation and medical oncologists, and when available, anesthesiologists. METHODS: Forty-eight patients (36 men and 12 women) with a mean cohort age of 77.5 years (range: 52 - 89 years) were referred from the multidisciplinary conference for palliation of pelvic bone metastases. The inclusion criteria included patients with metastases greater or equal to 5.0 cm and significant pain refractory to conventional pain management regimens. All of the patients were deemed not to be surgical candidates. Mean pain scores were collected at numerous time-points along with procedural technical success rates and complication rates. RESULTS: Combination cryoablation and cementoplasty was performed on 48 consecutively referred patients with a 100% technical success rate and no immediate complications. The pain levels demonstrated a significant decrease (P < 0.001) following intervention, with mean pain scores of 7.9 (range: 5 - 10) and 1.2 (range: 0 - 7) throughout the week prior to intervention and at 24 hours post-intervention, respectively. The post-intervention pain scores remained stable at 1 to 9 weeks follow-up (mean: 4.1 weeks). Three patents (6.3%) reported no change in pain following the intervention; however, no patients reported worsened pain. LIMITATIONS: The limitations of this study include its retrospective nature and the length of follow-up, which was often restricted given the life expectancy of our patient cohort. CONCLUSION: Combination cryoablation and cementoplasty is a novel and efficacious treatment option for palliation of large pelvic bone metastases. Marked improvements in pain, as well as mobility and quality of life, are often attainable. KEY WORDS: Pain, palliative care, palliation, percutaneous, cryoablation, cementoplasty, metastases, pelvis, interventional radiology, thermal ablation. PMID- 29149151 TI - Sacroplasty: A Ten-Year Analysis of Prospective Patients Treated with Percutaneous Sacroplasty: Literature Review and Technical Considerations. AB - BACKGROUND: The treatment of sacral fractures has evolved since its first description in 1982. Several techniques for sacral augmentation have been developed since 2001, and the rate of improvement is rapid with over 50% reduction in pain achieved prior to post-procedure discharge of the patient. Pain reduction occurs primarily within the first 3 months and is sustained at 12 months; however, the long-term outcomes have not previously been studied. OBJECTIVES: We aim to evaluate the long-term efficacy of sacroplasty versus non surgical management (NSM) in treating sacral insufficiency fractures (SIFs), including the effect on pain relief, opioid and other analgesic use, patient satisfaction, and complication rates. Additionally, we aim to review the most current sacroplasty literature. STUDY DESIGN: A 10-year prospective, observational cohort study of patients with SIFs treated with sacral augmentation. SETTING: A single-center interventional pain management private practice. METHODS: Two-hundred and forty-four patients with SIFs were treated with sacroplasty (210 patients) or NSM (34 patients) beginning in January 2004 and then followed for 10 years. The patients' gender, age, pre-procedure pain duration, analgesic use, pain level, and satisfaction were recorded at baseline and at post-procedure follow-up intervals of 2, 4, 12, 24, 52 weeks, and 2 years. The experimental group was then contacted at 10 years. Post-procedure complications before discharge and at each follow-up were also evaluated. RESULTS: Both NSM and sacroplasty resulted in statistically significant drops in visual analog scale (VAS) scores from pre-treatment to 2-year follow-up (P < 0.001). When measured from follow-up to follow-up, the NSM group's only significant decrease in the mean VAS score was between pre-treatment and 2 weeks (P = 0.002). The experimental group had significant decreases over the periods pre-op through post-op (P < 0.001), post-op through 2 weeks (P < 0.001), 12 weeks through 24 weeks (P = 0.014), and 24 weeks through one year (P = 0.002). The experimental cohort experienced statistically significant drops in the mean VAS scores between follow-ups for a longer period of time. Opioid and non-opioid analgesic use was markedly decreased preoperatively to postoperatively and was sustained at the 10-year follow-up. LIMITATIONS: Patients were placed into the control group, NSM, if they did not meet inclusion criteria for sacroplasty. However, the baseline characteristics of the sacroplasty versus NSM group were not statistically different. Additionally, the control group was only followed through 2 years and was not contacted at the 10-year follow-up. CONCLUSIONS: Our results and those reported in previous studies establish that sacroplasty allows for decreased use of medications and results in pain relief, greater patient mobility, and improved patient satisfaction. In addition to the published body of literature, our results show strong evidence in support of sacroplasty as a safe and efficacious treatment of SIFs. KEY WORDS: Sacroplasty, sacral fracture, fracture, osteoporosis, insufficiency, radiology. PMID- 29149152 TI - Loss of Efficacy to Spinal Cord Stimulator Therapy: Clinical Evidence and Possible Causes. AB - BACKGROUND: Although spinal cord stimulation (SCS) therapy has been shown to be efficacious in various pain conditions, the ability for SCS therapy to maintain long-term efficacy has been questioned. OBJECTIVE: The purpose of this study was to investigate whether a loss of efficacy (LOE) phenomenon exists with SCS therapy and to investigate if this phenomenon is more apparent in any specific patient population. STUDY DESIGN: A retrospective, observation chart review was conducted to evaluate the patient response to SCS therapy over time. SETTING: Massachusetts General Hospital, Boston, Massachusetts. METHODS: Patients who received a SCS at the Massachusetts General Hospital, between January 1, 2002 and December 31, 2012, were invited to participate. A total of 62 patients were included in this study. Various models were created to analyze pain score changes over time using 2-tailed statistical analysis. Additionally, one-way ANOVA and Pearson's chi-square tests were used to determine if certain patient characteristics were associated with LOE. RESULTS: Compared to the visual analog scale (VAS) score at one month after device implantation, pain scores increased 1.95 points after 2 years (95% CI: 1.06 to 2.84, P = < 0.001). There were no significant differences in baseline characteristics between the groups of patients who did and did not lose efficacy of their therapy. However, those who experienced LOE had a baseline SCS therapy VAS score 3.09 points lower than those who did not (95% CI: 1.69 to 4.48, P = < 0.001). LIMITATIONS: This study had several limitations including the retrospective nature of its design, confounders to VAS scores, small sample size, missing data points, and the evaluation of only conventional, low-frequency SCS therapy. CONCLUSIONS: Patients who received a SCS had a significant increase in VAS scores over time. Our data did not show any baseline patient characteristic that helped predict LOE. However, patients who have significant baseline response to therapy may be more likely to experience LOE. KEY WORDS: Spinal cord stimulation, chronic pain, retrospective study, low frequency electrical stimulation, efficacy, chronic pain therapy. PMID- 29149153 TI - Analysis of Reporting Bias in Vertebral Augmentation. AB - : Osteoporotic vertebral compression fractures (OVCFs) are a significant cause of morbidity and mortality in the United States and worldwide, with estimates of 750,000 to 1.5 million occurring annually. As the elderly population continues to increase, the incidence of OVCFs will continue to rise, as will the morbidity and mortality associated with this condition. Vertebral augmentation (VA) was almost universally accepted as the appropriate treatment modality prior to 2 sham trials published in 2009 by the New England Journal of Medicine (NEJM). Subsequently, there is now significant controversy regarding the optimal treatment of OVCFs. Since 2009 there have been 6 prospective randomized controlled studies (PRCTs) and 2 meta-analyses on VA for the treatment of OVCFs. Five of the PRCTs and both of the meta-analyses have shown superior results with VA as compared with nonsurgical management (NSM). However, a recent health technology assessment and review article continue to over-emphasize the 2 NEJM sham trials, despite the most current literature. These are examples of inconsistent or biased data reporting with overemphasis on certain trial types and exclusion of other types of data, resulting in the reporting of conclusions that are partially representative or not representative of the complete data. As clinical investigators, we have a responsibility to limit bias and ensure that the appropriate treatment modalities are made available to vulnerable populations.The aim of this perspective analysis is to examine sources of bias in reporting and some of the publications that contain it, along with comparing the publications to the current body of published literature relevant to this topic. KEY WORDS: Vertebral augmentation, vertebroplasty, kyphoplasty, bias, osteoporosis, compression fracture. PMID- 29149154 TI - Philosophical Issues and Psychological Variables that Influence the Determination of Opioid Effectiveness: A Narrative Review. AB - BACKGROUND: The prescribing of opioids in the chronic pain setting is often based on the pharmacodynamics, pharmacokinetics, and pharmacogenetics of the drug obtained during development and clinical trials. However, the effectiveness of opioids varies widely and often appears to bear no relationship to the aforementioned variables. The impact of philosophical issues and psychological factors on determining how clinically effective opioid therapy is has often been over looked. OBJECTIVES: This manuscript provides a selective review and narrative summary of the philosophical issues and psychological factors which can influence opioid effectiveness. STUDY DESIGN: A selective review and narrative analysis of the literature. METHODS: Experimental and clinical-based studies examining the impact of psychological factors on the effectiveness of opioids were extracted from the literature. Studies in which psychological factors were used as an independent variable were given preference. RESULTS: The philosophical issues reviewed include: (a) one's understanding of the nature of chronic pain, (b) the meaning of the score on the pain numerical rating scale (NRS), and (c) the selection of outcome measures. The psychological factors found to influence the effectiveness of opioids include: (a) role conditioning and learning, especially as they relate to conditioned analgesia, non-associative tolerance, and the nocebo effect, (b) dosing pattern, (c) patient specific factors, e.g., mood, overall psychological and neurocognitive status, (d) social variables, e.g., personal environment and the media, and (e) the dysfunctional endogenous opioid system and its relationship to various psychological disorders. LIMITATIONS: This is a selective review of the literature. Some of the hypotheses presented have not been experimentally validated. The review includes animal, human, experimental, and clinical studies. CONCLUSIONS: In general, the effectiveness of opioids may be influenced as much by the overall context in which they are used, including the physician-patient relationship as well as their pharmacological properties. Data obtained from short-term and well controlled trials may not generalize to the clinical setting, which is often more complex and dynamic. Appreciating the impact of psychological factors may assist the clinician in proper patient selection, monitoring, and improved outcomes. KEY WORDS: Psychological factors, philosophical issues, chronic pain, opioid therapy, effectiveness, conditioning, placebo, cognitive dysfunction. PMID- 29149155 TI - Lower Cutoffs for LC-MS/MS Urine Drug Testing Indicates Better Patient Compliance. AB - BACKGROUND: Urine drug testing is used by health care providers to determine a patient's compliance to their prescribed regimen and to detect non-prescribed medications and illicit drugs. However, the cutoff levels used by clinical labs are often arbitrarily set and may not reflect the urine drug concentrations of compliant patients. OBJECTIVES: Our aim was to test the hypothesis that commonly used cutoffs for many prescribed and illicit drugs were set too high, and methods using these cutoffs may yield a considerable number of false-negative results. The goals of this study were to outline the way to analyze patient results and estimate a more appropriate cutoff, develop and validate a high sensitivity analytical method capable of quantitating drugs and metabolites at lower than the commonly used cutoffs, and determine the number of true positive results that would have been missed when using the common cutoffs. STUDY DESIGN: This was a retrospective study of urine specimens submitted for urine drug testing as part of the monitoring of prescription drug compliance described in chronic opioid therapy treatment guidelines. SETTING: The study was set in a clinical toxicology laboratory, using specimens submitted for routine analysis by health care providers in the normal course of business. METHODS: Lognormal distributions of test results were generated and fitted with a trendline to estimate the required cutoff level necessary to capture the normal distributions of each drug for the patient population study. A validated laboratory derived liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis capable of achieving the required cutoff levels was developed for each drug and/or metabolite. RESULTS: The study shows that a lognormal distribution of patient urine test results fitted with a trendline is appropriate for estimating the required cutoff levels needed to assess medication adherence. The study showed a wide variation in the false negative rate, ranging from 1.5% to 94.3% across a range of prescribed and illicit drugs. LIMITATIONS: The patient specimens were largely sourced from patients in either a long-term pain management program or in treatment for substance use disorder in the US. These specimens may not be representative of patients in other types of treatment or in countries with different approaches to these issues. CONCLUSIONS: The high-sensitivity method reduces false-negative results which could negatively impact patient care. Clinicians using less sensitive methods for detecting and quantifying drugs and metabolites in urine should exercise caution in assessing patient adherence using and changing the treatment plan based on those results. KEY WORDS: Urine drug testing, patient adherence, clinical toxicology, immunoassay, LC-MS, definitive drug testing, REMS, negative test results, false negative. PMID- 29149156 TI - Survival Analysis of Occipital Nerve Stimulator Leads Placed under Fluoroscopic Guidance with and without Ultrasonography. AB - BACKGROUND: Electrical stimulation of the greater occipital nerves is performed to treat pain secondary to chronic daily headaches and occipital neuralgia. The use of fluoroscopy alone to guide the surgical placement of electrodes near the greater occipital nerves disregards the impact of tissue planes on lead stability and stimulation efficacy. OBJECTIVE: We hypothesized that occipital neurostimulator (ONS) leads placed with ultrasonography combined with fluoroscopy would demonstrate increased survival rates and times when compared to ONS leads placed with fluoroscopy alone. STUDY DESIGN: A 2-arm retrospective chart review. SETTING: A single academic medical center. METHODS: This retrospective chart review analyzed the procedure notes and demographic data of patients who underwent the permanent implant of an ONS lead between July 2012 and August 2015. Patient data included the diagnosis (reason for implant), smoking tobacco use, disability, and age. ONS lead data included the date of permanent implant, the imaging modality used during permanent implant (fluoroscopy with or without ultrasonography), and, if applicable, the date and reason for lead removal. A total of 21 patients (53 leads) were included for the review. Chi-squared tests, Fishers exact tests, 2-sample t-tests, and Wilcoxon rank-sum tests were used to compare fluoroscopy against combined fluoroscopy and ultrasonography as implant methods with respect to patient demographics. These tests were also used to evaluate the primary aim of this study, which was to compare the survival rates and times of ONS leads placed with combined ultrasonography and fluoroscopy versus those placed with fluoroscopy alone. Survival analysis was used to assess the effect of implant method, adjusted for patient demographics (age, smoking tobacco use, and disability), on the risk of lead explant. RESULTS: Data from 21 patients were collected, including a total of 53 ONS leads. There was no statistically significant difference in the lead survival rate or time, disability, or patient age with respect to the implant method with or without ultrasonography. There was a statistically significant negative effect on the risk of explant with regards to lead removal in smoking patients compared to non smoking patients (hazard ratio 0.36). There was also a statistically significant difference in smoking tobacco use with respect to the implant method, such that a greater number of patients whose leads were placed with combined fluoroscopy and ultrasonography had a history of smoking (P = 0.048). LIMITATIONS: This study is a retrospective chart review that had statistically significant differences in the patient groups and a small sample size. CONCLUSION: This study assessed the survival rates and times of ONS leads placed with ultrasonography and fluoroscopy versus fluoroscopy alone. We did not observe an effect to suggest that the incremental addition of ultrasound guidance to fluoroscopy as the intraoperative imaging modality used during the permanent implant of ONS leads yields statistically significant differences in lead survival rate or time. Medical comorbidities, including age and smoking status, may play a role in determining the risk of surgical revision and should be considered in future studies. KEY WORDS: Neuromodulation, peripheral nerve stimulation, occipital nerve stimulation, occipital neuralgia, chronic daily headaches, ultrasonography. PMID- 29149159 TI - In Errata: Cost Utility Analysis of Lumbar Interlaminar Epidural Injections in the Treatment of Lumbar Disc Herniation, Central Spinal Stenosis, and Axial or Discogenic Low Back Pain. PMID- 29149157 TI - Full-Endoscopic Procedures Versus Traditional Discectomy Surgery for Discectomy: A Systematic Review and Meta-analysis of Current Global Clinical Trials. PMID- 29149162 TI - [Switching from one drug therapy to another with the same therapeutic indication without harms.] AB - The loss of exclusivity from several drug therapies largely used bring new attention the issues of safety, efficacy and following the switch from one drug to another (i.e., biosimilar and/or generics) with the same indication. This is not a problem that can be related to regulatory or economical factors. The increase of patients exposed to chronic conditions and the introductions or more pharmaceutical alternatives with same therapeutic indications yield for studies able to verify the effectiveness and safety even when switch from more drugs is considered by practitioners. Recent multiregional studies showed that the switch from phenomenon is not a rare event, especially with biologic drugs, frequent even before the introduction of biosimilar not only because of economical reasons. For instance, a study made in our region (Lazio) showed that around 17% of patients treated with epoetins have been exposed to same kind of switch between drugs with same therapeutic indications. In this context it became crucial to explore new methodologies in order to verify before and after drug registrations how the potential switching affect final health outcomes. Limitations and design of the new studies need to be critically analysed. PMID- 29149163 TI - [Recommandation for patient engagement promotion in care and cure for chronic conditions.] AB - The concept of patient engagement is receiving a growing attention in the healthcare field. The last decades have seen a deep revision of care models in the aim of a greater acknowledge of the patient role, seen as an expert actor, in the healthcare process. On the other side, healthcare systems are facing a growing request for participation expressed by citizens and patients. People claim for being more involved in all the crucial turning point of their healthcare journey and of being better aware of their right and duties. They require a deeper knowledge about all the different therapeutic options with the related risks and advantages. However, although all the different stakeholders agree in considering patient engagement a pragmatic further then ethical priority, a shared consensus related to the strategies and instrument to promote has still to come. Patients and healthcare professional perspective about the factors that may hinder or sustain patient engagement still need to be further studied and at shared recommendations - about the programs better effective and efficient in promoting patient engagement - are still missed. Based on these premises, Universita Cattolica of Milano and DG Welfare of Regione Lombardia, under the methodological supervision of the Istituto Superiore di Sanita, promoted a consesus conference entitled "Recommendation for promoting patient engagement in healthcare for chronic conditions". This consensus conferences constituted the occasion of sharing and discussion among experts belonging to different clinical and institutional contexts as well as with representative of patients associations in order to identify good practices and effective tools to promote patient engagement in the care and cure process for chronic conditions. PMID- 29149164 TI - [OssERvare Project: direct observation of use of the Safety Surgery CheckList in the operating room.] AB - INTRODUCTION: Safety Surgery CheckList (SSCL) is a support tool for operating teams, used to carry out safety checks while also encouraging compliance with the implementation of recommended quality and safety standards. In Emilia-Romagna it was deemed appropriate to check actual surgical team compliance with correct checklist application in the operating theatre, through a project called "OssERvare". METHODS: Direct observation was identified as the preferred inspection method. With the use of special report sheets, observers proceeded with the guided observation of behaviour in the operating room, recording any inconsistencies with correct SSCL use methods. The project began in January 2017 and all observations were carried out from 1st January-15th April 2017. RESULTS: In 43% of observed operation sign in, all three team members were not present, whereas in 7% of observed cases, sign out was not carried out. All three team members were present in 88% of observed operation time out. There are two evidently critical phases: sign in and sign out. Results obtained for time out were better. DISCUSSION AND CONCLUSION: Compliance data collected from observations differed markedly from reported compliance in administrative flow records. The results of the observational study indicate that the SSCL is not properly filled in many times; there is also a great possibility to improve the correct use of this tool. In conclusion, we think that the combined approach of use of administrative data and assessing compliance appeared to be a useful instrument to investigate the implementation and to promote the real utilization of safety tools such as the SSCL. PMID- 29149165 TI - [Reflections on the death of my father.] AB - This short essay aims to provide the reader with some general considerations from a private matter, namely the death of the author's father after a long and disabling neurodegenerative disease. The author's reflection revolves around the meaning of death, the relationship between children and parents, the importance of individual and collective memory, and the role that physicians should have in dealing with relatives of subjects suffering from this type of disease. PMID- 29149166 TI - ? PMID- 29149167 TI - ? PMID- 29149168 TI - Airway expression of Transient Receptor Potential (TRP) Vanniloid-1 and Ankyrin-1 channels is not increased in patients with Idiopathic Pulmonary Fibrosis. AB - Dry cough is a common symptom described in patients with Idiopathic Pulmonary Fibrosis (IPF) and impairs quality of life. The exact mechanisms causing cough in IPF remain unclear, however evidence suggests altered cough neurophysiology and sensitisation plays a role; IPF patients have an enhanced cough reflex sensitivity to inhaled capsaicin. The Transient Receptor Potential Vanniloid-1 channel (TRPV-1) has a role in the cough reflex and airway expression is increased in patients with chronic cough. The Ankyrin-1 receptor (TRPA-1) is often co-expressed. It was hypothesised that, like chronic cough patients, IPF patients have increased airway TRP receptor expression. Bronchial biopsies were obtained from 16 patients with IPF, 11 patients with idiopathic chronic cough and 8 controls without cough. All other causes of cough were rigorously excluded. Real-time quantitative Polymerase Chain Reaction was used to detect TRPV-1 and TRPA-1 mRNA expression with Immunohistochemistry demonstrating protein expression. Mean TRPV-1 and TRPA-1 gene expression was higher in IPF patients compared with controls, but the difference did not reach statistical significance. Immunostaining supported these findings. This study suggests that structural up-regulation of central airway TRP receptors is not the key mechanism for cough in IPF patients. It is probable that IPF cough results from altered neuronal sensitivity at multiple levels of the cough pathway. PMID- 29149169 TI - The role of Allee effect in modelling post resection recurrence of glioblastoma. AB - Resection of the bulk of a tumour often cannot eliminate all cancer cells, due to their infiltration into the surrounding healthy tissue. This may lead to recurrence of the tumour at a later time. We use a reaction-diffusion equation based model of tumour growth to investigate how the invasion front is delayed by resection, and how this depends on the density and behaviour of the remaining cancer cells. We show that the delay time is highly sensitive to qualitative details of the proliferation dynamics of the cancer cell population. The typically assumed logistic type proliferation leads to unrealistic results, predicting immediate recurrence. We find that in glioblastoma cell cultures the cell proliferation rate is an increasing function of the density at small cell densities. Our analysis suggests that cooperative behaviour of cancer cells, analogous to the Allee effect in ecology, can play a critical role in determining the time until tumour recurrence. PMID- 29149170 TI - Vibrio parahaemolyticus VtrA is a membrane-bound regulator and is activated via oligomerization. AB - Vibrio parahaemolyticus is a Gram-negative pathogen that causes food-borne gastroenteritis. A major virulence determinant of the organism is a type III secretion system (T3SS2) encoded on a pathogenicity island, Vp-PAI. Vp-PAI gene expression is regulated by two transcriptional regulators, VtrA and VtrB, whose N terminal regions share homology with an OmpR-family DNA-binding domain. VtrA activates the gene expression of VtrB, which in turn activates Vp-PAI gene expression; however, the mechanism of this transcriptional activation by VtrA is not well understood. In this study, we determined that VtrA is a membrane protein with a transmembrane (TM) domain, which was required for its transcriptional regulatory activity. Although the N-terminal region of VtrA alone is insufficient for its transcriptional regulatory activity, forced oligomerization using the leucine-zipper dimerization domain of yeast GCN4 conferred transcriptional regulatory activity and a greater affinity for the promoter region of vtrB. A ToxR-based assay demonstrated that VtrA oligomerizes in vivo. We also showed that bile, a host-derived activator of VtrA, induces the oligomerization of VtrA, which requires the C-terminal domain. The promoter region of vtrB contained repetitive T-rich DNA elements, which are important for vtrB transcriptional activation and are conserved among T3SS2-possessing Vibrio species. These findings propose that VtrA is active as oligomers, which may facilitate its N terminus binding the target DNA, thus enhancing its transcriptional regulatory activity. PMID- 29149171 TI - Risk factors for hospitalizations among patients with cirrhosis: A prospective cohort study. AB - This study was designed to assess unique baseline factors associated with subsequent hospitalizations in a cohort of outpatients with cirrhosis. A cohort of 193 patients with cirrhosis was recruited from an outpatient liver disease clinic at a single, tertiary medical center. Comorbidities, prescription medications, liver disease symptoms and severity, and psychiatric and pain symptoms were assessed at baseline using validated instruments. Inflammatory markers were measured using standardized Luminex assays. Subsequent hospitalizations and the primary admission diagnoses were collected via chart review. Multivariable models were used to evaluate which baseline factors were associated with time to hospitalization and number of hospitalizations. The cohort consisted of 193 outpatients, with an average age of 58+/-9 and model for end-stage liver disease (MELD) score of 12+/-5. Over follow-up, 57 (30%) were admitted to the hospital. The factors associated with time to hospitalization included the severity of liver disease (HR/MELD point:1.10, 95% CI:1.04,1.16), ascites (HR: 1.90, 95% CI: 1.01, 3.58), baseline symptoms of depression (HR:2.34, 95% CI:1.28,4.25), sleep medications (HR:1.81, 95% CI:1.01, 3.22) and IL-6 (HR:1.43, 95% CI: 1.10, 1.84). Similarly the number admissions was significantly associated with MELD (IIR: 1.08, CI: 1.07,1.09), ascites (IIR: 4.15, CI:3.89, 4.43), depressive symptoms (IIR:1.54, CI:1.44,1.64), IL-6 (IIR:1.26, CI:1.23,1.30), sleep medications (IIR:2.74, CI:2.57, 2.93), and widespread pain (IIR: 1.61, CI: 1.50, 1.73). In conclusion, consistent with prior studies, MELD and ascites were associated with subsequent hospitalization. However, this study also identified other factors associated with hospitalization including inflammation, depressive symptoms, sleep medication use, and pain. PMID- 29149172 TI - Spectroscopic characterization of DOM and the nitrogen removal mechanism during wastewater reclamation plant. AB - The performance of the Sha-he wastewater reclamation plant was evaluated in this study. To remove residual nitrogen after Anaerobic-Anoxic-Oxic (A2O) treatment, three multistage Anoxic-Oxic (A/O) were added to investigate the nitrogen removal efficiency and its mechanism. In addition, the constituents and evolution of dissolved organic matter (DOM) during wastewater reclamation was also investigated using a method combining fluorescence spectroscopy with fluorescence regional integration (FRI). The results suggested that multistage A/O treatment can effectively improve the nitrogen removal ability under low concentrations of carbon sources. The total nitrogen (TN) exhibits significantly positive correlation with fulvic acid-like materials and humic acid-like materials. The correlation coefficient for TN and fulvic acid-like substances (R2 = 0.810, P < 0.01) removal was greater than that of humic acid-like substances (R2 = 0.636, P < 0.05). The results indicate that nitrogen removal may be achieved with the fulvic-like and humic-like substances, and the removal effects were higher by fulvic acid-like substances than humic-like substances, mostly due to that the latter were relatively more difficult to be utilized as carbon source during the nitrogen removal process. The effluent water quality of biological treatment reached the first grade A standard of "Cities sewage treatment plant pollutant discharge standard" (GB18918-2002). In addition, the effluent from the membrane bioreactor reached the "Standards of reclaimed water quality" (SL368-2006). PMID- 29149173 TI - Trade-off and flexibility in the dynamic regulation of the cullin-RING ubiquitin ligase repertoire. AB - Cullin-RING ubiquitin ligases (CRLs) catalyze the ubiquitylation of substrates many of which are degraded by the 26S proteasome. Their modular architecture enables recognition of numerous substrates via exchangeable substrate receptors that competitively bind to a cullin scaffold with high affinity. Due to the plasticity of these interactions there is ongoing uncertainty how cells maintain a flexible CRL repertoire in view of changing substrate loads. Based on a series of in vivo and in vitro studies, different groups proposed that the exchange of substrate receptors is mediated by a protein exchange factor named Cand1. Here, we have performed mathematical modeling to provide a quantitative underpinning of this hypothesis. First we show that the exchange activity of Cand1 necessarily leads to a trade-off between high ligase activity and fast receptor exchange. Supported by measurements we argue that this trade-off yields an optimal Cand1 concentration in cells where the time scale for substrate degradation becomes minimal. In a second step we show through simulations that (i) substrates bias the CRL repertoire leading to preferential assembly of ligases for which substrates are available and (ii) differences in binding affinities or substrate receptor abundances create a temporal hierarchy for the degradation of substrates. Finally, we compare the Cand1-mediated exchange cycle with an alternative architecture lacking Cand1 which indicates superiority of a system with exchange factor if substrate receptors bind substrates and the cullin scaffold in a random order. Together, our results provide general constraints for the operating regimes of molecular exchange systems and suggest that Cand1 endows the CRL network with the properties of an "on demand" system allowing cells to dynamically adjust their CRL repertoire to fluctuating substrate abundances. PMID- 29149174 TI - Cystatin B, cathepsin L and D related to surrogate markers for cardiovascular disease in children. AB - OBJECTIVE: This study investigated potential associations between novel biomarkers for cardiovascular disease and other surrogate markers for health. METHODS: Community sample of 170 (92 boys and 78 girls) children aged 8-11 years. Total fat mass (TBF) and abdominal fat (AFM) were measured by Dual-energy x-ray absorptiometry (DXA). Total body fat was also expressed as percentage of total body mass (BF%), and body fat distribution was calculated as AFM/TBF. Maximal oxygen uptake (VO2PEAK), systolic and diastolic blood pressure (SBP and DBP) and pulse pressure (PP) were measured. Echocardiography was performed. Left atrial size (LA) and left ventricular mass (LVM) were measured. A follow-up DXA scan was available in 152 children (84 boys and 68 girls). Frozen serum samples were analyzed for cystatin B, cathepsin L and cathepsin D. RESULTS: Partial correlations between cystatin B versus lnTBF, lnBF%, lnAFM, AFM/TBF, VO2PEAK and PP were; r = 0.38, 0.36, 0.38, 0.29, -0.25 and 0.25, P = 0.001 or less for all. Weaker predominantly non-significant correlations were found for cathepsin L, whereas cathepsin D was not related to any surrogate markers for health. No significant correlations were found between biomarkers and change in body fat over 2 years. CONCLUSION: Findings from this community-based cohort of young children show that surrogate markers for cardiovascular disease such as total fat mass, percent body fat, abdominal fat, body fat distribution, maximal oxygen uptake and pulse pressure were all associated with cystatin B. This was not found for cathepsin L or cathepsin D. PMID- 29149175 TI - The introduction of dengue follows transportation infrastructure changes in the state of Acre, Brazil: A network-based analysis. AB - Human mobility, presence and passive transportation of Aedes aegypti mosquito, and environmental characteristics are a group of factors which contribute to the success of dengue spread and establishment. To understand this process, we assess data from dengue national and municipal basins regarding population and demographics, transportation network, human mobility, and Ae. aegypti monitoring for the Brazilian state of Acre since the first recorded dengue case in the year 2000 to the year 2015. During this period, several changes in Acre's transport infrastructure and urbanization have been started. To reconstruct the process of dengue introduction in Acre, we propose an analytic framework based on concepts used in malaria literature, namely vulnerability and receptivity, to inform risk assessments in dengue-free regions as well as network theory concepts for disease invasion and propagation. We calculate the probability of dengue importation to Acre from other Brazilian states, the evolution of dengue spread between Acrean municipalities and dengue establishment in the state. Our findings suggest that the landscape changes associated with human mobility have created favorable conditions for the establishment of dengue virus transmission in Acre. The revitalization of its major roads, as well as the increased accessibility by air to and within the state, have increased dengue vulnerability. Unplanned urbanization and population growth, as observed in Acre during the period of study, contribute to ideal conditions for Ae. aegypti mosquito establishment, increase the difficulty in mosquito control and consequently its local receptivity. PMID- 29149176 TI - A simple way for targeted delivery of an antibiotic: In vitro evaluation of a nanoclay-based composite. AB - The sodium-modified form of fluorohectorite nanoclay (NaFh) is introduced as a potential drug carrier, demonstrating its ability for the controlled release of the broad-spectrum antibiotic Ciprofloxacin through in vitro tests. The new clay drug composite is designed to target the local infections in the large intestine, where it delivers most of the incorporated drug thanks to its pH-sensitive behavior. The composite has been conceived to avoid the use of coating technology and to decrease the side-effects commonly associated to the burst-release of the ciprofloxacin at the stomach level. NaFh was obtained from lithium fluorohectorite by ion exchange, and its lack of toxicity was demonstrated by in vivo studies. Ciprofloxacin hydrochloride (Cipro) was encapsulated into the clay at different values of the pH, drug initial concentration, temperature and time. Systematic studies by X-ray diffraction (XRD), infrared and visible spectrophotometry (FT-IR and UV-vis), and thermal analysis (TGA) indicated that the NaFh host exhibits a high encapsulation efficiency for Cipro, which reaches a 90% of the initial Cipro in solution at 65 oC, with initial concentration of drug in solution of 1.36 x 10-2 mol L-1 at acid pH. XRD revealed that a true intercalation of Cipro takes place between clay layers. TG showed an increased thermal stability of the drug when intercalated into the clay, as compared to the "free" Cipro. IR suggested a strong clay-Cipro interaction via ketone group, as well as the establishment of hydrogen bonds between the two materials. In vitro drug release tests revealed that NaFh is a potentially efficient carrier to deliver Cipro in the large intestine, where the release process is mediated by more than just one mechanism. PMID- 29149177 TI - New brain lesions with no impact on physical disability can impact cognition in early multiple sclerosis: A ten-year longitudinal study. AB - OBJECTIVE: In early multiple sclerosis, although brain T2 lesions accrual are hallmark of the disease, only weak correlations were found between T2 lesions accrual and EDSS progression, the disability scale commonly used in multiple sclerosis studies. This may be related to the very poor sensitivity of EDSS to cognitive dysfunctions that may occur and progress from the first stage of the disease. In the present study, we aimed to demonstrate that cognitive deficits progress during the first ten years of MS and are significantly impacted by new T2 lesions. METHODS: EDSS and extensive neuropsychological battery (22 measures) exploring memory, attention/speed of information processing and executive functions were assessed at baseline, Year 1 and Year 10 in 26 patients enrolled after their first clinical attack. To limit the bias of test-retest effect, only measures obtained at Year 1 and Year 10 were reported in the analysis. Raw scores of patients were transformed into z-scores using published normative data when available or scores of matched controls. Lesion probability mapping was used to assess the potential relationships between T2 lesions accumulation, cognitive decline and EDSS progression (P<0.05, FWE-corrected). RESULTS: At Year 1, 27% of patients showed attention/speed of information processing deficits, 11.5% executive dysfunction and 11.5% memory impairment. During the follow-up, frequency and severity of executive dysfunction increased (from 11.5% of patients at Year 1 to 42% at Year 10, p<0.01) while no significant changes were evidenced for the other cognitive domains. Median EDSS increased from 0.5 [range: 0-3] at Year 1 to 2.5 [range: 0-6.5] at Year 10 (p<0.001). During the ten-year follow-up, lesions accumulation in the left cerebellum and semi-ovale centers was associated with EDSS progression. In contrast, most lesions accumulation in the frontal, parietal and temporal lobes were associated with cognitive decline but had no effect on EDSS progression. CONCLUSION: The present study provides strong evidence that clinically silent T2 lesions impact cognition in early MS. In daily practice, early prevention of T2 lesions accrual may be useful to limit cognitive decline. PMID- 29149178 TI - Drivers of genetic diversity in secondary metabolic gene clusters within a fungal species. AB - Filamentous fungi produce a diverse array of secondary metabolites (SMs) critical for defense, virulence, and communication. The metabolic pathways that produce SMs are found in contiguous gene clusters in fungal genomes, an atypical arrangement for metabolic pathways in other eukaryotes. Comparative studies of filamentous fungal species have shown that SM gene clusters are often either highly divergent or uniquely present in one or a handful of species, hampering efforts to determine the genetic basis and evolutionary drivers of SM gene cluster divergence. Here, we examined SM variation in 66 cosmopolitan strains of a single species, the opportunistic human pathogen Aspergillus fumigatus. Investigation of genome-wide within-species variation revealed 5 general types of variation in SM gene clusters: nonfunctional gene polymorphisms; gene gain and loss polymorphisms; whole cluster gain and loss polymorphisms; allelic polymorphisms, in which different alleles corresponded to distinct, nonhomologous clusters; and location polymorphisms, in which a cluster was found to differ in its genomic location across strains. These polymorphisms affect the function of representative A. fumigatus SM gene clusters, such as those involved in the production of gliotoxin, fumigaclavine, and helvolic acid as well as the function of clusters with undefined products. In addition to enabling the identification of polymorphisms, the detection of which requires extensive genome-wide synteny conservation (e.g., mobile gene clusters and nonhomologous cluster alleles), our approach also implicated multiple underlying genetic drivers, including point mutations, recombination, and genomic deletion and insertion events as well as horizontal gene transfer from distant fungi. Finally, most of the variants that we uncover within A. fumigatus have been previously hypothesized to contribute to SM gene cluster diversity across entire fungal classes and phyla. We suggest that the drivers of genetic diversity operating within a fungal species shown here are sufficient to explain SM cluster macroevolutionary patterns. PMID- 29149179 TI - Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies. AB - BACKGROUND: Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT. METHODS AND FINDINGS: Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out. CONCLUSIONS: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk. PMID- 29149180 TI - Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a highly specific signaling protein for vascular endothelial cells that plays a critical role in tumor growth and invasion through angiogenesis, and may contribute to cell migration and activation of pre-osteoclasts, osteoclasts and some tumor cells. OBJECTIVES: We aimed to clarify the detailed roles of VEGF-Flt-1 signaling in bone invasion of oral squamous cell carcinoma (OSCC) cells. RESULTS: Forty-two (42) of 54 cases with gingival SCC (77.8%) strongly expressed VEGF, and had a significantly increased number of Flt-1+ osteoclasts (p<0.01) and more aggressive bone invasion (p<0.05). PlGF, a ligand of Flt-1, induced osteoclastogenesis in single culture of bone marrow cells (BMCs), and inhibition of Flt-1-signaling by VEGF tyrosine kinase inhibitor and It's down stream (Akt and ERK1/2) inhibitos reduced osteoclastogenesis in PlGF-stimulated BMCs (p<0.01). In molecular level, PlGF stimulation significantly upregulated RANKL expression in Flt-1-expressing HSC2 cells via phosphorylation of Akt and ERK1/2. In the co-culture of VEGF producing HSC2 cells and BMCs, number of TRAP-positive osteoclasts markedly increased (p<0.01). The osteoclastogenesis was significantly inhibited by RANKL neutralizing antibody (p<0.01) as well as by VEGF tyrosine kinase inhibitor (p<0.01) and it's downstream (Akt and ERK1/2) inhibitors (p<0.01, p<0.05, respectively). CONCLUSION: VEGF-Flt-1 signaling induces osteoclastogenesis in OSCC through two possible ways: 1) VEGF produced from OSCC cells can directly stimulate the Flt-1 pathway in preosteoclasts to induce migration to future bone resorbing area and differentiation into osteoclasts, and 2) VEGF-Flt-1 signaling upregulates RANKL expression in OSCC cells, which indirectly leads to osteoclast differentiation. Therefore, blocking of the VEGF-Flt-1 signaling may help inhibit bone invasion of OSCC. PMID- 29149181 TI - Hospital utilization and out of pocket expenditure in public and private sectors under the universal government health insurance scheme in Chhattisgarh State, India: Lessons for universal health coverage. AB - Research on impact of publicly financed health insurance has paid relatively little attention to the nature of healthcare provision the schemes engage. India's National Health Insurance Scheme or RSBY was made universal by Chhattisgarh State in 2012. In the State, public and private sectors provide hospital services in a context of extensive gender, social, economic and geographical inequities. This study examined enrolment, utilization (public and private) and out of pocket (OOP) expenditure for the insured and uninsured, in Chhattisgarh. The Chhattisgarh State Central sample (n = 6026 members) of the 2014 National Sample Survey (71st Round) on Health was extracted and analyzed. Variables of enrolment, hospitalization, out of pocket (OOP) expenditure and catastrophic expenditure were descriptively analyzed. Multivariate analyses of factors associated with enrolment, hospitalization (by sector) and OOP expenditure were conducted, taking into account gender, socio-economic status, residence, type of facility and ailment. Insurance coverage was 38.8%. Rates of hospitalization were 33/1000 population among the insured and 29/1000 among the uninsured. Of those insured and hospitalized, 67.2% utilized the public sector. Women, rural residents, Scheduled Tribes and poorer groups were more likely to utilize the public sector for hospitalizations. Although the insured were less likely to incur out of pocket (OOP) expenditure, 95.1% of insured private sector users and 66.0% of insured public sector users, still incurred costs. Median OOP payments in the private sector were eight times those in the public sector. Of households with at least one member hospitalized, 35.5% experienced catastrophic health expenditures (>10% monthly household consumption expenditure). The study finds that despite insurance coverage, the majority still incurred OOP expenditure. The public sector was nevertheless less expensive, and catered to the more vulnerable groups. It suggests the need to further examine the roles of public and private sectors in financial risk protection through government health insurance. PMID- 29149182 TI - Comparison between public and private sectors of care and disparities in adverse neonatal outcomes following emergency intrapartum cesarean at term - A retrospective cohort study. AB - BACKGROUND: Perinatal outcomes may be influenced by a variety of factors including maternal demographics and medical condition as well as socio-economic status. The evidence for disparities in health outcomes stratified by type of care (public or private) is lacking. The aim of this study was to investigate short term neonatal outcomes following category 1 and 2 emergency cesareans at term between publicly and privately funded women at a single major tertiary centre in Australia. Category 1-immediate threat to life (maternal or fetal); Category 2-maternal or fetal compromise that is not immediately life-threatening. METHODS: This was a retrospective, cross sectional study of 61355 term singleton babies born at the Mater Mother's Hospital in Brisbane, Australia in 2007-2014. We collected data from the hospital's maternity database and compared maternal demographics, indications for cesarean and neonatal outcomes for publicly and privately funded women. RESULTS: Over the study period there were 32477 public and 28878 private, term singleton births. Compared to the publicly funded cohort, privately insured women were older, had lower BMI, were of Caucasian ethnicity, Australian born, nulliparous, had shorter labors and had lower rates of hypertensive disorders and diabetes. The most common indications for category 1 and category 2 cesareans in combination were non-reassuring fetal status followed by failure to progress in labor and malpresentation. For both category 1 and 2 cesareans, neonatal outcomes (Apgar score <7 at 5 minutes, abnormal cord gases, Neonatal Critical Care Unit admission rates, rates of severe respiratory distress and jaundice) were significantly worse in the publicly funded compared to the privately insured cohort Multivariate analyses controlling for maternal age, ethnicity, country of birth, parity, hypertension, diabetes mellitus, gestational age at birth and length of labour confirmed that private insurance status was highly protective for the perinatal outcomes of Apgar score <7 at 5 minutes (aOR 0.26, 95% CI 0.13-0.55), admission to NCCU (OR 0.51, 95% CI 0.30-0.92) and respiratory distress (aOR 0.60, 95% CI 0.41-0.86). CONCLUSION: Birth in the private health sector was inversely associated with adverse neonatal outcomes following category 1 and 2 cesareans. PMID- 29149183 TI - Vaccine effectiveness against laboratory-confirmed influenza hospitalizations among young children during the 2010-11 to 2013-14 influenza seasons in Ontario, Canada. AB - Uncertainty remains regarding the magnitude of effectiveness of influenza vaccines for preventing serious outcomes, especially among young children. We estimated vaccine effectiveness (VE) against laboratory-confirmed influenza hospitalizations among children aged 6-59 months. We used the test-negative design in hospitalized children in Ontario, Canada during the 2010-11 to 2013-14 influenza seasons. We used logistic regression models adjusted for age, season, and time within season to calculate VE estimates by vaccination status (full vs. partial), age group, and influenza season. We also assessed VE incorporating prior history of influenza vaccination. We included specimens from 9,982 patient hospitalization episodes over four seasons, with 12.8% testing positive for influenza. We observed variation in VE by vaccination status, age group, and influenza season. For the four seasons combined, VE was 60% (95%CI, 44%-72%) for full vaccination and 39% (95%CI, 17%-56%) for partial vaccination. VE for full vaccination was 67% (95%CI, 48%-79%) for children aged 24-59 months, 48% (95%CI, 12%-69%) for children aged 6-23 months, 77% (95%CI, 47%-90%) for 2010-11, 59% (95%CI, 13%-81%) for 2011-12, 33% (95%CI, -18% to 62%) for 2012-13, and 72% (95%CI, 42%-86%) for 2013-14. VE in children aged 24-59 months appeared similar between those vaccinated in both the current and previous seasons and those vaccinated in the current season only, with the exception of 2012-13, when VE was lower for those vaccinated in the current season only. Influenza vaccination is effective in preventing pediatric laboratory-confirmed influenza hospitalizations during most seasons. PMID- 29149184 TI - Health effects of saturated and trans-fatty acid intake in children and adolescents: Systematic review and meta-analysis. AB - BACKGROUND: Elevated cholesterol has been linked to cardiovascular disease in adults and preclinical markers of atherosclerosis in children, thus reducing saturated (SFA) and trans-fatty acids (TFA) intake from an early age may help to reduce cholesterol and the risk of cardiovascular disease later in life. The aim of this review is to examine the evidence for health effects associated with reducing SFA and TFA intake in free-living children, adolescents and young adults between 2 to 19 years of age. DESIGN: Systematic review and meta-analysis of randomised controlled trials (RCTs) and prospective cohort studies. Study selection, assessment, validity, data extraction, and analysis were undertaken as specified by the Cochrane Collaboration and the GRADE working group. Data were pooled using inverse variance models with random effects. DATA SOURCES: EMBASE; PubMed; Cochrane Central Register of Controlled Trials; LILACS; and WHO Clinical Trial Registry (up to July 2016). ELIGIBILITY CRITERIA FOR SELECTING TRIALS: RCTs involving dietary interventions aiming to reduce SFA or TFA intakes and a control group, and cohort studies reporting the effects of SFA or TFA exposures, on outcomes including blood lipids; measures of growth; blood pressure; insulin resistance; and potential adverse effects. Minimum duration was 13 days for RCTs and one year for cohort studies. Trials of weight loss or confounded by additional medical or lifestyle interventions were excluded. RESULTS: Compared with control diets, there was a highly statistically significant effect of reduced SFA intake on total cholesterol (mean difference (MD) -0.16 mmol/l, [95% confidence interval (CI): -0.25 to -0.07]), LDL cholesterol (MD -0.13 mmol/l [95% CI:-0.22 to -0.03]) and diastolic blood pressure (MD -1.45 mmol/l [95% CI:-2.34 to -0.56]). There were no significant effects on any other risk factors and no evidence of adverse effects. CONCLUSIONS: Advice to reduce saturated fatty acids intake of children results in a significant reduction in total and LDL cholesterol levels as well as diastolic blood pressure without evidence of adverse effects on growth and development. Dietary guidelines for children and adolescents should continue to recommend diets low in saturated fat. PMID- 29149185 TI - Linezolid and atorvastatin impact on pneumonia caused by Staphyloccocus aureus in rabbits with or without mechanical ventilation. AB - Pneumonia may involve methicillin-resistant Staphylococcus aureus (MRSA), with elevated rates of antibiotics failure. The present study aimed to assess the effect of statins given prior to pneumonia development. Spontaneously breathing (SB) or mechanically ventilated (MV) rabbits with pneumonia received atorvastatin alone, linezolid (LNZ) alone, or a combination of both (n = 5 in each group). Spontaneously breathing and MV untreated infected animals (n = 11 in each group), as well as uninfected animals (n = 5 in each group) were used as controls. Microbiological features and inflammation were evaluated. Data are presented as medians (interquartile range). Linezolid alone tended to reduce pulmonary MRSA load in both SB and MV rabbits, but failed to prevent bacteremia (59%) in the latter. Linezolid alone dampened TNF-alpha lung production in both SB and MV rabbits (e.g., 2226 [789] vs. 11478 [10251] pg/g; p = 0.022). Statins alone did the same in both SB and MV animals (e.g., 2040 [133]; p = 0.016), and dampened systemic inflammation in the latter, possibly through TLR2 down-regulation within the lung. However, the combination of LNZ and statin led to an increased rate of bacteremia in MV animals up to 75%. Statins provide an anti-inflammatory effect in rabbits with MRSA pneumonia, especially in MV ones. However, dampening the systemic inflammatory response with statins could impede blood defenses against MRSA. PMID- 29149186 TI - Cell cycle time series gene expression data encoded as cyclic attractors in Hopfield systems. AB - Modern time series gene expression and other omics data sets have enabled unprecedented resolution of the dynamics of cellular processes such as cell cycle and response to pharmaceutical compounds. In anticipation of the proliferation of time series data sets in the near future, we use the Hopfield model, a recurrent neural network based on spin glasses, to model the dynamics of cell cycle in HeLa (human cervical cancer) and S. cerevisiae cells. We study some of the rich dynamical properties of these cyclic Hopfield systems, including the ability of populations of simulated cells to recreate experimental expression data and the effects of noise on the dynamics. Next, we use a genetic algorithm to identify sets of genes which, when selectively inhibited by local external fields representing gene silencing compounds such as kinase inhibitors, disrupt the encoded cell cycle. We find, for example, that inhibiting the set of four kinases AURKB, NEK1, TTK, and WEE1 causes simulated HeLa cells to accumulate in the M phase. Finally, we suggest possible improvements and extensions to our model. PMID- 29149187 TI - Epidemiology and impact on all-cause mortality of sepsis in Norwegian hospitals: A national retrospective study. AB - BACKGROUND: Although sepsis is the leading cause of death from infection, there are few population-level epidemiological sepsis reports. The impact of sepsis related deaths on all-cause hospital mortality is insufficiently described, in particular in Europe where data are non-existent. The objective of this study was to provide nationwide epidemiological results on sepsis hospitalizations in Norway and to estimate sepsis' contribution to overall hospital mortality in a European setting. METHODS: We performed a retrospective study using data from the Norwegian Patient Registry and Statistics Norway. The occurrence, patient characteristics and outcomes of sepsis hospitalizations during the years 2011 and 2012 were estimated and compared with Norwegian population data. Sepsis was defined as organ dysfunction caused by a dysregulated host response to infection and identified with International Classification of Diseases 10th revision codes. RESULTS: We identified 18 460 sepsis admissions occurring in 13 582 individuals. The annual population incidence of hospitalized sepsis was 140 patients per 100 000 inhabitants; ranging from 10 to 2270 per 100 000 in different age groups and with statistically significant male predominance in all adult cohorts. Hospital mortality for sepsis admissions was 19.4% and overall, 26.4% of the included patients died while hospitalized for sepsis. Sepsis related deaths constituted 12.9% of all hospital fatalities, while hospitalizations with sepsis accounted for 1.0% of the total number of admissions and 3.5% of the total admission days during 2011 and 2012. CONCLUSIONS: This study confirms that hospitalized sepsis is frequent in Norway and a major contributor to hospital fatalities in a European setting. The incidence is higher among men than women. Sepsis is in particular a disease of the elderly, and its impact on health-care will assumingly continue to increase in parallel with an aging population. Improvements in treatment and survival of sepsis could influence population mortality, and sepsis should receive greater attention in official death statistics in the future. PMID- 29149188 TI - Orienting the causal relationship between imprecisely measured traits using GWAS summary data. AB - Inference about the causal structure that induces correlations between two traits can be achieved by combining genetic associations with a mediation-based approach, as is done in the causal inference test (CIT). However, we show that measurement error in the phenotypes can lead to the CIT inferring the wrong causal direction, and that increasing sample sizes has the adverse effect of increasing confidence in the wrong answer. This problem is likely to be general to other mediation-based approaches. Here we introduce an extension to Mendelian randomisation, a method that uses genetic associations in an instrumentation framework, that enables inference of the causal direction between traits, with some advantages. First, it can be performed using only summary level data from genome-wide association studies; second, it is less susceptible to bias in the presence of measurement error or unmeasured confounding. We apply the method to infer the causal direction between DNA methylation and gene expression levels. Our results demonstrate that, in general, DNA methylation is more likely to be the causal factor, but this result is highly susceptible to bias induced by systematic differences in measurement error between the platforms, and by horizontal pleiotropy. We emphasise that, where possible, implementing MR and appropriate sensitivity analyses alongside other approaches such as CIT is important to triangulate reliable conclusions about causality. PMID- 29149189 TI - Perioperative body weight change is associated with in-hospital mortality in cardiac surgical patients with postoperative acute kidney injury. AB - BACKGROUND: Postoperative acute kidney injury (AKI) is common following cardiac surgery (CS). Body weight (BW) may be an amenable variable by representing the summation of the nutritional and the fluid status. However, the predictive role of perioperative BW changes in CS patients with severe postoperative AKI is never explored. This study aimed to evaluate this association. METHODS: This study was conducted using a prospectively collected multicenter cohort, NSARF (National Taiwan University Hospital Study Group on Acute Renal Failure) database. The adult CS patients with postoperative AKI requiring renal replacement therapy (RRT), who had clear initial consciousness, received CS within 14 days of hospitalization, and underwent RRT within seven days after CS in intensive care units from January 2001 to January 2014 were enrolled. With the endpoint of 30 day postoperative mortality, we evaluated the association between the clinical factors denoting fluid status and patients outcomes. RESULTS: A total of 188 patients (70 female, mean age 63.7 +/- 15.2 years) were enrolled. Comparing with the survivors (n = 124), the non-survivors (n = 64) had a significantly higher perioperative BW change [3.6 +/- 6.1% versus 0.1 +/- 8.3%, p = 0.003] but not the postoperative and pre-RRT BW changes. By using multivariate Cox proportional hazards model, the independent indicators of 30-day postoperative mortality included perioperative BW change (p = 0.026) and packed red blood cells transfusion (p = 0.007), postoperative intra-aortic balloon pump (p = 0.001) and central venous pressure level (p = 0.005), as well as heart rate (p = 0.022), sequential organ failure assessment score (p < 0.001), logistic organ dysfunction score (p = 0.001), and blood total bilirubin level (p = 0.044) at RRT initiation. The generalized additive models further demonstrated, in a multivariate manner, that the mortality risk rose significantly during a perioperative BW change of 2% to 15%. CONCLUSIONS: Perioperative BW change was independently associated with an increased risk for 30-day postoperative mortality in CS patients with RRT requiring AKI. PMID- 29149190 TI - Improved capture of Drosophila suzukii by a trap baited with two attractants in the same device. AB - The improvement of trap-lure combinations is an important part of integrated pest management programs that involve monitoring pests for timely insecticide applications, or for their use in control strategies such as mass trapping or bait stations. In this study improvements in the capture of Drosophila suzukii were not observed following the inclusion of different color stimuli with respect to a red-black stripe cup trap. This red-black stripe trap with a hemispherical dome-shaped lid had a significantly improved physical retention of flies compared to traps fitted with a flat lid. Retention was further improved when an additional tube device, which could be baited with a supplemental attractant, was introduced through the dome-shaped lid. Under laboratory conditions, this trap, in which apple cider vinegar + 10% ethanol was present as the drowning solution and the additional tube device was baited with a fermenting mixture of sugar and yeast, was significantly more effective in catching D. suzukii flies than other conventional attractants or a commercial lure. The capture rate of this trap-lure combination remained higher than that of a commercial lure, even after 20 days of use under laboratory conditions. In a guava orchard this trap was 15-fold more effective in catching D. suzukii flies than similar traps baited with apple cider vinegar alone, 4 to 7 fold more effective than similar traps baited with a commercial lure, and 1.7-fold more effective than a fermenting mixture of yeasts and wheat flour. In commercial blackberry orchards, this trap was 6-fold more effective in trapping D. suzukii flies than the clear trap baited with apple cider vinegar used by growers. The efficacy of this trap presents a promising line of future research for monitoring and control of D. suzukii and likely other drosophilid pests. PMID- 29149191 TI - Resting-state fMRI in sleeping infants more closely resembles adult sleep than adult wakefulness. AB - Resting state functional magnetic resonance imaging (rs-fMRI) in infants enables important studies of functional brain organization early in human development. However, rs-fMRI in infants has universally been obtained during sleep to reduce participant motion artifact, raising the question of whether differences in functional organization between awake adults and sleeping infants that are commonly attributed to development may instead derive, at least in part, from sleep. This question is especially important as rs-fMRI differences in adult wake vs. sleep are well documented. To investigate this question, we compared functional connectivity and BOLD signal propagation patterns in 6, 12, and 24 month old sleeping infants with patterns in adult wakefulness and non-REM sleep. We find that important functional connectivity features seen during infant sleep closely resemble those seen during adult sleep, including reduced default mode network functional connectivity. However, we also find differences between infant and adult sleep, especially in thalamic BOLD signal propagation patterns. These findings highlight the importance of considering sleep state when drawing developmental inferences in infant rs-fMRI. PMID- 29149192 TI - Diet improvement for western corn rootworm (Coleoptera: Chrysomelidae) larvae. AB - The western corn rootworm (WCR), Diabrotica virgifera virgifera LeConte, is the most serious insect pest of corn (Zea mays L.) in the United States and parts of Europe, and arguably one of the world's most expensive pests to control. Several diet formulations are currently used by industry and public researchers to evaluate WCR larvae in diet-toxicity bioassays. However, a publicly available diet that produces normative insects that are physiologically similar to WCR larvae reared on corn roots will accelerate development of management technologies. We report a new diet formulation that supports improved weight gain, larval development and survival compared with the only public diet for WCR that is currently available in the refereed literature. The formulation was created by using response surface methods combined with n-dimensional mixture designs to identify and improve the formulation of key ingredients. Weight gain increased two-fold, and survival and molting rates increased from 93% and 90%, respectively when reared on the public diet, to approximately 99% for both survival and molting at 11 days when reared on our new formulation. This new formulation provides a standardized growth medium for WCR larvae that will facilitate comparison of research results from various working groups and compliance with regulatory requirements. PMID- 29149193 TI - Correction: The Effect of Alignment Changes on Unilateral Transtibial Amputee's Gait: A Systematic Review. AB - [This corrects the article DOI: 10.1371/journal.pone.0167466.]. PMID- 29149194 TI - Understanding linkage to care with HIV self-test approach in Lusaka, Zambia - A mixed method approach. AB - INTRODUCTION: HIV self-testing (HIVST) is a novel approach designed to assist in achieving the goal of at least 90% of the population that learn their HIV status. A self-test user with a positive test is required to visit a clinic to link into HIV care, yet little is known about patient preferences for linkage strategies. We examined the intention to link to care amongst potential HIVST users and the suitability of three linkage to care strategies in Lusaka Province, Zambia. METHODS: We conducted a representative cross sectional survey of 1,617 individuals aged 16-49 years old in Lusaka Province. Participants were shown a video of the HIVST. Data on intention to link to care and preferred linkage to care strategies-text message, phone call and home visits were collected. Eight focus group discussions were held concurrently with survey respondents to understand their preferences between the three linkage to care strategies. RESULTS: Of 1617 enrolled, 60% were women, 40% were men, with an average age of 27years (IQR = 22, 35). More men than women had at least secondary education (84% vs 77%) and were either employed or self-employed (67% vs. 41%). 85% (95%CI = 83 to 86) of participants said they would link to care within the first week of a positive self-test. Income >2,000 Kwacha (USD 200) per month versus income < 2,000 Kwacha (Adjusted odds ratio (AOR) = 0.59; 95%CI: 0.40 to 0.88; p = 0.009) and never versus prior HIV testers (AOR = 0.54; 95%CI: 0.32 to 0.91; p = 0.020) were associated with reduced odds of intention to link to care. 53% (95%CI = 50 to 55) preferred being prompted to link to care by home visits compared to phone call (30%) or SMS (17%). CONCLUSION: We found almost nine out of ten potential HIVST users in the general population intend to link to care shortly after a positive test, and preferred home visits or phone calls to facilitate linkage, rather than SMS. Also, higher income earners and those who never tested for HIV were associated with reduced odds of intention to link to care. Policy guidelines and implementation strategies for HIVST should be responsive to patient preferences for linkage to care strategies to achieve the continuum of HIV care. PMID- 29149195 TI - Age of heart disease presentation and dysmorphic nuclei in patients with LMNA mutations. AB - Nuclear shape defects are a distinguishing characteristic in laminopathies, cancers, and other pathologies. Correlating these defects to the symptoms, mechanisms, and progression of disease requires unbiased, quantitative, and high throughput means of quantifying nuclear morphology. To accomplish this, we developed a method of automatically segmenting fluorescently stained nuclei in 2D microscopy images and then classifying them as normal or dysmorphic based on three geometric features of the nucleus using a package of Matlab codes. As a test case, cultured skin-fibroblast nuclei of individuals possessing LMNA splice site mutation (c.357-2A>G), LMNA nonsense mutation (c.736 C>T, pQ246X) in exon 4, LMNA missense mutation (c.1003C>T, pR335W) in exon 6, Hutchinson-Gilford Progeria Syndrome, and no LMNA mutations were analyzed. For each cell type, the percentage of dysmorphic nuclei, and other morphological features such as average nuclear area and average eccentricity were obtained. Compared to blind observers, our procedure implemented in Matlab codes possessed similar accuracy to manual counting of dysmorphic nuclei while being significantly more consistent. The automatic quantification of nuclear defects revealed a correlation between in vitro results and age of patients for initial symptom onset. Our results demonstrate the method's utility in experimental studies of diseases affecting nuclear shape through automated, unbiased, and accurate identification of dysmorphic nuclei. PMID- 29149196 TI - Easy xeno-free and feeder-free method for isolating and growing limbal stromal and epithelial stem cells of the human cornea. AB - Epithelial and stromal stem cells are required to maintain corneal transparency. The aim of the study was to develop a new method to isolate and grow both corneal stromal (SSC) and epithelial limbal (LSC) stem cells from small human limbal biopsies under culture conditions in accordance with safety requirements mandatory for clinical use in humans. Superficial limbal explants were retrieved from human donor corneo-scleral rims. Human limbal cells were dissociated by digestion with collagenase A, either after epithelial scraping or with no scraping. Isolated cells were cultured with Essential 8 medium (E8), E8 supplemented with EGF (E8+) or Green's medium with 3T3 feeder-layers. Cells were characterized by immunostaining, RT-qPCR, colony forming efficiency, sphere formation, population doubling, second harmonic generation microscopy and differentiation potentials. LSC were obtained from unscraped explants in E8, E8+ and Green's media and were characterized by colony formation and expression of PAX6, DeltaNP63alpha, Bmi1, ABCG2, SOX9, CK14, CK15 and vimentin, with a few cells positive for CK3. LSC underwent 28 population doublings still forming colonies. SSC were obtained from both scraped and unscraped explants in E8 and E8+ media and were characterized by sphere formation, expression of PAX6, SOX2, BMI1, NESTIN, ABCG2, KERATOCAN, VIMENTIN, SOX9, SOX10 and HNK1, production of collagen fibrils and differentiation into keratocytes, fibroblasts, myofibroblasts, neurons, adipocytes, chondrocytes and osteocytes. SSC underwent 48 population doublings still forming spheres, Thus, this new method allows both SSC and LSC to be isolated from small superficial limbal biopsies and to be primary cultured in feeder-free and xeno-free conditions, which will be useful for clinical purposes. PMID- 29149198 TI - Experiences of older people with dementia participating in a high-intensity functional exercise program in nursing homes: "While it's tough, it's useful". AB - The objective of the study was to describe the views and experiences of participation in a high-intensity functional exercise (HIFE) program among older people with dementia in nursing homes. The study design was a qualitative interview study with 21 participants (15 women), aged 74-96, and with a Mini Mental State Examination score of 10-23 at study start. The HIFE-program comprises exercises performed in functional weight-bearing positions and including movements used in everyday tasks. The exercise was individually designed, supervised in small groups in the nursing homes and performed during four months. Interviews were performed directly after exercise sessions and field notes about the sessions were recorded. Qualitative content analysis was used for analyses. The analysis revealed four themes: Exercise is challenging but achievable; Exercise gives pleasure and strength; Exercise evokes body memories; and Togetherness gives comfort, joy, and encouragement. The intense and tailored exercise, adapted to each participant, was perceived as challenging but achievable, and gave pleasure and improvements in mental and bodily strength. Memories of previous physical activities aroused and participants rediscovered bodily capabilities. Importance of individualized and supervised exercise in small groups was emphasized and created feelings of encouragement, safety, and coherence. The findings from the interviews reinforces the positive meaning of intense exercise to older people with moderate to severe dementia in nursing homes. The participants were able to safely adhere to and understand the necessity of the exercise. Providers of exercise should consider the aspects valued by participants, e.g. supervision, individualization, small groups, encouragement, and that exercise involved joy and rediscovery of body competencies. PMID- 29149197 TI - Sieve analysis of breakthrough HIV-1 sequences in HVTN 505 identifies vaccine pressure targeting the CD4 binding site of Env-gp120. AB - Although the HVTN 505 DNA/recombinant adenovirus type 5 vector HIV-1 vaccine trial showed no overall efficacy, analysis of breakthrough HIV-1 sequences in participants can help determine whether vaccine-induced immune responses impacted viruses that caused infection. We analyzed 480 HIV-1 genomes sampled from 27 vaccine and 20 placebo recipients and found that intra-host HIV-1 diversity was significantly lower in vaccine recipients (P <= 0.04, Q-values <= 0.09) in Gag, Pol, Vif and envelope glycoprotein gp120 (Env-gp120). Furthermore, Env-gp120 sequences from vaccine recipients were significantly more distant from the subtype B vaccine insert than sequences from placebo recipients (P = 0.01, Q value = 0.12). These vaccine effects were associated with signatures mapping to CD4 binding site and CD4-induced monoclonal antibody footprints. These results suggest either (i) no vaccine efficacy to block acquisition of any viral genotype but vaccine-accelerated Env evolution post-acquisition; or (ii) vaccine efficacy against HIV-1s with Env sequences closest to the vaccine insert combined with increased acquisition due to other factors, potentially including the vaccine vector. PMID- 29149200 TI - Heterozygous deletion of both sclerostin (Sost) and connexin43 (Gja1) genes in mice is not sufficient to impair cortical bone modeling. AB - Connexin43 (Cx43) is the main gap junction protein expressed in bone forming cells, where it modulates peak bone mass acquisition and cortical modeling. Genetic ablation of the Cx43 gene (Gja1) results in cortical expansion with accentuated periosteal bone formation associated with decreased expression of the Wnt inhibitor sclerostin. To determine whether sclerostin (Sost) down-regulation might contribute to periosteal expansion in Gja1 deficient bones, we took a gene interaction approach and crossed mice harboring germline null alleles for Gja1 or Sost to generate single Gja1+/-and Sost+/-and double Gja1+/-;Sost+/-heterozygous mice. In vivo MUCT analysis of cortical bone at age 1 and 3 months confirmed increased thickness in Sost-/-mice, but revealed no cortical abnormalities in single Gja1+/-or Sost+/-mice. Double heterozygous Gja1+/-Sost+/-also showed no differences in mineral density, cortical thickness, width or geometry relative to wild type control mice. Likewise, 3-point bending measurement of bone strength revealed no significant differences between double Gja1+/-;Sost+/-or single heterozygous and wild type mice. Although these data do not exclude a contribution of reduced sclerostin in the cortical expansion seen in Gja1 deficient bones, they are not consistent with a strong genetic interaction between Sost and Gja1 dictating cortical modeling. PMID- 29149199 TI - Epidemiology and clinical profile of pathogens responsible for the hospitalization of children in Sousse area, Tunisia. AB - This study aimed to identify a broad spectrum of respiratory pathogens from hospitalized and not-preselected children with acute respiratory tract infections in the Farhat Hached University-hospital of Sousse, Tunisia. Between September 2013 and December 2014, samples from 372 children aged between 1 month and 5 years were collected, and tested using multiplex real-time RT-PCR by a commercial assay for 21 respiratory pathogens. In addition, samples were screened for the presence of Streptococcus pneumoniae 16S rDNA using real-time PCR. The viral distribution and its association with clinical symptoms were statistically analyzed. Viral pathogens were detected in 342 (91.93%) of the samples of which 28.76% were single positive and 63.17% had multiple infections. The most frequent detected viruses were rhinovirus (55.64%), respiratory syncytial virus A/B (33.06%), adenovirus (25.00%), coronavirus NL63, HKU1, OC43, and 229E (21.50%), and metapneumovirus A/B (16.12%). Children in the youngest age group (1-3 months) exhibited the highest frequencies of infection. Related to their frequency of detection, RSV A/B was the most associated pathogen with patient's demographic situation and clinical manifestations (p<0.05). Parainfluenza virus 1-4 and parechovirus were found to increase the risk of death (p<0.05). Adenovirus was statistically associated to the manifestation of gastroenteritis (p = 0.004). Rhinovirus infection increases the duration of oxygen support (p = 0.042). Coronavirus group was statistically associated with the manifestation of bronchiolitis (p = 0.009) and laryngitis (p = 0.017). Streptococcus pneumoniae DNA was detected in 143 (38.44%) of tested samples. However, only 53 samples had a concentration of C-reactive protein from equal to higher than 20 milligrams per liter, and 6 of them were single positive for Streptocuccus pneumoniae. This study confirms the high incidence of respiratory viruses in children hospitalized for acute respiratory tract infections in the Sousse area, Tunisia. PMID- 29149201 TI - The influence of filtering and downsampling on the estimation of transfer entropy. AB - Transfer entropy (TE) provides a generalized and model-free framework to study Wiener-Granger causality between brain regions. Because of its nonparametric character, TE can infer directed information flow also from nonlinear systems. Despite its increasing number of applications in neuroscience, not much is known regarding the influence of common electrophysiological preprocessing on its estimation. We test the influence of filtering and downsampling on a recently proposed nearest neighborhood based TE estimator. Different filter settings and downsampling factors were tested in a simulation framework using a model with a linear coupling function and two nonlinear models with sigmoid and logistic coupling functions. For nonlinear coupling and progressively lower low-pass filter cut-off frequencies up to 72% false negative direct connections and up to 26% false positive connections were identified. In contrast, for the linear model, a monotonic increase was only observed for missed indirect connections (up to 86%). High-pass filtering (1 Hz, 2 Hz) had no impact on TE estimation. After low-pass filtering interaction delays were significantly underestimated. Downsampling the data by a factor greater than the assumed interaction delay erased most of the transmitted information and thus led to a very high percentage (67-100%) of false negative direct connections. Low-pass filtering increases the number of missed connections depending on the filters cut-off frequency. Downsampling should only be done if the sampling factor is smaller than the smallest assumed interaction delay of the analyzed network. PMID- 29149202 TI - Intraspecific evolutionary relationships among peregrine falcons in western North American high latitudes. AB - Subspecies relationships within the peregrine falcon (Falco peregrinus) have been long debated because of the polytypic nature of melanin-based plumage characteristics used in subspecies designations and potential differentiation of local subpopulations due to philopatry. In North America, understanding the evolutionary relationships among subspecies may have been further complicated by the introduction of captive bred peregrines originating from non-native stock, as part of recovery efforts associated with mid 20th century population declines resulting from organochloride pollution. Alaska hosts all three nominal subspecies of North American peregrine falcons-F. p. tundrius, anatum, and pealei for which distributions in Alaska are broadly associated with nesting locales within Arctic, boreal, and south coastal maritime habitats, respectively. Unlike elsewhere, populations of peregrine falcon in Alaska were not augmented by captive-bred birds during the late 20th century recovery efforts. Population genetic differentiation analyses of peregrine populations in Alaska, based on sequence data from the mitochondrial DNA control region and fragment data from microsatellite loci, failed to uncover genetic distinction between populations of peregrines occupying Arctic and boreal Alaskan locales. However, the maritime subspecies, pealei, was genetically differentiated from Arctic and boreal populations, and substructured into eastern and western populations. Levels of interpopulational gene flow between anatum and tundrius were generally higher than between pealei and either anatum or tundrius. Estimates based on both marker types revealed gene flow between augmented Canadian populations and unaugmented Alaskan populations. While we make no attempt at formal taxonomic revision, our data suggest that peregrine falcons occupying habitats in Alaska and the North Pacific coast of North America belong to two distinct regional groupings-a coastal grouping (pealei) and a boreal/Arctic grouping (currently anatum and tundrius)-each comprised of discrete populations that are variously intra regionally connected. PMID- 29149203 TI - ALC1/CHD1L, a chromatin-remodeling enzyme, is required for efficient base excision repair. AB - ALC1/CHD1L is a member of the SNF2 superfamily of ATPases carrying a macrodomain that binds poly(ADP-ribose). Poly(ADP-ribose) polymerase (PARP) 1 and 2 synthesize poly(ADP-ribose) at DNA-strand cleavage sites, promoting base excision repair (BER). Although depletion of ALC1 causes increased sensitivity to various DNA-damaging agents (H2O2, UV, and phleomycin), the role played by ALC1 in BER has not yet been established. To explore this role, as well as the role of ALC1's ATPase activity in BER, we disrupted the ALC1 gene and inserted the ATPase-dead (E165Q) mutation into the ALC1 gene in chicken DT40 cells, which do not express PARP2. The resulting ALC1-/- and ALC1-/E165Q cells displayed an indistinguishable hypersensitivity to methylmethane sulfonate (MMS), an alkylating agent, and to H2O2, indicating that ATPase plays an essential role in the DNA-damage response. PARP1-/- and ALC1-/-/PARP1-/- cells exhibited a very similar sensitivity to MMS, suggesting that ALC1 and PARP1 collaborate in BER. Following pulse-exposure to H2O2, PARP1-/- and ALC1-/-/PARP1-/- cells showed similarly delayed kinetics in the repair of single-strand breaks, which arise as BER intermediates. To ascertain ALC1's role in BER in mammalian cells, we disrupted the ALC1 gene in human TK6 cells. Following exposure to MMS and to H2O2, the ALC1-/- TK6 cell line showed a delay in single-strand-break repair. We therefore conclude that ALC1 plays a role in BER. Following exposure to H2O2, ALC1-/- cells showed compromised chromatin relaxation. We thus propose that ALC1 is a unique BER factor that functions in a chromatin context, most likely as a chromatin-remodeling enzyme. PMID- 29149204 TI - Evaluation of osseous integration of titanium orthopedic screws with novel SLA treatment in porcine model. AB - The success of many endosseous implants in orthopaedic and dental applications depends on the surface characteristics, as they affect osseous integration. Previous investigations indicated that a novel large-grit sand-blasted and acid etched (SLA) titanium (denoted as SLAffinity-Ti) implant had better bone integration than that of a comparably shaped implant with a plasma-sprayed titanium surface. The purpose of the present investigation was to create a SLAffinity surface on pedicle screws and trauma screws and to compare it with the surfaces of a sand-blasted-only implant and commercial implants in terms of bone integration. The cortical bone and spine of twelve minipigs were implanted with 3 and 4 implants, respectively, and the bone integration was evaluated using micro computed tomography (micro-CT), mechanical tests (pull-out strength and stripping torque), and histological analysis (toluidine blue and hematoxylin and eosin staining) one and three months after implantation. The micro-CT images showed that the gap between the bone and implant was consistently higher in the sand blasted-only and commercial groups compared to that in the SLAffinity group 1 and 3 months after implantation. Moreover, the bone volume of implant inserted into bone and the percentage of implant inside bone tissue were greater in the SLAffinity screws 1 and 3 months after implantation, as compared to the sand blasted and commercial screws. In the mechanical tests, the removal torque and pull-out strength (p < 0.05) were higher in the SLAffinity group at 1 and 3 months. The histological results were consistent with mechanical testing, showing that the SLAffinity group had the most mineralized matrix, the most bone formation around the screws, and the most bone cells in bone tissue. These findings indicate that a SLAffinity surface can effectively enhance the holding strength and integration of pedicle screws and cortical screws, promoting early healing and improving outcomes, compared to sand-blasted-only and commercial implants. PMID- 29149206 TI - Automatic structural scene digitalization. AB - In this paper, we present an automatic system for the analysis and labeling of structural scenes, floor plan drawings in Computer-aided Design (CAD) format. The proposed system applies a fusion strategy to detect and recognize various components of CAD floor plans, such as walls, doors, windows and other ambiguous assets. Technically, a general rule-based filter parsing method is fist adopted to extract effective information from the original floor plan. Then, an image processing based recovery method is employed to correct information extracted in the first step. Our proposed method is fully automatic and real-time. Such analysis system provides high accuracy and is also evaluated on a public website that, on average, archives more than ten thousands effective uses per day and reaches a relatively high satisfaction rate. PMID- 29149205 TI - KIR content genotypes associate with carriage of hepatitis B surface antigen, e antigen and HBV viral load in Gambians. AB - BACKGROUND: Hepatocellular carcinoma (HCC) causes over 800,000 deaths worldwide annually, mainly in low income countries, and incidence is rising rapidly in the developed world with the spread of hepatitis B (HBV) and C (HCV) viruses. Natural Killer (NK) cells protect against viral infections and tumours by killing abnormal cells recognised by Killer-cell Immunoglobulin-like Receptors (KIR). Thus genes and haplotypes encoding these receptors may be important in determining both outcome of initial hepatitis infection and subsequent chronic liver disease and tumour formation. HBV is highly prevalent in The Gambia and the commonest cause of liver disease. The Gambia Liver Cancer Study was a matched case-control study conducted between September 1997 and January 2001 where cases with liver disease were identified in three tertiary referral hospitals and matched with out-patient controls with no clinical evidence of liver disease. METHODS: We typed 15 KIR genes using the polymerase chain reaction with sequence specific primers (PCR-SSP) in 279 adult Gambians, 136 with liver disease (HCC or Cirrhosis) and 143 matched controls. We investigated effects of KIR genotypes and haplotypes on HBV infection and associations with cirrhosis and HCC. RESULTS: Homozygosity for KIR group A gene-content haplotype was associated with HBsAg carriage (OR 3.7, 95% CI 1.4-10.0) whilst telomeric A genotype (t-AA) was associated with reduced risk of e antigenaemia (OR 0.2, 95% CI 0.0-0.6) and lower viral loads (mean log viral load 5.2 vs. 6.9, pc = 0.022). One novel telomeric B genotype (t-ABx2) containing KIR3DS1 (which is rare in West Africa) was also linked to e antigenaemia (OR 8.8, 95% CI 1.3-60.5). There were no associations with cirrhosis or HCC. CONCLUSION: Certain KIR profiles may promote clearance of hepatitis B surface antigen whilst others predispose to e antigen carriage and high viral load. Larger studies are necessary to quantify the effects of individual KIR genes, haplotypes and KIR/HLA combinations on long-term viral carriage and risk of liver cancer. KIR status could potentially inform antiviral therapy and identify those at increased risk of complications for enhanced surveillance. PMID- 29149207 TI - Evolution of the metabolome in response to selection for increased immunity in populations of Drosophila melanogaster. AB - We used NMR-based metabolomics to test two hypotheses-(i) there will be evolved differences in the metabolome of selected and control populations even under un infected conditions and (ii) post infection, the metabolomes of the selected and control populations will respond differently. We selected replicate populations of Drosophila melanogaster for increased survivorship (I) against a gram-negative pathogen. We subjected the selected (I) and their control populations (S) to three different treatments: (1) infected with heat-killed bacteria (i), (2) sham infected (s), and (3) untreated (u). We performed 1D and 2D NMR experiments to identify the metabolic differences. Multivariate analysis of the metabolic profiles of the untreated (Iu and Su) flies yielded higher concentrations of lipids, organic acids, sugars, amino acids, NAD and AMP in the Iu treatment as compared to the Su treatment, showing that even in the absence of infection, the metabolome of the I and S regimes was different. In the S and I regimes, post infection/injury, concentration of metabolites directly or indirectly associated with energy related pathways (lipids, organic acids, sugars) declined while the concentration of metabolites that are probably associated with immune response (amino acids) increased. However, in most cases, the I regime flies had a higher concentration of such metabolites even under un-infected conditions. The change in the metabolite concentration upon infection/injury was not always comparable between I and S regimes (in case of lactate, alanine, leucine, lysine, threonine) indicating that the I and S regimes had evolved to respond differentially to infection and to injury. PMID- 29149208 TI - Synergistic effects of the components of global change: Increased vegetation dynamics in open, forest-steppe grasslands driven by wildfires and year-to-year precipitation differences. AB - Climate change and land use change are two major elements of human-induced global environmental change. In temperate grasslands and woodlands, increasing frequency of extreme weather events like droughts and increasing severity of wildfires has altered the structure and dynamics of vegetation. In this paper, we studied the impact of wildfires and the year-to-year differences in precipitation on species composition changes in semi-arid grasslands of a forest-steppe complex ecosystem which has been partially disturbed by wildfires. Particularly, we investigated both how long-term compositional dissimilarity changes and species richness are affected by year-to-year precipitation differences on burnt and unburnt areas. Study sites were located in central Hungary, in protected areas characterized by partially-burnt, juniper-poplar forest-steppe complexes of high biodiversity. Data were used from two long-term monitoring sites in the Kiskunsag National Park, both characterized by the same habitat complex. We investigated the variation in species composition as a function of time using distance decay methodology. In each sampling area, compositional dissimilarity increased with the time elapsed between the sampling events, and species richness differences increased with increasing precipitation differences between consecutive years. We found that both the long-term compositional dissimilarity, and the year-to-year changes in species richness were higher in the burnt areas than in the unburnt ones. The long-term compositional dissimilarities were mostly caused by perennial species, while the year-to-year changes of species richness were driven by annual and biennial species. As the effect of the year-to-year variation in precipitation was more pronounced in the burnt areas, we conclude that canopy removal by wildfires and extreme inter-annual variability of precipitation, two components of global environmental change, act in a synergistic way. They enhance the effect of one another, resulting in greater long-term and year-to-year changes in the composition of grasslands. PMID- 29149209 TI - Correction: Comparison of porous and nano zinc oxide for replacing high-dose dietary regular zinc oxide in weaning piglets. AB - [This corrects the article DOI: 10.1371/journal.pone.0182550.]. PMID- 29149210 TI - Development and validation of open-source software for DNA mixture interpretation based on a quantitative continuous model. AB - In criminal investigations, forensic scientists need to evaluate DNA mixtures. The estimation of the number of contributors and evaluation of the contribution of a person of interest (POI) from these samples are challenging. In this study, we developed a new open-source software "Kongoh" for interpreting DNA mixture based on a quantitative continuous model. The model uses quantitative information of peak heights in the DNA profile and considers the effect of artifacts and allelic drop-out. By using this software, the likelihoods of 1-4 persons' contributions are calculated, and the most optimal number of contributors is automatically determined; this differs from other open-source software. Therefore, we can eliminate the need to manually determine the number of contributors before the analysis. Kongoh also considers allele- or locus-specific effects of biological parameters based on the experimental data. We then validated Kongoh by calculating the likelihood ratio (LR) of a POI's contribution in true contributors and non-contributors by using 2-4 person mixtures analyzed through a 15 short tandem repeat typing system. Most LR values obtained from Kongoh during true-contributor testing strongly supported the POI's contribution even for small amounts or degraded DNA samples. Kongoh correctly rejected a false hypothesis in the non-contributor testing, generated reproducible LR values, and demonstrated higher accuracy of the estimated number of contributors than another software based on the quantitative continuous model. Therefore, Kongoh is useful in accurately interpreting DNA evidence like mixtures and small amounts or degraded DNA samples. PMID- 29149211 TI - Occupational exposure to unburnt tobacco and potential risk of toxic optic neuropathy: A cross-sectional study among beedi rollers in selected rural areas of coastal Karnataka, India. AB - BACKGROUND: Beedi also known as poor man's cigarette is manufactured in almost all major states of India. Beedi workers are exposed to various health risks. There is an increased risk of systemic absorption of tobacco through skin and mucous membrane. The optic nerve is susceptible to damage from several toxic substances including tobacco. This group of disorders is known as toxic optic neuropathy (TON). The association of TON with occupational exposure to unburnt tobacco in beedi rollers has not been explored. OBJECTIVES: Among the beedi rollers in Mangaluru and Bantwal talukas of Dakshina Kannada District, Karnataka, India: to assess the magnitude of potential TON utilizing colour vision and contrast sensitivity as screening tools and to identify the demographic, biological and occupational factors associated with potential TON. METHODS: A community-based cross-sectional study was conducted from April-Sept 2016 in Mangaluru and Bantwal talukas, of Dakshina Kannada district, Karnataka. Beedi rollers from twelve villages (six from each taluka) were included. In each of the selected villages, the investigators identified beedi collection centres and all the eligible beedi rollers were included in the study till the required number of beedi rollers for that village was achieved. Participants were screened at the study site for visual acuity, colour vision and contrast sensitivity and those with abnormal colour and contrast sensitivity in the presence of good visual acuity were considered to have potential TON. RESULTS: A total of 377 beedi rollers were approached; of which 365 consented to take part in the study (response rate: 96.81%). Women constituted the majority of the participants (n = 338, 92.6%). Based on the screening criteria, the prevalence of potential TON was 17.5% (n = 64, 95% CI: 13.5-21.9). On multiple logistic regression analysis, duration of beedi rolling (Adj OR: 1.061; 95% CI 1.015-1.109, p = 0.009), advancing age (Adj OR: 1.096; 95% CI 1.058-1.136, p<0.001) and presence of diabetes (Adj OR: 6.315; 95% CI 1.4572-27.376, p = 0.014) were independent correlates of potential TON. CONCLUSION: In the present study, almost one out of six beedi rollers displayed clinical signs of potential TON. Increased duration of beedi rolling, advancing age and presence of diabetes were the independent correlates of potential TON. However, with this cross-sectional study it is not possible to conclude if these factors play a role individually or collectively or are a serendipitous association, for which large scale analytical studies are required. PMID- 29149212 TI - Mycolactone displays anti-inflammatory effects on the nervous system. AB - BACKGROUND: Mycolactone is a macrolide produced by the skin pathogen Mycobacterium ulcerans, with cytotoxic, analgesic and immunomodulatory properties. The latter were recently shown to result from mycolactone blocking the Sec61-dependent production of pro-inflammatory mediators by immune cells. Here we investigated whether mycolactone similarly affects the inflammatory responses of the nervous cell subsets involved in pain perception, transmission and maintenance. We also investigated the effects of mycolactone on the neuroinflammation that is associated with chronic pain in vivo. METHODOLOGY/ PRINCIPLE FINDINGS: Sensory neurons, Schwann cells and microglia were isolated from mice for ex vivo assessment of mycolactone cytotoxicity and immunomodulatory activity by measuring the production of proalgesic cytokines and chemokines. In all cell types studied, prolonged (>48h) exposure to mycolactone induced significant cell death at concentrations >10 ng/ml. Within the first 24h treatment, nanomolar concentrations of mycolactone efficiently suppressed the cell production of pro-inflammatory mediators, without affecting their viability. Notably, mycolactone also prevented the pro-inflammatory polarization of cortical microglia. Since these cells critically contribute to neuroinflammation, we next tested if mycolactone impacts this pathogenic process in vivo. We used a rat model of neuropathic pain induced by chronic constriction of the sciatic nerve. Here, mycolactone was injected daily for 3 days in the spinal canal, to ensure its proper delivery to spinal cord. While this treatment failed to prevent injury induced neuroinflammation, it decreased significantly the local production of inflammatory cytokines without inducing detectable cytotoxicity. CONCLUSION/ SIGNIFICANCE: The present study provides in vitro and in vivo evidence that mycolactone suppresses the inflammatory responses of sensory neurons, Schwann cells and microglia, without affecting the cell viability. Together with previous studies using peripheral blood leukocytes, our work implies that mycolactone mediated analgesia may, at least partially, be explained by its anti-inflammatory properties. PMID- 29149213 TI - Optimal design and control of an electromechanical transfemoral prosthesis with energy regeneration. AB - In this paper, we present the design of an electromechanical above-knee active prosthesis with energy storage and regeneration. The system consists of geared knee and ankle motors, parallel springs for each motor, an ultracapacitor, and controllable four-quadrant power converters. The goal is to maximize the performance of the system by finding optimal controls and design parameters. A model of the system dynamics was developed, and used to solve a combined trajectory and design optimization problem. The objectives of the optimization were to minimize tracking error relative to human joint motions, as well as energy use. The optimization problem was solved by the method of direct collocation, based on joint torque and joint angle data from ten subjects walking at three speeds. After optimization of controls and design parameters, the simulated system could operate at zero energy cost while still closely emulating able-bodied gait. This was achieved by controlled energy transfer between knee and ankle, and by controlled storage and release of energy throughout the gait cycle. Optimal gear ratios and spring parameters were similar across subjects and walking speeds. PMID- 29149214 TI - New insights on the species-specific allelopathic interactions between macrophytes and marine HAB dinoflagellates. AB - Macrophytes are known to release allelochemicals that have the ability to inhibit the proliferation of their competitors. Here, we investigated the effects of the fresh leaves of two magnoliophytes (Zostera noltei and Cymodocea nodosa) and thalli of the macroalgae Ulva rigida on three HAB-forming benthic dinoflagellates (Ostreopsis cf. ovata, Prorocentrum lima, and Coolia monotis). The effects of C. nodosa and U. rigida were also tested against the neurotoxic planktonic dinoflagellate Alexandrium pacificum Litaker sp. nov (former Alexandrium catenella). Co-culture experiments were conducted under controlled laboratory conditions and potential allelopathic effects of the macrophytes on the growth, photosynthesis and toxin production of the targeted dinoflagellates were evaluated. Results showed that U. rigida had the strongest algicidal effect and that the planktonic A. pacificum was the most vulnerable species. Benthic dinoflagellates seemed more tolerant to potential allelochemicals produced by macrophytes. Depending on the dinoflagellate/macrophyte pairs and the weight of leaves/thalli tested, the studied physiological processes were moderately to heavily altered. Our results suggest that the allelopathic activity of the macrophytes could influence the development of HAB species. PMID- 29149216 TI - Correction: Saccharomyces boulardii CNCM I-745 supplementation reduces gastrointestinal dysfunction in an animal model of IBS. AB - [This corrects the article DOI: 10.1371/journal.pone.0181863.]. PMID- 29149217 TI - Per-service supervised learning for identifying desired WoT apps from user requests in natural language. AB - Web of Things (WoT) platforms are growing fast so as the needs for composing WoT apps more easily and efficiently. We have recently commenced the campaign to develop an interface where users can issue requests for WoT apps entirely in natural language. This requires an effort to build a system that can learn to identify relevant WoT functions that fulfill user's requests. In our preceding work, we trained a supervised learning system with thousands of publicly available IFTTT app recipes based on conditional random fields (CRF). However, the sub-par accuracy and excessive training time motivated us to devise a better approach. In this paper, we present a novel solution that creates a separate learning engine for each trigger service. With this approach, parallel and incremental learning becomes possible. For inference, our system first identifies the most relevant trigger service for a given user request by using an information retrieval technique. Then, the learning engine associated with the trigger service predicts the most likely pair of trigger and action functions. We expect that such two-phase inference method given parallel learning engines would improve the accuracy of identifying related WoT functions. We verify our new solution through the empirical evaluation with training and test sets sampled from a pool of refined IFTTT app recipes. We also meticulously analyze the characteristics of the recipes to find future research directions. PMID- 29149218 TI - Carbonaceous particulate matter on the lung surface from adults living in Sao Paulo, Brazil. AB - OBJECTIVES: We therefore sought to identify the exposures associated with lung surface in long-term residents of Sao Paulo, Brazil. METHODS: Lung surface carbon were analyzed in 72 autopsy specimens by image analysis. Smoking history, measured PM10 nearest to the home, distance to main road, and distance-weighted traffic density were used as exposure variables. Data are summarized as median (IQR), and compared by Mann Whitney Test, with correlations done by Spearman's correlation. RESULTS: There was no association between lung surface and age or gender. There was no statistically significant association in lung surface between smokers and non-smokers 6.74 cm2 (3.47 to 10.02) versus 5.20cm2 (2.29 to 7.54), and there was no significant association between lung surface carbon and exposure to environmental PM and markers of traffic exposure. CONCLUSION: We did not find a statistically significant association between lung surface and smokers and non-smokers, and no statistically significant association between lung surface carbon and environmental exposure variables. These results suggest that lung surface carbon in long-term residents of Sao Paulo may predominately be from environmental PM, but the most appropriate environmental exposure marker remains unclear. PMID- 29149215 TI - Longitudinal survey of two serotine bat (Eptesicus serotinus) maternity colonies exposed to EBLV-1 (European Bat Lyssavirus type 1): Assessment of survival and serological status variations using capture-recapture models. AB - This study describes two longitudinal serological surveys of European Bat Lyssavirus type 1 (EBLV-1) antibodies in serotine bat (Eptesicus serotinus) maternity colonies located in the North-East of France. This species is currently considered as the main EBLV-1 reservoir. Multievent capture-recapture models were used to determine the factors influencing bat rabies transmission as this method accounts for imperfect detection and uncertainty in disease states. Considering the period of study, analyses revealed that survival and recapture probabilities were not affected by the serological status of individuals, confirming the capacity of bats to be exposed to lyssaviruses without dying. Five bats have been found with EBLV-1 RNA in the saliva at the start of the study, suggesting they were caught during virus excretion period. Among these bats, one was interestingly recaptured one year later and harbored a seropositive status. Along the survey, some others bats have been observed to both seroconvert (i.e. move from a negative to a positive serological status) and serorevert (i.e. move from a positive to a negative serological status). Peak of seroprevalence reached 34% and 70% in site A and B respectively. On one of the 2 sites, global decrease of seroprevalence was observed all along the study period nuanced by oscillation intervals of approximately 2-3 years supporting the oscillation infection dynamics hypothesized during a previous EBLV-1 study in a Myotis myotis colony. Seroprevalence were affected by significantly higher seroprevalence in summer than in spring. The maximum time observed between successive positive serological statuses of a bat demonstrated the potential persistence of neutralizing antibodies for at least 4 years. At last, EBLV-1 serological status transitions have been shown driven by age category with higher seroreversion frequencies in adults than in juvenile. Juveniles and female adults seemed indeed acting as distinct drivers of the rabies virus dynamics, hypothesis have been addressed but their exact role in the EBLV-1 transmission still need to be specified. PMID- 29149219 TI - Characterization and classification of lupus patients based on plasma thermograms. AB - OBJECTIVE: Plasma thermograms (thermal stability profiles of blood plasma) are being utilized as a new diagnostic approach for clinical assessment. In this study, we investigated the ability of plasma thermograms to classify systemic lupus erythematosus (SLE) patients versus non SLE controls using a sample of 300 SLE and 300 control subjects from the Lupus Family Registry and Repository. Additionally, we evaluated the heterogeneity of thermograms along age, sex, ethnicity, concurrent health conditions and SLE diagnostic criteria. METHODS: Thermograms were visualized graphically for important differences between covariates and summarized using various measures. A modified linear discriminant analysis was used to segregate SLE versus control subjects on the basis of the thermograms. Classification accuracy was measured based on multiple training/test splits of the data and compared to classification based on SLE serological markers. RESULTS: Median sensitivity, specificity, and overall accuracy based on classification using plasma thermograms was 86%, 83%, and 84% compared to 78%, 95%, and 86% based on a combination of five antibody tests. Combining thermogram and serology information together improved sensitivity from 78% to 86% and overall accuracy from 86% to 89% relative to serology alone. Predictive accuracy of thermograms for distinguishing SLE and osteoarthritis / rheumatoid arthritis patients was comparable. Both gender and anemia significantly interacted with disease status for plasma thermograms (p<0.001), with greater separation between SLE and control thermograms for females relative to males and for patients with anemia relative to patients without anemia. CONCLUSION: Plasma thermograms constitute an additional biomarker which may help improve diagnosis of SLE patients, particularly when coupled with standard diagnostic testing. Differences in thermograms according to patient sex, ethnicity, clinical and environmental factors are important considerations for application of thermograms in a clinical setting. PMID- 29149220 TI - A novel method to rapidly distinguish the geographical origin of traditional fermented-salted vegetables by mass fingerprinting. AB - The geographical origin of kimchi is of interest to consumers and producers because the prices of commercial kimchi products can vary significantly according to the geographical origin. Hence, social issues related to the geographical origin of kimchi in Korea have emerged as a major problem. In this study, the geographical origin of kimchi was determined by comparing the mass fingerprints obtained for Korean and Chinese kimchi samples by MALDI-TOF MS with multivariate analysis. The results obtained herein provide an accurate, powerful tool to clearly discriminate kimchi samples based on their geographical origin within a short time and to ensure food authenticity, which is of significance in the kimchi industry. Furthermore, our MALDI-TOF MS method could be applied to determining the geographical origin of other fermented-salted vegetables at a reduced cost in shorter times. PMID- 29149221 TI - Dietary protein sources differentially affect microbiota, mTOR activity and transcription of mTOR signaling pathways in the small intestine. AB - Dietary protein sources can have profound effects on host-microbe interactions in the gut that are critically important for immune resilience. However more knowledge is needed to assess the impact of different protein sources on gut and animal health. Thirty-six wildtype male C57BL/6J mice of 35 d age (n = 6/group; mean +/- SEM body weight 21.9 +/- 0.25 g) were randomly assigned to groups fed for four weeks with semi synthetic diets prepared with one of the following protein sources containing (300 g/kg as fed basis): soybean meal (SBM), casein, partially delactosed whey powder, spray dried plasma protein, wheat gluten meal and yellow meal worm. At the end of the experiment, mice were sacrificed to collect ileal tissue to acquire gene expression data, and mammalian (mechanistic) target of rapamycin (mTOR) activity, ileal digesta to study changes in microbiota and serum to measure cytokines and chemokines. By genome-wide transcriptome analysis, we identified fourteen high level regulatory genes that are strongly affected in SBM-fed mice compared to the other experimental groups. They mostly related to the mTOR pathway. In addition, an increased (P < 0.05) concentration of granulocyte colony-stimulating factor was observed in serum of SBM-fed mice compared to other dietary groups. Moreover, by 16S rRNA sequencing, we observed that SBM-fed mice had higher (P < 0.05) abundances of Bacteroidales family S24-7, compared to the other dietary groups. We showed that measurements of genome-wide expression and microbiota composition in the mouse ileum reveal divergent responses to diets containing different protein sources, in particular for a diet based on SBM. PMID- 29149224 TI - Correction: Evaluation of Acute Toxicity and Early Clinical Outcome in Head and Neck Cancers Treated With Conventional Radiotherapy and Simultaneous Integrated Boost Arc Radiotherapy. AB - [This corrects the article DOI: 10.14740/wjon1049w.]. PMID- 29149222 TI - Personalized medicine and Hispanic health: improving health outcomes and reducing health disparities - a National Heart, Lung, and Blood Institute workshop report. AB - Persons of Hispanic/Latino descent may represent different ancestries, ethnic and cultural groups and countries of birth. In the U.S., the Hispanic/Latino population is projected to constitute 29% of the population by 2060. A personalized approach focusing on individual variability in genetics, environment, lifestyle and socioeconomic determinants of health may advance the understanding of some of the major factors contributing to the health disparities experienced by Hispanics/Latinos and other groups in the U.S., thus leading to new strategies that improve health care outcomes. However, there are major gaps in our current knowledge about how personalized medicine can shape health outcomes among Hispanics/Latinos and address the potential factors that may explain the observed differences within this heterogeneous group, and between this group and other U.S. demographic groups. For that purpose, the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Food and Drug Administration (FDA), held a workshop in which experts discussed (1) potential approaches to study medical treatments and health outcomes among Hispanics/Latinos and garner the necessary evidence to fill gaps of efficacy, effectiveness and safety of therapies for heart, lung, blood and sleep (HLBS) disorders and conditions--and their risk factors; (2) research opportunities related to personalized medicine to improve knowledge and develop effective interventions to reduce health disparities among Hispanics/Latinos in the U.S.; and (3) the incorporation of expanded sociocultural and socioeconomic data collection and genetic/genomic/epigenetic information of Hispanic/Latino patients into their clinical assessments, to account for individual variability in ancestry; physiology or disease risk; culture; environment; lifestyle; and socioeconomic determinants of health. The experts also provided recommendations on: sources of Hispanic/Latino health data and strategies to enhance its collection; policy; genetics, genomics and epigenetics research; and integrating Hispanic/Latino health research within clinical settings. PMID- 29149225 TI - Chemical analysis in saliva and the search for salivary biomarkers - a tutorial review. AB - Biomarkers refer to analytes that can be used in the diagnosis of diseases or disorders. In saliva, there are many components that are potential biomarkers, and increasing research has focussed on the development of saliva as a diagnostic fluid. This review summarizes the existing uses of salivary biomarkers and highlights the importance of the choice of saliva collection as well as the storage procedures. A case study on the effect of collection tools on the concentrations of one of the potential biomarkers, glutathione, is highlighted. Moreover, molecular diagnosis requires reliable measurement assays. This review presents electroanalytical methods for the detection of salivary biomarkers. It further reviews approaches that can be taken to improve the selectivity of electroanalytical assays without the use of biologically selective materials, notably without the use of enzymes or antibodies. PMID- 29149223 TI - Two genetic codes: Repetitive syntax for active non-coding RNAs; non-repetitive syntax for the DNA archives. AB - Current knowledge of the RNA world indicates 2 different genetic codes being present throughout the living world. In contrast to non-coding RNAs that are built of repetitive nucleotide syntax, the sequences that serve as templates for proteins share-as main characteristics-a non-repetitive syntax. Whereas non coding RNAs build groups that serve as regulatory tools in nearly all genetic processes, the coding sections represent the evolutionarily successful function of the genetic information storage medium. This indicates that the differences in their syntax structure are coherent with the differences of the functions they represent. Interestingly, these 2 genetic codes resemble the function of all natural languages, i.e., the repetitive non-coding sequences serve as appropriate tool for organization, coordination and regulation of group behavior, and the non repetitive coding sequences are for conservation of instrumental constructions, plans, blueprints for complex protein-body architecture. This differentiation may help to better understand RNA group behavioral motifs. PMID- 29149226 TI - Nanostructured silicon ferromagnet collected by a permanent neodymium magnet. AB - Nanostructured silicon (N-Si) was prepared by anodic electroetching of p-type silicon wafers. The obtained magnetic particles were separated by a permanent neodymium magnet as a magnetic nanostructured silicon (mN-Si). The N-Si and mN-Si exhibited different magnetic properties: the N-Si exhibited ferromagnetic-like behaviour, whereas the mN-Si exhibited superparamagnetic-like behaviour. PMID- 29149227 TI - Synthesis of Z-alkenes via visible light promoted photocatalytic E -> Z isomerization under metal-free conditions. AB - A green approach for the synthesis of thermodynamically less stable Z-alkenes has been presented through the exploration of visible light promoted photocatalytic E to-Z isomerization. This protocol features metal-free conditions, which is operationally simple, remarkably clean, and allows the synthesis of both electron rich and electron-deficient Z-alkenes with diverse functional groups. PMID- 29149228 TI - Correction: Two-dimensional boron: structures, properties and applications. AB - Correction for 'Two-dimensional boron: structures, properties and applications' by Zhuhua Zhang et al., Chem. Soc. Rev., 2017, DOI: . PMID- 29149229 TI - Van't Hoff's law for active suspensions: the role of the solvent chemical potential. AB - We extend Van't Hoff's law for the osmotic pressure to a suspension of active Brownian particles. The propelled particles exert a net reaction force on the solvent, and thereby either drive a measurable solvent flow from the connecting solvent reservoir through the semipermeable membrane, or increase the osmotic pressure and cause the suspension to rise to heights as large as micrometers for experimentally realized microswimmers described in the literature. The increase in osmotic pressure is caused by the background solvent being, in contrast to passive suspensions, no longer at the chemical potential of the solvent reservoir. The difference in solvent chemical potentials depends on the colloid membrane interaction potential, which implies that the osmotic pressure is a state function of a state that itself is influenced by the membrane potential. PMID- 29149230 TI - Light enhanced energy storage ability through a hybrid plasmonic Ag nanowire decorated hydroxide "skin structure". AB - By decorating nickel copper hydroxide (NCH) with Ag nanowires (Ag NWs), a 1.7 fold enhancement in areal capacitance (5.4 F cm-2) and a 1.8 fold increment in gravimetric capacitance (3182 F g-1) under light illumination were achieved. The improved supercapacitor performances of the composites under visible-light illumination were demonstrated and a reasonable explanation for this newly discovered phenomenon was proposed. The plasmonic effect of Ag NWs was demonstrated by hot-electron generation. The decorated Ag NWs served as a stimulus for redox reactions. This research provides a tantalizing opportunity for enhancing the supercapacitor performance by exploiting surface plasmon metals. The finding from this study will be informative for the future design of supercapacitor electrodes. PMID- 29149231 TI - Field-, strain- and light-induced superconductivity in organic strongly correlated electron systems. AB - Stimulated by the discovery of high-temperature superconductivity in 1986, band filling control of strongly correlated electron systems has been a persistent challenge over the past three decades in condensed matter science. In particular, recent efforts have been focused on electrostatic carrier doping of these materials, utilising field-effect transistor (FET) structures to find novel superconductivity. Our group found the first field-induced superconductivity in an organic-based material in 2013 and has been developing various types of superconducting organic FETs. In this perspective, we summarise our recent results on the development of novel superconducting organic FETs. In addition, this perspective describes novel functionality of superconducting FETs, such as strain- and light-responsivity. We believe that the techniques and knowledge described here will contribute to advances in future superconducting electronics as well as the understanding of superconductivity in strongly correlated electron systems. PMID- 29149232 TI - Stabilized electrically induced Helfrich deformation and enhanced color tuning in cholesteric liquid crystals. AB - When subjected to an AC electric field perpendicular to its layers, the cholesteric planar state may undergo a periodic layer undulation, known as the Helfrich deformation, which generates a color change of the reflected light. The Helfrich deformation of regular cholesteric liquid crystals is, however, unstable and easily taken over by the focal conic state, and thus the color tuning range is narrow. We demonstrated that the Helfrich deformation can be stabilized in a large electric field region by doping a bent dimer with an anomalously small bend elastic constant and dispersing a small amount of polymer network. By varying the dimer concentration, we were able to systematically change the bend elastic constant and thus verify the theoretical prediction of the undulation threshold electric field and periodicity. We also achieved reflectance tuning with electric field less than 2 V MUm-1 and color tuning covering the entire visible light region with electric field as low as 4 V MUm-1. PMID- 29149233 TI - Lighting up long-range charge-transfer states by a localized plasmonic field. AB - The long-range charge-transfer states in a donor-acceptor system exhibit well separated electron-hole pairs, but are often difficult to achieve by optical means owing to a very small overlap between the wave functions of the donor and acceptor. We have found that the introduction of a spatially confined plasmon can enhance the transition probability to the long-range charge-transfer states as it can effectively break the intrinsic symmetry selection rule imposed on the system. Meanwhile, the intensity borrowed from local excitations could also be selectively promoted, allowing the manipulation of the excited quantum states. In addition, our calculations reveal that the donor and acceptor moieties can be unambiguously visualized in real space by tip-enhanced resonance Raman images. These findings can benefit light-harvesting and also be readily extended to diverse optical processes. PMID- 29149234 TI - Calcium-dependent hydrolysis of supported planar lipids was triggered by honey bee venom phospholipase A2 with the right orientation at the interface. AB - Hydrolysis of planar phospholipids catalyzed by honey bee venom phospholipase A2 (bvPLA2) was studied. Experiments demonstrated that Ca2+ ions mediated between the lipids and bvPLA2, induced reorientation of bvPLA2, and activated hydrolysis. One of the hydrolysis products, fatty acids, was desorbed, and the other one, lysophospholipids, self-organized at the interface. PMID- 29149235 TI - Isolated complexes of the amino acid arginine with polyether and polyamine macrocycles, the role of proton transfer. AB - The distinct basicity of the guanidinium side-group of arginine (Arg) sustains specific interactions involved in essential biochemical processes. The sensing of arginine is therefore key in modern biotechnology and bioanalysis. In this context, the development of molecular receptors based on crown ether building blocks has demonstrated great potential. We investigate the complexes formed by arginine with two benchmark macrocycles, 12-crown-4 (1,4,7,10 tetraoxacyclododecane) and its N-substituted analog cyclen (1,4,7,10 tetraazacyclododecane). Isolated complexes with a net charge +1 are characterized with infrared action vibrational spectroscopy and quantum mechanical computations in order to determine the most stable coordination arrangements and to elucidate the location of the protons involved. Remarkably, although arginine retains a net positive charge in its complex with 12-crown-4, it becomes zwitterionic in the cyclen complex. In this latter case, the guanidinium group remains protonated while a proton transfer from the carboxylic group occurs, leading to a charged NH2+ moiety in cyclen. Natural bond orbital analysis is employed to characterize the intermolecular H-bonds responsible for the stability of both complexes. Protonated arginine interacts with 12-crown-4 through the guanidinium side group, in a conformation that resembles the one expected for crown-Arg binding in peptidic chains. In contrast, the cyclen complex involves the coordination of the carboxylate anionic group with a N-H bond of the protonated amine group cyclen, and plausible but less relevant interactions with the guanidinium group. PMID- 29149236 TI - Mutations affecting glycinergic neurotransmission in hyperekplexia increase pain sensitivity. AB - See Dickenson (doi:10.1093/brain/awx334) for a scientific commentary on this article.Inhibitory interneurons in the spinal cord use glycine and GABA for fast inhibitory neurotransmission. While there is abundant research on these inhibitory pain pathways in animal models, their relevance in humans remains unclear, largely due to the limited possibility to manipulate selectively these pathways in humans. Hyperekplexia is a rare human disease that is caused by loss of-function mutations in genes encoding for glycine receptors and glycine transporters. In the present study, we tested whether hyperekplexia patients display altered pain perception or central pain modulation compared with healthy subjects. Seven patients with genetically and clinically confirmed hyperekplexia were compared to 14 healthy age- and sex-matched controls. The following quantitative sensory tests were performed: pressure pain detection threshold (primary outcome), ice water tolerance, single and repeated electrical pain detection thresholds, nociceptive withdrawal reflex threshold, and conditioned pain modulation. Statistical analysis was performed using linear mixed models. Hyperekplexia patients displayed lower pain thresholds than healthy controls for all of the quantitative sensory tests [mean (standard deviation)]: pressure pain detection threshold [273 (170) versus 475 (115) kPa, P = 0.003], ice water tolerance [49.2 (36.5) versus 85.7 (35.0) s, P = 0.015], electrical single pain detection threshold [5.42 (2.64) versus 7.47 (2.62) mA, P = 0.012], electrical repeated pain detection threshold [3.76 (1.41) versus 5.8 (1.73) mA, P = 0.003], and nociceptive withdrawal reflex [7.42 (3.63) versus 14.1 (6.9) mA, P = 0.015]. Conditioned pain modulation was significantly reduced in hyperekplexia [increase to baseline: 53.2 (63.7) versus 105 (57) kPa, P = 0.030]. Our data demonstrate increased pain sensitivity and impaired central pain modulation in hyperekplexia patients, supporting the importance of glycinergic neurotransmission for central pain modulation in humans. PMID- 29149238 TI - Diabetic Neuroglial Changes in the Superficial and Deep Nonperfused Areas on Optical Coherence Tomography Angiography. AB - Purpose: To evaluate the relationship between lamellar capillary nonperfusion on optical coherence tomography angiography (OCTA) images and neuroglial changes on structural optical coherence tomography (OCT) images in diabetic retinopathy (DR). Methods: We retrospectively reviewed 101 consecutive eyes of 69 patients with DR. OCTA and OCT images within a 3 * 3-mm square centered on the fovea were acquired simultaneously. The nonperfused areas (NPAs) in the superficial capillary layer (sNPA) (from the nerve fiber layer [NFL] to the inner plexiform layer [IPL]), the deep layer (dNPA) (corresponding mainly to the inner nuclear layer [INL]), or both layers (bNPA) were measured individually along 10 transverse lines. The corresponding lamellar neuroglial changes also were evaluated on OCT images. Results: The transverse lengths of the sNPA, dNPA, and bNPA were 2.34% (interquartile range, 0.81-5.55), 0.61% (0-1.99), and 5.96% (4.02 10.88), respectively. The length of the sNPA was correlated significantly with the lengths of no boundary between the NFL and ganglion cell layer (GCL)/IPL and the spots with inverted OCT reflectivity in the sNPA. The transverse length of the dNPA was associated with the length of cystoid spaces in the INL or Henle's fiber layer (HFL) in the dNPA. There was a significant correlation between the transverse lengths of the bNPA and no boundary between the NFL and GCL/IPL within the bNPA. Conclusions: Systematic evaluation of the OCTA-OCT association showed structural changes in the neuroglial tissues corresponding to the lamellar NPAs and suggested the feasibility of layer-by-layer evaluation of the capillary nonperfusion in DR. PMID- 29149237 TI - Multimorbidity Among Persons Living with Human Immunodeficiency Virus in the United States. AB - Background: Age-associated conditions are increasingly common among persons living with human immunodeficiency virus (HIV) (PLWH). A longitudinal investigation of their accrual is needed given their implications on clinical care complexity. We examined trends in the co-occurrence of age-associated conditions among PLWH receiving clinical care, and differences in their prevalence by demographic subgroup. Methods: This cohort study was nested within the North American AIDS Cohort Collaboration on Research and Design. Participants from HIV outpatient clinics were antiretroviral therapy-exposed PLWH receiving clinical care (ie, >=1 CD4 count) in the United States during 2000-2009. Multimorbidity was irreversible, defined as having >=2: hypertension, diabetes mellitus, chronic kidney disease, hypercholesterolemia, end-stage liver disease, or non-AIDS-related cancer. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) comparing demographic subgroups were obtained by Poisson regression with robust error variance, using generalized estimating equations for repeated measures. Results: Among 22969 adults, 79% were male, 36% were black, and the median baseline age was 40 years (interquartile range, 34-46 years). Between 2000 and 2009, multimorbidity prevalence increased from 8.2% to 22.4% (Ptrend < .001). Adjusting for age, this trend was still significant (P < .001). There was no difference by sex, but blacks were less likely than whites to have multimorbidity (aPR, 0.87; 95% CI, .77-.99). Multimorbidity was the highest among heterosexuals, relative to men who have sex with men (aPR, 1.16; 95% CI, 1.01 1.34). Hypertension and hypercholesterolemia most commonly co-occurred. Conclusions: Multimorbidity prevalence has increased among PLWH. Comorbidity prevention and multisubspecialty management of increasingly complex healthcare needs will be vital to ensuring that they receive needed care. PMID- 29149239 TI - Label-Free In Vivo Imaging of Corneal Lymphatic Vessels Using Microscopic Optical Coherence Tomography. AB - Purpose: Corneal neovascularization, in particular lymphangiogenesis, is a limiting factor in corneal transplant survival. Novel treatment approaches focus on (selective) inhibition and regression of lymphatic vessels. Imaging clinically invisible corneal lymphatic vessels is a prerequisite for these strategies. Using a murine model, this study investigates whether corneal lymphatic vessels can be imaged using microscopic optical coherence tomography (mOCT). Methods: Corneal neovascularization was induced by intrastromal placement of 11.0 nylon sutures in one eye of BALB/c mice. After 2 weeks, cross-sectional images and volumes of the corneas with a 0.5 mm lateral and axial field of view were acquired using a custom-built mOCT system enabling a resolution of 1 MUm at a B-scan rate of 165/s. Three of the six animals received an additional intrastromal injection of India ink 24 hours before the measurement to stain the corneal lymphatic system in vivo. Immunohistochemistry using CD31 and LYVE-1 was used to validate the mOCT findings. Results: Using mOCT, lymphatic vessels were visible as dark vessel-like structures with the lumen lacking a hyperreflective wall and mostly lacking cells. However, individual, slowly moving particles, which most likely are immune cells, occasionally could be observed inside the lumen. In lymphatic vessels of ink-stained corneas, hyperreflection and shadowing underneath was observed. Ink filled lymphatic vessels were colocalized in consecutive corneal flat mounts of the same specimen. Conclusions: Corneal lymphatic vessels can be imaged using mOCT. This novel approach opens new options for noninvasive clinical imaging of corneal lymphatic vessels for diagnostic and therapeutic indications. PMID- 29149240 TI - Z-scores-based methods and their application to biological monitoring: an example in professional soccer players. AB - The clinical and biological follow-up of individuals, such as the biological passport for athletes, is typically based on the individual and longitudinal monitoring of hematological or urine markers. These follow-ups aim to identify abnormal behavior by comparing the individual's biological samples to an established baseline. These comparisons may be done via different ways, but each of them requires an appropriate extra population to compute the significance levels, which is a non-trivial issue. Moreover, it is not necessarily relevant to compare the measures of a biomarker of a professional athlete to that of a reference population (even restricted to other athletes), and a reasonable alternative is to detect the abnormal values by considering only the other measurements of the same athlete. Here we propose a simple adaptive statistic based on maxima of Z-scores that does not rely on the use of an extra population. We show that, in the Gaussian framework, it is a practical and relevant method for detecting abnormal values in a series of observations from the same individual. The distribution of this statistic does not depend on the individual parameters under the null hypothesis, and its quantiles can be computed using Monte Carlo simulations. The proposed method is tested on the 3-year follow-up of ferritin, serum iron, erythrocytes, hemoglobin, and hematocrit markers in 2577 elite male soccer players. For instance, if we consider the abnormal values for the hematocrit at a 5% level, we found that 5.57% of the selected cohort had at least one abnormal value (which is not significantly different from the expected false-discovery rate). The approach is a starting point for more elaborate models that would produce a refined individual baseline. The method can be extended to the Gaussian linear model, in order to include additional variables such as the age or exposure to altitude. The method could also be applied to other domains, such as the clinical patient follow-up in monitoring abnormal values of biological markers. PMID- 29149241 TI - Statistical Learning in Specific Language Impairment: A Meta-Analysis. AB - Purpose: The current meta-analysis provides a quantitative overview of published and unpublished studies on statistical learning in the auditory verbal domain in people with and without specific language impairment (SLI). The database used for the meta-analysis is accessible online and open to updates (Community-Augmented Meta-Analysis), which facilitates the accumulation and evaluation of previous and future studies on statistical learning in this domain. Method: A systematic literature search identified 10 unique experiments examining auditory verbal statistical learning in 213 participants with SLI and 363 without SLI, aged between 6 and 19 years. Data from qualifying studies were extracted and converted to Hedges' g effect sizes. Results: The overall standardized mean difference between participants with SLI and participants without SLI was 0.54, which was significantly different from 0 (p < .001, 95% confidence interval [0.36, 0.71]). Conclusion: Together, the results of our meta-analysis indicate a robust difference between people with SLI and people without SLI in their detection of statistical regularities in the auditory input. The detection of statistical regularities is, on average, not as effective in people with SLI compared with people without SLI. The results of this meta-analysis are congruent with a statistical learning deficit hypothesis in SLI. Supplemental Material: https://doi.org/10.23641/asha.5558074. PMID- 29149242 TI - Long-term Carriage of Extended-Spectrum beta-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae in the General Population in The Netherlands. AB - Background: This longitudinal study aimed to investigate (risk factors for) persistence of carriage and molecular characteristics of extended-spectrum and plasmid-encoded AmpC beta-lactamase-producing (ESBL/pAmpC) Escherichia coli and Klebsiella pneumoniae (ESBL-E/K) in adults in the Dutch community. Methods: Following a cross-sectional study (ESBL-E/K prevalence, 4.5%), a subset of ESBL E/K-positive (n = 76) and -negative (n = 249) individuals volunteered to provide 5 monthly fecal samples and questionnaires. ESBL-E/K was cultured using selective enrichment/culture, and multilocus sequence types (MLSTs) were determined. ESBL/pAmpC-genes were analyzed using polymerase chain reaction (PCR) and sequencing. Plasmids were characterized and subtyped by plasmid MLST. Risk factors for persistent carriage were analyzed using logistic regression. Results: Of the initially ESBL-E/K-positive participants, 25 of 76 (32.9%) remained positive in all subsequent samples; 51 of 76 persons (67.1%) tested ESBL-E/K negative at some time point during follow-up, of which 31 (40.8%) stayed negative throughout the longitudinal study. Carriers often carried the same ESBL gene and plasmid, but sometimes in different ESBL-E/K strains, indicative for horizontal transfer of plasmids. Of the 249 initially ESBL-E/K-negative participants, the majority (n = 218 [87.6%]) tested negative during 8 months of follow-up, whereas 31 of 249 (12.4%) participants acquired an ESBL-E/K. Escherichia coli phylogenetic group B2 and D and travel to ESBL high-prevalence countries were associated with prolonged carriage. Conclusions: ESBL-E/K carriage persisted for >8 months in 32.9% of the initially ESBL-positive individuals, while 12.4% of initially negative individuals acquired ESBL-E/K during the study. A single positive test result provides no accurate prediction for prolonged carriage. Acquisition/loss of ESBL-E/K does not seem to be a random process, but differs between bacterial genotypes. PMID- 29149243 TI - Biosimilars in oncology: much ado about nothing? PMID- 29149244 TI - Dr W. H. R. Rivers: Siegfried Sassoon and Robert Graves' 'fathering friend'. PMID- 29149245 TI - High-dimensional therapeutic inference in the focally damaged human brain. AB - See Thiebaut de Schotten and Foulon (doi:10.1093/brain/awx332) for a scientific commentary on this article.Though consistency across the population renders the extraordinarily complex functional anatomy of the human brain surveyable, the inverse inference-from common functional maps to individual behaviour-is constrained by marked individual deviation from the population mean. Such inference is fundamental to the evaluation of therapeutic interventions in focal brain injury, where the impact of an induced structural change in the brain is quantified by its behavioural consequences, inevitably refracted through the lens of lesion-outcome relations. Current therapeutic evaluations do not incorporate inferences to the individual outcome derived from a detailed specification of the lesion anatomy, relying only on reductive parameters such as lesion volume and crudely discretised location. Examining 1172 patients with anatomically registered focal brain lesions, here we show that such low-dimensional models are highly insensitive to therapeutic effects. In contrast, high-dimensional models supported by machine learning dramatically improve sensitivity by leveraging complex individuating patterns in the functional architecture of the brain. The failure to replicate in humans positive interventional effects in experimental animals is thus revealed to have a remediable inferential cause, forcing a radical re-evaluation of therapeutic inference in the human brain. PMID- 29149246 TI - Asian Cleft Rhinoplasty: The Open Structural Approach. AB - Background: Asian cleft rhinoplasty is a unique procedure with specific challenges. Objectives: This paper presents our experience with the use of an open structural technique for Asian cleft rhinoplasty utilizing a complete autologous approach. Methods: An open approach that reconstructs the malpositioned nasal cartilage was utilized. Centrally, the septocolumella graft fixed securely in the midline with extender spreader grafts was utilized to project and lengthen the nose. The dislocated lateral crura on the cleft side was completely detached from the accessory cartilages and mobilized off the vestibular lining. The deficient medial crura was lengthened with the lateral crural steal procedure. The resultant shortened lateral crura was then reconstructed with the lateral crural strut graft (LCSG). This gave the versatility needed to bring the tip cartilages into a more anatomic and symmetrical position. Tip suturing and grafting was performed and dorsal augmentation achieved through diced cartilage wrapped in deep temporal fascia. At closure, when indicated, a modified Tajima reverse-U excision of the vestibular lining was performed to correct the alar hooding on the cleft side. Alar base modifications were done as indicated. Results: From January 2010 to December 2015, 35 Asian patients underwent open cleft rhinoplasty. There were 18 female patients and 17 male patients. Twenty-nine patients were unilateral cleft and 6 were bilateral cleft. The mean follow up was 23 months. All patients were highly satisfied with the functional and aesthetic improvement of the procedure. The complications and revision rates were low. Conclusions: The autologous open structural approach can predictably and consistently give excellent results for Asian cleft rhinoplasty. The result attainable is superior to results attainable before adopting this approach for our patients. Level of Evidence: 4. PMID- 29149248 TI - Erratum to: Response to "Commentary on: Gluteal Augmentation Techniques: A Comprehensive Literature Review". PMID- 29149247 TI - Quantitative proteomic profiling of bovine follicular fluid during follicle development. AB - Bovine follicular fluid (FF) constitutes the microenvironment of follicles and includes various biologically active proteins. We performed a study involving 18 healthy nonlactating Holstein cows to determine the protein expression profile of FF at key stages of follicular development. Follicles were individually aspirated in vivo at predeviation (F1 ~ 7.0 mm), deviation (F1 ~ 8.5 mm), postdeviation (F1 ~ 12.0 mm), and preovulatory stages of follicle development, which were confirmed by measurement of follicular estradiol and progesterone concentrations. The FFs from nine cows were selected for proteomic analysis. After albumin depletion, triplicates of pooled FF were reduced, alkylated, and digested with trypsin. The resulting peptides were labeled with TMTsixplex and quantified using liquid chromatography-mass spectrometry/mass spectrometry. A total of 143 proteins were identified and assigned to a variety of biological processes, including response to stimulus and metabolic processes. Twenty-two differentially (P < 0.05) expressed proteins were found between stages indicating intrafollicular changes over development, with expected deviation time critical to modulate the protein expression. For instance, high concentrations of follistatin, inhibin, serglycin, spondin-1, fibrinogen, and anti-testosterone antibody were found during early stages of follicular development. In contrast, apolipoprotein H, alpha-2 macroglobulin, plasminogen, antithrombin-III, and immunoglobulins were increased after deviation. Among the differentially abundant proteins, 19 were found to be associated with steroidogenesis. Pathway analysis identified proteins that were mainly associated with the acute phase response signaling, coagulation system, complement system, liver/retinoid X receptor activation, and biosynthesis of nitric oxide and reactive oxygen. The differentially expressed proteins provide insights into the size-dependent protein changes in the ovarian follicle microenvironment that could influence follicular function. PMID- 29149251 TI - Parental Age and Risk of Lymphoid Neoplasms. AB - High parental age at childbirth has repeatedly been linked to childhood malignancies, while few studies have focused on the offspring's risk of adult cancer. In this population-based case-control study, we identified 32,000 patients with lymphoid neoplasms, diagnosed at ages 0-79 years during the period 1987-2011, and 160,000 matched controls in Sweden. Using prospectively registered data on their first-degree relatives, we evaluated the impact of parental age on the risk of lymphoid neoplasms by subtype. Overall, each 5-year increment in maternal age was associated with a 3% increase in incidence of offspring lymphoid neoplasms (hazard ratio = 1.03, 95% confidence interval: 1.02, 1.04). The association was similar for paternal age and present even among individuals older than 70 years of age at diagnosis. Stratified analyses further revealed that the association was limited to certain subtypes, mostly of indolent nature. Risks of chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma were 5%-10% higher per 5-year increment in maternal age, but no associations were observed for acute lymphoblastic leukemia, plasma cell neoplasms, or diffuse large B-cell lymphoma. These findings indicated that prenatal genetic or epigenetic changes influence risk of adult lymphoid neoplasms and suggest a difference in this association between aggressive and indolent lymphoma subtypes. PMID- 29149250 TI - Modeling the Causal Role of DNA Methylation in the Association Between Cigarette Smoking and Inflammation in African Americans: A 2-Step Epigenetic Mendelian Randomization Study. AB - The association between cigarette smoking and inflammation is well known. However, the biological mechanisms behind the association are not fully understood, particularly the role of DNA methylation, which is known to be affected by smoking. Using 2-step epigenetic Mendelian randomization, we investigated the role of DNA methylation in the association between cigarette smoking and inflammation. In 822 African Americans from the Genetic Epidemiology Network of Arteriopathy, phase 2 (Jackson, Mississippi; 2000-2005), study population, we examined the association of cigarette smoking with DNA methylation using single nucleotide polymorphisms identified in previous genome-wide association studies of cigarette smoking. We then investigated the association of DNA methylation with levels of inflammatory markers using cis-methylation quantitative trait loci single nucleotide polymorphisms. We found that current smoking status was associated with the DNA methylation levels (M values) of cg03636183 in the coagulation factor II (thrombin) receptor-like 3 gene (F2RL3) (M = -0.64, 95% confidence interval (CI): -0.84, -0.45) and of cg19859270 in the G protein-coupled receptor 15 gene (GPR15) (M = -0.21, 95% CI: -0.27, -0.15). The DNA methylation levels of cg03636183 in F2RL3 were associated with interleukin-18 concentration (-0.11 pg/mL, 95% CI: -0.19, -0.04). These combined negative effects suggest that cigarette smoking increases interleukin-18 levels through the decrease in DNA methylation levels of cg03636183 in F2RL3. PMID- 29149253 TI - Dasgupta and Pace Respond to "Gestational Hypertension and Diabetes". PMID- 29149249 TI - Human Accelerated Regions and Other Human-Specific Sequence Variations in the Context of Evolution and Their Relevance for Brain Development. AB - The review discusses, in a format of a timeline, the studies of different types of genetic variants, present in Homo sapiens, but absent in all other primate, mammalian, or vertebrate species, tested so far. The main characteristic of these variants is that they are found in regions of high evolutionary conservation. These sequence variations include single nucleotide substitutions (called human accelerated regions), deletions, and segmental duplications. The rationale for finding such variations in the human genome is that they could be responsible for traits, specific to our species, of which the human brain is the most remarkable. As became obvious, the vast majority of human-specific single nucleotide substitutions are found in noncoding, likely regulatory regions. A number of genes, associated with these human-specific alleles, often through novel enhancer activity, were in fact shown to be implicated in human-specific development of certain brain areas, including the prefrontal cortex. Human-specific deletions may remove regulatory sequences, such as enhancers. Segmental duplications, because of their large size, create new coding sequences, like new functional paralogs. Further functional study of these variants will shed light on evolution of our species, as well as on the etiology of neurodevelopmental disorders. PMID- 29149252 TI - Shared Genomic Variants: Identification of Transmission Routes Using Pathogen Deep-Sequence Data. AB - Sequencing pathogen samples during a communicable disease outbreak is becoming an increasingly common procedure in epidemiologic investigations. Identifying who infected whom sheds considerable light on transmission patterns, high-risk settings and subpopulations, and the effectiveness of infection control. Genomic data shed new light on transmission dynamics and can be used to identify clusters of individuals likely to be linked by direct transmission. However, identification of individual routes of infection via single genome samples typically remains uncertain. We investigated the potential of deep sequence data to provide greater resolution on transmission routes, via the identification of shared genomic variants. We assessed several easily implemented methods to identify transmission routes using both shared variants and genetic distance, demonstrating that shared variants can provide considerable additional information in most scenarios. While shared-variant approaches identify relatively few links in the presence of a small transmission bottleneck, these links are highly accurate. Furthermore, we propose a hybrid approach that also incorporates phylogenetic distance to provide greater resolution. We applied our methods to data collected during the 2014 Ebola outbreak, identifying several likely routes of transmission. Our study highlights the power of data from deep sequencing of pathogens as a component of outbreak investigation and epidemiologic analyses. PMID- 29149254 TI - Invited Commentary: Gestational Hypertension and Diabetes-A Major Public Health Concern. AB - The obesity epidemic in the United States and other countries has contributed to an increase in the rates of gestational diabetes and hypertension. In the past, it was thought that most cases of gestational diabetes and hypertension would resolve after completion of pregnancy. In this issue of the Journal, Pace et al. (Am J Epidemiol. 2017;186(10):1115-1124) clearly documented that both gestational diabetes and hypertension lead to diabetes and hypertension and that the combination of both during pregnancy leads to very high rates of subsequent diabetes and hypertension. A new generation of epidemiology studies using the evolving new technologies and genetics (host susceptibility studies) are needed to improve our understanding of the etiology of gestational diabetes and hypertension. Early identification of women at risk of gestational diabetes and hypertension, better treatment during pregnancy, and preventive and clinical therapies for treatment of diabetes and hypertension after pregnancy are very important for improving women's health and reducing risk of cardiovascular disease later in life. PMID- 29149255 TI - Conjoint Associations of Gestational Diabetes and Hypertension With Diabetes, Hypertension, and Cardiovascular Disease in Parents: A Retrospective Cohort Study. AB - The conjoint association of gestational diabetes mellitus (GDM) and gestational hypertension (GH) with cardiometabolic disease has not been well studied. We evaluated a combined GDM/GH risk indicator in both mothers and fathers because of shared spousal behaviors and environments. In the present population-based retrospective cohort study, GH was identified in matched pairs of mothers with GDM or without GDM (matched on age group, health region, and year of delivery) who had singleton live births in Quebec, Canada (1990-2007). A total of 64,232 couples were categorized based on GDM/GH status (neither, either, or both). Associations with diabetes, hypertension, and a composite of cardiovascular disease (CVD) and mortality were evaluated using Cox proportional hazard models (from 12 weeks postpartum to March 2012). Compared with having neither GDM nor GH, having either was associated with incident diabetes (hazard ratio (HR) = 14.7, 95% confidence interval (CI): 12.9, 16.6), hypertension (HR = 1.9, 95% CI: 1.8, 2.0), and CVD/mortality (HR = 1.4, 95% CI: 1.2, 1.7). We found associations of greater magnitude among participants who had both (for diabetes, HR = 36.9, 95% CI: 26.0, 52.3; for hypertension, HR = 5.7, 95% CI: 4.9, 6.7; and for CVD/mortality, HR = 2.4, 95% CI: 1.6, 3.5). Associations with diabetes were also observed in fathers (for either, HR = 1.2, 95% CI: 1.1, 1.3; for both, HR = 1.8, 95% CI: 1.4, 2.3). In conclusion, we found associations of a combined GDM/GH indicator with cardiometabolic disease in mothers and with diabetes in fathers, with stronger associations when both GDM and GH were present. PMID- 29149256 TI - Structural and Immunodiagnostic Characterization of Synthetic Antigen B Subunits From Echinococcus granulosus and Their Evaluation as Target Antigens for Cyst Viability Assessment. AB - Background: Several tools have been proposed for serodiagnosis of cystic echinococcosis (CE), but none seems promising for cyst viability assessment. Antigens with stage-specific diagnostic value have been described, but few studies with well-characterized antigens and human serum samples have been performed. Antigen B (AgB) proteoforms hold promise as markers of viability, due to their differential stage-related expression and immunoreactivity. Methods: Four AgB subunits (AgB1, AgB2, AgB3, AgB4) were synthesized and structurally characterized. Based on the preliminary evaluation of the subunits by western immunoblotting and enzyme-linked immunosorbent assay (ELISA), AgB1 and AgB2 were further tested in two ELISA setups and extensively validated on 422 human serum samples. Results: All subunits showed a high degree of spontaneous oligomerization. Interacting residues within oligomers were identified, showing that both the N-terminal and C-terminal of each subunit are involved in homo oligomer contact interfaces. No hetero-oligomer was identified. AgB1 and AgB2 ELISAs revealed different sensitivities relative to cyst stage. Of note, besides high specificity (97.2%), AgB1 revealed a higher sensitivity for active transitional cysts (100% for CE1, 77.8% for CE2, 81.5% for CE3a, and 86.3% for CE3b) than for inactive cysts (41.7% for CE4 and 11.1% for CE5) and postsurgical patients (44%). Interestingly, 19 of 20 patients with spontaneously inactive cysts and 6 of 9 treated with albendazole >5 years earlier were negative on the AgB1 assay. Conclusions: The structural characterization of subunits provides insights into the synthetic antigen conformation. The stage-related sensitivity of synthetic AgB1 holds promise as part of a multiantigen setting and deserves further longitudinal evaluation as marker of cyst viability. PMID- 29149258 TI - Edge-to-edge repair for mitral regurgitation associated with isolated double orifice mitral valve. AB - We report the case of a patient with severe mitral regurgitation who was diagnosed with double-orifice mitral valve by preoperative transthoracic and transoesophageal echocardiography. During surgery, it was revealed that the mitral valve was divided into 2 orifices, anterolateral and posteromedial, by a fibrous bridging tissue that was supported by the chordae tendineae originating from an accessory middle papillary muscle. The posterior scallop of the anterolateral orifice was prolapsed due to chordal elongation. Six interrupted sutures were made between the anterior leaflet and the posterior leaflet at the prolapsed site. Additional interrupted sutures were made at the sites of 2 clefts, and a ring annuloplasty was added. Residual mitral regurgitation was trivial, and the mean postoperative pressure gradient through each orifice was approximately 6 mmHg. To the best of our knowledge, this is the first case report of an edge-to-edge mitral repair for mitral regurgitation associated with a double-orifice mitral valve. PMID- 29149257 TI - Eleven Telomere, Epigenetic Clock, and Biomarker-Composite Quantifications of Biological Aging: Do They Measure the Same Thing? AB - The geroscience hypothesis posits that therapies to slow biological processes of aging can prevent disease and extend healthy years of life. To test such "geroprotective" therapies in humans, outcome measures are needed that can assess extension of disease-free life span. This need has spurred development of different methods to quantify biological aging. But different methods have not been systematically compared in the same humans. We implemented 7 methods to quantify biological aging using repeated-measures physiological and genomic data in 964 middle-aged humans in the Dunedin Study (New Zealand; persons born 1972 1973). We studied 11 measures in total: telomere-length and erosion, 3 epigenetic clocks and their ticking rates, and 3 biomarker-composites. Contrary to expectation, we found low agreement between different measures of biological aging. We next compared associations between biological aging measures and outcomes that geroprotective therapies seek to modify: physical functioning, cognitive decline, and subjective signs of aging, including aged facial appearance. The 71-cytosine-phosphate-guanine epigenetic clock and biomarker composites were consistently related to these aging-related outcomes. However, effect sizes were modest. Results suggested that various proposed approaches to quantifying biological aging may not measure the same aspects of the aging process. Further systematic evaluation and refinement of measures of biological aging is needed to furnish outcomes for geroprotector trials. PMID- 29149260 TI - An aorto-oesophageal fistula caused by a fish bone resulting in an accidental discovery of an invasive adenocarcinoma in the lung. AB - An aorto-oesophageal fistula is a rare, life-threatening complication caused by sharp foreign bodies in the oesophagus. We report an aorto-oesophageal fistula in the inferior segment of thoracic oesophagus caused by a fish bone. Multiplanar reconstruction of computed tomography and computed tomography angiography demonstrated that a foreign body had pierced from the left posterior wall of the oesophagus into the descending aortic wall. These computed tomography images can help radiologists make the correct diagnosis and provide precise evidence for clinicians to perform a timely surgical intervention. In addition, a nodule in the upper lobe of the left lung was found by accident. The pathological finding after surgery revealed an invasive adenocarcinoma. PMID- 29149259 TI - Pancreatic cancer incidence trends: evidence from the Surveillance, Epidemiology and End Results (SEER) population-based data. AB - Background: Annual pancreatic cancer incidence rates have been increasing. We examine pancreatic cancer incidence trends by demographics and histologic type. Methods: Data from the Surveillance, Epidemiology and End Results (SEER) registries were available to assess temporal trends and pancreatic cancer rates from 1974 to 2013. Results: Pancreatic cancer incidence rates declined between the 1970s and 1990s but increased from 1994 to 2013 among White males. Among non Hispanic White and Hispanic males, the annual percent change (APC) in incidence between 1992 and 2013 was 0.84% and 0.73%, respectively. Rates also rose among White non-Hispanic, Hispanic and Asian females (APC = 0.81%, 0.56% and 1.23%, respectively) and even more rapidly among females aged 25-34 years (APC > 2.5%). Rates among Black males and females remained unchanged, but higher compared with the other racial/ethnic groups. By histologic type, the increases were greatest for non-secretory endocrine cancers ( > 6%), followed by ductal adenocarcinomas (~5%) and adenocarcinoma, NOS (~1.4%)-the largest histologic subgroup of pancreatic cancer. Rates for mucinous adenocarcinomas and poorly specified pancreatic cancer decreased. Overall, incidence rates during 2000-13 were higher among males than females [MF incidence rate ratio (IRR) = 1.28]. The IRR was >1.00 at all ages >= 35, but rates among females were higher at younger ages (IRRs 15-24: 0.66, 25-34: 0.81). The MF IRRs for most of the histologic types were elevated among males apart from solid pseudopapillary adenocarcinoma and cystic carcinomas (IRR = 0.22, confidence interval: 0.14-0.34 and 0.52, 0.41 0.65, respectively). Conclusion: Pancreatic cancer has been increasing overall, but patterns differ by demographic group and histologic type. Many of the trends parallel changing prevalence of lifestyle risk factors such as smoking, overweight and obesity, and diabetes in the USA, particularly for pancreatic adenocarcinoma, and improved diagnosis methods during the past 40 years. PMID- 29149261 TI - GLUT10 maintains the integrity of major arteries through regulation of redox homeostasis and mitochondrial function. AB - Glucose transporter 10 (GLUT10) is a member of the GLUT family of membrane transporters, and mutations in this gene cause arterial tortuosity syndrome (ATS). However, the physiological role and regulation of GLUT10 in arteries remains unclear. To further understand its physiological roles in major arteries, we examined the regulatory mechanisms of GLUT10 in ASMCs and aortic tissues. Interestingly, we find that targeting of GLUT10 to mitochondria is increased in ASMCs under both stress and aging conditions, which enhances dehydroascorbic acid (DHA) uptake and maintains intracellular ascorbic acid (AA) levels. We further demonstrate that the targeting of GLUT10 to mitochondria is important to maintain redox homeostasis, mitochondrial structure and mitochondrial function in ASMCs. A missense mutation of GLUT10 (Glut10G128E) impairs mitochondrial targeting in ASMCs. Consequently, ASMCs isolated from Glut10G128E mice exhibit increased reactive oxygen species (ROS) levels, fragmented mitochondria and impaired mitochondrial function, as well as enhanced cell proliferation and migration. In vivo, mitochondrial structure is altered, and ROS levels are heightened in aortic tissues of Glut10G128E mice. Furthermore, increased number and disorganization of ASMCs, along with progressive arterial wall remodeling were observed in aortic tissues of Glut10G128E mice. These defects were coincident with elevated systolic blood pressure in aged Glut10G128E animals. Our results describe a novel mechanism that GLUT10 targeting to mitochondria under stress and aging condition has a critical role in maintaining AA levels, redox homeostasis and mitochondrial structure and function in ASMCs, which is likely to contribute to the maintenance of healthy vascular tissue. PMID- 29149262 TI - A food environments feedback system (FoodBack) for empowering citizens and change agents to create healthier community food places. AB - This study developed a systems-based approach (called FoodBack) to empower citizens and change agents to create healthier community food places. Formative evaluations were held with citizens and change agents in six diverse New Zealand communities, supplemented by semi-structured interviews with 85 change agents in Auckland and Hamilton in 2015-2016. The emerging system was additionally reviewed by public health experts from diverse organizations. A food environments feedback system was constructed to crowdsource key indicators of the healthiness of diverse community food places (i.e. schools, hospitals, supermarkets, fast food outlets, sport centers) and outdoor spaces (i.e. around schools), comments/pictures about barriers and facilitators to healthy eating and exemplar stories on improving the healthiness of food environments. All the information collected is centrally processed and translated into 'short' (immediate) and 'long' (after analyses) feedback loops to stimulate actions to create healthier food places. FoodBack, as a comprehensive food environment feedback system (with evidence databases and feedback and recognition processes), has the potential to increase food sovereignty, and generate a sustainable, fine-grained database of food environments for real-time food policy research. PMID- 29149263 TI - Vitamin D and assisted reproductive treatment outcome: a systematic review and meta-analysis. AB - STUDY QUESTION: Is serum vitamin D associated with live birth rates in women undergoing ART? SUMMARY ANSWER: Women undergoing ART who are replete in vitamin D have a higher live birth rate than women who are vitamin D deficient or insufficient. WHAT IS KNOWN ALREADY: Vitamin D deficiency has been associated with an increased risk of abnormal pregnancy implantation as well as obstetric complications such as pre-eclampsia and fetal growth restriction. However, the effect of vitamin D on conception and early pregnancy outcomes in couples undergoing ART is poorly understood. STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis of 11 published cohort studies (including 2700 women) investigating the association between vitamin D and ART outcomes. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Literature searches were conducted to retrieve studies which reported on the association between vitamin D and ART outcomes. Databases searched included MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL. Eleven studies matched the inclusion criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth was reported in seven of the included studies (including 2026 patients). Live birth was found to be more likely in women replete in vitamin D when compared to women with deficient or insufficient vitamin D status (OR 1.33 [1.08-1.65]). Five studies (including 1700 patients) found that women replete in vitamin D were more likely to achieve a positive pregnancy test than women deficient or insufficient in vitamin D (OR 1.34 ([1.04-1.73]). All 11 of the included studies (including 2700 patients) reported clinical pregnancy as an outcome. Clinical pregnancy was found to be more likely in women replete in vitamin D (OR 1.46 [1.05-2.02]). Six studies (including 1635 patients) reported miscarriage by vitamin D concentrations. There was no association found between miscarriage and vitamin D concentrations (OR 1.12 [0.81-1.54]. The included studies scored well on the Newcastle-Ottawa quality assessment scale. LIMITATIONS REASONS FOR CAUTION: Although strict inclusion criteria were used in the conduct of the systematic review, the included studies are heterogeneous in population characteristics and fertility treatment protocols. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this systematic review show that there is an association between vitamin D status and reproductive treatment outcomes achieved in women undergoing ART. Our results show that vitamin D deficiency and insufficiency could be important conditions to treat in women considering ARTs. A randomized controlled trial to investigate the benefits of vitamin D deficiency treatment should be considered to test this hypothesis. STUDY FUNDING/COMPETING INTERESTS: No external funding was either sought or obtained for this study. The authors have no competing interests to declare. REGISTRATION NUMBER: N/A. PMID- 29149264 TI - Sim3C: simulation of Hi-C and Meta3C proximity ligation sequencing technologies. AB - Background: Chromosome conformation capture (3C) and Hi-C DNA sequencing methods have rapidly advanced our understanding of the spatial organization of genomes and metagenomes. Many variants of these protocols have been developed, each with their own strengths. Currently there is no systematic means for simulating sequence data from this family of sequencing protocols, potentially hindering the advancement of algorithms to exploit this new datatype. Findings: We describe a computational simulator that, given simple parameters and reference genome sequences, will simulate Hi-C sequencing on those sequences. The simulator models the basic spatial structure in genomes that is commonly observed in Hi-C and 3C datasets, including the distance-decay relationship in proximity ligation, differences in the frequency of interaction within and across chromosomes, and the structure imposed by cells. A means to model the 3D structure of randomly generated topologically associating domains is provided. The simulator considers several sources of error common to 3C and Hi-C library preparation and sequencing methods, including spurious proximity ligation events and sequencing error. Conclusions: We have introduced the first comprehensive simulator for 3C and Hi-C sequencing protocols. We expect the simulator to have use in testing of Hi-C data analysis algorithms, as well as more general value for experimental design, where questions such as the required depth of sequencing, enzyme choice, and other decisions can be made in advance in order to ensure adequate statistical power with respect to experimental hypothesis testing. PMID- 29149265 TI - Survey of Reproductive Experiences and Outcomes of Cancer Survivors Who Stored Reproductive Material Before Treatment. PMID- 29149266 TI - Association between prior antibiotic therapy and subsequent risk of community acquired infections: a systematic review. AB - Background: Antibiotic use can have negative unintended consequences including disruption of the human microbiota, which is thought to protect against pathogen overgrowth. We conducted a systematic review to assess whether there is an association between exposure to antibiotics and subsequent risk of community acquired infections. Methods: We searched MEDLINE, EMBASE and Web of Science for studies published before 30 June 2017, examining the association between antibiotic use and subsequent community-acquired infection. Infections caused by Clostridium difficile and fungal organisms were excluded. Studies focusing exclusively on resistant organism infections were also excluded. Results: Eighteen of 22588 retrieved studies met the inclusion criteria. From these, 16 studies reported a statistically significant association between antibiotic exposure and subsequent risk of community-acquired infection. Infections associated with prior antibiotic use included Campylobacter jejuni infection (one study), recurrent furunculosis (one study), invasive Haemophilus influenzae type b infection (one study), infectious mastitis (one study), meningitis (one study), invasive pneumococcal disease (one study), Staphylococcus aureus skin infection (one study), typhoid fever (two studies), recurrent boils and abscesses (one study), upper respiratory tract infection and urinary tract infection (one study) and Salmonella infection (five studies), although in three studies on Salmonella infection the effect was of marginal statistical significance. Conclusions: We found an association between prior antibiotic use and subsequent risk of a diverse range of community-acquired infections. Gastrointestinal and skin and soft tissue infections were most frequently found to be associated with prior antibiotic exposure. Our findings support the hypothesis that antibiotic use may predispose to future infection risk, including infections caused by both antibiotic-resistant and non-resistant organisms. PMID- 29149267 TI - Taiwan Biobank: making cross-database convergence possible in the Big Data era. AB - The Taiwan Biobank (TWB) is a biomedical research database of biopsy data from 200 000 participants. Access to this database has been granted to research communities taking part in the development of precision medicines; however, this has raised issues surrounding TWB's access to electronic medical records (EMRs). The Personal Data Protection Act of Taiwan restricts access to EMRs for purposes not covered by patients' original consent. This commentary explores possible legal solutions to help ensure that the access TWB has to EMR abides with legal obligations, and with governance frameworks associated with ethical, legal, and social implications. We suggest utilizing "hash function" algorithms to create nonretrospective, anonymized data for the purpose of cross-transmission and/or linkage with EMR. PMID- 29149268 TI - Mitral valve replacement with the novel TRIBIO and an established stented bioprosthesis in a sheep model. AB - OBJECTIVES: Heart valve replacement with a bioprosthesis is one of the most frequently performed procedures in cardiac surgery and represents a highly effective therapy to relieve diseased heart valves. Nevertheless, as postoperatively elevated transvalvular gradients and prosthesis-patient mismatch are reported as shortcomings of the procedure or of the currently used devices, there is a need for novel bioprostheses with improved haemodynamics. This study presents preclinical haemodynamic results after mitral valve replacement with the novel TRIBIO bioprosthesis (TRIBIO) compared with an established bioprosthesis in a sheep model. METHODS: Six female sheep had their mitral valves replaced with the TRIBIO and 3 with the Carpentier-Edwards Perimount, both sized 19 mm. The TRIBIO consists of a flexible valve-bearing crown, a force-decoupled interface and an intra-annular base ring. Mean and peak transvalvular gradients as well as an effective orifice area were monitored in both groups using transthoracic echocardiography over the course of the 90-day study. RESULTS: In both groups, haemodynamic performance diminished over time. The TRIBIO demonstrated overall superior haemodynamics, i.e. lower transvalvular gradients and a larger effective orifice area, although the results were not statistically significant. On Day 90, the mean values for the mean and peak transvalvular gradients and the effective orifice area were 6 mmHg, 10.2 mmHg and 1.2 cm2 for the TRIBIO and 10 mmHg, 15.8 mmHg and 0.8 cm2 for the Carpentier-Edwards Perimount, respectively. CONCLUSIONS: This study demonstrates a trend towards improved preclinical haemodynamic performance following mitral valve replacement with the TRIBIO compared to that with an established bioprosthesis in a sheep model. PMID- 29149269 TI - Effects of a healthy-eater self-schema and nutrition literacy on healthy-eating behaviors among Taiwanese college students. AB - Unhealthy eating behaviors contribute to obesity and chronic illness. This study examined the relative contributions of a healthy-eater self-schema (a self conception as a healthy eater) and nutrition literacy on healthy-eating behaviors and whether nutrition literacy was a mediator among Taiwanese college students. A total of 1216 undergraduate students from six universities in Taiwan participated in the study from April to June 2016. Healthy-eating behaviors, nutrition literacy, healthy-eater self-schema and known determinants of eating behaviors (e.g. nutrition-related information, health status, nutrition knowledge needs, sex, year in college and residence) were measured by a self-report questionnaire. A hierarchical multiple regression and mediation analysis were conducted with the known determinants of eating behaviors as covariates. Results showed that a healthy-eater self-schema and nutrition literacy explained 9% and 12% of the variance in healthy-eating behaviors, respectively, and both had unique effects on healthy-eating behaviors. The effect of a healthy-eater self-schema on healthy eating behaviors was partially mediated through nutrition literacy. Findings suggest that both a healthy-eater self-schema and nutrition literacy should be considered when promoting healthy-eating behaviors. Additionally, nutrition literacy interventions should be tailored to the healthy-eater self-schema status and emphasize the personal relevance of being a healthy-eater to improve the intervention's effectiveness. PMID- 29149271 TI - Rangatahi Tu Rangatira: innovative health promotion in Aotearoa New Zealand. AB - Rangatahi Tu Rangatira (R2R) is a national health promotion programme in Aotearoa New Zealand which aims to promote cultural and physical wellbeing for rangatahi (young people) and their whanau (family). Grounded in tikanga Maori, the programme focuses on total wellbeing, leadership and cultural awareness providing rangatahi opportunities to increase their participation in physical activity and cultural knowledge through nga taonga takaro (Maori ancestral games). This paper focuses on an evaluation of this innovative health promotion programme focussing on the delivery of R2R by a local iwi provider in a rural area. Kanohi ki te kanohi (face-to-face) interviews and focus groups were used to collect data from a range of stakeholders including rangatahi, whanau, programme developers, and collaborating community organizations. A whanau ora (holistic) framework incorporating five core outcomes and key indicators specific to the programme was developed to assess the impact of delivery. Results demonstrated that rangatahi and their whanau were living healthier lifestyles through being more physically active; had gained an increased desire to succeed in their education and extra curriculum activities; and felt more connected to their community and te ao Maori. This demonstrates the importance of incorporating cultural elements to support improved lifestyle changes for rangatahi and their whanau and the connection between enhanced cultural identity and good health. PMID- 29149270 TI - ANISEED 2017: extending the integrated ascidian database to the exploration and evolutionary comparison of genome-scale datasets. AB - ANISEED (www.aniseed.cnrs.fr) is the main model organism database for tunicates, the sister-group of vertebrates. This release gives access to annotated genomes, gene expression patterns, and anatomical descriptions for nine ascidian species. It provides increased integration with external molecular and taxonomy databases, better support for epigenomics datasets, in particular RNA-seq, ChIP-seq and SELEX-seq, and features novel interactive interfaces for existing and novel datatypes. In particular, the cross-species navigation and comparison is enhanced through a novel taxonomy section describing each represented species and through the implementation of interactive phylogenetic gene trees for 60% of tunicate genes. The gene expression section displays the results of RNA-seq experiments for the three major model species of solitary ascidians. Gene expression is controlled by the binding of transcription factors to cis-regulatory sequences. A high-resolution description of the DNA-binding specificity for 131 Ciona robusta (formerly C. intestinalis type A) transcription factors by SELEX-seq is provided and used to map candidate binding sites across the Ciona robusta and Phallusia mammillata genomes. Finally, use of a WashU Epigenome browser enhances genome navigation, while a Genomicus server was set up to explore microsynteny relationships within tunicates and with vertebrates, Amphioxus, echinoderms and hemichordates. PMID- 29149274 TI - Meretoja Syndrome: General Considerations and Contributions of Plastic Surgery in Surgical Treatment. PMID- 29149272 TI - Use of paracetamol, ibuprofen or aspirin in pregnancy and risk of cerebral palsy in the child. AB - Background: It has been debated whether mild analgesics, mainly paracetamol, adversely affect aspects of neurodevelopment. We examined whether mother's use of paracetamol, aspirin or ibuprofen in pregnancy is associated with increased risk of cerebral palsy (CP) in the child. Method: We included 185 617 mother-child pairs from the Danish National Birth Cohort and the Norwegian Mother and Child Cohort Study. We created harmonized definitions of analgesic use in pregnancy, as well as indications for analgesic use and other potential confounders. Children with CP were identified in nationwide registers. We estimated the average causal effect of analgesics on risk of CP using marginal structural models with stabilized inverse probability weights. Results: Paracetamol use was reported in 49% of all pregnancies, aspirin in 3% and ibuprofen in 4%. Prenatal exposure to paracetamol ever in pregnancy was associated with increased risk of overall CP [adjusted odds ratio (aOR) 1.3, 95% confidence interval (CI): 1.0-1.7] and unilateral spastic CP (aOR 1.5, 95% CI: 1.0-2.2). The association appeared to be driven by an increased risk of unilateral spastic CP in children exposed in second trimester (aOR 1.6, 95% CI: 1.0-2.5). Children ever prenatally exposed to aspirin in pregnancy had an elevated risk of bilateral spastic CP (aOR 2.4, 95% CI: 1.1-5.3) compared with unexposed. Conclusion: We observed an increased risk of spastic CP in children prenatally exposed to paracetamol and aspirin. Although we controlled for several important indications for analgesic use, we cannot exclude the possibility of confounding by underlying diseases. PMID- 29149273 TI - The efficacy and safety of bronchial thermoplasty in severe persistent asthma on extended follow-up. AB - Background: Asthma is a common condition and there remains a subset of patients who are poorly controlled on maximal therapy. Bronchial thermoplasty (BT) is a bronchoscopic therapy using radiofrequency energy to reduce airway smooth muscle, which has been shown to improve asthma control although further evidence regarding long-term efficacy and safety is required. Aim: We aimed to demonstrate safety and efficacy of BT on extended follow-up. Our initial experience with this group was previously reported in 2016, where patients were shown to have a significant improvement in asthma control test (ACT) scores 1-year post treatment. Design: We carried out a retrospective observational study of seven patients who underwent BT between 2012 and 2013 in an Irish severe asthma centre. The primary endpoint was change in ACT scores from baseline to present. Methods: Seven patients underwent BT at a tertiary referral centre in Ireland. ACT scores and data on hospital admissions, exacerbations, maintenance corticosteroid requirements, rescue bronchodilator use and forced expiratory volume for 1 s (FEV1) prior to the procedure and on extended follow-up were collected. Mean follow-up was 49.42 months. Results: A trend towards improvement was seen in median hospitalisations (respective values for median over 12 months 3, 1 P = 0.059) and ACT scores, from 9 to 13 (P = 0.249). Mean FEV1 was 1.68 l prior to treatment and 1.46 l 4 years post-treatment (P = 0.237). There was no mortality among the group. Conclusions: These data support the safety of BT and suggest extended efficacy. PMID- 29149275 TI - Erratum. PMID- 29149276 TI - Urban renewal, gentrification and health equity: a realist perspective. AB - Background: Up to now, research has focused on the effects of urban renewal programs and their impacts on health. While some of this research points to potential negative health effects due to gentrification, evidence that addresses the complexity associated with this relation is much needed. This paper seeks to better understand when, why and how health inequities arise from urban renewal interventions resulting in gentrification. Methods: A realist review, a qualitative systematic review method, aimed to better explain the relation between context, mechanism and outcomes, was used. A literature search was done to identify theoretical models of how urban renewal programs can result in gentrification, which in turn could have negative impacts on health. A systematic approach was then used to identify peer-reviewed studies that provided evidence to support or refute the initial assumptions. Results: Urban renewal programs that resulted in gentrification tended to have negative health effects primarily in residents that were low-income. Urban renewal policies that were inclusive of populations that are vulnerable, from the beginning were less likely to result in gentrification and more likely to positively impact health through physical and social improvements. Conclusions: Research has shown urban renewal policies have significant impacts on populations that are vulnerable and those that result in gentrification can result in negative health consequences for this population. A better understanding of this is needed to impact future policies and advocate for a community-participatory model that includes such populations in the early planning stages. PMID- 29149277 TI - Cardiomyopathy in muscular dystrophy. PMID- 29149278 TI - Interdisciplinary STEM education reform: dishing out art in a microbiology laboratory. AB - In the modern educational framework, life science and visual art are usually presented as mutually exclusive subjects. Despite this perceived disciplinary contrast, visual art has the ability to engage and provoke students in ways that can have important downstream effects on scientific discovery, especially when applied in a practical setting such as a laboratory course. This review broadly examines the benefit of interdisciplinary fusions of science and art as well as recent ways in which art strategies have been used in undergraduate biology classrooms. In a case study, we found that undergraduate students in an introductory microbiology laboratory course who participated in open-inquiry activities involving agar art had greater confidence in their personal efficacy as scientists compared to a control class. Collectively, these observations suggest that visual art can be a useful enhancement in the course-based undergraduate research setting, and science educators at all levels should consider incorporating artistic creativity in their own classroom strategies. PMID- 29149279 TI - Impact of Isolating Clostridium difficile Carriers on the Burden of Isolation Precautions: A Time Series Analysis. AB - Background: The isolation of asymptomatic Clostridium difficile (CD) carriers may decrease the incidence of hospital-associated C. difficile infections (CDI), but its impact on isolation precaution needs is unknown. Methods: A time series analysis was conducted to investigate the impact of isolating CD carriers on the burden of isolation precautions from 2008 to 2016 in a Canadian hospital. To account for the changes in C. difficile infection control policies, the series was divided into 3 intervention periods: period 1 (2008-2011), isolation of patients with CDI until symptom resolution; period 2 (2011-2013), isolation of patients with CDI until discharge; and period 3 (2013-2016), isolation of patients with CDI and CD carriers until discharge. We compared the prevalence of isolation-days for C. difficile (ie, for either CDI or carriage) per 1000 patient days between study periods. Changes in trend were analyzed by segmented regression analysis. Results: A total of 806357 patient-days and 20455 isolation days were included. Isolation-day prevalence during periods 1, 2, and 3 were 12.9, 26.2, and 37.8 isolation-days per 1000 patient-days, respectively (P < .001 between periods). Isolating CD carriers was associated with an increase in isolation-days' prevalence compared with period 2 (rate ratio [RR], 1.66; P < .001) followed by a significant decrease in trend (RR per 4-week period, 0.97; P < .001). The downward trend was mainly due to decreasing isolation needs for patients with CDI (RR per 4-week period, 0.94; P < .001) rather than for carriage (RR per 4-week period, 0.996; P = .21). Conclusions: Isolating CD carriers led to an initial increase in isolation needs that was partially compensated by a decrease in isolation needs for CDI. PMID- 29149281 TI - Seroreactivity to the C6 Peptide in Borrelia miyamotoi Infections Occurring in the Northeastern United States. AB - Background: There are no US Food and Drug Administration (FDA)-approved diagnostic tests for Borrelia miyamotoi infection, an emerging tick-borne illness in the United States. The purpose of this study was to evaluate whether the FDA approved C6 peptide enzyme-linked immunosorbent assay (ELISA) currently used to diagnose Lyme disease may potentially serve as a diagnostic test for B. miyamotoi infections. Methods: Serum specimens from 30 patients from the northeastern United States with B. miyamotoi infection established by a polymerase chain reaction assay of a blood specimen were tested using the C6 ELISA. To reduce confounding with Borrelia burgdorferi coinfection, 6 sera were excluded: 3 from patients with a positive Western immunoblot for antibodies to B. burgdorferi and 3 from patients for whom immunoblot testing had not been performed. Results: Twenty-two of 24 (91.7% [95% confidence interval, 73.0%-98.8%]) evaluable B. miyamotoi patients were C6 ELISA reactive, principally on a convalescent-phase serum specimen. C6 ELISA index values were often well above the positive cutoff value of 1.1, exceeding 4 in 11 of the 22 (50.0%) C6 ELISA-reactive patients. Conclusions: Although previously regarded as a highly specific test for Lyme disease, the C6 ELISA is also regularly reactive on convalescent-phase serum samples of patients from the northeastern United States with B. miyamotoi infection. PMID- 29149280 TI - Whole-genome re-sequencing of two Italian tomato landraces reveals sequence variations in genes associated with stress tolerance, fruit quality and long shelf-life traits. AB - Tomato is a high value crop and the primary model for fleshy fruit development and ripening. Breeding priorities include increased fruit quality, shelf life and tolerance to stresses. To contribute towards this goal, we re-sequenced the genomes of Corbarino (COR) and Lucariello (LUC) landraces, which both possess the traits of plant adaptation to water deficit, prolonged fruit shelf-life and good fruit quality. Through the newly developed pipeline Reconstructor, we generated the genome sequences of COR and LUC using datasets of 65.8 M and 56.4 M of 30-150 bp paired-end reads, respectively. New contigs including reads that could not be mapped to the tomato reference genome were assembled, and a total of 43, 054 and 44, 579 gene loci were annotated in COR and LUC. Both genomes showed novel regions with similarity to Solanum pimpinellifolium and Solanum pennellii. In addition to small deletions and insertions, 2, 000 and 1, 700 single nucleotide polymorphisms (SNPs) could exert potentially disruptive effects on 1, 371 and 1, 201 genes in COR and LUC, respectively. A detailed survey of the SNPs occurring in fruit quality, shelf life and stress tolerance related-genes identified several candidates of potential relevance. Variations in ethylene response components may concur in determining peculiar phenotypes of COR and LUC. PMID- 29149283 TI - Multivalent Rotavirus Vaccine and Wild-type Rotavirus Strain Shedding in Australian Infants: A Birth Cohort Study. AB - Background: Rotavirus vaccines have reduced moderate-to-severe gastroenteritis episodes in infants and young children. Nevertheless, knowledge gaps exist concerning rotavirus vaccine shedding and vaccine impact upon mild and asymptomatic wild-type infections. Our primary objective was to investigate vaccine shedding in Australian infants where the multivalent human-bovine reassortant rotavirus vaccine, RotaTeq, was part of the routine vaccination schedule. Methods: The Observational Research in Childhood Infectious Diseases (ORChID) birth cohort study was conducted in Brisbane, Australia, from September 2010 to October 2014. Newborn infants were enrolled progressively and followed until their second birthday. Parents recorded daily symptoms and mailed weekly stool swab samples from their infants to the laboratory where reverse transcription polymerase chain reaction testing was performed, and rotavirus positive samples underwent genotyping to distinguish between vaccine and wild type strains. Results: Rotavirus was detected in 1068 of 11139 (9.6%) stool swabs from 158 infants, and 994 (93.1%) were genotyped. RotaTeq vaccine strains accounted for 951 of 994 (95.7%) typed rotavirus-positive swabs. Proportions of infants shedding RotaTeq after the first, second, and third vaccine doses were 87.0%, 57.4%, and 47.3%, respectively, and median (interquartile range) shedding duration after vaccine doses 1-3 was 3 (1-8), 1.5 (1-3), and 1 (1-2), weeks, respectively. In contrast, the incidence rate of wild-type rotavirus episodes was 10.3 (95% confidence interval, 6.8-15.6) per 100 child-years of observation. Conclusions: RotaTeq vaccine virus was detected in stool samples from 47%-87% of infants after each vaccine dose. Genotyping is an essential tool for differentiating between rotavirus vaccine and wild-type strains and monitoring vaccine impact in children. Clinical Trial Registration: NCT01304914. PMID- 29149284 TI - Millennial-minded approach for the management of diabetic retinopathy. PMID- 29149282 TI - Structure-Related Differences between Cytochrome Oxidase I Proteins in a Stable Heteroplasmic Mitochondrial System. AB - Many bivalve species have two types of mitochondrial DNA passed independently through the female line (F genome) and male line (M genome). Here we study the cytochrome oxidase I protein in such bivalve species and provide evidence for differences between the F and M proteins in amino acid property values, particularly relating to hydrophobicity and helicity. The magnitude of these differences varies between different regions of the protein and the change from the ancestor is most marked in the M protein. The observed changes occur in parallel and in the same direction in the different species studied. Two possible causes are considered, first relaxation of purifying selection with drift and second positive selection. These may operate in different ways in different regions of the protein. Many different amino acid substitutions contribute in a small way to the observed variation, but substitutions involving alanine and serine have a quantitatively large effect. Some of these substitutions are potential targets for phosphorylation and some are close to residues of functional importance in the catalytic mechanism. We propose that the observed changes in the F and M proteins might contribute to functional differences between them relating to ATP production and mitochondrial membrane potential with implications for sperm function. PMID- 29149285 TI - Draft genome analysis provides insights into the fiber yield, crude protein biosynthesis, and vegetative growth of domesticated ramie (Boehmeria nivea L. Gaud). AB - Plentiful bast fiber, a high crude protein content, and vigorous vegetative growth make ramie a popular fiber and forage crop. Here, we report the draft genome of ramie, along with a genomic comparison and evolutionary analysis. The draft genome contained a sequence of approximately 335.6 Mb with 42,463 predicted genes. A high-density genetic map with 4,338 single nucleotide polymorphisms (SNPs) was developed and used to anchor the genome sequence, thus, creating an integrated genetic and physical map containing a 58.2-Mb genome sequence and 4,304 molecular markers. A genomic comparison identified 1,075 unique gene families in ramie, containing 4,082 genes. Among these unique genes, five were cellulose synthase genes that were specifically expressed in stem bark, and 3 encoded a WAT1-related protein, suggesting that they are probably related to high bast fiber yield. An evolutionary analysis detected 106 positively selected genes, 22 of which were related to nitrogen metabolism, indicating that they are probably responsible for the crude protein content and vegetative growth of domesticated varieties. This study is the first to characterize the genome and develop a high-density genetic map of ramie and provides a basis for the genetic and molecular study of this crop. PMID- 29149286 TI - Economic costs attributable to smoking in Hong Kong in 2011: a possible increase from 1998. AB - Background: Reduction in smoking prevalence does not necessarily reduce the costs of smoking as evidence shows in developed countries. We provide up-to-date estimates for direct and indirect costs attributable to smoking in Hong Kong in 2011 and compare with our 1998 estimates. Methods: We took a societal perspective to include lives and life years lost, health care costs and time lost from work in the costing. We followed guidelines on estimating costs of active smoking for those aged 35 years or above (35+) and costs due to SHS exposure for 35+, infants aged 12 months and under and children aged 15 and below. All costs are in US$. Results: We estimated that 6154 deaths among 35+ in Hong Kong in 2011 were attributable to active smoking, an increase of 10% from 1998. Besides, 672 deaths were attributable to SHS exposure, i.e. 10% of the total 6826 smoking attributable deaths. The estimate of productive life lost due to deaths from active smoking by those aged under 65 years in 2011 was $166 million, an increase of about 4% over the estimate in 1998. Our conservative estimate of the annual tobacco-related disease cost in 2011 was $716 million which accounted for 0.3% of GDP. If we added the value of attributable lives lost, the annual cost would be $4.7 billion. Conclusion: Despite the reduction in smoking prevalence, smoking attributable disease still imposes a substantial economic burden on Hong Kong society. These findings support more stringent and effective tobacco control legislation, polices and measures. Implications: Current evidence shows reduction in smoking prevalence does not necessarily reduce the economic costs of smoking. Most studies in developed countries employed a societal perspective, including costs of productivity loss and indirect costs, but not all studies estimated costs associated with second-hand smoking (SHS). The present study estimated the total costs of smoking in Hong Kong including direct and indirect costs attributable to active smoking and to SHS exposure. Our study confirms the pattern of smoking epidemic in developed countries, forewarns the increasing economic burdens from tobacco, and provides East Asian countries with a prediction of their own future costs. PMID- 29149288 TI - Overexpression of Seipin1 Increases Oil in Hydroxy Fatty Acid-Accumulating Seeds. AB - While plant oils are an important source of food, plants also produce oils containing specialized fatty acids with chemical and physical properties valued in industry. Ricinoleic acid, a hydroxy fatty acid (HFA) produced in the seed of castor (Ricinus communis), is of particular value, with a wide range of applications. Since castor cultivation is currently successful only in tropical climates, and because castor seed contain the toxin ricin, there are ongoing efforts to develop a temperate crop capable of HFA biosynthesis. In castor, ricinoleic acid is incorporated into triacylglycerol (TAG) which accumulates in the seed lipid droplets. Research in the model plant Arabidopsis (Arabidopsis thaliana) has successfully produced HFA constituting 30% of the total seed oil, but this is far short of the level required to engineer commercially viable crops. Strategies to increase HFA have centered on co-expression of castor TAG biosynthesis enzymes. However, since lipid droplets are the location of neutral lipid storage, manipulating droplets offers an alternative method to increase oil that contains specialized fatty acids. The Arabidopsis Seipin1 protein modulates TAG accumulation by affecting lipid droplet size. Here, we overexpress Seipin1 in a hydroxylase-expressing Arabidopsis line, increasing seed HFA by 62% and proportionally increasing total oil. Increased seed oil was concomitant with a 22% increase in single seed weight and a 69% increase in harvest weight, while seed germination rose by 45%. Because Seipin1 function is unaffected by the structure of the HFA, these results demonstrate a novel strategy that may increase accumulation of many specialized seed oils. PMID- 29149287 TI - Genomic and epigenomic immunity in common bean: the unusual features of NB-LRR gene family. AB - In plants, a key class of genes comprising most of disease resistance (R) genes encodes Nucleotide-binding leucine-rich repeat (NL) proteins. Access to common bean (Phaseolus vulgaris) genome sequence provides unparalleled insight into the organization and evolution of this large gene family (~400 NL) in this important crop. As observed in other plant species, most common bean NL are organized in cluster of genes. However, a particularity of common bean is that these clusters are often located in subtelomeric regions close to terminal knobs containing the satellite DNA khipu. Phylogenetically related NL are spread between different chromosome ends, suggesting frequent exchanges between non-homologous chromosomes. NL peculiar location, in proximity to heterochromatic regions, led us to study their DNA methylation status using a whole-genome cytosine methylation map. In common bean, NL genes displayed an unusual body methylation pattern since half of them are methylated in the three contexts, reminiscent of the DNA methylation pattern of repeated sequences. Moreover, 90 NL were also abundantly targeted by 24 nt siRNA, with 90% corresponding to methylated NL genes. This suggests the existence of a transcriptional gene silencing mechanism of NL through the RdDM (RNA-directed DNA methylation) pathway in common bean that has not been described in other plant species. PMID- 29149289 TI - Rheumatoid arthritis patients treated in trial and real world settings: comparison of randomized trials with registries. AB - Objective: To investigate whether patients with RA enrolled in randomized controlled trials (RCTs) and observational studies may differ in terms of characteristics that could modify treatment effects, leading to an efficacy effectiveness gap. Methods: We conducted systematic literature reviews to identify RCTs and observational studies with RA, treated with rituximab, tocilizumab or etanercept. We extracted baseline characteristics and compared the data of RCTs and observational studies using fixed-effects meta-analyses for the RCTs and random-effects meta-analyses for the observational studies. We also assessed whether the baseline characteristics changed over time. Results: Compared with patients enrolled in RCTs, those from observational studies were on average 3.0 years older (P < 0.001), suffered from RA for 3.1 years longer (P < 0.001), had 1.6 more prior disease modifying drugs (P = 0.001), and had a lower DAS-28 (difference -0.6, P < 0.001). CRP and ESR levels were slightly higher in RCTs. The HAQ-Disability Index (HAQ-DI) score was slightly lower in the RCT group. No differences were found in the percentages of included females or RF positivity. Over time, we found a significant decrease of - 0.08 in DAS-28 and a decrease of - 0.04 in HAQ-DI both in patients in RCTs and in patients from registries. Furthermore, ESR and CRP declined over time in RCT patients, but not in patients participating in observational studies. Conclusion: There are substantial systematic differences in patient characteristics between RCTs and registries in RA. The efficacy seen in RCTs may not reflect real-world effectiveness. PMID- 29149291 TI - Creatinine generation from kinetic modeling with or without postdialysis serum creatinine measurement: results from the HEMO study. PMID- 29149292 TI - In Reply: The Use of Vancomycin Powder for Surgical Prophylaxis Following Craniotomy. PMID- 29149293 TI - Distribution of putative virulence markers in Enterococcus faecium: towards a safety profile review. AB - Objectives: The criteria for identification of Enterococcus faecium (Efm) with the ability to cause human infections are currently being debated by the European Food Safety Authority (EFSA). Strains that have an MIC of ampicillin of <= 2 mg/L and lack IS16/esp/hyl genes should be regarded as safe for use as feed additives in animal nutrition, despite the lack of knowledge about putative virulence marker (PVM) distribution in community Efm. We analysed the distribution of major PVM and ampicillin phenotypes in large Efm collections to investigate further the safety of strains from a public health perspective. Methods: Thirty-three PVM were assessed by PCR/sequencing among clonally disparate Efm (n = 328; 1986-2015) from different origins. We analysed ampicillin susceptibility (Etest/broth microdilution) according to EUCAST guidelines, clonal relationship (MLST) and genomic location of PVM (S1-PFGE/hybridization). Results: Infection-derived Efm were more enriched in PVM and the increase in ampicillin MIC was positively correlated with an enrichment in different PVM. PVM coding for surface (esp/sgrA/ecbA/complete acm) and pili proteins, or others enhancing colonization (hyl/ptsD/orf1481) or plasticity (IS16), were strongly associated with clinical Efm (mostly clade A1), but also observed in clades A2/B at different rates. ptsD was a good marker of ampicillin-resistant Efm. ptsD, IS16, orf1481, sgrA and hospital variants of complete pili gene clusters are proposed as markers to assess the safety of Efm strains. Conclusions: Our study expands on the distribution of PVM in diverse Efm lineages and demonstrates the enrichment in infection-derived strains of PVM not previously included in EFSA's list of Efm safety criteria. The evidence of relevant Efm infection markers can impact the risk assessment of Efm strains in different public health contexts. PMID- 29149290 TI - Discovering the 3' UTR-mediated regulation of alpha-synuclein. AB - Recent evidence indicates a link between Parkinson's Disease (PD) and the expression of a-synuclein (SNCA) isoforms with different 3' untranslated regions (3'UTRs). Yet, the post-transcriptional mechanisms regulating SNCA expression are unknown. Using a large-scale in vitro /in silico screening we identified RNA binding proteins (RBPs) that interact with SNCA 3' UTRs. We identified two RBPs, ELAVL1 and TIAR, that bind with high affinity to the most abundant and translationally active 3' UTR isoform (575 nt). Knockdown and overexpression experiments indicate that both ELAVL1 and TIAR positively regulate endogenous SNCA in vivo. The mechanism of regulation implies mRNA stabilization as well as enhancement of translation in the case of TIAR. We observed significant alteration of both TIAR and ELAVL1 expression in motor cortex of post-mortem brain donors and primary cultured fibroblast from patients affected by PD and Multiple System Atrophy (MSA). Moreover, trans expression quantitative trait loci (trans-eQTLs) analysis revealed that a group of single nucleotide polymorphisms (SNPs) in TIAR genomic locus influences SNCA expression in two different brain areas, nucleus accumbens and hippocampus. Our study sheds light on the 3' UTR mediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration. PMID- 29149294 TI - Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniae in mouse thigh and lung infection models. AB - Background: The pharmacokinetic/pharmacodynamic (PK/PD) relationship for polymyxin B against Klebsiella pneumoniae infections is not known. Methods: Dose fractionation studies with subcutaneous polymyxin B were conducted in neutropenic mice in which infection with three strains of K. pneumoniae had been produced in thighs or lungs. Dosing (thigh infection 0.5-120 mg/kg/day; lung infection 5-120 mg/kg/day) commenced 2 h after inoculation, and bacterial burden was measured 24 h later. Plasma exposure measures for unbound polymyxin B were from population pharmacokinetic analysis of single doses and plasma protein binding by ultracentrifugation. The inhibitory sigmoid dose-effect model was employed to determine the relationship between exposure and efficacy. Antibacterial activities of polymyxin B and colistin against thigh infection were compared at equimolar doses generating exposures resulting in maximal antibacterial activity. Results: The pharmacokinetics of polymyxin B were well described by a model comprising parallel linear and saturable pathways for absorption and elimination. Plasma binding of polymyxin B was constant (P > 0.05) over the range ~0.9-37 mg/L; average (+/-SD) percentage bound was 91.4 +/- 1.65. In thigh infection, antibacterial effect was well correlated with fAUC/MIC (R2 = 0.89). Target values of fAUC/MIC for stasis and 1 log10 kill were 1.22-13.5 and 3.72-28.0, respectively; 2 log10 kill was not achieved for any strain, even at the highest tolerated dose. There was no difference (P > 0.05) in antibacterial activity between polymyxin B and colistin with equimolar doses. It was not possible to achieve stasis in lung infection, even at the highest dose tolerated by mice. Conclusions: The results will assist in the design of optimized dosage regimens of polymyxin B. PMID- 29149295 TI - Implementation of Health 2015 public health program in Finland: a welfare state in transition. AB - Our study sought to examine the implementation of Health 2015 [a public health programme prepared following the principles of Health in All Policies (HiAP)] between 2001 and 2015 in the context of welfare state restructuring. We used data from the realist multiple explanatory case study by HARMONICS, which focused on political factors (processes) that lead to the (un)successful implementation of programmes following the principles of HiAP. We analyzed data-key informant interviews, grey and scholarly literature-from our Finnish case to examine how Health 2015 implementation has been affected by the changing role of the state. We find that the dismantling of formal funding allocation decreased the capacity of national authorities to exert control over municipalities' health promotion work, diluting the financial arrangements regarding municipal obligations. As a result, most municipalities failed to contribute to Health 2015, resulting in losses for health promotion activities. Our results also point to joining the EU. Whereas the procedures for preparing Finland's unanimous positions on EU matters were useful in harmonizing ideologies on various policy issues between different ministries, joining the EU also increased commercial interests and the strength of the lobby system, leading to the prioritization of economic objectives over public health objectives. Finally, our informants also highlighted the changing relationship between the state and the market, manifested in market deregulation and increasing influence of pro-growth arguments during the implementation of Health 2015. PMID- 29149296 TI - Comparative transcriptomics of 5 high-altitude vertebrates and their low-altitude relatives. AB - Background: Species living at high altitude are subject to strong selective pressures due to inhospitable environments (e.g., hypoxia, low temperature, high solar radiation, and lack of biological production), making these species valuable models for comparative analyses of local adaptation. Studies that have examined high-altitude adaptation have identified a vast array of rapidly evolving genes that characterize the dramatic phenotypic changes in high-altitude animals. However, how high-altitude environment shapes gene expression programs remains largely unknown. Findings: We generated a total of 910 Gb of high-quality RNA-seq data for 180 samples derived from 6 tissues of 5 agriculturally important high-altitude vertebrates (Tibetan chicken, Tibetan pig, Tibetan sheep, Tibetan goat, and yak) and their cross-fertile relatives living in geographically neighboring low-altitude regions. Of these, ~75% reads could be aligned to their respective reference genomes, and on average ~60% of annotated protein coding genes in each organism showed FPKM expression values greater than 0.5. We observed a general concordance in topological relationships between the nucleotide alignments and gene expression-based trees. Tissue and species accounted for markedly more variance than altitude based on either the expression or the alternative splicing patterns. Cross-species clustering analyses showed a tissue-dominated pattern of gene expression and a species-dominated pattern for alternative splicing. We also identified numerous differentially expressed genes that could potentially be involved in phenotypic divergence shaped by high altitude adaptation. Conclusions: These data serve as a valuable resource for examining the convergence and divergence of gene expression changes between species as they adapt or acclimatize to high-altitude environments. PMID- 29149297 TI - DNA knots occur in intracellular chromatin. AB - In vivo DNA molecules are narrowly folded within chromatin fibers and self interacting chromatin domains. Therefore, intra-molecular DNA entanglements (knots) might occur via DNA strand passage activity of topoisomerase II. Here, we assessed the presence of such DNA knots in a variety of yeast circular minichromosomes. We found that small steady state fractions of DNA knots are common in intracellular chromatin. These knots occur irrespective of DNA replication and cell proliferation, though their abundance is reduced during DNA transcription. We found also that in vivo DNA knotting probability does not scale proportionately with chromatin length: it reaches a value of ~0.025 in domains of ~20 nucleosomes but tends to level off in longer chromatin fibers. These figures suggest that, while high flexibility of nucleosomal fibers and clustering of nearby nucleosomes facilitate DNA knotting locally, some mechanism minimizes the scaling of DNA knot formation throughout intracellular chromatin. We postulate that regulation of topoisomerase II activity and the fractal architecture of chromatin might be crucial to prevent a potentially massive and harmful self entanglement of DNA molecules in vivo. PMID- 29149298 TI - Vector-borne diseases and climate change: a European perspective. AB - Climate change has already impacted the transmission of a wide range of vector borne diseases in Europe, and it will continue to do so in the coming decades. Climate change has been implicated in the observed shift of ticks to elevated altitudes and latitudes, notably including the Ixodes ricinus tick species that is a vector for Lyme borreliosis and tick-borne encephalitis. Climate change is also thought to have been a factor in the expansion of other important disease vectors in Europe: Aedes albopictus (the Asian tiger mosquito), which transmits diseases such as Zika, dengue and chikungunya, and Phlebotomus sandfly species, which transmits diseases including Leishmaniasis. In addition, highly elevated temperatures in the summer of 2010 have been associated with an epidemic of West Nile Fever in Southeast Europe and subsequent outbreaks have been linked to summer temperature anomalies. Future climate-sensitive health impacts are challenging to project quantitatively, in part due to the intricate interplay between non-climatic and climatic drivers, weather-sensitive pathogens and climate-change adaptation. Moreover, globalisation and international air travel contribute to pathogen and vector dispersion internationally. Nevertheless, monitoring forecasts of meteorological conditions can help detect epidemic precursors of vector-borne disease outbreaks and serve as early warning systems for risk reduction. PMID- 29149299 TI - TWJ-Screen: an isothermal screening assay to assess ligand/DNA junction interactions in vitro. AB - The quest for chemicals able to operate at selected genomic loci in a spatiotemporally controlled manner is desirable to create manageable DNA damages. Mounting evidence now shows that alternative DNA structures, including G quadruplexes and branched DNA (or DNA junctions), might hamper proper progression of replication fork, thus triggering DNA damages and genomic instability. Therefore, small molecules that stabilize these DNA structures are currently scrutinized as a promising way to create genomic defects that cannot be dealt with properly by cancer cells. While much emphasis has been recently given to G quadruplexes and related ligands, we report herein on three-way DNA junctions (TWJ) and related ligands. We first highlight the biological implications of TWJ and their strategic relevance as triggers for replicative stress. Then, we describe a new in vitro high-throughput screening assay, TWJ-Screen, which allows for identifying TWJ ligands with both high affinity and selectivity for TWJ over other DNA structures (duplexes and quadruplexes), in a convenient and unbiased manner as demonstrated by the screening of a library of 25 compounds from different chemical families. TWJ-Screen thus represents a reliable mean to uncover molecular tools able to foster replicative stress through an innovative approach, thus providing new strategic opportunities to combat cancers. PMID- 29149300 TI - The Effect of Nonreversibility on Inferring Rooted Phylogenies. AB - Most phylogenetic models assume that the evolutionary process is stationary and reversible. In addition to being biologically improbable, these assumptions also impair inference by generating models under which the likelihood does not depend on the position of the root. Consequently, the root of the tree cannot be inferred as part of the analysis. Yet identifying the root position is a key component of phylogenetic inference because it provides a point of reference for polarizing ancestor-descendant relationships and therefore interpreting the tree. In this paper, we investigate the effect of relaxing the unrealistic reversibility assumption and allowing the position of the root to be another unknown. We propose two hierarchical models that are centered on a reversible model but perturbed to allow nonreversibility. The models differ in the degree of structure imposed on the perturbations. The analysis is performed in the Bayesian framework using Markov chain Monte Carlo methods for which software is provided. We illustrate the performance of the two nonreversible models in analyses of simulated data using two types of topological priors. We then apply the models to a real biological data set, the radiation of polyploid yeasts, for which there is robust biological opinion about the root position. Finally, we apply the models to a second biological alignment for which the rooted tree is controversial: the ribosomal tree of life. We compare the two nonreversible models and conclude that both are useful in inferring the position of the root from real biological data. PMID- 29149301 TI - Use of Domain-Swapping to Identify Candidate Amino Acids Involved in Differential Interactions between Two Allelic Variants of Type-1 S-Locus F-Box Protein and S3 RNase in Petunia inflata. AB - Petunia inflata possesses a self-incompatibility (SI) mechanism, which involves S RNase and multiple S-locus F-box (SLF) genes at the polymorphic S-locus. For a given S-haplotype, each SLF is thought to interact with some of its non-self S RNases, but not with its self S-RNase. In this work, we studied an allelic pair of SLF1, S2-SLF1 and S3-SLF1, which differ in 44 amino acids and show differential interactions with S3-RNase. We first used an in vivo transgenic assay to determine whether four chimeric proteins of S2-SLF1 and S3-SLF1, each with one of the three functional domains swapped, interact with S3-RNase. The results narrowed the candidate amino acids for specific interaction of S2-SLF1 with S3-RNase to the 16 in domain FD3. We then examined seven additional chimeric proteins by dividing FD3 into two subdomains and four mini-domains (A, B, C and D). The results further narrowed the candidate amino acids to four in mini-domain A and four in mini-domain D. Molecular modeling of interactions between S3-RNase and S2-SLF1 revealed that three of these eight are at the interaction surface, and all three are conserved in S1-SLF1 and S6a-SLF1, both of which interact with S3-RNase based on the in vivo transgenic assay. Three of the chimeric proteins were used for the in vivo transgenic assay to determine whether FD3 alone contains the amino acids required for S2-SLF1 to interact with S7-RNase and S13 RNase. The results revealed the diversity and complexity of interactions between SLF proteins and S-RNases. PMID- 29149302 TI - Activity of colistin alone or in combination with rifampicin or meropenem in a carbapenem-resistant bioluminescent Pseudomonas aeruginosa intraperitoneal murine infection model. AB - Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections represent a major therapeutic problem and combination therapy may be the chemotherapeutic option. Methods: Bioluminescent CRPA was developed through sequential subcultures in subinhibitory concentrations of meropenem from an engineered strain of bioluminescent PA Xen5. Then CRPA was injected intraperitoneally to establish an intraperitoneal murine infection model. Treatments of colistin alone or combined with rifampicin or meropenem were started 1 h after infection. In vivo bioluminescence imaging was applied dynamically at 0 h, and 2 and 5 h after treatment. Ex vivo bacterial counts from liver, kidney, spleen, lung and blood samples were also determined 5 h after treatment. Results: In vivo imaging showed that both low- and high-dose colistin combined with rifampicin resulted in a significant decrease in bioluminescence signals compared with monotherapy of colistin or rifampicin alone, whereas colistin and meropenem combination therapy did not show a greater bactericidal effect compared with monotherapy. Ex vivo bacterial count results also confirmed that combination of both low- and high-dose colistin with rifampicin resulted in significantly reduced colony counts from five kinds of tissue samples. However, only combination of high-dose colistin + meropenem resulted in reduced colony counts merely in lung and blood samples. Conclusions: Compared with single drugs, colistin and rifampicin combination therapy could exert synergistic effects, which might provide a better alternative when treating CRPA infections in clinical practice. Combination of colistin and meropenem should be considered with caution because it barely shows any synergism in the present in vivo model. PMID- 29149304 TI - Tobacco Content in Video Games: Categorization of Tobacco Typologies and Gamer Recall. AB - Introduction: Tobacco content has been identified in popular video games played by adolescents. To date, there are no established instruments for categorizing tobacco content. We describe development and demonstrate the use of an instrument to categorize types of tobacco content. Methods: Interviews were conducted with 61 participants: 20 adolescents (mean age 17.7), and 41 adults (mean age 23.9), who discussed favorite games and recalled tobacco content. All games mentioned were examined for tobacco content by watching movies of game play on YouTube, examining individual game Wiki sites, and reviewing content descriptors provided by the Entertainment Software Rating Board (ESRB), Common Sense Media and the Internet Movie Database (IMDb). A typology of tobacco content was created and correlated with gamer recall of tobacco content. Results: Participants together mentioned 366 games, of which 152 were unique. Tobacco content was verified in 39.5% (60/152) of games. Six categories of content were identified, including "no tobacco content." Of games containing tobacco, 88% (53/60) contained at least two categories of content. Games with more categories were associated with greater gamer recall of tobacco content. Conclusion: Tobacco content is present in video games and consciously recalled by players, with higher accuracy of recall associated with games featuring multiple types of tobacco content and more engaging, player-active content. Implications: Playing video games is now a daily part of most adolescents' lives. Tobacco content is present in many popular games. Currently there are no published instruments to assist in categorizing tobacco content in video games. This study describes a systematic approach to categorizing tobacco content in video games and demonstrates that games featuring more categories of tobacco content are associated with more accurate gamer recall of the presence of tobacco content when compared with games with fewer categories of content. Understanding the extent of such content will be essential in formulating tobacco control strategies to address tobacco content in games. PMID- 29149303 TI - Changes in Cytokine, Filarial Antigen, and DNA Levels Associated With Adverse Events Following Treatment of Lymphatic Filariasis. AB - Background: Mild to moderate adverse events (AEs) are common after treatment of lymphatic filariasis (LF) and pose a major challenge for the global LF elimination program. We studied changes in cytokine levels and filarial worm components in plasma of subjects with and without AEs following treatment of LF. Methods: Participants (n = 24) were hospitalized and monitored for AEs following treatment. Cytokines (27), filarial DNA, circulating filarial antigen (CFA), and immune complexes were measured in plasma samples collected before and after treatment. Results: Levels for 16 cytokines increased after treatment in individuals with moderate AEs compared to individuals with no and/or mild AEs. These included 3 major proinflammatory cytokines (interleukin 6, tumor necrosis factor alpha, and interleukin 1beta). Eotaxin-1 levels were elevated at baseline in individuals who developed moderate AEs after treatment; thus, eotaxin-1 is a potential biomarker for AE risk. CFA and filarial DNA levels increased more in individuals with moderate AEs after treatment than in people with no/mild AEs. Conclusions: Increases in cytokine, filarial DNA, and CFA levels were associated with development of AEs following treatment of LF. Improved understanding of the pathogenesis of AEs may lead to improved methods for their prevention or management that could increase compliance in elimination programs. PMID- 29149305 TI - Rituximab for non-responsive idiopathic membranous nephropathy in a Chinese cohort. AB - Background: Rituximab had been shown to be effective in inducing remission of nephrotic syndrome in patients with idiopathic membranous nephropathy (iMN). This study applied rituximab therapy for 36 non-responsive iMN patients to investigate its effects and safety. Methods: Thirty-six iMN patients who were non-responsive to prior immunosuppression were enrolled. Rituximab was used for B-cell depletion in patients, with a goal of <5 B cells/mm3 in the circulation. After completing the study, patients were monitored for a median of 12.0 months [interquartile range (IQR) 9.0-19.3]. Results: Fifteen of the 36 (41.7%) patients achieved partial (n = 13) or complete (n = 2) response to the rituximab treatment. The median time for achieving partial response was 4.0 months (IQR 3.0-6.0). The responders had relatively lower levels (118 +/- 112 U/mL versus 345 +/- 357 U/mL, P = 0.03) of anti-phospholipase 2 receptor (PLA2R) antibodies before the rituximab treatment, and all of them achieved antibody depletion or reduction. B cell depletion was achieved in all patients. Renal function remained stable in the responders [estimated glomerular filtration rate (eGFR) 53.3 +/- 40.5 versus 55.6 +/- 33.2 mL/min/1.73 m2, P = 0.67] but deteriorated in the non-responders (eGFR 57.5 +/- 29.3 versus 45.3 +/- 32.8 mL/min/1.73 m2, P = 0.02) with two patients reaching end-stage kidney disease. Two of the 15 patients relapsed during the follow-up period with anti-PLA2R antibody reoccurrence and B-cell reconstitution. The second course of rituximab combined with tacrolimus induced a faster partial response again in one patient. Conclusion: Rituximab therapy could induce remission of proteinuria and stabilization of renal function in non responsive iMN patients, even those with damaged renal function. Anti-PLA2R antibodies may be used as a marker for individualized rituximab dosage and treatment monitoring. PMID- 29149306 TI - Pakistan: a transplant tourism resort? PMID- 29149308 TI - Paternity Analysis of Wood Turtles (Glyptemys insculpta) Reveals Complex Mating Patterns. AB - Mating system characteristics are of great importance as they may influence male and female reproductive success and reproductive isolation. The wood turtle (Glyptemys insculpta) is a terrestrial freshwater species listed as endangered by the International Union for Conservation of Nature. Considering its conservation status and the paucity of information currently available on parentage relationship for the species, we performed a microsatellite analysis to study the mating system of wood turtles in the Shawinigan River (Quebec). We sampled 38 clutches over 2 years (14 in 2006 and 24 in 2007), for a total of 248 offspring genotyped with 7 microsatellite loci. The reconstructed genotypes of the fathers revealed that reproductive success in the sampled clutches varied greatly between males and are positively correlated with the number of mates and clutches sired. Frequency of multiple paternity was estimated at 37% through a consensus of 3 different estimation methods. Positive correlation was observed between the genetic diversity of clutches and the number of fathers. Repeat paternity, however, was observed in 88% of the clutches by the same female in successive years, which suggests either a frequent use of sperm storage, or remating with the same partner in successive years. PMID- 29149309 TI - A comparable yardstick: adjusting for education bias in South African health system responsiveness ratings. AB - Health-system responsiveness (HSR) measures the experience of health-system users in terms of the non-clinical aspects of the health system. This has been operationalized as a measurable construct in multiple surveys and studies. According to the literature, reporting behaviour may vary systematically across socio-demographic characteristics. In this study we explore the association between education levels and reporting behaviour in terms of HSR in South Africa using data from the World Health Organization Study on Global Ageing and Adult Health for South Africa (WHO SAGE) conducted in 2007 and 2008. We consider the reporting behaviour of 1499 adults aged 50 and older in terms of the reported HSR for their most recent outpatient provider visit during the preceding 12 months. More specifically, we explore whether there are systematic biases in reporting behaviour by education levels and other socio-economic covariates through the use of data from anchoring vignettes. These are questions depicting hypothetical HSR scenarios which provide a fixed benchmark for comparing individuals' own HSR ratings and identifying potential reporting biases. Using a hierarchical-ordered probit model in regression analysis, we found large differences in HSR ratings between the lowest and highest education groups after adjusting for reporting bias using the anchoring vignettes. This finding holds across all seven HSR domains captured in the WHO SAGE dataset. In the most extreme case, individuals with no education are likely to underreport poor HSR by between 2.6 and 9.4% percentage points compared with individuals with secondary schooling or higher. Policy-makers need to take cognizance of potential reporting biases in HSR ratings and make the necessary adjustments to obtain data that are as true and accurate as possible. The need for this is especially acute in a country such as South Africa with large socio-economic inequalities and disparities in access to healthcare. PMID- 29149307 TI - Tumour TIF1 mutations and loss of heterozygosity related to cancer-associated myositis. AB - Objectives: To analyse the influence of genetic alterations and differential expression of transcription intermediary factor 1 (TIF1) genes in the pathophysiology of cancer-associated myositis (CAM). Methods: Paired blood and tumour DNA samples from patients with anti-TIF1gamma-positive CAM and from controls were analysed by whole-exome sequencing for the presence of somatic mutations and loss of heterozygosity (LOH) in their TIF1 genes. The genesis and maintenance of the autoimmune process were investigated immunohistochemically by studying TIF1gamma expression in the different tissues involved in CAM (skin, muscle and tumour) based on the immunohistochemical H-score. Results: From seven patients with anti-TIF1gamma-positive CAM, we detected one somatic mutation and five cases of LOH in one or more of the four TIF1 genes compared with just one case of LOH in tumours from TIF1gamma-negative myositis patients (86% vs 17%; P = 0.03). Compared with type-matched control tumours from non-myositis patients, TIF1gamma staining was more intense in tumours from anti-TIF1gamma-positive patients (H-score 255 vs 196; P = 0.01). Also, TIF1gamma staining in muscle was slightly more intense in anti-TIF1gamma-positive than in anti-TIF1gamma-negative myositis (H-score 22 vs 5; P = 0.03). In contrast, intense TIF1gamma staining was detected in the skin of both myositis and control patients. Conclusion: Tumours from paraneoplastic anti-TIF1gamma-positive patients showed an increased number of genetic alterations, such as mutations and LOH, in TIF1 genes. These genetic alterations, in the context of a high expression of TIF1gamma in the tumour, muscle and skin of these patients may be key to understanding the genesis of paraneoplastic myositis. PMID- 29149310 TI - Counting indirect crisis-related deaths in the context of a low-resilience health system: the case of maternal and neonatal health during the Ebola epidemic in Sierra Leone. AB - Although the number of direct Ebola-related deaths from the 2013 to 2016 West African Ebola outbreak has been quantified, the number of indirect deaths, resulting from decreased utilization of routine health services, remains unknown. Such information is a key ingredient of health system resilience, essential for adequate allocation of resources to both 'crisis response activities' and 'core functions'. Taking stock of indirect deaths may also help the concept of health system resilience achieve political traction over the traditional approach of disease-specific surveillance. This study responds to these imperatives by quantifying the extent of the drop in utilization of essential reproductive, maternal and neonatal health services in Sierra Leone during the Ebola outbreak by using interrupted time-series regression to analyse Health Management Information System (HMIS) data. Using the Lives Saved Tool, we then model the implication of this decrease in utilization in terms of excess maternal and neonatal deaths, as well as stillbirths. We find that antenatal care coverage suffered from the largest decrease in coverage as a result of the Ebola epidemic, with an estimated 22 percentage point (p.p.) decrease in population coverage compared with the most conservative counterfactual scenario. Use of family planning, facility delivery and post-natal care services also decreased but to a lesser extent (-6, -8 and -13 p.p. respectively). This decrease in utilization of life-saving health services translates to 3600 additional maternal, neonatal and stillbirth deaths in the year 2014-15 under the most conservative scenario. In other words, we estimate that the indirect mortality effects of a crisis in the context of a health system lacking resilience may be as important as the direct mortality effects of the crisis itself. PMID- 29149311 TI - Beyond the crisis: did the Ebola epidemic improve resilience of Liberia's health system? AB - Resilience was widely identified as a critical attribute for strong health systems following the 2014-15 West Africa Ebola epidemic. In Liberia, Sierra Leone and Guinea, struggles to control the disease and suspension of the operation of many health services demonstrated that health systems must plan for resilience long before a crisis. However, the operational elements of resilience and ways that a crisis experience can shape resilience are not well described in the literature. To understand how a health system adapts to crisis and how the priorities of different health system actors influence this response we conducted interviews with global, national, and local respondents in Liberia between July and September 2015 (n = 108), several months after the country was first declared Ebola-free. We found that health system resilience functions prioritized by global and national actors improved to a greater extent than those valued by community leaders and local health actors over the course of the epidemic. Although the Ebola epidemic stimulated some positive adaptations in Liberia's health system, building a truly resilient health system will require longer-term investments and sustained attention long beyond the crisis. PMID- 29149312 TI - Who are more responsive? Mixed-methods comparison of public and private sector physicians in rural Bangladesh. AB - Responsiveness of physicians (ROPs) reflects the social actions by physicians to meet the legitimate expectations of health care users. Responsiveness is important since it improves understanding and care seeking by users, as well as fostering trust in health systems rather than replicating discrimination and entrenching inequality. Given widespread public and private sector health care provision in Bangladesh, we undertook a mixed-methods study comparing responsiveness of public and private physicians in rural Bangladesh. The study included in-depth interviews with physicians (n = 12, seven public, five private) and patients (n = 7, three male, four female); focus group discussions with users (four sessions, two male and two female); and observations in consultation rooms of public and private sector physicians (1 week in each setting). This was followed by structured observation of patient consultations with 195 public and 198 private physicians using the ROPs Scale, consisting of five domains (Friendliness; Respecting; Informing and guiding; Gaining trust; and Financial sensitivity). Qualitative data were analysed by framework analysis and quantitative data were analyzed using two-sample t-test, multiple linear regression, multivariate analysis of variance, and descriptive discriminant analyses. The mean responsiveness score of public sector physicians was statistically different from private sector physicians: -0.29 vs 0.29, i.e. a difference of - 0.58 (P-value < 0.01; 95% CI - 0.77, -0.39) on a normalized scale. Despite relatively higher level of responsiveness of private sector, according to qualitative findings, neither of the sectors performed optimally. Private physicians scored higher in Friendliness, Respecting and Informing and guiding; while public sector physicians scored higher in other domains. 'Respecting' domain was found as the most important. Unlike findings from other studies in Bangladesh, instead of seeing one sector as better than the other, this study identified areas of responsiveness where each sector needs improvements. PMID- 29149313 TI - How do health workers experience and cope with shocks? Learning from four fragile and conflict-affected health systems in Uganda, Sierra Leone, Zimbabwe and Cambodia. AB - This article is grounded in a research programme which set out to understand how to rebuild health systems post-conflict. Four countries were studied-Uganda, Sierra Leone, Zimbabwe and Cambodia-which were at different distances from conflict and crisis, as well as having unique conflict stories. During the research process, the Ebola epidemic broke out in West Africa. Zimbabwe has continued to face a profound economic crisis. Within our research on health worker incentives, we captured insights from 128 life histories and in-depth interviews with a variety of staff that had remained in service. This article aims to draw together lessons from these contexts which can provide lessons for enhancing staff and therefore health system resilience in future, especially in similarly fragile and conflict-affected contexts. We examine the reported effects, both personal and professional, of the three different types of shock (conflicts, epidemics and prolonged political-economic crises), and how staff coped. We find that the impact of shocks and coping strategies are similar between conflict/post-conflict and epidemic contexts-particularly in relation to physical threats and psychosocial threats-while all three contexts create challenges and staff responses for working conditions and remuneration. Health staff showed considerable inventiveness and resilience, and also benefited from external assistance of various kinds, but there are important gaps which point to ways in which they should be better protected and supported in the future. Health systems are increasingly fragile and conflict-prone, and shocks are often prolonged or repeated. Resilience should not be taken for granted or used as an excuse for abandoning frontline health staff. Strategies should be in place at local, national and international levels to prepare for predictable crises of various sorts, rather than waiting for them to occur and responding belatedly, or relying on personal sacrifices by staff to keep services functioning. PMID- 29149314 TI - How the introduction of a human resources information system helped the Democratic Republic of Congo to mobilise domestic resources for an improved health workforce. AB - The Democratic Republic of Congo has flagged health workforce management and compensation as issues requiring attention, including the problem of ghost workers (individuals on payroll who do not exist and/or show up at work). Recognising the need for reliable health workforce information, the government has worked to implement iHRIS, an open source human resources information system that facilitates health workforce management. In Kasai Central and Kasai Provinces, health workers brought relevant documentation to data collection points, where trained teams interviewed them and entered contact information, identification, photo, current job, and employment and education history into iHRIS on laptops. After uploading the data, the Ministry of Public Health used the database of over 11 500 verified health worker records to analyse health worker characteristics, density, compensation, and payroll. Both provinces had less than one physician per 10 000 population and a higher urban versus rural health worker density. Most iHRIS-registered health workers (57% in Kasai Central and 73% in Kasai) reported receiving no regular government pay of any kind (salaries or risk allowances). Payroll analysis showed that 27% of the health workers listed as salary recipients in the electronic payroll system were ghost workers, as were 42% of risk allowance recipients. As a result, the Ministries of Public Health, Public Service, and Finance reallocated funds away from ghost workers to cover salaries (n = 781) and risk allowances (n = 2613) for thousands of health workers who were previously under- or uncompensated due to lack of funds. The reallocation prioritised previously under- or uncompensated mid-level health workers, with 49% of those receiving salaries and 68% of those receiving risk allowances representing cadres such as nurses, laboratory technicians, and midwifery cadres. Assembling accurate health worker records can help governments understand health workforce characteristics and use data to direct scarce domestic resources to where they are most needed. PMID- 29149315 TI - A cross-sectional study of malaria endemicity and health system readiness to deliver services in Kenya, Namibia and Senegal. AB - Despite good progress towards elimination, malaria continues to contribute substantially to the sub-Saharan African disease burden. Sustaining previous gains requires continued readiness to deliver malaria services in response to actual disease burden, which in turn contributes to health systems strengthening. This study investigates a health system innovation. We examined whether malaria prevalence, or endemicity, is a driver of health facility readiness to deliver malaria services. To estimate this association, we geo-linked cross-sectional facility survey data to endemicity data for Kenya, Namibia and Senegal. We tested the validity and reliability of the primary study outcome, the malaria service readiness index and mapped service readiness components in a geographic information system. We conducted a weighted multivariable linear regression analysis of the relationship between endemicity and malaria service readiness, stratified for urban or rural facility location. As endemicity increased in rural areas, there was a concurrent, modest increase in service readiness at the facility level [beta: 0.028; (95% CI 0.008, 0.047)], whereas no relationship existed in urban settings. Private-for-profit facilities were generally less prepared than public [beta: -0.102; (95% CI - 0.154, -0.050)]. Most facilities had the necessary supplies to diagnose malaria, yet availability of malaria guidelines and adequately trained staff as well as medicines and commodities varied. Findings require cautious interpretation outside the study sample, which was a more limited subset of the original surveys' sampling schemes. Our approach and findings may be used by national malaria programs to identify low performing facilities in malarious areas for targeted service delivery interventions. This study demonstrates use of existing data sources to evaluate health system performance and to identify within- and cross-country variations for targeted interventions. PMID- 29149316 TI - Use of information and communication technologies in the formal and informal health system responses to the 2015 Nepal earthquakes. AB - Information and Communication Technologies (ICTs) are increasingly recognized for their potential contributions to health service delivery in Low-and Middle-Income Countries (LMICs). As well as playing a role in improving the provision of health services under everyday 'normal' circumstances, ICTs can also be important in preparing for, mitigating, responding to and recovering from disasters. This research explores the use of ICTs in a natural disaster situation in Nepal, a country affected by a series of strong earthquakes in 2015. In March and April 2016, in-depth semi-structured interviews (n = 24) and focus group discussions (n = 4) were conducted with key informants: those affected by the earthquake, and those forming part of the formal or informal health system responses. Data were collected and analysed across three levels, from the bottom 'upwards', namely: (1) village level; (2) district level and (3) central/national level. Perceptions of the role and value of ICTs varied greatly-as did patterns of use. While access and capability were found to be key barriers to use rurally, ICTs were nevertheless an important part of the informal response, helping people to gather information, express needs and cope emotionally. They also helped relief agencies in allowing for networking and coordination among actors. Use of ICTs in the formal health system response, however, was severely lacking in many areas, relying more on traditional methods of disaster management. This reflects a general deficiency in, and underuse of, ICTs in the pre-earthquake Nepali healthcare system. We conclude by calling for a redoubling of efforts to improve and increase the adoption, diffusion, integration and regular use of ICTs within the Nepali health system-an approach that will assist with day-to-day service delivery but also provide a crucial platform upon which to build during future crises. PMID- 29149317 TI - Decision space for health workforce management in decentralized settings: a case study in Uganda. AB - The aim of this paper is to improve understanding about how district health managers perceive and use their decision space for human resource management (HRM) and how this compares with national policies and regulatory frameworks governing HRM. The study builds upon work undertaken by PERFORM Research Consortium in Uganda using action-research to strengthen human resources management in the health sector. To assess the decision space that managers have in six areas of HRM (e.g. policy, planning, remuneration and incentives, performance management, education and information) the study compares the roles allocated by Uganda's policy and regulatory frameworks with the actual room for decision-making that district health managers perceive that they have. Results show that in some areas District Health Management Team (DHMT) members make decisions beyond their conferred authority while in others they do not use all the space allocated by policy. DHMT members operate close to the boundaries defined by public policy in planning, remuneration and incentives, policy and performance management. However, they make decisions beyond their conferred authority in the area of information and do not use all the space allocated by policy in the area of education. DHMTs' decision-making capacity to manage their workforce is influenced by their own perceived authority and sometimes it is constrained by decisions made at higher levels. We can conclude that decentralization, to improve workforce performance, needs to devolve power further down from district authorities onto district health managers. DHMTs need not only more power and authority to make decisions about their workforce but also more control over resources to be able to implement these decisions. PMID- 29149318 TI - Resilient and responsive health systems in a changing world. PMID- 29149319 TI - From bouncing back, to nurturing emergence: reframing the concept of resilience in health systems strengthening. AB - Recent health system shocks such as the Ebola disease outbreak have focused global health attention on the notion of resilient health systems. In this commentary, we reflect on the current framing of the concept of resilience in health systems discourse and propose a reframing. Specifically, we propose that: (1) in addition to sudden shocks, health systems face the ongoing strain of multiple factors. Health systems need the capacity to continue to deliver services of good quality and respond effectively to wider health challenges. We call this capacity everyday resilience; (2) health system resilience entails more than bouncing back from shock. In complex adaptive systems (CAS), resilience emerges from a combination of absorptive, adaptive and transformative strategies; (3) nurturing the resilience of health systems requires understanding health systems as comprising not only hardware elements (such as finances and infrastructure), but also software elements (such as leadership capacity, power relations, values and appropriate organizational culture). We also reflect on current criticisms of the concept of resilient health systems, such as that it assumes that systems are apolitical, ignoring actor agency, promoting inaction, and requiring that we accept and embrace vulnerability, rather than strive for stronger and more responsive systems. We observe that these criticisms are warranted to the extent that they refer to notions of resilience that are mismatched with the reality of health systems as CAS. We argue that the observed weaknesses of resilience thinking can be addressed by reframing and applying a resilience lens that is better suited to the attributes of health systems as CAS. PMID- 29149321 TI - Biosimilars Forum Applauds Food and Drug Administration on New Educational Program Promoting Safety and Effectiveness of Biosimilars. PMID- 29149320 TI - ORGANIC SCINTILLATOR FOR REAL-TIME NEUTRON DOSIMETRY. AB - We developed a radiation detector based on an organic scintillator for spectrometry and dosimetry of out-of-field secondary neutrons from clinical proton beams. The detector consists of an EJ-299-34 crystalline organic scintillator, coupled by fiber optic cable to a silicon photomultiplier (SiPM). Proof of concept measurements were taken with 137Cs and 252Cf, and corresponding simulations were performed in MCNPX-PoliMi. Despite its small size, the detector is able to discriminate between neutron and gamma-rays via pulse shape discrimination. We simulated the response function of the detector to monoenergetic neutrons in the 100 keV-0 MeV range using MCNPX-PoliMi. The measured unfolded 252Cf neutron spectrum is in good agreement with the theoretical Watt fission spectrum. We determined the ambient dose equivalent by folding the spectrum with the fluence-to-ambient dose conversion coefficient, with a 1.4% deviation from theory. Some preliminary proton beam experiments were preformed at the Bronowice Cyclotron Center patient treatment facility using a clinically relevant proton pencil beam for brain tumor and craino-spinal treatment directed at a child phantom. PMID- 29149322 TI - Altruistic and self-serving goals modulate behavioral and neural responses in deception. AB - People tell lies not only for their own self-interests but sometimes also to help others. Little is known about the ways in which different types of goals modulate behaviors and neural responses in deception. The present study investigated the neural processes associated with spontaneous deception that occurs with altruistic reasons (i.e. the money would be donated to charity), self-serving reasons (i.e. the participant receives all of the money) and mixed goals (i.e. the money would be equally split between the participant and the charity). Altruistic motivation for deception reduced the intensity of moral conflict and the subsequent mental cost of resolving this conflict, reflected by a smaller N2 P3 effect in the purely altruistic condition. When making decisions about whether to lie, self-interest was a stronger motivator than others' interests, and the participants tended to lie more for themselves than for others. When the lie could be mutually beneficial for both of the self and others, the participants tended to lie even when they knew that they could be easily caught, but they actually lied for their own self-interest rather than for altruistic reasons. These findings shed light on the neural basis of 'good lies' and decision-making in mutually beneficial situations. PMID- 29149323 TI - Should the dilated ascending aorta be repaired at the time of bicuspid aortic valve replacement? AB - OBJECTIVES: Bicuspid aortic valve (BAV) is the most common congenital valvular abnormality and frequently presents with accelerated calcific aortic valve disease, requiring aortic valve replacement (AVR) and thoracic aortic aneurysm and dissection. Supporting evidence for Association Guidelines of aortic dimensions for aortic resection is sparse. We sought to determine whether concurrent repair of dilated or aneurysmal aortic disease during AVR in patients with BAV substantially improves morbidity and mortality outcomes. METHODS: Mortality and reoperation outcomes of 1301 adults with BAV and dilated aorta undergoing AVR-only surgery were compared to patients undergoing AVR with aortic resection (AVR-AR) using Cox proportional hazards modelling and patient matching. RESULTS: Clinically important differences in patient characteristics, aortic valve function and aortic dimensions were identified between cohorts. Event rates were low, with rates of reoperation and death within 1 year of only 1.8% and 5.4%, respectively, and no aortic dissection observed during follow-up. There were no significant differences in reoperation or mortality outcomes between the AVR-only and AVR-AR cohorts. Age, aortic dimension or a combination thereof was not associated with better or worse outcomes after each AVR-AR compared with AVR. CONCLUSIONS: We conclude AVR-only and AVR-AR surgery have low morbidity and mortality and have utility over a wide range of age and aortic sizes. Our results do not provide support for the 45-mm aortic dimension recommended in the current guidelines for aortic resection while performing AVR or any other specific dimension. PMID- 29149324 TI - Pyrethroid Insecticide Cypermethrin Modulates Gonadotropin Synthesis via Calcium Homeostasis and ERK1/2 Signaling in LbetaT2 Mouse Pituitary Cells. AB - Pyrethroids are a class of widely used insecticides. Cypermethrin (CP) is one of most commonly used pyrethroid insecticides and its residue has been frequently detected in environmental media. Our recent animal study reported that early postnatal exposure to CP induced an increase in serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as well as the expression of gonadotropin subunit genes (chorionic gonadotropin alpha [CGalpha], LHbeta and FSHbeta) in pituitary tissues. In this study, we further investigated the precise mechanism by which CP at concentrations of 1-100 nM affected the synthesis of gonadotropins using a murine pituitary gonadotropic cell line LbetaT2. We found that calcium (Ca2+)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) activity was required for CP-regulated transcription of CGalphas, LHbeta and FSHbeta. We provided the novel evidence that CP caused both influx of extracellular Ca2+ through L-type voltage-gated calcium channels (VGCCs) and release of intracellular Ca2+ from endoplasmic reticulum (ER) via inhibition of Ca2+-ATPase. Our results showed that CP disrupted Ca2+ homeostasis via these two separate and independent pathways, thus resulting in the activation of protein kinase C /c-Raf/ERK1/2/immediate-early genes pathways and subsequent increase in the transcription of gonadotropin subunit genes. Our findings would have important implications for understanding the underlying mechanisms of the disrupting effects of some pyrethroids (such as CP) on the synthesis of pituitary gonadotropins. PMID- 29149325 TI - The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. AB - The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, www.guidetopharmacology.org) and its precursor IUPHAR-DB, have captured expert-curated interactions between targets and ligands from selected papers in pharmacology and drug discovery since 2003. This resource continues to be developed in conjunction with the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS). As previously described, our unique model of content selection and quality control is based on 96 target-class subcommittees comprising 512 scientists collaborating with in-house curators. This update describes content expansion, new features and interoperability improvements introduced in the 10 releases since August 2015. Our relationship matrix now describes ~9000 ligands, ~15 000 binding constants, ~6000 papers and ~1700 human proteins. As an important addition, we also introduce our newly funded project for the Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb, www.guidetoimmunopharmacology.org). This has been 'forked' from the well established GtoPdb data model and expanded into new types of data related to the immune system and inflammatory processes. This includes new ligands, targets, pathways, cell types and diseases for which we are recruiting new IUPHAR expert committees. Designed as an immunopharmacological gateway, it also has an emphasis on potential therapeutic interventions. PMID- 29149327 TI - Focused time-lapse analysis reveals novel aspects of human fertilization and suggests new parameters of embryo viability. AB - STUDY QUESTION: Can focused application of time-lapse microscopy (TLM) lead to a more detailed map of the morphokinetics of human fertilization, revealing novel or neglected aspects of this process? SUMMARY ANSWER: Intensive harnessing of TLM reveals novel or previously poorly characterised phenomena of fertilization, such as a cytoplasmic wave (CW) preceding pronuclear formation and kinetics of pronuclear chromatin polarization, thereby suggesting novel non-invasive biomarkers of embryo quality. WHAT IS KNOWN ALREADY: In recent years, human preimplantation development has been the object of TLM studies with the intent to develop morphokinetic algorithms able to predict blastocyst formation and implantation. Regardless, our appreciation of the morphokinetics of fertilization remains rather scarce, currently including only times of polar body II (PBII) emission, pronuclear appearance and fading, and first cleavage. This is not consistent with the complexity and importance of this process, calling for further TLM studies aimed at describing previously unrecognized or undetected morphokinetic events and identifying novel developmental biomarkers. STUDY DESIGN, SIZE, DURATION: The study involved a retrospective observation by TLM of the fertilization process in 500 oocytes utilized in consecutive ICSI cycles carried out in 2016. A maximum of five fertilized oocytes per patients were included in the analysis to reduce possible patient-specific biases. Oocytes of patients with different diagnoses of infertility where included in the analysis, while cases involving cryopreserved gametes or surgically retrieved sperm were excluded. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Microinjected oocytes where assessed by a combined TLM-culture system (Embryoscope). Oocytes that were not amenable to TLM assessment, due to excess of residual corona cells or inadequate orientation for the observation of PBII emission, were not analysed. We identified and monitored 28 parameters relevant to meiotic resumption, pronuclear dynamics, chromatin organization, and cytoplasmic/cortical modifications. Times (T) were expressed as mean +/- SD hours post-insemination (p.i.) and analysed, where appropriate, by Paired T Student or Fisher's exact tests. MAIN RESULTS AND ROLE OF CHANCE: PBII emission was occasionally followed (4.3% of cases) by the transient appearance of a protrusion of the cell surface, the fertilization cone (FC), probably resulting from interaction of the male chromatin with the oocyte cortex. Pronuclear formation was always preceded by a radial CW originating from the initial position of the male pronucleus (PN) and extending towards the oocyte periphery. The appearance of the CW followed a precise sequence, occurring always 2-3 h after PBII emission and shortly before PN appearance. Male and female PN appeared virtually simultaneously at approximately 6.2 h p.i. However, while the female PN always formed cortically and near the site of emission of the PBII, the initial position of the male PN was cortical, intermediate, or central (15.2%, 31.2% and 53.6%, respectively). PN juxtaposition involved rapid and straight movement of the female PN towards the male PN. In addition, the initial position of male PN formation was predictive of the position of PN juxtaposition. It was also observed that nucleolar precursor bodies (NPBs) aligned along the juxtaposition area and this happened considerably earlier for the female PN (8.2 +/- 2.6 vs.11.2 +/- 4.1 h, P = 0.0001). Although it occurred rarely, displacement of juxtaposed PN to the cortex was strongly associated (P < 0.0001) with direct cleavage into three blastomeres at the first cell division. The times of PN breakdown and first cleavage showed a very consistent trend, occurring earlier or progressively later depending on whether initial male PN positioning was central, intermediate or cortical, respectively. Finally, time intervals between discrete fertilization events were strongly associated with embryo quality on Day 3. For example, longer intervals between disappearance of the cytoplasmic halo and PN breakdown were highly predictive of reduced blastomere number and increased fragmentation (P = 0.0001). LARGE SCALE DATA: N/A. LIMITATIONS, REASON FOR CAUTION: Some of the morphokinetic parameters assessed in this study may require better definition to reduce inter-operator annotation variability. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, overall, these data represent the most detailed morphokinetic description of human fertilization. Many of the illustrated parameters are novel and may be amenable to further elaboration into algorithms able to predict embryo quality, as suggested by the findings presented in this study. STUDY FUNDING/COMPETING INTERESTS: None. PMID- 29149326 TI - Virtually 'in the heat of the moment': insula activation in safe sex negotiation among risky men. AB - HIV is most prevalent among men who have sex with men (MSM), and although most MSM use condoms consistently during casual sex, some take risks. To better understand the psychology of those risky decisions, we examined neural correlates of playing a virtual sexual 'hook up' game in an functional magnetic resonance imaging scanner in MSM who had, in the past 90 days, been sexually risky (N = 76) or safe (N = 31). We found that during potentially risky sexual choices, previously risky MSM had more right insula activity than previously safe MSM. Real-life sexual risk was related to trait positive and negative urgency. Insula activity that differentiated risky and safe MSM was related to trait positive and negative urgency. Future work should further examine if, and to what extent, insula activation during safe sex negotiation drives MSM's rash risky sexual decision-making. PMID- 29149328 TI - MiR858-Mediated Regulation of Flavonoid-Specific MYB Transcription Factor Genes Controls Resistance to Pathogen Infection in Arabidopsis. AB - MicroRNAs (miRNAs) are a class of short endogenous non-coding small RNAs that direct post-transcriptional gene silencing in eukaryotes. In plants, the expression of a large number of miRNAs has been shown to be regulated during pathogen infection. However, the functional role of the majority of these pathogen-regulated miRNAs has not been elucidated. In this work, we investigated the role of Arabidopsis miR858 in the defense response of Arabidopsis plants to infection by fungal pathogens with necrotrophic (Plectosphaerella cucumerina) or hemibiotrophic (Fusarium oxysporum and Colletotrichum higginsianum) lifestyles. Whereas overexpression of MIR858 enhances susceptibility to pathogen infection, interference with miR858 activity by target mimics (MIM858 plants) results in disease resistance. Upon pathogen challenge, stronger activation of the defense genes PDF1.2 and PR4 occurs in MIM858 plants than in wild-type plants, whereas pathogen infection induced weaker activation of these genes in MIR858 overexpressor plants. Reduced miR858 activity, and concomitant up-regulation of miR858 target genes, in MIM858 plants, also leads to accumulation of flavonoids in Arabidopsis leaves. The antifungal activity of phenylpropanoid compounds, including flavonoids, is presented. Furthermore, pathogen infection or treatment with fungal elicitors is accompanied by a gradual decrease in MIR858 expression in wild-type plants, suggesting that miR858 plays a role in PAMP (pathogen associated molecular pattern)-triggered immunity. These data support that miR858 is a negative regulator of Arabidopsis immunity and provide new insights into the relevant role of miR858-mediated regulation of the phenylpropanoid biosynthetic pathway in controlling Arabidopsis immunity. PMID- 29149329 TI - Polymyxin derivatives NAB739 and NAB815 are more effective than polymyxin B in murine Escherichia coli pyelonephritis. AB - Objectives: Extremely multiresistant strains of Enterobacteriaceae, such as those of Escherichia coli and Klebsiella pneumoniae, are emerging and spreading at a worrisome speed. Polymyxins (polymyxin B, colistin) are used as last-line therapy against such strains, in spite of their notable nephrotoxicity that may even require discontinuation of the therapy. We have previously developed polymyxin derivatives NAB739 and NAB815 that are better tolerated in cynomolgus monkeys than polymyxin B and are, in contrast to polymyxin B, excreted in the cynomolgus urine to a very significant degree. Here we have compared the efficacy of these NAB compounds and polymyxin B in the therapy of murine pyelonephritis caused by E. coli. Methods: The challenge organism was a uropathogenic E. coli clinical isolate. Mice were inoculated via urethral catheterization with 5 * 108 cfu. All treatment groups consisted of 12 animals. On day 1 and day 2 post-infection, the mice were treated subcutaneously with NAB739, NAB815, polymyxin B or vehicle twice a day and on day 3 post-infection the animals were sacrificed. cfu in the kidney and bladder tissues and in the urine were determined. Results: NAB739 reduced the bacterial burden in the kidney, urine and bladder at doses approximately 10-fold lower than those of polymyxin B. In the kidneys, the half maximal effective dose (ED50) was 9-fold lower for NAB739 than for polymyxin B (0.24 mg/kg versus 2.1 mg/kg, respectively). NAB815 was as effective as NAB739. Conclusions: NAB739 and NAB815 were unequivocally more effective than polymyxin B in the murine pyelonephritis model. PMID- 29149330 TI - S101, an Inhibitor of Proliferating T Cells, Rescues Mice From Superantigen Induced Shock. AB - Superantigens (SAgs) are extremely potent bacterial toxins, which evoke a virulent immune response, inducing nonspecific T-cell proliferation, rapid cytokine release, and lethal toxic shock, for which there is no effective treatment. We previously developed a small molecule, S101, which potently inhibits proliferating T cells. In a severe mouse model of toxic shock, a single injection of S101 given together with superantigen challenge rescued 100% of the mice. Even when given 2 hours after challenge, S101 rescued 40% of the mice. S101 targets the T-cell receptor, inflammatory response, and actin cytoskeleton pathways. S101 inhibits the aryl hydrocarbon receptor, a ligand-activated transcription factor that is involved in the differentiation of T-helper cells, especially Th17, and regulatory T cells. Our results provide the rationale for developing S101 to treat superantigen-induced toxic shock and other pathologies characterized by T-cell activation and proliferation. PMID- 29149331 TI - The Ethics of Organ Tourism: Role Morality and Organ Transplantation. AB - Organ tourism occurs when individuals in countries with existing organ transplant procedures, such as the United States, are unable to procure an organ by using those transplant procedures in enough time to save their life. In this paper, I am concerned with the following question: When organ tourists return to the United States and need another transplant, do US transplant physicians have an obligation to place them on a transplant list? I argue that transplant physicians have a duty not to relist organ tourists. Specifically, I contend that we should locate physicians' duties in these cases within the new role of "transplant physician." This role results from transplant physicians' participation in a system that depends on organ donors' voluntary act of donation. PMID- 29149332 TI - Kidney Sales and Market Regulation: A Reply to Semrau. AB - Luke Semrau argues that the documented harms of existing organ markets do not undermine the case for establishing regulated systems of paid kidney donation. He offers two arguments in support of this conclusion. First, Semrau argues that the harms of kidney selling are straightforwardly amenable to regulatory solution. Second, Semrau argues that even in existing black markets, sellers would likely have experienced greater harm if the option of selling a kidney were not available. This commentary challenges both of Semrau's claims. I argue that there is no reason to believe that kidney sellers benefit from the current black market trade in organs, and highlight a number of potential issues regarding the effectiveness and feasibility of Semrau's proposed market regulations. PMID- 29149333 TI - Misleading by Omission: Rethinking the Obligation to Inform Research Subjects about Funding Sources. AB - Informed consent requirements for medical research have expanded over the past half-century. The Declaration of Helsinki now includes an explicit positive obligation to inform subjects about funding sources. This is problematic in a number of ways and seems to oblige researchers to disclose information irrelevant to most consent decisions. It is argued here that such a problematic obligation involves an "informational fallacy." The aim in the second part of the paper is to provide a better approach to making sense of how a failure to inform about funding sources wrongs subjects: by making appeals to obligations to refrain from misleading by omission. This alternative approach-grounded in a general obligation to refrain from misleading, an obligation that is independent of informed consent-provides a basis for a norm that protects subjects' interests, without the informational fallacy. The approach developed here avoids the problems identified with the currently specified general obligation to inform about funding sources. PMID- 29149334 TI - Reassessing the Likely Harms to Kidney Vendors in Regulated Organ Markets. AB - Julian Koplin, drawing extensively on empirical data, has argued that vendors, even in well-regulated kidney markets, are likely to be significantly harmed. I contend that his reasoning to this conclusion is dangerously mistaken. I highlight two failures. First, Koplin is insufficiently attentive to the differences between existing markets and the regulated markets proposed by advocates. On the basis of this error, he wrongly concludes that many harms will persist even in a well-regulated system. Second, Koplin misunderstands the utilitarian assessment of the market. He focuses on the costs and benefits of the transaction for the vendor. But, the relevant comparison is between an individual's welfare across different courses of action, namely, vending and the nonvending alternative. Although Koplin's empirically informed contribution is a welcome addition to this literature, the mistakes that pervade his interpretation of the data demand correction. PMID- 29149335 TI - Liberty in Health Care: A Comparative Study Between Hong Kong and Mainland China. AB - This essay contends that individual liberty, understood as the permissibility of making choices about one's own health care in support of one's own good and the good of one's family utilizing private resources, is central to the moral foundations of a health care system. Such individual freedoms are important not only because they often support more efficient and effective health care services, but because they permit individuals to fulfill important moral duties. A comparative study of the health care systems in Hong Kong and mainland China is utilized to illustrate the conceptual and moral concerns at stake. Both regions have implemented two-tier health care systems with a public tier of basic health care services together with a second tier of privately purchased health care. As we document, Hong Kong permits patients and doctors significantly greater opportunities to choose private health care of typically higher medical quality than their mainland counterparts. As a result, individuals are able to obtain higher quality health care while also fulfilling important moral duties for themselves and their families. In this sense, Hong Kong's health care system is morally superior to mainland China's. In each case, Confucianism's concerns regarding equality are partly satisfied through the provision of public health care services on the basic tier, while appropriate use of private resources in support of oneself and one's family is permissibly exercised on the private tier. Although it is true that inequalities in health care access and outcome are inevitable within a system that permits such individual freedoms, we argue that such inequalities are morally justifiable in terms of Confucian ethical thought. PMID- 29149336 TI - Military Neurosurgery Socioeconomic Data: Benefits, Challenges, and Opportunities. AB - Military conflict and neurosurgery date back to antiquity. Neurosurgery's development is intimately linked with Harvey Cushing's military experience. Previous papers highlighted unique opportunities and socioeconomic challenges facing military neurosurgeons. Here, we provide objective data from military neurosurgeons surrounding these issues.Internet survey responses were solicited from current, separated, and retired military neurosurgeons regarding workforce issues and their perception of military neurosurgery.A total of 80.9% (98/121) of respondents enjoyed their military experience, 63.6% (77/121) were very pleased with their service; 97.4% (114/117) enjoyed treating military patients, and 78.2% (93/119) would recommend military service. Positives included feelings of patriotism (87.4%), development of camaraderie (71.4%), and deployment experience (93.8%).However, 76.5% of respondents noted concerns regarding military and civilian pay disparity. 37.5% were overwhelmed with administrative responsibilities, and over 50% desired higher case volume.Multivariate analysis showed those who failed to develop a sense of camaraderie were more likely to be dissatisfied (P = .02). Those still currently serving trended towards dissatisfaction (P = .08), and current military neurosurgeons were only 0.29 times as likely to recommend military service to another neurosurgeon as compared to those who were retired or separated (P < .024).Service as a military neurosurgeon is an overwhelmingly positive experience but opportunities exist for mechanisms to increase operative case load, reduce administrative responsibilities, and reduce military-civilian income disparity. Addressing these issues is important as current military neurosurgeons were more likely to be dissatisfied with their military experience and less likely to recommend military service to another neurosurgeon. PMID- 29149337 TI - Mechanisms leading to in vivo ceftolozane/tazobactam resistance development during the treatment of infections caused by MDR Pseudomonas aeruginosa. AB - Objectives: Characterization of the mechanisms driving ceftolozane/tazobactam resistance development in 5 of 47 (10.6%) patients treated for MDR Pseudomonas aeruginosa infections in a Spanish hospital. Methods: Five pairs of ceftolozane/tazobactam-susceptible/resistant P. aeruginosa isolates were studied. MICs were determined by broth microdilution, clonal relatedness was assessed by MLST and resistance mechanisms were investigated by phenotypic and genotypic methods, including WGS. ampC variants were cloned to assess their impact on resistance. Results: In all five cases, the same clone was detected for the susceptible/resistant pairs; the widespread ST175 high-risk clone in four of the cases and ST179 in the remaining case. Genomic analysis of the four initial ST175 isolates revealed the characteristic OprD mutation (Q142X) responsible for carbapenem resistance and the AmpR mutation (G154R) responsible for AmpC overexpression and beta-lactam resistance. The final isolates had developed ceftolozane/tazobactam and ceftazidime/avibactam resistance, and each additionally showed a mutation in AmpC: E247K in one of the isolates, T96I in two isolates and a deletion of 19 amino acids (G229-E247) in the remaining isolate. The cloned AmpC variants showed greatly increased ceftolozane/tazobactam and ceftazidime/avibactam MICs compared with WT AmpC, but, in contrast, yielded lower MICs of imipenem, cefepime and particularly piperacillin/tazobactam. On the other hand, ceftolozane/tazobactam resistance development in ST179 was shown to be driven by the emergence of the extended-spectrum OXA beta-lactamase OXA-14, through the selection of an N146S mutation from OXA-10. Conclusions: Modification of intrinsic (AmpC) and horizontally acquired beta-lactamases appears to be the main mechanism leading to ceftolozane/tazobactam resistance in MDR P. aeruginosa. PMID- 29149340 TI - Erratum. PMID- 29149339 TI - Human Immunodeficiency Virus Infection Increases the Risk of Incident Autoimmune Hemolytic Anemia: A Population-Based Cohort Study in Taiwan. AB - Background: Currently, the association between human immunodeficiency virus (HIV) infection and subsequent development of autoimmune hemolytic anemia (AIHA) remains unclear. This nationwide population-based cohort study aimed to determine the association between incident AIHA and HIV infection in Taiwan. Methods: During 2000-2012, we identified people aged ?15 years living with HIV (PLWH) from the Taiwan Centers for Disease Control HIV Surveillance System. Individuals were considered to be infected with HIV on the basis of positive results of an HIV type 1 Western blot. Age- and sex-matched controls without HIV infection were selected from the Taiwan National Health Insurance Research Database for comparison. All patients were followed until 31 December 2012 and observed for occurrence of AIHA. Results: Of 171468 subjects (19052 PLWH and 152416 controls), 30 (0.02%) had incident AIHA during a mean follow-up of 5.45 years, including 23 PLWH (0.12%) and 7 controls (0.01%). After adjustment for age, sex, and comorbidities, HIV infection was found to be an independent risk factor of incident AIHA (adjusted hazard ratio, 20.9; 95% confidence interval, 8.34-52.3). Moreover, PLWH who were receiving highly active antiretroviral therapy were more likely to develop AIHA than those who were not receiving these drugs (adjusted hazard ratio, 16.2; 95% confidence interval, 3.52-74.2). Conclusions: Our study suggests that HIV infection is an independent risk factor for incident AIHA. PMID- 29149341 TI - Erratum. PMID- 29149342 TI - Erratum. PMID- 29149338 TI - Multiplex Respiratory Virus Testing for Antimicrobial Stewardship: A Prospective Assessment of Antimicrobial Use and Clinical Outcomes Among Hospitalized Adults. AB - Background: Respiratory tract infections are frequent causes of hospitalization and initiation of empirical antimicrobial therapy. Testing for a broad panel of respiratory viruses has been advocated as a useful tool for antibiotic stewardship. We conducted a prospective observational study to assess the impact of rapid viral test results on antimicrobial prescriptions and clinical outcomes among hospitalized adults. Methods: Eight hundred patients admitted with respiratory symptoms were tested by a 12-virus respiratory panel (RVP) during 3 consecutive winters in Montreal, Canada. The primary outcome measure was change in antimicrobial prescriptions (ie, de-escalation of empirical antimicrobial therapy or commencement of new antimicrobial therapy) after RVP results were available. Clinical outcomes were also assessed. Results: Influenza virus was identified in 53% of individuals in the study population, and other viruses were identified in 10%. Influenza virus positivity was associated with shorter duration of hospitalization and appropriate antiviral management. Antibiotic management was most significantly correlated with radiographic suspicion of pneumonia and less so with results of the RVP. Positivity for viruses other than influenza virus was not correlated with significantly different outcomes. Conclusions: Physicians respond to results of testing for influenza virus when managing hospitalized adult patients but respond less to test results for other viruses. These data can inform the design of stewardship interventions and the selection of viral testing panels for hospitalized patients. PMID- 29149343 TI - Erratum. PMID- 29149344 TI - APPLICATION OF DROPLET DETECTORS TO ALPHA RADIATION DETECTION. AB - Superheated droplet detectors (SDDs) are traditionally employed in the detection of neutrons. In this work the focus is on the detection of alpha particles using C2ClF5 as the target liquid. The alpha-droplet interaction is examined via computational studies, and a geometric model developed to describe the expected detector response. Experiments with alpha-emitting uranium- and samarium-doped SDDs at temperatures of 5-12 degrees C confirm that the event rate is related to the size of the droplets, and are in model agreement for temperatures below 8 degrees C; above this temperature, the acoustic sensitivity is reduced by signal attenuation as a result of the increasing bubble population, for which the addition of an attenuation coefficient restores the agreement with experiment. The results suggest the viability of a SDD-based alpha spectrometer using mono sized droplets. PMID- 29149345 TI - Predictive Indicators to Identify High-Risk Paediatric Febrile Neutropenia in Paediatric Oncology Patients in a Middle-Income Country. AB - Purpose: To validate a clinical risk prediction score (Ammann score) to predict adverse events (AEs) in paediatric febrile neutropenia (FN). Patients and methods: Patients <16 years of age were enrolled. A risk prediction score (based on haemoglobin >= 9 g/dl, white cell count (WCC) < 0.3 G/l, platelet count <50 G/l and chemotherapy more intensive than acute lymphoblastic leukaemia maintenance therapy) was calculated and AEs were documented. Results: In total, 100 FN episodes occurred in 52 patients, male:female ratio was 1.8:1 and median age was 56 months. At reassessment, AEs occurred in 18 of 55 (45%) low-risk FN episodes (score < 9) and 21 of 42 (55%) high-risk episodes (score >=9) (sensitivity 60%, specificity 65%, positive predictive value 53%, negative predictive value 71%). Total WCC and absolute monocyte count (AMC) were significantly associated with AEs. Conclusion: This study identified total WCC and AMC as significantly associated with AEs but failed to validate the risk prediction score. PMID- 29149346 TI - Novel Pathways of Endocrine Disruption Through Pesticides Interference With Human Mineralocorticoid Receptors. AB - Mineralocorticoid receptor (MR) is one member of the steroid receptor family. In addition to its important role in Na+/K+ homeostasis, MR is reported as a tumor suppressor in carcinogenesis. So far, little was known about the ability of pesticides to interfere with MR. In this study, a total of 43 pesticides and/or metabolites were investigated for their potential effects on human MR. None of the tested pesticides exhibited MR agonistic potency, whereas 16 compounds showed antagonistic activities. Further investigations indicated that these 16 chemicals individually antagonized aldosterone-induced alkaline phosphatase expression in vascular smooth muscle cells and aldosterone-inhibited hepatocellular carcinoma cell proliferation at higher concentrations, and the mixture of these 16 pesticides at environmentally relevant concentrations significantly disrupted MR activity. The additional quantitative mixture experiments indicated a good agreement between the combined anti-mineralocorticoidic activities of 16 pesticides and the responses predicted by concentration addition model instead of independent action model. The interruption of nuclear translocation of MR was clarified as a main mechanism for the anti-mineralocorticoidic activities by these pesticides. These data suggest that the health risk may increase when multiple MR antagonists cooperate following concentration addition model and exhibit a combined effect. Our findings emphasize that comprehensive risk assessment of adverse effects of environmental MR ligands on human health should be considered. PMID- 29149347 TI - Signal recognition particle binds to translating ribosomes before emergence of a signal anchor sequence. AB - The bacterial signal recognition particle (SRP) is part of the machinery that targets ribosomes synthesizing membrane proteins to membrane-embedded translocons co-translationally. Recognition of nascent membrane proteins occurs by virtue of a hydrophobic signal-anchor sequence (SAS) contained in the nascent chain, usually at the N terminus. Here we use fluorescence-based stopped-flow to monitor SRP-ribosome interactions with actively translating ribosomes while an SRP substrate is synthesized and emerges from the peptide exit tunnel. The kinetic analysis reveals that, at cellular concentrations of ribosomes and SRP, SRP rapidly binds to translating ribosomes prior to the emergence of an SAS and forms an initial complex that rapidly rearranges to a more stable engaged complex. When the growing peptide reaches a length of ~50 amino acids and the SAS is partially exposed, SRP undergoes another conformational change which further stabilizes the complex and initiates targeting of the translating ribosome to the translocon. These results provide a reconciled view on the timing of high-affinity targeting complex formation, while emphasizing the existence of preceding SRP recruitment steps under conditions of ongoing translation. PMID- 29149350 TI - A Data Fusion Pipeline for Generating and Enriching Adverse Outcome Pathway Descriptions. AB - Increasing amounts of systems toxicology data, including omics results, are becoming publically available and accessible in databases. Data-driven and informatics-tool supported pipeline schemas for fitting such data into Adverse Outcome Pathway (AOP) descriptions could potentially aid the development of nonanimal-based hazard and risk assessment methods. We devised a 6-step workflow that integrated diverse types of toxicology data into a novel AOP scheme for pulmonary fibrosis. Mining of literature references and diverse data sources covering previous pathway descriptions and molecular results were coupled in a stepwise manner with informatics tools applications that enabled gene linkage and pathway identification in molecular interaction maps. Ultimately, a network of functional elements coupled 64 pulmonary fibrosis-associated genes into a novel, open-source AOP-linked molecular pathway, now available for commenting and improvements in WikiPathways (WP3624). Applying in silico-based knowledge extraction and modeling, the pipeline enabled screening and fusion of many different complex data types, including the integration of omics results. Overall, the taken, stepwise approach should be generally useful to construct novel AOP descriptions as well as to enrich developing AOP descriptions in progress. PMID- 29149351 TI - [Medical examination: Preparation for ENT specialisation : Part 33]. PMID- 29149348 TI - Mechanistic insight into the assembly of the HerA-NurA helicase-nuclease DNA end resection complex. AB - The HerA-NurA helicase-nuclease complex cooperates with Mre11 and Rad50 to coordinate the repair of double-stranded DNA breaks. Little is known, however, about the assembly mechanism and activation of the HerA-NurA. By combining hybrid mass spectrometry with cryo-EM, computational and biochemical data, we investigate the oligomeric formation of HerA and detail the mechanism of nucleotide binding to the HerA-NurA complex from thermophilic archaea. We reveal that ATP-free HerA and HerA-DNA complexes predominantly exist in solution as a heptamer and act as a DNA loading intermediate. The binding of either NurA or ATP stabilizes the hexameric HerA, indicating that HerA-NurA is activated by substrates and complex assembly. To examine the role of ATP in DNA translocation and processing, we investigated how nucleotides interact with the HerA-NurA. We show that while the hexameric HerA binds six nucleotides in an 'all-or-none' fashion, HerA-NurA harbors a highly coordinated pairwise binding mechanism and enables the translocation and processing of double-stranded DNA. Using molecular dynamics simulations, we reveal novel inter-residue interactions between the external ATP and the internal DNA binding sites. Overall, here we propose a stepwise assembly mechanism detailing the synergistic activation of HerA-NurA by ATP, which allows efficient processing of double-stranded DNA. PMID- 29149349 TI - Social exclusion weakens storage capacity and attentional filtering ability in visual working memory. AB - Social exclusion has been found to impair visual working memory (WM), while the underlying neural processes are currently unclear. Using two experiments, we tested whether the poor WM performance caused by exclusion was due to reduced storage capacity, impaired attentional filtering ability or both. The Cyberball game was used to manipulate social exclusion. Seventy-four female participants performed WM tasks while event-related potentials were recorded. In Experiment 1, participants were made to remember the orientations of red rectangles while ignoring salient green rectangles. Results showed that exclusion impaired the ability to filter out irrelevant items from WM, as reflected by the similar contralateral delay activity (CDA) amplitudes for one-target-one-distractor condition and two-targets condition, as well as the similar CDA amplitudes for two-targets-two-distractors condition and four-targets condition in excluded individuals. In Experiment 2, participants were asked to remember 1-5 colored squares. Results showed that exclusion reduced storage capacity, as the CDA amplitudes reached asymptote at loads of two items for exclusion group and at loads of three items for inclusion group. Together, these two experiments provided complementary evidence that WM deficits caused by social exclusion were due to reduced storage capacity and impaired attentional filtering ability. PMID- 29149352 TI - Prognostic potential of markers of bone turnover in delayed-healing tibial diaphyseal fractures. AB - INTRODUCTION: Clinical and radiographic examinations detect delayed or nonunion only after the event has occurred. Biochemical markers of bone turnover (BTMs) are promising laboratory tools that offer an early insight into the likelihood of delayed union. We hypothesized that BTMs display temporal variations following fractures and the behavior of BTMs differ between normal and delayed union of fractures. METHODS: This was a prospective study of patients with closed fracture of tibia treated with intramedullary, interlocking nailing. BTM assays (NTX, BSAP, P1NP and osteocalcin) and clinical and radiographic assessments were obtained preoperatively and postoperatively at 8,12, 24, 36 and 72 weeks. Temporal trend of elevation of serum levels of BTMs post-fracture was the primary assessment criterion and radiographic and clinical assessment of fracture union were the secondary assessment criteria. RESULTS: The average time for fracture union was 15.24 weeks (range 15-19 weeks). The values of both bone formation and resorption markers peaked at the eighth week following the fracture. Resorption markers returned to baseline by 36 weeks. Among the formation markers, BSAP levels showed the smallest increase and returned to baseline earlier (36 weeks) than P1NP and osteocalcin (72 weeks). P1NP showed the most dramatic change, increasing to 2.5 times the mean baseline level at 8 weeks in normal union of fractures. The levels of bone formation markers (BSAP, OC, PINP) were significantly lower in patients with delayed union. There was no significant difference in the levels of the resorption marker (NTX) between normal and delayed union patients. CONCLUSION: Serial monitoring of biochemical markers of bone turnover can be used as an adjunct to clinical and radiological observations to predict delayed union LEVEL OF EVIDENCE: Level 2 (prospective observational study). PMID- 29149353 TI - [Surf the allergy Tsunami : Future chances for ENT]. PMID- 29149354 TI - [Trauma surgery in Third World countries]. PMID- 29149355 TI - Find Applications. PMID- 29149356 TI - Early Occurrence of Sinking Skin Flap Syndrome in a State of Intracranial Hypertension : Case Report. PMID- 29149358 TI - Clinically Directed Neuroimaging of Ophthalmoplegia. AB - PURPOSE: Ophthalmoplegia (OP) can have numerous etiologies and different clinical presentations. Most causes of OP can be narrowed down to specific anatomical locations based on clinical information. The aim of this study was to outline the different categories of diseases encountered in patients with OP, based on the location along the ocular motor pathways, and the most appropriate imaging modality for the given scenarios. METHODS: Representative neuroimaging examples of pathological processes causing OP are displayed, sequenced by anatomical location and disease category. Correlations between the clinical presentation and site of pathology with imaging protocol recommendations are also presented. RESULTS: Diseases affecting ocular movement can be divided into categories including: injuries or diseases of the cerebral hemispheres, midbrain, pons, and cerebellum, ocular motor nerve palsies, intrinsic extraocular muscle diseases and orbital diseases secondarily affecting the extraocular muscles. The cranial nerves responsible for ocular movements can be affected intrinsically or extrinsically along their nuclei, their course in the brainstem, in the cisterns, skull base, cavernous sinuses and orbits. The extraocular muscles can be affected primarily or secondarily by adjacent pathological processes in the orbit. Clinical information can help narrow down the differential diagnoses in terms of anatomical site of involvement and prompt the most appropriate neuroimaging techniques. CONCLUSION: By understanding the pathophysiology of OP the neuroradiologist can discuss clinical cases with the referring clinician and determine a timely, accurate method of imaging to achieve the most precise differential diagnosis. PMID- 29149357 TI - Recommendations for Mechanical Thrombectomy in Patients with Acute Ischemic Stroke : A Clinical Guide by the Hellenic Stroke Organization. AB - This document presents the consensus recommendations of the Hellenic Stroke Organization which can be of assistance to the treating stroke physicians. PMID- 29149359 TI - [Preclinical and intrahospital management of mass casualties and terrorist incidents]. AB - Due to the recent terrorist attacks in Paris, Brussels, Ansbach, Munich, Berlin and more recently Manchester and London, terrorism is realized as a present threat to our society and social life, as well as a challenge for the health care system. Without fueling anxiety, there is a need for sensitization to this subject and to familiarize all concerned with the special kind of terrorist attack-related injuries, the operational priorities and tactics and the individual basic principles of preclinical and hospital care. There is a need to adapt the known established medical structure for a conventional mass casualty situation to the special requirements that are raised by this new kind of terrorist threat to our social life. It is the aim of this article, from a surgical point of view, to depict the tactics and challenges of preclinical care of the special kind of terrorist attack-related injuries from the site of the incident, via the advanced medical post or casualty collecting point, to the triage point at the hospital. The special needs of medical care and organizational aspects of the primary treatment in the hospital are highlighted and possible decisional options and different approaches are discussed. PMID- 29149360 TI - [Transplantation of large osteochondral allografts-old wine in new bottles or a paradigm shift?] PMID- 29149361 TI - [Light at the end of the tunnel]. PMID- 29149362 TI - [Traumatic brain injury in polytrauma patients]. PMID- 29149363 TI - Indications for extracorporeal support: why do we need the results of the EOLIA trial? AB - Acute respiratory distress syndrome (ARDS) is a severe lung disease, with an associated mortality rate exceeding 60% for the most severe forms of the disease. In these situations, establishing an extracorporeal circuit, combining a centrifugal pump and a membrane oxygenator (extra-corporeal membrane oxygenation, ECMO), can ensure total pulmonary assistance and allow the lungs to rest under ultraprotective mechanical ventilation. Unfortunately, former trials of ECMO in ARDS were negative or highly criticized due to many technical and methodological shortcomings. Prior to the widespread use of venovenous ECMO for severe ARDS, new trials are needed to test the efficacy of early initiation of the technique with tight control of mechanical ventilation in the control group, initiation of ECMO prior to transportation to ECMO centers, and the use of ECMO in all patients randomly assigned to receive this treatment. Therefore, the international multicenter randomized EOLIA (ECMO to rescue Lung Injury in severe ARDS) trial was designed to test the benefit of systematic and early installation of the latest-generation ECMO circuits in patients with very severe ARDS. Patients randomized to the control group were managed with tight control of mechanical ventilation and recourse to paralyzing agents and prone positioning, while an ethical crossover option to ECMO was permitted only if refractory hypoxemia (SaO2 < 80%) lasted for > 6 h despite all possible conventional emergency interventions. The primary endpoint of the study was the 60-day mortality rate, with an expected 20% absolute mortality reduction with ECMO. PMID- 29149364 TI - Bioecological Aspects and Heavy Metal Contamination of the Mollusk Donax denticulatus in the Colombian Caribbean Coastline. AB - Donax denticulatus is a key mollusk for the ecology of sandy beaches, serving as a controller of organic matter, microorganisms, and as bioindicator of heavy metals pollution. The goal of this study was to characterize some ecological aspects of D. denticulatus and its relationship with the content of heavy metals in their tissue, in three beaches of the Caribbean coast of Colombia. The results showed the study populations were different in terms of morphological characteristics and density (Berrugas-Sucre < Cartagena-Bolivar < Riohacha Guajira), but not in sexual proportion; although density was clearly related to beach occupancy by tourists. Analysis of metals revealed tissue concentrations varied depending on the location (Greater means: Hg = 0.018 +/- 0.004 in Riohacha; Pb = 0.110 +/- 0.060 in Berrugas and Cd = 0.040 +/- 0.010 ug/g in Cartagena). No relationships were found between morphometric variables and heavy metals content. Principal components analysis highlighted Riohacha for presenting differences respecting to Bocagrande and Berrugas in terms of physicochemical water parameters such as pH, temperature, salinity, dissolved oxygen and conductivity. Results suggest tourism rather than environmental pollution could be a sensitive factor for biota survival in Caribbean beaches. PMID- 29149367 TI - [Current meniscus treatment]. PMID- 29149366 TI - Prescribing of NOACs has outnumbered warfarin: exploring how physicians choose anticoagulant treatments. AB - PURPOSE: The development of non-vitamin K-dependent oral anticoagulants (NOACs) is a new alternative to treatment with warfarin. The purpose of this study was to explore drug prescription decisions of NOACs or warfarin from hospital physicians in cardiovascular departments. METHODS: A qualitative study with focus group interviews was conducted in three different hospitals. The interview guide explored the background of prescribing anticoagulants (warfarin, dabigatran, rivaroxaban, and apixaban) and experiences with effect and side-effects they had observed in patients. RESULTS: The systematic text condensation eluded four main themes: when to prescribe NOACs, concern about side-effects, pharmaceutical properties and patient adherence, and prescribing policy and intra-professional communication. All available anticoagulants were prescribed. However, no specific NOAC was preferred. Factors perceived as contraindications for NOACs varied among the doctors. Most had observed side-effects of NOACs; however, these rarely influenced prescribing decisions due to small differences in safety profiles. Few drug-drug interactions and fixed daily doses made NOACs easy to prescribe; but some doctors had experienced lack of drug effect for some patients. Non-adherence with NOACs was harder to spot. Some different prescribing cultures had evolved between the different hospitals and between general practitioners. CONCLUSION: The hospital physicians chose anticoagulants based on patient conditions as renal function, bleeding risks, and drug interactions being the most common taken into account. They could not say which NOAC was best, and wish that future studies could compare the different NOACs, and not just compare with warfarin. PMID- 29149365 TI - Percutaneous nephrolithotomy: complications and how to deal with them. AB - Percutaneous nephrolithotomy is a common surgical treatment for large and complex stones within the intrarenal collecting system. A wide variety of complications can result from this procedure, including bleeding, injury to surrounding structures, infection, positioning-related injuries, thromboembolic disease, and even death. Knowledge of the different types of complications can be useful in order to prevent, diagnose, and treat these problems if they occur. This review describes the diversity of complications with the goal of improving their avoidance and treatment. PMID- 29149368 TI - Dietary guidance for lutein: consideration for intake recommendations is scientifically supported. AB - Lutein, a yellow xanthophyll carotenoid found in egg yolks and many colorful fruits and vegetables, has gained public health interest for its putative role in visual performance and reducing the risk of age-related macular degeneration. The National Academies of Sciences, Engineering and Medicine's recommended Dietary Reference Intakes (DRIs) focus on preventing deficiency and toxicity, but there is a budding interest in establishing DRI-like guidelines for non-essential bioactives, like lutein, that promote optimal health and/or prevent chronic diseases. Lupton et al. developed a set of nine criteria to determine whether a bioactive is ready to be considered for DRI-like recommendations. These criteria include: (1) an accepted definition; (2) a reliable analysis method; (3) a food database with known amounts of the bioactive; (4) cohort studies; (5) clinical trials on metabolic processes; (6) clinical trials for dose-response and efficacy; (7) safety data; (8) systematic reviews and/or meta-analyses; (9) a plausible biological rationale. Based on a review of the literature supporting these criteria, lutein is ready to be considered for intake recommendations. Establishing dietary guidance for lutein would encourage the consumption of lutein-containing foods and raise public awareness about its potential health benefits. PMID- 29149369 TI - The OsPS1-F gene regulates growth and development in rice by modulating photosynthetic electron transport rate. AB - KEY MESSAGE: Ds insertion in rice OsPS1-F gene results in semi-dwarf plants with reduced tiller number and grain yield, while genetic complementation with OsPS1-F rescued the mutant phenotype. Photosynthetic electron transport is regulated in the chloroplast thylakoid membrane by multi-protein complexes. Studies about photosynthetic machinery and its subunits in crop plants are necessary, because they could be crucial for yield enhancement in the long term. Here, we report the characterization of OsPS1-F (encoding Oryza sativa PHOTOSYSTEM 1-F subunit) using a single copy Ds insertion rice mutant line. The homozygous mutant (osps1-f) showed striking difference in growth and development compared to the wild type (WT), including, reduction in plant height, tiller number, grain yield as well as pale yellow leaf coloration. Chlorophyll concentration and electron transport rate were significantly reduced in the mutant compared to the WT. OsPS1-F gene was highly expressed in rice leaves compared to other tissues at different developmental stages tested. Upon complementation of the mutant with proUBI::OsPS1-F, the observed mutant phenotypes were rescued. Our results illustrate that OsPS1-F plays an important role in regulating proper growth and development of rice plants. PMID- 29149370 TI - [Hematological diagnosis in the corneal consultation]. AB - This case report describes a diagnostic chain in a patient with atypical bilateral corneal opacity, which led to the diagnosis of a hematological disorder. The patient's medical history, clinical appearance and findings in confocal microscopy gave rise to the suspicion of a paraproteinemic keratopathy. The hematological laboratory diagnostics revealed a monoclonal gammopathy of the IgG kappa type. The bone marrow puncture led to the diagnosis of a lymphoplasmacytic lymphoma, which belongs to the group of B-cell non-Hodgkin's lymphomas. This case demonstrates that paraproteinemic keratopathy can be associated with potentially life-threatening hematological diseases. PMID- 29149374 TI - 'Point-of-care ultrasound' - legitimate terminology. PMID- 29149371 TI - Imaging patterns of venous-related brain injury in children. AB - Venous-related brain injury is a common form of cerebrovascular injury in children and encompasses a diverse group of cerebrovascular diagnoses. The purpose of this pictorial essay is to introduce the relevant anatomy, pathophysiology and various imaging patterns of venous-related cerebral injury in children. Unifying concepts to better understand the effects of venous hypertension in the developing brain will be emphasized. These unifying concepts will provide the imaging professional with a conceptual framework to better understand and confidently identify imaging patterns of venous-related cerebral injury. PMID- 29149376 TI - Reply to Andronikou and Sergot: 'point-of-care' ultrasound. PMID- 29149377 TI - Multi-patch and multi-group epidemic models: a new framework. AB - We develop a multi-patch and multi-group model that captures the dynamics of an infectious disease when the host is structured into an arbitrary number of groups and interacts into an arbitrary number of patches where the infection takes place. In this framework, we model host mobility that depends on its epidemiological status, by a Lagrangian approach. This framework is applied to a general SEIRS model and the basic reproduction number [Formula: see text] is derived. The effects of heterogeneity in groups, patches and mobility patterns on [Formula: see text] and disease prevalence are explored. Our results show that for a fixed number of groups, the basic reproduction number increases with respect to the number of patches and the host mobility patterns. Moreover, when the mobility matrix of susceptible individuals is of rank one, the basic reproduction number is explicitly determined and was found to be independent of the latter if the matrix is also stochastic. The cases where mobility matrices are of rank one capture important modeling scenarios. Additionally, we study the global analysis of equilibria for some special cases. Numerical simulations are carried out to showcase the ramifications of mobility pattern matrices on disease prevalence and basic reproduction number. PMID- 29149378 TI - [Ocular sarcoidosis : Diagnosis and therapy]. AB - Sarcoidosis is a multisystem disorder of unknown cause. Ophthalmic involvement occurs in up to 60% of all patients, often as the first manifestation of sarcoidosis. Because of the heterogeneous clinical presentation diagnosis can be difficult; therefore the International Workshop on Ocular Sarcoidosis (IWOS 2009) diagnostic criteria based on clinical presentation, laboratory investigations and imaging techniques enable establishment of the diagnosis. Patients suffering from sarcoidosis should be treated by both ophthalmologists and internal physicians. Corticosteroids are commonly used for treatment, although in some patients the therapy has to be escalated by further immunosuppressants. Finally, a good cooperation between ophthalmologists and internal physicians results in a mostly good prognosis. PMID- 29149379 TI - Efficacy of systemic and intratympanic corticosteroid combination therapy versus intratympanic or systemic therapy in patients with idiopathic sudden sensorineural hearing loss: a randomized controlled trial. AB - OBJECTIVE: The present study was conducted to compare the rates of recovery from idiopathic sudden deafness after the treatment with oral and intratympanic corticosteroids in both mono and combination therapies. STUDY DESIGN: Triple blind randomized clinical trial. SETTINGS: Tertiary referral hospital. SUBJECTS AND METHODS: A total of 112 patients who were admitted to the ENT emergency department randomly divided into three groups: an oral corticosteroid plus intratympanic placebo (systemic corticosteroid monotherapy group); an intratympanic corticosteroid plus oral placebo group (IT monotherapy group); and a combination therapy group (IT plus systemic combination group). All patients were treated additionally with antiviral and proton pomp inhibitor. An audiometry was performed once before beginning the therapies and again at the end of the therapy. RESULTS: Of the total of 112 patients, 32 received intratympanic (IT) corticosteroids, 45 were receiving systemic corticosteroids, and 35 were receiving a combination of the two. A total of 74 patients (66.1%) responded positively [response to treatment was calculated as gain of at least 10 dB in 10 dB in average threshold or with the minimum improvement of 15% in speech discrimination scores (SDS)] to corticosteroid therapy. No significant differences were observed between the three groups (IT, systemic group, and combination therapy group) in their overall response to treatment (p = 0.5). Patients who suffered from concomitant tinnitus and dizziness responded less positively to the treatment (p < 0.002). Positive family history of SSNHL seems to be negative prognostic factors in the response to treatment (p < 0.001). The response to treatment was not related to the pattern (p = 0.04) and initial severity of hearing loss (p = 0.9). CONCLUSION: This study did not find any difference in the rate of hearing improvement between systemic, intratympanic, and combined corticosteroid therapy for sudden hearing loss. LEVEL OF EVIDENCE: 1b. PMID- 29149380 TI - PSA kinetics following primary focal cryotherapy (hemiablation) in organ-confined prostate cancer patients. AB - PURPOSE: We aim to evaluate prostate-specific antigen (PSA) trends in post primary focal cryotherapy (PFC) patients. MATERIALS AND METHODS: This was an institutional review board-approved retrospective study of PFC patients from 2010 to 2015. Patients with at least one post-PFC PSA were included in the study. Biochemical recurrence (BCR) was determined using the Phoenix criteria. PSA bounce was also assessed. We analyzed rates of change of PSA over time of post PFC between BCR and no BCR groups. PSA-derived variables were analyzed as potential predictors of BCR. RESULTS: A total of 104 PFC patients were included in our analysis. Median (range) age and follow-up time were 66 (48-82) years and 19 (6.3-38.6) months, respectively. Four (3.8%) patients experienced PSA bounce. The median percent drop in first post-PFC PSA of 80.0% was not associated with BCR (p = 0.256) and may indicate elimination of the index lesion. The rate of increase of PSA in BCR patients was significantly higher compared to patients who did not recur (median PSA velocity (PSAV): 0.15 vs 0.04 ng/ml/month, p = 0.001). Similar to PSAV (HR 9.570, 95% CI 3.725-24.592, p < 0.0001), PSA nadir >= 2 ng/ml [HR (hazard ratio) 1.251, 95% CI 1.100-1.422, p = 0.001] was independently associated with BCR. CONCLUSION: A significant drop in post-PFC PSA may indicate elimination of the index lesion. Patients who are likely to recur biochemically have a significantly higher PSAV compared to those who do not recur. Nadir PSA of less than 2 ng/ml may be considered the new normal PSA in focal cryotherapy (hemiablation) follow-up. PMID- 29149381 TI - Substantial improvement in HbA1c following a treatment and teaching programme for people with type 2 diabetes on conventional insulin therapy in an in- and outpatient setting. AB - AIMS: The aim of the study was to assess the efficacy of a patient education programme (DTTP) for the optimisation of conventional insulin therapy in patients with type 2 diabetes in an in- and outpatient setting. METHODS: The study was designed as a prospective, longitudinal trial. Thirty-three people with diabetes (females 54.5%, age 61.0 years, diabetes duration 12.7 years, HbA1c 9.3%) from ten general practices in Thuringia (outpatient group) participated in a DTTP for conventional insulin therapy. Thirty-three individuals-matched pairs-(female 72.7%, age 63.2 years, diabetes duration 13.6 years, HbA1c 9.7%) who were hospitalised for the optimisation of conventional insulin therapy participated in the same DTTP during their hospitalisation. All individuals were invited to participate in an outpatient follow-up visit 12 months after participation in the DTTP. RESULTS: All participants were re-examined after 1.0 +/- 0.2 years. HbA1c improved in both groups equally by 1.2% in the outpatient group and 1.3% in the inpatient group. Insulin dosage increased marginally within the outpatient group (+ 0.09 units/kg/day, p = 0.023) and remained stable within the inpatients. Blood glucose self-monitoring increased significantly in both groups without inter group difference (+ 7.9 vs. + 6.4 tests per week). CONCLUSION: Participation in an out- or inpatient DTTP improved substantially HbA1c levels in people with type 2 diabetes on conventional insulin treatment. Probably, the improved adjustment of the eating behaviour to the insulin therapy was the reason for improved metabolic control. Guidelines should recommend "refresher" programmes when metabolic control deteriorates before an intensification of blood glucose lowering treatment. PMID- 29149382 TI - Local and global challenges in pediatric traumatic brain injury outcome and rehabilitation assessment. AB - Traumatic brain injury (TBI) is a major public health problem associated with high morbidity and mortality rates in children in both high- and low- and middle income countries. Predicting outcome after pediatric TBI is challenging given the wide range of injury and non-injury-related factors which may have an impact. Some of these factors are relevant globally (like heterogeneity in patient and injury-related factors and research methodology) and others are more specific to local contexts (like sociodemographic and cultural factors). The assessment of rehabilitation outcomes post-TBI are similarly challenging given the various methodological limitations, disparities in access to rehabilitation, and limited awareness of deficits, which are encountered globally, as well as the lack of services in the local settings. In this article, we discuss these global and local challenges to outcome and rehabilitation assessment following pediatric TBI. PMID- 29149384 TI - Brain metabolism and severe pediatric traumatic brain injury. AB - Age-dependent changes in brain metabolism may influence the response to and tolerance of secondary insults, potentially affecting outcomes. More complete characterization of brain metabolism across the clinical trajectory of severe pediatric TBI is needed to improve our ability to measure and better mitigate the impact of secondary insults. Better management of secondary insults will impact clinical care and the probability of success of future neuroprotective clinical trials. Improved bedside monitoring and imaging technologies will be required to achieve these goals. Effective and sustained integration of brain metabolism information into the pediatric critical care setting will be equally challenging and important. PMID- 29149383 TI - Diffusion MRI in pediatric brain injury. AB - Traumatic brain injury (TBI) is a major public health issue around the world and can be especially devastating in children as TBI can derail cognitive and social development. White matter (WM) is particularly vulnerable to disruption post-TBI, as myelination is ongoing during this period. Diffusion magnetic resonance imaging (dMRI) is a versatile modality for identifying and quantifying WM disruption and can detect diffuse axonal injury (DAI or TAI (traumatic axonal injury)). This review covers dMRI studies of pediatric TBI, including mild to severe injuries, and covering all periods post-injury. While there have been considerable advances in our understanding of pediatric TBI through the use of dMRI, there are still large gaps in our knowledge, which will be filled in by larger studies and more longitudinal studies. Heterogeneity post-injury is an obstacle in all TBI studies, but we expect that larger better-characterized samples will aid in identifying clinically meaningful subgroups within the pediatric TBI patient population. PMID- 29149385 TI - Pre-clinical models in pediatric traumatic brain injury-challenges and lessons learned. AB - PURPOSE: Despite the enormity of the problem and the lack of new therapies, research in the pre-clinical arena specifically using pediatric traumatic brain injury (TBI) models is limited. In this review, some of the key models addressing both the age spectrum of pediatric TBI and its unique injury mechanisms will be highlighted. Four topics will be addressed, namely, (1) unique facets of the developing brain important to TBI model development, (2) a description of some of the most commonly used pre-clinical models of severe pediatric TBI including work in both rodents and large animals, (3) a description of the pediatric models of mild TBI and repetitive mild TBI that are relatively new, and finally (4) a discussion of challenges, gaps, and potential future directions to further advance work in pediatric TBI models. METHODS: This narrative review on the topic of pediatric TBI models was based on review of PUBMED/Medline along with a synthesis of information on key factors in pre-clinical and clinical developmental brain injury that influence TBI modeling. RESULTS: In the contemporary literature, six types of models have been used in rats including weight drop, fluid percussion injury (FPI), impact acceleration, controlled cortical impact (CCI), mechanical shaking, and closed head modifications of CCI. In mice, studies are largely restricted to CCI. In large animals, FPI and rotational injury have been used in piglets and shake injury has also been used in lambs. Most of the studies have been in severe injury models, although more recently, studies have begun to explore mild and repetitive mild injuries to study concussion. CONCLUSIONS: Given the emerging importance of TBI in infants and children, the morbidity and mortality that is produced, along with its purported link to the development of chronic neurodegenerative diseases, studies in these models merit greater systematic investigations along with consortium type approaches and long-term follow-up to translate new therapies to the bedside. PMID- 29149386 TI - Glucose metabolism in pediatric traumatic brain injury. AB - Traumatic brain injury is the number one cause of death and disability among the pediatric population in the USA. The heterogeneity of the pediatric population is reflected by both the normal cerebral maturation and the age differences in the causes of TBI, which generate unique age-related pathophysiology responses and recovery profiles. This review will address the normal changes in cerebral glucose metabolism throughout developmental phases and how TBI alters glucose metabolism. Evidence has shown that TBI disrupts the biochemical processing of glucose to energy. This brings to question, "What is the optimal substrate to manage a pediatric TBI patient?" Issues related to glycemic control and alternative substrate metabolism are addressed specifically in regard to pediatric TBI. Research into pediatric glucose metabolism after TBI is limited, and understanding these age-related differences within the pediatric population have great potential to improve support for the injured younger brain. PMID- 29149387 TI - Analgosedation in paediatric severe traumatic brain injury (TBI): practice, pitfalls and possibilities. AB - Analgosedation is a fundamental part of traumatic brain injury (TBI) treatment guidelines, encompassing both first and second tier supportive strategies. Worldwide analgosedation practices continue to be heterogeneous due to the low level of evidence in treatment guidelines (level III) and the choice of analgosedative drugs is made by the treating clinician. Current practice is thus empirical and may result in unfavourable (often hemodynamic) side effects. This article presents an overview of current analgosedation practices in the paediatric intensive care unit (PICU) and addresses pitfalls both in the short and long term. We discuss innovative (pre-)clinical research that can provide the framework for initiatives to improve our pharmacological understanding of analgesic and sedative drugs used in paediatric severe TBI and ultimately facilitate steps towards evidence-based and precision pharmacotherapy in this vulnerable patient group. PMID- 29149388 TI - Problems of reconstructive cranioplasty after traumatic brain injury in children. AB - Cranial repair after traumatic brain injury in children is still burdened by unsolved problems and controversial issues, mainly due to the high rate of resorption of autologous bone as well as the absence of valid alternative material to replace the autologous bone. Indeed, inert biomaterials are associated to satisfactory results in the short period but bear the continuous risk of complications related to the lack of osteointegration capacity. Biomimetic materials claiming osteoconductive properties that could balance their mechanical limits seem to allow good cranial bone reconstruction. However, these results should be confirmed in the long term and in larger series. Further complicating factors that may affect cranial reconstruction after head injury should be identified in the possible associated alterations of CSF dynamics and in difficulties to manage the traumatic skin lesion and the surgical wound, which also might impact on the cranioplasty outcome. All the abovementioned considerations should be taken into account when dealing with the cranial reconstruction after decompressive craniectomy in children. PMID- 29149389 TI - Autoregulation in paediatric TBI-current evidence and implications for treatment. AB - BACKGROUND: Children who survive acute traumatic brain injury are at risk of death from subsequent brain swelling and secondary injury. Strict physiologic management in the ICU after traumatic brain injury is believed to be key to survival, and cerebral perfusion pressure is a prominent aspect of post brain injury care. However, optimal cerebral perfusion pressure targets for children are not known. Autoregulation monitoring has been used to delineate individualized optimal perfusion pressures for patients with traumatic brain injury. The methods to do so are diverse, confusing, and not universally validated. METHODS: In this manuscript, we discuss the history of autoregulation monitoring, outline and categorize the methods used to measure autoregulation, and review the available validation data for methods used to monitor autoregulation. CONCLUSIONS: Impaired autoregulation after traumatic brain injury is associated with a poor prognosis. Observational data suggests that optimal neurologic outcome and survival are associated with optimal perfusion pressure defined by autoregulation monitoring. No randomized, controlled, interventional data is available to assess autoregulation monitoring after pediatric traumatic brain injury. PMID- 29149390 TI - Decompressive craniectomy and CSF disorders in children. AB - INTRODUCTION: Decompressive craniectomy (DC) is a lifesaving procedure but is associated to several post-operative complications, namely cerebrospinal fluid (CSF) dynamics impairment. The aim of this multicentric study was to evaluate the incidence of such CSF alterations after DC and review their impact on the overall outcome. MATERIAL AND METHODS: We performed a retrospective multicentric study to analyze the CSF disorders occurring in children aged from 0 to 17 years who had undergone a DC for traumatic brain injury (TBI) in the major Departments of Pediatric Neurosurgery of France between January 2006 and August 2016. RESULTS: Out of 150 children, ranging in age between 7 months and 17 years, mean 10.75 years, who underwent a DC for TBI in 10 French pediatric neurosurgical centers. Sixteen (6 males, 10 females) (10.67%) developed CSF disorders following the surgical procedure and required an extrathecal CSF shunting. External ventricular drainage increased the risk of further complications, especially cranioplasty infection (p = 0.008). CONCLUSION: CSF disorders affect a minority of children after DC for TBI. They may develop early after the DC but they may develop several months after the cranioplasty (8 months), consequently indicating the necessity of clinical and radiological close follow-up after discharge from the neurosurgical unit. External ventricular drainage and permanent CSF shunt placement increase significantly the risk of cranioplasty infection. PMID- 29149391 TI - Decompressive craniectomy for traumatic intracranial hypertension: application in children. AB - Traumatic brain injury remains prevalent in children, particularly within the adolescent age group. In severe injury, the priority of treatment is to stabilise the patient initially and prevent the evolution of brain swelling and secondary ischaemia using tiers of medical therapy. The final stage of intervention for such patients is a decompressive craniectomy. Here in, we identify the current evidence for performing decompressive crainectomy in children including the results from the RESCUEicp study. PMID- 29149392 TI - When in doubt, sit it out! Pediatric concussion-an update. AB - Concussion is a major public health issue that has received much publicity in recent years. Reported concussions are increasing across all ages, including the highest rates in pediatric age ranges. Due to the age-related physiological responses and differential recovery of symptoms after concussion, special consideration must be given to youth concussions. Concussion can affect each child differently and likely affects children differently than adults. Until the past decade, there has been a scarcity of scientifically rigorous studies examining concussions in children. This increasing amount of research and consensus has begun to influence the definition, evaluation, management, return to school and play recommendations, prevention, and education relating to pediatric concussion. The purpose of this article is a review of relevant research published in the last few years (2015-2017) with highlights of these updates summarized for clinical use. PMID- 29149393 TI - Challenges in minor TBI and indications for head CT in pediatric TBI-an update. AB - INTRODUCTION: Pediatric head trauma is one of the commonest presentations to emergency departments. Over 90% of such head injuries are considered mild, but still present risk acute clinical deterioration and longer term morbidity. Identifying which children are at risk of clinically important brain injuries remains challenging and much of the data on minor head injuries is based on the adult population. CHALLENGES IN PEDIATRICS: Children, however, are different, both anatomically and in terms of mechanism of injury, to adults and, even within the pediatric group, there are differences with age and stage of development. IMAGING: CT scans have added to the repertoire of clinicians in the assessment of pediatric head injury population, but judicious use is required given radiation exposure, malignancy risk, and resource constraints. Guidelines and head injury rules have been developed, for adults and children, to support decision-making in the emergency department though whether their use is applicable to all population groups is debatable. Further challenges in mild pediatric head trauma also include appropriate recommendations for school attendance and physical activity after discharge. FURTHER DEVELOPMENTS: Concern remains for second-impact syndrome and, in the longer term, for post-concussive syndrome and further research in both is still needed. Furthermore, the development of clinical decision rules raises further questions on the purpose of admitting children with minor head injuries and answering this question may aid the evolution of clinical decision guidelines. CONCLUSIONS: The next generation of catheter with homogeneous flow patterns based on parametric designs may represent a step forward for the treatment of hydrocephalus, by possibly broadening their lifespan. PMID- 29149395 TI - Shaken baby syndrome: what certainty do we have? AB - BACKGROUND: Shaken baby syndrome is a common and devastating disease in infants. In spite of its frequency, many controversies persist, regarding the pathophysiology, diagnosis, and management. AIM OF THE STUDY: We reviewed several salient and challenging issues related to SBS, like its pathogenesis, predisposing factors, differential diagnosis, and prevention programs. MATERIAL AND METHODS: We derive arguments from the literature and from our prospective registry of accidental and non-accidental traumas in infants. CONCLUSIONS: Much remains to be understood in SBS, and prevention programs for this entirely man made disaster are still in their infancy. Pediatric neurosurgeons should be involved actively in the medical management and research on SBS. PMID- 29149394 TI - Challenges and opportunities for pediatric severe TBI-review of the evidence and exploring a way forward. AB - Traumatic brain injury (TBI) is a leading killer of children in the developed and developing world. Despite evidence-based guidelines and several recent clinical trials, the progress in developing best practices for children with severe TBI has been slow. This article describes (i) the burden of the disease, (ii) the inadequacies of the evidence-based guidelines, (iii) the failure of the largest clinical trials to prove their primary hypotheses, and (iv) possible advances from an observational cohort study called the Approaches and Decisions for Acute Pediatric TBI (ADAPT) Trial that has recently completed enrollment. PMID- 29149396 TI - A survey on pediatric brain death and on organ transplantation: how did the law amendment change the awareness of pediatric healthcare providers? AB - OBJECTIVES: In Japanese society taking a cautious attitude towards organ transplantation, we investigate how amendment of the Organ Transplant Law which legalized brain death (BD) determination criteria changed the awareness concerning BD and organ transplantation of pediatric healthcare providers. METHODS: The questionnaire survey adopted the bearer method and was sent to members of the Japanese Society of Emergency Pediatrics (JSEP). In both the surveys of 2008 and 2016, the same item "Questionnaire survey on BD and organ transplant" was disseminated. We compared the responses of the two surveys. Statistical analysis was performed using chi-square test. Significance was observed when p value was less than 0.05. RESULTS: Comparison of the results of the two surveys in this study showed a change in awareness of BD/organ transplantation held by pediatric healthcare providers in Japan. It was suggested that Japanese pediatric healthcare providers tend to explain to the family that it is BD with incomplete diagnosis of BD. In the 2016 survey, there is an increase in the response "There is experience of children diagnosed with BD" and it might be due to the effect of the amendment of the law (p = 0.0038). CONCLUSION: In July 2010, the "Amendment of the Organ Transplant Law" became effective, and it became possible to provide organs with family member consent even if the intention of the patient to provide organs was unknown. Since this amendment made it possible to provide children under 15 years of age with BD donors, we assumed that there was a change in awareness concerning BD determination and organ transplantation for pediatric healthcare providers. PMID- 29149397 TI - Heavily Graphitic-Nitrogen Self-doped High-porosity Carbon for the Electrocatalysis of Oxygen Reduction Reaction. AB - Large-scale production of active and stable porous carbon catalysts for oxygen reduction reaction (ORR) from protein-rich biomass became a hot topic in fuel cell technology. Here, we report a facile strategy for synthesis of nitrogen doped porous nanocarbons by means of a simple two-step pyrolysis process combined with the activation of zinc chloride and acid-treatment process, in which kidney bean via low-temperature carbonization was preferentially adopted as the only carbon-nitrogen sources. The results show that this carbon material exhibits excellent ORR electrocatalytic activity, and higher durability and methanol tolerant property compared to the state-of-the-art Pt/C catalyst for the ORR, which can be mainly attributed to high graphitic-nitrogen content, high specific surface area, and porous characteristics. Our results can encourage the synthesis of high-performance carbon-based ORR electrocatalysts derived from widely-existed natural biomass. PMID- 29149398 TI - Heroin-induced acute longitudinally extensive transverse myelopathy. PMID- 29149400 TI - Letter from the President of the EANS. PMID- 29149399 TI - Overcoming HIV Stigma? A Qualitative Analysis of HIV Cure Research and Stigma Among Men Who Have Sex with Men Living with HIV. AB - Despite global progress in HIV stigma reduction, persistent HIV stigma thwarts effective HIV service delivery. Advances in HIV biomedical research toward a cure may shift perceptions of people living with HIV and HIV stigma. The purpose of this study was to examine how men who have sex with men (MSM) living with HIV in Guangzhou, China perceive HIV cure research and its potential impact on MSM and HIV stigma. We conducted in-depth interviews with 26 MSM living with HIV about their perceptions of HIV cure research and the potential impact of an HIV cure on their lives. Thematic coding was used to identify themes and structure the analysis. Two overarching themes emerged. First, participants stated that an HIV cure may have a limited impact on MSM-related stigma. Men noted that most stigma toward MSM was linked to stereotypes of promiscuity and high rates of sexual transmitted diseases in the MSM community and might persist even after a cure. Second, participants believed that an HIV cure could substantially reduce enacted, anticipated, and internalized stigma associated with HIV. These findings suggest that a biomedical cure alone would not remove the layered stigma facing MSM living with HIV. Comprehensive measures to reduce stigma are needed. PMID- 29149401 TI - Introduction: How We Encountered TCTP and Our Purpose in Studying It. AB - In this brief introduction, we describe our encounter with TCTP. Back in 2000, we discovered TCTP in two quite different ways: first, we looked at protein partners of TSAP6 and one of them was TCTP. Then, in collaboration with Sidney Brenner, we performed a high-throughput differential screening comparing the parental cancer cells with revertants. The results indicated that TCTP was of the most differentially expressed genes. These two approaches were carried out only months apart. They guided our research and led to the discoveries of drugs that inhibit the function of TCTP. Much of the preclinical data on sertraline as an inhibitor of TCTP in cancer were obtained with Judith Karp at Johns Hopkins. This drug is now given in combination with Ara-C to patients in a phase I clinical trial for Acute Myeloid Leukemia. We will here detail how all this happened in our lab while working around one central project: tumor reversion. PMID- 29149402 TI - Structural Insights into TCTP and Its Interactions with Ligands and Proteins. AB - The 19-24 kDa Translationally Controlled Tumor Protein (TCTP) is involved in a wide range of molecular interactions with biological and nonbiological partners of various chemical compositions such as proteins, peptides, nucleic acids, carbohydrates, or small molecules. TCTP is therefore an important and versatile binding platform. Many of these protein-protein interactions have been validated, albeit only few received an in-depth structural characterization. In this chapter, we will focus on the structural analysis of TCTP and we will review the available literature regarding its interaction network from a structural perspective. PMID- 29149403 TI - Structure-Function Relationship of TCTP. AB - The translationally controlled tumor protein (TCTP) is a small, multifunctional protein found in most, if not all, eukaryotic lineages, involved in a myriad of key regulatory processes. Among these, the control of proliferation and inhibition of cell death, as well as differentiation, are the most important, and it is probable that other responses are derived from the ability of TCTP to influence them in both unicellular and multicellular organisms. In the latter, an additional function for TCTP stems from its capacity to be secreted via a nonclassical pathway and function in a non-cell autonomous (paracrine) manner, thus affecting the responses of neighboring or distant cells to developmental or environmental stimuli (as in the case of serum TCTP/histamine-releasing factor in mammals and phloem TCTP in Arabidopsis). The additional ability to traverse membranes without a requirement for transmembrane receptors adds to its functional flexibility. The long-distance transport of TCTP mRNA and protein in plants via the vascular system supports the notion that an important aspect of TCTP function is its ability to influence the response of neighboring and distant cells to endogenous and exogenous signals in a supracellular manner. The predicted tridimensional structure of TCTPs indicates a high degree of conservation, more than its amino acid sequence similarity could suggest. However, subtle differences in structure could lead to different activities, as evidenced by TCTPs secreted by Plasmodium spp. Similar structural variations in animal and plant TCTPs, likely the result of convergent evolution, could lead to deviations from the canonical function of this group of proteins, which could have an impact from a biomedical and agricultural perspectives. PMID- 29149404 TI - The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation. AB - The Translational Controlled Tumour Protein TCTP (gene symbol TPT1, also called P21, P23, Q23, fortilin or histamine-releasing factor, HRF) is a highly conserved protein present in essentially all eukaryotic organisms and involved in many fundamental cell biological and disease processes. It was first discovered about 35 years ago, and it took an extended period of time for its multiple functions to be revealed, and even today we do not yet fully understand all the details. Having witnessed most of this history, in this chapter, I give a brief overview and review the current knowledge on the structure, biological functions, disease involvements and cellular regulation of this protein.TCTP is able to interact with a large number of other proteins and is therefore involved in many core cell biological processes, predominantly in the response to cellular stresses, such as oxidative stress, heat shock, genotoxic stress, imbalance of ion metabolism as well as other conditions. Mechanistically, TCTP acts as an anti-apoptotic protein, and it is involved in DNA-damage repair and in cellular autophagy. Thus, broadly speaking, TCTP can be considered a cytoprotective protein. In addition, TCTP facilitates cell division through stabilising the mitotic spindle and cell growth through modulating growth signalling pathways and through its interaction with the proteosynthetic machinery of the cell. Due to its activities, both as an anti-apoptotic protein and in promoting cell growth and division, TCTP is also essential in the early development of both animals and plants.Apart from its involvement in various biological processes at the cellular level, TCTP can also act as an extracellular protein and as such has been involved in modulating whole body defence processes, namely in the mammalian immune system. Extracellular TCTP, typically in its dimerised form, is able to induce the release of cytokines and other signalling molecules from various types of immune cells. There are also several examples, where TCTP was shown to be involved in antiviral/antibacterial defence in lower animals. In plants, the protein appears to have a protective effect against phytotoxic stresses, such as flooding, draught, too high or low temperature, salt stress or exposure to heavy metals. The finding for the latter stress condition is corroborated by earlier reports that TCTP levels are considerably up-regulated upon exposure of earthworms to high levels of heavy metals.Given the involvement of TCTP in many biological processes aimed at maintaining cellular or whole-body homeostasis, it is not surprising that dysregulation of TCTP levels may promote a range of disease processes, foremost cancer. Indeed a large body of evidence now supports a role of TCTP in at least the most predominant types of human cancers. Typically, this can be ascribed to both the anti-apoptotic activity of the protein and to its function in promoting cell growth and division. However, TCTP also appears to be involved in the later stages of cancer progression, such as invasion and metastasis. Hence, high TCTP levels in tumour tissues are often associated with a poor patient outcome. Due to its multiple roles in cancer progression, TCTP has been proposed as a potential target for the development of new anti-cancer strategies in recent pilot studies. Apart from its role in cancer, TCTP dysregulation has been reported to contribute to certain processes in the development of diabetes, as well as in diseases associated with the cardiovascular system.Since cellular TCTP levels are highly regulated, e.g. in response to cell stress or to growth signalling, and because deregulation of this protein contributes to many disease processes, a detailed understanding of regulatory processes that impinge on TCTP levels is required. The last section of this chapter summarises our current knowledge on the mechanisms that may be involved in the regulation of TCTP levels. Essentially, expression of the TPT1 gene is regulated at both the transcriptional and the translational level, the latter being particularly advantageous when a rapid adjustment of cellular TCTP levels is required, for example in cell stress responses. Other regulatory mechanisms, such as protein stability regulation, may also contribute to the regulation of overall TCTP levels. PMID- 29149405 TI - Current Understanding of the TCTP Interactome. AB - Evolutionarily conserved and pleiotropic, the translationally controlled tumor protein (TCTP) is a housekeeping protein present in eukaryotic organisms. It plays an important role in regulating many fundamental processes, such as cell proliferation, cell death, immune responses, and apoptosis. As a result of the pioneer work by Adam Telerman and Robert Amson, the critical role of TCTP in tumor reversion was revealed. Moreover, TCTP has emerged as a regulator of cell fate determination and a promising therapeutic target for cancers. The multifaceted action of TCTP depends on its ability to interact with different proteins. Through this interaction network, TCTP regulates diverse physiological and pathological processes in a context-dependent manner. Complete mapping of the entire sets of TCTP protein interactions (interactome) is essential to understand its various cellular functions and to lay the foundation for the rational design of TCTP-based therapeutic approaches. So far, the global profiling of the interacting partners of TCTP has rarely been performed, but many interactions have been identified in small-scale studies in a specific biological system. This chapter, based on information from protein interaction databases and the literature, illustrates current knowledge of the TCTP interactome. PMID- 29149406 TI - Role and Fate of TCTP in Protein Degradative Pathways. AB - This chapter focuses on published studies specifically concerning TCTP and its involvement in degradation or stabilization of various proteins, and also in its own degradation in different ways. The first part relates to the inhibition of proteasomal degradation of proteins. This can be achieved by masking ubiquitination sites of specific partners, by favoring ubiquitin E3 ligase degradation, or by regulating proteasome activity. The second part addresses the ability of TCTP to favor degradation of specific proteins through proteasome or macroautophagic pathways. The third part discusses about the different ways by which TCTP has been shown to be degraded. PMID- 29149407 TI - Roles of the Translationally Controlled Tumor Protein (TCTP) in Plant Development. AB - The Translationally Controlled Tumor Protein (TCTP) is a conserved protein which expression was associated with several biochemical and cellular functions. Loss of-function mutants are lethal both in animals and in plants, making the identification of its exact role difficult. Recent data using the model plant Arabidopsis thaliana provided the first viable adult knockout for TCTP and helped addressing the biological role of TCTP during organ development and the functional conservation between plants and animals. This chapter summarizes our up to date knowledge about the role of TCTP in plants and discuss about conserved functions and mechanisms between plants and animals. PMID- 29149408 TI - Function of Translationally Controlled Tumor Protein in Organ Growth: Lessons from Drosophila Studies. AB - Regulation of cell growth and proliferation is crucial for development and function of organs in all animals. Genetic defects in growth control can lead to developmental disorders and cancers. Translationally controlled tumor protein (TCTP) is a family of evolutionarily conserved proteins implicated in cancer. Recent studies have revealed multiple roles of TCTP in diverse cellular events, but TCTP functions in vivo are poorly understood in vertebrate systems. We have used Drosophila melanogaster, the fruit fly, as a model organism for genetic dissection of Tctp function. Our studies have shown that Tctp is essential for organ development by regulating growth signaling. Furthermore, it is required for genome stability by promoting DNA repair and chromatin remodeling in the nucleus. Thus, Tctp acts as a multifaceted cytosolic and nuclear factor for regulating organ growth and genome stability. In this chapter, we describe an overview of our findings on Tctp functions in Drosophila and discuss their implications in cancer. PMID- 29149409 TI - Translationally Controlled Tumor Protein (TCTP/HRF) in Animal Venoms. AB - Proteins from TCTP/HRF family were identified as venom toxins of spiders from different genus. We have found a TCTP toxin in the venom gland of Loxosceles intermedia, a venomous spider very common in South Brazil. TCTP from L. intermedia, named LiTCTP, was cloned, produced in a heterologous prokaryotic system, and the recombinant toxin was biochemically characterized. Our results point that LiTCTP is involved in the inflammatory events of Loxocelism, the clinical signs triggered after Loxosceles sp. bite, which include intense inflammatory reaction at the bite site followed by local necrosis. TCTP toxins were also identified in spiders from different genus. There are very few articles about TCTP toxins in other venomous animals in the literature, although a NCBI database search on the protein sequences reveals TCTP on snake's venom glands transcriptomic and genomic studies. Studies on TCTP as a venom toxin are very few and its biological role as a venom component in prey capture is still unknown. PMID- 29149410 TI - Tctp in Neuronal Circuitry Assembly. AB - Although tctp expression in many areas of the human brain was reported more than 15 years ago, little was known about how it functions in neurons. The early notion that Tctp is primarily expressed in mitotic cells, together with reports suggesting a relative low abundance in the brain, has perhaps potentiated this almost complete disregard for the study of Tctp in the context of neuron biology. However, recent evidence has challenged this view, as a number of independent genome-wide profiling studies identified tctp mRNA among the most enriched in the axonal compartment across diverse neuronal populations, including embryonic retinal ganglion cells. Considering the emerging parallels between axon guidance and cancer cell invasion, the axonal expression of cancer-associated tctp was suggestive of it holding an unexplored role in the wiring of neuronal circuits. Our study revealed that Tctp is necessary for the accurate and timely development of axon projections during the formation of vertebrate retinal circuits via its association with the survival machinery of the axon. Globally, the findings indicate that compromised pro-survival signaling in Tctp-deficient axons results in mitochondrial dysfunction and a subsequent decrease in axonal mitochondrial density. These effects likely translate into a metabolic state inadequate to support the normal guidance and extension processes of a developing axon. PMID- 29149411 TI - Elusive Role of TCTP Protein and mRNA in Cell Cycle and Cytoskeleton Regulation. AB - Translationally Controlled Tumor-associated Protein (TCTP) is a small, 23 kDa multifunctional and ubiquitous protein localized both in the cytoplasm and in the nucleus of eukaryotic cells. It is evolutionarily highly conserved. Certain aspects of its structure show remarkable similarities to guanine nucleotide-free chaperons Mss4 and Dss4 suggesting that at least some functions of TCTP may depend on its chaperon-like action on other proteins. Besides other functions, TCTP is clearly involved in cell cycle regulation. It is also regulated in a cell cycle-dependent manner suggesting a reciprocal interaction between this protein and the cell cycle-regulating machinery. TCTP also interacts with the cytoskeleton, mostly with actin microfilaments (MFs) and microtubules (MTs). It regulates the cytoskeleton organization and through this action it also influences cell shape and motility. The exact role of TCTP in cell cycle and cytoskeleton regulation is certainly not fully understood. In this chapter, we summarize recent data on cell cycle and cytoskeletal aspects of TCTP regulatory role. PMID- 29149412 TI - The Translationally Controlled Tumor Protein and the Cellular Response to Ionizing Radiation-Induced DNA Damage. AB - The absorption of ionizing radiation by living cells can directly disrupt atomic structures, producing chemical and biological changes. It can also act indirectly through radiolysis of water, thereby generating reactive chemical species that may damage nucleic acids, proteins, and lipids. Together, the direct and indirect effects of radiation initiate a series of biochemical and molecular signaling events that may repair the damage or culminate in permanent physiological changes or cell death. In efforts to gain insight into the mechanisms underlying these effects, we observed a prominent upregulation of the Translationally Controlled Tumor Protein (TCTP) in low dose/low dose rate 137Cs gamma-irradiated cells that was associated with adaptive responses that reduced chromosomal damage to a level lower than what occurs spontaneously. Therefore, TCTP may support the survival and genomic integrity of irradiated cells through a role in the DNA damage response. Consistent with this postulate, TCTP was shown to physically interact with ATM, an early sensor of DNA damage, and to exist in a complex with gammaH2A.X, in agreement with its distinct localization with the foci of the DNA damage marker proteins gammaH2A.X, 53BP1, and P-ATM. Cells lacking TCTP failed to repair chromosomal damage induced by gamma-rays. Further, TCTP was shown to interact with the DNA-binding subunits, Ku70 and Ku80, of DNA-PK, a major participant in nonhomologous end joining of DNA double strand breaks. Moreover, TCTP physically interacted with p53, and its knockdown attenuated the radiation induced G1 delay, but prolonged the G2 delay. Here, we briefly review the biochemical events leading to DNA damage by ionizing radiation and to its sensing and repair, and highlight TCTP's critical role in maintaining genomic integrity in response to DNA-damaging agents. PMID- 29149413 TI - TCTP Has a Crucial Role in the Different Stages of Prostate Cancer Malignant Progression. AB - Prostate cancer (PC) is the second most common cause of cancer-related mortality in men in the western world after lung cancer. Many patients are not candidates for resection given the advanced stage of their cancer. The primary treatment for advanced PC is the castration therapy which supresses the production of androgens, hormone that promotes PC growth. Despite the efficiency of the castration therapy, most patients develop castration resistant disease which remains uncurable. Clearly, novel approaches are required to effectively treat castration resistant PC (CRPC). New strategies that identify the molecular mechanisms by which PC becomes resistant to conventional therapies may enable the identification of novel therapeutic targets that could improve clinical outcome. Recent studies have demonstrated the implication of TCTP's over-expression in PC and CRPC, and its role in resistance to treatment. TCTP's interaction with p53 and their negative feedback loop regulation have also been described to be causal for PC progression and invasion. A novel nanotherapy that inhibits TCTP has been developed as a new therapeutical strategy in CRPC. This chapter will highlight the role of TCTP as new therapeutic target in PC, in particular, therapy resistant advanced PC and report the development of novel nanotherapy against TCTP that restore treatment-sensitivity in CRPC that deserve to be tested in clinical trial. PMID- 29149414 TI - Role of TCTP for Cellular Differentiation and Cancer Therapy. AB - The translationally controlled tumor protein (TCTP) is a highly conserved protein that is regulated due to a high number of extracellular stimuli. TCTP has an important role for cell cycle and normal development. On the other side, tumor reversion and malignant transformation have been associated with TCTP. TCTP has been found among the 12 genes that are differentially expressed during mouse oocyte maturation, and an overexpression of this gene was reported in a wide variety of different cancer types. Its antiapoptotic effect is indicated by the interaction with several proapoptotic proteins of the Bcl-2 family and the p53 tumor suppressor protein. In this article, we draw attention to the role of TCTP in cancer, especially, focusing on cell differentiation and tumor reversion, a biological process by which highly tumorigenic cells lose their malignant phenotype. This protein has been shown to be the most strongly downregulated protein in revertant cells compared to the parental cancer cells. Decreased expression of TCTP results either in the reprogramming of cancer cells into reversion or apoptosis. As conventional chemotherapy is frequently associated with the development of drug resistance and high toxicity, the urge for the development of new or additional scientific approaches falls into place. Differentiation therapy aims at reinducing differentiation backward to the nonmalignant cellular state. Here, different approaches have been reported such as the induction of retinoid pathways and the use of histone deacetylase inhibitors. Also, PPARgamma agonists and the activation of the vitamin D receptor have been reported as potential targets in differentiation therapy. As TCTP is known as the histamine-releasing factor, antihistaminic drugs have been shown to target this protein. Antihistaminic compounds, hydroxyzine and promethazine, inhibited cell growth of cancer cells and decreased TCTP expression of breast cancer and leukemia cells. Recently, we found that two antihistaminics, levomepromazine and buclizine, inhibited cancer cell growth by direct binding to TCTP and induction of cell differentiation. These data confirmed that TCTP is an exquisite target for anticancer differentiation therapy and antihistaminics have potential to be lead compounds for the direct interaction with TCTP as new inhibitors of human TCTP and tumor growth. PMID- 29149415 TI - Targeting TCTP with Sertraline and Thioridazine in Cancer Treatment. AB - We have initially demonstrated in knocking down experiments that decreasing TCTP in cancer cells leads in some tissues to cell death while in others to a complete reorganization of the tumor into architectural structures reminiscent of normal ones. Based on these experiments and a series of other findings confirming the key role of TCTP in cancer, it became important to find pharmacological compounds to inhibit its function, and this became for us a priority. In the present text, we explain in detail the experiments that were performed and the perspectives of sertraline in cancer treatment, as this became today a reality with a clinical study that started in collaboration with Columbia University and Johns Hopkins University. PMID- 29149416 TI - History of Histamine-Releasing Factor (HRF)/Translationally Controlled Tumor Protein (TCTP) Including a Potential Therapeutic Target in Asthma and Allergy. AB - Histamine-releasing factor (HRF) also known as translationally controlled tumor protein (TCTP) is a highly conserved, ubiquitous protein that has both intracellular and extracellular functions. Here we will highlight the subcloning of the molecule, its clinical implications, as well as an inducible-transgenic mouse. Particular attention will be paid to its extracellular functioning and its potential role as a therapeutic target in asthma and allergy. The cells and the cytokines that are produced when stimulated or primed by HRF/TCTP will be detailed as well as the downstream signaling pathway that HRF/TCTP elicits. While it was originally thought that HRF/TCTP interacted with IgE, the finding that cells not binding IgE also respond to HRF/TCTP called this interaction into question. HRF/TCTP or at least its mouse counterpart appears to interact with some, but not all IgE and IgG molecules. HRF/TCTP has been shown to activate multiple human cells including basophils, eosinophils, T cells, and B cells. Since many of the cells that are activated by HRF/TCTP participate in the allergic response, the extracellular functions of HRF/TCTP could exacerbate the allergic, inflammatory cascade. Particularly exciting is that small molecule agonists of the phosphatase SHIP-1 have been shown to modulate the P13 kinase/AKT pathway and may control inflammatory disorders. This review discusses this possibility in light of HRF/TCTP. PMID- 29149417 TI - SPL13 regulates shoot branching and flowering time in Medicago sativa. AB - KEY MESSAGE: Our results show SPL13 plays a crucial role in regulating vegetative and reproductive development in Medicago sativa L. (alfalfa), and that MYB112 is targeted and downregulated by SPL13 in alfalfa. We previously showed that transgenic Medicago sativa (alfalfa) plants overexpressing microRNA156 (miR156) show a bushy phenotype, reduced internodal length, delayed flowering time, and enhanced biomass yield. In alfalfa, transcripts of seven SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors, including SPL13, are targeted for cleavage by miR156. Thus, association of each target SPL gene to a trait or set of traits is essential for developing molecular markers for alfalfa breeding. In this study, we investigated SPL13 function using SPL13 overexpression and silenced alfalfa plants. Severe growth retardation, distorted branches and up curled leaves were observed in miR156-impervious 35S::SPL13m over-expression plants. In contrast, more lateral branches and delayed flowering time were observed in SPL13 silenced plants. SPL13 transcripts were predominantly present in the plant meristems, indicating that SPL13 is involved in regulating shoot branch development. Accordingly, the shoot branching-related CAROTENOID CLEAVAGE DIOXYGENASE 8 gene was found to be significantly downregulated in SPL13 RNAi silencing plants. A R2R3-MYB gene MYB112 was also identified as being directly silenced by SPL13 based on Next Generation Sequencing-mediated transcriptome analysis and chromatin immunoprecipitation assays, suggesting that MYB112 may be involved in regulating alfalfa vegetative growth. PMID- 29149418 TI - Randomized, multicenter trial of lateral Trendelenburg versus semirecumbent body position for the prevention of ventilator-associated pneumonia. AB - PURPOSE: The lateral Trendelenburg position (LTP) may hinder the primary pathophysiologic mechanism of ventilator-associated pneumonia (VAP). We investigated whether placing patients in the LTP would reduce the incidence of VAP in comparison with the semirecumbent position (SRP). METHODS: This was a randomized, multicenter, controlled study in invasively ventilated critically ill patients. Two preplanned interim analyses were performed. Patients were randomized to be placed in the LTP or the SRP. The primary outcome, assessed by intention-to-treat analysis, was incidence of microbiologically confirmed VAP. Major secondary outcomes included mortality, duration of mechanical ventilation, and intensive care unit length of stay. RESULTS: At the second interim analysis, the trial was stopped because of low incidence of VAP, lack of benefit in secondary outcomes, and occurrence of adverse events. A total of 194 patients in the LTP group and 201 in the SRP group were included in the final intention-to treat analysis. The incidence of microbiologically confirmed VAP was 0.5% (1/194) and 4.0% (8/201) in LTP and SRP patients, respectively (relative risk 0.13, 95% CI 0.02-1.03, p = 0.04). The 28-day mortality was 30.9% (60/194) and 26.4% (53/201) in LTP and SRP patients, respectively (relative risk 1.17, 95% CI 0.86 1.60, p = 0.32). Likewise, no differences were found in other secondary outcomes. Six serious adverse events were described in LTP patients (p = 0.01 vs. SRP). CONCLUSIONS: The LTP slightly decreased the incidence of microbiologically confirmed VAP. Nevertheless, given the early termination of the trial, the low incidence of VAP, and the adverse events associated with the LTP, the study failed to prove any significant benefit. Further clinical investigation is strongly warranted; however, at this time, the LTP cannot be recommended as a VAP preventive measure. CLINICALTRIALS. GOV IDENTIFIER: NCT01138540. PMID- 29149419 TI - Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness. AB - Although a growing body of evidence indicates that phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in active (H3K4me3) and repressive (H3K27me3) histone modifications accompanying the repression of glioblastoma stem-like cells tumorigenicity. Genes with changing histone marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, highlighting a previously unsuspected association between repression of ARNT2 and loss of cell tumorigenicity. Immunohistochemistry confirmed ARNT2 expression in cell sub-populations within proliferative zones of patients' glioblastoma. Decreased ARNT2 expression was consistently observed in non tumorigenic glioblastoma cells, compared to tumorigenic cells. Moreover, ARNT2 expression correlated with a tumorigenic molecular signature at both the tissue level within the tumor core and at the single cell level in the patients' tumors. We found that ARNT2 knockdown decreased the expression of SOX9, POU3F2 and OLIG2, transcription factors implicated in glioblastoma cell tumorigenicity, and repressed glioblastoma stem-like cell tumorigenic properties in vivo. Our results reveal ARNT2 as a pivotal component of the glioblastoma cell tumorigenic signature, located at a node of a transcription factor network controlling glioblastoma cell aggressiveness. PMID- 29149420 TI - Blood clearance and occupational exposure for 177Lu-DOTATATE compared to 177Lu PSMA radionuclide therapy. AB - The main target of this work is to examine blood clearance and external exposure for 177Lu-DOTATATE compared with new emerging 177Lu-PSMA therapy. Blood clearance and radiation exposure of 31 patients treated with 5.5 +/- 1.1 GBq 177Lu-DOTATATE were compared to those of 23 patients treated with 7.4 GBq 177Lu-PSMA. Dose rates were measured at several distances and time points up to 120 h after treatment. Blood samples were collected conjunctively after infusion. Caregiver's cumulative dose was measured by means of an OSL (optically stimulated luminescence) dosimeter for 4-5 days and medical staff's dose was also estimated using electronic personal dosimeters. Finger dose was determined via ring TLD (Thermoluminescence Dosimeter) for radiopharmacists and nurses. Dose rates due to 177Lu-DOTATATE at a distance of 1 m, 4 h and 6 h after infusion, were 3.0 +/- 2.8 and 2 +/- 1.9 uSv/(h GBq), respectively, while those due to 177Lu-PSMA were 3.1 +/- 0.8 and 2.2 +/- 0.9 uSv/(h GBq). Total effective dose of 17 caregivers was 100-200 uSv for 177Lu-DOTATATE therapy. Mean effective doses to nurses and radiopharmacists were 5 and 4 uSv per patient, respectively, while those for physicists and physicians were 2 uSv per patient. For 177Lu-DOTATATE, effective half-life in blood and early elimination phase were 0.31 +/- 0.13 and 4.5 +/- 1 h, while they were found as 0.4 +/- 0.1 and 5 +/- 1 h, respectively, for 177Lu PSMA. The first micturition time following 177Lu-DOTATATE infusion was noted after 36 +/- 14 min, while the second and third voiding times were after 74 +/- 9 and 128 +/- 41 min, respectively. It is concluded that blood clearance and radiation exposure for 177Lu-DOTATATE are very similar to those for 177Lu-PSMA, and both treatment modalities are reasonably reliable for outpatient treatment, since the mean dose rate [2.1 uSv/(h GBq)] decreased below the dose rate that allows release of the patient from the hospital (20 uSv/h) after 6 h at 1 m distance. PMID- 29149421 TI - Kribbella podocarpi sp. nov., isolated from the leaves of a yellowwood tree (Podocarpus latifolius). AB - An endophytic actinobacterial strain was isolated from a yellowwood tree growing on the slope of Devil's Peak, Cape Town, South Africa. Analysis of the 16S rRNA gene showed that the strain belongs to the genus Kribbella. Phylogenetic analyses using the 16S rRNA gene and multilocus sequence analysis using the concatenated gene sequences of the gyrB, rpoB, relA, recA and atpD genes showed that strain YPL1T is closely related to the type strains of Kribbella karoonensis and Kribbella shirazensis. DDH experiments showed that strain YPL1T is a distinct genomic species from its close phylogenetic relative, K. karoonensis Q41T. Physiological comparisons further showed that strain YPL1T is phenotypically distinct from the type strains of Kribbella jejuensis, Kribbella aluminosa, K. karoonensis, K. shirazensis and Kribbella swartbergensis. Strain YPL1T is thus presented as the type strain of a novel species, for which the name Kribbella podocarpi sp. nov. (= DSM 29424T = NRRL B-65063T), is proposed. PMID- 29149422 TI - Interrelationships among hydrogen permeation, physiochemical properties and early adsorption abilities of titanium. AB - This study aimed to investigate if the titanium samples with low hydrogen permeation which treated with a novel etching combination: phosphoric acid and sodium fluoride could influence the surface physiochemical properties and early adsorption ability. Titanium samples were treated with three different concentrations of the new formula, as groups A, B and C, and treated with the traditional etching formula, as group T. Zeta potential, contact angle, X-ray photoelectron spectroscopy (XPS) and fibronectin (FN)/vitronectin (VN) adsorption of Sprague-Dawley (SD) rat tibial osteotomies in the initial 30min and MG-63 adsorption in the initial 24 h were detected. Basing on the results of trails and pearson correlation analysis, the low hydrogen permeation into titanium didn't exert an impact on the surface morphology and surface stability. The adsorptions of F, P, S, acid hydroxyl and basic hydroxyl on the surfaces brought no bear on them as well. Surface concave depth and surface skewness showed highly positive correlation and moderate negative correlation with adsorption ability, respectively. Therefore, the surface morphology of titanium treated with the novel etching formula plays the only and primary role on the early adsorption. Because of its specific surface topography, group C showed the best performance which possessed slightly superiority than those of group B and group T, and with the lowest being group A. The low hydrogen permeation into titanium substrate was just benefit for improving the titanium mechanical properties, but not for the surface biochemical traits. PMID- 29149423 TI - Structural and Visible-Near Infrared Optical Properties of Cr-Doped TiO2 for Colored Cool Pigments. AB - Chromium-doped TiO2 pigments were synthesized via a solid-state reaction method and studied with X-ray diffraction, SEM, XPS, and UV-VIS-NIR reflectance spectroscopy. The incorporation of Cr3+ accelerates the transition from the anatase phase to the rutile phase and compresses the crystal lattice. Moreover, the particle morphology, energy gap, and reflectance spectrum of Cr-doped TiO2 pigments is affected by the crystal structure and doping concentration. For the rutile samples, some of the Cr3+ ions are oxidized to Cr4+ after sintering at a high temperature, which leads to a strong near-infrared absorption band due to the 3A2 -> 3 T1 electric dipole-allowed transitions of Cr4+. And the decrease of the band gap causes an obvious redshift of the optical absorption edges as the doping concentration increases. Thus, the VIS and near-infrared average reflectance of the rutile Ti1 - x Cr x O2 sample decrease by 60.2 and 58%, respectively, when the Cr content increases to x = 0.0375. Meanwhile, the color changes to black brown. However, for the anatase Ti1 - x Cr x O2 pigments, only the VIS reflection spectrum is inhibited by forming some characteristic visible light absorption peaks of Cr3+. The morphology, band gap, and NIR reflectance are not significantly affected. Finally, a Cr-doped anatase TiO2 pigment with a brownish-yellow color and 90% near-infrared reflectance can be obtained. PMID- 29149424 TI - Botanical origin and chemical constituents of commercial Saposhnikoviae radix and its related crude drugs available in Shaanxi and the surrounding regions. AB - Saposhnikoviae radix (SR) is described in the Japanese Pharmacopoeia as a crude drug derived from the root of Saposhnikovia divaricata Schischkin (Umbelliferae). According to Flora of China, the root of Peucedanum ledebourielloides K. F. Fu is used as a regional substitute for SR. Therefore, we surveyed the botanical origin of the drug used in China, especially Shaanxi and the surrounding regions, through nucleotide sequence analysis of the internal transcribed spacer region of rDNA. As a result, several samples from Shaanxi () and Shanxi () provinces were identified as Peucedanum ledebourielloides. To prevent this substitute from being distributed as genuine SR, we developed a thin-layer chromatography analysis condition to enable a specific compound of this species to be easily detected. The specific compound was identified as xanthalin, based on 1D- and 2D-NMR and high-resolution mass spectrometry data. The established TLC conditions were as follows-extraction solvent, n-hexane; applied volume, 5 uL; chromatographic support, silica gel; developing solvent, n-hexane:ethyl acetate:acetic acid (20:10:1); developing length, 7 cm; detection, UV (365 nm); R f value, 0.4 (blue fluorescence; xanthalin). PMID- 29149425 TI - Correction to: Efficacy and safety of full-length pegylated recombinant factor VIII with extended half-life in previously treated patients with hemophilia A: comparison of data between the general and Japanese study populations. AB - The authors would like to correct the error in Table 2 in the original publication of the article. The "Blood type" is not described in any part of "Results" and "Discussion" and had no impact on the conclusion hence the bottom of the table is removed. PMID- 29149426 TI - Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma. AB - PURPOSE: L-type amino acid transporter 1 (LAT1) is linked to tumor cell proliferation, angiogenesis, and survival in various human cancers. Although the expression of LAT1 was identified as a significant prognostic predictor after surgery in patients with pancreatic ductal adenocarcinoma (PDAC), little is known about the clinical significance of LAT1 as a chemotherapeutic resistance factor in PDAC. METHODS: A total of 110 patients with surgically resected PDAC were retrospectively reviewed as the training set. Immunohistochemical staining of resected tumor specimens was assessed using anti-LAT1 antibodies. In vitro analysis of chemotherapy resistance and LAT1 function using PDAC cell lines was also performed. RESULTS: The rate of high expression of LAT1 was 64.1% (71/110). The high expression of LAT1 protein was significantly associated with tumor differentiation, tumor depth (T factor), lymph node metastasis, venous invasion, recurrence, and clinical response. By multivariate analysis, LAT1 was validated as an independent prognostic factor for predicting worse survival after surgery. We analyzed the TCGA data set and obtained similar results that the survival rates of SLC7A5 high expression group were poorer than that of low expression group. LAT1 could successfully predict the outcome of patients who received adjuvant chemotherapy after surgery (n = 88) and systemic chemotherapy after recurrence (n = 56). All patients with high LAT1 expression were non-responders, whereas approximately 30% of the patients with low LAT1 expression responders (p = 0.0002). By analyzing the TCGA online database, it was found that LAT1 closely correlated with hypoxia-induced genes, such as PTGES, PYGL, and KPNA2. CONCLUSION: LAT1 as an independent prognostic marker is a potential molecular targeting gene to reduce chemoresistance and tumor growth in patients with PDAC, supported by our in vitro study. PMID- 29149427 TI - The impact of the national bowel screening program in the Netherlands on detection and treatment of endoscopically unresectable benign polyps. AB - BACKGROUND: In January 2014, a national bowel cancer screening program started in the Netherlands. The program is being implemented in phases until 2019. Due to this program, an increase in patients referred for a colorectal resection for benign, but endoscopically unresectable polyps, is expected. So far, most resections are performed according to oncological principles despite no pre operative histological diagnosis of malignancy. The aim of this study was to analyze the increase in referred patients during the first year of the screening program and to compare pathological results and clinical outcome of resections of patients undergoing resection for benign polyps before and after implementation of screening. METHODS: Patients referred for colorectal resection without biopsy proven cancer between January 2009 and January December 2014 were identified from a prospectively maintained database. Patients with endoscopically macroscopic features of carcinoma were excluded. RESULTS: Seventy-six patients were included. Forty-seven patients (61.8%) were operated on in the 5 years prior to implementation of the screening program, and 29 patients (38.2%) were operated during the first year of implementation of the screening program. The overall malignancy rate before the introduction of the program was 14.1 and 6.6% after it had started (p = .469). All resections were performed laparoscopically; the conversion rate was 3.9% (n = 3). The overall mortality rate was 2.7% (n = 2), major complications (Clavien-Dindo > 3b) occurred in 11.8% (n = 9) of patients. The anastomotic leakage rate was 3.9% (n = 3). CONCLUSIONS: The number of patients referred for benign polyps tripled after introduction of the screening program. With an overall major morbidity and mortality rate of 11.8%, it seems valid to discuss whether an endoscopic excision with advanced techniques with or without laparoscopic assistance would be preferable in this patient group, accepting a 6.6% reoperation rate for additional oncological resection with lymph node sampling in patients in whom a malignancy is found on histological analysis of the complete polyp. PMID- 29149428 TI - The effect of purse-string approximation versus linear approximation of ileostomy reversal wounds on morbidity rates and patient satisfaction: the 'STOMA' trial. AB - BACKGROUND: Ileostomy reversal is associated with surgical site infection (SSI) rates as high as 37%. Recent literature suggests that employing a purse-string approximation (PSA) of the reversal wound reduces this rate of SSI. Thus we wished to perform a randomised controlled trial to compare SSI rates in purse string versus linear closure (PLC) wounds following ileostomy reversal. METHODS: A randomised, controlled trial was conducted at University Hospital Limerick. Sixty-one patients undergoing ileostomy reversal were included. Thirty-four patients were randomised to PSA and 27 patients to linear closure. The primary endpoint was incidence of SSI and secondary endpoints measured were quality of life and satisfaction with cosmesis. Statistical analysis was performed on a per protocol basis using SPSS version 22.0. RESULTS: Three patients in the PSA group developed an SSI compared to 8 in the PLC group at 30 days (8 vs 30%, p = 0.03). The mean time to SSI diagnosis was faster in the PSA group (3 vs 12.3 days, p = 0.08). Patients who developed SSI experienced a longer mean length of stay (6.8 vs 11.4 days, p = 0.012). On multivariate analysis, PLC was the only predictive factor of SSI formation (p < 0.001). There was no difference in patient satisfaction between the two study groups (p = 0.14). CONCLUSIONS: PSA of wounds following ileostomy reversal significantly reduces SSI formation compared to linear approximation without any effect on patient satisfaction. PMID- 29149429 TI - Population analysis of predictors of difficult intubation with direct laryngoscopy in pediatric patients with and without thyroid disease. AB - PURPOSE: There are no data on the prevalence and predictors of difficult intubation (DI) in pediatric patients with thyroid disease. This study (1) assesses the prevalence of DI in patients with thyroid disease undergoing elective operations, (2) identifies other predictors of DI in children, and (3) evaluates the effect of DI on postoperative care and length-of-stay. METHODS: A single-center retrospective cohort analysis of procedures in patients assigned with an ICD-9 code for thyroid disease between June 2012 and February 2016. A comparative group was created which comprised of patients without thyroid disease receiving orthopedic or urologic surgeries to determine differences in DI prevalence. Univariate analyses compared demographics and intubation details between groups, and logistic regression identified independent variables associated with DI. Patients with and without DI were compared based on procedure duration, PACU-LOS, and escalation-of-care. RESULTS: DI prevalence was greater in the thyroid group (4.9%, 51/1046) compared to the non-thyroid group (2.6%, 33/1289) (OR 1.95, 95% CI 1.25-3.05; p = 0.003). DI was associated with younger age, higher American Society of Anesthesiologists (ASA) class, and smaller body habitus (p < 0.001 for all comparisons). Congenital hypothyroidism (OR 2.49, 95% CI 1.44-4.32; p = 0.002)) and acquired hypothyroidism (OR 2.20, 95% CI 1.42-3.41; p < 0.001) were seen in a greater proportion of DI patients. After adjustment for demographic confounders, age and ASA class were independently associated with DI (p < 0.05), while hypothyroidism did not reach statistical significance (p = 0.077). Direct laryngoscopy (DL) was most frequently used as the successful subsequent maneuver in securing the airway in DI patients. A longer PACU length of-stay was seen after procedures with DI (p < 0.001). CONCLUSION: Elective pediatric surgical patients with thyroid-related diagnoses at our institution had a higher prevalence of DI than those without thyroid disease, but this finding could not be isolated to thyroid pathology. Repeat DL achieves successful intubation in the majority of DI patients. DI patients often require longer recovery times due to prolonged cardiopulmonary monitoring. PMID- 29149431 TI - SEOM clinical guidelines in gestational trophoblastic disease (2017). AB - Gestational trophoblastic disease (GTD) is a rare but curable disease. Recent improvements in diagnosis and molecular biology have resulted in changes in staging and treatment. These guidelines provide evidence-based recommendation on how to manage GTD. PMID- 29149432 TI - Ebola in the Netherlands, 2014-2015: costs of preparedness and response. AB - The recent epidemic of Ebola virus disease (EVD) resulted in countries worldwide to prepare for the possibility of having an EVD patient. In this study, we estimate the costs of Ebola preparedness and response borne by the Dutch health system. An activity-based costing method was used, in which the cost of staff time spent in preparedness and response activities was calculated based on a time recording system and interviews with key professionals at the healthcare organizations involved. In addition, the organizations provided cost information on patient days of hospitalization, laboratory tests, personal protective equipment (PPE), as well as the additional cleaning and disinfection required. The estimated total costs averaged ?12.6 million, ranging from ?6.7 to ?22.5 million. The main cost drivers were PPE expenditures and preparedness activities of personnel, especially those associated with ambulance services and hospitals. There were 13 possible cases clinically evaluated and one confirmed case admitted to hospital. The estimated total cost of EVD preparedness and response in the Netherlands was substantial. Future costs might be reduced and efficiency increased by designating one ambulance service for transportation and fewer hospitals for the assessment of possible patients with a highly infectious disease of high consequences. PMID- 29149433 TI - Predictive values of pulse pressure variation and stroke volume variation for fluid responsiveness in patients with pneumoperitoneum. AB - Animal studies suggest that dynamic predictors remain useful in patients with pneumoperitoneum, but human data is conflicting. Our aim was to determine predictive values of pulse pressure variation (PPV) and stroke volume variation (SVV) in patients with pneumoperitoneum using LiDCORapidTM haemodynamic monitor. Standardised fluid challenges of colloid were administered to patients undergoing laparoscopic procedures, one fluid challenge per patient. Intra-abdominal pressure was automatically held at 12 mmHg. Fluid responsiveness was defined as an increase in nominal stroke index (nSI) >= 10%. Linear regression was used to assess the ability of PPV and SVV to track the changes of nSI and logistic regression and area under the receiver operating curve (AUROC) to assess the predictive value of PPV and SVV for fluid responsiveness. Threshold values for PPV and SVV were obtained using the "gray zone" approach. A p < 0.05 was considered as statistically significant. 56 patients were included in analysis. 41 patients (73%) responded to fluids. Both PPV and SVV tracked changes in nSI (Spearman correlation coefficients 0.34 for PPV and 0.53 for SVV). Odds ratio for fluid responsiveness for PPV was 1.163 (95% CI 1.01-1.34) and for SVV 1.341 (95% CI 1.10-1.63). PPV achieved an AUROC of 0.674 (95% CI 0.518-0.830) and SVV 0.80 (95% CI 0.668-0.932). The gray zone of PPV ranged between 6.5 and 20.5% and that of SVV between 7.5 and 13%. During pneumoperitoneum, as measured by LiDCORapidTM, PPV and SVV can predict fluid responsiveness, however their sensitivity is lower than the one reported in conditions without pneumoperitoneum. Trial registry number: (with the Australian New Zealand Clinical Trials Registry): ACTRN12612000456853. PMID- 29149434 TI - Enhancement of therapeutic DNA vaccine potency by melatonin through inhibiting VEGF expression and induction of antitumor immunity mediated by CD8+ T cells. AB - To be effective, therapeutic cancer vaccines should stimulate both an effective cell-mediated and a robust cytotoxic CD8+ T-cell response against human papillomavirus (HPV)-infected cells to treat the pre-existing tumors and prevent potential future tumors. In this study, the therapeutic experiments were designed in order to evaluate antitumor effect against the syngeneic TC-1 tumor model. The anti-tumor efficacy of a HPV-16 E7 DNA vaccine adjuvanted with melatonin (MLT) was evaluated in a C57BL/6 mouse tumor model by measuring tumor growth post vaccination and the survival rate of tumor-bearing mice, analyzing the specific lymphocyte proliferation responses in control and vaccinated mice by MTT assay. The E7-specific cytotoxic T cells (CTL) were analyzed by lymphocyte proliferation and lactate dehydrogenates (LDH) release assays. IFN-gamma, IL-4 and TNF-alpha secretion in splenocyte cultures as well as vascular endothelial growth factor (VEGF) and IL-10 in the tumor microenvironment were assayed by ELISA. Our results demonstrated that subcutaneous administration of C57BL/6 mice with a DNA vaccine adjuvanted with MLT dose-dependently and significantly induced strong HPV16 E7 specific CD8+ cytotoxicity and IFN-gamma and TNF-alpha responses capable of reducing HPV-16 E7-expressing tumor volume. A significantly higher level of E7 specific T-cell proliferation was also found in the adjuvanted vaccine group. Furthermore, tumor growth was significantly inhibited when the DNA vaccine was combined with MLT and the survival time of TC-1 tumor bearing mice was also significantly prolonged. In vivo studies further demonstrated that MLT decreased the accumulation of IL-10 and VEGF in the tumor microenvironment of vaccinated mice. These data indicate that melatonin as an adjuvant augmented the cancer vaccine efficiency against HPV-associated tumors in a dose dependent manner. PMID- 29149435 TI - Equine herpesvirus type 1 ORF51 encoding UL11 as an essential gene for replication in cultured cells. AB - Equine herpesvirus type 1 (EHV-1) UL11 is a 74-amino-acid tegument protein encoded by ORF51 of the EHV-1 genome. EHV-1 UL11 was previously reported by other researchers using the RacL22 and RacH strains to be nonessential for viral replication in cultured cells. Here, we constructed UL11 mutant viruses including a UL11 null mutant and three C-terminal truncated mutants, for further characterization of EHV-1 UL11 using bacterial artificial chromosome (BAC) technology based on the neuropathogenic strain Ab4p. EHV-1 Ab4p UL11 was localized to juxtanuclear and Golgi regions as reported by other researchers. We found that no progeny viruses were produced by transfection of fetal equine kidney cells and rabbit kidney (RK-13) cells with the UL11 null mutant and truncation mutant BAC DNAs. However, mutant viruses were generated after transfection of RK13-UL11 cells constitutively expressing EHV-1 UL11 with the mutant BAC DNAs. In conclusion, UL11 of EHV-1 Ab4p is essential for replication in cultured cells. PMID- 29149436 TI - Introduction: Special Issue in Honor of Bruce Ransom. PMID- 29149437 TI - A Blinded, Randomized, Placebo-Controlled Study to Investigate the Efficacy and Safety of Ferric Carboxymaltose in Iron-Deficient Patients with Fibromyalgia. AB - INTRODUCTION: This study sought to compare efficacy and safety of ferric carboxymaltose vs. placebo in iron-deficient patients with fibromyalgia. METHODS: This blinded, placebo-controlled, phase 2 study randomized adults with fibromyalgia and Revised Fibromyalgia Impact Questionnaire (FIQR) scores >= 60, ferritin levels < 0.05 ug/ml, and transferrin saturation < 20% (1:1) to receive ferric carboxymaltose [15 mg/kg (up to 750 mg)], or placebo (15 cc normal saline) intravenously on study days 0 and 5. Patients visited the clinic on days 14, 28, and 42 for efficacy and safety assessments. The primary efficacy endpoint was proportion of patients with a >= 13-point improvement from baseline to day 42 in FIQR scale score. Secondary endpoints included changes from baseline in FIQR scale, Brief Pain Inventory (BPI) total score, Medical Outcomes Study (MOS) Sleep scale, Fatigue Visual Numeric Scale (VNS), iron indices (transferrin saturation and ferritin), and safety. RESULTS: The efficacy analysis group comprised 80 patients, and the safety analysis group comprised 81. More ferric carboxymaltose patients (77%) vs. placebo patients (67%) achieved the primary endpoint, but the difference was not significant. Greater improvements from baseline to day 42 were observed for ferric carboxymaltose vs. placebo in FIQR total score, BPI total score, Fatigue VNS score, and iron indices. Mean changes in MOS Sleep scale scores were similar between groups. Ferric carboxymaltose was safe and well tolerated. CONCLUSIONS: Compared with placebo, ferric carboxymaltose improved measures of fibromyalgia severity and was well tolerated. The current results suggest that ferric carboxymaltose shows benefit in iron-deficient patients with concurrent fibromyalgia. FUNDING: Luitpold Pharmaceuticals, Inc. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02409459. PMID- 29149438 TI - Patient-predicted sleep position vs. HST data: a tendency to underestimate supine sleep. AB - PURPOSE: The purpose of this study is to measure people's accuracy when they estimate what proportion of their nightly sleep at home is supine vs. non-supine. METHODS: A series of patients referred for obstructive sleep apnea (OSA) evaluation were asked if they "knew with confidence" how they slept with regard to their body position. "Yes" responders were then asked to estimate what percentage of their sleep was supine vs. non-supine. This value was compared with the actual proportion of supine vs. non-supine sleep that they exhibited in a home sleep test (HST) that followed. RESULTS: We obtained data from 49 subjects who expressed that they "knew with confidence" how they sleep in terms of body position. Subjects in aggregate underestimated their proportion of supine sleep by 21.6% (p < .001). Thirty-nine subjects (80%) slept supine more in the HST whereas 8 (16%) slept supine less compared to their pre-test estimates. Using a common classification of OSA severity, 9 subjects (18%) demonstrated a more severe degree of OSA than would have occurred had they slept as they had predicted. CONCLUSIONS: Subjects in this study frequently underestimated their proportion of supine sleep compared to values measured in an HST. Because of the increased supine sleep they exhibited, the severity of their OSA was often greater in the test than it would have been had the subjects slept as they predicted. Sleep physicians should take into account the tendency of people to underestimate supine sleep. If patients with positional sleep apnea assert that they "always sleep laterally" when at home, they may be underestimating their true night-by-night OSA disease burden. PMID- 29149439 TI - Trends in Utilization of Outpatient Respiratory Syncytial Virus Prophylaxis with Palivizumab among Medicaid- and Commercially Insured Infants. AB - INTRODUCTION: Palivizumab is indicated for the prevention of respiratory syncytial virus (RSV) infection in high-risk children. Previous palivizumab utilization studies examined prior authorization claims but did not examine utilization within insured populations as a whole. This study describes outpatient palivizumab utilization trends and characterizes high-risk infants receiving palivizumab within Medicaid- and commercially insured populations. METHODS: Infants born July 1, 2003 through June 30, 2013 were identified in the MarketScan(r) Multistate Medicaid and Commercial claims databases. Infants with >= 18 months of continuous medical insurance enrollment with pharmacy benefits after birth and evidence of chronic lung disease of prematurity (CLDP), congenital heart disease (CHD), or preterm birth without CLDP or CHD were studied. Palivizumab use and demographic and clinical characteristics were measured in infant subgroups. Outpatient palivizumab utilization rates were calculated for each seasonal year (July-June) and for each infant subgroup. RESULTS: In total, 29,350 (2.1%) Medicaid-insured and 9589 (2.5%) commercially insured infants received palivizumab and had CLDP, CHD, or were born at < 37 weeks gestational age (wGA). Infants with CLDP (82%) and those < 29 wGA (78%) had the highest utilization. Decreases in utilization rates between the 2003-2004 and 2012-2013 seasons were seen among Medicaid-insured infants born at 29-36 wGA (all P < .0001), and commercially insured infants born at 31-32 wGA (P < .0001), 33-34 wGA (P = .055), 35-36 wGA (P < .0001), and with CHD (P = .003). Utilization by month was consistent across subgroups among Medicaid- and commercially insured infants, with most doses administered from November to March. CONCLUSION: Palivizumab use is targeted to a small percentage of infants who are at highest risk of hospitalization for RSV disease. Utilization declined in recent years in both Medicaid- and commercially insured infant groups. Most palivizumab doses were administered from November to March, with most infants receiving <= 5 doses. FUNDING: AstraZeneca. PMID- 29149440 TI - Recent advances in assessment on clear water, soil and air. PMID- 29149441 TI - Evidence on the longitudinal construct validity of major generic and utility measures of health-related quality of life in teens with depression. AB - PURPOSE: To examine the longitudinal construct validity in the assessment of changes in depressive symptoms of widely used utility and generic HRQL instruments in teens. METHODS: 392 teens enrolled in the study and completed HRQL and diagnostic measures as part of the baseline interview. HRQL measures included EuroQol (EQ-5D-3L), Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3), Quality of Well-Being Scale (QWB), Pediatric Quality of Life Inventory (PEDS-QL), RAND-36 (SF-6D), and Quality of Life in Depression Scale (QLDS). Youth completed follow-up interviews 12 weeks after baseline. Sixteen youth (4.1%) were lost to follow-up. We examined correlations between changes in HRQL instruments and the Children's Depression Rating Scale-Revised (CDRS-R) and assessed clinically meaningful change in multi-attribute utility HRQL measures using mean change (MC) and standardized response mean (SRM) among youth showing at least moderate (20%) improvement in depression symptomology. RESULTS: Spearman's correlation coefficients demonstrated moderate correlation between changes in CDRS-R and the HUI2 (r = 0.38), HUI3 (r = 0.42), EQ-5D-3L (r = 0.36), SF-6D (r = 0.39), and PEDS QL (r = 0.39) and strong correlation between changes in CDRS-R and QWB (r = 0.52) and QLDS (r = - 0.71). Effect size results are also reported. Among multi attribute utility measures, all showed clinically meaningful improvements in the sample of youth with depression improvement (HUI2, MC = 0.20, SRM = 0.97; HUI3, MC = 0.32, SRM = 1.17; EQ-5D-3L, MC = 0.08, SRM = 0.51; QWB, MC = 0.11, SRM = 0.86; and SF-6D, MC = 0.12, SRM = 1.02). CONCLUSIONS: Findings support the longitudinal construct validity of included HRQL instruments for the assessment of change in depression outcomes in teens. Results of this study can help inform researchers about viable instruments to include in economic evaluations for this population. PMID- 29149442 TI - Assessment of the relative contribution of volume and concentration changes in Yttrium-90 labelled resin microspheres on ionization chamber measurements. PMID- 29149443 TI - Migration of Interneuron Precursors in the Nascent Cerebellar Cortex. AB - The cerebellum arguably constitutes one of the best characterized central nervous circuits, and its structure, cellular function, and histogenesis have been described in exceptional quantitative detail. A notable exception to this is the development of its inhibitory interneurons, and in particular the extensive migrations of future basket and stellate cells. Here, we used acute slices from 8 day-old mice to assess the migration of Pax2-EGFP-tagged precursors of these cells en route to the molecular layer during their transit through the nascent cerebellar cortex. We document that movement of these cells is highly directed. Their speed and directional persistence are larger in the nascent granule cell layer than in the molecular layer. And they migrate periodically, with periods of effective, directed translocation separated by bouts of rather local movement. Finally, we document that the arrangement of these cells in the adult molecular layer is characterized by clustering. These data are discussed with a focus on potential generative mechanisms for the developmental pattern observed. PMID- 29149444 TI - Morphology, molecular structure, and stable carbon isotopic composition of black carbon (BC) in urban topsoils. AB - Urban soils contain significant amounts of black carbon (BC) from biomass and fossil fuel combustion and regard to be a pool of BC. BC in urban soils has multiple effects on environmental processes in urban system, such as global climate change, air quality, and public health. Urban topsoil samples (0-10 cm) were collected from Anshan, Liaoning Province, northeast China, which is one of the most important old steel industrial bases in China. The BC in urban topsoils was extracted using the density method. Their chemical composition, morphology, molecular structure, and stable carbon isotopic composition were examined using elemental analysis, scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDS), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and stable carbon isotope (delta13C). Elemental analysis shows that carbon content in the BC of studied soils ranged from 64.5 to 78.4%, with the average more than 70%. The O/C atomic ratio of BC is on average 0.18. The BC particle displays different morphology, including porous spherical, irregular porous fragmentary, and blocky shapes. The porous spherical BC particles has atomic molar O/C ratio determined by SEM-EDS ranging from 0.04 to 0.37. XRD indicates that BC exists in mainly combining with mineral phases hematite (Fe2O3), kaolinite (Al2Si2O5(OH)4), quartz (SiO2), and calcite (CaCO3). The FTIR spectra of BC particles show major bands at approximately 3400 cm-1 (O-H), 2920 cm-1 (C = H), 1600 cm-1 (C = C), 1230 cm-1 (C = O), and 1070 cm-1 (C = O). The stable carbon isotope (delta13C) of BC ranges from -24.48 to -23.180/00 with the average of -23.79 +/- 0.390/00. The concentration of BC in the industrial area is significantly (p < 0.05) higher than that in the roadside area. The BC of industrial area is characterized by porous spherical structure, suggesting that they are mainly derived from fossil fuel combustion. Results indicated that a combination of atomic O/C ratio, porous structure, and stable carbon isotopic (delta13C) of BC could reflect effectively the origin of BC in urban topsoils. It could conclude that BC in Anshan urban topsoil was mainly from fossil fuel combustion. PMID- 29149445 TI - The influences of separators on capacitive deionization systems in the cycle of adsorption and desorption. AB - This research focused on the influence of different separator compartments on the performance of capacitive deionization (CDI) cells in terms of brackish water treatment. For comparison, different separators including filter paper(FP), carbon nanotube (CNT), and stainless steel fiber (SSF) on deionization and desorption rate of salt were examined. The best performance was obtained when the CNT separator was packed, followed by SSF and FP. Reducing the cell voltage from 1.2 to 0.4 V decreased the salt removal and electrode regeneration rate of SSF CDI. Electrochemical impedance spectrometry (EIS) analysis revealed that the resistance and specific capacitance of separator materials are essential to the desalination and desorption performance of CDI. The electric double layers (EDLs) accelerated the ion transfer in the flow chamber due to storing excess ions, therefore increasing the desalination and electrode regeneration rate. PMID- 29149446 TI - A Flood of Problems. AB - Hurricane Harvey devastated the Texas coast in late August. Widespread flooding in the Houston area wiped out thousands of homes and businesses, including countless medical facilities and practices. Although the short-term health concerns may be apparent, longer-term effects associated with stress and environmental issues can be harder to spot. PMID- 29149447 TI - A Wealth of Information. AB - The Center for Health Care Research Data at The University of Texas Health Science Center at Houston School of Public Health has earned a certification that will allow it to analyze and report on Medicare claims data from Texas. PMID- 29149448 TI - Crisis in the Country. AB - Since 2010, Texas has seen more rural hospitals close than has any other state, leaving huge gaps in health care; however, the state's rural areas have options for maintaining health care facilities. PMID- 29149449 TI - Facing More Hoops. AB - Opioid abuse has killed tens of thousands of Americans in recent years, prompting health plans to adjust their prescription drug policies, including changing formularies and prior-authorization processes. PMID- 29149450 TI - A prospective, observational cohort study comparing cancer clinical trial availability and enrollment between early adolescents/young adults and children. AB - BACKGROUND: Poor enrollment of adolescents and young adults (AYAs) (ages 15-39 years) onto cancer clinical trials (CCTs) may contribute to inferior survival gains compared with children. In this study, the authors assessed whether differences in CCT availability would explain lower CCT enrollment for early AYAs (eAYAs) (ages 15-21 years). METHODS: This prospective, observational cohort study was conducted at a single academic children's hospital. For consecutive patients who were newly diagnosed with cancer over a 13-month period, it was determined whether an appropriate CCT existed nationally or was available locally and whether enrollment on that CCT occurred. The proportions of eAYAs versus children in each category were compared using the chi-square test. The impact of age and other factors on enrollment status was assessed using logistic regression analysis. RESULTS: Among 216 patients, 58 were eAYAs, and 158 were children. There was no difference in the proportion of eAYAs versus children who had an existing CCT (28 of 58 eAYAs [48.3%] vs 85 of 158 children [53.8%]; P = .47) or an available CCT (23 of 58 eAYAs [39.7%] vs 75 of 158 children [47.5%]; P = .31). However, significantly fewer eAYAs were enrolled when a CCT was available (7 of 23 eAYAs [30.4%] vs 50 of 75 children [67.7%]; P = .002). In multivariable analysis, eAYAs were significantly less likely than children to be enrolled in an available CCT (adjusted odds ratio, 0.22; 95% confidence interval, 0.08-0.62). CONCLUSIONS: Equal proportions of children and eAYAs had CCTs available, but significantly fewer eAYAs were enrolled. These findings suggest that, for eAYAs, factors other than CCT availability are important enrollment barriers and should be addressed. Cancer 2018;124:983-90. (c) 2017 American Cancer Society. PMID- 29149452 TI - Contextual and individual determinants of periodontal disease: Multilevel analysis based on Andersen's model. AB - AIM: To investigate the relationship of contextual and individual factors with periodontal disease in dentate adults and older people using the Andersen's behavioural model. METHODS: Secondary individual data from 6011 adults and 2369 older people from the Brazilian Oral Health Survey (2010) were combined with contextual data for 27 cities. Attachment loss (AL) categories for each sextant were coded and summed to obtain the periodontal disease measure. The association of predisposing, enabling and need characteristics at city and individual level with periodontal disease was assessed using an adapted version of the Andersen's behavioural model. Multilevel Poisson regression was used to estimate rate ratios (RR) and 95% CIs. RESULTS: Periodontal disease was associated with contextual predisposing (RR 0.93; 95% CI = 0.87-0.99) and enabling factors (RR 0.99; 95% CI = 0.98-0.99) in adults. Contextual predisposing was also associated with periodontal disease in older people (RR 0.82; 95% CI = 0.73-0.92). Individual predisposing (age, sex and schooling) and need characteristics (perceived treatment need) were common predictors of periodontal disease in adults and older people. Periodontal disease was also associated with behaviours in the latter age group. CONCLUSION: Contextual predisposing factors and individual characteristics influenced periodontal disease experience in adults and older people. Contextual enabling factors were also meaningful determinants of periodontal disease in the former age group. PMID- 29149451 TI - Transcriptional alterations in hereditary and sporadic nonfunctioning pancreatic neuroendocrine tumors according to genotype. AB - BACKGROUND: Nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) may be sporadic or inherited because of germline mutations associated with von Hippel Lindau disease (VHL) or multiple endocrine neoplasia type 1 (MEN1). The clinical behavior of NFPanNETs is difficult to predict, even in tumors of the same stage and grade. The authors analyzed genotype-specific patterns of transcriptional messenger RNA (mRNA) levels of NFPanNETs to understand the molecular features that determine PanNET phenotype. METHODS: Thirty-two samples were included for genome-wide mRNA gene expression analysis (9 VHL-associated, 10 MEN1-associated, and 9 sporadic NFPanNETs and 4 purified normal islet cell [NIC] samples). Validation of genes was performed by real-time polymerase chain reaction analysis and immunohistochemistry. Gene expression profiles were analyzed by tumor genotype, and pathway analysis was curated. RESULTS: Consensus clustering of mRNA expression revealed separate clustering of NICs, VHL-associated NFPanNETs, and MEN1-associated NFPanNETs; whereas some sporadic tumors clustered with MEN1. Four of 5 MEN1-like sporadic PanNET subtypes had loss of heterozygosity at the MEN1 gene locus. Pathway analysis demonstrated subtype-specific pathway activation, comprising angiogenesis and immune response in VHL; neuronal development in MEN1; protein ubiquitination in the new MEN1/sporadic subtype; and cytokinesis and cilium/microtubule development in sporadic NFPanNETs. Among many genes, platelet derived growth factor receptor beta (PDGFRB), lymphoid enhancer-binding factor-1 (Lef-1), cyclin-dependent kinase 4 (CDK4), and CDK6 were upregulated in VHL or MEN1 NFPanNETs, providing potential subtype-specific treatment targets. CONCLUSIONS: Distinct mRNA expression patterns were identified in sporadic associated, VHL-associated, and MEN1-associated NFPanNETs. The current results uncover new pathways involved in NFPanNETs that are subtype-specific and provide potential new diagnostic or therapeutic targets based on tumor subtype. Cancer 2018;124:636-47. (c) 2017 American Cancer Society. PMID- 29149453 TI - Melatonin and serotonin: Mediators in the symphony of plant morphogenesis. AB - Melatonin and serotonin are important signaling and stress mitigating molecules that play important roles across growth and development in plants. Despite many well-documented responses, a systematic investigation of the entire metabolic pathway (tryptophan, tryptamine, and N-acetylserotonin) does not exist, leaving many open questions. The objective of this study was to determine the responses of Hypericum perforatum (L.) to melatonin, serotonin, and their metabolic precursors. Two well-characterized germplasm lines (#4 and 112) created by mutation and a haploid breeding program were compared to wild type to identify specific responses. Germplasm line 4 has lower regenerative and photosynthetic capacity than either wild type or line 112, and there are documented significant differences in the chemistry and physiology of lines 4 and 112. Supplementation of the culture media with tryptophan, tryptamine, N-acetylserotonin, serotonin, or melatonin partially reversed the regenerative recalcitrance and growth impairment of the germplasm lines. Quantification of phytohormones revealed crosstalk between the indoleamines and related phytohormones including cytokinin, salicylic acid, and abscisic acid. We hypothesize that melatonin and serotonin function in coordination with their metabolites in a cascade of phytochemical responses including multiple pathways and phytohormone networks to direct morphogenesis and protect photosynthesis in H. perforatum. PMID- 29149454 TI - Melatonin alleviates adipose inflammation through elevating alpha-ketoglutarate and diverting adipose-derived exosomes to macrophages in mice. AB - Obesity is associated with macrophage infiltration and metabolic inflammation, both of which promote metabolic disease progression. Melatonin is reported to possess anti-inflammatory properties by inhibiting inflammatory response of adipocytes and macrophages activation. However, the effects of melatonin on the communication between adipocytes and macrophages during adipose inflammation remain elusive. Here, we demonstrated melatonin alleviated inflammation and elevated alpha-ketoglutarate (alphaKG) level in adipose tissue of obese mice. Mitochondrial isocitrate dehydrogenase 2 (Idh2) mRNA level was also elevated by melatonin in adipocytes leading to increase alphaKG level. Further analysis revealed alphaKG was the target for melatonin inhibition of adipose inflammation. Moreover, sirtuin 1 (Sirt1) physically interacted with IDH2 and formed a complex to increase the circadian amplitude of Idh2 and alphaKG content in melatonin inhibited adipose inflammation. Notably, melatonin promoted exosomes secretion from adipocyte and increased adipose-derived exosomal alphaKG level. Our results also confirmed that melatonin alleviated adipocyte inflammation and increased ratio of M2 to M1 macrophages by transporting of exosomal alphaKG to macrophages and promoting TET-mediated DNA demethylation. Furthermore, exosomal alphaKG attenuated signal transducers and activators of transduction-3 (STAT3)/NF-kappaB signal by its receptor oxoglutarate receptor 1 (OXGR1) in adipocytes. Melatonin also attenuated adipose inflammation and deceased macrophage number in chronic jet-lag mice. In summary, our results demonstrate melatonin alleviates metabolic inflammation by increasing cellular and exosomal alphaKG level in adipose tissue. Our data reveal a novel function of melatonin on adipocytes and macrophages communication, suggesting a new potential therapy for melatonin to prevent and treat obesity caused systemic inflammatory disease. PMID- 29149455 TI - Positive effect on patient experience of video information given prior to cardiovascular magnetic resonance imaging: A clinical trial. AB - AIMS AND OBJECTIVES: To evaluate the effect of video information given before cardiovascular magnetic resonance imaging on patient anxiety and to compare patient experiences of cardiovascular magnetic resonance imaging versus myocardial perfusion scintigraphy. To evaluate whether additional information has an impact on motion artefacts. BACKGROUND: Cardiovascular magnetic resonance imaging and myocardial perfusion scintigraphy are technically advanced methods for the evaluation of heart diseases. Although cardiovascular magnetic resonance imaging is considered to be painless, patients may experience anxiety due to the closed environment. DESIGN: A prospective randomised intervention study, not registered. METHODS: The sample (n = 148) consisted of 97 patients referred for cardiovascular magnetic resonance imaging, randomised to receive either video information in addition to standard text-information (CMR-video/n = 49) or standard text-information alone (CMR-standard/n = 48). A third group undergoing myocardial perfusion scintigraphy (n = 51) was compared with the cardiovascular magnetic resonance imaging-standard group. Anxiety was evaluated before, immediately after the procedure and 1 week later. Five questionnaires were used: Cardiac Anxiety Questionnaire, State-Trait Anxiety Inventory, Hospital Anxiety and Depression scale, MRI Fear Survey Schedule and the MRI-Anxiety Questionnaire. Motion artefacts were evaluated by three observers, blinded to the information given. Data were collected between April 2015-April 2016. The study followed the CONSORT guidelines. RESULT: The CMR-video group scored lower (better) than the cardiovascular magnetic resonance imaging-standard group in the factor Relaxation (p = .039) but not in the factor Anxiety. Anxiety levels were lower during scintigraphic examinations compared to the CMR-standard group (p < .001). No difference was found regarding motion artefacts between CMR-video and CMR standard. CONCLUSION: Patient ability to relax during cardiovascular magnetic resonance imaging increased by adding video information prior the exam, which is important in relation to perceived quality in nursing. No effect was seen on motion artefacts. RELEVANCE TO CLINICAL PRACTICE: Video information prior to examinations can be an easy and time effective method to help patients cooperate in imaging procedures. PMID- 29149456 TI - Effect of a thermal care bundle on the prevention, detection and treatment of perioperative inadvertent hypothermia. AB - AIMS AND OBJECTIVES: To improve the prevention, detection and treatment of perioperative inadvertent hypothermia in adult surgical patients by implementing a Thermal Care Bundle. BACKGROUND: Keeping patients normothermic perioperatively prevents adverse surgical outcomes. Hypothermia leads to serious complications including increased risk of surgical bleeding, surgical site infections and morbid cardiac events. The Thermal Care Bundle consists of three elements: (i) assess risk; (ii) record temperature; and (iii) actively warm. DESIGN: A pre- and postimplementation study was conducted to determine the impact of the Thermal Care Bundle on the prevention, detection and treatment of perioperative inadvertent hypothermia. METHODS: The Thermal Care Bundle was implemented using an adapted version of the Institute of Healthcare Improvement's Breakthrough Series Collaborative Model. Data were collected from auditing medical records. RESULTS: Data from 729 patients (pre-implementation: n = 351; postimplementation: n = 378) at four sites were collected between December 2014-January 2016. Improvements were recorded in the percentage of patients with a risk assessment; at least one documented temperature recording per perioperative stage; and appropriate active warming. Despite this, the overall incidence of perioperative inadvertent hypothermia increased postimplementation. CONCLUSION: The Thermal Care Bundle facilitated improved management of perioperative inadvertent hypothermia through increased risk assessment, temperature recording and active warming but did not impact on perioperative inadvertent hypothermia incidence. Increased temperature recording may have more accurately revealed the true extent of perioperative inadvertent hypothermia in this population. RELEVANCE TO CLINICAL PRACTICE: This study showed that a collaborative, context specific implementation method, such as the IHI Breakthrough Series Model, is effective at improving practices, which can improve thermal care. PMID- 29149458 TI - Hormone therapy and patient satisfaction with treatment, in a large cohort of diverse disorders of sex development. AB - OBJECTIVES: To describe and investigate the hormone treatments in individuals with different forms of disorders of sex development (DSD) and the patients' own views on their treatment. DESIGN: Multicentre cross-sectional clinical evaluation, dsd-LIFE in 6 European countries from February 2014 to September 2015. PARTICIPANTS: A total of 1040 adolescents and adults (>=16 years) with different DSD conditions. MAIN OUTCOMES MEASURES: Hormone replacement, information received and patient satisfaction. RESULTS: Included were women with Turner syndrome (301), 46,XX GD (n = 20), and women with 45,X/46XY (n = 24). Individuals with Klinefelter syndrome (n = 218), 46,XX males (n = 6), individuals with different forms of 46,XY DSD (n = 243): 46,XY DSD conditions (n = 222), men with 45,X/46XY (n = 21) 46,XX CAH, (n = 226). Oestrogen +/- progestin was used by 306 (81%) individuals, 72 (19%) received ethinylestradiol and 198 had testosterone treatment. The overall adherence was good, with 10% of women with oestrogen and 5% of those on testosterone had stopped the medication despite 20% reporting dissatisfaction with the treatment, mostly because of psychological side effects. Glucocorticoid replacement in patients with CAH was very seldom stopped. More than 75% were satisfied with the information about the treatment, but the satisfaction with information about treatment options and side effects was lower. CONCLUSIONS: More than 50% in the total cohort had hormone replacement. Although adherence was generally good, this study shows that hormone replacement therapy may be improved. This may be achieved by better individualization of the treatment and by providing specific information to patients regarding both long-term and short-term hormonal effects and side effects. PMID- 29149459 TI - The economic impact of nursing. PMID- 29149457 TI - High mobility group protein B1 controls liver cancer initiation through yes associated protein -dependent aerobic glycolysis. AB - : Emerging studies have suggested that the Hippo pathway is involved in the tumorigenesis of hepatocellular carcinoma (HCC). However, the key regulator of the Hippo pathway in liver tumor metabolic reprogramming remains elusive. Here, we provide evidence that high mobility group box 1 (HMGB1), a chromosomal protein, plays a role in the regulation of the Hippo pathway during liver tumorigenesis. Cre/loxP recombination-mediated HMGB1 depletion in hepatocytes blocks diethylnitrosamine-induced liver cancer initiation in mice, whereas short hairpin RNA-mediated gene silencing of HMGB1 inhibits HCC cell proliferation. Mechanistically, the binding of HMGB1 to GA-binding protein alpha promotes the expression of yes-associated protein (YAP), a major downstream effector of the Hippo pathway that contributes to liver tumorigenesis by inducing hypoxia inducible factor 1alpha (HIF1alpha)-dependent aerobic glycolysis. Like wild-type YAP-complementary DNA, YAP-5SA-S94A can restore HIF1alpha DNA binding activity, glycolysis-associated gene expression, and HIF1alpha-YAP complex formation in YAP knockdown HCC cell lines. In contrast, verteporfin, a reagent targeting the interface between YAP and TEA domain transcription factor, has the ability to block YAP-HIF1alpha complex formation. Notably, genetic or pharmacologic inhibition of the HMGB1-YAP-HIF1alpha pathway confers protection against excessive glycolysis and tumor growth in mice. CONCLUSION: These findings demonstrate that HMGB1 plays a novel role in modulating the YAP-dependent HIF1alpha pathway and shed light on the development of metabolism-targeting therapeutics for HCC chemoprevention. (Hepatology 2018;67:1823-1841). PMID- 29149460 TI - The impact of a prolonged stay in the ICU on patients' fundamental care needs. AB - AIMS AND OBJECTIVES: To explore patients', families' and health professionals' experiences of a long-stay patient in an intensive care unit. BACKGROUND: The fast-paced technologically driven intensive care unit environment, designed for a short patient stay, supports the provision of complex physiologically focused care for those with life-threatening illnesses. Long-stay patients with pronounced fundamental care needs fall outside predicted patient pathways, and nurses can find caring for these patients challenging. DESIGN AND METHODS: A longitudinal, qualitative, multicase study of six cases from four New Zealand units. Case participants were patients, family members, nurses and other health professionals. Data collection methods included observation, conversations, interviews and document review. Data were analysed using thematic analysis, vignette development and trajectory mapping. RESULTS: Challenges and successes of providing fundamental care for long-stay ICU patients are attributed to two interlinked factors. First, the biomedical model influences ICU nursing practices, resulting in prioritising tasks and technology for patient survival while simultaneously devaluing relational and comfort work. Fundamental psychosocial needs such as family presence, comfort, relationships and communication may be unmet. Second, the unit environment and culture have a significant impact on long-stay patients' ICU experiences and form physical and psychological barriers to families being present and involved. Some nurses negotiated these challenges to provide fundamental, patient- and family-centred care by adopting an approach of knowing the patient and these nurses reported satisfaction when seeing patients' positive responses. CONCLUSION: The care environment and culture provide challenges to the provision of patient- and family-centred care for long-stay patients; however, when nurses prioritise knowing their patient these challenges can be overcome and patient and family distress reduced with the potential to improve patient outcomes. RELEVANCE TO CLINICAL PRACTICE: Recognition that patients have fundamental care needs irrespective of the setting where they receive care. Intensive care environments and cultures create challenges for nurses when there is such a heavy burden of physiological needs to be met and technological tasks to be undertaken, with a focus on acuity; however, improving provision fundamental care can result in positive patient outcomes. PMID- 29149462 TI - A multi-institutional study of the perceived barriers and facilitators to implementing evidence-based practice. AB - AIMS AND OBJECTIVES: To examine perceived barriers and facilitators to implementing evidence-based practice among nurses working in psychiatric, geriatric, hospital and community settings in The Bahamas. BACKGROUND: It is evident from previous studies that a number of factors exist which either obstruct or promote the utilisation of research evidence in nursing practice. Identifying these factors is vital to the successful uptake of evidence-based practice in nursing. DESIGN: Descriptive, comparative study. METHOD: Data were collected using self-administered questionnaires. A stratified random sample (n = 100) of registered nurses participated; 5-point Likert-like scales were used to examine nurses' perceptions of barriers and facilitators of evidence-based practice. Descriptive statistics were used to describe demographic characteristics and to compare responses of nurses. RESULTS: Participants were predominantly female (98.4%), in the 25 to <35 years age group (45.9%). Of nurses surveyed, 72.1% had never tried to implement evidence-based practice previously. The greatest barriers identified were as follows: "Inadequate resources for implementing research findings" (85.2%; n = 52) and "Inadequate training in research methods" (83.6%; n = 51). The top facilitators identified were as follows: "Training in research methods" (88.5%; n = 54) and "Organisational policies and protocols that are evidence-based" (86.9%; n = 53). CONCLUSIONS: Nurses generally expressed that they required additional training in research and evidence-based practice concepts. Although some nurses had a desire to implement evidence-based practice to provide quality care and improve patient outcomes, many expressed that they lacked the required resources. The study draws attention to the need for prioritisation of evidence-based practice both at institutional and governmental levels. RELEVANCE TO CLINICAL PRACTICE: Successful adoption of evidence-based practice implies combined efforts of nurses, healthcare providers and policymakers. Further research is needed to determine the best method for successfully incorporating evidence-based practice into nursing practice in The Bahamas. PMID- 29149461 TI - Long noncoding RNAs involve in resistance to Verticillium dahliae, a fungal disease in cotton. AB - Long noncoding RNAs (lncRNAs) have several known functions in plant development, but their possible roles in responding to plant disease remain largely unresolved. In this study, we described a comprehensive disease-responding lncRNA profiles in defence against a cotton fungal disease Verticillium dahliae. We further revealed the conserved and specific characters of disease-responding process between two cotton species. Conservatively for two cotton species, we found the expression dominance of induced lncRNAs in the Dt subgenome, indicating a biased induction pattern in the co-existing subgenomes of allotetraploid cotton. Comparative analysis of lncRNA expression and their proposed functions in resistant Gossypium barbadense cv. '7124' versus susceptible Gossypium hirsutum cv. 'YZ1' revealed their distinct disease response mechanisms. Species-specific (LS) lncRNAs containing more SNPs displayed a fiercer inducing level postinfection than the species-conserved (core) lncRNAs. Gene Ontology enrichment of LS lncRNAs and core lncRNAs indicates distinct roles in the process of biotic stimulus. Further functional analysis showed that two core lncRNAs, GhlncNAT-ANX2 and GhlncNAT-RLP7-silenced seedlings, displayed an enhanced resistance towards V. dahliae and Botrytis cinerea, possibly associated with the increased expression of LOX1 and LOX2. This study represents the first characterization of lncRNAs involved in resistance to fungal disease and provides new clues to elucidate cotton disease response mechanism. PMID- 29149463 TI - Need of support in people with chronic obstructive pulmonary disease. AB - AIM AND OBJECTIVE: The aim of this study was to describe peoples' experiences and expectations of support when living with chronic obstructive pulmonary disease. METHOD: We conducted and analysed face-to-face or telephone interviews with 17 individuals (aged 44-77 years) diagnosed with chronic obstructive pulmonary disease. The interviewer asked open-ended questions aimed at encouraging further narration, and we analysed the participants' narratives using a phenomenological hermeneutical approach. This report adheres to the COREQ guidelines. RESULTS: The overall theme suggests that people with chronic obstructive pulmonary disease describe support as shared knowledge and experiences, based on the following subthemes; similar experiences, the need of genuine professional knowledge, self reliance versus self-blame, and the Internet - feeling safe but uncertain. CONCLUSIONS: People with chronic obstructive pulmonary disease find their strength through shared knowledge and dialogical support with others who have similar experiences and with professionals. A person-centred eHealth approach may be suitable for this group as it offers both collaboration and support. RELEVANCE TO CLINICAL PRACTICE: There is a demand for access to genuine professional knowledge as additional support to patients' own capabilities and needs. Patient associations were assessed as reliable sources of information and to some extent also support, but the importance of access to professional sources was also stressed. PMID- 29149464 TI - Novel intraoperative management in the model for end-stage liver disease-sodium era: Continuous venovenous hemofiltration for severe hyponatremia in liver transplantation. PMID- 29149465 TI - Controlled Sol-Gel Transitions of a Thermoresponsive Polymer in a Photoswitchable Azobenzene Ionic Liquid as a Molecular Trigger. AB - Producing ionic liquids (ILs) that function as molecular trigger for macroscopic change is a challenging issue. Photoisomerization of an azobenzene IL at the molecular level evokes a macroscopic response (light-controlled mechanical sol gel transitions) for ABA triblock copolymer solutions. The A endblocks, poly(2 phenylethyl methacrylate), show a lower critical solution temperature in the IL mixture containing azobenzene, while the B midblock, poly(methyl methacrylate), is compatible with the mixture. In a concentrated polymer solution, different gelation temperatures were observed in it under dark and UV conditions. Light controlled sol-gel transitions were achieved by a photoresponsive solubility change of the A endblocks upon photoisomerization of the azobenzene IL. Therefore, an azobenzene IL as a molecular switch can tune the self-assembly of a thermoresponsive polymer, leading to macroscopic light-controlled sol-gel transitions. PMID- 29149466 TI - Microsecond Timescale Protein Dynamics: a Combined Solid-State NMR Approach. AB - Conformational exchange in proteins is a major determinant in protein functionality. In particular, the MUs-ms timescale is associated with enzymatic activity and interactions between biological molecules. We show here that a comprehensive data set of R1rho relaxation dispersion profiles employing multiple effective fields and tilt angles can be easily obtained in perdeuterated, partly back-exchanged proteins at fast magic-angle spinning and further complemented with chemical-exchange saturation transfer NMR experiments. The approach exploits complementary sources of information and enables the extraction of multiple exchange parameters for MUs-ms timescale conformational exchange, most notably including the sign of the chemical shift differences between the ground and excited states. PMID- 29149467 TI - Geophysical Assessment of Groundwater Potential: A Case Study from Mian Channu Area, Pakistan. AB - An integrated study using geophysical method in combination with pumping tests and geochemical method was carried out to delineate groundwater potential zones in Mian Channu area of Pakistan. Vertical electrical soundings (VES) using Schlumberger configuration with maximum current electrode spacing (AB/2 = 200 m) were conducted at 50 stations and 10 pumping tests at borehole sites were performed in close proximity to 10 of the VES stations. The aim of this study is to establish a correlation between the hydraulic parameters obtained from geophysical method and pumping tests so that the aquifer potential can be estimated from the geoelectrical surface measurements where no pumping tests exist. The aquifer parameters, namely, transmissivity and hydraulic conductivity were estimated from Dar Zarrouyk parameters by interpreting the layer parameters such as true resistivities and thicknesses. Geoelectrical succession of five layer strata (i.e., topsoil, clay, clay sand, sand, and sand gravel) with sand as a dominant lithology was found in the study area. Physicochemical parameters interpreted by World Health Organization and Food and Agriculture Organization were well correlated with the aquifer parameters obtained by geoelectrical method and pumping tests. The aquifer potential zones identified by modeled resistivity, Dar Zarrouk parameters, pumped aquifer parameters, and physicochemical parameters reveal that sand and gravel sand with high values of transmissivity and hydraulic conductivity are highly promising water bearing layers in northwest of the study area. Strong correlation between estimated and pumped aquifer parameters suggest that, in case of sparse well data, geophysical technique is useful to estimate the hydraulic potential of the aquifer with varying lithology. PMID- 29149468 TI - Pneumoparotitis as a complication of long-term oronasal positive airway pressure for sleep apnea. AB - BACKGROUND: Parotid swelling is rarely caused by pneumoparotitis from retrograde insufflation of air into Stensen's duct. Previous reports have identified occupational exposures, self-induced habits, exercise, spirometry, and short-term positive pressure airway ventilation as causes of salivary duct insufflation. METHODS: We present 2 cases of pneumoparotitis in patients on long-term oronasal continuous positive airway pressure (CPAP) for obstructive sleep apnea. RESULTS: A diagnosis of pneumoparotitis was made by CT scan in case 1 and sialography in case 2. Patients were advised to transition from oronasal to nasal-only CPAP. One patient was successfully transferred and had good symptomatic improvement, whereas the second patient did not tolerate nasal CPAP and had persistent symptoms on oronasal CPAP. CONCLUSION: Long-term use of oronasal CPAP is a potential cause of pneumoparotitis. PMID- 29149469 TI - Cuffed versus uncuffed endotracheal tubes for general anaesthesia in children aged eight years and under. AB - BACKGROUND: Since the introduction of endotracheal intubation in paediatrics, uncuffed endotracheal tubes (ETTs) have been the standard of care for children under eight years old, based on the presumption that complications, particularly postoperative stridor, are higher with cuffed ETTs. The major disadvantages of uncuffed ETTs cited for this shift in procedure include the difficulty in achieving tidal volumes due to leakage around an uncuffed ETT. To seal the airway adequately, uncuffed tubes may need to be exchanged for another tube with a larger diameter, which sometimes requires several attempts before the appropriate size is found. Uncuffed tubes also allow waste anaesthetic gases to escape, contributing significantly to operating room contamination and rendering the anaesthetic procedure more expensive. Our review summarizes the available data, to provide a current perspective on the use of cuffed versus uncuffed endotracheal tubes in children of eight years old or less. OBJECTIVES: To assess the risks and benefits of cuffed versus uncuffed endotracheal tubes during general anaesthesia in children up to eight years old. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS and Google Scholar databases from their inception until March 2017. We also searched databases of ongoing trials, and checked references and citations. We imposed no restriction by language. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials in which the effects of using cuffed and uncuffed tubes were investigated in children up to eight years old undergoing general anaesthesia. We excluded studies conducted solely in newborn babies. DATA COLLECTION AND ANALYSIS: We applied standard methodological procedures, as defined in the Methodological Expectations of Cochrane Intervention Reviews (MECIR). MAIN RESULTS: We included three trials (2804 children), comparing cuffed with uncuffed ETTs. We rated the risks of bias in all three trials as high. Outcome data were limited. The largest trial was supported by Microcuff GmbH, who provided the cuffed tubes used. The other two trials were small, and should be interpreted with caution. Based on the GRADE approach, we rated the quality of evidence as low to very low.Two trials comparing cuffed versus uncuffed ETTs found no difference between the groups for postextubation stridor (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.65 to 1.33; 2734 children; quality of evidence very low). However, those two trials demonstrated a statistically significantly lower rate of endotracheal tube exchange in the cuffed ETT group (RR 0.07, 95% CI 0.05 to 0.10; 2734 children; quality of evidence very low).One trial with 70 participants found that costs per case were lower in the cuffed ETT group (mean difference (MD) EUR 19.0 lower; 95% CI 24.23 to 13.77 lower; quality of evidence low), since the higher cost of the cuffed tubes may be offset by the savings made with anaesthetic gases.No clear evidence emerged to suggest any difference between cuffed and uncuffed tubes for outcomes such as the need to treat postextubation stridor with tracheal re-intubation (RR 1.85, 95% CI 0.17 to 19.76; 115 children; 2 trials; quality of evidence very low), epinephrine (RR 0.70, 95% CI 0.38 to 1.28; 115 children; 2 trials; quality of evidence very low) or corticosteroid (RR 0.87, 95% CI 0.51 to 1.49; 102 children; 1 trial; quality of evidence very low), or need for intensive care unit (ICU) admission to treat postextubation stridor (RR 2.77, 95% CI 0.30 to 25.78; 102 children; 1 trial; quality of evidence very low).None of the trials included in this review evaluated the ability to deliver appropriate tidal volume. AUTHORS' CONCLUSIONS: Implications for practiceWe are unable to draw definitive conclusions about the comparative effects of cuffed or non-cuffed endotracheal tubes in children undergoing general anaesthesia. Our confidence is limited by risks of bias, imprecision and indirectness. The lower requirement for exchange of tubes with cuffed ETTs was very low-quality evidence, and the requirement for less medical gas used and consequent lower cost was low-quality evidence. In some cases, tracheal re-intubation is required to guarantee an open airway when adequate oxygenation is difficult after removal of the tube, for a variety of reasons including stridor, muscle weakness or obstruction. No data were available to permit evaluation of whether appropriate tidal volumes were delivered. Implications for researchLarge randomized controlled trials of high methodological quality should be conducted to help clarify the risks and benefits of cuffed ETTs for children. Such trials should investigate the capacity to deliver appropriate tidal volume. Future trials should also address cost effectiveness and respiratory complications. Such studies should correlate the age of the child with the duration of intubation, and with possible complications. Studies should also be conducted in newborn babies. Future research should be conducted to compare the effects of the different types or brands of cuffed tubes used worldwide. Finally, trials should be designed to perform more accurate assessments and to diagnose the complications encountered with cuffed compared to uncuffed ETTs. PMID- 29149470 TI - International survey of practices used in the diagnosis and management of placenta accreta spectrum disorders. AB - OBJECTIVE: To identify geographic differences in diagnostic and treatment practices during the perinatal management of placenta accreta spectrum (PAS) disorders. METHODS: An online survey was conducted from May 1 to August 1, 2017. The 18-item questionnaire was emailed to all members of the expert panel for the 2018 International Federation of Gynecology and Obstetrics consensus guidelines on PAS (n=34), as well as international experts who had contributed to the content of these guidelines (n=16). RESULTS: Questionnaires were returned by 36 of the 50 experts (72% response rate). Most respondents were from Europe (n=22; 61%) or Asia (n=9; 25%). Despite large disparity in the number of patients with PAS disorders managed surgically or conservatively (range from 0 to >1000) and the different techniques used by the respondents, the screening and diagnostic methods used were similar, with transvaginal imaging used by 31 (86%) experts, and both ultrasonography and magnetic resonance imaging used by 22 (61%). In all, 22 (61%) experts indicated a preference for radical surgery, with primary cesarean hysterectomy leaving the placenta in situ reported as the most frequent approach (n=20; 55%). CONCLUSION: Wide variation found in global PAS practices indicated a need for standardized data and an evidence-based approach to the diagnosis and management of PAS disorders. PMID- 29149471 TI - Polyaniline Derived N-Doped Carbon-Coated Cobalt Phosphide Nanoparticles Deposited on N-Doped Graphene as an Efficient Electrocatalyst for Hydrogen Evolution Reaction. AB - The development of highly efficient and durable non-noble metal electrocatalysts for the hydrogen evolution reaction (HER) is significant for clean and renewable energy research. This work reports the synthesis of N-doped graphene nanosheets supported N-doped carbon coated cobalt phosphide (CoP) nanoparticles via a pyrolysis and a subsequent phosphating process by using polyaniline. The obtained electrocatalyst exhibits excellent electrochemical activity for HER with a small overpotential of -135 mV at 10 mA cm-2 and a low Tafel slope of 59.3 mV dec-1 in 0.5 m H2 SO4 . Additionally, the encapsulation of N-doped carbon shell prevents CoP nanoparticles from corrosion, exhibiting good stability after 14 h operation. Moreover, the as-prepared electrocatalyst also shows outstanding activity and stability in basic and neutral electrolytes. PMID- 29149472 TI - Which commonly monitored chemical contaminant in the Bohai region and the Yangtze and Pearl Rivers of China poses the greatest threat to aquatic wildlife? AB - The present study assessed the relative risk of 29 chemical contaminants to aquatic wildlife in the Bohai region and the Yangtze and Pearl Rivers of China. River monitoring data from 2010 to 2015 for metals, pesticides, plasticizers, surfactants, polyaromatic hydrocarbons, flame retardants, and ammonia were collected. For each chemical, ecotoxicity data were compiled for Chinese-relevant aquatic species. The chemicals were ranked by relative risk either by comparing the ratios of the median river concentration divided by the median ecotoxicity concentration or by the percentage of river measurements which exceeded the lower 10th percentile ecotoxicity value. To provide context, these results were compared with the same analysis for rivers in the United Kingdom. From this collection of chemicals in Chinese rivers, the highest risks appear to be from Cu, closely followed by Zn, Fe, and Ni together with linear alkyl benzene sulfonate, nonylphenol, and NH3 . This risk, particularly from the metals, can be several times higher than that experienced in UK rivers when using the same analysis. Ammonia median concentrations were notably higher in the Pearl and Yangtze than in UK rivers. The results suggest that China should focus on controlling metal contamination to protect its aquatic wildlife. Environ Toxicol Chem 2018;37:1115-1121. (c) 2017 SETAC. PMID- 29149473 TI - Exploring communication during the journey from noticing bodily changes to a diagnosis of endometrial cancer. AB - AIMS AND OBJECTIVES: To understand women's perspectives about the trajectory from first bodily changes to diagnosis. BACKGROUND: With endometrial cancer, as with all gynaecological cancers, early diagnosis is key to successful outcomes. However, women do not always seek clinical advice early. Previously, this gap has been referred to as a "delay," blamed on fear or refusal to acknowledge symptoms. METHODS: A qualitative research project which involved face-to-face interviews with 16 women who had presented with symptoms of endometrial cancer. The paucity of research in the trajectory of women who experience a diagnosis of endometrial cancer required an exploratory overview of the data. Accordingly, an inductive thematic analysis was conducted using the framework of Braun and Clarke (Qualitative Research in Psychology, 3, 2006, 77). RESULTS: Women and health professionals both resorted to satisficing, using heuristics to make decisions about the importance of symptoms depending on their severity and duration. Most women initially determined that the bodily changes were within the realms of normal. Time to diagnosis was also affected by the following: women's long standing assumptions; communication with health professionals; liminality-women oscillating between their self-assessment that these changes were something significant or nothing important; and gaps in health literacy. CONCLUSIONS: The journey from noticing bodily changes to diagnosis was a nonlinear trajectory. Women worked to make sense of what was happening to them, informed by their sociocultural environment. In particular, confusion about the purpose of cervical screening led a number of participants who had regular smears to assume they were "safe" from cancer worries. RELEVANCE TO CLINICAL PRACTICE: Women and some health professionals may be unfamiliar with symptoms potentially indicative of endometrial cancer. There may be structural and communication barriers for women navigating healthcare systems. It is vital that nurses take time both to listen to women and to provide them with resources to enhance their health literacy. PMID- 29149474 TI - Interventions for Old World cutaneous leishmaniasis. AB - BACKGROUND: Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008. OBJECTIVES: To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis. SEARCH METHODS: We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co-ordinators, directors, clinicians, WHO-EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE. SELECTION CRITERIA: Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search. MAIN RESULTS: We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow-up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons. AUTHORS' CONCLUSIONS: There was very low-certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well-designed international studies that evaluate long-term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring. PMID- 29149475 TI - Reply to Letter to the Editor regarding "Robotic or non-robotic transoral laryngectomy". PMID- 29149476 TI - Clinical parameters before and after the transition to dialysis. AB - INTRODUCTION: The transition from pre-dialysis chronic kidney disease (CKD) to post-dialysis start is a critical period associated with high patient mortality and increased hospital admissions. Little is known about the trends of key clinical and laboratory parameters through this time of transition to start dialysis. METHODS: De-identified data including demographics, vital signs, lab results, and eGFR from the Fresenius Medical Care-CKD Registry were analyzed to determine trends in clinical and laboratory parameters through the time of transition from 12 months pre-dialysis start to 12 months post-dialysis start. Trends in key clinical and laboratory parameters associated with cardiovascular, nutritional, mineral metabolism and inflammatory domains were examined in association with the transition to dialysis start and first year dialysis survival. FINDINGS: All parameters show divergence for patients who survive vs. do not survive the first year of dialysis. Of note, during pre-dialysis CKD the absolute systolic blood pressure (SBP) level is lower and the slope for SBP decline is significantly steeper for patients who do not survive the first year on dialysis. DISCUSSION: This study uniquely demonstrates the trajectories of key parameters though the transition from pre-dialysis to post-dialysis start. Significant differences are noted in the pre-dialysis period for patients who survive vs. those who do not survive the first year of dialysis. Early recognition of adverse trends in the pre-dialysis period may create opportunity to intervene to improve early dialysis outcomes. PMID- 29149477 TI - Pathfinders in oncology from the beginning of the 19th century to the inauguration of the first cancer hospital in the United States. AB - The fields of medicine and oncology made substantial progress between 1800 and 1885. The first half of this period was dominated by the spectacular progress in physiology, cytology, histology, histopathology, and diagnostic microscopy. In the second half of the period, advancements in surgical techniques, anesthesia, asepsis, and laboratory medicine, including bacteriology, chemistry, and biochemistry, led to the development of medical specialties, including surgical pathology and surgical oncology. Although wars, revolutions, and socioeconomic upheavals interrupted the daily life of the populace, distinguished artists, scientists, and physicians continued, against all odds, to advance their field of interest. Among the many eminent individuals, there were 7 renowned physicians (4 pathologists and 3 surgeons) who revolutionized medical and oncology thinking in ways that are still felt today. They were polyglots with formidable erudition, beloved teachers, and mentors, and are remembered eponymically for their contributions to oncology to this day. As a passing note, the 3 surgeons also were skillful microscopists. Cancer 2018;124:230-41. (c) 2017 American Cancer Society. PMID- 29149478 TI - Hospital quality, patient risk, and Medicare expenditures for cancer surgery. AB - BACKGROUND: Surgical resection is a cornerstone of curative-intent therapy for patients with solid organ malignancies. With increasing attention paid to the costs of surgical care, there is a new focus on variations in the costs of cancer surgery. This study evaluated the potential interactive effect of hospital quality and patient risk on expenditures for cancer resections. METHODS: With 100% Medicare claim data for 2010-2013, patients aged 65 to 99 years who had undergone cancer resection were identified. Medicare payments were calculated for the surgical episode from the index admission through 30 days after discharge. Risk- and reliability-adjusted hospital rates of serious complications and mortality within 30 days of the index operation were assessed to categorize high- and low-quality hospitals. RESULTS: There was no difference in patient characteristics between the highest and lowest quality hospitals. There were substantial increases in expenditures for procedures performed at the lowest quality hospitals for each procedure. Increased expenditures at the lowest quality hospitals were found for all patients, but they were highest for the highest risk patients. At low-quality hospitals, low-risk patients undergoing pancreatectomy had payments of $29,080, whereas high-risk patients had average payments of $62,687; this was a difference of $33,607 per patient episode. CONCLUSIONS: Total episode expenditures for cancer resections were lower when care was delivered at low-complication, high-quality hospitals. Expenditure differences were particularly large for high-risk patients, and this suggests that the selective referral of high-risk patients to high-quality centers may be an effective strategy for optimizing value in cancer surgery. Cancer 2018;124:826 32. (c) 2017 American Cancer Society. PMID- 29149479 TI - CRISPR-Cas Expands Dynamic Range of Gene Expression From T7RNAP Promoters. AB - Reducing leaky gene expression is critical for improving protein yield of recombinant bacteria and stability of engineered cellular circuits in synthetic biology. Leaky gene expression occurs when a genetic promoter is not fully repressed, leading to unintended protein synthesis in the absence of stimuli. Existing work have devised specific molecular strategies for reducing leaky gene expression of each promoter. In contrast, we describe a repurposed, modular CRISPRi system that attenuates leaky gene expression using a series of single guide RNAs targeting the PT7/LacO1 promoter. Furthermore, we demonstrate the efficacy of CRISPRi to significantly increase the dynamic range of T7 RNA Polymerase (T7RNAP) promoters. In addition, we demonstrate that the CRISPRi system can be applied to enhance growth of bacteria that suffer from leaky expression of a toxic protein. Our work establishes a new application of CRISPRi in genomic engineering to improve the control of recombinant gene expression. The approach is potentially generalizable to other gene expression system by changing the single-guide RNAs. PMID- 29149480 TI - The characterization of iron (III) in seawater and related toxicity to early life stages of scleractinian corals. AB - Currently toxicity data for iron (Fe) in seawater are limited; furthermore, these data are of poor quality as a result of the importance of Fe solubility in test solutions being overlooked. The present study characterized the solubility and lability of Fe(III) in seawater and then examined the effects of Fe(III) on the fertilization success and larval survival of the tropical marine scleractinian corals Acropora spathulata and Platygyra daedalea. We present the first assessment of the effects of Fe on the early life stages of scleractinian corals. Concentrations of both soluble and labile forms of Fe were very low, with dissolved Fe concentrations <=0.195 mg/L in bioassay test solutions and chemical determinations revealing labile Fe concentrations <=1.21 mg/L. For fertilization experiments, the median effect concentration (EC50) value for total Fe was 25 mg/L for the most sensitive species, P. daedalea, whereas the EC50 values for A. spathulata ranged between 40 and 66 mg/L. The median lethal concentration value for P. daedalea larval survival was 47 mg/L Fe after 72-h exposure. We provide Fe toxicity data for tropical marine keystone species that could be used to help generate more reliable guideline values for Fe in marine waters. Environ Toxicol Chem 2018;37:1104-1114. (c) 2017 SETAC. PMID- 29149481 TI - Neuroprotective effects of melatonin on amphetamine-induced dopaminergic fiber degeneration in the hippocampus of postnatal rats. AB - Chronic amphetamine (AMPH) abuse leads to damage of the hippocampus, the brain area associated with learning and memory process. Previous results have shown that AMPH-induced dopamine neurotransmitter release, reactive oxygen species formation, and degenerative protein aggregation lead to neuronal death. Melatonin, a powerful antioxidant, plays a role as a neuroprotective agent. The objective of this study was to investigate whether the protective effect of melatonin on AMPH-induced hippocampal damage in the postnatal rat acts through the dopaminergic pathway. Four-day-old postnatal rats were subcutaneously injected with 5-10 mg/kg AMPH and pretreated with 10 mg/kg melatonin prior to AMPH exposure for seven days. The results showed that melatonin decreased the AMPH-induced hippocampal neuronal degeneration in the dentate gyrus, CA1, and CA3. Melatonin attenuated the reduction in the expression of hippocampal synaptophysin, PSD-95, alpha-synuclein, and N-methyl-D-aspartate (NMDA) receptor protein and mRNA caused by AMPH. Melatonin attenuated the AMPH-induced reduction in dopamine transporter (DAT) protein expression in the hippocampus and the reduction in mRNA expression in the ventral tegmental area (VTA). Immunofluorescence demonstrated that melatonin not only prevented the AMPH induced loss of DAT and NMDA receptor but also prevented AMPH-induced alpha synuclein overexpression in the dentate gyrus, CA1, and CA3. Melatonin decreased the AMPH-induced reduction in the protein and mRNA of the NMDA receptor downstream signaling molecule, calcium/calmodulin-dependent protein kinase II (CaMKII), and the melatonin receptors (MT1 and MT2). This study showed that melatonin prevented AMPH-induced toxicity in the hippocampus of postnatal rats possibly via its antioxidative effect and mitochondrial protection. PMID- 29149482 TI - Melatonin alleviates low PS I-limited carbon assimilation under elevated CO2 and enhances the cold tolerance of offspring in chlorophyll b-deficient mutant wheat. AB - Melatonin is involved in the regulation of carbohydrate metabolism and induction of cold tolerance in plants. The objective of this study was to investigate the roles of melatonin in modulation of carbon assimilation of wild-type wheat and the Chl b-deficient mutant ANK32B in response to elevated CO2 concentration ([CO2 ]) and the transgenerational effects of application of exogenous melatonin (hereafter identified as melatonin priming) on the cold tolerance in offspring. The results showed that the melatonin priming enhanced the carbon assimilation in ANK32B under elevated [CO2 ], via boosting the activities of ATPase and sucrose synthesis and maintaining a relatively higher level of total chlorophyll concentration in leaves. In addition, melatonin priming in maternal plants at grain filling promoted the seed germination in offspring by accelerating the starch degradation and improved the cold tolerance of seedlings through activating the antioxidant enzymes and enhancing the photosynthetic electron transport efficiency. These findings suggest the important roles of melatonin in plant response to future climate change, indicating that the melatonin priming at grain filling in maternal plants could be an effective approach to improve cold tolerance of wheat offspring at seedling stage. PMID- 29149483 TI - Factors influencing the quality of vital sign data in electronic health records: A qualitative study. AB - AIMS AND OBJECTIVES: To investigate reasons for inadequate documentation of vital signs in an electronic health record. BACKGROUND: Monitoring vital signs is crucial to detecting and responding to patient deterioration. The ways in which vital signs are documented in electronic health records have received limited attention in the research literature. A previous study revealed that vital signs in an electronic health record were incomplete and inconsistent. DESIGN: Qualitative study. METHODS: Qualitative study. Data were collected by observing (68 hr) and interviewing nurses (n = 11) and doctors (n = 3), and analysed by thematic analysis to examine processes for measuring, documenting and retrieving vital signs in four clinical settings in a 353-bed hospital. RESULTS: We identified two central reasons for inadequate vital sign documentation. First, there was an absence of firm guidelines for observing patients' vital signs, resulting in inconsistencies in the ways vital signs were recorded. Second, there was a lack of adequate facilities in the electronic health record for recording vital signs. This led to poor presentation of vital signs in the electronic health record and to staff creating paper "workarounds." CONCLUSIONS: This study demonstrated inadequate routines and poor facilities for vital sign documentation in an electronic health record, and makes an important contribution to knowledge by identifying problems and barriers that may occur. Further, it has demonstrated the need for improved facilities for electronic documentation of vital signs. RELEVANCE TO CLINICAL PRACTICE: Patient safety may have been compromised because of poor presentation of vital signs. Thus, our results emphasised the need for standardised routines for monitoring patients. In addition, designers should consult the clinical end-users to optimise facilities for electronic documentation of vital signs. This could have a positive impact on clinical practice and thus improve patient safety. PMID- 29149484 TI - Comparative analysis of proteomes between diabetic and normal human sperm: Insights into the effects of diabetes on male reproduction based on the regulation of mitochondria-related proteins. AB - This study sought to identify sources of the reduced fertility of men with type 2 diabetes mellitus. Significant reductions in semen volume, sperm concentration, and total sperm count were observed in diabetic individuals, while transmission electron microscopy revealed that the structure of mitochondria in the tail of sperm from diabetic patients was damaged. Proteins potentially associated with these sperm defects were identified using proteomics. Isobaric tagging for relative and absolute quantitation labeling and high-performance liquid chromatography-tandem mass spectrometry allowed us to identify 357 proteins significantly differentially expressed in diabetic versus control semen (>1.2 or <0.83). According to gene ontology enrichment and pathway analyses, many of these differentially expressed proteins are associated with sperm function, including binding of sperm to the zona pellucida and proteasome function; of particular interest, half of these proteins were related to mitochondrial metabolism. Protein-interaction networks revealed that a decrease in Cystatin C and Dipeptidyl peptidase 4 in the mitochondria may be sources of the decreased motility of sperm from diabetic patients. PMID- 29149485 TI - Factors influencing the delivery of the fundamentals of care: Perceptions of nurses, nursing leaders and healthcare consumers. AB - AIMS AND OBJECTIVES: To explore the factors described by nurses and consumer representatives influencing the delivery of the fundamentals of care. BACKGROUND: An ongoing challenge facing nursing is ensuring the "basics" or fundamentals of care are delivered optimally. The way nurses and patients perceive the delivery of the fundamentals of care had not been explored. Once identified, the factors that promote the delivery of the fundamentals of care may be facilitated. DESIGN: Inductive content analysis of scenario based focus groups. METHODS: A qualitative approach was taken using three stages, including direct observation, focus groups and interviews. This paper reports the second stage. Focus groups discussed four patient care scenarios derived from the observational data. Focus groups were conducted separately for registered nurses, nurses in leadership roles and consumer representatives. Content analysis was used. RESULTS: The analysis of the focus group data resulted in three themes: Organisational factors; Individual nurse or patient factors; and Interpersonal factors. Organisational factors include nursing leadership, the context of care delivery and the availability of time. Individual nurse and patient factors include the specific care needs of the patient and the individual nurse and patient characteristics. Interpersonal factors include the nurse-patient relationship; involving the patient in their care, ensuring understanding and respecting choices; communication; and setting care priorities. CONCLUSIONS: Seeking the perspective of the people involved in delivering and receiving the fundamentals of care showed a shared understanding of the factors influencing the delivery of the fundamentals of care. The influence of nursing leadership and the quality of the nurse-patient relationship were perceived as important factors. RELEVANCE TO CLINICAL PRACTICE: Nurses and consumers share a common perspective of the factors influencing the delivery of the fundamentals of care and both value a therapeutic nurse-patient relationship. Clinical nursing leaders must understand the impact of their role in shaping the delivery of the fundamentals of care. PMID- 29149486 TI - Vitellogenin and vitellogenin receptor gene expression profiles in Spodoptera exigua are related to host plant suitability. AB - BACKGROUND: The beet armyworm Spodoptera exigua, a worldwide phytophagous pest, causes considerable economic agricultural losses. Understanding the relationship between its fecundity and the host plant is a basic and important component of early forecasting of beet armyworm outbreaks. However, little is known about the molecular mechanism by which distinct hosts affect S. exigua fecundity. RESULTS: In this study, key life-history parameters of S. exigua reared on distinct hosts were investigated; the host plants could be ranked as lettuce > shallot > tomato > celery in their order of suitability. Full-length S. exigua vitellogenin receptor (SeVgR) cDNA was cloned, and sex-, stage- and tissue-specific expression characteristics were assessed. Spodoptera exigua vitellogenin (SeVg) and SeVgR expression levels were markedly modulated by host nutrients (P < 0.05). SeVg and SeVgR expression levels were significantly higher in S. exigua reared on lettuce, the most preferred and most nutritive host, than in those reared on tomato and celery. Interestingly, significant linear regression correlations were found between SeVg and SeVgR expression levels and key S. exigua life-history parameters, especially life span, pupa weight, and female fecundity (P < 0.01). CONCLUSION: Host plant type and suitability could affect the expression pattern of SeVg and SeVgR, which influenced S. exigua fecundity. Vg and VgR have the potential to be used as molecular markers of S. exigua fecundity and for forecasting outbreaks of S. exigua on different hosts. (c) 2017 Society of Chemical Industry. PMID- 29149487 TI - Fabrication of chelate-setting alpha-tricalcium phosphate cement using sodium citrate and sodium alginate as mixing solution and its in vivo osteoconductivity. AB - Moldable and injectable calcium-phosphate cements (CPCs) are material candidates for bone replacement applications. In the present study, we examined the effectiveness of sodium alginate and sodium citrate additives to the liquid phase of CPC, in improving its handling property as well as mechanical strength. The use of these additives enhanced the handling property significantly, in terms of consistency as compared to CPC without additives due to the liquefying effect caused by the adsorption of citrate ions on the cement particles. Sodium alginate and sodium citrate were added to CPC, which was set by the chelate-bonding capability of inositol phosphate, and was composed of mainly alpha-tricalcium phosphate (alpha-TCP) phase (>90%). The compressive strength of the CPC containing sodium alginate and sodium citrate was 3.4 +/- 0.3 MPa, which was significantly higher than cement without additives. Furthermore, this cement exhibited favorable osteoconductivity and bioresorbability, and remained the alpha-TCP phase after 4-week implantation in a pig tibiae model. These results suggested that the cement is a potential candidate as a bioresorbable paste-like artificial bone. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2361-2370, 2018. PMID- 29149488 TI - Response to cautious use of platelet as relevant inducer of liver regeneration following partial hepatectomy in patients with metastatic hepatic carcinoma. PMID- 29149489 TI - Altered distal-proximal temperature gradient as a possible explanation for sleep wake disturbances in cirrhotic patients. PMID- 29149490 TI - Multilevel heterogeneity of biliary tract cancers may affect the modelling of prognosis. PMID- 29149491 TI - Response to the role of platelets on regenerating liver: Thoughts beyond parenchymal proliferation. PMID- 29149492 TI - Effects of Tao-Hong-Si-Wu decoction on acute blood stasis in rats based on a LC Q/TOF-MS metabolomics and network approach. AB - A novel approach using metabolomics coupled with a metabolic network was used to investigate the effects of Tao-Hong-Si-Wu decoction (THSWD) on the rat model of acute blood stasis syndrome. Acute blood stasis syndrome was induced by placing the rats in ice-cold water following two injections with epinephrine. The hemorheological indicators [whole blood viscosity (WBV) and plasma viscosity (PV)] and the blood coagulation indicators [thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen (FIB)] were detected. The nonparametric univariate method and multivariate statistical analysis were performed for determining the potential biomarkers. A correlation map was structured between biochemical indicators and hub metabolites to explain the effects mechanism of THSWD. After the administration of THSWD, the levels of WBV, PV, TT, APTT and FIB returned to levels observed in the control group. According to metabolomics coupled with metabolic network analysis, the intervention of THSWD in rats with acute blood stasis syndrome induced substantial and characteristic changes in their metabolic profiles. Fifteen metabolites were screened, which mainly involved 10 pathways and five hub metabolites, namely, l-glutamate, l-phenylalanine, N-acylsphingosine, arachidonic acid and phosphatidate. The biochemical indicators and hub metabolites could be adjusted to close to normal levels by THSWD. Therefore, combining metabolomics and metabolic network helped to evaluate the effects of THSWD on acute blood stasis. PMID- 29149493 TI - Impact of chronic hepatitis C virus infection on the survival of patients with oropharyngeal cancer. AB - BACKGROUND: Although an association between hepatitis C virus (HCV) infection and oropharyngeal cancers (OPCs) has been reported, to the authors' knowledge the clinical significance of this epidemiological finding remains unknown. Therefore, the authors analyzed the oncologic outcomes of HCV-infected patients with OPCs. METHODS: In this retrospective cohort study, all patients with OPCs who were seen at The University of Texas MD Anderson Cancer Center between January 2004 and December 2015 were reviewed. HCV infection was defined as detectable HCV RNA in the serum. Five-year overall survival and progression-free survival rates were compared between patients infected with HCV and those not infected. RESULTS: A total of 161 patients were examined. The majority of the patients were white (141 patients; 88%) and male (132 patients; 82%) and had TNM stage III or IV disease (147 patients; 91%). The OPC involved the tonsils (83 patients; 52%), base of the tongue (67patients; 42%), or the soft palate (11 patients; 7%). The median follow up after an OPC diagnosis was 3 years (range, 1-13 years). HCV-infected patients (25 patients) and HCV-uninfected patients (136 patients) were comparable with regard to smoking and alcohol status. In multivariate analysis, HCV was associated with increased cancer-specific mortality (hazard ratio, 2.15; 95% confidence interval, 1.08-6.85 [P = .02]) and risk of OPC progression (hazard ratio, 5.42; 95% confidence interval, 2.64-11.14 [P = .0008]) independent of age and cirrhosis status. Antivirals were administered after the diagnosis of OPC in 8 of the 25 HCV-infected patients (32%). HCV-infected patients who received antivirals were found to have better 5-year overall survival (70% vs 12%; P = .005) and progression-free survival (72% vs 19%; P = .005) compared with patients who did not. CONCLUSIONS: The early detection of HCV is important in patients with OPC because this infection may affect their oncologic outcomes. Cancer 2018;124:960-5. (c) 2017 American Cancer Society. PMID- 29149495 TI - A Redox-Activated G-Quadruplex DNA Binder Based on a Platinum(IV)-Salphen Complex. AB - There has been increasing interest in the development of small molecules that can selectively bind to G-quadruplex DNA structures. The latter have been associated with a number of key biological processes and therefore are proposed to be potential targets for drug development. Herein, we report the first example of a reduction-activated G-quadruplex DNA binder. We show that a new octahedral platinum(IV)-salphen complex does not interact with DNA in aqueous media at pH 7.4; however, upon addition of bioreductants such as ascorbic acid or glutathione, the compound is readily reduced to the corresponding square planar platinum(II) complex. In contrast to the parent platinum(IV) complex, the in situ generated platinum(II) complex has good affinity for G-quadruplex DNA. PMID- 29149494 TI - Inhibiting MT2-TFE3-dependent autophagy enhances melatonin-induced apoptosis in tongue squamous cell carcinoma. AB - Autophagy modulation is a potential therapeutic strategy for tongue squamous cell carcinoma (TSCC). Melatonin possesses significant anticarcinogenic activity. However, whether melatonin induces autophagy and its roles in cell death in TSCC are unclear. Herein, we show that melatonin induced significant apoptosis in the TSCC cell line Cal27. Apart from the induction of apoptosis, we demonstrated that melatonin-induced autophagic flux in Cal27 cells as evidenced by the formation of GFP-LC3 puncta, and the upregulation of LC3-II and downregulation of SQSTM1/P62. Moreover, pharmacological or genetic blockage of autophagy enhanced melatonin induced apoptosis, indicating a cytoprotective role of autophagy in melatonin treated Cal27 cells. Mechanistically, melatonin induced TFE3(Ser321) dephosphorylation, subsequently activated TFE3 nuclear translocation, and increased TFE3 reporter activity, which contributed to the expression of autophagy-related genes and lysosomal biogenesis. Luzindole, a melatonin membrane receptor blocker, or MT2-siRNA partially blocked the ability of melatonin to promote mTORC1/TFE3 signaling. Furthermore, we verified in a xenograft mouse model that melatonin with hydroxychloroquine or TFE3-siRNA exerted a synergistic antitumor effect by inhibiting autophagy. Importantly, TFE3 expression positively correlated with TSCC development and poor prognosis in patients. Collectively, we demonstrated that the melatonin-induced increase in TFE3-dependent autophagy is mediated through the melatonin membrane receptor in TSCC. These data also suggest that blocking melatonin membrane receptor-TFE3-dependent autophagy to enhance the activity of melatonin warrants further attention as a treatment strategy for TSCC. PMID- 29149496 TI - Predictive factors for osteoradionecrosis of the jaws: A retrospective study. AB - BACKGROUND: Osteoradionecrosis of the jaw (ORNJ) is a well-recognized complication of radiotherapy. The purpose of this study was to assess predictive factors for the development of ORNJ. METHODS: A retrospective study of 325 patients with head and neck squamous cell carcinoma (HNSCC) treated at one institution between January 1, 1999, and December 31, 2008, was conducted. Outcome measure was the presence/absence of ORNJ. Time to event was recorded and Cox proportional hazard regression analysis was used to determine statistically significant predictive factors. RESULTS: Fifty-nine patients had ORNJ. Statistical analysis using Cox regression analysis identified several statistically significant variables: dentoalveolar surgery; peri-resective surgery of the jaw; continued tobacco usage after radiotherapy, diabetes mellitus type 2 (DM2); and total radiation dose. CONCLUSION: Patients at greater risk of developing ORNJ can be identified and measures can be instituted to reduce its incidence and expedite management when it does occur. PMID- 29149497 TI - Perceptions of general and postpresidential election discrimination are associated with loss of control eating among racially/ethnically diverse young men. AB - OBJECTIVE: The purpose of this study was to examine the association between young men's perceived experiences with discrimination, both general and following the 2016 presidential election, and their loss of control (LOC) eating. The degree to which men identified with their ethnic identity was evaluated as a moderator. METHOD: The sample included 798 men (18-30 years; M = 24.0 +/- 3.6) who identified as African American (n = 261), Asian/Asian American (n = 266), or Hispanic/Latino (n = 271). Participants completed an online survey of items assessing demographic characteristics; perceived discrimination; perceptions of race-related discrimination following the 2016 U.S. presidential election; ethnic identity; and LOC eating. RESULTS: After adjusting for income, education, generational status and body mass index, perceived discrimination was positively associated with LOC eating frequency in African American and Hispanic/Latino men (ps < .01). Ethnic identity was inversely associated with LOC eating frequency in Hispanic/Latino men (p < .001). In Asian/Asian American men, perceived discrimination was only associated with more LOC eating among those with a low ethnic identity (p < .001). Higher levels of perceived discrimination following the presidential election were uniquely associated with more frequent LOC eating (p < .01) only among Asian/Asian American men who were not born in the United States or whose parents were not born in the United States. DISCUSSION: LOC eating may partially explain known associations between discrimination and heightened risk for obesity and chronic diseases among African American and Hispanic/Latino men. Asian/Asian American men's LOC eating may be linked to postpresidential election and general experiences with racial discrimination, particularly if they report a low sense of belonging to their ethnic group. PMID- 29149498 TI - Association between a single-nucleotide polymorphism in the GREM1 gene and non syndromic orofacial cleft in the Chinese population. AB - BACKGROUND: Non-syndromic orofacial cleft (NSOC) is a common craniofacial deformity among newborns. The GREM1 gene is correlated with orofacial development. The aim of our study was to investigate the association between a single-nucleotide polymorphism in the GREM1 gene and this malformation in the Chinese population. METHODS: The SNaPshot mini-sequencing technique was used to genotype the locus rs1258763 of the GREM1 gene in 331 patients with NSOC and 271 individuals in a control group. RESULTS: For GREM1 rs1258763, there was a significant difference between the NSOC case group and control group (P = .022). Children carrying GA and GA/AA genotypes had an increased risk of NSOC (OR=1.62, 95%CI: 1.15-2.30; OR=1.52, 95%CI: 1.09-2.12). In the cleft subgroup, we found that the GREM1 rs1258763 GA genotype might contribute to the elevated risk of the cleft lip with or without cleft palate (CL/P) (P = .029). Non-significant differences were found between the cleft palate only (CPO) and control groups (P = .077). CONCLUSION: Our findings revealed that the GREM1 polymorphism was significantly associated with the risk of NSOC in the Chinese population. PMID- 29149499 TI - Being there and reconnecting: Midwives' perceptions of the impact of Mindfulness training on their practice. AB - OBJECTIVE: To ascertain how midwives perceived attending a mindfulness course impacted on their professional practice, particularly in regard to any stress they experienced at work. DESIGN: A qualitative study using Interpretive Phenomenological Analysis. Semi-structured interviews were conducted with nine midwives. SETTING: A large maternity Trust in the United Kingdom. INTERVENTION: An eight-week mindfulness course, adapted from mindfulness-based cognitive therapy. FINDINGS: Four superordinate themes were identified as follows: "being challenged and committing," "containing the self," "reconnecting" and "moving forward with confidence." Focusing on the present moment enabled participants better to identify the boundary between self and other. This led to an increased sense of control and a reconnection with and reframing of relationships with colleagues and the women in their care. KEY CONCLUSIONS: Mindfulness may provide an effective way to address the high levels of stress, role dissatisfaction and workplace bullying found in midwifery, by improving both the working environment and patient care. The pivotal role of positive workplace relationships in this process resonates with other nursing research and with contemporary philosophical thought. RELEVANCE TO CLINICAL PRACTICE: This study adds to a body of evidence which suggests investing in the well-being of midwifery staff improves both job satisfaction and women's experiences of care. PMID- 29149500 TI - EP radiofrequency generators: Significant offsets between selected and delivered power? AB - INTRODUCTION: For radiofrequency (RF) ablation, the EP Shuttle(r) (Stockert GmbH, Freiburg, Germany), Ampere(r) (St. Jude Medical, St. Paul, MN, USA), and SmartAblate(r) (Biosense Webster, Diamond Bar, CA, USA) generator models are most frequently used in clinical practice. The aim of this study was to assess the correlation between selected and delivered RF power for different generators. METHODS AND RESULTS: In an experimental setup, ablation catheters were connected to the EP Shuttle(r) , Ampere(r) , and SmartAblate(r) generators. The power delivered by the generators was measured using a current converter and an oscilloscope. The selected power displayed on the generator was compared to the actually delivered power measured by the experimental setup (n = 800 measurements). The offsets between selected and delivered power increased significantly with impedance (EP Shuttle(r) ). For example, at a selected power of 30 W, the delivered power was 40.3 W (EP Shuttle(r) ), 30.1 W (Ampere(r) ), and 28.1 W (SmartAblate(r) ) at an impedance of 200 Omega. In addition, ablation lesions (n = 80) were created in ex vivo porcine cardiac muscle preparations. The resulting ablation lesion size was calculated in caliper measurements. When the EP Shuttle(r) generator was operated at 200 Omega, the resulting lesion size was significantly larger than at 100 Omega. There were no significant offsets between power delivery and lesion size when using the Ampere(r) or SmartAblate(r) generators. CONCLUSIONS: The Ampere(r) and SmartAblate(r) generator models deliver accurate power as selected by the user. The power delivered by the EP Shuttle(r) generator exceeds the selected power by up to 40% depending on impedance. The findings were confirmed in ex vivo porcine heart experiments and should be considered in clinical practice. PMID- 29149501 TI - The Weakly Coordinating Tris(trichlorosilyl)silyl Anion. AB - Closely following the procedure for the preparation of the base-stabilized dichlorosilylene complex NHCDipp ?SiCl2 reported by Roesky, Stalke, and co workers (Angew. Chem. Int. Ed. 2009, 48, 5683-5686), a few crystals of the salt [NHCDipp -H???Cl???H-NHCDipp ]Si(SiCl3 )3 were isolated, aside from the reported byproduct [NHCDipp -H+ ???Cl- ], and characterized by X-ray crystallography (NHCDipp =N,N-di(2,6-diisopropylphenyl)imidazo-2-ylidene). They contain the weakly coordinating anion Si(SiCl3 )3- , which was also obtained in high yields upon deprotonation of the conjugate Bronsted acid HSi(SiCl3 )3 with NHCDipp or PMP (PMP=1,2,2,6,6-pentamethylpiperidine). The acidity of HSi(SiCl3 )3 was estimated by DFT calculations to be substantially higher than those of other H silanes. Further DFT studies on the electronic structure of Si(SiCl3 )3- , including the electrostatic potential and the electron localizability, confirmed its low basicity and nucleophilicity compared with other silyl anions. PMID- 29149502 TI - Annual banned-substance review: Analytical approaches in human sports drug testing. AB - Several high-profile revelations concerning anti-doping rule violations over the past 12 months have outlined the importance of tackling prevailing challenges and reducing the limitations of the current anti-doping system. At this time, the necessity to enhance, expand, and improve analytical test methods in response to the substances outlined in the World Anti-Doping Agency's (WADA) Prohibited List represents an increasingly crucial task for modern sports drug-testing programs. The ability to improve analytical testing methods often relies on the expedient application of novel information regarding superior target analytes for sports drug-testing assays, drug elimination profiles, alternative test matrices, together with recent advances in instrumental developments. This annual banned substance review evaluates literature published between October 2016 and September 2017 offering an in-depth evaluation of developments in these arenas and their potential application to substances reported in WADA's 2017 Prohibited List. PMID- 29149503 TI - Sexual functioning among young adult cancer patients: A 2-year longitudinal study. AB - BACKGROUND: Cancer-related sexual dysfunction has been reported among adolescents and young adults (AYAs); however, its prevalence over time has not been examined. This longitudinal study investigated sexual dysfunction in AYAs over the course of 2 years after the initial diagnosis. METHODS: Young adult patients (18-39 years old) completed the Medical Outcomes Study Sexual Functioning Scale within the first 4 months of their diagnosis (n = 123) and again 6 (n = 107) and 24 months later (n = 95). An ordered multinomial response model analyzed changes in the probability of reporting sexual dysfunction over time and the independent effects of demographic, clinical, and psychosocial variables. RESULTS: More than half of the participants reported sexual functioning to be problematic at each assessment. The probability of reporting sexual dysfunction increased over time (P < .01) and was greater for cancer patients who were female (P < .001), older (P < .01), married or in a committed relationship (P < .001), treated with chemotherapy (P < .05), and reporting comorbid psychological distress (P < .001) and lower social support (P < .05). For women, being in a relationship increased the likelihood of reporting sexual problems over time; for men, the likelihood of reporting sexual problems increased regardless of their relationship status. CONCLUSIONS: A substantial proportion of young adults report ongoing problems with sexual functioning in the first 2 years after their cancer diagnosis. These findings justify the need to evaluate and monitor sexual functioning throughout a continuum of care. Cancer 2018;124:398-405. (c) 2017 American Cancer Society. PMID- 29149505 TI - An International Continence Society (ICS) report on the terminology for adult neurogenic lower urinary tract dysfunction (ANLUTD). AB - INTRODUCTION: The terminology for adult neurogenic lower urinary tract dysfunction (ANLUTD) should be defined and organized in a clinically based consensus Report. METHODS: This Report has been created by a Working Group under the auspices and guidelines of the International Continence Society (ICS) Standardization Steering Committee (SSC) assisted at intervals by external referees. All relevant definitions for ANLUTD were updated on the basis of research over the last 14 years. An extensive process of 18 rounds of internal and external review was involved to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A Terminology Report for ANLUTD, encompassing 97 definitions (42 NEW and 8 CHANGED, has been developed. It is clinically based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different groups involved not only in lower urinary tract dysfunction but additionally in many other medical specialties. CONCLUSION: A consensus-based Terminology Report for ANLUTD has been produced to aid clinical practice and research. PMID- 29149504 TI - MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene. AB - Breast adenoid cystic carcinoma (AdCC), a rare type of triple-negative breast cancer, has been shown to be driven by MYB pathway activation, most often underpinned by the MYB-NFIB fusion gene. Alternative genetic mechanisms, such as MYBL1 rearrangements, have been reported in MYB-NFIB-negative salivary gland AdCCs. Here we report on the molecular characterization by massively parallel sequencing of four breast AdCCs lacking the MYB-NFIB fusion gene. In two cases, we identified MYBL1 rearrangements (MYBL1-ACTN1 and MYBL1-NFIB), which were associated with MYBL1 overexpression. A third AdCC harboured a high-level MYB amplification, which resulted in MYB overexpression at the mRNA and protein levels. RNA-sequencing and whole-genome sequencing revealed no definite alternative driver in the fourth AdCC studied, despite high levels of MYB expression and the activation of pathways similar to those activated in MYB-NFIB positive AdCCs. In this case, a deletion encompassing the last intron and part of exon 15 of MYB, including the binding site of ERG-1, a transcription factor that may downregulate MYB, and the exon 15 splice site, was detected. In conclusion, we demonstrate that MYBL1 rearrangements and MYB amplification probably constitute alternative genetic drivers of breast AdCCs, functioning through MYBL1 or MYB overexpression. These observations emphasize that breast AdCCs probably constitute a convergent phenotype, whereby activation of MYB and MYBL1 and their downstream targets can be driven by the MYB-NFIB fusion gene, MYBL1 rearrangements, MYB amplification, or other yet to be identified mechanisms. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29149506 TI - Integrating soft and hard tissues via interface tissue engineering. AB - The enthesis, or interface between bone and soft tissues such as ligament and tendon, is prone to injury and often does not heal, even post surgical intervention. Interface tissue engineering represents an integrative strategy for regenerating the native enthesis by functionally connecting soft and hard tissues and thereby improving clinical outcome. This review focuses on integrative and cell-instructive scaffold designs that target the healing of the two most commonly injured soft tissue-bone junctions: tendon-bone interface (e.g., rotator cuff) and ligament-bone interface (e.g., anterior cruciate ligament). The inherent connectivity between soft and hard tissues is instrumental for musculoskeletal motion and is therefore a key design criterion for soft tissue regeneration. To this end, scaffold design for soft tissue regeneration have progressed from single tissue systems to the emerging focus on pre-integrated and functional composite tissue units. Specifically, a multifaceted, bioinspired approach has been pursued wherein scaffolds are tailored to stimulate relevant cell responses using spatially patterned structural and chemical cues, growth factors, and/or mechanical stimulation. Moreover, current efforts to elucidate the essential scaffold design criteria via strategic biomimicry are emphasized as these will reduce complexity in composite tissue regeneration and ease the related burden for clinical translation. These innovative studies underscore the clinical relevance of engineering connective tissue integration and have broader impact in the formation of complex tissues and total joint regeneration. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1069-1077, 2018. PMID- 29149507 TI - Registered nurse and midwife experiences of using videoconferencing in practice: A systematic review of qualitative studies. AB - AIM AND OBJECTIVE: To synthesise evidence of registered nurses' and midwives' experiences with videoconferencing and identify perceptions of the appropriateness, meaningfulness and feasibility of this technology in professional and clinical practice. BACKGROUND: Videoconferencing is a form of telehealth that can facilitate access to high-quality care to improve health outcomes for patients and enable clinicians working in isolation to access education, clinical supervision, peer support and case review. Yet use of videoconferencing has not translated smoothly into routine practice. Understanding the experiences of registered nurses and midwives may provide practitioners, service managers and policymakers with vital information to facilitate use of the technology. DESIGN: A qualitative meta-synthesis of primary qualitative studies undertaken according to Joanna Briggs Institute methodology. METHOD: A systematic search of 19 databases was used to identify qualitative studies that reported on registered nurses' or midwives' experiences with videoconferencing in clinical or professional practice. Two reviewers independently appraised studies, extracted data and synthesised findings to construct core concepts. RESULTS: Nine studies met the criteria for inclusion. Five key synthesised findings were identified: useful on a continuum; broader range of information; implications for professional practice; barriers to videoconferencing; and technical support, training and encouragement. CONCLUSIONS: While videoconferencing offers benefits, it comes with personal, organisational and professional consequences for nurses and midwives. Understanding potential benefits and limitations, training and support required and addressing potential professional implications all influence adoption and ongoing use of videoconferencing. RELEVANCE TO CLINICAL PRACTICE: Registered nurses and midwives are well placed to drive innovations and efficiencies in practice such as videoconferencing. Nursing and midwifery practice must be reframed to adapt to the virtual environment while retaining valued aspects of professional practice. This includes ensuring professional standards keep pace with the development of knowledge in this area and addressing the findings highlighted in this meta-synthesis. PMID- 29149508 TI - Implementing Quantum Search Algorithm with Metamaterials. AB - Metamaterials, artificially structured electromagnetic (EM) materials, have enabled the realization of many unconventional EM properties not found in nature, such as negative refractive index, magnetic response, invisibility cloaking, and so on. Based on these man-made materials with novel EM properties, various devices are designed and realized. However, quantum analog devices based on metamaterials have not been achieved so far. Here, metamaterials are designed and printed to perform quantum search algorithm. The structures, comprising of an array of 2D subwavelength air holes with different radii perforated on the dielectric layer, are fabricated using a 3D-printing technique. When an incident wave enters in the designed metamaterials, the profile of beam wavefront is processed iteratively as it propagates through the metamaterial periodically. After ~N roundtrips, precisely the same as the efficiency of quantum search algorithm, searched items will be found with the incident wave all focusing on the marked positions. Such a metamaterial-based quantum searching simulator may lead to remarkable achievements in wave-based signal processors. PMID- 29149509 TI - Promoting person-centred care in the perioperative setting through patient advocacy: An observational study. AB - AIMS AND OBJECTIVES: To examine the extent to which the findings from an integrative review regarding perioperative patient advocacy could be empirically supported, and to describe Swedish registered nurse anaesthetists' patient advocacy actions and interactions during the perioperative period. BACKGROUND: Patient advocacy is practiced by various healthcare professionals in promoting the well-being of patients. It is complex, and in a general healthcare context, it has been described as supporting the patients both physiologically and psychologically. During general anaesthesia, the patient enters an unconscious state, and the registered nurse anaesthetist safeguards patient privacy and autonomy. DESIGN: Qualitative descriptive. METHODS: Individual, nonparticipant observations (n = 16) with eight registered nurse anaesthetists. The observer followed the nurses unobtrusively by shadowing them during the perioperative phase on two separate occasions. The analysis was conducted with a directed content analysis in the light of four predetermined categories, identified in a previous integrative review of patient advocacy in the perioperative setting: protecting, value preserving, supporting and informing. RESULTS: The predetermined categories were empirically supported. They were further refined by identifying 11 new subcategories leading to a conceptual extension of the theoretical frame. The registered nurse anaesthetists interacted with the patient and all members of the surgical team when practicing perioperative patient advocacy and the actions were mostly initiated by the registered nurse anaesthetists themselves. CONCLUSIONS: The findings offer a new insight into the registered nurse anaesthetist's professional role. The observations deepen the understanding of the registered nurse anaesthetists' perioperative patient advocacy actions and can contribute to a more reflective and theory-oriented view of practice. RELEVANCE TO CLINICAL PRACTICE: The results from this study could be used to help registered nurse anaesthetists and their students understand practice in a more complete and insightful way. PMID- 29149511 TI - Depression During Pregnancy. PMID- 29149510 TI - Transferrin as a predictor of survival in cirrhosis. AB - Patients with cirrhosis frequently present with high serum ferritin and low transferrin concentrations, reflecting impaired liver function and inflammation. Recent studies have shown that transferrin and its saturation with iron are Model for End-Stage Liver Disease-independent predictors of mortality in patients with acute-on-chronic liver failure or decompensated cirrhosis. The aim of this study was to evaluate the prognostic utility of serum iron parameters in relation to markers of liver function and immune activation. Clinical, demographic, and biochemical data were retrospectively analyzed from a cohort of 1255 consecutive patients with cirrhosis (age >= 18 years) who presented from August 1, 2004 until December 31, 2014 at the University Hospital of Innsbruck. Patients with malignancies at diagnosis including hepatocellular carcinoma were excluded. Survival analysis was carried out by Cox regression by using baseline laboratory parameters, and findings were validated in an independent patient cohort. During a median follow-up of 2.4 years, 193 deaths occurred and 254 patients underwent liver transplantation. In patients with transferrin < 180 mg/dL, 3-month, 1-year, and 5-year transplant-free survival estimates were significantly lower (91.7%, 79.0%, and 30.5%) when compared with the group of patients with transferrin >= 180 mg/dL (98.9%, 95.5%, and 68.0%, P < 0.001). Transferrin predicted transplant free survival independently of Model for End-Stage Liver Disease-sodium (MELD-Na) and C-reactive protein (CRP) in multivariate regression analysis including all patients. When patients with alcoholic or nonalcoholic fatty liver disease were excluded, transferrin was in addition an albumin-independent predictor of transplant-free survival. In conclusion, the association of transferrin with transplant-free survival is independent of MELD-Na score and CRP. In patients without fatty liver disease, transferrin also predicts survival independently of albumin. Liver Transplantation 24 343-351 2018 AASLD. PMID- 29149512 TI - AACR publishes first set of childhood cancer predisposition screening recommendations. PMID- 29149513 TI - Physicians discuss ramifications of studies pointing to breast cancer overdiagnosis: New research under way attempts to better define who should be screened and treated. PMID- 29149514 TI - Isolation and characterization of high protein and phycocyanin producing mutants of Arthrospira platensis. AB - Cyanobacteria are known to exhibit their efficiency in producing high concentrations of compounds of commercial value. Arthrospira is one such cyanobacterium which is considered as important source of protein (65%) and other nutrients. In present study, chemical mutagenesis using N-methyl-N-Nitro nitrosoguanidine (NTG), a proven potent mutagen for cyanobacteria was used to bring stable and desirable alteration in Arthrospira platensis ARM 730. Three morphological mutants (G-1, G-2, and SF) were selected and characterized. The G-1 and G-2 were helical, more bluish in pigmentation than the wild type strain where G-1 also showed enlarged cell size. The SF mutant was an altered straight filament having maximum biomass. Among three mutants, higher protein and phycocyanin contents were observed in G-1 and G-2 mutants whereas chlorophyll was less in these mutants as compared to wild type strain indicating change in the pigment ratio. Carotenoid content was higher in SF mutant as compared to wild type and other mutants. Variation in total sugar content was not observed in comparison to wild type strain. The analysis of amino acid spectrum of all the mutants and wild type showed significant increase in proline content. Overall, it is revealed from the results that G-1 and G-2 mutants showed higher biomass, phycocyanin, and protein contents in comparison to wild type which indicated their great potential to be used in food and pharmaceutical industries. PMID- 29149515 TI - Outcomes in chronic rhinosinusitis. PMID- 29149516 TI - Feasibility of percutaneous left atrial appendage closure using a novel LAmbre occluder in patients with atrial fibrillation: Initial results from a prospective cohort registry study. AB - BACKGROUND: The LAmbreTM occluder is a novel device for percutaneous left atrial appendage closure (LAAC). The presented study aimed to report the initial experience in implantation of the novel LAmbre for LAAC in patients with nonvalvular AF. METHODS: We conducted a prospective, observational, cohort registry study to evaluate the feasibility of percutaneous LAAC using the LAmbre system. RESULTS: Thirty patients (15 female, mean age 77.6 +/- 8.9 years) who had high risks of stroke and contraindications for oral anticoagulation were prospectively enrolled in this registry study. The mean CHA2DS2-VaSc was 3.9 +/- 1.5, and the mean HAS-BLED score was 4.1 +/- 1.0. Twenty (66.7%) patients had chicken-wing LAA morphology. The implant success rate was 100%. The mean fluoroscopic time and procedure time were 3.5 +/- 1.9 and 29.0 +/- 10.1 minutes, respectively. No significant procedure-related complications were observed during in-hospital and acute clinical follow-up. CONCLUSION: In this preliminary study, the LAmbre occluder showed an excellent implant success rate, favorable implant property, and very low incidence of complications. Larger sample, randomized studies are further warranted. PMID- 29149517 TI - Resolving a Reactive Organometallic Intermediate from Dynamic Directing Group Systems by Selective C-H Activation. AB - Catalyst discovery from systems of potential precursors is a challenging endeavor. Herein, a new strategy applying dynamic chemistry to the identification of catalyst precursors from C-H activation of imines is proposed and evaluated. Using hydroacylation of imines as a model reaction, the selection of an organometallic reactive intermediate from a dynamic imine system, involving many potential directing group/metal entities, is demonstrated. The identity of the amplified reaction intermediate with the best directing group could be resolved in situ by ESI-MS, and coupling of the procedure to an iterative deconvolution protocol generated a system with high screening efficiency. PMID- 29149518 TI - Control of N-Heterocyclic Carbene Catalyzed Reactions of Enals: Asymmetric Synthesis of Oxindole-gamma-Amino Acid Derivatives. AB - A strategy to control the switch between a non-cycloaddition reaction and a cycloaddition reaction of enals, using N-heterocyclic carbene (NHC) catalyisis, has been developed. The new scalable protocol leads to gamma-amino-acid esters bearing a tetrasubstituted stereocenter in good yields and high stereoselectivities by homo-Mannich reactions of enals and isatin-derived ketimines. By simply changing the N-ketimine substituent to an ortho-hydroxy phenyl group, the corresponding spirocyclic oxindolo-gamma-lactams are obtained. PMID- 29149519 TI - Early executive dysfunction in ASD: Simple versus complex skills. AB - : Despite the strong evidence of executive function (EF) impairment in Autism Spectrum Disorder (ASD), findings in the preschool period have been inconsistent. Whereas some research has supported an early deficit, many studies have not found early differences in EF. The present study assessed simple and complex components of three EF abilities: working memory, inhibition, and shifting, using a novel battery, the Preschool EF Battery (PEFB; Garon, Smith & Bryson, Child Neuropsychology, 20, 713-736, 2014). Previous research has indicated that the PEFB is sensitive to age differences in typically developing (TD) children aged 18-60 months. Current participants were 34 preschoolers (M = 54.79 months) diagnosed with ASD and 255 TD preschoolers (M = 42.98 months). Results indicated significant differences between the two groups in the three EF abilities, but specific findings were moderated by mental and chronological age. The findings highlight the importance of testing simpler EF skills in very young children with ASD. Autism Res 2018, 11: 318-330. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Given that executive functions (EF) have been found to predict various outcomes such as academic ability and occupational success, sensitive early assessment is important. The current study suggests the presence of early EF deficits in preschool children with autism spectrum disorder. The study highlights the importance of considering how EF develops during early life in typically developing children in order to design sensitive EF measures. PMID- 29149520 TI - Compassion in practice-Evaluating the awareness, involvement and perceived impact of a national nursing and midwifery strategy amongst healthcare professionals in NHS Trusts in England. AB - AIMS AND OBJECTIVES: To report the findings from an evaluation of the impact of the Compassion in Practice Vision and Strategy (National Health Service England (NHSE), 2012) on nursing, midwifery and care staff. BACKGROUND: The Compassion in Practice Vision and Strategy was a programme of work to highlight the importance of compassionate care following the Francis Report in 2013 into the deficits in care in an NHS Hospital Trust. It was launched by NHS England in 2012 at a time when fiscal cuts were introduced by the Department of Health in England. DESIGN AND SETTING: Mixed methods. RESULTS: Inferential statistics were used to test whether there were significant differences between staff at different levels of seniority with regard to awareness and involvement in Compassion in Practice Vision and Strategy and their attitudes to it. Awareness and involvement of staff in Compassion in Practice Vision and Strategy were high amongst middle and senior management but limited at ward level. Staff involvement in Compassion in Practice Vision and Strategy was limited due to a lack of awareness. Ward level staff who were aware and involved, perceived a lack of support and communication from senior leadership to deliver the Compassion in Practice Vision and Strategy. DISCUSSION: Results reveal professional anger, distress and resistance to the Compassion in Practice Vision and Strategy and a view of the programme as a top down initiative which did not sufficiently recognise structural constraints on nurses' ability to deliver compassionate care. We discuss the implications of our findings for global nursing. CONCLUSION: Participants emphasised that compassion for patients is only sustainable where there is compassion for staff and many participants felt that they were not being treated with compassion. RELEVANCE FOR CLINICAL PRACTICE: National Health Service England should strongly affirm that nurses and midwives in general provide compassionate care. Trust leadership should provide support for ward level staff who deliver compassionate care in difficult circumstances. PMID- 29149521 TI - Addressing the Unmet Need for Maternal Mental Health Services in Low- and Middle Income Countries: Integrating Mental Health Into Maternal Health Care. PMID- 29149523 TI - Amniocentesis is still the best option for advanced genomic testing in case of fetal malformations. PMID- 29149522 TI - Melatonin improves the meiotic maturation of porcine oocytes by reducing endoplasmic reticulum stress during in vitro maturation. AB - Under endoplasmic reticulum (ER)-stress conditions, the unfolded protein response (UPR) generates a defense mechanism in mammalian cells. The regulation of UPR signaling is important in oocyte maturation, embryo development, and female reproduction of pigs. Recent studies have shown that melatonin plays an important role as an antioxidant to improve pig oocyte maturation. However, there is no report on the role of melatonin in the regulation of UPR signaling and ER-stress during in vitro maturation (IVM) of porcine oocytes. Therefore, the objective of this study was to investigate the antioxidative effects of melatonin on porcine oocyte maturation through the regulation of ER-stress and UPR signaling. We investigated the changes in the mRNA/protein expression levels of three UPR signal genes (Bip/Grp78, ATF4, P90/50ATF6, sXbp1, and CHOP) on oocytes, cumulus cells, and cumulus-oocyte complexes (COCs) during IVM (metaphase I; 22 hours and metaphase II; 44 hours) by Western blot and reverse transcription-polymerase chain reaction analysis. Treatment with the ER-stress inducer, tunicamycin (Tm), significantly increased expression of UPR markers. Additionally, cumulus cell expansion and meiotic maturation of oocytes were reduced in COCs of Tm-treated groups (1, 5, and 10 MUg/mL). We confirmed the reducing effects of melatonin (0.1 MUmol/L) on ER-stress after pretreatment with Tm (5 MUg/mL; 22 hours) in maturing COCs. Addition of melatonin (0.1 MUmol/L) to Tm-pretreated COCs recovered meiotic maturation rates and expression of most UPR markers. In conclusion, we confirmed a role for melatonin in the modulation of UPR signal pathways and reducing ER stress during IVM of porcine oocytes. PMID- 29149524 TI - A systematic review and meta-analysis of fetal outcomes following the administration of influenza A/H1N1 vaccination during pregnancy. AB - BACKGROUND: Pregnant women were identified as a population of priority for vaccination during the H1N1 influenza pandemic outbreak in 2009. OBJECTIVES: To assess adverse fetal outcomes following the administration of H1N1 pandemic vaccination during pregnancy. SEARCH STRATEGY: PubMed, Embase, and Cochrane Library were searched up to January 2017. SELECTION CRITERIA: Cohort studies investigating fetal outcomes after H1N1 influenza vaccination during pregnancy were eligible. The language was limited to English. DATA COLLECTION AND ANALYSIS: Pairs of reviewers independently screened studies for eligibility, assessed the risk of bias, and extracted data from the included studies. MAIN RESULTS: A total of 19 cohort studies were eligible. The use of vaccines during any period of pregnancy was associated with lower risk of stillbirth (adjusted hazard ratio 0.80, 95% confidence interval 0.69-0.92). No significant differences were found between the vaccinated versus unvaccinated groups in terms of the risks of spontaneous abortion, premature birth, and small for gestational age. CONCLUSIONS: The administration of H1N1 vaccines during pregnancy might reduce the risk of stillbirth, a complication associated with H1N1 infection. The quality of evidence was, however, not adequate to reach a definitive conclusion. PMID- 29149526 TI - Biofilm dynamics at the gingival frontier. AB - Microbial biofilms are common in the human body and in the environment. In recent years, dental plaque has been identified as a biofilm, and the structure, microbiology, and pathophysiology of dental biofilms have been characterised. The nature of the biofilm enhances the component bacterias' resistance to both the host's defence system and antimicrobials. If not removed regularly the biofilm undergoes maturation, resulting in dental caries, gingivitis, and periodontitis. The control of biofilm accumulation on teeth has been the cornerstone of periodontal disease prevention for decades. However, the widespread prevalence of gingivitis suggests the inefficiency of self-performed mechanical plaque control in preventing gingival inflammation. Studies indicate that effective antiseptic mouth-washes can provide significant gingivitis reduction beyond what can be accomplished with only brushing and flossing. Particularly, mouthrinses containing essential oils have well documented clinical antiplaque and antigingivitis effects. These mouthrinses have a positive track record of safety and their use does not increase the levels of resistant species. In summary, use of a well-established, essential oil mouthrinse can be recommended for daily use as an adjunct to mechanical methods of plaque control. PMID- 29149525 TI - Top 10 research priorities in head and neck cancer: Results of an Alberta priority setting partnership of patients, caregivers, family members, and clinicians. AB - BACKGROUND: The epidemiology, etiology, and management of head and neck cancer are evolving. Understanding the perspectives and priorities of nonresearchers regarding treatment uncertainties is important to inform future research. METHODS: Using the James Lind Alliance approach, patients, caregivers, and clinicians responded to a survey regarding their unanswered questions about treating and managing head and neck cancer. Distinct uncertainties were extracted from responses and sorted into themes. Uncertainties already answered in the literature were removed. Those remaining were ranked by patients and clinicians to develop a short list of priorities, which were discussed at a workshop and reduced to the top 10. RESULTS: One hundred sixty-one respondents posed 818 uncertainties, culminating in 77 for interim ranking and 27 for discussion at a workshop. Participants reached consensus on the top 10, which included questions on prevention, screening, treatment, and quality of life. CONCLUSION: Nonresearchers can effectively collaborate to establish priorities for future research in head and neck cancer. PMID- 29149527 TI - Burden of oral disease in the Middle East: Opportunities for dental public health. AB - A significant increase in the burden of oral-health related diseases in the Middle East has been observed recently. This increase has been largely the result of poor awareness concerning the importance of oral health and best practices towards achieving good oral hygiene. Contributing factors to this burden include but are not limited to: increased sugar consumption, inadequate oral hygiene practices and a high prevalence of smoking. All these factors are known to have considerable influence on the development of the most common oral diseases, such as dental caries, periodontal diseases, oral precancerous lesions and cancer. Although oral diseases represent a significant burden on the quality of life and healthcare economics of Middle Eastern countries, restorative and preventive dental care have not been given nearly enough attention. The prevention of dental diseases is critical to preserving not only oral health but also to maintaining general well being. This Supplement will address the need for oral disease preventative approaches with the use of epidemiological data, and will focus on the management and prevention of dental caries and periodontal disease, providing practical advice on for the management of plaque biofilm. There is a significant need for increased public awareness and regular surveillance of oral hygiene practices in the Middle East, as well as the complications associated with poor oral hygiene. In addition, development of guidelines, public health awareness programmess and dental community educational programmes are urgently needed. PMID- 29149528 TI - Improving oral health in the Middle East - recommendations from the first Middle East Oral Hygiene Advisory Board meeting. AB - Chronic periodontitis may be a sequela of chronic gingivitis, usually because of accumulation of plaque and calculus. Consistent good dental hygiene can help prevent gingivitis and periodontitis. Mechanical removal of plaque through frequent and efficacious brushing and flossing is the principal means of preventing periodontal diseases and diminishing the risk of caries. According to the American Dental Association (ADA), antimicrobial mouth-washes may provide additional oral health benefits, in addition to brushing and flossing, for preventing and reducing gingivitis and plaque. There is a multitude of mouthwashes available for these purposes. The consensus panel of the Middle East Oral Hygiene Advisory Board has recommended that an antiseptic mouthwash should be used as a daily adjunct to mechanical cleaning for prevention of oral disease. Recommending particular mouthwashes should take into consideration the patient's ability to perform good oral hygiene practices (tooth brushing and dental flossing), the condition of the patient's teeth, gingivae and oral mucosa, and the proven efficacy of the mouthwash along with its potential adverse effects. Of the many mouth rinses available, only a few contain chemical agents that have some ability to penetrate biofilm and to kill plaque biofilm bacteria. Currently, only chlorhexidine mouthrinse and Listerine (an essential oil-containing mouth rinse) products, with the claim of plaque and gingivitis reduction, have been accepted for that purpose by the ADA and have a proven record of safety and efficacy. Essential oil-containing mouthrinses have been clinically proven as effective in reducing plaque and gingivitis. Dental care professionals should spend time discussing biofilm control with their patients, and be an information source for the best oral care products. Therefore, it is essential that dental care professionals should continue to monitor published research and work with their colleagues to make evidence-based decisions. In this way, patients will be directed to dental hygiene aids, including antiseptic mouthwashes that can be most effective for improving their oral health. PMID- 29149529 TI - Scalable Fabrication of Highly Active and Durable Membrane Electrodes toward Water Oxidation. AB - The electrocatalytic oxygen evolution reaction (OER) is a highly important reaction that requires a relatively high overpotential and determines the rate of water splitting-a process for producing hydrogen. The overall OER performance is often largely limited by uncontrollable interface when active catalysts are loaded on conductive supports, for which polymer binders are widely used, but inevitably block species transportation channels. Here, a scalable fabrication approach to freestanding graphitized carbon nanofiber networks is reported, which provides abundant sites for in situ growing Fe/Ni catalysts with the improved interface. The fabricated hybrid membrane exhibits high activity and durability toward OER, with an overpotential of 280 mV at a geometrical current density of 10 mA cm-2 and a Tafel slope of 30 mV dec-1 in alkaline medium. As implemented as a freestanding electrode, the 3D hybrid structure achieves further enhanced OER performance with an overpotential down to 215 mV at 10 mA cm-2 . This work provides fresh insights into rationally fabricating OER electrocatalysts from the angle of electrode design. PMID- 29149530 TI - Proteases and protease inhibitors in infectious diseases. AB - There are numerous proteases of pathogenic organisms that are currently targeted for therapeutic intervention along with many that are seen as potential drug targets. This review discusses the chemical and biological makeup of some key druggable proteases expressed by the five major classes of disease causing agents, namely bacteria, viruses, fungi, eukaryotes, and prions. While a few of these enzymes including HIV protease and HCV NS3-4A protease have been targeted to a clinically useful level, a number are yet to yield any clinical outcomes in terms of antimicrobial therapy. A significant aspect of this review discusses the chemical and pharmacological characteristics of inhibitors of the various proteases discussed. A total of 25 inhibitors have been considered potent and safe enough to be trialed in humans and are at different levels of clinical application. We assess the mechanism of action and clinical performance of the protease inhibitors against infectious agents with their developmental strategies and look to the next frontiers in the use of protease inhibitors as anti infective agents. PMID- 29149531 TI - Solution Adsorption Formation of a pi-Conjugated Polymer/Graphene Composite for High-Performance Field-Effect Transistors. AB - Semiconducting polymers with pi-conjugated electronic structures have potential application in the large-scale printable fabrication of high-performance electronic and optoelectronic devices. However, owing to their poor environmental stability and high-cost synthesis, polymer semiconductors possess limited device implementation. Here, an approach for constructing a pi-conjugated polymer/graphene composite material to circumvent these limitations is provided, and then this material is patterned into 1D arrays. Driven by the pi-pi interaction, several-layer polymers can be adsorbed onto the graphene planes. The low consumption of the high-cost semiconductor polymers and the mass production of graphene contribute to the low-cost fabrication of the pi-conjugated polymer/graphene composite materials. Based on the pi-conjugated system, a reduced pi-pi stacking distance between graphene and the polymer can be achieved, yielding enhanced charge-transport properties. Owing to the incorporation of graphene, the composite material shows improved thermal stability. More generally, it is believed that the construction of the pi-conjugated composite shows clear possibility of integrating organic molecules and 2D materials into microstructure arrays for property-by-design fabrication of functional devices with large area, low cost, and high efficiency. PMID- 29149532 TI - Exploitation of microRNAs by Japanese Encephalitis virus in human microglial cells. AB - JEV infection in CNS leads to the JE neuroinflammation. Children and old age individual have been reported to be more prone to JEV infection. MicroRNAs are endogenous, small non-coding RNAs, which regulate the gene expression. These are ~22 nucleotide long, conserved RNA sequence that binds at the 3'UTR of a target mRNA and regulate the post-transcriptional gene expression. The role of microRNAs has been reported in several diseases like cancer, viral infection, neuro degeneration, diabetes etc. In the present study, the human microglial cells were infected with JEV (JaOArS982). The control and infected samples were subject to microarray profiling for microRNA expression. The microarray profile yielded differentially expressed microRNAs from JEV infected samples. The microRNA gene targets, gene ontology, annotations, and pathways were identified through various bioinformatics tools. Additionally, the pathways were mostly found common to "ubiquitin mediated proteolysis," "cytokine signaling," "maintenance of barrier function/cell junctions," JAK/STAT pathway" "Toll-like receptor signaling," "Wnt signaling," "adhesion molecules," "apoptosis," "endocytosis," "vesicle mediated transport" etc. PMID- 29149533 TI - Monocyte-Specific Knockout of C/ebpalpha Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebpalpha in Osteoclast Differentiation and Function. AB - CCAAT/enhancer-binding protein alpha (C/ebpalpha) is critical for osteoclastogenesis by regulating osteoclast (OC) lineage commitment and is also important for OC differentiation and function in vitro. However, the role of C/ebpalpha in postnatal skeletal development has not been reported owing to lethality in C/ebpalpha-/- mice from hypoglycemia within 8 hours after birth. Herein, we generated conditional knockout mice by deleting the C/ebpalpha gene in monocyte via LysM-Cre to examine its role in OC differentiation and function. C/ebpalphaf/f LysM-Cre mice exhibited postnatal osteopetrosis due to impaired osteoclastogenesis, OC lineage priming defects, as well as defective OC differentiation and activity. Furthermore, our ex vivo analysis demonstrated that C/ebpalpha conditional deletion significantly reduced OC differentiation, maturation, and activity while mildly repressing macrophage development. At the molecular level, C/ebpalpha deficiency significantly suppresses the expressions of OC genes associated with early stages of osteoclastogenesis as well as genes associated with OC differentiation and activity. We also identified numerous C/ebpalpha critical cis-regulatory elements on the Cathepsin K promoter that allow C/ebpalpha to significantly upregulate Cathepsin K expression during OC differentiation and activity. In pathologically induced mouse model of osteoporosis, C/ebpalpha deficiency can protect mice against ovariectomy-induced bone loss, uncovering a central role for C/ebpalpha in osteolytic diseases. Collectively, our findings have further established C/ebpalpha as a promising therapeutic target for bone loss by concurrently targeting OC lineage priming, differentiation, and activity. (c) 2017 American Society for Bone and Mineral Research. PMID- 29149535 TI - A Valence-Delocalised Osmium Dimer capable of Dinitrogen Photocleavage: Ab Initio Insights into Its Electronic Structure. AB - The search for molecular catalysts that efficiently activate or cleave the dinitrogen molecule is an active field of research. While many thermal dinitrogen cleavage catalysts are known, the photochemical activation of N2 has received considerably less attention. In this paper, the first computational study of the osmium dimer [Os(II,III)2 (MU-N2 )(NH3 )10 ]5+ , which was shown to be capable of dinitrogen photocleavage, is presented. Despite its deceptively simple geometry, it has a complex electronic structure with a valence-delocalized and electronically degenerate ground state. Using multiconfigurational methods, the electronic structure at the ground state geometry and along the dinitrogen cleavage coordinate was investigated. The results indicate that an unoccupied molecular orbital with sigma-bonding character between osmium and MU-N atoms and sigma-antibonding dinitrogen character is most affected by N-N distance elongation. This implies that a lower barrier for thermal or photochemical N2 activation in linear M-N-N-M complexes can be achieved by lowering the energetic separation between this unoccupied orbital and the HOMO, representing a specific target for future catalyst design. PMID- 29149534 TI - Novel N-propylphthalimide- and 4-vinylbenzyl-substituted benzimidazole salts: Synthesis, characterization, and determination of their metal chelating effects and inhibition profiles against acetylcholinesterase and carbonic anhydrase enzymes. AB - The novel N-propylphthalimide-substituted and 4-vinylbenzyl-substituted N heterocyclic carbene (NHC) precursors were synthesized by N-substituted benzimidazolium with aryl halides. The novel N-propylphthalimide-substituted and 4-vinylbenzyl-substituted NHC precursors have been characterized by using 1 H NMR, 13 C NMR, FTIR spectroscopy, and elemental analysis techniques. They were tested for the inhibition of AChE and hCA enzymes and demonstrated efficient inhibition profiles with Ki values in the range of 351.0-1269.9 nM against hCA I, 346.6-1193.1 nM against hCA II, and 19.0-76.3 nM against AChE. On the other hand, acetazolamide, a clinically used molecule, utilized as CA inhibitor, obtained a Ki value of 1246.7 nM against hCA I and 1407.6 nM against hCA II. Additionally, tacrine inhibited AChE and obtained a Ki value of 174.6 nM. PMID- 29149536 TI - Letter to the Editor regarding "Robotic or non-robotic transoral laryngectomy". PMID- 29149537 TI - Multifunctional Cellular Materials Based on 2D Nanomaterials: Prospects and Challenges. AB - Recent advances in emerging 2D nanomaterial-based cellular materials (2D-CMs) open up new opportunities for the development of next generation cellular solids with exceptional properties. Herein, an overview of the current research status of 2D-CMs is provided and their future opportunities are highlighted. First, the unique features of 2D nanomaterials are introduced to illustrate why these nanoscale building blocks are promising for the development of novel cellular materials and what the new features of 2D nanoscale building blocks can offer when compared to their 0D and 1D counterparts. An in-depth discussion on the structure-property relationships of 2D-CMs is then provided, and the remarkable functions that can be achieved by engineering their cellular architecture are highlighted. Additionally, the use of 2D-CMs to tackle key challenges in different practical applications is demonstrated. In conclusion, a personal perspective on the challenges and future research directions of 2D-CMs is given. PMID- 29149538 TI - Psychologic intimate partner violence and the risk of intrauterine growth restriction in Rio de Janeiro. AB - OBJECTIVE: To evaluate whether psychologic intimate partner violence (IPV) during pregnancy is a risk factor for intrauterine growth restriction (IUGR). METHODS: The cross-sectional study enrolled randomly selected mothers of infants younger than 5 months attending basic health services in Rio de Janeiro, Brazil, from January to July 2007. Psychologic and physical IPV were evaluated by the Revised Conflict Tactics Scale; IUGR was defined as below the 10th percentile of the Alexander curve. Socioeconomic status, housing conditions, stressful events, life habits, social support, and medical information were obtained by interview or from medical records. Multivariate hierarchical logistic regression models, taking into account potential confounders, were used to evaluate the relationship between mounting acts of psychologic IPV and IUGR. RESULTS: There were 810 women included in the study. Psychologic IPV during pregnancy was reported by 665 women (82.1%) and 126 newborns (15.6%) showed growth restriction. In the final model, each 1-unit increase in psychologic IPV score during pregnancy led to a 15% higher risk of IUGR at birth (odds ratio 1.15; P<0.001). CONCLUSION: Psychologic IPV during pregnancy seems to be a significant and independent risk factor for IUGR. This finding reinforces the importance of preventive and intervention procedures for IPV to reduce adverse perinatal outcomes. PMID- 29149539 TI - Dynamic Cross-Exchange in Halophosphonium Species: Direct Observation of Stereochemical Inversion in the Course of an SN 2 Process. AB - The complex fluxional interconversions between otherwise very similar phosphonium bromides and chlorides R3 PX+ X- (R=Alk, Ar, X=Cl or Br) were studied by NMR techniques. Their energy barriers are typically ca. 11 kcal mol-1 , but rise rapidly as bulky groups are attached to phosphorus, revealing the importance of steric factors. In contrast, electronic effects, as measured by Hammett analysis, are modest (rho 1.46) but still clearly indicate negative charge flow towards phosphorus in the transition state. Most significantly, detailed analysis of the exchange pathways unequivocally, and for the first time in any such process, shows that nucleophilic attack of the nucleophilic anion on the tetrahedral centre results in inversion of configuration. PMID- 29149540 TI - Controllable Synthesis of Organic Microcrystals with Tunable Emission Color and Morphology Based on Molecular Packing Mode. AB - Organic microcrystals are of essential importance for high fluorescence efficiency, ordered molecular packing mode, minimized defects, and smooth shapes, which are extensively applied in organic optoelectronics. The molecular packing mode significantly influences the optical/electrical properties of organic microcrystals, which makes the controllable preparation of organic microcrystals with desired molecular packing mode extremely important. In the study, yellow emissive alpha phase organic microcrystals with rectangular morphology and green emissive beta phase perylene microcrystals with rhombic morphology are separately prepared by simply controlling the solution concentration. The distinct molecular staking modes of the H/J-aggregate are found in these two types of perylene microcrystals, which contribute to the different emission color, morphology, and radiative decay rate. What is more interesting, the alpha-doped beta phase and the beta-doped alpha phase organic microcrystals can also be fabricated by modulating the evaporation rate from 100 to 10 uL min-1 . The findings can contribute to the future development of organic optoelectronics at the microscale. PMID- 29149541 TI - Diagnostic accuracy of serum miR-122 and miR-199a in women with endometriosis. AB - OBJECTIVE: To evaluate the value of serum microRNA-122 (miR-122) and miR-199a as reliable noninvasive biomarkers in the diagnosis of endometriosis. METHODS: During 2015-2016, at a teaching hospital in Egypt, a prospective cohort study was conducted on 45 women with pelvic endometriosis and 35 women who underwent laparoscopy for pelvic pain but were not diagnosed with endometriosis. Blood and peritoneal fluid (PF) samples were collected; interleukin-6 (IL-6) was detected by enzyme-linked immunosorbent assay and miR-122 and miR-199a expression was measured by quantitative real-time polymerase chain reaction. RESULTS: The serum and PF levels of IL-6, miR-122, and miR-199a were significantly higher in women with endometriosis than in controls (P<0.001 for all comparisons). Serum miR-122 expression was positively correlated with serum IL-6 (r=0.597), PF IL-6 (r=0.603), PF miR-122 (r=0.934), serum miR-199a (r=0.727), and PF miR-199a (r=0.653). Serum miR-199a expression was positively correlated with serum IL-6 (r=0.677), PF IL-6 (r=0.678), PF miR-122 (r=0.744), and PF miR-199a (r=0.932). Serum miR-122 and miR-199a had a sensitivity of 95.6% and 100.0%, and a specificity of 91.4% and 100%, respectively, for the detection of endometriosis. CONCLUSION: Serum miR-122 and miR-199a were significantly increased in endometriosis, indicating that these microRNAs might serve as biomarkers for the diagnosis of endometriosis. PMID- 29149542 TI - Spectrally encoded coherence tomography and reflectometry: Simultaneous en face and cross-sectional imaging at 2 gigapixels per second. AB - Non-invasive biological imaging is crucial for understanding in vivo structure and function. Optical coherence tomography (OCT) and reflectance confocal microscopy are two of the most widely used optical modalities for exogenous contrast-free, high-resolution, three-dimensional imaging in non-fluorescent scattering tissues. However, sample motion remains a critical barrier to raster scanned acquisition and reconstruction of wide-field anatomically accurate volumetric datasets. We introduce spectrally encoded coherence tomography and reflectometry (SECTR), a high-speed, multimodality system for simultaneous OCT and spectrally encoded reflectance (SER) imaging. SECTR utilizes a robust system design consisting of shared optical relays, scanning mirrors, swept laser and digitizer to achieve the fastest reported in vivo multimodal imaging rate of 2 gigapixels per second. Our optical design and acquisition scheme enable spatiotemporally co-registered acquisition of OCT cross-sections simultaneously with en face SER images for multivolumetric mosaicking. Complementary axial and lateral translation and rotation are extracted from OCT and SER data, respectively, for full volumetric estimation of sample motion with micron spatial and millisecond temporal resolution. PMID- 29149545 TI - Mechanical Properties in Metal-Organic Frameworks: Emerging Opportunities and Challenges for Device Functionality and Technological Applications. AB - Some of the most remarkable recent developments in metal-organic framework (MOF) performance properties can only be rationalized by the mechanical properties endowed by their hybrid inorganic-organic nanoporous structures. While these characteristics create intriguing application prospects, the same attributes also present challenges that will need to be overcome to enable the integration of MOFs with technologies where these promising traits can be exploited. In this review, emerging opportunities and challenges are identified for MOF-enabled device functionality and technological applications that arise from their fascinating mechanical properties. This is discussed not only in the context of their more well-studied gas storage and separation applications, but also for instances where MOFs serve as components of functional nanodevices. Recent advances in understanding MOF mechanical structure-property relationships due to attributes such as defects and interpenetration are highlighted, and open questions related to state-of-the-art computational approaches for quantifying their mechanical properties are critically discussed. PMID- 29149546 TI - Photophysical and Photoacoustic Properties of Quadrupolar Borondifluoride Curcuminoid Dyes. AB - The synthesis and characterization of a series of donor-pi-acceptor-pi-donor (D-A D) curcuminoid molecules is presented herein that incorporates pi-extended aryl and electron-donating amino terminal functionalization. Computational evaluation shows these molecules possess quadrupolar character with the lowest energy transitions displaying high molar extinction coefficients with broad tunability through manipulation of terminal donating groups. Consistent with their quadrupolar nature, these molecules show varying degrees of solvatochromic behavior in both their absorption and emission spectra, which has been analyzed by Lippert-Mataga and Kamlet-Taft analysis. Photophysical and photoacoustic (PA) properties of these molecules have been investigated by the optical photoacoustic z-scan (OPAZ) method. Selected curcuminoid molecules display nonlinear behavior at a high laser fluence through excited state absorption that translates to the production of an enhanced photoacoustic emission. A relative comparison of "molar PA emission" is also presented with the crystal violet linear optical absorbing/linear PA emitting system being utilized as a standard reference material for OPAZ experiments. Furthermore, PA tomography experiments are presented to illustrate the enhanced PA contrast obtainable via an excited state absorption. PMID- 29149547 TI - Engineering Escherichia coli Co-Cultures for Production of Curcuminoids From Glucose. AB - Curcuminoids (cus) have attracted increasing attention because of the antioxidant, anticancer, and antitumor activities while their production is limited because of its main source, turmeric plant, demonstrates extensive seasonal variation. In this study, we constructed Escherichia coli co-culture system for the rapid production of curcuminoids from glucose. Firstly, the overexpression of curcuminoid synthase and four different strategies related to increasing the intracellular malonyl-CoA pool were conducted in engineered E. coli. We found that bisdemethoxycurcumin (BDMC) is the main product and that high level of malonyl-CoA pool is essential for BDMC production. We also obtained the maximum titer (13.8 mg L-1 ) of BDMC within 4 h by fast preparation directly from p-coumaric acid. Secondly, we developed a process for BDMC synthesis from glucose using a co-culture system where an E. coli strain is used to produce p-coumaric acid from glucose and another E. coli strain converted p-coumaric acid into the final product. Compared to the mono-culture system, the co-culture is more potent and resulted in 6.28 mg L-1 of BDMC from glucose within 22 h of fermentation in a 3-L bioreactor. This is the first time a co-culture method is employed for the production of curcuminoids from glucose in a lab scale bioreactor. This system provides a new method transforming inexpensive substrate into value-added products. PMID- 29149548 TI - Case of the month. PMID- 29149549 TI - Workflow for Target-Oriented Parametrization of an Enhanced Mechanistic Cell Culture Model. AB - The goal of this study is to develop a macroscopic mechanistic model describing growth and production within fed-batch cultivations of CHO cells. The model should be used for process characterization as well as for process monitoring including real-time parameter adaptations. The model proved to be able to describe a data-set of 40 processes differing in clones, scales, and process conditions with a normalized root mean square error of approximately 10%. However, due to limited parameter identifiability and limited knowledge about physiologically meaningful parameter values, a broad range of parameters could describe the data with similar quality. This hampered comparison of the model parameters as well as their real-time estimation. Therefore an iterative workflow combining techniques like sensitivity and identifiability analysis, analysis of the specific rates as well as structural adaptations of the parameter space is developed. By applying it the parameter variability could be reduced by 80% with similar predictive power as the original parameters. Summing up, based on a mechanistic CHO model, a generic and transferrable workflow is created for target oriented parameter estimation in case of limited parameter identifiability. Finally, we suggest a methodology, which fits ideally into the frame of Process Analytical Technology aiming to increase process understanding. PMID- 29149550 TI - A promising on-demand treatment option for bleeding events in haemophilia patients with inhibitors. PMID- 29149551 TI - Can you grow out of von Willebrand disease? PMID- 29149553 TI - Cobalt Sulfide Quantum Dot Embedded N/S-Doped Carbon Nanosheets with Superior Reversibility and Rate Capability for Sodium-Ion Batteries. AB - Metal sulfides are promising anode materials for sodium-ion batteries due to their large specific capacities. The practical applications of metal sulfides in sodium-ion batteries, however, are still limited due to their large volume expansion, poor cycling stability, and sluggish electrode kinetics. In this work, a two-dimensional heterostructure of CoSx (CoS and Co9S8) quantum dots embedded N/S-doped carbon nanosheets (CoSx@NSC) is prepared by a sol-gel method. The CoSx quantum dots are in situ formed within ultrafine carbon nanosheets without further sulfidation, thus resulting in ultrafine CoSx particle size and embedded heterostructure. Meanwhile, enriched N and S codoping in the carbon nanosheets greatly enhances the electrical conductivity for the conductive matrix and creates more active sites for sodium storage. As a result, the hybrid CoSx@NSC electrode shows excellent rate capability (600 mAh g-1 at 0.2 A g-1 and 500 mAh g 1 at 10 A g-1) and outstanding cycling stability (87% capacity retention after 200 cycles at 1 A g-1), making it promising as an anode material for high performance sodium-ion batteries. A CoSx@NSC//Na0.44MnO2 full cell is demonstrated, and it can deliver a specific capacity of 414 mAh g-1 (based on the mass of CoSx@NSC) at a current density of 0.2 A g-1. PMID- 29149552 TI - Predicting Nano-Bio Interactions by Integrating Nanoparticle Libraries and Quantitative Nanostructure Activity Relationship Modeling. AB - The discovery of biocompatible or bioactive nanoparticles for medicinal applications is an expensive and time-consuming process that may be significantly facilitated by incorporating more rational approaches combining both experimental and computational methods. However, it is currently hindered by two limitations: (1) the lack of high-quality comprehensive data for computational modeling and (2) the lack of an effective modeling method for the complex nanomaterial structures. In this study, we tackled both issues by first synthesizing a large library of nanoparticles and obtained comprehensive data on their characterizations and bioactivities. Meanwhile, we virtually simulated each individual nanoparticle in this library by calculating their nanostructural characteristics and built models that correlate their nanostructure diversity to the corresponding biological activities. The resulting models were then used to predict and design nanoparticles with desired bioactivities. The experimental testing results of the designed nanoparticles were consistent with the model predictions. These findings demonstrate that rational design approaches combining high-quality nanoparticle libraries, big experimental data sets, and intelligent computational models can significantly reduce the efforts and costs of nanomaterial discovery. PMID- 29149554 TI - Boron Dissolved and Particulate Atmospheric Inputs to a Forest Ecosystem (Northeastern France). AB - Boron concentrations and isotopic compositions of atmospheric dust and dissolved depositions were monitored over a two-year period (2012-2013) in the forest ecosystem of Montiers (Northeastern France). This time series allows the determination of the boron atmospheric inputs to this forest ecosystem and contributes to refine our understanding of the sources and processes that control the boron atmospheric cycle. Mean annual dust and dissolved boron atmospheric depositions are comparable in size (13 g.ha-1.yr-1 and 16 g.ha-1.yr-1, respectively), which however show significant intra- and interannual variations. Boron isotopes in dust differ from dissolved inputs, with an annual mean value of +1 0/00 and +18 0/00 for, respectively. The notable high boron contents (190-390 MUg.g-1) of the dust samples are interpreted as resulting from localized spreading of boron-rich fertilizers, thus indicating a significant local impact of regional agricultural activities. Boron isotopes in dissolved depositions show a clear seasonal trend. The absence of correlation with marine cyclic solutes contradicts a control of atmospheric boron by dissolution of seasalts. Instead, the boron data from this study are consistent with a Rayleigh-like evolution of the atmospheric gaseous boron reservoir with possible but limited anthropogenic and/or biogenic contributions. PMID- 29149555 TI - Mapping the Reactions in a Single Zero-Valent Iron Nanoparticle. AB - Nanoscale zerovalent iron (nZVI) possesses unique functionalities for metal metalloid removal and sequestration. So far, direct evidence on the heavy metal nZVI reactions in the solid phase is still limited due to low concentration of heavy metals and small size of nanoparticles. In this work, angstrom-resolution spectral mappings on the reactions of nZVI with chromate, arsenate, nickel, silver, cesium, and zinc ions are presented. This work was achieved with spherical aberration-corrected scanning transmission electron microscopy integrated with high-sensitivity X-ray energy-dispersive spectroscopy-scanning transmission electron microscopy (XEDS-STEM). Results confirm that iron nanoparticles have a core-shell structure. In addition, the removal mechanism significantly depends on the standard potential E0 (E0 is standard potential w.r.t. standard hydrogen electrode at 25 degrees C when free ion activity is 1.). For strong oxidizing agents, such as Cr(VI), the removal mechanism is diffusion and encapsulation in the core area of the nZVI particle. For moderate oxidizers, such as As(V) with E0 more positive than that of iron, the removal mechanism is adsorption at the surface, followed by diffusion and encapsulation into the particle between the core and the shell. For metal cations with an E0 close to or more negative than that of iron, such as Cs(I) and Zn(II), the removal mechanism is sorption or surface-complex formation. For metal cations with E0 much more positive than that of iron, such as Ag(I), the removal mechanism is rapid reduction on the surface of nZVI. Meanwhile, metals with E0 slightly more positive than that of iron, such as Ni(II), can be immobilized at the nanoparticle surface via sorption and reduction. The synergetic effects of sorption, reduction, and encapsulation mechanisms of nZVI lead to rapid reactions and high efficiency for treatment and immobilization of many toxic heavy metals. Results also demonstrate that the XEDS-STEM technique is a powerful tool for studying reactions in individual nanoparticles and is particularly valuable for mapping trace-level elements in environmental media. PMID- 29149556 TI - Evaluating Force-Field London Dispersion Coefficients Using the Exchange-Hole Dipole Moment Model. AB - London dispersion interactions play an integral role in materials science and biophysics. Force fields for atomistic molecular simulations typically represent dispersion interactions by the 12-6 Lennard-Jones potential using empirically determined parameters. These parameters are generally underdetermined, and there is no straightforward way to test if they are physically realistic. Alternatively, the exchange-hole dipole moment (XDM) model from density functional theory predicts atomic and molecular London dispersion coefficients from first principles, providing an innovative strategy to validate the dispersion terms of molecular-mechanical force fields. In this work, the XDM model was used to obtain the London dispersion coefficients of 88 organic molecules relevant to biochemistry and pharmaceutical chemistry and the values compared with those derived from the Lennard-Jones parameters of the CGenFF, GAFF, OPLS, and Drude polarizable force fields. The molecular dispersion coefficients for the CGenFF, GAFF, and OPLS models are systematically higher than the XDM-calculated values by a factor of roughly 1.5, likely due to neglect of higher order dispersion terms and premature truncation of the dispersion-energy summation. The XDM dispersion coefficients span a large range for some molecular mechanical atom types, suggesting an unrecognized source of error in force-field models, which assume that atoms of the same type have the same dispersion interactions. Agreement with the XDM dispersion coefficients is even poorer for the Drude polarizable force field. Popular water models were also examined, and TIP3P was found to have dispersion coefficients similar to the experimental and XDM references, although other models employ anomalously high values. Finally, XDM-derived dispersion coefficients were used to parametrize molecular-mechanical force fields for five liquids-benzene, toluene, cyclohexane, n-pentane, and n hexane-which resulted in improved accuracy in the computed enthalpies of vaporization despite only having to evaluate a much smaller section of the parameter space. PMID- 29149557 TI - Enantiospecific and Iterative Suzuki-Miyaura Cross-Couplings. AB - The Suzuki-Miyaura cross-coupling reaction has emerged as one of the most powerful methods for the construction of carbon-carbon bonds. Though most widely utilized for the synthesis of sp2-sp2 linkages, the use of this reaction to form stereochemistry-bearing sp2-sp3 bonds has received widespread attention over the past decade. This Perspective highlights approaches to the synthesis of enantioenriched molecules via the Suzuki-Miyaura reaction. Particular focus is placed on the use of enantiomerically enriched organoboron compounds as coupling partners in stereospecific processes, as well as the development of enantioconvergent and group-selective reactions. In addition, progress in the development of chemoselective, iterative cross-coupling methods will be discussed. PMID- 29149558 TI - Quantification of Humic Substances in Natural Water Using Nitrogen-Doped Carbon Dots. AB - Dissolved organic matter (DOM) is ubiquitous in aqueous environments and plays a significant role in pollutant mitigation, transformation and organic geochemical circulation. DOM is also capable of forming carcinogenic byproducts in the disinfection treatment processes of drinking water. Thus, efficient methods for DOM quantification are highly desired. In this work, a novel sensor for rapid and selective detection of humic substances (HS), a key component of DOM, based on fluorescence quenching of nitrogen-doped carbon quantum dots was developed. The experimental results show that the HS detection range could be broadened to 100 mg/L with a detection limit of 0.2 mg/L. Moreover, the detection was effective within a wide pH range of 3.0 to 12.0, and the interferences of ions on the HS measurement were negligible. A good detection result for real surface water samples further validated the feasibility of the developed detection method. Furthermore, a nonradiation electron transfer mechanism for quenching the nitrogen-doped carbon-dots fluorescence by HS was elucidated. In addition, we prepared a test paper and proved its effectiveness. This work provides a new efficient method for the HS quantification than the frequently used modified Lowry method in terms of sensitivity and detection range. PMID- 29149559 TI - Core/Shell Microstructure Induced Synergistic Effect for Efficient Water-Droplet Formation and Cloud-Seeding Application. AB - Cloud-seeding materials as a promising water-augmentation technology have drawn more attention recently. We designed and synthesized a type of core/shell NaCl/TiO2 (CSNT) particle with controlled particle size, which successfully adsorbed more water vapor (~295 times at low relative humidity, 20% RH) than that of pure NaCl, deliquesced at a lower environmental RH of 62-66% than the hygroscopic point (hg.p., 75% RH) of NaCl, and formed larger water droplets ~6-10 times its original measured size area, whereas the pure NaCl still remained as a crystal at the same conditions. The enhanced performance was attributed to the synergistic effect of the hydrophilic TiO2 shell and hygroscopic NaCl core microstructure, which attracted a large amount of water vapor and turned it into a liquid faster. Moreover, the critical particle size of the CSNT particles (0.4 10 MUm) as cloud-seeding materials was predicted via the classical Kelvin equation based on their surface hydrophilicity. Finally, the benefits of CSNT particles for cloud-seeding applications were determined visually through in situ observation under an environmental scanning electron microscope on the microscale and cloud chamber experiments on the macroscale, respectively. These excellent and consistent performances positively confirmed that CSNT particles could be promising cloud-seeding materials. PMID- 29149560 TI - Extended Zinc AMBER Force Field (EZAFF). AB - An empirical approach based on the previously developed zinc AMBER force field (ZAFF) is proposed for the determination of the parameters for bonds and angles involving zinc. We call it the extended ZAFF (EZAFF) model because the original ZAFF model was only formulated for four-coordinated systems, while EZAFF additionally can tackle five- and six-coordinated systems. Tests were carried out for six metalloproteins and six organometallic compounds with different coordination spheres. Results validated the reliability of the current model to handle a variety of zinc containing complexes. Meanwhile, benchmark calculations were performed to assess the performance of three bonded molecular mechanics models (EZAFF, Seminario, and Z-matrix models), four nonbonded parameter sets (the HFE, IOD, CM, and 12-6-4 models), and four semiempirical quantum mechanical methods (AM1, PM3, PM6, and SCC-DFTB methods) for simulating zinc containing systems. The obtained results indicate that, even with their increased computational cost, the semiempirical quantum methods only offered slightly better accuracy for the computation of relative energies and only afforded similar molecular geometries, when compared to the investigated molecular mechanics models. PMID- 29149561 TI - Electrochemical Cobalt-Catalyzed C-H Oxygenation at Room Temperature. AB - Electrochemical cobalt-catalyzed C-H functionalizations were achieved in terms of C-H oxygenation under mild conditions at 23 degrees C. The robust electrochemical C-H functionalization was characterized by ample substrate scope, whereas mechanistic studies provided support for a facile C-H cleavage. The electrochemical cobalt-catalyzed C-H oxygenation proved viable on arenes and alkenes with excellent levels of positional and diastereo-selectivity, avoiding the use of stoichiometric silver(I) oxidants under ambient conditions. PMID- 29149562 TI - Nickel-Catalyzed Formation of 1,3-Dienes via a Highly Selective Cross Tetramerization of Tetrafluoroethylene, Styrenes, Alkynes, and Ethylene. AB - In the presence of a catalytic amount of Ni(cod)2 (cod = 1,5-cyclooctadiene) and PCy3 (Cy = cyclohexyl), the cross-tetramerization of tetrafluoroethylene (TFE), alkynes, and ethylene occurred in a highly selective manner to afford a variety of 1,3-dienes with a 3,3,4,4-tetrafluorobutyl chain. In addition, a Ni(0) catalyzed cross-tetramerization of TFE, alkynes, ethylene, and styrenes was developed. These catalytic reactions might proceed via partially fluorinated five and seven-membered nickelacycle key intermediates. PMID- 29149563 TI - Zein Nanoparticles Uptake by Hydroponically Grown Soybean Plants. AB - In the interest of developing and characterizing a polymeric nanoparticle pesticide delivery vehicle to soybeans, zein nanoparticle (ZNP) uptake by the roots and biodistribution to the leaves of soybean plants was measured. Zein was tagged with fluorescein isothiocyanate (FITC) and made into nanoparticles (135 +/ 3 nm diameter. 0.202 +/- 0.034 PDI and 81 +/- 4 mV zeta-potential at pH 6) using an emulsion-diffusion method. After 10 days of hydroponic exposure, association between particles and roots of plants was found to vary based on bulk nanoparticle concentration. While 0.37 mg NP/mg dry weight were detected in roots immersed in 0.88 mg NP/mL nanoparticle suspension, 0.58 mg NP/mg dry weight associated with roots immersed in a high dose nanoparticle suspension of 1.75 mg NP/mL at 10 days. Nanoparticle root uptake followed second order kinetics. A small amount of increased fluorescence was detected in the hydroponically exposed plant's leaves, suggesting that either small amounts of particles or other fluorescent contaminants of zein were up taken by the roots and biodistributed within the plant. To the authors' knowledge, this is the first study in which the uptake and time-dependent association between polymeric nanoparticles and soybeans are quantified. PMID- 29149565 TI - Enhanced Magnetic Hybridization of a Spinterface through Insertion of a Two Dimensional Magnetic Oxide Layer. AB - Interfaces between organic semiconductors and ferromagnetic metals offer intriguing opportunities in the rapidly developing field of organic spintronics. Understanding and controlling the spin-polarized electronic states at the interface is the key toward a reliable exploitation of this kind of systems. Here we propose an approach consisting in the insertion of a two-dimensional magnetic oxide layer at the interface with the aim of both increasing the reproducibility of the interface preparation and offering a way for a further fine control over the electronic and magnetic properties. We have inserted a two-dimensional Cr4O5 layer at the C60/Fe(001) interface and have characterized the corresponding morphological, electronic, and magnetic properties. Scanning tunneling microscopy and electron diffraction show that the film grows well-ordered both in the monolayer and multilayer regimes. Electron spectroscopies confirm that hybridization of the electronic states occurs at the interface. Finally, magnetic dichroism in X-ray absorption shows an unprecedented spin-polarization of the hybridized fullerene states. The latter result is discussed also in light of an ab initio theoretical analysis. PMID- 29149566 TI - iEDDA Reaction of the Molecular Iodine-Catalyzed Synthesis of 1,3,5-Triazines via Functionalization of the sp3 C-H Bond of Acetophenones with Amidines: An Experimental Investigation and DFT Study. AB - The present work reports an inverse electron demand Diels-Alder (iEDDA)-type reaction to synthesize 1,3,5-trizines from acetophenones and amidines. The use of molecular iodine in a catalytic amount facilitates the functionalization of the sp3 C-H bond of acetophenones. This is a simple and efficient methodology for the synthesis of 1,3,5-triazines in good to excellent yields under transition-metal free and peroxide-free conditions. The reaction is believed to take place via an in situ iodination-based oxidative elimination of formaldehyde. DFT calculations at the M062X/6-31+G(d,p) level were employed to investigate the reaction mechanism. Reaction barriers for the cycloaddition as well as a formaldehyde expulsion steps were computed, and a multistep mechanism starting with the nucleophilic attack by benzamidine on an in situ generated imine intermediate has been proposed. Both local and global reactivity descriptors were used to study the regioselectivity of the addition steps. PMID- 29149564 TI - Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition. AB - Understanding the fine balance between changes of entropy and enthalpy and the competition between a guest and water molecules in molecular binding is crucial in fundamental studies and practical applications. Experiments provide measurements. However, illustrating the binding/unbinding processes gives a complete picture of molecular recognition not directly available from experiments, and computational methods bridge the gaps. Here, we investigated guest association/dissociation with beta-cyclodextrin (beta-CD) by using microsecond-time-scale molecular dynamics (MD) simulations, postanalysis and numerical calculations. We computed association and dissociation rate constants, enthalpy, and solvent and solute entropy of binding. All the computed values of kon, koff, DeltaH, DeltaS, and DeltaG using GAFF-CD and q4MD-CD force fields for beta-CD could be compared with experimental data directly and agreed reasonably with experiment findings. In addition, our study further interprets experiments. Both force fields resulted in similar computed DeltaG from independently computed kinetics rates, DeltaG = -RT ln(kon.C0/koff), and thermodynamics properties, DeltaG = DeltaH - TDeltaS. The water entropy calculations show that the entropy gain of desolvating water molecules are a major driving force, and both force fields have the same strength of nonpolar attractions between solutes and beta-CD as well. Water molecules play a crucial role in guest binding to beta-CD. However, collective water/beta-CD motions could contribute to different computed kon and DeltaH values by different force fields, mainly because the parameters of beta-CD provide different motions of beta-CD, hydrogen-bond networks of water molecules in the cavity of free beta-CD, and strength of desolvation penalty. As a result, q4MD-CD suggests that guest binding is mostly driven by enthalpy, while GAFF-CD shows that gaining entropy is the major driving force of binding. The study deepens our understanding of ligand-receptor recognition and suggests strategies for force field parametrization for accurately modeling molecular systems. PMID- 29149567 TI - Preparation of Lithium Titanate/Reduced Graphene Oxide Composites with Three Dimensional "Fishnet-Like" Conductive Structure via a Gas-Foaming Method for High Rate Lithium-Ion Batteries. AB - With use of ammonium chloride (NH4Cl) as the pore-forming agent, three dimensional (3D) "fishnet-like" lithium titanate/reduced graphene oxide (LTO/G) composites with hierarchical porous structure are prepared via a gas-foaming method. Scanning electron microscopy and transmission electron microscopy images show that, in the composite prepared with the NH4Cl concentration of 1 mg mL-1 (1 LTO/G), LTO particles with sizes of 50-100 nm disperse homogeneously on the 3D "fishnet-like" graphene. The nitrogen-sorption analyses reveal the existence of micro-/mesopores, which is attributed to the introduction of NH4Cl into the gap between the graphene sheets that further decomposes into gases and produces hierarchical pores during the thermal treatment process. The loose and porous structure of 1-LTO/G composites enables the better penetration of electrolytes, providing more rapid diffusion channels for lithium ion. As a result, the 1-LTO/G electrode delivers an ultrahigh specific capacity of 176.6 mA h g-1 at a rate of 1 C. Even at 3 and 10 C, the specific capacity can reach 167.5 and 142.9 mA h g 1, respectively. Moreover, the 1-LTO/G electrode shows excellent cycle performance with 95.4% capacity retention at 10 C after 100 cycles. The results demonstrate that the LTO/G composite with these properties is one of the most promising anode materials for lithium-ion batteries. PMID- 29149568 TI - Individual Atomic Imaging of Multiple Dopant Sites in As-Doped Si Using Spectro Photoelectron Holography. AB - The atomic scale characterization of dopant atoms in semiconductor devices to establish correlations with the electrical activation of these atoms is essential to the advancement of contemporary semiconductor process technology. Spectro photoelectron holography combined with first-principles simulations can determine the local three-dimensional atomic structures of dopant elements, which in turn affect their electronic states. In the work reported herein, this technique was used to examine arsenic (As) atoms doped into a silicon (Si) crystal. As 3d core level photoelectron spectroscopy demonstrated the presence of three types of As atoms at a total concentration of approximately 1020 cm-3, denoted as BEH, BEM, and BEL. On the basis of Hall effect measurements, the BEH atoms corresponded to electrically active As occupying substitutional sites and exhibiting larger thermal fluctuations than the Si atoms, while the BEM atoms corresponded to electrically inactive As embedded in the AsnV (n = 2-4) type clusters. Finally, the BEL atoms were assigned to electrically inactive As in locally disordered structures. PMID- 29149569 TI - Blue Thermally Activated Delayed Fluorescence Polymers with Nonconjugated Backbone and Through-Space Charge Transfer Effect. AB - We demonstrate novel molecular design for thermally activated delayed fluorescence (TADF) polymers based on a nonconjugated polyethylene backbone with through-space charge transfer effect between pendant electron donor (D) and acceptor (A) units. Different from conventional conjugated D-A polymers with through-bond charge transfer effect, the nonconjugated architecture avoids direct conjugation between D and A units, enabling blue emission. Meanwhile, spatial pi pi interaction between the physically separated D and A units results in both small singlet-triplet energy splitting (0.019 eV) and high photoluminescence quantum yield (up to 60% in film state). The resulting polymer with 5 mol % acceptor unit gives efficient blue electroluminescence with Commission Internationale de l'Eclairage coordinates of (0.176, 0.269), together with a high external quantum efficiency of 12.1% and low efficiency roll-off of 4.9% (at 1000 cd m-2), which represents the first example of blue TADF nonconjugated polymer. PMID- 29149570 TI - Seagrass-Mediated Phosphorus and Iron Solubilization in Tropical Sediments. AB - Tropical seagrasses are nutrient-limited owing to the strong phosphorus fixation capacity of carbonate-rich sediments, yet they form densely vegetated, multispecies meadows in oligotrophic tropical waters. Using a novel combination of high-resolution, two-dimensional chemical imaging of O2, pH, iron, sulfide, calcium, and phosphorus, we found that tropical seagrasses are able to mobilize the essential nutrients iron and phosphorus in their rhizosphere via multiple biogeochemical pathways. We show that tropical seagrasses mobilize phosphorus and iron within their rhizosphere via plant-induced local acidification, leading to dissolution of carbonates and release of phosphate, and via local stimulation of microbial sulfide production, causing reduction of insoluble Fe(III) oxyhydroxides to dissolved Fe(II) with concomitant phosphate release into the rhizosphere porewater. These nutrient mobilization mechanisms have a direct link to seagrass-derived radial O2 loss and secretion of dissolved organic carbon from the below-ground tissue into the rhizosphere. Our demonstration of seagrass derived rhizospheric phosphorus and iron mobilization explains why seagrasses are widely distributed in oligotrophic tropical waters. PMID- 29149571 TI - Imaging and Spectroscopy of Single Metal Nanostructure Absorption. AB - The highly tunable optical properties of metal nanoparticles make them an ideal building block in any application that requires control over light, heat, or electrons on the nanoscale. Because of their size, metal nanoparticles both absorb and scatter light efficiently. Consequently, improving their performance often involves shifting the balance between absorption and scattering to promote desirable features of their optical properties. Scattering by single metal nanoparticles is commonly characterized using dark-field scattering spectroscopy, but routine methods to characterize pure absorption over a broad wavelength range are much more complex. This article reviews work from our lab using photothermal imaging in combination with dark-field scattering and electron microscopy to separate radiative and nonradiative properties of single nanoparticles and their assemblies. We present both initial work using different laser wavelengths to explore pure absorption free from scattering contributions based on the heat released into the environment as well as the development of photothermal spectroscopy over a broad wavelength range, making it possible to resolve details that are otherwise hidden in ensemble measurements that most of the time also do not separate radiative and nonradiative properties. PMID- 29149572 TI - Au(I)-Catalyzed Dimerization of Two Alkyne Units-Interplay between Butadienyl and Cyclopropenylmethyl Cation: Model Studies and Trapping Experiments. AB - In recent years, Au(I)-catalyzed reactions proved to be a valuable tool for the synthesis of substituted cycles by cycloaromatization and cycloisomerization starting from alkynes. Despite the myriad of Au(I)-catalyzed reactions of alkynes, the mono Au(I)-catalyzed pendant to the radical dimerization of nonconjugated alkyne units has not been investigated by quantum chemical calculations. Herein, by means of quantum chemical calculations, we describe the mono Au(I)-catalyzed dimerization of two alkyne units as well as the transannular ring closure reaction of a nonconjugated diyne. We found that depending on the system and the method used either the corresponding cyclopropenylmethyl cation or the butadienyl cation represents the stable intermediate. This circumstance could be explained by different stabilizing effects. Moreover, the calculation reveals a dramatic (>1012-fold) acceleration of the Au(I)-catalyzed reaction compared to that of the noncatalyzed radical variant. Trapping experiments with a substituted 1,6-cyclodecadiyne using benzene as a solvent at room temperature as well as studies with deuterated solvents confirm the calculations. In this context, we also demonstrate that trapping of the cationic intermediate with benzene does not proceed via a Friedel-Crafts-type reaction. PMID- 29149573 TI - The intrinsic genetic and epigenetic regulator factors as therapeutic targets, and the effect on fetal globin gene expression. AB - INTRODUCTION: The effort to induce fetal globin or Hb F gene expression as an alternative therapy for blood transfusion has been ongoing for few decades, with promising results evident in patients with hemoglobinopathies. Although the clinical outcomes have been satisfactory and significant, there are still concerns about the safety of Hb F inducers in the long-term. There are potent inducers which lose their potency and safety over the course of therapy. Area covered: In this work, efforts have been made to review the latest findings on intrinsic genetic and epigenetic factors which are able to induce the gene expression of fetal globin in adult patients with beta (beta)-thalassemia Major, Intermedia and sickle cell disease (SCD). Expert commentary: To meet a satisfying therapeutic outcome in patients with hemoglobinopathies, in addition to adopting a potent Hb F inducer, a continuous level of gamma (gamma)-globin gene over the course of therapy in safety condition also needs to be considered. Therefore, to reach this aim, it is suggested that the experiment designers consider the safety and long-term characteristics of the inducers simultaneously, by examining their synergistic effects. PMID- 29149574 TI - Transscleral passive and iontophoretic transport: theory and analysis. AB - INTRODUCTION: The sclera is considered the 'static barrier,' a main barrier for transscleral drug delivery. The characterization of passive and iontophoretic transport across the sclera in vitro is the first step toward our ability to predict transscleral drug delivery. Although previous studies have investigated this topic, the quantitative structure permeation relationships (QSPR) for passive and iontophoretic transscleral transport are not available. Areas covered: This review evaluated previous results of transscleral passive and iontophoretic transport in vitro and examined QSPR for transscleral permeation of small permeants and macromolecules. Passive permeation data in the literature were compared with respective to the animal species employed in the studies. Data variability was investigated. Electrotransport theory and the mechanisms of iontophoresis were reviewed and used to analyze the iontophoresis data. Expert opinion: QSPR was examined for passive transscleral permeation, showing correlations between logarithm of permeability coefficient and logarithm of molecular weight. Potential causes of data variability were proposed. QSPR were established for electroosmosis using the molecular weight of neutral permeants and for iontophoresis enhancement using the molecular weight and charge of ionic permeants. However, QSPR for charged macromolecules were empirical; iontophoretic flux enhancement was significantly smaller than Nernst-Planck model prediction due to complicating factors. PMID- 29149575 TI - Researchers of Color, Fame, and Impact. AB - Fame and eminence, as traditionally measured, limit the definition of impact to the publication world. We add two types of impact to the traditional measures of fame and eminence. Many of the traditional measures of fame or eminence are based on social-network connections, whereby individuals appoint other people to positions of eminence. Editorial boards are one specific example. Eminence is also limited to number of publications, for example, with little regard for the impact of those publications at the societal level. In addition to the dominant measures of eminence, societal impact broadens the definition of impact to reflect real-world changes. Two examples include mentoring, which is rarely mentioned as a criterion for eminence, and policy value, such as when research influences important public policy. These additions are discussed in reference to the general underrepresentation of researchers of color in academia. PMID- 29149577 TI - Introduction to a Follow-Up Symposium on "Am I Famous Yet?": Judging Scholarly Merit in Psychological Science. AB - I introduce a follow-up symposium to "'Am I Famous Yet?' Judging Scholarly Merit in Psychological Science," which was published in Perspectives on Psychological Science in November 2016. The follow-up symposium is intended to increase the diversity of contributors and contributions and thereby to continue and expand the discussion of how scholarly merit can be usefully evaluated in psychological science. PMID- 29149576 TI - Scholarly Merit in a Global Context: The Nation Gap in Psychological Science. AB - Psychologists from the United States are extremely prominent in psychological science, publishing more articles and receiving more citations than researchers from other nations. In this brief article, I review some previous research on this "nation gap" in psychology and highlight relevant data from journals published by the Association for Psychological Science. I then discuss some possible explanations for the nation gap and touch on some of its implications for thinking about scholarly merit and scientific eminence. I hope that the research and data discussed here will stimulate further consideration of the role of author nationality for both judgments of scholarly merit and psychological science more generally. PMID- 29149578 TI - Afterword: In the Matter of Judging Scientific Merit. AB - In this afterword, I suggest expanding upon some of the criteria for judging scientific merit that have been discussed in the two symposia on "judging scholarly merit in psychological science." I discuss in particular the value of creativity, analysis, common sense, and wisdom and ethics in scientific contributions and discourse. In the course of this discussion, I consider where the field of judging scientific merit has been, where it is now, and where it may go. PMID- 29149579 TI - Doing for the Greater Good: What Price, in Academe? AB - In discussing how merit is commonly judged in academia, my focus in this article is not on dimensions that are currently considered but on those that warrant more attention. Grounded in suggestions offered by Sternberg, I argue here for increased recognition of faculty's commitment to intrinsic values-focused on community and relationships-and not just extrinsic ones that connote personal fame or status. I first summarize evidence of disillusionment among today's promising young scholars and then provide exemplars of role models who have, in fact, maintained high standards in both intrinsic and extrinsic domains. I illustrate how commitment to intrinsic goals in everyday professional responsibilities (such as peer reviews or teaching) can come at the cost to personal success and suggest ways of providing appropriate recognition in faculty evaluations. At the macro level, I describe how positive work communities can enhance productivity, foster resilience, and mitigate burnout in the competitive world of contemporary academe. Finally, I underscore the critical role of psychologists in spurring greater dialogue about the messages conveyed by higher education, to the next generation, about what truly matters in making "a life well lived." PMID- 29149580 TI - Will Analytics Suppress a Diversity of Ideas in Psychological Science? AB - In this article, I suggest that an overreliance on analytics to assess faculty productivity and the diffusion of ideas may inadvertently suppress innovation. Even when these productivity-diffusion metrics are used to promote an individual's work, the use of such external guideposts may bias scientific choices and curb a psychological scientist's earnest inclination to synthesize or take scientific risks. Analytics are not inert but can change the path and progress of science itself, potentially reducing the diversity of ideas in psychological science. This potential harm may most affect new scholars at the beginning of their independent research careers. PMID- 29149581 TI - Family Matters: Measuring Impact Through One's Academic Descendants. AB - Scientific contributions take many forms, not all of which result in fame or are captured in traditional metrics of success (e.g., h factor). My focus is on one of the most lasting and important contributions a scientist can make: training scientists who go on to train scientists, who in turn train more scientists, etc. Academic genealogies provide many examples of scientists whose names might not be recognizable today but who trained psychologists that went on to publish very influential work. Of course success results from a combination of many factors (including but not limited to the student's abilities and motivation, luck, institutional resources, mentoring, etc.), but the field should find more ways to acknowledge the role that mentoring does play. PMID- 29149582 TI - Corrigendum: The Science and Practice of Self-Control. AB - Original article: Duckworth, A. L., & Seligman, M. E. P. (2017). The science and practice of self-control. Perspectives on Psychological Science, 12, 715-718. doi:10.1177/1745691617690880 On p. 715, right column, first paragraph, Duckworth, Tsukayama, and May (2010) should have been cited instead of Emanuele et al. (2010). The reference list should not have included Emanuele et al. (2010). Instead, the following reference should have been included: Duckworth, A. L., Tsukayama, E., & May, H. (2010). Establishing causality using longitudinal hierarchical linear modeling: An illustration predicting achievement from self control. Social Psychology and Personality Science, 1, 311-317. These errors are now being corrected. PMID- 29149583 TI - Why Traditional Metrics May Not Adequately Represent Ethnic Minority Psychology. AB - The first Perspectives on Psychological Science symposium on eminence in psychology focused almost exclusively on "traditional" markers of success (e.g., citation counts, awards, grants). In this essay, I argue that the context of the research and the context of the researchers are crucial components of ethnic minority psychology. First, I describe structural reasons for why ethnic minority researchers might have less impressive traditional markers of success; then, I highlight how the "minority tax" contours the scholarly activities of ethnic minority researchers. Any conceptualization of eminence must take these additional considerations into account. PMID- 29149584 TI - The Ill-Fated Quest for Fame in Psychological Research. AB - The question "Am I famous yet?" directs our attention to the outcome of the journey of being a psychological scientist. There is nothing inherently wrong with wanting to achieve the highest possible outcomes when pursuing a goal. However, for a researcher, fame is an outcome that is very vague, abstract, distal, and unlikely to be attained. Focusing on this outcome might undermine motivation and persistence in the difficult endeavor of doing excellent research and contributing to psychological knowledge. To become an excellent psychological scientist might be a better outcome to which to aspire. However, focusing on the outcome seems generally less adaptive than focusing on the process of goal pursuit. A focus on the process of research is more likely to lead to higher motivation and persistence, and it might increase performance. In sum, the question "Am I famous yet?" might be ill conceived and might be better replaced by the question "How do I make a contribution to psychological science?" PMID- 29149585 TI - Are Twitter and Blogs Important Tools for the Modern Psychological Scientist? AB - Psychological scientists have many roles, one of which is, arguably, to communicate their research findings to a broader audience. Twitter and blogging offer relatively inexpensive options for this type of outreach. Engagement in these outreach efforts can lead to career enhancement, but also comes at a cost. We examined a sample of 327 psychological scientists to determine the prevalence of this type of outreach; while the use of Twitter appears to be on the rise, blogging remains very rare. In this piece, we explore the costs and benefits for psychological scientists of blogging and engaging with the general public on Twitter, and how tweeting and blogging might relate to academic merit and varieties of fame in psychology. PMID- 29149586 TI - Scholarly Merits: From Measurement to Judgment. AB - The discussion in Perspectives on Psychological Science about criteria for scholarly merit shows a potential bias of quantitative measurements compared with informed judgments of scholarly merits. This comment argues for a selection procedure that is open for qualitative arguments. PMID- 29149587 TI - ... and the Wisdom to Know the Difference: Scholarly Success From a Wisdom Perspective. AB - What makes a researcher wise? At least for the field of psychology, I argue that the two main characteristics of scholarly wisdom are a desire to understand, rather than to be right, and an orientation toward ethical values. These characteristics do not necessarily produce the highest levels of academic success. Because wisdom is partly context dependent, the actual wisdom of our scientific output could be increased by making some changes to our publication and evaluation culture-changes that might benefit our field and even the world around us. PMID- 29149588 TI - NIH Support for FDA-Approved Medicines. PMID- 29149589 TI - Bond with Me If You Can! Natural Product, Covalent Ligand, and Reactivity-Based Probe Compete for Cysteine in PP2A Complex. AB - In this issue of Cell Chemical Biology, Grossman et al. (2017) disclose a chemoproteomics-enabled strategy to identify the cysteine-reactive target(s) of the anti-cancer natural product withaferin A and then screen a cysteine-reactive fragment library to discover a covalent ligand for the same target. PMID- 29149590 TI - Just a Spoonful of Sugar, HTLV-1 Style. AB - Host cell metabolism regulates viral infection. In this issue of Cell Chemical Biology, Kulkarni et al. (2017) reveal the importance of oxygen concentrations and glycolysis in the reactivation of human T cell leukemia virus (HTLV-1). Identifying the host metabolic networks that regulate infection will foster our understanding of HTLV-1-associated pathologies. PMID- 29149591 TI - Mitochondrial Sterol Oxidation Marks the Spot. AB - Maintenance of mitochondrial function during stress conditions is vital for cellular survival. In this issue of Molecular Cell, Nielson et al. (2017) characterize a unique domain within Vms1 that allows this protein quality control component to specifically recognize damaged or stressed compartments within the mitochondrial network. PMID- 29149592 TI - Dynamics under the Telomeric Bridge. AB - In this issue of Molecular Cell, Kim et al. (2017) have studied the structure and organization of the shelterin protein complex protecting telomeres in Schizosaccharomyces pombe and humans and discovered an allosteric structural transition that drives the formation of the shelterin complex and participates in telomere length regulation. PMID- 29149593 TI - NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis. AB - Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acro-osteolysis, severe osteoporosis, short stature, neurological symptoms, cardiovascular defects, and polycystic kidneys. Recent studies identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with the bone-related disorder pathogenesis, but the exact molecular mechanisms remain unclear. Here, we demonstrate that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C terminus that escapes FBW7-mediated ubiquitination and degradation. Mice with osteoclast-specific Fbw7 ablation revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 signaling. Importantly, administration of Notch inhibitors in Fbw7 conditional knockout mice alleviated progressive bone resorption. These findings highlight the molecular basis of HCS pathogenesis and provide clinical insights into potential targeted therapeutic strategies for skeletal disorders associated with the aberrant FBW7/NOTCH2 pathway as observed in patients with HCS. PMID- 29149594 TI - Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design. AB - Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation. PMID- 29149596 TI - Rational Design of Evolutionarily Stable Microbial Kill Switches. AB - The evolutionary stability of synthetic genetic circuits is key to both the understanding and application of genetic control elements. One useful but challenging situation is a switch between life and death depending on environment. Here are presented "essentializer" and "cryodeath" circuits, which act as kill switches in Escherichia coli. The essentializer element induces cell death upon the loss of a bi-stable cI/Cro memory switch. Cryodeath makes use of a cold-inducible promoter to express a toxin. We employ rational design and a toxin/antitoxin titering approach to produce and screen a small library of potential constructs, in order to select for constructs that are evolutionarily stable. Both kill switches were shown to maintain functionality in vitro for at least 140 generations. Additionally, cryodeath was shown to control the growth environment of a population, with an escape frequency of less than 1 in 105 after 10 days of growth in the mammalian gut. PMID- 29149595 TI - Sterol Oxidation Mediates Stress-Responsive Vms1 Translocation to Mitochondria. AB - Vms1 translocates to damaged mitochondria in response to stress, whereupon its binding partner, Cdc48, contributes to mitochondrial protein homeostasis. Mitochondrial targeting of Vms1 is mediated by its conserved mitochondrial targeting domain (MTD), which, in unstressed conditions, is inhibited by intramolecular binding to the Vms1 leucine-rich sequence (LRS). Here, we report a 2.7 A crystal structure of Vms1 that reveals that the LRS lies in a hydrophobic groove in the autoinhibited MTD. We also demonstrate that the oxidized sterol, ergosterol peroxide, is necessary and sufficient for Vms1 localization to mitochondria, through binding the MTD in an interaction that is competitive with binding to the LRS. These data support a model in which stressed mitochondria generate an oxidized sterol receptor that recruits Vms1 to support mitochondrial protein homeostasis. PMID- 29149597 TI - Structural Basis for Shelterin Bridge Assembly. AB - Telomere elongation through telomerase enables chromosome survival during cellular proliferation. The conserved multifunctional shelterin complex associates with telomeres to coordinate multiple telomere activities, including telomere elongation by telomerase. Similar to the human shelterin, fission yeast shelterin is composed of telomeric sequence-specific double- and single-stranded DNA-binding proteins, Taz1 and Pot1, respectively, bridged by Rap1, Poz1, and Tpz1. Here, we report the crystal structure of the fission yeast Tpz1475-508-Poz1 Rap1467-496 complex that provides the structural basis for shelterin bridge assembly. Biochemical analyses reveal that shelterin bridge assembly is a hierarchical process in which Tpz1 binding to Poz1 elicits structural changes in Poz1, allosterically promoting Rap1 binding to Poz1. Perturbation of the cooperative Tpz1-Poz1-Rap1 assembly through mutation of the "conformational trigger" in Poz1 leads to unregulated telomere lengthening. Furthermore, we find that the human shelterin counterparts TPP1-TIN2-TRF2 also assemble hierarchically, indicating cooperativity as a conserved driving force for shelterin assembly. PMID- 29149599 TI - Autophagosomal Content Profiling Reveals an LC3C-Dependent Piecemeal Mitophagy Pathway. AB - Autophagy allows the degradation of cytosolic endogenous and exogenous material in the lysosome. Substrates are engulfed by double-membrane vesicles, coined autophagosomes, which subsequently fuse with lysosomes. Depending on the involvement of specific receptor proteins, autophagy occurs in a selective or nonselective manner. While this process is well understood at the level of bulky cargo such as mitochondria and bacteria, we know very little about individual proteins and protein complexes that are engulfed and degraded by autophagy. In contrast to the critical role of autophagy in balancing proteostasis, our current knowledge of the autophagic degradome is very limited. Here, we combined proximity labeling with quantitative proteomics to systematically map the protein inventory of autophagosomes. Using this strategy, we uncovered a basal, housekeeping mitophagy pathway that involves piecemeal degradation of mitochondrial proteins in a LC3C- and p62-dependent manner and contributes to mitochondrial homeostasis maintenance when cells rely on oxidative phosphorylation. PMID- 29149598 TI - Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene. AB - Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2. Epigenomic profiling and genome editing revealed that AMIGO2 is regulated by a melanoma-specific BRD2/4-bound promoter and super-enhancer configuration. Upon BETi treatment, BETs are evicted from these regulatory elements, resulting in AMIGO2 silencing and changes in PTK7 proteolytic processing. Collectively, this study uncovers mechanisms underlying the therapeutic effects of BETi in melanoma and reveals the AMIGO2-PTK7 axis as a targetable pathway for metastatic melanoma. PMID- 29149600 TI - Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH. AB - DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defects. There are currently no curative therapies available. Here we performed a high-throughput chemical screen for agents that could alleviate the cellular sensitivity of NER-deficient cells to UV-induced DNA damage. This led to the identification of the clinically approved anti-diabetic drug acetohexamide, which promoted clearance of UV-induced DNA damage without the accumulation of chromosomal aberrations, hence promoting cellular survival. Acetohexamide exerted this protective function by antagonizing expression of the DNA glycosylase, MUTYH. Together, our data reveal the existence of an NER independent mechanism to remove UV-induced DNA damage and prevent cell death. PMID- 29149601 TI - Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability. PMID- 29149602 TI - Specification of Physiologic and Disease States by Distinct Proteins and Protein Conformations. AB - Protein conformational states-from intrinsically disordered ensembles to amyloids that underlie the self-templating, infectious properties of prion-like proteins have attracted much attention. Here, we highlight the diversity, including differences in biophysical properties, that drive distinct biological functions and pathologies among self-templating proteins. Advances in chemical genomics, gene editing, and model systems now permit deconstruction of the complex interplay between these protein states and the host factors that react to them. These methods reveal that conformational switches modulate normal and abnormal information transfer and that intimate relationships exist between the intrinsic function of proteins and the deleterious consequences of their misfolding. PMID- 29149603 TI - Structural Basis of Mitochondrial Transcription Initiation. AB - Transcription in human mitochondria is driven by a single-subunit, factor dependent RNA polymerase (mtRNAP). Despite its critical role in both expression and replication of the mitochondrial genome, transcription initiation by mtRNAP remains poorly understood. Here, we report crystal structures of human mitochondrial transcription initiation complexes assembled on both light and heavy strand promoters. The structures reveal how transcription factors TFAM and TFB2M assist mtRNAP to achieve promoter-dependent initiation. TFAM tethers the N terminal region of mtRNAP to recruit the polymerase to the promoter whereas TFB2M induces structural changes in mtRNAP to enable promoter opening and trapping of the DNA non-template strand. Structural comparisons demonstrate that the initiation mechanism in mitochondria is distinct from that in the well-studied nuclear, bacterial, or bacteriophage transcription systems but that similarities are found on the topological and conceptual level. These results provide a framework for studying the regulation of gene expression and DNA replication in mitochondria. PMID- 29149604 TI - NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis. AB - Cholesterol is a critical nutrient requiring tight constraint in the endoplasmic reticulum (ER) due to its uniquely challenging biophysical properties. While the mechanisms by which the ER defends against cholesterol insufficiency are well described, it remains unclear how the ER senses and effectively defends against cholesterol excess. Here, we identify the ER-bound transcription factor nuclear factor erythroid 2 related factor-1, Nrf1/Nfe2L1, as a critical mediator of this process. We show that Nrf1 directly binds to and specifically senses cholesterol in the ER through a defined domain and that cholesterol regulates Nrf1 turnover, processing, localization, and activity. In Nrf1 deficiency, in vivo cholesterol challenges induce massive hepatic cholesterol accumulation and damage, which is rescued by replacing Nrf1 exogenously. This Nrf1-mediated mechanism involves the suppression of CD36-driven inflammatory signaling and derepression of liver X receptor activity. These findings reveal Nrf1 as a guardian of cholesterol homeostasis and a core component of adaptive responses to excess cellular cholesterol. PMID- 29149605 TI - Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics. AB - Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit betaarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias. We find that betaarrestin biased compounds, such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression. PMID- 29149606 TI - Chronic Stress Alters Striosome-Circuit Dynamics, Leading to Aberrant Decision Making. AB - Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, "rational" decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict. VIDEO ABSTRACT. PMID- 29149608 TI - A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor Infiltrating T Cells. PMID- 29149609 TI - SnapShot: Functions of Endoplasmic Reticulum Membrane Contact Sites. AB - The endoplasmic reticulum (ER) consists of the nuclear envelope and a reticulated interconnected network of tubules and sheets. ER sheets are studded with ribosomes and provide the entryway for proteins into the secretory pathway. ER tubules move dynamically on microtubules and form membrane contact sites with other organelles, where membranes are tethered, but not fused. This Snapshot reviews key biological processes that take place at ER contact sites with the Golgi, endosomes, and mitochondria. PMID- 29149607 TI - Classifying Drosophila Olfactory Projection Neuron Subtypes by Single-Cell RNA Sequencing. AB - The definition of neuronal type and how it relates to the transcriptome are open questions. Drosophila olfactory projection neurons (PNs) are among the best characterized neuronal types: different PN classes target dendrites to distinct olfactory glomeruli, while PNs of the same class exhibit indistinguishable anatomical and physiological properties. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomes of most PN classes and unequivocally mapped transcriptomes to specific olfactory function for six classes. Transcriptomes of closely related PN classes exhibit the largest differences during circuit assembly but become indistinguishable in adults, suggesting that neuronal subtype diversity peaks during development. Transcription factors and cell-surface molecules are the most differentially expressed genes between classes and are highly informative in encoding cell identity, enabling us to identify a new lineage-specific transcription factor that instructs PN dendrite targeting. These findings establish that neuronal transcriptomic identity corresponds with anatomical and physiological identity defined by connectivity and function. PMID- 29149610 TI - First Approved Kinase Inhibitor for AML. AB - Activating mutations of FLT3 occur in about 30% of acute myeloid leukemia (AML) cases and are associated with relapse and poor prognosis. Midostaurin is the first drug approved for AML since 2000, and the first multi-kinase inhibitor approved for the FLT3-mutant subtype. To view this Bench to Bedside, open or download the PDF. PMID- 29149612 TI - Cancer Evolution: No Room for Negative Selection. AB - In this issue of Cell, Martincorena et al. and Campbell et al. interrogated the selection dynamics during tumor evolution using large-scale genomics datasets. They found that somatic mutations in cancer are largely neutral, highlighting a near-complete absence of negative selection. Neutral evolution enables tolerance of hypermutation, which defines a surprisingly large fraction of adult cancer. PMID- 29149611 TI - Core Clinical Data Elements for Cancer Genomic Repositories: A Multi-stakeholder Consensus. AB - The Center for Medical Technology Policy and the Molecular Evidence Development Consortium gathered a diverse group of more than 50 stakeholders to develop consensus on a core set of data elements and values essential to understanding the clinical utility of molecularly targeted therapies in oncology. PMID- 29149613 TI - Tuning Biased GPCR Signaling for Physiological Gain. AB - Effective and safe doses of opiate painkillers, like morphine, can be limited by respiratory depression. Schmid et al. (2017) now present a quantitative method to design ligands and correlate GPCR signaling bias to the dose separation between therapeutic and adverse effects in animals. PMID- 29149614 TI - Risky Business: The Circuits that Impact Stress-Induced Decision-Making. AB - How does stress promote risky decision-making? Friedman et al. find that stress disrupts inhibition of striatal circuits by prefrontal cortex, rendering animals insensitive to potential losses. This may help explain how stress contributes to substance abuse and how it can disinhibit automatic behaviors, such as tics in Tourette syndrome. PMID- 29149615 TI - Rethinking Unconventional Translation in Neurodegeneration. AB - Eukaryotic translation is tightly regulated to ensure that protein production occurs at the right time and place. Recent studies on abnormal repeat proteins, especially in age-dependent neurodegenerative diseases caused by nucleotide repeat expansion, have highlighted or identified two forms of unconventional translation initiation: usage of AUG-like sites (near cognates) or repeat associated non-AUG (RAN) translation. We discuss how repeat proteins may differ due to not just unconventional initiation, but also ribosomal frameshifting and/or imperfect repeat DNA replication, expansion, and repair, and we highlight how research on translation of repeats may uncover insights into the biology of translation and its contribution to disease. PMID- 29149617 TI - Decoding early and late cortical contributions to individuation of attended and unattended objects. AB - To isolate a visual stimulus as a unique object with a specific spatial location and time of occurrence, it is necessary to first register (individuate) the stimulus as a distinct perceptual entity. Recent investigations into the neural substrates of object individuation have suggested it is subserved by a distributed neural network, but previous manipulations of individuation load have introduced extraneous visual confounds, which might have yielded ambiguous findings, particularly in early cortical areas. Furthermore, while it has been assumed that selective attention is required for object individuation, there is no definitive evidence on the brain regions recruited for attended and ignored objects. Here we addressed these issues by combining functional magnetic resonance imaging (fMRI) with a novel object-enumeration paradigm in which to-be individuated objects were defined by illusory contours, such that the physical elements of the display remained constant across individuation conditions. Multi voxel pattern analyses revealed that attended objects modulated patterns of activity in early visual cortex, as well as frontal and parietal brain areas, as a function of object-individuation load. These findings suggest that object individuation recruits both early and later cortical areas, consistent with theoretical accounts proposing that this operation acts at the junction of feed forward and feedback processing stages in visual analysis. We also found dissociations between brain regions involved in individuation of attended and unattended objects, suggesting that voluntary spatial attention influences the brain regions recruited for this process. PMID- 29149616 TI - Protective effects of proanthocyanidins against cadmium-induced testicular injury through the modification of Nrf2-Keap1 signal path in rats. AB - The purpose of this study was to evaluate the potential chemoprotective effects of proanthocyanidins (PAs) against cadmium (Cd)-induced oxidative damage of testes via Nrf2-Keap1 signal pathway in rats. Briefly, by using biochemical histological analysis, as well as the real time PCR and western blot approach, oxidative damage in rat testicular tissue was observed after exposure to Cd. In addition, significant down-regulations of mRNA and protein levels of nuclear erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), gamma-glutamyl cysteine synthetase (gamma-GCS), glutathione peroxidase (GSH-Px) and quinone oxidoreductase 1 (NQO1), as well as a significant up-regulation of Kelch sample related protein-1 (Keap1) levels in testicular tissue were observed after Cd exposure. Notably, these alterations were reverted back to near normalcy in Cd+PAs group rats. In conclusion, PAs exhibited a significant chemopreventive potential against Cd-induced testicular oxidative damage in rats, possibly through the modification of Nrf2-Keap1 signal path. PMID- 29149618 TI - Effectiveness of a patient-centred, empowerment-based intervention programme among patients with poorly controlled type 2 diabetes: A randomised controlled trial. AB - BACKGROUND: Despite extensive efforts and advances in evidence-based diabetes management, poor glycaemic control still remains a challenge in many countries. There is a paucity of research addressing the needs of patients with poorly controlled type 2 diabetes, or exploring the effectiveness of empowerment-based interventions in this vulnerable population. OBJECTIVES: To evaluate the effectiveness of a patient-centred, empowerment-based programme on glycaemic control and self-management behaviours among patients with poorly controlled type 2 diabetes. DESIGN: A prospective multi-centre, single-blind, randomised controlled trial. SETTINGS AND PARTICIPANTS: Adult patients with poorly controlled type 2 diabetes [Haemoglobin A1c (HbA1c) >=7.5% in the recent six months] were recruited from two tertiary hospitals in Xi'an city, China. METHODS: A total of 242 eligible patients were recruited and randomly assigned to the intervention or attentional control groups after baseline measurement. Participants in the intervention group received a 6-week patient-centred, empowerment-based self-management programme, which is theoretically grounded on the principles of the Empowerment Process Model-setting personally meaningful goals, taking action towards goals and reflecting on the impact of action plans. Those in the attentional control group received health education classes and post discharge follow-up. Outcome measures included glycaemic control (measured by HbA1c) and self-management behaviours. Data were collected at baseline, and at 8th and 20th week after enrolment. Intervention effect were analysed using the generalised estimating equation model on the basis of the intention-to-treat principle. RESULTS: Compared with the attention control group, the intervention group showed a non-significant HbA1c reduction of 0. 476% (Cohen's d effect size=0.31, p=0.162). The intervention group exhibited significant improvements in general diet management at the 8th-week (beta=0.740; p=0.013), specific diet management at 8th-week (beta=0.646; p=0.022) and 20th-week (beta=0.517; p=0.043), and blood glucose self-monitoring at both the 8th- (beta=0.793; p=0.009) and 20th week (beta=0.739; p=0.017) follow-ups. No intervention-related adverse events were observed. CONCLUSIONS: Findings indicate that the patient-centred, empowerment-based self-management intervention program did not induce a significant HbA1c reduction. Whereas this intervention yields improvements in diet management and blood glucose self-monitoring among patients with poorly controlled type 2 diabetes. PMID- 29149619 TI - Association of SNPs in genes encoding zinc transporters on blood zinc levels in humans. AB - Zinc homeostasis in cells depends on zinc transporters, which are divided into 2 families: ZnT (SLC30A) and ZIP (SLC39A). In this study, we examined the effect of 20 single nucleotide polymorphisms (SNPs) in 10 genes encoding zinc transporters on blood zinc concentration in Japanese subjects (n = 102). Blood zinc levels were determined by microwave plasma-atomic emission spectrometry, and SNPs were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Among the 20 SNPs examined, 3 SNPs (SLC30A3 rs11126936, SLC39A8 rs233804, and SLC39A14 rs4872479) were significantly associated with blood zinc concentration. Individuals with genotype TT and TG in rs11126936 showed significantly higher blood zinc concentrations than those with GG. As for rs233804, individuals harboring the A allele had significantly higher blood zinc concentrations than those without this allele. Furthermore, the genotype TT and TG in rs4872479 had significantly higher blood zinc concentrations than those with GG. Among these three SNPs, combination of SLC30A3 rs11126936 and SLC39A8 rs233804 may strongly affect blood zinc levels. This study is the first comprehensive investigation of the effect of SNPs in genes encoding zinc transporters on blood zinc concentration. Adverse effects of zinc deficiency are reported and above 3 SNPs may be related to genetic susceptibility to zinc deficiency. PMID- 29149620 TI - The dopamine D4 receptor gene, birth weight, maternal depression, maternal attention, and the prediction of disorganized attachment at 36 months of age: A prospective gene*environment analysis. AB - BACKGROUND: Efforts to understand the developmental pathways for disorganized attachment reflect the importance of disorganized attachment on the prediction of future psychopathology. The inconsistent findings on the prediction of disorganized attachment from the dopamine D4 receptor (DRD4) gene, birth weight, and maternal depression as well as the evidence supporting the contribution of early maternal care, suggest the importance of exploring a gene by environment model. METHODS: Our sample is from the Maternal Adversity, Vulnerability, and Neurodevelopment project; consisting of 655 mother-child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 genotype was obtained with buccal swabs and categorized according to the presence of the 7-repeat allele. Maternal depression was assessed with the Center for Epidemiologic Studies Depression Scale at the prenatal, 6-, 12-, and 24-month assessments. Maternal attention was measured at 6-months using a videotaped session of a 20-min non-feeding interaction. Attachment was assessed at 36-months using the Strange Situation Procedure. RESULTS: The presence of the DRD4 7-repeat allele was associated with less disorganized attachment, beta=-1.11, OR=0.33, p=0.0008. Maternal looking away frequency showed significant interactions with maternal depression at the prenatal assessment, beta=0.003, OR=1.003, p=0.023, and at 24 months, beta=0.004, OR=1.004, p=0.021, as at both time points, women suffering from depression and with frequent looking away behavior had an increased probability of disorganized attachment in their child, while those with less looking away behavior had a decreased probability of disorganized attachment in their child at 36 months. CONCLUSIONS: Our models support the contribution of biological and multiple environmental factors in the complex prediction of disorganized attachment at 36 months. PMID- 29149621 TI - The risk factors related to bruxism in children: A systematic review and meta analysis. AB - OBJECTIVE: This systematic review was performed to determine the risk factors related to bruxism in children. DESIGN: This systematic review was conducted with reporting in agreement to the PRISMA statement and according to guidelines from the Cochrane Handbook for Systematic Reviews of Interventions. We conducted a systematic search of seven online databases, with the last search updated on 1st October 2016. The seven databases were Pubmed, Embase, Cochrane Library database, Web of Science, CNKI, CBM, and WF. The included trial type were RCT, cohort studies, and case-control studies, and bruxism symptoms were assessed by questionnaires and examinations. Eighteen out of the 5637 initially identified studies met the inclusion and exclusion criteria. RESULTS: gender, age, gene, mixed position, anxiety, the nervous, secondhand smoke, high psychological reactions, responsibility, move a lot during sleep, sleeps with mouth open, snores loudly, restless sleep, sleep hours, sleep with light on, noise in room, headache, biting, cheeks tonus, perioral musculature participation, conduct problems, peer problems, emotional symptoms, mental health problems, birth weight, occupation of family head, maternal marital status, hyperactivity, family income seemed to have statistical significance from the present systematic review and meta-analysis. CONCLUSIONS: The risk factors related to bruxism were as follows: Male, gene, mixed position, moves a lot, anxiety, the nervous, psychological reactions, responsibility, secondhand smoke, snore loudly, restless sleep, sleep with light on, noise in room, "sleep hours, <=8h", headache, objects biting, conduct problems, peer problems, emotional symptoms and mental health problems. PMID- 29149622 TI - The chemokine receptor type 4 antagonist, AMD3100, interrupts experimental tooth movement in rats. AB - OBJECTIVE: The aim of this study was to clarify the role of the stromal cell derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) axis in osteoclast accumulation, and the influence of orthodontic tooth movement (OTM) under mechanical force application to periodontal tissues, by administration of the CXCR4 antagonist AMD3100. DESIGN: The upper right first molar (M1) of rats was moved mesially with a 10-g force titanium-nickel closed coil spring. Rats were treated with phosphate-buffered saline or AMD3100 (5mg/kg), which is a SDF-1 antagonist. After 0, 1, 3, and 7days, alveolar bones in all groups were examined at each time point by micro-computed tomography and histological analysis. RESULTS: Tooth movement was decreased significantly in the AMD3100-treated group at 1, 3, and 7days after beginning OTM. The numbers of tartrate-resistant acid phosphatase-positive multinucleated cells in the periodontal ligament around the maxillary M1 were decreased significantly in the treated as compared to the control group on Days 1 and 3. CONCLUSION: Administration of AMD3100 decreases OTM and osteoclast accumulation in rat molars under orthodontic force application. These findings suggest that the SDF-1/CXCR4 axis plays an important role in alveolar bone metabolism during OTM. PMID- 29149624 TI - A PVC/polypyrrole sensor designed for beef taste detection using electrochemical methods and sensory evaluation. AB - An electrochemical sensor for detection of beef taste was designed in this study. This sensor was based on the structure of polyvinyl chloride/polypyrrole (PVC/PPy), which was polymerized onto the surface of a platinum (Pt) electrode to form a Pt-PPy-PVC film. Detecting by electrochemical methods, the sensor was well characterized by electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The sensor was applied to detect 10 rib-eye beef samples and the accuracy of the new sensor was validated by sensory evaluation and ion sensor detection. Several cluster analysis methods were used in the study to distinguish the beef samples. According to the obtained results, the designed sensor showed a high degree of association of electrochemical detection and sensory evaluation, which proved a fast and precise sensor for beef taste detection. PMID- 29149625 TI - The effects of pre-and post-slaughter spray application with organic acids on microbial population reductions on beef carcasses. AB - As an attempt to control bacterial cross-contamination of beef carcasses, in the present investigation acetic acid and lactic acid (3% v/v) were used for bacterial decontamination. For the decontamination, cows were sprayed with each above acid at two different stages; (i) on live animal's hides, (ii) on carcass surfaces immediately after slaughter. Microbiological samples were taken on different hide areas of animals before spraying and on carcass surfaces at 24h after spraying. Meat quality traits were also analyzed on the sprayed animals. The detected microorganisms were identified using 16SrRNA gene sequencing. A diversity of bacterial species such as Staphylococcus, Shigella, Bacillus, Escherichia and Salmonella etc. were found on both external hide and carcass surface samples. The decontamination sprays significantly reduced the numbers (2 5 log unit) of all aforementioned bacterial species on carcass surfaces as compared with non-sprayed control. Thus, the two times-spray applications with the acid could be an effective tool for reducing bacterial cross-contaminations of beef carcass without adverse effect on meat quality. PMID- 29149623 TI - The effect of surgical approach on gait mechanics after total hip arthroplasty. AB - BACKGROUND: Few studies have compared the biomechanical outcomes of different surgical approaches for hip arthroplasty. The purpose of this study was to compare hip, pelvic, and trunk kinematics and kinetics between individuals who underwent a posterior or anterolateral approach. METHODS: Forty-five individuals between 40 and 80 years old underwent motion analysis during overground gait prior to hip arthroplasty and 3 months after surgery. Walking speed, hip flexion angle, hip extension angle, adduction angle and moment, trunk angle, trunk lean, and pelvis drop were compared between approaches. FINDINGS: There were 30 subjects in the posterior group and 15 subjects in the anterolateral group. The groups did not change differently over time as there were no significant interaction effects. However, there were main effects for time; walking speed increased 19.9% (p < .001), hip flexion angle increased 3.3 degrees (p = 0.014) and peak hip extension increased 4.5 degrees (p = .001), and peak hip adduction significantly increased 1.9 degrees (p = .004) for the sample as a whole. Trunk angle (p = .283) and trunk lean (p = .401) did not significantly change between time points, but there was a significant increase in pelvic drop (p = .003). INTERPRETATION: Surgical approach did not affect biomechanical outcomes 3 months after arthroplasty. Both groups showed improvement in sagittal plane hip kinetics and kinematics. However, increased pelvic drop may be indicative of residual hip weakness in both groups. PMID- 29149626 TI - Crossbred young bulls and heifers sired by double-muscled Piemontese or Belgian Blue bulls exhibit different effects of sexual dimorphism on fattening performance and muscularity but not on meat quality traits. AB - As double-muscled Belgian Blue (BB) and Piemontese (PIEM) breeds are heavily selected for different objectives (the former mainly for muscularity, the latter for ease of calving), the aim of this study was to compare sexual dimorphism in 56 crossbred young bulls and heifers obtained from dairy cows mated to bulls of the two beef breeds. Young PIEM- and BB-sired bulls had similar fattening performances and beef traits, although the BB crossbreds were slightly more muscular. Otherwise, the BB-sired heifers exceeded the PIEM-sired heifers in growth rate (1.12 vs. 0.98kg/d), feed efficiency (0.129 vs. 0.121kg/kg DM), increases in muscle scores (1.45 vs. 0.98 SEUROP scores) and carcass yield (0.612 vs. 0.605), but not in fatness, retail cut proportions and meat quality traits. Sexual dimorphism is, therefore, less distinct in BB than in PIEM crossbreds. In conclusion, BB sires are to be preferred for "product quality", and PIEM sires for "process quality", on account of welfare and ethical issues. PMID- 29149627 TI - A simple and sensitive two-tube multiplex PCR assay for simultaneous detection of ten meat species. AB - A sensitive and reliable technique for meat species identification is required to prevent food adulteration, particularly in meat production. This work developed an optimized multiplex PCR assay for simultaneous identification of five commonly consumed and five commonly banned meat species in meat products. We designed primers that specifically amplified mitochondrial ATPase subunit 8 gene regions of different lengths of bovine, ovine, swine, chicken, turkey, cat, dog, mouse and human DNAs. The developed multiplex PCR assay proved to be specific, sensitive down to 30pg DNA per reaction, reproducible and economical. It could be used with a variety of raw meats and processed food samples and is easily applicable in a routine laboratory analysis without specific sophisticated equipment. PMID- 29149628 TI - Multiplex TaqMan locked nucleic acid real-time PCR for the differential identification of various meat and meat products. AB - Meat adulteration incidents have been reported frequently over the past few years, and the corresponding traceability issues attracted much more attention due to the customer's demands and administration's responsibility. Therefore, it is important to develop high-throughput and rapid detection methods to identify the specific sources from meat samples. In this study, a multiplex TaqMan locked nucleic acid real-time polymerase chain reaction assay (MLNA-RT-PCR) was developed to simultaneously detect multiple meat sources (duck, pork, beef and chicken). PCR primers and TaqMan-LNA probes were designed based on species specific mitochondrial gene sequences, and the MLNA-RT-PCR was developed and optimized for better performance. The specificity of this assay was verified through identifying unrelated (sheep, horse, deer, donkey, rabbit, goose, goat, shrimp, salmon and maize) mitochondrial DNA as species-specific targets. The detection limit for MLNA-RT-PCR reached to the level of 0.01% of each species. The assay was then used to identify the meat sources of commercial meat and meat derived products that were obtained from markets in Shantou, and the results were 98% consistent with that obtained from detection based on the national standard. In conclusion, this MLNA-RT-PCR is a high-throughput, sensitive and specific method that can be used to identify multiple meat sources in meat and meat derived products. PMID- 29149629 TI - Development and application of RTi-PCR method for common food pathogen presence and quantity in beef, sheep and chicken meat. AB - Two different RTi-PCR protocol were designed and quantifications were validated by using various amounts of DNA. Multiplex AGR1 and AGR2 RTi-PCR amplification reactions quantified successfully for Clostridium perfringens, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli O157:H7 and Salmonella enterica. Using the validated multiplex RTi-PCR reactions, the presence and quantification of pathogens were investigated in 40 beef, 41 sheep and 30 chicken meat samples. Results showed that the existence of C. perfringens, E. faecalis and S. aureus was 79%, 86% and 94%, respectively in the samples. Presence of E. coli O157:H7 and S. enterica were 90% and 91% in meat samples. The results showed that many meat samples were contaminated by examined five pathogens. Therefore, it is considered that these samples may pose a potential risk to the human health since same equipment are used for different animals in the slaughterhouse. This neglect increases the amount of pathogenic contamination. PMID- 29149630 TI - Age-related vulnerability of pattern separation in C57BL/6J mice. AB - Aging is associated with impaired performance in behavioral pattern separation (PS) tasks based on similarities in object features and in object location. These deficits have been attributed to functional alterations in the dentate gyrus (DG) CA3 region. Animal studies suggested a role of adult-born DG neurons in PS performance. The present study investigated the effect of aging in C57BL/6J mice performing PS tasks based on either object features or object location. At the age of 18 months or more, performance was severely impaired in both tasks. Spatial PS performance declined gradually over adult lifespan from 3 to 21 months. Subchronic treatment with the cognitive enhancer D-serine fully rescued spatial PS performance in 18-month-old mice and induced a modest increase in the number of 4-week-old adult-born cells in the DG. Performance of mice in these PS tasks shows an age dependence, which appears to translate well to that found in humans. This model should help in deciphering physiological changes underlying PS deficits and in identifying future therapeutic targets. PMID- 29149631 TI - Prostaglandin J2 promotes O-GlcNAcylation raising APP processing by alpha- and beta-secretases: relevance to Alzheimer's disease. AB - Regulation of the amyloid precursor protein (APP) processing by alpha- and beta secretases is of special interest to Alzheimer's disease (AD), as these proteases prevent or mediate amyloid beta formation, respectively. Neuroinflammation is also implicated in AD. Our data demonstrate that the endogenous mediator of inflammation prostaglandin J2 (PGJ2) promotes full-length APP (FL-APP) processing by alpha- and beta-secretases. The decrease in FL-APP was independent of proteasomal, lysosomal, calpain, caspase, and gamma-secretase activities. Moreover, PGJ2-treatment promoted cleavage of secreted APP, specifically sAPPalpha and sAPPbeta, generated by alpha and beta-secretase, respectively. Notably, PGJ2-treatment induced caspase-dependent cleavage of sAPPbeta. Mechanistically, PGJ2-treatment selectively diminished mature (O- and N glycosylated) but not immature (N-glycosylated only) FL-APP. PGJ2-treatment also increased the overall levels of protein O-GlcNAcylation, which occurs within the nucleocytoplasmic compartment. It is known that APP undergoes O-GlcNAcylation and that the latter protects proteins from proteasomal degradation. Our results suggest that by increasing protein O-GlcNAcylation levels, PGJ2 renders mature APP less prone to proteasomal degradation, thus shunting APP toward processing by alpha- and beta-secretases. PMID- 29149634 TI - Patient participation in nursing bedside handover: A systematic mixed-methods review. AB - BACKGROUND: Numerous reviews of nursing handover have been undertaken, but none have focused on the patients' role. OBJECTIVES: To explore how patient participation in nursing shift-to-shift bedside handover can be enacted. DESIGN: Systematic mixed- methods review. DATA SOURCES: Three search strategies were undertaken in July-August 2016: database searching, backwards citation searching and forward citation searching. To be included, papers had to either be research or quality improvement (QI) projects focusing on the patient role. Fifty-four articles were retrieved, including 21 studies and 25 QI projects. REVIEW METHODS: Screening, data extraction and quality appraisal was undertaken systematically by two reviewers. Research studies and QI projects were synthesised separately using thematic synthesis, then the results of this synthesis were combined using a mixed-method synthesis table. RESULTS: Segregated synthesis of research of patients' perceptions revealed two contrasting categories; patient-centred handover and nurse-centred handover. Segregated synthesis of research of nurses' perceptions included three categories: viewing the patient as an information resource; dealing with confidential and sensitive information; and enabling patient participation. The segregated synthesis of QI projects included two categories: nurse barrier to enacting patient participation in bedside handover; and involving patients in beside handover. Once segregated findings were configured, we discovered that the patient's role in bedside handover involves contributing clinical information related to their care or progress, which may influence patient safety. Barriers related to nurses' concerns for the consequences of encouraging patient participation, worries for sharing confidential and sensitive information and feeling hesitant in changing their handover methods. The way nurses approach patients, and how patient-centred they are, constitute further potential barriers. Strategies to improve patient participation in handover include training nurses, making handovers predictable for patients and involving both patients and nurses throughout the change process. CONCLUSIONS: Using research and QI projects allowed diverse findings to expand each other and identify gaps between research and heuristic knowledge. Our review showed the tension between standardising handovers and making them predictable for patient participation, while promoting tailored and flexible handovers. Further investigation of this issue is required, to understand how to train nurses and patient views. Many barriers and strategies identified were from QI projects and the nurse perspective, thus caution interpreting results is required. We recommend steps be taken in the future to ensure high quality QI projects. PMID- 29149633 TI - Neonatal and long-term ophthalmological findings in infants with symptomatic and asymptomatic congenital cytomegalovirus infection. AB - BACKGROUND: Congenital cytomegalovirus (cCMV) infection is responsible of a high burden of neurosensory impairment in children. OBJECTIVES: To report incidence and consequences of ophthalmological abnormalities in infants with cCMV infection and better define their long-term ophthalmological management. STUDY DESIGN: Infants with cCMV infection were enrolled in a 6-year follow-up. Infants were classified as symptomatic or asymptomatic based on complete clinical, laboratory and instrumental evaluations. All infants underwent funduscopic evaluation in neonatal period, and yearly complete ophthalmological evaluation, including funduscopic, motility and visual acuity assessments. RESULTS: Forty-eight infants were enrolled, 18/48 (37.5%) symptomatic and 30/48 (62.5%) asymptomatic. Mean duration of follow-up was 34.9+/-22.2 vs. 34.8+/-20.1months (P=0.98). Funduscopic abnormalities were identified in neonatal period in 7/18 (39%) symptomatic infants and in none of the infants without other clinical and instrumental abnormalities at birth (P<0.001); chorioretinal scars were the most common finding (5/18 cases, 28%). Strabismus was detected in 1/18 (5.5%) symptomatic infants during the first years of life. Visual impairment at last follow-up evaluation was suspected or detected in 4/18 (22%) symptomatic infants and in none of the asymptomatic infants at birth (P=0.01). Ophthalmological abnormalities were associated with other signs of central nervous system (CNS) involvement (P<0.001). No correlation was found with the type of maternal infection. CONCLUSIONS: Ophthalmological abnormalities were common in symptomatic infants though often not associated with long-term visual impairment, and correlated with the presence of CNS involvement. Neonatal and periodical ophthalmological evaluations throughout childhood seem prudential for symptomatic babies. No ophthalmological abnormalities were detected in asymptomatic infants, who might therefore undergo more deferred evaluations. PMID- 29149632 TI - Brain structural differences between 73- and 92-year olds matched for childhood intelligence, social background, and intracranial volume. AB - Fully characterizing age differences in the brain is a key task for combating aging-related cognitive decline. Using propensity score matching on 2 independent, narrow-age cohorts, we used data on childhood cognitive ability, socioeconomic background, and intracranial volume to match participants at mean age of 92 years (n = 42) to very similar participants at mean age of 73 years (n = 126). Examining a variety of global and regional structural neuroimaging variables, there were large differences in gray and white matter volumes, cortical surface area, cortical thickness, and white matter hyperintensity volume and spatial extent. In a mediation analysis, the total volume of white matter hyperintensities and total cortical surface area jointly mediated 24.9% of the relation between age and general cognitive ability (tissue volumes and cortical thickness were not significant mediators in this analysis). These findings provide an unusual and valuable perspective on neurostructural aging, in which brains from the 8th and 10th decades of life differ widely despite the same cognitive, socioeconomic, and brain-volumetric starting points. PMID- 29149635 TI - The association between adolescent cannabis use and anxiety: A parallel process analysis. AB - INTRODUCTION: Associations between anxiety symptoms and cannabis use have been previously explored, yet the directionality of these associations remains highly debatable. The present study aims to prospectively examine patterns of cannabis use and anxiety during adolescence focusing on their co-development and bidirectional influences. METHODS: Adolescents (n=250) of predominantly Hispanic ethnicity, aged 14-17 at baseline, exposed to drugs, alcohol, or cigarettes completed three (bi-annual) assessments across a 1-year period. Latent growth curve modeling (LGCM) and parallel process growth curves were conducted to examine potential associations in the joint development of anxiety and cannabis use. RESULTS: Our results suggest that, during adolescence, early cannabis use has a greater influence on prospective reports of anxiety, than vice versa. Specifically, adolescents exhibiting higher initial levels of cannabis use displayed more persisting self-reported anxiety across time, as compared to those with less frequent use (b=0.28, p=0.024). In contrast, early levels of anxiety were not found to influence rates of change in cannabis use. These analyses considered concurrent depression, alcohol, and nicotine use. CONCLUSIONS: Our findings suggest that prevention and targeted intervention programs for cannabis use in adolescence would benefit from anxiety management strategies; in order to reduce subsequent anxiety associated with cannabis use. Future studies should continue to employ longitudinal designs across larger time periods and aim to replicate these findings with more diverse samples. PMID- 29149637 TI - Antiviral potential of natural compounds against influenza virus hemagglutinin. AB - Influenza virus of different subtypes H1N1, H2N2, H3N2 and H5N1 cause many human pandemic deaths and threatening the people worldwide. The Hemagglutinin (HA) protein mediates viral attachment to host receptors act as an attractive target. The sixteen natural compounds have been chosen to target the HA protein. Molecular docking studies have been performed to find binding affinity of the compounds. Out of the sixteen, three compounds CI, CII and CIII found to posses a higher binding affinity. The molecular dynamics (MD) simulation has been performed to study the structural, dynamical properties for the nine different complexes CI, CII, CIII bound with H1, H2, H3 proteins and the results were compared. The molecular mechanics Poission-Boltzmann surface area (MM-PBSA) method is used to compare the binding free energy, its different energy components and per residue binding contribution. The H1 subtype shows higher binding preference for all the curcumin derivatives than H2 and H3. The binding capability of protein subtypes with curcumin derivatives and the binding affinity of curcumin compounds are in the order H1>H2>H3 and CI>CII>CIII respectively. The two -O-CH3- groups present in the CI compound help to have strong binding with HA protein than CII and CIII. The van der Waals interaction energy plays a significant role for binding in all the complexes. The hydrogen bonding interactions were monitored throughout the MD simulation. The conserved region (153-155) and the helix region (193-194) of H1, H2, H3 protein subtypes are found to possess higher binding susceptibility for binding of the curcumin derivatives. PMID- 29149636 TI - Examining characteristics associated with quitting smoking during pregnancy and relapse postpartum. AB - INTRODUCTION: Smoking during pregnancy is a significant public health concern that can cause adverse health outcomes for both the mother and fetus. Studies have shown only 40% of women quit smoking during pregnancy, with more than half relapsing within 6months, and up to 90% relapsing within one year. This study investigates differences in demographics and smoking-related symptomatology between pregnant smokers and pregnant quitters, as well as factors associated with postpartum relapse. METHODS: Data on pregnant smokers and pregnant quitters were obtained from two separate parent studies. Data on smoking demographics and smoking-related symptomatology were collected at screening visits. RESULTS: Compared to pregnant smokers, pregnant quitters had more favorable smoking characteristics (e.g., smoked fewer cigarettes per day, reported higher motivation for abstinence and less dependency). They also had more favorable relationship characteristics (e.g., were more likely to be married, less likely to have a significant other who smokes) and had less reproductive liability (e.g., fewer pregnancies, fewer children). In terms of symptomatology, pregnant quitters reported more positive affect, negative affect, physical symptoms and withdrawal but less craving. Predictors of postpartum relapse included increased maternal age, having a significant other who smokes and an increased likelihood of returning to smoking after pregnancy (self-reported prior to delivery). CONCLUSIONS: Several demographics and smoking-related symptomatology were significantly different between pregnant quitters and pregnant smokers. In addition, multiple factors predicting postpartum relapse were identified. This information can inform personalized interventions for high risk pregnant smokers and pregnant quitters at risk for postpartum relapse. PMID- 29149638 TI - Roles of N- and C-terminal domains in the ligand-binding properties of cytoglobin. AB - Cytoglobin (Cygb) is a member of the hexacoordinated globin protein family and is expressed ubiquitously in rat and human tissues. Although Cygb is reportedly upregulated under hypoxic conditions both in vivo and in vitro, suggesting a physiological function to protect cells under hypoxic/ischemic conditions by scavenging reactive oxygen species or by signal transduction, the mechanisms associated with this function have not been fully elucidated. Recent studies comparing Cygbs among several species suggest that mammalian Cygbs show a distinctly longer C-terminal domain potentially involved in unique physiological functions. In this study, we prepared human Cygb mutants (DeltaC, DeltaN, and DeltaNC) with either one or both terminal domains truncated and investigated the enzymatic functions and structural features by spectroscopic methods. Evaluation of the superoxide-scavenging activity between Cygb variants showed that the DeltaC and DeltaNC mutants exhibited slightly higher activity involving superoxide scavenging as compared with wild-type Cygb. Subsequent experiments involving ligand titration, flash photolysis, and resonance Raman spectroscopic studies suggested that the truncation of the C- and N-terminal domains resulted in less effective to dissociation constants and binding rates for carbon monoxide, respectively. Furthermore, structural stability was assessed by guanidine hydrochloride and revealed that the C-terminal domain might play a vital role in improving structure, whereas the N-terminal domain did not exert a similar effect. These findings indicated that long terminal domains could be important not only in regulating enzymatic activity but also for structural stability, and that the domains might be relevant to other hypothesized physiological functions for Cygb. PMID- 29149639 TI - Translation, cross-cultural adaptation, and measurement properties of the Brazilian version of the Identification of Functional Ankle Instability (IdFAI) questionnaire. AB - OBJECTIVES: The aim of this research was to describe the translation and cultural adaptation, and to test the validity and reliability of the Brazilian version of the Identification of Functional Ankle Instability (IdFAI) questionnaire. DESIGN: This was a clinical measurement. SETTING: This research took place at the Federal University of Sao Paulo in Brazil. PARTICIPANTS: Fifty college students participated in the translation and cultural adaptation, while another 50 students participated in the measurements (validity and reliability). MAIN OUTCOME MEASURES: The cross-cultural adaptation of the Brazilian IdFAI was accomplished using standard guidelines. For the validity and reliability, the individuals were asked to complete the IdFAI tests on the same day, and after two weeks maximum. The validity was assessed by correlating the Brazilian IdFAI with the Visual Analog Scale for Instability (VAS-I), the Cumberland Ankle Instability Tool (CAIT), and the Lower Extremity Functional Scale (LEFS) using Spearman's correlation coefficient. The test-retest reliability and internal consistency were determined by using an intraclass correlation (ICC2,1) and Cronbach's alpha, respectively. The agreement [standard error of measurement (SEM) and minimal detectable change at 90% (MDC90)] and the floor and ceiling effects were also assessed. RESULTS: The Brazilian IdFAI had strong correlation with the CAIT and moderate correlations with the VAS-I and LEFS scale, with excellent reliability, internal consistency and agreement. No ceiling or floor effects were observed. CONCLUSION: The Brazilian IdFAI questionnaire is a valid and reliable instrument to identify functional ankle instability. It can be used in both clinical and research settings. PMID- 29149640 TI - Change to ecosystem properties through changing the dominant species: Impact of Pteridium aquilinum-control and heathland restoration treatments on selected soil properties. AB - It is well known that soils are influenced by the plant species that grow in them. Here we consider the effects of management-induced changes to plant communities and their soils during restoration within a 20-year manipulative experiment where the aim was to change a late-successional community dominated by the weed, Pteridium aquilinum, to an earlier-successional grass-heath one. The ecological restoration treatments altered the above- and below-ground components of the community substantially. Untreated plots maintained a dense Pteridium cover with little understory vegetation, cutting treatments produce significant reductions of Pteridium, whereas herbicide (asulam) produced significant immediate reductions in Pteridium but regressed towards the untreated plots within 10 years. Thereafter, all asulam-treated plots were re-treated in year 11, and then were spot-sprayed annually. Both cutting and asulam treatments reduced frond density to almost zero and resulted in a grass-heath vegetation. There was also a massive change in biomass distribution, untreated plots had a large above ground biomass/necromass that was much reduced where Pteridium was controlled. Below-ground in treated plots, there was a replacement of the substantive Pteridium rhizome mass with a much greater root mass of other species. The combined effects of Pteridium-control and restoration treatment, reduced soil total C and N as and available P concentrations, but increased soil pH and available N. Soil biological activity was also affected with a reduction in soil N mineralization rate, but an increased soil-root respiration. Multivariate analysis showed a clear trend along a pH/organic matter gradient, with movement along it correlated to management intensity from the untreated plots with low pH/high organic matter and treated plots with to a higher pH/lower organic matter in the sequence asulam treatment, cut once per year to cut twice per year. The role that these changed soil conditions might have in restricting Pteridium recovery are discussed. PMID- 29149641 TI - Site closure management strategies and the responsiveness of conservation outcomes in recreational fishing. AB - We develop and use an empirically based model, which integrates fishing behaviour and a coral reef system, to evaluate outcomes from site closure strategies to manage the effects of recreational fishing. The model is designed to estimate management effects in complex settings with two-way feedback effects (between fishing and ecosystem dynamics) as well as spillover effects where the closure of a site (or sites) leads to the redistribution of fishing effort. An iconic coral reef system is used as a case study. The results demonstrate that some site closure strategies provide little incremental benefits over less stringent approaches. They also show that some strategies targeting more sites are actually inferior to more limited strategies, demonstrating that, in the analysis of complex problems involving feedback effects and substitutions, there is little substitute for the use of empirically based and sound modelling as the basis for informed conservation decision making and stakeholder consultation. These findings have direct relevance not only for policies aimed at improving recreational fishing management but also for securing the supply of marine ecosystem services. PMID- 29149642 TI - Oxidative stress, cell cycle arrest, DNA damage and apoptosis in adult zebrafish (Danio rerio) induced by tris(1,3-dichloro-2-propyl) phosphate. AB - Tris(1,3-dichloro-2-propyl)phosphate (TDCPP) is an additive flame retardant of high production volume, and frequently detected in biota and environment. However, knowledge on its potential risk and toxicological mechanism still remains limited. In this study, DNA damage, transcriptomic responses and biochemical changes in the liver of zebrafish (Danio rerio) induced by TDCPP were investigated. Zebrafish was exposed to 45.81MUg/L (1/100 (96h-LC50)) and 229.05MUg/L (1/20 (96h-LC50)) TDCPP for 7 d. The reactive oxygen species (ROS) and GSH contents, in addition to antioxidant enzyme activities in the liver changed significantly, and the mRNA levels of genes related to oxidative stress were alerted in a dose-dependent and/or sex-dependent manner after exposure to TDCPP. Significant DNA damage in zebrafish liver was found, and olive tail moment increased in a concentration-dependent manner. Moreover, exposure of TDCPP at 45.81MUg/L level activated the cell cycle arrest, DNA repair system and apoptosis pathway in male zebrafish, and 229.05MUg/L TDCPP exposure inhibited those pathways in both male and female zebrafish. The cell apoptosis was confirmed in TUNEL assay as higher incidence of TUNEL-positive cells were observed in zebrafish exposed to 229.05MUg/L TDCPP. Our results also indicated that males were more sensitive to TDCPP exposure compared with females. Taken together, our results showed that TDCPP could induce oxidative stress, cell cycle arrest, DNA damage and apoptosis in adult zebrafish liver in sex- and concentration-dependent manners. PMID- 29149644 TI - Assessing the risk of laparoscopic morcellation of occult uterine sarcomas during hysterectomy and myomectomy: Literature review and the ISGE recommendations. AB - OBJECTIVE: This project of the International Society for Gynecologic Endoscopy (ISGE) had the objective to review the literature and provide recommendations on the occult sarcoma risk assessment in patients who are candidates for minimally invasive gynecological surgery involving intra-abdominal electromechanical tissue morcellation. STUDY DESIGN: The ISGE Task Force for Estimation of the Risk in Endoscopic Morcellation initially defined key topics and clinical questions which may guide a comprehensive preoperative patient assessment. A literature search within the Medline/PubMed and Cochrane Database was carried out using keywords "morcellation", "uterine fibroids", "uterine sarcoma", "myomectomy" and "hysterectomy". Relevant publications (original studies, meta-analyses and previous reviews), written in English and published until May 30th, 2017, were selected and analyzed. Previously emitted statements of 12 recognized professional societies or government institutions and their supporting literature were also studied. For each topic/clinical question, the available information was graded by the level of evidence. The ISGE recommendations were established in accordance with the evidence quality. RESULTS: In the light of available information, 9 recommendations on preoperative clinical, laboratorial and imaging evaluation of the candidates for intracorporeal uterus/leiomyoma morcellation were formulated, mainly based on consensus and expert opinions. There is a lack of high-quality evidence, which does not allow the establishment of strong recommendations. CONCLUSION: Electromechanical tissue morcellation may be used in gynecological patients who are considered "low risk" upon appropriate preoperative evaluation; however, further studies and prospective data collection are greatly needed to improve sarcoma risk assessment in women with presumed uterine leiomyomas. PMID- 29149643 TI - The role of the p38-activated protein kinase signaling pathway-mediated autophagy in cadmium-exposed monogonont rotifer Brachious koreanus. AB - Autophagy is a 'self-eating' system that regulates the degradation of cellular components and is involved in various biological processes including survival and development. However, despite its crucial role in organisms, the regulatory mechanism of autophagy remains largely unclear, particularly in invertebrates. In this study, conserved autophagy in the rotifer Brachionus koreanus in response to cadmium (Cd) exposure was verified by measuring acidic vesicle organelles using acridine orange (AO) and neutral red (NR) staining, and by detecting LC3 I/II on Western blot and immunofluorescence. We also demonstrated activation of p38 mitogen-activated protein kinase (MAPK) in response to Cd-induced oxidative stress, leading to the induction of autophagy in B. koreanus. This was further verified by analysis of MAPK protein levels and immunofluorescence of LC3 I/II after treatment with reactive oxygen species (ROS) scavengers and inhibitors specific to MAPKs. We propose a p38 MAPK-mediated regulatory mechanism of autophagy in B. koreanus in response to Cd-induced oxidative stress. This study will contribute to a better understanding of autophagic processes in invertebrates and its modulation by environmental stressors. PMID- 29149645 TI - Xylella fastidiosa induces differential expression of lignification related-genes and lignin accumulation in tolerant olive trees cv. Leccino. AB - Recently, Xylella fastidiosa was reported in Italy, associated with the "Olive Quick Decline Syndrome". The cv. Leccino exhibits an evident tolerance with a slow disease progression compared with the other cultivars. Between the mechanisms proposed to explain the putative tolerance of some hosts to X. fastidiosa diseases, lignin deposition plays an important role. Analysis of phenolic compounds in healthy and infected Leccino and Cellina di Nardo leaves showed, in the two cultivars, a reduction of hydroxytyrosol glucoside (usually associated with drought and cold stress) and, only in Leccino, an increase of quinic acid, precursor of lignin. To determine if lignin biosynthesis is involved in defence response, we investigated the expression of genes coding for entry point enzymes in different branches of the phenylpropanoid pathway. In stems of Cellina di Nardo infected plants, Cinnamate-4-Hydroxylase (C4H) and 4 Coumarate:CoA Ligase (4CL) resulted strongly down-regulated, indicating a plant disease response since the inhibition of C4H is reported to promote the accumulation of benzoic acid and salicylic acid as defence signals. Instead, in the cv. Leccino, Cinnamoyl-CoA Reductase (CCR, reported to be strongly induced during the formation of lignin defence response associated) was up-regulated in the stem of infected plants; moreover, Polyphenol oxidase (PPO), coding for an enzyme involved in the hydroxytyrosol biosynthesis, was down-regulated. The quantification of lignin in healthy and infected branches of both cultivars, showed a significant increase of total lignin in infected Leccino compared with the sensitive cultivar; moreover, histochemical observations of stem sections exhibited a different lignin distribution in the sclerenchyma and in the xylem tissue of infected Leccino plants compared to sections of healthy ones. Results suggest a critical role for lignin in X. fastidiosa tolerance of cv. Leccino. PMID- 29149646 TI - Dependence of growth inhibiting action of increased planting density on capacity of lettuce plants to synthesize ABA. AB - Inhibition of lettuce plant growth under increased planting density was accompanied by accumulation of abscisic acid (ABA) in the shoots of competing plants. To check causal relationship between these responses we studied the effect of decreased synthesis of ABA on growth indexes and hormonal balance of lettuce plants under elevated density of their planting (one (single) or three (competing) plants per pot). Herbicide fluridone was used to inhibit ABA synthesis. Preliminary experiments with single plants showed that presence of fluridone in the soil solution at rather low concentration (0.001mg/L) did not affect either chlorophyll content or growth rate of shoots and roots during at least one week. Treatment of competing (grouped) plants with this concentration of fluridone prevented both accumulation of ABA and competition induced growth inhibition. These results confirm important role of this hormone in the growth inhibiting effect of increased planting density. Furthermore, as in the case of ABA, fluridone prevented allocation of indoleacetic acid (IAA) to the shoots of competing plants likely contributing to leveling off the increase in the ratio of leaf area to their mass that is characteristic effect of shading in the dense plant populations. The results suggest involvement of ABA in allocation of IAA in competing plants. Application of fluridone did not influence the concentration of cytokinins in the shoots, whose level was decreased by competition either in fluridone treated or control (untreated with fluridone) plants. Accumulation of ABA in the shoots of competing plants accompanied by inhibition of their growth and the absence of either accumulation of ABA or inhibition of their growth in fluridone treated grouped plants confirms importance of ABA synthesis for growth response to competition. PMID- 29149647 TI - Dietary fish oil differentially ameliorates high-fructose diet-induced hepatic steatosis and hyperlipidemia in mice depending on time of feeding. AB - Chrononutrition is the science of nutrition based on chronobiology. Numerous epidemiological studies have shown that fish oil (FO) reduces the risk of cardiovascular events through various actions such as lowering triglycerides. The present study aimed to determine the time of day when the hypertriglyceridemia decreasing ability of FO is optimal in mice. A high-fructose diet (HFrD) that induces hyperlipidemia in mice was replaced with the same diet containing 4% FO (HFrD-4% FO) at different times of the day for 2 weeks as described below. Mice were fed with HFrD alone (CTRL) or with HFrD containing 4% FO for 12 h around the time of activity onset [breakfast (BF)-FO] or offset [dinner (DN)-FO]. Plasma and liver concentrations of triglycerides and total cholesterol were reduced in BF-FO but not in DN-FO mice compared with CTRL mice. The temporal expression of genes associated with fatty acid synthesis such as Fasn, Acaca, Scd1 and Acly in the liver was significantly suppressed in both BF-FO and DN-FO mice. Expression levels of Scd1 in epididymal adipose tissue were significantly suppressed only in the BF-FO mice. Plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid were far more increased in BF-FO than in DN-FO mice. Significantly more of these n-3 polyunsaturated fatty acids (PUFAs) were excreted in the feces of DN-FO than of BF-FO mice. These findings suggest that dietary FO exerts more hypolipidemic activity at the time of breakfast than dinner because the intestinal absorption of n-3 PUFAs is more effective at that time. PMID- 29149648 TI - Dried plum alleviates symptoms of inflammatory arthritis in TNF transgenic mice. AB - Dried plum (DP), a rich source of polyphenols has been shown to have bone preserving properties in both animal models of osteoporosis and postmenopausal women. We evaluated if DP alleviated the destruction of joints in transgenic mice (TG) that overexpress human tumor necrosis factor (TNF), a genetic model of rheumatoid arthritis (RA). A four-week treatment of 20% DP diet in TG slowed the onset of arthritis and reduced bone erosions in the joints compared to TG on a regular diet. This was associated with fewer tartrate-resistant acid phosphatase (TRAP) positive cells, suggesting decreased osteoclastogenesis. A DP diet also produced significant protection of articular cartilage and reduction of synovitis. Cultures of human synovial fibroblast in the presence of TNF showed a significant increase in inflammatory interleukin (IL)-1beta, chemokines (monocyte chemoattractant protein-1: MCP1 & macrophage inflammatory protein-1 alpha: MIP1alpha), cartilage matrix metalloproteinases (MMP1&3), and an osteoclastogenic cytokine (receptor activator of nuclear factor-kappaB ligand: RANKL) compared to controls. Addition of neochlorogenic acid (NC), a major polyphenol in DP to these cultures resulted in down-regulation of these genes. In the cultures of mouse bone marrow macrophage, NC also repressed TNF-induced formation of osteoclasts and mRNA levels of cathepsin K and MMP9 through inhibition of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) expression and nuclear factor kappa B (NF-kappaB) activation. Our data suggested that dietary supplementation with DP inhibited TNF singling; leading to decreased erosions of bone and articular cartilage as well as synovitis. PMID- 29149649 TI - Chk1 inhibitors overcome imatinib resistance in chronic myeloid leukemia cells. AB - Drug resistance to tyrosine kinase inhibitors (TKIs) is currently a clinical problem of chronic myelogenous leukemia (CML). Bcr-Abl protein depletion is considered as a way to overcome drug resistance to TKIs. In our study, Chk1 inhibitors, AZD7762 and MK-8776, had strong antitumor effects on CML cell line KBM5 and imatinib-resistant form KBM5T315I. Moreover, Chk1 inhibitors showed a strong cytotoxic effect on leukemia cells from primary CML and imatinib resistance CML patients, but low cytotoxic effect on normal human mononuclear cells. Then, we found that Chk1 inhibitors induced apoptosis and increased DNA damage in CML cell lines with the degradation of the Bcr-Abl protein. Using the proteasome inhibitor and an immunoprecipitation assay, we found that Chk1 inhibitors triggered the degradation of Bcr-Abl through ubiquitination, which is depending on E3 ubiquitin ligase CHIP. At last, MK-8776 showed a significant tumor-suppressive effect of KBM5T315I cell in xenograft tumor models. Taking together, these findings suggest that targeting Chk1 may overcome TKIs resistance for the treatment of CML. PMID- 29149650 TI - Iron chelation therapy in lower IPSS risk myelodysplastic syndromes; which subtypes benefit? AB - BACKGROUND: Analyses suggest MDS patients with higher serum ferritin levels (SF) have inferior overall survival (OS), in one study across MDS subtypes. Multiple analyses suggest those with high SF receiving iron chelation therapy (ICT) have superior OS, but which MDS subtypes benefit from ICT remains undefined. METHODS: We performed survival analyses of MDS subtypes by receipt of ICT. RESULTS: 182 MDS were lower IPSS risk and received red blood cell (RBC) transfusions; 63 received ICT. For the entire cohort, receiving ICT independently predicted superior OS in a multivariate analysis (hazard ratio for death 0.3, p=0.01). Features differing for ICT and non-ICT patients, respectively, were: age; IPSS risk group; number of RBC units transfused; and SF, p<=0.03 for all. At a median follow up of 76.5 and 28.4 months, 65.1% and 63.0% were alive. Median OS (months) for ICT and non-ICT patients was: RA, 140.9 and 36.3, p=0.0008; RARS/RARS-t, 133.4 and 73.3, p=0.02. For RCMD/RCMD-RS, p=NS, however, 3 (20%) had significant erythroid improvement with ICT; other subtypes had small numbers. DISCUSSION: In this retrospective analysis, RA and RARS/RARS-t patients receiving ICT had superior OS to non-ICT patients. These findings should be verified and other MDS subtypes examined in larger prospective analyses. PMID- 29149651 TI - Anthropometric measurements in Iranian men. AB - There is inevitable need for data regarding anthropometric measurements of each community's population. These anthropometric data have various applications, including health assessment, industrial designing, plastic & orthopedic surgery, nutritional studies, anatomical studies and forensic medicine investigations. Anthropometric parameters vary from race to race throughout the world, hence providing an anthropometric profile model of residents of different geographic regions seems to be necessary. To our knowledge, there is no report of bone parameters of the Iranian population. The present study was carried out to provide data on anthropomorphic bone parameters of the Iranian population, as a basis for future relevant studies. We calculated most of the known anthropometric parameters including skull, mandible, clavicle, scapula, humerus, radius, ulna, sacrum, hip, femur, tibia and fibula of 225 male corpses during a period of 2 years (2014-2016). Data expression was done as mean +/- standard deviation. The results consist the first documented report on anthropometric bone measurement profile of Iranian male population, that can be considered a valuable source of data for future research on Iranian population in this regard. PMID- 29149652 TI - Estimation of stature from hand and handprint measurements in Iban population in Sarawak, Malaysia and its applications in forensic investigation. AB - Handprints and dismembered hands are commonly found during crime scene investigations and disaster victim identifications, respectively. It has been indicated that the accuracy of handprint and hand measurements for estimating stature maybe population specific. Since Iban is the largest ethnic population in Sarawak, Malaysia and because the application of anthropometry of hand and handprint within this population as well as other populations within the Southeast Asian countries remain unreported, this present study that investigated the reliability and accuracy of these two anthropometric aspects acquires forensic significance. Upon measuring the height, 21 measurements were recorded on each hand and the corresponding handprint of 50 male and 52 female consented adult Iban subjects. Using univariate statistics as well as simple and multiple regression analyses, interpretation of the measurements examined here was attempted. Results revealed that lengths of hand and handprint are the more reliable traits for estimating stature in both the male and female Iban subjects (p < 0.05) with correlation strength ranging from 0.60 to 0.76. Comparable to the established skeletal standards for hand, the stature prediction accuracy using hand and handprint measurements investigated in this research ranged between 4.29 and 5.78 cm. Hence, this research provided the first forensic standard for estimation of stature among the Iban population in Sarawak that may prove useful for crime scene investigations and disaster victim identifications in Malaysia. PMID- 29149653 TI - Prevalence of internet addiction and its risk and protective factors in a representative sample of senior high school students in Taiwan. AB - The aim of this study investigated the prevalence of Internet addiction (IA) in a large representative sample of secondary school students and identified the risk and protective factors. Using a crosssectional design, 2170 participants were recruited from senior high schools throughout Taiwan using both stratified and cluster sampling. The prevalence of IA was 17.4% (95% confidence interval, 15.8% 19.0%). High impulsivity, low refusal self-efficacy of Internet use, high positive outcome expectancy of Internet use, high disapproving attitude of Internet use by others, depressive symptoms, low subjective well-being, high frequency of others' invitation to Internet use, and high virtual social support was all independently predictive in the logistic regression analysis. The prevalence of IA among secondary school students in Taiwan was high. Results from this study can be used to help educational agencies and mental health organizations create policies and design programs that will help in the prevention of IA in adolescents. PMID- 29149654 TI - Classifying binge eating-disordered adolescents based on severity levels. AB - The new severity criterion for binge-eating disorder (BED), introduced by the most recent (fifth) edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a means of addressing within-group variability in severity, was tested in 223 Italian (13-18-year-old) adolescents (86.1% females) with (DSM 5) BED presenting for treatment. Analyses revealed that participants classified with mild (35.9% of the sample), moderate (38.1%) severe (13.4%), and extreme (12.6%) severity of BED, based on their clinician-rated weekly frequency of binge eating (BE) episodes, were statistically distinguishable in physical characteristics (body mass index) and a range of clinical variables regarding eating-related psychopathology and putative maintenance factors, health-related quality of life, and mood and anxiety disorder comorbidity (medium-to-large effect sizes). Between-group differences in age-at-onset of BED or demographics were not detected. The findings provide support for the utility of BE frequency as a severity criterion for BED in adolescence. Implications for future studies are discussed. PMID- 29149655 TI - One year after ischemic stroke: Changes in leg movement path stability in a speed accuracy task but no major effects on the hands. AB - First year after the stroke is essential for motor recovery. The main motor control strategy (i.e., faster movement production at the expense of lower movement accuracy and stability, or greater movement accuracy and stability at the expense of slower movement) selected by poststroke patients during a unilateral speed-accuracy task (SAT) remains unclear. We aimed to investigate the poststroke (12 months after stroke) effects on the trade-off between movement speed and accuracy, and intraindividual variability during a motor performance task. Healthy right-handed men (n = 20; age ~ 66 years) and right-handed men after ischemic stroke during their post rehabilitation period (n = 20; age ~ 69 years) were asked to perform a simple reaction task, a maximal velocity performance task and a SAT with the right and left hand, and with the right and left leg. In the hand movement trial, reaction time and movement velocity (Vmax) in the SAT were slower and time to Vmax in the SAT was longer in the poststroke group (P < .01). In the leg movement trial, poststroke participants reached a greater Vmax in the SAT than the healthy participants (P < .01). The greatest poststroke effect on intraindividual variability in movements was found for movement path in the SAT, which was significantly greater in the legs than in the hands. Poststroke patients in the first year after stroke mainly selected an impulsive strategy for speed over hand and leg motor control, but at the expense of lower movement accuracy and greater variability in movement. PMID- 29149656 TI - Location-specific mechanical response and morphology of facial soft tissues. AB - The facial tissue of 9 healthy volunteers (m/f; age: 23-60y) is characterized at three different locations using a procedure combining suction measurements and 18MHz ultrasound imaging. The time-dependent and multilayered nature of skin is accounted for by adopting multiple loading protocols which differ with respect to suction probe opening size and rate of tissue deformation. Over 700 suction measurements were conducted and analyzed according to location-specific mechanical and morphological characteristics. All corresponding data are reported and made available for facial tissue analysis and biomechanical modeling. Higher skin stiffness is measured at the forehead in comparison to jaw and parotid; these two regions are further characterized by lower creep deformation. Thicker tissue regions display a tendency towards a more compliant and less dissipative response. Comparison of superficial layer thickness and corresponding mechanical measurements suggests that connective tissue density determines the resistance to deformation in suction experiments. PMID- 29149657 TI - The mechanical behavior of nacre across length scales. AB - Nacre achieves excellent mechanical properties with a relatively simple hierarchical structure. Analyses suggest that a significant gain in toughness is realized with a modest reduction in strength, with increasing levels of hierarchy. This study probes the role of different hierarchical length scales in governing the strength and modulus of nacre using a combination of bulk compression tests, microindentation and nanoindentation tests. The variability in the measured properties is assessed through Weibull analyses. The transition from elastic deformation is characterized using spherical indentation tests at the micro and nano scales together with a Herztian analysis. The modulus of the organic phase at different scales was deduced using indentation data and appropriate micromechanical models. The results show a minimal influence of length scales on elastic-plastic transitions, suggesting that initiation of plasticity occurs through a common biomineral sliding mechanism across length scales. However the ultimate strengths follow the trends of models for hierarchical materials, with the strength reducing by a factor of ~2 with each increase in level of hierarchy. The modulus of the organic phase was higher at the lowest scale, in contrast to an earlier study, indicating that confinement significantly modifies the effective properties of the organic. PMID- 29149658 TI - Evaluating Casama: Contextualized semantic maps for summarization of lung cancer studies. AB - OBJECTIVE: It is crucial for clinicians to stay up to date on current literature in order to apply recent evidence to clinical decision making. Automatic summarization systems can help clinicians quickly view an aggregated summary of literature on a topic. Casama, a representation and summarization system based on "contextualized semantic maps," captures the findings of biomedical studies as well as the contexts associated with patient population and study design. This paper presents a user-oriented evaluation of Casama in comparison to a context free representation, SemRep. MATERIALS AND METHODS: The effectiveness of the representation was evaluated by presenting users with manually annotated Casama and SemRep summaries of ten articles on driver mutations in cancer. Automatic annotations were evaluated on a collection of articles on EGFR mutation in lung cancer. Seven users completed a questionnaire rating the summarization quality for various topics and applications. RESULTS: Casama had higher median scores than SemRep for the majority of the topics (p<= 0.00032), all of the applications (p<= 0.00089), and in overall summarization quality (p<= 1.5e-05). Casama's manual annotations outperformed Casama's automatic annotations (p = 0.00061). DISCUSSION: Casama performed particularly well in the representation of strength of evidence, which was highly rated both quantitatively and qualitatively. Users noted that Casama's less granular, more targeted representation improved usability compared to SemRep. CONCLUSION: This evaluation demonstrated the benefits of a contextualized representation for summarizing biomedical literature on cancer. Iteration on specific areas of Casama's representation, further development of its algorithms, and a clinically-oriented evaluation are warranted. PMID- 29149659 TI - Validation of differential cross sections by means of 252Cf spectral averaged cross sections. AB - The results of systematic evaluations of the spectrum-averaged cross section measurements performed in the spontaneous fission 252Cf neutron field are presented. The Following threshold reactions were investigated: 23Na(n,2n)22Na, 54Fe(n,p)54Mn, 54Fe(n,alpha) 51Cr, 27Al(n,p)27Mg, 27Al(n,alpha)24Na, 19F(n,2n)18F, 90Zr(n,2n)89Zr and 89Y(n,2n)88Y. The spectrum-averaged cross sections for 23Na(n,2n)22Na, 54Fe(n,alpha)51Cr and 89Y(n,2n)88Y reactions were measured for the first time. This quantity is compared with calculations carried with the IRDFF-v1.05 library. There is a notable disagreement exceeding uncertainties only for 54Fe(n,p)54Mn and 54Fe(n,alpha) 51Cr reactions. The spectrum-averaged cross sections were inferred from experimentally determined reaction rates. The experimental reaction rates were derived for irradiated samples from the Net Peak Areas measured using the semiconductor high purity germanium spectroscopy. The presented experimental data can be used to validate nuclear data libraries and reactions used in the practical reactor dosimetry and to specify high energy tail of the 252Cf neutron spectrum. PMID- 29149660 TI - A systems-level approach for investigating organophosphorus pesticide toxicity. AB - The full understanding of the single and joint toxicity of a variety of organophosphorus (OP) pesticides is still unavailable, because of the extreme complex mechanism of action. This study established a systems-level approach based on systems toxicology to investigate OP pesticide toxicity by incorporating ADME/T properties, protein prediction, and network and pathway analysis. The results showed that most OP pesticides are highly toxic according to the ADME/T parameters, and can interact with significant receptor proteins to cooperatively lead to various diseases by the established OP pesticide -protein and protein disease networks. Furthermore, the studies that multiple OP pesticides potentially act on the same receptor proteins and/or the functionally diverse proteins explained that multiple OP pesticides could mutually enhance toxicological synergy or additive on a molecular/systematic level. To the end, the integrated pathways revealed the mechanism of toxicity of the interaction of OP pesticides and elucidated the pathogenesis induced by OP pesticides. This study demonstrates a systems-level approach for investigating OP pesticide toxicity that can be further applied to risk assessments of various toxins, which is of significant interest to food security and environmental protection. PMID- 29149661 TI - Unraveling the effects of arbuscular mycorrhizal fungus on uptake, translocation, and distribution of cadmium in Phragmites australis (Cav.) Trin. ex Steud. AB - Phragmites australis (Cav.) Trin. ex Steud. has been reported to form a symbiosis with arbuscular mycorrhizal fungus (AMF). However, the tolerance mechanism for AMF symbiosis on cadmium (Cd) phytotoxicity still remains unclear. In this study, we investigated the effects of Rhizophagus irregularis inoculation on Cd-stressed (0, 1, and 20mgL-1) roots, stems, and leaves of P. australis with regard to subcellular Cd distribution and chemical forms of Cd. In addition, transmission electron microscopy and Fourier transform infrared spectroscopy were used to investigate variations in subcellular structures and functional groups in plant organs. The results showed that AMF inoculation could induce selective Cd distribution at subcellular levels, depending on different Cd treatments. The investigation of the chemical forms illustrated that AMF inoculation could alleviate Cd toxicity in all organs. Increases were observed in the ratios of undissolved Cd (FHAc) and oxalate Cd (FHCl), while decreases were observed in pectates and protein-integrated Cd (FNaCl) as well as water soluble Cd (FW). Hydroxyl (-OH), amide (-NH), carboxyl (C=O), and phosphate (P=O) groups as well as C-O and C-N stretching played predominant roles for the enhancement of Cd tolerance in response to AMF inoculation. These results provide instructive evidence for the mechanisms by which AMF inoculation enhances the Cd tolerance of P. australis via Cd uptake and distribution. PMID- 29149662 TI - In ovo transformation of two emerging flame retardants in Japanese quail (Coturnix japonica). AB - Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and Dechlorane Plus (DP) are two chlorinated, alternative flame retardants that have been found in wild birds and bird eggs. Little is known about the fate and effect of these compounds in birds, especially during the vulnerable stages of embryonic development. To investigate the ability of birds to biotransform these compounds, an in ovo exposure experiment with Japanese quail eggs was performed. Quail eggs were injected in the yolk sac with 1000ng/g egg of TDCIPP (2.3 nmol/g ww), DP (1.5 nmol/g ww) or a mixture of both and were then incubated at 37.5 degrees C for 17 days. To get a time-integrated understanding of the in ovo transformation of the compounds, one egg per treatment was removed from the incubator every day and analyzed for TDCIPP and its metabolite bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and/or for DP. By the end of the incubation period, TDCIPP was completely metabolized, while simultaneously BDCIPP was formed. The conversion of the parent compound into the metabolite did not occur proportionally and the concentration of BDCIPP showed a tendency to decrease when TDCIPP became depleted, both indicating that BDCIPP was further transformed into compounds not targeted for analysis. Further untargeted investigations did not show the presence of other metabolites, possibly due to the volatility of the metabolites. On the other hand, the DP concentration did not decrease during egg incubation. This study indicates that within the incubation period, avian embryos are able to biotransform TDCIPP, but not DP. PMID- 29149663 TI - alpha-Keto tetrahydrofuran lignan glucosides from the Bangladeshi medicinal plant Terminalia citrina inhibit estradiol (E2) induced proliferation in cancer cells. AB - EtOAc extract from the leaves of Terminalia citrina collected in Bangladesh were separated, and seven previously undescribed alpha-keto tetrahydrofuran lignan glucosides (terminalosides Q to W) were isolated and characterized. NOESY analysis of 1H NMR spectra and ECD spectroscopic data analysis revealed the absolute stereochemistry of the tetrahydrofuran ring of the isolated constituents as being a (7S,8R,8'S)- configuration in terminalosides Q to U and a (7R,8R,8'S)- configuration in terminalosides V and W. All of the isolated compounds were evaluated for their estrogenic and anti-estrogenic properties using two types of estrogen-responsive human breast cancer cell lines (MCF-7 and T47D). Terminaloside R, which has a dioxymethylene group in its aromatic ring, inhibited 90% of estradiol-enhanced cell proliferation in T47D and MCF-7 cells at concentrations of 0.01 MUM and 0.1 MUM, respectively. On the other hand, terminaloside T, the analogous compound which has two oxymethyl groups in place of dioxymethylene, suppressed 90% of cell proliferation selectively in T47D cells at a concentration of 0.01 MUM. However, terminaloside W, the 7R-stereoisomer of terminaloside R, only showed moderate activity. PMID- 29149664 TI - Copper-phospholipid interaction at cell membrane model hydrophobic surfaces. AB - Detailed investigation of Cu (II) binding with natural lipid phosphatidylglycerol (PG) in aqueous solution was carried out by voltammetric measurements at the mercury drop electrode, complemented by monolayer studies in a Langmuir trough and electrophoretic measurements, all used as models for hydrophobic cell membranes. Penetration of copper ions into the PG layer was facilitated by the formation of hydrophilic Cu-Phenanthroline (Phen) complex in the subphase, followed by the mixed ligand Cu-Phen-PG complex formation at the hydrophobic interface. Electrophoretic measurements indicated a comparatively low abundance of the formed mixed ligand complex within the PG vesicles, resulting it the zeta potential change of +0.83mV, while monolayer studies confirmed their co-existence at the interface. The Cu-Phen-PG complex was identified in the pH range from 6 to 9. The stoichiometry of the complex ([PhenCuOHPG]), as well as its stability and kinetics of formation, were determined at the mercury drop electrode. Cu-Phen-PG reduces quasireversibly at about -0.7V vs. Ag/AgCl including reactant adsorption, followed by irreversible mixed complex dissociation, indicating a two-electron transfer - chemical reaction (EC mechanism). Consequently, the surface concentration (gamma) of the adsorbed [PhenCuOHPG] complex at the hydrophobic electrode surface was calculated to be (3.35+/-0.67)*10-11molcm-2. Information on the mechanism of Cu (II) - lipid complex formation is a significant contribution to the understanding of complex processes at natural cell membranes. PMID- 29149665 TI - A study of microbial communities on terracotta separator and on biocathode of air breathing microbial fuel cells. AB - Recently, terracotta has attracted interest as low-cost and biocompatible material to build separators in microbial fuel cells (MFCs). However, the influence of a non-conductive material like terracotta on electroactive microbiological communities remains substantially unexplored. This study aims at describing the microbial pools developed from two different seed inocula (bovine and swine sewage) in terracotta-based air-breathing MFC. A statistical approach on microbiological data confirmed different community enrichment in the MFCs, depending mainly on the inoculum. Terracotta separators impeded the growth of electroactive communities in contact with cathodes (biocathodes), while a thick biofilm was observed on the surface (anolyte-side) of the terracotta separator. Terracotta-free MFCs, set as control experiments, showed a well-developed biocathode, Biocathode-MFCs resulted in 4 to 6-fold higher power densities. All biofilms were analyzed by high-throughput Illumina sequencing applied to 16S rRNA gene. The results showed more abundant (3- to 5-fold) electroactive genera (mainly Geobacter, Pseudomonas, Desulfuromonas and Clostridia MBA03) in terracotta-free biocathodes. Nevertheless, terracotta separators induced only slight changes in anodic microbial communities. PMID- 29149666 TI - Relationship between radiographic patella-alta pathology and walking dysfunction in children with bilateral spastic Cerebral Palsy. AB - BACKGROUND: Patella-alta is very common in patients with Cerebral Palsy (CP). While several diagnostic x-ray indices have been developed for patella-alta in general, the specific relationship with walking dysfunction in CP is only partly understood. METHODS: 33 participants with bilateral spastic CP between 4 and 20 years (GMFCS I-II without previous surgery) that underwent 3D gait analysis as well as a radiographic exam within 0.8 (SD 1.2) months were retrospectively included. The Caton-Deschamps, the Insall-Salvati and the Koshino-Index, as well as the moment-arms of the quadriceps, the pattelar-tendon length and patellar tilt angle were analyzed from x-rays. During gait, tempo-spatial parameters, the knee flexion kinematics, the knee moments and the moment impulse were calculated and correlated to x-ray parameters. RESULTS: Smaller quadriceps moment-arms were related to slower walking speed (r=0.48, P=0.005) and less knee extension during stance (r=0.68 P<0.001). Smaller quadriceps moment arms and longer patellar tendons were also significantly related to a larger knee flexion moment impulse in the second half of the stance phase (r=-0.36, P=0.045 and r=0.39, P=0.028) and hence to more abnormal knee loads. Yet, none of the traditional indices was related to any parameter of gait. INTERPRETATION: Traditional radiographic indices for patella-alta possess little to no informative value for walking dysfunction in individuals with CP suspected to have knee pathology. Smaller moment-arms are a key feature of patellofemoral pathology in CP reducing the knee extensor mechanism, an aspect which is not sufficiently picked up by traditional indices. PMID- 29149667 TI - Tumor Acidosis and Hypoxia Differently Modulate the Inflammatory Program: Measurements In Vitro and In Vivo. AB - Inflammatory mediators produced by the tumor cells are of importance for immune response but also for malignant progression. The aim of the study was to analyze the expression of monocyte chemoattractant protein-1, interleukin-6 (IL-6), tumor necrosis factor-alpha, inducible isoform of nitric oxide synthase (iNOS), cyclooxygenase-2, and osteopontin in vitro in two different tumor cell lines under hypoxia (pO2~1.5 mmHg) and/or acidosis (pH=6.6) for up to 24 hours since hypoxia and acidosis are common characteristics of solid tumors. Additionally, the same tumor cell lines implanted in vivo were made hypoxic and acidotic artificially for 24 hours, after which the cytokine expression was measured. Finally, the activation of ERK1/2 and p38 by acidosis/hypoxia and their impact on cytokine expression were studied. The results indicate that acidosis and hypoxia have fundamentally different (often opposing) effects on cytokine expression. In addition, these effects were tumor cell line specific. When combining hypoxia and acidosis, the overall changes reflect an additive effect of both conditions alone, indicating that hypoxia and acidosis act by independent mechanisms. The in vivo changes corresponded well with the results obtained in the isolated tumor cells. Only iNOS expression was downregulated in vivo but increased in cell culture. For IL-6 expression, the acidosis-induced changes were dependent on ERK1/2 activation. In conclusion, it was demonstrated that the environmental pO2 and pH strongly affect the expression of inflammatory mediators in tumor cells. In vivo, most of the inflammatory mediators were downregulated, which could limit the activation of immune cells and by this foster the immune escape of tumors. PMID- 29149668 TI - Parental knowledge and attitudes towards epilepsy -A study from Jordan. AB - PURPOSE: To explore the knowledge, attitudes and behaviors of parents whose children were diagnosed with epilepsy. METHODS: Cross-sectional questionnaire based study of parents who accompanied their children with epilepsy to the child neurology clinics at three university hospitals in Jordan. RESULTS: Most parents (427, 90.3%) knew that epilepsy is not related to a psychiatric disease. Approximately half of the parents (245, 51.8%) used the internet as their source of knowledge, and most used Arabic websites. Searching the word epilepsy was rarely used (51, 10.8%). Most of the parents (428,90.5%) were not restricting their children from watching TV or from using the computer (358,75.5%).However, many parents (280,59.2%) were restricting them from participating in sports. Parents had negative attitudes towards epilepsy; 189 (40.0%)thought that epileptic children can have normal intelligence, and 292 (61.7%) thought that they can continue into higher education. Greater parental knowledge of epilepsy was found to be correlated with the parental education level (p<0.05).Positive attitudes and behaviors towards epilepsy were found to be correlated with a higher parental education level, control of epilepsy,an absence of associated co morbidities, a higher income and internet use (p<0.05). CONCLUSION: This study sheds an important light on the current knowledge status and attitudes of parents of children with epilepsy, and is an invaluable tool for tailoring the delivery of information and support resources for families in our region. PMID- 29149669 TI - Effective clinical classification of chronic epilepsy into focal and generalized: A cross sectional study. AB - PURPOSE: Investigations such as EEG and brain imaging are often difficult to obtain in primary care settings of resource-limited regions impacting millions of epilepsy patients. We wanted to test the hypothesis that classification of chronic epilepsy into focal and generalized based on clinical history and examination alone would be comparable to making such a classification with additional inputs from EEG and brain imaging. METHODS: Two investigators independently classified consecutive chronic epilepsy patients into focal, generalized and unclassified epilepsy. Investigator 1 made this determination using clinical history and examination alone whereas Investigator II additionally used EEG and brain imaging too. We calculated inter observer agreement between the two investigators and also looked at the predictors of focal and generalized epilepsy. RESULTS: Five hundred and twelve patients were recruited. Inter observer agreement between the two investigators in making the focal versus generalized classification was 96.8%, kappa 0.91 (p<0.0001). When EEG and neuroimaging findings were added to clinical information, there was a change in classification in 3.2% patients. Several predictors of focal and generalized epilepsy were identified. CONCLUSIONS: Classification of chronic epilepsy into focal and generalized can be done reliably in most patients using clinical information alone. Investigating chronic epilepsy patients with EEG and brain imaging may not be necessary in every patient. The results of our study are especially significant for epilepsy patients living in resource-limited regions where such investigations may not always be available. PMID- 29149670 TI - An updated review on tritium in the environment. AB - Various studies indicated more or less recently that organically bound tritium (OBT) formed from gaseous or liquid tritium releases into the environment potentially accumulates in organisms contradicting hypotheses associated to methods used to assess the biological impact of tritium on humans (ASN, 2010). Increasing research works were then performed during the last decade in order to gain knowledge on this radionuclide expected to be increasingly released by nuclear installations in the near future within the environment. This review focusses on publications of the last decade. New unpublished observations revealing the presence of technogenic tritium in a sedimentary archive collected in the upper reaches of the Rhone river and findings from the Northwestern Mediterranean revealing in all likelihood the impact of terrigenous tritium inputs on OBT levels recorded in living organisms are also presented. Identifying and understanding the physicochemical forms of tritium and the processes leading to its persistence in environmental compartments would explain most observations regarding OBT concentrations in organisms and definitively excludes that tritium would "bio accumulate" within living organisms. PMID- 29149671 TI - Silver nanoparticles stimulate the proliferation of sulfate reducing bacterium Desulfovibrio vulgaris. AB - The intensive use of silver nanoparticles (AgNPs) in cosmetics and textiles causes their release into sewer networks of urban water systems. Although a few studies have investigated antimicrobial activities of nanoparticles against environmental bacteria, little is known about potential impacts of the released AgNPs on sulfate reducing bacteria in sewers. Here, we investigated the effect of AgNPs on Desulfovibrio vulgaris Hidenborough (D. vulgaris), a typical sulfate reducing bacterium (SRB) in sewer systems. We found AgNPs stimulated the proliferation of D. vulgaris, rather than exerting inhibitory or biocidal effects. Based on flow cytometer detections, both the cell growth rate and the viable cell ratio of D. vulgaris increased during exposure to AgNPs at concentrations of up to 100 mg/L. The growth stimulation was dependent on the AgNP concentration. These results imply that the presence of AgNPs in sewage may affect SRB abundance in sewer networks. Our findings also shed new lights on the interactions of nanoparticles and bacteria. PMID- 29149672 TI - The application of bacteriophages as novel indicators of viral pathogens in wastewater treatment systems. AB - Many wastewater treatment technologies have been shown to remove bacterial pathogens more effectively than viral pathogens and, in aquatic environments, levels of traditional faecal indicator bacteria (FIB) do not appear to correlate consistently with levels of human viral pathogens. There is, therefore, a need for novel viral indicators of faecal pollution and surrogates of viral pathogens, especially given the increasing importance of indirect and direct wastewater reuse. Potential candidates include bacteriophages (phages) and the study described here sought to elucidate the relationship between three groups of phages (somatic coliphages (SOMPH), F-RNA coliphages (F-RNAPH) and human-specific phages infecting B. fragilis (Bf124PH) - enumeration using double layer agar technique) and viral pathogens (human adenovirus (HuAdV) and norovirus (NoV) - enumeration using molecular methods) through full-scale municipal wastewater treatment processes. FIB (faecal coliforms (FC) and intestinal enterococci (ENT) enumeration using membrane filtration) were also monitored. Samples were collected every fortnight, during a twelve-month period, at each stage of four full-scale wastewater treatment plants (WWTP) in southern England (two activated sludge (AS) and two trickling filter (TF) plants) (n = 360 samples). FIB and SOMPH were consistently found in all samples tested, whereas F-RNAPH, Bf124PH and HuAdV were less frequently detected, especially following AS treatment. The detection rate of NoV was low and consequently discussion of this group of viruses is limited. Concentrations of SOMPH and FIB were statistically higher (p value < 0.05) than concentrations of F-RNAPH, Bf124PH and HuAdV in raw wastewater. FIB were more effectively removed than phages in both systems. Removal rates of HuAdV were similar to those of phages at the secondary treatment stage of both systems. In TF systems, HuAdV were removed at the same rate as F RNAPH, but at lower rates than SOMPH and Bf124PH. The findings suggest that phages (in particular SOMPH) are better indicators of the fate of viral pathogens in WWTP than existing FIB and that these organisms may have a useful role to play in future sanitation safety planning. PMID- 29149673 TI - The feasibility of nanofiltration membrane bioreactor (NF-MBR)+reverse osmosis (RO) process for water reclamation: Comparison with ultrafiltration membrane bioreactor (UF-MBR)+RO process. AB - This study examines the feasibility of a novel nanofiltration membrane bioreactor (NF-MBR) followed by reverse osmosis (RO) process for water reclamation at 90% recovery and using an ultrafiltration MBR (UF-MBR)+RO as baseline for comparison. Both MBRs adopted the same external hollow fiber membrane configurations and operating conditions. The collected permeates of the MBRs were subsequently fed to the respective RO systems. The results showed that the NF-MBR (operated at a constant flux of 10 L/m2h) achieved superior MBR permeate quality due to enhanced biodegradation and high rejection capacity of the NF membrane, leading to lower RO fouling rates (~3.3 times) as compared to the UF-MBR. Further analysis indicated that the cake layer fouling that caused the cake-enhanced osmotic pressure (CEOP) effect contributed predominantly to the transmembrane pressure (TMP) increase in the NF-MBR, while irreversible pore fouling was the major reason for UF membrane fouling. Furthermore, it was found that the biopolymers (i.e., organics with MW > 10 kDa) were the main components present in the foulants of the NF/UF membranes and RO membranes. The analysis indicated that the NF-MBR + RO system at recovery of 90% has comparable energy consumption as the UF MBR + RO system at recovery of 75%. Our findings proved the feasibility of the NF MBR + RO for water reclamation at a high recovery rate. PMID- 29149674 TI - The impact of operational strategies on the performance of a photo-EBPR system. AB - A novel Phototrophic - Enhanced Biological Phosphorus Removal (Photo-EBPR) system, consisting of a consortium of photosynthetic organisms and polyphosphate accumulating organisms (PAOs), was studied in this work. A sequencing batch reactor was fed with a mixture of acetate and propionate (75%-25%) and subjected to dark/light cycles in order to select a photo-EBPR system containing PAOs and photosynthetic organisms, the latter likely providers of oxygen to the system. The results from the selection period (stage 1) showed that the photo-EBPR culture was capable of performing P release in the dark and P uptake in the presence of light, under limited oxygen concentrations. During the optimization period, the aeration period, which was initially provided at the end of the light phase, was gradually reduced until a non-aerated system was achieved, while the light intensity was increased. After optimization of the operational conditions, the selected consortium of photosynthetic organisms/PAOs showed high capacity of P removal in the light phase in the absence of air or other electron acceptor. A net P removal of 34 +/- 3 mg-P/L was achieved, with a volumetric P removal rate of 15 +/- 2 mg-P/L.h, and 79 +/- 8% of P removal from the system. Also, in limiting oxygen conditions, the P uptake rate was independent of the PHA consumption, which demonstrates that the organisms obtained energy for P removal from light. These results indicated that a photo-EBPR system can be a potential solution for P removal with low COD/P ratios and in the absence of air, prospecting the use of natural sunlight as illumination, which would reduce the costs of EBPR operation regarding aeration. PMID- 29149675 TI - Evaluation of potassium ferrate as an alternative disinfectant on cyanobacteria inactivation and associated toxin fate in various waters. AB - Potassium ferrate (K2FeO4) is an effective oxidant that may be used as a pre- or post-oxidant in the purification of source water with cyanobacterial issues. To provide a better basis for the application of this oxidant during water treatment processes, the impacts of K2FeO4 on the cell viability of Microcystis aeruginosa and the fate of associated microcystins (MCs) were investigated in various water matrices. The results showed that a water matrix can significantly affect the effectiveness of K2FeO4 on cyanobacteria inactivation. 10 mg L-1 K2FeO4 induced significant cell lysis of M. aeruginosa in Ran Yi Tan Reservoir (RYTR) water while the membrane integrity was relatively unaffected in ASM-1 media and Cheng Kung Lake (CKL) water. The reduced efficiency of K2FeO4 oxidation may be attributed to the manganese (Mn2+) and organic matter (Ethylenediaminetetraacetic acid, EDTA) in the ASM-1 media and high concentrations of natural organic matters (NOMs) in the CKL water. A delayed Chick-Watson model was applied to simulate the experimental data for cyanobacterial cell rupture, and the cell lysis rates of the M. aeruginosa samples were determined to be 128-242 M-1 s-1 (mol L-1 s-1). Generally, no significant increases in extracellular MCs were observed in the three different waters, even in the RYTR water where the membrane integrity of the cyanobacterial cells was severely disrupted. Therefore, K2FeO4 could be a potential pre-oxidant to enhance subsequent treatments for cyanobacteria removal without affecting the cell integrity, or could serve as a post-oxidant to inactivate cyanobacterial cells and degrade MCs effectively, depending on the specific water matrix. PMID- 29149676 TI - High salt diet decreases reproductive performance in rams and down-regulates gene expression of some components of the renin-angiotensin system in the testis. AB - Although salt-tolerant plants can be used to combat dryland salinity, these plants contain high concentrations of salt (NaCl), which may have deleterious effects if fed to livestock. Twenty-four Merino rams (9 mo of age) with similar body weight were equally allocated to two groups and fed a normal- or high-salt diet (0.5 and 12% NaCl, respectively) for 3 mo. Rams fed the high-salt diet had lower live weight gains, higher water intake, smaller testes (466 +/- 48.4 vs 604 +/- 51.1 g) and reductions (P <0.05) in spermatogenesis, ejaculate volumes (0.89 +/- 0.18 vs 1.24 +/- 0.15 mL/ejaculate), sperm concentration (14.3 +/- 2.05 vs 22.3 +/- 2.33 * 109 sperm/mL) and DNA integrity (DNA fragmentation rate: 5.85 +/- 1.09 vs 1.13 +/- 0.14%) compared to controls. For in vitro fertilization, although cleavage percentage was not significantly affected, hatching rate was lower (30.8 +/- 3.81 vs 52.8 +/- 4.08%, P <0.05) for sperm from rams on the high salt diet. Furthermore, the 12% salt diet decreased plasma concentrations of metabolic (leptin and insulin) and sex (T, FSH and LH) hormones, but did not affect the plasma renin-angiotensin system (RAS) component (REN, Ang II, ACE and ALD). Regarding components of the testicular RAS, the 12% salt diet decreased (P <0.05) expression of REN, Ang II and AT2 mRNA, although ACE and AT1 were unaffected. Furthermore, the 12% salt diet decreased (P <0.05) mRNA expression of key genes for spermatogenesis (Hsp70, c-kit and Cyclin A), and sex hormone receptors (AR, FSHR, LHR, CYP11A1 and CYP17A1), but there were no significant effects on key enzymes (LDH, SDH, AKP and ATPase) in the testis. In conclusion, the high-salt diet reduced ram reproductive performance; we inferred that changes in testis RAS may have had an important role in these reproductive defects. PMID- 29149677 TI - Effects of deslorelin implants on reproduction and feeding behavior in Tasmanian devils (Sarcophilus harrisii) housed in free-range enclosures. AB - In captive breeding programs, it is becoming increasingly important to maximize the retention of genetic diversity by managing the reproductive contribution of each individual, which can be facilitated through the use of selective contraception. This becomes critical when captive populations are held for several generations, and managers must prevent the confines of housing space and financial support from compromising genetic integrity. For example, the Tasmanian devil insurance population, established in 2006, is strategically managed to equalize founder representation. This becomes difficult when devils are housed in large groups in free-range enclosures (FREs). This study examined the efficacy, duration and potential side effects of Suprelorin(r) contraceptive implants (containing 4.7 mg of deslorelin) on Tasmanian devils housed in FREs. Females were monitored to assess post-treatment reproductive rates, feeding behavior and weight changes. Suprelorin(r) successfully prevented reproduction in all treated females (P < 0.001) for at least one breeding season. For one year after contraception, there was no difference in proportion of time spent feeding between contraception and control groups (P > 0.05) and there was no effect of contraception on order of arrival at food (P = 0.632), suggesting no alterations to social structure. Devils with pouch young spent more time feeding than those without (P < 0.001). Treatment and month had an interactive effect on weight (P < 0.001), yet contracepted females were only heavier than controls in one season, indicating no overall excessive weight gain. Suprelorin(r) implants inhibit reproduction for at least one breeding season, with no apparent negative effects on feeding behavior or social dynamic. Selective contraception has the potential to become an important tool for conservation managers, to meet multiple reproductive, genetic and behavioral goals for this species. PMID- 29149678 TI - Housing conditions and birth outcomes: The National Child Development Study. AB - BACKGROUND: Despite their importance to respiratory and other health outcomes, housing conditions have been little-studied with respect to perinatal outcomes. METHODS: 1927 participants in the British National Child Development Study reported on housing conditions and pregnancy outcomes, including presence/severity of mold/dampness; type of heating; and whether remodeling of various sorts had been conducted. Crowding, based on the number of people in the residence and the number of rooms, was also considered. Outcomes assessed were low birthweight (< 2500g), preterm birth (< 37 weeks), and small-for-gestational age (< 10th percentile for gestational age). Multiple logistic regression with adjustment for maternal, sociodemographic, and housing factors was conducted. RESULTS: Women who reported serious problems with mold were more likely to give birth to a low birthweight (adjusted OR 1.98, 95% CI 1.13-3.47) or small-for gestational-age (2.06, 1.25-3.38) baby; no consistent associations were seen with preterm birth. Crowding was associated only with small-for-gestational-age (1.73, 1.11-2.76). CONCLUSIONS: Exposure to mold or dampness, and housing conditions generally, is a potentially important but under-investigated aspect of women's lives during pregnancy. Future studies should more thoroughly investigate housing characteristics and their relationship with birth outcomes. PMID- 29149679 TI - Innovative urban forestry governance in Melbourne?: Investigating "green placemaking" as a nature-based solution. AB - A nature-based approach to climate resilience aims to challenge and re-frame conventional environmental management methods by refocusing solutions from technological strategies to socio-ecological principles such as human well-being and community-based governance models, thereby improving and legitimizing the delivery of ecosystem services (ES). There are, however, many challenges to applying a socio-ecological agenda to urban climate resilience and thereby re framing ES delivery as community and people focused, a knowledge gap extensively outlined in the environmental governance literature. In this paper, we aim to contribute to this re-assesment of urban environmental governance by examining the City of Melbourne's approach to urban re-naturing governance from a place based perspective. Here we focus on the city's internationally-acclaimed urban forest strategy (UFS), investigating how and to which extent the governance arrangements embedded within the UFS draw strength from diverse perspectives and allow for institutional arrangements that support "situated" reflexive decision making and co-creation. We find that Melbourne's UFS governance process fosters green placemaking by re-focusing climate adaptation solutions from technological strategies to situated socio-ecological principles such as human well-being and community-based decision making. In this sense, this case provides valuable insight for the broader UGI governance field regarding the opportunities and challenges associated with a socio-cultural approach to urban re-naturing and ES delivery. PMID- 29149680 TI - Modification of the association between high ambient temperature and health by urban microclimate indicators: A systematic review and meta-analysis. AB - BACKGROUND: Landscape characteristics, including vegetation and impervious surfaces, influence urban microclimates and may lead to within-city differences in the adverse health effects of high ambient temperatures. OBJECTIVE: Our objective was to quantitatively summarize the epidemiologic literature that assessed microclimate indicators as effect measure modifiers (EMM) of the association between ambient temperature and mortality or morbidity. METHODS: We systematically identified papers and abstracted relative risk estimates for hot and cool microclimate indicator strata. We calculated the ratio of the relative risks (RRR) and 95% confidence intervals (95% CI) to assess differences in health effects across strata, and pooled the RRR estimates using random effects meta analyses. RESULTS: Eleven papers were retained. In the pooled analyses, people living in hotter areas within cities (based on land surface temperature or modeled estimates of air temperature) had 6% higher risk of mortality/morbidity compared to those in cooler areas (95% CI: 1.03-1.09). Those living in less vegetated areas had 5% higher risk compared to those living in more vegetated areas (95% CI: 1.00-1.11). DISCUSSION: There is epidemiologic evidence that those living in hotter, and less vegetated areas of cities have higher risk of morbidity or mortality from higher ambient temperature. Further research with improved assessment of landscape characteristics and investigation of the joint effects of physiologic adaptation and landscape will advance the current understanding. CONCLUSION: This review provides quantitative evidence that intra urban differences in landscape characteristics and micro-urban heat islands contribute to within-city variability in the health effects of high ambient temperatures. PMID- 29149681 TI - Mechanistic insight into contextual TGF-beta signaling. AB - Transforming growth factor-beta (TGF-beta) controls a wide range of cellular functions by activating both SMADs and non-SMAD pathways. In different tissue or physiological environment, cellular responses to TGF-beta can be diverse, even opposite. Complex regulations at the level of ligand mobilization, receptor presentation, and the network of intracellular signal transducers afford the TGF beta pathway with versatile means to induce precise cellular responses in accordance to specific contextual demands. This article summarizes recent development in how cells manage their responses to TGF-beta through ligand activation, receptor abundance, as well as SMAD-dependent and SMAD-independent mechanisms. PMID- 29149682 TI - Signalling for B cell survival. AB - The number of mature B cells is carefully controlled by signalling from receptors that support B cell survival. The best studied of these are the B cell antigen receptor (BCR) and BAFFR. Recent work has shown that signalling from these receptors is closely linked, involves the CD19 co-receptor, and leads to activation of canonical and non-canonical NF-kappaB pathways, ERK1, ERK2 and ERK5 MAP kinases, and PI-3 kinases. Importantly, studies show that investigation of the importance of signalling molecules in cell survival requires the use of inducible gene deletions within mature B cells. This overcomes the limitations of many earlier studies using constitutive gene deletions which were unable to distinguish between requirements for a protein in development versus survival. PMID- 29149683 TI - Online sexual solicitation by adults and peers - Results from a population based German sample. AB - Prevalence of Internet use among adolescents is high, but little is known about the online sexual activities of German adolescents. This study aimed to describe the 12-month prevalence of German adolescents' online sexual experiences with a focus on Online Sexual Solicitation (OSS, subjectively negative online sexual experiences with a peer or any sexual online experience, positive or negative, with an adult). A sample of male and female adolescents aged 14-17 (N=2238) was recruited using online survey panel. The sample was representative for gender and education. Subjects completed an online survey reporting their online sexual activities (i.e., sexual conversation, exchanging pictures, and cybersex) with peers (14-17y.) and/or adults (>=18y.). Findings illustrated that 51.3% (n=1148) of adolescents had experienced online sexual activity, which mostly involved peers (n=969; 84.4%). In contrast, 23.2% (n=519) of the adolescents experienced OSS with 2.6% (n=57) reporting subjectively negative online sexual interactions with peers and 22.2% (n=490) reporting online sexual interactions with adults, of which 10.4% (n=51) were perceived as negative. The findings suggest that adolescents frequently engage in sexual interactions on the Internet with only a relatively small number perceiving such contacts as exploitative. In addition, females and adolescents with incomplete family situation, foreign nationality, higher education, homo- or bisexual orientation, and those without perceived social support reported OSS significantly more often. PMID- 29149684 TI - Combining Benford's Law and machine learning to detect money laundering. An actual Spanish court case. AB - OBJECTIVES: This paper is based on the analysis of the database of operations from a macro-case on money laundering orchestrated between a core company and a group of its suppliers, 26 of which had already been identified by the police as fraudulent companies. In the face of a well-founded suspicion that more companies have perpetrated criminal acts and in order to make better use of what are very limited police resources, we aim to construct a tool to detect money laundering criminals. METHODS: We combine Benford's Law and machine learning algorithms (logistic regression, decision trees, neural networks, and random forests) to find patterns of money laundering criminals in the context of a real Spanish court case. RESULTS: After mapping each supplier's set of accounting data into a 21-dimensional space using Benford's Law and applying machine learning algorithms, additional companies that could merit further scrutiny are flagged up. CONCLUSIONS: A new tool to detect money laundering criminals is proposed in this paper. The tool is tested in the context of a real case. PMID- 29149685 TI - Simultaneous drug identification in urine of sexual assault victims by using liquid chromatography tandem mass spectrometry. AB - According to domestic and international epidemiological investigation, the proportion of substance involved sexual assault has the trend of ascent. In the past, laboratory methods that investigated urine sample of the sexual assault victims was to screen with enzyme immunoassay and then confirmed with mass spectrometry. The objective of the study is to simultaneously identify abused drugs in 126 decoded urine samples of sexual assault victims by liquid chromatography tandem mass spectrometry. The instrument was operated in multiple reaction monitoring with an electro-spray positive ionization mode. Chromatograms were separated with ACE5 C18 column on a gradient of acetonitrile. After liquid liquid extraction, samples were passed through a 0.22MUm PVDF filter before injection into the system. The limits of quantitation ranged from 0.2 to 10ng/mL. The precision (CV) results were below 12.9% (intraday) and 15.0% (interday). The intraday accuracy ranged from 84.8 to 121.0%, interday accuracy ranged from 72.0 to 117.3%. We found that 29 (23.0%) were positive for drugs. The most common drug identified is flunitrazepam (11.1%), followed by nimetazepam and ketamine (7.9%), some new psychoactive substances, such as 2C-B, mephedrone, methylone, PMA and PMMA were also identified. We identified abused drugs, benzodiazepines, and new psychoactive substances in urine of sexual assault victims by using liquid chromatography tandem mass spectrometry. PMID- 29149686 TI - Preliminary application of Structure from Motion and GIS to document decomposition and taphonomic processes. AB - Over the past decade, Structure from Motion (SfM) has increasingly been used as a means of digital preservation and for documenting archaeological excavations, architecture, and cultural material. However, few studies have tapped the potential of using SfM to document and analyze taphonomic processes affecting burials for forensic sciences purposes. This project utilizes SfM models to elucidate specific post-depositional events that affected a series of three human cadavers deposited at the South East Texas Applied Forensic Science Facility (STAFS). The aim of this research was to test the ability for untrained researchers to employ spatial software and photogrammetry for data collection purposes. For a series of three months a single lens reflex (SLR) camera was used to capture a series of overlapping images at periodic stages in the decomposition process of each cadaver. These images are processed through photogrammetric software that creates a 3D model that can be measured, manipulated, and viewed. This project used photogrammetric and geospatial software to map changes in decomposition and movement of the body from original deposition points. Project results indicate SfM and GIS as a useful tool for documenting decomposition and taphonomic processes. Results indicate photogrammetry is an efficient, relatively simple, and affordable tool for the documentation of decomposition. PMID- 29149687 TI - Pyrrolidinyl PNA polypyrrole/silver nanofoam electrode as a novel label-free electrochemical miRNA-21 biosensor. AB - A label-free electrochemical miRNA biosensor was developed based on a pyrrolidinyl peptide nucleic acid (acpcPNA)/polypyrrole (PPy)/silver nanofoam (AgNF) modified electrode. The AgNF was electrodeposited as redox indicator on a gold electrode, which was then functionalized with an electropolymerized layer of PPy, a conducting polymer, to immobilize the PNA probes. The fabrication process was investigated by electrochemical impedance spectroscopy. The biosensor was used to detect miRNA-21, a biomarker abnormally expressed in most cancers. The signal was monitored by the change in current of the AgNF redox reaction before and after hybridization using cyclic voltammetry. Two PNA probe lengths were investigated and the longer probe exhibited a better performance. Nucleotide overhangs on the electrode side affected the signal more than overhangs on the solution side due to the greater insulation of the sensing surface. Under optimal conditions, the electrochemical signal was proportional to miRNA-21 concentrations between 0.20fM and 1.0nM, with a very low detection limit of 0.20fM. The biosensor showed a high specificity which could discriminate between complementary, single-, doubled-base mismatched, and non-complementary targets. Three out of the seven tested plasma samples provided detectable concentrations (63 +/- 4, 111 +/- 4 and 164 +/- 7fM). The sensor also showed good recoveries (81 119%). The results indicated the possibilities of this biosensor for analysis without RNA extraction and/or amplification, making the sensor potentially useful for both the prognosis and diagnosis of cancer in clinical application. PMID- 29149688 TI - Ultrahigh sensitive enhanced-electrochemiluminescence detection of cancer biomarkers using silica NPs/graphene oxide: A comparative study. AB - The increasing progress in using nano-biomaterials for medical purposes has opened new horizons toward researchers around the globe. To investigate the presence of these nanomaterials and the impacts they might have, a comparative enhanced-electrochemiluminescence immunosensing study has been designed. The effects of utilizing graphene oxide, silica, and gold nanoparticles in cancer diagnosis were evaluated during the quantification of two major cancer biomarkers (CEA and AFP) in different approaches. In other words, first and second approaches were designed to employ nanomaterials while third and fourth approaches were developed in absence of those. Accordingly, resulted LODs experienced dramatic amplification when nano-biomaterials were included in the immunosensor modification (for AFP: 1st and 3rd approaches: 1.36fg/ml in comparison with 0.39ng/ml, and for CEA: 2nd and 4th approaches: 1.90fg/ml versus 0.46ng/ml, respectively). Correspondingly, capability of nano-biomaterials for developing highly sensitive and more efficient immunosensors was validated through selectivity, stability, reproducibility, and feasibility examinations. PMID- 29149689 TI - An extended sequence specificity for UV-induced DNA damage. AB - The sequence specificity of UV-induced DNA damage was determined with a higher precision and accuracy than previously reported. UV light induces two major damage adducts: cyclobutane pyrimidine dimers (CPDs) and pyrimidine(6 4)pyrimidone photoproducts (6-4PPs). Employing capillary electrophoresis with laser-induced fluorescence and taking advantages of the distinct properties of the CPDs and 6-4PPs, we studied the sequence specificity of UV-induced DNA damage in a purified DNA sequence using two approaches: end-labelling and a polymerase stop/linear amplification assay. A mitochondrial DNA sequence that contained a random nucleotide composition was employed as the target DNA sequence. With previous methodology, the UV sequence specificity was determined at a dinucleotide or trinucleotide level; however, in this paper, we have extended the UV sequence specificity to a hexanucleotide level. With the end-labelling technique (for 6-4PPs), the consensus sequence was found to be 5'-GCTC*AC (where C* is the breakage site); while with the linear amplification procedure, it was 5'-TCTT*AC. With end-labelling, the dinucleotide frequency of occurrence was highest for 5'-TC*, 5'-TT* and 5'-CC*; whereas it was 5'-TT* for linear amplification. The influence of neighbouring nucleotides on the degree of UV induced DNA damage was also examined. The core sequences consisted of pyrimidine nucleotides 5'-CTC* and 5'-CTT* while an A at position "1" and C at position "2" enhanced UV-induced DNA damage. PMID- 29149690 TI - A modified Montpellier protocol for intubating intensive care unit patients is associated with an increase in first-pass intubation success and fewer complications. AB - BACKGROUND: The Montpellier protocol for intubating patients in the intensive care unit (ICU) is associated with a decrease in intubation-related complications. We sought to determine if implementation of a simplified version of the Montpellier protocol that removed selected components and allowed for a variety of pre-oxygenation modalities increased first-pass intubation success and reduced intubation-related complications. METHODS: A prospective pre/post comparison of a modified Montpellier protocol in two medical and one medical/surgical/cardiac ICU within a hospital system. The modified eight-point protocol included: fluid administration, ordering sedation, two intubation trained providers, pre-oxygenation with non-invasive positive pressure ventilation, nasal high flow cannula or non-rebreather mask, rapid sequence intubation, capnography, sedation administration, and vasopressors for shock. RESULTS: Patient characteristics and indications for intubation were similar for the 275 intubations in the control (137) and intervention (138) periods. In the intervention vs. control periods, the modified Montpellier protocol was associated with a significant 16.2% [95% CI: 5.1-30.0%] increase in first-pass intubation success and a 12.6% [95% CI: 1.2-23.6%] reduction in all intubation related complications. CONCLUSION: A simplified version of the Montpellier intubation protocol for intubating ICU patients was associated with an improvement in first-pass intubation success rates and a reduction in the rate of intubation-related complications. PMID- 29149691 TI - The influence of intention and outcome on evaluations of social interaction. AB - Reading and making sense of social interactions between individuals is an important part of our daily social lives. Given that actions tend to be interpreted in terms of intent within the observed outcome, we investigated how intent and outcome interactively influence evaluations of social interactions. Through visual animations, intent was operationalized as an agent's (i.e., actor's) act intentionally or unintentionally having an influence on another agent (i.e., affectee). In Experiment 1, the act was helpful and the consequences brought small or great benefits to the affectee. In Experiment 2, the act was harmful and brought small or great losses to the affectee. We found that for both helpful and harmful contexts, social interaction evaluations were influenced by an interaction between the intent and outcome of the act. Specifically, great help/harm (i.e., the great-benefits or great-losses condition) was rated as a stronger social interaction than small help/harm, and the difference was larger in the intentional condition than in the unintentional condition. Furthermore, regardless of the interaction valence, the effect of the intent was larger than the effect of the outcome when evaluating social interaction. This result suggests that observers consider the intent and outcome jointly when evaluating a given social interaction, and the intent has a privileged role in this process. These findings are consistent with the idea that the intent is often deemed to be the cause driving the effect of outcome, and they help us to understand how social interactions are constructed within the action understanding system. PMID- 29149692 TI - Acute stress affects prospective memory functions via associative memory processes. AB - Recent findings suggest that acute stress can improve the execution of delayed intentions (prospective memory, PM). However, it is unclear whether this improvement can be explained by altered executive control processes or by altered associative memory functioning. To investigate this issue, we used physical psychosocial stressors to induce acute stress in laboratory settings. Then participants completed event- and time-based PM tasks requiring the different contribution of control processes and a control task (letter fluency) frequently used to measure executive functions. According to our results, acute stress had no impact on ongoing task performance, time-based PM, and verbal fluency, whereas it enhanced event-based PM as measured by response speed for the prospective cues. Our findings indicate that, here, acute stress did not affect executive control processes. We suggest that stress affected event-based PM via associative memory processes. PMID- 29149693 TI - Near infrared spectroscopy based monitoring of extraction processes of raw material with the help of dynamic predictive modeling. AB - The control of batch-to-batch quality variations remains a challenging task for pharmaceutical industries, e.g., traditional Chinese medicine (TCM) manufacturing. One difficult problem is to produce pharmaceutical products with consistent quality from raw material of large quality variations. In this paper, an integrated methodology combining the near infrared spectroscopy (NIRS) and dynamic predictive modeling is developed for the monitoring and control of the batch extraction process of licorice. With the spectra data in hand, the initial state of the process is firstly estimated with a state-space model to construct a process monitoring strategy for the early detection of variations induced by the initial process inputs such as raw materials. Secondly, the quality property of the end product is predicted at the mid-course during the extraction process with a partial least squares (PLS) model. The batch-end-time (BET) is then adjusted accordingly to minimize the quality variations. In conclusion, our study shows that with the help of the dynamic predictive modeling, NIRS can offer the past and future information of the process, which enables more accurate monitoring and control of process performance and product quality. PMID- 29149694 TI - A high brightness probe of polymer nanoparticles for biological imaging. AB - Conjugated polymer nanoparticles (CPNs) with high brightness in long wavelength region were prepared by the nano-precipitation method. Based on fluorescence resonance energy transfer (FRET) mechanism, the high brightness property of the CPNs was realized by four different emission polymers. Dynamic light scattering (DLS) and scanning electron microscopy (SEM) displayed that the CPNs possessed a spherical structure and an average diameter of ~75nm. Analysis assays showed that the CPNs had excellent biocompatibility, good photostability and low cytotoxicity. The CPNs were bio-modified with a cell penetrating peptide (Tat, a targeted element) through covalent link. Based on the entire wave fluorescence emission, the functionalized CPNs1-4 can meet multichannel and high throughput assays in cell and organ imaging. The contribution of the work lies in not only providing a new way to obtain a high brightness imaging probe in long wavelength region, but also using targeted cell and organ imaging. PMID- 29149695 TI - Rheo-optical near-infrared (NIR) spectroscopy study of partially miscible polymer blend of polymethyl methacrylate (PMMA) and polyethylene glycol (PEG). AB - Tensile deformations of a partially miscible blend of polymethyl methacrylate (PMMA) and polyethylene glycol (PEG) is studied by a rheo-optical characterization near-infrared (NIR) technique to probe deformation behavior during tensile deformation. Sets of NIR spectra of the polymer samples were collected by using an acousto-optic tunable filter (AOTF) NIR spectrometer coupled with a tensile testing machine as an excitation device. While deformations of the samples were readily captured as strain-dependent NIR spectra, the entire feature of the spectra was overwhelmed with the baseline fluctuation induced by the decrease in the sample thickness and subsequent change in the light scattering. Several pretreatment techniques, including multiplicative scatter collection (MSC) and null-space projection, are subjected to the NIR spectra prior to the determination of the sequential order of the spectral intensity changes by two-dimensional (2D) correlation analysis. The comparison of the MSC and null-space projection provided an interesting insight into the system, especially deformation-induced variation of light scattering observed during the tensile testing of the polymer sample. In addition, the sequential order determined with the 2D correlation spectra revealed that orientation of a specific part of PMMA chain occurs before that of the others because of the interaction between CO group of PMMA and terminal OH group of PEG. PMID- 29149696 TI - Clearance of plasmin-PN-1 complexes by vascular smooth muscle cells in human aneurysm of the ascending aorta. AB - Plasminogen is a circulating zymogen which enters the arterial wall by radial, transmural hydraulic conductance, where it is converted to plasmin by tissue plasminogen activator t-PA on an activation platform involving S100A4 on the vascular smooth muscle cell (vSMC) membrane. Plasmin is involved in the progression of human thoracic aneurysm of the ascending aorta (TAA). vSMCs protect the TAA wall from plasmin-induced proteolytic injury by expressing high levels of antiproteases. Protease nexin-1 (PN-1) is a tissue antiprotease belonging to the serpin superfamily, expressed in the vascular wall, and is able to form a covalent complex with plasmin. LDL receptor-related protein-1 (LRP-1) is a scavenger receptor implicated in protease-antiprotease complex internalization. In this study, we investigated whether PN-1 and LRP-1 are involved in the inhibition and clearance of plasminogen by the SMCs of human TAA. We demonstrated an overexpression of S100A4, PN-1, and LRP-1 in the medial layer of human TAA. Plasminogen activation taking place in the media of TAA was revealed by immunohistochemical staining and plasmin activity analyses. We showed by cell biology studies that plasmin-PN-1 complexes are internalized via LRP-1 in vSMCs from healthy and TAA media. Thus, two complementary mechanisms are involved in the protective role of PN-1 in human TAA: one involving plasmin inhibition and the other involving tissue clearance of plasmin-PN1 complexes via the scavenger receptor LRP-1. PMID- 29149698 TI - Ectrodactyly in a Chinese patient born to a mother with neuromyelitis optica spectrum disorder. AB - NMOSD develops primarily in women of childbearing age, and several previous studies have shown that the disorder may increase the risk of miscarriage. However, there are no reports, to our knowledge, of fetal malformation, other than neonatal hydrocephalus, related to NMOSD. We report a 30-year-old woman who experienced recurrent neuritis and who was seropositive for AQP4-IgG. She became pregnant, and the fetus was found to have ectrodactyly. Histological analysis of the placenta showed moderate inflammatory infiltration; however, whether fetal malformation in NMOSD is related to inflammation and AQP4-IgG remains to be determined. PMID- 29149697 TI - Characteristics of motor speech phenotypes in multiple sclerosis. AB - BACKGROUND: Motor speech disorders in multiple sclerosis (MS) are poorly understood and their quantitative, objective acoustic characterization remains limited. Additionally, little data regarding relationships between the severity of speech disorders and neurological involvement in MS, as well as the contribution of pyramidal and cerebellar functional systems on speech phenotypes, is available. METHODS: Speech data were acquired from 141 MS patients with Expanded Disability Status Scale (EDSS) ranging from 1 to 6.5 and 70 matched healthy controls. Objective acoustic speech assessment including subtests on phonation, oral diadochokinesis, articulation and prosody was performed. RESULTS: The prevalence of dysarthria in our MS cohort was 56% while the severity was generally mild and primarily consisted of a combination of spastic and ataxic components. Prosodic-articulatory disorder presenting with monopitch, articulatory decay, excess loudness variations and slow rate was the most salient. Speech disorders reflected subclinical motor impairment with 78% accuracy in discriminating between a subgroup of asymptomatic MS (EDSS < 2.0) and control speakers. Speech disorder severity was related to the severity of neurological involvement. Decreased articulation rate was moderately correlated to EDSS as well as all subtests of the multiple sclerosis functional composite. The strongest correlation was observed between irregular oral diadochokinesis and the 9-Hole Peg Test (r = - 0.65, p < 0.001). Irregular oral diadochokinesis and excess loudness variations significantly separated pure pyramidal and mixed pyramidal-cerebellar MS subgroups. CONCLUSIONS: Automated speech analyses may provide valuable biomarkers of disease progression in MS as dysarthria represents common and early manifestation that reflects disease disability and underlying pyramidal-cerebellar pathophysiology. PMID- 29149699 TI - Tetrahymena Cilia Cap is Built in a Multi-step Process: A Study by Atomic Force Microscopy. AB - Cilia are complex and dynamic organelles that have motility and sensory functions. Defects in cilia biogenesis and function are at the origin of human ciliopathies. In motile cilia, a basal body organizes the axoneme composed of nine microtubule doublets surrounding a central pair of singlet microtubules. The distal ends of axonemal microtubules are attached to the membrane by microtubule capping structures. Little is known about the early steps of cilium assembly. Although cilia grow and resorb from their distal tips, it remains poorly understood where and when the components of the caps are first assembled. By using Atomic Force Microscopy in tapping mode, with resolution at the nanometer range and with minimum sample manipulation, we show that Tetrahymena cilia assembly requires transient assembly of structures, composed of three components that are placed asymmetrically on an early elongating axoneme. In small uncapped axonemes the microtubule central pair was never observed. Additionally, we show that cilia cap assembly is a multi-step process in which structures of different sizes and shapes are put together in close proximity before the axoneme appears capped. We propose that the cap modifies the axoneme microtubule rate of polymerization and present a model for Tetrahymena cilia cap assembly. PMID- 29149700 TI - Protective role of biosynthesized silver nanoparticles against early blight disease in Solanum lycopersicum. AB - Tomato suffers a huge loss every year because of early blight disease. This study focuses on efficient inhibition of Alternaria solani, the causative agent of early blight disease in tomato in vitro and in vivo. Foliar spray of 5 MUg/mL of biosynthesized silver nanoparticles in A. solani infected plants resulted in significant increase of 32.58% in fresh weight and 23.52% in total chlorophyll content of tomato as compared to A. solani infected plants. A decrease of 48.57, 30, 39.59 and 28.57% was observed in fungal spore count, lipid peroxidation, proline content and superoxide dismutase respectively in infected tomato plants after treatment with synthesized silver nanoparticles as compared to A. solani infected plants. No significant variation in terms of soil pH, cultured population, carbon source utilization pattern and soil enzymes including dehydrogenase, urease, protenase and beta-glucosidase was observed after foliar spray of nanoparticles. It was revealed that direct killing of pathogens, increased photosynthetic efficiencies, increased plant resistance and decrease in stress parameters and stress enzymes are the mechanisms employed by plants and nanoparticles simultaneously to combat the biotic stress. Biosynthesized silver nanoparticles bear the potential to revolutionize plant disease management, though the molecular aspects of increased resistance must be looked upon. PMID- 29149702 TI - An HPLC tandem mass spectrometry for quantification of ET-26-HCl and its major metabolite in plasma and application to a pharmacokinetic study in rats. AB - ET-26-HCl is a new analog of etomidate, a short-acting anesthetic drug, with less adrenal cortex inhibition. The pharmacokinetics of ET-26-HCl in rats needs to be determined for future clinical trials in human subjects. In order to facilitate the pharmacokinetic study, a liquid chromatography based tandem mass spectrometric (HPLC-MS/MS) method was developed and validated for quantification of ET-26-HCl and its major metabolite, ET-26-acid. These two compounds and gabapentin (internal standard) were extracted using a protein precipitation method with methanol and detected by Multiple Reaction Monitoring of m/z transition of 275.6-170.9, 217.7-113.1, and 172.5-154.3 for ET-26-HCl, ET-26 acid, and gabapentin respectively. This method was validated in terms of sensitivity, linearity, reproducibility, and stability. The HPLC-MS/MS method was found linear over the concentration ranges of 21.76-4352ng/mL, and 18.62 3724ng/mL with LLOQ of 21.76 and 18.62ng/mL for ET-26-HCl and ET-26-acid respectively. The mean intra-day and inter-day accuracy was between 94.11 107.78%, while the precision was within the limit of 15.0% for all the quality control samples. A pharmacokinetic study was then conducted in rats following intravenous injection of 2.1, 4.2, and 8.4mg/kg. The linear pharmacokinetics of ET-26-HCl was observed over the dose range of 2.1-8.4mg/kg. The average terminal phase elimination half-lives were 0.87 and 1.03h for ET-26-HCl and ET-26-acid respectively. In summary, an HPLC-MS/MS method for quantification of ET-26-HCl in rat plasma has been developed and successfully applied to a pharmacokinetic study. PMID- 29149701 TI - Risk factor analysis of equine strongyle resistance to anthelmintics. AB - Intestinal strongyles are the most problematic endoparasites of equids as a result of their wide distribution and the spread of resistant isolates throughout the world. While abundant literature can be found on the extent of anthelmintic resistance across continents, empirical knowledge about associated risk factors is missing. This study brought together results from anthelmintic efficacy testing and risk factor analysis to provide evidence-based guidelines in the field. It involved 688 horses from 39 French horse farms and riding schools to both estimate Faecal Egg Count Reduction (FECR) after anthelmintic treatment and to interview farm and riding school managers about their practices. Risk factors associated with reduced anthelmintic efficacy in equine strongyles were estimated across drugs using a marginal modelling approach. Results demonstrated ivermectin efficacy (96.3% +/- 14.5% FECR), the inefficacy of fenbendazole (42.8% +/- 33.4% FECR) and an intermediate profile for pyrantel (90.3% +/- 19.6% FECR). Risk factor analysis provided support to advocate for FEC-based treatment regimens combined with individual anthelmintic dosage and the enforcement of tighter biosecurity around horse introduction. The combination of these measures resulted in a decreased risk of drug resistance (relative risk of 0.57, p = 0.02). Premises falling under this typology also relied more on their veterinarians suggesting practitionners play an important role in the sustainability of anthelmintic usage. Similarly, drug resistance risk was halved in premises with frequent pasture rotation and with stocking rate below five horses/ha (relative risk of 0.53, p < 0.01). This is the first empirical risk factor analysis for anthelmintic resistance in equids. Our findings should guide the implementation of more sustained strongyle management in the field. PMID- 29149703 TI - Quercetin attenuates collagen-induced arthritis by restoration of Th17/Treg balance and activation of Heme Oxygenase 1-mediated anti-inflammatory effect. AB - Quercetin (QU) has been shown obvious anti-arthritic property in pre-clinical studies or clinical studies. Howbeit, the underlying mechanism of it is still not revealed distinctly and should be gotten further insight into. QU at a dosage of 150 mg/kg was administered orally in collagen-induced arthritis rats and then the clinical symptoms were monitored. The protein levels of Th17/Treg-related cytokines were determined by ELISA, and the mRNA levels of cytokines and transcription factors associated with the Th17 and Treg phenotypes were evaluated by real-time PCR, the proportions of Th17 and Treg cells were assessed by flow cytometry. The results showed that QU administration yielded an obvious mitigation of arthritic manifestations including high arthritic scores and paw edema, which was accompanied with decrement of Th17-related cytokines (IL-17A and IL-21) and increment of Treg-related cytokines (IL-10 and TGF-beta). QU decreased the percentage of Th17 cells, while increased the percentage of Treg cells. In addition, the activation of NLRP3 inflammasome which plays a crucial role in the development of RA was determined and found that the protein expressions of NLRP3, Caspase-1 and IL-1beta were diminished by QU significantly. Moreover, the protein levels of inflammatory mediators which were recognized as chief culprits in inflammatory reaction were assayed. The contents of inflammatory mediators inclusive of TNF-alpha, IL-1beta, IL-6, PGE2, COX-2 and iNOS were down-regulated markedly by QU. But the inhibitory effect of QU on inflammatory mediators was nearly abolished by Heme Oxygenase 1 (HO-1) siRNA. Taken together, QU attenuates CIA via modulating the Th17/Treg balance, inhibiting NLRP3 inflammasome activation as well as activating HO-1-mediated anti-inflammatory response. PMID- 29149704 TI - Gold nanoparticles as an adjuvant: Influence of size, shape, and technique of combination with CpG on antibody production. AB - Gold nanoparticles (GNPs) are advantageous as an adjuvant in the design of effective vaccines and in the preparation of high-affinity antibodies to haptens and complete antigens. Another method of activating immunocompetent cells with colloidal gold is to conjugate GNPs with CpG oligodeoxynucleotides (ODNs). We examined how the size and shape of GNPs and various combinations of GNPs and CpG ODNs 1826 affect the immune response. When animals were injected with a model antigen (BSA) coupled to gold nanospheres (diameters, 15 and 50nm), nanorods, nanoshells, and nanostars, the titers of the resultant antibodies differed substantially. The antibody titers decreased in the sequence GNPs-50nm>GNPs 15nm>nanoshells>nanostars>nanorods>native BSA. We conclude that 50 and 15nm gold nanospheres are the optimal antigen carrier and adjuvant for immunization. The highest titer of anti-BSA antibodies was detected in the blood serum of mice immunized simultaneously with BSA-GNP and CpG-GNP conjugates. PMID- 29149705 TI - Toll-like receptor 4 deficiency increases resistance in sepsis-induced immune dysfunction. AB - Sepsis constitutes a serious life-threatening syndrome associated with complications of deregulated inflammatory response against endotoxin/lipopolysaccharide (LPS)-mediated severe infection. Toll-like receptor 4 (TLR4) plays a critical role in the activation of innate immunity through recognition of LPS. However, the impact of TLR4 signaling on the development of sepsis-induced immune dysfunction remains unclear. The aim of this study was to investigate the effect of TLR4 on regulatory T cells (Tregs) and its potential mechanism. To simulate sepsis, male C57BL/6 (wild-type) and C57BL/10ScNJNJU (TLR4 /-) mice were subjected to cecal ligation and puncture (CLP). After 24h, pro- and anti-inflammatory cytokine secretion, neutrophil and macrophage lung and liver infiltration were assessed to evaluate the sepsis-induced inflammatory response. The quantity and apoptotic rate of Tregs were measured. The expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and forkhead/winged helix transcription factor p3 (Foxp3) were analyzed. Cytokine (i.e., TNF-alpha, IL-2, IL-10, and IL-4) secretion by Tregs in the cell suspensions and the suppressive activity on CD4+CD25- T cell proliferation were also determined in vitro. At 24h after the CLP procedure, the wild-type mice exhibited increased Treg levels and expression, and secreted inflammatory factors in the serum were markedly overproduced. However, the TLR4-/- mice attenuated the increased Treg expression and inflammatory factor overproduction. These results indicate that in a model of post-septic mice, TLR4 deficiency improves immune paralysis by attenuating Treg activity and restoring a pro-inflammatory cytokine balance. Thus, modulation of the TLR4 activity may be useful in preventing immune dysfunction in sepsis. PMID- 29149706 TI - Exploring the impact of route of administration on medication acceptance in hospitalized patients: Implications for venous thromboembolism prevention. AB - BACKGROUND: Non-administration of venous thromboembolism (VTE) prophylaxis contributes to preventable patient harm. We hypothesized that non-administration would be more common for parenteral VTE prophylaxis than oral infectious disease or cardiac prophylaxis or for treatment medications. The primary study goal was to determine if non-administration of parenteral VTE prophylaxis is more frequent than other prophylactic or treatment medications. METHODS: In this retrospective cohort study of consecutive admissions we used descriptive statistics and risk ratios (RR) to compare the number of non-administered doses of VTE prophylaxis, oral infectious disease and cardiovascular prophylaxis and treatment medications. To quantify the influence of demographic and clinical characteristics on non administration, we estimated incidence rate ratios from Poisson regression models. RESULTS: 645 patients were admitted from July 1, 2014 through March 31, 2015. Median age was 52years (Interquartile range 43-57) and 365 (56.6%) were male. Subcutaneous VTE prophylaxis doses were not administered nearly 4-fold more frequently than oral infectious disease and cardiovascular prophylaxis (RR=3.93; 95% CI 3.36-4.59) and 3-fold more frequently than treatment medications (RR=3.06; 95% CI 2.91-3.22). Ninety percent of non-administered doses of VTE prophylaxis were refused. Risk factors for non-administration included younger age (age 18 35years), male sex, uninsured status, HIV-positivity and high VTE risk status. CONCLUSIONS: Subcutaneous VTE prophylaxis is not administered more frequently than oral infectious diseases or cardiac prophylaxis and treatment medications. These data suggest that availability of an oral medication could improve the effectiveness of VTE prophylaxis in real world settings. PMID- 29149707 TI - Over-expression of cyclooxygenase-2 in increased reticulated platelets leads to aspirin resistance after elective off-pump coronary artery bypass surgery. AB - INTRODUCTION: Aspirin resistance (AR) has been reported to present after coronary artery bypass graft causing saphenous vein graft failure. We aimed to investigate the factors that affect the anti-platelet effect of aspirin after off-pump coronary artery bypass surgery (OPCAB). MATERIALS AND METHODS: Thirty OPCAB candidates were successively recruited. Platelet count, platelet aggregation, reticulated platelet (RP), platelets' cyclooxygenase (COX)-1 and COX-2 expressions were determined during the peri-operative period. Besides, 10 healthy volunteers were enrolled to determine the onset of the anti-platelet effect of aspirin as comparison. RESULTS AND CONCLUSIONS: The arachidonic acid-induced platelet aggregation (PLAA) decreased to <20% within 8h after taking 100mg aspirin in healthy volunteers. However, in the OPCAB patients, PLAA levels remained over 20% in 16 (53.3%) patients after resuming aspirin for 24h. The surgical bleeding volumes were higher in the AR patients compared to the normal responders (512.5+/-192.8 vs. 314.3+/-94.9, p=0.002). The platelet count on Day 8, RP proportions on Days 1, 4, 8, and COX-2 level on Day 4 were significantly increased compared to their baseline levels in AR group but not in AS group. Platelet count on Day 8, RP proportion and COX-2 on Day 4 were all significantly higher in AR group than those in AS group. The surgical bleeding volume and COX-2 over-expression were predictors of post-OPCAB AR. As a conclusion, the inability of aspirin to inhibit the COX-2 created by increased RP would account for the post-OPCAB AR. PMID- 29149708 TI - Photodegradation of novel oral anticoagulants under sunlight irradiation in aqueous matrices. AB - Kinetics of photodegradation of novel oral anticoagulants dabigatran, rivaroxaban, and apixaban were studied under simulated solar light irradiation in purified, mineral, and river waters. Dabigatran and rivaroxaban underwent direct photolysis with polychromatic quantum yields of 2.2 * 10-4 and 4.4 * 10-2, respectively. The direct photodegradation of apixaban was not observed after 19 h of irradiation. Kinetics of degradation of rivaroxaban was not impacted by the nature of the aqueous matrix while photosensitization from nitrate ions was observed for dabigatran and apixaban dissolved in a mineral water. The photosensitized reactions were limited in the tested river water (Isle River, Perigueux, France) certainly due to the hydroxyl radical scavenging effect of the dissolved organic matter. The study of photoproduct structures allowed to identify two compounds for dabigatran. One of them is the 4-aminobenzamidine while the second one is a cyclization product. In the case of rivaroxaban, as studied by very high field NMR, only one photoproduct was observed i.e. a photoisomer. Finally, seven photoproducts were clearly identified from the degradation of apixaban under simulated solar light. PMID- 29149709 TI - Performance and microbial communities in a combined bioelectrochemical and sulfur autotrophic denitrification system at low temperature. AB - Combined bioelectrochemical and sulfur autotrophic denitrification (CBSAD) system had proven to be feasible for nitrate removal at low temperature. This system obtained excellent denitrification efficiency 96.55% at 10 +/- 2 degrees C long term operation. Nitrate removal efficiency presented increased tendency with applied current increased from 50 to 200 mA and then decreased when the applied current was further increased to 300 mA. The CBSAD system owned the most abundant and rich communities at current 200 mA, and the community structures of the microbial samples at different current conditions were clearly different from each other. Phyla Firmicutes, Proteobacteria and classes Epsilonproteobacteria, Gammaproteobacteria, Betaproteobacteria, Clostridia dominated in all the communities in the system. The largest genus at current 50 mA was Arcobacter, whereas Pseudomonas was the most dominant genus at current 100-300 mA condition, suggesting that high current changed the bacterial structure in this CBSAD reactor. PMID- 29149710 TI - Prevalence and sources of polychlorinated biphenyls in the atmospheric environment of Lake Victoria, East Africa. AB - The large surface area of Lake Victoria (about 68,800 km2) makes it vulnerable to high atmospheric deposition of chemical pollutants. We present measurements of polychlorinated biphenyls (PCBs) from the lake's atmospheric environment. High volume air (24 h) samples were collected within the northern Lake Victoria watershed in Uganda over two periods; 1999-2004 [at Kakira (KAK) and Entebbe (EBB)] and 2008-2010 (at EBB only). Precipitation samples were also collected monthly during the 2008-2010 period at EBB. Analysis for PCBs was done using GC MUECD in a dual column approach. The ranges of SigmaPCB concentrations in the KAK air samples were 154-462 pg m-3 (KAK 1999-2000), 26.7-226 pg m-3 (KAK 2003-2004), 27.0-186 pg m-3 (EBB 2003), 46.8-174 pg m-3 (EBB 2004), 19.2-128 pg m-3 (EBB 2008), 45.8-237 pg m-3 (EBB 2009) and 65.6-244 pg m-3 (EBB 2010). The di-, tri-, tetra- and penta-PCBs were predominant in air sample sets while the tetra- and penta-PCBs were predominant in precipitation samples. The mean flux of SigmaPCBs in the precipitation samples was 26.9 ng m-2 (range of 14.8-41.5 and median of 27.5). Concentrations at EBB were lower than those reported elsewhere for urban sites in the East and Central African region. Multivariate analysis and analysis of air mass movements suggested influence of combustion sources on the PCB profiles from the region, especially, from the major East African urbanized regions. PMID- 29149711 TI - Enantiomeric characterization of herbicide lactofen: Enantioseparation, absolute configuration assignment and enantioselective activity and toxicity. AB - Chiral herbicides consist of two or more enantiomers, which usually differ in their biological properties and behave enantioselectively in biochemical process. Scant studies have been published in the past decades to characterize the enantiomers of herbicide lactofen. In this study, a laboratory method was developed to prepare the lactofen enantiomers using normal phase high performance liquid chromatography with an AD-H column, and MUg level production yield was achieved in a single run. The two separated enantiomers had purity of ?99%, with their absolute configurations assigned by experimental and calculated electronic and vibrational circular dichroism. Spectral analyses including semi-empirical rules as well as comparisons with the results of quantum chemical calculations confirmed the molecular configurations of R-lactofen and S-lactofen, in this elution order. The enantioselective bioactivity toward weed (Echinochloa crusgalli) and toxicity toward aquatic algae (Microcystis aeruginosa) was assessed by measuring their growth rates after the treatments with lactofen enantiomers and racemate. The results showed that R-lactofen affected E. crusgalli more severely, while S-lactofen was more toxic to algae. Using active enantiomer instead of racemate may be more efficient and safe. Therefore, a more comprehensive understanding of the behaviors of chiral enantiomers is a need to improve activity and risk assessment and regulations of chiral compounds. Our work will be helpful to easily prepare single enantiomers from racemic mixtures and to establish effective absolute configurations of the enantiomers. PMID- 29149712 TI - Detection of perfluoroalkyl acids and sulphonates in Italian eel samples by HPLC HRMS Orbitrap. AB - Perfluoroalkyl substances (PFASs) contain one or more carbon-bound hydrogens substituted by fluorine. Since the 1950s, these compounds have been used to manufacture fat- and water-resistant fabrics, paper and food containers, and to produce photographic films, firefighting foams, detergents and insecticides. The widespread use and global distribution of PFASs, have led to their accumulation in the environment. Food, particularly fish and other seafood, is considered the main route of human exposure to PFASs. Consequently, the European Food Safety Authority (EFSA) recommends that more data be collected, to build a database on the contamination levels of the individual PFASs in food, to evaluate a reliable chronic risk to the European consumers. This requires high-sensitivity analytical methods, to increase the number of quantifiable samples and, thereby, improve the credibility of exposure assessments. In this context, the aim of the present research is to develop and validate a sensitive and specific method based on high performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) analysis, to monitor the presence of 16 PFASs in Italian eels (Anguilla anguilla) from the Italian Lake Garda. The detection limits (CCalpha) and detection capability (CCbeta) in the order of pg g-1, the recoveries between 80 and 101% and the other validation parameters fulfilled the requirements of Commission Decision 657/2002/EC. The identification and quantification of PFASs, up to 11 in the same sample, showed a similar distribution among 90 eels. Perfluorooctane sulphonic acid (PFOS) and perfluorobutanoic acid (PFBA) were the analytes more frequently found in the eel samples (94 and 82%, respectively). PMID- 29149713 TI - Adult exposure to bisphenol A in rare minnow Gobiocypris rarus reduces sperm quality with disruption of testicular aquaporins. AB - Bisphenol A (BPA) is an endocrine disrupter which has adverse effects on male reproduction. Aquaporins (AQPs), well known water-selective channels, play important roles in spermatogenesis and sperm functions. However, whether AQPs participate in the process that BPA induces abnormal sperms has not been investigated to date. In the present study, adult male rare minnows Gobiocypris rarus were exposed to environmentally relevant concentrations BPA (15 and 225 MUg/L) for 1, 2 and 3 weeks. Results showed that BPA exposure disrupted sperm motility, increased the percentage of abnormal sperm cells, and decreased sperm tolerance to hypotonic solution and sperm fertilization capacity. Meanwhile, protein levels of AQPs were up-regulated, and their distribution in the testis was abnormal following BPA exposure. The following chromatin immune coprecipitation showed that BPA could regulate aqp3 and 8 expression through the ERE in their 5'-flanking region. The present study demonstrated that BPA could decrease the sperm quality in rare minnow, and AQP3 and 8 might play significant roles in this process. PMID- 29149715 TI - Robust brain ROI segmentation by deformation regression and deformable shape model. AB - We propose a robust and efficient learning-based deformable model for segmenting regions of interest (ROIs) from structural MR brain images. Different from the conventional deformable-model-based methods that deform a shape model locally around the initialization location, we learn an image-based regressor to guide the deformable model to fit for the target ROI. Specifically, given any voxel in a new image, the image-based regressor can predict the displacement vector from this voxel towards the boundary of target ROI, which can be used to guide the deformable segmentation. By predicting the displacement vector maps for the whole image, our deformable model is able to use multiple non-boundary predictions to jointly determine and iteratively converge the initial shape model to the target ROI boundary, which is more robust to the local prediction error and initialization. In addition, by introducing the prior shape model, our segmentation avoids the isolated segmentations as often occurred in the previous multi-atlas-based methods. In order to learn an image-based regressor for displacement vector prediction, we adopt the following novel strategies in the learning procedure: (1) a joint classification and regression random forest is proposed to learn an image-based regressor together with an ROI classifier in a multi-task manner; (2) high-level context features are extracted from intermediate (estimated) displacement vector and classification maps to enforce the relationship between predicted displacement vectors at neighboring voxels. To validate our method, we compare it with the state-of-the-art multi-atlas-based methods and other learning-based methods on three public brain MR datasets. The results consistently show that our method is better in terms of both segmentation accuracy and computational efficiency. PMID- 29149714 TI - Influence of Fe(II) on the Se(IV) sorption under oxic/anoxic conditions using bentonite. AB - 79Se, one of the key radionuclides for nuclear waste disposal, threatens the quality of the environment, as well as human health. Therefore, it needs to be permanently isolated from the biosphere. The aim of the study was to investigate the effects of Fe(II)/Fe(III) on the removal of 79Se using bentonite in the pH range of 2.0-10.0 under oxic/anoxic conditions. Under oxic conditions, Se(IV) prefers to form inner-sphere complexes with Fe(III)-oxyhydroxide, derived from the oxidization of Fe(II) using oxygen. Interestingly, Se(IV) will interact with Fe(III) and form a poorly soluble ferric selenite at pH ~4 under oxic conditions. Under anoxic conditions, however, the concentration of Fe(II) is closely related to the sorption process of Se(IV) on bentonite. When the concentration of Fe(II) was less than 1%, Fe(II) combined with the hydroxyl, forming Fe(OH)2, which generated a disproportionation at pH ~8 and formed a new sorbent, Fe3O4. However, when the concentration of Fe(II) was increased to 5%, reduction precipitation was the primary way to remove Se(IV) in aqueous solution. XANES (X-ray Absorption Near Edge Structure) spectra showed that higher pH values are beneficial for the formation of the final thermodynamic reduction product, Fe selenide. These results suggested that Fe(II) significantly affect the Se(IV) sorption. Overall, this study confirmed the significant role of Fe(II) on the retardation of 79Se and on remediation for Se(IV) contamination in the hydrosphere. PMID- 29149716 TI - Longitudinal associations between resilience and quality of life in eating disorders. AB - OBJECTIVE: This study examined the longitudinal reciprocal associations between resilience factors, quality of life (QoL) domains, and symptoms of eating disorders (EDs). Hypotheses included predictive paths from resilience factors of "acceptance of self and life" and "personal competence" to increased QoL and predictive paths from previous levels of QoL to resilience. METHOD: A total of 184 patients with EDs (mean age = 29.55, SD = 9.17, 94.8% women) completed measures of resilience, QoL, and EDs symptoms over three waves spaced six month apart. Hypotheses were tested by path analysis. RESULTS: Resilience factors predicted improvements in psychological health and social relationship domains of QoL and a reduction of ED symptoms over time. In addition, psychological health increased acceptance of self and life consistently over time, whereas physical health increased the competence component of resilience. DISCUSSION: The relationships between resilience factors and QoL are reciprocal, with several mediational paths. A spiral of recursive influences between resilience factors and QoL can take place in people with EDs. This possibility offers new perspectives to understanding the process of recovery in patients with ED. PMID- 29149717 TI - Usefulness of the Montreal Cognitive Assessment (MoCA) to monitor cognitive impairments in depressed patients receiving electroconvulsive therapy. AB - There is a lack of consensual tools for evaluating the cognitive side-effects in patients with depression who are treated with electroconvulsive therapy (ECT). The objective of this study was to evaluate the usefulness of the Montreal Cognitive Assessment (MoCA) and of the Mini Mental State Examination (MMSE) to monitor cognitive changes in patients with depression receiving ECT. Cognitive functioning was assessed prospectively in 48 patients with unipolar or bipolar depression before and after an ECT course. ECT-induced cognitive impairments were defined as a decrease of at least 2 points on the MoCA and the MMSE total scores and of at least one point on each sub-score. At baseline, the MoCA detected a higher number of patients with cognitive deficits than the MMSE. After ECT, the MoCA and MMSE total scores were comparable, but the MoCA detected more impairments than did the MMSE for visuo-executive, memory and language subscores. ECT significantly decreased the language capacities but improved the visuo executive and abstraction performances measured by MoCA. In remitters, the MoCA total score and visuo-executive and abstraction performances were significantly improved, while other cognitive functions remained unchanged. The MoCA is a useful screening tool for monitoring cognitive functioning during an ECT course. PMID- 29149718 TI - Coronary risk assessment at X-ray dose equivalent ungated chest CT: Results of a multi-reader study. AB - OBJECTIVES: To determine the value of ultra-low dose chest CT with tin filtration for ordinal coronary artery calcium (CAC) risk scoring. METHODS: 50 patients were prospectively included and underwent clinical standard dose chest CT (1.8+/ 0.7mSv) and ultra-low dose CT (0.13+/-0.01mSv). Four radiologists estimated presence and extent of CAC. RESULTS: Weighted kappa values for CAC were 0.76-0.97 in standard dose and 0.75-0.95 in ultra-low dose CT (p<0.001). Good to excellent agreement was observed for CAC ordinal risk assessment, with readers reporting identical risk in 81% of cases. CONCLUSION: CAC risk can be qualitatively assessed from X-ray dose equivalent ungated chest CT. PMID- 29149719 TI - Tissue-specific bioaccumulation of long-chain perfluorinated carboxylic acids and halogenated methylbipyrroles in Dall's porpoises (Phocoenoides dalli) and harbor porpoises (Phocoena phocoena) stranded in northern Japan. AB - This study investigated accumulation of perfluoroalkyl substances (PFASs), persistent organochlorines (OCs), and naturally produced halogenated compounds (NHCs), including brominated methylbipyrroles and methoxylated bromodiphenyl ethers, in liver, blood, and blubber from Dall's porpoises (Phocoenoides dalli) and harbor porpoises (Phocoena phocoena) stranded in Hokkaido, northern Japan. Profiles of the PFASs were dominated by perfluoroundecanoic acid and perfluorotridecanoic acid, both of which accounted for 70% of the total measured PFAS concentrations in both porpoise species. The mean concentrations of the ?PFCA were 573ng/g wet weight (ng/g-wet) in liver, 62ng/g-wet in whole blood, and 28ng/g-wet in blubber from the Dall's porpoises, and were significantly higher (p<0.05) than those in the harbor porpoises. The hepatic concentrations of perfluorooctane sulfonate (PFOS) were <14ng/g-wet, and accounted for only 3% of the total measured PFASs. The profiles of PFASs in the porpoises resembled those in fish species in this area, implying a common source of exposure to PFASs in East Asia. On the other hand, in the blubber of Dall's porpoises, NHCs were dominated by 2,3,3',4,4',5,5'-heptachloro-1'-methyl-1,2'-bipyrrole (867ng/g-wet), 5,5'-dichloro-1,1'-dimethyl-3,3',4,4'-tetrabromo-2,2'-bipyrrole (481ng/g-wet), and 6-methoxy-2,2',4,4'-tetrabromodiphenyl ether (30ng/g-wet), which were present at higher concentrations than in harbor porpoises. Factor analysis with varimax rotation revealed that factor 1 had higher eigenvectors (element in eigenvalues) for long-chain PFCAs and PFOS, which was found in the highest concentrations in the liver, whereas factor 2 was mainly associated with lipid soluble NHCs and OCs in both species. No correlations were observed between long-chain PFCAs and NHCs in the porpoises, probably because of the different sources and accumulation kinetics. Future research should assess the temporal trends and long-term effects of PFASs and NHCs in the tissues of mammals from the Asia-Pacific region. PMID- 29149720 TI - A robust strategy for preparation of sequential stimuli-responsive block copolymer prodrugs via thiolactone chemistry to overcome multiple anticancer drug delivery barriers. AB - Block copolymer prodrugs (BCPs) have attracted considerable attentions in clinical translation of nanomedicine owing to their self-assembly into well defined core-shell nanoparticles for improved pharmacokinetics, stability in blood circulation without drug leakage, and optimized biodistribution. However, a cascade of physiological barriers against specific delivery of drugs into tumor cells limit the final therapeutic efficacy. Herein, we report a robust and facile strategy based on thiolactone chemistry to fabricate well-defined BCPs with sequential tumor pH-promoted cellular internalization and intracellular stimuli responsive drug release. A series of BCPs were prepared through one-pot synthesis from clinically used small molecule anticancer drugs. The ring-opening reaction of drug-conjugated thiolactones releases mercapto groups via aminolysis by N-(3 aminopropyl)-imidazole, which further react with poly(ethylene glycol)-block poly(pyridyldisulfide ethylmethacrylate) (PEG-PDSEMA) to produce imidazole and disulfide bonds-incorporated BCPs. Taking paclitaxel (PTX) for example, PTX BCPs exhibited high drug-loading content (>50%) and low critical micellization concentration (5 * 10-3 g/L), which can self-assemble into micellar nanoparticles in aqueous solution with a small size (~40 nm). The nanoparticles showed high tumor accumulation and uniform distribution in hypopermeable tumors via systemic administration. Meanwhile, imidazole moieties endow nanoparticles tumor pH sensitive charge transition from nearly neutral to positive, which promoted cellular internalization. Disulfide bonds can be cleaved by intracellular glutathione (GSH) of cancer cells, which accelerate the release of active PTX drug inside cells. Finally, highly aggressive murine breast cancer 4T1 tumor and hypopermeable human pancreatic adenocarcinoma BxPC3 tumor were completely ablated after treatment by PTX BCP nanoparticles. Consequently, the robust and facile preparation strategy based on thiolactone chemistry represents an efficient approach to construct multifunctional BCPs for better therapeutic efficacy via addressing multiple physiological barriers. PMID- 29149722 TI - Effects of middle ear quasi-static stiffness on sound transmission quantified by a novel 3-axis optical force sensor. AB - BACKGROUND: Intra-operative quantification of the ossicle mobility could provide valuable feedback for the current status of the patient's conductive hearing. However, current methods for evaluation of middle ear mobility are mostly limited to the surgeon's subjective impression through manual palpation of the ossicles. This study investigates how middle ear transfer function is affected by stapes quasi-static stiffness of the ossicular chain. The stiffness of the middle ear is induced by a) using a novel fiber-optic 3-axis force sensor to quantify the quasi static stiffness of the middle ear, and b) by artificial reduction of stapes mobility due to drying of the middle ear. METHODS: Middle ear transfer function, defined as the ratio of the stapes footplate velocity versus the ear canal sound pressure, was measured with a single point LDV in two conditions. First, a controlled palpation force was applied at the stapes head in two in-plane (superior-inferior or posterior-anterior) directions, and at the incus lenticular process near the incudostapedial joint in the piston (lateral-medial) direction with a novel 3-axis PalpEar force sensor (Sensoptic, Losone, Switzerland), while the corresponding quasi-static displacement of the contact point was measured via a 3-axis micrometer stage. The palpation force was applied sequentially, step wise in the range of 0.1-20 gF (1-200 mN). Second, measurements were repeated with various stages of stapes fixation, simulated by pre-load on the stapes head or drying of the temporal bone, and with severe ossicle immobilization, simulated by gluing of the stapes footplate. RESULTS: Simulated stapes fixation (forced drying of 5-15 min) severely decreases (20-30 dB) the low frequency (<1 kHz) response of the middle ear, while increasing (5-10 dB) the high frequency (>4 kHz) response. Stapes immobilization (gluing of the footplate) severely reduces (20-40 dB) the low and mid frequency response (<4 kHz) but has lesser effect (<10 dB) at higher frequencies. Even moderate levels of palpation force (<3gF, <30 mN), regardless of direction, have negative effect (10-20 dB) on the low frequency (<2 kHz) response, but with less significant (5-10 dB) effect at higher frequencies. Force-displacement measurements around the incudostapedial joint showed quasi-static stiffness in the range of 200-500 N/m for normal middle ears, and 1000-2500 N/m (5-8-fold increase) after artificially (through forced drying) reducing the middle ear transfer function with 10-25 dB at 1 kHz. CONCLUSION: Effects of the palpation force level and direction, as well as stapes fixation and immobilization have been analyzed based on the measurement of the stapes footplate motion, and controlled application of 3D force and displacement. PMID- 29149721 TI - Biological safety and tissue distribution of (16 mercaptohexadecyl)trimethylammonium bromide-modified cationic gold nanorods. AB - The exceptionally high cellular uptake of gold nanorods (GNRs) bearing cationic surfactants makes them a promising tool for biomedical applications. Given the known specific toxic and stress effects of some preparations of cationic nanoparticles, the purpose of this study was to evaluate, in an in vitro and in vivo in mouse, the potential harmful effects of GNRs coated with (16 mercaptohexadecyl)trimethylammonium bromide (MTABGNRs). Interestingly, even after cellular accumulation of high amounts of MTABGNRs sufficient for induction of photothermal effect, no genotoxicity (even after longer-term accumulation), induction of autophagy, destabilization of lysosomes (dominant organelles of their cellular destination), alterations of actin cytoskeleton, or in cell migration could be detected in vitro. In vivo, after intravenous administration, the majority of GNRs accumulated in mouse spleen followed by lungs and liver. Microscopic examination of the blood and spleen showed that GNRs interacted with white blood cells (mononuclear and polymorphonuclear leukocytes) and thrombocytes, and were delivered to the spleen red pulp mainly as GNR-thrombocyte complexes. Importantly, no acute toxic effects of MTABGNRs administered as 10 or 50 MUg of gold per mice, as well as no pathological changes after their high accumulation in the spleen were observed, indicating good tolerance of MTABGNRs by living systems. PMID- 29149723 TI - Residual effects of biochar on growth, photosynthesis and cadmium uptake in rice (Oryza sativa L.) under Cd stress with different water conditions. AB - Soil cadmium (Cd) contamination and drought stress are among the main issues hindering global food security. Biochar has been used to reduce metal uptake by plants and water stress mitigation, but long-term residual effects of biochar under Cd stress at different moisture levels needs to be investigated. A following rice (Oryza sativa L.) was grown after wheat on Cd-contaminated soil amended with different levels of biochar (0, 3.0, and 5.0%, w/w). Thirty five days old plants were irrigated with three moisture levels including zero drought as a control (1-2 cm water layer on soil), mild drought (MD, 50% of soil water holding capacity, WHC), and severe drought (SD, 35% of soil WHC) for an accompanying 35 days. Plant height, biomass and photosynthesis were reduced whereas oxidative stress increased under MD and SD than control in un-amended soil while opposite trends were observed in plants grown in biochar amended soil. At the same biochar addition, Cd concentrations in seedlings were lower in continuous flooding than MD and SD treatments. The biochar supply reduced the bioavailable Cd in the soil whereas increased the soil EC and pH than the control treatment. In conclusion, continuous flooding plus residual biochar can be strategized in mitigating Cd-contamination in paddy soils and decreased Cd concentrations in rice which may reduce the potential risks to humans. PMID- 29149724 TI - Peri-ultrasound modeling for surface wave propagation. AB - The interaction between surface wave and a surface breaking crack is studied using a novel fast modeling tool called peri-ultrasound that can model both linear and nonlinear ultrasonic response. This modeling approach is based on peridynamic theory. In this study, the surface wave is modeled by applying a triangular pulse excitation function on the surface of a large structure. The particle movements are simulated on both sides of the surface crack to investigate transmitted and reflected fields. This investigation shows that: (1) the computed amplitude spectra of the Rayleigh wave agrees with the experimental observation; and (2) the structure containing a surface breaking crack shows noticeable increase in its nonlinear behavior. The computed results have been also verified against the analytical solution for a half-plane problem made of homogenous, isotropic, linear elastic material (Lamb's Problem). PMID- 29149725 TI - A method for the design of ultrasonic devices for scanning acoustic microscopy using impulsive signals. AB - Scanning acoustic microscopy (SAM) using impulsive signals is useful for characterization of biological tissues and cells. The operating center frequency of an ultrasonic device strongly depends on the performance characteristics of the device if the measurement is conducted by using impulsive signals. In this paper, a method for the design of ultrasonic devices for SAM using impulsive signals was developed. A new plane-wave model was introduced to calculate frequency characteristics of loss of ultrasonic devices by taking into account the conversion loss at the ultrasonic transducer, the transmission loss at the acoustic anti-reflection coating, and the propagation loss in the couplant. Ultrasonic devices were fabricated with a ZnO ultrasonic transducer using two acoustic lenses with aperture radii of 1.0 mm and 0.5 mm, respectively. The frequencies at which measured losses became minima corresponded to the calculation results by the plane-wave model. This numerical calculation method is useful for designing ultrasonic devices for acoustic microscopy using impulsive signals. PMID- 29149726 TI - Protein structure-based drug design: from docking to molecular dynamics. AB - Recent years have witnessed rapid developments of computer-aided drug design methods, which have reached accuracy that allows their routine practical applications in drug discovery campaigns. Protein structure-based methods are useful for the prediction of binding modes of small molecules and their relative affinity. The high-throughput docking of up to 106 small molecules followed by scoring based on implicit-solvent force field can robustly identify micromolar binders using a rigid protein target. Molecular dynamics with explicit solvent is a low-throughput technique for the characterization of flexible binding sites and accurate evaluation of binding pathways, kinetics, and thermodynamics. In this review we highlight recent advancements in applications of ligand docking tools and molecular dynamics simulations to ligand identification and optimization. PMID- 29149727 TI - Surface modification of electrospun poly-(l-lactic) acid scaffolds by reactive magnetron sputtering. AB - In this study, we modified the surface of bioresorbable electrospun poly-(l lactic) acid (PLLA) scaffolds by reactive magnetron sputtering of a titanium target under a nitrogen atmosphere. We examined the influence of the plasma treatment time on the structure and properties of electrospun PLLA scaffolds using SEM, XRF, FTIR, XRD, optical goniometry, and mechanical testing. It was observed that the coating formed did not change physicomechanical properties of electrospun PLLA scaffolds and simultaneously, increased their hydrophilicity. No adverse tissue reaction up to 3 months after subcutaneous implantation of the modified scaffolds was detected in in-vivo rat model. The rate of scaffold replacement by the recipient tissue in-vivo was observed to depend on the plasma treatment time. PMID- 29149728 TI - Tuning magnetic relaxation properties of "hard cores" in core-shell colloids by modification of "soft shell". AB - The present work introduces an impact of polyelectrolyte-based hydrophilic shell on magnetic relaxivity and luminescence of hard cores built from isostructural complexes of Tb(III) and Gd(III) in the core-shell aqueous colloids. Microscopic and scattering techniques reveal "plum pudding" morphology of the colloids, where polyelectrolyte-coated ultrasmall (<5nm) hard cores form aggregates in aqueous solutions. Interaction of bovine serum albumin (BSA) with the colloids provides a tool to modify the polyelectrolyte-based shell, which is the reason for the improvement in both aggregation behavior of the colloids and their relaxivity. The modification of the hydrophilic polyelectrolyte-based shell enables to tune the longitudinal relaxivity from 5.9 to 23.3mM-1s-1 at 0.47T. This tendency is the reason for significant improvement of contrasting effect of the colloids in T1- and T2-weighted images obtained by whole body scanner at 1.5T. High contrasting effect of the colloids, together with low cytotoxicity towards Wi-38 diploid human cells makes them promising MRI contrast agents. PMID- 29149729 TI - Functionalized gold nanoparticles as affinity nanoprobes for multiple lectins. AB - Glycan-lectin interactions are commonly observed in nature. Analytical methods, which are used to detect lectins that rely on the use of glycan ligand-modified nanoprobes as affinity probes, have been developed. Most of the existing methods are focused on the use of synthetic glycan ligands. Nevertheless, naturally available glycoproteins, such as ovalbumin in chicken egg whites, are good sources for fabricating glycan-immobilized nanoprobes. In this study, we generated functionalized gold nanoparticles (Au NPs) from a one-pot reaction by reacting chicken egg white (cew) proteins with aqueous tetrachloroaurate. The generated Au@cew NPs are mainly encapsulated by ovalbumin, in which the surface is decorated by abundant hybrid mannose and Galbeta(1->4)GlcNAc-terminated glycan ligands. Thus, the generated Au@cew NPs containing hybrid mannose and Galbeta(1 >4)GlcNAc have the capability to selectively bind with their corresponding lectins. Lectins including concanavalin A, banana lectin, and ricin B that have binding moieties toward specific sugars were used as the model samples. Our results showed that the generated AuNPs can be used as multiplex affinity probes for these model lectins. Lectins can be selectively released from the Au@cew NP lectin conjugates by using specific sugars, such as mannose, glucose, and beta lactose, as the releasing agents to release specific lectins from the conjugates. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) was used as the tool to characterize the released species from the nanoprobes. The limit of detection of these model lectins using the current approach was low (in nM). The feasibility of using the Au@cew NP-based affinity MALDI-MS to selectively detect specific lectins from complex samples was also demonstrated. PMID- 29149730 TI - Divergence of insulin superfamily ligands, receptors and Igf binding proteins in marine versus freshwater stickleback: Evidence of selection in known and novel genes. AB - Three-spine stickleback (Gasterosteus aculeatus) is a teleost model for understanding genetic, physiological and morphological changes accompanying freshwater (FW) adaptation. There is growing evidence that the insulin superfamily plays important roles in traits involved in marine and FW adaptation. We performed a candidate gene analysis to look for evidence of selection on 33 insulin superfamily ligand-receptor genes and insulin-like growth factor binding proteins (Igfbp's) in stickleback. Using genotype data from 11 marine and 10 FW populations, we calculated the number of SNPs per site in regulatory and intronic regions, the number of synonymous and nonsynonymous mutations in coding regions, Wright's fixation index (Fst), and performed t-tests to identify SNPs with divergent genotype frequencies between marine/FW versus Atlantic/Pacific populations. Next, we analysed genome-wide transcriptome data from eight tissues to assess differential gene expression. Two Igfbp's (Igfbp2a and Igfbp5a) show evidence of divergent adaptation between life-history types, and a cluster of nonsynonymous mutations in Igfbp5a exhibit high Fst in exons apparently alternatively spliced in gill. We find evidence of selection on the relaxin family ligand-receptor gene pair, Insl3-Rxfp2, known to be involved in male spermatogenesis and bone metabolism, and in the 5' regulatory region of Igf2. We also confirmed the gene and coding sequence of two unannotated relaxin family ligands. These analyses underscore the utility of candidate gene studies and indicate directions for further exploration of the function of insulin superfamily genes in FW adaptation. PMID- 29149732 TI - Hepatitis B immunoglobulin-induced hypercoagulability complicating liver transplantation necessitating ECMO, rescue hepatectomy, and retransplantation. PMID- 29149733 TI - Movement of sciatic nerve with dorsiflexion and plantar flexion of foot: A new identification method by ultrasound. PMID- 29149731 TI - Purinergic drug targets for gastrointestinal disorders. AB - Purinergic receptors are implicated in the pathogenesis of gastrointestinal disorders and are being explored as potential therapeutic targets. Gut inflammation releases ATP that acts on neuronal, glial, epithelial and immune cells. Purinergic signalling in glia and neurons is implicated in enteric neuropathies. Inflammation activates glia to increase ATP release and alter purinergic signalling. ATP release causes neuron death and gut motor dysfunction in colitis via a P2X7-dependent neural-glial pathway and a glial purinergic connexin-43 pathway. The latter pathway also mediates morphine-induced constipation and gut inflammation that may differ from opioid-induced constipation. P2X7R antagonists are protective in inflammatory bowel disease (IBD) models, where as AZD9056 is questionable in Crohn's disease, but is potentially beneficial for chronic abdominal pain. Drug targets under investigation for IBD, irritable bowel syndrome and motility disorders include P2X7R, P2X3R, P2Y2R, A2A/A2BAR, enzymes and transporters. PMID- 29149734 TI - Ultrasound guided Erector Spinae Plane block at L-4 transverse process level provides effective postoperative analgesia for total hip arthroplasty. PMID- 29149735 TI - Carbamazepine, lamotrigine, levetiracetam and valproic acid in dried blood spots with liquid chromatography tandem mass spectrometry; method development and validation. AB - Monitoring of antiepileptic drugs in children with epilepsy require multiple visits at a clinic for blood collection. Dried blood spot sampling is an alternative way of collection, performed at home by self-collection and can save time and costs for patients and family members. The aim was to develop and validate an LC-MS/MS dried blood spot method for carbamazepine, lamotrigine, levetiracetam and valproic acid with the requirements of using standard equipment and material in a routine laboratory setting. Whatman-903 filter paper was utilized, and discs were punched into a 96 well plate with an automated puncher and barcode reading. Extraction with methanol/water solution including internal standards on an orbital shaker was followed by a vacuum centrifuge step and reconstitution in mobile phase. Bioanalytical validation was performed according to guidelines from European Medicines Agency and additional dried blood spot specific validation. Calibration curves of the four included drugs had R2 values >=0.994. Therapeutic relevant concentrations were well within measuring ranges. Within and -between run precision had %CV:s of 2.9-10.5%. Accuracy (%bias) was between -16.5% (lower limit of quantification) to +7.4%. Blood spots in a volume range of 15-50MUL with hematocrit in expected ranges for this patient group were within precision and accuracy limits. To test the method, concentrations from dried blood spot venous and capillary patient samples (n=50) were compared with plasma concentrations. Good correlations for all four drugs with R2 of >0.92 was shown. In summary, a fast method for dried blood spots based on a 96 well format was developed for four commonly prescribed antiepileptic drugs. This validated method with traceability in sample preparation by bar code reading makes it suitable for the clinical laboratory. PMID- 29149736 TI - Graphene oxide reinforced ionic liquid-functionalized adsorbent for solid-phase extraction of phenolic acids. AB - An environmental friendly sorbent of polymeric ionic liquids modified graphene oxide-grafted silica (PILs@GO@Sil) was synthesized for solid-phase extraction (SPE) of phenolic acids. The sorbent was prepared via a chemical layer-to-layer fabrication including amidation reaction, surface radical chain-transfer polymerization and in situ anion exchange. After modification with PILs, the silica surface had higher positive potential so that it would exhibit stronger electrostatic interaction for acidic compounds compared with GO@Sil. The adsorption performance of phenolic acids was investigated through the theoretical calculation and static, kinetic state adsorption experiments. Under the optimized conditions, wide linear ranges were obtained with correlation coefficients ranging from 0.9912 to 0.9998, and limits of detection were in the range of 0.20 0.50MUgL-1. Compared with other reported methods, the proposed PILs@GO@Sil-SPE HPLC showed higher extraction efficiency. Finally, the black wolfberry yogurt and urine were analyzed as real samples and good recoveries spiked with standard solution were obtained. PMID- 29149737 TI - Source apportionment of black carbon during winter in Beijing. AB - Black carbon (BC) in PM2.5 was measured at an urban site in Beijing during winter 2015 using an aethalometer. The characteristics and sources of BC during pollution episodes and clean days were analyzed. The average hourly mass concentration of BC during the study period was 5.31+/-6.27MUg/m3. BC was highly correlated with PM2.5 (R2=0.80), with its concentration ranging from 0.17MUg/m3 in clean days to 35.33MUg/m3 in haze days. Source apportionment results showed that the average contribution of liquid fuel source (e.g., vehicle emission) to BC was around 50% in clean days. While during the pollution episodes, solid fuel sources including coal combustion and biomass burning were the predominant sources, accounting for 61-83% of BC. Specific source tracers suggested that coal combustion and biomass burning dominated in different pollution episodes. Ratios of BC/PM2.5 and BC/CO as well as source tracers provided further supportive evidences for the source apportionment results. Our findings suggest that it is more important to control solid fuel sources such as coal combustion for BC abatement in Beijing during haze days, while liquid fuel source (e.g., vehicle emission) plays a relatively more important role in clean days compared to pollution episodes. PMID- 29149738 TI - Associations of urinary polycyclic aromatic hydrocarbon metabolites with fractional exhaled nitric oxide and exhaled carbon monoxide: A cross-sectional study. AB - Exposure to Polycyclic aromatic hydrocarbons (PAHs) has been associated with inflammatory responses. Fractional exhaled nitric oxide (FeNO) and exhaled carbon monoxide (eCO) are both important inflammatory mediators especially in airways. However, few studies have investigated associations of PAH exposures with FeNO or eCO. Therefore, we aimed to quantify the associations of urinary PAH metabolites with FeNO and eCO levels, and investigate their potential effect modifiers by linear mixed models among 4133 participants from the Wuhan-Zhuhai cohort in China. We further performed stratified analyses to estimate effect modification. We found significant associations of increased urinary PAH metabolites with elevated eCO and FeNO. Among all participants, each 1% increase of 1 hydroxynaphthalene, 2-hydroxynaphthalene, 2-hydroxyfluorene, 4 hydroxyphenanthrene, 3-hydroxyphenanthrene, and total PAH metabolites was significantly associated with a 12.6% (95% confidence interval: 9.3%, 15.9%), 9.7% (6.5%, 12.9%), 7.5% (4.1%, 10.9%), 3.2% (0.2%, 6.2%), 2.7% (0.1%, 5.3%), and 6.5% (2.7%, 10.4%) increased eCO level, respectively; while each 1% increase of urinary 1-hydroxynaphthalene, 9-hydroxyphenanthrene, 3-hydroxyphenanthrene, and 2 hydroxyphenanthrene was associated with a -3.0% (-5.8%, -0.2%), 2.9% (0.3%, 5.6%), 3.2% (1.0%, 5.4%), and 4.5% (2.2%, 6.9%) change of FeNO level, respectively. Positive associations between certain urinary PAH metabolites and eCO were observed among both ever-smokers and non-smokers, and the associations were stronger among ever-smokers than that among non-smokers. Increased urinary PAH metabolites were associated with decreased FeNO among ever-smokers and elevated FeNO levels among non-smokers. Our findings suggest that PAH exposures may impair airway through inducing inflammatory response, especially among ever smokers. PMID- 29149739 TI - Removal of TiO2 nanoparticles from water by low pressure pilot plant filtration. AB - Rising use of nanoparticles in manufacturing as well as in commercial products bring issues related to environmental release and human exposure. A large amount of TiO2 nanoparticles will eventually reach wastewater treatment plants. Low pressure membrane filtration has been suggested as a feasible treatment of water streams. This study investigated first at laboratory scale the influence of: i) membrane material, ii) pore size and iii) water chemistry on nTiO2 removal. TiO2 retention was governed by the cake layer formation mechanism and significant retention of nanoparticles was observed even for filters having considerably larger pores than nTiO2. PVDF showed a great potential for nTiO2 rejection. Additionally, filtration pilot plant experiments were carried out using PVDF membranes (0.03 and 0.4MUm pore size). The release of nTiO2 in the pilot scale filtration system was always above the instrumental detection limit (>1.5MUg/L) and in most cases below 100MUg/L regardless of the pore size and applied conditions. The nTiO2 membrane breakthrough predominantly occurred in the first few minutes after backwashes and ceased when the cake layer was formed. Ultrafiltration and microfiltration were comparable with rejection of nTiO2 above 95% at similar permeate flow rates. Nevertheless, ultrafiltration is more promising than microfiltration because it allowed longer operation times between backwash cycles. PMID- 29149740 TI - Skin-reducing mastectomy and direct-to-implant reconstruction in giant phyllodes tumour of breast: case report. AB - BACKGROUND: The phyllodes tumour of the breast comprises about 0.5% of all neoplasms of the breast. CASE REPORT: we present the case of a female patient (55 years old) suffering from giant phyllodes tumour (>10cm) of the left breast, who underwent Skin Reducing Mastectomy (SRM) and reconstruction with silicone breast implant (Bostwick Technique). DISCUSSION AND CONCLUSION: In selected patients with large sized breasts (C-D cup) and poor surface area of skin involved, a valid technique in the treatment of this pathology is the Skin-Reducing Mastectomy and immediate reconstruction with implants (DTI=direct to implant). PMID- 29149741 TI - The isolated posterior malleolar fracture and syndesmotic instability: A case report and review of the literature. AB - INTRODUCTION: Ankle fractures are among the most common type of fractures in the lower extremity. A posterior malleolar fracture is frequently part of a more complex ankle fracture and only in rare cases it occurs as isolated injury. Posterior malleolar fractures often occur with associated injuries, such as a Maisonneuve fracture or with bi- or trimalleolar ligamentous injuries. Knowledge about these associated injuries is essential to prevent missed diagnoses. The aim of this article is to describe the isolated posterior malleolar fracture, the possible associated injuries, the diagnostic work-up and therapeutic consequences. PRESENTATION OF CASE: We present a case of a 26-year-old male patient who sustained an isolated posterior malleolar fracture with 4.5 years follow-up. DISCUSSION: Isolated fractures of the posterior malleolus are uncommon injuries. Diagnosis, treatment and outcome can seldom be extracted from large series. However, several cases have been described in literature, which we have summarized. CONCLUSION: This case report and literature review shows that isolated posterior malleolar fractures might occur as part of a more complex ankle injury, in combination with a fracture of the lower leg or after high energy trauma. Physicians should be aware of these associated injuries. Diagnostic work-up should include X-rays of the knee and lower leg and a CT scan of the ankle. If diagnosed and treated properly, isolated posterior malleolar fractures have a good long-term functional outcome. PMID- 29149742 TI - Stability of heavy metals in soil washing residue with and without biochar addition under accelerated ageing. AB - Soil washing residue (SWR), which typically concentrates the washed toxic metals and is comprised of high contents of clay particles, may pose risks to the surrounding environment. This study aims to simulate accelerated ageing to assess the stability of selected metals (Cd2+ (132mg/kg), Cu2+ (248mg/kg) and Pb2+ (3470mg/kg)) in a SWR (89.68% of clay) with and without biochar treatment. The soil was incubated under constant moisture and wet-dry cycles (accelerated ageing), respectively, and the mobility and fractions of heavy metals in the soils with and without biochar treatment were examined. Under the constant moisture condition, biochar addition at 5% w/w reduced the leached Cd2+ (by 1.81%) and Cu2+ (by 8.70%) from SWR at day 1 and the leached Cu2+ (by 51.08%) and Pb2+ (by 25.36%) from SWR at day 14; however, the leached metals in the TCLP solution from the biochar-amended soils still exceed the regulatory limits (1mg/L for Cd2+, 5mg/L for Pb2+, no regulatory limits for Cu2+). Conversely, accelerated ageing (14days) significantly increased the fractions of exchangeable Cd2+ (from 3.63-3.94% to 6.21-6.29%) and Pb2+ (from 0.025-0.027% to 0.034-0.041%) as well as the TCLP leachabilities of Cd2+ (from 2.91-3.28% to 3.46-3.73%), Cu2+ (from 0.08 0.10% to 0.03-0.06%) and Pb2+ (from 0.25-0.35% to 0.52-0.57%) in the soils, as compared with those incubated under constant moisture, regardless of biochar addition. This study reveals challenges associated with stabilising SWR due to the presence of residual fine-grained particles. PMID- 29149743 TI - Multigenerational effects of salinity in six clonal lineages of Daphnia longispina. AB - Sea level rise, as a consequence of climate changes, is already causing seawater intrusion in some freshwater coastal ecosystems worldwide. The increase in salinity at these freshwater coastal ecosystems may occur gradually (through groundwater) or abruptly (through extreme weather events). Moreover, many of them are also being altered and threatened by anthropogenic activities. Accordingly, the present study aimed at assessing the multigenerational lethal and sublethal effects caused by increased salinity in six clonal lineages of the freshwater cladoceran Daphnia longispina differing in their sensitivity to lethal levels of copper. Three specific objectives were delineated: i) to compare the lethal and sublethal toxicity of sodium chloride (NaCl) and natural seawater (SW); ii) to evaluate possible multigenerational effects after exposure to low levels of salinity, and iii) to evaluate if an association exists between tolerance to lethal and sublethal levels of salinity and tolerance to metals. Overall, NaCl was found to elicit sublethal effects at lower or similar concentrations than SW, suggesting its use as a protective surrogate of SW in early phases of ecological risk assessment schemes. Multigenerational exposure to conductivities of 0.73+/ 0.015mScm-1 led to dissimilar responses by the six clonal lineages. Significant associations were found neither between lethal and sublethal endpoints nor between salinity and metals, possibly indicating the absence of common mechanisms responsible to confer metal tolerance and salt stress. However, some clonal lineages presented an inverse sensitivity to lethal levels of NaCl and of copper. These results suggest that natural populations of D. longispina, by exhibiting clonal lineages with differential tolerance to increased salinity, may cope with long-term exposure to small increases of this stressor. However, over time those populations may face the occurrence of genetic erosion due to the loss of the most sensitive genotypes before or after a multigenerational exposure. PMID- 29149744 TI - Bacterial community structure along the subtidal sandy sediment belt of a high Arctic fjord (Kongsfjorden, Svalbard Islands). AB - Open fjords are subject to contrasting environmental conditions, owing to meltwater glacial inputs, terrestrial runoff, and marine water mass exchanges, which are exacerbated by anthropogenic and climate perturbations. Following a slope-dependent water circulation, the subtidal sandy sediment belt regulates the convergent transport of nutrients downward the fjord depths, and the effective entrapment of suspended particles and microorganisms. In this study, we aimed at testing how glacial and seawater inputs may influence the bacterial community structure of subtidal sand deposits in the Kongsfjorden. Through total and viable cell counting and an amplicon sequencing approach, we found relevant differences in bacterial community structure along the glacio-marine sampling transect. Viable and high nucleic acid content (HNA) cells represented an important fraction of the total community, generally decreasing toward the glacier front. Besides the predominance of Alpha- and Gammaproteobacteria, Bacteroidetes, Firmicutes and Parcubacteria, the bacterial community structure was likely affected by the glacial activity in the inner fjord, with the occurrence of distinctive phylotypes belonging to Gemmatimonadates, Nitrospirae, Acidobacteria, and Chloroflexi. Overall, our outcomes highlighted that exploring the bacterial community distribution and structure can provide new insights into the active role of sand deposits in coastal cold environments. PMID- 29149745 TI - Household air pollution and chronic hypoxia in the placenta of pregnant Nigerian women: A randomized controlled ethanol Cookstove intervention. AB - BACKGROUND: Household air pollution (HAP) is associated with adverse pregnancy outcomes. OBJECTIVES: Investigate impact of in-utero HAP exposure on placental development and chronic hypoxia. METHODS: Markers of chronic placental hypoxia [Hofbauer cells (HBC), syncytial knots (SK), chorionic vascular density (cVD) and hypoxia-inducible factor (HIF)] were stained by hematoxylin-eosin and/or immunohistochemically in placenta samples collected from firewood-/kerosene-users (A,n=16), and ethanol-users (B,n=20) that participated in a randomized controlled intervention trial in Ibadan, Nigeria. A third group of non-smoking and presumed natural gas-using Chicago women (C,n=12) were included in this exploratory pilot to assess for possible differences in placenta histology between similar racial groups. All patients had uncomplicated pregnancies and delivered at term. RESULTS: HBC, SK and cVD were significantly increased among firewood-/kerosene users compared to ethanol-users and natural gas-using Chicago women (HBC medians 5.5, 3.5, and 2.0, respectively; SK means 55.6, 41.8 and 30.1; cVD means 8.8, 6.2, and 5.2; all p<0.01). HIF expression was significantly higher in Group A compared to B and C (all p<0.001). CONCLUSIONS: In-utero exposure to HAP is associated with pathologic changes and HIF expression consistent with chronic hypoxia in placenta of firewood/kerosene-users compared to ethanol-users with less HAP exposure and Chicago women with no presumed HAP exposure. Presence of chronic hypoxic signature in placenta of women exposed to HAP has implications for adverse pregnancy complications and future growth and development of the young children. Future larger studies need to focus on HAP exposure and placental disorders like preeclampsia and long-term health impact of in-utero exposure to HAP. PMID- 29149746 TI - Habitat mosaics and path analysis can improve biological conservation of aquatic biodiversity in ecosystems with low-head dams. AB - Conserving native biodiversity depends on restoring functional habitats in the face of human-induced disturbances. Low-head dams are a ubiquitous human impact that degrades aquatic ecosystems worldwide. To improve our understanding of how low-head dams impact habitat and associated biodiversity, our research examined complex interactions among three spheres of the total environment. i.e., how low head dams (anthroposphere) affect aquatic habitat (hydrosphere), and native biodiversity (biosphere) in streams and rivers. Creation of lake-like habitats upstream of low-head dams is a well-documented major impact of dams. Alterations downstream of low head dams also have important consequences, but these downstream dam effects are more challenging to detect. In a multidisciplinary field study at five dammed and five undammed sites within the Neosho River basin, KS, we tested hypotheses about two types of habitat sampling (transect and mosaic) and two types of statistical analyses (analysis of covariance and path analysis). We used fish as our example of biodiversity alteration. Our research provided three insights that can aid environmental professionals who seek to conserve and restore fish biodiversity in aquatic ecosystems threatened by human modifications. First, a mosaic approach identified habitat alterations below low head dams (e.g. increased proportion of riffles) that were not detected using the more commonly-used transect sampling approach. Second, the habitat mosaic approach illustrated how low-head dams reduced natural variation in stream habitat. Third, path analysis, a statistical approach that tests indirect effects, showed how dams, habitat, and fish biodiversity interact. Specifically, path analysis revealed that low-head dams increased the proportion of riffle habitat below dams, and, as a result, indirectly increased fish species richness. Furthermore, the pool habitat that was created above low-head dams dramatically decreased fish species richness. As we show here, mosaic habitat sampling and path analysis can help conservation practitioners improve science-based management plans for disturbed aquatic systems worldwide. PMID- 29149747 TI - Analysis of effect of particles on cake layer compressibility during ultrafiltration of upflow biological activated carbon effluent. AB - Three different hollow-fibre ultrafiltration (UF) membranes were applied to treat upflow biological activated carbon (UBAC) effluent to determine the characteristics of membrane biofouling by microorganisms and particles. At the beginning of filtration, the cake layer formed on the membrane was loose and highly compressible, and the trans-membrane pressure (TMP) rapidly increased. When compressed to a certain extent, cake layer with low compressibility was formed by the accumulated particles and resulted in slower TMP increment. Thus, the decreased compressibility of the cake layer formed on the UF membrane during filtration of UBAC effluent led to the rapid increase in TMP at the beginning and slow increment in subsequently. The results were confirmed by filtering Escherichia coli, Staphylococcus aureus and kaolinite mixed suspensions with flat sheet UF membrane. Our findings provide a new insight into membrane biofouling control and may facilitate better membrane application in drinking water treatment. PMID- 29149748 TI - In situ long-term modeling of phenanthrene dynamics in an aged contaminated soil using the VSOIL platform. AB - Management and remediation actions of polycyclic aromatic hydrocarbons (PAH) contaminated sites require an accurate knowledge of the dynamics of these chemicals in situ under real conditions. Here we developed, under the Virtual Soil Platform, a global model for PAH that describes the principal physical and biological processes controlling the dynamics of PAH in soil under real climatic conditions. The model was applied first to simulate the observed dynamics of phenanthrene in situ field experimental plots of industrial contaminated soil. In a second step, different long-term scenarios of climate change or bioavailability increase were applied. Our results show that the model can adequately predict the fate of phenanthrene and can contribute to clarify some of unexplored aspects regarding the behavior of phenanthrene in soil like its degradation mechanism and stabilization. Tested prospective scenarios showed that bioavailability increase (through the addition of solvent or surfactants) resulted in significant increase in substrate transfer rate, hence reducing remediation time. Regarding climate change effect, the model indicated that phenanthrene concentration decreased by 54% during 40years with a natural attenuation and both scenarios chosen for climatic boundaries provided very similar results. PMID- 29149749 TI - The role of satellite remote sensing in structured ecosystem risk assessments. AB - The current set of global conservation targets requires methods for monitoring the changing status of ecosystems. Protocols for ecosystem risk assessment are uniquely suited to this task, providing objective syntheses of a wide range of data to estimate the likelihood of ecosystem collapse. Satellite remote sensing can deliver ecologically relevant, long-term datasets suitable for analysing changes in ecosystem area, structure and function at temporal and spatial scales relevant to risk assessment protocols. However, there is considerable uncertainty about how to select and effectively utilise remotely sensed variables for risk assessment. Here, we review the use of satellite remote sensing for assessing spatial and functional changes of ecosystems, with the aim of providing guidance on the use of these data in ecosystem risk assessment. We suggest that decisions on the use of satellite remote sensing should be made a priori and deductively with the assistance of conceptual ecosystem models that identify the primary indicators representing the dynamics of a focal ecosystem. PMID- 29149750 TI - Friends or foes? Monetized Life Cycle Assessment and Cost-Benefit Analysis of the site remediation of a former gas plant. AB - Site contamination is a global concern because of the potential risks for human health and ecosystem quality. Every contaminated site has its own specific characteristics and the increased availability and efficiency of remediation techniques makes the choice of remediation alternative increasingly complicated. In this paper an attributional Life Cycle Assessment (LCA) of the secondary environmental impacts of a site remediation is performed and its results are monetized using two different monetization techniques, namely Stepwise 2006 and Ecovalue 08. Secondly, we perform a social Cost-Benefit Analysis (CBA) on the same case study using the same data sources. The case study used in this paper entails the soil and groundwater remediation of a tar, poly-aromatic hydrocarbons (PAH) and cyanide contamination of a school ground by a former gas plant. The remediation alternative chosen in this case study is excavation with off-site thermal treatment of the contaminated soil. The outcome of the social CBA, stating that the remediation project is socially beneficial in the long term, is critically compared to the outcome of the different LCA monetization methods. This comparison indicates that monetized LCA is a good complement to social CBA when it comes to the assessment of secondary environmental impacts. Combining the two methods provides decision makers with a more extensive and detailed assessment of the soil remediation project. PMID- 29149751 TI - Massive arrival of desalinated seawater in a regional urban water cycle: A multi isotope study (B, S, O, H). AB - "Man-made" or unconventional freshwater, like desalinated seawater or reclaimed effluents, is increasingly introduced into regional water cycles in arid or semi arid countries. We show that the breakthrough of reverse osmosis-derived freshwater in the largely engineered water cycle of the greater Tel Aviv region (Dan Region) has profoundly changed previous isotope fingerprints. This new component can be traced throughout the system, from the drinking water supply, through sewage, treated effluents, and artificially recharged groundwater at the largest Soil-Aquifer Treatment system in the Middle East (Shafdan) collecting all the Dan region sewage. The arrival of the new water type (desalinated seawater) in 2007 and its predominance since 2010 constitutes an unplanned, large-scale, long-term tracer test and the monitoring of the breakthrough of desalination specific fingerprints in the aquifer system of Shafdan allowed to get new insights on the water and solute flow and behavior in engineered groundwater systems. Our approach provides an investigation tool for the urban water cycle, allowing estimating the contribution of diverse freshwater sources, and an environmental tracing method for better constraining the long-term behavior and confinement of aquifer systems with managed recharge. PMID- 29149752 TI - Hazard assessment of hydraulic fracturing chemicals using an indexing method. AB - The rapid expansion of unconventional natural gas production has triggered considerable public concerns, particularly regarding environmental and human health (EHH) risks posed by various chemical additives used in hydraulic fracturing (HF) operations. There is a need to assess the potential EHH hazards of additives used in real-world HF operations. In this study, HF additive and fracturing fluid data was acquired, and EHH hazards were assessed using an indexing approach. The indexing system analyzed chemical toxicological data of different ingredients contained within additives and produced an aggregated EHH safety index for each additive, along with an indicator describing the completeness of the chemical toxicological data. The results show that commonly used additives are generally associated with medium-level EHH hazards. In each additive category, ingredients of high EHH concern were identified, and the high hazard designation was primarily attributed to ingredients' high aquatic toxicity and carcinogenic effects. Among all assessed additive categories, iron control agents were identified as the greatest EHH hazards. Lack of information, such as undisclosed ingredients and chemical toxicological data gaps, has resulted in different levels of assessment uncertainties. In particular, friction reducers show the highest data incompleteness with regards to EHH hazards. This study reveals the potential EHH hazards associated with chemicals used in current HF field operations and can provide decision makers with valuable information to facilitate sustainable and responsible unconventional gas production. PMID- 29149753 TI - Identifying relapse prevention elements during psychological treatment of depression: Development of an observer-based rating instrument. AB - BACKGROUND: Although observer-rated instruments assessing therapist's adherence to relapse-preventive treatments are available, they do not adequately cover specific relapse-preventive elements that focus on implementation of strategies after terminating treatment. This study describes the development of the KERI-D (Kodierbogen zur Erfassung Ruckfallprophylaktischer Interventionen bei Depression/Coding System to Assess Interventions of Relapse Prevention in Depression). The KERI-D is a new observer-based rating tool for acute or continuation/maintenance-phase sessions and assesses relapse-prevention elements including implementation into patient's daily routines. METHODS: The development of the KERI-D included iterative steps referring to theoretical, clinical and empirical sources. It consists of 19 content items within four categories (self care, early warning signs, triggering events/situations, termination of therapy) and one global item. For empirical analyses, videotaped psychotherapy sessions of 36 psychotherapies were rated by three independent observers and analyzed for their psychometric properties. RESULTS: Most items showed moderate to good inter rater reliability (median ICC = .80) and retest reliability (median ICC = .93). Principal-axis factor analysis revealed three subscales, and first evidence of content validity was demonstrated. No associations with clinical follow-up data were found. LIMITATIONS: Analysis was limited to a relatively small sample of selected psychotherapy sessions. Evaluation of predictive validity is a desirable next step to further examine applicability and scope of the instrument. CONCLUSIONS: The KERI-D is the first observer-based rating instrument measuring specific relapse-prevention strategies in psychotherapy for depression. It may help to identify elements that prove effective in reducing relapse/recurrence in the long-term and thereby help to optimize effect duration of depression treatment. PMID- 29149754 TI - The effect of comorbid depression on the use of unscheduled hospital care by people with a long term condition: A retrospective observational study. AB - BACKGROUND: The prevalence of long-term conditions (LTCs) and multiple-morbidity is increasing. Depression prevalence increases with the number of LTCs. Self management of LTCs improves outcomes, but depression impacts on self-management. Unscheduled hospital care may be a proxy for failure of planned care to support successful self-management. METHODS: Retrospective observational study based on routine NHS datasets covering 19 LTCs. Prevalence of LTCs and depression was identified in all primary care registered adults in one English city (n = 469,368). Chi squared was used for hypothesis testing, and logistic regression to determine the influence of depression and LTC(s) on the use of unscheduled hospital care. RESULTS: At least one LTC was identified in 220,010 (46.9%) adults; 75,107 (16.0%) had depression; and 38,232 (8.1%) had LTC plus comorbid depression. A significantly greater proportion of individuals with LTC and comorbid depression had >= 1 unscheduled event over 12 months (31.5%) compared to individuals with LTC(s) only (24.0%), X2(1) = 883.860, p < .001. The logistic regression model explained 4.4% of the variation in unscheduled care use. Individuals with depression plus >= 1 LTC were 1.59 times more likely to use unscheduled hospital care than individuals with LTC only (p < .001), after controlling for deprivation, age and number of LTCs. LIMITATIONS: Cross-sectional data precluded identification of the direction of influence between LTCs and depression. Only 19 major LTCs were studied, so overall LTC prevalence will be under-represented, and other significant predictors may be omitted. CONCLUSION: In people with a LTC, comorbidity with depression increases use of unscheduled hospital care. PMID- 29149755 TI - A randomized clinical trial of adjunctive ketamine anesthesia in electro convulsive therapy for depression. AB - BACKGROUND: Electroconvulsive therapy (ECT) is a rapid acting and effective treatment for both major depressive disorder (MDD) and bipolar disorder (BP). Both propofol and ketamine are commonly used anesthetic agents but recent clinical studies suggest that ketamine has rapid-acting antidepressant properties, itself, at sub-anesthetic doses. METHODS: A total of 77 inpatients (41 MDD and 36 BP) were randomly assigned to receive ECT with propofol (1mg/kg) anesthesia or with ketamine (0.5mg/kg) plus propofol (0.5mg/kg). Depressive symptoms were assessed with the 24-item Hamilton Depression Rating Scale (HAMD 24) and Montgomery-Asberg Rating Scale (MADRS), before and after 1, 2, 4, and 6 ECT treatments, and 1-4 weeks following the last treatment. The MATRICS Consensus Cognitive Battery (MCCB) was evaluated at baseline,after the sixth ECT, and 1-4 weeks following the final ECT. Adverse effects were assessed at baseline and 4 weeks after the last treatment. RESULTS: There were no significant differences in depressive symptoms, MCCB performance, or adverse effects between the treatment groups at any time. The electrical dose required to generate seizures in the ketamine plus propofol group was lower than that of the propofol only group at every time point. The seizure energy index and seizure duration in the ketamine plus propofol group was higher and longer than those in the propofol only group. LIMITATIONS: The diagnoses of MDD and BP were unevenly distributed across treatment groups. CONCLUSIONS: Ketamine plus propofol anesthesia in the ECT treatment of MDD and BP was not superior on any measure to propofol alone. PMID- 29149756 TI - Residual anxiety may be associated with depressive relapse during continuation therapy of bipolar II depression. AB - BACKGROUND: Anxiety symptoms are common in bipolar disorder. We explored the effect of anxiety on the outcome of acute and continuation pharmacotherapy of bipolar II depression. METHODS: Data were derived from a randomized double-blind 12-week acute (N = 129) and 6-month continuation (N = 55) comparison of venlafaxine versus lithium monotherapy in bipolar II depression in adults. We distinguished between the items of the Hamilton Rating Scale for Depression (HRSD) that capture depression vs. anxiety (i.e., psychomotor agitation, psychic anxiety, somatic anxiety, hypochondriasis, and obsessive-compulsive concerns) and examined the effect of treatment on depression and anxiety. Additionally, we explored whether baseline anxiety or depression predicted changes over time in depression and anxiety ratings or moderated treatment outcomes. We also explored whether residual depressive and anxious symptoms predicted relapse during continuation therapy. RESULTS: Venlafaxine was superior to lithium in reducing both depression and anxiety, though its effects on anxiety were more modest than those on depression. Baseline anxiety predicted change over time in anxiety, but not depression. By contrast, baseline depression did not predict change over time in depression or anxiety. Residual anxiety, specifically uncontrollable worry, was a stronger predictor of relapse than residual depression. CONCLUSION: Successful treatment of symptoms of anxiety in bipolar depression may protect against depressive relapse. PMID- 29149757 TI - Comparing the screening property of the shortened versions of the Hypomania Checklist-32 (HCL-32): Cross-validation in Korean patients with bipolar disorder and major depressive disorder. AB - BACKGROUND: To date, shortened versions of the Hypomania Checklist-32 (HCL-32) were proposed to overcome the limitation of a lengthy format; however, a cross validation study is currently needed to identify which shorter version may function optimally in a clinical sample. METHODS: In a Korean patient sample with bipolar disorder (BD) and major depressive disorder (MDD) (BD-I n = 84, BD = II n = 145, MDD n = 285), we examined the reliability and screening property of three shorter versions of the HCL (HCL-20, -16, -8) in comparison with the full HCL-32. Diagnosis was confirmed by the structured clinical interview (SCID-I). RESULTS: All three shortened HCLs demonstrated a fair screening ability (Area Under the Curve = .72~.74) to discriminate BD patients from MDD patients, which was comparable to that of the HCL-32. When sensitivity and specificity were considered, the HCL-20 showed relatively superior performance among the shortened versions. LIMITATIONS: The shorter versions were not administered in a 'stand alone' manner. CONCLUSIONS: This is the first cross-validation study in a large clinical sample with an increased statistical power to compare the screening property of the shortened HCLs. Our results suggest that briefer versions of the HCL could be reliably and economically utilized in clinical and research settings to enhance detection of BD. PMID- 29149758 TI - Oligotrophy as a major driver of mercury bioaccumulation in medium-to high trophic level consumers: A marine ecosystem-comparative study. AB - Mercury (Hg) is a global contaminant of environmental concern. Numerous factors influencing its bioaccumulation in marine organisms have already been described at both individual and species levels (e.g., size or age, habitat, trophic level). However, few studies have compared the trophic characteristics of ecosystems to explain underlying mechanisms of differences in Hg bioaccumulation and biomagnification among food webs and systems. The present study aimed at investigating the potential primary role of the trophic status of systems on Hg bioaccumulation and biomagnification in temperate marine food webs, as shown by their medium-to high-trophic level consumers. It used data from samples collected at the shelf-edge (i.e. offshore organisms) in two contrasted ecosystems: the Bay of Biscay in the North-East Atlantic Ocean and the Gulf of Lion in the North-West Mediterranean Sea. Seven species including crustaceans, sharks and teleost fish, previously analysed for their total mercury (T-Hg) concentrations and their stable carbon and nitrogen isotope compositions, were considered for a meta analysis. In addition, methylated mercury forms (or methyl-mercury, Me-Hg) were analysed. Mediterranean organisms presented systematically lower sizes than Atlantic ones, and lower delta13C and delta15N values, the latter values especially highlighting the more oligotrophic character of Mediterranean waters. Mediterranean individuals also showed significantly higher T-Hg and Me-Hg concentrations. Conversely, Me-Hg/T-Hg ratios were higher than 85% for all species, and quite similar between systems. Finally, the biomagnification power of Hg was different between systems when considering T-Hg, but not when considering Me-Hg, and was not different between the Hg forms within a given system. Overall, the different parameters showed the crucial role of the low primary productivity and its effects rippling through the compared ecosystems in the higher Hg bioaccumulation seen in organisms from oligotrophic Mediterranean waters. PMID- 29149759 TI - DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. AB - Mitochondrial fission and selective mitochondrial autophagy (mitophagy) form an essential axis of mitochondrial quality control that plays a critical role in the development of cardiac ischemia-reperfusion (IR) injury. However, the precise upstream molecular mechanism of fission/mitophagy remains unclear. Dual specificity protein phosphatase1 (DUSP1) regulates cardiac metabolism, but its physiological contribution in the reperfused heart, particularly its influence on mitochondrial homeostasis, is unknown. Here, we demonstrated that cardiac DUSP1 was downregulated following acute cardiac IR injury. In vivo, compared to wild type mice, DUSP1 transgenic mice (DUSP1TG mice) demonstrated a smaller infarcted area and the improved myocardial function. In vitro, the IR-induced DUSP1 deficiency promoted the activation of JNK which upregulated the expression of the mitochondrial fission factor (Mff). A higher expression level of Mff was associated with elevated mitochondrial fission and mitochondrial apoptosis. Additionally, the loss of DUSP1 also amplified the Bnip3 phosphorylated activation via JNK, leading to the activation of mitophagy. Increased mitophagy overtly consumed mitochondrial mass resulting into the mitochondrial metabolism disorder. However, the reintroduction of DUSP1 blunted Mff/Bnip3 activation and therefore alleviated the fatal mitochondrial fission/mitophagy by inactivating the JNK pathway, providing a survival advantage to myocardial tissue following IR stress. The results of our study suggest that DUSP1 and its downstream JNK pathway are therapeutic targets for conferring protection against IR injury by repressing Mff-mediated mitochondrial fission and Bnip3-required mitophagy. PMID- 29149760 TI - Patterns of relapse in poor-prognosis germ-cell tumours in the GETUG 13 trial: Implications for assessment of brain metastases. AB - BACKGROUND: The GETUG 13 phase III trial tested personalised chemotherapy based on tumour marker decline in patients with poor-prognosis germ-cell tumour (GCT) and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavourable decline. We investigated the pattern of relapse for patients included in GETUG 13. METHODS: We conducted an analysis of relapse events in patients from GETUG 13. Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic computed tomography scan and a magnetic resonance imaging of the brain. RESULTS: With a median follow-up of 4.1 years (0.3; 8.8 years), a progression event was observed in 109/254 patients (43%). First event consisted in a marker progression only in 47 patients (43%), a radiographic progression only in 35 patients (32%), a mix progression on both markers and imaging in 12 patients (11%) and death in 15 patients (14%). In patients with radiographic progression only, brain was the predominant site (n = 19/35, 54%). Among patients with unfavourable decline who experienced a radiographic progression (as first and subsequent progression event, n = 58), brain was a site of progression in 28 patients (48%): 12/30 (40%) in patients treated with cisplatin, bleomycin and etoposide and 16/28 (57%) in those treated with dose-dense chemotherapy. CONCLUSIONS: Brain metastases develop often, early and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and optimal treatment of brain metastases in these patients, e.g. by integrating a systematic brain MRI after 2 3 months of chemotherapy. PMID- 29149762 TI - Interaction of biologically relevant ions and organic molecules with titanium oxide (rutile) surfaces: A review on molecular dynamics studies. AB - The surface of a biomaterial can play a major role in its biological fate since the surface is the primary pathway for its interaction with the body. As the natural response of the body to a foreign material is to encapsulate it with a fibrous material, the interactions between the body and the biomaterial are mediated by this fibrous layer. Initial interactions occur between the biomaterial surface, water, ionic species and organic molecules, which then mediate further interactions with body tissues. Surface engineering can influence these interactions and hence, improve the biocompatibility of the biomaterial. Therefore, both experimental and computational studies have been interested in phenomena happening at the solid-solution interface as their mechanisms and driving forces can point to new directions for biomaterial design and evaluation. In this review, we summarize the computational work on the interaction of titanium oxide surfaces (mainly rutile) with solvated ions and organic molecules by means of molecular dynamics, with a certain relevance to bioactivity testing protocols. The primary goal of this review is to present the current state of the art and draw attention to points where further investigations are required. PMID- 29149761 TI - Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET mutations or amplification. EORTC 90101 CREATE trial. AB - PURPOSE: Papillary renal-cell carcinoma type 1 (PRCC1) is associated with MET gene alterations. Our phase II trial prospectively assessed the efficacy and safety of crizotinib in patients with advanced/metastatic PRCC1 with or without MET mutations (MET+ and MET-). EXPERIMENTAL DESIGN: Eligible patients with reference pathology-confirmed PRCC1 received 250 mg oral crizotinib twice daily. Patients were attributed to MET+/MET- sub-cohorts by the sequencing of exons 16 19 of the MET gene in tumour tissue. The primary end-point was objective response rate (ORR). If at least two of the first 12 eligible and evaluable MET+ patients achieved a confirmed partial response (PR) or complete response (CR) (in accordance with the Response Evaluation Criteria in Solid Tumours, version 1.1), a maximum of 35 patients were enrolled. Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), PFS rate (PFSR), overall survival (OS) and safety. RESULTS: Forty-one patients provided consent, of whom 23 were eligible, treated and evaluable. In four MET+ patients, two achieved PR and one had stable disease (SD) (ORR 50%; 95% confidence interval [CI]: 6.8-93.2), DOR was 21.8 and 37.3 months, 1-year PFSR: 75.0% (95% CI: 12.8-96.1) and 1-year OS: 75.0% (95% CI: 12.8-96.1). Among 16 MET- patients, one achieved a PR lasting more than 9.9 months and 11 had SD (ORR: 6.3%; 95% CI: 0.2-30.2), 1-year PFSR: 27.3% (95% CI: 8.5-50.4) and 1-year OS: 71.8% (95% CI: 41.1-88.4). Among three patients with unknown MET status (MET?) due to technical failure, one achieved PR lasting more than 6.9 months, and one had SD (ORR 33.3%, 95% CI: 0.8-90.6), 1-year PFSR: 66.7% (95% CI: 5.4-94.5) and 1 year OS: 100%. MET amplification was found post hoc in one MET+ patient (PR, DOR: 37.3 months), and one MET- case who had SD. Common treatment-related adverse events were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%) and blurred vision (34.8%). CONCLUSION: Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in patients with MET mutations or amplification. Sporadic, durable responses are also seen in MET- and MET? cases, suggesting the presence of other alterations of MET or alternative pathways. PMID- 29149763 TI - Formulation and anti-neurotoxic activity of baicalein-incorporating neutral nanoliposome. AB - Despite extensive studies of the effects of herbal-derived small molecules in the biopharmaceutical and biomedical sciences, their low solubility and stability remain a challenge. Here we focus on baicalein, a small molecule showing potential against neurodegenerative diseases such as Parkinson's and Alzheimer's. However, therapeutic usage in vivo is challenged by low solubility and stability. To address this we have applied neutrally-charged nanoliposome (NLP) as carrier for baicalein. Baicalein was incorporated into NLP to form NLP-Ba at molar baicalain:lipid ratios of up to 1:3, giving a drug entrapment efficiency of 96.71%, slow release of approximately 22% after a week and increased baicalein stability up to 27%. Ascorbic acid increased baicalein's stability further, particularly when incorporated in NLP where baicalein stability intensified by 53% in NLP-Ba. Moreover, NLP-Ba did not show significant cytotoxic effects against neurons; rather, showed considerable protective effect against reactive oxygen species. In addition, NLP promoted internalization of baicalein into cells, showing good biocompatibility. We conclude that NLP-Ba can enhance baicalein's therapeutic potential in neurodegenerative diseases. PMID- 29149764 TI - Human saliva as a diagnostic material. AB - Today blood biochemical laboratory tests are essential elements to the diagnosis and monitoring of the treatment of diseases. However, many researchers have suggested saliva as an preferable diagnostic material. The collection of saliva is simple, painless, cheap and safe, both for patients and medical staff. An additional advantage of saliva is the fact that it may be retrieved several times a day, which makes repeat analysis much easier. Furthermore, saliva has very high durability. Although 94-99% of salivary content is water, saliva also contains numerous cellular elements and many organic and inorganic substances, including most biological markers present in the blood and urine that may be used in the early detection and monitoring of many dental and general diseases. PMID- 29149765 TI - Sorption-desorption of antimony species onto calcined hydrotalcite: Surface structure and control of competitive anions. AB - Calcined hydrotalcite can be applied to remove anionic contaminants from aqueous systems such as antimony species due to its great anion exchange capacity and high surface area. Hence, this study evaluated antimonite and antimonate sorption desorption processes onto calcined hydrotalcite in the presence of nitrate, sulfate and phosphate. Sorption and desorption experiments of antimonite and antimonate were carried out in batch equilibrium and the post-sorption solids were analyzed by X-ray fluorescence (EDXRF). Sorption data were better fitted by dual-mode Langmuir-Freundlich model (R2>0.99) and desorption data by Langmuir model. High maximum sorption capacities were found for the calcined hydrotalcite, ranging from 617 to 790meqkg-1. The competing anions strongly affected the antimony sorption. EDXRF analysis and mathematical modelling showed that sulfate and phosphate presented higher effect on antimonite and antimonate sorption, respectively. High values for sorption efficiency (SE=99%) and sorption capacity were attributed to the sorbent small particles and the large surface area. Positive hysteresis indexes and low mobilization factors (MF>3%) suggest very low desorption capacity to antimony species from LDH. These calcined hydrotalcite characteristics are desirable for sorption of antimony species from aqueous solutions. PMID- 29149767 TI - The effects of sleep on the neural correlates of pattern separation. AB - Effective memory representations must be specific to prevent interference between episodes that may overlap in terms of place, time, or items present. Pattern separation, a computational process performed by the hippocampus, overcomes this interference by establishing nonoverlapping memory representations. Although it is widely accepted that declarative memories are consolidated during sleep, the effects of sleep on pattern separation have yet to be elucidated. We used whole brain, high-resolution functional neuroimaging to investigate the effects of sleep on a task that places high demands on pattern separation. Sleep had a selective effect on memory specificity and not general recognition memory. Activity in brain regions related to memory retrieval and cognitive control demonstrated an interaction between sleep and delay. Surprisingly, there was no effect of sleep on hippocampal activity using a group-level analysis. To further understand the role of the hippocampus on our task, we performed a representational similarity analysis, which showed that hippocampal activation was biased toward pattern separation relative to cortical activation and that this bias increased following a delay (regardless of sleep). Cortical activation, conversely, was biased toward pattern completion and this bias was preferentially enhanced by sleep. PMID- 29149766 TI - Numerosity estimation benefits from transsaccadic information integration. AB - Humans achieve a stable and homogeneous representation of their visual environment, although visual processing varies across the visual field. Here we investigated the circumstances under which peripheral and foveal information is integrated for numerosity estimation across saccades. We asked our participants to judge the number of black and white dots on a screen. Information was presented either in the periphery before a saccade, in the fovea after a saccade, or in both areas consecutively to measure transsaccadic integration. In contrast to previous findings, we found an underestimation of numerosity for foveal presentation and an overestimation for peripheral presentation. We used a maximum likelihood model to predict accuracy and reliability in the transsaccadic condition based on peripheral and foveal values. We found near-optimal integration of peripheral and foveal information, consistently with previous findings about orientation integration. In three consecutive experiments, we disrupted object continuity between the peripheral and foveal presentations to probe the limits of transsaccadic integration. Even for global changes on our numerosity stimuli, no influence of object discontinuity was observed. Overall, our results suggest that transsaccadic integration is a robust mechanism that also works for complex visual features such as numerosity and is operative despite internal or external mismatches between foveal and peripheral information. Transsaccadic integration facilitates an accurate and reliable perception of our environment. PMID- 29149768 TI - Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson disease. AB - In Parkinson disease (PD), mitochondrial dysfunction associates with nigral dopaminergic neuronal loss. Cholinergic neuronal loss co-occurs, particularly within a brainstem structure, the pedunculopontine nucleus (PPN). We isolated single cholinergic neurons from postmortem PPNs of aged controls and PD patients. Mitochondrial DNA (mtDNA) copy number and mtDNA deletions were increased significantly in PD patients compared to controls. Furthermore, compared to controls the PD patients had significantly more PPN cholinergic neurons containing mtDNA deletion levels exceeding 60%, a level associated with deleterious effects on oxidative phosphorylation. The current results differ from studies reporting mtDNA depletion in nigral dopaminergic neurons of PD patients. Ann Neurol 2017;82:1016-1021. PMID- 29149769 TI - NeuroNEXT is at your service. PMID- 29149771 TI - HOXC13 and HSP27 Expression in Skin and the Periodic Growth of Secondary Fiber Follicles from Longdong Cashmere Goats Raised in Different Production Systems. AB - This experiment was conducted to identify periodic changes in secondary follicles (SFs) over one year of extensive (grazed) and intensive (housed and fed supplement) farming of Longdong cashmere goats. One-year old goats (n = 24, 12 extensively fed and 12 intensively fed) were studied. The diameter, depth, density, activity, and ultra-structural features of SFs were assessed using light microscopy and transmission electron microscopy. HOXC13 and HSP27 expression were studied using immunohistochemistry and immunofluorescence method. The anagen stage in the extensively grazed goats was from April to September, but was longer (April to October) in the housed, supplementary fed group. The depth and activity of the SF in anagen and catagen differed (P < 0.05) between the groups. HSP27 and HOXC13 protein were present in both the epidermis and dermis, with HSP27 immunoreactivity highest in the hair shaft (HS), outer root sheath (ORS) and inner root sheath (IRS). HOXC13 expression was prominent in both the eprdermis and ORS. HSP27 and HOXC13 expression were prominent during anagen, and less so during catagen and telogen. In anagen, HSP27 expression in the HS, IRS, and ORS of the extensively fed group was higher than in the intensively fed group (p < 0.05). In contrast, HOXC13 expression in HS, IRS and ORS of the extensively fed group was lower than in the intensively fed group (P < 0.05). This suggests the growth of cashmere is influenced by nutrition and that housed goats could be used in cashmere production. Anat Rec, 301:742-752, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29149770 TI - A multicenter, retrospective medical record review of X-linked myotubular myopathy: The recensus study. AB - INTRODUCTION: X-linked myotubular myopathy (XLMTM), characterized by severe hypotonia, weakness, respiratory distress, and early mortality, is rare and natural history studies are few. METHODS: RECENSUS is a multicenter chart review of male XLMTM patients characterizing disease burden and unmet medical needs. Data were collected between September 2014 and June 2016. RESULTS: Analysis included 112 patients at six clinical sites. Most recent patient age recorded was <=18 months for 40 patients and >18 months for 72 patients. Mean (SD) age at diagnosis was 3.7 (3.7) months and 54.3 (77.1) months, respectively. Mortality was 44% (64% <=18 months; 32% >18 months). Premature delivery occurred in 34/110 (31%) births. Nearly all patients (90%) required respiratory support at birth. In the first year of life, patients underwent an average of 3.7 surgeries and spent 35% of the year in the hospital. DISCUSSION: XLMTM is associated with high mortality, disease burden, and healthcare utilization. Muscle Nerve 57: 550-560, 2018. PMID- 29149773 TI - War Horse, Whistlejacket, and an Anatomist. PMID- 29149774 TI - Hippocampal CA1 activity correlated with the distance to the goal and navigation performance. AB - Coding the distance to a future goal is an important function of a neural system supporting navigation. While some evidence indicates the hippocampus increases activity with proximity to the goal, others have found activity to decrease with proximity. To explore goal distance coding in the hippocampus we recorded from CA1 hippocampal place cells in rats as they navigated to learned goals in an event arena with a win-stay lose-shift rule. CA1 activity was positively correlated with the distance - decreasing with proximity to the goal. The stronger the correlation between distance to the goal and CA1 activity, the more successful navigation was in a given task session. Acceleration, but not speed, was also correlated with the distance to the goal. However, the relationship between CA1 activity and navigation performance was independent of variation in acceleration and variation in speed. These results help clarify the situations in which CA1 activity encodes navigationally relevant information and the extent to which it relates to behavior. PMID- 29149772 TI - Natural history of infantile-onset spinal muscular atrophy. AB - OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed. RESULTS: Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17). INTERPRETATION: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891. PMID- 29149775 TI - Lentiviral Vectors and Adeno-Associated Virus Vectors: Useful Tools for Gene Transfer in Pain Research. AB - Pain, especially chronic pain, has always been a heated point in both basic and clinical researches since it puts heavy burdens on both individuals and the whole society. A better understanding of the role of biological molecules and various ionic channels involved in pain can shed light on the mechanism under pain and advocate the development of pain management. Using viral vectors to transfer specific genes at targeted sites is a promising method for both research and clinical applications. Lentiviral vectors and adeno-associated virus (AAV) vectors which allow stable and long-term expression of transgene in non-dividing cells are widely applied in pain research. In this review, we thoroughly outline the structure, category, advantages and disadvantages and the delivery methods of lentiviral and AAV vectors. The methods through which lentiviral and AAV vectors are delivered to targeted sites are closely related with the sites, level and period of transgene expression. Focus is placed on the various delivery methods applied to deliver vectors to spinal cord and dorsal root ganglion both of which play important roles in primary nociception. Our goal is to provide insight into the features of these two viral vectors and which administration approach can be chosen for different pain researches. Anat Rec, 301:825-836, 2018. (c) 2017 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists. PMID- 29149776 TI - Effect of Nebulized 3% Hypertonic Saline with Salbutamol on Management of Acute Asthma in Outpatient Adults: A Double-blind, Randomized Clinical Trial in Emergency Department. AB - Asthma is one of the most common disorders of respiratory tract, management of which still remains as a serious health problem. This study aimed to compare the efficacy of 3% hypertonic saline (HS) plus salbutamol with solely salbutamol on management of acute adults' asthma based on peak flow meter findings. In this double-blind randomized clinical trial, 340 adult patients with acute asthma attacks admitted to emergency department of Ahvaz Golestan and Emam hospitals were enrolled during 2014-2015. The patients were allocated randomly to intervention group (nebulized 2.5 mg of salbutamol and 2.5 mL of 3% HS solution for three consecutive 20-min periods) and control group (nebulized only salbutamol in the same dose and time of the intervention group). The principal outcome measures were forced expiratory volume in 1 second (FEV1) and peak expiratory flow rate (PEFR), which were assessed at baseline, and 20, 40 and 60 minutes after treatment in both groups. HS plus salbutamol resulted in a significant increase compared with solely salbutamol in both PEFR and FEV1 in 40th min (0.11+/-1.36; p=0.036 and 0.05+/-1.16; p=0.033, respectively) and 60th min (0.15+/-1.12; p<0.001 and 0.11+/-1.22; p=0.011, respectively), while no significant difference was observed in baseline and 20th min. Also, PEFR and FEV1 in both groups significantly increased as the treatment processed and the time passed. The results showed the beneficial effects of 3% HS in management of adults with acute asthma in the short term. PMID- 29149777 TI - Investigating the Association of ADAM33 Single Nucleotide Polymorphisms (SNPs) with Susceptibility to Allergic Asthma in Azerbaijan Population of Iran: A Case control Study. AB - Asthma, affecting a growing number of populations, is a clinical condition with complex cellular and genetic factors. Single nucleotide polymorphisms (SNPs) in gene coding for molecules, which play major roles in the immunopathogenesis of asthma have been considered recently as genetic predisposing factors this disease. Possible association between two SNPs in a disintegrin and metalloprotease 33 (ADAM33), which participates in airway remodeling, and susceptibility to asthma was studied in this study. 190 patients with asthma and 180 healthy controls were enrolled in this case-control study. Using conventional PCR method, specific bands were amplified and the frequency of genotypes of T1 (rs2280091) and V4 (rs2787094) ADAM33 SNPs were determined by digestion with NcoI and PstI, respectively. The results showed that the frequency of genotypes of T1 and V4 were not significantly different between patients and controls (p=0.54 and p=0.85, respectively). On the other hand, no significant differences were seen in allele frequency of both T1 and V4 SNPs (p=0.15 and p=0.47, respectively). In agreement with some other studies in different populations, our results showed no association between frequency of genotype or alleles of both T1 and V4 SNPs in ADAM33 gene and predisposition to asthma in Azerbaijan population of Iran. Genetic differences in different ethnic groups might be involved in such inconsistent results. More studies in populations with larger number of patients and healthy individuals are needed for concluding remarks for involvement of ADAM33 SNPs in asthma. PMID- 29149778 TI - The Changes of Th17/Treg and Related Cytokines: IL-17, IL-23, IL-10, and TGF-beta in Respiratory Syncytial Virus Bronchiolitis Rat Model. AB - Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and hospitalization that lead to high morbidity and mortality among young infants. T helper 17 (Th17) cells and regulatory T cells (Tregs) play essential roles in the pathogenesis of autoimmune, cancer, and inflammatory diseases. However, whether changes in T-cell subsets are related to the systemic immune responses in RSV caused bronchiolitis merit further investigation. Three-week-old Sprague Dawley (SD) rats were randomly divided into the normal control (NC) and RSV bronchiolitis (RSV-B) groups. An RSV-B model was successfully established using nasal drip containing RSV. Furthermore, pathological changes in the lung tissues were observed using hematoxylin and eosin staining. Flow cytometry determined the levels of Th17 and Treg subsets. The related cytokines were measured using enzyme linked immunosorbent assay (ELISA). The expression levels of related transcription factors, such as RORgammat and FOXP3, were examined using real-time quantitative PCR and western blot analysis. The RSV-B group exhibited pulmonary interstitial hyperemia and edema, inflammatory cell infiltration, wide alveolar septa, and bronchial collapse and deformation. The percentage of Th17 cells in RSV-B group was about 2.3 fold higher than that of NC group, and the concentration of IL-17, IL-23 and RORgammat was higher than in NC group. In contrast, the percentage of Treg cells in the RSV-B group was approximately 0.7 fold lower than that in the NC group, and the levels of IL-10, TGF-beta, and FOXP3 in the RSV-B group were lower than those in the NC group. The above results were statistically significant. The changes of Th17/Treg, and their associated cytokines, specific transcription factors, are present in RSV bronchiolitis model rats, which may play an important role in the pathogenesis of RSV bronchiolitis. PMID- 29149779 TI - Increased Genes Expression Levels of Cytokines Related to Th17/Treg Cells in Peripheral Blood Mononuclear Cell Correlate with Clinical Severity in COPD and Mustard Gas-exposed Patients. AB - The long lasting inflammation and immune dysregulation is one of the main mechanisms involved in lung complication of veterans exposed to sulfur mustard (SM) gas. Th17/Treg cells have an important role in immunopathogenesis of chronic obstructive pulmonary disease (COPD) and mustard lung disease. In this study, expression of cytokines genes levels related to Th17/Treg cells was determined in peripheral blood mononuclear (PBMC) of mustard lung patients and was compared with COPD patients and healthy controls (HC). Real time-polymerase chain reaction was used to assay genes expression levels of Th17 related cytokines (IL-17, IL-6 and TGF-beta) and Treg related cytokines (IL-10, TGF-beta). IL-17 gene expression level considerably was higher in SM patients (9.98+/-0.65, p<0.001), and COPD (4.75+/-0.71, p<0.001), compare to HC group. Also, gene expression level of IL-6 in the SM group (3.31+/-0.93, p<0.001) and COPD group (2.93+/-0.21, p<0.001) were significantly higher than the HC group. The IL-10 gene expression level showed a high increase in SM patients (4.12+/-0.91, p<0.01), and COPD (2.1+/-0.45, p<0.01). Finally, the TGF-beta gene expression level was increased in SM patients (4.91+/-0.69, p<0.001) as well as in COPD group (5.41+/-0.78, p<0.001). In SM patients, IL-17 (R=-0.721, p<0.05), IL-6 (R=-0.621, p<0.05) and TGF-beta (R= 0.658, p<0.05) had significant negative association with FEV1 (%). Inversely, Il 10 showed positive correlation (R=0.673) with FEV1 (%). Th17/Treg cells related cytokines genes were highly expressed and imbalanced in peripheral blood mononuclear cells of SM and COPD patients which correlated with pulmonary dysfunction. PMID- 29149780 TI - Interleukin-37 Relieves Allergic Inflammation in a House Dust Mite Allergic Rhinitis Murine Model. AB - The purpose of this study was to investigate the effects of interleukin-37 (IL 37) on a Dermatophagoides farinae (Der f)-induced murine model of allergic rhinitis (AR). BALB/c mice, except the control groups, were sensitized intraperitoneally and challenged intranasally with Der f (Der f group). The IL-37 and IL-37+anti-CD25 groups were administered IL-37 intranasally. The IL-37+anti CD25 groups were administered anti-CD25 monoclonal antibody intraperitoneally before challenge. Allergic symptoms and the average eosinophil number were counted. The levels of cytokines and transcription factors in the nasal mucosa were measured by Real-Time polymerase chain reaction (PCR) and western blotting. The levels of Der f-specific immunoglobulin E (IgE) were measured. The CD4+CD25+Foxp3+T cells among splenic mononuclear cells were analyzed by flow cytometry. The allergic symptom scores and Der f-specific IgE levels were lower in the IL-37 group compared to the Der f group. Additionally, the levels of the transcription factor GATA-3 and ROR-gammat and those of the cytokines IL-4, IL-5, IL-13, and IL-17, representing both T helper (Th)2 and Th17 responses, were lower in the IL-37 group in comparison with the Der f group. However, the Th1 responsewas not suppressed after administration of IL-37. IL-37 increased the IL 10 level; however, Real-Time PCR, western blotting, and flow cytometry results showed the limited action of IL-37 on CD4+CD25+Foxp3+T cells. This study demonstrates that intranasal IL-37 can suppress Th2 and Th17 responses in an AR murine model. Furthermore, these data suggest that IL-10 is increased, but CD4+CD25+Foxp3+T cells are not correlated with the IL-37-induced mechanism. PMID- 29149781 TI - Macrophages from Behcet's Disease Patients Express Decreased Level of Aryl Hydrocarbon Receptor (AHR) mRNA. AB - Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, connecting environmental stimulators with the immune system. M1 macrophages are a part of immune system that contribute to the inflammatory events in the pathogenesis of Behcet's disease (BD). The effect of AHR on the macrophages in BD patients is still unclear. In this study, we investigated the mRNA expression of AHR in the monocyte-derived and M1 macrophages in active BD patients in comparison to healthy controls. Isolated monocytes from 10 healthy controls and 10 active BD patients were differentiated to macrophages by macrophage-colony stimulating factor (M-CSF) for 7 days. Cells were then polarized to M1 macrophages by lipopolysaccharide (LPS) and interferon-gamma (IFNgamma) for 24h. Monocyte purity and macrophage markers expression were analyzed by flow cytometry. Analysis of AHR mRNA expression was performed by SYBR Green real-time PCR. Our results showed that AHR expression is significantly down-regulated in M1 macrophages compare to monocyte-derived macrophages. It was shown that both monocyte-derived macrophages and M1 macrophages from BD patients significantly express lower level of AHR mRNA compared to healthy individuals. Our results demonstrate an anti-inflammatory role for AHR in macrophages, which suggest that decreased AHR expression is associated with pro-inflammatory M1 macrophage and BD susceptibility. PMID- 29149782 TI - Frequency of Circulatory Regulatory Immune Cells in Iranian Patients with Type 1 Diabetes. AB - Type 1 diabetes (T1D) is the result of the autoimmune destruction of insulin producing beta cells. Regulatory T cells (Tregs) and plasmacytoid dendritic cells (PDCs) act as mediators of peripheral tolerance. We investigated the possible alterations of such cells in peripheral blood of patients with T1D compared to normal individuals. This comparison may lead to a better understanding of the immunopathogenesis processes involved in T1D. 92 participants, including 49 patients with T1D and 43 healthy controls were studied. 3 mL of blood was taken from all participants. After isolating peripheral blood mononuclear cells (PBMCs), PDCs as well as 2 subtypes of Tregs, CD4+CD25+FoxP3+ and CD8+CD28- cells were counted by 3-colorflow cytometry. The association between such enumeration and T1D was studied by multivariate regression and discriminate function models. The frequency of CD4+CD25+FoxP3+Tregs (p=0.038) and PDCs (p=0.039) in the peripheral blood of diabetic patients was less than that in healthy subjects. Having compared some models consisting different cells as well as their combinations, we did not find any profound explanation of each subset or their combinations to identify T1D. The decrease of CD4+CD25+FoxP3+cells and PDCs in diabetic patients may suggest their role in the onset or development of the disease. Therefore, it is likely that their pharmacologic stimulation may direct immune responses towards tolerance and prevent the development or even the onset of diabetes in susceptible individuals. PMID- 29149783 TI - Hematological Improvement of Patients with Active Rheumatoid Arthritis by beta-D Mannuronic Acid (M2000) as a Novel NSAID with Immunosuppressive Property. AB - The aim of this study was to investigate the effect of beta-D-mannuronic acid (M2000) on hematological parameters in patients with active rheumatoid arthritis. This study was conducted on 25 patients with active rheumatoid arthritis (RA) (identifier: IRCT2014011213739N2). M2000 was administered orally for anemic and non-anemic RA patients at a dose of 500 mg twice daily for 12 weeks. The patients were permitted to continue the conventional treatments excluding NSAIDs. Blood samples were collected at baseline, 4 and 12 weeks after drug administration and were tested for hematological parameters. Moreover, serum levels of TNF-alpha and IL-6 were analysed before and after M2000 therapy compared to healthy controls using enzyme linked immunosorbent assay method. We found a significant increase in the count of red blood cells and also hemoglobin (Hb) concentration (0.9 g/dL) in anemic patients after 12 weeks of M2000 therapy (p<0.02 and p<0.01, respectively). Furthermore, our results showed an improvement in Hb level (0.45 g/dL) even in non-anemic patients who were treated by M2000 (p<0.04). The leukocytosis in RA patients, significantly decreased in both anemic and non anemic patients after 12 weeks of M2000 therapy (p<0.02 and p<0.03, respectively). The percent of neutrophils significantly increased in anemic patients (p<0.01) while in non-anemic patients it significantly decreased after 12 weeks of M2000 therapy (p<0.01). The serum levels of IL-6 and TNF-alpha significantly decreased after 12 weeks of M2000 therapy (p<0.01 and p<0.04, respectively). M2000 improves hematological parameters in RA patients by its potent inhibitory effect on serum levels of TNF-alpha and IL-6. PMID- 29149784 TI - Anti-inflammatory Property of beta-D-Mannuronic Acid (M2000) on Expression and Activity of Matrix Metalloproteinase-2 and -9 through CD147 Molecule in Phorbol Myristate Acetate-differentiated THP-1 Cells. AB - The aim of this study was to evaluate the effects of M2000, a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive property and without gastro nephrotoxicitic effects on matrix metalloproteinases (MMP)-2 and (MMP)-9 in phorbol myristate acetate (PMA)-differentiated THP-1 cells. Gene expression and activity of MMP-2 and MMP-9 are inhibited respectively by the tissue inhibitor of matrix metalloproteinase (TIMP)-2 and (TIMP)-1 and are induced by extracellular matrix metalloproteinase inducer (CD147/EMMPRIN). In this study, real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to determine gene expression of MMP-2, MMP-9, TIMP-1, and TIMP-2. Flow cytometry and zymography were applied to determine cellular surface expression of CD147 and activity of MMP-2 and MMP-9, respectively. Our results showed that treatment of THP-1 cells with high concentration (25 ug/mL) of M2000 significantly decreased the cellular surface expression of CD147 (p<0.05) and the gene expression of MMP 2, MMP-9 and TIMP-1 (p<0.05), and inhibited the gelatinolytic activity of MMP-2 and MMP-9 (p<0.05). According to our results, M2000 can reduce inflammation through inhibition of the cellular surface expression of CD147 and decrease the gene expression and gelatinolytic activity of MMP-2 and MMP-9 in PMA differentiated THP-1 cells. PMID- 29149785 TI - Association Study of HLA-DQB1*0602 Allele in Iranian Patients with Narcolepsy. AB - Narcolepsy is a rare, disabling disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. Several studies demonstrated its association with HLA-DQB1*0602 in various ethnic groups. Our study aimed to determine the prevalence of HLA-DQB1*0602 allele in Iranian patients with narcolepsy and assess its predictive parameters for diagnosing narcolepsy. In addition, car accidents and job problems were assessed among narcoleptic patients. We studied 44 narcoleptic patients, 30 patients with other types of excessive daytime sleepiness (EDS) and 50 healthy age and sex matched individuals in this case-control study. Patients and controls filled out a questionnaire including items about car accidents due to sleepiness and job problems. International classification of sleep disorders-2 criteria was used as the gold standard for diagnosis of narcolepsy. The DNAs isolated from whole blood samples were collected from the patients and controls to assess the presence of HLA-DQB1*0602. The results showed that HLA DQB1*0602 was present in 4 (8%) individual of controls and 20 (45.5%) patients with higher prevalence in patients with cataplexy (78.9%) than patients without cataplexy (p<0.001). The sensitivities of the DQB1*0602 for diagnosing narcolepsy with cataplexy and narcolepsy without cataplexy were 78.9 and 20; specificities were 88 and 72.4, respectively. 18.2% of patients had car accidents due to sleepiness and 68.2% suffered from job problems. Our study shows that evaluation of DQB1*0602 in patients suspected to narcolepsy could be helpful especially in complex cases with atypical cataplexy and indistinguishable multiple sleep latency test MSLT results. Moreover, high rates of car accidents and job problems are found among narcoleptic patients. PMID- 29149786 TI - Unsuccessful Desensitization in a Child with Hypersensitivity to Diazoxide. AB - No Abstract. PMID- 29149787 TI - The role of the home environment in dementia care and support: Systematic review of qualitative research. AB - Background The domestic home is the preferred site for care provision for people with dementia and their families, therefore creating a dementia and caring friendly home environment is crucial. This systematic review synthesised qualitative studies to explore the role of the home environment and identify potential barriers and facilitators in home dementia care and support to inform future practice and research. Methods A systematic search in 12 databases identified international qualitative literature on perceptions and experiences of community-dwelling people with dementia, family and formal carers regarding the role of the home environment and ways to tackle daily challenges. Results Forty qualitative studies were included and analysed using thematic synthesis. The main three themes were: 'home as a paradox', 'there is no magic formula' and 'adapting the physical space, objects and behaviour'. Findings indicate that home is an important setting and is likely to change significantly responding to the changing nature of dementia. Themes were later validated by family carers of people with dementia. Conclusions The home environment is an important setting for care and needs to remain flexible to accommodate changes and challenges. Family carers and people with dementia implement and often improvise, various environmental strategies. Continuous and tailor-made support at home is required. PMID- 29149788 TI - Knowledge of Alzheimer's disease among Vietnamese Americans and correlates of their knowledge about Alzheimer's disease. AB - The present study examined the knowledge of Alzheimer's disease and correlates of the disease knowledge among Vietnamese Americans. Cross-sectional survey interviews were conducted with 95 middle-aged and older Vietnamese Americans. Vietnamese Americans showed limited knowledge about Alzheimer's disease. Normalization of Alzheimer's disease in old age was prevalent. They lacked knowledge about treatment and cure of Alzheimer's disease. Those who reside longer in the U.S. and are more exposed to Alzheimer's disease are likely to have higher levels of Alzheimer's disease knowledge. Our study identified current Alzheimer's disease knowledge level and status, and areas of misconceptions and knowledge gaps among Vietnamese Americans, calling for urgent needs for educational outreach to improve knowledge about Alzheimer's disease among Vietnamese Americans. Information about who can be more or less knowledgeable about Alzheimer's disease can be used to strategize and tailor outreach efforts for different segments of the Vietnamese American population. PMID- 29149789 TI - Involving institutionalized people with dementia in their care-planning meetings: Impact on their quality of life measured by a proxy method. AB - The objective of the study was to assess the impact of an intervention in which people with dementia attended meetings to discuss their individual care plans on their quality of life. Fifty-two older people ( M = 86.7 years, SD = 7.3) diagnosed with moderate-to-severe dementia living in four nursing homes in Spain participated in the study. The intervention was implemented with 27 residents at two of the nursing homes; the other 25 cases at the other two homes acted as controls. A proxy measure of quality of life was used. Improvements were found in quality of life as assessed by staff members, in both within and between-group comparisons, which suggests that including older people with dementia in care planning meetings may improve their quality of life. However, further controlled studies are needed to confirm these preliminary results. PMID- 29149790 TI - Impressions of using the Cohen-Mansfield Agitation Inventory as an outcome measure: Lessons learnt for future clinical researchers (innovative practice). AB - The Cohen-Mansfield Agitation Inventory was a tool originally developed for use in research to measure agitation and subsequently used in clinical settings. It was the primary outcome measure for a randomised controlled trial which evaluated the effects and feasibility of a physiotherapist-led physical exercise intervention on agitation and physical performance of individuals living with dementia in nursing homes. The study produced weak results in regards to the Cohen-Mansfield Agitation Inventory due to small sample size and perceived issues with the use of the Cohen-Mansfield Agitation Inventory. Therefore, the focus of this paper is consideration of the identified issues by the research team: learnt effect and Hawthorn effect, misunderstanding of behaviours and inaccurate recall and observation. It is important that tools originally developed for research are still valid and reliable in the clinical setting. PMID- 29149791 TI - The Dementia Care Coordination Program: Engaging health systems in caregiver supports. AB - This paper reports on a process evaluation using mixed methods to assess a Dementia Care Coordination Program, which is distinctive in using the medical system, rather than direct outreach, to identify and refer families to supports provided by an Alzheimer's Association chapter via dedicated care consultants. One care consultant received referrals from individual physicians, while the other, employed by a health plan, received referrals from health plan case managers. Through key informant interviews, focus groups, and physician and caregiver surveys, we identified key issues, finding high rates of stakeholder satisfaction, but some practical issues around information sharing and data tracking. We further found the health plan model of collaboration to offer significant potential for the systematic and early detection of potential clients, provided investments in minor systems change. The Dementia Care Coordination Program, therefore, represents a minimalist model of dementia specific support, which could be further supplemented via more focused outreach and education. PMID- 29149792 TI - Case management for people with dementia and its translations: A discussion paper. AB - Case management is generally seen as a way to provide efficient, cost-saving person-centred care for people with dementia by connecting together fragmented services, but the available evidence in favour of its merits is often considered inconclusive, unclear and sketchy. This discussion paper investigates the evidence of the benefit of case management for people with dementia and explores the complexity of the concept and the experiences of its implementation. It offers a comprehensive framework for conceptualising various types of case management and asks the question: who can be a case manager? Building on examples from three European countries it addresses the problem of the expansion and adoption of the case management method. It compares the conventional model of diffusion of innovation with the ideas of interessement and co-constitution and envisions a successful model of case management as a fluid technology that is both friendly and flexible, allowing it to adapt to different settings and systems. PMID- 29149793 TI - Improving quality of work life for care providers by fostering the emotional well being of persons with dementia: A cluster-randomized trial of a nursing intervention in German long-term care settings. AB - We tested the feasibility of a nursing intervention (DEMIAN) in routine care and its effects on care providers' job satisfaction, motivation, and work strain. This cluster-randomized trial was conducted in 20 German long-term care facilities. We randomly assigned 20 facilities to an intervention group (84 care providers, 42 residents with dementia) or a control group (96 care providers, 42 residents with dementia). Intervention group providers received two training days on the intervention; 68 providers attended both training days. Sixty two providers completed both baseline and follow-up questionnaires. Trained providers created individualized mini-intervention plans for participating residents. Control group residents received 'usual care'. Intervention group providers stated that the intervention was feasible and helped them improve emotional well being of residents with dementia. We found significantly decreased time pressure and decreased job dissatisfaction for intervention group providers. DEMIAN is an effective and pragmatic contribution to implementing person-centred care in long term care, with positive effects on providers' working conditions. PMID- 29149794 TI - Love, intimacy and sexuality in residential dementia care: A spousal perspective. AB - The experiences and needs of spouses of residential care facility residents with dementia, regarding friendship, love, intimacy, and sexuality were explored. Understanding of how spouses make sense of their experiences was pursued. Semi structured interviews were held with nine spouses of people with dementia, living in high intensive 24-hour care units within residential care facilities. The results show that friendship, love, intimacy, and sexuality were still embedded in the couples' marital lives, but all in their own way. Changing roles and a shift in purpose of the relationship recurred. Although intimacy was found to be still important in the lives of spouses, emotional, and practical residential care facility barriers were experienced by the spouses, of which the absence of communication were most important. Our findings on the experiences of spouses with regard to intimacy and sexuality can help residential care facility staff and policymakers to recognize the needs of couples and take these into account. PMID- 29149795 TI - Development of a psycho-educational support program for individuals with primary progressive aphasia and their care-partners. AB - Primary progressive aphasia is a language-based dementia that initially spares other cognitive domains; however, aphasia interferes with many life roles such as work and interpersonal relationships. Psycho-educational programs, such as support groups have been shown to be effective for persons with Alzheimer's dementia; however, little is known regarding their effectiveness for persons with primary progressive aphasia. This paper describes the development of a program that offers support, education and activities for persons with primary progressive aphasia and their care-partners and its feasibility. Development and structure of pilot and formal intervention groups are described. Thematic analysis of both groups included the following themes: (1) coping with limitations and language decline; (2) dealing with increased dependency; (3) expressing resilience and making adaptations; (4) experiencing stigma (pilot group) and confronting stigma (intervention group); (5) experiencing self confidence; and (6) feeling a sense of belonging. The knowledge gained from this process may be useful in designing programs for individuals with aphasic dementia and preserved insight. Evidence-based data from supportive interventions for persons with primary progressive aphasia and their care-partners are needed. PMID- 29149796 TI - Effectiveness of treatment in wards for patients with dementia and issues associated with this treatment: A prospective analysis. AB - In order to optimize the treatment in wards for patients with dementia, we investigated predictors of the length of stay in the ward for patients with dementia. A prospective analysis of 72 patients with dementia was conducted in two wards for patients with dementia. Severity of dementia was assessed by the Clinical Dementia Rating, basic activities of daily living were evaluated using the Physical Self-Maintenance Scale, and severity of behavioral and psychological symptoms of dementia and caregiver distress were determined with the Nursing Home version of the Neuropsychiatric Inventory. Stepwise regression analysis was used to identify predictors of the length of stay. Fewer patients were discharged to home compared to those discharged to institutions or transferred to a different hospital or ward. The mean length of stay was 92.0 days. Clinical Dementia Rating and total distress scale score on the Nursing Home version of the Neuropsychiatric Inventory were significant independent predictors of the length of stay. The total Nursing Home version of the Neuropsychiatric Inventory score and total distress scale score on the Nursing Home version of the Neuropsychiatric Inventory were significantly improved through treatment. Our results suggest that treatment in the wards for patients with dementia is effective for improvement of behavioral and psychological symptoms of dementia. However, some patients could not be discharged to their home despite improvement of behavioral and psychological symptoms of dementia, and this may be related to caregiver burden at admission. PMID- 29149797 TI - Findings from a strength-based moderate-intensity exercise interventions for individuals with dementia (innovative practice). AB - Limited evidence exists regarding exercise interventions with individuals with dementia, which is often due to heterogeneity of methodology and outcomes being assessed. This led to the development and evaluation of a moderate-intensity home based functional exercise program guided by theories from exercise science and the Strength-Based Approach. Data indicated excellent treatment adherence (99.04%) along with high levels of acceptability and feasibility in this sample (age 76.63 years (9.84); Mini Mental State Exam 18.87 (6.40)). This article informs future practice by highlighting the merits of a Strength-Based Approach in research examining exercise and physical rehabilitation to improve adherence and compliance with individuals with dementia. PMID- 29149798 TI - Reconstructing Biosynthetic Pathway of the Plant-Derived Cancer Chemopreventive Precursor Glucoraphanin in Escherichia coli. AB - Epidemiological data confirmed a strong correlation between regular consumption of cruciferous vegetables and lower cancer risk. This cancer preventive property is mainly attributed to the glucosinolate products, such as glucoraphanin found in broccoli that is derived from methionine. Here we report the first successful reconstruction of the complete biosynthetic pathway of glucoraphanin from methionine in Escherichia coli via gene selection, pathway design, and protein engineering. We used branched-chain amino transferase 3 to catalyze two transamination steps to ensure the purity of precursor molecules and used cysteine as a sulfur donor to simplify the synthesis pathway. Two chimeric cytochrome P450 enzymes were engineered and expressed in E. coli functionally. The original plant C-S lyase was replaced by the Neurospora crassa hercynylcysteine sulfoxide lyase. Other pathway enzymes were successfully mined from Arabidopsis thaliana, Brassica rapa, and Brassica oleracea. Biosynthesis of glucoraphanin upon coexpression of the optimized enzymes in vivo was confirmed by liquid chromatography-tandem mass spectrometry analysis. No other glucosinolate analogues (except for glucoiberin) were identified that could facilitate the downstream purification processes. Production of glucoraphanin in this study laid the foundation for microbial production of such health-beneficial glucosinolates in a large-scale. PMID- 29149799 TI - Two new sucrose esters from the rhizome of Sparganium stoloniferum Buch.-Ham. AB - Two new sucrose esters, beta-D-(1-O-acetyl-3,6-O-trans-diferuloyl)fructofuranosyl alpha-D-2'-O-acetylglucopyranoside (1) and beta-D-(1-O-acetyl-3-O-cis-feruloyl-6 O-trans-feruloyl)fructofuranosyl-alpha-D-2',4',6'-O-triacetylglucopyranoside (2), together with four known sucrose esters (3-6) have been isolated from the rhizome of Sparganium stoloniferum Buch.-Ham. Their structures were elucidated by physical and chemical evidence and spectral analysis. PMID- 29149800 TI - Longitudinal Improvement in Balance Error Scoring System Scores among NCAA Division-I Football Athletes. AB - The Balance Error Scoring System (BESS) is a commonly used concussion assessment tool. Recent studies have questioned the stability and reliability of baseline BESS scores. The purpose of this longitudinal prospective cohort study is to examine differences in yearly baseline BESS scores in athletes participating on an NCAA Division-I football team. NCAA Division-I freshman football athletes were videotaped performing the BESS test at matriculation and after 1 year of participation in the football program. Twenty-three athletes were enrolled in year 1 of the study, and 25 athletes were enrolled in year 2. Those athletes enrolled in year 1 were again videotaped after year 2 of the study. The paired t test was used to assess for change in score over time for the firm surface, foam surface, and the cumulative BESS score. Additionally, inter- and intrarater reliability values were calculated. Cumulative errors on the BESS significantly decreased from a mean of 20.3 at baseline to 16.8 after 1 year of participation. The mean number of errors following the second year of participation was 15.0. Inter-rater reliability for the cumulative score ranged from 0.65 to 0.75. Intrarater reliability was 0.81. After 1 year of participation, there is a statistically and clinically significant improvement in BESS scores in an NCAA Division-I football program. Although additional improvement in BESS scores was noted after a second year of participation, it did not reach statistical significance. Football athletes should undergo baseline BESS testing at least yearly if the BESS is to be optimally useful as a diagnostic test for concussion. PMID- 29149801 TI - Response to Phillips et al. (doi: 10.1089/neu.2017.5082): An Autonomic Neuroprosthesis: Non-Invasive Electrical Spinal Cord Stimulation Restores Autonomic Cardiovascular Function in Individuals with Spinal Cord Injury. PMID- 29149802 TI - Associations of short-term exposure to ambient air pollutants with emergency ambulance calls for the exacerbation of essential arterial hypertension. AB - We investigated the association between daily emergency ambulance calls (EAC) for elevated blood pressure that occurred during the time intervals of 8:00-13:59, 14:00-21:59, and 22:00-7:59, and exposure to CO, PM10, and ozone. We used Poisson regression to explore the association between the risk of EAC and short-term variation of pollutants, adjusting for seasonality and weather variables. Before noon, the risk was associated with an interquartile range (IQR) (7.9 MUg/m3) increase in PM10 at lag 2-4 days below the median (RR = 1.08, p = 0.031) and with an IQR (0.146 mg/m3) increase in CO at lag 6-7 below the median (RR = 1.05, p = 0.028). During 14:00-21:59, the risk was associated with an IQR (18.8 MUg/m3) increase in PM10 on the previous day below the median (RR = 1.04, p = 0.031). At night, EAC were negatively affected by lower O3 (lag 0-2) below the median (per IQR decrease RR = 1.10, p = 0.018) and a higher PM10 at lag 0-1 above the median for the elderly (RR = 1.07, p = 0.030). PMID- 29149803 TI - Chemical composition, antioxidant, antibacterial and cytotoxic activities of essential oil of Leontopodium leontopodioides (Willd.) Beauverd. AB - The essential oil (EO) from the aerial parts of Leontopodium leontopodioides (Willd.) Beauverd was obtained by hydrodistillation and analysed by GC-FID and GC MS. Sixty-five compounds were identified which represent 96.2% of the total composition of the EO. The major components of the EO were palmitic acid (11.6%), n-pentadecanal (5.7%), linalool (3.8%), beta-ionone (3.3%), hexahydrofarnesyl acetone (3.2%), bisabolone (3.2%) and beta-caryophyllene (3.2%). The EO exhibited an excellent antibacterial activity against Staphylococcus aureus and Bacillus subtilis according to the MIC values tested by micro-dilution method. It also exhibited a significant cytotoxicity against HepG2 and MCF-7 cell lines with the IC50 values of 67.44 and 70.49 MUg/mL according to the MTT assay. However, the antioxidant activity test revealed that the EO exhibited a weak DPPH radical scavenging activity. In conclusion, the EO of L. leontopodioides could be regarded as a bioactive natural product and deserves further study for its potential therapeutic effects. PMID- 29149804 TI - Systematic literature review and network meta-analysis of cladribine tablets versus alternative disease-modifying treatments for relapsing-remitting multiple sclerosis. AB - OBJECTIVE: To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing-remitting multiple sclerosis (RRMS), and in a subgroup with high disease activity (HRA + DAT), using systematic literature review (SLR) and network meta-analysis (NMA). METHODS: MEDLINE, Embase, MEDLINE In-Process and CENTRAL databases were systematically searched to identify English-language publications of relevant studies of approved DMTs for RRMS. Searches were conducted from database inception to January 2017. Conference websites and trial registries were also searched. NMA considered the effects of DMTs on annualized relapse rate (ARR), confirmed disease progression (CDP), no evidence of disease activity (NEDA) and safety. RESULTS: Of 10,825 articles retrieved and screened, 44 studies assessing 12 DMTs contributed to the NMA. In patients with active RRMS, cladribine tablets were associated with a significant 58% reduction in ARR versus placebo (p < .05); cladribine tablets were similar or significantly better than other DMT regimens and ranked fourth among DMTs, behind alemtuzumab, natalizumab and ocrelizumab. For CDP for 6 months and NEDA, improvements with cladribine tablets were significantly greater than those of placebo (p < .05), with no comparator DMT demonstrating significantly better results. Similar findings were reported in the HRA + DAT population. Overall adverse event risk for cladribine tablets did not differ significantly from that of placebo and most alternative DMTs. CONCLUSION: In this first NMA to consider cladribine tablets, ocrelizumab and daclizumab for treatment of RRMS, cladribine tablets are a comparatively effective and safe alternative to other DMTs in both active RRMS and HRA + DAT populations. PMID- 29149805 TI - Observational cohort study: safety outcomes in children using proton pump inhibitors or histamine-2 receptor antagonists. AB - OBJECTIVE: Acid suppression with histamine-2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) is recommended for children with persistent gastroesophageal reflux disease symptoms. In this retrospective, observational postauthorization study, we aimed to assess and compare safety outcomes in pediatric first-time users of esomeprazole, other PPIs or H2RAs. METHODS: Data on children (aged 0-18 years) first dispensed esomeprazole, other PPIs or H2RAs between September 2008 and August 2011 was obtained from the Dutch PHARMO Database Network. Hospitalizations for seven predefined safety outcomes were evaluated (maximum follow-up: 18 months). Rate ratios were calculated using Poisson regression adjusted for baseline imbalances. Discharge letters were reviewed for event occurrence confirmation. RESULTS: Of 23,470 included children, 2820 (median age: 3 years) were prescribed esomeprazole, 13,818 (median age: 15 years) other PPIs and 6832 (median age: 5 years) H2RAs. In total, 504 (2%) children were hospitalized for 762 predefined events: gastroenteritis (246); convulsion/seizure (200); pneumonia (154); failure to thrive (119); acute interstitial nephritis (19); thrombocytopenia (23); and angioneurotic edema (1). Significant differences between cohorts were observed only for failure to thrive, with adjusted rate ratios (95% confidence interval) for esomeprazole of 6.1 (2.4 15.7) vs. other PPIs and 6.1 (2.9-12.8) vs. H2RAs among current users. Occurrence was confirmed for 74% of assessable events. Confirmation rates were highest for pneumonia (81%) and lowest for failure to thrive (40%). CONCLUSIONS: Hospitalization rates for predefined outcomes were low and mostly similar in pediatric first-time users of PPIs and of H2RAs. TRIAL REGISTRATION: NCT01338363. PMID- 29149806 TI - Occurrence of aflatoxin M1 in milk samples from Italy analysed by online-SPE UHPLC-MS/MS. AB - The occurrence of aflatoxin M1 in 69 milk samples collected in a south region of Italy in 2016 was evaluated. The samples were analysed using an automated method based on online SPE coupled with UHPLC tandem mass spectrometry. After a salt induced liquid-liquid extraction with acetonitrile to remove protein from milk, the extract was diluted with water and analysed using an automated online SPE MS/MS method. Among the analysed samples no one had AFM1 higher than the legally allowable limits whereas 71.4% of the other analysed samples were above the LOD of the method. The highest contamination level of AFM1 was found in pasteurised milk (44.39 ng kg-1). The results show the worrying and widespread of AFM1 contamination, highlighting the necessity of monitoring studies in order to evaluate the reduction of the maximum legal limit. PMID- 29149807 TI - Three new flavonoid glycosides from Smilax glabra and their anti-inflammatory activity. AB - Three new flavonoid glycosides, 2(S)-5-hydroxy-6,8-dimethoxyflavonone-7-O-beta-D glucopyranosyl-(1->6)-O-beta-D-glucopyranoside (1), 5-hydroxy-3,8 dimethoxyflavone-7-O-beta-D-glucopyranosyl-(1->6)-O-beta-D-glucopyranoside (2) and 3,7-dihydroxy-8-methoxyflavone-6-O-beta-D-glucopyranosyl-(1->6)-O-beta-D glucopyranoside (3), together with five known flavonoids (4-8) were isolated from the roots of Smilax glabra Roxb. Their structures were elucidated on the basis of chemical and spectral evidence, as well as by comparison with literature data. Three new flavonoids were subjected to evaluate anti-inflammatory activity. Compounds 1-3 inhibited the NF kappaB induction by 32.2, 55.8 and 61.7%, respectively. PMID- 29149809 TI - Introductory paragraph. PMID- 29149808 TI - Delayed Hypoxemia after Traumatic Brain Injury Exacerbates Long-Term Behavioral Deficits. AB - Hypoxemia during initial stabilization of patients with severe traumatic brain injury (TBI) has been associated with poorer outcomes. However, the effects of delayed hypoxemia occurring during intensive care post-TBI on outcome is unclear. Pre-clinical models of TBI have rarely shown cognitive or behavioral deficits beyond 6 weeks post-injury and commonly have not included modeling of secondary insults. We have previously developed a murine model of TBI followed by delayed hypoxemia to model the secondary insult of hypoxemia and brain hypoxia occurring in the intensive care setting. Understanding long-term effects of delayed hypoxemia post-TBI in our murine model is critical for future testing of candidate therapeutics targeting secondary brain hypoxia. For this study, forty 5 week-old male mice were randomized to controlled cortical impact (CCI; N = 24) or sham surgery (N = 16). One day later, awake animals were randomized to 60 min of hypoxemia or normoxemia. Six months after initial injury, animals underwent behavior testing (Morris water maze, social interaction, and tail suspension) before euthanasia for immunohistochemistry (IHC) assessments. At 6 months post injury, mice experiencing CCI and hypoxemia (CCI+H) had longer swim distances to the hidden platform (51 cm) compared to CCI alone (26 cm) or sham animals (22 cm). During social interaction assessments, CCI + H mice spent less time interacting with novel stimulus mice (79 sec) than CCI alone (101 sec) or sham animals (139 sec). CCI + H had larger lesion volumes compared to CCI alone (14.0% vs. 9.9%; p < 0.003). Glial fibrillary acidic protein IHC at 6 months post-injury demonstrated increased astrogliosis in the ipsilateral white matter of CCI + H compared to CCI alone. To summarize, this clinically relevant model of delayed hypoxia post-TBI resulted in long-term behavioral deficits and evidence of exacerbated structural injury. PMID- 29149810 TI - Exacerbation of Acute Traumatic Brain Injury by Circulating Extracellular Vesicles. AB - Inflammatory lesions in the brain activate a systemic acute-phase response (APR), which is dependent on the release of extracellular vesicles (EVs) into the circulation. The resulting APR is responsible for regulating leukocyte mobilization and subsequent recruitment to the brain. Factors that either exacerbate or inhibit the APR will also exacerbate or inhibit central nervous system (CNS) inflammation as a consequence and have the potential to influence ongoing secondary damage. Here, we were interested to discover how the circulating EV population changes after traumatic brain injury (TBI) and how manipulation of the circulating EV pool impacts on the outcome of TBI. We found the number of circulating EVs increased rapidly post-TBI, and this was accompanied by an increase in CNS and hepatic leukocyte recruitment. In an adoptive transfer study, we then evaluated the outcomes of TBI after administering EVs derived from either in vitro macrophage or endothelial cell lines stimulated with lipopolysaccharide (LPS), or from murine plasma from an LPS challenge using the air-pouch model. By manipulating the circulating EV population, we were able to demonstrate that each population of transferred EVs increased the APR. However, the characteristics of the response were dependent on the nature of the EVs; specifically, it was significantly increased when animals were challenged with macrophage-derived EVs, suggesting that the cellular origins of EVs may determine their function. Selectively targeting EVs from macrophage/monocyte populations is likely to be of value in reducing the impact of the systemic inflammatory response on the outcome of traumatic CNS injury. PMID- 29149811 TI - Testing the Actions of a Multi-action Emollient: Patient's Acceptability Determines Product Efficacy. AB - AIM: Eczema or Atopic Dermatitis (AD) is associated with itch, sleep disturbance, impaired life quality, reduced skin hydration, impaired epidermal barrier function and colonization by Staphylococcus aureus (SA). We investigated an emollient with claimed multi-actions on barrier repair, antihistaminergic and antimicrobial effects. METHODS: Consecutive AD patients were recruited. Swabs and cultures from eczematous areas, disease severity (SCOring Atopic Dermatitis score: SCORAD), quality-of-life (Children Dermatology Life Quality Index, CDLQI), Skin Hydration (SH), and Transepidermal Water Loss (TEWL) were obtained before and 4-week following usage of the emollient. Global or General Acceptability of Treatment (GAT) was obtained (as very good, good, fair or poor). RESULTS: 30 AD patients were recruited. 73% reported "very good" or "good", whereas 27% reported "fair" or "poor" GAT of the emollient. Following the use of the multi-action emollient, area affected, disease intensity and severity significantly improved, especially in the very good/good group (p=0.006-0.035). There was no significant improvement of itch or sleep scores, quality of life, SH, TEWL, S. aureus colonization status, or use of topical treatments. When compared with the historical data of another product, there was no statistical difference between the two creams. CONCLUSION: The emollient is acceptable in nearly three-quarter of AD patients. Patients that accept the moisturizer have less area affected, disease intensity and severity than the non-accepting counterparts following its usage. Despite claim for multi-action, there were no appreciable quality-oflife, anti-itch, skin barrier, and anti-microbial effects. PMID- 29149812 TI - Architectures and Mechanical Properties of Drugs and Complexes of Surface-active Compounds at Air-water and Oil-water Interfaces. AB - BACKGROUND: Drugs can represents a multitude of compounds from proteins and peptides, such as growth hormones and insulin and on to simple organic molecules such as flurbiprofen, ibuprofen and lidocaine. Given the chemical nature of these compounds two features are always present. A portion or portions of the molecule that has little affinity for apolar surfaces and media and the opposite a series of part or one large part that has considerable affinity for hydrophilic, polar or charged media and surfaces. A series of techniques are routinely used to probe the molecular interactions that can arise between components, such as the drug, a range of surface-active excipients and flavor compounds, for example terpenoids and the solvent or dispersion medium. RESULTS: Fifty-eight papers were included in the review, a large number (16) being of a theoretical nature and an equally large number (14) directly pertaining to medicine and pharmacy; alongside experimental data and phenomenological modelling. The review therefore simultaneously represents an amalgam of review article and research paper, with routinely used or established (10) and well-reported methodologies (also included in the citations within the review). Experimental data included from various sources as diverse as foam micro-conductivity, interferometric measurements of surface adsorbates and laser fluorescence spectroscopy (FRAP) are used to indicate the complexity and utility of foams and surface soft matter structures for a range of purposes but specifically, here for encapsulation and incorporation of therapeutics actives (pharmaceutical molecules, vaccines and excipients used in medicaments). Techniques such as interfacial tensiometry, interfacial rheology (viscosity, elasticity and visco-elasticity) and nanoparticle particle size (hydrodynamic diameter) and charge measurements (zeta potential), in addition to atomic force and scanning electron microscopy have proven to be very useful in understanding how such elemental components combine, link or replace one another (competitive displacement). They have also proved both beneficial and worthwhile in the sense of quantifying the unseen actions and interplay of adsorbed molecules and the macroscopic effects, such as froth formation, creaming or sedimentation that can occur as a result of these interactions. CONCLUSION: The disclosures and evaluations presented in this review confirm the importance of a theoretical understanding of a complex model of the molecular interactions, network and present a framework for the understanding of really very complex physical forms. Future therapeutic developer rely on an understanding of such complexity to garner a route to a more successful administration and formulation of a new generation of therapeutic delivery systems for use in medicine. PMID- 29149813 TI - Structural Analysis of CD59 of Chinese Tree Shrew: A New Reference Molecule for Human Immune System Specific CD59 Drug Discovery. AB - BACKGROUND: Chinese tree shrews (Tupaia belangeri chinensis) bear several characteristics that are considered to be very crucial for utilizing in animal experimental models in biomedical research. Subsequent to the identification of key aspects and signaling pathways in nervous and immune systems, it is revealed that tree shrews acquire common as well as unique characteristics, and hence offer a genetic basis for employing them as a prospective model for biomedical research. CD59 glycoprotein, commonly referred to as MAC-inhibitory protein (MAC IP), membrane inhibitor of reactive lysis (MIRL), or protectin, is encoded by the CD59 gene in human beings. It is the member of the LY6/uPAR/alpha-neurotoxin protein family. OBJECTIVES: With this initial point, the objective of this study was to determine a comparative composite based structure of CD59 of Chinese tree shrew. The additional objective of this study was to examine the distribution of negatively and positively charged amino acid over molecular modeled structure, distribution of secondary structural elements, hydrophobicity molecular surface analysis and electrostatic potential analysis with the assistance of several bioinformatical analytical tools. METHODS: CD59 Amino acid sequence of Chinese tree shrew was collected from the online database system of National Centre for Biotechnology Information. SignalP 4.0 online server was employed for detection of signal peptide instance within the protein sequence of CD59. Molecular model structure of CD59 protein was generated by the Iterative Threading ASSEmbly Refinement (I-TASSER) suite. The confirmation for three-dimensional structural model was evaluated by structure validation tools. Location of negatively and positively charged amino acid over molecular modeled structure, distribution of secondary structural elements, and hydrophobicity molecular surface analysis was performed with the help of Chimera tool. Electrostatic potential analysis was carried out with the adaptive Poisson-Boltzmann solver package. Subsequently validated model was used for the functionally critical amino acids and active site prediction. The functionally critical amino acids and ligand- binding site (LBS) of the proteins (modeled) were determined using the COACH program. RESULT: Analysis of Ramachandran plot for Chinese tree shrew depicted that overall, 100% of the residues in homology model were observed in allowed and favored regions, sequentially leading to the validation of the standard of generated protein structural model. In case of CD59 of Chinese tree shrew, the total score of G factor was found to be -0.66 that was generally larger than the acceptable value. This approach suggests the significance and acceptability of the modeled structure of CD59 of Chinese tree shrew. The molecular model data in cooperation to other relevant post model analysis data put forward molecular insight into protecting activity of CD59 protein molecule of Chinese tree shrew. CONCLUSION: In the present study, we have proposed the first molecular model structure of uncharted CD59 of Chinese tree shrew by significantly utilizing the comparative composite modeling approach. Therefore, the development of a structural model of the CD59 protein was carried out and analyzed further for deducing molecular enrichment technique. The collaborative effort of molecular model and other relevant data of post model analysis carry forward molecular understanding to protecting activity of CD59 functions towards better insight of features of this natural lead compound. PMID- 29149814 TI - Calcium Sensitizers in Cardiac Surgery: Who, When, How and Why? AB - Inodilators are a heterogeneous group of drugs with vasodilatory and inotropic effects. The cardioprotective effect of levosimendan is multifactorial, but now research on levosimendan is focused on the organ-protective properties of this drug in different settings, the regimen that seems to provide the greatest cardiologic and systemic benefits is early administration of levosimendan. We try to answer four questions in this review, which type of patients need this drug? what is the best time to start with it? and the best way that we could give it and finally the reasons for use it. PMID- 29149815 TI - Stroke and Hypertension: An Appraisal from Pathophysiology to Clinical Practice. AB - Stroke as a cause of long-term disability is a growing public health burden. Therefore, focusing on prevention is important. The most prominent aim of this strategy is to treat modifiable risk factors, such as arterial hypertension, the leading modifiable contributor to stroke. Thus, efforts to adequately reduce Blood Pressure (BP) among hypertensives are mandatory. In this respect, although safety and benefits of BP control related to long-term outcome have been largely demonstrated, there are open questions that remain to be addressed, such as optimal timing to initiate BP reduction and BP goals to be targeted. Moreover, evidence on antihypertensive treatment during the acute phase of stroke or BP management in specific categories (i.e. patients with carotid stenosis and post acute stroke) remain controversial. This review provides a critical update on the current knowledge concerning BP management and stroke pathophysiology in patients who are either at risk for stroke or who experienced stroke. PMID- 29149816 TI - Maternal Dyslipidaemia in Pregnancy with Gestational Diabetes Mellitus: Possible Impact on Foetoplacental Vascular Function and Lipoproteins in the Neonatal Circulation. AB - Dyslipidaemia occurs in pregnancy to secure foetal development. The mother shows a physiological increase in plasma total cholesterol and Triglycerides (TG) as pregnancy progresses (i.e. maternal physiological dyslipidaemia in pregnancy). However, in some women pregnancy-associated dyslipidaemia exceeds this physiological adaptation. The consequences of this condition on the developing fetus include endothelial dysfunction of the foetoplacental vasculature and development of foetal aortic atherosclerosis. Gestational Diabetes Mellitus (GDM) associates with abnormal function of the foetoplacental vasculature due to foetal hyperglycaemia and hyperinsulinaemia, and associates with development of cardiovascular disease in adulthood. Supraphysiological dyslipidaemia is also detected in GDM pregnancies. Although there are several studies showing the alteration in the maternal and neonatal lipid profile in GDM pregnancies, there are no studies addressing the effect of dyslipidaemia in the maternal and foetal vasculature. The literature reviewed suggests that dyslipidaemia in GDM pregnancy should be an additional factor contributing to worsen GDM-associated endothelial dysfunction by altering signalling pathways involving nitric oxide bioavailability and neonatal lipoproteins. PMID- 29149817 TI - High-density Lipoprotein (HDL) Dysfunction and the Future of HDL. AB - Although High Density Lipoprotein Cholesterol (HDL-C) levels are inversely proportional to cardiovascular risk in many studies, recent pharmacological interventional studies with HDL-C raising strategies did not show a benefit in terms of vascular events. The HDL particle is heterogenous with anti-atherogenic functions and non-vascular effects. Many factors affect HDL components and may either cause compositional changes, post-translational modifications of proteins, or alter lipids and other cargo molecules; generally these factors cause more than one of these changes, resulting in functional differences. Therefore, the role of lipoproteins change in different physical and disease conditions. Mainly, in proteome, Apolipoprotein A1 (Apo-A1), Myeloperoxidase (MPO), Paroxonase (PON) are affected by inflammation or glycation-related factors; and especially esterification or unesterification of lipids, changes in phospholipid or unsaturated lipid content change the HDL function. Measuring the HDL-C level is probably not a good predictor of its cardiovascular benefits, and methods to evaluate HDL functions are required. In current medical practice, it is not simple and feasible to measure different functions of this lipoprotein, but near future strategies may be developed. Meanwhile, as we learn more about HDL structure and the role of each component, we can develop therapeutic approaches to improve HDL function. Apo-A1-mimetics, reconstituted HDL, nanoparticles and microRNA therapies could be promising as anti-atherosclerotic therapies. They may even provide useful therapies for the treatment of some non-cardiovascular diseases. PMID- 29149818 TI - Renal Dysfunction Following Elective Endovascular Aortic Aneurysm Repair. AB - Abdominal aortic aneurysm (AAA) is a degenerative disease of the aortic wall with potentially fatal complications. Open repair (OR) was considered the gold standard, until the emergence of endovascular aneurysm repair (EVAR), which is less invasive and equally (if not more) effective. As the popularity of endovascular procedures grows, related complications become more evident, with kidney damage being one of them. Although acute kidney injury (AKI) following EVAR is relatively common, its true incidence is still uncertain. Also, there is insufficient data concerning long-term renal outcomes after EVAR, especially with repeated contrast agent exposure. Despite the lack of firm evidence on the effectiveness of individual strategies, it is evident that prevention of AKI following EVAR requires a multifactorial approach. This review focuses on recent findings based on human studies regarding the current evidence of renal impairment after EVAR, its quantification and strategies for its prevention. PMID- 29149819 TI - Cardiovascular Risk in Psoriasis: Current State of the Art. AB - Psoriasis (Pso) is a chronic inflammatory immune-mediated skin disease associated with several comorbidities. Despite the growing number of studies providing evidence for the link between Pso and Cardiovascular (CV) disorders, there are still many unsolved questions, dealing with the role of the skin disease as an independent risk factor for CV events, the influence of Pso severity and duration on CV damage, the presence of Psoriatic Arthritis (PsA) as a predictor of increased CV mortality and morbidity and the detection of reliable clinical, laboratory and/or instrumental parameters to stratify CV risk in psoriatic patients. Moreover, it remains to clarify if the early treatment of the dermatosis may lower CV risk. In this paper we will try to provide answers to these queries in the light of the updated data of the literature. PMID- 29149820 TI - Mechanisms of Cardioprotection of Halogenated Agents During Extracorporeal Circulation in Cardiac Surgery. AB - The implementation of cardioprotective strategies involving pre-, intra-, and postoperative interventions is key during cardiac surgery requiring extracorporeal circulation (ECC). The primary goal of this study was to review the physiopathology and protection strategies against myocardial damage secondary to ECC during cardiac surgery. The administration halogenated anesthetics for cardiac anesthesia is common place due to their well-known cardioprotective effects and their capacity to ensure hypnosis. An optimal myocardial protection strategy requires that a comprehensive approach should be adopted to cover pre-, intra-, and post-operative interventions. Pre-conditioning and post-conditioning share numerous pathways, mainly based on mitochondrial signaling, antiapoptotic pathways, and reduced inflammatory mediators. However, volatile anesthetic can also be administered during ECC, in which mechanism of action has been scantly investigated, during this period and its biology is still unknown. PMID- 29149821 TI - Statins Therapy for Connective Tissue Diseases: New Therapeutic Opportunities. AB - BACKGROUND AND OBJECTIVE: Statins, 3-hydroxyl-3-methyl-glutharyl Coenzyme A reductase inhibitors showed their therapeutic potential in the treatment of atherosclerosis-related diseases. Recently, the properties of statins, separate from their lipid lowering activity have attracted much attention. These properties that cover a wide area of physiopathological activities including cell maturation, immune response regulation, tissue fibrosis, endothelial activity and are called pleiotropic activity. Many in vitro studies demonstrated significant, statins-dependent regulation of immune system reactivity, reduction of pro inflammatory and pro-fibrotic cytokines as well as suppression of endothelial activity and damage. METHODS: The present study reviewed the potential utility of statins as a concomitant regimen in the treatment of various connective tissue diseases. To address this we performed a methodical search though Pubmed database searching for term statins and pleiotropic effects and connective tissue disease or rheumatology. RESULTS: One hundred and thirty one prominent research and review papers were identified and analyzed. Majority of research papers focused on laboratory models of statins activity, only a few of them analyzed data from human studies. CONCLUSION: Statins may have a therapeutic potential as a concomitant treatment for connective tissue diseases, that has been elegantly proven in many animal and laboratory studies. They deep interfere with immunological mechanism of autoantigen presentation, expressions of adhesion molecules. These phenomena may be recognized as the most important mode of action. Less is known about the potential of statins in clinical practice. Many small trials examined therapeutic potentials in various autoimmune diseases with contradictory results, disabling making the final conclusions. The future human studies should answer what patients population may benefit with concomitant statins' treatment. PMID- 29149822 TI - Olive Leaf Extracts Act as Modulators of the Human Immune Response. AB - BACKGROUND: Olive tree leaves have been used in the Mediterranean area as traditional medicine in virtue of their healthy effects. Olive leaf extracts (OLEs) contain higher amounts of polyphenols than those detected in the extra virgin olive oil and fruit. Several lines of evidence support the cardioprotective, anti-oxidant and anti-inflammatory activities exerted by OLEs. METHODS: Peripheral blood mononuclear cells from twenty-five healthy donors were cultured in the presence of 3 ug of two OLE extracts, extract A (resuspended in water) and extract B (resuspended in 70% ethanol). After harvesting, cell pellets were used for cytofluorimetric phenotyping, while supernatants were assayed for cytokine release by means of ELISA. Furthermore, in the same supernatants nitric oxide (NO) content was determined. RESULTS: Both extracts, but especially extract A, increased absolute numbers of CD8+ and natural killer (NK) cells. In addition, an increased production of interferon (IFN)-gamma by both extracts as an expression of T helper (h)1 activation was observed. Finally, both extracts enhanced NO release. CONCLUSION: OLEs, and mostly extract A, are able to in vitro modify healthy human immune response by increasing IFN-gamma production which seems to be associated to the higher absolute numbers of CD8+ and NK cells and this may suggest a reinforcement of the anti-tumor activity. Furthermore, increased levels of NO may indicate the potential cardioprotective effects exerted by OLEs in virtue of their vasodilation dependent activity. Finally, OLEs are able to maintain the equilibrium between T regulatory cells and Th17 cells as evidenced by unmodified levels of interleukin (IL)-IL-10 and IL-17, respectively. In the light of these results, OLEs are potential therapeutic compounds for the treatment of chronic inflammatory disease, also preventing cardiovascular event outcome. PMID- 29149823 TI - Olive Oil-related Anti-inflammatory Effects on Atherosclerosis: Potential Clinical Implications. AB - BACKGROUND AND OBJECTIVE: Atherosclerosis is characterized by a chronic low-grade inflammatory process which can result in atherothrombosis and a number of cardiovascular diseases (CVD). It is believed to be caused by multiple processes that involve inflammation and immunity. Mediterranean Diet (MedD) has been discovered to possess anti-inflammatory properties and associated with a reduction in the CVD risk and mortality. Its main component, extra-virgin olive oil (EVOO), is believed to be largely responsible for these effects and therefore, has been investigated in various studies. The present review article aims to summarize the available literature on the antiinflammatory and cardio protective effects of EVOO. METHODS: A search based on the key concepts "olive oil", "atherosclerosis", "inflammation" and "cardiovascular disease" was performed to retrieve relevant studies and articles on the association between the consumption of EVOO and the levels of inflammatory biomarkers as well as CVD incidence and mortality from online databases; Pubmed, Embase and Cochrane Library. RESULTS: Consumption of EVOO is associated with a reduction in inflammatory biomarkers and molecules implicated in atherosclerosis as well as CVD incidence and mortality as well as other complications such as heart failure and atrial fibrillation. Moreover, these anti-inflammatory and cardioprotective effects of EVOO are mostly attributable to its high content of polyphenol molecules. CONCLUSION: Currently available evidence supports the anti inflammatory and cardio-protective roles of EVOO. However, there is limited amount of available randomized controlled trials especially lacking those investigating the use of EVOO as secondary prevention, heterogeneity of study design, limited generalization to wide population groups, and inability to determine the minimum intake of EVOO required to clinically achieve the anti inflammatory and cardioprotective effects. Therefore, more highquality randomized controlled trials still need to be carried out to overcome these challenges to further assess the health benefits of EVOO consumption and potentially translate it into clinical practice as primary or secondary prevention of atherosclerosis related conditions. PMID- 29149824 TI - The Role of Gene Therapy in the Treatment of Retinal Diseases: A Review. AB - BACKGROUND: Gene therapy represents the therapeutic delivery of nucleic acid polymers into patient cells with the aim of treating an underlying disease. Over the past 2 decades this new therapy has made substantial progress owing to better understanding of the pathobiologic basis of various diseases coupled with growth of gene transfer biotechnologies. The eye, in particular, represents a suitable target for such therapy due to the immune privilege provided by the blood-ocular barrier, the ability to directly visualize, access and locally treat the cells and the minimal amount of vector needed given the size of this organ. It is not surprising therefore that several clinical trials are now ongoing in this field. OBJECTIVE: The purpose of this review was to provide an update on gene therapy for retinal diseases, discussing differences in treatment strategies, vector designs and surgical techniques. METHOD: Research was performed on PubMed, ClinicalTrials.gov, and Home Genetic Reference. We additionally utilized the internet database for genetics of retinal diseases, the portal for rare diseases and orphan drugs and the NCBI database Online Mendelian Inheritance in Man. No restriction was applied on the language of publications. RESULTS: We present the available results of current active clinical trials for inherited retinal disease such as Leber's congenital amaurosis type 2, choroideremia, Stargardt disease, achromatopsia and juvenile X-linked retinoschisis. We also illustrate a new approach of this therapy for the treatment of much more common ocular diseases such as age-related macular degeneration and diabetic retinopathy. CONCLUSION: Gene therapy represents an emerging and promising therapeutic approach for the treatment not only of rare inherited retinal diseases but also much more common retinal pathologies. PMID- 29149825 TI - Dopamine: Agonists and Neurodegenerative Disorders. AB - BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons within the substantia nigra pars compacta (SNpc). Despite many researches, there is still no cure for this disease. Levodopa is the first line treatment of PD, but the long term use of it leads to motor impairments and dyskinesias. The dopamine agonists are the preferred choice for the treatment of PD. They are neuroprotective in nature but have side effects. OBJECTIVE: Our aim was to review the work that has been carried out on dopamine agonists and the future possibilities to reduce their side effects. CONCLUSION: In this review, we highlighted the metabolism of dopamine, different types of dopamine agonists with their properties and possible side effects. PMID- 29149826 TI - Novel Functions of MicroRNA-17-92 Cluster in the Endocrine System. AB - BACKGROUND: MiR-17-92 cluster is coded by MIR17HG in chromosome 13, which is highly conserved in vertebrates. Published literatures have proved that miR-17-92 cluster critically regulates tumorigenesis and metastasis. Recent researches showed that the miR-17-92 cluster also plays novel functions in the endocrine system. OBJECTIVE: To summarize recent findings on the physiological and pathological roles of miR-17-92 cluster in bone, lipid and glucose metabolisms. RESULTS: MiR-17-92 cluster plays significant regulatory roles in bone development and metabolism through regulating the differentiation and function of osteoblasts and osteoclasts. In addition, miR-17- 92 cluster is nearly involved in every aspect of lipid metabolism. Last but not the least, the miR-17-92 cluster is closely bound up with pancreatic beta cell function, development of type 1 diabetes and insulin resistance. However, whether miR-17-92 cluster is involved in the communication among bone, fat and glucose metabolisms remains unknown. CONCLUSION: Growing evidence indicates that miR-17-92 cluster plays significant roles in bone, lipid and glucose metabolisms through a variety of signaling pathways. Fully understanding its modulating mechanisms may necessarily facilitate to comprehend the clinical and molecule features of some metabolic disorders such as osteoporosis, arthrosclerosis and diabetes mellitus. It may provide new drug targets to prevent and cure these disorders. PMID- 29149827 TI - Therapeutic Applications of Capsaicin in Upper Airways. AB - BACKGROUND: Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the substance responsible of the irritation caused by the contact of chili peppers with the skin or mucous membranes. This protoalkaloid acts by stimulating the transient receptor potential cation channel subfamily V member 1 (TRPV1), which is mainly expressed by nociceptive fibers of peripheral sensory neurons, but is also present in the central nervous system, and in some non-neuronal cells. Following the initial, intense neuronal excitation, a brief refractory period occurs. However, repeated and massive exposures to capsaicin can impair nociceptive fiber function for weeks or months. During this lapse of time, disorders related to the hyperreactivity of peripheral nociceptors are abolished or greatly reduced. Capsaicin has been utilized to treat several diseases of upper airways. OBJECTIVE: The objective of this review was to report the latest findings on the use of Capsaicin in the treatment of upper airway diseases. RESULTS: Capsaicin effectiveness has been proved in non allergic rhinitis. Some studies suggest that this substance may be also effective in nasal polyposis and in the burning mouth syndrome. No clear evidence has been obtained about its use in allergic rhinitis. CONCLUSION: To date, the use of capsaicin to treat upper airway diseases is still limited in clinical practice. This may originate by the lack of strong, conclusive evidences of its effectiveness, by the variety of therapeutic schemes used in literature, and finally by the unpleasant effects of the exposure to capsaicin, which are only partly relieved by the pretreatment with local anesthetics. PMID- 29149828 TI - Vortioxetine Treatment for Anxiety Disorder: A Meta-Analysis Study. AB - BACKGROUND: Vortioxetine is a multimodal antidepressant that has been developed for the treatment of major depressive and anxiety disorders. The aim of this review is to quantitatively synthesize all data of the efficacy, safety and tolerability of Vortioxetine in treating anxiety disorder. METHOD: Terms of "Vortioxetine" OR "LuAA21004" AND "anxiety" OR "fear" OR "panic" OR "phobia" were searched. A total of two phase II and five phase III clinical trials were found. RESULTS: Vortioxetine was overall superior to placebo in terms of the mean change from baseline in HAM-A total score at week 8 with the pool effect size of -2.95, 95% CIs, -4.37 to -1.53, p<0.01. The patients who received 5 mg of Vortioxetine had higher response rate when compared to placebo (pooled odds ratio=1.4, 95% CI = 1.08 to 1.82, p=0.01). However, the pooled odds ratio of the HAMA remission rate was not statistically significant for both Vortioxetine and placebo (pooled odds ratio= 1.06, 95% CI = 0.86 to 1.30, p=0.62). Although the discontinuation due to adverse effects was higher in Vortioxetine than placebo group (pooled OR= 1.55, 95% CI = 1.04 to 2.31, P= 0.037), the lack of efficacy (pooled OR= 0.39, 95% CI = 0.27 to 0.57, P<0.01) was higher in placebo than Vortioxetine group. Most of the adverse effects were mild and moderate. Overall, Vortioxetine displayed a good safety and tolerability profile. CONCLUSION: This review supports the use of Vortioxetine for anxiety disorder. However, further longterm placebo-control observational study or a post market survey would help in strengthening the evidence for this treatment modality. PMID- 29149829 TI - The Validation Path of Hypoxia PET Imaging: Focus on Brain Tumours. AB - BACKGROUND: Gliomas are brain tumours arising from the glia, the supportive tissue of the central nervous system (CNS), and constitute the commonest primary malignant brain tumours. Gliomas are graded from grade I to IV according to their appearance under the microscope. One of the most significant adverse features of high-grade gliomas is hypoxia, a biological phenomenon that develops when the oxygen concentration becomes insufficient to guarantee the normal tissue functions. Since tumour hypoxia influences negatively patient outcome and targeting hypoxia has potential therapeutic implications, there is currently great interest in imaging techniques measuring hypoxia. OBJECTIVES: The aim of this review is to provide up to date evidence on the radiotracers available for measuring hypoxia in brain tumours by means of positron emission tomography (PET), the most extensively investigated imaging approach to quantify hypoxia. METHODS: The review is based on preclinical and clinical papers and describes the validation status of the different available radiotracers. RESULTS: To date, [F 18] fluoromisonidazole ([18F]FMISO) remains the most widely used radiotracer for imaging hypoxia in patients with brain tumours, but experience with other radiotracers has expanded in the last two decades. Validation of hypoxia radiotracers is still on-going and essential before these radiopharmaceuticals can become widely used in the clinical setting. CONCLUSION: Availability of a non invasive imaging method capable of reliably measuring and mapping different levels of oxygen in brain tumours would provide the critical means of selecting patients that may benefit from tailored treatment strategies targeting hypoxia. PMID- 29149830 TI - Diagnostic Devices for Circulating Biomarkers Detection and Quantification. AB - Nowadays, fast and sensitive methods for biomarkers detection exist, but the performance of most of them still rely in centralized laboratory testing. The development of small, fast and simple to use medical device that can help in making diagnosis accurate and with low-invasiveness is now a major challenge for nanotechnology. To develop diagnostic devices for cancer detection, nanomaterials based systems have significant advantages over current conventional approaches in terms of simplicity, sensitivity, specificity and rapidity. In this review, we describe the most interesting nanotechnological devices/approaches applied for circulating biomarkers detection in oncology. A survey of new applicable nanobiosensors for nucleic acids and proteins identification is provided, here and classified for the four most interesting nanotechnologies applicable such as: the bio-barcode, Quantum Dots, metal nanoparticles and carbon-based nanosensors. Their versatility has been demonstrated in different applications aiming to detect and quantify cancer biomarkers in real biological samples in order to show how these methods can lead, in the future, to the development of devices for routinely clinical application. PMID- 29149831 TI - Molecular Mechanisms Triggered by Bile Acids on Intestinal Ca2+ Absorption. AB - BACKGROUND: Bile acids (BAs) are among the main components of bile. Lately, they are also considered important signaling molecules, not only by regulating their own synthesis, but also having a role in several metabolic diseases. OBJECTIVE: In this review we focus on the effect of sodium deoxycholate (NaDOC), ursodeoxycholic (UDCA) and litocholic (LCA) acids and their combination upon the intestinal Ca2+ absorption. To make clear the actions of those BAs on this physiological process, an overview of current information about the mechanisms by which the intestinal Ca2+ occurs is described. METHODS: The PubMed database was searched until 2017, using the keywords bile acids, NaDOC, UDCA and LCA and redox state, apoptosis, autophagy and intestinal Ca2+ absorption. RESULTS: The modulation of redox state, apoptosis and autophagy are mechanisms that are involved in the action of BAs on intestinal Ca2+ absorption. Although the mechanisms are still not completely understood, we provide the latest knowledge regarding the effect of BAs on intestinal Ca2+ absorption. CONCLUSION: The response of the intestine to absorb Ca2+ is affected by BAs, but it is different according to the type and dose of BA. When there is a single administration, NaDOC has an inhibitory effect, UDCA is an stimulator whereas LCA does not have any influence. However, the combination of BAs modifies the response. Either UDCA or LCA protects the intestine against the oxidative injury caused by NaDOC by blocking the oxidative/nitrosative stress, apoptosis and autophagy. PMID- 29149832 TI - Metallodrugs in targeted cancer therapeutics. Aiming at chemoresistance-related patterns and immunosuppressive tumor networks AB - Tumor cell chemoresistance is a major challenge in cancer therapeutics. Major select metal-based drugs are potent anticancer agents yet they exhibit undesirable side-effects and are effective against only a few types of cancers. A need, therefore, arises for new metallodrugs with an improved spectrum of efficacy and lower toxicity. Development of anticancer drugs based on antitumor metals is currently a very active field, with considerable efforts having been made toward elucidating the mechanisms of immune action of complex metalloforms and optimizing their immunoregulatory bioactivity through appropriate structural modification. In that respect, comprehending the molecular factors involved in drug resistance and immune response may help us develop new strategies toward more promising chemotherapies, reducing the rate of relapse and overcoming chemoresistance. In this review, a) molecular immune-related mechanisms in the tumor microenvironment, leading to decreased drug sensitivity, along with b) strategies for reversing drug resistance and targeting immunosuppressive tumor networks, while concurrently optimizing the design of complex metalloforms bearing anti-tumor activity, are discussed in an effort to identify and overcome underlying mechanisms of chemoresistance to both standard chemotherapeutic agents and targeted molecular therapies. PMID- 29149833 TI - G4-Interacting DNA Helicases and Polymerases: Potential Therapeutic Targets. AB - Guanine-rich DNA can fold into highly stable non-canonical four-stranded DNA structures called G-quadruplexes. These structures present obstacles for the DNA replication machinery, and it has been hypothesized that both eukaryotic DNA helicases and polymerases have evolved to resolve G4 DNA in vivo. Since the discovery of G-quadruplex DNA in the early 1960's, a number of studies have emerged reporting G-quadruplex DNA unfolding by helicase enzymes and DNA synthesis past G4 by specialized translesion polymerase enzymes. Recently, the discovery of the primase-polymerase PrimPol and its role in G4 bypass has sparked even more excitement in the G-quadruplex and DNA replication fields. This review presents an overview of the molecular interactions of G-quadruplexes with DNA helicases and polymerases implicated in their resolution, with an emphasis on how the regulation and coordination of these enzymes is critical for genome homeostasis. Targeting G4-interacting DNA helicases and polymerases for therapeutic strategies is discussed. PMID- 29149834 TI - Cystatin C in Cerebrovascular Disorders. AB - Cystatin C (CysC), a cysteine protease inhibitor, has been widely proven to be a highly sensitive biomarker to predict the kidney function. The similarity of the renal and cerebral small vessels has awakened a surge of studies suggesting that CysC plays a key role in various cerebrovascular disorders. This review focuses on four major mechanisms of CysC in a variety of cerebrovascular diseases. (1) The property of the CysC Leu-68-Gln (L68Q) variant to aggregate and the property of the wild type CysC protein to co-aggregate with Amyloid-beta (Abeta); (2) The disruption of equilibrium between CysC and related cysteine proteases; (3) The function of CysC as an inflammatory inducing factor; (4) The ability of CysC to induce autophagy. The combination of these CysC properties provides a well supported novel biomarker for cerebrovascular diseases. PMID- 29149836 TI - Are there Different Kinds of Aging? AB - BACKGROUND: Most syndromes of accelerated aging are caused by mutations affecting the integrity of the genetic material. Among them, the most studied is Werner's syndrome, "adult progeria", caused by a recessive autosomal mutation with a frequency of 1 in 10 million, which affects a helicase involved in DNA repair. In Werner syndrome, there is a loss of heterochromatin, though the stability of heterochromatin is also affected in "normal" aging. The Hutchinson-Gilford Progeria Syndrome (HGPS), "child progeria", has an even lower frequency. In most cases, it is caused by a point mutation of a gene coding a protein in the nuclear envelope, lamin A. OBJECTIVES: HGPS may provide valuable insights into the aging process. The symptoms of this condition do not entirely overlap with those of "normal" aging. METHOD: A critical analysis of the accelerated aging syndromes may explain what aging is, and also why some tissues and organs age at accelerated rates as compared to other tissues. RESULTS: In this article, we will discuss the implications of HGPS and other accelerated aging syndromes in the light of the biochemical hypothesis of aging we advanced. According to this hypothesis, some reactions are less stimulated and diminish in time, affecting not only specific biochemical functions, but cellular energy, and therefore its capacity for synthesis. CONCLUSION: Besides, a new vision on aging, possible therapeutic strategies for these conditions and others, with similar mechanisms, are also presented. PMID- 29149835 TI - Forkhead Transcription Factors: Formulating a FOXO Target for Cognitive Loss. AB - BACKGROUND: With almost 47 million individuals worldwide suffering from some aspect of dementia, it is clear that cognitive loss impacts a significant proportion of the global population. Unfortunately, definitive treatments to resolve or prevent the onset of cognitive loss are limited. In most cases such care is currently non-existent prompting the need for novel treatment strategies. METHODS: Mammalian forkhead transcription factors of the O class (FoxO) are one such avenue of investigation that offer an exciting potential to bring new treatments forward for disorders that involve cognitive loss. Here we examine the background, structure, expression, and function of FoxO transcription factors and their role in cognitive loss, programmed cell death in the nervous system with apoptosis and autophagy, and areas to target FoxOs for dementia and specific disorders such as Alzheimer's disease. RESULTS: FoxO proteins work in concert with a number of other cell survival pathways that involve growth factors, such as erythropoietin and neurotrophins, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), Wnt signaling, and cancer-related pathways. FoxO transcription factors oversee proinflammatory pathways, affect nervous system amyloid (Abeta) production and toxicity, lead to mitochondrial dysfunction, foster neuronal apoptotic cell death, and accelerate the progression of degenerative disease. However, under some scenarios such as those involving autophagy, FoxOs also can offer protection in the nervous system and reduce toxic intracellular protein accumulations and potentially limit Abeta toxicity. CONCLUSION: Given the ability of FoxOs to not only promote apoptotic cell death in the nervous system, but also through the induction of autophagy offer protection against degenerative disease that can lead to dementia, a fine balance in the activity of FoxOs may be required to target cognitive loss in individuals. Future work should yield exciting new prospects for FoxO proteins as new targets to treat the onset and progression of cognitive loss and dementia. PMID- 29149837 TI - Assessment of genetic diversity in Vigna unguiculata L. (Walp) accessions using inter-simple sequence repeat (ISSR) and start codon targeted (SCoT) polymorphic markers. AB - BACKGROUND: Assessment of genetic diversity of Vigna unguiculata (L.) Walp (cowpea) accessions using informative molecular markers is imperative for their genetic improvement and conservation. Use of efficacious molecular markers to obtain the required knowledge of the genetic diversity within the local and regional germplasm collections can enhance the overall effectiveness of cowpea improvement programs, hence, the comparative assessment of Inter-simple sequence repeat (ISSR) and Start codon targeted (SCoT) markers in genetic diversity of V. unguiculata accessions from different regions in Nigeria. Comparative analysis of the genetic diversity of eighteen accessions from different locations in Nigeria was investigated using ISSR and SCoT markers. DNA extraction was done using Zymogen Kit according to its manufacturer's instructions followed by amplifications with ISSR and SCoT and agarose gel electrophoresis. The reproducible bands were scored for analyses of dendrograms, principal component analysis, genetic diversity, allele frequency, polymorphic information content, and population structure. RESULTS: Both ISSR and SCoT markers resolved the accessions into five major clusters based on dendrogram and principal component analyses. Alleles of 32 and 52 were obtained with ISSR and SCoT, respectively. Numbers of alleles, gene diversity and polymorphic information content detected with ISSR were 9.4000, 0.7358 and 0.7192, while SCoT yielded 11.1667, 0.8158 and 0.8009, respectively. Polymorphic loci were 70 and 80 in ISSR and SCoT, respectively. Both markers produced high polymorphism (94.44-100%). The ranges of effective number of alleles (Ne) were 1.2887 +/- 0.1797-1.7831 +/- 0.2944 and 1.7416 +/- 0.0776-1.9181 +/- 0.2426 in ISSR and SCoT, respectively. The Nei's genetic diversity (H) ranged from 0.2112 +/- 0.0600-0.4335 +/- 0.1371 and 0.4111 +/- 0.0226-0.4778 +/- 0.1168 in ISSR and SCoT, respectively. Shannon's information index (I) from ISSR and SCoT were 0.3583 +/- 0.0639-0.6237 +/- 0.1759 and 0.5911 +/- 0.0233-0.6706 +/- 0.1604. Total gene diversity (Ht), gene diversity within population (Hs), coefficient of gene differentiation (Gst) and level of gene flow (Nm) revealed by ISSR were 0.4498, 0.3203, 0.2878 and 1.2371 respectively, while SCoT had 0.4808, 0.4522, 0.0594 and 7.9245. CONCLUSIONS: Both markers showed highest genetic diversity in accessions from Ebonyi. Our study demonstrated that SCoT markers were more efficient than ISSR for genetic diversity studies in V. unguiculata and can be integrated in the exploration of their genetic diversity for improvement and germplasm utilization. PMID- 29149838 TI - Genetic variation in populations of the earthworm, Lumbricus rubellus, across contaminated mine sites. AB - BACKGROUND: Populations of the earthworm, Lumbricus rubellus, are commonly found across highly contaminated former mine sites and are considered to have under gone selection for mitigating metal toxicity. Comparison of adapted populations with those found on less contaminated soils can provide insights into ecological processes that demonstrate the long-term effects of soil contamination. Contemporary sequencing methods allow for portrayal of demographic inferences and highlight genetic variation indicative of selection at specific genes. Furthermore, the occurrence of L. rubellus lineages across the UK allows for inferences of mechanisms associated with drivers of speciation and local adaptation. RESULTS: Using RADseq, we were able to define population structure between the two lineages through the use of draft genomes for each, demonstrating an absence of admixture between lineages and that populations over extensive geographic distances form discrete populations. Between the two British lineages, we were able to provide evidence for selection near to genes associated with epigenetic and morphological functions, as well as near a gene encoding a pheromone. Earthworms inhabiting highly contaminated soils bare close genomic resemblance to those from proximal control soils. We were able to define a number of SNPs that largely segregate populations and are indicative of genes that are likely under selection for managing metal toxicity. This includes calcium and phosphate-handling mechanisms linked to lead and arsenic contaminants, respectively, while we also observed evidence for glutathione-related mechanisms, including metallothionein, across multiple populations. Population genomic end points demonstrate no consistent reduction in nucleotide diversity, or increase in inbreeding coefficient, relative to history of exposure. CONCLUSIONS: Though we can clearly define lineage membership using genomic markers, as well as population structure between geographic localities, it is difficult to resolve markers that segregate entirely between populations in response to soil metal concentrations. This may represent a highly variable series of traits in response to the heterogenous nature of the soil environment, but ultimately demonstrates the maintenance of lineage-specific genetic variation among local populations. L. rubellus appears to provide an exemplary system for exploring drivers for speciation, with a continuum of lineages coexisting across continental Europe, while distinct lineages exist in isolation throughout the UK. PMID- 29149839 TI - Vitamin D, parathyroid hormone and metabolic syndrome - the PORMETS study. AB - BACKGROUND: Vitamin D (VitD) and parathyroid hormone (PTH) play important roles in calcium metabolism and skeletal homeostasis. Estimates of the VitD status in several European countries show large variations between them. In addition, no national population-based estimate has been published. VitD and PTH may also play important roles in cardiovascular risk, which has been suggested to be associated with metabolic syndrome (MetS) and is very prevalent in Portugal. The goal of our study was to evaluate the prevalence of hypovitaminosis D and its determinants as well as PTH serum level determinants and associations of the 25-hydroxyvitamin D and PTH serum levels with MetS and its individual components in a sample of the Portuguese mainland population. METHODS: PORMETS is a national cross-sectional study that includes a total sample of 4095 adults. A subsample, including 500 participants, was randomly selected for the present study. A structured questionnaire was administered to collect information on personal medical histories and socio-demographic and behavioral characteristics. Blood pressure and anthropometrics measurements were performed. Fasting venous samples were collected and PTH and 25-hydroxyvitamin D were measured. VitD adequacy was classified according to the Institute of Medicine, and MetS was classified according to the Joint Interim Statement recommendations. Multiple linear regression and unconditional logistic regression models were used to estimate the associations between the levels of PTH and 25-hydroxyvitamin D and with MetS and its individual components. RESULTS: The prevalence of VitD deficiency was 37.7%, and MetS was present in 191 participants (38.4%). The serum PTH levels showed a positive association (OR: 1.014; 95%CI: 1.002, 1.026) with the waist circumference component of MetS. The serum 25-hydroxyvitamin D levels were negatively associated with MetS (OR: 0.957; 95%CI: 0.922, 0.993) as well as with its blood pressure (OR: 0.949; 95%CI: 0.912, 0.987) and triglycerides (OR: 0.930; 95%CI: 0.892, 0.969) components. CONCLUSION: This study showed a high national prevalence of hypovitaminosis D. The PTH levels showed a significant positive association with the WC component of MetS, and the VitD levels were negatively associated with the BP and triglycerides components as well as with the MetS. PMID- 29149840 TI - Geometric morphometrics reveals shifts in flower shape symmetry and size following gene knockdown of CYCLOIDEA and ANTHOCYANIDIN SYNTHASE. AB - BACKGROUND: While floral symmetry has traditionally been assessed qualitatively, recent advances in geometric morphometrics have opened up new avenues to specifically quantify flower shape and size using robust multivariate statistical methods. In this study, we examine, for the first time, the ability of geometric morphometrics to detect morphological differences in floral dorsoventral asymmetry following virus-induced gene silencing (VIGS). Using Fedia graciliflora Fisch. & Meyer (Valerianaceae) as a model, corolla shape of untreated flowers was compared using canonical variate analysis to knockdown phenotypes of CYCLOIDEA2A (FgCYC2A), ANTHOCYANIDIN SYNTHASE (FgANS), and empty vector controls. RESULTS: Untreated flowers and all VIGS treatments were morphologically distinct from each other, suggesting that VIGS may cause subtle shifts in floral shape. Knockdowns of FgCYC2A were the most dramatic, affecting the position of dorsal petals in relation to lateral petals, thereby resulting in more actinomorphic-like flowers. Additionally, FgANS knockdowns developed larger flowers with wider corolla tube openings. CONCLUSIONS: These results provide a method to quantify the role that specific genes play in the developmental pathway affecting the dorsoventral axis of symmetry in zygomorphic flowers. Additionally, they suggest that ANS may have an unintended effect on floral size and shape. PMID- 29149841 TI - Establishment of rat ankle post-traumatic osteoarthritis model induced by malleolus fracture. AB - BACKGROUND: Malleolar fracture, which is present in 37-53% of human ankle osteoarthritis (OA), is the most common type of fracture in the ankle joint. In spite of this, no rat animal model has been developed for this type of injury to date. Here, we established a rat ankle post-traumatic OA (PTOA) model induced by malleolar fracture; this model will be useful in ankle OA research. METHODS: Two month-old male Sprague Dawley (SD) rats were randomized into 2 groups (n = 19 per group): 1) malleolus articular fracture, dislocation, and immediate reduction on the right joints and 2) malleolus articular fracture on the right ankle. The contralateral ankle joints were used as controls. The fracture and healing processes were confirmed and monitored by radiography. Changes in inflammation were monitored in vivo by fluorescence molecular tomography (FMT). Cartilage damage and changes in expression of OA-related genes were analyzed by histology, immunohistochemistry, Real-time quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) at 8 weeks post-surgery. RESULTS: X-rays showed that all fractures were healed at 8 weeks post-surgery. A reproducible, mild to moderate degree of OA cartilage damage with reduced aggrecan was detected by histology in all animals in both groups but there was no significant difference between the two groups. Decreased Col-II and increased Col-X and MMP-13 levels were detected by qPCR, immunohistochemistry, ELISA and FMT from both groups cartilage. CONCLUSIONS: Malleolus articular fracture alone induces ankle OA with lesions on the central weight bearing area of the tibiotalar joint in rats. This model will provide a reproducible and useful tool for researchers to study ankle OA. PMID- 29149842 TI - Italian version of Nursing Students' Perception of Instructor Caring (I-NSPIC): assessment of reliability and validity. AB - BACKGROUND: Clinical experience is an essential component of nursing education since it provides students with the opportunity to construct and develop clinical competencies. Instructor caring is a pivotal facilitator at the forefront of clinical education, playing a key and complex educating role in clinical sectors. For these reasons the aims of this study was to assess the validity and reliability of the Italian version of NSPIC (I-NSPIC). METHODS: A validation multicentre study was conducted in three different Italian universities. A total of 333 nursing students were enrolled in the 2014/2015 academic year. Exploratory factor analysis (EFA) with oblique rotation was performed to test the construct validity of I-NSPIC. The Cronbach's alpha coefficient and test retest via Intraclass Correlation Coefficient (ICC) analyses were done to assess the internal consistency and stability of the scale. A Spearman's correlation with another scale (CLES-T) was used to examine the concurrent validities. RESULTS: Four factors (control versus flexibility, supportive learning climate, confidence through caring, appreciation of life meaning and respectful sharing) were identified in EFA. The Cronbach's alpha value showed that I-NSPIC was a reliable instrument (alpha = 0.94) and the ICC coefficient was satisfactory. CONCLUSION: The I-NSPIC is a valid instrument for assessing the perception of instructor caring in Italian nursing students. It may also prove helpful in promoting the caring ability of nursing students and in increasing the caring interactions in the relationship between instructor and nursing students. The knowledge emerged from this study provide important insight in developing effective training strategies in the clinical training of undergraduate nursing students. PMID- 29149844 TI - Use of artificial primary teeth for endodontic laboratory research: experiments related to canal length determination. AB - BACKGROUND: Due to the scarcity of exfoliated/extracted human primary teeth with complete roots, artificial teeth were developed as an alternative to be used for educational and laboratory research purposes. This study aimed to assess the feasibility of using artificial primary teeth for conducting laboratory research through an experiment related to canal length determination, comparing artificial teeth with natural teeth. METHODS: Thirty anterior and 21 posterior artificial teeth, and the same number of natural primary teeth were selected. After preparing the access cavity, the root canal length was determined by two examiners twice using three different methods: radiography and two electronic apex locators. Then, the actual root canal length was measured by inserting a K file up to the apical foramen (reference standard). Accuracy was calculated using Bland-Altman analysis and intraclass correlation coefficient (ICC). The inter- and intra-examiner reproducibility was also calculated using the ICC. RESULTS: The methods using the electronic apex locators showed better accuracy in both artificial and natural teeth. Trends observed with artificial primary teeth were similar to those observed with natural teeth, except for the results in artificial anterior teeth. CONCLUSIONS: The model of artificial teeth might be a good alternative for educational purposes; however, improvements are necessary to employ these teeth for research purposes when considering experiments for canal length determination. PMID- 29149843 TI - Characterization of a novel bioflocculant from a marine bacterium and its application in dye wastewater treatment. AB - BACKGROUND: The identification of microorganisms with excellent flocculant producing capability and optimization of the fermentation process are necessary for the wide-scale application of bioflocculants. Thus, we evaluated the flocculant-producing ability of a novel strain identified by the screening of marine bacteria, and we report for the first time the properties of the bioflocculant produced by Alteromonas sp. in the treatment of dye wastewater. RESULTS: A bioflocculant-producing bacterium was isolated from seawater and identified as Alteromonas sp. CGMCC 10612. The optimal carbon and nitrogen sources for the strain were 30 g/L glucose and 1.5 g/L wheat flour. In a 2-L fermenter, the flocculating activity and bioflocculant yield reached maximum values of 2575.4 U/mL and 11.18 g/L, respectively. The bioflocculant was separated and showed good heat and pH stability. The purified bioflocculant was a proteoglycan consisting of 69.61% carbohydrate and 21.56% protein (wt/wt). Infrared spectrometry further indicated the presence of hydroxyl, carboxyl and amino groups preferred for flocculation. The bioflocculant was a nanoparticle polymer with an average mass of 394,000 Da. The purified bioflocculant was able to remove Congo Red, Direct Black and Methylene Blue at efficiencies of 98.5%, 97.9% and 72.3% respectively. CONCLUSIONS: The results of this study indicated that the marine strain Alteromonas sp. is a good candidate for the production of a novel bioflocculant and suggested its potential industrial utility for biotechnological processes. PMID- 29149845 TI - Early nutritional programming affects liver transcriptome in diploid and triploid Atlantic salmon, Salmo salar. AB - BACKGROUND: To ensure sustainability of aquaculture, plant-based ingredients are being used in feeds to replace marine-derived products. However, plants contain secondary metabolites which can affect food intake and nutrient utilisation of fish. The application of nutritional stimuli during early development can induce long-term changes in animal physiology. Recently, we successfully used this approach to improve the utilisation of plant-based diets in diploid and triploid Atlantic salmon. In the present study we explored the molecular mechanisms occurring in the liver of salmon when challenged with a plant-based diet in order to determine the metabolic processes affected, and the effect of ploidy. RESULTS: Microarray analysis revealed that nutritional history had a major impact on the expression of genes. Key pathways of intermediary metabolism were up-regulated, including oxidative phosphorylation, pyruvate metabolism, TCA cycle, glycolysis and fatty acid metabolism. Other differentially expressed pathways affected by diet included protein processing in endoplasmic reticulum, RNA transport, endocytosis and purine metabolism. The interaction between diet and ploidy also had an effect on the hepatic transcriptome of salmon. The biological pathways with the highest number of genes affected by this interaction were related to gene transcription and translation, and cell processes such as proliferation, differentiation, communication and membrane trafficking. CONCLUSIONS: The present study revealed that nutritional programming induced changes in a large number of metabolic processes in Atlantic salmon, which may be associated with the improved fish performance and nutrient utilisation demonstrated previously. In addition, differences between diploid and triploid salmon were found, supporting recent data that indicate nutritional requirements of triploid salmon may differ from those of their diploid counterparts. PMID- 29149846 TI - The impact of bone morphology on the outcome of the pivot shift test: a cohort study. AB - BACKGROUND: The presence of a positive pivot shift after surgical repair of the ACL is considered an important indicator of a failed reconstruction. The ability to predict the result of a pivot shift test after an ACL reconstruction using variables that can be measured prior to surgery could provide an indication of which patients may be at-risk of a poor surgical outcome.The purpose of this study was to determine whether structural characteristics of the femur and tibia, measured using plain radiographs, were associated with the result of the pivot shift test in unilateral ACL reconstructed patients. METHODS: Sixteen patients who had undergone unilateral ACL reconstruction were divided into two groups based on the results of manual pivot shift testing: 1) Pivot group; and 2) No pivot group. All patients had standing true lateral radiographs of both knees. Structural measurements of the tibia and femur were made on both knees. In addition, two new variables were created to describe the tibiofemoral mismatch: 1) Femur Tibia Size Ratio (FTSR); and 2) Tibia to Posterior Femoral Condyle Ratio (TPFCR). These measures were compared within groups and between groups. RESULTS: None of the individual structural characteristics were significantly different when compared between groups. No individual structural characteristics had a significant association with the presence of a positive pivot shift. When a between-group analysis was performed, both the FTSR (p < 0.03) and the TPFCR (p < 0.01) were significantly different between the Pivot group and the No Pivot group. A larger FTSR ratio, or a larger femur relative to the tibia, was associated with a positive pivot shift. A smaller TPFCR ratio, or a smaller tibial depth relative to the depth of the lateral posterior femoral condyle, was associated with a positive pivot shift. CONCLUSIONS: Structural characteristics in the lateral femoral condyle and lateral tibial plateau were found to be associated with the presence of a positive pivot shift. These characteristics could separate between patients in the Pivot group and the No Pivot group. Two indices, the FTSR and the TPFCR, provided better predictive value than individual characteristics in identifying patients with a knee that was structurally "at risk" for developing a positive pivot shift. PMID- 29149847 TI - Individuals' explanations for their persistent or recurrent low back pain: a cross-sectional survey. AB - BACKGROUND: Most people experience low back pain (LBP), and it is often ongoing or recurrent. Contemporary research knowledge indicates individual's pain beliefs have a strong effect on their pain experience and management. This study's primary aim was to determine the discourses (patterns of thinking) underlying people's beliefs about what causes their LBP to persist. The secondary aim was to investigate what they believed was the source of this thinking. METHODS: We used a primarily qualitative survey design: 130 participants answered questions about what caused their LBP to persist, and where they learned about these causes. We analysed responses about what caused their LBP using discourse analysis (primary aim), and mixed methods involving content analysis and descriptive statistics to analyse responses indicating where participants learnt these beliefs (secondary aim). RESULTS: We found that individuals discussed persistent LBP as 1) due to the body being like a 'broken machine', 2) permanent/immutable, 3) complex, and 4) very negative. Most participants indicated that they learnt these beliefs from health professionals (116, 89%). CONCLUSIONS: We concluded that despite continuing attempts to shift pain beliefs to more complex biopsychosocial factors, most people with LBP adhere to the traditional biomedical perspective of anatomical/biomechanical causes. Relatedly, they often see their condition as very negative. Contrary to current "best practice" guidelines for LBP management, a potential consequence of such beliefs is an avoidance of physical activities, which is likely to result in increased morbidity. That health professionals may be the most pervasive source of this thinking is a cause for concern. A small number of people attributed non-physical, unknown or complex causes to their persistent LBP - indicating that other options are possible. PMID- 29149848 TI - The patterns of loss of correction after posterior wedge osteotomy in ankylosing spondylitis-related thoracolumbar kyphosis: a minimum of five-year follow-up. AB - BACKGROUND: Short-term studies have demonstrated good surgical outcomes after pedicle subtraction osteotomy (PSO) in ankylosing spondylitis (AS) patients, but there is a paucity of literature focused on middle-term results, especially regarding patterns of loss of correction. The objective of this study is to assess the durability of surgical outcomes and the patterns of loss of correction in thoracolumbar kyphosis secondary to AS following lumbar PSO with over 5-year follow-up. METHODS: We performed a retrospective review of 155 consecutive AS patients undergoing lumbar PSO from January 2001 to December 2011. Twenty-four patients were included with an average follow-up of 6.9 years (range, 5-15 years). Radiographical evaluations included global kyphosis (GK), lumbar lordosis (LL), sagittal vertical axis, spinal-sacral angle, kyphosis of proximal non-fused segments (KPNS), angle of fused segments (AFS), osteotomized vertebra angle (OVA), distal intervertebral disc wedging (DIDW) and proximal junctional angle. Meanwhile, clinical outcomes were assessed by the Oswestry disability index (ODI) and Numerical rating scale (NRS). RESULTS: The average correction per PSO segment was 34.9 degrees . Significant improvement in sagittal parameters were found postoperatively, and no obvious deterioration was noticed during the follow-up. Mild loss of correction in GK (2.82 degrees ) and LL (3.77 degrees ) were observed at the final follow-up (P < 0.05). The KPNS and DIDW increased from 26 degrees and -5.0 degrees postoperatively to 30 degrees and -2.2 degrees at the final follow-up (P < 0.05), respectively. In contrast, no significant diminishment was identified in OVA and AFS (P > 0.05). The ODI and NRS improved significantly from 20.6 and 6.6 preoperatively to 5.9 and 2.3 at the final follow up (P < 0.05). CONCLUSIONS: PSO is an effective procedure for treating AS-related thoracolumbar kyphosis and can maintain sustained surgical outcomes during the middle-term follow-up. The loss of correction was mainly attributable to non instrumented segments without fully ossified bridging syndesmophyte in the thoracolumbar region instead of instrumented levels. PMID- 29149849 TI - Biobanking in Israel 2016-17; expressed perceptions versus real life enrollment. AB - BACKGROUND: As part of the preparations to establish a population-based biobank in a large Israeli health organization, we aimed to investigate through focus groups the knowledge, perceptions and attitudes of insured Israelis, toward biobanking, and then, after input from focus groups' participants, to empirically assess the impact of a revised recruitment process on recruitment rates. METHODS: 1) Six Focus group discussions were conducted (n = 10 per group) with individuals who had routine blood laboratory tests taken in the last 2 years. 2) After addressing the issues raised in the focus groups and revising the recruitment process, individuals undergoing routine blood tests in phlebotomy clinics (N = 10,262) were invited to participate in the future biobank. RESULTS: At the outset of the focus groups there was an overall positive response to the prospect of a population-based biobank. Concerns revolved around infringement on privacy, fears of the "big brother"(e.g. insurance companies), and anxiety about inequality. Reaction to the language of the informed consent document revolved around concerns over ability to maintain anonymity, to withdraw consent, involvement of commercial entities, and the general tenor of the informed consent, which was perceived as legalistic and unilateral. In general, the longer participants were exposed to discussion about the biobank, the less likely they were to consent to sign in. Overall, only 20% (12) of the 60 participants stated they would agree to sign in by the end of the 2 hour group session. The feedback obtained from the focus groups was used in the second stage ("real life") of the study. A team of recruiters received extensive training to enable fruitful discussion and a detailed explanation to questions and concerns raised during the recruitment process. During the second stage of the study, after revising the consent form and training recruiters, a 53% consent rate was observed among 10,262 participants, more than 4 fold higher than estimated at the focus group stage. CONCLUSIONS: The qualitative focus group research helped identify important perceptions and concerns, which were subsequently addressed in the revised consent form and in the discussion the recruiters had with potential biobank donors. PMID- 29149850 TI - A cross-sectional examination of psychological distress, positive mental health and their predictors in medical students in their clinical clerkships. AB - BACKGROUND: Medical students can experience the transition from theory to clinical clerkships as stressful. Scientific literature on the mental health of clinical clerkship students is scarce and mental health is usually defined as absence of psychological distress without assessing psychological, emotional and social wellbeing, together called 'positive mental health'. This cross-sectional study examines the prevalence of psychological distress and positive mental health and explores possible predictors in a Dutch sample of clinical clerkship students. METHODS: Fourth-year medical students in their first year of clinical clerkships were invited to complete an online questionnaire assessing demographics, psychological distress (Brief Symptom Inventory), positive mental health (Mental Health Continuum- SF), dysfunctional cognitions (Irrational Beliefs Inventory) and dispositional mindfulness skills (Five Facet Mindfulness Questionnaire). Multiple linear regression analysis was used to explore relationships between psychological distress, positive mental health (dependent variables) and demographics, dysfunctional cognitions and dispositional mindfulness skills (predictors). RESULTS: Of 454 eligible students, 406 (89%) completed the assessment of whom 21% scored in the clinical range of psychological distress and 41% reported a flourishing mental health. These proportions partially overlap each other. Female students reported a significantly higher mean level of psychological distress than males. In the regression analysis the strongest predictors of psychological distress were 'acting with awareness' (negative) and 'worrying' (positive). Strongest predictors of positive mental health were 'problem avoidance' (negative) and 'emotional irresponsibility' (negative). CONCLUSIONS: The prevalence of psychopathology in our sample of Dutch clinical clerkship students is slightly higher than in the general population. Our results support conclusions of previous research that psychological distress and positive mental health are not two ends of one continuum but partially overlap. Although no conclusion on causality can be drawn, this study supports the idea that self-awareness and active, nonavoidant coping strategies are related to lower distress and higher positive mental health. PMID- 29149851 TI - Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness. AB - BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of alpha-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of alpha glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants. RESULTS: A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c. 13 T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease. CONCLUSIONS: Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders. PMID- 29149852 TI - Access to health care for persons with disabilities in rural South Africa. AB - BACKGROUND: Global research suggests that persons with disabilities face barriers when accessing health care services. Yet, information regarding the nature of these barriers, especially in low-income and middle-income countries is sparse. Rural contexts in these countries may present greater barriers than urban contexts, but little is known about access issues in such contexts. There is a paucity of research in South Africa looking at "triple vulnerability" - poverty, disability and rurality. This study explored issues of access to health care for persons with disabilities in an impoverished rural area in South Africa. METHODS: The study includes a quantitative survey with interviews with 773 participants in 527 households. Comparisons in terms of access to health care between persons with disabilities and persons with no disabilities were explored. The approach to data analysis included quantitative data analysis using descriptive and inferential statistics. Frequency and cross tabulation, comparing and contrasting the frequency of different phenomena between persons with disabilities and persons with no disabilities, were used. Chi-square tests and Analysis of Variance tests were then incorporated into the analysis. RESULTS: Persons with disabilities have a higher rate of unmet health needs as compared to non disabled. In rural Madwaleni in South Africa, persons with disabilities faced significantly more barriers to accessing health care compared to persons without disabilities. Barriers increased with disability severity and was reduced with increasing level of education, living in a household without disabled members and with age. CONCLUSIONS: This study has shown that access to health care in a rural area in South Africa for persons with disabilities is more of an issue than for persons without disabilities in that they face more barriers. Implications are that we need to look beyond the medical issues of disability and address social and inclusion issues as well. PMID- 29149853 TI - Cost of delivering health care services at primary health facilities in Ghana. AB - BACKGROUND: There is limited knowledge on the cost of delivering health services at primary health care facilities in Ghana which is posing a challenge in resource allocations. This study therefore estimated the cost of providing health care in primary health care facilities such as Health Centres (HCs) and Community based Health Planning and Services (CHPS) in Ghana. METHODS: The study was cross sectional and quantitative data was collected from the health provider perspective. Data was collected between July and August, 2016 at nine primary health facilities (six CHPS and three HCs) from the Upper West region of Ghana. All health related costs for the year 2015 and revenue generated for the period were collected. Data were captured and analysed using Microsoft excel. Costs of delivery health services were estimated. In addition, unit costs such as cost per Outpatient Department (OPD) attendance were estimated. RESULTS: The average annual cost of delivering health services through CHPS and HCs was US$10,923 and US$44,638 respectively. Personnel cost accounted for the largest proportion of cost (61% for CHPS and 59% for HC). The cost per OPD attendance was higher at CHPS (US$8.79) than at HCs (US$5.16). The average Internally Generated Funds (IGF) recorded for the period at CHPS and HCs were US$2327 and US$ 15,795 respectively. At all the facilities, IGFs were greatly lower than costs of running the health facilities. Also, at both the CHPS and HCs, the National Health Insurance Scheme (NHIS) reimbursement was the main source of revenue accounting for over 90% total IGF. CONCLUSIONS: The average annual cost of delivering primary health services through CHPS and HCs is US$10,923 and US$44,638 respectively and personnel cost accounts for the major cost. The government should be guided by these findings in their financial planning, decision making and resource allocation in order to improve primary health care in the country. However, more similar studies involving large numbers of primary health facilities in different parts of the country are needed to assess the cost of providing primary health care. PMID- 29149854 TI - Cardiac arrest in a toddler treated with propranolol for infantile Hemangioma: a case report. AB - BACKGROUND: Propranolol has become the first-line treatment for complicated Infantile Hemangioma (IH), showing so far a good risk-benefit profile. CASE PRESENTATION: We report the case of a toddler, on propranolol, who suffered cardiac arrest during an acute viral infection. She had a neurally-mediated syncope that progressed to asystole, probably because of concurrent factors as dehydration, beta-blocking and probably individual susceptibility to vaso-vagal phenomena. In fact a significant history of breath-holding spells was consistent with vagal hyperactivity. CONCLUSIONS: The number of patients treated with propranolol for IHs will increase and sharing experience will help to better define the safety profile of this drug. PMID- 29149856 TI - Naukan ethnobotany in post-Soviet times: lost edibles and new medicinals. AB - BACKGROUND: This study focuses on health-related plant use among speakers of the critically endangered Naukan language (Inuit-Yupik-Unangan family) in the Russian Far East. The Naukan people were forced, in 1958, under Soviet consolidation, to move from their original settlement on Cape Dezhnev, leading to significant changes in spiritual worldview, subsistence, social structure, and language proficiency in the years that followed. Here, we focus on changes that elders report in their edible, medicinal, and spiritual uses of local plant species since their childhood. METHODS: The authors worked from 2014 to 2016 in the villages of Lavrentiya, Lorino, and Uelen, in the Chukotskiy district of the Chukotka autonomous region, directly adjacent to the Bering Strait. We conducted structured interviews, using an oral history approach, along with participant observation and collection of voucher specimens from the local arctic tundra. Those with Naukan names and uses represent 42 species in 25 families. RESULTS: Participants reported a decrease of 13% in the number of edible species that people currently harvest, from what they recall harvesting in their youth. On the other hand, the number of local species considered to be medicinal has actually increased by 225%. Current and past Naukan medicinal practices diverge in some notable ways from those of neighboring societies on the Alaskan side of the Bering Strait. Most of the spiritual significance of local plants species is remembered by only a few elders. CONCLUSIONS: Naukan elders explained the large increase in use of medicinal plants by noting that their original concept of medicine emphasized prevention and that illnesses were often assigned a spiritual rather than physical cause. Increased integration with ethnic Russians after moving from Naukan led to the adoption not only of new plant uses, but also of an entirely different, more naturalistic way of viewing illness and treatment. PMID- 29149855 TI - Increasing upper limb training intensity in chronic stroke using embodied virtual reality: a pilot study. AB - BACKGROUND: Technology-mediated neurorehabilitation is suggested to enhance training intensity and therefore functional gains. Here, we used a novel virtual reality (VR) system for task-specific upper extremity training after stroke. The system offers interactive exercises integrating motor priming techniques and embodied visuomotor feedback. In this pilot study, we examined (i) rehabilitation dose and training intensity, (ii) functional improvements, and (iii) safety and tolerance when exposed to intensive VR rehabilitation. METHODS: Ten outpatient stroke survivors with chronic (>6 months) upper extremity paresis participated in a ten-session VR-based upper limb rehabilitation program (2 sessions/week). RESULTS: All participants completed all sessions of the treatment. In total, they received a median of 403 min of upper limb therapy, with 290 min of effective training. Within that time, participants performed a median of 4713 goal-directed movements. Importantly, training intensity increased progressively across sessions from 13.2 to 17.3 movements per minute. Clinical measures show that despite being in the chronic phase, where recovery potential is thought to be limited, participants showed a median improvement rate of 5.3% in motor function (Fugl-Meyer Assessment for Upper Extremity; FMA-UE) post intervention compared to baseline, and of 15.4% at one-month follow-up. For three of them, this improvement was clinically significant. A significant improvement in shoulder active range of motion (AROM) was also observed at follow-up. Participants reported very low levels of pain, stress and fatigue following each session of training, indicating that the intensive VR intervention was well tolerated. No severe adverse events were reported. All participants expressed their interest in continuing the intervention at the hospital or even at home, suggesting high levels of adherence and motivation for the provided intervention. CONCLUSIONS: This pilot study showed how a dedicated VR system could deliver high rehabilitation doses and, importantly, intensive training in chronic stroke survivors. FMA-UE and AROM results suggest that task-specific VR training may be beneficial for further functional recovery both in the chronic stage of stroke. Longitudinal studies with higher doses and sample sizes are required to confirm the therapy effectiveness. TRIAL REGISTRATION: This trial was retrospectively registered at ClinicalTrials.gov database (registration number NCT03094650 ) on 14 March 2017. PMID- 29149857 TI - Putative progressive and abortive feline leukemia virus infection outcomes in captive jaguarundis (Puma yagouaroundi). AB - BACKGROUND: Feline leukemia virus (FeLV) is an exogenous gammaretrovirus of domestic cats (Felis catus) and some wild felids. The outcomes of FeLV infection in domestic cats vary according to host susceptibility, virus strain, and infectious challenge dose. Jaguarundis (Puma yagouaroundi) are small wild felids from South and Central America. We previously reported on FeLV infections in jaguarundis. We hypothesized here that the outcomes of FeLV infection in P. yagouaroundi mimic those observed in domestic cats. The aim of this study was to investigate the population of jaguarundis at Fundacao Parque Zoologico de Sao Paulo for natural FeLV infection and resulting outcomes. METHODS: We investigated the jaguarundis using serological and molecular methods and monitored them for FeLV-related diseases for 5 years. We retrieved relevant biological and clinical information for the entire population of 23 jaguarundis held at zoo. Post-mortem findings from necropsies were recorded and histopathological and immunohistopathological analyses were performed. Sequencing and phylogenetic analyses were performed for FeLV-positive samples. For sample prevalence, 95% confidence intervals (CI) were calculated. Fisher's exact test was used to compare frequencies between infected and uninfected animals. P-values <0.05 were considered significant. RESULTS: In total, we detected evidence of FeLV exposure in four out of 23 animals (17%; 95% CI 5-39%). No endogenous FeLV (enFeLV) sequences were detected. An intestinal B-cell lymphoma in one jaguarundi was not associated with FeLV. Two jaguarundis presented FeLV test results consistent with an abortive FeLV infection with seroconversion, and two other jaguarundis had results consistent with a progressive infection and potentially FeLV-associated clinical disorders and post-mortem changes. Phylogenetic analysis of env revealed the presence of FeLV-A, a common origin of the virus in both animals (100% identity) and the closest similarity to FeLV-FAIDS and FeLV-3281 (98.4% identity), originally isolated from cats in the USA. CONCLUSIONS: We found evidence of progressive and abortive FeLV infection outcomes in jaguarundis, and domestic cats were probably the source of infection in these jaguarundis. PMID- 29149858 TI - Famine food of vegetal origin consumed in the Netherlands during World War II. AB - BACKGROUND: Periods of extreme food shortages during war force people to eat food that they normally do not consider edible. The last time that countries in Western Europe experienced severe scarcities was during World War II. The so called Dutch famine or Hunger Winter (1944-1945) made at least 25,000 victims. The Dutch government took action by opening soup kitchens and providing information on wild plants and other famine food sources in "wartime cookbooks." The Dutch wartime diet has never been examined from an ethnobotanical perspective. METHODS: We interviewed 78 elderly Dutch citizens to verify what they remembered of the consumption of vegetal and fungal famine food during World War II by them and their close surroundings. We asked whether they experienced any adverse effects from consuming famine food plants and how they knew they were edible. We identified plant species mentioned during interviews by their local Dutch names and illustrated field guides and floras. We hypothesized that people living in rural areas consumed more wild species than urban people. A Welch t test was performed to verify whether the number of wild and cultivated species differed between urban and rural citizens. RESULTS: A total number of 38 emergency food species (14 cultivated and 21 wild plants, three wild fungi) were mentioned during interviews. Sugar beets, tulip bulbs, and potato peels were most frequently consumed. Regularly eaten wild species were common nettle, blackberry, and beechnuts. Almost one third of our interviewees explicitly described to have experienced extreme hunger during the war. People from rural areas listed significantly more wild species than urban people. The number of cultivated species consumed by both groups was similar. Negative effects were limited to sore throats and stomachache from the consumption of sugar beets and tulip bulbs. Knowledge on the edibility of famine food was obtained largely by oral transmission; few people remembered the written recipes in wartime cookbooks. CONCLUSION: This research shows that 71 years after the Second World War, knowledge on famine food species, once crucial for people's survival, is still present in the Dutch society. The information on famine food sources supplied by several institutions was not distributed widely. For the necessary revival of famine food knowledge during the 1940s, people needed to consult a small group of elders. Presumed toxicity was a major reason given by our participants to explain why they did not collect wild plants or mushrooms during the war. PMID- 29149859 TI - Medicinal plants used by women in Mecca: urban, Muslim and gendered knowledge. AB - BACKGROUND: This study explores medicinal plant knowledge and use among Muslim women in the city of Mecca, Saudi Arabia. Ethnobotanical research in the region has focused on rural populations and male herbal healers in cities, and based on these few studies, it is suggested that medicinal plant knowledge may be eroding. Here, we document lay, female knowledge of medicinal plants in an urban centre, interpreting findings in the light of the growing field of urban ethnobotany and gendered knowledge and in an Islamic context. METHODS: Free-listing, structured and semi-structured interviews were used to document the extent of medicinal plant knowledge among 32 Meccan women. Vernacular names, modes of preparation and application, intended therapeutic use and emic toxicological remarks were recorded. Women were asked where they learnt about medicinal plants and if and when they preferred using medicinal plants over biomedical resources. Prior informed consent was always obtained. We compared the list of medicinal plants used by these Meccan women with medicinal plants previously documented in published literature. RESULTS: One hundred eighteen vernacular names were collected, corresponding to approximately 110 plants, including one algae. Of these, 95 were identified at the species level and 39 (41%) had not been previously cited in Saudi Arabian medicinal plant literature. Almost one half of the plants cited are food and flavouring plants. Meccan women interviewed learn about medicinal plants from their social network, mass media and written sources, and combine biomedical and medicinal plant health care. However, younger women more often prefer biomedical resources and learn from written sources and mass media. CONCLUSIONS: The fairly small number of interviews conducted in this study was sufficient to reveal the singular body of medicinal plant knowledge held by women in Mecca and applied to treat common ailments. Plant availability in local shops and markets and inclusion in religious texts seem to shape the botanical diversity used by the Meccan women interviewed, and the use of foods and spices medicinally could be a global feature of urban ethnobotany. Ethnobotanical knowledge among women in Islamic communities may be changing due to access to mass media and biomedicine. We recognise the lack of documentation of the diversity of medicinal plant knowledge in the Arabian Peninsula and an opportunity to better understand gendered urban and rural knowledge. PMID- 29149860 TI - Anaphylactic shock with methylprednisolone sodium succinate in a child with short bowel syndrome and cow's milk allergy. AB - BACKGROUND: Medications with methyl-prednisolone sodium succinate containing lactose, which potentially contains traces of cow's milk proteins (CMP), could cause allergic reactions or compromise treatment of acute allergic reactions in sensitized patients. CASE PRESENTATION: We describe the unusual case of a one year-old child affected by short bowel syndrome and history of severe cow's milk allergy (CMA) and anaphylactic reaction due to intravenous administration of methyl-prednisolone sodium succinate (Solu-Medrol 40 mg, Pfizer). He was admitted to our hospital for severe respiratory failure and was initially treated with methyl-prednisolone (Urbason 40 mg, Sanofi Aventis), then with methyl prednisolone sodium succinate (Solu-Medrol 40 mg, Pfizer). After the intravenous administration of second steroid, immediate anaphylaxis was recorded and treatment was stopped. Antihistamine and epinephrine were required and symptom resolution occurred. CONCLUSION: Children who are highly sensitive to milk may have severe allergic reactions also after exposure to CMP through a different administration route than the oral one. Patients who have food allergies need to pay particular attention to the prescription of drugs and their formulation. PMID- 29149861 TI - Weekend effect: a great problem with a potential solution. PMID- 29149862 TI - Telemedicine as an effective intervention to improve antibiotic appropriateness prescription and to reduce costs in pediatrics. AB - Implementation of antimicrobial stewardship program is a pivotal practice element for healthcare institution. We developed a remote infectious disease consultancy program via telemedicine in a high-specialized pediatric cardiac hospital. A consultation for antibiotic strategy for each patient was available via telemedicine in addition to biweekly discussion of all clinical cases. Aim of this study was to evaluate the impact of the remote stewardship program in terms of a) appropriateness of antibiotic prescription; b) incidence of multi-resistant infection; and c) cost. A 'before - after' study was performed comparing the period immediately before starting the program and one year after. There was a trend in the reduction of nosocomial infectious disease rate (9.5 vs 6.5 per 1000 person days), with a reduction in the overall antibiotic cost (25,000 vs 15,000 EUR) and in the average antibiotics packages used per admission (9 vs 6.7 packages). A significant reduction in the multi-drug resistant isolation rate was observed (104 vs 79 per 1000 person days, p = 0.01). In conclusion, the infectious disease meeting via telemedicine has been an effective tool for economic and professional development and multidisciplinary management of complex patients. The appropriate use of antibiotics reduced the multi-drug resistant bacteria selection, thus improving patient safety. PMID- 29149863 TI - Pearls and pitfalls in comprehensive critical care echocardiography. AB - Critical care echocardiography is developing rapidly with an increasing number of specialists now performing comprehensive studies using Doppler and other advanced techniques. However, this imaging can be challenging, interpretation is far from simple in the complex critically ill patient and mistakes can be easy to make. We aim to address clinically relevant areas where potential errors may occur and suggest methods to hopefully improve accuracy of imaging and interpretation. PMID- 29149864 TI - Kinetic estimated glomerular filtration rate in critically ill patients: beyond the acute kidney injury severity classification system. AB - BACKGROUND: Although significant advances have been achieved in acute kidney injury (AKI) research following its classification, potential pitfalls can be identified in clinical practice. The nonsteady-state (kinetic) estimated glomerular filtration rate (KeGFR) could add clinical and prognostic information in critically ill patients beyond the current AKI classification system. METHODS: This was a retrospective analysis using data from the Multiparameter Intelligent Monitoring in Intensive Care II project. The KeGFR was calculated during the first 7 days of intensive care unit (ICU) stay in 13,284 patients and was correlated with outcomes. RESULTS: In general, there was not a good agreement between AKI severity and the worst achieved KeGFR. The stepwise reduction in the worst achieved KeGFR conferred an incremental risk of death, rising from 7.0% (KeGFR > 70 ml/min/1.73 m2) to 27.8% (KeGFR < 30 ml/min/1.73 m2). This stepwise increment in mortality remained in each AKI severity stage. For example, patients with AKI stage 3 who maintained KeGFR had a mortality rate of 16.5%, close to those patients with KeGFR < 30 ml/min/1.73 m2 but no AKI; otherwise, mortality increased to 40% when both AKI stage 3 and KeGFR < 30 ml/min/1.73 m2 were present. In relation to another outcome-renal replacement therapy (RRT)-patients with the worst achieved KeGFR < 30 ml/min/1.73 m2 and KDIGO stage 1/2 had a rate of RRT of less than 10%. However, this rate was 44% when both AKI stage 3 and a worst KeGFR < 30 ml/min/1.73 m2 were observed. This interaction between AKI and KeGFR was also present when looking at long-term survival. CONCLUSION: Both the AKI classification system and KeGFR are complementary to each other. Assessing both AKI stage and KeGFR can help to identify patients at different risk levels in clinical practice. PMID- 29149865 TI - Cytoreductive surgery and Hyperthermic intra-operative peritoneal chemotherapy with Cisplatin for gastric peritoneal Carcinomatosis Monocentric phase-2 nonrandomized prospective clinical trial. AB - BACKGROUND: Cytoreductive surgery (CRS) plus hyperthermic intra-operative peritoneal chemotherapy (HIPC) for gastric peritoneal carcinomatosis (PC) is controversial, and selection criteria for this treatment modality are lacking. METHODS: Thirty-two patients (F/M ratio 12/20; median (range) age 58 (32-75) years) underwent CRS + HIPC with cisplatin for PC from gastric adenocarcinoma in 2010-2014. This monocentric phase-2 nonrandomized prospective study with a power of 90% aimed to improve the 1-year overall survival (OS) rate with 40% (historical reference of 52% to 72%). Median PCI score was 8 (range 1-20), number of regions involved was 6 (range 1-11). The impact of 16 prognostic factors on survival was evaluated using univariable and multivariable Cox regression models. Follow-up was complete in all patients, and closed 2 years after patient inclusion. RESULTS: All patients had complete cytoreduction (CCR-0) and histopathological R0 resection. PCI 7-unit scale). CONCLUSIONS: The Envisia test demonstrates the robust analytical performance required of an LDT. Envisia can be used to inform the diagnoses of patients with suspected IPF. PMID- 29149881 TI - How effective are interventions to improve social outcomes among offenders with personality disorder: a systematic review. AB - BACKGROUND: Offenders with personality disorder are supported by health, criminal justice, social care and third sector services. These services are tasked with reducing risk, improving health and improving social outcomes. Research has been conducted into interventions that reduce risk or improve health. However, interventions to improve social outcomes are less clearly defined. METHODS: To review the effectiveness of interventions to improve social outcomes we conducted a systematic review using Cochrane methodology, expanded to include non randomised trials. Anticipated high heterogeneity of the studies informed narrative synthesis. RESULTS: Eleven studies met inclusion criteria. Five contained extractable data. No high-quality studies were identified. Outcomes measured clustered around employment and social functioning. Interventions vary and their mechanisms for influencing social outcomes are poorly operationalised. Although change was observed in employment rates, there was no evidence for the effectiveness of these interventions. CONCLUSIONS: There is a lack of evidence for effective interventions that improve social outcomes. Further research is recommended to reach consensus on the outcomes of importance, identify the factors that influence these and design theoretically-informed and evidence-based interventions. PMID- 29149882 TI - Cost-effectiveness analysis of the introduction of S-1 therapy for first-line metastatic breast cancer treatment in Japan: results from the randomized phase III SELECT BC trial. AB - BACKGROUND: This study evaluated the cost-effectiveness of replacing standard intravenous therapy (taxane) with oral S-1 therapy for first-line metastatic breast cancer treatment. METHODS: This cost-effectiveness analysis was based on data from a randomized phase III trial (SELECT BC). As cost-effectiveness was a secondary endpoint of the SELECT BC trial, some of the randomized patients participated in an EQ-5D survey (N = 391) and health economic survey (N = 146). The EQ-5D responses, claims, and prescription data were collected for as long as possible until death. The expected quality-adjusted life years (QALY) obtained from each treatment were calculated using patient-level EQ-5D data, and the expected cost was calculated using patient-level claim data. The analysis was performed from the perspective of public healthcare payers. RESULTS: The estimated EQ-5D least-square means and 95% CI up to 48 months were 0.764 (95% CI, 0.741-0.782) and 0.742 (95% CI, 0.720-0.764) in the S-1 and taxane arms, respectively. The expected QALY was 2.11 for the S-1 arm and 2.04 for the taxane arm, with expected costs of JPY 5.13 million (USD 46,600) and JPY 5.56 million (USD 50,500), respectively. These results show that S-1 is cost-saving. According to probabilistic sensitivity analysis, S-1 was dominant with a probability of 63%. When the willingness to pay (WTP) value was JPY 5 million (USD 45,500) per QALY, the probability of being cost-effective was 92%. CONCLUSIONS: Our results show that the introduction of oral S-1 therapy for metastatic breast cancer is highly likely to be cost-effective. TRIAL REGISTRATION: UMIN CTR C000000416 . Registered on May 10, 2006. PMID- 29149883 TI - Serum concentrations of Krebs von den Lungen-6, surfactant protein D, and matrix metalloproteinase-2 as diagnostic biomarkers in patients with asbestosis and silicosis: a case-control study. AB - BACKGROUND: Asbestosis and silicosis are progressive pneumoconioses characterized by interstitial fibrosis following exposure to asbestos or silica dust. We evaluated the potential diagnostic biomarkers for these diseases. METHODS: The serum concentrations of Krebs von den Lungen-6 (KL-6), surfactant protein D (SP D), and matrix metalloproteinase-2 (MMP-2), MMP-7, and MMP-9 were measured in 43 patients with asbestosis, 45 patients with silicosis, 40 dust-exposed workers (DEWs) without pneumoconiosis, and 45 healthy controls (HCs). Chest high resolution computed tomography (HRCT) images were reviewed by experts blinded to the clinical data. According to the receiver operating characteristic (ROC) curve, the ideal level of each biomarker and its diagnostic sensitivity were obtained. RESULTS: The serum KL-6 and MMP-2 concentrations were highest in patients with asbestosis, particularly in comparison with those in DEWs and HCs (P<0.05). The serum SP-D concentration was significantly higher in patients with asbestosis than in patients with silicosis, DEWs, and HCs (P<0.01), whereas no significant difference was noted among patients with silicosis, DEWs, and HCs. No significant difference in the serum MMP-7 or -9 concentration was found among patients with asbestosis, patients with silicosis, DEWs, or HCs. Among patients with asbestosis, the serum KL-6 concentration was significantly correlated with the lung fibrosis scores on HRCT and negatively correlated with the forced vital capacity (FVC) % predicted and diffusing capacity of the lung for carbon monoxide (DLCO) % predicted. The serum SP-D and MMP-2 concentrations were negatively correlated with the DLCO % predicted (all P<0.05). The order of diagnostic accuracy according to the ROC curve was KL-6, SP-D, and MMP-2 in patients with asbestosis alone and in the combination of both patients with asbestosis and those with silicosis. The combination of all three biomarkers may increase the possibility of diagnosing asbestosis (sensitivity, 93%; specificity, 57%) and both asbestosis and silicosis (sensitivity, 83%; specificity, 62%). CONCLUSIONS: KL-6, SP-D, and MMP-2 are available biomarkers for the adjuvant diagnosis of asbestosis and silicosis. The combination of all three biomarkers may improve the diagnostic sensitivity for asbestosis and silicosis. PMID- 29149884 TI - Predictors of early-onset post-ischemic stroke depression: a cross-sectional study. AB - BACKGROUND: Post-stroke depression (PSD) seriously affects the rehabilitation of nerve function and quality of life. However, the pathogenesis of PSD is still not clear. This study aimed to investigate the demographic, clinical, and biochemical factors in patients with PSD. METHODS: Patients with an acute ischemic stroke, who met the inclusion criteria at Shanghai Tenth People's Hospital from April 2016 to September 2016, were recruited for this study. The stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), and the mental state was assessed using Mini-Mental State Examination (MMSE), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA) at 1 week of admission. The patients were divided into PSD and non-PSD groups. The demographic and clinical characteristics, as well as the biochemical factors, were compared between the two groups. A logistic regression analysis was performed to identify the risk factors for depression following stroke. RESULTS: A total of 83 patients with acute ischemic stroke were recruited. Of these, 36 (43.4%) developed depression. The multivariate logistic regression analysis indicated that high NIHSS [odds ratio (OR): 1.84, 95% confidence interval (CI): 1.09-3.12, P = 0.023] and high HAMD scores (OR: 2.38, 95% CI: 1.61-3.50, P < 0.001) were independent risk predictors for PSD and so were lower dopamine level (OR: 0.64, 95% CI: 0.45 0.91, P = 0.014), lower 5-hydroxytryptamine level (OR: 0.99, 95% CI: 0.98-1.00, P = 0.046), higher tumor necrosis factor-alpha level (OR: 1.05, 95% CI: 1.00-1.09, P = 0.044), and lower nerve growth factor level (OR: 0.06, 95% CI: 0.01-0.67, P = 0.022). CONCLUSIONS: The identification of higher NIHSS scores, higher HAMD scores, lower dopamine level, lower 5-hydroxytryptamine level, higher tumor necrosis factor-alpha level, and lower nerve growth factor level might be useful for clinicians in recognizing and treating depression in patients after a stroke. PMID- 29149885 TI - Setting the pace: insights and advancements gained while preparing for an FES bike race. AB - The reduction in physical activity following a spinal cord injury often leads to a decline in mental and physical health. Developing an exercise program that is effective and enjoyable is paramount for this population. Although functional electrical stimulation (FES) stationary cycling has been utilized in rehabilitation settings, implementing an overground cycling program for those with spinal cord injuries has greater technical challenges. Recently our laboratory team focused on training five individuals with compete spinal cord injuries utilizing an implanted pulse generator for an overground FES bike race in CYBATHLON 2016 held in Zurich, Switzerland. The advancements in muscle strength and endurance and ultimately cycling power our pilots made during this training period not only helped propel our competing pilot to win gold at the CYBATHLON 2016, but allowed our pilots to ride their bikes outside within their communities. Such a positive outcome has encouraged us to put effort into developing more widespread use of FES overground cycling as a rehabilitative tool for those with spinal cord injuries. This commentary will describe our approach to the CYBATHLON 2016 including technological advancements, bike design and the training program. PMID- 29149886 TI - Antibiotic susceptibility profiles of Mycoplasma synoviae strains originating from Central and Eastern Europe. AB - BACKGROUND: Mycoplasma synoviae causes infectious synovitis and respiratory diseases in chickens and turkeys and may lead to egg shell apex abnormalities in chickens; hence possesses high economic impact on the poultry industry. Control of the disease consists of eradication, vaccination or medication. The aim of the present study was to determine the in vitro susceptibility to 14 different antibiotics and an antibiotic combination of M. synoviae strains originating from Hungary and other countries of Central and Eastern Europe. RESULTS: Minimal inhibitory concentration (MIC) values of a total of 41 M. synoviae strains were determined by the microbroth dilution method. The strains were collected between 2002 and 2016 and originated from Hungary (n = 26), Austria (n = 3), the Czech Republic (n = 3), Slovenia (n = 3), Ukraine (n = 3), Russia (n = 2) and Serbia (n = 1). Tetracyclines (with MIC50 values of 0.078 MUg/ml, <=0.25 MUg/ml and 0.5 MUg/ml for doxycycline, oxytetracycline and chlortetracycline, respectively), macrolides (with MIC50 values of <=0.25 MUg/ml for tylvalosin, tylosin and tilmicosin), pleuromutilins (with MIC50 values of 0.078 MUg/ml and <=0.039 MUg/ml for tiamulin and valnemulin) and the combination of lincomycin and spectinomycin (MIC50 1 MUg/ml (0.333/0.667 MUg/ml)) were found to be the most effective antibiotic agents against M. synoviae in vitro. High MIC values were detected in numerous strains for fluoroquinolones (with MIC50 values of 1.25 MUg/ml and 2.5 MUg/ml for enrofloxacin and difloxacin), neomycin (MIC50 32 MUg/ml), spectinomycin (MIC50 2 MUg/ml), lincomycin (MIC50 0.5 MUg/ml) and florfenicol (MIC50 4 MUg/ml). Nevertheless, strains with elevated MIC values were detected for most of the applied antibiotics. CONCLUSIONS: In the medical control of M. synoviae infections the preliminary in vitro antibiotic susceptibility testing and the careful evaluation of the data are crucial. Based on the in vitro examinations doxycycline, oxytetracycline, tylvalosin, tylosin and pleuromutilins could be recommended for the therapy of M. synoviae infections in the region. PMID- 29149888 TI - Correction to: Analysis of plasma multiplex cytokines and increased level of IL 10 and IL-1Ra cytokines in febrile seizures. AB - After publication of the article [1], it has been brought to our attention that several of the authors' names were formatted incorrectly in the original version of the article. The corrections are listed below -"Byungok Kwak" should be "Byung Ok Kwak""Soojin Kim" should be "Soo-Jin Kim""Sunwhan Bae" should be "Sun Whan Bae""Jaesung Son" should be "Jae Sung Son""Soonyung Kim" should be "Soo-Nyung Kim"The original version of the article has now been revised. PMID- 29149887 TI - Prostate cancer in firefighting and police work: a systematic review and meta analysis of epidemiologic studies. AB - OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate potential associations between firefighting and police occupations, and prostate cancer incidence and mortality. METHODS: Original epidemiological studies published from 1980 to 2017 were identified through PubMed and Web of Science. Studies were included if they contained specific job titles for ever/never firefighting and police work and associated prostate cancer risk estimates with 95% confidence intervals (CI). Study quality was assessed using a 20-point checklist. Prostate cancer meta-risk estimates (mRE) and corresponding 95% CIs were calculated for firefighting and police work separately and by various study characteristics using random effects models. Between-study heterogeneity was evaluated using the I2 score. Publication bias was assessed using Begg's and Egger's tests. RESULTS: A total of 26 firefighter and 12 police studies were included in the meta-analysis, with quality assessment scores ranging from 7 to 19 points. For firefighter studies, the prostate cancer incidence mRE was 1.17 (95% CI = 1.08-1.28, I2 = 72%) and the mortality mRE was 1.12 (95% CI = 0.92 1.36, I2 = 50%). The mRE for police incidence studies was 1.14 (95% CI = 1.02 1.28; I2 = 33%); for mortality studies, the mRE was 1.08 (95% CI = 0.80-1.45; I2 = 0%). By study design, mREs for both firefighter and police studies were similar to estimates of incidence and mortality. CONCLUSION: Small excess risks of prostate cancer were observed from firefighter studies with moderate to substantial heterogeneity and a relatively small number of police studies, respectively. There is a need for further studies to examine police occupations and to assess unique and shared exposures in firefighting and police work. PMID- 29149889 TI - Electronic cigarette vapor alters the lateral structure but not tensiometric properties of calf lung surfactant. AB - BACKGROUND: Despite their growing popularity, the potential respiratory toxicity of electronic cigarettes (e-cigarettes) remains largely unknown. One potential aspect of e-cigarette toxicity is the effect of e-cigarette vapor on lung surfactant function. Lung surfactant is a mixture of lipids and proteins that lines the alveolar region. The surfactant layer reduces the surface tension of the alveolar fluid, thereby playing a crucial role in lung stability. Due to their small size, particulates in e-cigarette vapor can penetrate the deep lungs and come into contact with the lung surfactant. The current study sought to examine the potential adverse effects of e-cigarette vapor and conventional cigarette smoke on lung surfactant interfacial properties. METHODS: Infasurf(r), a clinically used and commercially available calf lung surfactant extract, was used as lung surfactant model. Infasurf(r) films were spread on top of an aqueous subphase in a Langmuir trough with smoke particulates from conventional cigarettes or vapor from different flavors of e-cigarettes dispersed in the subphase. Surfactant interfacial properties were measured in real-time upon surface compression while surfactant lateral structure after exposure to smoke or vapor was examined using atomic force microscopy (AFM). RESULTS: E-cigarette vapor regardless of the dose and flavoring of the e-liquid did not affect surfactant interfacial properties. In contrast, smoke from conventional cigarettes had a drastic, dose-dependent effect on Infasurf(r) interfacial properties reducing the maximum surface pressure from 65.1 +/- 0.2 mN/m to 46.1 +/- 1.3 mN/m at the highest dose. Cigarette smoke and e-cigarette vapor both altered surfactant microstructure resulting in an increase in the area of lipid multilayers. Studies with individual smoke components revealed that tar was the smoke component most disruptive to surfactant function. CONCLUSIONS: While both e cigarette vapor and conventional cigarette smoke affect surfactant lateral structure, only cigarette smoke disrupts surfactant interfacial properties. The surfactant inhibitory compound in conventional cigarettes is tar, which is a product of burning and is thus absent in e-cigarette vapor. PMID- 29149890 TI - Physical activity and calorie intake mediate the relationship from depression to body fat mass among female Mexican health workers. AB - BACKGROUND: Depression is a foremost cause of morbidity throughout the world and the prevalence of depression in women is about twice as high as men. Additionally, overweight and obesity are major global health concerns. We explored the relationship between depression and body fat, and the role of physical activity and diet as mediators of this relationship in a sample of 456 adult female Mexican health workers. METHOD: Longitudinal and cross-sectional analyses using data from adult women of the Health Workers Cohort Study (HWCS) Measures of body fat mass (kg from DEXA), dietary intake (kcal from FFQ), leisure time activity (METs/wk) and depression (CES-D) were determined in two waves (2004 2006 and 2010-2011). We explored the interrelation between body fat, diet, leisure time, physical activity, and depression using a cross-lagged effects model fitted to longitudinal data. We also fitted a structural equations model to cross-sectional data with body fat as the main outcome, and dietary intake and physical activity from leisure time as mediators between depression and body fat. RESULTS: Baseline depression was significantly related to higher depression, higher calorie intake, and lower leisure time physical activity at follow-up. From our cross-sectional model, each standard deviation increase in the depression score was associated with an average increase of 751 +/- 259 g (+/- standard error) in body fat through the mediating effects of calorie intake and physical activity. CONCLUSIONS: The results of this study show how depression may influence energy imbalance between calories consumed and calories expended, resulting in higher body fat among those with a greater depression score. Evaluating the role of mental conditions like depression in dietary and physical activity behaviors should be positioned as a key research goal for better designed and targeted public health interventions. TRIAL REGISTRATION: The HealthWorkers Cohort Study (HWCS) has been approved by the Institutional IRB. Number: 2005-785-012. PMID- 29149891 TI - How do occupational rehabilitation clinicians approach participants on long-term sick leave in order to facilitate return to work? A focus group study. AB - BACKGROUND: The objective of this study was to explore occupational rehabilitation clinicians' experiences on how to approach their participants on long-term sick leave in order to facilitate return to work (RTW). METHODS: An exploratory qualitative design was used. Four focus groups were conducted with 29 clinicians working on interdisciplinary inpatient and outpatient occupational rehabilitation teams in Norway. The clinicians shared narratives from clinical practice. Transcripts were analysed, and results were reported by use of systematic text condensation. RESULTS: The clinicians used several approaches to facilitate RTW among individuals on sick leave. Three themes emerged as especially important in order to succeed: 1) To get a basic understanding of the participant's life-world through a mapping process; 2) To build a therapeutic alliance through communication characterised by sensitivity to the participants' needs and emotional concerns; and 3) To initiate processes of change that increase the possibilities for RTW. Four main areas targetable for change were identified, three directed at the individual and one encompassing the participants' surroundings. These approaches were: a) To increase feelings of confidence and coping; b) To increase the participants' awareness of their own limits; c) To challenge inefficient and negative attitudes and thoughts related to the sick-role; and d) Close and immediate dialogue with key stakeholders. CONCLUSIONS: To increase the possibilities for RTW among individuals on long-term sick leave, a thorough mapping process and the construction of a therapeutic alliance are seen as crucial elements in approaches by occupational rehabilitation clinicians. By gaining the participants' trust and identifying their barriers and possibilities for work, the clinicians can target modifiable factors, especially at the individual level, and obstacles for RTW in their individual surroundings. This study elucidates what occupational rehabilitation clinicians do, say and provide to increase their participants' abilities and possibilities to RTW. PMID- 29149892 TI - Monitoring of long-lasting insecticidal nets (LLINs) coverage versus utilization: a community-based survey in malaria endemic villages of Central India. AB - BACKGROUND: Despite the known effectiveness of long-lasting insecticidal nets (LLINs) in providing protection against malaria, high level of ownership and use are very difficult to achieve and maintain. Nearly 40,000 LLINs were distributed in 2014 as an intervention tool against malaria transmission in 80 villages of Keshkal sub-district in Chhattisgarh, India. This study assessed LLIN coverage, access, utilization pattern, and key determinants for the net use 1 year after mass distribution. METHODS: In 2015, a cross-sectional household survey was carried out in 80 study clusters (whole village or part of village). From each cluster, 40 households were randomly selected and interviewed using a structured questionnaire adapted from the malaria indicator survey of Roll Back Malaria guidelines. Information on demographic characteristics, LLIN ownership, and its use on the night before the survey, and physical condition of LLINs were recorded. RESULTS: 2970 households were interviewed with a total of 15,003 individuals present in the households during the night before the survey. Nearly 98% of households had at least one LLIN and 59.4% of the surveyed population reportedly used an LLIN the previous night. LLIN use varied from 41 to 94% between the study clusters. Nearly 89% of the LLINs were found in good physical condition (without holes). However, proportion of household with at least one LLIN per two persons was only 39%. CONCLUSION: Universal coverage of LLINs was inadequate in the study clusters making it difficult for all household members to use an LLIN. LLIN use varied between clusters and was highest in children under 5 years of age. Health education campaigns and creating awareness about the benefit of sleeping under the LLINs in providing protection against malaria is required not only to high risk groups of pregnant women and children below 5 years of age but all the members of the family to have an epidemiological impact of this intervention at the community level. Relatively high net use despite poor access to LLINs indicates an overall desire to use nets when they are available. The main barrier to increased use of nets is the low coverage at household level. PMID- 29149893 TI - Association between severity of illicit drug dependence and quality of life in a psychosocial care center in BRAZIL: cross-sectional study. AB - BACKGROUND: Quality of life must be one of the main purposes for the treatment of drug users, requiring a better understanding of the association between the quality of life and the severity of dependency. This study aimed to investigate the correlation between severity of substance use in various areas of human functioning and quality of life of illicit drug users in a psychosocial care center for alcohol and drugs. METHODS: This cross-sectional study included 60 participants - illicit drug users - treated at a psychosocial care center for alcohol and drugs. Participants were evaluated with the short version of World Health Organization Quality of Life (WHOQOL-Bref) instrument to measure the quality of life, the 6th version of Addiction Severity Index (ASI-6) to assess the severity of dependence in several areas and the Mini International Neuropsychiatric Interview (MINI) to identify the presence of psychiatric disorders. Pearson and Spearman correlation tests and linear regression were applied to verify the association between the severity of dependence and the quality of life, and Student's t-test to compare the mean quality of life between individuals with and without psychiatric comorbidities. RESULTS: Negative correlation was found between the severity of dependence on the drugs dimensions: alcohol, psychiatric, medical, legal, family/social support and family/social problems of ASI-6, and the quality of life domains measured by the WHOQOL-Bref. The evidence was strongest in the psychiatric and medical dimensions. There was a significant difference in the quality of life mean among participants presenting or not presenting psychiatric comorbidities, for the psychological domain in anxiety disorders, and for the physical and psychological domains in mood disorders. CONCLUSION: The quality of life decreased as the severity of dependence increased, with different results in the various areas of the participant's life. This result emphasizes the need for training the professional team which works in the substance use disorders area for more comprehensive diagnostic evaluations and more appropriate therapeutic interventions for each area. The associations were more evident in the medical and psychiatric fields, indicating the need for greater attention to be paid in relation to medical and psychiatric comorbidities. PMID- 29149894 TI - Comments on "Incidence of cancer among licensed commercial pilots flying North Atlantic routes". AB - Gudmundsdottir et al. in their paper entitled "Incidence of cancer among licensed commercial pilots flying North Atlantic routes" published in Environmental Health have evaluated the effects of exposure to higher levels of cosmic radiation on cancer incidence in the pilots of commercial flights. Despite its remarkable strengths, the paper authored by Gudmundsdottir et al. has some shortcomings. The shortcomings of this paper such as not determining the shape of dose-response relationship for radiation-induced cancers, limitations in flight dose calculations, the weaknesses of CARI-6 as the program used by Gudmundsdottir et al. to estimate the effective dose of galactic cosmic rays, and the problems associated with unpredictable nature of the magnitude and duration of solar particle events are discussed. PMID- 29149897 TI - Enablers and barriers to secondary prophylaxis for rheumatic fever among Maori aged 14-21 in New Zealand: a framework method study. AB - BACKGROUND: Acute rheumatic fever (ARF) rates have declined to near zero in nearly all developed countries. However, in New Zealand rates have not declined since the 1980s. Further, ARF diagnoses in New Zealand are inequitably distributed--occurring almost exclusively in Maori (the indigenous population) and Pacific children--with very low rates in the majority New Zealand European population. With ARF diagnosis, secondary prophylaxis is key to prevent recurrence. The purpose of this study was to identify the perceived enablers and barriers to secondary recurrence prophylaxis following ARF for Maori patients aged 14-21. METHODS: This study took a systems approach, was informed by patient voice and used a framework method to explore potential barriers and enablers to ongoing adherence with monthly antibiotic injections for secondary prophylaxis. Qualitative interviews were conducted with 19 Maori ARF patients receiving recurrence prophylaxis in the Waikato District Health Board region. Participants included those fully adherent to treatment, those with intermittent adherence or those who had been "lost to follow-up." RESULTS: Barriers and enablers were presented around three factors: system (including access/resources), relational and individual. Access and resources included district nurses coming to patients as an enabler and lack of income and time off work as barriers. Relational characteristics included support from family and friends as enablers and district nurse communication as predominantly a positive although not enabling factor. Individual characteristics included understanding, personal responsibility and fear/pain of injections. CONCLUSION: This detailed exploration of barriers and enablers for ongoing secondary prophylaxis provides important new information for the prevention of recurrent ARF. Among other considerations, a national register, innovative engagement with youth and their families and a comprehensive pain management programme are likely to improve adherence to ongoing secondary prophylaxis and reduce the burden of RHD for New Zealand individuals, families and health system. PMID- 29149898 TI - Detection of Plasmodium falciparum male and female gametocytes and determination of parasite sex ratio in human endemic populations by novel, cheap and robust RTqPCR assays. AB - BACKGROUND: The presence of Plasmodium falciparum gametocytes in peripheral blood is essential for human to mosquito parasite transmission. The detection of submicroscopic infections with gametocytes and the estimation of the gametocyte sex ratio are crucial to assess the human host potential ability to infect mosquitoes and transmit malaria parasites. AIM AND OBJECTIVES: The aim of this work was to develop sensitive and cheap Real Time qPCR assays for large-scale epidemiological surveys, based on detection and amplification of gametocyte sex specific transcripts selected from the literature: the female-specific pfs25 and pf glycerol kinase (pfGK) and the male-specific pfs230p and pf13 transcripts. METHODS: RTqPCR assays were used to test the gametocyte- and sex-specific expression of the target genes using asexual stages of the gametocyteless parasite clone F12 and FACS purified male and female gametocytes of the PfDynGFP/P47mCherry line. Assays were performed on 50 blood samples collected during an epidemiological survey in the Soumousso village, Burkina Faso, West Africa, and amplification of the human housekeeping gene 18S rRNA was employed to normalize RNA sample variability. RESULTS: SYBR Green assays were developed that showed higher sensitivity compared to Taqman assays at a reduced cost. RTqPCR results confirmed that expression of pfs25 and pfs230p are female and male specific, respectively, and introduced two novel markers, the female-specific pfGK and the male-specific pf13. A formula was derived to calculate the ratio of male to female gametocytes based on the ratio of male to female transcript copy number. Use of these assays in the field samples showed, as expected, a higher sensitivity of RTqPCR compared to microscopy. Importantly, similar values of gametocyte sex-ratio were obtained in the field samples based on the four different target combinations. CONCLUSION: Novel, sensitive, cheap and robust molecular assays were developed for the detection and quantification of female and male P. falciparum gametocytes. In particular, the RTqPCR assays based on the female-specific pfs25 and the newly described male gametocyte-specific pf13 transcripts, including normalization by the human 18S, reliably assess presence and abundance of female and male gametocytes and enable to determine their sex ratio in human subjects in endemic areas. PMID- 29149895 TI - Novel insights into chromosomal conformations in cancer. AB - Exploring gene function is critical for understanding the complexity of life. DNA sequences and the three-dimensional organization of chromatin (chromosomal interactions) are considered enigmatic factors underlying gene function, and interactions between two distant fragments can regulate transactivation activity via mediator proteins. Thus, a series of chromosome conformation capture techniques have been developed, including chromosome conformation capture (3C), circular chromosome conformation capture (4C), chromosome conformation capture carbon copy (5C), and high-resolution chromosome conformation capture (Hi-C). The application of these techniques has expanded to various fields, but cancer remains one of the major topics. Interactions mediated by proteins or long noncoding RNAs (lncRNAs) are typically found using 4C-sequencing and chromatin interaction analysis by paired-end tag sequencing (ChIA-PET). Currently, Hi-C is used to identify chromatin loops between cancer risk-associated single-nucleotide polymorphisms (SNPs) found by genome-wide association studies (GWAS) and their target genes. Chromosomal conformations are responsible for altered gene regulation through several typical mechanisms and contribute to the biological behavior and malignancy of different tumors, particularly prostate cancer, breast cancer and hematologic neoplasms. Moreover, different subtypes may exhibit different 3D-chromosomal conformations. Thus, C-tech can be used to help diagnose cancer subtypes and alleviate cancer progression by destroying specific chromosomal conformations. Here, we review the fundamentals and improvements in chromosome conformation capture techniques and their clinical applications in cancer to provide insight for future research. PMID- 29149896 TI - Liposomal vaccine formulations as prophylactic agents: design considerations for modern vaccines. AB - Vaccinology is one of the most important cornerstones in modern medicine, providing better quality of life. The human immune system is composed of innate and adaptive immune processes that interplay when infection occurs. Innate immunity relies on pathogen-associated molecular patterns which are recognized by pathogen recognition receptors localized in antigen presenting cells. After antigen processing and presentation, CD4+ T cell polarization occurs, further leading to B cell and CD8+ activation and humoral and cell-mediated adaptive immune responses. Liposomes are being employed as vaccine technologies and their design is of importance to ensure proper immune responses. Physicochemical parameters like liposome size, charge, lamellarity and bilayer fluidity must be completely understood to ensure optimal vaccine stability and efficacy. Liposomal vaccines can be developed to target specific immune cell types for the induction of certain immune responses. In this review, we will present promising liposomal vaccine approaches for the treatment of important viral, bacterial, fungal and parasitic infections (including tuberculosis, TB). Cationic liposomes are the most studied liposome types due to their enhanced interaction with the negatively charged immune cells. Thus, a special section on the cationic lipid dimethyldioctadecylammonium and TB is also presented. PMID- 29149899 TI - Selective depletion of microglial progranulin in mice is not sufficient to cause neuronal ceroid lipofuscinosis or neuroinflammation. AB - BACKGROUND: Progranulin deficiency due to heterozygous null mutations in the GRN gene are a common cause of familial frontotemporal lobar degeneration (FTLD), while homozygous loss-of-function GRN mutations are thought to be a rare cause of neuronal ceroid lipofuscinosis (NCL). Aged progranulin-knockout (Grn-null) mice display highly exaggerated lipofuscinosis, microgliosis, and astrogliosis, as well as mild cell loss in specific brain regions. In the brain, progranulin is predominantly expressed in neurons and microglia, and previously, we demonstrated that neuronal-specific depletion of progranulin does not recapitulate the neuropathological phenotype of Grn-null mice. In this study, we evaluated whether selective depletion of progranulin expression in myeloid-lineage cells, including microglia, causes NCL-like neuropathology or neuroinflammation in mice. METHODS: We generated mice with progranulin depleted in myeloid-lineage cells by crossing mice homozygous for a floxed progranulin allele to mice expressing Cre recombinase under control of the LyzM promotor (Lyz-cKO). RESULTS: Progranulin expression was reduced by approximately 50-70% in isolated microglia compared to WT levels. Lyz-cKO mice aged to 12 months did not display any increase in lipofuscin deposition, microgliosis, or astrogliosis in the four brain regions examined, though increases were observed for many of these measures in Grn-null animals. To evaluate the functional effect of reduced progranulin expression in isolated microglia, primary cultures were stimulated with controlled standard endotoxin and cytokine release was measured. While Grn-null microglia display a hyper-inflammatory phenotype, Lyz-cKO and WT microglia secreted similar levels of inflammatory cytokines. CONCLUSION: We conclude that progranulin expression from either microglia or neurons is sufficient to prevent the development of NCL-like neuropathology in mice. Furthermore, microglia that are deficient for progranulin expression but isolated from a progranulin-rich environment have a normal inflammatory profile. Our results suggest that progranulin acts, at least partly, in a non-cell autonomous manner in the brain. PMID- 29149900 TI - Immunogenic potential of a Salmonella Typhimurium live vaccine for pigs against monophasic Salmonella Typhimurium DT 193. AB - BACKGROUND: Monophasic Salmonella Typhimurium (mSTM) strains account for up to 8.6% of all human Salmonellosis cases. They have an increasing prevalence during recent years and several human cases with hospitalisation were reported. These strains are often isolated from pigs and pork - one primary source of human infection. A Salmonella Typhimurium (STM) live vaccine has been proven successful in controlling of STM infections in pigs for many years. The aim of this study was to test the immunogenicity of the vaccine in weaners during oral challenge with a virulent mSTM strain and to examine the kinetics of STM-specific IgA, IgM and IgG antibodies induced by vaccination and infection. RESULTS: Despite clinical signs being present in both groups, the vaccination led to a significant reduction of diarrhoea, overall clinical symptoms and a milder elevation of the body temperature. Necropsy revealed fewer pathological lesions in the gastrointestinal tract of vaccinated compared to control animals. Moreover, in the ileal and caecal mucosa and in the ileocaecal lymph nodes the challenge strain burden was significantly reduced by vaccination. Significant differences in the antibody responses of both groups were present during the vaccination period and after infection. In vaccinated animals Salmonella-specific IgA and IgG antibody levels increased significantly after vaccination and were even more pronounced in response to challenge. In contrast, similarly low levels of IgM antibodies were detected during the vaccination period in both vaccinated and non vaccinated animals. However, after challenge IgM antibody levels increased significantly in control pigs while neither IgA nor IgG antibodies were detectable. CONCLUSION: The data demonstrate that mSTM can evoke clinical signs in weaners. Due to the vaccination their incidence and magnitude were significantly milder. Vaccination also led to a significantly reduced challenge strain burden in the intestine and the lymph nodes which is comparable to previous studies using the same vaccine in a challenge with biphasic STM. Therefore, it is concluded that this vaccine induces immunity against monophasic and biphasic STM strains. Furthermore, the results of antibody profiles in response to vaccination and infection provide additional evidence for humoral immune mechanisms triggered during Salmonella infection or vaccination. PMID- 29149901 TI - Development and exploration of the content validity of a patient-reported outcome measure to evaluate the impact of migraine- the migraine physical function impact diary (MPFID). AB - BACKGROUND: Adults with migraine experience substantial reductions in quality of life during and in-between migraine attacks. Clinical and regulatory guidelines encourage the inclusion of patient reported outcomes for the evaluation of benefits of interventions for migraine. METHODS: The conceptual framework and items for a new patient-reported outcome (PRO) instrument, the Migraine Physical Function Impact Diary (MPFID), were developed using scientific methods recommended to ensure content validity of PRO instruments. The MPFID was developed to measure the impact of migraine on physical functioning based on themes raised in concept elicitation (CE) interviews (conducted previously) with adults with migraine. Cognitive interviews were conducted with adults with migraine to further explore content validity. The instrument was modified following an interim analysis of a first round of cognitive interviews, to assess comprehensiveness and clarity of items, instructions, and response options. Refinements were subsequently tested in additional cognitive interviews. RESULTS: The conceptual framework included impacts on physical functioning experienced by most adults with migraine and deemed clinically relevant for measuring the outcome of an intervention for migraine. Concepts in the framework included the impact of migraine on physical impairments (acts) and ability to complete day-to day activities and perform everyday activities (tasks). MPFID items were generated to evaluate functioning over the past 24 h and to collect data daily, to capture experiences on days with migraine as well as the days in-between migraines. Items asked about needing to rest or lie down; ability to get out of bed, stand up, bend over, walk, perform household chores, do tasks outside the home, keep routines or schedules, get ready for the day, do activities that require concentration or clear thinking; difficulty moving head and body, doing activities requiring physical effort; avoiding interacting with others. Initial modifications based on the first round of cognitive interviews (n = 8) included clarifying instructions, updating three items to enhance specificity and clarity, and revising one item to include gender-neutral language. The second round of interviews (n = 9) confirmed acceptability of revisions and supported content validity. CONCLUSIONS: The results provide qualitative evidence supporting the content validity of the MPFID for evaluating outcomes of interventions for migraine. PMID- 29149902 TI - Metabolism of aromatics by Trichosporon oleaginosus while remaining oleaginous. AB - BACKGROUND: The oleaginous yeast, Trichosporon oleaginosus, has been extensively studied for its ability to metabolize non-conventional feedstocks. These include phenol-containing waste streams, such as distillery wastewater, or streams consisting of non-conventional sugars, such as hydrolyzed biomass and various bagasse. An initial BLAST search suggests this yeast has putative aromatic metabolizing genes. Given the desirability to valorize underutilized feedstocks such as lignin, we investigated the ability of T. oleaginosus to tolerate and metabolize lignin-derived aromatic compounds. RESULTS: Trichosporon oleaginosus can tolerate and metabolize model lignin monoaromatics and associated intermediates within funneling pathways. Growth rates and biomass yield were similar to glucose when grown in 4-hydroxybenzoic acid (pHBA) and resorcinol, but had an increased lag phase when grown in phenol. Oleaginous behavior was observed using resorcinol as a sole carbon source. Fed-batch feeding resulted in lipid accumulation of 69.5% on a dry weight basis. CONCLUSIONS: Though the exact pathway of aromatic metabolism remains to be determined for T. oleaginosus, the results presented in this work motivate use of this organism for lignin valorization and phenolic wastewater bioremediation. Trichosporon oleaginosus is the first yeast shown to be oleaginous while growing on aromatic substrates, and shows great promise as a model industrial microbe for biochemical and biofuel production from depolymerized lignin. PMID- 29149903 TI - Improving access to school health services as perceived by school professionals. AB - BACKGROUND: The organisation of health assessments by preventive health services focusing on children's health and educational performance needs to be improved due to evolving health priorities such as mental health problems, reduced budgets and shortages of physicians and nurses. We studied the impact on the school professionals' perception of access to school health services (SHS) when a triage approach was used for population-based health assessments in primary schools. The triage approach involves pre-assessments by SHS assistants, with only those children in need of follow-up being assessed by a physician or nurse. The triage approach was compared with the usual approach in which all children are assessed by physicians and nurses. METHODS: We conducted a cross-sectional study, comparing school professionals' perceptions of the triage and the usual approach to SHS. The randomly selected school professionals completed digital questionnaires about contact frequency, the approachability of SHS and the appropriateness of support from SHS. School care coordinators and teachers were invited to participate in the study, resulting in a response of 444 (35.7%) professionals from schools working with the triage approach and 320 (44.6%) professionals working with the usual approach. RESULTS: Respondents from schools using the triage approach had more contacts with SHS and were more satisfied with the appropriateness of support from SHS than respondents in the approach-as-usual group. No significant differences were found between the two groups in terms of the perceived approachability of SHS. CONCLUSIONS: School professionals were more positive about access to SHS when a triage approach to routine assessments was in place than when the usual approach was used. Countries with similar population based SHS systems could benefit from a triage approach which gives physicians and nurses more opportunities to attend schools for consultations and assessments of children on demand. PMID- 29149904 TI - Concomitant, sequential, and 7-day triple therapy in first-line treatment of Helicobacter pylori infection in Korea: study protocol for a randomized controlled trial. AB - BACKGROUND: Most international guidelines recommend triple-therapy regimens consisting of a proton pump inhibitor, clarithromycin, and amoxicillin/metronidazole for at least 7 days for the eradication of Helicobacter pylori. However, the efficacy of 7-day clarithromycin-based standard triple therapy for H. pylori infection is currently unacceptable in Korea. In this study, we will compare the efficacy and safety of 7-day standard triple therapy, 10-day sequential therapy, and 10-day concomitant therapy for the first-line treatment of H. pylori infection in Korea. METHODS/DESIGN: In this multicenter, investigator-blinded, randomized trial we are recruiting adult patients with H. pylori infection from 15 hospitals in Korea to determine whether sequential or concomitant treatment is superior to standard triple therapy. Patients are randomly assigned to receive either standard triple therapy (lansoprazole, amoxicillin, and clarithromycin) for 7 days, or sequential treatment (lansoprazole and amoxicillin for the first 5 days, followed by lansoprazole, clarithromycin, and metronidazole for another 5 days) for 10 days, or concomitant therapy (lansoprazole, amoxicillin, clarithromycin, and metronidazole) for 10 days. The primary outcome is the rate of H. pylori eradication in the intention to-treat population. DISCUSSION: The results of this study will be crucial for determining the optimal regimen for the primary treatment of H. pylori infection in Korea. This study will produce vital evidence that will lead to revisions to guidelines concerning first-line treatment regimens for H. pylori infection. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), Republic of Korea, KCT0001980 . Registered on 25 July 2016. PMID- 29149905 TI - The Kusamala Program for primary caregivers of children 6-59 months of age hospitalized with severe acute malnutrition in Malawi: study protocol for a cluster-randomized controlled trial. AB - BACKGROUND: Severe acute malnutrition (SAM) is associated with high mortality rates and impairments in growth and development in children that do survive. There are complex nutritional, health, and behavioural risk factors involving severely malnourished children and their primary caregivers, requiring integrated intervention approaches. METHODS: A cluster-randomized controlled trial at the Queen Elizabeth Central Hospital in Blantyre, Malawi will be conducted to evaluate the effectiveness of a 4-day hospital-based intervention programme directed at primary caregivers. This programme, titled the Kusamala Program, aims to improve developmental and nutritional outcomes in children with SAM. Up to six primary caregivers and their children will be enrolled to groups each week, which will be randomly allocated to intervention or comparison arms. The intervention package consists of interactive counselling on three modules: 1) nutrition and feeding; 2) water, sanitation, and hygiene (WASH); and 3) psychosocial stimulation. Data collection will be performed at enrolment, at discharge from hospital, and at 6 months following discharge. The primary outcome is child development assessed with the Malawi Developmental Assessment Tool (MDAT), a validated measure of gross and fine motor, language, and social development. DISCUSSION: This intervention programme is unique because it utilizes primary caregivers' time spent in-hospital while children receive treatment for SAM. The programme has the potential to be effective in addressing multiple aspects of child, nutrition and development. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03072433 . Registered on 7 March 2017. PMID- 29149907 TI - Mapping evidence on the distribution of human papillomavirus-related cancers in sub-Saharan Africa: scoping review protocol. AB - BACKGROUND: Despite the introduction of HPV vaccines, the incidence of HPV related cancers (cervical, penile, anal, vulvar, vagina, head, and neck) in sub Saharan Africa has been rising. The increasing incidence of these HPV-related cancers has been attributed to changes in lifestyle-related risk factors, most notably sexual behavior. The main objective of this study is to map evidence on the distribution of HIV-related cancers in sub-Saharan Africa (SSA). METHODS AND ANALYSIS: We will conduct a scoping review to explore, describe, and map literature on the distribution of HPV-related cancers in sub-Saharan Africa. The primary search will include peer-reviewed and review articles. The list of references from included studies will also be searched. The search will be performed using EBSCOhost platform by searching the following databases within the platform: Academic search complete, health source: nursing/academic edition, CINAHL with full text, PubMed, Science Direct, Google scholar and World Health Organization (WHO) library databases, and gray literature. The researcher will search the articles using keywords, from the included studies; abstract and full articles will be screened by two independent reviewers. The screening will be guided by the inclusion and exclusion criteria. A thematic content analysis will be used to present the narrative account of the reviews, using NVivo version 10. DISCUSSION: We anticipate finding relevant literature on the distribution of HPV related cancers in sub-Saharan Africa. The study findings will help reveal research gaps to guide future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017062403. PMID- 29149906 TI - Forebrain-specific, conditional silencing of Staufen2 alters synaptic plasticity, learning, and memory in rats. AB - BACKGROUND: Dendritic messenger RNA (mRNA) localization and subsequent local translation in dendrites critically contributes to synaptic plasticity and learning and memory. Little is known, however, about the contribution of RNA binding proteins (RBPs) to these processes in vivo. RESULTS: To delineate the role of the double-stranded RBP Staufen2 (Stau2), we generate a transgenic rat model, in which Stau2 expression is conditionally silenced by Cre-inducible expression of a microRNA (miRNA) targeting Stau2 mRNA in adult forebrain neurons. Known physiological mRNA targets for Stau2, such as RhoA, Complexin 1, and Rgs4 mRNAs, are found to be dysregulated in brains of Stau2-deficient rats. In vivo electrophysiological recordings reveal synaptic strengthening upon stimulation, showing a shift in the frequency-response function of hippocampal synaptic plasticity to favor long-term potentiation and impair long-term depression in Stau2-deficient rats. These observations are accompanied by deficits in hippocampal spatial working memory, spatial novelty detection, and in tasks investigating associative learning and memory. CONCLUSIONS: Together, these experiments reveal a critical contribution of Stau2 to various forms of synaptic plasticity including spatial working memory and cognitive management of new environmental information. These findings might contribute to the development of treatments for conditions associated with learning and memory deficits. PMID- 29149908 TI - Exosomal microRNAs as potential circulating biomarkers in gastrointestinal tract cancers: a systematic review protocol. AB - BACKGROUND: Metastasis is the most frequent type of recurrence in gastrointestinal (GI) cancers, and there is an emerging potential for new diagnostic and therapeutic approaches, especially in the cases of metastatic GI carcinomas. The expression profiles of circulating exosomal microRNAs are of particular interest as novel non-invasive diagnostic and prognostic biomarkers for improved detection of GI cancers in body fluids, especially in the serum of patients with recurrent cancers. The aim of this study is to systematically review primary studies and identify the miRNA profiles of serum exosomes of GI cancers. METHODS AND DESIGN: This systematic review will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidance. Relevant studies will be identified through a comprehensive search of the following main electronic databases: PubMed, Web of Science, Embase, Scopus, and Google Scholar, with no language restrictions (up to July 2017). Full copies of articles will be identified by a defined search strategy and will be considered for inclusion against pre-defined criteria. The quality assessment of the included studies will be performed by the Newcastle-Ottawa Scale (NOS). Data will be analyzed using Stata software V.12. Publication bias will be assessed by funnel plots, Beggs' and Eggers' tests. The levels of evidence for primary outcomes will be evaluated using the GRADE criteria. DISCUSSION: The analysis of circulating exosomal miRNA profiles provides attractive screening and non invasive diagnostic tools for the majority of solid tumors including GI cancers. There is limited information regarding the relationship between serum exosomal miRNA profiles and the pathological condition of patients with different GI cancers. Since there is no specific biomarker for GI cancers, we aim to suggest a number of circulating exosomal miRNA candidates as potential multifaceted GI cancer biomarkers for clinical utility. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017057129. PMID- 29149910 TI - Sodium chloride pica causing recurrent nephrolithiasis in a patient with iron deficiency anemia: a case report. AB - BACKGROUND: Iron deficiency anemia is a common finding in women of child-bearing age. Pica, or the ingestion of non-food or non-nutritive items, is a well-known manifestation of iron deficiency. A high sodium diet increases risk for nephrolithiasis. We describe the case of a 31-year-old woman with recurrent calcium nephrolithiasis and anemia who ate ice chips as well as spoons of salt daily. Treatment of pica may prove effective in preventing recurrent nephrolithiasis. CASE PRESENTATION: A 31-year-old white woman with a past medical history of menorrhagia, anemia, and recurrent calcium nephrolithiasis presented for preoperative evaluation prior to ureterolithotomy. She described a daily pattern of eating continually from a cup of ice chips accompanied by multiple spoons of salt directly out of a salt shaker. These cravings had been present for many years, were bothersome to her, and interfered with her daily life. Laboratory findings revealed hemoglobin of 10.9 g/dL with ferritin of 3 ng/mL. History, physical, and laboratory data were consistent with pica secondary to iron deficiency anemia. She was prescribed orally administered ferrous sulfate 325 mg three times a day with meals. She continues to struggle with the symptoms of pica and orally administered supplementation. CONCLUSIONS: It is important that clinicians consider the possible diagnosis of sodium chloride pica in patients with iron deficiency anemia and recurrent nephrolithiasis. Treatment of anemia and resolution of pica may prove effective in preventing future nephrolithiasis. Specific questioning about pica symptoms in patients with iron deficiency anemia and recurrent nephrolithiasis may be helpful diagnostically and therapeutically. PMID- 29149909 TI - Testing the implementation and sustainment facilitation (ISF) strategy as an effective adjunct to the Addiction Technology Transfer Center (ATTC) strategy: study protocol for a cluster randomized trial. AB - BACKGROUND: Improving the extent to which evidence-based practices (EBPs) treatments that have been empirically shown to be efficacious or effective-are integrated within routine practice is a well-documented challenge across numerous areas of health. In 2014, the National Institute on Drug Abuse funded a type 2 effectiveness-implementation hybrid trial titled the substance abuse treatment to HIV Care (SAT2HIV) Project. Aim 1 of the SAT2HIV Project tests the effectiveness of a motivational interviewing-based brief intervention (MIBI) for substance use as an adjunct to usual care within AIDS service organizations (ASOs) as part of its MIBI Experiment. Aim 2 of the SAT2HIV Project tests the effectiveness of implementation and sustainment facilitation (ISF) as an adjunct to the Addiction Technology Transfer Center (ATTC) model for training staff in motivational interviewing as part of its ISF Experiment. The current paper describes the study protocol for the ISF Experiment. METHODS: Using a cluster randomized design, case management and leadership staff from 39 ASOs across the United States were randomized to receive either the ATTC strategy (control condition) or the ATTC + ISF strategy (experimental condition). The ATTC strategy is staff-focused and includes 10 discrete strategies (e.g., provide centralized technical assistance, conduct educational meetings, provide ongoing consultation). The ISF strategy is organization-focused and includes seven discrete strategies (e.g., use an implementation advisor, organize implementation team meetings, conduct cyclical small tests of change). Building upon the exploration-preparation-implementation sustainment (EPIS) framework, the effectiveness of the ISF strategy is examined via three staff-level measures: (1) time-to-proficiency (i.e., preparation phase outcome), (2) implementation effectiveness (i.e., implementation phase outcome), and (3) level of sustainment (i.e., sustainment phase outcome). DISCUSSION: Although not without limitations, the ISF experiment has several strengths: a highly rigorous design (randomized, hypothesis-driven), high-need setting (ASOs), large sample size (39 ASOs), large geographic representation (23 states and the District of Columbia), and testing along multiple phases of the EPIS continuum (preparation, implementation, and sustainment). Thus, study findings will significantly improve generalizable knowledge regarding the best preparation, implementation, and sustainment strategies for advancing EBPs along the EPIS continuum. Moreover, increasing ASO's capacity to address substance use may improve the HIV Care Continuum. Trial registration ClinicalTrials.gov: NCT03120598. PMID- 29149911 TI - The analysis of novel microRNA mimic sequences in cancer cells reveals lack of specificity in stem-loop RT-qPCR-based microRNA detection. AB - OBJECTIVE: MicroRNAs are frequently downregulated in cancer, and restoring expression has tumour suppressive activity in tumour cells. Our recent phase I clinical trial investigated microRNA-based therapy in patients with malignant pleural mesothelioma. Treatment with TargomiRs, microRNA mimics with novel sequence packaged in EGFR antibody-targeted bacterial minicells, revealed clear signs of clinical activity. In order to detect delivery of microRNA mimics to tumour cells in future clinical trials, we tested hydrolysis probe-based assays specific for the sequence of the novel mimics in transfected mesothelioma cell lines using RT-qPCR. RESULTS: The custom assays efficiently and specifically amplified the consensus mimics. However, we found that these assays gave a signal when total RNA from untransfected and control mimic-transfected cells were used as templates. Further investigation revealed that the reverse transcription step using stem-loop primers appeared to introduce substantial non-specific amplification with either total RNA or synthetic RNA templates. This suggests that reverse transcription using stem-loop primers suffers from an intrinsic lack of specificity for the detection of highly similar microRNAs in the same family, especially when analysing total RNA. These results suggest that RT-qPCR is unlikely to be an effective means to detect delivery of microRNA mimic-based drugs to tumour cells in patients. PMID- 29149912 TI - Trial to Incentivise Adherence for Diabetes (TRIAD): study protocol for a randomised controlled trial. AB - BACKGROUND: Many people with diabetes have suboptimal glycaemic control due to not being adherent to their treatment regimen. Behavioural economic theory suggests that the lack of adherence results from the disconnect between the timing of when costs and benefits accrue. One strategy to address this discontinuity is to offer patients a near-term benefit, such as a financial reward. Whereas there is evidence that rewards can improve treatment adherence and sometimes health outcomes, further research is needed to determine whether rewards are more effective when targeting processes or intermediary health outcomes. In the Trial to Incentivise Adherence for Diabetes (TRIAD) we test whether adding financial incentives to usual care can improve HbA1c levels among people with diabetes and whether the financial incentives work better when targeting processes (adherence to blood glucose testing, medication, and daily physical activity) or the primary intermediary health outcome of self-monitored blood glucose within an acceptable range. METHODS/DESIGN: TRIAD is a randomised, controlled, open-label, single-centre superiority trial with three parallel arms. A total of 240 patients with suboptimally controlled diabetes (HbA1c >= 8%) from a polyclinic in Singapore are block-randomised (blocking factor: current vs. new glucometer users) into three arms, namely (1) usual care (UC) only, (2) UC with process incentive and (3) UC with outcome incentive, in a 2:3:3 ratio. Masking the arm allocation will be precluded by the behavioural nature of the intervention but blocking size will not be disclosed to protect concealment. The primary outcome (change in HbA1c level at month 6) will be measured by a laboratory that is independent from the study team. Secondary outcomes (at month 6) include the number of blood glucose testing days, glucose readings within the normal range (between 4 to 7 mmol/L), medication-adherent days, physically active days, and average incentives earned and time spent administrating the incentives. DISCUSSION: This study will provide evidence on whether financial incentives can cost-effectively improve glycaemic control. It will also provide evidence on the benefit incidence of interventions involving financial incentives. By comparing process to outcome incentives, this study will inform the design of future incentive strategies in chronic disease management and beyond. TRIAL REGISTRATION: ClinicalTrials.gov registry, ID: NCT02224417 . Registered on 22 August 2014. PMID- 29149913 TI - Subadditive responses to extremely short blue and green pulsed light on visual evoked potentials, pupillary constriction and electroretinograms. AB - BACKGROUND: The simultaneous exposure to blue and green light was reported to result in less melatonin suppression than monochromatic exposure to blue or green light. Here, we conducted an experiment using extremely short blue- and green pulsed light to examine their visual and nonvisual effects on visual evoked potentials (VEPs), pupillary constriction, electroretinograms (ERGs), and subjective evaluations. METHODS: Twelve adult male subjects were exposed to three light conditions: blue-pulsed light (2.5-ms pulse width), green-pulsed light (2.5 ms pulse width), and simultaneous blue- and green-pulsed light with white background light. We measured the subject's pupil diameter three times in each condition. Then, after 10 min of rest, the subject was exposed to the same three light conditions. We measured the averaged ERG and VEP during 210 pulsed-light exposures in each condition. We also determined subjective evaluations using a visual analog scale (VAS) method. RESULTS: The pupillary constriction during the simultaneous exposure to blue- and green-pulsed light was significantly lower than that during the blue-pulsed light exposure despite the double irradiance intensity of the combination. We also found that the b/|a| wave of the ERGs during the simultaneous exposure to blue- and green-pulsed light was lower than that during the blue-pulsed light exposure. We confirmed the subadditive response to pulsed light on pupillary constriction and ERG. However, the P100 of the VEPs during the blue-pulsed light were smaller than those during the simultaneous blue and green-pulsed light and green-pulsed light, indicating that the P100 amplitude might depend on the luminance of light. CONCLUSIONS: Our findings demonstrated the effect of the subadditive response to extremely short pulsed light on pupillary constriction and ERG responses. The effects on ipRGCs by the blue-pulsed light exposure are apparently reduced by the simultaneous irradiation of green light. The blue versus yellow (b/y) bipolar cells in the retina might be responsible for this phenomenon. PMID- 29149914 TI - Testing the effectiveness of a motivational interviewing-based brief intervention for substance use as an adjunct to usual care in community-based AIDS service organizations: study protocol for a multisite randomized controlled trial. AB - BACKGROUND: In 2010, the first comprehensive National HIV/AIDS Strategy for the United States was released and included three goals: (1) reducing the number of people who become infected with HIV, (2) increasing access to care and improving health outcomes for people living with HIV, and (3) reducing HIV-related health disparities and health inequities. In 2013, as part of its effort to help address the National HIV/AIDS Strategy, the National Institute on Drug Abuse (NIDA) funded a type 2 effectiveness-implementation hybrid trial titled the Substance Abuse Treatment to HIV Care (SAT2HIV) Project. Aim 1 of the SAT2HIV Project tests the effectiveness of a motivational interviewing-based brief intervention (MIBI) for substance use as an adjunct to usual care within AIDS Service Organizations (ASOs) as part of its MIBI Experiment. Aim 2 of the SAT2HIV Project tests the effectiveness of implementation and sustainment facilitation (ISF) as an adjunct to the Addiction Technology Transfer Center (ATTC) model for training staff in motivational interviewing as part of its ISF Experiment. The current paper describes the study protocol for the ISF Experiment. METHODS: As part of a multisite randomized controlled trial, individuals with comorbid HIV/AIDS and problematic substance use are randomized to receive either the ASOs' usual care (control condition) or usual care plus a MIBI for substance use (experimental condition) delivered by trained ASO case-management staff. Primary outcome measures are reductions in days of primary substance use, number of substance related problems, times engaging in risky behaviors, days of non-adherence to HIV medications, and increases in substance use treatment. As part of this paper, we describe the trial protocol in accordance with the Standard Protocol Items: Recommendations for Interventional Trials guidelines. DISCUSSION: If successfully able to implement MIBI as an effective adjunct to usual care, the current trial may have a significant impact on increasing the capacity of ASOs to address problematic substance use among individuals living with HIV/AIDS. Reducing the prevalence of problematic substance use among individuals living with HIV/AIDS within the United States may lead to significant improvements on key performance measures (i.e., the HIV Care Continuum and the 90-90-90 target). Trial registration ClinicalTrials.gov: NCT02495402. PMID- 29149915 TI - Quality of intervention delivery in a cluster randomised controlled trial: a qualitative observational study with lessons for fidelity. AB - BACKGROUND: Understanding intervention fidelity is an essential part of the evaluation of complex interventions because fidelity not only affects the validity of trial findings, but also because studies of fidelity can be used to identify barriers and facilitators to successful implementation, and so provide important information about factors likely to impact the uptake of the intervention into clinical practice. Participant observation methods have been identified as being particularly valuable in studies of fidelity, yet are rarely used. This study aimed to use these methods to explore the quality of implementation of a complex intervention (Safewards) on mental health wards during a cluster randomised controlled trial. Specific aims were firstly to describe the different ways in which the intervention was implemented, and secondly to explore the contextual factors moderating the quality of intervention delivery, in order to inform 'real world' implementation of the intervention. METHODS: Safewards was implemented on 16 mental health wards in England. We used Research Assistants (RAs) trained in participant observation to record qualitative observational data on the quality of intervention delivery (n = 565 observations). At the end of the trial, two focus groups were conducted with RAs, which were used to develop the coding framework. Data were analysed using thematic analysis. RESULTS: There was substantial variation in intervention delivery between wards. We observed modifications to the intervention which were both fidelity consistent and inconsistent, and could enhance or dilute the intervention effects. We used these data to develop a typology which describes the different ways in which the intervention was delivered. This typology could be used as a tool to collect qualitative observational data about fidelity during trials. Moderators of Safewards implementation included systemic, interpersonal, and individual factors and patient responses to the intervention. CONCLUSIONS: Our study demonstrates how, with appropriate training in participant observation, RAs can collect high-quality observational data about the quality of intervention delivery during a trial, giving a more complete picture of 'fidelity' than measurements of adherence alone. TRIAL REGISTRATION: ISRCTN registry; IRSCTN38001825 . Registered 29 August 2012. PMID- 29149917 TI - Treatment outcome with a short multidrug-resistant tuberculosis regimen in nine African countries. AB - SETTING: Nine countries in West and Central Africa. OBJECTIVE: To assess outcomes and adverse drug events of a standardised 9-month treatment regimen for multidrug resistant tuberculosis (MDR-TB) among patients never previously treated with second-line drugs. DESIGN: Prospective observational study of MDR-TB patients treated with a standardised 9-month regimen including moxifloxacin, clofazimine, ethambutol (EMB) and pyrazinamide (PZA) throughout, supplemented by kanamycin, prothionamide and high-dose isoniazid during an intensive phase of a minimum of 4 to a maximum of 6 months. RESULTS: Among the 1006 MDR-TB patients included in the study, 200 (19.9%) were infected with the human immunodeficiency virus (HIV). Outcomes were as follows: 728 (72.4%) cured, 93 (9.2%) treatment completed (81.6% success), 59 (5.9%) failures, 78 (7.8%) deaths, 48 (4.8%) lost to follow-up. The proportion of deaths was much higher among HIV-infected patients (19.0% vs. 5.0%). Treatment success did not differ by HIV status among survivors. Fluoroquinolone resistance was the main cause of failure, while resistance to PZA, ethionamide or EMB did not influence bacteriological outcome. The most important adverse drug event was hearing impairment (11.4% severe deterioration after 4 months). CONCLUSIONS: The study results support the use of the short regimen recently recommended by the World Health Organization. Its high level of success even among HIV-positive patients promises substantial improvements in TB control. PMID- 29149918 TI - Oxygen Transfer in Moving Bed Biofilm Reactor and Integrated Fixed Film Activated Sludge Processes. AB - A demonstrated approach to design the, so-called, medium-bubble air diffusion oxygen transfer system for moving bed biofilm reactor (MBBR) and integrated fixed film activated sludge (IFAS) processes is described. Operational full-scale biological water resource recovery systems treating municipal sewage, designed using this methodology, provide reliable service. Further improvement is possible, however, as knowledge gaps are filled and results in more rationally based system designs. Pilot-scale testing demonstrates significant enhancement of oxygen transfer capacity from the presence of media. Establishment of the relationship in full-scale systems between diffuser submergence, aeration rate, and biofilm carrier fill fraction will enhance MBBR and IFAS aerobic process design, cost, and performance. Limited testing of full-scale systems prevents computation of alpha values and can be addressed by further full-scale testing under actual operating conditions. Control of MBBR and IFAS aerobic zone oxygen transfer systems can be optimized by recognizing that varying residual dissolved oxygen concentrations are needed, depending on operating conditions. Further application of oxygen transfer control approaches used in activated sludge systems, such as ammonia-based oxygen transfer system control, further improves MBBR and IFAS system energy efficiency. PMID- 29149916 TI - Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals. METHODS: WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 * 10-5 in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran-Mantel-Haenszel test to compare gene-level variant counts in cases vs controls. RESULTS: No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p = 8.3 * 10 12), SOD1 (p = 8.9 * 10-9) and NEK1 (p = 1.1 * 10-9). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p = 0.04 and p = 7 * 10-3, respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p = 0.14). CONCLUSIONS: While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans. PMID- 29149919 TI - Gastrointestinal and Hepatic Disease in Vasculitis. AB - Vasculitis is an inflammatory condition that targets the blood vessels, which may occur in isolation or as a component of a systemic inflammatory condition. Although many of the vasculitides can directly affect the organs of the gastrointestinal system, some types exhibit a proclivity for certain gastrointestinal and hepatic organs. Often a patient presents with nonspecific symptoms, delaying the diagnosis and treatment of the underlying vasculitis. Vasculitis can also present with severe manifestations, such as upper gastrointestinal bleeds and bowel perforation. It is important to identify the signs and symptoms of vasculitis in gastrointestinal system and institute appropriate treatment. PMID- 29149920 TI - Gastrointestinal and Hepatic Disease in the Inflammatory Myopathies. AB - Although muscle weakness is the pathognomonic feature of idiopathic inflammatory myopathies, systemic organ involvement is not uncommon. The gastrointestinal and hepatic manifestations are well known. Oropharyngeal dysphagia is the most common gastrointestinal symptom and can be severe. Gastric and small intestinal motility disorders, including chronic intestinal pseudo-obstruction, celiac disease, and inflammatory bowel disease have been described. Comprehensive cancer screening is warranted soon after the diagnosis of inflammatory myopathies due to high risk of occult malignancies. Elevated aminotransferases may suggest muscular injury rather than hepatic dysfunction. Knowledge regarding systemic involvement of inflammatory myopathies can assist in timely diagnosis of these complex disorders. PMID- 29149921 TI - Gastrointestinal and Hepatic Disease in Fibromyalgia. AB - Fibromyalgia (FM) has historically been associated with several diseases in gastroenterology and hepatology. The most substantiated evidence pertains to irritable bowel syndrome (IBS). The pathogeneses of FM and IBS remain unclear, but it is likely related to dysregulation within the brain-gut axis, resulting in a hyperalgesic state. IBS and FM share other similarities, including a female predominance, fatigue, insomnia, and susceptibility to psychiatric state. These common manifestations and pathogeneses serve as a foundation for overlapping, multidisciplinary treatment modalities. PMID- 29149922 TI - Gastrointestinal and Hepatic Disease in Sjogren Syndrome. AB - Sjogren syndrome (SS) is a lymphocyte-mediated, infiltrative autoimmune disorder characterized by destruction of exocrine glands leading to secretory dysfunction. The typical manifestations include xerostomia and xerophthalmia; however, extensive gastrointestinal involvement is increasingly being recognized, emphasizing the variable and systemic nature of SS. PMID- 29149924 TI - Gastrointestinal and Hepatic Disease in Spondyloarthritis. AB - The association of inflammatory arthritis with intestinal pathology extends back more than 100 years. This association is now supported by epidemiologic studies demonstrating an elevated prevalence of inflammatory bowel disease in spondyloarthritis and vice versa, compared with the general population. Genetic and intestinal microbiome studies have further linked these diseases. Although diabetes and nonalcoholic fatty liver disease disproportionately affect individuals with psoriatic arthritis, diseases of the esophagus, stomach, pancreas, and liver are not particularly common in spondyloarthritis. Clinicians should be aware of the differential diagnosis and the appropriate diagnostic tools available when evaluating digestive and hepatic disorders in spondyloarthritis. PMID- 29149923 TI - Gastrointestinal and Hepatic Disease in Systemic Sclerosis. AB - Although classification criteria for systemic sclerosis (SSc) do not incorporate gastrointestinal tract (GIT) manifestations often present in this disease, the GIT is the most common internal organ involved. Pathophysiology of GIT involvement is thought to be similar to other organs in SSc with fibroproliferative vascular lesions of small arteries and arterioles, increased production of profibrotic growth factors, and alterations of innate, humoral, and cellular immunity. These processes result in neuropathy progressing to myopathy with eventual fibrosis. Proper diagnostics and therapeutics for SSc-GIT involvement require the treating physician to have an understanding of an integrated approach and potential medication adverse effects. PMID- 29149925 TI - Gastrointestinal and Hepatic Disease in Systemic Lupus Erythematosus. AB - Gastrointestinal (GI) symptoms are common among patients with systemic lupus erythematosus (SLE), although only rarely are they caused by active organ system involvement from SLE itself. Rapid diagnosis and appropriate treatment of lupus enteritis and other GI manifestations of SLE are critical, because of the potential for organ and life-threatening complications. The 3 main variants of lupus enteritis are lupus mesenteric vasculitis, intestinal pseudo-obstruction, and protein-losing enteropathy. These GI manifestations and others in patients with SLE are reviewed here. PMID- 29149926 TI - Drug-Induced Gastrointestinal and Hepatic Disease Associated with Biologics and Nonbiologic Disease-Modifying Antirheumatic Drugs. AB - A variety of gastrointestinal adverse drug reactions are seen in nearly all conventional antirheumatic medications, ranging from nausea to life-threatening drug-induced liver injury. Rheumatologists should be particularly familiar with hepatotoxicity associated with long-term methotrexate use, and the range of unique hepatic, biliary, and pancreatic manifestations associated with azathioprine. Hepatitis B virus reactivation is the most serious gastrointestinal disease risk associated with many biological therapies, particularly rituximab. Gastrointestinal perforation may be a specific concern for agents directed at interleukin-6 pathways, and some reports have raised the question of whether interleukin-17 inhibition may elevate inflammatory bowel disease risk. PMID- 29149927 TI - Gastrointestinal Involvement in Behcet Disease. AB - Behcet disease (BD) is a variable vessel vasculitis that can involve several organs and systems. Gastrointestinal (GI) involvement has an acute exacerbating course with ulcers, most commonly in the ileocolonic area. These ulcers can be large and deep, causing perforation and massive bleeding. This article highlights the current knowledge on the epidemiology, clinical findings, diagnosis, and management of GI involvement of BD, with emphasis on recent findings. PMID- 29149928 TI - Rheumatic Manifestations in Autoimmune Liver Disease. AB - Autoimmune liver diseases coexist with rheumatic disorders in approximately 30% of cases and may also share pathogenic mechanisms. Autoimmune liver diseases result from an immune-mediated injury of different tissues, with autoimmune hepatitis (AIH) targeting hepatocytes, and primary biliary cholangitis (PBC) and primary sclerosing cholangitis targeting cholangiocytes. Sjogren syndrome is diagnosed in 7% of AIH cases and serologic autoimmunity profiles are a common laboratory abnormality, particularly in the case of serum antimitochondrial (PBC) or anti-liver kidney microsomal antibodies (AIH). Therapeutic strategies may overlap between rheumatic and autoimmune liver diseases and practitioners should be vigilant in managing bone loss. PMID- 29149930 TI - Digestive and Hepatic Aspects of the Rheumatic Diseases. PMID- 29149931 TI - The Intersection of Autoimmunity, Arthritis, and the Alimentary Canal. PMID- 29149932 TI - Sepsis Definitions: A Work in Progress. AB - The word, sepsis, dates back more than 2 millennia but has, over the past 2 centuries, come to be applied first to the clinical state evoked by invasive infection and, more recently, to describe the syndrome resulting from the host response to infection. Further refinements embodied in the recently published Sepsis-3 definition underline the concept of a dysregulated immune response resulting in potentially modifiable life-threatening organ dysfunction. This review summarizes the evolution and limitations of efforts to characterize a common and complex disorder. PMID- 29149934 TI - Common Sense Approach to Managing Sepsis. AB - Sepsis results in many deaths, prolonged suffering among survivors and relatives, and high use of resources both in developed and developing countries. The updated Surviving Sepsis Campaign guidelines should aid clinicians in improving the identification and management of these patients, but many uncertainties remain because most of the guidance is based on low-quality evidence. This article discusses how to use some of the specific items of the guidelines together with a common-sense approach to aid clinical management of patients with sepsis while trying to balance the potential benefit and harm of the items. PMID- 29149933 TI - Nutrition Therapy in Sepsis. AB - Sepsis is characterized by early massive catabolism, lean body mass (LBM) loss, and escalating hypermetabolism persisting for months to years. Early enteral nutrition should attempt to correct micronutrient/vitamin deficiencies, deliver adequate protein and moderated nonprotein calories, as well-nourished patients can generate reasonable endogenous energy. After resuscitation, increasing protein/calories are needed to attenuate LBM loss and promote recovery. Malnutrition screening is essential, and parenteral nutrition can be safely added when enteral nutrition is failing based on preillness malnutrition. Following discharge from intensive care unit, significantly increased protein/calorie delivery is required for months to years to facilitate functional and LBM recovery. PMID- 29149935 TI - Biomarkers in Sepsis. AB - A biomarker is a characteristic by which a (patho)physiologic process can be identified. Biomarkers can be of diagnostic value (to discriminate infection from noninfectious conditions or to determine the causative pathogen), of prognostic value (assigning risk profiles and predict outcome), and in the future may be of theranostic value (aid in selection and monitoring of therapy). Systems biology provides a promising tool for the discovery of novel biomarkers. Biomarkers can be the key to personalized targeted treatment in the future clinical management of sepsis. PMID- 29149929 TI - Gastrointestinal and Hepatic Disease in Rheumatoid Arthritis. AB - Gastrointestinal (GI) manifestations of rheumatoid arthritis (RA) are rare, but can be impactful for patients. Some GI processes are directly related to RA, whereas others may be sequelae of treatment or caused by concomitant autoimmune diseases. This article discusses the role of the GI tract in RA pathogenesis; the presentation, epidemiology, and diagnosis of RA-related GI manifestations; concomitant GI autoimmune diseases that may affect those with RA; and GI side effects of RA treatment. The importance of appropriately considering conditions unrelated to RA in the differential diagnosis when evaluating new GI symptoms in patients with RA is noted. PMID- 29149937 TI - Personalizing Sepsis Care. AB - Sepsis describes a broad-based syndrome covering many infectious agents, affecting various sites in patients of differing age, gender, and comorbidity and resulting in varying degrees and combinations of organ dysfunction. Protocolized care with rigid goals may suit populations, assuming the evidence-lite recommendations are beneficial, but not necessarily individual patients. A personalized approach to management is rational and preferable. Other than clinical heterogeneity, a range of biological signatures exist in sepsis, and these fluctuate over the disease course. Subsets of septic patients can display distinct biological signatures that may potentially be used to identify suitability for different treatments and titration to optimal effect. PMID- 29149936 TI - Epidemiology and Outcomes. AB - Sepsis is a global public health concern. Internationally it contributes to more than 5 million deaths annually. Although rates are variable between countries, over the past 40 years reported incidence has continued to increase. Aside from potential differences in patient populations, the variation in reported rates also reflects differences in identification strategies, access to health care, and awareness of the diagnosis. Factors such as age, sex, socioeconomic status, comorbid disease, and type and site of infection impact the development of and outcomes from sepsis. Although advances have been made in treatment, its impact remains substantial. PMID- 29149938 TI - Novel Interventions: What's New and the Future. AB - Despite decades of sepsis research, no specific therapies for sepsis have emerged and current management still relies on source control, antibiotics, and organ support. With improved understanding of sepsis pathophysiology and the development of new techniques to enable better characterization of patients with sepsis, clinical trials are beginning to better target new interventions at those patients most likely to respond. This article discusses advances in sepsis therapeutics designed to improve endothelial cell function, purify the blood to help restore immune homeostasis, and provide immunostimulation for patients with immune exhaustion. PMID- 29149940 TI - Immune Activation in Sepsis. AB - Sepsis is caused by a dysregulated host response to infection. Immune responses determine the characteristics of sepsis. The body's protection against infection involves danger signal surveillance and recognition from nonself, effector functions in response to sensing danger signals, homeostatic regulation, and generation of immunologic memory. During sepsis, the immune system is activated by pathogen-associated and host-derived molecular patterns. Detecting these molecular patterns generates multisystem responses. Impaired organ function remote to the site of infection is the unifying feature. The processes by which an appropriate response to a microbial invader change from adaptive to maladaptive and dysregulated remain unclear. PMID- 29149939 TI - Improving Long-Term Outcomes After Sepsis. AB - Although acute survival from sepsis has improved in recent years, a large fraction of sepsis survivors experience poor long-term outcomes. In particular, sepsis survivors have high rates of weakness, cognitive impairment, hospital readmission, and late death. To improve long-term outcomes, in-hospital care should focus on early, effective treatment of sepsis; minimization of delirium, distress, and immobility; and preparing patients for hospital discharge. In the posthospital setting, medical care should focus on addressing new disability and preventing medical deterioration, providing a sustained period out of the hospital to allow for recovery. PMID- 29149941 TI - Pathophysiology of Septic Shock. AB - Fundamental features of septic shock are vasodilation, increased permeability, hypovolemia, and ventricular dysfunction. Vasodilation owing to increased nitric oxide and prostaglandins is treated with vasopressors (norepinephrine first). Increased permeability relates to several pathways (Slit/Robo4, vascular endothelial growth factor, angiopoietin 1 and 2/Tie2 pathway, sphingosine-1 phosphate, and heparin-binding protein), some of which are targets for therapies. Hypovolemia is common and crystalloid is recommended for fluid resuscitation. Cardiomyocyte-inflammatory interactions decrease contractility and dobutamine is recommended to increase cardiac output. There is benefit in decreasing heart rate in selected patients with esmolol. Ivabradine is a novel agent for heart rate reduction without decreasing contractility. PMID- 29149942 TI - Mechanisms of Organ Dysfunction in Sepsis. AB - Sepsis-associated organ dysfunction involves multiple responses to inflammation, including endothelial and microvascular dysfunction, immune and autonomic dysregulation, and cellular metabolic reprogramming. The effect of targeting these mechanistic pathways on short- and long-term outcomes depends highly on the timing of therapeutic intervention. Furthermore, there is a need to understand the adaptive or maladaptive character of these mechanisms, to discover phase specific biomarkers to guide therapy, and to conceptualize these mechanisms in terms of resistance and tolerance. PMID- 29149943 TI - Endocrine and Metabolic Alterations in Sepsis and Implications for Treatment. AB - Sepsis induces profound neuroendocrine and metabolic alterations. During the acute phase, the neuroendocrine changes are directed toward restoration of homeostasis, and also limit unnecessary energy consumption in the setting of restricted nutrient availability. Such changes are probably adaptive. In patients not recovering quickly, a prolonged critically ill phase may ensue, with different neuroendocrine changes, which may represent a maladaptive response. Whether stress hyperglycemia should be aggressively treated or tolerated remains a matter of debate. Until new evidence from randomized controlled trials becomes available, preventing severe hyperglycemia is recommended. Evidence supports withholding parenteral nutrition in the acute phase of sepsis. PMID- 29149944 TI - Management of Sepsis-Induced Immunosuppression. AB - It is now well established that profound immunosuppression develops within a few days after sepsis onset in patients. This should be considered additional organ failure because it is associated with increased rate of nosocomial infections, mortality, and long-term complications, thus constituting the rationale for immunomodulation in patients. Nevertheless, the demonstration of the efficacy of such therapeutic strategy in improving deleterious outcomes in sepsis remains to be made. Results from clinical trials based on interleukin 7 and granulocyte macrophage colony-stimulating factor immunoadjuvant therapies in septic shock patients are expected for 2018. PMID- 29149945 TI - Caring for Sepsis Patients: An Update. PMID- 29149946 TI - Organ Donation: A Comparison of Donating and Nondonating Families in Turkey. AB - Based on public opinion surveys, although 75% of people state that they would donate the organs of one of their relatives, in reality, the rate of the people who donate the organs of their relatives is 24%. To decrease the organ shortage, the key point is to understand the difference between intention and real behavior. For this reason, in this study, analyses of variables related to the potential organ donor families' decisions of approval or refusal for organ harvesting were analyzed. The interviews were conducted with 101 families who made a decision about organ donation between 2010 and 2014. The variables, strongly related with the family decision, are the wishes of the deceased persons about donation, suspicions regarding brain death, the desire to protect body integrity, and the satisfaction levels of the families with the approaches of medical personnel. The findings, obtained from qualitative data, also support the quantitative data. The results indicate that both education of the public about maintaining a positive attitude toward organ donation and education of health professionals can be key factors in decreasing the organ shortage. PMID- 29149947 TI - Impact Factors and Attitudes Toward Organ Donation Among Transplantation Patients and Their Caregivers in China. AB - PURPOSE: This study's purpose was to investigate the attitudes toward organ donation among renal transplantation patients and their caregivers. In addition, we sought to explore the impact factors that affect their attitudes toward deceased organ donation. DESIGN AND METHODS: A self-administrated questionnaire was used, which consisted of two parts: 1) demographic data, and 2) transplantation and donation-related data. This study was conducted in three transplantation follow-up centers in three hospitals using a cross-sectional approach. SPSS 17.0 software was used to analysis descriptive and inferential statistics for data. The responses were analyzed using descriptive statistics and logistic regression analysis. RESULTS: We received 426 effective questionnaires. The renal transplantation patients' mean age was 40.84 years. Among these patients, 67.8% were willing to accept the organ transplantation surgery for their relatives, 67.4% were willing to donate a living kidney to a close relative, 62.7% were willing to donate organs after death, 53.5% were willing to register in the national organ donation system, and 51.4% were willing to sign the organ donation consent when facing their relatives becoming a potential organ donor. Age, marriage status, education level, understanding of transplantation procedures and understanding of donation procedures had statistical significance in the difference of the attitudes toward donate their organs after death (P < .05). CONCLUSIONS: Renal transplantation patients in our study are more willing to donate organs after death than their caregivers, but both their attitudes toward deceased donation were not very optimistic. There is a significant relationship between participants' willingness and knowledge of organ donation; patients with more understanding of the transplantation and donation procedure were more willing to donate organs after death. Affected by traditional values such as Confucianism, many people still cannot accept registering in the national organ donation system or sign the organ donation consent when facing their relatives becoming potential organ donors. CLINICAL RELEVANCE: There is a need to give adequate training regarding donation to increase donation rates. The government must provide education from the perspective of scientific knowledge to change the traditional views of the public, which may then increase the donation rate in China. PMID- 29149948 TI - Knowledge and Attitudes Toward Organ Donation in Health Care Undergraduate Students in Italy. AB - INTRODUCTION: The number of organ donors in Italy is increasing, but with still disappointing living donation activity and relatively frequent objection by potential deceased donors' relatives to organ recovery. Few studies have assessed health care students' knowledge and attitude on donation. METHODS: We administered a questionnaire to medical (MS) and nursing students (NS) at University of Modena and Reggio Emilia, Italy, and 749 students (406 MS and 343 NS) completed the questionnaire. RESULTS: Although 95% of students were in favor of donation, only 21.9% of NS and 24.9% of MS were registered as donors. One quarter of students reported family disagreement. MS appeared more confident with personnel involved in donation. Overall, 60% of students knew the term donation after brain death but only 40% were aware of the criteria used to define it. Barely 27.1% of NS and 15.3% of MS believed they had received sufficient information in lessons. Backward logistic regression demonstrated that students whose families agree with them and who knew the definition of donation after brain death were more likely to express the disposition of registering, and those who showed distrust in the declaration of brain death were half as likely to register as donors. DISCUSSION: Students expressed a lack of knowledge, controversial attitudes on donation, and strong need for education; increased awareness may help increase donation rates. The majority of educational institutions in Italy do not directly address training on organ donation and transplantation for health care students; an integrated curriculum favoring interpersonal discussion including practical aspects is urgently required. PMID- 29149949 TI - Attitudes Toward Organ Donation Among Relatives of the Patients Who Are Being Followed Up in Intensive Care and Dialysis Units. AB - INTRODUCTION: This study sought to investigate attitudes toward organ donation (OD) among the relatives of patients who are being followed up in intensive care units (ICU) and dialysis units. MATERIALS AND METHODS: This cross-sectional study was conducted with relatives of the patients who were being followed up in hemodialysis (HD) and peritoneal dialysis (PD) units and Neurosurgery, Neurology, Anesthesia, and Reanimation ICUs of Adana Numune Research and Training Hospital. A questionnaire investigating sociodemographic data and knowledge level about OD and an attitude scale about OD was applied with face-to-face interviews. RESULTS: A total of 111 subjects (50 from ICU, 61 from HD and PD units) participated in the study. Mean age was 42.7 +/- 13.4 years, 63 (56.8%) were female, 84 (75.7%) were married; education level was low for 49 (44.1%), moderate for 41 (36.9%), and high for 21 (18.9%) subjects; 53 (47.7%) patients were waiting for OD. It was found that sufficient knowledge was low, OD was not unfavorable according to religious beliefs, they knew little about the fact that OD is legally available, and promotions about OD are insufficient in our country. Mean score of Attitudes Toward Organ Donation Scale was 58.6 +/- 11.2, and was lower among females (55.7 +/- 11.7) compared to males (t = 3.177, P = .002). CONCLUSIONS: Education and promotion activities would decrease the refusal rate, which is the main obstacle against OD from cadavers, a procedure that has quite low rate in our country. Organ transplantations may increase with providing sufficient knowledge about the laws concerned and general considerations. PMID- 29149950 TI - Structural and Functional Adaptation of the Remnant Kidney After Living Kidney Donation: Long-Term Follow-up. AB - OBJECTIVE: Several adjustments occur after nephrectomy (NT) in the donor's remnant kidney. We investigated kidney donors 10 years after NT and compared several parameters before and after transplantation. METHODS: A total of 42 kidney donors of the University of Luebeck's Transplant Center were scheduled for a 10-year follow-up and were offered several investigations: laboratory tests, urinalysis and kidney ultrasound examination including determination of kidney volume (KV), resistive index (RI) and pulsatility index (PI). Moreover, a 24-hour ambulatory blood pressure monitoring (ABPM) was performed. A review of the medical records allowed comparison of the investigated parameters before (t0), 1 month after (t0.1), and 10 (t10) years after NT. RESULTS: Creatinine clearance decreased from 94.3 +/- 23 (t0) to 52.4 +/- 22 mL/min/1.73 m2 (t0.1) and increased to 78.2 +/- 19 mL/min/1.73 m2 after 10 years (t10). Tubular proteinuria (alpha1-microglobuline) increased from 6.1 +/- 1.5 (t0) to 63 +/- 4.8 (t0.1) (P < .05) and decreased to 36 +/- 2.4 mg/g creatinine at t10 (P < .05). Ultrasound examinations revealed a growth of the KV from 159.8 +/- 23.1 (t0) to 175.5 +/- 22.1 mL (t10) (P < .05) and an increase of RI and PI from t0 of 0.63 +/- 0.01 and 1.03 +/- 0.03 to t10 of 0.72 +/- 0.04 (P < .05) and 1.24 +/- 0.11 (P < .05), respectively. Post-NT ABPM values were not significantly different from pre-NT values. CONCLUSIONS: NT leads to hypertrophy of the remnant kidney associated with an increase of organ volume and creatinine clearance after 10 years of follow-up. Our results indicate an excellent prognosis for the kidney donors without any signs of renal damage. PMID- 29149952 TI - Financial Impact of Incidental Radiologic Findings During Living Kidney Donor Evaluation. AB - Living kidney donor (LKD) transplantation is an important alternative for the end stage renal disease population and is preferred due to superior outcomes when compared with dialysis or deceased donor transplantation. LKD evaluation includes a computed tomography angiogram (CTA) for assessment of renal and renovascular anatomy. Incidental nonrenal findings are frequently noted during the CTAs, and these may have variable clinical significance. These incidental findings lead to further testing, procedures, and referrals, which incur additional cost. We conducted a retrospective analysis of the incidental findings noted during CTA of 632 LKDs evaluated at our institution from 2008 to 2013. All extrarenal findings were categorized as pulmonary, hepatic, pancreatic-biliary, adrenal, bowel, gynecologic, and miscellaneous. Further testing, diagnostic procedures, referrals, and management were determined based on chart review. Our results showed that there were 525 extrarenal incidental findings in 632 potential living donors. Appropriate clinical follow-up was required in 20% at an additional cost of US dollars (USD) 63,035. Additional cost per incidental finding requiring follow-up was USD 407 +/- 818. The median cost for follow-up was USD 168 (168 317). The detection of findings during imaging leads to apprehension for the donor and contribute to additional costs. Appropriate counseling is warranted prior to evaluation of the LKD. PMID- 29149951 TI - Predictive Factors of Renal Adaptation After Nephrectomy in Kidney Donors. AB - BACKGROUND: Despite compensatory hyperfiltration in remaining nephrons following donor nephrectomy, some donors show impaired renal adaptation and low estimated glomerular filtration rate (eGFR). We investigated the factors predicting early renal adaptation after nephrectomy and identified kidney donors at risk of inadequate renal adaptation. METHODS: A total of 265 living kidney donors from 2010 to 2013 were retrospectively analyzed. Renal function was serially followed for 6 months after the operation. Regression analyses were performed to identify the independent predictors of low eGFR (eGFR <60 mL/min/1.73 m2) and impaired renal adaptation (%Modification of Diet in Renal Disease [MDRD] <66% of baseline eGFR). RESULTS: A total of 148 donors belonged to the low eGFR group, and changes in eGFR (DeltaeGFR) at postoperative (PO) 1 day and 1 month were identified as independent predictors of low eGFR. Impaired renal adaptation was related to age, DeltaeGFR PO 2-3 days, and DeltaeGFR PO 1 month. Early renal adaptation was associated with age, male gender, and residual kidney computerized tomography angiography (CTA) volume. The best sensitivity and specificity were obtained with a cutoff value of DeltaeGFR 31 at PO 1 day and 1 month for predicting low eGFR and with a value of DeltaeGFR 27 at PO 2-3 days and 1 month for predicting impaired renal adaptation. CONCLUSIONS: Our study showed that the degree of early renal adaptation determines subsequent renal function in kidney donors. Closer monitoring and management may be required in old or male donors with small residual CTA kidney volume as well as donors with persistent DeltaeGFR >27 within 1 month of nephrectomy. PMID- 29149953 TI - Myocardial Perfusion Scans and Mortality in Asymptomatic Patients Awaiting Renal Transplantation. AB - Cardiac risk assessment for asymptomatic patients awaiting renal transplantation is controversial. Patients awaiting renal transplantation in Southern Saskatchewan from 2005 to 2015 were retrospectively reviewed. Patients underwent cardiac risk stratification with stress myocardial perfusion scan. Baseline clinical characteristics, nuclear scan results, all-cause mortality, and cardiovascular events were analyzed. Abnormal scans were defined as studies with reversible defects, wall motion abnormalities, lung uptake, or transient ischemic dilation. Descriptive statistics and survival analysis were calculated. Charts from 285 consecutive patients with 608 nuclear scans were analyzed. Mean age was 55.2 +/- 11.7 years and 34.7% were female. Forty-three (15.1%) patients were transplanted and 99 (40.9%) patients died while awaiting renal transplantation. One hundred fifty-three patients (63.2%) had at least one abnormal scan. The mean follow-up period was 5.47 +/- 3.11 years. An abnormal scan was not associated with decreased survival and/or coronary events (hazard ratio: 0.94, P = .77; 95% confidence intervals: 0.62 to 1.43). Patients awaiting renal transplantation in Saskatchewan with abnormal myocardial perfusion scans were not at greater risk of death or coronary events. PMID- 29149954 TI - Preoperative Risk Factors Associated With Urinary Complications After Kidney Transplantation. AB - BACKGROUND: Only surgically irrelevant risk factors including sex, African American ancestry, or exceptional U-stitch anastomosis have been identified to associate with urinary complications after kidney transplantation. The objective was to identify modifiable and nonmodifiable risk factors associated with urinary complications after kidney transplantation. METHODS: A single-center study of 3,129 kidney transplants performed over 40 years was conducted to identify independent risk factors using chi2 tests and logistic regression analysis. RESULTS: We identified the quality of the transplant's ureter, cystographic abnormalities in the recipient, and repeat transplantations as independent risk factors for overall urinary complications occurring after kidney transplantation in multivariable analysis. Obesity was associated with an increased risk of urinary fistula, while the presence of a JJ stent was associated with a reduced risk of urinary fistula. The risk of urinary surgical complications for kidney transplantations was reduced when the kidney was recovered from a living related compared to a deceased donor. CONCLUSIONS: The risk factors identified in the present study will allow candidates for kidney transplantation to be more informed and will also allow for surgical modifications to limit the occurrence of urinary complications. PMID- 29149955 TI - Hemodialysis Patients' Willingness to Undergo Kidney Transplantation: An Observational Study. AB - BACKGROUND: The number of dialysis patients is increasing, with only 20% undergoing kidney transplantation. In Saudi Arabia, no studies had examined transplantation barriers from the patients' perspectives. We aimed in this study to estimate hemodialysis (HD) patients' willingness to undergo kidney transplantation and to explore its underlying determinants. METHODS: In an observational cross-sectional study involving adult HD patients from King Abdulaziz Medical City and King Abdullah Dialysis Center-Jeddah, patients were interviewed through a pre-tested questionnaire. Calculated sample size was 243. RESULTS: Among the 252 HD patients (mean age, 55 years [standard deviation = 15.21]; 59% men; median duration on HD, 24 months [interquartile range, 11.1, 60]), 61% described their knowledge about kidney transplantation as "poor" or "very poor." Only 69% chose "willingness to undergo kidney transplantation" (proportion, 0.69; 95% confidence interval [CI], 0.64-0.75). The main reported reasons against willingness were being too old for transplantation (61%) and fear of surgical complications (26%). Less willingness was shown with age >=60 years (adjusted odds ratio [AOR], 0.2; 95% CI, 0.11-0.36; P < .001), duration on HD >=5 years (AOR, 0.47; 95% CI, 0.25-0.89; P = .021), and being non-married (AOR, 0.47; 95% CI, 0.24-0.93; P = .03). CONCLUSIONS: Approximately one third of the respondents did not choose "willingness to undergo kidney transplantation." Willingness was negatively associated with older age, lack of spouse, and longer duration on HD. The majority of HD patients reported poor knowledge about kidney transplantation. Therefore, structured education may optimize the knowledge, perceptions, and attitudes of HD patients toward kidney transplantation and hence improve their transplantation willingness. PMID- 29149956 TI - Comparison Between Total IgG, C1q, and C3d Single Antigen Bead Assays in Detecting Class I Complement-Binding Anti-HLA Antibodies. AB - BACKGROUND: Complement-binding donor-specific antibodies (DSAs) are associated with antibody-mediated rejection and allograft loss. Novel single antigen bead (SAB) assays-that is, complement component 1q (C1q) and complement component 3d (C3d) assays-have been developed to specifically detect complement-binding DSA, but it remains unclear whether these assays have an improved ability to detect complement-binding DSA as compared with using the total IgG SAB assay with a high mean fluorescence intensity (MFI) cutoff. The aim of this study was to compare the ability of the total IgG, C1q, and C3d SAB assays in detecting complement binding anti-HLA antibodies. METHODS: Twenty sera known to have complement binding anti-HLA antibodies (serologic class I HLA typing by complement-dependent cytotoxicity method) were tested with 3 different SAB assays: total IgG (undiluted and 1:8 dilution), C1q, and C3d. Serologic anti-HLA specificities were compared with those obtained by IgG, C1q, and C3d SAB assays. RESULTS: IgG SAB was more sensitive in detecting complement-binding antibodies (sensitivity 24 of 24 = 1, odds ratio infinity). Pearson correlation showed the association between (1) C1q and IgG SAB assays (cutoff C1q SAB 1000 MFI, cutoff IgG SAB 5000 MFI: r = 0.347, P < .0001) and (2) C3d and IgG SAB assays (cutoff 500 MFI C3d SAB, 5000 MFI for IgG SAB: r = -0.173, P = .279). CONCLUSIONS: For class I anti-HLA antibodies, IgG SAB (cutoff MFI > 5000) was more sensitive in detecting complement-binding antibodies when compared with C1q and C3d SAB assays. PMID- 29149957 TI - Positive and Negative Affects in Living Kidney Donors. AB - OBJECTIVE: This study aimed to identify the factors influencing the positive and negative affects and the health-related quality of life (HRQOL) of living kidney donors. METHODS: With the use of a cross-sectional study design and a structured questionnaire, information on the basic characteristics, positive affect, negative affect, and HRQOL of 41 living kidney donors were compared. RESULTS: The negative affect in living kidney donors was similar to that of the general population, but the positive affect was slightly lower. The physical HRQOL of living kidney donors was slightly higher than that of the general population, and the mental HRQOL was similar. Female donors showed a greater positive affect than male donors. The donors who were siblings of the recipients showed a more negative affect. Donors without chronic disease and with good perceived physical health showed improved positive affect, negative affect, and mental HRQOL. Furthermore, living kidney donors with better positive and negative affects showed improved physical and mental HRQOLs. CONCLUSIONS: Clinical health providers should evaluate and determine the positive affect, negative affect, and quality of life of living kidney donors, especially in men, siblings of the recipients, those with chronic disease, and those with poorer perceived physical health. Moreover, psychosocial interventions should be provided to improve these factors. PMID- 29149958 TI - Efficacy of Prolonged- and Immediate-release Tacrolimus in Kidney Transplantation: A Pooled Analysis of Two Large, Randomized, Controlled Trials. AB - BACKGROUND: Two large, prospective studies (12-03; OSAKA) compared the efficacy and tolerability of prolonged-release versus immediate-release tacrolimus in kidney transplant patients also receiving mycophenolate mofetil and low-dose corticosteroids (without induction therapy). METHODS: Data were combined into one database to compare results over 24 weeks using 3 alternative endpoints: biopsy confirmed acute rejection (BCAR); the Food and Drug Administration composite endpoint (graft loss, BCAR, and loss to follow-up), and the European Medicines Agency composite endpoint (graft loss, BCAR, and graft dysfunction). The 95% confidence intervals were calculated (10% noninferiority margin). RESULTS: Overall, 633 patients received prolonged-release tacrolimus (12-03, n = 331; OSAKA, n = 302) and 645 received immediate-release tacrolimus (n = 336; n = 309). Baseline characteristics were comparable. Proportionately more patients receiving prolonged-release tacrolimus had trough levels of 5-15 ng/mL on day 1 (60.8%) and 2 (56.6%) versus immediate-release tacrolimus (42.5% and 43.9%, respectively, both P < .001). Efficacy of prolonged-release and immediate-release tacrolimus were similar as assessed by BCAR (13.9% vs 14.1%, respectively), European Medicines Agency composite endpoint (40.3% vs 38.3%) and US Food and Drug Administration composite endpoint (21.5% vs 19.8%). CONCLUSIONS: Novel efficacy endpoints as required by the European Medicines Agency and US Food and Drug Administration demonstrate noninferiority of prolonged-release versus immediate release tacrolimus. Significantly more patients treated with prolonged-release tacrolimus versus immediate-release tacrolimus achieved trough levels of 5 to 15 ng/mL early after transplantation. ClinicalTrials.govNCT00189839; NCT00717470. PMID- 29149959 TI - Urinary Tissue Inhibitor of Metalloproteinase and Insulin-like Growth Factor-7 as Early Biomarkers of Delayed Graft Function After Kidney Transplantation. AB - BACKGROUND: Recently, urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-7 (IGFBP-7), markers for G1 cell cycle arrest, have been identified and validated in predicting the development of acute kidney injury in critically ill patients. It is unknown, however, whether these two biomarkers could predict the development of delayed graft function (DGF) after kidney transplantation (KT). METHODS: This is a single-center, prospective, observational study. We enrolled 74 patients who underwent KT between August 2013 and December 2016. Urine sample were collected immediately after the operation. The primary outcome was development of DGF as defined by need for dialysis of more than 1 session within 7 days of KT. RESULTS: Twenty-three patients (31%) were diagnosed with DGF. In univariate analysis, kidneys from expanded criteria donors, higher donor serum creatinine, lower donor estimated glomerular filtration rate, antithymoglobulin exposure, neutrophil gelatinase associated lipocalin, and urinary [TIMP-2].[IGFBP7] were significantly different between early graft function and DGF. However, in multivariate analysis adjusting other factors, deceased donor and urinary [TIMP-2].[IGFBP7] at 0 hours post transplantation could predict the development of DGF. The receiver operating characteristic curve for prediction of DGF showed an area under the curve of 0.867 (sensitivity 0.86, specificity 0.71) for a cutoff value of 1.39. CONCLUSIONS: Our results indicate that urine [TIMP-2].[IGFBP7] immediately after transplantation could be an early, predictive biomarker of DGF in kidney transplantation. PMID- 29149960 TI - Real Renal Function After Renal Autotransplantation Through the Analysis of Solitary Kidney Autotransplantation Cases. AB - INTRODUCTION: Previous studies of the safety of renal autotransplantation (RAT) have been limited by a lack of evidence. Because of the influence of the opposite kidney, it is difficult to evaluate actual renal function. This study evaluated the actual results of RAT by collecting only cases involving a solitary kidney. METHODS: Between September 1, 1999, and November 30, 2015, 9 RAT procedures were performed in 9 patients with a solitary kidney. We retrospectively evaluated medical data collected prospectively. Renal function was evaluated using the creatinine level and the estimated glomerular filtration rate (eGFR). RESULTS: The indications for RAT differed among the nin9e study patients. Five patients had complex renovascular problems, 2 were treated for partial nephrectomy, 1 was had a radically resected ureter due to ureteral cancer, 1 patient underwent RAT for the preservation of renal function during suprarenal-type abdominal aortic aneurysm repair. The mean cold ischemic time was 116.66 minutes (range, 21-256), and the mean follow-up duration was 54.2 months (range, 1 to 184). There were no significant decreases in eGFR until 12 months except 1 patient who underwent RAT with partial nephrectomy due to renal cell cancer. CONCLUSIONS: We report stable renal function after RAT in patients with solitary kidney. Postoperative complications were rare. This is evidence for the safety of RAT. PMID- 29149961 TI - Practice Variation in the Immediate Postoperative Care of Pediatric Kidney Transplantation: A National Survey. AB - INTRODUCTION: Advances in organ allocation, surgical technique, immunosuppression, and long-term follow-up have led to a significant improvement in kidney transplant outcomes. Although there are clear recommendations for several aspects of kidney transplant management, there are no pediatric-specific guidelines for immediate postoperative care. The aim of this survey is to examine practice variations in the immediate postoperative care of pediatric kidney transplant patients. METHODS: We surveyed medical directors of Pediatric Acute Lung Injury and Sepsis Investigators (PALISI)-affiliated pediatric intensive care units regarding center-specific immediate postoperative management of pediatric kidney transplantation. RESULTS: The majority of PALISI centers admit patients to the pediatric intensive care unit postoperatively, and 97% of the centers involve a pediatric nephrologist in immediate postoperative care. Most patients undergo invasive hemodynamic monitoring; 97% of centers monitor invasive arterial blood pressure and 88% monitor central venous pressure. Most centers monitor serum electrolytes every 4 to 6 hours. Wide variation exists regarding blood pressure goal, fluid replacement type, frequency of obtaining kidney ultrasound, and use of prophylactic anticoagulation. CONCLUSION: There is consistent practice across PALISI centers in regards to many aspects of immediate postoperative management of pediatric kidney transplantation. However, variation still exists in some management aspects that warrant further discussions to reach a national consensus. PMID- 29149962 TI - Impact of Acute Infection Requiring Hospitalization on Tacrolimus Blood Levels in Kidney Transplant Recipients. AB - BACKGROUND: Tacrolimus is metabolized by members of the cytochrome p450 3A subfamily, and its bioavailability depends also on P-glycoprotein. We have observed that some patients admitted for infection presented with increased tacrolimus trough levels (TLs). The aim of the study was to assess the impact of infection on tacrolimus TLs and to determine the factors involved in TL fluctuations. METHODS: This retrospective cohort study included patients transplanted with a kidney between 2009 and 2011 who were hospitalized for an acute infection. Tacrolimus TLs and dosages were recorded before hospitalization, at admission, and 1 month after discharge. Increased levels of tacolimus were defined as TL 25% higher on admission than those recorded at the last visit before hospitalization. RESULTS: Seventy-seven patients were hospitalized 138 times for infection. More than two thirds of first hospitalizations occurred during the first post-transplant year. Causes of hospitalization were urinary (33%), cytomegalovirus (27%), digestive (15%), and pulmonary (12%) infections. Thirty-five percent of kidney transplant recipients had increased tacrolimus TLs (27/77 patients) in 24% of the hospitalizations (34/138). In 34 hospitalizations occurring in 27 patients, TL at admission was >=25% compared with the last visit before admission. Comparing these 34 hospitalizations with the other 104, no significant differences were noted, except for a greater fraction of digestive infections in the group with elevated tacrolimus TLs, independent of diarrhea occurrence. CONCLUSIONS: Up to 35% of kidney transplant recipients admitted for acute infection present with high tacrolimus TLs, requiring a dose reduction. How acute infection precisely affects metabolism and bioavailability of tacrolimus remains to be investigated. PMID- 29149963 TI - Urinary Tract Infections in the First Year Post-Kidney Transplantation: Potential Benefits of Treating Asymptomatic Bacteriuria. AB - BACKGROUND: Urinary tract infections (UTIs) are the commonest infectious complication in kidney transplant recipients (KTRs). No recommendations exist regarding treatment of asymptomatic bacteriuria. We aimed to identify potential risk factors and microbiological profile for UTIs, the role of treatment of asymptomatic bacteriuria, and effects on graft outcomes of bacteriuria within the first year post-transplantation. METHODS: We performed a retrospective analysis of UTIs in KTRs transplanted between January 2012 and December 2013 in 2 transplantation centers. Patients were routinely commenced on prophylactic sulfamethoxazole-trimethoprim. Clinical and microbiological data were analyzed for the first year following transplantation. RESULTS: In all, 276 KTRs were evaluated; 67% were men, with a mean age of 51 years. At 12 months post transplantation 158 (57%) KTRs had no bacteriuria, 75 (27%) had asymptomatic bacteriuria, 21 (8%) had symptomatic UTIs without further complication, and 22 (8%) with UTIs developed either pyelonephritis or urosepsis. Most frequent pathogens identified were Enterococcus faecalis and Escherichia coli, and 36% of organisms were multidrug resistant. Female sex was a risk factor for infection (P = .002), and presence of a double-J ureteral stent significantly increased the risk of asymptomatic bacteriuria and symptomatic UTIs (P = .003). Diabetes, age, and prior transplantation did not increase risk. Presence of infection was not associated with increased rejection, with similar renal function at 12 months. For episodes of bacteriuria (n = 420, asymptomatic n = 324), untreated asymptomatic bacteriuria (n = 185) followed by symptomatic UTI with the same organism was significantly higher (P = .002) compared with cases of treated asymptomatic bacteriuria (n = 139). CONCLUSION: Bacteriuria post-kidney transplantation is common, affecting nearly half of KTRs in the first year after transplantation. Treatment of asymptomatic bacteriuria may be beneficial to prevent subsequent episodes of symptomatic UTIs. PMID- 29149964 TI - Chikungunya Infection in Solid Organ Transplant Recipients. AB - BACKGROUND: Chikungunya virus (CHIKV) is an emerging mosquito-borne disease that causes acute febrile polyarthralgia and arthritis. CHIKV has spread rapidly to the Americas and, in Brazil, autochthonous cases are increasingly been reported. Solid organ transplant (SOT) recipients who travel to or live in CHIKV endemic areas are under high risk of acquiring the disease. Few data exist regarding the clinical characteristics of CHIKV infections in this population. We report the first case series of CHIKV infection in SOT recipients. METHODS: We retrospectively evaluated 13 cases of CHIKV infection in SOT recipients between January 2016 and December 2016 confirmed by laboratory tests and transplanted in the Renal and Liver Transplant Units of Walter Cantidio University Hospital from Federal University of Ceara. RESULTS: Positive CHIKV serology (enzyme-linked immunosorbent assay immunoglobulin M) was found in all patients (9 kidney and 4 liver transplant recipients). All of these patients had been living in endemic areas for dengue and CHIKV in the past months before the illness. The mean time between transplantation and CHIKV infection was of 7.2 years. Fever presented in 11 (84.6%) patients and 5 (38.5%) presented with a maculopapular rash. All cases had joint symptoms: 11 (84.6%) with symmetrical and peripheral polyarthralgia/polyarthritis and 2 (15.3%) with monoarthralgia/monoarthritis. Six (46%) patients had a joint complaint that lasted 3 months. Two patients had concomitant positive dengue serology (enzyme-linked immunosorbent assay immunoglobulin M). There were no cases of complications or deaths. CONCLUSION: SOT with CHIKV infection seems to have a clinical presentation and evolution similar to those seen in the general population, with no apparent damage to the graft. PMID- 29149965 TI - Comparision of Ureteral Stent Colonization Between Deceased and Live Donor Renal Transplant Recipients. AB - BACKGROUND: The use of a ureteral stent can cause a urinary tract infection (UTI), although it reduces urologic complications. UTIs are associated with a higher rate of ureteral stent colonization (USC). The aim of this study was to compare USC in living and deceased donor renal transplant recipients. MATERIAL AND METHODS: We conducted a prospective study of 48 patients who underwent renal transplantation between January and December 2016. The stents were removed aseptically, the inner surface of proximal and distal ends of stents were irrigated with liquid culture medium, and then they were vortexed for bacteriological investigation. Urine cultures were taken at the same time. RESULTS: A total of 45 renal transplantation patients (21 from cadavers, 24 from live donors) were evaluated in the study. The duration time of stent retention in patients with live donors was 25.04 +/- 4.55 and in patients with deceased donors was 26.19 +/- 4.08 days (P = .376). USC was observed in 12 (57.1%) and 6 (25%) patients while positive urine culture (PUC) was detected in 5 (23.8%) and 2 (8.3%) patients in deceased and live donor transplant recipients, respectively. Although the USC rate was significantly higher in the deceased donor renal transplant group (P = .022), there was no significant different in the rates of PUC (P = .137). Enterecoccus species was the common pathogen isolated from ureteral stent and urine. The micro-organisms isolated from ureteral stent in deceased and live donors, respectively, were distributed as follows: Enterococcus 5/3, Candida 3/1, Escherichia coli 2/1, Klebsiella pneumonia 1/1, and staphylococci in 1/0 patients. All E coli and K pneumoniae are extended spectrum beta-lactamase (ESBL)-positive isolates and resistant to sulfamethoxazole trimethoprim (SMX/TMP). CONCLUSIONS: We report a high incidence of USC in deceased renal transplants. Enterecoccus instead of E coli is the most common pathogen during the first month after transplantation. Transplantation centers should be aware that deceased donor renal transplant recipients are more prone to stent-related infection and the antibacterial resistance rapidly increases in uropathogens. PMID- 29149966 TI - Seasonal Variation of Vitamin D Status in Long-Term Kidney Transplant Recipients. AB - BACKGROUND: There is little information about circannual rhythm of vitamin D level in kidney transplantation (KTx) patients. MATERIAL AND METHODS: In 71 patients (27 females; 44 males) in the long term after KTx (5.5 +/- 2.6 years) during the winter and summer months plasma concentration of 25-hydroxyvitamin D (25(OH)D), 1,25-hydroxyvitamin D, parathormone (PTH), fibroblast growth factor 23 (FGF-23), calcium, and phosphorus were assessed. Vitamin D status was classified according to 25(OH)D level (ie, insufficiency, <=30 ng/mL; deficiency, <15 ng/mL). RESULTS: In this study, 96% of KTx patients had vitamin D insufficiency including 37% deficiency during winter and 89% of KTx patients had vitamin D insufficiency and 24% had vitamin D deficiency, respectively, during summer. Mean 25(OH)D level during winter was lower than in summer (17.4 +/- 7.1 vs 20.2 +/- 7.2 ng/mL; P = .02), similar to calcitriol (163.6 +/- 37.4 vs 284.5 +/- 77.8 pmol/L; P = .001). There were no significant differences in winter and summer levels of calcium, phosphorus, and PTH. The 25(OH)D level was significantly higher in patients with estimated glomerular filtration rate (eGFR) >=45 mL/min/1.73 m2 compared with those with lower eGFR (21.6 +/- 7.5 vs 17.6 +/- 6.0; P = .02) only in the summer time. CONCLUSIONS: Most of the KTx patients have vitamin D insufficiency during both winter and summer with higher concentration of vitamin D metabolites in summer. Other factors than graft function may have an impact on vitamin D levels in KTx patients. PMID- 29149967 TI - Early Prediction of Cardiovascular Disease in Kidney Transplant Recipients. AB - Cardiovascular disease (CVD) is frequent after kidney transplantation (KT). This study investigated CVD prediction in KT by information available before KT or within 6 months after KT. The study cohort consisted of 629 patients with KT in 2005-10 and with adult age at KT. The end point was incidence up to 2015 of CVD (coronary heart disease, cerebrovascular disease, peripheral artery disease). Graft failure, non-CVD death with functioning graft, and loss to follow-up were considered competing events. CVD prediction was investigated for 34 variables by means of competing-risks regression. Follow-up range was 0.28-10.00 years (mean +/- SD, 7.30 +/- 3.10). First incident event was CVD in 103 patients and competing events in 146 patients. In the multivariable model for pre-KT variables only, CVD predictors were male sex (hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.06-2.66), diabetic nephropathy (HR, 6.63; 95% CI, 1.81-24.35), pre-KT dialysis for >=5 years (HR, 1.52; 95% CI, 1.02-2.27), pre-KT CVD (HR, 4.87; 95% CI, 2.84-8.35), and age at KT >=45 years (HR, 2.98; 95% CI, 1.83-4.87). In the model for pre-KT and post-KT variables together, the sole post-KT CVD predictor was estimated glomerular filtration rate <60 mL/min at the 6-month visit (HR, 1.75; 95% CI, 1.11-2.77). Diabetic nephropathy, pre-KT dialysis, pre KT CVD, and age at KT predicted 91.2% of incident CVD. Early available information effectively predicted CVD in KT independently from competing events. PMID- 29149968 TI - Effects of Renal Transplantation on Female Sexual Dysfunction: Comparative Study With Hemodialysis and a Control Group. AB - OBJECTIVES: Sexual dysfunction occurs commonly in individuals with end-stage renal disease. Chronic renal failure as well as the treatments used for it generally has a negative impact on sexual function with a subsequent increase in the risk of depression. There is scarcity of published data on female sexual dysfunction and the degree of improvement in patients on hemodialysis (HD) and transplant (Tx) recipients. The aim of this study was to compare the sexual function and degree of depression in HD and Tx patients with control group. For this purpose, we used the validated Female Sexual Function Index (FSFI) and Beck Depression Inventory (BDI). MATERIALS AND METHODS: A total of 23 renal Tx, 29 HD, and 30 control patients were enrolled in the study. HD patients were required to be undergoing HD for >=6 months, and for renal Tx recipients, the Tx had to be performed >=6 months before study entry. All women underwent a general and urogynecologic examination. Demographic and clinical variables were documented. FSFI and BDI scale scores were compared among groups. RESULTS: The rates of female sexual dysfunction were 56.7%, 89.7%, and 73.9% in the control, HD, and Tx, patients respectively. Total FSFI scores in HD group were significantly lower than those in Tx and control patients (P < .05). FSFI scores improved significantly in the Tx group. BDI scores in HD and control subjects were 23.24 and 14.17, respectively, with a significant difference between the 2 groups (P < .005). BDI score in the Tx group was 16.65 and the difference was statistically insignificant. CONCLUSIONS: This preliminary study documented that successful Tx may positively affect sexual life in women with chronic renal failure. A diagnosis of female sexual dysfunction should be made routinely in patients with chronic renal failure. PMID- 29149969 TI - Indicators of Complex Care During the Consultation-Liaison Psychiatry Activity at the Transplant Center of the Policlinico Hospital, Modena. AB - OBJECTIVE: The objective of this study was to identify possible biopsychosocial predictors of organizational complexity in patients referred to the consultant psychiatrist for assessment before liver transplantation. METHODS: This was a case-control study. All psychiatric consultations performed before and after liver transplantation from January 1, 2008 to December 31, 2013 were included. Complexity was operationalized as "undergoing two or more psychiatric consultations". Controls were defined as patients who were assessed only once by the consultant. Cases were represented by patients who underwent two or more consultations. Statistical analysis was performed with STATA 13.1, using logistic regressions. RESULTS: In this study, 515 consultations were requested for 309 patients potentially eligible for liver transplantation. Controls were 209 (67.6%); cases were 100 (32.4%). Positive psychiatric history (odds ratio [OR] = 2.44; 95% confidence interval [CI], 1.43-4.16), viral or toxic (alcohol- or drug related) liver disease (OR = 1.93; 95% CI, 1.09-3.42), use of psychotropic medications at the baseline (OR = 2.15; 95% CI, 1.14-4.07), and female gender (OR = 1.77; 95% CI, 1.01-3.11) were significantly associated with an increased probability of being cases. CONCLUSIONS: Positive psychiatric history, viral or toxic liver disease, use of psychotropic medications at the index referral, and female gender are possible biopsychosocial predictors of complexity in patients eligible for liver transplantation. PMID- 29149970 TI - Thromboelastography as a Predictor of Outcomes Following Liver Transplantation. AB - BACKGROUND: Thromboelastography (TEG) has been used perioperatively during liver transplantation (LT) to provide a real-time global hemostasis assessment for targeted blood product replacement. We aimed to analyze the relationship between post-LT TEG results and outcomes. METHODS: We retrospectively analyzed patients undergoing LT from November 2008 to December 2014 at Mayo Clinic Florida. All 441 single-organ 1st-time LT patients aged >=18 years requiring post-LT intensive care unit management were included. TEG parameters including r time, k time, alpha angle, and maximum amplitude were measured regularly during the first 24 hours after LT. Outcomes included return to the operating room secondary to bleeding, length of hospitalization, survival, and early allograft dysfunction. RESULTS: A prolonged and/or lengthening r time, k time, and r+k time were all independently associated with increased length of hospitalization after LT. Increased maximum amplitude on the first post-LT TEG was associated with early allograft dysfunction. No notable associations of TEG parameters with survival or return to operating room were observed. CONCLUSIONS: The association of absolute and temporal TEG value changes with increased length of hospitalization and early allograft dysfunction suggests that TEG may have a role in identifying patients at high risk for these outcomes. PMID- 29149971 TI - Fibrinolysis in Living Donor Liver Transplantation Recipients Evaluated Using Thromboelastometry: Impact on Mortality. AB - BACKGROUND: Inadequate hemostasis during living donor liver transplantation (LDLT) is mainly due to coagulopathy but may also include fibrinolysis. The purpose of this study was to determine the incidence of fibrinolysis and assess its relevance to mortality in LDLT. METHODS: The incidence and prognosis of fibrinolysis were retrospectively studied in 76 patients who underwent LDLT between April 2010 and February 2013. Fibrinolysis was evaluated and defined by maximum lysis (ML) >15% within a 60-minute run time using thromboelastometry (ROTEM). RESULTS: Fibrinolysis was observed in 19 of the 76 (25%) patients before the anhepatic (pre-anhepatic) phase and was developed in 24 (32%) patients during and after the anhepatic (post-anhepatic) phase. In these 43 patients who had fibrinolysis, spontaneous recovery occurred in 29 patients (73%) within 3 hours after reperfusion of the liver graft. Recovery with tranexamic acid was noted in 2 patients with fibrinolysis in the post-anhepatic phase. Thrombosis in the portal vein and liver artery was noted in 14 patients, and the incidence was significantly greater in patients with post-anhepatic fibrinolysis than in those with pre-anhepatic fibrinolysis (P = .0017). Fibrinolysis that developed in the pre-anhepatic phase was associated with increased 30-day and 6-month mortalities (P = .0003 and .0026, respectively). CONCLUSIONS: Fibrinolysis existed and developed in a large percentage of patients during LDLT. Thrombosis in the portal vein and hepatic artery was more common in patients with fibrinolysis in the post anhepatic phase. Fibrinolysis that developed in the pre-anhepatic phase was associated with increased 30-day and 6-month mortalities. PMID- 29149972 TI - Right Extended Split Liver Transplantation Compared With Whole Liver Transplantation: Lessons Learned at a Single Center in Latin America-Results From a Match Case-Control Study. AB - BACKGROUND: Despite the progressively increasing gap between patients waiting for liver transplant under the Model for End-stage Liver Disease MELD system and the availability of deceased donor organs, the use of right extended split liver grafts (RESLG) has not been accepted by all centers. In this study, we compared the results obtained using RESLG vs a group of matched whole liver graft (WLG) recipients at a single center in Latin America. METHODS: A single-center retrospective review performed between August 2009 and December 2015. RESULTS: Fifteen RESLGs were implanted to recipients between 13 and 70 years of age; 80% were performed ex situ. The "biological MELD" score for the RESLG group was 17.5 +/- 5.6, and it was 12.8 +/- 4.5 for the WLG group (P = .01). Cold ischemia times were significantly longer in RESLG recipients compared with WLG recipients (528 minutes vs 420 minutes; P < .01). No significant differences were found in biliary (leak or strictures P = .40) and arterial complications (hepatic artery thrombosis, P = .06). RESLG patients benefited from a considerable reduction on their waiting time in list. The 1-, 3-, and 5-year patient survival rates were 93%, 93%, and 93% respectively, for RESLG recipients vs 100%, 95.7%, and 86.1%, respectively, for WLG recipients. The 1-, 3-, and 5-year graft survival rates were 79.4%, 79.4%, and 79.4% for RESLG recipients and 89.7%, 89.7%, and 89.7% for WLG recipients, respectively. No statistical differences were observed. CONCLUSION: RESLG allows expeditious transplantation for low MELD recipients. Its use should be expanded in Latin America and worldwide as a valid alternative to increase the donor pool as it has been used in other regions. PMID- 29149973 TI - Hepatitis C Virus Recurrence Occurs Earlier in Patients Receiving Donation After Circulatory Death Liver Transplant Grafts Compared With Those Receiving Donation After Brainstem Death Grafts. AB - INTRODUCTION: Hepatitis C virus (HCV)-related cirrhosis remains the commonest indication for liver transplantation worldwide, yet few studies have investigated the impact of donation after circulatory death (DCD) graft use on HCV recurrence and patient outcomes. DCD grafts have augmented the limited donor organ pool and reduced wait-list mortality, although concerns regarding graft longevity and patient outcome persist. METHODS: This was a single-center study of all HCV + adults who underwent DCD liver transplantation between 2004 and 2014. 44 HCV+ patients received DCD grafts, and were matched with 44 HCV+ recipients of donation after brainstem death (DBD) grafts, and their outcomes examined. RESULTS: The groups were matched for age, sex, and presence of hepatocellular carcinoma; no significant differences were found between the group's donor or recipient characteristics. Paired and unpaired analysis demonstrated that HCV recurrence was more rapid in recipients of DCD organs compared with DBD grafts (408 vs 657 days; P = .006). There were no significant differences in graft survival, patient survival, or rates of biliary complications between the cohorts despite DCD donors being 10 years older on average than those used in other published experience. CONCLUSIONS: In an era of highly effective direct acting antiviral therapy, rapid HCV recrudescence in grafts from DCD donors should not compromise long-term morbidity or mortality. In the context of rising wait-list mortality, it is prudent to use all available sources to expand the pool of donor organs, and our data support the practice of using extended-criteria DCD grafts based on donor age. Notwithstanding that, clinicians should be aware that HCV recrudescence is more rapid in DCD recipients, and early post-transplant anti viral therapy is indicated to prevent graft injury. PMID- 29149974 TI - Liver Transplantation With Old Grafts: A Ten-Year Experience. AB - BACKGROUND: The persistent scarcity of donors has prompted liver transplantation teams to find solutions for increasing graft availability. We report our experience of liver transplantations performed with grafts from older donors, specifically over 70 and 80 years old. PATIENTS AND METHODS: We analyzed our prospectively maintained single-center database from January 1, 2005, to December 31, 2014, with 380 liver transplantations performed in 354 patients. Six groups were composed according to donor age: <40 (n = 84), 40 to 49 (n = 67), from 50 to 59 (n = 62), from 60 to 69 (n = 76), from 70 to 79 (n = 64), and >=80 years (n = 27). RESULTS: Donors <40 years of age had a lower body mass index, died more often from trauma, and more often had cardiac arrest and high transaminase levels. In contrast, older donors (>=70 years of age) died more often from stroke. Recipients of grafts from donors <50 years of age were more frequently infected by hepatitis C virus; recipients of oldest grafts more often had hepatocellular carcinoma. Cold ischemia time was the shortest in donors >80 years of age. Patient survival was not significantly different between the groups. In multivariate analysis, factors predicting graft loss were transaminase peak, retransplantation and cold ischemia time but not donor age. CONCLUSIONS: Older donors >70 and >80 years of age could provide excellent liver grafts. PMID- 29149975 TI - Clinical Outcomes of Living Liver Transplantation According to the Presence of Sarcopenia as Defined by Skeletal Muscle Mass, Hand Grip, and Gait Speed. AB - BACKGROUND: Sarcopenia is an independent predictor of death after living-donor liver transplantation (LDLT). However, the ability of the Asian Working Group for Sarcopenia criteria for sarcopenia (defined as reduced skeletal muscle mass plus low muscle strength) to predict surgical outcomes in patients who have undergone LDLT has not been determined. METHODS: This study prospectively enrolled 366 patients who underwent LDLT at Kyushu University Hospital. Skeletal muscle area (determined by computed tomography), hand-grip strength, and gait speed were measured in 102 patients before LDLT. We investigated the relationship between sarcopenia and surgical outcomes after LDLT performed in three time periods. RESULTS: The number of patients with lower skeletal muscle area has increased to 52.9% in recent years. The incidence of sarcopenia according to the Asian Working Group for Sarcopenia criteria was 23.5% (24/102). Patients with sarcopenia (defined by skeletal muscle area and functional parameters) had significantly lower skeletal muscle area and weaker hand-grip strength than did those without sarcopenia. Compared with non-sarcopenic patients, patients with sarcopenia also had significantly worse liver function, greater estimated blood loss, greater incidence of postoperative complications of Clavien-Dindo grade IV or greater (including amount of ascites on postoperative day 14, total bilirubin on postoperative day 14, and postoperative sepsis), and longer postoperative hospital stay. Multiple logistic regression analysis revealed sarcopenia as a significant predictor of 6-month mortality. CONCLUSIONS: The combination of skeletal muscle mass and function can predict surgical outcomes in LDLT patients. PMID- 29149976 TI - Clinical Challenges of Tacrolimus for Maintenance Immunosuppression Post-Lung Transplantation. AB - Lung transplantation (LTx) is a successful treatment option for end-stage lung disease, and immunosuppressant regimens, utilized to prevent rejection of the transplanted graft, are paramount to maintaining long-term graft survival. Immunosuppression can be classified as induction, maintenance, and antirejection therapy. This article focuses on maintenance immunosuppression that includes a combination of a calcineurin inhibitor (CNI), cell cycle inhibitor, and corticosteroid. CNIs remain the cornerstone of immunosuppression following LTx, and tacrolimus is now the preferred CNI, based on a better adverse effect profile and some limited evidence for enhanced efficacy. Tacrolimus is associated with a number of unique challenges post-LTx, with erratic and highly variable absorption making it difficult to achieve and maintain therapeutic levels. Current methods of therapeutic drug monitoring are extrapolated from models in liver and kidney transplants and are not validated in the LTx population. Alternative methods of delivering tacrolimus can address some of the issues associated with their use and can be utilized in particular clinical scenarios. Long-term toxicities attributed to tacrolimus, such as nephrotoxicity and neurotoxicity, can limit the long-term success of tacrolimus in preventing allograft rejection. This article emphasizes the current clinical challenges faced when managing LTx recipients with tacrolimus, offers strategies to manage these issues, and highlights the areas that need further research. PMID- 29149977 TI - Donor Smoking and Older Age Increases Morbidity and Mortality After Lung Transplantation. AB - BACKGROUND: The lack of lung transplant donors has necessitated the use of donors with a smoking history and donors of older age. We have evaluated the effects of donor smoking history and age on recipient morbidity and mortality with baseline values of pulmonary function and survival free of chronic lung allograft dysfunction (CLAD) as morbidity variables. METHODS: This is a retrospective analysis of 588 consecutive lung transplant recipients and their corresponding 454 donors. Donors were divided into three groups: group 1 included smokers, group 2 nonsmokers, and group 3 had unknown smoking status; these were further divided into three age groups: group A: 0 to 39 years; group B: 40 to 54 years; and group C: >=55 years. RESULTS: One hundred fifty-one donors were former or actual smokers, 175 were nonsmokers, and 128 had unknown smoking histories. Baseline forced expiratory volume in 1 second, forced vital capacity, and diffusion capacity of carbon monoxide were lowest in the groups who received lungs from a smoking donor. CLAD-free survival was identical in all smoking groups, and overall survival was better both for lungs from nonsmoking donors and donors with unknown smoking status compared to lungs from smoking donors. One hundred sixty-nine donors were in age group A, 203 in B, and 82 in C. Baseline forced expiratory volume in 1 second, forced vital capacity, and diffusion capacity of carbon monoxide were lowest in the groups who received lungs from donors older than 55 years. Overall survival as well as CLAD-free survival was significantly lower with donors >=55 years. CONCLUSIONS: Donor smoking history and older donor age impact lung function, mortality, and CLAD-free survival after transplantation. Because of a shortage of organs, extended donor criteria may be considered while taking waiting list mortality into account. PMID- 29149978 TI - Perioperative Prophylaxis for Total Artificial Heart Transplantation. AB - BACKGROUND: Practice variation regarding perioperative antimicrobial prophylaxis in total artificial heart transplantations (TAH-t) across institutions is unknown. The aim of our survey was to assess the current practices for prevention of infection in TAH-t recipients among different programs. METHODS: An electronic survey was sent to programs that implant Syncardia TAH (Syncardia Systems, Tuscon, Ariz, USA). Proportions were analyzed for categorical variables; means and SDs were analyzed for continuous variables. RESULTS: The majority of centers (80.8%) had a formal surgical infection prophylaxis protocol. For non-penicillin allergic patients, five (20.1%) institutions reported using a 4-drug regimen, seven (29.2%) used a 3-drug regimen, five (20.1%) used a 2-drug regimen, and seven (29.2%) used a cephalosporin alone. Similar data was seen in the penicillin allergic patients. Infections were reported to occur postoperatively in 52.2% centers. During the first month after TAH-t, bacteremia represented 27.3%, driveline infections 27.2%, pulmonary infections 9%, and mediastinal infections 18.2%. The most common organisms seen within the first month were Candida spp., Escherichia coli, and Pseudomonas aeruginosa (21.4%). In 65% of centers, the mean rate of death post-TAH-t due to infection was 14.5% (SD, 22.3%). The mean rate of patients surviving until orthotopic heart transplantation was 58.6% (SD, 27.7%). CONCLUSIONS: Preventing infections post-TAH-t is key to decreasing morbidity and mortality. All institutions administered perioperative prophylaxis for TAH-t with significant variation among the centers. The majority of the centers have a formal perioperative prophylactic protocol. PMID- 29149979 TI - Influence of Oral Anaerobic Bacteria on Hematopoietic Stem Cell Transplantation Patients: Oral Mucositis and General Condition. AB - OBJECTIVE: Oral mucositis (OM) caused by infection facilitated by myelosuppression and immunosuppression can be controlled through oral care. We investigated changes in oral anaerobic bacterial flora during the onset of OM with hematopoietic stem cell transplantation (HSCT). METHODS: This study included 19 patients who underwent HSCT. All received professional oral care before initiating the preparative regimen. We assessed OM, oral health and obtained microbial samples from the oral cavity during 5 assessment points: before initiating the preparative regimen; the day before HSCT (day 1); and at 7, 14, and 30 days after HSCT. Microbial species were identified by using a mass spectrometer. RESULTS: The number of patients with serious OM increased initially after HSCT and decreased thereafter. Many Streptococcus species were identified before HSCT, but these gradually decreased and were replaced by coagulase negative staphylococci. An increase in Candida species after HSCT and the identification of Enterococcus species were significantly associated with OM. Nutritional status recovery and prognosis were significantly worse in patients who developed OM. CONCLUSIONS: To the best of our knowledge, this study is the first which shows that anaerobic bacteria were identified in patients' oral flora before and after HSCT by using a mass spectrometer. These results indicate that Enterococcus species and Candida species may have been associated with OM. OM affected the patients' improvement in nutritional status and their prognosis. We concluded that it is important to provide more complete oral care instructions and interventions to prevent these bacterial infections. PMID- 29149980 TI - Incidence of Infectious Complications in Children With Acute Lymphoblastic Leukemia Treated With Hematopoietic Stem Cell Transplantation. AB - OBJECTIVE: We analyzed incidence and profile of infections in children with acute lymphoblastic leukemia (ALL) treated with hematopoietic stem cell transplantation (HSCT) in Polish pediatric HSCT departments, over a 2-year period. PATIENTS AND METHODS: Hospital records of 67 patients, who underwent allogeneic HSCT for ALL, were analyzed retrospectively for microbiologically documented infection: bacterial infection (BI), viral infection (VI), and fungal infection (FI). The majority of patients (40/67; 59.7%) underwent HSCT from matched unrelated donors (MUD). RESULTS: In total, 84 BI in 31 patients, 93 VI in 50 patients, and 27 FI in 22 patients were diagnosed. No differences were found in the frequency of occurrence of BI according to the type of transplant (P = .16); the occurrence of VI was statistically more frequent in MUD transplant recipients as compared with matched sibling donors (MSD) and mismatched related donors (MMFD; P = .001) and there was a trend in MUD patients for the higher occurrence of FI in comparison with MSD and MMFD transplants (P = .08). Regarding disease status, the occurrence of BI, VI, and FI was statistically more frequent in children who underwent transplantation in their first complete remission (CR1), rather than those who underwent transplantation in >=CR2 (P < .05). In conclusion, infectious complications are an important cause of morbidity in children with ALL treated with allogeneic HSCT and the incidence of infections is high in this group of patients. PMID- 29149981 TI - Ischemic Preconditioning Produces Comparable Protection Against Hepatic Ischemia/Reperfusion Injury Under Isoflurane and Sevoflurane Anesthesia in Rats. AB - BACKGROUND: Various volatile anesthetics and ischemic preconditioning (IP) have been demonstrated to exert protective effect against ischemia/reperfusion (I/R) injury in liver. We aimed to determine whether application of IP under isoflurane and sevoflurane anesthesia would confer protection against hepatic I/R injury in rats. METHODS: Thirty-eight rats weighing 270 to 300 grams were randomly divided into 2 groups: isoflurane (1.5%) and sevoflurane (2.5%) anesthesia groups. Each group was subdivided into sham (n = 3), non-IP (n = 8; 45 minutes of hepatic ischemia), and IP (n = 8, IP consisting of 10-minute ischemia plus 15-minute reperfusion before prolonged ischemia) groups. The degree of hepatic injury and expressions of B-cell lymphoma 2 (Bcl-2) and caspase 3 were compared at 2 hours after reperfusion. RESULTS: Hepatic ischemia induced significant degree of I/R injuries in both isoflurane and sevoflurane non-IP groups. In both anesthetic groups, introduction of IP dramatically attenuated I/R injuries as marked by significantly lower aspartate aminotransferase and aminotransferase levels and better histologic grades compared with corresponding non-IP groups. There were 2.3- and 1.7-fold increases in Bcl-2 mRNA levels in isoflurane and sevoflurane IP groups, respectively, compared with corresponding non-IP groups (both P < .05). Caspase 3 level was significantly high in the isoflurane non-IP group compared with the sham group; however, there were no differences among the sevoflurane groups. CONCLUSIONS: The degree of hepatic I/R injury was significantly high in both isoflurane and sevoflurane groups in rats. However, application of IP significantly protected against I/R injury in both volatile anesthetic groups to similar degrees, and upregulation of Bcl-2 might be an important mechanism. PMID- 29149982 TI - Marrow Mesenchymal Stem Cells Effectively Reduce Histologic Changes in a Rat Model of Chronic Renal Allograft Rejection. AB - BACKGROUND: Chronic allograft rejection remains as the leading cause of the chronic renal grafts loss post-transplantation. No therapy has been found really effective to prevent and treat chronic allograft rejection. Mesenchymal stem cells (MSCs) have characteristics of immunomodulation and are expected to be used for inducing graft immune tolerance in organ transplantation. We investigated the efficacy and safety of early infusion of donor-derived marrow MSCs in a rat model of chronic renal allograft rejection. METHODS: Orthotopic kidney transplantations were performed in a rat strain combination of Sprague-Dawley (SD) -> Wistar. The native right kidneys of recipient rats were kept intact as internal control of each graft. Twenty-three successfully transplanted recipient rats were divided into 3 groups: group 1 (the MSCs therapy group) (n = 8) and group 2 (the control group) (n = 8) both received a 10-day course of cyclosporine (CsA) (2 mg/kg intraperitoneally) to prevent initial acute rejection. MSCs (1 * 107) of first dosage and an additional dosage were injected into group 1 postoperative days (PODs) 0, 3, and 7. Group 2 received 0.9% saline solution in addition to CsA as the control group. Group 3 consisted of recipients (n = 7) receiving neither immunosuppression nor MSCs. Renal histopathology and immunohistochemistry of transforming growth factor beta1 (TGF-beta1) was examined at week 12. Safety of MSC infusion was determined by observing symptoms and signs after infusion and performing gross anatomy at week 12. RESULTS: All the grafts of group 3 developed acute rejection and were rejected within 4 weeks. Bone marrow MSCs significantly decreased the severity of mononuclear cell interstitial inflammation, tubular atrophy, interstitial fibrosis, and vascular fibrous intimal thickening in renal grafts (P < .001). MSCs also greatly reduced the glomerulosclerosis rate of the transplanted kidneys of group 1 (P < .001). The TGF-beta1 expression of group 1 was weaker than that of group 2 (P = .043). There were no symptoms or signs of severe adverse side effects observed. CONCLUSIONS: Early bone marrow MSCs infusion on PODs 0, 3, and 7 are effective and safe for chronic renal allograft rejection in rats. MSCs hold significant promise for clinical transplantation to treat chronic renal allograft rejection and prolong the renal graft survival. PMID- 29149983 TI - A Novel Model of Mouse-to-Rat Kidney Xenotransplantation. AB - Transplantation animal models require 2 animals for each experiment, 1 as a donor and 1 as a recipient. At the present time, developing microsurgical instruments and refining surgical techniques should allow us to reduce the number of animal used for transplantation research. In this study, we aimed to harvest 2 kidneys from 1 donor to be able to minimize the number of animals needed for transplantation studies. For this purpose, we developed a kidney xenotransplantation model from mouse to rat, in which only 1 animal was used as the donor for 2 kidney recipients. Ten male Balb/c mice weighing from 25 to 30 g were used as donors, and 20 male Sprague-Dawley rats weighing from 150 to 200 g were used as recipients. In this study, the harvesting of 2 kidneys from a mouse as well as the recipient operation were described with technical detail. Although harvesting 2 kidneys from a mouse and mouse-to-rat kidney xenotransplantation is a highly challenging microsurgical procedure, we believe that every experienced surgeon should be capable of performing this surgery with some practice. This model allows us to reduce the number of animals in transplantation studies without compromising the graft quality. We strongly recommend our refined harvesting technique to researchers, particularly in terms of animal rights. PMID- 29149984 TI - Corneal Xenotransplantation From Pig to Rhesus Monkey: No Signs of Transmission of Endogenous Porcine Retroviruses. AB - BACKGROUND: Xenotransplantations of pig corneas have become an attractive alternative to human corneas. Such xenotransplantations carry the danger, however, of transmission of porcine endogenous retroviruses (PERVs). Here, we investigated whether porcine corneas harbor viral DNA and RNA and whether transplantation to a nonhuman primate would lead to host PERV infection. METHODS: Monkey vein endothelial cells (MVECs) were inoculated with porcine aortic endothelial cell (PAEC) supernatants, and DNA and total RNA of MVECs were tested for PERV by polymerase chain reaction (PCR) and reverse transcription PCR (RT PCR) assays. Corneas were harvested from Wuzhishan miniature pigs, and the presence of PERV proviral DNA and RNA was analyzed by PCR and RT-PCR, respectively. Fresh or dehydrated corneas were then transplanted to rhesus monkeys, and PERV proviral DNA and RNA were analyzed in host peripheral blood lymphocytes at 6 and 24 months. Furthermore, the presence of PERV sequences was analyzed in the transplant at 24 months. RESULTS: PCR analysis showed PERV transfection from PAECs to MVECs in vitro. PCR and RT-PCR gave positive signals for PERV subtypes A and B, but not PERV-C, regardless of how the corneas were prepared. No evidence was found for PERV transmission to the host, and the transplant had lost its viral signal at the end of the 24-month period. CONCLUSIONS: Regardless of cornea preparation and storage, PERV transmission from pig to host could not be detected, despite that the transplant was initially PERV positive. The use of the Wuzhishan miniature pig as the donor may be advantageous because it lacks PERV-C and hence potentially infectious A/C recombinants. PMID- 29149985 TI - Acute Rejection Pattern of an Outbred Strain Combination on Mouse-to-Rat Heterotopic Heart Xenotransplantation. AB - OBJECTIVES: This study aimed to investigate the acute rejection patterns of outbred mice and rats on a xenotransplantation model. MATERIALS AND METHODS: Thirty male Balb/c mice weighing from 30 to 40 g were used as donors, and 30 male outbred Sprague-Dawley rats weighing from 150 to 200 g were used as recipients for heterotopic heart xenotransplantation models. Animals were allocated into 5 groups according to their killed days, and each group had 6 animals. Animals in group 1 were followed for 1 day and then killed; animals in groups 2, 3, 4, and 5 were followed up 2, 3, 4, and 5 days after transplantation, respectively. Operative findings, the appearance and heartbeat strength of the grafts, and histopathologic examinations of the grafts were evaluated to determine acute rejection. RESULTS: There were no mortalities during the study period, and the animal survival rate was 100%. Heartbeat strengths were strong (4.5 +/- 0.5) and graft appearances were normal in group 1 animals. The heartbeat scores of the xenografts dramatically declined thereafter. Histopathologically, there were inflammation patterns in all xenografts. The infiltration of neutrophils and the formation of platelet and fibrin thrombi were seen in the first postoperative day and gradually increased daily. CONCLUSIONS: This study concluded that outbred Balb/c mouse to Sprague-Dawley rat combination has reliable acute xenograft rejection patterns microscopically and macroscopically in the heterotopic heart xenotransplantation model. PMID- 29149986 TI - Effects of Cyclosporine, Tacrolimus, and Rapamycin on Osteoblasts. AB - PURPOSE: One factor that can contribute to severe bone loss after transplantation is the direct action of immunosuppressants on bone cells. The aim of this work was to study the effects of cyclosporine (CsA), tacrolimus (FK-506), and rapamycin (RAPA) on the release of three local factors directly implicated in bone-remodeling regulation and apoptosis of human osteoblasts: interleukin (IL) 6, osteoprotegerin, and receptor activator of nuclear factor kappabeta (RANKL). BASIC PROCEDURES: Human osteoblasts were obtained from five different patients who underwent orthopedic surgery. These cells were treated with what are considered to be a clinically high dose and an acceptable dose of each immunosuppressant-RAPA 50 ng/mL and 12 ng/mL, FK-506 20 ng/mL and 5 ng/mL, CsA 1000 ng/mL and 250 ng/mL-or vehicle. Apoptotic cell death was quantified using flow cytometry of DNA content in permeabilized, propidium iodide-stained cells. IL-6 was measured using enzyme-linked immunosorbent assay (ELISA; Quantikine Human IL6, R&D Systems, Minneapolis, Minn, United States). Messenger RNA (mRNA) expression of osteoprotegerin, RANKL, and IL-6 was measured using quantitative RT PCR. MAIN FINDINGS: A significant increase in IL-6 (mRNA and released protein) was observed in the presence of FK-506 and RAPA. Addition of RAPA to the cultures of osteoblasts produced a significant increase in the OPG/RANKL ratio. A significant increase in osteoblast apoptosis was observed in the cells treated with FK-506 and RAPA 24 hours after the addition of immunosuppressants. CsA did not produce any significant changes in osteoblasts. PRINCIPAL CONCLUSIONS: These results suggest that an increase in osteoblast apoptosis by osteoblasts may be one of the mechanisms by which bone loss occurs after RAPA and FK-506 treatments. PMID- 29149988 TI - Erratum. PMID- 29149987 TI - Inhibition of Porcine Endogenous Retrovirus by Multi-Targeting Micro RNA Against Long Terminal Region. AB - BACKGROUND: There might be much benefit in xenotransplantation, however, the risk of infections across species barriers remains, especially porcine endogenous retrovirus (PERV). To date, many attempts have been made to knock down active PERVs by inhibitory RNA (RNAi) and micro RNA (miRNA), which target different genes of PERV. There are a few studies that have explored whether targeting promoter regions of PERV could exert an inhibition effect. METHODS: miRNAs were automatically selected based on an online program BLOCK-iT RNAi Designer. The inhibition efficiency between miRNAs was compared based on their inhibition of different PERV genes: long terminal repeats (LTR), gag, and pol. Both relative quantitative real-time polymerase chain reaction (PCR) and C-type reverse transcriptase activity were performed. RESULTS: The results demonstrated that miRNA targeting the LTR region degraded the target sequence, and simultaneously inhibited the mRNA expression of both gag and pol genes of PERV. The LTR1, LTR2, and dual LTR1 + LTR2 miRNA inhibited 76.2%, 22%, and 76.8% of gag gene expression, respectively. Similarly, the miRNA was found to knock down the pol gene expression of 69.8%, 25.5%, and 77.7% for single targeting miRNA (LTR1 and LTR2) and multi-targeting miRNA (LTR1 + LTR2), respectively. A stable PK15 clone constitutively expressed dual LTR1 + LTR2 miRNA and exhibited higher inhibitory up to 82.8% and 92.7% of the expressions of the gag and pol genes, respectively. Also, the result of co-cultivation of dual LTR1 + LTR2 miRNA transfected PK15 cell with a human cell line inhibited expression of LTR, gag, and pol genes of PERV. CONCLUSIONS: In conclusion, this study suggested that the LTR might be an alternative target for gene silencing of PERV, and that multi-targeting miRNA had better inhibitory effect than single- targeting miRNA. In an in vitro model, the presence of miRNA was able to reduce PERV infectivity in a human cell line. PMID- 29149989 TI - Low-background and visual detection of antibiotic based on target-activated colorimetric split peroxidase DNAzyme coupled with dual nicking enzyme signal amplification. AB - Herein, we have reported the development of a simple, rapid, and low cost colorimetric method for the detection of antibiotic based on target-activated split peroxidase DNAzyme coupled with dual nicking enzyme signal amplification (NESA). To lower background signal in G-quadruplex DNAzyme-based detection, the two split G-rich parts are caged into two different hairpin probes, respectively, preventing the two parts from assembling into the G-quadruplex structure. By the combination of restriction endonuclease-assisted cleavage reaction with the spilt G-quadruplex probes, target-modulated release of the two split G-rich parts is achieved, affording high specificity of antibiotic detection. Our strategy features with several aspects. First, the less background signal produced by the self-assembly of G-quadruplex in the absence of target is effectively eliminated owing to the pre-blocking of the two split G-rich parts. Second, dual NESA coupled G-quadruplex DNAzyme amplification strategy is integrated with colorimetric assay of antibiotic, which significantly improves the detection sensitivity. Third, peroxidase-mimicking DNAzyme is used as biocatalyst in our reaction system, which can catalyze the oxidation of 2,2' - azino - bis (3 - ethylbenzothiozoline - 6 - sulfonic acid) (ABTS2-) mediated by H2O2 to generate the colored radical anion (ABTS*-), allowing to low cost and visual detection of antibiotic by the naked eye. Under optimized conditions, the results revealed the proposed biosensor exhibits excellent specificity and sensitivity toward kanamycin with a detection limit as low as 14.7 pM. Hence, the target-activated split G-quadruplex DNAzyme and dual NESA-based strategy provides a useful and practical platform for antibiotic residues determination and other analytes detection in bio-analysis. PMID- 29149990 TI - Simultaneous determination of renal function biomarkers in urine using a validated paper-based microfluidic analytical device. AB - In this paper, we describe a validated paper-based microfluidic analytical device for the simultaneous quantification of two important biomarkers of renal function in urine. This paper platform provides an inexpensive, simple, and easy to use colorimetric method for the quantification of creatinine (CRN) and uric acid (UA) in urine samples. The microfluidic paper-based analytical device (MUPAD) consists of a main channel with three identical arms, each containing a circular testing zone and a circular uptake zone. Creatinine detection is based on the Jaffe reaction, in which CRN reacts with picrate to form an orange-red product. Uric acid quantification is based on the reduction of Fe3+ to Fe2+ by UA, which is detected in a colorimetric reaction using 1,10-phenanthroline. Under optimum conditions, obtained through chemometrics, the concentrations of the analytes showed good linear correlations with the effective intensities, and the method presented satisfactory repeatability. The limits of detection and the linear ranges, respectively, were 15.7 mg L-1 and 50-600 mg L-1 for CRN and 16.5 mg L-1 and 50-500 mg L-1 for UA. There were no statistically significant differences between the results obtained using the MUPAD and a chromatographic comparative method (Student's t-test at 95% confidence level). PMID- 29149991 TI - A fast and low-cost microfabrication approach for six types of thermoplastic substrates with reduced feature size and minimized bulges using sacrificial layer assisted laser engraving. AB - Since polydimethylsiloxane (PDMS) is notorious for its severe sorption to biological compounds and even nanoparticles, thermoplastics become a promising substrate for microdevices. Although CO2 laser engraving is an efficient method for thermoplastic device fabrication, it accompanies with poor bonding issues due to severe bulging and large feature size determined by the diameter of laser beam. In this study, a low-cost microfabrication method is proposed by reversibly sealing a 1 mm thick polymethylmethacrylate (PMMA) over an engraving substrate to reduce channel feature size and minimize bulges of laser engraved channels. PMMA, polycarbonate (PC), polystyrene (PS), perfluoroalkoxy alkane (PFA), cyclic-olefin polymers (COP) and polylactic acid (PLA) were found compatible with this sacrificial layer assisted laser engraving technique. Microchannel width as small as ~40 MUm was attainable by a laser beam that was 5 times larger in diameter. Bulging height was significantly reduced to less 5 MUm for most substrates, which facilitated leak proof device bonding without channel deformation. Microdevices with high aspect ratio channels were prepared to demonstrate the applicability of this microfabrication method. We believe this fast and low-cost fabrication approach for thermoplastics will be of interest to researchers who have encountered problem with polydimethylsiloxane based microdevices in their applications. PMID- 29149992 TI - A separable surface-enhanced Raman scattering substrate modified with MIL-101 for detection of overlapping and invisible compounds after thin-layer chromatography development. AB - By coupling surface-enhanced Raman spectroscopy (SERS) with thin-layer chromatography (TLC), a powerful method for detecting complex samples was successfully developed. However, in the TLC-SERS method, metal nanoparticles serving as the SERS-active substrate are likely to disturb the detection of target compounds, particularly in overlapping compounds after TLC development. In addition, the SERS detection of compounds that are invisible under both visible light and UV254/365 after TLC development is still a significant challenge. In this study, we demonstrated a facile strategy to fabricate a TLC plate with metal organic framework-modified gold nanoparticles as a separable SERS substrate, on which all separated components, including overlapping and invisible compounds, could be detected by a point-by-point SERS scan along the developing direction. Rhodamine 6G (R6G) was used as a probe to evaluate the performance of the substrate. The results indicated that the substrate provided good sensitivity and reproducibility, and optimal SERS signals could be collected in 5 s. Furthermore, this new substrate exhibited a long shelf life. Thus, our method has great potential for the sensitive and rapid detection of overlapping and invisible compounds in complex samples after TLC development. PMID- 29149993 TI - Label-free determination of prostate specific membrane antigen in human whole blood at nanomolar levels by magnetically assisted surface enhanced Raman spectroscopy. AB - Prostate cancer is one of the most common cancers among men and can in its later stages cause serious medical problems. Due to the limited suitability of current diagnostic biochemical markers, new biomarkers for the detection of prostate cancer are highly sought after. An ideal biomarker should serve as a reliable prognostic marker, be applicable for early diagnosis, and be applicable for monitoring of therapeutic response. One potential candidate is glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA), which has a promising role for direct imaging. GCPII is considerably over expressed on cancerous prostatic epithelial cells; its analysis typically follows radiological or spectrophotometric principles. Its role as a biomarker present in blood has been recently investigated and potential correlation between a concentration of GCPII and prostate cancer has been proposed. The wider inclusion of GCPII detection in clinical praxis limits mainly the time and cost per analysis. Here, we present a novel analytical nanosensor applicable to quantification of GCPII in human whole blood consisted of Fe3O4@Ag magnetic nanocomposite surface-functionalized by an artificial antibody (low-molecular weight GCPII synthetic inhibitor). The nanocomposite allows a simple magnetic isolation of GCPII using external magnetic force and its consecutive determination by magnetically assisted surface enhanced Raman spectroscopy (MA SERS) with a limit of detection 6 pmol. L-1. This method enables a rapid determination of picomolar concentrations of GCPII in whole human blood of healthy individuals using a standard addition method without a complicated sample pre-treatment. PMID- 29149994 TI - A novel fluorescence biosensor for sensitivity detection of tyrosinase and acid phosphatase based on nitrogen-doped graphene quantum dots. AB - In this paper, we developed a sensitive fluorescence biosensor for tyrosinase (TYR) and acid phosphatase (ACP) activity detection based on nitrogen-doped graphene quantum dots (N-GQDs). Tyrosine could be catalyzed by TYR to generate dopaquinone, which could efficiently quench the fluorescence of N-GQDs, and the degree of fluorescence quenching of N-GQDs was proportional to the concentration of TYR. In the presence of ACP, l-Ascorbic acid-2-phosphate (AAP) was hydrolyzed to generate ascorbic acid (AA), and dopaquinone was reduced to l-dopa, resulting in the fluorescence recovery of the quenched fluorescence by dopaquinone. Thus, a novel fluorescence biosensor for the detection of TYR and ACP activity based on N GQDs was constructed. Under the optimized experimental conditions, the fluorescence intensity was linearly correlated with the concentration of TYR and ACP in the range of 0.43-3.85 U mL-1 and 0.04-0.7 mU mL-1 with a detection limit of 0.15 U mL-1 and 0.014 mU mL-1, respectively. The feasibility of the proposed biosensor in real samples assay was also studied and satisfactory results were obtained. PMID- 29149995 TI - Facile synthesis of polyaniline-polythionine redox hydrogel: Conductive, antifouling and enzyme-linked material for ultrasensitive label-free amperometric immunosensor toward carcinoma antigen-125. AB - Sensitivity enhancement and proteins adsorption are the common challenges faced in protein immunoassays. In this work, an ultrasensitive and protein-resistant label-free amperometric immunosening platform for carcinoma antigen-125 (CA125) based on redox polyaniline-polythionine hydrogel (PANI-PThi gel) was developed. The as-prepared hydrogel, which was facilely synthesized by electropolymerization, exhibited good conductivity and strong hydrophilicity while the sensitivity and specificity of the immunosensor can be enhanced. Furthermore, the as-prepared AuNPs functionalized PANI-PThi gel exhibited strong current signal and H2O2 electrocatalytic ability, which guaranteed a large current variable range. Based on these, the prepared immunosensor revealed a wide linear range from 0.0001 U mL-1 to 1 kU mL-1, a limit of detection of 0.00125 U mL-1 and its sensitivity was at least three-fold higher than previous works. More importantly, the prepared immunosensor exhibited excellent specificity, making it capable of assaying CA125 in human serum. PMID- 29149996 TI - Coupling of two centrifugeless ultrasound-assisted dispersive solid/liquid phase microextractions as a highly selective, clean, and efficient method for determination of ultra-trace amounts of non-steroidal anti-inflammatory drugs in complicated matrices. AB - In this work, a new, simple, rapid, and environmentally friendly method with a high sample clean-up capability termed as centrifugeless ultrasound-assisted dispersive micro solid-phase extraction coupled with salting-out ultrasound assisted liquid-liquid microextraction based on solidification of a floating organic droplet followed by high performance liquid chromatography is introduced for the first time. In this method, the three non-steroidal anti-inflammatory drugs diclofenac, ibuprofen, and mefenamic acid are first extracted based on an effective nanoadsorbent named as the layered double hydroxide-carbon nanotube nanohybrid. The first step provides a rapid and convenient way to separate the adsorbent from the sample matrix by a syringe nanofilter without additional centrifugation. In the next step, which is based upon the salting-out effect, after emulsification in the presence of ultrasonic irradiation, the phase separation is simply achieved through the salting-out phenomenon, and the extracting solvent is suspended on top of the sample solution. Under the optimal experimental conditions including the initial pH value of 6.0, 8.0 mg of the nanohybrid, 3 min ultrasonic time, 100 MUL elution solvent (first step), secondary pH value of 3.0, 60 MUL of 1-undecanol, 60 s ultrasonic time, and flow rate of 3 mL min-1 (second step), good responses were obtained for diclofenac, ibuprofen, and mefenamic acid in the concentration ranges of 0.8-2000, 0.8-2500, and 0.5-2000 ng mL-1, respectively, with low limits of detection ranging from 0.1 to 0.2 ng mL-1. The intra-day and inter-day precisions for the target analytes at the three concentration levels were in the ranges of 6.1-7.8% and 6.3-8.1%, respectively. The proposed method was also successfully applied to the biological and waste water samples, and excellent recoveries were obtained in the range of 92.9-103.1% even when the matrix was complex. PMID- 29149997 TI - Surface sieving coordinated IMAC material for purification of His-tagged proteins. AB - Tailor-made materials for the purification of proteins with His-tag was designed through synergizing the selectivity of surface sieving and metal ion affinity. By excluding impurity proteins out of the surface polymer network, such materials could purify His-tagged proteins from the crude cell lysis with purity up to 90%, improved by 14% compared to that obtained by the commercial metal chelating affinity materials. This study might promote the His-tagged protein purification to a new level. PMID- 29149998 TI - Computational Complexity and Human Decision-Making. AB - The rationality principle postulates that decision-makers always choose the best action available to them. It underlies most modern theories of decision-making. The principle does not take into account the difficulty of finding the best option. Here, we propose that computational complexity theory (CCT) provides a framework for defining and quantifying the difficulty of decisions. We review evidence showing that human decision-making is affected by computational complexity. Building on this evidence, we argue that most models of decision making, and metacognition, are intractable from a computational perspective. To be plausible, future theories of decision-making will need to take into account both the resources required for implementing the computations implied by the theory, and the resource constraints imposed on the decision-maker by biology. PMID- 29150000 TI - Towards a Unitary Approach to Human Action Control. AB - From its academic beginnings the theory of human action control has distinguished between endogenously driven, intentional action and exogenously driven, habitual, or automatic action. We challenge this dual-route model and argue that attempts to provide clear-cut and straightforward criteria to distinguish between intentional and automatic action have systematically failed. Specifically, we show that there is no evidence for intention-independent action, and that attempts to use the criterion of reward sensitivity and rationality to differentiate between intentional and automatic action are conceptually unsound. As a more parsimonious, and more feasible, alternative we suggest a unitary approach to action control, according to which actions are (i) represented by codes of their perceptual effects, (ii) selected by matching intention-sensitive selection criteria, and (ii) moderated by metacontrol states. PMID- 29150001 TI - CRISPR History: Discovery, Characterization, and Prosperity. AB - CRISPR research is a very young research field since it was only 10years ago when the system was found to confer antiviral defense. Nevertheless, there has been an explosion of publications in CRISPR research in the past 5years. The research was started with the comparative genomics of microbial genomes early this century, which revealed the prevalence of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) in bacteria and archaea. Series of hypotheses were made based on bioinformatics analyses and tested experimentally within a few years after the CRISPR acronym was coined. These findings have not only led to the discovery of the unique antiviral system and the involved molecular mechanisms, but also to the development of CRISPR technology with various well-developed applications, such as genome editing in all three domains of life. Currently, widespread research efforts in multiple research disciplines have constantly yielded new insights into molecular mechanisms of CRISPR antiviral immunity, and new applications in scientific research and biomedical applications. Retrospectively, it is worth pointing out that close interdisciplinary interactions have fostered series of discoveries in the CRISPR research and worked as the driving force in the fast developing research field. PMID- 29150002 TI - Gene Editing and CRISPR Therapeutics: Strategies Taught by Cell and Gene Therapy. AB - A few years ago, we assisted in the demonstration for the first time of the revolutionary idea of a type of adaptive-immune system in the bacteria kingdom. This system, named CRISPR, and variants engineered in the lab, have been demonstrated as functional with extremely high frequency and fidelity in almost all eukaryotic cells studied to date. The capabilities of this RNA-guided nuclease have added to the interest that was announced with the advent of previous technologies for genome editing tools, such as ZFN and TALEN. The capabilities exhibited by these gene editors, opens up a novel scenario that indicates the promise of a next-generation medicine based on precision and personalized objectives, mostly due to the change in the paradigm regarding gene surgery. This has certainly attracted, like never before, the attention of the biotech business and investor community. This chapter offers a brief overview of some of the factors that have contributed to a rapid entry into the biotech and pharmaceutical company's pipeline, focusing on how cell and gene therapies (CGT), collectively known as advanced therapies, have become the driving forces toward the therapeutic uses of gene editing technology. The sum of all those efforts for more than 30years has contributed to the new paradigm of considering genes as medicines. PMID- 29149999 TI - Expansion and Renormalization of Human Brain Structure During Skill Acquisition. AB - Research on human brain changes during skill acquisition has revealed brain volume expansion in task-relevant areas. However, the large number of skills that humans acquire during ontogeny militates against plasticity as a perpetual process of volume growth. Building on animal models and available theories, we promote the expansion-renormalization model for plastic changes in humans. The model predicts an initial increase of gray matter structure, potentially reflecting growth of neural resources like neurons, synapses, and glial cells, which is followed by a selection process operating on this new tissue leading to a complete or partial return to baseline of the overall volume after selection has ended. The model sheds new light on available evidence and current debates and fosters the search for mechanistic explanations. PMID- 29150003 TI - CRISPR/Cas9 Technology: Applications and Human Disease Modeling. AB - The CRISPR/Cas9 system development has revolutionized the field of genome engineering through the efficient creation of targeted breaks in the DNA of almost any organism and cell type, opening an avenue for a wide range of applications in biomedical research and medicine. Apart from gene edition through knock-in or knock-out approaches, CRISPR/Cas9 technology has been used for many other purposes, including regulation of endogenous gene expression, epigenome editing, live-cell imaging of chromosomal loci, edition of RNA and high throughput screening. With all those technological improvements, CRISPR/Cas9 system has broadened the number of alternatives for studying gene function and the generation of more accurate disease models. Although many mechanistic questions remain to be answered and several challenges have yet to be addressed, the use of CRISPR/Cas9-based genome engineering technologies will increase our knowledge of disease processes and their treatment in the near future. PMID- 29150004 TI - Dynamics of Indel Profiles Induced by Various CRISPR/Cas9 Delivery Methods. AB - The introduction of CRISPR/Cas9 gene editing in mammalian cells is a scientific breakthrough, which has greatly affected basic research and gene therapy. The simplicity and general access to CRISPR/Cas9 reagents has in an unprecedented manner "democratized" gene targeting in biomedical research, enabling genetic engineering of any gene in any cell, tissue, organ, and organism. The ability for fast, precise, and efficient profiling of the double-stranded break induced insertions and deletions (indels), mediated by any of the available programmable nucleases, is paramount to any given gene targeting approach. In this study we review the most commonly used indel detection methods and using a robust, sensitive, and cost efficient Indel Detection by Amplicon Analysis method, we have investigated the impact of the most commonly used CRISPR/Cas9 delivery formats, including lentivirus transduction, plasmid lipofection, and ribo nuclear protein electroporation, on the dynamics of indel profile formation. We observe rapid indel formation using RNP electroporation, especially with synthetic stabilized gRNA, as well as long-term decline in overall indel frequency with lipofectamine-based, plasmid transfection methods. Most methods reach peak editing on day 2-3 postdelivery. Furthermore, we find relative increase in frequency of larger size indels (>6bp) under condition of persistent editing using stably integrated lentiviral gRNA and Cas9 vectors. PMID- 29150005 TI - CRISPR Libraries and Screening. AB - CRISPR-Cas9 technology has revolutionized large-scale functional genomic screening in mammalian cell-culture systems. Due in part to optimized lentiviral delivery vectors; it is now possible to perform CRISPR-Cas9 screens in animals in order to study biological processes in the context of a whole organism and within more physiologically relevant environment. This chapter focuses primarily on mouse models of human cancers; viral vectors used for simultaneous tumor initiation and genome editing and sgRNA library design considerations. Experience with direct and indirect in vivo RNAi screens in the literature is also discussed in order to highlight the challenges of delivering diverse libraries of small RNAs in vivo. PMID- 29150006 TI - Genome Engineering Using Haploid Embryonic Stem Cells. AB - Haploidy is a useful feature for the study of gene function because disruption of one allele in haploid cells, which contain only a single set of chromosomes, can cause loss-of-function phenotypes. Recent success in generating haploid embryonic stem (ES) cells from several mammalian species, including human, provides a new platform for simple genetic manipulation of the mammalian genome. The genome editing potential of the CRISPR/Cas system is enhanced by the use of haploid ES cells. For example, CRISPR/Cas has been used for high-efficiency generation of multiple knockouts and knockins in haploid ES cells, with potential application in genome-wide screening. In addition, live mice can be successfully obtained by nuclear transplantation of haploid ES cells into oocytes, providing a novel approach for the generation of gene-modified animals. PMID- 29150007 TI - CRISPR in Animals and Animal Models. AB - CRISPR-Cas9 has revolutionized the generation of transgenic animals. This system has demonstrated an unprecedented efficiency, multiplexability, and ease of use, thereby reducing the time and cost required for genome editing and enabling the production of animals with more extensive genetic modifications. It has also been shown to be applicable to a wide variety of animals, from early-branching metazoans to primates. Genome-wide screens in model organisms have been performed, accurate models of human diseases have been constructed, and potential therapies have been tested and validated in animal models. Several achievements in genetic modification of animals have been translated into products for the agricultural and pharmaceutical industries. Based on the remarkable progress to date, one may anticipate that in the future, CRISPR-Cas9 technology will enable additional far-reaching advances, including understanding the bases of diseases with complex genetic origins, engineering animals to produce organs for human transplantation, and genetically transforming entire populations of organisms to prevent the spread of disease. PMID- 29150008 TI - Learning's from the Editors Desk - 2017. PMID- 29150009 TI - New Comorbidities in the Changing Face of Cystic Fibrosis Care. PMID- 29150010 TI - Androgen Deprivation Alters Attention to Sexually Provocative Visual Stimuli in Elderly Men. AB - INTRODUCTION: Testosterone is known to regulate male sexual interest, but the exact way that androgens influence men's sexual cognition remains unclear. AIM: To investigate the influence of androgen deprivation (AD) on visual responses to sexually suggestive stimuli in men treated for prostate cancer with AD therapy. METHODS: Patients with AD-treated prostate cancer, patients with prostate cancer not on AD therapy, and age-matched healthy control participants were exposed to images of male and female runway models fully or minimally clothed. Eye tracking was used to compare looking behavior among groups. MAIN OUTCOME MEASURES: Proportion of fixations on fully clothed vs minimally clothed models and proportion of fixations on target areas of interest (ie, legs, chest, pelvis, and face) of fully clothed and minimally clothed models were analyzed and compared among groups. RESULTS: Although men not on AD exhibited a larger proportion of fixations on the minimally clothed compared with the fully clothed images, there was no difference between the 2 image types for men on AD. This was true regardless of whether the images depicted male or female models. Groups did not differ in their fixations to target areas of interest. CONCLUSION: These results suggest that testosterone can influence men's visual attention to sexual stimuli; specifically, AD can attenuate the time spent fixated on sexualized targets. Palmer-Hague JL, Tsang V, Skead C, et al. Androgen Deprivation Alters Attention to Sexually Provocative Visual Stimuli in Elderly Men. Sex Med 2017;5:e245-e254. PMID- 29150011 TI - Optimization of CRISPR/Cas9 genome editing for loss-of-function in the early chick embryo. AB - The advent of CRISPR/Cas9 has made genome editing possible in virtually any organism, including those not previously amenable to genetic manipulations. Here, we present an optimization of CRISPR/Cas9 for application to early avian embryos with improved efficiency via a three-fold strategy. First, we employed Cas9 protein flanked with two nuclear localization signal sequences for improved nuclear localization. Second, we used a modified guide RNA (gRNA) scaffold that obviates premature termination of transcription and unstable Cas9-gRNA interactions. Third, we used a chick-specific U6 promoter that yields 4-fold higher gRNA expression than the previously utilized human U6. For rapid screening of gRNAs for in vivo applications, we also generated a chicken fibroblast cell line that constitutively expresses Cas9. As proof of principle, we performed electroporation-based loss-of-function studies in the early chick embryo to knock out Pax7 and Sox10, key transcription factors with known functions in neural crest development. The results show that CRISPR/Cas9-mediated deletion causes loss of their respective proteins and transcripts, as well as predicted downstream targets. Taken together, the results reveal the utility of this optimized CRISPR/Cas9 method for targeted gene knockout in chicken embryos in a manner that is reproducible, robust and specific. PMID- 29150012 TI - Rethinking the accuracy of 75g glucose used in the oral glucose tolerance test in the diagnosis and management of diabetes. AB - AIMS: We investigated the specificity of the 75g oral glucose tolerance test (OGTT) and the clinical usefulness of the 2h post loading glucose (2h PLG) value in the clinical care of diabetes patients. METHODS: The 75g OGTT data of 1755 subjects were analyzed. The relationships and degrees of consistency among 2h PLG, fasting plasma glucose (FPG), and HbA1c values were assessed. We also investigated the degree of contribution of 2h PLG in the prescription of glucose lowering agents and in the pitfall group for use of 75g OGTT. RESULTS: Among 595 subjects with normal FPG, only 329 (55.3%) showed normal 2h PLG level, and 66 (11.1%) patients could be considered as having diabetes. Among 454 diabetes patients (based on FPG and HbA1c), 409(90.1%) showed 2h PLG values in the range of diabetes, 45 (9.9%) subjects did not exhibit diabetes. Pitfall group who used 75g OGTT for diagnosis diabetes (lower 2h PLG value compared to fasting and upper 2h PLG value compared to fasting) showed differences in body weight and height. CONCLUSIONS: Based on OGTT results, around 10% patients cannot be diagnosed with diabetes based solely on the 2h PLG value. Further studies on differences in glucose loading according to body weight, individual life pattern, and calorie requirement are needed for improvement of the specificity of the OGTT in the clinical management of diabetes. PMID- 29150013 TI - RETRACTED: Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease. PMID- 29150014 TI - RETRACTED: Etidronate for fracture prevention in amyotrophic lateral sclerosis: A randomized controlled trial. PMID- 29150016 TI - Low-level laser therapy may reduce postoperative pain levels after root canal retreatment in patients with low preoperative pain levels. PMID- 29150017 TI - Insufficient evidence about sleep bruxism being a risk factor for ceramic restoration failure. PMID- 29150015 TI - The flotation and adsorption of mixed collectors on oxide and silicate minerals. AB - The analysis of flotation and adsorption of mixed collectors on oxide and silicate minerals is of great importance for both industrial applications and theoretical research. Over the past years, significant progress has been achieved in understanding the adsorption of single collectors in micelles as well as at interfaces. By contrast, the self-assembly of mixed collectors at liquid/air and solid/liquid interfaces remains a developing area as a result of the complexity of the mixed systems involved and the limited availability of suitable analytical techniques. In this work, we systematically review the processes involved in the adsorption of mixed collectors onto micelles and at interface by examining four specific points, namely, theoretical background, factors that affect adsorption, analytical techniques, and self-assembly of mixed surfactants at the mineral/liquid interface. In the first part, the theoretical background of collector mixtures is introduced, together with several core solution theories, which are classified according to their application in the analysis of physicochemical properties of mixed collector systems. In the second part, we discuss the factors that can influence adsorption, including factors related to the structure of collectors and environmental conditions. We summarize their influence on the adsorption of mixed systems, with the objective to provide guidance on the progress achieved in this field to date. Advances in measurement techniques can greatly promote our understanding of adsorption processes. In the third part, therefore, modern techniques such as optical reflectometry, neutron scattering, neutron reflectometry, thermogravimetric analysis, fluorescence spectroscopy, ultrafiltration, atomic force microscopy, analytical ultracentrifugation, X-ray photoelectron spectroscopy, Vibrational Sum Frequency Generation Spectroscopy and molecular dynamics simulations are introduced in virtue of their application. Finally, focusing on oxide and silicate minerals, we review and summarize the flotation and adsorption of three most widely used mixed surfactant systems (anionic-cationic, anionic-nonionic, and cationic-nonionic) at the liquid/mineral interface in order to fully understand the self-assembly progress. In the end, the paper gives a brief future outlook of the possible development in the mixed surfactants. PMID- 29150018 TI - Nontailored dietary advice may result in increase in some nutrient intake 3 months after delivering complete dentures, but there is no evidence that this improves health outcomes. PMID- 29150019 TI - Definitive abutments probably result in minimal decrease in bone loss and buccal gingival recession compared with traditional implants. PMID- 29150020 TI - Inconclusive evidence about the effects of resin viscosity for resin composite restorations in noncarious cervical lesions. PMID- 29150021 TI - Uncertainty about the accuracy of panoramic radiography for detecting asymptomatic apical lesions owing to limitations in a study assessing the performance of this method. PMID- 29150022 TI - Poppers regulation for public sale: No measure in France yet. AB - AIM: Poppers have become legal in France since June 2013. Is their liberalisation associated with an increase of severe side effects observed? METHODS: To identify elevated methaemoglobinaemia related to poppers abuse, we reviewed all methaemoglobin concentrations measured in Nantes university hospital, during 12 months. RESULTS: Methaemoglobin concentrations were superior to 25% in three cases of poppers consumption that occurred after the legalisation. CONCLUSION: Evaluating the prevalence of elevated methaemoglobinaemia could help to monitor severe complications of poppers use in France. PMID- 29150023 TI - Re: After 50 years and 200 papers, what can the Midspan cohort studies tell us about our mortality? PMID- 29150025 TI - Discussion. PMID- 29150024 TI - Decreased UCHL1 expression as a cytologic biomarker for aggressive behavior in pancreatic neuroendocrine tumors. AB - BACKGROUND: There are currently no reliable markers associated with aggressive behavior in well-differentiated and moderately differentiated pancreatic neuroendocrine tumors. We aimed to determine whether expression of ubiquitin carboxyl-terminal hydrolase L1 in conjunction with Ki67 can identify metastatic potential of well-differentiated and moderately differentiated pancreatic neuroendocrine tumors from fine-needle aspiration samples obtained by endoscopic ultrasound. METHODS: Retrospective review of 48 patients with well-differentiated and moderately differentiated pancreatic neuroendocrine tumors diagnosed by endoscopic ultrasound fine-needle aspiration at a single center identified 35 biopsy samples with adequate material for analysis. Ubiquitin carboxyl-terminal esterase L1 immunocytochemistry of primary pancreatic neuroendocrine tumors was performed along with Ki67 staining and scored semiquantitatively. The combination of ubiquitin carboxyl-terminal esterase L1 score <=4 (weak) and Ki67 >=3% (high) was considered a positive test for predicting tumors associated with metastases. RESULTS: Weak ubiquitin carboxyl-terminal hydrolase L1 staining had 80% sensitivity, 65% specificity, 63% positive predictive value, and 81% negative predictive value to identify primary tumors associated with metastatic disease. The combination of weak ubiquitin carboxyl-terminal hydrolase L1 staining and high Ki67 staining increased the test specificity to 95%. On multivariable analysis, combined positive test of weak ubiquitin carboxyl-terminal esterase L1 staining and high Ki67 staining was an independent predictor of metastatic disease (P = .047). CONCLUSION: Ubiquitin carboxyl-terminal hydrolase L1 is a novel biomarker for identifying malignant potential of primary well differentiated and moderately differentiated pancreatic neuroendocrine tumors and in combination with Ki67 is an independent predictor of development of metastatic disease. PMID- 29150026 TI - Regulatory T cells: Friends or foe in human Mycobacterium leprae infection? AB - Regulatory T cells (Tregs) are known to control immune responses by suppressing the antigen-presenting and effector T cells. Some mechanisms adopted by Tregs in combating Mycobacterium infections have been proposed. Nevertheless, in M. leprae infection, also known as leprosy or Hansen's disease, the role of Tregs has not been completely elucidated. Using multicolor flow cytometry, we evaluated the expression of different cell surface and intracellular molecules present in Tregs from peripheral blood samples of leprosy patients. Before initiating treatment, thirteen new cases of leprosy were grouped according to the Ridley-Jopling classification in to the paucibacilary (PB) or multibacilary (MB) group. Fifteen non-infected individuals (NI) were included as control subjects. Tregs were higher in the MB group than in the NI group. Tregs also co-expressed high amounts of PD1 and PDL-1, indicating that these cells could induce apoptosis of effector cells and simultaneously prevent their own apoptosis. Our data showed that compared to the NI group, Tregs from the PB group expressed higher levels of CD95L, which may be associated with other apoptotic pathways that may decrease Tregs in these patients. Correlation analysis reinforced that PD1 and CD95L are efficient apoptosis' pathway that decreased levels of Tregs in the NI and PB groups. We also observed significant differences in cytokine expression of Tregs from the PB and MB groups. Compared to the NI group, Tregs from the MB group showed higher IL-17 expression; however, compared to the PB group, the expression of IL-10 in Tregs from the MB group was lower, suggesting inefficient control of inflammation. Therefore, we concluded that different pathways were involved in Treg-induced suppression of leprosy. Moreover, Treg-mediated regulation of inflammation via IL-10 and IL-17 expression in leprosy patients was inefficient. Thus, we propose that during M. leprae infection, Tregs may impair the immune responses elicited against this bacillus, favor bacterial replication, and aid in persistence of a disseminated multibacillary disease. PMID- 29150027 TI - Tailored resections in oral and oropharyngeal cancer using narrow band imaging. AB - PURPOSE: In a previous pilot study we observed that intra-operative narrow-band imaging (NBI) helps achieve clear superficial resection margins. The aim of this study was to verify if the use of intra-operative NBI can help to obtain tailored resections and if it is influenced by the lesion site, aspects not investigated in our previous study. MATERIALS AND METHODS: The resection margins of 39 oral and 22 oropharyngeal squamous cell carcinomas were first set at 1.5cm from the macroscopic lesion boundary (white light, WL, tattoo). Then, the superficial tumor extension was more precisely defined with NBI, giving rise to three possible situations: NBI tattoo larger than the WL tattoo, NBI tattoo coinciding with the WL tattoo, or NBI tattoo smaller than the WL tattoo. For each of these situations the space comprised between the NBI and WL tattoos was defined "NBI positive", "NBI null", and "NBI negative", respectively. Resections were performed following the outer tattoo. The number of clear superficial resection margins, and the pathological response on the "NBI-positive" and the "NBI negative" areas were recorded. RESULTS: We obtained 80.3% negative superficial resection margins. NBI provided a more precise definition of superficial tumor extension in 43 patients. Sensitivity, specificity, positive and negative predictive values were 94.4%, 64%, 79.1% and 88.9%, respectively; a test of proportions demonstrated they were not influenced by tumor site. CONCLUSIONS: NBI could allow for real-time definition of superficial tumor extension with possible tailored resections and fewer positive superficial resection margins; it is not influenced by tumor site. PMID- 29150028 TI - [A series of 20 cases of endogenous endophthalmitis]. AB - BACKGROUND: The purpose of this case series was to evaluate both the visual and systemic prognosis of patients with endogenous endophthalmitis. MATERIAL AND METHODS: We reported a series of 20 cases of endogenous endophthalmitis occurring between 2012 and 2015 at the university medical center in Toulouse. RESULTS: The mean age was 67 (+/-43.3) years with a male predominance (n=11). The site of entry was found in 14 cases (87.5%). In 11 cases (69%), the causative agent was a bacterium; a fungal infection was found in five cases. Visual acuity after maximal medical and surgical treatment was limited to "no light perception" in 7 cases (35%), "hand motion" in 2 cases (10%), "finger counting" in 3 cases (15%) and 10/10 in 2 cases (10%). One case had no final data. The main site of entry was found to be associated endocarditis (n=7), central venous line or venipuncture (n=6). The main local complications were retinal detachment (n=6), cataract (n=5) and choroidal neovascularization secondary to scarring (n=2). CONCLUSIONS: Endogenous endophthalmitis is associated with poor visual prognosis. It is also often associated with systemic complications that may be life threatening. PMID- 29150029 TI - [Fungal keratitis]. AB - Fungal keratitis, or keratomycoses, are corneal infections which must be considered in cases of corneal trauma, prior corneal surgery, chronic ocular surface disease, topical corticosteroids or contact lens wear. Filamentous fungi or yeasts may be involved. Presenting clinical features such as corneal infiltrates with feathery edges and/or raised surface, intact epithelium with deep stromal involvement, satellite lesions, endothelial plaques, lack of improvement with antibiotics and worsening with steroids are suggestive of fungal keratitis. Corneal scraping for laboratory examination is mandatory. Medical management with antifungal eye drops and systemic agents should be started as soon as possible. Surgical interventions are required in a significant number of cases to control the infection. The prognosis of fungal keratitis is worse than that of bacterial keratitis. PMID- 29150030 TI - [Retinal phacomas in tuberous sclerosis in a 18-year old patient]. PMID- 29150031 TI - Thoracic Surgery in the Pregnant Patient. AB - Thoracic surgeons are sometimes asked to consult on the management of a patient who is pregnant. Conditions commonly encountered are empyema, spontaneous pneumothorax, and diaphragmatic hernia. Lung cancer is rarely seen in pregnancy, but its incidence is rising. Diagnostic imaging and perioperative management involve the navigation of fetal risks and nuances in maternal physiology. Shared decision making within a multidisciplinary framework will optimally guide the course of management. PMID- 29150032 TI - Thoracic Surgery in Patients with AIDS. AB - The picture of human immunodeficiency virus (HIV)-infected patients has changed dramatically since the original description in 1981. The introduction of antiretroviral drugs in 1987 and combination antiretroviral therapy has decreased mortality by as much as 80%. We now see patients in their 60s and 70s, having lived decades with HIV and living a normal live. As outlined in the article, despite good viral control, patients with HIV may present with solid organ cancers earlier than noninfected patients and are also prone to other complications of their disease that may require the attention of a thoracic surgeon. PMID- 29150033 TI - Lung Cancer and Lung Transplantation. AB - Lung transplantation remains a viable option for patients with endstage pulmonary disease. Despite removing the affected organ and replacing both lungs, the risk of lung malignancies still exists. Regardless of the mode of entry, lung cancer affects the prognosis in these patients and diligence is required. PMID- 29150034 TI - Lung Resection in the Postpneumonectomy Patient. AB - Pulmonary resection after pneumonectomy is a reasonable option in selected patients. Wedge resection for single peripheral metachronous disease has the best outcome with 5-year survival as high as 63%. Current and predicted postoperative cardiopulmonary reserve should be evaluated carefully. Stereotactic body radiotherapy is a promising alternative for inoperable patients. PMID- 29150035 TI - Thoracic Surgery Considerations in Obese Patients. AB - The obesity epidemic in the United States has increased greatly over the past several decades, and thoracic surgeons are likely to see obese patients routinely in their practices. Obesity has direct deleterious health effects such as metabolic disorder and cardiovascular disease, and is associated with many cancers. Obese patients who need thoracic surgery pose practical challenges to many of the routine elements in perioperative management. Preoperative assessment of obesity-related comorbid conditions and risk stratification for surgery, thorough intraoperative planning for anesthesia and surgery, and postoperative strategies to optimize pulmonary hygiene and mobility minimize the risk of adverse outcomes. PMID- 29150036 TI - Thoracic Surgery Considerations in the Child and Young Adult. AB - Vascular rings and slings may represent life-threatening compression of the esophagus and trachea. Such anatomic variants, although rare, are encountered by all thoracic surgeons in the scope of their practice at some time. The thoracic surgeon, whether treating such patients in the practice of congenital heart surgery, or in the practice of adult cardiac or thoracic surgery must have a requisite understanding of such anatomic variants, their diagnostic workup and radiologic interpretation, as well as their surgical management. Primary tracheobronchial disorders are also frequently encountered in the scope of a thoracic surgical practice and also are discussed. PMID- 29150037 TI - Esophagectomy After Weight-Reduction Surgery. AB - Obesity is now epidemic worldwide, and an increasing number of patients have undergone a weight-loss procedure. Although obesity is a risk factor for esophageal cancer, there are few reports on esophagectomy after bariatric procedures. Careful understanding of the patient's gastroesophageal anatomy as a result of the bariatric procedure and attention to the creation of the esophageal replacement conduit are fundamental for the success of esophagectomy after bariatric surgery. PMID- 29150038 TI - Thoracic Surgery Considerations in the Mentally Ill or Handicapped Patient. AB - Increasing prevalence of mentally ill and handicapped populations requiring surgical thoracic interventions has brought to light their worse associated morbidity and mortality. Baseline functional status, caretaker environment, and mental limitations in day to day life have an impact in the short and long term from these interventions. Aggressive perioperative care, multispecialty approach, technical aspects, palliative procedures, and ethical considerations all play a part in improving outcomes. In this article real cases are presented illustrating points of care and situations for discussion. PMID- 29150039 TI - Management of Lung Cancer with Concomitant Cardiac Disease. AB - This article discusses the numerous issues surrounding lung cancer treatment in patients with concomitant cardiac disease. It also addresses the preoperative work-up of these patients and the specifics of surgical intervention. PMID- 29150040 TI - Management of Malignant Lung Entrapment, the Oncothorax. AB - Pleural metastasis is a common occurrence in up to 30% of patients with metastatic cancer. When lung entrapment and loculation of fluid occur, treatment is more difficult and we have named this condition "oncothorax." The malignant adhesions that entrap the lung in an oncothorax are not typically amenable to surgical decortication. The standard approach for managing these patients is to place an indwelling catheter. Other options may include pleurectomy and decortication, intrapleural hyperthermic chemoperfusion, and intrapleural photodynamic therapy. However, these procedures should be provided selectively depending on patient performance status, extent of metastatic disease, and level of experience. PMID- 29150041 TI - Thoracic Surgery in Early-Stage Small Cell Lung Cancer. AB - Small cell lung cancer (SCLC) has a complex history and remains difficult to treat. Most patients with SCLC present with metastases or extensive stage disease, rendering most not amenable to surgical resection. Until recently, chemoradiotherapy had become the standard of care for all patients with SCLC. However, recent studies have shown improved survival following surgical resection with chemotherapy in patients with early-stage SCLC, specifically those with stage I disease. This article presents the literature on treatment of early-stage SCLC and addresses the question of whether surgery should be considered a viable treatment modality. PMID- 29150042 TI - Empyema from Obstructing Lung Cancer. AB - Pleural collections on the side of an obstructing bronchial cancer pose a particular challenge. All efforts should be placed into determining whether the collection is malignant or para-malignant with its significant implications on cancer staging. This article discusses various diagnostic modalities and therapeutic interventions needed for the optimal management of patients presenting with this situation. The order of interventions is dictated by the individual circumstances that patients present with, often requiring the pleural interventions to take place ahead of the bronchial obstruction management. PMID- 29150043 TI - Synchronous Esophageal and Lung Cancer. AB - Synchronous lung and esophageal cancers are rare but represent a unique challenge to thoracic surgeons. The literature is limited but series describe long-term survival with curative surgery for concomitant esophageal and lung cancer. Preoperative risk assessment is critical because surgical resection of both cancers requires adequate cardiopulmonary function and performance status. Chemotherapy and radiation are used as adjuvant therapy or as primary treatment of unresectable lesions. Although long-term survival for patients with concomitant lung and esophageal cancer is lower than that of patients with either one alone, survival with curative surgery is higher than that of patients with metastatic disease of either primary. PMID- 29150044 TI - Thoracic Surgery in the Special Care Patient. PMID- 29150045 TI - Spectrum of benzo[a]pyrene-induced mutations in the Pig-a gene of L5178YTk+/- cells identified with next generation sequencing. AB - We used Sanger sequencing and next generation sequencing (NGS) for analysis of mutations in the endogenous X-linked Pig-a gene of clonally expanded L5178YTk+/- cells. The clones developed from single cells that were sorted on a flow cytometer based upon the expression pattern of the GPI-anchored marker, CD90, on their surface. CD90-deficient and CD90-proficient cells were sorted from untreated cultures and CD90-deficient cells were sorted from cultures treated with benzo[a]pyrene (B[a]P). Pig-a mutations were identified in all clones developed from CD90-deficient cells; no Pig-a mutations were found in clones of CD90-proficient cells. The spectrum of B[a]P-induced Pig-a mutations was dominated by basepair substitutions, small insertions and deletions at G:C, or at sequences rich in G:C content. We observed high concordance between Pig-a mutations determined by Sanger sequencing and by NGS, but NGS was able to identify mutations in samples that were difficult to analyze by Sanger sequencing (e.g., mixtures of two mutant clones). Overall, the NGS method is a cost and labor efficient high throughput approach for analysis of a large number of mutant clones. PMID- 29150046 TI - Oxidative stress and DNA damage in the cord blood of preterm infants. AB - Preterm birth infants are more susceptible to oxidative stress and aftermaths unwanted outcomes such as DNA damage due to hyperoxic stress. In this study, we compared the DNA strand breaks as one of the results of DNA oxidation in white blood cells, malondialdehyde (oxidative stress marker), catalase and superoxide dismutase activity, and total antioxidant capacity (markers of antioxidant defense) in a cord blood plasma of a group of preterm (n=25) and full term births (n=25). The primary DNA damage and plasma oxidative stress markers were significantly higher in a preterm group (p<0.05). Cord plasma activity of superoxide dismutase was significantly lower in preterm infants (p<=0.001). However, there were no significant differences in the cord blood total antioxidant capacity, catalase activity and malondialdehyde in preterm and term infants. Among the oxidative stress markers, the malondialdehyde concentration showed the strongest effect size (1.54; 95%CI: 0.9-2.17). For comet parameters, the most powerful effect size was observed for tail length (5.24; 95% CI: 4.05 6.42). However, tail DNA percent and tail moment were also significantly higher in cases compared to controls. Significant negative correlation was observed between comet assay parameters and birth weight and gestational age when all cases and controls entered into the analysis. There was no significant association between the levels of oxidative stress markers and early DNA damage in cord blood plasma with future nutritional tolerance in preterm infants. In the present study, the primary DNA damage and plasma oxidative stress markers significantly were increased in a preterm group. Preterm babies are more prone to the outcomes related to the early DNA damage. Tail DNA percent does not depend on experimental conditions as other parameters (tail length and thus also tail moment) and can be used for comparison with other studies. PMID- 29150047 TI - Cytogenetic damage in peripheral blood lymphocytes of children exposed to pesticides in agricultural areas of the department of Cordoba, Colombia. AB - Pesticides offer benefits, like optimization of agricultural production and disease control; however, these toxic substances can contaminate the environment and pose risks to human health. The aim of this study was to assess pesticide exposure and frequency of cytogenetic damage in infant populations in agricultural areas of the department of Cordoba, Colombia. Urine and peripheral blood samples were taken from children living in the villages of La Ceibita (municipality of Cerete), Cabuya (municipality of San Carlos), Aguas Negras (municipality of Monteria), Pelayito (municipality of San Pelayo), and the city of Monteria (control group). The work evaluated biomarkers of exposure to pesticides (atrazine urinary concentrations (ATZ) and its metabolites) and biomarkers of cytogenetic damage (micronucleus frequency (MN), nuclear buds, and apoptotic cells in peripheral blood lymphocytes). Measurable ATZ concentrations and/or its metabolites were recorded in the Pelayito, Aguas Negras, and Cabuya zones, which had higher MN frequencies, nuclear buds, and apoptotic cells than the control. Infant exposure to one of the more-often used pesticides in the agricultural areas evaluated and an increasing trend in the frequency of markers of cytogenetic damage in the groups of the agricultural areas, as compared to the control group, were evident. PMID- 29150048 TI - DNA-dependent protein kinase modulates the anti-cancer properties of silver nanoparticles in human cancer cells. AB - Silver nanoparticles (Ag-np) were reported to be toxic to eukaryotic cells. These potentially detrimental effects of Ag-np can be advantageous in experimental therapeutics. They are currently being employed to enhance the therapeutic efficacy of cancer drugs. In this study, we demonstrate that Ag-np treatment trigger the activation of DNA-PKcs and JNK pathway at selected doses, presumably as a physiologic response to DNA damage and repair in normal and malignant cells. Ag-np altered the telomere dynamics by disrupting the shelterin complex located at the telomeres and telomere lengths. The genotoxic effect of Ag-np was not restricted to telomeres but the entire genome as Ag-np induced gamma-H2AX foci formation, an indicator of global DNA damage. Inhibition of DNA-PKcs activity sensitised the cancer cells towards the cytotoxicity of Ag-np and substantiated the damaging effect of Ag-np at telomeres in human cancer cells. Abrogation of JNK mediated DNA repair and extensive damage of telomeres led to greater cell death following Ag-np treatment in DNA-PKcs inhibited cancer cells. Collectively, this study suggests that improved anti-proliferative and cytotoxic effects of Ag np treatment in cancer cells can be achieved by the inhibition of DNA-PKcs. PMID- 29150049 TI - Generation of Advanced Glycation End-Products (AGEs) by glycoxidation mediated by copper and ROS in a human serum albumin (HSA) model peptide: reaction mechanism and damage in motor neuron cells. AB - Glucose, in the presence of reactive oxygen species (ROS), acts as an as an oxidative agent and drives deleterious processes in Diabetes Mellitus. We have studied the mechanism and the toxicological effects of glucose-dependent glycoxidation reactions driven by copper and ROS, using a model peptide based on the exposed sequence of Human Serum Albumin (HSA) and containing a lysine residue susceptible to copper complexation. The main products of these reactions are Advanced Glycation End-products (AGEs). Carboxymethyl lysine and pyrraline condensed on the model peptide, generating a Modified Peptide (MP). These products were isolated, purified, and tested on cultured motor neuron cells. We observed DNA damage, enhancement of membrane roughness, and formation of domes. We evaluated nuclear abnormalities by the cytokinesis-blocked micronucleus assay and we measured cytostatic and cytotoxic effects, chromosomal breakage, nuclear abnormalities, and cell death. AGEs formed by glycoxidation caused large micronucleus aberrations, apoptosis, and large-scale nuclear abnormalities, even at low concentrations. PMID- 29150050 TI - Cytogenetic changes in the Bhopal population exposed to methyl isocyanate (MIC) in 1984: Then and 30 years later. AB - Following the 1984 Bhopal methyl isocyanate (MIC) gas disaster, genetic alterations were sporadically reported on small cohorts. However, the outcome of the multi-center cytogenetic screening conducted at that time remains unknown and no follow-up studies on the long-term effects of MIC exposure have been published. The present work examines genetic changes in the exposed population,with the aim of identifying any long-term effects of MIC. G-Banded metaphases were studied in lymphocytes of 130 individuals. Chromosomal aberrations (CA) were broadly grouped as abnormal cells (Abc), aberrations (Abn), and aberration/abnormal cell (Abn/Abc). From the previous multi-center screening, 946 records were retrieved, from which CA, sister chromatid exchanges (SCE), and cell-cycle kinetics (RI) were computed. In our analysis of the previous study, Abc and Abn were higher in the moderately and severely exposed groups than in the unexposed population. Abc appeared uniform in all groups of the present study, although Abn and Abn/Abc were higher in the exposed groups. Aberrations were now significantly higher in the unexposed and moderately exposed groups than in the previous screening. Although Abn and Abc now appeared lower in severely exposed subjects, the Abn/Abc ratio was higher, perhaps due to more rearrangements and damage in a smaller number of Abc. This result may be attributed to differences between the methods used in the studies, then and now. Elevated SCEs and reduced RI were seen in the severely exposed population shortly after exposure, and stable/clonal rearrangements were seen 30 y later. Follow-up of index cases and their progenies is needed. PMID- 29150051 TI - Glutamate is down-regulated and tinnitus loudness-levels decreased following rTMS over auditory cortex of the left hemisphere: A prospective randomized single blinded sham-controlled cross-over study. AB - Using a prospective randomized single-blinded sham-controlled cross-over design, we studied the efficacy of low frequency (1-Hz) repetitive transcranial magnetic stimulation (rTMS) over auditory cortex of the left temporal lobe as an experimental treatment modality for noise-induced tinnitus. Pre/post outcome measures for sham vs. active rTMS conditions included differential changes in tinnitus loudness, self-perceived changes in the Tinnitus Handicap Questionnaire (THQ), and neurochemical changes of brain metabolite concentrations using single voxel proton magnetic resonance spectroscopy (1H-MRS) obtained from left and right auditory cortical areas. While no subject in our sample had complete abatement of their tinnitus percept, active but not sham rTMS significantly reduced the loudness level of the tinnitus perception on the order of 4.5 dB; improved subscales in several content areas on the THQ, and down regulated (reduced) glutamate concentrations specific to the auditory cortex of the left temporal lobe that was stimulated. In addition, significant pair-wise correlations were observed among questionnaire variables, metabolite variables, questionnaire-metabolite variables, and metabolite-loudness variables. As part of this correlation analysis, we demonstrate for the first time that active rTMS produced a down regulation in the excitatory neurotransmitter glutamate that was highly correlated (r = 0.77, p < 0.05) with a reduction in tinnitus loudness levels measured psychoacoustically with a magnitude estimation procedure. Overall, this study provides unique information on neurochemical, psychoacoustic, and questionnaire-related profiles which emphasizes the emerging fields of perceptual and cognitive MRS and provides a perspective on a new frontier in auditory and tinnitus-related research. PMID- 29150052 TI - Congenital microcephaly: Case definition & guidelines for data collection, analysis, and presentation of safety data after maternal immunisation. PMID- 29150053 TI - Failure to thrive: Case definition & guidelines for data collection, analysis, and presentation of maternal immunisation safety data. PMID- 29150054 TI - Low birth weight: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data. PMID- 29150055 TI - Neonatal encephalopathy: Case definition & guidelines for data collection, analysis, and presentation of maternal immunisation safety data. PMID- 29150056 TI - Respiratory distress in the neonate: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data. PMID- 29150058 TI - Antenatal bleeding: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data. PMID- 29150057 TI - Small for gestational age: Case definition & guidelines for data collection, analysis, and presentation of maternal immunisation safety data. PMID- 29150059 TI - Dysfunctional labor: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data. PMID- 29150060 TI - Fetal growth restriction: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data. PMID- 29150061 TI - Gestational diabetes mellitus: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data. PMID- 29150063 TI - Lactose avoidance and bone. PMID- 29150064 TI - Metal-organic frameworks as stationary phase for application in chromatographic separation. AB - Metal-organic frameworks (MOFs) as a subclass of coordination polymers, have attracted wide interest in various field. Herein, we focus on its application in chromatographic separation due to its excellent physical and chemical properties such as large surface area, high porosity, uniform pore sizes and structural diversity. In 2014, a review was published to summarize the most significant advances in MOFs, and their applications in separation science. The present review was an extensive update on applications of MOFs in chromatographic separation from 2014 to the present such as high-performance liquid chromatography (HPLC), capillary electrochromatography (CEC), nano-liquid chromatography (nano-LC), and gas chromatography (GC). Besides, the typical applications of MOFs in solid-phase microextraction (SPME) were also discussed. Except the presentation of experimental data, the limitations and prospects were also summarized in this review, which can offer an outlook and reference on further study of applications of MOFs. PMID- 29150062 TI - Spontaneous abortion and ectopic pregnancy: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data. PMID- 29150065 TI - Tryptophan metabolic pathway, airway nitric oxide, and allergy. PMID- 29150066 TI - Treatment with omalizumab or cyclosporine for resistant chronic spontaneous urticaria. PMID- 29150067 TI - Blepharochalasis: A rare cause of eye swelling. PMID- 29150068 TI - Sensitization to Staphylococcus aureus enterotoxins in smokers with asthma. AB - BACKGROUND: Sensitization to Staphylococcus aureus enterotoxins (SEs) augments eosinophilic inflammation in asthma. Recent epidemiologic studies demonstrate that sensitization to SEs is increased in healthy smokers; however, there is no evidence on the association between sensitization to SEs and eosinophilic inflammation in smokers with asthma. OBJECTIVE: To clarify the role of SEs on clinical indexes, including eosinophilic inflammation and lung function in smokers with asthma. METHODS: The frequency of atopic sensitization to SEs was examined in adult patients with asthma. In current or ex-smokers with asthma, the association of sensitization to SEs with eosinophilic inflammation, airflow limitation, or treatment steps was determined. Clinical indexes were examined at the first visit, and treatment steps were assessed 6 months after enrollment. RESULTS: Overall, 23 current smokers, 40 ex-smokers, and 118 never smokers with asthma were enrolled. The frequency of sensitization to SEs, but not to other aeroallergens, was significantly higher in current, ex-, and never smokers, in decreasing order. In current or ex-smokers with asthma, patients with sensitization to SEs exhibited higher serum levels of total and specific IgE to aeroallergens, higher blood eosinophil counts, greater airflow limitation, and more severe disease 6 months later than those without sensitization to SE. A longer smoking abstinence period was associated with serum specific IgE levels to SEs, and 3 years was the best cutoff of abstinence period to predict the absence of sensitization to SEs. CONCLUSION: Sensitization to SEs is increased in smokers with asthma, and it may be a marker of eosinophilic inflammation and severe asthma in smokers with asthma. TRIAL REGISTRATION: umin.ac.jp Identifier: UMIN000007818. PMID- 29150069 TI - Effect of a mobile health, sensor-driven asthma management platform on asthma control. AB - BACKGROUND: Asthma inflicts a significant health and economic burden in the United States. Self-management approaches to monitoring and treatment can be burdensome for patients. OBJECTIVE: To assess the effect of a digital health management program on asthma outcomes. METHODS: Residents of Louisville, Kentucky, with asthma were enrolled in a single-arm pilot study. Participants received electronic inhaler sensors that tracked the time, frequency, and location of short-acting beta-agonist (SABA) use. After a 30-day baseline period during which reference medication use was recorded by the sensors, participants received access to a digital health intervention designed to enhance self management. Changes in outcomes, including mean daily SABA use, symptom-free days, and asthma control status, were compared among the initial 30-day baseline period and all subsequent months of the intervention using mixed-model logistic regressions and chi2 tests. RESULTS: The mean number of SABA events per participant per day was 0.44 during the control period and 0.27 after the first month of the intervention, a 39% reduction. The percentage of symptom-free days was 77% during the baseline period and 86% after the first month, a 12% improvement. Improvement was observed throughout the study; each intervention month demonstrated significantly lower SABA use and higher symptom-free days than the baseline month (P < .001). Sixty-nine percent had well-controlled asthma during the baseline period, 67% during the first month of the intervention. Each intervention month demonstrated significantly higher percentages than the baseline month (P < .001), except for month 1 (P = .80). CONCLUSION: A digital health asthma management intervention demonstrated significant reductions in SABA use, increased number of symptom-free days, and improvements in asthma control. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02162576. PMID- 29150070 TI - Decreased expression of indolamine 2,3-dioxygenase in childhood allergic asthma and its inverse correlation with fractional concentration of exhaled nitric oxide. AB - BACKGROUND: The tryptophan metabolic pathway mediated by indolamine 2,3 dioxygenase (IDO), a tryptophan-degrading enzyme, plays an important role in controlling the development of allergic inflammation. The fractional concentration of exhaled nitric oxide (FeNO) is closely associated with the allergic state and is extensively used for the clinical evaluation of airway allergic inflammation. Clinical trials have rarely assessed the expression of IDO in childhood allergic asthma and its correlation with FeNO. OBJECTIVE: To evaluate the IDO level in children with childhood allergic asthma and the relation between IDO levels and FeNO. METHODS: Thirty children older than 5 years who were diagnosed the first time with allergic asthma were selected from the pediatric outpatient department. Another 30 healthy children were selected as controls. The subjects were evaluated by complete medical history, pulmonary function test results, skin prick test reaction, FeNO concentration test result, eosinophil count, and a disease severity score. Peripheral venous blood and induced sputum were obtained to measure the concentrations of IDO metabolites (ie, tryptophan and kynurenine). RESULTS: The IDO levels in the peripheral blood and induced sputum were significantly lower in patients with childhood allergic asthma than in children in the control group. The IDO level was negatively correlated with FeNO but was not significantly correlated with age, sex, blood eosinophil count, or disease severity scale. CONCLUSION: The expression of IDO was significantly lower in childhood allergic asthma, particularly in children with high FeNO levels. There was no significant relation between IDO levels and asthma severity. TRIAL REGISTRATION: Chinese Clinical Trial Register (www.chictr.org.cn) Identifier: ChiCTR-COC-15006080. PMID- 29150071 TI - Efficacy of bleach baths in reducing severity of atopic dermatitis: A systematic review and meta-analysis. AB - BACKGROUND: Bleach baths have been proposed as a treatment for decreasing the severity of atopic dermatitis (AD). However, conflicting results have been found regarding their efficacy. OBJECTIVE: To determine the efficacy of bleach vs water baths at decreasing AD severity. METHODS: We performed a systematic review of all studies evaluating the efficacy of bleach baths for AD. Cochrane, EMBASE, GREAT, LILACS, MEDLINE, and Scopus were searched. Two authors independently performed study selection and data extraction. RESULTS: Five studies were included in the review. Four studies reported significantly decreased AD severity in patients treated with bleach on at least 1 time point. However, of 4 studies comparing bleach with water baths, only 2 found significantly greater decreases in AD severity with bleach baths, 1 found greater decreases with water baths, and 1 found no significant differences. In pooled analyses, there were no significant differences observed between bleach vs water baths at 4 weeks vs baseline for the Eczema Area and Severity Index (I2 = 98%; random effect regression model, P = .16) or body surface area (I2 = 96%; P = .36). CONCLUSION: Although bleach baths are effective in decreasing AD severity, they do not appear to be more effective than water baths alone. Future larger-scale, well-designed randomized controlled trials are needed. PMID- 29150072 TI - Shiitake mushroom-induced flagellate dermatitis. PMID- 29150073 TI - DRESS syndrome associated with splenic thrombosis. PMID- 29150074 TI - Comorbidity of atopy in urban adolescents with asthma. PMID- 29150075 TI - Diagnosis and treatment of food allergic reactions in pediatric emergency settings. PMID- 29150076 TI - Cockroach hypersensitivity is associated with greater severity of chronic rhinosinusitis. PMID- 29150077 TI - Unique arginine array improves cytosolic localization of hydrocarbon-stapled peptides. AB - We have previously reported that miniature proteins containing a distinct array of 5 arginine residues on a folded alpha-helix - a penta-arg motif - traffic with high efficiency from endosomes into the cytosol and nucleus of mammalian cells. Here we evaluate whether a penta-arg motif can improve the intracellular trafficking of an otherwise impermeant hydrocarbon-stapled peptide, SAH-p53-4Rho. We prepared a panel of SAH-p53-4Rho variants containing penta-arg sequences with different spacings and axial arrangement and evaluated their overall uptake (as judged by flow cytometry) and their intracellular access (as determined by fluorescence correlation spectroscopy, FCS). One member of this panel reached the cytosol extremely well, matching the level achieved by SAH-p53-8Rho, a previously reported and highly permeant hydrocarbon-stapled peptide. Notably, we found no relationship between cellular uptake as judged by flow cytometry and cytosolic access as determined by FCS. This result reiterates that overall uptake and endosomal release represent fundamentally different biological processes. To determine cytosolic and/or nuclear access, one must measure concentration directly using a quantitative and non-amplified tool such as FCS. As has been observed for highly cell permeant miniature proteins such as ZF5.3, optimal penetration of hydrocarbon-stapled peptides into the cell cytosol results when the penta-arg motif is located within more (as opposed to less) structured regions. PMID- 29150078 TI - Bimodal fluorescence/129Xe NMR probe for molecular imaging and biological inhibition of EGFR in Non-Small Cell Lung Cancer. AB - Although Non-Small Cell Lung Cancer (NSCLC) is one of the main causes of cancer death, very little improvement has been made in the last decades regarding diagnosis and outcomes. In this study, a bimodal fluorescence/129Xe NMR probe containing a xenon host, a fluorescent moiety and a therapeutic antibody has been designed to target the Epidermal Growth Factor Receptors (EGFR) overexpressed in cancer cells. This biosensor shows high selectivity for the EGFR, and a biological activity similar to that of the antibody. It is detected with high specificity and high sensitivity (sub-nanomolar range) through hyperpolarized 129Xe NMR. This promising system should find important applications for theranostic use. PMID- 29150079 TI - Mechanism hypotheses for the electrophysiological manifestations of two cases of endplate acetylcholinesterase deficiency related congenital myasthenic syndrome. AB - OBJECTIVE: To summarize the electrophysiological characteristics of two cases of endplate acetylcholinesterase deficiency (EAD) related congenital myasthenic syndrome (CMS) caused by COLQ mutation and to discuss the possible mechanism of these electrophysiological phenomena. METHODS: Electrophysiological examinations were conducted including nerve conduction studies, routine electromyography (EMG), repetitive nerve stimulation (RNS) and single fiber EMG (SFEMG). The ulnar nerve was also stimulated at 50 Hz followed by 0.5 Hz to record the recovery process of compound muscle action potential (CMAP). RESULTS: Repetitive CMAP (R CMAP) was found in motor nerve conduction in both cases. Needle EMG showed myogenic damages and SFEMG showed remarkably increased jitter values. Of note, the amplitude of CMAP and R-CMAP showed regular changing trends, and so did their time intervals in RNS studies. CONCLUSIONS: The change patterns of CMAP and R CMAP, in combination with other electrophysiological features are very useful for the diagnosis of EAD related CMS, especially in predicting the presence of correct gene mutations. PMID- 29150080 TI - Outcomes of thoracic discectomy: A single center retrospective series. PMID- 29150081 TI - Turning Over a New Leaf: Bacteriocins Going Green. AB - Bacteriocins are potent antibacterial proteins that selectively kill phylogenetic relatives of the producer. Their polymorphic nature, most prominent in gamma Proteobacteria, offers potential for the design of customized bacteriocin cocktails targeting Gram-negative pathogens. As an alternative to recombinant production in bacteria, they are eligible for large-scale production in plants. PMID- 29150082 TI - Lung radiodensity along the needle passage is a quantitative predictor of pneumothorax after CT-guided percutaneous core needle biopsy. AB - AIM: To analyse whether the lowest value of lung radiodensity along the passage of the biopsy needle is a quantitative predictor of pneumothorax. MATERIALS AND METHODS: CT-guided percutaneous core needle biopsy (PCNB) procedures performed at Zhongnan Hospital were analysed retrospectively. Age, gender, lesion size, lesion depth, lesion location, patient position, number of passages, needle pleural angle, pulmonary bleeding, and lung radiodensity along the needle passage were collected and classified by the extent of pneumothorax. Univariate analysis and multiple logistic regression analysis were assessed to explore the independent risk factors for pneumothorax. RESULTS: Six hundred and seventy-seven cases were included in the study, including 456 males and 221 females. Pneumothorax occurred in 40.18% of cases, of which 82.4% were mild, 14% were moderate, and 3.7% were severe. Univariate and multivariate analysis showed that lesion size <=2 cm (p=0.002), two or more passages (p=0.033), and lung radiodensity of -850 HU or less (p<=0.001) were independent risk factors for pneumothorax; bleeding (p<0.001) was a protective factor for pneumothorax. CONCLUSIONS: The lowest value of lung radiodensity along the needle passage was a quantitative predictor of pneumothorax. A value of -850 HU or less was an independent risk factor for pneumothorax. As the value decreased, there was a higher risk of occurrence of more severe pneumothorax. PMID- 29150083 TI - CT imaging features of symptomatic and asymptomatic floating aortic thrombus. AB - AIM: To present the computed tomography (CT) imaging features of floating aortic thrombus with emphasis on clinical and radiographic predictors for systemic shower emboli. MATERIALS AND METHODS: A retrospective computerised search for patients with protruding thoracic aortic thrombus on CT was conducted. Clinical and demographic characteristics were retrieved from medical files. Patients were divided into two groups: symptomatic and asymptomatic, based on the presence or absence of documented systemic emboli at the time of diagnosis or during follow up. CT imaging features were analysed: location and extent of systemic emboli, presence or absence of thrombus insertion calcification, percentage of thrombus circumference that is attached to the aortic wall and thrombus volume. Clinical and demographic variables and CT imaging features were analysed as potentially associated with symptomatic emboli. RESULTS: The symptomatic group included 6/15 (40%) patients and the asymptomatic group included 9/15 (60%) patients. Patients in the symptomatic group were significantly younger (symptomatic: 53.3+/-11.7 years, asymptomatic: 76.9+/-8.4 years, p=0.003). All the symptomatic patients were women (100%), while 2/9 (22.2%) of the asymptomatic patients were women, (p=0.007). A non-calcified insertion site was more frequent in the symptomatic group (symptomatic 4/6 [66.7%] versus asymptomatic group 1/9 [11.1%], p=0.011). The percentage of thrombus circumference attached to the aortic wall was significantly smaller in symptomatic patients (symptomatic: 31.8+/-8.4%, asymptomatic: 43.7+/-5%, p=0.003). CONCLUSION: The imaging features of symptomatic floating thrombus include a narrow base of attachment and lack of insertion calcification. Free-floating thrombus should be actively sought and diagnosed or excluded when performing CT andiography for emboli. PMID- 29150084 TI - Radiology-led lung escalation pathway: a streamlined innovative service expediting the diagnosis of lung cancer. PMID- 29150085 TI - Pinocembrin alleviates cognition deficits by inhibiting inflammation in diabetic mice. AB - Diabetic encephalopathy (DE) is one of the most common diabetic complications in diabetes mellitus and is characterized by cognitive impairment and neuroinflammation. It has been reported that hyperglycemia can induce hippocampal and cortical neuronal damage, which can result in severe spatial learning and memory impairment. Pinocembrin (Pino) has been widely used in the therapy of cancer and other diseases due to its anti-inflammatory, anti-allergic, anti oxidant, anti-carcinogenic, and anti-viral activities. However, the effects of Pino on DE-induced cognition deficits and its precise mechanisms remain largely unknown. Therefore, the aim of this study was to investigate the neuroprotective effects of Pino on cognition and its potential mechanisms in a DE mouse model induced by streptozotocin (STZ, 150mg/kg). Here, we demonstrated that Pino significantly improved the behavior and cognitive deficits of DE mice in open field tasks and the Morris water maze. Pino also markedly increased neuronal survival in the frontal cortex and hippocampal CA3 region. Furthermore, western blotting was performed to measure nuclear translocation of nuclear factor-kappaB (NF-kappaB) and the expression of tumor necrosis factor-alpha (TNF-alpha) in the frontal cortex and hippocampus. The results demonstrated that Pino could suppress the nuclear translocation of NF-kappaB and decrease TNF-alpha expression in the cerebral cortex and the hippocampus of DE mice. Taken together, the results suggest that Pino alleviates cognition deficits by protecting neurons from inflammation injury in diabetic mice. PMID- 29150086 TI - The ex vivo toll-like receptor 7 tolerance induction in donor lymphocytes prevents murine acute graft-versus-host disease. AB - BACKGROUND AIMS: Acute graft-versus-host disease (aGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation, mediated by alloreactive donor T cells. Toll-like receptors (TLRs), a family of conserved pattern-recognition receptors (PRRs), represent key players in donors' T-cell activation during aGVHD; however, a regulatory, tolerogenic role for certain TLRs has been recognized in a different context. We investigated whether the ex vivo-induced TLR-2,-4,-7 tolerance in donor cells could prevent alloreactivity in a mismatched transplantation model. METHODS: TLR-2,-4,-7 tolerance was induced in mouse splenocytes, after stimulation with low doses of corresponding ligands. Cellular and molecular changes of the TLR-tolerant splenocytes and purified T cells were assessed by immunophenotypic and gene expression analyses. Incidence of aGVHD was evaluated by the clinical score and survival as well as histopathology of target tissues. RESULTS: Only the R848 induced TLR7 tolerance prevented aGVHD. The TLR7 ligand-induced tolerance lasted for a critical post-transplant period and was associated with distinct cellular and molecular signatures characterized by induction of regulatory T cells, reduced alloreactivity and balanced regulation of inflammatory signaling and innate immune responses. The TLR7-tolerant T cells preserved the immunological memory and generated in vitro virus-specific T cells upon antigen stimulation. The anti-aGVHD tolerization effect was direct and specific to TLR7 and required the receptor-ligand interaction; TLR7-/- T cells isolated from B6 TLR7-/- mice presented a distinct gene expression profile but failed to prevent aGVHD. DISCUSSION: We propose an effective and clinically applicable ex vivo approach for aGVHD prevention through a transient and reversible immune reprogramming exerted by TLR7-tolerant donor lymphocytes. PMID- 29150087 TI - Dexmedetomidine-methadone-ketamine versus dexmedetomidine-methadone-alfaxalone for cats undergoing ovariectomy. AB - OBJECTIVE: To compare the duration, quality of anaesthesia and analgesia, and quality of recovery of dexmedetomidine and methadone combined with either ketamine or alfaxalone. STUDY DESIGN: Randomized, prospective clinical trial. ANIMALS: A group of 44 healthy client-owned cats presenting for ovariectomy. METHODS: Cats were randomly assigned to one of the two treatment groups: DAM (n=22), which was administered intramuscularly (IM) dexmedetomidine (15 MUg kg 1), methadone (0.3 mg kg-1) and alfaxalone (3 mg kg-1), and DKM (n=22), which was administered IM dexmedetomidine (15 MUg kg-1), methadone (0.3 mg kg-1) and ketamine (3 mg kg-1). During anaesthesia, heart rate, respiratory rate and systolic arterial pressure were measured every 5 minutes. Cats that moved or had poor muscle relaxation were administered an additional 1 mg kg-1 of either alfaxalone (DAM) or ketamine (DKM) intravenously (IV). In cases of increased autonomic responses to surgical stimulation, fentanyl (2 MUg kg-1) was administered IV. At the end of the surgery, atipamezole (75 MUg kg-1) was administered IM, and the times to both sternal recumbency and active interaction were recorded. Quality of recovery was evaluated with a simple descriptive scale. The UNESP-Botucatu multidimensional composite pain scale and a visual analogue scale were used to evaluate postoperative analgesia at the return of active interaction and 1, 2 and 3 hours later. RESULTS: The additional anaesthesia and rescue fentanyl requirements were similar between groups. The quality of recovery was better in the DAM group than in the DKM group [simple descriptive scale scores: 0 (0-1) and 1 (0-3), respectively; p=0.002]. Postoperative pain scores decreased progressively over time in both groups, with no significant differences (p=0.08) between them. CONCLUSIONS AND CLINICAL RELEVANCE: Both protocols provided comparable quality of anaesthesia and analgesia and were suitable for cats undergoing ovariectomy. In combination with methadone and dexmedetomidine, alfaxalone and ketamine showed comfortable and reliable recoveries. PMID- 29150089 TI - Lupus Nephritis: Persistent Challenges, New Approaches. PMID- 29150088 TI - The Risk of Remaining Silent: Addressing the Current Threats to Women's Health. PMID- 29150090 TI - Graph-based representation of behavior in detection and prediction of daily living activities. AB - Various surveillance systems capture signs of human activities of daily living (ADLs) and store multimodal information as time line behavioral records. In this paper, we present a novel approach to the analysis of a behavioral record used in a surveillance system designed for use in elderly smart homes. The description of a subject's activity is first decomposed into elementary poses - easily detectable by dedicated intelligent sensors - and represented by the share coefficients. Then, the activity is represented in the form of an attributed graph, where nodes correspond to elementary poses. As share coefficients of poses are expressed as attributes assigned to graph nodes, their change corresponding to a subject's action is represented by flow in graph edges. The behavioral record is thus a time series of graphs, which tiny size facilitates storage and management of long-term monitoring results. At the system learning stage, the contribution of elementary poses is accumulated, discretized and probability ordered leading to a finite list representing the possible transitions between states. Such a list is independently built for each room in the supervised residence, and employed for assessment of the current action in the context of subject's habits and a room purpose. The proposed format of a behavioral record, applied to an adaptive surveillance system, is particularly advantageous for representing new activities not known at the setup stage, for providing a quantitative measure of transitions between poses and for expressing the difference between a predicted and actual action in a numerical way. PMID- 29150091 TI - Prediction of menarcheal status of girls using voice features. AB - A method for evaluating the menarcheal status of girls on the basis of their voice features is presented in the paper. The registration procedure consists of voice recording and measuring 20 anthropological features. The input feature vector is a combination of voice and anthropometric parameters, counting 220 features. The optimal set of parameters was selected using five different methods: Method A - stepwise regression (first forward, then backward regression) performed on features with statistically different means/medians; Method B - stepwise regression (forward and backward) on all features, with age; Method C - stepwise regression as in B; including age, Method D - all features with statistically different means/medians, Method E - all features excluding age. For classification purposes three methods were employed: random forest (RF), support vector machine (SVM) and linear discriminant analysis (LDA) classifier. They were tested with 10-fold cross validation. The classification accuracy for RF using only voice features is higher than using only anthropometric data: 86.86% vs. 81.02% respectively. For the other two classifiers, the results do not show as large a difference: 80.60% vs. 82.80% for SVM and 80.66% vs. 82.34% for LDA. The advantage of voice features is more noticeable with sensitivity: 91.92% vs. 83.06% for RF. The obtained results suggest that the presented method can be used for automatic recognition of girls' menarcheal status using voice signal. PMID- 29150092 TI - Generation of integration-free induced pluripotent stem cell lines derived from two patients with X-linked Alport syndrome (XLAS). AB - Skin biopsies were obtained from two male patients with X-linked Alport syndrome (XLAS) with hemizygous COL4A5 mutations in exon 41 or exon 46. Dermal fibroblasts were extracted and reprogrammed by nucleofection with episomal plasmids carrying OCT3/4, SOX2, KLF4 LIN28, L-MYC and p53 shRNA. The generated induced Pluripotent Stem Cell (iPSC) lines AS-FiPS2-Ep6F-28 and AS-FiPS3-Ep6F-9 were free of genomically integrated reprogramming genes, had the specific mutations, a stable karyotype, expressed pluripotency markers and generated embryoid bodies which were differentiated towards the three germ layers in vitro. These iPSC lines offer a useful resource to study Alport syndrome pathomechanisms and drug testing. PMID- 29150093 TI - Corrigendum to "Pseudogene PDIA3P1 promotes cell proliferation, migration and invasion, and suppresses apoptosis in hepatocellular carcinoma by regulating the p53 pathway" [Cancer Lett. 407C (2017) 76-83]. PMID- 29150094 TI - [Geriatric assessment and prognostic scores in older cancer patient: Additional support to the therapeutic decision?] AB - Cancer is a disease of the elderly as demonstrated by the epidemiological evolution of Western countries. Indeed, two third of cancers newly diagnosed occur over 65 years. However, older cancer patients have been often excluded from clinical trials in oncology and the extrapolation of cancer treatments in this population remains difficult in practice. Scientific societies recommend that a comprehensive geriatric assessment (CGA) be performed in patients aged 70 and over and selected using screening tools for frailty such as the G8 index. The CGA allows to detect aging-related vulnerabilities in various domains (comorbidities, polypharmacy, autonomy, nutrition, mobility, cognition, mood, social) and associated with adverse outcomes during cancer treatment (reduced overall survival, perioperative complications, toxicity-related chemotherapy). The CGA is allow to elaborate a personalized treatment plan in geriatric oncology. However, to date, no algorithms based on CGA is validated to guide therapeutic decision in geriatric oncology. The collaboration between geriatrician and oncologist remains essential to elaborate an appropriate therapeutic strategy and limit the situations of over- and under-treatment. This article presents the set of tools and scores used in geriatric oncology to guide the therapeutic decision. PMID- 29150097 TI - Kidd system antigens and kidney disease. PMID- 29150095 TI - [Towards a better use of midazolam in end of life: A survey in a department of medical oncology]. AB - INTRODUCTION: At the end of life of cancer patients, sedation is sometimes needed, in order to palliate unbearable symptoms that other treatments fail to relieve. Midazolam is currently recommended for sedation and its prescription is guided by national guidelines. The aim of the present study was to evaluate the practices of midazolam prescription in a department of medical oncology and to compare the results with French national recommendations in order to improve the midazolam use in case of sedation. METHODS: We conducted a retrospective survey studying midazolam prescriptions in patients who died between 2014 and 2015 in the medical oncology department. Compliance rates with recommendations were reviewed. RESULTS: A total of 99 medical files were analyzed. Fifty-three patients received midazolam: 64.4% for refractory symptoms, 22% for anxiolyse, 10.2% for acute respiratory distress syndrome. When reported, the titration indications and modalities systematically conformed to guidelines. In case of sedation for refractory symptoms, adherence to guidelines was 76% regarding the family information, 63% regarding the patient information, 61% regarding the collegial nature of the initiation decision, 34% regarding the titration achievement and 5% regarding the pluridisciplinary nature of the initiation decision. CONCLUSION: Although limited justifications in midazolam prescriptions could have resulted in an overestimate of sedation and in an underestimate of titrations, current guideline are not enough applied in routine, especially regarding the necessity of a pluridisciplinary decision-making. A list of requirements before midazolam initiation is suggested, to increase the adherence to guidelines. Our results highlight the necessity of a better midazolam use in life-end sedations. PMID- 29150098 TI - Blood film in the era of streaming cells. PMID- 29150099 TI - Body composition assessment in hematopoietic stem cell transplantation. PMID- 29150096 TI - Flexible Roles for Proteoglycan Sulfation and Receptor Signaling. AB - Proteoglycans (PGs) in the extracellular matrix (ECM) play vital roles in axon growth and navigation, plasticity, and regeneration of injured neurons. Different classes of PGs may support or inhibit cell growth, and their functions are determined in part by highly specific structural features. Among these, the pattern of sulfation on the PG sugar chains is a paramount determinant of a diverse and flexible set of outcomes. Recent studies of PG sulfation illustrate the challenges of attributing biological actions to specific sulfation patterns, and suggest ways in which highly similar molecules may exert opposing effects on neurons. The receptors for PGs, which have yet to be fully characterized, display a similarly nuanced spectrum of effects. Different classes of PG function via overlapping families of receptors and signaling pathways. This enables them to control axon growth and guidance with remarkable specificity, but it poses challenges for determining the precise binding interactions and downstream effects of different PGs and their assorted sulfated epitopes. This review examines existing and emerging evidence for the roles of PG sulfation and receptor interactions in determining how these complex molecules influence neuronal development, growth, and function. PMID- 29150100 TI - Hodgkin's lymphoma in developing countries: can we go further? PMID- 29150101 TI - Lack of association between Kidd blood group system and chronic kidney disease. AB - BACKGROUND: The Kidd blood group system has three antigens, Jka, Jkb and Jk3, found on red blood cells and on endothelial cells of the inner lining of blood vessels in the renal medulla. These are known as urea transporter B (UT-B). Researchers have found that individuals carrying the Jk(a-b-) or Jk-null (UT-B null) phenotypes have a lower urine-concentrating capability and risk of severe renal impairment. This study evaluated the distribution of the Kidd phenotypes in patients with chronic kidney disease and a possible association of Kidd antigens with the development of renal disease. METHODS: Jka and Jkb antigens were phenotyped using the gel column agglutination test (ID-cards Bio-RAD) in 197 patients with chronic kidney disease and 444 blood donors, as the control group. The phenotype and antigen frequencies between patients and controls were evaluated using the Chi-square method with Yates correction and logistic regression after adjustments for gender and age. RESULTS: No differences were observed between the Kidd phenotypes frequency distribution between patients with chronic kidney disease and blood donors [Jk(a-b+)=22.3% and 27.2%; Jk(a+b-)=30.5% and 24.3%; Jk(a+b+)=47.25% and 48.4%, respectively]. CONCLUSION: The distribution of Kidd phenotypes found in the studied population is expected for Caucasians; Jka and Jkb antigens and phenotypes were not found to be related to susceptibility for chronic kidney disease. PMID- 29150102 TI - Evaluation of criteria of manual blood smear review following automated complete blood counts in a large university hospital. AB - BACKGROUND: There is great interest in reducing the number of automated complete blood counts requiring manual blood smear reviews without sacrificing the quality of patient care. This study was aimed at evaluating and establishing appropriate screening criteria for manual blood smear reviews to improve the performance in a hematology laboratory. METHOD: A total of 1977 consecutive samples from the daily workload were used to evaluate four sets of screening criteria for manual blood smear reviews to identify samples with positive smear findings. Three sets of screening criteria were arbitrarily proposed in this study: Group 1 (narrow ranges), Group 2 (intermediate ranges), and Group 3 (wide limits) and one set (Group 4) was adapted from the International Society for Laboratory Hematology. All samples were run on Sysmex hematology analyzers and were investigated using manual blood smear reviews. Diagnostic accuracy and agreement were performed for each set of screening criteria, including an investigation of microscopic review rate and efficiency. RESULTS: The microscopic review rates for Groups 1, 2, 3 and 4 were 73.85%, 54.52%, 46.33% and 46.38%, respectively; the false-negative rates were 0.50%, 1.97%, 2.73% and 3.95%, respectively. The efficiency and negative predictive values of Group 3 were 73.04% and 4.91%, respectively. CONCLUSIONS: Group 3 had the best relationship between safety (false-negative rate: <=3%) and efficiency to estimate the limits of automation in performing complete blood counts. This study strengthens the importance of establishing screening criteria for manual blood smear reviews, which account for the different contexts in which hematological determinations are performed. Each laboratory should optimize the screening criteria for manual blood smear reviews in order to maximize their efficiency and safety. PMID- 29150103 TI - Body composition of Fanconi anemia patients after hematopoietic stem cell transplantation. AB - INTRODUCTION: Fanconi anemia is a rare genetic disease linked to bone marrow failure; a possible treatment is hematopoietic stem cell transplantation. Changes in the nutritional status of Fanconi anemia patients are not very well known. This study aimed to characterize body composition of adult, children and adolescent patients with Fanconi anemia who were submitted to hematopoietic stem cell transplantation or not. METHODS: This cross-sectional study enrolled 63 patients (29 adults and 34 children and adolescents). Body composition was assessed based on diverse methods, including triceps skin fold, arm circumference, arm muscle area and bioelectrical impedance analysis, as there is no established consensus for this population. Body mass index was also considered as reference according to age. RESULTS: Almost half (48.3%) of the transplanted adult patients were underweight considering body mass index whereas eutrophic status was observed in 66.7% of the children and adolescents submitted to hematopoietic stem cell transplantation and in 80% of those who were not. At least 50% of all groups displayed muscle mass depletion. Half of the transplanted children and adolescents presented short/very short stature for age. CONCLUSION: All patients presented low muscle stores, underweight was common in adults, and short stature was common in children and adolescents. More studies are needed to detect whether muscle mass loss measured at the early stages of treatment results in higher risk of mortality, considering the importance of muscle mass as an essential body component to prevent mortality related to infectious and non infectious diseases and the malnutrition inherent to Fanconi anemia. PMID- 29150105 TI - For survival, the emergence of oligoclonal bands after multiple myeloma treatment is less important than achieving complete remission. AB - BACKGROUND: The emergence of oligoclonal bands, proteins differing from those originally identified at diagnosis, has been reported in multiple myeloma patients after high-dose chemotherapy followed by autologous stem cell transplantation and after successful conventional chemotherapy. The clinical relevance of oligoclonal bands remains unclear, but their emergence has been associated with better prognosis. The aim of the present study was to determine the prevalence, clinical characteristics and prognostic impact of the presence of oligoclonal bands in multiple myeloma patients. METHODS: A retrospective cohort study was conducted. The study included newly diagnosed multiple myeloma patients with at least very good partial response after conventional dose or high-dose chemotherapy followed by autologous stem cell transplantation. The emergence of oligoclonal bands was identified using serum protein electrophoresis as well as serum and urine immunofixation techniques. RESULTS: A total of 101 patients were included with a median follow-up of 42 months. In total, 55% were male, and the median age was 58 years (29-87 years). Fifty-one (50.5%) patients developed oligoclonal bands. They comprised 60% (45/75) of patients treated with autologous stem cell transplantation and 23% (6/26) of those who were not transplanted. Patients with oligoclonal bands showed better progression-free survival than those without the emergence of oligoclonal bands (p-value=0.0075). CONCLUSION: The prevalence of oligoclonal bands in this study population was 50.5% with its frequency being greater in cases treated with autologous stem cell transplantation and in those attaining complete remission. Complete remission was more important than the emergence of oligoclonal bands on progression-free survival. PMID- 29150104 TI - High frequency of primary refractory disease and low progression-free survival rate of Hodgkin's lymphoma: a decade of experience in a Latin American center. AB - BACKGROUND: Reports dealing with clinical outcomes of classical Hodgkin's lymphoma in low- to middle-income countries are scarce and response to therapy is poorly documented. This report describes the characteristics and clinical outcomes of patients with classical Hodgkin's lymphoma from a single institution in Latin America. METHOD: A retrospective study was conducted over ten years of patients with classical Hodgkin's lymphoma treated at a referral center. Progression-free and overall survival rates were estimated by Kaplan-Meier analysis. The univariate Cox regression model was used to estimate associations between important variables and clinical outcomes. MAIN RESULTS: One hundred and twenty-eight patients were analyzed. The mean age was 28.5 years. The five-year progression-free and overall survival were 37.3% and 78.9%, respectively. Of the whole group, 55 (43%) were primary refractory cases. Only 39/83 (47%) patients with advanced disease vs. 34/45 (75.6%) in early stages (p-value=0.002) achieved complete remission. Those with advanced disease had a five-year overall survival of 68.7% vs. 91.8% for early disease (p-value=0.132). Thirty-one patients relapsed (24.2%) and 20 (64.5%) received a transplant. The hazard ratio for progression with bone marrow infiltration was 2.628 (p-value=0.037). For death, an International Prognostic Score >=4 had a hazard ratio of 3.355 (p-value=0.050) in univariate analysis. Two-thirds of classical Hodgkin's lymphoma patients diagnosed at advanced stages had a low progression-free survival but an overall survival similar to high-income countries. CONCLUSION: Patients diagnosed with classical Hodgkin's lymphoma in Northeastern Mexico had a significantly low progression-free survival rate and presented with advanced disease, underscoring the need for earlier diagnosis and improved contemporary therapeutic strategies in these mainly young productive-age Hodgkin's lymphoma patients. PMID- 29150106 TI - Reactions related to asparaginase infusion in a 10-year retrospective cohort. AB - INTRODUCTION: Although it is an essential component of the treatment of acute lymphoid leukemia in children, asparaginase causes adverse reactions that sometimes make it impossible to use it fully. Hypersensitivity reactions are the most frequent and may lead to early discontinuation of treatment. The present study aimed to investigate suspicions of adverse reactions during the infusion of asparaginase in a pediatric cohort. METHODS: A retrospective observational study was carried out at a university pediatric institute in the state of Rio de Janeiro. Information regarding clinical features and characteristics of adverse reactions was collected from hospital medical records. Suspicions of adverse reactions were classified regarding causality and severity. RESULTS: Seventy three suspicions of adverse reactions were recorded during asparaginase infusion in 72 children in the study period. Allergic hypersensitivity reactions were suspected in 60.5% of the cases. Of these, 25% of the reactions occurred during induction and 61.1% in concomitant use with vincristine, findings that diverge from other studies. High-risk classification and younger age were considered risk factors for these reactions. A total of 72.4% of the reactions were classified as grade 1 or 2, which suggest that not all are related to antibody formation; this highlights the importance of differential diagnosis with other reactions, such as non-allergic hypersensitivity and hyperammonemia. CONCLUSION: The implementation of the differential diagnosis of reactions related to infusion of asparaginase with ammonia dosage and classification of the grade of reactions is crucial to facilitate the identification and proper management of each type of reaction. PMID- 29150107 TI - Pre-sarcopenia and bone mineral density in adults submitted to hematopoietic stem cell transplantation. AB - BACKGROUND: The aim of this study was to evaluate the prevalence of pre sarcopenia and bone mineral density after hematopoietic stem cell transplantation. METHODS: The study group consisted of over 18-year-old patients who had been submitted to allogeneic transplantation at least one year previously. Patients and healthy controls were matched by sex, ethnic background, age, and body mass index. Body composition and bone mineral density were measured by dual-energy X-ray absorptiometry. A 24-h food recall and food frequency survey were performed. The biochemical evaluation included calcium, parathormone and vitamin D. Eighty-seven patients (52 men; age: 37.2+/-12.7 years; body mass index: 25+/-4.5kg/m2) were compared to 68 controls [31 men; age 35.4+/-15.5 years (p=0.467); body mass index 25.05+/-3.7kg/m2 (p=0.927)]. RESULTS: There was no significant difference in the dietary intake between patients and controls. The mean levels of vitamin D were 23.5+/-10.3ng/mL; 29 patients (41.0%) had insufficient and 26 (37.14%) deficient levels. A higher prevalence of reduced bone mineral density was observed in 24 patients (25%) compared to 12 controls (19.1% - p<0.001). Pre-sarcopenia was diagnosed in 14 (14.4%) patients and none of the controls (p=0.05). There was a higher prevalence of pre-sarcopenia (66%) in patients with grades III and IV compared to those with grades 0-II graft versus-host disease (10.9%) (p=0.004). CONCLUSION: patients submitted to transplantation had a higher prevalence of pre-sarcopenia and greater changes in bone mineral density compared to controls; the severity of graft-versus-host disease had an impact on the prevalence of pre-sarcopenia. PMID- 29150108 TI - Economy class syndrome: what is it and who are the individuals at risk? AB - The term 'economy class syndrome' refers to the occurrence of thrombotic events during long-haul flights that mainly occur in passengers in the economy class of the aircraft. This syndrome results from several factors related to the aircraft cabin (immobilization, hypobaric hypoxia and low humidity) and the passenger (body mass index, thrombophilia, oral contraceptives or hormone replacement therapy, cancer), acting together to predispose to excessive blood coagulation, which can result in venous thromboembolism. Several risk factors, both genetic and acquired, are associated with venous thromboembolism. The most important genetic risk factors are natural anticoagulant deficiencies (antithrombin, protein C and protein S), factor V Leiden, prothrombin and fibrinogen gene mutations and non-O blood group individuals. Acquired risk factors include age, pregnancy, surgery, obesity, cancer, hormonal contraceptives and hormone replacement therapy, antiphospholipid syndrome, infections, immobilization and smoking. People who have these risk factors are predisposed to hypercoagulability and are more susceptible to suffer venous thromboembolism during air travel. For these individuals, a suitable outfit for the trip, frequent walks, calf muscle exercises, elastic compression stockings and hydration are important preventive measures. Hence, it is essential to inform about economic class syndrome in an attempt to encourage Brazilian health and transport authorities to adopt measures, in partnership with the pharmaceutical industry, to prevent venous thromboembolism. PMID- 29150109 TI - Recurrent thromboembolism after splenectomy in a patient with complex hemoglobin disease: a case report. PMID- 29150110 TI - Autoimmune hemolytic anemia and hyperglobulinemia leading to the diagnosis of multiple myeloma. PMID- 29150111 TI - Primary imatinib failure rescued by dasatinib and maintained by reintroduction of imatinib. PMID- 29150112 TI - Passenger lymphocyte syndrome in liver transplantation. PMID- 29150113 TI - DNA microarray expression profiling of a new t(8;13) AML case allows identification of possible leukemogenic transformation markers. PMID- 29150114 TI - Osteopetrosis in twin infants mimicking leukemia. PMID- 29150115 TI - Role of daratumumab in transfusion medicine: a must know entity. PMID- 29150116 TI - Acute myeloid leukemia with e1a2 BCR-ABL1 fusion gene: two cases with peculiar molecular and clinical presentations. PMID- 29150117 TI - Molecular genetic techniques for gains and losses of genomic material in a case of acute myeloid leukemia. PMID- 29150118 TI - Chromosomal aberrations detected by Fluorescence in situ hybridization in 344 Brazilian chronic lymphocytic leukemia patients. PMID- 29150119 TI - Capecitabine-induced pancreatitits. PMID- 29150121 TI - Gastric wall and splenic abscess in the background of an invasive salmonellosis caused by Salmonella enteritidis. PMID- 29150120 TI - Cushing's syndrome caused by a neuroendocrine carcinoma of the ampulla of Vater with ectopic adrenocorticotropic hormone secretion. PMID- 29150122 TI - Neonatal sepsis secondary to chorioamnionitis by Actinomyces neuii in a 25 weeks pregnant woman. PMID- 29150123 TI - Pathophysiology of rhabdomyolysis subcutaneous swelling and its ultrasonographic significant. PMID- 29150124 TI - Generalized non-evanescents wheals with targetoid purpuric plaques. PMID- 29150125 TI - Multifocal atypical teratoid rhabdoid tumor of the central nervous system in an adult patient. PMID- 29150126 TI - Hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy is the most common inherited cardiovascular disease. It is characterized by increased ventricular wall thickness and is highly complex due to its heterogeneous clinical presentation, several phenotypes, large number of associated causal mutations and broad spectrum of complications. It is caused by mutations in sarcomeric proteins, which are identified in up to 60% of cases of the disease. Clinical manifestations of Hypertrophic Cardiomyopathy include shortness of breath, chest pain, palpitations and syncope, which are related to the onset of diastolic dysfunction, left ventricular outflow tract obstruction, ischemia, atrial fibrillation and abnormal vascular responses. It is associated with an increased risk of sudden cardiac death, heart failure and thromboembolic events. In this article, we discuss the diagnostic and therapeutic aspects of this disease. PMID- 29150127 TI - Purulent pericarditis by Salmonella enteritidis in a patient with chronic kidney disease. PMID- 29150128 TI - Sprue-like enterophaty asscociated with valsartan. PMID- 29150129 TI - Diagnostic accuracy of 4 intraoral radiographic techniques for misfit detection at the implant abutment joint. AB - STATEMENT OF PROBLEM: A misfit or gap at the implant-abutment joint (IAJ) requires detection as it may compromise the health of the peri-implant tissue. However, which radiographic technique provides the most orthogonal relationship between the central beam and the implant/image receptor is unclear. PURPOSE: The purpose of this in vitro study was to evaluate the diagnostic accuracy of 4 intraoral radiographic techniques on misfit detection at the IAJ. MATERIAL AND METHODS: Twenty implants were placed in polyamide jaws, and customized dental implant abutments with a metal collar were installed. Different gaps were simulated by placing one or three 50-MUm-thick polyester strips at the IAJ; the absence of the strip represented the control group (no gap). The 4 radiographic techniques were evaluated by using different film holders: a periapical with bisecting angle (PBA), a bitewing interproximal (BI), a periapical with standard paralleling (PSP), and a periapical with modified paralleling (PMP) holder (with a custom-made paralleling index). A total of 240 digital radiographs were evaluated by 4 clinicians experienced with dental implants. Differences were evaluated by using receiver operating characteristic (ROC) curves (Az) and Fisher tests (alpha=.05). Diagnostic values (sensitivity, specificity, accuracy, and positive and negative predictive values) were also obtained. The Kappa test was used to assess intra- and interevaluator reproducibility, which ranged from moderate to almost perfect. RESULTS: All diagnostic values, except specificity, were lower for the PBA technique for both the 50- and 150-MUm gaps. Az values for the PBA technique were significantly lower than those obtained for the other 3 techniques (P<.05), which did not differ from each other. The 150-MUm gaps were more easily detected than the 50-MUm gaps only for PBA (P<.05). CONCLUSIONS: The BI, PSP, and PMP techniques detected misfits at the IAJ most accurately. The PBA technique is not recommended for this purpose. PMID- 29150130 TI - Aluminum barrier laminate or plastic tube as a dispenser for modeling plastic impression compound for border molding. PMID- 29150131 TI - A 3D-printed guide for lateral approach sinus grafting: A dental technique. AB - Lateral approach sinus grafting has become a routine and predictable surgical method of augmenting the pneumatized sinus for implant placement. Outlining the lateral window access can be a challenging task for the clinician to envision and execute. Improper extension and access to the maxillary sinus can prevent proper placement of graft materials and lead to complications. The purpose of this report was to demonstrate a technique that will allow the precise planning of the lateral approach using radiographic information and 3-dimensional (3D) software to 3D-print a surgical guide. PMID- 29150132 TI - Prosthodontic rehabilitation with monolithic, multichromatic, CAD-CAM complete overdentures in an adolescent patient with ectodermal dysplasia: A clinical report. AB - Ectodermal dysplasia is a rare, hereditary, congenital disease that affects the normal development of certain tissues and structures of ectodermal origin. The disease is manifested to different degrees of severity and may involve the nose, eyes, hair, nails, sweat glands, and enamel. This report describes a 14-year-old boy with ectodermal dysplasia, rehabilitated with monolithic, multichromatic maxillary and mandibular computer-aided design and computer-aided manufacturing (CAD-CAM) acrylic resin complete overdentures. PMID- 29150133 TI - Effect of coloring and sintering on the translucency and biaxial strength of monolithic zirconia. AB - STATEMENT OF PROBLEM: The influences of coloring and sintering procedures on the optical and mechanical properties of monolithic zirconia have not been thoroughly investigated. PURPOSE: The purpose of this in vitro study was to investigate the effects of the coloring procedure and of varying final sintering temperatures on the translucency parameter (TP) and biaxial flexural strength (BFS) of monolithic zirconia. MATERIAL AND METHODS: Disk-shaped specimens (N=210) of 2 different monolithic zirconia brands (Vita YZ HTWhite [VYZa]; Vita YZ HTColor A2 [VYZb]; Prettau Zirkonzahn [PZ]; Prettau Anterior Zirkonzahn [PZA]) with a diameter of 15 mm and a thickness of 1.0 +/-0.05 mm were prepared. Half of the specimens prepared from noncolored blocks (VYZa, PZ, and PZA) received coloring liquid application. Then, the specimens were divided into 3 subgroups (n=10) according to the final sintering temperatures (1350 degrees C, 1450 degrees C, and 1600 degrees C). The TP was determined by using a reflection spectrophotometer, and the BFS was tested with the piston-on-3-ball method in a universal testing machine. Data were statistically analyzed by multivariate multiple regression and Bonferroni tests (alpha=.05). RESULTS: Significant differences were obtained among the groups based on the results of the TP and BFS (P<.05). The TP was affected by the changes in final sintering temperature. The varying final sintering temperatures demonstrated no significant effect on the BFS, except in group PZ (noncolored) that produced lower BFS when sintered at 1350 degrees C than the subgroups sintered at 1450 degrees C and 1600 degrees C (P<.05). Coloring liquid application significantly decreased the TP of VYZa (sintered at 1350 degrees C) but produced no significant effect on the groups PZ and PZA. Additionally, the coloring procedure had no significant effect on the BFS of tested materials (VYZa, PZ, and PZA) (P>.05). CONCLUSIONS: Increased sintering temperature leads to increased translucency with minimal impact on the BFS. The coloring procedure should be considered at the time of material selection to avoid possible reduction in translucency. PMID- 29150134 TI - Stress generation in mandibular anterior teeth restored with different types of post-and-core at various levels of ferrule. AB - STATEMENT OF PROBLEM: Pertinent evidence regarding the mechanical integrity of mandibular anterior teeth restored with a post-and-core is limited. PURPOSE: The purpose of this finite element analysis study was to compare the impact of the post type (glass fiber post-and-resin core or cast post-and-core) along with the ferrule effect on the stress fields generated in endodontically treated mandibular lateral incisors and canines. MATERIAL AND METHODS: Three-dimensional models of the segmented mandible were developed. Mandibular incisors and canines with or without a 2-mm circular ferrule and restored with a cast post-and-core or glass fiber post-and-resin core were simulated and subjected to linear elastic static analysis. The principal stress values were calculated. von Mises equivalent stresses were used to evaluate the stress. RESULTS: Maximum principal stresses in dentin were highest in incisors, with a ferrule. Stress parameters in composite resin core in both incisors and canines were critically close to the tensile failure limit of the core material. Cast post-and-cores cemented in incisors without a ferrule accumulated the highest stresses, exceeding the tensile failure limit of resin-modified glass ionomer cement. CONCLUSIONS: Tooth preparation with a ferrule led to a remarkable rise in stress in the dentin of mandibular incisors but favored the mechanical integrity of the restoration. PMID- 29150135 TI - Effect of different resin luting cements on the marginal fit of lithium disilicate pressed crowns. AB - STATEMENT OF PROBLEM: The vertical marginal discrepancy of restorations can increase upon cementation, and poor marginal fit can lead to cement dissolution, marginal discoloration, microleakage, and secondary caries. The amount of increase is related to the type of luting cement used, but how lithium disilicate pressed crowns are affected by different resin cements is unclear. PURPOSE: The purpose of this in vitro study was to compare the effect of using different resin luting cements on the vertical marginal discrepancy of lithium disilicate pressed crowns. MATERIAL AND METHODS: A total of 18 intact extracted mandibular third molars were disinfected in a solution of 10% formalin for 7 days and were then prepared to receive a ceramic crown. Impressions were made with polyvinyl siloxane and lithium disilicate pressed crowns made and cemented with 1 of 3 resin luting cements. The marginal discrepancy was measured at 4 points on the finishing line of each tooth, with optical microscopy at *200 magnification before and after cementation. Statistical analysis was done with the Kruskal Wallis test to compare the median marginal increase among the 3 groups (a=.05). RESULTS: The least amount of marginal increase after cementation was with Harvard PremiumFlow cement, with an average marginal increase of 42 +/-11 MUm. RelyX Ultimate cement increased the margins by an average 45 +/-29 MUm. The highest marginal increase was found in the Enamel Plus HRi preheated composite resin group (116 +/-47 MUm). CONCLUSIONS: The marginal increase of pressed crowns cemented with preheated composite resin (Enamel Plus HRi) exceeded the clinically acceptable range of marginal discrepancy. PMID- 29150136 TI - Associations between cortical thickness, structural connectivity and severity of dimensional bulimia nervosa symptomatology. AB - Bulimia nervosa (BN) is a psychiatric illness defined by preoccupation with body image (cognitive 'symptoms'), binge eating and compensatory behaviors. Although diagnosed BN has been related to grey matter alterations, characterization of brain structure in women with a range of BN symptoms has not been made. This study examined whether cortical thickness (CT) values scaled with severity of BN cognitions in 33 women with variable BN pathology. We then assessed global structural connectivity (SC) of CT to determine if individual differences in global SC relate to BN symptom severity. We used the Eating Disorder Examination Questionnaire (EDE-Q) as a continuous measure of BN symptom severity. EDE-Q score was negatively related to global CT and local CT in the left middle frontal gyrus, right superior frontal gyrus and bilateral orbitofrontal cortex (OFC) and temporoparietal regions. Moreover, cortical thinning was most pronounced in regions with high global connectivity. Finally, individual contributions to global SC at the group level related to EDE-Q score, where increased EDE-Q score correlated with reduced connectivity of the left OFC and middle temporal cortex and increased connectivity of the right superior parietal lobule. Findings represent the first evidence of cortical thinning that relates to cognitive BN symptoms. PMID- 29150137 TI - Knowledge translation in pediatric rehabilitation: expanding access to scientific knowledge. PMID- 29150138 TI - New hybrid adsorbent based on porphyrin functionalized silica for heavy metals removal: Synthesis, characterization, isotherms, kinetics and thermodynamics studies. AB - The pollution of water resources due to the disposal of toxic heavy metals has been a growing global concern for the last decades. For this purpose, the search for effective and economic material based adsorbents is required, due to the efficiency of the process. In this work, a novel inorganic-organic hybrid material based on silica chemically modified with a porphyrin (SiNTPP), with a high metal removal efficiency, was developed. The new material was characterized using a set of suitable techniques such as 13C NMR of the solid state, elemental analysis, FTIR, nitrogen adsorption-desorption isotherm, BET surface area, BJH pore sizes and scanning electron microscopy (SEM). The new material surface exhibits good chemical and thermal stability based on the obtained thermogravimetric curves (TGA). An adsorption study was accomplished to investigate the effect of porphyrin-silica hybrid on the removal of Pb(II), Zn(II), Cd(II) and Cu(II) from aqueous solutions using a batch method. The effect of various parameters, such as initial metal concentration, pH, temperature, as well as the kinetics and thermodynamics for sorption on SiNTPP were investigated. The studies demonstrate that adsorption is fast, as proved by the equilibrium achievement within 25min. The metals removal from aqueous solution are better adapted to the Langmuir isotherm model than to the Freundlich model. The thermodynamic parameters (DeltaG degrees , DeltaH degrees and DeltaS degrees ) disclose that the process was endothermic and spontaneous in nature, and the adsorption process follows a pseudo-second order kinetics. The adsorbent can be regenerated continuously without affecting its extraction percentage. Its effectiveness is highly justified compared to previous described materials. PMID- 29150139 TI - Visual working memory performance in aphantasia. AB - Aphantasia, i.e., the congenital inability to experience voluntary mental imagery, offers a new model for studying the functional role of mental imagery in (visual) cognition. However, until now, there have been no studies investigating whether aphantasia can be linked to specific impairments in cognitive functioning. Here, we assess visual working memory performance in an aphantasic individual. We find that she performs significantly worse than controls on the most difficult (i.e., requiring the highest degree of precision) visual working memory trials. Surprisingly, her performance on a task designed to involve mental imagery did not differ from controls', although she lacked metacognitive insight into her performance. Together, these results indicate that although a lack of mental imagery can be compensated for under some conditions, mental imagery has a functional role in other areas of visual cognition, one of which is high precision working memory. PMID- 29150140 TI - Visual pathways from the perspective of cost functions and multi-task deep neural networks. AB - Vision research has been shaped by the seminal insight that we can understand the higher-tier visual cortex from the perspective of multiple functional pathways with different goals. In this paper, we try to give a computational account of the functional organization of this system by reasoning from the perspective of multi-task deep neural networks. Machine learning has shown that tasks become easier to solve when they are decomposed into subtasks with their own cost function. We hypothesize that the visual system optimizes multiple cost functions of unrelated tasks and this causes the emergence of a ventral pathway dedicated to vision for perception, and a dorsal pathway dedicated to vision for action. To evaluate the functional organization in multi-task deep neural networks, we propose a method that measures the contribution of a unit towards each task, applying it to two networks that have been trained on either two related or two unrelated tasks, using an identical stimulus set. Results show that the network trained on the unrelated tasks shows a decreasing degree of feature representation sharing towards higher-tier layers while the network trained on related tasks uniformly shows high degree of sharing. We conjecture that the method we propose can be used to analyze the anatomical and functional organization of the visual system and beyond. We predict that the degree to which tasks are related is a good descriptor of the degree to which they share downstream cortical-units. PMID- 29150141 TI - Hepatocellular carcinoma in the era of immunotherapy. AB - Hepatocellular carcinoma is a common malignancy which usually emerges on a background of chronic liver disease. Unfortunately, with contemporary management, patients with advanced hepatocellular carcinoma have few treatment options, and prognosis is poor. The emergence of immunotherapy has afforded new therapeutic opportunities. This article reviews the clinical evidence for immunotherapy in advanced hepatocellular carcinoma and presents ideas for future drug development. PMID- 29150142 TI - Association between non-alcoholic fatty liver disease and cancer incidence rate. AB - BACKGROUND & AIMS: Little is known about the association between non-alcoholic fatty liver disease (NAFLD) and cancer development. This study investigated the cancer incidence rates in NAFLD and analysed the association between NAFLD and cancer development. METHODS: This historical cohort study included subjects who were followed up for >1 year after having a heath checkup at a tertiary hospital in Korea from September 1, 2004 to December 31, 2005. NAFLD was diagnosed by ultrasonographic detection of hepatic steatosis in the absence of other known liver disease, including alcoholic or viral hepatitis. Cox proportional hazards regression model was conducted to assess the association between NAFLD and cancer development. RESULTS: Of 25,947 subjects, 8,721 (33.6%) had NAFLD. During the total follow-up of 164,671 person-years (median 7.5 years), the cancer incidence rate of the NAFLD group was higher than that of the non-NAFLD group (782.9 vs. 592.8 per 100,000 person-years; hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.17-1.49; p <0.001). When demographic and metabolic factors were adjusted for, NAFLD showed a strong association with three cancers: hepatocellular carcinoma ([HCC]; HR 16.73; 95% CI 2.09-133.85; p = 0.008), colorectal cancer in males (HR 2.01; 95% CI 1.10-3.68; p = 0.02), and breast cancer in females (HR 1.92; 95% CI 1.15-3.20; p = 0.01). A high NAFLD fibrosis score (NFS) and a high fibrosis-4 (FIB-4) score were associated with the development of all cancers and HCC. CONCLUSION: NAFLD was associated with the development of HCC, colorectal cancer in males, and breast cancer in females. A high NFS and a high FIB-4 score showed a strong association with the development of all cancers and HCC. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is associated with developing hepatocellular carcinoma (HCC). There have been limited data on the association between NAFLD and extrahepatic cancers. This study demonstrated that patients with NAFLD showed a higher association with the development of HCC, colorectal cancer in males, and breast cancer in females. A high NAFLD fibrosis score and a high fibrosis-4 score showed a strong association with the development of all cancers and HCC. PMID- 29150143 TI - Life after endometrial cancer: A systematic review of patient-reported outcomes. AB - BACKGROUND: Women with endometrial cancer (EC) are the second largest population of female cancer survivors in the United States. However, the outcomes of EC survivors, from the patient perspective, are not well-understood. Therefore, we conducted a systematic review of patient-reported outcomes (PROs) following an EC diagnosis. METHODS: We searched MEDLINE, EMBASE, Scopus, CINAHL, and reference lists to identify published observational studies that examined PROs among women with EC. Reviewers independently reviewed eligible full-text study articles and conducted data extraction. We qualitatively summarized included articles according to exposures [e.g. body mass index (BMI), treatment, etc.] or specific PROs (e.g. sexual function). RESULTS: Of 1722 unique studies, 102 full-text articles were reviewed, of which a total of 27 studies fulfilled the inclusion criteria. The most commonly used PRO questionnaires were the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) (n=9), Short Form 36 Questionnaire (SF-36, n=8), the Functional Assessment of Cancer Therapy-General (FACT-G, n=5), and the Female Sexual Function Index (FSFI, n=4). Obesity was associated with lower quality of life (QOL) and physical functioning. Treatment type affected several outcomes. Laparoscopy generally resulted in better QOL outcomes than laparotomy. Likewise, vaginal brachytherapy was associated with better outcomes compared to external beam radiation. Sexual function outcomes were dependent on age, time since diagnosis, and having consulted a physician before engaging in sexual activities. In addition, a physical activity intervention was associated with improved sexual interest but not sexual function. CONCLUSIONS: Our review provides insight into the experience of EC survivors from the patient perspective. Factors that contribute to QOL, such as pain, fatigue, emotional and social functioning, should be monitored following an EC diagnosis. PMID- 29150144 TI - Atypical depression and non-atypical depression: Is HPA axis function a biomarker? A systematic review. AB - BACKGROUND: The link between the abnormalities of the Hypothalamic-pituitary adrenal (HPA) axis and depression has been one of the most consistently reported findings in psychiatry. At the same time, multiple studies have demonstrated a stronger association between the increased activation of HPA-axis and melancholic, or endogenous depression subtype. This association has not been confirmed for the atypical subtype, and some researchers have suggested that as an antinomic depressive subtype, it may be associated with the opposite type, i.e. hypo-function, of the HPA-axis, similarly to PTSD. The purpose of this systematic review is to summarise existing studies addressing the abnormalities of the HPA-axis in melancholic and/or atypical depression. METHOD: We conducted a systematic review in the literature by searching MEDLINE, PsycINFO, OvidSP and Embase databases until June 2017. The following search items were used: "hypothalamic-pituitary-adrenal" OR "HPA" OR "cortisol" OR "corticotropin releasing hormone" OR "corticotropin releasing factor" OR "glucocorticoid*" OR "adrenocorticotropic hormone" OR "ACTH" AND "atypical depression" OR "non atypical depression" OR "melancholic depression" OR "non-melancholic depression" OR "endogenous depression" OR "endogenomorphic depression" OR "non-endogenous depression". Search limits were set to include papers in English or German language published in peer-reviewed journals at any period. All studies were scrutinized to determine the main methodological characteristics, and particularly possible sources of bias influencing the results reported. RESULTS: We selected 48 relevant studies. Detailed analysis of the methodologies used in the studies revealed significant variability especially regarding the samples' definition comparing the HPA axis activity of melancholic patients to atypical depression, including healthy controls. The results were subdivided into 4 sections: (1) 27 studies which compared melancholic OR endogenous depression vs. non-melancholic or non-endogenous depression or controls; (2) 9 studies which compared atypical depression or atypical traits vs. non-atypical depression or controls; (3) 7 studies which compared melancholic or endogenous and atypical depression subtypes and (4) 5 studies which used a longitudinal design, comparing the measures of HPA-axis across two or more time points. While the majority of studies did confirm the association between melancholic depression and increased post-challenge cortisol levels, the association with increases in basal cortisol and basal ACTH were less consistent. Some studies, particularly those focusing on reversed vegetative symptoms, demonstrated a decrease in the activity of the HPA axis in atypical depression compared to controls, but the majority did not distinguish it from healthy controls. CONCLUSIONS: In conclusion, our findings indicate that there is a difference in the activity of the HPA-axis between melancholic and atypical depressive subtypes. However, these are more likely explained by hypercortisolism in melancholia; and most often normal than decreased function in atypical depression. Further research should seek to distinguish a particular subtype of depression linked to HPA-axis abnormalities, based on symptom profile, with a focus on vegetative symptoms, neuroendocrine probes, and the history of adverse childhood events. New insights into the dichotomy addressed in this review might be obtained from genetic and epigenetic studies of HPA-axis related genes in both subtypes, with an emphasis on the presence of vegetative symptoms. PMID- 29150145 TI - Neuroimaging biomarkers as predictors of treatment outcome in Major Depressive Disorder. AB - BACKGROUND: Current practice for selecting pharmacological and non pharmacological antidepressant treatments has yielded low response and remission rates in Major Depressive Disorder (MDD). Neuroimaging biomarkers of brain structure and function may be useful in guiding treatment selection by predicting response vs. non-response outcomes. METHODS: In this review, we summarize data from studies examining predictors of treatment response using structural and functional neuroimaging modalities, as they pertain to pharmacotherapy, psychotherapy, and stimulation treatment strategies. A literature search was conducted in OVID Medline, EMBASE, and PsycINFO databases with coverage from January 1990 to January 2017. RESULTS: Several imaging biomarkers of therapeutic response in MDD emerged: frontolimbic regions, including the prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, and insula were regions of interest. Since these sub-regions are implicated in the etiology of MDD, their association with response outcomes may be the result of treatments having a normalizing effect on structural or activation abnormalities. LIMITATIONS: The direction of findings is inconsistent in studies examining these biomarkers, and variation across 'biotypes' within MDD may account for this. Limitations in sample size and differences in methodology likely also contribute. CONCLUSIONS: The identification of accurate, reliable neuroimaging biomarkers of treatment response holds promise toward improving treatment outcomes and reducing burden of illness for patients with MDD. However, before these biomarkers can be translated into clinical practice, they will need to be replicated and validated in large, independent samples, and integrated with data from other biological systems. PMID- 29150146 TI - Annual Trends in Follow-Up Visits for Pediatric Concussion in Emergency Departments and Physicians' Offices. AB - OBJECTIVE: To assess whether children and youth with concussion receive follow-up visits in accordance with the recommended guidelines. STUDY DESIGN: We conducted a retrospective, population-based study using linked health administrative data from all concussion-related visits to emergency department and physician offices by children aged 5 through 18 years (range, 5.00-18.99) in Ontario between 2003 and 2013. We analyzed the percentage of children and youth seen for follow-up. The Mann-Kendall test for trends was used to assess a monotonic increasing trend over time in concussion follow-up visits. RESULTS: A total of 126 654 children and youth were evaluated for an index concussion visit. The number of children and youth assessed for concussion follow-up (N = 45 155) has increased significantly over time (P < .001). In 2003, 781 of 7126 patients (11.0%; 95% CI, 10.3-11.7) with an index visit for concussion had a follow-up assessment. By 2013, 6526 of 21 681 (30.1%; 95% CI, 29.5-30.7) patients received follow-up care. CONCLUSIONS: The proportion of children and youth receiving follow-up after an acute concussion has significantly increased between 2003 and 2013. Nevertheless, more than two-thirds of all patients do not seek medical follow-up or clearance as recommended by current concussion guidelines, suggesting that ongoing efforts to improve and monitor compliance with recommended guidelines by patients and physicians are important. PMID- 29150147 TI - Clinic and Home-Based Behavioral Intervention for Obesity in Preschoolers: A Randomized Trial. AB - OBJECTIVE: To test the hypotheses that an innovative skills-based behavioral family clinic and home-based intervention (LAUNCH) would reduce body mass index z score (BMIz) compared with motivational interviewing and to standard care in preschool-aged children with obesity. STUDY DESIGN: Randomized controlled trial with children between the ages of 2 and 5 years above the 95th percentile for body mass index for age and sex recruited from 27 pediatrician offices across 10 recruitment cycles between March 12, 2012 and June 8, 2015. Children were randomized to LAUNCH (an 18-session clinic and home-based behavioral intervention), motivational interviewing (delivered at the same frequency as LAUNCH), or standard care (no formal intervention). Weight and height were measured by assessors blinded to participant assignment. The primary outcome, BMIz at month 6 after adjusting for baseline BMIz, was tested separately comparing LAUNCH with motivational interviewing and LAUNCH with standard care using regression-based analysis of covariance models. RESULTS: A total of 151 of the 167 children randomized met intent-to-treat criteria and 92% completed the study. Children were 76% White and 57% female, with an average age of 55 months and BMI percentile of 98.57, with no demographic differences between the groups. LAUNCH participants demonstrated a significantly greater decrease in BMIz (mean = -0.32, SD = +/-0.33) compared with motivational interviewing (mean = -0.05, SD = +/-0.27), P < .001, omega2 = 0.74 and compared with standard care (mean = -0.13, SD = +/-0.31), P < .004, omega2 = 0.75. CONCLUSIONS: In preschool-age children, an intensive 6-month behavioral skills-based intervention is necessary to reduce obesity. TRIAL REGISTRATION: Clinicaltrials.gov NCT01546727. PMID- 29150148 TI - [Family, socioeconomic status and health services: Clues to health care in diabetic patients with lower limb amputations in Andalusia. A qualitative study]. AB - AIM: To examine the experience of diabetic care in patients undergoing lower limb amputation. DESIGN: A qualitative study using the phenomenological approach. SETTING: Cadiz Health District. PARTICIPANTS: A total of 16 patients (11 men and 5 women) diagnosed with diabetes mellitus type 2 and with non-traumatic lower limb amputation. METHODS: Semi-structured interviews were performed, followed by a content analysis according Graneheim and Lundman. RESULTS: Four categories were identified: 1. The family is the cornerstone for diabetic care. 2. The socio economic and working conditions determine the quality of self-care. 3. The patient-health professional interaction facilitates patient care. 4. Limitations in the provision of health services. CONCLUSION: Family, economic and working conditions, along with health system-related factors are the most important elements in the care of patients with diabetes and amputations. Social, economic and working conditions determine diabetic complications. In order to enhance health care impact on the prevention of diabetes mellitus complications, health system policy makers must take these facts seriously into consideration and in a more personalised manner. PMID- 29150149 TI - Pregnancy and Heart Disease: Pregnancy-Associated Hypertension and Peripartum Cardiomyopathy. AB - Cardiovascular diseases are major complications in pregnancy worldwide and the number of patients who develop cardiac problems during pregnancy is increasing. Pregnancy-associated hypertensive complications such as pre-eclampsia (PE) or peripartum cardiomyopathy (PPCM) are potentially life-threatening heart diseases emerging during pregnancy, under delivery or in the first postpartal months in previously healthy women. Both disease entities display substantial morbidity and mortality in the acute phase. Long-term effects are just beginning to be evaluated. Pathophysiologies are not clear but may to some degree overlap with regard to angiogenic imbalance and endothelial damage. Genetics, lifestyle, and comorbidities are important modulators of PE and PPCM. The present review summarizes the current knowledge on epidemiology and pathophysiology, provides information on diagnostic and prognostic biomarkers and highlights promising novel therapeutic approaches for PE and PPCM. PMID- 29150150 TI - Biocompatible hollow polymeric particles produced by a mild solvent- and template free strategy. AB - Macroscopic hollow polymeric particles are attractive materials for various applications such as surgery, food industry, agriculture, etc. However, protocols reporting their synthesis have hitherto made use of organic solvents and/or sacrificial templates, compromising the encapsulation of different bioactive compounds and the process yield. Here, millimeter-size, hollow polymeric particles were synthesized, for the first time, in a solvent- and template free manner onto superhydrophobic surfaces (SHS). The particles were produced upon assembly and double superficial crosslinking of liquid droplets of DNA and methacrylamide chitosan aqueous solutions (CH:MA), leading to liquid-core particles with a hardened hydrogel shell. The particles displayed appealing physical and biological properties. The millimeter-size hydrogel shell, resulting from the double ionic/covalent crosslinking of CH:MA, endowed the hollow particles with softness to the touch and an outstanding structural stability against manipulation by hand and with forceps. Meanwhile, the liquid DNA core guaranteed a biocompatible cell encapsulation followed by a superior release and proliferation of viable cells, as compared to solid CH:MA particles prepared as a blank. Particles with these characteristics show promise for surgical protocols practiced in Tissue Engineering and Regenerative Medicine, where manipulable and biocompatible synthetic implants are often needed to supply living cells and other sensitive bioactive compounds. PMID- 29150151 TI - Evaluating short- and long-term impacts of a Medicaid "lock-in" program on opioid and benzodiazepine prescriptions dispensed to beneficiaries. AB - BACKGROUND: Insurance-based "lock-in" programs (LIPs) have become a popular strategy to address controlled substance (CS) (e.g., opioid) misuse. However, little is known about their impacts. We examined changes in CS dispensing to beneficiaries in the 12-month North Carolina Medicaid LIP. METHODS: We analyzed Medicaid claims linked to Prescription Drug Monitoring Program (PDMP) records for beneficiaries enrolled in the LIP between October 2010 and September 2012 (n=2702). Outcomes of interest were 1) number of dispensed CS prescriptions and 2) morphine milligram equivalents (MMEs) of dispensed opioids while a) locked-in and b) in the year following release. RESULTS: Compared to a period of stable CS dispensed prior to LIP enrollment, numbers of dispensed CS during lock-in and post-release were lower (count difference per person-month: -0.05 (95% CI: -0.11, 0.01); -0.23 (95% CI: -0.31, -0.15), respectively). However, beneficiaries' average daily MMEs of opioids were elevated during both lock-in and post-release (daily mean difference per person: 18.7 (95% CI: 13.9, 23.6); 11.1 (95% CI: 5.1, 17.1), respectively). Stratification by payer source revealed increases in using non-Medicaid (e.g., out-of-pocket) payment during lock-in that persisted following release. CONCLUSION: While the LIP reduced the number of CS dispensed, the program was also associated with increased acquisition of CS prescriptions using non-Medicaid payment. Moreover, beneficiaries acquired greater dosages of dispensed opioids from both Medicaid and non-Medicaid payment sources during lock in and post-release. Refining LIPs to increase beneficiary access to substance use disorder screening and treatment services and provider use of PDMPs may address important unintended consequences. PMID- 29150152 TI - 50 years of medical health geography(ies) of health and wellbeing. PMID- 29150153 TI - [Dermatologic surgery, hemophilia and Von Willebrand disease]. AB - BACKGROUND: Von Willebrand disease (VWD) and hemophilia A and B are the most common types of hereditary coagulation-factor deficiencies. The frequency and type of complications of skin surgery in these patients are unknown. The increasing incidence of skin cancer prompted us to reflect upon this issue. While the incidence of skin cancer is increasing, the complications of skin surgery or ablative laser treatment remain unknown in this population. AIM: The aim of this study was to determine the frequency of bleeding complications during and after skin surgery in patients with a hereditary coagulation-factor deficiency (hemophilia or VWD). PATIENTS AND METHODS: We conducted a retrospective study in patients with hemophilia A or B or VWD undergoing skin surgery or ablative laser treatment at the Dermatology Department of the Cochin Hospital in Paris, France. RESULTS: Fourteen procedures were performed in 8 patients. Three episodes of bleeding occurred (n=3/14, 21.4%): one hematoma, one delayed bleed and one immediate bleed. None of these complications required surgical revision or resuscitation. DISCUSSION: The rate of hemorrhagic complications was higher than in the general population. However, these complications can be considered non serious and the risk-benefit ratio remains favorable. Multidisciplinary management and coordination with the reference hemophilia center are mandatory in this population to establish a coagulation-factor (CF) substitution protocol suited to the disease characteristics and the surgical procedure. PMID- 29150154 TI - Cutaneous squamous cell carcinomas (SCC) associated with cosmetic skin whitening: 8 cases reported in Senegal. AB - BACKGROUND: The cosmetic use of bleaching products is common among women from sub Saharan Africa. The most frequently used products are highly potent corticosteroids (clobetasol propionate) and hydroquinone. Herein, we report 8 cases of SCC in women using skin bleaching products for cosmetic purposes. Our aim is to describe the epidemiological, clinical and pathological aspects of the carcinomas observed during the course of skin lightening. METHODS: We conducted a descriptive multicentre study from August 2005 to January 2016 in three dermatology units in Senegal. We included all patients consulting for cutaneous squamous cell carcinoma associated with skin bleaching. Sociodemographic, clinical, paraclinical and therapeutic data were recorded. RESULTS: A total of 8 female patients were included. The mean age was 48.1 years (37-63 years). Topical hydroquinone and highly potent corticosteroids were the main products used over the whole body, for an average duration of 20.3 years. No pre-neoplastic skin disease was found in our patients. The clinical aspects of tumours were as follows: cauliflower-like (n=4), ulcerated (n=3) and nodular (n=1). The average development time before consultation was 6.75 months. All the cutaneous squamous cell carcinomas were localized to lichenoid lesions or exogenous ochronotic lesions on photo-exposed areas: face (n=1), neck (n=3) or upper back (n=4). The most common histopathological type was the infiltrating form and there was one case of in situ carcinoma. The outcome was favourable in six of eight patients after surgical resection. Two deaths occurred: one through tumour recurrence and the other through haemorrhagic shock. CONCLUSIONS: From 2005 to 2016, eight cases of cutaneous squamous cell carcinomas associated with cosmetic use of bleaching products were reported in Senegal. The mechanism was not fully elucidated and further studies are necessary. These observations provide an additional argument for combating this practice and including skin bleaching among known risk factors for squamous cell carcinoma. PMID- 29150155 TI - The Association of Functional Capacity With Right Atrial Deformation in Patients With Pulmonary Arterial Hypertension: A Study With Two-Dimensional Speckle Tracking. AB - BACKGROUND: The purpose of this study was to assess right atrial (RA) myocardial mechanics in pulmonary hypertension (PH) patients using two-dimensional speckle tracking (2D-STE), and define the relationship between RA function and exercise capacity in PH patients. METHODS: Thirty-eight consecutive PH patients were studied and compared with a control group of 25 healthy volunteers. Peak atrial longitudinal strain (PALS), RA strain rate were measured in all subjects. PALS values were obtained by averaging all segments (global PALS), and by averaging segments measured in the four-chamber view. RESULTS: Right atrial PALS was significantly lower in PH patients than in controls, and gradually reduced with the development of cardiac insufficiency. A significantly positive correlation between global PALS and 6-minute walk distance (6MWD) was found (p=0.003). Furthermore, global PALS demonstrated the highest diagnostic accuracy (AUC of 0.979) and excellent sensitivity and specificity of 86.8% and 84%, respectively, to predict functional status using a cut-off value less than 38.08%. CONCLUSIONS: Right atrial deformation is significantly damaged in PH patients. Right atrial reservoir function can be estimated using 2D-STE, which gradually decreases in PH patients with different World Health Organization-functional class (WHO-FC). Right atrial PALS is a valuable factor for predicting the functional status and exercise capacity in PH patients. PMID- 29150156 TI - The Efficacy of Danshen Injection as Adjunctive Therapy in Treating Angina Pectoris: A Systematic Review and Meta-Analysis. AB - BACKGROUND: During the last 40 years, Danshen injection has been widely used as an adjunctive therapy for angina pectoris in China, but its efficacy is not yet well defined. The objective of this study was to verify the efficacy of Danshen injection as adjunctive therapy in treating angina pectoris. METHODS: The major databases including PubMed, Cochrane Library, Sino-Med, Medline, Embase, Google Scholar, China National Knowledge Infrastructure, Wanfang Databases, Chinese Scientific Journal Database, Chinese Biomedical Literature Database and the Chinese Science Citation Database were systematically searched for the published randomised controlled trials (RCTs) on Danshen injection until April 2016. Meta analysis was conducted on the primary outcomes (i.e., the improvements in symptoms and electrocardiography (ECG)). The quality of the included RCTs was evaluated with the M scoring system (the refined Jadad scale). Based on the quality, year of publication and sample size of RCTs, sensitivity analysis and subgroup analysis were performed in this study. RESULTS: Ten RCTs, including 944 anginal patients, were identified in this meta-analysis. Compared with using antianginal agents (beta-blockers, calcium antagonists, nitrates, etc.) alone, Danshen injection combined with antianginal agents had a better therapeutic effect in symptom improvement (odds ratio [OR], 3.66; 95% confidence interval [CI]: 2.50-5.36) and in ECG improvement (OR, 3.25; 95% CI: 1.74-6.08). CONCLUSIONS: This study showed that Danshen injection as adjunctive therapy seemed to be more effective than antianginal agents alone in treating angina pectoris. However, more evidence is needed to accurately evaluate the efficacy of Danshen injection because of the low methodological quality of the included RCTs. PMID- 29150157 TI - All-Cause Mortality Following an Acute Coronary Syndrome: 12-Year Follow-Up of the Comprehensive 2002 New Zealand Acute Coronary Syndrome Audit. AB - BACKGROUND: To describe the long-term mortality of a complete national cohort of acute coronary syndrome (ACS) patients enrolled in 2002, to compare this with a national age, sex and Maori ethnicity matched population, and to assess the influence of baseline factors on the 12-year mortality. METHODS: We reviewed 721 patients with a discharge diagnosis of an ACS who were enrolled in the first New Zealand ACS audit group cohort over 14days in May 2002. We matched the cohort to the national mortality database using each patient's unique national identity number. RESULTS: Over a median follow-up of 12.7 years of 721 patients discharged with an ACS, overall mortality was 52%: ST-elevation myocardial infarction (STEMI) (58%), non-ST-elevation myocardial infarction (NSTEMI) (61%) and unstable angina pectoris (UAP) (42%) patients, p<0.0001. In an age-adjusted survival model, males had a 29% increased mortality rate compared to females with a hazard ratio of 1.29 (95% CI 1.04, 1.61, p=0.019). Over 12 years there were 339 (47%) deaths, compared to 284 (39%) deaths observed in the matched population. The standardised mortality ratio for patients admitted with an ACS in New Zealand is 1.3 (95% CI 1.2, 1.5) with eight patients per 100 not surviving to 12 years compared to this matched population. CONCLUSIONS: The high mortality rate in this ACS cohort is a stark reminder of the prognostic implications of a presentation with an ACS. It emphasises the on-going need for optimal management of these patients throughout every stage of their initial treatment and subsequent on going care. PMID- 29150158 TI - Peripheral Arterial Disease. AB - Peripheral arterial disease (PAD) affects 15% of the Australian population and is a powerful and serious predictor of cardiovascular mortality yet continues to be under-recognised and undertreated. Diagnosis is simple and management is centred upon symptom relief and risk minimisation. While novel and specialised therapies play a role, the bulk of management is approachable and feasible. In this review, we cover the epidemiology, risk factors, associated conditions, classification, and natural history of PAD. We then discuss current diagnostic and therapeutic options as well as emerging therapies for this common condition. PMID- 29150159 TI - Diagnostic Performance of Pulmonary Capacitance at Rest and During Exercise in Idiopathic Pulmonary Arterial Hypertension. AB - BACKGROUND: Reliable markers of early disease are needed in pulmonary arterial hypertension (PAH). As measures of the contribution of abnormal vascular compliance to overall vascular resistance, resting and exercise pulmonary capacitance-defined as the stroke volume divided by the change in pulmonary pulse pressure-may be sensitive markers of early disease. METHODS: We examined all patients in our pulmonary hypertension database with idiopathic PAH, who had undergone rest and exercise right heart catheterisation in one sitting. Standard haemodynamic measurements were obtained, including pulmonary capacitance. These results were compared to age- and sex-matched normal controls. RESULTS: We analysed 27 right heart catheterisations in idiopathic PAH patients and 23 in controls. Mean pulmonary artery pressure (MPAP), mean pulmonary capillary wedge pressure (mPCWP), pulmonary vascular resistance (PVR) and right ventricular stroke work index (RVSWI) were significantly higher at baseline in diseased patients, while CI and pulmonary capacitance were significantly lower. MPAP, mPCWP, cardiac index and RVSWI increased significantly in both groups with exercise. Pulmonary capacitance decreased significantly in both groups. Pulmonary vascular resistance decreased with exercise in the control group only. Capacitance and PVR were inversely correlated at rest (time-constant of 0.79s) and with exercise (time-constant of 0.56s). The receiver operating characteristic (ROC) curve for capacitance as a diagnostic marker demonstrated an AUC of 0.96 at rest and 0.95 with exercise. CONCLUSIONS: In idiopathic pulmonary arterial hypertension (IPAH) there is a reduction in pulmonary capacitance at baseline and left-shift of the inverse capacitance-PVR relationship with exercise. Both resting and exercise pulmonary capacitance have potential as diagnostic markers in early disease. PMID- 29150160 TI - Medical physics in radiation Oncology: New challenges, needs and roles. PMID- 29150161 TI - Improved pharmacodynamic (PD) assessment of low dose PARP inhibitor PD activity for radiotherapy and chemotherapy combination trials. AB - BACKGROUND: PARP inhibitors are currently evaluated in combination with radiotherapy and/or chemotherapy. As sensitizers, PARP inhibitors are active at very low concentrations therefore requiring highly sensitive pharmacodynamic (PD) assays. Current clinical PD-assays partly fail to provide such sensitivities. The aim of our study was to enable sensitive PD evaluation of PARP inhibitors for clinical sensitizer development. MATERIAL AND METHODS: PBMCs of healthy individuals and of olaparib and radiotherapy treated lung cancer patients were collected for ELISA-based PD-assays. RESULTS: PAR-signal amplification by ex vivo irradiation enabled an extended quantification range for PARP inhibitory activities after ex vivo treatment with inhibitors. This "radiation-enhanced-PAR" (REP) assay provided accurate IC50 values thereby also revealing differences among healthy individuals. Implemented in clinical radiotherapy combination Phase I trials, the REP-assay showed sensitive detection of PARP inhibition in patients treated with olaparib and establishes strong PARP inhibitory activities at low daily doses. CONCLUSIONS: Combination trials of radiotherapy and novel targeted agent(s) often require different and more sensitive PD assessments than in the monotherapy setting. This study shows the benefit and relevance of sensitive and adapted PD-assays for such combination purposes and provides proof of clinically relevant cellular PARP inhibitory activities at low daily olaparib doses. PMID- 29150162 TI - Distribution of clinical risk factors for fracture in a Brussels cohort of postmenopausal women: The FRISBEE study and comparison with other major cohort studies. AB - OBJECTIVES: The estimation of fracture risk using clinical risk factors (CRFs) is of primary concern in osteoporosis management, but only some risk factors have been thoroughly evaluated and incorporated in predictive models. We have launched a large prospective study, the 'Fracture Risk Brussels Epidemiological Enquiry' (FRISBEE), to develop a new predictive model for osteoporotic fractures. The aims of this report are to describe the methodology of the FRISBEE study and to compare the distribution of CRFs in our cohort with those reported in other large studies. STUDY DESIGN: FRISBEE is a new study that prospectively evaluates a cohort of 3560 post-menopausal women (aged 60-85 years) followed yearly for the occurrence of fragility fractures. Multiple validated CRFs, densitometry (DXA) values and intake of medication were systematically registered at baseline. The distribution of the FRISBEE CRFs has been compared with the distributions of CRFs in the cohorts used to develop the FRAX(r) model as well as in more recent cohorts. For these recent cohorts, we focused on CRFs not included in FRAX(r). RESULTS: The most frequently encountered CRFs used in FRAX(r) were a prior fragility fracture (27.1%) and a parental history of hip fracture (13.4%). The prevalence of some CRFs not integrated in FRAX(r) was relatively high, such as the use of proton pump inhibitors (20.8%) and a history of fall(s) (19.7%). The prevalence of many CRFs was quite variable between cohorts; for example, the prevalence of 'personal prior fragility fracture' ranged from 9% to 51%. CONCLUSION: We found considerable heterogeneity in the prevalence of CRFs between cohort studies. The impact of these differences on the predictive value of a particular CRF is unknown. We will construct a predictive model calibrated to the Belgian population. More importantly, the FRISBEE study should allow us to determine the predictive value of newly recognized CRFs in addition to the FRAX(r) algorithm to reliably estimate fracture risk. PMID- 29150163 TI - The management of diagnosed heart failure in older people in primary care. AB - Heart failure (HF) is a common condition affecting predominantly older people. Symptoms include breathlessness and fatigue, and can significantly reduce quality of life. HF rarely occurs in isolation, with most patients having several co existing diseases requiring multiple medications. There is a large evidence base for treatment of HF with reduced ejection fraction, or HFrEF; however, many of the trials did not include older people with multimorbidity so their findings should be applied to this group with some caution. The evidence for treatment of HF with preserved ejection fraction, or HFpEF, is much less well established in all age groups. Older people with HF are usually managed in primary care with input from specialist HF teams when needed. General practitioners are trained to take a generalist approach, which allows them to deliver holistic, person-centred care. The wider multidisciplinary team is also important during the patient's HF journey, with a particular need to consider palliative care towards the end of life. This article summarises the important aspects of HF management in older people from the perspective of primary care. PMID- 29150164 TI - Testosterone replacement therapy and the risk of stroke in men: A systematic review. AB - In recent years, questions have been raised regarding the cardiovascular safety of testosterone replacement therapy (TRT). The objective of this study was to systematically review the available evidence on TRT safety in men, specifically with respect to the risk of stroke. We identified publications from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to May 2017. Articles eligible for review included observational studies evaluating TRT and the risk of stroke among men aged 18 or older. Randomized controlled trials (RCTs) comparing testosterone to placebo in men were also eligible, provided stroke was identified as an adverse event. Among seven cohort studies of hypogonadal men, one study reported that TRT was associated with a significant decrease in the risk of ischemic stroke (hazard ratio (HR) 0.64; 95% confidence interval (CI) 0.52-0.80). Another reported a similar decrease in risk (HR 0.64; 95% CI 0.43-0.96) among treated men who achieved normalized levels of testosterone. Limitations in study design, including immortal time bias and residual confounding, may have influenced both of these results. The remaining observational studies did not report measures of association to estimate the independent risk of stroke associated with TRT. Among eight RCTs, a low frequency of stroke events (<5) was observed across both testosterone and control groups, thus precluding any definitive conclusions. Based on these findings, the association between TRT and the risk of stroke in men remains unclear, and further large and methodologically robust studies are needed to establish this relationship. PMID- 29150165 TI - Effects of programmed exercise on depressive symptoms in midlife and older women: A meta-analysis of randomized controlled trials. AB - OBJECTIVE: To perform a systematic review and meta-analysis to clarify the effect of programmed exercise on depressive symptoms (DSs) in midlife and older women. METHODS: We carried out a structured search of PubMed-Medline, Web of Science, Scopus, Embase, Cochrane Library and Scielo, from database inception through June 29, 2017, without language restriction. The search included the following terms: "depression", "depressive symptoms", "exercise", "physical activity", "menopause", and "randomized controlled trial" (RCTs) in midlife and older women. The US, UK and Australian Clinical Trials databases were also searched. We assessed randomized controlled trials (RCTs) that compared the effect of exercise for at least 6 weeks versus no intervention on DSs as the outcome (as defined by trial authors). Exercise was classified according to duration as "mid-term exercise intervention" (MTEI; lasting for 12 weeks to 4 months), and "long-term exercise intervention" (LTEI; lasting for 6-12 months). Mean changes (+/-standard deviations) in DSs, as assessed with different questionnaires, were extracted to calculate Hedges' g and then used as the effect size for meta-analysis. Standardized mean differences (SMDs) of DSs after intervention were pooled using a random-effects model. RESULTS: Eleven publications were included for analysis related to 1943 midlife and older women (age range 44-55 years minimum to 65.5+/ 4.0 maximum), none of whom was using a hormone therapy. Seven MTEIs were associated with a significant reduction in DSs (SMD=-0.44; 95% CI -0.69, -0.18; p=0.0008) compared with controls. The reduction in DSs was also significant in six LTEIs (SMD=- 0.29; 95% CI -0.49; -0.09; p=0.005). Heterogeneity of effects among studies was moderate to high. Less perceived stress and insomnia (after exercise) were also found as secondary outcomes. CONCLUSION: Exercise of low to moderate intensity reduces depressive symptoms in midlife and older women. PMID- 29150166 TI - Exercise and mental health. AB - There is a growing body of literature that recognizes the positive effects of exercise on mood states such as anxiety, stress and depression, through physiological and biochemical mechanisms, including endorphins, mitochondria, mammalian target of rapamycin, neurotransmitters and the hypothalamic-pituitary adrenal axis, and via the thermogenic hypothesis. In addition, psychological mechanisms influence the effects of exercise on mood states, as suggested by both the distraction hypothesis and the self-efficacy hypothesis. Exercise has also been shown to reduce inflammation via several different processes (inflammation, cytokines, toll-like receptors, adipose tissue and via the vagal tone), which can contribute to better health outcomes in people suffering from mood disorders. PMID- 29150167 TI - Reproductive factors in relation to heart failure in women: A systematic review. AB - BACKGROUND: The biological mechanisms underlying the sex-related differences in risk of heart failure are still not well understood. The aim of this review was to provide an overview of the current evidence on the association between reproductive factors and risk of heart failure in women. METHODS: A systematic review of the literature was conducted. PubMed and Embase databases were searched for publications on the following reproductive factors as potential risk factors for heart failure in women: age at menarche, duration and frequency of the menstrual cycle, reproductive lifespan, use of contraception, polycystic ovarian syndrome (PCOS), pregnancy characteristics (e.g. parity), pregnancy complications (e.g. preeclampsia), induced abortion, history of breastfeeding, fertility status, use of assisted reproductive methods, hysterectomy, age at menopause, and use of hormone replacement therapy (HRT). RESULTS: Twenty-one studies were eligible for inclusion. Hypertensive pregnancy disorders, preterm delivery or small-for-gestational-age (SGA) infants, shorter reproductive duration, and early menopause were risk factors for heart failure in women. It was suggested that PCOS, fertility therapy, gestational diabetes, and age at first pregnancy were not related to risk of heart failure, but a potential relation cannot be fully excluded as most studies were not of sufficient quality. Conflicting results were found for the associations between risk of heart failure and hysterectomy, gravidity and parity, and HRT. CONCLUSION: Although some reproductive factors were considered risk factors for heart failure in women, the results were mostly conflicting or inconclusive. Further research is needed to confirm and expand the current evidence on the association between reproductive factors and risk of heart failure. PMID- 29150168 TI - Exploring the path between depression, anxiety and 10-year cardiovascular disease incidence, among apparently healthy Greek middle-aged adults: The ATTICA study. AB - OBJECTIVES: Although there is substantial evidence that psychological factors play an important role in the onset and course of cardiovascular disease (CVD), less is known about their combined effect and the pathways by which they affect cardiovascular health. The present work aimed to prospectively explore the effects of depression and anxiety on the 10-year CVD incidence, in relation to other lifestyle determinants, as linking factors in the context of the ATTICA study. Study design/Main outcome measures: The ATTICA study is a population based, health and nutrition prospective cohort study (2002-2012), during which 853 middle-aged participants without a history of CVD [453 men (aged 45+/ 13years) and 400 women (aged 44+/-18years)], underwent psychological evaluations at enrollment. The latent trait of depression and anxiety combined measure was estimated and referred as "Psychological distress"; path analysis was applied to describe the relationships among the different factors. RESULTS: "Psychological distress" was positively associated with the 10-year CVD incidence (adjusted OR per 10 units: 1.4, 95% CI: 1.1, 1.7). Three linking pathways were revealed: sedentariness, inflammation and metabolic syndrome. Moreover, "Psychological distress" mediated the association between socioeconomic status (SES) and CVD, with participants of low SES scoring higher on the psychological measure (adjusted linear regression coefficient b: -7.1, 95% CI: -9.7, -4.5). CONCLUSIONS: Lifestyle and clinical factors seem to link psychological distress with CVD development. Joint psychological assessments should be considered for inclusion in CVD preventive strategies, which should incorporate interventions for interrupting the linking pathways. PMID- 29150169 TI - Vitamin D and walking speed in older adults: Systematic review and meta-analysis. AB - Vitamin D is involved in musculoskeletal health. There is no consensus on a possible association between circulating 25-hydroxyvitamin D (25OHD) concentrations and walking speed, a 'vital sign' in older adults. Our objective was to systematically review and quantitatively assess the association of 25OHD concentration with walking speed. A Medline search was conducted on June 2017, with no limit of date, using the MeSH terms "Vitamin D" OR "Vitamin D Deficiency" combined with "Gait" OR "Gait disorders, Neurologic" OR "Walking speed" OR "Gait velocity". Fixed-effect meta-analyses were performed to compute: i) mean differences in usual and fast walking speeds and Timed Up and Go test (TUG) between participants with severe vitamin D deficiency (<=25nmol/L) (SVDD), vitamin D deficiency (<=50nmol/L) (VDD), vitamin D insufficiency (<=75nmol/L) (VDI) and normal vitamin D (>75nmol/L) (NVD); ii) risk of slow walking speed according to vitamin D status. Of the 243 retrieved studies, 22 observational studies (17 cross-sectional, 5 longitudinal) met the selection criteria. The number of participants ranged between 54 and 4100 (0-100% female). Usual walking speed was slower among participants with hypovitaminosis D, with a clinically relevant difference compared with NVD of -0.18m/s for SVDD, -0.08m/s for VDD and 0.12m/s for VDI. We found similar results regarding the fast walking speed (mean differences -0.04m/s for VDD and VDI compared with NVD) and TUG (mean difference 0.48s for SVDD compared with NVD). A slow usual walking speed was positively associated with SVDD (summary OR=2.17[95%CI:1.52-3.10]), VDD (OR=1.38[95%CI:1.01 1.89]) and VDI (OR=1.38[95%CI:1.04-1.83]), using NVD as the reference. In conclusion, this meta-analysis provides robust evidence that 25OHD concentrations are positively associated with walking speed among adults. PMID- 29150170 TI - Evaluating the content and development of decision aid tools for the management of menopause: A scoping review. AB - OBJECTIVE: Decision-making during menopause (especially surgical menopause) can be complex given the variability in risk-benefit perceptions of menopausal treatments. Decision aid tools (DATs) help women participate in decision-making about options. Our objective is to identify and evaluate the content and development of DATs for managing menopause, with a special focus on surgical menopause. METHODS: We systematically searched electronic databases, including MEDLINE and EMBASE, from inception to March 2017 for relevant records. The principal inclusion criterion was that papers reported studies on DATs for managing menopause. Search terms were derived from two concepts: menopause and DATs. Data extracted were presented in written evidence tables and narrative summaries. RESULTS: Our search yielded 18,801 records. Of these, 26 records met our inclusion criteria, which gave rise to 12 DATs from peer-reviewed literature and 6 from grey literature. Seventeen DATs were focused on natural menopause and two targeted surgical menopause, both identified from grey literature. More than half were published before the Women's Health Initiative (WHI) publication and 70% before the release of the International Patient Decision Aid Standards (IPDAS). Very few studies reported the full development of the DAT involved, and less than half of DATs were informed by a needs assessment to identify the decisional needs of their target population. Most DATs focused on hormone therapy as a treatment option and did not provide a comprehensive overview of other options. None of the DATs reported the steps involved in finding, appraising and summarizing scientific content of the tool. CONCLUSION: This review highlights several limitations in the content and development of DATs for managing menopause. No peer-reviewed DATs were identified for surgical menopause. A need for a complete, evidence-based DAT in the context of surgical menopause is identified. PMID- 29150171 TI - Similar pro-NT and pro-RLX2 levels after preeclampsia and after uncomplicated pregnancy. AB - OBJECTIVE: Women are at increased risk of developing cardiovascular disease (CVD) after preeclampsia. Proneurotensin 1-117 (pro-NT) and prorelaxin 2 connecting peptide (pro-RLX2) have recently emerged as potential biomarkers for CVD risk in women. We assessed pro-NT and pro-RLX2 levels in women with and without a history of preeclampsia. STUDY DESIGN: 339 women with a history of early-onset preeclampsia and 327 women with an uncomplicated pregnancy underwent cardiovascular screening 10 years after delivery (the Preeclampsia Risk EValuation in FEMales (PREVFEM) cohort). MAIN OUTCOME MEASURES: Pro-NT, a stable fragment of the neurotensin precursor, was assessed in the whole cohort. Pro RLX2, the stable connecting peptide of the relaxin 2 prohormone, was assessed in a subset of this cohort, consisting of 27 women with a history of preeclampsia and 23 healthy controls. Associations between biomarker levels and traditional CVD risk factors in the preeclampsia and control group were assessed by Pearson's correlation coefficient. RESULTS: We found no differences in pro-NT and pro-RLX2 levels between the preeclampsia and control group. Pro-NT levels were associated with higher HbA1c levels (r=0.113, p-value 0.045) and with BMI (r=0.124, p-value 0.027), but only in the control group. Pro-RLX2 was related to current smoking and triglyceride levels in women with a history of preeclampsia and related to LDL-cholesterol in women with an uncomplicated pregnancy. CONCLUSIONS: Pro-NT and pro-RLX2 levels were comparable in women 10 years after preeclampsia and women with an uncomplicated pregnancy. The role of pro-NT and pro-RLX2 in CVD development after preeclampsia should be further investigated. PMID- 29150172 TI - Handgrip strength and its association with functional independence, depressive symptoms and quality of life in older adults. AB - We assessed the associations between handgrip strength and functional independence, quality of life and depressive symptoms in 947 participants aged 65 years or over. Handgrip strength was measured with a dynamometer. Use of formal support and family/friend support was self-reported. Activities of daily living (ADL), quality of life and depressive symptoms were assessed using validated scales. Mean handgrip strength was 27.1kg (+/-10.3). Each 10kg increase in handgrip strength was associated with 39% reduced odds of impaired instrumental ADL. Handgrip strength was inversely associated with use of both formal and family/friend support. Handgrip strength was independently associated with functional independence. PMID- 29150173 TI - Genetic studies to re-affiliate Edwardsiella tarda fish isolates to Edwardsiella piscicida and Edwardsiella anguillarum species. AB - Until 2012, the genus Edwardsiella was composed by three species Edwardsiella tarda, Edwardsiella hoshinae and Edwardsiella ictaluri. In 2013, Edwardsiella piscicida, compiling fish pathogenic strains previously identified as E. tarda was described, and more recently a new species isolated from diseased eel was reported, namely Edwardsiella anguillarum. The incorporation of these species into the genus makes necessary a revision of the taxonomic position of the isolates previously identified as E. tarda. Using AFLP technique, MLSA studies and in silico DNA-DNA hybridization, 46 of 49 E. tarda isolates were re-assigned as E. piscicida and 2 as E. anguillarum, whereas it was confirmed previous classification of the Edwardsiella types and reference strains used. The study of the taxonomic resolution of the genes 16S rRNA, adk, atpD, dnaJ, glnA, hsp60, tuf as well as the possible combinations among housekeeping genes, showed that the gene dnaJ was the more resolutive. In conclusion, the use of molecular techniques is necessary to accurately identify Edwardsiella isolates, especially when differentiating new species from E. tarda. PMID- 29150174 TI - A new species of Discocyrtanus from Mato Grosso, Brazil (Opiliones: Gonyleptidae) with a key to the species of the genus. AB - Discocyrtanus canjinjim sp. n., belonging to the family Gonyleptidae Sundevall, 1833 is described based on nineteen specimens, eleven adult males and eight adult females, collected in the Vila Bela da Santissima Trindade, in the State of Mato Grosso, Brazil. This new species represents an endemic component for the harvestmen fauna of Chiquitano Dry Forests terrestrial eco-region, being the most occidental point of distribution of the genus, notably found in the Cerrado and the Atlantic Forest. The new species is characterized by femur IV swollen with the same length of dorsal scutum, trochanter IV with prodorsal distal apophysis as a stout hook not bifurcated, and a unique form of genitalia in the genus. This paper also includes the first identification key to the species of the genus after its revalidation. PMID- 29150175 TI - [Erratum to "Synthesis and binding affinity to human steroid hormone receptors of 3-phenoxy-4-hydroxycoumarins and 3-phenoxy-4-phenylcoumarins" [Ann. Pharm. Fr. 2017;75:455-462]]. PMID- 29150176 TI - Studies on in-vitro hypoglycemic effects of root bark of Caesalpinia bonducella. AB - OBJECTIVE: The present investigation was undertaken to assess the hypoglycemic potential of ethanolic (ECB) and aqueous extracts (ACB) of root bark of Caesalpinia bonducella using various in vitro techniques. METHOD: The ethanolic and aqueous extracts of root bark of C. bonducella were studied for their effects on glucose adsorption capacity, in vitro glucose diffusion, in-vitro amylolysis kinetics and glucose transport across membrane of yeast cells. RESULT: It was observed that the extracts under study adsorbed glucose and the adsorption of glucose increased remarkably with an increase in glucose concentration. The results of amylolysis kinetic experimental model revealed that the rate of glucose diffusion was found to be increased with time from 30 to 180min and both the extracts demonstrated significant inhibitory effects on movement of glucose into external solution across dialysis membrane as compared to control. Also, the extracts under study promoted glucose uptake by the yeast cells. It was observed that the enhancement of glucose uptake was dependent on both the sample and glucose concentration. Ethanolic extract of C. bonducella extract exhibited significantly higher (P<=0.05) activity than the aqueous extract at all concentrations. CONCLUSION: The results of the study verified the hypoglycemic activity of the extracts of root bark of C. bonducella. However, the observed effects need to be confirmed by using different in vivo models and clinical trials for its effective utilization as a therapeutic agent in effective management of diabetes mellitus. PMID- 29150177 TI - The sociocultural context of emotion socialization in African American families. AB - The current paper systematically reviews empirical research on parental emotion socialization in African American families, addressing gaps in a literature that has historically focused on White middle class samples. Of the 1210 studies screened, 329 were inspected, 280 were excluded, and 49 were included. Studies addressed emotion-related beliefs and attitudes, emotion expressiveness, discussion of emotion, and responses to children's emotion. Mixed findings are interpreted in light of sociocultural factors. An emerging body of research suggests that the celebration and restriction of children's emotions coexist closely in African American families, perhaps reflecting the joint influence of traditional Afro-cultural values and the historical context of slavery and discrimination. Methodological issues are identified and future directions for research and practice are discussed. PMID- 29150178 TI - [Relationships between COPD and nontuberculous mycobacteria pulmonary infections]. AB - Nontuberculous mycobacteria (NTM) pulmonary infections are increasingly frequent in pneumological practice. The diagnosis is based on an association of clinical, microbiological and radiological criteria. Some risk factors for NTM disease have been described, including chronic respiratory diseases, but without specific focus on chronic obstructive pulmonary disease (COPD). COPD patients have more risk to be infected by NTM than patients with the main other chronic respiratory diseases (except cystic fibrosis) (odds ratio [OR] at 15.7 in a case-control study). This NTM pulmonary infection is associated with a greater decline in forced expiratory volume in one second (FEV1) and an increased exacerbation rate. Inhaled corticosteroids (ICS) increase the risk of COPD patients developing an NTM infection (OR at 16.9), especially if ICS are still used at the time of diagnosis. Chronic macrolide treatment could possibly select resistant NTM strains and so could make the treatment clearly more difficult as macrolides are the cornerstone NTM treatment. NTM infections in patients with COPD are probably underestimated and should be kept in mind, particularly when patients have frequent exacerbations and display accelerated respiratory function decline, before implementing ICS or macrolides. PMID- 29150179 TI - [Therapeutic strategies in patients undergoing surgery for non-small cell lung cancer. Results of the ESCAP-2011-CPHG study, promoted by the French College of General Hospital Respiratory Physicians (CPHG)]. AB - BACKGROUND: The aim of ESCAP-2011-CPHG, promoted by the French College of General Hospital Respiratory Physicians, was to describe therapeutic strategies in lung cancer in the first 2 years after diagnosis, in a real-life setting. This article focuses on patients undergoing surgical management of a non-small cell lung cancer (NSCLC). METHODS: A prospective multicentre study was conducted in 53 French general hospitals. For each patient with lung cancer diagnosed in 2010, a standardised form was completed following each change in treatment strategy up to 2 years after diagnosis. RESULTS: Overall, 3418 of the 3943 included patients had NSCLC. 741 patients (21.7%) underwent curative surgery (stage 0-II, IIIA, IIIB, and IV: 65%, 27%, 3% and 5%, respectively). The therapeutic strategy changed less often in surgical than non-surgical patients and average follow-up time was longer: 23.3 months (SD: 9.3) versus 10.4 months (SD: 9.5) for non-surgical patients. Among patients with a surgical first strategy (92.6% of surgical patients as a whole), 56.9% did not receive any other treatment, 34.7% received chemotherapy, 5.9% radio-chemotherapy, 2.6% radiotherapy. At the end of follow up, 55.8% were still alive without any other strategy, 13.1% had died, and 31.1% had received at least one more strategy. Among patients with a surgical second strategy, 63% had received chemotherapy alone during the first strategy. CONCLUSIONS: ESCAP -2011- CPHG assessed everyday professional practice in the surgical management of NSCLC in general hospitals. It pointed out the discrepancies between current guidelines and the therapeutic strategies applied in real life conditions. PMID- 29150180 TI - Family-centered bereavement practices in Danish intensive care units: a cross sectional national survey. AB - BACKGROUND: Mortality in Danish intensive care units (ICUs) continues at 27%, resulting in a large number of bereaved family members being cared for in the ICU. OBJECTIVES: To investigate the provision of bereavement care and follow-up services for bereaved families in Danish ICUs. METHODOLOGY: Self-administered computerized cross-sectional nation-wide survey of Danish ICUs. RESULTS: Nurses at 46 of 48 (96%) ICUs in Denmark responded. Bereavement care at the time of patient death included viewing the patient in ICU (100%), and in the hospital mortuary (59%). Information about hospital-based follow-up for the family was provided in 72% of units, whereas only one unit provided information on community based bereavement follow-up. Bereavement follow-up services after hospitalization were offered to families in 59% of ICUs and included an ICU visit, meeting with the staff present at the time of death, a letter of condolence, a phone call to the family, referral to a priest or clergyman, or referral to other counseling. Although many interventions were common, there were variations within the elements offered. Nurses and physicians were the most consistent health care staff involved in bereavement services. CONCLUSION: Most ICUs in Denmark offered bereavement follow-up services, but these varied in their approach, were not evidence-based, and lacked formal evaluation. More systematic quality improvement of bereavement practices is required. PMID- 29150181 TI - Corrigendum to 'Chloroquine enhances the antimycobacterial activity of isoniazid and pyrazinamide by reversing inflammation-induced macrophage efflux' [The International Journal of Antimicrobial Agents 50/1 (2017) 55-62]. PMID- 29150182 TI - Mature Hippocampal Neurons Require LIS1 for Synaptic Integrity: Implications for Cognition. AB - BACKGROUND: Platelet-activating factor acetylhydrolase 1B1 (LIS1), a critical mediator of neuronal migration in developing brain, is expressed throughout life. However, relatively little is known about LIS1 function in the mature brain. We previously demonstrated that LIS1 involvement in the formation and turnover of synaptic protrusions and synapses of young brain after neuronal migration is complete. Here we examine the requirement for LIS1 to maintain hippocampal circuit function in adulthood. METHODS: Effects of conditional Lis1 inactivation in excitatory pyramidal neurons, starting in juvenile mouse brain, were probed using high-resolution approaches combining mouse genetics, designer receptor exclusively activated by designer drug technology to specifically manipulate CA1 pyramidal neuron excitatory activity, electrophysiology, hippocampus-selective behavioral testing, and magnetic resonance imaging tractography to examine the connectivity of LIS1-deficient neurons. RESULTS: We found progressive excitatory and inhibitory postsynaptic dysfunction as soon as 10 days after conditional inactivation of Lis1 targeting CA1 pyramidal neurons. Surprisingly, by postnatal day 60 it also caused CA1 histological disorganization, with a selective decline in parvalbumin-expressing interneurons and further reduction in inhibitory neurotransmission. Accompanying these changes were behavioral and cognitive deficits that could be rescued by either designer receptor exclusively activated by designer drug-directed specific increases in CA1 excitatory transmission or pharmacological enhancement of gamma-aminobutyric acid transmission. Lagging behind electrophysiological changes was a progressive, selective decline in neural connectivity, affecting hippocampal efferent pathways documented by magnetic resonance imaging tractography. CONCLUSIONS: LIS1 supports synaptic function and plasticity of mature CA1 neurons. Postjuvenile loss of LIS1 disrupts the structure and cellular composition of the hippocampus, its connectivity with other brain regions, and cognition dependent on hippocampal circuits. PMID- 29150183 TI - Genetic analysis of 29 Y-STR loci in the Chinese Han population from Shanghai. AB - The analysis of Y chromosomal short tandem repeats (Y-STRs) provides important information that can be used to forensic investigation and population studies. In this study, typing of 29 Y-STRs included in the PowerPlex(r) Y23 system (PPY23) and YfilerTM Plus system (Yfiler plus) was performed on 843 unrelated male samples from Han population in Shanghai. Besides null, duplicate, and intermediate alleles reported in previous studies, an allele of 10 at DYS643 with a 2-base deletion in the flanking region was initially observed. The gene diversity (GD) values of the 29 Y-STRs range from 0.4186 at DYS438 to 0.9653 at DYS385a/b. The haplotype diversity of two commonly used haplotype sets, PPY23 set and Yfiler plus set is 0.999980 and 0.999997, respectively. Pairwise genetic distances between Han population in Shanghai and other Han populations estimated using Yfiler plus set are slightly larger than that between other Han populations. Visualization of pairwise genetic distances between 17 worldwide populations using multidimensional scaling (MDS) demonstrates the distribution of populations according to their ethno-geographic patterns. Compared with Yfiler set, Yfiler plus set appears to have a relatively high population discrimination capacity for these tested populations. Altogether, these results can provide useful information of Y-STRs for forensic investigation and population studies. PMID- 29150184 TI - [Glutamate dehydrogenase. Its diagnostic value in Clostridioides difficile diarrhea]. AB - Clostridioides difficile is the main etiological agent of diarrhea associated with health care, it produces toxins and glutamate dehydrogenase (GDH), an enzyme that is highly conserved in this species. Rapid diagnosis and effective treatment produce prompt improvement of the patient and subsequent control of the microorganism spread. There are several techniques whose results are interpreted in the context of algorithms. However, the optimal diagnostic method is yet unknown. The performance of GDH as a screening test for the diagnosis of C. difficile diarrhea was assessed. Six hundred and fifteen stool samples were studied. The presence of GDH and toxins presence was determined by TECHLAB(r) C. DIFF QUIK-CHEK COMPLETE and the samples were cultured for the search of C. difficile. The values of sensitivity, specificity, PPV and NPV were calculated with a p value of 0.05 or less. GDH was detected in 266 samples (43.25%), with a sensitivity of 100% and specificity of 87.10%, IC95: 84.58-91.42; toxin/s were detected in 218 (35.45%) and C. difficile developed in 235 cultures (38.21%). From 48 samples with positive GDH and negative toxin/s, 15 toxigenic and 2 non toxigenic isolates were obtained, the remaining 31 samples were negative for C. difficile. All GDH-negative samples were negative for toxins or culture, therefore, GDH NPV was 100%, while PPV was 81.9%. We conclude that GDH is a suitable screening test for the diagnostic algorithm of C. difficile diarrhea. PMID- 29150185 TI - Editorial commentary: Heart failure in systemic lupus erythematosus: A problem to address. PMID- 29150186 TI - Articular scaling and body mass estimation in platyrrhines and catarrhines: Modern variation and application to fossil anthropoids. AB - Body mass is an important component of any paleobiological reconstruction. Reliable skeletal dimensions for making estimates are desirable but extant primate reference samples with known body masses are rare. We estimated body mass in a sample of extinct platyrrhines and Fayum anthropoids based on four measurements of the articular surfaces of the humerus and femur. Estimates were based on a large extant reference sample of wild-collected individuals with associated body masses, including previously published and new data from extant platyrrhines, cercopithecoids, and hominoids. In general, scaling of joint dimensions is positively allometric relative to expectations of geometric isometry, but negatively allometric relative to expectations of maintaining equivalent joint surface areas. Body mass prediction equations based on articular breadths are reasonably precise, with %SEEs of 17-25%. The breadth of the distal femoral articulation yields the most reliable estimates of body mass because it scales similarly in all major anthropoid taxa. Other joints scale differently in different taxa; therefore, locomotor style and phylogenetic affinity must be considered when calculating body mass estimates from the proximal femur, proximal humerus, and distal humerus. The body mass prediction equations were applied to 36 Old World and New World fossil anthropoid specimens representing 11 taxa, plus two Haitian specimens of uncertain taxonomic affinity. Among the extinct platyrrhines studied, only Cebupithecia is similar to large, extant platyrrhines in having large humeral (especially distal) joints. Our body mass estimates differ from each other and from published estimates based on teeth in ways that reflect known differences in relative sizes of the joints and teeth. We prefer body mass estimators that are biomechanically linked to weight-bearing, and especially those that are relatively insensitive to differences in locomotor style and phylogenetic history. Whenever possible, extant reference samples should be chosen to match target fossils in joint proportionality. PMID- 29150187 TI - 137Cs in mushrooms from Croatia sampled 15-30 years after Chernobyl. AB - The aim of this study was to select species with higher potential to accumulate 137Cs among the available mushroom species, by determining the activity concentrations of 137Cs in mushrooms collected along north and north-western part of Croatia. A total of 55 samples of 14 different species were analyzed and the potential of mycorrhizal and saprotrophic species to accumulate 137Cs was compared. A wide range of the dry weight activity concentrations of 137Cs was detected, ranging from 0.95 to 1210 Bq/kg (154 Bq/kg mean value; 52.3 Bq/kg geometric mean) in mycorrhizal and 1.05-36.8 Bq/kg (8.90 Bq/kg mean value; 5.49 Bq/kg geometric mean) in saprotrophic species. Statistical analyses showed that mycorrhizal species accumulate significantly higher concentrations of 137Cs and thus could perform better as long-term bioindicators of environmental pollution by radiocaesium then saprotrophic species. The comparison of Boletus sp. and Hydnum repandum (both mycorrhizal species commonly found in Croatia) showed, in general order of magnitude, higher accumulation in Hydnum repandum. Clearly, mushrooms, especially mycorrhizal species, can be used as significant indicators even decades after the occurrence of any serious 137Cs contamination event. However, as a wide range of values indicates that various parameters may influence the total uptake of the 137Cs into the mushroom fruit bodies, it is necessary to emphasize that 137Cs activity detected in a single mushroom sample is very site-specific. PMID- 29150188 TI - Nitrogen species coupled with transpiration enhance Fe plaque assisted aquatic uranium removal via rhizofiltration of Phragmites australis Trin ex Steud. AB - The influences of N species and transpiration on the Fe plaque (IP) formation and related aquatic U rhizofiltration had not revealed yet, especially when these factors were co-existed. It was evaluated in a mesocosm experiment in the condition of respective ammonium (NH4+)/nitrate (NO3-) cultivation of Phragmites australis Trin ex Steud. coupled with different transpiration rates (TRs). The results suggested that the enhanced transpiration of P. australis improved the aquatic U rhizofiltration in both NO3- and NH4+ rich milieus. However, the NO3- dependent oxidizing milieu restricted aquatic U uptake by the root of P. australis (up to 47.6 +/- 1.8 mg kg-1 under high TR) via IP assisted rhizofiltration. The high aquatic U availability and limited IP formation in NO3- rich milieu benefited the U retention within root tissue. On the contrary, the aquatic U rhizofiltration (up to 62.1 +/- 1.0 mg kg-1 under high TR) was enhanced under NH4+ dependent reductive milieu. It was mainly contributed by U retention within IP. The area related U accumulation in different N species cultured roots was enhanced but did not significantly different under higher TR condition. The result suggested that the supplied NH4+ coupled with enhanced transpiration was supposed to be more optimized option for IP assisted aquatic U rhizofiltration via P. australis. PMID- 29150189 TI - Uranium mobility across annual growth rings in three deciduous tree species. AB - Black walnut (Juglans nigra), slippery elm (Ulmus rubra), and white ash (Fraxinus americana) trees were evaluated as potential archives of past uranium (U) contamination. Like other metals, U mobility in annual growth rings of trees is dependent on the tree species. Uranium concentrations and isotopic compositions (masses 234, 235, 236, and 238) were analyzed by thermal ionization mass spectrometry to test the efficacy of using tree rings to retroactively monitor U pollution from the FFMPC, a U purification facility operating from 1951 to 1989. This study found non-natural U (depleted U and detectable 236U) in growth rings of all three tree species that pre-dated the start of operations at FFMPC and compositional trends that did not correspond with known contamination events. Therefore, the annual growth rings of these tree species cannot be used to reliably monitor the chronology of U contamination. PMID- 29150190 TI - Metabolic adaptation of intracellular bacteria and fungi to macrophages. AB - The mature phagosome of macrophages is a hostile environment for the vast majority of phagocytosed microbes. In addition to active destruction of the engulfed microbes by antimicrobial compounds, restriction of essential nutrients in the phagosomal compartment contributes to microbial growth inhibition and killing. However, some pathogenic microorganisms have not only developed various strategies to efficiently withstand or counteract antimicrobial activities, but also to acquire nutrients within macrophages for intracellular replication. Successful intracellular pathogens are able to utilize host-derived amino acids, carbohydrates and lipids as well as trace metals and vitamins during intracellular growth. This requires sophisticated strategies such as phagosome modification or escape, efficient nutrient transporters and metabolic adaptation. In this review, we discuss the metabolic adaptation of facultative intracellular bacteria and fungi to the intracellular lifestyle inside macrophages. PMID- 29150191 TI - [Big data, generalities and integration in radiotherapy]. AB - The many advances in data collection computing systems (data collection, database, storage), diagnostic and therapeutic possibilities are responsible for an increase and a diversification of available data. Big data offers the capacities, in the field of health, to accelerate the discoveries and to optimize the management of patients by combining a large volume of data and the creation of therapeutic models. In radiotherapy, the development of big data is attractive because data are very numerous et heterogeneous (demographics, radiomics, genomics, radiogenomics, etc.). The expectation would be to predict the effectiveness and tolerance of radiation therapy. With these new concepts, still at the preliminary stage, it is possible to create a personalized medicine which is always more secure and reliable. PMID- 29150192 TI - Thirty-Day Reoperation and/or Admission After Elective Hand Surgery in Adults: A 10-Year Review. AB - PURPOSE: Whereas acute complications following elective hand surgery have been assumed to be rare, the incidence of 30-day unplanned reoperation and/or admission for the most common elective procedures has not been well described. Our goal was to calculate the incidence and identify the risk factors associated with these complications in a busy academic practice. METHODS: Our institution's quality assurance database was examined retrospectively for unplanned reoperations and/or admissions within 30 days in adults undergoing elective procedures with 2 senior attending surgeons from February 2006 to January 2016. Each event was categorized by causative factor and charts were reviewed to establish risk factors and cultured organisms. Our billing database was examined for the concomitant procedural volume. RESULTS: In our cohort of 18,081 surgeries (57.6% carpal tunnel or trigger digit releases), 27 patients had an unplanned reoperation and/or admission within 30 days (0.15% total incidence; including carpal tunnel release, 0.10%; trigger digit release, 0.09%; major wrist surgery, 0.74%) including 17 infections (0.09%). These were unevenly distributed over time after surgery with 29.6% occurring within 7 days, 59.2% in 8 to 14 days, 11.1% in 15 to 21 days, and none between 22 and 30 days. CONCLUSIONS: Reoperations and/or unplanned admission within 30 days after elective hand surgery are infrequent (15 per 10,000 cases) and are most commonly related to infections (63.0%). More invasive surgeries are associated with a higher incidence than simpler procedures, and these complications are most likely to occur within 3 weeks after surgery. These data in elective patients do not cover certain clinically relevant outcomes, such as chronic pain or limited function, and may not be generalizable to all practices. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29150193 TI - Descriptive epidemiology of traumatic spinal injury in Japan. AB - BACKGROUND: Spine injury epidemiology in Japan has not been studied since the 1990s when its incidence was 39.4-40.2 per million and the major cause of injury was motor vehicle crashes. We elucidate the current epidemiological state of spinal injury and spinal injury patients in Japan for the clinicians and public health prevention programs. METHODS: Spine injury patients were retrospectively selected from the Japan Trauma Data Bank (JTDB) from 2004 to 2013 for all ages and all spinal injuries. The Abbreviated Injury Scale codes (AIS98) were translated into injuries. The dataset was contributed by 241 hospitals nationwide. The data was analysed for the causes of spinal injury, injury severity, age, gender differences, injury types, survival, anatomic location, circumstances of injury and medical history. RESULTS: A total of 25,792 (M, 70.1%, F, 29.9%, mean age: 53.4 years) spinal injury patients were recorded in the JTDB from 2004 to 2013, when multiple injuries were included the number of cases swelled to 33,892 (M, 70.4%, F, 29.6%). The number of patients with spinal injuries as a percentage of all traumatic patients in the JTDB was observed to increase from 2004 (15.4%) to 2013 (17.6%). The aetiology of the injuries was mostly falls (52.4%) and motor vehicle crashes (39.8%). Most injuries occurred at the cervical spine level (49.7%). Medical histories of cardiovascular diseases were found, due mostly to hypertension (19.6%). In total, most of the injuries were associated with fractures (64.8%) and others (30.7%) involved the spinal cord. Suicides (12.0%) and industrial accidents (9.0%) caused spine injury were uniquely prevalent in the population. CONCLUSION: The number of spine injuries has increased in the JTDB between 2004 and 2013. Motor vehicle crashes have been replaced by falls due to various causes as the leading cause of spine injury. Suicides and industrial accidents are becoming a burden. More studies are needed to verify the actual incidence. PMID- 29150194 TI - Booster influenza vaccination confers additional immune responses in an elderly, rural community-dwelling population. AB - This study aimed to examine the effects of a booster vaccination in elderly people using 2 doses of trivalent inactivated influenza vaccine during the 2012 2013 influenza epidemic. Seroprotection rates against the A(H1N1)pdm09 strain in younger elderly people (aged 61-75 years) and the A(H3N2) and B strains in both younger elderly people (aged 61-75 years) as well as very elderly people (aged 76 102 years) did not decrease at 22 weeks after vaccination. This approach confers long-lasting antibody responses and may be useful in clinical practice. PMID- 29150195 TI - Anatomic findings associated with epispadias in boys: Implications for surgical management and urinary continence. AB - INTRODUCTION: Pre-operative physical examination of male epispadias allows for classification of epispadias level as glanular (GE), penile (PE) or penopubic (PPE), and for delineation of anatomic anomalies. The incidence of associated extragenital abnormalities, such as vesicoureteral reflux (VUR), bladder neck (BN) abnormality and abnormal pubic diastasis (PD), and their impact on urinary continence has not yet been systematically studied. OBJECTIVE: The goal of this study was to evaluate whether the more proximal level of epispadias correlated with associated extragenital anatomic anomalies seen on initial imaging or endoscopic evaluation, and whether these pre-operative findings contributed to subsequent surgical management and impacted on achieving urinary continence. It was hypothesized that the more severe forms of epispadias may be associated with a higher frequency of associated anomalies. STUDY DESIGN: The study was an IRB approved, retrospective case study of all male patients treated initially for isolated epispadias at the current institution between 1994 and 2011. Data collection was achieved by chart and radiology review evaluating PD, BN appearance, presence of VUR, surgical treatment, and urinary continence. RESULTS: A total of 26 patients were identified and divided into three groups based on appearance at physical examination: four glanular (GE), eight penile (PE), and 14 penopubic (PPE); 17 patients had an abnormal BN. Reflux was noted in nine of 20 patients who had a voiding cystourethrogram (VCUG), two of which had an episode of pyelonephritis. Of the 22 patients past the age of toilet training, 17 were continent (64% (9/14) penopubic, 63% (5/8) penile, and 75% (3/4) glanular). DISCUSSION: Anatomic classification for male epispadias did not provide sufficient information regarding extragenital findings. This study provided new information regarding PD, BN appearance, presence of reflux, and ultimate urinary continence. Pubic diastasis and BN abnormalities were more frequently seen in more severe forms of epispadias, whereas VUR seemed more prevalent in less severe forms. A template for pre-operative evaluation was outlined. Limitations of the study were its retrospective design and relatively small cohort of patients, which reflected the rarity of the condition. CONCLUSION: Based on the information generated, additional anatomic information was generated regarding boys with epispadias. This information will help guide the evaluation and the management of these patients in the future. PMID- 29150196 TI - Single-stage urethroplasty with buccal mucosal inlay graft for stricture caused by balanitis xerotica obliterans in boys: Outcomes in the medium term. AB - INTRODUCTION: Balanitis xerotica obliterans (BXO) is a common condition that can affect the foreskin, glans, meatus, and urethra, and rarely can also involve urethra leading to stricture. Numerous procedures have been suggested to treat urethral stricture secondary to BXO but these have had variable results. OBJECTIVE: We describe the first prospective study of a single stage buccal mucosal inlay grafting in children with urethral strictures resistant to existing remedies. MATERIALS AND METHODS: We treated five boys with resistant urethral strictures secondary to BXO with a single stage buccal mucosal inlay graft (BMIG, Figure). Uroflowmetry was performed both pre- and post-operatively. Functional outcome was the prime measure determining success. RESULT: All the boys had a successful functional outcome and all expressed satisfaction with cosmetic outcome as well. Uroflow parameters improved remarkably, with maximum and mean urinary flow rates significantly improved from 4.2 mL/s to 26 mL/s (p = 0.0002) and from 1.6 mL/s to 12.2 mL/s (p = 0.003), respectively. Median follow-up was 34 months (range 30-42 months). DISCUSSION: This paper is the first to describe the successful use of buccal mucosal inlay grafts to treat refractory BXO stricture in children. Various surgical techniques have been proposed particularly in adults including single vs. staged procedures, preputial and post auricular grafts, circular mucosal buccal grafts, as well as double mucosal grafts placed both ventrally and dorsally. All of these procedures are not without problems, and had variable results and outcome. Most of the procedures have been described in adult urethra and are not suitable for paediatric small calibre urethra. Our technique of dorsal inlay graft gives a robust structure to the distal urethra avoiding diverticula, pooling or urine spraying and can be placed onto proximal urethra as well. We have not seen recurrence of BXO in our buccal grafts, which is reported in other grafts from prepuce and post auricular grafts. The number of patients presented in our study is limited, nonetheless an excellent result in all our cases makes this a compelling approach to manage BXO urethral strictures. An early intervention in such cases is paramount to convert a salvage operation to a pre-emptive procedure. CONCLUSION: A single stage buccal mucosal inlay grafting in children with BXO stricture can offer an excellent outcome. PMID- 29150197 TI - Preface: Ultrafast magic-angle spinning NMR. PMID- 29150199 TI - Medications for opioid use disorder: bridging the gap in care. PMID- 29150198 TI - Comparative effectiveness of extended-release naltrexone versus buprenorphine naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. AB - BACKGROUND: Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX. METHODS: We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433. FINDINGS: Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0.0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1.36, 95% CI 1.10 1.68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0.44). Opioid-negative urine samples (p<0.0001) and opioid abstinent days (p<0.0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0.0012), then converged by week 24 (p=0.20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group). INTERPRETATION: In this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications. FUNDING: NIDA Clinical Trials Network. PMID- 29150200 TI - Extended-release naltrexone: good but not a panacea. PMID- 29150202 TI - The health system in India: the underserved majority. PMID- 29150203 TI - India-a tale of one country, but stories of many states. PMID- 29150204 TI - Lalit Dandona: surveying the burden of disease in India. PMID- 29150205 TI - Department of Error. PMID- 29150206 TI - Sustained response to rituximab in a TNFi-induced ANCA-vasculitis developed in a patient with rheumatoid arthritis. PMID- 29150201 TI - Nations within a nation: variations in epidemiological transition across the states of India, 1990-2016 in the Global Burden of Disease Study. AB - BACKGROUND: 18% of the world's population lives in India, and many states of India have populations similar to those of large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state of India as part of the Global Burden of Disease (GBD) Study 2016. METHODS: Using all available data sources, the India State-Level Disease Burden Initiative estimated burden (metrics were deaths, disability adjusted life-years [DALYs], prevalence, incidence, and life expectancy) from 333 disease conditions and injuries and 84 risk factors for each state of India from 1990 to 2016 as part of GBD 2016. We divided the states of India into four epidemiological transition level (ETL) groups on the basis of the ratio of DALYs from communicable, maternal, neonatal, and nutritional diseases (CMNNDs) to those from non-communicable diseases (NCDs) and injuries combined in 2016. We assessed variations in the burden of diseases and risk factors between ETL state groups and between states to inform a more specific health-system response in the states and for India as a whole. FINDINGS: DALYs due to NCDs and injuries exceeded those due to CMNNDs in 2003 for India, but this transition had a range of 24 years for the four ETL state groups. The age-standardised DALY rate dropped by 36.2% in India from 1990 to 2016. The numbers of DALYs and DALY rates dropped substantially for most CMNNDs between 1990 and 2016 across all ETL groups, but rates of reduction for CMNNDs were slowest in the low ETL state group. By contrast, numbers of DALYs increased substantially for NCDs in all ETL state groups, and increased significantly for injuries in all ETL state groups except the highest. The all-age prevalence of most leading NCDs increased substantially in India from 1990 to 2016, and a modest decrease was recorded in the age standardised NCD DALY rates. The major risk factors for NCDs, including high systolic blood pressure, high fasting plasma glucose, high total cholesterol, and high body-mass index, increased from 1990 to 2016, with generally higher levels in higher ETL states; ambient air pollution also increased and was highest in the low ETL group. The incidence rate of the leading causes of injuries also increased from 1990 to 2016. The five leading individual causes of DALYs in India in 2016 were ischaemic heart disease, chronic obstructive pulmonary disease, diarrhoeal diseases, lower respiratory infections, and cerebrovascular disease; and the five leading risk factors for DALYs in 2016 were child and maternal malnutrition, air pollution, dietary risks, high systolic blood pressure, and high fasting plasma glucose. Behind these broad trends many variations existed between the ETL state groups and between states within the ETL groups. Of the ten leading causes of disease burden in India in 2016, five causes had at least a five-times difference between the highest and lowest state-specific DALY rates for individual causes. INTERPRETATION: Per capita disease burden measured as DALY rate has dropped by about a third in India over the past 26 years. However, the magnitude and causes of disease burden and the risk factors vary greatly between the states. The change to dominance of NCDs and injuries over CMNNDs occurred about a quarter century apart in the four ETL state groups. Nevertheless, the burden of some of the leading CMNNDs continues to be very high, especially in the lowest ETL states. This comprehensive mapping of inequalities in disease burden and its causes across the states of India can be a crucial input for more specific health planning for each state as is envisioned by the Government of India's premier think tank, the National Institution for Transforming India, and the National Health Policy 2017. FUNDING: Bill & Melinda Gates Foundation; Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India; and World Bank. PMID- 29150207 TI - Carotid and femoral atherosclerosis in antiphospholipid syndrome: Equivalent risk with diabetes mellitus in a case-control study. AB - BACKGROUND: Antiphospholipid syndrome (APS) may carry a worse prognosis for vascular complications when co-existing with subclinical atherosclerosis; however, the association between the two conditions remains ambiguous. METHODS: We evaluated ultrasonographic markers of subclinical atherosclerosis in carotid and femoral arteries of 86 patients with thrombotic APS [43 primary APS (PAPS), 43 systemic lupus erythematosus-associated APS (SLE/APS)], 86 patients with diabetes mellitus (DM) and 86 healthy controls, individually matched for age and gender, and investigated their associations with traditional and disease-related factors in APS. RESULTS: Carotid plaques were found in 28% of PAPS, 23% of SLE/APS, and 30% of DM patients versus 9% of controls (p = 0.006). Femoral plaques were found in 33% of PAPS, 19% of SLE/APS, 20% of DM, and 9% of controls (p = 0.032). Multivariate regression-derived relative risk estimates for atherosclerotic plaques in any location were 2.72 for PAPS, 2.63 for SLE/APS, and 1.98 for DM (p = 0.004, 0.009, and 0.032 respectively), after adjusting for age, gender, hypertension, dyslipidemia, smoking, BMI, and family history of coronary disease. Among patients with APS, atherosclerotic plaques were associated with the number of traditional CVD risk factors in both PAPS (RR = 2.75, p < 0.001) and SLE/APS (RR = 1.84, p < 0.001), and with IgG anti-beta2-glycoprotein I antibodies in SLE/APS. CONCLUSIONS: Patients with PAPS and SLE/APS have a nearly 2.5-fold risk of atherosclerotic plaques in carotid and femoral arteries compared to healthy controls, similar to DM patients. Atherosclerotic plaques are associated with the number of traditional risk factors in both APS and SLE/APS, and with IgG anti-beta2-glycoprotein I antibodies in SLE/APS. PMID- 29150208 TI - Development of a synthetic Vi polysaccharide vaccine for typhoid fever. AB - Typhoid fever remains a serious public health problem with a high impact on toddlers and young children. Vaccines against the Vi capsular polysaccharide are efficacious against typhoid fever demonstrating that antibodies against Vi confer protection. The currently licensed Vi typhoid vaccines have however limited efficacy and are manufactured by a complex process from wild-type bacteria. Due to these inherent issues with the current vaccines, an alternative vaccine based on an O-acetylated high molecular weight (HMW) polygalacturonic acid (GelSite OAcTM) was generated. The HMW polygalacturonic acid shares the same backbone as the Vi polysaccharide of Salmonella Typhi. The GelSite-OAcTM has a high molecular weight (>1 * 106 Da) and a high degree of O-acetylation (DOAc) (>5 MUmole/mg), both exceeding the potency specifications of the current Vi vaccine. Studies in Balb/c mice demonstrated that GelSite-OAcTM was highly immunogenic, inducing a strong antigen-specific antibody response in a DOAc- and dose-dependent manner which was comparable to or higher than those induced by the licensed Vi vaccine. Importantly, the GelSite-OAcTM was shown to be fully protective in mice against lethal challenge with Salmonella Typhi. Furthermore, the GelSite-OAcTM demonstrated a boosting effect or memory response, exhibiting a >2-fold increase in antibody levels upon the second immunization with either GelSite-OAcTM or the Vi vaccine. This novel boosting effect is unique among polysaccharide antigens and potentially makes GelSite-OAcTM effective in people under 2 years old. Together these results suggest that the GelSite-OAcTM could be a highly effective vaccine against Salmonella Typhi. PMID- 29150210 TI - A behavioral economics approach to the failed HPV vaccination program in Japan. PMID- 29150209 TI - Exploring the relationship between polio type 2 serum neutralizing antibodies and intestinal immunity using data from two randomized controlled trials of new bOPV IPV immunization schedules. AB - BACKGROUND: Inactivated polio vaccine (IPV) is now the only source of routine type 2 protection. The relationship, if any, between vaccine-induced type 2 humoral and intestinal immunity is poorly understood. METHODS: Two clinical trials in five Latin American countries of mixed or sequential bOPV-IPV schedules in 1640 infants provided data on serum neutralizing antibodies (NAb) and intestinal immunity, assessed as viral shedding following oral mOPV2 challenge. Analyses with generalized additive and quantile regression models examined the relationships between prechallenge NAb titers and proportion, duration and titers (magnitude) of viral shedding. RESULTS: We found a statistically significant (p < .0001) but weak relationship between NAb titer at the time of mOPV2 challenge and the Shedding Index Endpoint, the mean log10 stool viral titer over 4 post challenge assessments. Day 28 post-challenge shedding was 13.4% (8.1%, 18.8%) lower and the Day 21 post-challenge median titer of shed virus was 3.10 log10 (2.21, 3.98) lower for subjects with NAb titers at the ULOQ as compared with LLOQ on day of challenge. Overall, there was a weak but significant negative relationship, with high NAb titers associated with lower rates of viral shedding, an effect supported by subset analysis to elucidate between-country differences. CONCLUSIONS: Taken alone, the weak association between pre-challenge NAb titers following IPV or mixed/sequential bOPV/IPV immunization and differences in intestinal immunity is insufficient to predict polio type 2 intestinal immunity; even very high titers may not preclude viral shedding. Further research is needed to identify predictive markers of intestinal immunity in the context of global OPV cessation and IPV-only immunization. PMID- 29150211 TI - Challenges Faced When Caring for Foreign Nationals With Comorbid Medical and Psychiatric Problems in the General Hospital. PMID- 29150212 TI - Response to Letter to the Editor: Psychiatric Disease Among Patients with Takotsubo Syndrome. PMID- 29150213 TI - Targeted Electroconvulsive Therapy for Super Refractory Status Epilepticus: A Case Report and Literature Review. PMID- 29150214 TI - Multifocal Best's disease: The importance of genetic tests. AB - OBJECTIVES AND METHODS: Our objective is to describe a multifocal vitelliform presentation of Best's disease. The lesions in this disease may vary in size and shape, some may be a disc diameter in size, and often have some irregularity in their contour. The case is described of a 21-year-old male patient referred to our ophthalmology department due to a progressive loss of vision. His poor visual acuity was confirmed, and a complete examination was performed, in which macular flecks were observed, with yellow pigment arranged in oval distribution near their periphery. Due to the suspicion of Best's multifocal disease, genetic tests were performed. Multifocal vitelliform disease with the same features as those in Best's disease occurs most frequently in patients with a normal electro-oculogram (EOG), and a normal family history. CONCLUSION: Best's multifocal disease must be suspected in case of multiple vitelliruptive lesions close to the posterior pole. Genetic testing is essential for its diagnosis. PMID- 29150215 TI - Lifestyles guide and glaucoma (II). Diet, supplements, drugs, sleep, pregnancy, and systemic hypertension. AB - PURPOSE: To establish evidence based guidelines to advise patients on the relationship between habits, diet, certain circumstances, diseases and glaucoma. METHODS: Review of all published articles on glaucoma and sports or other activities. The papers were classified according to the level of scientific evidence based on the Oxford Centre for Evidence-based Medicine classification. RESULTS: The evidence on the relationship between diet or supplements and the incidence or progression of glaucoma is insufficient to make a general recommendation for glaucoma patients. Although some studies on normal tension glaucoma suggest that Gingko biloba could reduce glaucoma progression, the results do not allow a general recommendation for all these patients. Similarly, the evidence on the usefulness of vitamin supplements is not conclusive. The studies on smoking do not clearly demonstrate the relationship between this habit and incidence of glaucoma. Marihuana is not a useful treatment for glaucoma. Although the results on the relationship between sleep apnoea and glaucoma are heterogeneous, it is recommended that patients with moderate to intense apnoea are tested for glaucoma. Pregnancy does not influence the course of the disease, but several hypotensive drugs may be harmful for the foetus. Nocturnal systemic hypotension is a risk factor for glaucoma progression. CONCLUSIONS: Certain habits, circumstances, or diseases may have an influence on the onset or progression of glaucoma. It is important to have adequate information about the scientific evidence in the publications in order to properly advise patients. PMID- 29150216 TI - Prepapillary vascular loops. PMID- 29150217 TI - Idiopathic macular telangiectasia type 2: Prevalence and a morphometric and phenotypic study. AB - OBJECTIVE: Type 2 idiopathic macular telangiectasia (MacTel2) is a rare retinal disease that has still not been well-defined. The aim of the present manuscript is to describe the clinical features by multimodal retinal imaging, to present the functional characteristics, and to estimate the prevalence of the disease. METHODS: A retrospective study was conducted on the 12 eyes of 6 patients with MacTel2. Fundus colour photographs, fundus autofluorescence, fluorescein angiography, optical coherence tomography (OCT), and OCT-angiography were performed and subsequently analysed. Visual acuity (VA) was prospectively recorded. The prevalence was established based on the patients referred to a specialised macular diseases unit. Minimum follow-up period was 18 months. RESULTS: Prevalence of MacTel 2 in our study was 0.12%. Clinical features were presented using multimodal retinal imaging. VA remained stable during follow-up. Three patients developed choroidal neovascularisation (CNV), requiring intravitreal treatment with antiangiogenic agents. CONCLUSIONS: The prevalence of the disease found was 0.12%. The study using multimodal imaging allows a more accurate diagnosis and follow-up of this pathology. The VA is maintained during the 18-month follow-up (P=.492). Patients who develop CNV and are treated with antiangiogenic agents appear to respond adequately to them. More studies are needed to establish these conclusions. PMID- 29150218 TI - Keratitis secondary to Fusarium spp. in Spain 2012-2014. AB - OBJECTIVE: To describe the clinical-epidemiological characteristics of a case series of fungal keratitis associated with Fusarium spp.., in Spain during the years 2012 to 2014. METHODS: A retrospective study of a case series was conducted on a systematic random sample of 10% of patients identified in Health Centres of provincial capitals (n=250). The centres were asked whether they had been presented with cases of Fusarium spp. keratitis characterised by microbiological methods. Of the 23 centres that responded, 14 had detected cases, with 13 of them accepting to participate, and 11 of them completing the study. The latter being sent a previously validated questionnaire. The variables analysed were: age, gender, habitual residence, profession, disease and medical history (previous systemic and ocular diseases, previous eye surgeries), and their outcomes. RESULTS: The response rate was 92%, identifying 23 cases of Fusarium spp.. of which 21 (91.3%) of them lived in urban areas. The professions most affected by the disease included chefs, administrative, and technical, with 13 cases (56.5%). The treatment guidelines established to confirm the infection showed the combined use of topical antibiotics associated with antiviral and/or antifungal agents. The use of contact lenses (86.9%) was the main risk factor. DISCUSSION: This study showed that this is a rare disease in Spain, but that a large percentage of people who present with the disease are resident in urban areas, and they work in closed environments, focusing attention on microtraumas caused by use of contact lenses. PMID- 29150220 TI - Celebrating thirty years of deep brain stimulation in movement disorders patients: A successful marriage between neurologists and neurosurgeons. PMID- 29150221 TI - A direct duodeno-jejunal anastomosis: A solution for a difficult duodenal stump. PMID- 29150222 TI - Retrospective study of thoracotomy performed in a French level 1-trauma center. AB - OBJECTIVE: Resuscitative thoracotomy, a potentially life-saving procedure, is used exceptionally, and essentially for penetrating trauma. Most of the available literature is American while reports from Europe are sparse. We report our experience in a French level 1-trauma center. MATERIAL AND METHODS: Patient records (patient age, gender, mechanism of injury, indication for emergency thoracotomy, anatomic injuries, interventions and survival) for all patients who underwent emergency thoracotomy between January 2005 and December 2015 were analyzed. RESULTS: Twenty-two patients (19 males) underwent emergency thoracotomy. Median age was 27.5 (12-67) years. Twelve were performed for blunt trauma (55%) and 10 for penetrating injuries (45%). Thirteen patients presented with cardiac arrest, while nine had deep and refractory hypotension. Overall, survival was 32% (n=7). There were no survivors in the blunt trauma group while seven of ten with penetrating injuries survived. All patients presenting with cardiac arrest died. CONCLUSION: The survival rate in this French retrospective study was in accordance with the literature. PMID- 29150223 TI - Do factors related to participation in physical activity change following restrictive bariatric surgery? A qualitative study. AB - AIMS: To explore participants' ability to participate in physical activity (PA), and barriers and facilitators to PA, at 12 months following restrictive bariatric surgery, and how these differed from participants' pre-surgery perceptions. Motivators for PA post-surgery were also explored. METHODS: Qualitative one-on one in-depth interviews were conducted pre- and 12 months post-surgery. Data were analysed using inductive thematic analysis. RESULTS: Fourteen adults (12 females), with a mean (range) age of 41.4 years (25.0-56.0), body mass index (BMI) of 31.7kg/m2 (22.3-48.2), and excess weight loss of 66% (2-127) completed both interviews. Lack of participation in PA during the first 3-6 months post surgery was a common theme. Although participants reported increased ability to participate in PA, attributing this to a reduction in obesity-related physical barriers to PA, many participants reported that some pre-surgery obesity-related barriers to PA remained at 12 months post-surgery. For most participants, pre surgery non-obesity related barriers to PA also remained at 12 months post surgery. Facilitators to PA were consistent pre- and post-surgery. Weight loss and improvement in physical appearance were the most common motivators for PA post-surgery. CONCLUSIONS: At 12 months following surgery, many participants reported residual obesity and non-obesity related barriers to PA. These barriers may explain the small, if any, pre- to post-surgery change in PA levels reported by earlier research. Facilitators to PA did not change and post-surgery motivators for PA were mostly esteem-related. These data are relevant to shape interventions aimed at optimising PA in this population. PMID- 29150219 TI - Non-neoplastic histiocytic and dendritic cell disorders in lymph nodes. AB - Benign and malignant proliferations of histiocytes and dendritic cells may be encountered in lymph nodes. Reactive histiocytic and dendritic cell infiltrates occur in response to diverse stimuli and in addition to causing lymphadenopathy, may be present unexpectedly in lymph nodes excised for other indications. This review summarizes the pathogenesis and histopathological features of the various non-neoplastic histiocytic and dendritic cell infiltrates that can occur in lymph nodes. PMID- 29150224 TI - Reduced gene expression of sirtuins and active AMPK levels in children and adolescents with obesity and insulin resistance. AB - BACKGROUND: Sirtuins, including SIRT1 and SIRT2, are longevity-associated deacetylase enzymes that modulate metabolic homeostasis in response to the cellular energy state. Adenosine monophosphate activated protein kinase (AMPK) and SIRT1 are interrelated and share several common target pathways. This study aimed to evaluate the SIRT1 and SIRT2 gene expression in peripheral blood mononuclear cells (PBMCs) as well as plasma levels of AMPK, in obese children and adolescents. MATERIALS AND METHODS: Participants included 60 children and adolescents (30 obese and 30 age- and gender-matched control subjects). Real-time polymerase chain reaction (PCR) was used to assess the SIRT1 and SIRT2 gene expression in PBMCs. Serum phospho-AMPK and insulin were measured using enzyme linked immunosorbent assay (ELISA), and insulin resistance (IR) was calculated by the Homeostasis Model of Assessment of Insulin Resistance (HOMA-IR). Glucose and lipid profile were also measured. RESULTS: SIRT1 gene expression and phospho-AMPK plasma levels were significantly diminished in obese subjects compared to the control group, and both SIRT1 and SIRT2 were significantly lower in obese children with IR compared to those without IR. SIRT1 expression revealed significant negative correlations with body mass index and waist circumference as well as insulin and HOMA-IR and a positive correlation with AMPK. SIRT2 negatively correlated with SIRT1 and positively correlated with high density lipoprotein-cholesterol (HDL-C). CONCLUSION: SIRT1 and SIRT2 expression and AMPK levels decrease in children with obesity and IR. Targeting SIRT1 can be valuable in preventing obesity-associated IR in childhood and adolescence. PMID- 29150225 TI - Nondisplaced pubic ramus fracture associated with exsanguination and death. AB - We present a case of an elderly man who sustained non-displaced fractures through the right superior and inferior pubic rami after a fall from standing and had a tragic outcome. While minimally displaced pubic ramus fractures are typically stable and require only symptomatic treatment, there have been reports, such as this one, of low-energy pubic rami fractures resulting in massive hemorrhage. Despite aggressive resuscitation and embolization of the right obturator artery, our patient ultimately died during his hospitalization. This report highlights the need to maintain a high index of suspicion for intrapelvic bleeds even in patients with nondisplaced pubic rami fractures. Rapid recognition and treatment of intrapelvic bleeds can be lifesaving. PMID- 29150226 TI - Comments on prognostic role of copeptin after traumatic brain injury: A systematic review and meta-analysis of observational studies. PMID- 29150227 TI - Case report: C3 glomerulopathy advancing atypical hemolytic uremic syndrome. PMID- 29150228 TI - Surgeons' Perceptions of the Causes of Preventable Harm in Arterial Surgery: A Mixed-Methods Study. AB - BACKGROUND: System factors contributing to preventable harm in vascular patients have not been previously reported in detail. The aim of this exploratory mixed methods study was to describe vascular surgeons' perceptions of factors contributing to adverse events (AEs) in arterial surgery. A secondary aim was to report recommendations to improve patient safety. METHODS: Vascular consultants/registrars working in the British National Health Service were questioned about the causes of preventable AEs through survey and semi-structured interview (response rates 77% and 83%, respectively). Survey respondents considered a recent AE, indicating on a 5 point Likert scale the extent to which various factors from a validated framework contributed toward the incident. Semi structured interviews were conducted to obtain detailed accounts of contributory factors, and to elicit recommendations to improve safety. RESULTS: Seventy-seven surgeons completed the survey on 77 separate AEs occurring during open surgery (n = 41) and in endovascular procedures (n = 36). Ten interviewees described 15 AEs. The causes of AEs were multifactorial (median number of factors/AE = 5, IQR 3-9, range 0-25). Factors frequently reported by survey respondents were communication failures (36.4%; n = 28/77); inadequate staffing levels/skill mix (32.5%; n = 25/77); lack of knowledge/skill (37.3%; n = 28/75). Themes emerging from interviews were team factors (communication failure, lack of team continuity, lack of clarity over roles/responsibilities); work environment factors (poor staffing levels, equipment problems, distractions); inadequate training/supervision. Knowledge/skill (p = .034) and competence (p = .018) appeared to be more prominent in causing AEs in open procedures compared with endovascular procedures; organisational structure was more frequently implicated in AEs occurring in endovascular procedures (p = .017). To improve safety, interviewees proposed team training programmes (5/10 interviewees); additional protocols/checklists (4/10); improved escalation procedures (3/10). CONCLUSION: Vascular surgeons believe that AEs in arterial operations are caused by multiple, modifiable system factors. Larger studies are needed to establish the relative importance of these factors and to determine strategies that can effectively address system failures. PMID- 29150229 TI - Corrigendum to "Danshen improves survival of patients with colon cancer and dihydroisotanshinone I inhibit the proliferation of colon cancer cells via apoptosis and skp2 signaling pathway" [J. Ethnopharmacol. 209 (2017) 305-316]. PMID- 29150230 TI - Cesarean birth - What's in a name? AB - BACKGROUND: Cesarean birth is known as both cesarean section (CS) and cesarean delivery (CD). The International Journal of Obstetric Anesthesia (IJOA) is the leading obstetric anesthesia journal, and a barometer of attitudes within the profession. The journal recently published the hundredth issue, spanning 25 years (to December 2016). It is an opportune time to examine the evolution of surgical birth terminology (CS versus CD) during that period. METHODS: We examined 1583 articles in IJOA, subdividing them into editorials, papers, review articles, debates and case reports. We searched for the terms CS, CD, neither or both; and examined the geographical origin of the articles, dividing them into "North America", Europe" and "Rest of the World". RESULTS: There has been a change in terminology from CS towards CD - mainly from the mid-2000s onwards. Cesarean delivery was predominantly used in North American publications, while CS was predominantly favoured in European publications. It is possible that some of these trends represent policies of journal reviewers, although this does not explain all geographical differences. CONCLUSION: The term CS may represent tautology as the Latin roots of "cesarean" and "section" both refer to cutting. This would suggest CD to be the preferred terminology. Cesarean delivery also aligns with other terminology, for example vaginal and forceps delivery. A consistent approach would improve clarity. PMID- 29150231 TI - Diagnosis of hyperferritinemia in routine clinical practice. AB - The discovery of hyperferritinemia is often fortuitous, revealed in results from a laboratory screening or follow-up test. The aim of the diagnostic procedure is therefore to identify its cause and to identify or rule out hepatic iron overload, in a three-stage process. In the first step, clinical findings and several simple laboratory tests are sufficient to detect four of the most frequent causes of high ferritin concentrations: alcoholism, inflammatory syndrome, cytolysis, and metabolic syndrome. None of these causes is associated with substantial hepatic iron overload. If transferrin saturation is high (> 50%), hereditary hemochromatosis will be considered in priority. In the second phase, rarer diseases will be sought. Among them, only chronic hematologic diseases (acquired or congenital) and excessive iron intake or infusions (patients on chronic dialysis and high-level athletes) are at risk of iron overload. In the third stage, if a doubt persists about the cause or if the ferritin concentration is very high or continues to rise, it is essential to verify the hepatic iron concentration to rule out overload. The principal examination to guide diagnosis and treatment is hepatic MRI to assess its iron concentration. It is essential to remember that more than 40% of patients with hyperferritinemia have several causes simultaneously present. PMID- 29150232 TI - [Pathogenesis, genetics and diagnosis of endometriosis]. AB - Endometriosis is a multifactorial pathology. Trans-tubal reflux theory remains valid. Genetic and epigenetic factors associated with immunological perturbations are involved. The role of endocrine disruptors is discussed although epidemiological studies are contradictory. Therapeutics are primarily based on hormonal treatments but better understanding of pathophysiology should allow targeted non-hormonal therapy. The clinical examination is sometimes negative, which should not eliminate the diagnosis and imposes complementary examinations as best as possible by referents. PMID- 29150233 TI - Management of first depression or generalized anxiety disorder episode in adults in primary care: A systematic metareview. AB - CONTEXT: General Practitioners (GPs) are the leading antidepressants prescribers in Europe and in France. Difficulties in implementing existing recommendations in daily practice have been described. OBJECTIVE: The objective of this study was to elaborate two algorithms to guide GPs in the patient management for a first major depressive disorder (MDD) or generalized anxiety disorder (GAD) episode in primary care. DATA SOURCES: PubMed, Cochrane, and ISI Web of Science were explored using mainly the following keywords: depressive disorder, anxiety disorders, antidepressive agents or antidepressant. PubMed was explored using Medical Subject Headings (MeSH). Grey literature was also considered through the analysis of articles references, congress publications, guidelines and clinical practice recommendations. STUDY SELECTION: A systematic meta-review (overview of reviews) including systematic reviews, meta-analyses, guidelines and clinical practice recommendations, published from January 2002 to December 2015, was performed. The methodological and report qualities were assessed by the AGREE II, PRISMA checklist and R-AMSTAR grid. Each step was performed independently by two researchers following a process derived from the PRISMA statement. A narrative synthesis on main clinical data to collect before prescription in primary care, key information for patients, and recommended follow-up was realized. RESULTS: Thirty articles were included: 11 meta-analyses, 19 guidelines. For moderate to severe MDD, selective serotonin reuptake inhibitors (SSRI) should be associated with psychotherapy (cognitive behavioral therapy). For GAD, SSRI or CBT should be proposed if functional impairment is marked. Two algorithms to guide GPs for the management of MDD and or the management of GAD were created based on the data synthesis of this review. A GPs expert group discussed and adapted the algorithms to match with GPs expectancies. LIMITS: Few articles dealt specifically with primary care practice, and only one meta-analysis of clinical trial on antidepressants in primary care was found. CONCLUSIONS: From the best evidence based data, we created two algorithms to guide GPs for the management of MDD and or the management of GAD. These algorithms will be implemented through a website available for GPs consultation. PMID- 29150234 TI - [Medical studies in France: How to cope with such a disaster?] PMID- 29150235 TI - Elective Intraoperative Use of an Avalon Elite Catheter During Lung Transplantation. PMID- 29150236 TI - Lung Cancer and Risk of Cardiovascular Disease: A Meta-analysis of Cohort Studies. PMID- 29150237 TI - [Maternal deaths due to amniotic fluid embolism. Results from the French confidential enquiry into maternal deaths, 2010-2012]. AB - Amniotic fluid embolism (AFE) is an unpredictable, dreadful complication of pregnancy or childbirth. EA typically includes in the same lapse of time respiratory, haemodynamic, neurological and hemorrhagic symptoms (from early and severe coagulopathy). Immediate supportive treatment by a multidisciplinary team is the cornerstone of the management. Between 2010 an 2012 in France, 24 deaths were related to AFE giving a maternal mortality ratio of 1/100,000 live births (CI 95% 0.6-1.4). AFE ranks as the second leading cause of direct maternal death. Eight cases over 23 were classified as having some degree of substandard care. Substandard care included delays in performing aggressive surgical treatment or delays in the diagnosis and the treatment of the coagulopathy. Learning points focus on the importance to pay attention on premonitory symptoms, to early assess the clotting status and to train in multidisciplinary team. PMID- 29150238 TI - A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene. AB - Immune response (Ir) genes, originally proposed by Baruj Benacerraf to explain differential antigen-specific responses in animal models, have become synonymous with the major histocompatibility complex (MHC). We discovered a non-MHC-linked Ir gene in a T cell receptor (TCR) locus that was required for CD8+ T cell responses to the Plasmodium berghei GAP5040-48 epitope in mice expressing the MHC class I allele H-2Db. GAP5040-48-specific CD8+ T cell responses emerged from a very large pool of naive Vbeta8.1+ precursors, which dictated susceptibility to cerebral malaria and conferred protection against recombinant Listeria monocytogenes infection. Structural analysis of a prototypical Vbeta8.1+ TCR-H 2Db-GAP5040-48 ternary complex revealed that germline-encoded complementarity determining region 1beta residues present exclusively in the Vbeta8.1 segment mediated essential interactions with the GAP5040-48 peptide. Collectively, these findings demonstrated that Vbeta8.1 functioned as an Ir gene that was indispensable for immune reactivity against the malaria GAP5040-48 epitope. PMID- 29150240 TI - Dichotomous Expression of TNF Superfamily Ligands on Antigen-Presenting Cells Controls Post-priming Anti-viral CD4+ T Cell Immunity. AB - T cell antigen-presenting cell (APC) interactions early during chronic viral infection are crucial for determining viral set point and disease outcome, but how and when different APC subtypes contribute to these outcomes is unclear. The TNF receptor superfamily (TNFRSF) member GITR is important for CD4+ T cell accumulation and control of chronic lymphocytic choriomeningitis virus (LCMV). We found that type I interferon (IFN-I) induced TNFSF ligands GITRL, 4-1BBL, OX40L, and CD70 predominantly on monocyte-derived APCs and CD80 and CD86 predominantly on classical dendritic cells (cDCs). Mice with hypofunctional GITRL in Lyz2+ cells had decreased LCMV-specific CD4+ T cell accumulation and increased viral load. GITR signals in CD4+ T cells occurred after priming to upregulate OX40, CD25, and chemokine receptor CX3CR1. Thus IFN-I (signal 3) induced a post-priming checkpoint (signal 4) for CD4+ T cell accumulation, revealing a division of labor between cDCs and monocyte-derived APCs in regulating T cell expansion. PMID- 29150239 TI - Tissue-Resident Macrophages Are Locally Programmed for Silent Clearance of Apoptotic Cells. AB - Although apoptotic cells (ACs) contain nucleic acids that can be recognized by Toll-like receptors (TLRs), engulfment of ACs does not initiate inflammation in healthy organisms. Here we identified macrophage populations that continually engulf ACs in distinct tissues and found that these macrophages share characteristics compatible with immunologically silent clearance of ACs; such characteristics include high expression of AC recognition receptors, low expression of TLR9, and reduced TLR responsiveness to nucleic acids. Removal of the macrophages from tissues resulted in loss of many of these characteristics and the ability to generate inflammatory responses to AC-derived nucleic acids, suggesting that cues from the tissue microenvironment program macrophages for silent AC clearance. The transcription factors KLF2 and KLF4 control the expression of many genes within this AC clearance program. The coordinated expression of AC receptors with genes that limit responses to nucleic acids might ensure maintenance of homeostasis and thus represent a central feature of tissue macrophages. PMID- 29150242 TI - Anterior Inferior Cerebellar Artery Strokes Based on Variant Vascular Anatomy of the Posterior Circulation: Clinical Deficits and Imaging Territories. AB - We report imaging findings of 3 patients with anterior inferior cerebellar artery (AICA) infarcts who presented with atypical clinical findings of cerebellar strokes. AICA strokes are rare, and diagnosis can be difficult because of the high variability of the posterior circulation vascular anatomy. We describe the embryology and variant anatomy of AICA so that clinicians can understand and recognize the patterns of these infarcts. PMID- 29150241 TI - Targeting Interleukin-1beta Protects from Aortic Aneurysms Induced by Disrupted Transforming Growth Factor beta Signaling. AB - Aortic aneurysms are life-threatening conditions with effective treatments mainly limited to emergency surgery or trans-arterial endovascular stent grafts, thus calling for the identification of specific molecular targets. Genetic studies have highlighted controversial roles of transforming growth factor beta (TGF beta) signaling in aneurysm development. Here, we report on aneurysms developing in adult mice after smooth muscle cell (SMC)-specific inactivation of Smad4, an intracellular transducer of TGF-beta. The results revealed that Smad4 inhibition activated interleukin-1beta (IL-1beta) in SMCs. This danger signal later recruited innate immunity in the adventitia through chemokine (C-C motif) ligand 2 (CCL2) and modified the mechanical properties of the aortic wall, thus favoring vessel dilation. SMC-specific Smad4 deletion in Il1r1- or Ccr2-null mice resulted in milder aortic pathology. A chronic treatment with anti-IL-1beta antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-beta signaling, such as those driven by SMAD4 mutations. PMID- 29150243 TI - Effects of N-carbamylglutamate and L-arginine on steroidogenesis and gene expression in bovine granulosa cells. AB - Feeding N-carbamylglutamate (NCG) and arginine (ARG) improves reproductive measures in pigs and reduces systemic steroid levels in pregnant ewes. We hypothesized that the effects of NCG and ARG on reproduction were due to direct effects on the ovary. Thus, the objectives of this study were to investigate the effects of NCG and ARG on granulosa cell (GC) steroidogenesis, gene expression, and cell proliferation in vitro. GC were collected from small (1-5mm) bovine follicles and treated in vitro with NCG or ARG in serum-free medium for 24h to 48h. Both NCG and ARG inhibited (P<0.05) IGF1- and FSH-induced GC estradiol production but only NCG inhibited (P<0.05) progesterone production. In contrast, NCG and ARG increased (P<0.05) GC numbers induced by IGF1 and FSH. NCG inhibited (P<0.05) StAR, CYP11A1 and CYP19A1 mRNA abundance in small-follicle GC, whereas ARG had no effect (P>0.10) on StAR, CYP11A1 or CYP19A1 mRNA abundance. We conclude that NCG and ARG may act directly on GC and therefore may regulate ovarian function by slowing follicular differentiation via inhibiting IGF1 action, and steroid synthesis while stimulating GC proliferation in cattle. PMID- 29150245 TI - [Skin manifestations of tularemia]. PMID- 29150244 TI - Proteomic analysis of follicular fluid from tropically-adapted goats. AB - The present study was conducted to characterize the major proteome of ovarian follicular fluid from locally-adapted, "Caninde" goats in the northeast of Brazil. Eight estrous cycling goats received a hormonal treatment consisting of medroxyprogesterone acetate, D-cloprostenol and FSH. Fluid was collected by laparoscopy from small (<3mm), medium (3-4mm) and large (>4mm) follicles and then, proteins were analyzed by 2-D SDS-PAGE and tandem mass spectrometry. Thirty six proteins were identified in the goat follicular fluid, including albumin, immunoglobulins, ceruloplasmin, complement factor B, alpha-1B-glycoprotein precursor, serotransferrin, complement C3 and serpins, among others. Albumin and immunoglobulins were the most abundant proteins. Protein concentrations were similar in the fluid from small (45.3+/-3.1mg/mL), medium (44.2+/-3.3mg/mL) and large follicles (45.1+/-2.3mg/mL). The intensities of spots identified in 2-D gels as serotransferrin, zinc-alpha-2-glycoprotein-like, complement factor B and complement protein C3 differed (P<0.05) among follicle categories. The amount of serotransferrin was greater in the medium than small follicles (P<0.05). Content of zinc-alpha-2-glycoprotein-like, complement factor B and complement C3 was greater (P<0.05) in the fluid of large follicles than in medium follicles. Based on gene ontology, the major molecular functions associated with goat follicular fluid proteins were binding and catalytic activity, while the main biological processes were related to regulation, cellular processing, location and the immune system. In conclusion, the major proteome of the follicular fluid from goats subjected to hormonal stimulation was elucidated in the present study. Also, molecules associated with follicle development are potential biomarkers of oocyte competence were prevalent. PMID- 29150246 TI - Development of the Autosomal Dominant Polycystic Kidney Disease Impact Scale: A New Health-Related Quality-of-Life Instrument. AB - BACKGROUND: The impact of autosomal dominant polycystic kidney disease (ADPKD) on health-related quality of life (HRQoL) is not well understood due to a lack of instruments specific to the condition. STUDY DESIGN: Content for a new self administered patient-reported outcome (PRO) questionnaire to assess ADPKD-related HRQoL was developed through clinical expert and patient focus group discussions. The new PRO instrument was administered to study patients with ADPKD to evaluate its reliability and validity. SETTING & PARTICIPANTS: 1,674 adult patients with ADPKD participated in this research: 285 patients in focus groups to generate questionnaire content, 15 patients in debriefing interviews to refine the PRO questionnaire, and 1,374 patients to assess the performance and measurement properties of the PRO questionnaire. OUTCOME: A new PRO questionnaire. RESULTS: The ADPKD Impact Scale (ADPKD-IS), consisting of 14 items representing 3 conceptual domains (physical, emotional, and fatigue) plus 4 additional questions, was developed. The instrument's reliability (regarding internal consistency and test-retest consistency) and validity (content and construct) were supported. LIMITATIONS: Need for more responsiveness testing when more data from clinical use become available over time. Complex concepts such as ADPKD related pain and impact on a patient's HRQoL need further evaluation. CONCLUSIONS: The ADPKD-IS is a new patient-centric tool that reliably and validly provides a standardized method for assessing HRQoL and overall disease burden in patients with ADPKD. PMID- 29150247 TI - The Adoption of a One-Day Donor Assessment Model in a Living Kidney Donor Transplant Program: A Quality Improvement Project. AB - BACKGROUND: Survival of kidney transplants and their recipients is significantly better after living donor than after deceased donor transplantation. However, historically, Northern Ireland has had a low rate of living donor kidney transplantation. The length and complexity of donor evaluation has been one of the main factors contributing to this pattern. STUDY DESIGN: Quality improvement project. SETTINGS & PARTICIPANTS: All people in Northern Ireland expressing an interest in becoming a living kidney donor between 2010 and 2015. QUALITY IMPROVEMENT INTERVENTION: Potential donors deemed to be suitable after a screening questionnaire attended a comprehensive 1-day evaluation including all investigations that had been previously been implemented across multiple clinical visits. OUTCOME: Change in rate of living donor transplantation following the quality improvement intervention. MEASUREMENTS: Demographic data and reasons for nondonation. RESULTS: 431 potential donors underwent a 1-day assessment, with 284 (66%) ultimately donating and 12 (3%) still active in the program. Of the 135 (31%) potential donors who did not donate, 48 were unsuitable due to medical or surgical issues, 2 became pregnant, and 18 withdrew. For 38 (9%) potential donors, intended recipients found an alternative living or deceased donor transplant. For 29 (6%) potential donors, the transplantation did not proceed because of recipient-related issues. The annual rate of living donor kidney transplantation in Northern Ireland increased from a mean of 4.3 per million population (pmp) between 2000 and 2009 to 32.6 pmp between 2011 and 2015. LIMITATIONS: Single geographical region with a potentially unrepresentative population and health care organization. Retrospective observational study. Paucity of data from the preintervention period. CONCLUSIONS: Following implementation of a 1-day assessment process, we observed a considerable and sustained increase in the rate of living donor kidney transplantation. Making donor evaluation easier holds promise to increase the number of living donor kidney transplants, potentially optimizing outcomes for both recipients and donors. PMID- 29150249 TI - Accuracy of the cobas EGFR Mutation Assay in Non-small-cell Lung Cancer Compared With Three Laboratory-developed Tests. AB - BACKGROUND: The reliability of the cobas EGFR assay to detect epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) as an in vitro diagnostic test was compared with 3 laboratory-developed tests (LDTs). MATERIALS AND METHODS: After screening for EGFR mutations using formalin-fixed paraffin-embedded NSCLC tissue sections using the cobas EGFR assay, 151 samples were further tested with 3 LDTs; the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PCR) clamp, PCR invader, and Cycleave assays. The cobas EGFR assay performance was evaluated by determining the concordance rate and kappa-coefficient between the assays. In samples exhibiting discrepancies in the EGFR mutation status in the 4 assays, next-generation sequencing was performed to confirm mutated sequences. RESULTS: Concordance rates and kappa coefficients between the cobas EGFR assay and the other tests were 96.0% and 0.921 for the peptide nucleic acid-locked nucleic acid PCR clamp assay, 94.0% and 0.881 for the PCR invader assay, and 96.7% and 0.934 for the Cycleave assay, respectively. Data showed very good agreement with the other assays. Precise mutated sequences or exons in the EGFR gene matched in 137 samples (90.7%). Different results were obtained in 4 samples (2.6%), owing to systemic limitations of the assay. Next-generation sequencing of 10 (6.6%) samples with discordant results exhibited a concordance rate of 60% to 80% in each assay. CONCLUSIONS: The cobas EGFR assay showed high concordance rates and kappa coefficients between the 3 compared LDTs and can be used to select patients who would benefit from EGFR-tyrosine kinase inhibitors. PMID- 29150248 TI - Cryopreservation at -75 degrees C of Agaricus subrufescens on wheat grains with sucrose. AB - Agaricus subrufescens is a basidiomycete which is studied because of its medicinal and gastronomic importance; however, less attention has been paid to its preservation. This study aimed to evaluate the effect of sucrose addition to substrate and cryotube on the viability of Agaricus subrufescens cryopreserved at -20 degrees C and at -75 degrees C for one and two years. Zero, 10% or 20% sucrose was added to potato dextrose agar or wheat grain. The mycelia were cryopreserved in the absence of cryoprotectant or with sucrose solutions at 15%, 30% or 45%. After one or two years at -75 degrees C or at -20 degrees C, mycelia were thawed and evaluated about viability, initial time of growth, colony diameter and genomic stability. Cryopreservation at -20 degrees C is not effective to keep mycelial viability of this fungus. Cryopreservation at -75 degrees C is effective when sucrose is used in substrates and/or cryotubes. Without sucrose, cryopreservation at -75 degrees C is effective only when wheat grains are used. Physiological characteristic as mycelial colony diameter is negatively affected when potato dextrose agar is used and unaffected when wheat grain is used after two-year cryopreservation at -75 degrees C. The fungus genome does not show alteration after two-year cryopreservation at -75 degrees C. PMID- 29150251 TI - Validity of Birth Certificate and Hospital Discharge Data Reporting of Labor Induction. AB - PURPOSE: To examine the concordance of labor induction measures derived from birth certificate and hospital discharge data with each other and with maternal report. METHODS: Birth certificate data were linked with hospital discharge data and structured interviews of 2,851 mothers conducted 1 month after first childbirth. Those who reported that a doctor or nurse tried to cause their labor to begin, and were not in labor before that event, were classified as undergoing labor induction. The mothers were aged 18 to 35 years at study entry and delivered at 78 hospitals (76 in Pennsylvania and 2 out of state) from 2009 to 2011. RESULTS: The labor induction rate was 34.3% measured by maternal report, 29.4% by birth certificate data, and 26.2% by hospital discharge data. More than one-third of the women who reported labor induction were not reported as having been induced in the birth certificate data (33.6%), with similar results for the hospital discharge data (36.5%). The rate of underreporting of labor induction in the birth certificate data was higher for inductions occurring before 39 weeks of gestation (43.9%) than for inductions at 39 weeks or later (29.9%; p < .0001). Agreement between birth certificate and hospital discharge data was relatively low (kappa = 0.56), as was agreement between maternal report and birth certificate data (kappa = 0.58), and maternal report and hospital discharge data (kappa = 0.60). CONCLUSIONS: Both the birth certificate and hospital discharge data exhibit relatively poor agreement with maternal report of labor induction and seem to miss a substantial portion of labor inductions. PMID- 29150250 TI - A Randomized, Multicenter, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and the Tolerability of a Triple Combination of Amlodipine/Losartan/Rosuvastatin in Patients With Comorbid Essential Hypertension and Hyperlipidemia. AB - PURPOSE: The objective of this study was to evaluate the efficacy and tolerability of a triple combination of amlodipine/losartan/rosuvastatin in patients with hypertension and hypercholesterolemia. METHODS: A randomized, multicenter, double-blind, placebo-controlled study was conducted. Eligible patients with hypertension and a sitting diastolic blood pressure (SiDBP) of >90 mm Hg and LDL-C levels <250mg/dL were screened. After a 4-week run-in period with therapeutic lifestyle changes and losartan potassium 100mg once daily, patients who met both blood pressure criteria (80 mm Hg <= SiDBP < 110 mm Hg) and the LDL C level criteria (defined in the National Cholesterol Education Program Adult Treatment Panel III cardiovascular risk categories) were randomized to 1 of 3 groups and treated once daily for 8 weeks: losartan potassium 100mg + rosuvastatin 20mg treatment (L/R 100/20) group, amlodipine camsylate 5mg + losartan potassium 100mg treatment (A/L 5/100) group, and amlodipine 5mg+ losartan potassium 100mg + rosuvastatin 20mg (A/L/R 5/100/20) group. The primary efficacy variables were the percent change in LDL-C in the A/L/R 5/100/20 and A/L 5/100 groups and the mean change of SiDBP in the A/L/R 5/100/20 and L/R 100/20 groups after 8 weeks of treatment, relative to baseline values. FINDINGS: A total of 146 patients were enrolled and the demographic characteristics were similar among the 3 treatment groups. After 8 weeks of treatment, the mean (SD) percent change in LDL-C was significantly greater in the A/L/R group than in the A/L group (-48.40% [2.77%] vs -6.70% [3.00%]; P < 0.0001). Moreover, the mean change in SiDBP was significantly greater in the A/L/R group than in the L/R group ( 9.75 [0.92] mm Hg vs -1.73 [1.03] mm Hg; P < 0.0001). SiDBP and LDL-C reductions in the A/L/R group were comparable to reductions in the A/L and L/R groups, respectively. Ten adverse events were reported in 7 patients (4.83%), and 1 patient from the A/L group (0.69%) experienced 2 adverse drug reactions (tachycardia and face edema), which were mild and resolved without specific treatment. There were no clinically significant tolerability issues during the treatment period. IMPLICATIONS: Triple combination therapy with amlodipine/losartan/rosuvastatin can be an effective therapeutic strategy in patients with hypertension combined with dyslipidemia. These findings will form the foundation of the future development of a single-pill triple combination. ClinicalTrials.gov identifier: NCT02899455. PMID- 29150252 TI - Resolution of extensive vulvovaginal condylomatosis following immunoglobulin replacement in primary immunodeficiency disorders. PMID- 29150253 TI - Anti-IgE or Anti-IL5: That Is the Question. PMID- 29150254 TI - Subcellular distribution and biotransformation of phenanthrene in pakchoi after inoculation with endophytic Pseudomonas sp. as probed using HRMS coupled with isotope-labeling. AB - Contamination of food-crops with polycyclic aromatic hydrocarbons (PAHs) poses a grave concern to food safety, especially when PAHs are internalized. We have demonstrated in our previous study that inoculation of crop with a phenanthrene degrading endophytic Pseudomonas sp. Ph6-gfp could overcome this problem. Here, the subcellular distribution and biotransformation mechanism of phenanthrene in pakchoi (Brassica chinensis L.) seedlings with inoculation of Ph6-gfp were further investigated both in vitro and in vivo. The possible biotransformation products of phenanthrene were identified by high-resolution mass spectrometry (HRMS) coupled with 13C2-phenanthrene labeling. Results indicated that Ph6-gfp colonized pakchoi interior and reduced the content of phenanthrene in different cell compartments. Notably, the inoculation hindered the subcellular distribution of phenanthrene from intercellular space to subcellular fractions (i.e., cell wall, cell membrane, cell solution, and cell organelles), likely resulting from the interception and biodegradation of phenanthrene by the bacterium between the cell wall and intercellular space. Additionally, the conjugation reactions of phenanthrene-metabolites and endogenous plant compounds were enhanced as a result of the inoculation. We propose that endophytic degradation, plant metabolism, and conjugation reaction are the three possible biotransformation mechanisms that could account for the changes in phenanthrene inside the plant cell compartments. This is the first observation of endophytic bacteria (EB)-enhanced biotransformation and conjugation of phenanthrene in pakchoi at the subcellular level, which drive novel insights in regulating food-crop contamination with endophytes in PAH-contaminated matrices. PMID- 29150255 TI - Effects of red earthworms (Eisenia fetida) on leachability of lead minerals in soil. AB - Contamination of soils by metals and metalloids is an important environmental problem in many residential and industrial sites around the world. Lead is a common contaminant, which enters the soil through mining, industrial activities and waste disposal. A range of technologies can be used to remediate soil lead, however most remediation technologies adversely affect the environment and particularly soil biota. We have assessed the efficacy of vermiremediation (the use of earthworms for remediation) to reduce water extractable lead concentrations in soil. Earthworms were introduced to a sandy soil spiked with the common lead minerals cotunnite (PbCl2), cerussite (PbCO3), massicot (PbO) or galena (PbS) at 1000 mg (Pb) kg-1. Lead concentrations in pore water extracted during the experiment were not significantly different in contaminated soil with and without worms. However, concentrations of lead in water from a deionised water extraction (washing) of contaminated soil were significantly lower in soil with earthworms than in soil without. Earthworms accumulated on average (+/-1 standard deviation) 276 +/- 118, 235 +/- 66, 241 +/- 58 and 40 +/- 30 mg kg-1 (dry weight of earthworms) of lead in their bodies, in PbCl2, PbCO3, PbO and PbS dosed soils, respectively. During the experiment, earthworms lost weight in all contaminated soils, except those containing PbS. PMID- 29150257 TI - Utilization of organic residues using heterotrophic microalgae and insects. AB - Various organic residues occur globally in the form of straw, wood, green biomass, food waste, feces, manure etc. Other utilization strategies apart from anaerobic digestion, composting and incineration are needed to make use of the whole potential of organic residues as sources of various value added compounds. This review compares the cultivation of heterotrophic microalgae and insects using organic residues as nutrient sources and illuminates their potential with regard to biomass production, productivity and yield, and utilization strategies of produced biomasses. Furthermore, cultivation processes as well as advantages and disadvantages of utilization processes are identified and discussed. It was shown that both heterotrophic algae and insects are able to reduce a sufficient amount of organic residues by converting it into biomass. The biomass composition of both organisms is similar which allows similar utilization strategies in food and feed, chemicals and materials productions. Even though insect is the more complex organism, biomass production can be carried out using simple equipment without sterilization and hydrolysis of organic residues. Contrarily, heterotrophic microalgae require a pretreatment of organic residues in form of sterilization and in most cases hydrolysis. Interestingly, the volumetric productivity of insect biomass exceeds the productivity of algal biomass. Despite legal restrictions, it is expected that microalgae and insects will find application as alternative food and feed sources in the future. PMID- 29150256 TI - Reproductive effects linked to DNA methylation in male zebrafish chronically exposed to environmentally relevant concentrations of di-(2-ethylhexyl) phthalate. AB - Di-(2-ethylhexyl) phthalate (DEHP) possesses the potential to interfere with the male reproductive endocrine system in mammals; however, its reproductive toxicity in male zebrafish and associated epigenetic studies have not been explored. In this study, three-month-old male zebrafish were exposed to environmentally relevant concentrations of DEHP (0, 10, 33 and 100 MUg/L) for 3 months, and then the impact on the reproduction of males and the underlying mechanism were investigated. Histological testing showed that an exposure concentration of 100 MUg/L DEHP significantly inhibited spermatogenesis, with an associated decline in capability to fertilize untreated oocytes. Electron microscopic examinations also revealed noticeable damage to the testicular ultrastructure at the 100 MUg/L DEHP exposure level. In addition, exposure to 33 and 100 MUg/L of DEHP resulted in a decline of circulating testosterone (T) and an increase in the level of 17beta estradiol (E2), both of which were possibly derived from the downregulation of cyp17a1 and hsd17b3 genes and the upregulation of the cyp19a1a gene in the gonads. The DNA methylation statuses of these genes were altered within their promoter regions. A significant increase in global DNA methylation in both the male testes and their offspring larvae was observed at higher exposure concentration of DEHP. Our findings demonstrate that exposure to environmentally relevant concentrations of DEHP can damage the testes, disturbe the sex hormones production, and inhibite spermatogenesis, which ultimately impairs the reproduction of male zebrafish. PMID- 29150258 TI - A spent coffee grounds based biorefinery for the production of biofuels, biopolymers, antioxidants and biocomposites. AB - Spent coffee grounds are composed of lipid, carbohydrates, carbonaceous, and nitrogen containing compounds among others. Using n-hexane and n hexane/isopropanol mixture highest oil yield was achived during soxhlet extraction of oil from spent coffee grounds. Alternatively, supercritical carbon dioxide can be employed as a green solvent for the extraction of oil. Using advanced chemical and biotechnological methods, spent coffee grounds are converted to various biofuels such as, biodiesel, renewable diesel, bioethanol, bioethers, bio-oil, biochar, and biogas. The in-situ transesterification of spent coffee grounds was carried out in a large scale (4 kg), which led to 80-83% biodiesel yield. In addition, a large number of value added and diversified products viz. polyhydroxyalkanoates, biosorbent, activated carbon, polyol, polyurethane foam, carotenoid, phenolic antioxidants, and green composite are obtained from spent coffee grounds. The principles of circular economy are applied to develop a sustanaible biorefinery based on valorisation of spent coffee grounds. PMID- 29150259 TI - Reduction of CO2 emission by INCAM model in Malaysia biomass power plants during the year 2016. AB - As the world's second largest palm oil producer and exporter, Malaysia could capitalize on its oil palm biomass waste for power generation. The emission factors from this renewable energy source are far lower than that of fossil fuels. This study applies an integrated carbon accounting and mitigation (INCAM) model to calculate the amount of CO2 emissions from two biomass thermal power plants. The CO2 emissions released from biomass plants utilizing empty fruit bunch (EFB) and palm oil mill effluent (POME), as alternative fuels for powering steam and gas turbines, were determined using the INCAM model. Each section emitting CO2 in the power plant, known as the carbon accounting center (CAC), was measured for its carbon profile (CP) and carbon index (CI). The carbon performance indicator (CPI) included electricity, fuel and water consumption, solid waste and waste-water generation. The carbon emission index (CEI) and carbon emission profile (CEP), based on the total monthly carbon production, were determined across the CPI. Various innovative strategies resulted in a 20%-90% reduction of CO2 emissions. The implementation of reduction strategies significantly reduced the CO2 emission levels. Based on the model, utilization of EFB and POME in the facilities could significantly reduce the CO2 emissions and increase the potential for waste to energy initiatives. PMID- 29150260 TI - Prioritizing and optimizing sustainable measures for food waste prevention and management. AB - Food waste has gained prominence in the European political debate thanks to the recent Circular Economy package. Currently the waste hierarchy, introduced by the Waste Framework Directive, has been the rule followed to prioritize food waste prevention and management measures according to the environmental criteria. But when considering other criteria along with the environmental one, such as the economic, other tools are needed for the prioritization and optimization. This paper addresses the situation in which a decision-maker has to design a food waste prevention programme considering the limited economic resources in order to achieve the highest environmental impact prevention along the whole food life cycle. A methodology using Life Cycle Assessment and mathematical programing is proposed and its capabilities are shown through a case study. Results show that the order established in the waste hierarchy is generally followed. The proposed methodology revealed to be especially helpful in identifying "quick wins" - measures that should be always prioritized since they avoid a high environmental impact at a low cost. Besides, in order to aggregate the environmental scores related to a variety of impact categories, different weighting sets were proposed. In general, results show that the relevance of the weighting set in the prioritization of the measures appears to be limited. Finally, the correlation between reducing food waste generation and reducing environmental impact along the Food Supply Chain has been studied. Results highlight that when planning food waste prevention strategies, it is important to set the targets at the level of environmental impact instead of setting the targets at the level of avoided food waste generation (in mass). PMID- 29150261 TI - Additional evidence supporting the central sensitization inventory (CSI) as an outcome measure among chronic pain patients in functional restoration program care. PMID- 29150262 TI - The Central Sensitization Inventory (CSI): some background and current trends. PMID- 29150263 TI - Reply to "Letter to Editor, in response to Narain et al." PMID- 29150264 TI - Letter to Editor, in response to Narain et al. PMID- 29150265 TI - Hypothesis: Watershed zones in the human eye are a key for understanding glaucomatous retinal damage. AB - The pathogenesis of glaucoma is complex which has led to numerous hypothesizes concerning the important factors creating this specific type of inner retinal degeneration namely apoptosis of retinal ganglion cells. We favor a primary vascular etiology and provide evidence that the pathogenesis of glaucoma should not be confined to changes exclusively at the optic nerve head but must include changes occurring in the peripheral retina with particular emphasis on the watershed zones of both the retina and choroid. This focus may help to sharpen ones awareness for early glaucoma treatment particularly in patients with minimal findings suggestive of glaucoma. PMID- 29150266 TI - Interleukin 35 and Hepatocyte Growth Factor; as a novel combined immune gene therapy for Multiple Sclerosis disease. AB - An autoimmune demyelination disease of the Central Nervous System, Multiple Sclerosis, is a chronic inflammation which mostly involves young adults. Suffering people face functional loss with a severe pain. Most current MS treatments are focused on the immune response suppression. Approved drugs suppress the inflammatory process, but factually, there is no definite cure for Multiple Sclerosis. Recently developed knowledge has demonstrated that gene and cell therapy as a hopeful approach in tissue regeneration. The authors propose a novel combined immune gene therapy for Multiple Sclerosis treatment using anti inflammatory and remyelination of Interleukine-35 and Hepatocyte Growth Factor properties, respectively. In this hypothesis Interleukine-35 and Hepatocyte Growth Factor introduce to Mesenchymal Stem Cells of EAE mouse model via an adenovirus based vector. It is expected that Interleukine-35 and Hepatocyte Growth Factor genes expressed from MSCs could effectively perform in immunotherapy of Multiple Sclerosis. PMID- 29150267 TI - Can memory exist outside of brain and be transferred? Historical review, issues & ways forward. AB - Learning and memory are among the executive functions attributed to intelligent forms of life. Unfortunately, there is a lack of clear understanding regarding the underlying mechanisms governing these functions. Most of the modern day scientists attribute these functions solely to brain. However, in the latter half of last century, a number of reports suggested existence of extra-cranial memory and potential of its transfer between animals. Some have linked this phenomenon to RNA while others believed that peptides were responsible. The terms like "educated RNA" and "scotophobin" were coined. This atypical work involving flatworms, yeast RNA and scotophobin was received with deep skepticism and ultimately disregarded. However, the recent reproduction of some of this earlier work by scientists at Tufts University has reignited the debate on the mechanisms of learning and memory. Keeping this in view, we believe it is high time to summarize this historical work and discuss the possibilities to delineate these atypical claims. The objective is to incite the present day researchers to explore this opportunity under the perspective of newer advancements in science. PMID- 29150268 TI - Adipose-derived stem cell sheet encapsulated construct of micro-porous decellularized cartilage debris and hydrogel for cartilage defect repair. AB - Challenges of repairing injuries and damage to the cartilage still remain in orthopedics. The characteristics of cartilage structure, especially avascular, make it a limited capacity of self-renewal. Articular cartilage defect or damage result from various causes will lead to degenerative osteoarthritis (OA). Surgical treatment and non-surgical treatment can temporarily alleviate symptoms to some extent but can't fundamentally restore the normal structure and function of cartilage, and therefore give rise to progressive degeneration. Autologous or allogeneic cartilage transplantation has been employed to the treatment of osteoarthritis for years. Nevertheless, the major deficiency of cartilage grafting is the inability and insufficiency to repair large cartilage defect. Implants are also unable to integrate with native tissue well. Adipose-derived stem cells (ASCs) can be easily isolated from subcutaneous fat tissues and harvest as intact cell sheets containing extracellular matrix (ECM), intercellular connect, ion channel, growth factor receptors, nexin and other important cell surface proteins by means of temperature-responsive culture dish (TCD). A cell sheet can provide a large amount of extracellular matrix, fibronectin, and cells contributing to the integration of cartilage. Decellularized extracellular matrix (DECM) of cartilage debris with excellent cell affinity and signal transduction is capable of driving cartilage homeostasis and regeneration. Appropriate decellularization process would remove cellular remnants of cartilage debris, keep the mechanical properties, and avoid the adverse immune response of allografts effectively. Micro-porous cartilage debris conduces to cell migration and angiogenesis. The cell-round shape of adipose derived stem cells cultured in the three-dimensional (3D) system provided by hydrogel is more susceptible to chondrogenic stimulation and prevents it from fibroblast-like phenotypic conversion. We hypothesize that adipose-derived stem cell sheet encapsulated construct of micro-porous decellularized cartilage debris and hydrogel can effectively promote regeneration of cartilage defect. The construct of decellularized cartilage debris and hydrogel provide a favorable microenvironment for stem cells. Adipose-derived stem cells sheet supply fibronectin, collagen, and cells contributing to integration and regeneration of cartilage restore. Moreover, the constructs can be shaped and fabricated according to the configuration of target defect, especially in osteoarthritis, which is promising for clinical application. PMID- 29150269 TI - Potential role of the Virchow Robin space in the pathogenesis of bacterial meningitis. AB - Meningitis is an infectious disease commonly arising from a bacterial etiology. The rapid progression of morbidity and mortality due to bacterial meningitis requires critical and imminent time-dependent clinical intervention. Although it is unambiguously clear that bacteria must infiltrate the cerebrospinal fluid, the sequence of events in the pathogenesis of bacterial meningitis has not been fully elucidated. Most reviews of the pathogenesis of bacterial meningitis do not specify the anatomical location of bacteria following BBB traversal. We propose an additional hypothesis focusing on the Virchow-Robin space (VRS). The VRS consists of a small, but identifiable perivascular space formed by a sheath of cells derived from the pia mater. The VRS has been described as an immunological space and possibly having a role in several neuropathological diseases. Solute exchange between cerebrospinal fluid and extracellular fluid occurs at the VRS, with subsequent drainage into the subarachnoid space. Because the VRS is continuous with the subpial space, a more direct route to the meninges is facilitated. The involvement of the VRS may have profound implications on the pathogenesis and therapeutic strategies: (1) nasopharyngeal colonization; (2) penetration into the blood stream after crossing the mucosal and epithelial membranes; (3) proliferation in the bloodstream; (4) extravasations through the endothelium of the post-capillary venules to the perivascular VRS; (5) migration from VRS to subpial space; (6) traversal through pia mater, entering the CSF in the subarachnoid space; (7) invasion of the meninges. The implication of the VRS in the pathogenesis of bacterial meningitis would be twofold. First, the VRS could provide an additional route of entry of bacteria into the brain. Second, the VRS could provide an area for bacterial proliferation, and thereby serve as a bacterial reservoir in relatively close proximity to the meninges. The clinical consequences of this hypothesis are: 1) clinical interpretation of laboratory findings, and 2) effective antibiotic delivery into the VRS. If the role of the VRS is established as part of bacterial meningitis pathogenesis, antibiotic pharmacokinetics and pharmacodynamics in the VRS need to be determined. This may result in developing novel antibiotic delivery and clinical strategies to improve morbidity and mortality. PMID- 29150270 TI - M. biceps femoris - A wolf in sheep's clothing: The downside of a lower limb injury prevention training. AB - Both, hamstring and ACL injuries are among the most typical injuries, particularly in change of direction and high speed running sports. They're also difficult to treat. Therefore, in the past few years, sports medicine practitioners and exercise scientists have mainly been focusing on the development and implementation of preventive programs in order to reduce the number of lower limb injuries, mainly by improving knee alignment. A number of studies have been able to prove the success of these training interventions, which are mainly addressing sensorimotor abilities and plyometric activities. The number of non-contact hamstring injuries has nevertheless been on the rise, particularly in sports like soccer and football. Therefore, the purpose of the following article is to introduce the hypothesis that the above-mentioned training interventions have a massive influence on the activation patterns on the targeted muscle group, and on the M. biceps femoris in particular. Muscle function and the resulting internal load are directly related to muscle architecture at the insertion. Training induced adaptations in hamstring activation patterns can thus lead to an increased injury susceptibility. In this case, a simulation model that directly relates to an acute deceleration maneuver provides valuable insights into the function of the biceps femoris muscle, especially when the rate of activity and the muscle geometry at the insertion area are taken into consideration. We conclude that there needs to be a greater individualization of prevention programs, especially in regards to anatomical requirements, in order to further reduce injury rates in elite sports. Moreover, it would also seem reasonable to apply a similar approach to aspects of chronic pain such as chronic non-specific low back pain. PMID- 29150271 TI - Xenohormesis in early life: New avenues of research to explore anti-aging strategies through the maternal diet. AB - Aging is a progressive internal physiological deterioration of the organism, leading to the occurrence of age-related lethal diseases. It has become a major societal challenge to understand the processes that drive aging and to develop rational pharmacological agents and dietary approaches to fight against age related deterioration and diseases. Interestingly, several lines of evidence highlight an influence of the developmental period on the risk of age-related diseases later in life. This field is known as the developmental origins of health and disease. Following this logic, studying the modification of maternal diet during early life may provide innovative new anti-aging approaches. Nutritional and psychological stresses during gestation are associated with poorer offspring health conditions in late life, and must be avoided during pregnancy. Besides these recommendations, very little has been published about the possible use of maternal diet to program offspring for healthy aging and an extended lifespan. Such health benefits may be provided by different foreign molecules, and particularly the phytochemicals produced by stressed plants, or xenohormetins. The xenohormesis hypothesis proposes that xenohormetins are signals of environmental change and trigger a beneficial adaptive response in individuals who consume them. No studies to date have investigated whether the consumption of stressed plants during pregnancy and lactation could provide chemical cues that impact early life programming and thus influence the future health and lifespan of offspring. Investigating the effect of xenohormesis in early life will involve adding edible plants exposed to different stressors (i.e. UV light, heat, ozone, etc.) to maternal diet and the exposure of offspring to this xenohormetin-enriched maternal diet at different periods of their prenatal life. The hypothesis proposed in this article is a potential tool to decipher the possible impact of xenohormesis during early life, and paving the way toward an innovative maternal diet that ensures the healthy aging of the progeny. PMID- 29150272 TI - Proposed biochemistry of Parkinson's and Alzheimer's diseases. AB - The formation of brain compounds linked to Parkinson's and Alzheimer's brain diseases are described. Metabolic mechanisms involved in the control of reacting biochemicals are detailed. Relationships are established between the biochemical reactions, biochemical control mechanisms and the onset of Parkinson's, Alzheimer's. Treatments based on these relationships are proposed. PMID- 29150273 TI - Recurrent and disseminated pityriasis versicolor: A novel clinical form consequent to Malassezia-host interaction? AB - Pityriasis versicolor is a superficial fungal infection caused by Malassezia spp. The aim of this study is to propose the definition of a new clinical entity: the recurrent and disseminated pityriasis versicolor (RDPV). All patients with RDPV were enrolled over an eight-month period. Clinical and epidemiological data were obtained, Malassezia (M.) species were isolated in cultures and identified by phenotypic and molecular characterization, skin biopsies were taken from active lesions, serum levels of immunoglobulin E were obtained and therapeutic schemes were evaluated. A total of 16 patients were included (11 male, 5 female). The most frequently isolated species were M. japonica (n = 3) and M. furfur (n = 3). This is the first study that isolates M. japonica in patients with pityriasis versicolor; interestingly, those were recalcitrant patients. Seven patients (43.8%) had no cure with any of the proposed treatments; among those, 5 (71.4%) had increased serum IgE levels. The most effective treatment was itraconazole 200 mg daily for 28 days. The RDPV has very different features from the classic form, including a poor response to treatment, and the isolation of different Malassezia species; therefore, we propose a hypothesis for the definition of a new clinical condition (RDPV), which could be a result of the interaction Malassezia-host. PMID- 29150274 TI - Neuroprotective potential of high-dose biotin. AB - A recent controlled trial has established that high-dose biotin supplementation - 100 mg, three times daily - has a stabilizing effect on progression of multiple sclerosis (MS). Although this effect has been attributed to an optimization of biotin's essential cofactor role in the brain, a case can be made that direct stimulation of soluble guanylate cyclase (sGC) by pharmacological concentrations of biotin plays a key role in this regard. The utility of high-dose biotin in MS might reflect an anti-inflammatory effect of cGMP on the cerebral microvasculature, as well on oligodendrocyte differentiation and on Schwann cell production of neurotrophic factors thought to have potential for managing MS. But biotin's ability to boost cGMP synthesis in the brain may have broader neuroprotective potential. In many types of neurons and neural cells, cGMP exerts neurotrophic-mimetic effects - entailing activation of the PI3K-Akt and Ras-ERK pathways - that promote neuron survival and plasticity. Hippocampal long term potentiation requires nitric oxide synthesis, which in turn promotes an activating phosphorylation of CREB via a pathway involving cGMP and protein kinase G (PKG). In Alzheimer's disease (AD), amyloid beta suppresses this mechanism by inhibiting sGC activity; agents which exert a countervailing effect by boosting cGMP levels tend to restore effective long-term potentiation in rodent models of AD. Moreover, NO/cGMP suppresses amyloid beta production within the brain by inhibiting expression of amyloid precursor protein and BACE1. In conjunction with cGMP's ability to oppose neuron apoptosis, these effects suggest that high-dose biotin might have potential for the prevention and management of AD. cGMP also promotes neurogenesis, and may lessen stroke risk by impeding atherogenesis and hypertrophic remodeling in the cerebral vasculature. The neuroprotective potential of high-dose biotin likely could be boosted by concurrent administration of brain-permeable phosphodiesterase-5 inhibitors. PMID- 29150275 TI - Ketogenic diet and anorexia nervosa. AB - This hypothesis suggest that starvation-induced ketosis, which leads to a fundamental biochemical change in the metabolic fuel supply of the brain, is uniquely anxiolytic and rewarding to patients prone to AN. Ketosis can easily be replicated by a unique diet marked by high fat, moderate protein, and very low carbohydrate. This diet, known as a ketogenic diet (KGD) mimics starvation, thus allowing the patient to experience the anxiolytic state of ketosis, and yet avoid the morbidity of starvation. PMID- 29150276 TI - Reactions between methylglyoxal and its scavengers in-vivo appear to be catalyzed enzymatically. AB - Methylglyoxal (MGO) is thought to be an important contributor to the development of diabetic complications. In this paper I propose that MGO, not detoxified by the glyoxalase system, is removed from circulation by MGO-scavengers. Furthermore, since intrinsic rates of reactions between MGO and its scavengers are low, I propose that, in-vivo, these reactions are catalyzed enzymatically. PMID- 29150277 TI - The VEGF paradox: Does diabetic retinopathy protect from age related macular degeneration? AB - Age-related macular disease (AMD) and diabetic retinopathy (DR) are prevalent diseases. Vascular endothelial growth factor (VEGF) related retinal neovascularization is a common feature in both. Consequently, both pathologies are treated with anti-VEGF therapy. We have previously reported a lower incidence of AMD in patients with DR compared to controls. The present study hypothesizes that DR in stages in which the concentration of intravitreal VEGF is increased, might have a protective role for both the onset and development of AMD. PMID- 29150278 TI - A hypothetical role for Notch signaling pathway in immunopathogenesis of leprosy. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae mainly affecting skin and peripheral nerves. Leprosy has a broad range of clinical manifestations that range from mild (tuberculoid leprosy) to severe (lepromatous leprosy) forms, and are highly dependent on the host's immune response. Among the immune response elements involved in the pathogenesis of leprosy are the Toll like receptors (TLRs), vitamin D receptor (VDR), natural killer cells (NK), and T cells. These innate and adaptive immune response elements may be related to the Notch signaling pathway, which is involved in immune cell growth, differentiation, and proliferation. We hypothesize that failure in Notch signaling in leprosy patients may be associated to: 1) compromising NK cell maturation, lysing of infected cells, and CD4+ Th1 differentiation. 2) VDR alterations and TLR polymorphisms may affect expression of Notch Delta-like ligands (DLL) in antigen presenting cells (APCs). 3) altered DLL expression by APCs could compromise CD4+ T cell differentiation towards the Th1 and Th17 effector phenotypes; and finally 4) expression of Notch Jagged ligands would induce CD4+ T cell differentiation towards Th2 effector phenotype and alternative activation of macrophages. Altogether, these signaling failures could favor proliferation of M. leprae in the host. Therefore, evidence of the proposed immunologic failures in leprosy patients would be essential for the better understanding of immunopathogenesis of this disease, and would ultimately enable detection of susceptible individuals, providing a valuable tool for prevention of this debilitating disease. PMID- 29150279 TI - Resolution of recurrent tonsillitis in a non-smoker who became a vaper. A case study and new hypothesis. AB - BACKGROUND: Evidence concerning the impact of vaping on respiratory infections remains contradictory. Cell and animal studies suggested that vaping may increase vulnerability to respiratory infections, but human data do not confirm this concern. CASE PRESENTATION: We present a case of a never-smoker who became a vaper and after a few months of e-cigarette use experienced a complete resolution of chronic tonsillitis and a marked improvement in tonsilloliths. CONCLUSIONS: As this is a never-smoker, the improvements cannot be attributed to smoking cessation. One possible explanation is that the improvement was due to antimicrobial properties of propylene glycol. The hypothesis could be tested by a trial of zero-nicotine e-cigarettes in patients with recurrent bacterial throat infection. PMID- 29150280 TI - NK cell recruitment and exercise: Potential immunotherapeutic role of shear stress and endothelial health. AB - Positive cancer patient outcomes, including increased time to recurrent events, have been associated with increased counts and function of natural killer (NK) cells. NK cell counts and function are elevated following acute exercise, and the generally accepted mechanism of increased recruitment suggests that binding of epinephrine releases NK cells from endothelial tissue via decreases in adhesion molecules following. I propose that blood flow-induced shear stress may also play a role in NK cell recruitment from the endothelium. Additionally, shear stress may play a role in improving NK cell function by decreasing oxidative stress. The relationship between shear stress and NK cell count and function can be tested by utilizing exercise and local heating with cuff inflation. If shear stress does play an important role, NK cell count and function will be improved in the non cuffed exercise group, but not the cuffed limb. This paper will explore the mechanisms potentially explaining exercise-induced improvements in NK cell count and function, and propose a model for investigating these mechanisms. This mechanistic insight could aid in providing a novel, safe, relatively inexpensive, and non-invasive target for immunotherapy in cancer patients. PMID- 29150281 TI - Antonio Ligabue: "the Madman". PMID- 29150282 TI - Artesunate-quercetin/luteolin dual drug nanofacilitated synergistic treatment for malaria: A plausible approach to overcome artemisinin combination therapy resistance. AB - Malaria is one of the major global health challenge with 300 million new cases annually. The best regimen for treating Plasmodium falciparum induced malaria is based on artemisinin and its derivatives which were prescribed as artemisinin combination therapy (ACT). These are highly effective drugs resulting in rapid clearance of parasites even in severe P. falciparum induced malaria patients. However, from the past few years parasites resistant to ACT's have begun to emerge in various parts of the world such as Cambodia and Greater Mekong Subregion. Currently, the ACT's resistance is comparatively low with clinical presentation of hindered artemisinin clearance and a small reduction in artemisinin sensitivity in cultured isolates. In order to counteract this, we hypothesize artesunate and quercetin/luteolin loaded self-nanoemulsifying drug delivery system (SNEDDS) which could provide an alternate drug combination to ACT induced P. falciparum resistance to treat malaria. The proposed formulation design can significantly help in reduction of dose and dosing frequency, which ultimately enhance patient compliance with decreased drug toxicity. We presume that if this hypothesis proves correct, it may become an additional novel tool and one of the plausible therapeutic options in treating malaria. PMID- 29150283 TI - Transcutaneous neuromuscular electrical stimulation may be beneficial in the treatment of premature ejaculation. AB - Approximately 20-30% of sexually active men suffer from Premature Ejaculation (PE), but the pathophysiology still remains unclear and the current available treatments for PE are unsatisfying. Considering the role of rhythmic bulbospongiosus and ischiocavernosus Muscles contractions on the ejaculatory reflex, we hypothesize that weakening this muscles via inhibiting it's contractions by Application of Neuromuscular Electrical Stimulation prior to the planned sexual activity, may have a beneficial effect in the treatment of PE. Using miniaturized perineal on-demand stimulation device, in a home setting during sexual intercourse may become the first line of treatment for PE. PMID- 29150284 TI - The 'Displacing Foods of Modern Commerce' Are the Primary and Proximate Cause of Age-Related Macular Degeneration: A Unifying Singular Hypothesis. AB - Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss and blindness in developed nations. AMD is anticipated to affect 196 million people worldwide, by 2020. However, the etiology of this disease remains unknown. Aging, genetic, and environmental influences have generally been implicated as major etiologic factors. We sought to examine the hypothesis that consumption of the 'displacing foods of modern commerce,' which equate to processed, nutrient-deficient and potentially toxic foods, may be the primary and proximate cause of AMD. To evaluate this hypothesis, we ran correlative AMD prevalence data against well-known proxy markers of processed food consumption, namely, sugar and vegetable oils, in 25 nations. In twenty-one nations, published studies provided AMD prevalence data and in four Pacific Island nations, practicing ophthalmologists in the regions completed retrospective chart analyses to estimate AMD prevalence in their respective regions. To estimate AMD prevalence historically, an extensive review of published papers and ophthalmic literature was completed. This review indicates that, between the years 1851 and 1930, AMD was a medical rarity worldwide, which then rose modestly in prevalence in the 1930s in the U.S. and U.K, finally elevating to epidemic proportions by 1975 in the U.S. Numerous developed nations have followed suit in recent decades. Simultaneously, between approximately 1880 and 2009, processed, nutrient deficient foods gradually supplanted and displaced whole, unprocessed, nutrient dense foods in developed nations, such that by 2009, 63 percent of the American diet was made up of nutrient-deficient foods in the form of refined white flour, added sugars, vegetable oils, and artificially created trans fats. The correlative data in 25 nations shows that increasing sugar and polyunsaturated vegetable oil consumption is invariably associated with new onset or rising prevalence of AMD, generally within about 30-40years of the beginning of increasing consumption of these proxy marker processed food components. The correlative data also demonstrates that, when consumption of sugar is moderate, but "harmful vegetable oil" consumption remains extremely low or absent, the prevalence of AMD remains rare. This study supports the hypothesis that the 'displacing foods of modern commerce,' which equate to processed, nutrient deficient, and potentially toxic foods, are the primary and proximate cause of AMD. This study also supports the conclusion that macular degeneration is entirely preventable, through ancestral dietary strategy and avoidance of processed foods. Finally, this research has implications for patients with existing early and intermediate stages of AMD. PMID- 29150285 TI - A review of prevalence studies of Autism Spectrum Disorder by latitude and solar irradiance impact. AB - Autism Spectrum Disorder (ASD) is a lifelong disability with no known cause or cure. Among the suggested etiologies, is Cannell's hypothesis of a deficiency in Vitamin D the main natural source of which is Solar Ultraviolet-B (UVB) radiation. The aim in this paper is to build on this hypothesis and explore the relationship of solar irradiance of which UVB is a component, by latitude with the prevalence rates of ASD. Twenty-five reports published between 2011 and 2016 using comparable diagnostic criteria were reviewed. The results suggest a tendency for the prevalence rates of ASD to be lowest in countries near the equator and for this rate to increase as the latitude increases. These findings provide some support not just for the Vitamin D hypothesis, but also for a new proposition that along with UVB radiation, the entire solar radiation spectrum which reaches the earth, may play a role in ASD. While these results are both novel and encouraging in terms of the potential efficacy of exposure to natural sunlight, further research is warranted before results can be considered definitive, and before the implications of the findings can be implemented clinically. PMID- 29150286 TI - Service animal as adjuvant treatment for restless leg syndrome. PMID- 29150287 TI - Anastasis and the ER stress response: Solving the paradox of the unfolded protein response in cancer. AB - In recent years, studies have suggested a novel pathway for cell survival, which faces scientific skepticism and interest in its concept of cell 'resurrection' - that is, the anastasis of cells at late-stage apoptosis. While biomarkers have been discovered, many of these are related to the endoplasmic reticulum (ER) stress response - acting also to promote cell survival in the presence of perturbation. The promises of anastasis, if accepted, will greatly impact translational medicine especially in the treatment of cancer, since apoptosis is generally irreversible in the late stages, and chemotherapy is performed to maximize tumor death and minimize off-target effects. As with all new concepts, there is a need to demarcate anastasis from a well-studied survival mechanism - the ER stress response - if the concept is to progress any further. In this article, it is proposed that anastasis and the ER stress response are one and the same mechanism, demarcated only by the presence of persistent stress. Further, anastasis solves the paradox of the unfolded protein response (UPR) in cancer by providing rationale in C/EBP homologous protein (CHOP)-induced tumor survival, such that CHOP-mediated apoptosis initiates genetic alterations in favor of its survival. After which, the cell regenerates through an enhanced ER stress response. Hence, anastatic cell recovery is the ER stress response post apoptosis. PMID- 29150288 TI - Letter to the editor: Hepatitis B vaccine non-response: A predictor of latent autoimmunity? PMID- 29150289 TI - The cause of multiple sclerosis is autoimmune attack of adenosyltransferase thereby limiting adenosylcobalamin production. AB - The pathogenesis of multiple sclerosis (MS) begins with an infection by a bacterium from the class of bacteria that produce and utilize adenosylcobalamin (AdoCbl) and possess an adenosyl transferase enzyme (ATR); these bacteria are the exogenous antigens that cause MS. Human ATR is homologous to bacterial ATR and B cells produce anti-ATR antibodies as an autoimmune response thereby reducing the concentration of ATR and thus limiting production of AdoCbl, one of the two bioactive forms of vitamin B12. The next step in MS pathogenesis is a period of subclinical AdoCbl deficiency over a period of many years resulting in production of odd-carbon-number fatty acids that are incorporated into myelin rendering it antigenic. The next step in MS pathogenesis is breach of the blood brain barrier thereby introducing leukocytes into the brain's blood supply resulting in T cell attack of antigenic myelin. All epidemiological clusters are regions wherein the major agricultural products are legumes that produce a high percentage of odd carbon-number fatty acids and contain symbiotic rhizobia type bacteria in root nodules and in the soil. This novel etiological hypothesis is called "multiple sclerosis due to adenosylcobalamin deficiency" (MS-AdoCbl). Creation of realistic animal models based on the MS-AdoCbl hypothesis is presented. Methods for testing predictions made by the MS-AdoCbl hypothesis are described. PMID- 29150290 TI - Premature atherosclerosis in premenopausal women: Does cytokine balance play a role? AB - Contributory risk factors to premature coronary artery disease (CAD) in premenopausal women are poorly understood and data on this subset of women is lacking. There is growing evidence that the process of inflammation is a part of the atherosclerotic process. Mechanistic insights from animal work suggest that the profile of circulating cytokines reflects both endothelial integrity and the presence of immune and progenitor cells. Significant differences in pro- and anti inflammatory cytokine concentrations between patients with and without CAD exist. Young women with obstructive CAD may experience differences in pro-inflammatory cytokines and the recruitment of reparative cells that secrete T-Helper (Th2 cytokines compared to women without CAD. Thus, cytokine balance may play a role in obstructive CAD in young women. In this pilot study we set out to identify an array of circulating inflammatory marker profiles which could be useful for the development of risk assessment and preventive strategies. We tested the hypothesis that an increase in serologic Th1 cytokines relative to Th2)/hematopoietic regulatory (HR) cytokines is related to premature coronary atherosclerosis in premenopausal women. PMID- 29150292 TI - Neonatal and regressive forms of autism: Diseases with similar symptoms but a different etiology. AB - Autistic Spectrum Disorder (ASD) can be a debilitating, life-long neurocognitive disease. ASD is caused by genetic and epigenetic factors and largely unknown and poorly understood environmental triggers. Signs and symptoms of ASD often appear in the first year of life while the disease strikes other infants who had previously been developing normally at around 2years of age. Ozonoff and her colleagues recently suggested that there are three different pathways or trajectories for the development of ASD in infants 6-24months of age. I hypothesize that pathway 1 is caused by in utero insult/injury, pathway 2 by obstetric complications at birth, and pathway 3 by environmental triggers of ASD affecting infants 0-3years of age. Faster progress can be made in elucidating the underlying causes of neonatal and regressive forms of ASD if the diseases are investigated separately, instead of being part of the same disorder. PMID- 29150291 TI - Ruxolitinib-conjugated gold nanoparticles for topical administration: An alternative for treating alopecia? AB - Alopecia is a dermatological condition for which Janus kinase (JAK) inhibitors have recently emerged as potential therapy options, but with limited practical use because of the systemic side effects. The topical use of Ruxolitinib in alopecia universalis has been demonstrated, but little is known about the pharmacodynamics and pharmacokinetics of this way of administration. Nanomedicine provides improved therapeutics. In the current paper we present preliminary data regarding the potential use of Ruxolitinib-conjugated gold nanoparticles (GNPs) in dermatological conditions, as GNPs have been proven to have a reduced absorption rate into the systemic blood flow for cutaneous administration. Internalization of the newly formed bioconjugate was assessed by electron microscopy and the functional effects of the drug were investigated by cell counting, flow cytometry and western blotting. Our data show that gold nanoparticles conjugated with Ruxolitinib inhibit the proliferation of fibroblasts by inhibiting JAK2 protein. Ruxolitinib carried by gold nanoparticles alters the proliferation of human fibroblasts, which is of great clinical importance as it can be readily administered on the skin with minimal risk of systemic side effects. PMID- 29150293 TI - A unique and promising combination of medications for the treatment of Alzheimer's disease. AB - At present there is no therapy for Alzheimer's Disease which completely stops the progressive dementia effecting late onset Alzheimer's Disease (AD) patients. It is felt that the main reason for this failure is that AD appears to be a disease caused by four major pathological processes. To date, efforts to develop treatments have addressed only one or another of these four etiologies. However, even a partially effective therapy against one cause allows the others, untreated, to continue their inexorable destruction of the neurons of the brain. It is suggested that a therapy is required which inhibits all four causes of the disease. Just such a therapy is proposed here with four specific drugs and a vitomer together in a combination treatment. The four major pathologic processes causing AD are: I. vascular hypoperfusion of the brain with associated mitochondrial dysfunction. II. destructive protein occlusions. III. uncontrolled oxidate stress and IV: pro-inflammatory immune processes secondary to microglial and astrocytic dysfunction in the brain. A detailed literature search has provided four drugs and a B6 vitomer which together provide an ideal combination to treat the four etiologies of AD. All four drugs are used clinically for various indications and would be used "off label" in combination to treat AD. The drugs have been used in preliminary studies to treat dementia with favorable indications in all of them inhibiting dementia with only modest side effects. In in vitro studies all five of the combination have been shown effective in inhibiting one or more of the four disease etiologies and together they are effective against all four. The four drugs are Trental, Nicergoline, Nilotinib, and Methylene blue. The vitamer is B6 pyridoxamine. The cumulative benefits of this combination should provide an effective treatment to completely stop the progressive dementia of AD, measured in 12-18months. The use of an endpoint of complete cessation of progressive dementia rather than the standard of a statistical determination of the slowing of progressive dementia allows the study to be conducted with a cohort of only 15 patients (no statistics and no placebo patients) as every AD patient would otherwise show progressive dementia without the effective treatment. PMID- 29150294 TI - Small groups, open doors: Fostering individual and group creativity within research communities. AB - While abundant publications attempt to analyze and understand what makes humans creative, much less attention is being paid to institutional conditions which may enhance or impede creative work. On the basis of evidence from Cambridge and AT&T's Bell Laboratories, and as a condensation of the Janelia Experiment, an institutional focus on "small groups" and "open doors" may foster individual and group creativity. The evidence suggests that small organizational units of up to seven scientists and open door concepts could nurture interactions within and between groups and enhance the critical mass for individual and group creativity. PMID- 29150295 TI - Paternal transmission of early life traumatization through epigenetics: Do fathers play a role? AB - Traumatizing events are known to have consequences for the victim which may lead to the development of several well-known mental disorders. Recent research has shown that traumatic events may affect not only the victims' lives, but also that of their progeny. It is generally accepted that this transmission of trauma occurs through parental behavior; however as has been recently discovered, the effects of trauma may also be inherited due to induced alterations in gene expression. These changes, so called epigenetic modifications, illuminate the interaction between genes and the environment. In contrast to mutations, epigenetic alterations do not change the DNA code, but rather modify the DNA structure, thus being capable of regulating gene expression and in turn making it possible for an individual to genetically respond to environmental changes. There are four possible epigenetic mechanisms: paramutation, DNA methylation, posttranslational modification of histones, and non-coding RNA. All of these mechanisms can be found both in somatic cells and in germ cells, leading to the putative transmission of alterations upon fertilization. To date, little is known regarding the epigenetic inheritance of trauma in humans. In this review, we elucidate the hypothesis that males may transmit biological correlates of traumatization through the germline to their offspring. This model of epigenetic inheritance has been supported by some evidence from animal studies. Overall, by considering findings on the epigenetic inheritance of traumatizing events in other mammals as well as findings on epigenetic transmission of acquired traits in humans, it should be possible through future research to confirm the transmission of traumatic effects in humans. By doing so, new possibilities of trauma treatment through modulation of epigenetic pathways might arise. PMID- 29150296 TI - Structural MRI-based measures of neuroplasticity in an extended amygdala network as a target for attention bias modification treatment outcome. AB - Increased attentional bias to threat has been identified as a causal mechanism in the development of anxiety. As such, attention bias modification (ABM) was conceived as a treatment option where anxiety is alleviated through a computerized cognitive training regimen that reduces an individual's attentional bias to threat. Although ABM appears to be a promising treatment option for anxiety, the mechanism of action by which the treatment is effective is unknown. We hypothesize that effective ABM treatment is associated with neuroplasticity related structural changes in an extended amygdala - prefrontal cortex network that can be detected with standard T1-weighted magnetic resonance imaging (MRI). Literature regarding [1] effects of brain damage on attention bias, [2] functional neuroimaging of attention bias, [3] structural neuroimaging of attention bias, and [4] functional neuroimaging of ABM training all support the role of this network as the underlying mechanism of attention bias behavior and neuroplasticity-related changes in attentional bias. Additionally, we provide proof of principle pilot data that ABM training reduces MRI measures of gray matter volume in the basal forebrain/extended amygdala and medial prefrontal cortex. Greater reduction in gray matter volume corresponds to greater reduction in attentional bias. In addition, level of pre-training bias appears to be a strong indicator of treatment outcome. In short, we provide converging evidence for the hypothesis that the mechanism underlying effective ABM training is reduced gray matter volume in an extended amygdala network. MRI-based measures of neuroplasticity in this network could be an important target outcome for the treatment of anxiety with ABM. PMID- 29150297 TI - Prolonged stretching of the ankle plantarflexors elicits muscle-tendon adaptations relevant to ankle gait kinetics in children with spastic cerebral palsy. AB - Tissue related ankle hyper-resistance has been reported to contribute to equinus gait in children with spastic cerebral palsy. Hence, ankle plantarflexor stretching programs have been developed in order to restore passive ankle dorsiflexion. Despite high quality evidence on the limited effects of stretching on passive joint mobility, further muscle-tendon adaptations have been reported which may impact gait performance. As such, children with spastic cerebral palsy subject to long-term manual static stretching achieved dorsiflexion gains through the reduction of muscle and fascicle strain whilst preserving tendon strain, and prolonged use of ankle-foot orthoses achieved similar dorsiflexion gains through increased tendon strain whilst preserving muscle and fascicle strain. The latter concurred with normalization of early stance plantarflexor moment yet reductions in push-off plantarflexor moment given the increase in tendon compliance. Therefore, similar limited gains in passive ankle joint mobility in response to stretching may be achieved either by preserving/restoring optimal muscle-tendon function, or at the expense of muscle-tendon function and thus contributing gait impairments. The largest increase in ankle passive joint mobility in children with SCP has been obtained through prolonged plantarflexor stretching through ankle casting combined with botulinum neurotoxin type A. However, to our knowledge, there are no published studies on muscle-tendinous adaptations to ankle casting combined with botulinum toxin type A and its effect on ankle joint gait kinetics. Therefore, we hypothesized that ankle casting elicits muscle tendon adaptations which concur with altered ankle joint kinetics during the stance phase of gait in children with SCP. More information is needed about the relationships between muscle structure and function, and the effect of specific interventions designed to alter muscle properties and associated functional outcomes in children with spastic cerebral palsy. PMID- 29150298 TI - Spontaneous osteoclastogenesis: Hypothesis for gender-unrelated osteoporosis screening and diagnosis. AB - Women are at greater risk of developing osteoporosis (OP). However, in the past few years it has become more widely recognized that OP is a significant problem also in men although OP is frequently under-diagnosed and, consequently, under treated in men. Most guidelines, screening and fracture risk evaluation methods as well as pharmacologic agents have been developed for women and then adapted to men. Bone Mineral Density (BMD) measurement by Dual X-ray Absorptiometry (DEXA) is reported as T score and the capability of DEXA to diagnose OP and predict fracture risk is still debated. In addition, the use of female T score references for the diagnosis of OP in men is incorrect for the following reasons: 1) DXA definition was developed just for Caucasian women, 2) men and women display structural differences in terms of bone growth, catabolism and size; 3) aging men have more periosteal apposition, less cortical porosity and endocortical resorption than aging women; and 4) T scores results, both in man and in women, can be affected by the presence of co-morbidities and it is known that in men OP is often secondary. From a biological point of view, OP is mainly due to increased osteoclastic activity leading to an imbalance in bone remodeling that favors resorption. However, some evidence suggests a more complex identity for osteoclasts (OCs) over and above their simple role of 'bone eaters'. In our laboratory, we observed spontaneous OCs formation in vitro in peripheral blood mononuclear cells (PBMC) from OP patients (n.12 female patients and n.6 male patients; DXA T score-2.5 or less). Some researchers demonstrated OCs gender differences in bone resorption activity of female-derived versus male-derived OCs. Indeed, further data from our laboratory also showed gender differences in number of spontaneously differentiated OCs and differentiation time. Therefore, we hypothesized that it would be possible to perform OP screening and diagnosis observing and measuring PBMCs different ability to differentiate spontaneously into OCs in male and female patients. If this hypothesis will be confirmed, it will result in an effective and efficient strategy for OP screening, diagnosis, monitoring and fracture prevention, targeting health service resources on selected patients. However, our hypothesis must be tested in a properly designed clinical trial and several key issues still need to be addressed. PMID- 29150299 TI - A new analytical model for the changes of vascular endothelial growth factor in ischemic diseases. AB - Vascular endothelial growth factors (VEGFs) play an important role in ischemic diseases. However, few studies focused on the generation and decay process of VEGF and no model yet can quantify different VEGF behavior caused in different area, like heart or brain. We compare the results across different groups and quantify the effectiveness of the selected training protocols. By applying the model to experimental data, the analytical model has been proposed to simulate the changes of vascular endothelial growth factor as a function of time and training protocols in ischemic diseases. The model is also used to study the generation and decay processes of VEGF and bFGF. A good quantitative correlation between the stroke area and parameters used in the model has been discovered. PMID- 29150300 TI - Permanent His bundle pacing to replace biventricular pacing for cardiac resynchronization therapy. AB - INTRODUCTION: Cardiac resynchronization therapy (CRT) or biventricular pacing (BIVP) has become a common procedure for the treatment of ventricular dyssynchrony in patients with heart failure, particularly in those with bundle branch block patterns (QRS durations >150ms) on the electrocardiogram (ECG). However, a large group of non-responders are made up of patients with dyssynchrony and QRS duration below 130ms. Recent studies have introduced permanent His bundle pacing as another method for achieving normalization of the QRS duration even in a majority of patients with right or left bundle branch block pattern on the ECG. HYPOTHESES: We hypothesize 1. Biventricular pacing, (BIVP) performed as the standard procedure for CRT is inherently abnormal, spatially, at the right and left ventricular apex, and temporally, in regard to the timing of normal activation of the interventricular conduction system. Corollary 1. Permanent, selective, His bundle pacing (PHBP) is the most physiological form of ventricular pacing which replicates the normal activation of the interventricular conduction system. Corollary 2. An appropriately powered, prospective, crossover trial comparing PHBP with BIVP will show that the former is associated with the same benefits in patients with heart failure and QRS durations >130ms and would improve, rather than worsen, outcomes in heart failure patients with QRS duration <130ms. We present experimental and clinical evidence in support of these hypotheses. PMID- 29150301 TI - Is subchondral bone cyst formation in non-load-bearing region of osteoarthritic knee a vascular problem? AB - Subchondral bone cyst is common in the progressive knee osteoarthritis yet its underlying mechanism remains unclear. In addition to the existing theories such as synovial fluid influx and mechanical contusion, we identified the potential link between vascular pathology and osteoarthritic bone pathologies including cystic lesion formation, particularly in the non-load-bearing region. This new hypothesis for SBC formation in non-load-bearing region for knee, which cannot be explained by the existing theories, will provide us a new angle to understand the pathomechanism and pathophysiology of subchondral bone disturbance in osteoarthritis in addition to the classical biomechanical overloading theories. It might guide us to develop a novel diagnostic and therapeutic approach to treat progressive osteoarthritis via targeting vascular pathology. PMID- 29150302 TI - Skin advanced glycation content reflects vaginal tissue glycation level in relation to pregnancy. AB - A few studies have revealed that the advanced glycation content of the vaginal wall in pelvic organ prolapse tissues is elevated. This elevation makes advanced glycation a significant association with the disease. Early detection of vaginal wall glycation could therefore be relevant in the prevention and management of pelvic organ prolapse. A vaginal wall biopsy to detect this would be ideal, but is invasive. Therefore the use of a more accessible organ to access, such as skin, would be beneficial. Our previous independent study suggests that conditions such as pregnancy, can induce a change in the vaginal tissues' glycation content. The aim of this study was to assess whether the skin glycation undergoes similar changes as observed in vaginal tissue glycation in the same subjects in order to prove the hypothesis that skin advanced glycation content can predict vaginal tissue glycation. A rat model was used. The vaginal tissues from non-pregnant and E15-E18 pregnant rats and skin tissues from the same rats were taken for the measurement of advanced glycation content. The glycation marker, pentosidine, was quantified by a high performance liquid chromatography. Our results demonstrated that glycation content in vaginal wall tissues from pregnant rats was lower than the tissues from non-pregnant ones, and a strong positive association between skin and vaginal wall pentosidine level was observed. We conclude that skin pentosidine is reflective of vaginal wall pentosidine. Skin glycation may therefore be a potential tool in the prediction and management of pelvic organ prolapse. PMID- 29150303 TI - Oxytocin intranasal administration as a new hope for hypogonadotropic hypogonadism patients. AB - Hypogonadotropic hypogonadism (HH) is a form of hypogonadism which also known as secondary or central hypogonadism. Congenital HH can occur due to defect in gonadotropin releasing hormone (GnRH) neurons, upstream regulators of GnRH neurons or pituitary gonadotropic cells. Testosterone or gonadotropins therapy are widely used to treat HH patients, however both have undesirable effects and GnRH treatment for HH patients is time and cost consuming. Direct delivery of therapeutics to the brain via the nasal route is located in the center of attention during the last decade and trial application of intranasal oxytocin as a method of enhancing social interactions are reported. It has been delineated that oxytocin stimulates GnRH release from the rat hypothalamic explants and intranasal applied oxytocin up-regulates GnRH expression in the male rat hypothalamus. Therefore application of intranasal oxytocin might be a new strategy to cure HH patients. PMID- 29150304 TI - Are the estrogenic hormonal effects of environmental toxins affecting small intestinal bacterial and microfilaria overgrowth? AB - The important role of microfilaria (worms) in human and animal disease remains an area of key disagreement between the naturopathic and allopathic physicians. While microfilaria infections are rampart in undeveloped countries, they rarely rise to identification as a cause of disease in Western countries. New research studies in the diagnosis and treatment of SIBO (Small Intestinal Bacterial Overgrowth) and (IBD) Inflammatory Bowel Diseases of ulcerative colitis, Crohn's Disease and microcytic colitis may make both sides equally correct. A study of rifaximin failures in SIBO positive individuals finds biomarkers of decreased Free Androgen Index (FAI), high incidence of autoimmune disease and elevated Sex Hormone Binding Globulin (SHBG). The author hypothesizes that the underlying pathophysiology is increased exposure to Endocrine Disrupting Chemicals (EDCs) which hormonally act as xeno-estrogens. These xeno-estrogens increase the host production of SHBG, reduce pituitary stimulation of androgen product and result in a shift to estrogen dominance. Estrogen dominance is associated with autoimmune diseases and catabolic states. Treatment with a mixture of anabolic steroids that raises the FAI and lowers SHBG results in dramatic improvement in the signs and symptoms and recovery of the vast percentage of severe SIBO sufferers the author has treated. Similar results have been seen in severe pre surgical cases of IBD whom fail all pharmaceutical interventions. Based on the recent recognition of the biological importance of Wolbachia in the occurrence of major diseases in the underdeveloped countries such as onchocerciasis, and the sexual nature of Wolbachia's role in helminths reproduction, the author hypothesizes that the EDCs are shifting the host's hormonal milieu in a more estrogenic direction and increasing reproduction of helminths changing the gastrointestinal microbiota. Present allopathic treatment of onchocerciasis utilizes albendazole and avermectin as therapy against the microfilaria larvae and doxycycline as bactericidal for Wolbachia. The allopathic treatments are unacceptable for pregnancy and children. Both naturopathic and allopathic treatments share a common focus on the suppression of the underlying bacterium Wolbachia infestation. The author hypothesizes that treatment of these two very different gastrointestinal diseases involves first establishing a normal, anabolic hormonal milieu and concurrently controlling an underlying yet unrecognized microfilaria overgrowth through naturopathic and allopathic treatments prescribed to the host. A case report of one such critically ill individual is noted. A thorough case controlled observation of symptoms matched with biological culture colony count and concentration of microfilaria in disease before and after the aforementioned anabolic treatment may answer the hypothesis. PMID- 29150305 TI - Calf hemodialysate hypothesis: Nutritive value plus placebo effect. PMID- 29150306 TI - A proposal for a noninvasive monitoring of sympathetic nerve activity in patients with takotsubo syndrome. AB - The pathophysiology of takotsubo syndrome (TTS) is still elusive; many hypotheses of its cause have been proposed with a heightened activity of the peripheral autonomic sympathetic nervous system (PASNS) via local norepinephrine release, and direct cardiomyocyte toxicity mediated by blood-borne catecholamines, being among the most currently entertained. Monitoring of PASNS during hospitalization will provide a metric which could be of immense value in unraveling of the pathophysiology and aiding in the management of the patients with TTS by predicting in-hospital complications, long-term outcome, and its recurrence. Recent work with noninvasive monitoring of skin sympathetic nerve activity (SKNA), via conventional electrodes used for the recording of the electrocardiogram have shown that the filtered signals >500 Hz originate in the cervical and stellate ganglia, which also innervate the heart, and thus they provide an estimate of stellate ganglion nerve activity. Such information may prove invaluable for the management of patients with TTS. PMID- 29150307 TI - Approaching Retention within the ABCD Study. AB - Retention efforts are critical to maintain relationships with research participants over time. This is especially important for the Adolescent Brain Cognitive Development (ABCD) study, where families are asked to stay engaged with the study throughout the course of 10 years. This high-degree of involvement is essential to longitudinally track child and adolescent development. At a minimum, we will connect with families every 6 months by telephone, and every year in person, with closer contact with the youth directly as they transition into adolescence. Differential retention, when related to non-random issues pertaining to demographic or risk features, can negatively impact the generalizability of study outcomes. Thus, to ensure high rates of retention for all participants, the ABCD study employs a number of efforts to support youth and families. This overview details the framework and concrete steps for retention. PMID- 29150308 TI - Pulmonary edema ex vacuo after drainage of pneumothorax. PMID- 29150309 TI - Erratum in: "Care ethics. A new bioethical approach to humanize the ICU" [Med Intensiva. 2016;40(8):511-513]. PMID- 29150310 TI - Zika virus in French Polynesia 2013-14: anatomy of a completed outbreak. AB - The Zika virus crisis exemplified the risk associated with emerging pathogens and was a reminder that preparedness for the worst-case scenario, although challenging, is needed. Herein, we review all data reported during the unexpected emergence of Zika virus in French Polynesia in late 2013. We focus on the new findings reported during this outbreak, especially the first description of severe neurological complications in adults and the retrospective description of CNS malformations in neonates, the isolation of Zika virus in semen, the potential for blood-transfusion transmission, mother-to-child transmission, and the development of new diagnostic assays. We describe the effect of this outbreak on health systems, the implementation of vector-borne control strategies, and the line of communication used to alert the international community of the new risk associated with Zika virus. This outbreak highlighted the need for careful monitoring of all unexpected events that occur during an emergence, to implement surveillance and research programmes in parallel to management of cases, and to be prepared to the worst-case scenario. PMID- 29150311 TI - Functional connectivity of the vigilant-attention network in children and adolescents with attention-deficit/hyperactivity disorder. AB - The ability to maintain attention to simple tasks (i.e., vigilant attention, VA) is often impaired in attention-deficit/hyperactivity disorder (ADHD), but the underlying pathophysiological mechanisms at the brain network level are not clear yet. We therefore investigated ADHD-related differences in resting-state functional connectivity within a meta-analytically defined brain network of 14 distinct regions subserving VA (comprising 91 connections in total), as well as the association of connectivity with markers of behavioural dysfunction in 17 children (age range: 9-14 years) with a diagnosis of ADHD and 21 age-matched neurotypical controls. Our analyses revealed selective, rather than global, differences in the intrinsic coupling between nodes of the VA-related brain network in children with ADHD, relative to controls. In particular, ADHD patients showed substantially diminished intrinsic coupling for 7 connections and increased coupling for 4 connections, with many differences involving connectivity with the anterior insula. Moreover, connectivity strength of several aberrant connections was found to be associated with core aspects of ADHD symptomatology, such as poor attention, difficulties with social functioning, and impaired cognitive control, attesting to the behavioural relevance of specific connectivity differences observed in the resting state. PMID- 29150312 TI - The effect of a physical activity intervention on preschoolers' fundamental motor skills - A cluster RCT. AB - OBJECTIVES: To assess the effect of a physical activity intervention delivered in the childcare centres (CC), with or without a parent-driven home physical activity component, on children's fundamental motor skills (FMS). DESIGN: Six month 3-arm cluster randomized controlled trial. METHODS: Preschoolers were recruited from 18 licensed CC. CC were randomly assigned to a typical curriculum comparison group (COM), childcare intervention alone (CC), or childcare intervention with parental component (CC+HOME). FMS was measured with the Test of Gross Motor Development-2. Linear mixed models were performed at the level of the individual while accounting for clustering. RESULTS: Raw locomotor skills score increased significantly in the CC group (mean difference=2.5 units, 95% Confidence Intervals, CI, 1.0-4.1, p<0.001) and the CC+HOME group (mean difference=2.4 units, 95% CI, 0.8-4.0, p<0.001) compared to the COM group. No significant (p>0.05) between group differences were observed in the raw object control skills, sum of raw scores, or gross motor quotient. No significant sex differences were found in any of the measured outcomes. CONCLUSIONS: A physical activity intervention delivered in childcare with or without parents' involvement was effective in increasing locomotor skills in preschoolers. PMID- 29150314 TI - Connecting qualitative research on exercise and environment to public health agendas requires an equity lens. AB - In this commentary, I respond to the special section in Health & Place (vol. 46) on "Exercise and environment: new qualitative work to link popular practice and public health" edited by Hitchings and Latham. I argue that if qualitative research is to effectively inform public health policy and practice it cannot ignore the fact that physical activity participation is inequitable. Without building in a critical equity lens, geographers risk perpetuating the "inequality paradox"-that is, the potential for population health interventions to inadvertently exacerbate health inequalities. Related to this, I challenge the editors' assumption that geographers' critiques of public health approaches to physical activity and our applied efforts to foster physical activity participation are mutually exclusive endeavours. Rather, I argue they are mutually necessary within a social justice agenda. Finally, I close this commentary by offering ways forward for qualitative research on exercise and environment to connect with public health agendas and inform interventions. PMID- 29150313 TI - Safety practices, perceptions, and behaviors in radiation oncology: A national survey of radiation therapists. AB - PURPOSE: Radiation therapy is complex and demands high vigilance and precise coordination. Radiation therapists (RTTs) directly deliver radiation and are often the first to discover an error. Yet, few studies have examined the practices of RTTs regarding patient safety. We conducted a national survey to explore the perspectives of RTTs related to quality and safety. METHODS AND MATERIALS: In 2016, an electronic survey was sent to a random sample of 1500 RTTs in the United States. The survey assessed department safety, error reporting, safety knowledge, and culture. Questions were multiple choice or recorded on a Likert scale. Results were summarized using descriptive statistics and analyzed using multivariate logistic regression. RESULTS: A total of 702 RTTs from 49 states (47% response rate) completed the survey. Respondents represented a broad distribution across practice settings. Most RTTs rated department patient safety as excellent (61%) or very good (32%), especially if they had an incident learning system (ILS) (odds ratio, 2.0). Only 21% reported using an ILS despite 58% reporting an accessible ILS in their department. RTTs felt errors were most likely to occur with longer shifts and poor multidisciplinary communication; 40% reported that burnout and anxiety negatively affected their ability to deliver care. Workplace bullying was also reported among 17%. Overall, there was interest (62%) in improving knowledge in patient safety. CONCLUSIONS: Although most RTTs reported excellent safety cultures within their facilities, overall, there was limited access to and utilization of ILSs by RTTs. Workplace issues identified may also represent barriers to delivering quality care. RTTs were also interested in additional resources regarding quality and safety. These results will further enhance safety initiatives and inform future innovative educational efforts in radiation oncology. PMID- 29150315 TI - Surgical options for osteoporotic vertebral compression fractures complicated with spinal deformity and neurologic deficit. AB - INTRODUCTION: This paper describes surgical options for Osteoporotic vertebral compression fracture (OVCF) with acute flexible or chronic rigid kyphosis, and pseudarthrosis complicated with pain and neurologic deficit. METHODS: This study has two components. a) A prospective clinical study of surgical treatment of 31 patients (age: 69+/-11 years) with either acute flexible or progressive pseudarthrotic kyphosis manifested with severe pain or neurological deficit between 2010 and 2014. Eleven patients exhibited neurocompression (Frankel B, C, D). Surgery consisted in indirect reduction, kyphoplasty, and short posterior instrumentation in 28 patients and multilevel instrumentation in three. b) The second component involved a literature search of OVCF complicated with acute or painful chronic deformities and neurologic deficit, managed with open surgical approach. RESULTS: Indirect reduction, kyphoplasty and short posterior stabilization can restore satisfactory anatomic alignment and neurological deficit. Multilevel instrumentation was used for rigid long kyphosis. Complications were related to a) screw pull out and junctional kyphosis (4 patients) one of the patients also developed anterior migration of cement, b) cement leakage (4 patients). L5 radiculopathy occurred in one patient. The others remained asymptomatic. The literature review concluded that corpectomy with anterior, posterior or combined instrumentations is indicated for burst fractures, or rigid kyphosis with neurocompression. Prompt decompression with anatomical alignment may restore paraplegia. Complications were germane to osteoporotic bone predisposing to hardware loosening or cut out and dislodgement of instrumentation. DISCUSSION: Neurologic deficit associated with fractures or progressive pseudarthrotic kyphosis effectively may respond to indirect postural reduction, kyphoplasty and posterior percutaneous short segment transpedicle instrumentation. For burst fractures and rigid chronic kyphosis corpectomy reconstructed with cages and anterior, or posterior or combined instrumentations can restore and maintain normal anatomy. The following guidelines for optimal surgical instrumentation have been established: To prevent screw loosening and junctional kyphosis the instrumentation should not end within the kyphotic segment. Screws for anterior instrumentation should penetrate the contralateral cortex. Multiple site of fixation or combined anterior and posterior instrumentations dissipate stresses at any one site. Augmentation of transpedicle screw fixation with cement is a sound technical principle. Cement should inserted in a doughy state with minimal pressure to prevent cement complications. PMID- 29150316 TI - Low-threshold extended-release naltrexone for high utilizers of public services with severe alcohol use disorder: A pilot study. AB - Extended-release naltrexone (XRNTX) is an effective treatment for alcohol use disorder (AUD). We sought to evaluate the feasibility, acceptability, and preliminary effectiveness and cost-effectiveness of XRNTX delivered as a stand alone service to persons with severe AUD who are high utilizers of multiple urgent and emergency medical services (HUMS). Of 15 HUMS persons with severe AUD selected based on chart review, 11 agreed to participate. Participants received a mean of 4.5 injections (range 2-7). Modest benefits from XRNTX were observed in terms of patients' Urge-to-Drink Score and the costs of emergency medical services utilized. Though limited by a small sample size, costs including client utilization and study related expenses during the post-enrollment period were less than client utilization costs in the pre-enrollment period. We also observed non-significant improvements in the number of drinking days, but no change in quality of life as measured by the EQ-5D. Eighty-eight percent of participants perceived XRNTX as helping with their drinking. Findings need to be replicated in a larger study, however if replicated, the cost savings could be substantial. PMID- 29150317 TI - AMP-Activated Protein Kinase Regulation of the NLRP3 Inflammasome during Aging. AB - The NLRP3 inflammasome has recently emerged as an unexpected marker of stress and metabolic risk and has also been implicated in the development of major aging related diseases such as gout, type 2 diabetes, obesity, cancer, and neurodegenerative and cardiovascular disorders. Several pathways regulating the NLRP3 inflammasome are currently being studied, but how the NLRP3 inflammasome is regulated remains unknown. AMP-activated protein kinase (AMPK), a central regulator of multiple metabolic pathways involved in the pathophysiology of aging and age-related diseases, has emerged as an important integrator of signals controlling inflammation including the inflammasome. In this Opinion article, we show that several AMPK-dependent pathways regulate NLRP3 inflammasome activation during aging, suggesting NLRP3 as a potential pharmacological target in age related diseases. PMID- 29150318 TI - Postsurgical Management of Differentiated Thyroid Cancer in China. AB - Postsurgical management of differentiated thyroid cancer in China has gained a great success in the last twenty years, but there are still gaps to be filled. Here, we briefly review the current status and also extend an outlook for future development. PMID- 29150319 TI - Analytical design of an industrial two-term controller for optimal regulatory control of open-loop unstable processes under operational constraints. AB - This paper proposes a novel optimization-based approach for the design of an industrial two-term proportional-integral (PI) controller for the optimal regulatory control of unstable processes subjected to three common operational constraints related to the process variable, manipulated variable and its rate of change. To derive analytical design relations, the constrained optimal control problem in the time domain was transformed into an unconstrained optimization problem in a new parameter space via an effective parameterization. The resulting optimal PI controller has been verified to yield optimal performance and stability of an open-loop unstable first-order process under operational constraints. The proposed analytical design method explicitly takes into account the operational constraints in the controller design stage and also provides useful insights into the optimal controller design. Practical procedures for designing optimal PI parameters and a feasible constraint set exclusive of complex optimization steps are also proposed. The proposed controller was compared with several other PI controllers to illustrate its performance. The robustness of the proposed controller against plant-model mismatch has also been investigated. PMID- 29150320 TI - Fractional observer to estimate periodical forces. AB - In the present work we propose a fractional state observer with constant gain to estimate the periodical force exerted on a mechanical system by measuring only its displacement. The state observer is designed from both the Fourier series that approximates the periodical force and the equations of the damped harmonic oscillator that represents the behavior of the system. Specifically, the reconstruction of the force is carried out from the estimates of the series coefficients, which in fact are part of the dynamical system that composes the observer. Adams-Bashforth-Moulton method is used to compute the fractional derivatives of the observer in the Liouville-Caputo sense. Experiments based on real data are presented to show the advantages of using a fractional observer in the reconstruction of forces. PMID- 29150321 TI - A description of the sequence of long-term behavior of autogenous boneblock in maxillary sinus augmentation in sheep: Additional morphologic and histomorphometric evidence. AB - OBJECTIVE: To document the behavior of autogenous bone block in sinus lift and surgical consequences. STUDY DESIGN: Twelve sinus lifts with autogenous hip bone blocks and simultaneous insertion of two implants in 6 adult female sheep. Polychrome sequential labelling and histologic and histomorphometric evaluation after 6, 16, and 26 weeks. RESULTS: Augmentation material in the apical third was almost fully resorbed after 26 weeks (P = .00388). Percentage of bone tissue increased 0.5-1.0 mm from the implant in crestal region (15.3 +/- 7.5% to 16.2 +/ 10.1%), whereas it vanished in the apical region from 16 to 26 weeks (4.2 +/- 10.4% to 0%) (P = .363). CONCLUSIONS: Autogenous bone block leaves an apical thin but functionally crucial layer covering implants in a form follows function way. Denial of animal-originated biomaterials and prion diseases remain a rarely discussed issue. The use of an implant length-adapted autogenous transplant with osseoinductive advantages should be taken into consideration. PMID- 29150322 TI - Sex ratios of the tick Ixodes arboricola are strongly female-biased, but there are no indications of sex-distorting bacteria. AB - Studies on sex ratio are of fundamental importance for understanding the biology of populations and biological control of pests and pathogens. In most Ixodes tick species, only females feed in the adult stage and, hence, contribute to pathogen transmission. The tree-hole tick Ixodes arboricola infests cavity-nesting birds and has limited dispersal possibilities. It plays an important role in the maintenance of zoonotic disease cycles. Here, we quantified the sex ratio of 718 adult I. arboricola ticks obtained from a laboratory stock at nine distinct periods (cohorts) from 2008 to 2015. In addition, we screened 93 specimens, collected from four study sites in 2011 and 2012, for the presence of six maternally inherited bacterial parasites known to manipulate arthropod sex ratios. We found significantly female-biased sex ratios in seven out of nine cohorts. There were no infections with members of the Wolbachia, Arsenophonus or Cardinium bacterial genera, whereas 96.8% of the screened ticks were infected with Rickettsia vini, 22.6% with Rickettsiella sp., and 14.0% with Spiroplasma ixodetis. Male and female I. arboricola were found equally infected. Our results suggest skewed sex ratios in I. arboricola are not caused by these bacterial infections, although there may be other, untested candidates driving sex ratios. Alternatively, female-biased sex ratios may be an adaptation in females to high local densities and low dispersal, where the production of daughters has a selective advantage because a few sons can fertilise all daughters. PMID- 29150323 TI - Screening of patient blood samples for babesiosis using enzymatic assays. AB - Human babesiosis is an emerging tick-borne disease in the United States and Europe. Transmitted by Ixodes ticks, the causative agent Babesia microti is an intraerythrocytic parasite that causes mild to deadly disease. Transmission of B. microti can also occur by transfusion of infected blood and blood products resulting in transfusion-transmitted babesiosis (TTB), which carries a high risk of fatality. To effectively manage this rise in B. microti infections, better screening tools are needed, which require minimal manipulation of the samples before testing. To this end, we tested two enzymatic assays, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), for efficacy in diagnosis of babesiosis. The results show that AST and ALT activity is significantly higher in the plasma of B. microti-infected patients. Moreover, statistical analysis revealed that these assays have high sensitivity and positive predictive values, which highlights their usefulness as diagnostics for babesiosis. These standardized enzymatic assays can be used to perform high throughput, large-scale screens of blood and blood products before they are certified safe for transfusion. PMID- 29150324 TI - Venous thromboembolism in Portuguese hospitals: Where we stand and how we can improve. PMID- 29150325 TI - Ilex paraguariensis: Potential antioxidant on aluminium toxicity, in an experimental model of Alzheimer's disease. AB - Ilex paraguariensis, yerba mate is a native plant from the southern region of Brazil. Studies showed that yerba mate has an antioxidant potential, which could help to reduce the risk of developing neurodegenerative diseases, as Alzheimer's Disease (AD). It's known that I. paraguariensis grows in acid soils with aluminium (Al), which is bioavailable in these soils. Al has a neurotoxic potential related with the progression of neurological disorders. This study aim was to evaluate the potential of I. paraguariensis in the etiology of AD using strains of Caenorhabditis elegans and the concentration of Al and antioxidants in the yerba mate extract. The results of the I. paraguariensis infusions made at 65 degrees C and at 75 degrees C show that there was no significant difference between both temperatures when preparing the tea infusion in relation to the presence of Al, methylxanthines, phenolic compounds and flavonoids. Additionally, in the case of Al, there was no difference between the extracts prepared at both temperatures. The behavioral parameters of C. elegans were altered after a long term exposure to both factors: I. paraguariensis extract and Al. Through the antioxidant levels results along with the Al content on the Acetylcholinesterase (AChE) activity it is possible to observe that the acute and chronic exposure to Al and I. paraguariensis leaves extract are very similar to wild-type worms. Moreover, we can observe that the results in both the transgenic strains long term exposed to I. paraguariensis leaves extract and to the Al concentrations presented an increase in the AChE activity. PMID- 29150326 TI - Concomitant mitral valve procedures in patients undergoing implantation of continuous-flow left ventricular assist devices: An INTERMACS database analysis. AB - BACKGROUND: Management of existing mitral valve (MV) disease in patients undergoing left ventricular assist device (LVAD) implantation remains controversial. METHODS: Among continuous-flow LVAD patients with moderate to severe mitral regurgitation entered into the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database between April 2008 and March 2014 (n = 4,930), outcomes were compared between patients who underwent MV repair (MVr, n = 252), MV replacement (MVR, n = 11) and no MV procedure (no MVP, n = 4,667). Impact on survival was analyzed by stratified actuarial and hazard function multivariable methodology. Post-operative functional capacity and quality of life were assessed. RESULTS: Patients who underwent MVPs had higher pre-operative pulmonary vascular resistance (3.6 +/- 2.9 vs 2.9 +/- 2.6 Wood units; p = 0.0006) and higher pulmonary artery systolic pressures (55.1 +/- 13.8 vs 51.5 +/- 14.0 mm Hg; p = 0.0003). Two-year survival was 76% for patients with concomitant MVr, 57% for those with MVR and 71% for those with no MVP (p = 0.15). By multivariable analysis, neither MVr nor MVR affected early or late survival. Although improvements in post-operative functional status as evaluated by 6 minute walk distances were comparable across groups, visual analog score assessments of quality of life suggested a benefit of concomitant MVPs at 1-year post-implant (79.00 +/- 1.73 vs 74.45 +/- 0.51; p = 0.03), with fewer re admissions observed for MVP patients (p < 0.0001). CONCLUSIONS: Concomitant MVPs are not associated with increased survival overall. However, MVPs are associated with benefits in terms of reduced hospital re-admission and improved quality of life in select patients. PMID- 29150327 TI - Diagnostic accuracy of point shear wave elastography in the detection of portal hypertension in pediatric patients. AB - PURPOSE: The purpose of this study was to determine the usefulness of point shear wave elastography (p-SWE) of the liver and spleen for the detection of portal hypertension in pediatric patients. MATERIALS AND METHODS: The study consisted of 38 healthy children and 56 pediatric patients with biopsy-proven liver disease who underwent splenic and liver p-SWE. The diagnostic performance of p-SWE in detecting clinically significant portal hypertension was assessed using receiver operating characteristic (ROC) curves. RESULTS: Reliable measurements of splenic and liver stiffness with p-SWE were obtained in 76/94 (81%) and 80/94 patients (85%), respectively. The splenic stiffness was highest in the portal hypertension group (P<0.01). At ROC curve analysis, the area under the curve in the detection of portal hypertension was lower for splenic p-SWE than for liver p-SWE (0.906 vs. 0.746; P=0.0239). The cut-off value of splenic p-SWE for portal hypertension was 3.14m/s, with a specificity of 98.59% and a sensitivity of 68.18%. The cut off value of liver p-SWE for portal hypertension was 2.09m/s, with a specificity of 80.28% and a sensitivity of 77.27%. CONCLUSION: In pediatric patients, p-SWE is a reliable method for detecting portal hypertension. However, splenic p-SWE is less accurate than liver p-SWE for the diagnosis of portal hypertension. PMID- 29150328 TI - Randomized phase 2 therapeutic equivalence study of abiraterone acetate fine particle formulation vs. originator abiraterone acetate in patients with metastatic castration-resistant prostate cancer: The STAAR study. AB - BACKGROUND: This multicenter, randomized, open-label, active-controlled study evaluated therapeutic equivalence, steady-state pharmacokinetics, and safety of a novel abiraterone acetate fine particle formulation (AAFP) 500mg plus methylprednisolone vs. the originator AA (OAA) 1000mg plus prednisone in men with metastatic castrate-resistant prostate cancer (mCRPC). The primary endpoint was a comparison of average of serum testosterone levels on treatment days 9 and 10 between groups. METHODS: Men with progressive mCRPC, receiving gonadotropin releasing hormone agonist or antagonist therapy, and with a serum testosterone level of <50ng/dl were randomized 1:1 to either AAFP 500mg daily plus 4mg methylprednisolone orally twice daily (BID), or OAA 1000mg daily plus 5mg prednisone BID for 84 days. Serum testosterone, serum prostate-specific antigen (PSA), steady-state (trough) abiraterone pharmacokinetics, and safety were evaluated. RESULTS: Fifty-three patients were enrolled (n = 24, AAFP; n = 29, OAA). Mean age was 75.1 years and 54.7% had Gleason>7. Over 90% of patients in each group achieved absolute testosterone levels of <=1ng/dl during the study. The averaged absolute testosterone levels <=0.1ng/dl were achieved in 25% of AAFP treated patients and 17% of OAA-treated patients. A PSA-50 response was observed in>65% of patients in both groups on days 28, 56, and 84 (P = NS, all timepoints). Days 9 and 10 averaged rounded-up least squares (LS) mean (SE) serum testosterone levels were comparable (1.05ng/dl [0.04], AAFP; 1.02ng/dl [0.03], OAA; P = 0.4703 for LS mean difference). The geometric mean ratio between groups was 1.021 (90% CI: 0.965-1.081); the 90% CI fell within 80.0% to 125.0% equivalence limits. The LS mean differences in abiraterone trough plasma concentrations were not statistically significant at any visit. Adverse event frequency was comparable between arms (75.0%, AAFP; 82.8%, OAA). Musculoskeletal events were more common among OAA-treated patients (37.9% vs. 12.5%). CONCLUSION: Therapeutic equivalence between AAFP 500mg daily and OAA 1000mg daily based on serum testosterone levels was confirmed in mCRPC patients. Both agents led to similar PSA-50 response rates. Abiraterone trough levels were similar between treatments. No new safety concerns were observed. PMID- 29150329 TI - Interleukin-18 in cardiomyocyte: A novel therapeutic target for attenuating cardiac remodeling. PMID- 29150331 TI - Anti-amyloidogenic and anti-apoptotic effect of alpha-bisabolol against Abeta induced neurotoxicity in PC12 cells. AB - Alzheimer's disease (AD) is a life-threatening neurodegenerative disorder leading to dementia, with a progressive decline in memory and other thinking skills of elderly populace. Of the multiple etiological factors of AD, the accumulation of senile plaques (SPs) particularly as Abeta oligomers correlates with the relentlessness cognitive impairment in AD patients and play a vital role in AD pathology. Since natural essential oil constituents have successfully served as a source of drugs for AD treatment, the present study aims at the in vitro and in silico investigation of anti-amyloidogenic potential and anti-apoptotic property of the alpha-bisabolol against Abeta25-35 induced neurotoxicity in PC12 cells. Treatment with alpha-bisabolol (5 MUg/ml) after 24 h incubation with Abeta25-35 reduced the aggregation propensity of Abeta (p < 0.05), as observed by the reduced fluorescence intensity of thioflavin T (ThT). Confocal laser scanning microscopy (CLSM) analysis, Transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopic analysis and molecular dynamics simulation study also substantiated the Abeta fibril formation hampering ability of alpha-bisabolol even after 9 days of incubations. The results of antiaggregation and disaggregation assay showed an increase in fluorescence intensity in Abeta treated group, whereas the co-treatment of alpha-bisabolol (5 MUg/ml) with Abeta25-35 showed an extensive decrease in the fluorescence intensity, which suggests that alpha-bisabolol prevents the oligomers formation as well as disaggregates the matured fibrils. FACS analysis of the cells revealed the competency of alpha-bisabolol in rescuing the PC12 cells from Abeta induced neurotoxicity and chromosomal damage and clonogenic assay proved its ability to retain the colony survival of cells. Overall, the anti-amyloidogenic and anti apoptotic effect of alpha-bisabolol proves that it could be used as an excellent therapeutic drug to combat AD. PMID- 29150330 TI - The structural requirements of histone deacetylase inhibitors: C4-modified SAHA analogs display dual HDAC6/HDAC8 selectivity. AB - Histone deacetylase (HDAC) enzymes govern the post-translational acetylation state of lysine residues on protein substrates, leading to regulatory changes in cell function. Due to their role in cancers, HDAC proteins have emerged as promising targets for cancer treatment. Four HDAC inhibitors have been approved as anti-cancer therapeutics, including SAHA (Suberoylanilide hydroxamic acid, Vorinostat, Zolinza). SAHA is a nonselective HDAC inhibitor that targets most of the eleven HDAC isoforms. The nonselectivity of SAHA might account for its clinical side effects, but certainly limits its use as a chemical tool to study cancer-related HDAC cell biology. Herein, the nonselective HDAC inhibitor SAHA was modified at the C4 position of the linker to explore activity and selectivity. Several C4-modified SAHA analogs exhibited dual HDAC6/8 selectivity. Interestingly, (R)-C4-benzyl SAHA displayed 520- to 1300-fold selectivity for HDAC6 and HDAC8 over HDAC1, 2, and 3, with IC50 values of 48 and 27 nM with HDAC6 and 8, respectively. In cellulo testing of the inhibitors was consistent with the observed in vitro selectivity. Docking studies provided a structural rationale for selectivity. The C4-SAHA analogs represent useful chemical tools to understand the role of HDAC6 and HDAC8 in cancer biology and exciting lead compounds for targeting of both HDAC6 and HDAC8 in various cancers. PMID- 29150333 TI - Design, synthesis and evaluation of novel dihydrostilbene derivatives as potential anti-melanogenic skin-protecting agents. AB - The stems of Dendrobium orchids (Orchidaceae), also known as Shi Hu, have been used for medicinal purposes for centuries in oriental countries. In fact, the health benefits of Shi Hu have been evidenced by its modern pharmacological actions on conquering oxidative stress in pathological conditions. From the extracts of two commonly used Dendrobium species, we obtained discernible amounts of stilbenoids, explicitly trans-resveratrol (1) and dihydro-resveratrol (2), which are prototypical antioxidants. When applied to cultured melanocytes, these stilbenoids, dihydro-resveratrol (2) in particular, significantly reduced melanin formation via inhibiting tyrosinase activity and expression of tyrosinase-related proteins. By utilizing dihydro-resveratrol (2) as the basic structural unit, we synthesized 11 novel dihydrostilbene derivatives (3-13) in good yields and purity, with manipulative steps. In addition to their anti-melanogenic activity, some of the novel derivatives are indeed potential antioxidants as they quenched intracellular oxidative radicals in a manner more efficient than Trolox, a water soluble analogue of vitamin E, and thus premeditated beneficial to skin protection. PMID- 29150332 TI - Organic arsenicals target thioredoxin reductase followed by oxidative stress and mitochondrial dysfunction resulting in apoptosis. AB - Considering the vital role of cellular redox state, more and more researches focus on the design of drugs targeting thioredoxin reductase (TrxR), an important enzyme in maintaining the balance of cellular redox. Here two organic arsenicals, 2-(((4-(1,3,2-dithiarsinan-2-yl) phenyl) imino) methyl) phenol (PIM-PAO-PDT) and N-(4-(1,3,2-dithiarsinan-2-yl) phenyl)-2-hydroxybenzamide (PAM-PAO-PDT), bearing the S-As-S chemical scaffold and different linking groups have been synthesized, and both of them show the better inhibitory activity and selectivity towards HL 60 cells. Importantly, it is illustrated that they can target TrxR selectively and inhibit its activity via the disturbance for Cys83 and Cys88 located in conserved active sites. Afterwards, the cells suffer from the burst of ROS, consumption of antioxidants and high sensitivity for oxidants, which further damage the mitochondria leading to dysfunction including the collapse of membrane potential, ATP level decline, mitochondrial membrane swelling, MPTP opening, Ca2+ and cytochrome c release. Then the mitochondria-dependent apoptosis is triggered by PIM-PAO-PDT and PAM-PAO-PDT, which can also be deterred in the presence of NAC, DTT or LA. Although the organic arsenicals can suppress TrxR activity, the following oxidative stress and mitochondrial dysfunction are the main causes for apoptosis. PMID- 29150334 TI - A routinely used protein staining dye acts as an inhibitor of wild type and mutant alpha-synuclein aggregation and modulator of neurotoxicity. AB - Inhibition of amyloid formation along with modulation of toxicity employing small molecules is emerging as a potential therapeutic approach for protein misfolding disorders which includes Parkinson's disease, Alzheimer's disease and Multiple System Atrophy etc. Countless current interventional strategies for treating alpha-synucleinopathies consider using peptidic and non-peptidic inhibitors for arresting fibrillisation, disrupting existing fibrils and reducing associated toxicity. One group of molecules less exploited in this regard are triphenylmethane dyes. Herein we tested the inhibitory effect of two routinely used protein staining dyes viz Coomassie Brilliant blue G (CBBG) and Coomassie Brilliant blue R (CBBR) employing several biophysical and cell based methods. Our results showed that both the dyes not only efficiently inhibit fibrillisation but also disrupt existing fibrils. Nonetheless, only CBBR prevented the appearance of A11 epitopes which are marker of toxicity. Moreover, CBBR was also able to stall fibrillisation of A53T mutant alpha-synuclein and reduce associated neurotoxicity. This study thus reports the potential of CBBR as a therapeutic molecule. PMID- 29150335 TI - Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors. AB - Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability. PMID- 29150336 TI - Urinary tract infections in neonates with unexplained pathological indirect hyperbilirubinemia: Prevalence and significance. AB - BACKGROUND: It is controversial to test for urinary tract infection (UTI) in patients with unexplained indirect hyperbilirubinemia in the first 2 weeks of life. We aimed to study the prevalence and significance of UTIs in such neonates who were requiring phototherapy. METHODS: Subjects were 2- to 14-day-old neonates with indirect bilirubin levels above phototherapy limit with no other abnormality in their bilirubinaemia-related etiologic workup. UTI was diagnosed by 2 consecutive positive cultures obtained by catheterisation, documenting growth of >10,000 colonies of the same microorganism with consistent antibiograms. The UTI (+) patients were evaluated by renal ultrasonography (US), and some were followed up for possible recurrent UTI. RESULTS: 262 neonates were included in the study. UTI prevalence was 12.2%, and bacteraemia was 6.2% among UTI (+) patients. The two most common pathogens (81.2%) were Escherichiacoli and Klebsiella. pneumonia. All UTI (+) patients had undergone US, revealing 12.5% pelvicaliectasis, other 12.5% increased renal parenchymal echogenicity, 3.1% concurrent pelvicaliectasis and increased renal parenchymal echogenicity. 53.1% of UTI (+) patients had undergone follow-up, after which 23.5% recurrent UTI were found at the end of a mean of 52 months. CONCLUSION: We suggest that the neonates with unexplained pathological jaundice should be tested for possible UTI. Consequently, all newborns with UTI shall be evaluated by the urinary US and followed up for recurrent UTI. PMID- 29150337 TI - Increased human Chorionic Gonadotropin levels five years before diagnosis of an ovarian dysgerminoma. PMID- 29150339 TI - Hair concentration of trace elements and growth in homeless children aged <6years: Results from the ENFAMS study. AB - BACKGROUND: Growth is an important indicator of health in early childhood. This is a critical developmental period, during which a number of factors, including exposure to metals, might play a role in later physical and metabolic functions. OBJECTIVE: To study the association between exposure to arsenic (As), cadmium (Cd), mercury (Hg), lead (Pb) and selenium (Se), and physical growth of children from homeless families aged <6years. METHODS: This study was based on data of the cross-sectional survey (ENFAMS), which was conducted by the Observatoire du Samu Social on a random sample of homeless sheltered families in the Paris region during winter 2013. Families with children under 6years (N=324) were interviewed in 17 languages using face-to-face questionnaires. A nurse took anthropometric measures and collected hair samples where As, Cd, Hg, Pb and Se levels were measured. We calculated weight-for-age Z-score (WAZ), height-for-age Z-score (HAZ) and BMI-for-age Z-score (BMIZ) of children, using the 2006 WHO Child Growth Standards as a reference. Associations between ln-transformed metal exposures and growth outcomes were tested by multivariable linear regression models with adjustment for potential confounders (including maternal anthropometrical and socio-demographical characteristics, gestational age, child birthweight, breastfeeding, food insecurity of the child). Due to missing data (1.6% to 14.2% depending on the variables), we used multiple imputation by chained equations. RESULTS: A strong positive correlation was found between Pb and Cd levels (r=0.65; p<0.001). Positive associations between Se level and HAZ (beta=0.61; p=0.05) and between Cd and BMIZ (beta=0.21; p=0.03) and negative associations between As and HAZ (beta=-0.18; p=0.05) were no more significant after multiple imputation. A weak negative trend was observed between Cd and HAZ (beta=-0.14; p=0.14), while positive trends were found between Se and both WAZ (beta=0.55; p=0.10) and HAZ (beta=0.51; p=0.06) after multiple imputation. CONCLUSION: Overall, our results found no strong association between exposure to metals and physical growth of homeless children but we observed some trends that were consistent with previous studies. More research is required studying these associations longitudinally, along with higher sample sizes, for better understanding the sources of exposure in homeless population and the potential effects on growth. PMID- 29150338 TI - Impacts of prenatal triclosan exposure on fetal reproductive hormones and its potential mechanism. AB - BACKGROUND: Triclosan (TCS) has been widely detected in pregnant women. The reproductive endocrine-disrupting effects of TCS have been observed in humans and animals. Little is known about the potential impact of prenatal TCS exposure on fetal reproductive development as well as its potential mechanism. OBJECTIVES: We investigated the potential effect of prenatal TCS exposure on fetal reproductive hormones in cord blood and its potential mechanism in relation to placental steroidogenic enzymes. METHODS: Urinary TCS was detected among 537 healthy pregnant women from a prospective cohort in China. Four reproductive hormones in cord blood, namely E2 (n=430), T (n=424), LH (n=428) and FSH (n=373), and three steroidogenic enzymes in placenta, namely P450arom (n=233), 3beta-HSD (n=227) and 17beta-HSD (n=222), were measured. RESULTS: Prenatal TCS exposure was associated with increased testosterone concentrations in cord blood in a dose-dependent manner. Infants with prenatal TCS levels >0.6MUg/L had, on average, a 0.23ng/mL (95% CI: 0.05, 0.45, p=0.02) higher testosterone concentrations in cord blood compared to those with prenatal TCS levels <0.1MUg/L. Of note, prenatal TCS exposure was associated with increased testosterone and decreased E2 concentrations in cord blood among male infants. Adverse associations were found between the prenatal TCS exposure and concentrations of three placental steroidogenic enzymes. 3beta-HSD and P450arom demonstrated mediating effects in the association between prenatal TCS exposure and testosterone concentrations in cord blood. CONCLUSIONS: Our findings suggested potential impacts of prenatal TCS exposure on reproductive hormones in cord blood mediated by steroidogenic enzymes, and male infants were more vulnerable. PMID- 29150340 TI - Placental transfer and levels of mercury, selenium, vitamin E, and docosahexaenoic acid in maternal and umbilical cord blood. AB - Methylmercury (MeHg) is a neurotoxicant known to affect the developing fetal brain as a sensitive target organ. As most mercury (Hg) in blood is MeHg, total mercury (THg) levels in blood are used to estimate the body burden of MeHg. The nutrients selenium (Se), vitamin E, and docosahexaenoic acid (DHA) are protective against MeHg toxicity. We compared maternal and cord blood concentrations of biochemical substances, THg and Se, vitamin E, DHA, and other elements, fatty acids, and amino acids in 54 Japanese mother-newborn pairs to elucidate the fetal risk of MeHg toxicity. Cord blood had higher hematocrit and amino acid values and lower concentrations of lipid components, including fatty acids compared with maternal blood. THg levels in cord blood (7.26ng/g) were 1.9 times higher than levels in maternal blood (3.79ng/g). Se concentrations in cord blood (176ng/g) were slightly higher than concentrations in maternal blood (156ng/g). Levels of vitamin E (0.31mg/dL) and DHA (58.8MUg/mL) in cord blood were much lower than levels in maternal blood (1.38mg/dL and 147MUg/mL, respectively). The ratios of Se/THg, vitamin E/THg, and DHA/THg in cord blood were lower than ratios in maternal blood. These results suggest that fetuses are at higher risk to MeHg toxicity. PMID- 29150341 TI - Increased prevalence of clinical and subclinical atherosclerosis in patients with damaging mutations in ABCA1 or APOA1. AB - BACKGROUND: A low level of high-density lipoprotein cholesterol (HDL-C) is a common clinical scenario and poses challenges for management. Many patients with low HDL-C harbor a damaging mutation in ABCA1 or APOA1, but the clinical implications of genetic testing for these mutations are unclear. OBJECTIVE: The purpose of this study was to investigate the prevalence of clinical or subclinical atherosclerosis among patients with low HDL-C due to a mutation in ABCA1 or APOA1, compared with patients with low HDL-C without such a mutation. METHODS: We performed targeted next-generation sequencing to identify mutations in ABCA1 and APOA1 in 72 patients with HDL-C levels below the 10th percentile. We examined the prevalence of clinical atherosclerosis and subclinical atherosclerosis in these patients. We also measured cholesterol efflux capacity (CEC) in plasma. RESULTS: We identified a known disease-causing or likely pathogenic variant in the ABCA1 or APOA1 genes in 22% of patients with low HDL-C. Eighty-three percent of patients with a damaging mutation in ABCA1 or APOA1 had evidence of atherosclerosis compared with 38.6% with low HDL-C without such a mutation (P = .04). Patients with damaging mutations in ABCA1 or APOA1 had lower CEC compared with patients without a mutation (25.9% vs 30.1%). CONCLUSION: The presence of a damaging mutation in ABCA1 or APOA1 confers an increased risk of atherosclerosis relative to patients without such a mutation at a comparable level of HDL cholesterol, possibly because of a reduction in CEC. PMID- 29150342 TI - Does sex influence biceps brachii muscle stiffness? PMID- 29150343 TI - Response to "Does sex influence biceps brachii muscle stiffness?" PMID- 29150344 TI - Biomechanical mechanism of lateral trunk lean gait for knee osteoarthritis patients. AB - The biomechanical mechanism of lateral trunk lean gait employed to reduce external knee adduction moment (KAM) for knee osteoarthritis (OA) patients is not well known. This mechanism may relate to the center of mass (COM) motion. Moreover, lateral trunk lean gait may affect motor control of the COM displacement. Uncontrolled manifold (UCM) analysis is an evaluation index used to understand motor control and variability of the motor task. Here we aimed to clarify the biomechanical mechanism to reduce KAM during lateral trunk lean gait and how motor variability controls the COM displacement. Twenty knee OA patients walked under two conditions: normal and lateral trunk lean gait conditions. UCM analysis was performed with respect to the COM displacement in the frontal plane. We also determined how the variability is structured with regards to the COM displacement as a performance variable. The peak KAM under lateral trunk lean gait was lower than that under normal gait. The reduced peak KAM observed was accompanied by medially shifted knee joint center, shortened distance of the center of pressure to knee joint center, and shortened distance of the knee ground reaction force lever arm during the stance phase. Knee OA patients with lateral trunk lean gait could maintain kinematic synergy by utilizing greater segmental configuration variance to the performance variable. However, the COM displacement variability of lateral trunk lean gait was larger than that of normal gait. Our findings may provide clinical insights to effectively evaluate and prescribe gait modification training for knee OA patients. PMID- 29150345 TI - Hydrostatic pressure as epigenetic modulator in chondrocyte cultures: A study on miRNA-155, miRNA-181a and miRNA-223 expression levels. AB - Mechanical stimuli and hydrostatic pressure (HP) play an important role in the regulation of chondrocytes metabolism. Growing evidence demonstrated the ability of mechanical loading to modulate the expression of microRNA (miRNA) involved in chondrocytes homeostasis and in the pathogenesis of osteoarthritis (OA). The expression of miR-155, miR-181a and miR-223 in normal and OA chondrocyte cultures, and their potential modifications following exposure to three hours of a cyclic HP (1-5 MPa, frequency 0.25 Hz) were investigated. Also evaluated the expression of Chuk, regulator of the NF-kB pathway activation, which is a target gene of miR-223, was evaluated. Chondrocytes were collected immediately after pressurization (T0), and following 12, 24, and 48 h. Total RNA was extracted, reverse transcribed and used for real-time PCR. At basal condition, a significant increase of miR-155 and miR-181a was observed in OA in comparison to normal cells; on the contrary, no differences in miR-223 and Chuk expression levels were detected between normal and OA chondrocytes. miR-155 and miR-181a resulted significantly downregulated immediately after pressurization (T0) in OA cells. The pressure effect on miR-155 and miR-181a levels was maintained over time. No modifications of miR-223 were observed in response to HP, while Chuk levels resulted significantly reduced at T0 and after 12 h. Pressurization did not cause any modifications in normal cells. In conclusion, HP was able to modulate the expression of miRNA associated to OA pathogenesis. The preliminary results about Chuk response to pressure raised interest in its involvement in the possible HP induced NF-kB pathway modulation. PMID- 29150346 TI - Aerodynamic study of time-trial helmets in cycling racing using CFD analysis. AB - The aerodynamic drag of three different time-trial cycling helmets was analyzed numerically for two different cyclist head positions. Computational Fluid Dynamics (CFD) methods were used to investigate the detailed airflow patterns around the cyclist for a constant velocity of 15 m/s without wind. The CFD simulations have focused on the aerodynamic drag effects in terms of wall shear stress maps and pressure coefficient distributions on the cyclist/helmet system. For a given head position, the helmet shape, by itself, obtained a weak effect on a cyclist's aerodynamic performance (<1.5%). However, by varying head position, a cyclist significantly influences aerodynamic performance; the maximum difference between both positions being about 6.4%. CFD results have also shown that both helmet shape and head position significantly influence drag forces, pressure and wall shear stress distributions on the whole cyclist's body due to the change in the near-wake behavior and in location of corresponding separation and attachment areas around the cyclist. PMID- 29150347 TI - [Perineal groove: Case report and review of the literature]. AB - Perineal groove is a rare anoperineal congenital malformation, usually occurring in girls, unknown to many pediatricians. We report the case of a 17-day-old girl admitted for urinary infection, who presented a wet sulcus with mucous membrane, extending from the vaginal fourchette to the anterior border of the anus. The diagnosis of perineal groove was clinically confirmed, after elimination of misdiagnosis such as infection or trauma. This benign malformation tends to be self-epithelialized in the 1st year of life, and no surgical treatment is recommended, except for cosmetic reasons or for recurrent infections. This diagnosis must be known so as to avoid unnecessary explorations and anxiogenic misdiagnosis. PMID- 29150348 TI - De novo head and neck cancer arising in solid organ transplantation recipients: The Asan Medical Center experience. AB - OBJECTIVE: De novo cancers of head and neck area in solid organ transplantation recipients show standardized incidence ratio (SIR) of 3.8. Immunosuppression following transplantation is suggested to play as a crucial factor in pathogenesis of secondary malignancy. Prognosis of head and neck cancer arising in solid organ transplantation recipients is proven to have poor prognosis. The incidence, risk, prognosis, and survival of de novo malignancy of head and neck area in solid organ transplantation recipients in single-tertiary medical center followed up for 20 years. METHODS: A retrospective medical record review of the patients who received solid organ transplantation in Asan Medical Center from 1997 to 2016 was conducted. Patients confirmed as de novo malignancy in the head and neck area after organ transplantation were included, and presented as in the case-series format. Patients with previous history of head and neck malignancy, irradiation history of head and neck area, cutaneous malignant lesion, hematopoietic malignant lesion, malignancy of thyroid and parathyroid gland and metastatic lesions newly developed in head and neck area were excluded. The incidence of head and neck malignancy in South Korea were reviewed from the National Cancer Information Center of South Korea. For the statistical analysis, standardized incidence ratio (SIR) was obtained with 95% confidence interval. RESULTS: Solid organ transplantation recipients show 20 times higher incidence of de novo cancer of head and neck area compared to general population. Of 13 de novo head and neck malignancy arising after solid organ transplantation, 2 (15.4%) patients were unable to withstand definitive management due to poor general condition. 2 (15.4%) patients had loco-regional recurrence, 1 (7.7%) patient with distant metastasis, and 3 (23.1%) patients died of cancer progression. CONCLUSION: Immunosuppression following solid organ transplantation gives a twenty-fold increased risk for the development of de novo head and neck cancer. A more precise and frequent checkup on head and area should be planned, suggesting a multi-disciplinary approach in combination with organ transplantation team. PMID- 29150350 TI - Vitamin D supplementation for women during pregnancy. PMID- 29150349 TI - Frontal sinus revision rate after nasal polyposis surgery including frontal recess clearance and middle turbinectomy: A long-term analysis. AB - OBJECTIVE: To determine the frontal sinus revision rate after nasal polyposis (NP) surgery including frontal recess clearance (FRC) and middle turbinectomy (MT), to search for predictive factors and to analyse surgical management. METHODS: Longitudinal analysis of 153 patients who consecutively underwent bilateral sphenoethmoidectomy with FRC and MT for NP with a minimum follow-up of 7 years. Decision of revision surgery was made in case of medically refractory chronic frontal sinusitis or frontal mucocele. Univariate and multivariate analysis incorporating clinical and radiological variables were performed. RESULTS: The frontal sinus revision rate was 6.5% (10/153). The mean time between the initial procedure and revision surgery was 3 years, 10 months. Osteitis around the frontal sinus outflow tract (FSOT) was associated with a higher risk of frontal sinus revision surgery (p=0.01). Asthma and aspirin intolerance did not increase the risk, as well as frontal sinus ostium diameter or residual frontoethmoid cells. Among revised patients, 60% required multiple procedures and 70% required frontal sinus ostium enlargement. CONCLUSIONS: Our long-term study reports that NP surgery including FRC and MT is associated with a low frontal sinus revision rate (6.5%). Patients developing osteitis around the FSOT have a higher risk of frontal sinus revision surgery. As mucosal damage can lead to osteitis, FSOT mucosa should be preserved during initial NP surgery. However, as multiple procedures are common among NP patients requiring frontal sinus revision, frontal sinus ostium enlargement should be considered during first revision in the hope of reducing the need of further revisions. PMID- 29150351 TI - Combined Hormonal Contraceptive Use and Risk of Breast Cancer in a Population of Women With a Family History. AB - BACKGROUND: We estimated the association between combined hormonal contraceptive (CHC) use and breast cancer (BC) incidence in a well-selected population of women at familial risk of BC at the Modena Family Cancer Clinic. MATERIALS AND METHODS: We performed a retrospective cohort study by reviewing the data from 2527 women (4.5% BRCA mutation carriers, 72.2% high risk, and 23.3% intermediate risk using the Modena criteria and the Tyrer-Cuzick model). RESULTS: We did not find any specific feature of breast cancer (infiltration, hormone receptor and HER2 status, onset before age 35 years, multiple diagnoses) in the CHC users (P > .05). Only 2.0% of women used a preparation with >= 50 MUg of ethinylestradiol (EE). The use of CHCs was not associated with an increased risk of breast cancer (cumulative hazard: never used, 0.17; CHC users, 0.20; P = .998), regardless of the duration of use (cumulative hazard: never used, 0.17, used < 5 years, 0.20; used 5-10 years, 0.14; used > 10 years, 0.25; P = .414). This was confirmed for the different risk groups when interacted in a Cox proportional hazard regression model. The EE dose did not influence the risk of BC (cumulative hazard, 2.37; 95% confidence interval, 0.53-10.1; never used, 0.18; EE < 20 MUg used, 0.04; EE >= 20 MUg used, 0.16; P = .259). The types of progestins used might influence the risk, with some, such as gestodene (P = .028) and cyproterone acetate (P = .031), associated with an even greater reduced risk. CONCLUSIONS: CHC use does not increase the risk of BC in a population of women with a family history, encouraging CHC use in this group of women. PMID- 29150353 TI - Barrier dysfunction in the nasal allergy. AB - Epithelial cells form the first physiological barrier against invasion by pathogens and the infiltration of allergens. Tight junctions (TJ), a cell-cell junctional complex located on the apical side of epithelial cells, have a critical role in the maintenance of epithelial barrier function. Impaired TJ structures are observed in patients with asthma, atopic dermatitis and nasal allergy; therefore, the dysfunction of epithelial barriers might be involved in the initiation or progression of allergic diseases. Protease-containing allergens and environmental pollutants enhance paracellular transport in epithelial cells through disruption of epithelial barrier function. This suggests that the disruption of TJ leads to the promotion of allergen delivery into the subepithelia, resulting in the progression of allergic diseases. Thus, protection of the epithelial barrier function might prevent or inhibit the development or exacerbation of allergic diseases. Recently, we reported that diesel exhaust particles (DEP), the main component of particulate patter 2.5, exacerbated allergic rhinitis (AR) in a mouse model through TJ disruption. In addition, we revealed that the oxidative stress-mediated pathway is involved in the effects caused by DEP and that nasal treatment with a reactive oxygen species (ROS) scavenger suppressed DEP-induced TJ disruption and exacerbation of AR. In this review, we focus on the relationship between TJ disruption and allergic disease. Furthermore, we discuss our recent findings regarding TJ disruption and the exacerbation of AR. PMID- 29150354 TI - Editorial: Integration of omics into MRA. PMID- 29150352 TI - Dysregulation of mRNA translation and energy metabolism in cancer. AB - Dysregulated mRNA translation and aberrant energy metabolism are frequent in cancer. Considering that mRNA translation is an energy demanding process, cancer cells must produce sufficient ATP to meet energy demand of hyperactive translational machinery. In recent years, the mammalian/mechanistic target of rapamycin (mTOR) emerged as a central regulatory node which coordinates energy consumption by the translation apparatus and ATP production in mitochondria. Aberrant mTOR signaling underpins the vast majority of cancers whereby increased mTOR activity is thought to be a major determinant of both malignant translatomes and metabolomes. Nonetheless, the role of mTOR and other related signaling nodes (e.g. AMPK) in orchestrating protein synthesis and cancer energetics is only recently being unraveled. In this review, we discuss recent findings that provide insights into the molecular underpinnings of coordination of translational and metabolic programs of cancer cells, and potential strategies to translate these findings into clinical treatments. PMID- 29150355 TI - Contribution of nitric oxide synthase from coagulase-negative staphylococci to the development of red myoglobin derivatives. AB - As part of the microbial community of meat or as starter cultures, coagulase negative staphylococci (CNS) serve several essential technological purposes in meat products, such as color development through the reduction of nitrate to nitrite. As the safety of nitrite as an additive has been questioned, we explored the potential of CNS to develop red myoglobin derivatives such as oxymyoglobin and nitrosomyoglobin. Nitrosoheme was extracted to evaluate NO production. This production could be due to a nitric oxide synthase (NOS) activity. In all CNS strains, a nos gene was identified. The NOS sequences deduced were highly conserved within CNS. A phylogenetic tree based on the NOS sequences revealed that the strains within species were clustered. Ninety-one percent of the strains, whatever the species, were able to form red myoglobin derivatives in aerobic conditions, but a high variability was observed between strains within species. However, NO production was low as nitrosomyoglobin represented 8% to 16% of the red pigments according to the species. Formation of oxymyoglobin, especially under aerobic conditions, was substantial, but varied greatly within species. The mechanism involved in the formation of oxymyoglobin could rely on staphylococcal reductases and remains to be explored. PMID- 29150356 TI - Cryptococcosis manifesting as isolated biliary infection: Case report and brief review of literature. AB - BACKGROUND: Biliary cryptococci infection is rare, which is frequently diagnosed by exploratory laparotomy, preoperative diagnosis is difficult. CASE PRESENTATION: A 14-year-old girl presented with intermittent jaundice for 6 years. She had no pruritus, anorexia, nausea or vomiting, fever, abdominal pain, or clay stools. Laboratory tests showed obstructive jaundice, eosinophilia, and increased IgE levels. The patient was ultimately diagnosed as Cryptococcal infection by bone marrow culture. The patient responded to antifungal therapy. CONCLUSION: Unnecessary surgical intervention was avoided by an early and accurate diagnosis. Cryptococcosis infection of bile duct should be highly suspected, when the children with obstructive jaundice have eosinophilia and increased IgE levels. PMID- 29150357 TI - Caregiver burden of parents of young children with cystic fibrosis. AB - BACKGROUND: There is a paucity of research examining the impact of informal caregiving on parents of young children with cystic fibrosis (CF). The aim of this study was to examine caregiver burden and identify risk factors associated with high caregiver burden in mothers and fathers of young children with CF. METHODS: This was a cross-sectional study of parents of young children with CF. A total of 213 families were invited to complete the CarerQoL questionnaire, a validated tool composed of two parts: (i) the CarerQol-7D which describes the care situation in terms of the negative and positive effects of caregiving and (ii) the visual analogue scale (VAS) which measures happiness on a scale from 0 to 10 (0=completely unhappy and 10=completely happy). The utility score (US) is a weighted average of the subjective burden derived from the CarerQol-7D (0-100); higher US indicates reduced burden. Differences in mother-father dyad median utility scores were examined using Wilcoxon signed rank test. Generalised linear mixed models were used to identify factors associated with high caregiver burden. RESULTS: At least one parent from 195 families completed the questionnaire (130 mother-father dyads, 189 mothers and 137 fathers). Fathers had a significantly higher median utility score than mothers [(89.2 (IQR 79.6-96.5) vs. 84.7 (74.5 88.0) p<0.001]. Factors found to be significantly associated with higher caregiver burden were increasing child age (OR 1.02; CI: 1.00-1.04), having a child ever positive for Pseudomonas aeruginosa (Pa) (OR 2.48; CI: 1.30-4.73) and being a mother (OR 1.65; CI: 1.02-2.65). CONCLUSIONS: This study contributes new findings to the sparse literature on caregiver burden of parents of young children with CF. Increasing child age and infection with Pa, associated with higher morbidity, were linked to greater parental burden. PMID- 29150358 TI - Development of the First Model of Radical Prostatectomy in the Mouse: A Feasibility Study. PMID- 29150359 TI - Azathioprine-induce acute submandibular sialadenitis in a patient with Crohn's disease. PMID- 29150360 TI - Changes in the epidemiology and distribution of the hepatitis C virus genotypes in North-Eastern Spain over the last 35 years. AB - BACKGROUND: Genotypic distribution and epidemiology of HCV infection in Western Europe countries has changed over the last decades. AIM: To establish the local genotypic profile and characterize the associated demographic variables. MATERIAL AND METHOD: All the genotyping from 1988 to 2015 were considered. Associated demographic variables were included in logistic regression models. Genotyping was carried out with updated commercial kits. RESULTS: Genotype 1b was the most prevalent (42.4%) followed by 1a (22.5%), 3 (18.6%), 4 (10.6%) and 2 (4.6%). The prevalence of 1a was higher in males, in patients younger than 45 and in intravenous drug users (IDU). 1b was more frequent in older than 45, with transfusion-associated and parenteral/nosocomial infections and in immigrants from Eastern Europe. Genotype 2 was highly prevalent in the postransfusional route (54.9%). Genotype 3 prevalence was high in males, in patients younger than 45, in IDU (69.3%) and in Asian and Eastern European immigrants. Genotype 4 was high in males, in patients younger than 45, and in IDU (63.5%). 1a, 3, 4 were the most prevalent genotypes in HIV-coinfected patients. There was a significant decline in genotype 1b and an increase in genotypes 3 and 4 over time. CONCLUSIONS: There has been a decline of genotype 1b, associated with transfusion or parenteral/nosocomial infections, and increases in the prevalence of genotypes 1a, 3 and 4 associated with male gender and IDU, now the most prevalent infection route. Immigration contributed with genotype 2 infections from Africa and genotype 1b and 3 infections from Eastern Europe and Asia. PMID- 29150361 TI - Post-translational Mechanisms of Host Subversion by Bacterial Effectors. AB - Bacterial effector proteins are a specialized class of secreted proteins that are translocated directly into the host cytoplasm by bacterial pathogens. Effector proteins have diverse activities and targets, and many mediate post-translational modifications of host proteins. Effector proteins offer potential in novel biotechnological and medical applications as enzymes that may modify human proteins. Here, we discuss the mechanisms used by effectors to subvert the human host through blocking, blunting, or subverting immune mechanisms. This capacity allows bacteria to control host cell function to support pathogen survival, replication and dissemination to other hosts. In addition, we highlight that knowledge of effector protein activity may be used to develop chemical inhibitors as a new approach to treat bacterial infections. PMID- 29150362 TI - Prevalence of Pediculus capitis in schoolchildren in Battambang, Cambodia. AB - BACKGROUND/PURPOSE: Pediculus capitis is the most common human ectoparasite. When it feeds on the blood through the scalp of its host, the anticoagulant in its saliva causes scalp inflammation and itching, and consequent scratching by the host causes further inflammation from bacterial infection. P. capitis infestation is currently a common parasitic dermatosis and a critical public health concern in underdeveloped countries. METHODS: Through naked eye inspection of P. capitis on or in the hair from 323 school children in Cambodia. RESULTS: A total of 143 children (44.3%) were found to have P. capitis infestation. Univariate analysis revealed that girls had a significantly higher infection rate than boys. Overall, young aged schoolchildren (10 yrs old <=) showed significantly higher infection rate than old aged schoolchildren (>10 yrs old). Groups stratified by time revealed that schoolchildren studied at the afternoon classes than morning classes in Tuol Prum Muoy Primary School had a significantly higher risk in acquisition of P. capitis infestation. Multivariate analysis results indicated that relative to the boys, the girls were at a significantly higher risk of contracting P. capitis infection. When stratified by inspection time with the Tuol Prum Muoy Primary School morning classes as the reference, the Tuol Prum Muoy Primary School afternoon classes exhibited a significantly higher risk of P. capitis infection. CONCLUSION: Primary school children in Cambodia have a high P. capitis infection rate and thus require effective treatment and prevention measures to treat symptoms and lower the infection rate. PMID- 29150363 TI - Development of a 3 French Dual-Frequency Intravascular Ultrasound Catheter. AB - Coronary plaque morphology, including plaque size and fibrous cap thickness, is thought to contribute to the risk of plaque rupture and future cardiac events. Dual-frequency intravascular ultrasound has been proposed as a possible technique to visualize both large-scale features and superficial detail of coronary plaque; however, it has not been found to be feasible within the constraints of a clinically functional intravascular ultrasound catheter. In this study, we describe the design and fabrication of a dual-frequency catheter using a bidirectional transducer stack with center frequencies of approximately 30 and 80 MHz. We describe how the high-frequency transducer achieves significantly improved axial and lateral resolution (16 and 120 um, respectively, vs. 50 and 220 um) at the expense of penetration depth. Finally, imaging of ex vivo human coronary artery segments reveals that the catheter can provide complementary images of the deeper arterial wall and superficial plaque features. PMID- 29150364 TI - Transbulbar B-Mode Sonography in Multiple Sclerosis: Clinical and Biological Relevance. PMID- 29150365 TI - Correlation between Ultrasound Appearance of Small Breast Cancer and Axillary Lymph Node Metastasis. AB - To study the correlation of ultrasonographic signs of small breast cancer (maximum diameter <=2.0 cm) with axillary lymph node metastasis, pre-operative ultrasonographic images of 153 small breast malignant neoplasms in 143 breast cancer patients were analyzed according to their pathologic features. Of the small breast tumors included, 47 showed axillary lymph node metastasis. Diagnosis of all patients was obtained with radical axillary surgery or a sentinel lymph node biopsy procedure. Ultrasonographic signs included irregular shape, microlobulated contour, spiculation, microcalcification, posterior echo attenuation, blood-flow grade, perforating vessels, changes in fascia or cooper's ligament and maximum cortical thickness of lymph nodes. The relationship between ultrasonographic features and axillary lymph node metastasis was analyzed using a chi-square test for univariate distributions and logistic regression for multivariate analysis. A logistic regression model was established by taking the pathologic diagnosis of lymph node metastasis as the dependent variable and the ultrasonographic signs of each small breast cancer as independent variables. In small breast cancer, characteristics such as perforating vessels and maximum cortical thickness of lymph nodes >3.0 mm correlated well with axillary lymph node metastasis as determined by univariate analysis (chi2 = 13.945, 51.276, respectively, p <0.05) and multivariate analysis (OR = 48.783, 46.754, respectively, p <0.05). PMID- 29150366 TI - Optimal Ultrasound Criteria for Grading Stenosis of the Superficial Femoral Artery. AB - This retrospective study determined the duplex ultrasound scanning criteria for detecting 50%-69% and 70%-99% stenosis of the superficial femoral artery (SFA). Examinations of 278 limbs in 185 patients with peripheral arterial disease were performed. Duplex ultrasound scanning was used to measure the diameter of the vascular lumen, the peak systolic velocity (PSV) at the stenotic segment of the SFA (PSVst), the segment proximal to the stenosis (PSVpro) and the popliteal artery (PSVpop, distal to the stenosis). The ratios PSVst/PSVpro and PSVst/PSVpop were calculated. Receiver operator characteristic curves were plotted, with digital subtraction angiography as the reference. PSVst and PSVst/PSVpop had the highest diagnostic value for stenosis. Cut-off thresholds were: for 50%-69% stenosis, PSVst >= 210 cm/s, PSVst/PSVpop >= 2.5, with PSVst the better parameter; for 70%-99% stenosis, PSVst >= 275 cm/s, PSVst/PSVpop >= 4.0, with PSVst/PSVpop superior. PSVst/PSVpop may be a better parameter than PSVst/PSVpro for diagnosing SFA stenosis. PMID- 29150367 TI - Ileocolic intussusception: Predicting the probability of success of ultrasound guided saline enema from clinical and sonographic data. AB - BACKGROUND/PURPOSE: To identify factors that dim the efficacy of ultrasound guided saline enema (USGSE) and to design a mathematical model for predicting the probability of success of USGSE. METHODS: Retrospective review of patients admitted with the diagnosis of ileocolic intussusception from 2009 to 2014. Demographics, clinical and sonographic data were reviewed. RESULTS: 116 first episodes of ileocolic intussusceptions. 109 USGSE attempts were analyzed. Composite reduction rate was 77%. A significant relationship was found between initial location of the intussusception, free peritoneal fluid (OR=0.329, 95% CI: 0.124-0.875), negative Doppler signal and sonographic signs of intestinal occlusion and unsuccessful USGSE. Initial location beyond the splenic angle was an independent risk factor for USGSE failure (OR=0.053, 95% CI: 0.005-0.534). A predictive model based on onset of symptoms, free peritoneal fluid and intussusception location was a reliable tool for prediction (AUC 0.63, 95% CI: 0.53-0.817). Assuming that a patient with less than 75.3% chance of USGSE success is going to fail, we would identify more than 80.9% of the real failures. CONCLUSIONS: This predictive model could be a filter selection for the patients at risk of USGSE failure and therefore candidates to further imaging investigations or referral to a surgical unit. LEVEL OF EVIDENCE: III. PMID- 29150368 TI - The utility of ERCP in pediatric pancreatic trauma. AB - BACKGROUND/PURPOSE: Endoscopic retrograde cholangiopancreatography (ERCP) is an adjunct for pediatric pancreatic injury management, but its use and utility in pediatric patients are unclear. We set out to evaluate the use of ERCP and its effects on outcomes. METHODS: A retrospective review was performed for children who had pancreatic injuries at 22 pediatric trauma centers between 2010 and 2015. ERCP details and outcomes were collected. Analysis was performed using descriptive statistics and Wilcoxon rank-sum tests. RESULTS: ERCP was used at 14/22 centers for 26 patients. Indications were duct evaluation, duct leak control, pseudocyst, fistula, and stricture. ERCP altered management or improved outcomes in 13/26 (50%), most commonly in patients with ERCP for duct evaluation, stricture, and fistula. In patients managed nonoperatively, those with early endoscopic intervention (within one week of injury) with stent or sphincterotomy (n=9) had similar time to regular diet [median (IQR)]: [10 (7-211) vs 7 (4-12) days; p=0.55], similar hospital days: [12 (8-20) vs 11 (6-19) days, p=0.63], and similar time on parenteral nutrition: [17 (10-40) vs 10 (6-18) days; p=0.19] compared to patients who were only observed. CONCLUSIONS: In children with blunt pancreatic injury, ERCP can be useful to diagnose duct injury and for management of late complications such as stricture and fistula. However, early endoscopic intervention for pancreatic duct disruption may not improve outcome or expedite recovery. Further study is needed. STUDY TYPE: Retrospective Study; Treatment Study. LEVEL OF EVIDENCE: III. PMID- 29150369 TI - Trial registration in pediatric surgery trials. AB - BACKGROUND: Prospective clinical trial registration serves to increase transparency and to mitigate selective reporting bias. An assessment of adult surgical trials revealed poor trial registration practice with incomplete provision of information in registries and inconsistent information in the corresponding publication. The extent and completeness of pediatric surgical trial registration are unknown. We aimed to determine the proportion and adequacy of clinical trial registration in pediatric surgery trials published in 2014. METHODS: Using sensitive search strategies in MEDLINE, abstracts and full-texts of prospective pediatric intervention studies published in 2014 were screened in duplicate. Pediatric surgical trials were included. Clinical trial registration numbers obtained from publications were searched in trial registries. Data were extracted based on WHO 20-item minimum data set to determine the completeness of registration data. The proportion of registered trials was recorded and registration data were compared to reported data in the corresponding publication. RESULTS: Our search and abstract screening identified 3375 articles for full text review. Following coding, a total of 54 pediatric surgical trials were included and analyzed; 28% (15/54) of which published a registration number. In trials which reported a registration number, 40% (6/15) were retrospectively registered and 40% (6/15) had made changes to their registered primary and/or secondary outcome measures. One included published trial reported an incorrect registration number. CONCLUSIONS: Analysis of pediatric surgery trials published in 2014 revealed a poor prospective trial registration rate and incomplete registration data. Our study supports future initiatives for improved registration behaviors in pediatric surgery trials to ensure high-quality, transparent, reproducible evidence is generated. STUDY TYPE: Therapeutic (clinical trials), level II. PMID- 29150370 TI - Emergence of sequence type 252 Enterobacter cloacae producing GES-5 carbapenemase in a Czech hospital. AB - ST252 Enterobacter cloacae, producing GES-5 carbapenemase, was isolated in a Czech hospital. blaGES-5 was part of a novel class 1 integron, In1406, which also included a new allele of the aadA15 gene cassette. In1406 was located on a ColE2 like plasmid, pEcl-35771cz (6953bp). PMID- 29150371 TI - Emergence of polymyxin B resistance in a polymyxin B-susceptible KPC-producing Klebsiella pneumoniae causing bloodstream infection in a neutropenic patient during polymyxin B therapy. AB - The emergence of resistance to polymyxins in KPC-producing Klebsiella pneumoniae isolates has been a major clinical problem. This study evaluated the molecular mechanisms associated with polymyxin B (PMB) resistance that emerged in a previously PMB-susceptible KPC-2-producing K. pneumoniae during PMB therapy for a bloodstream infection in a neutropenic patient. The first isolate (PMB susceptible) was obtained while the patient was receiving meropenem and other isolates were recovered from 2 sets of blood cultures in different dates while the patient was receiving PMB therapy (4 of 6 blood cultures bottles yielded isolates with full PMB resistance). The population analysis profile of the first isolate revealed the growth of resistant subpopulations with PFGE profile distinct from the parental isolate but undistinguishable from those obtained in subsequent days under PMB exposure. Resistant subpopulations were obtained from all parental PMB-susceptible and in one PMB-resistant isolate recovered from the patient. The molecular mechanism observed in the hetero-resistant subpopulations (IS1-like in mgrB-promoter region, increased rstB transcription with no mutation and non-identified mechanism) differed from those found in the PMB-resistant isolates, in which no mutation or transcriptional alterations were detected. This study showed that the mechanism of resistance to PMB that emerged during PMB therapy was not related to those observed in subpopulations selected in vitro from PMB-susceptible isolates recovered from the patient. The absence of mutations in the former isolates may be due to adaptive resistance occurred because of sub-optimal PMB levels as well as amikacin and meropenem used in combination. PMID- 29150372 TI - Duration of Group A Streptococcus PCR positivity following antibiotic treatment of pharyngitis. AB - BACKGROUND: Polymerase chain reaction (PCR) has high sensitivity and specificity for detection of group A streptococcus (GAS) in throat swabs and is routinely used for GAS pharyngitis diagnosis at our institution. Herein we defined the natural history of throat swab GAS PCR and culture positivity during and following treatment of GAS pharyngitis. METHODS: Fifty children with a PCR positive GAS throat swab were recruited for participation. Four additional throat swabs were collected over 2 weeks following the initial positive PCR result (during and following a standard course of antibiotic therapy) and tested for GAS using rapid real-time PCR and culture. RESULTS: After the initial positive swab, 45% had a positive PCR 2-4 days, 20% 5-7 days, 18% 8-10 days, 25% 11-13days, and 20% 14-18days later. The median time to a negative PCR was 4 days with the nadir in positive PCR results approximating the end of a typical 10-day treatment interval. Seven subjects remained persistently PCR positive. Culture results remained positive at a stable rate for each time interval, ranging from 5-10%. CONCLUSIONS: If a patient presents with symptoms of GAS pharyngitis after previous positive GAS PCR testing and treatment with appropriate antibiotics, it is reasonable to use PCR testing for GAS pharyngitis testing beginning one week after initial testing. Further studies are warranted to determine if this time frame can be applied to PCR testing used to detect other infections. PMID- 29150373 TI - CHROMagar mSuperCARBA and RAPIDEC(r) Carba NP test for detection of carbapenemase producing Enterobacteriaceae. AB - A novel chromogenic medium CHROMagar mSuperCARBA was evaluated to detect carbapenem-resistant Gram-negatives. This medium is as sensitive and as specific as the SUPERCARBA medium for detecting KPC, MBL and OXA-48-type producers (100% and 100%, respectively) and is compatible with subsequent testing of carbapenemase activity using the RAPIDEC(r) CARBA NP. PMID- 29150374 TI - Occurrence of Enterobacter hormaechei carrying blaNDM-1 and blaKPC-2 in China. AB - Three carbapenem-resistant clinical isolates of the Enterobacter cloacae complex (ECC) were recovered from different patients in a hospital. All 3 isolates carried 2 carbapenemase genes blaKPC-2 and blaNDM-1. A study was performed to characterize their relatedness and to investigate possible links among the patients. Whole genome sequencing revealed that the isolates were Enterobacter hormaechei and belonged to ST177 of the ECC. There were 19-142 single nucleotide polymorphisms (SNPs) between the isolates, suggesting that the isolates were likely from a central reservoir, which might have existed for some time. blaKPC-2 and blaNDM-1 were carried on 2 different IncF-type plasmids in the isolates. The 3 blaNDM-1-carrying plasmids were almost identical and were self-transmissible, while the blaKPC-2-carrying plasmids were only transmissible in the presence of the blaNDM-1-carrying plasmid. The source of and direct links among them were not identified, suggesting a hospital transmission of a common multidrug resistant strain. PMID- 29150375 TI - Type I interferon and proinflammatory cytokine levels in cerebrospinal fluid of newborns with rotavirus-associated leukoencephalopathy. AB - OBJECTIVE: The purpose of this study was to identify whether there is an increase in type I interferon and proinflammatory cytokine levels in the cerebrospinal fluid of newborns with rotavirus-associated leukoencephalopathy. METHODS: Levels of type I interferons (interferon-alpha and interferon-beta) and proinflammatory cytokines (interleukin-6 and interferon-gamma) were measured in the cerebrospinal fluid of 23 newborns with rotavirus-associated leukoencephalopathy (patient group) and 39 infants under 90 days-of-age (control group). RESULTS: Cerebrospinal fluid pleocytosis was not observed in either group. Cerebrospinal fluid interleukin-6 levels were significantly higher in the patient group (7.02 +/- 5.88 pg/mL) than in the control group (1.14 +/- 1.90 pg/mL) (p < .0001). The mean cerebrospinal fluid interferon-gamma levels of the patient group (24.43 +/- 40.16 pg/mL) were also significantly higher than those of the controls group (0.0 +/- 0.0 pg/mL) (p < .0001). Cerebrospinal fluid interferon-alpha was not detected in any patient (0%) from the patient group, but was detected in four (10.3%) of the controls. Interferon-beta was detected in only two patients (8.7%) from the patient group and in one (2.6%) of the controls. Cerebrospinal fluid interleukin 6 levels correlated positively with the extent of white matter lesions on diffusion-weighted magnetic resonance imaging (r = 0.607, p = .002). CONCLUSIONS: Significant increases in proinflammatory cytokine levels accompanied by very low detection rates of type I interferon in cerebrospinal fluid indicate that rotavirus-associated leukoencephalopathy in newborns can be correlated with central nervous system inflammatory processes without direct virus invasion into the central nervous system. PMID- 29150376 TI - Timing of antiretroviral therapy in children with advanced HIV. PMID- 29150377 TI - Urgent versus post-stabilisation antiretroviral treatment in hospitalised HIV infected children in Kenya (PUSH): a randomised controlled trial. AB - BACKGROUND: Urgent antiretroviral therapy (ART) among hospitalised HIV-infected children might accelerate recovery or worsen outcomes associated with immune reconstitution. We aimed to compare urgent versus post-stabilisation ART among hospitalised HIV-infected children in Kenya. METHODS: In this unmasked randomised controlled trial, we randomly assigned (1:1) HIV-infected, ART-naive children aged 0-12 years who were eligible for treatment to receive ART within 48 h (urgent group) or in 7-14 days (post-stabilisation group) at four hospitals in Kenya (two in Nairobi and two in western Kenya). We excluded children with suspected or confirmed CNS infection. A statistician not involved in study procedures did block randomisation with variable block sizes generated using STATA version 12. We followed children for 6 months for primary outcomes: mortality, drug toxicity, and immune reconstitution inflammatory syndrome (IRIS). We did all analyses in a modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02063880. FINDINGS: We began enrolment on April 24, 2013, and completed follow-up on Nov 17, 2015. We enrolled 191 (76%) of 250 hospitalised HIV-infected children. Of these, 183 children were randomly assigned: 90 to urgent ART and 93 to post-stabilisation ART. 181 (99%) of 183 children were included in the modified intention-to-treat analysis. Median age was 1.9 years (IQR 0.8-4.8). Baseline sociodemographic, clinical, and virological characteristics did not differ between groups except median CD4 cell percentage, which was lower in the urgent group (13% [IQR 9-18] vs 17% [IQR 9 24]; p=0.052). Of 181 admission diagnoses, 118 (65%) were pneumonia, 58 (32%) malnutrition, and 27 (15%) suspected tuberculosis. Median time to ART was 1 day (IQR 1-1) in the urgent group and 8 days (IQR 7-11) in the post-stabilisation group. Overall, mortality risk at 6 months was 61 per 100 person-years. Mortality risk did not differ by group (70 per 100 person-years in the urgent group vs 54 per 100 person-years in the post-stabilisation group; hazard ratio [HR] 1.26, 95% CI 0.67-2.37) p=0.47, even after adjusting for baseline CD4 cell percentage (adjusted HR 1.30, 95% CI 0.69-2.45; p=0.41). The incidence of IRIS, and drug toxicity was not significantly different between trial arms. There were no differences between treatment groups in the proportion of grade 3 or 4 adverse events (34 [38%] of 90 children in the urgent group vs 40 [44%] of 91 children in the post-stabilisation group; p=0.40) or the proportion of any change in ART regimen (five [7%] vs six [8%]; p=0.79). We discontinued randomisation at interim review when the futility boundary was crossed. INTERPRETATION: Early mortality risk was extremely high among hospitalised HIV-infected children. Urgent ART did not improve survival. FUNDING: National Institute of Child Health and Human Development, National Institutes of Health, USA. PMID- 29150378 TI - Enhanced antibacterial effects of green synthesized ZnO NPs using Aristolochia indica against Multi-drug resistant bacterial pathogens from Diabetic Foot Ulcer. AB - BACKGROUND: Increased incidence of Multi-drug resistance in microorganisms has become the greatest challenge in the treatment of Diabetic Foot Ulcer (DFU) and urges the need of a new antimicrobial agent. In this study, we determined the bactericidal effects of ZnO nanoparticles (ZnO NPs) green synthesized from Aristolochia indica against Multi-drug Resistant Organisms (MDROs) isolated from pus samples of DFU patients attending in a tertiary care hospital in South India. METHODS: ZnO NPs were characterized by UV-vis-DRS spectroscopy, Atomic Force Microscopy (AFM), Transmission Electron Microscopy (TEM) and for its zeta potential value. MIC/MBC assays were performed to determine bactericidal or bacteriostatic effects. Time-kill assays, Protein leakage and Flow cytometric analysis evaluated bacterial cell death at 1x MIC and 2x MIC concentrations of ZnO NPs. RESULTS: ZnO NPs of size 22.5nm with a zeta potential of -21.9+/-1mV exhibited remarkable bactericidal activity with MIC/MBC ranging from 25 to 400MUg/ml with a significant reduction in viable count from 2h onwards. Protein leakage and Flow cytometric analysis confirmed bacterial cell death due to ZnO NPs. CONCLUSION: This study concluded that green synthesis protocol offers reliable, eco-friendly approach towards the development of antimicrobial ZnO NPs to combat antibiotic drug resistance. PMID- 29150379 TI - Changes in maxillofacial morphology and velopharyngeal function with two-stage maxillary distraction-mandibular setback surgery in patients with cleft lip and palate. AB - Maxillary distraction is increasingly used for the correction of severe maxillary retrusion in patients with cleft lip and palate. However, control of the maxillary movement is difficult, and the need to wear visible distractors for a long period of time causes psychosocial problems. A two-stage surgical approach consisting of maxillary distraction and mandibular setback was developed to overcome these problems. In this study, changes in maxillofacial morphology and velopharyngeal function were examined in 22 patients with cleft lip and palate who underwent this two-stage approach. Lateral cephalograms taken just before the first surgery, immediately after the second surgery, and at completion of the active post-surgical orthodontic treatment were used to examine maxillofacial morphology. Velopharyngeal function was evaluated by speech therapists using a 4 point scale for hypernasality. The average forward movement of the maxilla with surgery at point A was 7.5mm, and the average mandibular setback at pogonion was 8.6mm. The average relapse rate during post-surgical orthodontic treatment was 25.2% for the maxilla and 11.2% for the mandible. After treatment, all patients had positive overjet, and skeletal relapse was covered by tooth movement during postoperative orthodontics. Velopharyngeal function was not changed by surgery. This method can shorten the period during which the distractors have to be worn and reduce the patient burden. PMID- 29150380 TI - Comparison of two physiotherapy programmes for rehabilitation after temporomandibular joint arthroscopy. AB - The purpose of this study was to compare two physiotherapy programmes for rehabilitation after temporomandibular joint (TMJ) arthroscopy. The medical files of 137 consecutive patients diagnosed with closed lock and treated by arthroscopic lysis and lavage were analyzed retrospectively. Sixty-eight patients were rehabilitated with gradually increasing range of motion self-exercises (gradual programme) and 69 patients were rehabilitated with immediate full range of motion self-exercises (immediate programme). The outcome variables were maximum mouth opening (MMO) and pain (on a visual analogue scale). The postoperative measurements taken at 1 month, 6 months, and last follow-up examination available (mean of 10 months postoperative) were analyzed and compared between the two groups. The results showed significantly better MMO and pain outcomes for the immediate group than for the gradual group at the 1-month and 6-month postoperative evaluations. The results of the two groups were comparable at the last follow-up examination available. It is concluded that after arthroscopic treatment of closed lock of the TMJ, a physiotherapy programme consisting of immediate postoperative full range of motion mobilizations achieves better results (in terms of pain and mouth opening) than a physiotherapy programme consisting of gradual and controlled increases in range of motion. PMID- 29150381 TI - A Plea for the Renewal of the ISBR. AB - The recent meeting of the International Society for Biosafety Research (ISBR) focused on so-called genetically modified organisms. For decades, in most regulatory frameworks, recombinant DNA-modified organisms have been the wrong focus of unbalanced agri-food regulations. The ISBR should instead adopt a scientifically defensible and truly risk-based perspective, abandoning a misleading pseudo-category. PMID- 29150382 TI - Changes in fall risk and functional status in women aged 50 years and older after distal radius fracture: A prospective 1-year follow-up study. AB - STUDY DESIGN: Prospective cohort study. INTRODUCTION: Few studies have evaluated the course of recovery after distal radius fracture (DRF) when functional decline and fracture risk may be affected. PURPOSE OF THE STUDY: The purpose of this study was to determine changes in overall functional status over the first year after a DRF in women aged 50 years and older. METHODS: Seventy-eight women were assessed for balance, balance confidence, lower extremity strength, gait speed, fall history, physical activity levels, and self-reported wrist pain and function (Patient-Rated Wrist Evaluation) at weeks 1, 3, 9, 12, 26, and 52 after DRF. Descriptive data were generated for all variables; a 3-way mixed analysis of variance with repeated measures was used to compare differences between participants aged 50-65 years and 65 years and older. RESULTS: There was a significant improvement in functional status measures for both age categories except single-leg balance and fast gait speed, from 1 week after fracture extending up to 1 year after fracture (ranging from 6.1% improvement to 25% improvement, P < .05). There was no significant time * age interaction, as both age groups had the same pattern of recovery; however, there was significantly lower functional status in the older group across all time points. CONCLUSION: Regardless of age, monitoring and addressing functional status including upper limb function, overall strength, balance, confidence, usual gait speed, and physical activity right up to 1 year after fracture is an important consideration for clinicians treating women recovering from DRF. Given the high future fracture risk for these women, identifying functional recovery patterns can help to direct future research and determine preventative strategies. PMID- 29150383 TI - The diagnostic clinical value of thumb metacarpal grind, pressure-shear, flexion, and extension tests for carpometacarpal osteoarthritis. AB - STUDY DESIGN: Clinical measurement. INTRODUCTION: Common provocative maneuvers to differentiate thumb carpometacarpal (CMC) osteoarthritis from other sources of pain are the grind, metacarpal (MC) flexion, and MC extension tests. A maneuver known as the pressure-shear test is described here. PURPOSE OF THE STUDY: To compare the diagnostic value of the grind, metacarpal flexion, metacarpal extension, and pressure-shear tests for CMC osteoarthritis of the thumb. METHODS: The diagnostic accuracy of each test was compared in 127 thumbs from 104 patients. Sensitivity, specificity, and predictive values of each test were calculated. In a secondary analysis, polychoric correlation coefficients were used to assess the correlation of each test with severity defined by Eaton Littler stage. RESULTS: The overall diagnostic accuracy of the thumb MC grind, pressure-shear, flexion, and extension tests were 70%, 98%, 47%, and 55%, respectively. The sensitivities were 64%, 99%, 36%, and 46%, respectively, and specificities were 100%, 95%, 100%, and 100%, respectively. For the diagnosis of Thumb CMC arthritis, the MC pressure-shear test was superior overall in terms of overall diagnostic accuracy and sensitivity, while having comparable specificity to the other maneuvers. CONCLUSION: The pressure-shear test was found to be superior to the commonly used grind maneuver and the provocative maneuvers of MC flexion and extension tests to confirm diagnosis of CMC osteoarthritis. PMID- 29150384 TI - The effect of sensory-motor training on hand and upper extremity sensory and motor function in patients with idiopathic Parkinson disease. AB - STUDY DESIGN: Blinded randomized controlled trial. INTRODUCTION: Patients with Parkinson disease (PD) have sensory problems, but there is still no accurate understanding of the effects of sensory-motor interventions on PD. PURPOSE OF THE STUDY: To investigate the effects of sensory-motor training (SMT) on hand and upper extremity sensory and motor function in patients with PD. METHODS: Forty patients with PD were allocated to the SMT group or the control group (CG) (mean ages +/- standard deviation: SMT, 61.05 +/- 13.9 years; CG, 59.15 +/- 11.26 years). The CG received the common rehabilitation therapies, whereas the SMT group received SMT. The SMT included discrimination of temperatures, weights, textures, shapes, and objects and was performed 5 times each week for 2 weeks. RESULTS: Significantly reducing the error rates in the haptic object recognition test (dominant hand [DH]: F = 15.36, P = .001, and effect size [ES] = 0.29; nondominant hand [NDH]: F = 9.33, P = .004, and ES = 0.21) and the error means in the wrist proprioception sensation test (DH: F = 9.11, P = .005, and ES = 0.19; NDH: F = 13.04, P = .001, and ES = 0.26) and increasing matched objects in the hand active sensation test (DH: F = 12.15, P = .001, and ES = 0.24; NDH: F = 5.03, P = .03, and ES = 0.12) founded in the SMT. Also, the DH (F = 6.65, P = .01, and ES = 0.15), both hands (F = 7.61, P = .009, and ES = 0.17), and assembly (F = 7.02, P = .01, and ES = 0.15) subtests of fine motor performance, as well as DH (F = 10.1, P = .003, and ES = 0.21) and NDH (F = 8.37, P = .006, and ES = 0.18) in upper extremity functional performance, were improved in the SMT. DISCUSSION: SMT improved hand and upper extremity sensory-motor function in patients with PD. CONCLUSION: The SMT group showed improved sensory and motor function. But these results were limited to levels 1 to 3 of the Hoehn and Yahr Scale. PMID- 29150385 TI - IGF-1R mRNA expression is increased in obese children. AB - OBJECTIVES: Obese children are often taller than age-matched subjects. Reports on GH and IGF-I levels in obese individuals are controversial, with normal and reduced GH-IGF-I levels having been reported in this group of patients. Thus, the aim of this study was to analyse insulin-like growth factor type 1 receptor (IGF IR) mRNA expression in obese children. METHODS: Forty-seven pre-pubertal children were included in this study: 29 were obese and taller than their target height, and 18 were normal eutrophic controls. Fasting blood samples were collected for IGF-IR mRNA expression in isolated lymphocytes and serum IGF-I, ALS, IGFBP-3, and IGFBP-1 concentration analysis. RESULTS: Relative IGF-IR gene expression (2 DeltaDeltaCT) was significantly (P=0.025) higher in obese children (median 1.87) than in controls (1.15). Fourteen of the 29 obese subjects showed 2-DeltaDeltaCT values greater than or equal to 2, while only 2 individuals in the control group showed values above 2 (P=0.01). Obese children showed significantly (P=0.01) higher IGF-I concentrations than the control group (237ng/ml and 144ng/ml, respectively). Among obese patients, 65.5% had IGF-I values above the 75 percentile of the control group (P=0.02). ALS concentration was significantly (P=0.04) higher in the obese group, while IGFBP-3 levels were similar in obese and control children. IGFBP-1 concentration was lower in obese children, while insulin levels and HOMA-IR index were higher than in controls. CONCLUSIONS: The higher IGF-IR mRNA expression observed in obese children, associated with the higher IGF-I and ALS and the lower IGFBP-1 levels, suggest that the higher stature observed in these children may be due to increased IGF-I bioactivity. PMID- 29150386 TI - Role of Endosymbionts in Insect-Parasitic Nematode Interactions. AB - Endosymbiotic bacteria exist in many animals where they develop relationships that affect certain physiological processes in the host. Insects and their nematode parasites form great models for understanding the genetic and molecular basis of immune and parasitic processes. Both organisms contain endosymbionts that possess the ability to interfere with certain mechanisms of immune function and pathogenicity. This review summarizes recent information on the involvement of insect endosymbionts in the response to parasitic nematode infections, and the influence of nematode endosymbionts on specific aspects of the insect immune system. Analyzing this information will be particularly useful for devising endosymbiont-based strategies to intervene in insect immunity or nematode parasitism for the efficient management of noxious insects in the field. PMID- 29150387 TI - The effect of social fathers on the cognitive skills of out-of-wedlock children in the U.S. AB - There are two competing views regarding the presence of social fathers on childrens' cognitive ability: (1) either the social father provides more financial resources which benefit the children or (2) the mother with new partners may shift the focus away from the children. Previous research focused on older children or adolescents and ignored the self-selection problem. We use data from the Fragile Families and Child Wellbeing Study (FFCWS), and a sample of younger children. Using propensity score matching method (nonparametric methods), we find that children with social fathers scored around three points less in a cognitive ability test than children living only with biological mothers (assuming that self-selection is based on observables). The result remains robust when using a control-function analysis (parametric method). PMID- 29150388 TI - Is vascular cognitive impairment more common in Asia? PMID- 29150389 TI - Galantamine and memantine combination for cognition: Enough or more than enough to translate from murines and macaques to men with schizophrenia? PMID- 29150391 TI - Diagnosing pulmonary embolism: we are not so different after all.... PMID- 29150390 TI - Pulmonary embolism rule-out criteria (PERC) rule in European patients with low implicit clinical probability (PERCEPIC): a multicentre, prospective, observational study. AB - BACKGROUND: The ability of the pulmonary embolism rule-out criteria (PERC) to exclude pulmonary embolism without further testing remains debated outside the USA, especially in the population with suspected pulmonary embolism who have a high prevalence of the condition. Our main objective was to prospectively assess the predictive value of negative PERC to rule out pulmonary embolism among European patients with low implicit clinical probability. METHODS: We did a multicentre, prospective, observational study in 12 emergency departments in France and Belgium. We included consecutive patients aged 18 years or older with suspected pulmonary embolism. Patients were excluded if they had already been hospitalised for more than 2 days, had curative anticoagulant therapy in progress for more than 48 h, or had a diagnosis of thromboembolic disease documented before admission to emergency department. Physicians completed a standardised case report form comprising implicit clinical probability assessment (low, moderate, or high) and a list of risk factors including criteria of the PERC rule. They were asked to follow international recommendations for diagnostic strategy, masked to PERC assessment. The primary endpoint was the proportion of patients with low implicit clinical probability and negative PERC who had venous thromboembolic events, diagnosed during initial diagnostic work-up or during 3 month follow-up, as externally adjudicated by an independent committee masked to the PERC and clinical probability assessment. The upper limit of the 95% CI around the 3-month thromboembolic risk was set at 3%. We did all analyses by intention to treat, including all patients with complete follow-up. This trial is registered with ClinicalTrials.gov, number NCT02360540. FINDINGS: Between May 1, 2015, and April 30, 2016, 1773 consecutive patients with suspected pulmonary embolism were prospectively assessed for inclusion, of whom 1757 were included. 1052 (60%) patients were classed as having low clinical probability, 49 (4.7%, 95% CI 3.5-6.1) of whom had a venous thromboembolic event. In patients with a low implicit clinical probability, 337 (32%) patients had negative PERC, of whom four (1.2%; 95% CI 0.4-2.9) went on to have a pulmonary embolism. INTERPRETATION: In European patients with low implicit clinical probability, PERC can exclude pulmonary embolism with a low percentage of false-negative results. The results of our prospective, observational study allow and justify an implementation study of the PERC rule in Europe. FUNDING: French Ministry of Health. PMID- 29150392 TI - Improvement in quality of life after bariatric surgery: sleeve versus bypass. AB - BACKGROUND: Obesity is steadily growing to be the largest threat to human health in this century, not only increasing prevalence of obesity-related co-morbidity but also impairing health-related quality of life (QoL). Bariatric surgery has shown to improve co-morbidity as well as QoL. OBJECTIVES: To assess the differences in improvement in QoL for the 2 most performed procedures: laparoscopic sleeve gastrectomy (SG) and laparoscopic Roux-en-Y gastric bypass (RYGB). SETTING: Obesity center, the Netherlands. METHODS: All patients who underwent either SG or RYGB as a primary operation from January 2012 until January 2017 were eligible. Included, were only those who completed preoperatively and 1-year postoperatively the QoL questionnaire. The RAND 36-item Health Survey was used to assess QoL. RESULTS: A total of 1184 cases were included in analysis of which 666 patients underwent SG and 518 patients underwent RYGB. Groups significantly differed in body mass index, weight, waist circumference, prevalence of gastroesophageal reflux disease, obstructive sleep apnea syndrome, and hypertension. All QoL domains greatly improved after bariatric surgery. Physical functioning increased more in patients who underwent gastric bypass. This remained significant after correcting for differences between groups. Other domains were not significantly different. CONCLUSION: QoL is greatly improved at 1 year after bariatric surgery. The improvement was comparable after SG and RYGB, expect for more increase in physical functioning after RYGB. QoL could influence decision-making between SG and RYGB. So far, no clinically relevant differences were found. Future research should focus on both longer follow-up and more specific questionnaires. PMID- 29150393 TI - Considerations regarding sarcoidosis in the bariatric surgical patient. AB - The sarcoidosis patient who seeks surgical management for obesity presents many challenges. The interaction between sarcoidosis and obesity complicates both disorders and creates special issues to consider when contemplating surgery. This manuscript will review the approach to pre- and postoperative management of the sarcoidosis patient undergoing bariatric surgery. PMID- 29150394 TI - Efficacy of Prostatic Artery Embolization for Catheter-Dependent Patients with Large Prostate Sizes and High Comorbidity Scores. AB - PURPOSE: To evaluate efficacy and safety of prostate artery embolization (PAE) in urinary catheter-dependent patients with large prostate volumes and high comorbidity scores. MATERIALS AND METHODS: A retrospective single-center review was conducted of 30 patients with urinary retention at time of PAE from November 2014 through February 2017. Mean (range) age was 73.1 years (48-94 y), age adjusted Charlson comorbidity index was 4.5 (0-10), duration of urinary retention was 63.4 days (2-224 d), International Prostate Symptom Score quality-of-life (IPSS-QOL) was 5.3 (3-6), and prostate volume was 167.3 cm3 (55-557 cm3). These parameters were collected at 3, 6, and 12 months after PAE. Trials of voiding were performed approximately 2 weeks after PAE and, if failed, every 2 weeks thereafter. Adverse events were graded using the Clavien-Dindo classification. RESULTS: At a mean (range) of 18.2 days (1-72 d), 26 (86.7%) patients were no longer reliant on catheters. Follow-up was obtained in all patients eligible at 3 and 6 months and 17 of 20 (85.0%) patients eligible at 1 year. Mean (range) IPSS QOL improved significantly to 1.2 (0-5), 0.7 (0-4), and 0.6 (0-4) at 3, 6, and 12 months (all P < .001). Mean (range) prostate volume decreased significantly to 115.9 cm3 (27-248 cm3) at 3 months (P < .001). Two patients experienced grade II urosepsis complications, which were successfully treated with intravenous antibiotics. All other complications were self-limited grade I complications. CONCLUSIONS: PAE represents a safe and effective option for management of patients with urinary retention, especially patients with large prostates who are not ideal surgical candidates. PMID- 29150395 TI - Transradial Versus Transfemoral Arterial Access in Liver Cancer Embolization: Randomized Trial to Assess Patient Satisfaction. AB - PURPOSE: To determine whether transradial access (TRA) or transfemoral access (TFA) provides better patient satisfaction during intra-arterial therapy (IAT) for liver cancer. MATERIALS AND METHODS: This randomized, prospective, intra- and interpatient controlled trial compared TRA vs TFA accesses in patients with primary or metastatic liver cancer undergoing IAT. After having one of each type of access (1 TRA and 1 TFA), all patients selected their preferred access regardless of whether a third intervention was indicated. The primary endpoint was patient access preference; secondary endpoints were access-related complications, procedure time, contrast agent volume, and radiation doses to the patient and operator. Patients were evaluated on postprocedure days 1 and 30. RESULTS: Fifty-five patients with liver cancer (31 hepatocellular carcinoma, 24 metastatic disease) were enrolled, and 124 IAT procedures were performed. A total of 36 patients underwent at least 1 intervention each with TRA and TFA. Of those, 29 patients (81%) preferred TRA and 7 (19%) preferred TFA (ratio, 4:1; P < .001). Median radiation exposure to the operator was significantly lower for TRA (5.5 mrem) vs TFA (13 mrem; P = .01). Incidences of complications, procedure time, contrast agent volume, and radiation exposure to patients were similar between groups. CONCLUSIONS: TRA was the preferred access for the majority of patients and was associated with less radiation exposure to the operator. No differences were detected in incidence of adverse events, procedure time, contrast agent volume, or patient radiation exposure. PMID- 29150396 TI - Identification of pyruvate dehydrogenase kinase 1 inhibitors with anti osteosarcoma activity. AB - Overexpression of pyruvate dehydrogenase kinases (PDKs), especially PDK1 has been observed in a variety of cancers. Thus, targeting PDK1 offers an attractive opportunity for the development of cancer therapies. In this letter, we reported the identification of two novel PDK1 inhibitors as anti-osteosarcoma agents. We found that TM-1 and TM-2 inhibited PDK1 with the IC50 values of 2.97 and 3.41 MUM, respectively. Furthermore, TM-1 and TM-2 dose-dependently reduced phosphorylation of pyruvate dehydrogenase complex in MG-63 osteosarcoma cells. Finally, TM-1 and TM-2 were found to inhibit the proliferation of MG-63 cells with the EC50 values of 14.5, and 11.0 MUM, respectively, meaning TM-1 and TM-2 could be promising leads for the discovery of potent PDK1 inhibitors. PMID- 29150397 TI - Fragment-based design, synthesis, biological evaluation, and SAR of 1H benzo[d]imidazol-2-yl)-1H-indazol derivatives as potent PDK1 inhibitors. AB - In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC50 of 80 nM and 94 nM, respectively. Further biological evaluation showed that, at the low nanomolar concentration, the drug had potent ability to inhibit phosphorylation of AKT and p70S6, and selectively kill the cancer cells with mutations in both PTEN and PI3K. The microarray data showed that DUSP6, DUSP4, and FOSL1 were down-regulated in the sensitive cell lines with the compound treatment. The in vivo test showed that 35 can significantly inhibit tumor growth without influencing body weight growth. Our results suggest that these compounds, especially 35, merit further pre-clinical evaluation. PMID- 29150399 TI - A Plate Waste Evaluation of the Farm to School Program. AB - OBJECTIVE: To investigate the impacts of the Farm to School (FTS) Program on the selection and consumption of fruits and vegetables. DESIGN: Plate waste data were recorded using the visual inspection method before and after implementation of the program. SETTING: Six elementary schools in Florida: 3 treatment and 3 control schools. PARTICIPANTS: A total of 11,262 meal observations of National School Lunch Program (NSLP) participants in grades 1-5. INTERVENTION: The FTS Program, specifically local procurement of NSLP offerings, began in treatment schools in November, 2015 after the researchers collected preintervention data. MAIN OUTCOME MEASURES: The NSLP participants' selection and consumption of fruits and vegetables. ANALYSIS: Data were analyzed using Mann-Whitney U and proportions tests and difference-in-difference regressions. RESULTS: The NSLP participants at the treatment schools consumed, on average, 0.061 (P = .002) more servings of vegetables and 0.055 (P = .05) more servings of fruit after implementation of the FTS Program. When school-level fixed effects are included, ordinary least squares and tobit regression results indicated that NSLP participants at the treatment schools respectively consumed 0.107 (P < .001) and 0.086 (P < .001) more servings of vegetables, on average, after implementation of the FTS Program. CONCLUSIONS AND IMPLICATIONS: Local procurement positively affected healthy eating. PMID- 29150400 TI - Changes in Student-Athletes' Self-Efficacy for Making Healthful Food Choices and Food Preparation Following a Cooking Education Intervention. PMID- 29150398 TI - Glycyrrhiza glabra extract and quercetin reverses cisplatin resistance in triple negative MDA-MB-468 breast cancer cells via inhibition of cytochrome P450 1B1 enzyme. AB - The development of multi-drug resistance to existing anticancer drugs is one of the major challenges in cancer treatment. The over-expression of cytochrome P450 1B1 enzyme has been reported to cause resistance to cisplatin. With an objective to discover cisplatin-resistance reversal agents, herein, we report the evaluation of Glycyrrhiza glabra (licorice) extracts and its twelve chemical constituents for inhibition of CYP1B1 (and CYP1A1) enzyme in Sacchrosomes and live human cells. The hydroalcoholic extract showed potent inhibition of CYP1B1 in both Sacchrosomes as well as in live cells with IC50 values of 21 and 16 ug/mL, respectively. Amongst the total of 12 constituents tested, quercetin and glabrol showed inhibition of CYP1B1 in live cell assay with IC50 values of 2.2 and 15 uM, respectively. Both these natural products were found to be selective inhibitors of CYP1B1, and does not inhibit CYP2 and CYP3 family of enzymes (IC50 > 20 uM). The hydroalcoholic extract of G. glabra and quercetin (4) showed complete reversal of cisplatin resistance in CYP1B1 overexpressing triple negative MDA-MB-468 breast cancer cells. The selective inhibition of CYP1B1 by quercetin and glabrol over CYP2 and CYP3 family of enzymes was studied by molecular modeling studies. PMID- 29150401 TI - Choose Health: Food, Fun and Fitness, an Experiential Youth Curriculum That Promotes Healthy Eating and Active Play. PMID- 29150402 TI - Network science of biological systems at different scales: A review. AB - Network science is today established as a backbone for description of structure and function of various physical, chemical, biological, technological, and social systems. Here we review recent advances in the study of complex biological systems that were inspired and enabled by methods of network science. First, we present research highlights ranging from determination of the molecular interaction network within a cell to studies of architectural and functional properties of brain networks and biological transportation networks. Second, we focus on synergies between network science and data analysis, which enable us to determine functional connectivity patterns in multicellular systems. Until now, this intermediate scale of biological organization received the least attention from the network perspective. As an example, we review the methodology for the extraction of functional beta cell networks in pancreatic islets of Langerhans by means of advanced imaging techniques. Third, we concentrate on the emerging field of multilayer networks and review the first endeavors and novel perspectives offered by this framework in exploring biological complexity. We conclude by outlining challenges and directions for future research that encompass utilization of the multilayer network formalism in exploring intercellular communication patterns in tissues, and we advocate for network science being one of the key pillars for assessing physiological function of complex biological systems-from organelles to organs-in health and disease. PMID- 29150403 TI - The cortisol reactivity threshold model: Direction of trait rumination and cortisol reactivity association varies with stressor severity. AB - Various internalizing risk factors predict, in separate studies, both augmented and reduced cortisol responding to lab-induced stress. Stressor severity appears key: We tested whether heightened trait-like internalizing risk (here, trait rumination) predicts heightened cortisol reactivity under modest objective stress, but conversely predicts reduced reactivity under more robust objective stress. Thus, we hypothesized that trait rumination would interact with a curvilinear (quadratic) function of stress severity to predict cortisol reactivity. Evidence comes from 85 currently non-depressed emerging adults who completed either a non-stressful control protocol (n = 29), an intermediate difficulty Trier Social Stress Test (TSST; n = 26), or a robustly stressful negative evaluative TSST (n = 30). Latent growth curve models evaluated relationships between trait rumination and linear and quadratic effects of stressor severity on the change in cortisol and negative affect over time. Among other findings, a significant Trait Rumination x Quadratic Stress Severity interaction effect for cortisol's Quadratic Trend of Time (i.e., reactivity, B = .125, p = .017) supported the hypothesis. Rumination predicted greater cortisol reactivity to intermediate stress (rp = .400, p = .043), but blunted reactivity to more robust negative evaluative stress (rp = -0.379, p = 0.039). Contrasting hypotheses, negative affective reactivity increased independently of rumination as stressor severity increased (B = .453, p = 0.044). The direction of the relationship between an internalizing risk factor (trait rumination) and cortisol reactivity varies as a function of stressor severity. We propose the Cortisol Reactivity Threshold Model, which may help reconcile several divergent reactivity literatures and has implications for internalizing psychopathology, particularly depression. PMID- 29150404 TI - Stress hormones concentrations in the normal microenvironment predict risk for chemically induced cancer in rats. AB - Evidence show that stress hormones can influence cancer progression, but its role in carcinogenesis is poorly understood. In this study, we used a new method based on oral carcinogenesis model in rats to test the hypothesis that physiological levels of stress hormones in the normal tissue microenvironment would have significant predictive value for chemically induced cancer occurrence. Male Wistar rats were submitted to a tongue biopsy for measuring not-stress induced levels of norepinephrine, corticosterone, adrenocorticotropic hormone (ACTH) and brain-derived neurotrophic factor (BDNF) in the tissue before carcinogenic induction. Rats were treated with the 4-nitroquinoline-1-oxide (4NQO) chemical carcinogen for twenty weeks and then euthanized for microscopic evaluation of the tongue lesions. Increased pre-carcinogen norepinephrine concentrations and reduced basal corticosterone levels in the normal tissue microenvironment were predictive for oral squamous cell carcinoma (OSCC) occurrence. Likewise, increased pre-carcinogen norepinephrine levels in the normal microenvironment were associated a lower expression of pCDKN2a-p16 in OSCCs. Post-carcinogen levels of corticosterone and BDNF in oral leukoplakia tissues (precursor lesion of OSCC) and post-carcinogen corticosterone concentrations in OSCCs were higher than basal levels in the normal mucosa. Increased norepinephrine concentrations in OSCCs were associated to a greater tumor volume and thickness. Furthermore, higher levels of norepinephrine, ACTH and BDNF in OSCCs were associated to a lesser intensity of the lymphoplasmocytic infiltrate. This study shows that pre carcinogen stress hormones levels in the normal microenvironment may be predictive for chemically induced cancer in rats. Moreover, chemical carcinogenesis can promote stressor-like effects with hormonal changes in the tissue microenvironment, which may be associated to tumor progression. PMID- 29150405 TI - Cirrhosis with ascites in the last year of life: a nationwide analysis of factors shaping costs, health-care use, and place of death in England. AB - BACKGROUND: Liver disease mortality increased by 400% in the UK between 1970 and 2010, resulting in rising pressures on acute hospital services, and an increasing need for end-of-life care. We aimed to assess the effect of demographic, clinical, and health-care factors on costs, patterns of health-care use, and place of death in a national cohort of patients with cirrhosis and ascites in their last year of life. METHODS: We did a retrospective, nationwide analysis of all patients who died from cirrhosis in England between 2013 and 2015, who required large-volume paracentesis in their last year of life. The outcomes measured were health-care costs accrued in the last year of life, number of inpatient days in last year of life, 30-day readmission rate, and occurrence of unplanned hospital death (probability of dying in hospital after unplanned admission). Using generalised linear and logistic regression models, we examined the effect of 12 independent variables on each outcome: sex, ethnicity, age at death, index of multiple deprivation quintile, year of death, liver disease causing death, place of death, time from index presentation in last year of life to death, whether enrolled in a day-case paracentesis service (care group), paracentesis ratio (number of day-case large-volume paracentesis procedures as a proportion of the total number of procedures in the last year of life), number of hospital episodes in the last year of life (not involving large-volume paracentesis), and number of large-volume paracentesis procedures in the last year of life. FINDINGS: Between Jan 1, 2013, and Dec 31, 2015, 13 818 people in England died from liver disease and had large-volume paracentesis within their last year of life. For all patients, mean cost of the last year of life was L21 113 (SD 16 881), 17 888 (52.5%) of 34 068 readmissions occurred within 30 days of discharge, and 10 341 (74.8%) of 13 818 deaths occurred in hospital, of which 10 045 (97.1%) followed an emergency hospital admission. Patients who attended a day case large-volume paracentesis service within their last year of life had significant reductions in cost (-L4240, 95% CI -4829 to -3651; p<0.0001), number of inpatient bed days (-16.98 days, -18.45 to -15.51; p<0.0001), probability of early readmission (odds ratio [OR] 0.35, 95% CI 0.31 to 0.40; p<0.0001), and probability of dying in hospital after unplanned admission (0.31, 0.27 to 0.34; p<0.0001), compared with patients who had unplanned care. For patients enrolled in day-case services, improvements in outcomes correlated with the proportion of large-volume paracentesis procedures done in a day-case (vs unplanned) setting. INTERPRETATION: The use of day-case large-volume paracentesis services in the last year of life was associated with lower costs, reduced pressure on acute hospital services, and a lower probability of dying in hospital, compared with patients who received exclusively unplanned care in their last year of life. Wider adoption of day-case models of care could reduce costs and improve outcomes in the last year of life. FUNDING: David Telling Charitable Trust. PMID- 29150406 TI - Towards patient-centred and cost-effective care for patients with cirrhosis and ascites. PMID- 29150407 TI - Disease trends over time and CD4+CCR5+ T-cells expansion predict carotid atherosclerosis development in patients with systemic lupus erythematosus. AB - BACKGROUND AND AIM: Patients with Systemic Lupus Erythematosus (SLE) present increased cardiovascular mortality compared to the general population. Few studies have assessed the long-term development and progression of carotid atherosclerotic plaque in SLE patients. Our aim was to investigate the association of clinical and laboratory markers of disease activity and classical cardiovascular risk factors (CVRF) with carotid atherosclerosis development in SLE patients in a prospective 5-year study. METHODS AND RESULTS: Clinical history and information on principal CVRFs were collected at baseline and after 5 years in 40 SLE patients (36 women, mean age 42 +/- 9 years; 14.4 +/- 7 years of mean disease duration) and 50 age-matched controls. Carotid Doppler ultrasonography was employed to quantify the atherosclerotic burden at baseline and at follow up. Clinimetrics were applied to assess SLE activity over time (SLEDAI). The association between basal circulating T cell subsets (including CD4+CCR5+; CD4+CXCR3+; CD4+HLADR+; CD4+CD45RA+RO-, CD4+CD45RO+RA- and their subsets) and atherosclerosis development was evaluated. During the 5-year follow up, 32% of SLE patients, developed carotid atherosclerosis compared to 4% of controls. Furthermore, considering SLEDAI changes over time, patients within the highest tertile were those with increased incidence of carotid atherosclerosis independently of CVRF. In addition, increased levels of CD4+CCR5+ T cells were independently associated with the development of carotid atherosclerosis in SLE patients. CONCLUSION: Serial clinical evaluations over time, rather than a single point estimation of disease activity or CVRF burden, are required to define the risk of carotid atherosclerosis development in SLE patients. Specific T cell subsets are associated with long-term atherosclerotic progression and may further be of help in predicting vascular disease progression. PMID- 29150408 TI - Predicting the future of patients with idiopathic pulmonary fibrosis: another step forward. PMID- 29150409 TI - Low lung function in early adulthood: morbidity and death. PMID- 29150410 TI - Lung function in early adulthood and health in later life: a transgenerational cohort analysis. AB - BACKGROUND: Early life events can affect health in later life. We hypothesised that low lung function (FEV1 <80% predicted) in early adulthood (25-40 years) is associated with higher prevalence and earlier incidence of respiratory, cardiovascular, and metabolic abnormalities, and premature death. METHODS: In this cohort analysis, we tested this hypothesis using data from the Framingham Offspring Cohort (FOC) and validated our observations in CARDIA (an independent cohort) and GenIII (which includes the direct descendants of FOC participants). These were three general population cohorts that included men and women, who were regularly and prospectively followed up to collect extensive clinical, physiological, biological, and imaging information. Main outcomes were prevalence (in early adulthood) and incidence (during follow-up) of comorbidity, and all cause mortality. chi2 test, unpaired t test, Fisher's exact test, and Cox proportional hazards models were used for data analysis. Differential dropout rates during follow-up were regarded as a potential source of bias. FINDINGS: We found that 111 (10%) of 1161 participants in FOC, 338 (13%) of 2648 participants in CARDIA, and 71 (4%) of 1912 participants in GenIII had FEV1 of less than 80% predicted at the age of 25-40 years. These individuals also had higher prevalence of respiratory, cardiovascular, and metabolic abnormalities in early adulthood; higher and earlier (about a decade) incidence of comorbidities during follow-up (39 years vs 47 years in FOC; 30 years vs 37 years in CARDIA, p<0.0001); and higher all-cause mortality than individuals with normal lung function in early adulthood (in FOC, hazard ratio 2.3 [95% CI 1.4-3.7], p=0.001), which was independent of, but additive with, cumulative smoking exposure. In GenIII, we observed that individuals with at least one parent stratified as having low lung function in early adulthood in FOC (n=115) had lower FEV1 in early adulthood (10% had FEV1 of less than 80% predicted; this proportion was 3% in those with both parents classified as normal in FOC [n=248]; p<0.0001); and early adulthood FEV1 of GenIII participants was related (R2=0.28, p<0.0001) to FOC parents' average FEV1 in early adulthood. INTERPRETATION: Low peak lung function in early adulthood is common in the general population and could identify a group of individuals at risk of early comorbidities and premature death. FUNDING: Fondo de Investigacion Sanitaria, Sociedad Espanola de Neumologia y Cirurgia Toracica, Formacio Personal Investigador, Agencia de Gestio d'Ajuts de Recerca 2016, and AstraZeneca Foundation Young Researcher Award. PMID- 29150411 TI - An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess potential biomarkers to predict outcomes for people with IPF. METHODS: PROFILE is a large prospective longitudinal cohort of treatment-naive patients with IPF. We adopted a two-stage discovery and validation design using patients from the PROFILE cohort. For the discovery analysis, we examined 106 patients and 50 age and sex matched healthy controls from Nottingham University Hospitals NHS Trust and the Royal Brompton Hospital. We did an unbiased, multiplex immunoassay assessment of 123 biomarkers. We further investigated promising novel markers by immunohistochemical assessment of IPF lung tissue. In the validation analysis, we examined samples from 206 people with IPF from among the remaining 212 patients recruited to PROFILE Central England. We used the samples to attempt to replicate the biomarkers identified from the discovery analysis by use of independent immunoassays for each biomarker. We investigated the predictive power of the selected biomarkers to identify individuals with IPF who were at risk of progression or death. The PROFILE studies are registered on ClinicalTrials.gov, numbers NCT01134822 (PROFILE Central England) and NCT01110694 (PROFILE Royal Brompton Hospital). FINDINGS: In the discovery analysis, we identified four serum biomarkers (surfactant protein D, matrix metalloproteinase 7, CA19-9, and CA-125) that were suitable for replication. Histological assessment of CA19-9 and CA-125 suggested that these proteins were markers of epithelial damage. Replication analysis showed that baseline values of surfactant protein D (46.6 ng/mL vs 34.6 ng/mL, p=0.0018) and CA19-9 (53.7 U/mL vs 22.2 U/mL; p<0.0001) were significantly higher in patients with progressive disease than in patients with stable disease, and rising concentrations of CA-125 over 3 months were associated with increased risk of mortality (HR 2.542, 95% CI 1.493-4.328, p=0.00059). INTERPRETATION: We have identified serum proteins secreted from metaplastic epithelium that can be used to predict disease progression and death in IPF. FUNDING: GlaxoSmithKline R&D and the UK Medical Research Council. PMID- 29150412 TI - Clinical benefits of using inulin clearance and cystatin C for determining glomerular filtration rate in HIV-1-infected individuals treated with dolutegravir. AB - INTRODUCTION: Dolutegravir may inhibit creatinine transporters in renal tubules and elevate serum creatinine levels. We investigated the usefulness of glomerular filtration rate (GFR) measured using inulin clearance (Cin), creatinine clearance (Ccr), and estimated GFR based on both serum creatinine (eGFRcre) and serum cystatin C (eGFRcys). PATIENTS & METHODS: HIV-1-infected Japanese patients with suppressed viremia and whose antiretroviral drug was switched to dolutegravir from other drugs were included (n = 108, Study 1). We compared eGFRcre and eGFRcys at the start and after 48 weeks of dolutegravir administration. For the patients providing consent, we measured Cin and Ccr (n = 15, Study 2). We assessed biases and accuracy and compared Cin with eGFRcre, eGFRcys, and Ccr. RESULTS: There were no differences in serum cystatin C and eGFRcys between baseline and at 48 weeks. Moreover, eGFRcre was significantly less accurate (within 30% of measured GFR) than both eGFRcys and Ccr (40% accuracy compared to 93% and 93%, respectively). eGFRcys was significantly less biased than eGFRcre and Ccr (p < 0.0001, p = 0.00036, respectively). No significant difference between Cin and eGFRcys was observed. eGFRcys was significantly correlated with Cin (gamma = 0.85, p < 0.0001). CONCLUSIONS: eGFRcys provided the most precise estimate and most closely approximate Cin in HIV-1-infected Japanese patients with suppressed viremia treated with dolutegravir. We demonstrated clinical benefits of inulin clearance and eGFRcys. This is the first study performing inulin clearance for HIV-1-infected individuals and to show data for eGFRcys from a large cohort following a switch to dolutegravir from other antiretroviral agents. PMID- 29150413 TI - [The situation as regards diabetes mellitus type 1 in Andalusia. Care data, use of advanced therapies and human resources]. AB - INTRODUCTION: The representation of Spain in European epidemiological studies on diabetes is limited, with only one centre in the Hvidoere study and another in the SWEET study. No Spanish studies have been published that combine epidemiological data and care resources. The aim of this study was to determine the epidemiological data, care resources, and use of new technologies in all Andalusian hospitals that care for children with Diabetes Mellitus type 1 (DM1) under 14 years. MATERIAL AND METHODS: An electronic questionnaire of 18 questions was sent to all paediatric endocrinologists who treated children with diabetes in Andalusian hospitals. RESULTS: There was a mean of 3.12 (SD: 2.58) paediatric endocrinologist for every 100 patients, with a mean diabetes nurse educator ratio of 2.50 (SD: 3.94) per 100 patients and centre. Only 1 of the 29 centres had a psychologist, 9/29 had a day hospital, and 11/29 had a 24-hour telephone line. The mean of days of consultations exclusively for patients with DM1 was 1.56 days (SD: 1.21) per week. Continuous insulin infusion was used to treat 5% of patients, with a significant increase in centres with more than 150 patients. CONCLUSIONS: This study offers, for the first time, current data on the epidemiological situation related to health care data, comparing them with the recommendations of European standards, highlighting a low ratio of endocrinologists and educators in diabetes, absence of psychologists and low technology penetrance. PMID- 29150415 TI - [Initiating hemodialysis in Morocco: Impact of late referral]. AB - INTRODUCTION: End-stage renal disease (ESRD) is a major public health concern in Morocco with an incidence in constant progression according to MAGREDIAL "Morocco Dialysis Registry". Patients are often sent late to nephrologists, which is a source of complications recognized in several countries. For these reasons, we tried to evaluate, in our context, the prevalence and factors of this late referral (LR). METHODS: This is a retrospective study which included all patients initiating hemodialysis between January 2007 and December 2015. We found the history of following these patients and sought their clinical characteristics at the time of setting hemodialysis. RESULTS: During the study, 318 patients were admitted for management of ESRD. Their average age was 54.31 years and diabetic nephropathy was the most common cause of 41% of cases. Only 105 patients (33%) had a nephrological follw up in almost two thirds of cases, hemodialysis was started by using a temporary central venous catheter especially femoral. we have identified five factors associated with LR: nemia, hypoalbuminemia, inflammatory syndrome, a longer initial hospitalization, a greater use of temporary catheterization as first access. CONCLUSION: LR patients with ESRD remains very common in our context. It is about 67% and complicates implementation hemodialysis patients with anemia and more use of central catheters that are predictors of mortality previously described in the literature. Economically, LR significantly increases the cost of care by significantly increasing the duration of hospitalization. PMID- 29150416 TI - [Bicarbonate: From physiology to treatment for all clinicians]. AB - Acid-base regulation is essential to maintain homeostasis in humans. Carbonic acid/bicarbonate (H2CO3/HCO3-) couple is the most predominant extracellular buffer to keep plasma pH within a physiological range. The ability to (re)generate such a buffer is a key milestone that necessitates to understand a precise physiology of both renal tubule and digestive tract. Here, we first reviewed renal and digestive cycles of bicarbonate in physiology. We also reviewed pathological findings where acid-base disequilibrium is involved and nutritional and/or alkali therapy could be necessary. Secondly, data from clinical trials were synthesized. Alkali therapy, oral and parenteral, from mineral-based water, masterful preparations or pharmaceutics drugs, is regularly used in a wide range of clinical findings, even if supporting data are (often) of a low level of evidence. Bicarbonate is primarily used during contrast-induced nephropathy, metabolic acidosis in chronic kidney disease or nephrolithiasis in which alkaline urine is necessary. Cast nephropathy, rhabdomyolysis and tumor lysis syndrome make usually physicians prescribe alkali therapy even if this prescription is only supported by physiopathological data without any proven clinical results. Finally, bicarbonate is essential in the composition of dialysate in both hemodialysis and peritoneal dialysis. PMID- 29150414 TI - Constraints on Statistical Learning Across Species. AB - Both human and nonhuman organisms are sensitive to statistical regularities in sensory inputs that support functions including communication, visual processing, and sequence learning. One of the issues faced by comparative research in this field is the lack of a comprehensive theory to explain the relevance of statistical learning across distinct ecological niches. In the current review we interpret cross-species research on statistical learning based on the perceptual and cognitive mechanisms that characterize the human and nonhuman models under investigation. Considering statistical learning as an essential part of the cognitive architecture of an animal will help to uncover the potential ecological functions of this powerful learning process. PMID- 29150417 TI - Using Facebook to Recruit Young Australian Men Into a Cross-Sectional Human Papillomavirus Study. AB - BACKGROUND: Young men can be difficult to engage in health research using traditional methods of recruitment. Social networking sites are increasingly being used to recruit participants into health research, due to their cost effectiveness, overall generalizability, and wide reach. OBJECTIVE: The aim of this study was to determine the feasibility of using Facebook to recruit young Australian men into a human papillomavirus (HPV) prevalence study. METHODS: We recruited male permanent residents of Australia, aged 18 to 35 years, into the HPV in Young Males (HYM) study through targeted advertising placed on Facebook. Consenting participants completed an online questionnaire and provided a self collected penile swab for HPV DNA detection and genotyping. We compared sociodemographic characteristics of the study population with those of the general Australian male population, based on Australian 2011 census data. RESULTS: Between February 2015 and February 2017, targeted Facebook advertisements reached 1,523,239 men, resulting in 41,811 clicks through to the study website, with 1072 (2.56%) converting to lodgment of an expression of interest. Of these, 681 (63.53%) provided written informed consent and 535 (78.6% of recruited participants) completed all the study requirements. Reasons for participating in the study included altruism, past history of HPV, gaining more knowledge about HPV or the vaccine, working in the health industry, and the monetary compensation. The average advertising cost per completed study participant was Aus $48. Compared with the census population, HYM study participants were more likely to be Australian born (P<.001), be from Victoria (P=.003) or the Australian Capital Territory (P=.004), reside in a major city (P<.001), and have completed undergraduate (P<.001) or postgraduate education (P<.001). HYM study participants were less likely to report being a current smoker (P=.03), but were more likely to identify as bisexual or homosexual (294/529, 55.6%, P<.001), than the general population. CONCLUSIONS: Using Facebook is a feasible and efficient strategy for the recruitment of men from across Australia for HPV testing. This method could be used for monitoring the impact of HPV vaccination. Additional targeting may achieve a sample that is broadly demographically representative of the Australian population. Future research should explore how the sexual risk behavior characteristics of populations recruited through Facebook compare with those of traditional recruitment methods. PMID- 29150418 TI - Immune-Enhancing Formulas for Patients With Cancer Undergoing Esophagectomy: Systematic Review Protocol. AB - BACKGROUND: Adult patients with an esophageal cancer can potentially be compromised with postoperative leaks or fistulae if patients' nutritional status is in a vulnerable stage. Currently in Australia, there is a growing need for clinicians to know whether use of immune-enhancing formulas (IEFs) containing Arg, omega-3, and RNA are a cost-effective approach compared with isonitrogenous isocaloric formulas to reduce postoperative infectious complications in esophagectomy patients. Since IEFs may carry higher costs, this has led to inconsistencies in practice among clinicians and hospitals. OBJECTIVE: Our aim is to compile and present the most up-to-date nutrition evidence available regarding the provision of IEFs containing Arg, omega-3, and RNA to help clinicians develop an evidence-based nutrition care plan; identify available evidence of whether an esophagectomy patient should receive IEF; determine the cost-effectiveness and safety of such nutrition; and determine appropriate administration quantity and timing (pre-, peri-, or postesophagectomy). METHODS: This review will include RCTs involving the use of IEFs enriched with Arg, omega-3 polyunsaturated fatty acids, and RNA in the pre-, peri-, or postoperative period (for at least 5-7 days) given orally or via enteral feeding tube, in adult cancer patients undergoing esophageal resection. Lower gastrointestinal, gastric, or head cancer surgery with parenteral nutrition or non-IEF or use of isolated immunonutrient (Arg vs omega-3 vs RNA) will be excluded. Primary outcome comprises postoperative infectious complications. Secondary outcomes (pre/postoperatively) consist of cost-effectiveness, length of stay, survival/mortality, quality of life, nutritional status, percentage of weight loss, and biochemical changes. The risk of bias will be independently assessed by the reviewers, using a domain-based evaluation tool. Blinding will be assessed for subjective and objective outcome measures. Publication bias will be visually assessed by funnel plots. A meta analysis will be generated by the Review Manager 5.3 software and represented in forest plots. RESULTS: The first results are expected in 2018. Outlining the protocol will ensure transparency for the completed review. CONCLUSIONS: This protocol for a systematic review and meta-analysis will enable a comprehensive appraisal of the literature to help determine whether overall institutional savings are associated with this approach. Findings will form a knowledge base relevant to stakeholders across the health system and researchers who are involved in decision making on evidence-based nutrition care plan pathways for patients undergoing esophagectomy, as well as the use of IEF, timing, and administration quantity. TRIAL REGISTRATION: PROSPERO Registration Number: CRD42017056908; http://www.crd.york.ac.uk/PROSPERO/ display_record.asp? ID=CRD42017056908 (Archived by WebCite at http://www.webcitation.org/6rLyeqaD6). PMID- 29150420 TI - Return to firm structure could help boost trainee morale, says Royal College of Surgeons. PMID- 29150419 TI - Adapting clinical guidelines in India-a pragmatic approach. PMID- 29150422 TI - Woman who rejected breast cancer diagnosis may undergo surgery without her consent. PMID- 29150423 TI - Including children and young people in assessments: a practical guide. AB - The ability to interact with children and young people (CYP), appropriately examine and competently interpret signs is an essential skill for many medical practitioners and allied healthcare professionals; yet, how do we ensure competence in our students and trainees? One method is to include CYP in both formative and summative assessments; this provides an invaluable opportunity for examiners not only to evaluate the clinical interaction but also to gain an understanding of the CYP experience and what characteristics they value in a 'good children's doctor'. This paper explores the benefits and challenges of involving CYP in assessments and provides practical advice for course organisers, assessors and students when encountering CYP in assessment. PMID- 29150421 TI - Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. AB - This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified >=60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ~30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39. PMID- 29150424 TI - How to use peak expiratory flow rate. PMID- 29150425 TI - Amino-bisphosphonates, gammadeltaT cells, and their roles in Rheumatoid Arthritis. PMID- 29150426 TI - Long-Term Outcomes in Patients With Type 2 Myocardial Infarction and Myocardial Injury. AB - BACKGROUND: Type 2 myocardial infarction and myocardial injury are common in clinical practice, but long-term consequences are uncertain. We aimed to define long-term outcomes and explore risk stratification in patients with type 2 myocardial infarction and myocardial injury. METHODS: We identified consecutive patients (n=2122) with elevated cardiac troponin I concentrations (>=0.05 ug/L) at a tertiary cardiac center. All diagnoses were adjudicated as per the universal definition of myocardial infarction. The primary outcome was all-cause death. Secondary outcomes included major adverse cardiovascular events (eg, nonfatal myocardial infarction or cardiovascular death) and noncardiovascular death. To explore competing risks, cause-specific hazard ratios were obtained using Cox regression models. RESULTS: The adjudicated index diagnosis was type 1 or 2 myocardial infarction or myocardial injury in 1171 (55.2%), 429 (20.2%), and 522 (24.6%) patients, respectively. At 5 years, all-cause death rates were higher in those with type 2 myocardial infarction (62.5%) or myocardial injury (72.4%) compared with type 1 myocardial infarction (36.7%). The majority of excess deaths in those with type 2 myocardial infarction or myocardial injury were because of noncardiovascular causes (hazard ratio, 2.32; 95% confidence interval, 1.92-2.81 versus type 1 myocardial infarction). Despite this finding, the observed crude major adverse cardiovascular event rates were similar between groups (30.6% versus 32.6%), with differences apparent after adjustment for covariates (hazard ratio, 0.82; 95% confidence interval, 0.69-0.96). Coronary heart disease was an independent predictor of major adverse cardiovascular events in those with type 2 myocardial infarction or myocardial injury (hazard ratio, 1.71; 95% confidence interval, 1.31-2.24). CONCLUSIONS: Despite an excess in noncardiovascular death, patients with type 2 myocardial infarction or myocardial injury have a similar crude rate of major adverse cardiovascular events as those with type 1 myocardial infarction. Identifying underlying coronary heart disease in this vulnerable population may help target therapies that could modify future risk. PMID- 29150428 TI - New guideline will put 30 million more Americans in high BP group. PMID- 29150427 TI - Delayed Encounter of Parental Genomes Can Lead to Aneuploidy in Saccharomyces cerevisiae. AB - We have investigated an extreme deviation from the norm of genome unification that occurs during mating in the yeast, Saccharomyces cerevisiae This deviation is encountered when yeast that carry a mutation of the spindle pole body protein, Kar1, are mated with wildtype cells. In this case, nuclear fusion is delayed and the genotypes of a fraction of zygotic progeny suggest that chromosomes have "transferred" between the parental nuclei in zygotes. This classic, yet bizarre, occurrence is routinely used to generate aneuploid (disomic) yeast. [kar1 * wt] zygotes, like [wt * wt] zygotes, initially have a single spindle pole body per nucleus. Unlike [wt * wt] zygotes, in [kar1 * wt] zygotes, the number of spindle pole bodies per nucleus then can increase before nuclear fusion. When such nuclei fuse, the spindle pole bodies do not coalesce efficiently, and subsets of spindle pole bodies and centromeres can enter buds. The genotypes of corresponding biparental progeny show evidence of extensive haplotype-biased chromosome loss, and can also include heterotypic chromosomal markers. They thus allow rationalization of chromosome "transfer" as being due to an unanticipated yet plausible mechanism. Perturbation of the unification of genomes likely contributes to infertility in other organisms. PMID- 29150429 TI - cGAMP: A tale of two signals. AB - In this issue of JEM, Swanson et al. (https://doi.org/10.1084/jem.20171749) report an unanticipated role for cGAMP in priming and activation of inflammasomes in addition to its well-characterized function as an endogenous second messenger inducing type I interferons in the cytosolic DNA-sensing pathway. PMID- 29150430 TI - Interferon-gamma Signaling in Melanocytes and Melanoma Cells Regulates Expression of CTLA-4. AB - CTLA4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti-CTLA4 immunotherapy is highly effective at reactivating T-cell responses against melanoma, which is postulated to be due to targeting CTLA4 on T cells. Here, we report that CTLA4 is also highly expressed by most human melanoma cell lines, as well as in normal human melanocytes. Interferon-gamma (IFNG) signaling activated the expression of the human CTLA4 gene in a melanocyte and melanoma cell-specific manner. Mechanistically, IFNG activated CTLA4 expression through JAK1/2-dependent phosphorylation of STAT1, which bound a specific gamma-activated sequence site on the CTLA4 promoter, thereby licensing CBP/p300-mediated histone acetylation and local chromatin opening. In melanoma cell lines, elevated baseline expression relied upon constitutive activation of the MAPK pathway. Notably, RNA-seq analyses of melanoma specimens obtained from patients who had received anti-CTLA4 immunotherapy (ipilimumab) showed upregulation of an IFNG-response gene expression signature, including CTLA4 itself, which correlated significantly with durable response. Taken together, our results raise the possibility that CTLA4 targeting on melanoma cells may contribute to the clinical immunobiology of anti CTLA4 responses.Significance: These findings show that human melanoma cells express high levels of the immune checkpoint molecule CTLA4, with important possible implications for understanding how anti-CTLA4 immunotherapy mediates its therapeutic effects. Cancer Res; 78(2); 436-50. (c)2017 AACR. PMID- 29150431 TI - The E3 ubiquitin ligase APC/CCdh1 degrades MCPH1 after MCPH1-betaTrCP2-Cdc25A mediated mitotic entry to ensure neurogenesis. AB - Mutations of microcephalin (MCPH1) can cause the neurodevelopmental disorder primary microcephaly type 1. We previously showed that MCPH1 deletion in neural stem cells results in early mitotic entry that distracts cell division mode, leading to exhaustion of the progenitor pool. Here, we show that MCPH1 interacts with and promotes the E3 ligase betaTrCP2 to degrade Cdc25A independent of DNA damage. Overexpression of betaTrCP2 or the knockdown of Cdc25A remedies the high mitotic index and rescues the premature differentiation of Mcph1-deficient neuroprogenitors in vivo MCPH1 itself is degraded by APC/CCdh1, but not APC/CCdc20, in late mitosis and G1 phase. Forced MCPH1 expression causes cell death, underlining the importance of MCPH1 turnover after mitosis. Ectopic expression of Cdh1 leads to premature differentiation of neuroprogenitors, mimicking differentiation defects of Mcph1-knockout neuroprogenitors. The homeostasis of MCPH1 in association with the ubiquitin-proteasome system ensures mitotic entry independent of cell cycle checkpoint. This study provides a mechanistic understanding of how MCPH1 controls neural stem cell fate and brain development. PMID- 29150434 TI - Campaigners vow to fight on after report finds no link between hormone test and birth defects. PMID- 29150432 TI - The IKK-related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists. AB - The innate immune kinase TBK1 initiates inflammatory responses to combat infectious pathogens by driving production of type I interferons. TBK1 also controls metabolic processes and promotes oncogene-induced cell proliferation and survival. Here, we demonstrate that TBK1 activates mTOR complex 1 (mTORC1) directly. In cultured cells, TBK1 associates with and activates mTORC1 through site-specific mTOR phosphorylation (on S2159) in response to certain growth factor receptors (i.e., EGF-receptor but not insulin receptor) and pathogen recognition receptors (PRRs) (i.e., TLR3; TLR4), revealing a stimulus-selective role for TBK1 in mTORC1 regulation. By studying cultured macrophages and those isolated from genome edited mTOR S2159A knock-in mice, we show that mTOR S2159 phosphorylation promotes mTORC1 signaling, IRF3 nuclear translocation, and IFN beta production. These data demonstrate a direct mechanistic link between TBK1 and mTORC1 function as well as physiologic significance of the TBK1-mTORC1 axis in control of innate immune function. These data unveil TBK1 as a direct mTORC1 activator and suggest unanticipated roles for mTORC1 downstream of TBK1 in control of innate immunity, tumorigenesis, and disorders linked to chronic inflammation. PMID- 29150433 TI - Tyrosine phosphorylation of Munc18-1 inhibits synaptic transmission by preventing SNARE assembly. AB - Tyrosine kinases are important regulators of synaptic strength. Here, we describe a key component of the synaptic vesicle release machinery, Munc18-1, as a phosphorylation target for neuronal Src family kinases (SFKs). Phosphomimetic Y473D mutation of a SFK phosphorylation site previously identified by brain phospho-proteomics abolished the stimulatory effect of Munc18-1 on SNARE complex formation ("SNARE-templating") and membrane fusion in vitro Furthermore, priming but not docking of synaptic vesicles was disrupted in hippocampal munc18-1-null neurons expressing Munc18-1Y473D Synaptic transmission was temporarily restored by high-frequency stimulation, as well as by a Munc18-1 mutation that results in helix 12 extension, a critical conformational step in vesicle priming. On the other hand, expression of non-phosphorylatable Munc18-1 supported normal synaptic transmission. We propose that SFK-dependent Munc18-1 phosphorylation may constitute a potent, previously unknown mechanism to shut down synaptic transmission, via direct occlusion of a Synaptobrevin/VAMP2 binding groove and subsequent hindrance of conformational changes in domain 3a responsible for vesicle priming. This would strongly interfere with the essential post-docking SNARE-templating role of Munc18-1, resulting in a largely abolished pool of releasable synaptic vesicles. PMID- 29150435 TI - Biochemical characterization of INTS3 and C9ORF80, two subunits of hNABP1/2 heterotrimeric complex in nucleic acid binding. AB - Human nucleic acid-binding protein 1 and 2 (hNABP1 and hNABP2, also known as hSSB2 and hSSB1 respectively) form two separate and independent complexes with two identical proteins, integrator complex subunit 3 (INTS3) and C9ORF80. We and other groups have demonstrated that hNABP1 and 2 are single-stranded (ss) DNA- and RNA-binding proteins, and function in DNA repair; however, the function of INTS3 and C9OFR80 remains elusive. In the present study, we purified recombinant proteins INTS3 and C9ORF80 to near homogeneity. Both proteins exist as a monomer in solution; however, C9ORF80 exhibits anomalous behavior on SDS-PAGE and gel filtration because of 48% random coil present in the protein. Using electrophoretic mobility shift assay (EMSA), INTS3 displays higher affinity toward ssRNA than ssDNA, and C9ORF80 binds ssDNA but not ssRNA. Neither of them binds dsDNA, dsRNA, or RNA : DNA hybrid. INTS3 requires minimum of 30 nucleotides, whereas C9OFR80 requires 20 nucleotides for its binding, which increased with the increasing length of ssDNA. Interestingly, our GST pulldown results suggest that the N-terminus of INTS3 is involved in protein-protein interaction, while EMSA implies that the C-terminus is required for nucleic acid binding. Furthermore, we purified the INTS3-hNABP1/2-C9ORF80 heterotrimeric complex. It exhibits weaker binding compared with the individual hNABP1/2; interestingly, the hNABP1 complex prefers ssDNA, whereas hNABP2 complex prefers ssRNA. Using reconstituted heterotrimeric complex from individual proteins, EMSA demonstrates that INTS3, but not C9ORF80, affects the nucleic acid-binding ability of hNABP1 and hNABP2, indicating that INTS3 might regulate hNABP1/2's biological function, while the role of C9ORF80 remains unknown. PMID- 29150436 TI - Microvesicles derived from human Wharton's Jelly mesenchymal stem cells ameliorate ischemia-reperfusion-induced renal fibrosis by releasing from G2/M cell cycle arrest. AB - Studies have demonstrated that microvesicles (MVs) derived from human Wharton's Jelly mesenchymal stromal cells (hWJMSCs) could ameliorate renal ischemia/reperfusion injury (IRI); however, the underlying mechanisms were not clear yet. Here, MVs were isolated and injected intravenously into rats immediately after ischemia of the left kidney, and Erk1/2 activator hepatocyte growth factor (HGF) or inhibitor U0126 was administrated. Tubular cell proliferation and apoptosis were identified by Ki67 or terminal-deoxynucleotidyl transferase-mediated nick end labeling immunostaining. Masson's tri-chrome straining and alpha-smooth muscle actin staining were used for assessing renal fibrosis. The mRNA or protein expression in the kidney was measured by quantitative reverse transcription-PCR or Western blot, respectively. The total collagen concentration was also determined. In vitro, NRK-52E cells that treated with MVs under hypoxia injury and with HGF or U0126 administration were used, and cell cycle analysis was performed. The effects of hWJMSC-MVs on enhancing the proliferation and mitigating the apoptosis of renal cells, abrogating IRI-induced fibrosis, improving renal function, decreasing collagen deposition, and altering the expression levels of epithelial-mesenchymal transition and cell cycle-related proteins in IRI rats were found. In vitro experiment showed that hWJMSC-MVs could induce G2/M cell cycle arrest and decrease the expression of collagen deposition related proteins in NRK-52E cells after 24 or 48 h. However, U0126 treatment reversed these effects. In conclusion, MVs derived from hWJMSCs ameliorate IR induced renal fibrosis by inducing G2/M cell cycle arrest via Erk1/2 signaling. PMID- 29150437 TI - Mechanism of activation of SGK3 by growth factors via the Class 1 and Class 3 PI3Ks. AB - Derailment of the PI3K-AGC protein kinase signalling network contributes to many human diseases including cancer. Recent work has revealed that the poorly studied AGC kinase family member, SGK3, promotes resistance to cancer therapies that target the Class 1 PI3K pathway, by substituting for loss of Akt kinase activity. SGK3 is recruited and activated at endosomes, by virtue of its phox homology domain binding to PtdIns(3)P. Here, we demonstrate that endogenous SGK3 is rapidly activated by growth factors such as IGF1, through pathways involving both Class 1 and Class 3 PI3Ks. We provide evidence that IGF1 enhances endosomal PtdIns(3)P levels via a pathway involving the UV-RAG complex of hVPS34 Class 3 PI3K. Our data point towards IGF1-induced activation of Class 1 PI3K stimulating SGK3 through enhanced production of PtdIns(3)P resulting from the dephosphorylation of PtdIns(3,4,5)P3 Our findings are also consistent with activation of Class 1 PI3K promoting mTORC2 phosphorylation of SGK3 and with oncogenic Ras-activating SGK3 solely through the Class 1 PI3K pathway. Our results highlight the versatility of upstream pathways that activate SGK3 and help explain how SGK3 substitutes for Akt following inhibition of Class 1 PI3K/Akt pathways. They also illustrate robustness of SGK3 activity that can remain active and counteract physiological conditions or stresses where either Class 1 or Class 3 PI3K pathways are inhibited. PMID- 29150438 TI - A PIP2-derived amplification loop fuels the sustained initiation of B cell activation. AB - Lymphocytes have evolved sophisticated signaling amplification mechanisms to efficiently activate downstream signaling after detection of rare ligands in their microenvironment. B cell receptor microscopic clusters (BCR microclusters) are assembled on the plasma membrane and recruit signaling molecules for the initiation of lymphocyte signaling after antigen binding. We identified a signaling amplification loop derived from phosphatidylinositol 4,5-biphosphate (PIP2) for the sustained B cell activation. Upon antigen recognition, PIP2 was depleted by phospholipase C-gamma2 (PLC-gamma2) within the BCR microclusters and was regenerated by phosphatidic acid-dependent type I phosphatidylinositol 4 phosphate 5-kinase outside the BCR microclusters. The hydrolysis of PIP2 inside the BCR microclusters induced a positive feedback mechanism for its synthesis outside the BCR microclusters. The falling gradient of PIP2 across the boundary of BCR microclusters was important for the efficient formation of BCR microclusters. Our results identified a PIP2-derived amplification loop that fuels the sustained initiation of B cell activation. PMID- 29150440 TI - License to kill: IFN-lambda regulates antifungal activity of neutrophils. AB - Interferon-lambda mediates antifungal immunity by stimulating neutrophils to generate reactive oxygen species. PMID- 29150439 TI - Suppression of FIP200 and autophagy by tumor-derived lactate promotes naive T cell apoptosis and affects tumor immunity. AB - Naive T cells are poorly studied in cancer patients. We report that naive T cells are prone to undergo apoptosis due to a selective loss of FAK family-interacting protein of 200 kDa (FIP200) in ovarian cancer patients and tumor-bearing mice. This results in poor antitumor immunity via autophagy deficiency, mitochondria overactivation, and high reactive oxygen species production in T cells. Mechanistically, loss of FIP200 disables the balance between proapoptotic and antiapoptotic Bcl-2 family members via enhanced argonaute 2 (Ago2) degradation, reduced Ago2 and microRNA1198-5p complex formation, less microRNA1198-5p maturation, and consequently abolished microRNA1198-5p-mediated repression on apoptotic gene Bak1 Bcl-2 overexpression and mitochondria complex I inhibition rescue T cell apoptosis and promoted tumor immunity. Tumor-derived lactate translationally inhibits FIP200 expression by down-regulating the nicotinamide adenine dinucleotide level while potentially up-regulating the inhibitory effect of adenylate-uridylate-rich elements within the 3' untranslated region of Fip200 mRNA. Thus, tumors metabolically target naive T cells to evade immunity. PMID- 29150441 TI - Co(II) and Ni(II) binding of the Escherichia coli transcriptional repressor RcnR orders its N terminus, alters helix dynamics, and reduces DNA affinity. AB - RcnR, a transcriptional regulator in Escherichia coli, derepresses the expression of the export proteins RcnAB upon binding Ni(II) or Co(II). Lack of structural information has precluded elucidation of the allosteric basis for the decreased DNA affinity in RcnR's metal-bound states. Here, using hydrogen-deuterium exchange coupled with MS (HDX-MS), we probed the RcnR structure in the presence of DNA, the cognate metal ions Ni(II) and Co(II), or the noncognate metal ion Zn(II). We found that cognate metal binding altered flexibility from the N terminus through helix 1 and modulated the RcnR-DNA interaction. Apo-RcnR and RcnR-DNA complexes and the Zn(II)-RcnR complex exhibited similar 2H uptake kinetics, with fast-exchanging segments located in the N terminus, in helix 1 (residues 14-24), and at the C terminus. The largest difference in 2H incorporation between apo- and Ni(II)- and Co(II)-bound RcnR was observed in helix 1, which contains the N terminus and His-3, and has been associated with cognate metal binding. 2H uptake in helix 1 was suppressed in the Ni(II)- and Co(II)-bound RcnR complexes, in particular in the peptide corresponding to residues 14-24, containing Arg-14 and Lys-17. Substitution of these two residues drastically affected DNA-binding affinity, resulting in rcnA expression in the absence of metal. Our results suggest that cognate metal binding to RcnR orders its N terminus, decreases helix 1 flexibility, and induces conformational changes that restrict DNA interactions with the positively charged residues Arg-14 and Lys-17. These metal-induced alterations decrease RcnR-DNA binding affinity, leading to rcnAB expression. PMID- 29150442 TI - Functional analyses of a human vascular tumor FOS variant identify a novel degradation mechanism and a link to tumorigenesis. AB - Epithelioid hemangioma is a locally aggressive vascular neoplasm, found in bones and soft tissue, whose cause is currently unknown, but may involve oncogene activation. FOS is one of the earliest viral oncogenes to be characterized, and normal cellular FOS forms part of the activator protein 1 (AP-1) transcription factor complex, which plays a pivotal role in cell growth, differentiation, and survival as well as the DNA damage response. Despite this, a causal link between aberrant FOS function and naturally occurring tumors has not yet been established. Here, we describe a thorough molecular and biochemical analysis of a mutant FOS protein we identified in these vascular tumors. The mutant protein lacks a highly conserved helix consisting of the C-terminal four amino acids of FOS, which we show is indispensable for fast, ubiquitin-independent FOS degradation via the 20S proteasome. Our work reveals that FOS stimulates endothelial sprouting and that perturbation of normal FOS degradation could account for the abnormal vessel growth typical of epithelioid hemangioma. To the best of our knowledge, this is the first functional characterization of mutant FOS proteins found in tumors. PMID- 29150443 TI - Kinetic mechanism of controlled Fab-arm exchange for the formation of bispecific immunoglobulin G1 antibodies. AB - Bispecific antibodies (bsAbs) combine the antigen specificities of two distinct Abs and demonstrate therapeutic promise based on novel mechanisms of action. Among the many platforms for creating bsAbs, controlled Fab-arm exchange (cFAE) has proven useful based on minimal changes to native Ab structure and the simplicity with which bsAbs can be formed from two parental Abs. Despite a published protocol for cFAE and its widespread use in the pharmaceutical industry, the reaction mechanism has not been determined. Knowledge of the mechanism could lead to improved yields of bsAb at faster rates as well as foster adoption of process control. In this work, a combination of Forster resonance energy transfer (FRET), nonreducing SDS-PAGE, and strategic mutation of the Ab hinge region was employed to identify and characterize the individual steps of cFAE. Fluorescence correlation spectroscopy (FCS) was used to determine the affinity of parental (homodimer) and bispecific (heterodimer) interactions within the CH3 domain, further clarifying the thermodynamic basis for bsAb formation. The result is a clear sequence of events with rate constants that vary with experimental conditions, where dissociation of the K409R parental Ab into half-Ab controls the rate of the reaction. PMID- 29150445 TI - The antiapoptotic protein HAX-1 mediates half of phospholamban's inhibitory activity on calcium cycling and contractility in the heart. AB - The antiapoptotic protein HAX-1 (HS-associated protein X-1) localizes to sarcoplasmic reticulum (SR) in the heart and interacts with the small membrane protein phospholamban (PLN), inhibiting the cardiac sarco/endoplasmic reticulum calcium ATPase 2a (SERCA2a) in the regulation of overall calcium handling and heart muscle contractility. However, because global HAX-1 deletion causes early lethality, how much endogenous HAX-1 contributes to PLN's inhibitory activity on calcium cycling is unknown. We therefore generated a cardiac-specific and inducible knock-out mouse model. HAX-1 ablation in the adult heart significantly increased contractile parameters and calcium kinetics, associated with increased SR calcium load. These changes occurred without any changes in the protein expression of SERCA2a, PLN, and ryanodine receptor or in the PLN phosphorylation status. The enhanced calcium cycling in the HAX-1-depleted heart was mediated through increases in the calcium affinity of SERCA2a and reduced PLN-SERCA2a binding. Comparison of the HAX-1 deletion-induced stimulatory effects with those elicited by PLN ablation indicated that HAX-1 mediates ~50% of the PLN-associated inhibitory effects in the heart. Stimulation with the inotropic and lusitropic agent isoproterenol eliminated the differences among wild-type, HAX-1-deficient, and PLN-deficient hearts, and maximally stimulated contractile and calcium kinetic parameters were similar among these three groups. Furthermore, PLN overexpression in the HAX-1-null cardiomyocytes did not elicit any inhibitory effects, indicating that HAX-1 may limit PLN activity. These findings suggest that HAX-1 is a major mediator of PLN's inhibitory activity and a critical gatekeeper of SR calcium cycling and contractility in the heart. PMID- 29150444 TI - Toll-like receptor 4-induced ryanodine receptor 2 oxidation and sarcoplasmic reticulum Ca2+ leakage promote cardiac contractile dysfunction in sepsis. AB - Studies suggest the potential role of a sarcoplasmic reticulum (SR) Ca2+ leak in cardiac contractile dysfunction in sepsis. However, direct supporting evidence is lacking, and the mechanisms underlying this SR leak are poorly understood. Here, we investigated the changes in cardiac Ca2+ handling and contraction in LPS treated rat cardiomyocytes and a mouse model of polymicrobial sepsis produced by cecal ligation and puncture (CLP). LPS decreased the systolic Ca2+ transient and myocyte contraction as well as SR Ca2+ content. Meanwhile, LPS increased Ca2+ spark-mediated SR Ca2+ leak. Preventing the SR leak with ryanodine receptor (RyR) blocker tetracaine restored SR load and increased myocyte contraction. Similar alterations in Ca2+ handling were observed in cardiomyocytes from CLP mice. Treatment with JTV-519, an anti-SR leak drug, restored Ca2+ handling and improved cardiac function. In the LPS-treated cardiomyocytes, mitochondrial reactive oxygen species and oxidative stress in RyR2 were increased, whereas the levels of the RyR2-associated FK506-binding protein 1B (FKBP12.6) were decreased. The Toll like receptor 4 (TLR4)-specific inhibitor TAK-242 reduced the oxidative stress in LPS-treated cells, decreased the SR leak, and normalized Ca2+ handling and myocyte contraction. Consistently, TLR4 deletion significantly improved cardiac function and corrected abnormal Ca2+ handling in the CLP mice. This study provides evidence for the critical role of the SR Ca2+ leak in the development of septic cardiomyopathy and highlights the therapeutic potential of JTV-519 by preventing SR leak. Furthermore, it reveals that TLR4 activation-induced mitochondrial reactive oxygen species production and the resulting oxidative stress in RyR2 contribute to the SR Ca2+ leak. PMID- 29150446 TI - Biogenesis of the bacterial cbb3 cytochrome c oxidase: Active subcomplexes support a sequential assembly model. AB - The cbb3 oxidase has a high affinity for oxygen and is required for growth of bacteria, including pathogens, in oxygen-limited environments. However, the assembly of this oxidase is poorly understood. Most cbb3 are composed of four subunits: the catalytic CcoN subunit, the two cytochrome c subunits (CcoO and CcoP) involved in electron transfer, and the small CcoQ subunit with an unclear function. Here, we address the role of these four subunits in cbb3 biogenesis in the purple bacterium Rubrivivax gelatinosus Analyses of membrane proteins from different mutants revealed the presence of active CcoNQO and CcoNO subcomplexes and also showed that the CcoP subunit is not essential for their assembly. However, CcoP was required for the oxygen reduction activity in the absence of CcoQ. We also found that CcoQ is dispensable for forming an active CcoNOP subcomplex in membranes. CcoNOP exhibited oxygen reductase activity, indicating that the cofactors (hemes b and copper for CcoN and cytochromes c for CcoO and CcoP) were present within the subunits. Finally, we discovered the presence of a CcoNQ subcomplex and showed that CcoN is the required anchor for the assembly of the full CcoNQOP complex. On the basis of these findings, we propose a sequential assembly model in which the CcoQ subunit is required for the early maturation step: CcoQ first associates with CcoN before the CcoNQ-CcoO interaction. CcoP associates to CcoNQO subcomplex in the late maturation step, and once the CcoNQOP complex is fully formed, CcoQ is released for degradation by the FtsH protease. This model could be conserved in other bacteria, including the pathogenic bacteria lacking the assembly factor CcoH as in R. gelatinosus. PMID- 29150448 TI - Taking a goal-centred dynamic snapshot as a possibility for local homing in initially naive bumblebees. AB - It is essential for central place foragers, such as bumblebees, to return reliably to their nest. Bumblebees, leaving their inconspicuous nest hole for the first time need to gather and learn sufficient information about their surroundings to allow them to return to their nest at the end of their trip, instead of just flying away to forage. Therefore, we assume an intrinsic learning programme that manifests itself in the flight structure immediately after leaving the nest for the first time. In this study, we recorded and analysed the first outbound flight of individually marked naive bumblebees in an indoor environment. We found characteristic loop-like features in the flight pattern that appear to be necessary for the bees to acquire environmental information and might be relevant for finding the nest hole after a foraging trip. Despite common features in their spatio-temporal organisation, first departure flights from the nest are characterised by a high level of variability in their loop-like flight structure across animals. Changes in turn direction of body orientation, for example, are distributed evenly across the entire area used for the flights without any systematic relationship to the nest location. By considering the common flight motifs and this variability, we came to the hypothesis that a kind of dynamic snapshot is taken during the early phase of departure flights centred at the nest location. The quality of this snapshot is hypothesised to be 'tested' during the later phases of the departure flights concerning its usefulness for local homing. PMID- 29150447 TI - The prototypical proton-coupled oligopeptide transporter YdgR from Escherichia coli facilitates chloramphenicol uptake into bacterial cells. AB - Chloramphenicol (Cam) is a broad-spectrum antibiotic used to combat bacterial infections in humans and animals. Cam export from bacterial cells is one of the mechanisms by which pathogens resist Cam's antibacterial effects, and several different proteins are known to facilitate this process. However, to date no report exists on any specific transport protein that facilitates Cam uptake. The proton-coupled oligopeptide transporter (POT) YdgR from Escherichia coli is a prototypical member of the POT family, functioning in proton-coupled uptake of di and tripeptides. By following bacterial growth and conducting LC-MS-based assays we show here that YdgR facilitates Cam uptake. Some YdgR variants displaying reduced peptide uptake also exhibited reduced Cam uptake, indicating that peptides and Cam bind YdgR at similar regions. Homology modeling of YdgR, Cam docking, and mutational studies suggested a binding mode that resembles that of Cam binding to the multidrug resistance transporter MdfA. To our knowledge, this is the first report of Cam uptake into bacterial cells mediated by a specific transporter protein. Our findings suggest a specific bacterial transporter for drug uptake that might be targeted to promote greater antibiotic influx to increase cytoplasmic antibiotic concentration for enhanced cytotoxicity. PMID- 29150449 TI - claudin-10 isoform expression and cation selectivity change with salinity in salt secreting epithelia of Fundulusheteroclitus. AB - To provide insight into claudin (Cldn) tight junction (TJ) protein contributions to branchial salt secretion in marine teleost fishes, this study examined cldn-10 TJ protein isoforms of a euryhaline teleost (mummichog; Fundulus heteroclitus) in association with salinity change and measurements of transepithelial cation selectivity. Mummichogs were transferred from freshwater (FW) to seawater (SW, 350/00) and from SW to hypersaline SW (2SW, 600/00) in a time course with transfer control groups (FW to FW, and SW to SW). FW to SW transfer increased mRNA abundance of cldn-10d and cldn-10e twofold, whilst cldn-10c and cldn-10f transcripts were unchanged. Transfer from SW to 2SW did not alter cldn-10d, and transiently altered cldn-10e abundance, but increased cldn-10c and cldn-10f fourfold. This was coincident with an increased number of single-stranded junctions (observed by transmission electron microscopy). For both salinity transfers, (1) cldn-10e mRNA was acutely responsive (i.e. after 24 h), (2) other responsive cldn-10 isoforms increased later (3-7 days), and (3) cystic fibrosis transmembrane conductance regulator (cftr) mRNA was elevated in accordance with established changes in transcellular Cl- movement. Changes in mRNA encoding cldn 10c and -10f appeared linked, consistent with the tandem repeat locus in the Fundulus genome, whereas mRNA for tandem cldn-10d and cldn-10e seemed independent of each other. Cation selectivity sequence measured by voltage and conductance responses to artificial SW revealed Eisenman sequence VII: Na+>K+>Rb+~Cs+>Li+ Collectively, these data support the idea that Cldn-10 TJ proteins create and maintain cation-selective pore junctions in salt-secreting tissues of teleost fishes. PMID- 29150450 TI - Aerobic power and flight capacity in birds: a phylogenetic test of the heart-size hypothesis. AB - Flight capacity is one of the most important innovations in animal evolution; it only evolved in insects, birds, mammals and the extinct pterodactyls. Given that powered flight represents a demanding aerobic activity, an efficient cardiovascular system is essential for the continuous delivery of oxygen to the pectoral muscles during flight. It is well known that the limiting step in the circulation is stroke volume (the volume of blood pumped from the ventricle to the body during each beat), which is determined by the size of the ventricle. Thus, the fresh mass of the heart represents a simple and repeatable anatomical measure of the aerobic power of an animal. Although several authors have compared heart masses across bird species, a phylogenetic comparative analysis is still lacking. By compiling heart sizes for 915 species and applying several statistical procedures controlling for body size and/or testing for adaptive trends in the dataset (e.g. model selection approaches, phylogenetic generalized linear models), we found that (residuals of) heart size is consistently associated with four categories of flight capacity. In general, our results indicate that species exhibiting continuous hovering flight (i.e. hummingbirds) have substantially larger hearts than other groups, species that use flapping flight and gliding show intermediate values, and that species categorized as poor flyers show the smallest values. Our study reveals that on a broad scale, routine flight modes seem to have shaped the energetic requirements of birds sufficiently to be anatomically detected at the comparative level. PMID- 29150451 TI - Elucidating mechanisms for insect body size: partial support for the oxygen dependent induction of moulting hypothesis. AB - Body size is a key life history trait, and knowledge of its mechanistic basis is crucial in life history biology. Such knowledge is accumulating for holometabolous insects, whose growth is characterised and body size affected by moulting. According to the oxygen-dependent induction of moulting (ODIM) hypothesis, moult is induced at a critical mass at which oxygen demand of growing tissues overrides the supply from the tracheal respiratory system, which principally grows only at moults. Support for the ODIM hypothesis is controversial, partly because of a lack of proper data to explicitly test the hypothesis. The ODIM hypothesis predicts that the critical mass is positively correlated with oxygen partial pressure (PO2 ) and negatively with temperature. To resolve the controversy that surrounds the ODIM hypothesis, we rigorously test these predictions by exposing penultimate-instar Orthosia gothica (Lepidoptera: Noctuidae) larvae to temperature and moderate PO2 manipulations in a factorial experiment. The relative mass increment in the focal instar increased along with increasing PO2 , as predicted, but there was only weak suggestive evidence of the temperature effect. Probably owing to a high measurement error in the trait, the effect of PO2 on the critical mass was sex specific; high PO2 had a positive effect only in females, whereas low PO2 had a negative effect only in males. Critical mass was independent of temperature. Support for the ODIM hypothesis is partial because of only suggestive evidence of a temperature effect on moulting, but the role of oxygen in moult induction seems unambiguous. The ODIM mechanism thus seems worth considering in body size analyses. PMID- 29150452 TI - A metabolic hypothesis for the evolution of temperature effects on the arterial PCO2 and pH of vertebrate ectotherms. AB - Body temperature increases in ectothermic vertebrates characteristically lead to both increases in arterial PCO2 (PaCO2 ) and declines in resting arterial pH (pHa) of about 0.017 pH units per 1 degrees C increase in temperature. This 'alphastat' pH pattern has previously been interpreted as being evolutionarily driven by the maintenance of a constant protonation state on the imidazole moiety of histidine protein residues, hence stabilizing protein structure-function. Analysis of the existing data for interclass responses of ectothermic vertebrates shows different degrees of PaCO2 increases and pH declines with temperature between the classes, with reptiles>amphibians>fish. The PaCO2 at the temperature where maximal aerobic metabolism (VO2,max) is achieved is significantly and positively correlated with temperature for all vertebrate classes. For ectotherms, the PaCO2 where VO2,max is greatest is also correlated with VO2,max, indicating there is an increased driving force for CO2 efflux that is lowest in fish, intermediate in amphibians and highest in reptiles. The pattern of increased PaCO2 and the resultant reduction of pHa in response to increased body temperature would serve to increase CO2 efflux, O2 delivery and blood buffering capacity and maintain ventilatory scope. This represents a new hypothesis for the selective advantage of arterial pH regulation from a systems physiology perspective in addition to the advantages of maintenance of protein structure function. PMID- 29150457 TI - Combination Analgesia for Neonatal Circumcision: A Randomized Controlled Trial. AB - OBJECTIVES: There is no consensus on the most effective pain management for neonatal circumcision. We sought to compare different modalities. METHODS: This is a double-blinded randomized controlled trial comparing 3 combination analgesics used during circumcision (EMLA + sucrose; EMLA + sucrose + dorsal penile nerve block [DPNB]; EMLA + sucrose + ring block [RB]) with the traditional topical analgesic cream EMLA alone. The trial was set in the normal nursery of a teaching hospital. The sample included 70 healthy male newborns, randomly assigned to intervention and control groups at a 2:1 ratio. Infants were videotaped (face and torso) during the procedure for assessment of pain by 2 blinded, independent reviewers. The primary outcome measure is the Neonatal Infant Pain Scale score. Secondary outcomes include heart rate, oxygen saturation, and crying time. RESULTS: Neonatal Infant Pain Scale scores were significantly lower in the intervention groups (EMLA + sucrose, mean [SD]: 3.1 [1.33]; EMLA + sucrose + DPNB: 3 [1.33]; EMLA + sucrose + RB: 2.45 [1.27]) compared with the control (5.5 [0.53]). Between-group analyses showed RB + EMLA + sucrose to be significantly more effective than EMLA + sucrose; EMLA + sucrose + DPNB (P = .009 and P = .002, respectively). Interrater reliability was kappa = 0.843. Significant increase in heart rate (139.27 [9.63] to 163 [13.23] beats per minute) and crying time (5.78 [6.4] to 45.37 [12.39] seconds) were noted in the EMLA group. CONCLUSIONS: During neonatal circumcision in boys, the most effective analgesia is RB combined with oral sucrose and EMLA cream. PMID- 29150458 TI - Diagnostic Accuracy of Neonatal Assessment for Gestational Age Determination: A Systematic Review. AB - CONTEXT: An estimated 15 million neonates are born preterm annually. However, in low- and middle-income countries, the dating of pregnancy is frequently unreliable or unknown. OBJECTIVE: To conduct a systematic literature review and meta-analysis to determine the diagnostic accuracy of neonatal assessments to estimate gestational age (GA). DATA SOURCES: PubMed, Embase, Cochrane, Web of Science, POPLINE, and World Health Organization library databases. STUDY SELECTION: Studies of live-born infants in which researchers compared neonatal signs or assessments for GA estimation with a reference standard. DATA EXTRACTION: Two independent reviewers extracted data on study population, design, bias, reference standard, test methods, accuracy, agreement, validity, correlation, and interrater reliability. RESULTS: Four thousand nine hundred and fifty-six studies were screened and 78 included. We identified 18 newborn assessments for GA estimation (ranging 4 to 23 signs). Compared with ultrasound, the Dubowitz score dated 95% of pregnancies within +/-2.6 weeks (n = 7 studies), while the Ballard score overestimated GA (0.4 weeks) and dated pregnancies within +/-3.8 weeks (n = 9). Compared with last menstrual period, the Dubowitz score dated 95% of pregnancies within +/- 2.9 weeks (n = 6 studies) and the Ballard score, +/-4.2 weeks (n = 5). Assessments with fewer signs tended to be less accurate. A few studies showed a tendency for newborn assessments to overestimate GA in preterm infants and underestimate GA in growth-restricted infants. LIMITATIONS: Poor study quality and few studies with early ultrasound-based reference. CONCLUSIONS: Efforts in low- and middle-income countries should focus on improving dating in pregnancy through ultrasound and improving validity in growth-restricted populations. Where ultrasound is not possible, increased efforts are needed to develop simpler yet specific approaches for newborn assessment through new combinations of existing parameters, new signs, or technology. PMID- 29150459 TI - Lessons From History: Parents Anonymous and Child Abuse Prevention Policy. PMID- 29150460 TI - Ring Block of the Penis: A Proven Addition to Multimodal Pain Relief for Newborn Circumcision. PMID- 29150461 TI - GABA Type A Receptor Activation in the Allosteric Coagonist Model Framework: Relationship between EC50 and Basal Activity. AB - The concerted transition model for multimeric proteins is a simple formulation for analyzing the behavior of transmitter-gated ion channels. We used the model to examine the relationship between the EC50 for activation of the GABA type A (GABAA) receptor by the transmitter GABA and basal activity employing concatemeric ternary GABAA receptors expressed in Xenopus oocytes. Basal activity, reflecting the receptor function in the absence of the transmitter, can be changed either by mutation to increase constitutive activity or by the addition of a second agonist (acting at a different site) to increase background activity. The model predicts that either mechanism for producing a change in basal activity will result in identical effects on the EC50 We examined receptor activation by GABA while changing the level of basal activity with the allosterically acting anesthetics propofol, pentobarbital, or alfaxalone. We found that the relationship between EC50 and basal activity was well described by the concerted transition model. Changes in the basal activity by gain-of-function mutations also resulted in predictable changes in the EC50 Finally, we altered the number of GABA-binding sites by a mutation and again found that the relationship could be well described by the model. Overall, the results support the idea that interactions between the transmitter GABA and the allosteric agonists propofol, pentobarbital, or alfaxalone can be understood as reflecting additive and independent free energy changes, without assuming any specific interactions. PMID- 29150463 TI - Month of birth and risk of autism spectrum disorder: a retrospective cohort of male children born in Israel. AB - BACKGROUND: Increased incidence and prevalence of autism spectrum disorder (ASD) over the last two decades have prompted considerable efforts to investigate its aetiological factors. We examined an association between month of birth and ASD incidence. METHODS: In a retrospective cohort of male children born from January 1999 to December 2008 in a large health organisation in Israel (Maccabi Healthcare Services), ASD was followed from birth through December 2015. RESULTS: Of 108 548 boys, 975 cases of ASD were identified. The highest rates (10.3 and 10.2 per 1000 male live births) were recorded for children born in May and August, respectively, and the lowest rates for February (7.6 per 1000 male live births). Among lower socioeconomic status households, boys born in August were more likely (OR=1.71; 95% CI 1.06 to 2.74) of being diagnosed with ASD than children born in January. Significantly higher rates were not observed for other months. CONCLUSIONS: In line with several previous studies, we found a modestly higher likelihood of autism occurrence among male children of lower socioeconomic levels born in August. PMID- 29150462 TI - Comprehensive analysis of vitreous specimens for uveitis classification: a prospective multicentre observational study. AB - PURPOSE: To determine the clinical relevance of vitreous biomarkers in patients with uveitis. DESIGN: Multicentre, prospective, observational study. SETTING: Uveitis outpatient clinics of two academic medical centres in Japan. PATIENT POPULATION: This study included 234 eyes of 191 patients with various uveitis aetiologies: definitive sarcoidosis (61 eyes of 46 patients), suspected sarcoidosis (60 eyes of 45 patients), intraocular tumour (34 eyes of 27 patients), viral infection (20 eyes of 18 patients), non-sarcoidosis (16 eyes of 16 patients) and unknown aetiology (43 eyes of 39 patients). OBSERVATION PROCEDURE: Vitreous samples (taken by pars planta vitrectomy) were analysed with flow cytometry, cytology and multiplex PCR analysis. MAIN OUTCOME MEASURES: The primary outcome measures were the diagnostic values of various biomarkers (T cells, B cells and pathogen DNA) in vitreous samples. The secondary outcome was visual acuity after vitrectomy. RESULTS: Sarcoidosis showed higher CD4/CD8 or CD4+ measurements than other aetiologies (p<0.01). In samples with viral infection, pathogen DNA was detected, and CD8+ counts were higher than the other aetiologies (p<0.01). Eyes with tumour had higher CD19+ (p<0.05). Non-sarcoidosis had lower CD4/CD8 than sarcoidosis, higher CD8+ than sarcoidosis and lower CD19+ than tumour (p<0.01). Unknown uveitis had lower CD4/CD8 than sarcoidosis (p<0.01), and higher CD4/CD8 than non-sarcoidosis, viral infection or tumour (p<0.001). Visual acuity improved after vitrectomy (p<0.001). CONCLUSIONS: Uveitis aetiologies had distinct vitreous biomarker profiles, especially of infiltrating lymphocytes. Analyses of CD4/CD8 ratio, T-lymphocyte and B lymphocyte subset, and pathogen DNA in vitreous samples have good safety profiles and high diagnostic value for uveitis classification. TRIAL REGISTRATION NUMBER: UMIN000004980; Pre-results. PMID- 29150464 TI - Testosterone therapy in hypogonadal men: a systematic review and network meta analysis. AB - OBJECTIVE: To assess the relative effects of individual testosterone products among hypogonadal men. DESIGN: Systematic review and network meta-analysis. METHODS: We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (25 May 2017) for randomised-controlled trials (RCTs) and non-randomised studies (NRS) that involved hypogonadal men given testosterone replacement therapy (TRT) for >=3 months. Comparators were placebo, another TRT, or the same product at a different dose. Outcomes were quality of life, depression, libido, erectile function, activities of daily living and testosterone levels, as well as cardiovascular death, myocardial infarction, stroke, prostate cancer, heart disease, diabetes, serious adverse events, withdrawals due to adverse events and erythrocytosis. RCT data were pooled via meta-analysis and network meta-analysis. Risk of bias was assessed using Cochrane's risk of bias tool (RCTs) andScottish Intercollegiate Guidelines Network (SIGN)50 (NRS). RESULTS: Eighty-seven RCTs and 51 NRS were included. Most were at high or unclear risk of bias, with short treatment duration and follow-up. When compared as a class against placebo, TRT improved quality of life (standardised mean difference (SMD) -0.26, 95% CI -0.41 to -0.11), libido (SMD 0.33, 95% CI 0.16 to 0.50), depression (SMD -0.23, 95% CI 0.44 to -0.01) and erectile function (SMD 0.25, 95% CI 0.10 to 0.41). Most individual TRTs were significantly better than placebo at improving libido (6/10). Only one TRT was better than placebo at improving quality of life, and no individual TRTs improved depression or erectile function. There was no increased risk of adverse events, with the exception of withdrawals due to adverse events with the use of some TRTs. CONCLUSION: Despite a class effect of improving quality of life, depression, erectile function and libido, major improvements were not observed with the use of any individual product. We observed no statistically significant increase in the risk of adverse events; however, longer term high-quality trials are needed to fully assess the risk of harm. PROSPERO REGISTRATION NUMBER: CRD42014009963. PMID- 29150465 TI - Differences in optimality index between planned place of birth in a birth centre and alternative planned places of birth, a nationwide prospective cohort study in The Netherlands: results of the Dutch Birth Centre Study. AB - OBJECTIVES: To compare the Optimality Index of planned birth in a birth centre with planned birth in a hospital and planned home birth for low-risk term pregnant women who start labour under the responsibility of a community midwife. DESIGN: Prospective cohort study. SETTING: Low-risk pregnant women under care of a community midwife and living in a region with one of the 21 participating Dutch birth centres or in a region with the possibility for midwife-led hospital birth. Home birth was commonly available in all regions included in the study. PARTICIPANTS: 3455 low-risk term pregnant women (1686 nulliparous and 1769 multiparous) who gave birth between 1 July 2013 and 31 December 2013: 1668 planned birth centre births, 701 planned midwife-led hospital births and 1086 planned home births. MAIN OUTCOME MEASUREMENTS: The Optimality IndexNL-2015, a tool to measure 'maximum outcome with minimal intervention', was assessed by planned place of birth being a birth centre, a hospital setting or at home. Also, a composite maternal and perinatal adverse outcome score was calculated for the different planned places of birth. RESULTS: There were no differences in Optimality Index NL-2015 for pregnant women who planned to give birth in a birth centre compared with women who planned to give birth in a hospital. Although effect sizes were small, women who planned to give birth at home had a higher Optimality Index NL-2015 than women who planned to give birth in a birth centre. The differences were larger for multiparous than for nulliparous women. CONCLUSION: The Optimality Index NL-2015 for women with planned birth centre births was comparable with planned midwife-led hospital births. Women with planned home births had a higher Optimality Index NL-2015, that is, a higher sum score of evidence-based items with an optimal value than women with planned birth centre births. PMID- 29150466 TI - Are the early predictors of long-term work absence following injury time dependent? Results from the Prospective Outcomes of Injury Study. AB - OBJECTIVES: Few studies examine the influence of early predictors of work absence beyond 12 months following injury or the time-dependent relative importance of these factors. This study aimed to identify the most important sociodemographic, occupational, health, lifestyle and injury predictors of work absence at 12 and 24 months following injury and to examine changes in the relative importance of these over time. DESIGN: Prospective cohort study. SETTING: The Prospective Outcomes of Injury Study, New Zealand. PARTICIPANTS: 2626 injured New Zealand workers aged 18-64 years were identified from the Prospective Outcomes of Injury Study recruited form New Zealand's monopoly injury compensation provider injury claims register: 2092 completed the 12-month interview (80% follow-up) and 2082 completed the 24-month interview (79% follow-up). PRIMARY AND SECONDARY OUTCOMES MEASURES: The primary outcomes of interest was absence from work at the time of the 12-month and 24-month follow-up interviews. RESULTS: Using modified Poisson regression to estimate relative risks, important groups of workers were identified at increased risk of work absence at both 12 and 24 months: males, low income workers, trade/manual workers, temporary employees, those reporting two or more comorbidities and those experiencing a work-related injury. Important factors unique to predicting work absence at 12 months included financial insecurity, fixed-term employment and long weekly hours worked; unique factors at 24 months included job dissatisfaction, long weekly days worked, a prior injury and sustaining an injury that was perceived to be a threat to life. CONCLUSIONS: Important early predictors of work absence at 12 or 24 months following injury are multidimensional and have a time dependent pattern. A consistent set of predictors was, however, present at both time periods that are prime for early intervention. Understanding the multidimensional, time-dependent patterns of early predictors of long-term disability is important to optimally target timely interventions to prevent long-term work disability. PMID- 29150467 TI - Interventions to improve adherence to reporting guidelines in health research: a scoping review protocol. AB - INTRODUCTION: There is evidence that the use of some reporting guidelines, such as the Consolidated Standards for Reporting Trials, is associated with improved completeness of reporting in health research. However, the current levels of adherence to reporting guidelines are suboptimal. Over the last few years, several actions aiming to improve compliance with reporting guidelines have been taken and proposed. We will conduct a scoping review of interventions to improve adherence to reporting guidelines in health research that have been evaluated or suggested, in order to inform future interventions. METHODS AND ANALYSIS: Our review will follow the Joanna Briggs Institute scoping review methods manual. We will search for relevant studies in MEDLINE, EMBASE and Cochrane Library databases. Moreover, we will carry out lateral searches from the reference lists of the included studies, as well as from the lists of articles citing the included ones. One reviewer will screen the full list, which will be randomly split into two halves and independently screened by the other two reviewers. Two reviewers will perform data extraction independently. Discrepancies will be solved through discussion. In addition, this search strategy will be supplemented by a grey literature search. The interventions found will be classified as assessed or suggested, as well as according to different criteria, in relation to their target (journal policies, journal editors, authors, reviewers, funders, ethical boards or others) or the research stage at which they are performed (design, conducting, reporting or peer review). Descriptive statistical analysis will be performed. ETHICS AND DISSEMINATION: A paper summarising the findings from this review will be published in a peer-reviewed journal. This scoping review will contribute to a better understanding and a broader perspective on how the problem of adhering better to reporting guidelines has been tackled so far. This could be a major first step towards developing future strategies to improve compliance with reporting guidelines in health research. PMID- 29150468 TI - Prevalence and recognition of obesity and its associated comorbidities: cross sectional analysis of electronic health record data from a large US integrated health system. AB - OBJECTIVE: To determine the prevalence of obesity and its related comorbidities among patients being actively managed at a US academic medical centre, and to examine the frequency of a formal diagnosis of obesity, via International Classification of Diseases, Ninth Revision (ICD-9) documentation among patients with body mass index (BMI) >=30 kg/m2. DESIGN: The electronic health record system at Cleveland Clinic was used to create a cross-sectional summary of actively managed patients meeting minimum primary care physician visit frequency requirements. Eligible patients were stratified by BMI categories, based on most recent weight and median of all recorded heights obtained on or before the index date of 1July 2015. Relationships between patient characteristics and BMI categories were tested. SETTING: A large US integrated health system. RESULTS: A total of 324 199 active patients with a recorded BMI were identified. There were 121 287 (37.4%) patients found to be overweight (BMI >=25 and <29.9), 75 199 (23.2%) had BMI 30-34.9, 34 152 (10.5%) had BMI 35-39.9 and 25 137 (7.8%) had BMI >=40. There was a higher prevalence of type 2 diabetes, pre-diabetes, hypertension and cardiovascular disease (P value<0.0001) within higher BMI compared with lower BMI categories. In patients with a BMI >30 (n=134 488), only 48% (64 056) had documentation of an obesity ICD-9 code. In those patients with a BMI >40, only 75% had an obesity ICD-9 code. CONCLUSIONS: This cross-sectional summary from a large US integrated health system found that three out of every four patients had overweight or obesity based on BMI. Patients within higher BMI categories had a higher prevalence of comorbidities. Less than half of patients who were identified as having obesity according to BMI received a formal diagnosis via ICD-9 documentation. The disease of obesity is very prevalent yet underdiagnosed in our clinics. The under diagnosing of obesity may serve as an important barrier to treatment initiation. PMID- 29150469 TI - Impact of preterm birth on parental separation: a French population-based longitudinal study. AB - OBJECTIVE: The objective of this study was to investigate both the effects of low gestational age and infant's neurodevelopmental outcome at 2 years of age on the risk of parental separation within 7 years of giving birth. DESIGN: Prospective. SETTING: 24 maternity clinics in the Pays-de-la-Loire region. PARTICIPANTS: This study included 5732 infants delivered at <35 weeks of gestation born between 2005 and 2013 who were enrolled in the population-based Loire Infant Follow-up Team cohort and who had a neurodevelopmental evaluation at 2 years. This neurodevelopmental evaluation was based on a physical examination, a psychomotor evaluation and a parent-completed questionnaire. OUTCOME MEASURE: Risk of parental separation (parents living together or parents living separately). RESULTS: Ten percent (572/5732) of the parents reported having undergone separation during the follow-up period. A mediation analysis showed that low gestational age had no direct effect on the risk of parental separation. Moreover, a non-optimal neurodevelopment at 2 years was associated with an increased risk of parental separation corresponding to a HR=1.49(1.23 to 1.80). Finally, the increased risk of parental separation was aggravated by low socioeconomic conditions. CONCLUSIONS: The effect of low gestational age on the risk of parental separation was mediated by the infant's neurodevelopment. PMID- 29150470 TI - Platelet rich Plasma in Achilles Tendon Healing 2 (PATH-2) trial: protocol for a multicentre, participant and assessor-blinded, parallel-group randomised clinical trial comparing platelet-rich plasma (PRP) injection versus placebo injection for Achilles tendon rupture. AB - BACKGROUND: Achilles tendon injuries give rise to substantial long-lasting morbidity and pose considerable challenges for clinicians and patients during the lengthy healing period. Current treatment strategies struggle to curb the burden of this injury on health systems and society due to lengthy rehabilitation, work absence and reinjury risk. Platelet-rich plasma (PRP) is an autologous preparation that has been shown to improve the mechanobiological properties of tendons in laboratory and animal studies. The use of PRP in musculoskeletal injuries is on the increase despite the lack of adequately powered clinical studies. METHODS AND DESIGN: This is a multicentre randomised controlled trial to evaluate the efficacy and mechanism of PRP in patients with acute Achilles tendon rupture (ATR). All adults with acute ATR presenting within 12 days of the injury who are to be treated non-operatively are eligible. A total of 230 consenting patients will be randomly allocated via a remote web-based service to receive PRP injection or placebo injection to the site of the injury. All participants will be blinded to the intervention and will receive standardised rehabilitation to reduce efficacy interference.Participants will be followed up with blinded assessments of muscle-tendon function, quality of life, pain and overall patient's functional goals at 4, 7, 13, 24 weeks and 24 months post-treatment. The primary outcome is the heel-rise endurance test (HRET), which will be supervised by a blinded assessor at 24 weeks. A subgroup of 16 participants in one centre will have needle biopsy under ultrasound guidance at 6 weeks. Blood and PRP will be analysed for cell count, platelet activation and growth factor concentrations. ETHICS AND DISSEMINATION: The protocol has been approved by the Oxfordshire Research Ethics Committee (Oxfordshire Research Ethics Committee A, reference no 14/SC/1333). The trial will be reported in accordance with the CONSORT statement and published in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: ISRCTN: 54992179, assigned 12 January 2015. ClinicalTrials.gov: NCT02302664, received 18 November 2014. UK Clinical Research Network Study Portfolio Database: ID 17850. PMID- 29150471 TI - Biochemical monitoring after initiation of aldosterone antagonist therapy in users of renin-angiotensin system blockers: a UK primary care cohort study. AB - OBJECTIVE: To determine the frequency of biochemical monitoring after initiation of aldosterone antagonists(AA) in patients also using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB). SETTING: UK primary care. PARTICIPANTS: ACEI/ARB users who initiated AA between 2004 and 2014. OUTCOMES: We calculated the proportions with: (1) biochemical monitoring <=2 weeks post initiation of AA, (2) adverse biochemical values <=2 months (potassium >=6 mmol/L, creatinine >=220 umol/L and >=30% increase in creatinine from baseline) and (3) discontinuers of AA in those with an adverse biochemical value. We used logistic regression to study patient characteristics associated with monitoring and adverse biochemical values. RESULTS: In 10 546 initiators of AA, 3291 (31.2%) had a record of biochemical monitoring <=2 weeks post initiation. A total of 2.0% and 2.7% of those with follow-up monitoring within 2 months of initiation experienced potassium >=6 mmol/L and creatinine >=220 umol/L, respectively, whereas 13.5% had a >=30% increase in creatinine. Baseline potassium (OR 3.59, 95% CI 2.43 to 5.32 for 5.0-5.5 mmol/L compared with <5.0 mmol/L) and estimated glomerular filtration rate 45-59 ml/min/1.73 m2 (OR 2.06, 95% CI 1.26 to 3.35 compared with >=60 ml/min/1.73 m2) were independently predictive of potassium >=6 mmol/L. Women and people with diabetes had higher odds of >=30% increase in creatinine. CONCLUSION: Less than one-third of patients taking ACEI/ARB had biochemical monitoring within 2 weeks of initiating AAs. Higher levels of monitoring may reduce adverse biochemical events. PMID- 29150472 TI - Are food and drink retailers within NHS venues adhering to NICE Quality standard 94 guidance on childhood obesity? A cross-sectional study of two large secondary care NHS hospitals in England. AB - OBJECTIVE: To assess whether the food and drink retail outlets in two major National Health Service (NHS) district general hospitals in England adhere to quality statements 1-3 of the UK National Institute for Health and Care Excellence (NICE) quality standard 94. DESIGN: Cross-sectional, descriptive study to assess the food and drink options available in vending machines, restaurants, cafes and shops in two secondary care hospitals. MAIN OUTCOME MEASURES: Adherence to quality statement 1 whereby the food and drink items available in the vending machines were classified as either healthy or less healthy using the Nutrient Profiling Model (NPM). Compliance with quality statements 2 and 3 was assessed through the measurement of how clearly the shops, cafes and restaurants displayed nutrition information on menus, and the availability and prominent display of healthy food and drink options in retail outlets, respectively. RESULTS: Adherence to quality statement 1 was poor. Of the 18 vending machines assessed, only 7 (39%) served both a healthy food and a healthy drink option. Neither hospital was compliant with quality statement 2 wherein nutritional information was not available on menus of food providers in either hospital. There was inconsistent compliance with quality standard 3 whereby healthy food and drink options were prominently displayed in the two main hospital restaurants, but all shops and cafes prioritised the display of unhealthy items. CONCLUSIONS: Neither hospital was consistently compliant with quality statements 1-3 of the NICE quality standard 94. Improving the availability of healthy foods and drinks while reducing the display and accessibility to less healthy options in NHS venues may improve family awareness of healthy alternatives. Making it easier for parents to direct their children to healthier choices is an ostensibly central component of our healthcare system. PMID- 29150474 TI - Core Outcome Sets in Miscarriage Trials (COSMisT) study: a study protocol. AB - INTRODUCTION: 'Core outcome sets' are an agreed, standardised set of outcomes based on what key stakeholders (clinicians, patients, their partners, researchers, service developers, funding organisations and so on) consider the important outcomes in the management or prevention of a condition. This paper describes the rationale and design for the development of Core Outcome Sets for Miscarriage Trials. METHODS AND ANALYSIS: Systematic reviews, interviews and focus groups with patients and their partners will be conducted to identify potential core outcomes that will be introduced into a modified Delphi survey. To ensure all key stakeholders are included, patients, partners, clinicians, charities and researchers will be invited to take part in the modified Delphi survey. There will be three rounds of scoring and rescoring during the Delphi survey to reach consensus regarding outcomes to be included in the core set, which will be subsequently refined through face-to-face consensus discussions. ETHICS AND DISSEMINATION: The use of core outcome sets allows results from different studies to be compared and combined, thereby reducing inconsistency and aiding interpretation of study findings. It also means research is more likely to report relevant outcomes and so can reduce reporting bias. Understanding which outcomes are important to patients has the potential to act as a driver to improve both the quality and cost-effectiveness of miscarriage services. PMID- 29150473 TI - Patient-level and practice-level factors associated with consultation duration: a cross-sectional analysis of over one million consultations in English primary care. AB - OBJECTIVES: Consultation duration has previously been shown to be associated with patient, practitioner and practice characteristics. However, previous studies were conducted outside the UK, considered only small numbers of general practitioner (GP) consultations or focused primarily on practitioner-level characteristics. We aimed to determine the patient-level and practice-level factors associated with duration of GP and nurse consultations in UK primary care. DESIGN AND SETTING: Cross-sectional data were obtained from English general practices contributing to the Clinical Practice Research Datalink (CPRD) linked to data on patient deprivation and practice staffing, rurality and Quality and Outcomes Framework (QOF) achievement. PARTICIPANTS: 218 304 patients, from 316 English general practices, consulting from 1 April 2013 to 31 March 2014. ANALYSIS: Multilevel mixed-effects models described the association between consultation duration and patient-level and practice-level factors (patient age, gender, smoking status, ethnic group, deprivation and practice rurality, number of full-time equivalent GPs/nurses, list size, consultation rate, quintile of overall QOF achievement and training status). RESULTS: Mean duration of face-to face GP consultations was 9.24 min and 5.32 min for telephone consultations. Nurse face-to-face and telephone consultations lasted 9.70 and 5.73 min on average, respectively. Longer GP consultation duration was associated with female patient gender, practice training status and older patient age. Shorter duration was associated with higher deprivation and consultation rate. Longer nurse consultation duration was associated with male patient gender, older patient age and ever smoking; and shorter duration with higher consultation rate. Observed differences in duration were small (eg, GP consultations with female patients compared with male patients were 8 s longer on average). CONCLUSIONS: Small observed differences in consultation duration indicate that patients are treated similarly regardless of background. Increased consultation duration may be beneficial for older or comorbid patients, but the benefits and costs of increased consultation duration require further study. PMID- 29150475 TI - UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. AB - INTRODUCTION: UpToDate is widely used by clinicians worldwide and includes more than 9400 recommendations that apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. GRADE guidance warns against strong recommendations when certainty of the evidence is low or very low (discordant recommendations) but has identified five paradigmatic situations in which discordant recommendations may be justified. OBJECTIVES: Our objective was to document the strength of recommendations in UpToDate and assess the frequency and appropriateness of discordant recommendations. DESIGN: Analytical survey of all recommendations in UpToDate. METHODS: We identified all GRADE recommendations in UpToDate and examined their strength (strong or weak) and certainty of the evidence (high, moderate or low certainty). We identified all discordant recommendations as of January 2015, and pairs of reviewers independently classified them either into one of the five appropriate paradigms or into one of three categories inconsistent with GRADE guidance, based on the evidence presented in UpToDate. RESULTS: UpToDate included 9451 GRADE recommendations, of which 6501 (68.8%) were formulated as weak recommendations and 2950 (31.2%) as strong. Among the strong, 844 (28.6%) were based on high certainty in effect estimates, 1740 (59.0%) on moderate certainty and 366 (12.4%) on low certainty. Of the 349 discordant recommendations 204 (58.5%) were judged appropriately (consistent with one of the five paradigms); we classified 47 (13.5%) as good practice statements; 38 (10.9%) misclassified the evidence as low certainty when it was at least moderate and 60 (17.2%) warranted a weak rather than a strong recommendation. CONCLUSION: The proportion of discordant recommendations in UpToDate is small (3.7% of all recommendations) and the proportion that is truly problematic (strong recommendations that would best have been weak) is very small (0.6%). Clinicians should nevertheless be cautious and look for clear explanations-in UpToDate and elsewhere-when guidelines offer strong recommendations based on low certainty evidence. PMID- 29150476 TI - Predictive value of apelin-12 in patients with ST-elevation myocardial infarction with different renal function: a prospective observational study. AB - OBJECTIVES: To investigate factors predicting the onset of major adverse cardiovascular events (MACEs) after primary percutaneous coronary intervention (pPCI) for patients with ST-segment elevation myocardial infarction (STEMI) . BACKGROUND: Apelin-12 plays an essential role in cardiovascular homoeostasis. However, current knowledge of its predictive prognostic value is limited. METHODS: 464 patients with STEMI (63.0+/-11.9 years, 355 men) who underwent successful pPCI were enrolled and followed for 2.5 years. Multivariate cox regression analysis and receiver operating characteristic (ROC) curve analysis were performed to determine the factors predicting MACEs. RESULTS: 118 patients (25.4%) experienced MACEs in the follow-up period. Multivariate cox regression analysis found low apelin-12 (HR=0.132, 95% CI 0.060 to 0.292, P<0.001), low left ventricular ejection fraction (HR=0.965, 95% CI 0.941 to 0.991, P=0.007), low estimated glomerular filtration rate (eGFR) (HR=0.985, 95% CI 0.977 to 0.993, P<0.001), Killip's classification>I (HR=0.610, 95% CI 0.408 to 0.912, P=0.016) and pathological Q-wave (HR=1.536, 95% CI 1.058 to 2.230, P=0.024) were independent predictors of MACEs in the 2.5 year follow-up period. Low apelin-12 also predicted poorer in-hospital prognosis and MACEs in the 2.5 years follow-up period compared with Deltaapelin-12 (P=0.0115) and eGFR (P=0.0071) among patients with eGFR>90 mL/min*1.73 m2. Further analysis showed Deltaapelin-12 <20% was associated with MACEs in patients whose apelin-12 was below 0.76 ng/mL (P=0.0075) on admission. CONCLUSIONS: Patients with STEMI receiving pPCI with lower apelin 12 are more likely to suffer MACEs in hospital and 2.5 years postprocedure, particularly in those with normal eGFR levels. PMID- 29150477 TI - Risk factors for recurrent intussusception in children: a retrospective cohort study. AB - OBJECTIVE: The aim of this study was to assess the frequency of clinical features and pathological lead points in recurrent intussusception, with a special focus on the risk factors that lead to recurrent intussusception. DESIGN: This is a retrospective cohort study. A 5-year retrospective study was performed between January 2012 and July 2016 in the Children's Hospital of Soochow University, Suzhou, China, to determine the clinical features and pathological lead points of recurrent intussusception. SETTING: This is a retrospective chart review of recurrent intussusception cases in a large university teaching hospital. PARTICIPANTS: The medical records were obtained for 1007 cases with intussusception, including demographics, clinical signs and symptoms, imaging and recurrence times if available. INTERVENTIONS: Univariate and multivariate logistic regression analyses were used to measure significant factors affecting recurrent intussusception and recurrent intussusception with pathological lead points. RESULTS: There were 481 total episodes of recurrence in 191 patients. Among these, 87 had one recurrence and 104 had multiple recurrences. After comparing recurrent and non-recurrent intussusception cases using univariate analysis, it was determined that the factors associated with recurrent intussusception were age (>1 year), duration of symptoms (<=12 hours), the lack of bloody stool, paroxysmal crying or vomiting, the mass location (right abdomen) and pathological lead point (P<0.05). Age (>1 year), duration of symptoms (<=12 hours), the absence of vomiting, mass location (right abdomen) and pathological lead point were significantly independently predictive of recurrent intussusception. The factors associated with recurrent intussusception with lead points present were vomiting and mass location in the right abdomen (P<0.05). Vomiting and mass location (left abdomen) were significantly predictive of recurrent intussusception with lead points. CONCLUSIONS: Age (>1 year), symptom duration (<=12 hours), the absence of vomiting, mass location (right abdomen) and pathological lead points were significantly predictive of recurrent intussusception. Vomiting and mass location (left abdomen) were significantly predictive of recurrent intussusception with lead points. PMID- 29150478 TI - Early versus Late Application of Subthalamic deep brain Stimulation to Parkinson's disease patients with motor complications (ELASS): protocol of a multicentre, prospective and observational study. AB - INTRODUCTION: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established surgical treatment for Parkinson's disease (PD). However, there is currently no consensus on the best timing for this surgery. The aim of our study is to compare the therapeutic efficacy of bilateral STN DBS in patients with PD with early and late motor complications. METHODS AND ANALYSIS: 200 patients with PD will be enrolled in this multicentre, prospective, observational study, and will be followed up for 4 years. Patients with PD who meet the criteria for STN DBS surgery will be allocated to either the early stimulation group or the late stimulation group based on the duration of their motor complications. The primary outcome will be changes in quality of life from baseline to 4 years, measured using the 39-item Parkinson's Disease Questionnaire Summary Index. The secondary outcomes include changes in motor function measured using Movement Disorder Society-revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, self-reported experiences of daily living measured using MDS-UPDRS Part I B and Part II, good 'on' time recorded by the patients using a diary and safety profile of both groups. ETHICS AND DISSEMINATION: The study received ethical approval from the Medical Ethical Committee of the First Affiliated Hospital, Sun Yat-sen University. The results of this study will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT01922388; Pre-results. PMID- 29150479 TI - Impact of variation in functions and delivery on the effectiveness of behavioural and mood management interventions for smoking cessation in people with depression: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Tobacco is the world's leading preventable cause of disease and death. People with depression are twice as likely to smoke and are less responsive to standard tobacco treatments as compared with the general population. A Cochrane systematic review of randomised controlled trials of smoking cessation treatment for smokers with current or historical depression found that adding mood management to usual smoking treatment improved quit rates. However, the review did not examine if variation in intervention delivery or intervention functions impacted on treatment effectiveness.With the aim of providing information to develop tailored approaches to treating smoking for people with current depression, we will add-on to the Cochrane review in three ways: (1) use the Template for Intervention Description and Replication checklist to determine if variations in mood management delivery have impact on intervention effectiveness, (2) use the Taxonomy of Behaviour Change techniques for smoking cessation to examine which behaviour change functions are most effective for smoking cessation in people with current depression and (3) examine the difference in change in depression scores between intervention and control arms. METHODS AND ANALYSIS: We will include randomised controlled trials of smokers with current depression as identified by a previous Cochrane review and the in-progress update of this Cochrane review. We will use meta-regression to examine (1) if variations in delivery of mood management impact on smoking cessation intervention effectiveness, (2) determine which behaviour change functions are most effective for smoking cessation and (3) use meta-analysis of the difference in change in depression scores between treatment arms from baseline to follow-up to determine if offering smoking cessation treatment causes psychological harm. ETHICS AND DISSEMINATION: Ethical approval is not required for this study. We will disseminate the findings of this work at national and international conferences, and to relevant patient panels. PROSPERO REGISTRATION NUMBER: CRD42017070741. PMID- 29150480 TI - Effect of Time to Diagnostic Testing for Breast, Cervical, and Colorectal Cancer Screening Abnormalities on Screening Efficacy: A Modeling Study. AB - Background: Patients who receive an abnormal cancer screening result require follow-up for diagnostic testing, but the time to follow-up varies across patients and practices.Methods: We used a simulation study to estimate the change in lifetime screening benefits when time to follow-up for breast, cervical, and colorectal cancers was increased. Estimates were based on four independently developed microsimulation models that each simulated the life course of adults eligible for breast (women ages 50-74 years), cervical (women ages 21-65 years), or colorectal (adults ages 50-75 years) cancer screening. We assumed screening based on biennial mammography for breast cancer, triennial Papanicolaou testing for cervical cancer, and annual fecal immunochemical testing for colorectal cancer. For each cancer type, we simulated diagnostic testing immediately and at 3, 6, and 12 months after an abnormal screening exam.Results: We found declines in screening benefit with longer times to diagnostic testing, particularly for breast cancer screening. Compared to immediate diagnostic testing, testing at 3 months resulted in reduced screening benefit, with fewer undiscounted life years gained per 1,000 screened (breast: 17.3%, cervical: 0.8%, colorectal: 2.0% and 2.7%, from two colorectal cancer models), fewer cancers prevented (cervical: 1.4% fewer, colorectal: 0.5% and 1.7% fewer, respectively), and, for breast and colorectal cancer, a less favorable stage distribution.Conclusions: Longer times to diagnostic testing after an abnormal screening test can decrease screening effectiveness, but the impact varies substantially by cancer type.Impact: Understanding the impact of time to diagnostic testing on screening effectiveness can help inform quality improvement efforts. Cancer Epidemiol Biomarkers Prev; 27(2); 158-64. (c)2017 AACR. PMID- 29150482 TI - Effect of Mammography Screening on Mortality by Histological Grade. AB - Background: It has been asserted that mammography screening preferentially benefits those with less aggressive cancers, with lesser or no impact on more rapidly progressing and therefore more life-threatening tumors.Methods: We utilized data from the Swedish Two-County Trial, which randomized 77,080 women ages 40 to 74 to invitation to screening and 55,985 for usual care. We tabulated cancers by histologic grade and then compared mortality from cancers specific to histologic grade between the invited and control group using Poisson regression, with specific interest in the effect on mortality from grade 3 cancers. We used incidence-based mortality from tumors diagnosed within the screening phase of the trial. Finally, we cross-tabulated grade with tumor size and node status, to assess downstaging within tumor grades.Results: There was a major reduction in mortality from grade 3 tumors (RR = 0.65; 95% CI, 0.53-0.80; P < 0.001), and more deaths prevented from grade 3 tumors (n = 95) than grade 1 and 2 tumors combined (n = 48) in the invited group. The proportions of tumors >=15 mm or larger and node-positive tumors were substantially reduced in the grade 3 tumors in the invited group.Conclusions: The combination of prevention of tumors progressing to grade 3 and detection at smaller sizes and lesser rates of lymph node metastases within grade 3 tumors results in a substantial number of deaths from grade 3 cancers being prevented by invitation to mammographic screening.Impact: Mammography screening prevents deaths from aggressive cancers. Cancer Epidemiol Biomarkers Prev; 27(2); 154-7. (c)2017 AACR. PMID- 29150481 TI - Identification of Pleiotropic Cancer Susceptibility Variants from Genome-Wide Association Studies Reveals Functional Characteristics. AB - Background: There exists compelling evidence that some genetic variants are associated with the risk of multiple cancer sites (i.e., pleiotropy). However, the biological mechanisms through which the pleiotropic variants operate are unclear.Methods: We obtained all cancer risk associations from the National Human Genome Research Institute-European Bioinformatics Institute GWAS Catalog, and correlated cancer risk variants were clustered into groups. Pleiotropic variant groups and genes were functionally annotated. Associations of pleiotropic cancer risk variants with noncancer traits were also obtained.Results: We identified 1,431 associations between variants and cancer risk, comprised of 989 unique variants associated with 27 unique cancer sites. We found 20 pleiotropic variant groups (2.1%) composed of 33 variants (3.3%), including novel pleiotropic variants rs3777204 and rs56219066 located in the ELL2 gene. Relative to single cancer risk variants, pleiotropic variants were more likely to be in genes (89.0% vs. 65.3%, P = 2.2 * 10-16), and to have somewhat larger risk allele frequencies (median RAF = 0.49 versus 0.39, P = 0.046). The 27 genes to which the pleiotropic variants mapped were suggestive for enrichment in response to radiation and hypoxia, alpha-linolenic acid metabolism, cell cycle, and extension of telomeres. In addition, we observed that 8 of 33 pleiotropic cancer risk variants were associated with 16 traits other than cancer.Conclusions: This study identified and functionally characterized genetic variants showing pleiotropy for cancer risk.Impact: Our findings suggest biological pathways common to different cancers and other diseases, and provide a basis for the study of genetic testing for multiple cancers and repurposing cancer treatments. Cancer Epidemiol Biomarkers Prev; 27(1); 75-85. (c)2017 AACR. PMID- 29150483 TI - Correction for de Moraes et al., "Murine Model for Preclinical Studies of Var2CSA Mediated Pathology Associated with Malaria in Pregnancy". PMID- 29150484 TI - Correction for Bortolotti et al., "Pseudomonas aeruginosa Quorum Sensing Molecule N-(3-Oxododecanoyl)-l-Homoserine-Lactone Induces HLA-G Expression in Human Immune Cells". PMID- 29150485 TI - Correction for Ebner et al., "Excreted Cytoplasmic Proteins Contribute to Pathogenicity in Staphylococcus aureus". PMID- 29150487 TI - Dynamin inhibitors block activation of mTORC1 by amino acids independently of dynamin. AB - mTORC1 plays a crucial role in protein synthesis and cell proliferation and growth. It is activated by growth factors and amino acids, including essential amino acids (EAAs), such as leucine; Leu enters cells via the Leu transporter LAT1-4F2hc (also known as SLC7A5-SLC3A2) and potentially via endocytosis. Here, we investigated the contribution of the different routes of Leu entry into cells to mTORC1 activation using pharmacological inhibitors and cells that lack LAT1 or dynamin-1, -2 and -3. Our results show that LAT1 is the major route of Leu entry into cells and mTORC1 activation (~70%), whereas dynamin-dependent endocytosis and macropinocytosis contribute minimally to both (5-15%). However, macropinocytosis contributes significantly (~40%) to activation of mTORC1 by other EAAs. Surprisingly, the dynamin inhibitors dynasore and Dyngo 4A, which minimally inhibited Leu uptake, abolished mTORC1 activation independently of dynamin. Instead, dynasore inhibited RagA binding to Raptor, reduced mTORC1 recruitment to the lysosome, and inhibited Akt activation and TSC2-S939 phosphorylation; this resulted in inhibition of Rheb and mTORC1 activity. Our results suggest that these commonly used inhibitors of dynamin and endocytosis are potent suppressors of mTORC1 activation via off-target effects and not via dynamin inhibition.This article has an associated First Person interview with the first author of the paper. PMID- 29150488 TI - A self-inhibitory interaction within Nup155 and membrane binding are required for nuclear pore complex formation. AB - Nuclear pore complexes (NPCs) are gateways through the nuclear envelope. How they form into a structure containing three rings and integrate into the nuclear envelope remains a challenging paradigm for coordinated assembly of macro complexes. In vertebrates, the cytoplasmic and nucleoplasmic rings of NPCs are mostly formed by multiple copies of the Nup107-Nup160 complex, whereas the central, or inner ring is composed of Nup53, Nup93, Nup155 and the two paralogues Nup188 and Nup205. Inner ring assembly is only partially understood. Using in vitro nuclear assembly reactions, we show that direct pore membrane binding of Nup155 is crucial for NPC formation. Replacing full-length Nup155 with its N terminal beta-propeller allows assembly of the outer ring components to the NPC backbone that also contains Nup53. However, further assembly, especially recruitment of the Nup93 and Nup62 complexes, is blocked. Self-interaction between the N- and C-terminal domains of Nup155 has an auto-inhibitory function that prevents interaction between the N-terminus of Nup155 and the C-terminal region of Nup53. Nup93 can overcome this block by binding to Nup53, thereby promoting formation of the inner ring and the NPC. PMID- 29150489 TI - Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study. AB - OBJECTIVE: Ulcerative colitis (UC) is a dynamic disease with its severity continuously changing over time. We hypothesised that the risk of colorectal neoplasia (CRN) in UC closely follows an actuarial accumulative inflammatory burden, which is inadequately represented by current risk stratification strategies. DESIGN: This was a retrospective single-centre study. Patients with extensive UC who were under colonoscopic surveillance between 2003 and 2012 were studied. Each surveillance episode was scored for a severity of microscopic inflammation (0=no activity; 1=mild; 2=moderate; 3=severe activity). The cumulative inflammatory burden (CIB) was defined as sum of: average score between each pair of surveillance episodes multiplied by the surveillance interval in years. Potential predictors were correlated with CRN outcome using time-dependent Cox regression. RESULTS: A total of 987 patients were followed for a median of 13 years (IQR, 9-18), 97 (9.8%) of whom developed CRN. Multivariate analysis showed that the CIB was significantly associated with CRN development (HR, 2.1 per 10 unit increase in CIB (equivalent of 10, 5 or 3.3 years of continuous mild, moderate or severe active microscopic inflammation); 95% CI 1.4 to 3.0; P<0.001). Reflecting this, while inflammation severity based on the most recent colonoscopy alone was not significant (HR, 0.9 per-1-unit increase in severity; 95% CI 0.7 to 1.2; P=0.5), a mean severity score calculated from all colonoscopies performed in preceding 5 years was significantly associated with CRN risk (HR, 2.2 per-1-unit increase; 95% CI 1.6 to 3.1; P<0.001). CONCLUSION: The risk of CRN in UC is significantly associated with accumulative inflammatory burden. An accurate CRN risk stratification should involve assessment of multiple surveillance episodes to take this into account. PMID- 29150490 TI - Gut roundtable meeting paper: selected recent advances in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) ranks number three among the most frequent causes of death from solid tumors worldwide. With obesity and fatty liver diseases as risk factors on the rise, HCC represents an ever increasing challenge. While there is still no curative treatment for most patients numerous novel drugs have been proposed, but most ultimately failed in phase III trials. This manuscript targets therapeutic advances and most burning issues. Expert key point summaries and urgent research agenda are provided regarding risk factors, including microbiota, need for prognostic and predictive biomarkers and the equivocal role of liver biopsy. Therapeutic topics highlighted are locoregional techniques, combination therapies and the potential of immunotherapy. Finally the manuscript provides a critical evaluation of novel targets and strategies for personalized treatment of HCC. PMID- 29150491 TI - Hypothermia Modulates Arrhythmia Substrates During Different Phases of Resuscitation From Ischemic Cardiac Arrest. AB - BACKGROUND: We designed an innovative porcine model of ischemia-induced arrest to determine dynamic arrhythmia substrates during focal infarct, global ischemia from ventricular tachycardia or fibrillation (VT/VF) and then reperfusion to determine the effect of therapeutic hypothermia (TH) on dynamic arrhythmia substrates and resuscitation outcomes. METHODS AND RESULTS: Anesthetized adult pigs underwent thoracotomy and regional plunge electrode placement in the left ventricle. Subjects were then maintained at either control (CT; 37 degrees C, n=9) or TH (33 degrees C, n=8). The left anterior descending artery (LAD) was occluded and ventricular fibrillation occurred spontaneously or was induced after 30 minutes. Advanced cardiac life support was started after 8 minutes, and LAD reperfusion occurred 60 minutes after occlusion. Incidences of VF/VT and survival were compared with ventricular ectopy, cardiac alternans, global dispersion of repolarization during LAD occlusion, and LAD reperfusion. There was no difference in incidence of VT/VF between groups during LAD occlusion (44% in CT versus 50% in TH; P=1s). During LAD occlusion, ectopy was increased in CT and suppressed in TH (33+/-11 ventricular ectopic beats/min versus 4+/-6 ventricular ectopic beats/min; P=0.009). Global dispersion of repolarization and cardiac alternans were similar between groups. During LAD reperfusion, TH doubled the incidence of cardiac alternans compared with CT, with a marked increase in VF/VT (100% in TH versus 17% in CT; P=0.004). Ectopy and global dispersion of repolarization were similar between groups during LAD reperfusion. CONCLUSIONS: TH alters arrhythmia substrates in a porcine translational model of resuscitation from ischemic cardiac arrest during the complex phases of resuscitation. TH worsens cardiac alternans, which was associated with an increase in spontaneous VT/VF during reperfusion. PMID- 29150492 TI - Predictors of Mortality in Patients With Severe Ischemic Cardiomyopathy Undergoing Surgical Mitral Valve Intervention. AB - BACKGROUND: Ischemic mitral regurgitation is associated with substantial risk of death. Although surgical mitral valve intervention (MVi) may improve symptoms, it has not been shown to improve survival. The aim of this study was to identify predictors of mortality in patients with ischemic mitral regurgitation and MVi. METHODS AND RESULTS: We evaluated 117 consecutive patients (age, 65+/-10 years) with advanced ischemic cardiomyopathy who underwent cardiac magnetic resonance and subsequent MVi between January 1, 2002 and January 1, 2012. Cardiac magnetic resonance was used to assess left ventricular remodeling and myocardial scarring. The effective regurgitant orifice area was calculated from the proximal isovelocity surface area by echocardiography. There were 43 deaths (37%) during follow-up (median, 62 months). On multivariable analysis, age >=70 years (P=0.013), diabetes mellitus (P=0.001), dyslipidemia (P=0.012), papillary muscle scar (P=0.010), incomplete revascularization (P=0.001), and total scar %*effective regurgitant orifice area >=0.20 cm2 (P=0.005) were each independently associated with all-cause mortality. Although patients with effective regurgitant orifice area <0.2 cm2 at baseline demonstrated an increased hazard ratio of 3.3 for every 10% increase in scar, the hazard ratio increased to 9 for every 10% increase in scar in those with baseline effective regurgitant orifice area >=0.20 cm2. Mortality also was significantly higher in patients with incomplete revascularization compared with those with vascularized viable myocardium (61% versus 28%; P<0.001). CONCLUSIONS: Increased total scar burden and the presence of incomplete revascularization are powerful predictors of mortality in patients with advanced ischemic cardiomyopathy undergoing MVi. Viability assessment with cardiac magnetic resonance imaging can identify which patients with ischemic mitral regurgitation are at highest risk for mortality after surgical MVi. PMID- 29150494 TI - Strong Implications But Weak Evidence for Strength Training. PMID- 29150493 TI - Very Late Pathological Responses to Cobalt-Chromium Everolimus-Eluting, Stainless Steel Sirolimus-Eluting, and Cobalt-Chromium Bare Metal Stents in Humans. AB - BACKGROUND: The "very late" clinical outcomes for durable polymer drug-eluting stents and bare metal stents (BMSs) have been shown to be dissimilar in clinical studies. Conceptually, the long-term vascular compatibility of BMSs is still regarded to be superior to drug-eluting stents; however, no pathologic study to date has specifically addressed this issue. We evaluated the very late (>=1 year) pathologic responses to durable polymer drug-eluting stents (cobalt-chromium [CoCr] everolimus-eluting stents [EESs] and stainless steel sirolimus-eluting stents [SS-SESs]) versus BMSs (CoCr-BMSs). METHODS AND RESULTS: From the CVPath stent registry, we studied a total of 119 lesions (40 CoCr-EESs, 44 SS-SESs, 35 CoCr-BMSs) from 92 autopsy cases with a duration ranging from 1 to 5 years. Sections of stented coronary segments were pathologically analyzed. Inflammation score and the percentage of struts with giant cells were lowest in CoCr-EESs (median inflammation score: 0.6; median percentage of struts with giant cells: 3.8%) followed by CoCr-BMSs (median inflammation score: 1.3 [P<0.01]; median percentage of struts with giant cells: 8.9% [P=0.02]) and SS-SESs (median inflammation score: 1.7 [P<0.01]; median percentage of struts with giant cells: 15.3% [P<0.01]). Polymer delamination was observed exclusively in SS-SESs and was associated with increased inflammatory and giant cell reactions. The prevalence of neoatherosclerosis with CoCr-EESs (50%) was significantly less than with SS SESs (77%, P=0.02) but significantly greater than with CoCr-BMSs (20%, P<0.01). CONCLUSIONS: CoCr-EESs, SS-SESs, and BMSs each demonstrated distinct vascular responses. CoCr-EESs demonstrated the least inflammation, near-equivalent healing to BMSs, and lower neointimal formation. These results challenge the belief that BMSs have superior biocompatibility compared with some polymeric coated drug eluting stents and may have implications for future stent design. PMID- 29150495 TI - Small dense HDLs display potent vasorelaxing activity, reflecting their elevated content of sphingosine-1-phosphate. AB - The functional heterogeneity of HDL is attributed to its diverse bioactive components. We evaluated whether the vasodilatory effects of HDL differed across HDL subpopulations, reflecting their distinct molecular composition. The capacity of five major HDL subfractions to counteract the inhibitory effects of oxidized LDL on acetylcholine-induced vasodilation was tested in a rabbit aortic rings model. NO production, an essential pathway in endothelium-dependent vasorelaxation, was studied in simian vacuolating virus 40-transformed murine endothelial cells (SVECs). Small dense HDL3 subfractions displayed potent vasorelaxing activity (up to +31% vs. baseline, P < 0.05); in contrast, large light HDL2 did not induce aortic-ring relaxation when compared on a total protein basis. HDL3 particles were enriched with sphingosine-1-phosphate (S1P) (up to 3 fold vs. HDL2), with the highest content in HDL3b and -3c that concomitantly revealed the strongest vasorelaxing properties. NO generation was enhanced by HDL3c in SVECs (1.5-fold, P < 0.01), a phenomenon that was blocked by the S1P receptor antagonist, VPC 23019. S1P-enriched reconstituted HDL (rHDL) was a 1.8 fold (P < 0.01) more potent vasorelaxant than control rHDL in aortic rings. Small dense HDL3 particles displayed potent protective effects against oxidative stress associated endothelium dysfunction, potentially reflecting their elevated content of S1P that might facilitate interaction with S1P receptors and ensuing NO generation. PMID- 29150496 TI - Diversity of Three-Dimensional Structures and Catalytic Mechanisms of Alginate Lyases. AB - Alginate is a linear polysaccharide produced mainly by brown algae in marine environments. Alginate consists of a linear block copolymer made up of two monomeric units, beta-d-mannuronate (M) and its C-5 epimer alpha-l-guluronate (G). Alginate lyases are polysaccharide lyases (PL) that degrade alginate via a beta-elimination reaction. These enzymes play an important role in marine carbon recycling and also have widespread industrial applications. So far, more than 1,774 alginate lyase sequences have been identified and are distributed into 7 PL families. In this review, the folds, conformational changes during catalysis, and catalytic mechanisms of alginate lyases are described. Thus far, structures for 15 alginate lyases have been solved and are divided into 3 fold classes: the beta jelly roll class (PL7, -14, and -18), the (alpha/alpha)n toroid class (PL5, -15, and -17), and the beta-helix fold (PL6). These enzymes adopt two different mechanisms for catalysis, and three kinds of conformational changes occur during this process. Moreover, common features in the structures, conformational changes, and catalytic mechanisms are summarized, providing a comprehensive understanding on alginate lyases. PMID- 29150497 TI - Low molecular weight thiols and thioredoxins are important players in Hg(II) resistance in Thermus thermophilus HB27. AB - Mercury (Hg), one of the most toxic and widely distributed heavy metals, has a high affinity for thiol groups. Thiol groups reduce and sequester Hg. Therefore, low molecular weight and protein thiols may be important cell components used in Hg resistance. To date, the role of low molecular weight thiols in Hg detoxification remains understudied. The mercury resistance (mer) operon of Thermus thermophilus suggests an evolutionary link between Hg(II) resistance and low molecular weight thiol metabolism. This mer operon encodes for an enzyme involved in methionine biosynthesis, Oah. Challenge with Hg(II) resulted in increased expression of genes involved in the biosynthesis of multiple low molecular weight thiols (cysteine, homocysteine, and bacillithiol), as well as the thioredoxin system. Phenotypic analysis of gene replacement mutants indicated that Oah contributes to Hg resistance under sulfur limiting conditions, and strains lacking bacillithiol and/or thioredoxins are more sensitive to Hg(II) than the wild type. Growth in presence of either a thiol oxidizing agent or a thiol alkylating agent increased sensitivity to Hg(II). Furthermore, exposure to 3 MUM Hg(II) consumed all intracellular reduced bacillithiol and cysteine. Database searches indicate that oah2 is present in all Thermus spp. mer operons. The presence of a thiol related gene was also detected in some alphaprotobacterial mer operons, in which a glutathione reductase gene was present, supporting the role of thiols in Hg(II) detoxification. These results have led to a working model in which LMW thiols act as Hg(II) buffering agents while Hg is reduced by MerA.ImportanceThe survival of microorganisms in presence of toxic metals is central to life's sustainability. The affinity of thiol groups to toxic heavy metals drives microbe-metal interactions and modulate metal toxicity. Mercury detoxification (mer) genes likely originated early in microbial evolution among geothermal environments. Little is known about how mer systems interact with cellular thiol systems. Thermus spp. possess a simple mer operon in which a low molecular weight thiol biosynthesis gene is present, along with merR and merA In this study, we present experimental evidence for the role of thiol systems in mercury resistance. Our data suggest that in T. thermophilus thiolated compounds may function side-by-side with mer genes to detoxify mercury. Thus, thiol systems function in consort with mer-mediated resistance to mercury, suggesting exciting new questions for future research. PMID- 29150498 TI - A cheZ-Like Gene in Azorhizobium caulinodans Is a Key Gene in the Control of Chemotaxis and Colonization of the Host Plant. AB - Chemotaxis can provide bacteria with competitive advantages for survival in complex environments. The CheZ chemotaxis protein is a phosphatase, affecting the flagellar motor in Escherichia coli by dephosphorylating the response regulator phosphorylated CheY protein (CheY~P) responsible for clockwise rotation. A cheZ gene has been found in Azorhizobium caulinodans ORS571, in contrast to other rhizobial species studied so far. The CheZ protein in strain ORS571 has a conserved motif similar to that corresponding to the phosphatase active site in E. coli The construction of a cheZ deletion mutant strain and of cheZ mutant strains carrying a mutation in residues of the putative phosphatase active site showed that strain ORS571 participates in chemotaxis and motility, causing a hyperreversal behavior. In addition, the properties of the cheZ deletion mutant revealed that ORS571 CheZ is involved in other physiological processes, since it displayed increased flocculation, biofilm formation, exopolysaccharide (EPS) production, and host root colonization. In particular, it was observed that the expression of several exp genes, involved in EPS synthesis, was upregulated in the cheZ mutant compared to that in the wild type, suggesting that CheZ negatively controls exp gene expression through an unknown mechanism. It is proposed that CheZ influences the Azorhizobium-plant association by negatively regulating early colonization via the regulation of EPS production. This report established that CheZ in A. caulinodans plays roles in chemotaxis and the symbiotic association with the host plant.IMPORTANCE Chemotaxis allows bacteria to swim toward plant roots and is beneficial to the establishment of various plant-microbe associations. The level of CheY phosphorylation (CheY~P) is central to the chemotaxis signal transduction. The mechanism of the signal termination of CheY~P remains poorly characterized among Alphaproteobacteria, except for Sinorhizobium meliloti, which does not contain CheZ but which controls CheY~P dephosphorylation through a phosphate sink mechanism. Azorhizobium caulinodans ORS571, a microsymbiont of Sesbania rostrata, has an orphan cheZ gene besides two cheY genes similar to those in S. meliloti In addition to controlling the chemotaxis response, the CheZ-like protein in strain ORS571 is playing a role by decreasing bacterial adhesion to the host plant, in contrast to the general situation where chemotaxis-associated proteins promote adhesion. In this study, we identified a CheZ-like protein among Alphaproteobacteria functioning in chemotaxis and the A. caulinodans-S. rostrata symbiosis. PMID- 29150499 TI - Understanding Functional Roles of Native Pentose-Specific Transporters for Activating Dormant Pentose Metabolism in Yarrowia lipolytica. AB - Pentoses, including xylose and arabinose, are the second most prevalent sugars in lignocellulosic biomass that can be harnessed for biological conversion. Although Yarrowia lipolytica has emerged as a promising industrial microorganism for production of high-value chemicals and biofuels, its native pentose metabolism is poorly understood. Our previous study demonstrated that Y. lipolytica (ATCC MYA 2613) has endogenous enzymes for d-xylose assimilation, but inefficient xylitol dehydrogenase causes Y. lipolytica to assimilate xylose poorly. In this study, we investigated the functional roles of native sugar-specific transporters for activating the dormant pentose metabolism in Y. lipolytica By screening a comprehensive set of 16 putative pentose-specific transporters, we identified two candidates, YALI0C04730p and YALI0B00396p, that enhanced xylose assimilation. The engineered mutants YlSR207 and YlSR223, overexpressing YALI0C04730p and YALI0B00396p, respectively, improved xylose assimilation approximately 23% and 50% in comparison to YlSR102, a parental engineered strain overexpressing solely the native xylitol dehydrogenase gene. Further, we activated and elucidated a widely unknown native l-arabinose assimilation pathway in Y. lipolytica through transcriptomic and metabolic analyses. We discovered that Y. lipolytica can coconsume xylose and arabinose, where arabinose utilization shares transporters and metabolic enzymes of some intermediate steps of the xylose assimilation pathway. Arabinose assimilation is synergistically enhanced in the presence of xylose, while xylose assimilation is competitively inhibited by arabinose. l Arabitol dehydrogenase is the rate-limiting step responsible for poor arabinose utilization in Y. lipolytica Overall, this study sheds light on the cryptic pentose metabolism of Y. lipolytica and, further, helps guide strain engineering of Y. lipolytica for enhanced assimilation of pentose sugars.IMPORTANCE The oleaginous yeast Yarrowia lipolytica is a promising industrial-platform microorganism for production of high-value chemicals and fuels. For decades since its isolation, Y. lipolytica has been known to be incapable of assimilating pentose sugars, xylose and arabinose, that are dominantly present in lignocellulosic biomass. Through bioinformatic, transcriptomic, and enzymatic studies, we have uncovered the dormant pentose metabolism of Y. lipolytica Remarkably, unlike most yeast strains, which share the same transporters for importing hexose and pentose sugars, we discovered that Y. lipolytica possesses the native pentose-specific transporters. By overexpressing these transporters together with the rate-limiting d-xylitol and l-arabitol dehydrogenases, we activated the dormant pentose metabolism of Y. lipolytica Overall, this study provides a fundamental understanding of the dormant pentose metabolism of Y. lipolytica and guides future metabolic engineering of Y. lipolytica for enhanced conversion of pentose sugars to high-value chemicals and fuels. PMID- 29150500 TI - Dynamics of Heterotrophic Bacterial Assemblages within Synechococcus Cultures. AB - Interactions between photoautotrophic and heterotrophic microorganisms are central to the marine microbial ecosystem. Lab cultures of one of the dominant marine photoautotrophs, Synechococcus, have historically been difficult to render axenic, presumably because these bacteria depend upon other organisms to grow under these conditions. These tight associations between Synechococcus and heterotrophic bacteria represent a good relevant system to study interspecies interactions. Ten individual Synechococcus strains, isolated from eutrophic and oligotrophic waters, were chosen for investigation. Four to six dominant associated heterotrophic bacteria were detected in the liquid cultures of each Synechococcus isolate, comprising members of the Cytophaga-Flavobacteria Bacteroides (CFB) group (mainly from Flavobacteriales and Cytophagales), Alphaproteobacteria (mainly from the Roseobacter clade), Gammaproteobacteria (mainly from the Alteromonadales and Pseudomonadales), and Actinobacteria The presence of the CFB group, Gammaproteobacteria, and Actinobacteria showed clear geographic patterns related to the isolation environments of the Synechococcus bacteria. An investigation of the population dynamics within a growing culture (XM-24) of one of the isolates, including an evaluation of the proportions of cells that were free-living versus aggregated/attached, revealed interesting patterns for different bacterial groups. In Synechococcus sp. strain XM-24 culture, flavobacteria, which was the most abundant group throughout the culture period, tended to be aggregated or attached to the Synechococcus cells, whereas the actinobacteria demonstrated a free-living lifestyle, and roseobacters displayed different patterns depending on the culture growth phase. Factors contributing to these succession patterns for the heterotrophs likely include interactions among the culture community members, their relative abilities to utilize different compounds produced by Synechococcus cells and changes in the compounds released as culture growth proceeds, and their responses to other changes in the environmental conditions throughout the culture period.IMPORTANCE Marine microbes exist within an interactive ecological network, and studying their interactions is an important part of understanding their roles in global biogeochemical cycling and the determinants of microbial diversity. In this study, the dynamic relationships between Synechococcus spp. and their associated heterotrophic bacteria were investigated. Synechococcus-associated heterotrophic bacteria had similar geographic distribution patterns as their "host" and displayed different lifestyles (free-living versus attached/aggregated) according to the Synechococcus culture growth phases. Combined organic carbon composition and bacterial lifestyle data indicated a potential for succession in carbon utilization patterns by the dominant associated heterotrophic bacteria. Comprehending the interactions between photoautotrophs and heterotrophs and the patterns of organic carbon excretion and utilization is critical to understanding their roles in oceanic biogeochemical cycling. PMID- 29150502 TI - Hyperthermophilic Carbamate Kinase Stability and Anabolic In Vitro Activity at Alkaline pH. AB - Carbamate kinases catalyze the conversion of carbamate to carbamoyl phosphate, which is readily transformed into other compounds. Carbamate forms spontaneously from ammonia and carbon dioxide in aqueous solutions, so the kinases have potential for sequestrative utilization of the latter compounds. Here, we compare seven carbamate kinases from mesophilic, thermophilic, and hyperthermophilic sources. In addition to the known enzymes from Enterococcus faecalis and Pyrococcus furiosus, the previously unreported enzymes from the hyperthermophiles Thermococcus sibiricus and Thermococcus barophilus, the thermophiles Fervidobacterium nodosum and Thermosipho melanesiensis, and the mesophile Clostridium tetani were all expressed recombinantly, each in high yield. Only the clostridial enzyme did not show catalysis. In direct assays of carbamate kinase activity, the three hyperthermophilic enzymes display higher specific activities at elevated temperatures, greater stability, and remarkable substrate turnover at alkaline pH (9.9 to 11.4). Thermococcus barophilus and Thermococcus sibiricus carbamate kinases were found to be the most active when the enzymes were tested at 80 degrees C, and maintained activity over broad temperature and pH ranges. These robust thermococcal enzymes therefore represent ideal candidates for biotechnological applications involving aqueous ammonia solutions, since nonbuffered 0.0001 to 1.0 M solutions have pH values of approximately 9.8 to 11.8. As proof of concept, here we also show that carbamoyl phosphate produced by the Thermococcus barophilus kinase is efficiently converted in situ to carbamoyl aspartate by aspartate transcarbamoylase from the same source organism. Using acetyl phosphate to simultaneously recycle the kinase cofactor ATP, at pH 9.9 carbamoyl aspartate is produced in high yield and directly from solutions of ammonia, carbon dioxide, and aspartate.IMPORTANCE Much of the nitrogen in animal wastes and used in fertilizers is commonly lost as ammonia in water runoff, from which it must be removed to prevent downstream pollution and evolution of nitrogenous greenhouse gases. Since carbamate kinases transform ammonia and carbon dioxide to carbamoyl phosphate via carbamate, and carbamoyl phosphate may be converted into other valuable compounds, the kinases provide a route for useful sequestration of ammonia, as well as of carbon dioxide, another greenhouse gas. At the same time, recycling the ammonia in chemical synthesis reduces the need for its energy-intensive production. However, robust catalysts are required for such biotransformations. Here we show that carbamate kinases from hyperthermophilic archaea display remarkable stability and high catalytic activity across broad ranges of pH and temperature, making them promising candidates for biotechnological applications. We also show that carbamoyl phosphate produced by the kinases may be efficiently used to produce carbamoyl aspartate. PMID- 29150501 TI - glnA truncation in Salmonella enterica results in a small colony variant phenotype, attenuated host cell entry, and reduced expression of flagellin and SPI-1 associated effector genes. AB - Many pathogenic bacteria use sophisticated survival strategies to overcome harsh environmental conditions. One is the formation of slow-growing subpopulations termed small colony variants (SCVs). Here we characterize an SCV, which spontaneously emerged from an axenic Salmonella enterica serovar Typhimurium water culture. We found that the SCV harbors a frameshift mutation in the glutamine synthetase gene glnA leading to a ~90% truncation of the corresponding protein. Glutamine synthetase, a central enzyme in nitrogen assimilation, converts glutamate and ammonia to glutamine. Glutamine is an important nitrogen donor required for the synthesis of cellular compounds. The internal glutamine pool serves as an indicator for nitrogen availability in Salmonella In our study, the SCV and a constructed glnA knockout mutant showed reduced growth rates compared to the wild type. Moreover, the SCV and glnA mutant displayed attenuated entry into host cells and severely reduced levels of exoproteins, including flagellin and several Salmonella pathogenicity island 1 (SPI-1)-dependent secreted virulence factors. We found that these proteins were also depleted in cell lysates indicating their diminished synthesis. Accordingly, the SCV and glnA mutant had severely decreased expression of flagellin genes, several SPI-1 effector genes and a class-2 (flgB) motility gene. However, the expression of a class 1 motility gene (flhD) was not affected. Supplementation with glutamine or genetic reversion of glnA truncation restored growth, cell entry, gene expression and protein abundance. In summary, our data show that glnA is essential for growth of S. enterica and controls important motility- and virulence-related traits in response to glutamine availability.IMPORTANCESalmonella enterica serovar Typhimurium is a significant pathogen causing food-borne infections. Here we describe an S Typhimurium small colony variant (SCV) that spontaneously emerged from a long-term starvation experiment in water. It is important to study SCVs because they a) may arise spontaneously upon stress exposure including environmental and host-defense stresses, b) are slow growing and difficult to eradicate, and c) only few descriptions of Senterica SCVs are available. We clarify the genetic basis of the SCV described here as frameshift mutation in the gene of glutamine synthetase, glnA, leading to glutamine auxotrophy. In Salmonella, internal glutamine limitation serves as a signal for external nitrogen deficiency and is thought to regulate cell growth. In addition to its impaired growth, the SCV showed reduced host cell entry and reduced expression of SPI-1 virulence and flagellin genes. PMID- 29150503 TI - Carbon Amendments Alter Microbial Community Structure and Net Mercury Methylation Potential in Sediments. AB - Neurotoxic methylmercury (MeHg) is produced by anaerobic Bacteria and Archaea possessing the genes hgcAB, but it is unknown how organic substrate and electron acceptor availability impacts the distribution and abundance of these organisms. We evaluated the impact of organic substrate amendments on mercury (Hg) methylation rates, microbial community structure, and the distribution of hgcAB+ microbes with sediments. Sediment slurries were amended with short-chain fatty acids, alcohols, or a polysaccharide. Minimal increases in MeHg were observed following lactate, ethanol, and methanol amendments, while a significant decrease (~70%) was observed with cellobiose incubations. Postincubation, microbial diversity was assessed via 16S rRNA amplicon sequencing. The presence of hgcAB+ organisms was assessed with a broad-range degenerate PCR primer set for both genes, while the presence of microbes in each of the three dominant clades of methylators (Deltaproteobacteria, Firmicutes, and methanogenic Archaea) was measured with clade-specific degenerate hgcA quantitative PCR (qPCR) primer sets. The predominant microorganisms in unamended sediments consisted of Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria Clade-specific qPCR identified hgcA+Deltaproteobacteria and Archaea in all sites but failed to detect hgcA+Firmicutes Cellobiose shifted the communities in all samples to ~90% non hgcAB-containing Firmicutes (mainly Bacillus spp. and Clostridium spp.). These results suggest that either expression of hgcAB is downregulated or, more likely given the lack of 16S rRNA gene presence after cellobiose incubation, Hg methylating organisms are largely outcompeted by cellobiose degraders or degradation products of cellobiose. These results represent a step toward understanding and exploring simple methodologies for controlling MeHg production in the environment.IMPORTANCE Methylmercury (MeHg) is a neurotoxin produced by microorganisms that bioacummulates in the food web and poses a serious health risk to humans. Currently, the impact that organic substrate or electron acceptor availability has on the mercury (Hg)-methylating microorganisms is unclear. To study this, we set up microcosm experiments exposed to different organic substrates and electron acceptors and assayed for Hg methylation rates, for microbial community structure, and for distribution of Hg methylators. The sediment and groundwater was collected from East Fork Poplar Creek in Oak Ridge, TN. Amendment with cellobiose (a lignocellulosic degradation by-product) led to a drastic decrease in the Hg methylation rate compared to that in an unamended control, with an associated shift in the microbial community to mostly nonmethylating Firmicutes This, along with previous Hg-methylating microorganism identification methods, will be important for identifying strategies to control MeHg production and inform future remediation strategies. PMID- 29150504 TI - Temporal Stability of Escherichia coli Concentrations in Waters of Two Irrigation Ponds in Maryland. AB - Fecal contamination of water sources is an important water quality issue for agricultural irrigation ponds. Escherichia coli concentrations are commonly used to evaluate recreational and irrigation water quality. We hypothesized that there may exist temporally stable spatial patterns of E. coli concentrations across ponds, meaning that some areas mostly have higher and other areas mostly lower than average concentrations of E. coli To test this hypothesis, we sampled two irrigation ponds in Maryland at nodes of spatial grids biweekly during the summer of 2016. Environmental covariates-temperature, turbidity, conductivity, pH, dissolved oxygen, chlorophyll a, and nutrients-were measured in conjunction with E. coli concentrations. Temporal stability was assessed using mean relative differences between measurements in each location and averaged measurements across ponds. Temporally stable spatial patterns of E. coli concentrations and the majority of environmental covariates were expressed for both ponds. In the pond interior, larger relative mean differences in chlorophyll a corresponded to smaller mean relative differences in E. coli concentrations, with a Spearman's rank correlation coefficient of 0.819. Turbidity and ammonium concentrations were the two other environmental covariates with the largest positive correlations between their location ranks and the E. coli concentration location ranks. Tenfold differences were found between geometric mean E. coli concentrations in locations that were consistently high or consistently low. The existence of temporally stable patterns of E. coli concentrations can affect the results of microbial water quality assessment in ponds and should be accounted for in microbial water quality monitoring design.IMPORTANCE The microbial quality of water in irrigation water sources must be assessed to prevent the spread of microbes that can cause disease in humans because of produce consumption. The microbial quality of irrigation water is evaluated based on concentrations of Escherichia coli as the indicator organism. Given the high spatial and temporal variability of E. coli concentrations in irrigation water sources, recommendations are needed on where and when samples of water have to be taken for microbial analysis. This work demonstrates the presence of a temporally stable spatial pattern in the distributions of E. coli concentrations across irrigation ponds. The ponds studied had zones where E. coli concentrations were mostly higher than average and zones where the concentrations were mostly lower than average over the entire observation period, covering the season when water was used for irrigation. Accounting for the existence of such zones will improve the design and implementation of microbial water quality monitoring. PMID- 29150505 TI - Cry64Ba and Cry64Ca, Two ETX/MTX2-Type Bacillus thuringiensis Insecticidal Proteins Active against Hemipteran Pests. AB - Genetically modified crops that express insecticidal Bacillus thuringiensis (Bt) proteins have become a primary approach for control of lepidopteran (moth) and coleopteran (beetle) pests that feed by chewing the plants. However, the sap sucking insects (Hemiptera) are not particularly susceptible to Bt toxins. In this study, we describe two Cry toxins (Cry64Ba and Cry64Ca) from Bt strain 1012 that showed toxicity against two important hemipteran rice pests, Laodelphax striatellus and Sogatella furcifera Both of these proteins contain an ETX/MTX2 domain and share common sequence features with the beta-pore-forming toxins. Coexpression of cry64Ba and cry64Ca genes in the acrystalliferous Bt strain HD73- resulted in high insecticidal activity against both hemipteran pests. No toxicity was observed on other pests such as Ostrinia furnacalis, Plutella xylostella, or Colaphellus bowringi Also, no hemolytic activity or toxicity against cancer cells was detected. Binding assays showed specific binding of the Cry64Ba/Cry64Ca toxin complex to brush border membrane vesicles isolated from L. striatellus Cry64Ba and Cry64Ca are Bt Cry toxins highly effective against hemipteran pests and could provide a novel strategy for the environmentally friendly biological control of rice planthoppers in transgenic plants.IMPORTANCE In Asia, rice is an important staple food, whose production is threatened by rice planthoppers. To date, no effective Bacillus thuringiensis (Bt) protein has been shown to have activity against rice planthoppers. We cloned two Bt toxin genes from Bt strain 1012 that showed toxicity against small brown planthoppers (Laodelphax striatellus) and white-backed planthoppers (Sogatella furcifera). To our knowledge, the proteins encoded by the cry64Ba and cry64Ca genes are the most efficient insecticidal Bt Cry proteins with activity against hemipteran insects reported so far. Cry64Ba and Cry64Ca showed no toxicity against some lepidopteran or coleopteran pests. These two proteins should be able to be used for integrated hemipteran pest management. PMID- 29150506 TI - The swinholide biosynthetic gene cluster from a terrestrial cyanobacterium Nostoc sp. UHCC 0450. AB - Swinholides are 42-carbon ring polyketides with a twofold axis of symmetry. They are potent cytotoxins that disrupt the actin cytoskeleton. Swinholides were discovered from the marine sponge Theonella sp. and were long-suspected to be produced by symbiotic bacteria. Misakinolide, a structural variant of swinholide, was recently demonstrated to be the product of the symbiotic heterotrophic proteobacterium. Here we report the production of swinholide A by an axenic strain of the terrestrial cyanobacterium Nostoc sp. UHCC 0450. We located the 85 kb trans-AT PKS swinholide gene cluster from a draft genome of Nostoc sp. UHCC 0450. The swinholide and misakinolide biosynthetic gene clusters share an almost identical order of catalytic domains, 85% nucleotide sequence identity and they group together in phylogenetic analysis. Our results resolve speculation around the true producer of swinholides and demonstrate that bacteria belonging to two distantly related phyla both produce structural variants of the same natural product. In addition, we described a biosynthetic cluster from Anabaena sp. UHCC 0451 for the synthesis of the cytotoxic and antifungal scytophycin. All of these biosynthetic clusters were closely related to each other and created a group of cytotoxic macrolide compounds produced by trans-AT PKSs of cyanobacteria and proteobacteria.Importance Many of the drugs in use today originate from natural products. New candidate compounds for drug development are needed due to increased drug resistance. An increased knowledge of the biosynthesis of bioactive compounds can be used to aid chemical synthesis to produce novel drugs. Here we show that terrestrial axenic culture of Nostoc cyanobacterium produces swinholides, which have been previously found only from marine sponge or samples related to them. Swinholides are polyketides with a twofold axis of symmetry and they are potent cytotoxins that disrupt the actin cytoskeleton. We describe the biosynthetic gene clusters of swinholide from Nostoc, as well as the related cytotoxic and antifungal scytophycin from Anabaena, and study the evolution of their trans-AT polyketide synthases. Interestingly, swinholide is closely related to misakinolide produced by a symbiotic heterotrophic proteobacterium, demonstrating that bacteria belonging to two distantly related phyla and different habitats can produce similar natural products. PMID- 29150507 TI - Divalent Metal Cations Potentiate the Predatory Capacity of Amoeba for Cryptococcus neoformans. AB - Among the best-studied interactions between soil phagocytic predators and a human pathogenic fungus is that of Acanthamoeba castellanii and Cryptococcus neoformans The experimental conditions used in amoeba-fungus confrontation assays can have major effects on whether the fungus or the protozoan is ascendant in the interaction. In the presence of Mg2+ and Ca2+ in phosphate-buffered saline (PBS), C. neoformans was consistently killed when incubated with A. castellaniiA. castellanii survived better in the presence of Mg2+ and Ca2+, even when incubated with C. neoformans In the absence of Mg2+ and Ca2+, C. neoformans survived when incubated with A. castellanii, and the percentage of dead amoebae was higher than when incubated without yeast cells. These results show that the presence of Mg2+ and Ca2+ can make a decisive contribution toward tilting the outcome of the interaction in favor of the amoeba. Of the two metals, Mg2+ had a stronger effect than Ca2+ The cations enhanced A. castellanii activity against C. neoformans via enhanced phagocytosis, which is the major mechanism by which amoebae kill fungal cells. We found no evidence that amoebae use extracellular killing mechanisms in their interactions with C. neoformans In summary, the presence of Mg2+ and Ca2+ enhanced the cell adhesion on the surfaces and the motility of the amoeba, thus increasing the chance for contact with C. neoformans and the frequency of phagocytosis. Our findings imply that the divalent cation concentration in soils could be an important variable for whether amoebae can control C. neoformans in the environment.IMPORTANCE The grazing of soil organisms by phagocytic predators such as amoebae is thought to select for traits that enable some of them to acquire the capacity for virulence in animals. Consequently, knowledge about the interactions between amoebae and soil microbes, such as pathogenic fungi, is important for understanding how virulence can emerge. We show that the interaction between an amoeba and the pathogenic fungus C. neoformans is influenced by the presence in the assay of magnesium and calcium, which potentiate amoebae. The results may also have practical applications, since enriching soils with divalent cations may reduce C. neoformans numbers in contaminated soils. PMID- 29150508 TI - Community Composition and Ultrastructure of a Nitrate-Dependent Anaerobic Methane Oxidizing Enrichment Culture. AB - Methane is a very potent greenhouse gas and can be oxidized aerobically or anaerobically through microbe-mediated processes, thus decreasing methane emissions in the atmosphere. Using a complementary array of methods, including phylogenetic analysis, physiological experiments, and light and electron microscopy techniques (including electron tomography), we investigated the community composition and ultrastructure of a continuous bioreactor enrichment culture, in which anaerobic oxidation of methane (AOM) was coupled to nitrate reduction. A membrane bioreactor was seeded with AOM biomass and continuously fed with excess methane. After 150 days, the bioreactor reached a daily consumption of 10 mmol nitrate . liter-1 . day-1 The biomass consisted of aggregates that were dominated by nitrate-dependent anaerobic methane-oxidizing "Candidatus Methanoperedens"-like archaea (40%) and nitrite-dependent anaerobic methane oxidizing "Candidatus Methylomirabilis"-like bacteria (50%). The "Ca Methanoperedens" spp. were identified by fluorescence in situ hybridization and immunogold localization of the methyl-coenzyme M reductase (Mcr) enzyme, which was located in the cytoplasm. The "Ca Methanoperedens" sp. aggregates consisted of slightly irregular coccoid cells (~1.5-MUm diameter) which produced extruding tubular structures and putative cell-to-cell contacts among each other. "Ca Methylomirabilis" sp. bacteria exhibited the polygonal cell shape typical of this genus. In AOM archaea and bacteria, cytochrome c proteins were localized in the cytoplasm and periplasm, respectively, by cytochrome staining. Our results indicate that AOM bacteria and archaea might work closely together in the process of anaerobic methane oxidation, as the bacteria depend on the archaea for nitrite. Future studies will be aimed at elucidating the function of the cell-to cell interactions in nitrate-dependent AOM.IMPORTANCE Microorganisms performing nitrate- and nitrite-dependent anaerobic methane oxidation are important in both natural and man-made ecosystems, such as wastewater treatment plants. In both systems, complex microbial interactions take place that are largely unknown. Revealing these microbial interactions would enable us to understand how the oxidation of the important greenhouse gas methane occurs in nature and pave the way for the application of these microbes in wastewater treatment plants. Here, we elucidated the microbial composition, ultrastructure, and physiology of a nitrate-dependent AOM community of archaea and bacteria and describe the cell plan of "Ca Methanoperedens"-like methanotrophic archaea. PMID- 29150509 TI - The Tape Measure Protein Is Involved in the Heat Stability of Lactococcus lactis Phages. AB - Virulent lactococcal phages are still a major risk for milk fermentation processes as they may lead to slowdowns and low-quality fermented dairy products, particularly cheeses. Some of the phage control strategies used by the industry rely on heat treatments. Recently, a few Lactococcus lactis phages were found to be highly thermo-resistant. To identify the genetic determinant(s) responsible for the thermal resistance of lactococcal phages, we used the virulent phage CB14 (of the Lactococcus lactis 936 [now Sk1virus] phage group) to select for phage mutants with increased heat stability. By treating phage CB14 to successive low and high temperatures, we were able to select two CB14 derivatives with increased heat stability. Sequencing of their genome revealed the same nucleotide sequences as the wild-type phage CB14, except for a same-sized deletion (120 bp) in the gene coding for the tape measure protein (TMP) of each phage mutant, but at a different position. The TMP protein sequences of these mutant phages were compared with their homologues in other wild-type L. lactis phages with a wide diversity in heat stability. Comparative analysis showed that the same nucleotide deletion appears to have also occurred in the gene coding for the TMP of highly thermo-resistant lactococcal phages P1532 and P680. We propose that the TMP is, in part, responsible for the heat stability of the highly predominant lactococcal phages of the Sk1virus group.IMPORTANCE Virulent lactococcal phages still represent a major risk for milk fermentation as they may lead to slowdowns and low-quality fermented dairy products. Heat treatment is one of the most commonly used methods to control these virulent phages in cheese by-products. Recently, a few Lactococcus lactis phages, members of the Sk1virus group, have emerged with high thermal stability. To our knowledge, the genetic determinant(s) responsible for this thermal resistance in lactococcal phages is unknown. A better understanding of the thermal stability of these emerging virulent lactococcal phages is needed to improve industrial control strategies. In this work, we report the identification of a phage structural protein that is involved in the heat stability of a virulent Sk1virus phage. Identifying such a genetic determinant for heat stability is a first step in understanding the emergence of this group of thermostable phages. PMID- 29150510 TI - Vibrio parahaemolyticus and Vibrio vulnificus Recovered from Oysters during an Oyster Relay Study. AB - Vibrio parahaemolyticus and Vibrio vulnificus are naturally occurring estuarine bacteria and are the leading causes of seafood-associated infections and mortality in the United States. Though multiple-antibiotic-resistant V. parahaemolyticus and V. vulnificus strains have been reported, resistance patterns in vibrios are not as well documented as those of other foodborne bacterial pathogens. Salinity relaying (SR) is a postharvest processing (PHP) treatment to reduce the abundances of these pathogens in shellfish harvested during the warmer months. The purpose of this study was to evaluate the antimicrobial susceptibility (AMS), pathogenicity, and genetic profiles of V. parahaemolyticus and V. vulnificus recovered from oysters during an oyster relay study. Isolates (V. parahaemolyticus [n = 296] and V. vulnificus [n = 94]) were recovered from oysters before and during the 21-day relaying study to detect virulence genes (tdh and trh) and genes correlated with virulence (vcgC) using multiplex quantitative PCR (qPCR). AMS to 20 different antibiotics was investigated using microbroth dilution, and pulsed-field gel electrophoresis (PFGE) was used to study the genetic profiles of the isolates. Twenty percent of V. vulnificus isolates were vcgC+, while 1 and 2% of V. parahaemolyticus were tdh+ and trh+, respectively. More than 77% of the V. vulnificus isolates and 30% of the V. parahaemolyticus isolates were resistant to at least one antimicrobial. Forty-eight percent of V. vulnificus and 8% of V. parahaemolyticus isolates were resistant to two or more antimicrobials. All isolates demonstrated a high genetic diversity, even among those isolated from the same site and having a similar AMS profile. No significant effects of the relaying process on AMS, virulence genes, or PFGE profiles of V. vulnificus and V. parahaemolyticus were observed.IMPORTANCE Analysis of the antibiotic resistance profiles of V. vulnificus and V. parahaemolyticus isolated from oysters during this study indicated that more than 48% of V. vulnificus isolates were resistant to two or more antimicrobials, including those recommended by the CDC for treating Vibrio infections. Also, the V. parahaemolyticus isolates showed high MICs for some of the Vibrio infection treatment antibiotics. Monitoring of AMS profiles of this bacterium is important to ensure optimal treatment of infections and improve food safety. Our study showed no significant differences in the AMS profiles of V. vulnificus (P = 0.26) and V. parahaemolyticus (P = 0.23) isolated from the oysters collected before versus after relaying. This suggests that the salinity of the relaying sites did not affect the AMS profiles of the Vibrio isolates, although it did reduce the numbers of these bacteria in oysters (S. Parveen et al., J Food Sci 82:484-491, 2017, https://doi.org/10.1111/1750-3841.13584). PMID- 29150511 TI - Sulfolobus acidocaldarius uptakes pentoses via a cut2-type ABC transporter and metabolizes them through the aldolase-independent Weimberg pathway. AB - Sulfolobus spp. possess a great metabolic versatility and grow heterotrophically on various carbon sources such as different sugars and peptides. Known sugar transporters in Archaea predominantly belong to ABC transport systems. Although several ABC transporters for sugar uptake have been characterized in the crenarchaeon Sulfolobus solfataricus, only one homologue of these transporters, the maltose/maltooligomer transporter, could be identified in the closely related Sulfolobus acidocaldarius Comparison of the transcriptome of S. acidocaldarius grown on peptides alone and peptides in presence of D-xylose allowed for the identification of the ABC transporter for D-xylose and L-arabinose transport and to gain deeper insights into pentose catabolism under the respective growth conditions. The D-xylose/L-arabinose substrate binding protein (SBP) (Saci_2122) of the ABC transporter is unique in Archaea and shares more similarity to bacterial SBPs of the Carbohydrate Uptake Transporter-2 (CUT2) family than to any characterized archaeal one. The identified pentose transporter is the first CUT2 family ABC transporter analyzed in the domain of Archaea. Single gene deletion mutants of the ABC transporter subunits exemplified the importance of the transport system for D-xylose and L-arabinose uptake. Next to the transporter operon, enzymes of the aldolase-independent pentose catabolism branch were found to be upregulated in N-Z-Amine and D-xylose medium. The alpha-ketoglutarate semialdehyde dehydrogenase (KGSADH; Saci_1938) seemed not to be essential for growth on pentoses. However, the deletion mutant of the 2-keto-3 deoxyarabinoate/xylonate dehydratase (KDXD/KDAD; Saci_1939) was no longer able to catabolize D-xylose or L-arabinose suggesting the absence of the aldolase dependent branch in S. acidocaldariusImportance Thermoacidophilic microorganisms are emerging model organisms for biotechnological applications as their optimal growth conditions resemble conditions used in certain biotechnologies such as plant waste industrial degradation. Because of its high genome stability Sulfolobus acidocaldarius is especially suited as a platform organism for such applications. For the use in (ligno)cellulose degradation, it was important to understand the pentose uptake and metabolism in S. acidocaldarius This study revealed that only the aldolase-independent Weimberg pathway is required for growth of S. acidocaldarius on D-xylose and L-arabinose. Moreover, S. acidocaldarius employs a CUT2 ABC transporter for pentose uptake, which is more similar to bacterial than to archaeal ABC transporters. The identification of pentose inducible promoters will expedite the metabolic engineering of S. acidocaldarius for its development into a platform organism for (ligno)cellulose degradation. PMID- 29150512 TI - A Genetic System for the Thermophilic Acetogenic Bacterium Thermoanaerobacter kivui. AB - Thermoanaerobacter kivui is one of the very few thermophilic acetogenic microorganisms. It grows optimally at 66 degrees C on sugars but also lithotrophically with H2 + CO2 or with CO, producing acetate as the major product. While a genome-derived model of acetogenesis has been developed, only a few physiological or biochemical experiments regarding the function of important enzymes in carbon and energy metabolism have been carried out. To address this issue, we developed a method for targeted markerless gene deletions and for integration of genes into the genome of T. kivui The strain naturally took up plasmid DNA in the exponential growth phase, with a transformation frequency of up to 3.9 * 10-6 A nonreplicating plasmid and selection with 5-fluoroorotate was used to delete the gene encoding the orotate phosphoribosyltransferase (pyrE), resulting in a DeltapyrE uracil-auxotrophic strain, TKV002. Reintroduction of pyrE on a plasmid or insertion of pyrE into different loci within the genome restored growth without uracil. We subsequently studied fructose metabolism in T. kivui The gene fruK (TKV_c23150) encoding 1-phosphofructosekinase (1-PFK) was deleted, using pyrE as a selective marker via two single homologous recombination events. The resulting DeltafruK strain, TKV003, did not grow on fructose; however, growth on glucose (or on mannose) was unaffected. The combination of pyrE as a selective marker and the natural competence of the strain for DNA uptake will be the basis for future studies on CO2 reduction and energy conservation and their regulation in this thermophilic acetogenic bacterium.IMPORTANCE Acetogenic bacteria are currently the focus of research toward biotechnological applications due to their potential for de novo synthesis of carbon compounds such as acetate, butyrate, or ethanol from H2 + CO2 or from synthesis gas. Based on available genome sequences and on biochemical experiments, acetogens differ in their energy metabolism. Thus, there is an urgent need to understand the carbon and electron flows through the Wood Ljungdahl pathway and their links to energy conservation, which requires genetic manipulations such as deletion or overexpression of genes encoding putative key enzymes. Unfortunately, genetic systems have been reported for only a few acetogenic bacteria. Here, we demonstrate proof of concept for the genetic modification of the thermophilic acetogenic species Thermoanaerobacter kivui The genetic system will be used to study genes involved in biosynthesis and energy metabolism, and may further be applied to metabolically engineer T. kivui to produce fuels and chemicals. PMID- 29150513 TI - High Prevalence and Genetic Diversity of Large phiCD211 (phiCDIF1296T)-Like Prophages in Clostridioides difficile. AB - Clostridioides difficile (formerly Clostridium difficile) is a pathogenic bacterium displaying great genetic diversity. A significant proportion of this diversity is due to the presence of integrated prophages. Here, we provide an in depth analysis of phiCD211, also known as phiCDIF1296T, the largest phage identified in C. difficile so far, with a genome of 131 kbp. It shares morphological and genomic similarity with other large siphophages, like phage 949, infecting Lactococcus lactis, and phage c-st, infecting Clostridium botulinum A PhageTerm analysis indicated the presence of 378-bp direct terminal repeats at the phiCD211 genome termini. Among striking features of phiCD211, the presence of several transposase and integrase genes suggests past recombination events with other mobile genetic elements. Several gene products potentially influence the bacterial lifestyle and fitness, including a putative AcrB/AcrD/AcrF multidrug resistance protein, an EzrA septation ring formation regulator, and a spore protease. We also identified a CRISPR locus and a cas3 gene. We screened 2,584 C. difficile genomes available and detected 149 prophages sharing >=80% nucleotide identity with phiCD211 (5% prevalence). Overall, phiCD211-like phages were detected in C. difficile strains corresponding to 21 different multilocus sequence type groups, showing their high prevalence. Comparative genomic analyses revealed the existence of several clusters of highly similar phiCD211-like phages. Of note, large chromosome inversions were observed in some members, as well as multiple gene insertions and module exchanges. This highlights the great plasticity and gene coding potential of the phiCD211/phiCDIF1296T genome. Our analyses also suggest active evolution involving recombination with other mobile genetic elements.IMPORTANCEClostridioides difficile is a clinically important pathogen representing a serious threat to human health. Our hypothesis is that genetic differences between strains caused by the presence of integrated prophages could explain the apparent differences observed in the virulence of different C. difficile strains. In this study, we provide a full characterization of phiCD211, also known as phiCDIF1296T, the largest phage known to infect C. difficile so far. Screening 2,584 C. difficile genomes revealed the presence of highly similar phiCD211-like phages in 5% of the strains analyzed, showing their high prevalence. Multiple-genome comparisons suggest that evolution of the phiCD211 like phage community is dynamic, and some members have acquired genes that could influence bacterial biology and fitness. Our study further supports the relevance of studying phages in C. difficile to better understand the epidemiology of this clinically important human pathogen. PMID- 29150514 TI - Sinorhizobium meliloti Glutathione Reductase Is Required for both Redox Homeostasis and Symbiosis. AB - Glutathione (l-gamma-glutamyl-l-cysteinylglycine) (GSH), one of the key antioxidants in Sinorhizobium meliloti, is required for the development of alfalfa (Medicago sativa) nitrogen-fixing nodules. Glutathione exists as either reduced glutathione (GSH) or oxidized glutathione (GSSG), and its content is regulated by two pathways in S. meliloti The first pathway is the de novo synthesis of glutathione from its constituent amino acids, namely, Glu, Cys, and Gly, catalyzed by gamma-glutamylcysteine synthetase (GshA) and glutathione synthetase (GshB). The second pathway is the recycling of GSSG via glutathione reductase (GR). However, whether the S. meliloti GR functions similarly to GshA and GshB1 during symbiotic interactions with alfalfa remains unknown. In this study, a plasmid insertion mutation of the S. melilotigor gene, which encodes GR, was constructed, and the mutant exhibited delayed alfalfa nodulation, with 75% reduction in nitrogen-fixing capacity. The gor mutant demonstrated increased accumulation of GSSG and a decreased GSH/GSSG ratio in cells. The mutant also showed defective growth in rich broth and minimal broth and was more sensitive to the oxidants H2O2 and sodium nitroprusside. Interestingly, the expression of gshA, gshB1, katA, and katB was induced in the mutant. These findings reveal that the recycling of glutathione is important for S. meliloti to maintain redox homeostasis and to interact symbiotically with alfalfa.IMPORTANCE The antioxidant glutathione is regulated by its synthetase and reductase in cells. In the symbiotic bacterium S. meliloti, the de novo synthesis of glutathione is essential for alfalfa nodulation and nitrogen fixation. In this study, we observed that the recycling of glutathione from GSSG not only was required for redox homeostasis and oxidative stress protection in S. meliloti cells but also contributed to alfalfa nodule development and competition capacity. Our findings demonstrate that the recycling of glutathione plays a key role in nitrogen fixation symbiosis. PMID- 29150515 TI - Loop of Streptomyces Feruloyl Esterase Plays an Important Role in the Enzyme's Catalyzing the Release of Ferulic Acid from Biomass. AB - Feruloyl esterases (FAEs) are key enzymes required for the production of ferulic acid from agricultural biomass. Previously, we identified and characterized R18, an FAE from Streptomyces cinnamoneus NBRC 12852, which showed no sequence similarity to the known FAEs. To determine the region involved in its catalytic activity, we constructed chimeric enzymes using R18 and its homolog (TH2-18) from S. cinnamoneus strain TH-2. Although R18 and TH2-18 showed 74% identity in their primary sequences, the recombinant proteins of these two FAEs (recombinant R18 [rR18] and rTH2-18) showed very different specific activities toward ethyl ferulate. By comparing the catalytic activities of the chimeras, a domain comprised of residues 140 to 154 was found to be crucial for the catalytic activity of R18. Furthermore, we analyzed the crystal structure of rR18 at a resolution of 1.5 A to elucidate the relationship between its activity and its structure. rR18 possessed a typical catalytic triad, consisting of Ser-191, Asp 214, and His-268, which was characteristic of the serine esterase family. By structural analysis, the above-described domain was found to be present in a loop like structure (the R18 loop), which possessed a disulfide bond conserved in the genus Streptomyces Moreover, compared to rTH2-18 of its parental strain, the TH2 18 mutant, in which Pro and Gly residues were inserted into the domain responsible for forming the R18 loop, showed markedly high kcat values using artificial substrates. We also showed that the FAE activity of TH2-18 toward corn bran, a natural substrate, was improved by the insertion of the Gly and Pro residues.IMPORTANCEStreptomyces species are widely distributed bacteria that are predominantly present in soil and function as decomposers in natural environments. They produce various enzymes, such as carbohydrate hydrolases, esterases, and peptidases, which decompose agricultural biomass. In this study, based on the genetic information on two Streptomyces cinnamoneus strains, we identified novel feruloyl esterases (FAEs) capable of producing ferulic acid from biomass. These two FAEs shared high similarity in their amino acid sequences but did not resemblance any known FAEs. By comparing chimeric proteins and performing crystal structure analysis, we confirmed that a flexible loop was important for the catalytic activity of Streptomyces FAEs. Furthermore, we determined that the catalytic activity of one FAE was improved drastically by inserting only 2 amino acids into its loop-forming domain. Thus, differences in the amino acid sequence of the loop resulted in different catalytic activities. In conclusion, our findings provide a foundation for the development of novel enzymes for industrial use. PMID- 29150516 TI - Differential RNA Sequencing Implicates Sulfide as the Master Regulator of S0 Metabolism in Chlorobaculum tepidum and Other Green Sulfur Bacteria. AB - The green sulfur bacteria (Chlorobiaceae) are anaerobes that use electrons from reduced sulfur compounds (sulfide, S0, and thiosulfate) as electron donors for photoautotrophic growth. Chlorobaculum tepidum, the model system for the Chlorobiaceae, both produces and consumes extracellular S0 globules depending on the availability of sulfide in the environment. These physiological changes imply significant changes in gene regulation, which has been observed when sulfide is added to Cba. tepidum growing on thiosulfate. However, the underlying mechanisms driving these gene expression changes, i.e., the specific regulators and promoter elements involved, have not yet been defined. Here, differential RNA sequencing (dRNA-seq) was used to globally identify transcript start sites (TSS) that were present during growth on sulfide, biogenic S0, and thiosulfate as sole electron donors. TSS positions were used in combination with RNA-seq data from cultures growing on these same electron donors to identify both basal promoter elements and motifs associated with electron donor-dependent transcriptional regulation. These motifs were conserved across homologous Chlorobiaceae promoters. Two lines of evidence suggest that sulfide-mediated repression is the dominant regulatory mode in Cba. tepidum First, motifs associated with genes regulated by sulfide overlap key basal promoter elements. Second, deletion of the Cba. tepidum1277 (CT1277) gene, encoding a putative regulatory protein, leads to constitutive overexpression of the sulfide:quinone oxidoreductase CT1087 in the absence of sulfide. The results suggest that sulfide is the master regulator of sulfur metabolism in Cba. tepidum and the Chlorobiaceae Finally, the identification of basal promoter elements with differing strengths will further the development of synthetic biology in Cba. tepidum and perhaps other ChlorobiaceaeIMPORTANCE Elemental sulfur is a key intermediate in biogeochemical sulfur cycling. The photoautotrophic green sulfur bacterium Chlorobaculum tepidum either produces or consumes elemental sulfur depending on the availability of sulfide in the environment. Our results reveal transcriptional dynamics of Chlorobaculum tepidum on elemental sulfur and increase our understanding of the mechanisms of transcriptional regulation governing growth on different reduced sulfur compounds. This report identifies genes and sequence motifs that likely play significant roles in the production and consumption of elemental sulfur. Beyond this focused impact, this report paves the way for the development of synthetic biology in Chlorobaculum tepidum and other Chlorobiaceae by providing a comprehensive identification of promoter elements for control of gene expression, a key element of strain engineering. PMID- 29150517 TI - Multi-omics reveal the lifestyle of the acidophilic, mineral-oxidizing model species Leptospirillum ferriphilumT. AB - Leptospirillum ferriphilum plays a major role in acidic, metal rich environments where it represents one of the most prevalent iron oxidizers. These milieus include acid rock and mine drainage as well as biomining operations. Despite its perceived importance, no complete genome sequence of this model species' type strain is available, limiting the possibilities to investigate the strategies and adaptations Leptospirillum ferriphilumT applies to survive and compete in its niche. This study presents a complete, circular genome of Leptospirillum ferriphilumT DSM 14647 obtained by PacBio SMRT long read sequencing for use as a high quality reference. Analysis of the functionally annotated genome, mRNA transcripts, and protein concentrations revealed a previously undiscovered nitrogenase cluster for atmospheric nitrogen fixation and elucidated metabolic systems taking part in energy conservation, carbon fixation, pH homeostasis, heavy metal tolerance, oxidative stress response, chemotaxis and motility, quorum sensing, and biofilm formation. Additionally, mRNA transcript counts and protein concentrations were compared between cells grown in continuous culture using ferrous iron as substrate and bioleaching cultures containing chalcopyrite (CuFeS2). Leptospirillum ferriphilumT adaptations to growth on chalcopyrite included a possibly enhanced production of reducing power, reduced carbon dioxide fixation, as well as elevated RNA transcripts and proteins involved in heavy metal resistance, with special emphasis on copper efflux systems. Finally, expression and translation of genes responsible for chemotaxis and motility were enhanced.IMPORTANCELeptospirillum ferriphilum is one of the most important iron oxidizers in the context of acidic and metal rich environments during moderately thermophilic biomining. A high-quality circular genome of Leptospirillum ferriphilumT coupled with functional omics data provides new insights into its metabolic properties, such as the novel identification of genes for atmospheric nitrogen fixation, and represents an essential step for further accurate proteomic and transcriptomic investigation of this acidophile model species in the future. Additionally, light is shed on Leptospirillum ferriphilumT adaptation strategies to growth on the copper mineral chalcopyrite. This data can be applied to deepen our understanding and optimization of bioleaching and biooxidation, techniques that present sustainable and environmentally friendly alternatives to many traditional methods for metal extraction. PMID- 29150518 TI - Molecular Characterization of an Endozoicomonas-Like Organism Causing Infection in the King Scallop (Pecten maximus L.). AB - One of the fastest growing fisheries in the UK is the king scallop (Pecten maximus L.), also currently rated as the second most valuable fishery. Mass mortality events in scallops have been reported worldwide, often with the causative agent(s) remaining uncharacterized. In May 2013 and 2014, two mass mortality events affecting king scallops were recorded in the Lyme Bay marine protected area (MPA) in Southwest England. Histopathological examination showed gill epithelial tissues infected with intracellular microcolonies (IMCs) of bacteria resembling Rickettsia-like organisms (RLOs), often with bacteria released in vascular spaces. Large colonies were associated with cellular and tissue disruption of the gills. Ultrastructural examination confirmed the intracellular location of these organisms in affected epithelial cells. The 16S rRNA gene sequences of the putative IMCs obtained from infected king scallop gill samples, collected from both mortality events, were identical and had a 99.4% identity to 16S rRNA gene sequences obtained from "Candidatus Endonucleobacter bathymodioli" and 95% with Endozoicomonas species. In situ hybridization assays using 16S rRNA gene probes confirmed the presence of the sequenced IMC gene in the gill tissues. Additional DNA sequences of the bacterium were obtained using high-throughput (Illumina) sequencing, and bioinformatic analysis identified over 1,000 genes with high similarity to protein sequences from Endozoicomonas spp. (ranging from 77 to 87% identity). Specific PCR assays were developed and applied to screen for the presence of IMC 16S rRNA gene sequences in king scallop gill tissues collected at the Lyme Bay MPA during 2015 and 2016. There was 100% prevalence of the IMCs in these gill tissues, and the 16S rRNA gene sequences identified were identical to the sequence found during the previous mortality event.IMPORTANCE Molluscan mass mortalities associated with IMCs have been reported worldwide for many years; however, apart from histological and ultrastructural characterization, characterization of the etiological agents is limited. In the present work, we provide detailed molecular characterization of an Endozoicomonas-like organism (ELO) associated with an important commercial scallop species. PMID- 29150519 TI - Biological Containment of Genetically Modified Bacillus subtilis. AB - Genetic manipulation of bacterial spores of the genus Bacillus has shown potential for vaccination and for delivery of drugs or enzymes. Remarkably, proteins displayed on the spore surface retain activity and generally are not degraded. The heat stability of spores coupled with their desiccation resistance makes them suitable for delivery to humans or to animals by the oral route. Despite these attributes one regulatory obstacle has remained regarding the fate of recombinant spores shed into the environment as viable spores. We have addressed the biological containment of spore GMOs by utilizing the concept of a 'thymine-less death', a phenomenon first reported six decades ago. Using Bacillus subtilis we have inserted chimeric genes in the two thymidylate synthase genes, thyA and thyB, using a two-step process. Insertion is made first at thyA followed by thyB where resistance to trimethoprim enables selection of recombinants. Importantly, this method requires introduction of no new antibiotic resistance genes. Recombinant spores have a strict dependence on thymine (or thymidine) and in their absence cells lyse and die. Insertions are stable with no evidence for suppression or reversion. Using this system we have successfully created a number of spore vaccines as well as spores displaying active enzymes.Importance Genetic manipulation of bacterial spores offers a number of exciting possibilities for public and animal health including their use as heat stable vehicles for delivering vaccines or enzymes. Despite this, one remaining problem is the fate of recombinant spores if released to the environment where they could survive in a dormant form indefinitely. We describe a solution whereby following genetic manipulation the bacterium is rendered dependent on thymine. As a consequence spores if released would produce bacteria unable to survive and they would exhibit a thymine-less death due to rapid cessation of metabolism. The method we describe has been validated using a number of exemplars and solves a problem for containing spore GMOs in the environment. PMID- 29150521 TI - Telephone counselling for subdermal implants and intrauterine contraceptives. PMID- 29150520 TI - Dopaminergic neurotoxins induce cell death by attenuating NF-kappaB-mediated regulation of TRPC1 expression and autophagy. AB - Alterations in Ca2+ homeostasis affect neuronal survival. However, the identity of Ca2+ channels and the mechanisms underlying neurotoxin-induced neuronal degeneration are not well understood. In this study, the dopaminergic neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridium ions (MPP+)/1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP), which mimic Parkinson's disease (PD), induced neuronal degeneration by decreasing store-mediated Ca2+ entry. The function of the transient receptor potential canonical (TRPC)-1 channel was decreased upon exposure to the neurotoxins, followed by a decrease in TRPC1 expression. Similar to neurotoxins, samples from patients with PD exhibited attenuated TRPC1 expression, which was accompanied by a decrease in autophagic markers and a subsequent increase in apoptosis markers. Furthermore, exposure to neurotoxins attenuated PKC phosphorylation, decreased expression of autophagic markers, and increased apoptosis in SHSY-5Y neuroblastoma cells, which was again dependent on TRPC1. Prolonged neurotoxin treatment attenuated the binding of NF kappaB to the TRPC1 promoter, which resulted in a decrease in TRPC1 expression, thereby attenuating autophagy and activating cell death. Restoration of TRPC1 expression rescued the effects of the dopaminergic neurotoxins in neuroblastoma cells by increasing Ca2+ entry, restoring NF-kappaB activity, and promoting autophagy. Overall, these results suggest that dopaminergic neurotoxins initially decreased Ca2+ entry, which inhibited the binding of NF-kappaB to the TRPC1 promoter, thereby inhibiting TRPC1 expression and resulting in cell death by preventing autophagy.-Sukumaran, P., Sun, Y., Antonson, N., Singh, B. B. Dopaminergic neurotoxins induce cell death by attenuating NF-kappaB-mediated regulation of TRPC1 expression and autophagy. PMID- 29150523 TI - Infection 10 months after insertion of Nexplanon implant. PMID- 29150522 TI - Addressing decisional conflict about fertility preservation: helping young female cancer survivors' family planning decisions. AB - BACKGROUND: Health professionals are challenged by a growing number of young long term cancer survivors with their specific needs with regard to family planning. This study aimed at assessing decisional conflict (DC) in young female cancer patients regarding fertility preservation, identifying demographic, fertility and fertility preservation related factors, which may affect DC, and assessing the helpfulness of various decision-supports. METHODS: A retrospective, cross sectional, web-based survey via an online questionnaire available in three languages with specific items concerning cancer, fertility, fertility preservation and the validated Decisional Conflict Scale targeted at current or former female cancer patients aged 18-45 years, with cancer types or treatment potentially affecting reproductive function. RESULTS: The 155 participating women showed considerable DC, especially with regard to missing information and support. DC was significantly lower in patients when the risk of infertility was discussed with a health professional, when they had undergone any procedure to preserve fertility, and when they had a university education. A longer time interval since cancer diagnosis was associated with higher DC. The most helpful decision-support tools were specialised websites and leaflets. CONCLUSIONS: Young female cancer patients' DC with regard to fertility preservation is very high. Information and support seem to be deficient. More information through standardised information tools might be an effective strategy to lower their DC at the time when treatment decisions need to be taken, and to improve their reproductive health after they have overcome cancer in the future. PMID- 29150524 TI - Breaking the scale: how disrupting the karyoplasmic ratio gives cancer cells an advantage for metastatic invasion. AB - Nuclear size normally scales with the size of the cell, but in cancer this 'karyoplasmic ratio' is disrupted. This is particularly so in more metastatic tumors where changes in the karyoplasmic ratio are used in both diagnosis and prognosis for several tumor types. However, the direction of nuclear size changes differs for particular tumor types: for example in breast cancer, larger nuclear size correlates with increased metastasis, while for lung cancer smaller nuclear size correlates with increased metastasis. Thus, there must be tissue-specific drivers of the nuclear size changes, but proteins thus far linked to nuclear size regulation are widely expressed. Notably, for these tumor types, ploidy changes have been excluded as the basis for nuclear size changes, and so, the increased metastasis is more likely to have a basis in the nuclear morphology change itself. We review what is known about nuclear size regulation and postulate how such nuclear size changes can increase metastasis and why the directionality can differ for particular tumor types. PMID- 29150525 TI - Distinct RNA-unwinding mechanisms of DEAD-box and DEAH-box RNA helicase proteins in remodeling structured RNAs and RNPs. AB - Structured RNAs and RNA-protein complexes (RNPs) fold through complex pathways that are replete with misfolded traps, and many RNAs and RNPs undergo extensive conformational changes during their functional cycles. These folding steps and conformational transitions are frequently promoted by RNA chaperone proteins, notably by superfamily 2 (SF2) RNA helicase proteins. The two largest families of SF2 helicases, DEAD-box and DEAH-box proteins, share evolutionarily conserved helicase cores, but unwind RNA helices through distinct mechanisms. Recent studies have advanced our understanding of how their distinct mechanisms enable DEAD-box proteins to disrupt RNA base pairs on the surfaces of structured RNAs and RNPs, while some DEAH-box proteins are adept at disrupting base pairs in the interior of RNPs. Proteins from these families use these mechanisms to chaperone folding and promote rearrangements of structured RNAs and RNPs, including the spliceosome, and may use related mechanisms to maintain cellular messenger RNAs in unfolded or partially unfolded conformations. PMID- 29150526 TI - The devil is in the domain: understanding protein recognition of multiple RNA targets. AB - RNA regulation provides a finely tuned and highly co-ordinated control of gene expression. Regulation is mediated by hundreds to thousands of multi-functional RNA-binding proteins which often interact with large sets of RNAs. In this brief review, we focus on a recent work that highlights how the proteins use multiple RNA-binding domains to interact selectively with the different RNA targets. Deconvoluting the molecular complexity of the RNA regulatory network is essential to understanding cell differentiation and function, and requires accurate models for protein-RNA recognition and protein target selectivity. We discuss that the structural and molecular understanding of the key determinant of recognition, together with the availability of methods to examine protein-RNA interactions at the transcriptome level, may provide an avenue to establish these models. PMID- 29150527 TI - Transcriptional regulators of redox balance and other homeostatic processes with the potential to alter neurodegenerative disease trajectory. AB - Diverse neurodegenerative diseases share some common aspects to their pathology, with many showing evidence of disruption to the brain's numerous homeostatic processes. As such, imbalanced inflammatory status, glutamate dyshomeostasis, hypometabolism and oxidative stress are implicated in many disorders. That these pathological processes can influence each other both up- and downstream makes for a complicated picture, but means that successfully targeting one area may have an effect on others. This targeting requires an understanding of the mechanisms by which homeostasis is maintained during health, in order to uncover strategies to boost homeostasis in disease. A case in point is redox homeostasis, maintained by antioxidant defences co-ordinately regulated by the transcription factor Nrf2, and capable of preventing not only oxidative stress but also inflammation and neuronal loss in neurodegenerative disease models. The emergence of other master regulators of homeostatic processes in the brain controlling inflammation, mitochondrial biogenesis, glutamate uptake and energy metabolism raises the question as to whether they too can be targeted to alter disease trajectory. PMID- 29150528 TI - Autophagy in the context of the cellular membrane-trafficking system: the enigma of Atg9 vesicles. AB - Macroautophagy is an intracellular degradation system that involves the de novo formation of membrane structures called autophagosomes, although the detailed process by which membrane lipids are supplied during autophagosome formation is yet to be elucidated. Macroautophagy is thought to be associated with canonical membrane trafficking, but several mechanistic details are still missing. In this review, the current understanding and potential mechanisms by which membrane trafficking participates in macroautophagy are described, with a focus on the enigma of the membrane protein Atg9, for which the proximal mechanisms determining its movement are disputable, despite its key role in autophagosome formation. PMID- 29150529 TI - Impact of the 2013 National Rollout of CMS Competitive Bidding Program: The Disruption Continues. AB - OBJECTIVE: Use of glucose monitoring is essential to the safety of individuals with insulin-treated diabetes. In 2011, the Centers for Medicare & Medicaid Services (CMS) implemented the Medicare Competitive Bidding Program (CBP) in nine test markets. This resulted in a substantial disruption of beneficiary access to self-monitoring of blood glucose (SMBG) supplies and significant increases in the percentage of beneficiaries with either reduced or no acquisition of supplies. These reductions were significantly associated with increased mortality, hospitalizations, and costs. The CBP was implemented nationally in July 2013. We evaluated the impact of this rollout to determine if the adverse outcomes seen in 2011 persisted. RESEARCH DESIGN AND METHODS: This longitudinal study followed 529,627 insulin-treated beneficiaries from 2009 through 2013 to assess changes in beneficiary acquisition of testing supplies in the initial nine test markets (TEST, n = 43,939) and beneficiaries not affected by the 2011 rollout (NONTEST, n = 485,688). All Medicare beneficiary records for analysis were obtained from CMS. RESULTS: The percentages of beneficiaries with partial/no SMBG acquisition were significantly higher in both the TEST (37.4%) and NONTEST (37.6%) groups after the first 6 months of the national CBP rollout, showing increases of 48.1% and 60.0%, respectively (both P < 0.0001). The percentage of beneficiaries with no record for SMBG acquisition increased from 54.1% in January 2013 to 62.5% by December 2013. CONCLUSIONS: Disruption of beneficiary access to their prescribed SMBG supplies has persisted and worsened. Diabetes testing supplies should be excluded from the CBP until transparent, science-based methodologies for safety monitoring are adopted and implemented. PMID- 29150531 TI - Risk of AMD has decreased over the past few generations, study finds. PMID- 29150532 TI - Looking to the Past to Predict Future Outcomes: Improving Cardiovascular Disease Prediction Models Using Periodic Health Screening Summary Measures. PMID- 29150530 TI - Declining Rates of Hospitalization for Selected Cardiovascular Disease Conditions Among Adults Aged >=35 Years With Diagnosed Diabetes, U.S., 1998-2014. AB - OBJECTIVE: Reductions in heart attack and stroke hospitalizations are well documented in the U.S. population with diabetes. We extended trend analyses to other cardiovascular disease (CVD) conditions, including stroke by type, and used four additional years of data. RESEARCH DESIGN AND METHODS: Using 1998-2014 National (Nationwide) Inpatient Sample (NIS) data, we estimated the number of discharges having acute coronary syndrome (ACS) (ICD-9 codes 410-411), cardiac dysrhythmia (427), heart failure (428), hemorrhagic stroke (430-432), or ischemic stroke (433.x1, 434, and 436) as first-listed diagnosis and diabetes (250) as secondary diagnosis. Hospitalization rates for adults aged >=35 years were calculated using estimates from the population with and the population without diabetes from the National Health Interview Survey (NHIS) and age-adjusted to the 2000 U.S. standard population. Joinpoint regression was used to analyze trends and calculate an average annual percentage change (AAPC) with 95% confidence limits (CLs). RESULTS: From 1998 to 2014, in the population with diabetes, age adjusted hospitalization rates declined significantly for ACS (AAPC -4.6% per year [95% CL -5.3, -3.8]), cardiac dysrhythmia (-0.7% [-1.1, -0.2]), heart failure (-3.6% [-4.6, -2.7]), hemorrhagic stroke (-1.1% [-1.4, -0.7]), and ischemic stroke (-2.9% [-3.9, -1.8]). In the population without diabetes, rates also declined significantly for these conditions, with the exception of dysrhythmia. By 2014, rates in the population with diabetes population remained two to four times as high as those for the population without diabetes, with the largest difference in heart failure rates. CONCLUSIONS: CVD hospitalization rates declined significantly in both the population with diabetes and the population without diabetes. This may be due to several factors, including new or more aggressive treatments and reductions in CVD risk factors and CVD incidence. PMID- 29150533 TI - Disparity Between Indications for and Utilization of Implantable Cardioverter Defibrillators in Asian Patients With Heart Failure. AB - BACKGROUND: Implantable cardioverter defibrillators (ICDs) are lifesaving devices for patients with heart failure (HF) and reduced ejection fraction. However, utilization and determinants of ICD insertion in Asia are poorly defined. We determined the utilization, associations of ICD uptake, patient-perceived barriers to device therapy and, impact of ICDs on mortality in Asian patients with HF. METHODS AND RESULTS: Using the prospective ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry, 5276 patients with symptomatic HF and reduced ejection fraction (HFrEF) from 11 Asian regions and across 3 income regions (high: Hong Kong, Japan, Korea, Singapore, and Taiwan; middle: China, Malaysia, and Thailand; and low: India, Indonesia, and Philippines) were studied. ICD utilization, clinical characteristics, as well as device perception and knowledge, were assessed at baseline among ICD-eligible patients (EF <=35% and New York Heart Association Class II-III). Patients were followed for the primary outcome of all-cause mortality. Among 3240 ICD-eligible patients (mean age 58.9+/ 12.9 years, 79.1% men), 389 (12%) were ICD recipients. Utilization varied across Asia (from 1.5% in Indonesia to 52.5% in Japan) with a trend toward greater uptake in regions with government reimbursement for ICDs and lower out-of-pocket healthcare expenditure. ICD (versus non-ICD) recipients were more likely to be older (63+/-11 versus 58+/-13 year; P<0.001), have tertiary (versus <=primary) education (34.9% versus 18.1%; P<0.001) and be residing in a high (versus low) income region (64.5% versus 36.5%; P<0.001). Among 2000 ICD nonrecipients surveyed, 55% were either unaware of the benefits of, or needed more information on, device therapy. ICD implantation reduced risks of all-cause mortality (hazard ratio, 0.71; 95% confidence interval, 0.52-0.97) and sudden cardiac deaths (hazard ratio, 0.33; 95% confidence interval, 0.14-0.79) over a median follow-up of 417 days. CONCLUSIONS: ICDs reduce mortality risk, yet utilization in Asia is low; with disparity across geographic regions and socioeconomic status. Better patient education and targeted healthcare reforms in extending ICD reimbursement may improve access. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT01633398. Unique identifier: NCT01633398. PMID- 29150534 TI - Migration and Cardiovascular Disease Risk Among Ghanaian Populations in Europe: The RODAM Study (Research on Obesity and Diabetes Among African Migrants). AB - BACKGROUND: For migrant populations from sub-Saharan Africa, adverse cardiovascular disease (CVD) risk factors have been observed to be higher than found in their home country-based counterparts or among the host populations in high-income countries. Differences in absolute overall CVD risk, however, remain largely unexplained. We, therefore, predicted the differences in 10-year CVD risk among sub-Saharan African migrants (Ghanaians) living in 3 European cities and Ghana. METHODS AND RESULTS: For 3864 subjects aged 40 to 70 years from the multicenter RODAM study (Research on Obesity and Diabetes Among African Migrants) conducted among Ghanaian adults residing in rural and urban Ghana and 3 European cities (Amsterdam, Berlin, and London), 10-year risk of CVD was estimated using the Pooled Cohort Equations with estimates >=7.5% defining high CVD risk. Logistic regressions were used to determine the association of migration on CVD risk. The proportion with CVD risk >=7.5% among Ghanaian men was 34.7% in rural Ghana, 45.4% in urban Ghana, 53.9% in Amsterdam, 61.0% in Berlin, and 52.2% in London. Compared with rural Ghana, CVD risk was significantly increased for Ghanaian men living in Berlin (adjusted odds ratio, 2.80; 95% confidence interval, 1.76-4.45) and Amsterdam (1.88; 1.25-2.84). Increased risk observed for men was largely not seen for women. CVD risk increased with longer stay in Europe. CONCLUSIONS: Knowledge about predictors of increased CVD risk among sub Saharan African migrants in Europe and nonmigrants in urban centers will inform and support targeted health care and interventions to these populations. PMID- 29150535 TI - Disparities in Management of Cardiovascular Disease in Rural South Africa: Data From the HAALSI Study (Health and Aging in Africa: Longitudinal Studies of International Network for the Demographic Evaluation of Populations and Their Health Communities). AB - BACKGROUND: Optimal secondary prevention is critical for the reduction of repeated cardiovascular events, and the control of cardiovascular risk factors in this context is essential. Data on secondary prevention of cardiovascular disease (CVD) in sub-Saharan Africa are needed to inform intervention strategies with a particular focus on local disparities. The aim of this study was to assess CVD management in a rural community in northeast South Africa. METHODS AND RESULTS: We recruited adults aged >=40 years residing in the Agincourt subdistrict of Mpumalanga province. Data collection included socioeconomic and clinical data, anthropometric measures, blood pressure, human immunodeficiency virus status, and point-of-care glucose and lipid levels. CVD was defined as self-report of myocardial infarction and stroke or angina diagnosed by Rose Criteria. A linear regression model was built to identify variables independently associated with the number of cardiovascular risk factors controlled. Of 5059 subjects, 592 (11.7%) met CVD diagnostic criteria. Angina was reported in 77.0% of these subjects, stroke in 25.2%, and myocardial infarction in 3.7%. Percent controlled of the 5 individual risk factors assessed were as follows: tobacco 92.9%; blood pressure 51.2%; body mass index 33.8%; low-density lipoprotein 31.4%; and waist to-hip ratio 29.7%. Only 4.4% had all 5 risk factors controlled and 42.4% had >=3 risk factors controlled. Male sex (beta coefficient=0.44; 95% confidence interval, 0.25-0.63; P<0.001), absence of physical disability (beta coefficient=0.40; 95% confidence interval, 0.16-0.65; P=0.001), and socioeconomic status (beta coefficient=0.10; 95% confidence interval, 0.01-0.19; P=0.035) were directly associated with the number of risk factors controlled. CONCLUSIONS: Currently, CVD is not being optimally managed in this rural area of South Africa. There are significant disparities in control of CVD risk factors by sex, socioeconomic status, and level of disability. Efforts to improve secondary prevention in this population should be focused on females, subjects from lower socioeconomic status, and those with physical disabilities. PMID- 29150537 TI - Incremental Value of Repeated Risk Factor Measurements for Cardiovascular Disease Prediction in Middle-Aged Korean Adults: Results From the NHIS-HEALS (National Health Insurance System-National Health Screening Cohort). AB - BACKGROUND: Increasing evidence suggests that repeatedly measured cardiovascular disease (CVD) risk factors may have an additive predictive value compared with single measured levels. Thus, we evaluated the incremental predictive value of incorporating periodic health screening data for CVD prediction in a large nationwide cohort with periodic health screening tests. METHODS AND RESULTS: A total of 467 708 persons aged 40 to 79 years and free from CVD were randomly divided into development (70%) and validation subcohorts (30%). We developed 3 different CVD prediction models: a single measure model using single time point screening data; a longitudinal average model using average risk factor values from periodic screening data; and a longitudinal summary model using average values and the variability of risk factors. The development subcohort included 327 396 persons who had 3.2 health screenings on average and 25 765 cases of CVD over 12 years. The C statistics (95% confidence interval [CI]) for the single measure, longitudinal average, and longitudinal summary models were 0.690 (95% CI, 0.682-0.698), 0.695 (95% CI, 0.687-0.703), and 0.752 (95% CI, 0.744-0.760) in men and 0.732 (95% CI, 0.722-0.742), 0.735 (95% CI, 0.725-0.745), and 0.790 (95% CI, 0.780-0.800) in women, respectively. The net reclassification index from the single measure model to the longitudinal average model was 1.78% in men and 1.33% in women, and the index from the longitudinal average model to the longitudinal summary model was 32.71% in men and 34.98% in women. CONCLUSIONS: Using averages of repeatedly measured risk factor values modestly improves CVD predictability compared with single measurement values. Incorporating the average and variability information of repeated measurements can lead to great improvements in disease prediction. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02931500. PMID- 29150536 TI - Availability, Sales, and Affordability of Tobacco Cessation Medicines in Kerala, India. AB - BACKGROUND: India is the world's second largest consumer of tobacco, but tobacco cessation remains uncommon due, at least in part, to underutilization of cessation pharmacotherapy. We evaluated the availability, sales, and affordability of nicotine replacement therapy, bupropion, and varenicline in the South Indian state of Kerala to understand potential reasons for underutilization. METHODS AND RESULTS: From November 2016 to April 2017, we collected data on availability, inventory, and pricing of cessation medication through a cross-sectional survey of 199 public, semiprivate (Karunya), and private pharmacies across 5 districts in Kerala using World Health Organization/Health Action International methodology. Revenue and sales data were obtained from the latest Pharmatrac medication database. We assessed affordability using individual- and household-level income and expenditure data collected from November 2014 to November 2016 through the Acute Coronary Syndrome Quality Improvement in Kerala randomized trial. Cessation medications were not available in public hospitals (0%, n=58) nor in public specialty centers (0%, n=10) including those designated to provide cessation services. At least 1 cessation medicine was available at 63% of private pharmacies (n=109) and 27% of Karunya (semiprivate) pharmacies (n=22). Among the 75 pharmacies that stocked cessation medications, 96% had nicotine replacement therapy, 28% had bupropion, and 1% had varenicline. No outlets had sufficient inventory for a patient to purchase a 12-week treatment regimen. There were an estimated 253 270 treatment regimens sold throughout India and 14 092 in Kerala in 2013 to 2014. Treatment regimens cost 1.9 to 13.0* the median amount spent on smoked tobacco and between 8% and 52% of nonsubsistence income. CONCLUSIONS: Tobacco cessation medications are unavailable in the Kerala public sector and have limited availability in the private and semiprivate sectors. When available, medications are unaffordable for most patients. Addition of tobacco cessation medication onto national and state essential medicines lists may help increase access. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02256657. PMID- 29150538 TI - Nasser Rusan: Scoping out centrosomes. AB - Rusan investigates how centrosomes control cell behavior and differentiation during development. PMID- 29150541 TI - Beyond the Nursery: Postnatal Care in the 21st Century. PMID- 29150540 TI - Increased florbetapir binding in the temporal neocortex from age 20 to 60 years. AB - OBJECTIVE: To improve our understanding of early beta-amyloid (Abeta) accumulation processes using florbetapir-PET scan in 20- to 60-year-old individuals. METHODS: Seventy-six cognitively normal individuals aged 20 to 60 years, 57 cognitively normal older individuals (61-84 years old), and 70 patients with mild cognitive impairment or probable Alzheimer disease (AD) underwent a florbetapir-PET scan. Images were spatially normalized and scaled using the whole cerebellum. The relationship with age was assessed on the mean neocortical standardized uptake value ratio (SUVR) and voxelwise in the younger group to assess early Abeta accumulation processes. To compare the topography of early-age related vs AD-related changes, Abeta increase in patients vs cognitively normal older adults was also assessed. RESULTS: A linear increase of Abeta deposition from 20 to 60 years old was found on the mean neocortical SUVR, and more specifically on the temporal neocortex. By contrast, increase in patients predominated in frontal and medial parietal areas. The temporal increase in healthy participants was still significant when including only the 20- to 50-year old individuals and controlling for several possible methodologic confounds. CONCLUSIONS: Florbetapir binding increases linearly from 20 to 60 years old in the temporal lobe. Pending replication, including with other PET tracers, this study suggests that the well-described medial frontal and parietal accumulation in late adulthood and AD might superimpose to a physiologic accumulation of Abeta, starting from young adulthood, in temporal lobes. PMID- 29150539 TI - ROS and glutathionylation balance cytoskeletal dynamics in neutrophil extracellular trap formation. AB - The antimicrobial defense activity of neutrophils partly depends on their ability to form neutrophil extracellular traps (NETs), but the underlying mechanism controlling NET formation remains unclear. We demonstrate that inhibiting cytoskeletal dynamics with pharmacological agents or by genetic manipulation prevents the degranulation of neutrophils and mitochondrial DNA release required for NET formation. Wiskott-Aldrich syndrome protein-deficient neutrophils are unable to polymerize actin and exhibit a block in both degranulation and DNA release. Similarly, neutrophils with a genetic defect in NADPH oxidase fail to induce either actin and tubulin polymerization or NET formation on activation. Moreover, neutrophils deficient in glutaredoxin 1 (Grx1), an enzyme required for deglutathionylation of actin and tubulin, are unable to polymerize either cytoskeletal network and fail to degranulate or release DNA. Collectively, cytoskeletal dynamics are achieved as a balance between reactive oxygen species regulated effects on polymerization and glutathionylation on the one hand and the Grx1-mediated deglutathionylation that is required for NET formation on the other. PMID- 29150542 TI - Tackling the health burden of air pollution in South Asia. PMID- 29150543 TI - Toxicokinetics and Physiologically Based Pharmacokinetic Modeling of the Shellfish Toxin Domoic Acid in Nonhuman Primates. AB - Domoic acid (DA), a neurotoxin, is produced by marine algae and has caused toxications worldwide in animals and humans. However, the toxicokinetics of DA have not been fully evaluated, and information is missing on the disposition of DA following oral exposures at doses that are considered safe for human consumption. In this study, toxicokinetics of DA were investigated in cynomolgus monkeys following single doses of 5 ug/kg DA intravenously, 0.075 mg/kg DA orally, and 0.15 mg/kg DA orally. After intravenous dosing, DA had a systemic clearance of 124 +/- 71 (ml/h)/kg, volume of distribution at steady state of 131 +/- 71 ml/kg and elimination half-life of 1.2 +/- 1.1 hours. However, following oral dosing, the average terminal half-life of DA was 11.3 +/- 2.4 hours, indicating that DA disposition follows flip-flop kinetics with slow, rate limiting absorption. The absorption of DA was low after oral dosing with absolute bioavailability of 6% +/- 4%. The renal clearance of DA was variable [21-152 (ml/h)/kg] with 42% +/- 11% of the intravenous DA dose recovered in urine. A physiologically based pharmacokinetic model was developed for DA in monkeys and humans that replicated the flip-flop kinetics observed after oral administration and allowed simulation of urinary excretion and brain and kidney distribution of DA following intravenous and oral dosing. This study is the first to characterize DA disposition at exposure levels close to the current estimated tolerable daily intake and to mechanistically model DA disposition in a model species, providing important information of the toxicokinetics of DA for human safety assessment. PMID- 29150544 TI - Estimation of Circulating Drug Metabolite Exposure in Human Using In Vitro Data and Physiologically Based Pharmacokinetic Modeling: Example of a High Metabolite/Parent Drug Ratio. AB - (R)-4-((4-(((4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3 yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol (TBPT), a serotonin 4 receptor partial agonist, is metabolized to two metabolites: an N-dealkylation product [(R)-3-(piperidin-4-ylmethoxy)-4-((tetrahydrofuran-3 yl)oxy)benzo[d]isoxazole (M1)] and a cyclized oxazolidine structure [7-(((4-(((R) tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)octahydro-3H (M2)]. After administration of TBPT to humans the exposure to M1 was low and the exposure to M2 was high, relative to the parent drug, despite this being the opposite in vitro. In this study, projection of the plasma metabolite/parent (M/P) ratios for M1 and M2 was attempted using in vitro metabolism, binding, and permeability data in static and dynamic physiologically based pharmacokinetic (PBPK) models. In the static model, the fraction of parent clearance yielding the metabolite (which also required taking into account secondary metabolites of M1 and M2), the clearance of the metabolites and parent, and an estimate of the availability of the metabolites from the liver were combined to yield estimated parent/metabolite ratios of 0.32 and 23 for M1 and M2, respectively. PBPK modeling that used in vitro and physicochemical data input yielded estimates of 0.26 and 20, respectively. The actual values were 0.12 for M1/TBPT and 58 for M2/TBPT. Thus, the ratio for M1 was overpredicted, albeit at values less than unity. The ratio for M2/TBPT was underpredicted, and the high ratio of 58 may exceed a limiting ceiling of the approach. Nevertheless, when considered in the context of determining whether a potential circulating metabolite may be quantitatively important prior to administration of a drug for the first time to humans, the approaches succeeded in highlighting the importance of M2 (M/P ratio >> 1) relative to M1, despite M1 being much greater than M2 in vitro. PMID- 29150545 TI - Tumour diameter is not reliable for management of non-secreting pancreatic neuroendocrine tumours. AB - Small non-functioning pancreatic NETs (pNETs) <=2 cm can pose a management dilemma in terms of surveillance or resection. There is evidence to suggest that a surveillance approach can be considered since there are no significant radiological changes observed in lesions during long-term follow-up. However, other studies have suggested loco-regional spread can be present in <=2 cm pNETs. The aim of this study was to characterise the prevalence of malignant features and identify any useful predictive variables in a surgically resected cohort of pNETs. 418 patients with pNETs were identified from 5 NET centres. Of these 227 were included for main analysis of tumour characteristics. Mean age of patients was 57 years, 47% were female. The median follow-up was 48.2 months. Malignant features were identified in 38% of <=2 cm pNETs. ROC analysis showed that the current cut-off of 20 mm had a sensitivity of 84% for malignancy. The rate of malignant features is in keeping with other surgical series and challenges the belief that small pNETs have a low malignant potential. This study does not support a 20 mm size cut-off as being a solitary safe parameter to exclude malignancy in pNETs. PMID- 29150546 TI - Differential Regulation of Two-Tiered Plant Immunity and Sexual Reproduction by ANXUR Receptor-Like Kinases. AB - Plants have evolved two tiers of immune receptors to detect infections: cell surface-resident pattern recognition receptors (PRRs) that sense microbial signatures and intracellular nucleotide binding domain leucine-rich repeat (NLR) proteins that recognize pathogen effectors. How PRRs and NLRs interconnect and activate the specific and overlapping plant immune responses remains elusive. A genetic screen for components controlling plant immunity identified ANXUR1 (ANX1), a malectin-like domain-containing receptor-like kinase, together with its homolog ANX2, as important negative regulators of both PRR- and NLR-mediated immunity in Arabidopsis thaliana ANX1 constitutively associates with the bacterial flagellin receptor FLAGELLIN-SENSING2 (FLS2) and its coreceptor BRI1 ASSOCIATED RECEPTOR KINASE1 (BAK1). Perception of flagellin by FLS2 promotes ANX1 association with BAK1, thereby interfering with FLS2-BAK1 complex formation to attenuate PRR signaling. In addition, ANX1 complexes with the NLR proteins RESISTANT TO PSEUDOMONAS SYRINGAE2 (RPS2) and RESISTANCE TO P. SYRINGAE PV MACULICOLA1. ANX1 promotes RPS2 degradation and attenuates RPS2-mediated cell death. Surprisingly, a mutation that affects ANX1 function in plant immunity does not disrupt its function in controlling pollen tube growth during fertilization. Our study thus reveals a molecular link between PRR and NLR protein complexes that both associate with cell surface-resident ANX1 and uncovers uncoupled functions of ANX1 and ANX2 during plant immunity and sexual reproduction. PMID- 29150547 TI - The Tomato DELLA Protein PROCERA Acts in Guard Cells to Promote Stomatal Closure. AB - Plants employ stomatal closure and reduced growth to avoid water deficiency damage. Reduced levels of the growth-promoting hormone gibberellin (GA) lead to increased tolerance to water deficit, but the underlying mechanism is unknown. Here, we show that the tomato (Solanum lycopersicum) DELLA protein PROCERA (PRO), a negative regulator of GA signaling, acts in guard cells to promote stomatal closure and reduce water loss in response to water deficiency by increasing abscisic acid (ABA) sensitivity. The loss-of-function pro mutant exhibited increased stomatal conductance and rapid wilting under water deficit stress. Transgenic tomato overexpressing constitutively active stable DELLA proteins (S della) displayed the opposite phenotype. The effects of S-della on stomatal aperture and water loss were strongly suppressed in the ABA-deficient mutant sitiens, indicating that these effects of S-della are ABA dependent. While DELLA had no effect on ABA levels, guard cell ABA responsiveness was increased in S della and reduced in pro plants compared with the wild type. Expressing S-della under the control of a guard-cell-specific promoter was sufficient to increase stomatal sensitivity to ABA and to reduce water loss under water deficit stress but had no effect on leaf size. This result indicates that DELLA promotes stomatal closure independently of its effect on growth. PMID- 29150549 TI - Psychometric validation of the needs assessment tool: progressive disease in interstitial lung disease. AB - The inter-rater/test-retest reliability and construct validity of a palliative care needs assessment tool in interstitial lung disease (NAT:PD-ILD) were tested using NAT:PD-ILD-guided video-recorded consultations, and NAT:PD-ILD-guided consultations, and patient and carer-report outcomes (St George's Respiratory Questionnaire (SGRQ)-ILD, Carer Strain Index (CSI)/Carer Support Needs Assessment Tool (CSNAT)). 11/16 items reached at least fair inter-rater agreement; 5 items reached at least moderate test-retest agreement. 4/6 patient constructs demonstrated agreement with SGRQ-I scores (Kendall's tau-b, 0.24-20.36; P<0.05). 4/7 carer constructs agreed with the CSI/CSNAT items (kappa, 0.23-20.53). The NAT:PD-ILD is reliable and valid. Clinical effectiveness and implementation are to be evaluated. PMID- 29150550 TI - Journal Clubs: 1. Origins. PMID- 29150548 TI - Defense against Reactive Carbonyl Species Involves at Least Three Subcellular Compartments Where Individual Components of the System Respond to Cellular Sugar Status. AB - Methylglyoxal (MGO) and glyoxal (GO) are toxic reactive carbonyl species generated as by-products of glycolysis. The pre-emption pathway for detoxification of these products, the glyoxalase (GLX) system, involves two consecutive reactions catalyzed by GLXI and GLXII. In Arabidopsis thaliana, the GLX system is encoded by three homologs of GLXI and three homologs of GLXII, from which several predicted GLXI and GLXII isoforms can be derived through alternative splicing. We identified the physiologically relevant splice forms using sequencing data and demonstrated that the resulting isoforms have different subcellular localizations. All three GLXI homologs are functional in vivo, as they complemented a yeast GLXI loss-of-function mutant. Efficient MGO and GO detoxification can be controlled by a switch in metal cofactor usage. MGO formation is closely connected to the flux through glycolysis and through the Calvin Benson cycle; accordingly, expression analysis indicated that GLXI is transcriptionally regulated by endogenous sugar levels. Analyses of Arabidopsis loss-of-function lines revealed that the elimination of toxic reactive carbonyl species during germination and seedling establishment depends on the activity of the cytosolic GLXI;3 isoform. The Arabidopsis GLX system involves the cytosol, chloroplasts, and mitochondria, which harbor individual components that might be used at specific developmental stages and respond differentially to cellular sugar status. PMID- 29150551 TI - Journal Clubs: 2. Why and how to run them and how to publish them. PMID- 29150552 TI - Evaluation of a 0-hour/1-hour algorithm in the diagnosis of myocardial infarction with high-sensitivity cardiac troponin T1. PMID- 29150553 TI - What evidence affects clinical practice? An analysis of Evidence-Based Medicine commentaries. PMID- 29150555 TI - Reply to Read: Middle Stone Age cultural variability and the risk hypothesis. PMID- 29150556 TI - Still Bay and Howiesons Poort sites (South Africa) are consistent with the risk hypothesis. PMID- 29150554 TI - Cancer cells induce interleukin-22 production from memory CD4+ T cells via interleukin-1 to promote tumor growth. AB - IL-22 has been identified as a cancer-promoting cytokine that is secreted by infiltrating immune cells in several cancer models. We hypothesized that IL-22 regulation would occur at the interface between cancer cells and immune cells. Breast and lung cancer cells of murine and human origin induced IL-22 production from memory CD4+ T cells. In the present study, we found that IL-22 production in humans is dependent on activation of the NLRP3 inflammasome with the subsequent release of IL-1beta from both myeloid and T cells. IL-1 receptor signaling via the transcription factors AhR and RORgammat in T cells was necessary and sufficient for IL-22 production. In these settings, IL-1 induced IL-22 production from a mixed T helper cell population comprised of Th1, Th17, and Th22 cells, which was abrogated by the addition of anakinra. We confirmed these findings in vitro and in vivo in two murine tumor models, in primary human breast and lung cancer cells, and in deposited expression data. Relevant to ongoing clinical trials in breast cancer, we demonstrate here that the IL-1 receptor antagonist anakinra abrogates IL-22 production and reduces tumor growth in a murine breast cancer model. Thus, we describe here a previously unrecognized mechanism by which cancer cells induce IL-22 production from memory CD4+ T cells via activation of the NLRP3 inflammasome and the release of IL-1beta to promote tumor growth. These findings may provide the basis for therapeutic interventions that affect IL-22 production by targeting IL-1 activity. PMID- 29150558 TI - Branched Pectic Galactan in Phloem-Sieve-Element Cell Walls: Implications for Cell Mechanics. AB - A major question in plant biology concerns the specification and functional differentiation of cell types. This is in the context of constraints imposed by networks of cell walls that both adhere cells and contribute to the form and function of developing organs. Here, we report the identification of a glycan epitope that is specific to phloem sieve element cell walls in several systems. A monoclonal antibody, designated LM26, binds to the cell wall of phloem sieve elements in stems of Arabidopsis (Arabidopsis thaliana), Miscanthus x giganteus, and notably sugar beet (Beta vulgaris) roots where phloem identification is an important factor for the study of phloem unloading of Suc. Using microarrays of synthetic oligosaccharides, the LM26 epitope has been identified as a beta-1,6 galactosyl substitution of beta-1,4-galactan requiring more than three backbone residues for optimized recognition. This branched galactan structure has previously been identified in garlic (Allium sativum) bulbs in which the LM26 epitope is widespread throughout most cell walls including those of phloem cells. Garlic bulb cell wall material has been used to confirm the association of the LM26 epitope with cell wall pectic rhamnogalacturonan-I polysaccharides. In the phloem tissues of grass stems, the LM26 epitope has a complementary pattern to that of the LM5 linear beta-1,4-galactan epitope, which is detected only in companion cell walls. Mechanical probing of transverse sections of M x giganteus stems and leaves by atomic force microscopy indicates that phloem sieve element cell walls have a lower indentation modulus (indicative of higher elasticity) than companion cell walls. PMID- 29150560 TI - CCGs consider bringing in minimum waiting times. PMID- 29150557 TI - ROP GTPases Structure-Function and Signaling Pathways. PMID- 29150559 TI - A Program for Iron Economy during Deficiency Targets Specific Fe Proteins. AB - Iron (Fe) is an essential element for plants, utilized in nearly every cellular process. Because the adjustment of uptake under Fe limitation cannot satisfy all demands, plants need to acclimate their physiology and biochemistry, especially in their chloroplasts, which have a high demand for Fe. To investigate if a program exists for the utilization of Fe under deficiency, we analyzed how hydroponically grown Arabidopsis (Arabidopsis thaliana) adjusts its physiology and Fe protein composition in vegetative photosynthetic tissue during Fe deficiency. Fe deficiency first affected photosynthetic electron transport with concomitant reductions in carbon assimilation and biomass production when effects on respiration were not yet significant. Photosynthetic electron transport function and protein levels of Fe-dependent enzymes were fully recovered upon Fe resupply, indicating that the Fe depletion stress did not cause irreversible secondary damage. At the protein level, ferredoxin, the cytochrome-b6f complex, and Fe-containing enzymes of the plastid sulfur assimilation pathway were major targets of Fe deficiency, whereas other Fe-dependent functions were relatively less affected. In coordination, SufA and SufB, two proteins of the plastid Fe sulfur cofactor assembly pathway, were also diminished early by Fe depletion. Iron depletion reduced mRNA levels for the majority of the affected proteins, indicating that loss of enzyme was not just due to lack of Fe cofactors. SufB and ferredoxin were early targets of transcript down-regulation. The data reveal a hierarchy for Fe utilization in photosynthetic tissue and indicate that a program is in place to acclimate to impending Fe deficiency. PMID- 29150561 TI - Influence of Enzalutamide on Cabazitaxel Pharmacokinetics: a Drug-Drug Interaction Study in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients. AB - Purpose: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, that is, enzalutamide and abiraterone, is currently being explored. Because enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated.Experimental Design: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m2). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg once daily) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added.Results: A potential clinically relevant 22% (95% CI, 9%-34%; P = 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0-24h of cabazitaxel was 181 ng*h/mL (95% CI, 150-219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95% CI, 209-261 ng*h/mL) in cycle 1. This combination did not result in excessive toxicity, whereas PSA response was promising.Conclusions: We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug drug interactions. Because recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, because the addition of enzalutamide may result in subtherapeutic cabazitaxel exposure. Clin Cancer Res; 24(3); 541-6. (c)2017 AACR. PMID- 29150563 TI - NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes. AB - Macrophages are exquisite sensors of tissue homeostasis that can rapidly switch between pro- and anti-inflammatory or regulatory modes to respond to perturbations in their microenvironment. This functional plasticity involves a precise orchestration of gene expression patterns whose transcriptional regulators have not been fully characterized. We had previously identified the transcription factor NFAT5 as an activator of TLR-induced responses, and in this study we explore its contribution to macrophage functions in different polarization settings. We found that both in classically and alternatively polarized macrophages, NFAT5 enhanced functions associated with a proinflammatory profile such as bactericidal capacity and the ability to promote Th1 polarization over Th2 responses. In this regard, NFAT5 upregulated the Th1-stimulatory cytokine IL-12 in classically activated macrophages, whereas in alternatively polarized ones it enhanced the expression of the pro-Th1 mediators Fizz-1 and arginase 1, indicating that it could promote proinflammatory readiness by regulating independent genes in differently polarized macrophages. Finally, adoptive transfer assays in vivo revealed a reduced antitumor capacity in NFAT5 deficient macrophages against syngeneic Lewis lung carcinoma and ID8 ovarian carcinoma cells, a defect that in the ID8 model was associated with a reduced accumulation of effector CD8 T cells at the tumor site. Altogether, detailed analysis of the effect of NFAT5 in pro- and anti-inflammatory macrophages uncovered its ability to regulate distinct genes under both polarization modes and revealed its predominant role in promoting proinflammatory macrophage functions. PMID- 29150564 TI - Essential Role of CARD14 in Murine Experimental Psoriasis. AB - Caspase recruitment domain family member 14 (CARD14) was recently identified as a psoriasis-susceptibility gene, but its immunological role in the pathogenesis of psoriasis in vivo remains unclear. In this study, we examined the role of CARD14 in murine experimental models of psoriasis induced by either imiquimod (IMQ) cream or recombinant IL-23 injection. In all models tested, the psoriasiform skin inflammation was abrogated in Card14-/- mice. Comparison of the early gene signature of the skin between IMQ-cream-treated Card14-/- mice and Tlr7-/-Tlr9-/- mice revealed not only their similarity, but also distinct gene sets targeted by IL-23. Cell type-specific analysis of these mice identified skin Langerinhigh Langerhans cells as a potent producer of IL-23, which was dependent on both TLR7 and TLR9 but independent of CARD14, suggesting that CARD14 is acting downstream of IL-23, not TLR7 or TLR9. Instead, a bone marrow chimera study suggested that CARD14 in radio-sensitive hematopoietic cells was required for IMQ-induced psoriasiform skin inflammation, controlling the number of Vgamma4+ T cells producing IL-17 or IL-22 infiltrating through the dermis to the inflamed epidermis. These data indicate that CARD14 is essential and a potential therapeutic target for psoriasis. PMID- 29150562 TI - The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques. AB - MHC-E is a highly conserved nonclassical MHC class Ib molecule that predominantly binds and presents MHC class Ia leader sequence-derived peptides for NK cell regulation. However, MHC-E also binds pathogen-derived peptide Ags for presentation to CD8+ T cells. Given this role in adaptive immunity and its highly monomorphic nature in the human population, HLA-E is an attractive target for novel vaccine and immunotherapeutic modalities. Development of HLA-E-targeted therapies will require a physiologically relevant animal model that recapitulates HLA-E-restricted T cell biology. In this study, we investigated MHC-E immunobiology in two common nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM). Compared to humans and MCM, RM expressed a greater number of MHC-E alleles at both the population and individual level. Despite this difference, human, RM, and MCM MHC-E molecules were expressed at similar levels across immune cell subsets, equivalently upregulated by viral pathogens, and bound and presented identical peptides to CD8+ T cells. Indeed, SIV-specific, Mamu-E-restricted CD8+ T cells from RM recognized antigenic peptides presented by all MHC-E molecules tested, including cross-species recognition of human and MCM SIV-infected CD4+ T cells. Thus, MHC-E is functionally conserved among humans, RM, and MCM, and both RM and MCM represent physiologically relevant animal models of HLA-E-restricted T cell immunobiology. PMID- 29150565 TI - The Role of Macrophages in the Response to TNF Inhibition in Experimental Arthritis. AB - The reduction of synovial tissue macrophages is a reliable biomarker for clinical improvement in patients with rheumatoid arthritis (RA), and macrophages are reduced in synovial tissue shortly after initiation of TNF inhibitors. The mechanism for this initial response is unclear. These studies were performed to identify the mechanisms responsible for the initial reduction of macrophages following TNF inhibition, positing that efflux to draining lymph nodes was involved. RA synovial tissue and synovial fluid macrophages expressed CCR7, which was increased in control macrophages following incubation with TNF-alpha. Human TNF transgenic (hTNF-Tg) mice were treated with infliximab after development of arthritis. Ankles were harvested and examined by histology, immunohistochemistry, quantitative RT-PCR, ELISA, and flow cytometry. hTNF-Tg mice treated with infliximab demonstrated significant clinical and histologic improvement 3 d after the initiation of therapy, at which time Ly6C+ macrophages were significantly reduced in the ankles. However, no evidence was identified to support a role of macrophage efflux to draining lymph nodes following treatment with infliximab. In contrast, apoptosis of Ly6C+ macrophages in the ankles and popliteal lymph nodes, decreased migration of monocytes into the ankles, and a reduction of CCL2 were identified following the initiation of infliximab. These observations demonstrate that Ly6C+ macrophage apoptosis and decreased ingress of circulating monocytes into the joint are responsible for the initial reduction of macrophages following infliximab treatment in hTNF-Tg mice. PMID- 29150568 TI - The importance of learning from errors. PMID- 29150569 TI - Government responds to public support for mandatory CCTV in slaughterhouses. PMID- 29150566 TI - The Loss of TET2 Promotes CD8+ T Cell Memory Differentiation. AB - T cell differentiation requires appropriate regulation of DNA methylation. In this article, we demonstrate that the methylcytosine dioxygenase ten-eleven translocation (TET)2 regulates CD8+ T cell differentiation. In a murine model of acute viral infection, TET2 loss promotes early acquisition of a memory CD8+ T cell fate in a cell-intrinsic manner without disrupting Ag-driven cell expansion or effector function. Upon secondary recall, TET2-deficient memory CD8+ T cells demonstrate superior pathogen control. Genome-wide methylation analysis identified a number of differentially methylated regions in TET2-deficient versus wild-type CD8+ T cells. These differentially methylated regions did not occur at the loci of differentially expressed memory markers; rather, several hypermethylated regions were identified in known transcriptional regulators of CD8+ T cell memory fate. Together, these data demonstrate that TET2 is an important regulator of CD8+ T cell fate decisions. PMID- 29150567 TI - Amplifying IFN-gamma Signaling in Dendritic Cells by CD11c-Specific Loss of SOCS1 Increases Innate Immunity to Infection while Decreasing Adaptive Immunity. AB - Although prophylactic vaccines provide protective humoral immunity against infectious agents, vaccines that elicit potent CD8 T cell responses are valuable tools to shape and drive cellular immunity against cancer and intracellular infection. In particular, IFN-gamma-polarized cytotoxic CD8 T cell immunity is considered optimal for protective immunity against intracellular Ags. Suppressor of cytokine signaling (SOCS)1 is a cross-functional negative regulator of TLR and cytokine receptor signaling via degradation of the receptor-signaling complex. We hypothesized that loss of SOCS1 in dendritic cells (DCs) would improve T cell responses by accentuating IFN-gamma-directed immune responses. We tested this hypothesis using a recombinant Listeria monocytogenes vaccine platform that targets CD11c+ DCs in mice in which SOCS1 is selectively deleted in all CD11c+ cells. Unexpectedly, in mice lacking SOCS1 expression in CD11c+ cells, we observed a decrease in CD8+ T cell response to the L. monocytogenes vaccine. NK cell responses were also decreased in mice lacking SOCS1 expression in CD11c+ cells but did not explain the defect in CD8+ T cell immunity. We found that DCs lacking SOCS1 expression were functional in driving Ag-specific CD8+ T cell expansion in vitro but that this process was defective following infection in vivo. Instead, monocyte-derived innate TNF-alpha and inducible NO synthase producing DCs dominated the antibacterial response. Thus, loss of SOCS1 in CD11c+ cells skewed the balance of immune response to infection by increasing innate responses while decreasing Ag-specific adaptive responses to infectious Ags. PMID- 29150571 TI - Using big data to improve patient safety. PMID- 29150574 TI - 'Use local knowledge and trends data to inform future plans', say market experts. PMID- 29150576 TI - Resistance is futile: 'vets must engage with innovation or be left behind'. AB - New technologies have the potential to revolutionise animal health and welfare, and it is time for vets to embrace them, reports Emma Dahm. PMID- 29150575 TI - Time to get act together on banning wild animals in UK circuses. AB - As Ireland becomes the latest country to ban the use of wild animals in circuses, Kathryn Clark reviews the current situation in the UK. PMID- 29150577 TI - Criticism for WHO guidance on using antimicrobials in food-producing animals. PMID- 29150579 TI - Septicaemic pasteurellosis in unvaccinated lambs in Northern Ireland. AB - Northern ireland disease surveillance, july to september 2017Bibersteinia trehalosi causing septicaemic pasteurellosis in lambsAbortion due to Streptococcus pluranimalium in cattleLymphoma in cattleAcute fasciolosis in sheepErysipelas in pigsMarek's disease in chickens. PMID- 29150580 TI - Odontogenic abscesses in pet rabbits. PMID- 29150582 TI - RCVS stand on homeopathy. PMID- 29150583 TI - Vets' responsibility to tackle antimicrobial resistance. PMID- 29150584 TI - Who owns the countryside? PMID- 29150585 TI - End of veterinary school as we know it. AB - Disruptive innovation will transform veterinary education in the next 10 years, predicts Andrew Maccabe. PMID- 29150587 TI - A passion for cats and people. AB - Sheila Wills has worked extensively but not exclusively with cats. More recently she was appointed director of an organisation that accredits veterinary CPD and awards veterinary qualifications worldwide. PMID- 29150586 TI - Megan Brannigan. AB - An unconventional boss with an astonishing sense of humour, Megan welcomed a diverse team into her practices. She was a humanist, feminist and connoisseur of fine food and wine. PMID- 29150589 TI - Change in hydration indices associated with an increase in total water intake of more than 0.5 L/day, sustained over 4 weeks, in healthy young men with initial total water intake below 2 L/day. AB - This secondary data analysis addressed gaps in knowledge about effects of chronic water intake. Longitudinal data from the Adapt Study were used to describe effects of prescribing a sustained increase in water intake relative to baseline, for 4 weeks, on multiple indices of total body water (TBW) flux, regulation, distribution, and volume in five healthy, free-living, young men, with mean total water intake initially below 2 L/day. Indices were measured weekly. Within-person fixed effect models tested for significant changes in indices over time and associations between changes in indices. Agreement between indices was described. Mixed models tested if baseline between-person differences in hydration indices modified changes in indices over time. Body water flux: The half-life of water in the body decreased significantly. Body water regulation: Serum osmolality decreased significantly. Urine anti-diuretic hormone, sodium, potassium, and osmolality decreased significantly. Plasma aldosterone and serum sodium increased significantly. Body water distribution: No significant changes were observed. Body water volume: Saliva osmolality decreased significantly. Body weight increased significantly by a mean +/- SEM of 1.8% +/- 0.5% from baseline over 4 weeks. Changes in indices were significantly inter-correlated. Agreement between indices changed over 4 weeks. Baseline saliva osmolality significantly modified responses to chronic water intake. The results motivate hypotheses for future studies: Chronic TBW deficit occurs in healthy individuals under daily life conditions and increases chronic disease risk; Sustained higher water intake restores TBW through gradual isotonic retention of potassium and/or sodium; Saliva osmolality is a sensitive and specific index of chronic hydration status. PMID- 29150590 TI - Subtype-specific effects of dopaminergic D2 receptor activation on synaptic trains in layer V pyramidal neurons in the mouse prefrontal cortex. AB - In humans, prefrontal cortical areas are known to support executive functions. In mice, these functions are mediated by homologous regions in the medial prefrontal cortex (mPFC). Executive processes are critically dependent on optimal levels of dopamine (DA), but the cellular mechanisms of DA modulation are incompletely understood. Stable patterns of neuronal activity may be sensitive to frequency dependent changes in synaptic transmission. We characterized the effects of D2 receptor (D2R) activation on short-term excitatory postsynaptic potential (EPSP) dynamics evoked at varying frequencies in the two subtypes of layer V pyramidal neurons in mouse mPFC We isolated NMDA receptor and non-NMDA receptor-mediated components of EPSP trains evoked by stimulating fibers within layer V or layer I. All significant effects of D2 receptor activation were confined to type I (corticopontine) cells. First, we found that with layer I stimulation, D2R activation reduces the amplitude of NMDAR-mediated EPSPs, with no effect on facilitation or depression of these responses at lower frequencies, but leading to facilitation with high frequency stimulation. Further, the non-NMDA component also underwent synaptic depression at low frequencies. Second, with layer V stimulation, D2R activation had no effect on NMDA or non-NMDA receptor-mediated EPSP components. Overall, our results suggest that D2R activation may modulate memory functions by inhibiting 'top-down' influences from apical tuft inputs activated at low frequencies, while promoting 'top-down' influences from inputs activated at higher frequencies. These data provide further insight into mechanisms of dopamine's modulation of executive functions. PMID- 29150591 TI - Cholesterol depletion does not alter the capacitance or Ca handling of the surface or t-tubule membranes in mouse ventricular myocytes. AB - Cholesterol is a key component of the cell plasma membrane. It has been suggested that the t-tubule membrane of cardiac ventricular myocytes is enriched in cholesterol and that this plays a role in determining t-tubule structure and function. We have used methyl-beta-cyclodextrin (MbetaCD) to deplete cholesterol in intact and detubulated mouse ventricular myocytes to investigate the contribution of cholesterol to t-tubule structure, membrane capacitance, and the distribution of Ca flux pathways. Depletion of membrane cholesterol was confirmed using filipin; however, di-8-ANEPPS staining showed no differences in t-tubule structure following MbetaCD treatment. MbetaCD treatment had no significant effect on the capacitance:volume relationship of intact myocytes or on the decrease in capacitance:volume caused by detubulation. Similarly, Ca influx and efflux were not altered by MbetaCD treatment and were reduced by a similar amount following detubulation in untreated and MbetaCD-treated cells. These data show that cholesterol depletion has similar effects on the surface and t-tubule membranes and suggest that cholesterol plays no acute role in determining t tubule structure and function. PMID- 29150592 TI - The Influence of Genetic Stability on Aspergillus fumigatus Virulence and Azole Resistance. AB - Genetic stability is extremely important for the survival of every living organism, and a very complex set of genes has evolved to cope with DNA repair upon DNA damage. Here, we investigated the Aspergillus fumigatus AtmA (Ataxia telangiectasia mutated, ATM) and AtrA kinases, and how they impact virulence and the evolution of azole resistance. We demonstrated that A. fumigatus atmA and atrA null mutants are haploid and have a discrete chromosomal polymorphism. The DeltaatmA and DeltaatrA strains are sensitive to several DNA-damaging agents, but surprisingly both strains were more resistant than the wild-type strain to paraquat, menadione, and hydrogen peroxide. The atmA and atrA genes showed synthetic lethality emphasizing the cooperation between both enzymes and their consequent redundancy. The lack of atmA and atrA does not cause any significant virulence reduction in A. fumigatus in a neutropenic murine model of invasive pulmonary aspergillosis and in the invertebrate alternative model Galleria mellonela Wild-type, DeltaatmA, and DeltaatrA populations that were previously transferred 10 times in minimal medium (MM) in the absence of voriconazole have not shown any significant changes in drug resistance acquisition. In contrast, DeltaatmA and DeltaatrA populations that similarly evolved in the presence of a subinhibitory concentration of voriconazole showed an ~5-10-fold increase when compared to the original minimal inhibitory concentration (MIC) values. There are discrete alterations in the voriconazole target Cyp51A/Erg11A or cyp51/erg11 and/or Cdr1B efflux transporter overexpression that do not seem to be the main mechanisms to explain voriconazole resistance in these evolved populations. Taken together, these results suggest that genetic instability caused by DeltaatmA and DeltaatrA mutations can confer an adaptive advantage, mainly in the intensity of voriconazole resistance acquisition. PMID- 29150593 TI - Rapid and Efficient CRISPR/Cas9-Based Mating-Type Switching of Saccharomyces cerevisiae. AB - Rapid and highly efficient mating-type switching of Saccharomyces cerevisiae enables a wide variety of genetic manipulations, such as the construction of strains, for instance, isogenic haploid pairs of both mating-types, diploids and polyploids. We used the CRISPR/Cas9 system to generate a double-strand break at the MAT locus and, in a single cotransformation, both haploid and diploid cells were switched to the specified mating-type at ~80% efficiency. The mating-type of strains carrying either rod or ring chromosome III were switched, including those lacking HMLalpha and HMRa cryptic mating loci. Furthermore, we transplanted the synthetic yeast chromosome V to build a haploid polysynthetic chromosome strain by using this method together with an endoreduplication intercross strategy. The CRISPR/Cas9 mating-type switching method will be useful in building the complete synthetic yeast (Sc2.0) genome. Importantly, it is a generally useful method to build polyploids of a defined genotype and generally expedites strain construction, for example, in the construction of fully a/a/alpha/alpha isogenic tetraploids. PMID- 29150594 TI - Mating Design and Genetic Structure of a Multi-Parent Advanced Generation Intercross (MAGIC) Population of Sorghum (Sorghum bicolor (L.) Moench). AB - Multi-parent advanced generation intercross (MAGIC) populations are powerful next generation mapping resources. We describe here the mating design and structure of the first MAGIC population in sorghum, and test its utility for mapping. The population was developed by intercrossing 19 diverse founder lines through a series of paired crosses with a genetic male sterile (MS) source, followed by 10 generations of random mating. At the final stage of random mating, 1000 random fertile plants in the population were identified and subjected to six generations of selfing to produce 1000 immortal MAGIC inbred lines. The development of this sorghum MAGIC population took over 15 yr. Genotyping-by-sequencing (GBS) of a subset of 200 MAGIC lines identified 79,728 SNPs, spanning high gene-rich regions. Proportion of SNPs per chromosome ranged from 6 to 15%. Structure analyses produced no evidence of population stratification, portraying the desirability of this population for genome-wide association studies (GWAS). The 19 founders formed three clusters, each with considerable genetic diversity. Further analysis showed that 73% of founder alleles segregated in the MAGIC population. Linkage disequilibrium (LD) patterns depicted the MAGIC population to be highly recombined, with LD decaying to r2 [Formula: see text] 0.2 at 40 kb and down to r2 [Formula: see text] 0.1 at 220 kb. GWAS detected two known plant height genes, DWARF1 (chromosome 9) and DWARF3 (chromosome 7), and a potentially new plant height quantitative trait locus (QTL) (QTL-6) on chromosome 6. The MAGIC population was found to be rich in allelic content with high fragmentation of its genome, making it fit for both gene mapping and effective marker-assisted breeding. PMID- 29150595 TI - Notch1 Signaling Activation Contributes to Adult Hippocampal Neurogenesis Following Traumatic Brain Injury. AB - BACKGROUND Neural stem cells are reported to exist in the hippocampus of adult mammals and are important sources of neurons for repair. The Notch1 signaling pathway is considered as one of the important regulators of neural stem cells, but its role in adult brains is unclear. We aimed to describe the role of Notch1 signaling in the adult rat hippocampus after traumatic brain injury. MATERIAL AND METHODS The model rats were randomly divided into 4 groups as follows: sham, sham TBI, sham-Ad-TBI, and NICD-Ad-TBI. We used adenovirus-mediated gene transfection to upregulate endogenous NICD in vivo. Firstly, a TBI rat model was constructed with lateral fluid percussion. Then, the hippocampus was collected to detect the expression of Notch1 markers and stem cell markers (DCX) by Western blot analysis, immunohistochemistry, and immunofluorescence. The prognosis after TBI treatment was evaluated by the Morris Water Maze test. RESULTS First, we found the expression of NICD in vivo was significantly increased by adenovirus-mediated gene transfection as assessed by Notch1 immunofluorescence and Western blot analysis. Second, enhancing NICD stimulated the regeneration of neural stem cells in the DG of the adult rat brain following traumatic brain injury, as evaluated by DCX and NeuN double-staining. Furthermore, Notch1 signaling activation can promote behavioral improvement after traumatic brain injury, including spatial learning and memory capacity. CONCLUSIONS Our findings suggest that targeted regulation of Notch1 signaling may have a useful effect on stem cell transformation. Notch1 signaling may have a potential brain-protection effect, which may result from neurogenesis. PMID- 29150596 TI - Forming a three-dimensional porous organic network via solid-state explosion of organic single crystals. AB - Solid-state reaction of organic molecules holds a considerable advantage over liquid-phase processes in the manufacturing industry. However, the research progress in exploring this benefit is largely staggering, which leaves few liquid phase systems to work with. Here, we show a synthetic protocol for the formation of a three-dimensional porous organic network via solid-state explosion of organic single crystals. The explosive reaction is realized by the Bergman reaction (cycloaromatization) of three enediyne groups on 2,3,6,7,14,15 hexaethynyl-9,10-dihydro-9,10-[1,2]benzenoanthracene. The origin of the explosion is systematically studied using single-crystal X-ray diffraction and differential scanning calorimetry, along with high-speed camera and density functional theory calculations. The results suggest that the solid-state explosion is triggered by an abrupt change in lattice energy induced by release of primer molecules in the 2,3,6,7,14,15-hexaethynyl-9,10-dihydro-9,10-[1,2]benzenoanthracene crystal lattice. PMID- 29150597 TI - Author Correction: Two-magnon scattering in the 5d all-in-all-out pyrochlore magnet Cd2Os2O7. AB - A correction to this article has been published and is linked from the HTML version of this article. PMID- 29150598 TI - Redox-independent chromium isotope fractionation induced by ligand-promoted dissolution. AB - The chromium (Cr) isotope system has emerged as a potential proxy for tracing the Earth's atmospheric evolution based on a redox-dependent framework for Cr mobilization and isotope fractionation. Although studies have demonstrated that redox-independent pathways can also mobilize Cr, no quantitative constraints exist on the associated isotope fractionations. Here we survey the effects of common environmental ligands on the dissolution of Cr(III)-(oxy)hydroxide solids and associated Cr isotope fractionation. For a variety of organic acids and siderophores, delta53Cr values of dissolved Cr(III) are -0.27 to 1.230/00, within the range of previously observed Cr isotope signatures in rock records linked to Cr redox cycling. Thus, ligand-promoted dissolution of Cr-containing solids, a redox-independent process, must be taken into account when using sedimentary Cr isotope signatures to diagnose atmospheric oxygen levels. This work provides a step towards establishing a more robust framework for using Cr isotopes to track the evolution of the Earth's atmosphere. PMID- 29150599 TI - Publisher Correction: Interlayer excitons in a bulk van der Waals semiconductor. AB - A correction to this article has been published and is linked from the HTML version of this article. PMID- 29150600 TI - Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers. AB - Pattern recognition underpins innate immunity; the accurate identification of danger, including infection, injury, or tumor, is key to an appropriately targeted immune response. Pathogen detection is increasingly well defined mechanistically, but the discrimination of endogenous inflammatory triggers remains unclear. Tenascin-C, a matrix protein induced upon tissue damage and expressed by tumors, activates toll-like receptor 4 (TLR4)-mediated sterile inflammation. Here we map three sites within tenascin-C that directly and cooperatively interact with TLR4. We also identify a conserved inflammatory epitope in related proteins from diverse families, and demonstrate that its presence targets molecules for TLR detection, while its absence enables escape of innate immune surveillance. These data reveal a unique molecular code that defines endogenous proteins as inflammatory stimuli by marking them for recognition by TLRs. PMID- 29150601 TI - Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition. AB - Long non-coding RNA (lncRNA) are emerging as contributors to malignancies. Little is understood about the contribution of lncRNA to epithelial-to-mesenchymal transition (EMT), which correlates with metastasis. Ovarian cancer is usually diagnosed after metastasis. Here we report an integrated analysis of >700 ovarian cancer molecular profiles, including genomic data sets, from four patient cohorts identifying lncRNA DNM3OS, MEG3, and MIAT overexpression and their reproducible gene regulation in ovarian cancer EMT. Genome-wide mapping shows 73% of MEG3 regulated EMT-linked pathway genes contain MEG3 binding sites. DNM3OS overexpression, but not MEG3 or MIAT, significantly correlates to worse overall patient survival. DNM3OS knockdown results in altered EMT-linked genes/pathways, mesenchymal-to-epithelial transition, and reduced cell migration and invasion. Proteotranscriptomic characterization further supports the DNM3OS and ovarian cancer EMT connection. TWIST1 overexpression and DNM3OS amplification provides an explanation for increased DNM3OS levels. Therefore, our results elucidate lncRNA that regulate EMT and demonstrate DNM3OS specifically contributes to EMT in ovarian cancer. PMID- 29150602 TI - TLR7 mediated viral recognition results in focal type I interferon secretion by dendritic cells. AB - Plasmacytoid dendritic cells (pDC) sense viral RNA through toll-like receptor 7 (TLR7), form self-adhesive pDC-pDC clusters, and produce type I interferons. This cell adhesion enhances type I interferon production, but little is known about the underlying mechanisms. Here we show that MyD88-dependent TLR7 signaling activates CD11a/CD18 integrin to induce microtubule elongation. TLR7+ lysosomes then become linked with these microtubules through the GTPase Arl8b and its effector SKIP/Plekhm2, resulting in perinuclear to peripheral relocalization of TLR7. The type I interferon signaling molecules TRAF3, IKKalpha, and mTORC1 are constitutively associated in pDCs. TLR7 localizes to mTORC1 and induces association of TRAF3 with the upstream molecule TRAF6. Finally, type I interferons are secreted in the vicinity of cell-cell contacts between clustered pDCs. These results suggest that TLR7 needs to move to the cell periphery to induce robust type I interferon responses in pDCs. PMID- 29150603 TI - Bacterially derived synthetic mimetics of mammalian oligomannose prime antibody responses that neutralize HIV infectivity. AB - Oligomannose-type glycans are among the major targets on the gp120 component of the HIV envelope protein (Env) for broadly neutralizing antibodies (bnAbs). However, attempts to elicit oligomannose-specific nAbs by immunizing with natural or synthetic oligomannose have so far not been successful, possibly due to B cell tolerance checkpoints. Here we design and synthesize oligomannose mimetics, based on the unique chemical structure of a recently identified bacterial lipooligosaccharide, to appear foreign to the immune system. One of these mimetics is bound avidly by members of a family of oligomannose-specific bnAbs and their putative common germline precursor when presented as a glycoconjugate. The crystal structure of one of the mimetics bound to a member of this bnAb family confirms the antigenic resemblance. Lastly, immunization of human-antibody transgenic animals with a lead mimetic evokes nAbs with specificities approaching those of existing bnAbs. These results provide evidence for utilizing antigenic mimicry to elicit oligomannose-specific bnAbs to HIV-1. PMID- 29150604 TI - Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis. AB - We have previously reported the molecular signature of murine pathogenic TH17 cells that induce experimental autoimmune encephalomyelitis (EAE) in animals. Here we show that human peripheral blood IFN-gamma+IL-17+ (TH1/17) and IFN-gamma IL-17+ (TH17) CD4+ T cells display distinct transcriptional profiles in high throughput transcription analyses. Compared to TH17 cells, TH1/17 cells have gene signatures with marked similarity to mouse pathogenic TH17 cells. Assessing 15 representative signature genes in patients with multiple sclerosis, we find that TH1/17 cells have elevated expression of CXCR3 and reduced expression of IFNG, CCL3, CLL4, GZMB, and IL10 compared to healthy controls. Moreover, higher expression of IL10 in TH17 cells is found in clinically stable vs. active patients. Our results define the molecular signature of human pro-inflammatory TH17 cells, which can be used to both identify pathogenic TH17 cells and to measure the effect of treatment on TH17 cells in human autoimmune diseases. PMID- 29150605 TI - Global role of the bacterial post-transcriptional regulator CsrA revealed by integrated transcriptomics. AB - CsrA is a post-transcriptional regulatory protein that is widely distributed among bacteria. This protein influences bacterial lifestyle decisions by binding to the 5' untranslated and/or early coding regions of mRNA targets, causing changes in translation initiation, RNA stability, and/or transcription elongation. Here, we assess the contribution of CsrA to gene expression in Escherichia coli on a global scale. UV crosslinking immunoprecipitation and sequencing (CLIP-seq) identify RNAs that interact directly with CsrA in vivo, while ribosome profiling and RNA-seq uncover the impact of CsrA on translation, RNA abundance, and RNA stability. This combination of approaches reveals unprecedented detail about the regulatory role of CsrA, including novel binding targets and physiological roles, such as in envelope function and iron homeostasis. Our findings highlight the integration of CsrA throughout the E. coli regulatory network, where it orchestrates vast effects on gene expression. PMID- 29150607 TI - Author Correction: Tunable two-dimensional interfacial coupling in molecular heterostructures. AB - We regretfully omitted to give credit to a previous figure upon which the surface tension scheme in Fig. 1b is based. The caption to Fig. 1 should have included the following: "The surface-tension scheme in Fig. 1b is adapted from Fig. 1a in Noh, J., Jeong, S. & Lee, J.-Y. Ultrafast formation of air-processable and high quality polymer films on an aqueous substrate. Nat. Commun. 7, 12374 (2016)." PMID- 29150606 TI - Loss of HIF-1alpha in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis. AB - Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1alpha in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1alpha in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes tumour growth by allowing the formation of functionally improved vessels. PMID- 29150608 TI - Rapid neo-sex chromosome evolution and incipient speciation in a major forest pest. AB - Genome evolution is predicted to be rapid following the establishment of new (neo) sex chromosomes, but it is not known if neo-sex chromosome evolution plays an important role in speciation. Here we combine extensive crossing experiments with population and functional genomic data to examine neo-XY chromosome evolution and incipient speciation in the mountain pine beetle. We find a broad continuum of intrinsic incompatibilities in hybrid males that increase in strength with geographic distance between reproductively isolated populations. This striking progression of reproductive isolation is coupled with extensive gene specialization, natural selection, and elevated genetic differentiation on both sex chromosomes. Closely related populations isolated by hybrid male sterility also show fixation of alternative neo-Y haplotypes that differ in structure and male-specific gene content. Our results suggest that neo-sex chromosome evolution can drive rapid functional divergence between closely related populations irrespective of ecological drivers of divergence. PMID- 29150609 TI - Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin. AB - Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to a poor selection of drugs that mostly target elements in the parasite's cell envelope. Here we determined the atomic resolution electron cryo-microscopy (cryo-EM) structure of the Leishmania ribosome in complex with paromomycin (PAR), a highly potent compound recently approved for treatment of the fatal visceral leishmaniasis (VL). The structure reveals the mechanism by which the drug induces its deleterious effects on the parasite. We further show that PAR interferes with several aspects of cytosolic translation, thus highlighting the cytosolic rather than the mitochondrial ribosome as the primary drug target. The results also highlight unique as well as conserved elements in the PAR-binding pocket that can serve as hotspots for the development of novel therapeutics. PMID- 29150610 TI - Implications of improved representations of plant respiration in a changing climate. AB - Land-atmosphere exchanges influence atmospheric CO2. Emphasis has been on describing photosynthetic CO2 uptake, but less on respiration losses. New global datasets describe upper canopy dark respiration (R d) and temperature dependencies. This allows characterisation of baseline R d, instantaneous temperature responses and longer-term thermal acclimation effects. Here we show the global implications of these parameterisations with a global gridded land model. This model aggregates R d to whole-plant respiration R p, driven with meteorological forcings spanning uncertainty across climate change models. For pre-industrial estimates, new baseline R d increases R p and especially in the tropics. Compared to new baseline, revised instantaneous response decreases R p for mid-latitudes, while acclimation lowers this for the tropics with increases elsewhere. Under global warming, new R d estimates amplify modelled respiration increases, although partially lowered by acclimation. Future measurements will refine how R d aggregates to whole-plant respiration. Our analysis suggests R p could be around 30% higher than existing estimates. PMID- 29150611 TI - Uplift of the central transantarctic mountains. AB - The Transantarctic Mountains (TAM) are the world's longest rift shoulder but the source of their high elevation is enigmatic. To discriminate the importance of mechanical vs. thermal sources of support, a 550 km-long transect of magnetotelluric geophysical soundings spanning the central TAM was acquired. These data reveal a lithosphere of high electrical resistivity to at least 150 km depth, implying a cold stable state well into the upper mantle. Here we find that the central TAM most likely are elevated by a non-thermal, flexural cantilever mechanism which is perhaps the most clearly expressed example anywhere. West Antarctica in this region exhibits a low resistivity, moderately hydrated asthenosphere, and concentrated extension (rift necking) near the central TAM range front but with negligible thermal encroachment into the TAM. Broader scale heat flow of east-central West Antarctica appears moderate, on the order of 60-70 mW m-2, lower than that of the U.S. Great Basin. PMID- 29150612 TI - Health impact of E-cigarettes: a prospective 3.5-year study of regular daily users who have never smoked. AB - Although electronic cigarettes (ECs) are a much less harmful alternative to tobacco cigarettes, there is concern as to whether long-term ECs use may cause risks to human health. We report health outcomes (blood pressure, heart rate, body weight, lung function, respiratory symptoms, exhaled breath nitric oxide [eNO], exhaled carbon monoxide [eCO], and high-resolution computed tomography [HRCT] of the lungs) from a prospective 3.5-year observational study of a cohort of nine daily EC users (mean age 29.7 (+/-6.1) years) who have never smoked and a reference group of twelve never smokers. No significant changes could be detected over the observation period from baseline in the EC users or between EC users and control subjects in any of the health outcomes investigated. Moreover, no pathological findings could be identified on HRCT of the lungs and no respiratory symptoms were consistently reported in the EC user group. Although it cannot be excluded that some harm may occur at later stages, this study did not demonstrate any health concerns associated with long-term use of EC in relatively young users who did not also smoke tobacco. PMID- 29150613 TI - A study of the ground-attachment process in natural lightning with emphasis on its breakthrough phase. AB - Synchronized high-speed (124 or 210 kiloframes per second) video images and wideband electromagnetic field records of the attachment process were obtained for 4 negative strokes in natural lightning at the Lightning Observatory in Gainesville, Florida. The majority of imaged upward connecting leaders (UCLs) and upward unconnected leaders, inferred to be mostly initiated from trees, exhibited a pulsating behavior (brightening/fading cycles). UCLs, whose maximum extent ranged from 11 to 25 m, propagated in virgin air at speeds ranging from 1.8 * 105 to 6.0 * 105 m/s with a mean of 3.4 * 105 m/s. Within about 100 m of the ground, the ratio of speeds of the downward negative leader and the corresponding positive UCL was about 3-4 for 2 events and 0.5 for 1 event. The breakthrough phase (final jump) was imaged for 2 events. The initial length of the common streamer zone (CSZ) was estimated to be about 30-40 m. For 2 events, speeds of positive and negative leaders developing toward each other inside the CSZ were found to be between 2.4 * 106 and 3.7 * 106 m/s. For 1 event, opposite polarity leaders were observed to accelerate inside the CSZ. The current at the end of the breakthrough phase, lasting on average 4.7 MUs, was estimated to be approximately one-half of the overall current peak. Thus, about one-half of the current peak traditionally attributed to the return-stroke process is actually associated with two leaders extending toward each other to collision inside the CSZ. PMID- 29150614 TI - Spatial regulation of contractility by Neuralized and Bearded during furrow invagination in Drosophila. AB - Embryo-scale morphogenesis arises from patterned mechanical forces. During Drosophila gastrulation, actomyosin contractility drives apical constriction in ventral cells, leading to furrow formation and mesoderm invagination. It remains unclear whether and how mechanical properties of the ectoderm influence this process. Here, we show that Neuralized (Neur), an E3 ubiquitin ligase active in the mesoderm, regulates collective apical constriction and furrow formation. Conversely, the Bearded (Brd) proteins antagonize maternal Neur and lower medial apical contractility in the ectoderm: in Brd-mutant embryos, the ventral furrow invaginates properly but rapidly unfolds as medial MyoII levels increase in the ectoderm. Increasing contractility in the ectoderm via activated Rho similarly triggers furrow unfolding whereas decreasing contractility restores furrow invagination in Brd-mutant embryos. Thus, the inhibition of Neur by Brd in the ectoderm differentiates the mechanics of the ectoderm from that of the mesoderm and patterns the activity of MyoII along the dorsal-ventral axis. PMID- 29150615 TI - Balancing a genetic toggle switch by real-time feedback control and periodic forcing. AB - Cybergenetics is a novel field of research aiming at remotely pilot cellular processes in real-time with to leverage the biotechnological potential of synthetic biology. Yet, the control of only a small number of genetic circuits has been tested so far. Here we investigate the control of multistable gene regulatory networks, which are ubiquitously found in nature and play critical roles in cell differentiation and decision-making. Using an in silico feedback control loop, we demonstrate that a bistable genetic toggle switch can be dynamically maintained near its unstable equilibrium position for extended periods of time. Importantly, we show that a direct method based on dual periodic forcing is sufficient to simultaneously maintain many cells in this undecided state. These findings pave the way for the control of more complex cell decision making systems at both the single cell and the population levels, with vast fundamental and biotechnological applications. PMID- 29150616 TI - NMR Metabolomics for Stem Cell type discrimination. AB - Cell metabolism is a key determinant factor for the pluripotency and fate commitment of Stem Cells (SCs) during development, ageing, pathological onset and progression. We derived and cultured selected subpopulations of rodent fetal, postnatal, adult Neural SCs (NSCs) and postnatal glial progenitors, Olfactory Ensheathing Cells (OECs), respectively from the subventricular zone (SVZ) and the olfactory bulb (OB). Cell lysates were analyzed by proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy leading to metabolites identification and quantitation. Subsequent multivariate analysis of NMR data by Principal Component Analysis (PCA), and Partial Least Square Discriminant Analysis (PLS-DA) allowed data reduction and cluster analysis. This strategy ensures the definition of specific features in the metabolic content of phenotypically similar SCs sharing a common developmental origin. The metabolic fingerprints for selective metabolites or for the whole spectra demonstrated enhanced peculiarities among cell types. The key result of our work is a neat divergence between OECs and the remaining NSC cells. We also show that statistically significant differences for selective metabolites characterizes NSCs of different ages. Finally, the retrived metabolome in cell cultures correlates to the physiological SC features, thus allowing an integrated bioengineering approach for biologic fingerprints able to dissect the (neural) SC molecular specificities. PMID- 29150617 TI - Carbon Contamination During Ion Irradiation - Accurate Detection and Characterization of its Effect on Microstructure of Ferritic/Martensitic Steels. AB - Accelerator-based ion beam irradiation techniques have been used to study radiation effects in materials for decades. Although carbon contamination induced by ion beams in target materials is a well-known issue in some material systems, it has not been fully characterized nor quantified for studies in ferritic/martensitic (F/M) steels that are candidate materials for applications such as core structural components in advanced nuclear reactors. It is an especially important issue for this class of material because of the strong effect of carbon level on precipitate formation. In this paper, the ability to quantify carbon contamination using three common techniques, namely time-of flight secondary ion mass spectroscopy (ToF-SIMS), atom probe tomography (APT), and transmission electron microscopy (TEM) is compared. Their effectiveness and shortcomings in determining carbon contamination are presented and discussed. The corresponding microstructural changes related to carbon contamination in ion irradiated F/M steels are also presented and briefly discussed. PMID- 29150618 TI - Lexical processing of Chinese sub-character components: Semantic activation of phonetic radicals as revealed by the Stroop effect. AB - Most Chinese characters are compounds consisting of a semantic radical indicating semantic category and a phonetic radical cuing the pronunciation of the character. Controversy surrounds whether radicals also go through the same lexical processing as characters and, critically, whether phonetic radicals involve semantic activation since they can also be characters when standing alone. Here we examined these issues using the Stroop task whereby participants responded to the ink color of the character. The key finding was that Stroop effects were found when the character itself had a meaning unrelated to color, but contained a color name phonetic radical (e.g., "guess", with the phonetic radical "cyan", on the right) or had a meaning associated with color (e.g., "pity", with the phonetic radical "blood" on the right which has a meaning related to "red"). Such Stroop effects from the phonetic radical within a character unrelated to color support that Chinese character recognition involves decomposition of characters into their constituent radicals; with each of their meanings including phonetic radicals activated independently, even though it would inevitably interfere with that of the whole character. Compared with the morphological decomposition in English whereby the semantics of the morphemes are not necessarily activated, the unavoidable semantic activation of phonetic radicals represents a unique feature in Chinese character processing. PMID- 29150620 TI - The role of forelimb motor cortex areas in goal directed action in mice. AB - Mammalian motor cortex consists of several interconnected subregions thought to play distinct roles in voluntary movements, yet their specific role in decision making and execution is not completely elucidated. Here we used transient optogenetic inactivation of the caudal forelimb area (CFA) and rostral forelimb area (RFA) in mice as they performed a directional joystick task. Based on a vibrotactile cue applied to their forepaw, mice were trained to push or pull a joystick after a delay period. We found that choice and execution are temporally segregated processes. CFA and RFA were both essential during the stimulus delivery for correct choice and during the answer period for motor execution. Fine, distal motor deficits were restricted to CFA inactivation. Surprisingly, during the delay period neither area alone, but only combined inactivation was able to affect choice. Our findings suggest transient and partially distributed neural processing of choice and execution across different subregions of the motor cortex. PMID- 29150619 TI - Reduced orbitofrontal-thalamic functional connectivity related to suicidal ideation in patients with major depressive disorder. AB - Despite recent developments in neuroimaging, alterations of brain functional connectivity in major depressive disorder (MDD) patients with suicidal ideation are poorly understood. This study investigated specific changes of suicidal ideation in functional connectivity of MDD patients. Whole brain functional connectivity in 46 patients with MDD (23 with suicidal ideation and 23 without) and 36 age- and gender- matched healthy controls were compared using resting state functional Magnetic Resonance Imaging (fMRI) analyzed with network-based statistics (NBS) and graph-theoretical methods. Decreased functional connectivity in a characterized sub-network was observed in patients with MDD and suicidal ideation (FDR-adjusted p < 0.05). The sub-network included the regions of the fronto-thalamic circuits in the left hemisphere. The network measures of the left superior frontal gyrus, pars orbitalis (r = -0.40, p = 0.009), left thalamus (r = -0.41, p = 0.009), and right thalamus (r = -0.51, p = -0.002) were shown, through graph theoretical analysis, to be significantly negatively correlated with severity of suicidal ideation. The reduced functional connectivity in left orbitofrontal-both thalamic regions with suicidal ideation in MDD were inversely proportional to the severity of suicidality independent from depression severity. These findings suggest problems with decision-making and information integration in MDD patients with suicidal ideation. PMID- 29150622 TI - Evidence of quantum phase transition in real-space vacuum entanglement of higher derivative scalar quantum field theories. AB - In a bipartite set-up, the vacuum state of a free Bosonic scalar field is entangled in real space and satisfies the area-law- entanglement entropy scales linearly with area of the boundary between the two partitions. In this work, we show that the area law is violated in two spatial dimensional model Hamiltonian having dynamical critical exponent z = 3. The model physically corresponds to next-to-next-to-next nearest neighbour coupling terms on a lattice. The result reported here is the first of its kind of violation of area law in Bosonic systems in higher dimensions and signals the evidence of a quantum phase transition. We provide evidence for quantum phase transition both numerically and analytically using quantum Information tools like entanglement spectra, quantum fidelity, and gap in the energy spectra. We identify the cause for this transition due to the accumulation of large number of angular zero modes around the critical point which catalyses the change in the ground state wave function due to the next-to-next-to-next nearest neighbor coupling. Lastly, using Hubbard Stratanovich transformation, we show that the effective Bosonic Hamiltonian can be obtained from an interacting fermionic theory and provide possible implications for condensed matter systems. PMID- 29150621 TI - PNPLA3 variant and portal/periportal histological pattern in patients with biopsy proven non-alcoholic fatty liver disease: a possible role for oxidative stress. AB - Pathogenesis of non-alcoholic fatty liver disease (NAFLD) is influenced by predisposing genetic variations, dysmetabolism, systemic oxidative stress, and local cellular and molecular cross-talks. Patatin-like phospholipase domain containing 3 (PNPLA3) gene I148M variant is a known determinant of NAFLD. Aims were to evaluate whether PNPLA3 I148M variant was associated with a specific histological pattern, hepatic stem/progenitor cell (HpSC) niche activation and serum oxidative stress markers. Liver biopsies were obtained from 54 NAFLD patients. The activation of HpSC compartment was evaluated by the extension of ductular reaction (DR); hepatic stellate cells, myofibroblasts (MFs), and macrophages were evaluated by immunohistochemistry. Systemic oxidative stress was assessed measuring serum levels of soluble NOX2-derived peptide (sNOX2-dp) and 8 isoprostaglandin F2alpha (8-iso-PGF2alpha). PNPLA3 carriers showed higher steatosis, portal inflammation and HpSC niche activation compared to wild-type patients. DR was correlated with NAFLD activity score (NAS) and fibrosis score. Serum 8-iso-PGF2alpha were significantly higher in I148M carriers compared to non carriers and were correlated with DR and portal inflammation. sNox2-dp was correlated with NAS and with HpSC niche activation. In conclusion, NAFLD patients carrying PNPLA3 I148M are characterized by a prominent activation of HpSC niche which is associated with a more aggressive histological pattern (portal fibrogenesis) and increased oxidative stress. PMID- 29150623 TI - Effective mechanical properties of multilayer nano-heterostructures. AB - Two-dimensional and quasi-two-dimensional materials are important nanostructures because of their exciting electronic, optical, thermal, chemical and mechanical properties. However, a single-layer nanomaterial may not possess a particular property adequately, or multiple desired properties simultaneously. Recently a new trend has emerged to develop nano-heterostructures by assembling multiple monolayers of different nanostructures to achieve various tunable desired properties simultaneously. For example, transition metal dichalcogenides such as MoS2 show promising electronic and piezoelectric properties, but their low mechanical strength is a constraint for practical applications. This barrier can be mitigated by considering graphene-MoS2 heterostructure, as graphene possesses strong mechanical properties. We have developed efficient closed-form expressions for the equivalent elastic properties of such multi-layer hexagonal nano hetrostructures. Based on these physics-based analytical formulae, mechanical properties are investigated for different heterostructures such as graphene-MoS2, graphene-hBN, graphene-stanene and stanene-MoS2. The proposed formulae will enable efficient characterization of mechanical properties in developing a wide range of application-specific nano-heterostructures. PMID- 29150624 TI - Semiquantative Visual Assessment of Sub-solid Pulmonary Nodules ?3 cm in Differentiation of Lung Adenocarcinoma Spectrum. AB - We aimed to analyze CT features of persistent subsolid nodules (SSN) ?3 cm diagnosed pathologically as adenocarcinoma spectrum to investigate whether parameters enable distinction between invasive pulmonary adenocarcinomas (IPAs) and pre-invasive lesions. A total of 129 patients with 141 SSNs confirmed with surgically pathologic proof were retrospectively reviewed. Of 141 SSNs, there were 57 pure ground-glass nodules (GGNs), 22 heterogeneous GGNs, and 62 part solid nodules. SSN subclassification showed a significant linear trend with invasive degree of the adenocarcinoma spectrum (pure GGNs 7%; heterogeneous GGNs 36.4%; part-solid nodules 85.5%, P for trend <0.0001). For IPA detection in 141 SSNs, a solid part of ?3 mm was the most specificity (sensitivity, 76.9%; specificity, 94.7%), followed by air-bronchogram sign (sensitivity, 53.8%; specificity, 89.5%), SSN subclassification (sensitivity, 81.5%; specificity, 88.2%), and a lesion size ?12 mm (sensitivity, 84.6%; specificity, 76.3%). For IPA detection in 79 pure or heterogeneous GGNs, the heterogeneous GGN sign was the most useful finding, with most specificity (sensitivity, 66.7%; specificity, 79.1%), followed by CT attenuation (HU) of ?-493 (sensitivity, 75%; specificity, 74.6%) and a lesion size ?10 mm (sensitivity, 83.3%; specificity, 70.1%). In conclusion, this simple combined visual and semiquantitative analysis of CT features helps distinguish IPAs from pre-invasive lesions. PMID- 29150625 TI - Porphyromonas gingivalis lipopolysaccharides act exclusively through TLR4 with a resilience between mouse and human. AB - Porphyromonas gingivalis is a key bacterium in chronic periodontitis, which is associated with several chronic inflammatory diseases. Lipopolysaccharides from P. gingivalis (Pg LPS) can activate multiple cell types via the production of pro inflammatory cytokines. The receptors for Pg LPS have initially been reported as TLR2, contrasting with the well-studied TLR4 receptor for E. coli LPS; this observation remains controversial since synthetic Pg lipid A activates TLR4 but not TLR2. Despite this observation, the dogma of Pg LPS-mediated TLR2 activation remains the basis of many hypotheses and result interpretations. In the present work, we aimed at determining whether TLR4 or TLR2, or both, mediate Pg LPS pro inflammatory activity using Pg LPS with different grades of purity, instead of synthetic lipid A from Pg LPS. Here we show that Pg LPS 1) acts exclusively through TLR4, and 2) are differently recognized by mouse and human TLR4 both in vitro and in vivo. Taken together, our results suggest that Pg LPS activity is mediated exclusively through TLR4 and only weakly induces proinflammatory cytokine secretion in mouse models. Caution should be taken when extrapolating data from mouse systems exposed to Pg or Pg LPS to humans. PMID- 29150626 TI - Constructing Genetic Networks using Biomedical Literature and Rare Event Classification. AB - Text mining has become an important tool in bioinformatics research with the massive growth in the biomedical literature over the past decade. Mining the biomedical literature has resulted in an incredible number of computational algorithms that assist many bioinformatics researchers. In this paper, we present a text mining system called Gene Interaction Rare Event Miner (GIREM) that constructs gene-gene-interaction networks for human genome using information extracted from biomedical literature. GIREM identifies functionally related genes based on their co-occurrences in the abstracts of biomedical literature. For a given gene g, GIREM first extracts the set of genes found within the abstracts of biomedical literature associated with g. GIREM aims at enhancing biological text mining approaches by identifying the semantic relationship between each co occurrence of a pair of genes in abstracts using the syntactic structures of sentences and linguistics theories. It uses a supervised learning algorithm, weighted logistic regression to label pairs of genes to related or un-related classes, and to reflect the population proportion using smaller samples. We evaluated GIREM by comparing it experimentally with other well-known approaches and a protein-protein interactions database. Results showed marked improvement. PMID- 29150627 TI - High-efficiency backward four-wave mixing by quantum interference. AB - Electromagnetically-induced-transparency-based four-wave mixing (FWM) in a resonant four-level double-Lambda system has a maximum conversion efficiency (CE) of 25% due to spontaneous emission. Herein, we demonstrate that spontaneous emission can be considerably suppressed by arranging the applied laser beams in a backward configuration. With the backward double-Lambda FWM scheme, we observe a CE of 63% in cold rubidium atoms with an optical depth (OD) of 48. To the best of our knowledge, this is the first observation of a CE exceeding the conversion limit in resonant FWM processes. Furthermore, we present a theoretical model that includes the phase-mismatch effect in the backward double-Lambda FWM system. According to the theoretical model, the present scheme can achieve 96% CE using a medium with a large OD of 200 under ideal conditions. Such an efficient frequency conversion scheme has potential applications in optical quantum information technology. PMID- 29150628 TI - Artificial topography changes the growth strategy of Spartina alterniflora, case study with wave exposure as a comparison. AB - This paper reports findings about the growth of Spartina alterniflora (Loisel.) near an engineered coastal protection defences to discover the potential influences on vegetation growth from the artificial topography. Impacts of the artificial topography on the sediment element composition were detected by comparing the fixed effects caused by artificial topography and wave exposure using linear mixed models. Surficial sediments under the impacts of artificial topography contain elevated levels of biogenic elements and heavy metals, including C (and organic carbon), N, S, Al, Fe, Mn, Cu, Zn, As, Cd, Cr, Ni, and Pb. The results showed that element enrichment caused by artificial topography reduced the vegetation sexual reproduction. Contrary to the potential inhibition caused by direct wave exposure, which was due to the biomass accumulation limit, the inhibition caused by artificial topography was related to the transition of growth strategy. The contents of Cu, Mn, N, Ni, S and As in the sediments were critical in considering the relationship between the change in the sediment element composition and the alteration in the plant growth. Our study emphasizes the importance of rethinking the impacts of coastal development projects, especially regarding the heterogeneity of sediment element composition and its ecological consequences. PMID- 29150629 TI - Statistically strong label-free quantitative identification of native fluorophores in a biological sample. AB - Bioimaging using endogenous cell fluorescence, without any external biomarkers makes it possible to explore cells and tissues in their original native state, also in vivo. In order to be informative, this label-free method requires careful multispectral or hyperspectral recording of autofluorescence images followed by unsupervised extraction (unmixing) of biochemical signatures. The unmixing is difficult due to the scarcity of biochemically pure regions in cells and also because autofluorescence is weak compared with signals from labelled cells, typically leading to low signal to noise ratio. Here, we solve the problem of unsupervised hyperspectral unmixing of cellular autofluorescence by introducing the Robust Dependent Component Analysis (RoDECA). This approach provides sophisticated and statistically robust quantitative biochemical analysis of cellular autofluorescence images. We validate our method on artificial images, where the addition of varying known level of noise has allowed us to quantify the accuracy of our RoDECA analysis in a way that can be applied to real biological datasets. The same unsupervised statistical minimisation is then applied to imaging of mouse retinal photoreceptor cells where we establish the identity of key endogenous fluorophores (free NADH, FAD and lipofuscin) and derive the corresponding molecular abundance maps. The pre-processing methodology of image datasets is also presented, which is essential for the spectral unmixing analysis, but mostly overlooked in the previous studies. PMID- 29150630 TI - Inhibition of myeloid differentiation primary response protein 88 provides neuroprotection in early brain injury following experimental subarachnoid hemorrhage. AB - Accumulating of evidence suggests that activation of nuclear factor-kappa B (NF kappaB) and mitogen-activated protein kinases (MAPKs) exacerbates early brain injury (EBI) following subarachnoid hemorrhage (SAH) by provoking pro inflammatory and pro-apoptotic signaling. Myeloid differentiation primary response protein 88 (MyD88) is an endogenous adaptor protein in the toll-like receptors (TLRs) and interleukin (IL) -1beta family signaling pathways and acts as a bottle neck in the NF-kappaB and MAPK pathways. Here, we used ST2825, a selective inhibitor of MyD88, to clarify whether inhibiting MyD88 could provide neuroprotection in EBI following SAH. Our results showed that the expression of MyD88 was markedly increased at 24 h post SAH. Intracerebroventricular injection of ST2825 significantly reduced the expression of MyD88 at 24 h post SAH. Involvement of MAPKs and NF-kappaB signaling pathways was revealed that ST2825 inhibited SAH-induced phosphorylation of TAK1, p38 and JNK, the nuclear translocation of NF-kappaB p65, and degradation of IkappaBalpha. Further, ST2825 administration diminished the SAH-induced inflammatory response and apoptosis. As a result, SAH-induced EBI was alleviated and neurological deficits caused by SAH were reversed. Our findings suggest that MyD88 inhibition confers marked neuroprotection against EBI following SAH. Therefore, MyD88 might be a promising new molecular target for the treatment of SAH. PMID- 29150631 TI - Effect of Long-term Incretin-Based Therapies on Ischemic Heart Diseases in Patients with Type 2 Diabetes Mellitus: A Network Meta-analysis. AB - Patients with type 2 diabetes mellitus (T2DM) experience many cardiovascular complications. Several studies have demonstrated the cardioprotective effects of incretin-based therapies; however, there are few studies on the effects of long term incretin-based therapies on cardiovascular events. Therefore, the present study conducted a systematic review and network meta-analysis to evaluate the effects of long-term incretin-based therapies on ischaemic diseases. We searched PubMed, CENTRAL, and Clinicaltrial.gov to retrieve randomised control trials reported until December 2016 and enrolled only RCTs with more than a 1-year follow-up. The network meta-analysis was performed using R Software with a GeMTC package. A total of 40 trials were included. Dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 agonists were associated with a lower risk of myocardial infarction (MI) than were sulfonylureas (odds ratio [95% credible interval] 0.41 [0.24-0.71] and 0.48 [0.27-0.91], respectively). These results suggested that patients with T2DM receiving long-term incretin-based therapies have a lower risk of MI than do those receiving sulfonylurea-based therapy. These findings highlight the risks of cardiovascular events in patients who receive long-term incretin-based therapies, and may provide evidence for the selection of antidiabetic therapy in the future. PMID- 29150632 TI - Mucoadhesive functionality of cell wall structures from fruits and grains: Electrostatic and polymer network interactions mediated by soluble dietary polysaccharides. AB - We demonstrate the enhancement of intestinal mucin (Muc2) binding to plant cell wall structures from fruit (parenchymal apple tissue) and grain (wheat endosperm) mediated by soluble dietary fibers embedded within cellulose networks. Mucin binding occurs through two distinct mechanisms; for pectin polysaccharides characteristic of fruits and vegetables, it is governed by molecular mucoadhesive interactions, while for neutral polysaccharides, arabinoxylan and beta-glucan characteristic of cereal grains, the interaction stems from the properties of their polymer network. Based on microrheological and microscopic measurements, we show that neutral dietary fiber polysaccharides do not adhere to intestinal mucin, but are capable of disrupting the mucin network, which facilitates interpenetration of mucin molecules into the polysaccharide mesh. This effect becomes significant in the context of 'whole foods', where soluble fibers are incorporated within the gel-like matrix of cellulose-reinforced plant cell wall structures. The result of mucoadhesion assay and analysis of microscopy images points to the critical role of entanglements between mucin and polysaccharides as a lock-in mechanism preventing larger mucin from escaping out of plant cell wall structures. These results provide the first indication that non-pectin soluble dietary fiber may influence mucosal interactions, mucus barrier properties, and transmucosal transport of nutrients. PMID- 29150633 TI - Ketamine's antidepressant effect is mediated by energy metabolism and antioxidant defense system. AB - Fewer than 50% of all patients with major depressive disorder (MDD) treated with currently available antidepressants (ADs) show full remission. Moreover, about one third of the patients suffering from MDD does not respond to conventional ADs and develop treatment-resistant depression (TRD). Ketamine, a non-competitive, voltage-dependent N-Methyl-D-aspartate receptor (NMDAR) antagonist, has been shown to have a rapid antidepressant effect, especially in patients suffering from TRD. Hippocampi of ketamine-treated mice were analysed by metabolome and proteome profiling to delineate ketamine treatment-affected molecular pathways and biosignatures. Our data implicate mitochondrial energy metabolism and the antioxidant defense system as downstream effectors of the ketamine response. Specifically, ketamine tended to downregulate the adenosine triphosphate (ATP)/adenosine diphosphate (ADP) metabolite ratio which strongly correlated with forced swim test (FST) floating time. Furthermore, we found increased levels of enzymes that are part of the 'oxidative phosphorylation' (OXPHOS) pathway. Our study also suggests that ketamine causes less protein damage by rapidly decreasing reactive oxygen species (ROS) production and lend further support to the hypothesis that mitochondria have a critical role for mediating antidepressant action including the rapid ketamine response. PMID- 29150634 TI - Incomplete resection and linitis plastica are factors for poor survival after extended multiorgan resection in gastric cancer patients. AB - The aim of this retrospective study was to analyze the morbidity, mortality, and survival rates of extended multiorgan resection (EMR) for locally advanced gastric cancer patients compared to gastrectomy alone and a palliative operation. 893 locally advanced gastric cancer patients without distant metastasis had surgery including gastrectomy alone (GA group, n = 798), EMR resection (EMR group, n = 75), and palliative operation (palliative gastrectomy or gastrojejunostomy (PO group, n = 20)). Postoperative mortality and complication rates in the EMR group were significantly higher than in the GA group (2.7% vs 0.4%, P = 0.010 and 25.3% vs 8.1%, P < 0.001, respectively), but similar in the PO group. The median survival time of the EMR group was significantly longer than in the PO group (27 months vs 11 months, P = 0.020), but significantly worse (P = 0.020) than in the GA group (44 months). Incompleteness of resection (R1) and linitis plastica were independent prognostic factors for survival in the EMR group. Three different gastric cancer surgeries led to different postoperative mortality and complication rates. EMR had a better survival rate compared with PO while GA had the longest survival time with the lowest mortality and complication rates. PMID- 29150635 TI - One-pot synthesis of trifunctional chitosan-EDTA-beta-cyclodextrin polymer for simultaneous removal of metals and organic micropollutants. AB - The global contamination of water resources with inorganic and organic micropollutants, such as metals and pharmaceuticals, poses a critical threat to the environment and human health. Herein, we report on a bio-derived chitosan EDTA-beta-cyclodextrin (CS-ED-CD) trifunctional adsorbent fabricated via a facile and green one-pot synthesis method using EDTA as a cross-linker, for the adsorption of toxic metals and organic micropollutants from wastewater. In this system, chitosan chain is considered as the backbone, and the immobilized cyclodextrin cavities capture the organic compounds via host-guest inclusion complexation, while EDTA-groups complex metals. The thoroughly characterized CS ED-CD was employed for batch adsorption experiments. The adsorbent displayed a monolayer adsorption capacity of 0.803, 1.258 mmol g-1 for Pb(II) and Cd(II) respectively, while a heterogeneous sorption capacity of 0.177, 0.142, 0.203, 0.149 mmol g-1 for bisphenol-S, ciprofloxacin, procaine, and imipramine, respectively. The adsorption mechanism was verified by FT-IR and elemental mapping. Importantly, the adsorbent perform is effective in the simultaneous removal of metals and organic pollutants at environmentally relevant concentrations. All these findings demonstrate the promise of CS-ED-CD for practical applications in the treatment of micropollutants. This work adds a new insight to design and preparation of efficient trifunctional adsorbents from sustainable materials for water purification. PMID- 29150636 TI - A genetic system for targeted mutations to disrupt and restore genes in the obligate bacterium, Ehrlichia chaffeensis. AB - Obligate intracellular bacteria (obligates) belonging to Rickettsiales and Chlamydiales cause diseases in hundreds of millions of people worldwide and in many animal species. Lack of an efficient system for targeted mutagenesis in obligates remains a major impediment in understanding microbial pathogenesis. Challenges in creating targeted mutations may be attributed to essential nature of majority of the genes and intracellular replication dependence. Despite success in generating random mutations, a method that works well in creating mutations in specific genes of interest followed by complementation remains problematic for obligates and is a highly sought-after goal. We describe protocols to generate stable targeted mutations by allelic exchange in Ehrlichia chaffeensis, an obligate intracellular tick-borne bacterium responsible for human monocytic ehrlichiosis. Targeted mutations in E. chaffeensis were created to disrupt two genes, and also to restore one gene by another allelic exchange mutation leading to the restoration of transcription and protein expression from the inactivated gene and the recovered organisms also express mCherry, which distinguishes from the wild type. We expect that the methods developed are broadly applicable to other obligates, particularly to rickettsial pathogens, to routinely perform targeted mutations to enable studies focused on protein structure-function analyses, host-pathogen interactions and in developing vaccines. PMID- 29150637 TI - Ml proteins from Mesorhizobium loti and MucR from Brucella abortus: an AT-rich core DNA-target site and oligomerization ability. AB - Mesorhizobium loti contains ten genes coding for proteins sharing high amino acid sequence identity with members of the Ros/MucR transcription factor family. Five of these Ros/MucR family members from Mesorhizobium loti (Ml proteins) have been recently structurally and functionally characterized demonstrating that Ml proteins are DNA-binding proteins. However, the DNA-binding studies were performed using the Ros DNA-binding site with the Ml proteins. Currently, there is no evidence as to when the Ml proteins are expressed during the Mesorhizobium lo ti life cycle as well as no information concerning their natural DNA-binding site. In this study, we examine the ml genes expression profile in Mesorhizobium loti and show that ml1, ml2, ml3 and ml5 are expressed during planktonic growth and in biofilms. DNA-binding experiments show that the Ml proteins studied bind a conserved AT-rich site in the promoter region of the exoY gene from Mesorhizobium loti and that the proteins make important contacts with the minor groove of DNA. Moreover, we demonstrate that the Ml proteins studied form higher-order oligomers through their N-terminal region and that the same AT-rich site is recognized by MucR from Brucella abortus using a similar mechanism involving contacts with the minor groove of DNA and oligomerization. PMID- 29150638 TI - The Kohlschutter-Tonz syndrome associated gene Rogdi encodes a novel presynaptic protein. AB - Mutations in the human homolog of the Drosophila gene Rogdi cause Kohlschutter Tonz syndrome. This disorder is characterised by amelogenesis imperfecta, as well as severe neurological symptoms including epilepsy and psychomotor delay. However, little is known about the protein encoded by Rogdi, and hence the pathogenic mechanisms underlying Kohlschutter-Tonz syndrome have remained elusive. Using immunofluorescence of rat cultured hippocampal neurons and brain sections we find that Rogdi is enriched at synaptic sites. In addition, recombinant GFP-Rogdi expressed in cultured neurons was efficiently targeted to presynaptic sites, where it colocalised with the presynaptic scaffolding protein Bassoon and the synaptic vesicle markers Synaptophysin, Synapsin-1, VAMP2/Synaptobrevin and Mover. Our data indicate that GFP-Rogdi harbours efficient signals for presynaptic targeting, and that Rogdi is a presynaptic protein. Thus, the neurological symptoms associated with Kohlschutter-Tonz syndrome may arise from presynaptic dysfunction. PMID- 29150639 TI - In Vitro Maturation and In Vivo Integration and Function of an Engineered Cell Seeded Disc-like Angle Ply Structure (DAPS) for Total Disc Arthroplasty. AB - Total disc replacement with an engineered substitute is a promising avenue for treating advanced intervertebral disc disease. Toward this goal, we developed cell-seeded disc-like angle ply structures (DAPS) and showed through in vitro studies that these constructs mature to match native disc composition, structure, and function with long-term culture. We then evaluated DAPS performance in an in vivo rat model of total disc replacement; over 5 weeks in vivo, DAPS maintained their structure, prevented intervertebral bony fusion, and matched native disc mechanical function at physiologic loads in situ. However, DAPS rapidly lost proteoglycan post-implantation and did not integrate into adjacent vertebrae. To address this, we modified the design to include polymer endplates to interface the DAPS with adjacent vertebrae, and showed that this modification mitigated in vivo proteoglycan loss while maintaining mechanical function and promoting integration. Together, these data demonstrate that cell-seeded engineered discs can replicate many characteristics of the native disc and are a viable option for total disc arthroplasty. PMID- 29150640 TI - Early endosome motility mediates alpha-amylase production and cell differentiation in Aspergillus oryzae. AB - Recent research in filamentous fungi has revealed that the motility of an endocytic organelle early endosome (EE) has a versatile role in many physiological functions. Here, to further examine the motility of EEs in the industrially important fungus Aspergillus oryzae, we visualized these organelles via the Rab5 homolog AoRab5 and identified AoHok1, a putative linker protein between an EE and a motor protein. The Aohok1 disruptant showed retarded mycelial growth and no EE motility, in addition to an apical accumulation of EEs and peroxisomes. We further demonstrated that the Aohok1 disruptant exhibited less sensitivity to osmotic and cell wall stresses. Analyses on the protein secretory pathway in DeltaAohok1 cells showed that, although distribution of the endoplasmic reticulum and Golgi was not affected, formation of the apical secretory vesicle cluster Spitzenkorper was impaired, probably resulting in the observed reduction of the A. oryzae major secretory protein alpha-amylase. Moreover, we revealed that the transcript level of alpha-amylase-encoding gene amyB was significantly reduced in the Aohok1 disruptant. Furthermore, we observed perturbed conidial and sclerotial formations, indicating a defect in cell differentiation, in the Aohok1 disruptant. Collectively, our results suggest that EE motility is crucial for alpha-amylase production and cell differentiation in A. oryzae. PMID- 29150641 TI - Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis. AB - One of the major challenges of the current Zika virus (ZIKV) epidemic is to prevent congenital foetal abnormalities, including microcephaly, following ZIKV infection of pregnant women. Given the urgent need for ZIKV prophylaxis and treatment, repurposing of approved drugs appears to be a viable and immediate solution. We demonstrate that the common anti-malaria drug chloroquine (CQ) extends the lifespan of ZIKV-infected interferon signalling-deficient AG129 mice. However, the severity of ZIKV infection in these mice precludes the study of foetal (vertical) viral transmission. Here, we show that interferon signalling competent SJL mice support chronic ZIKV infection. Infected dams and sires are both able to transmit ZIKV to the offspring, making this an ideal model for in vivo validation of compounds shown to suppress ZIKV in cell culture. Administration of CQ to ZIKV-infected pregnant SJL mice during mid-late gestation significantly attenuated vertical transmission, reducing the ZIKV load in the foetal brain more than 20-fold. Given the limited side effects of CQ, its lack of contraindications in pregnant women, and its worldwide availability and low cost, we suggest that CQ could be considered for the treatment and prophylaxis of ZIKV. PMID- 29150642 TI - Rescue of PFOS-induced human Sertoli cell injury by overexpressing a p-FAK-Y407E phosphomimetic mutant. AB - : PFOS induces Sertoli cell injury using testicular cells isolated from rodent testes, but it remains unknown if PFOS has similar effects in humans. Herein, we maintained human Sertoli cells in a mitotically active state in vitro, thus enabling transfection experiments that altered gene expression to explore the molecular mechanism(s) underlying toxicant-induced cell injury. Human Sertoli cells obtained from men at ages 15, 23, 36 and 40 were cultured in vitro. These differentiated Sertoli cells remained mitotically active when cultured in the presence of 10% FBS (fetal bovine serum), with a replication time of ~1-3 weeks. At ~80% confluency, they were used for studies including toxicant exposure, immunoblotting, immunofluorescence analysis, tight junction (TJ)-permeability assessment, and overexpression of BTB (blood-testis barrier) regulatory genes such as FAK and its phosphomimetic mutants. PFOS was found to induce Sertoli cell injury through disruptive effects on actin microfilaments and microtubule (MT) organization across the cell cytosol. As a consequence, these cytoskeletal networks failed to support cell adhesion at the BTB. Overexpression of a FAK phosphomimetic and constitutively active mutant p-FAK-Y407E in these cells was capable of rescuing the PFOS-induced injury through corrective cellular organization of cytoskeletal elements. SUMMARY: PFOS induces human Sertoli cell injury which can be rescued by overexpressing p-FAK-Y407E mutant. PMID- 29150643 TI - beta-Eudesmol, an oxygenized sesquiterpene, stimulates appetite via TRPA1 and the autonomic nervous system. AB - Transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable non selective cation channel, which is activated by various noxious or irritant substances in nature. TRPA1 activators have been generally recognized as noxious, however, foods and beverages containing TRPA1 activators are preferably consumed; the reasons for this discrepancy are not well understood. We demonstrate that TRPA1 is involved in the stimulatory appetite control mechanism. beta-Eudesmol is an oxygenated sesquiterpene contained in medicinal or edible plants which activates TRPA1. Oral administration of beta-eudesmol brought significant increments in food intake in rats and elevated plasma ghrelin levels. Gastric vagal nerve activity (GVNA) has been reported to affect feeding behavior. In vivo electrophysiological measurement of GVNA revealed that oral-ingestion of beta eudesmol significantly increased GVNA. This GVNA elevation was eliminated by TRPA1 inhibitor (HC-030031) treatment prior to beta-eudesmol administration. The physiological effects of beta-eudesmol, for example, incremental increase in food intake, ghrelin elevation and activation of GVNA, were significantly reduced in TRPA1 knockout rats. Our results indicated that beta-eudesmol stimulates an increase in appetite through TRPA1, and suggests why TRPA1 activator containing foods and beverages are preferably consumed. PMID- 29150644 TI - Therapeutic effects of hepatocyte growth factor-overexpressing dental pulp stem cells on liver cirrhosis in a rat model. AB - Cirrhosis is the terminal stage of hepatic diseases and is prone to develop into hepatocyte carcinoma. Increasing evidence suggests that the transplantation of dental pulp stem cells (DPSCs) may promote recovery from cirrhosis, but the key regulatory mechanisms involved remain to be determined. In this study, we overexpressed human hepatocyte growth factor (hHGF) in primary rat DPSCs and evaluated the effects of HGF overexpression on the biological behaviors and therapeutic efficacy of grafted DPSCs in cirrhosis. Liver cirrhosis was induced via the intraperitoneal injection of CCl4 twice weekly for 12 weeks and was verified through histopathological and serological assays. HGF was overexpressed in DPSCs via transduction with a hHGF-lentiviral vector and confirmed based on the elevated expression and secretion of HGF. The HGF-overexpressing DPSCs were transplanted into rats intravenously. The HGF-overexpressing DPSCs showed increased survival and hepatogenic differentiation in host liver tissue at 6 weeks after grafting. They also exhibited a significantly greater repair potential in relation to cirrhosis pathology and impaired liver function than did DPSCs expressing HGF at physiological levels. Our study may provide an experimental basis for the development of novel methods for the treatment of liver cirrhosis in clinical practice. PMID- 29150645 TI - Axonemal Lumen Dominates Cytosolic Protein Diffusion inside the Primary Cilium. AB - Transport of membrane and cytosolic proteins in primary cilia is thought to depend on intraflagellar transport (IFT) and diffusion. However, the relative contribution and spatial routes of each transport mechanism are largely unknown. Although challenging to decipher, the details of these routes are essential for our understanding of protein transport in primary cilia, a critically affected process in many genetic diseases. By using a high-speed virtual 3D super resolution microscopy, we have mapped the 3D spatial locations of transport routes for various cytosolic proteins in the 250-nm-wide shaft of live primary cilia with a spatiotemporal resolution of 2 ms and <16 nm. Our data reveal two spatially distinguishable transport routes for cytosolic proteins: an IFT dependent path along the axoneme, and a passive-diffusion route in the axonemal lumen that escaped previous studies. While all cytosolic proteins tested primarily utilize the IFT path in the anterograde direction, differences are observed in the retrograde direction where IFT20 only utilizes IFT, and approximately half of KIF17 and one third of alpha-tubulin utilizes diffusion besides IFT. PMID- 29150646 TI - Body size estimation in women with anorexia nervosa and healthy controls using 3D avatars. AB - A core feature of anorexia nervosa is an over-estimation of body size. However, quantifying this over-estimation has been problematic as existing methodologies introduce a series of artefacts and inaccuracies in the stimuli used for judgements of body size. To overcome these problems, we have: (i) taken 3D scans of 15 women who have symptoms of anorexia (referred to henceforth as anorexia spectrum disorders, ANSD) and 15 healthy control women, (ii) used a 3D modelling package to build avatars from the scans, (iii) manipulated the body shapes of these avatars to reflect biometrically accurate, continuous changes in body mass index (BMI), (iv) used these personalized avatars as stimuli to allow the women to estimate their body size. The results show that women who are currently receiving treatment for ANSD show an over-estimation of body size which rapidly increases as their own BMI increases. By contrast, the women acting as healthy controls can accurately estimate their body size irrespective of their own BMI. This study demonstrates the viability of combining 3D scanning and CGI techniques to create personalised realistic avatars of individual patients to directly assess their body image perception. PMID- 29150647 TI - Impact of Multidecadal Climate Variability on United Kingdom Rickets Rates. AB - Children who receive inadequate exposure to sunlight have reduced levels of vitamin D, resulting in rickets, a disease that is characterized by bone deformity, stunted growth, and long term pronounced disability. The United Kingdom rickets incidence rates declined from the early 1960's to mid-1990's, after which there was a dramatic increase. The reason for this change is not well understood. Here we show that an important low frequency mode of climate variability, the Atlantic Multidecadal Oscillation (AMO), with a period of ~60-80 years, has an impact on rickets incidence rates in the United Kingdom through changes in sea level pressure, cloud cover and sunshine duration. This research highlights the important role that multidecadal climate variability can play in human morbidity and suggests that future changes in the AMO may modulate rickets incidence rates throughout the United Kingdom. PMID- 29150648 TI - Shedding light on the neonatal brain: probing cerebral hemodynamics by diffuse optical spectroscopic methods. AB - Investigating the cerebral physiology of healthy term newborns' brains is important for better understanding perinatal brain injuries, of which the most common etiologies are hypoxia and ischemia. Hence, cerebral blood flow and cerebral oxygenation are important biomarkers of brain health. In this study, we employed a hybrid diffuse optical system consisting of diffuse correlation spectroscopy (DCS) and frequency-domain near infrared spectroscopy (FDNIRS) to measure hemoglobin concentration, oxygen saturation, and indices of cerebral blood flow and metabolism. We measured 30 term infants to assess the optical and physiological characteristics of the healthy neonatal brain in the frontal, temporal, and parietal lobes. We observed higher metabolism in the right hemisphere compared to the left and a positive correlation between gestational age and the level of cerebral hemoglobin concentration, blood volume, and oxygen saturation. Moreover, we observed higher cerebral blood flow and lower oxygen saturation in females compared to males. The delayed maturation in males and the sexual dimorphism in cerebral hemodynamics may explain why males are more vulnerable to perinatal brain injuries than females. PMID- 29150649 TI - Non-empirical atomistic dipole-interaction-model for quantum plasmon simulation of nanoparticles. AB - Plasmonic nanoparticles in the quantum regime exhibit characteristic optical properties that cannot be described by classical theories. Time-dependent density functional theory (TDDFT) is rising as a versatile tool for study on such systems, but its application has been limited to very small clusters due to rapidly growing computational costs. We propose an atomistic dipole-interaction model for quantum plasmon simulations as a practical alternative. Namely the atomic dipole approximation represents induced dipoles with atomic polarizabilities obtained from TDDFT without empirical parameters. It showed very good agreement with TDDFT for plasmonic spectra of small silver clusters at much lower computational cost, though it is not appropriate for molecular-like excitations. It could also reproduce the plasmonic band shift experimentally observed in sub-10 nm silver particles. PMID- 29150650 TI - Transcriptome sequencing and differential gene expression analysis of the schistosome-transmitting snail Oncomelania hupensis inhabiting hilly and marshland regions. AB - The freshwater snail Oncomelania hupensis is the unique intermediate host of the blood fluke Schistosoma japonicum, which is the major cause of schistosomiasis. The snail inhabits two contrasting environments: the hilly and marshland regions. The hilly snails are smaller in size and have the typical smooth shell, whereas the marshland snails are larger and possess the ribbed shell. To reveal the differences in gene expression between the hilly and marshland snails, a total of six snails, three per environment, were individually examined by RNA sequencing technology. All paired-end reads were assembled into contigs from which 34,760 unigenes were predicted. Based on single nucleotide polymorphisms, principal component analysis and neighbor-joining clustering revealed two distinct clusters of hilly and marshland snails. Analysis of expression changes between environments showed that upregulated genes relating to immunity and development were enriched in hilly snails, while those associated with reproduction were over represented in marshland snails. Eight differentially expressed genes between the two types of snails were validated by qRT-PCR. Our study identified candidate genes that could be targets for future functional studies, and provided a link between expression profiling and ecological adaptation of the snail that may have implications for schistosomiasis control. PMID- 29150652 TI - Evidence for frozen melts in the mid-lithosphere detected from active-source seismic data. AB - The interactions of the lithospheric plates that form the Earth's outer shell provide much of the evidentiary basis for modern plate tectonic theory. Seismic discontinuities in the lithosphere arising from mantle convection and plate motion provide constraints on the physical and chemical properties of the mantle that contribute to the processes of formation and evolution of tectonic plates. Seismological studies during the past two decades have detected seismic discontinuities within the oceanic lithosphere in addition to that at the lithosphere-asthenosphere boundary (LAB). However, the depth, distribution, and physical properties of these discontinuities are not well constrained, which makes it difficult to use seismological data to examine their origin. Here we present new active-source seismic data acquired along a 1,130 km profile across an old Pacific plate (148-128 Ma) that show oceanic mid-lithosphere discontinuities (oceanic MLDs) distributed 37-59 km below the seafloor. The presence of the oceanic MLDs suggests that frozen melts that accumulated at past LABs have been preserved as low-velocity layers within the current mature lithosphere. These observations show that long-offset, high-frequency, active source seismic data can be used to image mid-lithospheric structure, which is fundamental to understanding the formation and evolution of tectonic plates. PMID- 29150651 TI - Comprehensive functional enrichment analysis of male infertility. AB - Spermatogenesis is a multifactorial process that forms differentiated sperm cells in a complex microenvironment. This process involves the genome, epigenome, transcriptome, and proteome to ensure the stability of the spermatogonia and supporting cells. The identification of signaling pathways linked to infertility has been hampered by the inherent complexity and multifactorial aspects of spermatogenesis. Systems biology is a promising approach to unveil underlying signaling pathways and genes and identify putative biomarkers. In this study, we analyzed thirteen microarray libraries of infertile humans and mice, and different classes of male infertility were compared using differentially expressed genes and functional enrichment analysis. We found regulatory processes, immune response, glutathione transferase and muscle tissue development to be among the most common biological processes in up-regulated genes, and genes involved in spermatogenesis were down-regulated in maturation arrest (MArrest) and oligospermia cases. We also observed the overexpression of genes involved in steroid metabolism in post-meiotic and meiotic arrest. Furthermore, we found that the infertile mouse model most similar to human MArrest was the Dazap1 mutant mouse. The results of this study could help elucidate features of infertility etiology and provide the basis for diagnostic markers. PMID- 29150653 TI - A theoretical quest for high temperature superconductivity on the example of low dimensional carbon structures. AB - High temperature superconductivity does not necessarily require correlated electron systems with complex competing or coexisting orders. Instead, it may be achieved in a phonon-mediated classical superconductor having a high Debye temperature and large electronic density of states at the Fermi level in a material with light atoms and strong covalent bonds. Quasi-1D conductors seem promising due to the Van Hove singularities in their electronic density of states. In this sense, quasi-1D carbon structures are good candidates. In thin carbon nanotubes, superconductivity at ~15 K has been reported, and it is likely the strong curvature of the graphene sheet which enhances the electron-phonon coupling. We use an ab-initio approach to optimize superconducting quasi-1D carbon structures. We start by calculating a T c of 13.9 K for (4.2) carbon nanotubes (CNT) that agrees well with experiments. Then we reduce the CNT to a ring, open the ring to form chains, optimize bond length and kink structure, and finally form a new type of carbon ring that reaches a T c value of 115 K. PMID- 29150654 TI - Primary aldosteronism patients show skin alterations and abnormal activation of glucocorticoid receptor in keratinocytes. AB - Primary aldosteronism (PA) is a disease characterized by high aldosterone levels caused by benign adrenal tumors being the most frequent cause of secondary hypertension. Aldosterone plays vital physiological roles through the mineralocorticoid receptor (MR) but in certain cell types, it can also activate the glucocorticoid (GC) receptor (GR). Both MR and GR are structurally and functionally related and belong to the same family of ligand-dependent transcription factors that recognize identical GC regulatory elements (GREs) on their target genes. GCs play key roles in skin pathophysiology acting through both GR and MR; however, the effects of aldosterone and the potential association of PA and skin disease were not previously addressed. Skin samples from PA revealed histopathological alterations relative to control subjects, featuring epidermal hyperplasia, impaired differentiation, and increased dermal infiltrates, correlating with increased NF-kappaB signaling and up-regulation of TNF-A and IL-6 cytokines. PA skin samples also showed significantly higher expression of MR, GR, and HSD11B2. In cultured keratinocytes, aldosterone treatment increased GRE transcriptional activity which was significantly inhibited by co-treatment with GR- and MR-antagonists. This study demonstrates that high levels of aldosterone in PA patients correlate with skin anomalies and inflammatory features associated with abnormal GR/MR activation in epidermal keratinocytes. PMID- 29150655 TI - Reverse engineering protocols for controlling spin dynamics. AB - We put forward reverse engineering protocols to shape in time the components of the magnetic field to manipulate a single spin, two independent spins with different gyromagnetic factors, and two interacting spins in short amount of times. We also use these techniques to setup protocols robust against the exact knowledge of the gyromagnetic factors for the one spin problem, or to generate entangled states for two or more spins coupled by dipole-dipole interactions. PMID- 29150656 TI - Publisher Correction: Global trade statistics lack granularity to inform traceability and management of diverse and high-value fishes. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29150657 TI - Specific heat, Electrical resistivity and Electronic band structure properties of noncentrosymmetric Th7Fe3 superconductor. AB - Noncentrosymmetric superconductor Th7Fe3 has been investigated by means of specific heat, electrical resisitivity measurements and electronic properties calculations. Sudden drop in the resistivity at 2.05 +/- 0.15 K and specific heat jump at 1.98 +/- 0.02 K are observed, rendering the superconducting transition. A model of two BCS-type gaps appears to describe the zero-magnetic-field specific heat better than those based on the isotropic BCS theory or anisotropic functions. A positive curvature of the upper critical field H c2(T c) and nonlinear field dependence of the Sommerfeld coefficient at 0.4 K qualitatively support the two-gap scenario, which predicts H c2(0) = 13 kOe. The theoretical densities of states and electronic band structures (EBS) around the Fermi energy show a mixture of Th 6d- and Fe 3d-electrons bands, being responsible for the superconductivity. Furthermore, the EBS and Fermi surfaces disclose significantly anisotropic splitting associated with asymmetric spin-orbit coupling (ASOC). The ASOC sets up also multiband structure, which presumably favours a multigap superconductivity. Electron Localization Function reveals the existence of both metallic and covalent bonds, the latter may have different strengths depending on the regions close to the Fe or Th atoms. The superconducting, electronic properties and implications of asymmetric spin-orbit coupling associated with noncentrosymmetric structure are discussed. PMID- 29150658 TI - Differential regulation of synaptic AP-2/clathrin vesicle uncoating in synaptic plasticity. AB - AP-1/sigma1B-deficiency causes X-linked intellectual disability. AP-1/sigma1B -/- mice have impaired synaptic vesicle recycling, fewer synaptic vesicles and enhanced endosome maturation mediated by AP-1/sigma1A. Despite defects in synaptic vesicle recycling synapses contain two times more endocytic AP-2 clathrin-coated vesicles. We demonstrate increased formation of two classes of AP 2/clathrin coated vesicles. One which uncoats readily and a second with a stabilised clathrin coat. Coat stabilisation is mediated by three molecular mechanisms: reduced recruitment of Hsc70 and synaptojanin1 and enhanced MU2/AP-2 phosphorylation and activation. Stabilised AP-2 vesicles are enriched in the structural active zone proteins Git1 and stonin2 and synapses contain more Git1. Endocytosis of the synaptic vesicle exocytosis regulating Munc13 isoforms are differentially effected. Regulation of synaptic protein endocytosis by the differential stability of AP-2/clathrin coats is a novel molecular mechanism of synaptic plasticity. PMID- 29150659 TI - Ectopic FOXP3 Expression Preserves Primitive Features Of Human Hematopoietic Stem Cells While Impairing Functional T Cell Differentiation. AB - FOXP3 is the transcription factor ruling regulatory T cell function and maintenance of peripheral immune tolerance, and mutations in its coding gene causes IPEX autoimmune syndrome. FOXP3 is also a cell-cycle inhibitor and onco suppressor in different cell types. In this work, we investigate the effect of ectopic FOXP3 expression on HSC differentiation and we challenged this approach as a possible HSC-based gene therapy for IPEX. FOXP3-expressing HSC showed reduced proliferation ability and increased maintenance of primitive markers in vitro in both liquid and OP9-DeltaL1 co-cultures. When transplanted into immunodeficient mice, FOXP3-expressing HSC showed significantly enhanced engraftment ability. This was due to a pronounced increase in the frequency of repopulating cells, as assessed by extreme limiting dilution assay. Likely underlying the increased repopulating ability, FOXP3 expressing HSC showed significantly enhanced expression of genes controlling stemness features. However, peripheral T cells developed in the FOXP3-humanized mice were quantitatively reduced and hyporesponsive to cytokine and polyclonal stimulation. Our findings reveal unpredicted effects of FOXP3 in the biology of HSC and may provide new tools to manipulate primitive features in HSC for clinical applications. Moreover, they formally prove the need of preserving endogenous FOXP3 regulation for an HSC-based gene therapy approach for IPEX syndrome. PMID- 29150660 TI - Gene expression profile changes in the jejunum of weaned piglets after oral administration of Lactobacillus or an antibiotic. AB - The small intestine plays an essential role in the health and well-being of animals. Previous studies have shown that Lactobacillus has a protective effect on intestinal morphology, intestinal epithelium integrity and appropriate maturation of gut-associated tissues. Here, gene expression in jejunum tissue of weaned piglets was investigated by RNA-seq analysis after administration of sterile saline, Lactobacillus reuteri, or an antibiotic (chlortetracycline). In total, 401 and 293 genes were significantly regulated by chlortetracycline and L. reuteri, respectively, compared with control treatment. Notably, the HP, NOX1 and GPX2 genes were significantly up-regulated in the L. reuteri group compared with control, which is related to the antioxidant ability of this strain. In addition, the expression of genes related to arachidonic acid metabolism and linoleic acid metabolism enriched after treatment with L. reuteri. The fatty acid composition in the jejunum and colon was examined by GC-MS analysis and suggested that the MUFA C18:1n9c, and PUFAs C18:2n6c and C20:4n6 were increased in the L. reuteri group, verifying the GO enrichment and KEGG pathway analyses of the RNA-seq results. The results contribute to our understanding of the probiotic activity of this strain and its application in pig production. PMID- 29150661 TI - Morphological differentiation of Brachionus calyciflorus caused by predation and coal ash pollution. AB - Different rotifer stains exhibited remarkably morphological differences which could not be eliminated under laboratory conditions. In the present study, we hypothesized that predation pressure and pollution might be two forces driving morphological differentiation of rotifer. To test this hypothesis, rotifers (Brachionus calyciflorus) belonging to two sibling species were collected from three special lakes (with coal ash pollution, high predation pressure or neither) and cultured for more than three months to investigate their potential differentiation in morphology. Twelve morphological parameters were measured and compared among three lakes at four food density (Scenedesmus obliquus). The results showed that most of the tested morphological parameters changed in response to food level and differed among three habitats. Rotifers from the habitat with high predation pressure evolved stable long posterior lateral spine and relatively small body size. Rotifers collected from the polluted habitat was of smaller body size, compared with those from ordinary habitat. Bigger eggs were laid by rotifers from polluted area or lake with high predation pressure, enabling newborns more resistant to pollution or predation, and thus ensuring the survival rate of newborns. Finally, we concluded that both predation and pollution could affect the morphological differentiation and evolution of rotifers. PMID- 29150662 TI - Turbulent mass transfer caused by vortex induced reconnection in collisionless magnetospheric plasmas. AB - Magnetic reconnection is believed to be the main driver to transport solar wind into the Earth's magnetosphere when the magnetopause features a large magnetic shear. However, even when the magnetic shear is too small for spontaneous reconnection, the Kelvin-Helmholtz instability driven by a super-Alfvenic velocity shear is expected to facilitate the transport. Although previous kinetic simulations have demonstrated that the non-linear vortex flows from the Kelvin Helmholtz instability gives rise to vortex-induced reconnection and resulting plasma transport, the system sizes of these simulations were too small to allow the reconnection to evolve much beyond the electron scale as recently observed by the Magnetospheric Multiscale (MMS) spacecraft. Here, based on a large-scale kinetic simulation and its comparison with MMS observations, we show for the first time that ion-scale jets from vortex-induced reconnection rapidly decay through self-generated turbulence, leading to a mass transfer rate nearly one order higher than previous expectations for the Kelvin-Helmholtz instability. PMID- 29150663 TI - Publisher Correction: Genome-wide identification and expression analyses of the homeobox transcription factor family during ovule development in seedless and seeded grapes. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29150664 TI - Histological evidence for a dynamic dental battery in hadrosaurid dinosaurs. AB - The first histological study of an entire hadrosaurid dental battery provides a comprehensive look at tooth movement within this complex structure. Previous studies have focused on isolated teeth, or in-situ batteries, but this is the first study to examine an entire dental battery of any dinosaur. The absence of direct tooth-to-tooth contact across the entire battery and a unique arrangement of the dental tissues in hadrosaurids led us to compare their teeth with the ever growing incisors of mammals. The similarity in the distributions of tissues along the incisor, coupled with continuous eruption, make for helpful comparisons to hadrosaurid teeth. The mammalian ever-growing incisor can be used as a model to extrapolate the soft tissue connections and eruptive mechanisms within the hadrosaurid dental battery. Serial sections across the adult dental battery reveal signs of gradual ontogenetic tooth migration. Extensive remodeling of the alveolar septa and the anteroposterior displacement of successive generations of teeth highlight the gradual migration of tooth generations within the battery. These eruptive and ontogenetic tooth movements would not be possible without a ligamentous connection between successive teeth and the jaws, underscoring the dynamic nature of one of the most unique and complex dental systems in vertebrate history. PMID- 29150665 TI - A streamlined cloning workflow minimising the time-to-strain pipeline for Pichia pastoris. AB - Although recent advances in E. coli self-assembly have greatly simplified cloning, these have not yet been harnessed for the high-throughput generation of expression strains in the early research and discovery phases of biopharmaceutical production. Here, we have refined the technique and incorporated it into a streamlined workflow for the generation of Pichia pastoris expression strains, reducing the timeline by a third and removing the reliance on DNA editing enzymes, which often require troubleshooting and increase costs. We have validated the workflow by cloning 24 human proteins of biopharmaceutical value, either as direct therapeutics or as research targets, which span a continuous range in size and GC content. This includes demonstrating the applicability of the workflow to three-part assemblies for a monoclonal antibody and its single-chain antibody fragments derivatives. This workflow should enable future research into recombinant protein production by P. pastoris and a synthetic biology approach to this industrial host. PMID- 29150666 TI - Dogs' reaction to inequity is affected by inhibitory control. AB - Inequity aversion is thought to act as a mechanism to ensure cooperation and has been studied in many different species, consistently revealing inter-individual variation. Inhibitory control has been proposed to act as one factor responsible for this variation since individuals need to inhibit performing the required action and/or refuse rewards in order to exhibit inequity aversion. Here, we investigated if dogs' sensitivity to inequity is affected by their capacity for inhibitory control, assessed in a test battery and questionnaire. Overall, dogs showing high compulsivity scores (i.e. repetitive behaviours independent of feedback) were more motivated to participate in the inequity task independent of the rewarding scheme. Dogs were more sensitive to inequity and individual contrast if they exhibited a slower decision speed in the inhibition tasks. Furthermore, less persistent and more impulsive dogs were more sensitive to reward inequity, potentially due to having a lower tolerance level for frustration. Results indicate that aspects of inhibitory control can explain the variation in dogs' inequity response, highlighting one of the mechanisms underlying responses to inequity. Emphasising the importance to design paradigms, which allow us to disentangle capacities to recognise inequity from the inability to react to it due to poor inhibitory control abilities. PMID- 29150667 TI - A molecular mechanism of symmetry breaking in the early chick embryo. AB - The first obvious sign of bilateral symmetry in mammalian and avian embryos is the appearance of the primitive streak in the future posterior region of a radially symmetric disc. The primitive streak marks the midline of the future embryo. The mechanisms responsible for positioning the primitive streak remain largely unknown. Here we combine experimental embryology and mathematical modelling to analyse the role of the TGFbeta-related molecules BMP4 and Vg1/GDF1 in positioning the primitive streak. Bmp4 and Vg1 are first expressed throughout the embryo, and then become localised to the future anterior and posterior regions of the embryo, where they will, respectively, inhibit or induce formation of the primitive streak. We propose a model based on paracrine signalling to account for the separation of the two domains starting from a homogeneous array of cells, and thus for the topological transformation of a radially symmetric disc to a bilaterally symmetric embryo. PMID- 29150668 TI - Publisher Correction: The influence of liposomal quercetin on liver damage induced by microwave ablation. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29150669 TI - Genome-wide survey indicates diverse physiological roles of the turnip (Brassica rapa var. rapa) calcium-dependent protein kinase genes. AB - Calcium-dependent protein kinases (CDPKs) as crucial sensors of calcium concentration changes play important roles in responding to abiotic and biotic stresses. In this study, 55 BrrCDPK genes, which were phylogenetically clustered into four subfamilies, were identified. Chromosome locations indicated that the CDPK family in turnip expanded by segmental duplication and genome rearrangement. Moreover, gene expression profiles showed that different BrrCDPKs were expressed in specific tissues or stages. Transcript levels of BrrCDPKs indicated that they were involved in abiotic and biotic stresses and that paralogs exhibited functional divergence. Additionally, we identified 15 Rboh genes in turnip; the results of yeast two-hybrid analysis suggested that BrrRbohD1 interacted only with BrrCDPK10 and that BrrRbohD2 interacted with BrrCDPK4/7/9/10/17/22/23. Most of the genes play an important role in pst DC3000 defense by regulating the accumulation of H2O2 and stomatal closure. Our study may provide an important foundation for future functional analysis of BrrCDPKs and reveal further biological roles. PMID- 29150670 TI - Ultrahigh field MR imaging of a subconjunctival anti-glaucoma drug delivery system in a rabbit model. AB - Local drug delivery systems (DDS) have become a favourable approach for the treatment of numerous diseases. Biomedical imaging techniques such as ultrahigh field magnetic resonance imaging (UHF-MRI) offer unique insight into DDS biodegradation in vivo. We describe the establishment of a 7 Tesla MRI routine for longitudinal in vivo examinations of a subconjunctival DDS for the treatment of glaucoma in a rabbit model. In initial in vitro examinations the T2-relaxation times of the polymeric DDS components were assessed. Imaging of enzymatically degraded depot samples in vitro did not reveal changes in sample morphology or T2 relaxation time. Ex vivo investigations with an enucleated porcine eye showed good correlation of anatomical MRI and histological data. In longitudinal in vivo studies in rabbits, we repeatedly scanned the depot in the same animal over the course of 5 months with an in-plane resolution of 130 um at scan times of less than 30 minutes. The degradation was quantified using volumetric analysis showing a volume reduction of 82% between 3 and 21 weeks after depot implantation. We have thereby demonstrated the feasibility of our UHF-MRI protocol as a non invasive imaging routine for qualitative and quantitative, longitudinal evaluation of biodegradable subconjunctival DDS. PMID- 29150671 TI - Urothelial cancer proteomics provides both prognostic and functional information. AB - Traditionally, bladder cancer has been classified based on histology features. Recently, some works have proposed a molecular classification of invasive bladder tumors. To determine whether proteomics can define molecular subtypes of muscle invasive urothelial cancer (MIUC) and allow evaluating the status of biological processes and its clinical value. 58 MIUC patients who underwent curative surgical resection at our institution between 2006 and 2012 were included. Proteome was evaluated by high-throughput proteomics in routinely archive FFPE tumor tissue. New molecular subgroups were defined. Functional structure and individual proteins prognostic value were evaluated and correlated with clinicopathologic parameters. 1,453 proteins were quantified, leading to two MIUC molecular subgroups. A protein-based functional structure was defined, including several nodes with specific biological activity. The functional structure showed differences between subtypes in metabolism, focal adhesion, RNA and splicing nodes. Focal adhesion node has prognostic value in the whole population. A 6 protein prognostic signature, associated with higher risk of relapse (5 year DFS 70% versus 20%) was defined. Additionally, we identified two MIUC subtypes groups. Prognostic information provided by pathologic characteristics is not enough to understand MIUC behavior. Proteomics analysis may enhance our understanding of prognostic and classification. These findings can lead to improving diagnosis and treatment selection in these patients. PMID- 29150672 TI - FMNH2-dependent monooxygenases initiate catabolism of sulfonamides in Microbacterium sp. strain BR1 subsisting on sulfonamide antibiotics. AB - We report a cluster of genes encoding two monooxygenases (SadA and SadB) and one FMN reductase (SadC) that enable Microbacterium sp. strain BR1 and other Actinomycetes to inactivate sulfonamide antibiotics. Our results show that SadA and SadC are responsible for the initial attack of sulfonamide molecules resulting in the release of 4-aminophenol. The latter is further transformed into 1,2,4-trihydroxybenzene by SadB and SadC prior to mineralization and concomitant production of biomass. As the degradation products lack antibiotic activity, the presence of SadA will result in an alleviated bacteriostatic effect of sulfonamides. In addition to the relief from antibiotic stress this bacterium gains access to an additional carbon source when this gene cluster is expressed. As degradation of sulfonamides was also observed when Microbacterium sp. strain BR1 was grown on artificial urine medium, colonization with such strains may impede common sulfonamide treatment during co-infections with pathogens of the urinary tract. This case of biodegradation exemplifies the evolving catabolic capacity of bacteria, given that sulfonamide bacteriostatic are purely of synthetic origin. The wide distribution of this cluster in Actinomycetes and the presence of traA encoding a relaxase in its vicinity suggest that this cluster is mobile and that is rather alarming. PMID- 29150674 TI - Quantum steerability based on joint measurability. AB - Occupying a position between entanglement and Bell nonlocality, Einstein-Podolsky Rosen (EPR) steering has attracted increasing attention in recent years. Many criteria have been proposed and experimentally implemented to characterize EPR steering. Nevertheless, only a few results are available to quantify steerability using analytical results. In this work, we propose a method for quantifying the steerability in two-qubit quantum states in the two-setting EPR-steering scenario, using the connection between joint measurability and steerability. We derive an analytical formula for the steerability of a class of X-states. The sufficient and necessary conditions for two-setting EPR-steering are presented. Based on these results, a class of asymmetric states, namely, one-way steerable states, are obtained. PMID- 29150673 TI - Muller glial microRNAs are required for the maintenance of glial homeostasis and retinal architecture. AB - To better understand the roles of microRNAs in glial function, we used a conditional deletion of Dicer1 (Dicer-CKOMG) in retinal Muller glia (MG). Dicer1 deletion from the MG leads to an abnormal migration of the cells as early as 1 month after the deletion. By 6 months after Dicer1 deletion, the MG form large aggregations and severely disrupt normal retinal architecture and function. The most highly upregulated gene in the Dicer-CKOMG MG is the proteoglycan Brevican (Bcan) and overexpression of Bcan results in similar aggregations of the MG in wild-type retina. One potential microRNA that regulates Bcan is miR-9, and overexpression of miR-9 can partly rescue the effects of Dicer1 deletion on the MG phenotype. We also find that MG from retinitis pigmentosa patients display an increase in Brevican immunoreactivity at sites of MG aggregation, linking the retinal remodeling that occurs in chronic disease with microRNAs. PMID- 29150675 TI - Mechanisms by which in vitro meiotic arrest and sexual maturity improve developmental potential of mouse oocytes. AB - To study the relationship between chromatin condensation, gene transcription and developmental competence during oocyte maturation and to explore the mechanisms by which meiotic arrest maintenance (MAM) and sexual maturity improve oocyte competence, we examined effects of MAM with roscovitine or db-cAMP on chromatin condensation, gene transcription and developmental potential of NSN or SN oocytes from prepubertal or adult mice. MAM with roscovitine improved the developmental competence and global gene transcription of prepubertal NSN (prep-NSN) and adult SN oocytes while having no effect on those of prep-SN oocytes. MAM with db-cAMP facilitated neither development nor transcription in any type of oocytes. MAM with either roscovitine or db-cAMP promoted chromatin condensation of prep-NSN oocytes. MAM with roscovitine promoted gene transcription and chromatin condensation simultaneously through inhibiting cyclin-dependent kinase (CDK) 5 and 2, respectively. The results suggested that MAM with roscovitine improved oocyte competence by promoting gene transcription via inhibiting CDK5. Oocyte cytoplasmic maturation is correlated with gene transcription but not with chromatin condensation. The difference in developmental competence between prepubertal NSN and SN oocytes and between prepubertal and adult SN oocytes was because while the former had not, the latter had completed or acquired the ability for transcription of important genes. PMID- 29150676 TI - Severe Pollution in China Amplified by Atmospheric Moisture. AB - In recent years, severe haze events often occurred in China, causing serious environmental problems. The mechanisms responsible for the haze formation, however, are still not well understood, hindering the forecast and mitigation of haze pollution. Our study of the 2012-13 winter haze events in Beijing shows that atmospheric water vapour plays a critical role in enhancing the heavy haze events. Under weak solar radiation and stagnant moist meteorological conditions in winter, air pollutants and water vapour accumulate in a shallow planetary boundary layer (PBL). A positive feedback cycle is triggered resulting in the formation of heavy haze: (1) the dispersal of water vapour is constrained by the shallow PBL, leading to an increase in relative humidity (RH); (2) the high RH induces an increase of aerosol particle size by enhanced hygroscopic growth and multiphase reactions to increase particle size and mass, which results in (3) further dimming and decrease of PBL height, and thus further depressing of aerosol and water vapour in a very shallow PBL. This positive feedback constitutes a self-amplification mechanism in which water vapour leads to a trapping and massive increase of particulate matter in the near-surface air to which people are exposed with severe health hazards. PMID- 29150678 TI - Dog ownership and the risk of cardiovascular disease and death - a nationwide cohort study. AB - Dogs may be beneficial in reducing cardiovascular risk in their owners by providing social support and motivation for physical activity. We aimed to investigate the association of dog ownership with incident cardiovascular disease (CVD) and death in a register-based prospective nation-wide cohort (n = 3,432,153) with up to 12 years of follow-up. Self-reported health and lifestyle habits were available for 34,202 participants in the Swedish Twin Register. Time to-event analyses with time-updated covariates were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). In single- and multiple-person households, dog ownership (13.1%) was associated with lower risk of death, HR 0.67 (95% CI, 0.65-0.69) and 0.89 (0.87-0.91), respectively; and CVD death, HR 0.64 (0.59-0.70), and 0.85 (0.81-0.90), respectively. In single-person households, dog ownership was inversely associated with cardiovascular outcomes (HR composite CVD 0.92, 95% CI, 0.89-0.94). Ownership of hunting breed dogs was associated with lowest risk of CVD. Further analysis in the Twin Register could not replicate the reduced risk of CVD or death but also gave no indication of confounding by disability, comorbidities or lifestyle factors. In conclusion, dog ownership appears to be associated with lower risk of CVD in single-person households and lower mortality in the general population. PMID- 29150677 TI - Phosphatidylserine decarboxylase CT699, lysophospholipid acyltransferase CT775, and acyl-ACP synthase CT776 provide membrane lipid diversity to Chlamydia trachomatis. AB - De novo lipid synthesis and scavenging of fatty acids (FA) are processes essential for the formation of the membrane of the human pathogen Chlamydia trachomatis (C.t.). Host FA are assimilated via esterification by the bacterial acyl-acyl carrier protein (ACP) synthase AasC but inhibitors of the host acyl-CoA synthetase enymes ACSL also impaired growth of C.t. in human cells. In E. coli, activity of AasC was sensitive to triacsin C and rosiglitazone G. The absence of a triacsin C-insensitive pathway and the increased inhibition by rosiglitazone G confirmed the sensitivity of the bacterial acyl-ACP synthase to these drugs in infected human cells. We found no evidence that the human ACSL enzymes are required for lipid formation by C.t. The broad substrate specificity of acyltransferase CT775 provides C.t. with the capacity to incorporate straight chain and bacterial specific branched-chain fatty acids. CT775 accepts both acyl ACP and acyl-CoA as acyl donors and, 1- or 2-acyl isomers of lysophosphoplipids as acyl acceptors. The enzyme responsible for remodeling of human phosphatidylserine to bacterial phosphatidylethanolamine was identified as CT699. These findings provide evidence that the pathogen has the ability to extend the lipid diversity of its membrane. PMID- 29150679 TI - Dynamics of high frequency brain activity. AB - Evidence suggests that electroencephalographic (EEG) activity extends far beyond the traditional frequency range. Much of the prior study of >120 Hz EEG is in epileptic brains. In the current work, we measured EEG activity in the range of 200 to 2000 Hz, in the brains of healthy, spontaneously behaving rats. Both arrhythmic (1/f-type) and rhythmic (band) activities were identified and their properties shown to depend on EEG-defined stage of sleep/wakefulness. The inverse power law exponent of 1/f-type noise is shown to decrease from 3.08 in REM and 2.58 in NonREM to a value of 1.99 in the Waking state. Such a trend represents a transition from long- to short-term memory processes when examined in terms of the corresponding Hurst index. In addition, treating the 1/f-type activity as baseline noise reveals the presence of two, newly identified, high frequency EEG bands. The first band (psi) is centered between 260-280 Hz; the second, and stronger, band is a broad peak in the 400-500 Hz range (termed omega). Both of these peaks display lognormal distributions. The functional significance of these frequency bands is supported by the variation in the strength of the peaks with EEG-defined sleep/wakefulness. PMID- 29150680 TI - Potential landscape of high dimensional nonlinear stochastic dynamics with large noise. AB - Quantifying stochastic processes is essential to understand many natural phenomena, particularly in biology, including the cell-fate decision in developmental processes as well as the genesis and progression of cancers. While various attempts have been made to construct potential landscape in high dimensional systems and to estimate transition rates, they are practically limited to the cases where either noise is small or detailed balance condition holds. A general and practical approach to investigate real-world nonequilibrium systems, which are typically high-dimensional and subject to large multiplicative noise and the breakdown of detailed balance, remains elusive. Here, we formulate a computational framework that can directly compute the relative probabilities between locally stable states of such systems based on a least action method, without the necessity of simulating the steady-state distribution. The method can be applied to systems with arbitrary noise intensities through A-type stochastic integration, which preserves the dynamical structure of the deterministic counterpart dynamics. We demonstrate our approach in a numerically accurate manner through solvable examples. We further apply the method to investigate the role of noise on tumor heterogeneity in a 38-dimensional network model for prostate cancer, and provide a new strategy on controlling cell populations by manipulating noise strength. PMID- 29150681 TI - The structure-function relationship measured with optical coherence tomography and a microperimeter with auto-tracking: the MP-3, in patients with retinitis pigmentosa. AB - The purpose of the current study was to investigate the structure-function relationship in patients with retinitis pigmentosa (RP) using optical coherence tomography and the MP-3 microperimeter. Visual field (VF) measurements were carried out using MP-3 microperimetry and the Humphrey Field Analyzer (HFA, Carl Zeiss, CA), 22 eyes of 11 patients with a clinical diagnosis of RP, both with the 10-2 test grid pattern. Optical coherence tomography (OCT, Spectralis, Heidelberg, Germany) was also performed and the ellipsoid zone (EZ) was identified in the OCT image. The mean (+/-SD) number of test points located within the EZ edge was 11.6 (+/-5.9). There was a significant relationship between mean retinal sensitivity measured with MP-3 and the area surrounded by the EZ circular line: AEZ (p < 0.05), but this was not the case with HFA (p > 0.05). The difference between retinal sensitivity inside and outside the EZ edge was significantly larger with MP-3 than with HFA (p < 0.001). Our findings suggest that retinal sensitivity measured with MP-3 better reflects the magnitude of structural damage observed with OCT, compared with HFA. Further, the difference in retinal sensitivity between the inside and outside EZ edge is significantly larger for the MP-3 test, compared with the HFA. PMID- 29150682 TI - Enantioselective transformation of fluoxetine in water and its ecotoxicological relevance. AB - European legislation focusing on water quality is expected to broaden to encompass several pharmaceuticals as priority hazardous substances. This manuscript aims to challenge current regulatory approaches that do not recognize stereochemistry of chiral pharmaceuticals by testing the hypothesis that environmental transformation and effects of chiral pharmaceuticals are stereoselective. Our experiments revealed that, while degradation of chiral fluoxetine (FL) in river water occurs via non-enantioselective photochemical and mildly-enantioselective microbial processes favoring the (R)-enantiomer, a pronounced enantioselectivity favoring (S)-FL (leading to the formation of (S) NFL (norfluoxetine)) is observed during activated sludge treatment. Toxicity tests proved strong enantiomer-specific toxicity in the case of Tetrahymena thermophila, protozoa that are utilized during activated sludge treatment ((R)-FL is 30* more toxic than (S)-FL; (S)-NFL is 10* more toxic than (S)-FL). This is of paramount importance as preferential degradation of (S)-FL in activated sludge microcosms leads to the enrichment of FL with 30* more toxic (R)-FL and formation of 10* more toxic (S)-NFL. It is commonly assumed that a decreased concentration of FL leads to decreased biological impact. Our study proves that despite the overall decrease in FL concentration, accumulation of toxic (R)-FL and formation of toxic (S)-NFL leads to much higher than presumed toxicological effects. PMID- 29150683 TI - Null functions in three-dimensional imaging of alpha and beta particles. AB - Null functions of an imaging system are functions in the object space that give exactly zero data. Hence, they represent the intrinsic limitations of the imaging system. Null functions exist in all digital imaging systems, because these systems map continuous objects to discrete data. However, the emergence of detectors that measure continuous data, e.g. particle-processing (PP) detectors, has the potential to eliminate null functions. PP detectors process signals produced by each particle and estimate particle attributes, which include two position coordinates and three components of momentum, as continuous variables. We consider Charged-Particle Emission Tomography (CPET), which relies on data collected by a PP detector to reconstruct the 3D distribution of a radioisotope that emits alpha or beta particles, and show empirically that the null functions are significantly reduced for alpha particles if >=3 attributes are measured or for beta particles with five attributes measured. PMID- 29150686 TI - Twenty-first century botany. PMID- 29150684 TI - Global and Regional Effects of Bladder Cancer Risk Associated with Pioglitazone Therapy in Patients with Diabetes. AB - It has been debated for several years as to whether the antidiabetic drug pioglitazone increases the risk for bladder cancer. A series of recent large population studies yielded conflicting results. To investigate why the observational studies yielded conflicting results, we conducted stratified analyses to analyze the potential confounders behind these discordant outcomes. A total of 2,764,731 participants from observational (OB) studies and 9,999 from randomized control trials (RCTs) were identified for these analyses. The stratified analysis revealed that the study type, adjustment for age/sex, treatment duration, cumulative dose, agents used in a control group, mean period of follow-up and study population region might contribute to the discordant outcomes. In terms of population regions, pioglitazone increased the risk for bladder cancer could be found in European population, and patients who undergo treatment with pioglitazone for longer durations (>12 months) or are administrated a larger cumulative dose (>28,000 mg) might require more attention, and the long-term effects (>=3.6 years) of pioglitazone needs be monitored more carefully. PMID- 29150688 TI - Crops can be strong and sensitive. PMID- 29150689 TI - Distinct genetic architectures for phenotype means and plasticities in Zea mays. AB - Phenotypic plasticity describes the phenotypic variation of a trait when a genotype is exposed to different environments. Understanding the genetic control of phenotypic plasticity in crops such as maize is of paramount importance for maintaining and increasing yields in a world experiencing climate change. Here, we report the results of genome-wide association analyses of multiple phenotypes and two measures of phenotypic plasticity in a maize nested association mapping (US-NAM) population grown in multiple environments and genotyped with ~2.5 million single-nucleotide polymorphisms. We show that across all traits the candidate genes for mean phenotype values and plasticity measures form structurally and functionally distinct groups. Such independent genetic control suggests that breeders will be able to select semi-independently for mean phenotype values and plasticity, thereby generating varieties with both high mean phenotype values and levels of plasticity that are appropriate for the target performance environments. PMID- 29150690 TI - Towards a universal model for carbon dioxide uptake by plants. AB - Gross primary production (GPP)-the uptake of carbon dioxide (CO2) by leaves, and its conversion to sugars by photosynthesis-is the basis for life on land. Earth System Models (ESMs) incorporating the interactions of land ecosystems and climate are used to predict the future of the terrestrial sink for anthropogenic CO21 . ESMs require accurate representation of GPP. However, current ESMs disagree on how GPP responds to environmental variations 1,2 , suggesting a need for a more robust theoretical framework for modelling 3,4 . Here, we focus on a key quantity for GPP, the ratio of leaf internal to external CO2 (chi). chi is tightly regulated and depends on environmental conditions, but is represented empirically and incompletely in today's models. We show that a simple evolutionary optimality hypothesis 5,6 predicts specific quantitative dependencies of chi on temperature, vapour pressure deficit and elevation; and that these same dependencies emerge from an independent analysis of empirical chi values, derived from a worldwide dataset of >3,500 leaf stable carbon isotope measurements. A single global equation embodying these relationships then unifies the empirical light-use efficiency model 7 with the standard model of C3 photosynthesis 8 , and successfully predicts GPP measured at eddy-covariance flux sites. This success is notable given the equation's simplicity and broad applicability across biomes and plant functional types. It provides a theoretical underpinning for the analysis of plant functional coordination across species and emergent properties of ecosystems, and a potential basis for the reformulation of the controls of GPP in next-generation ESMs. PMID- 29150691 TI - Mechanical regulation of organ asymmetry in leaves. AB - How appendages, such as plant leaves or animal limbs, develop asymmetric shapes remains a fundamental question in biology. Although ongoing research has revealed the genetic regulation of organ pattern formation, how gene activity ultimately directs organ shape remains unclear. Here, we show that leaf dorsoventral (adaxial-abaxial) polarity signals lead to mechanical heterogeneity of the cell wall, related to the methyl-esterification of cell-wall pectins in tomato and Arabidopsis. Numerical simulations predicate that mechanical heterogeneity is sufficient to produce the asymmetry seen in planar leaves. Experimental tests that alter pectin methyl-esterification, and therefore cell wall mechanical properties, support this model and lead to polar changes in gene expression, suggesting the existence of a feedback mechanism for mechanical signals in morphogenesis. Thus, mechanical heterogeneity within tissue may underlie organ shape asymmetry. PMID- 29150692 TI - Plants are not so different. PMID- 29150693 TI - A collection of genetically engineered Populus trees reveals wood biomass traits that predict glucose yield from enzymatic hydrolysis. AB - Wood represents a promising source of sugars to produce bio-based renewables, including biofuels. However, breaking down lignocellulose requires costly pretreatments because lignocellulose is recalcitrant to enzymatic saccharification. Increasing saccharification potential would greatly contribute to make wood a competitive alternative to petroleum, but this requires improving wood properties. To identify wood biomass traits associated with saccharification, we analyzed a total of 65 traits related to wood chemistry, anatomy and structure, biomass production and saccharification in 40 genetically engineered Populus tree lines. These lines exhibited broad variation in quantitative traits, allowing for multivariate analyses and mathematical modeling. Modeling revealed that seven wood biomass traits associated in a predictive manner with saccharification of glucose after pretreatment. Four of these seven traits were also negatively associated with biomass production, suggesting a trade-off between saccharification potential and total biomass, which has previously been observed to offset the overall sugar yield from whole trees. We therefore estimated the "total-wood glucose yield" (TWG) from whole trees and found 22 biomass traits predictive of TWG after pretreatment. Both saccharification and TWG were associated with low abundant, often overlooked matrix polysaccharides such as arabinose and rhamnose which possibly represent new markers for improved Populus feedstocks. PMID- 29150695 TI - New angle measurement device to control the posterior tibial slope angle in medial opening wedge high tibial osteotomy. AB - INTRODUCTION: Medial opening wedge high tibial osteotomy has been associated with an unintentional increase in the posterior tibial slope angle. We aimed to evaluate the effectiveness of a novel bone spreader angle rod to maintain the native posterior tibial slope angle in medial opening wedge high tibial osteotomy. MATERIALS AND METHODS: Data from 92 consecutive knees in 83 patients who underwent medial opening wedge high tibial osteotomy for knee osteoarthritis between March 2015 and June 2016 were analysed. The osteotomy was performed without the use of a bone spreader angle rod in the first 50 cases (control group) and with the use of the angle rod in the subsequent 42 cases (angle rod group). The wedge insertion angle, defined as the angle between a line drawn along the posterior aspect of the wedge spacer and a line tangential to the posterior aspect of the femoral condyles, and the posterior tibial slope angle were evaluated on pre- and postoperative lateral knee radiographs and postoperative computed tomography images. RESULTS: Wedge insertion angle showed that wedge spacers were inserted in a more direct horizontal direction in the angle rod group than in the control group (16.0 +/- 8.8 degrees and 23.0 +/- 10.0 degrees , respectively, P < 0.001). The pre- to postoperative change in posterior tibial slope angle was significantly smaller in the angle rod group (0.6 +/- 1.6 degrees ) compared to that in the control group (3.2 +/- 3.2 degrees ; P < 0.0001). A change of posterior tibial slope angle > 3 degrees (outlier) was identified in 1 case (2.4%) in the angle rod group compared to 27 cases in the control group (54.0%). CONCLUSIONS: The direct horizontal insertion of wedge spacers with the assistance of our novel bone spreader angle rod maintains the native posterior tibial slope angle better than conventional methods. LEVEL OF EVIDENCE: IV. PMID- 29150694 TI - Inhibition of intimal hyperplasia in murine aortic allografts by administration of a small-molecule TLR4 inhibitor TAK-242. AB - Graft arteriosclerosis (GA) is the leading cause of late cardiac allograft dysfunction. The innate immune system plays a major role in GA, paprticularly Toll-like receptor 4 (TLR4) signaling. Here we characterized the role of TLR4 and its antagonist TAK-242 in a mouse model of GA. BALB/c (H-2d) donor aortas were transplanted into C57BL/6 (H-2b) recipients, and the mice received intraperitoneal injection of 3 or 10 mg/kg of TAK-242 or vehicle every other day for 1, 2, 4, 6, 8 and 12 weeks. With TAK-242 administration, intimal hyperplasia initially appeared at 2 weeks after transplantation, and TAK-242 postponed the progression of neointimal formation in allogeneic aortic grafts. TAK-242 treatment reduced CD68+ macrophage accumulation in the allografts, reduced the levels of ly-6Chi monocytes in peripheral blood, bone marrow and spleen, and downregulated proinflammatory cytokine and chemokine levels. Ex vivo we observed that TAK-242 could improve the graft microenvironment by interfering the Tck/Mphi IL12p70 and IFNgamma axis, reducing CCL2-mediated migration of vascular smooth cells. PMID- 29150696 TI - Impact of prolonged overfeeding on skeletal muscle mitochondria in healthy individuals. AB - AIMS/HYPOTHESES: Reduced mitochondrial capacity in skeletal muscle has been observed in obesity and type 2 diabetes. In humans, the aetiology of this abnormality is not well understood but the possibility that it is secondary to the stress of nutrient overload has been suggested. To test this hypothesis, we examined whether sustained overfeeding decreases skeletal muscle mitochondrial content or impairs function. METHODS: Twenty-six healthy volunteers (21 men, 5 women, age 25.3 +/- 4.5 years, BMI 25.5 +/- 2.4 kg/m2) underwent a supervised protocol consisting of 8 weeks of high-fat overfeeding (40% over baseline energy requirements). Before and after overfeeding, we measured systemic fuel oxidation by indirect calorimetry and performed skeletal muscle biopsies to measure mitochondrial gene expression, content and function in vitro. Mitochondrial function in vivo was measured by 31P NMR spectroscopy. RESULTS: With overfeeding, volunteers gained 7.7 +/- 1.8 kg (% change 9.8 +/- 2.3). Overfeeding increased fasting NEFA, LDL-cholesterol and insulin concentrations. Indirect calorimetry showed a shift towards greater reliance on lipid oxidation. In skeletal muscle tissue, overfeeding increased ceramide content, lipid droplet content and perilipin-2 mRNA expression. Phosphorylation of AMP-activated protein kinase was decreased. Overfeeding increased mRNA expression of certain genes coding for mitochondrial proteins (CS, OGDH, CPT1B, UCP3, ANT1). Despite the stress of nutrient overload, mitochondrial content and mitochondrial respiration in muscle did not change after overfeeding. Similarly, overfeeding had no effect on either the emission of reactive oxygen species or on mitochondrial function in vivo. CONCLUSIONS/INTERPRETATION: Skeletal muscle mitochondria are significantly resilient to nutrient overload. The lower skeletal muscle mitochondrial oxidative capacity in human obesity is likely to be caused by reasons other than nutrient overload per se. TRIAL REGISTRATION: ClinicalTrials.gov NCT01672632. PMID- 29150697 TI - A novel allele of TaGW2-A1 is located in a finely mapped QTL that increases grain weight but decreases grain number in wheat (Triticum aestivum L.). AB - KEY MESSAGE: A novel TaGW2-A1 allele was identified from a stable, robust QTL region, which is pleiotropic for thousand grain weight, grain number per spike, and grain morphometric parameters in wheat. Thousand grain weight (TGW) and grain number per spike (GNS) are two crucial determinants of wheat spike yield, and genetic dissection of their relationships can help to fine-tune these two components and maximize grain yield. By evaluating 191 recombinant inbred lines in 11 field trials, we identified five genomic regions on chromosomes 1B, 3A, 3B, 5B, or 7A that solely influenced either TGW or GNS, and a further region on chromosome 6A that concurrently affected TGW and GNS. The QTL of interest on chromosome 6A, which was flanked by wsnp_BE490604A_Ta_2_1 and wsnp_RFL_Contig1340_448996 and designated as QTgw/Gns.cau-6A, was finely mapped to a genetic interval shorter than 0.538 cM using near isogenic lines (NILs). The elite NILs of QTgw/Gns.cau-6A increased TGW by 8.33%, but decreased GNS by 3.05% in six field trials. Grain Weight 2 (TaGW2-A1), a well-characterized gene that negatively regulates TGW and grain width in wheat, was located within the finely mapped interval of QTgw/Gns.cau-6A. A novel and rare TaGW2-A1 allele with a 114 bp deletion in the 5' flanking region was identified in the parent with higher TGW, and it reduced TaGW2-A1 promoter activity and expression. In conclusion, these results expand our knowledge of the genetic and molecular basis of TGW-GNS trade-offs in wheat. The QTLs and the novel TaGW2-A1 allele are likely useful for the development of cultivars with higher TGW and/or higher GNS. PMID- 29150698 TI - Surgical techniques for left atrial appendage exclusion. AB - The increasing prevalence of atrial fibrillation with the aging population and its associated major morbidity and mortality due to thromboembolic stroke have resulted in intensive research on stroke prevention or stroke risk reduction strategies. Several surgical techniques for left atrial appendage (LAA) occlusion have evolved over the past decades. Surgeons have been using different techniques leading to highly variable and, in particular, poor data on outcomes. LAA closure is performed either as a concomitant procedure during open-heart surgery or as a stand-alone surgical procedure as part of minimally invasive (mini-thoracotomy or thoracoscopy) arrhythmia surgery. Data on the safety and feasibility of surgical LAA occlusion are derived mainly from nonrandomized case series, observational and cohort studies, or registries with mostly inconclusive and conflicting results. Increased awareness of the high failure rates in attaining complete LAA occlusion, thus avoiding poor surgical techniques (e. g., simple suture ligation, endocardial suturing etc.), and the availability of newer devices (e. g., AtriClip device) have recently led to improved surgical results in the literature. If further validated in large-scale studies, these recent promising developments in the field of surgical LAA treatment seem to offer alternatives for patients ineligible for oral anticoagulation therapy with vitamin K antagonists or newer non-vitamin-K-dependent oral anticoagulants. PMID- 29150699 TI - Three new species of Gyrodactylus von Nordmann, 1832 described from Goodea atripinnis (Pisces: Goodeidae), an endemic freshwater fish from the central highlands of Mexico. AB - Goodea atripinnis Jordan, 1880 has a broad range of habitats and is the most widespread species of the endemic goodeid fishes, which inhabit the central highlands of Mexico. This species is known to be host to a high diversity of helminth parasites from which only three belong to the genus Gyrodactylus von Nordmann, 1832: G. lamothei Mendoza-Palmero, Sereno-Uribe et Salgado-Maldonado, 2009, G. mexicanus Mendoza-Palmero, Sereno-Uribe et Salgado-Maldonado, 2009, and G. tomahuac Rubio-Godoy, Razo-Mendivil, Garcia-Vasquez, Freeman, Shinn et Paladini, 2016. Here, we describe three new species of Gyrodactylus collected from G. atripinnis, which were characterised morphologically (sclerites of the attachment apparatus) and molecularly (sequences of the internal transcribed spacer region of the rDNA): Gyrodactylus iunuri n. sp., Gyrodactylus katamba n. sp. and Gyrodactylus tepari n. sp. These new species were collected in three different states in the Mexican Highlands: Guanajuato, Jalisco and Queretaro. Both morphological and molecular data support the hypothesis that two distinct groups of gyrodactylids infect goodeid fishes: G. iunuri n. sp., G. tepari n. sp. and G. tomahuac possess robust hamuli and are closely related phylogenetically; while G. katamba n. sp. resembles G. lamothei in having slender hamuli with accessory sclerites adjacent to the hamuli root, and apparently shares a common ancestor with gyrodactylids infecting poeciliid fishes. New locality records of G. tomahuac are presented. The addition of the three new species of Gyrodactylus as parasites of G. atripinnis makes monogeneans the second most abundant parasite group known to infect this host. PMID- 29150700 TI - Prevalence of intestinal parasites in companion dogs with diarrhea in Beijing, China, and genetic characteristics of Giardia and Cryptosporidium species. AB - Companion animals including dogs are one of the important components in One Health. Parasites may cause not only diseases in pet animals but also many zoonotic diseases infecting humans. In this study, we performed a survey of intestinal parasites in fecal specimens (n = 485) collected from outpatient pet dogs with diarrhea in Beijing, China, for the entire year of 2015 by microscopic examination (all parasites) and SSU rRNA-based nested PCR detection (Giardia and Cryptosporidium). We observed a total of 124 (25.6%) parasite-positive specimens that contained one or more parasites, including Giardia duodenalis (12.8%), Cryptosporidium spp. (4.9%), Cystoisospora spp. (4.3%), trichomonads (4.3%), Toxocara canis (3.5%), Trichuris vulpis (0.6%), and Dipylidium caninum (0.2%). Among the 55 dog breeds, infection rates were significantly higher in border collies and bulldogs, but lower in poodles (p < 0.05). Risk factor analysis suggested that age was negatively correlated with the infection rate (p < 0.00001), while vaccination and deworming in the past 12 months could significantly reduce the parasite infections (p < 0.01). Among the 62 Giardia positive specimens, 21 were successfully assigned into assemblages using glutamate dehydrogenase (gdh) and/or beta-giardin (bg) genes, including assemblage D (n = 15), C (n = 5), and F (n = 1). Among the 24 Cryptosporidium positive specimens by SSU rRNA PCR, 20 PCR amplicons could be sequenced and identified as Cryptosporidium canis (n = 20). Collectively, this study indicates that parasites are a significant group of pathogens in companion dogs in Beijing, and companion dogs may potentially transmit certain zoonotic parasites to humans, particularly those with weak or weakened immunity. PMID- 29150701 TI - Process development of oxalic acid production in submerged culture of Aspergillus niger F22 and its biocontrol efficacy against the root-knot nematode Meloidogyne incognita. AB - Oxalic acid has potent nematicidal activity against the root-knot nematode Meloidogyne incognita. In this study, fermentation parameters for oxalic acid production in submerged culture of Aspergillus niger F22 at 23, 25, and 30 degrees C were optimized in 5-L jar fermenters. The viscosity of the culture broth increased with increasing temperature. There was a negative correlation between oxalic acid production and the apparent viscosity; high volumetric productivity of oxalic acid was obtained at low apparent viscosity (less than 1000 cP), with a productivity of more than 100 mg/L h. When the apparent viscosity was over 2500 cP, the volumetric productivity decreased below 50 mg/L h. In addition, the volumetric mass transfer coefficient, K L a, positively correlated with volumetric productivity. When the K L a value increased from 0.0 to 0.017 /s, the volumetric productivity proportionally increased up to 176 mg/L h. When the temperature decreased, K L a increased due to the decrease in viscosity, leading to increased volumetric productivity. The highest productivity of 7453.3 mg/L was obtained at the lowest temperature, i.e., 23 degrees C. The nematicidal activity of culture filtrate was proportional to the content of oxalic acid. Based on a constant impeller tip speed, oxalic acid production was successfully scaled up to a 500-L pilot vessel, producing a final concentration comparable to that in the 5-L jar. PMID- 29150702 TI - High PDL1 mRNA expression predicts better survival of stage pT1 non-muscle invasive bladder cancer (NMIBC) patients. AB - INTRODUCTION AND OBJECTIVES: Checkpoint inhibition has emerged as new therapeutic option in muscle-invasive bladder cancer. The objective of the present study was to evaluate the prognostic role of PD1 and PDL1 expression in non-muscle-invasive bladder cancer (NMIBC) and establish an objective measuring method using RNA quantification. MATERIALS AND METHODS: We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder. mRNA expression of PD1, PDL1 and CD3 was measured by single step RT-qPCR and correlated to clinicopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS) and carcinoma-specific survival (CSS). RESULTS: We have analyzed 334 patients with NMIBC at stage pT1 for mRNA analysis. Data from 296 patients (79% male, median age: 72 years) could be used. Spearman correlation revealed significant associations between mRNA expressions of PD1/PDL1 (rho: 0.6024, p < 0.0001), CD3/PDL1 (rho: 0.5728, p < 0.0001) and CD3/PD1 (rho: 0.7005, p < 0.0001). Kaplan-Meier analysis revealed that high PDL1 mRNA expression (>= 33.83) is a favorable prognostic factor with regard to better RFS (p = 0.0018), PFS (p = 0.021) and CSS (p = 0.012). Multivariate Cox-regression analysis proved PDL1 expression to be an independent prognosticator for RFS [HR 0.48 (0.31-0.72), p = 0.0005], PFS [HR 0.45 (0.24-0.80), p = 0.0059] and CSS [HR 0.31 (0.13-0.67), p = 0.0021]. CONCLUSION: High mRNA expression of PDL1 predicts improved RFS, PFS and CSS of pT1 NMIBC. Following prospective validation, this objective measurement of PD-L1 might help stratify patients with NMIBC for immunotherapy and identify patients who might benefit from early cystectomy. PMID- 29150703 TI - Transcriptome Analysis Reveals the Mechanism of Fungicidal of Thymol Against Fusarium oxysporum f. sp. niveum. AB - Fusarium oxysporum: f. sp. niveum (Fusarium oxysporum) causes watermelon wilt, drastically reducing its yield. Thymol (5-methyl-2-(1-methylethyl) phenol, PubChem CID: 6989) has been extensively reported to have antimicrobial activity against pathogenic microorganisms. In this study, the growth of F. oxysporum was significantly inhibited by thymol in vitro. The dry weight of F. oxysporum was decreased significantly. Thymol-induced cell membrane damage was observed at 24 hpi (hours post-incubation). Therefore, the changes in the gene expression level of F. oxysporum after treatment with 80 MUg/mL (average EC50 value) of thymol were analyzed using RNA-Seq to reveal the underlying fungicidal mechanisms of thymol. Among the 5057 differentially expressed genes (DEGs), 2440 and 2617 were up-regulated and down-regulated, respectively. Bioinformatics analysis demonstrated that the expression levels of most genes, including glycosphingolipid biosynthesis and sphingolipid metabolism, were down-regulated. However, the genes involved in antioxidant activity, chitin biosynthesis, and cell wall modification were up-regulated. These results were verified by quantitative reverse transcription PCR (qRT-PCR). According to these results, thymol produces reactive oxygen species (ROS) accumulation and destroys the integrity of the cell wall and cell membrane by inhibiting the genes involved in cell wall and cell membrane synthesis. PMID- 29150704 TI - Evaluation of immune-mediated idiosyncratic drug toxicity using chimeric HLA transgenic mice. AB - Immune-mediated idiosyncratic drug toxicity (IDT) is a rare adverse drug reaction, potentially resulting in death. Although genome-wide association studies suggest that the occurrence of immune-mediated IDT is strongly associated with specific human leukocyte antigen (HLA) allotypes, these associations have not yet been prospectively demonstrated. In this study, we focused on HLA-B*57:01 and abacavir (ABC)-induced immune-mediated IDT, and constructed transgenic mice carrying chimeric HLA-B*57:01 (B*57:01-Tg) to determine if this in vivo model may be useful for evaluating immune-mediated IDT. Local lymph node assay (LLNA) results demonstrated that percentages of BrdU+, IL-2+, and IFN-gamma+ in CD8+ T cells of ABC (50 mg/kg/day)-applied B*57:01-Tg mice were significantly higher than those in littermates (LMs), resulting in the infiltration of inflammatory cells into the ear. These immune responses were not observed in B*57:03-Tg mice (negative control). Furthermore, oral administration of 1% (v/v) ABC significantly increased the percentage of CD44highCD62Llow CD8+ memory T cells in lymph nodes and spleen derived from B*57:01-Tg mice, but not in those from B*57:03-Tg mice and LMs. These results suggest that B*57:01-Tg mice potentially enable the reproduction and evaluation of HLA-B*57:01 and ABC-induced immune mediated IDT. PMID- 29150705 TI - Novel polycondensed biopolyamide generated from biomass-derived 4 aminohydrocinnamic acid. AB - Biomass plastics are expected to contribute to the establishment of a carbon neutral society by replacing conventional plastics derived from petroleum. The biomass-derived aromatic amine 4-aminocinnamic acid (4ACA) produced by recombinant bacteria is applied to the synthesis of high-performance biopolymers such as polyamides and polyimides. Here, we developed a microbial catalyst that hydrogenates the alpha,beta-unsaturated carboxylic acid of 4ACA to generate 4 aminohydrocinnamic acid (4AHCA). The ability of 10 microbial genes for enoate and xenobiotic reductases expressed in Escherichia coli to convert 4ACA to 4AHCA was assessed. A strain producing 2-enoate reductase from Clostridium acetobutylicum (ca2ENR) reduced 4ACA to 4AHCA with a yield of > 95% mol mol-1 and reaction rates of 3.4 +/- 0.4 and 4.4 +/- 0.6 mM h-1 OD600-1 at the optimum pH of 7.0 under aerobic and anaerobic conditions, respectively. This recombinant strain reduced caffeic, cinnamic, coumaric, and 4-nitrocinnamic acids to their corresponding propanoic acid derivatives. We polycondensed 4AHCA generated from biomass-derived 4ACA by dehydration under a catalyst to form high-molecular-weight poly(4AHCA) with a molecular weight of M n = 1.94 MDa. This polyamide had high thermal properties as indicated by a 10% reduction in weight at a temperature of T d10 = 394 degrees C and a glass transition temperature of T g = 240 degrees C. Poly(4AHCA) derived from biomass is stable at high temperatures and could be applicable to the production of high-performance engineering plastics. PMID- 29150706 TI - Application of directed evolution to develop ethanol tolerant Oenococcus oeni for more efficient malolactic fermentation. AB - Malolactic fermentation (MLF) is an important step in winemaking, which can be notoriously unreliable due to the fastidious nature of Oenococcus oeni. This study aimed to use directed evolution (DE) to produce a more robust strain of O. oeni having the ability to withstand high ethanol concentrations. DE involves an organism mutating and potentially adapting to a high stress environment over the course of extended cultivation. A continuous culture of O. oeni was established and exposed to progressively increasing ethanol content such that after approximately 330 generations, an isolate from this culture was able to complete MLF in high ethanol content medium earlier than its parent. The ethanol tolerance of a single isolate, A90, was tested to confirm the phenotype and its fermentation performance in wine. In order to investigate the genotypic differences in the evolved strain that led to the ethanol tolerance phenotype, the relative expression of a number of known stress response genes was compared between SB3 and A90. Notably, there was increase in hsp18 expression in 20% (v/v) ethanol by both strains with A90 exhibiting a higher degree of expression. This study is the first to use directed evolution for O. oeni strain improvement and confirms that this technique can be used successfully for the development of new candidate strains for the wine industry. This study also adds to the current knowledge on the genetic basis of ethanol tolerance in this bacterium. PMID- 29150707 TI - A guard-killer phage cocktail effectively lyses the host and inhibits the development of phage-resistant strains of Escherichia coli. AB - In recent years, after the emergence of a large number of multidrug-resistant bacteria, phages and phage-associated products for the prevention and control of bacterial disease have revealed prominent advantages as compared with antibiotics. However, bacteria are susceptible to becoming phage-resistant, thus severely limiting the application of phage therapy. In this study, Escherichia coli cells were incubated with lytic bacteriophages to obtain mutants that were resistant to the lytic phages. Then, bacteriophages against the phage-resistant variants were isolated and subsequently mixed with the original lytic phage to prepare a novel phage cocktail for bactericidal use. The data showed that our phage cocktail not only had notable bactericidal effects, including a widened host range and rapid lysis, but also decreased the generation and mutation frequency of phage-resistant strains in vitro. In addition, we tested our cocktail in a murine bacteremia model. The results suggested that compared with the single phage, fewer phage-resistant bacteria appeared during the treatment of phage cocktail, thus prolonging the usable time of the phage cocktail and improving its therapeutic effect in phage applications. Importantly, our preparation method of phage cocktail was proved to be generalizable. Because the bacteriophage against the phage-resistant strain is an ideal guard that promptly attacks potential phage resistance, this guard-killer dual-function phage cocktail provides a novel strategy for phage therapy that allows the natural ecology to be sustained. PMID- 29150708 TI - Production of arabitol from enzymatic hydrolysate of soybean flour by Debaryomyces hansenii fermentation. AB - Arabitol is a low-calorie sugar alcohol with anti-cariogenic properties. Enzymatic hydrolysate of soybean flour is a new renewable biorefinery feedstock containing hexose, pentose, and organic nitrogen sources. Arabitol production by Debaryomyces hansenii using soybean flour hydrolysate was investigated. Effects of medium composition, operating conditions, and culture stage (growing or stationary phase) were studied. Production was also compared at different culture volumes to understand the effect of dissolved oxygen concentration (DO). Main factors examined for medium composition effects were the carbon to nitrogen concentration ratio (C/N), inorganic (ammonium) to organic nitrogen ratio (I/O N), and sugar composition. Arabitol yield increased with increasing C/N ratio and a high I/O-N (0.8-1.0), suggesting higher yield at stationary phase of low pH (3.5-4.5). Catabolite repression was observed, with the following order of consumption: glucose > fructose > galactose > xylose > arabinose. Arabitol production also favored hexoses and, among hexoses, glucose. DO condition was of critical importance to arabitol production and cell metabolism. The yeast consumed pentoses (xylose and arabinose) only at more favorable DO conditions. Finally, arabitol was produced in fermentors using mixed hydrolysates of soy flour and hulls. The process gave an arabitol yield of 54%, volumetric productivity of 0.90 g/L-h, and specific productivity of 0.031 g/g-h. PMID- 29150709 TI - Simultaneous detection of NADPH consumption and H2O2 production using the AmplifluTM Red assay for screening of P450 activities and uncoupling. AB - Cytochrome P450s belong to a large and diverse group of heme-containing enzymes. These monooxygenases catalyze the incorporation of a single atom of molecular oxygen into their substrate. In contrast to most other enzymes, the activity of P450 enzymes is not only dependent on substrate and cofactor availability and reaction conditions, but also depends on the coupling efficiency of the catalytic cycle itself. Through the electron transfer from NAD(P)H to the heme-center of the P450, the enzyme becomes activated and binds oxygen. The thereby generated iron-oxygen complex undergoes multiple reductive steps forming different activated oxygen species. These intermediates can decay easily, releasing the reactive oxygen species superoxide anion and hydrogen peroxide (H2O2), which can also be further reduced to water. This so-called uncoupling of the reaction cycle drains electrons from the system, which consequently does not lead to the desired product, but merely H2O2 formation with stoichiometric consumption of NAD(P)H. Hence, measuring NAD(P)H consumption only can lead to an overestimation of substrate conversion. To measure this uncoupling, we herein report a microtiter plate-based assay for the simultaneous quantification of hydrogen peroxide formation and NAD(P)H consumption using AmplifluTM Red as reporter. This was exemplified for the P450 monooxygenase from Bacillus megaterium (P450 BM3) and five mutants, using different substrates. We demonstrate the applicability of the assay, which provides a versatile basis for a high-throughput preliminary screening of P450 enzyme libraries without the need for GC or HPLC analysis and clear indication of the extent of hydrogen peroxide uncoupling. PMID- 29150710 TI - Computed Tomography Perfusion is a Useful Adjunct to Computed Tomography Angiography in the Diagnosis of Brain Death. AB - BACKGROUND: In the diagnosis of brain death (BD), computed tomography angiography (CTA) results in some cases show intracranial filling, leading to diagnostic confusion. Because cerebral circulatory arrest commences at the capillary level, we hypothesized that computed tomography perfusion (CTP) would be a more sensitive approach than CTA; therefore, the aim of the study was to compare the sensitivities of CTP and CTA in the diagnosis of BD. MATERIAL AND METHODS: Whole brain CTP was performed in patients in the intensive care unit diagnosed with BD and CTA was derived from CTP datasets. Cerebral blood flow (CBF) and volume (CBV) were calculated in all brain regions. The CTP findings were interpreted as being consistent with a diagnosis of BD (positive) when CBF and CBV in all regions of interest (ROIs) were below 10 ml/100 g/min and 1.0 ml/100 g, respectively. The CTA findings were interpreted using a 4-point grading system. RESULTS: A total of 50 patients were included in the study. The CTP results revealed CBF from 0.00 to 9.98 ml/100 g/min (mean, 1.98 +/- 1.68 ml/100 g/min) and CBV from 0.00 to 0.99 ml/100 g (mean, 0.14 +/- 0.12 ml/100 g) and were thus interpreted as positive in all 50 patients. In contrast, the CTA results suggested 7 negative cases, providing a sensitivity of 86%. The difference between the CTP and CTA sensitivity results for the diagnosis of BD was statistically significant (p = 0.006). CONCLUSION: Whole brain CTP may potentially be a feasible and highly sensitive test for diagnosing BD: therefore, performing CTP in combination with CTA in cases when CTA results are negative for BD could increase the sensitivity of CTA. PMID- 29150711 TI - Epidemiology of peritonitis following maintenance peritoneal dialysis catheter placement during infancy: a report of the SCOPE collaborative. AB - BACKGROUND: Maintenance peritoneal dialysis (PD) is the dialysis modality of choice for infants and young children. However, there are limited outcome data for those who undergo PD catheter insertion and initiate maintenance PD within the first year of life. METHODS: Using data from the Children's Hospital Association's Standardizing Care to Improve Outcomes in Pediatric End Stage Renal Disease (ESRD) Collaborative (SCOPE), we examined peritonitis rates and patient survival in 156 infants from 29 North American pediatric dialysis centers who had a chronic PD catheter placed prior to their first birthday. RESULTS: In-hospital and overall annualized rates of peritonitis were 1.73 and 0.76 episodes per patient-year, respectively. Polycystic kidney disease was the most frequent renal diagnosis and pulmonary hypoplasia the most common co-morbidity in infants with peritonitis. Multivariable regression models demonstrated that nephrectomy at or prior to PD catheter placement and G-tube insertion after catheter placement were associated with a nearly sixfold and nearly threefold increased risk of peritonitis, respectively. Infants with peritonitis had longer initial hospital stays and lower overall survival (86.3 vs. 95.6%, respectively; P < 0.02) than those without an episode of peritonitis. CONCLUSIONS: In this large cohort of infants with ESRD, the frequency of peritonitis was high and several risk factors associated with the development of peritonitis were identified. Given that peritonitis was associated with a longer duration of initial hospitalization and increased mortality, increased attention to the potentially modifiable risk factors for infection is needed. PMID- 29150712 TI - Unacylated ghrelin and obestatin: promising biomarkers of protein energy wasting in children with chronic kidney disease. AB - BACKGROUND: Impairment in orexigenic/anorexigenic hormone balance may be key in the pathogenesis of protein energy wasting in children with chronic kidney disease (CKD). Measurement of ghrelin and obestatin concentrations in children with CKD would help assess the potential contribution of these hormones to uremic protein energy wasting. METHODS: This was a cross-sectional case-control study. Acylated and unacylated ghrelin and obestatin were measured in 42 children on conservative treatment (CT), 20 children on hemodialysis, 48 pediatric renal transplant (RTx) recipients and 43 controls (CTR) (mean age 11.9, range 5-20 years). Weight, height and bicipital, tricipital, subscapular and suprailiac folds were measured, and the body mass index-standard deviation score (BMI-SDS), percentage of fat mass and fat-free mass were calculated. Urea and creatinine were measured and the glomerular filtration rate (GFR) calculated. RESULTS: Unacylated ghrelin level was higher in patients than controls (p = 0.0001), with the highest levels found in hemodialysis patients (p = 0.001 vs. CKD-CT, p = 0.0001 vs. RTx, p < 0.0001 vs. CTR). Obestatin level was significantly higher in patients on hemodialysis than those on conservative treatment, RTx recipients and controls (p < 0.0001 in each case). Unacylated ghrelin negatively correlated with weight-SDS (p < 0.0001), BMI-SDS (p = 0.0005) and percentage fat mass (p = 0.004) and positively correlated with percentage fat-free mass (p = 0.004). Obestatin concentration negatively correlated with weight-SDS (p = 0.007). Unacylated ghrelin and obestatin concentrations positively correlated with creatinine and urea and inversely with eGFR, even after adjustments for gender, age, puberty and BMI-SDS (p < 0.0001 for each model). CONCLUSIONS: Unacylated ghrelin and obestatin, negatively related to renal function, seem to be promising inverse indicators of nutritional status in children with CKD. Potential therapeutic implications in terms of optimization of their removal in patients on hemodialysis could be hypothesized. PMID- 29150713 TI - Efficacy of Silexan in subthreshold anxiety: meta-analysis of randomised, placebo controlled trials. AB - Subthreshold psychiatric disorders do not fully meet the diagnostic criteria of syndromal disorders but may be associated with comparable disability. To investigate the anxiolytic effect of Silexan, an active substance from lavender oil for oral administration, in patients with subthreshold anxiety, a meta analysis that included all published trials with Silexan in this indication was performed. Three randomised, placebo-controlled trials in subthreshold anxiety disorders (anxiety disorder not otherwise specified, restlessness and agitation, mixed anxiety and depressive disorder) were included. Eligible participants with a baseline Hamilton Anxiety Rating Scale (HAMA) total score >= 18 points received 1 * 80 mg/day Silexan or placebo for 10 weeks. Outcomes included the HAMA, the Pittsburgh Sleep Quality Index, the Zung Self-rating Anxiety Scale, the Clinical Global Impressions questionnaire and the SF-36 health status inventory. Data were analysed using meta-analysis based on pooled raw data of individual patients (random effects models). A total of 697 patients were assessed for efficacy. Silexan was superior to placebo in reducing the HAMA total score during 10 weeks' treatment [mean value difference, 95% confidence interval: 3.83 (1.28; 6.37) points]. Superiority was comparably pronounced for psychic and somatic anxiety as well as for observer- and self-rated anxiety. Silexan had a beneficial effect on sleep (secondary to the anxiolytic effect) without causing sedation and improved the patients' health-related quality of life. Adverse event incidence in both treatment groups was comparable [risk ratio: 1.06 (0.85; 1.33)]. Silexan has a significant and clinically meaningful anxiolytic effect in subthreshold anxiety. The results cannot be generalised to other lavender oil products. PMID- 29150714 TI - Stochastic Lotka-Volterra food chains. AB - We study the persistence and extinction of species in a simple food chain that is modelled by a Lotka-Volterra system with environmental stochasticity. There exist sharp results for deterministic Lotka-Volterra systems in the literature but few for their stochastic counterparts. The food chain we analyze consists of one prey and [Formula: see text] predators. The jth predator eats the [Formula: see text]th species and is eaten by the [Formula: see text]th predator; this way each species only interacts with at most two other species-the ones that are immediately above or below it in the trophic chain. We show that one can classify, based on an explicit quantity depending on the interaction coefficients of the system, which species go extinct and which converge to their unique invariant probability measure. Our work can be seen as a natural extension of the deterministic results of Gard and Hallam '79 to a stochastic setting. As one consequence we show that environmental stochasticity makes species more likely to go extinct. However, if the environmental fluctuations are small, persistence in the deterministic setting is preserved in the stochastic system. Our analysis also shows that the addition of a new apex predator makes, as expected, the different species more prone to extinction. Another novelty of our analysis is the fact that we can describe the behavior of the system when the noise is degenerate. This is relevant because of the possibility of strong correlations between the effects of the environment on the different species. PMID- 29150715 TI - RETRACTED ARTICLE: Interleukin-33 promotes helper T cell type-2/17 inflammation in children with allergic rhinitis. PMID- 29150716 TI - Slow life histories in lizards living in the highlands of the Andes Mountains. AB - In the highlands of the Andes, lizards must balance precisely the allocation of energy for growth and reproduction to ensure their survival. We studied the individuals' age, growth rates, age at sexual maturity, and maximum life span of the viviparous lizard Phymaturus antofagastensis, endemic of cold and harsh environments at high altitudes in the Andes Mountains of Catamarca province, Argentina. We also estimated key life history parameters like reproductive effort, lifetime reproductive effort, net reproductive rate, and relative reproductive time in P. antofagastensis as well as in other Phymaturus to compare the interplay among growth, maintenance, and reproduction in species that live across a latitudinal and altitudinal gradient. We found that females and males of P. antofagastensis mature late in life, at 6-7 years old, respectively, and some individuals reached 20 years of age. Adult females showed higher specific growth rates than males and an adult life span of 9 years which, due to their biennial reproduction, results in an estimated production of only four litters in life. This species exhibits one of the highest lifetime reproductive efforts described for lizards. Our results indicate the existence of a tradeoff between the number of reproductive events throughout life and reproductive effort devoted to each event in Phymaturus, related to the phylogenetic group. The palluma group shows low reproductive effort but high number of reproductive events throughout their lives, whereas the patagonicus group shows high reproductive efforts in low number of reproductive events. PMID- 29150717 TI - Genetic diversity and phylogenetic study of the Chinese Gelao ethnic minority via 23 Y-STR loci. AB - Haplotype diversity for 23 Y chromosomal short tandem repeat (Y-STR) loci included in the PowerPlex(r) Y23 System was analyzed in the Chinese Gelao minority group of 234 unrelated males living in Daozhen Gelao-Miao Autonomous County in Guizhou Province, southwest China. A total of 216 different haplotypes were detected, of which 199 haplotypes were unique. The overall haplotype diversity (HD) and discrimination capacity (DC) were 0.9996 and 0.9231, respectively. The gene diversity (GD) ranged from 0.4159 (DYS438) to 0.9650 (DYS385a/b). The haplotype frequencies varied from 0.0043 to 0.0128. The population data presented here showed high genetic polymorphism and extraordinary discriminatory power in the studied population. Population difference was observed between the Chinese Gelao ethnicity and 42 populations out of overall 59 neighboring populations in Asia region. Both multidimensional scaling (MDS) and the phylogenetic tree demonstrated that the genetic structure affinity and differentiation with Chinese Gelao ethnicity were identified in those populations geographically adjacent (Hunan Han) and distant (Chinese Tibetan), respectively. In conclusion, our study enriched the Chinese ethnic genetic information and could be used as a powerful tool in forensic genetics for male testing, paternal lineage analysis, and Gelao ethnic population evolutionary studies. PMID- 29150718 TI - Re-educating immunity in respiratory allergies: the potential for hematopoietic stem cell-mediated gene therapy. AB - Respiratory allergies represent a significant disease burden worldwide affecting up to 300 million people globally. Medication and avoidance of known triggers do not address the underlying pathology. Traditional immunotherapies for allergy aim to reinstate immune homeostasis but require years of treatment and have poor long term efficacy. Novel approaches, such as gene-engineered hematopoietic stem cell transplantation, induce profound antigen-specific tolerance in autoimmunity. Recent evidence shows this approach may also have therapeutic utility for allergy. Here, we review the mechanisms of antigen-specific tolerance and the potential of stem cell-mediated gene therapy to induce tolerance in allergic respiratory diseases. PMID- 29150720 TI - Assessing Restoration Effects on River Hydromorphology Using the Process-based Morphological Quality Index in Eight European River Reaches. AB - The Morphological Quality Index (MQI) and the Morphological Quality Index for monitoring (MQIm) have been applied to eight case studies across Europe with the objective of analyzing the hydromorphological response to various restoration measures and of comparing the results of the MQI and MQIm as a morphological assessment applied at the reach scale, with a conventional site scale physical habitat assessment method. For each restored reach, the two indices were applied to the pre-restoration and post-restoration conditions. The restored reach was also compared to an adjacent, degraded reach. Results show that in all cases the restoration measures improved the morphological quality of the reach, but that the degree of improvement depends on many factors, including the initial morphological conditions, the length of the restored portion in relation to the reach length, and on the type of intervention. The comparison with a conventional site scale physical-habitat assessment method shows that the MQI and MQIm are best suited for the evaluation of restoration effects on river hydromorphology at the geomorphologically-relevant scale of the river reach. PMID- 29150719 TI - Preoperative optimization for major hepatic resection. AB - PURPOSE: Major hepatic resections are performed for primary hepatobiliary malignancies, metastatic disease, and benign lesions. Patients with chronic liver disease, including cirrhosis and steatosis, are at an elevated risk of malnutrition and impaired strength and exercise capacity, deficits which cause increased risk of postoperative complications and mortality. The aims of this report are to discuss the pathophysiology of changes in nutrition, exercise capacity, and muscle strength in patient populations likely to require major hepatectomy, and review recommendations for preoperative evaluation and optimization. METHODS: Nutritional and functional impairment in preoperative hepatectomy patients, especially those with underlying liver disease, have a complex and multifactorial physiologic basis that is not completely understood. RESULTS: Recognition of malnutrition and compromised strength and exercise tolerance preoperatively can be difficult, but is critical in providing the opportunity to intervene prior to major hepatic resection and potentially improve postoperative outcomes. There is promising data on a variety of nutritional strategies to ensure adequate intake of calories, proteins, vitamins, and minerals in patients with cirrhosis and reduce liver size and degree of fatty infiltration in patients with hepatic steatosis. Emerging evidence supports structured exercise programs to improve exercise tolerance and counteract muscle wasting. CONCLUSIONS: The importance of nutrition and functional status in patients indicated for major liver resection is apparent, and emerging evidence supports structured preoperative preparation programs involving nutritional intervention and exercise training. Further research is needed in this field to develop optimal protocols to evaluate and treat this heterogeneous cohort of patients. PMID- 29150721 TI - Adaptive SNP-Set Association Testing in Generalized Linear Mixed Models with Application to Family Studies. AB - In genome-wide association studies (GWAS), it has been increasingly recognized that, as a complementary approach to standard single SNP analyses, it may be beneficial to analyze a group of functionally related SNPs together. Among the existent population-based SNP-set association tests, two adaptive tests, the aSPU test and the aSPUpath test, offer a powerful and general approach at the gene- and pathway-levels by data-adaptively combining the results across multiple SNPs (and genes) such that high statistical power can be maintained across a wide range of scenarios. We extend the aSPU and the aSPUpath test to familial data under the framework of the generalized linear mixed models (GLMMs), which can take account of both subject relatedness and possible population structure. As in population-based GWAS, the proposed aSPU and aSPUpath tests require only fitting a single and common GLMM (under the null hypothesis) for all the SNPs, thus are computationally efficient and feasible for large GWAS data. We illustrate our approaches in identifying genes and pathways associated with alcohol dependence in the Minnesota Twin Family Study. The aSPU test detected a gene associated with the trait, in contrast to none by the standard single SNP analysis. Our aSPU test also controlled Type I errors satisfactorily in a small simulation study. We provide R code to conduct the aSPU and aSPUpath tests for familial and other correlated data. PMID- 29150723 TI - A Grapevine-Inducible Gene Vv-alpha-gal/SIP Confers Salt and Desiccation Tolerance in Escherichia coli and Tobacco at Germinative Stage. AB - Grapevine is an important fruit crop cultivated worldwide. Previously, we have reported the characterization of a salt stress-inducible gene Vv-alpha-gal/SIP isolated from the tolerant grapevine cultivar Razegui. In this study, we performed functional studies in both Escherichia coli and tobacco systems to gain more insights in the role of the Vv-alpha-gal/SIP gene. Our data revealed that the recombinant E. coli cells harboring the pET24b+ expression vector with the Vv alpha-gal/SIP showed higher tolerance to desiccation and salinity compared to E. coli cells harboring the vector alone. In addition, the transgenic tobacco plants expressing the Vv-alpha-gal/SIP gene exhibited a higher percentage of seed germination and better growth under salt stress than the wild-type (WT) tobacco seedlings. This stress mitigation might be related to the putative function of this gene, which is thought to be involved in carbohydrate metabolism regulation. Collectively, these results suggest that Vv-alpha-gal/SIP is potentially a candidate gene for engineering drought and salt tolerance in cultivated plants. PMID- 29150722 TI - Cross-Lagged Analysis of Interplay Between Differential Traits in Sibling Pairs: Validation and Application to Parenting Behavior and ADHD Symptomatology. AB - Understanding the factors that contribute to behavioral traits is a complex task, and partitioning variance into latent genetic and environmental components is a useful beginning, but it should not also be the end. Many constructs are influenced by their contextual milieu, and accounting for background effects (such as gene-environment correlation) is necessary to avoid bias. This study introduces a method for examining the interplay between traits, in a longitudinal design using differential items in sibling pairs. The model is validated via simulation and power analysis, and we conclude with an application to paternal praise and ADHD symptoms in a twin sample. The model can help identify what type of genetic and environmental interplay may contribute to the dynamic relationship between traits using a cross-lagged panel framework. Overall, it presents a way to estimate and explicate the developmental interplay between a set of traits, free from many common sources of bias. PMID- 29150724 TI - Presence of Chlamydia trachomatis and Mycoplasma spp., but not Neisseria gonorrhoeae and Treponema pallidum, in women undergoing an infertility evaluation: high prevalence of tetracycline resistance gene tet(M). AB - Chlamydia trachomatis, Mycoplasma spp., Neisseria gonorrhoeae and Treponema pallidum are sexually transmitted pathogens that threaten reproductive health worldwide. In this study, vaginal swabs obtained from women (n = 133) that attended an infertility clinic in China were tested with qPCRs for C. trachomatis, Mycoplasma spp., N. gonorrhoeae, T. pallidum and tetracycline resistance genes. While none of vaginal swabs were positive for N. gonorrhoeae and T. pallidum, 18.8% (25/133) of the swabs were positive for Chlamydia spp. and 17.3% of the swabs (23/133) were positive for Mycoplasma species. All swabs tested were positive for tetracycline resistance gene tet(M) which is the most effective antibiotic for bacterial sexually transmitted infections. The qPCRs determined that the gene copy number per swab for tet(M) was 7.6 times as high as that of C. trachomatis 23S rRNA, and 14.7 times of Mycoplasma spp. 16S rRNA. In China, most hospitals do not detect C. trachomatis and Mycoplasma spp. in women with sexually transmitted infections and fertility problems. This study strongly suggests that C. trachomatis and Mycoplasma spp. should be routinely tested in women with sexually transmitted infections and infertility in China, and that antimicrobial resistance of these organisms should be monitored. Further studies are warranted to determine the prevalences in different regions and associated risk factors. PMID- 29150726 TI - TSPO imaging using the novel PET ligand [18F]GE-180: quantification approaches in patients with multiple sclerosis. AB - BACKGROUND: PET ligands targeting the translocator protein (TSPO) represent promising tools to visualise neuroinflammation. Here, we analysed parameters obtained in dynamic and static PET images using the novel TSPO ligand [18F]GE-180 in patients with relapsing remitting multiple sclerosis (RRMS) and an approach for semi-quantitative assessment of this disease in clinical routine. Seventeen dynamic [18F]GE-180 PET scans of RRMS patients were evaluated (90 min). A pseudo reference region (PRR) was defined after identification of the least disease affected brain area by voxel-based comparison with six healthy controls (HC) and upon exclusion of voxels suspected of being affected in static 60-90 min p.i. images. Standardised uptake value ratios (SUVR) obtained from static images normalised to PRR were correlated to the distribution volume ratios (DVR) derived from dynamic data with Logan reference tissue model. RESULTS: Group comparison with HC revealed white matter and thalamus as most affected regions. Fewest differences were found in grey matter, and normalisation to frontal cortex (FC) yielded the greatest reduction in variability of healthy grey and white matter. Hence, FC corrected for affected voxels was chosen as PRR, leading to time activity curves of FC which were congruent to HC data (SUV60-90 0.37, U test P = 0.42). SUVR showed a very strong correlation with DVR (Pearson rho > 0.9). Focal MS lesions exhibited a high SUVR (range, 1.3-3.2). CONCLUSIONS: This comparison with parameters from dynamic data suggests that SUVR normalised to corrected frontal cortex as PRR is suitable for the quantification of [18F]GE-180 uptake in lesions and different brain regions of RRMS patients. This efficient diagnostic protocol based on static [18F]GE-180 PET scans acquired 60-90 min p.i. allows the semi-quantitative assessment of neuroinflammation in RRMS patients in clinical routine. PMID- 29150727 TI - Measuring Emotional Intelligence Enhances the Psychological Evaluation of Chronic Pain. AB - The assessment of emotional factors, in addition to other psychosocial factors, has been recommended as a means of identifying individuals with chronic pain who may not respond to certain pain treatments. Systematic reviews of the evidence regarding the prediction of responsiveness to a treatment called the spinal cord stimulator (SCS) have yielded inconclusive results. Emotional intelligence is a term which refers to the ability to identify and manage emotions in oneself and others and has been shown to be inversely associated with emotional distress and acute pain. This study aims to investigate the relationship between emotional intelligence, chronic pain, and the more established psychosocial factors usually used for SCS evaluations by clinical psychologists in medical settings. A sample of 112 patients with chronic pain on an acute hospital waiting list for SCS procedures in a pain medicine service were recruited. Psychological measures were completed including: a novel measure of emotional intelligence; usual measures of emotional distress and catastrophizing; and a numerical rating scale designed to assess pain intensity, pain-related distress, and interference. As predicted, findings revealed significant associations between most of the measures analyzed and current pain intensity. When entered into a simultaneous regression analysis, emotional intelligence scores remained the only significant predictor of current pain intensity. There are potential clinical, ethical, and organizational implications of emotional intelligence processes partially predicting pain in patients on a waiting list for a medical procedure. These results may offer new insight, understanding, and evaluation targets for clinical psychologists in the field of pain management. PMID- 29150728 TI - The plant pathogen Gluconobacter cerinus strain CDF1 is beneficial to the fruit fly Bactrocera dorsalis. AB - Plant pathogens can build relationships with insect hosts to complete their life cycles, and they often modify the behavior and development of hosts to improve their own fitness. In order to unravel whether some bacteria that can make fruit rot could have developed symbiotic interactions with Bactrocera dorsalis, we studied the symbiont bacteria profiles of the fly. We identified the bacterium Gluconobacter cerinus strain CDF1 from the ovaries and eggs of the oriental fruit fly B. dorsalis and the amount of Gluconobacter cerinus strain CDF1 increased significantly as the ovaries developed and in fruits on which non-sterile eggs were laid. Gluconobacter cerinus strain CDF1 addition to bananas fastens the rotting process and its addition to the eggs fastens their development/hatching rate. All in all, our data suggest that Gluconobacter cerinus strain CDF1 is beneficial to the fruit fly. PMID- 29150729 TI - Effect of Microemulsion Structure on Fluorescence and Nonlinear Optical Properties of Rhodamine 6G. AB - This study is conducted to investigate the effect of nano-droplets concentration and size on linear and nonlinear optical properties of Rhodamine 6G by UV-Vis, spectrofluorometer and Z-Scan techniques. Nano-droplets were prepared by mixture of AOT, n-Decane and Water at three different water to surfactant molar ratios (W = 3, 6.7 and 40) and two dye to water mass ratios (R). At high enough dye concentration, the fluorescence intensity and its red shift depend on the concentration of dye in water nano-droplets (R). Moreover, the fluorescence spectra of R6G can be enhanced by confined water nano-droplets (microemulsion) at higher dye to water mass ratios. The Raman Spectra reveal no dependence of R6G local polarity in the AOT reversed micelles to nano-droplet size. From the Bakhshiev equation, the excited to ground state dipole moment ratio (MU e /MU g ) was calculated through solvatochromic shift method for different nano-droplet concentrations. The results show that MU e /MU g of R6G in water nano-droplets is smaller than that of bulk water. At high enough dye concentration, MU e /MU g depends on the nano-droplets' dye content. The dye aggregation can affect the dipole moment R6G in microemulsion. Two photon absorption coefficient (beta), nonlinear refractive index (n 2), the real third order susceptibility ([Formula: see text]) and the second order hyperpolarizability ([Formula: see text]) were measured using the Z-Scan technique at different nano-droplet concentration and two sizes of nano-droplet. The results show a good compatibility with the attained consequence by Quantum Perturbation theory. In this content, the interaction of nano-droplet was studied by dynamic light scattering, whose results indicate an ascending trend in mobility of nano-droplets by the increase of nano-droplets dye content. Hence increase of dye in nano-droplets influences the dye aggregation, fluorescence red shift and dipole moment ratio (MU e /MU g ) by the nano-droplet collision. PMID- 29150730 TI - Racial differences in symptom management experiences during breast cancer treatment. AB - PURPOSE: Racial disparities in cancer treatment-related symptom burden are well documented and linked to worse treatment outcomes. Yet, little is known about racial differences in patients' treatment-related symptom management experiences. Such understanding can help identify modifiable drivers of symptom burden inequities. As part of the Cancer Health Accountability for Managing Pain and Symptoms (CHAMPS) study, we examined racial differences in symptom management experiences among Black and White breast cancer survivors (BCS). METHODS: We conducted six focus groups (n = 3 Black BCS groups; n = 3 White BCS groups) with 22 stages I-IV BCS at two cancer centers. Focus groups were audio-recorded and transcribed verbatim. Based on key community-based participatory research principles, our community/academic/medical partner team facilitated focus groups and conducted qualitative analyses. RESULTS: All BCS described positive symptom management experiences, including clinician attentiveness to symptom concerns and clinician recommendations for pre-emptively managing symptoms. Black BCS commonly reported having to advocate for themselves to get information about treatment related symptoms, and indicated dissatisfaction regarding clinicians' failure to disclose potential treatment-related symptoms or provide medications to address symptoms. White BCS often described dissatisfaction regarding inadequate information on symptom origins and clinicians' failure to offer reassurance. CONCLUSIONS: This study elucidates opportunities for future research aimed at improving equity for cancer treatment-related symptom management. For Black women, warnings about anticipated symptoms and treatment for ongoing symptoms were particular areas of concern. Routine symptom assessment for all women, as well as clinicians' management of symptoms for racially diverse cancer patients, need to be more thoroughly studied and addressed. PMID- 29150731 TI - Cellular and molecular responses of adult zebrafish after exposure to CuO nanoparticles or ionic copper. AB - Due to their antimicrobial, electrical and magnetic properties, copper nanoparticles (NPs) are suitable for a vast array of applications. Copper can be toxic to biota, making it necessary to assess the potential hazard of copper nanomaterials. Zebrafish (Danio rerio) were exposed to 10 ug Cu/L of CuO NPs of ~100 nm (CuO-poly) or ionic copper to compare the effects provoked after 3 and 21 days of exposure and at 6 months post-exposure (mpe). At 21 days, significant copper accumulation was only detected in fish exposed to ionic copper. Exposure to both copper forms caused histopathological alterations that could reduce gill functionality, more markedly in the case of ionic copper. Nevertheless, at 6 mpe higher prevalences of gill lesions were detected in fish previously exposed to CuO-poly NPs. No relevant histological alterations were detected in liver, but the lysosomal membrane stability test showed significantly impaired general health status after exposure to both metal forms that lasted up to 6 mpe. 69 transcripts appeared regulated after 3 days of exposure to CuO-poly NPs, suggesting that NPs could produce oxidative stress and reduce metabolism and transport processes. Thirty transcripts were regulated after 21 days of exposure to ionic copper, indicating possible DNA damage. Genes of the circadian clock were identified as the key genes involved in time-dependent differences between the two copper forms. In conclusion, each copper form showed a distinct pattern of liver transcriptome regulation, but both caused gill histopathological alterations and long lasting impaired health status in adult zebrafish. PMID- 29150732 TI - Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is frequently upregulated in prostate cancer, and its overexpression conveys tumor growth and angiogenesis by metabolizing asymmetric dimethylarginine (ADMA). AB - Tissue microarray analysis confirmed higher dimethylarginine dimethylaminohydrolase-1 (DDAH1) expression in prostate cancer (PCa) compared to benign and normal prostate tissues. DDAH1 regulates nitric oxide (NO) production by degrading endogenous nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA). This study examined whether DDAH1 has any physiological role in PCa progression. Using overexpression of DDAH1 in PCa (PC3 and LNCaP) cell lines, we found that DDAH1 promotes cell proliferation, migration and invasion by lowering ADMA levels, as well as increasing NO production. VEGF, HIF 1alpha and iNOS were upregulated in DDAH1 expressing cells as result of elevated NO. DDAH1 increased secretion of pro-angiogenic signals bFGF and IL-8, into conditioned media. Treatment of DDAH1-positive PCa cells with NOS inhibitors (L NAME and 1400 W) attenuated DDAH1 activity to promote cell growth. Xenografts derived from these cells grew significantly faster (> twofold) than those derived from control cells. Proliferation rate of cells stably expressing mutant DDAH1 was same as control cells unlike wild-type DDAH1-positive PCa cells. Xenograft tumors derived from mutant-positive cells did not differ from control tumors. VEGF, HIF-1alpha and iNOS expression did not differ in DDAH1 mutant-positive tumors compared to control tumors, but was upregulated in wild-type DDAH1 overexpressing tumors. Furthermore, CD31 immunostaining on xenograft tissues demonstrated that DDAH1 tumors had high endothelial content than mutant DDAH1 tumors. These data suggest that DDAH1 is an important mediator of PCa progression and NO/DDAH pathway needs to be considered in developing therapeutic strategies targeted at PCa. PMID- 29150733 TI - Correction to: Coral Symbiodinium Community Composition Across the Belize Mesoamerican Barrier Reef System is Influenced by Host Species and Thermal Variability. AB - The authors regret that acknowledgment for Dr. Adrian Marchetti was omitted from the manuscript. The correct acknowledgment is written below. PMID- 29150734 TI - The sirtuin 1/2 inhibitor tenovin-1 induces a nonlinear apoptosis-inducing factor dependent cell death in a p53 null Ewing's sarcoma cell line. AB - The sirtuin 1/2 inhibitor tenovin-1 activates p53 and may have potential in the management of cancer. Here, we investigated the responsiveness of Ewing's sarcoma cells to tenovin-1. We examined its effects in two Ewing's sarcoma cell lines with different p53 status, i.e. in p53 wild-type and p53 null cells. Effects were assessed by flow cytometric analyses of cell death, mitochondrial membrane depolarization and reactive oxygen species (ROS) generation, by caspase 3/7 activity measurement, by mRNA expression profiling and by immunoblotting. Tenovin 1 elicited caspase-mediated cell death in p53 wild-type cells, but caspase independent cell death in p53 null cells. Remarkably, it induced a nonlinear concentration response in the latter: low concentrations of tenovin-1 were much more effective than were higher concentrations. Tenovin-1's effects in p53 null cells involved gene expression changes of Bcl-2 family members, mitochondrial membrane depolarization, nuclear translocation of apoptosis-inducing factor, ROS formation and DNA damage; all these effects followed a bell-shaped pattern. In conclusion, our results provide new insights into tenovin-1's mode of action by demonstrating that it can induce different pathways of cell death. PMID- 29150735 TI - Glycomics of human embryonic stem cells and human induced pluripotent stem cells. AB - Most cells are coated by a dense glycocalyx composed of glycoconjugates such as glycosphingolipids, glycoproteins, and proteoglycans. The overall glycomic profile is believed to be crucial for the diverse roles of glycans, which are mediated by specific interactions that regulate cell-cell adhesion, the immune response, microbial pathogenesis, and other cellular events. Many cell surface markers were discovered and identified as glycoconjugates such as stage-specific embryonic antigen, Tra-1-60/81 and various other cell surface molecules (e.g., cluster of differentiation). Recent progress in the development of analytical methodologies and strategies has begun to clarify the cellular glycomics of various cells including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). The glycomic profiles of these cells are highly cell type-specific and reflect cellular alterations, such as development, differentiation and cancerous change. In this mini review, we briefly summarize the glycosylation spectra specific to hESCs and hiPSCs, which cover glycans of all major glycoconjugates (i.e., glycosphingolipids, N- and O-glycans of glycoproteins, and glycosaminoglycans) and free oligosaccharides. PMID- 29150736 TI - Effect of erythrocyte-sperm separation medium on nuclear, acrosomal, and membrane maturity parameters in human sperm. AB - PURPOSE: The purpose of this study is to investigate whether erythrocyte-sperm separation medium (ESSM) has effects on human sperm motility, morphology, viability, membrane maturity, acrosome integrity, and nuclear attributes before and after cryopreservation. METHODS: Semen samples from normozoospermic (n = 36) and oligozoospermic (n = 9) patients were analyzed. Samples from the same patient were divided into three aliquots: group 1 and group 2 were resuspended in sperm washing media and ESSM, respectively. Group 3 was resuspended in ESSM with blood sample to mimic the extensive number of erythrocytes in the testicular sperm extraction (TESE) material. All groups were evaluated for sperm concentration, motility, Kruger/Tygerberg strict morphology, viability by eosin-nigrosin staining, membrane maturity by hyaluronic acid-binding assay (HBA), acrosomal integrity by Pisum sativum lectin staining, chromatin maturity by aniline blue staining, and DNA integrity by TUNEL assay before and after cryopreservation. RESULTS: No significant difference was determined between ESSM-treated and ESSM untreated sperm samples for the sperm parameters tested (p > 0.05). After cryopreservation, total sperm motility and viability decreased regardless of ESSM used. The percentages of sperm with Tygerberg normal morphology, intact acrosome, and HA-bound sperm were found to be lower in oligozoospermic samples before cryopreservation in each group. However, no statistically significant differences were found between oligozoospermic and normozoospermic samples when all groups were compared. Thus, ESSM treatment did not cause a significant change on sperm motility, normal morphology, viability, HA-binding capacity, chromatin maturity, and DNA fragmentation. CONCLUSION: ESSM can enhance the efficiency of sperm retrieval protocol and can also decrease the time required to collect spermatozoa while not affecting sperm morphogenetic properties. PMID- 29150737 TI - Risk of active tuberculosis in patients with inflammatory arthritis receiving TNF inhibitors: a look beyond the baseline tuberculosis screening protocol. AB - Tuberculosis (TB) is a major concern in patients receiving TNF inhibitors (TNFi). This study aimed to assess the incidence of active TB and the efficacy of TB prevention measures used over the years, and to determine risk factors for developing TB, in a single-centre cohort of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) receiving TNFi. Data of all patients in whom treatment with TNFi was initiated in our rheumatology clinic until December 1st 2014 have been retrospectively analysed. The cohort was divided into 3 groups per the mandatory LTBI screening method at baseline: tuberculin skin test (TST) with a positive threshold of either 10 mm (group TST1), or 5 mm (group TST2), and QuantiFERON(r)-TB Gold test (group QFT). The incidence of active TB was analysed for each group and compared to TB incidence data in general population. Five hundred fifty patients were included (305 RA, 42 PsA, 203 AS); 97 patients belonged to the TST1, 229 to the TST2 and 224 to the QFT group. The number of active TB cases/time of exposure to TNFi (person-years, PY) was 8/593.5, 9/1044.0 and 3/555.3, respectively, accounting for an incidence of 1348.0, 862.1 and 540.2 cases per 105 PY. Active TB cases occurring in the first year of TNFi treatment (early TB) per total TB cases were only 3/8, 1/9 and 1/3, respectively, too few to identify statistically significant differences between the 3 LTBI screening protocols. However, less TB cases per total observation time were registered in the QFT group, probably due to the reduced duration of exposure to TNFi. All cases of active TB were registered among patients receiving monoclonal antibodies TNFi agents. We have found no significant risk factors for developing active TB. In our cohort, TB occurring after 1 year of TNFi treatment exceeds 'early TB', suggesting the necessity of further TB prevention measures besides baseline screening for LTBI. PMID- 29150738 TI - The Autism Family Experience Questionnaire (AFEQ): An Ecologically-Valid, Parent Nominated Measure of Family Experience, Quality of Life and Prioritised Outcomes for Early Intervention. AB - There is a lack of measures that reflect the intervention priorities of parents of children with autism spectrum disorder (ASD) and that assess the impact of interventions on family experience and quality of life. The Autism Family Experience Questionnaire (AFEQ) was developed through focus groups and online consultation with parents, and reflected parental priorities. It was then administered to the parents of children enrolled in the Pre-school Autism Communication Trial and its 6-year follow-up study. The AFEQ showed good convergent validity with well-established measures of child adaptive functioning, parental mental health and parental wellbeing. It was sensitive to change in response to a parent-mediated intervention for young children with autism, showing treatment effect at treatment endpoint which increased at six-year follow up. PMID- 29150740 TI - Severe rigid Scheuermann kyphosis in adult patients; correction with posterior only approach. AB - PURPOSE: Scheuermann kyphosis is the most common structural kyphosis among adolescence and young people. Surgical treatment may be performed through combined anterior and posterior or posterior-only approaches; to our knowledge, the efficacy of posterior-only approach as less invasive procedure is not well studied in case of severe rigid Scheuermann kyphosis. MATERIALS AND METHODS: Eighteen patients with severe rigid Scheuermann kyphosis operated through only posterior approach from 2013 to 2016 were evaluated. All information regarding demographic data, curve size before and after the surgery, surgical time, amount of blood loss, correction loss during follow-up and also complications was collected. RESULT: There were six females and 12 males. Mean age of the patients was 22.4 years (range 17-38). Mean kyphosis angle before surgery was 87.2 degrees (range 85-105), and that reduced to 47.4 degrees (range 45-55) after the surgery. Mean curve size in hyperextension view was 73.8 degrees . Mean postoperative Cobb angle was 50-55 percent of preoperative curves. Mean hospital admission duration was 3.5 days after the index surgery (range 3-5 days). Mean blood loss during the surgery was 250 ml. Mean surgical duration time was 150 min. Mean follow-up period was 9 months (range 8-48 months). No complication was found among the patients. CONCLUSION: Posterior-only approach using advanced osteotomy techniques and posterior release is a safe and reliable approach for treatment of patients suffering from severe rigid Scheuermann kyphosis and provides acceptable deformity correction. PMID- 29150741 TI - Prevalence of Micronutrient Deficiency in Patients with Morbid Obesity Before Bariatric Surgery: What About Celiac Disease? PMID- 29150742 TI - Associations Between Nucleus Size, and Immunohistochemical Galectin-3, Cytokeratine-19 and Hbme-1 Markers in Thyroid Papillary Carcinoma: A Morphometric Analyze. AB - This study aimed to evaluate the morphometric measurements in cases with papillary thyroid carcinoma, and determine a cut-off value to support diagnosis. Fifty cases with a diagnosis of papillary thyroid carcinoma (PTC) were included in the study with their Galectine-3, CK-19 and HBME-1 immunohistochemical staining results. Demographic and clinical data gathered from pathology reports, which included demographic information such as patients' sex, age, macroscopic tumor size, number of tumor focuses; prognostic parameters such as lenfovascular invasion, perineural invasion, thyroid capsule invasion; and results of immunohistochemical CK- 19, Galectin-3 and HBME-1 staining. Longest nuclear diameters of 150 tumor cells and 150 normal thyrocytes of each case were manually measured in an image analysis software, and mean longest nuclear diameters (MLND TC and MLND-NC), and also tumor cell/normal cell longest nuclear diameter ratio (TC/NC-LNDR) were calculated. MLND-TC was higher than MLND-NC. The cases with higher MLND-TC had increased risk of capsule invasion in case of a negative staining with Galectine-3, HBME-1, or CK-19. When TC/NC-LNDR was high, number of tumor focus tended to be multiple and lymphovascular invasion risk was also increased. Subtypes of PTC were not differed regarding staining patterns. And finally, increased TC/NC-LNDR was associated with increased risk of having poor prognostic factors. The results of this study suggest that MLND-NC, MLND-TC, and TC/NCLNDR are valuable and easy-to-use measures, which can assist routine histology practice. PMID- 29150739 TI - Cell Therapy in Stroke-Cautious Steps Towards a Clinical Treatment. AB - In the future, stroke patients may receive stem cell therapy as this has the potential to restore lost functions. However, the development of clinically deliverable therapy has been slower and more challenging than expected. Despite recommendations by STAIR and STEPS consortiums, there remain flaws in experimental studies such as lack of animals with comorbidities, inconsistent approaches to experimental design, and concurrent rehabilitation that might lead to a bias towards positive results. Clinical studies have typically been small, lacking control groups as well as often without clear biological hypotheses to guide patient selection. Furthermore, they have used a wide range of cell types, doses, and delivery methods, and outcome measures. Although some ongoing and recent trial programs offer hints that these obstacles are now being tackled, the Horizon2020 funded RESSTORE trial will be given as an example of inconsistent regulatory requirements and challenges in harmonized cell production, logistic, and clinical criteria in an international multicenter study. The PISCES trials highlight the complex issues around intracerebral cell transplantation. Therefore, a better understanding of translational challenges is expected to pave the way to more successful help for stroke patients. PMID- 29150743 TI - Differential Response of Neural Cells to Trauma-Induced Swelling In Vitro. AB - Brain edema and the associated increase in intracranial pressure are major consequences of traumatic brain injury (TBI) that accounts for most early deaths after TBI. We recently showed that acute severe trauma to cultured astrocytes results in cell swelling. We further examined whether trauma induces cell swelling in neurons and microglia. We found that severe trauma also caused cell swelling in cultured neurons, whereas no swelling was observed in microglia. While severe trauma caused cell swelling in both astrocytes and neurons, mild trauma to astrocytes, neurons, and microglia failed to cell swelling. Since extracellular levels of glutamate are increased in brain post-TBI and microglia are known to release cytokine, and direct exposure of astrocytes to these molecules are known to stimulate cell swelling, we examined whether glutamate or cytokines have any additive effect on trauma-induced cell swelling. Exposure of cultured astrocytes to trauma caused cell swelling, and such swelling was potentiated by the exposure of traumatized astrocytes to glutamate and cytokines. Conditioned medium (CM) from traumatized astrocytes had no effect on neuronal swelling post-trauma, while CM from traumatized neurons and microglia potentiated the effect of trauma on astrocyte swelling. Further, trauma significantly increased the Na-K-Cl co-transporter (NKCC) activity in neurons, and that inhibition of NKCC activity diminished the trauma-induced neuronal swelling. Our results indicate that a differential sensitivity to trauma-induced cell swelling exists in neural cells and that neurons and microglia are likely to be involved in the potentiation of the astrocyte swelling post-trauma. PMID- 29150744 TI - Reply to: "Predelivery uterine artery embolization for placental anomalies: some clarifications". PMID- 29150745 TI - Alignment in the transverse plane, but not sagittal or coronal plane, affects the risk of recurrent patella dislocation. AB - PURPOSE: Abnormalities of lower extremity alignment (LEA) in recurrent patella dislocation (RPD) have been studied mostly by two-dimensional (2D) procedures leaving three-dimensional (3D) factors unknown. This study aimed to three dimensionally examine risk factors for RPD in lower extremity alignment under the weight-bearing conditions. METHODS: The alignment of 21 limbs in 15 RPD subjects was compared to the alignment of 24 limbs of 12 healthy young control subjects by an our previously reported 2D-3D image-matching technique. The sagittal, coronal, and transverse alignment in full extension as well as the torsional position of the femur (anteversion) and tibia (tibial torsion) under weight-bearing standing conditions were assessed by our previously reported 3D technique. The correlations between lower extremity alignment and RPD were assessed using multiple logistic regression analysis. The difference of lower extremity alignment in RPD between under the weight-bearing conditions and under the non weight-bearing conditions was assessed. RESULTS: In the sagittal and coronal planes, there was no relationship (statistically or by clinically important difference) between lower extremity alignment angle and RPD. However, in the transverse plane, increased external tibial rotation [odds ratio (OR) 1.819; 95% confidence interval (CI) 1.282-2.581], increased femoral anteversion (OR 1.183; 95% CI 1.029-1.360), and increased external tibial torsion (OR 0.880; 95% CI 0.782-0.991) were all correlated with RPD. The tibia was more rotated relative to femur at the knee joint in the RPD group under the weight-bearing conditions compared to under the non-weight-bearing conditions (p < 0.05). CONCLUSIONS: This study showed that during weight-bearing, alignment parameters in the transverse plane related to the risk of RPD, while in the sagittal and coronal plane alignment parameters did not correlate with RPD. The clinical importance of this study is that the 3D measurements more directly, precisely, and sensitively detect rotational parameters associated with RPD and hence predict risk of RPD. LEVEL OF EVIDENCE: III. PMID- 29150748 TI - An Evaluation of a Rural Community-Based Breast Education and Navigation Program: Highlights and Lessons Learned. AB - Cancer has become the leading cause of death in North Carolina (NC) (North Carolina DHHS, State Center for Health Statistics 2015) and the eastern region of North Carolina (ENC) has experienced greater cancer mortality than the remainder of the state. The Pitt County Breast Wellness Initiative-Education (PCBWI-E) provides culturally tailored breast cancer education and navigation to screening services for uninsured/underinsured women in Pitt and Edgecombe Counties in ENC. PCBWI-E created a network of 23 lay breast health educators, and has educated 735 women on breast health and breast cancer screening guidelines. Navigation services have been provided to 365 women, of which 299 were given breast health assessments, 193 were recommended for a mammogram, and 138 were screened. We have identified five lessons learned to share in the successful implementation of a community-based breast cancer screening intervention: (1) community partnerships are critical for successful community-based cancer screening interventions; (2) assuring access to free or low-cost screening and appropriate follow-up should precede interventions to promote increased use of breast cancer screening; (3) the reduction of system-based barriers is effective in increasing cancer screening; (4) culturally tailored interventions can overcome barriers to screening for diverse racial/ethnic and socioeconomic groups; and (5) multi component interventions that include multiple community health strategies are effective in increasing screening. PMID- 29150746 TI - Correlation between quantitative pivot shift and generalized joint laxity: a prospective multicenter study of ACL ruptures. AB - PURPOSE: To investigate whether an increased magnitude of quantitative rotatory knee laxity is associated with a greater level of generalized joint laxity in ACL injured and contralateral knees. METHODS: A total of 103 patients were enrolled across four international centers to undergo anatomic ACL reconstruction. Rotatory knee laxity was evaluated preoperatively, both in the awake state and under anesthesia, using the standardized pivot shift test. Two devices were used to quantify rotatory knee laxity; an inertial sensor, measuring the joint acceleration, and an image analysis system, measuring the lateral compartment translation of the tibia. The presence of generalized joint laxity was determined using the Beighton Hypermobility Score. The correlation between the level of generalized joint laxity and the magnitude of rotatory knee laxity was calculated for both the involved knee and the non-involved knee. Further, patients were dichotomized into low (0-4) or high (5-9) Beighton Score groups. Alpha was set at < 0.05. RESULTS: Ninety-six patients had complete datasets, 83 and 13 in the low and high Beighton Score groups respectively. In anesthetized patients, there was a significant correlation between the degree of Beighton Score and quantitative pivot shift when analyzing the non-involved knee using the image analysis system (r = 0.235, p < 0.05). When analyzing the same knee, multivariate analysis adjusted for meniscal injury, age and gender revealed an increased odds ratio for patients with increased lateral compartment translation to be part of the high Beighton Score group (OR 1.86, 95% CI 1.10-3.17, p < 0.05). No other correlation was significant. When analyzing the dichotomized subgroups, no significant correlations could be established. CONCLUSION: The findings in this study suggest that there is a weak correlation between generalized joint laxity and the contralateral healthy knee, indicating increased rotatory knee laxity in these patients. Generalized joint laxity does not appear to correlate with rotatory knee laxity in ACL-injured knees. LEVEL OF EVIDENCE: Prospective cohort study; level of evidence, 2. PMID- 29150747 TI - For Whom Do Parenting Interventions to Prevent Adolescent Substance Use Work? AB - Adolescent substance use continues to be a significant public health problem. Parent training interventions are effective preventive strategies to reduce youth substance use. However, little is known about differences in effectiveness for youth across demographic characteristics. This review assessed the effectiveness of parent training programs at reducing adolescent substance use by participant gender, age, and race/ethnicity. Pubmed/MEDLINE, ERIC, CINAHL, and PsycINFO were searched from database origin to October 31, 2016. We included randomized controlled trials that evaluated parent training interventions; reported youth initiation or use of tobacco, alcohol, or other illicit substances; and included adolescents aged 10 to 19. Two independent reviewers extracted data. Disagreements were resolved by consensus or a third researcher. Data were synthesized using harvest plots stratified by participant demographics. A total of 1806 publications were identified and reviewed; 38 unique studies were included. Risk of bias of included studies was high. No studies targeted male teens or youth in late adolescence. Few studies targeted Asian-American, Black/African-American, or Hispanic/Latino adolescents. Overall, interventions including male and female youth and youth in early adolescence (age 10 to 14 or in 5th to 8th grade) were more beneficial than interventions including female only or both young and older adolescents. Programs tailored to specific racial/ethnic groups, as well as programs designed for youth from multiple races/ethnic groups, were effective. Current evidence supports the benefits of offering parenting guidance to all families with adolescent children, regardless of the gender, age, or race/ethnicity of the adolescent. PMID- 29150750 TI - Technical considerations for quantification of 18F-FDG uptake in carotid atherosclerosis. PMID- 29150749 TI - Study on the interaction of paeoniflorin with human serum albumin (HSA) by spectroscopic and molecular docking techniques. AB - The interaction of paeoniflorin with human serum albumin (HSA) was investigated using fluorescence, UV-vis absorption, circular dichroism (CD) spectra and molecular docking techniques under simulative physiological conditions. The results clarified that the fluorescence quenching of HSA by paeoniflorin was a static quenching process and energy transfer as a result of a newly formed complex (1:1). Paeoniflorin spontaneously bound to HSA in site I (subdomain IIA), which was primarily driven by hydrophobic forces and hydrogen bonds (DeltaH degrees = - 9.98 kJ mol-1, DeltaS degrees = 28.18 J mol-1 K-1). The binding constant was calculated to be 1.909 * 103 L mol-1 at 288 K and it decreased with the increase of the temperature. The binding distance was estimated to be 1.74 nm at 288 K, showing the occurrence of fluorescence energy transfer. The results of CD and three-dimensional fluorescence spectra showed that paeoniflorin induced the conformational changes of HSA. Meanwhile, the study of molecular docking also indicated that paeoniflorin could bind to the site I of HSA mainly by hydrophobic and hydrogen bond interactions. PMID- 29150751 TI - Comparison of ESC and ACC/AHA guidelines for the diagnosis and management of patients with stable coronary heart disease: Are the differences clinically relevant? An American perspective. PMID- 29150752 TI - Women's Reproductive Health in Sociocultural Context. AB - PURPOSE: The special issue on Women's Reproductive Health in Cultural Context covers multiple dimensions of women's reproductive health and how it might be shaped by cultural meanings, social and gender inequities, and power differentials, employing a variety of methodological approaches. On the one hand, it aims to bring to the forefront the conversation about how women's health is uniquely experienced and constructed in local settings, and on the other hand, it aims to draw broader conclusions from a perspective of interconnectedness of women and the shared issues that they face. METHODS AND RESULTS: The special issue was initiated through a call for submissions and includes ten articles on the topic of women's reproductive health in cultural context. CONCLUSIONS: The articles provide many insights into how the context in which they live can disadvantage women and endanger their health, as well as offer perspectives on women's resistance to disempowering and stigmatizing discourses and practices. It aims to be of interest to scholars in behavioral medicine, psychology, and other social sciences. PMID- 29150753 TI - Psychological Aspects of Obesity in Children and Adolescents. AB - Childhood obesity is multi factorial health condition, so the simple evaluation of body fat will not be sufficed to manage the global epidemic of childhood obesity. Literature consistently provides evidence for physical health risks associated with childhood obesity; however in recent times, mental health of the obese children has also gained attention of the researchers as well as clinicians. Obese children experience number of psycho-social problems that significantly affect their quality of life and wellbeing. Co-morbid psychosocial and emotional problems of obesity generally act as causal or maintaining factors of obesity and thus significantly affect the treatment outcome. Therefore it becomes imperative for the clinicians/pediatricians to broaden their clinical assessment and include screening of important psycho-social factors within the clinical examination of childhood obesity. This article provides an evidence based comprehensive overview about the psychological factors and psychiatric factors (depression, anxiety, eating disorder, stress, body shape concerns, low self esteem) associated with childhood obesity that can further be utilized in the evaluation and management of this epidemic. The article also elaborates the role of current evidence based psychological approaches such as Cognitive Behavior Therapy (CBT) for management of obesity in children and adolescents. CBT techniques combined with lifestyle intervention and involving parents have been recommended by literature repetitively. However, there are a number of environmental, familial and personal barriers that hinder the whole process of weight loss in children. The article also discusses potential strategies to overcome those barriers. PMID- 29150754 TI - Detoxification of Aflatoxin B1 by Antifungal Compounds from Lactobacillus brevis and Lactobacillus paracasei, Isolated from Dairy Products. AB - Aflatoxins are a large group of highly toxic, mutagenic, and carcinogenic mycotoxins produced by specific species of fungi. Potential contamination of food commodities by these compounds causes extensive damage that lead to great economic losses. This study explored the potential use of antifungal compounds, produced by Lactobacillus brevis and Lactobacillus paracasei, for growth inhibition and subsequent aflatoxin B1 production from select strains of Aspergillus flavus and Aspergillus parasiticus. Lactobacilli strains were isolated from traditional Egyptian dairy products, whereas fungal strains were isolated from infected cereal seeds. There were noticeable decreases in mycelium biomass and aflatoxin production as well. L. brevis exhibited the highest reduction of aflatoxin B1 production by A. flavus and A. parasiticus, 96.31 and 90.43%, respectively. The concentrations of amino acids of the antifungal compound produced by L. brevis were significantly higher than that produced by L. paracasei. Asparagine, glutamine, glycine, alanine, and leucine were the most concentrated amino acids for both strains. The antifungal compounds produced by L. brevis and L. paracasei were active in a wide range of pH, heat stable and inactivated by proteolytic enzymes (protease K and trypsin A). The expression of Omt-A gene that involved in the later step of aflatoxin production was evaluated by real-time PCR. There was a vigorous reduction at transcriptional level of Omt A gene observed in A. flavus that is treated by L. brevis and L. paracasei (80 and 70%, respectively). However, the reduction of Omt-A gene observed in A. parasiticus that is treated by L. brevis and L. paracasei was 64.5 and 52%, respectively. Treating maize seeds with antifungal compounds exhibited great efficiency in controlling fungal infection and increasing seed germination. The results confirmed that lactic acid bacteria are a promising strategy to control food contamination of fermented food and dairy products. PMID- 29150755 TI - Comparative Hair Trace Element Profile in the Population of Sakhalin and Taiwan Pacific Islands. AB - The objective of the current study is to perform a comparative analysis of hair trace element content in 393 apparently healthy adults living in Taipei, Taiwan, Republic of China (94 women and 46 men) and Yuzhno-Sakhalinsk, Sakhalin, Russia (186 women and 67 men). The obtained data indicate that Yuzhno-Sakhalinsk inhabitants were characterized by significantly higher hair Co, Cr, Mn, and V levels, exceeding the respective Taipei values by a factor of 3, 2, 7, and 5, respectively (all p < 0.001). Hair Cu, Fe, and Si levels were also higher in examinees from Yuzhno-Sakhalinsk than those from Taipei by 10% (p = 0.001), 61% (p < 0.001), and 68% (p < 0.001), respectively. It is notable that the only essential element, being significantly higher (+ 30%; p < 0.001) in Taipei inhabitants, is selenium. Yuzhno-Sakhalinsk inhabitants were characterized by 60% higher levels of hair Sn, and nearly two- and threefold higher scalp hair content of Be and Cd in comparison to Taipei values, respectively (all p < 0.001). Oppositely, the examinees from Taipei had 14% (p = 0.040) and 47% (p = 0.001) higher levels of hair As and Hg as compared to Yuzhno-Sakhalinsk inhabitants. Further analysis demonstrated that men from both Yuzhno-Sakhalinsk and Taipei were characterized by significantly higher hair Mn, As, and Pb levels in comparison to women. The intensive development of heavy industry in Yuzhno Sakhalinsk may result in increased metal emissions, whereas fish consumption may result in elevation of hair Hg, As, and Se levels in Taiwan inhabitants. PMID- 29150756 TI - Impact of risk factors for gestational diabetes (GDM) on pregnancy outcomes in women with GDM. AB - PURPOSE: In this study, we evaluated the impact of risk factors for gestational diabetes on clinical/biochemical parameters and maternal/fetal outcomes. METHODS: One hundred eighty-three (n 183) women (age 33.8 +/- 5.5 years, 59% Caucasians, 41% non-Caucasians) with gestational diabetes were included in the study. Anamnestic information, anthropometric and laboratory parameters, and maternal and fetal outcomes at delivery were collected. RESULTS: Insulin therapy prevalence was higher in Asians vs Caucasians (p = 0.006), despite lower pre pregnancy BMI in Asians (p = 0.0001) and in pre-pregnancy overweight vs normal weight patients (p = 0.04). Insulin-treated patients had higher fasting OGTT glucose than patients on diet therapy (p = 0.003). In multivariate analysis, Asian ethnicity, age >= 35 years and pre-pregnancy BMI >= 25 kg/m2 were independent predictors of insulin therapy. Cesarean section occurred more in women aged >= 35 years than < 35 years (p = 0.02). Duration of pregnancy and age showed inverse correlation (r - 0.3 p = 0.013). Week of delivery was lower in patients >= 35 years vs patients < 35 years (p = 0.013). Fasting OGTT glucose was higher in overweight than in normal weight patients (p = 0.016). 1-h OGTT glucose was lower in obese vs normal weight (p = 0.03) and overweight patients (p = 0.03). Prevalence of prior gestational diabetes was higher in overweight/obese women (p = 0.002). CONCLUSIONS: Ethnicity, age, and BMI have the heaviest impact on pregnancy outcomes. PMID- 29150757 TI - Invisible side of emotions: somato-motor responses to affective facial displays in alexithymia. AB - According to recent theories, the detection of emotions involves somatic experiences. In this study, we investigated the relation between somatic responses to affective stimuli, emotion perception, and alexithymia. Variations in automatic rapid facial reactions (RFRs) were measured in a selected population of participants with high and low levels of alexithymia (HA and LA, respectively). Electromyographic activity was recorded from the corrugator supercilii and the zygomaticus major, while participants performed a gender classification task on faces expressing various emotional states. LA participants showed congruent RFRs in response to both fearful and happy stimuli. On the other hand, HA participants did not show congruent RFRs in response to fearful faces. They showed congruent, but delayed, RFRs in response to happy faces. These results provide evidence of a deficit in somato-motor emotional processing in people with high alexithymic personality traits, and thus support the hypothesis that alexithymia is associated with a deficit in emotional embodiment. PMID- 29150758 TI - Predictors for achieving adequate protein and energy intake in nursing home rehabilitation patients. AB - BACKGROUND: Adequate energy and protein intake could be essential for contributing significantly to the rehabilitations process. Data on the actual nutritional intake of older nursing home rehabilitation patients have not yet been investigated. AIMS: To investigate the nutritional intake and predictors for achieving protein and energy requirements on the 14th day of admission in nursing home rehabilitation patients. METHODS: Fifty-nine patients aged 65+ years newly admitted to nursing home rehabilitation wards were included. Data on potential variables were collected on admission. On the fourteenth day nutritional intake was assessed. Intake was considered 'adequate' if patients had achieved >= 1.2 g of protein/kg bodyweight and >= 85% of their energy needs according to Harris and Benedict + 30%. Multiple logistic regression analyses were performed to select predictors for adequate intake. RESULTS: Protein and energy intake was assessed in 79 patients [67% female, mean age 82 +/- (SD) 8 years, BMI 25 +/- 6 kg/m2]. Mean energy intake was 1677 kcal (+/- 433) and mean protein intake was 68 g (+/- 20). Fourteen patients (18%) achieved an adequate protein and energy intake. Predictors for adequate intake were use of sip/tube feeding (OR = 7.7; 95% CI = 1.35-44.21), BMI (0.68; 0.53-0.87) and nausea (8.59; 1.42-52.01). CONCLUSION: Only 18% of older nursing home rehabilitation patients had an adequate protein and energy intake at 14 days after admission. Patients with higher BMI were less likely, while those using sip/tube feeding or feeling nauseous were more likely to achieve an adequate protein and energy intake. PMID- 29150759 TI - From Experiment to Theory: What Can We Learn from Growth Curves? AB - Finding an appropriate functional form to describe population growth based on key properties of a described system allows making justified predictions about future population development. This information can be of vital importance in all areas of research, ranging from cell growth to global demography. Here, we use this connection between theory and observation to pose the following question: what can we infer about intrinsic properties of a population (i.e., degree of heterogeneity, or dependence on external resources) based on which growth function best fits its growth dynamics? We investigate several nonstandard classes of multi-phase growth curves that capture different stages of population growth; these models include hyperbolic-exponential, exponential-linear, exponential-linear-saturation growth patterns. The constructed models account explicitly for the process of natural selection within inhomogeneous populations. Based on the underlying hypotheses for each of the models, we identify whether the population that it best fits by a particular curve is more likely to be homogeneous or heterogeneous, grow in a density-dependent or frequency-dependent manner, and whether it depends on external resources during any or all stages of its development. We apply these predictions to cancer cell growth and demographic data obtained from the literature. Our theory, if confirmed, can provide an additional biomarker and a predictive tool to complement experimental research. PMID- 29150760 TI - Slow Passage Through a Hopf Bifurcation in Excitable Nerve Cables: Spatial Delays and Spatial Memory Effects. AB - It is well established that in problems featuring slow passage through a Hopf bifurcation (dynamic Hopf bifurcation) the transition to large-amplitude oscillations may not occur until the slowly changing parameter considerably exceeds the value predicted from the static Hopf bifurcation analysis (temporal delay effect), with the length of the delay depending upon the initial value of the slowly changing parameter (temporal memory effect). In this paper we introduce new delay and memory effect phenomena using both analytic (WKB method) and numerical methods. We present a reaction-diffusion system for which slowly ramping a stimulus parameter (injected current) through a Hopf bifurcation elicits large-amplitude oscillations confined to a location a significant distance from the injection site (spatial delay effect). Furthermore, if the initial current value changes, this location may change (spatial memory effect). Our reaction-diffusion system is Baer and Rinzel's continuum model of a spiny dendritic cable; this system consists of a passive dendritic cable weakly coupled to excitable dendritic spines. We compare results for this system with those for nerve cable models in which there is stronger coupling between the reactive and diffusive portions of the system. Finally, we show mathematically that Hodgkin and Huxley were correct in their assertion that for a sufficiently slow current ramp and a sufficiently large cable length, no value of injected current would cause their model of an excitable cable to fire; we call this phenomenon "complete accommodation." PMID- 29150761 TI - Comparative study of fluvial lakes in floodplains of the Elbe, Luznice and Svratka Rivers based on hydrochemical and biological approach. AB - The aim of the thesis was to specify key differences in chemistry and biota (zooplankton communities) among fluvial lakes in three regions of the Czech Republic: the central part of the Elbe River, the upper part of the Luznice River and the upper part of the Svratka River. The ten studied lakes of the three regions differ in size, geology, shading, connection with the river and the level of anthropogenic impact. The following hypotheses were tested: (1) The water chemistry of fluvial lakes significantly differs in different floodplains. In the central Elbe River floodplain, there are the highest values of conductivity and concentrations of organic matter and nutrients. Fluvial lakes of the Svratka River floodplain show the lowest level of these parameters, and fluvial lakes of the upper Luznice River have levels intermediate between the two previous regions. (2) The chemistry of fluvial lakes that have contact with the river through surface connection is significantly influenced by the river. (3) The structure of zooplankton differs in different lakes due to the geographical distance between locations, their different altitude and water chemistry. The PCA analysis of selected parameters of the water chemistry revealed a close relationship of locations in the central Elbe River floodplain on the one side and close relationship of the locations in the upper Luznice River and Svratka River on the other. However, the amount of organic matter, nitrogen (with the exception of nitrates) and phosphorus was independent of the region. The relationship between the extent of the lake-river connection and the water chemistry was not significant. The hypothesis that the zooplankton differ in different lakes was not proved-the species composition was similar in all the lakes. PMID- 29150762 TI - Seasonal influence on adherence to and effects of an interval walking training program on sedentary female college students in Japan. AB - Habitual exercise training is recommended to young people for their health promotion, but adherence may be influenced by atmospheric temperature (T a ) if performed outdoors. We compared the adherence to and the effects of a home-based interval walking training (IWT) program on sedentary female college students between winter and summer. For summer training over 176 days, 48 subjects (18-22 years old) were randomly divided into two groups: the control group (CNTsummer, n = 24), which maintained a sedentary lifestyle as before, and the IWT group (IWTsummer, n = 24), which performed IWT while energy expenditure was monitored by accelerometry. For winter training over 133 days, another group of 47 subjects (18-24 years old) was randomly divided into CNTwinter (n = 24) and IWTwinter (n = 23), as in summer. The peak T a per day was 26 +/- 6 degrees C (SD) (range of 9 35 degrees C) in summer, much higher than 7 +/- 5 degrees C (range of - 3-20 degrees C) in winter (P < 0.001). During a ~ 50-day vacation period, participants walked 2.1 +/- 0.3 (SE) days/week in IWTsummer, less than 4.2 +/- 0.3 days/week in IWTwinter (P < 0.001), with half of the energy expenditure/week for fast walking during the winter vacation (P < 0.02), whereas both IWT groups walked ~ 2 days/week during a school period (P > 0.8). After training, the peak aerobic capacity and knee flexion force increased in IWTwinter (P < 0.01) but not in CNTwinter (P > 0.3). Conversely, these parameters decreased in the summer groups. Thus, the adherence to and effects of IWT on sedentary female college students in Japan decreased in summer at least partially due to a high T a . PMID- 29150763 TI - Heat stress in cows at pasture and benefit of shade in a temperate climate region. AB - Under temperate climates, cattle are often at pasture in summer and are not necessarily provided with shade. We aimed at evaluating in a temperate region (Belgium) to what extent cattle may suffer from heat stress (measured through body temperature, respiration rate and panting score, cortisol or its metabolites in milk, and feces on hot days) and at assessing the potential benefits of shade. During the summer of 2012, 20 cows were kept on pasture without access to shade. During the summer of 2011, ten cows had access to shade (young trees with shade cloth hung between them), whereas ten cows had no access. Climatic conditions were quantified by the Heat Load Index (HLI). In animals without access to shade respiration rates, panting scores, rectal temperatures, and milk cortisol concentrations increased as HLI increased in both 2011 and 2012. Fecal cortisol metabolites varied with HLI in 2011 only. When cattle had access to shade, their use of shade increased as the HLI increased. This effect was more pronounced during the last part of the summer, possibly due to better acquaintance with the shade construction. In this case, shade use increased to 65% at the highest HLI (79). Shade tempered the effects on respiration, rectal temperature, and fecal cortisol metabolites. Milk cortisol was not influenced by HLI for cows using shade for > 10% of the day. Therefore, even in temperate areas, cattle may suffer from heat when they are at pasture in summer and providing shade can reduce such stress. PMID- 29150765 TI - Finite Element Design Optimization of a Hyaluronic Acid-Based Hydrogel Drug Delivery Device for Improved Retention. AB - Drug-loaded hydrogel devices are emerging as an effective means of localized and sustained drug delivery for the treatment of corneal conditions and injuries. One such device uses a novel, thiolated crosslinked carboxymethylated, hyaluronic acid-based hydrogel (CMHA-S) film to deliver drug to the ocular surface upon placement into the inferior fornix of the eye. While proven to be very safe and effective, the CMHA-S film tends to dislodge in the highly-lubricated ocular environment, thereby reducing drug delivery efficiency and drug efficacy. In this study, we used a three-dimensional computational finite element model of the eye to determine the effect of geometry and surface friction on film retention in the inferior fornix, and to evaluate multiple geometrical film designs. Retention of the film was dependent on geometry and on the friction ratio of the film to the eyelid and globe. These effects were interactive. When the ratio of friction on the lid side to the globe side of the film was low, geometry played a large role in the film's displacement. When this ratio was high, differences in displacement due to geometry were negligible. The optimal relationship of friction between the film and its eyelid-side and globe-side surfaces was found to be linear with at least 1.4 times greater friction required on the eyelid-side for immobilization. A geometry similar to a half cylinder was found to be most effective with this friction ratio in retaining the film in the inferior fornix and in contact with the globe. Other geometries will likely require other friction ratios. In summary, CMHA-S film retention can be achieved through simple modifications of geometry and manipulation of surface interaction with the eye. PMID- 29150764 TI - Projections for the changes in growing season length of tree-ring formation on the Tibetan Plateau based on CMIP5 model simulations. AB - The response of the growing season to the ongoing global warming has gained considerable attention. In particular, how and to which extent the growing season will change during this century is essential information for the Tibetan Plateau, where the observed warming trend has exceeded the global mean. In this study, the 1960-2014 mean length of the tree-ring growing season (LOS) on the Tibetan Plateau was derived from results of the Vaganov-Shashkin oscilloscope tree growth model, based on 20 composite study sites and more than 3000 trees. Bootstrap and partial correlations were used to evaluate the most significant climate factors determining the LOS in the study region. Based on this relationship, we predicted the future variability of the LOS under three emission scenarios (Representative Concentration Pathways (RCP) 2.6, 6.0, and 8.5, representing different concentrations of greenhouse gasses) derived from 17 Earth system models participating in the Coupled Model Intercomparison Project Phase 5 (CMIP5). The averaged LOS on the Tibetan Plateau is 103 days during the period 1960-2014, and April-September minimum temperature is the strongest factor controlling the LOS. We detected a general increase in the LOS over the twenty-first century under all the three selected scenarios. By the middle of this century, LOS will extend by about 3 to 4 weeks under the RCPs 2.6 and 6.0, and by more than 1 month (37 days) under the RCP 8.5, relative to the baseline period 1960-2014. From the middle to the end of the twenty-first century, LOS will further extend by about 3 to 4 weeks under the RCPs 6.0 and 8.5, respectively. Under the RCP 2.6 scenario, however, the extension reaches a plateau at around 2050 and about 2 weeks LOS extension. In total, we found an average rate of 2.1, 3.6, and 5.0 days decade-1 for the LOS extension from 2015 to 2100 under the RCPs 2.6, 6.0, and 8.5, respectively. However, such estimated LOS extensions may be offset by other ecological factors that were not included into the growth model. The estimated lengthening of the growing season could substantially affect carbon sequestration and forest productivity on the Tibetan Plateau. PMID- 29150766 TI - SpinoBot: An MRI-Guided Needle Positioning System for Spinal Cellular Therapeutics. AB - The neurodegenerative disease amyotrophic lateral sclerosis (ALS) results in the death of motor neurons in voluntary muscles. There are no cures for ALS and few available treatments. In studies with small animal models, injection of cellular therapeutics into the anterior horn of the spinal cord has been shown to inhibit the progression of ALS. It was hypothesized that spinal injection could be made faster and less invasive with the aid of a robot. The robotic system presented SpinoBot-uses MRI guidance to position a needle for percutaneous injection into the spinal cord. With four degrees of freedom (DOF) provided by two translation stages and two rotational axes, SpinoBot proved capable of advanced targeting with a mean error of 1.12 mm and standard deviation of 0.97 mm in bench tests, and a mean error of 2.2 mm and standard deviation of 0.85 mm in swine cadaver tests. SpinoBot has shown less than 3% signal-to-noise ratio reduction in 3T MR imaging quality, demonstrating its compliance to the MRI environment. With the aid of SpinoBot, the length of the percutaneous injection procedure is reduced to less than 60 min with 10 min for each additional insertion. Although SpinoBot is designed for ALS treatment, it could potentially be used for other procedures that require precise access to the spine. PMID- 29150767 TI - Cell Migration in 1D and 2D Nanofiber Microenvironments. AB - Understanding how cells migrate in fibrous environments is important in wound healing, immune function, and cancer progression. A key question is how fiber orientation and network geometry influence cell movement. Here we describe a quantitative, modeling-based approach toward identifying the mechanisms by which cells migrate in fibrous geometries having well controlled orientation. Specifically, U251 glioblastoma cells were seeded onto non-electrospinning Spinneret based tunable engineering parameters fiber substrates that consist of networks of suspended 400 nm diameter nanofibers. Cells were classified based on the local fiber geometry and cell migration dynamics observed by light microscopy. Cells were found in three distinct geometries: adhering two a single fiber, adhering to two parallel fibers, and adhering to a network of orthogonal fibers. Cells adhering to a single fiber or two parallel fibers can only move in one dimension along the fiber axis, whereas cells on a network of orthogonal fibers can move in two dimensions. We found that cells move faster and more persistently in 1D geometries than in 2D, with cell migration being faster on parallel fibers than on single fibers. To explain these behaviors mechanistically, we simulated cell migration in the three different geometries using a motor-clutch based model for cell traction forces. Using nearly identical parameter sets for each of the three cases, we found that the simulated cells naturally replicated the reduced migration in 2D relative to 1D geometries. In addition, the modestly faster 1D migration on parallel fibers relative to single fibers was captured using a correspondingly modest increase in the number of clutches to reflect increased surface area of adhesion on parallel fibers. Overall, the integrated modeling and experimental analysis shows that cell migration in response to varying fibrous geometries can be explained by a simple mechanical readout of geometry via a motor-clutch mechanism. PMID- 29150768 TI - Toe web intertrigo in Kaposi's sarcoma patients: a microbiological study in a large cohort of patients. AB - Kaposi 's sarcoma (KS) is a rare multifocal angioproliferative disease associated with human herpes virus 8 (HHV-8) infection, characterized by cutaneous nodules or plaques especially on the lower limbs. Some skin modifications, such as chronic lymphedema, plantar hyperkeratosis and interdigital desquamation, may be associated with consequent impairment of the local immunosurveillance and increased risk of some bacterial or mycotic infections. With the objective of evaluating if bacterial or mycotic infections in KS patients are supported by different microorganisms compared to control patients, we performed an observational retrospective study, comparing positive cultural swabs of interdigital intertrigo of KS patients with positive cultural swabs of interdigital intertrigo of patients admitted to our dermatologic unit during the last 10 years. One hundred KS patients and 84 control patients were admitted to this study. Some of the skin swabs from interdigital spaces were positive for more than one microorganism, and therefore we found 187 microorganisms among the KS group and 182 microorganisms in the control group. The most common microrganisms among KS patients were T. mentagrophytes (16%), S. aureus (14.9%), P. aeruginosa (13.9%), S. marcescens (5,9%), while among non-KS patients were S. aureus (26,9%), C. albicans (22%), S. agalactiae (7.7%) and E. coli (9.9%). These differences are statistically significant (p < 0.01). KS patients may be more affected by toe web intertrigo due to other bacteria and dermatophytes than the general population. During clinical examination, a careful inspection is necessary for an early diagnosis of toe web intertrigo, in order to prevent serious complications, such as cellulitis and sepsis. Consequently, a cultural examination with antibiogram is required to identify the causative agent of intertrigo and guide antimicrobial therapy. PMID- 29150770 TI - Population in vitro-in vivo pharmacokinetic model of first-pass metabolism: itraconazole and hydroxy-itraconazole. AB - The aim of this study was to develop a population in vitro-in vivo pharmacokinetic model that simultaneously describe the absorption and accumulation kinetics of itraconazole (ICZ) and hydroxy-itraconazole (HICZ) in healthy subjects. The model integrated meta-models of gastrointestinal pH and gastrointestinal transit time and in vitro dissolution models of ICZ with the absorption and disposition kinetics of ICZ and HICZ. Mean concentration intravenous data, and single- and multi-dose oral data were used for model development. Model development was conducted in NONMEM in a stepwise manner. First, a model of intravenous data (systemic kinetics) was established and then extended to include the oral data. The latter was then extended to establish the in vitro-in vivo pharmacokinetic model. The systemic disposition of ICZ was best described by a 3-compartment model with oral absorption described by 4-transit compartments and HICZ distribution by a 1-compartment model. ICZ clearance was best described using a mixed inhibition model that allowed HICZ concentrations to inhibit the clearance of parent drug. HICZ clearance was described by Michaelis Menten elimination kinetics. An in vitro-in vivo model was successfully established for both formulations. The presented model was able to describe ICZ and HICZ plasma concentrations over a wide range of oral and intravenous doses and allowed the exploration of complexities associated with the non-linear ICZ and HICZ kinetics. The model may provide insight into the variability in exposure of ICZ with respect to relating in vivo dissolution characteristics with in vivo disposition kinetics. PMID- 29150769 TI - Changes in Expression of the Membrane Receptors CD14, MHC-II, SR-A, and TLR4 in Tissue-Specific Monocytes/Macrophages Following Porphyromonas gingivalis-LPS Stimulation. AB - The aim of the study was to provide a theoretical foundation for understanding the relationship between periodontal diseases and systemic diseases by examining the inflammatory effect of Porphyromonas gingivalis lipopolysaccharide (LPS) on monocytes/macrophages isolated from tissues distinct from the oral cavity in normal and hyperlipidemic New Zealand white rabbits. Macrophages were isolated from four separate tissues (mononuclear cells from blood, alveolar macrophages, peritoneal macrophages, and Kupffer cells) from both normal and hyperlipidemic New Zealand white rabbits. Cells were either stimulated for 24 h in vitro with P. gingivalis-LPS or Escherichia coli-LPS, or were pre-treated with IL-10 before P. gingivalis-LPS treatment. RNA was isolated and the expression of SR-A, TLR4, CD14, and MHC-II measured by RT-PCR. For MHC-II, the suppression effects of P. gingivalis-LPS were similar to the effects of E. coli-LPS in all macrophages examined. In general, the magnitude of the effects of P. gingivalis-LPS on gene expression was lower than that of E. coli-LPS, and there were differences in the relative membrane receptors between the two, implying that the two LPSs stimulate different responses. IL-10 increased the expression of the defensive receptor SR A and decreased the expression of CD14, TLR4, and the antigen-presenting molecule MHC-II in all types of macrophages examined, regardless of hyperlipidemic state. These data are consistent with an anti-inflammatory effect of IL-10. P. gingivalis-LPS is an activator of gene expression in macrophages isolated from tissues distinct from the oral cavity. PMID- 29150771 TI - Occurrence and Partition of Perfluorinated Compounds (PFCs) in Water and Sediment from the Songhua River, China. AB - This study provided the first evidence that perfluorinated compounds (PFCs) were widely detected in the Songhua River, China. Seventeen surface water and sediment samples were collected and analyzed for the determination of 14 PFCs. The total concentrations of PFCs (Sigma PFCs) ranged from 0.143 to 1.41 ng L-1 in water samples. Perfluorooctanoic acid (PFOA) was detected with the highest detection frequency (%) ranging from below LOQ to 0.678 ng L-1. Sigma PFCs were relatively low in sediments, and only four individual homologues were detected. Perfluorooctane sulfonate (PFOS) and PFOA were detected with the lowest levels in this study compared with other PFCs detected in all the rivers of China in previous studies. The concentrations of PFCs were highly influenced by distribution of wastewater treatment plants (WWTPs). The effluents from WWTPs, which are discharged into the Songhua River, are regarded as the main contamination sources of PFCs in this study. Even though low risk for the concentrations of PFOS and PFOA to aquatic ecosystem of the Songhua River was found in the analysis of potential adverse effect, further experimental studies on occurrence of PFCs and their potential adverse effects to wildlife and humans should be conducted continuously in the Songhua River basin because of the increasing discharge. The mean partition coefficients (log K oc) of PFOS between sediment and water was 4.49 cm3 g-1, which was probably influenced by the sediment characteristics and hydrodynamic parameters. PFCs tend to accumulate in water compared with other persistent organic pollutants. PMID- 29150772 TI - Norovirus GII.17 Associated with a Foodborne Acute Gastroenteritis Outbreak in Brazil, 2016. AB - Foodborne transmission gastroenteritis (AGE) outbreak occurred during a celebration lunch in July, 2016, Brazil. All stool samples tested were positive for noroviruses (NoV) and phylogenetic analysis revealed that strains were genetically close to GII.17 Kawasaki_2014. These findings indicated circulation of NoV GII.17 Kawasaki_2014 in the Brazilian population, associated with AGE outbreak. PMID- 29150773 TI - Overexpression of a Cellobiose-Glucose-Halotolerant Endoglucanase from Scytalidium thermophilum. AB - Enzyme reaction products and by-products from pretreatment steps can inhibit endoglucanases and are major factors limiting the efficiency of enzymatic lignocellulosic biomass hydrolysis. The gene encoding the endoglucanase from Scytalidium thermophilum (egst) was cloned and expressed as a soluble protein in Pichia pastoris GS115. The recombinant enzyme (Egst) was monomeric (66 kDa) and showed an estimated carbohydrate content of 53.3% (w/w). The optimum temperature and pH of catalysis were 60-70 degrees C and pH of 5.5, respectively. The enzyme was highly stable at pH 3.0-8.0 with a half-life in water of 100 min at 65 degrees C. The Egst presented good halotolerance, retaining 84.1 and 71.4% of the control activity in the presence of 0.5 and 2.0 mol L-1 NaCl, respectively. Hydrolysis of medium viscosity carboxymethylcellulose (CMC) by Egst was stimulated 1.77-, 1.84-, 1.64-, and 1.8-fold by dithiothreitol, beta mercaptoethanol, cysteine, and manganese at 10, 10, 10, and 5 mmol L-1 concentration, respectively. The enzyme hydrolyzed CMC with maximal velocity and an apparent affinity constant of 432.10 +/- 16.76 and 10.5 +/- 2.53 mg mL-1, respectively. Furthermore, the Egst was tolerant to reaction products and able to act on pretreated fractions sugarcane bagasse demonstrating excellent properties for application in the hydrolysis of lignocellulosic biomass. PMID- 29150774 TI - Co-expression of Exo-inulinase and Endo-inulinase Genes in the Oleaginous Yeast Yarrowia lipolytica for Efficient Single Cell Oil Production from Inulin. AB - Yarrowia lipolytica is a promising platform for the single cell oil (SCO) production. In this study, a transformant X+N8 in which exo- and endo-inulinase genes were co-expressed could produce an inulinase activity of 124.33 U/mL within 72 h. However, the inulinase activity of a transformant X2 carrying a single exo inulinase gene was only 47.33 U/mL within 72 h. Moreover, the transformant X+N8 could accumulate 48.13% (w/w) SCO from inulin and the cell dry weight reached 13.63 g/L within 78 h, which were significantly higher than those of the transformant X2 (41.87% (w/w) and 11.23 g/L) under the same conditions. In addition, inulin hydrolysis and utilization of the transformant X+N8 were also more efficient than those of the transformant X2 during the fermentation process. These results demonstrated that the co-expression of the exo- and endo-inulinase genes significantly enhanced the SCO production from inulin due to the improvement of the inulinase activity and the synergistic action of exo- and endo inulinase. Besides, over 95.01% of the fatty acids from the transformant X+N8 were C16-C18, especially C18:1 (53.10%), suggesting that the fatty acids could be used as feedstock for biodiesel production. PMID- 29150775 TI - Influences of obstructive sleep apnea on blood pressure variability might not be limited only nocturnally in middle-aged hypertensive males. AB - PURPOSE: In this cross-sectional study, we analyzed the potential association between sleep measures and blood pressure variability. METHODS: Ninety-three middle-aged hypertensive males, who underwent polysomnography and 24-h ambulatory blood pressure monitoring, were enrolled. Blood pressure variability was assessed by blood pressure standard deviation. Obstructive sleep apnea (apnea hypopnea index >= 15) was diagnosed in 52 (55.91%) patients. Mean body mass index and age were 27.77 +/- 3.11 kg/m2 and 44.05 +/- 8.07 years, respectively. RESULTS: Hypertensive males with obstructive sleep apnea showed significantly higher 24-h, diurnal, and nocturnal diastolic blood pressure variability, compared to those without obstructive sleep apnea. While total cohort was further divided into two groups using the median of oxygen desaturation index, another indicator for severity of OSA, significant differences were also observed in 24-h, diurnal, and nocturnal diastolic blood pressure variability between two groups with higher and lower oxygen desaturation index. While subjects were also divided into two groups via the mean of sleep stage 1, hypertensive males with sleep stage 1 >= 8.1% showed significantly higher diurnal diastolic blood pressure variability than those with sleep stage 1 < 8.1%. Apnea hypopnea index was independently associated with 24-h and nocturnal diastolic blood pressure variability; oxygen desaturation index of 3% with 24-h diastolic, diurnal, and nocturnal diastolic blood pressure; and sleep stage 1 was with 24-h and with diurnal diastolic blood pressure variability in all study subjects. CONCLUSION: Effects of obstructive sleep apnea on blood pressure variability may not be limited nocturnally. PMID- 29150776 TI - Hyperpyrexia as the Presenting Symptom of Intracranial Hypotension. AB - INTRODUCTION: Hyperpyrexia is a severely elevated core body temperature secondary to an elevated hypothalamic set thermo-regulatory threshold. Hyperthermia is an elevated core body temperature beyond the normal hypothalamic set thermo regulatory threshold. Intracranial hypotension can present with a wide variety of symptoms ranging from orthostatic headache up to coma. We report a rare case of hyperpyrexia associated with intracranial hypotension. METHODS: A case report of a 55-year-old female patient with a history of angiogram-negative subarachnoid hemorrhage status post-ventriculoperitoneal (VP) shunt placement six years prior to admission who suddenly developed encephalopathy and high fever. Conventional management of the fever was unsuccessful. RESULTS AND MANAGEMENT: Brain magnetic resonance imaging revealed signs of significant intracranial hypotension. When the VP shunt was tapped, no cerebrospinal fluid (CSF) could be obtained. Once the VP shunt settings were adjusted, the patient's encephalopathy and hyperpyrexia resolved. CONCLUSION: Hyperpyrexia might be a presenting symptom of intracranial hypotension, likely, secondary to hypothalamic dysfunction and compression. In our case, hyperpyrexia was reversible as the intracranial hypotension was emergently treated. Spontaneous intracranial hypotension might be difficult to diagnose, especially if it presented with non-classical symptoms like fever; thus, physicians should be aware of such association. PMID- 29150777 TI - Glibenclamide and Therapeutic Hypothermia Have Comparable Effect on Attenuating Global Cerebral Edema Following Experimental Cardiac Arrest. AB - BACKGROUND: Cerebral edema is one of the major causes of mortality following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). A subunit of the sulfonylurea receptor 1-transient receptor potential M4 (Sur1-TRPM4) channel has been implicated in the pathogenesis of ischemia-evoked cerebral edema. In this study, we examined whether glibenclamide (GBC), a Sur1-TRPM4 channel inhibitor, attenuates cerebral edema following CA/CPR and further examined the efficacy of GBC combined with therapeutic hypothermia. METHODS: Isoflurane-anesthetized adult male wild-type C57Bl/6 mice subjected to 7-min CA/CPR were randomized into five groups: sham operation, control with normothermia, GBC with normothermia, control with hypothermia, and GBC with hypothermia. The primary outcome was to evaluate regional brain water content; the secondary outcome was to measure blood glucose level, Sur1-TRPM4 expression, and pro-inflammatory factor expression. RESULTS: Compared with normothermia, GBC treatment or hypothermia significantly attenuated brain water content in mice subjected to CA/CPR. GBC combined with hypothermia had no additional effects on attenuating cerebral edema. Pro-inflammatory factor messenger RNA expression (TNF-alpha and IL-6), NFkappabeta activation, and SUR1 TRPM4 levels were upregulated after CA/CPR. Compared with normothermia, hypothermia, but not GBC, partly suppressed these factors' expression. CONCLUSIONS: GBC attenuated cerebral edema following CA/CPR by blocking Sur1 TRPM4 channels upregulated by CA insult. The effect of GBC was comparable with that of therapeutic hypothermia alone. These results suggest that GBC is an alternative approach for treating CA-evoked cerebral edema. PMID- 29150778 TI - Withholding and withdrawing life-sustaining treatment: The Canadian Critical Care Society position paper. PMID- 29150780 TI - Anesthesiologists' perception of perioperative stroke risk during non-neurologic and non-cardiac surgery. PMID- 29150781 TI - A technique for securing the Aintree Intubation CatheterTM to a flexible bronchoscope. PMID- 29150779 TI - Perioperative transesophageal echocardiography for non-cardiac surgery. AB - PURPOSE: The use of transesophageal echocardiography (TEE) has evolved to include patients undergoing high-risk non-cardiac procedures and patients with significant cardiac disease undergoing non-cardiac surgery. Implementation of basic TEE education in training programs has increased across a broad spectrum of procedures in the perioperative arena. This paper describes the use of perioperative TEE in non-cardiac surgery and provides an overview of the basic TEE examination. PRINCIPAL FINDINGS: Perioperative TEE is used to monitor hemodynamic parameters in non-cardiac procedures where there is a high risk of hemodynamic instability. Its use extends to include moderate-risk procedures for patients with significant cardiac diseases such as low ejection fraction, hypertrophic cardiomyopathy, severe valve lesions, or congenital heart disease. Vascular procedures involving the aorta, blunt trauma, and liver transplantation are all examples of procedures that may benefit from TEE. Transesophageal echocardiography examination allows assessment of volume status, ventricular function, diagnosis of gross valvular pathology and pericardial tamponade, as well as close monitoring of cardiac output, response to therapy, and the impact of ongoing surgical manipulation. In patients with unexplained and unexpected hemodynamic instability, "rescue TEE" can be used to help identify the underlying cause. CONCLUSIONS: Perioperative TEE is emerging as a preferred tool to manage hemodynamics in high-risk procedures and in high-risk patients undergoing non cardiac surgery. A rescue TEE examination protocol is a helpful approach for early identification of the etiology of hemodynamic instability. PMID- 29150782 TI - Nitrous oxide added at the end of isoflurane anesthesia hastens early recovery without increasing the risk for postoperative nausea and vomiting: a randomized clinical trial. AB - BACKGROUND: Nitrous oxide (N2O) has been reported to increase the risk of postoperative nausea and vomiting (PONV) in a dose-dependent manner. We investigated the effect of adding N2O at the end of isoflurane inhalational anesthesia on the recovery and incidence of PONV. Our hypothesis was that N2O would reduce the time to early recovery without increasing the incidence of PONV. METHODS: After obtaining ethics committee approval and written informed consent, 100 women at American Society of Anesthesiologists physical status I-III and scheduled for laparoscopic-assisted vaginal hysterectomy were randomized into two groups (G) according to the carrier gas: GO2 (air in 30% oxygen) and GN2O (the same mixture until the last 30 min of surgery, when 70% N2O in 30% oxygen was used). No PONV prophylaxis was given. Anesthesia was induced with thiopental 5 mg.kg-1, vecuronium 0.1 mg.kg-1, and fentanyl 1-2 MUg.kg-1 iv and maintained with isoflurane. Indicators of early recovery (time to extubation, eye opening, following commands, orientation) were assessed by an anesthesiologist unaware of the group assignment. The incidence and severity of PONV was measured at two and 24 hr postoperatively. RESULTS: Altogether, 82 participants completed the study (42 in GO2, 40 in GN2O) and were analyzed. The mean (SD) time of N2O administration in GN2O patients was 27.1 (10.1) min. The mean (SD) time to extubation was faster in GN2O patients [5.4 (2.9) min] than in GO2 patients [7.5 (3.7) min] (mean difference, 2.0 min; 95% confidence interval [CI], 0.6 to 3.4, P = 0.009). The ability to open eyes, follow commands, and being oriented were all faster in GN2O patients than in GO2 patients (differences of 3.9 min, 95% CI, 1.6 to 6.1, P = 0.001; 3.4 min, 95% CI, 1.0 to 5.7, P = 0.006; 3.8 min, 95% CI, 0.9 to 6.7, P = 0.010, respectively). The incidence of PONV was not different between the groups, but the rescue antiemetic was required less often in the GN2O patients (mean difference in metoclopramide dose between the GN2O and GO2 groups, 5.1 mg; 95% CI, 0.8 to 9.4, P = 0.019). CONCLUSIONS: Adding N2O during the last 30 min of an isoflurane-based inhalational anesthetic reduced the time to extubation, eye opening, and orientation. PMID- 29150784 TI - Characteristics and outcomes of patients who underwent bedside surgical tracheostomy performed in the intensive care unit: a retrospective study. PMID- 29150783 TI - Incidence of non-physiologically complex surgical procedures performed in children: an Ontario population-based study of health administrative data. AB - PURPOSE: Quantification of surgical procedures undertaken by hospitals is necessary for informing resource allocation and modelling healthcare services. Our objective was to quantify the incidence, similarity, and diversity of non physiologically complex surgical procedures performed at pediatric specialist hospitals and other hospitals performing pediatric surgery. METHODS: We conducted a population-based cohort study of children aged 28 days to 18 yr who underwent surgery in the province of Ontario from 2007 to 2015 using healthcare administrative databases. We estimated the incidence of non-physiologically complex procedures (i.e., <= 7 basic units in the 2015 Ontario Health Insurance Plan Schedule of Benefits) performed in pediatric specialist hospitals and other hospitals performing pediatric surgery. We used Yue and Clayton's index and the effective number of common procedures (1/Herfindahl index) to quantify the similarity and diversity of pediatric surgical procedures performed in these hospital types. RESULTS: Overall, 830,830 pediatric surgical procedures were performed in 158 Ontario hospitals during the eight-year study period. Most surgical procedures performed at hospitals performing pediatric surgery were non physiologically complex (vs 50%, P < 0.001). The incidence of non-physiologically complex procedures increased progressively each year at pediatric specialist hospitals and was associated with a reciprocal decline among the other hospitals. Comparing pediatric specialist hospitals with the other hospitals, the mean similarity index for non-physiologically complex procedures was less than moderate (0.52; 95% confidence interval [CI], 0.51 to 0.54). The mean effective number of common non-physiologically complex procedures (i.e., the diversity) among the pediatric specialist hospitals was greater than at the other 154 hospitals performing pediatric surgery (65.3 vs 21.8 procedures, respectively; mean difference, 43.5; 95% CI, 42.2 to 44.8; P < 0.001). CONCLUSIONS: Non physiologically complex procedures have progressively migrated to pediatric specialist hospitals from other hospitals in Ontario. Specialty pediatric hospitals are principally dissimilar from other hospitals performing pediatric surgery based not on physiological complexity, but on their diversity. These findings suggest that some types of surgical procedures may be redistributed from specialist pediatric hospitals to other hospitals performing pediatric surgery. TRIAL REGISTRATION: www.clinicaltrials.gov , number NCT03144544. Registered 2 May 2016. PMID- 29150785 TI - Survey of medical students' knowledge and perceptions of anesthesiology at one Canadian university: pre-clerkship and during clinical clerkship, a cohort study. PMID- 29150786 TI - The gas has the last laugh. PMID- 29150787 TI - The Young Investigator Retreat of the Canadian Critical Care Trials Group: mentorship and self-discovery. PMID- 29150788 TI - CDK4, CDK6, cyclin D1, p16(INK4a) and EGFR expression in glioblastoma with a primitive neuronal component. AB - Glioblastoma with primitive neuroectodermal tumor-like component (GBM-PNET) is a rare variant of glioblastoma, which was renamed as glioblastoma with a primitive neuronal component (GBM-PN) in new WHO classification of tumours of the central nervous system in 2016. There are few publications on the investigation of GBM PN. In this study, PCR mRNA arrays on 6 cases of conventional GBM and 10 cases of GBM-PN showed high mRNA level of CDK4 in GBM-PN and low mRNA level of EGFR in GBM PN. Immunohistochemical stains on tissue microarrays with 28 cases of conventional GBM and 13 cases of GBM-PN demonstrated that CDK4 was selectively expressed in the primitive neuronal component of all GBM-PN cases while EGFR was positive in conventional GBM and glial component of GBM-PN, but was negative in the primitive neuronal component of all GBM-PN cases. Immunohistochemical stains with antibodies against proteins that interact with CDK4 in cell cycle regulation, such as CDK6, cyclin D1 and p16(INK4a), were performed on these GBM PN and GBM cases. CDK6 was patchily positive in rare cases of GBM-PN and cyclin D1 was negative in GBM-PN cases. p16(INK4a) is traditionally known as an inhibitor of CDK4 and CDK6. p16(INK4a) might not be the inhibitor of CDK4 in GBM PN cases because seven GBM-PN cases were positive for both CDK4 and p16(INK4a). It indicates that CDK4 and p16(INK4a) might play a crucial role in GBM-PN pathogenesis. Since CDK4 and EGFR are highly expressed in the primitive neuronal component and in the glial component of GBM-PN respectively, the combination of CDK4/6 inhibitor and targeted therapy against EGFR might be potential effective therapeutic regimen for GBM-PN. CDK4 and EGFR immuohistochemical stain patterns make the diagnosis of GBM-PN much easier. PMID- 29150789 TI - Radial pulse and electrocardiography modulation by mild thermal stresses applied to feet: An exploratory study with randomized, crossover design. AB - OBJECTIVE: To investigate the changes in radial pulse induced by thermal stresses (TSs). METHODS: Sixty subjects were enrolled. Using an open-label, 2*2 crossover randomization design, both feet of each subject were immersed in 15 degrees C water for cold stress (CS) and in 40 degrees C water for heat stress (HS) for 5 min each. Radial pulse, respiration and electrocardiogram (ECG) signals were recorded before, during and immediately after the TSs. RESULTS: The analysis of heart rate variability revealed that CS increased the low-frequency (LF) and high frequency (HF) components (P <0.05) and that HS reduced the LF and HF components (P <0.01). Both TSs reduced the normalized LF, increased the normalized HF, and reduced the LF/HF ratio. The differences in the ECG signals were more dominant during the TS sessions, but those in the radial pulse signals became more dominant immediately after the TS sessions. CS decreased the pulse depth (P <0.01) and increased the radial augmentation index (P <0.1), and HS increased the pulse pressure (P <0.1) and subendocardial viability ratio (P <0.01). There were no significant differences in pulse rate during the three time sequences of each TS. The respiration rate was increased (P <0.1), and the pulse rate per respiration (P/R ratio) was significantly decreased (P <0.05) with CS. The HF region (10-30 Hz) of the pulse spectral density was suppressed during both TSs. CONCLUSIONS: CS induced vasoconstriction and sympathetic reactions, and HS induced vasodilation and parasympathetic reactions. Based on definitions used in pulse diagnosis, we made the novel discoveries that the pulse became slower (decreased P/R ratio), more floating and tenser under CS and that the HF region of the spectral power decreased significantly under both TSs. PMID- 29150790 TI - Clinical study on Yishen Qufeng Shengshi Recipe () for glomerular proteinuria patients: A randomized controlled trial. AB - OBJECTIVE: To explore the therapeutic effect of Yishen Qufeng Shengshi Recipe (, YQSR) in patients with glomerular proteinuria METHODS: A total of 145 patients with glomerular proteinuria were selected and randomly assigned to the treatment group (108 cases) and the control group (37 cases) according to a random number table in a ratio of 3:1. All patients received conventional and symptomatic treatment. In addition, patients in the treatment and control groups were given YQSR (200 mL, twice per day, orally) and losartan (50 mg/d orally), respectively for 6 months. The 24-h urine protein quantity, blood urea nitrogen, and serum creatinine in the two groups were measured at multiple time points before and after treatment. RESULTS: At the end of the study, 5 cases were lost to follow-up in the treatment group and 1 in the control group. Finally, the statistical data included 103 cases in the treatment group and 36 cases in the control group. The total effectiveness after 2, 4, and 6 months was 81.6% (84/103), 87.4% (90/103), and 92.2% (95/103), respectively, in the treatment group and 47.2% (17/36), 55.6% (20/36), and 61.1% (22/36), respectively, in the control group, with significant difference between the two groups (P<0.01 at all observation points). In the treatment group, the curative effect after 6 months was better than that after 2 months (P<0.05). The 24-h urine protein quantity was significantly lower in the treatment group at 3, 4, 5, and 6 months than that in the control group (P<0.05 or P<0.01, respectively) CONCLUSION: YQSR could significantly reduce the amount of glomerular proteinuria in the early stage. PMID- 29150791 TI - 16-Channel Flexible System to Measure Electrophysiological Properties of Bioengineered Hearts. AB - As tissue engineering continues to mature, it is necessary to develop new technologies that bring insight into current paradigms and guide improvements for future experiments. To this end, we have developed a system to characterize our bioartificial heart model and compare them to functional native structures. In the present study, the hearts of adult Sprague-Dawley were decellularized resulting in a natural three-dimensional cardiac scaffold. Neonatal rat primary cardiac cells were then cultured within a complex 3D fibrin gel, forming a 3 dimensional cardiac construct, which was sutured to the acellular scaffold and suspended in media for 24-48 h. The resulting bioartificial hearts (BAHs) were then affixed with 16 electrodes, in different configurations to evaluate not only the electrocardiographic characteristics of the cultured tissues, but to also test the system's consistency. Histological evaluation showed cellularization and cardiac tissue formation. The BAHs and native hearts were then evaluated with our 16-channel flexible system to acquire the metrics associated with their respective electrophysiological properties. Time delays between the native signals were in the range of 0-95 ms. As well, color maps revealed a trend in impulse propagation throughout the native hearts. After evaluation of the normal rat QRS complex we found the average amplitude of the R-wave to be 5351.48 +/- 44.92 MUV and the average QRS duration was found to be 10.61 +/- 0.18 ms. In contrast, BAHs exhibited more erratic and non-uniform activity that garnered no appreciable quantification. The data collected in this study proves our system's efficacy for EKG data procurement. PMID- 29150792 TI - Correlation between MGMT promoter methylation and response to temozolomide-based therapy in neuroendocrine neoplasms: an observational retrospective multicenter study. AB - PURPOSE: Temozolomide (TEM) based therapy has been reported being effective in the treatment of metastatic neuroendocrine neoplasms (NEN), with response rates ranging from 30 to 70%. Among patients affected by advanced glioblastoma or melanoma and treated with TEM, loss of tumoral O6-methylguanine DNA methyltransferase (MGMT) is correlated with improved survival. In NEN patients, the role of MGMT deficiency in predicting clinical outcomes of TEM treatment is still under debate. METHODS: In this study we evaluated 95 patients with advanced NENs undergoing treatment with TEM-based therapy. MGMT promoter methylation status was evaluated with two techniques: methylation specific-polymerase chain reaction or pyrosequencing. RESULTS: Treatment with TEM-based therapy was associated with an overall response rate of 27.4% according to RECIST criteria (51.8% of patients with and 17.7% without MGMT promoter methylation). Response to therapy, progression free survival and overall survival was correlated to MGMT status at univariate and multivariate analysis. Methylation of MGMT promoter could be a strong predictive factor of objective response and an important prognostic factor of a longer PFS and OS. CONCLUSION: According to our results, MGMT methylation status, evaluated with methylation specific-polymerase chain reaction or pyrosequencing, should have an important role in patients with metastatic NENs, in order to guide therapeutic options. These results need further confirmation with prospective studies. PMID- 29150793 TI - High-Efficient Liquid Exfoliation of Boron Nitride Nanosheets Using Aqueous Solution of Alkanolamine. AB - As one of the simple and efficient routes to access two-dimensional materials, liquid exfoliation has received considerable interest in recent years. Here, we reported on high-efficient liquid exfoliation of hexagonal boron nitride nanosheets (BNNSs) using monoethanolamine (MEA) aqueous solution. The resulting BNNSs were evaluated in terms of the yield and structure characterizations. The results show that the MEA solution can exfoliate BNNSs more efficiently than the currently known solvents and a high yield up to 42% is obtained by ultrasonic exfoliation in MEA-30 wt% H2O solution. Finally, the BNNS-filled epoxy resin with enhanced performance was demonstrated. PMID- 29150794 TI - Shunt surgery in idiopathic normal pressure hydrocephalus is cost-effective-a cost utility analysis. AB - BACKGROUND: The objective was to evaluate the cost-effectiveness of shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Health related quality of life was evaluated before and 6 months after surgery using the EQ-5D-3 L (EuroQOL group five-dimensions health survey) in 30 patients (median age, 71 years; range, 65-89 years) diagnosed with iNPH. The costs associated with shunt surgery were assessed by a detailed survey with interviews and extraction of register data concerning the cost of hospital care, primary care, residential care, home-care service and informal care. The cost of untreated patients was derived from the cost of dementia disorders in Sweden in 2012, as reported by the National Board of Health and Welfare. The cost effectiveness analysis used a decision-analytic Markov model. We used a societal perspective and a lifelong time horizon to estimate costs and effects. One-way sensitivity analysis and probabilistic sensitivity analysis were carried out to test the robustness of the model. RESULTS: The shunt surgery model as the standard treatment in iNPH resulted in a gain of 2.2 life years and 1.7 quality-adjusted life years (QALY), along with an incremental cost per patient of ?7,500/QALY. The sensitivity analysis showed that the results were not sensitive to changes in uncertain parameters or assumptions. CONCLUSIONS: Shunt surgery in iNPH, an underdiagnosed condition severely impairing elderly patients, is not only an effective medical treatment, it is also cost-effective, adding 2.2 additional life years and 1.7 QALYs at a low cost, a remarkable gain for an individual aged around 70 years. PMID- 29150795 TI - Navigated 3D-ultrasound versus conventional neuronavigation during awake resections of eloquent low-grade gliomas: a comparative study at a single institution. AB - BACKGROUND: The data showing usefulness of navigated 3D-ultrasound (3DUS) during awake resections of eloquent gliomas are sparse. Results of surgeries performed using 3DUS were never compared to procedures guided by standard neuronavigation. The aim of this work is to assess the effectiveness of 3DUS during awake resections of eloquent low-grade gliomas (LGGs) by comparing surgical results of two series of patients operated on using conventional neuronavigation and using 3DUS. To our knowledge, a similar study is lacking in the literature. METHODS: During a 4-year period (September 2006 to August 2010) 21 awake resections of LGGs guided by neuronavigation (series 1, S1) were consecutively performed in Department of Neurosurgery in Bratislava. During another 4-year period (August 2010 to July 2014) 28 awake resections of LGGs guided by 3DUS (series 2, S2) were consecutively conducted. In both patients series, the eloquent cortical and subcortical structures were intraoperatively detected by direct electrical stimulation. Extent of tumor resection (EOR) and functional outcome in both series were compared. RESULTS: EOR was significantly greater (p = 0.022) in S2 (median = 93.25%; mean = 86.79%), as compared to S1 (median 87.1%; mean = 75.85%). One permanent minor deficit in S1 and 2 minor deficits in S2 occurred, the difference was not significant (p = 0.999). CONCLUSIONS: Our work represents the first study comparing results of surgeries guided by 3DUS versus conventional navigation. The extent of awake resections of eloquent LGG guided by 3DUS was greater comparing to awake resections guided by standard neuronavigation; use of 3DUS had no impact on the number of new permanent deficits. PMID- 29150797 TI - No Place to Call Home. PMID- 29150798 TI - Reframing Narratives as a Means of Building Self-Efficacy in Medical Students. PMID- 29150796 TI - Gender differences in chronic liver diseases in two cohorts of 2001 and 2014 in Italy. AB - BACKGROUND: Gender differences in chronic liver disease (CLD) have been partially investigated. To extend the present knowledge, we evaluated 12,263 patients with CLD enrolled in two national surveys (9997 in 2001 and 2557 in 2014). METHODS: The two surveys prospectively recruited patients aged >= 18 referring to Italian liver units throughout the country using a similar clinical approach and analytical methods. RESULTS: The overall male to female ratio (M/F) was 1.4 (7138/5124). Compared with females, males were significantly more likely to be younger (52.9 vs. 58.7 yrs.), with HBV infection alone (13.2% vs. 9.2%) and with alcoholic liver disease alone (11.4% vs. 6.9%), but less likely to show HCV infection alone (48.0% vs. 67.9%). A male preponderance was observed in HBV related cases (1.99) and in alcoholic-related cases (2.3), a preponderance observed both in the 2001 and in 2014 cases. In HCV-related cases, however, females predominated in 2001 (M/F 0.9) and males in 2014 (M/F 1.5).The rate of cirrhosis in alcohol-related etiology was close to 36% in both genders, a finding much higher than that observed for both sexes in HBV and HCV etiologies.Both males and females enrolled in 2014 were older (p < 0.001) and with a higher rate of cirrhosis and/or HCC (p < 0.001) than those investigated in 2001. There was a remarkable increase over time in the proportion of male abstainers (36.7% in 2001 and 64.3% in 2014). CONCLUSION: This study highlights important inter- and intra gender differences in the characteristics and etiological factors of patients with CLD in Italy. PMID- 29150799 TI - A hybrid approach based on logistic classification and iterative contrast enhancement algorithm for hyperintense multiple sclerosis lesion segmentation. AB - Multiple sclerosis (MS) is a neurodegenerative disease with increasing importance in recent years, in which the T2 weighted with fluid attenuation inversion recovery (FLAIR) MRI imaging technique has been addressed for the hyperintense MS lesion assessment. Many automatic lesion segmentation approaches have been proposed in the literature in order to assist health professionals. In this study, a new hybrid lesion segmentation approach based on logistic classification (LC) and the iterative contrast enhancement (ICE) method is proposed (LC+ICE). T1 and FLAIR MRI images from 32 secondary progressive MS (SPMS) patients were used in the LC+ICE method, in which manual segmentation was used as the ground truth lesion segmentation. The DICE, Sensitivity, Specificity, Area under the ROC curve (AUC), and Volume Similarity measures showed that the LC+ICE method is able to provide a precise and robust lesion segmentation estimate, which was compared with two recent FLAIR lesion segmentation approaches. In addition, the proposed method also showed a stable segmentation among lesion loads, showing a wide applicability to different disease stages. The LC+ICE procedure is a suitable alternative to assist the manual FLAIR hyperintense MS lesion segmentation task. PMID- 29150800 TI - Beat-to-beat estimation of stroke volume using impedance cardiography and artificial neural network. AB - Impedance cardiography is a low-cost noninvasive technique, based on monitoring of the thoracic impedance, for estimation of stroke volume (SV). Impedance cardiogram (ICG) is the negative of the first derivative of the impedance signal. A technique for beat-to-beat SV estimation using impedance cardiography and artificial neural network (ANN) is proposed. A three-layer feed-forward ANN with error back-propagation algorithm is optimized by examining the effects of number of neurons in the hidden layer, activation function, training algorithm, and set of input parameters. The input parameters are obtained by automatic detection of the ICG characteristic points, and the target values are obtained by beat-to-beat SV measurements from time-aligned Doppler echocardiogram. The technique is evaluated using an ICG-echocardiography database with recordings from subjects with normal health in the under-rest and post-exercise conditions and from subjects with cardiovascular disorders in the under-rest condition. The proposed technique performed much better than the earlier established equation-based estimations, and it resulted in correlation coefficient of 0.93 for recordings from subjects with cardiovascular disorders. It may be helpful in improving the acceptability of impedance cardiography in clinical practice. Graphical abstract ?. PMID- 29150801 TI - Soil physical properties response to tillage practices during summer fallow of dryland winter wheat field on the Loess Plateau. AB - Soil physical properties are a greatly important part of the soil and indicator of soil quality, which can directly affect soil nutrient turnover and crop yields in dryland. This study was carried out with three tillage practices during the summer fallow season since 2011, including no tillage (NT), plow tillage (PT), and subsoiling (ST) in dryland winter wheat fields of the Loess Plateau. Results showed that soil tillage during the summer fallow had a small effect on soil bulk density (rho b) in the 0-50-cm soil profile before sowing and after harvesting of winter wheat. Soil rho b under NT at a depth of 20-30 cm was significantly greater than those under PT in both seasons. Both soil gravimetric water content (theta g) and volumetric moisture content (theta v) after harvesting increased by 28.8-78.6% and 37.5-87.3%, respectively, compared with those before sowing. Adoption of PT significantly increased soil theta g and theta v in the entire 0 50-cm profile before sowing compared with NT and ST (P < 0.05). In addition, there was a small effect on soil porosity (e.g., total porosity, air-filled porosity, and capillary porosity) in the profile of 0-50 cm both before sowing and after harvesting. Overall, short-term tillage during summer fallow mainly affected soil water content in the 0-50-cm soil profile, and it had a slight effect on other physical soil properties. PMID- 29150802 TI - Ion-imprinted electrospun nanofibers of chitosan/1-butyl-3-methylimidazolium tetrafluoroborate for the dynamic expulsion of thorium (IV) ions from mimicked effluents. AB - The present study explores the innocuous, biocompatible, and extremely competent molecularly imprinted chitosan/RTIL electrospun nanofibers having average diameter of 30 nm for the expulsion of thorium (IV) ions from the mimicked effluent waste. The extended Flory-Huggins theory and three-dimensional molecular modeling have been effectively premeditated via Materials Studio software for enumerating the inter-miscibility and compatibility (Chi parameter (chi) = 1.019, mixing energy (Emix) = 0.603 kcal/mol) of the chitosan/RTIL (1-butyl-3 methylimidazolium tetrafluoroborate). The maximum adsorption efficiency is found to be 90% at a neutral pH of 7, and a temperature of 298 K within 120 min. The adsorption process was extensively studied by two-parameter adsorption isotherms like Langmuir, Freundlich, Temkin, and Dubinin-Radushkevich (D-R) and three parameter models like Redlich-Paterson and Sips isotherm. Pseudo-second-order kinetics model (R2 = 0.982) and Langmuir isotherm (R2 = 0.994) bestowed the best fitting on chitosan/RTIL nanofibers for the adsorption of Th (IV) ions. The thermodynamic study reveals the spontaneity and exothermic nature of the reaction. The experimental analysis conjoint with isotherm and kinetic models, and simulation study establish the applicability of chitosan/RTIL nanofibers for the expulsion of Th (IV) and other toxic metal ions from the effluents. Graphical abstract Ion-imprinted electrospun nanofiber for expulsion of thorium (IV) ion. PMID- 29150803 TI - Comprehensive study of the mountainous lake sediments in relation to natural and anthropogenic processes and time (Maly Staw Lake, Poland). AB - The Sudety Mts. form a chain of mountains in the South of Poland and during the last 200 years were subjected to strong industrial and agricultural pressure. The records of these human-induced changes are stored in natural archives like lake sediments. For the comprehensive study, three sediment cores taken from Maly Staw Lake (Sudety Mts.) were analyzed for the concentration of K, Na, Mn, Fe, Cu, Mg, Zn, Cd, Cr, Ni, Pb and radioactivity of 137Cs and 210Pb. As a result of the studies, the bathymetry map was developed and the sources of solid material supplied to the lake were identified. The geochronology studies of the cores were performed using 210Pb method, to evaluate model of time changes in the sediment. Radioactivity of 210Pbuns (determined indirectly by 210Po) ranged from 1051 +/- 64 to 12 +/- 8 Bq kg-1. The 137Cs radioactivity was determined directly by gamma spectrometry and varied from 525 +/- 37 Bq kg-1 for top layers to 9.80 +/- 5.40 Bq kg-1 for the bottom of the core. Two characteristic peaks of 137Cs radioactivity related to the global fallouts after nuclear weapons testing and the Chernobyl accident were observed and used to confirm 210Pb dating method. Chemometrics analysis of the chosen metal's concentrations combined with sample dating showed distinct imprint of human activity on the studied area. PMID- 29150804 TI - Using Citrus aurantifolia essential oil for the potential biocontrol of Colocasia esculenta (taro) leaf blight caused by Phytophthora colocasiae. AB - The aim of this work was to evaluate the antimicrobial activities of leaves and epicarp of Citrus aurantifolia essential oil against Phytophthora colocasiae, the causative agent of taro leaf blight. Oils were extracted by hydrodistillation, and their chemical composition was determined by gas chromatography and gas chromatography coupled with mass spectrometry. Antimicrobial activities of oils were tested in vitro against mycelium growth and sporangium production. In situ tests were done on healthy taro leaves, and the necrosis symptoms were evaluated. Results showed that the essential oil extraction yields from leaves and epicarp were 0.61 and 0.36%, respectively. Limonene (48.96%), bornyl acetate (14.18%), geraniol (10.53%), geranial (3.93%), and myrcene (3.14%) were the main components in leaf oil, while limonene (59.09%), cis-hydrate sabinene (7.53%), geranial (5.61%), myrtenol (5.02%), and terpinen-4-ol (3.48%) were the main components in epicarp oil. Both oils exhibited antimicrobial activities with total inhibition of the mycelium growth at 500 and 900 ppm for leaf and epicarp, respectively. The highest inhibitory concentration of sporangium production was 400 (72.84%) and 800 ppm (80.65%) for leaf and epicarp oil, respectively. For the standard fungicide (metalaxyl), the total inhibition value of mycelial growth and sporangium production was 750 ppm. In situ tests showed that, at 5000 ppm, total inhibition (100%) was obtained for a preventive test, while 50% of the inhibition was observed for a curative test when leaf oil was applied. When epicarp essential oil was applied at 5000 ppm, 47.5 and 16.66% of the reduction of leaf necrosis were observed for the preventive and curative test, respectively. There were positive correlations between both the oil concentration and the reduction of necrosis caused by P. colocasiae. These findings suggest that the C. aurantifolia essential oil could serve as an eco-friendly biocontrol for the management of taro leaf blight. PMID- 29150805 TI - Aspergillus terreus treated rice straw suppresses methane production and enhances feed digestibility in goats. AB - The objectives of this study were to test the efficacy of producing lovastatin in rice straw treated with Aspergillus terreus in larger laboratory scale following the procedure previously reported and to investigate the effectiveness of the treated rice straw containing lovastatin on methane mitigation in goats. The concentration of lovastatin in the treated rice straw was 0.69 +/- 0.05 g/kg dry matter (DM) rice straw. Our results showed that supplementation of lovastatin at 4.14 mg/kg BW reduced methane production by 32% while improving the DM digestibility by 13% (P < 0.05) in goats fed fermented rice straw compared to those fed untreated rice straw. Populations of total methanogens and Methanobacteriales species were significantly reduced (P < 0.05) while the population of total bacteria and Ruminococcus albus were increased in the treatment group (P < 0.05). Our results demonstrated that lovastatin in the treated rice straw acted specifically on the methanogens by inhibiting the activity of HMG-CoA reductase in the methanogens' cell membrane biosynthesis pathway and thus the growth of rumen methanogens as previously reported. This study provides a simple yet practical approach to mitigate enteric methane production particularly in the developing countries which depend heavily on the use of agro-biomass such as rice straw to feed their ruminant animals. PMID- 29150806 TI - Ticagrelor: A Review in Long Term Secondary Prevention of Cardiovascular Events. AB - Ticagrelor (Brilique(r)) is an orally administered P2Y12 inhibitor. A long-term (maintenance) regimen of ticagrelor 60 mg twice daily is indicated in the EU for coadministration with low-dose aspirin 75-150 mg/day for the secondary prevention of atherothrombotic events in high-risk patients with a history of myocardial infarction (MI) of at least 1 year. Approval is based on the results of the PEGASUS-TIMI 54 trial that compared ticagrelor with placebo (in conjunction with low-dose aspirin) in stable patients who had had a spontaneous MI 1-3 years prior to enrolment and were at high risk of atherothrombotic events. At 3 years, the composite primary efficacy endpoint of cardiovascular (CV) death, MI or stroke occurred in significantly fewer ticagrelor 60 mg twice daily than placebo recipients. Long-term ticagrelor had a manageable tolerability and safety profile. The risk of TIMI major bleeding (primary safety endpoint) was significantly increased in ticagrelor 60 mg twice daily versus placebo recipients; however, the risk appeared to decline after the first year of therapy. Landmark analyses have demonstrated that patients with a history of MI remain at a persistent high risk of the composite primary endpoint up to 5 years after the event. Furthermore, these analyses demonstrated that the efficacy of ticagrelor 60 mg twice daily was maintained over time, with less excess in bleeding after the first year. Thus, long-term dual antiplatelet therapy with ticagrelor 60 mg twice daily and low-dose aspirin is a valuable new option for the secondary prevention of atherothrombotic events in stable, high-risk patients with a history of MI of at least 1 year. PMID- 29150807 TI - Single cell versus large population analysis: cell variability in elemental intracellular concentration and distribution. AB - The quantification of elemental concentration in cells is usually performed by analytical assays on large populations missing peculiar but important rare cells. The present article aims at comparing the elemental quantification in single cells and cell population in three different cell types using a new approach for single cells elemental analysis performed at sub-micrometer scale combining X-ray fluorescence microscopy and atomic force microscopy. The attention is focused on the light element Mg, exploiting the opportunity to compare the single cell quantification to the cell population analysis carried out by a highly Mg selective fluorescent chemosensor. The results show that the single cell analysis reveals the same Mg differences found in large population of the different cell strains studied. However, in one of the cell strains, single cell analysis reveals two cells with an exceptionally high intracellular Mg content compared with the other cells of the same strain. The single cell analysis allows mapping Mg and other light elements in whole cells at sub-micrometer scale. A detailed intensity correlation analysis on the two cells with the highest Mg content reveals that Mg subcellular localization correlates with oxygen in a different fashion with respect the other sister cells of the same strain. Graphical abstract Single cells or large population analysis this is the question! PMID- 29150808 TI - Monitoring enzymatic degradation of emerging contaminants using a chip-based robotic nano-ESI-MS tool. AB - Up to now, knowledge of enzymes capable of degrading various contaminants of emerging concern (CEC) is limited, which is especially due to the lack of rapid screening methods. Thus, a miniaturized high-throughput setup using a chip-based robotic nanoelectrospray ionization system coupled to mass spectrometry has been developed to rapidly screen enzymatic reactions with environmentally relevant CECs. Three laccases, two tyrosinases, and two peroxidases were studied for their ability to transform ten pharmaceuticals and benzotriazole. Acetaminophen was most susceptible to enzymatic conversion by horseradish peroxidase (HRP), laccase from Trametes versicolor (LccTV), and a tyrosinase from Agaricus bisporus (TyrAB). Diclofenac and mefenamic acid were converted by HRP and LccTV, whereas sotalol was solely amenable to HRP conversion. Benzotriazole, carbamazepine, gabapentin, metoprolol, primidone, sulfamethoxazole, and venlafaxine remained persistent in this study. The results obtained here emphasize that enzymes are highly selective catalysts and more effort is required in the use of fast monitoring technologies to find suitable enzyme systems. Despite the methodological limitations discussed in detail, the automated tool provides a routine on-line screening of various enzymatic reactions to identify potential enzymes that degrade CECs. Graphical abstract A chip-based robotic nano-ESI-MS tool to rapidly monitor enzymatic degradation of environmentally relevant emerging contaminants. PMID- 29150809 TI - Molecular properties of metal difluorides and their interactions with CO2 and H2O molecules: a DFT investigation. AB - A computational study of metal difluorides (MF2; M = Ca to Zn) and their interactions with carbon dioxide and water molecules was performed. The structural parameter values obtained and the results of AIM analysis and energy decomposition analysis indicated that the Ca-F bond is weaker and less ionic than the bonds in the transition metal difluorides. A deformation density plot revealed the stablizing influence of the Jahn-Teller effect in nonlinear MF2 molecules (e.g., where M= Sc, Ti, Cr). An anaysis of the metal K-edge peaks of the difluorides showed that shifts in the edge energy were due to the combined effects of the ionicity, effective nuclear charge, and the spin state of the metal. The interactions of CO2 with ScF2 (Scc3 geometry) and TiF2 (Tic2 geometry) caused CO2 to shift from its usual linear geometry to a bent geometry (eta2(C=O) binding mode), while it retained its linear geometry (eta1(O) binding mode) when it interacted with the other metal difluorides. Energy decomposition analysis showed that, among the various geometries considered, the Scc3 and Tic2 geometries possessed the highest interaction energies and orbital interaction energies. Heavier transition metal difluorides showed stronger affinities for H2O, whereas the lighter transition metal (Sc and Ti) difluorides preferred CO2. Overall, the results of this study suggest that fluorides of lighter transition metals with partially filled d orbitals (e.g., Sc and Ti) could be used for CO2 capture under moist conditions. Graphical abstract Interaction of metal difluorides with carbon dioxide and water. PMID- 29150810 TI - Liver fibrosis alleviation after co-transplantation of hematopoietic stem cells with mesenchymal stem cells in patients with thalassemia major. AB - The aims of this study are to determine the replacement rate of damaged hepatocytes by donor-derived cells in sex-mismatched recipient patients with thalassemia major and to determine whether co-transplantation of mesenchymal stem cells and hematopoietic stem cells (HSCs) can alleviate liver fibrosis. Ten sex mismatched donor-recipient pairs who received co-transplantation of HSCs with mesenchymal stem cells were included in our study. Liver biopsy was performed before transplantation. Two other liver biopsies were performed between 2 and 5 years after transplantation. The specimens were studied for the presence of donor derived epithelial cells or hepatocytes using fluorescence in situ hybridization by X- and Y-centromeric probes and immunohistochemical staining for pancytokeratin, CD45, and a hepatocyte-specific antigen. All sex-mismatched tissue samples demonstrated donor-derived hepatocyte independent of donor gender. XY-positive epithelial cells or hepatocytes accounted for 11 to 25% of the cells in histologic sections of female recipients in the first follow-up. It rose to 47 95% in the second follow-up. Although not statistically significant, four out of ten patients showed signs of improvement in liver fibrosis. Our results showed that co-transplantation of HSC with mesenchymal stem cells increases the rate of replacement of recipient hepatocytes by donor-derived cells and may improve liver fibrosis. PMID- 29150811 TI - ALK expression plays different roles in anaplastic large-cell lymphomas and outcome of crizotinib use in relapsed/refractory ALK+ patients in a Chinese population. AB - The prognostic value of anaplastic lymphoma kinase (ALK) expression in patients with anaplastic large-cell lymphoma (ALCL) remains controversial. Data on the clinical features of ALCL in a Chinese population are limited. We retrospectively reviewed 1293 patients with pathologically diagnosed lymphoma at Guangdong General Hospital from June 2007 through August 2016. We evaluated the incidence of ALCL, clinical characteristics, survival status, and outcome of crizotinib use in four relapsed/refractory ALK-positive patients. Among the 1293 patients, 1193 (92.3%) were non-Hodgkin's lymphoma, and 53 (4.4%) of whom were ALCL. Of the 50 ALCL patients, with a median age of 34 years, were evaluated. Among them, 33 (66.0%) were ALK-positive and 17 (34.0%) were ALK-negative. Significantly, more patients younger than 40 years old were ALK-positive than ALK-negative (66.7 vs. 23.5%; P = 0.003). The 5-year progression-free survival (PFS) for ALK-positive and ALK-negative patients were 61 and 11%, and the 5-year overall survival (OS) were 70 and 22%, respectively. Median PFS and OS were significantly better for patients with ALK-positive than ALK-negative (60.1 vs. 9.4 months, P = 0. 017; not reached vs. 32.7 months, P = 0.021). Multivariate analyses identified ALK expression, stage, and bone marrow involvement as independent prognostic factors for PFS and OS. Four relapsed ALK-positive patients were treated with crizotinib and two died. Our results suggest that ALK expression has different prognostic significance in patients with ALCL. Mechanisms underlying early relapse after chemotherapy and resistance to crizotinib need further investigation. PMID- 29150812 TI - Factors influencing platelet transfusion refractoriness in patients undergoing allogeneic hematopoietic stem cell transplantation. AB - Hematopoietic stem cell transplantation has been considered a risk factor for development of platelet transfusion refractoriness. The objective of this study was to assess the platelet transfusion refractoriness rate in patients undergoing allogeneic hematopoietic stem cell transplantation from different sources. We retrospectively reviewed the charts and transfusion records of patients who underwent allogeneic stem cell transplantation at our institution between 2013 and 2015. The evaluation of post-transfusion platelet count was assessed for each transfusion given, from day of progenitor infusion to day 30 after transplantation. Of 167 patients included in this study, 101 received peripheral blood stem cell transplantation (PBSCT) and 66 received umbilical cord blood transplantation (UCBT). Overall, the percentage of platelet transfusions with a 14-h CCI lower than 5000 was 59.3%, being these data significantly higher for UCBT (67.6%) than for PBSCT (31.0%). Seventy-eight percent of patients underwent UCBT become refractory, while 38.6% of patients who received PBSCT were refractory. Factors associated to platelet refractoriness were lower CD34+ cell dose infused, higher number of antibiotics used, presence of anti-HLA I antibodies, and reduced-intensity conditioning regimen. Platelet refractoriness is a frequent and complex adverse event and remains a therapeutic challenge in the management of patients undergoing HSCT. There is a higher rate of platelet refractoriness in patients who received UCBT as compared to patients who received PBSCT. PMID- 29150813 TI - A social cichlid fish failed to pass the mark test. AB - Since the pioneering work in chimpanzees, mirror self-recognition (MSR), the ability to recognise oneself in a mirror, has been reported in great apes, Asian elephants, dolphins, and some social birds using the mark test, in which animals that possess MSR touch an imperceptible mark on their own bodies only when a mirror is present. However, giant pandas, which are solitary, failed to pass the mark test, suggesting that MSR evolved solely in highly social animals. In contrast to the increasing evidence of MSR in mammals and birds, little is known about MSR in fish. A Tanganyikan cichlid, Neolamprologus pulcher, is a good candidate for study because these fish live in highly social groups and recognise conspecifics about as rapidly as primates. We examined their responses to a mirror image and tested whether N. pulcher could pass the mark test. When the mirror was first exposed, they stayed in front of the mirror and exhibited aggressive behaviour towards the mirror image. These social behaviours suggested that the focal fish perceived the mirror image as an unfamiliar conspecific. The social responses decreased over the following days, as has generally been the case in animals with MSR. After mark injection, we found no increase in scraping behaviour or prolonged observation of the marked side. These results show a lack of contingency checking and mark-directed behaviours, meaning that N. pulcher failed to pass the mark test and did not recognise their self-image in the mirror. PMID- 29150814 TI - Detecting Multiple Random Changepoints in Bayesian Piecewise Growth Mixture Models. AB - Piecewise growth mixture models are a flexible and useful class of methods for analyzing segmented trends in individual growth trajectory over time, where the individuals come from a mixture of two or more latent classes. These models allow each segment of the overall developmental process within each class to have a different functional form; examples include two linear phases of growth, or a quadratic phase followed by a linear phase. The changepoint (knot) is the time of transition from one developmental phase (segment) to another. Inferring the location of the changepoint(s) is often of practical interest, along with inference for other model parameters. A random changepoint allows for individual differences in the transition time within each class. The primary objectives of our study are as follows: (1) to develop a PGMM using a Bayesian inference approach that allows the estimation of multiple random changepoints within each class; (2) to develop a procedure to empirically detect the number of random changepoints within each class; and (3) to empirically investigate the bias and precision of the estimation of the model parameters, including the random changepoints, via a simulation study. We have developed the user-friendly package BayesianPGMM for R to facilitate the adoption of this methodology in practice, which is available at https://github.com/lockEF/BayesianPGMM . We describe an application to mouse-tracking data for a visual recognition task. PMID- 29150815 TI - Score-Based Tests of Differential Item Functioning via Pairwise Maximum Likelihood Estimation. AB - Measurement invariance is a fundamental assumption in item response theory models, where the relationship between a latent construct (ability) and observed item responses is of interest. Violation of this assumption would render the scale misinterpreted or cause systematic bias against certain groups of persons. While a number of methods have been proposed to detect measurement invariance violations, they typically require advance definition of problematic item parameters and respondent grouping information. However, these pieces of information are typically unknown in practice. As an alternative, this paper focuses on a family of recently proposed tests based on stochastic processes of casewise derivatives of the likelihood function (i.e., scores). These score-based tests only require estimation of the null model (when measurement invariance is assumed to hold), and they have been previously applied in factor-analytic, continuous data contexts as well as in models of the Rasch family. In this paper, we aim to extend these tests to two-parameter item response models, with strong emphasis on pairwise maximum likelihood. The tests' theoretical background and implementation are detailed, and the tests' abilities to identify problematic item parameters are studied via simulation. An empirical example illustrating the tests' use in practice is also provided. PMID- 29150817 TI - Two-Step Estimation of Models Between Latent Classes and External Variables. AB - We consider models which combine latent class measurement models for categorical latent variables with structural regression models for the relationships between the latent classes and observed explanatory and response variables. We propose a two-step method of estimating such models. In its first step, the measurement model is estimated alone, and in the second step the parameters of this measurement model are held fixed when the structural model is estimated. Simulation studies and applied examples suggest that the two-step method is an attractive alternative to existing one-step and three-step methods. We derive estimated standard errors for the two-step estimates of the structural model which account for the uncertainty from both steps of the estimation, and show how the method can be implemented in existing software for latent variable modelling. PMID- 29150816 TI - Cognitive Diagnosis for Small Educational Programs: The General Nonparametric Classification Method. AB - The focus of cognitive diagnosis (CD) is on evaluating an examinee's strengths and weaknesses in terms of cognitive skills learned and skills that need study. Current methods for fitting CD models (CDMs) work well for large-scale assessments, where the data of hundreds or thousands of examinees are available. However, the development of CD-based assessment tools that can be used in small scale test settings, say, for monitoring the instruction and learning process at the classroom level has not kept up with the rapid pace at which research and development proceeded for large-scale assessments. The main reason is that the sample sizes of the small-scale test settings are simply too small to guarantee the reliable estimation of item parameters and examinees' proficiency class membership. In this article, a general nonparametric classification (GNPC) method that allows for assigning examinees to the correct proficiency classes with a high rate when sample sizes are at the classroom level is proposed as an extension of the nonparametric classification (NPC) method (Chiu and Douglas in J Classif 30:225-250, 2013). The proposed method remedies the shortcomings of the NPC method and can accommodate any CDM. The theoretical justification and the empirical studies are presented based on the saturated general CDMs, supporting the legitimacy of using the GNPC method with any CDM. The results from the simulation studies and real data analysis show that the GNPC method outperforms the general CDMs when samples are small. PMID- 29150819 TI - Examining reading comprehension text and question answering time differences in university students with and without a history of reading difficulties. AB - The current study aimed to examine performance times during text reading and question answering of students with and without a history of reading difficulties. Forty-three university students with a history of reading difficulties (HRD) were compared to 124 university students without a history of reading difficulties on measures of word and nonword reading rate, text reading rate and comprehension, and question answering times. Results showed that students with HRD demonstrated slower word, nonword, and text reading rates than their peers, but had comparable reading comprehension scores. Results also showed that students with HRD took longer to answer specific types of questions even when reading rate was controlled. Specifically, when word reading rate was controlled, students with HRD took longer to answer vocabulary, literal, inferential, and background knowledge questions. When text reading rate was controlled, they still took longer to answer literal, inferential, and background knowledge questions. These results suggest that students with a history of reading difficulties require extra time to complete reading comprehension measures for reasons other than just slower word and text reading rate. Findings of this study have implications for supporting university students with a history of reading difficulties. PMID- 29150821 TI - Cd271 mediates proliferation and differentiation of epidermal stem cells to support cutaneous burn wound healing. AB - Burn wounds can significantly reduce the quality of life of patients with respect to their physiology and psychology and can even threaten their lives. Many treatments have been proposed, including stem cell therapy but no effective method can as yet cure such damage. Our study highlights the role of Cd271 in epidermal stem cells (eSC) during the healing of burn wounds. The expression of Cd271 increases together with burn wound healing. Injection of Cd271-over expressing eSC into wounds promotes the healing rate in a mouse burn model. Over expression of Cd271 enhances the abilities of eSC with regard to their differentiation, proliferation and migration and even their resistance to apoptosis in vitro. These results are in accordance with a hypothesis suggesting that Cd271 promotes the healing of skin burn wounds by improving the potential of eSC for differentiation, proliferation and migration. Our findings shed light on the role of Cd271 in wound healing and may provide new therapeutic approaches for curing burn wounds of the skin. PMID- 29150822 TI - Philips Intellivue NMT module: variability of initial measurements. PMID- 29150823 TI - Metabolic dynamics and physiological adaptation of Panax ginseng during development. AB - KEY MESSAGE: The dynamics of metabolites from leaves to roots of Panax ginseng during development has revealed the tissue-specific and year-specific metabolic networks. Being an essential Oriental medicinal plant, ginseng (Panax ginseng Meyer) is a slow-growing perennial herb-accumulating pharmaceutically active metabolites such as ginsenosides in roots during growth. However, little is known about how ginseng plants survive in the harsh environments such as winter cold and summer heat for a longer period and accumulates those active metabolites as the plant grows. To understand the metabolic kinetics in both source and sink organs such as leaves and roots of ginseng plant, respectively, and to assess the changes in ginsenosides biosynthesis during ginseng growth, we investigated the metabolic profiles from leaves and roots of 1-, 4-, and 6-year-old field-grown ginseng plants. Using an integrated non-targeted metabolomic approach, we identified in total 348 primary and secondary metabolites, which provided us for the first time a global metabolomic assessment of ginseng during growth, and morphogenesis. Strikingly, the osmoprotectants and oxidized chemicals were highly accumulated in 4- and 6-year-old ginseng leaves suggested that ginseng develop a wide range of metabolic strategies to adapt unfavorable conditions as they mature. In 6-year-old plants, ginsenosides were decreased in leaves but increased in roots up to 1.2- to sixfold, supporting the view that there is a long-distance transport of ginsenosides from leaves to roots as ginseng plants mature. Our findings provide insights into the metabolic kinetics during the development of ginseng plant and this could complement the pharmacological importance of ginseng and its compounds according to their age. PMID- 29150825 TI - Correction to: Phylogenetic Insight into Zika and Emerging Viruses for a Perspective on Potential Hosts. AB - The article Phylogenetic Insight into Zika and Emerging Viruses for a Perspective on Potential Hosts, written by Diana S. Weber, Karen A. Alroy, and Samuel M. Scheiner, was originally published Online First without open access. PMID- 29150824 TI - Legislation of direct-to-consumer genetic testing in Europe: a fragmented regulatory landscape. AB - Despite the increasing availability of direct-to-consumer (DTC) genetic testing, it is currently unclear how such services are regulated in Europe, due to the lack of EU or national legislation specifically addressing this issue. In this article, we provide an overview of laws that could potentially impact the regulation of DTC genetic testing in 26 European countries, namely Austria, Belgium, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, the Netherlands and the United Kingdom. Emphasis is placed on provisions relating to medical supervision, genetic counselling and informed consent. Our results indicate that currently there is a wide spectrum of laws regarding genetic testing in Europe. There are countries (e.g. France and Germany) which essentially ban DTC genetic testing, while in others (e.g. Luxembourg and Poland) DTC genetic testing may only be restricted by general laws, usually regarding health care services and patients' rights. PMID- 29150826 TI - Rethinking Human-Nonhuman Primate Contact and Pathogenic Disease Spillover. AB - Zoonotic transmissions are a major global health risk, and human-animal contact is frequently raised as an important driver of transmission. A literature examining zooanthroponosis largely agrees that more human-animal contact leads to more risk. Yet the basis of this proposition, the term contact, has not been rigorously analyzed. To understand how contact is used to explain cross-species spillovers, we conducted a multi-disciplinary review of studies addressing human nonhuman primate (NHP) engagements and pathogenic transmissions and employing the term contact. We find that although contact is frequently invoked, it is employed inconsistently and imprecisely across these studies, overlooking the range of pathogens and their transmission routes and directions. We also examine a related but more expansive approach focusing on human and NHP habitats and their spatial overlap, which can potentially facilitate pathogenic transmission. Contact and spatial overlap investigations cannot, however, explain the processes that bring together people, animals and pathogens. We therefore examine another approach that enhances our understanding of zoonotic spillovers: anthropological studies identifying such historical, social, environmental processes. Comparable to a One Health approach, our ongoing research in Cameroon draws contact, spatial overlap and anthropological-historical approaches into dialog to suggest where, when and how pathogenic transmissions between people and NHPs may occur. In conclusion, we call for zoonotic disease researchers to specify more precisely the human-animal contacts they investigate and to attend to how broader ecologies, societies and histories shape pathogen-human-animal interactions. PMID- 29150827 TI - Implications of Tourist-Macaque Interactions for Disease Transmission. AB - During wildlife tourism, proximity or actual contact between people and animals may lead to a significant risk of anthropozoonotic disease transmission. In this paper, we use social network analysis, disease simulation modelling and data on animal health and behaviour to investigate such risks at a site in Morocco, where tourists come to see wild Barbary macaques (Macaca sylvanus). Measures of individual macaques' network centrality-an index of the strength and distribution of their social relationships and thus potentially their ability to spread disease-did not show clear and consistent relationships with their time spent in close proximity to, or rate of interacting with, tourists. Disease simulation modelling indicated that while higher-ranked animals had a significantly greater ability to spread disease within the group, in absolute terms there was little difference in the size of outbreaks that different individuals were predicted to cause. We observed a high rate of physical contact and close proximity between humans and macaques, including during three periods when the macaques were coughing and sneezing heavily, highlighting the potential risk of disease transmission. We recommend that general disease prevention strategies, such as those aimed at reducing opportunities for contact between tourists and macaques, should be adopted. PMID- 29150829 TI - Brain Metastasis Of Penile Angiosarcoma. AB - Angiosarcoma is a rare malignancy originating from vascular endothelial cells. Brain metastasis of aniosarcomas are uncommon up to the literature. Penile angiosarcomas are also seldom among all anjiosarcomas. A case with penile angiosarcoma with confirmed brain metastasis is aimed to be reported and contribute to the literature for similar cases. PMID- 29150828 TI - Vectors, Hosts, and Control Measures for Zika Virus in the Americas. AB - We examine Zika virus (ZIKV) from an ecological perspective and with a focus on the Americas. We assess (1) the role of wildlife in ZIKV disease ecology, (2) how mosquito behavior and biology influence disease dynamics, and (3) how nontarget species and ecosystems may be impacted by vector control programs. Our review suggests that free-ranging, non-human primates may be involved in ZIKV transmission in the Old World; however, other wildlife species likely play a limited role in maintaining or transmitting ZIKV. In the Americas, a zoonotic cycle has not yet been definitively established. Understanding behaviors and habitat tolerances of Aedes aegypti and Aedes albopictus, two ZIKV competent vectors in the Americas, will allow more accurate modeling of disease spread and facilitate targeted and effective control efforts. Vector control efforts may have direct and indirect impacts to wildlife, particularly invertebrate feeding species; however, strategies could be implemented to limit detrimental ecological effects. PMID- 29150830 TI - Does Preoperative Use of Dutasteride Decrease Bleeding During Open Prostatectomy? AB - PURPOSE: To investigate whether use of dutasteride, a 5-alpha reductase inhibitor, for at least four weeks preoperatively affected the blood loss during open prostatectomy (OP). MATERIALS AND METHODS: Retrospective analysis was made of the data of 110 patients who had undergone OP. Group I comprised 50 patients that used dutasteride for 4 weeks preoperatively, and Group II comprised 60 patients that did not use the drug. The groups were compared in respect of age, total prostate specific antigen (TPSA) levels, prostate volumes, preoperative hemoglobin (Hgb) and hematocrit (Hct) levels, postoperative reduction of Hgb and Hct, percentage reduction in Hgb and Hct, and the administration of postoperative blood products. RESULTS: No differences were determined between the two groups in respect of prostate volumes, TPSA, preoperative Hgb and Hct levels (P = .813, P = .978, P = .422, P =.183, respectively). Postoperative Hgb reduction was 2.19 +/- 1.36 g/dL in Group I, and 2.5 +/- 1.47 g/dL in Group II (P = .260). Hgb reduction was calculated as 16.4 +/- 9.7% in Group I and 17.6 +/- 9.7% in Group II (P = .505). Reductions in Hct were 5.8 +/- 3.7% in Group I, and 7.3 +/- 4.4% in Group II, and percent reductions were 14.8 +/- 9.4% in Group I and 17.3 +/- 10.2% in Group II (P = .068, P = .182, respectively). CONCLUSION: The use of dutasteride before OP did not affect blood loss during surgery, therefore surgery should not be delayed for the administration of dutasteride to patients. PMID- 29150832 TI - Terbinafine induced liver injury may be asymptomatic: need for regular monitoring. PMID- 29150831 TI - The extracellular membrane-proximal domain of membrane-bound IgE restricts B cell activation by limiting B cell antigen receptor surface expression. AB - Immunoglobulin E (IgE) antibodies are key mediators of allergic reactions. Due to their potentially harmful anaphylactic properties, their production is tightly regulated. The membrane-bound isoform of IgE (mIgE), which is an integral component of the B cell antigen receptor, has been shown to be critical for the regulation of IgE responses in mice. In primate species including humans, mIgE can be expressed in two isoforms that are produced by alternative splicing of the primary epsilon Ig heavy chain transcript, and differ in the absence or presence of an extracellular membrane-proximal domain (EMPD) consisting of 52 amino acids. However, the function of the EMPD remains unclear. Here, we demonstrate that the EMPD restricts surface expression of mIgE-containing BCRs in human and murine B cells. The EMPD does not interfere with BCR assembly but acts as an autonomous endoplasmic reticulum retention domain. Limited surface expression of EMPD containing mIgE-BCRs caused impaired activation of intracellular signaling cascades and hence represents a regulatory mechanism that may control the production of potentially anaphylactic IgE antibodies in primate species. PMID- 29150833 TI - Response to: 'Interleukin-36 in hidradenitis suppurativa: evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop'. PMID- 29150835 TI - The expanding spectrum of clinical phenotypes associated with PSTPIP1 mutations: from PAPA to PAMI syndrome and beyond. PMID- 29150836 TI - Serum thymus and activation-regulated chemokine is associated with the severity of drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome. PMID- 29150834 TI - IL-22 neutralizing autoantibodies impair fungal clearance in murine oropharyngeal candidiasis model. AB - Protection against mucocutaneous candidiasis depends on the T helper (Th)17 pathway, as gene defects affecting its integrity result in inability to clear Candida albicans infection on body surfaces. Moreover, autoantibodies neutralizing Th17 cytokines have been related to chronic candidiasis in a rare inherited disorder called autoimmune polyendocriopathy candidiasis ectodermal dystrophy (APECED) caused by mutations in autoimmune regulator (AIRE) gene. However, the direct pathogenicity of these autoantibodies has not yet been addressed. Here we show that the level of anti-IL17A autoantibodies that develop in aged Aire-deficient mice is not sufficient for conferring susceptibility to oropharyngeal candidiasis. However, patient-derived monoclonal antibodies that cross-react with murine IL-22 increase the fungal burden on C. albicans infected mucosa. Nevertheless, the lack of macroscopically evident infectious pathology on the oral mucosa of infected mice suggests that additional susceptibility factors are needed to precipitate a clinical disease. PMID- 29150837 TI - Aprepitant improves refractory pruritus in primary cutaneous T-cell lymphomas: experience of the Spanish Working Group on Cutaneous Lymphomas. PMID- 29150839 TI - Liver injury induced by clomiphene citrate: A case report and literature reviews. AB - WHAT IS KNOWN AND OBJECTIVE: Clomiphene citrate is used to cause ovulation in females and to increase semen production in males. Clomiphene citrate is well tolerated in most patients and rarely induces liver injury. We report a case of liver injury which is associated with administration of clomiphene citrate in a male patient. CASE SUMMARY: A 31-year-old man who was treated by clomiphene citrate for 5 days was transferred to our emergency room with reddish-brown urine and upper abdominal pain. The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were elevated. Based on the subsequent examination, he was diagnosed with liver injury and cholecystitis. The levels of AST and ALT returned to normal range after discontinuation of clomiphene citrate and symptomatic treatment. WHAT IS NEW AND CONCLUSION: The mechanism of liver injury caused by clomiphene citrate is still unclear. Polymorphism of CYP2D6 may have had an effect. Liver function tests should be performed when there is upper abdominal pain after administration of clomiphene citrate. PMID- 29150838 TI - GI-530159, a novel, selective, mechanosensitive two-pore-domain potassium (K2P ) channel opener, reduces rat dorsal root ganglion neuron excitability. AB - BACKGROUND AND PURPOSE: TREK two-pore-domain potassium (K2P ) channels play a critical role in regulating the excitability of somatosensory nociceptive neurons and are important mediators of pain perception. An understanding of the roles of TREK channels in pain perception and, indeed, in other pathophysiological conditions, has been severely hampered by the lack of potent and/or selective activators and inhibitors. In this study, we describe a new, selective opener of TREK channels, GI-530159. EXPERIMENTAL APPROACH: The effect of GI-530159 on TREK channels was demonstrated using 86 Rb efflux assays, whole-cell and single channel patch-clamp recordings from recombinant TREK channels. The expression of K2P 2.1 (TREK1), K2P 10.1 (TREK2) and K2P 4.1 (TRAAK) channels was determined using transcriptome analysis from single dorsal root ganglion (DRG) cells. Current-clamp recordings from cultured rat DRG neurons were used to measure the effect of GI-530159 on neuronal excitability. KEY RESULTS: For recombinant human TREK1 channels, GI-530159 had similar low EC50 values in Rb efflux experiments and electrophysiological recordings. It activated TREK2 channels, but it had no detectable action on TRAAK channels nor any significant effect on other K channels tested. Current-clamp recordings from cultured rat DRG neurones showed that application of GI-530159 at 1 MUM resulted in a significant reduction in firing frequency and a small hyperpolarization of resting membrane potential. CONCLUSIONS AND IMPLICATIONS: This study provides pharmacological evidence for the presence of mechanosensitive TREK K2P channels in sensory neurones and suggests that development of selective K2P channel openers like GI-530159 could aid in the development of novel analgesic agents. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. PMID- 29150840 TI - Longitudinal pathways between mental health difficulties and academic performance during middle childhood and early adolescence. AB - There is a growing appreciation that child functioning in different domains, levels, or systems are interrelated over time. Here, we investigate links between internalizing symptoms, externalizing problems, and academic attainment during middle childhood and early adolescence, drawing on two large data sets (child: mean age 8.7 at enrolment, n = 5,878; adolescent: mean age 11.7, n = 6,388). Using a 2-year cross-lag design, we test three hypotheses - adjustment erosion, academic incompetence, and shared risk - while also examining the moderating influence of gender. Multilevel structural equation models provided consistent evidence of the deleterious effect of externalizing problems on later academic achievement in both cohorts, supporting the adjustment-erosion hypothesis. Evidence supporting the academic-incompetence hypothesis was restricted to the middle childhood cohort, revealing links between early academic failure and later internalizing symptoms. In both cohorts, inclusion of shared-risk variables improved model fit and rendered some previously established cross-lag pathways non-significant. Implications of these findings are discussed, and study strengths and limitations noted. Statement of contribution What is already known on this subject? Longitudinal research and in particular developmental cascades literature make the case for weaker associations between internalizing symptoms and academic performance than between externalizing problems and academic performance. Findings vary in terms of the magnitude and inferred direction of effects. Inconsistencies may be explained by different age ranges, prevalence of small-to-modest sample sizes, and large time lags between measurement points. Gender differences remain underexamined. What does this study add? The present study used cross-lagged models to examine longitudinal associations in age groups (middle child and adolescence) in a large-scale British sample. The large sample size not only allows for improvements on previous measurement models (e.g., allowing the analysis to account for nesting, and estimation of latent variables) but also allows for examination of gender differences. The findings clarify the role of shared-risk factors in accounting for associations between internalizing, externalizing, and academic performance, by demonstrating that shared-risk factors do not fully account for relationships between internalizing, externalizing, and academic achievement. Specifically, some pathways between mental health and academic attainment consistently remain, even after shared-risk variables have been accounted for. Findings also present consistent support for the potential impact of behavioural problems on children's academic attainment. The negative relationship between low academic attainment and subsequent internalizing symptoms for younger children is also noteworthy. PMID- 29150841 TI - How well are reporting guidelines and trial registration used by dermatology journals to limit bias? A meta-epidemiological study. PMID- 29150842 TI - The effect of 6% hydroxyethyl starch (130/0.4) on acute kidney injury in paediatric cardiac surgery: a prospective, randomised trial. AB - We have evaluated the effect of a colloid solution on acute kidney injury in paediatric cardiac surgery. A total of 195 patients were ramdomly divided into an hydroxyethyl starch group and a control group. In the starch group, 6% hydroxyethyl starch 130/0.4 (Volulyte(r) ) was used as the primary fluid for volume resuscitation but was limited to 30 ml.kg-1 . In the control group, only crystalloid fluid was used during the peri-operative period. The incidence of acute kidney injury, peri-operative transfusion, clinical outcomes and laboratory data were compared. The incidence of acute kidney injury determined by Paediatric Risk, Injury, Failure, Loss, End-stage renal disease (pRIFLE) and Acute Kidney Injury Network (AKIN) criteria were no different between the two groups (starch group 40.8% vs. control group 30.0%; p = 0.150 using pRIFLE; 19.6% vs. 21.1% respectively, p = 0.602 using AKIN). There were no differences in clinical outcomes such as mortality, major adverse events, intensive care unit stay or duration of mechanical ventilation. Clotting time as measured using rotational thromboelastometry (ROTEM) was prolonged, and clot firmness after 10 min and maximal clot firmness were shorter in the starch group compared with the control group after sternal closure. There was no difference in transfusion between the two groups. Patients with acute kidney injury had worse clinical courses than those without acute kidney injury. We conclude that intra-operative use of 6% hydroxyethyl starch 130/0.4 up to 30 ml.kg-1 was not associated with postoperative acute kidney injury in paediatric cardiac patients. PMID- 29150843 TI - Liver fibrosis is associated with cutaneous inflammation in the imiquimod-induced murine model of psoriasiform dermatitis. AB - BACKGROUND: Psoriasis exhibits several extracutaneous manifestations. Little is known about hepatic parameters specifically associated with psoriasis. OBJECTIVES: To study whether psoriasiform dermatitis is associated with liver injury. METHODS: We studied liver parameters of inflammation and fibrosis in a murine model of psoriasiform dermatitis induced by topical application of imiquimod for 9 weeks. RESULTS: Topical treatment with imiquimod induced a form of psoriasiform dermatitis reminiscent of the human disorder, characterized by thickened and scaly skin, psoriasiform epidermal hyperplasia, altered keratinocyte differentiation and cutaneous overexpression of interleukin-17A. Mice with dermatitis displayed hepatitis, as shown by elevation of plasma transaminase levels, as well as portal and periportal hepatitis, characterized by T-lymphocyte (CD3epsilon+ ) and polymorphonuclear cell (Gr1+ ) infiltrates. The hepatitis progressed towards liver fibrogenesis, as shown by excessive Sirius red staining, which is consistent with the expression of alpha-smooth muscle actin by hepatic stellate cells. CONCLUSIONS: These results indicate that liver inflammation and fibrosis are associated with experimental psoriasiform dermatitis. Our results suggest that psoriatic inflammation may be associated with specific liver injury. PMID- 29150844 TI - A phase I randomized controlled trial to evaluate safety and clinical effect of topically applied GSK2981278 ointment in a psoriasis plaque test. PMID- 29150845 TI - Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in Adults: An Open-Label, Randomized Study. AB - In children aged <=4 years, the relative bioavailability of lamivudine oral solution was 37% lower than that of a tablet formulation. An open-label, four-way crossover study was conducted in healthy adults to evaluate the effect of sorbitol, a common liquid excipient, on the pharmacokinetics of lamivudine oral solution (ClinicalTrials.gov identifier, NCT02634073). Sixteen subjects were randomized to one of four sequences consisting of four doses of lamivudine 300 mg (10 mg/mL) alone or with sorbitol 3.2, 10.2, or 13.4 g. Sorbitol 3.2, 10.2, and 13.4 g decreased lamivudine maximum concentration (Cmax ) by 28%, 52%, and 55% and area under the concentration-time curve from time 0 to 24 h (AUC0-24 ) by 20%, 39%, and 44%, respectively. Three subjects (19%) reported five nonserious adverse events (one drug-related). The dose-dependent effects of sorbitol on lamivudine Cmax and AUC0-24 reveal an absorption-based interaction that may decrease lamivudine exposure in patients coadministered sorbitol-containing medicines. PMID- 29150847 TI - Chronic sun exposure is associated with distinct histone acetylation changes in human skin. AB - BACKGROUND: Photoageing is attributed to continuous sunlight or artificial ultraviolet exposure and manifests as clinical and histological changes in skin. Epigenetic changes have been found to be involved in the pathogenesis of photoageing. However, the underlying mechanisms are unclear. OBJECTIVES: To analyse histone modification patterns in sun-exposed and nonexposed skin, and to identify the abnormally histone-modified genes related to photoageing. METHODS: Skin biopsies were collected from both the outer forearm (sun-exposed area) and the buttock (sun-protected area) in 20 healthy middle-aged female volunteers. Global histone H3/H4 acetylation and H3K4/H3K9 methylation statuses were assessed by enzyme-linked immunosorbent assay. Expression levels of histone acetyltransferases and histone deacetylases were measured by reverse transcriptase quantitative polymerase chain reaction (qPCR) and Western blot. Chromatin immunoprecipitation combined with DNA microarray (ChIP-chip) assay with anti-acetyl-histone H3 antibody in a sun-exposed pool (combining six sun-exposed skin samples) and a nonexposed pool (combining six nonexposed skin samples) was conducted to explore the abnormally acetylated histone H3 genes related to photoageing; ChIP-qPCR was then used to verify the results of ChIP-chip. RESULTS: We observed higher global histone H3 acetylation levels increased EP300 and decreased HDAC1 and SIRT1 expression in sun-exposed skin compared with matched nonexposed skin. Furthermore, the ChIP-chip assay showed that 227 genes displayed significant hyperacetylation of histone H3, and 81 genes displayed significant hypoacetylation of histone H3 between the two groups. Histone H3 acetylation levels on the promoters of PDCD5, ITIH5, MMP1 and AHR were positively correlated with the mRNA expression of the corresponding gene. CONCLUSIONS: Chronic sun exposure-induced histone H3 hyperacetylation may play a critical role in the pathogenesis of skin photoageing. PMID- 29150849 TI - Prognosis of sentinel lymph node biopsy in patients with thick melanoma by a propensity score matching prospective study. PMID- 29150846 TI - Cancer stem cells as targets for immunotherapy. AB - Current cancer therapies target the bulk of the tumour, while a population of highly resistant tumour cells may be able to repopulate the tumour and metastasize to new sites. Cancer cells with such stem cell-like characteristics can be identified based on their phenotypical and/or functional features which may open up ways for their targeted elimination. In this review we discuss potential off-target effects of inhibiting cancer stem-cell self-renewal pathways on immune cells, and summarize some recent immunological studies specifically targeting cancer stem cells based on their unique antigen expression. PMID- 29150848 TI - Allergen manufacturing and quality aspects for allergen immunotherapy in Europe and the United States: An analysis from the EAACI AIT Guidelines Project. AB - Adequate quality is essential for any medicinal product to be eligible for marketing. Quality includes verification of the identity, content and purity of a medicinal product in combination with a specified production process and its control. Allergen products derived from natural sources require particular considerations to ensure adequate quality. Here, we describe key aspects of the documentation on manufacturing and quality aspects for allergen immunotherapy products in the European Union and the United States. In some key parts, requirements in these areas are harmonized while other fields are regulated separately between both regions. Essential differences are found in the use of Reference Preparations, or the requirement to apply standardized assays for potency determination. As the types of products available are different in specific regions, regulatory guidance for such products may also be available in one specific region only, such as for allergoids in the European Union. Region specific issues and priorities are a result of this. As allergen products derived from natural sources are inherently variable in their qualitative and quantitative composition, these products present special challenges to balance the variability and ensuring batch-to-batch consistency. Advancements in scientific knowledge on specific allergens and their role in allergic disease will consequentially find representation in future regulatory guidelines. PMID- 29150850 TI - Comparison of pharmacodynamic effects of ticagrelor vs prasugrel in type 2 diabetes mellitus patients with coronary heart disease. AB - WHAT IS KNOWN AND OBJECTIVE: Patients with type 2 diabetes mellitus (T2DM) are at higher risk of thrombotic complications. Studies have indicated that patients with T2DM have impaired clopidogrel-induced antiplatelet effect. Ticagrelor and prasugrel are two latest generation P2Y12 inhibitors with advantageous platelet inhibitory profiles. However, the pharmacodynamic differences between the two drugs in patients with T2DM remain poorly explored. METHODS: This study, involving 140 patients with T2DM following percutaneous coronary intervention (PCI), evaluated the efficacy of aspirin upon concomitant use of prasugrel (10 mg/d) or ticagrelor (90 mg/d). Platelet reactivity was assessed by value of ADP induced light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) at baseline, 7 and 30 days after randomized P2Y12 inhibitor treatment. RESULTS: The study showed a decreased platelet reactivity after use of P2Y12 inhibitors (both P < .001). On the basis of comparison between regimens, apart from the prasugrel group having a significantly higher LTA value at the 30-day time point (P = .043), there existed no significant differences in platelet reactivity at separate time points (all P > .05). As for intragroup measurements, when compared with 7-day and 30-day time points, similar platelet reactivity was documented in the ticagrelor group (both P > .05), but LTA tests showed a significant increase with time (days 7-30) in the prasugrel group (P = .050). WHAT IS NEW AND CONCLUSION: Although ticagrelor and prasugrel have similar platelet inhibitory effects in patients with T2DM, if a P2Y12 inhibitor is necessitated in patients with T2DM, ticagrelor might exert a more stable antiplatelet effect with 30-day short-term treatment. PMID- 29150851 TI - Outgroup members' internal criticism promotes intergroup openness: The role of perceived risk. AB - Research suggests that hearing an outgroup member voice internal criticism increases individuals' openness to the outgroup's perspective. We replicate and extend these findings in the context of the Israeli-Palestinian conflict. Israeli participants exposed to a Palestinian official voicing internal criticism reported more openness to the Palestinian narrative of the conflict, an effect that was mediated by an increase in participants' perception that Palestinians are open-minded and a subsequent increase in their hope for more positive relations between the two groups. In our extension of these findings, we examined a complementary mechanism contributing to the effectiveness of the criticism manipulation, specifically the extent to which participants perceive that the Palestinian official took a risk voicing criticism of Palestinians. Positive messages from a hostile outgroup may be received with suspicion, but if they are articulated under great risk to the speaker, greater credibility may be granted. Across two studies, we demonstrate that the criticism conveys risk to the speaker and that this risk is predictive of the perceived credibility of the speaker, and participants' subsequent openness to the outgroup's perspective. PMID- 29150852 TI - Panel Report, IPA Congress Buenos Aires 2017: Listening for echoes of the child in adult psychoanalysis. PMID- 29150853 TI - Poor agreement in questionnaire-based diagnostic criteria for adult atopic dermatitis is a challenge when examining cardiovascular comorbidity. AB - BACKGROUND: The association between atopic dermatitis (AD) and cardio-metabolic risk factors is not yet established. Furthermore, no validated questionnaire based method of identifying adults with AD is currently available. OBJECTIVES: To assess the cardio-metabolic risk in adults with a history of AD using 3 different questionnaire-based diagnostic criteria. METHODS: We utilized data from a general population study including questionnaire data and objective measurements of 9656 Danish adults. To identify adults with a history of AD, we used a question regarding physician-diagnosed AD and 2 versions of the UK Working Party Diagnostic Criteria. Associations between AD status and cardio-metabolic endpoints were estimated using survey weighted logistic and linear regression analysis. RESULTS: We identified 462 (4.8%) adults with self-reported physician diagnosed AD, whereas 903 (9.4%) and 226 (2.3%) had AD according to the UK Working Party Criteria when at least 2 and 3of 4 minor criteria were fulfilled. The populations were not comparable in terms of occurrence of cardio-metabolic risk factors. For example, the prevalence of obesity was lower in participants with physician-diagnosed AD but overall higher in UK 2/4 and UK 3/4. CONCLUSION: Due to the heterogeneity in the captured study populations in terms of the studied outcomes and absence of a gold standard, no conclusions regarding the cardio-metabolic risk in adults with AD in a general population could be made. This study serves as an example of the challenges that are often encountered in questionnaire-based epidemiologic studies and highlights the need of better definitions for this patient group. PMID- 29150854 TI - Rhinitis and its impact on quality of life in swimmers. AB - INTRODUCTION: Limited data suggest that swimmers might be affected by rhinitis significantly more often than the general population. This can have impact on quality of life but also on performance. The aim of this study was to determine the prevalence and impact of QOL of rhinitis in swimming compared to nonswimming athletes and controls. MATERIALS AND METHODS: This was an observational case control, questionnaire-based study involving elite (n = 101) and nonelite swimming athletes (n = 107), nonswimming athletes (n = 38) and sex- and age matched controls (n = 50). The survey instrument consisted of a general and the miniRQLQ. Main question used to assess the prevalence of rhinitis was from the ISAAC study. RESULTS: Rhinitis was reported significantly more often by the elite swimmers (45%) than nonelite swimmers (31%), nonswimming athletes (32%) and controls (24%). Allergic rhinitis prevalence was similar in all groups (12%-18%). The prevalence of nonallergic rhinitis (NAR) was significantly higher in elite swimmers (33%) and nonelite swimmers (22%) compared to nonswimming athletes and controls. Overall mean miniRQLQ score and all subdomains except the "eye" domain showed significantly reduced QOL in elite and nonelite swimmers compared to nonswimming athletes and controls. Regular nasal medication was used significantly less by elite swimmers (18%) compared to controls (67%) and nonswimming athletes (42%). CONCLUSION: This study revealed a high prevalence of NAR in swimmers and related impact on QoL. These findings highlight the importance to increase the awareness towards upper airway disorders in the swimming athletes and to ensure adequate management. PMID- 29150855 TI - Thalamic volume reduction in drug-naive patients with new-onset genetic generalized epilepsy. AB - OBJECTIVE: Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED-naive patients with GGE at disease onset. We hypothesize that drug-naive patients at disease onset have gray matter changes compared to age-matched healthy controls. METHODS: We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED-naive patients with new-onset GGE and compared them to 32 age-matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups. RESULTS: The thalamus was the only structure to show reduced gray matter volume in AED-naive patients with new onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions. SIGNIFICANCE: Structural abnormalities in the thalamus are present at the initial onset of GGE in AED naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration. PMID- 29150858 TI - Q-switched 532-nm laser energy causes significant vascular damage in the capillary plexus: how does this affect laser tattoo removal? PMID- 29150857 TI - A randomized, double-blind, placebo-controlled, dose-finding trial with Lolium perenne peptide immunotherapy. AB - BACKGROUND: A novel subcutaneous allergen immunotherapy formulation (gpASIT+TM) containing Lolium perenne peptides (LPP) and having a short up-dosing phase has been developed to treat grass pollen-induced seasonal allergic rhinoconjunctivitis. We investigated peptide immunotherapy containing the hydrolysate from perennial ryegrass allergens for the optimum dose in terms of clinical efficacy, immunogenicity and safety. METHODS: This prospective, double blind, placebo-controlled, phase IIb, parallel, four-arm, dose-finding study randomized 198 grass pollen-allergic adults to receive placebo or cumulative doses of 70, 170 or 370 MUg LPP. All patients received weekly subcutaneous injections, with the active treatment groups reaching assigned doses within 2, 3 and 4 weeks, respectively. Efficacy was assessed by comparing conjunctival provocation test (CPT) reactions at baseline, after 4 weeks and after completion. Grass pollen-specific immunoglobulins were analysed before and after treatment. RESULTS: Conjunctival provocation test (CPT) response thresholds improved from baseline to V7 by at least one concentration step in 51.2% (170 MUg; P = .023), 46.3% (370 MUg), and 38.6% (70 MUg) of patients receiving LPP vs 25.6% of patients receiving placebo (modified per-protocol set). Also, 39% of patients in the 170-MUg group became nonreactive to CPT vs 18% in the placebo group. Facilitated allergen-binding assays revealed a highly significant (P < .001) dose dependent reduction in IgE allergen binding across all treatment groups (70 MUg: 17.1%; 170 MUg: 18.8%; 370 MUg: 26.4%). Specific IgG4 levels increased to 1.6 fold (70 MUg), 3.1-fold (170 MUg) and 3.9-fold (370 MUg) (mPP). CONCLUSION: Three week immunotherapy with 170 MUg LPP reduced CPT reactivity significantly and increased protective specific antibodies. PMID- 29150859 TI - Coordinated reset vibrotactile stimulation shows prolonged improvement in Parkinson's disease. PMID- 29150856 TI - Defining sepsis on the wards: results of a multi-centre point-prevalence study comparing two sepsis definitions. AB - Our aim was to prospectively determine the predictive capabilities of SEPSIS-1 and SEPSIS-3 definitions in the emergency departments and general wards. Patients with National Early Warning Score (NEWS) of 3 or above and suspected or proven infection were enrolled over a 24-h period in 13 Welsh hospitals. The primary outcome measure was mortality within 30 days. Out of the 5422 patients screened, 431 fulfilled inclusion criteria and 380 (88%) were recruited. Using the SEPSIS-1 definition, 212 patients had sepsis. When using the SEPSIS-3 definitions with Sequential Organ Failure Assessment (SOFA) score >= 2, there were 272 septic patients, whereas with quickSOFA score >= 2, 50 patients were identified. For the prediction of primary outcome, SEPSIS-1 criteria had a sensitivity (95%CI) of 65% (54-75%) and specificity of 47% (41-53%); SEPSIS-3 criteria had a sensitivity of 86% (76-92%) and specificity of 32% (27-38%). SEPSIS-3 and SEPSIS-1 definitions were associated with a hazard ratio (95%CI) 2.7 (1.5-5.6) and 1.6 (1.3-2.5), respectively. Scoring system discrimination evaluated by receiver operating characteristic curves was highest for Sequential Organ Failure Assessment score (0.69 (95%CI 0.63-0.76)), followed by NEWS (0.58 (0.51-0.66)) (p < 0.001). Systemic inflammatory response syndrome criteria (0.55 (0.49-0.61)) and quickSOFA score (0.56 (0.49-0.64)) could not predict outcome. The SEPSIS-3 definition identified patients with the highest risk. Sequential Organ Failure Assessment score and NEWS were better predictors of poor outcome. The Sequential Organ Failure Assessment score appeared to be the best tool for identifying patients with high risk of death and sepsis-induced organ dysfunction. PMID- 29150860 TI - Quality of life outcome after subthalamic stimulation in Parkinson's disease depends on age. AB - OBJECTIVE: The purpose of this study was to investigate how quality of life outcome after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) depends on age. METHODS: In this prospective, open label, multicenter study including 120 PD patients undergoing bilateral STN-DBS, we investigated the PDQuestionnaire-8 (PDQ-8), Unified PD Rating Scale-III, Scales for Outcomes in PD-motor examination, complications, activities of daily living, and levodopa equivalent daily dose preoperatively and at 5 months follow up. Significant changes at follow-up were analyzed with Wilcoxon signed-rank test and Bonferroni correction for multiple comparisons. To explore the influence of age post hoc, the patients were classified into 3 age groups (<=59, 60-69, >=70 years). Intragroup changes were analyzed with Wilcoxon signed-rank and intergroup differences with Kruskal-Wallis tests. The strength of clinical responses was evaluated using effect size. RESULTS: The PDQuestionnaire-8, Scales for Outcomes in PD-motor complications, activities of daily living, and levodopa equivalent daily dose significantly improved in the overall cohort and all age groups with no significant intergroup differences. However, PDQuestionnaire-8 effect sizes for age groups <=59, 60 to 69, and >=70 years, respectively, were strong, moderate, and small. Furthermore, PDQuestionnaire-8 domain analyses revealed that all domains except cognition and emotional well-being significantly improved in patients aged <=59 years, whereas only communication, activities of daily living, and stigma improved in patients aged 60-69 years, and activities of daily living and stigma in patients aged >=70 years. CONCLUSIONS: Although quality of life, motor complications, and activities of daily living significantly improved in all age groups after bilateral STN-DBS, the beneficial effect on overall quality of life was more pronounced and affected a wider range of quality of life domains in younger patients. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29150861 TI - Cost-effectiveness of the psycho-educational blended (group and online) intervention HypoAware compared with usual care for people with Type 1 and insulin-treated Type 2 diabetes with problematic hypoglycaemia: analyses of a cluster-randomized controlled trial. AB - AIMS: To evaluate the cost-effectiveness of HypoAware, a blended (group and online) psycho-educational intervention based on the evidence-based Blood Glucose Awareness Training, in comparison with usual care in people with Type 1 and Type 2 diabetes with a high risk of severe hypoglycaemia. METHODS: We performed an economic evaluation, from a societal and healthcare perspective, that used data from a 6-month, multicentre, cluster-randomized controlled trial (n = 137). RESULTS: The proportion of people with at least one severe hypoglycaemic event per 6 months was 0.22 lower (95% CI -0.39 to -0.06) and the proportion of people with impaired hypoglycaemia awareness was 0.16 lower (95% CI -0.34 to 0.02) in the HypoAware group. There was no difference in quality-adjusted life-years ( 0.0; 95% CI -0.05 to 0.05). The mean total societal costs in the HypoAware group were EUR708 higher than in the usual care group (95% CI -951 to 2298). The mean incremental cost per severe hypoglycaemic event prevented was EUR2,233. At a willingness-to-pay threshold of EUR20,000 per event prevented, the probability that HypoAware was cost-effective in comparison with usual care was 54% from a societal perspective and 55% from a healthcare perspective. For quality-adjusted life-years the incremental cost-effectiveness ratio was EUR119,360/quality adjusted life-year gained and the probability of cost-effectiveness was low at all ceiling ratios. CONCLUSIONS: Based on the present study, we conclude that HypoAware is not cost-effective compared to usual care. Further research in less well-resourced settings and more severely affected patients is warranted. (Clinical Trials Registry no: Dutch Trial Register NTR4538.). PMID- 29150862 TI - Randomised crossover trial showed that using breast milk or sucrose provided the same analgesic effect in preterm infants of at least 28 weeks. AB - AIM: Repeated, ongoing exposure to pain influences the growth, cognitive and motor functions, behaviour, personality and neurodevelopment of preterm infants. We compared the analgesic effects of expressed breast milk (EBM) and 24% oral sucrose on preterm neonates during venipuncture. METHODS: This multicentre randomised, noninferiority, crossover trial focused on five neonatal university units in Madrid, Spain, from October 2013 to October 2014. It comprised 66 preterm infants born at less than 37 weeks and randomly split into two groups. They received either EBM or sucrose two minutes before venepuncture, together with nonnutritive sucking and swaddling, then the opposite procedure at a later point. Pain was measured with the premature infant pain profile (PIPP) and crying was also measured. RESULTS: There were no statistically significant differences between the groups. The PIPP scores were seven (4-9) with breast milk and six (4 8.25) with sucrose (p = 0.28). The 11 infants born at under 28 weeks of age showed higher median scores of nine (9-14) for breast milk and four (4-7) for sucrose (p = 0.009). CONCLUSION: EBM and 24% sucrose had the same analgesic effect during venipuncture in most of the preterm neonates, but sucrose worked better in extremely preterm infants. PMID- 29150863 TI - Family behaviours that have an impact on the self-management activities of adults living with Type 2 diabetes: a systematic review and meta-synthesis. AB - AIMS: To identify family behaviours that adults with Type 2 diabetes' perceive as having an impact on their diabetes self-management. BACKGROUND: Research suggests that adults with Type 2 diabetes perceive that family members have an important impact on their self-management; however, it is unclear which family behaviours are perceived to influence self-management practices. METHODS: This meta synthesis identified and synthesized qualitative studies from the databases EMBASE, Medline and CINAHL published between the year 2000 and October 2016. Studies were eligible if they provided direct quotations from adults with Type 2 diabetes, describing the influence of families on their self-management. This meta-synthesis adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. RESULTS: Of the 2606 studies screened, 40 were included. This meta-synthesis identified that adults with Type 2 diabetes perceive family behaviours to be either: 1) facilitators of diabetes self management; 2) barriers to diabetes self-management; or 3) equivocal behaviours with the potential to both support and/or impede diabetes self-management. Seven sub-themes were identified within these themes, including: four facilitator sub themes ('positive care partnerships'; 'family watchfulness'; 'families as extrinsic motivator' and 'independence from family'); two barrier sub-themes ('obstructive behaviours' and 'limited capacity for family support'); and one equivocal behaviours subtheme ('regular reminders and/or nagging'). CONCLUSION: While most family behaviours are unambiguously perceived by adults with Type 2 diabetes to act as facilitators of or barriers to self-management, some behaviours were perceived as being neither clear facilitators nor barriers; these were termed 'equivocal behaviours'. If the concept of 'equivocal behaviours' is confirmed, it may be possible to encourage the adult living with Type 2 diabetes to reframe these behaviours so that they are perceived as enabling their diabetes self-management. PMID- 29150864 TI - Seeing is believing: A review of apheresis therapy in the treatment of ophthalmologic disease. AB - Apheresis procedures have a role in treatment of disparate diseases involving many different organ systems. Often the disease processes where apheresis plays a role in treatment are considered "orphan diseases"-relatively rare disease processes that lack specific pharmaceutical agents or established treatment protocols. Many of these disease processes can affect the eye with devastating results for the eyesight of these patients. The unique ability of apheresis to affect disease by modifying blood plasma and modulating disease-causing agents therein renders apheresis procedures valuable tools in the treatment of certain ophthalmologic diseases. This review comprehensively evaluates the role of apheresis in the treatment of ophthalmologic diseases of the eye and surrounding orbit including age-related macular degeneration, bilateral diffuse uveal melanocytic proliferation, paraneoplastic retinopathy, atopic keratoconjunctivitis, sympathetic ophthalmia, and endocrine-associated ophthalmopathy. Apheresis procedure parameters are provided for the apheresis practitioner based on review of the relevant literature. PMID- 29150865 TI - Enhanced mu opioid receptor-dependent opioidergic modulation of striatal cholinergic transmission in DYT1 dystonia. AB - BACKGROUND: Mu opioid receptor activation modulates acetylcholine release in the dorsal striatum, an area deeply involved in motor function, habit formation, and reinforcement learning as well as in the pathophysiology of different movement disorders, such as dystonia. Although the role of opioids in drug reward and addiction is well established, their involvement in motor dysfunction remains largely unexplored. METHODS: We used a multidisciplinary approach to investigate the responses to mu activation in 2 mouse models of DYT1 dystonia (Tor1a+/Deltagag mice, Tor1a+/- torsinA null mice, and their respective wild types). We performed electrophysiological recordings to characterize the pharmacological effects of receptor activation in cholinergic interneurons as well as the underlying ionic currents. In addition, an analysis of the receptor expression was performed both at the protein and mRNA level. RESULTS: In mutant mice, selective mu receptor activation caused a stronger G-protein-dependent, dose-dependent inhibition of firing activity in cholinergic interneurons when compared with controls. In Tor1a+/- mice, our electrophysiological analysis showed an abnormal involvement of calcium-activated potassium channels. Moreover, in both models we found increased levels of mu receptor protein. In addition, both total mRNA and the mu opioid receptor splice variant 1S (MOR-1S) splice variant of the mu receptor gene transcript, specifically enriched in striatum, were selectively upregulated. CONCLUSION: Mice with the DYT1 dystonia mutation exhibit an enhanced response to mu receptor activation, dependent on selective receptor gene upregulation. Our data suggest a novel role for striatal opioid signaling in motor control, and more important, identify mu opioid receptors as potential targets for pharmacological intervention in dystonia. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29150866 TI - The minimum test battery to screen for binocular vision anomalies: report 3 of the BAND study. AB - PURPOSE: This study aims to report the minimum test battery needed to screen non strabismic binocular vision anomalies (NSBVAs) in a community set-up. When large numbers are to be screened we aim to identify the most useful test battery when there is no opportunity for a more comprehensive and time-consuming clinical examination. METHODS: The prevalence estimates and normative data for binocular vision parameters were estimated from the Binocular Vision Anomalies and Normative Data (BAND) study, following which cut-off estimates and receiver operating characteristic curves to identify the minimum test battery have been plotted. In the receiver operating characteristic phase of the study, children between nine and 17 years of age were screened in two schools in the rural arm using the minimum test battery, and the prevalence estimates with the minimum test battery were found. RESULTS: Receiver operating characteristic analyses revealed that near point of convergence with penlight and red filter (> 7.5 cm), monocular accommodative facility (< 10 cycles per minute), and the difference between near and distance phoria (> 1.25 prism dioptres) were significant factors with cut-off values for best sensitivity and specificity. This minimum test battery was applied to a cohort of 305 children. The mean (standard deviation) age of the subjects was 12.7 (two) years with 121 males and 184 females. Using the minimum battery of tests obtained through the receiver operating characteristic analyses, the prevalence of NSBVAs was found to be 26 per cent. Near point of convergence with penlight and red filter > 10 cm was found to have the highest sensitivity (80 per cent) and specificity (73 per cent) for the diagnosis of convergence insufficiency. For the diagnosis of accommodative infacility, monocular accommodative facility with a cut-off of less than seven cycles per minute was the best predictor for screening (92 per cent sensitivity and 90 per cent specificity). CONCLUSION: The minimum test battery of near point of convergence with penlight and red filter, difference between distance and near phoria, and monocular accommodative facility yield good sensitivity and specificity for diagnosis of NSBVAs in a community set-up. PMID- 29150867 TI - Near-infrared diffuse reflectance signals for monitoring spreading depolarizations and progression of the lesion in a male rat focal cerebral ischemia model. AB - In ischemic stroke research, a better understanding of the pathophysiology and development of neuroprotection methods are crucial, for which in vivo imaging to monitor spreading depolarizations (SDs) and evolution of tissue damage is desired. Since these events are accompanied by cellular morphological changes, light-scattering signals, which are sensitive to cellular and subcellular morphology, can be used for monitoring them. In this study, we performed transcranial imaging of near-infrared (NIR) diffuse reflectance at ~800 nm, which sensitively reflects light-scattering change, and examined how NIR reflectance is correlated with simultaneously measured cerebral blood flow (CBF) for a rat middle cerebral artery occlusion (MCAO) model. After MCAO, wavelike NIR reflectance changes indicating occurrence of SDs were generated and propagated around the ischemic core for ~90 min, during which time NIR reflectance increased not only within the ischemic core but also in the peripheral region. The area with increased reflectance expanded with increase in the number of SD occurrences, the correlation coefficient being 0.7686 (n = 5). The area with increased reflectance had become infarcted at 24 hr after MCAO. The infarct region was found to be associated with hypoperfusion or no-flow response to SD, but hyperemia or hypoperfusion followed by hyperemia response to SD was also observed, and the regional heterogeneity seemed to be connected with the rat cerebrovasculature and hence existence/absence of collateral flow. The results suggest that NIR reflectance signals depicted early evolution of tissue damage, which was not seen by CBF changes, and enabled lesion progression monitoring in the present stroke model. PMID- 29150868 TI - Patient-reported health outcomes in patients with non-melanoma skin cancer and actinic keratosis: results from a large-scale observational study analysing effects of diagnoses and disease progression. AB - BACKGROUND: Non-melanoma skin cancer (NMSC) and actinic keratosis (AK) are very common among fair-skinned individuals. A disease continuum from AK to squamous cell carcinoma (SCC) has been frequently postulated. AK and NMSC may influence quality of life (QL) of patients, and it can be suspected that disease progression entails a QL reduction. The purpose of this study was to document QL in patients with NMSC and AK using the health-outcome questionnaire EQ-5D-5L. METHODS: The study was designed as a non-interventional, prospective, cross sectional study. Patients with AK, SCC, basal cell carcinoma (BCC) or multiple diagnoses were enrolled in this study in 29 dermatological centres across Germany. Patients were asked to complete the EQ-5D-5L (compromising EQ Index and EQ VAS), and the dermatologists provided diagnosis, disease history and treatment data. RESULTS: A total of 1184 patients were enrolled and diagnosed as follows: 73% AK, 49% BCC and 17% SCC. 66% had a single diagnosis, 28% two different diagnoses and 6% three different diagnoses. QL was strongly associated with patients' diagnosis. Patients with a single AK diagnosis had significantly higher mean EQ VAS (78) than patients with BCC (74), SCC (72), and BCC plus SCC (69), P < 0.050. When the effects of disease progression were calculated, patients with AK plus SCC reported significantly less mean EQ VAS (71) than patients with a single AK diagnosis (78), P < 0.011. CONCLUSIONS: While rarely being imminently life-threatening, NMSC and AK have an impact on QL as quantified by the EQ-5D-5L. This impact is associated with diagnosis (AK vs. NMSC) and clinical progression (AK vs. AK plus SCC). Both lead to a clear decline in QL. This shows that disease progression is perceived and judged as detrimental by patients and that AK and NMSC should be diligently treated to preserve and restore QL. PMID- 29150870 TI - Acute and recurrent facial pustulosis: a unique clinical entity? PMID- 29150869 TI - Maternal mood disorders and lithium exposure in utero were not associated with poor cognitive development during childhood. AB - AIM: This study evaluated whether maternal mood disorders (MMD), particularly bipolar disorder, and lithium treatment during pregnancy influenced the neonatal health and cognition of children born from 2006 to 2010. METHODS: Our study at Karolinska University Hospital, Stockholm, Sweden, focused on women with and without mood disorders and their children. Information on pharmacotherapy, mental health, delivery and neonatal complications was retrospectively collected from electronic patient records. Children were tested in a blinded manner at four to five years of age with the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition. Maternal health, child health and social situations were evaluated. RESULTS: Of the 39 children, 20 were exposed to lithium and MMD during pregnancy, eight were exposed to MMD but not lithium and 11 were not exposed to MMD or lithium. The children's full scale intelligence quotient (IQ), performance IQ and verbal IQ results did not differ significantly between the groups. The processing speed quotient was significantly lower in children exposed to mood disorders, but there was a high level of missing data for this subtest. CONCLUSION: This small, clinical cohort showed no significant association between mothers' prenatal exposure to lithium or mood disorders and their offspring's IQ. PMID- 29150871 TI - Reversing dopaminergic sensitization. PMID- 29150872 TI - Predicting the onset of freezing of gait: A longitudinal study. AB - BACKGROUND: Freezing of gait is a disabling symptom of Parkinson's disease that ultimately affects approximately 80% of patients, yet very little research has focused on predicting the onset of freezing of gait and tracking the longitudinal progression of symptoms prior to its onset. The objective of the current study was to examine longitudinal data spanning the transition period when patients with PD developed freezing of gait to identify symptoms that may precede freezing and create a prediction model that identifies those "at risk" for developing freezing of gait in the year to follow. METHODS: Two hundred and twenty-one patients with PD were divided into 3 groups (88 nonfreezers, 41 transitional freezers, and 92 continuing freezers) based on their responses to the validated Freezing of Gait-Questionnaire item 3 at baseline and follow-up. Critical measures across motor, cognitive, mood, and sleep domains were assessed at 2 times approximately 1 year apart. RESULTS: A logistic regression model that included age, disease duration, gait symptoms, motor phenotype, attentional set shifting, and mood measures could predict with 70% and 90% accuracy those patients who would and would not develop, respectively, freezing of gait over the next year. Notably, the Freezing of Gait-Questionnaire total and the anxiety section of the Hospital Anxiety and Depression Scale were the strongest predictors and alone could significantly predict if one might develop freezing of gait in the next 15 months with 82% accuracy. CONCLUSIONS: Our results suggest that it is possible to identify the majority of patients who will develop freezing of gait in the following year, potentially allowing targeted interventions to delay or possibly even prevent the onset of freezing. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29150874 TI - Sickle hemoglobin oxygen affinity-shifting strategies have unequal cerebrovascular risks. PMID- 29150873 TI - Survival in patients with Parkinson's disease after deep brain stimulation or medical management. AB - OBJECTIVE: Deep brain stimulation has been shown to have a significant long-term beneficial effect on motor function. However, whether it affects survival is not clear. In this study, we compared survival rates for Parkinson's disease (PD) patients who underwent deep brain stimulation (DBS) with those who were medically managed. METHODS: A retrospective analysis of Veterans Affairs and Medicare administrative data of veterans with PD who received DBS and were propensity score matched to a cohort of veterans with PD who did not receive DBS between 2007-2013. RESULTS: Veterans with PD who received DBS had a longer survival measured in days than a matched group of veterans who did not undergo DBS (mean = 2291.1 [standard error = 46.4] days [6.3 years] vs 2063.8 [standard error = 47.7] days [5.7 years]; P = .006; hazard ratio = 0.69 [95% confidence interval 0.56 0.85]). Mean age at death was similar for both groups (76.5 [standard deviation = 7.2] vs 75.9 [standard deviation = 8.4] years, P = .67), respectively, and the most common cause of death was PD. CONCLUSIONS: DBS is associated with a modest survival advantage when compared with a matched group of patients who did not undergo DBS. Whether the survival advantage reflects a moderating influence of DBS on PD or on comorbidities that might shorten life or whether differences may be a result of unmeasured differences between groups is not known. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 29150875 TI - Treatment of acquired Thrombotic Thrombocytopenic Purpura in the U.S. remains heterogeneous: Current and future points of clinical equipoise. AB - BACKGROUND: The purpose of this survey was to describe current practices in the U.S. for treatment of acquired Thrombotic Thrombocytopenic Purpura (TTP), compare these with prior U.S. and current Canadian practices, and identify areas of clinical equipoise. STUDY DESIGN AND METHODS: A research team member administered the survey by telephone. Questions included an estimate of the annual patient volume treated, apheresis and medical therapy practices for acquired TTP. RESULTS: 32 centers from 22 states were surveyed. ADAMTS13 activity is used for confirmation of the diagnosis of acquired TTP (97%). Most commonly, daily plasma exchange (therapeutic plasma exchange [TPE]) is initiated with plasma as replacement fluid (91%) at 1.0 Plasma Volume (72%) and stopped with a platelet count of 150 * 109 /L (66%), and then TPE is tapered off (69%). Compared with a U.S. survey from 1998, a greater proportion of centers use plasma exclusively as the replacement fluid exclusively (29/32 vs 2/14 in 1998; P < .0001) and taper TPE (22/32 vs 8/20 in 1998, P = .0499). Compared with Canadian survey in 2016, a greater proportion of U.S. centers use plasma over cryosupernatant (29/32 vs 2/13 CAG centers, P < .0001) and initiate TPE with 1.0 PV compared with 1.5 PV (23/32 vs 0/14 CAG centers, P < .0001). Corticosteroid use is common but not universal (U.S. and CAG) and use of rituximab heterogeneous. CONCLUSION: Treatment of acquired TTP in the U.S. remains heterogeneous. Points of clinical equipoise identified were PV exchanged (1.0 vs >1.0), tapering of TPE versus none, and rituximab use. PMID- 29150876 TI - Toxicological characterization of ZnO nanoparticles in malignant and non malignant cells. AB - The increasing usage of zinc oxide nanoparticles (ZnO-NPs) in industrial applications as well as in consumer products raises concern regarding their potential adverse effects to a greater extend. Numerous studies have demonstrated toxic properties of NPs, however there is still a lack of knowledge concerning the underlying mechanisms. This study was designed to systematically investigate cytotoxicity, apoptosis, cell cycle alterations, and genotoxicity induced by ZnO NP. Moreover, it was an aim of the investigations to specify the diverse effects of nanoparticle exposure in malignant in comparison with non-malignant cells. Therefore, human head and neck squamous cell carcinoma-derived FaDu cells were incubated with 4-20 ug/ml of ZnO-NPs for 1-48 hr and tested for cell viability, cell cycle alterations, apoptosis and caspase-3 gene expression as a sensitive marker of molecular apoptotic processes with regard to time- and dose-dependent effects. Human mesenchymal bone marrow stem cells were used as non-malignant representatives to examine oxidative stress-related genotoxicity. Results showed a significant reduction in cell viability as well as dose- and time-dependent increase of apoptotic cells following nanoparticle treatment. Likewise, caspase-3 gene expression enhanced already before first apoptotic cells were detectable. It could be observed that doses that were cytotoxic in tumor cells did not reduce viability in stem cells. However, the same concentrations already induced significant DNA damage. The findings of the study suggest to keep a more critical eye on the use of nanoparticles as anti-cancer agents. Yet, additional in vivo studies are needed to assess safety concerns for consumers and patients. Environ. Mol. Mutagen. 59:247-259, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29150877 TI - Patients with Spitz naevi in the Greek population: Epidemiologic, Clinical and Histopathological characteristics. AB - BACKGROUND: Spitz naevi may present with clinical and histopathological atypical features that do not affect patient prognosis but may become worrisome for patients >=40 years presenting with newly appearing SN. OBJECTIVE: Patient characteristics and sun behaviour patterns were investigated in correlation with age. SN characteristics and histopathological attributes were also investigated in correlation with age. METHODS: Patients with histopathologically confirmed diagnosis of SN were invited for a clinical examination. Data such as skin type, number of banal/atypical naevi, sun exposure patterns and personal/family history were collected. Histopathology preparations were re-examined by two different histopathologists, and characteristics were collected based on a prespecified checklist. Patients were afterwards followed up every 6 months. RESULTS: A total of 110 patients with SN were identified and assigned to three age groups. The most common area of presentation was the trunk, for the >=40 years age group, and the limbs for the other age groups. Patients >=40 years had a higher possibility of presenting with a naevus count >=50 and at least one atypical naevus compared to the other age groups. Patients >=40 years presented more commonly with a history of painful sunburn (100%) before the appearance of the SN, used less sunscreen, had higher sun exposure times and more clinical signs of solar skin damage compared to the other age groups. Finally, patients >=40 years presented more commonly with signs of histopathological atypia such as the presence of mitoses, cellular atypia and prominent nucleolus. CONCLUSION: Patients >=40 were more likely to report a history of longer sun exposure times, of never using a sunscreen and of having a history of painful sunburn. However, the importance of this observation remains to be elucidated as these patients also presented more commonly with lesions located on non-sun-exposed areas (trunk) and higher naevus/atypical naevus counts. PMID- 29150878 TI - Cyclooxygenase 2 is upregulated in the gastrointestinal tract in Parkinson's disease. PMID- 29150879 TI - Modification of the lipid profile and antioxidant status of the blood plasma of turkey hens fed mixtures with raw or extruded linseed. AB - The aim of the study was to determine the most beneficial proportion of raw linseed in complete feed mixtures for turkey hens on the basis of lipid and redox indicators in the blood. In experiment 1, the turkey hens received the complete mixture with 2%, 4% or 6% linseed. On the basis of the results obtained in experiment 1, we selected the most effective proportion of linseed, which was given to the birds in the group receiving a 4% linseed additive. In experiment 2, the birds were fed mixtures with a 4% addition of raw or extruded linseed. The use of 4% raw linseed was found to improve production effects (improvement of weight gain, and lower feed conversion ratios), while extruded linseed in the diet of turkey hens did not affect growth performance. The use of linseed (4% and 6%) as a feed component for turkey hens led to an increase in indicators of antioxidant potential, that is the total antioxidant potential of the plasma, vitamins E and C, bilirubin and creatinine. A benefit resulting from the use of linseed, particularly in the amounts of 2% and 4% was a marked improvement in lipid indicators in the blood. The reduced percentage of unsaturated fatty acids (n-3) following the use of extruded linseed resulted in a decrease in lipid peroxidation (lower content of malondialdehyde, superoxide and vitamins C and E in the blood). The most effective dose and form of linseed in the diet of turkey hens is 4% raw linseed. PMID- 29150880 TI - A slowly developed severe cutaneous adverse reaction to idelalisib. PMID- 29150881 TI - Genotoxicity of 11 heavy metals detected as food contaminants in two human cell lines. AB - Heavy metals, such as arsenic (As), antimony (Sb), barium (Ba), cadmium (Cd), cobalt (Co), germanium (Ge), lead (Pb), nickel (Ni), tellurium (Te), and vanadium (V) are widely distributed in the environment and in the food chain. Human exposure to heavy metals through water and food has been reported by different international agencies. Although some of these heavy metals are essential elements for human growth and development, they may also be toxic at low concentrations due to indirect mechanisms. In this study, the genotoxic and cytotoxic properties of 15 different oxidation statuses of 11 different heavy metals were investigated using high-throughput screening (gammaH2AX assay) in two human cell lines (HepG2 and LS-174T) representative of target organs (liver and colon) for food contaminants. Base on their lowest observed adverse effect concentration, the genotoxic potency of each heavy metal in each cell line was ranked in decreasing order, NaAsO2 > CdCl2 > PbCl2 (only in LS-174T cells) > As2 O5 > SbCl3 > K2 TeO3 > As2 O3 . No significant genotoxicity was observed with the other heavy metals tested. Cell viability data indicate that several heavy metals (As, Cd, Co, Ni, Sb, and Te) induce cytotoxicity at high concentrations, whereas an increase in the number of cells was observed for lead concentrations >100 uM in both cell lines tested, suggesting that lead stimulates cell growth. All these results highlight the possible human health hazards associated with the presence of heavy metals present in food. Environ. Mol. Mutagen. 59:202-210, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29150882 TI - Plantar Eumycetoma by Madurella mycetomatis in a heart-transplanted patient living in Portugal. PMID- 29150883 TI - Finding the needle in the haystack is teledermoscopy's task. PMID- 29150885 TI - Recognizing the haystack is the task of the primary care physician. PMID- 29150884 TI - Directional local field potentials: A tool to optimize deep brain stimulation. AB - BACKGROUND: Although recently introduced directional DBS leads provide control of the stimulation field, programing is time-consuming. OBJECTIVES: Here, we validate local field potentials recorded from directional contacts as a predictor of the most efficient contacts for stimulation in patients with PD. METHODS: Intraoperative local field potentials were recorded from directional contacts in the STN of 12 patients and beta activity compared with the results of the clinical contact review performed after 4 to 7 months. RESULTS: Normalized beta activity was positively correlated with the contact's clinical efficacy. The two contacts with the highest beta activity included the most efficient stimulation contact in up to 92% and that with the widest therapeutic window in 74% of cases. CONCLUSION: Local field potentials predict the most efficient stimulation contacts and may provide a useful tool to expedite the selection of the optimal contact for directional DBS. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 29150886 TI - Ruxolitinib-associated infections: A systematic review and meta-analysis. AB - Ruxolitinib exerts immunosuppressive activity that may increase the risk of infectious complications. We performed a systematic review of the literature with the aim of estimating the risk of infections in patients treated with ruxolitinib. Studies were identified by electronic search of MEDLINE and EMBASE database. Differences in the incidence of infectious events between ruxolitinib and comparison groups were expressed as odds ratios (ORs) and 95% confidence intervals (95% CI). Five phase III randomized clinical trials (RCTs) (3 phase IIIa with their extended phase and 2 phase IIIb), 6 phase IV studies and 28 case reports were included in this systematic review. Ruxolitinib was associated with a statistically significant increased risk of herpes zoster infection compared to control group in 3 RCTs including patients with polycythemia vera (OR 7.39 [1.33, 41.07]) and in a pooled analysis of the extended phase IIIa RCTs (OR 5.20 [95%CI 1.27, 21.18]). In the larger phase IV post-marketing study, the incidence of the most frequent infections was 8% for herpes zoster, 6.1% for bronchitis and 6% for urinary tract infections. In the published case reports, the most frequent infections were tuberculosis (N = 10), hepatitis B reactivation (N = 5) and pneumocystis jeroveci infection (N = 2). Evidence is not solid enough to accurately estimate the risk of infection in ruxolitinib-treated patients. However, published data clearly suggest that the infection risk may be clinically relevant. Well-designed studies are warranted to evaluate the risk of ruxolitinib associated infection, in order to identify the most appropriate antimicrobial prophylactic strategy. PMID- 29150887 TI - Is there also room for rational thought? PMID- 29150888 TI - Systematic review of disparities in surgical care for Maori in New Zealand. AB - BACKGROUND: Health equity for Indigenous peoples in the context of surgery has recently become topical amongst surgeons in Australasia. Health inequities are amongst the most consistent and compelling disparities between Maori and New Zealand Europeans (NZE) in New Zealand (NZ). We aimed to investigate where ethnic disparities in surgical care may occur and highlight some of the potential contributing factors, over all surgical specialties, between Maori and NZE adults in NZ. METHODS: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A series of electronic searches were performed in Medline, Embase, PubMed and CINAHL. RESULTS: Ten studies met the inclusion criteria. All studies employed a range of indicators for surgical care including receipt of surgery following diagnosis, delays to treatment and post-operative morbidity and mortality. Disparities in the receipt of surgical treatment for several cancers were observed for Maori and remained after adjustment for socioeconomic variables and extent of disease. Maori were more likely to experience delays in treatment and referral to other medical specialties involved in their care. CONCLUSION: Despite the significant variation in the types of diseases, procedures and indicators of surgical care of the included studies, consistent findings are that disparities in different aspects of surgical care exist between Maori and NZE in NZ. This review highlights the need to better quantify the important issue of health equity for Maori in surgery given the lack of studies over the majority of surgical specialties. PMID- 29150889 TI - Novel aqueous oil-in-water emulsions containing extracts of natural coniferous resins are strongly antimicrobial against enterobacteria, staphylococci and yeasts, as well as on bacterial biofilms. AB - AIMS: The aim of this study was to examine the antimicrobial properties of novel aqueous natural rapeseed oil/saline emulsions containing different soluble components of spruce resin. METHODS AND RESULTS: The composition of aqueous resin emulsions was analysed by GC-MS and their antimicrobial properties were studied with challenge tests and with turbidometric assays. The emulsions were strongly antimicrobial against common Gram-positive and Gram-negative bacteria (including MRSA) as well as common yeasts. Furthermore, they inhibited the biofilm formation and eradicated the microbial biofilms on tested microbes. Characteristic for the emulsions was the presence of oxidized resin acids. Other main components present in emulsions, such as lignans and coumaric acids, were not antimicrobial, when tested separately. CONCLUSIONS: The results indicated that the oxidized resin acids were the antimicrobial components in the emulsions. Also, there appears to be a stoichiometric relationship between the number of resin acid molecules and the number microbe cells in the antimicrobial action. SIGNIFICANCE AND IMPACT OF THE STUDY: The fact that these solutions do not contain abietic acid, which is the main allergenic compound in resins, suggests that these solutions would be suitable, well-tolerated antimicrobials for various medical applications. The aqueous formulation will also allow the expansion of the use of these emulsions in from medical applications to the food preservatives and disinfectants. PMID- 29150890 TI - Suspended animation: the past, present and future of major cardiothoracic trauma. AB - About 50% of the trauma victims die at the scene mostly because of exsanguinating haemorrhage. Most trials of resuscitation fail in face of the ongoing bleeding. Ongoing research/studies to save these victims by inducing rapid hypothermia using cardiopulmonary bypass as an emergency initial measure along with delayed resuscitation show improved outcomes. A comprehensive review of this research and analysis of studies showed that rapid induction of hypothermia within 5 min of cardiac arrest is associated with better survival and improved neurological outcome. This led us to conclude that suspended animation is a lifesaving modality for the treatment of trauma victims, otherwise hurtling towards certain death. This should be integrated into regular clinical practice. The US Food and Drug Administration has given its approval for clinical trials on such an intervention. PMID- 29150891 TI - What the neighbors say. PMID- 29150893 TI - Identifying and addressing sexual health in serious mental illness: Views of mental health staff working in two National Health Service organizations in England. AB - People with serious mental illness (service users) have needs related to sexual health and sexuality, yet these have been poorly addressed in mental health services. In the present study, we report the current practice of mental health professionals in relation to sexual health. Focus groups conducted in two mental health trusts explored routine practice in relation to discussing, assessing, and planning care in relation to sexual health. A thematic analysis identified seven themes: (i) sexual health provision is a complex issue; (ii) mental health staff are aware of sexual health needs; (iii) current provision regarding sexual health is 'neglected'; (iv) barriers to sexual health provision; (v) enabling a discussion around sexual health; (vi) sexual health provision is a role for mental health professionals; and (vii) training needs. Mental health staff are aware of complex issues related to sexual health for service users, but this is mainly seen through the lens of risk management and safeguarding. We need to develop the mental health workforce to be able to incorporate sexual health into routine health care. PMID- 29150892 TI - Expanding the neurodevelopmental phenotype of PURA syndrome. AB - PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox-Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype-phenotype associations. PMID- 29150894 TI - Unique association of hypochondroplasia with craniosynostosis and cleft palate in a Mexican family. AB - Hypochondroplasia (HCH) is a skeletal dysplasia caused by an abnormal function of the fibroblast growth factor receptor 3. Although believed to be relatively common, its prevalence and phenotype are not well established owing to its clinical, radiological, and genetic heterogeneity. Here we report on a molecularly proven HCH family with an affected father and two children. The siblings (male and female) with HCH also had craniosynostosis and cleft palate, respectively. The present report supports the conclusion that the full clinical spectrum of HCH is not completely delineated. It also suggests that secondary, as yet unknown, modifying factors can influence the final phenotype. PMID- 29150895 TI - Rapid and green determination of 58 fragrance allergens in plush toys. AB - This paper presents a simple, rapid, and green method based on a static headspace gas chromatography-mass spectrometry for determining 58 fragrance allergens in plush toys. This study is the first to meet the requirement for simultaneously determining 66 fragrances, except for eight natural extracts restricted by the European Toy Safety Directive 2009/48/EC. A minimal amount of sample (20 mg) and acetone solvent (20 MUL) were placed in a headspace vial. A gas-solid equilibration of fragrances between the headspace and the sample was achieved within 10 min under the vapor atmosphere of acetone at 200 degrees C, which allowed the fragrances in the sample to be measured by gas chromatography-mass spectrometry. Results showed that the interference caused by different sample matrices was negligible. The proposed method exhibited determination results that were highly similar to those of traditional ultrasonic extraction with sufficient sensitivity (limits of quantification: 0.02-10 mg/kg) for 58 fragrances, indicating its accuracy and reliability. The average recoveries ranged from 71.3 to 137.4%, and the relative standard deviation (n = 6) varied from 1.1 to 18.0%. Finally, the method was applied to monitor the fragrances in 20 commercial toys. This study provides a good reference for rapidly and greenly determining the semi volatile analytes in toys, textiles, and other products. PMID- 29150896 TI - Stereospecific control of peptide gas-phase ion chemistry with cis and trans cyclo ornithine residues. AB - We report non-chiral amino acid residues cis- and trans-1,4-diaminocyclohexane-1 carboxylic acid (cyclo-ornithine, cO) that exhibit unprecedented stereospecific control of backbone dissociations of singly charged peptide cations and hydrogen rich cation radicals produced by electron-transfer dissociation. Upon collision induced dissociation (CID) in the slow heating regime, peptide cations containing trans-cO residues undergo facile backbone cleavages of amide bonds C-terminal to trans-cO. By contrast, peptides with cis-cO residues undergo dissociations at several amide bonds along the peptide ion backbone. Diastereoisomeric cO containing peptides thus provide remarkably distinct tandem mass spectra. The stereospecific effect in CID of the trans-cO residue is explained by syn-facially directed proton transfer from the 4-ammonium group at cO to the C-terminal amide followed by neighboring group participation in the cleavage of the CO-NH bond, analogous to the aspartic acid and ornithine effects. Backbone dissociations of diastereoisomeric cO-containing peptide ions generate distinct [bn ]+ -type fragment ions that were characterized by CID-MS3 spectra. Stereospecific control is also reported for electron-transfer dissociation of cis- and trans-cO containing doubly charged peptide ions. The stereospecific effect upon electron transfer is related to the different conformations of doubly charged peptide ions that affect the electron attachment sites and ensuing N-Calpha bond dissociations. PMID- 29150897 TI - Determining best outcomes from community-acquired pneumonia and how to achieve them. AB - Community-acquired pneumonia (CAP) is a common acute medical illness with a standard, effective treatment that was introduced before the evidenced-based medicine era. Mortality rates have improved in recent decades but improvements have been minimal when compared to other conditions such as acute coronary syndromes. The standardized approach to treatment makes CAP a target for comparative performance and outcome measures. While easy to collect, simplistic outcomes such as mortality, readmission and length of stay are difficult to interpret as they can be affected by subjective choices and health care resources. Proposed clinical- and patient-reported outcomes are discussed below and include measures such as the time to clinical stability (TTCS) and patient satisfaction, which can be compared between health institutions. Strategies to improve these outcomes include use of a risk stratification tool, local antimicrobial guidelines with antibiotic stewardship and care bundles to include early administration of antibiotics and early mobilization. PMID- 29150898 TI - A model to characterize psychopathological features in adults with Prader-Willi syndrome. AB - High prevalence of behavioral and psychiatric disorders in adults with Prader Willi Syndrome (PWS) has been reported in last few years. However, data are confusing and often contradictory. In this article, we propose a model to achieve a better understanding of the psychopathological features in adults with PWS. The study is based on clinical observations of 150 adult inpatients, males and females. Non-parametric statistics were performed to analyse the association of psychopathological profiles with genotype, gender and age. We propose a model of psychiatric disorders in adults with PWS based on cognitive, emotional and behavioural issues. This model defines four psychopathological profiles: Basic, Impulsive, Compulsive, and Psychotic. The Basic profile is defined by traits and symptoms that are present in varying degrees in all persons with PWS. In our cohort, this Basic profile corresponds to 55% of the patients. The rest show, in addition to these characteristics, salient features of impulsivity (Impulsive profile, 19%), compulsivity (Compulsive profile, 7%), or psychosis (Psychotic profile, 19%). The analysis of factors associated with different profiles reveals an effect of genotype on Basic and Psychotic profiles (Deletion: 70% Basic, 9% Psychotic; Non-deletion: 23% Basic, 43% Psychotic) and a positive correlation between male sex and impulsivity, unmediated by sex hormone treatment. This is a clinical study, based on observation proposing an original model to understand the psychiatric and behavioural disorders in adults with PWS. Further studies are needed in order to test the validity of this model. PMID- 29150899 TI - p.Arg69Trp in RNASEH2C is a founder variant in three Indian families with Aicardi Goutieres syndrome. AB - Aicardi-Goutieres syndrome is an early-onset severe neurological disorder characterized by intracranial calcification, white matter abnormalities, hepatosplenomegaly, cerebrospinal fluid lymphocytosis, and elevated interferon alpha levels, thus mimicking congenital viral infections. It is a genetically heterogeneous condition and autosomal recessive and autosomal dominant forms with variations in seven genes known till date. Variations in RNASEH2C cause an autosomal recessive form of AGS. Here we report three Indian families with variant, c.205C>T (NM_032193.3, p.Arg69Trp) in RNASEH2C gene identified by whole exome sequencing and targeted molecular testing of the variant. Review of literature and our data suggest this is likely to be a founder variant in Asians and it would be a good initial variant to screen in patients with Aicardi Goutieres syndrome in Indians. PMID- 29150900 TI - Genetic overlap between epilepsy and schizophrenia: Evidence from cross phenotype analysis in Hong Kong Chinese population. AB - Epilepsy and schizophrenia are common and typical neurological or mental illness respectively, and sometimes they comorbid in the same patients, however the underlying genetic relationship between the two brain diseases is still not fully understood. To investigate the possible genetic contribution to their comorbidity, we performed polygenic risk score (PRS) analyses and genetic correlation estimation so as to identify the overall genetic overlap between the two diseases. The global schizophrenia PRS is strongly associated with schizophrenia phenotype in Hong Kong population (odds ratio = 1.7, p = 2.26E-16), and focal epilepsy PRS is moderately associated with epilepsy phenotype in Hong Kong population (odds ratio = 1.14, p = 0.013). However the disease-specific PRS can only predict its own well-matched phenotype but not the other ones (p > 0.05). This pattern is further supported by non-significant pairwise genetic correlation and insufficient statistical power for PRS association from the cross phenotype analyses. Our study reveals there's limited shared genetic aetiology between schizophrenia and epilepsy, and thus supports a model of shared environmental factors to explain the comorbidity between the two phenotypes. PMID- 29150901 TI - Expression of the clock gene Rev-erbalpha in the brain controls the circadian organisation of food intake and locomotor activity, but not daily variations of energy metabolism. AB - The nuclear receptor REV-ERBalpha is part of the molecular clock mechanism and is considered to be involved in a variety of biological processes within metabolically active peripheral tissues as well. To investigate whether Rev erbalpha (also known as Nr1d1) in the brain plays a role in the daily variations of energy metabolism, feeding behaviour and the sleep-wake cycle, we studied mice with global (GKO) or brain (BKO) deletion of Rev-erbalpha. Mice were studied both in a light/dark cycle and in constant darkness, and then 24-hour variations of Respiratory quotient (RQ) and energy expenditure, as well as the temporal patterns of rest-activity and feeding behaviour, were recorded. The RQ increase of GKO mice was not detected in BKO animals, indicating a peripheral origin for this metabolic alteration. Arrhythmic patterns of locomotor activity were only found in BKO mice. By contrast, the circadian rhythm of food intake was lost both in GKO and BKO mice, mostly by increasing the number of daytime meals. These changes in the circadian pattern of feeding behaviour were, to some extent, correlated with a loss of rhythmicity of hypothalamic Hcrt (also named Orx) mRNA levels. Taken together, these findings highlight that Rev-erbalpha in the brain is involved in the temporal partitioning of feeding and sleep, whereas its effects on energy metabolism are mainly exerted through its peripheral expression. PMID- 29150902 TI - Wieacker-Wolff syndrome with associated cleft palate in a female case. AB - Wieacker-Wolff syndrome is a rare congenital syndrome with few reported cases in the current literature. It is traditionally described in males as an X-linked recessive disorder associated with congenital contractures of the feet, progressive neurologic muscular atrophy, and intellectual delay caused by ZC4H2 mutations. The purpose of this paper is to present a female individual with a classic phenotype and cleft palate, a previously undescribed finding in this syndrome. Recent reports have demonstrated that females are rarely severely affected and phenotypic expression is difficult to predict [Zanzottera et al. (); American Journal of Medical Genetics Part A 173A: 1358-1363]. This case supports the unpredictability of Wieacker-Wolff syndrome severity and prompts future questions regarding female mutations and phenotypic expression. PMID- 29150903 TI - Phylogenetic and genetic variation analyses of porcine circovirus type 2 isolated from China. AB - Porcine circovirus type 2 (PCV2) is a causative agent of PCV2-associated disease, which is a growing problem in the swine industry worldwide. High nucleotide substitution occurs in the capsid (Cap) gene of PCV2, which allows the continuous evolution and the emergence of novel PCV2 strains. In this study, we sequenced 24 Chinese PCV2 strains collected from healthy and diseased pigs between 2013 and 2015. Analyses of the genome, Cap and phylogeny classified the 24 Chinese PCV2 strains as PCV-2a (four of 24), PCV-2b (five of 24) and PCV-2d (15 of 24). All strains shared 89.5%-100% and 87.2%-100% identities with the nucleotide and amino acid (aa) sequences of Cap, respectively. Selection pressure analysis showed that five sites at the epitope regions in Cap were under positive selection. Further analysis by Jameson-Wolf antigenic index indicated that aa substitutions occurring at the epitope regions contributed to the antigenic alterations of the different PCV2 strains. High genetic variation and genotype shift to PCV2d occurred in recent years, and different genotypes coexisted in Chinese pig herds. The data provide evidence for the increased genetic diversity and insights into the molecular epidemiology of PCV2. PMID- 29150904 TI - Endobronchial drug delivery: Expanding techniques and possibilities in interventional pulmonology. PMID- 29150905 TI - Sarcoptic mange in wombats-A review and future research directions. AB - Sarcoptic mange is caused by the mite Sarcoptes scabiei and has recently been recognized as an emerging infectious disease of wildlife worldwide. The mite is one of the main causes of population decline in southern hairy-nosed (Lasiorhinus latifrons) and bare-nosed wombats (Vombatus ursinus). This review focuses on Sarcoptes scabiei infestations in wombats and provides insights into why the disease may be so prevalent in wombats. Current treatment practices and trials conducted in the field to reduce the incidence of sarcoptic mange in wombats are described and critically reviewed. Current and potential future avenues of research are discussed. PMID- 29150906 TI - Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non-small cell lung cancer. AB - Programmed death-ligand 1 (PD-L1) expression status is inadequate for indicating nivolumab in patients with non-small cell lung cancer (NSCLC). Because the baseline advanced lung cancer inflammation index (ALI) is reportedly associated with patient outcomes, we investigated whether the pretreatment ALI is prognostic in NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of all patients treated with nivolumab for advanced NSCLC between December 2015 and May 2016 at three Japanese institutes. Multivariate logistic regression and Cox proportional hazards models were used to assess the impact of the pretreatment ALI (and other inflammation-related parameters) on progression free survival (PFS) and early progression (i.e., within 8 weeks after starting nivolumab). A total of 201 patients were analyzed; their median age was 68 years (range, 27-87 years), 67% were men, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher. An ECOG performance status >=2, serum albumin <3.7 g/dL, neutrophil-to-lymphocyte ratio >=4, and ALI <18 were significantly associated with poor PFS and early progression on univariate analysis. Multivariate analyses revealed that pretreatment ALI <18 was independently associated with inferior PFS (median, 1.4 vs. 3.7 months, P < 0.001) and a higher likelihood of early progression (odds ratio, 2.76; 95% confidence interval 1.44-5.34; P = 0.002). The pretreatment ALI was found to be a significant independent predictor of early progression in patients with advanced NSCLC receiving nivolumab, and may help identify patients likely to benefit from continued nivolumab treatment in routine clinical practice. PMID- 29150907 TI - Sensitivity of doping biomarkers after administration of a single dose testosterone gel. AB - Micro-doping with testosterone (T) is challenging to detect with the current doping tests. Today, the methods available to detect T are longitudinally monitoring of urine biomarkers in the Athlete Biological Passport (ABP) and measuring the isotopic composition of excreted biomarkers to distinguish the origin of the molecule. In this study, we investigated the detectability of a single dose of 100 mg T gel in 8 healthy male subjects. We also studied which biomarkers were most sensitive to T gel administration, including blood biomarkers. The ABP successfully detected T gel administration in all 8 subjects. The most sensitive ratio was 5alphaAdiol/E, however, all ratios showed atypical findings. Isotope ratio mass spectrometry (IRMS) was performed on 5 subjects and only 2 met all the criteria for a positive test according to the rules set by the World Anti-Doping Agency (WADA). The other 3 showed inconclusive results. Other markers that were affected by T gel administration, not used for this detection today, were serum dihydrotestosterone (DHT) and T as well as reticulocyte count and percentage in whole blood. miRNA-122 was not significantly affected by the single T dose. A single dose of 100 mg T gel is possible to detect with today's doping tests. Since a single dose of T gel has an impact on some hematological biomarkers, access to both modules of the ABP when evaluating the athletes' profiles will increase the possibility to detect micro-doses of T. In addition, serum DHT and T may be a useful addition to the future endocrine module of the ABP. PMID- 29150908 TI - 10 years of Drug Testing and Analysis. PMID- 29150910 TI - Educating youth swine exhibitors on influenza A virus transmission at agricultural fairs. AB - Influenza A virus (IAV) is a major zoonotic pathogen that threatens global public health. Novel strains of influenza A viruses pose a significant risk to public health due to their pandemic potential, and transmission of influenza A viruses from animals to humans is an important mechanism in the generation and introduction of IAVs that threaten human health. The purpose of this descriptive correlational study was to develop real-life training scenarios to better inform swine exhibitors of the risks they may encounter when influenza A viruses are present in swine. Educational activities were implemented in five Ohio counties where exhibition swine had historically been shedding influenza A viruses during the county fair. A total of 146 youth swine exhibitors participated in the educational programme, and an increase in the knowledge base of these youth was documented. It is expected that educating youth exhibitors about exposure to influenza A virus infections in the swine they are exhibiting will result in altered behaviours and animal husbandry practices that will improve both human and animal health. PMID- 29150909 TI - Genetic analysis of osteogenesis imperfecta in the Palestinian population: molecular screening of 49 affected families. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous hereditary connective tissue disorder clinically hallmarked by increased susceptibility to bone fractures. METHODS: We analyzed a cohort of 77 diagnosed OI patients from 49 unrelated Palestinian families. Next-generation sequencing technology was used to screen a panel of known OI genes. RESULTS: In 41 probands, we identified 28 different disease-causing variants of 9 different known OI genes. Eleven of the variants are novel. Ten of the 28 variants are located in COL1A1, five in COL1A2, three in BMP1, three in FKBP10, two in TMEM38B, two in P3H1, and one each in CRTAP, SERPINF1, and SERPINH1. The absence of disease-causing variants in the remaining eight probands suggests further genetic heterogeneity in OI. In general, most OI patients (90%) harbor mainly variants in type I collagen resulting in an autosomal dominant inheritance pattern. However, in our cohort almost 61% (25/41) were affected with autosomal recessive OI. Moreover, we document a 21-kb genomic deletion in the TMEM38B gene identified in 29% (12/41) of the tested probands, making it the most frequent OI-causing variant in the Palestinian population. CONCLUSION: This is the first genetic screening of an OI cohort from the Palestinian population. Our data are important for genetic counseling of OI patients and families in highly consanguineous populations. PMID- 29150911 TI - JAK2 V617F mutation can be reliably detected in serum using droplet digital PCR. AB - INTRODUCTION: Detection of the JAK2 V617F mutation is a key step in the diagnosis of myeloproliferative neoplasms (MPN). Sensitive real-time quantitative PCR (qPCR) detection on peripheral blood (PB) is the most widely used method. The main objective of this study was to determine whether serum, the most common material available in archival biobanks, is a good liquid biopsy for detecting and quantifying the JAK2 V617F mutation using droplet digital PCR (ddPCR). METHODS: Paired PB and serum samples from 66 patients with MPN were used. Serum samples were frozen at -25 degrees C before analysis. DNA was extracted from 200 MUL PB and 400 MUL serum, and ddPCR analysis was performed. RESULTS: Among the 47 patients with detectable mutation in their PB samples, the overall sensitivity for the detection of JAK2 mutation in serum was of 96% (45 of 47); V617F was detected in all cases where mutation load was above 1%. Our results showed very strong correlation between PB and serum (Spearman r: 0.989, P < .0001). Significantly higher allele burden was detected in serum compared to PB (Wilcoxon signed ranks test, Z = -5.672, P < .0001). CONCLUSION: In our study, JAK2 V617F mutation load as low as 1% was reliably detected in serum using ddPCR. PMID- 29150912 TI - Sustaining an efficient and effective CHO cell line development platform by incorporation of 24-deep well plate screening and multivariate analysis. AB - Efficient and effective cell line screening is paramount toward a successful biomanufacturing program. Here we describe the implementation of 24-deep well plate (24-DWP) screening of CHO lines as part of the cell line development platform at AbbVie. Incorporation of this approach accelerated the identification of the best candidate lines for process development. In an effort to quantify and predict process performance comparability, we compared cell culture performance in and in shake flasks, for a panel of Chinese Hamster Ovary cell lines expressing a monoclonal antibody. The results in 24-DWP screening showed reduced growth profiles, but comparable viability profiles. Slow growers in 24-DWP achieved the highest productivity improvement upon scaling-up to shake flasks. Product quality of the protein purified from shake flasks and 24-DWP were also compared. The 24-DWP culture conditions were found to influence the levels of acidic species, reduce the G0 N-glycan species, and increase the high-mannose N glycan species. Nevertheless, the identification of undesirable profiles is executed consistently with the scaled-up culture. We further employed multivariate data analysis to capture differences depending on the two scales and we could demonstrate that cell line profiles were adequately clustered, regardless of the vessel used for the development. In conclusion, the 24-DWP platform was reasonably predictive of the parameters crucial for upstream process development activities, and has been adapted as part of the AbbVie cell line development platform. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:175-186, 2018. PMID- 29150914 TI - Navigating the Clinical Translation of Medical Devices: The Case of Radiofrequency Ablation. PMID- 29150913 TI - Molecular epidemiology of goat pox viruses. AB - Goat pox disease outbreaks were observed in different places affecting Black Bengal Goats in West Bengal (WB) and Tellicherry, Vembur and non-descriptive breeds in Tamil Nadu (TN) causing severe lesions and mortality up to 30%. Clinical specimens from all the outbreaks were screened by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) and confirmed the diseases as Goat Pox. Virus isolation in Vero cell line was done with randomly selected ten samples, cytopathic effects (CPE) characterized by syncytia and intracytoplasmic inclusion bodies were observed after several blind passages. Nucleotide sequence of complete p32 gene using randomly selected two isolates and three clinical specimens revealed presence of Goat pox virus (GTPV) specific signature residues in all the sequences. Phylogenetic analysis using the present five sequences along with GenBank data of GTPV complete p32 gene sequences showed all the GTPV sequences cluster together except Pellor strain (NC004003) and FZ Chinese strain (KC951854). The five sequences either from WB or TN cluster more closely with GTPV isolates of Maharashtra state that were responsible for cross species outbreak of pox disease in both sheep (KF468759) and goats (KF468762) in India during the year 2010. All the Indian goat pox viruses, including the Mukteswar strain, isolated in 1946 and sequence reported in 2004 clustered together with the GTPVs causing the recent outbreaks. It was observed that GTPVs caused similar clinical manifestation irrespective of their geographical locations and breed characteristics, no variation observed among the Indian isolates based on p32 gene over the period of seventy years and disease outbreaks could not be observed or reported in vaccinated goats. PMID- 29150915 TI - Epidemiology of RHDV2 (Lagovirus europaeus/GI.2) in free-living wild European rabbits in Portugal. AB - As the detection of the first outbreak of a novel aetiological agent of rabbit haemorrhagic disease commonly called RHDV2 or RHDVb (Lagovirus europaeus/GI.2, henceforth GI.2) in France in 2010, the virus rapidly spread throughout continental Europe and nearby islands such as Great Britain, Sardinia, Sicily, the Azores and the Canary Islands among others. The outbreaks of this new lagovirus cause important economic losses in rabbitries, and ecological disruptions by affecting the conservation of rabbit-sensitive top predators. We analysed 550 rabbit carcasses collected in the field between May 2013 and March 2016, to investigate the epidemiology of GI.2 in free-living populations and to perform a comparative analysis with the epidemiology of classical rabbit haemorrhagic disease virus forms (RHDV, henceforth GI.1) in Portugal. Rabbits were sexed, aged and liver and blood samples were collected for subsequent RHDV screening and serology. A total of 172 samples were PCR-positive to GI.2, whereas GI.1 strains were not detected in any of the samples. The outbreaks of GI.2 revealed a marked seasonality, with peaks during the breeding season (November May). We also found that approximately, one-third of free-ranging European rabbits in Portugal have seroconverted to GI.2. We demonstrate that the GI.2 lagovirus is currently widespread in wild populations in Portugal and is affecting a high proportion of adults and juveniles. Therefore, ongoing monitoring and surveillance are required to assess the effects of GI.2 on wild rabbit populations, its evolution, and to guide management actions aimed at mitigating the impacts of rabbit declines in the ecosystem and in rural economies. PMID- 29150916 TI - Outbreak investigation and molecular diagnosis of Lumpy skin disease among livestock in Saudi Arabia 2016. AB - Lumpy skin disease (LSD) is a highly infectious disease of cattle caused by a virus of the Capripoxvirus genus in the family Poxviridae. The disease is a major concern for the dairy industry in Saudi Arabia. In this study, an outbreak of LSD in cattle herds was detected in Saudi Arabia in 2016. LSD outbreak was investigated in five regions of Saudi Arabia: Al-Hassa, Al-Sharqia, Al-Qassim, Riyadh and Al-Taif during the period from April to July 2016. Tissues from skin nodules were collected to characterize the virus by a real-time polymerase chain reaction (rt-PCR). During this period, 64,109 cattle were examined and morbidity, mortality and case fatality rates were 6%, 0.99% and 16.6%, respectively. The analysis showed 3,852 infected cases and 641 deaths. highest number of infected animals was reported in Al-Hassa (2,825), followed by Al-Qassim (547), Riyadh (471), Al-Sharqia (6) and Al-Taif (3). The highest morbidity rates were observed in Al-Qassim (6.8%), Al-Hassa (6.2%), Riyadh (5.5%) and Al-Taif (0.96%), while the lowest morbidity rates were recorded in Al-Sharqia (0.27%). The highest mortality rates were also observed in Al-Qassim (2.3%), followed by Al-Hassa (0.97%), Riyadh (0.19%) and lowest in Al-Sharqia and Taif (0%). LSD virus was detected in all samples (n = 191) by real-time PCR analysis. The disease has been observed in the cattle regardless of previous vaccination using the locally Romanian-pox vaccine; therefore, vaccination programme and vaccine efficacy should be assessed under field conditions. PMID- 29150917 TI - Regulation of Mesenchymal Stem Cell Differentiation by Transforming Growth Factor Beta Superfamily. AB - The ability to differentiate into cells of different lineage, such as muscle, bone, cartilage and fat, is the chief value of adult mesenchymal stem cells (MSCs) which can be used with the final aim to regenerate damaged tissue. Due to potential use, as well as importance in tissue development, a number of questions have been raised regarding the molecular mechanisms of MSC differentiation. As one of the crucial mediators in organism development, transforming growth factor beta (TGF-beta) superfamily directs MSCs commitment in the selection of differentiation pathways. In this review we aim to give an overview of the current knowledge on the mechanisms of MSCs differentiation, on the involvement of TGF-beta superfamily in MSCs differentiation with additional insight into the mutual regulation of microRNAs and TGF-beta in MSCs differentiation. Particular focus has been given to the signaling and transcriptional networks governing the differentiation processes. PMID- 29150918 TI - Central Role of Transforming Growth Factor Type Beta 1 in Skeletal Muscle Dysfunctions: An Update on Therapeutic Strategies. AB - Among the soluble factors that regulate skeletal muscle function, Transforming Growth Factor type Beta 1 (TGF-beta1) is one of the most studied. This factor inhibits myogenesis and regeneration by regulating the activity and function of satellite cells (SCs). Indeed, TGF-beta has a central role in muscle pathologies in which there is development of fibrosis and/or atrophy of skeletal muscle. Thus, in this review we present the critical and recent antecedents regarding the mechanisms and cellular targets involved in the effects of TGF-beta1 in the muscle, in pathological processes such as the inhibition of regeneration, fibrosis and atrophy. In addition, an update on the development of new strategies with therapeutic potential to inhibit the deleterious actions of TGF-beta in skeletal muscle is discussed. PMID- 29150920 TI - Two Elution Mechanisms of MEP Chromatography. AB - MEP (mercapto-ethyl-pyridine) HyperCel is one of the hydrophobic charge induction chromatography (HCIC) resins. Under normal operation, proteins are bound to the MEP resin at neutral pH, at which MEP is not charged, mostly via hydrophobic interaction. MEP has a pyridine group, whose pK is 4.8, and hence is positively charged at acidic pH range. Based on the binding mechanism (i.e., hydrophobic interaction) and the induced positive charge at acidic pH, there may be two ways to elute the bound proteins. One way is to bring the pH down to protonate both MEP resin and the bound protein, leading to charge repulsion and thereby elution. Another way is to use hydrophobic interaction modifiers, which are often used in hydrophobic interaction chromatography, to reduce hydrophobic interaction. Here, we summarize such two possible elution approaches. PMID- 29150921 TI - TGF-beta and Hepatocellular Carcinoma: When A Friend Becomes An Enemy. AB - Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide accounting for more than 700 thousand deaths per year. Most of the HCC develops in a cirrhotic liver, a microenvironment where fibrotic tissue replaces parenchymal cells. Thus, there is a close connection between fibrosis and HCC development. Understanding the cellular and molecular mechanisms involved in this process is a crucial step to advance in novel therapeutic or pharmacological strategies to prevent or improve the course of this malignancy. A key molecular player capable of modulating cell growth and fibrosis is the Transforming Growth Factor-beta (TGF-beta). Interestingly, TGF-beta seems to act like a switch, since it has dual and opposite roles during early and late phases of cancer development. Therefore to develop therapies that target TGF-beta signaling pathway for HCC treatment is important to understand the underlying pathogenetic mechanisms at play with special emphasis in the crosstalk between TGF-beta and other signaling pathways. In recent years, a plethora of TGR-beta have been developed and some of them are under clinical investigations for testing in patients with advanced HCC. In this review, we summarize recent knowledge about the role of TGF-beta signaling pathway in HCC progression. PMID- 29150922 TI - Prospective evaluation of a nonsurgical device for rhinoplasty. AB - BACKGROUND: Rhinoplasty represents one of the most challenging and frequently performed procedures in plastic surgery and non-surgical rhinoplasty is rarely considered. The aim of this study was to investigate whether the Nasella Nose Former (NNF), a newly developed non-surgical rhinoplasty device, could improve objective and subjective results following surgical rhinoplasty and even correct the shape of the nose without any surgery at all. METHODOLOGY: In this prospective, monocentric, two-armed, non-blinded randomized, controlled clinical trial, a total of 43 participants were included. In the Surgical group, 22 patients undergoing open or closed rhinoplasty with osteotomies were randomised based on their birth year; 15 of them got to wear the NNF over 8 weeks postoperatively and 7 patients getting surgery without the NNF formed the control group. In the Cosmetic group, 21 participants wore the NNF without surgery over 14 months. At every follow-up exam, angles for crookedness, nasal hump and width were measured, the investigator assessed the patients nose and asked for patient satisfaction using a Likert-scale. RESULTS: Patients in the Surgical group wearing the NNF did not show any significant difference concerning objective measurements, investigator assessments and patient satisfaction compared to those not wearing the NNF. In the Cosmetic group, participants did not show objective improvements in measurements and investigator assessment. However, participants were significantly more satisfied after 14 months with their nasal back, nasal axis and outer nose in general. CONCLUSIONS: Considering the results of this study, we conclude that this perfectly customised external device to enhance surgical rhinoplasty outcomes or correct the shape of the nose without surgery does not seem to be effective and that further investigations in this field are not meaningful. PMID- 29150919 TI - A Focus on the Beneficial Effects of Alpha Synuclein and a Re-Appraisal of Synucleinopathies. AB - Alpha synuclein (alpha-syn) belongs to a class of proteins which are commonly considered to play a detrimental role in neuronal survival. This assumption is based on the occurrence of a severe neuronal degeneration in patients carrying a multiplication of the alpha-syn gene (SNCA) and in a variety of experimental models, where overexpression of alpha-syn leads to cell death and neurological impairment. In these conditions, a higher amount of normally structured alpha-syn produces a damage, which is even worse compared with that produced by alpha-syn owning an abnormal structure (as occurring following point gene mutations). In line with this, knocking out the expression of alpha-syn is reported to protect from specific neurotoxins such as 1-methyl, 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). In the present review we briefly discuss these well-known detrimental effects but we focus on findings showing that, in specific conditions alpha-syn is beneficial for cell survival. This occurs during methamphetamine intoxication which is counteracted by endogenous alpha-syn. Similarly, the dysfunction of the chaperone cysteine-string protein- alpha leads to cell pathology which is counteracted by over-expressing alpha-syn. In line with this, an increased expression of alpha-syn protects against oxidative damage produced by dopamine. Remarkably, when the lack of alpha-syn is combined with a depletion of beta- and gamma- synucleins, alterations in brain structure and function occur. This review tries to balance the evidence showing a beneficial effect with the bulk of data reporting a detrimental effect of endogenous alpha-syn. The specific role of alpha-syn as a chaperone protein is discussed to explain such a dual effect. PMID- 29150923 TI - PKG II effectively reversed EGF-induced protein expression alterations in human gastric cancer cell lines. AB - Epidermal growth factor receptor (EGFR) plays an important role in gastric cancer (GC) progression. Our previous data demonstrated that type II cGMP-dependent protein kinase (PKG II) could block the EGF-EGFR axis as well as down-stream signaling pathways, for example, MAPK, PI3 K, and PLC in GC cells. However, the exact mechanisms of PKG II against cancer remain unclear. Therefore, the present work was to address the above question. Human GC cell line AGS was infected with adenoviral construct encoding cDNA of PKG II (Ad-PKG II) to up-regulate PKG II and then treated with 8-pCPT-cGMP. Two-dimensional electrophoresis (2-DE) was used to analyze the changes of protein expression in the cells. The results showed that 17 proteins had more than twofold changes in EGF-treated group compared with control. However, Ad-PKG II could effectively reversed the changes. Furthermore, far upstream element-binding protein 1 (FUBP1) and MarvelD3 were chosen and PKG II activation reversed EGF/EGFR-induced up-regulation of FUBP1 and downregulation of MarvelD3, respectively. MarvelD3 silence effectively abolished the inhibitory effect of PKG II on EGF-triggered migration. These data indicated that the inhibitory effect of PKG II partially was associated with MarvelD3. PMID- 29150924 TI - Comprehensive Profiling of Lysine Acetylome in Baculovirus Infected Silkworm (Bombyx mori) Cells. AB - Bombyx mori is one of the key lepidopteran model species, and is economically important for silk production and proteinaceous drug expression. Baculovirus and insect host are important natural biological models for studying host-pathogen interactions. The impact of Bombyx mori nucleopolyhedrovirus (BmNPV) infection on the proteome and acetylome of Bombyx mori ovarian (BmN) cells are explored to facilitate a better understanding of infection-driven interactions between BmNPV and host in vitro. The proteome and acetylome are profiled through six-plex Tandem mass tag (TMT) labeling-based quantitative proteomics. A total of 4194 host proteins are quantified, of which 33 are upregulated and 47 are downregulated in BmN cells at 36 h post-infection. Based on the proteome, quantifiable differential Kac proteins are identified and functionally annotated to gene expression regulation, energy metabolism, substance synthesis, and metabolism after BmNPV infection. Altogether, 644 Kac sites in 431 host proteins and 39 Kac sites in 22 viral proteins are identified and quantified in infected BmN cells. Our study demonstrates that BmNPV infection globally impacts the proteome and acetylome of BmN cells. The viral proteins are also acetylated by the host acetyltransferase. Protein acetylation is essential for cellular self regulation and response to virus infection. This study provides new insights for understanding the host-virus interaction mechanisms, and the role of acetylation in BmN cellular response to viral infection. PMID- 29150925 TI - One-pot synthesis of a multi-template molecularly imprinted polymer for the extraction of six sulfonamide residues from milk before high-performance liquid chromatography with diode array detection. AB - A highly selective molecularly imprinted polymer sorbent was synthesized and employed for the simultaneous determination of six sulfonamide antibiotic residues (sulfanilamide, sulfacetamide, sulfadiazine, sulfathiazole, sulfamerazine, and sulfamethizole) in milk samples. Multi-analyte imprinted particles were used as a sorbent in solid-phase extraction. Sulfonamides were separated on a high-performance liquid chromatography column (Merck-Lichrospher RP18e, 5 MUm 250 * 4 mm) and further identified and quantified by diode array detection. Several parameters including required loading of the molecularly imprinted polymer sorbent, mass of milk, volume, and type of elution solvent, as well as time for absorption and elution were investigated to obtain optimal experimental conditions. For comparison purpose, a non-imprinted polymer was applied under the optimum conditions. The validation study according to the European Union Decision 2002/657/EC was based on the investigation of linearity, selectivity, stability, limits of detection and quantitation, decision limit, detection capability, trueness, precision, and ruggedness according to Youden's approach. The decision limit and detection capability values in the milk were achieved from 101.9 to 113.5 MUg/kg and from 114.4 to 135.4 MUg/kg, respectively, depending on the target sulfonamide drug. Finally, the optimized protocol was successfully applied to commercial milk samples and human breast milk. PMID- 29150926 TI - Viral Short ORFs and Their Possible Functions. AB - Definition of functional genomic elements is one of the greater challenges of the genomic era. Traditionally, putative short open reading frames (sORFs) coding for less than 100 amino acids were disregarded due to computational and experimental limitations; however, it has become clear over the past several years that translation of sORFs is pervasive and serves diverse functions. The development of ribosome profiling, allowing identification of translated sequences genome wide, revealed wide spread, previously unidentified translation events. New computational methodologies as well as improved mass spectrometry approaches also contributed to the task of annotating translated sORFs in different organisms. Viruses are of special interest due to the selective pressure on their genome size, their rapid and confining evolution, and the potential contribution of novel peptides to the host immune response. Indeed, many functional viral sORFs were characterized to date, and ribosome profiling analyses suggest that this may be the tip of the iceberg. Our computational analyses of sORFs identified by ribosome profiling in DNA viruses demonstrate that they may be enriched in specific features implying that at least some of them are functional. Combination of systematic genome editing strategies with synthetic tagging will take us into the next step-elucidation of the biological relevance and function of this intriguing class of molecules. PMID- 29150927 TI - Identification of proteins, drying oils, waxes and resins in the works of art micro-samples by chromatographic and mass spectrometric techniques. AB - Simplified method for simultaneous identification of proteins, drying oils, waxes, and resins in the works-of-art samples was developed. Liquid chromatography with mass spectrometry and gas chromatography with mass spectrometry were used to identify natural materials most frequently encountered in historical paintings. Protein binders were extracted with ammonia and purified using miniaturized solid-phase microextraction (Omix tips) to efficiently suppress matrix interferences. Zwitterionic stationary phase was used for separation of 16 underivatized amino acids analysis with hydrophilic interaction liquid chromatography that was subsequently quantified with liquid chromatography with mass spectrometry. Gas chromatography with mass spectrometry was used to analyze drying oils, waxes, and resins after one-step saponification/transmethylation with (m-trifluoromethylphenyl)trimethylammonium hydroxide (Meth-Prep II). While the drawback of this reagent is low reactivity towards hydroxyl groups, sample pretreatment was much simpler as compared to the other methods. Fatty acids derivatization with the Meth-Prep II reagent was compared with their silylation using N,O-bis(trimethylsilyl) trifluoroacetamide/trimethylchlorosilane mixture. It was concluded that fatty acids analysis as their methyl esters instead of trimethylsilyl esters had a minor impact on the method sensitivity. The developed method was used to analyze samples from 16th and 17th century historical paintings. PMID- 29150928 TI - Application of high-speed counter-current chromatography and HPLC to separate and purify of three polyacetylenes from Platycodon grandiflorum. AB - Three polyacetylenes were isolated and purified from Platycodon grandiflorum A. DC for the first time by high-speed counter-current chromatography using a two phase solvent system composed of hexane/ethyl acetate/methanol/water (1:31:1:31, v/v/v/v) and high-performance liquid chromatography with an Agilent ZORBAX(r) SB C18 column (4.6 mm * 150 mm, 5 MUm). After separation by high-speed counter current chromatography and high-performance liquid chromatography, we obtained 3.5 mg of platetyolin A, 4.1 mg of platetyolin B, and 18.1 mg of lobetyolin with purities of 97.2, 96.7, and 96.9%, respectively. The purity of each compound was assessed by high-performance liquid chromatography and the chemical structures were evaluated by high-resolution electrospray ionization time-of-flight mass spectrometry and one- and two-dimensional NMR spectroscopy. Among the isolated compounds, platetyolin A and platetyolin B are newly reported compounds. PMID- 29150929 TI - Biomechanical properties of feline ventral abdominal wall and celiotomy closure techniques. AB - OBJECTIVE: To compare biomechanical properties and mechanism of failure of 3 regions of ventral abdominal wall in cats by using 2 suture materials, 2 suture bite-to-stitch intervals (SBSI), and full-thickness versus fascia-only closure. STUDY DESIGN: Randomized, cadaveric, ex vivo mechanical testing. SAMPLE POPULATION: 16 adult cat cadavers, 3 samples per cat. METHODS: Three regions of ventral abdominal wall were mechanically tested (N = 48 samples). Preumbilical, umbilical (U), and postumbilical (POU) regions were harvested by using a template. The thickness of the linea alba was recorded. Six samples without celiotomy served as controls. Twenty-eight samples were randomized to SBSI (2 * 2 or 5 * 5 mm) and suture material (3-0 polyglactin 910 or 3-0 polydioxanone) for simple continuous celiotomy closure. Fourteen samples were randomized to full thickness or fascia-only closure. Samples were tested by linear distraction; tensile strength and mechanism of failure were recorded. Effects of body weight, thickness of linea alba, anatomic region, SBSI, type of closure, and suture material were evaluated by mixed model linear analysis. Load to failure was compared between males and females, full-thickness and fascia-only closure by independent t test, with P < .05 considered statistically significant. RESULTS: The POU region achieved lower loads to failure. Load to failure was greater in males compared with females. No difference was detected between full-thickness and fascia-only closure. Failure most commonly occurred by tearing of suture through tissues. Tissue failure with suture line loosening occurred mainly in the 5 * 5-mm SBSI group. CONCLUSION: The POU region is biomechanically weak and may therefore be predisposed to incisional herniation. PMID- 29150930 TI - Photoautotrophic production of macular pigment in a Chlamydomonas reinhardtii strain generated by using DNA-free CRISPR-Cas9 RNP-mediated mutagenesis. AB - Lutein and zeaxanthin are dietary carotenoids reported to be protective against age-related macular degeneration. Recently, the green alga Chlamydomonas reinhardtii has received attention as a photosynthetic cell factory, but the potential of this alga for carotenoid production has not yet been evaluated. In this study, we selected the C. reinhardtii CC-4349 strain as the best candidate among seven laboratory strains tested for carotenoid production. A knock-out mutant of the zeaxanthin epoxidase gene induced by preassembled DNA-free CRISPR Cas9 ribonucleoproteins in the CC-4349 strain had a significantly higher zeaxanthin content (56-fold) and productivity (47-fold) than the wild type without the reduction in lutein level. Furthermore, we produced eggs fortified with lutein (2-fold) and zeaxanthin (2.2-fold) by feeding hens a diet containing the mutant. Our results clearly demonstrate the possibility of cost-effective commercial use of microalgal mutants induced by DNA-free CRISPR-Cas9 ribonucleoproteins in algal biotechnology for the production of high-value products. PMID- 29150931 TI - MicroRNA-497 accelerates apoptosis while inhibiting proliferation, migration, and invasion through negative regulation of the MAPK/ERK signaling pathway via RAF-1. AB - The aim of this study is to explore the various modes of action miR-497 has on human cervical cancer (CC) cell behavior. We also speculate that miR-497 achieves its anti-tumor role by governing RAF-1 via MAPK/ERK signaling pathway. CC tissues with corresponding adjacent normal tissues were collected from 168 CC patients. RAF-1-positive cells were identified by means of immunohistochemistry in tissues. A series of inhibitors, mimics and siRNA against RAF-1 were introduced to validate regulatory mechanisms for miR-497 and RAF-1. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assay were employed for evaluating alternations of miR-497, RAF-1, and MAPK/ERK signaling pathway. HeLa cell proliferation, invasion, migration, cycle progression, and apoptosis were assessed by means of CCK-8, wound-healing, transwell invasion assays, and flow cytometry, respectively. The target prediction program and luciferase activity determination were used to identify miR-497 targeting RAF-1. We determined reduced miR-497 expression and elevated expression of RAF-1 in CC tissues as opposed to adjacent tissues. Transfection of miR-497 mimics and siRNA-RAF-1 both decreased levels of MEK1, ERK1, and p38 phosphorylation in HeLa cells, inhibited cell proliferation, migration and invasion, induced more cells arrested in the G0/G1 phase, and promoted cell apoptosis; while miR-497 inhibitors led to opposite results. These findings indicate miR-497 as a tumor suppressor results from negative regulation of the MAPK/ERK signaling pathway via RAF-1 in CC. PMID- 29150932 TI - High fat diet-induced oxidative stress blocks hepatocyte nuclear factor 4alpha and leads to hepatic steatosis in mice. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease with manifestation of over-accumulation of fat in liver. Increasing evidences indicate that NAFLD may be in part caused by malfunction of very low density lipoprotein (VLDL) secretion. Hepatocyte nuclear factor 4alpha (HNF4alpha), a nuclear receptor protein, plays an important role in sustain hepatic lipid homeostasis via transcriptional regulation of genes involved in secretion of VLDL, such as apolipoprotein B (ApoB). However, the exact functional change of HNF4alpha in NAFLD remains to be elucidated. In the present study, we found that high fat diet (HFD) induced cytoplasmic retention of HNF4alpha in hepatocytes, which led to down-regulation of hepatic ApoB expression and its protein level in serum, as well as reduced secretion of VLDL. We further revealed that oxidative stress, elevated in fatty liver, was the key factor inducing the cytoplasmic retention of HNF4alpha in hepatocytes by activating protein kinase C (PKC)-mediated phosphorylation in HNF4alpha. Thus, our findings reveal a novel mechanism underlying HFD-induced fatty liver that oxidative stress impairs function of HNF4alpha on ApoB expression and VLDL secretion via PKC activation, eventually promoting fat accumulation in the liver. Therefore, oxidative stress/PKC/HNF4alpha pathway may be a novel target to treat diet-induced fatty liver. PMID- 29150933 TI - Design of a novel continuous flow reactor for low pH viral inactivation. AB - Insufficient mixing in laminar flow reactors due to diffusion-dominated flow limits their use in applications where narrow residence time distribution (RTD) is required. The aim of this study was to design and characterize a laminar flow (Re 187.7-375.5) tubular reactor for low pH viral inactivation with enhanced radial mixing via the incorporation of curvature and flow inversions. Toward this aim, the reactor described here, Jig in a Box (JIB), was designed with a flow path consisting of alternating 270 degrees turns. The design was optimized by considering the strength of secondary flows characterized by the Dean No., the corresponding secondary flow development length, and the reactor turn lengths. Comprehensive CFD analysis of the reactor centerline velocity profile, cross sectional velocity, and secondary flow streamlines confirmed enhanced radial mixing due to secondary flows and changes in flow direction. For initial CFD and experimental studies the reactor was limited to a 16.43 m length. Pulse tracer studies for the reactor were computationally simulated and experimentally generated to determine the RTD, RTD variance, and minimum residence time for the tracer fluid elements leaving the reactor, as well as to validate the computational model. The reactor was scaled length wise to increase incubation time and it was observed that as the reactor length increases the RTD variance increases linearly and the dimensionless RTD profile becomes more symmetrical and tighter about the mean residence time. PMID- 29150934 TI - The current status and perspectives regarding the clinical implication of intracellular calcium in breast cancer. AB - Calcium ions (Ca2+ ) act as second messengers in intracellular signaling. Ca2+ pumps, channels, sensors, and calcium binding proteins, regulate the concentrations of intracellular Ca2+ as a key regulator of important cellular processes such as gene expression, proliferation, differentiation, DNA repair, apoptosis, metastasis, and hormone secretion. Intracellular Ca2+ also influences the functions of several organelles, that include: the endoplasmic reticulum, mitochondria, the Golgi, and cell membrane both in normal and breast cancer cells. In breast cancer, the disruption of intracellular: Ca2+ homeostasis may cause tumor progression by affecting key factors/pathways including phospholipase C (PLC), inositol 1,4,5-trisphosphate (IP3), calmodulin (CaM), nuclear factor of activated T-cells (NFAT), calpain, calmodulin-dependent protein kinase II (CaMKII), mitogen-activated protein kinase (MAPK), epithelial-mesenchymal transition (EMT), vascular endothelial growth factor (VEGF), poly (ADP-Ribose) polymerase-1 (PARP1), estrogen, and estrogen receptor. Because the foregoing molecules play crucial roles in breast cancer, the factors/pathways influencing intracellular Ca2+ concentrations are putative targets for cancer treatment, using drugs such as Mephebrindole, Tilapia piscidin 4, Nifetepimine, Paricalcitol, and Prednisolone. We have explored the factors/pathways which are related to breast cancer and Ca2+ homeostasis and signaling in this review, and also discussed their potential as biomarkers for breast cancer staging, prognosis, and therapy. PMID- 29150935 TI - Generation of insulin-producing cells from human adipose-derived mesenchymal stem cells on PVA scaffold by optimized differentiation protocol. AB - The studies have been done on patient-specific human adipose-derived from mesenchymal stem cells (hADSCs) like a series of autologous growth factors and nanofibrous scaffolds (3D culture) will probably have many benefits for regenerative medicine in type 1 diabetes mellitus (TIDM) patients in the future. For this purpose, we established a polyvinyl alcohol (PVA) scaffold and a differentiation protocol by adding platelet-rich plasma (PRP) that induces the hADSCs into insulin-producing cells (IPCs). The characteristics of the derived IPCs in 3D culture were compared with conventional culture (2D) groups evaluated at the mRNA and protein levels. The viability of induced pancreatic cells was 14 days. The in vitro studies showed that the treatment of hADSCs in the 3D culture resulted in differentiated cells with strong characteristics of IPCs including pancreatic-like cells, the expression of the islet-associated genes at the mRNA and protein levels in comparison of 2D culture group. Furthermore, the immunoassay tests showed that these differentiated cells in these two groups are functional and secreted C-peptide and insulin in a glucose stimulation challenge. The results of our study for the first time demonstrated that the PVA nanofibrous scaffolds along with the optimized differentiation protocol with PRP can enhance the differentiation of IPCs from hADSCs. In conclusion, this study provides a new approach to the future pancreatic tissue engineering and beta cell replacement therapies for T1DM. PMID- 29150936 TI - The roles of Wnt/beta-catenin pathway in tissue development and regenerative medicine. AB - Regenerative medicine is a translational field which combines tissue engineering and molecular biology to construct spare organs or help injured or defective tissues to regenerate or restore their normal functions. This is particularly important with specific organs such as heart, central nervous system, retina, or limbs which possess very limited regenerative capacity. As such, regenerative medicine has received peculiar attention in the last decade. In this regard, Wnt/beta-catenin signaling pathway has been subject to intensive research, since it plays many essential roles in the regulation of the progenitor cell fate, developmental decisions, proliferation during embryonic development, and adult tissue homeostasis. In this paper, we will briefly introduce Wnt/beta-catenin signaling pathway and discuss how it integrally contributes to both stem and cancer stem cell maintenance. Finally, we summarize the current understanding of the role of Wnt/beta-catenin signaling in the development and regeneration of heart, lung, liver, bone, and cartilage. PMID- 29150938 TI - Regulation of calcification in human aortic smooth muscle cells infected with high-glucose-treated Porphyromonas gingivalis. AB - Porphyromonas (P.) gingivalis infection leading to the periodontitis has been associated with the development of systemic diseases, including cardiovascular diseases and diabetes. However, the effect of a high concentration of glucose (HG) on the invasion efficiency of P. gingivalis and the consequent modulation of pathogenesis in vascular cells, especially in the vascular smooth muscle cells (VSMCs), remains unclear. Hence, the aim of this study was to investigate whether treating P. gingivalis with HG could change its invasion capability and result in VSMC calcification and the underlying mechanism. Human aortic SMCs (HASMCs) and P. gingivalis strain CCUG25226 were used in this study. We found that HGPg infection of HASMCs could initiate the HASMC calcification by stimulating the autocrine regulation of bone morphogenetic protein (BMP) 4 in HASMCs. The upregulation of BMP4 expression in HASMCs was mediated by toll-like receptor 4 and ERK1/2-p38 signaling after P. gingivalis infection. Moreover, the autocrine action of BMP4 in HGPg infection-initiated HASMC calcification upregulated BMP4 specific downstream smad1/5/8-runx2 signaling to increase the expressions of bone related matrix proteins, that is, osteopontin, osteocalcin, and alkaline phosphatase. This study elucidates the detailed mechanism of HGPg infection initiated calcification of HASMCs and indicates a possible therapeutic role of BMP4 in P. gingivalis infection-associated vascular calcification. PMID- 29150937 TI - cGMP production and analysis of BG505 SOSIP.664, an extensively glycosylated, trimeric HIV-1 envelope glycoprotein vaccine candidate. AB - We describe the properties of BG505 SOSIP.664 HIV-1 envelope glycoprotein trimers produced under current Good Manufacturing Practice (cGMP) conditions. These proteins are the first of a new generation of native-like trimers that are the basis for many structure-guided immunogen development programs aimed at devising how to induce broadly neutralizing antibodies (bNAbs) to HIV-1 by vaccination. The successful translation of this prototype demonstrates the feasibility of producing similar immunogens on an appropriate scale and of an acceptable quality for Phase I experimental medicine clinical trials. BG505 SOSIP.664 trimers are extensively glycosylated, contain numerous disulfide bonds and require proteolytic cleavage, all properties that pose a substantial challenge to cGMP production. Our strategy involved creating a stable CHO cell line that was adapted to serum-free culture conditions to produce envelope glycoproteins. The trimers were then purified by chromatographic methods using a 2G12 bNAb affinity column and size-exclusion chromatography. The chosen procedures allowed any adventitious viruses to be cleared from the final product to the required extent of >12 log10 . The final cGMP production run yielded 3.52 g (peptidic mass) of fully purified trimers (Drug Substance) from a 200 L bioreactor, a notable yield for such a complex glycoprotein. The purified trimers were fully native-like as judged by negative-stain electron microscopy, and were stable over a multi-month period at room temperature or below and for at least 1 week at 50 degrees C. Their antigenicity, disulfide bond patterns, and glycan composition were consistent with trimers produced on a research laboratory scale. The methods reported here should pave the way for the cGMP production of other native-like Env glycoprotein trimers of various designs and genotypes. PMID- 29150939 TI - miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS induced acute lung injury mouse model by targeting progranulin. AB - Inflammation and apoptosis play important roles in the initiation and progression of acute lung injury (ALI). Our previous study has shown that progranulin (PGRN) exerts lung protective effects during LPS-induced ALI. Here, we have investigated the potential roles of PGRN-targeting microRNAs (miRNAs) in regulating inflammation and apoptosis in ALI and have highlighted the important role of PGRN. LPS-induced lung injury and the protective roles of PGRN in ALI were first confirmed. The function of miR-34b-5p in ALI was determined by transfection of a miR-34b-5p mimic or inhibitor in intro and in vivo. The PGRN level gradually increased and subsequently significantly decreased, reaching its lowest value by 24 hr; PGRN was still elevated compared to the control. The change was accompanied by a release of inflammatory mediators and accumulation of inflammatory cells in the lungs. Using bioinformatics analysis and RT-PCR, we demonstrated that, among 12 putative miRNAs, the kinetics of the miR-34b-5p levels were closely associated with PGRN expression in the lung homogenates. The gain- and loss-of-function analysis, dual-luciferase reporter assays, and rescue experiments confirmed that PGRN was the functional target of miR-34b-5p. Intravenous injection of miR-34b-5p antagomir in vivo significantly inhibited miR 34b-5p up-regulation, reduced inflammatory cytokine release, decreased alveolar epithelial cell apoptosis, attenuated lung inflammation, and improved survival by targeting PGRN during ALI. miR-34b-5p knockdown attenuates lung inflammation and apoptosis in an LPS-induced ALI mouse model by targeting PGRN. This study shows that miR-34b-5p and PGRN may be potential targets for ALI treatments. PMID- 29150941 TI - MicroRNAs as predictive biomarkers for myocardial injury in aged mice following myocardial infarction. AB - The occurrence of myocardial infarction (MI) increases appreciably with age. In the Framingham Heart Study, the incidence of MI more than doubles for men and increases more than five-fold in women (ages 55-64 years compared to 85-94 years). MicroRNAs (miRNAs) quantitatively regulate their target's expression post transcriptionally by either silencing action through binding at the 3'UTR domains or degrading the messages at their coding regions. In either case, these regulations affect the cardiac transcriptional output and cardiac function. Among the known cardiac associated miRNA, miRNA-1, miRNA-133a, and miRNA-34a have been shown to induce adverse structural remodeling to impair cardiac contractile function. In the present study, an in vivo model of MI in young (3 month) and old (22 month) mice is used to investigate the possible role whereby these three miRNAs exert negative effects on heart function following MI. Herein we demonstrate that in older mouse heart, all three microRNAs show increased levels of expression, while miRNA-1 shows a further increase in old mouse heart following MI, which corresponds to left ventricular (LV) wall thinning. These structural changes in cardiac tissue may causes downstream LV dilation and subsequent LV dysfunction. Results presented here suggest that significantly elevated levels of miRNA-1 in post-MI old heart could be predictive of cardiac injury in older mice as the high risk biomarker for MI in older individuals. PMID- 29150940 TI - Tumor-suppressive roles of DeltaNp63beta-miR-205 axis in epithelial-mesenchymal transition of oral squamous cell carcinoma via targeting ZEB1 and ZEB2. AB - We previously revealed that epithelial-to-mesenchymal transition (EMT) was mediated by DeltaNp63beta, a splicing variant of DeltaNp63, in oral squamous cell carcinoma (OSCC). Recent studies have highlighted the involvement of microRNA (miRNA) in EMT of cancer cells, though the mechanism remains unclear. To identify miRNAs responsible for DeltaNp63beta-mediated EMT, miRNA microarray analyses were performed by DeltaNp63beta-overexpression in OSCC cells; SQUU-B, which lacks DeltaNp63 expression and displays EMT phenotypes. miRNAs microarray analyses revealed miR-205 was the most up-regulated following DeltaNp63beta overexpression. In OSCC cells, miR-205 expression was positively associated with DeltaNp63 and negatively with zinc-finger E-box binding homeobox (ZEB) 1 and ZEB2, potential targets of miR-205. miR-205 overexpression by miR-205 mimic transfection into SQUU-B cells led to decreasing ZEB1, ZEB2, and mesenchymal markers, increasing epithelial markers, and reducing cell motilities, suggesting inhibition of EMT phenotype. Interestingly, the results opposite to this phenomenon were obtained by transfection of miR-205 inhibitor into OSCC cells, which express DeltaNp63 and miR-205. Furthermore, target protector analyses revealed direct regulation by miR-205 of ZEB1 and ZEB2 expression. These results showed tumor-suppressive roles of DeltaNp63beta and miR-205 by inhibiting EMT thorough modulating ZEB1 and ZEB2 expression in OSCC. PMID- 29150942 TI - A novel epididymal quiescence factor inhibits sperm motility by modulating NOS activity and intracellular NO-cGMP pathway. AB - Mature and potentially motile spermatozoa stored in cauda epididymis in an inactive state for approximately 30 days; however, during ejaculation they regain motility. To understand the actual molecular mechanism of the sperm quiescence during caudal stay, a proteinaceous quiescence factor (QF) has been purified from caprine epididymal plasma to apparent homogeneity. In the present study complete purification, detailed characterization as well as mechanistic pathway of QF has been described. QF is purified to 215-fold with 45% activity recovery. It is a 59 kDa monomeric protein with isoelectric point 5.8 and optimally active at pH 7.5. Circular dichroism spectroscopy and atomic force microscopy study confirm its alpha-helical secondary structure and globular tertiary conformation. QF is a thermo-stable protein as higher temperature does not alter its helical structure. N-terminal amino acid sequencing and MALDI analysis of QF did not find 100% similarity with any available protein of the database, proved its novelty. QF at 2 MUM dose inhibits sperm progressive forward motility within 10 min. This motility inhibitory activity of QF is mediated by reducing NOS enzyme activity and subsequently decreasing the intracellular NO and cGMP concentration. It does not modulate intracellular Ca++ and cAMP concentration. QF has no adverse effect on DNA integrity and morphology of spermatozoa. Motility inhibitory action of QF is reversible. Thus, the role of QF in maintaining energy saving quiescence state of mature cauda spermatozoa and its reactive nitrogen species reducing activity may lead to a new direction for storage of spermatozoa and idiopathic male infertility. PMID- 29150943 TI - Muscle regeneration potential and satellite cell activation profile during recovery following hindlimb immobilization in mice. AB - Reduced muscle activity leads to muscle atrophy and function loss in patients and animal models. Satellite cells (SCs) are postnatal muscle stem cells that play a pivotal role in skeletal muscle regeneration following injury. The regenerative potential, satellite cell numbers, and markers during recovery following immobilization of the hindlimb for 7 days were explored. In mice exposed to 7 days of hindlimb immobilization, in those exposed to recovery (7 days, splint removal), and in contralateral control muscles, muscle precursor cells were isolated from all hindlimb muscles (fluorescence-activated cell sorting, FACS) and SCs, and muscle regeneration were identified using immunofluorescence (gastrocnemius and soleus) and electron microscopy (EM, gastrocnemius). Expression of ki67, pax7, myoD, and myogenin was quantified (RT-PCR) from SC FACS yields. Body and grip strength were determined. Following 7 day hindlimb immobilization, a decline in SCs (FACS, immunofluorescence) was observed together with an upregulation of SC activation markers and signs of muscle regeneration including fusion to existing myofibers (EM). Recovery following hindlimb immobilization was characterized by a program of muscle regeneration events. Hindlimb immobilization induced a decline in SCs together with an upregulation of markers of SC activation, suggesting that fusion to existing myofibers takes place during unloading. Muscle recovery induced a significant rise in muscle precursor cells and regeneration events along with reduced SC activation expression markers and a concomitant rise in terminal muscle differentiation expression. These are novel findings of potential applicability for the treatment of disuse muscle atrophy, which is commonly associated with severe chronic and acute conditions. PMID- 29150944 TI - Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer. AB - Toll like receptor (TLR) signaling is involved in activating innate and adaptive immune responses and plays a critical role in inflammation-induced diseases such as colorectal cancer (CRC). Dysregulation of this signaling pathway can result in disturbance of epithelial layer hemostasis, chronic inflammatory, excessive repair responses, and development of CRC. There is now substantial evidence for the benefit of targeting of this pathway in cancer treatment, and several agents have been approved, such as BCG (Bacillus Calmette Guerin), MPL (monophosphoryl lipid A) and imiquimod. This review summarizes the current knowledge about the different functions of TLRs on tumor cells and their application in cancer therapy with particular emphasis on recent preclinical and clinical research in treatment of CRC. PMID- 29150945 TI - Development of an in vivo mouse model of discogenic low back pain. AB - Discogenic low back pain (DLBP) is extremely common and costly. Effective treatments are lacking due to DLBP's unknown pathogenesis. Currently, there are no in vivo mouse models of DLBP, which restricts research in this field. The aim of this study was to establish a reliable DLBP model in mouse that captures the pathological changes in the disc and allows longitudinal pain testing. The model was generated by puncturing the mouse lumbar discs (L4/5, L5/6, and L6/S1) and removing the nucleus pulposus using a microscalpel under the microscope. Histology, molecular pathways, and pain-related behaviors were examined. Over 12 weeks post-surgery, animals displayed the mechanical, heat, and cold hyperalgesia along with decreased burrowing and rearing. Histology showed progressive disc degeneration with loss of disc height, nucleus pulposus reduction, proteoglycan depletion, and annular fibrotic disorganization. Immunohistochemistry revealed a substantial increase in inflammatory mediators at 2 and 4 weeks. Nerve growth factor was upregulated from 2 weeks to the end of the experiment. Nerve fiber ingrowth was induced in the injured discs after 4 weeks. Disc-puncture also produced an upregulation of neuropeptides in dorsal root ganglia neurons and an activation of glial cells in the spinal cord dorsal horn. These findings indicate that the cellular and structural changes in discs, as well as peripheral and central nervous system plasticity, paralleled persistent, and robust behavioral pain responses. Therefore, this mouse DLBP model could be used to investigate mechanisms underlying discogenic pain, thereby facilitating effective drug screening and development of treatments for DLBP. PMID- 29150946 TI - LncRNA-TCONS_00034812 in cell proliferation and apoptosis of pulmonary artery smooth muscle cells and its mechanism. AB - Long noncoding RNAs (lncRNAs) have been discovered to be playing important role in various biological processes. However, the contribution of lncRNAs to pulmonary artery hypertension (PAH) remains largely unknown. Pulmonary vascular remodeling is an important pathological feature of PAH, leading to increased vascular resistance and reduced compliance. Here, we investigated the biological role of lncRNAs in PAH. Differences in the lncRNAs and mRNAs between hypoxia PAH rats and normoxia rats were screened using microarray analysis. The results showed that 36 lncRNAs and 519 mRNAs were upregulated in the pulmonary arteries (PAs) of hypoxia PAH rats, whereas 111 lncRNAs and 246 mRNAs were downregulated. Expressions of the screened lncRNAs, including TCONS_00034812, were validated by real-time PCR. We revealed that the expression of TCONS_00034812 was significantly downregulated in PAs of PAH rats and hypoxia pulmonary artery smooth muscle cells (PASMCs). TCONS_00034812 knockdown promoted proliferation and inhibited apoptosis of PASMCs in vitro. Moreover, TCONS_00034812 regulated PASMCs function in vitro. We found that TCONS_00034812 increased the expression of transcription factors Stox1. TCONS_00034812 and Stox1 knockdown mediated PASMCs function through MAPK signaling. Our findings imply lncRNA as a critical regulator in PAH and demonstrate the potential of gene therapy and drug development for treating PAH. The present study reveals a novel mechano responsive lncRNA-TCONS_00034812, which modulates PASMCs proliferation and apoptosis, and participates in vascular remodeling during PAH. PMID- 29150947 TI - Levels of serum retinol-binding protein 4 before and after non-surgical periodontal treatment in lean and obese subjects: An interventional study. AB - AIM: We aimed to evaluate serum RBP4 levels before and after periodontal therapy in lean and obese subjects with chronic periodontitis (CP) in order to determine its possible association with periodontitis. MATERIALS AND METHODS: This is an interventional study for which a total of 112 lean and 119 obese subjects were recruited. Patients with CP were evaluated before and after three months of non surgical periodontal treatment. Periodontal, anthropometric, biochemical parameters and serum levels of TNF-alpha, IL-6, hs-CRP and RBP4 were assessed. RESULTS: Serum RBP4 levels were associated with an increased probability of periodontitis (OR = 1.60; 95% CI: 1.02-2.50), showing patients with CP to have higher RBP4 levels than those without CP in both lean and obese populations (3.35 vs 3.06 and 3.74 vs 3.21, respectively). Following periodontal treatment, RBP4 and TNF-alpha decreased, and all periodontal parameters improved to the same extent in both groups, except for number of teeth with probing depth (PD) >=4 mm, which improved to a less extent in obese than in lean subjects. In the multivariable regression model, the number of teeth with PD >=4 mm was independently associated with RBP4 (beta = 0.192). CONCLUSION: RBP4 was associated with chronic periodontitis before and after non-surgical periodontal treatment. PMID- 29150948 TI - Methylation-associated DOK1 and DOK2 down-regulation: Potential biomarkers for predicting adverse prognosis in acute myeloid leukemia. AB - DOK-1 and DOK-2 (DOK1/2) are closely related members of downstream of tyrosine kinase (DOK) family genes, which are found to be frequently rearranged in several hematopoietic cancers. However, the clinical implications of DOK1/2 in acute myeloid leukemia (AML) remain largely unknown. To investigate the clinical significance, real-time quantitative PCR (RQ-PCR) was carried out to detect DOK1/2 expressions in 125 de novo AML patients and 28 healthy controls. Real-time quantitative methylation-specific PCR (RQ-MSP) and bisulfite sequencing PCR (BSP) were applied to detect DOK1/2 methylation level and density. DOK1/2 expressions were significantly down-regulated in AML patients. The promoters of DOK1/2 were highly hypermethylated and negatively correlated with DOK1/2 expressions in AML patients. In addition, we also confirmed that DOK1/2 expressions could be restored by DOK1/2 demethylation using 5-aza-2'-deoxycytidine in leukemia cell line THP-1. Survival analyses showed that low-expressed DOK1/2 were associated with markedly shorter overall survival and leukemia free survival in both whole cohort AML and non-M3 AML patients. Multivariate analyses further revealed that DOK1/2 were act as independent prognostic factors in AML patients. These findings indicate that decreased DOK1/2 expressions associated with their promoter hypermethylations predict adverse prognosis in AML. PMID- 29150949 TI - Chromium hazard and risk assessment: New insights from a detailed speciation study in a standard test medium. AB - Despite the consensus about the importance of chemical speciation in controlling the bioavailability and ecotoxicity of trace elements, detailed speciation studies during laboratory ecotoxicity testing remain scarce, contributing to uncertainty when extrapolating laboratory findings to real field situations in risk assessment. We characterized the speciation and ecotoxicological effects of chromium (CrIII and CrVI ) in the International Organization for Standardization (ISO) medium for algal ecotoxicity testing. Total and dissolved (< 0.22 MUm) Cr concentrations showed little variability in media spiked with CrVI , whereas dissolved Cr concentration decreased by as much as 80% over a 72-h time period in medium amended with CrIII . Analyses by ion chromatography inductively coupled plasma mass spectrometry (IC-ICP-MS) highlighted the absence of redox interconversion between CrIII or CrVI both in the presence and absence of algal cells (Raphidocelis subcapitata). Furthermore, the concentration of ionic CrIII dropped below detection limits in less than 2 h with the corresponding formation of carbonate complexes and Cr hydroxides. Precipitation of CrIII in the form of colloidal particles of variable diameters was confirmed by nanoparticle (NP) tracking analysis, single particle ICP-MS, and single particle counting. In terms of time-weighted dissolved (< 0.22 MUm) Cr concentration, CrIII was 4 to 10 times more toxic than CrVI . However, CrIII ecotoxicity could arise from interactions between free ionic CrIII and algae at the beginning of the test, from the presence of Cr-bearing NPs, or from a combination of the 2. Future ecotoxicological studies must pay more attention to Cr speciation to reliably compare the ecotoxicity of CrIII and CrVI . Environ Toxicol Chem 2018;37:983-992. (c) 2017 SETAC. PMID- 29150950 TI - Perspectives on a career in NMR. An interview with James Keeler. PMID- 29150951 TI - Inflammasome: Its role in traumatic brain and spinal cord injury. AB - Traumatic brain injury (TBI) and spinal cord injury (SCI) are pathological events that lead to neuropathological conditions which have in consequence the initiation of pro-inflammatory cytokine production. Neuroinflammation plays a key role in the secondary phase of both TBI and SCI after initial cell death. Activation of cytoplasmic inflammasome complexes is regarded as the essential step of neuroinflammation and a key trigger for neuronal death called pyroptosis. Inflammasome complexes are involved in activation of caspase-1 which catalyzes the cleavage of pro-interleukins into their active forms (including interleukin 18 [IL-18] and IL-1beta). The focus of this article is to discuss the time-course and regulation of inflammasome assembly and activation during TBI and SCI and their targeting in designing therapeutic approaches. We particularly focus on the inflammasomes NLRP1 and NLRP3 which play a pivotal function during TBI and SCI in the central nervous system (CNS). PMID- 29150952 TI - CK-2127107 amplifies skeletal muscle response to nerve activation in humans. AB - INTRODUCTION: Three studies evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of CK-2127107 (CK-107), a next-generation fast skeletal muscle troponin activator (FSTA), in healthy participants. We tested the hypothesis that CK-107 would amplify the force-frequency response of muscle in humans. METHODS: To assess the force-frequency response, participants received single doses of CK 107 and placebo in a randomized, double-blind, 4-period, crossover study. The force-frequency response of foot dorsiflexion following stimulation of the deep fibular nerve to activate the tibialis anterior muscle was assessed. RESULTS: CK 107 significantly increased tibialis anterior muscle response with increasing dose and plasma concentration in a frequency-dependent manner; the largest increase in peak force was ~60% at 10 Hz. DISCUSSION: CK-107 appears more potent and produced larger increases in force than tirasemtiv-a first-generation FSTA-in a similar pharmacodynamic study, thereby supporting its development for improvement of muscle function of patients. Muscle Nerve 57: 729-734, 2018. PMID- 29150953 TI - New algorithm for simulation of proteoglycan loss and collagen degeneration in the knee joint: Data from the osteoarthritis initiative. AB - Osteoarthritis is a harmful joint disease but prediction of disease progression is problematic. Currently, there is only one modeling framework which can be applied to predict the progression of knee osteoarthritis but it only considers degenerative changes in the collagen fibril network. Here, we have developed the framework further by considering all of the major tissue changes (proteoglycan content, fluid flow, and collagen fibril network) occurring in osteoarthritis. While excessive levels of tissue stresses controlled degeneration of the collagen fibril network, excessive levels of tissue strains controlled the decrease in proteoglycan content and the increase in permeability. We created four knee joint models with increasing degrees of complexity based on the depth-wise composition. Models were tested for normal and abnormal, physiologically relevant, loading conditions in the knee. Finally, the predicted depth-wise compositional changes from each model were compared against experimentally observed compositional changes in vitro. The model incorporating the typical depth-wise composition of cartilage produced the best match with experimental observations. Consistent with earlier in vitro experiments, this model simulated the greatest proteoglycan depletion in the superficial and middle zones, while the collagen fibril degeneration was located mostly in the superficial zone. The presented algorithm can be used for predicting simultaneous collagen degeneration and proteoglycan loss during the development of knee osteoarthritis. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1673-1683, 2018. PMID- 29150955 TI - Structural elucidation of a series of benzamide derivatives. PMID- 29150954 TI - Physiological role of urothelial cancer-associated one long noncoding RNA in human skeletogenic cell differentiation. AB - A vast number of long-noncoding RNAs (lncRNA) are found expressed in human cells, which RNAs have been developed along with human evolution. However, the physiological functions of these lncRNAs remain mostly unknown. In the present study, we for the first time uncovered the fact that one of such lncRNAs plays a significant role in the differentiation of chondrocytes and, possibly, of osteoblasts differentiated from mesenchymal stem cells, which cells eventually construct the human skeleton. The urothelial cancer-associated 1 (UCA1) lncRNA is known to be associated with several human malignancies. Firstly, we confirmed that UCA1 was expressed in normal human chondrocytes, as well as in a human chondrocytic cell line; whereas it was not detected in human bone marrow mesenchymal stem cells (hBMSCs). Of note, although UCA1 expression was undetectable in hBMSCs, it was markedly induced along with the differentiation toward chondrocytes, suggesting its critical role in chondrogenesis. Consistent with this finding, silencing of the UCA1 gene significantly repressed the expression of chondrogenic genes in human chondrocytic cells. UCA1 gene silencing and hyper-expression also had a significant impact on the osteoblastic phenotype in a human cell line. Finally, forced expression of UCA1 in a murine chondrocyte precursor, which did not possess a UCA1 gene, overdrove its differentiation into chondrocytes. These results indicate a physiological and important role of this lncRNA in the skeletal development of humans, who require more sustained endochondral ossification and osteogenesis than do smaller vertebrates. PMID- 29150956 TI - Sewage sludge biochars management-Ecotoxicity, mobility of heavy metals, and soil microbial biomass. AB - Production of biochar from sewage sludge may be a promising solution for sewage sludge management and improvement of soil properties, including carbon dioxide sequestration. The aim of the present study was to compare the effects of biochars derived from different sewage sludges on soil physicochemical and biological properties, ecotoxicity, and plant yield. Three biochars (produced at a temperature of 300 degrees C) were applied into sandy acid soil in doses of 0.5, 1, and 2% (w/w). Depending on the type and dose, the application of sewage sludge biochars into the soil caused diverse effects on the parameters of soil biological activity (microbial biomass [Cmic], soil respiration, and value of metabolic quotient). No correlation between the applied dose of biochars and inhibition of Vibrio fischeri luminescence was observed. The factor with a stronger impact on the activity of V. fischeri was the type of biochar. The use of the OSTRACODTOXKIT F test (MicroBioTests) showed that the addition of sewage sludge biochar (regardless of its dose) reduced the soil toxicity to Heterocypris incongruens compared with the control soil. A significant increase of Poa pratensis L. biomass was obtained in soils with 1 and 2% additions of each of the biochars. The addition of biochars in doses of 1 and 2% to the soil had greater effect on the content of mobile forms of Cu, Pb, and Cd than the 0.5% dose compared with the control. Environ Toxicol Chem 2018;37:1197-1207. (c) 2017 SETAC. PMID- 29150957 TI - Randomized, controlled clinical two-centre study using xenogeneic block grafts loaded with recombinant human bone morphogenetic protein-2 or autogenous bone blocks for lateral ridge augmentation. AB - OBJECTIVES: To test whether or not the use of a xenogeneic block loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2) results in different bone quantity and quality compared to an autogenous bone block. MATERIALS AND METHODS: Twenty-four patients with insufficient bone volume for implant placement were randomly assigned to two treatment modalities: a xenogeneic bone block loaded with rhBMP-2 (test) and an autogenous bone block (control). The horizontal ridge width was evaluated prior to augmentation, after augmentation and at 4 months. Patient-reported outcome measures (PROMs) were assessed at suture removal and at 4 months. Biopsies were obtained at 4 months and histologically evaluated. Intergroup comparisons were tested by a two-sided Wilcoxon-Mann-Whitney test, intra-group comparisons were performed with Wilcoxon-signed rank test, and all categorical variables were tested with Chi-squared tests. RESULTS: One autogenous bone block failed. This patient was replaced, and in all subsequently treated 24 patients, implant placement was possible 4 months later. The median ridge width increased from 4.0 mm (Q1 = 2.0; Q3 = 4.0) (test) and 2.0 mm (Q1 = 2.0; Q3 = 3.0) (control) to 7.0 mm (Q1 = 6.0; Q3 = 8.0) (test) and 7.0 mm (Q1 = 6.0; Q3 = 8.0) (control) at 4 months (intergroup p > .05). A higher morbidity was reported at the augmented site in the control group during surgery. Sensitivity was more favourable in the test than that in the control group at 4 months. The biopsies revealed more mineralized tissue in the control group (p < .0043). CONCLUSIONS: Both treatment modalities were successful in regenerating bone to place dental implants. PROMs did not reveal any significant differences between the groups except for pain during surgery at the recipient site (in favour of the test group). Histologically, a higher amount of mineralized tissue was observed for the control group at 4 months. PMID- 29150958 TI - Inhibition of miR-200b/miR-429 contributes to neuropathic pain development through targeting zinc finger E box binding protein-1. AB - Many studies have reported that microRNAs participate in neuropathic pain development. Previously, miR-200b and miR-429 are reported to be involved in various diseases. In our current study, we focused on their roles in neuropathic pain and we found that miR-200b and miR-429 were significantly decreased in chronic constriction injury (CCI) rat spinal cords and isolated microglials. miR 200b and miR-429 overexpression were able to relieve neuropathic pain through modulating PWT and PWL in CCI rats. Meanwhile, we observed that both miR-200b and miR-429 upregulation could repress neuroinflammation via inhibiting inflammatory cytokines such as IL-6, IL-1beta, and TNF-alpha in CCI rats. By carry out bioinformatics technology, Zinc finger E box binding protein-1 (ZEB1) was predicted as target of miR-200b, and miR-429 and dual-luciferase reporter assays confirmed the correlation between them. ZEB1 has been reported to regulate a lot of diseases. Here, we found that ZEB1 was greatly increased in CCI rats and miR 200b and miR-429 overexpression markedly suppressed ZEB1 mRNA expression in rat microglial cells. In addition, knockdown of ZEB1 can reduce neuropathic pain development and co-transfection of LV-anti-miR-200b/miR-429 reversed this phenomenon in vivo. Taken these together, our results suggested that miR-200b/miR 429 can serve as an important regulator of neuropathic pain development by targeting ZEB1. PMID- 29150959 TI - NONO ubiquitination is mediated by FBW7 and GSK3 beta via a degron lost upon chromosomal rearrangement in cancer. AB - NONO is an RNA-binding protein involved in transcription, mRNA splicing, DNA repair, and checkpoint activation in response to UV radiation. NONO expression has been found altered in several tumor types, including prostate, colon, breast, melanoma, and in papillary renal carcinoma, in which an X chromosome inversion generates a NONO-TFE3 fusion protein. Upon such rearrangement, NONO loses its C terminal domain. Through bioinformatics analysis, we identified a putative degron motif, known to be recognized by the Skp1-Cul1-F-box-protein (SCF) complex. Here, we evaluated how this domain could affect NONO protein biology. We showed that NONO interacts with the nuclear FBW7alpha isoform and its ubiquitination is regulated following modulation of the GSK3beta kinase. Mutation of T428A/T432A within the degron impaired polyubiquitination upon FBW7alpha and GSK3beta overexpression. Overall, our data suggest that NONO is likely subjected to proteasome-mediated degradation and add NONO to the list of proteins targeted by FBW7, which is itself often deregulated in cancer. PMID- 29150960 TI - Epithelial cell adhesion molecule fragments and signaling in primary human liver cells. AB - Epithelial Cell Adhesion Molecule (EpCAM), or CD326, is a trans-membrane glycoprotein expressed by multiple normal epithelia as well as carcinoma. Human hepatic stem cells and bile duct epithelium of the liver are EpCAM positive. In tumor cell lines, its intracellular domain can be released after cleavage of the extracellular domain. Within the cell nucleus, it induces cell proliferation, but cleavage depends on cell contact. Fragments of various lengths have been described in tumor cells. Despite its described important role in proliferation in tumor cells, there is not much known about the expression and role of EpCAM fragments in primary human liver cells. Here, we demonstrate that EpCAM protein fragments and function are considerable different between tumor cells, normal fetal and adult liver cells. Contrary to previously reported findings in tumor cells, gene knockdown or treatment with an inhibitor of the cleavage enzyme ADAM17 (TACE) rather increased cell numbers in primary human fetal liver-derived EpCAM-positive cells. EpCAM fragment sizes were not affected by treatment with inhibitor. Knockdown of EPCAM gene expression by siRNA in sorted cells did not significantly affect proliferation-associated genes or cell numbers. The intracellular domain could not be detected within cell nuclei of fetal and adult liver cells. In conclusion, signaling through the intracellular domain of EpCAM appears to be a mechanism that induces proliferation specifically in tumorigenic cells but not in normal primary EpCAM-positive liver cells. PMID- 29150961 TI - Modulation of IgG1 immunoeffector function by glycoengineering of the GDP-fucose biosynthesis pathway. AB - Cross-linking of the Fcgamma receptors expressed on the surface of hematopoietic cells by IgG immune complexes triggers the activation of key immune effector mechanisms, including antibody-dependent cell mediated cytotoxicity (ADCC). A conserved N-glycan positioned at the N-terminal region of the IgG CH 2 domain is critical in maintaining the quaternary structure of the molecule for Fcgamma receptor engagement. The removal of a single core fucose residue from the N glycan results in a considerable increase in affinity for FcgammaRIIIa leading to an enhanced receptor-mediated immunoeffector function. The enhanced potency of the molecule translates into a number of distinct advantages in the development of IgG antibodies for cancer therapy. In an effort to significantly increase the potency of an anti-CD20, IgG1 molecule, we selectively targeted the de novo GDP fucose biosynthesis pathway of the host CHO cell line to generate >80% afucosylated IgG1 resulting in enhanced FcgammaRIIIa binding (13-fold) and in vitro ADCC cell-based activity (11-fold). In addition, this effective glycoengineering strategy also allowed for the utilization of the alternate GDP fucose salvage pathway to provide a fast and efficient mechanism to manipulate the N-glycan fucosylation level to modulate IgG immune effector function. PMID- 29150962 TI - Genotype and diet affect resistance, survival, and fecundity but not fecundity tolerance. AB - Insects are exposed to a variety of potential pathogens in their environment, many of which can severely impact fitness and health. Consequently, hosts have evolved resistance and tolerance strategies to suppress or cope with infections. Hosts utilizing resistance improve fitness by clearing or reducing pathogen loads, and hosts utilizing tolerance reduce harmful fitness effects per pathogen load. To understand variation in, and selective pressures on, resistance and tolerance, we asked to what degree they are shaped by host genetic background, whether plasticity in these responses depends upon dietary environment, and whether there are interactions between these two factors. Females from ten wild type Drosophila melanogaster genotypes were kept on high- or low-protein (yeast) diets and infected with one of two opportunistic bacterial pathogens, Lactococcus lactis or Pseudomonas entomophila. We measured host resistance as the inverse of bacterial load in the early infection phase. The relationship (slope) between fly fecundity and individual-level bacteria load provided our fecundity tolerance measure. Genotype and dietary yeast determined host fecundity and strongly affected survival after infection with pathogenic P. entomophila. There was considerable genetic variation in host resistance, a commonly found phenomenon resulting from for example varying resistance costs or frequency-dependent selection. Despite this variation and the reproductive cost of higher P. entomophila loads, fecundity tolerance did not vary across genotypes. The absence of genetic variation in tolerance may suggest that at this early infection stage, fecundity tolerance is fixed or that any evolved tolerance mechanisms are not expressed under these infection conditions. PMID- 29150963 TI - Detection and Quantification of Two Parasitic Ciliates Boveria labialis and Boveria subcylindrica (Ciliophora: Scuticociliatia) by Fluorescence in situ Hybridization. AB - The thigmotrich scuticociliates Boveria labialis and Boveria subcylindrica are obligate parasites that may cause high mortality in cultured sea cucumbers and bivalves. Morphological methods can identify these organisms in active state, but are unable to discern them in resting stages. In aquaculture practice, these parasitic ciliates are hard to eradicate when massive infection occurs in sea cucumbers. Thus, early detection and precaution are crucial for the control of these pathogens. Under such circumstances, fluorescence in situ hybridization (FISH) will serve as a fast way to detect and monitor the occurrence of these parasites. We designed two SSU-rDNA targeted oligonucleotide probes labeled with fluorochromes, and optimized the FISH protocols for the detection of B. labialis and B. subcylindrica from the host sea cucumber Apostichopus japonicus and the bivalve Atrina pectinata, respectively. The assays resulted in a clear differentiation of the two similar species by strong fluorescence signals from the oligonucleotide probes. Moreover, we successfully used the FISH protocol to detect the cysts of B. labialis and variation in abundance of active parasites to evaluate the efficacy of chemical treatments. This is the first report and detection of the cysts of B. labialis from the host sea cucumber A. japonicus. PMID- 29150965 TI - I Thought He Was Going to Set Our House on Fire. PMID- 29150964 TI - De novo donor-specific HLA antibodies after combined intestinal and vascularized composite allotransplantation - a retrospective study. AB - Combining vascularized composite allotransplantation (VCA) with intestinal transplantation to achieve primary abdominal closure has become a feasible procedure. Besides facilitating closure, the abdominal wall can be used to monitor intestinal rejection. As the inclusion of a VCA raises the possibility of an enhanced alloimmune response, we investigated the incidence and clinical effect of de novo donor-specific HLA antibodies (dnDSA) in a cohort of patients receiving an intestinal transplant with or without a VCA. The sequential clinical study includes 32 recipients of deceased donor intestinal and VCA transplants performed between 2008 and 2015; eight (25%) modified multivisceral transplants and 24 (75%) isolated small bowel transplants. A VCA was used in 18 (56.3%) cases. There were no episodes of intestinal rejection without VCA rejection. Fourteen patients (14 of 29; 48.3%) developed dnDSA. In the VCA group, fewer patients developed dnDSA; six of 16 (37.5%) VCA vs. eight of 13 (61.5%) non-VCA. There was no statistically significant difference in one- and 3-year overall graft survival stratified for the presence of dnDSA; P = 0.286. In the study, there is no evidence that the addition of a VCA increases the incidence of dnDSA formation compared to transplantation of the intestine alone. PMID- 29150966 TI - Current policy for allocation of donor livers in the Netherlands advantages primary sclerosing cholangitis patients on the liver transplantation waiting list a retrospective study. AB - Studies from the USA and Nordic countries indicate primary sclerosing cholangitis (PSC) patients have low mortality on the liver transplantation (LTx) waiting list. However, this may vary among geographical areas. Therefore, we compared waiting list mortality and post-transplant survival between laboratory model for end-stage liver disease (LM) and MELD exception (ME)-prioritized PSC and non-PSC candidates in a nationwide study in the Netherlands. A retrospective analysis of patients waitlisted from 2006 to 2013 was conducted. A total of 852 candidates (146 PSC) were waitlisted of whom 609 (71.5%) underwent LTx and 159 (18.7%) died before transplantation. None of the ME PSC patients died, and they had a higher probability of LTx than LM PSC [HR obtained by considering ME as a time-dependent covariate (HRME 9.86; 95% CI 6.14-15.85)] and ME non-PSC patients (HRME 4.60; 95% CI 3.78-5.61). After liver transplantation, PSC patients alive at 3 years of follow-up had a higher probability of relisting than non-PSC patients (HR 7.94; 95% CI 1.98-31.85) but a significantly lower mortality (HR 0.51; 95% CI 0.27 0.95). In conclusion, current LTx prioritization advantages PSC patients on the LTx waiting list. Receiving ME points is strongly associated with timely LTx. PMID- 29150967 TI - Drug delivery strategies for chemoprevention of UVB-induced skin cancer: A review. AB - Annually, more skin cancer cases are diagnosed than the collective incidence of the colon, lung, breast, and prostate cancer. Persistent contact with sunlight is a primary cause for all the skin malignancies. UVB radiation induces reactive oxygen species (ROS) production in the skin which eventually leads to DNA damage and mutation. Various delivery approaches for the skin cancer treatment/prevention have been evolving and are directed toward improvements in terms of delivery modes, therapeutic agents, and site-specificity of therapeutics delivery. The effective chemoprevention activity achieved is based on the efficiency of the delivery system used and the amount of the therapeutic molecule deposited in the skin. In this article, we have discussed different studies performed specifically for the chemoprevention of UVB-induced skin cancer. Ultra flexible nanocarriers, transethosomes nanocarriers, silica nanoparticles, silver nanoparticles, nanocapsule suspensions, microemulsion, nanoemulsion, and polymeric nanoparticles which have been used so far to deliver the desired drug molecule for preventing the UVB-induced skin cancer. PMID- 29150968 TI - Effects of blue light on inflammation and skin barrier recovery following acute perturbation. Pilot study results in healthy human subjects. AB - BACKGROUND/PURPOSE: While growing evidence supports the therapeutic effect of 453 nm blue light in chronic inflammatory skin diseases, data on its effects on acutely perturbed human skin are scarce. In this study, we investigated the impact of 453 nm narrow-band LED light on healthy skin following acute perturbation. METHODS: Tape stripping and histamine iontophoresis were performed on the forearm of 22 healthy volunteers on 2 consecutive weeks. In 1 week, challenges were followed by irradiation for 30 minutes. In the other week (control), no light was administered. Reactions were evaluated up to 72 hours thereafter by transepidermal water loss (TEWL), diffuse reflectance spectroscopy, and skin surface biomarkers. RESULTS: Skin barrier disruption resulted in upregulation of IL-1alpha at 24 hours after tape stripping (P = .029). In contrast, irradiation abrogated this effect (P > .05). Irradiation also resulted in higher TEWL at 24 hours and in higher b* value at 72 hours after tape stripping compared to the control (P = .034 and P = .018, respectively). At 30 minutes following histamine iontophoresis and irradiation, a trend toward a higher a* value compared to the control was observed (P = .051). CONCLUSION: We provide the first in vivo evidence that blue light at 453 nm exerts biological effects on acutely perturbed healthy human skin. PMID- 29150969 TI - Non-operative treatment as a strategy for patients with parastomal hernia: a multicentre, retrospective cohort study. AB - AIM: Parastomal hernia is the most common complication following stoma construction. Surgical treatment is usually chosen over non-operative treatment, but a clear rationale for the choice of management is often lacking. This study aims to investigate the reasons for non-operative treatment, cross-over rates and postoperative complications. METHOD: A multicentre, retrospective cohort study was conducted. Patients diagnosed with a parastomal hernia between January 2007 and December 2012 were included. Data on baseline characteristics, primary surgery and hernias were collected. For non-operative treatment, reasons for this treatment and cross-over rates were evaluated. For all patients undergoing surgery (surgical treatment and cross-overs), complication and recurrence rates were analysed. RESULTS: Of the 80 patients included, 42 (53%) were in the surgical treatment group and 38 (48%) in the non-operative treatment group. Median follow-up was 46 months (interquartile range 24-72). The reasons for non operative treatment were absence of symptoms in 12 patients (32%), comorbidities in nine (24%) and patient preference in three (7.9%). In 14 patients (37%) reasons were not documented. Eight patients (21%) crossed over from non-operative treatment to surgical treatment, of whom one needed emergency surgery. In 23 patients (55%), parastomal hernia recurred after the original surgical treatment, of whom 21 (91%) underwent additional repair. CONCLUSION: Parastomal hernia repair is associated with high recurrence and additional repair rates. Non operative treatment has a relatively low cross-over and emergency surgery rate. Given these data, non-operative treatment might be a better choice for patients without complaints or with comorbidities. PMID- 29150970 TI - A Family Reunion. PMID- 29150971 TI - Reply from the authors. PMID- 29150972 TI - Patient-level Factors and the Quality of Care Delivered in Pediatric Emergency Departments. AB - OBJECTIVE: Quality of care delivered to adult patients in the emergency department (ED) is often associated with demographic and clinical factors such as a patient's race/ethnicity and insurance status. We sought to determine whether the quality of care delivered to children in the ED was associated with a variety of patient-level factors. METHODS: This was a retrospective, observational cohort study. Pediatric patients (<18 years) who received care between January 2011 and December 2011 at one of 12 EDs participating in the Pediatric Emergency Care Applied Research Network (PECARN) were included. We analyzed demographic factors (including age, sex, and payment source) and clinical factors (including triage, chief complaint, and severity of illness). We measured quality of care using a previously validated implicit review instrument using chart review with a summary score that ranged from 5 to 35. We examined associations between demographic and clinical factors and quality of care using a hierarchical multivariable linear regression model with hospital site as a random effect. RESULTS: In the multivariable model, among the 620 ED encounters reviewed, we did not find any association between patient age, sex, race/ethnicity, and payment source and the quality of care delivered. However, we did find that some chief complaint categories were significantly associated with lower than average quality of care, including fever (-0.65 points in quality, 95% confidence interval [CI] = -1.24 to -0.06) and upper respiratory symptoms (-0.68 points in quality, 95% CI = -1.30 to -0.07). CONCLUSION: We found that quality of ED care delivered to children among a cohort of 12 EDs participating in the PECARN was high and did not differ by patient age, sex, race/ethnicity, and payment source, but did vary by the presenting chief complaint. PMID- 29150973 TI - Characterization of the Parasitic Dinoflagellate Amoebophrya sp. Infecting Akashiwo sanguinea in Coastal Waters of China. AB - The endoparasitic dinoflagellate Amoebophrya infects a number of free-living marine dinoflagellates, including harmful algal bloom species. The parasitoid eventually kills its host and has been proposed to be a significant loss factor for dinoflagellate blooms in restricted coastal waters. For several decades, the difficulties of culturing host-parasitoid systems have been a great obstacle for further research on the biology of Amoebophrya. Here, we established an Akashiwo sanguinea-Amoebophrya sp. coculture from Chinese coastal waters and studied the parasitoid's generation time, dinospore survival and infectivity, as well as its host specificity. The lifespan of Amoebophrya sp. ex. A. sanguinea was approximately 58 h. The infective dinospores can survive up to 78 h in ambient waters but gradually lose their infectivity. The parasitoid was unable to infect other dinoflagellate species, its infection rate reached as high as 91% when the ratio of dinospores to host cells was 20:1. The high infectivity of dinospores suggests that the Amoebophrya strain was capable of removing a considerable fraction of host biomass within a short period, but that it is probably unable to maintain high infection levels under nonbloom conditions of its host, due to limited survival and time constraints in encountering host cells. PMID- 29150974 TI - Reciprocal interactions between bile acids and gut microbiota in human liver diseases. AB - The gut microbiota (GM) play a central role in their host's metabolism of bile acids (BAs) by regulating deconjugation, dehydroxylation, dehydrogenation, and epimerization reactions to generate unconjugated free BAs and secondary BAs. These BAs generated by the GM are potent signaling molecules that interact with BA receptors, such as the farnesoid X receptor and Takeda G-protein-coupled receptor 5. Each BA has a differential affinity to these receptors; therefore, alterations in BA composition by GM could modify the intensity of receptor signaling. Bile acids also act as antimicrobial agents by damaging bacterial membranes and as detergents by altering intracellular macromolecular structures. Therefore, BAs and the GM reciprocally control each other's compositions. In this review, we discuss the latest findings on the mutual effects of BAs and GM on each other; we also describe their roles in the pathophysiology of liver disease progression and potential therapeutic applications of targeting this cross-talk. PMID- 29150975 TI - Downregulation of dual-specificity phosphatase 4 enhances cell proliferation and invasiveness in colorectal carcinomas. AB - It is widely accepted that aberrant activation of the Wnt signaling pathway is responsible for the development of precursor lesions of colorectal cancer (CRC). However, the molecular mechanisms involved in the process of progression from these precursor lesions to invasive lesions of CRC are not fully understood. Recently, we reported that constitutive activation of MAPK accompanied by downregulation of dual-specificity phosphatase 4 (DUSP4), a MAPK phosphatase, contributes to the progression of precursor lesions in the pancreas. In this study, we found that downregulation of DUSP4 was related to constitutive activation of ERKs in CRC cells. Restoration of DUSP4 resulted in inactivation of ERKs, leading to suppression of both proliferation and invasiveness, as shown by treatment with an MEK inhibitor. Furthermore, immunohistochemistry revealed that DUSP4 expression was upregulated in the superficial region of CRC tissue, whereas it was significantly downregulated in the deep region. In contrast, ERKs in the deep region were markedly hyperactivated compared to those in the superficial region. These results suggest that activation of the MAPK signaling pathway caused by downregulation of DUSP4 is responsible for progression of CRCs and would be a promising therapeutic target. PMID- 29150976 TI - Salt bridge interactions within the beta2 integrin alpha7 helix mediate force induced binding and shear resistance ability. AB - The functional performance of the alphaI domain alpha7 helix in beta2 integrin activation depends on the allostery of the alpha7 helix, which axially slides down; therefore, it is critical to elucidate what factors regulate the allostery. In this study, we determined that there were two conservative salt bridge interaction pairs that constrain both the upper and bottom ends of the alpha7 helix. Molecular dynamics (MD) simulations for three beta2 integrin members, lymphocyte function-associated antigen-1 (LFA-1; alphaL beta2 ), macrophage-1 antigen (Mac-1; alphaM beta2 ) and alphax beta2 , indicated that the magnitude of the salt bridge interaction is related to the stability of the alphaI domain and the strength of the corresponding force-induced allostery. The disruption of the salt bridge interaction, especially with double mutations in both salt bridges, significantly reduced the force-induced allostery time for all three members. The effects of salt bridge interactions of the alphaI domain alpha7 helix on beta2 integrin conformational stability and allostery were experimentally validated using Mac-1 constructs. The results demonstrated that salt bridge mutations did not alter the conformational state of Mac-1, but they did increase the force induced ligand binding and shear resistance ability, which was consistent with MD simulations. This study offers new insight into the importance of salt bridge interaction constraints of the alphaI domain alpha7 helix and external force for beta2 integrin function. PMID- 29150977 TI - The Cellular Composition and Glia-Neuron Ratio in the Spinal Cord of a Human and a Nonhuman Primate: Comparison With Other Species and Brain Regions. AB - The cellular composition of brains shows largely conserved, gradual evolutionary trends between species. In the primate spinal cord, however, the glia-neuron ratio was reported to be greatly increased over that in the rodent spinal cord. Here, we re-examined the cellular composition of the spinal cord of one human and one nonhuman primate species by employing two different counting methods, the isotropic fractionator and stereology. We also determined whether segmental differences in cellular composition, possibly reflecting increased fine motor control of the upper extremities, may explain a sharply increased glia-neuron ratio in primates. In the cynomolgus monkey spinal cord, the isotropic fractionator and stereology yielded 206-275 million cells, of which 13.3-25.1% were neurons (28-69 million). Stereological estimates yielded 21.1% endothelial cells and 65.5% glial cells (glia-neuron ratio of 4.9-5.6). In human spinal cords, the isotropic fractionator and stereology generated estimates of 1.5-1.7 billion cells and 197-222 million neurons (13.4% neurons, 12.2% endothelial cells, 74.8% glial cells), and a glia-neuron ratio of 5.6-7.1, with estimates of neuron numbers in the human spinal cord based on morphological criteria. The non neuronal to neuron ratios in human and cynomolgus monkey spinal cords were 6.5 and 3.2, respectively, suggesting that previous reports overestimated this ratio. We did not find significant segmental differences in the cellular composition between cervical, thoracic and lumbar levels. When compared with brain regions, the spinal cord showed gradual increases of the glia-neuron ratio with increasing brain mass, similar to the cerebral cortex and the brainstem. Anat Rec, 301:697 710, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29150979 TI - Anterior thalamic nuclei lesions have a greater impact than mammillothalamic tract lesions on the extended hippocampal system. AB - The anterior thalamic nuclei (ATN), mammillary bodies and their interconnecting fiber tract, the mammillothalamic tract (MTT), are important components of an extended hippocampal circuit for episodic memory. In humans, damage to the MTT or ATN in many disorders is associated with severe anterograde amnesia and it is assumed that their influence on memory is functionally equivalent. The relative influence of these two structures on memory has not, however, been assessed explicitly. Here, a direct comparison found that only ATN lesions impaired spatial reference memory in rats. ATN lesions produced more severe deficits on spatial working memory and reduced zif268 expression to a greater degree and in more corticolimbic sites than did MTT lesions. Conversely, MTT lesions reduced NeuN cell counts in all three subregions of the MB to a greater extent than did ATN lesions, so their relative impact cannot be explained by retrograde neuropathology of the MB. Hence ATN injury causes a more critical dysfunction than would be expected by an emphasis on the indirect influence of brainstem inputs to the extended memory system. The greater ATN lesion deficits found here may represent the consequence of disruption to the direct connections of the ATN with both hippocampal and cortical sites. PMID- 29150978 TI - Mice lacking a functional NMDA receptor exhibit social subordination in a group housed environment. AB - Social dominance, in which an individual asserts control over others or benefits most after social conflict, has an influence on social behaviour. However, the mechanisms mediating social dominance remain unclear. Social dominance within social groups determines the distribution of rewards such as food and access to mating partners, which can act as reinforcers. In this study, we used the water competition test to determine whether mice were dominant or subordinate. It has been previously reported that mice heterozygous for a missense mutation in Grin1 (Grin1Rgsc174 ) showed altered social behaviour, with increased locomotor activity, novelty seeking and anxiety. However, social dominance in these mice has not been previously investigated. We subjected Grin1Rgsc174/+ mice to the water competition test using IntelliCage and observed that Grin1 influences competitive dominance. We found that Grin1Rgsc174/+ mice exhibited social subordination characterised by decreased corner visit frequency and occupancy time at the beginning of the task. However, Grin1Rgsc174/+ mice retained increased basal activity and exploring behaviour under a group-housed environment. Our findings suggested that Grin1 plays an important role in determining social dominance. PMID- 29150980 TI - Adjuvant radiotherapy in sinonasal mucosal melanoma: A retrospective analysis. AB - OBJECTIVES: Evaluation of outcome after curative treatment for sinonasal mucosal melanoma focused on the effect of adjuvant radiotherapy on recurrence and survival. DESIGN: Retrospective chart analysis. SETTING: Tertiary referral hospital. PARTICIPANTS: Fifty-one patients with primary sinonasal mucosal melanoma who underwent surgical resection with curative intention between 1980 and 2016 at Erasmus Medical Center, Rotterdam. MAIN OUTCOME MEASURES: Patients were categorised into 2 groups: surgery alone and surgery with adjuvant radiotherapy. Log-rank test was used to compare rates of recurrence and survival between treatment groups. Predictors for treatment modality, recurrence and survival were assessed with multivariate statistical analysis. RESULTS: Of all patients, 23.5% developed local recurrence and 47.1% developed distant metastasis. Estimated 5-year disease-free survival was 25.2%, and 5-year overall survival (OS) was 38.1%. Forty-three patients (84.3%) were treated with post operative radiotherapy. Patients who underwent surgery with adjuvant radiotherapy presented more often with high tumour stage, tumour involving multiple sites and positive margins. Post-operative radiotherapy seemed to be associated with better local control (P = .549). No effect was found on occurrence of distant metastasis and OS. Positive margin status was an independent negative predictor for distant metastasis-free survival and overall survival. CONCLUSIONS: Our treatment outcomes are consistent with literature. Post-operative radiotherapy seems to be associated with improved local control despite advanced disease and positive margin status in this treatment group. PMID- 29150981 TI - Systematic Proteomic Analysis of Protein Methylation in Prokaryotes and Eukaryotes Revealed Distinct Substrate Specificity. AB - The studies of protein methylation mainly focus on lysine and arginine residues due to their diverse roles in essential cellular processes from gene expression to signal transduction. Nevertheless, atypical protein methylation occurring on amino acid residues, such as glutamine and glutamic acid, is largely neglected until recently. In addition, the systematic analysis for the distribution of methylation on different amino acids in various species is still lacking, which hinders our understanding of its functional roles. In this study, we deeply explored the methylated sites in three species Escherichia coli, Saccharomyces cerevisiae, and HeLa cells by employing MS-based proteomic approach coupled with heavy methyl SILAC method. We identify a total of 234 methylated sites on 187 proteins with high localization confidence, including 94 unreported methylated sites on nine different amino acid residues. KEGG and gene ontology analysis show the pathways enriched with methylated proteins are mainly involved in central metabolism for E. coli and S. cerevisiae, but related to spliceosome for HeLa cells. The analysis of methylation preference on different amino acids is conducted in three species. Protein N-terminal methylation is dominant in E. coli while methylated lysines and arginines are widely identified in S. cerevisiae and HeLa cells, respectively. To study whether some atypical protein methylation has biological relevance in the pathological process in mammalian cells, we focus on histone methylation in diet-induced obese (DIO) mouse. Two glutamate methylation sites showed statistical significance in DIO mice compared with chow-fed mice, suggesting their potential roles in diabetes and obesity. Together, these findings expanded the methylome database from microbes to mammals, which will benefit our further appreciation for the protein methylation as well as its possible functions on disease. PMID- 29150982 TI - Visualization Within the Ventricles of the Brain: A Micro-Focus X-Ray Study. AB - Conceptualization of the ventricular system of the brain by macroscopic studies is complicated by the lack of physical structure of these interconnected cavities. Dissection procedures designed to display the structures in the walls of the ventricles are destructive and not conducive for the appreciation of the ventricular system in its entirety. The application of Micro-focus X-ray tomography affords the possibility to appreciate hidden structures in a nondestructive manner. The aim of this study was to explore the possibility of using micro-focus X-ray tomography in the three-dimensional (3D) visualization of the ventricular system as well as the various neuroanatomical structures within its walls for educational purposes. Randomly selected embalmed human cadaver brains were scanned at Necsa (South African Nuclear Energy Corporation) housing the MIXRAD laboratory consisting of a Nikon XTH 225 ST micro-focus X-ray tomography facility. A 3D flythrough video of the ventricular system was reconstructed from these scans using software to view the inner surface of the ventricles. Micro-focus X-ray tomography provides feasible means of delivering high-resolution images in a nondestructive way to design a representation of the ventricular system. In addition, structures in the walls of the ventricular system could be appreciated in a novel way. It is envisaged that this 3D-fly through video of the ventricular system will be valuable when integrated with standard prosections and atlas pictures in the educational setting. Further studies evaluating the use of this integrative visualization of the ventricular system of the brain for its applicability in the educational setting should be performed. Anat Rec, 00:000-000, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 29150983 TI - Ontogeny of the Postcranial Axial Skeleton of Melanosuchus niger (Crocodylia, Alligatoridae). AB - This study proposes the description of the development of the postcranial axial skeleton, including vertebrae, gastralium, ribs, sternum, and interclavicle, in Melanosuchus niger. Six nests were marked and two eggs removed from each nest at 24-hr intervals until hatching. For posthatching evaluation, 30 hatchlings were kept in captivity and one exemplar was euthanized at three-day intervals. Samples were diaphanized using potassium hydroxide (KOH), alizarin red S, and Alcian blue. A routinely generally used method was applied for histological evaluation. It was difficult to define in which vertebrae the development of cartilaginous centers began, but it was possible to observe that this condensation advanced in the craniocaudal direction. The condensation started in the vertebral arches and was visibly stronger in the cervical and dorsal regions, advancing to the lumbar, sacral and, last, to the caudal region. The atlas showed a highly different morphology compared with the other cervical vertebrae, with a short intercenter, two neural arches, and a proatlas. The ossification process began in the body of cervical vertebrae III to VIII and alizarin retention decreased in the last vertebrae, indicating a craniocaudal direction in bone development, similar to cartilage formation. In the histological sections of gastralium and interclavicles of M. niger at several development stages, it was possible to observe that these elements showed intramembranous development. Anat Rec, 301:607 623, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29150984 TI - How the environment shapes animal signals: a test of the acoustic adaptation hypothesis in frogs. AB - Long-distance acoustic signals are widely used in animal communication systems and, in many cases, are essential for reproduction. The acoustic adaptation hypothesis (AAH) implies that acoustic signals should be selected for further transmission and better content integrity under the acoustic constraints of the habitat in which they are produced. In this study, we test predictions derived from the AAH in frogs. Specifically, we focus on the difference between torrent frogs and frogs calling in less noisy habitats. Torrents produce sounds that can mask frog vocalizations and constitute a major acoustic constraint on call evolution. We combine data collected in the field, material from scientific collections and the literature for a total of 79 primarily Asian species, of the families Ranidae, Rhacophoridae, Dicroglossidae and Microhylidae. Using phylogenetic comparative methods and including morphological and environmental potential confounding factors, we investigate putatively adaptive call features in torrent frogs. We use broad habitat categories as well as fine-scale habitat measurements and test their correlation with six call characteristics. We find mixed support for the AAH. Spectral features of torrent frog calls are different from those of frogs calling in other habitats and are related to ambient noise levels, as predicted by the AAH. However, temporal call features do not seem to be shaped by the frogs' calling habitats. Our results underline both the complexity of call evolution and the need to consider multiple factors when investigating this issue. PMID- 29150985 TI - General illness and psychological factors in patients with chronic nasal symptoms. AB - OBJECTIVES: Only a minority of patients referred to specialists with sinonasal symptoms have clear evidence of chronic rhinosinusitis (CRS). This study aims to estimate the prevalence of and associations between (i) general illness factors (fatigue, autonomic dysfunction) and (ii) psychological factors (anxiety, depression, somatisation, personality traits) in patients presenting with sinonasal symptoms. DESIGN: The following validated questionnaires were administered to patients: the Sino-Nasal Outcome Test-22 (SNOT-22) identifying symptom burden, Composite Autonomic Symptom Score-31 (COMPASS-31) measuring autonomic function, Chalder Fatigue Questionnaire, Patient Health Questionnaire 15 (PHQ-15) addressing somatisation symptoms, Hospital Anxiety and Depression Scale (HADS), and the International Personality Item Pool-50 (IPIP-50). Comparisons were made with normative and general population data, and relationships were analysed using nonparametric correlation. SETTING: Secondary care ENT outpatients. PARTICIPANTS: Adults referred with chronic sinonasal symptoms. MAIN OUTCOME MEASURES: SNOT-22, COMPASS-31, Chalder, PHQ-15, HADS, and IPIP-50 questionnaire scores. RESULTS: Sixty-one patients were included. There was a high prevalence of all general and psychological factors assessed compared with controls. Total SNOT-22 scores showed significant correlation with Chalder fatigue scores, total autonomic dysfunction score, anxiety, depression, somatisation tendencies and the emotionally unstable personality trait. Emotional instability and psychological dysfunction correlated significantly with sleep and psychological subscales of SNOT-22 but not the rhinological or ear/facial subscales. CONCLUSION: Patients with sinonasal symptoms demonstrate high prevalence and complex associations of general illness factors, psychological distress and certain personality traits. The SNOT-22 is a valuable tool, but its utility is limited by correlations with these confounding factors (eg psychological factors) that may exaggerate the total score. The use of the SNOT 22 component subscales is likely to provide more clinically meaningful and discriminant information. PMID- 29150987 TI - Therapeutic Effect of Curcumin and Methylprednisolone in the Rat Spinal Cord Injury. AB - In addition to imperiling an individual's daily life, spinal cord injury (SCI), a catastrophic medical damage, can permanently impair an individual's body function. Methylprednisolone (MP), a medically accepted therapeutic drug for SCI, is highly controversial for the lack of consensus on its true therapeutic effect. In recent years, curcumin has served as a potential and novel therapeutic drug in SCI. Our study was intended to investigate the precise effect of MP and curcumin in SCI. We examined the function of MP and curcumin in a SCI model rat, both in vivo and in vitro, and found that there was a momentous improvement in Basso Beattie-Bresnahan scores in the MP-treated group when compared with Cur-treated group within 14 days. Results obtained from the histological, immunohistochemistry and ultrastructural examinations evidenced the curative effect of MP was better than curcumin before Day 14. Nonetheless, there was a significant variation in the treatment effect between the MP-treated and Cur treated groups after 14 days. The curcumin's effectiveness was more obvious than MP after 14 days following SCI. As such, we surmise that curcumin has a better therapeutic potential than MP with a prolong treatment time in the wake of SCI. Anat Rec, 301:686-696, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29150986 TI - Memory T cells are significantly increased in rejected liver allografts of rhesus monkeys. AB - The rhesus monkey (RM) is an excellent preclinical model in kidney, heart, and islet transplantation that has provided the basis for new immunosuppressive protocols for clinical studies. However, there remain relatively few liver transplantation (LT) models in nonhuman primates. In this study, we analyzed the immune cell populations of peripheral blood mononuclear cells (PBMCs) and secondary lymphoid organs along with livers of normal RMs and compared them with those of rejected LT recipients following withdrawal of immunosuppression. We undertook 5 allogeneic ABO compatible orthotopic LTs in monkeys using 5 normal donor monkey livers. We collected tissues including lymph nodes, spleens, blood, and recipient livers, and we performed flow cytometric analysis using isolated immune cells. We found that CD4 or CD8 naive T cells were normally seen at low levels, and memory T cells were seen at high levels in the liver rather than lymphoid organs or PBMC. However, regulatory cells such as CD4+ forkhead box P3+ T cells and CD8+ CD28- cells remained in high numbers in the liver, but not in the lymph nodes or PBMC. The comparison of CD4/8 T subpopulations in normal and rejected livers and the various tissues showed that naive cells were dramatically decreased in the spleen, lymph node, and PBMCs of rejected LT monkeys, but rather, the memory CD4/8 T cells were increased in all tissues and PBMC. The normal liver has large numbers of CD4 regulatory T cells, CD8+ CD28-, and myeloid derived suppressor cells, which are known immunosuppressive cells occurring at much higher levels than those seen in lymph node or peripheral blood. Memory T cells are dramatically increased in rejected liver allografts of RMs compared with those seen in normal RM tissues. Liver Transplantation 24 256-268 2018 AASLD. PMID- 29150988 TI - Patterns and Correlates of Grip Strength in Older Americans. AB - BACKGROUND: Muscle strength is a sensitive indicator of morbidity and mortality in older adults. Loss of muscle strength contributes to a decline in physical functioning. Hand grip strength is a simple measurement but correlated with total body muscle strength. This study evaluated the patterns and correlates of grip strength among older adults in the United States. METHOD: The grip strength data were analyzed from the National Health and Nutrition Examination Survey. RESULT: Individuals (n=1009) aged >=65 years old who had a grip strength measure were included in this analysis. Age distribution was 31.5%, 27.2%, 16.2%, and 25.0% for 65-69, 70-74, 75-79, and 80+ respectively. Race distribution was 81.1%, 8.3%, 7.1%, and 3.5% for Whites, Blacks, Hispanics, and Asians respectively. The mean grip strength was 71.7kg in males and 44.6kg in females, and declined as age increased (p<.0001). Blacks had the highest grip strength, followed by Whites and Hispanics, and Asians had the lowest measure (p<.0001). Although several variables were found to be correlated with grip strength univariately, after adjusting for gender, age, and race, the factors that remained significantly and independently associated with weak grip strength were lower body weight, not being in good health status, and physical limitations. CONCLUSION: Grip strength reduced as age increased. Blacks and Whites displayed higher grip strength than Asians and Hispanics. General health status, weight status and physical functioning were independently associated with grip strength. These findings suggest that grip strength could be a useful indicator for overall health assessment in older adults. PMID- 29150989 TI - An evaluation of the SENTiFIT 270 analyser for quantitation of faecal haemoglobin in the investigation of patients with suspected colorectal cancer. AB - BACKGROUND: An evaluation of SENTiFIT(r) 270 (Sentinel Diagnostics, Italy; Sysmex, Spain) analyser for the quantitation of faecal haemoglobin (f-Hb) was performed. METHODS: The analytical imprecision, linearity, carry over and f-Hb stability were determined. Evaluation of the diagnostic accuracy was performed on 487 patients. RESULTS: Within-run and between-run imprecision ranged 1.7%-5.1% and 3.8%-6.2%, respectively. Linearity studies revealed a mean recovery of 101.1% (standard deviation, 6.7%) for all dilutions. No carry over was detected below 7650 MUg Hb/g faeces. Decay of f-Hb in refrigerated samples ranged 0.2%-0.5% per day. f-Hb in patients with advanced colorectal neoplasia (ACRN) (colorectal cancer [CRC] plus advanced adenoma [AA]) were significantly higher than from those with a normal colonoscopy. Sensitivity for ACRN at f-Hb cutoffs from 10 to 60 MUg Hb/g faeces ranged from 28.9% (95% confidence interval [CI], 21.7%-37.2%) to 46.5% (95% CI, 38.1%-55%), the specificity ranged from 85% (95% CI, 82.3% 87.3%) to 93.2% (95% CI, 91.2%-94.8%), positive predictive values for detecting CRC and AA ranged from 11.6% (95% CI, 7.6%-17.2%) to 20.6% (95% CI, 13.3%-30.3%) and from 34.7% (95% CI, 28.1%-42%) to 42.3% (95% CI, 32.4%-52.7%), respectively, and the negative predictive value for ACRN ranged from 90.2% (95% CI, 87.9% 92.2%) to 88.4% (95% CI, 86%-90.4%). Using two samples per patient sensitivity increased with a slight decrease in specificity. CONCLUSIONS: The analytical and clinical performances of SENTiFIT assay demonstrate a specific and accurate test for detecting ACRN in symptomatic patients and those undergoing surveillance. PMID- 29150990 TI - Prevalence of dry eye disease and its association with dyslipidemia. AB - BACKGROUND: Dry eye disease (DED) is a common ocular surface disease significantly affecting the quality of life of patients. The aim of our study is to focus on the prevalence of DED and to determine the relationship between dyslipidemia and DED. METHODS: The study was performed with the age group of 25 70 years, who attended the ophthalmology outpatient department at Sri Lakshmi Narayana Institute of Medical Sciences with complaints of dry eye. A standard questionnaire was taken, and tear film tests were performed to diagnose dry eye. Further eyelid margin was examined to detect meibomian gland dysfunction. Based on the tests and examination, patients were grouped as men with and without DED and women with and without DED. Fasting lipid profile was investigated for these groups. RESULTS: The study showed the prevalence of DED mainly in women and found significant association between DED and dyslipidemia. There is a significant relationship between total cholesterol and DED groups especially in women (p<0.001). We also found the association between triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol and DED particularly in women as compared to men. CONCLUSIONS: Based on the findings, we emphasize that there is a strong relationship between dyslipidemia and the progression of DED particularly in women. Ophthalmologists may increase their role to educate themselves to diagnose dyslipidemia and ensure comprehensive eye care to prevent blindness and cardiovascular disease. Recent treatment modalities could be aimed to improve the quality of life of women and elderly patients suffering from DED. PMID- 29150991 TI - Population-based differences in immune system response contribute to an increased risk of schizophrenia in African migrants? AB - Among the highest incidences of schizophrenia is the one documented in second generation migrants of African descent in the Western countries. Interestingly, people of African and European ancestry demonstrate significant genetic-based differences in immune system regulation and response. As a result, the pro inflammatory phenotype is more pronounced in people of African descent than it is in Europeans. At the same time, the role of the immune system in the etiology of schizophrenia is gaining increased recognition. Here, we propose that the population-specific genetic variation within the immune system interacts with unfavourable environments to contribute to a higher risk of schizophrenia in people of African ancestry. Our hypothesis is supported by recent findings from two separate fields of research-population genetics and psychoneuroimmunology. Moreover, we highlight the need to include African populations in genetic studies of schizophrenia. PMID- 29150992 TI - Accelerated aging and aging process in the brain. AB - One of the approaches to the research of the problem of aging is the study of genetic pathologies leading to accelerated aging, such as the Hutchinson-Gilford progeria syndrome, Werner syndrome, and Down syndrome. Probably, this approach can be used in an attempt to understand the neuronal mechanisms underlying normal and pathological brain aging. The analysis of the current state of scientific knowledge about these pathologies shows that in the Hutchinson-Gilford progeria and Werner syndrome, the rate of brain aging is significantly lower than the rate of whole body aging, whereas in Down syndrome, the brain ages faster than other organs due to amyloid-beta accumulation and chronic oxidative stress in the brain tissue. The main point of a previously proposed hypothesis is that the aging of higher animals and humans is associated with an increased level of reactive oxygen species in mitochondria with age, which activates apoptosis, thus reducing the number of functioning cells. PMID- 29150994 TI - Combating the Spread of Ineffective Medical Procedures: A Lesson Learned From Multiple Sclerosis. PMID- 29150993 TI - Overexpression of miR-31 in Peripheral Blood Mononuclear Cells (PBMC) from Patients with Ankylosing Spondylitis. AB - BACKGROUND miRNAs play vital roles in regulating immunologic functions and autoimmunity. However, the levels of miR-31, miR-155, miR-16, and miR-181a have not been explored in AS, but were verified to play vital roles in other immunological diseases. The aim of our study was to examine whether the expressions of miR-31, miR-155, miR-16, and miR-181a are abnormal in AS. MATERIAL AND METHODS Real-time transcription-polymerase chain reaction analysis (RT-PCR) was used to determine the expression of miR-31, miR-155, miR-16, and miR-181a in peripheral blood mononuclear cells (PBMC) from 40 patients with AS and 40 healthy controls. RESULTS The expression of miR-31 was increased in AS patients compared with healthy controls (p=0.001). Furthermore, we detected no significant differences in the expressions of miR-155, miR-16, and miR-181a between AS patients and healthy controls. However, the expression levels of the 4 miRNAs were all significantly different between less active AS and more active AS, with higher levels in more active AS. Moreover, no significant correlations were found between the 4 miRNAs levels with the clinical characteristics in the patients with AS. Interestingly, the expression levels of miR-31, miR-155, and miR-16 in PBMCs were significantly positively correlated with the ESR in new AS patients but not old AS patients. CONCLUSIONS Our results suggest that miR-31 is overexpressed in PBMCs of AS patients. Furthermore, miR-31, miR-155, miR-16 and miR-181a may be associated with AS disease activity. PMID- 29150995 TI - Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis: A Randomized Clinical Trial. AB - Importance: Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial. Objective: To determine the efficacy and safety of venous PTA in patients with MS and CCSVI. Design, Setting, and Participants: We analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have CCSVI on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6 MS centers in Italy. The trial began in August 2012 and concluded in March 2016; data were analyzed from April 2016 to September 2016. The analysis was intention to treat. Interventions: Patients were randomly allocated (2:1) to either venous PTA or catheter venography without venous angioplasty (sham). Main Outcomes and Measures: Two primary end points were assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on magnetic resonance imaging, including the proportion of lesion-free patients. Combined lesions included T1 gadolinium-enhancing lesions plus new or enlarged T2 lesions. Results: Of the included 115 patients with relapsing remitting MS, 76 were allocated to the PTA group (45 female [59%]; mean [SD] age, 40.0 [10.3] years) and 39 to the sham group (29 female [74%]; mean [SD] age, 37.5 [10.6] years); 112 (97.4%) completed follow-up. No serious adverse events occurred. Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups (41.7% vs 48.7%; odds ratio, 0.75; 95% CI, 0.34-1.68; P = .49). The mean (SD) number of combined lesions on magnetic resonance imaging at 6 to 12 months were 0.47 (1.19) in the PTA group vs 1.27 (2.65) in the sham group (mean ratio, 0.37; 95% CI, 0.15-0.91; P = .03: adjusted P = .09) and were 1.40 (4.21) in the PTA group vs 1.95 (3.73) in the sham group at 0 to 12 months (mean ratio, 0.72; 95% CI, 0.32-1.63; P = .45; adjusted P = .45). At follow-up after 6 to 12 months, 58 of 70 patients (83%) in the PTA group and 22 of 33 (67%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 2.64; 95% CI, 1.11-6.28; P = .03; adjusted P = .09). At 0 to 12 months, 46 of 73 patients (63.0%) in the PTA group and 18 of 37 (49%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 1.80; 95% CI, 0.81-4.01; P = .15; adjusted P = .30). Conclusion and Relevance: Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS. Trial Registration: clinicaltrials.gov Identifier: NCT01371760. PMID- 29150996 TI - The SEP-1 quality mandate may be harmful: How to drown a patient with 30 mL per kg fluid! PMID- 29150997 TI - The future of evidence-based medicine: is the frog still boiling? PMID- 29150998 TI - A whiter shade of pale: the ongoing challenge of haemorrhagic shock. PMID- 29150999 TI - Focus on focus: lack of coherence between systemic and microvascular indices of oedema formation. AB - BACKGROUND: Fluid therapy remains a cornerstone of therapy in shock states. However, fluid overloading ultimately results in oedema formation which is related to excess morbidity and mortality. Handheld microscopes are now frequently used to study the sublingual microcirculation. As a corollary, these devices measure focal distance, or surface to capillary distance. Physiologically, this could represent a microvascular index of oedema formation and could have the potential to guide fluid therapy. This potential tool should be investigated, especially given the frequently reported lack of coherence between systemic and microvascular parameters in the critically ill. Therefore, we set out to assess the correlation between microvascular focal distance and systemic indices of oedema formation, specifically fluid balance and weight gain. METHODS: Following ex vivo testing of focal distance measurement reliability, we conducted a prospective observational cohort study in patients admitted to the intensive care unit of our university teaching hospital. We determined surface to capillary distance using sidestream dark field (SDF) and incident dark field (IDF) imaging by assessing the focal distance point or object distance range at which a sharp recording could be made. Measurements were performed in post cardiac surgery patients and in patients following emergency admission at two time points separated by at least several hours. Data on fluid balance, weight and weight gain were collected simultaneously. RESULTS: Sixty patients were included. The focal setting, focus point for SDF and the object distance range for IDF did not differ significantly between time points. Focus was not correlated with difference in fluid balance or weight gain. CONCLUSIONS: There is a lack of coherence between surface to capillary distance as determined by SDF or IDF imaging and fluid balance or weight gain. Thus, focal distance as a microvascular index of oedema formation cannot currently be used as a proxy for systemic indices of oedema formation. However, given the lack of coherence, further research should determine whether focal distance may provide better guidance for fluid therapy than traditional markers of overzealous fluid administration. RESULTS: Sixty patients were included. Focal setting, focus point for SDF and an object distance range for IDF did not differ significantly between time points. Focus was not correlated with difference in fluid balance or weight gain. CONCLUSIONS: There is a lack of coherence between surface to capillary distance as determined by SDF or IDF imaging and fluid balance or weight gain. Thus, focal distance as a microvascular index of edema formation cannot currently be used as a proxy for systemic indices of edema formation. However, given the lack of coherence, further research should determine whether focal distance may provide better guidance for fluid therapy than traditional markers of overzealous fluid administration. PMID- 29151000 TI - Implementing clinical practice changes in critical care: lessons learned in a national collaborative of over 60 ICU teams. AB - Improving care in the intensive care unit (ICU) is a global area of focus for clinicians worldwide. The complexity of the ICU environment, compounded by multiple patient comorbidities and high acuity levels, makes the ICU a unique and challenging area of clinical practice. The essence of quality improvement - designing and implementing strategies to enhance care - fit well with the ICU setting. However, implementing clinical change is challenging, regardless of the clinical setting. A national collaborative targeting ICU settings was initiated which provided a number of lessons learned regarding implementing quality of care initiatives in critical care. This article highlights quality improvement strategies for implementing clinical practice changes in the ICU to enhance care, based on reports from over 60 ICUs participating in the collaborative. PMID- 29151001 TI - Intravenous fluid therapy for hospitalized and critically ill children: rationale, available drugs and possible side effects. AB - Human beings are constituted mainly of water. In particular, children's total body water might reach 75-80% of their body weight, compared to 60-70% in adults. It is therefore not surprising, that children, especially hospitalized newborns and infants, are markedly prone to water and electrolyte imbalances. Parenteral fluid therapy is a cornerstone of medical treatment and is thus of exceptional relevance in this patient population. It is crucial to appreciate the fact that intravenous fluids are drugs with very different characteristics, different indications, contraindications and relevant side effects. In the present review, we will summarize the physiology and pathophysiology of water and electrolyte balance, underlining the importance and high prevalence of non-osmotic antidiuretic hormone release in hospitalized and critically ill children. Furthermore, we will discuss the characteristics and potential side effects of available crystalloids for the paediatric population, making a clear distinction between fluids that are hypotonic or isotonic as compared to normal plasma. Finally, we will review the current clinical practice regarding the use of different parenteral fluids in children, outlining both the current consensus on fluids employed for resuscitation and replacement and the ongoing debate concerning parenteral maintenance fluids. PMID- 29151002 TI - Management of arrhythmia in sepsis and septic shock. AB - The occurrence of supraventricular arrhythmias is associated with an unfavourable prognosis in septic shock. Available trials are difficult to apply in sepsis and septic shock patients due to included cohorts, control groups and because "one size does not fit all". The priorities in the critically ill are maintenance of the sinus rhythm and diastolic ventricular filling. The rate control modality should be reserved for chronic AF and in situations when the sinus rhythm is difficult to maintain due to extreme stress conditions resulting from a high dosage of vasoactive agents. Electric cardioversion is indicated in unstable patients with an absence of contraindications and is more feasible in combination with an antiarrhythmic agent. Besides amiodarone being preferred for its lower cardiodepressant side effect compared to other agents, drugs with a different degree of betablocking activity are very useful in supraventricular arrhythmias and septic shock, providing echocardiography is routinely used to support their indications within the current summary of product characteristics. A typical patient benefiting from propafenone is without significant structural heart disease, i.e. typically with normal to moderately reduced left ventricular systolic function. Future research should be channelled towards echocardiography guided prospective controlled trials on antiarrhythmic therapy which may clarify the issue of rhythm versus rate control, the effects of various antiarrhythmic drugs, and a place for electric cardioversion in critically ill patients in septic shock. PMID- 29151003 TI - Lung ultrasound in the critically ill (LUCI): A translational discipline. AB - In the early days of ultrasound, it was not a translational discipline. The heart was claimed by cardiologists, with others, such as gynaecologists, urologists and vascular surgeons claiming their part while the rest was given to radiologists. Only recently, ultrasound transgressed and crossed the usual borders between the different disciplines, such as emergency and critical care medicine. The advent of portable machines in the early 1980s, allowed the critical care physician to perform bedside ultrasound, and the development of whole body critical care ultrasound (CCUS) was born. It may sound cynical that radiologists were the first to state that diagnostic sonography was truly the next stethoscope: poorly utilized by many but understood by few. Exactly the same radiologists then abandoned the use of ultrasound outside the radiology department, leaving a vast domain to other disciplines eager to welcome the modern stethoscope. In this review, we list the possibilities of lung ultrasound as a translational holistic discipline. PMID- 29151004 TI - Differentiation of wood-derived vanillin from synthetic vanillin in distillates using gas chromatography/combustion/isotope ratio mass spectrometry for delta13 C analysis. AB - RATIONALE: Typical storage in oak barrels releases in distillates different degradation products such as vanillin, which play an important role in flavour and aroma. The addition of vanillin, as well as other aroma compounds, of different origin is prohibited by European laws. As vanillin samples from different sources have different delta13 C values, the delta13 C value could be used to determine whether the vanillin is authentic (lignin-derived), or if it has been added from another source (e.g. synthetic). METHODS: The delta13 C values for vanillin derived from different sources, including natural, synthetic and tannins, were measured by gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS), after diethyl ether addition and/or ethanol dilution. A method for analysing vanillin in distillates after dichloromethane extraction was developed. Tests were undertaken to prove the reliability, reproducibility and accuracy of the method with standards and samples. Distillate samples were run to measure the delta13 C values of vanillin and to compare them with values for other sources of vanillin. RESULTS: delta13 C values were determined for: natural vanillin extracts (-21.0 to -19.30/00, 16 samples); vanillin ex-lignin ( 28.20/00, 1 sample); and synthetic vanillin (-32.6 to -29.30/00, 7 samples). Seventeen tannin samples were found to have delta13 C values of -29.5 to 26.70/00, which were significantly different (p < 0.05) from those of the natural and synthetic vanillins. The vanillin delta13 C values measured in distillates ( 28.9 to -25.70/00) were mainly in the tannin range, although one spirit ( 32.50/00) was found to contain synthetic vanillin. CONCLUSIONS: The results show that synthetic vanillin added to a distillate could be differentiated from vanillin derived from oak barrels by their respective delta13 C values. The GC/C/IRMS method could be a useful tool in the determination of adulteration of distillates. PMID- 29151005 TI - Synthesis of a novel polymeric magnetic solid phase extraction adsorbent for selective extraction of amphetamine from urine samples coupled with high performance liquid chromatography. AB - A novel pH-responsive block copolymer (Poly ethylene glycol-b-poly (N,N dimethylaminoethylmethacrylate-co-maleic acid) was designed for the decoration and stabilization of magnetic nanoparticles (MNPs) as an efficient magnetic nano adsorbent for extraction of amphetamine (AM) from biological urine samples to be determined by high performance liquid chromatography-ultra violet detector (HPLC UV). Full characterization of the synthesized polymeric magnetic nanoparticles (PMNPs) were followed by various techniques like Fourier transform infrared (FT IR) spectroscopy, powder x-ray diffraction (XRD), scanning electron microscopy (SEM), and vibrating sample magnetometer (VSM). Important extraction parameters including pH, amount of sample volume, amount of adsorbent, type and amount of extraction organic solvent, time of extraction and desorption, agitation rate (rpm), and ionic strength of the extraction medium were studied and optimized. Under optimized extraction conditions, good linearity was observed in the concentration range of 30-2000 ng/mL for AM. The amount of the qe was calculated as 0.18 (mg/g). The method was applied in determination of AM from positive urine samples with the recovery of 99.84%. Results indicated that the proposed method could be applied in clinical and forensic laboratories for simple, selective, and fast determination of AM from urine samples. PMID- 29151006 TI - The practical update for family physicians in the diagnosis and management of overactive bladder and lower urinary tract symptoms. AB - OBJECTIVE: To provide family physicians with an up-to-date, practical overview of the diagnosis and management of overactive bladder (OAB) alone or with bladder outlet obstruction. MAIN MESSAGE: OAB is urinary urgency with or without incontinence, often accompanied by frequency and nocturia, in the absence of urinary tract infection and can affect both men and women. Men often have co existing OAB associated with bladder outlet obstruction, and benign prostatic hyperplasia. OAB can interfere with sleep, social activities, and sexual encounters, and it increases the risk of falls. CONCLUSION: Many patients with OAB seek initial evaluation and treatment from their family physicians. Optimal management of OAB by family physicians will improve patients' quality of life. More severe cases or 'red flags' uncovered while making the diagnosis, might warrant referral to a urologist. PMID- 29151007 TI - Sagittal Pelvic Orientation A Comparison of Two Methods of Measurement. AB - Pelvic tilt is an essential parameter in spinal deformity surgery and in acetabular positioning for total hip arthroplasty. However, the measurement of tilt varies between the hip and spine literature. Hip surgeons measure the anterior pelvic plane tilt, whereas spine surgeons measure the spinopelvic tilt. This study uses stereoradiography (EOS imaging SA, Paris, France) to assess the relationship and the inter-observer and intra-observer reliability of measuring these two common references for pelvic tilt. Retrospective analysis of full-body, standing stereoradiographic studies of 100 patients with varying degrees of spinal deformity was performed at a single institution. Assessment of anterior pelvic plane and spinopelvic tilt were undertaken by two orthopaedic surgeons and two orthopaedic residents using validated software. The pelvic incidence and sacral slope were also measured. The mean difference between anterior pelvic plane and spinopelvic tilt was 13.98 degrees +/- 7.04 degrees , and the values were linearly inversely related. Both measures of tilt were strongly correlated with each other. Spinopelvic tilt has greater inter- and intra-user reliability and was a more precise measurement than anterior pelvic plane. Spinopelvic tilt is a more precise and reliable measurement than the anterior pelvic plane tilt; however, both measurements are strongly correlated. The clinical implications of this are not completely understood; however, it may be important for hip surgeons when placing acetabular components with precision. Further investigation is needed to assess which is a more accurate reference for the placement of acetabular components in hip arthroplasty. PMID- 29151008 TI - Suture Anchor Repair of Complete Proximal Hamstring Ruptures A Cadaveric Biomechanical Evaluation. PMID- 29151009 TI - Risk Stratification, Triage, and Implementation of an Expedited Hip Fracture Treatment Protocol Is it Safe and Effective? AB - INTRODUCTION: The population of patients in the USA over the age of 65 is expected to significantly increase over the next 40 years. These patients are at increased risk for hip fractures and will pose a burden to providers in the near future. In order to provide high value care, providers will need to maintain positive outcomes, mitigate complications, and reduce overall cost burdens. This study was designed to investigate the safety and efficacy of a patient transfer protocol between a large academic medical center and a single specialty orthopaedic institution. The protocol was, in turn, designed to provide high value care to the patients by safely redirecting a large volume of patients to the single specialty institution. MATERIALS AND METHODS: Over one calendar year, data was prospectively gathered on all patients admitted to our academic center's ER with hip fractures. Patients were then triaged to high or low risk for transfer according to an established set of medical criteria. Patients deemed low risk for transfer were sent to our single specialty orthopaedic institution for management. Data capture and analysis were completed using MS Excel and SPSS, respectively. RESULTS: Patients treated at the single specialty orthopaedic institution experienced shorter overall hospital stays and were more likely to be discharged to home than a rehabilitation facility (6.35 versus 8.79 days, p < 0.0001; 22% versus 4%, p = 0.49). There was no significant delay in time to surgery for patients that were transferred (65 versus 79 hours, p = 0.18). CONCLUSION: The transfer protocol was both safe and effective for patients with hip fractures. Transferring patients for treatment at single specialty institutions has the potential to significantly reduce hospital stays and is more likely to result in discharge to home than a rehabilitation facility, thus successfully providing high value care to patients. PMID- 29151010 TI - Same Day Discharge After Total Joint Arthroplasty The Future May Be Now. AB - Total joint arthroplasty has traditionally been performed as an inpatient procedure to mitigate the risks of perioperative complications, limited mobility, and pain control issues. Reducing readmissions and complications is increasingly important with the push toward outcomes based reimbursement. Nonetheless, there is a definite trend toward not only shortening postoperative length of stay but also toward considering a same day discharge arthroplasty model in appropriately selected patients. In this review, we outline the literature evidence regarding same day discharge in total joint arthroplasty and discuss our own institutional guidelines for appropriate patient selection as well as contraindications. PMID- 29151011 TI - The Association Between Scholarly Impact and National Institutes of Health Funding in Orthopaedic Surgery. AB - The assessment of scholarly productivity assumes a strong role in evaluating faculty in academic orthopaedic surgery. The investigators examine the association between scholarly impact, as measured by the h-index, and National Institutes of Health (NIH) funding in orthopaedic surgery. Orthopaedic surgery faculty from 20 randomly chosen departments that received NIH-funding were compared to non-NIH funded faculty from the same departments. Faculty members in orthopaedic surgery departments who received NIH funding had higher scholarly impact as measured by h-index than their non-funded peers (h = 11.98 versus 4.45; p < 0.0001). This relationship holds across academic ranks, terminal degrees, and institutions. Investigators with higher academic rank had higher scholarly impact (h = assistant 3.29 versus associate 5.12 versus full professor 7.94; p < 1 x 10 7) as well as higher NIH-funding (assistant $16,580 versus associate $26,368 versus full professor $113,129; p < 1 x 10-7). Increasing individual NIH funding is correlated with elevated scholarly impact (beta = 4.64; p < 0.0001). Increasing total departmental NIH funding is correlated to increased departmental scholarly impact (beta = 1.04; p < 0.0001). The h-index is strongly associated with NIH funding, academic rank, and sole PhD holding faculty. Increasing scholarly impact is also correlated with higher NIH funding. The h-index is an objective and easily calculable measure of assessing individual research productivity. PMID- 29151012 TI - The Role and Timing of Treatment Strategies During Two-Stage Revision for Periprosthetic Joint Infections. AB - INTRODUCTION: Prosthetic joint infection continues to be a source of significant morbidity to patients and an economic burden to society as a whole. Two-stage revision is the current gold standard for treatment of periprosthetic joint infection in North America. Despite this, much discussion persists about treatment strategies surrounding the interim of the two-stage revision and treatment beyond reimplantation. The aim of this review is to answer some of these questions, specifically: are C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) helpful prior to reimplantation, is aspiration helpful, what is the role and timing for systemic antibiotics, and is there a role for oral suppression following second-stage reimplantation? METHODS: A literature review was completed in an attempt to address unanswered questions associated with two-stage reimplantation. Investigators' recommendations and current practices are described. RESULTS: ESR and CRP are less reliable in the interim of a two-stage revision than for diagnosis of infection in a primary total joint arthroplasty. There is inconclusive evidence regarding the utility of joint aspiration in two-stage revisions. Additionally, no evidence has been developed for length of IV antibiotic treatment after second-stage reimplantation, and in a few studies, oral antibiotic suppression has shown some benefit in reducing reinfection rates. CONCLUSION: The question of optimum treatment strategies has yet to be answered: attempts are underway to obtain suitable data with multi center studies and large patient populations. Periprosthetic joint infection is a serious and life altering complication and with continued research we can further clarify treatment strategies. PMID- 29151013 TI - Decreasing the Incidence of Surgical Site Infections Following Joint Replacement Surgery. AB - OBJECTIVE: Despite the generalized use of prophylactic antibiotics in orthopaedic surgery, Surgical Site Infections (SSIs) are still a major source of morbidity, mortality, and hospital cost. This is due in part to the increasing prevalence of antibiotic resistant organisms. METHODS: A review of local epidemiology, the importance of an antibiotic stewardship program, patient optimization, and risk stratification options to reduce SSIs. RESULTS: The proportion of revisions due to infection is projected to rise rapidly over the next 25 years. The economic burden of infections is expected to exceed 50% of the inpatient resources available for revision arthroplasties in 2016 total hip arthroplasty (THA) and 2030 total knee arthroplasty (TKA). CONCLUSION: Appropriate evidence-based epidemiological strategies must be implemented to reduce SSIs. PMID- 29151014 TI - Consent in Elective Hip Arthroplasty What Has Changed Over the Last 15 Years? AB - PURPOSE: It is regular practice that patients undergoing orthopaedic procedures particularly those related to arthroplasty are given both verbal and written information prior to their surgery. The aim of this study was to complete a 15 year audit cycle by assessing the patient understanding of the consent process in elective orthopaedic surgery following the introduction of patient information booklets, DVDs, web links, and "joint school." METHODS: 150 patients (50 patients in each cycle of the study) undergoing primary total hip arthroplasty were counselled about the audit and prospectively enrolled. Consent was obtained by either the specialist registrar or by the consultant. All patients were asked to complete a questionnaire relating to the consent process. The same questionnaire has been used for the past 15 years. RESULTS: There was no significant difference in the overall scores of the questionnaires over the past 15 years. There was no significant improvement in the number of patients stating awareness that infection, dislocation, and mortality are potential complications associated with hip arthroplasty. CONCLUSION: There have been several technological advances over the past 15 years in an attempt to improve patients' understanding and comprehension of the consent process in total hip replacement surgery. This study has shown that despite these efforts, there has been very little improvement in patients' understanding. However, patients remain satisfied with this extra information. The remaining underlying question is whether patients actually want to know all the potential complications that can occur. PMID- 29151015 TI - Diffuse Idiopathic Skeletal Hyperostosis (DISH) as a Cause of Failure Following Distal Clavicle Excision A Case Report and Review of the Literature. AB - Diffuse idiopathic skeletal hyperostosis (DISH) is common spinal condition characterized by increased calcification and ossification of ligaments and entheses, typically in the anterior aspect of the spine. However, extraspinal manifestations of the disease can occur and depending on the degree and location of involvement, may become symptomatic. We present the case of a 63-year-old male with a history of DISH, who failed initial open distal clavicle excision due to the postoperative development of heterotopic bone bridging across the acromioclavicular joint. Revision open distal clavicle excision coupled with postoperative heterotopic ossification prophylaxis led to a successful clinical and functional outcome without heterotopic bone recurrence. The case description is followed by a review of the extraspinal manifestations of DISH and the recommended prophylactic management in patients with DISH and similar risk factors for the development of heterotopic ossification. PMID- 29151016 TI - Osteomyelitis After Calcium Phosphate Subchondroplasty A Case Report. AB - Subchondroplasty is a relatively new procedure developed to treat bone marrow lesions by injecting a calcium phosphate bone substitute into the pathologic, subchondral area of bone under fluoroscopic guidance. The procedure is described as a minimally invasive strategy that provides reliable relief of pain while preserving the native joint with minimal risk of significant complications. No prospective, randomized clinical trials have reported the efficacy of the procedure. Here, we present the case of a 64-year-old healthy male who developed Staphylococcus aureus osteomyelitis following subchondroplasty requiring further surgical intervention and intravenous antibiotic therapy. PMID- 29151017 TI - Neuroleptic Malignant Syndrome Following Bilateral Cemented Total Hip Replacements. AB - Neuroleptic malignant syndrome (NMS) is a rare, serious complication caused by neuroleptic medications. It is characterized by rigidity, hyperthermia, tachycardia, leukocytosis, and an elevated creatine kinase (CK). We present a case of a 50-year-old male who underwent bilateral total hip replacements and subsequently developed NMS. This condition is typically triggered by the sudden introduction, omission, or change in dose of a neuroleptic; in contrast with previous case reports of post-surgical NMS, however, no such trigger was identifiable for our patient. Moreover, this is the first reported case of NMS after single-stage bilateral hip arthroplasty. Consequently, by presenting this case report we hope to make clinicians aware of the possibility of NMS occurring after hip arthroplasty in any patient taking longterm neuroleptics. PMID- 29151018 TI - Study of the NLRP3 inflammasome component genes and downstream cytokines in patients with type 2 diabetes mellitus with carotid atherosclerosis. AB - BACKGROUND: A role for the NLRP3 inflammasome has been reported in various diseases, such as diabetes mellitus, atherosclerosis (AS), nephropathy, rheumatism, and others, although limited information is available concerning the role of the NLRP3 inflammasome, interleukin-1beta (IL-1beta) and interleukin-18 (IL-18) in patients with type 2 diabetes mellitus (T2DM) and carotid atherosclerosis (CAS). Therefore, this cross-sectional study investigated these inflammatory components in patients with T2DM complicated with carotid atherosclerosis (T2DM + CAS). METHODS: A total of 107 inpatients or outpatients were included,including 81 T2DM + CAS patients and 26 T2DM patients. Patients with T2DM or T2DM + CAS were recruited to compare the expression levels of NLRP3 pathway genes (NLRP3, ASC and caspase-1 mRNA) and the serum IL-1beta and IL-18 concentrations. In the T2DM + CAS group, patients with thickened intima media thickness (IMT) and those with plaques were compared, and the correlation of the 5 variables with Crouse scores were analyzed. RESULTS: The expression of NLRP3 pathway genes except caspase-1 was significantly higher in patients with T2DM and CAS compared to T2DM patients. Serum IL-1beta and IL-18 concentrations shows no difference between the T2DM + CAS and T2DM group. In the T2DM + CAS group, the expression levels of the three inflammasome genes and IL-18 were increased in patients with thickened IMT compared to those with the plaque. All of the above factors negatively correlated with Crouse scores. CONCLUSION: NLRP3 inflammasome pathway activity is significantly increased in patients with AS and T2DM at the early stage of plaque formation. PMID- 29151019 TI - bcROCsurface: an R package for correcting verification bias in estimation of the ROC surface and its volume for continuous diagnostic tests. AB - BACKGROUND: Receiver operating characteristic (ROC) surface analysis is usually employed to assess the accuracy of a medical diagnostic test when there are three ordered disease status (e.g. non-diseased, intermediate, diseased). In practice, verification bias can occur due to missingness of the true disease status and can lead to a distorted conclusion on diagnostic accuracy. In such situations, bias corrected inference tools are required. RESULTS: This paper introduce an R package, named bcROCsurface, which provides utility functions for verification bias-corrected ROC surface analysis. The shiny web application of the correction for verification bias in estimation of the ROC surface analysis is also developed. CONCLUSION: bcROCsurface may become an important tool for the statistical evaluation of three-class diagnostic markers in presence of verification bias. The R package, readme and example data are available on CRAN. The web interface enables users less familiar with R to evaluate the accuracy of diagnostic tests, and can be found at http://khanhtoduc.shinyapps.io/bcROCsurface_shiny/ . PMID- 29151020 TI - Complications of regional citrate anticoagulation: accumulation or overload? AB - Regional citrate anticoagulation (RCA) is now recommended over systemic heparin for continuous renal replacement therapy in patients without contraindications. Its use is likely to increase throughout the world. However, in the absence of citrate blood level monitoring, the diagnosis of citrate accumulation, the most feared complication of RCA, remains relatively complex. It is therefore commonly mistaken with other conditions. This review aims at providing clarifications on RCA-associated acid-base disturbances and their management at the bedside. In particular, the authors wish to propose a clear distinction between citrate accumulation and net citrate overload. PMID- 29151021 TI - Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells. AB - Regulatory T cells play a crucial role in the homeostasis of the immune response. In addition to CD4+Foxp3+ regulatory T cells, several subsets of Foxp3- regulatory T cells, such as T helper 3 (Th3) cells and type 1 regulatory T (Tr1) cells, have been described in mice and human. Accumulating evidence shows that naive B cells contribute to tolerance and are able to promote regulatory T cell differentiation. Naive B cells can convert CD4+CD25- T cells into CD25+Foxp3- regulatory T cells, named Treg-of-B cells by our group. Treg-of-B cells express LAG3, ICOS, GITR, OX40, PD1, and CTLA4 and secrete IL-10. Intriguingly, B-T cell cell contact but not IL-10 is essential for Treg-of-B cells induction. Moreover, Treg-of-B cells possess both IL-10-dependent and IL-10-independent inhibitory functions. Treg-of-B cells exert suppressive activities in antigen-specific and non-antigen-specific manners in vitro and in vivo. Here, we review the phenotype and function of Foxp3+ regulatory T cells, Th3 cells, Tr1 cells, and Treg-of-B cells. PMID- 29151022 TI - Quality of care for people with multimorbidity - a case series. AB - BACKGROUND: Multimorbidity is becoming increasingly prevalent and presents challenges for healthcare providers and systems. Studies examining the relationship between multimorbidity and quality of care report mixed findings. The purpose of this study was to investigate quality of care for people with multimorbidity in the publicly funded healthcare system in Denmark. METHODS: To investigate the quality of care for people with multimorbidity different groups of clinicians from the hospital, general practice and the municipality reviewed records from 23 persons with multimorbidity and discussed them in three focus groups. Before each focus group, clinicians were asked to review patients' medical records and assess their care by responding to a questionnaire. Medical records from 2013 from hospitals, general practice, and health centers in the local municipality were collected and linked for the 23 patients. Further, two clinical pharmacologists reviewed the appropriateness of medications listed in patient records. RESULTS: The review of the patients' records conducted by three groups of clinicians revealed that around half of the patients received adequate care for the single condition which prompted the episode of care such as a hospitalization, a visit to an outpatient clinic or the general practitioner. Further, the care provided to approximately two-thirds of the patients did not take comorbidities into account and insufficiently addressed more diffuse symptoms or problems. The review of the medication lists revealed that the majority of the medication lists contained inappropriate medications and that there were incongruity in medication listed in the primary and secondary care sector. Several barriers for providing high quality care were identified. These included relative short consultation times in general practice and outpatient clinics, lack of care coordinators, and lack of shared IT-system proving an overview of the treatment. CONCLUSIONS: Our findings reveal quality of care deficiencies for people with multimorbidity. Suggestions for care improvement for people with multimorbidity includes formally assigned responsibility for care coordination, a change in the financial incentive structure towards a system rewarding high quality care and care focusing on prevention of disease exacerbation, as well as implementing shared medical record systems. PMID- 29151023 TI - Quadriceps force and anterior tibial force occur obviously later than vertical ground reaction force: a simulation study. AB - BACKGROUND: Although it is well known that quadriceps force generates anterior tibial force, it has been unclear whether quadriceps force causes great anterior tibial force during the early phase of a landing task. The purpose of the present study was to examine whether the quadriceps force induced great anterior tibial force during the early phase of a landing task. METHODS: Fourteen young, healthy, female subjects performed a single-leg landing task. Muscle force and anterior tibial force were estimated from motion capture data and synchronized force data from the force plate. One-way repeated measures analysis of variance and the post hoc Bonferroni test were conducted to compare the peak time of the vertical ground reaction force, quadriceps force and anterior tibial force during the single-leg landing. In addition, we examined the contribution of vertical and posterior ground reaction force, knee flexion angle and moment to peak quadriceps force using multiple linear regression. RESULTS: The peak times of the estimated quadriceps force (96.0 +/- 23.0 ms) and anterior tibial force (111.9 +/- 18.9 ms) were significantly later than that of the vertical ground reaction force (63.5 +/ 6.8 ms) during the single-leg landing. The peak quadriceps force was positively correlated with the peak anterior tibial force (R = 0.953, P < 0.001). Multiple linear regression analysis showed that the peak knee flexion moment contributed significantly to the peak quadriceps force (R 2 = 0.778, P < 0.001). CONCLUSION: The peak times of the quadriceps force and the anterior tibial force were obviously later than that of the vertical ground reaction force for the female athletes during successful single-leg landings. Studies have reported that the peak time of the vertical ground reaction force was close to the time of anterior cruciate ligament (ACL) disruption in ACL injury cases. It is possible that early contraction of the quadriceps during landing might induce ACL disruption as a result of excessive anterior tibial force in unanticipated situations in ACL injury cases. PMID- 29151024 TI - Insecticide resistance in Anopheles arabiensis from Ethiopia (2012-2016): a nationwide study for insecticide resistance monitoring. AB - BACKGROUND: Indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) remain the cornerstones of malaria vector control. However, the development of insecticide resistance and its implications for operational failure of preventative strategies are of concern. The aim of this study was to characterize insecticide resistance among Anopheles arabiensis populations in Ethiopia and describe temporal and spatial patterns of resistance between 2012 and 2016. METHODS: Between 2012 and 2016, resistance status of An. arabiensis was assessed annually during the long rainy seasons in study sites from seven of the nine regions in Ethiopia. Insecticide resistance levels were measured with WHO susceptibility tests and CDC bottle bioassays using insecticides from four chemical classes (organochlorines, pyrethroids, organophosphates and carbamates), with minor variations in insecticides tested and assays conducted between years. In selected sites, CDC synergist assays were performed by pre-exposing mosquitoes to piperonyl butoxide (PBO). In 2015 and 2016, mosquitoes from DDT and deltamethrin bioassays were randomly selected, identified to species-level and screened for knockdown resistance (kdr) by PCR. RESULTS: Intense resistance to DDT and pyrethroids was pervasive across Ethiopia, consistent with historic use of DDT for IRS and concomitant increases in insecticide-treated net coverage over the last 15 years. Longitudinal resistance trends to malathion, bendiocarb, propoxur and pirimiphos-methyl corresponded to shifts in the national insecticide policy. By 2016, resistance to the latter two insecticides had emerged, with the potential to jeopardize future long-term effectiveness of vector control activities in these areas. Between 2015 and 2016, the West African (L1014F) kdr allele was detected in 74.1% (n = 686/926) of specimens, with frequencies ranging from 31 to 100% and 33 to 100% in survivors from DDT and deltamethrin bioassays, respectively. Restoration of mosquito susceptibility, following pre-exposure to PBO, along with a lack of association between kdr allele frequency and An. arabiensis mortality rate, both indicate metabolic and target-site mutation mechanisms are contributing to insecticide resistance. CONCLUSIONS: Data generated by this study will strengthen the National Malaria Control Programme's insecticide resistance management strategy to safeguard continued efficacy of IRS and other malaria control methods in Ethiopia. PMID- 29151025 TI - A meta-analysis of positive airway pressure treatment for cardiovascular prevention: why mix apples and pears? PMID- 29151026 TI - Regional Validation and Recalibration of Clinical Predictive Models for Patients With Acute Heart Failure. AB - BACKGROUND: Heart failure clinical practice guidelines recommend applying validated clinical predictive models (CPMs) to support decision making. While CPMs are now widely available, the generalizability of heart failure CPMs is largely unknown. METHODS AND RESULTS: We identified CPMs derived in North America that predict mortality for patients with acute heart failure and validated these models in different world regions to assess performance in a contemporary international clinical trial (N=4133) of patients with acute heart failure treated with guideline-directed medical therapy. We performed independent external validations of 3 CPMs predicting in-hospital mortality, 60-day mortality, and 1-year mortality, respectively. CPM discrimination decreased in all regional validation cohorts. The median change in area under the receiver operating curve was -0.09 (range -0.05 to -0.23). Regional calibration was highly variable (90th percentile of absolute difference between smoothed observed and predicted values range <1% to >50%). Calibration remained poor after global recalibrations; however, region-specific recalibration procedures significantly improved regional performance (recalibrated 90th percentile of absolute difference range <1% to 5% across all regions and all models). CONCLUSIONS: Acute heart failure CPM discrimination and calibration vary substantially across different world regions; region-specific (as opposed to global) recalibration techniques are needed to improve CPM calibration. PMID- 29151027 TI - Plasma Nitrate and Incidence of Cardiovascular Disease and All-Cause Mortality in the Community: The Framingham Offspring Study. AB - BACKGROUND: Nitrate is a dietary component as well as an endogenously formed metabolite and source of the signaling molecule nitric oxide. Harmful as well as beneficial effects of nitrate have been advocated. Data regarding the prognostic relevance of plasma nitrate are limited. The aim of this study was to evaluate the prospective association of plasma nitrate with cardiovascular disease (CVD) and all-cause mortality. METHODS AND RESULTS: We assayed plasma nitrate in 2855 Framingham Offspring Study participants (mean age 59 years, 54% women) by gas chromatography-mass spectrometry and evaluated its association with all-cause mortality and incident CVD. On follow-up (median 17.3 years), 775 participants died and 522 developed new-onset CVD (of 2546 participants free of CVD at baseline). In multivariable models adjusting for standard risk factors, plasma nitrate was associated with an increased risk of death in participants (hazard ratio per unit increase in log-nitrate 1.21; 95% confidence interval, 1.04-1.40 [P=0.015]). The strength of the association was attenuated by additional adjustment for estimated glomerular filtration rate (hazard ratio, 1.16; 95% confidence interval, 1.00-1.35 [P=0.057]). In contrast, no evidence was found for an association of plasma nitrate with incident CVD (multivariable-adjusted hazard ratio per unit increase log-nitrate 1.08; 95% confidence interval, 0.89-1.31 [P=0.42]). CONCLUSIONS: In our prospective community-based investigation, a higher plasma nitrate concentration was associated with all-cause mortality but not with incident CVD. The association of nitrate with mortality may at least in part be attributable to its association with renal function. PMID- 29151028 TI - Variations in Use of Optimal Medical Therapy in Patients With Nonobstructive Coronary Artery Disease: A Population-Based Study. AB - BACKGROUND: There is a paucity of data on the need for optimal medical therapy (OMT) in nonobstructive coronary artery disease . We sought to understand if there was variation in the use of OMT between hospitals for patients with nonobstructive coronary artery disease, the factors associated with such variation, and its clinical consequences. METHODS AND RESULTS: Using a population level clinical registry in Ontario, Canada, we identified all patients >66 years undergoing coronary angiography for the indication of stable angina, who had nonobstructive coronary artery disease between November 1, 2010, and October 31, 2013. Hierarchical multivariable logistic models were developed to identify the factors associated with OMT use, with median odds ratio used to quantify the degree of variation between hospitals not explained by the modeled risk factors. Clinical outcomes of interest were all-cause mortality and rehospitalization, with follow-up until March 31, 2015. Our cohort consisted of 5413 patients, of whom 2554 (47.2%) were receiving OMT within 1 year. There was a 2-fold variation in OMT across hospitals (30.4%-61.8%). The variation between hospitals was fully explained by preangiography medication use (median odds ratio of 1.21 in the null model and 1.03 in the full model). There was no difference in risk-adjusted mortality (hazard ratio, 0.94; 95% confidence interval, 0.76-1.16); however, patients receiving OMT had a lower risk of all-cause hospital readmission (hazard ratio, 0.89; 95% confidence interval, 0.84-0.95). CONCLUSIONS: There is wide variation in the use of OMT in patients with nonobstructive coronary artery disease, the major driver of which is differences in baseline medication use. PMID- 29151029 TI - Inorganic Nitrate: Marker or Mediator of Mortality? PMID- 29151030 TI - Occurrence and Features of Childhood Myocarditis: A Nationwide Study in Finland. AB - BACKGROUND: Epidemiology of myocarditis in childhood is largely unknown. Men are known to have a higher incidence of myocarditis than women in adults aged <50 years, but whether this is true by sex in pediatric age groups is unknown. We set out to study the occurrence and potential sex differences of myocarditis in a general pediatric population. METHODS AND RESULTS: Data of all hospital admissions with myocarditis in Finland occurring in patients aged <=15 years from 2004 to 2014 were collected from a mandatory nationwide registry. All patients with myocarditis as a primary, secondary, or tertiary cause of admission were included. Total and age- and sex-specific incidence rates were calculated using corresponding population data. There were 213 admissions with myocarditis in pediatric patients. Myocarditis was the primary cause of admission in 86%. The overall incidence rate of myocarditis was 1.95/100 000 person-years. Of all patients, 77% were boys, but sex differences in incidence rates were age dependent. In children aged 0 to 5 years, there was no sex difference in the occurrence of myocarditis. Boys aged 6 to 10 years had a higher incidence rate compared with girls (72% boys; incidence rate ratio: 2.46; 95% confidence interval, 1.03-5.89; P=0.04). Sex difference further increased in children aged 11 to 15 years (80% boys; incidence rate ratio: 3.5; 95% confidence interval, 2.68-5.67; P<0.0001). CONCLUSIONS: Myocarditis leading to hospital admission is relatively uncommon in children, but occurrence of myocarditis increases with age. There is no sex difference in the risk of myocarditis during the first 6 years of life, but boys have a significantly higher risk at ages 6 to 15 years. PMID- 29151031 TI - Significant Association Between Low Mitochondrial DNA Content in Peripheral Blood Leukocytes and Ischemic Stroke. AB - BACKGROUND: Cumulative evidence has shown that low mitochondrial DNA (mtDNA) content is related to elevated oxidative stress and atherosclerosis, which play important roles in ischemic stroke. The objective of this study was to explore the association between mtDNA content in peripheral blood leukocytes and ischemic stroke. METHODS AND RESULTS: A total of 350 patients with first-ever ischemic stroke and 350 healthy controls were recruited in this case-control study. The mtDNA content in peripheral blood leukocytes was determined by quantitative real time polymerase chain reaction. The levels of oxidized glutathione, reduced glutathione, and 8-hydroxy-2'-deoxyguanosine were measured by ELISA kits. Multivariate logistic regression models were used to analyze the relationship between mtDNA content in peripheral blood leukocytes and ischemic stroke. Our results show that mtDNA content of patients with ischemic stroke was notably lower compared with controls. A significant association was found between low mtDNA content and ischemic stroke. Furthermore, significant interactions were identified between low mtDNA and proven risk factors in patients with ischemic stroke. The levels of oxidized glutathione and 8-hydroxy-2'-deoxyguanosine were significantly greater in patients with ischemic stroke compared with controls. CONCLUSIONS: Our results demonstrate that low mtDNA content in peripheral blood leukocytes is associated with ischemic stroke. The relationship of low mtDNA content and ischemic stroke was particularly notable in individuals who had low mtDNA content combined with diabetes mellitus, metabolic syndrome, or cigarette smoking. Oxidative stress may be one of the contributory factors to decreased mtDNA content in patients with ischemic stroke. PMID- 29151032 TI - Elevated Baseline Serum Fibrinogen: Effect on 2-Year Major Adverse Cardiovascular Events Following Percutaneous Coronary Intervention. AB - BACKGROUND: Elevated fibrinogen is associated with short-term major adverse cardiovascular events (MACE) after percutaneous coronary intervention, but the relation with late MACE is unknown. METHODS AND RESULTS: Baseline demographics and 2-year MACE were recorded among subjects undergoing nonemergent percutaneous coronary intervention. A total of 332 subjects (66.6+/-19.5 years, 69.9% male, 25.3% acute coronary syndrome) were enrolled. Two-year MACE (periprocedural myocardial infarction 9.0%, rehospitalization 6.3%, revascularization 12.7%, non periprocedural myocardial infarction 4.5%, stent thrombosis 0.9%, stroke 1.8%, and death 0.6%) were associated with higher fibrinogen (352.8+/-123.4 mg/dL versus 301.6+/-110.8 mg/dL; P<0.001), longer total stent length (40.1+/-25.3 mm versus 32.1+/-19.3 mm; P=0.004), acute coronary syndrome indication (38.7% versus 17.8%; P<0.001), number of bare-metal stents (0.5+/-1.1 versus 0.2+/-0.5; P=0.002), and stent diameter <=2.5 mm (55.8% versus 38.4%, P=0.003). No relation between platelet reactivity and 2-year MACE was observed. Fibrinogen >=280 mg/dL (odds ratio [OR] 3.0, confidence interval [CI], 1.6-5.4, P<0.001), total stent length >=32 mm (OR 2.2, CI, 1.3-3.8, P<0.001), acute coronary syndrome indication (OR 4.1, CI, 2.3-7.5, P<0.001), any bare-metal stents (OR 3.2, CI, 1.6-6.1, P<0.001), and stent diameter <=2.5 mm (OR 2.0, CI, 1.2-3.5, P=0.010) were independently associated with 2-year MACE. Following a landmark analysis excluding periprocedural myocardial infarction, fibrinogen >=280 mg/dL remained strongly associated with 2-year MACE (37.0% versus 17.4%, log-rank P<0.001). CONCLUSIONS: Elevated baseline fibrinogen level is associated with 2-year MACE after percutaneous coronary intervention. Acute coronary syndrome indication for percutaneous coronary intervention, total stent length implanted, and use of bare metal stents or smaller-diameter stents are also independently associated with 2 year MACE, while measures of on-thienopyridine platelet reactivity are not. PMID- 29151033 TI - Induction of Dendritic Cell-Mediated Activation of T Cells From Atherosclerotic Plaques by Human Heat Shock Protein 60. AB - BACKGROUND: Atherosclerosis is characterized by the presence of activated immune competent cells including dendritic cells (DCs) and T cells, dead cells, and oxidized low-density lipoprotein. HSP60 (Heat shock protein 60) has been implicated in atherosclerosis. A plasma protein, Annexin A5, has atheroprotective properties. METHODS AND RESULTS: Human DCs differentiated from peripheral blood monocytes were treated with human HSP60 or HSP90 and autologous T cells were cocultured with these pretreated DCs (mDCs). HSP60 induced mDCs and T-cell activation as determined by FACScan (Fluorescence associated cell scan), gene activation, and cytokine production. HSP60-induced T-cell activation was partly major histocompatibility complex class II-dependent. T cells exposed to HSP60 treated mDCs produced interferon-gamma, interleukin-17, but not transforming growth factor-beta. HSP60 did not promote expression of Toll-like receptors 2 or 4. HSP90 promoted mDCs maturation but had no effect on T-cell activation. Annexin A5 inhibited HSP60-proinflammatory Th1/Th17 effects on mDCs and T cells, and partly bound HSP60. Further, Annexin A5 inhibited HSP-induced activation of mDCs and also oxidized low-density lipoprotein-induced HSP-production from mDCs. Experiments on mDCs and T cells derived from carotid atherosclerotic plaques from patients with symptomatic carotid disease gave similar results as from blood donors. CONCLUSIONS: HSP60 induces mDCs activation and partly major histocompatibility complex class II-dependent activation of blood- and plaque derived T cells, which is mostly of Th1/Th17 type. HSP60 could thus be an important T-cell antigen in plaques, and also mediate oxidized low-density lipoproteins immunogenic effects on DC-T-cell activation, promoting plaque rupture and clinical manifestations of cardiovascular disease. Annexin A5 inhibits both oxidized low-density lipoprotein-induced HSP60, and HSP60-mediated immune activation, which suggests a potential therapeutic role. PMID- 29151034 TI - Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). AB - BACKGROUND: IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) showed that adding the nonstatin ezetimibe to statin therapy further reduced cardiovascular events in patients after an acute coronary syndrome. In a prespecified analysis, we explore results stratified by sex. METHODS AND RESULTS: In IMPROVE-IT, patients with acute coronary syndrome and low density lipoprotein cholesterol of 50 to 125 mg/dL were randomized to placebo/simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg. They were followed up for a median of 6 years for the primary composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, coronary revascularization >=30 days, and stroke. Among 18 144 patients in IMPROVE-IT, 4416 (24%) were women. At 12 months, the addition of ezetimibe to simvastatin significantly reduced low-density lipoprotein cholesterol from baseline compared with simvastatin monotherapy in men and women equally (absolute reduction, 16.7 mg/dL in men and 16.4 mg/dL in women). Women receiving ezetimibe/simvastatin had a 12% risk reduction over those receiving placebo/simvastatin for the primary composite end point (hazard ratio, 0.88; 95% confidence interval, 0.79-0.99) compared with a 5% reduction for men (hazard ratio, 0.95; 95% confidence interval, 0.90-1.01; P=0.26 for interaction). When the total number of primary events was considered, women had an 18% reduction with the addition of ezetimibe (relative risk, 95% confidence interval, 0.81; 0.71-0.94) and men had a 6% reduction (relative risk, 0.94; 95% confidence interval, 0.87-1.02; P=0.08 for interaction). The addition of ezetimibe did not increase the rates of safety events in either women or men. CONCLUSIONS: IMPROVE-IT demonstrated that the benefit of adding ezetimibe to statin is present in both women and men, with a good safety profile supporting the use of intensive, combination, lipid-lowering therapy to optimize cardiovascular outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00202878. PMID- 29151035 TI - Hypertension in Obese Black Women is Not Caused by Increased Sympathetic Vascular Tone. AB - BACKGROUND: Black women have one of the highest prevalence rates of hypertension and obesity in the United States. We previously reported that sympathetic activation induced by obesity is a significant contributor to hypertension in white patients. It is unknown whether sympathetic activity similarly contributes to hypertension in obese black women. METHODS AND RESULTS: We studied 42 obese women (16 white, body mass index 36+/-4 kg/m2, 44% with hypertension; 26 black, body mass index 35+/-4 kg/m2, 46% with hypertension). Antihypertensive medications were discontinued for 2 weeks before the day of the study. All patients underwent complete autonomic blockade with trimethaphan at a dosage of 4 mg/min. Resting sympathetic activity determined from muscle sympathetic nerve recordings was similar between obese black women with hypertension and those with normotension. In whites, sympathetic activity was elevated in obese patients with hypertension compared with normotension; the decrease in mean arterial blood pressure produced by trimethaphan was greater in obese white patients with hypertension compared with those with normotension (-26.8+/-9.7 mm Hg versus 14.8+/-7.9 mm Hg, P=0.02). In contrast, there was no difference in the depressor responses induced by trimethaphan between obese black women with hypertension and those with normotension (-15.5+/-10.5 mm Hg versus -12.3+/-10.2 mm Hg, P=0.45). Mean arterial blood pressure remained elevated in obese blacks with hypertension compared with those with normotension during trimethaphan infusion (83.7+/-15.0 mm Hg versus 71.7+/-9.8 mm Hg, P=0.02). Heart rate increased similarly with trimethaphan between white (P=0.11) and black (P=0.76) women with hypertension and normotension. CONCLUSIONS: These findings suggest that sympathetic activity does not contribute to hypertension in obese black women and provide further evidence for racial differences in hypertension mechanisms. PMID- 29151036 TI - Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension: A Double-Blind Randomized Controlled Trial. AB - BACKGROUND: Guidelines for hypertension vary in their preference for initial combination therapy or initial monotherapy, stratified by patient profile; therefore, we compared the efficacy and tolerability of these approaches. METHODS AND RESULTS: We performed a 1-year, double-blind, randomized controlled trial in 605 untreated patients aged 18 to 79 years with systolic blood pressure (BP) >=150 mm Hg or diastolic BP >=95 mm Hg. In phase 1 (weeks 0-16), patients were randomly assigned to initial monotherapy (losartan 50-100 mg or hydrochlorothiazide 12.5-25 mg crossing over at 8 weeks), or initial combination (losartan 50-100 mg plus hydrochlorothiazide 12.5-25 mg). In phase 2 (weeks 17 32), all patients received losartan 100 mg and hydrochlorothiazide 12.5 to 25 mg. In phase 3 (weeks 33-52), amlodipine with or without doxazosin could be added to achieve target BP. Hierarchical primary outcomes were the difference from baseline in home systolic BP, averaged over phases 1 and 2 and, if significant, at 32 weeks. Secondary outcomes included adverse events, and difference in home systolic BP responses between tertiles of plasma renin. Home systolic BP after initial monotherapy fell 4.9 mm Hg (range: 3.7-6.0 mm Hg) less over 32 weeks (P<0.001) than after initial combination but caught up at 32 weeks (difference 1.2 mm Hg [range: -0.4 to 2.8 mm Hg], P=0.13). In phase 1, home systolic BP response to each monotherapy differed substantially between renin tertiles, whereas response to combination therapy was uniform and at least 5 mm Hg more than to monotherapy. There were no differences in withdrawals due to adverse events. CONCLUSIONS: Initial combination therapy can be recommended for patients with BP >150/95 mm Hg. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00994617. PMID- 29151038 TI - Initial Single-Pill Blood Pressure-Lowering Therapy: Should It Be for Most People? PMID- 29151037 TI - Combining ECG Criteria for Left Ventricular Hypertrophy Improves Risk Prediction in Patients With Hypertension. AB - BACKGROUND: Patients with hypertension with ECG left ventricular hypertrophy (LVH) have higher cardiovascular morbidity and mortality, but single ECG criteria may underestimate risk. Whether continued presence or new development of ECG LVH by 2 criteria can further concentrate risk during blood pressure lowering is unclear. METHODS AND RESULTS: Incident stroke, myocardial infarction, cardiovascular death, the composite of these outcomes, and all-cause mortality were examined in relation to the presence of on-treatment ECG LVH by Cornell product and/or Sokolow-Lyon voltage during a mean of 4.8+/-0.9 years follow-up in 9193 patients with hypertension randomized to losartan- or atenolol-based regimens. Patients were categorized into 4 groups according to the presence or absence of ECG LVH by each criterion at baseline and yearly during the study. At baseline, LVH by both criteria was present in 960 patients (10.4%). Compared with the absence of ECG LVH by both criteria, persistence or development of ECG LVH by both criteria entered as a time-varying covariate was associated with >3-fold increased risks of events in multivariable Cox analyses adjusting for randomized treatment, baseline risk factors, and on-treatment heart rate and systolic and diastolic blood pressures. Patients with ECG LVH by either Cornell product or Sokolow-Lyon voltage had 45% to 140% higher risks of all end points. CONCLUSIONS: Persistence or development of ECG LVH by both Cornell product and Sokolow-Lyon voltage criteria during antihypertensive therapy is associated with markedly increased risks of cardiovascular end points and all-cause mortality. Further study is indicated to determine whether additional therapy in these patients can reduce their risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00338260. PMID- 29151039 TI - Pretibial myxoedema without thyroid associated orbitopathy in a patient with Graves' disease. PMID- 29151040 TI - Meningoencephalitis in a Royal Marine after skinning reindeer in Norway. AB - Meningoencephalitis presenting in service personnel overseas may present a diagnostic challenge due to the broad range of potential differential diagnosis as well as the requirement for rapid assessment and treatment. A 25-year-old Royal Marine was evacuated to the Royal Centre for Defence Medicine in Birmingham, UK, with a history of rash consistent with erythema chronicum migrans, a seizure, and lymphocytic pleocytosis after skinning reindeer in Norway. Neuroborreliosis was suspected and empirical antibiotics were administered. Despite subsequent negative serology for Borrelia burgdorferi, given the clinical features and lymphocytic pleocytosis, an atypical presentation of neuroborreliosis remains a possible diagnosis in this scenario. This case serves to illustrate that British military personnel on exercise are potentially at risk of contracting borreliosis both in the UK and abroad, serological tests can be unreliable, and the differential diagnosis of meningoencephalitis can be broad with specialist input often required. PMID- 29151041 TI - Assessment of thrombus length in acute ischemic stroke by post-contrast magnetic resonance angiography. AB - OBJECTIVES: Post-contrast magnetic resonance angiography (PC-MRA) enables visualization of vessel segments distal to an intra-arterial thrombus in acute ischemic stroke. We hypothesized that PC-MRA also allows clot length measurement in different intracranial vessels. METHODS: Patients with MRI-confirmed ischemic stroke and intracranial artery occlusion within 24 hours of symptom onset were prospectively evaluated. PC-MRA was added to a standard stroke MRI protocol. Thrombus length was measured on thick slab maximum intensity projection images. Clinical outcome at hospital discharge was assessed by modified Rankin Scale (mRS). RESULTS: Thirty-four patients (median age 72 years) presenting with a median National Institutes of Health Stroke Scale score of 11 and a median onset to imaging time of 116 min were included. PC-MRA enabled precise depiction of proximal and distal terminus of the thrombus in 31 patients (91%), whereas in three patients (9%) PC-MRA presented a partial occlusion. Median thrombus length in patients with complete occlusion was 9.9 mm. In patients with poor outcome (mRS >=3) median thrombus length was significantly longer than in those with good outcome (mRS <=2;P=0.011). CONCLUSIONS: PC-MRA demonstrates intra-arterial thrombus length at different vessel occlusion sites. Longer thrombus length is associated with poor clinical outcome. CLINICAL TRIAL REGISTRATION: NCT02077582; Results. PMID- 29151042 TI - Patient-centered assessment on disease burden, quality of life, and treatment satisfaction associated with acromegaly. AB - The study aimed to assess the economic burden, health-related quality of life (HRQoL), and acromegaly treatment satisfaction in the USA. A web-based, cross sectional survey was distributed to members of Acromegaly Community. Data related to comorbidities, treatment patterns, and treatment satisfaction were collected. The costs over the past 3 months included out-of-pocket cost, sick leave, leave of absence, direct loss of job due to acromegaly, unemployment, assistance to perform household chores, and family member loss of income. The HRQoL was assessed by Acromegaly Quality of Life (AcroQoL) and EQ-5D-3L questionnaires. Among 106 patients who completed the survey (mean age: 46 years, female: 76.4%), 44.3% presented with >=5 comorbidities, and 90.6% reporting acromegaly-related symptoms. Compared with the low-symptom group 0-3 (n=41), the 4+ symptoms group (n=65) was more likely to have depression (OR=2.3, 95% CI 1.1 to 5.2) and cardiovascular disease (OR=5.8, 95% CI 2.0 to 16.7), and experienced higher costs (loss of job: $8874 vs $1717, P=0.02; unemployment disability: $17,102 vs $429, P=0.003; household chores: $2160 vs $932, P=0.0003; family members' income loss: $692 vs $122, P=0.03). The high-symptom group had lower HRQoL scores, compared with the low-symptom group (EQ-5D-3L: 0.53 vs 0.75, P<0.0001; AcroQoL: 27 vs 56, P<0.0001). Only 55.7% among patients requiring injections for acromegaly were satisfied. Patients with acromegaly who presented with multiple acromegaly related symptoms were evidenced to have experienced higher economic burden and poorer quality of life than patients with the same diagnosis but fewer symptoms. The low rate of treatment satisfaction warrants need for further studies. PMID- 29151043 TI - Personality and interpersonal behaviour may impact on burnout in nurses. PMID- 29151044 TI - Mortality among referrals to a community-based intermediate care team. AB - OBJECTIVES: Intermediate care services have been introduced to help mitigate unnecessary hospital demand and premature placement in long-term residential care. Many patients are elderly and/or with complex comorbidities, but little consideration has been given to the palliative care needs of patients referred to intermediate care services. The objective of this study is to determine the proportion of patients referred to a community-based intermediate care team who died during care and up to 24 months after discharge and so to help inform the development of supportive and palliative care in this setting. METHODS: A retrospective cohort study of all 4770 adult patients referred to Northamptonshire Intermediate Care Team (ICT) between 11 April 2010 and 10 April 2011. RESULTS: Of 4770 patients referred, 60% were 75 years or older and 32% were 85 years of age or older. 4.0% of patients died during their ICT stay and 11% within 30 days of discharge. At the end of 12 months, 25% of the patients had died, increasing to 32% before the end of the second year. About 34% of all deaths occurred during the ICT stay or within 30 days of discharge, and a further 46% by the end of the first year. Male gender and higher age were associated with greater likelihood of death. CONCLUSIONS: It is important for ICT clinicians to consider immediate and longer-term palliative care needs among patients referred to ICTs. Care models involving ICTs and palliative care teams working together could enable more people with end-stage non-cancer illnesses to die at home. PMID- 29151045 TI - The physical and mental health problems of refugee and migrant fathers: findings from an Australian population-based study of children and their families. AB - OBJECTIVES: The aim of this study was to report on the physical and mental health of migrant and refugee fathers participating in a population-based study of Australian children and their families. DESIGN: Cross-sectional survey data drawn from a population-based longitudinal study when children were aged 4-5 years. SETTING: Population-based study of Australian children and their families. PARTICIPANTS: 8137 fathers participated in the study when their children were aged 4-5 years. There were 131 (1.6%) fathers of likely refugee background, 872 (10.7%) fathers who migrated from English-speaking countries, 1005 (12.4%) fathers who migrated from non-English-speaking countries and 6129 (75.3%) Australian-born fathers. PRIMARY OUTCOME MEASURES: Fathers' psychological distress was assessed using the self-report Kessler-6. Information pertaining to physical health conditions, global or overall health, alcohol and tobacco use, and body mass index status was obtained. RESULTS: Compared with Australian-born fathers, fathers of likely refugee background (adjusted OR(aOR) 3.17, 95% CI 2.13 to 4.74) and fathers from non-English-speaking countries (aOR 1.79, 95%CI 1.51 to 2.13) had higher odds of psychological distress. Refugee fathers were more likely to report fair to poor overall health (aOR 1.95, 95% CI 1.06 to 3.60) and being underweight (aOR 3.49, 95% CI 1.57 to 7.74) compared with Australian-born fathers. Refugee fathers and those from non-English-speaking countries were less likely to report light (aOR 0.25, 95% CI 0.15 to 0.43, and aOR 0.30, 95% CI 0.24 to 0.37, respectively) and moderate to harmful alcohol use (aOR 0.04, 95% CI 0.10 to 0.17, and aOR 0.14, 95% CI 0.10 to 0.19, respectively) than Australian-born fathers. Finally, fathers from non-English-speaking and English-speaking countries were less likely to be overweight (aOR 0.62, 95% CI 0.51 to 0.75, and aOR 0.84, 95% CI 0.68 to 1.03, respectively) and obese (aOR 0.43, 95% CI 0.32 to 0.58, and aOR 0.77, 95% CI 0.61 to 0.98, respectively) than Australian-born fathers. CONCLUSION: Fathers of refugee background experience poorer mental health and poorer general health than Australian-born fathers. Fathers who have migrated from non-English-speaking countries also report greater psychological distress than Australian-born fathers. This underscores the need for primary healthcare services to tailor efforts to reduce disparities in health outcomes for refugee populations that may be vulnerable due to circumstances and sequelae of forced migration and to recognise the additional psychological stresses that may accompany fatherhood following migration from non-English-speaking countries. It is important to note that refugee and migrant fathers report less alcohol use and are less likely to be overweight and obese than Australian-born fathers. PMID- 29151046 TI - The association between gastro-oesophageal reflux disease and subsequent rheumatoid arthritis occurrence: a nested case-control study from Taiwan. AB - OBJECTIVE: Gastro-oesophageal reflux disease (GORD) is a common comorbidity among patients with rheumatoid arthritis (RA). While GORD has been attributed to the antirheumatic medications, no studies of human cohorts have investigated a link between GORD and RA. This study investigates whether GORD is associated with a subsequent RA diagnosis over a 5-year follow-up using a population-based dataset. SETTING: Taiwan PARTICIPANTS: We used data from the Taiwan Longitudinal Health Insurance Database. The study group consisted of 13 645 patients with an ambulatory claim showing a GORD diagnosis. We used propensity score matching to select 13 645 comparison patients (one per study patient with GORD). INTERVENTION: We tracked each patient's claims over a 5-year period to identify those who subsequently received a diagnosis of RA. Cox proportional hazard (PH) regression modelling was used for analysis. RESULTS: Over 5-year follow-up, RA incidence rate per 1000 person-years was 2.81 among patients with GORD and 0.84 among the comparison group. Cox PH modelling showed that GORD was independently associated with a 2.84-fold increased risk of RA (95% CI 2.09 to 3.85) over 5 year follow-up, after adjusting for the number of ambulatory care visits within the year following the index date (to mitigate surveillance bias). CONCLUSIONS: We observed that GORD might associate with subsequent RA occurrence. Because current treatment guidelines for RA emphasise early diagnosis and prompt treatment, the observed association between GORD and RA may help acquaint clinicians to patients with GORD with higher RA risk and facilitate early diagnosis and treatment. PMID- 29151047 TI - Interpretation of health news items reported with or without spin: protocol for a prospective meta-analysis of 16 randomised controlled trials. AB - INTRODUCTION: We aim to compare the interpretation of health news items reported with or without spin. 'Spin' is defined as a misrepresentation of study results, regardless of motive (intentionally or unintentionally) that overemphasises the beneficial effects of the intervention and overstates safety compared with that shown by the results. METHODS AND ANALYSIS: We have planned a series of 16 randomised controlled trials (RCTs) to perform a prospective meta-analysis. We will select a sample of health news items reporting the results of four types of study designs, evaluating the effect of pharmacological treatment and containing the highest amount of spin in the headline and text. News items reporting four types of studies will be included: (1) preclinical studies; (2) phase I/II (non randomised) trials; (3) RCTs and (4) observational studies. We will rewrite the selected news items and remove the spin. The original news and rewritten news will be appraised by four types of populations: (1) French-speaking patients; (2) French-speaking general public; (3) English-speaking patients and (4) English speaking general public. Each RCT will explore the interpretation of news items reporting one of the four study designs by each type of population and will include a sample size of 300 participants. The primary outcome will be participants' interpretation of the benefit of treatment after reading the news items: (What do you think is the probability that treatment X would be beneficial to patients? (scale, 0 (very unlikely) to 10 (very likely)).This study will evaluate the impact of spin on the interpretation of health news reporting results of studies by patients and the general public. ETHICS AND DISSEMINATION: This study has obtained ethics approval from the Institutional Review Board of the Institut national de la sante et de la recherche medicale (INSERM) (registration no: IRB00003888). The description of all the steps and the results of this prospective meta-analysis will be available online and will be disseminated as a published article. On the completion of this study, the results will be sent to all participants. PROSPERO REGISTRATION NUMBER: CRD42017058941. PMID- 29151048 TI - Early vasopressor use following traumatic injury: a systematic review. AB - OBJECTIVES: Current guidelines suggest limiting the use of vasopressors following traumatic injury; however, wide variations in practice exist. Although excessive vasoconstriction may be harmful, these agents may help reduce administration of potentially harmful resuscitation fluids. This systematic review aims to compare early vasopressor use to standard resuscitation in adults with trauma-induced shock. DESIGN: Systematic review. DATA SOURCES: We searched MEDLINE, EMBASE, ClinicalTrials.gov and the Central Register of Controlled Trials from inception until October 2016, as well as the proceedings of 10 relevant international conferences from 2005 to 2016. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials and controlled observational studies that compared the early vasopressor use with standard resuscitation in adults with acute traumatic injury. RESULTS: Of 8001 citations, we retrieved 18 full-text articles and included 6 studies (1 randomised controlled trial and 5 observational studies), including 2 published exclusively in abstract form. Across observational studies, vasopressor use was associated with increased short-term mortality, with unadjusted risk ratios ranging from 2.31 to 7.39. However, the risk of bias was considered high in these observational studies because patients who received vasopressors were systematically sicker than patients treated without vasopressors. One clinical trial (n=78) was too imprecise to yield meaningful results. Two clinical trials are currently ongoing. No study measured long-term quality of life or cognitive function. CONCLUSIONS: Existing data on the effects of vasopressors following traumatic injury are of very low quality according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. With emerging evidence of harm associated with aggressive fluid resuscitation and, in selected subgroups of patients, with permissive hypotension, the alternatives to vasopressor therapy are limited. Observational data showing that vasopressors are part of usual care would provide a strong justification for high-quality clinical trials of early vasopressor use during trauma resuscitation. TRIAL REGISTRATION NUMBER: CRD42016033437. PMID- 29151049 TI - Contribution of short sleep duration to ethnic differences in cardiovascular disease: results from a cohort study in the Netherlands. AB - OBJECTIVES: We analysed association between short sleep duration and prevalence of cardiovascular disease (CVD) in a multiethnic population living in the Netherlands, and the contribution of short sleep to the observed ethnic differences in the prevalence of CVD, independent of CVD risk factors. METHODS: 20 730 participants (aged 18-71 years) of the HELIUS (Healthy Life in an Urban Setting) Study were investigated. Self-reported sleep duration was classified as: short (<7 hours/night) and healthy (7-9 hours/night). Prevalence of CVD was assessed using the Rose Questionnaire on angina pectoris, intermittent claudication and possible myocardial infarction. Association of short sleep duration with prevalent CVD and the contribution of short sleep to the observed ethnic differences in the prevalence of CVD were analysed using adjusted prevalence ratio(s) (PRs) with 95% CI. RESULTS: Results indicate that short sleep was associated with CVD among all ethnic groups with PRs ranging from 1.41 (95% CI 1.21 to 1.65) in Moroccans to 1.62 (95% CI 1.20 to 2.18) in Dutch after adjustment for age, sex and conventional CVD risk factors. The independent contributions of short sleep (in percentage) to ethnic differences in CVD compared with Dutch were 10%, 15%, 15%, 5% and 5% in South-Asian Surinamese, African-Surinamese, Ghanaian, Turkish and Moroccan, respectively. CONCLUSION: Short sleep contributed to ethnic differences in CVD independent of well-known CVD risk factors particularly in Surinamese and Ghanaian groups. Reducing sleep deprivation may be a relevant entry point for reducing increased CVD risks among the various ethnic minority groups. PMID- 29151050 TI - Physical activity in former elite cricketers and strategies for promoting physical activity after retirement from cricket: a qualitative study. AB - OBJECTIVES: The health benefits of professional sport dissipate after retirement unless an active lifestyle is adopted, yet reasons for adopting an active or inactive lifestyle after retirement from sport are poorly understood. Elite cricket is all-encompassing, requiring a high volume of activity and unique physical demands. We aimed to identify influences on physical activity behaviours in active and insufficiently active former elite cricketers and provide practical strategies for promoting physical activity after cricket retirement. DESIGN: 18 audio-recorded semistructured telephone interviews were performed. An inductive thematic approach was used and coding was iterative and data-driven facilitated by NVivo software. Themes were compared between sufficiently active and insufficiently active participants. SETTING: All participants formerly played professional cricket in the UK. PARTICIPANTS: Participants were male, mean age 57+/-11 (range 34-77) years, participated in professional cricket for 12+/-7 seasons and retired on average 23+/-9 years previously. Ten participants (56%) were classified as sufficiently active according to the UK Physical Activity Guidelines (moderate-intensity activity >=150 min per week or vigorous-intensity activity >=75 min per week). Eight participants did not meet these guidelines and were classified as insufficiently active. RESULTS: Key physical activity influences were time constraints, habit formation, intrinsic and extrinsic motivation, physical activity preferences, pain/physical impairment and cricket coaching. Recommendations for optimising physical activity across the lifespan after cricket retirement included; prioritise physical activity, establish a physical activity plan prior to cricket retirement and don't take a break from physical activity, evaluate sources of physical activity motivation and incorporate into a physical activity plan, find multiple forms of satisfying physical activity that can be adapted to accommodate fluctuations in physical capabilities across the lifespan and coach cricket. CONCLUSIONS: Physically active and less active retired cricketers shared contrasting attributes that informed recommendations for promoting a sustainable, physically active lifestyle after retirement from professional cricket. PMID- 29151051 TI - Subclinical Propionibacterium acnes infection estimation in the intervertebral disc (SPInE-ID): protocol for a prospective cohort. AB - INTRODUCTION: Low back pain and vertebral endplate abnormalities are common conditions within the population. Subclinical infection caused by indolent pathogens can potentially lead to these findings, with differentiation between them notably challenging from a clinical perspective. Progressive infection of the intervertebral disc has been extensively associated with increasing low back pain, with Propionibacterium acnes specifically implicated with in relation to sciatica. The main purpose of this study is to identify if the presence of an infective pathogen within the intervertebral disc is primary or is a result of intraoperative contamination, and whether this correlates to low back pain. METHODS AND ANALYSIS: An open prospective cohort study will be performed. Subjects included within the study will be between the ages of 18 and 65 years and have a diagnosis of lumbar disc herniation requiring open decompression surgery. Excised herniated disc fragments, muscle and ligamentum flavum samples will be collected during surgery and sent to microbiology for tissue culture and pathogen identification. Score questionnaires for pain, functionality and quality of life will be given preoperatively and at 1, 3, 6 and 12 months postoperatively. A MRI will be performed 12 months after surgery for analysis of Modic changes and baseline comparison. The primary endpoint is the rate of disc infection in patients with symptomatic degenerative disc disease. The secondary endpoints will be performance scores, Modic incidence and volume. ETHICS AND DISSEMINATION: This study was approved by our Institutional Review Board and was only initiated after it (CAAE 65102617.2.0000.0071). Patients agreeing to participate will sign an informed consent form before entering the study. Results will be published in a peer reviewed medical journal irrespective of study findings. If shown to be the case, this would have profound effects on the way physicians treat chronic low back pain, even impacting health costs. TRIALS REGISTRATION NUMBER: NCT0315876; Pre-results. PMID- 29151052 TI - Prevalence of health services usage and associated factors in the Amazon region of Brazil: a population-based cross-sectional study. AB - OBJECTIVES: To estimate the prevalence of healthcare use and associated factors in the Manaus metropolitan region and to describe the reasons for lack of access. DESIGN: Cross-sectional population-based study. SETTING: A survey conducted between May and August of 2015 in eight cities from Manaus metropolitan region, Amazonas, Brazil. PARTICIPANTS: 4001 adults >=18 years of age. PRIMARY OUTCOMES MEASURES: Physician visits, dentist visits and hospitalisations in the last 12 months were the primary outcomes. Associated factors were investigated through the calculation of prevalence ratio (PR) obtained by hierarchical Poisson regression modelling. RESULTS: 4001 adults were included in the study, 53% of whom were women. The self-reported prevalence of medical visits was 77% (95% CI 75% to 77%); dentist visits, 36% (95% CI 34% to 37%) and hospital admission, 7% (95% CI 6% to 7%). Physician visits were higher in women PR=1.18 (95% CI 1.14 to 1.23), the elderly PR=1.18 (95% CI 1.10 to 1.26) and people with health insurance PR=1.14 (95% CI 1.10 to 1.19). Dentist visits declined with older age PR=0.38 (95% CI 0.30 to 0.49), lower education level PR=0.62 (95% CI 0.51 to 0.74) and lower economic class PR=0.65 (95% CI 0.57 to 0.75). Hospitalisations were found to be twice as frequent for women than for men and three times as frequent among those who reported very poor health status. Among the individuals who did not receive medical attention in the previous 2 weeks, 58% reported lack of facilities or appointment unavailable and 14% reported lack of doctors. CONCLUSION: While more than half visited the doctor in the last year, a lower proportion of people with socioeconomic inequities visited the dentist. Organisational and service policies are needed to increase equity in health services in the region. PMID- 29151053 TI - Protocol of the sepsivit study: a prospective observational study to determine whether continuous heart rate variability measurement during the first 48 hours of hospitalisation provides an early warning for deterioration in patients presenting with infection or sepsis to the emergency department of a Dutch academic teaching hospital. AB - INTRODUCTION: One in five patients with sepsis deteriorates within 48 hours after hospital admission. Regrettably, a clear tool for the early detection of deterioration is still lacking. The SepsiVit study aims to determine whether continuous heart rate variability (HRV) measurement can provide an early warning for deterioration in patients presenting with suspected infection or sepsis to the emergency department (ED). METHODS AND ANALYSIS: The protocol of a prospective observational study in the ED. We will include 171 adult medical patients presenting with suspected infection or sepsis and at least two systemic inflammatory response syndrome criteria. Patients with known pregnancy, cardiac transplantation or not admitted to our hospital are excluded.High sample frequency ECG signals (500 Hz), respiratory rate, blood pressure and peripheral oxygen saturation will be recorded continuously during the first 48 hours of hospitalisation using a bedside patient monitor (Philips IntelliVue MP70). Primary endpoint is patient deterioration, defined as the development of organ dysfunction, unplanned intensive care unit admission or in-hospital mortality. The ECG data will be used for offline HRV analysis. We will compare the HRV between two groups (deterioration/no deterioration) and analyse whether HRV provides an early warning for deterioration. Furthermore, we will create a multivariate predictive model for deterioration based on heart rate, respiratory rate and HRV. As planned secondary analyses, we (1) perform a subgroup analysis for patients with pneumosepsis and urosepsis and (2) determine whether HRV using lower sample frequencies (1 Hz or less) suffices to predict deterioration. ETHICS AND DISSEMINATION: The Institutional Review Board of the University Medical Center Groningen granted a waiver for the study (METc 2015/164). Results will be disseminated through international peer-reviewed publications and conference presentations. A lay summary of the results will be provided to the study participants. TRIAL REGISTRATION NUMBER: NTR6168; Pre-results. PMID- 29151054 TI - Effect of ephedrine and phenylephrine on brain oxygenation and microcirculation in anaesthetised patients with cerebral tumours: study protocol for a randomised controlled trial. AB - INTRODUCTION: During brain tumour surgery, vasopressor drugs are commonly administered to increase mean arterial blood pressure with the aim of maintaining sufficient cerebral perfusion pressure. Studies of the commonly used vasopressors show that brain oxygen saturation is reduced after phenylephrine administration, but unaltered by ephedrine administration. These findings may be explained by different effects of phenylephrine and ephedrine on the cerebral microcirculation, in particular the capillary transit-time heterogeneity, which determines oxygen extraction efficacy. We hypothesised that phenylephrine is associated with an increase in capillary transit-time heterogeneity and a reduction in cerebral metabolic rate of oxygen compared with ephedrine. Using MRI and positron emission tomography (PET) as measurements in anaesthetised patients with brain tumours, this study will examine whether phenylephrine administration elevates capillary transit-time heterogeneity more than ephedrine, thereby reducing brain oxygenation. METHODS AND ANALYSIS: This is a double-blind, randomised clinical trial including 48 patients scheduled for surgical brain tumour removal. Prior to imaging and surgery, anaesthetised patients will be randomised to receive either phenylephrine or ephedrine infusion until mean arterial blood pressure increases to above 60 mm Hg or 20% above baseline. Twenty four patients were allocated to MRI and another 24 patients to PET examination. MRI measurements include cerebral blood flow, capillary transit-time heterogeneity, cerebral blood volume, blood mean transit time, and calculated oxygen extraction fraction and cerebral metabolic rate of oxygen for negligible tissue oxygen extraction. PET measurements include cerebral metabolic rate of oxygen, cerebral blood flow and oxygen extraction fraction. Surgery is initiated after MRI/PET measurements and subdural intracranial pressure is measured. ETHICS AND DISSEMINATION: This study was approved by the Central Denmark Region Committee on Health Research Ethics (12 June 2015; 1-10-72-116-15). Results will be disseminated via peer-reviewed publication and presentation at international conferences. TRIAL REGISTRATION NUMBER: NCT02713087; Pre-results. 2015-001359-60; Pre-results. PMID- 29151055 TI - Exploring the effects of transfers and readmissions on trends in population counts of hospital admissions for coronary heart disease: a Western Australian data linkage study. AB - OBJECTIVES: To develop a method for categorising coronary heart disease (CHD) subtype in linked data accounting for different CHD diagnoses across records, and to compare hospital admission numbers and ratios of unlinked versus linked data for each CHD subtype over time, and across age groups and sex. DESIGN: Cohort study. DATA SOURCE: Person-linked hospital administrative data covering all admissions for CHD in Western Australia from 1988 to 2013. MAIN OUTCOME: Ratios of (1) unlinked admission counts to contiguous admission (CA) counts (accounting for transfers), and (2) 28-day episode counts (accounting for transfers and readmissions) to CA counts stratified by CHD subtype, sex and age group. RESULTS: In all CHD subtypes, the ratios changed in a linear or quadratic fashion over time and the coefficients of the trend term differed across CHD subtypes. Furthermore, for many CHD subtypes the ratios also differed by age group and sex. For example, in women aged 35-54 years, the ratio of unlinked to CA counts for non-ST elevation myocardial infarction admissions in 2000 was 1.10, and this increased in a linear fashion to 1.30 in 2013, representing an annual increase of 0.0148. CONCLUSION: The use of unlinked counts in epidemiological estimates of CHD hospitalisations overestimates CHD counts. The CA and 28-day episode counts are more aligned with epidemiological studies of CHD. The degree of overestimation of counts using only unlinked counts varies in a complex manner with CHD subtype, time, sex and age group, and it is not possible to apply a simple correction factor to counts obtained from unlinked data. PMID- 29151056 TI - Between professional values, social regulations and patient preferences: medical doctors' perceptions of ethical dilemmas. AB - BACKGROUND: We present and discuss the results of a Norwegian survey of medical doctors' views on potential ethical dilemmas in professional practice. METHODS: The study was conducted in 2015 as a postal questionnaire to a representative sample of 1612 doctors, among which 1261 responded (78%). We provided a list of 41 potential ethical dilemmas and asked whether each was considered a dilemma, and whether the doctor would perform the task, if in a position to do so. Conceptually, dilemmas arise because of tensions between two or more of four doctor roles: the patient's advocate, a steward of societal interests, a member of a profession and a private individual. RESULTS: 27 of the potential dilemmas were considered dilemmas by at least 50% of the respondents. For more than half of the dilemmas, the anticipated course of action varied substantially within the professional group, with at least 20% choosing a different course than their colleagues, indicating low consensus in the profession. CONCLUSIONS: Doctors experience a large range of ethical dilemmas, of which many have been given little attention by academic medical ethics. The less-discussed dilemmas are characterised by a low degree of consensus in the profession about how to handle them. There is a need for medical ethicists, medical education, postgraduate courses and clinical ethics support to address common dilemmas in clinical practice. Viewing dilemmas as role conflicts can be a fruitful approach to these discussions. PMID- 29151057 TI - Nudges to reason: not guilty. PMID- 29151058 TI - Nudging, informed consent and bullshit. AB - Some philosophers have argued that during the process of obtaining informed consent, physicians should try to nudge their patients towards consenting to the option the physician believes best, where a nudge is any influence that is expected to predictably alter a person's behaviour without (substantively) restricting her options. Some proponents of nudging even argue that it is a necessary and unavoidable part of securing informed consent. Here I argue that nudging is incompatible with obtaining informed consent. I assume informed consent requires that a physician tells her patient the truth about her options and argue that nudging is incompatible with truth-telling. Instead, nudging satisfies Harry Frankfurt's account of bullshit. PMID- 29151060 TI - Genetics of Parkinson's disease and related disorders. AB - Parkinson's disease (PD) is a complex and heterogeneous neurological condition characterised mainly by bradykinesia, resting tremor, rigidity and postural instability, symptoms that together comprise the parkinsonian syndrome. Non-motor symptoms preceding and following clinical onset are also helpful diagnostic markers revealing a widespread and progressive pathology. Many other neurological conditions also include parkinsonism as primary or secondary symptom, confounding their diagnosis and treatment. Although overall disease course and end-stage pathological examination single out these conditions, the significant overlaps suggest that they are part of a continuous disease spectrum. Recent genetic discoveries support this idea because mutations in a few genes (alpha-synuclein, LRRK2, tau) can cause partially overlapping pathologies. Additionally, mutations in causative genes and environmental toxins identify protein homeostasis and the mitochondria as key mediators of degeneration of dopaminergic circuits in the basal ganglia. The evolving mechanistic insight into the pathophysiology of PD and related conditions will contribute to the development of targeted and effective symptomatic treatments into disease-modifying therapies that will reduce the burden of these dreadful conditions. PMID- 29151061 TI - Evolution of sanitary-epidemiological services in Poland in the years 1944-2014. AB - This paper presents the history of sanitary-epidemiological services in the context of the health, economic and socio-political situation in Poland in the years 1944-2014, with a critical analysis of legal restraints, efficiency and achievements. Polish Sanitary Services, established in 1919, as a state service, have preserved for more than 95 years (also during World War II and the occupation) the continuity of its structures and essential objectives to enable their implementation in the field of public health protection. The unique effectiveness of actions was recorded in the years 1954-1998 and 2002-2009 in the time of central (vertical) subordination of sanitary-epidemiological services. The pre-accession preparation to the European Union (EU) strongly accelerated the development of sanitary-epidemiological services in Poland. Polish accession to the European Union has promoted the implementation of the WHO document "Health for All in the 21st Century" and the reduction of "health inequalities". PMID- 29151059 TI - Genome-wide association study of telomere length among South Asians identifies a second RTEL1 association signal. AB - BACKGROUND: Leucocyte telomere length (TL) is a potential biomarker of ageing and risk for age-related disease. Leucocyte TL is heritable and shows substantial differences by race/ethnicity. Recent genome-wide association studies (GWAS) report ~10 loci harbouring SNPs associated with leucocyte TL, but these studies focus primarily on populations of European ancestry. OBJECTIVE: This study aims to enhance our understanding of genetic determinants of TL across populations. METHODS: We performed a GWAS of TL using data on 5075 Bangladeshi adults. We measured TL using one of two technologies (qPCR or a Luminex-based method) and used standardised variables as TL phenotypes. RESULTS: Our results replicate previously reported associations in the TERC and TERT regions (P=2.2*10-8 and P=6.4*10-6, respectively). We observed a novel association signal in the RTEL1 gene (intronic SNP rs2297439; P=2.82*10-7) that is independent of previously reported TL-associated SNPs in this region. The minor allele for rs2297439 is common in South Asian populations (>=0.25) but at lower frequencies in other populations (eg, 0.07 in Northern Europeans). Among the eight other previously reported association signals, all were directionally consistent with our study, but only rs8105767 (ZNF208) was nominally significant (P=0.003). SNP-based heritability estimates were as high as 44% when analysing close relatives but much lower when analysing distant relatives only. CONCLUSIONS: In this first GWAS of TL in a South Asian population, we replicate some, but not all, of the loci reported in prior GWAS of individuals of European ancestry, and we identify a novel second association signal at the RTEL1 locus. PMID- 29151062 TI - Instruments to assess stigmatization in dermatology. AB - Stigmatization is the assignment of negative perceptions to an individual because of a perceived difference from the population at large. Skin conditions are frequently the reason of social rejection with a consequent negative influence on the personal and social life of patients. The aim of the current study was to review the available instruments that can be successfully utilized to measure the stigmatization level among dermatological patients. We performed our search on PubMed up to November 2016 and utilized combinations of key phrases containing such words as stigmatization, skin, dermatology, names of various skin conditions (psoriasis, vitiligo, acne, etc.), measurement. The search found a considerable number of articles - 548. After filtering them through a precise selection process, 58 articles remained. We concentrated only on the methodological aspects to assess stigmatization in various dermatoses. The review ascertained that there exist numerous instruments in the form of questionnaires. They were utilized in various researches in order to assess the stigmatization level in patients with skin problems. We divided them into two main groups: dermatology specific instruments (6 questionnaires) and dermatosis/disease specific ones (8 questionnaires). It is recommended to use dermatology-specific instruments to compare the stigmatization level in various skin conditions. They can be utilized as well as a first line tools to study the feeling of stigmatization in specific skin diseases; however, where it is possible, they should be supplemented with the disease-specific instrument for deeper analysis of both qualities of life and stigmatization. PMID- 29151063 TI - Predation among microorganisms: A huge potential of interspecies dependencies. AB - There are many interactions between species (including bacteria) in the environment. One of them is predation, which always leads to the death of a prey. Described in this review Bdellovibrio bacteriovorus (Deltaproteobacteria) and Micavibrio aeruginosavorus (Alfaproteobacteria) are uniflagellate, rod shaped and curved obligate predators of Gram-negative bacteria. Both species belong to the group of BALOs (Bdellovibrio and like organisms). B. bacteriovorus use periplasmic predatory strategy and M. aeruginosavorus are epibiotic hunters. BALOs have found application in both medicine in combating microorganisms responsible for food poisoning and outside of medicine (agriculture and food) as plant protection products and as measures used to prevent the spoiling of food. As a result of searching for effective therapies in the treatment of infections caused by drug-resistant strains of bacteria, it has been shown that predators feed on pathogenic bacteria without showing immunogenicity to humans. Predatory bacteria are able to destroy the multi - and single-species biofilms. Recent studies have indicated the possibility of B. bacteriovorus to destroy the biofilm formed by Staphylococcus aureus. It is postulated that a double predatory strategy of B. bacteriovorus and harmless BALOs towards mammalian cells could be used to treat infections in vivo, particularly in those cases when standard therapy fails. PMID- 29151064 TI - The oral cavity - potential source of stem cells. AB - The purpose of this review is to present the current knowledge regarding the hierarchy of stem cells originating from the oral cavity, which could have a potential value when applied to regenerative stomatology. It must be particularly emphasized that the heterogenous nature of its biology and function within oral compartment may predispose them to different types of applications. Stem cells can be perceived as immature, primitive and unspecialized types of cells with the ability to proliferate, self-renew and differentiate into specialized progeny according to the compartmental signaling. Their presence in tissue reservoirs was already discovered in many organs and tissues as well as in the stomatognathic system. The oral cavity appears to be an exceptionally attractive site to acquire stem cells. The common presence and easy access to these cells in dental and peridental tissues provides a real chance to apply them for therapeutic purposes. Such an opportunity would also be neutral to bioethical and moral issues, assuming autologous stem cells employment. Many authors suspect that stem cells have epigenetic memory, so some of their features can be inherited through generations. They are not connected, however, with DNA sequence modifications. It is, therefore, justified to apply the cells, which have the oral cavity as their natural reservoir, in interventions associated with tissue engineering within the stomatognathic system. An increasing number of clinical trials, among which the number of randomized studies with large group of patients is progressively carried out, allows for a prediction that shortly therapeutic methods based on stem cells of dental origin may be implemented to the routine repertoire of clinical practice. PMID- 29151065 TI - The mRNA expression levels of uncoupling proteins 1 and 2 in mononuclear cells from patients with metabolic disorders: obesity and type 2 diabetes mellitus. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) and obesity are metabolic disorders whose major hallmark is insulin resistance. Impaired mitochondrial activity, such as reduced ratio of energy production to respiration, has been implicated in the development of insulin resistance. Uncoupling proteins (UCPs) are proton carriers, expressed in the mitochondrial inner membrane, that uncouple oxygen consumption by the respiratory chain from ATP synthesis. AIM: The aim of the study was to determine transcriptional levels of UCP1 and UCP2 in peripheral blood mononuclear cells (PBMCs) from patients with metabolic disorders: T2DM, obesity and from healthy individuals. MATERIAL/METHODS: The mRNA levels of UCP1, UCP2 were determined by Real-Time PCR method using Applied Biosystems assays. RESULTS: The UCP1 mRNA expression level was not detectable in the majority of studied samples, while very low expression was found in PBMCs from 3 obese persons. UCP2 mRNA expression level was detectable in all samples. The median mRNA expression of UCP2 was lower in all patients with metabolic disorders as compared to the controls (0.20+0.14 vs. 0.010+0.009, p=0.05). When compared separately, the differences of medians UCP2 mRNA expression level between the obese individuals and the controls as well as between the T2DM patients and the controls did not reach statistical significance. CONCLUSIONS: Decreased UCP2 gene expression in mononuclear cells from obese and diabetic patients might contribute to the immunological abnormalities in these metabolic disorders and suggests its role as a candidate gene in future studies of obesity and diabetes. PMID- 29151067 TI - The X/A-like cell revisited - spotlight on the peripheral effects of NUCB2/nesfatin-1 and ghrelin. AB - The gastric X/A-like cell was long thought to be restricted to the production of acyl ghrelin. However, the subsequent years witnessed the discovery of other peptide products derived from this cell, namely desacyl ghrelin, obestatin and nesfatin-1. While the role of obestatin remains highly questionable and is very critically discussed in the literature, besides acyl ghrelin also desacyl ghrelin and nesfatin-1 have been implicated in the regulation of food intake. As observed for several other peptide hormones before, ghrelin and nesfatin-1 are not restricted to one function but rather exert pleiotropic actions including effects on gastrointestinal motility, thermogenesis, lipid and glucose homeostasis, stress mediation, cardiovascular as well as reproductive functions. These often counter-regulatory effects of nesfatin-1 and ghrelin will be discussed in the present review. PMID- 29151068 TI - Crataegus special extract WS 1442: up-to-date review of experimental and clinical experiences. AB - Extracts and tinctures made from Crataegus spp. (Hawthorn) have been used as cardioprotective remedies since ancient times. WS 1442 special extract, manufactured by Dr. W. Schwabe Pharmaceuticals(c), made from Crataegus spp. Leaves and flowers is one of the most studied and popular of preparations received from Hawthorn. It is integral, and most important active component of such herbal drugs as Crataegutt(r) novo 450, and CardioMax(r). This standardized extract contains 18.75% oligomeric procyanidins (OPC), which have beneficial cardioprotective values and play a role as free-radicals scavengers, that protect the ischemic heart tissue from neutrophile elastase action successions. Moreover, WS 1442 also carries proven vasorelaxant activity, via affecting eNOS synthase, and prevents ischemic heart tissue swelling by influence on calcium signaling pathways, and thus detain hyperpermeability of endothelium. Actions of WS 1442 special extract were investigated in in vitro as well as in vivo studies including large clinical trials. In this review authors present current state of knowledge about possible beneficial effects of WS 1442 special extract on cardiovascular system. PMID- 29151070 TI - Circadian rhythms of melatonin and cortisol in manifest Huntington's disease and in acute cortical ischemic stroke. AB - Recent studies indicate disruptions to the circadian system in brain injury and neurodegeneration. The results, however, are often not consistent and limited by measurement of only one circadian marker and by infrequent sampling rates. In this study, we examined diurnal rhythmicity in different stages of Huntington (HD) disease and in patients with acute moderate ischemic stroke (AIS) outside the retinohypothalamic pathway by evaluating serum concentrations of melatonin and cortisol at twelve timepoints. All study participants were subjected to the same study protocol of 12-hour light/dark cycle and controlled room conditions. Using cosinor analysis of data and comparing the results with the controls we found melatonin phase delay with lowered amplitude and mesor in stage III HD patients. These changes coexisted with phase advanced rhythm and elevated values of mesor and amplitude for cortisol. Early and mid-stages of HD showed only a phase advance in cortisol secretion. In AIS the circadian rhythm of serum melatonin was sustained without any phase shift and exhibited more flattened profile (lowered mesor and amplitude values), while advanced rhythm with higher mesor for cortisol was present. In conclusion, 1) abnormal pattern of melatonin release in the late stages of HD and in moderate AIS occurs in conjunction with phase-advanced rhythm of cortisol; 2) changes observed in late stages of HD are similar to those that occur with ageing; 3) brain regions other than the presumptive retinopineal neural pathway may play an important role in the pineal production of melatonin in humans; 4) lesion in extrahypothalamic region is related to the strong adrenal stimulation in response to AIS. PMID- 29151069 TI - Nitroso-sulfide coupled signaling triggers specific vasoactive effects in the intrarenal arteries of patients with arterial hypertension. AB - In normotensive conditions, it has been confirmed that S-nitrosothiols (RSNO), can interact with hydrogen sulfide (H2S) and create new substances with specific vasoactive effects. This interaction could also represent a new regulator signaling pathway in conditions of hypertension. Until now, these effects were studied only in normotensive rats, and they have not been carried out in humans yet. We investigated the vasoactive effects of the products of the H2S/S nitrosoglutathione (S/GSNO) interaction in lobar arteries (LA) isolated from the nephrectomized kidneys of patients suffering from arterial hypertension and in renal arteries (RA) of spontaneously hypertensive rats (SHR). The changes in the isometric tension of pre-contracted arteries were evaluated. Acetylcholine induced vasorelaxation of LA was reduced compared to the effect induced by an NO donor, sodium nitroprusside suggesting an endothelium dysfunction. While 1 MUmol/L Na2S had a minimal effect on the vascular tone, the concentration 20 MUmol/L evoked a slight vasorelaxation. GSNO at 0.1 MUmol/L induced vasorelaxation, which was less pronounced compared to the effect induced by 1 MUmol/L. The S/GSNO products (final concentration 0.1 MUmol/L) prepared as the mixture of GSNO (0.1 MUmol/L) + Na2S (1 MUmol/L) induced a higher vasorelaxation compared to GSNO (0.1 MUmol/L) alone only in the 5th minute and without the differences in the speed. On the other hand, the S/GSNO products (final concentration 1 MUmol/L) prepared as the mixture of GSNO (1 MUmol/L) + Na2S (10 MUmol/L) induced a higher and faster vasorelaxation compared to the effect induced by GSNO (1 MUmol/L) alone. In RA of SHR this S/GSNO products induced similar vasorelaxation (higher and faster than GSNO) with involvement of HNO (partially) and cGMP as mediators. However, the products of the H2S/NO donor (DEA NONOate) manifested differently than S/GSNO indicating the unique interaction between GSNO and H2S. In this study, we confirmed for the first time that specific vasoactive effects of coupled nitroso-sulfide signaling were also triggered in human arterial tissue. We suggest that in hypertension, H2S in interaction with GSNO regulated a vasoconstrictor-induced increase in arterial tone towards a stronger vasorelaxation compared to GSNO alone or H2S alone. PMID- 29151071 TI - An observational cohort study of 3 units versus 5 units slow intravenous bolus oxytocin in women undergoing elective caesarean delivery. AB - This study sought to compare postpartum blood loss and maternal outcomes after 3IU and 5IU oxytocin at elective caesarean delivery. In a prospective observational study, 73 women undergoing elective caesarean delivery under spinal anaesthetic received a slow I.V. injection of either 3IU (n = 35) or 5IU (n = 38) oxytocin after delivery. The main outcome was gravimetrically measured 24-hour postpartum blood loss with a non-inferiority margin of 300 mL. Uterine tone, phenylephrine dose, emesis and hypotension after oxytocin administration were secondary outcomes. Gravimetric postpartum blood loss was lower in the 3IU group (-58.8 mL [95% CI: -212.1, 94.3]) after adjusting for BMI, pre-delivery vasopressor dose, parity, and risk of uterine atony, with the upper confidence limit below the 300 mL margin in support of non-inferiority. Patients receiving 3IU had a higher (non-significant) rate of having post-delivery phenylephrine to treat hypotension (RR = 1.59 [95% CI: 0.97, 2.63]), but of those treated, the 3IU group required significantly less (-427 mcg [95% CI: -740, -114]). The 3IU group had a lower prevalence of vomiting compared to those receiving 5IU (6% versus 24%; P = 0.047). Administration of 3IU oxytocin was non-inferior compared to standard 5IU with respect to blood loss in women undergoing elective caesarean delivery. PMID- 29151072 TI - The lactate receptor (HCAR1/GPR81) contributes to doxorubicin chemoresistance via ABCB1 transporter up-regulation in human cervical cancer HeLa cells. AB - The lactate receptor, also known as hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), plays a vital role in cancer biology. Recently, HCAR1 was reported to enhance metastasis, cell growth, and survival of pancreatic, breast, and cervical cancer cells. This study showed, for the first time, the mechanism of HCAR1-mediated chemoresistance to doxorubicin through regulation of ABCB1 transporter. We observed the HCAR1 agonists L-lactate, D-lactate and 3,5 dihydroxybenzoic acid (DHBA) induced up-regulation of ABCB1. HCAR1 silencing decreased ABCB1 mRNA and protein by 80% and 40%, respectively. Moreover, cellular doxorubicin accumulation decreased by 30% after DHBA treatment, while HCAR1 silencing increased accumulation of ABCB1 substrates by nearly 2-fold. Based on growth inhibition assays, cell cycle analysis, and annexin V staining assays, we demonstrated that HCAR1 enhances cell survival and doxorubicin resistance. Finally, DHBA-stimulated up-regulation of ABCB1 functionality was suppressed by pharmacological inhibition of the PKC pathway. Taken together, our study shows the novel role of HCAR1 in development of chemoresistance in cervical carcinoma HeLa cells via ABCB1 transporter up-regulation. PMID- 29151073 TI - Effect of the different doses of acrylamide on acetylocholinoesterase activity, thiol groups, malondialdehyde concentrations in hypothalamus and selected muscles of mice. AB - Acrylamide is a chemical compound that typically forms in starchy food products during high-temperature cooking, including frying, baking and roasting. Acrylamide is a known lethal neurotoxin. Its discovery in some cooked starchy foods in 2002 prompted concerns about the carcinogenicity of those foods. Little is known about acrylamide's influence on the peripheral nerves. In our research we measured acrylamide's influence on the acetylcholinesterase activity in hypothalamus, heart muscle, skeletal muscles of the thigh and smooth muscle of the small intestine (males, Swiss strain) in relation to the thiol groups and malondialdehyde concentration. Acrylamide was injected intraperitoneally (20 and 40 mg/kg, i.e. 0.52 and 1.04 mg per animal). The hypothalamus and muscles were taken 24, 48, and 192 h after the injection. Acetylcholinesterase activity was significantly lower (P < 0.001 to P < 0.05) in all structures. It was accompanied by the statistically significant (P < 0.001 to P < 0.05) increase in malondialdehyde concentrations in most of the studied structures time periods and ACR doses. -SH groups concentrations were significantly depleted in selected structures (P < 0.001 to P < 0.05). The AChE activity evaluation in mice muscles and hypothalamus was very important because there are many evidences that acrylamide affects directly on the peripheral nerves. Thus, it causes structural damages and physiological changes. The results obtained in the present study provide evidence for the occurrence of oxidative stress after intraperitoneal injection of acrylamide to hypothalamus, heart muscle, skeletal muscles of the thigh and smooth muscle of the small intestine. PMID- 29151074 TI - Interferon lambda 2 promotes mammary tumor metastasis via angiogenesis extension and stimulation of cancer cell migration. AB - Myeloid-derived suppressor cells (MDSCs) support tumor development by stimulation of angiogenesis and immune response inhibition. In our previous study, we showed that interferon lambda 2 (IFN-lambda2), secreted by MDSCs, enhances production of pro-angiogenic factors by cancer cells via phosphorylation of STAT3 and therefore promotes blood vessels formation. In the present study IFN-lambda2 level was evaluated by ELISA in serum of tumor-bearing mice, whereas its expression in MDSCs isolated from the lungs with metastatic tumors and normal lungs was assessed by qPCR. The effect of IFN-lambda2 on mouse mammary cancer cells motility was tested in Boyden chamber migration assay. In order to evaluate its pro-angiogenic function we performed in vitro tubule formation assay and in ovo angiogenesis assay on chicken embryo chorioallantoic membrane (CAM). Moreover, in order to design small molecule inhibitors of IFN-lambda2 and its receptor we performed molecular modeling followed by the identification of potential natural inhibitors. Then, we examined their ability to inhibit angiogenesis in vitro. Our results showed that IFN-lambda2 predisposed mouse mammary cancer cells to migration in vitro. It also enhanced angiogenesis induced by mouse mammary cancer cells in vitro and in ovo. For the first time we selected potential IFN-lambda2 inhibitors and we validated that they were capable to abolish pro-angiogenic effect of IFN-lambda2, similarly to blocking antibodies. Therefore, IFN-lambda2 and its receptor may become targets of anti-cancer therapy, but their mechanism of action requires further investigation. PMID- 29151075 TI - Formation of new blood vessels during gastric ulcer healing. Role of bone marrow derived endothelial progenitor cells. AB - Regeneration of blood vessels (neovascularization) is critical for gastric ulcer (GU) healing. The contributions of bone marrow-derived endothelial progenitor cells (BMD-EPCs) to neovascularization during GU healing are not fully elucidated. Our specific aims were to determine whether in GU, BMD-EPCs are incorporated into blood vessels of GU granulation tissue jointly with ECs, thus forming hybrid vessels; or, form separate vessels consisting of only BMD-EPCs. GUs were induced in rats by serosal application of acetic acid. Vascular cast studies were performed at 7, 21 and 60 days after GU induction and tissue specimens were immunostained for CD34, CD133, VEGFR2, and SDF-1 at 14 days. Human relevance was determined using archival human GU specimens. In rat GU granulation tissue BMD-EPCs constituted 28 +/- 3% of all cells lining newly formed blood vessels, and were nested between fully differentiated ECs. In rat GU granulation tissue, expression of stromal derived factor-1 (SDF-1) - the major chemoattractant for BMD-EPCs was strongly upregulated. In human GU specimens, BMD EPCs were also present in granulation tissue constituting 34 +/- 3% of all cells lining blood vessels and jointly formed hybrid vessels with differentiated ECs. Our study uncovered that BMD-EPCs incorporate into newly formed blood vessels in GU granulation tissue; and, together with ECs of pre-existing vessels, contribute to and support neovascularization through vasculogenesis. This study is the first demonstration that vasculogenesis occurs during GU healing in both humans and in rats. PMID- 29151076 TI - Modulation of the endocannabinoid system by the fatty acid amide hydrolase, monoacylglycerol and diacylglycerol lipase inhibitors as an attractive target for secretory diarrhoea therapy. AB - Secretory diarrhoea is a leading cause of mortality and morbidity worldwide. Our aim was to characterize the effect of inhibition of selected enzymes involved in the synthesis or degradation of endocannabinoids on electrolyte equilibrium in the mouse colonic tissue. The aim of this study was to evaluate the effects of PF 3845, JZL-184 and RHC-80267, as inhibitors of fatty acid amide hydrolase (FAAH), monoacylglycerol (MAGL) and diacylglycerol lipase (DAGL), respectively on epithelial ion transport in isolated mouse colon stimulated by forskolin (FSK), veratridine (VER) and bethanechol (BET). Next, colonic tissue was co-incubated with selected inhibitors and cannabinoid receptor antagonists: AM 251 and AM 630 (CB1 and CB2 antagonists, respectively). We found that PF-3845 induced antisecretory effect in FSK-stimulated colonic tissue (P < 0.01), which was significantly reversed by AM 251 (P < 0.001) and AM 630 (P < 0.01). JZL-184 significantly reduced DeltaIsc (P < 0.05) in FSK-stimulated conditions and co incubation with AM 630, but not AM 251 reversed this effect when compared to JZL 184 alone (P < 0.05). After addition of PF-3845 and JZL-184 to colon tissue stimulated by VER, we did not observe any significant effect on DeltaIsc. PF 3845, JZL-184 or RHC-80267 were without any statistically significant effect on BET-evoked ion transport when compared to control. Our findings showed that indirect modulation of the endocannabinoid system could be an attractive target for novel effective treatment of secretory diarrhoea, which is devoid of side effects on the central nervous system caused by direct administration of cannabinoid receptor agonists. PMID- 29151077 TI - Weight loss-dependent and -independent effects of moderate calorie restriction on endothelial cell markers in obesity. AB - Endothelial cell dysfunction in obesity can be reduced by calorie restriction (CR), however it is unclear whether this benefit requires a concomitant weight loss or is it simply related to the reduced calorie intake per se. In our study serum was drawn from 41 obese women who were undergoing an 8-week dietary intervention with 15 - 30% energy deficit, and from 48 age- and sex-matched controls of normal weight. Serum was analysed for biomarkers of endothelial cell function, oxidative stress and inflammation. Compared with non-obese individuals, the obese patients had lower serum levels of nitric oxide (NO), adiponectin, and decreased serum antioxidant status. They also had significantly higher levels of adhesive molecules, thrombomodulin (TM), von Wilebrand factor (vWF), asymmetric dimethylarginine (ADMA), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and leptin. To further characterize the effect of moderate CR, the patients were ranked into two comparable groups according to the extent of weight loss - below and above the median (-5.8 kg). A moderate dietary intervention did not correct adiponectin, antioxidant status, vWF, TM, and plasminogen activator inhibitor-1 (PAI-1) but ameliorated changes in other parameters. Only changes in NO and - to a lesser degree - in sE-selectin showed a clear relationship with the magnitude of weight reduction. By contrast, a beneficial reduction in TNF-alpha occurred equally in patients who lost more or less weight after caloric restriction. We concluded that moderate calorie restriction could still improve several parameters of endothelial cell function irrespective of whether it was accompanied by changes in body mass. However, a significant improvement in nitric oxide, a key mediator of endothelial well-being, requires a substantial reduction in body weight. PMID- 29151078 TI - Therapeutic effect of exogenous ghrelin in the healing of gingival ulcers is mediated by the release of endogenous growth hormone and insulin-like growth factor-1. AB - Ghrelin, an acylated 28-amino acid polypeptide, was primary isolated from the stomach, and the stomach is a main source of circulating ghrelin. Ghrelin strongly and dose-dependently stimulates release of growth hormone from the anterior pituitary, as well as increases food intake and fat deposition. Previous studies showed that ghrelin exhibits protective and therapeutic effect in different parts of the gastrointestinal system, including the oral cavity. The aim of present study was to examine the role of growth hormone and insulin-like growth factor-1 (IGF-1) in the healing of gingival ulcers. Studies were performed on rats with the intact pituitary gland and hypophysectomized rats. In anesthetized rats, chronic ulcers of the gum were induced by acetic acid. Rats were treated intraperitoneally twice a day with saline or ghrelin (4, 8 or 16 nmol/kg/dose) for six days. In pituitary-intact rats, administration of ghrelin significantly increased serum concentration of growth hormone and IGF-1 and this effect was associated with a significant increase in the healing rate of gingival ulcers. Moreover, treatment with ghrelin increased mucosal blood flow and DNA synthesis in the gum, while a local inflammation was decreased what was observed as a reduction in mucosal concentration of pro-inflammatory interleukin-1beta. Hypophysectomy decreased serum level of growth hormone below a detection limit; whereas serum concentration of IGF-1 was reduced by 90%. On the other hand, removal of the pituitary gland was without any significant effect on the healing rate of gingival ulcers or on the ulcer-induced increase in DNA synthesis and concentration of pro-inflammatory interleukin-1beta in gingival mucosa. Administration of ghrelin failed to affect serum level of growth hormone and IGF 1 in hypophysectomized rats, and was without any effect on the healing rate of gingival ulcers, mucosal blood flow, DNA synthesis or concentration of interleukin-1beta in gingival mucosa. Neither induction of gingival ulcers nor hypophysectomy nor administration of ghrelin significantly affected serum concentration of pro-inflammatory interleukin-1beta. We concluded that endogenous growth hormone and IGF-1 were involved in the therapeutic effect of exogenous ghrelin in the healing of gingival mucosa damage. PMID- 29151079 TI - Mechanisms of vasorelaxation induced by total flavonoids of Euphorbia humifusa in rat aorta. AB - Euphorbia humifusa Willd. (EH), rich in flavonoids, has long been used for the treatment of bacillary dysentery and enteritis in China, and is known to have antioxidant, hypotensive and hypolipidemic properties. However, the vasorelaxant effect of total flavonoids of EH (TFEH) and action mechanisms are not clearly defined yet. The aim of the present study was to investigate the effects of TFEH on the vascular tension and its underlying mechanisms. Experiments were performed in rat thoracic aorta using the organ bath system. TFEH (0.01 - 100 MUg/ml) caused a concentration-dependent vasorelaxation, which was dependent on a functional endothelium, and were significantly attenuated by inhibitors of endothelial NO synthase, its upstream signaling pathway, PI3K/Akt, and soluble guanylate cyclase, but not by blockade of KCa channel, KATP channel, cyclooxygenase, muscarinic and beta-adrenergic receptors. Extracellular Ca2+ depletion, and pre-treatment with modulators of the store-operated Ca2+ entry channels, Gd3+ and 2-aminoethyl diphenylborinate, significantly attenuated the TFEH-induced vasorelaxation. Our findings suggest that TFEH elicit vasorelaxation via endothelium-dependent NO-cGMP pathway through activation of PI3K/Akt- and Ca2+-eNOS-NO signaling. Further, it is suggested that TFEH-induced activation of the NO-soluble guanylate cyclase-cGMP-protein kinase G signaling relaxes vascular smooth muscle cells through an inhibition of the L-type Ca2+ channel activity. PMID- 29151080 TI - Changes in U937 cell viability induced by stress factors - possible role of calmodulin. AB - Current studies were aimed to elucidate influence of magnetic field (MF) stimulation on cell viability and its effect on expression of calmodulin (CaM) and Hsp70 protein which plays a role of cell stress indicator and is a Ca2+ dependent CaM-binding protein. For the experimental model we have chosen U937 cell line exposed to chemical- and/or physical stress factors. Puromycin (PMC) was used as a chemical apoptosis inducer. Alternating (AC) (6.5rms mT, 35 Hz) magnetic field combined with 6 mT static (DC) component, or pulsed electromagnetic field (45 +/- 5)mT, 50 Hz (PEMF) acted as physical stressors. Cell viability was assessed by flow cytometry, and the Western blot analysis was carried out for CaM and Hsp70 levels in cytosolic extracts of U937 cells. Cell viability in samples exposed to MF alone did not differ from sham sample, for both types of MF exposure systems. Simultaneous action of MF and PMC influenced cell viability in type of MF stimulation-dependent manner. In contrast to PEMF + PMC stimulated samples, combination of ACDCMF with PMC enhanced cell death compared to PMC control. The observed changes in cell viability were correlated with changes in level of CaM and Hsp70 proteins. Immunoblots have shown, that cytosolic content of both CaM and Hsp70 proteins was enhanced in PMC-treated sample, and further elevated for ACDCMF + PMC. For PEMF + PMC stimulated samples, level of CaM was reduced compared to PMC-treated sample. The results suggest that the changes in expression of CaM and CaM-dependent proteins might modulate effectiveness of cell death under stimulation with MF and/or cytotoxic agents. PMID- 29151081 TI - Association between standard laboratory and functional tests of coagulation in dilutional coagulopathy: an in vitro study. AB - Standard laboratory tests (SLTs) of coagulation are in common use in clinical practice. We aimed to determine the association between SLTs and functional tests of coagulation in blood samples diluted with balanced crystalloid and colloid solutions in an ex vivo setting. The study group comprised 32 healthy young male volunteers. Whole blood samples were diluted at a 4:1 ratio with balanced crystalloid (Plasmalyte(r)) and two balanced colloids, 6% hydroxyethyl starch 130/0.4 (Volulyte(r)) and succinylated gelatin (Geloplasma(r)). SLTs included aPTT (activated partial thromboplastin time), PT (prothrombin time), fibrinogen concentration (FIB), D-dimers and number of platelets (PLT). Platelet aggregation was determined using multiple electrode aggregometry (MEA) with TRAP (thrombin receptor activating protein-6) as an assay activator. Coagulation and fibrinolysis were assessed functionally using rotational thromboelastometry (ROTEM). We found correlation between aPTT and INTEM (i.e. intrinsic coagulation pathway screening test) clotting time (R = 0.38 to 0.77; P < 0.05) for both undiluted and diluted samples. FIB and PLT were shown to be correlated with alpha angle in both INTEM and EXTEM (i.e. extrinsic coagulation pathway screening test) (FIB: R = 0.38 to 0.69; P < 0.05; PLT: 0.41 to 0.56; P < 0.05) again for both undiluted and diluted samples. FIB and PLT were associated with clot formation time in both INTEM and EXTEM (FIB: R = -0.44 to -0.70; P < 0.05; PLT: -0.36 to 0.58; P < 0.05). MEA results shown no correlation with ROTEM findings. There was also no correlation between number of platelets and their function as determined by MEA. Fibrinogen concentration correlated positively with fibrinogen function as determined by FIBTEM (i.e. fibrinogen deficiency/dysfunction screening test) maximum clot firmness (R = 0.49 to 0.73; P < 0.05). ROTEM results were predominantly associated with fibrinogen concentration and number of platelets. When there is no access to functional tests, concentration of fibrinogen is the most reliable test of coagulation, also in the context of fluid-induced coagulopathy. PMID- 29151082 TI - Survey on Paediatric Differentiated Thyroid Cancer Care in Europe. AB - BACKGROUND/AIMS: Thyroid cancer among children is a very rare disease. Although survival is favourable, morbidity caused by the treatment remains considerable, so there is a great need to optimize management by international cooperation. For this reason, the 2016 European Thyroid Association-Cancer Research Network (ETA CRN) meeting in Copenhagen, Denmark, paid considerable attention to this topic and aimed to give an overview of the care for this paediatric patient group in different European countries. METHODS: An inventory of data on thyroid cancer treatment among children in Europe was generated by questionnaires focused on treatment and organization of care. RESULTS: The treatment of paediatric thyroid cancer appears to be scattered in each European country with limited centralization of care, and different European countries use different treatment and follow-up protocols. CONCLUSION: Collaboration in a European network to optimize treatment and minimize long-term consequences for paediatric thyroid cancer survivors is necessary. During this meeting, the ETA-CRN has endorsed the initiative to collaborate on this rare endocrine cancer within a European network. PMID- 29151083 TI - Screening for Congenital Cytomegalovirus Is Recommended in Every Newborn. PMID- 29151084 TI - Formal Neurocognitive Testing in 60 Patients with Congenital Hyperinsulinism. AB - BACKGROUND: Congenital hyperinsulinism (CHI) is hallmarked by persistent hypoketotic hypoglycemia in infancy. In the majority of all patients, CHI is caused by mutations in the KATP channel genes ABCC8 and KCNJ11, but other genes in the insulin-regulatory pathway have also been described. Repeated episodes of hypoglycemia include an increased risk of seizures and intellectual disability. So far, controlled psychometric studies on cognitive, motor, speech, and social emotional outcome of CHI patients are missing. Until now, neurodevelopmental long term outcome in CHI patients has only been measured by questionnaires, self-, parental-, or caregiver-administered instruments. METHODS: This is a prospective study of 60 patients (median age 3.3 years, range 3 months to 57 years): 48 with a diffuse, 9 with a focal, and 3 with an atypical histology. Neurodevelopmental outcome was assessed using standardized psychological tests and questionnaires. RESULTS: 28 of 60 patients showed developmental delay (46.7%). 9 of 57 patients had cognitive deficits (15.8%), 7 of 26 patients had speech problems (26.9%), and 17 of 44 patients had motor problems (38.6%). In 5 of 53 patients, social emotional problems were reported. Outcome and the underlying genetic defect were not correlated. CONCLUSIONS: Motor problems seem to be prominent in CHI patients. Despite a high incidence of developmental delay, a permanent cognitive defect was only detectable in 9 of 58 patients. PMID- 29151085 TI - A Novel Mutation in the Critical P-Box Residue of Steroidogenic Factor-1 Presenting with XY Sex Reversal and Transient Adrenal Failure. AB - BACKGROUND: Although the importance of steroidogenic factor-1 (SF1, NR5A1) for adrenal development is supported by numerous in vitro and in vivo studies, cases of SF1 deficiency associated with adrenal failure are exceptionally rare. The first human NR5A1 mutation was a heterozygous de novo p.G35E variant identified in a patient with disorder of sex development (DSD) 46,XY and primary adrenal insufficiency. Here we describe another association of the "classic" SF1 phenotype with a novel NR5A1 mutation affecting G35 residue. METHODS: We describe the clinical characteristics of a phenotypically female patient presenting at 2 months with signs of adrenal insufficiency. DSD 46,XY was diagnosed at 4 years. The NR5A1 gene was analyzed by Sanger sequencing. Minigene splicing and dual luciferase reporter assays were used to characterize effects of the novel mutation on splicing and transcription, respectively. RESULTS: Sequencing of the NR5A1 gene revealed a de novo heterozygous c.104G>A:p.G35D substitution. The minigene experiments demonstrated that c.104G>A substitution did not affect splicing. However, transactivation activity of the p.G35D mutant was clearly impaired, which was comparable with the effect of the p.G35E mutation. CONCLUSIONS: The findings stress the importance of G35 residue for adrenal development. The current observation also suggests that some patients with SF1 deficiency may present with transient adrenal failure. PMID- 29151086 TI - Analysis of the Cytomorphological Features in Atypical Urine Specimens following Application of The Paris System for Reporting Urinary Cytology. AB - BACKGROUND: This study investigates the use of The Paris System (TPS) for Reporting Urinary Cytopathology and examines the performance of individual and combined morphological features in atypical urine cytologies. METHODS: We reviewed 118 atypical cytologies with subsequent bladder biopsies for the presence of several morphological features and reclassified them into Paris System categories. The sensitivity and specificity of individual and combined features were calculated along with the risk of malignancy. RESULTS: An elevated nuclear-to-cytoplasmic ratio was only predictive of malignancy if seen in single cells, while irregular nuclear borders, hyperchromasia, and coarse granular chromatin were predictive in single cells and in groups. Identification of coarse chromatin alone yielded a malignancy risk comparable to 2-feature combinations. The use of TPS criteria identified the specimens at a higher risk of malignancy. CONCLUSION: Our findings support the use of TPS criteria, suggesting that the presence of coarse chromatin is more specific than other individual features, and confirming that cytologic atypia is more worrisome in single cells than in groups. PMID- 29151087 TI - Ganser Syndrome. AB - Ganser's syndrome is a rare and controversial condition, whose main and most striking feature is the production of approximate answers (or near misses) to very simple questions. For instance, asked how many legs a horse has, Ganser patients will reply "5", and answers to plain arithmetic questions will likewise be wrong, but only slightly off the mark (e.g., 2 + 2 = 3). This symptom was originally described by Sigbert Ganser in 1897 in prisoners on remand and labeled Vorbeigehen ("to pass by"), although the term Vorbeireden ("to talk beside the point") is also frequently used. A number of associated symptoms were also reported: "clouding of consciousness," somatoform conversion disorder, hallucinations, sudden and spontaneous recovery, subsequent amnesia for the episode, premorbid traumatic psychosocial experience and/or (usually mild) head trauma. Etiological, epidemiological and diagnostic issues have never been resolved for Ganser's syndrome. Ganser saw it as a form of "twilight hysteria," whereas others suggested that malingering, psychosis or dissociation were more appropriate labels, oftentimes combined with organic impairment and a subjectively intolerable psychosocial context. A central conundrum of Ganser's syndrome is whether it could simultaneously be a cultural and pathological representation of insanity, whereas cognitive, organic, affective, motivational and social factors would converge towards a naive idea of what mental illness should look like, especially through the provision of approximate answers. PMID- 29151088 TI - Cotard Syndrome. AB - Cotard's syndrome is often described as the delusional belief that one is dead or non-existent. However, Jules Cotard's initial description (1880) of the "delusion of negations" was much richer and also involved delusions and claims of immortality and enormity, feelings of damnation, and illusions of bodily dissolution and transformation. Alternatively conceived as an extreme case of depression, hypochondria, or psychosis, the condition is considered rare and remains poorly understood. Cotard himself provided a taxonomy and several explanations for the condition, focusing on its distinction from classical persecutory delusions and suggesting that it could be a kind of reversed grandiosity. He proposed a psychosensory basis in the dissolution of mental imagery, which he then extended to a more general psychomotor impairment of volition. Other early authors highlighted a disorder of the bodily self, and more recent theories postulated an impairment of right hemispheric functions, leading to perceptual and somatosensory feelings of unreality, which coupled with reasoning impairments and an internalized attributional style led in turn to beliefs of non-existence. However, despite its striking presentation and its relevance to our understanding of self-awareness, Cotard's syndrome remains an elusive condition, rarely reported and poorly researched. PMID- 29151089 TI - Capgras Syndrome and Other Delusional Misidentification Syndromes. AB - The delusional misidentification syndromes (DMS) are a group of disorders, characterized by patients mistaking the identity of people they know, although they recognize them physically. The term DMS is an umbrella term which may cover disorders whose definition extends to objects other than people, such as animals, places, or familiar material objects. The most common and best known DMS is Capgras syndrome. In this disorder, the misidentification leads to the delusional conviction that a close friend or relative has been replaced by an identical - or almost identical - "double," whose original has disappeared. This double is an imposter without name or identity. Most often considered as a persecutor, the double may be subjected to aggression, which may be very violent. Neuropsychological hypotheses based on cerebral dysfunctions are now commonly considered to be at the origin of the disorder. They have been elaborated from achievements in the neurosciences, particularly the facial recognition models. In return, knowledge about the normal cognitive processes involved in recognition and familiarity has benefited from the work that cognitive neuropsychiatry has invested in these disorders. The DMS are observed in various contexts of morbidity: primary psychiatric diagnosis, or secondary to various organic disorders, particularly in neurodegenerative disease; they are rarely met in isolated form. Most often, they develop in line with the associated pathology. In the absence of consensual clinical description, the epidemiology of DMS is uncertain; they may be more frequent than previously supposed. There is no specific treatment for these disorders; neuroleptics are generally used in association with treatment of the concomitant disorder. The frequent association of DMS with organic disorders which may be curable and the particularly dangerous profile of these patients are factors that underline the need for better screening. PMID- 29151090 TI - De Clerambault Syndrome, Othello Syndrome, Folie a Deux and Variants. AB - Non-bizarre delusion, defined as a false belief possible although highly unlikely, is the main manifestation of delusional disorders, previously known as paranoia. Based on the predominant delusional themes, 5 main subtypes may be described - erotomanic, grandiose, jealous, persecutory, and somatic. We present here 2 main delusional disorders, the De Clerambault syndrome and the Othello syndrome, and another closely related to the previous ones - Folie a deux. In the De Clerambault syndrome, the main delusional theme is erotomanic type, related to passional delirium where the patient has strong sexual feelings towards another person and has the belief that this other person is deeply in love with him or her. Patients with the Othello syndrome present a delusional disorder of jealous type, a pathological delusion that the partner is unfaithful. In Folie a deux, 2 individuals shared the same psychiatric symptom. However it may be variable, describing variants such as folie imposee or folie simultenee. The risk of aggressive behavior exists in these patients. Knowledge of these syndromes is essential to allow an accurate diagnosis and prompt treatment. PMID- 29151091 TI - Couvade Syndrome - Custom, Behavior or Disease? AB - The custom of Couvade and Couvade syndrome is a phenomenon observed since ancient times. Whether it constitutes a disease entity or it should be considered a ritual or custom remains a matter of debate. Historical transcripts shed light into the distinct origins and inclinations of couvade behaviors, some of them having religious inclinations. Currently, there are several views on this phenomenon including medical, psychoanalytic, and psychological. Some explain this syndrome as part of men's preparation and participation in pregnancy and post-partum period. Others see it as men rivalling with women for procreative ability or ability to carry an unborn child in the womb. There are a set of criteria that can be used in diagnosing Couvade syndrome, which may be helpful in standardizing clinical detection and management of patients. It is important to embed this syndrome in contemporary society to understand the complexity of male involvement in pregnancy and fatherhood, which at the end may not be a disease. In this review, the authors will guide the reader through history, possible etiologies, and clinical aspects of Couvade syndrome. PMID- 29151092 TI - Conversion, Factitious Disorder and Malingering: A Distinct Pattern or a Continuum? AB - This chapter is aimed at highlighting the recent findings concerning physiopathology, diagnosis, and management of conversion, factitious disorder, and malingering. Conversion disorder is the unintentional production of neurological symptom, whereas malingering and factitious disorder represent the voluntary production of symptoms with internal or external incentives. They have a close history and this has been frequently confounded. Practitioners are often confronted to medically unexplained symptoms; they represent almost 30% of neurologist's consultation. The first challenge is to detect them, and recent studies have confirmed the importance of "positive" clinical bedside signs based on incoherence and discordance, such as the Hoover's sign for the diagnosis of conversion disorder. Functional neuroimaging has allowed a better understanding of the pathophysiology, and highlighted abnormal cerebral activation patterns in conversion disorder in relation to motor, emotional, and limbic networks, different from feigners. This supports the theory evoked by Charcot of a "psychodynamic lesion," which is also reflected by the new term introduced in the DSM-5: functional neurological disorder. Multidisciplinary therapy is recommended with behavioral cognitive therapy, antidepressant to treat frequent comorbid anxiety or depression, and physiotherapy. Factitious disorder and malingering should be clearly delineated from conversion disorder. Factitious disorder should be considered as a mental illness and more research on its physiopathology and treatment is needed, when malingering is a non-medical condition encountered in medico-legal cases. PMID- 29151093 TI - Munchausen Syndrome and the Wide Spectrum of Factitious Disorders. AB - Since its initial description in 1851, Munchausen syndrome has been widely used interchangeably with factitious disorder. Nevertheless, this syndrome is only one form of factitious disorder that is both severe and chronic. The syndrome was named after Karl Friedrich Hieronymus, Baron von Munchhausen (1720-1797), a German nobleman who became famous as a narrator of false and exaggerated exploits. His name was progressively corrupted to Munchausen. Factitious disorders and Munchausen syndrome remain a great diagnosis challenge for physicians. All medical specialities are concerned by these disorders. The diagnosis process involves a first step to exclude an unusual presentation of a common medical condition. The second step consists of excluding somatoform disorders and malingering. Unfortunately, the boundaries between factitious disorder, somatization, and malingering are often unclear. In 1977, the term "Munchausen's syndrome by proxy" was coined to define a situation where a person produces false symptoms in another one, especially a child. This term was extended to similar interactions between human and pets. Because varied conditions have been included in the definition of this syndrome, there is ongoing debate about alternative names. PMID- 29151094 TI - Glossolalia and Aphasia: Related but Different Worlds. AB - The word glossolalia, also referred to as "speaking in tongues," originates from the Greek "glossa" which means "language" and "Lalia" which means "speak." It simply means to talk language. On a linguistic perspective, glossolalia is characterized by almost no recognizable words or semantic content, apart from biblical words and phrases, with an overrepresentation of a small phonemes number, accelerated speech output, and modification of accents and melody. Its phonemic properties have been said to resemble those of the language(s) of the speaker. It is generally a voluntary intimate communication act associated with religious spiritual thoughts, although it has also been described in mental disorders. Glossolalia state is a special mental state, completely different from aphasia. Aphasia is characterized by some phonological and grammatical rules; however, these are related to neurolinguistics and not to developmental principles. Unlike aphasia, glossolalia is not associated with central nervous system affection. There is, however, a psychiatric type of glossolalia, which, although similar in terms of phenomenology, is probably a different phenomenon. A common thought is that there is a linguistic trend, whose basic component is a stream of speech. This stream is suggested to use early-acquired rules of phonation, adapted according to socially meaningful values and attitudes, in an unconscious way. Therefore, the act of glossolalia is out of the "glossolalists" control. It would appear, therefore, that there is a broad spectrum of anomalous speech, of which religious glossolalia is only one manifestation. The aim of this chapter is to understand the mental state of glossolalia in comparison to aphasia in the light of neurolinguistic and psychiatric features. Moreover, we tried to highlight the underlying brain network. Pilot neuroscientific data suggest that it is associated with a deactivation of the cognitive system and an activation of some parts of the mirror neuron networks. PMID- 29151095 TI - Violent Behavior. AB - Violence is a significant public health problem representing one of the leading causes of death worldwide for people aged 15-44 years. Although violence and aggression are more frequent in adolescence and early adult life and decline with advancing age, these conditions can still develop for the first time in old age especially in association with organic brain disorder. Rates of violent death vary according to country income levels and are twice as higher in low- to middle income countries than in high-income countries. Males are more affected than females. Violence is a multifactorial condition. A combination of biologic, psychodynamic, and social factors may play a role in development of violence and aggression. Since it may accompany or be result of different medical conditions it is important to determine the underlying condition or disease including mental illness for targeting the proper therapeutic strategy. In the acute setting with a behavioral emergency the primary task for the clinician is to act as soon as possible in order to stop the violence from escalating and to find the quickest way to keep the patient's agitation and violence under control with the maximum of safety for everybody using the less severe yet effective interventions. Multiple steps of talk down interventions and non-coercive behavioral and environmental treatments have been proposed. If such an approach is not effective, more coercive interventions are needed including involuntary medications and chemical restrain as well as physical restraint or seclusion in some cases. PMID- 29151096 TI - Jumping Frenchmen, Miryachit, and Latah: Culture-Specific Hyperstartle-Plus Syndromes. AB - In the late 19th century, jumping (French Canadians in Maine, USA), miryachit (Siberia), and latah (Southeast Asia) were among a group of similar disorders described around the world, each of which manifests as an exaggerated startle response with additional late-response features that were felt by some to overlap with hysteria or tics. The later features following the exaggerated startle reaction variably include mimesis (e.g., echopraxia, echolalia) and automatic obedience. These reaction patterns tended to persist indefinitely in affected individuals. Because of their dramatic stimulus-driven behaviors, affected individuals were prone to be teased and tormented by being repeatedly and intentionally startled. Despite clinical overlap between jumping and Tourette syndrome, these entities are now recognized as distinct: in jumping, the key feature is an abnormal startle response, the abnormal reaction is always provoked, and tics are absent, whereas in Tourette syndrome, the key feature is spontaneous motor and vocal tics, although patients with Tourette syndrome may occasionally also have an exaggerated startle response. These disorders have been conceptualized from anthropological, psychodynamic, and neurobiologic perspectives, with no complete resolution to date. Attempts at treatment have been generally unsuccessful, including attempts with bromization and hypnosis, although anecdotal reports of successful deconditioning have been published. In population groups affected, these disorders are usually considered as behavioral peculiarities and not as diseases per se, and there is no apparent tendency to develop disabling mental illness or neurodegenerative disorders. The genesis of these disorders, their cultural and social components, and their interactions with the presumed underlying physiological substrate need further study. Careful descriptive and analytic epidemiological studies are also lacking for all of these disorders. PMID- 29151097 TI - The Dancing Manias: Psychogenic Illness as a Social Phenomenon. AB - The dancing mania erupted in the 14th century in the wake of the Black Death, and recurred for centuries in central Europe - particularly Germany, the Netherlands, and Belgium - finally abating in the early 17th century. The term "dancing mania" was derived from "choreomania," a concatenation of choros (dance) and mania (madness). A variant, tarantism, was prevalent in southern Italy from the 15th to the 17th centuries, and was attributed at the time to bites from the tarantula spider. Affected individuals participated in continuous, prolonged, erratic, often frenzied and sometimes erotic, dancing. In the 14th century, the dancing mania was linked to a corruption of the festival of St. John's Day by ancient pagan customs, but by the 16th century it was commonly considered an ordeal sent by a saint, or a punishment from God for people's sins. Consequently, during outbreaks in the 14th and 15th centuries, the dancing mania was considered an issue for magistrates and priests, not physicians, even though the disorder proved intractable to decrees and exorcisms. However, in the 16th century Paracelsus discounted the idea that the saints caused or interceded in the cure of the dancing mania; he instead suggested a psychogenic or malingered etiology, and this reformulation brought the dancing mania within the purview of physicians. Paracelsus advocated various mystical, psychological, and pharmacological approaches, depending on the presumptive etiologic factors with individual patients. Only music provided any relief for tarantism. Later authors suggested that the dancing mania was a mass stress-induced psychosis, a mass psychogenic illness, a culturally determined form of ritualized behavior, a manifestation of religious ecstasy, or even the result of food poisoning caused by the toxic and psychoactive chemical products of ergot fungi. In reality, dancing manias did not have a single cause, but component causes likely included psychogenic illness, malingering, and ritualized behaviors. PMID- 29151098 TI - The Alice-in-Wonderland Syndrome. AB - In 1955, English psychiatrist John Todd defined the Alice-in-Wonderland syndrome (AIWS) as self-experienced paroxysmal body-image illusions involving distortions of the size, mass, or shape of the patient's own body or its position in space, often accompanied by depersonalization and/or derealization. AIWS had been described by American Neurologist Caro Lippman in 1952, but Todd's report was the most influential. Todd named the syndrome for the perceptual disorder of altered body image experienced by the protagonist in Alice's Adventures in Wonderland (1865) by Lewis Carroll (Charles Lutwidge Dodgson). In Carroll's original story, Alice experienced several dramatic changes in body size and shape (e.g., shrinking to 10 inches high, growing unnaturally tall but not any wider, and growing unnaturally large). Todd reported 6 cases of AIWS, all of whom had episodic body-image distortions like those experienced by Lewis Carroll's Alice character; some also had visual perceptual disturbances, but none had visual perceptual disorders without body-image distortions. Therefore, AIWS may be accompanied by visual perceptual disorders (e.g., micropsia, macropsia, telopsia, pelopsia), but basing the diagnosis of AIWS on isolated visual perceptual disorders, as has subsequently been done by a number of authors, is inaccurate and misleading. Cases of isolated visual illusions without self-perceived distortions of body size, shape, or form, do not meet Todd's original criteria, nor are they commensurate with the experiences of the protagonist in Alice's Adventures in Wonderland. Furthermore, such cases differ by age and etiology from those that involve somesthetic perceptual disorders. Therefore, the use of the term AIWS for isolated visual illusions is problematic and should be discouraged. Although Todd's and Lippman's cases were adolescents or adults, AIWS is most commonly reported in children. Reported causes include infection (especially with Epstein Barr virus), migraine, epilepsy, depression, and toxic and febrile delirium. PMID- 29151099 TI - Camptocormia: New Signs in an Old Syndrome. AB - Camptocormia is defined as an involuntary flexion of the thoracolumbar spine, without fixed kyphosis, which increases during walking and standing, and abates in the supine position. First described during World War 1 in soldiers suffering from war psychoneuroses, camptocormia has progressively come to refer to any cause of trunk forward-flexed posture during standing and ambulation. It is now admitted that camptocormia should be considered as a syndrome related to many etiologies. In this chapter, we present the historical aspects of the syndrome and its main etiologies. We highlight camptocormia in Parkinson disease and its relationships with Pisa syndrome. PMID- 29151100 TI - Correlation between Cosyntropin Stimulation Study and Disease Severity in Children with Fluid- and Catecholamine-Refractory Shock in the Pediatric and Cardiovascular Intensive Care Unit. AB - BACKGROUND: The cosyntropin stimulation study (CSS) measures the patient's ability to adequately mount a cortisol response. Clinically, CSS results may not be used to guide hydrocortisone use. The objective of this study was to examine how the CSS results are associated with clinical parameters, mortality/disease severity, and use of glucocorticoids in pediatric patients with catecholamine- and fluid-resistant shock. METHODS: This was a retrospective cohort study of patients who had a CSS during 2009-2014 in the intensive care unit at a children's hospital. Data collected included clinical variables, mortality, biochemical studies, and glucocorticoid use. PRISM III scores were used to determine the association between CSS results and disease severity. Adequate response to cosyntropin was defined as peak cortisol of 18 ug/dL or higher. RESULTS: Of the 76 patients that underwent CSS, 68 (89%) had an adequate response to cosyntropin. There was a positive correlation between peak cortisol and PRISM III score (r = 0.45, r2 = 0.2). Glucocorticoid was administered in 52/76 (68%) despite several patients with normal CSS results. CONCLUSIONS: Sicker patients were more likely to have an adequate response to CSS. Clinically, glucocorticoid supplementation was not based on CSS results. Further prospective studies are needed to elucidate if CSS is a valuable clinical tool. PMID- 29151101 TI - Psychoacoustics and Neurophysiological Alterations after 30-36 Hours of Sleep Deprivation. AB - BACKGROUND AND AIM: Sleep deprivation (SD) may result in perceptual and cognitive alterations in healthy subjects. Our objective was to compare whether psychoacoustics and neurophysiological variables in healthy subjects were altered after SD of 30-36 h. METHOD: We examined 22 subjects by means of several psychoacoustics tests, P300 and mismatch negativity (MMN) recordings, and brainstem auditory evoked potentials (BAEP) before and after 30-36 h of SD. RESULTS: In the psychoacoustics tests, we found that after SD, difficulties were experienced by the left ear in the discrimination of words in noise and by the right ear in music discrimination. In the neurophysiological tests, we found delayed latencies of P300 and MMN wave; there was a delay of wave I in both ears, and wave V in the right ear in BAEP. We found significant correlations with positive direction between P300 latency and words in noise and music discrimination in the right ear. CONCLUSIONS: SD results in alterations of central auditory processing perception and delays of brain neurophysiological responses, with some correlations between the psychoacoustics and neurophysiological tests. These alterations may relate to other cognitive alterations that deserve more research in future studies. PMID- 29151102 TI - The Effect of Genistein Supplementation on Vitamin D Levels and Bone Turnover Markers during the Summer in Healthy Postmenopausal Women: Role of Genotypes of Isoflavone Metabolism. AB - AIMS: The objective of this study was to determine whether vitamin D and genistein supplementation had an additive beneficial effect on levels of vitamin D and bone markers and whether this effect was mediated by genes regulating isoflavone metabolism. MATERIALS AND METHODS: We carried out a prospective study in postmenopausal women randomized to calcium and vitamin D supplementation or calcium, vitamin D, and genistein supplementation. Vitamin D, parathyroid hormone (PTH), cross-linked C-telopeptide (CTX), and procollagen 1 N-terminal (P1NP) were determined by electrochemiluminescence. Three SNPs - rs2231142 (ABCG2), rs358231 (cytosolic beta-glucosidase [CBG]), and rs2273697 (ABCC2) - were determined. RESULTS: We included 102 women. The effects on bone remodeling were similar: rises in vitamin D were significantly associated with reductions in PTH, CTX, and P1NP. Pharmacogenomic analysis of the genotypes showed that, in AT heterozygotes of the CBG1368T>A polymorphism, CTX and P1NP were not reduced. CONCLUSION: Genistein added to calcium and vitamin D supplementation had no additional effect. The supplementation of individual AT heterozygotes of the CBG1368T>A polymorphism had no effect on markers of bone remodeling. PMID- 29151103 TI - Immunoregulatory Role of Cannabinoids during Infectious Disease. AB - Although the endocannabinoid system (ECS) is involved in the regulation of several physiological processes, including sleep and the immune response, its role during infections has not been fully studied. It is well known that the use of this drug increases susceptibility to infections because of the impact on the modulation of the immune system. Concerning the medicinal or recreational use of marijuana, its influence on the course of an infection, whether this has been caused by bacteria, viruses, parasites, and to a lesser degree, fungi, has been reported. Furthermore, there is evidence suggesting the involvement of the ECS in the control and elimination of infectious agents such as bacteria, viruses, and some protozoa; in the case of fungi, few studies are available so far. The purpose of this review is to present the existing studies related to infections and the ECS, the microbicidal effects of compounds isolated from Cannabis sativa, and the association between marijuana use and the development of rare pathologies in specific diseases. PMID- 29151104 TI - Clinical Efficacy and Safety of First-Line Dasatinib Therapy and the Relevance of Velocity of BCR-ABL1 Transcript Decline for Achievement of Molecular Responses in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Report from the Juntendo Yamanashi Cooperative Study Group. AB - OBJECTIVE: The use of tyrosine kinase inhibitors led to an improvement in the prognoses of patients with chronic myeloid leukemia (CML). The aims of this study were to investigate the efficacy and safety of dasatinib in Japanese patients and to explore the factors that affect the achievement of molecular responses. METHODS: The primary endpoint was a major molecular response (MMR) by 12 months. The halving time for BCR-ABL1 transcripts was calculated using transcript levels. RESULTS: Thirty-two patients with chronic-phase CML (CML-CP) were enrolled and 30 received 100 mg dasatinib once daily. At 24 months of follow-up, 21 (72%) and 24 (83%) patients achieved an MMR by 12 and 24 months, respectively; the rates of a deep molecular response (DMR) by 12 and 24 months were 48 and 59%, respectively. A shorter halving time of BCR-ABL1 transcripts (<=10.6 days) accurately predicted both an MMR and a DMR. The incidence of pleural effusion was 50%. Our study reconfirmed the efficacy and safety of dasatinib treatment in Japanese patients with newly diagnosed CML-CP. In addition, the usefulness of the halving time of BCR-ABL1 transcripts was validated. CONCLUSION: These data emphasize the significance of an early treatment response in achieving a DMR during dasatinib therapy. PMID- 29151105 TI - Eryptosis - the Neglected Cause of Anemia in End Stage Renal Disease. AB - End stage renal disease (ESRD) invariably leads to anemia which has been mainly attributed to compromised release of erythropoietin from the defective kidneys with subsequent impairment of erythropoiesis. However, erythropoietin replacement only partially reverses anemia pointing to the involvement of additional mechanisms. As shown more recently, anemia of ESRD is indeed in large part a result of accelerated erythrocyte loss due to suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the cell surface. Phosphatidylserine exposing erythrocytes are bound to and engulfed by macrophages and are thus rapidly cleared from circulating blood. If the loss of erythrocytes cannot be fully compensated by enhanced erythropoiesis, stimulation of eryptosis leads to anemia. Eryptotic erythrocytes may further adhere to the vascular wall and thus impair microcirculation. Stimulators of eryptosis include complement, hyperosmotic shock, energy depletion, oxidative stress, and a wide variety of xenobiotics. Signaling involved in the stimulation of eryptosis includes increase of cytosolic Ca2+ activity, ceramide, caspases, calpain, p38 kinase, protein kinase C, Janus activated kinase 3, casein kinase 1alpha, and cyclin-dependent kinase 4. Eryptosis is inhibited by AMP-activated kinase, p21-activated kinase 2, cGMP dependent protein kinase, mitogen- and stress-activated kinase MSK1/2, and some illdefined tyrosine kinases. In ESRD eryptosis is stimulated at least in part by a plasma component, as it is triggered by exposure of erythrocytes from healthy individuals to plasma from ESRD patients. Several eryptosis-stimulating uremic toxins have been identified, such as vanadate, acrolein, methylglyoxal, indoxyl sulfate, indole-3-acetic acid and phosphate. Attempts to fully reverse anemia in ESRD with excessive stimulation of erythropoiesis enhances the number of circulating suicidal erythrocytes and bears the risk of interference with micocirculation, At least in theory, anemia in ESRD could preferably be treated with replacement of erythropoietin and additional inhibition of eryptosis thus avoiding eryptosis-induced impairment of microcirculation. A variety of eryptosis inhibitors have been identified, their efficacy in ESRD remains, however, to be shown. PMID- 29151106 TI - Survival Outcome of Intermediate-Grade Salivary Gland Carcinoma. AB - OBJECTIVE: Histological grade is the most important factor for defining treatment strategies and predicting prognosis for salivary gland carcinoma (SGC). We examined factors affecting long-term recurrence and survival among intermediate grade SGC (IGSGC) patients to define optimal treatment modalities and outcomes. METHODS: We reviewed the clinical and pathological data on 108 IGSGC patients who underwent definitive surgery with or without postoperative radiotherapy. We compared treatment outcomes by treatment strategies such as surgical extent for the primary tumor, neck dissection, or postoperative radiotherapy. RESULTS: During a 103-month median follow-up, local, regional, and distant recurrences were detected in 14 (13.0%), 3 (2.8%), and 21 (19.4%) patients, respectively. The 10-year locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) rates were 83.1, 76.0, and 80.1%, respectively. Multivariate analyses identified a nonparotid primary site as an independent prognostic factor for LRC (p = 0.018). Adenoid cystic carcinoma and a positive pN classification were significantly unfavorable prognostic factors for DMFS (p = 0.025 and p = 0.030, respectively); overall advanced stage was an independent prognostic factor for OS (p = 0.020). Surgical extent, elective neck dissection, and postoperative adjuvant radiotherapy did not significantly affect treatment outcomes. CONCLUSION: Patients with early-stage IGSGC of parotid origin can achieve favorable treatment outcomes with conservative surgery alone. PMID- 29151107 TI - Repeated Micro-Trauma of the Penile Tunica Albuginea: A New Animal Model of Peyronie's Disease. AB - OBJECTIVES: To compare effects of repairing injured tunica albuginea (PTA) of rat penis by single or repeated local injections of chlorhexidine ethanol (ChE) into the PTA and to establish a new animal model of Peyronie's disease (PD). MATERIALS AND METHODS: Forty-two rats were divided into 7 groups. Rats either served as the normal control group with 1-5 injections of 0.9% saline or they received a single injection, 2, 3, 4, or 5 injections of ChE (0.1% chlorhexidine gluconate plus 15% ethanol dissolved in saline); rats in the positive control group were injected with TGF-beta1. At 60 days after the last injection, the intracavernous pressure, degree of penile curvature, and histology were evaluated. RESULTS: Compared with the single injection of the ChE group, we found the following in the repeat ChE injections groups: an increase in the degree of penile curvature, fibrous plaques in the PTA and/or corpus cavernosum, broken elastic fibers, slightly decreased erectile function, and an increased expression of TGF-beta1 and alphaSMA. CONCLUSIONS: Repeated ChE injuries of PTA may lead to fibrosis. This represents an excellent model of PD that involves repeated injections of ChE into the local PTA as well as reveals the pathophysiologic mechanism of PD. PMID- 29151108 TI - A Phenomenological Account of Sensorimotor Difficulties in Autism: Intentionality, Movement, and Proprioception. AB - During the last decades, the focus in autism research has been progressively extended. Today it offers a large amount of material on sensorimotor disturbances as well as perceptive-cognitive preferences of people with autism. However, there are more and more critical voices against an intellectualist perspective in the cognitive sciences. The "enactive approach" as well as a new "movement perspective" to autism challenge the view of autism as a mere "cognitive" disturbance. They criticize the conception of a cognizing subject which is only interested in the world in as much as she/he can extract knowledge and organize it rationally. The present paper discusses fundamental insights from this critical sensorimotor perspective to autism from a phenomenological standpoint. Several important papers have already proven the fruitful combination of phenomenology with sensorimotor-focused research in the field of autism. However, these writings generally concentrate on problems of embodied intersubjectivity as an alternative approach to leading "theory of mind" paradigms. The present article reflects on the role and dimension of sensorimotor problems in themselves and not primarily in the intersubjective encounter. The notion of body intentionality will turn out to be a central heuristic device in order to understand the subject's relationship to the world within a holistic framework, in which the person's way to move, feel, and perceive are manners of understanding his/her own world. Empirical findings on difficulties in proactive and anticipatory control of movement as well as research outcome on proprioception and kinesthetic feedback will provide suitable material for discussing the transformation of body intentionality in autism. Phenomenology will provide the theoretical foundation in order to understand atypical movement patterns as alternative ways for producing alternative meanings. PMID- 29151109 TI - Reporting of Randomized Trials in Common Cancers in the Lay Media. AB - BACKGROUND: Limited data exist about the role of the lay media in the dissemination of results of randomized controlled trials (RCTs) in common cancers. METHODS: Completed phase III RCTs evaluating new drugs in common cancers between January 2005 and October 2016 were identified from ClinicalTrials.gov. Lay media reporting was identified by searching LexisNexis Academic. Scientific reporting was defined as presentation at an academic conference or publication in full. Associations between reporting in the lay media before scientific reporting and study design and sponsorship were evaluated using logistic regression. RESULTS: Of 180 RCTs identified, 52% were reported in the lay media and in 27%, lay media reporting occurred before scientific reporting with an increasing trend over time (p = 0.009). Reporting in the lay media before scientific reporting was associated with positive results (OR: 2.10, p = 0.04), targeted therapy compared to chemotherapy (OR: 4.75, p = 0.006), immunotherapy compared to chemotherapy (OR: 7.60, p = 0.02), and prostate cancer compared to breast cancer (OR: 3.25, p = 0.02). CONCLUSIONS: Over a quarter of all RCTs in common cancers are reported in the lay media before they are reported scientifically with an increasing proportion over time. Positive trials, studies in prostate cancer, and trials of immunotherapy are associated with early reporting in the lay media. PMID- 29151110 TI - Family-Oriented Rehabilitation (FOR) and Rehabilitation of Adolescents and Young Adults (AYA) in Pediatric Oncology. AB - This paper describes the function and contribution of family-oriented oncologic rehabilitation (FOR) and of oncologic rehabilitation for adolescents and young adults (AYA). The rehabilitation of children with cancer and their families and that of AYA is an integral component of pediatric oncologic treatment regimens. 32 years ago, FOR was developed in Germany and continues in a select number of highly-specialized rehabilitation centers recommended by the GPOH (Gesellschaft fur Padiatrische Onkologie und Hamatologie, Society of Pediatric Oncology and Hematology). After oncologic treatment, the patient, along with his or her family, begins an individualized rehabilitation process. The whole family participates in this process to ensure success. AYA patients are rehabilitated in small peer groups. In FOR, the immediate goal is to stabilize the family system in order to ensure maximum success for the patient. The long-term goal of FOR and AYA rehabilitation is to provide support for a return to as normal and self determined a life as possible. Patients who suffer from chronic illnesses due to their oncologic disease and therapy (for example, a significant number of brain tumor patients) need long-term help in various areas. Here, multiple 4-week cycles of oncologic rehabilitation may be necessary throughout a patient's lifetime. PMID- 29151111 TI - Readability Assessment of Patient Education Material Published by German-Speaking Associations of Urology. AB - OBJECTIVE: To assess the readability and comprehensibility of web-based German language patient education material (PEM) issued by urological associations. MATERIALS AND METHODS: German PEM available in June 2017 was obtained from the European Association of Urology (EAU), German (DGU), Swiss (SGU) and Austrian (OGU) Association of Urology websites. Each educational text was analyzed separately using 4 well-established readability assessment tools: the Amstad Test (AT), G-SMOG (SMOG), Wiener Sachtextformel (WS) and the Lesbarkeitsindex (LIX). RESULTS: The EAU has issued PEM on 8 topics, the DGU 22 and the SGU 5. The OGU refers to the PEMs published by the DGU. Calculation of grade levels (SMOG, WS, LIX) showed readability scores of the 7th-14th grades. The easiest readability was found for materials on Nocturia and Urinary Incontinence issued by the EAU. Kidney Cancer and Infertility, issued by the DGU had the hardest readability. The EAU achieved the best median AT score, followed by the SGU, and the DGU. CONCLUSION: Remarkable differences between readability were found for the PEMs issued by EAU, DGU and SGU. Materials published by the EAU were the easiest to read. Improving the readability of certain PEMs is of crucial importance to meet patient needs and act in the interests of a growing, self-informing German speaking patient community. PMID- 29151112 TI - Phase Difference-Enhanced Magnetic Resonance (MR) Imaging (PADRE) Technique for the Detection of Age-Related Microstructural Changes in Optic Radiation: Comparison with Diffusion Tensor Imaging (DTI). AB - BACKGROUND The optic radiation (OR) is a white-matter bundle connecting the lateral geniculate body and the visual cortex. Phase difference-enhanced imaging (PADRE) is a new MRI technique that is able to achieve precise delineation of the OR. The aim of this study was to investigate the effect of age on the volume and signal intensity of the OR using PADRE, and to establish a volumetric reference of the OR from a healthy population, compared with diffusion tensor imaging (DTI). MATERIAL AND METHODS Thirty-nine healthy volunteers underwent MR imaging with PADRE and DTI sequences on a 3.0-T scanner. For the volumetric analysis with PADRE, the OR corresponding to the external sagittal stratum was manually traced, while an automated thresholding method was used for the DTI-based volumetric analysis of the OR. RESULTS The mean right and left OR volumes measured from the PADRE images were 1469.0+/-242.4 mm3 and 1372.6+/-310.2 mm3, respectively. Although OR volume showed no significant correlation with age, the normalized OR signal intensity showed a linear correlation with increasing age (r2=0.50-0.53; P<0.01). The OR signal intensity on PADRE and DTI-related quantitative parameters for the OR showed significant correlations (r2=0.46-0.49; P<0.01). CONCLUSIONS The PADRE technique revealed exceptional preservation of OR volume, even in later life. Moreover, PADRE was able to detect age-related changes in signal intensity of the OR and may contribute to future analyses of pathological neurodegeneration in patients with glaucoma and multiple sclerosis. PMID- 29151113 TI - CPNE1 Is a Useful Prognostic Marker and Is Associated with TNF Receptor Associated Factor 2 (TRAF2) Expression in Prostate Cancer. AB - BACKGROUND CPNE1 plays a vital role in regulating cell differentiation. The clinical and biological values of CPNE1 in prostate cancer are still unclear. The aim of this study was to investigate the clinicopathological value of CPNE1 and the association of CPNE1 with TRAF2 expression in patients with prostate cancer. MATERIAL AND METHODS CPNE1 expression in prostate cancer was analyzed using Gene Expression Omnibus (GEO) databases. The Cancer Genome Atlas (TCGA) dataset was used to investigate the association of CPNE1 expression with TRAF2 expression in prostate cancer. The association of CPNE1 expression with recurrence-free survival in patients was also analyzed using the TCGA dataset. Immunohistochemistry assay was performed to examine CPNE1 expression in 65 normal prostate samples and 114 prostate cancer samples. The recurrence-free survival in patients was evaluated using Kaplan-Meier curves and log-rank test. In addition, multivariate and univariate analyses of prognostic factors were investigated by Cox regression. The effect of CPNE1 on TRAF2 expression was explored in human prostate cancer DU-145 cells. RESULTS Our results showed that expression level of CPNE1 is higher in prostate cancer than in normal prostate tissues (P=0.006). In the GSE35988 dataset, CPNE1 expression was found to be upregulated in castration resistant prostate cancer compared with non-castration-resistant prostate cancer (P<0.001). Furthermore, we found that CPNE1 high expression was significantly related to tumor stage, Gleason score, and poorer biochemical recurrence-free survival in prostate cancer patients. Co-expression analysis of TCGA data showed that CPNE1 is significantly associated with TRAF2 expression. CPNE1 overexpression can upregulate TRAF2 expression in prostate cancer DU-145 cells as determined by Western blotting and immunofluorescence assays. CONCLUSIONS Overall, our findings suggest that CPNE1 is a valuable prognostic marker for evaluating recurrence-free survival and is positively related to TRAF2 expression in prostate cancer. PMID- 29151115 TI - Supramodal effect of rightward prismatic adaptation on spatial representations within the ventral attentional system. AB - Rightward prismatic adaptation (R-PA) was shown to alleviate not only visuo spatial but also auditory symptoms in neglect. The neural mechanisms underlying the effect of R-PA have been previously investigated in visual tasks, demonstrating a shift of hemispheric dominance for visuo-spatial attention from the right to the left hemisphere both in normal subjects and in patients. We have investigated whether the same neural mechanisms underlie the supramodal effect of R-PA on auditory attention. Normal subjects underwent a brief session of R-PA, which was preceded and followed by an fMRI evaluation during which subjects detected targets within the left, central and right space in the auditory or visual modality. R-PA-related changes in activation patterns were found bilaterally in the inferior parietal lobule. In either modality, the representation of the left, central and right space increased in the left IPL, whereas the representation of the right space decreased in the right IPL. Thus, a brief exposure to R-PA modulated the representation of the auditory and visual space within the ventral attentional system. This shift in hemispheric dominance for auditory spatial attention offers a parsimonious explanation for the previously reported effects of R-PA on auditory symptoms in neglect. PMID- 29151114 TI - Non-canonical heterogeneous cellular distribution and co-localization of CaMKIIalpha and CaMKIIbeta in the spinal superficial dorsal horn. AB - Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key enzyme in long-term plasticity in many neurons, including in the nociceptive circuitry of the spinal dorsal horn. However, although the role of CaMKII heterooligomers in neuronal plasticity is isoform-dependent, the distribution and co-localization of CaMKII isoforms in the dorsal horn have not been comprehensively investigated. Here, quantitative immunofluorescence analysis was used to examine the distribution of the two major neuronal CaMKII isoforms, alpha and beta, in laminae I-III of the rat dorsal horn, with reference to inhibitory interneurons and neuronal populations defined by expression of parvalbumin, calretinin, and calbindin D28k. Unexpectedly, all or nearly all inhibitory and excitatory neurons showed both CaMKIIalpha and CaMKIIbeta immunoreactivity, although at highly variable levels. Lamina III neurons showed less CaMKIIalpha immunoreactivity than laminae I-II neurons. Whereas CaMKIIalpha immunoreactivity was found at nearly similar levels in inhibitory and excitatory neurons, CaMKIIbeta generally showed considerably lower immunoreactivity in inhibitory neurons. Distinct populations of inhibitory calretinin neurons and excitatory parvalbumin neurons exhibited high CaMKIIalpha to-CaMKIIbeta immunoreactivity ratios. CaMKIIalpha and CaMKIIbeta immunoreactivity showed positive correlation at GluA2+ puncta in pepsin-treated tissue. These results suggest that, unlike the forebrain, the dorsal horn is characterized by similar expression of CaMKIIalpha in excitatory and inhibitory neurons, whereas CaMKIIbeta is less expressed in inhibitory neurons. Moreover, CaMKII isoform expression varies considerably within and between neuronal populations defined by laminar location, calcium-binding protein expression, and transmitter phenotype, suggesting differences in CaMKII function both between and within neuronal populations in the superficial dorsal horn. PMID- 29151116 TI - Do alpha-1 antagonist medications affect the success of semi-rigid ureteroscopy? A prospective, randomised, single-blind, multicentric study. AB - The objective of this study is to assess the efficacy of adjunctive silodosin therapy in improving the success rate of semi-rigid ureteroscopy for removing ureteral stones. Prospective randomised controlled clinical trial performed between July 2016 and September 2016. All the patients underwent ureteroscopic holmium lithotripsy with a YAG laser. The patients were randomised into one of three groups: those who did not use an alpha-1 blocker (AB) (Group 1, n = 50), those who used an AB for one day (Group 2, n = 50), and those who used an AB for three days (Group 3, n = 47). The following information was recorded for each patient: the side, location, and surface area of the stone; successful access; operative success; complications; and operative time. There were no significant differences between the three groups in terms of demographics, stone location or size, and number of doses of an analgesic drug used. Access to the stone and the stone-free rate were significantly higher in group 3 (95.7, 93.6%) than in group 1 (76, 74%) and group 2 (78, 74%) (p = 0.018, p = 0.021), respectively. Balloon dilatation and complication rates were significantly lower in group 3 (12.8, 0%) than in group 1 (34, 12%) and group 2 (22, 4%) (p = 0.045, p = 0.029), respectively. The use of silodosin for 3 days before ureteroscopy for ureteral stones increased the rate of access to all ureter stones and decreased the complication rate. PMID- 29151117 TI - Risks of flexible ureterorenoscopy: pathophysiology and prevention. AB - Currently, indications for flexible ureterorenoscopy (fURS) are expanding, mainly due to technological advancements. Although data from clinical series definitely presents fURS as a safe procedure, serious complications including sepsis and ureteral lesions do occur. These complications seem to be a result of the unique elements of fURS, ureteral access and irrigation, pushing normal upper urinary tract physiology into pathophysiological processes, including intrarenal/pyelo veneous backflow and ureteral contractions, potentially resulting in septic, haemorrhagic and ureteral lesional complications. Knowledge on normal upper urinary tract physiology are crucial for understanding how these harmful effects of fURS may be avoided or minimized. The pathophysiology of intrarenal pressure increases and ureteral access will be discussed as a basis for understanding preventive measures. Role of antibiotics, ureteral access sheaths, safty guidewires, pain medication, prestenting and pharmacologic modulation of pyeloureteral dynamics are reviewed from a pathophysiological perspective. PMID- 29151118 TI - Semi-rigid ureteroscopy: indications, tips, and tricks. AB - Advances in ureteroscopic technology, alongside broadening treatment options have fuelled the rapid expansion of endourology. Semi-rigid ureteroscopy is a well known procedure used globally for varying urological conditions, with high success rates. This article aims to provide 'tips and tricks' for the semi-rigid ureteroscopy procedure, and the management of commonly encountered pathology such as renal stones, ureteric strictures, and urothelial tumours. PMID- 29151119 TI - Whole-body magnetic resonance imaging for detection of skeletal metastases in children and young people with primary solid tumors - systematic review. AB - BACKGROUND: Many solid neoplasms have a propensity for osteomedullary metastases of which detection is important for staging and subsequent treatment. Whole-body magnetic resonance imaging (WB-MRI) has been shown to accurately detect osteomedullary metastases in adults, but these findings cannot be unconditionally extrapolated to staging of children with malignant solid tumors. OBJECTIVE: To conduct a literature review on the sensitivity of WB-MRI for detecting skeletal metastases in children with solid tumors. MATERIALS AND METHODS: Searches in MEDLINE and EMBASE databases up to 15 May 2017 were performed to identify studies on the diagnostic value of WB-MRI. Inclusion criteria were children and adolescents (age <21 years) with a primary solid tumor who were evaluated for skeletal metastases by WB-MRI and compared to any type of reference standard. The number of included patients had to be at least five and data on true positives, true negatives, false-positives and false-negatives had to be extractable. RESULTS: Five studies including 132 patients (96 patients with solid tumors) were eligible. Patient groups and used reference tests were heterogeneous, producing unclear or high risk of bias. Sensitivity of WB-MRI ranged between 82% and 100%. The positive predictive value of WB-MRI was variable among the studies and influenced by the used reference standard. CONCLUSION: Although WB-MRI may seem a promising radiation-free technique for the detection of skeletal metastases in children with solid tumors, published studies are small and too heterogeneous to provide conclusive evidence that WB-MRI can be an alternative to currently used imaging techniques. PMID- 29151120 TI - Biomechanical stress in myocardial infarctions: can endothelin-1 and growth differentiation factor 15 serve as immunohistochemical markers? AB - Myocardial infarctions go along with biomechanical stress, i.e. stretching of muscle fibres, and the expression of certain marker molecules. We tested if two of those markers, endothelin-1 (ET-1) and growth differentiation factor 15 (GDF 15), can be used as immunohistochemical markers for myocardial ischaemia/infarctions. The study included experiments with an animal model, the isolated perfused Langendorff heart, as well as the investigation of human tissue samples drawn during autopsies. The overall picture of our results showed that GDF-15 is very sensitive and expressed very fast, not only as a consequence of ischaemia/infarctions, but also under other circumstances. Even an expression only caused by agony had to be discussed. ET-1, on the other hand, was less sensitive but only positive in those human cases with ischaemia/infarction that also showed typical alterations in conventional histology. Therefore, both markers did not proof to be a suitable diagnostic tool for myocardial infarctions. However, positive staining for ET-1 was also seen in rats' hearts that suffered from arrhythmias after electric shock and in the myocardium of the right ventricle in human control cases in which a right heart failure has to be discussed. Thus, especially ET-1 should be subject of further studies that focus on these pathologies. PMID- 29151121 TI - Impact of several wearers on the persistence of DNA on clothes-a study with experimental scenarios. AB - The detection of DNA of a certain person on the inside of a piece of clothing involved in a crime scene is usually seen as confirmation that this person is the owner or bearer and therefore participated in this crime. However, besides the possibilities of secondary or even tertiary transfer of DNA, the accused often argues that he lent the garment to another person who by chance did not leave any DNA while committing the crime. Then, forensic genetic scientists have to answer the question how long DNA persists on an item used in daily routine and how long a piece of clothing must be worn to definitively leave detectable DNA behind. In an attempt to answer these questions, several scenarios with two or three individuals wearing the same sweatband for different time periods were set up. DNA left on the sweatbands was isolated, quantified, and then analyzed using the Powerplex(r) ESX17fast kit. The majority of samples displayed all alleles of both/all three wearers on the outside (67%) as well as on the inside (80%) of the sweatbands. In contrast, a single profile of the first wearer could only be found once among all 204 samples, a single profile of the second wearer in 7% of samples. Wearing the sweatband for only 10 min was enough to result in a complete profile of the second wearer in 79% of samples. So, it is highly unlikely to wear/use a piece of clothing for even a short period of time without leaving own DNA behind. PMID- 29151122 TI - Genetic polymorphisms in 18 autosomal STR loci in the Tibetan population living in Tibet Chamdo, Southwest China. AB - Short tandem repeats (STRs) play a vitally important role in forensics. Population data is needed to improve the field. There is currently no large population data-based data set in Chamdo Tibetan. In our study, the allele frequencies and forensic statistical parameters of 18 autosomal STR loci (D5S818, D21S11, D7S820, CSF1PO, D2S1338, D3S1358, VWA, D8S1179, D16S539, PentaE, TPOX, TH01, D19S433, D18S51, FGA, D6S1043, D13S317, and D12S391) included in the DNATyperTM19 kit were investigated in 2249 healthy, unrelated Tibetan subjects living in Tibet Chamdo, Southwest China. The combined power of discrimination and the combined probability of exclusion of all 18 loci were 0.9999999999999999999998174 and 0.99999994704, respectively. Furthermore, the genetic relationship between our Tibetan group and 33 previously published populations was also investigated. Phylogenetic analyses revealed that the Chamdo Tibetan population is more closely related genetically with the Lhasa Tibetan group. Our results suggest that these autosomal STR loci are highly polymorphic in the Tibetan population living in Tibet Chamdo and can be used as a powerful tool in forensics, linguistics, and population genetic analyses. PMID- 29151124 TI - Ten tips for ICU sedation. PMID- 29151123 TI - A Coxsackievirus B vaccine protects against virus-induced diabetes in an experimental mouse model of type 1 diabetes. AB - AIMS/HYPOTHESIS: Epidemiological studies suggest a role for Coxsackievirus B (CVB) serotypes in the pathogenesis of type 1 diabetes, but their actual contribution remains elusive. In the present study, we have produced a CVB1 vaccine to test whether vaccination against CVBs can prevent virus-induced diabetes in an experimental model. METHODS: NOD and SOCS1-tg mice were vaccinated three times with either a formalin-fixed non-adjuvanted CVB1 vaccine or a buffer control. Serum was collected for measurement of neutralising antibodies using a virus neutralisation assay. Vaccinated and buffer-treated mice were infected with CVB1. Viraemia and viral replication in the pancreas were measured using standard plaque assay and PCR. The development of diabetes was monitored by blood glucose measurements. Histological analysis and immunostaining for viral capsid protein 1 (VP1), insulin and glucagon in formalin-fixed paraffin embedded pancreas was performed. RESULTS: The CVB1 vaccine induced strong neutralising antibody responses and protected against viraemia and the dissemination of virus to the pancreas in both NOD mice (n = 8) and SOCS1-tg mice (n = 7). Conversely, 100% of the buffer-treated NOD and SOCS1-tg mice were viraemic on day 3 post infection. Furthermore, half (3/6) of the buffer-treated SOCS1-tg mice developed diabetes upon infection with CVB1, with a loss of the insulin-positive beta cells and damage to the exocrine pancreas. In contrast, all (7/7) vaccinated SOCS1-tg mice were protected from virus-induced diabetes and showed no signs of beta cell loss or pancreas destruction (p < 0.05). CONCLUSIONS/INTERPRETATION: CVB1 vaccine can efficiently protect against both CVB1 infection and CVB1-induced diabetes. This preclinical proof of concept study provides a base for further studies aimed at developing a vaccine for use in elucidating the role of enteroviruses in human type 1 diabetes. PMID- 29151125 TI - Ventricular septal defect without tamponade after penetrating trauma. PMID- 29151126 TI - Nutritional Programming of Bone Structure in Male Offspring by Maternal Consumption of Citrus Flavanones. AB - Maternal exposure to hesperidin (HSP) and naringin (NAR) during pregnancy and lactation transiently compromised bone mineral density (BMD) and bone structure at the proximal tibia in female CD-1 offspring. We examined whether maternal consumption of HSP + NAR during pregnancy and lactation compromises BMD, bone structure, and bone strength in male CD-1 offspring. Male CD-1 offspring, from mothers fed a control diet (CON, n = 10) or a 0.5% HSP + 0.25% NAR diet (HSP + NAR, n = 8) for 5 weeks before mating and throughout pregnancy and lactation, were weaned and fed CON until 6 months of age. In vivo micro-computed tomography (uCT) measured tibia BMD and structure at 2, 4, and 6 months of age. Ex vivo uCT measured femur and lumbar vertebrae (LV) structure at age 6 months. Ex vivo BMD (femur, LV) and biomechanical strength (femur and tibia midpoint, femur neck) were assessed at age 6 months by dual energy x-ray absorptiometry and strength testing, respectively. At all ages, HSP + NAR offspring had greater (p < 0.05) proximal tibia cortical structure compared to CON offspring. At age 4 months, proximal tibia trabecular structure was greater (p < 0.05) than CON offspring. At age 6 months, femur neck and LV trabecular structure were greater (p < 0.05) than CON offspring. Our results demonstrate that unlike our previous study of female offspring, maternal consumption of HSP + NAR resulted in greater bone structure at the proximal tibia in male CD-1 offspring that persisted to 6 months of age. Thus, maternal programming of offspring BMD and bone structure from consumption of HSP + NAR occurred as a sex-specific response. PMID- 29151127 TI - Permeability of hair to cadmium, copper and lead in five species of terrestrial mammals and implications in biomonitoring. AB - The capacity of mammal hair to absorb toxic metals and its utility in biomonitoring has been broadly studied. Though these metal-binding properties has generally been attributed to the sulphur contained in cysteine, an amino acid that forms part of keratin, there are not many experimental studies that analyze the role of sulphur in the external deposition of potentially toxic metallic elements in order to better understand the potential of hair in biomonitoring and generate better tools for differentiating between internal and external deposition of contaminants. In this study, an experimental analysis is carried out using a scanning electron microscope on hairs of five terrestrial mammal species (Peromyscus furvus, P. maniculatus, Glossophaga soricina, Artibeus jamaicensis and Marmosa mexicana) treated with cadmium, copper and lead salts. We quantified absorbed metals as well as natural elements of the hair by energy dispersive X-ray spectroscopy (EDS) to analyze using simple statistics the role of sulphur in the absorption Cd, Cu and Pb. Given the lack of studies comparing the mechanisms of deposition of metal elements among different orders of Class Mammalia, external morphology was considered to be an important factor in the deposition of metallic particles of Cd, Cu and Pb. Bat species (Glossophaga soricina, Artibeus jamaicensis) showed a high concentration of particles in their scales, however, no between-species differences in metal absorption were observed, and during the exogenous deposition metal particles do not permeate the medulla. These results suggest that the sulphur in hair itself cannot bind metals to hair cuticle and that hair absorption capacity depends on a variety of factors such as aspects of hair morphology. PMID- 29151128 TI - Physical activity in patients with systemic sclerosis. AB - OBJECTIVES: To compare self-reported levels of physical activity (PA) of systemic sclerosis (SSc) patients with the general population. To evaluate in SSc patients factors associated with PA levels and needs and preferences regarding PA. METHODS: Fifty nine SSc patients completed the Short QUestionnaire to ASsess Health-Enhancing PA. The proportion of patients meeting the Dutch Recommendation for PA (= moderate PA for 30 min on >= 5 days/week) and total minutes of PA per week were calculated and compared with similar data from the Dutch population. Characteristics were univariately and multivariately compared between patients with low and high PA levels (either <= or > mean minutes/week of the Dutch population). Needs and preferences regarding PA promotion and guidance related to exercise were assessed by questionnaires. RESULTS: Stratified for age (< 55 or >= 55 years) and gender, the proportion SSc patients meeting the Dutch recommendation for PA was not significantly different from the Dutch population. The total minutes of PA per week was significantly lower among SSc patients (1704 vs. 2614, P < 0.001). Multivariable analyses showed that in SSc patients the male gender, scleroderma health assessment questionnaire (SHAQ) and lack of energy were significantly associated with lower PA levels (P = 0.007; P = 0.042; P = 0.025). Two-third of patients required more information about PA. CONCLUSION: In SSc patients, the total minutes of PA per week are significantly lower compared to the general population. The male gender, functional ability as reflected by SHAQ and lack of energy seem to interfere with PA. These results might guide health professionals in providing their patients with appropriate information on PA. PMID- 29151129 TI - One novel and two uncommon MEFV mutations in Japanese patients with familial Mediterranean fever: a clinicogenetic study. AB - Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in the MEFV gene and characterized by recurrent episodes of fever and polyserositis. To date, over 317 MEFV mutations have been reported, only nine of which account for almost all Japanese patients with FMF. Therefore, the prevalence of rare MEFV variants and their clinical characteristics remains unclear. This study identified MEFV mutations previously unreported in the Japanese population and described their clinical features. We performed MEFV genetic testing in 488 Japanese patients with clinically suspected FMF. Of these patients, we retrospectively analyzed three patients with novel or very uncommon MEFV mutations. In all patients, the clinical diagnosis of FMF was made according to Tel-Hashomer's criteria. One novel missense mutation (N679H) and two rare mutations (T681I and R410H) were identified in the MEFV gene. These mutations were found in compound heterozygous or complex genotypes with other known mutations in exons 1 or 2. According to clinical images, all three patients exhibited typical FMF symptoms. A number of patients with FMF caused by novel or uncommon MEFV variants might exist in the Japanese population; therefore, careful genetic testing is required for accurate diagnosis of this curable genetic disorder. PMID- 29151130 TI - Layered PEGDA hydrogel for islet of Langerhans encapsulation and improvement of vascularization. AB - Islets of Langerhans need to maintain their round morphology and to be fast revascularized after transplantation to preserve functional insulin secretion in response to glucose stimulation. For this purpose, a non-cell-adhesive environment is preferable for their embedding. Conversely, nutrient and oxygen supply to islets is guaranteed by capillary ingrowth within the construct and this can only be achieved in a matrix that provides adhesion cues for cells. In this study, two different approaches are explored, which are both based on a layered architecture, in order to combine these two opposite requirements. A non adhesive islet encapsulation layer is based on polyethyleneglycole diacrylate (PEGDA). This first layer is combined with a second hydrogel based on thiolated gelatin, thiolated-heparin and thiolated-hyaluronic acid providing cues for endothelial cell adhesion and acting as a growth factor releasing matrix. In an alternative approach, a conformal PEGDA coating is covalently applied on the surface of the islets. The coated islets are subsequently embedded in the previously mentioned hydrogel containing thiolated glycosaminoglycans. The suitability of this approach as a matrix for controlled growth factor release has been demonstrated by studying the controlled release of VEGF and bFGF for 14 days. Preliminary tube formation has been quantified on the growth factor loaded hydrogels. This approach should facilitate blood vessel ingrowth towards the embedded islets and maintain islet round morphology and functionality upon implantation. PMID- 29151131 TI - Contrast-enhanced ultrasound of the liver: technical and lexicon recommendations from the ACR CEUS LI-RADS working group. AB - Contrast-enhanced ultrasound (CEUS) is a specific form of ultrasound imaging performed with intravenous administration of microbubble contrast agents. It has been extensively used for liver tumor characterization and was recently added to the American College of Radiology Liver Imaging Reporting and Data System (CEUS LI-RADS). This paper describes technical recommendations for successful liver CEUS lesion characterization, and provides imaging protocol and Lexicon of imaging findings. PMID- 29151132 TI - Safety of intrathecal route: focus to methylprednisolone acetate (Depo-Medrol) use. AB - PURPOSE: Complications of the intrathecal route may cause potential toxicity related to the medical device and properties of the administered drug and/or excipient. A description of clinical and histological effects of polyethylene glycol and miripirium after Depo-Medrol injection, and the adverse reactions of particulate methylprednisolone acetate was conducted. The safety of the intrathecal route with excipients, label and off-label drugs is discussed. METHODS: A bibliographic search in Medline, Google, and Cochrane database from 1940 to June 2016 was performed. The keywords included 'intrathecal methylprednisolone acetate', 'miripirium', 'myristyl-gamma-picolinium', 'side effects', 'intrathecal Depo-Medrol', 'polyethylene glycol', and 'intrathecal devices' used individually or in combination. RESULTS: Adverse reactions have been reported with this intrathecal administration route such as arachnoiditis, bladder dysfunction, headache, meningitis. Some pharmaceutical excipients have been associated with specific toxicity issues and with allergic and anaphylaxis reactions. Additives of methylprednisolone acetate formulations such as polyethylene glycol and miripirium chloride can be neurotoxic when injected intrathecally. Polyethylene glycol-an antimicrobial agent widely used in pharmaceutical drugs-has been associated with cardiovascular, hepatic, respiratory, and CNS toxicity. CONCLUSIONS: Intrathecal methylprednisolone acetate (Depo-Medrol) therapy seems not fully safe due to reported adverse events. The use of other forms of corticosteroid therapy free from excipients should be emphasized such as soluble methylprednisolone sodium succinate. PMID- 29151133 TI - Treatment of relapsed AML and MDS after allogeneic stem cell transplantation with decitabine and DLI-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group. AB - In contrast to the evidence regarding azacitidine (Aza), there is limited knowledge about the combination of decitabine (DAC) and donor lymphocyte infusions as salvage therapy for relapse after allogeneic stem cell transplantation (allo-SCT) so far. We retrospectively analyzed data of 36 patients with hematological (n = 35) or molecular relapse (n = 1) of acute myeloid leukemia (AML, n = 29) or myelodysplastic syndrome (MDS, n = 7) collected from 6 German transplant centers. Patients were treated with a median of 2 cycles DAC (range, 1 to 11). DAC was the first salvage therapy in 16 patients (44%), whereas 20 patients (56%) had previously received 1 to 5 lines of salvage therapy including 16 of them had been treated with Aza. In 22 patients (61%), a median of 2 DLI per patient (range, 1 to 5) was administered in addition to DAC. As a result, overall response rate was 25% including 6 complete remissions (CR, 17%) and 3 partial remissions (PR, 8%). Three patients within the first-line group achieved CR, while also 3 patients receiving DAC as second-line treatment reached CR including 2 patients with previous Aza failure. Median duration of CR was 10 months (range, 2 to 33) and no patient relapsed so far. The 2-year OS rate was 11% (+/- 6%) without any difference between first-line and pretreated patients. Incidence of acute and chronic graft-versus-host disease was 19 and 5%. Taken together, DAC exerts clinical efficacy in patients with AML or MDS relapsing after allo-SCT and is able to induce durable remissions in individual patients suggesting that DAC may be an alternative to Aza or even a second choice after Aza failure. PMID- 29151135 TI - Classification of G-protein coupled receptors based on a rich generation of convolutional neural network, N-gram transformation and multiple sequence alignments. AB - Sequence classification is crucial in predicting the function of newly discovered sequences. In recent years, the prediction of the incremental large-scale and diversity of sequences has heavily relied on the involvement of machine-learning algorithms. To improve prediction accuracy, these algorithms must confront the key challenge of extracting valuable features. In this work, we propose a feature enhanced protein classification approach, considering the rich generation of multiple sequence alignment algorithms, N-gram probabilistic language model and the deep learning technique. The essence behind the proposed method is that if each group of sequences can be represented by one feature sequence, composed of homologous sites, there should be less loss when the sequence is rebuilt, when a more relevant sequence is added to the group. On the basis of this consideration, the prediction becomes whether a query sequence belonging to a group of sequences can be transferred to calculate the probability that the new feature sequence evolves from the original one. The proposed work focuses on the hierarchical classification of G-protein Coupled Receptors (GPCRs), which begins by extracting the feature sequences from the multiple sequence alignment results of the GPCRs sub-subfamilies. The N-gram model is then applied to construct the input vectors. Finally, these vectors are imported into a convolutional neural network to make a prediction. The experimental results elucidate that the proposed method provides significant performance improvements. The classification error rate of the proposed method is reduced by at least 4.67% (family level I) and 5.75% (family Level II), in comparison with the current state-of-the-art methods. The implementation program of the proposed work is freely available at: https://github.com/alanFchina/CNN . PMID- 29151134 TI - KIT D816V- chronic myelomonocytic leukemia progressing to KIT D816V+ associated to mast cell leukemia responding to allogeneic hematopoietic cell transplantation. PMID- 29151136 TI - Whole milk consumption and risk of cardiovascular disease and mortality: Isfahan Cohort Study. AB - BACKGROUND: The association between milk intake and cardiovascular disease (CVD) and mortality risk is still controversial but data from Middle-Eastern populations are scarce. We aimed to study these associations in an Iranian population. METHODS: We used the Isfahan Cohort Study, a population-based prospective study of 6504 adult Iranians. In this analysis, we included 5432 participants free of CVD at baseline with at least one follow-up. Data on whole milk intake and other dietary factors were collected by a food frequency questionnaire at baseline. Cox proportional hazard regression was used to predict risk of CVD events, comprising coronary heart disease (CHD) and stroke, and mortality according to frequency of whole milk intake with adjustment for other potential confounders. RESULTS: During a median 10.9 years of follow-up, we documented 705 new cases of CVD comprising 564 CHD and 141 stroke cases. Compared with non-consumers, less than daily intake of whole milk was significantly associated with lower risk of CVD (HR 0.80, 95% CI 0.65-0.97), CHD (HR 0.81, 95% CI 0.65-0.99), and a non-significant lower risk of stroke (HR 0.79, 95% CI 0.50 1.27). Daily intake of whole milk was not significantly associated with CVD (HR 1.25, 95% CI 0.89-1.75), CHD, and stroke, but was associated with higher risk of all-cause mortality (HR 1.54, 95% CI 1.04-2.29). CONCLUSIONS: Less than daily intake of whole milk was associated with a statistically significant, although modest, lower risk of CVD compared with non-consumption, but this potential benefit may not extend to daily intake in this population. PMID- 29151137 TI - Blood-brain barrier transport and neuroprotective potential of blackberry digested polyphenols: an in vitro study. AB - PURPOSE: Epidemiological and intervention studies have attempted to link the health effects of a diet rich in fruits and vegetables with the consumption of polyphenols and their impact in neurodegenerative diseases. Studies have shown that polyphenols can cross the intestinal barrier and reach concentrations in the bloodstream able to exert effects in vivo. However, the effective uptake of polyphenols into the brain is still regarded with some reservations. Here we describe a combination of approaches to examine the putative transport of blackberry-digested polyphenols (BDP) across the blood-brain barrier (BBB) and ultimate evaluation of their neuroprotective effects. METHODS: BDP was obtained by in vitro digestion of blackberry extract and BDP major aglycones (hBDP) were obtained by enzymatic hydrolysis. Chemical characterization and BBB transport of extracts were evaluated by LC-MSn. BBB transport and cytoprotection of both extracts was assessed in HBMEC monolayers. Neuroprotective potential of BDP was assessed in NT2-derived 3D co-cultures of neurons and astrocytes and in primary mouse cerebellar granule cells. BDP-modulated genes were evaluated by microarray analysis. RESULTS: Components from BDP and hBDP were shown to be transported across the BBB. Physiologically relevant concentrations of both extracts were cytoprotective at endothelial level and BDP was neuroprotective in primary neurons and in an advanced 3D cell model. The major canonical pathways involved in the neuroprotective effect of BDP were unveiled, including mTOR signaling and the unfolded protein response pathway. Genes such as ASNS and ATF5 emerged as novel BDP-modulated targets. CONCLUSIONS: BBB transport of BDP and hBDP components reinforces the health benefits of a diet rich in polyphenols in neurodegenerative disorders. Our results suggest some novel pathways and genes that may be involved in the neuroprotective mechanism of the BDP polyphenol components. PMID- 29151138 TI - Optical coherence tomography-guided percutaneous coronary intervention compared with other imaging guidance: a meta-analysis. AB - The use of optical coherence tomography (OCT) in PCI guidance is limited perhaps by the lack of adequately powered studies which compare its efficacy and outcomes to the other more popular imaging modalities. We therefore performed a meta analysis to compare clinical outcomes following OCT-guided PCI with the other imaging modalities in two separate comparisons. We abstracted data from randomized control trials and observational comparative studies focusing on OCT versus either angiography- or IVUS-guided PCI outcomes identified following a systematic search (April 2006 and May 2017). This meta-analysis included a total of 2781 patients; OCT-guidance versus Angiography guidance (n = 1753) and OCT guidance versus IVUS-guidance (n = 1028). Pooled estimates of outcomes, presented as odds ratios (OR) [95% confidence intervals], were generated with random-effect models. OCT guidance showed lower rates of MACE (OR 0.70 [0.49, 1.00] p = 0.05) and cardiac deaths (OR 0.40 [0.18, 0.90] p = 0.03) compared to Angiography guidance alone but no statistical significant results for myocardial infarction (OR 0.70 [0.42, 1.16] p = 0.17), stent thrombosis (OR 1.17 [0.40, 3.43] p = 0.77) and target lesion revascularizations (OR 1.07 [0.48, 2.38] p = 0.86).No statistical significance was observed in the OCT versus IVUS comparison; MACE (OR 0.89 [0.46, 1.73] p = 0.73), cardiac deaths (OR 0.56 [0.12, 2.70] p = 0.47), MI (OR 0.56 [0.12, 2.70] p = 0.47), ST (OR 0.43 [0.06, 2.95] p = 0.39), and TLR(OR 0.99 [0.45, 2.18] p = 0.99). OCT-guided PCI in comparison with angiography-guided was associated with reduction in adverse events for the composite of cardiac deaths, myocardial infarction and repeat revascularizations. There was no statistically significant difference in clinical outcomes observed in the comparison between OCT- and IVUS-guidance. PMID- 29151139 TI - Integration of Bacterial Expansin on Agarolytic Complexes to Enhance the Degrading Activity of Red Algae by Control of Gelling Properties. AB - Expansin act by loosening hydrogen bonds in densely packed polysaccharides. This work characterizes the biological functions of expansin in the gelling and degradation of algal polysaccharides. In this study, the bacterial expansin BpEX from Bacillus pumilus was fused with the dockerin module of a cellulosome system for assembly with agarolytic complexes. The assembly of chimeric expansin caused an indicative enhancement in agarase activity. The enzymatic activities on agar substrate and natural biomass were 3.7-fold and 3.3-fold higher respectively than that of agarase as a single enzyme. To validate the effect on the agar degradation, the regulation potential of parameters related to gel rheology by bacterial expansin was experimentally investigated to indicate that the bacterial expansin lowered the gelling temperature and viscosity of agar. Thus, these results demonstrated the possibility of advancing more efficient strategies for utilizing agar as oligo sugar source in the biorefinery field that uses marine biomass as feedstocks. PMID- 29151140 TI - Effects of Oxygen Availability on Oxidative Stress Biomarkers in the Mediterranean Mussel Mytilus galloprovincialis. AB - In aquatic environments, hypoxia and oxygen-deficient areas are increasing worldwide. Transitions in oxygen levels can influence the production of reactive oxygen species (ROS), eventually leading to oxidative stress. The transcriptional response of oxidative stress biomarkers was evaluated by qPCR in gill tissue from Mytilus galloprovincialis experimentally subjected to 48-h air exposure followed by 48-h re-oxygenation, as compared to normoxic control mussels. Superoxide dismutases (CuZnsod and Mnsod), catalase (cat), and glutathione S-transferase (gst) were over-expressed early after 8-h air exposure and returned to normoxic levels during re-oxygenation. Moreover, the mRNAs and protein expression patterns of heat shock proteins (HSP70 and HSP90) and metallothioneins (MT-10 and MT-20) were modulated by oxygen availability with increased levels during re-oxygenation suggesting the participation of these cytoprotective mechanisms in the physiological oxidative stress response when oxygen concentration was restored. Overall, the observed modulation of the oxidative stress-related and general stress genes indicates that M. galloprovincialis responds to changes in oxygen availability enhancing the antioxidant potential under low oxygen conditions for dealing with the oxidative burst during future re-oxygenation. The present investigation brings further insights in understanding how intertidal molluscs cope with short-term oxygen variations and gives useful biomarkers for environmental monitoring of hypoxic areas that are predicted to occur in the next future. PMID- 29151141 TI - Mechanical perturbations can elicit triggered reactions in the absence of a startle response. AB - Perturbations delivered to the upper limbs elicit reflexive responses in stretched muscle at short- (M1: 25-50 ms) and long- (M2: 50-100 ms) latencies. When presented in a simple reaction time (RT) task, the perturbation can also elicit a preprogrammed voluntary response at a latency (< 100 ms) that overlaps the M2 response. This early appearance of the voluntary response following a proprioceptive stimulus causing muscle stretch is called a triggered reaction. Recent work has demonstrated that a perturbation also elicits activity in sternocleidomastoid (SCM) over a time-course consistent with the startle response and it was, therefore, proposed that the StartReact effect underlies triggered reactions (Ravichandran et al., Exp Brain Res 230:59-69, 2013). The present work investigated whether perturbation-evoked SCM activity results from startle or postural control and whether triggered reactions can also occur in the absence of startle. In Experiment 1, participants "compensated" against a wrist extension perturbation. A prepulse inhibition (PPI) stimulus (known to attenuate startle) was randomly presented before the perturbation. Rather than attenuating SCM activity, the responses in SCM were advanced by the PPI stimulus. In Experiment 2, participants "assisted" a wrist extension perturbation. The perturbation did not reliably elicit startle but despite this, two-thirds of trials had RTs of less than 100 ms and the earliest responses began at ~ 70 ms. These findings suggest that SCM activity following a perturbation is the result of postural control and is not related to startle. Moreover, an overt startle response is not a prerequisite for the elicitation of a triggered reaction. PMID- 29151142 TI - MR imaging perfusion and diffusion analysis to assess preoperative Short Course Radiotherapy response in locally advanced rectal cancer: Standardized Index of Shape by DCE-MRI and intravoxel incoherent motion-derived parameters by DW-MRI. AB - Our aim is to assess preoperative Short Course Radiotherapy (SCR) tumor response in locally advanced rectal cancer (LARC) through Standardized Index of Shape (SIS) by DCE-MRI, apparent diffusion coefficient (ADC) and intravoxel incoherent motion-derived parameters by DW-MRI. 35 patients with LARC underwent MR scan before and after SCR followed by delayed surgery, retrospectively, were enrolled. SIS, ADC, tissue diffusion (D t), pseudodiffusion (D p), and perfusion fraction (f) were extracted by MRI for each patient before and after SCR. Tumor regression grade (TRG) was estimated. Receiver operating characteristic curve and linear classification were performed. Sixteen patients were classified as responders (TRG <= 2) and 19 as non-responders. Seven patients had TRG1 [pathological complete response (pCR)]. The best parameter to discriminate responders by non responders was SIS (sensitivity 94%, specificity 84%, accuracy 89%, cutoff value = - 7.8%). SIS obtained the best diagnostic performance also to discriminate pCR (sensitivity 86%, specificity 89%, accuracy 89%, cutoff value = 68.2%). No accuracy increase was obtained combining linearly each possible parameters couple or all functional MR-derived parameters. SIS is a hopeful DCE-MRI angiogenic biomarker to assess preoperative treatment response after SCR with delayed surgery, and it permits to discriminate pCR allowing to direct surgery for tailored and conservative treatment. PMID- 29151143 TI - Salinity reduces 2,4-D efficacy in Echinochloa crusgalli by affecting redox balance, nutrient acquisition, and hormonal regulation. AB - Distinct salinity levels have been reported to enhance plants tolerance to different types of stresses. The aim of this research is to assess the interaction of saline stress and the use of 2,4-D as a means of controlling the growth of Echinochloa crusgalli. The resultant effect of such interaction is vital for a sustainable approach of weed management and food production. The results showed that 2,4-D alone treatment reduces the chlorophyll contents, photosynthetic capacity, enhanced MDA, electrolyte leakage, and ROS production (H2O2, O2.-) and inhibited the activities of ROS scavenging enzymes. Further analysis of the ultrastructure of chloroplasts indicated that 2,4-D induced severe damage to the ultrastructure of chloroplasts and thylakoids. Severe saline stress (8 dS m-1) followed by mild saline stress treatments (4 dS m-1) also reduced the E. crusgalli growth, but had the least impact as compared to the 2,4 D alone treatment. Surprisingly, under combined treatments (salinity + 2,4-D), the phytotoxic effect of 2,4-D was reduced on saline-stressed E. crusgalli plants, especially under mild saline + 2,4-D treatment. This stimulated growth of E. crusgalli is related to the higher activities of enzymatic and non-enzymatic antioxidants and dynamic regulation of IAA, ABA under mild saline + 2,4-D treatment. This shows that 2,4-D efficacy was affected by salinity in a stress intensity-dependent manner, which may result in the need for greater herbicide application rates, additional application times, or more weed control operations required for controlling salt-affected weed. PMID- 29151144 TI - Parosteal extra-axial chordoma of the second metacarpal bone: a case report with literature review. AB - Extra-axial chordoma is a chordoma that occurs in non-axial locations. It is a very rare tumor, with 20 cases reported to date; 14 in bone and six in soft tissue. Of the 14 skeletal extra-axial chordomas, ten were intramedullary and four were intracortical. We report the first case of parosteal extra-axial chordoma arising in the second metacarpal bone, expressing brachyury on immunohistochemical analysis, and describe the pathologic and radiologic findings. We suggest that extra-axial chordoma can occur in parosteal bone lesions or the hand, without features of bone distribution or bone-specific sites. PMID- 29151145 TI - Pendimethalin induces oxidative stress, DNA damage, and mitochondrial dysfunction to trigger apoptosis in human lymphocytes and rat bone-marrow cells. AB - Pendimethalin (PM) is a dinitroaniline herbicide extensively applied against the annual grasses and broad-leaved weeds. There is no report available on PM-induced low-dose genotoxicity in human primary cells and in vivo test models. Such data gap has prompted us to evaluate the genotoxic potential of PM in human lymphocytes and rats. PM selectively binds in the minor groove of DNA by forming covalent bonds with G and C nitrogenous bases, as well as with the ribose sugar. PM induces micronucleus formation (MN) in human lymphocytes, indicating its clastogenic potential. Comet assay data showed 35.6-fold greater DNA damage in PM (200 MUM)-treated human lymphocytes. Rat bone-marrow cells, at the highest dose of 50 mg/kg b w/day of PM also exhibited 10.5-fold greater DNA damage. PM at 200 MUM and 50 mg/kg b w/day induces 193.4 and 229% higher reactive oxygen species generation in human lymphocytes and rat bone-marrow cells. PM-treated human lymphocytes and rat bone-marrow cells both showed dysfunction of mitochondrial membrane potential (DeltaPsi m). PM exposure results in the appearance of 72.2 and 35.2% sub-G1 apoptotic peaks in human lymphocytes and rat bone-marrow cells when treated with 200 MUM and 50 mg/kg b w/day of PM. Rats exposed to PM also showed imbalance in antioxidant enzymes and histological pathology. Overall, our data demonstrated the genotoxic and apoptotic potentials of PM in human and animal test models. PMID- 29151146 TI - Mapping and confirmation of loci for salt tolerance in a novel soybean germplasm, Fiskeby III. AB - KEY MESSAGE: The confirmation of a major locus associated with salt tolerance and mapping of a new locus, which could be beneficial for improving salt tolerance in soybean. Breeding soybean for tolerance to high salt conditions is important in some regions of the USA and world. Soybean cultivar Fiskeby III (PI 438471) in maturity group 000 has been reported to be highly tolerant to multiple abiotic stress conditions, including salinity. In this study, a mapping population of 132 F2 families derived from a cross of cultivar Williams 82 (PI 518671, moderately salt sensitive) and Fiskeby III (salt tolerant) was analyzed to map salt tolerance genes. The evaluation for salt tolerance was performed by analyzing leaf scorch score (LSS), chlorophyll content ratio (CCR), leaf sodium content (LSC), and leaf chloride content (LCC) after treatment with 120 mM NaCl under greenhouse conditions. Genotypic data for the F2 population were obtained using the SoySNP6K Illumina Infinium BeadChip assay. A major allele from Fiskeby III was significantly associated with LSS, CCR, LSC, and LCC on chromosome (Chr.) 03 with LOD scores of 19.1, 11.0, 7.7 and 25.6, respectively. In addition, a second locus associated with salt tolerance for LSC was detected and mapped on Chr. 13 with an LOD score of 4.6 and an R 2 of 0.115. Three gene-based polymorphic molecular markers (Salt-20, Salt14056 and Salt11655) on Chr.03 showed a strong predictive association with phenotypic salt tolerance in the present mapping population. These molecular markers will be useful for marker-assisted selection to improve salt tolerance in soybean. PMID- 29151147 TI - The relationship of five boarding school experiences and physical health status among Northern Plains Tribes. AB - PURPOSE: American Indian (AI) boarding school attendance is related to poor physical health status; however, little is known about how specific aspects of this experience contribute to poor health. Five experiences (age of first attendance, limited family visits, forced church attendance, prohibition on practicing AI culture and traditions, and punishment for use of AI language) may be independently associated with physical health status in adulthood. We expected the effect to be greater for those who began boarding school at older ages. METHODS: Data on AI boarding school attenders (n = 771) came from the AI-Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project. Multiple linear regression models examined the association of these five experiences with physical health status. Additionally, we conducted a separate set of regressions to test for an interaction effect of age of first attendance. RESULTS: Each of the five experiences noted above were independently associated with poorer physical health status compared to those who did not have these experiences. An interaction effect for those punished for use of AI language and who were aged 8 or older was confirmed. CONCLUSIONS: Findings are consistent with reports that boarding school attendance is related to poor AI adult health. To inform AI health programs, the relationship of specific diseases and boarding school attendance should be considered. PMID- 29151148 TI - Development and preliminary validation of the food intolerance Quality of Life Questionnaire (FIQLQ): Adult Form. AB - BACKGROUND: Approximately 20% of children and adults avoid certain foods because of perceived food intolerance. Valid and reliable health-related quality of life instruments are needed to measure changes following clinical, therapeutic or policy interventions. However, there are no disease-specific quality of life instruments for adults with food intolerances. OBJECTIVE: To develop the Food Intolerance Quality of Life Questionnaire FIQLQ. Then to conduct psychometric validation including reliability and construct validity. METHODS: We adapted the existing Food Allergy Quality of Life questionnaire (FAQLQ) for interviews with 14 adults with food intolerance. For preliminary psychometric validation, 229 adults with food intolerances completed the online electronic version of FIQLQ. RESULTS: The resultant FIQLQ had 18 items which loaded onto 3 subscales-Emotional Impact, Social and Dietary Restrictions, Reactions and Avoidance. Each subscale had excellent internal consistency reliability (Cronbach's alpha 0.81-0.94). Content, convergent and construct validity was supported by significant correlations of FIQLQ subscale scores with hypothesised variables including age, numbers of symptoms and level of stress experienced due to intolerance. CONCLUSION: The FIQLQ has good reliability, construct validity and internal consistency. It is short and easy to use, providing a good tool for evaluating quality of life in the clinical research setting and to inform health and regulatory policies. PMID- 29151149 TI - Impact of Xist RNA on chromatin modifications and transcriptional silencing maintenance at different stages of imprinted X chromosome inactivation in vole Microtus levis. AB - In vole Microtus levis, cells of preimplantation embryo and extraembryonic tissues undergo imprinted X chromosome inactivation (iXCI) which is triggered by a long non-coding nuclear RNA, Xist. At early stages of iXCI, chromatin of vole inactive X chromosome is enriched with the HP1 heterochromatin-specific protein, trimethylated H3K9 and H4K20 attributable to constitutive heterochromatin. In the study, using vole trophoblast stem (TS) cells as a model of iXCI, we further investigated chromatin of the inactive X chromosome of M. levis and tried to find out the role of Xist RNA. We demonstrated that chromatin of the inactive X chromosome in vole TS cells also contained the SETDB1 histone methyltransferase and KAP1 protein. In addition, we observed that Xist RNA did not contribute significantly to maintenance of X chromosome inactive state during iXCI in vole TS cells. Xist repression affected neither transcriptional silencing caused by iXCI nor maintenance of trimethylated H3K9 and H4K20 as well as HP1, KAP1, and SETDB1 on the inactive X chromosome. Moreover, the unique repertoire of chromatin modifications on the inactive X chromosome in vole TS cells could be disrupted by a chemical compound, DZNep, and then restored even in the absence of Xist RNA. However, Xist transcript was necessary for recruitment of an additional repressive histone modification, trimethylated H3K27, to the inactive X chromosome during vole TS cell differentiation. PMID- 29151150 TI - A comparison of cancer risk assessment and testing outcomes in patients from underserved vs. tertiary care settings. AB - In cancer genetics, technological advances (next generation sequencing) and the expansion of genetic test options have resulted in lowered costs and increased access to genetic testing. Despite this, the majority of patients utilizing cancer genetics services lack diversity of gender, ethnicity, and socioeconomic status. Through retrospective chart review, we compared outcomes of cancer genetics consultations at a tertiary cancer center and a Federally Qualified Health Center (FQHC) (58 tertiary and 23 FQHC patients) from 2013 to 2015. The two groups differed in race, ethnicity, use of translator services, and type of insurance coverage. There were also significant differences in completeness of family history information, with more missing information about relatives in the FQHC group. In spite of these differences, genetic testing rates among those offered testing were comparable across the two groups with 74% of tertiary patients and 60% of FQHC patients completing testing. Implementation of community based cancer genetics outreach clinics represents an opportunity to improve access to genetic counseling services, but more research is needed to develop effective counseling models for diverse patient populations. PMID- 29151151 TI - Long-term treatment of diabetic rats with vanadyl sulfate or insulin attenuate acute focal cerebral ischemia/reperfusion injury via their antiglycemic effect. AB - It is well-known that patients with diabetes mellitus have worse clinical outcomes following acute ischemic stroke. The intensifying effects of diabetes on ischemic brain injury have been shown to be mostly due to hyperglycemia, rather than the lack of insulin direct effects on brain. It is also well-approved that vanadium compounds have insulin-like and anti-diabetic effects, and the present study was designed to compare the protective effects of diabetes treatment with vanadium or insulin on ischemic/reperfused brain injury. Male Sprague-Dawley rats were divided into 4 groups (n = 21). Two groups of streptozotocin-induced diabetic rats were treated with either vanadyl sulfate or insulin at proper doses to similarly attenuate hyperglycemia during 45 days, while there was no treatment in the control diabetic and non-diabetic sham groups. Thereafter, all treated and non-treated diabetic rats were subjected to 60-min of the right middle cerebral artery occlusion followed by 12-h reperfusion, and then their brains were removed for evaluating blood-brain barrier leakage, tissue swelling, infarct size and oxidant status in both hemispheres. Vanadium and insulin that equally reduced blood glucose and water intake had some differences in their antidiabetic effects of ameliorating weight loss and hypertension during 45-days treatment period. However, they caused similar decrements in levels of Evans blue dye extravastion, edema, infarct volume and malondialdehyde in ischemic/reperfused cerebral hemisphere. Therefore, it can be suggested that insulin and vanadium via their antiglycemic effect cause reduction in cerebral production of oxidants following acute focal ischemia/reperfusion, which attenuate BBB disruption and brain tissue injury. PMID- 29151152 TI - A Maize Inbred Exhibits Resistance Against Western Corn Rootwoorm, Diabrotica virgifera virgifera. AB - Insect resistance against root herbivores like the western corn rootworm (WCR, Diabrotica virgifera virgifera) is not well understood in non-transgenic maize. We studied the responses of two American maize inbreds, Mp708 and Tx601, to WCR infestation using biomechanical, molecular, biochemical analyses, and laser ablation tomography. Previous studies performed on several inbreds indicated that these two maize genotypes differed in resistance to pests including fall armyworm (Spodoptera frugiperda) and WCR. Our data confirmed that Mp708 shows resistance against WCR, and demonstrates that the resistance mechanism is based in a multi trait phenotype that includes increased resistance to cutting in nodal roots, stable root growth during insect infestation, constitutive and induced expression of known herbivore-defense genes, including ribosomal inhibitor protein 2 (rip2), terpene synthase 23 (tps23) and maize insect resistance cysteine protease-1 (mir1), as well high constitutive levels of jasmonic acid and production of (E) beta-caryophyllene. In contrast, Tx601 is susceptible to WCR. These findings will facilitate the use of Mp708 as a model to explore the wide variety of mechanisms and traits involved in plant defense responses and resistance to herbivory by insects with several different feeding habits. PMID- 29151153 TI - (2E,6Z,9Z)-2,6,9-Pentadecatrienal as a Male-Produced Aggregation-Sex Pheromone of the Cerambycid Beetle Elaphidion mucronatum. AB - An increasing body of evidence suggests that the volatile pheromones of cerambycid beetles are much more diverse in structure than previously hypothesized. Here, we describe the identification, synthesis, and field testing of (2E,6Z,9Z)-2,6,9-pentadecatrienal as a male-produced aggregation-sex pheromone of the cerambycid Elaphidion mucronatum (Say) (subfamily Cerambycinae, tribe Elaphidiini). This novel structure is unlike any previously described cerambycid pheromone, and in field bioassays attracted only this species. Males produced about 9 MUg of pheromone per 24 h period, and, in field trials, lures loaded with 10, 25, and 100 mg of synthetic pheromone attracted beetles of both sexes, whereas lures loaded with 1 mg of pheromone or less were not significantly attractive. Other typical cerambycine pheromones such as 3-hydroxy-2-hexanone, syn-2,3-hexanediol, and anti-2,3-hexanediol were not attractive to E. mucronatum, and when combined with (2E,6Z,9Z)-2,6,9-pentadecatrienal, the former two compounds appeared to inhibit attraction. Unexpectedly, adults of the cerambycine Xylotrechus colonus (F.) were attracted in significant numbers to a blend of 3 hydroxyhexan-2-one and (2E,6Z,9Z)-2,6,9-pentadecatrienal, even though there is no evidence that this species produces the latter compound. From timed pheromone trap catches, adults of E. mucronatum were determined to be active from dusk until shortly after midnight. PMID- 29151154 TI - Visit-to-visit variability of systolic blood pressure predicts all-cause mortality in patients received percutaneous coronary intervention with drug eluting stents. AB - Blood pressure (BP) and its variability are associated with atherosclerotic disease and cardiovascular events. The prognostic implications of outpatient clinic visit-to-visit blood pressure variability (BPV) are unknown in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). A total of 1,463 patients undergoing PCI with DES were consecutively enrolled from January 2009 to December 2013. We analyzed the 1,234 patients, who measured clinic BP more than three times during the first year after PCI. The BPV is determined by standard deviation of systolic and diastolic BP, and coefficient of variation. Median follow-up duration was 905 days (interquartile range 529 1,310 days). All patients were divided into two groups according to the coefficient of variation of systolic BP (CVSBP); high CVSBP group (> 8.78, n = 617) and low CVSBP group (<= 8.78, n = 617). High CVSBP group had significantly higher all-cause mortality (7.9% versus 3.1%, p < 0.001) and composite of all cause mortality, myocardial infarction, and stroke (13.1% versus 6.2%, p < 0.001). In multivariate logistic regression analysis for prediction of all-cause mortality, and composite of all-cause mortality, myocardial infarction, and stroke after PCI with DES, hazard ratios of high CVSBP group were 2.441 (95% of confidence interval 1.042-5.718, p = 0.040), and 1.980 (95% of confidence interval 1.125-3.485, p = 0.018). The higher visit-to-visit BPV is associated higher mortality in patients undergoing PCI with DES. The clinic measured visit to-visit BPV may serve as a predictor of all-cause mortality after PCI with DES. PMID- 29151155 TI - Intraurethral injection with LPS: an effective experimental model of prostatic inflammation. AB - OBJECTIVE: Chronic inflammation has been recognized as having a prominent role pathogenesis of benign prostatic hyperplasia (BPH) and cancer. It is believed that chronic inflammation induces prostatic fibromuscular growth. This correlation has been clearly illustrated by both in vivo and in vitro studies; however, current experimental models of BPH require complex surgery or hormonal treatment. Therefore, the aim of the present study was to propose a new murine model of BPH/prostatitis induced by intraurethral injection of LPS. METHODS: Male Swiss and C57Bl/6 mice were then sacrificed 3, 7, 10, and 14 days after intraurethral injection of LPS. The prostates were quickly dissected and fixed for morphological and immunohistochemical analyses. RESULTS: The results showed that LPS played an important role in the cell proliferation of the prostate. Histological and ultrastructural analysis showed epithelial hyperplasia, clear stromal cells, little inflammatory infiltration, and heavy bleeding. Treatment with LPS also promoted the increase of growth factor (FGF-7 and TGF-beta), alpha actin, and proinflammatory cytokines (IL-1, IL-6, IL-17), both in the stroma and epithelium. CONCLUSION: According to the present findings, it can be concluded that the intraurethral administration of LPS promotes tissue remodeling, as well as stimulating the pattern of pro-inflammatory cytokines, and therefore, constitutes an effective experimental model of BPH/inflammation. PMID- 29151157 TI - Potent apoptosis-inducing activity of erypoegin K, an isoflavone isolated from Erythrina poeppigiana, against human leukemia HL-60 cells. AB - Erypoegin K is an isoflavone isolated from the stem bark of Erythrina poeppigiana. It contains a furan group at the A-ring of the core isoflavone structure and can inhibit the activity of glyoxalase I, an enzyme that catalyzes the detoxification of methylglyoxal (MG), a by-product of glycolysis. In the present study, we found that erypoegin K has a potent cytotoxic effect on human leukemia HL-60 cells. Its cytotoxic effect was much stronger than that of a known glyoxalase I inhibitor S-p-bromobenzylglutathione cyclopentyl diester. Conversely, erypoegin K demonstrated weak cytotoxicity toward normal human peripheral lymphocytes. The treatment of HL-60 cells with erypoegin K significantly induced caspase-3 activity, whereas the pretreatment of the cells with caspase-3 inhibitor suppressed erypoegin K-induced cell death. Furthermore, nuclear condensation and apoptotic genome DNA fragmentation were observed in erypoegin K-treated HL-60 cells. These results indicated that the observed cell death was mediated by apoptosis. In addition, the toxic compound MG was highly accumulated in the culture medium of erypoegin K-treated HL-60 cells, suggesting that cell apoptosis was triggered by extracellular MG. The present study showed that erypoegin K has a potent apoptosis-inducing effect on cancerous cell lines, such as HL-60. PMID- 29151158 TI - Guidelines to reach high-quality purified recombinant proteins. AB - The final goal in recombinant protein production is to obtain high-quality pure protein samples. Indeed, the successful downstream application of a recombinant protein depends on its quality. Besides production, which is conditioned by the host, the quality of a recombinant protein product relies mainly on the purification procedure. Thus, the purification strategy must be carefully designed from the molecular level. On the other hand, the quality control of a protein sample must be performed to ensure its purity, homogeneity and structural conformity, in order to validate the recombinant production and purification process. Therefore, this review aims at providing succinct information on the rational purification design of recombinant proteins produced in Escherichia coli, specifically the tagging purification, as well as on accessible tools for evaluating and optimizing protein quality. The classical techniques for structural protein characterization-denaturing protein gel electrophoresis (SDS PAGE), size exclusion chromatography (SEC), dynamic light scattering (DLS) and circular dichroism (CD)-are revisited with focus on the protein and their main advantages and disadvantages. Furthermore, methods for determining protein concentration and protein storage are also presented. The guidelines compiled herein will aid preparing pure, soluble and homogeneous functional recombinant proteins from the very beginning of the molecular cloning design. PMID- 29151156 TI - Deep RNAseq indicates protective mechanisms of cold-tolerant indica rice plants during early vegetative stage. AB - KEY MESSAGE: Cold-tolerance in rice may be related to increased cellulose deposition in the cell wall, membrane fatty acids unsaturation and differential expression of several newly identified genes. Low temperature exposure during early vegetative stages limits rice plant's growth and development. Most genes previously related to cold tolerance in rice are from the japonica subspecies. To help clarify the mechanisms that regulate cold tolerance in young indica rice plants, comparative transcriptome analysis of 6 h cold-treated (10 degrees C) leaves from two genotypes, cold-tolerant (CT) and cold-sensitive (CS), was performed. Differentially expressed genes were identified: 831 and 357 sequences more expressed in the tolerant and in the sensitive genotype, respectively. The genes with higher expression in the CT genotype were used in systems biology analyses to identify protein-protein interaction (PPI) networks and nodes (proteins) that are hubs and bottlenecks in the PPI. From the genes more expressed in the tolerant plants, 60% were reported as affected by cold in previous transcriptome experiments and 27% are located within QTLs related to cold tolerance during the vegetative stage. Novel cold-responsive genes were identified. Quantitative RT-PCR confirmed the high-quality of RNAseq libraries. Several genes related to cell wall assembly or reinforcement are cold-induced or constitutively highly expressed in the tolerant genotype. Cold-tolerant plants have increased cellulose deposition under cold. Genes related to lipid metabolism are more expressed in the tolerant genotype, which has higher membrane fatty acids unsaturation, with increasing levels of linoleic acid under cold. The CT genotype seems to have higher photosynthetic efficiency and antioxidant capacity, as well as more effective ethylene, Ca2+ and hormone signaling than the CS. These genes could be useful in future biotechnological approaches aiming to increase cold tolerance in rice. PMID- 29151159 TI - Enhanced catalytic efficiency and enantioselectivity of epoxide hydrolase from Agrobacterium radiobacter AD1 by iterative saturation mutagenesis for (R) epichlorohydrin synthesis. AB - Enantioselective hydrolysis of epoxides by epoxide hydrolase (EH) is one of the most attractive approaches for the synthesis of chiral epoxides. So far, attempts to develop an efficient epoxide hydrolase -mediated biotransformation have been limited by either the low activity or insufficient enantioselectivity of epoxide hydrolase. In this study, iterative saturation mutagenesis (ISM) of epoxide hydrolase from Agrobacterium radiobacter AD1 (ArEH) was performed for efficient production of (R)-epichlorohydrin. Six amino acid residues, I108, A110, D131, I133, T247, and G245, were selected for site saturation mutagenesis, and a sequential combination of positive mutants using ISM was constructed. Targeted mutagenesis generated five mutants (T247K, I108L, D131S, T247K/I108L, and T247K/I108L/D131S) with improved activity and enantioselectivity. Kinetics analysis showed that the best mutant, T247K/I108L/D131S, exhibited a 4.5-fold higher catalytic efficiency (k cat/K m) value and a 2.1-fold higher enantioselectivity (E value) towards epichlorohydrin than the wild-type (WT) enzyme. Molecular docking computations support the source of notably improved enantioselectivity. In addition, the triple mutant also displayed a significantly enhanced thermostability, with > 8-fold longer half-life at 50 degrees C than WT. A gram-scale kinetic resolution of (R,S)-epichlorohydrin was performed using T247K/I108L/D131S mutant as biocatalyst, affording a (R)-epichlorohydrin yield of 40.2% (> 99.9% enantiomeric excess) and an average productivity of 1410 g L-1 d 1. The engineered T247K/I108L/D131S variant is a promising biocatalyst for the enzymatic synthesis of (R)-epichlorohydrin. PMID- 29151160 TI - Tolerance improvement of Corynebacterium glutamicum on lignocellulose derived inhibitors by adaptive evolution. AB - Robustness of fermenting strains to lignocellulose derived inhibitors is critical for efficient biofuel and biochemical productions. In this study, the industrial fermenting strain Corynebacterium glutamicum S9114 was evolved for improved inhibitor tolerance using long-term adaptive evolution by continuously transferring into the inhibitors containing corn stover hydrolysate every 24 h, and finally a stably evolved C. glutamicum was obtained after 128 days of serial transfers. The evolved strain exhibited the highly increased conversion rate to the typical lignocellulose derived inhibitors including furfural, 5 hydroxymethylfurfural, vanillin, syringaldehyde, 4-hydroxybenzaldehyde, and acetic acid. Glucose consumption was obviously accelerated, and 22.4 g/L of glutamic acid was achieved in the corn stover hydrolysate, approximately 68.4% greater than that by the original strain. Whole genome re-sequencing revealed various mutations with the potential connection to the improved performance of the evolved strain. Transcriptional analysis further demonstrated that the glucose-PTS transport and the pentose phosphate pathway were significantly upregulated in the evolved strain, which very likely contributed to the accelerated glucose consumption, as well as sufficient NAD(P)H supply for aldehyde inhibitors reduction conversion and thus enhanced the inhibitor tolerance. This study provided important experimental evidences and valuable genetic information for robust strain construction and modification in lignocellulose biorefining processes. PMID- 29151161 TI - Fluorescent pseudomonads pursue media-dependent strategies to inhibit growth of pathogenic Verticillium fungi. AB - Verticillium species represent economically important phytopathogenic fungi with bacteria as natural rhizosphere antagonists. Growth inhibition patterns of Verticillium in different media were compared to saprophytic Aspergillus strains and were significantly more pronounced in various co-cultivations with different Pseudomonas strains. The Brassica napus rhizosphere bacterium Pseudomonas fluorescens DSM8569 is able to inhibit growth of rapeseed (Verticillium longisporum) or tomato (Verticillium dahliae) pathogens without the potential for phenazine or 2,4-diacetylphloroglucinol (DAPG) mycotoxin biosynthesis. Bacterial inhibition of Verticillium growth remained even after the removal of pseudomonads from co-cultures. Fungal growth response in the presence of the bacterium is independent of the fungal control genes of secondary metabolism LAE1 and CSN5. The phenazine producer P. fluorescens 2-79 (P_phen) inhibits Verticillium growth especially on high glucose solid agar surfaces. Additional phenazine-independent mechanisms in the same strain are able to reduce fungal surface growth in the presence of pectin and amino acids. The DAPG-producing Pseudomonas protegens CHA0 (P_DAPG), which can also produce hydrogen cyanide or pyoluteorin, has an additional inhibitory potential on fungal growth, which is independent of these antifungal compounds, but which requires the bacterial GacA/GacS control system. This translational two-component system is present in many Gram-negative bacteria and coordinates the production of multiple secondary metabolites. Our data suggest that pseudomonads pursue different media-dependent strategies that inhibit fungal growth. Metabolites such as phenazines are able to completely inhibit fungal surface growth in the presence of glucose, whereas GacA/GacS controlled inhibitors provide the same fungal growth effect on pectin/amino acid agar. PMID- 29151162 TI - Enrichment of lignocellulose-degrading microbial communities from natural and engineered methanogenic environments. AB - The aim of this study was to develop an effective bioaugmentation concept for anaerobic digesters treating lignocellulosic biomass such as straw. For that purpose, lignocellulose-degrading methanogenic communities were enriched on wheat straw from cow and goat rumen fluid as well as from a biogas reactor acclimated to lignocellulosic biomass (sorghum as mono-substrate). The bacterial communities of the enriched cultures and the different inocula were examined by 454 amplicon sequencing of 16S rRNA genes while the methanogenic archaeal communities were analyzed by terminal restriction fragment length polymorphism (T-RFLP) fingerprinting of the mcrA gene. Bacteroidetes was the most abundant phylum in all samples. Within the Bacteroidetes phylum, Bacteroidaceae was the most abundant family in the rumen-derived enrichment cultures, whereas Porphyromonadaceae was the predominant one in the reactor-derived culture. Additionally, the enrichment procedure increased the relative abundance of Ruminococcaceae (phylum: Firmicutes) in all cultures. T-RFLP profiles of the mcrA gene amplicons highlighted that the ruminal methanogenic communities were composed of hydrogenotrophic methanogens dominated by the order Methanobacteriales regardless of the host species. The methanogenic communities changed significantly during the enrichment procedure, but still the strict hydrogenotrophic Methanobacteriales and Methanomicrobiales were the predominant orders in the enrichment cultures. The bioaugmentation potential of the enriched methanogenic cultures will be evaluated in further studies. PMID- 29151163 TI - Strengthening the Healthy Start Workforce: A Mixed-Methods Study to Understand the Roles of Community Health Workers in Healthy Start and Inform the Development of a Standardized Training Program. AB - Introduction Healthy Start (HS) is dedicated to preventing infant mortality, improving birth outcomes, and reducing disparities in maternal and infant health. In 2014, the HS program was reenvisioned and standardization of services and workforce development were prioritized. This study examined how HS community health workers (CHW), as critical members of the workforce, serve families and communities in order to inform the development of a CHW training program to advance program goals. Methods In 2015, an online organizational survey of all 100 HS programs was conducted. Ninety-three sites (93%) responded. Three discussion groups were subsequently conducted with HS CHWs (n = 21) and two discussion groups with HS CHW trainers/supervisors (n = 14). Results Most (91%) respondent HS programs employed CHWs. Survey respondents ranked health education (90%), assessing participant needs (85%), outreach/recruitment (85%), and connecting participants to services (85%) as the most central roles to the CHW's job. Survey findings indicated large variation in CHW training, both in the amount and content provided. Discussion group findings provided further examples of the knowledge and skills required by HS CHWs. Conclusions The study results, combined with a scan of existing competencies, led to a tailored set of competencies that serve as the foundation for a HS CHW training program. This training program has the capacity to advance strategic goals for HS by strengthening HS CHWs' capacity nationwide to respond to complex participant needs. Other maternal and child health programs may find these results of interest as they consider how CHWs could be used to strengthen service delivery. PMID- 29151164 TI - Correction to: HDAC6 deacetylates alpha tubulin in sperm and modulates sperm motility in Holtzman rat. AB - The published online version contains mistake. The chimeric peptide should read as 'DPSVLYVSLHRYGGYMNEGELRV'. It was inadvertently written as 'DPSVLYVSLYVSLHRYGGYMNEGELR' a mistake which we missed during proof reading. PMID- 29151165 TI - Methods for understanding childhood trauma: modifying the adverse childhood experiences international questionnaire for cultural competency. PMID- 29151166 TI - T2-weighted images are superior to other MR image types for the determination of diffuse intrinsic pontine glioma intratumoral heterogeneity. AB - PURPOSE: Diffuse intrinsic pontine glioma (DIPG) remains the main cause of death in children with brain tumors. Given the inefficacy of numerous peripherally delivered agents to treat DIPG, convection enhanced delivery (CED) of therapeutic agents is a promising treatment modality. The purpose of this study was to determine which MR imaging type provides the best discrimination of intratumoral heterogeneity to guide future stereotactic implantation of CED catheters into the most cellular tumor regions. METHODS: Patients ages 18 years or younger with a diagnosis of DIPG from 2000 to 2015 were included. Radiographic heterogeneity index (HI) of the tumor was calculated by measuring the standard deviation of signal intensity of the tumor (SDTumor) normalized to the genu of the corpus callosum (SDCorpus Callosum). Four MR image types (T2-weighted, contrast-enhanced T1-weighted, FLAIR, and ADC) were analyzed at several time points both before and after radiotherapy and chemotherapy. HI values across these MR image types were compared and correlated with patient survival. RESULTS: MR images from 18 patients with DIPG were evaluated. The mean survival +/- standard deviation was 13.8 +/- 13.7 months. T2-weighted images had the highest HI (mean +/- SD, 5.1 +/- 2.5) followed by contrast-enhanced T1-weighted images (3.7 +/- 1.5), FLAIR images (3.0 +/- 1.1), and ADC maps (1.6 +/- 0.4). ANOVA demonstrated that HI values were significantly higher for T2-weighted images than FLAIR (p < 0.01) and ADC (p < 0.0001). Following radiotherapy, T2-weighted and contrast-enhanced T1-weighted image HI values increased, while FLAIR and ADC HI values decreased. Univariate and multivariate analyses did not reveal a relationship between HI values and patient survival (p > 0.05). CONCLUSIONS: For children with DIPG, T2-weighted MRI demonstrates the greatest signal intensity variance suggesting tumor heterogeneity. Within this heterogeneity, T2-weighted signal hypointensity is known to correlate with increased cellularity and thus may represent a putative target for CED catheter placement in future clinical trials. PMID- 29151167 TI - Prenatal ultrasonographic detection and prenatal (prior to birth) management of hereditary retinoblastoma. PMID- 29151168 TI - Strengthening validity in studies of pelvic floor disorders through qualitative research: an example from Ethiopia. AB - INTRODUCTION AND HYPOTHESIS: This formative qualitative follow-up study addresses validity concerns in the Dabat Incontinence and Prolapse (DABINCOP) study, which aimed to determine the prevalence of pelvic floor disorders in north-west Ethiopia. A pilot study using a questionnaire validated by pelvic exam showed severe underreporting of clinically relevant pelvic organ prolapse (POP). The objective of the follow-up study was to explore the reasons behind the underreporting and to gather information to strengthen the sensitivity and local relevance of the questionnaire to be employed in the main study. METHODS: A qualitative formative study nested within the DABINCOP study was carried out in rural and semiurban communities using an interpretive approach and in-depth qualitative interviews. Women (5) who had not self-reported POP in the pilot but were diagnosed with severe prolapse after pelvic examination, and health-care workers in the research team (7) were interviewed individually within 1 year of the pilot. Systematic text condensation was used in the analysis. RESULTS: The women explained that shame and fear of social exclusion, lack of trust in the study and data collectors, and lack of hope for cure prevented them from disclosing. The health-care workers reported weaknesses in the questionnaire and the research approach. Time pressure and competition among data collectors may have compromised women's motivation to disclose. CONCLUSIONS: The study indicates that qualitative research may fruitfully be employed in the formative phase of an epidemiological study on sensitive reproductive health problems to enhance local relevance of the tool and overall validity of the study. PMID- 29151170 TI - The function of the cellular prion protein in health and disease. AB - The essential role of the cellular prion protein (PrPC) in prion disorders such as Creutzfeldt-Jakob disease is well documented. Moreover, evidence is accumulating that PrPC may act as a receptor for protein aggregates and transduce neurotoxic signals in more common neurodegenerative disorders, such as Alzheimer's disease. Although the pathological roles of PrPC have been thoroughly characterized, a general consensus on its physiological function within the brain has not yet been established. Knockout studies in various organisms, ranging from zebrafish to mice, have implicated PrPC in a diverse range of nervous system related activities that include a key role in the maintenance of peripheral nerve myelination as well as a general ability to protect against neurotoxic stimuli. Thus, the function of PrPC may be multifaceted, with different cell types taking advantage of unique aspects of its biology. Deciphering the cellular function(s) of PrPC and the consequences of its absence is not simply an academic curiosity, since lowering PrPC levels in the brain is predicted to be a powerful therapeutic strategy for the treatment of prion disease. In this review, we outline the various approaches that have been employed in an effort to uncover the physiological and pathological functions of PrPC. While these studies have revealed important clues about the biology of the prion protein, the precise reason for PrPC's existence remains enigmatic. PMID- 29151171 TI - Clinical and serological associations of anti-ribosomal P0 protein antibodies in systemic lupus erythematosus. AB - The purpose of this study is to investigate the clinical and serological associations of anti-ribosomal P0 protein antibodies (anti-Rib-P0) in patients with systemic lupus erythematosus (SLE). The sera of 470 patients with SLE and 124 patients with primary Sjogren's Syndrome (pSS) were collected. Line immunoassay (LIA) was used to detect anti-Rib-P0 and other related antibodies. A complete laboratory evaluation and clinical examination were also performed in each SLE patient. The prevalence of anti-Rib-P0 in SLE patients was significantly higher than that in pSS patients (35.74 vs 6.45%) (P < 0.001). There was a significantly lower prevalence of cardiac involvement in anti-Rib-P0-positive SLE patients compared to anti-Rib-P0-negative SLE patients (P = 0.019); no significant associations of anti-Rib-P0 antibodies with encephalopathy manifestations and other vital organs involvement were observed. Anti nucleosomes, anti-dsDNA, anti-Histones, anti-SmD1, and anti-U1snRNP were significantly associated with serum anti-Rib-P0 antibodies positivity in SLE patients (all P < 0.05). The sensitivity and specificity of the anti-Rib-P0 antibodies to diagnose SLE were 35.74 and 93.55%, respectively. There is a higher prevalence of anti-Rib-P0 in SLE patients. Anti-Rib-P0 positivity may indicate lower cardiac involvement for SLE patients. It may serve as an important complementary parameter in SLE, in addition to anti-dsDNA, anti-SmD1, and anti nucleosomes. PMID- 29151169 TI - Parkinson's disease: experimental models and reality. AB - Parkinson's disease (PD) is a chronic, progressive movement disorder of adults and the second most common neurodegenerative disease after Alzheimer's disease. Neuropathologic diagnosis of PD requires moderate-to-marked neuronal loss in the ventrolateral substantia nigra pars compacta and alpha-synuclein (alphaS) Lewy body pathology. Nigrostriatal dopaminergic neurodegeneration correlates with the Parkinsonian motor features, but involvement of other peripheral and central nervous system regions leads to a wide range of non-motor features. Nigrostriatal dopaminergic neurodegeneration is shared with other parkinsonian disorders, including some genetic forms of parkinsonism, but many of these disorders do not have Lewy bodies. An ideal animal model for PD, therefore, should exhibit age dependent and progressive dopaminergic neurodegeneration, motor dysfunction, and abnormal alphaS pathology. Rodent models of PD using genetic or toxin based strategies have been widely used in the past several decades to investigate the pathogenesis and therapeutics of PD, but few recapitulate all the major clinical and pathologic features of PD. It is likely that new strategies or better understanding of fundamental disease processes may facilitate development of better animal models. In this review, we highlight progress in generating rodent models of PD based on impairments of four major cellular functions: mitochondrial oxidative phosphorylation, autophagy-lysosomal metabolism, ubiquitin-proteasome protein degradation, and endoplasmic reticulum stress/unfolded protein response. We attempt to evaluate how impairment of these major cellular systems contribute to PD and how they can be exploited in rodent models. In addition, we review recent cell biological studies suggesting a link between alphaS aggregation and impairment of nuclear membrane integrity, as observed during cellular models of apoptosis. We also briefly discuss the role of incompetent phagocytic clearance and how this may be a factor to consider in developing new rodent models of PD. PMID- 29151172 TI - Translation and validation of the Chinese Social Role Participation Questionnaire in patients with ankylosing spondylitis. AB - Social Role Participation Questionnaire (SRPQ) is used to evaluate the social participation with ankylosing spondylitis (AS). Although the SRPQ has English and Dutch versions, there is no Chinese version even though China has the largest population of patients with AS. The objective of our study was to translate the SRPQ into Chinese version and assess its reliability and validity in Chinese patients with AS. The C-SRPQ was developed in a five-step translation and cross cultural adaptation procedure. A total of 105 patients with AS were recruited during the time from September 2014 to June 2017. The intraclass correlation coefficient (ICC), Cronbach's alpha (alpha), and Spearman correlation coefficient (r) were used to evaluate test-retest reliability, internal consistency reliability, and the construct validity of C-SRPQ, respectively. All of the 105 patients with AS successfully completed the questionnaires. Ninety-eight patients (93.33%) participated in at least nine roles for satisfaction dimensions. No floor or ceiling effects were checked. The high value of ICC (> 0.8, 0.831-0.895) indicated the excellent test-retest reliability. In internal consistency reliability, most of Cronbach's alpha coefficient was strong (alpha >= 0.7, 0.534 0.962). In construct validity, more than half of the correlations between the dimensions of C-SRPQ and other questionnaires were good (r > 0.6). The correlations between all dimensions of C-SRPQ and BASDAI, BASFI, and ASQoL were strong negative (P < 0.01). There was a strong positive correlation (P < 0.01) between all dimensions of C-SRPQ and SF-36 physical component score (SF-36PCS), SF-36 mental component role score (SF-36MCS). The C-SRPQ is a reliable and valid questionnaire to evaluate the social participation in Chinese patients with AS. PMID- 29151173 TI - The relationship between childhood trauma and alcohol use initiation in Black and White adolescent girls: considering socioeconomic status and neighborhood factors. AB - PURPOSE: To assess whether the higher prevalence of childhood trauma exposure but lower prevalence of alcohol use in Black vs. White adolescent girls reflects a lower magnitude of association between trauma and alcohol use initiation in Black girls; and additionally, whether low socioeconomic status (SES) and neighborhood factors account in part for the link between trauma and early alcohol use. METHODS: Data were drawn from annual interviews conducted with an urban sample of girls and their primary caregivers from ages 5-8 (baseline) through age 17 (n = 2068, 57.7% Black, 42.3% White). Cox proportional hazards regression analyses using race and childhood trauma to predict alcohol use initiation were conducted in two stages, with SES and neighborhood factors added in the second stage. RESULTS: Childhood trauma was more prevalent (29.0 vs. 17.5%) and alcohol use initiation less prevalent (37.7 vs. 54.4%) in Black vs. White girls, but we found no evidence for differences in liability conferred by trauma. However, significant changes in hazards ratios (HRs) from the unadjusted to adjusted models were observed for Black race (HR = 0.57, CI 0.50-0.65 to HR = 0.66, CI 0.54-0.80) and childhood trauma (HR = 1.70, CI 1.46-1.99 to HR = 1.34, CI 1.05 1.71). CONCLUSIONS: Findings indicate that childhood trauma is an equally potent risk factor for early drinking onset for Black and White girls; the risk for early alcohol use in Black girls who have experienced traumatic events should not be underestimated. Results further indicate that low SES and neighborhood factors contribute to the associations of childhood trauma and race with alcohol use initiation. PMID- 29151174 TI - The impact of remission status on patients' experiences with acute myeloid leukemia (AML): an exploratory analysis of longitudinal patient-reported outcomes data. AB - PURPOSE: Shared decision-making in acute myeloid leukemia (AML) requires understanding patients' longitudinal experiences of illness, but little is known about the impact of remission status on patient-reported outcomes (PROs). We aimed to explore the association between remission status and PROs 6-12 months following induction chemotherapy. METHODS: Forty-two patients completed three validated instruments characterizing symptom burden (Patient Care Monitor v2.0), distress (NCCN Distress Thermometer), and QOL (FACT-Leu), as part of a longitudinal observational study. We used regression models to explore the relationship between remission status and PROs, and explore differences by initial disease type (de novo versus secondary/relapsed AML). RESULTS: Those with secondary or relapsed AML at study onset had marked impairments in all measures compared to de novo AML patients. After 6 months, their mean distress score was 4.8 (> 4.0 warrants intervention), they reported a mean of 14.1 moderate/severe symptoms and had a mean QOL score of 113.6, compared to 1.0, 1.7, and 155.2, respectively, for those with de novo AML (p < .0001). Similarly, patients in relapse had a mean distress score of 5.3, a mean of 12.8 moderate/severe symptoms, and a mean QOL score of 113.4, compared to 1.8, 5.7, and 143.8, respectively, among those in remission (p < .005). These patterns persisted after adjusting for baseline differences (p < .0001). CONCLUSION: Remission is associated with markedly better patient well-being in AML. Patients with secondary or relapsed AML face more severe symptom burden, distress, and QOL issues after induction. Interventions are needed to improve AML patients' experiences of illness. PMID- 29151175 TI - Demographic, clinical, lifestyle-related, and social-cognitive correlates of physical activity in head and neck cancer survivors. AB - PURPOSE: The purpose of the study is to identify demographic, clinical, lifestyle related, and social-cognitive correlates of physical activity (PA) intention and behavior in head and neck cancer (HNC) survivors using the theory of planned behavior (TPB). METHODS: Data from two cross-sectional studies on correlates of PA in HNC survivors were pooled. Both studies used self-reports to assess PA and social-cognitive correlates. Potential correlates were collected via self-report or medical records. Univariable and multivariable multilevel linear mixed-effects models were built to identify correlates of PA intention and PA behavior (Z scores). Structural equation model analyses were conducted to study the full TPB model in one analysis, taking into account relevant covariates. RESULTS: In total, 416 HNC survivors were surveyed. Their mean (SD) age was 66.6 (9.4) years; 64% were men, and 78% were diagnosed with laryngeal cancer. The structural equation model showed that PA intention was significantly higher in HNC survivors with a history of exercising, who had a more positive attitude, subjective norm, and perceived behavioral control. Patients with higher PA intention, higher PBC, a lower age, and without unintentional weight loss or comorbidities had higher PA behavior. The model explained 22.9% of the variance in PA intention and 16.1% of the variance in PA behavior. CONCLUSIONS: Despite significant pathways of the TPB model, the large proportion variance in PA intention and behavior remaining unexplained suggests the need for better PA behavior (change) models to guide the development of PA promotion programs, particularly for the elderly. Such programs should be tailored to comorbidities and nutritional status. PMID- 29151176 TI - Adherence to TKI in CML patients: more than reports. PMID- 29151177 TI - Mechanisms of drought-induced dissipation of excitation energy in sun- and shade adapted drought-tolerant mosses studied by fluorescence yield change and global and target analysis of fluorescence decay kinetics. AB - Some mosses stay green and survive long even under desiccation. Dissipation mechanisms of excess excitation energy were studied in two drought-tolerant moss species adapted to contrasting niches: shade-adapted Rhytidiadelphus squarrosus and sun-adapted Rhytidium rugosum in the same family. (1) Under wet conditions, a light-induced nonphotochemical quenching (NPQ) mechanism decreased the yield of photosystem II (PSII) fluorescence in both species. The NPQ extent saturated at a lower illumination intensity in R. squarrosus, suggesting a larger PSII antenna size. (2) Desiccation reduced the fluorescence intensities giving significantly lower F 0 levels and shortened the overall fluorescence lifetimes in both R. squarrosus and R. rugosum, at room temperature. (3) At 77 K, desiccation strongly reduced the PSII fluorescence intensity. This reduction was smaller in R. squarrosus than in R. rugosum. (4) Global and target analysis indicated two different mechanisms of energy dissipation in PSII under desiccation: the energy dissipation to a desiccation-formed strong fluorescence quencher in the PSII core in sun-adapted R. rugosum (type-A quenching) and (5) the moderate energy dissipation in the light-harvesting complex/PSII in shade-adapted R. squarrosus (type-B quenching). The two mechanisms are consistent with the different ecological niches of the two mosses. PMID- 29151178 TI - MRI findings for primary fallopian tube cancer: correlation with pathological findings. AB - PURPOSE: To clarify the MRI findings for primary fallopian tube cancer (PFTC). MATERIALS AND METHODS: MRI findings for 11 patients who were pathologically diagnosed with PFTC at our institute were retrospectively reviewed. MRI findings (shape, appearance, signal intensity, ADC value, enhancement patterns, and location of the primary tumor, the morphologic appearance of the ipsilateral ovary, and intrauterine fluid collection) were evaluated and compared with pathological findings including histological subtype and PFTC location. RESULTS: On MRI, PFTCs with a tubal component (n = 8) exhibited a sausage-like shape in five cases and a nodular or irregular shape in three cases. PFTCs located at the fimbria (n = 3) presented a nodular shape. The PFTC was solid in nine cases (82%), and the solid portion showed high intensity on diffusion-weighted images in all cases. The mean ADC value was 0.86 * 10-3 mm2/s. Rim enhancement of the tumor was seen in six of nine cases (67%), all with a tubal component. CONCLUSION: PFTCs with a tubal component are sausage-shaped and PFTCs located at the fimbria have a nodular shape. Rim enhancement is frequently seen in PFTCs with a tubal component, which may suggest a tubal origin. PMID- 29151179 TI - Comparison of three analgesic drug regimens with twelfth subcostal nerve block for pain control during extracorporeal shock wave lithotripsy. AB - INTRODUCTION AND OBJECTIVE: Extracorporeal shock wave lithotripsy (ESWL) is the first-line treatment in the majority of cases of upper urinary tract stones. Since its introduction, attempts have been made to establish the ideal accompanying analgesic method to enable the application of shock waves of adequate duration and intensity for efficacious stone fragmentation. An open, randomized, prospective, longitudinal, comparative, and experimental clinical study was conducted to evaluate the efficacy of subcostal nerve block with lidocaine, comparing it in combination with tramadol or diclofenac for pain control during ESWL. MATERIALS AND METHODS: Seventy patients of both sexes were included in the study. Thirty-five were men and 35 were women, all above 18 years of age, with kidney stones or ureteral stones smaller than 20 mm. The patients were randomly assigned to one of the following groups: Group 1 (24 patients) Twelfth subcostal nerve block with 10 ml of lidocaine 2%, 5 min before ESWL. Group 2 (25 patients) Twelfth subcostal nerve block with 10 ml lidocaine 2% + intramuscular diclofenac sodium 45 min before ESWL. Group 3 (21 patients) Twelfth subcostal nerve block with 10 ml of lidocaine 2% + tramadol at 1 mg/Kg of weight, 45 min before ESWL. The visual analog scale (VAS) for pain was applied at minutes 10, 20, and 30 of the procedure. RESULTS: No statistically significant differences were reported by the ANOVA test for comparing the mean pain values between the three groups at minutes 10, 20, and 30 of the ESWL. There were no adverse effects. CONCLUSIONS: Even though there were no statistically significant differences between the three groups, the analgesic regimen of twelfth subcostal nerve block with lidocaine 2%, alone, was as efficacious as its combination with other analgesics and therefore can be used as a sole analgesic method during ESWL. PMID- 29151180 TI - From bench to the hemodialysis clinic: protein-bound uremic toxins modulate NF kappaB/Nrf2 expression. AB - PURPOSE: Uremic toxins produced by gut microbiota (indoxyl sulfate-IS, p-cresyl sulfate-p-CS, and indole-3-acetic acid-IAA) accumulate in hemodialysis (HD) patients and exhibit potent inflammatory effects. However, the impact of these toxins on nuclear E2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF kappaB) expression in HD patients remains poorly defined. The aim of this study was to evaluate the association between uremic toxins and Nrf2/NF-kappaB expression in vitro (RAW 264.7 macrophage-like cells) and in peripheral blood mononuclear cells from HD patients. METHODS: Uremic toxins, C-reactive protein (CRP), interleukin-6 (IL-6) and malondialdehyde (MDA) levels were measured in fifteen HD patients and nine healthy individuals. RAW 264.7 macrophage-like cells were incubated with IS, as a prototype of protein-bound uremic toxin. Nrf2 and NF kappaB expressions were analyzed by RT-qPCR. RESULTS: HD patients presented high levels of inflammatory markers, MDA and uremic toxins. In addition, they presented high NF-kappaB and low Nrf2 expression. Uremic toxins were positively correlated with NF-kappaB expression (IS, rho = 0.58, p < 0.003; p-CS, rho = 0.71, p < 0.001; IAA, rho = 0.62, p < 0.001) and negatively with Nrf2 (IS, rho = 0.48, p = 0.01; p-CS, rho = - 0.46, p < 0.02). Uremic toxins also exhibited positive correlations with CRP and MDA levels. Multivariate analysis revealed that p-CS is a determinant factor of NF-kappaB expression. In RAW 264.7 culture, NF-kappaB mRNA expression was stimulated by IS, while Nrf2 was downregulated. CONCLUSIONS: Thus, uremic toxins may stimulate NF-kappaB mRNA and decrease Nrf2 expression in HD patients and, consequently, trigger inflammation and oxidative stress. PMID- 29151181 TI - Screening HCV genotype-specific epitope peptides based on conserved sequence analysis and B cell epitope prediction in HCV E2 region. AB - The high mutation rate of the hepatitis C virus (HCV) genome increases the genotype diversity and renders the detection of the virus more difficult. Therefore, prediction and assessment of highly conserved and strongly antigenic epitope polypeptide sequences have become a focus of current research. The E2 region is the target binding region of neutralizing antibodies. HCV genomics, especially the high mutation rate of E2 region sequence, makes its genotyping more and more diverse, and the detection of HCV and genotype is becoming more and more strict. In this study, four HCV B cell epitope polypeptides were constructed based on assessment of conserved sequences in the HCV E2 region and prediction of B cell epitopes, including sequences specific to genotype 1A (DC-13: 434 DTGWLAGLFYYHK-446), genotype 1B (HC-13: 434-HTGFLAALFYAKS-446), genotype 4D (NC 13: 434-NTGFLASLFYTHK-446), and a consensus sequence (FC-9: 447-FNSSGCPER-455). Epitope polypeptides combined with serum from 29 HCV-infected or 25 non-HCV infected individuals were assayed by enzyme-linked immunosorbent assay (ELISA), and differences were analyzed by T/T' test methods in SPSS v20.0 software. Binding levels of genotype 1A, 4D, and consensus epitope polypeptides with sera of HCV-infected patients were higher than those of non-infected individuals. Moreover, binding of genotype 1B epitope polypeptides with serum of HCV 1B infected patients was higher than that of HCV 2A-infected patients. While the screening results of HCV genotype-specific epitope polypeptides were preliminary, these findings indicated that we successfully established an HCV and genotype serological ELISA detection method. Such an approach would facilitate the discovery of epitope polypeptides which may become new antigen candidates in peptide vaccine development for the prevention of HCV infection. PMID- 29151183 TI - Correction to: A bibliometric analysis of research on haze during 2000-2016. AB - The original version of this article unfortunately contains mistakes. PMID- 29151182 TI - Electrical cardioversion of patients with implanted pacemaker or cardioverter defibrillator: results of a survey of german centers and systematic review of the literature. AB - AIMS: A relevant number of patients presenting for electrical cardioversion carry a pacemaker (PM) or ICD. Case reports suggest a potential hazard of external cardioversion/defibrillation. The incidence of shock related device complications is unknown. No guidelines or recommendations by international medical societies for a cardioversion protocol of cardiovascular implantable electronic device (CIED) patients exist. We conducted a nationwide survey to gather real-world clinical data on the current clinical approach towards these patients during electrical cardioversion and to estimate the incidence of shock-related complications. METHODS AND RESULTS: Ninety hospitals with > 380 ECV in 2014 were identified from mandatory hospital quality reports and 60 were randomly selected. All centers were provided with a standardized questionnaire on the general proceedings and complications during electrical cardioversion of pacemaker, ICD and CRT patients (CIED patients). Thirty-two centers (53%) participated in the survey. In total, 16,554 ECV were reported (534 +/- 314 per center). Biphasic cardioversion with a first shock energy of >= 150 J via adhesive patches in antero-posterior orientation was preferred by most centers (78%). Eleven percent (n = 1809) of pts were reported to carry a PM/ICD. The ECV protocol was heterogeneous among centers. Complications associated with electrical cardioversion were reported in 11/1809 patients (0.6%), all were transitory elevations of pacing thresholds. CONCLUSIONS: In this nationwide snapshot survey of cardioversion procedures in Germany, approximately 11% of patients presenting for elective electrical cardioversion were pacemaker or ICD carriers. Cardioversion protocols in these patients are heterogeneous throughout centers and mostly not in accordance with recommendation of the German Cardiac Society. Complications associated with external electrical cardioversion are rare. Controlled trials and large registries are necessary to provide evidence for future recommendations. PMID- 29151184 TI - Analysis of an optimal public transport structure under a carbon emission constraint: a case study in Shanghai, China. AB - Along with the rapid development of the transportation industry, the problems of the energy crisis and transport emissions have become increasingly serious. The success of traffic emission reduction is related to the realization of global low carbon goals. Placing priority on public transport is the internationally recognized traffic development model. This paper takes Shanghai, China, as an example to examine the optimal public transport structure. Five factors were selected from personal and public perspectives, including travel costs, crowding degree, occupied area, traffic emissions, and operating subsidies. The objective functions of these factors were transformed into satisfaction functions, and a multi-objective programming model was used to solve for the optimal proportions of the ground bus and rail transit, and the carbon emission reduction potential was analyzed in different scenarios. The study showed that the actual proportion of rail transit in Shanghai was slightly lower than the optimal value, and accompanied by low satisfaction with each factor relative to the optimal value. It was difficult to achieve the traffic emission reduction targets by only reducing satisfaction with other factors except carbon emissions assuming a fixed proportion of public transport. As the proportion of total travel represented by public transport increased, rail transit became the main mode of public transport and the usage trend was more obvious, but the structure of public transport gradually reached a relatively stable state after a certain level of development. Compared to reducing carbon emissions by changing satisfaction with other factors, it was easier to achieve traffic emission reduction targets by increasing the proportion of public transport. To increase the proportion of public transport travel and achieve the goal of traffic reduction in the future, further improvements are needed in the quality of public transport system services, public transport priority development must be differentiated, and the profitability of the public transport industry itself must be enhanced. PMID- 29151185 TI - Mercury in organs of Pacific walruses (Odobenus rosmarus divergens) from the Bering Sea. AB - The Pacific walrus (Odobenus rosmarus divergens) is still used as an important source of protein-rich food by indigenous peoples of Chukotka, Alaska, and other Arctic regions. Total mercury (THg) concentration was measured in eight internal organs of walruses. Samples were taken from 22 individuals (11 males and 11 females). Age of the animals ranged from 1 to 30 years. All the walruses were harvested by local hunters from the coastal waters off the Chukchi Peninsula (Russia) during the autumn of 2011. Total mercury concentration in the samples was determined by atomic absorption method. No statistically significant difference in the level of mercury was found between males and females. Mercury was detected in all the organs of the studied walruses. The highest total mercury concentration was recorded from excretory organs: liver and kidneys. The level of mercury in liver (mean = 1.87 MUg/g, range = 0.05-5.87) was by an order of magnitude higher than in kidneys (mean = 0.54 MUg/g, range = 0.09-1.64.); in kidneys, it was by an order of magnitude higher than in the rest of the organs. The analyzed organs can be arranged in the order of decreasing Hg concentration as follows: liver >> kidney >> muscle > spleen >= heart >= intestine > lung >= testis. The mercury concentration values in walruses from the coastal waters off the Chukchi Peninsula are lower than those obtained from walruses in Alaska and the Canadian Arctic. Our findings may provide a basis for the further long-term monitoring of the condition of the Pacific walrus population and pollution of the Arctic ecosystem. PMID- 29151186 TI - Biochar effects on uptake of cadmium and lead by wheat in relation to annual precipitation: a 3-year field study. AB - Biochar has been widely studied for its ability to reduce plant uptake of heavy metals by lowering metal bioavailabilities through adsorption and pH-driven fixation reactions. However, the long-term effect of biochar on heavy metal bioavailabilities in alkaline soils under natural redox condition is rarely studied. Here, we report a study examining the effects of biochar on bioavailability and partitioning of cadmium (Cd) and lead (Pb) among different soil fractions over 3 years in a field study with wheat (Triticum aestivum L.). Plots were established on two similar soils having low and high levels of contamination, both of which were amended in the first year with wheat straw biochar at 0, 20, and 40 t ha-1. Precipitation patterns varied greatly over the study period, with 2014 having record drought, which was followed by 2 years having extreme flooding events. Results showed a significant increase in grain yield and reductions in Cd and Pb concentrations in wheat grain in the biochar amended soils in 2014. In contrast, bioavailable (exchangeable) heavy metal concentrations and plant uptake of Cd and Pb were significantly higher in the subsequent very wet years in 2015 and 2016, where the effects of biochar were much more variable and had an overall lesser effect on reducing heavy metal uptake. The results suggest that fluctuations in soil pH and redox caused by periodic drought and flood cycles strongly drive metal cycling through mobilization and immobilization of metals associated with different mineral phases. Under these conditions, biochar may have reduced efficacy for reducing heavy metal uptake in wheat. PMID- 29151187 TI - Spatial distributions of hexachlorobutadiene in agricultural soils from the Yangtze River Delta region of China. AB - Hexachlorobutadiene (HCBD) is one of the persistent organic pollutants (POPs) listed by the Stockholm Convention and poses potential risks to human health and ecosystems. To reveal the regional-scale pollution status of HCBD in agricultural soils from fast-developing areas, an extensive investigation was conducted in the core Yangtze River Delta (YRD), China. The detectable concentrations of HCBD in 241 soil samples ranged from 0.07 to 8.47 ng g-1 dry weight, with an average value of 0.32 ng g-1 and a detection rate of 59.3%. Industrial emissions and intensive agricultural activities were the potential source of HCBD. The concentrations of HCBD were highly associated with the soil physicochemical properties such as organic matter contents. Higher concentrations of HCBD were found in paddy fields than other land-use types. The concentrations of HCBD were much lower than those of organochlorine pesticides and polychlorinated biphenyls. Significant positive correlations were found between HCBD and most organochlorine pesticides. HCBD was not found in ten vegetable samples due to its low concentration and detection rate. A positive relationship was observed between the level of HCBD and the biomass of fungi, indicating that the fungi in soils might be influenced by the existence of HCBD. The potential risks of HCBD to ecosystems and health of inhabitants were estimated to be negligible. The finding from this study provides an important basis for soil quality assessment and risk management of HCBD in China. PMID- 29151188 TI - Dry flue gas desulfurization by-product application effects on plant uptake and soil storage changes in a managed grassland. AB - Environmental regulations mandate that sulfur dioxide (SO2) be removed from the flue gases of coal-fired power plants, which results in the generation of flue gas desulfurization (FGD) by-products. These FGD by-products may be a viable soil amendment, but the large amounts of trace elements contained in FGD by-products are potentially concerning. The objective of this study was to evaluate the effects of land application of a high-Ca dry FGD (DFGD) by-product on trace elements in aboveground biomass and soil. A high-Ca DFGD by-product was applied once at a rate of 9 Mg ha-1 on May 18, 2015 to small plots with mixed-grass vegetation. Soil and biomass were sampled prior to application and several times thereafter. Aboveground dry matter and tissue As, Co, Cr, Hg, Se, U, and V concentrations increased (P < 0.05) following application, but did not differ (P > 0.05) from pre-application levels or the unamended control within 3 to 6 months of application. Soil pH in the amended treatment 6 months after application was greater (P < 0.05) than in the unamended control. Soil Ca, S, and Na contents also increased (P < 0.05), following by-product application compared to the unamended control. High-Ca DFGD by-products appear to be useful as a soil amendment, but cause at least a temporary increase in tissue concentrations of trace elements, which may be problematic for animal grazing situations. PMID- 29151189 TI - The environmental pollutant BDE-209 regulates NO/cGMP signaling through activation of NMDA receptors in neurons. AB - The common flame retardant decabrominated diphenyl ether (BDE-209) is a persistent organic pollutant. Epidemiological studies have revealed that prenatal or postnatal exposure to BDE-209 can result in delayed cognitive development, and BDE-209 has been shown to be toxic to cultured neurons with maturation interference effects. However, its neurotoxic mechanism remains unclear. Nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling plays an important role in regulating neuronal maturation. We examined the influence of BDE-209 (100, 200, and 400 nM) on NO production and cGMP levels signaling in rodent neurons in vitro, with or without pretreatment N-methyl-D-aspartate (NMDA) receptor antagonism. We found that nanomolar concentrations of BDE-209 affected levels of the second messengers NO and cGMP, and that these effects could be blocked by NMDA receptor antagonism. Moreover, BDE-209 activation of NMDA receptors inhibited the expression of phosphodiesterases (PDEs), which modulate intracellular cGMP levels, and increased the Bcl-2/Bax ratio, favoring apoptosis induction. Our studies implicate the NMDA-NO/cGMP pathway in the pathogenic mechanism through which BDE-209 induces neurotoxicity. PMID- 29151190 TI - Elucidation of functional chemical groups responsible of compost phytotoxicity using solid-state 13C NMR spectroscopy under different initial C/N ratios. AB - More than 1 million tons of fresh organic wastes is produced in the Souss-Massa region in Morocco. Tomato organic residues represent more than 25% of the total organic wastes and are deposited in uncontrolled landfills. Thus, composting can represent a valuable and pertinent solution to this environmental problem. The objectives of this experiment are to identify the potential functional groups responsible for compost phytotoxicity and to determine the optimum initial carbon to nitrogen ratio (C/N) for maximum recovery of tomato residues. The experiment consisted of the variation of the initial C/N ratios (25, 30, 35, and 40) using mixtures of different raw materials (tomato residues, melon residues, olive mill pomace, and sheep manure). Physicochemical parameters (pH, electrical conductivity, C/N ratio, and humic acid/fulvic acid ratio) were determined and spectroscopic analyses (UV-vis and NMR-13C) were performed during the composting process along with quality parameters (germination and phytotoxicity tests) at the end. The results showed that the compost with the initial C/N ratio of 35 is the most humified with the least phytotoxic effect. The germination and phytotoxicity tests were negatively correlated with the methoxyl/N-alkyl-C ratio and O-alkyl-C. These two functional groups are probably the origin of phytotoxicity expression in compost quality tests. Thus, a simple and precise quality test could be performed to evaluate directly the phytotoxicity and maturity of compost. PMID- 29151191 TI - Silica nanoparticle exposure inducing granulosa cell apoptosis and follicular atresia in female Balb/c mice. AB - Given that the effects of ultrafine fractions (< 0.1 MUm) on reproductive diseases are gaining attention, this study aimed to explore the influence of silica nanoparticle (SiNP)-induced female reproductive dysfunction. In this study, 80 female mice were randomly divided into four groups including a control group and three concentrations of SiNP groups (7, 21, 35 mg/kg). Mice were exposed to the vehicle control and silica nanoparticles by tracheal perfusion every 3 days a total of five times in 15 days. Then, half of the mice in each group were sacrificed on 15 and 30 days after the first dose, respectively. Our findings indicated that SiNPs can result in ovarian damage, cause an imbalance of sex hormones, increase the number of atretic and primary follicles, and induce oxidative stress and DNA strand breaks in ovary by day 15. The protein expressions of ATM, CHK-2, P53, E2F1, P73, BAX, Caspase-9, and Caspase-3 were significantly increased, while expressions of RAD51 were down-regulated after SiNP exposure by days 15. Estradiol increased, while progesterone increased in low dose and decreased in high dose after SiNP exposure by 15 days. However, these changes were recovered by 30 days. The results suggest that SiNPs can cause reversible damage to follicles in mice. SiNPs could primarily cause DNA damage and DNA damage response through oxidative stress, while DNA damage repair failure because of severe DNA damage activated the mitochondrial apoptosis pathway and therefore resulted in apoptosis of granulosa cell. In addition, the disorder of reproductive endocrine function caused by SiNPs could be another reason for SiNP induced reproductive dysfunction in mice. These events in turn induce the follicles to undergo atresia. PMID- 29151192 TI - Impact of oral ketamine augmentation on hospital admissions in treatment resistant depression and PTSD: a retrospective study. AB - RATIONALE: Depressive episodes are the leading cause of mental health-related hospital admissions in Australia, and 44% of those admitted have a previous history of hospitalisations for depression (Admitted patient mental health related care: (Australian Institute of Health and Welfare Aust Hospital Stat 2011 12, 2013). Despite numerous available antidepressant treatments, many patients do not respond to conventional therapy, having what is called 'treatment resistance' (Fava Biol Psychiatry 53:649-659, 2003). In recent years, ketamine has risen to prominence as an effective, rapidly acting antidepressant (Ketamine: a light in the darkness: Paleos and Ross 28-33, 2013). However, customary intravenous (IV) and intramuscular (IM) routes of administration and relapse rates after cessation remain barriers to more widely adopted usage. OBJECTIVES: This study represents the largest retrospective review of patients receiving long-term oral ketamine for treatment-resistant depression and post-traumatic stress disorder (PTSD). Our purpose was to examine the safety and efficacy of oral ketamine therapy in an outpatient setting as measured by changes in hospitalisation for psychiatric episodes. METHODS: Hospital records of 37 patients who received oral ketamine treatment were reviewed to compare the number and duration of psychiatric hospital admissions before and after treatment. Records were also screened for adverse medical events and changes in ketamine dosage over time. RESULTS: Following treatment, inpatient hospital days were reduced by 70%, and hospital admissions were reduced by 65%. The dose of ketamine patients required was stable over time with no evidence of tolerance building. There were no serious adverse events and no long-term negative effects associated with ketamine. CONCLUSIONS: Oral ketamine offers a promising pharmacologic adjunct to depression treatment. It may offer a more approachable alternative to IV or IM ketamine. The results warrant further investigation into the safety and efficacy of oral ketamine for psychiatric treatment. PMID- 29151193 TI - Disturbances of diurnal phase markers, behavior, and clock genes in a rat model of depression; modulatory effects of agomelatine treatment. AB - Major depressive disorder (MDD) is a growing problem worldwide. Though, the etiology remains unresolved, circadian rhythm disturbances are frequently observed in MDD and thus is speculated to play a key role herein. The present study focuses on circadian rhythm disturbances in the chronic mild stress (CMS) animal model of depression and examined whether the atypical antidepressant, agomelatine, which is mediating its action via melatonergic and serotonergic receptors, is capable of resynchronizing the perturbed rhythm. Melatonin is often used as a marker of the circadian phase, but the functional and behavioral output is dictated on a cellular level by the molecular clock, driven by the clock genes. We applied in situ hybridization histochemistry to measure the expression levels of the core clock genes, period (Per) 1 and 2 and bone and muscle ARNT like protein 1 (Bmal1), in multiple brain regions believed to be implicated in depression. Agomelatine showed an antidepressant-like effect in the sucrose consumption test and an anxiolytic-like profile in the elevated zero maze. We found that CMS increased nighttime melatonin release in rats and that agomelatine attenuated this effect. Stress was shown to have a time and region-specific effect on clock gene expression in the brain. Treatment with agomelatine failed to normalize clock gene expression, and the observed modifying effect on gene expression did not associate with the antidepressant-like effect. This suggests that the antidepressant actions of agomelatine are mainly independent of circadian rhythm synchronization and, in this regard, not superior to traditional antidepressants tested in our model. PMID- 29151194 TI - Highly immersive virtual reality laparoscopy simulation: development and future aspects. AB - PURPOSE: Virtual reality (VR) applications with head-mounted displays (HMDs) have had an impact on information and multimedia technologies. The current work aimed to describe the process of developing a highly immersive VR simulation for laparoscopic surgery. METHODS: We combined a VR laparoscopy simulator (LapSim) and a VR-HMD to create a user-friendly VR simulation scenario. Continuous clinical feedback was an essential aspect of the development process. We created an artificial VR (AVR) scenario by integrating the simulator video output with VR game components of figures and equipment in an operating room. We also created a highly immersive VR surrounding (IVR) by integrating the simulator video output with a [Formula: see text] video of a standard laparoscopy scenario in the department's operating room. RESULTS: Clinical feedback led to optimization of the visualization, synchronization, and resolution of the virtual operating rooms (in both the IVR and the AVR). Preliminary testing results revealed that individuals experienced a high degree of exhilaration and presence, with rare events of motion sickness. The technical performance showed no significant difference compared to that achieved with the standard LapSim. CONCLUSION: Our results provided a proof of concept for the technical feasibility of an custom highly immersive VR-HMD setup. Future technical research is needed to improve the visualization, immersion, and capability of interacting within the virtual scenario. PMID- 29151195 TI - Risk Factors in Preschool Children for Predicting Asthma During the Preschool Age and the Early School Age: a Systematic Review and Meta-Analysis. AB - PURPOSE OF REVIEW: The aim of this study was to identify risk factors of asthma among children < 6 years old (preschool age) for predicting asthma during the preschool age and early school age (<= 10 years of age). METHOD OF THE STUDY: MEDLINE, Cochrane, EMBASE, and Google Scholar databases were searched until June 30, 2017. Prospective or retrospective cohort and case-control studies were included. Studies had to have evaluated risk factors or a predictive model for developing asthma in children <= 6 years of age or persistent asthma in early school age. RECENT FINDINGS: A total of 17 studies were included in the analysis. Factors associated with developing asthma in children <= 10 years of age (both pre-school and early school age) included male gender (pooled OR = 1.70, P < 0.001), atopic dermatitis (pooled OR = 2.02, P < 0.001), a family history of asthma (pooled OR = 2.20, P < 0.001), and serum IgE levels >= 60 kU/l or having specific IgE (pooled OR = 2.36, P < 0.001). A history of exposure to smoke or wheezing was also associated with persistent asthma in early school age (pooled OR = 1.51, P = 0.030 and pooled OR = 2.59, P < 0.001, respectively). In general, asthma predictive models (e.g., API, PIAMA, PAPS) had relatively low sensitivity (range, 21% to 71.4%) but high specificity (range, 69% to 98%). The study found that male gender, exposure to smoke, atopic dermatitis, family history of asthma, history of wheezing, and serum IgE level >= 60 kU/l or having specific IgE were significantly associated with developing asthma by either preschool or early school age. Asthma predictive models can be developed by those risk factors. PMID- 29151196 TI - Oral cancer radiotherapy affects enamel microhardness and associated indentation pattern morphology. AB - OBJECTIVES: The aim of this study is to determine the effects of in vitro and in vivo high-dose radiotherapy on microhardness and associated indentation pattern morphology of enamel. MATERIALS AND METHODS: The inner, middle, and outer microhardness of enamel was evaluated using three experimental groups: control (non-radiated); in vitro irradiated; in vivo irradiated. In vitro specimens were exposed to simulated radiotherapy, and in vivo specimens were extracted teeth from oral cancer patients previously treated with radiotherapy. Indentations were measured via SEM images to calculate microhardness values and to assess the mechanomorphological properties of enamel before and after radiotherapy. RESULTS: Middle and outer regions of enamel demonstrated a significant decrease in microhardness after in vitro and in vivo irradiation compared to the control group (p < 0.05). Two indentation patterns were observed: pattern A-presence of microcracks around indent periphery, which represents local dissipation of deformation energy; pattern B-clean, sharp indents. The percentage of clean microindentation patterns, compared to controls, was significantly higher following in vitro and in vivo irradiation in all enamel regions. The highest percentage of clean microindentations (65%) was observed in the in vivo irradiated group in the inner region of enamel near the dentin-enamel junction. CONCLUSIONS: For the first time, this study shows that in vitro and in vivo irradiation alters enamel microhardness. Likewise, the indentation pattern differences suggest that enamel may become more brittle following in vitro and in vivo irradiation. CLINICAL RELEVANCE: The mechanomorphological property changes of enamel following radiation may be a contributory component of pathologic enamel delamination following oral cancer radiotherapy. PMID- 29151197 TI - Impact of the Dapivirine Vaginal Ring on Sexual Experiences and Intimate Partnerships of Women in an HIV Prevention Clinical Trial: Managing Ring Detection and Hot Sex. AB - Vaginally-inserted HIV prevention methods have been reported to impact the sexual experience for women and their partners, and hence impacts acceptability of and adherence to the method. We analyzed in-depth interviews and focus group discussions about participants' sexual experiences while wearing the ring, collected during the MTN-020/ASPIRE phase 3 safety and effectiveness trial of a dapivirine vaginal ring for HIV prevention in Malawi, South Africa, Uganda, and Zimbabwe. Most women reported that partners did not feel the ring during sex, however, women felt they had to manage their partners' interaction with or reaction to the ring. In maintaining positive relationships, women were concerned about partners' discovering ring use and about ensuring that partners had a good sexual experience with them. Finally women were concerned about how they themselves experienced sex with the ring. Some found that the ring made the vaginal environment more desirable for their partners and themselves. PMID- 29151198 TI - High Substance Use and HIV Risk Behavior Among Young Argentine Men Who Have Sex with Men. AB - In the United States young men who have sex with men have higher rates of substance use, higher HIV incidence, and less frequent HIV testing than their heterosexual counterparts and older MSM. Less is known about comparable populations in Latin America. As part of an epidemiological study, MSM were recruited through Respondent Driven Sampling in the metropolitan area of Buenos Aires, Argentina and answered a computerized behavioral survey. From the total of 500 MSM enrolled, a sub-sample of 233 aged 18-25 was analyzed. The sample was concentrated among lower socioeconomic strata, and only 16% identified as gay. Nearly half reported male, female, and transvestite sexual partners. Reported substance use was widespread ranging from 61% for marijuana to 20% for pasta base (cocaine sulfate). Seventy percent of the sample had never been tested for HIV infection; 3% tested positive for HIV and 8% for syphilis during the study. PMID- 29151199 TI - Loneliness in Older Adults Living with HIV. AB - We conducted a cross-sectional study among HIV-positive adults age >= 50 in San Francisco to evaluate the frequency of loneliness, characteristics of those who reported loneliness, and the association of loneliness with functional impairment and health-related quality of life (HRQoL). Participants (N = 356) were predominately male (85%); 57% were white; median age was 56. 58% reported any loneliness symptoms with 24% reporting mild, 22% moderate and 12% severe loneliness. Lonely participants were more likely to report depression, alcohol and tobacco use, and have fewer relationships. In unadjusted models, loneliness was associated with functional impairment and poor HRQoL. In adjusted models, low income and depression remained associated with poor HRQoL, while low income, higher VACS index and depression were associated with functional impairment. A comprehensive care approach, incorporating mental health and psychosocial assessments with more traditional clinical assessments, will be needed to improve health outcomes for the aging HIV-positive population. PMID- 29151200 TI - A Closer Look at Racism and Heterosexism in Medical Students' Clinical Decision Making Related to HIV Pre-Exposure Prophylaxis (PrEP): Implications for PrEP Education. AB - Social biases among healthcare providers could limit PrEP access. In this survey study of 115 US medical students, we examined associations between biases (racism and heterosexism) and PrEP clinical decision-making and explored prior PrEP education as a potential buffer. After viewing a vignette about a PrEP-seeking MSM patient, participants reported anticipated patient behavior (condomless sex, extra-relational sex, and adherence), intention to prescribe PrEP to the patient, biases, and background characteristics. Minimal evidence for racism affecting clinical decision-making emerged. In unadjusted analyses, heterosexism indirectly affected prescribing intention via all anticipated behaviors, tested as parallel mediators. Participants expressing greater heterosexism more strongly anticipated increased risk behavior and adherence problems, which were associated with lower prescribing intention. The indirect effect via condomless sex remained significant adjusting for background characteristics. Prior PrEP education did not buffer any indirect effects. Heterosexism may compromise PrEP provision to MSM and should be addressed in PrEP-related medical education. PMID- 29151201 TI - Administrative Stressors and Islamic Coping Strategies Among Muslim Primary Principals in Malaysia: A Mixed Method Study. AB - Principals are school leaders who experienced stress while leading their schools towards excellence. However, principals stress experiences are always ignored and least studied. This mixed-methods study investigates primary principals' stress experiences and their Islamic coping strategies used in incapacitating the stress experiences. A total of 216 Muslim primary principals across different gender, types of schools and years of experiences as school leaders responded to the administrative stress and the Islamic coping strategies items. In addition, seven primary principals were purposefully selected and interviewed in exploring their reasons of using Islamic coping strategies for their relieving process. Results discovered that primary principals experienced fairly stress level and they perceived managing students' academic achievement was the most stressor followed by managing teachers' capabilities. Although findings revealed that no significant differences in terms primary principals' demographics; male primary principals, and experienced between 6 and 10 years and positioned in schools with least students (SLS) category have slightly higher level of stress. In terms of Islamic coping strategies used by primary principals, saying dhua to Allah, performing dhikir and reciting the Yassen are selected coping approaches employed in handling their stress. From interviews, primary principals also revealed that they used Islamic religious approaches as part of meaningful activities not just to overcoming their stress but also as part of religious approaches in remembering Allah, thinking back their past mistakes as part of the Muhasabah process. Therefore, we believed that religious approaches should be taken into consideration in principals' training as it provides peaceful and treatment in managing principals' stress issue. PMID- 29151203 TI - Experimental Aspects of Polarization Optimized Experiments (POE) for Magic Angle Spinning Solid-State NMR of Microcrystalline and Membrane-Bound Proteins. AB - Conventional NMR pulse sequences record one spectrum per experiment, while spending most of the time waiting for the spin system to return to the equilibrium. As a result, a full set of multidimensional NMR experiments for biological macromolecules may take up to several months to complete. Here, we present a practical guide for setting up a new class of MAS solid-state NMR experiments (POE or polarization optimized experiments) that enable the simultaneous acquisition of multiple spectra of proteins, accelerating data acquisition. POE exploit the long-lived 15N polarization of isotopically labeled proteins and enable one to obtain up to eight spectra, by concatenating classical NMR pulse sequences. This new strategy propels data throughput of solid-state NMR spectroscopy of fibers, microcrystalline preparations, as well as membrane proteins. PMID- 29151205 TI - Filamentous Bacteriophage Viruses: Preparation, Magic-Angle Spinning Solid-State NMR Experiments, and Structure Determination. AB - Filamentous bacteriophages are elongated semi-flexible viruses that infect bacteria. They consist of a circular single-stranded DNA (ssDNA) wrapped by a capsid consisting of thousands of copies of a major coat protein subunit. Given the increasing number of discovered phages and the existence of only a handful of structures, the development of methods for phage structure determination is valuable for biophysics and structural virology. In recent years, we developed and applied techniques to elucidate the 3D atomic-resolution structures of intact bacteriophages using experimental magic-angle spinning (MAS) solid-state NMR data. The flexibility in sample preparation - precipitated homogeneous solids - and the fact that ssNMR presents no limitation on the size, weight or morphology of the system under study makes it an ideal approach to study phage systems in detail.In this contribution, we describe approaches to prepare isotopically carbon-13 and nitrogen-15 enriched intact phage samples in high yield and purity, and we present experimental MAS NMR methods to study the capsid secondary and tertiary structure, and the DNA-capsid interface. Protocols for the capsid structure determination using the Rosetta modeling software are provided. Specific examples are given from studies of the M13 and fd filamentous bacteriophage viruses. PMID- 29151202 TI - NMR of Macromolecular Assemblies and Machines at 1 GHz and Beyond: New Transformative Opportunities for Molecular Structural Biology. AB - As a result of profound gains in sensitivity and resolution afforded by ultrahigh magnetic fields, transformative applications in the fields of structural biology and materials science are being realized. The development of dual low temperature superconducting (LTS)/high-temperature superconducting (HTS) magnets has enabled the achievement of magnetic fields above 1 GHz (23.5 T), which will open doors to an unprecedented new range of applications. In this contribution, we discuss the promise of ultrahigh field magnetic resonance. We highlight several methodological developments pertinent at high-magnetic fields including measurement of 1H-1H distances and 1H chemical shift anisotropy in the solid state as well as studies of quadrupolar nuclei such as 17O. Higher magnetic fields have advanced heteronuclear detection in solution NMR, valuable for applications including metabolomics and disordered proteins, as well as expanded use of proton detection in the solid state in conjunction with ultrafast magic angle spinning. We also present several recent applications to structural studies of the AP205 bacteriophage, the M2 channel from Influenza A, and biomaterials such as human bone. Gains in sensitivity and resolution from increased field strengths will enable advanced applications of NMR spectroscopy including in vivo studies of whole cells and intact virions. PMID- 29151204 TI - Afterglow Solid-State NMR Spectroscopy. AB - Biomolecular solid-state NMR experiments have traditionally been collected through detection of 13C or 15N nuclei. Since these nuclei have relatively low sensitivity stemming from their smaller gyromagnetic ratios relative to 1H, the time required to collect multi-dimensional datasets serves as a limitation to resonance assignment and structure determination. One improvement in the field has been to employ simultaneous or parallel acquisition techniques with the goal of acquiring more than one dataset at a time and therefore speeding up the overall data collection process. Central to these experiments is the cross polarization (CP) element, which serves as a way to transfer magnetization between nuclei via magnetic dipolar couplings. In this chapter, we show how residual signal remaining after CP is a polarization source that can be used to acquire additional datasets. The setup of this class of experiments, referred to as Afterglow spectroscopy, is described and demonstrated using a membrane protein transporter involved in multidrug resistance. PMID- 29151206 TI - Spherical Nanoparticle Supported Lipid Bilayers: A Tool for Modeling Protein Interactions with Curved Membranes. AB - Mechanistic studies of protein-membrane interactions can be complicated by the limitations of the membrane model system chosen. Many of these limitations can be overcome by using a spherical silica nanoparticle to support the membrane. In this chapter, we present a detailed protocol for the construction of spherical nanoparticle supported lipid bilayers (SSLBs), with discussion of methods to improve production. PMID- 29151207 TI - Rapid Prediction of Multi-dimensional NMR Data Sets Using FANDAS. AB - Solid-state NMR (ssNMR) can provide structural information at the most detailed level and, at the same time, is applicable in highly heterogeneous and complex molecular environments. In the last few years, ssNMR has made significant progress in uncovering structure and dynamics of proteins in their native cellular environments [1-4]. Additionally, ssNMR has proven to be useful in studying large biomolecular complexes as well as membrane proteins at the atomic level [5]. In such studies, innovative labeling schemes have become a powerful approach to tackle spectral crowding. In fact, selecting the appropriate isotope labeling schemes and a careful choice of the ssNMR experiments to be conducted are critical for applications of ssNMR in complex biomolecular systems. Previously, we have introduced a software tool called FANDAS (Fast Analysis of multidimensional NMR DAta Sets) that supports such investigations from the early stages of sample preparation to the final data analysis [6]. Here, we present a new version of FANDAS, called FANDAS 2.0, with improved user interface and extended labeling scheme options allowing the user to rapidly predict and analyze ssNMR data sets for a given protein-based application. It provides flexible options for advanced users to customize the program for tailored applications. In addition, the list of ssNMR experiments that can be predicted now includes proton (1H) detected pulse sequences. FANDAS 2.0, written in Python, is freely available through a user-friendly web interface at http://milou.science.uu.nl/services/FANDAS . PMID- 29151208 TI - Strategies for Efficient Sample Preparation for Dynamic Nuclear Polarization Solid-State NMR of Biological Macromolecules. AB - Solid-state NMR (SSNMR) is a powerful tool for the elucidation of structure and dynamics in biological macromolecules. Over the years, SSNMR spectroscopists have developed an array of techniques enabling the measurement of internuclear correlations, distances, and torsional angles; these have been applied to the study of a number of biological systems that are difficult to study by X-ray crystallography and solution NMR, including key biological targets such as membrane proteins and amyloid fibrils. Applications of SSNMR to other topic areas, including materials science, pharmaceuticals, and small molecules, have also flourished in recent years. These studies, however, have always been hampered by the low inherent sensitivity of SSNMR, requiring large amounts of both sample and time for data collection. By taking advantage of unpaired electrons doped into a sample as a ready source of additional nuclear polarization, dynamic nuclear polarization (DNP) has brought about large improvements in SSNMR sensitivity. These, in turn, have enabled structural studies of previously inaccessible targets, such as large protein complexes, nucleic acids, viral capsids, and membrane proteins in vivo. Herein, we focus on sample preparation strategies and considerations for scientists interested in applying DNP to challenging systems. PMID- 29151209 TI - In-Vitro Dissolution Dynamic Nuclear Polarization for Sensitivity Enhancement of NMR with Biological Molecules. AB - Dissolution dynamic nuclear polarization (D-DNP) is a technique to prepare hyperpolarized nuclear spin states, yielding a signal enhancement of several orders of magnitude for liquid-state NMR. Here, we describe experimental procedures for the application of D-DNP in high-resolution NMR of biochemical compounds, to determine the time evolution of biochemical processes and intermolecular interactions. PMID- 29151210 TI - Determination of Protein ps-ns Motions by High-Resolution Relaxometry. AB - Many of the functions of biomacromolecules can be rationalized by the characterization of their conformational energy landscapes: the structures of the dominant states, transitions between states and motions within states. Nuclear magnetic resonance (NMR) spectroscopy is the technique of choice to study internal motions in proteins. The determination of motions on picosecond to nanosecond timescales requires the measurement of nuclear spin relaxation rates at multiple magnetic fields. High sensitivity and resolution are obtained only at high magnetic fields, so that, until recently, site-specific relaxation rates in biomolecules were only measured over a narrow range of high magnetic fields. This limitation was particularly striking for the quantification of motions on nanosecond timescales, close to the correlation time for overall rotational diffusion. High-resolution relaxometry is an emerging technique to investigate picosecond-nanosecond motions of proteins. This approach uses a high-field NMR spectrometer equipped with a sample shuttle device, which allows for the measurement of the relaxation rate constants at low magnetic fields, while preserving the sensitivity and resolution of a high-field NMR spectrometer. The combined analysis of high-resolution relaxometry and standard high-field relaxation data provides a more accurate description of the dynamics of proteins, in particular in the nanosecond range. The purpose of this chapter is to describe how to perform high-resolution relaxometry experiments and how to analyze the rates measured with this technique. PMID- 29151211 TI - Characterizing Protein Dynamics with NMR R 1rho Relaxation Experiments. AB - The measurement of R1rho , the longitudinal relaxation rate constant in the rotating frame, is one of the few available methods to characterize the MUs-ms functional dynamics of biomolecules. Here, we focus on 15N R1rho experiments for protein NH groups. We present protocols for both on- and off-resonance 15N R1rho measurements needed for relaxation dispersion studies, and describe the data analysis for extracting kinetic and thermodynamic parameters characterizing the motional processes. PMID- 29151212 TI - CPMG Experiments for Protein Minor Conformer Structure Determination. AB - CPMG relaxation dispersion NMR experiments have emerged as a powerful method to characterize protein minor states that are in exchange with a visible dominant conformation, and have lifetimes between ~0.5 and 5 milliseconds (ms) and populations greater than 0.5%. The structure of the minor state can, in favorable cases, be determined from the parameters provided by the CPMG relaxation dispersion experiments. Here, we go through the intricacies of setting up these powerful CPMG experiments. PMID- 29151213 TI - Probing the Atomic Structure of Transient Protein Contacts by Paramagnetic Relaxation Enhancement Solution NMR. AB - Important biological processes, including enzyme catalysis, signaling, and protein folding, proceed through lowly populated (<5%) states that elude structural characterization by conventional techniques. Here, we describe the steps required for visualization of these sparsely populated conformations and transient protein-protein interactions using paramagnetic relaxation enhancement solution NMR. We describe experimental design, sample preparation, data acquisition and processing, and the basics of data analysis of structural ensembles. PMID- 29151214 TI - From Raw Data to Protein Backbone Chemical Shifts Using NMRFx Processing and NMRViewJ Analysis. AB - Assignment of the chemical shifts of the backbone atoms (HN, N, CA, CB, and C) of proteins is often a prerequisite to using NMR information in the study of proteins. These chemical shifts and their perturbations are the basis for the analysis of protein dynamics, ligand binding, and backbone conformation. They are generally assigned prior to full side-chain assignments and the determination of the complete three-dimensional molecular structure. This chapter describes the use of two software packages, NMRFx Processor and NMRViewJ, in going from raw NMR data to backbone assignments. The step-by-step procedure describes processing of the data and the use of manual and automated features of the RunAbout tool in NMRViewJ to perform the assignments. PMID- 29151215 TI - Protein Structure Elucidation from NMR Data with the Program Xplor-NIH. AB - Xplor-NIH is a popular software package for biomolecular structure determination from NMR (and other) experimental data. This chapter illustrates its use with the de novo structure determination of the B1 domain of streptococcal protein G (GB1), based on distances from nuclear Overhauser effects, torsion angles from scalar couplings, and bond-vector orientations from residual dipolar couplings. Including Xplor-NIH's latest developments, a complete structure calculation script is discussed in detail, and is intended to serve as a basis for other applications. PMID- 29151216 TI - Practical Nonuniform Sampling and Non-Fourier Spectral Reconstruction for Multidimensional NMR. AB - A general approach to accelerating multidimensional NMR experiments via nonuniform sampling and maximum entropy spectral reconstruction was first demonstrated by Laue and colleagues in 1987. Following decades of continual improvements involving dozens of software packages for non-Fourier spectral analysis and many different schemes for nonuniform sampling, we still lack a clear consensus on best practices for sampling or spectral reconstruction, and programs for processing nonuniformly sampled data are not particularly user friendly. Nevertheless, it is possible to discern conservative and general guidelines for nonuniform sampling and spectral reconstruction. Here, we describe a robust semi-automated workflow that employs these guidelines for simplifying the selection of a sampling schedule and the processing of the resulting nonuniformly sampled multidimensional NMR data. Our approach is based on NMRbox, a shared platform for NMR software that facilitates workflow development and execution, and enables rapid comparison of alternate approaches. PMID- 29151217 TI - Covariance NMR Processing and Analysis for Protein Assignment. AB - During NMR resonance assignment it is often necessary to relate nuclei to one another indirectly, through their common correlations to other nuclei. Covariance NMR has emerged as a powerful technique to correlate such nuclei without relying on error-prone peak peaking. However, false-positive artifacts in covariance spectra have impeded a general application to proteins. We recently introduced pre- and postprocessing steps to reduce the prevalence of artifacts in covariance spectra, allowing for the calculation of a variety of 4D covariance maps obtained from diverse combinations of pairs of 3D spectra, and we have employed them to assign backbone and sidechain resonances in two large and challenging proteins. In this chapter, we present a detailed protocol describing how to (1) properly prepare existing 3D spectra for covariance, (2) understand and apply our processing script, and (3) navigate and interpret the resulting 4D spectra. We also provide solutions to a number of errors that may occur when using our script, and we offer practical advice when assigning difficult signals. We believe such 4D spectra, and covariance NMR in general, can play an integral role in the assignment of NMR signals. PMID- 29151218 TI - Structures of Dynamic Protein Complexes: Hybrid Techniques to Study MAP Kinase Complexes and the ESCRT System. AB - The integration of complementary molecular methods (including X-ray crystallography, NMR spectroscopy, small angle X-ray/neutron scattering, and computational techniques) is frequently required to obtain a comprehensive understanding of dynamic macromolecular complexes. In particular, these techniques are critical for studying intrinsically disordered protein regions (IDRs) or intrinsically disordered proteins (IDPs) that are part of large protein:protein complexes. Here, we explain how to prepare IDP samples suitable for study using NMR spectroscopy, and describe a novel SAXS modeling method (ensemble refinement of SAXS; EROS) that integrates the results from complementary methods, including crystal structures and NMR chemical shift perturbations, among others, to accurately model SAXS data and describe ensemble structures of dynamic macromolecular complexes. PMID- 29151219 TI - Implementation of the NMR CHEmical Shift Covariance Analysis (CHESCA): A Chemical Biologist's Approach to Allostery. AB - Mapping allosteric sites is emerging as one of the central challenges in physiology, pathology, and pharmacology. Nuclear Magnetic Resonance (NMR) spectroscopy is ideally suited to map allosteric sites, given its ability to sense at atomic resolution the dynamics underlying allostery. Here, we focus specifically on the NMR CHEmical Shift Covariance Analysis (CHESCA), in which allosteric systems are interrogated through a targeted library of perturbations (e.g., mutations and/or analogs of the allosteric effector ligand). The atomic resolution readout for the response to such perturbation library is provided by NMR chemical shifts. These are then subject to statistical correlation and covariance analyses resulting in clusters of allosterically coupled residues that exhibit concerted responses to the common set of perturbations. This chapter provides a description of how each step in the CHESCA is implemented, starting from the selection of the perturbation library and ending with an overview of different clustering options. PMID- 29151220 TI - High-Efficiency Expression of Yeast-Derived G-Protein Coupled Receptors and 19F Labeling for Dynamical Studies. AB - We describe a detailed protocol for heterologous expression of the human adenosine A2A G-protein coupled receptor (GPCR), using Pichia pastoris. Details are also provided for the reconstitution and functional purification steps. Yields of 2-6 mg/g membrane were obtained prior to functional purification (ligand column purification). Typically, functional purification reduced overall yields by a factor of 2-4, resulting in final functional production of 0.5-3 mg/L membrane. Yeast is an excellent protein expression system for NMR given its high tolerance for isotope-enriched solvents and its ability to grow in minimal media. PMID- 29151221 TI - Quantitative Determination of Interacting Protein Surfaces in Prokaryotes and Eukaryotes by Using In-Cell NMR Spectroscopy. AB - This paper describes three protocols for identifying interacting surfaces on 15N labeled target proteins of known structure by using in-cell NMR spectroscopy. The first protocol describes how to identify protein quinary structure interaction surfaces in prokaryotes by using cross-relaxation-induced polarization transfer, CRIPT, based in-cell NMR. The second protocol describes how to introduce labeled protein into eukaryotic (HeLa) cells via electroporation for CRIPT-based in-cell studies. The third protocol describes how to quantitatively map protein interacting surfaces by utilizing singular value decomposition, SVD, analysis of STructural INTeractions by in-cell NMR, STINT-NMR, data. PMID- 29151222 TI - Full genome sequences are key to disclose RHDV2 emergence in the Macaronesian islands. AB - A recent publication by Carvalho et al. in "Virus Genes" (June 2017) reported the presence of the new variant of rabbit hemorrhagic disease virus (RHDV2) in the two larger islands of the archipelago of Madeira. Based on the capsid protein sequence, the authors suggested that the high sequence identity, along with the short time spanning between outbreaks, points to dissemination from Porto Santo to Madeira. By including information of the full RHDV2 genome of strains from Azores, Madeira, and the Canary Islands, we confirm the results obtained by Carvalho et al., but further show that several subtypes of RHDV2 circulate in these islands: non-recombinant RHDV2 in the Canary Islands, G1/RHDV2 in Azores, Porto Santo and Madeira, and NP/RHDV2 also in Madeira. Here we conclude that RHDV2 has been independently introduced in these archipelagos, and that in Madeira at least two independent introductions must have occurred. We provide additional information on the dynamics of RHDV2 in the Macaronesian archipelagos of Azores, Madeira, and the Canary Islands and highlight the importance of analyzing RHDV2 complete genome. PMID- 29151223 TI - Correction to: Pain, Psychological Comorbidities, Disability, and Impaired Quality of Life in Hidradenitis Suppurativa. AB - The original version of this article contains an error in the spelling of the title. The title should read: Pain, Psychological Comorbidities, Disability, and Impaired Quality of Life in Hidradenitis Suppurativa. PMID- 29151224 TI - The potential role of the osteopontin-osteocalcin-osteoprotegerin triad in the pathogenesis of prediabetes in humans. AB - AIMS: To examine the relationship between hormones involved in bone remodeling and glucose metabolism alterations in prediabetes. METHODS: Individuals (n = 43) with NGT (BMI = 31.1 +/- 1.1 kg/m2) and individuals (n = 79) with impaired glucose regulation (IGR) (BMI = 31.9 +/- 1.2 kg/m2) including subjects with IFG, IGT, and IFG-IGT underwent OGTT and DXA. Osteopontin (OPN), osteocalcin (OCN), osteoprotegerin (OPG), and PTH levels were measured at fasting. Beta-cell function was calculated using C-peptide deconvolution. Dynamic indexes of insulin sensitivity were calculated from OGTT. A subgroup underwent to a euglycemic hyperinsulinemic clamp with 3-3H-glucose to estimate the endogenous glucose production (EGP) and insulin-mediated body glucose disposal (TGD/SSPI). RESULTS: OPN was higher in IGR compared to NGT (5.3 +/- 0.5 vs. 3.3 +/- 0.2 MUg/mL; p = 0.008) and in isolated IGT compared to IFG and IFG-IGT (6.3 +/- 0.5 vs. 4.5 +/- 0.3 and 5.4 +/- 0.5 MUg/mL; p = 0.02). OCN was similar in IFG and NGT but lower in IGT and IFG-IGT compared to NGT (7.2 +/- 0.3 and 5.4 +/- 0.2 vs. 8.3 +/- 0.3 ng/mL; p < 0.01). OPN was positively correlated with HbA1c, fasting and 2 h plasma glucose and PTH. OCN was negatively correlated with body fat, 2 h plasma glucose, insulin and positively correlated with Stumvoll index. OPG correlated with TGD/SSPI (r = - 0.29; p < 0.05), EGP, and hepatic insulin resistance index in IGR (r = 0.51, r = 0.43; p < 0.01). There was no correlation between PTH and insulin sensitivity or Beta-cell function parameters. CONCLUSIONS: In prediabetes, hormones known to be involved in bone remodeling may affect glucose metabolism before overt T2DM occurs with tissue-specific mechanisms. PMID- 29151226 TI - Erratum to: Sequential Super-Resolution Imaging of Bacterial Regulatory Proteins, the Nucleoid and the Cell Membrane in Single, Fixed E. coli Cells. PMID- 29151225 TI - Association between different dietary polyphenol subclasses and the improvement in cardiometabolic risk factors: evidence from a randomized controlled clinical trial. AB - AIMS: Due to their different chemical structures and metabolism, polyphenol subclasses may have specific impact on cardiometabolic risk factors. Our aim was to evaluate whether the intake of different polyphenol subclasses is associated with clinical outcomes beneficially improved by polyphenols in a nutritional trial performed by our group (postprandial lipid response, glucose homeostasis, early insulin secretion and oxidative stress). METHODS: The present study is a secondary analysis of a nutritional intervention study with a diet naturally rich in polyphenols. The data are derived from 78 participants at high cardiovascular risk who completed the ETHERPATH trial. The associations between variations in polyphenol subclasses (phenolic acids, anthocyanidins, flavones, flavan-3-ols, flavonols and flavanones) and clinical outcomes beneficially influenced by polyphenols were firstly explored by Spearman's correlation. Thereafter, adjustment for gender, age and body mass index (BMI) was run. Linear regression analysis was used to assess the class of polyphenols that best predicted the outcome. RESULTS: Flavanone intake was inversely correlated with postprandial lipid response, whereas flavone intake was related to postchallenge glucose response. Anthocyanidins and flavan-3-ols associated positively with early insulin secretion. The decrease in urinary isoprostanes correlated with anthocyanidins, flavan-3-ols and flavonols. Correlations did not change after adjustment for gender, age, and BMI. Linear regression analysis showed an independent association between flavonols and urinary isoprostanes, whereas early insulin secretion was mainly associated with flavan-3-ols intake. CONCLUSIONS: The results of this study show that a polyphenol-rich diet may have a pleiotropic effect on cardiometabolic risk factors thanks to the specific action of different polyphenol subclasses. PMID- 29151227 TI - Significance of prostate-specific antigen kinetics after three-dimensional conformal radiotherapy with androgen deprivation therapy in patients with localized prostate cancer. AB - BACKGROUND: To evaluate the relationship between biochemical recurrence and post radiation prostate-specific antigen (PSA) kinetics in patients with localized prostate cancer treated by radiotherapy with various durations of androgen deprivation therapy (ADT). METHODS: We reviewed our single-institution, retrospectively maintained data of 144 patients with T1c-T3N0M0 prostate cancer who underwent three-dimensional conformal radiotherapy (3D-CRT) between December 2005 and December 2015 and 113 patients were fulfilled the inclusion criteria. In this cohort, 3D-CRT was delivered with a dose in the range from 70.0 to 72.0 Gy with ADT. All patients received ADT as concurrent regimens. Biochemical recurrence was defined on the basis of the following: "PSA nadir + 2.0 ng/ml or the clinical judgement of attending physicians". Kaplan-Meier, log-rank, and Cox regression analyses were carried out. RESULTS: The median follow-up period was 54.0 months. The median duration of ADT was 17 months (interquartile range, 10-24 months). There was a trend toward statistical significant correlation between post-radiation PSA decline rate of >= 90% and PSA recurrence (p = 0.056). The same correlation could be observed in D'Amico high-risk patients (p = 0.036). However, it was not observed between PSA nadir and PSA recurrence (p = 0.40) in univariate analysis. Furthermore, multivariate analysis showed that post radiation PSA decline rate of >= 90% was a significant predictor of biochemical recurrence in patients who received radiotherapy with various durations of ADT (p = 0.044). CONCLUSIONS: Post-radiation PSA decline rate of >= 90% was a prognostic factor for biochemical recurrence in localized prostate cancer patients received 3D-CRT with various durations of ADT. PMID- 29151228 TI - Previously implanted intra-peritoneal mesh increases morbidity during re laparoscopy: a retrospective, case-matched cohort study. AB - PURPOSE: Laparoscopic ventral hernia repair (LVHR) with intra-peritoneal mesh placement is standard surgical treatment of abdominal wall hernias. During laparoscopic re-intervention, we examined adhesions that develop after previous intra-peritoneal mesh placement and ascertained morbidity and risk of adverse events. METHODS: This is a retrospective, case-matched comparison of three patient groups-previous intra-peritoneal mesh (Group A), previous abdominal surgery (Group B) and no previous abdominal surgery (Group C). Matching was based on surgical procedure performed during laparoscopic re-intervention in Group A. Adhesions were described as grade, extent of previous mesh/scar involvement, involvement of abdominal quadrants and dissection technique required for adhesiolysis, each component being assigned value from 0 to 4. Total adhesion score (TAS) was generated as summative score for each patient (0 to 16). Access/adhesiolysis-related injuries, additional port requirement, deviations from planned surgery, operative time and length of hospital stay was noted. Relative risk of adverse events, i.e., inadvertent injuries and deviations from planned surgery, was calculated for Group A. RESULTS: Adhesion characteristics were most severe (highest TAS) in Group A. Access injuries occurred in 5, 4, 1.3% in Groups A, B, C, respectively. Adhesiolysis-related injury rate was 9%, 2.6% in Groups A, B, respectively. Relative risk of adverse events was 4 for Group A (compared to Groups B and C combined). Additional port requirement was highest for Group A. Mean operative time and length of hospital stay was significantly longer in Group A for LVHR. CONCLUSIONS: Intra-peritoneal mesh placement is associated with adhesion formation that may increase risk during subsequent laparoscopic surgery. PMID- 29151230 TI - Intentional placental removal on suspicious placenta accreta spectrum: still prohibited? AB - INTRODUCTION: Intentional placental removal for abnormally invasive placenta (AIP) is fundamentally abandoned at planned surgery for it. Whether this holds true even after recent introduction of various hemostatic procedures is unclear. MATERIALS AND METHODS: We discussed on this issue based on our own experiences and also on the recent reports on various hemostatic procedures. RESULTS: Studies directly answering this question have been lacking. We must weigh the balance between the massive bleeding and possibility of uterus-preservation when intentional placental removal strategy is employed. CONCLUSION: An almost forgotten strategy, the "intentional placental removal" for planned AIP surgery may regain its position when appropriate hemostatic procedures are concomitantly used depending on the situation. Even employing this strategy, quick decision to perform hysterectomy under multidisciplinary team may be important. PMID- 29151231 TI - Sleep medicine is coming of age in military medicine : Report from the Military Health System Research Symposium (2017) in Kissimmee, Florida. AB - In August 2017, the US Military Health System held its sixth annual Research Symposium for medical researchers from the US Army, Navy, Air Force, and Public Health Service. The symposium provides a collaborative environment for academia, industry, and military researchers who address advancement in areas of Combat Casualty Care, Military Operational Medicine, Clinical and Rehabilitative Medicine, and Military Infectious Diseases. This year, Sleep Medicine received substantial attention with presentations scattered throughout the program, poster presentations as well as a scheduled breakout session with podium presentations. A brief description of the breakout session follows. PMID- 29151232 TI - Early promising outcome following arthroscopic implantation of the subacromial balloon spacer for treating massive rotator cuff tear. AB - BACKGROUND: Massive rotator cuff tear (RCT) can result in disability and severe pain. When conservative treatment fails, surgical treatment should be considered, as various surgical options can provide relatively satisfactory results. However, choosing an optimal treatment remains controversial. A relatively new treatment for irreparable RCT is the arthroscopic implantation of a biodegradable balloon spacer into the subacromial space. Here, we examined whether placement of this balloon spacer reduces pain and improves functional outcome in patients with an irreparable RCT. Patients were followed for 1 year following implantation. METHODS: In this prospective single-arm study, a biodegradable balloon spacer was implanted into the subacromial space of patients with a massive RCT. Pain was evaluated using a numeric rating scale (NRS), and functional outcome was evaluated using the Oxford shoulder score (OSS) and the Constant-Murley shoulder score (CMS). Five follow-up visits were performed during the first postoperative year. RESULTS: Forty-six shoulders in 44 patients with massive RCT were treated by surgical implantation of the subacromial balloon spacer. The mean reduction in NRS score was 3.5 points (95% CI 2.5-4.4), and 74% of patients achieved the minimal clinically important difference of 2 points by the 1-year follow-up visit. Functional outcome improved significantly based on OSS and CMS scores, and 80% of patients reported that they were satisfied with their outcome. No surgical or postoperative medical complications due to implantation of the balloon spacer were reported. CONCLUSIONS: Our results suggest that arthroscopic implantation of a biodegradable balloon spacer in the subacromial space significantly reduces pain and improves activities of daily living in patients with massive RCT during 1 year of follow-up. The specific contribution of the balloon with respect to improved clinical outcome needs further study, ideally in a randomized controlled trial. PMID- 29151233 TI - Clinical results of hemiarthroplasty using new bipolar cups for stage 3 or lower osteonecrosis of the femoral head: a retrospective study. AB - PURPOSE: The aim of this study was to evaluate clinical and radiographic findings of stage 3 or lower osteonecrosis of the femoral head (ONFH) with intact acetabular cartilage in patients treated with bipolar hemiarthroplasty (BHA). METHODS: A total of 79 hips that underwent BHA for ONFH were included in this study. The average observation period was 7.6 years. Clinical results were evaluated using the Harris hip score. We performed radiographic analysis to assess the migration of the outer cup, the permanent image around the outer cup, and loosening of the stem. RESULTS: The total Harris hip score improved from 50 points before surgery to 92 points at final follow-up, while pain improved from 14 points to 36 points. Flexion improved from 94 degrees to 120 degrees and abduction from 27 degrees to 37 degrees . One patient on dialysis showed progress in terms of inward migration, and revision surgery was performed on the patient 14 years after the original surgery. CONCLUSIONS: Midterm performance of BHA for stage 3 or lower ONFH at our hospital was good. PMID- 29151234 TI - Excavating the Psyche: A Social History of Soviet Psychiatry in Bulgaria. AB - This article investigates how an imported Soviet psychiatric model affected Bulgarians who experienced psychological crisis by examining therapeutic possibilities that were available and foreclosed in the People's Republic of Bulgaria. Bulgarians struggling with psychological disorders in the present day experience polar forms of marginalization: non-recognition on one extreme, and chronic medicalization on the other. Both tendencies can be traced to the Communist-period remodeling of mental healthcare, which outlawed private practice and individual-centered therapy, which reified empirically observable, physiological underpinnings of pathology while suppressing therapies that engaged with the existential context of mental illness. I argue that the reproduction of a Soviet psychiatric model instigated a modernization process but failed to anticipate the idiosyncrasy of economic and social conditions within the country. Furthermore, that this model rejected a therapeutic focus on the individual but developed no effective alternative for identifying and treating subjective characteristics of mental illness. Bulgaria's history of psychiatry has received little scholarly attention beyond Bulgarian psychiatrists who documented the development of their field. This article presents archival, literary and oral history footholds towards the development of a social history of Bulgarian psychiatry-a perspective that is especially and problematically missing. PMID- 29151235 TI - How 'The Urge to Kill' Feels: Articulations of Emic 'Appetitive Aggression' Experiences Among Former Forcefully Recruited Children and Youth in the Acholi Region of Northern Uganda. AB - Based on 10 months of fieldwork in the Acholi region of northern Uganda among youth and adults who were forcefully recruited into the Lord's Resistance Army (LRA) during the war, this article provides qualitative details to research on 'appetitive aggression.' Through two case-stories the article unfolds first person articulations of how 'appetitive aggression' is experienced as 'the urge to kill' and how it relates to the emic Acholi spiritual concept of 'cen'; a local Luo expression used to describe places and human beings possessed by evil spirits. The analysis illuminates what the individual and social implications of 'the urge to kill' and 'cen' entail for two Acholi men; first in a militia and then in a civil post-war context. The analysis then relates these findings to soldier experiences across cultures and time periods. While our analysis supports the findings in 'appetitive aggression' studies that appetitive aggression serves as a resilient protective factor against developing post-traumatic stress disorder (PTSD), this study documents that once the former forcefully recruited return to civilian life, 'appetitive aggression' and 'the urge to kill' precipitate individual and at times lethal social and moral complications in a fragile post-war community. Thus, the article argues that appetitive aggression and the emic perceptions and experiences of it among the local population are essential to consider in studies, processes and programs targeting demobilization, rehabilitation, reconciliation and re-integration. PMID- 29151229 TI - Effects of Female Sex Steroids Administration on Pathophysiologic Mechanisms in Traumatic Brain Injury. AB - Secondary brain damage following initial brain damage in traumatic brain injury (TBI) is a major cause of adverse outcomes. There are many gaps in TBI research and a lack of therapy to limit debilitating outcomes in TBI or enhance the neurogenesis, despite pre-clinical and clinical research performed in TBI. Females show harmful outcomes against brain damage including TBI less than males, independent of different TBI occurrence. A significant reduction in secondary brain damage and improvement in neurologic outcome post-TBI has been reported following the use of progesterone and estrogen in many experimental studies. Although useful features of sex steroids including progesterone have been identified in TBI clinical trials I and II, clinical trials III have been unsuccessful. This review article focuses on evidence of secondary injury mechanisms and neuroprotective effects of estrogen and progesterone in TBI. Understanding these mechanisms may enable researchers to achieve greater success in TBI clinical studies. It seems that the design of clinical studies should be revised due to translation loss of animal studies to clinical studies. The heterogeneous and complex nature of TBI, the endogenous levels of sex hormones at the time of taking these hormones, the therapeutic window of the drug, the dosage of the drug, the selection of appropriate targets in evaluation, the determination of responsive population, gender and age based on animal studies should be considered in the design of TBI human studies in future. PMID- 29151236 TI - Tauroursodeoxycholic acid alleviates secondary injury in the spinal cord via up regulation of CIBZ gene. AB - Spinal cord injury (SCI) is generally divided into primary and secondary injuries, and apoptosis is an important event of the secondary injury. As an endogenous bile acid and recognized endoplasmic reticulum (ER) stress inhibitor, tauroursodeoxycholic acid (TUDCA) administration has been reported to have a potentially therapeutic effect on neurodegenerative diseases, but its real mechanism is still unclear. In this study, we evaluated whether TUDCA could alleviate traumatic damage of the spinal cord and improve locomotion function in a mouse model of SCI. Traumatic SCI mice were intraperitoneally injected with TUDCA, and the effects were evaluated based on motor function assessment, histopathology, apoptosis detection, qRT-PCR, and western blot at different time periods. TUDCA administration can improve motor function and reduce secondary injury and lesion area after SCI. Furthermore, the apoptotic ratios were significantly reduced; Grp78, Erdj4, and CHOP were attenuated by the treatment. Unexpectedly, the levels of CIBZ, a novel therapeutic target for SCI, were specifically up-regulated. Taken together, it is suggested that TUDCA effectively suppressed ER stress through targeted up-regulation of CIBZ. This study also provides a new strategy for relieving secondary damage by inhibiting apoptosis in the early treatment of spinal cord injury. PMID- 29151237 TI - Health Risk Contamination of Heavy Metals in Yolk and Albumen of Duck Eggs Collected in Central and Western Thailand. AB - Two hundred duck egg samples were collected from 20 farms in Central and Western Thailand. The levels of Zn, Co, Mn, Fe, and Cr in yolks were found significantly higher than in albumen, whereas the levels of Cd and Cu contaminations in egg albumen were significantly higher than in yolks. The mean level of Pb contamination in whole eggs was 4.06 +/- 2.70 mg kg-1 dry weight. This level was higher than the Thai agricultural standard no. 6703-2005 for duck eggs set at 0.1 ppm for the magnitude of 40.6 times. In addition, 98% (196/200) of duck egg samples had Pb levels higher than the standard limit. However, the calculation of daily intakes of Pb, Cd, and Cu contamination in the current study of duck eggs shows that these metals were lower than the World Health Organization and the Food and Agriculture Organization provisional tolerated daily intake. These levels may, however, present a health risk resulting from a long-term exposure. It can be concluded that consumers may be at risk of Pb, Cd, and Cu contamination if they consume contaminated duck eggs. In addition, long-term monitoring of the health risks of heavy metals contamination should be conducted concerning the duck egg production system in Thailand. PMID- 29151238 TI - Predictability of hypoadrenalism occurrence and duration after adrenalectomy for ACTH-independent hypercortisolism. AB - OBJECTIVE: To evaluate if the parameters of hypothalamic-pituitary-adrenal (HPA) axis activity could predict the occurrence and duration of post-surgical hypocortisolism (PSH) in patients with Cushing's syndrome (CS) and with adrenal incidentaloma (AI). METHODS: We studied 80 patients (54 females, age 53.3 +/- 11 years), who underwent adrenalectomy for CS (17 patients) or for AI (53 patients). Before surgery, we measured adrenocorticotroph hormone (ACTH), urinary free cortisol (UFC) and serum cortisol after 1 mg dexamethasone suppression test (1 mg DST) levels. After surgery, all patients were given a steroid replacement therapy, and PSH was searched after 2 months by a low-dose (1 ug, iv) corticotropin stimulation test, that was repeated every 6 months in PSH patients for at least 4 years. RESULTS: The PSH occurred in 82.4 and 46% of CS and AI patients, respectively. In the whole sample and in AI patients separately considered, the PSH was independently predicted by the preoperative cortisol levels after 1 mg-DST, however, with a low (< 70%) accuracy. In AI patients the PSH occurrence was not ruled out even by the cortisol levels after 1 mg-DST lower than 1.8 MUg/dL (50 nmol/L). In the 50% of CS patients and in 31% of AI patients the PSH lasted more than 18 months and in 35.7% of CS patients it persisted for more than 36 months. In AI patients, the PSH duration was not predictable by any parameter. However, a PSH duration of at least 12 months was significantly predicted before adrenalectomy (sensitivity 91.7%, specificity 41.2%, positive predictive value 52.4%, negative predictive value 87.5%, p = 0.05) by the presence of at least 2 out of low ACTH levels, increased UFC levels and cortisol levels after 1 mg-DST >= 3.0 ug/dL (83 nmol/L). CONCLUSION: The PSH occurrence and its duration are hardly predictable before surgery. All patients undergoing unilateral adrenalectomy should receive a steroid substitutive therapy. PMID- 29151239 TI - Increased serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) levels are associated with glucose metabolism in Chinese pregnant women. AB - PURPOSE: Previous studies have found that 3-carboxy-4-methyl-5-propyl-2 furanpropanoic acid (CMPF) was associated with diabetes. This study aimed to investigate the relationship between abnormal increased CMPF levels and gestational diabetes mellitus (GDM). METHODS: We recruited 828 pregnant women, and all of them underwent an oral glucose tolerance test (OGTT). We screened out 141 GDM patients and 230 pregnant women with normal glucose tolerance as controls. The serum CMPF concentration in participants was measured, and the relationship between the serum CMPF concentration and various parameters and biochemical indices was analyzed. RESULTS: Compared with the serum levels in pregnant women with normal glucose tolerance, GDM patients exhibited markedly higher serum CMPF levels. The serum CMPF concentration showed an independent positive correlation with the blood glucose levels, glycated hemoglobin A1c(HbA1c), and the area under the glucose-time curve from the 2-h OGTT (AUC for glucose). Moreover, the CMPF concentration was independently negatively correlated with insulin secretion. However, CMPF was not significantly associated with lipid metabolism. CONCLUSIONS: Elevated serum CMPF levels are detrimental to the development of hyperglycemia and islet beta-cell functional failure in patients with GDM, which may promote the development of GDM. PMID- 29151240 TI - Rare Entities of Histopathological Findings in 755 Sleeve Gastrectomy Cases: a Synopsis of Preoperative Endoscopy Findings and Histological Evaluation of the Specimen. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is the most preferred technique in morbidly obese patients for weight loss. There is a controversy about the routine preoperative evaluation of the stomach and the routine microscopic examination of all LSG specimens. Our aim is to analyze the results of both preoperative upper gastrointestinal endoscopy and endoscopic biopsies and also the results of histopathological examination of LSG specimens. MATERIALS AND METHODS: The data of patients who underwent LSG from January 2011 to November 2016 were analyzed retrospectively from a prospectively collected database. Seven hundred fifty five of 819 patients who met the inclusion criteria were included in this study. Data on patients' demographic variables [age, gender, BMI (kg/m2)], preoperative upper GI endoscopy and biopsy results, postoperative histopathological results of the specimens, and the process of the patients with malignant histopathological investigation in the follow-up period were collected. RESULTS: This study involves 755 patients with a mean age of 39.6 +/- 11.7 years and has 496 (65.6%) to 259 (34.4%) female to male ratio. None of the patients harbored macroscopic or microscopic malignant pathological finding in the preoperative assessment. Hiatal hernia was detected in 78 (10.2%) patients and gastric/duodenal ulcers were detected in 52 (6.8%) patients in endoscopy. Incidental malignant and/or premalignant histopathological findings-intestinal metaplasia (1.4%) and malignant lesions (0.5%)-were rarely found in the evaluation of the surgical specimens. CONCLUSIONS: Both preoperative endoscopic assessment and postoperative histopathological examination of the specimen are mandatory in LSG patients. PMID- 29151241 TI - Liver Dysfunction with Both Roux-en-Y and One-Anastomosis Gastric Bypass Is Almost Exclusively Seen with Longer Than Standard Limb Lengths. PMID- 29151243 TI - UCD School of Medicine, Summer Student Research Awards 2017, 4th October 2017, UCD, Dublin, Ireland. PMID- 29151242 TI - A Qualitative Examination of Increased Alcohol Use after Bariatric Surgery among Racially/Ethnically Diverse Young Adults. AB - INTRODUCTION: Mounting evidence suggests that bariatric surgery, or weight loss surgery (WLS), patients might be vulnerable to developing post-operative alcohol use problems. While the majority of published research offers information concerning the prevalence of problematic alcohol use post-WLS, the literature lacks comprehensive, qualitative explorations examining why alcohol misuse might emerge after WLS. Such data-driven hypotheses are needed to effectively target this emerging concern. Additionally, young adults and racial/ethnic minorities are both increasingly undergoing WLS and are at heightened risk for problems related to alcohol use. To date, these groups have been under-represented in study samples. METHODS: To address these important gaps in the literature, racially/ethnically diverse, young adult WLS patients who indicated a post-WLS increase in alcohol use (n = 12) participated in an individual, semi-structured qualitative interview. Data were analyzed through two coding cycles; an external audit of the emerging themes was also conducted to further ensure the trustworthiness of the data. RESULTS: Interviews revealed four major themes prompting an increase in alcohol use after WLS: (1) increased sensitivity to alcohol intoxication, (2) utilizing alcohol as a replacement self-soothing mechanism for food, (3) increase in socialization, and (4) utilizing alcohol as a coping mechanism. CONCLUSIONS: By understanding the drivers of increases in alcohol use after WLS, precision-targeted pre- and post-surgical counseling interventions can be developed to address this emerging concern. PMID- 29151244 TI - Identification of rare noncoding sequence variants in gamma-aminobutyric acid A receptor, alpha 4 subunit in autism spectrum disorder. AB - Alterations of the gamma-aminobutyric acid (GABA) signaling system has been strongly linked to the pathophysiology of autism spectrum disorder (ASD). Genetic associations of common variants in GABA receptor subunits, in particular GABRA4 on chromosome 4p12, with ASD have been replicated by several studies. Moreover, molecular investigations have identified altered transcriptional and translational levels of this gene and protein in brains of ASD individuals. Since the genotyped common variants are likely not the functional variants contributing to the molecular consequences or underlying ASD phenotype, this study aims to examine rare sequence variants in GABRA4, including those outside the protein coding regions of the gene. We comprehensively re-sequenced the entire protein coding and noncoding portions of the gene and putative regulatory sequences in 82 ASD individuals and 55 developmentally typical pediatric controls, all homozygous for the most significant previously associated ASD risk allele (G/G at rs1912960). We identified only a single common, coding variant, and no association of any single marker or set of variants with ASD. Functional annotation of noncoding variants identified several rare variants in putative regulatory sites. Finally, a rare variant unique to ASD cases, in an evolutionary conserved site of the 3'UTR, shows a trend toward decreasing gene expression. Hence, GABRA4 rare variants in noncoding DNA may be variants of modest physiological effects in ASD etiology. PMID- 29151245 TI - Hearing impairment caused by mutations in two different genes responsible for nonsyndromic and syndromic hearing loss within a single family. AB - Usher syndrome is rare genetic disorder impairing two human senses, hearing and vision, with the characteristic late onset of vision loss. This syndrome is divided into three types. In all cases, the vision loss is postlingual, while loss of hearing is usually prelingual. The vestibular functions may also be disturbed in Usher type 1 and sometimes in type 3. Vestibular areflexia is helpful in making a proper diagnosis of the syndrome, but, often, the syndrome is misdiagnosed as a nonsyndromic hearing loss. Here, we present a Polish family with hearing loss, which was clinically classified as nonsyndromic. After excluding mutations in the DFNB1 locus, we implemented the next-generation sequencing method and revealed that hearing loss was syndromic and mutations in the USH2A gene indicate Usher syndrome. This research highlights the importance of molecular analysis in establishing a clinical diagnosis of congenital hearing loss. PMID- 29151246 TI - Fluorescent Benzocoumarin-pi-Extended Styryl Hybrids: Solvatochromism, Excess Dipole Moment, NLO Properties and DFT Study. AB - Four benzo[h]chromen-3-yl)ethylidene) malononitrilestyryl hybrid dyes are presented for their potential non-linear optical properties using solvatochromism and density functional theory. The dyes are characterized by 1H and 13C NMR and elemental analysis. They have different donor and same acceptor as dicyanovinyl coumarin. Absorption and emission properties are highly dependent on substituents and environment. Dyes 3a and 3c show absorption solvatochromism while 3b and 3d show emission solvatochromism. Solvatochromism is used for the evaluation of excited state dipole moment and nonlinear optical properties which are comparable with the computed values. Limits of hyperpolarizability are close to the experimental and calculated values. Results shows that these dyes having strong intramolecular charge transfer characters proposing their potential nonlinear optical character. PMID- 29151247 TI - Editorial Introduction to the Special Issue on Neuropsychological Assessment in Aging. PMID- 29151248 TI - Adiponectin and vitamin D-binding protein are independently associated at birth in both mothers and neonates. AB - CONTEXT: Adult body fat is associated with birth anthropometry, suggesting a role for metabolic regulators including vitamin D and the adipokines-adiponectin and irisin-which have been reported to interact but, as yet, data remain controversial. OBJECTIVE: To study (i) the relationship between vitamin D, its binding protein (VDBP) and the adipokines, adiponectin, and irisin in mothers and neonates at birth and (ii) their effects on neonate anthropometric outcomes. DESIGN: Cross-sectional study for healthy mothers with full-term and uncomplicated births. SETTING: Primary care. SUBJECTS: Seventy pairs of newly delivered neonates and their mothers. MAIN OUTCOMES FEATURES: Biochemical markers from maternal and cord: VDBP, adiponectin, irisin, calcium, albumin, parathyroid hormone, 25OHD, 1,25(OH)2D. Maternal demographic and social characteristics and neonate anthropometric parameters were recorded. RESULTS: Maternal VDBP levels (364.1 +/- 11.9 MUg/ml) demonstrated a strong positive correlation with maternal adiponectin (4.4 +/- 0.4 MUg/ml) and irisin (308.8 +/- 50.8 ng/ml) concentrations, which remained significant (p < 0.001 and p < 0.041, respectively) after adjustment with multiple parameters, including weeks of gestation, maternal age, and BMI. The finding of a strong association of VDBP (355.3 +/- 29.2 MUg/ml) and adiponectin (11.9 +/- 2.0 MUg/ml) but not irisin (174.4 +/- 26.0 ng/ml) was also evident in neonates (p = 0.03 and p = 0.94, respectively). No association was observed in both maternal and neonatal vitamin D, adiponectin, and irisin. CONCLUSIONS: The main findings of this study are (i) the perspective of a potential independent interaction of VDBP and adiponectin in both mothers and neonates and (ii) the lack of a causative model effect of both maternal/neonatal vitamin D status and adipokine profile on neonatal anthropometry at birth, as a surrogate marker of future metabolic health of the offspring. PMID- 29151249 TI - High-resolution ultrasound highlighting neovascularization in TIPIC syndrome. PMID- 29151250 TI - Mudskipper (Boleophthalmus pectinirostris) Hepcidin-1 and Hepcidin-2 Present Different Gene Expression Profile and Antibacterial Activity and Possess Distinct Protective Effect against Edwardsiella tarda Infection. AB - Hepcidins are small cysteine-rich antimicrobial peptides that play an important role in fish immunity against pathogens. Most fish species have two or more hepcidin homologs that have distinct functions. This study investigated the immune functions of mudskipper (Boleophthalmus pectinirostris) hepcidin-1 (BpHep 1) and hepcidin-2 (BpHep-2) in vitro and in vivo. Upon infection with Edwardsiella tarda, the expression of BpHep-1 and BpHep-2 mRNA in immune tissues was significantly upregulated, but the expression profiles were different. Chemically synthesized BpHep-1 and BpHep-2 mature peptides exhibited selective antibacterial activity against various bacterial species, and BpHep-2 exhibited a stronger antibacterial activity and broader spectrum than BpHep-1. BpHep-1 and BpHep-2 both inhibited the growth of E. tarda in vitro, with the latter being more effective than the former. In addition, both peptides induced hydrolysis of purified bacterial genomic DNA (gDNA) or gDNA in live bacteria. In vivo, an intraperitoneal injection of 1.0 MUg/g BpHep-2 significantly improved the survival rate of mudskippers against E. tarda infection compared with 0.1 MUg/g BpHep-2 or 0.1 and 1.0 MUg/g BpHep-1. Similarly, only BpHep-2 treatment effectively reduced the tissue bacterial load in E. tarda-infected mudskippers. Furthermore, treatment with 1.0 or 10.0 MUg/ml BpHep-2 promoted the phagocytic and bactericidal activities of mudskipper monocytes/macrophages (MO/MF). However, only the highest dose (10.0 MUg/ml) of BpHep-1 enhanced phagocytosis, and BpHep-1 exerted no obvious effects on bactericidal activity. In conclusion, BpHep-2 is a stronger bactericide than BpHep-1 in mudskippers, and acts not only by directly killing bacteria but also through an immunomodulatory function on MO/MF. PMID- 29151251 TI - Quality of life following hospitalization-associated acute kidney injury in children. AB - OBJECTIVES: Acute kidney injury (AKI) is common in hospitalized children. The impact of AKI following hospitalization is not fully understood, particularly the impact on health related quality of life (HRQOL). The goal of this study was to determine the relationship between hospitalization-associated AKI and HRQOL in a pediatric population. STUDY DESIGN: We conducted a retrospective cohort study of children with hospitalization-associated AKI. Eligible children were 1-19 years old with AKI defined by kidney disease improving global outcomes (KDIGO) criteria and had at least one completed pediatric quality of life (PedsQL) 4.0 Generic Core Scale survey (N = 139). Participants completed up to three surveys to reflect baseline, admission and follow-up status. We categorized children as having mild AKI (KDIGO stage 1, N = 73) or severe AKI (KDIGO stage 2 or 3, N = 66). Mean PedsQL scores were compared by AKI group. Those with both baseline and follow-up surveys were analyzed to determine the proportion who returned to their baseline level of function within 8 weeks of discharge. RESULTS: Children with mild and severe AKI had similar baseline and admission PedsQL scores. Although children with severe AKI had lower follow-up scores, the results were not statistically significant (78.9 vs. 85.8, p = 0.11). Of those with severe AKI, 48% returned to their baseline level of physical functioning by follow-up, compared to 73% with mild AKI (p = 0.05). CONCLUSIONS: This is the first study of HRQOL following hospitalization-associated AKI. We found that children with severe AKI had depressed physical functioning after discharge when compared to children with mild AKI. PMID- 29151252 TI - Dominant C3 glomerulopathy: new roles for an old actor in renal pathology. AB - Recently, a number of reports have described dominant C3 deposits in renal biopsies of patients with infection-related glomerulonephritis (GN). While acute post-infectious GN and membranoproliferative GN are commonly characterized by immune deposits containing C3 and/or C4, the absence of immunoglobulin (Ig) and/or immune complexes at light or electron microscopy is a rather unusual observation. Dominant C3 deposition is believed to result from the alternative pathway of complement activation via the C3bBb "tickover" convertase. The actual occurrence of C3 glomerulopathy could be underestimated, since infection-related GN often quickly subsides without the need for a renal biopsy. A more thorough understanding of the pathways that lead to complement assembly and deposition within the kidney is needed to support a new classification of complement-related lesions, including entities such as dense deposit disease, (atypical) hemolytic uremic syndrome, dominant C1q, CFHR5, C4d, and C3 glomerulopathies. We will briefly review recent work in this area, focusing on GN with selective complement C3 deposits. PMID- 29151253 TI - A Two-Week Fecal Microbiota Transplantation Course in Pediatric Patients with Inflammatory Bowel Disease. AB - Dysbiosis plays a major role in the etiology of inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) is a new promising option for IBD treatment. We aimed to assess the effectiveness of a two-week FMT course in children with IBD. Ten patients, 10-17 years of age with moderate to severe IBD received a course of eight doses of freshly prepared FMT via a naso-duodenal tube or gastroscopy. All of the patients had pancolitis. There were eight cases of ulcerative colitis (UC) and two of Crohn's disease (CD). Disease activity was evaluated using the Pediatric UC Activity Index (PUCAI) and Pediatric CD Activity Index (PCDAI) for UC and CD, respectively, CRP, and fecal calprotectin on the day before the first infusion and then on the day before the next course of FMT. Clinical response, defined as a decrease of 15 points in either index, was observed in 9/10 patients (seven UC and two CD). Clinical remission, defined as a PCDAI score <= 10 and PUCAI score < 10 measured at the same time point, was observed in 3/8 UC patients and 2/2 CD patients. Side effects observed were self limiting and benign. We conclude that a short, intensive course of FMT has a beneficial effect on UC and CD colitis. FMT was well-tolerated and safe. Nonetheless, an optimal protocol of FMT administration is crucial for treatment efficacy. PMID- 29151254 TI - Evaluation of the Implementation of Hospital Antibiotic Policy in Oncosurgery Ward: A Six-Year Experience. AB - The hospital antibiotic policy should be implemented to rationalize the antibiotic use and to decrease the risk of spread of resistant bacteria. The aim of this study was to describe the antibiotic consumption patterns in a single oncosurgery ward before and after the implementation of hospital antibiotic policy. We conducted a retrospective analysis of the antibiotic use at the oncosurgery ward in Warsaw, Poland, in the years 2011-2016. Calculations were based on daily defined doses (DDD), DDD/100 hospitalizations, and DDD/100 person days. Drug utilization rates (DU 90% and DU 100%) were also analyzed. After the implementation of hospital antibiotic policy, a total antibiotic consumption increased (365.35 DDD in 2011 vs. 1359.22 DDD in 2016). A significant change was observed in the antibiotic consumption patterns: the use of amoxicillin clavulanate and carbapenems or glycopeptides decreased significantly (p < 0.05), while the use of ciprofloxacin and aminoglycosides increased (p < 0.05). The DU100% rate varied from 6 in 2011 to 12 in 2016; while DU 90% rate varied from 2 in 2011 to 3-5 in 2013-2016. Although the implementation of hospital antibiotic policy did not result in a decrease in the antibiotic consumption, it seems to provide a favorable change into the antibiotic consumption pattern. PMID- 29151255 TI - Weight Disorders in Short Children. AB - This study aimed to determine the degree of adiposity and prevalence of weight disorders in short children and to assess relationships between selected birth parameters and actual body fat content and body mass indicators. The study encompassed 85 girls and 97 boys, aged 7-14 years, with height below the 10th centile of the age and sex standard. In addition, 609 normal-height children (height between 25th and 75th centile) served as a comparison group. The children underwent measurements of body mass and height, skinfold thickness, and waist circumference. Detailed history on pregnancy and neonatal status of short children was collected. Body mass index, waist-to-height ratio, and body fat percentage (%FAT) were assessed. We found that about 27% of short children had insufficient %FAT and about 14% of them had excessive %FAT, regardless of sex. In terms of BMI, 24% of short children were underweight and only 6% were overweight or obese, while in normal-height children these percentages were 6 and 27.5%, respectively. Abdominal obesity was observed in about 5% of short children and 18% of normal-height children (p < 0.001). There was no association between birth parameters and somatic indicators in short children. We conclude that the prevalence of overweight and obesity, including abdominal obesity, among short children is much lower than that in normal-height children. The insufficient fat tissue and body mass, observed in one out of four short children, are particularly disturbing in the context of ensuring their correct development. PMID- 29151256 TI - Melatonin and Metformin Diminish Oxidative Stress in Heart Tissue in a Rat Model of High Fat Diet and Mammary Carcinogenesis. AB - The aim of this study was to determine the effects of long-term administration of the oral antidiabetic metformin or the pineal hormone melatonin, and a combination thereof, in preventing oxidative stress in the heart tissue of female Sprague-Dawley rats with mammary tumors induced by N-methyl-N-nitrosourea (NMU) (50 mg/kg) given on the 42nd postnatal day. Metformin and melatonin were administered 12 days before and 16 weeks after the carcinogen. During the experiment, all animals were fed a high fat diet (10% total fat, 2.5% from lard, and 7.5% from palm oil). The findings are that mammary carcinogenesis generated oxidative stress. Reactive oxygen species (ROS) content, estimated from thiobarbituric acid reactive substances (TBARS), oxidatively modified protein content (aldehyde and ketone derivatives), and the activity of the antioxidant enzymes superoxide dismutase, glutathione reductase, and glutathione peroxidase were all augmented. Metformin caused a decrease in oxidative stress in the heart, accompanied by a decrease in diene conjugates, the elimination of ROS (stable total antioxidant status), and the activation of catalase and glutathione reductase. Melatonin caused an increase in total antioxidant status and a substantial reduction in ROS as estimated from aldehyde and ketone derivatives, lipid peroxidation at the initial (diene conjugates) and terminal stages (TBARS), and increased catalase and glutathione peroxidase activities. Metformin and melatonin combined reversed the effects of NMU on oxidative stress. In conclusion, melatonin reduces the level of oxidative stress in the heart tissue, caused by NMU carcinogenesis and a high fat diet, significantly stronger than metformin. PMID- 29151257 TI - Oral Cancer Knowledge, Attitudes, and Practices among Dentists in Khartoum State, Sudan. AB - The dental professions hold an important responsibility in the control of oral cancer and the early diagnosis highly depends on their knowledge. The present study was developed to assess the knowledge, attitude, and practice of dentists in Khartoum State regarding oral cancer prevention and early detection. An administered questionnaire was structured and sent to all licensed 130 dentists working in public dental clinics in Khartoum State. Responses to the questionnaire were analyzed using descriptive and analytical statistics. Although the majority of the dentists were knowledgeable about the major risk factors of oral cancer, more than half of the dentists reported they do not carry out any special examination to detect oral cancer in age 40 and above in asymptomatic patients. Dentists indicated their lack of training as the main barrier for conducting a comprehensive oral cancer examination. Interestingly, the vast majority of the dentists express their interest to have further oral cancer educational and training sessions. The findings of the present study suggested strongly that educational and training interventions are necessary to enhance preventive measures which may lead to reduce mortality and morbidity from oral cancer. PMID- 29151258 TI - Clinical significance of disease-specific MYD88 mutations in circulating DNA in primary central nervous system lymphoma. AB - Recent sequencing studies demonstrated the MYD88 L265P mutation in more than 70% of primary central nervous system lymphomas (PCNSL), and the clinical significance of this mutation has been proposed as diagnostic and prognostic markers in PCNSL. In contrast, mutational analyses using cell-free DNAs have been reported in a variety of systemic lymphomas. To investigate how sensitively the MYD88 L265P mutation can be identified in cell-free DNA from PCNSL patients, we carried out droplet digital PCR (ddPCR) and targeted deep sequencing (TDS) in 14 consecutive PCNSL patients from whom paired tumor-derived DNA and cell-free DNA was available at diagnosis. The MYD88 L265P mutation was found in tumor-derived DNA from all 14 patients (14/14, 100%). In contrast, among 14 cell-free DNAs evaluated by ddPCR (14/14) and TDS (13/14), the MYD88 L265P mutation was detected in eight out of 14 (ddPCR) and in 0 out of 13 (TDS) samples, implying dependence on the detection method. After chemotherapy, the MYD88 L265P mutation in cell free DNAs was traced in five patients; unexpectedly, the mutations disappeared after chemotherapy was given, and they remained undetectable in all patients. These observations suggest that ddPCR can sensitively detect the MYD88 L265P mutation in cell-free DNA and could be used as non-invasive diagnostics, but may not be applicable for monitoring minimal residual diseases in PCNSL. PMID- 29151259 TI - EXAT: EXcitonic analysis tool. AB - We introduce EXcitonic Analysis Tool (EXAT), a program able to compute optical spectra of large excitonic systems directly from the output of quantum mechanical calculations performed with the popular Gaussian 16 package. The software is able to combine in an excitonic scheme the single-chromophore properties and exciton couplings to simulate energies, coefficients, and excitonic spectra (UV-vis, CD, and LD). The effect of the environment can also be included using a Polarizable Continuum Model. EXAT also presents a simple graphical user interface, which shows on-screen both site and exciton properties. To show the potential of the method, we report two applications on a a chiral perturbed BODIPY system and DNA G-quadruplexes, respectively. The program is available online at http://molecolab.dcci.unipi.it/tools/. (c) 2017 Wiley Periodicals, Inc. PMID- 29151260 TI - The first case of "locked-in leaflet" after transcatheter aortic valve replacement in a patient with bicuspid aortic stenosis. AB - This case report is about an 85-year-old woman with bicuspid aortic stenosis (AS). Although preoperative multimodality imaging showed challenging anatomical aspects, transcatheter aortic valve replacement (TAVR) was selected to be performed as a less invasive alternative treatment approach, owing to her comorbidity. Postoperative transesophageal echocardiography and multidetector-row computed tomography revealed the presence of "locked-in leaflet" caused by stent distortion due to pinching by calcified native leaflets, with nodular calcification preventing the full expansion of the valve, which resulted in moderate perivalvular leakage. This is the first reported case of bicuspid AS treated with TAVR that eventually resulted in "locked-in leaflet." PMID- 29151262 TI - The Founding Fathers of the International Neuroendocrine Society. PMID- 29151261 TI - Mitochondrial intermediate peptidase is a novel regulator of sirtuin-3 activation by caloric restriction. AB - Sirtuin-3 (SIRT3) regulates mitochondrial quality and is involved in the anti ageing and pro-longevity actions of caloric restriction (CR). Here, we show that CR upregulates the mature form of SIRT3 and mitochondrial intermediate peptidase (MIPEP), a mitochondrial signal peptidase (MtSPase), in white adipose tissue. We also demonstrate that upregulation of mature SIRT3 is dependent on MIPEP in 3T3 L1 cells, suggesting that MIPEP may contribute to the maintenance of mitochondrial quality during CRvia activation of SIRT3. This novel mechanism of SIRT3 activation through MIPEP facilitates the elucidation of additional molecular pathways of CR. PMID- 29151263 TI - A reference-free stockholder partitioning method based on the force on electrons. AB - We argue that when one divides a molecular property into atom-in-a-molecule contributions, one should perform the division based on the property density of the quantity being partitioned. This is opposition to the normal approach, where the electron density is given a privileged role in defining the properties of atoms-in-a-molecule. Because partitioning each molecular property based on its own property density is inconvenient, we design a reference-free approach that does not (directly) refer atomic property densities. Specifically, we propose a stockholder partitioning method based on relative influence of a molecule's atomic nuclei on the electrons at a given point in space. The resulting method does not depend on an "arbitrary" choice of reference atoms and it has some favorable properties, including the fact that all of the electron density at an atomic nucleus is assigned to that nucleus and the fact all the atoms in a molecule decay at a uniform asymptotic rate. Unfortunately, the resulting model is not easily applied to spatially degenerate ground states. Furthermore, the practical realizations of this strategy that we tried here gave disappointing numerical results. (c) 2017 Wiley Periodicals, Inc. PMID- 29151264 TI - Renal protection strategies after heart transplantation. AB - Renal dysfunction caused by calcineurin inhibitor (CNI) nephrotoxicity occurs often and contributes significantly to late mortality after heart transplantation (HTx). Over the last decades, this has prompted many clinical studies in an effort to develop kidney-protecting immunosuppressive strategies including delayed CNI start, minimization, withdrawal, or even de novo CNI avoidance. In the past, these strategies often failed due to the lack of efficacy. Since 2009, novel CNI-reducing strategies have been under investigation. These strategies minimize renal damage using induction agents such as antithymocyte globulin and alternative immunosuppressive agents such as the mechanistic target of rapamycin inhibitors (sirolimus or everolimus) or mycophenolate. This review outlines the recent results of using these renal protection strategies including their drawbacks. We also discuss alternative approaches to optimize individual immunosuppressive therapies after HTx. PMID- 29151265 TI - Cnn3 regulates neural tube morphogenesis and neuronal stem cell properties. AB - Calponin 3 (Cnn3) is a member of the Cnn family of actin-binding molecules that is highly expressed in the mammalian brain and has been shown to control dendritic spine morphology, density, and plasticity by regulating actin cytoskeletal reorganization and dynamics. However, little is known about the role of Cnn3 during embryonic development. In this study, we analyzed mutant animals deficient in Cnn3 to gain a better understanding of its role in brain morphogenesis. Embryos lacking Cnn3 exhibited massive malformation of the developing brain including exoencephaly, closure defects at the rostral neural tube, and strong enlargement of brain tissue. In wild-type animals, we found Cnn3 being localized to the apical lining of the neuroepithelium in close vicinity to beta-Catenin and N-cadherin. By performing immunohistochemistry on beta-Catenin and p-Smad, and furthermore taking advantage of Wnt-reporter animals, we provide evidence that the loss of Cnn3 during development can affect signaling pathways crucial for correct morphogenesis of the neural tube. In addition, we used embryonic neurosphere cultures to investigate the role of Cnn3 in embryonic neuronal stem cells (NSC). Here, we observed that Cnn3 deficiency in NSCs increased the number of newly formed neurospheres and increased neurosphere size without perturbing their differentiation potential. Together, our study provides evidence for an important role of Cnn3 during development of the embryonic brain and in regulating NSC function. PMID- 29151266 TI - Crystal structure and catalytic characterization of the dehydrogenase/reductase SDR family member 4 (DHRS4) from Caenorhabditis elegans. AB - : The human dehydrogenase/reductase SDR family member 4 (DHRS4) is a tetrameric protein that is involved in the metabolism of several aromatic carbonyl compounds, steroids, and bile acids. The only invertebrate DHRS4 that has been characterized to date is that from the model organism Caenorhabditis elegans. We have previously cloned and initially characterized this protein that was recently annotated as DHRS4_CAEEL in the UniProtKB database. Crystallization and X-ray diffraction studies of the full-length DHRS4_CAEEL protein in complex with diacetyl revealed its tetrameric structure and showed that two subunits are connected via an intermolecular disulfide bridge that is formed by N-terminal cysteine residues (Cys5) of each protein chain, which increases the enzymatic activity. A more detailed biochemical and catalytic characterization shows that DHRS4_CAEEL shares some properties with human DHRS4 such as relatively low substrate affinities with aliphatic alpha-diketones and a preference for aromatic dicarbonyls such as isatin, with a 30-fold lower Km value compared with the human enzyme. Moreover, DHRS4_CAEEL is active with aliphatic aldehydes (e.g. hexanal), while human DHRS4 is not. Dehydrogenase activity with alcohols was only observed with aromatic alcohols. Protein thermal shift assay revealed a stabilizing effect of phosphate buffer that was accompanied by an increase in catalytic activity of more than two-fold. The study of DHRS4 homologs in simple lineages such as C. elegans may contribute to our understanding of the original function of this protein that has been shaped by evolutionary processes in the course of the development from invertebrates to higher mammalian species. DATABASE: Structural data are available in the PDB under the accession numbers 5OJG and 5OJI. PMID- 29151267 TI - Impaired permeability and antimicrobial barriers in type 2 diabetes skin are linked to increased serum levels of advanced glycation end-product. AB - The incidence of type 2 diabetes mellitus (DM) has been increasing rapidly, and the disease has become a serious sociomedical problem. Many skin problems, such as xerosis, pruritus, skin infections and delayed wound healing, that might be related to chronic impairment of skin barrier function decrease the quality of life in patients with DM. However, the status of the permeability and antimicrobial barrier of the skin in DM remains unknown. This study aimed to elucidate skin barrier impairment in patients with type 2 DM and its pathomechanisms using classic animal models of type 2 DM. Functional studies of the skin barrier and an analysis of stratum corneum (SC) lipids were compared between patients with type 2 DM and age- and sex-matched non-diabetes controls. Also, functional studies on the skin barrier, epidermal lipid analyses, and electron microscopy and biomolecular studies were performed using type 2 DM animal models, db/db and ob/ob mice. Patients with type 2 DM presented with epidermal barrier impairments, including SC hydration, which was influenced by blood glucose control (HbA1c level). In the lipid analysis of SC, ceramides, fatty acids and cholesterol were significantly decreased in patients with type 2 DM compared with controls. Type 2 DM murine models presented with severe hyperglycaemia, impairment of skin barrier homeostasis, decreases in epidermal proliferation and epidermal lipid synthesis, decreases in lamellar body (LB) and epidermal antimicrobial peptides (AMPs), an increase in receptors for advanced glycation end-product (AGE) in the epidermis and an increase in serum AGE. Impairment of the skin barrier was observed in type 2 DM, which results in part from a decrease in epidermal proliferation. Serum AGE and its epidermal receptors were increased in type 2 diabetic mice which display impaired skin barrier parameters such as epidermal lipid synthesis, LB production, epidermal AMP and SC lipids. PMID- 29151268 TI - Professor Tomisaku Kawasaki, my teacher and a friend : a tribute. PMID- 29151269 TI - How to practice person-centred care: A conceptual framework. AB - BACKGROUND: Globally, health-care systems and organizations are looking to improve health system performance through the implementation of a person-centred care (PCC) model. While numerous conceptual frameworks for PCC exist, a gap remains in practical guidance on PCC implementation. METHODS: Based on a narrative review of the PCC literature, a generic conceptual framework was developed in collaboration with a patient partner, which synthesizes evidence, recommendations and best practice from existing frameworks and implementation case studies. The Donabedian model for health-care improvement was used to classify PCC domains into the categories of "Structure," "Process" and "Outcome" for health-care quality improvement. DISCUSSION: The framework emphasizes the structural domain, which relates to the health-care system or context in which care is delivered, providing the foundation for PCC, and influencing the processes and outcomes of care. Structural domains identified include: the creation of a PCC culture across the continuum of care; co-designing educational programs, as well as health promotion and prevention programs with patients; providing a supportive and accommodating environment; and developing and integrating structures to support health information technology and to measure and monitor PCC performance. Process domains describe the importance of cultivating communication and respectful and compassionate care; engaging patients in managing their care; and integration of care. Outcome domains identified include: access to care and Patient-Reported Outcomes. CONCLUSION: This conceptual framework provides a step-wise roadmap to guide health-care systems and organizations in the provision PCC across various health-care sectors. PMID- 29151271 TI - Development of spin-orbit coupling for stochastic configuration interaction techniques. AB - To perform spin-orbit coupling calculations on atoms and molecules, good zeroth order wavefunctions are necessary. Here, we present the software development of the Monte Carlo Configuration Interaction (MCCI) method, to enable calculation of such properties, where MCCI iteratively constructs a multireference wavefunction using a stochastic procedure. In this initial work, we aim to establish the efficacy of this technique in predicting the splitting of otherwise degenerate energy levels on a range of atoms and small diatomic molecules. It is hoped that this work will subsequently act as a gateway toward using this method to investigate singlet-triplet interactions in larger multireference molecules. We show that MCCI can generate very good results using highly compact wavefunctions compared to other techniques, with no prior knowledge of important orbitals. Higher-order relativistic effects are neglected and spin-orbit coupling effects are incorporated using first-order degenerate perturbation theory with the Breit Pauli Hamiltonian and effective nuclear charges in the one-electron operator. Results are obtained and presented for B, C, O, F, Si, S, and Cl atoms and OH, CN, NO, and C2 diatomic radicals including spin-orbit coupling constants and the relative splitting of the lowest energy degenerate state for each species. Convergence of MCCI to the full configuration interaction result is demonstrated on the multireference problem of stretched OH. We also present results from the singlet-triplet interaction between the X3Sigmag- and both the a1Deltag and b1Sigmag+ states of the O2 molecule. (c) 2017 Wiley Periodicals, Inc. PMID- 29151270 TI - ASC amino acid transporter 2, defined by enzyme-mediated activation of radical sources, enhances malignancy of GD2-positive small-cell lung cancer. AB - Ganglioside GD2 is specifically expressed in small-cell lung cancer (SCLC) cells, leading to enhancement of malignant phenotypes, such as cell proliferation and migration. However, how GD2 promotes malignant phenotypes in SCLC cells is not well known. In this study, to reveal the mechanisms by which GD2 increases malignant phenotypes in SCLC cells, we used enzyme-mediated activation of radical sources combined with mass spectrometry in GD2+ SCLC cells. Consequently, we identified ASC amino acid transporter 2 (ASCT2), a major glutamine transporter, which coordinately works with GD2. We showed that ASCT2 was highly expressed in glycolipid-enriched microdomain/rafts in GD2+ SCLC cells, and colocalized with GD2 in both proximity ligation assay and immunocytostaining, and bound with GD2 in immunoprecipitation/TLC immunostaining. Malignant phenotypes of GD2+ SCLC cells were enhanced by glutamine uptake, and were suppressed by L-gamma-glutamyl p-nitroanilide, a specific inhibitor of ASCT2, through reduced phosphorylation of p70 S6K1 and S6. These results suggested that ASCT2 enhances glutamine uptake in glycolipid-enriched microdomain/rafts in GD2+ SCLC cells, leading to the enhancement of cell proliferation and migration through increased phosphorylation of the mTOR complex 1 signaling axis. PMID- 29151272 TI - Changes in alcohol policies and practices in bars and restaurants after completion of manager-focused responsible service training. AB - INTRODUCTION AND AIMS: Irresponsible and illegal serving practices at bars and restaurants, such as sales to obviously intoxicated patrons, can lead to various public health harms. Training managers of bars and restaurants in the development and promotion of responsible alcohol policies may help prevent risky and illegal alcohol serving practices. DESIGN AND METHODS: We implemented a training program for managers of bars/restaurants designed to establish and promote responsible beverage service policies/practices. The program included online and in-person components. Bars/restaurants were randomised to intervention (n = 171) and control (n = 163) groups. To assess changes in policies/practices, we surveyed managers prior to and at 1 and 6 months post-training. Logistic regression models assessed changes in policies/practices across time points. RESULTS: The proportion in the intervention group that had written alcohol policies increased from 62% to 95% by 6 months post-training while the control group increased from 65% to 79% (P < 0.05). Similarly, by 6 months post-training 70% of managers in the intervention group reported they had communicated to their staff how to cut off intoxicated patrons, a significant increase from baseline (37%) and from the change observed in the control group (43%-56%). Prevalence of other policies/practices also increased post-training but differences between intervention and control groups were not statistically significant. DISCUSSION AND CONCLUSIONS: Our training program appears to have led to implementation of some policies/practices. Additional studies are needed to determine how training can be combined with other strategies to further improve establishment policies and ultimately reduce alcohol-related harms. PMID- 29151274 TI - Effect of HMG CoA reductase inhibitors on the development of chronic lung allograft dysfunction. AB - Lung transplant recipients (LRs) have a reduced median 5-year survival of approximately 55% primarily due to chronic lung allograft dysfunction (CLAD). Statins have anti-inflammatory and immunomodulatory effects that may facilitate CLAD prevention. This study sought to evaluate statin effect on CLAD development. Adult bilateral LRs from January 2004 to October 2013 were included. Statin group included recipients with early statin use and continued for minimum 6 months. Propensity score matching was performed for age, gender, and native lung disease to select matched nonstatin group. Competing risk approach was used to evaluate statin effect on CLAD development at 3 years while controlling for acute rejection and CMV pneumonitis. A total of 130 patients were included in each group. CLAD cumulative incidence at 3 years for statin and nonstatin groups was 20.6% (CI: 11.8%-33.5%) and 22.4% (CI: 12.2%-27.3%). Statin use was not associated with a decreased risk of CLAD (subdistribution hazard ratio [SHR]: 0.93, 95% CI: 0.55-1.59, P = .80) but was associated with a decreased risk of death (SHR: 0.45, CI: 0.22-0.90, P = .024). At 3 years, patient survival was 81.7% in statin group and 68.3% in nonstatin group (P = .012). Statins did not significantly delay the time to development of CLAD in LR but did demonstrate a benefit in patient survival. PMID- 29151273 TI - After Treatment with Methylene Blue is Effective against Delayed Encephalopathy after Acute Carbon Monoxide Poisoning. AB - Delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP) is the most severe and clinically intractable complication that occurs following acute CO poisoning. Unfortunately, the mechanism of DEACMP is still vague. Growing evidence indicates that delayed cerebral damage after CO poisoning is related to oxidative stress, abnormal neuro-inflammation, apoptosis and immune-mediated injury. Our recent report indicated that methylene blue (MB) may be a promising therapeutic agent in the prevention of neuronal cell death and cognitive deficits after transient global cerebral ischaemia (GCI). In this study, we aimed to investigate the potential of MB therapy to ameliorate the signs and symptoms of DEACMP. Rats were exposed to 1000 ppm CO for 40 min. in the first step; CO was then increased to 3000 ppm, which was maintained for another 20 min. The rats were implanted with 7-day release Alzet osmotic mini-pumps subcutaneously under the back skin, which provided MB at a dose of 0.5 mg/kg/day 1 hr after CO exposure. The results showed that MB significantly suppressed oxidative damage and expression of pro-inflammatory factors, including tumour necrosis factor alpha and interleukin (IL)-1beta. MB treatment also suitably modulated mitochondrial fission and fusion, which is helpful in the preservation of mitochondrial function. Furthermore, MB dramatically attenuated apoptosis and neuronal death. Lastly, behavioural studies revealed that MB treatment preserved spatial learning and memory in the Barnes maze test. Our findings indicated that MB may have protective effects against DEACMP. PMID- 29151275 TI - RAV transcription factors are essential for disease resistance against cassava bacterial blight via activation of melatonin biosynthesis genes. AB - With 1 AP2 domain and 1 B3 domain, 7 MeRAVs in apetala2/ethylene response factor (AP2/ERF) gene family have been identified in cassava. However, the in vivo roles of these remain unknown. Gene expression assays showed that the transcripts of MeRAVs were commonly regulated after Xanthomonas axonopodis pv manihotis (Xam) and MeRAVs were specifically located in plant cell nuclei. Through virus-induced gene silencing (VIGS) in cassava, we found that MeRAV1 and MeRAV2 are essential for plant disease resistance against cassava bacterial blight, as shown by the bacterial propagation of Xam in plant leaves. Through VIGS in cassava leaves and overexpression in cassava leave protoplasts, we found that MeRAV1 and MeRAV2 positively regulated melatonin biosynthesis genes and the endogenous melatonin level. Further investigation showed that MeRAV1 and MeRAV2 are direct transcriptional activators of 3 melatonin biosynthesis genes in cassava, as evidenced by chromatin immunoprecipitation-PCR in cassava leaf protoplasts and electrophoretic mobility shift assay. Moreover, cassava melatonin biosynthesis genes also positively regulated plant disease resistance. Taken together, this study identified MeRAV1 and MeRAV2 as common and upstream transcription factors of melatonin synthesis genes in cassava and revealed a model of MeRAV1 and MeRAV2 melatonin biosynthesis genes-melatonin level in plant disease resistance against cassava bacterial blight. PMID- 29151276 TI - Microbial growth in building material samples and occupants' health in severely moisture-damaged homes. AB - There is no commonly approved approach to detect and quantify the health-relevant microbial exposure in moisture-damaged buildings. In 39 single-family homes with severe moisture damage, we studied whether concentrations of viable microbes in building material samples are associated with health among 71 adults and 68 children, and assessed with symptoms questionnaires, exhaled NO, and peak expiratory flow (PEF) variability. Symptoms were grouped into three scores: upper respiratory symptoms, lower respiratory symptoms, and general symptoms. The homes were divided into three groups based on viable counts of fungi, actinomycetes, and total bacteria cultivated from building material samples. Highest group of actinomycete counts was associated with more general symptoms, worse perceived health, and higher daily PEF variability (aOR 12.51; 1.10-141.90 as compared to the lowest group) among adults, and with an increase in lower respiratory symptoms in children, but the confidence intervals were wide. We observed significant associations of fungal counts and total microbial score with worse perceived health in adults. No associations with exhaled NO were observed. PMID- 29151278 TI - Tetrahydrobiopterin (BH4 ): Targeting endothelial nitric oxide synthase as a potential therapy for pulmonary hypertension. AB - PURPOSE: Pulmonary Hypertension (PH) is complex disease which is associated with endothelial and cardiac dysfunction. Tetrahydrobiopterin (BH4 ) regulates endothelial nitric oxide synthase (eNOS) to produce nitric oxide rather than superoxide which maintains normal endothelial and cardiac function. This study explores the therapeutic potential of BH4 in experimental PH. METHODS: Monocrotaline-induced PH in rats and Hph-1 deficiency in mice were used for animal experiments. Hemodynamic measurements using pressure transducers were conducted for pulmonary and cardiac pressures, and Langendorff apparatus was used for isolated heart experiments; preventive as well as rescue treatment protocols were conducted; tissues were collected for histological and biochemical studies. RESULTS: In vivo acute BH4 administration reduced pulmonary artery pressure (PAP) only in the MCT rat. In a Langendorff preparation, BH4 increased right ventricular systolic pressure (RVSP) in right ventricular hypertrophy (RVH) but not in control. In "prevention" therapy, BH4 (10 and 100 mg/kg) attenuated the development of PH in rat MCT model. eNOS protein levels in lung homogenates were maintained and cGMP levels were increased. In "rescue" therapy, BH4 (10 and 100 mg/kg) ameliorated pulmonary vascular muscularization in a dose-dependent manner. RVSP was reduced in RVH and pulmonary vascular muscularization was attenuated. BH4 at 10 mg/kg reduced RV myocyte diameter while BH4 at 100 mg/kg reversed it to control level. BH4 restored normal levels of eNOS protein and in a dose of 100 mg/kg enhanced lung tissue levels of BH4 , cGMP, and NO compared to placebo. CONCLUSION: The current study provides scientific evidence for a therapeutic potential of BH4 in PH and invites further investigation. PMID- 29151277 TI - Mammalian mitophagy - from in vitro molecules to in vivo models. AB - The autophagic turnover of mitochondria, termed mitophagy, is thought to play an essential role in not only maintaining the health of the mitochondrial network but also that of the cell and organism as a whole. We have come a long way in identifying the molecular components required for mitophagy through extensive in vitro work and cell line characterisation, yet the physiological significance and context of these pathways remain largely unexplored. This is highlighted by the recent development of new mouse models that have revealed a striking level of variation in mitophagy, even under normal conditions. Here, we focus on programmed mitophagy and summarise our current understanding of why, how and where this takes place in mammals. PMID- 29151279 TI - Detection of circulating tumor cells in cervical cancer using a conditionally replicative adenovirus targeting telomerase-positive cells. AB - Circulating tumor cells (CTC) are newly discovered biomarkers of cancers. Although many systems detect CTC, a gold standard has not yet been established. We analyzed CTC in uterine cervical cancer patients using an advanced version of conditionally replicative adenovirus targeting telomerase-positive cells, which was enabled to infect coxsackievirus-adenovirus receptor-negative cells and to reduce false-positive signals in myeloid cells. Blood samples from cervical cancer patients were hemolyzed and infected with the virus and then labeled with fluorescent anti-CD45 and anti-pan cytokeratin antibodies. GFP (+)/CD45 (-) cells were isolated and subjected to whole-genome amplification followed by polymerase chain reaction analysis of human papillomavirus (HPV) DNA. CTC were detected in 6 of 23 patients with cervical cancers (26.0%). Expression of CTC did not correlate with the stage of cancer or other clinicopathological factors. In 5 of the 6 CTC positive cases, the same subtype of HPV DNA as that of the corresponding primary lesion was detected, indicating that the CTC originated from HPV-infected cancer cells. These CTC were all negative for cytokeratins. The CTC detected by our system were genetically confirmed. CTC derived from uterine cervical cancers had lost epithelial characteristics, indicating that epithelial marker-dependent systems do not have the capacity to detect these cells in cervical cancer patients. PMID- 29151280 TI - Oral nutritional supplementation in patients undergoing peritoneal dialysis: a randomised, crossover pilot study. AB - BACKGROUND: Malnutrition is a significant problem in those undergoing peritoneal dialysis (PD). Factors such as gastrointestinal (GI) symptoms and the need for a fluid reduced diet can limit tolerance and thereby the efficacy of oral nutritional supplements to treat malnutrition. OBJECTIVES: To evaluate the acceptability and impact of two different forms of oral nutrition supplementation for 16 weeks on nutritional markers and quality of life of malnourished patients undergoing PD. DESIGN: A randomised, within-subject cross-over study. Patients assessed as malnourished or with serum albumin <35 g/l were recruited. Participants were randomised to receive either 200 ml of a 1.25 kcal/ml nutrition supplement or a high protein nutrition supplement bar, for eight weeks. Each group then crossed over to receive the alternative supplement for eight weeks. Total intervention time was 16 weeks. Serum albumin, serum transthyretin and food intake were evaluated at baseline, at 8 and 16 weeks. Subjective Global Assessment, the presence of GI symptoms and quality of life were evaluated at baseline and 16 weeks. RESULTS: Sixteen weeks of nutritional support was associated with statistically significant improvements in weight and a reduction in the proportion of patients who were malnourished. There was no difference in the impact of bars compared with liquid oral nutrition supplementation. Patients preferred the fluid supplement to the bars. CONCLUSION: Sixteen weeks of nutritional support improved nutritional status in malnourished patients on PD. PMID- 29151282 TI - Epidemiology and impact of bloodstream infections among kidney transplant recipients: A retrospective single-center experience. AB - BACKGROUND: Bloodstream infection (BSI) represents an important source of morbidity and mortality, as well as an increasing therapeutic challenge, among solid organ transplant recipients. Understanding the epidemiological and microbiological characteristics of BSI following renal transplantation is paramount to the implementation of appropriate preventative and therapeutic measures. METHODS: We conducted a retrospective review of all BSI episodes occurring between July 2009 and April 2016 in adult patients, who received a renal transplant at Royal Free London hospital. RESULTS: A total of 116 episodes of BSI occurred in 87 patients, 43 (49.4%) of them men. The mean age at BSI was 54.37 +/- 12.81 years. Late-onset BSI (>12 months post transplant) represented 55.2%, with the median time to BSI being 16.28 month. Sixty-seven patients had single BSI and 20 had recurrent episodes. Enterobacteriaceae were responsible for 73.7% of BSI, with Escherichia coli the commonest causative organism (46.6%). The urinary tract was the most frequent source of infection in 56.9%. Among the E. coli infections, 100% of the tested isolates were sensitive to meropenem, ertapenem, tigecycline, and fosfomycin, and >90% were sensitive to piperacillin tazobactam, amikacin, and colistin. Lower susceptibility rates were encountered for ceftriaxone (70.6%), amoxicillin-clavulanic acid (48.1%), cotrimoxazole (40.4%), trimethoprim (37.3%), and amoxicillin (21.6%). During BSI, the median serum creatinine increased from a reference of 131 MUmol/L to a peak of 219 MUmol/L. Acute kidney injury (AKI) complicated 75/116 BSI episodes (64.7%)-stage 1: 34, stage 2: 31, and stage 3 AKI: 10 episodes. After 3 months, the median creatinine remained elevated at 146 MUmol/L. The 3-month mortality rate was 8% (7/87), and the death-censored graft loss was 6.9% (6/87). No significant difference was seen between BSI of urinary and non-urinary sources in the incidence of AKI (chi2 = 0.24, P = .6) or the percentage of creatinine change between baseline and peak and 3-month creatinines (P = .2 and .7 respectively). CONCLUSIONS: Urinary tract infection remains the commonest source of systemic infection among kidney transplant recipients and resistance to commonly used frontline antibiotics is common; thus, prevention and early detection are paramount. The appropriate choice of initial empirical antibiotic is vital to improve the outcome. Each unit needs to understand the epidemiology of organisms causing BSI in their transplant patients and their antibiotic susceptibilities. PMID- 29151283 TI - Clinical significance of rituximab infusion-related reaction in diffuse large B cell lymphoma patients receiving R-CHOP. AB - Background/Aims: This study was to evaluate the clinical significance of infusion related reaction (IRR) of rituximab in diffuse large B-cell lymphoma (DLBCL) patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) as a first-line chemotherapy. Methods: The medical records of 326 patients diagnosed with DLBCL were re trospectively analyzed. Both doctor's progress records and nursing records were reviewed. IRR was graded according to the National Cancer Institute Common Terminology Criteria. Results: IRR was not associated with overall survival (OS) or progression-free survival (PFS) of DLBCL patients as compared to those who did not have IRR (OS: median 78.0 months vs. 69.0 months, p = 0.700; PFS: median 65.4 months vs. 64.0 months, p = 0.901). IRR grade did not affect OS or PFS. B symptoms was independently associated with IRR (hazard ratio [HR], 1.850; 95% confidence interval [CI], 1.041 to 3.290; p = 0.036). Further, bone marrow involvement was independently associated with re-IRR (HR, 4.904; 95% CI, 0.767 to 3.118; p = 0.029). Conclusions: Our study shows that IRR of rituximab is not associated with OS or PFS of DLBCL patients who received R-CHOP. Furthermore, our study suggests a need for more careful observation for IRR in patients with B symptoms or bone marrow involvement. PMID- 29151284 TI - Association between initial vascular access and survival in hemodialysis according to age. AB - Background/Aims: This study aims to demonstrate whether the association between initial vascular access and mortality among hemodialysis patients varies by age. Methods: We conducted a retrospective study that included 2,552 patients who started hemodialysis. Vascular access was divided into three categories: percutaneous catheter, tunneled cuffed catheter, and arteriovenous (AV) access. Results: Survival rates for patients who received a central venous catheter, such as percutaneous or tunneled cuffed catheter, aged 65 to 74 years and those >= 75 years were reduced, but not for those aged < 65 years (log-rank test; p < 0.001, p = 0.007, and p = 0.278). After fully adjusting for potential confounding factors in the patients aged < 65 years, percutaneous and tunneled cuffed catheter were not associated with 5-year mortality. On the other hand, for patients aged 65 to 74 or >= 75 years, percutaneous catheter and tunneled cuffed catheter were associated with higher 5-year mortality rates. As age increased, the conversion rate from central venous catheter, including percutaneous catheter and tunneled cuffed catheter, to AV access decreased (94.1%, 90.5%, and 80.3% for patients aged < 65, 65 to 74, and >= 75 years, respectively; p < 0.001). Conclusions: In patients aged >= 65 years, initial vascular access was associated with long-term mortality. We suggest that a "fistula first" strategy is superior for elderly patients and demonstrates that it is desirable to change to AV access, and not maintain an initial central vascular catheter. PMID- 29151285 TI - [AFP-producing gastric cancer and hepatoid gastric cancer]. AB - AFP-producing gastric cancer(AFPGC) and hepatoid adenocarcinoma of the stomach (HAS) are two special subtypes of gastric cancer. There are both correlation and difference between them. AFPGC is usually identified as primary gastric cancer with serum AFP level more than 20 ng/ml or showed AFP positive staining by immunohistochemistry. The diagnosis of HAS is mainly dependent on the pathological character of hepatocellular carcinoma-like differentiation of gastric cancer. The morbidity of AFPGC and HAS are rather low, especially the incidence of HAS is about 1%. The prognoses of these two subtypes are poorer than that of common gastric adenocarcinoma, due to a high incidence rate of liver metastasis and lymph node metastasis. With the development of next-generation sequencing and other genomic technologies, gastric cancers, including these two rare subtypes, are now being investigated in more detail at the molecular level. Treatment remains the biggest challenge, early diagnosis and radical resection can dramatically improve patients'prognosis. Monitoring serum AFP and abdominal imaging examination during follow-up is important for early detection of liver metastasis. In combination with local treatment methods such as transarterial chemoembolization and radiofrequency ablation of liver may further extend patients'survival time. Targeted therapy owes a great potential value in the future. PMID- 29151286 TI - [Experimental study of glioma stem cell-mediated immune tolerance in tumor microenvironment]. AB - Objective: To investigate the tumor microenvironment of immune tolerance induced by glioma stem cells (GSC). Methods: Human GSC SU3 cells transfected with red fluorescent protein (SU3-RFP) gene were implanted into the brain, subcutis (armpit and foot), liver and abdominal cavity of transgenic green fluorescence protein (GFP) nude mice to establish RFP(+) /GFP(+) dual fluorescence solid tumor model. The re-cultured cells derived from implanted tumor tissues, SU3-RFP cells co-cultured with peritoneal fluid of transgenic GFP nude mice and malignant ascites of tumor-bearing mice were observed by fluorescence microscopy and real time video image tracing to analyze the microenvironment of immune tolerance mediated by RFP(+) /GFP(+) implanted tumor. Results: Dual fluorescence labeled frozen section showed that all of cells in the tumor microenvironment were GFP(+) , while the pressed tissue-patch showed that the tumor blood vessels exhibited a RFP(+) /GFP(+) double-positioning yellow. In the GFP single fluorescence labeled tumor tissue, all of cells in the microenvironment were green, including tumor edge, necrotic foci and blood vessel. Among them, CD68(+) , F4/80(+) , CD11c(+) , CD11b(+) and CD80(+) cells were observed. In the dual fluorescence labeled co cultured cells, the phagocytosis and fusion between green host cells and red tumor cells were also observed, and these fusion cells might transfer to the malignant dendritic cells and macrophages. Conclusions: The tumor microenvironment of immune tolerance induced by GSC is not affected by the tissue types of tumor-inoculated sites, and the immune tolerance mediated by inflammatory cells is associated with the inducible malignant transformation, which may be driven by cell fusion. PMID- 29151281 TI - Skeletal muscle performance and ageing. AB - The world population is ageing rapidly. As society ages, the incidence of physical limitations is dramatically increasing, which reduces the quality of life and increases healthcare expenditures. In western society, ~30% of the population over 55 years is confronted with moderate or severe physical limitations. These physical limitations increase the risk of falls, institutionalization, co-morbidity, and premature death. An important cause of physical limitations is the age-related loss of skeletal muscle mass, also referred to as sarcopenia. Emerging evidence, however, clearly shows that the decline in skeletal muscle mass is not the sole contributor to the decline in physical performance. For instance, the loss of muscle strength is also a strong contributor to reduced physical performance in the elderly. In addition, there is ample data to suggest that motor coordination, excitation-contraction coupling, skeletal integrity, and other factors related to the nervous, muscular, and skeletal systems are critically important for physical performance in the elderly. To better understand the loss of skeletal muscle performance with ageing, we aim to provide a broad overview on the underlying mechanisms associated with elderly skeletal muscle performance. We start with a system level discussion and continue with a discussion on the influence of lifestyle, biological, and psychosocial factors on elderly skeletal muscle performance. Developing a broad understanding of the many factors affecting elderly skeletal muscle performance has major implications for scientists, clinicians, and health professionals who are developing therapeutic interventions aiming to enhance muscle function and/or prevent mobility and physical limitations and, as such, support healthy ageing. PMID- 29151287 TI - [DeSUMOylation of protein kinase B1 inhibits cell proliferation and metastasis of hepatocellular carcinoma]. AB - Objective: To investigate the effect of AKT1 deSUMOylation induced by Ubc9 silencing on the proliferation and metastasis of hepatocellular carcinoma (HCC) cells. Methods: The Ubc9 gene was silenced using RNA interference, and the expression levels of Ubc9, SUMO1 and AKT1 protein were detected by Western blot. Cell proliferation and cell cycle was analyzed by MTT and flow cytometry. Wound healing and transwell assays were used to detect the cell migration ability. Furthermore, the xenograft model was established, and tumor growth curves were drawn. The in situ apoptotic rates was measured using TUNEL Apoptosis Assay. The expression of proliferating cell nuclear antigen (PCNA), matrix metalloproteinase (MMP)-2 and MMP-9 were evaluated by immunohistochemical staining. Results: Knockdown of Ubc9 gene significantly decreased the protein expression levels of Ubc9, conjugated SUMO1, free SUMO1 and AKT1 in HCC cells (P<0.05 for all). In control, siR-neg and siR-Ubc9 groups, the cell proliferation indexes were 53.19%, 54.25% and 39.17%, respectively. Moreover, cell migration distance and migrating cells per low power field for all these three groups were (59.47+/-4.66) MUm and 89.44+/-8.36, (56.56+/-5.37) MUm and 93.84+/-8.79, as well as (34.57+/-6.61) MUm and 41.67+/-5.39, respectively. In the xenograft model, the weights of subcutaneous tumors for these three groups were (3.78+/-0.69) g, (3.72+/-0.72) g and (2.09+/-0.61) g, respectively. The corresponding apoptotic cell rates were (7.79+/-2.21)%, (6.45+/-2.48)% and (33.59+/-5.44)%, respectively. The expression levels of PCNA, MMP-2 and MMP-9 protein were significantly decreased in siR-Ubc9 group (P<0.05). Conclusions: Ubc9 silencing in HCC cells induces AKT1 deSUMOylation, and then inhibits the proliferation and metastasis. These results provide a new therapeutic strategy for liver cancer in the future. PMID- 29151288 TI - [The value of (18)F-FDG PET-CT imaging in predicting the malignant potential of GIST]. AB - Objective: To evaluate the value of (18)F-FDG PET-CT in predicting the malignant potential of Gastrointestinal Stromal Tumors (GIST). Methods: The clinical and pathological features of 31 patients with GIST confirmed by surgery or biopsy were retrospectively analyzed. The malignant potential of GIST before treatment was assessed by (18)F-FDG PET-CT. The GIST risk classification was graded according to the Standard revised by the National Institutes of Health (NIH) in 2008. The relationship between the maximal standard uptake value (SUVmax) and GIST risk classification, tumor diameter, Ki-67 index, and mitotic count were analyzed respectively. The cut-off level of SUVmax for the diagnosis of malignant GIST was calculated from the Receiver Operating Characteristic (ROC) curve. Results: Among the 31 cases of GIST patients, 14 cases were gastric primary (stomach group) and 17 cases were nongastric primary (outside stomach group). The SUVmax, tumor diameter, Ki-67 index and mitotic count of the 31 patients were 8.21+/-4.68, (7.82+/-5.12)cm, (10.03+/-11.07)% and (12.29+/-10.55)/50 HPF, respectively. SUVmax was significantly correlated with GIST risk classification (r=0.727, P<0.01), but not with tumor diameter, Ki-67 index and mitotic count (r=0.348, r=0.284, r=0.290, P=0.055, P=0.121, P=0.114). The SUVmax, tumor diameter, Ki-67 index and mitotic count in the stomach group were 4.36+/-2.36, (6.08+/-4.31)cm, (3.43+/-3.03)% and (5.71+/-2.20)/50 HPF, respectively. SUVmax was significantly correlated with tumor diameter, GIST risk classification and Ki 67 index (r=0.682, r=0.868, r=0.732, P<0.01) but not with mitotic count (r=0.510, P=0.063). The SUVmax of the GIST in the gastric group and the outside gastric group were 4.36+/-2.36 and 10.68+/-5.50, respectively. The difference was statistically significant (P=0.001). The SUVmax in the malignant group of GIST (middle or high risk grade) was 8.90+/-4.89, which was significantly higher than 2.22+/-0.86 in the benign group (low or very low risk grade). The difference was statistically significant between the two group (P<0.01). ROC curve analysis showed that a SUVmax cut-off of 3.75 was the most sensitive for predicting malignant GIST. When the area under the curve of 0.969, the sensitivity was 84.6% and the specificity was 100%. Conclusions: The SUVmax was strongly correlated with the GIST risk category and also with the tumor diameter and Ki-67 index in the gastric primary GIST, so it can be used as an effective indicator in predicting malignant potential of GIST before treatment. PMID- 29151289 TI - [Prognostic value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET-CT) in extensive-stage small cell lung cancer]. AB - Objective: To investigated the prognostic value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in extensive-stage small cell lung cancer (ES -SCLC). Methods: Fifty-five patients with ES-SCLC who underwent pretreatment (18)F-FDG PET-CT were retrospectively recruited in this study. The correlations of maximum standardized uptake value (SUVmax) of primary lesion, metabolic tumor volume (MTV) of primary lesion (MTVp), total lesion glycolysis (TLG) of primary lesion (TLGp), the highest SUVmax of all lesions, the sum of metabolic volume (MTV sum), the sum of total lesions glycolysis (TLGsum) and clinical factors were analyzed. Results: The SUVmax, MTVp, TLGp, the highest SUVmax, MTVsum and TLGsum of 55 patients were 11.34+/-7.02, 29.61 cm(3,) 207.72, 13.61+/-7.10, 123.57 cm(3) and 988.48, respectively. The SUVmax of primary lesion, MTVp and TLGp were correlated with tumor type and the maximal tumor length, respectively(all P<0.05). The correlations were also found between MTVp, TLGp and hydrothorax, respectively(both P<0.05). MTVsum and TLGsum were correlated with number of lesions, hydrothorax, LDH, hemoglobin and ECOG, respectively(all P<0.05). The association was also found between TLGsum and the maximal tumor length (P=0.039). 51 patients were progressive or recurrent with the median 6.9 months of progression free survival (PFS); and 50 patients were died with the median 11.7 months of overall survival (OS). Univariate analysis showed that MTVsum, TLGsum, number of lesions, ECOG, live metastasis, bone metastasis, the cycle of chemotherapy and thoracic radiation therapy were all associated with PFS and OS (all P<0.05); LDH and hemoglobin were only associated with PFS(both P<0.05). Multivariate analysis demonstrated that LDH, ECOG, live metastasis, the cycle of chemotherapy, MTVsum, TLGsum were the independent predictors of PFS (all P<0.05); and ECOG and TLG sum were the independent predictors of OS (all P<0.05). Conclusions: (18)F-FDG PET-CT has certain prognostic value of patients with ES-SCLC. MTVsum and TLGsum are the independent predictors of PFS, and TLGsum is also an independent predictor of OS. PMID- 29151290 TI - [Early detection of the cardiotoxicity induced by chemotherapy drug through two dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T]. AB - Objective: To investigate the clinical value of two-dimensional speckle tracking echocardiography(2D-STE) combined with high-sensitive cardiac troponin T (hs cTnT) in early detection of the cardiotoxicity induced by chemotherapy drug. Methods: Seventy-five non-Hodgkin's lymphoma patients who received the CHOP regimen were recruited in this study. Conventional echocardiography and 2D-STE were performed on these patients before chemotherapy, the second day after the third course of chemotherapy (during chemotherapy) and the second day after the last course of chemotherapy (after chemotherapy). The parameters included left ventricular ejection fraction (LVEF), global longitudinal strain (LS), global circumferential strain (CS) and global radial strain (RS). The serum hs-cTNT levels were tested simultaneously. Results: Three cycles of CHOP were completed in 30 patients and 6-8 cycles of CHOP were completed in 45 patients. The LVEF of 75 patients before, during and after chemotherapy was (63.8+/-2.6)%, (63.8+/ 2.8)% and (64.0+/-3.3)%, respectively, without significant difference (P=0.91). However, the LS of 75 patients before, during and after chemotherapy was (-18.5+/ 1.7)%, (-16.5+/-1.9)% and (-16.0+/-1.6)%, respectively. The CS was (-20.9+/ 2.9)%, (-19.3+/-3.5)% and (-19.2+/-3.2)%, respectively. The RS was (39.2+/-6.4)%, (35.3+/-5.2)% and (35.0+/-6.2)%, respectively. The hs-cTnT was (0.001 0+/-0.002 0)ng/ml, (0.006 3+/-0.008 9)ng/ml and (0.007 3+/-0.003 8)ng/ml, respectively. The LS, CS and RS were significantly decreased while hs-cTnT was significantly increased during chemotherapy when compared to those before chemotherapy (all of P<0.01). Alternatively, the LS, CS, RS and hs-cTnT after chemotherapy were marginally different from those during chemotherapy (all of P>0.05). Moreover, T(LS-SD), T(CS-SD) and T(RS-SD) showed no significant difference before, during and after chemotherapy (all of P>0.05). The reduction of LS was positively associated with the enhancement of hs-cTnT after chemotherapy (r=0.60, P<0.01). Conclusion: 2D-STE combined with hs-cTnT can effectively and precisely detect the occult cardiotoxicity induced by anthracycline. PMID- 29151291 TI - [Risk-adapted postmastectomy radiotherapy based on local-regional recurrence for T1-2N1M0 breast Cancer]. AB - Objective: To establish a risk-adapted postmastectomy radiotherapy strategy based on local-regional recurrence for intermediate-risk breast cancer (T1~2N1M0 stage). Methods: A total of 2413 patients with T1-2N1M0 breast cancer were retrospectively reviewed. Of them, 588 patients (24.4%) received postmastectomy radiotherapy (PMRT), while 1 825 (75.6%) patients did not. A comprehensive comparative study was performed by using multivariable and propensity score matched (PSM) analyses. Results: The median follow-up time was 67.0 months, the 5 year local region recurrence free-survival (LRRFS), disease-free survival (DFS) and overall survival (OS) were 93.8%, 85.7% and 93.3%, respectively. The 5-year local region recurrence (LRR) was 6.1%. For patients without PMRT, multivariable analysis indicated that age, tumor localization, molecular subtype, pathologic T stage and number of positive lymph node were independent factors for LRRFS (all of P<0.05). Patients with T1-2N1 breast cancer were classified into low-risk group (0-1 risk factor, 768 patients), intermediate-risk group (2 risk factors, 690 patients) and high-risk groups (>=3 risk factors, 544 patients) based on the five independent factors mentioned above. The 5-year LRRFS, DFS and OS were significantly different among the three groups (P<0.001). In low- and intermediate-risk groups, there were no significant differences in LRRFS, DFS and OS of patients who received PMRT or not (P>0.05). In high-risk group, the DFS of patients received PMRT or not were 79.8% and 74.4%, respectively (P=0.127), the OS of them were 86.8% and 87.1%, respectively (P=0.174), and the LRRFS were 93.3% and 84.3%, respectively (P=0.002). After PSM adjustment, no significant differences in LRRFS, DFS and OS were observed between PMRT-received subgroup and no PMRT subgroup of low-risk group (P>0.05). In intermediate-risk group, the LRRFS of patients received PMRT or not were 95.2% and 91.0%, respectively (P=0.037). However, in the high-risk group, the LRRFS, DFS and OS of patients received PMRT were 93.3%, 79.7% and 86.6%, respectively, while those of patients did not receive PMRT were 78.5% (P<0.001), 69.5% (P=0.038) and 85.7% (P=0.080), respectively. Conclusions: The local-regional recurrence risks of patients with pT1-2N1 breast cancer are viable and risk-adapted PMRT is available for them. Better prognoses can be achieved by the patients of intermediate and high-risk group. More samples on this subject are needed to validate the results. PMID- 29151292 TI - [The treatment and prognosis of peripheral primitive neuroectodermal tumor]. AB - Objective: To evaluate the treatment and prognosis of peripheral primitive neuroectodermal tumor (pPNET). Methods: From March 2006 to April 2015, 47 patients with pPNET who had undergone chemotherapy in our hospital were enrolled. The clinical data and survival information of these patients were collected and interpreted retrospectively to analyze the effect of each treatment on the survival of patients. Results: The median overall survival (OS) for whole group was 23.5 months, and 5-year survival rate was 33.8%. In the patients who underwent radical surgery, the median OS was 70.4 months, the 5-year survival rate was 54.4%, the median disease-free survival (DFS) was 23.1months, and 5-year DFS rate was 34.4%. Sixteen patients had recurrences or metastasis after surgery. Eighty-one percent of them (13/16) occurred within 2 years after surgery. The difference of median OS between patients who got adjuvant chemotherapy and those who did not was statistically significant (P=0.04). But the difference of median PFS between these two groups was not statistically significant (P=0.057). There was no statistically significant difference for median OS (P=0.619) and median DFS (P=0.191) between patients who got adjuvant radiotherapy and those who did not. The recurrence rate between these two groups was not statistically significant (P=0.40). The median OS and PFS for 34 patients who received first line palliative chemotherapy was 10.7 months and 3.2 months. 1-year and 2-year survival rates were 48.0% and 17.8%. The response rate and clinical benefit rate for first-line chemotherapy was 53.1% and 75.0%. The median PFS and OS for patients who received platinum-based regimens were 3.3 months and 14.5 months. The median PFS and OS for patients who got non-platinum regimens were 2.7 months and 10.3 months. There was no significant difference of PFS and OS between platinum-based and non-platinum regimens. Palliative surgery and radiotherapy did not improve the OS of pPNET this cohort. Conclusions: Comprehensive treatment including chemotherapy, radiotherapy and surgery is the standard treatment model for early pPNET patients. Adjuvant chemotherapy significantly improved the overall survival of early pPNET patients. Chemotherapy is the main treatment for patients with advanced pPNET. Platinum-based chemotherapy seem to be a good option. PMID- 29151293 TI - [Clinical analysis of 36 cases of advanced non-small cell lung cancer (NSCLC) with performance status (PS) scores between 2 and 4]. AB - Objective: To analyze the treatment of advanced non-small cell lung cancer (NSCLC) with performance status (PS) scores between 2 and 4, in order to improve the diagnosis and treatment of these patients. Methods: A total of 36 patients with advanced NSCLC with hypoxemia were reviewed. The clinical data of disease characteristics, etiology, complications, manifestation, therapy, progression, and secondary biopsy were collected. The clinical efficacy was graded according to the Response Evaluation Criteria In Solid Tumors (RECIST): complete response (CR), partial response (PR), stable disease (SD) and disease progression (PD). Results: All patients had hypoxemia, of whom 86.1% (31 patients) had complications and 55.6% (20 patients) had noninvasive ventilator for respiratory support. 77.8% (28 cases) received broad-spectrum antibiotic treatment, and 78.6% of them got lung osmotic relief after the anti-infection treatment. 15 cases received bedside fiberoptic bronchoscopy suction, of whom two cases were treated with airway stent deposition due to airway obstruction, four cases with thoracic drainage, four cases with anticoagulation, and one with thrombolytic therapy. After these supportive treatment, the PS score of these patients decreased from 3.4+/-0.5 to 2.5+/-0.7, while SPO(2) improved from (89.0+/-5.2)% to (95.0+/ 3.5)%. As first-ling anti-cancer treatment, nine patients were administrated with targeted medicine orally, 13 patients with a combined chemotherapy of pemetrexed plus bevacizumab or carboplatin, eight patients with paclitaxel plus carboplatin, four patients with gemcitabine plus carboplatin, and two patients with docetaxel plus gemcitabine. In the first response evaluation, there were one case of CR, 23 cases of PR, four cases of SD, and eight cases of PD, with a clinical benefit rate of 66.7% and a disease control rate of 77.8%. A total of 22 patients experienced disease progression, of whom eight cases had a secondary biopsy and six cases had gene sequencing. Of these 36 patients, 10 (27.8%) patients survived at the last follow-up, with a progression-free survival of (10.0+/-6.5) months. Conclusion: Besides prompt anti-cancer treatment and best supportive treatment should be incorporated to improve PS and improve outcome. PMID- 29151294 TI - [Analysis of Incidence and Mortality of Thyroid Cancer in China, 2013]. AB - Objective: To evaluate the incidence and mortality status of thyroid cancer in China, 2013. Methods: Incidence and mortality data of thyroid cancer were derived from 255 population-based cancer registries in China. Age-specific and age standardized incidence and mortality rates of thyroid cancer in different areas (urban and rural) with different gender were calculated based on the stratification of area (urban and rural), gender, age and tumor position. Chinese census in 2000 and the world Segi's population were used for age-standardized incidence/mortality rates. The incident cases and deaths were estimated using age specific rates and national population data in 2013. Results: The estimates of new cancer incident cases and deaths were 143.9 thousand and 6 500, respectively. The crude incidence rate was 10.58/100 000 (Male 5.12/100 000, Female 16.32/100 000). Age-standardized incidence rates by Chinese standard population (ASIRC, 2000) and by world standard population (ASIRW) were 8.82/100 000 and 7.67/100 000, respectively. Male to female ratio was 1?3.2. The crude incidence rate in urban and rural areas were 15.03/100 000 and 5.41/100 000, respectively. After adjustment by China standard population, the rate in urban areas was 2.57 times higher than that of rural areas. The crude mortality rate of thyroid cancer was 0.48/100 000 (Male 0.33/100 000, Female 0.63/100 000). Age-standardized mortality rates by Chinese standard population (ASIRC, 2000) and by world standard population (ASIRW) were 0.33/100 000 and 0.32/100 000, respectively. The crude mortality rate in urban and rural areas were 0.57/100 000 and 0.38/100 000, respectively. After adjustment by China standard population, the rate in urban areas was 1.41 times higher than that of rural areas. The cumulative incidence and mortality rates (0-74 years old) were 0.74% and 0.03%, respectively. According to the data from 255 cancer registries, papillary carcinoma is the main pathology type, which accounted for 89.9% of all malignant tumors. Conclusions: The disease burden of thyroid cancer in urban areas is higher than that in rural areas. Females have the higher incidence rate than that of males. The reasons related to the higher incidence rate of thyroid cancer should be further investigated to provide evidence for appropriate cancer control strategies and policies to be made in China. PMID- 29151295 TI - [Guidelines for standardizedmanagement of neutropenia induced by chemotherapy and radiotherapy]. AB - Neutropenia is the most common hematologic toxicity of myelosuppressive chemotherapy and radiotherapy. The degree and duration of neutropenia are directly related to the risk of infection and even death, which can also affect the relative dose intensity of chemotherapy and the prognosis of patients. At present, clinicians tend to underestimate the harm of neutropenia, and are in lack of knowledge on granulocyte colony-stimulating factor(G-CSF), especially on prevention and treatment of neutropenia. Based on clinical evidence, the Chinese Society of Clinical Oncology (CSCO) develops guidelines on the assessment, prevention and treatment of neutropenia and the application of G-CSF. It suggests a hierarchical management concept for neutropenia and establishes a clinical path of prevention and treatment, in order to provide guidance for standardized management of neutropenia and the rational use of G-CSF. PMID- 29151296 TI - [Immunoglobulin D multiple myeloma with elevated creatine kinase and numb chin syndrome: a case report]. PMID- 29151297 TI - The clinical features and outcomes of Turkish patients with IgG4-related disease:a single-center experience AB - Background/aim: Since the majority of the IgG4-related disease (IgG4-RD) patients in the literature are from the Far East and the United States, there is a lack of large series from other parts of the world. We aimed to identify the clinical characteristics and outcome of Turkish IgG4-RD patients from a tertiary center.Materials and methods: Fifty-two patients classified as having definite IgG4-RD according to comprehensive diagnostic criteria were included in the study. Patients not fulfilling the definite criteria due to lack of pathologic specimen and/or serum IgG4 levels were excluded (n = 47). Clinical, laboratory, and histopathological features and treatment approaches were analyzed.Results: Median age at diagnosis was 51.1 years and sex predominance was not observed (male/female: 26/26). Median follow-up duration was 18 (IQR 25-75: 8-35) months. Retroperitoneal fibrosis was the most frequent presentation. Twenty-four (46.1%) patients had localized involvement. Corticosteroids were the mainstay of treatment (92.5%). Rituximab had been used for cases resistant to previous treatment or with relapses in 19 (47.5%) patients. A complete response was achieved in 52.5% and partial response (<50% regression) in 40%. Conclusion: This large and first cohort of IgG4-RD patients from Turkey showed similar clinical features to European cohorts, except for the male predominance in previous cohorts. Corticosteroids and rituximab are effective in IgG4-RD but there is still uncertainty about the usage of corticosteroid-sparing agents. PMID- 29151298 TI - Impact of body mass index, waist circumference and Pfannenstiel sitetissue thickness, and elastosonography on operative parameters AB - Background/aim: This study aimed to evaluate the impact of body fat distribution measured by body mass index (BMI), waist circumference (WC) and Pfannenstiel incision site tissue thickness, and elastosonography on bleeding and operation time during cesarean delivery.Materials and methods: A prospective study was made of 52 healthy, term pregnant women with prior cesarean deliveries. The impact of BMI, WC, incision site thickness, and elastosonography on preoperative and postoperative differences in hemoglobin (Hb) and hematocrit (Htc) levels and operation times was evaluated.Results: A moderate negative relationship was found between Htc levels and WC. Htc levels were found to decrease by 0.148 units for each 1-cm increase in WC. Skin-to-fascia time was found to increase by 0.697 s with each 1-unit increase in BMI, whereas fascia-to-uterus time was found to increase by 1.117 s with each 1-cm increase in Pfannenstiel site tissue thickness. None of the elastosonographies or differences in Hb levels were found to be significant for any parameter.Conclusion: Each of the evaluated parameters was found to have an impact on different factors: WC on Htc levels, BMI on skin to-fascia time, and Pfannenstiel tissue thickness on fascia-to-uterus time. PMID- 29151299 TI - Eleven patients with primary thyroid lymphoma: a single center experience AB - Background/aim: Primary thyroid lymphoma (PTL) is a very rare thyroid malignancy. It should be diagnosed and treated immediately and accurately. Our aim was to evaluate the diagnostic methods and treatment results for patients with PTL.Materials and methods: We retrospectively evaluated the records of 11 patients with PTL from 2009 to 2015, diagnosed at our institute. Age, sex, stage, histopathologic type, presence of Hashimoto's thyroiditis, diagnostic methods, treatment types, and recurrence were examined.Results: Six patients were female, 5 were male, and the median age of the patients was 61 years (range: 15-76 years). All patients had a large palpable mass in the neck. Fine needle aspirate (FNA) biopsy was performed in all patients; however, it was useful only in the diagnosis of 7 patients. Excisional and surgical biopsy was performed in 4 patients. All patients had non-Hodgkin B-cell lymphoma, including 9 cases of diffuse large B-cell lymphoma (DLBCL), and 2 patients had mucosa-associated lymphoid tissue (MALT) lymphoma. Recurrence was observed in one patient. Median survival was 34 months.Conclusions: The preferred option for the diagnosis of PTL should be FNA biopsy, and the treatment should be decided on according to whether the disease is limited to the thyroid gland or not, its histological type, and its stage. PMID- 29151300 TI - The effect of antidiuretic hormone on urine and serum electrolyte levelsin children with primary monosymptomatic nocturnal enuresis AB - Background/aim: The data concerning the effects of desmopressin on water/electrolyte disturbances of children with primary monosymptomatic nocturnal enuresis (PMNE) are limited. In the present study we aimed to evaluate the effect and tolerability of desmopressin on blood and urine electrolytes and osmolality in PMNE.Materials and methods: Thirty-five children with PMNE between the ages of 5 and 15 participated in the study. Patients collected urine during the daytime and acknowledged the night time fluid restriction before starting to use the desmopressin tablets. The medication was taken orally at least 1 h before bedtime. Blood and urine samples were collected before the introduction of the treatment (day 0) and on the third and seventh days of the administration of desmopressin to determine osmolality and electrolyte levels.Results: Thirty-five patients participated in the study. Twenty-one patients (60%) were male and 14 (40%) were female. The mean age was 9.6 - 2.7 years. There were no significant changes in serum osmolality, urine osmolality, and serum sodium concentration. Mean urine calcium/creatinine ratio was 0.03 - 0.01 mg/mg at the beginning, 0.06 0.02 mg/mg on the third day, and 0.04 - 0.01 mg/mg on the seventh day of the study. No significant changes were seen in urine calcium/creatinine ratio before and after treatment.Conclusion: Desmopressin appeared to be a well-tolerated drug and provided a safe and effective treatment for children who were following fluid intake restriction for PMNE. PMID- 29151301 TI - Assessment of repolarization abnormalities in baseline electrocardiograms of patients with myocarditis AB - Background/aim: Myocarditis in the acute phase usually presents with sinus tachycardia but many other arrhythmias might be seen as well. In this study we aimed to investigate repolarization abnormalities in baseline ECG of patients with myocarditis for the first time.Materials and methods: Thirty patients diagnosed with myocarditis and 25 healthy age-matched controls were included. Two different cardiologists measured corrected QT (QTc), QT dispersion (QTd), QT peak (QTp), T wave peak to T wave end (TpTe), TpTe/QT ratio, and TpTe/QTc ratio in 12 lead ECG.Results: When compared with the control group, QTp (P: 0.021), QT (P: 0.003), TpTe (P < 0.001), TpTe/QTc ratio (P < 0.001), and TpTe/QT ratio (P: 0.005) were significantly higher in patients with myocarditis. A comparison of receiver operating characteristic (ROC) curves was conducted using the Hanley and McNeil method. The area under the curve (AUC) of the electrocardiographic characteristics QT (AUC: 0.736; 95% CI [0.600-0.846]), QTP (AUC: 0.680; 95% CI [0.540-0.799]), and TpTe (AUC: 0.771; 95% CI [0.638-873]) and TpTe/QTc (AUC: 0.774; 95% CI [0.641-0.876]) and TpTe/QT (AUC: 0.726; 95% CI [0.589-0.838]) in myocarditis were not significantly different from each other but all of them were different from 0.5.Conclusion: Baseline ECGs of patients with myocarditis were associated with repolarization abnormalities. These novel findings may be one of the reasons underlying arrhythmic events in patients with myocarditis. PMID- 29151302 TI - Relationship between kinesiophobia and pain, quality of life, functional status, disease activity, mobility, and depression in patients with ankylosing spondylitis AB - Background/aim: Our aim was to investigate the association of kinesiophobia with pain, quality of life, clinical measures, and depression in patients with ankylosing spondylitis (AS). Materials and methods: Patients with AS (n: 163) were enrolled in the study. Kinesiophobia was evaluated with the Tampa Scale of Kinesiophobia (TSK), pain with a visual analog scale (VAS), mobility with Bath Ankylosing Spondylitis Metrology Index (BASMI), disease activity with the Bath AS Disease Activity Index (BASDAI), functional status with the Bath AS Functional Index (BASFI), depression level with Beck's Depression Inventory (BDI), and quality of life with the AS Quality of Life Questionnaire (ASQoL). Besides correlation analysis, outcome measures were compared between patients with (TSK ? 37) and without (TSK < 37) kinesiophobia. Results: Kinesiophobia was found to be common with a percentage of 66.6%. TSK scores were correlated with VAS, BASFI, ASQoL, and BDI scores (r = 0.259, r = 0.294, r = 0.392, and r = 0.398, respectively; P < 0.05 for each). There were no correlations between TSK and the BASDAI and BASMI scores (r = 0.142, r = 0.198, respectively; P > 0.05). Patients with kinesiophobia had more pain and poorer BASFI, ASQoL, and BDI scores than patients without kinesiophobia (P < 0.05).Conclusion: Our study is the first study that investigated the relationship between kinesiophobia and other clinical measures in AS patients. Pain and psychological status have an impact on fear of movement and thus functional status and quality of life. PMID- 29151303 TI - Obstructive sleep apnea characteristics in patients with well-controlled acromegaly and their compliance with positive airway pressure therapy AB - Background/aim: Acromegaly is often associated with obstructive sleep apnea syndrome (OSAS) with a frequency between 40% and 80%. The aim of the present study was to evaluate the clinical and polysomnographic characteristics of acromegaly patients with sleep apnea symptoms and to identify positive airway pressure (PAP) adherence in acromegaly patients with OSAS diagnosis.Materials and methods: Twenty-eight well-controlled acromegaly patients (17 males, mean age 48.7 +/- 10.1 years) with sleep apnea symptoms were included in this prospective study. Demographic data, anthropometric measurements, and medical history were evaluated. Full-night in-laboratory polysomnography was performed.Results: Polysomnography results showed that 25 patients (89.3%) had OSAS with a mean apnea-hypopnea index (AHI) of 37.7 +/- 28.8/h. All 17 male patients were diagnosed with OSAS, whereas 8 female patients (72.7%) had OSAS (P = 0.05). Male patients also had more severe OSAS than females (AHI 48.3 +/- 29.0 vs. 21.3 +/- 20.1 events/h, respectively; P = 0.012). Twenty-two patients out of 28 were considered to be eligible candidates for PAP therapy. The PAP adherence rate was found to be 50% during follow-up. Conclusion: Our results confirm OSAS as a common disorder in acromegaly patients as well as PAP therapy being required for a majority of patients. Therefore, all acromegaly patients should be assessed in terms of OSAS and be followed closely for the evaluation of PAP adherence. PMID- 29151304 TI - EGFR, KRAS, and BRAF mutational profiles of female patients with micropapillary predominant invasive lung adenocarcinoma AB - Background/aim: This study aimed to analyze EGFR, KRAS, and BRAF mutations in females with micropapillary predominant invasive lung adenocarcinoma and their relationships with immunohistochemical and clinicopathological patterns.Materials and methods: A total of 15 females with micropapillary lung adenocarcinoma were selected. Mutational analysis of the EGFR, KRAS, and BRAF genes was carried out. Information regarding the demographic data, tumor size, treatment, and survival time for each patient was collated, and the predominant cell type, secondary architectural growth patterns, psammoma bodies, necrosis, and visceral pleural and angiolymphatic invasions were evaluated.Results: We identified EGFR mutation in six cases, KRAS mutation in three cases, and BRAF mutation in one case. EGFR, c-kit, VEGFR, and bcl-2 positivity was observed in ten, seven, four, and six cases, respectively. All cases were positive for VEGF (strong positivity in 11 cases and weak positivity in four cases) and bcl-2 (strong positivity in nine cases and weak positivity in six cases). Seven (46.6%) cases were positive for c kit and 10 (66.6%) cases were positive for EGFR. Conclusion: EGFR mutation occurred at a higher incidence rate in micropapillary predominant invasive adenocarcinoma than has previously been found in conventional lung adenocarcinomas. KRAS mutation was observed as having a similar frequency to what was previously observed, but the frequency of BRAF mutation was lower than previously reported. PMID- 29151305 TI - Comparison of nutritional risk screening tools for predictingsarcopenia in hospitalized patients AB - Background/aim: The aim of this study was to assess the risk of malnutrition in hospitalized patients with three different tests and to compare these tests in terms of long hospitalization periods and sarcopenia. Materials and methods: Hospitalized patients in an internal medicine clinic were enrolled in this cross sectional study. Patients were grouped as under 65 years (Group 1 = G1) and over 65 years old (Group 2 = G2). The nutritional status of the patients was evaluated with the Nutritional Risk Screening (NRS) 2002, Universal Malnutrition Screening Tool (MUST), Mini Nutritional Assessment Short Form (MNA-SF), and total Mini Nutritional Assessment (MNA) tests. Diagnosis of sarcopenia was assessed via bioimpedance analysis for muscle mass, a hand-grip strength test, and a "timed get up and go" test. Nutritional tests were compared in terms of sarcopenia and long hospitalization periods with receiver operating characteristic curve analysis. Results: Mean ages were 54 (G1, n = 84) and 76 (G2, n = 112) years old. Sarcopenia was found in 5% in G1 and 33% in G2. The MNA-SF in G1 (area under curve (AUC) = 0.585, P = 0.26; sensitivity 41%, specificity 44%) and the MUST in G2 (AUC = 0.614, P = 0.048; 25%, 86%) were better predictors of prolonged hospitalization. The MNA-SF was associated with sarcopenia in both groups (G1: AUC = 0.716, P = 0.147; 63%, 64% and G2: AUC = 0.762, P < 0.001; 86%, 48%). In addition, the MNA-SF was a better predictor of low lean muscle mass index (AUC = 0.762, P < 0.001; 86%, 48%), low grip strength (AUC = 0.594, P = 0.27; 65%, 50%), and reduced walking speed (AUC = 0.642, P = 0.01; 71%, 47%) in G2. Conclusion: None of the three tests are highly sensitive or specific for predicting sarcopenia. The MNA-SF is a better test to evaluate sarcopenia and/or related parameters than the others, and the MUST is related to prolonged hospitalization in older patients. PMID- 29151306 TI - Evaluation of risk factors for the recurrence of colorectal polyps and colorectal cancer AB - Background/aim: Colorectal adenomatous polyps are precursors of colorectal cancer (CRC), which can be prevented with surveillance colonoscopy. This study aimed to assess risk factors for the recurrence of colorectal polyps and CRC following polypectomy. Materials and methods: In this single-center trial, a total of 510 patients who applied to the endoscopy unit of Hacettepe University Hospital for various reasons and who were diagnosed with at least one colorectal adenomatous polyp between 2000 and 2010 were retrospectively analyzed. Patients with colorectal adenomatous polyps or CRC recurrences were examined in terms of clinical and histological risk factors. Results: A total of 190 (37.1%) patients had surveillance colonoscopy. Among them, 127 (66.3%) were found to have polyp recurrence. Of the parameters defined for polyp recurrence, no association was found between the number of polyps (1-2, >=3) (1-3, >=4) in the first colonoscopy and diabetes mellitus, hypertension, hyperlipidemia, sex, family history of colon malignancy, smoking, alcohol usage, size of polyp (<10 mm, >=10 mm), or advanced histologic type of polyp. The only significant difference was observed in patients who had left-sided colon polyps. In the basal colonoscopy, 130 patients had been diagnosed with CRC, and a significant correlation was found between the number of polyps (1, >=2) and polyp size (>=10 mm), anemia, high sedimentation rate (>25), and CRC. In the first surveillance colonoscopy, CRC was detected in 12 patients. There was a significant correlation between the development of CRC and advanced histological type, anemia with high erythrocyte sedimentation rate, polyp size (<10 mm, >=10 mm), and the number of polyps (<3, >=3). Conclusion: Patients with left-sided colon polyps had a high risk of developing colorectal polyp recurrence. Moreover, the risk of developing CRC increased in patients who had advanced histology, a polyp larger than 10 mm, or more than three polyps. PMID- 29151307 TI - Quality of life and fall risk in frail hospitalized elderly patients AB - Background/aim: Frailty is a complex, multifactorial, and important geriatric syndrome characterized by decline in physiological reserves and functional deficiency in multiple systems. The aim of the current study is to investigate the prevalence of frailty and to determine the correlation between quality of life (QoL) and falling risk in geriatric hospitalized patients. Materials and methods: A total of 420 patients, aged 65 years and above, were enrolled in the study. All participants were hospitalized at a university hospital in the internal medicine clinics. The Cardiovascular Health Study (CHS) frailty scale, Health-Related Quality of Life Short Form (SF-36) scale, and Hendrich II Fall Risk Model were administered to the patients. Demographic data of patients, number of chronic diseases, and information on used medication were also collected.Results: The median age of patients was 71.9 +/- 6.3 years and 49.5% of the patients were female. By applying the CHS frailty scale, the proportion of frail patients was determined to be 65.5%. There were statistically significant differences among quality of life mean scores of robust, prefrail, and frail patients (P < 0.001). Frail patients had the lowest scores in all SF-36 subgroups. Eighty-three (19.8%) patients were in the low-risk group while 337 (80.2%) were high-risk according to the Hendrich II Fall Risk Model. The rate of patients with high falling risk and poor QoL reached a maximum in the frail group (96%).Conclusion: Frailty is an important geriatric syndrome in elderly hospitalized patients. Poor QoL and high falling risk are issues commonly experienced with frailty. PMID- 29151308 TI - Unknown vascular compression of the airway in patients with congenitalheart disease and persistent lower respiratory symptoms AB - Background/aim: Airway compression (AC) by vascular structures is an important complication of congenital heart disease (CHD) that often goes unrecognized. It is not easy to identify whether CHD patients require additional invasive examinations or not. Therefore, the present study aims to develop an AC diagnostic algorithm for CHD patients. Materials and methods: CHD patients with persistent respiratory symptoms that were treated between January 2007 and December 2015 were retrospectively reviewed. The following data were recorded for all CHD patients with AC: age, cardiac anomalies, the compressed structure, the airway diameter ratio (ADR), the compressing structure(s), treatment, and follow up.Results: During the 8-year study period, 62 of 253 CHD patients had persistent respiratory symptoms, of which 11 cases were diagnosed as AC via bronchoscopy and/or thoracic computed tomography angiography. The most frequently affected structures were the left main bronchus and trachea, and the most common compressing structure was the right pulmonary artery. The ADR was near total compression in 3 patients and >0.50 in 3 patients. During follow-up, 5 of the 11 patients with AC underwent surgery, 2 died, and 4 were followed clinically. Patients with ADR of >0.50 did not require surgery and were followed clinically. Conclusion: CHD patients with persistent respiratory symptoms associated with lower respiratory airway obstruction should be evaluated via invasive examination. An AC diagnostic algorithm for pediatric CHD patients was developed. PMID- 29151309 TI - Evaluation of the general characteristics of patients aged 85 years and above admitted to a university hospital emergency department AB - Background/aim: The number of elderly people (>=65 years old) is increasing both in Turkey and internationally due to improved living conditions and decreased mortality rates. Knowing the characteristics of elderly patients admitted to emergency departments can provide guidance for diagnosis and treatment approaches. In this study, we analyzed the characteristics of very old patients (4>=85 years old) admitted to the emergency department and put together data for use in forward planning in healthcare services.Materials and methods: This retrospective study included all patients aged >=85 years admitted to the Adult Emergency Department of Gazi University Medical Faculty Hospital between 01.01.2014 and 31.12.2014. Data concerning the patients' age, sex, date of admission, weekday or weekend admission, reason for admission, length of stay, number of readmissions, admission from within or outside the province, and whether they were hospitalized or not were evaluated.Results: In this study, 1105 admissions of 780 patients aged >=85 years to the emergency department were analyzed. The median age of the patients was 87 years and 59% were female. The most frequent admissions were in January (11.4%). Most patients (63.1%) were admitted only once to our emergency department within the study period. A total of 40.5% of patients were hospitalized in the clinics or intensive care units. The rate of mortality at first admission was 1.5% (12 patients). The most common complaints at admission were infection (13.3%) and soft tissue traumas (crashes, sprains, fractures, dislocations) related to the musculoskeletal system (11.8%). Readmissions were more frequent in males. It was seen that male patients were more frequently admitted due to deterioration of general health status and genitourinary system symptoms, despite pain being more common among women.Conclusion: Due to the changing population structure, emergency staff in Turkey as well as internationally encounter old and very old patients more frequently. It is now imperative that emergency departments acquire the necessary infrastructure, human resources, knowledge, and equipment needed to meet the needs of these patients. PMID- 29151310 TI - Comparison of the cardioprotective effects of dexmedetomidineand remifentanil in cardiac surgery AB - Background/aim: Myocardial protection is an important factor of open heart surgery and biological biomarkers (lactate, CKMB, cardiac troponin I, and pyruvate) are used to assess myocardial damage. This study compares the effects of dexmedetomidine and remifentanil on myocardial protection during coronary artery bypass grafting (CABG) surgery. Materials and methods: Patients scheduled for elective CABG surgery (n = 60) were included in this study. Anesthesia induction was introduced with propofol, fentanyl, and vecuronium bromide. Anesthesia was maintained with remifentanil infusion and sevoflurane in the remifentanil group (Group R) and with dexmedetomidine infusion and sevoflurane in the dexmedetomidine group (Group D). Blood samples for biochemical markers were taken from the coronary sinus catheter before cardiopulmonary bypass (T1), 20 min after aortic cross-clamping (T2), 20 min after removal of the aortic cross clamping (T3), and 10 min after separation from cardiopulmonary bypass (T4).Results: Demographic data were similar between the groups. Lactate level at the T2 period and CKMB levels during the study period were lower in Group D than in Group R. In both groups, all values except pyruvate significantly increased over time. Conclusion: The dexmedetomidine-sevoflurane combination may improve the cardioprotective effect in comparison with remifentanil-sevoflurane in CABG surgery. PMID- 29151311 TI - How to manage pseudoangiomatous stromal hyperplasia: our clinical experience AB - Background/aim: Pseudoangiomatous stromal hyperplasia (PASH) is a rare and benign mesenchymal proliferative breast lesion. Our aim is to review the clinical and radiological features of PASH and define a standard approach for its diagnosis and management. Materials and methods: Clinical records of 35 consecutive patients with PASH were retrospectively reviewed between 2009 and 2015. Patients with clinically or radiologically detected mass and patients who underwent biopsy for other indications and were diagnosed incidentally were included in the study. Results: There were 34 female patients and one male patient with gynecomastia. Twenty-three patients had palpable masses, and 16 of them were diagnosed as PASH with a median size of 3.1 cm. PASH did not show any specific features in radiological imaging. Core needle biopsy was performed for 3 patients before surgical excision; however, the lesions had not been diagnosed as PASH. In pathological examination, lesions associated with PASH showed nonproliferative changes in 14 patients, proliferative changes without atypia in 17, one phyllodes tumor, one in situ tumor, and one invasive cancer. Conclusion: Imaging findings of PASH are nonspecific. It is difficult to give a true prognostic diagnosis through pathological evaluation of big masses with core needle biopsy. We recommend surgical excision, especially for big lesions with suspicious features. PMID- 29151312 TI - Role of baseline adenoma characteristics for adenoma recurrencein patients with high-risk adenoma AB - Background/aim: The present observational study aimed to determine the predictive value of 3-year recurrence adenoma characteristics at baseline conventional colonoscopy in patients with high-risk adenoma.Materials and methods: A total of 47 patients with high-risk adenoma at baseline colonoscopy were followed up and underwent a surveillance colonoscopy at 3 years. Correlations between adenoma recurrence and baseline adenoma characteristics (size, number, histological features, and location) were analyzed.Results: Among 135 patients with high-risk adenoma, 47 patients (35%) who underwent surveillance colonoscopy at 3 years following baseline colonoscopy were included in the study. In these 47 patients, at least one new adenoma was detected in 19 (40.4%) patients, and new advanced adenomas were detected in 5 (10.6%) patients during the surveillance colonoscopy. No significant difference was found in patients who had adenoma recurrence versus those who did not in terms of size of adenomas (P = 0.143), number of adenomas (P = 0.562), histological properties of adenomas (P = 0.658), or locations of adenomas (P = 0.567).Conclusion: Baseline adenoma characteristics were not associated with the recurrence of adenomas or advanced adenomas in patients with high-risk adenoma. PMID- 29151313 TI - The effects of the number of physical therapy sessions on pain, disability,and quality of life in patients with chronic low back pain AB - Background/aim: The aim of this study was to investigate and compare the effect of different physical therapy (PT) session numbers on pain, impairment. and quality of life in patients with chronic low back pain (LBP).Materials and methods: In this prospective, randomized-controlled, single-blind trial, a total of 60 patients with chronic LBP were divided into 2 groups with simple randomization within the scope of the study. A PT program of a total of 10 sessions was applied for patients in Group 10 (n = 30) and a total of 15 sessions for patients in Group 15 (n = 30). The main outcome measures were fingertip-to floor distance (FFD), a visual analog scale (VAS), the modified Oswestry Disability Index (mODI), and the Nottingham Health Profile (NHP).Results: We found statistically significant differences in both groups between the before treatment (BT) and after-treatment (AT) results in terms of all evaluation parameters. We detected significant differences between the 2 groups in terms of AT VAS, mODI, NHP Pain, and NHP Total; however, no significant differences were found in terms of FFD and the other NHP subdimension levels.Conclusion: We determined that 15 treatment sessions were more effective than 10 sessions on pain and disability in patients with chronic LBP. PMID- 29151315 TI - Effect of treatment of iron deficiency anemia onhemoglobin A1c in type 2 diabetic patients AB - Background/aim: Iron deficiency anemia (IDA) affects hemoglobin A1c (HbA1c) levels. This study aimed to evaluate the effect of treatment of iron deficiency anemia on hemoglobin A1c in type 2 diabetic patients.Materials and methods: Ninety type 2 diabetes mellitus (T2DM) patients with IDA were included in a randomized, placebo-controlled, single-blind clinical trial. The intervention group (n = 45) received 200 mg/day oral iron for 3 months and the control group (n = 45) received an oral placebo for the same period. Fasting blood sugar, complete blood count, and HbA1c were measured for all subjects at the beginning and the end of the trial.Results: The mean age of the treatment and control group was 51.47 +/- 1.05 and 52 +/- 1.1 years, respectively. The two groups were not statistically significantly different with regard to diabetes duration (P = 0.436) and age (P = 0.617). Hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, serum iron, ferritin, total iron-binding capacity, and HbA1c were significantly improved in the intervention group in comparison with the control group (P = 0.005).Conclusion: Iron status should be considered during the interpretation of the HbA1c concentrations in diabetes mellitus. Iron replacement therapy can decrease HbA1c in anemic patients with IDA and T2DM. PMID- 29151314 TI - Effect of inhaled steroids on clinical and inflammatoryparameters in children with cystic fibrosis AB - Background/aim: The effectiveness of inhaled corticosteroids (ICSs) in cystic fibrosis (CF) is controversial. The aim of this study was to investigate the effect of an ICS on bronchial hyperreactivity (BHR), oxidative status, and clinical and inflammatory parameters in CF patients. Materials and methods: CF patients were randomized to receive either 2 mg/day nebulized budesonide or 0.9% normal saline as placebo for 8 weeks. Results: Twenty-nine CF patients (mean age: 10.5 +/- 2.9 years) were enrolled in the study. There was no statistically significant difference between the two groups at the end of 8 weeks in terms of symptoms, pulmonary function, BHR, oxidative burst, hs-CRP, or ESR. Although there was a significant decrease in malondialdehyde levels in both groups, there was no difference between the two groups. Percentage of neutrophils in the sputum of patients decreased in the budesonide group (P = 0.006). Although sputum IL-8 levels significantly increased in both groups, there was no statistically significant difference between the two groups. Conclusion: Although there was a significant decrease in the percentage of neutrophils in sputum with budesonide, 8 weeks of 2 mg/day nebulized budesonide was not effective in terms of BHR, oxidative status, or clinical and other inflammatory parameters in children with CF. PMID- 29151316 TI - Frequencies and distributions of sex chromosome abnormalities in females with the Turner phenotype: a long-term retrospective study in the southern region of Turkey AB - Background/aim: The genetic background of Turner syndrome (TS) is highly variable. The correlation between genotype and phenotype is not yet well understood. The aim of this study was to describe the frequencies and distributions of Turner karyotypes and to discuss the phenotype/genotype relation in a very large group of individuals with TS. Materials and methods: The karyotype results of 248 female participants were evaluated retrospectively.Results: Of 248 females with the Turner phenotype, 14.5% had normal karyotypes and 85.5% had Turner karyotypes. About 72.2% of the abnormalities were numerical aberrations and 27.8% were structural aberrations. The most frequent karyotype was monosomy X, which was found in 135 females (63.7%), followed by 44 mosaics (21%), 40 isochromosomes of the long and short arms of chromosome X (19.1%), and 17 deletions of the short and long arms of chromosome X (8.0%). One case of Robertsonian translocation and one case of mosaic TS with marker chromosome were detected. Conclusion: This study shows the frequency and distribution of karyotypes in females with TS. There is great value to be gleaned from studies of females with TS in furthering our understanding of the atypical clinical features associated with TS. Studies involving genetic analyses will be necessary to examine gene expression profiles in girls with TS and identify potential candidate genes underlying the atypical clinical features associated with TS. PMID- 29151317 TI - Prevalence and risk factors for Helicobacter pylori infection in southwest China: a study of health examination participants based on 13C-urea breath test AB - Background/aim: Helicobacter pylori (H. pylori) has a high prevalence in developing countries. We aimed to investigate the current prevalence of H. pylori, as well as its potential serum risk factors, in a population from southwest China.Materials and methods: This cross-sectional study included 10,912 subjects who received medical examinations at the First Affiliated Hospital of Chongqing Medical University in 2014. Data regarding physical examinations and biochemical measurements were collected, and H. pylori infection was diagnosed with a 13C-urea breath test. Logistic regression was conducted to identify the risk factors for H. pylori infection.Results: The infection rate of H. pylori was 34.4% (3750/10,912). Older age, lower albumin levels, and higher total cholesterol, LDL-cholesterol, and fasting blood sugar were significantly associated with increased incidence of H. pylori infection. Moreover, logistic regression analysis showed that older age, low albumin, and hyperglycemia were independent risk factors for H. pylori infection after adjusting for other covariables.Conclusion: The results from our study showed that H. pylori was prevalent in southwest China. Older age, low albumin levels, and hyperglycemia were significant risk factors associated with H. pylori infection. PMID- 29151318 TI - Detection and molecular characterisation of adenovirus in children under 5 years old with diarrhoea AB - Background/aim: To determine the frequency, genotype distribution, and genetic relatedness of adenoviruses in children under 5 years old with diarrhoea and to investigate their distribution according to clinical findings, age, months, and seasons. Materials and methods: Stool samples were collected from 180 children with acute gastroenteritis who presented from July 2007 through June 2011 at the Ankara Training and Education Hospital. Stool samples were analysed by immune chromatographic test (ICT), enzyme immunoassay (EIA), and polymerase chain reaction (PCR). All adenovirus types were determined by nucleotide sequence analysis. A phylogenetic tree was constructed by Mega 6.0 using the neighbour joining method. Results: Five percent of the samples were positive for adenovirus (9/180) by ICT, 6.1% (11/180) by EIA, and 13.9% (25/180) by PCR. Adenovirus gastroenteritis did not show any differences in age group, sex, month, or season. In this study, 16 (64%) of the PCR positive samples were AdV41, 6 (24%) were AdV40, 2 (8%) were AdV31, and 1 (4%) was AdV7, as determined by nucleotide sequencing. Conclusion: AdV31 and AdV7 were associated with gastroenteritis. Adenovirus serotypes showed a similarity of 80% (20/25) and 20% (5/25) with Asian and American serotypes, respectively. PMID- 29151319 TI - Patients' attitudes and knowledge about drug use: a survey in Turkish family healthcare centres and state hospitals AB - Background/aim: Irrational drug use is a common problem. This study aimed to evaluate patients' knowledge and habits concerning drug use, and compare them in terms of some sociodemographic characteristics. Materials and methods: A face-to face questionnaire was given to outpatients from family healthcare centres (FHCs) and state hospitals (SHs) in 12 provinces in Turkey during May 2010. A total of 4470 patients (FHCs: 2209; SHs: 2261) responded to the questionnaire (response rate: 93.1%). Results: Getting prescriptions without a physical examination was common (second place in FHCs; third place in SHs); 51.0% stated that they wanted physicians to prescribe drugs that they had used before. More than half stated that antibiotics cured every illness. In addition, 55.9% reported that their relatives recommended drugs to them when they got ill; 37.1% reported that they recommended them to relatives as well. Of the survey respondents, 70.5% stated that they had stopped their medications before the recommended time. Patients' knowledge and attitudes about drug use showed significant differences in comparisons of sex, age, educational level, and social security. Conclusion: Patients' knowledge and attitudes about drugs were far from rational. To eliminate irrational use of drugs, public education about drug use is needed. PMID- 29151320 TI - Effects of whole blood viscosity and plasma NOx on cardiac function and cerebral blood flow in children with chronic kidney disease AB - Background/aim: The aim of the study was to investigate the effects of whole blood viscosity and plasma nitric oxide on cerebral and cardiovascular risks associated with chronic kidney disease. Materials and methods: The study group consisted of 40 pediatric patients and 21 healthy control subjects. Hematologic and biochemical variables, viscosity and plasma nitric oxide levels, echocardiographic findings, and middle cerebral artery blood flow velocity were examined. Results: Viscosity values of patients were significantly lower than those of the control group. Lower values of hematocrit, total protein, and albumin and higher values of ferritin in all patient groups resulted in significantly low viscosity levels. Plasma nitric oxide levels were higher in all patient groups than those in the controls. No statistically significant difference was present in middle cerebral artery blood flow velocity between the patient and control groups. Even when systolic functions were normal, the patient group had significant deterioration in diastolic functions, suggesting morbidity and mortality risks. Conclusions: Cerebral blood flow velocities were not affected by viscosity and nitric oxide levels, suggesting that cerebral circulation has the ability to make adaptive modulation. The metabolism of nitric oxide levels needs further investigation and studies in patients with chronic renal disease. PMID- 29151321 TI - Multiplex PCR detection of problematic pathogens of clinically heterogeneous bacterial vaginosis in Bulgarian women AB - Background/aim: This study aimed to investigate the correlation between the prevalence of problematic pathogens and the clinical status of women with bacterial vaginosis (BV). Materials and methods: Gardnerella vaginalis, Atopobium vaginae, and Mobiluncus spp. were detected using a multiplex PCR assay, and their role in the infection of Bulgarian women with clinically heterogeneous BV was evaluated. Results: The predominant BV-associated pathogen identified was G. vaginalis with an incidence of 98.39%, followed by A. vaginae (68.05%) and Mobiluncus spp. at 17.01%. The coexistence of A. vaginae and G. vaginalis was more common in women with discharge (in 72.04%) and in patients with chronic recurrent BV than among asymptomatic or newly diagnosed BV cases (P < 0.05). Mobiluncus spp. was detected mostly in coinfections, in association with Trichomonas vaginalis. The coinfections were predominantly related to recurrent BV and with complications (P < 0.05). Conclusion: This is the first study about the correlation between problematic pathogens and clinically heterogeneous BV in Bulgarian women. High frequency of infection with key BV-related pathogens was observed in childbearing women. The incidence was shown to often correlate with coexistent T. vaginalis, with severity of infection, and with complicated and recurrent BV after unsuccessful treatments. Screening should be considered in reproductive health programs. PMID- 29151322 TI - Intralesional epidermal growth factor therapy fordiabetic foot ulcers: an evaluation of 15 cases AB - Background/aim: Intralesional recombinant epidermal growth factor (EGF) is a new treatment approach for diabetic foot ulcer, approved in 2006. EGF therapy is given as an adjunct to the standard treatment regimen of antibiotics, surgery, and hyperbaric oxygen. EGF accelerates the healing of diabetic foot ulcers and reduces healing time. This single-center study was conducted to evaluate the outcomes of intralesional EGF therapy in patients with diabetic foot ulcers.Materials and methods: We present the data of the follow-up patients treated in our clinics. Fifteen patients with diabetic foot ulcers or infections, who had been followed up and treated in our clinics, were included in this retrospective study. All patients were administered intralesional injections of 75 MUg of EGF after treatment for infection on their diabetic foot ulcers, three times a week on alternate days. The patients were monitored with respect to treatment response and side effects of EGF.Results: Thirteen patients (86.7%) developed new granulation tissue, 10 patients (66.7%) had complete wound closure, and three patients (20%) showed partial wound closure. No serious side effects requiring discontinuation of EGF therapy were observed. A total of twenty-one bacterial agents were isolated in thirteen patients, and no bacterial growth was observed in the tissue cultures of two patients. Pseudomonas aeruginosa was the most common isolated infectious agent in the tissue cultures (n: 6, 28%). Conclusion: Intralesional injection of EGF on top of the standard treatment regimen appears to be a useful adjuvant therapy option in selected patients. PMID- 29151323 TI - Investigation of human leukocyte antigen in osteoarticular brucellosis AB - Background/aim: To determine the relationship between human leukocyte antigen (HLA) antigens and osteoarticular brucellosis by evaluating HLA Class I and II antigens in control subjects and patients developing osteoarticular brucellosis in Turkey.Materials and methods: The study included 28 patients with osteoarticular involvement diagnosed with brucellosis and 100 controls. The HLA Class I and II antigens were studied in isolated DNA samples using sequence specific oligonucleotide procedure.Results: The mean age of the 28 patients and 100 controls was 42.3 +/- 20.2 years and 50.1 +/- 16.3 years, respectively. When the frequency of HLA Class I was examined, HLA-A*02 and HLA-B*27 antigens were detected in 50% and 28.57% of the patients, respectively. However, there was no significant difference when compared to the control group. Among the HLA Class I antigens, HLA-Cw*10 was determined in 35.71% of the patients and 17% of the controls; the difference was significant (P = 0.039).Conclusion: In the development of brucellosis, the frequency of HLA-Cw*10 among HLA Class I antigens was observed to be increased, and HLA-Cw*10 was considered likely to cause predisposition to brucellosis. Further studies to be performed on a higher number of patients and controls could demonstrate that genetic factors play a role in the diagnosis of osteoarticular brucellosis. PMID- 29151324 TI - Thyroid malignancy risk in different clinical thyroid diseases AB - Background/aim: To evaluate the malignancy risk of thyroid nodules in different clinical thyroid diseases. Materials and methods: Patients who underwent thyroidectomy between 2007 and 2014 were grouped as euthyroid, hypothyroid, and hyperthyroid. Further classification was made depending on the presence of solitary/multiple thyroid nodules. Results: Among 2870 patients, 1719 (59.9%) were euthyroid, 962 (33.5%) were hyperthyroid, and 189 (6.6%) were hypothyroid. Overall malignancy was detected in 980 (34.1%) patients. Malignancy rates were 42.1%, 42.9%, and 18.3% in the euthyroid, hypothyroid, and hyperthyroid groups, respectively (P < 0.001). A total 41.4% of patients with euthyroid nodular goiter (ENG) and 46.3% of patients with euthyroid multinodular goiter (EMNG) had thyroid malignancy (P = 0.169). Mean tumor size and capsular and vascular invasion were significantly lower in EMNG than in ENG. Among hypothyroid patients, 45.7% with solitary and 42.2% with multiple nodules were malignant (P = 0.705). When toxic nodular goiter and toxic multinodular goiter were analyzed together, malignancy rate was 24.7% (104/421), and when Graves with nodule/nodules was considered, it was 19.7% (59/299). Conclusion: In hypothyroid or euthyroid patients who underwent thyroidectomy, malignancy rate was higher than 40%, and was lower in hyperthyroid patients. Patients with multiple nodules carry a similar risk of malignancy as patients with solitary nodules, independent of the functional status. PMID- 29151325 TI - Mean ADC values discriminate rectal mucinous carcinomafrom rectal nonmucinous adenocarcinoma AB - Background/aim: This study aimed to differentiate rectal mucinous carcinoma (MC) from nonmucinous rectal adenocarcinoma (AC) using mean apparent diffusion coefficient (mADC) values obtained with diffusion-weighted imaging.Materials and methods: Sixty-two pathologically confirmed rectal AC (n = 44) and MC (n = 18) patients were included in this study. The two groups underwent pelvic MRI to determine the local staging baseline for rectal tumors. Once the region of interest (ROI) was determined, a border was drawn around each hyperintense tumor (b = 1000 s/mm2 images). Following a repeat of this procedure for each patient, the ROIs were recorded to apparent diffusion coefficient (ADC) maps, and mADC values were measured. The mADC was determined per slice, followed by a calculation of whole tumor volume ADC mean using the individual mADC values. The Mann?Whitney test was performed to compare mADCs for the two groups. A receiver operating characteristic (ROC) curve was generated to determine the differentiating capacity of ADCs from MC to AC. Results: The mADC was higher in MC (1.631 +/- 0.375 x 10-3 mm2/s) (range: 0.95-2.36 x 10-3 mm2/s) than in AC (0.921 +/- 0.157 x 10-3 mm2/s) (range: 0.6-1.48 x 10-3 mm2/s) (P < 0.001). mADCs were effective in distinguishing MC from AC (area under the ROC curve, 0.972 (95% CI : 0.928-1.00)). A threshold of 1.27 x 10-3 mm2/s was set that corresponded with high sensitivity (94.4%) and specificity (97.7%). Twelve MCs (67%) were predominantly hypointense, and 6 MCs (33%) were seen as mixed signal intensity lesions. Forty ACs (91%) were observed as hyperintense lesions, and 4 ACs (9%) had mixed signal intensity. There was a significant difference in the signal intensities between MC and AC (c2 = 54.7, P < 0.001).Conclusion: MCs and ACs show different diffusion characteristics, which can be distinguished with high sensitivity and specificity and can help to improve prognostic treatment options. PMID- 29151326 TI - Treatment options after sorafenib failure in patients with hepatocellular carcinoma. AB - Second line therapy after failure of sorafenib continues to be under study. Prognosis of hepatocellular carcinoma is measured in months, with median overall survival reaching 10.7 months with sorafenib. Because of the modest net benefit sorafenib has contributed, and rising incidence of hepatocellular carcinoma in the world, continued efforts are ongoing to look for efficient upfront, second line, or combination therapies. Herein we review the most relevant to date published literature on treatment options beyond sorafenib, reported studies, ongoing investigational efforts, and possibilities for future studies in advanced hepatocellular carcinoma. PMID- 29151328 TI - Evaluation of pulmonary vein anatomy using 256-slice computed tomography AB - Background/aim: This study aimed to evaluate pulmonary vein (PV) anatomy using 256-slice computed tomography (CT), which may be necessary for electrophysiologists to know before radiofrequency catheter ablation (RFCA) therapy.Materials and methods: A total of 102 patients with paroxysmal and persistent atrial fibrillation underwent 256-slice cardiac CT angiography prior to catheter ablation. PV morphology, ostial diameter, ostial orientation, and distance from ostium to first bifurcation were evaluated using three-dimensional volume-rendering and multiplanar-reformatting technology. Results: We found that 72.5% of patients had four conventional PVs. On the right, 22.5% of patients had one accessory PV, 4.9% had 2 accessory PVs, 1% had one common PV, and 1% had one top vein. On the left, 27.5% of patients had one common PV. Additionally, 9.8% of patients had bilateral PV variation. Ostial size was larger for superior PVs than inferior PVs and larger for right PVs than left PVs. PV ostia on the right tended to be more circular. There was a rather wide variation of projective angle and distance from ostium to first bifurcation. Early branching occurred more often in the right inferior PV. Conclusion: 256-Slice CT can depict PV anatomy and afford substantial data, which will help electrophysiologists conduct the RFCA procedure safely and efficiently. PMID- 29151329 TI - Epidemiology and analysis of invasive fungal infections in patients withhematological malignancies: a single-center real-life experience AB - Background/aim: Invasive fungal infection (IFI) causes morbidity and mortality among patients with hematological malignancies. We evaluated the incidence and treatment characteristics of IFIs between October 2012 and December 2013. Materials and methods: Patients who received chemotherapy or stem cell transplantation were retrospectively evaluated. Fungal infections were classified according to EORTC criteria.Results: Prophylaxis and antifungal therapy were given in 30.5% and 23.6% of 522 chemotherapy courses, respectively. The incidence of proven/probable IFI was 6.7%. The incidence of IFI among patients who received prophylaxis was significantly higher than among those who did not receive it (11.3% vs. 4.6%, P = 0.005). There was no significant difference between patients who received mold-active and no mold-active prophylaxis (P = 0.098). The most common single agent therapy and causative pathogen was liposomal amphotericin B (57.1%) and Aspergillus (n = 5), respectively. IFI-attributable mortality rate was 14.2% in 6 weeks.Conclusion: The IFI incidence and mortality rate were similar to that reported in the literature. The IFI rate was higher in the group using prophylaxis, as this is a high-risk group. Although the IFI rate was not significantly different between groups using prophylaxis, patients should be followed closely for the effective use of posaconazole prophylaxis. PMID- 29151327 TI - Serum matrix metalloproteinase-1 level represents disease activity as opposed to fibrosis in patients with histologically proven nonalcoholic steatohepatitis. AB - BACKGROUND/AIMS: Nonalcoholic steatohepatitis (NASH) is prevalent in both economically developed and developing countries. Twenty percent of NASH progresses to cirrhosis with/without hepatocellular carcinoma, and there is an urgent need to find biomarkers for early diagnosis and monitoring progression of the disease. Using immunohistochemical and immunoelectron microscopic examination we previously reported that expression of matrix metalloproteinase-1 (MMP-1) increased in monocytes, Kupffer cells and hepatic stellate cells in early stage NASH. The present study investigated whether serum MMP-1 levels reflect disease activity and pharmaceutical effects in NASH patients. METHODS: We measured the serum levels of MMPs, tissue inhibitors of metalloproteinases (TIMPs), and several cytokines/chemokines in patients with histologically proven early and advanced stages of NASH and compared them with those in healthy controls. RESULTS: Serum MMP-1 levels in stage 1 fibrosis, but not in the more advanced fibrosis stages, were significantly higher than in healthy controls (P=0.019). There was no correlation between serum MMP-1 level and fibrosis stage. Serum MMP- 1 levels in NASH patients represented disease activity estimated by serum aminotransferase values during the follow-up period. In contrast, MMP-2, MMP-9 and TIMPs did not change with disease activity. Consistent with the finding that MMP-1 is expressed predominantly in monocytes and Kupffer cells, serum levels of monocyte chemotactic protein-1 and granulocyte-colony stimulating factor were significantly increased in NASH with stage 1 fibrosis. CONCLUSIONS: These results suggest that serum MMP-1 levels represent disease activity and may serve as a potential biomarker for monitoring the progression of NASH. PMID- 29151330 TI - Analysis of recurrent urethral strictures due to iatrogenic urethral trauma AB - Background/aim: We aimed to analyze the effects of stricture location, etiology, age, and catheterization time on recurrence rate and recurrence time in patients who underwent direct vision internal urethrotomy (DVIU) for urethral strictures. Materials and methods: Patients were divided into three groups according to the location of the stricture: penile urethra, membranous urethra, and prostatic urethra strictures. Patients were also divided into three groups according to etiologic factors: strictures secondary to endoscopic procedures, urethral catheterization, and open or radical prostatectomy (anastomotic strictures were included in this group). Patients were also divided into three groups according to catheterization time: <2, 2-5, and >5-7 days. Recurrence rate and time data were analyzed according to stricture location, etiology, age, and catheterization time. Results: The recurrence rate was significantly higher in endoscopic procedures. Recurrence rate was significantly lower and recurrence time was significantly earlier in penile urethral strictures. Recurrence rate was significantly lower and recurrence time was significantly longer in short catheterized group than in the other two groups. However, first recurrence time was not different between the groups, while second and multiple recurrence times were significantly earlier in patients <60 years old.Conclusion: Patients are exposed to multiple operations as a result of frequently recurring urethral strictures. Although DVIU is an important first-line treatment method for strictures, alternative methods should be considered for frequently recurring cases. PMID- 29151331 TI - Polymorphisms of cancer-related genes and risk of multipleprimary malignancies involving colorectal cancer AB - Background/aim: This study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of cancer-related genes and the risk of multiple primary malignancies involving colorectal cancer.Materials and methods: We collected tissue samples from 22 multiple primary cancer patients with primary colorectal cancer and performed genotyping assay for 116 SNP loci from 62 genes encoding peptides functioning in various signaling pathways using the DNA MassARRAY system. The chi-square test was used to compare the differences in base frequencies between patients and a control Chinese population from HapMap through the NCBI database.Results: No significant differences in frequencies were detected for 81 SNPs (P > 0.05), while serious frequency differences were observed for 35 SNPs from 31 genes (P < 0.05), which included ERCC6 (rs2228526), ERCC1 (rs3212986), CASP8 (rs3834129, rs3769818), and others presented. Five of these SNPs were previously reported to be associated with the pathogenesis of colorectal cancer.Conclusion: The 35 SNPs from 31 genes may be associated with the risk of multiple primary malignancies involving colorectal cancer. PMID- 29151332 TI - The relationship between the degree of skin fibrosis by sonoelastography and the degree of pulmonary involvement in scleroderma AB - Background/aim: This study aimed to assess the relationship between skin fibrosis as determined by sonoelastography and the degree of pulmonary involvement as determined by high-resolution computed tomography (HRCT) in patients with diffuse cutaneous systemic sclerosis (dcSSc).Materials and methods: This prospective study included 40 patients with dcSSc. All patients with HRCT scans underwent conventional ultrasonography and sonoelastography to determine skin thickness and degree of fibrosis. The degree of fibrosis was classified according to color scale sonoelastography. The degree of pulmonary involvement was classified according to HRCT grading groups. The relationship between skin fibrosis and pulmonary involvement was investigated.Results: There was a statistically significant difference between HRCT grading groups according to the sonoelastographic color scale (P < 0.001). Sonoelastographic color-scale groups showed a statistically significant difference in duration of disease (P = 0.013). No significant difference was found between the sonoelastographic color-scale groups in age, sex, or skin thickness.Conclusion: Sonoelastography is a useful and reliable tool for assessing skin involvement in dcSSc. We found a good correlation between the degree of skin fibrosis as determined by sonoelastography and the degree of pulmonary involvement. PMID- 29151333 TI - Isolated sphenoid sinus pathologies: a series of 40 cases AB - Background/aim: Isolated sphenoid sinus-derived lesions are rare and generally present with unclear symptoms. We are sharing our experience to be mindful of such lesions in differential diagnosis and to help accomplish successful treatment while avoiding revisions and complications.Materials and methods: Data from patients who underwent isolated sphenoid sinus surgeries (ISSs) were retrospectively extracted from the period of January 2005 to August 2015. Demographic data, chief complaints and presenting symptoms, imaging findings, surgical management, and results were evaluated. Results: There were 40 patients who underwent ISS. These patients had different pathologies. The chief complaint was nonspecific headache, except for cerebrospinal fluid leak patients who presented with serous rhinorrhea. Conclusion: It is critical to investigate suspicious symptoms with clinical findings and imaging techniques to avoid late diagnoses of isolated sphenoid pathologies. The transnasal approach is more minimally invasive and tissue-sparing. In our experience, we have noted that excising the inferior one-third of the superior turbinate decreases revisions. On the other hand, results show that the presence of concomitant pathology and invasive fungal disease increases the risk of revision surgery and complications. PMID- 29151334 TI - Investigation of glucocorticoid receptor and calpain-10 gene polymorphisms in Turkish patients with type 2 diabetes mellitus AB - Background/aim: We proposed to investigate the role of calpain-10 (CAPN10) gene single nucleotide polymorphism (SNP)-19 and SNP-44 and glucocorticoid receptor (NR3C1) gene N363S polymorphisms in Turkish patients with type 2 diabetes mellitus (T2DM).Materials and methods: Peripheral blood samples were obtained from 125 patients with T2DM and 112 healthy volunteers. Genotyping was carried out by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: There were no statistically significant differences found between the allele and genotype frequencies of CAPN10 SNP-19, CAPN10 SNP 44, and NR3C1 N363S polymorphisms and T2DM development (P > 0.05). The CAPN10 SNP 19 del-allele, CAPN10 SNP-44 C-allele, and NR3C1 N363S G-allele were determined to be risk factors for T2DM development. In T2DM patients an association was identified between the CAPN10 SNP-19 del-allele, homozygous del/del genotype, SNP 44 C-allele, heterozygous TC genotype, NR3C1 N363S G-allele, heterozygous AG genotype, and increased BMI. Conclusion: The present study demonstrates that the SNP-44 polymorphism is associated with T2DM susceptibility and contributes to the risk of T2DM. PMID- 29151335 TI - Comparison of tidal volume and deep breath preoxygenation techniquesundergoing coronary artery bypass graft surgery: effects of hemodynamicresponse and arterial oxygenation AB - Background/aim: Different techniques exist for the preoxygenation of patients that will be operated on under general anesthesia. Preoxygenation with the deep breath (DB) method may affect cardiovascular stability, which is crucial for coronary artery bypass graft (CABG) patients. In this study, we aimed to compare the effects of the 3 min TVB preoxygenation technique and 1 min 8DBs technique on hemodynamic response and arterial oxygenation in patients with normal ejection fraction that were scheduled for elective CABG surgery. Materials and methods: Forty patients classified as ASA II?III and scheduled for elective CABG surgery were randomly assigned to TVB/3 min or 8DBs/1 min for preoxygenation. Cardiovascular variables, i.e. heart rate, mean arterial pressure, central venous pressure, cardiac index, systemic vascular resistance index, and stroke volume index, and arterial blood gas samples were analyzed before and after preoxygenation and at the end of the apneic period before intubation. Results: The preoxygenation methods affected the hemodynamic response similarly. PaO2 increased significantly with 8DBs compared to the TVB at the end of preoxygenation but was similar between the groups at the end of the apneic period (respectively, P: 0.03; P: 0.15). PaCO2 changes were similar between the groups. Conclusion: In patients with normal ejection fraction scheduled for CABG, 8DBs can be an alternative to TVB preoxygenation. Our results should be compared with those of other studies. PMID- 29151336 TI - Efficacy of bispectral index monitoring for prevention of anestheticawareness and complications during oocyte pick-up procedure AB - Background/aim: This study was planned by considering that the use of bispectral index (BIS) monitoring ensures sufficient depth of anesthesia and avoids anesthetic awareness and patient movement in the oocyte pick-up (OPU) procedure.Materials and methods: Ninety-eight patients undergoing OPU were randomly divided into 2 groups as the control group (n = 48) and BIS group (n = 50). After propofol and remifentanil induction, the control group was given additional propofol according to reaction response, while the BIS group was given propofol at BIS values of 60 and above with the aim that BIS values be 40?60. Total procedure time, recovery time, patient movement, additional propofol consumption, total number of oocytes, and awareness during anesthesia were recorded. Results: Demographic data were similar in the two groups (P > 0.05 for all). The recovery time in the BIS group was significantly shorter compared to the control group (P < 0.001) while additional propofol consumption was found to be significantly lower (P < 0.001). Baseline BIS values fell compared to all other times after induction significantly (P < 0.001). No patient had anesthesia awareness.Conclusion: During the OPU procedure BIS monitoring is considered to prevent anesthesia awareness, intraoperative movement, and complications caused by insufficient anesthetic use as it ensures optimal doses of anesthetic agents used and early recovery. PMID- 29151337 TI - Coexistence of idiopathic granulomatous mastitis and erythemanodosum: successful treatment with corticosteroids AB - Background/aim: Idiopathic granulomatous mastitis (IGM) is a rare, chronic inflammatory disease of the breast. Erythema nodosum (EN) is a rare extramammary manifestation of IGM. The purpose of this study is to determine the clinical and demographic characteristics of 11 IGM and EN patients and to evaluate the efficacy of methylprednisolone treatment. Materials and methods: In our series, ten patients had EN bilaterally, whereas one patient had a lesion of the right pretibial area. The mean age of the patients was 35.5 years (range: 29-45 years). IGM and EN were diagnosed by the necessary serological, microbiological, radiological, and histopathological examination. After diagnosis, methylprednisolone was started in the first week at 0.8 mg/kg daily for treatment. The weekly dose was tapered to 0.1 mg/kg daily over 8 weeks.Results: We started with the treatment of methylprednisolone, and in all our cases the initial response was excellent. In 2 weeks the IGM symptoms had markedly declined, while signs of EN disappeared completely. Patients were followed for an average of 60 months after treatment. None of the 11 patients had recurrence.Conclusion: We herein report a rare series considering IGM cases complicated by EN. Few such cases have been reported in the literature. We advocate for an initial trial of methylprednisolone treatment, which proved to be very successful in our patients. PMID- 29151338 TI - Genotype distribution of Mycobacterium tuberculosis in theAegean Region and associated demographic factors AB - Background/aim: The Aegean Region is the second-ranking region in Turkey according to the Human Development Index and population density and it hosts 1/8 of Turkey's population. Izmir is the largest city of the region, receiving internal migration both from inside and outside the region. The tuberculosis incidence in Izmir is lower than overall in Turkey: 17.7/100,000 in 2011. Our aims were to determine genotypes of Mycobacterium tuberculosis isolates; to explore possible associations between genotypes with case-demographic data, clinical presentation, and antimicrobial susceptibility patterns; and to determine variations in genotype distribution of strains isolated in Ege University Hospital, Izmir. Materials and methods: Forty-nine M. tuberculosis isolates from 49 patients in 1996-2000 and 421 M. tuberculosis isolates from 421 patients in 2009-2014 were spoligotyped. Drug susceptibility testing and demographic data of the 421 isolates were investigated. Chi-square, Student's t, and Mann-Whitney U tests were used for analyses. Results: Among the 470 M. tuberculosis strains, 132 different spoligopatterns were identified and 46 different clusters for 384 strains were determined. The most predominant spoligotypes were ST53 (n = 116; 24.7%) and ST41 (n = 38; 8.1%), followed by ST50 (5.7%), ST284 (4.7%), and ST4 (4.3%), respectively. ST53 was the most predominant type in both sexes. Multidrug resistance (MDR) was determined in 12 isolates, of which six were ST1.Conclusion: As a consequence of worldwide migration and increasing status of HIV-infected hosts, the increasing prevalence of Beijing strains with higher MDR rates may threaten disease control programs. With its increasing trend, ST284 could replace ST41 in the following years in this region. PMID- 29151339 TI - Estrogenic Activity Measurements in Water Using Diffusive Gradients in Thin-Film Coupled with an Estrogen Bioassay. AB - A novel type of diffusive gradients in thin-film (DGT) was combined with a chemically activated luciferase gene expression bioassay (CALUX) to measure estrogens in aquatic systems. The performance of this novel method was assessed with 17beta-estradiol (E2) as the model steroid hormone, XAD 18 resin gel as the binding phase in the DGT method and VM7Luc4E2 cells (formerly BG1Luc4E2) for the Estrogen Responsive Element (ERE)-CALUX bioassay. The measured effective diffusion coefficient of E2 in agarose diffusive gel was 4.65 +/- 0.37 * 10-6 cm2 s-1 at 25 degrees C. The detection limit of this combined DGT/ERE-CALUX method for 1 day of sampling (0.026 +/- 0.003 ng L-1 of E2) is significantly lower than that obtained by spot sampling combined with GC-MS/MS or LC-MS/MS analysis (0.1 7.0 ng L-1). The method is independent of pH (5-8), ionic strength (0.001-0.5 M), and dissolved organic matter (DOM; concentrations up to 30 mg L-1). Field applications of this novel DGT in effluents of three sewage treatment plants in Beijing city (China) showed comparable results to conventional spot (grab) sampling. This study demonstrates that the combined DGT/ERE-CALUX approach is an effective and sensitive tool for in situ monitoring of estrogenic activity in waters and wastewaters. PMID- 29151340 TI - Coupling Microchip Electrospray Ionization Devices with High Pressure Mass Spectrometry. AB - A microchip electrospray ionization source was coupled with high pressure mass spectrometry (HPMS). A continuous atmospheric inlet consisting of a stainless steel capillary and DC ion optics was designed to conduct ions into the mass spectrometer. Infusions of amino acids and peptides were performed and detected with a miniature cylindrical ion trap (mini-CIT)-based mass spectrometer operated at >=1 Torr with air as the buffer gas. Detection of glycine and thymopentin (separately) demonstrated the mass range of the mini-CIT detector could span from m/z 75 to 681. A microchip capillary electrophoresis (CE) separation with mini CIT detection was performed, and the results were compared with detection using a commercial instrument (Waters Synapt G2). Comparable separation efficiencies were observed with both mass spectrometers as detectors, with about 6 times better signal-to-noise observed on the Synapt G2. Comparison of mass spectra in the two systems reveals similar features observed, but with wider peak widths in the mini CIT than on the Synapt G2 as expected due to high-pressure operation. PMID- 29151341 TI - Sequestration of U(VI) from Acidic, Alkaline, and High Ionic-Strength Aqueous Media by Functionalized Magnetic Mesoporous Silica Nanoparticles: Capacity and Binding Mechanisms. AB - Uranium(VI) exhibits little adsorption onto sediment minerals in acidic, alkaline or high ionic-strength aqueous media that often occur in U mining or contaminated sites, which makes U(VI) very mobile and difficult to sequester. In this work, magnetic mesoporous silica nanoparticles (MMSNs) were functionalized with several organic ligands. The functionalized MMSNs were highly effective and had large binding capacity for U sequestration from high salt water (HSW) simulant (54 mg U/g sorbent). The functionalized MMSNs, after U exposure in HSW simulant, pH 3.5 and 9.6 artificial groundwater (AGW), were characterized by a host of spectroscopic methods. Among the key novel findings in this work was that in the HSW simulant or high pH AGW, the dominant U species bound to the functionalized MMSNs were uranyl or uranyl hydroxide, rather than uranyl carbonates as expected. The surface functional groups appear to be out-competing the carbonate ligands associated with the aqueous U species. The uranyl-like species were bound with N ligand as eta2 bound motifs or phosphonate ligand as a monodentate, as well as on tetrahedral Si sites as an edge-sharing bidentate. The N and phosphonate ligand functionalized MMSNs hold promise as effective sorbents for sequestering U from acidic, alkaline or high ionic-strength contaminated aqueous media. PMID- 29151342 TI - Excited-State Aromatic Interactions in the Aggregation-Induced Emission of Molecular Rotors. AB - Small, apolar aromatic groups, such as phenyl rings, are commonly included in the structures of fluorophores to impart hindered intramolecular rotations, leading to desirable solid-state luminescence properties. However, they are not normally considered to take part in through-space interactions that influence the fluorescent output. Here, we report on the photoluminescence properties of a series of phenyl-ring molecular rotors bearing three, five, six, and seven phenyl groups. The fluorescent emissions from two of the rotors are found to originate, not from the localized excited state as one might expect, but from unanticipated through-space aromatic-dimer states. We demonstrate that these relaxed dimer states can form as a result of intra- or intermolecular interactions across a range of environments in solution and solid samples, including conditions that promote aggregation-induced emission. Computational modeling also suggests that the formation of aromatic-dimer excited states may account for the photophysical properties of a previously reported luminogen. These results imply, therefore, that this is a general phenomenon that should be taken into account when designing and interpreting the fluorescent outputs of luminescent probes and optoelectronic devices based on fluorescent molecular rotors. PMID- 29151343 TI - Deuterium-Labeling Studies Reveal the Mechanism of Cytochrome P450-Catalyzed Formation of 2-Aminoacetophenone from 3-Methylindole (Skatole) in Porcine Liver Microsomes. AB - 2-Aminoacetophenone, a product of the hepatic 3-methylindole (skatole) clearance in pigs, contributes to the specific aroma of fat from tainted boar meat. Surprisingly, high formation rates for 2-aminoacetophenone from skatole in microsomal preparations from Pietrain * Baden-Wurttemberg hybrid type boars have been previously demonstrated, but the mechanism of this cytochrome P450-mediated reaction remained unknown. Therefore, microsomal fractions from boars were incubated with deuterium-labeled skatole and with possible reaction intermediates. 3-Methyloxindole and 3-hydroxy-3-methyloxindole were identified as degradation products of skatole en route to 2-aminoacetophenone. Additionally, the labeling studies provided further evidence for a cytochrome P450-mediated lyase reaction that leads to the cleavage of the indole heterocyclic ring system in 3-hydroxy-3-methyloxindole and demonstrated the involvement of several cytochrome P450-isoforms by employing isotopically sensitive branching experiments. PMID- 29151344 TI - Computation of Hemagglutinin Free Energy Difference by the Confinement Method. AB - Hemagglutinin (HA) mediates membrane fusion, a crucial step during influenza virus cell entry. How many HAs are needed for this process is still subject to debate. To aid in this discussion, the confinement free energy method was used to calculate the conformational free energy difference between the extended intermediate and postfusion state of HA. Special care was taken to comply with the general guidelines for free energy calculations, thereby obtaining convergence and demonstrating reliability of the results. The energy that one HA trimer contributes to fusion was found to be 34.2 +/- 3.4kBT, similar to the known contributions from other fusion proteins. Although computationally expensive, the technique used is a promising tool for the further energetic characterization of fusion protein mechanisms. Knowledge of the energetic contributions per protein, and of conserved residues that are crucial for fusion, aids in the development of fusion inhibitors for antiviral drugs. PMID- 29151346 TI - Molecular Scaffolding Strategy with Synergistic Active Centers To Facilitate Electrocatalytic CO2 Reduction to Hydrocarbon/Alcohol. AB - A major impediment to the electrocatalytic CO2 reduction reaction (CRR) is the lack of electrocatalysts with both high efficiency and good selectivity toward liquid fuels or other valuable chemicals. Effective strategies for the design of electrocatalysts are yet to be discovered to substitute the conventional trial and-error approach. This work shows that a combination of density functional theory (DFT) computation and experimental validation of molecular scaffolding to coordinate the metal active centers presents a new molecular-level strategy for the development of electrocatalysts with high CRR selectivity toward hydrocarbon/alcohol. Taking the most widely investigated Cu as a probe, our study reveals that the use of graphitic carbon nitride (g-C3N4) as a molecular scaffold allows for an appropriate modification of the electronic structure of Cu in the resultant Cu-C3N4 complex. As a result, the adsorption behavior of some key reaction intermediates can be optimized on the Cu-C3N4 surface, which greatly benefits the activation of CO2 and leads to a more facile CO2 reduction to desired products as compared with those on the Cu(111) surface and other kinds of Cu complexes formed on nitrogen-doped carbons. Remarkably, different from the most studied elementary metal surfaces, an intramolecular synergistic catalysis with dual active centers was for the first time observed on the Cu-C3N4 complex model, which possesses a unique capability to generate C2 products. A good agreement between electrochemical measurements and the DFT analysis of the CRR has been achieved on the basis of the newly designed and synthesized Cu-C3N4 electrocatalyst. PMID- 29151345 TI - Slow-Down in Diffusion in Crowded Protein Solutions Correlates with Transient Cluster Formation. AB - For a long time, the effect of a crowded cellular environment on protein dynamics has been largely ignored. Recent experiments indicate that proteins diffuse more slowly in a living cell than in a diluted solution, and further studies suggest that the diffusion depends on the local surroundings. Here, detailed insight into how diffusion depends on protein-protein contacts is presented based on extensive all-atom molecular dynamics simulations of concentrated villin headpiece solutions. After force field adjustments in the form of increased protein-water interactions to reproduce experimental data, translational and rotational diffusion was analyzed in detail. Although internal protein dynamics remained largely unaltered, rotational diffusion was found to slow down more significantly than translational diffusion as the protein concentration increased. The decrease in diffusion is interpreted in terms of a transient formation of protein clusters. These clusters persist on sub-microsecond time scales and follow distributions that increasingly shift toward larger cluster size with increasing protein concentrations. Weighting diffusion coefficients estimated for different clusters extracted from the simulations with the distribution of clusters largely reproduces the overall observed diffusion rates, suggesting that transient cluster formation is a primary cause for a slow-down in diffusion upon crowding with other proteins. PMID- 29151347 TI - Simultaneous Speciation Analysis of Arsenic, Chromium, and Selenium in the Bioaccessible Fraction for Realistic Risk Assessment of Food Safety. AB - A simple and fast method was developed for risk assessment of As, Cr, and Se in food, which is demonstrated here using three cooked and uncooked rice samples (basmati as well as organic white and brown rice). The bioaccessible fraction was first determined through online leaching of rice minicolumns (maintained at 37 degrees C) sequentially with artificial saliva, gastric juice, and intestinal juice while continuously monitoring potentially toxic elements (As, Cr, and Se) by inductively coupled plasma mass spectrometry (ICPMS). Then, a new ion chromatography method with online detection by ICPMS was developed for the simultaneous speciation analysis of As, Cr, and Se in the bioaccessible fraction to determine the portion of these elements that was actually toxic. Using gradient elution, four As species [As(III), As(V), monomethylarsonic acid, and dimethylarsinic acid], two Cr species [Cr(III) and Cr(VI)], and two Se species [Se(IV) and Se(VI)] were separated within 12 min. The simultaneous speciation analysis of As, Cr, and Se revealed that the simple act of cooking can convert all of the carcinogenic Cr(VI) to the safer Cr(III). PMID- 29151348 TI - Polysulfone/SiO2 Hybrid Shell Microcapsules Synthesized by the Combination of Pickering Emulsification and the Solvent Evaporation Technique and Their Application in Self-Lubricating Composites. AB - Lubricant oil-filled polysulfone/SiO2 (PSF/SiO2) hybrid shell microcapsules are prepared by the combination of Pickering emulsification and the solvent evaporation technique. Silica particles are used as stabilizers. The structure and properties of the microcapsules are influenced by the silica particle concentration, agitation speed, and encapsulation temperature. The formation of PSF/SiO2 hybrid microcapsules is confirmed by a scanning electron microscope, Fourier transform infrared spectroscopy, and thermal gravimetric analysis. The resulting microcapsules prepared at the optimum synthetic parameters show a spherical, ideal structure with a rough outer surface, mean diameter of 5.0 +/- 0.6 MUm, shell thickness of 0.83 MUm, core content of 50.5 wt %, and excellent thermal stability with an initial evaporating temperature of 250 degrees C. The synthesized microcapsules are embedded into epoxy for application in self lubricating composites. Investigated by friction and wear tests, the tribological properties of the self-lubricating microcapsule-incorporated epoxy composites attain a significant improvement. PMID- 29151349 TI - Changes in Enzyme Structural Dynamics Studied by Hydrogen Exchange-Mass Spectrometry: Ligand Binding Effects or Catalytically Relevant Motions? AB - It is believed that enzyme catalysis is facilitated by conformational dynamics of the protein scaffold that surrounds the active site, yet the exact nature of catalytically relevant protein motions remains largely unknown. Hydrogen/deuterium exchange (HDX) mass spectrometry (MS) reports on backbone H bond fluctuations. HDX/MS thus represents a promising avenue for probing the relationship between enzyme dynamics and catalysis. A seemingly straightforward strategy for such studies involves comparative measurements during substrate turnover and in the resting state. We examined the feasibility of this approach using rabbit muscle pyruvate kinase (rM1-PK) which catalyzes the conversion of phosphoenolpyruvate and Mg-ADP to pyruvate and Mg-ATP. HDX/MS revealed that catalytically active rM1-PK undergoes significant rigidification in the active site. This finding is counterintuitive, considering the purported correlation between dynamics and catalysis. Interestingly, virtually the same rigidification was seen upon exposing rM1-PK to substrates or products in the absence of turnover. These data imply that the active site dynamics during turnover are dominated by protein-ligand binding interactions. These interactions stabilize H bonds in the vicinity of the active site, thereby masking subtle dynamic features that might be uniquely associated with catalysis. Our data uncover an inherent problem with side-by-side turnover/resting state measurements, i.e., the difficulty to design a suitable reference state against which the working enzyme can be compared. Comparative HDX/MS experiments on enzyme dynamics should therefore be interpreted with caution. PMID- 29151350 TI - Tracking of Fluorescently Labeled Polymer Particles Reveals Surface Effects during Shear-Controlled Aggregation. AB - Surface chemistry is believed to be the key parameter affecting the aggregation and breakage of colloidal suspensions when subjected to shear. To date, only a few works dealt with the understanding of the role of the physical and chemical properties of the particles' surface upon aggregation under shear. Previous studies suggested that surface modifications strongly affect polymer particles' adhesion, but it was very challenging to demonstrate this effect and monitor these alterations upon prolonged exposure to shear forces. More importantly, the mechanisms leading to these changes remain elusive. In this work, shear-induced aggregation experiments of polymer colloidal particles have been devised with the specific objective of highlighting material transfer and clarifying the role of the softness of the particle's surface. To achieve this goal, polymer particles with a core-shell structure comprising fluorescent groups have been prepared so that the surface's softness could be tuned by the addition of monomer acting as a plasticizer and the percentage of fluorescent particles could be recorded over time via confocal microscopy to detect eventual material transfer among different particles. For the first time, material exchange occurring on the soft surface of core-shell polymer microparticles upon aggregation under shear was observed and proved. More aptly, starting from a 50% labeled/nonlabeled mixture, an increase in the percentage of particles showing a fluorescent signature was recorded over time, reaching a fraction of 70% after 5 h. PMID- 29151352 TI - Plasmid DNA Delivery: Nanotopography Matters. AB - Plasmid DNA molecules with unique loop structures have widespread bioapplications, in many cases relying heavily on delivery vehicles to introduce them into cells and achieve their functions. Herein, we demonstrate that control over delicate nanotopography of silica nanoparticles as plasmid DNA vectors has significant impact on the transfection efficacy. For silica nanoparticles with rambutan-, raspberry-, and flower-like morphologies composed of spike-, hemisphere-, and bowl-type subunit nanotopographies, respectively, the rambutan like nanoparticles with spiky surfaces demonstrate the highest plasmid DNA binding capability and transfection efficacy of 88%, higher than those reported for silica-based nanovectors. Moreover, it is shown that the surface spikes of rambutan nanoparticles provide a continuous open space to bind DNA chains via multivalent interactions and protect the gene molecules sheltered in the spiky layer against nuclease degradation, exhibiting no significant transfection decay. This unique protection feature is in great contrast to a commercial transfection agent with similar transfection performance but poor protection capability against enzymatic cleavage. Our study provides new understandings in the rational design of nonviral vectors for efficient gene delivery. PMID- 29151353 TI - Challenges in Application of Langmuir Monolayer Studies To Determine the Mechanisms of Bactericidal Activity of Ruthenium Complexes. AB - The effects induced by antibiotics on the bacterial membrane may be correlated with their bactericidal activity, and such molecular-level interactions can be probed with Langmuir monolayers representing the cell membrane. In this study, we investigated the interaction between [Ru(mcbtz)2(PPh3)2] (RuBTZ, mcbtz = 2 mercaptobenzothiazoline) and [Ru(mctz)2(PPh3)2] (RuCTZ, mctz = 2 mercaptothiazoline) with Langmuir monolayers of a lipid extract of Escherichia coli, an extract of lipopolysaccharides (LPSs), and a zwitterionic phospholipid, dioleoylphosphatidyl choline (DOPC). RuBTZ and RuCTZ had little effects on DOPC, which is consistent with their negligible toxicity toward mammalian cells that may be approximated by a zwitterionic monolayer. Also little were their effects on LPSs. In contrast, RuBTZ and RuCTZ induced expansion in the surface pressure isotherms and decreased the compressional modulus of the E. coli lipid extract. While the more hydrophobic RuBTZ seemed to affect the hydrophobic tails of the E. coli extract monolayer to a larger extent, according to polarization modulation infrared reflection absorption spectroscopy results, evidence of a stronger RuBTZ interaction could not be confirmed unequivocally. Therefore, the interaction with the E. coli cell membrane cannot be directly correlated with the observed higher bactericidal activity of RuBTZ, in comparison to that of RuCTZ. This appears to be a case in which Langmuir monolayer studies do not suffice to determine the mechanisms responsible for the bactericidal activity. PMID- 29151351 TI - Immucillins in Infectious Diseases. AB - The Immucillins are chemically stable analogues that mimic the ribocation and leaving-group features of N-ribosyltransferase transition states. Infectious disease agents often rely on ribosyltransferase chemistry in pathways involving precursor synthesis for nucleic acids, salvage of nucleic acid precursors, or synthetic pathways with nucleoside intermediates. Here, we review three infectious agents and the use of the Immucillins to taget enzymes essential to the parasites. First, DADMe-Immucillin-G is a purine nucleoside phosphorylase (PNP) inhibitor that blocks purine salvage and shows clinical potential for treatment for the malaria parasite Plasmodium falciparum, a purine auxotroph requiring hypoxanthine for purine nucleotide synthesis. Inhibition of the PNPs in the host and in parasite cells leads to apurinic starvation and death. Second, Helicobacter pylori, a causative agent of human ulcers, synthesizes menaquinone, an essential electron transfer agent, in a pathway requiring aminofutalosine nucleoside hydrolysis. Inhibitors of the H. pylori methylthioadenosine nucleosidase (MTAN) are powerful antibiotics for this organism. Synthesis of menaquinone by the aminofutalosine pathway does not occur in most bacteria populating the human gut microbiome. Thus, MTAN inhibitors provide high specificity antibiotics for H. pylori and are not expected to disrupt the normal gut bacterial flora. Third, Immucillin-A was designed as a transition state analogue of the atypical PNP from Trichomonas vaginalis. In antiviral screens, Immucillin-A was shown to act as a prodrug. It is active against filoviruses and flaviviruses. In virus-infected cells, Immucillin-A is converted to the triphosphate, is incorporated into the viral transcript, and functions as an atypical chain-terminator for RNA-dependent RNA polymerases. Immucillin-A has entered clinical trials for use as an antiviral. We also summarize other Immucillins that have been characterized in successful clinical trials for T-cell lymphoma and gout. The human trials support the potential development of the Immucillins in infectious diseases. PMID- 29151354 TI - Discovery of a New Fungicide Candidate through Lead Optimization of Pyrimidinamine Derivatives and Its Activity against Cucumber Downy Mildew. AB - Downy mildew is one of the most highly destructive of the diseases that cause damage to fruits and vegetables. Because of the continual development of resistance, it is important to discover new fungicides with different modes of action from existing fungicides for the control of downy mildew. This study is a continuation of our previous work on the novel pyrimidinamine lead compound, 9, and includes field trials for the identification of the optimal candidate. A new compound, 1c, was obtained, which gave a lower EC50 value (0.10 mg/L) against downy mildew than lead compound 9 (0.19 mg/L) and the commercial fungicides diflumetorim, dimethomorph, and cyazofamid (1.01-23.06 mg/L). Compound 1c displayed similar broad-spectrum fungicidal activity to compound 9 but better field efficacy than compound 9, cyazofamid, and flumorph. The present work indicates that pyrimidinamine compound 1c is a candidate for further development as a commercial fungicide for the control of downy mildew. PMID- 29151355 TI - Matrix Effects Originating from Coexisting Minerals and Accurate Determination of Stable Silver Isotopes in Silver Deposits. AB - Except for extensive studies in core formation and volatile-element depletion processes using radiogenic Ag isotopes (i.e., the Pd-Ag chronometer), recent research has revealed that the mass fractionation of silver isotopes is in principle controlled by physicochemical processes (e.g., evaporation, diffusion, chemical exchange, etc.) during magmatic emplacement and hydrothermal alteration. As these geologic processes only produce very minor variations of delta109Ag from -0.5 to +1.10/00, more accurate and precise measurements are required. In this work, a robust linear relationship between instrumental mass discrimination of Ag and Pd isotopes was obtained at the Ag/Pd molar ratio of 1:20. In Au-Ag ore deposits, silver minerals have complex paragenetic relationships with other minerals (e.g., chalcopyrite, sphalerite, galena, pyrite, etc.). It is difficult to remove such abundant impurities completely because the other metals are tens to thousands of times richer than silver. Both quantitative evaluation of matrix effects and modification of chemical chromatography were carried out to deal with the problems. Isobaric inferences (e.g., 65Cu40Ar+ to 105Pd, 208Pb2+ to 104Pd, and 67Zn40Ar+ to 107Ag+) and space charge effects dramatically shift the measured delta109Ag values. The selection of alternative Pd isotope pairs is effective in eliminating spectral matrix effects so as to ensure accurate analysis under the largest possible ranges for metal impurities, which are Cu/Ag <= 50:1, Fe/Ag <= 600:1, Pb/Ag <= 10:1, and Zn/Ag <= 1:1, respectively. With the modified procedure, we reported silver isotope compositions (delta109Ag) in geological standard materials and typical Au-Ag ore deposit samples varying from -0.029 to +0.689 0/00 with external reproducibility of +/-0.009-0.084 0/00. A systemic survey of delta109Ag (or epsilon109Ag) variations in rocks, ore deposits, and environmental materials in nature is discussed. PMID- 29151356 TI - DNA Polymerases: From Molecular Mechanisms to Human Disease, a Special Issue. PMID- 29151358 TI - Exosomal microRNA: a novel biomarker for breast cancer. AB - Breast cancer is the most common invasive malignancy among females worldwide. microRNAs (miRNAs) are small noncoding RNAs that regulate post-transcriptional gene expression by binding to the 3'-untranslated regions of targeted mRNAs. Recently, exosomes have been recognized to play critical roles in breast cancer. miRNAs, as the most important inclusions in exosomes, are stable in the blood and other body fluids, making them ideal candidate biomarkers. In this review, we provide a complex overview of exosomal miRNAs in breast cancer. Particularly, we summarized their critical roles in tumorigenesis and tumor progression, expecting to lay the foundation for future studies using these potential biomarkers. PMID- 29151360 TI - Balancing the playing field: collaborative gaming for physical training. AB - BACKGROUND: Multiplayer video games promoting exercise-based rehabilitation may facilitate motor learning, by increasing motivation through social interaction. However, a major design challenge is to enable meaningful inter-subject interaction, whilst allowing for significant skill differences between players. We present a novel motor-training paradigm that allows real-time collaboration and performance enhancement, across a wide range of inter-subject skill mismatches, including disabled vs. able-bodied partnerships. METHODS: A virtual task consisting of a dynamic ball on a beam, is controlled at each end using independent digital force-sensing handgrips. Interaction is mediated through simulated physical coupling and locally-redundant control. Game performance was measured in 16 healthy-healthy and 16 patient-expert dyads, where patients were hemiparetic stroke survivors using their impaired arm. Dual-player was compared to single-player performance, in terms of score, target tracking, stability, effort and smoothness; and questionnaires probing user-experience and engagement. RESULTS: Performance of less-able subjects (as ranked from single-player ability) was enhanced by dual-player mode, by an amount proportionate to the partnership's mismatch. The more abled partners' performances decreased by a similar amount. Such zero-sum interactions were observed for both healthy-healthy and patient expert interactions. Dual-player was preferred by the majority of players independent of baseline ability and subject group; healthy subjects also felt more challenged, and patients more skilled. CONCLUSION: This is the first demonstration of implicit skill balancing in a truly collaborative virtual training task leading to heightened engagement, across both healthy subjects and stroke patients. PMID- 29151361 TI - Magnesium sulfate and ophthalmic artery Doppler velocimetry in patients with severe preeclampsia: a case series. AB - BACKGROUND: In the present study, we used Doppler velocimetry in the ophthalmic artery to evaluate the hemodynamic status of the intracranial vasculature. This is the first time in the literature that indices of ophthalmic artery Doppler sonography of women with preeclampsia were evaluated before and after the use of magnesium sulfate to prevent eclampsia. CASE PRESENTATION: Indices of ophthalmic artery Doppler sonography of six women with severe preeclampsia at 27 to 33 weeks of gestational age were evaluated before and after the use of magnesium sulfate (10 minutes, 30 minutes, and 60 minutes after the magnesium sulfate loading dosage. The patients' ages were 26 years (patient 01), 29 years (patient 02), 20 years (patient 03), 21 years (patient 04), 20 years (patient 05), and 19 years (patient 06). The ethnic group of patients 01 and 04 was white and the ethnic group of patients 02, 03, 05 and 06 was mulatto. CONCLUSIONS: The apparent increase in resistance index and pulsatility index values, although there is no statistical significance in this series of cases, and the decrease in peak ratio values after the administration of magnesium sulfate reflect an increase in the impedance to flow in the ophthalmic artery and consequently a reduction in cerebral perfusion after the use of magnesium sulfate. This may explain how magnesium sulfate protects women with severe preeclampsia against cerebral damage and prevents acute convulsions in these patients. We believe that this case series report may have a broader clinical impact across medicine because the mechanism of how magnesium sulfate can protect patients and prevent acute convulsions is controversial. PMID- 29151359 TI - Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. AB - BACKGROUND: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator assessed progression-free survival. RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%). CONCLUSIONS: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .). PMID- 29151363 TI - Functional assessment of human enhancer activities using whole-genome STARR sequencing. AB - BACKGROUND: Genome-wide quantification of enhancer activity in the human genome has proven to be a challenging problem. Recent efforts have led to the development of powerful tools for enhancer quantification. However, because of genome size and complexity, these tools have yet to be applied to the whole human genome. RESULTS: In the current study, we use a human prostate cancer cell line, LNCaP as a model to perform whole human genome STARR-seq (WHG-STARR-seq) to reliably obtain an assessment of enhancer activity. This approach builds upon previously developed STARR-seq in the fly genome and CapSTARR-seq techniques in targeted human genomic regions. With an improved library preparation strategy, our approach greatly increases the library complexity per unit of starting material, which makes it feasible and cost-effective to explore the landscape of regulatory activity in the much larger human genome. In addition to our ability to identify active, accessible enhancers located in open chromatin regions, we can also detect sequences with the potential for enhancer activity that are located in inaccessible, closed chromatin regions. When treated with the histone deacetylase inhibitor, Trichostatin A, genes nearby this latter class of enhancers are up-regulated, demonstrating the potential for endogenous functionality of these regulatory elements. CONCLUSION: WHG-STARR-seq provides an improved approach to current pipelines for analysis of high complexity genomes to gain a better understanding of the intricacies of transcriptional regulation. PMID- 29151362 TI - Elimination of schistosomiasis: the tools required. AB - BACKGROUND: Historically, the target in the schistosomiasis control has shifted from infection to morbidity, then back to infection, but now as a public health problem, before moving on to transmission control. Currently, all endemic countries are encouraged to increase control efforts and move towards elimination as required by the World Health Organization (WHO) roadmap for the global control of the neglected tropical diseases (NTDs) and the WHA65.21 resolution issued by the World Health Assembly. However, schistosomiasis prevalence is still alarmingly high and the global number of disability-adjusted life years (DALYs) due to this infection has in fact increased due to inclusion of some 'subtle' clinical symptoms not previously counted. MAIN BODY: There is a need to restart and improve efforts to reach the elimination goal. To that end, the first conference of the Global Schistosomiasis Alliance (GSA) Research Working Group was held in mid-June 2016 in Shanghai, People's Republic of China. It reviewed current progress in schistosomiasis control and elimination, identified pressing operational research gaps that need to be addressed and discussed new tools and strategies required to make elimination a reality. The articles emanating from the lectures and discussions during this meeting, together with some additional invited papers, have been collected as a special issue of the 'Infectious Diseases of Poverty' entitled 'Schistosomiasis Research: Providing the Tools Needed for Elimination', consisting of 26 papers in all. This paper refers to these papers and discusses critical questions arising at the conference related to elimination of schistosomiasis. CONCLUSION: The currently most burning questions are the following: Can schistosomiasis be eliminated? Does it require better, more highly sensitive diagnostics? What is the role of preventive chemotherapy at the elimination stage? Is praziquantel sufficient or do we need new drugs? Contemplating these questions, it is felt that the heterogeneity of the endemic areas in the world requires WHO policies to be upgraded instituting new, differentiated guidelines. PMID- 29151364 TI - A clinical prediction model to identify patients at high risk of hemodynamic instability in the pediatric intensive care unit. AB - BACKGROUND: Early recognition and timely intervention are critical steps for the successful management of shock. The objective of this study was to develop a model to predict requirement for hemodynamic intervention in the pediatric intensive care unit (PICU); thus, clinicians can direct their care to patients likely to benefit from interventions to prevent further deterioration. METHODS: The model proposed in this study was trained on a retrospective cohort of all patients admitted to a tertiary PICU at a single center in the United States, and validated on another retrospective cohort of all patients admitted to the PICU at a single center in the United Kingdom. The PICU clinical information system database (Intellivue Clinical Information Portfolio, Philips, UK) was interrogated to collect physiological and laboratory data. The model was trained using a variant of AdaBoost, which learned a set of low-dimensional classifiers, each of which was age adjusted. RESULTS: A total of 7052 patients admitted to the US PICU was used for training the model, and a total of 970 patients admitted to the UK PICU was used for validation. On the training/validation datasets, the model showed better prediction of hemodynamic intervention (area under the receiver operating characteristic (AUROC) = 0.81/0.81) than systolic blood pressure-based (AUCROC = 0.58/0.67) or shock index-based (AUCROC = 0.63/0.65) models. Both of these models were age adjusted using the same classifier. CONCLUSIONS: The proposed model reliably predicted the need for hemodynamic intervention in PICU patients and provides better classification performance when compared to systolic blood pressure-based or shock index-based models alone. This model could readily be built into a clinical information system to identify patients at risk of hemodynamic instability. PMID- 29151365 TI - Effectiveness of direct-acting antiviral therapy for hepatitis C in difficult-to treat patients in a safety-net health system: a retrospective cohort study. AB - BACKGROUND: Direct-acting antivirals (DAAs) have revolutionized chronic hepatitis C (HCV) treatment, but real-world effectiveness among vulnerable populations, including uninsured patients, is lacking. This study was conducted to characterize the effectiveness of DAAs in a socioeconomically disadvantaged and underinsured patient cohort. METHODS: This retrospective observational study included all patients undergoing HCV treatment with DAA-based therapy between April 2014 and June 2016 at a large urban safety-net health system (Parkland Health and Hospital System, Dallas, TX, USA). The primary outcome was sustained virologic response (SVR), with secondary outcomes including treatment discontinuation, treatment relapse, and loss to follow-up. RESULTS: DAA-based therapy was initiated in 512 patients. The cohort was socioeconomically disadvantaged (56% uninsured and 13% Medicaid), with high historic rates of alcohol (41%) and substance (50%) use, and mental health disorders (38%). SVR was achieved in 90% of patients (n = 459); 26 patients (5%) were lost to follow-up. SVR was significantly lower in patients with decompensated cirrhosis (82% SVR; OR 0.37, 95% CI 0.16-0.85) but did not differ by insurance status (P = 0.98) or alcohol/substance use (P = 0.34). Reasons for treatment failure included loss to follow-up (n = 26, 5%), viral relapse (n = 16, 3%), non-treatment-related death (n = 7, 1%), and treatment discontinuation (n = 4, 1%). Of patients with viral relapse, 6 reported non-compliance and have not been retreated, 5 have been retreated and achieved SVR, 4 have undergone resistance testing but not yet initiated retreatment, and 1 was lost to follow-up. CONCLUSIONS: Effective outcomes with DAA-based therapy can be achieved in difficult-to-treat underinsured populations followed in resource-constrained safety-net health systems. PMID- 29151366 TI - The 150 most important questions in cancer research and clinical oncology series: questions 76-85 : Edited by Chinese Journal of Cancer. AB - Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology to promote cancer research and accelerate collaborations. In this article, 10 questions are presented as followed. Question 76. How to develop effective therapeutics for cancer cachexia? Question 77. How can we develop preclinical animal models to recapitulate clinical situations of cancer patients for more effective anti cancer drug development? Question 78. How can we develop novel effective therapeutics for pancreatic cancer and hepatocellular carcinoma? Question 79. What are the true beneficial mechanisms of antiangiogenic therapy in cancer patients? Question 80. How to approach the complex mechanisms of interplay among various cellular and molecular components in the tumor microenvironment? Question 81. Can tissue oxygenation improve the efficacy of conventional chemotherapy on cancer? Question 82. Can tissue oxygenation improve the efficacy of radiotherapy on digestive system tumors including liver cancer? Question 83. Can we integrate metabolic priming into multimodal management of liver cancer? Question 84. Has the limit of anti-androgen strategy in prostate cancer treatment been reached by the new generation of anti-androgen drugs? Question 85. Can we identify individuals with early-stage cancers via analyzing their clinical and non clinical information collected from social media, shopping history, and clinical, pathological, and molecular traces? PMID- 29151367 TI - Surveillance of the armed forces as a sentinel system for detecting adverse effects of dietary supplements in the general population. AB - OBJECTIVE: Half the US population takes dietary supplements, but surveillance systems available to regulatory and public health authorities to determine whether specific dietary supplements present a risk are inadequate and numerous severe injuries and deaths have occurred from their consumption. Uniformed military personnel regularly use dietary supplements and are more likely to use potentially dangerous supplements than civilians. Recently, the supplement 1,3 dimethylamylamine (DMAA) was marketed for physical performance-enhancement and weight loss. However, after over 100 reports of illness attributed to DMAA, including six deaths, the Food and Drug Administration issued a warning to cease its sale. DESIGN: When DMAA was legal (2010-2011), we conducted, using convenience samples, supplement surveys of service members and determined prevalence of use and self-reported symptoms of DMAA use. SUBJECTS: We surveyed 4374 armed forces personnel using a standardized dietary supplement survey administered by local health-care professionals. RESULTS: Overall, 11 % of survey respondents used dietary supplements labelled as containing DMAA at least once/week. Regular users were over two times more likely to report tachycardia (P<0.0001), tremors (P<0.0001) and dizziness (P=0.0004), and over three times more likely to report numbness/tingling (P<0.0001) than non-users. CONCLUSIONS: Military services could readily monitor adverse events associated with dietary supplements using electronic surveys and medical records. Since armed forces personnel are much more likely than civilians to use potentially dangerous dietary supplements like DMAA, near real-time surveillance of them using electronic surveys and medical records would provide early warning to regulatory agencies and the medical and public health communities when high-risk dietary supplements are introduced. PMID- 29151368 TI - The Application of Scanning Electron Microscopy with Energy-Dispersive X-Ray Spectroscopy (SEM-EDX) in Ancient Dental Calculus for the Reconstruction of Human Habits. AB - The great potential of scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDX) is in detection of unusual chemical elements included in ancient human dental calculus to verify hypotheses about life and burial habits of historic populations and individuals. Elemental spectra were performed from archeological samples of three chosen individuals from different time periods. The unusual presence of magnesium, aluminum, and silicon in the first sample could confirm the hypothesis of high degree of dental abrasion caused by particles from grinding stones in flour. In the second sample, presence of copper could confirm that bronze jewelery could lie near the buried body. The elemental composition of the third sample with the presence of lead and copper confirms the origin of individual to Napoleonic Wars because the damage to his teeth could be explained by the systematic utilization of the teeth for the opening of paper cartridges (a charge with a dose of gunpowder and a bullet), which were used during the 18th and the 19th century AD. All these results contribute to the reconstruction of life (first and third individual) and burial (second individual) habits of historic populations and individuals. PMID- 29151369 TI - Fruit and vegetable consumption and risk of the metabolic syndrome: a meta analysis. AB - OBJECTIVE: Several epidemiological studies have been performed to evaluate the association of fruit and vegetable consumption with risk of the metabolic syndrome (MetS), but the results remain controversial. Thus, we conducted a systematic meta-analysis to assess the associations of fruit or/and vegetable consumption with risk of MetS, separately. DESIGN: We searched PubMed, EMBASE and Web of Science databases up to July 2017 for relevant available articles. Pooled OR with 95 % CI were calculated with the fixed- or random-effects model. RESULTS: A total of nine studies for fruit consumption, nine studies for vegetable consumption and seven studies for fruit and vegetable consumption were identified as eligible for the present meta-analysis. The pooled OR (95 % CI) of MetS for the highest v. lowest category were 0.87 (0.82, 0.92; I 2=46.7 %) for fruit consumption, 0.85 (0.80, 0.91; I 2=0.0 %) for vegetable consumption and 0.76 (0.62, 0.93; I 2=83.5 %) for fruit and vegetable consumption. In subgroup analyses stratified by continent where the study was conducted, the inverse association of fruit consumption (0.86 (0.77, 0.96)) and vegetable consumption (0.86 (0.80, 0.92)) with risk of MetS remained significant in Asia. There was no evidence of small-study effect. CONCLUSIONS: Our meta-analysis indicates that fruit or/and vegetable consumption may be inversely associated with risk of MetS. It suggests that people should consume more fruits and vegetables to decrease the risk of MetS. PMID- 29151370 TI - Systematic review of infant and young child complementary feeding practices in South Asian families: the Pakistan perspective. AB - OBJECTIVE: Suboptimal nutrition among children remains a problem among South Asian (SA) families. Appropriate complementary feeding (CF) practices can greatly reduce this risk. Thus, we undertook a systematic review of studies assessing CF (timing, dietary diversity, meal frequency and influencing factors) in children aged <2 years in Pakistan. DESIGN: Searches between January 2000 and June 2016 in MEDLINE, EMBASE, Global Health, Web of Science, OVID Maternity & Infant Care, CINAHL, Cochrane Library, BanglaJOL, POPLINE and WHO Global Health Library. Eligibility criteria: primary research on CF practices in SA children aged 0-2 years and/or their families. Search terms: 'children', 'feeding' and 'Asians' with their derivatives. Two researchers undertook study selection, data extraction and quality appraisal (EPPI-Centre Weight of Evidence). RESULTS: From 45 712 results, seventeen studies were included. Despite adopting the WHO Infant and Young Child Feeding guidelines, suboptimal CF was found in all studies. Nine of fifteen studies assessing timing recorded CF introduced between 6 and 9 months. Five of nine observed dietary diversity across four of seven food groups; and two of four, minimum meal frequency in over 50 % of participants. Influencing factors included lack of CF knowledge, low maternal education, socio-economic status and cultural beliefs. CONCLUSIONS: This is the first systematic review to evaluate CF practices in Pakistan. Campaigns to change health and nutrition behaviour are needed to meet the substantial unmet needs of these children. PMID- 29151371 TI - Maternal depression symptoms are highly prevalent among food-insecure households in Ethiopia. AB - OBJECTIVE: We aimed to evaluate the association between household food insecurity and maternal depression in Ethiopia. Design/Setting/Subjects In 2014, we conducted a cross-sectional study in southern Ethiopia, including 591 food-secure and 2500 food-insecure households. We measured depression status of women using the Patient Health Questionnaire-9 validated for Ethiopia, with a cut-off of >=5. We evaluated household-level food insecurity using a validated Household Food Insecurity Access Scale. We applied Bayesian modelling to evaluate the relationship between food insecurity and maternal depression accounting for other observed characteristics. RESULTS: Among the analytic sample, 80.8 (95 % CI 79.4, 82.2) % of women were living in food-insecure households. The overall prevalence of probable depression (mild and moderate forms) was 4.7 (95 % CI 4.1, 5.6) %. All individual depressive symptoms had a significantly higher prevalence in the food-insecure group, except for suicidal ideation (but small numbers; P<0.001). In the Bayesian model adjusting for paternal characteristics, there was a significant dose-response linear relationship (trend) between household food insecurity and maternal depression (P<0.01). The adjusted OR (95 % Bayesian credible interval) for depression for differing levels of food insecurity were: mild food insecurity, 3.29 (1.63, 6.18); moderate, 3.82 (1.91, 7.45); severe, 12.50 (3.38, 32.70). CONCLUSIONS: The study documented a high burden of depression among women who lived in food-insecure households. Given this finding, we recommend integrating mental health in the livelihood programmes in areas suffering from food insecurity. PMID- 29151372 TI - Being Whole. PMID- 29151373 TI - Nasoseptal flap for palatal reconstruction after hemi-maxillectomy: case report. AB - OBJECTIVE: Palatal reconstruction following maxillectomy is a surgical challenge, and a nasoseptal flap is a feasible approach. This paper reports the first known successful clinical case of a nasoseptal pedicle flap applied for the reconstruction of maxillary bone following hemi-maxillectomy. CASE REPORT: This report describes hemi-maxillectomy in a 60-year-old Italian male diagnosed with stage IV squamous cell carcinoma of the left maxilla. Endoscopic transnasal extended medial maxillectomy was performed, followed by a transoral modified midfacial degloving technique for removal of the maxillary bone. The contralateral nasoseptal pedicle flap was used to reconstruct the defect. The case was followed up prospectively for the assessment of flap reception and healing. CONCLUSION: The locally accessible nasoseptal flap is a viable alternative for palatal reconstruction; therefore, a second surgical procedure with its associated donor site morbidity can be avoided. Large-scale studies may help in establishing the cosmetic and functional outcomes. PMID- 29151374 TI - Mono- and diglycerides improve lutein absorption in healthy adults: a randomised, double-blind, cross-over, single-dose study. AB - With the association between increased carotenoid intake and lower risk of chronic diseases, the absorption of lutein from the diet becomes an important factor in its delivery and physiological action. The primary objective of this study was to gain an understanding of how a new formulation technology (mixture of mono- and diglycerides (MDG)), affected lutein absorption. Subjects (n 24) were randomised in a cross-over, double-blind study to receive a single dose of 6 mg lutein (FloraGLO 20 %) provided as capsules containing either high-oleic safflower (SAF) oil or a MDG oil. Subjects receiving a single dose of lutein in MDG showed a significantly greater change from baseline (0 h) to 4, 6, 8, 12, 24, 48 and 336 h (P<0.05) and baseline adjusted AUC for plasma lutein at 48 and 336 h (P<0.001) as compared with subjects given lutein in SAF. Analysis of the 48 h absorption kinetics of lutein showed that the time to peak level of lutein (12 h) was the same for SAF and MDG groups, but the change in plasma lutein at 12 and 48 h were 129 and 320 % higher, respectively, for MDG compared with SAF. This difference continued as the adjusted AUC 0-48 and 0-336 h for the MDG group was 232 and 900 % higher, respectively, v. SAF. The study data show that by changing the lipid that is combined with a lutein supplement results in significant increases in lutein absorption in healthy adults. PMID- 29151375 TI - MEASURING THE IMPACT OF CHILD MARRIAGE ON TOTAL FERTILITY: A STUDY FOR FIFTEEN COUNTRIES. AB - SummaryChild marriage has significant negative impacts, not only for girls, but also for a range of development outcomes. This study aimed to assess, in a more detailed way than done so far, the magnitude of the relationship between child marriage and total fertility in multiple countries representing diverse settings. Data from the most recent Demographic and Health Surveys in the fifteen countries of interest were used. Analysis was restricted to a subsample of women aged 35-49 years in order to capture completed fertility. Poisson regression was conducted to estimate the impact of each additional year of early marriage on the total number of births women have, controlling for selected sociodemographic characteristics. Counterfactual analyses were carried out to estimate the reduction in the number of children that women would have over their lifetime in the absence of child marriage. Controlling for socioeconomic and other characteristics, girls who marry as children have more children over their lifetime than women marrying after the age of 18. Nationally, across fifteen countries, the reduction in total fertility from ending child marriage ranges from 0.24 to 1.06 children per woman. The simulated change in total fertility that would result from ending child marriage tends to be higher in countries that have a higher incidence of child marriage. PMID- 29151376 TI - The debate continues: a prospective, randomised, single-blind study comparing Coblation and bipolar tonsillectomy techniques. AB - OBJECTIVES: Tonsillectomy is a common procedure with significant post-operative pain. This study was designed to compare post-operative pain, returns to a normal diet and normal activity, and duration of regular analgesic use in Coblation and bipolar tonsillectomy patients. METHODS: A total of 137 patients, aged 2-50 years, presenting to a single institution for tonsillectomy or adenotonsillectomy were recruited. Pain level, diet, analgesic use, return to normal activity and haemorrhage data were collected. RESULTS: Coblation tonsillectomy was associated with significantly less pain than bipolar tonsillectomy on post-operative days 1 (p = 0.005), 2 (p = 0.006) and 3 (p = 0.010). Mean pain scores were also significantly lower in the Coblation group (p = 0.039). Coblation patients had a significantly faster return to normal activity than bipolar tonsillectomy patients (p < 0.001). CONCLUSION: Coblation tonsillectomy is a less painful technique compared to bipolar tonsillectomy in the immediate post-operative period and in the overall post-operative period. This allows a faster return to normal activity and decreased analgesic requirements. PMID- 29151377 TI - Early childhood parenting and child impulsivity as precursors to aggression, substance use, and risky sexual behavior in adolescence and early adulthood. AB - The current study utilized a longitudinal design to explore the effect of early child impulsivity and rejecting parenting on the development of problematic behaviors in adolescence and early adulthood. Using a low-income sample of 310 mothers and their sons, we examined the direct and interactive effects of child impulsivity and rejecting parenting at age 2 on aggression and substance use at ages 12, 15, and 22, as well as risky sexual behavior at ages 15 and 22. Results revealed that rejecting parenting at age 2 predicted greater aggression at age 12 and risky sexual behavior at ages 15 and 22. Early impulsivity had few direct effects on later outcomes, with the exception of greater substance use at age 22. Instead, impulsivity emerged as a significant moderator in the link between rejecting parenting and aggression at all three ages and substance use at age 15. Specifically, early rejecting parenting predicted greater aggression and substance use only for children high in impulsivity. Findings highlight the potential for early child and parenting risk factors to have long-term implications for adjustment, with the combination of high impulsivity and rejecting parenting being particularly deleterious for problems of aggression throughout adolescence and into early adulthood. PMID- 29151378 TI - Therapeutic and protective effects of autologous serum in amikacin-induced ototoxicity. AB - OBJECTIVE: Possible therapeutic and protective benefits of intratympanic autologous serum application in amikacin-induced ototoxicity were investigated. METHODS: Twenty-four guinea pigs were separated equally into two groups: therapeutic (group A) and protective (group B). Transient evoked otoacoustic emissions were recorded before and after autologous serum application. Apoptotic cells were identified in the organ of Corti, spiral limbus and spiral ganglion by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling ('TUNEL') method. RESULTS: Transient evoked otoacoustic emission responses at 1, 1.4 and 2.8 kHz improved without significance after autologous serum application in group A (p > 0.05). A significantly protective effect of autologous serum was determined at 4 kHz in group B (p < 0.05). There were significantly fewer apoptotic cells at the spiral limbus in the therapeutic and protective groups compared to the control group (p < 0.05). CONCLUSION: Autologous serum may offer protection against ototoxicity-induced hearing loss, but it cannot restore hearing. Immunohistochemically, autologous serum significantly decreases activation of the intrinsic pathway of pro-apoptotic signalling in mesenchymal cells compared to neurons and neurosensory cells. PMID- 29151379 TI - A study of bacterial pathogens and antibiotic susceptibility patterns in chronic suppurative otitis media. AB - OBJECTIVE: To assess the frequency of bacterial agents in chronic suppurative otitis media and the antibiotic susceptibility patterns of isolates among patients. METHODS: A total of 185 patients clinically diagnosed with chronic suppurative otitis media were interviewed and middle-ear effusion samples were collected using sterile swabs. All bacterial isolates were identified by conventional microbiological methods. Antibiotic susceptibility patterns of the isolates were determined by Kirby-Bauer disc diffusion. RESULTS: Staphylococci spp. (64.9 per cent) were the most prevalent bacteria isolated, followed by Klebsiella spp. (12.9 per cent) and Pseudomonas aeruginosa (10.3 per cent). The most effective antibiotic for treatment of bacterial chronic suppurative otitis media was ciprofloxacin. Statistical analysis showed no significant difference in bacterial infestations among chronic suppurative otitis media patients and the antimicrobial susceptibility patterns of the bacterial isolates based on gender and age (p > 0.05). CONCLUSION: Our findings highlight the importance of a continuous and periodic evaluation of the bacteriological profile and antibiotic susceptibility patterns in chronic suppurative otitis media patients for efficacious treatment of the infection. PMID- 29151380 TI - STAKEHOLDERS' PERCEPTIONS OF HEALTH TECHNOLOGY ASSESSMENT IN TURKEY. AB - BACKGROUND: In April of 2014, the Turkish Ministry of Health held the First Annual Health Technology Assessment (HTA) Meeting in Antalya. OBJECTIVES: The objectives were to understand the perceptions of stakeholders regarding the current status of HTA and document their recommendations and strategies for promoting systematic use of HTA in Turkey. METHODS: The study was conducted using a qualitative written survey assessing current compliance with the fifteen HTA principles suggested by Drummond et al. (Key principles for the improved conduct of health technology assessments for resource allocation decision. Int J Technol Assess Health Care. 2008;24:244-258) and a qualitative method referred to as the Collective Intelligence Platform(r). RESULTS: A total of 216 stakeholders representing academic, public, and the private health sector attended the annual meeting; 178 completed the survey and 183 participated in the Platform. Quantitative Results: Survey participants reported that, although Turkey does not currently fully comply with any of the fifteen HTA principles, there is some compliance with all of them. The overall average score for all fifteen principles was 3.04. Quantitivate Results: Participants recommended a more transparent, independent, and evidence-based policy decision-making system through better coordination of HTA activities, data aggregation, capacity development, and a national HTA core model and framework. CONCLUSIONS: Platform participants described the current HTA environment as disjointed and lacking in resources and support from policy-making leaders. Despite the persisting challenges, awareness of the strengths and weaknesses of the current system combined with increasing interaction among Turkish stakeholders and the international HTA community can meaningfully contribute to the continued development and promotion of HTA in Turkey. PMID- 29151381 TI - Feasibility of a septal mucosal flap for preventing re-stenosis following the Draf III procedure. AB - BACKGROUND: Re-stenosis and a consequent need for revision surgery are the most common problems in the follow-up period following endoscopic modification of the Lothrop procedure. METHOD: This paper reports a new technique for reconstructing and resurfacing of the posterior frontal recess bone for prevention of re stenosis. RESULTS: A 46-year-old man presented with a frontal sinus osteoma, and treatment featured an endoscopic modification of the Lothrop procedure. A vascularised, posteriorly based, septal mucosal flap was used in reconstruction. There have been no reported issues over 24 months of follow up. CONCLUSION: The use of a nasoseptal flap seems feasible to reduce scarring and recurrence of (common) frontal recess stenosis after a Draf III operation. PMID- 29151382 TI - Exposure and perceptions of marketing for caffeinated energy drinks among young Canadians. AB - OBJECTIVE: To examine exposure to energy drink marketing among youth and young adults, and test perceptions of energy drink advertisements (ads) regarding target audience age and promoting energy drink use during sports. DESIGN: A between-group experiment randomly assigned respondents to view one of four energy drink ads (sport-themed or control) and assessed perceptions of the ad. Regression models examined marketing exposure and perceptions. SETTING: Online survey (2014). SUBJECTS: Canadians aged 12-24 years (n 2040) from a commercial panel. RESULTS: Overall, 83 % reported ever seeing energy drink ads through at least one channel, including on television (60 %), posters/signs in stores (49 %) and online (44 %). Across experimental conditions, most respondents (70.1 %) thought the ad they viewed targeted people their age or younger, including 42.2 % of those aged 12-14 years. Two sport-themed ads were more likely to be perceived as targeting a younger audience (adjusted OR (95 % CI): 'X Games' 36.5 %, 4.16 (3.00, 5.77); 'snowboard' 19.2 %, 1.50 (1.06, 2.13)) v. control (13.3 %). Participants were more likely to believe an ad promoted energy drink use during sports if they viewed any sport-themed ad ('X Games' 69.9 %, 8.29 (6.24, 11.02); 'snowboard' 76.7 %, 11.85 (8.82, 15.92); 'gym' 66.8 %, 7.29 (5.52, 9.64)) v. control (22.0 %). Greater reported exposure to energy drink marketing was associated with perceiving study ads as promoting energy drink use during sports. CONCLUSIONS: Energy drink marketing has a high reach among young people. Ads for energy drinks were perceived as targeting youth and promoting use during sports. Such ads may be perceived as making physical performance claims, counter to Canadian regulations. PMID- 29151383 TI - Spontaneous ventricular thrombosis in patients with inflammatory bowel disease. AB - Inflammatory bowel disease is closely associated with an increased risk for thrombotic events. Thrombosis mostly occurs in the extremities, lungs, and liver; but it can also occur in the ventricles of the heart. The primary goal of this article is to increase awareness of the risk for ventricular thrombosis in this patient population among healthcare professionals and, thus, appropriate prompt use of thromboprophylaxis therapy for these patients during acute flare-ups. Early diagnosis and intervention are critical for ventricular thrombosis to prevent systemic embolisation of the thrombus. Concisely, inflammatory bowel disease predisposes to the development of thrombi. A low threshold for the use of imaging studies to detect such thrombi is warranted. PMID- 29151384 TI - Endoscopic ear surgery in the ear camp setting; forward thinking or folly? AB - BACKGROUND: Endoscopic ear surgery is becoming an accepted technique in otological surgery, in the management of chronic otitis media. METHODS: The technique was introduced to the humanitarian care setting of an ear camp in Nepal to consider the appropriateness of the technique in this type of clinical setting. RESULTS: Fifteen cases of myringoplasty were successfully completed. CONCLUSION: The apparent advantages of the endoscopic approach over the traditional microscopic one were the ease of transporting the equipment and the optimal view obtained of the tympanic membrane. The ability for pathology and operative technique to be observed equally well by the surgeon and local staff was helpful for teaching, and enables a move towards self-sufficiency of care. Easy image capture also has potential for remote telemedicine applications. PMID- 29151385 TI - The compositional and metabolic responses of gilthead seabream (Sparus aurata) to a gradient of dietary fish oil and associated n-3 long-chain PUFA content. AB - The replacement of fish oil (FO) with vegetable oil (VO) in feed formulations reduces the availability of n-3 long-chain PUFA (LC-PUFA) to marine fish such as gilthead seabream. The aim of this study was to examine compositional and physiological responses to a dietary gradient of n-3 LC-PUFA. Six iso-energetic and iso-nitrogenous diets (D1-D6) were fed to seabream, with the added oil being a blend of FO and VO to achieve a dietary gradient of n-3 LC-PUFA. Fish were sampled after 4 months feeding, to determine biochemical composition, tissue fatty acid concentrations and lipid metabolic gene expression. The results indicated a disturbance to lipid metabolism, with fat in the liver increased and fat deposits in the viscera reduced. Tissue fatty acid profiles were altered towards the fatty acid compositions of the diets. There was evidence of endogenous modification of dietary PUFA in the liver which correlated with the expression of fatty acid desaturase 2 (fads2). Expression of sterol regulatory element binding protein 1 (srebp1), fads2 and fatty acid synthase increased in the liver, whereas PPARalpha1 pathways appeared to be supressed by dietary VO in a concentration-dependent manner. The effects in lipogenic genes appear to become measurable in D1-D3, which agrees with the weight gain data suggesting that disturbances to energy metabolism and lipogenesis may be related to performance differences. These findings suggested that suppression of beta-oxidation and stimulation of srebp1-mediated lipogenesis may play a role in contributing toward steatosis in fish fed n-3 LC-PUFA deficient diets. PMID- 29151386 TI - Dysregulation in children: Origins and implications from age 5 to age 28. AB - Research shows that childhood dysregulation is associated with later psychiatric disorders. It does not yet resolve discrepancies in the operationalization of dysregulation. It is also far from settled on the origins and implications of individual differences in dysregulation. This study tested several operational definitions of dysregulation using Achenbach attention, anxious/depressed, and aggression subscales. Individual growth curves of dysregulation were computed, and predictors of growth differences were considered. The study also compared the predictive utility of the dysregulation indexes to standard externalizing and internalizing indexes. Dysregulation was indexed annually for 24 years in a community sample (n = 585). Hierarchical linear models considered changes in dysregulation in relation to possible influences from parenting, family stress, child temperament, language, and peer relations. In a test of the meaning of dysregulation, it was related to functional and psychiatric outcomes in adulthood. Dysregulation predictions were further compared to those of the more standard internalizing and externalizing indexes. Growth curve analyses showed strong stability of dysregulation. Initial levels of dysregulation were predicted by temperamental resistance to control, and change in dysregulation was predicted by poor language ability and peer relations. Dysregulation and externalizing problems were associated with negative adult outcomes to a similar extent. PMID- 29151388 TI - Dynamic Ultrasonography for Supinator Syndrome: A Case Report. PMID- 29151389 TI - Bevacizumab in Recurrent High-Grade Gliomas: A Canadian Retrospective Study. AB - BACKGROUND: Bevacizumab has been used in recurrent glioblastoma (rGBM) since 2010 in Canada. Given its cost, potential toxicities, and unclear efficacy, further studies are required to better define suitable candidates for therapy. METHODS: A single-center retrospective review of patients started on bevacizumab for rGBM from 2012 to 2015 was performed. Patient demographics, tumor characteristics, treatment regimen, and dates of clinical progression and death were collected. Overall survival (OS) and progression-free survival (PFS) were used as clinical outcomes and estimates. Radiological response was assessed using modified Response Assessment in Neuro-Oncology criteria. RESULTS: A total of 80 patients were included. There were 67 reported deaths, and the median OS was 9.2 months (95% confidence interval [CI 95%]=7.0-10.1 months), with a 12-month OS of 31% (CI 95%=21.9-43.5%). Some 79 patients were included for analysis of clinical progression, among whom 61 had documented clinical progression. The median clinical PFS was 4.6 months (CI 95%=3.8-6.4 months), and the 6-month clinical PFS was 39% (CI 95%=29.0-52.9%). Addition of chemotherapy did not improve clinical outcomes. A total of 68 patients were included for radiological progression analysis, with 58 radiological progressions. The median radiological PFS was 5.8 months (CI 95%=4.2-6.7 months), and the 6-month radiological PFS was 46% (CI 95%=35.6-60.0%). CONCLUSIONS: This is the first reported Canadian experience with bevacizumab for rGBM. Our clinical outcomes are consistent with published data from multicenter phase II and III trials on bevacizumab in rGBM. More research is required to determine which subtype(s) of patients with rGBM could benefit from bevacizumab upon recurrence. PMID- 29151387 TI - Affective family interactions and their associations with adolescent depression: A dynamic network approach. AB - The prevalence of depression rises steeply during adolescence. Family processes have been identified as one of the important factors that contribute to affect (dys)regulation during adolescence. In this study, we explored the affect expressed by mothers, fathers, and adolescents during a problem-solving interaction and investigated whether the patterns of the affective interactions differed between families with depressed adolescents and families with nondepressed adolescents. A network approach was used to depict the frequencies of different affects, concurrent expressions of affect, and the temporal sequencing of affective behaviors among family members. The findings show that families of depressed adolescents express more anger than families of nondepressed adolescents during the interaction. These expressions of anger co occur and interact across time more often in families with a depressed adolescent than in other families, creating a more self-sustaining network of angry negative affect in depressed families. Moreover, parents' angry and adolescents' dysphoric affect follow each other more often in depressed families. Taken together, these patterns reveal a particular family dynamic that may contribute to vulnerability to, or maintenance of, adolescent depressive disorders. Our findings underline the importance of studying affective family interactions to understand adolescent depression. PMID- 29151390 TI - REFLECTIONS ON THE NICE DECISION TO REJECT PATIENT PRODUCTION LOSSES. AB - OBJECTIVES: Patient production losses occur when individuals' capacities to work, whether paid or unpaid, are impaired by illness, treatment, disability, or death. There is controversy about whether and how to include patient production losses in economic evaluations in health care. Patient production losses have not previously been considered when evaluating medications for reimbursement under the U.K. National Health Service. Proposals for value-based assessment of health technologies in the United Kingdom created renewed interest in whether and how to include costs from a wider societal perspective, such as patient production losses, within economic evaluation of healthcare interventions. METHODS: A narrative review was undertaken of theoretical, ethical, and policy issues that might inform decisions that involve the normative question of whether or not to include patient production losses in economic evaluation. RESULTS: It seems difficult to reconcile the implications of including patient production losses with the objectives of a healthcare system dedicated to providing universal healthcare coverage without regard to patients' ability to pay. CONCLUSIONS: Tax payer funded healthcare systems may legitimately adopt maximands other than health gain, but these will be at the opportunity cost of less than maximum health gains. PMID- 29151391 TI - Repeated treatment with nitric oxide synthase inhibitor attenuates learned helplessness development in rats and increases hippocampal BDNF expression. AB - BACKGROUND: Nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects in animal models sensitive to acute drug treatment such as the forced swimming test. However, it is not yet clear if repeated treatment with these drugs is required to induce antidepressant-like effects in preclinical models. OBJECTIVE: The aim of this study was to test the effect induced by acute or repeated (7 days) treatment with 7-nitroindazole (7-NI), a preferential inhibitor of neuronal NOS, in rats submitted to the learned helplessness (LH) model. In addition, we aimed at investigating if 7-NI treatment would increase brain derived neurotrophic factor (BDNF) protein levels in the hippocampus, similarly to the effect of prototype antidepressants. METHODS: Animals were submitted to a pre-test (PT) session with inescapable footshocks or habituation (no shocks) to the experimental shuttle box. Six days later they were exposed to a test with escapable footshocks. Independent groups received acute (a single injection after PT or before test) or repeated (once a day for 7 days) treatment with vehicle or 7-NI (30 mg/kg). RESULTS: Repeated, but not acute, treatment with 7-NI attenuated LH development. The effect was similar to repeated imipramine treatment. Moreover, in an independent experimental group, only repeated treatment with 7-NI and imipramine increased BDNF protein levels in the hippocampus. CONCLUSION: The results suggest the nitrergic system could be a target for the treatment of depressive-like conditions. They also indicate that, similar to the positive control imipramine, the antidepressant-like effects of NOS inhibition could involve an increase in hippocampal BDNF levels. PMID- 29151392 TI - Site of Acquisition of Clostridium difficile Colonization: Hospital or Nursing Home? PMID- 29151393 TI - ETHICS OF SMART HOUSE WELFARE TECHNOLOGY FOR OLDER ADULTS: A SYSTEMATIC LITERATURE REVIEW. AB - BACKGROUND: The University College of Southeast Norway has an on-going project to develop a smart house welfare system to allow older adults and people with disabilities to remain in their homes for as long as they wish in safe, dignified, living conditions. OBJECTIVES: This article reviews reported ethical challenges to implementing smart houses for older adults. METHODS: A systematic literature review identified twenty-four articles in English, French, Spanish, and Norwegian, which were analyzed and synthesized using Hofmann's question list to investigate the reported ethical challenges. RESULTS: Smart houses offer a promising way to improve access to home care for older adults and people with disabilities. However, important ethical challenges arise when implementing smart houses, including cost-effectiveness, privacy, autonomy, informed consent, dignity, safety, and trust. CONCLUSIONS: The identified ethical challenges are important to consider when developing smart house systems. Due to the limitations of smart house technology, designers and users should be mindful that smart houses can achieve a safer and more dignified life-style but cannot solve all the challenges related to ageing, disabilities, and disease. At some point, smart houses can no longer help persons as they develop needs that smart houses cannot meet. PMID- 29151394 TI - Opioid analgesics: Is it time for risk stratification prior to use? - ERRATUM. PMID- 29151396 TI - Effect of dietary sources of n-3 fatty acids on pig performance and technological, nutritional and sensory qualities of pork. AB - In France, animal products (dairy products, meat and eggs) are the main source of n-3 polyunsaturated fatty acids (PUFA) in the human diet; however, many individuals do not consume enough of this nutrient. The objective of this study was to increase n-3 PUFA precursor and derivative contents in tissues and test how they influence technological and sensory qualities of meat without negatively affecting growth performances of pigs. A total of 60 male pigs [(Large White*Landrace)*Pietrain] were assigned according to their initial liveweight (50.7+/-2.7 kg) to five experimental groups corresponding to five different diets that they received from 14 to 22 weeks of age. Dietary lipid supplements were composed of soybean and palm oil (SP), dehulled and extruded linseed (EL-), docosahexaenoic acid (DHA)-rich microalgae (MAG) or a mixture of linseed and microalgae at 75%/25% (3EL-/MAG) and 50%/50% (EL-/MAG), respectively. Diet did not influence growth performances of pigs or the technological quality of the meat. The n-3 PUFA content in the longissimus dorsi muscle, subcutaneous backfat (SCB) and liver increased with a dietary supply of linseed and microalgae and corresponded to circulating fatty acids (FA). The amount of malondialdehyde, representative of FA lipid peroxidation measured in SCB, increased significantly with the supply of microalgae, meaning that PUFA from the microalgae included in the diet increased the meat's susceptibility to oxidation. The MAG diet scored highest for 'abnormal' flavor, similar to that of fish or organ meat, but the n-3 PUFA-rich diet had no effect on other sensory characteristics. Results of this study indicate benefits of enriching animal feed with n-3 PUFA, but the inclusion of long-chain n-3 PUFA such as DHA must be limited to avoid oxidation susceptibility and development of an off-odor. PMID- 29151395 TI - Tziminema unachi n. gen., n. sp. (Nematoda: Strongylidae: Strongylinae) parasite of Baird's tapir Tapirus bairdii from Mexico. AB - A new genus and species of nematode, Tziminema unachi n. gen., n. sp. is described from the caecum and colon of Baird's tapir Tapirus bairdii (Gill, 1865), found dead in the Reserva de la Biosfera El Triunfo, Chiapas State, in the Neotropical realm of Mexico. Tziminema n. gen. differs from the other nine genera included in the Strongylinae by two main characteristics: having 7-9 posteriorly directed tooth-like structures at the anterior end of the buccal capsule, and the external surface of the buccal capsule being heavily striated. Phylogenetic analyses of the DNA sequences of the mitochondrial cytochrome c oxidase and nuclear DNA, including a partial sequence of the internal transcribed spacer 1, 5.8S and a partial sequence of the internal transcribed spacer 2 of the new taxon, confirmed its inclusion in Strongylinae and its rank as a new genus. PMID- 29151397 TI - "I Can't Do This Alone": a study on foreign domestic workers providing long-term care for frail seniors at home. AB - : ABSTRACTBackground:Foreign domestic workers (FDWs) play an important role in long-term caregiving of seniors at home. However, how FDWs cope with the caregiving demands, the dynamic interaction between familial and FDW caregivers and its impact on care recipients remain largely un-explored. Existing caregiver interventions mainly target familial caregivers; little assistance is available for FDW caregivers. This study explores FDWs' challenges, coping strategies, and the support they need in caring for seniors. METHODS: FDWs were recruited from a geriatric ward and outpatient clinic of a tertiary hospital in Singapore. Qualitative in-depth interviews were conducted with 25 FDWs caring for frail seniors and five healthcare staff. Interviews were transcribed and analyzed using thematic analysis. RESULTS: FDWs were from Indonesia, Philippines, and Myanmar. Nineteen cared for seniors with dementia (SWDs). We derived six subthemes, clustered into three salient themes: two described social support to FDWs by the senior's family members, two described their coping strategies, and two described their job satisfaction. Those who cared for SWDs faced more difficulties. We derived two family models of care: FDW-centered family dynamics, where family members rely on FDWs to perform most duties, causing poor impact on seniors' well being and team-based family dynamics, where family members and FDWs share the caregiving burden, resulting in better impact on seniors' well-being. CONCLUSION: FDWs face significant challenges in eldercare. Improving FDWs' access to training courses in eldercare, providing them with more emotional support, engaging employers to create healthy caregiving spaces at home, and improving access to senior care services can be helpful. PMID- 29151398 TI - Disaster Risk Reduction in Myanmar: A Need for Focus on Community Preparedness and Improved Evaluation of Initiatives. AB - Myanmar is a country in political and economic transition. Facing a wide-variety of natural hazards and ongoing conflict, the country's under-developed infrastructure has resulted in high disaster risk. Following the devastation of Cyclone Nargis in 2008 and increased global focus on disaster management and risk reduction, Myanmar has begun development of national disaster policies. Myanmar's Action Plan for Disaster Risk Reduction addressed multiple stages of disaster development and has made progress towards national projects, however, has struggled to implement community-based preparedness and response initiatives. This article analyses Myanmar's disaster strategy, though the use of a disaster development framework and suggests areas for possible improvement. In particular, the article aims to generate discussion regarding methods of supporting objective evaluation of risk reduction initiatives in developing countries. (Disaster Med Public Health Preparedness. 2018;12:422-426). PMID- 29151399 TI - Effect of neonatal orally administered S-allyl cysteine in high-fructose diet fed Wistar rats. AB - S-allyl cysteine (SAC) has antioxidant, antidiabetic and antiobesity properties. We hypothesized that neonatal oral administration of SAC would protect rats against neonatal and adulthood high-fructose diet-induced adverse metabolic outcomes in adulthood. In total, 112 (males=56; females=56), 4-day-old Wistar rat pups were randomly allocated to groups and administered the following treatment regimens daily for 15 days from postnatal day (PND) 6-20: group I - 10 ml/kg distilled water, group II - 10 ml/kg 20% fructose solution (FS), group III - 150 mg/kg SAC and group IV - SAC+FS. On PND 21, the pups were weaned and allowed to grow on a standard rat chow (SRC) until PND 56. The rats from each treatment regimen were then randomly split into two subgroups: one on a SRC and plain drinking water and another on SRC and 20% FS as drinking fluid and then subjected to these treatment regimens for 8 weeks after which they were euthanized and tissues collected for analyzes. Neonatal oral administration of SAC attenuated the neonatal high-fructose diet-induced programming for hepatic lipid accretion in adulthood but not against adulthood high-fructose diet-induced visceral obesity. Neonatal oral administration of SAC programmes for protection against neonatal fructose-induced programming for hepatic lipid accumulation thus could potentially protect against fat-mediated liver derangements in adult life. PMID- 29151400 TI - Review: Optimizing ruminant conversion of feed protein to human food protein. AB - Ruminant livestock have the ability to produce high-quality human food from feedstuffs of little or no value for humans. Balanced essential amino acid composition of meat and milk from ruminants makes those protein sources valuable adjuncts to human diets. It is anticipated that there will be increasing demand for ruminant proteins in the future. Increasing productivity per animal dilutes out the nutritional and environmental costs of maintenance and rearing dairy animals up to production. A number of nutritional strategies improve production per animal such as ration balancing in smallholder operations and small grain supplements to ruminants fed high-forage diets. Greenhouse gas emission intensity is reduced by increased productivity per animal; recent research has developed at least one effective inhibitor of methane production in the rumen. There is widespread over-feeding of protein to dairy cattle; milk and component yields can be maintained, and sometimes even increased, at lower protein intake. Group feeding dairy cows according to production and feeding diets higher in rumen undegraded protein can improve milk and protein yield. Supplementing rumen protected essential amino acids will also improve N efficiency in some cases. Better N utilization reduces urinary N, which is the most environmentally unstable form of excretory N. Employing nutritional models to more accurately meet animal requirements improves nutrient efficiency. Although smallholder enterprises, which are concentrated in tropical and semi-tropical regions of developing countries, are subject to different economic pressures, nutritional biology is similar at all production levels. Rather than milk volume, nutritional strategies should maximize milk component yield, which is proportional to market value as well as food value when milk nutrients are consumed directly by farmers and their families. Moving away from Holsteins toward smaller breeds such as Jerseys, Holstein-Jersey crosses or locally adapted breeds (e.g. Vechur) would also reduce lactose production and improve metabolic, environmental and economic efficiencies. Forages containing condensed tannins or polyphenol oxidase enzymes have reduced rumen protein degradation; ruminants capture this protein more efficiently for meat and milk. Although these forages generally have lower yields and persistence, genetic modification would allow insertion of these traits into more widely cultivated forages. Ruminants will retain their niches because of their ability to produce valuable human food from low value feedstuffs. Employing these emerging strategies will allow improved productive efficiency of ruminants in both developing and developed countries. PMID- 29151401 TI - Evaluation of a primary care paramedic STEMI bypass guideline. AB - OBJECTIVE: Limited evidence supports primary care paramedic (PCP) direct transport of ST-segment elevation myocardial infarction (STEMI) patients for percutaneous coronary intervention (PCI). The goal of this study was to evaluate an urban-based PCP STEMI bypass guideline. METHODS: We reviewed consecutive Toronto Paramedic Services call reports between April 7, 2015, and May 31, 2016, regarding STEMI patients identified by PCPs. The primary outcome was patient assignment (stable versus unstable) according to guideline criteria. Secondary outcomes were the proportion of PCP-transported patients who had an indication for an advanced care intervention (ACI) or who received an ACI when PCPs rendezvoused with an advanced care paramedic (ACP). Lastly, we reviewed prehospital outcomes of cardiac arrest patients and calculated the difference in transport intervals between direct PCP bypass and a PCI-centre and predicted transport interval to the closest emergency department (ED). RESULTS: Of 361 patients, 232 were PCP transports and 129 were ACP-rendezvous transports. There was a significant difference in the distribution of stable and unstable patients between PCPs and ACPs (p<0.001). For PCP patients, 21/232 (9.1%) had indications for an ACI, whereas 34/129 (26.4%) ACP patients received an ACI. Eleven patients experienced cardiac arrest; 10 were successfully resuscitated (5 of these by PCPs). The median difference between direct PCP bypass and a PCI-centre versus transport to the closest ED was 5.53 minutes (IQR=6.71). CONCLUSIONS: We found a significant difference in the distribution of stable and unstable patients and fewer patients with indications for an ACI in PCP patients. This PCP STEMI bypass guideline appears feasible. PMID- 29151402 TI - Difference in First Aid Activity During Mass Casualty Training Based on Having Taken an Educational Course. AB - BACKGROUND: The Japanese Association for Disaster Medicine developed a mass casualty life support (MCLS) course to improve cooperation among medical practitioners during a disaster, which is essential for reducing the rates of preventable disaster death. We investigated whether there was difference in first aid activity among members of the ambulance service during mass casualty training based on having taken the MCLS course. METHODS: Mass casualty training was held at the fire department of Numazu City. Twenty-one ambulance service parties participated in this training. They first evaluated the mass casualty situation, performed the appropriate services at the scene during the initial period, and then provided START triage for mock wounded patients. Throughout the training, 5 examiners evaluated their performance. RESULTS: Regarding the difference in first aid activity based on MCLS course attendance among the ambulance service members, the cooperative management (scored on a scale of 1 to 5) among the members who had taken the MCLS course was significantly better than that among those who had not taken the course (median [interquartile range]: 5 [0.5] vs. 4 [1.75], P<0.05). CONCLUSION: Attending an MCLS course may help to improve outcomes in the face of an actual mass casualty incident. (Disaster Med Public Health Preparedness. 2018;12:437-440). PMID- 29151403 TI - Mouse oocytes nucleoli rescue embryonic development of porcine enucleolated oocytes. AB - It is well known that nucleoli of fully grown mammalian oocytes are indispensable for embryonic development. Therefore, the embryos originated from previously enucleolated (ENL) oocytes undergo only one or two cleavages and then their development ceases. In our study the interspecies (mouse/pig) nucleolus transferred embryos (NuTE) were produced and their embryonic development was analyzed by autoradiography, transmission electron microscopy (TEM) and immunofluorescence (C23 and upstream binding factor (UBF)). Our results show that the re-injection of isolated oocyte nucleoli, either from the pig (P + P) or mouse (P + M), into previously enucleolated and subsequently matured porcine oocytes rescues their development after parthenogenetic activation and some of these develop up to the blastocyst stage (P + P, 11.8%; P + M, 13.5%). In nucleolus re-injected 8-cell and blastocyst stage embryos the number of nucleoli labeled with C23 in P + P and P + M groups was lower than in control (non manipulated) group. UBF was localized in small foci within the nucleoli of blastocysts in control and P + P embryos, however, in P + M embryos the labeling was evenly distributed in the nucleoplasm. The TEM and autoradiographic evaluations showed the formation of functional nucleoli and de novo rRNA synthesis at the 8-cell stage in both, control and P + P group. In the P + M group the formation of comparable nucleoli was delayed. In conclusion, our results indicate that the mouse nucleolus can rescue embryonic development of enucleolated porcine oocytes, but the localization of selected nucleolar proteins, the timing of transcription activation and the formation of the functional nucleoli in NuTE compared with control group show evident aberrations. PMID- 29151404 TI - The Causes of School Failure in Secondary School Students: Validation of a Psychosocial Model with Structural Equations. AB - The objective of the study was to determine the causal effects of school failure (SF) among secondary school students, belonging to five public schools within the region of Girardota, Colombia, through the validation of a psychosocial model with structural equations. A total of 319 students, 25% more males, enrolled in classes between 6th and 11th year, with an average age of 14 years. Furthermore, 265 parents and 200 teachers were also included in the sample. Participants answered the questions raised in 9 instruments. Of the total number of students, 63.8% were surveyed. The instruments were subjected to a pilot test and to the judgment of experts. In order to reduce the amount of data, exploratory and confirmatory factorial analyses were used. Other techniques of multivariate analysis such as decision trees and linear regressions were also used in order to previously evaluate the relationships between the independent variables (IV) and the dependent variable (DV). Afterwards, the Full SEM was calculated, yielding a model consisting of 34 variables (10 latent and 24 observable), with the following indexes of goodness of fit: CMIN/DF = 1.146, p = .058, IFI = 0.974, TLI = .970, CFI = .974, RMSEA = .027 and PCLOSE = 0.998. Theoretically, the model confirms the predictive value of the selected variables, with respect to school failure. The results are applicable to both the design of educational policies and the direct intervention in the classroom. In both contexts, strategies can be developed that reduce factors that negatively affect school performance, actively linking students, teachers and parents. PMID- 29151405 TI - Acta Neuropsychiatrica and social media. PMID- 29151406 TI - Towards operationalising internal distractibility (Mind Wandering) in adults with ADHD. AB - OBJECTIVE: To investigate whether specific symptoms of attention deficit hyperactivity disorder (ADHD) can help identify ADHD patients with mind wandering. METHODS: Subjects were adults ages 18-55 of both sexes (n=41) who completed the Mind-Wandering Questionnaire (MWQ) and the ADHD module of the Schedule for Affective Disorders and Schizophrenia for School-Age Children Epidemiologic Version. We used Spearman's rank correlation and Pearson's chi2 analyses to examine associations between the ADHD module and the MWQ and receiver operator characteristic (ROC) analyses to evaluate the diagnostic efficiency of the ADHD module. RESULTS: Out of the three ADHD domains, the inattentive ADHD scores had the strongest association with the MWQ (total: r s=0.34, df=39, p=0.03; inattentive: r s=0.38, df=39, p=0.02; Hyperactive: r s=0.17, df=39, p=0.28). Correlation analyses between individual items on the ADHD module and the MWQ showed that two inattention items ('failure to pay attention to detail' and 'trouble following instructions') were positively associated with total scores on the MWQ (p=0.02). These two inattention items had the strongest association with the MWQ (r s=0.45, df=38, p=0.004). ROC analyses showed that the combined score of the two significant inattention items had the highest efficiency (AUC=0.71) in classifying high-level mind wanderers as defined by scores greater than the median split on the MWQ. The combined score of the two inattention items best identified high-level mind wanderers. CONCLUSION: Results suggest a way to operationalise mind wandering using the symptoms of ADHD. PMID- 29151407 TI - Minerals and Trace Elements in Milk, Milk Products, Infant Formula, and Adult/Pediatric Nutritional Formula, ICP-MS Method: Collaborative Study, AOAC Final Action 2015.06, ISO/DIS 21424, IDF 243. AB - AOAC Final Action Official MethodSM 2015.06 "Minerals and Trace Elements in Milk, Milk Products, Infant Formula and Adult/Pediatric Nutritional Formula, ICP-MS Method" was collaboratively studied. Note that "milk, milk products" has now been added to the title of the Final Action method because whole milk and several dairy ingredients were successfully incorporated into the collaborative study for the purpose of developing an International Organization for Standardization/International Dairy Federation standard (ISO/DIS 21424; in progress). The method determines sodium, magnesium, phosphorus, potassium, calcium, iron, manganese, zinc, copper, chromium, molybdenum, and selenium by inductively coupled plasma (ICP)-MS after microwave digestion. Ten laboratories participated in the study, and data from five different model ICP-MS units were represented. Thirteen products, five placebo products, and six dairy samples were tested as blind duplicates in this study, along with a standard reference material, for a total 50 samples. The overall repeatability and reproducibility for all samples met Standard Method Performance Requirements put forth by the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals, with a few exceptions. Comparisons are made to ICP-atomic emission data from a collaborative study of AOAC Official Method 2011.14 carried out concurrently on these same samples. PMID- 29151408 TI - [Protective effect of 5-aminosalicylic acid on the kidney of paraquat poisoning rats by Nrf2-ARE signal pathway]. AB - OBJECTIVE: To investigate the protective effect of 5-aminosalicylic acid (5-ASA) on renal injury poisoned by paraquat (PQ) in rats and its mechanism. METHODS: Twenty-four healthy clean male Sprague-Dawley (SD) rats were randomly divided into four groups: normal saline (NS) control group, 5-ASA control group, PQ model group and 5-ASA treatment group, with 6 rats in each group. The rat model of PQ poisoning was reproduced by intraperitoneal injection of 2% PQ solution 20 mg/kg, and the same volume of NS was given in NS control group and 5-ASA control group. Two hours later, the rats in 5-ASA control group and 5-ASA treatment group were intragastrically administered with 1 mL 5-ASA (75 mg/kg) for one time after NS or PQ administration, and those in NS control group and PQ model group were administered with 1 mL double distilled water. Behavioral changes were observed in rats. Then the rats were sacrificed at 24 hours after starting of the experiment for cardiac blood harvest which could be used to detect the biomarkers of renal injury and oxidative stress parameters. The kidney tissue was collected, and the hematein-eosin (HE) staining was conducted for observation of pathological changes in renal tissue, and protein expressions of Nrf2 and heme oxygenase-1 (HO-1) were determined by Western Blot. RESULTS: At 30 minutes after PQ poisoning, rats appeared obvious poisoning symptoms and signs. Twenty-four hours after PQ poisoned, hemocoel of glomerular capillary, swelling of renal tubular epithelial cell and serious micronecrosis appeared under the light microscope. Compared with NS control group, blood urea nitrogen (BUN), serum creatinine (SCr), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) and glutathione (GSH) levels were significantly abnormal in PQ model group, and Nrf2 and HO-1 protein expressions in renal tissue were increased. After administration of 5-ASA, the morphological changes and pathological damage were mitigated as compared with those of PQ model group, the levels of BUN, SCr and MDA were decreased significantly [BUN (mmol/L): 11.98+/-1.81 vs. 18.56+/-2.32, SCr (MUmol/L): 30.67+/-2.31 vs. 43.67+/-9.02, MDA (MUmol/L): 5.28+/-0.43 vs. 6.81+/-1.00], and the SOD activity, CAT and GSH contents were significantly increased [SOD (kU/L): 125.49+/-7.63 vs. 106.76+/-7.94, CAT (ng/L): 30.68+/-3.51 vs. 23.05+/-1.55, GSH (MUmol/L): 3.81+/-0.44 vs. 3.14+/-0.17], while the protein expressions of Nrf2 and HO-1 were further increased [Nrf2 protein (gray value): 0.76+/-0.04 vs. 0.52+/-0.03, HO-1 protein (gray value): 0.56+/-0.02 vs. 0.31+/ 0.02, all P < 0.05]. Only 5-ASA intervention had no significant effect on behavior, pathology, renal injury markers and oxidative stress parameters, but it could induce the expressions of Nrf2 and HO-1 protein in renal tissue, which were significantly higher than those of NS control group [Nrf2 protein (gray value): 0.78+/-0.02 vs. 0.41+/-0.04, HO-1 protein (gray value): 0.51+/-0.03 vs. 0.23+/ 0.01, both P < 0.01]. CONCLUSIONS: 5-ASA attenuates the damage of acute renal injury (AKI) caused by PQ, which mechanism may be related with the activation of Nrf2-antioxidant response element (ARE) signaling pathway. PMID- 29151409 TI - [Curative effect of paraquat detoxification recipe combined with continuous hemoperfusion in the treatment of patients with APP and clinical value of Presepsin]. AB - OBJECTIVE: To investigate the clinical effect of paraquat (PQ) detoxification recipe combined with continuous hemoperfusion (HP) in the treatment of patients with acute paraquat poisoning (APP) and clinical significance of soluble CD14 subtype (sCD14-st, Presepsin). METHODS: A prospective randomized controlled trial was conducted. 152 patients with moderate APP admitted to Department of Emergency Medicine of Harrison International Peace Hospital Affiliated to Hebei Medical University from July 2013 to June 2017 were enrolled, and they were randomly divided into three groups. The patients in HP group (group A, n = 35) only received 2-hour HP for 3 times, 8 hours each time, those in PQ detoxification recipe combined with HP group (group B, n = 50) received PQ detoxification recipe 1 (once per 2 hours until no PQ component was found in faeces) and 2 (3 times a day for 14 days) beside HP. The others in PQ detoxification recipe combined with persistent HP group (group C, n = 67) received continuous HP until the PQ component in serum was not detected. The parameters of organ function and inflammatory factor, and blood Presepsin and PQ contents were determined before and after treatment. The curative effect and 28-day mortality were recorded. The correlations between serum Presepsin level and PQ content as well as 28-day mortality were analyzed with Pearson correlation analysis. Receiver operating characteristic curve (ROC) was plotted to analyze the predictive value of Presepsin on prognosis. RESULTS: The total effective rate of group C was significantly higher than that of groups A and B [70.1% (47/67) vs. 34.3% (12/35), 54.0% (27/50)], and 28-day mortality was significantly lowered [29.8% (20/67) vs. 65.7% (23/35), 46.0% (23/50), both P < 0.05]. There was no significant difference in alanine aminotransferase (ALT), MB isoenzyme of creatine kinase (CK-MB), serum creatinine (SCr), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and interleukins (IL-6 and IL-10) before treatment among the three groups. Five days after treatment, the above parameters in the three groups were increased as compared with those before treatment, but the increase degree in group C was the lowest. At 7 days after treatment, the parameters were decreased, especially in group C. There was no significant difference in serum Presepsin and PQ levels before treatment among the three groups. With the prolongation of treatment time, the Prespsin levels in groups A, B, and C were increased, and peaked at 12 hours (MUg/L: 4.28+/-0.20, 3.87+/-0.25, 3.53+/-0.23), then gradually decreased,and the PQ contents were lower than those before treatment from 8 hours (mg/L: 1.76+/-0.12 vs. 2.12+/-0.17, 1.57+/-0.08 vs. 2.24+/-0.16, 1.25+/-0.10 vs. 2.14+/-0.18), with a time dependence pattern, especially in group C (all P < 0.05) . Correlation analysis showed that blood Presepsin level was positively correlated with PQ content and 28-day mortality (r1 = 0.917, r2 = 0.864, both P = 0.001), suggesting that the higher the PQ content was, the higher the Presepsin level, and the higher the 28-day mortality was. ROC curve analysis showed that the area under ROC curve (AUC) of Presepsin predicting 28-day mortality was 0.863; when the cut-off value was 1.22 MUg/L, the sensitivity was 83.3%, the specificity was 81.4%, the positive predictive value was 77.46%, and the negative predictive value was 86.42%. CONCLUSIONS: Early administration of PQ detoxification recipe combined with continuous HP treatment can effectively reduce Presepsin level, decrease the mortality of patients with moderate APP, improve the prognosis. Presepsin can assess the prognosis of patients with APP. PMID- 29151410 TI - [Effects of curcumin on pulmonary fibrosis and functions of paraquat-challenged rats]. AB - OBJECTIVE: To observe the effects of curcumin on pulmonary fibrosis and functions on paraquat (PQ)-challenged rats, and investigate the possible mechanism. METHODS: 108 SPF Wistar rats were divided into three groups according to random number sheet: normal saline (NS) control group, PQ model group and curcumin treatment group. The rats in each group were subdivided into three subgroups according to different time points (3, 7, 14 days), with 12 rats in each subgroup. PQ-challenged models were reproduced by intragastrical administration of PQ solution 50 mg/kg, and those in NS control group were given the equal volume of NS. After 30 minutes, the rats in curcumin-treatment group were given 200 mg/kg of curcumin by intraperitoneal injection, and those in NS control group and PQ model group were given the equal volume of NS. At 3, 7, 14 days, the tidal volume (VT) was examined, and the blood was drawn from femoral artery for blood gas analysis. Then the rats were sacrificed and the lung tissues were harvested, the hydroxyproline (Hyp) content was measured by alkaline hydrolysis; the expression of transforming growth factor-beta1 (TGF-beta1) was determined by immuno-histochemistry; the distribution and the change of the pulmonary collagen fiber were observed after Masson staining. RESULTS: After exposure to PQ, the VT and arterial partial pressure of oxygen (PaO2) were decreased gradually, and the levels of Hyp and TGF-beta1 were increased gradually, reaching the trough or the peak at 14 days, which were significantly lower or higher than those in NS control group [14-day VT (mL): 1.52+/-0.33 vs. 2.81+/-0.47, 14-day PaO2 (kPa): 5.87+/-0.95 vs. 14.15+/-1.02, 14-day Hyp (MUg/mg): 3.12+/-0.06 vs. 1.14+/-0.05, 14-day TGF-beta1 (integral A value): 29.72+/-4.27 vs. 4.15+/-0.52, all P < 0.01]. After intervene of curcumin, the parameters were significantly improved as compared with those of PQ model group [14-day VT (mL): 2.34+/-0.19 vs. 1.52+/ 0.33, 14-day PaO2 (kPa): 10.23+/-1.01 vs. 5.87+/-0.95, 14-day Hyp (MUg/mg): 2.31+/-0.04 vs. 3.12+/-0.06, 14-day TGF-beta1 (integral A value): 15.46+/-2.89 vs. 29.72+/-4.27, all P < 0.01]. It was shown by Masson staining that in PQ model group, with the PQ-poisoned time prolonging, diffused pulmonary fibrosis and a large number of collagen deposition were observed gradually, and the most serious collagen deposition was observed at 14 days; after intervene of curcumin, pulmonary fibrosis was alleviated significantly at different time points as compared with the PQ model group. CONCLUSIONS: Curcumin can enhance the pulmonary function by reducing the deposition of collagen fiber and inhabiting pulmonary fibrosis of PQ-poisoned rats. PMID- 29151411 TI - [Protective effect of thalidomide on ALI induced by paraquat poisoning in rats and its mechanism]. AB - OBJECTIVE: To investigate the protective effect of thalidomide on acute lung injury (ALI) induced by paraquat (PQ) poisoning in rats and its possible mechanism. METHODS: Sixty SPF Wistar rats were randomly divided into six groups with 10 rats in each group. The rat model of PQ poisoning was reproduced by intraperitoneal injection of PQ solution 20 mg/kg (PQ model group), and the rats were treated by intraperitoneal injection of gradient thalidomide (50, 100, 200 mg/kg treatment groups) 30 minutes later continuously for 3 days. The normal saline (NS) control group and thalidomide control group (thalidomide 200 mg/kg) were established. After 3 days, the abdominal aorta blood was collected, and the superoxide dismutase (SOD) activity was determined by hydroxylamine method, serum malondialdehyde (MDA) content was determined by thiobarbituric acid method. The rats were sacrificed for lung tissue, the levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). The phosphorylation levels of p65 and inhibitor alpha of nuclear factor-kappaB (NF-kappaB) (IkappaB-alpha), which were the NF kappaB signaling pathway proteins, were determined by Western Blot. The pathological changes in lung tissue were observed under light microscope by hematoxylin-eosin (HE) staining. RESULTS: Under microscope, obvious congestion of pulmonary interstitial and alveolar septum, a large number of inflammatory cells infiltration and thickened alveolar wall were observed after 3 days of PQ poisoning, and the congestion of pulmonary interstitial and alveolar septum, edema and inflammatory cells infiltration in the lung tissue were significantly reduced after treatment of 50, 100, 200 mg/kg thalidomide, but compared with NS control group, there was still a small amount of edema fluid, inflammatory cells and erythrocytes in the lungs tissue. Compared with the NS control group, serum MDA content and the levels of TNF-alpha and IL-6, and the phosphorylation of p65 and IkappaB-alpha in lung tissue were significantly increased after PQ exposure, and the activity of serum SOD was significantly decreased. Treatment with 50, 100, 200 mg/kg thalidomide could significantly reduce the levels of MDA, TNF alpha, IL-6, and phosphorylation of IkappaB-alpha and p65, and increase SOD activity, in a dose-dependent manner, and the levels were significantly different from PQ model group [MDA (mmol/L): 8.26+/-1.20, 6.72+/-1.18, 5.51+/-1.44 vs. 9.02+/-1.03, TNF-alpha (ng/mg): 3.00+/-0.14, 1.84+/-0.18, 1.58+/-0.11 vs. 3.30+/ 0.14, IL-6 (ng/mg): 1.26+/-0.04, 1.06+/-0.04, 0.97+/-0.08 vs. 1.97+/-0.07, p p65/p65: 6.01+/-0.35, 3.64+/-0.15, 2.89+/-0.18 vs. 6.34+/-0.23, p-IkappaB alpha/IkappaB-alpha: 2.27+/-0.13, 2.14+/-0.22, 1.52+/-0.14 vs. 2.96+/-0.20, SOD (kU/L): 195.7+/-19.3, 207.1+/-25.6, 225.8+/-23.1 vs. 188.2+/-26.6, all P < 0.05]. There was no significant effect on lung by 200 mg/kg thalidomide alone. CONCLUSIONS: Thalidomide has a protective effect on ALI induced by PQ poisoning in rats in a dose-dependent manner, the mechanism may be achieved by reducing the level of oxygen free radicals, reducing the inflammatory factor and inhibiting the IkappaB-alpha/NF-kappaB signal pathway activation. PMID- 29151412 TI - [Methylene blue in the treatment of vasodilatory shock: a Meta-analysis]. AB - OBJECTIVE: To investigate the clinical efficacy of methylene blue in the treatment of refractory hypotension caused by vascular paralysis during the course of vasodilatory shock. METHODS: The related articles were searched by retrieving the terms using methylene blue, vascular paralysis, hemodynamics, hypotension, vasodilatory shock in CNKI, China Biomedical Literature database, Wanfang database, PubMed, Springer Link, and BIOSIS Previews database. The retrieval time was from January 1994 to June 2017. The randomized clinical trials (RCTs) which using methylene blue as the experimental group, normal saline or catecholamine as the control in the treatment of refractory hypotension caused by vascular paralysis during the course of vasodilatory shock were collected. The primary end points were mean arterial pressure (MAP) immediately or 1 hour after the methylene blue administration, and the mortality at the longest follow-up available; the secondary end point was serum lactic acid (Lac) 1 hour after the methylene blue administration. Literature screening, data extraction and quality evaluation were carried out by two researchers. Meta analysis was performed using RevMan 5.3 software. The sensitivity analysis was performed in two trials with low risk of bias. The funnel plot for MAP was performed in five relative trials to analyze the research and publication bias. RESULTS: Totally 269 relative articles were collected, according to the inclusion and exclusion criteria, finally 6 RCTs with 214 patients were enrolled, 108 in methylene blue group, and 106 in control group. Four of the studies were considered to have mild to moderate risk of bias, two studies of high risk of bias. The Meta-analysis demonstrated that compared with the control group, methylene blue could significantly improve MAP [mean difference (MD) = 4.87, 95% confidence interval (95%CI) = 2.61 to 7.13, P < 0.000 1], reduce the serum Lac levels (MD = -1.06, 95%CI = -1.98 to -0.14, P = 0.02), and the mortality was decreased without statistical difference [odds ratio (OR) = 0.58, 95%CI = 0.25 to 1.31, P = 0.19]. Sensitivity analysis was performed in two trials with low risk of bias, which demonstrated methylene blue could exactly increase MAP (MD = 8.93, 95%CI = 1.55 to 16.32, P = 0.02). Funnel plot for MAP was performed in five relative trials which found no obvious publication bias. CONCLUSIONS: Methylene blue could significantly increase MAP in the patients with refractory hypotension caused by vascular paralysis during the course of vasodilatory shock, decrease the Lac levels, and does not increase the risk of death. Therefore, methylene blue should be a potential and safe vasoconstrictor. PMID- 29151413 TI - [Effects of mechanical ventilation on diaphragmatic contractile function in patients with AECOPD]. AB - OBJECTIVE: To study diaphragmatic strength in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) during mechanical ventilation (MV), and to explore the predictive value of maximal transdiaphragm pressure (Pdi max) for successful extubation. METHODS: A prospective study was conducted. Twenty-one patients with AECOPD receiving MV admitted to intensive care unit (ICU) of Shanghai East Hospital of Tongji University of School Medicine from February 2015 to May 2017 were enrolled. Pdi max value was measured by using esophageal and gastric balloon catheters within 24 hours of intubation until the day the patient underwent extubation or died. In addition, the C-reactive protein (CRP), serum albumin (Alb) and prealbumin (PA) during MV were recorded. Pearson correlation was used to analyze the correlations between Pdi max and CRP, Alb and PA. The receiver operating characteristic curve (ROC) was used to cumulate Pdi max value of the successful weaning. RESULTS: Tracheotomy was done in 2 patients, and 2 patients quit the study. The remaining 17 patients were included in the investigative protocol. Six of the 17 patients died and 11 patients were successfully extubated. (1) Mean Pdi max decreased progressively over time in 17 patients of AECOPD during MV. There were no significant changes in Pdi max at 1-2 days of MV. Mean Pdi max at 7 days was significantly lower than that at 3 days [cmH2O (1 cmH2O = 0.098 kPa): 20.2+/-4.2 vs. 28.1+/-4.4, P < 0.01]. By the end of the evaluation period at 11 days of MV, mean Pdi max decreased about 38.7% to the 1 day of MV (cmH2O: 19.8+/-4.7 vs. 32.3+/-3.9, P < 0.01). During MV, CRP, Alb and PA showed a downward trend. (2) Mean Pdi max and the Pdi max before extubation in patients with difficulty extubation from MV was lower than that in successful weaning [Mean Pdi max (cmH2O): 25.2+/-5.4 vs. 28.9+/-5.8, Pdi max before extubation (cmH2O): 16.9+/-2.8 vs. 26.8+/-6.6, both P < 0.01]. (3) There was significantly negative correlation between Pdi max value and CRP (r = -0.799, P = 0.000). There was significantly positive correlation between Pdi max value and serum Alb (r = 0.613, P = 0.008) and PA (r = 0.661, P = 0.004). (4) ROC curve analysis showed that the area under the ROC curve (AUC) for predicting weaning success in the patients with AECOPD was 0.902. The sensitivity of the diagnosis was 81.8% and the specificity was 100% when cut-off value of Pdi max was 23.2 cmH2O. CONCLUSIONS: MV induced the reduction of diaphragmatic contractility in a time-dependent manner. The Pdi max in patients with difficult extubation from MV was lower than that in successful weaning. The Pdi max could be a parameter to predict the successful extubation in patients with AECOPD during MV. PMID- 29151414 TI - [Efficacy of noninvasive ventilation on treatment of ARDS caused by severe pneumonia after kidney transplantation]. AB - OBJECTIVE: To observe the clinical efficacy of noninvasive ventilation (NIV) on the treatment of acute respiratory distress syndrome (ARDS) caused by severe pneumonia after kidney transplantation. METHODS: The clinical data of 17 patients who were diagnosed as ARDS caused by severe pneumonia after kidney transplantation and treated with NIV in Sichuan Provincial People's Hospital from January 1st, 2014 to June 1st, 2016 were collected and retrospectively analyzed. According to the result of NIV treatment, the patients were divided into NIV success group (n = 9) and NIV failure group (n = 8). The differences in gender, age, underlying diseases, acute physiology and chronic health evaluation II (APACHE II) score, laboratory parameters on the day when ARDS was diagnosed, daily immunosuppressive dosage, NIV support condition and duration, arterial blood gas analysis and adverse reactions between the two groups were compared. Receiver operating characteristic curve (ROC) was plotted, and the predictive value of each parameters for NIV results was evaluated. RESULTS: The two groups were similar in gender, age, and underlying diseases. The APACHE II score, serum levels of procalcitonin (PCT) and brain natriuretic peptide (BNP), serum creatinine (SCr), daily tacrolimus dose, and NIV support condition in NIV failure group were significantly higher than those in NIV success group [APACHE II score: 16.7+/-5.7 vs. 10.3+/-2.1, PCT (MUg/L): 32.8 (1.2, 187.7) vs. 0.3 (0.1, 2.9), BNP (ng/L): 832.4 (263.7, 1 180.2) vs. 157.0 (33.9, 218.5), SCr (MUmol/L): 284.8 (90.5, 474.2) vs. 186.6 (76.7, 206.3), daily tacrolimus dose (mg): 3.6 (3.1, 4.0) vs. 2.6 (2.0, 3.5), inspiratory positive airway pressure (IPAP, cmH2O, 1 cmH2O = 0.098 kPa): 14.8+/-4.1 vs. 9.0+/-1.1, expiratory positive airway pressure (EPAP, cmH2O): 7.6+/-1.8 vs. 4.7+/-0.8, fraction of inspired oxygen (FiO2): 0.75+/-0.25 vs. 0.43+/-0.06, all P < 0.05], and the oxygenation index (PaO2/FiO2) after treatment was significantly lower than that of NIV success group [mmHg (1 mmHg = 0.133 kPa): 107.4+/-65.2 vs. 268.7+/-98.8, P < 0.05]. There was no significant difference in albumin (Alb), white blood cell count (WBC), daily mycophenolate mofetil dose, use of glucocorticold, NIV duration, pH value, arterial partial pressure of carbon dioxide (PaCO2), or the incidence of sputum drainage disorder or pneumothorax between the two groups. ROC curve analysis showed that the predictive value of APACHEII score, serum PCT and BNP levels, tacrolimus daily dosage and PaO2/FiO2 changes after NIV treatment for the efficacy of NIV was high, the area under the ROC curve (AUC) was 0.813, 0.778, 0.903, 0.778, 0.764, respectively; when the cut-off value of APACHE II score was 16.0, PCT was 4.1 MUg/L, BNP was 180.5 ng/L, tacrolimus daily dosage was 2.5 mg, PaO2/FiO2 increased 49.5 mmHg, the sensitivity was 87.5%, 75.2%, 87.5%, 87.5% and 75.0%, respectively, and the specificity was 77.8%, 66.7%, 88.9%, 74.4%, 88.9%, respectively. However, SCr was not sensitive to the NIV effect prediction. CONCLUSIONS: NIV in the treatment of ARDS caused by severe pneumonia after kidney transplantation has a certain value. The fewer tacrolimus daily dosage, the lower APACHE II score and levels of PCT and BNP, the more effective promotion of PaO2/FiO2 after NIV treatment, and the better curative effect is suggested. PMID- 29151415 TI - [Diagnostic value of citrulline and intestinal fatty acid binding protein on acute gastrointestinal injury in critical patients: a prospective study of 530 patients]. AB - OBJECTIVE: To observe the incidence of acute gastrointestinal injury (AGI) in intensive care unit (ICU) patients, and to approach the value of serum citrulline and intestinal fatty acid binding protein (IFABP) on diagnosis of AGI in critical patients. METHODS: A prospective study was conducted. 576 critical patients admitted to ICU of Yantai Yuhuangding Hospital from February 2016 to February 2017 were enrolled. According to the AGI classification proposed by European Society of Intensive Care Medicine (ESICM) in 2012, the AGI and severity of the patients were observed. The general data, severity and prognosis of patients with different AGI grades were recorded. According to the random number table, 20 patients with normal kidney function from AGI I to IV were selected. The femoral artery blood was collected within 12 hours of ICU admission, and serum citrulline level was detected by high performance liquid chromatography (HPLC). Serum IFABP level was determined by enzyme-linked immunosorbent assay (ELISA). Twenty healthy subjects were selected as controls. The receiver operating characteristic curve (ROC) was drawn, and the predictive values of citrulline and IFABP for AGI diagnosis were evaluated. RESULTS: (1) 576 patients were enrolled in the analysis. Of which 530 patients (92.0%) had AGI, and 289 patients with grade I (54.5%), 154 with grade II (29.1%), 64 with grade III (12.1%), and 23 with grade IV (4.3%). With the increase in AGI classification, acute physiology and chronic health evaluation system II (APACHE II) score, sequential organ failure score (SOFA), the length of ICU stay and 28-day mortality were gradually increased. (2) Compared with health control group, the levels of serum citrulline in patients with different AGI grades were significantly decreased, and IFABP was significantly increased. With the increase in AGI classification, the citrulline level was gradually decreased, and IFABP level was gradually increased [citrulline levels (MUmol/L) in AGI I,II,III,IV groups were 14.1+/-3.6, 12.7+/ 3.1, 8.3+/-2.7, and 5.6+/-3.4, F = 3.287, P = 0.027, and IFABP levels (ng/L) were 526.7+/-204.9, 698.4+/-273.8, 894.7+/-455.9, and 1 062.8+/-532.2, F = 2.903, P = 0.043]. ROC curve analysis showed that citrulline had a higher predictive value for AGI diagnosis. The area under the ROC curve (AUC) was 0.927. When the cut-off value of citrulline was 9.7 MUmol/L, the sensitivity and specificity were 87.5% and 87.5%, respectively. The AUC of IFABP was 0.043, which has no predictive value for the diagnosis of AGI. CONCLUSIONS: The AGI is extremely common in ICU. The higher the AGI grade is, the worse the prognosis is. Citrulline has high diagnostic value for AGI in critical patients, but IFABP has no predictive value on the diagnosis of AGI. PMID- 29151416 TI - [Short-term deep sedation strategy in patients with spontaneous intracerebral hemorrhage: a randomized controlled trial]. AB - OBJECTIVE: To evaluate the efficacy and safety of short-term deep sedation strategy in patients with spontaneous intracerebral hemorrhage (ICH) after surgery. METHODS: A perspective, randomized, parallel-group study was conducted. Adult patients with spontaneous ICH and undergoing craniotomy admitted to Daxing Teaching Hospital of Capital Medical University from December 2015 to November 2016 were enrolled. The patients who received surgery were randomly divided into a short-term deep sedation and a slight and middle sedation group. Sufentanil was used as an analgesic drug in all patients and midazolam was used as a sedative after the operation. The patients in the slight and middle sedation group received midazolam 0.05-0.10 mg/kg with a goal of mild sedation [Richmond agitation and sedation scale (RASS) score of -2-1]. The patients in the short term deep sedation group received midazolam 0.1-0.2 mg/kg with a goal of deep sedation (RASS score of -4 to -3) and a duration of no more than 12 hours. Postoperative sedation, blood pressure changes, laboratory indexes, residual hematoma and clinical outcomes were recorded in two groups. RESULTS: During the study, a total of 183 patients with spontaneous ICH were collected, excluding who was older than 65 years, with shock, and with preoperative Glasgow coma score (GCS) of 3. 106 patients were enrolled in this study, and 53 patients were assigned to the short-term deep sedation group and slight and middle sedation group, respectively. In the slight and middle sedation group, 4 patients received reoperation because of repeated hemorrhage and no patient operated repeatedly in the short-term deep sedation group, and there was a significant difference between the two groups (chi 2 = 4.000, P = 0.045). The number of patients undergoing tracheotomy in the short-term deep sedation group was significantly lower than that in the slight and middle sedation group (9 cases vs. 21 cases, P < 0.05). RASS score within 12 hours after operation of the patients in the short term deep sedation group was lower than that in slight and middle sedation group [-4 (-4, -2) vs. -2 (-3, -1) at 4 hours, -4 (-4, -2) vs. -1 (-2, 0) at 8 hours, 3 (-4, -2) vs. 0 (-2, 1) at 12 hours, all P < 0.01], sudden restlessness was significantly reduced [times: 1 (0, 1) vs. 3 (2, 3), P < 0.01], and postoperative sedation duration was significantly prolonged [hours: 14.0 (8.3, 20.8) vs. 8.9 (3.4, 15.3), P < 0.05]. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) within 12 hours after operation in the short-term deep sedation group were significantly lower than those of the slight and middle sedation group [SBP (mmHg, 1 mmHg = 0.133 kPa): 136.8+/-30.5 vs. 149.1+/-33.5, DBP (mmHg): 85.0 (70.8, 102.3) vs. 89.0 (69.2, 116.7), both P < 0.05]. There were no significant differences in the arterial blood gas, routine blood test or coagulation function between the two groups at 24 hours after operation. The volume of residual hematoma at 2, 7 and 14 days after operation in the short-term deep sedation group was significantly decreased as compared with slight and middle sedation group (mL: 16.4+/-15.6 vs. 38.2+/-22.2 at 2 days, 9.6+/-8.7 vs. 20.6+/-18.6 at 7 days, 1.2+/-1.0 vs. 4.4+/-3.6 at 14 days, all P < 0.05), number of deaths in 3 months were significantly less (5 cases vs. 13 cases), and the patients with favorable prognosis were increased significantly (39 cases vs. 12 cases, both P < 0.05). CONCLUSIONS: The study results showed that short-term deep sedation strategy after surgery can reduce the incidence of adverse events and improve the prognosis of patients with spontaneous ICH, so it is safe and effective. PMID- 29151417 TI - [Effect of early use of different doses of enteral nutrition on prognosis of patients with acute respiratory failure]. AB - OBJECTIVE: To observe the impact of initial low-dose (trophic type) enteral nutrition (EN) support on mechanical ventilation (MV) time, the incidence of complications and survival rate in patients with acute respiratory failure (ARF). METHODS: A prospective study was conducted. Forty-four patients with ARF undergoing MV admitted to Department of Critical Care Medicine of Hangzhou Traditional Chinese Medical Hospital from September 2015 to February 2017 were enrolled, and they were divided into a trophic feeding group (n = 23, study group) and a standard-dose feeding group (n = 21, control group). In the two groups, the EN support feeding was given to the patients through a nasogastric tube within 24-hour MV for consecutive 7 days, the protein supply to each one of all of them was 1.2-1.6 g*kg-1*d-1. The study group received EN according to non protein calories of 41.84-83.68 kJ*kg-1*d-1 to calculate, while the control group accepted EN according to non-protein calories of 104.60-125.50 kJ*kg-1*d-1 to calculate. The serum albumin (Alb) and fasting blood glucose (FBG) levels were measured in two groups 1 day before EN treatment and at 1, 2, 3, 7 days of treatment, and the energy levels in initial 3 days and 7 days of MV and the 24 hour urine creatinine (UCr) level on the 7th day after treatment were recorded. The creatinine-height index (CHI, CHI = actual UCr/standard UCr) was calculated. The incidence of intestinal intolerance (vomiting, gastric retention, diarrhea, gastrointestinal bleeding, etc.) in 7 days of treatment, MV time, the length of stay in ICU, the total length of stay in the hospital and the 28-day incidence of new infections (pulmonary, hematogenous, urinary, abdominal, and other infections) and 60-day survival rate were observed between the two groups. RESULTS: The EN supplies within 3 days and 7 days in the study group were significantly lower than those in the control group [within 3 days (kJ/d): 1 710.58+/-703.96 vs. 4 152.79+/-1 334.65, 7 days (kJ/d): 2 471.28+/-815.50 vs. 5 058.08+/-875.25, both P < 0.05]; there were no statistically significant differences in CHI after EN therapy for 7 days and serum Alb levels before and after EN between the two groups. FBG level of the study group was significantly lower than that of the control group since the 2nd day of treatment (mmol/L: 8.58+/-2.37 vs. 10.93+/-3.75), and continued to the 7th day (mmol/L: 8.96+/-1.76 vs. 10.97+/-4.11, both P < 0.05), the incidence of elevated blood glucose was also significantly lower than that of the control group [26.1% (6/23) vs. 66.7% (14/21), P < 0.05]. The incidence of feeding intolerance in the study group was significantly lower than that in the control group from 2 days of treatment till 7 days (26.1% vs. 47.6%, P < 0.05). There were no statistically significant differences in MV time (days: 15.04+/-6.75 vs. 16.14+/-8.51), the length of stay in ICU (days: 16.52+/-6.89 vs. 17.24+/-7.67), total length of stay in hospital (days: 26.35+/-9.69 vs. 25.33+/-7.73), 28-day new infection rate [26.1% (6/23) vs. 42.9% (9/21)] and 60-day survival rate [65.2% (15/23) vs. 66.7% (14/21)] between the study and control groups (all P > 0.05). CONCLUSIONS: Initial trophic EN feeding results in clinical outcomes similar to those of early standard-dose EN feeding in MV patients with ARF, but the former one has less incidence of high blood sugar and more satisfactory gastrointestinal tolerance situation. PMID- 29151418 TI - [VEGF165 transfected endothelial progenitor cells mediated by lentivirus alleviated ALI in rats]. AB - OBJECTIVE: To investigate the protective effects of vascular endothelial growth factor-165 (VEGF165) transfected the endothelial progenitor cells (EPCs) mediated by lentivirus on acute lung injury (ALI) in rats. METHODS: The mononuclear cells from the male Sprague-Dawley (SD) rats were isolated and cultured to get the EPCs for study. The lentivirus vector carrying the human VEGF165 gene was constructed. According to the random number table method, 90 male SD rats were divided into ALI model group, phosphate buffer solution (PBS) group, EPCs treatment group, none transfected EPCs treatment group and VEGF165 transfected EPCs treatment group, and the rats in each group were subdivided into 4, 12 and 48 hours subgroups, with 6 rats in each subgroup. The rat model of ALI was reproduced by intravenous injection of oleic acid (0.15 MUL/g). Then each treatment group was given PBS, EPCs, none transfected EPCs and VEGF165 transfected EPCs respectively with the same volume of 0.2 mL. For the groups with cells, about 1*106 cells were contained. Abdominal aortic blood and lung tissue were harvested at 4, 12 and 48 hours. Arterial blood gas analysis was performed. The lung wet/dry weight ratio (W/D) was calculated. The expressions of induced nitric oxide synthase (iNOS), endothelin-1 (ET-1) and VEGF165 were determined by enzyme-linked immunosorbent assay (ELISA). After dyed with hematoxylin-eosin (HE), the lung tissue pathology was observed and the lung injury score was performed. RESULTS: Compared with the ALI model group, the arterial partial pressure of oxygen (PaO2) in EPCs, none transfected EPCs and VEGF165 transfected EPCs treatment groups was significantly increased from 4 hours, and lung W/D, expressions of iNOS and ET-1 were significantly decreased, and VEGF165 expression was significantly increased. Compared with the EPCs treatment group, the increase in PaO2, the decrease in lung W/D and expressions of iNOS and ET-1, and the increase in VEGF165 expression in VEGF165 transfected EPCs treatment group were more significant [4 hours: PaO2 (mmHg, 1 mmHg = 0.133 kPa) was 82.84+/-10.69 vs. 72.34+/-9.36, lung W/D ratio was 4.83+/-0.23 vs. 5.55+/-0.37, iNOS (ng/mg) was 8.77+/-1.10 vs. 14.84+/-1.34, ET-1 (ng/mg) was 103.41+/-5.66 vs. 153.08+/-5.12, VEGF165 (ng/mg) was 130.56+/-12.16 vs. 83.03+/-5.95; 12 hours: PaO2 (mmHg) was 91.67+/-6.81 vs. 78.5+/-8.81, lung W/D ratio was 4.44+/-0.35 vs. 5.32+/-0.25, iNOS (ng/mg) was 7.23+/-0.24 vs. 14.04+/-1.18, ET-1 (ng/mg) was 91.98+/-3.52 vs. 125.99+/-7.55, VEGF165 (ng/mg) was 164.49+/-5.71 vs. 96.61+/-6.12]; individual parameters reached valley value or peak value at 48 hours [lung W/D ratio was 4.26+/-0.30 vs. 4.89+/-0.15, iNOS (ng/mg) was 5.79+/-0.85 vs. 12.72+/-1.10, ET-1 (ng/mg) was 74.53+/-7.10 vs. 108.33+/-5.84, VEGF165 (ng/mg) was 237.43+/-10.79 vs. 134.24+/-11.99, all P < 0.05]. Over time, lung tissue injury in each group was gradually increased, and the lung injury score was gradually increased. The lung injury score at 48 hours in the EPCs, none transfected EPCs and VEGF165 transfected EPCs treatment groups were lower than that in the ALI model group. Compared with the EPCs treatment group, the VEGF165 transfected EPCs treatment group had a lower score at 48 hours (8.50+/-1.05 vs. 10.50+/-1.05, P < 0.05). CONCLUSIONS: The transplantation of EPCs which were transfected with VEGF165 mediated by lentivirus could obviously improve the oxygen pressure, reduce the lung water seepage, decrease the iNOS and ET-1 expressions in lung tissue, and had obvious protective effects on ALI. PMID- 29151419 TI - [Preparation of paraoxonase liposomes and their pharmacokinetics in rats]. AB - OBJECTIVE: To prepare paraoxonase 1 (PON1) liposomes, and investigate pharmacokinetics of common PON1 liposomes (L-PON1) and polyethylene glycol modified PON1 long circulating liposomes (PEG-PON1-LCL) in rats after intravenous administration. METHODS: L-PON1 and PEG-PON1-LCL were prepared by film dispersion method. The entrapment efficiency, mean diameter and Zeta potential of the liposomes were measured, and the stability was evaluated. Thirty-six Wistar rats were divided into three groups according to random number table, with 12 rats in each group. The rats were intravenously administrated with PON1, L-PON1 or PEG PON1-LCL 700 U/kg, respectively. The activity of PON1 in serum was determined by phenyl acetate method, the activity of PON1 at different time points after drug administration was compared with that before drug administration, and the difference value was considered as the activity of exogenous PON1, and PON1 activity-time curve was plotted. The pharmacokinetic parameters were calculated and analyzed by DAS 2.0 pharmacokinetic program and SPSS 17.0. RESULTS: The entrapment efficiencies of L-PON1 and PEG-PON1-LCL were above 85%, the mean diameter was about 126 nm, and Zeta potential was -14.35 mV. After 2 weeks of preservation, the above parameters showed no obvious change, indicating that liposomes had good stability and the properties of preparations were basically stable. Compared with purified PON1 administration, after L-PON1 and PEG-PON1-LCL administration, the activity of PON1 was increased, the half-life of PON1 activity in rats was significantly prolonged [the half-life of distribution (T1/2alpha, hours): 0.142+/-0.018, 0.147+/-0.021 vs. 0.126+/-0.022; the half-life of clearance (T1/2beta, hours): 3.877+/-1.010, 4.520+/-1.117 vs. 1.226+/-0.422], the area under PON1 activity-time curve (AUC) was significantly increased [AUC from 0 hour to 24 hours (AUC0-24, U*h-1*L-1): 499.305+/-64.710, 563.576+/-70.450 vs. 18.053+/-2.190; AUC from the immediate injection to the disappearance of PON1 activity (AUC0-infinity, U*h-1*L-1): 516.256+/-60.940, 587.801+/-76.210 vs. 21.044+/-3.250], the apparent volume of distribution (Vd) and clearance (CL) were significantly decreased [Vd (L): 0.140+/-0.065, 0.144+/-0.064 vs. 0.493+/-0.032, CL (L/h): 0.039+/-0.008, 0.034+/-0.006 vs. 0.952+/-0.082, all P < 0.05]. There was no significant difference in pharmacokinetics between L-PON1 and PEG-PON1 LCL. CONCLUSIONS: The film dispersion method prepared PON1 liposomes have high entrapment efficiency and small particle size with a good stability. Both liposomes can raise PON1 activity in vivo, change the pharmacokinetics of PON1 in vivo, prolong the resident time of PON1 in the blood circulating system, and compensate for the short half-life of PON1 in vivo. PMID- 29151420 TI - [Clinical application of VSD negative pressure aspiration and detoxification in severe snake bite]. AB - OBJECTIVE: To assess the clinical efficacy of vacuum sealing drainage (VSD) in the treatment of mixed poisonous snake bite. METHODS: A prospective study was conducted. Forty-three snake bite patients by mixed poisonous snakes admitted to Department of Emergency of the 175th Hospital of People's Liberation Army from February 2015 to February 2017 were enrolled. All patients were divided into routine treatment group (n = 20) and VSD treatment group (n = 23) according to whether early incision decompression and using the VSD technique. The patients in the routine treatment group were treated with injection of antivenoms, Jidesheng snake tablets external coating, and wound incision detoxification. Beside the routine treatments, patients in the VSD treatment group were treated with incision decompression and the VSD suction aspiration for the swelling limb. Bite wound infection rate, local skin necrosis area, maximum level of C-reactive protein (CRP), length of hospital stay and disability rate were compared between the two groups. RESULTS: Forty-three patients were followed up for 6-12 months with average of (10.3+/-1.4) months postoperatively. There were no deaths in both groups. Compared with the routine treatment group, wound infection rate in the VSD treatment group was significantly lowered [8.7% (2/23) vs. 40.0% (8/20)], local skin necrosis area was significantly reduced (cm2: 4.2+/-0.8 vs. 6.0+/ 1.3), the maximum CRP was significantly lowered (mg/L: 50.0+/-12.1 vs. 68.0+/ 13.4), the hospitalization time was significantly shortened (days: 11.7+/-2.9 vs. 17.7+/-4.9), and the difference above was statistically significant (all P < 0.05). The disability rate of the VSD treatment group was lowered as compared with routine treatment group [13.0% (3/23) vs. 13.0% (6/20)] without statistically significant difference. CONCLUSIONS: Early incision decompression and VSD pressure suction of the swelling limb associated with combination therapy of drugs is a reliable and effective method for severe snakebite, and can promote physical rehabilitation and shorten hospital stay. PMID- 29151421 TI - [Disposable nursing applicator-pocket of indwelling central venous catheter]. AB - Catheter related infection is the most common complication of central venous catheter, which pathogen mainly originate from the pipe joint and the skin around puncture site. How to prevent catheter infection is an important issue in clinical nursing. The utility model disclosed a "disposable nursing applicator pocket of indwelling central venous catheter", which is mainly used for the fixation and the protection. The main structure consists of two parts, one is medical applicator to protect the skin around puncture site, and the other is gauze pocket to protect the catheter external connector. When in use, the catheter connector is fitted into the pocket, and then the applicator is applied to cover the puncture point of the skin. Integrated design of medical applicator and gauze pocket was designed to realize double functions of fixation and protection. The disposable nursing applicator-pocket is made of medical absorbent gauze (outer layer) and non-woven fabric (inner layer), which has the characteristics of comfortable, breathable, dust filtered, bacteria filtered, waterproof, antiperspirant and anti-pollution. The utility model has the advantages of simple structure, low cost, simple operation, effective protection, easy realization and popularization. PMID- 29151422 TI - [Successful perform of prolonged cardiopulmonary and cerebral resuscitation on repeated cardiac arrest: one case report]. AB - Cardiac arrest (CA) is the most serious clinical emergency situation and cardiopulmonary-cerebral resuscitation (CPCR) performed on site with high quality is the optional therapy for its management. It has been reported that prolonging the resuscitation time after 30-minute failed conventional cardiopulmonary resuscitation (CPR) could improve the in-hospital survival rate of CA patients, and how to improve the out-hospital survival rate and survival quality of these patients is a research hot focus at present. A male patient admitted to Emergency Center of Shihezi People's Hospital reported in Xinjiang in this study had two CAs. In 2002, he experienced Adams-Strokes syndrome due to acute myocardial infarction (AMI) and survived after 35-minute of successful CPR. The criminal vessel was judged to re-canalize clinically 2 hours after thrombolytic therapy with urokinase, and he was cured and discharged from hospital 25 days later. In 2016, the second CA insult him and after the 185-minute CPR, he survived but experienced the post-CA syndrome. As long as 7-day continuous mild hypothermia was performed, the temperature of displacement fluids in continuous blood purification (CBP) was adjusted to 35 centigrade to achieve the goal of brain protection management requirements. He was cured and discharged from hospital 75 days later. During the 9-month follow-up, he did well in activities of daily living and could engage in routine housework. This paper introduces the treatment process of the patient in detail, and provides experience for clinical treatment. PMID- 29151423 TI - [Guiding significance of diaphragm function evaluation in ventilation weaning]. AB - Diaphragm dysfunction is common in clinical work, which is a frequently important cause of ventilation weaning failure ignored by clinicians. Assessing diaphragmatic function while weaning helps early detection and prevention of weaning failure, so as to improve the clinical outcome of patients on mechanical ventilation (MV). Reviewing studies of diaphragmatic function evaluation in weaning, we can find that assessing diaphragmatic function during weaning can help guide weaning. Weaning predictors including pressure index, electrophysiological index and morphological index, among which bedside ultrasound as a morphological index is widely used in intensive care unit (ICU), which is simple, non-invasive, and easy to operate. It is also accurate in the assessment of diaphragmatic function and guidance on weaning, which is worthy of promotion and application. PMID- 29151424 TI - [Research progress of mesenchymal stem cells in the treatment of ALI]. AB - Acute lung injury (ALI) is one of the most common clinical critical illnesses. Its severe stage is acute respiratory distress syndrome (ARDS), characterized by rapid onset and high mortality. There is no effective treatment. Based on many preclinical studies, mesenchymal stem cells (MSCs) have great potential as a therapeutic strategy for ALI, clinical trials are underway, and studies on the therapeutic effects of MSCs progressively deep into the molecular mechanism and continue to make new progress. However, the use of MSCs, their specific methods and risks, especially on the risk of iatrogenic tumor formation remains unresolved. In this paper, we reviewed the main problems in the application of MSCs in the treatment of ALI and the main problems in the application of MSCs in order to explore the feasibility and future direction of MSCs in the treatment of ALI. PMID- 29151425 TI - [Paraquat poisoning mechanism and its clinical treatment progress]. AB - Paraquat (PQ) as a kind of sterile and herbicides, has effects of contact-kill and systemic action, which can be absorbed quickly by green plants and make them wither and die. Therefore, it is widely used in the agricultural production and occupies a large part in our country's pesticide market. PQ poisoning has become one of the most common pesticide poisoning in our country. PQ can be passivated when combining with soil, but it has great toxicity for human. There are still no specific antidotes for PQ poisoning at home and abroad, and the death rate of PQ oral poisoning is up to 95%. Clinically comprehensive treatment is adopted, including gastric lavage, intentional diarrhea, diuresis and blood perfusion. However, the therapeutic effect is not good and the case fatality rate keeps high. It has become one of the hot issues for emergency medicine study to search PQ's special efficiency measures. This paper briefly reviews PQ's poisoning mechanism and its clinical treatment progress to provide new exploration direction and treatment ideas for basic research and clinical treatment of PQ. PMID- 29151426 TI - [Effects of antibiotics on intestinal microflora and intestinal mucosal barrier function and its mechanisms]. AB - Antibiotics are the cornerstone to cure infectious diseases, however, it also destroys the intestinal inherent microflora, and may cause serious gastrointestinal dysfunction, such as abdominal distension, diarrhea, mucosal barrier damage etc. In severe conditions, it may induce intestinal sepsis. With the development of the human microbiology group program and the popularity of microbial sequencing technology, people can comprehend the effects of antibiotics on intestinal flora deeply, meanwhile the traditional biomedical model (the basis of bacterial disease) is questioned. It presents the effects and mechanisms of antibiotics on intestinal microflora and intestinal mucosal barrier function in detail and demonstrates the feasibility by the treatment of probiotics and fecal transplantation to construct "health-promoting microbes" to adjust gastrointestinal function, in addition, it can promote the rational use of antibiotics. PMID- 29151427 TI - [Precision nutrition for intensive care patients]. AB - Nutritional treatment of intensive care patients may require an accurate, effective and personalized approach in the future. Using nutritional risk assessment to guide nutritional treatment, factors including timing, energy expenditure and goal, pathway and dosage should be considered. Through testing the individual nutritional molecular markers, the benefits and risks can be evaluated. So nutritional therapy can enhance the nutritional and metabolic status of intensive care patients, and improve clinical outcomes. PMID- 29151429 TI - PAP and Cardiovascular Events in Adults With Sleep Apnea: Is PAP Useful? PMID- 29151430 TI - Clinical Prediction Rules, Adenotonsillectomy and Children With Obstructive Sleep Apnea: What's Next? PMID- 29151428 TI - Continuous Positive Airway Pressure in Patients With Obstructive Sleep Apnea and Non-Alcoholic Steatohepatitis: A Systematic Review and Meta-Analysis. AB - STUDY OBJECTIVES: Several studies have reported an association between obstructive sleep apnea (OSA) and several extra-pulmonary issues, such as arterial hypertension and insulin resistance. In recent years, the associations between OSA, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis (NASH) have been published; however, there is a gap between experimental and clinical studies regarding the efficacy of continuous positive airway pressure (CPAP) treatment in patient populations with these conditions. This issue should be considered when deciding on CPAP treatment in patients with OSA, especially in patients with moderate OSA. METHODS: We performed a systematic review and meta analysis of randomized controlled trials (RCTs) using the following databases: MEDLINE, Lilacs, and CENTRAL. Two independent reviewers performed the search, analysis, data extraction, and critical analysis. RESULTS: From 622 identified studies, we included 5 RCTs that involved patients with OSA and NASH and who were treated with a CPAP device. After CPAP treatment, no changes in liver steatosis, liver fibrosis, and aminotransferase levels (alanine aminotransferase and aspartate aminotransferase) were found. Finally, the quality of evidence using the GRADE approach was low and very low for several outcomes. CONCLUSIONS: According to the current analysis, no data regarding the efficacy of CPAP in patients with NASH are available to make recommendations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO; ID: CRD42015027981; URL: https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42015027981. PMID- 29151431 TI - Characterizing Sleepiness: Are We Drawing the Right Line in the Sand? PMID- 29151432 TI - Implementing a 6-day physiotherapy service in rehabilitation: exploring staff perceptions. AB - Objective Australian weekend rehabilitation therapy provision is increasing. Staff engagement optimises service delivery. The present mixed-methods process evaluation explored staff perceptions regarding implementation of a 6-day physiotherapy service in a private rehabilitation unit.Methods All multidisciplinary staff working in the rehabilitation unit were surveyed regarding barriers, facilitators and perceptions of the effect of a 6-day physiotherapy service on length of stay (LOS) and patient goal attainment at three time points: before and after implementation, as well as after modification of a 6-day physiotherapy service. Descriptive statistics and thematic analysis was used to analyse the data.Results Fifty-one staff (50%) responded. Before implementation, all staff identified barriers, the most common being staffing (62%) and patient selection (29%). After implementation, only 30% of staff identified barriers, which differed to those identified before implementation, and included staff rostering and experience (20%), timing of therapy (10%) and increasing the allocation of patients (5%). Over time, staff perceptions changed from being unsure to being positive about the effect of the 6-day service on LOS and patient goal attainment.Conclusion Staff perceived a large number of barriers before implementation of a 6-day rehabilitation service, but these did not eventuate following implementation. Staff perceived improved LOS and patient goal attainment after implementation of a 6-day rehabilitation service incorporating staff feedback.What is known about this topic? Rehabilitation weekend services improve patient quality of life and functional independence while reducing LOS.What does this study add? Staff feedback during implementation and modification of new services is important to address potential barriers and ensure staff satisfaction and support.What are the implications for practitioners? Staff engagement and open communication are important to successfully implement a new service in rehabilitation. PMID- 29151433 TI - Role of strategic human resource management in crisis management in Australian greenfield hospital sites: a crisis management theory perspective. AB - Objective This study examined strategic human resource management (SHRM) activities in two case hospitals relative to their approach to greenfield site success.Methods A comparative case study analysis approach was used, with documents sourced from public, open-access sites. The theoretical framework of crisis management theory's (CMT) proactive management and open communication channels was used to examine the documents, which were annual reports addressing both hospitals' first year of performance, union publications and transcripts of relevant parliamentary inquiries.Results The hospital that effectively used CMT in its first 12 months was demonstratively more 'successful' than the hospital that reported to not have effectively used CMT. 'Success' in this project was articulated as the hospital's ability to consolidate operations, without ongoing negative media attention, after 12 months.Conclusion This study provided an identification of how the use of CMT in a hospital's greenfield stage can increase the hospital's chances of 'success'.What is known about the topic? Journal and media articles illustrated a gap in greenfield human resource management (HRM) regarding successful consolidation, especially the healthcare context. Although manufacturing firms are addressed in academic literature in a greenfield context, there is a lack of knowledge concerning successful greenfield HRM in a healthcare context.What does this paper add? This study is among the first to identify the role of CMT in successful greenfield site establishment by identifying its presence in management activities.What are the implications for practitioners? The findings of this study suggest a potential link between the implementation of CMT and greenfield site success. This could allow future greenfield healthcare sites to operate with less cost and risk. The lack of stakeholder participation in the present study limits the applicability of its findings. However, archival document analysis provides a strong foundation for future studies. PMID- 29151434 TI - Dual antiplatelet therapy after acute coronary syndromes: no time for a CHANGE. PMID- 29151435 TI - Transcatheter or surgical valve replacement: which strategy when bioprosthetic valves fail? PMID- 29151436 TI - PCR London Valves Innovators Day 2017. Where will valve intervention be in 2025? PMID- 29151437 TI - Contemporary considerations in left main stem treatment. PMID- 29151439 TI - Clopidogrel or ticagrelor in acute coronary syndrome patients treated with newer generation drug-eluting stents: CHANGE DAPT. AB - AIMS: Acute coronary syndrome (ACS) guidelines have been changed, favouring more potent antiplatelet drugs. We aimed to evaluate the safety and efficacy of a ticagrelor- instead of a clopidogrel-based primary dual antiplatelet (DAPT) regimen in ACS patients treated with newer-generation drug-eluting stents (DES). METHODS AND RESULTS: CHANGE DAPT (clinicaltrials.gov: NCT03197298) assessed 2,062 consecutive real-world ACS patients, treated by percutaneous coronary intervention (PCI), the primary composite endpoint being net adverse clinical and cerebral events (NACCE: all-cause death, any myocardial infarction, stroke or major bleeding). In the clopidogrel (CP; December 2012-April 2014) and ticagrelor periods (TP; May 2014-August 2015), 1,009 and 1,053 patients were treated, respectively. TP patients were somewhat older, underwent fewer transfemoral procedures, and received fewer glycoprotein IIb/IIIa inhibitors. In the TP, the one-year NACCE rate was higher (5.1% vs. 7.8%; HR 1.53 [95% CI: 1.08-2.17]; p=0.02). Assessment of non-inferiority (pre-specified margin: 2.7%) was inconclusive (risk difference: 2.64 [95% CI: 0.52-4.77]; pnon-inferiority=0.48). TP patients had more major bleeding (1.2% vs. 2.7%; p=0.02) while there was no benefit in ischaemic endpoints. Propensity score-adjusted multivariate analysis confirmed higher NACCE (adj. HR 1.75 [95% CI: 1.20-2.55]; p=0.003) and major bleeding risks during TP (adj. HR 2.75 [95% CI: 1.34-5.61]; p=0.01). CONCLUSIONS: In this observational study, the guideline-recommended ticagrelor-based primary DAPT regimen was associated with an increased event risk in consecutive ACS patients treated with newer-generation DES. PMID- 29151440 TI - How should I treat this mini-crush stenting complication? PMID- 29151441 TI - Patients' initial steps to cancer diagnosis in Denmark, England and Sweden: what can a qualitative, cross-country comparison of narrative interviews tell us about potentially modifiable factors? AB - OBJECTIVES: To illuminate patterns observed in International Cancer Benchmarking Programme studies by extending understanding of the various influences on presentation and referral with cancer symptoms. DESIGN: Cross-country comparison of Denmark, England and Sweden with qualitative analysis of in-depth interview accounts of the prediagnostic process in lung or bowel cancer. PARTICIPANTS: 155 women and men, aged between 35 and 86 years old, diagnosed with lung or bowel cancer in 6 months before interview. SETTING: Participants recruited through primary and secondary care, social media and word of mouth. Interviews collected by social scientists or nurse researchers during 2015, mainly in participants' homes. RESULTS: Participants reported difficulties in interpreting diffuse bodily sensations and symptoms and deciding when to consult. There were examples of swift referrals by primary care professionals in all three countries. In all countries, participants described difficulty deciding if and when to consult, highlighting concerns about access to general practitioner appointments and overstretched primary care services, although this appears less prominent in the Swedish data. It was not unusual for there to be more than one consultation before referral and we noted two distinct patterns of repeated consultation: (1) situations where the participant left the primary care consultation with a plan of action about what should happen next; (2) participants were unclear about under which conditions to return to the doctors. This second pattern sometimes extended over many weeks during which patients described uncertainty, and sometimes frustration, about if and when they should return and whether there were any other feasible investigations. The latter pattern appeared more evident in the interviews in England and Denmark than Sweden. CONCLUSION: We suggest that if clear action plans, as part of safety netting, were routinely used in primary care consultations then uncertainty, false reassurance and the inefficiency and distress of multiple consultations could be reduced. PMID- 29151442 TI - Effects of short-lasting supramaximal-intensity exercise on diet-induced increase in oxygen uptake. AB - This study was undertaken to quantify the additional increase in diet-induced oxygen uptake after exhaustive high-intensity intermittent exercise (HIIE), consisting of 6-7 bouts of 20-sec bicycle exercise (intensity: 170% VO2max) with a 10-sec rest between bouts. Using a metabolic chamber, the oxygen uptake of ten men was measured from 10:30 am to 07:00 am the next day on two separate days with or without HIIE, with lunch (12:00) and supper (18:00) (Diet experiment). On two other days, the oxygen uptake of six different subjects was measured from 10:30 to 16:00 with or without HIIE, but without meals (Fasting experiment). Ten minutes of exercise at 50% VO2maxpreceded the HIIE in both experiments; EPOC (excess postexercise oxygen consumption) after HIIE was found to wear off before 12:00 in both experiments. In the Diet experiment, oxygen uptake during HIIE and EPOC were 123.4 +/- 12.0 and 115.3 +/- 32.3 mL.kg-1, respectively. Meals elevated resting oxygen uptake on both days, but those on the HIIE day were significantly higher than on the control day. This enhanced diet-induced oxygen uptake (difference in resting oxygen uptake from 12:00-23:00 between HIIE and control day: DeltaDIT) was 146.1 +/- 90.9 mL.kg-1, comparable to the oxygen uptake during the HIIE and EPOC The DeltaDIT was correlated with subjects' VO2max(52.1 +/- 6.6 mL.kg-1.min-1) (r = 0.76, n = 10, P < 0.05). We concluded that HIIE enhances diet induced oxygen uptake significantly, and that it is related to the cardiorespiratory fitness. PMID- 29151443 TI - Fasciola hepatica infection in water buffalo Bubalus bubalis in three provinces of the Nile Delta, Egypt: a cross-sectional study. AB - A cross-sectional study was conducted to estimate the prevalence of Fasciola hepatica (F. hepatica) infection in water buffalo (Bubalus bubalis) in Alexandria, Beheira, and Kafr el-Sheikh governorates (provinces) of the Nile Delta in Egypt and to identify the underlying risk factors associated with the infection. A total of 29 farms (10 in Alexandria, 10 in Beheira, and 9 in Kafr el Sheikh) were randomly selected and all the buffaloes that resided on these farms from 21 February 2015 to 20 February 2016 were included in the study. The sampling approach was target-based where all the buffaloes were examined and screened for clinical signs of Fasciola infection. All suspected buffaloes were then subjected to fecal examination, and those positive for Fasciola eggs underwent antibody testing using indirect hemagglutination test. Consequently, data on 3,356 buffaloes from 29 farms in these governorates was analyzed using a multiple logistic regression model. The final model showed that the age and body condition score of the buffalo, location and type of the farm, application of prophylactic treatment, and temperature and relative humidity of the farm's location significantly affected the rate of infection. The highest prevalence was observed in buffaloes from Alexandria governorate (19.6%), followed by Beheira and Kafr el-Sheikh governorates (15.5 and 9.1%, respectively). PMID- 29151444 TI - Effect of morphological changes in feather follicles of chicken carcasses after defeathering and chilling on the degree of skin contamination by Campylobacter species. AB - Campylobacter jejuni and C. coli are the leading causes of enteric infections in many developed countries. Healthy chickens are considered to act as reservoirs of campylobacters, as the organisms colonize the intestinal tract. Once infected birds enter a processing plant, contamination of chicken carcasses with campylobacters occurs over the entire skin during defeathering and evisceration due to leakage of crop and/or intestinal contents. Although the role of feather follicles in the contamination of chicken carcasses by campylobacters during processing is still debatable, it has been considered that the microorganisms would be entrapped and retained in the follicles due to the morphological changes resulting from defeathering and chilling. In the present study, we observed the morphology of feather follicles in chicken carcasses after defeathering and chilling. A total of 3,133 feather follicles were examined for morphological changes before and after chilling. Shortly after defeathering, most (91.5%) of the follicles were closed, whereas after chilling they were either closed (85.5%) or open (6%), although a small proportion of enlarged follicles became smaller or closed (2.6%). Moreover, 5.9% of the follicles that were slightly open became further enlarged after chilling. Furthermore, the proportion of enlarged feather follicles that became closed after chilling showed no discernible relationship with the degree of campylobacter contamination in different areas of the carcass skin, suggesting that campylobacters may not be confined to feather follicles as a result of the morphological changes attributable to defeathering and chilling. PMID- 29151446 TI - Nitrogen Fixation Mutants of the Actinobacterium Frankia Casuarinae CcI3. AB - Frankia is a representative genus of nitrogen-fixing (N2-fixing) actinobacteria; however, the molecular mechanisms underlying various phenomena such as the differentiation of a N2 fixation-specific structure (vesicle) and the regulation of N2 fixation (nif) genes, have yet to be elucidated in detail. In the present study, we screened hyphal fragments of Frankia casuarinae that were mutagenized by 1-methyl-3-nitro-1-nitrosoguanidine or gamma rays, and isolated 49 candidate N2 fixation mutants. Twelve of these mutants were selected for further study, and their abilities to grow in NH3-deficient (N-) liquid media and their rates of acetylene reduction activities were evaluated. Eleven mutant strains were confirmed to lack the ability to fix N2. Five mutant strains formed significantly reduced numbers of vesicles, while some failed to form large mature vesicles. These vesicle mutants also exhibited an aberrant hyphal morphology, suggesting a relationship between vesicle differentiation and hyphal branching. Ten mutants showed significant reductions in the expression of nifE, nifH, and nifV genes under N- conditions. The genome sequencing of eight mutants identified 20 to 400 mutations. Although mutant strains N3H4 and N6F4 shared a large number of mutations (108), most were unique to each strain. Mutant strain N7C9 had 3 mutations in the nifD and nifH genes that may result in the inability to fix N2. The other mutant strains did not have any mutations in any known N2 fixation related genes, indicating that they are novel N2 fixation mutants. PMID- 29151445 TI - Serum activities of two bone markers in captive Asian elephants (Elephas maximus) at different ages. AB - The blood biochemical analysis of bone markers could have a role in the early diagnosis of metabolic bone disease in animals; however, there is limited information on bone markers in captive Asian elephants (Elephas maximus). Serum samples from ten captive Asian elephants were obtained to clarify the relationship between age and the blood bone markers tartrate-resistant acid phosphatase isoform 5b (TRAP5b) and bone specific alkaline phosphatase (BALP). Serum TRAP5b and BALP activities were negatively correlated with age. A positive correlation was observed between TRAP5b activity and BALP activity. These results may contribute to the health management of captive Asian elephants. PMID- 29151447 TI - Ergonomic considerations for designing truck drivers' seats: The case of Bangladesh. AB - OBJECTIVES: The purpose of this work was to investigate the fitness of the existing truck seats for Bangladeshi truck drivers and suggest a guideline for drivers' seats based on their anthropometry. METHODOLOGY: In this study, eight anthropometric measurements of 120 Bangladeshi truck drivers and seven seat dimensions of ninety trucks of three brands namely, TATA, ASHOK LEYLAND, and ISUZU were considered for investigating the considerable mismatch between seat dimensions and drivers' anthropometry. The data were analyzed using two-sample t tests to identify the relationship between existing seat dimensions and drivers' anthropometry. RESULTS: The results showed a mismatch in seat dimensions and anthropometric measurements for nearly all truck brands and the existing seat dimensions were found to be inappropriate for Bangladeshi drivers. For all the truck brands, the percentage mismatch of seat height, seat depth, seat width, backrest height, and steering wheel clearance varied between 71% and 98%, 23% and 79%, 33% and 84%, 28% and 65%, and 53% and 100% respectively. Subsequently, an attempt was made to provide ergonomically correct seat dimensions for Bangladeshi truck drivers. Further, generalized equations to design the appropriate seat dimensions were developed using the least square regression technique. The recommended seat height, depth and width, backrest height, and steering wheel clearance were found to be appropriate for 82%, 79%, 76%, 98%, and 100% of drivers respectively. CONCLUSION: The analysis and results of this study can be useful in developing guidelines for design and manufacture of truck driver seats in Bangladesh. PMID- 29151448 TI - Underreporting trends of occupational illnesses in Mexico. AB - OBJECTIVE: To report trends underreporting levels of occupational illnesses (OI) in Mexico from 2000 to 2015. METHODS: An ecological study was conducted. Data on OI was obtained from the Statistical Memories of the Mexican Institute of Social Security. We used univariate sensitivity analysis to estimate the average value and range. RESULTS: During the 2000-2015 period, the estimated average OI underreporting in the Mexican population was 89.1%; the minimum was 81.8% in 2015 and the maximum 95% in 2007, with an annual decrement rate of 1% (p<0.05) was observed from 2007 to 2015. CONCLUSIONS: Important changes to improve reporting of OI have taken place since 2007, most likely due to the implementation of new policies in this matter. Even though the OI report in Mexico is higher than what the World Health Organization estimates for Latin America (18% in 2015), activities to address this problem remain insufficient. Furthermore, it is important to evaluate the current process of identification and registration of OI in order to identify those that need reinforcement, to guarantee adherence to regulations, to consolidate training systems, and importantly, to develop the governing capacity of the sanitation and labor authorities to exercise their coordinating and regulatory functions. PMID- 29151450 TI - Identification and expression analysis of cDNA encoding insulin-like growth factor 2 in horses. AB - Insulin-like growth factor 2 (IGF2) is responsible for a broad range of physiological processes during fetal development and adulthood, but genomic analyses of IGF2 containing the 5'- and 3'-untranslated regions (UTRs) in equines have been limited. In this study, we characterized the IGF2 mRNA containing the UTRs, and determined its expression pattern in the fetal tissues of horses. The complete equine IGF2 mRNA sequence harboring another exon approximately 2.8 kb upstream from the canonical transcription start site was identified as a new transcript variant. As this upstream exon did not contain the start codon, the amino acid sequence was identical to the canonical variant. Analysis of the deduced amino acid sequence revealed that the protein possessed two major domains, IlGF and IGF2_C, and analysis of IGF2 sequence polymorphism in fetal tissues of Hokkaido native horse and Thoroughbreds revealed a single nucleotide polymorphism (T to C transition) at position 398 in Thoroughbreds, which caused an amino acid substitution at position 133 in the IGF2 sequence. Furthermore, the expression pattern of the IGF2 mRNA in the fetal tissues of horses was determined for the first time, and was found to be consistent with those of other species. Taken together, these results suggested that the transcriptional and translational products of the IGF2 gene have conserved functions in the fetal development of mammals, including horses. PMID- 29151451 TI - Fracture risk assessment tool (FRAX) and for the diagnosis of osteoporosis in Japanese middle-aged and elderly women: Chiba bone survey. AB - Osteoporosis not only increases bone fracture risk but also affects survival in postmenopausal women. Although osteoporosis is diagnosed based on low bone mineral density (BMD) determined by dual energy X-ray absorptiometry (DXA), BMD measurement is sometimes difficult because DXA is not widely available in the community. The Fracture Risk Assessment tool (FRAX) can predict 10-year major osteoporotic fracture risk and hip fracture risk with or without femoral neck BMD. The FRAX has not been investigated adequately in community-dwelling Japanese women. We administered the FRAX tool in 13,421 Japanese women who underwent DXA based forearm BMD measurement in Chiba Bone Survey, a population-based, multicenter, cross-sectional study of postmenopausal osteoporosis conducted in Chiba, Japan. Mean age was 57.77 +/- 9.24 years. Mean forearm BMD was 87.94 +/- 17.00% of young adult mean (YAM). Mean FRAX major osteoporotic fracture risk without femoral neck BMD was 7.06 +/- 5.22%. BMD decreased and percentage of osteoporosis increased from age 55 onward. Age distribution of percentage of subjects with FRAX major osteoporotic fracture risk >15% was similar to that of percentage of osteoporosis subjects. We identified the cutoff value of FRAX major osteoporotic fracture risk for diagnosis of osteoporosis as 7.2%. With this cutoff, the positive likelihood ratio was over 1.0 at age 55 and above but accuracy was low. In conclusion, FRAX without femoral neck BMD reflects bone status, and may be useful to diagnose osteoporosis in Japanese women aged 55 and above, although the sensitivity was low for osteoporosis screening, especially in middle-aged women. PMID- 29151449 TI - Prevalence and associated factors of foot and ankle pain among nurses at a university hospital in Japan: A cross-sectional study. AB - OBJECTIVES: The purposes of this study were to clarify 1) the prevalence of foot and ankle pain and 2) the factors associated with foot and ankle pain among nurses. METHODS: Nurses working at a university hospital in Japan were recruited to participate in this cross-sectional, questionnaire-based study. The occurrence of foot and ankle pain in the previous month was assessed by using the Standardized Nordic Questionnaire and the Manchester Foot Pain and Disability Index. Subjects also answered questions on footwear-related factors, including using the visual analog scale for shoe comfort. In addition, information on personal factors and psychosocial factors was collected using the Job Content Questionnaire. The relationships between the presence of foot and ankle pain and the associated factors were examined using multiple logistic regression analysis. RESULTS: Responses of 636 nurses (response rate, 67%) were included for analysis. The prevalence of foot and ankle pain was 23% and 51% when using the Standardized Nordic Questionnaire and the Manchester Foot Pain and Disability Index, respectively. The prevalence of pain that prevented the nurses from performing activities of daily living and work was 4% and 17%, respectively. A low level of shoe comfort, personal factors (age and body mass index), and psychosocial factors (low job control and high job strain) was independently associated with the presence of foot and ankle pain. CONCLUSIONS: Foot and ankle pain occurred frequently in nurses. Shoe comfort, personal factors, and psychosocial factors were associated with foot and ankle pain. PMID- 29151452 TI - Development of a new diet-induced obesity (DIO) model using Wistar lean rats. AB - Obesity is an increasingly severe socioeconomic health issue worldwide. Rodents with diet-induced obesity (DIO) are widely used as models of obesity. The main aim of this study was to establish a DIO model using Wistar lean (+/+ or +/-) rats by feeding a high-fat diet (45 kcal% fat) to dams during the latter term of gestation and the lactation period. A second aim was to examine the effect of post-weaning nutrition independently of maternal nutrition. Some pups (group D) were fed the same high-fat diet after weaning, while others (group C) were fed a chow diet after weaning. In the control groups, the dams were fed only the chow diet and the pups were fed either the chow diet (group A) or high-fat diet (group B) after weaning. Between 16-21 weeks of age, group D showed the heaviest body weight and visceral adipose tissue weight among groups, in addition to glucose intolerance and high concentrations of glucose and cholesterol in plasma. Group B showed mild obesity with dysfunctions in glucose and lipid metabolism. Interestingly, group C showed mild obesity and impaired glucose tolerance, similar to the phenotype of group B. In summary, the high-fat diet challenge of dams during gestation and lactation caused an increase in adipose tissue weight and abnormalities of glucose and lipid metabolism in their adult offspring. Our results suggest the importance of both maternal and post-weaning nutrition for DIO production and provide useful DIO models. PMID- 29151453 TI - Diastolic Dysfunction Is a Risk of Perioperative Myocardial Injury Assessed by High-Sensitivity Cardiac Troponin T in Elderly Patients Undergoing Non-Cardiac Surgery. AB - BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) is useful for detecting myocardial injury and is expected to become a prognostic marker in patients undergoing non-cardiac surgery. The aim of this pilot study evaluating the efficacy of beta-blocker therapy in a perioperative setting (MAMACARI study) was to assess perioperative myocardial injury (PMI) in elderly patients with preserved ejection fraction (EF) undergoing non-cardiac surgery.Methods and Results:In this prospective observational cohort study of 151 consecutive patients with preserved EF and aged >60 years who underwent non-cardiac surgery, serum levels of hs-cTnT were measured before and on postoperative days 1 and 3 after surgery. PMI was defined as postoperative hs-cTnT >0.014 ng/mL and relative hs-cTnT change >=20%. A total of 36 (23.8%) of the patients were diagnosed as having PMI. The incidence of a composite of cardiovascular events within 30 days after surgery, including myocardial infarction, stroke, worsening heart failure, atrial fibrillation and pulmonary embolism, was significantly higher in patients with PMI than in patients without PMI (odds ratio (OR) 9.25, P<0.001, 95% confidence interval (CI) 2.65-32.3). Multivariate analysis revealed that left ventricular diastolic dysfunction defined by echocardiography was independently associated with PMI (OR: 3.029, 95% CI: 1.341-6.84, P=0.008). CONCLUSIONS: PMI is frequently observed in elderly patients undergoing non-cardiac surgery. Diastolic dysfunction is an independent predictor of PMI. PMID- 29151454 TI - Changes in Serum Fibroblast Growth Factor 23 in Patients With Acute Myocardial Infarction. AB - BACKGROUND: Fibroblast growth factor 23 (FGF23) induces cardiac remodeling. We investigated the changes in serum FGF23 levels in patients diagnosed with acute myocardial infarction (AMI).Methods and Results:A total of 44 patients diagnosed with AMI were included in the current study. All patients underwent emergency percutaneous coronary intervention (PCI). The median of peak creatine kinase (CK) and CKMB values was 1,816 U/L and 159 U/L, respectively. Serum levels of FGF23, calcium, and inorganic phosphate (iP) were measured before PCI, and on days 1, 3, 5, 7 after PCI. Serum FGF23 levels showed a slight, but significant decrease on days 1 and 3 after PCI, and a 1.5- and 2.0-fold increase on days 5 and 7, respectively, after PCI. As compared with propensity score-matched patients without AMI, serum FGF23 was significantly lower among the current cohort of AMI patients. In 22 subjects who underwent a follow-up echocardiographic examination at 6 months after the onset of AMI, the log-transformed relative increase in FGF23 on day 7 significantly and negatively correlated with changes between LVEF on admission and that at 6 months afterward. CONCLUSIONS: After a slight decrease on days 1 and 3 after admission, serum FGF23 increased significantly on days 5 and 7. The underlying mechanism and potential clinical importance of these observations require further investigation. PMID- 29151455 TI - piggyBac- and phiC31 integrase-mediated transgenesis in Drosophila prolongata. AB - The development of transgenesis systems in non-model organisms provides a powerful tool for molecular analysis and contributes to the understanding of phenomena that are not observed in model organisms. Drosophila prolongata is a fruit fly that has unique morphology and behavior not found in other Drosophila species including D. melanogaster. In this study, we developed a phiC31 integrase mediated transgenesis system for D. prolongata. First, using piggyBac-mediated transgenesis, 37 homozygous attP strains were established. These strains were further transformed with the nosP-Cas9 vector, which was originally designed for phiC31-mediated transgenesis in D. melanogaster. The transformation rate varied from 0% to 3.4%. Nine strains with a high transformation rate of above 2.0% were established, which will serve as host strains in future transformation experiments in D. prolongata. Our results demonstrate that genetic tools developed for D. melanogaster are applicable to D. prolongata with minimal modifications. PMID- 29151456 TI - Characterization of specimens obtained by different sampling methods for evaluation of periodontal bacteria. AB - Quantitative analysis of periodontal bacteria is considered useful for clinical diagnosis, evaluation and assessment of the risk of periodontal disease. The purpose of this study was to compare the effectiveness of sampling of saliva, supragingival and subgingival plaque for evaluation of periodontal bacteria. From each of 12 subjects, i) subgingival plaque was collected from the deepest pocket using a sterile paper point, ii) stimulated whole saliva was collected after chewing gum, and iii) supragingival plaque was collected using a tooth brush. These samples were sent to the medical examination laboratory for quantitative analysis of the counts of three periodontal bacterial species: Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. The proportions of these bacteria in subgingival plaque were higher than those in saliva or supragingival plaque, but lower in subgingival plaque than in saliva or supragingival plaque. In several cases, periodontal bacteria were below the levels of detection in subgingival plaque. We concluded that samples taken from subgingival plaque may be more useful for evaluating the proportion of periodontal bacteria in deep pockets than is the case for other samples. Therefore, for evaluation of periodontal bacteria, clinicians should consider the characteristics of the specimens obtained using different sampling methods. PMID- 29151457 TI - Anatomical profile of the mesial root of the Burmese mandibular first molar with Vertucci's type IV canal configuration. AB - This study evaluated the anatomical profile of the mesial root canals of the Burmese mandibular first molar with Vertucci's type IV canal configuration (VT4) using microcomputed tomography analysis. Seventy-five mesial roots of extracted mandibular first molars were scanned and evaluated. Fourteen middle mesial canals (MMCs) were observed in the specimens; each specimen had an average of 1.63 lateral canals and 3.77 apical foramina. The lateral canals arising from the mesiobuccal canal, mesiolingual canal, MMC, and isthmus terminated at an average distance of 0.92, 0.73, 2.11, and 1.89 mm, respectively, from the apex. The mean distance between the centers of the mesiobuccal and mesiolingual canals at 1.5 mm coronal to the furcation was 2.60 mm. A higher incidence of isthmus was observed in the apical 2-6-mm region compared with the apical 0-2-mm region (P < 0.05). The incidence of lateral canals in the isthmus was similar to that of the mesiobuccal and mesiolingual canals (P > 0.05). This study shows that the mesial root of the Burmese mandibular first molar with VT4 has complex anatomical profiles comprising MMCs and isthmus and their lateral canals. PMID- 29151458 TI - Comparison of efficacy and outcome satisfaction between in-office and home teeth bleaching in Chinese patients. AB - This in vivo study aimed to evaluate the efficacy of in-office and home teeth bleaching in Asian patients. Moreover, the correlation between tooth color change and patient's outcome satisfaction was investigated. Overall, 40 Chinese patients were randomly divided into two groups and prescribed in-office (OB) or take-home bleaching (HB). The color of the maxillary central incisor and canine were recorded at baseline, immediately after first treatment, 1 week, and 3 months after treatment by using a spectrophotometer. Bleaching sensitivity and outcome satisfaction were assessed using Likert and visual analogue scale (VAS), and the results were analyzed using independent t-test and Pearson correlation (P < 0.05). DeltaL*, Deltaa*, Deltab*, and DeltaE* values of HB were greater than those of OB. Color changes observed in canines were generally greater than those in incisors. Moreover, HB was generally associated with less tooth sensitivity than OB. Patients were satisfied with both treatments, but VAS scores were greater for HB. Furthermore, the correlation between DeltaE* and VAS was significant for canines immediately after the first treatment and 1 week after HB. In conclusion, HB was more effective in lightening teeth and reducing chromacity in Chinese patients. The correlation between tooth color change and outcome satisfaction was generally insignificant and weak. PMID- 29151460 TI - [Evaluation of Absorbed Dose by MRI Read-Out]. AB - Three dimensional dose distribution by gel dosimeters is often read out by an MRI scanner, which is readily available in most hospitals. Both the T1 and T2 relaxation rates are used to evaluate the absorbed dose. This paper will describe the principle of the imaging sequences (spin echo, multiple spin echo, and inversion recovery methods) to measure the relaxation rate and the factors to affect the precision (signal noise ratio, temperature during scanning, coil, imaging artefact). Additionally, the magnetization transfer method will be mentioned as an alternative for low-density foam gel dosimeters. PMID- 29151459 TI - The ball-on-disk cyclic wear of CAD/CAM machinable dental composite and ceramic materials. AB - The purpose of this study was to investigate the wear volume and the principal strain of machinable dental composite and ceramics in simulated mastication. A ball-on-disk wear test was performed for 3,000 cycles in water, using nine ball/disk combinations of three commercial CAD/CAM materials: feldspathic, lithium disilicate glass ceramics, and a highly loaded composite material (n = 7 for each combination). The wear volume was optically measured using a digital scanner and analyzed for statistical differences based on the materials (alpha = 0.05). We used non-linear finite element analysis to calculate the principal strain. The wear volume of the ball was significantly larger than that of the disk when hardness and fracture toughness of the former was lower than that of the latter and vice versa (P < 0.05). The lithium disilicate glass ceramic constantly showed lower wear volume than the opposing antagonist. Except for the same material pairs of feldspathic and composite, the ball or disk specimen that showed a larger wear in the occluding pair coincided with the one with higher maximum strain. It was not possible to predict the magnitude of wear, whereas the result suggested a strong association between the maximum strain and wear volume of the ceramic surface. PMID- 29151461 TI - [Optical Computed Tomography for Polymer Gel Dosimetry]. AB - This article describes an optical computed tomography (OCT) for polymer gel dosimetry, focusing on two systems recently constructed by us. The first OCT system, which is categorized as a first-generation system, comprised a single He Ne laser, photodiode, and mechanical stages for moving and turning gel dosimeter. Projection data per angle are acquired from turned gel dosimeter. In this system, the reconstructed image is obtained using filtered back-projection (FBP) method from projection data. The second OCT system is a 2D-OCT scanner that utilizes a light panel and a camera detector. The dose-response relationship between the optical density and radiation dose reconstructed from the scanning images is comparable to that obtained using magnetic resonance imaging. Although there is much room for improvement in the image artifacts due to reflection and refraction of light and so on, OCT is expected as a modality for the future polymer gel dosimetry as the rapid, high-resolution, highly accurate evaluation tool. PMID- 29151462 TI - [Evaluation of Radiochromic Gel Dosimeter and Optical CT]. AB - Three-dimensional (3D) radiation dosimeter has received growing interest with the implementation of highly conformal radiotherapy treatments. Optical Computed tomography (CT) scanners have been developed for 3D quantitative measurement of optical attenuation. Malachite green and Leuco Crystal Violet (LCV) dye radiochromic gels were recently developed as radiation dosimeters in combination with optical CT scanners. Malachite green and LCV are colorless dyes and they become green or violet after irradiation, respectively. The dyes mixed with gelatin and surfactant became hardened and can be used as a 3D gel dosimeter. The radiochromic gels dosimeter with optical CT scanners provides many of desired features such as: low cost, easy to fabricate, low toxicity and fast readout. In this article, the fundamental characteristics of radiochromic gel dosimeter with optical CT scanners are reviewed. PMID- 29151463 TI - [The Process and the Memory of Starting the Journal of Radiological Physics and Technology]. PMID- 29151465 TI - ? PMID- 29151464 TI - [Series: Basic Exercises Using Excel (4)]. PMID- 29151466 TI - ? PMID- 29151467 TI - [Preface to the Special Issue on 3D Gel Dosimeters]. PMID- 29151468 TI - [Numerical and Visual Evaluation of Compressed Sensing MRI Using 3D Cartesian Sampling]. AB - We performed numerical and visual evaluation of compressed sensing MRI (CS-MRI) using 3D Cartesian sampling by numerical simulation. Three brain anatomical ROIs (white matter, gray matter, cerebrospinal fluid) of a T1-weighted image (T1WI), a T2-weighted image (T2WI) and a proton density-weighted image (PDWI) were used for numerical evaluation. Sampling ratio of the Cartesian grid was 30%. Reconstruction was performed by the projection onto convex sets (POCS) method with soft thresholding, subject to data fidelity constraints. In the absence of noise, RMSE of 3D-T1WI was 1.50, ant that of the 2D-T1WI of the transverse plane was in the range of 1.06 to 1.54; anatomical ROIs was in the range of 0.75 to 2.80; those of T2WI were 3.20, 2.77 to 3.06, and 1.81 to 4.51; those of PDWI were 1.69, 1.33 to 1.49, and 1.08 to 1.86. Visual evaluation was performed by three radiologists on the basis of three categories: artifact, anatomical structure, and tissue contrast. Average score of the visual evaluation indicated that anatomical structure and tissue contrast of CS images were equal to those of the original image, although a few artifacts were visible. If noise level was assumed to be 20 dB or less, anatomical structure and tissue contrast were not significantly degraded compared to noise-free CS images. PMID- 29151469 TI - [Introduction of This Special Issue on 3D Gel Dosimeters]. PMID- 29151470 TI - [Polymer Gel Dosimeter]. AB - With rapid advances being made in radiotherapy treatment, three-dimensional (3D) dose measurement techniques of great precision are required more than ever before. It is expected that 3D polymer gel dosimeters will satisfy clinical needs for an effective detector that can measure the complex 3D dose distributions. Polymer gel dosimeters are devices that utilize the radiation-induced polymerization reactions of vinyl monomers in a gel to store information about radiation dose. The 3D absorbed dose distribution can be deduced from the resulting polymer distribution using several imaging modalities, such as MRI, X ray and optical CTs. In this article, the fundamental characteristics of polymer gel dosimeter are reviewed and some challenging keys are also suggested for the widely spread in clinical use. PMID- 29151471 TI - [Radiochromic Hydrogel Dosimeters]. AB - Radiochromic hydrogel dosimeters are a useful tool for the verification of 3D dose distributions using optical CT scanners which are lower cost and with higher spatial resolution in a limited time than MRI scanners. In this paper, recent development of radiochromic micelle gel and genipin-gelatin gel dosimeters are described. They have the advantage of water equivalency, low or no diffusion property, and lower toxicity. Micelle gels consist of leuco dye, surfactant, radical initiator (halocarbons), and gelling agent. The dose sensitivities are affected by the concentration of each component and the temperature during irradiation. In non-diffusing genipin-gelatin gels, radiation induced bleaching is observed. The dose sensitivity is strongly affected by the concentration of genipin and sulfuric acid and by the blending time with gelatin. Higher dose sensitivity and standardization of the dose evaluation procedure will be the future issue. PMID- 29151472 TI - [Fricke Gel Dosimeters]. AB - Fricke gel dosimeters are based on the aqueous ferrous sulfate solution that has been used as a reliable chemical dosimeter for more than 90 years. The amount of radiation-induced oxidation of ferrous ions to ferric ions could be evaluated three-dimensionally via optical computed tomography (OCT) or magnetic resonance imaging (MRI). Three-dimensional dosimetry is expected to be a useful tool, in particular, for the verification of complex radiation dose planning in advanced radiation cancer therapy. Compared with other 3D gel dosimeters, there are several problems such as retention of dose distribution or dose sensitivity; however, they can easily be prepared in a chemistry laboratory. In addition, a unique gel dosimeter was also reported for heavy-ion beam irradiation. In this review, recent papers concerning the Fricke gel dosimeter and its application in 3D dosimetry are summarized. PMID- 29151473 TI - Prevalence of Dizziness and Associated Factors in South Korea: A Cross-Sectional Survey From 2010 to 2012. AB - BACKGROUND: Dizziness is one of the most common complaints in medicine and a frequent symptom among older people. Dizziness has a considerable impact on life quality and is associated with high economic costs. The purpose of this study was to evaluate the prevalence of dizziness in the general population and to describe its clinical characteristics and associated factors. METHODS: The Korea National Health and Nutrition Examination Survey (KNHANES) is a cross-sectional survey of the civilian, non-institutionalized population of South Korea. We evaluated data for 12,653 participants (5,450 men and 7,203 women), aged 40 years and above, whom participated in the KNHANES between 2010 and 2012. RESULTS: In the age group over 40 years old, the 1-year prevalence of dizziness was 20.10%. Dizziness was more prevalent among women (25.18%) than among men (14.57%; P < 0.001) and the prevalence rate increased with age (P < 0.001). In multivariable analysis, female sex, older age, serum triglyceride level, experience of depression, limited functional status owing to visual acuity impairment, limited physical performance, smoking, alcohol consumption, and perception of stress were independently associated with dizziness. CONCLUSIONS: In our study, the prevalence of dizziness in the general population was 20.10%. There was a stronger relationship between dizziness and physical performance, chronic diseases, and health behaviors compared to that with otologic diseases. Interventions for dizziness should be approached in a multifactorial manner and an understanding of various factors is necessary for the prevention and management of this condition. PMID- 29151474 TI - Prevalence and Risk Factors of Internet Addiction Among Employed Adults in Japan. AB - BACKGROUND: The prevalence of Internet addiction (IA) among employed adults has not been reported using a large sample. To clarify the actual status of addictive Internet use among employed adults, this study aimed to evaluate the prevalence and the risk factors of IA and at-risk IA among employed adults in Japan. METHODS: This cross-sectional study surveyed all junior and senior high school personnel in Shimane Prefecture, a rural area in Japan. Eligible participants included 3,211 junior and senior high school personnel (1,259 men and 1,952 women). Participants completed a questionnaire on their activities and factors related to Internet use. RESULTS: The prevalence of IA and at-risk IA was 0.03% and 4.82%, respectively. Furthermore, game playing was shown to be the Internet activity most closely associated with at-risk IA. CONCLUSIONS: This study showed that around 5% of school personnel in a rural area in Japan are at risk for developing addiction to the Internet and that using the Internet for game playing is related to at-risk IA. Our results suggest that employed adults should be instructed to use the Internet properly. PMID- 29151475 TI - Coffee Consumption and Lung Cancer Risk: The Japan Public Health Center-Based Prospective Study. AB - BACKGROUND: Many epidemiological studies have indicated a positive association between coffee intake and lung cancer risk, but such findings were suggested to be confounded by smoking. Furthermore, only a few of these studies have been conducted in Asia. Here, we investigated the association between coffee intake and lung cancer risk in one of the largest prospective cohort studies in Japan. METHODS: We investigated the association of coffee drinking and subsequent incidence of lung cancer among 41,727 men and 45,352 women in the Japan Public Health Center-based Prospective Study using Cox proportional hazards regression, with adjustment for potential confounders and by strata of smoking status. Coffee and other dietary intakes were assessed once at baseline with a food frequency questionnaire (FFQ). RESULTS: During 1,481,887 person-years of follow-up between 1990 and 2011, a total of 1,668 lung cancer cases were identified. In a multivariate regression model, coffee consumption was not associated with risk of lung cancer (HR 1.16; 95% CI, 0.82-1.63; Ptrend = 0.285 for men and HR 1.49; 95% CI, 0.79-2.83; Ptrend = 0.942 for women). However, there was a significant increase in the risk for small cell carcinoma (HR 3.52; 95% CI, 1.49-8.28; Ptrend < 0.001). CONCLUSION: Our prospective study suggests that habitual consumption of coffee is not associated with an increased risk of lung cancer incidence, despite observing a significant increase in the risk for small cell carcinoma. PMID- 29151476 TI - Tobacco Control Measures to Reduce Socioeconomic Inequality in Smoking: The Necessity, Time-Course Perspective, and Future Implications. AB - Previous systematic reviews of population-level tobacco control interventions and their effects on smoking inequality by socioeconomic factors concluded that tobacco taxation reduce smoking inequality by income (although this is not consistent for other socioeconomic factors, such as education). Inconsistent results have been reported for socioeconomic differences, especially for other tobacco control measures, such as smoke-free policies and anti-tobacco media campaigns. To understand smoking inequality itself and to develop strategies to reduce smoking inequality, knowledge of the underlying principles or mechanisms of the inequality over a long time-course may be important. For example, the inverse equity hypothesis recognizes that inequality may evolve in stages. New population-based interventions are initially primarily accessed by the affluent and well-educated, so there is an initial increase in socioeconomic inequality (early stage). These inequalities narrow when the deprived population can access the intervention after the affluent have gained maximum benefit (late stage). Following this hypothesis, all tobacco control measures may have the potential to reduce smoking inequality, if they continue for a long term, covering and reaching all socioeconomic subgroups. Re-evaluation of the impact of the interventions on smoking inequality using a long time-course perspective may lead to a favorable next step in equity effectiveness. Tackling socioeconomic inequality in smoking may be a key public health target for the reduction of inequality in health. PMID- 29151477 TI - Nutrient-Derived Dietary Patterns and Their Association With Metabolic Syndrome in a Japanese Population. AB - BACKGROUND: Nutrients have been proposed to be related to metabolic syndrome (MetS). The aims of this study were to identify dietary patterns that correlated with several nutrients using reduced rank regression (RRR) and to examine the association between extracted dietary patterns and prevalence of MetS in a Japanese population. METHODS: The study population comprised 1,092 Japanese men and women (35-69 years old) who had participated in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study in Tokushima Prefecture. Dietary patterns were derived with RRR using 46 food items as predictors and six established nutrients (potassium, calcium, vitamin D, vitamin C, insoluble dietary fiber, and carotene) as response variables. Associations between extracted dietary patterns and MetS were then examined with logistic regression models. RESULTS: Among the six dietary patterns, dietary pattern 1 (DP1) explained the largest proportion (60.1%) of variance in the six nutrients. Therefore, only DP1 was selected for further analysis. DP1 was characterized by high intake frequency of vegetables, fruits, fish and small fish, natto (fermented soybeans), and deep-fried tofu. After adjustment for potential confounders, significant inverse associations were found between DP1 score and MetS (odds ratio [OR] for each quartile: 1.00, 0.58, 0.60, 0.52; Ptrend = 0.02); DP1 and high blood pressure (Ptrend = 0.0002); and DP1 and high blood glucose (Ptrend = 0.02). CONCLUSION: A dietary pattern characterized by high intake of vegetables, fruits, fish and small fish, natto, and deep-fried tofu was associated with reduced prevalence of MetS in a Japanese population. PMID- 29151479 TI - A Case of Loeffler Endocarditis That Showed Endomyocardial Systolic Dysfunction Detected by Layer Specific Strain Analysis. AB - Loeffler endocarditis is a rare comprehensive cardiac manifestation caused by eosinophilic cell infiltrations and is present in 50%-60% of patients with hypereosinophilic syndrome (HES). Left ventricle (LV) endocardial systolic dysfunction is a major cause of morbidity and mortality in HES and Loeffler endocarditis. We present a case of Loeffler endocarditis, whose left ventricular (LV) systolic dysfunction and endocardial systolic dysfunction were first neglected by conventional transthoracic echocardiography (TTE), but were later pointed out by layer-specific longitudinal strain analysis. With timely initial therapeutic management, the patient's outcome was remarkable. Thus, we strongly recommend strain analysis as a necessary supplementary test of conventional TTE in all patients with Loeffler endocarditis. PMID- 29151478 TI - Low Incidence of Esophageal Lesions After Pulmonary Vein Isolation Using Contact Force Sensing Catheter Without Esophageal Temperature Probe. AB - Pulmonary vein isolation (PVI) is a cornerstone therapy for atrial fibrillation (AF). Although severe complications are rather rare, the development of an atrio esophageal fistula (AEF) is a fatal complication with a very high mortality even after surgical treatment. The use of esophageal temperature probes (ETP) during PVI may protect the esophagus but it is still under debate since the ETP may also lead to esophageal lesions. The aim of this study was to evaluate the clinical safety of PVI using contact-force (CF) sensing catheter without esophageal temperature monitoring.We investigated 70 consecutive patients who underwent point-by-point PVI without usage of ETP and who underwent esophago-gastro duodenoscopy (EGD) with detailed evaluation of the esophagus after the index PVI procedure. The operator attempted to keep CF within the 10-40 g range. The incidences of esophageal lesions (EDEL) detected by endoscopy were then analyzed.Two of 70 patients (2.9%) showed EDEL consisting of one longitudinal ulcer-like erythematous lesion with fibrin and a different one consisting of a round-shaped lesion surrounded by erythema and petechial hemorrhage. All EDEL healed within two weeks under high proton-pump inhibitor therapy without developing AEF as proven by a second EGD of the esophagus.Point-by-point PVI without usage of ETP showed a low incidence of EDEL (2.9%); atrio-esophageal fistula was absent. Further studies on the necessity of ETP under CF control are necessary. PMID- 29151480 TI - The Refinement of Risk Stratification for Atrial Thrombus or Spontaneous Echo Contrast in Nonvalvular Atrial Fibrillation. AB - As for nonvalvular atrial fibrillation (NVAF) patients with left atrial thrombus or spontaneous echo contrast (LAT/SEC), we evaluated the additional predictive value of serum uric acid (SUA) and Left atrial diameter (LAD) for CHADS2 and CHA2DS2-VASc, and explored the influence from the level of SUA and LAD to LAT/SEC in moderate risk group. Thus, we put forward the concept of a borderline high risk group to guide clinical anticoagulant therapy in patients with NVAF.A total of 284 NVAF patients without the history of anticoagulant prior to hospitalization were enrolled. They were divided into LAT/SEC group or No LAT/SEC group according to transesophageal echocardiography (TEE). Then, we explored and compared the additional predictive value of serological and ultrasonic indexes after combining them to CHADS2/CHA2DS2-VASc.61 patients (21.48%) had LAT/SEC. SUA and LAD were the independent risk factors of LAT/SEC. After being added with LAD and SUA, the predictive value of CHADS2 and CHA2DS2-VASc were increased much more than others. In the moderate risk group, the incidence of LAT/SEC rose significantly when SUA or LAD was higher than cut-off values.SUA and LAD enhanced the predictive ability of CHADS2 and CHA2DS2-VASc for LAT/SEC as additional factors. For patients in moderate risk group, if SUA or LAD was higher than cut off values, the risk of thromboembolism events would rise accompanied by the elevated risk of LAT/SEC. PMID- 29151481 TI - A Low-Normal Free Triiodothyronine Level Is Associated with Adverse Prognosis in Euthyroid Patients with Heart Failure Receiving Cardiac Resynchronization Therapy. AB - Thyroid dysfunction is prevalent in patients with heart failure (HF) and hypothyroidism is related to the adverse prognosis of HF subjects receiving cardiac resynchronization therapy (CRT). We aim to investigate whether low-normal free triiodothyronine (fT3) level is related to CRT response and the prognosis of euthyroid patients with HF after CRT implantation.One hundred and thirteen euthyroid patients who received CRT therapy without previous thyroid disease and any treatment affecting thyroid hormones were enrolled. All of patients were evaluated for cardiac function and thyroid hormones (serum levels of fT3, free thyroxine [fT4] and thyroid-stimulating hormone [TSH]). The end points were overall mortality and hospitalization for HF worsening. During a follow-up period of 39 +/- 3 weeks, 36 patients (31.9%) died and 45 patients (39.8%) had hospitalization for HF exacerbation. A higher rate of NYHA III/IV class and a lower fT3 level were both observed in death group and HF event group. Multivariate Cox regression analyses disclosed that a lower-normal fT3 level (HR = 0.648, P = 0.009) and CRT response (HR = 0.441, P = 0.001) were both independent predictors of overall mortality. In addition, they were also both related to HF re-hospitalization event (P < 0.01 for both). Patients with fT3 < 3.00 pmol/L had a significantly higher overall mortality than those with fT3 >= 3.00 pmol/L (P = 0.027). Meanwhile, a higher HF hospitalization event rate was also found in patients with fT3 < 3.00 pmol/L (P < 0.001).A lower-normal fT3 level is correlated with a worse cardiac function an adverse prognosis in euthyroid patients with HF after CRT implantation. PMID- 29151482 TI - Radiation-Induced Coronary Artery Disease Manifested at Very Late Phase. AB - We report the case of a 51-year-old female, in whom coronary artery disease such as occlusion of septal perforators was manifested, on the occasion of hospitalization with congestive heart failure. The patient had a history of radiation therapy for a mediastinal tumor 19 years previously. As she had no conventional coronary risk factors, the cause of the coronary artery disease is thought to have been related to the radiation therapy. As survival rates of cancer patients improve as a consequence of therapeutic advances, we should be aware of the possibility of coronary artery disease as a very late complication of radiation therapy, even in patients who have no coronary risk factors. PMID- 29151484 TI - Oral Administration of Glucosamine Improves Vascular Endothelial Function by Modulating Intracellular Redox State. AB - Glucosamine, used to treat osteoarthritis, has been shown to have anti inflammatory and anti-atherosclerotic effects in experimental studies. A recent cohort study has demonstrated that the use of glucosamine was significantly associated with decreased total mortality. Vascular endothelial function is a potent surrogate marker of atherosclerosis and cardiovascular mortality where oxidative stress could participate. Therefore, we investigated whether glucosamine improves vascular endothelial function and intracellular redox state. We examined the effects of oral glucosamine administration (3000 mg/day) for 4 weeks on flow-mediated vasodilation (FMD) and intraerythrocyte glutathione parameters in 20 volunteers. Nineteen age-matched volunteers served as controls. Glucosamine administration significantly increased FMD (from 7.0 +/- 2.3 to 8.7 +/- 2.3%, P = 0.022). In the control group, FMD did not change. Glucosamine administration significantly increased intraerythrocyte total glutathione levels (from 212.9 +/- 46.2 to 240.6 +/- 49.4 MUmol/L, P = 0.006), intraerythrocyte reduced form of glutathione (GSH) levels (from 124.7 +/- 42.6 to 155.2 +/- 47.7 MUmol/L; P = 0.004) and intraerythrocyte GSH/oxidized form of glutathione (GSSG) ratios (from 3.18 +/- 1.64 to 3.88 +/- 1.61, P = 0.04). In the control group, any glutathione parameters did not change. Moreover, a stepwise multivariate analysis revealed percent change of GSH/GSSG is the only independent predictor for those of FMD (standardized beta = 0.58, P = 0.007) in the glucosamine group. Glucosamine administration improved FMD in association with amelioration of intraerythrocyte GSH/GSSG ratios. These results suggest that oral glucosamine administration might improve vascular endothelial function by modulating intracellular redox state. PMID- 29151483 TI - Imaging of Right-to-Left Shunt in an Adult Patient with Unroofed Coronary Sinus with Persistent Left Superior Vena Cava. AB - A 54-year-old woman with a history of multiple cardiac surgeries suffered from hypoxemia caused by a right-to-left intra-cardiac shunt due to coronary sinus (CS) anomaly with persistent left superior vena cava (PLSVC). Both the contrast echocardiography and enhanced computed tomography (CT) provided conclusive diagnosis of this rare congenital anomaly, which was overlooked for a long time. However, an important diagnostic clue was left-arm injection of the contrast media. In the present case, previously performed enhanced CT with its routine manner, i.e., contrast through the right arm, missed this anomaly. It is crucial to note that the unusual type of unroofed CS with PLSVC, presenting with an entirely right-to-left intra-cardiac shunt, cannot be delineated on an enhanced routine chest CT if the contrast media is injected through the right arm. PMID- 29151485 TI - Evolution of Vertebrate Ryanodine Receptors Family in Relation to Functional Divergence and Conservation. AB - Ryanodine receptors (RyRs), the large homotetrameric protein complexes, regulate the release of calcium from intracellular stores into the cytosol and play vital roles in the excitation-contraction coupling of cells. However, the evolutionary relationship of RyRs in vertebrates has yet to be elucidated. We identified 22 RyRs from Homo sapiens, Mus musculus, Rattus norvegicus, Gallus gallus, Anolis carolinensis, Rana catesbeiana, and Danio rerio. The phylogenetic relationship, motifs analysis and reconstruction of ancestral RyRs showed that the members of RyR family in vertebrates were grouped into three clades: the RyR1 clade, the RyR2 clade, and the RyR3 clade. Positive selection existed in RyR gene evolution, which is consistent in three site models, and gene ontology (GO) analysis showed that the evolution of RyR family in vertebrates promotes RyRs function differentiation. At last, we predicted 140 mutation sites which may be involved in diseases and 57 phosphorylation sites among RyR1 sequence in human, as well as 61 mutation sites and 70 phosphorylation sites in human RyR2 sequences. Most of these potential sites are arranged in clusters. Our work provides insight into the origin and evolutionary process of RyRs in vertebrates, facilitating their functional investigations in the future. PMID- 29151486 TI - Factors for C-Kit Expression in Cardiac Outgrowth Cells and Human Heart Tissue. AB - We determined the factors associated with the expression of c-kit in the heart and the proliferation of c-kit-positive (c-kitpos) cardiac stem cells among the outgrowth cells cultured from human cardiac explants.Samples of the right atrium (RA), left atrium (LA), and left ventricle obtained from patients during open heart surgery were processed for cell culture of outgrowth cells and tissue analysis. The total number of growing cells and the population of c-kitpos cells were measured and compared with c-kit expression in native tissues and characteristics of the patients according to the region of the heart.We analyzed 452 samples from 334 patients. Atrial fibrillation (AF) in the patients reduced the number of outgrowth cells from the RA and LA, and aging was a co-factor for the LA. The c-kitpos population from the RA was associated with serum brain natriuretic peptide (BNP). C-kit expression in native tissue was also associated with BNP expression. However, we observed no relationship in expression between outgrowth cells and native tissue. In addition, the RA tissue provided the highest number of c-kitpos cells, and the left ventricle provided the lowest.C kit was weakly expressed in response to damage. In addition, no correlation between outgrowth cells and native tissue was found for c-kit expression. PMID- 29151487 TI - Relationship between n-3 Polyunsaturated Fatty Acids and Extent of Vessel Disease in Patients with ST Elevation Myocardial Infarction. AB - A relationship between serum polyunsaturated fatty acids (PUFAs) and cardiovascular disease has been reported; however, the existence of a relationship between serum PUFAs and extent of vessel disease (VD) in patients with ST elevation myocardial infarction (STEMI) remains unclear.Between July 2011 and June 2015, 866 consecutive STEMI patients underwent emergent percutaneous coronary intervention, 507 of whom were enrolled and classified into three groups according to the initial angiograms: 1VD, 294 patients; 2VD, 110 patients; and 3VD/left main trunk disease (LMTD), 103 patients. Serum levels of PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid, and other laboratory data during hospitalization were evaluated.The serum EPA level in the 3VD/LMTD group was significantly lower than that in the 1VD group (55.5 +/- 22.1 versus 66.2 +/- 28.7, P = 0.002) and was slightly lower than that in the 2VD group (55.5 +/- 22.1 versus 65.2 +/- 28.9, P = 0.0167). Multivariate adjustment analysis revealed that age >= 70 years (odds ratio, 1.72; 95% confidence interval, 1.03-2.89; P = 0.038) and a low serum EPA level (odds ratio, 0.98; 95% confidence interval, 0.99-1.00; P = 0.023) were independent risk factors for 3VD/LMTD, while a low serum DHA level was not.A low serum EPA level may be more strongly related than a low serum DHA level to the extent of VD in STEMI patients. Age >= 70 years and a low serum EPA level may be independent risk factors for 3VD/LMTD. PMID- 29151489 TI - An Infectious Pseudoaneurysm Caused by Ventricular Septal Defect Occluder in Patent Ductus Arteriosus Closure in a Two-Year-Old Child. AB - We present a case of an infectious pseudoaneurysm after patent ductus arteriosus (PDA) closure with a ventricular septal defect (VSD) occluder in a two-year-old child. The aneurysm grew rapidly but was successfully removed in time and the patient survived. To our knowledge, this is the first report of an infectious pseudoaneurysm caused by VSD occluder in PDA closure. PMID- 29151488 TI - Impact of Coronary Stent Fracture on Restenotic Neointimal Tissue Characterization After Drug-Eluting Stent Implantation. AB - Although drug-eluting stents (DESs) reduce the rates of in-stent restenosis (ISR) and subsequent target lesion revascularization, stent fracture (SF) after DES implantation has become an important concern because of its potential association with restenosis and stent thrombosis. We aimed to assess the pathogenic impact of SF on in-stent restenotic neointimal tissue components after DES implantation. We analyzed 43 consecutive patients (14 with SF and 29 without SF) with ISR requiring revascularization after DES implantation between January 2008 and March 2014. For evaluation of in-stent tissue components, integrated backscatter intravascular ultrasound (IB-IVUS) was performed. SF was defined as complete or partial separation of stent segments observed using plain fluoroscopy or intravascular ultrasound. On volumetric IB-IVUS analyses, patients with SF had a significantly higher percentage of lipid tissue volume within the neointima and a significantly lower percentage of fibrous tissue volume than those without (37.3 +/- 18.9% versus 24.9 +/- 12.4%, P = 0.02, and 61.2 +/- 18.3 versus 72.6 +/- 12.1%, P = 0.04, respectively). Moreover, SF was positively correlated with the percentage of lipid volume on multiple linear regression analysis after adjustment for confounding factors (beta = 0.36, P = 0.03). The interval from stent implantation was similar in both groups (47.0 +/- 28.7 versus 37.7 +/- 33.3 months; P = 0.39). In conclusion, SF is associated with larger lipid tissue volume within the neointima after DES placement, suggesting a contribution to the development of neoatherosclerosis and vulnerable neointima. Thus SF might lead to future adverse coronary events. PMID- 29151490 TI - PPARgamma Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats. AB - Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling leading to right ventricular hypertrophy (RVH) and failure. Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of nuclear receptors, has been proved to ameliorate PAH. However, its effect on PAH-induced right ventricular failure (RVF) remains unknown. Therefore, we investigated the therapeutic potential of PPARgamma in preventing monocrotaline (MCT)-induced RV dysfunction. The PAH model was induced by MCT administration. Male rats were administered with MCT to develop PAH and RVF formed by approximately day 30. Significant increase in RV area, RVAW resulted in an ascending RV index. However, the LV function including EF, FS, and LVID did not change significantly. PPARgamma agonist prevented PAH-induced RVF by preserving RV index and preventing RVH. PPARgamma's beneficial effects seem to result from various factors, including anti-apoptosis, preservation RV index, reversal of inflammation, improvement of glucolipid metabolism, reduction of ROS. In a word, PPARgamma agonist prevents the development of RVF. PMID- 29151491 TI - Early Safety and Efficacy of Transcatheter Aortic Valve Implantation for Asian Nonagenarians (from KMH Registry). AB - As Japan has one of the most rapidly aging populations in the world, transcatheter aortic valve implantation (TAVI) is likely to be performed in increasing numbers of older people. There is little information on either the efficacy or the safety of TAVI in nonagenarians in Asia.From October 2013 to June 2015, 112 consecutive patients underwent TAVI with Edwards SAPIEN XT valves in our institution. We compared 25 patients aged at least 90 years (mean 91.6 +/- 1.7 years) with 87 patients aged under 90 years (mean 82.5 +/- 6.0 years) at the time of TAVI. All definitions of clinical endpoints and adverse events were based on the Valve Academic Research Consortium 2 definitions.The median follow-up interval was 561.5 days (the first and third quarters, 405.0 and 735.8 days). Nonagenarians had a higher logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE), Euro II score, and the Society of Thoracic Surgeons predictive risk of mortality (STS) score, and a prevalence of clinical frailty scale >= 4. The rate of device success, and the 30-day and 6-month mortalities were not different between patients aged >= 90 years and < 90 years (96.0% versus 92.0%, P = 0.68; both 0%, P = 1.00; 4.0% versus 3.5%, P = 0.32, respectively). At six months, clinical efficacy and time-related valve safety were also similar in the two groups (12.5% versus 13.4%, P = 1.00; 4.5% versus 10.3%, P = 0.68, respectively). The cumulative 1-year mortalities were not significantly different between the two groups (8.4% versus 9.4%, P = 0.94, respectively).TAVI can contribute to acceptable clinical results and benefits in a carefully selected group of nonagenarians in Asia. PMID- 29151493 TI - Surgical Treatment of Coronary to Pulmonary Artery Fistulas in Adults. AB - Coronary to pulmonary artery fistulas (CPAFs) are abnormal communications between the coronary and pulmonary arteries. They are an uncommon congenital heart disease and usually remain asymptomatic until later in life. However, there is no consensus on their management. We present four adult patients who required surgery for coronary to pulmonary artery fistulas to illuminate this issue. The clinical presentations were variable depending on the anatomical features of coronary to pulmonary artery fistulas and the presence or absence of other cardiac diseases. We successfully performed surgical closure of the coronary to pulmonary artery fistulas in each of the cases. In this report, we describe our experience with these cases and outline the available therapeutic strategies and treatment options for coronary to pulmonary artery fistulas. PMID- 29151492 TI - Determinants of the Change in Arterial Stiffness in Peritoneal Dialysis Patients. AB - Arterial stiffness is an important risk factor for cardiovascular disease (CVD) in patients with end-stage renal failure. However, little is known about the factors that contribute to arterial rigidity in peritoneal dialysis (PD) patients. The aim of this study was to define the pattern and determinants of the longitudinal change in arterial stiffness after PD initiation.Arterial stiffening was estimated for 46 PD patients by using brachial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (cIMT). The cross-sectional relationship between the arterial markers and their clinical determinants was studied. The longitudinal effects of blood pressure (BP), body fluid status, and glucose were studied over the two years after initiating PD.Multivariate analysis showed that higher baPWV was associated positively with urinary protein excretion (P < 0.001), systolic BP (P = 0.001), and hemoglobin A1c (P = 0.003). In contrast, increased cIMT correlated with smoking (P = 0.004) and hypoalbuminemia (P = 0.04), suggesting that endothelial dysfunction is implicated in the atherogenic process. Neither cIMT nor baPWV correlated significantly with other PD-related covariates of volume overload, peritoneal solute transport, kidney function, and C-reactive protein. Longitudinal observation demonstrated that BP had a greater influence on baPWV changes than hyperglycemia or fluid status.Our study indicates that 1) baPWV represent an arterial marker that integrates multifactorial interaction between modifiable variables including BP and plasma glucose; and 2) intervention aimed at controlling BP as well as nutritional conditions (glucose and albumin) may reduce CVD risk in PD patients. PMID- 29151494 TI - Amiodarone-Induced Hyponatremia Masked by Tolvaptan in a Patient with an Implantable Left Ventricular Assist Device. AB - A 43-year-old man was referred to our hospital in June 2014 because of severe heart failure. He was diagnosed with familial dilated cardiomyopathy and was administered oral tolvaptan and amiodarone for atrial and ventricular tachycardia. Since up-titration of carvedilol had failed and he was dependent on dobutamine, a left ventricular assist device (LVAD) was implanted. Tolvaptan and furosemide were both discontinued after LVAD implantation and he was discharged from the hospital. Thirteen months later, he was hospitalized for lethargy and hyponatremia of 108 mEq/L, with an antidiuretic hormone level of 2.5 pg/mL, which suggested syndrome of inappropriate antidiuretic hormone secretion (SIADH). We discontinued amiodarone and administered fludrocortisones. However, hyponatremia persisted for a few more days, eventually resulting in delirium and damage to the LVAD driveline. He received an urgent pump exchange and hyponatremia was gradually improved. We considered the possibility that amiodarone-induced SIADH was masked by tolvaptan therapy before LVAD implantation. PMID- 29151495 TI - Acute Pericarditis Following Acute Pulmonary Thromboembolism. AB - We describe the case of a 45-year-old Japanese man who developed acute pericarditis following an acute pulmonary thromboembolism. He had developed shortness of breath 7 days prior to hospitalization and was admitted with severe dyspnea. Echocardiography and laboratory results were compatible with acute pulmonary thromboembolism, which was confirmed by contrast-enhanced chest computed tomography. On the third hospital day, he experienced chest pain exacerbated by inspiration. On the fourth hospital day, his body temperature increased to 39 degrees C and echocardiography revealed circumferential pericardial effusion. A diagnosis of acute pericarditis was made and the patient was treated with colchicine and aspirin. On the fifth hospital day, his symptoms largely subsided. Auscultation revealed pericardial friction rub. Electrocardiography demonstrated diffuse ST-segment elevations. Twenty-four days later, computed tomography revealed the disappearance of both the pericardial effusion and pulmonary arterial emboli. This case was thought to be one of acute pericarditis following acute pulmonary thromboembolism. PMID- 29151496 TI - Cost-Effectiveness Analysis of Cardiovascular Disease Treatment in Japan. AB - The quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER) are important concepts in cost-effectiveness analysis, which is becoming increasingly important in Japan. QALY is used to estimate quality of life (QOL) and life years, and can be used to compare the efficacies of cancer and cardiovascular treatments. ICER is defined as the difference in cost between treatments divided by the difference in their effects, with a smaller ICER indicating better cost-effectiveness. Here, we present a review of cost effectiveness analyses in Japan as well other countries. A number of treatments were shown to be cost-effective, e.g., statin for secondary prevention of cardiovascular disease, aspirin for primary prevention of cardiovascular disease, DOAC for high-risk atrial fibrillation, beta blockers, ACE inhibitors, and ARB for heart failure, sildenafil and bosentan for pulmonary hypertension, CABG for multi-vessel coronary disease, ICD for ventricular tachycardia, and CRT for heart failure with low ejection fraction, while others were not cost-effective, e.g., epoprostenol for pulmonary hypertension and LVAD for end-stage heart failure. Further investigations are required regarding some treatments, e.g., PCSK-9 inhibitors for familial hypercholesterolemia, PCI for multi-vessel coronary disease, catheter ablation for atrial fibrillation, and TAVI for severe aortic stenosis. Ethical aspects should be taken into consideration when utilizing the results of cost-effectiveness analysis in medical policy. PMID- 29151497 TI - Omega-3 Polyunsaturated Fatty Acid and Coronary Atherosclerotic Plaques. PMID- 29151498 TI - Early Detection and Intervention of Coronary Artery Involvement in Immunoglobulin G4-related Disease. AB - A 59-year-old man with swollen submandibular glands developed an aortic aneurysm requiring aortic prosthesis implantation. Echocardiography performed to evaluate the cardiac function before the surgery incidentally revealed masses around the coronary arteries. The serum IgG4 levels were increased. A post-operational pathological examination of the abdominal aneurysms revealed infiltration of plasma cells, with the ratio of IgG4/IgG-positive cells being >80%. The patient was diagnosed with IgG4-related disease (RD) with coronary artery involvement. He was treated successfully with corticosteroid before any associated cardiovascular events occurred. Given the poor prognosis of IgG4-RD-associated coronary artery involvement, this case emphasizes the importance of the early assessment with echocardiography, even if patients have no cardiovascular symptoms. PMID- 29151499 TI - Effects of Rhubarb on Intestinal Dysmotility in Critically Ill Patients. AB - Intestinal dysmotility is a major problem in critically ill patients. This report describes the successful treatment of intestinal dysmotility with rhubarb as a laxative in six critically ill patients on mechanical ventilation. Bowel movement and defecation occurred in all patients an average of 1.8 days after the administration of powdered rhubarb. In 4 patients who also had gastric reflux, the reflux volume via nasal tube was decreased an average of 3.5 days after the initiation of rhubarb treatment, and enteral nutrition was able to be started. Rhubarb may be useful for the treatment of incompetent gastric and intestinal motility in critically ill patients. PMID- 29151500 TI - Nonmyelomatous Ascites Resulting from the Increased Secretion of Vascular Endothelial Growth Factor in Multiple Myeloma. AB - Ascites is a rare complication of multiple myeloma (MM); in most cases, the direct invasion of myeloma cells to the peritoneal cavity has been assumed to be the etiology because the effusion is usually exudative and contains a high proportion of myeloma cells. We herein report a case of MM with massive ascites containing only a small amount of myeloma cells. Instead, high levels of serum and ascitic vascular endothelial growth factor were detected. This was suggested to be a potential mechanism underlying the development of ascites. PMID- 29151501 TI - The Efficacy of Corticosteroid Therapy in a Patient with Non-alcoholic Steatohepatitis Overlapping Autoimmune Hepatitis. AB - The overlap of multiple liver diseases can cause the disease activity and severity to worsen rapidly in some cases. We rarely see patients with non alcoholic steatohepatitis (NASH) with overlapping autoimmune hepatitis (AIH). A 64-year-old woman who had been prescribed oral drugs to treat diabetes and hypertension (metformin 500 mg/day and voglibose 0.9 mg/day, and termisartan 40 mg/day and amlodipine 5 mg/day, respectively) was diagnosed with NASH with histological confirmation. At 68 years of age, her liver injury worsened with an IgG of 2,871 mg/dL and a high serum anti-nuclear antibody (ANA) level of 2,560. We repeated the liver biopsy, which revealed NASH and mild interface hepatitis with some lobular focal necrosis consisting of overlapping AIH. Therefore, she was treated with 30 mg of prednisolone daily. The treatment led to an improvement in her IgG levels and ANA in the serum and an improvement in the histology results. PMID- 29151502 TI - Isolated Pancreatic Myeloid Sarcoma Associated with t(8;21)/RUNX1-RUNX1T1 Rearrangement. AB - No valid treatment for isolated myeloid sarcoma (IMS) has yet been established, and no thorough genetic examinations have been performed because of its low incidence and unique manner of development. We herein report a 34-year-old man with pancreatic IMS with t(8;21)/RUNX1-RUNX1T1 rearrangement. He was treated with high-dose cytarabine followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). This is the first report of pancreatic IMS with t(8;21). Positron emission tomography/computed tomography and genetic study are useful for the diagnosis, and allo-HSCT achieved complete remission in this patient. PMID- 29151503 TI - Acute Megakaryoblastic Leukemia Developing as Donor Cell Leukemia after Umbilical Cord Blood Transplantation. AB - A 64-year-old man with acute myeloid leukemia underwent umbilical cord blood transplantation (UCBT). After 11 months of complete remission (CR) following UCBT, the bone marrow showed 7.5% myeloblasts. CR was obtained after a single course of azacitidine monotherapy, but the myeloblasts gradually increased in the blood. We made a diagnosis of acute megakaryoblastic leukemia derived from donor cell with a fluorescence in situ hybridization (FISH) analysis of the sex chromosomes and an immunophenotypic analysis. Azacitidine was administered again and produced a therapeutic effect of stable disease. This case suggests that azacitidine may be a useful therapy for patients with acute megakaryoblastic leukemia in situations in which intensive chemotherapy and transplantation are not indicated. PMID- 29151504 TI - Nomograms to Predict the Disease-free Survival and Overall Survival after Radiofrequency Ablation for Hepatocellular Carcinoma. AB - Objective The purpose of this study was to construct nomograms for the disease free survival (DFS) and overall survival (OS) of post-radiofrequency ablation (RFA) patients with hepatocellular carcinoma (HCC). Furthermore, we compared the prognostic predictive ability of these nomograms for estimating per-patient outcomes with that of traditional staging systems. Methods We retrospectively enrolled 298 patients in the training set and 272 patients in the validation set who underwent RFA for HCC. The nomograms for the DFS and OS were constructed from the training set using the multivariate Cox proportional hazards model. The discriminatory accuracy of the models was compared with traditional staging systems by analyzing the Harrell's C-index. Results The DFS nomogram was developed based on the tumor size, tumor number, aspartate aminotransferase (AST), albumin, age, and alpha-fetoprotein. The OS nomogram was developed based on the tumor size, the model for end-stage liver disease, AST, and albumin. Our DFS and OS nomograms had good calibration and discriminatory abilities in the training set, with C-indexes of 0.640 and 0.692, respectively, that were greater than those of traditional staging systems. The C-indexes of our DFS and OS nomograms were also greater than those of traditional staging systems in the validation set, with C-indexes of 0.614 and 0.657, respectively. RFA patients were stratified into low- and high-risk groups based on the median nomogram scores. High-risk patients receiving surgical resection (SR) were associated with a better DFS and OS than those undergoing RFA. However, the DFS and OS were similar between the low-risk RFA and SR groups. Conclusion We constructed reliable and useful nomograms that accurately predict the DFS and OS after RFA for early-stage HCC patients. These graphical tools are easy to use and will assist physicians during the therapeutic decision-making process. PMID- 29151506 TI - The Incidence of Complications in Single-stage Endoscopic Stone Removal for Patients with Common Bile Duct Stones: A Propensity Score Analysis. AB - Objective Single-stage endoscopic stone removal for choledocholithiasis is an advantageous approach because it is associated with a shorter hospital stay; however, few studies have reported the incidence of complications related to this procedure in detail. The aim of this study was to examine the incidence of complications and efficacy of this procedure. Methods This retrospective study investigated the incidence of complications in 345 patients with naive papilla who underwent therapeutic endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis at three institutions between April 2014 and March 2016 by a propensity score analysis. The efficacy of single-stage endoscopic stone removal was assessed based on a hospital stay of within 7 days and the number of ERCP attempts. Results Among 114 patients who underwent single-stage endoscopic stone removal, 15 patients (13.2%) experienced complications. Among the remaining 231 patients in the two-stage endoscopic stone removal group, complications were observed in 17 patients (7.4%). The propensity score analysis, which was adjusted for confounding factors, revealed that single-stage endoscopic stone removal was not a significant risk factor for complications (p=0.52). In patients in whom >10 min was required for deep cannulation, single-stage endoscopic stone removal was not a significant risk factor for complications in the propensity score analysis (p=0.37). In the single-stage group, the proportion of patients with a hospital stay of within 7 days was significantly higher and the number of ERCP attempts was significantly lower in comparison to the two-stage group (p <0.0001 and <0.0001, respectively). Conclusion Single-stage endoscopic stone removal did not increase the incidence of complications associated with ERCP and was effective for reducing the hospital stay and the number of ERCP attempts. PMID- 29151505 TI - Isolated Adrenocorticotropin Deficiency due to Nivolumab-induced Hypophysitis in a Patient with Advanced Lung Adenocarcinoma: A Case Report and Literature Review. AB - A 63-year-old Japanese woman with advanced lung adenocarcinoma developed isolated adrenocorticotropin deficiency caused by immune checkpoint inhibitor (ICI) related hypophysitis following 8 months of nivolumab therapy. Prompt corticosteroid replacement therapy effectively relieved her secondary adrenal insufficiency symptoms and allowed her to pursue nivolumab therapy, which had been effective for the control of lung adenocarcinoma. Human leukocyte antigen (HLA) typing revealed the presence of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which is associated with susceptibility to autoimmune polyglandular syndrome with pituitary disorder in the Japanese population. This case suggests that genetic factors, such as HLA, contribute to the development of endocrinopathies induced by ICIs. PMID- 29151508 TI - Cardiac Sarcoidosis Presenting as Acute Progressive Heart Failure with Abdominal Lymphadenopathy. AB - A 77-year-old Japanese woman presented with asymptomatic abdominal lymphadenopathy. Soluble interleukin-2 receptor (sIL2R) and angiotensin converting enzyme (ACE) levels were elevated, and a pathological examination of lymph-node biopsies revealed non-caseating granulomas, which was consistent with sarcoidosis. Fluorodeoxyglucose-positron emission tomography did not show a clear accumulation in the mediastinal lymph-nodes or heart. Five months later, she presented with acute progressive heart failure that was refractory to conventional treatment. Her sIL2R and ACE levels decreased spontaneously over time, without steroid treatment. Autopsy findings revealed non-caseating granulomas. Cardiac sarcoidosis presenting as acute, progressive, treatment refractory heart failure is rare. Steroid therapy after the resolution of inflammation did not affect the clinical outcome. PMID- 29151507 TI - Successful Endoscopic Treatment of Severe Pancreaticojejunostomy Strictures by Puncturing the Anastomotic Site with an EUS-guided Guidewire. AB - Pancreaticojejunostomy stricture (PJS) is a late complication of pancreaticoduodenectomy. The endoscopic treatment of PJS is very challenging due to the difficulty of locating the small anastomotic site and passing the stricture using a guidewire. We herein report two cases of severe PJS. These patients could not be treated using only double-balloon endoscopy or endoscopic ultrasound-guided puncture of the main pancreatic duct because of severe stenosis at the anastomotic site. However, we could treat them by the rendezvous technique using the rigid part of the guidewire to penetrate PJS. This method was useful and safe for treating severe PJS. PMID- 29151510 TI - The Clinical Features and Outcomes of Patients with Takotsubo Syndrome: The Experience at an Emergency General Hospital. AB - Objective We aimed to elucidate clinical characteristics, contemporary practice and outcomes of patients with takotsubo syndrome who were hospitalized in an emergency general hospital with angiography capabilities. Methods This retrospective study included a total of 42 consecutive patients who were admitted between January 2010 and August 2014. Results The study population included 11 men (26%) and 31 women (74%) [median age 76 years (interquartile range, 66-83)]. Physical stress and emotional stress were identified as triggers in 28 (67%) patients and 5 (12%) patients, respectively. Electrocardiographic changes were observed in 41 (98%) patients, with ST-segment elevation being the most common (71%) finding. In-hospital complications occurred in 24 (57%) patients, and acute pulmonary congestion or cardiogenic shock was seen in 21 (50%) patients. Five patients died during hospitalization (in-hospital mortality: 12%). Conclusion Takotsubo syndrome was associated with significant morbidity and mortality among elderly patients who were treated at an emergency general hospital. Physicians and surgeons in all departments should be aware of the condition, especially in acutely ill subjects. PMID- 29151509 TI - In Paroxysmal Atrial Fibrillation Patients, the Neutrophil-to-lymphocyte Ratio Is Related to Thrombogenesis and More Closely Associated with Left Atrial Appendage Contraction than with the Left Atrial Body Function. AB - Objective The neutrophil-to-lymphocyte ratio (NLR) is an inflammation marker that can be used to detect atrial inflammatory changes, which may contribute to a reduced left atrial (LA) function and thrombosis. Our study aimed to determine whether or not the association of NLR with the LA appendage (LAA) function in relation to thrombogenesis differs from the association with the LA body function in paroxysmal atrial fibrillation (PAF) patients. Methods A total of 183 PAF patients were studied. The LA volume index, mitral flow velocity (A), and mitral annular motion velocity (A') were examined using transthoracic echocardiography. The LAA area, LAA wall motion velocity, and presence of spontaneous echo contrast (SEC) were examined using transesophageal echocardiography. Results The NLR of patients with cerebral embolism was significantly greater than in patients without the disorder. A cut-off point of 2.5 for the NLR had a sensitivity of 71% and a specificity of 74% in predicting cerebral embolism. The patients with an NLR >=2.5 had a higher CHADS2 score and greater LA volume index or LAA area than those with an NLR <2.5. The NLR was an independent risk factor for SEC and was significantly correlated with the LAA wall motion velocity (r=-0.409) in 153 patients without SEC and with the LAA wall motion velocity and LAA area (r= 0.583, r=0.654, respectively) in 30 patients with SEC, but not with the LA volume index, A, or A' in either group. Conclusion In PAF patients, a high NLR indicates thrombogenesis with a high degree of certainty and is associated with reduced LAA contraction rather than with the LA body function. PMID- 29151512 TI - Emergency Radiotherapy for Spinal Cord Compression due to Bone Sarcoidosis. AB - Sarcoidosis is an inflammatory granulomatous disease that is systemic, but bone involvement is uncommon. A 68-year-old man was referred to our hospital complaining of right shoulder pain with numbness. Computed tomography revealed systemic lymphadenopathy and multiple bone lesions. Because malignant lymphoma with a mass lesion protruding into the vertebral canal was considered, he underwent urgent radiotherapy. Thereafter, a needle biopsy of the left parasternal node was performed and showed epithelioid granulomas, confirming a diagnosis of sarcoidosis. Since his neurologic symptoms improved, the patient was not given systemic corticosteroids. Radiotherapy may be useful for local control of bone sarcoidosis. PMID- 29151511 TI - An Intrapancreatic Accessory Spleen That Was Difficult to Diagnose Due to Temporal Changes after Splenectomy. AB - Accessory spleen (AS) is common anomaly, and 20% of AS cases occur in the pancreatic tail. An intrapancreatic AS can be difficult to distinguish from pancreatic neoplasms. In most cases, an AS is described as a hypervascular and solitary tumor, but an AS sometimes takes other forms. We herein report a rare case of an intrapancreatic AS with temporal changes in its appearance after splenectomy, which mimicked aspects of pancreatic cancer. Endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) and 99mTc sulfur colloid scintigraphy were useful for the diagnosis. PMID- 29151513 TI - A Favorable Response to Levetiracetam in a Patient with Metastatic Adenoid Cystic Carcinoma. AB - Adenoid cystic carcinoma (ACC) is a rare cancer, and there are no standard-of care treatments for patients with metastatic ACC. We herein report a patient with lung metastasis of ACC who achieved a favorable response to levetiracetam. A 52 year-old Japanese man was admitted to our hospital because of multiple lung metastases of ACC. We performed first-line chemotherapy with cisplatin plus gemcitabine, and subsequently oral S-1 as second-line chemotherapy, which resulted in disease progression. The patient developed symptomatic epilepsy and received levetiracetam (250 mg twice daily). At five months after the initiation of levetiracetam, chest computed tomography showed regression of the metastatic lung lesions. PMID- 29151514 TI - Dermatomyositis Complicated by Digital Ischemia and Lung Adenocarcinoma in a Patient with Positive Anti-signal Recognition Particle Antibodies. AB - A 58-year-old Japanese woman was diagnosed with anti-signal recognition particle (SRP)-positive dermatomyositis associated with Sjogren's syndrome, rheumatoid arthritis and lung adenocarcinoma. She presented with cutaneous lesions, including ulceration of her right middle finger. Tissue specimens obtained from her right deltoid muscle were positive for CD4+ T-cell infiltration and the sarcolemma showed the upregulation of major histocompatibility complex (MHC) class I antigens. The present case suggests that overlapping autoimmune diseases or complications of malignancy may result in an atypical clinical presentations and histological findings in patients with anti-SRP antibody-positive dermatomyositis. PMID- 29151515 TI - Vertebral Artery Stump Syndrome. AB - Carotid stump syndrome is a well-documented embolic source for ischemic stroke. However, few cases have been reported of a similar condition - termed vertebral artery stump syndrome - which affects the posterior circulation after vertebral artery origin occlusion. We herein report a case of infarction of the right superior cerebellar artery and left posterior inferior cerebellar artery territories due to vertebral artery stump syndrome. In this interesting case, a turbulent flow at the distal side of the vertebral artery occlusion was captured on ultrasonography, and was identified as the probable mechanism of vertebral artery stump syndrome. PMID- 29151517 TI - Thrombotic Microangiopathy Presenting with Intestinal Involvement Following Long term Interferon-beta1b Treatment for Multiple Sclerosis. AB - Thrombotic microangiopathies (TMAs) are systemic microvascular occlusive disorders. The present report describes a patient with relapsing-remitting multiple sclerosis who had been treated with interferon (IFN)-beta1b therapy for eight years and developed TMA. The patient presented with headache, thrombocytopenia, renal dysfunction, severe hypertension, posterior reversible encephalopathy syndrome, and gastrointestinal involvement. After discontinuation of the medication and initiation of antihypertensive treatment, the patient rapidly improved. This is the first report of TMA with gastrointestinal involvement (intestinal TMA) induced by IFN-beta. The new onset of hypertension or headache requires careful attention in cases of long-term administration of IFN-beta1b. PMID- 29151516 TI - Surgically Diagnosed Primary Hepatic Angiosarcoma. AB - Primary hepatic angiosarcoma is a rare tumor originating from endothelial cells in the liver and accounts for approximately 1% of all hepatic malignant tumors. It is difficult to diagnose due to the lack of specific symptoms or tumor markers. No effective treatment exists, but complete surgical resection may achieve a good outcome. Since most primary hepatic angiosarcomas are already at an advanced stage at diagnosis, few reports describe tumors smaller than 2 cm. We report a case of surgery for a 1.7-cm sized primary hepatic angiosarcoma. Further studies are required to improve the preoperative diagnosis of primary hepatic angiosarcoma. PMID- 29151518 TI - Prognostic Factors in the Acute Exacerbation of Idiopathic Pulmonary Fibrosis: A Retrospective Single-center Study. AB - Objectives Acute exacerbation of idiopathic pulmonary fibrosis (IPF-AE) has been recognized as a fatal pulmonary disorder, but the exact prognostic factors are unknown. The aim of the present study was to analyze the clinical characteristics of patients with IPF-AE and identify the prognostic factors. Methods The medical records of 59 cases of IPF-AE were retrospectively reviewed. Clinical data, laboratory data, radiographic findings, treatment, and time from the onset of symptoms to the initiation of corticosteroid pulse therapy, i.e. symptom duration, and outcome were analyzed. Results The IPF Stage, Gender-Age-Physiology (GAP) Index, symptom duration, and the high-resolution computed tomography (HRCT) score were significantly related to the prognosis in the univariate analysis. In the multivariate analysis, the symptom duration remained a significant prognostic factor (hazard ratio of 1-day increase, 1.11; 95% confidence interval, 1.01-1.15; p=0.0427). The area under the receiver operating characteristics curve of symptom duration was statistically significant for survivors versus non-survivors (area under the curve, 0.73; p=0.012). The survival period was significantly shorter in the late-treatment groups (>=5 days; n=30) than in the early-treatment groups (<5 days; n=29; log-rank test; p<0.0001). Conclusion The time interval between the onset of symptoms and the initiation of corticosteroid pulse therapy may be an independent prognostic factor in patients with IPF-AE. PMID- 29151519 TI - Tofacitinib Therapy for Rheumatoid Arthritis: A Direct Comparison Study between Biologic-naive and Experienced Patients. AB - Objective This study was designed to directly compare the outcomes of tofacitinib therapy for methotrexate-refractory rheumatoid arthritis (RA) between biologic naive patients and patients who had experienced an inadequate response to biological agents. Methods We prospectively enrolled and followed 113 patients who had a high or moderate clinical disease activity index (CDAI) (36 biologic naive patients and 77 biologic-experienced patients). Patients received 5 mg of tofacitinib twice daily. Effectiveness and adverse events were examined at month 6 of treatment. Results At month 6, 65 patients (57.5%) reached CDAI50, which is defined as achieving >=50% improvement. The number of previous biological agents was twice as high in CDAI50 non-responders as in responders (2.2 versus 1.1, p<0.001), but there was no significant difference in the type of previous agents or the reason for discontinuation. According to a multivariate logistic regression analysis, the previous use of biological agents [odds ratio (OR) 4.48, p=0.002] and the concurrent use of prednisolone (OR 2.40, p=0.047) were associated with a failure to achieve a CDAI 50 response. Biologic-naive patients were more likely to achieve CDAI50 than biologic-experienced patients (80.6% versus 46.8%, p=0.001). Mean CDAI values were higher in biologic-experienced patients (11.4 versus 4.8, p=0.001), and remission rates were higher in biologic naive patients (41.7% versus 11.7%, p=0.001). Biologic-naive patients more rapidly achieved remission. Rates of discontinuation resulting from adverse events were similar in both groups. Conclusion Although tofacitinib can provide an effective treatment option for intractable RA patients, its impact on outcomes is lower in patients with previous biologic failure. PMID- 29151521 TI - A 10-year History of a Diminutive Rectal Neuroendocrine Tumor. AB - A 39-year-old woman underwent a preoperative diagnostic colonoscopy for cervical cancer. A 3-mm neuroendocrine tumor (NET) was incidentally detected in the rectum. The NET was observed via 7 colonoscopies over 10 years while giving priority to treating the cervical cancer. Complete cervical cancer remission was confirmed at the 10-year follow-up examination; therefore, endoscopic treatment for the NET was subsequently performed. The NET showed almost no change in either size or morphology over the 10-year period. This case illustrates the possible very-slow progression of a small NET, suggesting its benign behavior. PMID- 29151520 TI - Dropped Head Syndrome and the Presence of Rimmed Vacuoles in a Muscle Biopsy in Scleroderma-polymyositis Overlap Syndrome Associated with Anti-Ku Antibody. AB - A 66-year-old woman with a history of interstitial lung disease presented with a 3-month history of dropped head syndrome (DHS), followed by camptocormia and extremity weakness. A clinical examination revealed Raynaud phenomenon, arthralgia, distal skin sclerosis, and microbleeds in the nailfold capillaries. An anti-Ku antibody test was positive. A muscle biopsy revealed inflammatory myopathy with rimmed vacuoles (RVs). The diagnosis of scleroderma-polymyositis (SSc-PM) overlap syndrome was made. RVs on a muscle biopsy in a patient with inflammatory myositis involving axial muscles may be seen either in inclusion body myositis or SSc-PM overlap syndrome. The examination of the skin and autoantibody testing help determine the diagnosis and treatment strategy. PMID- 29151522 TI - Large Cell Neuroendocrine Carcinoma Harboring an Anaplastic Lymphoma Kinase (ALK) Rearrangement with Response to Alectinib. AB - Anaplastic lymphoma kinase (ALK) rearrangement is most commonly observed in lung adenocarcinoma in a subset of lung cancer. Large cell neuroendocrine carcinoma (LCNEC) harboring an ALK rearrangement is very rare. Based on the findings from a transbronchial lung biopsy, a 75-year-old non-smoking woman was diagnosed with LCNEC with multiple liver and bone metastases. After seven cycles of cytotoxic chemotherapy, her genotype testing demonstrated ALK rearrangement. Subsequently, she was administered alectinib and exhibited a partial response. PMID- 29151524 TI - Atrioventricular Block-induced Torsades de Pointes Associated with KCNQ1-G269S. PMID- 29151523 TI - Neuroendocrine Carcinoma of the Stomach: A Response to Combination Chemotherapy Consisting of Ramucirumab Plus Paclitaxel. AB - Extrapulmonary neuroendocrine carcinoma (NEC) is a rare disease, and there is no standard chemotherapy. A 73-year-old man was diagnosed with advanced gastric NEC. He received chemotherapy of irinotecan plus cisplatin, and amrubicin monotherapy. After failure of second-line chemotherapy, he received ramucirumab plus paclitaxel; this treatment was chosen because vascular endothelial growth factor 2 was strongly expressed in the tumor endothelial cells. After two cycles, his NEC had markedly reduced in size, and he continued with this treatment for over eight months. In this case, the combination of an anti-angiogenic inhibitor and a cytotoxic agent was highly effective for gastric NEC. PMID- 29151525 TI - Achromobacter Infection Is Rare in Japanese Patients with Pulmonary B-cell Lymphoma. AB - Objective Achromobacter xylosoxidans (A. xylosoxidans) has been recently reported to have an association with the development of pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma in patients from European countries. However, the prevalence rates for A. xylosoxidans may vary significantly from country to country. To assess this association, the prevalence of A. xylosoxidans was analyzed in Japanese patients with pulmonary B-cell lymphoma. Methods DNA samples were obtained from formalin-fixed, paraffin-embedded sections of pulmonary MALT lymphomas (n=52), diffuse large B-cell lymphomas (DLBCLs, n=18), and benign pulmonary lesions (n=19). All samples were histopathologically reviewed by experienced hematopathologists, and the clonality of all MALT lymphoma cases was confirmed by a polymerase chain reaction (PCR)-based IGH rearrangement clonality assay. They were also tested for the API2-MALT1 fusion transcript. The presence of bacterial DNA was assessed with a nested PCR, and DNA sequencing was performed to confirm the PCR specificity. Results A. xylosoxidans DNA was detected in 1/52 cases of pulmonary MALT lymphoma, 2/18 cases of DLBCL, and 0/19 cases of benign pulmonary lesions. The prevalence of A. xylosoxidans in pulmonary lymphoma was not significantly higher than in benign lesions. Conclusion The present study shows that A. xylosoxidans infection may not be associated with pulmonary B-cell lymphoma in a Japanese case series. Large-scale international studies are needed to clarify the role of A. xylosoxidans in pulmonary lymphoma. PMID- 29151526 TI - Recent Inferior Myocardial Infarction Complicated with a Right Ventricular Thrombus Detected by Three Cardiac Imaging Modalities. AB - We report the case of a 71-year-old woman diagnosed with recent inferior myocardial infarction complicated with right ventricular infarction and a right ventricular thrombus. Three-dimensional transthoracic echocardiography, contrast enhanced computed tomography, and cardiac magnetic resonance imaging clearly detected a thrombus. We consider cases with a recent right ventricular infarction to require assessment for thrombus formations in the right ventricle. Fortunately, vigorous anticoagulation therapy resolved the thrombi in both the right ventricle and right coronary artery. PMID- 29151528 TI - Degeneration of the Substantia Nigra Following Ipsilateral Striatal Infarction. PMID- 29151527 TI - Gastrointestinal Involvement in m.3243A>G-associated MELAS. PMID- 29151529 TI - Rare Case of Pancreatic Cystic Lymphangioma. AB - Pancreatic cystic lymphangioma is an extremely rare tumor. The characteristic imaging findings are poorly defined, and distinguishing between this disease and other pancreatic cyst-related tumors is very difficult. We herein report a case of a Japanese woman in her 50s with this lesion, located in the tail of the pancreas. Pancreatic cystic lymphangioma should therefore be considered in the differential diagnosis of pancreatic cystic lesions. Laparoscopic resection can be a useful, minimally invasive surgical approach for treating these cysts as well as for the treatment of benign or low-grade malignant tumors located in the pancreatic body or tail. PMID- 29151531 TI - Repeated Hypoglycemic Episodes with Postprandial Hyperinsulinemia after the Recovery from Acute Weight Loss Revealed by Continuous Glucose Monitoring and the Oral Glucose Tolerance Test. AB - We herein report a case of a 20-year-old woman who experienced hypoglycemia in parallel with acute weight loss confirmed by continuous glucose motoring (CGM). When she recovered from the acute weight loss, CGM revealed nocturnal and postprandial hypoglycemia. Six months were required to resolve the hypoglycemia and hyperinsulinemia after the recovery of her weight. Our case suggests that the adaption of insulin secretion to the rapid loss of weight and to the recovery of weight may require a long period of time, leading to the excessive secretion of insulin relative to the glucose level and repeated hypoglycemic episodes with postprandial hyperinsulinemia. PMID- 29151530 TI - Successful Autologous Hematopoietic Stem Cell Transplantation Followed by Bortezomib Maintenance in a Patient with Relapsed CD138-low Multiple Solitary Plasmacytomas Harboring a 17p Deletion. AB - Solitary bone plasmacytoma (SBP) tends to progress to multiple myeloma (MM); however, progression to multiple solitary plasmacytomas (MSP) is rare. We report a case of CD138-low MSP with 17p deletion in a patient with relapsed SBP. 17p deletion is associated with a poor outcome in patients with MM, and the low expression of CD138 in myeloma cells is associated with drug resistance and a poor prognosis. The patient was successfully treated with bortezomib plus dexamethasone induction therapy and autologous hematopoietic stem cell transplantation followed by bortezomib maintenance therapy. Consequently, bortezomib treatment was stopped and a stringent complete response has been maintained. PMID- 29151533 TI - Acute Urinary Retention Induced by Chemical Meningitis Which Occurred Due to a Ruptured Dermoid Cyst. AB - Meningitis retention syndrome (MRS), a rare complication of aseptic meningitis, can present with acute urinary retention. The rupture of a dermoid cyst, which is a benign intracranial tumor, can sometimes induce chemical meningitis. We herein present a case of chemical meningitis and acute urinary retention that was induced by the rupture of a dermoid cyst. The patient experienced urinary retention for approximately 60 days, and then made a complete recovery thereafter. This is the first reported case of acute urinary retention due to the rupture of a dermoid cyst. PMID- 29151534 TI - A Case of Colobronchial Fistula Causing Foul-smelling Sputum with a Fecal Odor. PMID- 29151535 TI - Multiple Endotracheal Metastases of Lung Cancer after Bronchoscopic Intervention. AB - A 65-year-old man presented with obstructive pneumonia due to squamous cell carcinoma of the lung, which invaded the right main bronchus. Argon plasma coagulation was performed, which reduced his symptoms. Right pneumonectomy was performed after preoperative chemotherapy; the pathological diagnosis was T3N1M0 Stage IIIA. Fifteen months after surgery, he presented with bloody sputum. Bronchoscopy showed multiple endotracheal tumors, and a pathological examination revealed squamous cell carcinoma; the same histology as the primary lung cancer. We hypothesized that direct implantation during bronchoscopic therapy or hematogenous or lymphatic spread might have led to metastasis. A careful follow up is required after bronchoscopic therapy. PMID- 29151532 TI - Association of Admission Glucose Level and Improvement in Pulmonary Artery Pressure in Patients with Submassive-type Acute Pulmonary Embolism. AB - Objective The admission glucose level is a predictor of mortality even in patients with acute pulmonary embolism (APE). However, whether or not the admission glucose level is associated with the severity of APE itself or the underlying disease of APE is unclear. Methods This study was a retrospective observational study. A pulmonary artery (PA) catheter was used to accurately evaluate the severity of APE. The percentage changes in the mean PA pressure (PAPm) upon placement and removal of the inferior vena cava filter (IVCF) were evaluated. We hypothesized that the admission glucose level was associated with the improvement in the PA pressure in patients with APE. Patients A total of consecutive 22 patients with submassive APE who underwent temporary or retrievable IVCF insertion on admission and repetitive PA catheter measurements upon placement and removal of IVCFs were enrolled. Results There was a significant positive correlation between the admission glucose levels and the percentage changes in the PAPm (r=0.543, p=0.009). A univariate linear regression analysis showed that the admission glucose level was the predictor of the percentage change in PAPm (beta coefficient=0.169 per 1 mg/dL; 95% confidence interval, 0.047-0.291; p=0.009). A multivariate linear regression analysis with the forced inclusion model showed that the admission glucose level was the predictor of the percentage change in PAPm independent of diabetes mellitus, PAPm on admission, troponin positivity, and brain natriuretic peptide level (all p<0.05). Conclusion The admission glucose level was associated with the improvement in the PAPm in patients with submassive-type APE. PMID- 29151536 TI - Bilateral Hippocampal Infarction Mimicking Limbic Encephalitis. PMID- 29151537 TI - Ectopic Pancreatitis of the Jejunal Mesentery. PMID- 29151538 TI - Iron Deficiency Anemia Due to the Long-term Use of a Proton Pump Inhibitor. AB - A 52-year-old man who had been taking omeprazole, a proton pump inhibitor (PPI), for 25 years developed iron deficiency anemia. An evaluation of the entire gastrointestinal tract did not reveal any possible causes of gastrointestinal blood loss. The cause of the iron deficiency was considered to be a reduction in gastrointestinal iron absorption in association with the reduced secretion of gastric acid due to PPI use. This case demonstrates that long-term PPI use for as long as 25 years may cause iron deficiency anemia and should be considered in the differential diagnosis of iron deficiency anemia in long-term PPI users. PMID- 29151539 TI - Transient Collateral Arteries Developed during Coronary Vasospasm. PMID- 29151540 TI - Japanese Cardiovascular Disease Patients with Diabetes Mellitus Suffer Increased Tooth Loss in Comparison to Those without Diabetes Mellitus -A Cross-sectional Study. AB - Objective Tooth loss is an irreversible condition that reflects the end-stage of oral diseases, including periodontitis. Although periodontitis is a major factor in the progression of diabetes mellitus (DM) and cardiovascular disease (CVD), no previous studies have compared tooth loss in CVD patients with and without DM. Methods The subjects included CVD patients with (n=94) and without (n=145) DM who attended Tokyo Medical and Dental University Hospital. Blood examinations and periodontal measurements were performed. Results The oral and periodontal examinations revealed that the numbers of missing teeth in the DM group were increased in comparison to the non-DM group. There was no significant difference between the groups with regard to the incidence of edentulism, the probing pocket depth, the clinical attachment level or the incidence of bleeding on probing. Conclusion We showed that the numbers of missing teeth among CVD patients with DM was significantly higher than that among CVD patients without DM. PMID- 29151541 TI - Gastro-intestinal Involvement in m.3243A>G-associated Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes. PMID- 29151542 TI - Ramucirumab Plus Paclitaxel: A Possible New Chemotherapy Regimen for Neuroendocrine Carcinoma of the Stomach. PMID- 29151543 TI - [Preface for Special Issue on the Functional Image]. PMID- 29151544 TI - [Creation and Evaluation of Educational Programs for Additional Delayed Scan of FDG-PET/CT]. AB - : Generally, FDG-PET/CT image is acquired at the 60th minute after tracer administration. Depending on the clinical case, additional delayed scans may be useful. However, it is difficult to judge whether additional delayed scan is useful or not. The purposes of this study were creation and evaluation of educational programs to help radiological technologists to decide the usefulness of additional delayed scan of FDG-PET/CT. METHODS: Educational programs consisted of the instructional materials and the judgment test of clinical cases. The instructional materials provided the valuable findings for differentiation between uptake in the wall of the colon and colon content, distinction between uptake in the lymph node and urinary tract, and evaluation of malignancy. The judgment test of clinical cases consisted of 10 cases selected by a nuclear medicine physician (for 5 of that cases additional delayed scan was decided to be useful). Five experienced technologists and five inexperienced technologists scored the volubility of additional delayed scan pre- and post-training using the instructional materials (the full marks of score is 5). RESULTS: After the educational programs using the instructional materials, the score was improved with the significant difference in both experienced (pre: 3.6+/-1.4, post: 4.0+/ 1.2) and inexperienced (pre: 2.8+/-1.5, post: 3.7+/-1.5) groups (p<0.05). CONCLUSION: According to the educational programs, technologist might be able to decide whether the additional delayed scan is useful or not. The successful results of this study may improve the interpretation or reduce the total exposure dose of the PET/CT scan. PMID- 29151545 TI - [Novel Perfusion Evaluation Method Using Phase-ratio Image Map in Head 4D-CT]. AB - PURPOSE: CT perfusion (CTP) is a powerful tool for the assessment of cerebrovascular disease. However, CTP maps are significantly different depending on CTP software and algorithm, even when using identical image data. We developed a phase-ratio image map (PI map), which was a novel perfusion map, without using CTP software. The purpose of this study was to investigate the usefulness of the PI map by comparing it with a positron emission tomography (PET) image. METHODS: Twenty patients (16 men, 4 women; mean age: 61.6 years) with unilateral cervical and intracranial steno-occlusive disease underwent CTP. CTP source images were obtained at 1-s intervals of 23 times and 5 intervals using dynamic multiphase imaging. An early-phase image was generated by computing the average of CT images for 5 s in the vicinity of the peak enhancement curve of a normal hemisphere. A delayed-phase image was generated by computing the average of CT images for 5 s immediately after the early phase. The PI map was created by dividing the delayed phase image by the early-phase image. We investigated the validity of the PI map compared with PET-cerebral blood flow (CBF). Lesion-to-normal ratios between a PET-CBF and the PI map or two conventional CTP-CBFs were observed and compared, and the relative errors were also compared. RESULT: There was a strong correlation between the PET-CBF and the PI map (R=0.82). Correlations between the PET-CBF and two CTP-CBFs were weak (R=0.30) and middle (R=0.62), respectively. The relative error between the PI map and the PET-CBF was within 10% in most cases. CONCLUSION: The PI map was more similar to the PET-CBF on perfusion evaluation, and did not depend on CTP software. The robustness and simplicity of the PI mapping method would be advantageous compared with conventional CTP mapping methods. PMID- 29151546 TI - [A Comparison of Planar Sensitivity and Spatial Resolution among Different Collimators and Energy Windows on 223Ra Imaging]. AB - OBJECTIVE: The present study aimed to reveal the influence of combination of different collimators and energy windows on the planar sensitivity and the spatial resolution during experimental 223Ra imaging, and to determine optimal imaging parameters. METHODS: A vial type source containing 223Ra solution (4.55 MBq / 5.6 ml) was placed in the air at 100 mm away from the collimator surface. Planar images were acquired with LEHR, LMEGP, ELEGP and MEGP collimators on two dual-head gamma cameras (Symbia intevo (Siemens) and Infinia 3 (GE)). We compared three energy window combinations: 1) single window at 82 keV, 2) double window at 82+154 keV, 3) triple window at 82+154+270 keV. The energy spectrum, the sensitivity and the spatial resolution, such as full-width at half-maximum (FWHM) and full-width at tenth-maximum (FWTM), of each collimator were assessed. RESULTS: Five energy spectra (at around 82, 154, 270, 351 and 405 keV) were essentially observed among four collimators. The sensitivity was high for LEHR collimator, then ELEGP and LMEGP collimator was 3-4 fold, which is greater than MEGP collimator. The 82 keV energy window of four collimators has best spatial resolution. Moreover, the spatial resolution of the 82 keV energy window with LMEGP and ELEGP collimator was almost equal to that of the triple window with MEGP collimator. CONCLUSIONS: Optimal imaging parameters were single energy window using LMEGP or ELEGP, and then triple energy window using MEGP collimator. PMID- 29151547 TI - [The Effect of Reconstruction Method on the Ability to Analyze of FFR Using CT]. AB - BACKGROUND: Invasive-fractional flow reserve (FFR) is the reference standard to evaluate functional ischemia of coronary arteries, and is used to decide if percutaneous transluminal coronary angioplasty is necessary. Recently, computed tomography-derived FFR (CT-FFR) is emerged as an alternative non-invasive method. OBJECTIVES: To evaluate the effect of reconstruction methods and image parameters on the accuracy of CT-FFR calculation. METHODS: A total of 26 segments in the consecutive 10 coronary CT angiography (CCTA) studies were evaluated. All studies were reconstructed using three different techniques: 1) filtered back projection (FBP), 2) adaptive iterative dose reduction 3D (AIDR 3D), and 3) forward projected model-based iterative reconstruction solution (FIRST). Vessel segmentation was performed automatically by CT-FFR software, with manual adjustment if necessary. Calculated CT-FFR was compared with the invasive FFR data. RESULTS: Compared to FBP, AIDR 3D and FIRST resulted in more successful automatic segmentation. When using FIRST, 7 segments (27%) were completed without manual adjustment. These segments had relatively larger vessel diameter, higher CT number, and lower noise. The difference between the calculated CT-FFR and invasive-FFR was 0.02+/-0.01. Among the remaining, 10 segments (38%) required manual adjustments of centerline, 7 segments (27%) required manual adjustments of contour, and 2 segments (8%) did not reach to the CT-FFR calculation. CONCLUSION: AIDR 3D and FIRST were useful for reliable automatic segmentation and analysis of CT-FFR. PMID- 29151548 TI - [Functional Brain Imaging with MR Scanner]. PMID- 29151549 TI - [Evaluation of Brain Ischemia in CT Perfusion]. PMID- 29151550 TI - [Quantitative Assessment in Amyloid-PET Imaging]. PMID- 29151551 TI - [Standards for Dose Management on Radiation System]. PMID- 29151552 TI - [Let's Utilize Japanese Society of Radiological Technology]. PMID- 29151553 TI - Chinese single herbs and active ingredients for postmenopausal osteoporosis: From preclinical evidence to action mechanism. AB - Postmenopausal osteoporosis is a systemic metabolic skeletal disease generally ascribable to a dearth of estrogen. Whether traditional Chinese medicine is effective in management of postmenopausal osteoporosis remains unclear. This article reviews the experimental evidence of both in vitro and in vivo preclinical studies with the theme of the application of Chinese single herbs and active ingredients in postmenopausal osteoporosis. It includes three single herbs (Herba Epimedium, Rhizoma Drynariae, and Salvia miltiorrhiza) and eight active ingredients (saikosaponins, linarin, echinacoside, sweroside, psoralen, poncirin, vanillic acid, and osthole). The experimental studies indicated their potential use as treatment for postmenopausal osteoporosis and investigated the underlying mechanisms including osteoprotegerin/receptor activator of nuclear factor kappaB ligand (OPG/RANKL), extracellular-signal-regulated kinase/c-Jun N terminal kinase/mitogen-activated protein kinase (ERK/JNK/MAPK), estrogen receptor (ER), bone morphogenetic protein (BMP), transforming growth factor (TGF)-beta, Wnt/beta catenin, and Notch signaling pathways. This review contributes to a better understanding of traditional Chinese medicine and provides useful information for the development of more effective anti-osteoporosis drugs. PMID- 29151554 TI - Social support and care needs of the disabled elderly population: An empirical study based on survey data from Beijing, China. AB - In order to describe and examine differences in social support and care needs among disabled Chinese elderly, the current study used stratified sampling to survey local residents of Beijing age 60 or over in the districts of Xicheng, Chaoyang, and Tongzhou in 2016. Structured in-person interviews were conducted with a 7-domain questionnaire. Multiple logistic regressions were used to compare social support and care needs among functioning, partially disabled, and completely disabled elderly. All statistical analyses were performed using SPSS 19.0 with a significance level of 0.05 (two-sided). One thousand and eighty-three residents completed the survey. Based on Activities of Daily Living (ADL) scores, 736 (68.0%) respondents were functioning (ADL score = 14), 167 (15.4%) were partially disabled (14 < ADL score < 22), and 180 (16.6%) were fully disabled (ADL score >= 22). Most of the disabled had formal financial support, they received daily care at home, and they received modest emotional support. After controlling for confounding factors, fully disabled respondents were 2.35 times (p = 0.018) more likely to receive financial support and 3.65 times (p = 0.003) more likely to receive emotional support than functioning respondents. However, the fully functioning and partially disabled did not differ significantly in terms of financial or emotional support. Compared to fully functioning respondents, partially disabled respondents were 0.49 (p < 0.001) times less likely to be fully satisfied with their daily care while fully disabled respondents were 0.37 (p < 0.001) times less likely to be fully satisfied with that care. The current study provided a thorough depiction of the current status of social support and care needs of disabled Chinese elderly. More attention should be paid to social support for the partially disabled and daily care for both the partially and fully disabled. PMID- 29151555 TI - Activity outside the home, environmental barriers, and healthy aging for community-dwelling elderly individuals in China. AB - Elderly individuals benefit from frequently engaging in activities outside the home because such activities sustain the overall health and functioning of an aging body. However, environmental barriers can limit participation in activities outside the home by elderly individuals. The current study examined the factors that influence the frequency with which elderly individuals living in China engage in activity outside the home. Data were collected from 2,402 elderly individuals residing in the Jiangning district of Shanghai, China in 2015. Face to-face interviews were conducted based on a questionnaire, and multiple regression analysis was used to measure influencing factors. Results revealed that elderly respondents with a better self-reported health status (p = 0.2499) engaged in activities outside the home more frequently. In addition, elderly respondents residing on higher floors of multi-floor residential buildings (p < 0.001) were less likely to participate in activities outside of the home. This effect was virtually eliminated, however, when the residence in question was equipped with an elevator (p < 0.001). PMID- 29151556 TI - [An Integrative Review of Home Care Service for Pregnant Women, Mothers, Infants, and Toddlers in Vulnerable Group]. AB - PURPOSE: This study was intended to integrate the evidence of home care service intervention for mothers and children in vulnerable groups through an integrative literature review. METHODS: We searched the MEDLINE (PubMED), EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, DBpia databases. The quality of the articles was assessed by one doctoral researcher and verified by one professor of community health nursing who had participated in the systematic review of literature. A framework was developed to identify the intervention patterns in the selected papers and categorize various elements. The extracted intervention elements were grouped into potential themes, which were verified by assessors on whether they clearly reflected the interventions in the papers. RESULTS: Among 878 searched papers, we selected 16 papers after excluding literature that does not satisfy the selection criteria and quality evaluation. The intervention elements of 16 selected papers were categorized into six themes. The extracted intervention elements were divided into the themes of Patient specific/Situation-specific care planning and intervention, Emphasis on self care competency, Intense home visit by developmental milestone, Reinforcing and modeling mother-child attachment, Communication and interaction across the intervention, Linkage with community resource and multidisciplinary approach. CONCLUSION: As a result of the analysis of proper interventions of home care services for mothers and children in vulnerable groups, it was found that it is necessary to consider indispensable intervention elements that can standardize the quality of home care services, and conduct studies on developing intervention programs based on the elements. PMID- 29151557 TI - [Development of the Transition Shock Scale for Newly Graduated Nurses]. AB - PURPOSE: The purpose of this study was to develop a scale to assess the transition shock experienced by newly graduated nurses, and test the validity and reliability of the scale. METHODS: The initial items were identified through a review of literature and in-depth interviews with nine newly graduated nurses. Content validation of the items was evaluated by five nurse professors and three nurses. Participants were 269 newly graduated nurses who worked at six acute care hospitals in Busan, Ulsan, and Yangsan, South Korea. Data were analyzed using item analysis, exploratory and confirmatory factor analysis, criterion related validity, and internal consistency. RESULTS: The final scale consisted of 18 items and six factors (conflict between theory and practice, overwhelming workload, loss of social support, shrinking relationship with co-workers, confusion in professional nursing values, and incongruity in work and personal life), which explained 71.3% of the total variance. The six subscale model was validated by confirmatory factor analysis. Cronbach's alpha for the total items was. 89. Convergent validity was evaluated by analyzing total correlation with burnout (r=.71, p<.001) and turnover intention (t=5.84, p<.001). CONCLUSION: This scale can be used in the development of nursing interventions to reduce the transition shock experienced by newly graduated nurses. PMID- 29151558 TI - [A Comparison of Hospice Care Research Topics between Korea and Other Countries Using Text Network Analysis]. AB - PURPOSE: This study aimed to identify and compare hospice care research topics between Korean and international nursing studies using text network analysis. METHODS: The study was conducted in four steps: 1) collecting abstracts of relevant journal articles, 2) extracting and cleaning keywords (semantic morphemes) from the abstracts, 3) developing co-occurrence matrices and text networks of keywords, and 4) analyzing network-related measures including degree centrality, closeness centrality, betweenness centrality, and clustering using the NetMiner program. Abstracts from 347 Korean and 1,926 international studies for the period of 1998-2016 were analyzed. RESULTS: Between Korean and international studies, six of the most important core keywords-"hospice," "patient," "death," "RNs," "care," and "family"-were common, whereas "cancer" from Korean studies and "palliative care" from international studies ranked more highly. Keywords such as "attitude," "spirituality," "life," "effect," and "meaning" for Korean studies and "communication," "treatment," "USA," and "doctor" for international studies uniquely emerged as core keywords in recent studies (2011~2016). Five subtopic groups each were identified from Korean and international studies. Two common subtopics were "hospice palliative care and volunteers" and "cancer patients." CONCLUSION: For a better quality of hospice care in Korea, it is recommended that nursing researchers focus on study topics of patients with non-cancer disease, children and family, communication, and pain and symptom management. PMID- 29151559 TI - [Effects of Education about Action Plans according to Self-Monitoring on Self Management Adherence, Knowledge, Symptom Control, and Quality of Life among Adult Asthma Patients: A Randomized Controlled Trial]. AB - PURPOSE: This study was conducted to identify the effects of education regarding action plans according to a self-monitoring program on self-management adherence, knowledge, symptom control, and health-related quality of life (HRQoL) among adults with asthma. METHODS: Thirty-four patients were randomly assigned to the intervention group and thirty-two to the control group in this study. A tailored 50-minute intervention based on the contents of self-monitoring and action plans developed by the National Heart Lung and Blood Institute was provided to the intervention group. Structured and well developed questionnaires were used to measure the dependent variables. RESULTS: There were no differences in all general and clinical characteristics, and the dependent variables between two groups in the pre-test. In the post-test, there were differences in the level of self-management adherence (t=4.41, p<.001), knowledge (t=2.26, p=.027), symptom control (t=-2.56, p=.013), and total HRQoL (t=2.14, p=.036) between the two groups, although there was a difference only in the sub-domain of emotion (t=2.03, p=.047) in HRQoL. CONCLUSION: This study found that action plans according to self-monitoring that enhance a participatory interaction in the treatment and care could help patients with moderate to severe asthma to engagead equately in self-care, to control their symptoms, and to improve their HRQoL. Further studies are still needed to identify longitudinal effects of this program. PMID- 29151560 TI - [Structural Equation Modeling on Health-Related Quality of Life in Adults with Epilepsy]. AB - PURPOSE: This study aimed to identify variables influencing the health-related quality of life (HRQoL) of adults with epilepsy in order to establish a structural model and design an intervention strategy to improve patients' HRQoL. METHODS: The selected subjects were 212 patients with epilepsy aged between 18 and 70 years who were currently receiving treatment from hospital, general hospital, and clinic. They were surveyed using a structured questionnaire. RESULTS: The goodness of fit measures of the final hypothetical model were as follows: chi2/df=2.51, GFI=.91, AGFI=.90, CFI=.96, SRMR=.04, NFI=.93, and RMSEA=.08. The major variables influencing the HRQoL of adults with epilepsy were epilepsy self-efficacy, depression, social support, and side effects of anti epileptic drugs (AEDs), which were significant in the mentioned order, whereas the duration of AEDs use and perceived stigma did not show any effects. Six variables accounted for 75.6% of HRQoL. Variables having a direct and total effect on the HRQoL of adults with epilepsy were the side effects of AEDs, social support, epilepsy self-efficacy, and depression, and those with an indirect effect were the side effects of AEDs and social support. CONCLUSION: It is necessary to accurately identify the side effects of AEDs in adults with epilepsy and accurately observe the physical changes caused by depression. In addition, it is imperative to establish an active and effective nursing intervention program to strengthen the self-efficacy of the patients and to improve their quality of life through social support provided by family members and medical professionals. PMID- 29151561 TI - [Effects of a Positive Psychotherapy Program on Positive Affect, Interpersonal Relations, Resilience, and Mental Health Recovery in Community-Dwelling People with Schizophrenia]. AB - PURPOSE: Recently, the interest in positive psychotherapy is growing, which can help to encourage positive relationships and develop strengths of people. This study was conducted to investigate the effects of a positive psychotherapy program on positive affect, interpersonal relations, resilience, and mental health recovery in community-dwelling people with schizophrenia. METHODS: The research was conducted using a randomized control group pretest-posttest design. A total of 57 adults with schizophrenia participated in this study. The study participants in experimental group received a positive psychotherapy program (n=28) and the participants in control group received only the usual treatment in community centers (n=29). The positive psychotherapy program was provided for 5 weeks (of 10 sessions, held twice/week, for 60 minutes). The study outcomes included positive affect, interpersonal relations, resilience, and mental health recovery. The collected data were analyzed using repeated measures ANOVA for examining study hypothesis. RESULTS: Results showed that interpersonal relations (F=11.83, p=.001) and resilience (F=9.62, p=.003) significantly increased in the experimental group compared to the control group. Although experimental group showed a slight increase in positive affect, it was not significant. CONCLUSION: The study findings confirm that the positive psychotherapy program is effective for improving interpersonal relations and resilience of community-dwelling people with schizophrenia. Based on the findings, we believe that the positive psychotherapy program would be acceptable and helpful to improve recovery of mental health in schizophrenia. PMID- 29151562 TI - [Effects of a Sleep Improvement Program Combined with Aroma-Necklace on Sleep, Depression, Anxiety and Blood Pressure in Elderly Women]. AB - PURPOSE: The purpose of this study was to evaluate the effectiveness of a sleep improvement program combined with an aroma-necklace on sleep, depression, anxiety, and blood pressure in elderly women living at home. METHODS: A program consisting of a four-week (one hour per week) sleep improvement intervention plus use of an aroma-necklace, was developed based on Cox's Interaction Model of Client Health Behavior. 70 elderly women were assigned to the experimental (n=35) or control group with no intervention (n=35). Data from 62 participants (32 in the experimental and 30 in the control) were analyzed using the SPSS 21.0 program. Women in the experimental group were instructed to constantly wear the aroma necklace filled with marjoram and orange oil until the program was completed. Sleep quality, sleep duration, sleep satisfaction, depression, anxiety, and blood pressure were measured to identify the effectiveness of the program. RESULTS: Significant group differences were found in sleep quality (t= 5.10, p<.001), sleep duration (z=-3.10, p=.002), sleep satisfaction (z=-4.13, p=<.001), depression (t=2.53, p=.015), and anxiety (z=-2.47, p=.014). No differences were found in the systolic or diastolic blood pressure. CONCLUSION: The results indicate that a sleep improvement program combined with an aroma necklace was effective in improving sleep disturbances in elderly women living at home. Nurses may contribute to improving sleep among elderly women by applying this program to aged women living in various environments. PMID- 29151563 TI - [Structural Equation Modeling of Self-Management of Liver Transplant Recipients]. AB - PURPOSE: The purpose of this study was to construct and test a structural equation model of self-management of liver transplant recipients based on self determination theory. METHODS: Participants were 275 outpatients who received liver transplantation. A structured self-report questionnaire was used to assess health care providers' autonomy support, transplant-related characteristics, illness consequence perception, autonomy, competence, family relatedness, depression and self-management. Collected data were analyzed using SPSS/WIN 24.0 and AMOS 24.0 program. RESULTS: The modified model showed a good fitness with the data: GFI=.96, RMSEA=.06, CFI=.96, NFI=.93, TLI=.93, PGFI=.43, PNFI=.49. The health care providers' autonomy support, competence, family relatedness and depression were factors with a direct influence on the self-management of liver transplant recipients. The health care providers' autonomy support and illness consequence perception had an indirect influence through competence, family relatedness and depression. However, the transplant-related characteristics and autonomy did not have a significant effect on self-management. This model explained 59.4% of the variance in self-management. CONCLUSION: The result suggests that continuous education must be done to promote the competence of liver transplant recipients and to encourage the patient to positively perceive their current health condition with a view that enhances one's self-management. Additionally, the liver transplant recipients should be screened for depression, which would affect self-management. Most of all, health care providers, who have the most influence on self-management, should improve therapeutic communication and try to form a therapeutic relationship with the liver transplant recipients. PMID- 29151564 TI - [Patterns and Influential Factors of Inter-Regional Migration of New and Experienced Nurses in 2011~2015]. AB - PURPOSE: The purpose of this study was to analyze the migration patterns of new nurses and experienced nurses and to identify the factors influencing inter regional migration for solving regional imbalances of clinical nurses in South Korea. METHODS: This study involved a secondary analysis of data from the Health Insurance Review and Assessment Service (HIRA). Data were analyzed using descriptive statistics and multiple logistic regression analysis. RESULTS: New nurses tended to migrate from Kyunggi to Seoul. However, experienced nurses tended to migrate from Seoul and Chungchung to Kyunggi. Significant predictors of inter-regional migration among new nurses were location and nurse staffing grade of hospitals. Significant predictors of inter-regional migration among experienced nurses were location, hospital type, nurse staffing grade, ownership of hospitals and age of nurses. CONCLUSION: Inter-regional migration occupied a small portion of total hospital movement among clinical nurses. The regional imbalances of nurses were not caused by the migration from non-metropolitan areas to Seoul. Nurse shortage problems in the small and medium hospitals of the non metropolitan area can be solved only through improvement of work environment. PMID- 29151565 TI - Effects of a Cognitive Rehearsal Program on Interpersonal Relationships, Workplace Bullying, Symptom Experience, and Turnover Intention among Nurses: A Randomized Controlled Trial. AB - PURPOSE: This research aimed to investigate the effects of a cognitive rehearsal program (CRP) on workplace bullying among nurses. METHODS: A randomized controlled trial was performed. Participants were 40 nurses working in different university hospitals in B city, South Korea. The experimental group was provided with a 20-hour CRP comprising scenarios on bullying situations, standard communication, and role-playing. To evaluate effects of the CRP, we measured interpersonal relationships, workplace bullying, symptom experience, and turnover intention at preand post-intervention. Follow-up effect was measured in the experimental group only at 4 weeks after the intervention. RESULTS: After the intervention, there were significant differences in interpersonal relationships (F=6.21, p=.022) and turnover intention (F=5.55, p=.024) between experimental and wait-list groups. However, there was no significant difference in workplace bullying or symptom experience between the 2 groups. The beneficial effects on interpersonal relationships and turnover intention lasted at least up to 4 weeks after CRP. CONCLUSION: The CRP for workplace bullying improves interpersonal relationships and decreases turnover intention. So it can be utilized as one of the personal coping strategies to reduce the the turnover among nurses. Further studies on the effects of unit- or hospital-based CRP and on the long-term effects of CRP are necessary. PMID- 29151566 TI - Effects of Bullying Experience on Psychological Well-Being Mediated by Conflict Management Styles and Psychological Empowerment among Nursing Students in Clinical Placement: A Structural Equation Modeling Approach. AB - PURPOSE: This study aimed to test a proposed structural equation model in which bullying experience, conflict management styles and psychological empowerment predict psychological well-being among Chinese nursing students in clinical placement. METHODS: Three hundred and sixty-six nursing students recruited from five hospitals in J city and Y city were assessed with self-report questionnaires on bullying experience, conflict management styles, psychological empowerment and psychological well-being including depression, self-esteem, and academic major satisfaction. Data were analyzed using SPSS version 20.0 and AMOS version 22.0. RESULTS: The evaluation parameters included the comparative fit index at .90, the goodness of fit index at .93, the root mean square error of approximation at .07, and chi2/df ratio at 2.66, indicating that the proposed structural equation model provided a good fit to the data. Experience of being bullied during clinical placement, conflict management styles and psychological empowerment explained 93.0% of the variance and had significant effects on psychological well-being, with conflict management styles and psychological empowerment mediating the association between bullying and psychological well-being. CONCLUSION: The findings indicated that mediation by conflict management styles and psychological empowerment alleviated the negative influence of bullying on psychological well being. To limit bullying and its negative effects, development of effective guidelines to deal with bullying will be a critical tool for both Chinese nursing students and their instructors. Further research should incorporate conflict management styles and psychological empowerment into the specific intervention strategies for handling bullying behaviors among nursing students and staff nurses and promoting nursing students' psychological well-being. PMID- 29151567 TI - [Corrigendum: Evolutionary Concept Analysis of Spirituality]. AB - This corrects the article on p. 242 in vol. 47, PMID: 28470161. PMID- 29151568 TI - A Comparison of the Mini-Open Wiltse Approach with Pedicle Screw Fixation and the Percutaneous Pedicle Screw Fixation for Neurologically Intact Thoracolumbar Fractures. AB - BACKGROUND The thoracolumbar AO type A3 fracture is an incomplete burst fracture, which affects one vertebral body endplate. The objective of this study was to determine which of two minimal invasive techniques was more suitable for A3 fractures based on clinical and radiographic results. MATERIAL AND METHODS We studied 112 patients with A3 subtype fractures without neurological deficits. A total of 63 patients received percutaneous pedicle screw fixation (PPSF), and 49 patients were treated using mini-open Wiltse approach with pedicle screw fixation (MWPSF). The clinical outcomes, surgery-related results, and the pre-operative and post-operative radiological findings were compared between the two groups. RESULTS The length of incision, intra-operative blood loss, post-operative hospitalization time, visual analog score (VAS), Oswestry disability index (ODI), and accuracy rate of pedicle screw placement were compared between the PPSF and MWPSF groups, with no significant differences found (p>0.05). However, the vertebral body angle (VBA) and Cobb's angle in the MWPSF group was much better than in the PPSF group (p<0.05). The operating time and C-arm exposure time of the MWPSF group were significantly lower than the PPSF group (p<0.05). The operative and post-operative costs of the PPSF group were significantly higher than the MWPSF group (p<0.05). CONCLUSIONS Our study found no significant differences in some clinical outcomes between the two groups. Both treatments were safe and effective for A3 subtype fractures. Nevertheless, given the radiation exposure, reduction of kyphosis, special equipment required, learning curve and hospitalization costs associated with PPSF, we concluded that MWPSF was a better choice for A3 subtype fractures. PMID- 29151569 TI - What Kind of Incision Should Be Made to Reduce the Risk of Incisional Hernia in Kidney Transplantation? AB - BACKGROUND The incidence of incisional hernia following renal transplantation is 1.1% to 3.8%. The risk factors are immunosuppressive medications, impaired tissue quality, neuromuscular trauma due to the operation, and denervation. The incidence has been decreasing based on the shift from hockey-stick incision method to inguinal oblique incision method. The aim of this study was to minimize the development of incisional hernias due to renal transplantation. MATERIAL AND METHODS Twenty-four patients who underwent renal transplantation in 2015-2017 were retrospectively examined. All transplantations were performed with oblique incisions of 10-15 cm in the right or left inguinal region using polydioxanone (No. 2) loop sutures and continuous technique. RESULTS The mean age of study patients was 43 years (range 24-67 years). The mean body mass index (BMI) was 29 kg/m2 (range 25-38 kg/m2). Of these patients, one had diabetes mellitus, two had chronic pulmonary disease, six were obese, one had poliomyelitis sequelae, and seven had hypoalbuminemia. None of the patients had ascites; five patients had a history of surgery for peritoneal dialysis. At the end of the one-year follow-up period, none of the patients had developed an incisional hernia. CONCLUSIONS We conclude that using the smallest possible semilunar line incision in the inguinal region would aid in preventing post-transplantation incisional hernias. PMID- 29151570 TI - A Case Report of Refractory Notalgia Paresthetica Treated with Lidocaine Infusions. AB - BACKGROUND Notalgia paresthetica is a neuropathic condition that manifests as a chronic itch in the thoraco-dorsal region. It is often resistant to treatment, and specific guidelines for its management are lacking. As such, we present a treatment approach with intravenous lidocaine infusions. CASE REPORT The case involves a 50-year-old woman with spinal cord injury caused by an epidural abscess. The patient developed notalgia paresthetica and sublesional neuropathic pain following its drainage. In the course of her pain management, she was treated with intravenous lidocaine which resulted in profound relief of notalgia paresthetica. CONCLUSIONS Intravenous lidocaine was effective in relieving neuropathic itch in the patient case presented. PMID- 29151571 TI - Host-genotype dependent gut microbiota drives zooplankton tolerance to toxic cyanobacteria. AB - The gut microbiota impacts many aspects of its host's biology, and is increasingly considered as a key factor mediating performance of host individuals in continuously changing environments. Here we use gut microbiota transplants to show that both host genotype and gut microbiota mediate tolerance to toxic cyanobacteria in the freshwater crustacean Daphnia magna. Interclonal variation in tolerance to cyanobacteria disappears when Daphnia are made germ-free and inoculated with an identical microbial inoculum. Instead, variation in tolerance among recipient Daphnia mirrors that of the microbiota donors. Metagenetic analyses point to host genotype and external microbial source as important determinants of gut microbiota assembly, and reveal strong differences in gut microbiota composition between tolerant and susceptible genotypes. Together, these results show that both environmentally and host genotype-induced variations in gut microbiota structure mediate Daphnia tolerance to toxic cyanobacteria, pointing to the gut microbiota as a driver of adaptation and acclimatization to cyanobacterial harmful algal blooms in zooplankton. PMID- 29151573 TI - Mixing instabilities during shearing of metals. AB - Severe plastic deformation of solids is relevant to many materials processing techniques as well as tribological events such as wear. It results in microstructural refinement, redistribution of phases, and ultimately even mixing. However, mostly due to inability to experimentally capture the dynamics of deformation, the underlying physical mechanisms remain elusive. Here, we introduce a strategy that reveals details of morphological evolution upon shearing up to ultrahigh strains. Our experiments on metallic multilayers find that mechanically stronger layers either fold in a quasi-regular manner and subsequently evolve into periodic vortices, or delaminate into finer layers before mixing takes place. Numerical simulations performed by treating the phases as nonlinear viscous fluids reproduce the experimental findings and reveal the origin for emergence of a wealth of morphologies in deforming solids. They show that the same instability that causes kilometer-thick rock layers to fold on geological timescales is acting here at micrometer level. PMID- 29151572 TI - Determining therapeutic susceptibility in multiple myeloma by single-cell mass accumulation. AB - Multiple myeloma (MM) has benefited from significant advancements in treatment that have improved outcomes and reduced morbidity. However, the disease remains incurable and is characterized by high rates of drug resistance and relapse. Consequently, methods to select the most efficacious therapy are of great interest. Here we utilize a functional assay to assess the ex vivo drug sensitivity of single multiple myeloma cells based on measuring their mass accumulation rate (MAR). We show that MAR accurately and rapidly defines therapeutic susceptibility across human multiple myeloma cell lines to a gamut of standard-of-care therapies. Finally, we demonstrate that our MAR assay, without the need for extended culture ex vivo, correctly defines the response of nine patients to standard-of-care drugs according to their clinical diagnoses. This data highlights the MAR assay in both research and clinical applications as a promising tool for predicting therapeutic response using clinical samples. PMID- 29151574 TI - Machine learning meets complex networks via coalescent embedding in the hyperbolic space. AB - Physicists recently observed that realistic complex networks emerge as discrete samples from a continuous hyperbolic geometry enclosed in a circle: the radius represents the node centrality and the angular displacement between two nodes resembles their topological proximity. The hyperbolic circle aims to become a universal space of representation and analysis of many real networks. Yet, inferring the angular coordinates to map a real network back to its latent geometry remains a challenging inverse problem. Here, we show that intelligent machines for unsupervised recognition and visualization of similarities in big data can also infer the network angular coordinates of the hyperbolic model according to a geometrical organization that we term "angular coalescence." Based on this phenomenon, we propose a class of algorithms that offers fast and accurate "coalescent embedding" in the hyperbolic circle even for large networks. This computational solution to an inverse problem in physics of complex systems favors the application of network latent geometry techniques in disciplines dealing with big network data analysis including biology, medicine, and social science. PMID- 29151575 TI - New science of climate change impacts on agriculture implies higher social cost of carbon. AB - Despite substantial advances in climate change impact research in recent years, the scientific basis for damage functions in economic models used to calculate the social cost of carbon (SCC) is either undocumented, difficult to trace, or based on a small number of dated studies. Here we present new damage functions based on the current scientific literature and introduce these into an integrated assessment model (IAM) in order to estimate a new SCC. We focus on the agricultural sector, use two methods for determining the yield impacts of warming, and the GTAP CGE model to calculate the economic consequences of yield shocks. These new damage functions reveal far more adverse agricultural impacts than currently represented in IAMs. Impacts in the agriculture increase from net benefits of $2.7 ton-1 CO2 to net costs of $8.5 ton-1, leading the total SCC to more than double. PMID- 29151576 TI - Mapping the sugar dependency for rational generation of a DNA-RNA hybrid-guided Cas9 endonuclease. AB - The CRISPR-Cas9 RNA-guided endonuclease system allows precise and efficient modification of complex genomes and is continuously developed to enhance specificity, alter targeting and add new functional moieties. However, one area yet to be explored is the base chemistry of the associated RNA molecules. Here we show the design and optimisation of hybrid DNA-RNA CRISPR and tracr molecules based on structure-guided approaches. Through careful mapping of the ribose requirements of Cas9, we develop hybrid versions possessing minimal RNA residues, which are sufficient to direct specific nuclease activity in vitro and in vivo with reduced off-target activity. We identify critical regions within these molecules that require ribose nucleotides and show a direct correlation between binding affinity/stability and cellular activity. This is the first demonstration of a non-RNA-guided Cas9 endonuclease and first step towards eliminating the ribose dependency of Cas9 to develop a XNA-programmable endonuclease. PMID- 29151579 TI - TLR5: beyond the recognition of flagellin. PMID- 29151577 TI - Orexin modulates behavioral fear expression through the locus coeruleus. AB - Emotionally salient information activates orexin neurons in the lateral hypothalamus, leading to increase in sympathetic outflow and vigilance level. How this circuit alters animals' behavior remains unknown. Here we report that noradrenergic neurons in the locus coeruleus (NALC neurons) projecting to the lateral amygdala (LA) receive synaptic input from orexin neurons. Pharmacogenetic/optogenetic silencing of this circuit as well as acute blockade of the orexin receptor-1 (OX1R) decreases conditioned fear responses. In contrast, optogenetic stimulation of this circuit potentiates freezing behavior against a similar but distinct context or cue. Increase of orexinergic tone by fasting also potentiates freezing behavior and LA activity, which are blocked by pharmacological blockade of OX1R in the LC. These findings demonstrate the circuit involving orexin, NALC and LA neurons mediates fear-related behavior and suggests inappropriate excitation of this pathway may cause fear generalization sometimes seen in psychiatric disorders, such as PTSD. PMID- 29151580 TI - Rituximab or irradiation promotes IL-17 secretion and thereby induces resistance to rituximab or irradiation. PMID- 29151578 TI - Th1 cytokines, true functional signatures for protective immunity against TB? AB - The lack of an effective preventative vaccine against tuberculosis (TB) presents a great challenge to TB control. Since it takes an extremely long time to accurately determine the protective efficacy of TB vaccines, there is a great need to identify the surrogate signatures of protection to facilitate vaccine development. Unfortunately, antigen-specific Th1 cytokines that are currently used to evaluate the protective efficacy of the TB vaccine, do not align with the protection and failure of TB vaccine candidates in clinical trials. In this review, we discuss the limitation of current Th1 cytokines as surrogates of protection and address the potential elements that should be considered to finalize the true functional signatures of protective immunity against TB. PMID- 29151582 TI - IL-1alpha in acetaminophen toxicity: a sterile danger signal. PMID- 29151583 TI - Diagnostic thresholds for free light chains in multiple myeloma depend on the assay used. AB - Leukemia accepted article preview online, 20 November 2017. doi:10.1038/leu.2017.335. PMID- 29151581 TI - Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses. AB - Immunodeficient mice engrafted with human peripheral blood cells are promising tools for in vivo analysis of human patient individual immune responses. However, when human peripheral blood mononuclear cells (PBMCs) are transferred into NOG (NOD/Shi-scid, IL-2rgnull) mice, severe graft versus host disease (GVHD) hinders long term detailed analysis. Administration of human PBMCs into newly developed murine MHC class I- and class II-deficient NOG (NOG-dKO; NOG- Iab, B2m-double knockout) mice showed sufficient engraftment of human immune cells with little sign of GVHD. Immunization with influenza vaccine resulted in an increase in influenza-specific human IgG Ab, indicating induction of antigen-specific B cells in the NOG-dKO mice. Immunization with human dendritic cells pulsed with HLA-A2 restricted cytomegalovirus peptide induced specific cytotoxic T cells, indicating the induction of antigen-specific T cells in the NOG-dKO mice. Adoptive cell therapies (ACTs) using melanoma antigen recognized by T cells (MART-1)-specific TCR-transduced activated T cells showed strong tumor growth inhibition in NOG-dKO mice without any sign of GVHD accompanied by preferential expansion of the transferred MART-1-specific T cells. ACTs using cultured human melanoma infiltrating T cells also showed anti-tumor effects against autologous melanoma cells in NOG-dKO mice, in which changes in human cancer phenotypes by immune intervention, such as increased CD271 expression, could be evaluated. Therefore, NOG-dKO mice are useful tools for more detailed analysis of both the induction and effector phases of T-cell and B-cell responses for a longer period than regular NOG mice. PMID- 29151584 TI - Towards 'off-the-shelf' genetically modified T cells: prolonging functional engraftment in mice by CD8 veto T cells. PMID- 29151585 TI - Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system. AB - T-cell acute lymphoblastic leukemia (T-ALL) is caused by the accumulation of multiple mutations combined with the ectopic expression of transcription factors in developing T cells. However, the molecular basis underlying cooperation between transcription factor expression and additional oncogenic mutations in driving T-ALL has been difficult to assess due to limited robust T-cell model systems. Here we utilize a new ex vivo pro-T-cell model to study oncogenic cooperation. Using a systems biological approach we first dissect the pro-T-cell signaling network driven by interleukin-7, stem cell factor and Notch1 and identify key downstream Akt, Stat, E2f and Myc genetic signaling networks. Next, this pro-T-cell system was used to demonstrate that ectopic expression of the TAL1 transcription factor and Pten deletion are bona-fide cooperating events resulting in an increased stem cell signature, upregulation of a specific E2f signaling network and metabolic reprogramming with higher influx of glucose carbons into the tricarboxylic acid cycle. This ex vivo pro-T-cell system thereby provides a powerful new model system to investigate how normal T-cell signaling networks are perturbed and/or hijacked by different oncogenic events found in T ALL. PMID- 29151586 TI - H7N9 virulent mutants detected in chickens in China pose an increased threat to humans. AB - Certain low pathogenic avian influenza viruses can mutate to highly pathogenic viruses when they circulate in domestic poultry, at which point they can cause devastating poultry diseases and severe economic damage. The H7N9 influenza viruses that emerged in 2013 in China had caused severe human infections and deaths. However, these viruses were nonlethal in poultry. It is unknown whether the H7N9 viruses can acquire additional mutations during their circulation in nature and become lethal to poultry and more dangerous for humans. Here, we evaluated the evolution of H7N9 viruses isolated from avian species between 2013 and 2017 in China and found 23 different genotypes, 7 of which were detected only in ducks and were genetically distinct from the other 16 genotypes that evolved from the 2013 H7N9 viruses. Importantly, some H7N9 viruses obtained an insertion of four amino acids in their hemagglutinin (HA) cleavage site and were lethal in chickens. The index strain was not lethal in mice or ferrets, but readily obtained the 627K or 701N mutation in its PB2 segment upon replication in ferrets, causing it to become highly lethal in mice and ferrets and to be transmitted efficiently in ferrets by respiratory droplet. H7N9 viruses bearing the HA insertion and PB2 627K mutation have been detected in humans in China. Our study indicates that the new H7N9 mutants are lethal to chickens and pose an increased threat to human health, and thus highlights the need to control and eradicate the H7N9 viruses to prevent a possible pandemic. PMID- 29151589 TI - Transcription: Shedding light on alternative promoter selection. PMID- 29151587 TI - Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington's disease models. AB - Most neurodegenerative disorders are associated with accumulation of disease relevant proteins. Among them, Huntington disease (HD) is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene (HTT). Thus, lowering mutant HTT protein (mHTT) levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPK11 as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values. Interestingly, their effects on HTT levels are mHTT-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 significantly rescues disease-relevant behavioral phenotypes in a knockin HD mouse model. Collectively, our data reveal new therapeutic entry points for HD and target-discovery approaches for similar diseases. PMID- 29151588 TI - Prioritizing diversity in human genomics research. AB - Recent studies have highlighted the imperatives of including diverse and under represented individuals in human genomics research and the striking gaps in attaining that inclusion. With its multidecade experience in supporting research and policy efforts in human genomics, the National Human Genome Research Institute is committed to establishing foundational approaches to study the role of genomic variation in health and disease that include diverse populations. Large-scale efforts to understand biology and health have yielded key scientific findings, lessons and recommendations on how to increase diversity in genomic research studies and the genomic research workforce. Increased attention to diversity will increase the accuracy, utility and acceptability of using genomic information for clinical care. PMID- 29151591 TI - US health policy and prescription drug coverage of FDA-approved medications for the treatment of obesity. AB - OBJECTIVE: Obesity is now the most prevalent chronic disease in the United States, which amounts to an estimated $147 billion in health care spending annually. The Affordable Care Act (ACA) enacted in 2010 included provisions for private and public health insurance plans that expanded coverage for lifestyle/behavior modification and bariatric surgery for the treatment of obesity. Pharmacotherapy, however, has not been included despite their evidence based efficacy. We set out to investigate the coverage of Food and Drug Administration-approved medications for obesity within Medicare, Medicaid and ACA established marketplace health insurance plans. METHODS: We examined coverage for phentermine, diethylpropion, phendimetrazine, Benzphentamine, Lorcaserin, Phentermine/Topiramate (Qysmia), Liraglutide (Saxenda) and Buproprion/Naltrexone (Contrave) among Medicare, Medicaid and marketplace insurance plans in 34 states. RESULTS: Among 136 marketplace health insurance plans, 11% had some coverage for the specified drugs in only nine states. Medicare policy strictly excludes drug therapy for obesity. Only seven state Medicaid programs have drug coverage. CONCLUSIONS: Obesity requires an integrated approach to combat its public health threat. Broader coverage of pharmacotherapy can make a significant contribution to fighting this complex and chronic disease. PMID- 29151590 TI - Microglia and macrophages in brain homeostasis and disease. AB - Microglia and non-parenchymal macrophages in the brain are mononuclear phagocytes that are increasingly recognized to be essential players in the development, homeostasis and diseases of the central nervous system. With the availability of new genetic, molecular and pharmacological tools, considerable advances have been made towards our understanding of the embryonic origins, developmental programmes and functions of these cells. These exciting discoveries, some of which are still controversial, also raise many new questions, which makes brain macrophage biology a fast-growing field at the intersection of neuroscience and immunology. Here, we review the current knowledge of how and where brain macrophages are generated, with a focus on parenchymal microglia. We also discuss their normal functions during development and homeostasis, the disturbance of which may lead to various neurodegenerative and neuropsychiatric diseases. PMID- 29151593 TI - Gene expression profiles indicate tissue-specific obesity regulation changes and strong obesity relevant tissues. AB - BACKGROUND: With the growing evidence that other tissues, apart from adipose, could have strong relevance to obesity, it is necessary to comprehensively understand the relationship between obesity and other tissues, and to point out the most relevant tissues. METHODS: There were 549 participants with 20 different tissue types involved in this study. We firstly employed both Spearman's correlation test and WGCNA (weighted correlation network analysis) to identify body mass index (BMI)-related genes. Subsequently, we performed enrichment analyses with obesity genes and pathways to see the different regulation patterns among tissues. In addition, we compared obesity genes identified by genome-wide association studies (GWAS) with BMI-related genes to find the overlapping proportion in each tissue. Finally, we integrated preceding results to identify six strong obesity relevant tissues and indicate three categories to represent different obesity relevant tissues. RESULTS: Statistical analyses revealed diverse BMI-related genes and tissue-specific enrichment patterns among tissues. Comparison between BMI-related genes and GWAS findings showed tissue-specific expression changes of GWAS genes. Ultimately, six tissues that showed predominant performance in enrichment analyses and significantly embraced GWAS genes were referred to as strong obesity relevant tissues, including adipose, esophagus, nerve, pancreas, pituitary and skin. We also proposed three categories to represent different obesity relevant tissues. CONCLUSIONS: We performed the first study to investigate the BMI-related gene expression changes across 20 tissues at the same time. With valid data analyses and comparison with GWAS findings, our study provides a holistic view of how different tissues correlate with obesity, and proposes target tissues for obesity pathogenesis investigation. PMID- 29151594 TI - Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling. AB - BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPOCM) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSCCM) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPOCM induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells. CONCLUSIONS: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer. PMID- 29151592 TI - Diet-resistant obesity is characterized by a distinct plasma proteomic signature and impaired muscle fiber metabolism. AB - BACKGROUND/OBJECTIVES: Inter-individual variability in weight loss during obesity treatment is complex and poorly understood. Here we use whole body and tissue approaches to investigate fuel oxidation characteristics in skeletal muscle fibers, cells and distinct circulating protein biomarkers before and after a high fat meal (HFM) challenge in those who lost the most (obese diet-sensitive; ODS) vs the least (obese diet-resistant; ODR) amount of weight in a highly controlled weight management program. SUBJECTS/METHODS: In 20 weight stable-matched ODS and ODR women who previously completed a standardized clinical weight loss program, we analyzed whole-body energetics and metabolic parameters in vastus lateralis biopsies and plasma samples that were obtained in the fasting state and 6 h after a defined HFM, equivalent to 35% of total daily energy requirements. RESULTS: At baseline (fasting) and post-HFM, muscle fatty acid oxidation and maximal oxidative phosphorylation were significantly greater in ODS vs ODR, as was reactive oxygen species emission. Plasma proteomics of 1130 proteins pre and 1, 2, 5 and 6 h after the HFM demonstrated distinct group and interaction differences. Group differences identified S-formyl glutathione hydratase, heat shock 70 kDA protein 1A/B (HSP72), and eukaryotic translation initiation factor 5 (eIF5) to be higher in ODS vs ODR. Group-time differences included aryl hydrocarbon interacting protein (AIP), peptidylpropyl isomerase D (PPID) and tyrosine protein-kinase Fgr, which increased in ODR vs ODS over time. HSP72 levels correlated with muscle oxidation and citrate synthase activity. These proteins circulate in exosomes; exosomes isolated from ODS plasma increased resting, leak and maximal respiration rates in C2C12 myotubes by 58%, 21% and 51%, respectively, vs those isolated from ODR plasma. CONCLUSIONS: Findings demonstrate distinct muscle metabolism and plasma proteomics in fasting and post HFM states corresponding in diet-sensitive vs diet-resistant obese women. PMID- 29151595 TI - High fat diet consumption differentially affects adipose tissue inflammation and adipocyte size in obesity-prone and obesity-resistant rats. AB - BACKGROUND/OBJECTIVES: Expanding visceral adiposity is associated with increased inflammation and increased risk for developing obesity-related comorbidities. The goal of this study was to examine high fat diet (HFD)-induced differences in adipocyte size and cytokine/chemokine expression in visceral and subcutaneous adipose depots in obesity-prone (OP) and obesity-resistant (OR) rats. METHODS: OP and OR rats were fed either a low fat diet (LFD, 10% kilocalories from fat) or HFD (60% kilocalories from fat) for 7 weeks. Adipocyte size and the presence of crown-like structures in epididymal and inguinal adipose tissue were determined. A multiplex cytokine/chemokine panel was used to assess the expression of inflammatory markers in epididymal and inguinal adipose tissues. RESULTS: A higher percentage of large adipocytes (>5000 MUm2) was detected in the epididymal and inguinal adipose tissues of OP rats and a higher percentage of small adipocytes (<4000 MUm2) was detected in the epididymal and inguinal adipose tissues of OR rats. More crown-like structures were identified in epididymal adipose tissue of OP rats fed a LFD, compared to OR rats. Consumption of a HFD increased the number of crown-like structures in OR, but not OP rats. Epididymal expression of pro-inflammatory cytokines (IL-1beta and TNF-alpha) was higher in OP rats, compared to OR rats fed LFD. HFD consumption increased epididymal expression of GM-CSF, IL-1alpha, IL-1beta, IL-6, MIP-2 and TNF-alpha in OP and OR rats. Inguinal expression of pro-inflammatory cytokines (IL-1alpha, IL-1beta and TNF-alpha) was higher in OP rats, compared to OR rats. CONCLUSIONS: Overall, these data suggest that a higher susceptibility to developing obesity is characterized by large adipocytes and increased visceral adipose inflammation. Interestingly, in OR rats, the detrimental effects of HFD consumption on visceral adipose inflammation are evident with only small increases in weight and adiposity, suggesting that HFD also increases the risk for obesity-related comorbidities in OR rats. PMID- 29151596 TI - Comparison of regional fat measurements by dual-energy X-ray absorptiometry and conventional anthropometry and their association with markers of diabetes and cardiovascular disease risk. AB - BACKGROUND/OBJECTIVES: Fat distribution is a strong and independent predictor of type 2 diabetes (T2D) and cardiovascular disease (CVD) and is usually determined using conventional anthropometry in epidemiological studies. Dual-energy X-ray absorptiometry (DXA) can measure total and regional adiposity more accurately. Nonetheless, whether DXA provides more precise estimates of cardiovascular risk in relation to total and regional adiposity is not known. We determined the strength of the associations between DXA- and conventional anthropometry determined fat distribution and T2D and CVD risk markers. SUBJECTS/METHODS: Waist (WC) and hip circumference (HC) and DXA was used to measure total and regional adiposity in 4950 (2119 men) participants aged 29-55 years from the Oxford Biobank without pre-existing T2D or CVD. Cross-sectional associations were compared between WC and HC vs. DXA-determined regional adiposity (all z-score normalised) with impaired fasting glucose, hypertriglyceridemia, hypertension and insulin resistance (IR). RESULTS: Following adjustment for total adiposity, upper body adiposity measurements showed consistently increased risk of T2D and CVD risk markers except for abdominal subcutaneous fat in both sexes, and arm fat in men, which showed protective associations. Among upper adiposity depots, visceral fat mass showed stronger odds ratios (OR) ranging from 1.69 to 3.64 compared with WC 1.07-1.83. Among lower adiposity depots, HC showed modest protection for IR in both sexes (men: OR 0.80 (95% confidence interval 0.67, 0.96); women: 0.69 (0.56, 0.86)), whereas gynoid fat and in particular leg fat showed consistent and strong protective effects for all outcomes in both men and women. The differential effect of body fat distribution on CVD and T2D were more pronounced at higher levels of total adiposity. CONCLUSIONS: Compared with DXA, conventional anthropometry underestimates the associations of regional adiposity with T2D and CVD risk markers. After correcting for overall adiposity, greater subcutaneous fat mass in particular in the lower body is protective relative to greater android or visceral adipose tissue mass. PMID- 29151598 TI - Gene expression: Single-cell RNA sequencing of collecting duct cells. PMID- 29151597 TI - Association of plasma phospholipid polyunsaturated and trans fatty acids with body mass index: results from the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND/OBJECTIVE: Previous research has focused on associations between dietary fat and body mass index (BMI), but the contributions of different types of fat to BMI remain unclear. The purpose of this study is to estimate whether plasma phospholipid omega-3 (n-3), omega-6 (n-6) or trans fatty acids are associated with BMI at baseline and with subsequent BMI changes over time; and whether total phospholipid n-6 or trans fatty acids modify any association between phospholipid n-3 and BMI. METHODS: Cross-sectional and longitudinal linear mixed models include 6243 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Participants were 45-84 years old, had no history of cardiovascular disease at baseline (2000-2002) and were followed for up to 10 years. Plasma phospholipid fatty acids were measured using fasting plasma samples at baseline. Fully adjusted models include demographics, health behaviors and other fatty acids (n-3, n-6 and trans) as appropriate. RESULTS: In fully adjusted models, phospholipid n-3 fatty acid levels were inversely associated with baseline BMI (Ptrend <0.001). Baseline BMI was 1.14 (95% confidence interval (CI): 0.71, 1.57) kg m-2 lower among participants with total n-3 values in the highest vs the lowest quartiles, but was not associated with changes in BMI. Total phospholipid n-6 was positively associated with baseline BMI in partially adjusted but not fully adjusted models. No overall association was observed between fatty acid levels and changes in BMI. No clear association was observed between trans fatty acids and baseline BMI or BMI change. No effect modification in the association between phospholipid n-3 and baseline BMI or BMI change was observed by either phospholipid n-6 or trans fatty acids. CONCLUSIONS: Phospholipid total and specific n-3 fatty acid levels were inversely associated with BMI at baseline, whereas associations tended to be positive for total n-6 fatty acids. Significant associations between fatty acid levels and BMI changes were not observed. PMID- 29151599 TI - Epigenetics: EWAS of kidney function. PMID- 29151600 TI - Regenerative medicine: A step closer to kidneys in a dish. PMID- 29151601 TI - Antimicrobials: Daylight robbery by Acinetobacter. PMID- 29151602 TI - Why Data Citation Is a Computational Problem. PMID- 29151603 TI - Tolerant Barbary macaques maintain juvenile levels of social attention in old age, but despotic rhesus macaques do not. AB - Complex social life is thought to be a major driver of complex cognition in primates, but few studies have directly tested the relationship between a given primate species' social system and their social cognitive skills. We experimentally compared life span patterns of a foundational social cognitive skill (following another's gaze) in tolerant Barbary macaques, Macaca sylvanus, and despotic rhesus macaques, Macaca mulatta. Semi-free-ranging monkeys (N = 80 individuals from each species) followed gaze more in test trials where an actor looked up compared to control trials. However, species differed in ontogenetic trajectories: both exhibited high rates of gaze following as juveniles, but rhesus monkeys exhibited declines in social attention with age, whereas Barbary macaques did not. This pattern indicates that developmental patterns of social attention vary with social tolerance, and that diversity in social behaviour can lead to differences in social cognition across primates. PMID- 29151604 TI - Quantitative angle-insensitive flow measurement using relative standard deviation OCT. AB - Incorporating different data processing methods, optical coherence tomography (OCT) has the ability for high-resolution angiography and quantitative flow velocity measurements. However, OCT angiography cannot provide quantitative information of flow velocities, and the velocity measurement based on Doppler OCT requires the determination of Doppler angles, which is a challenge in a complex vascular network. In this study, we report on a relative standard deviation OCT (RSD-OCT) method which provides both vascular network mapping and quantitative information for flow velocities within a wide range of Doppler angles. The RSD values are angle-insensitive within a wide range of angles, and a nearly linear relationship was found between the RSD values and the flow velocities. The RSD OCT measurement in a rat cortex shows that it can quantify the blood flow velocities as well as map the vascular network in vivo. PMID- 29151605 TI - Sub-arcsecond imaging of the water emission in Arp 220. AB - Aims: Extragalactic observations of water emission can provide valuable insights into the excitation of the interstellar medium. In particular they allow us to investigate the excitation mechanisms in obscured nuclei, i.e. whether an active galactic nucleus or a starburst dominate. Methods: We use sub-arcsecond resolution observations to tackle the nature of the water emission in Arp 220. ALMA Band 5 science verification observations of the 183 GHz H2O 313-220 line, in conjunction with new ALMA Band 7 H2O 515-422 data at 325 GHz, and supplementary 22 GHz H2O 616 - 523 VLA observations, are used to better constrain the parameter space in the excitation modelling of the water lines. Results: We detect 183 GHz H2O and 325 GHz water emission towards the two compact nuclei at the center of Arp 220, being brighter in Arp 220 West. The emission at these two frequencies is compared to previous single-dish data and does not show evidence of variability. The 183 and 325 GHz lines show similar spectra and kinematics, but the 22 GHz profile is significantly different in both nuclei due to a blend with an NH3 absorption line. Conclusions: Our findings suggest that the most likely scenario to cause the observed water emission in Arp 220 is a large number of independent masers originating from numerous star-forming regions. PMID- 29151606 TI - A spectroscopic survey of Orion KL between 41.5 and 50 GHz. AB - Context: The nearby massive star-forming region Orion KL is one of the richest molecular reservoirs known in our Galaxy. The region hosts newly formed protostars, and the strong interaction between their radiation and their outflows with the environment results in a series of complex chemical processes leading to a high diversity of interstellar tracers. The region is therefore one of the most frequently observed sources, and the site where many molecular species have been discovered for the first time. Aims: With the availability of powerful wideband backends, it is nowadays possible to complete spectral surveys in the entire mm range to obtain a spectroscopically unbiased chemical picture of the region. Methods: In this paper we present a sensitive spectral survey of Orion KL, made with one of the 34 m antennas of the Madrid Deep Space Communications Complex in Robledo de Chavela, Spain. The spectral range surveyed is from 41.5 to 50 GHz, with a frequency spacing of 180 kHz (equivalent to ~ 1.2 km s-1, depending on the exact frequency). The rms achieved ranges from 8 to 12 mK. Results: The spectrum is dominated by the J = 1 -> 0 SiO maser lines and by radio recombination lines (RRLs), which were detected up to Deltan = 11. Above a 3 sigma level, we identified 66 RRLs and 161 molecular lines corresponding to 39 isotopologues from 20 molecules; a total of 18 lines remain unidentified, two of them above a 5 sigma level. Results of radiative modelling of the detected molecular lines (excluding masers) are presented. Conclusions: At this frequency range, this is the most sensitive survey and also the one with the widest band. Although some complex molecules like CH3CH2CN and CH2CHCN arise from the hot core, most of the detected molecules originate from the low temperature components in Orion KL. PMID- 29151607 TI - Zeeman effect in sulfur monoxide: A tool to probe magnetic fields in star forming regions. AB - Context: Magnetic fields play a fundamental role in star formation processes and the best method to evaluate their intensity is to measure the Zeeman effect of atomic and molecular lines. However, a direct measurement of the Zeeman spectral pattern from interstellar molecular species is challenging due to the high sensitivity and high spectral resolution required. So far, the Zeeman effect has been detected unambiguously in star forming regions for very few non-masing species, such as OH and CN. Aims: We decided to investigate the suitability of sulfur monoxide (SO), which is one of the most abundant species in star forming regions, for probing the intensity of magnetic fields via the Zeeman effect. Methods: We investigated the Zeeman effect for several rotational transitions of SO in the (sub-)mm spectral regions by using a frequency-modulated, computer controlled spectrometer, and by applying a magnetic field parallel to the radiation propagation (i.e., perpendicular to the oscillating magnetic field of the radiation). To support the experimental determination of the g factors of SO, a systematic quantum-chemical investigation of these parameters for both SO and O2 has been carried out. Results: An effective experimental-computational strategy for providing accurate g factors as well as for identifying the rotational transitions showing the strongest Zeeman effect has been presented. Revised g factors have been obtained from a large number of SO rotational transitions between 86 and 389 GHz. In particular, the rotational transitions showing the largest Zeeman shifts are: N, J = 2, 2 <- 1, 1 (86.1 GHz), N, J = 4, 3 <- 3, 2 (159.0 GHz), N, J = 1, 1 <- 0, 1 (286.3 GHz), N, J = 2, 2 <- 1, 2 (309.5 GHz), and N, J = 2, 1 <- 1, 0 (329.4 GHz). Our investigation supports SO as a good candidate for probing magnetic fields in high-density star forming regions. PMID- 29151609 TI - Clues to NaCN formation. AB - Context: ALMA is providing us essential information on where certain molecules form. Observing where these molecules emission arises from, the physical conditions of the gas, and how this relates with the presence of other species allows us to understand the formation of many species, and to significantly improve our knowledge of the chemistry that occurs in the space. Aims: We studied the molecular distribution of NaCN around IRC +10216, a molecule detected previously, but whose origin is not clear. High angular resolution maps allow us to model the abundance distribution of this molecule and check suggested formation paths. Methods: We modeled the emission of NaCN assuming local thermal equilibrium (LTE) conditions. These profiles were fitted to azimuthal averaged intensity profiles to obtain an abundance distribution of NaCN. Results: We found that the presence of NaCN seems compatible with the presence of CN, probably as a result of the photodissociation of HCN, in the inner layers of the ejecta of IRC +10216. However, similar as for CH3CN, current photochemical models fail to reproduce this CN reservoir. We also found that the abundance peak of NaCN appears at a radius of 3 * 1015cm, approximately where the abundance of NaCl, suggested to be the parent species, starts to decay. However, the abundance ratio shows that the NaCl abundance is lower than that obtained for NaCN. We expect that the LTE assumption might result in NaCN abundances higher than the real ones. Updated photochemical models, collisional rates, and reaction rates are essential to determine the possible paths of the NaCN formation. PMID- 29151610 TI - Photochemistry of coronene in cosmic water ice analogs at different concentrations. AB - This work presents the photochemistry of ultraviolet (UV) irradiated coronene in water ices at 15 K, studied using mid-infrared Fourier transform (FTIR) spectroscopy for C24H12:H2O at concentrations of (1:50), (1:150), (1:200), (1:300) and (1:400). Previous UV irradiation studies of anthracene:H2O, pyrene:H2O and benzo[ghi]perylene:H2O ices at 15 K have shown that aromatic alcohols and ketones, as well as CO2 and H2CO are formed at very low temperatures. Like-wise, here, in addition to the coronene cation, hydroxy-, keto , and protonated coronene (coronene-H+) are formed. The rate constants for the decay of neutral coronene and for the formation of photoproducts have been derived. It is shown that PAHs and their UV-induced PAH:H2O photoproducts have mid-infrared spectroscopic signatures in the 5-8 MUm region that can contribute to the interstellar ice components described by Boogert et al. (2008) as C1-C5. Our results suggest that oxygenated and hydrogenated PAHs could be in UV irradiated regions of the ISM where water-rich ices are important. PMID- 29151608 TI - The ESO Diffuse Interstellar Bands Large Exploration Survey: EDIBLES I. Project description, survey sample and quality assessment. AB - The carriers of the diffuse interstellar bands (DIBs) are largely unidentified molecules ubiquitously present in the interstellar medium (ISM). After decades of study, two strong and possibly three weak near-infrared DIBs have recently been attributed to the [Formula: see text] fullerene based on observational and laboratory measurements. There is great promise for the identification of the over 400 other known DIBs, as this result could provide chemical hints towards other possible carriers. In an effort to systematically study the properties of the DIB carriers, we have initiated a new large-scale observational survey: the ESO Diffuse Interstellar Bands Large Exploration Survey (EDIBLES). The main objective is to build on and extend existing DIB surveys to make a major step forward in characterising the physical and chemical conditions for a statistically significant sample of interstellar lines-of-sight, with the goal to reverse-engineer key molecular properties of the DIB carriers. EDIBLES is a filler Large Programme using the Ultraviolet and Visual Echelle Spectrograph at the Very Large Telescope at Paranal, Chile. It is designed to provide an observationally unbiased view of the presence and behaviour of the DIBs towards early-spectral type stars whose lines-of-sight probe the diffuse-to-translucent ISM. Such a complete dataset will provide a deep census of the atomic and molecular content, physical conditions, chemical abundances and elemental depletion levels for each sightline. Achieving these goals requires a homogeneous set of high-quality data in terms of resolution (R ~ 70 000 - 100 000), sensitivity (S/N up to 1000 per resolution element), and spectral coverage (305 1042 nm), as well as a large sample size (100+ sightlines). In this first paper the goals, objectives and methodology of the EDIBLES programme are described and an initial assessment of the data is provided. PMID- 29151611 TI - FOR LOVE OR REWARD? CHARACTERISING PREFERENCES FOR GIVING TO PARENTS IN AN EXPERIMENTAL SETTING. AB - Understanding the motivations behind intergenerational transfers is an important and active research area in economics. The existence and responsiveness of familial transfers have consequences for the design of intra and intergenerational redistributive programmes, particularly as such programmes may crowd out private transfers amongst altruistic family members. Yet, despite theoretical and empirical advances in this area, significant gaps in our knowledge remain. In this article, we advance the current literature by shedding light on both the motivation for providing intergenerational transfers, and on the nature of preferences for such giving behaviour, by using experimental techniques and revealed preference methods. PMID- 29151612 TI - Error Patterns with Fraction Calculations at Fourth Grade as a Function of Students' Mathematics Achievement Status. AB - The goal of the present study was to describe fraction-calculation errors among 4th-grade students and determine whether error patterns differed as a function of problem type (addition vs. subtraction; like vs. unlike denominators), orientation (horizontal vs. vertical), or mathematics-achievement status (low- vs. average- vs. high-achieving). We specifically addressed whether mathematics achievement status was related to students' tendency to operate with whole number bias. We extended this focus by comparing low-performing students' errors in two instructional settings that focused on two different types of fraction understandings: core instruction that focused on part-whole understanding vs. small-group tutoring that focused on magnitude understanding. Results showed students across the sample were more likely to operate with whole number bias on problems with unlike denominators. Students with low or average achievement (who only participated in core instruction) were more likely to operate with whole number bias than students with low achievement who participated in small-group tutoring. We suggest instruction should emphasize magnitude understanding to sufficiently increase fraction understanding for all students in the upper elementary grades. PMID- 29151613 TI - Heavy noble gases in solar wind delivered by Genesis mission. AB - One of the major goals of the Genesis Mission was to refine our knowledge of the isotopic composition of the heavy noble gases in solar wind and, by inference, the Sun, which represents the initial composition of the solar system. This has now been achieved with permil precision: 36Ar/38Ar = 5.5005 +/- 0.0040, 86Kr/84Kr = .3012 +/- .0004, 83Kr/84Kr = .2034 +/- .0002, 82Kr/84Kr = .2054 +/- .0002, 80Kr/84Kr = .0412 +/- .0002, 78Kr/84Kr = .00642 +/- .00005, 136Xe/132Xe = .3001 +/- .0006, 134Xe/132Xe = .3691 +/- .0007, 131Xe/132Xe = .8256 +/- .0012, 130Xe/132Xe = .1650 +/- .0004, 129Xe/132Xe = 1.0405 +/- .0010, 128Xe/132Xe = .0842 +/- .0003, 126Xe/132Xe = .00416 +/- .00009, and 124Xe/132Xe = .00491 +/- .00007 (error-weighted averages of all published data). The Kr and Xe ratios measured in the Genesis solar wind collectors generally agree with the less precise values obtained from lunar soils and breccias, which have accumulated solar wind over hundreds of millions of years, suggesting little if any temporal variability of the isotopic composition of solar wind krypton and xenon. The higher precision for the initial composition of the heavy noble gases in the solar system allows (1) to confirm that, exept 136Xe and 134Xe, the mathematically derived U-Xe is equivalent to Solar Wind Xe and (2) to provide an opportunity for better understanding the relationship between the starting composition and Xe-Q (and Q-Kr), the dominant current "planetary" component, and its host, the mysterious phase-Q. PMID- 29151614 TI - I-Xe systematics of the impact plume produced chondrules from the CB carbonaceous chondrites: Implications for the half-life value of 129I and absolute age normalization of 129I-129Xe chronometer. AB - It is inferred that magnesian non-porphyritic chondrules in the CB (Bencubbin type) carbonaceous chondrites formed in an impact generated plume of gas and melt at 4562.49 +/- 0.21 Ma (Bollard et al., 2015) and could be suitable for the absolute age normalization of relative chronometers. Here xenon isotopic compositions of neutron irradiated chondrules from the CB chondrites Gujba and Hammadah al Hamra (HH) 237 have been analyzed in an attempt to determine closure time of their I-Xe isotope systematics. One of the HH 237 chondrules, #1, yielded a well-defined I-Xe isochron that corresponds to a closure time of 0.29 +/- 0.16 Ma after the Shallowater aubrite standard. Release profiles and diffusion properties of radiogenic 129*Xe and 128*Xe, extracted from this chondrule by step wise pyrolysis, indicate presence of two iodine host phases with distinct activation energies of 73 and 120 kcal/mol. In spite of the activation energy differences, the I-Xe isotope systematics of these two phases closed simultaneously, suggesting rapid heating and cooling (possibly quenching) of the CB chondrules. The release profiles of U-fission Xe and I-derived Xe correlate in the high temperature host phase supporting simultaneous closure of 129I-129Xe and 207Pb-206Pb systematics. The absolute I-Xe age of Shallowater standard is derived from the observed correlation between I-Xe and Pb-Pb ages in a number of samples. It is re-evaluated here using Pb-Pb ages adjusted for an updated 238U/235U ratio of 137.794 and meteorite specific U-isotope ratios. With the addition of the new data for HH 237 chondrule #1, the re-evaluated absolute I-Xe age of Shallowater is 4562.4 +/- 0.2 Ma. The absolute I-Xe age of the HH 237 chondrule #1 is 4562.1 +/- 0.3 Ma, in good agreement with U-corrected Pb-Pb ages of the Gujba chondrules (Bollard et al., 2015) and HH 237 silicates (Krot et al., 2005). All I-Xe data used here, and in previous estimates of the absolute age of Shallowater, are calculated using 15.7 +/- 0.6 Ma value for 129I half-life. The slopes of I-Xe - Pb-Pb correlation lines plotted for different sets of samples for Shallowater normalization are always <=1. Assuming uranium half-life values are correct; this restricts the half-life of 129I to <=15.7 Ma. PMID- 29151615 TI - Effect of doping of KDP crystal with amino acid l-arginine on the strength properties and character of laser damage. AB - Studied were the strength characteristics of KDP crystals doped with l-arginine under a concentrated load and irradiation of the first harmonic YAG:Nd3+ laser. The crystals were obtained by means of the temperature reduction method on a point seed, the content of l-arginine in the aqueous solution being 0.3, 0.4, 1.0 and 1.4 wt%. The character of the dependence of KDP microhardness versus the concentration of amino acid in the crystal was investigated. The regularities of brittle damage of the doped KDP crystal at mechanical testing and laser irradiation were shown to be similar. As confirmed in the study, the planes of easy crack extension in the crystal are {2 2 1}, (1 0 0), and (0 0 1) planes, the cracks mainly propagate parallel to {2 2 1} planes. The mechanical and laser strength values of doped KDP crystals were evaluated. PMID- 29151617 TI - Poly[(arylene ethynylene)-alt-(arylene vinylene)]s Based on Anthanthrone and Its Derivatives: Synthesis and Photophysical, Electrochemical, Electroluminescent, and Photovoltaic Properties. AB - Anthanthrone and its derivatives are large polycyclic aromatic compounds (PACs) that pose a number of challenges for incorporation into the structure of soluble conjugated polymers. For the first time, this group of PACs was employed as the building blocks for the synthesis of copolymers (P1-P5) based on poly[(arylene ethynylene)-alt-(arylene vinylene)]s backbone (-Ph-C=C-Anth-C=C-Ph-CH=CH-Ph-CH=CH ) n . During the synthesis of P1-P5, different alkyloxy side chains were incorporated in order to tune the properties of the polymers. Of the copolymer series only P1 (containing anthanthrone and branched 2-ethylhexyloxy side chains on phenylenes), P2 and P3 (for which the anthanthrones containing carbonyl groups were converted to anthanthrene containing alkyloxy substituents) were soluble. The photophysical, electrochemical, electroluminescent and photovoltaic properties of P1-P3 are reported, compared and discussed with respect to the effects of side chains. PMID- 29151618 TI - Heterofunctional Poly(ethylene glycol) (PEG) Macroinitiator Enabling Controlled Synthesis of ABC Triblock Copolymers. AB - ABC triblock copolymers with a poly(ethylene glycol) (PEG) midblock have attractive properties for biomedical applications because of PEG's favorable properties regarding biocompatibility and hydrophilicity. However, easy strategies to synthesize polymers containing a PEG midblock are limited. In this study, the successful synthesis of a heterofunctional PEG macroinitiator containing both an azoinitiator and an atom transfer radical polymerization (ATRP) initiator is demonstrated. This novel PEG macroinitiator allows the development of elegant synthesis routes for PEG midblock-containing ABC copolymers that does not require protection of initiating sites or polymer end group postmodification. Polymers with outer blocks composed of different monomers were synthesized to illustrate the versatility of this macroinitiator. N Isopropylacrylamide (NIPAM) was included to obtain thermosensitive polymers, 2 (dimethylamino)ethyl methacrylate (DMAEMA) provided pH-sensitive properties, and 2-hydroxyethyl acrylate (HEA) functioned as a noncharged hydrophilic block that also allows for postmodifications reactions. This synthesis approach can further contribute to the design of high-precision polymers with tailorable block compositions and polymer topologies, which is highly attractive for applications in nanotechnology. PMID- 29151619 TI - Improving the Folding of Supramolecular Copolymers by Controlling the Assembly Pathway Complexity. AB - A family of amphiphilic, heterograft copolymers containing hydrophilic, hydrophobic, and supramolecular units based on Jeffamine M-1000, dodecylamine, and benzene-1,3,5-tricarboxamide (BTA) motifs, respectively, was prepared via a postfunctionalization approach. The folding of the copolymers in water into nanometer-sized particles was analyzed by a combination of dynamic and static light scattering, circular dichroism spectroscopy, and small-angle neutron scattering. The sample preparation protocol was crucial for obtaining reproducible and consistent results, showing that only full control over the structure and pathway complexity will afford the desired folded structure, a phenomenon similar to protein folding. The results revealed that relatively small changes in the polymer's graft composition strongly affected the intra- versus intermolecular assembly processes. Depending on the amount of the hydrophobic grafts based on either dodecyl or BTA groups, pronounced behavioral differences were observed for copolymers that comprise similar degrees of hydrophobic content. A high number of BTA grafts (>10%) resulted in the formation of multichain aggregates comprising around six polymer chains. In contrast, for copolymers comprising up to 10% BTA grafts the folding results in nanoparticles that adopt open, sparse conformations and comprise one to two polymer chains. Interestingly, predominantly single-chain polymeric nanoparticles were formed when the copolymer comprised only Jeffamine or Jeffamine and dodecyl grafts. In addition, replacing part of the BTA grafts by hydrophobic dodecyl grafts while keeping the hydrophobic content constant promoted single-chain folding and resulted in the formation of a compact, globular nanoparticle with a more structured interior. Thus, the intra- and intermolecular self-assembly pathways can be directed by carefully tuning the polymer's hydrophilic-hydrophobic balance in combination with the number of supramolecular grafts. PMID- 29151616 TI - Polymeric Biomaterials: Diverse Functions Enabled by Advances in Macromolecular Chemistry. AB - Biomaterials have been extensively used to leverage beneficial outcomes in various therapeutic applications, such as providing spatial and temporal control over the release of therapeutic agents in drug delivery as well as engineering functional tissues and promoting the healing process in tissue engineering and regenerative medicine. This perspective presents important milestones in the development of polymeric biomaterials with defined structures and properties. Contemporary studies of biomaterial design have been reviewed with focus on constructing materials with controlled structure, dynamic functionality, and biological complexity. Examples of these polymeric biomaterials enabled by advanced synthetic methodologies, dynamic chemistry/assembly strategies, and modulated cell-material interactions have been highlighted. As the field of polymeric biomaterials continues to evolve with increased sophistication, current challenges and future directions for the design and translation of these materials are also summarized. PMID- 29151621 TI - Error analysis for discretizations of parabolic problems using continuous finite elements in time and mixed finite elements in space. AB - Variational time discretization schemes are getting of increasing importance for the accurate numerical approximation of transient phenomena. The applicability and value of mixed finite element methods in space for simulating transport processes have been demonstrated in a wide class of works. We consider a family of continuous Galerkin-Petrov time discretization schemes that is combined with a mixed finite element approximation of the spatial variables. The existence and uniqueness of the semidiscrete approximation and of the fully discrete solution are established. For this, the Banach-Necas-Babuska theorem is applied in a non standard way. Error estimates with explicit rates of convergence are proved for the scalar and vector-valued variable. An optimal order estimate in space and time is proved by duality techniques for the scalar variable. The convergence rates are analyzed and illustrated by numerical experiments, also on stochastically perturbed meshes. PMID- 29151620 TI - In Silico Synthesis of Microgel Particles. AB - Microgels are colloidal-scale particles individually made of cross-linked polymer networks that can swell and deswell in response to external stimuli, such as changes to temperature or pH. Despite a large amount of experimental activities on microgels, a proper theoretical description based on individual particle properties is still missing due to the complexity of the particles. To go one step further, here we propose a novel methodology to assemble realistic microgel particles in silico. We exploit the self-assembly of a binary mixture composed of tetravalent (cross-linkers) and bivalent (monomer beads) patchy particles under spherical confinement in order to produce fully bonded networks. The resulting structure is then used to generate the initial microgel configuration, which is subsequently simulated with a bead-spring model complemented by a temperature induced hydrophobic attraction. To validate our assembly protocol, we focus on a small microgel test case and show that we can reproduce the experimental swelling curve by appropriately tuning the confining sphere radius, something that would not be possible with less sophisticated assembly methodologies, e.g., in the case of networks generated from an underlying crystal structure. We further investigate the structure (in reciprocal and real space) and the swelling curves of microgels as a function of temperature, finding that our results are well described by the widely used fuzzy sphere model. This is a first step toward a realistic modeling of microgel particles, which will pave the way for a careful assessment of their elastic properties and effective interactions. PMID- 29151622 TI - A posteriori error estimates for the virtual element method. AB - An posteriori error analysis for the virtual element method (VEM) applied to general elliptic problems is presented. The resulting error estimator is of residual-type and applies on very general polygonal/polyhedral meshes. The estimator is fully computable as it relies only on quantities available from the VEM solution, namely its degrees of freedom and element-wise polynomial projection. Upper and lower bounds of the error estimator with respect to the VEM approximation error are proven. The error estimator is used to drive adaptive mesh refinement in a number of test problems. Mesh adaptation is particularly simple to implement since elements with consecutive co-planar edges/faces are allowed and, therefore, locally adapted meshes do not require any local mesh post processing. PMID- 29151623 TI - Fast interior point solution of quadratic programming problems arising from PDE constrained optimization. AB - Interior point methods provide an attractive class of approaches for solving linear, quadratic and nonlinear programming problems, due to their excellent efficiency and wide applicability. In this paper, we consider PDE-constrained optimization problems with bound constraints on the state and control variables, and their representation on the discrete level as quadratic programming problems. To tackle complex problems and achieve high accuracy in the solution, one is required to solve matrix systems of huge scale resulting from Newton iteration, and hence fast and robust methods for these systems are required. We present preconditioned iterative techniques for solving a number of these problems using Krylov subspace methods, considering in what circumstances one may predict rapid convergence of the solvers in theory, as well as the solutions observed from practical computations. PMID- 29151624 TI - Biodiversity and human-pathogenicity of Phialophora verrucosa and relatives in Chaetothyriales. AB - Phialophora as defined by its type species P. verrucosa is a genus of Chaetothyriales, and a member of the group known as 'black yeasts and relatives'. Phialophora verrucosa has been reported from mutilating human infections such as chromoblastomycosis, disseminated phaeohyphomycosis and mycetoma, while morphologically similar fungi are rather commonly isolated from the environment. Phenotypes are insufficient for correct species identification, and molecular data have revealed significant genetic variation within the complex of species currently identified as P. verrucosa or P. americana. Multilocus analysis of 118 strains revealed the existence of five reproductively isolated species apparently having different infectious potentials. Strains of the sexual morph Capronia semiimmersa cluster within P. americana. The newly defined taxa differ markedly in their predilection for the human host. PMID- 29151625 TI - Colletotrichum species causing anthracnose disease of chili in China. AB - Anthracnose caused by Colletotrichum species is a serious disease of more than 30 plant genera. Several Colletotrichum species have been reported to infect chili in different countries. Although China is the largest chili-producing country, little is known about the species that have been infecting chili locally. Therefore, we collected samples of diseased chili from 29 provinces of China, from which 1285 strains were isolated. The morphological characters of all strains were observed and compared, and multi-locus phylogenetic analyses (ITS, ACT, CAL, CHS-1, GAPDH, TUB2, and HIS3) were performed on selected representative strains. Fifteen Colletotrichum species were identified, with C. fioriniae, C. fructicola, C. gloeosporioides, C. scovillei, and C. truncatum being prevalent. Three new species, C. conoides, C. grossum, and C. liaoningense, were recognised and described in this paper. Colletotrichum aenigma, C. cliviae, C. endophytica, C. hymenocallidis, C. incanum, C. karstii, and C. viniferum were reported for the first time from chili. Pathogenicity of all species isolated from chili was confirmed, except for C. endophytica. The current study improves the understanding of species causing anthracnose on chili and provides useful information for the effective control of the disease in China. PMID- 29151626 TI - Taxonomy of Tricholoma in northern Europe based on ITS sequence data and morphological characters. AB - Based on molecular and morphological data we investigated the taxonomy and phylogeny of the ectomycorrhizal genus Tricholoma in northern Europe. Our phylogenetic tree confirmed the presence of at least 72 well circumscribed species within the region. Of these, three species, viz. T. boreosulphurescens, T. bryogenum and T. ilkkae are described as new to science, based on morphological, distributional, ecological and molecular data. Several other terminal branches represent putative cryptic taxa nested within classical species or species groups. Molecular type studies and/or designation of sequenced neotypes are needed in these groups, before the taxonomy can be settled. In general our phylogenetic analysis supported previous suprageneric classification systems, but with some substantial changes. Most notably, T. virgatum and allies were found to belong to sect. Tricholoma rather than sect. Atrosquamosa, while T. focale was found to be clearly nested in sect. Genuina rather than in sect. Caligata. In total, ten sections are accepted, with five species remaining unassigned. The combination of morphological and molecular data showed pileus colour, pileipellis structure, presence of clamp connections and spore size to be rather conservative characters within accepted sections, while the presence of a distinct ring, and especially host selection were highly variable within these. PMID- 29151627 TI - A multi-gene phylogeny of Lactifluus (Basidiomycota, Russulales) translated into a new infrageneric classification of the genus. AB - Infrageneric relations of the genetically diverse milkcap genus Lactifluus (Russulales, Basidiomycota) are poorly known. Currently used classification systems still largely reflect the traditional, mainly morphological, characters used for infrageneric delimitations of milkcaps. Increased sampling, combined with small-scale molecular studies, show that this genus is underexplored and in need of revision. For this study, we assembled an extensive dataset of the genus Lactifluus, comprising 80 % of all known species and 30 % of the type collections. To unravel the infrageneric relationships within this genus, we combined a multi-gene molecular phylogeny, based on nuclear ITS, LSU, RPB2 and RPB1, with a morphological study, focussing on five important characteristics (fruit body type, presence of a secondary velum, colour reaction of the latex/context, pileipellis type and presence of true cystidia). Lactifluus comprises four supported subgenera, each containing several supported clades. With extensive sampling, ten new clades and at least 17 new species were discovered, which highlight the high diversity in this genus. The traditional infrageneric classification is only partly maintained and nomenclatural changes are proposed. Our morphological study shows that the five featured characteristics are important at different evolutionary levels, but further characteristics need to be studied to find morphological support for each clade. This study paves the way for a more detailed investigation of biogeographical history and character evolution within Lactifluus. PMID- 29151628 TI - Riding with the ants. AB - Isolates of Teratosphaeriaceae have frequently been found in the integument of attine ants, proving to be common and diverse in this microenvironment. The LSU phylogeny of the ant-isolated strains studied revealed that they cluster in two main lineages. The first was associated with the genus Xenopenidiella whereas the other represented two ant-isolated lineages sister to the taxa Penidiella aggregata and P. drakensbergensis, which are allocated to the new genus Penidiellomyces. The genus Penidiella is limited to the lineage containing P. columbiana, which is not congeneric with Penidiellomyces or Penidiellopsis, nor with Simplicidiella, a novel genus introduced here to accommodate a strain isolated from ants. For species level analysis, the final 26 aligned sequences of the ITS (498 characters), cmdA (389 characters), tef1 (342 characters) and tub2 (446 characters) gene regions lead to the introduction of six new species in Xenopenidiella, and one in respectively Penidiellopsis and Simplicidiella. The species described in this study were distinguished by the combination of morphological and phylogenetic data. Novelties on the integument of leaf-cutting ants from Brazil include: Penidiellopsis ramosus, Xenopenidiella clavata, X. formica, X. inflata, X. laevigata, X. nigrescens, X. tarda spp. nov., and Simplicidiella nigra gen. & sp. nov. Beta-tubulin is recommended as primary barcode for the distinction of species in Penidiellopsis, whereas ITS was sufficient to distinguish species of Xenopenidiella. PMID- 29151629 TI - Six new Phytophthora species from ITS Clade 7a including two sexually functional heterothallic hybrid species detected in natural ecosystems in Taiwan. AB - During a survey of Phytophthora diversity in natural ecosystems in Taiwan six new species were detected. Multigene phylogeny based on the nuclear ITS, beta-tubulin and HSP90 and the mitochondrial cox1 and NADH1 gene sequences demonstrated that they belong to ITS Clade 7a with P. europaea, P. uniformis, P. rubi and P. cambivora being their closest relatives. All six new species differed from each other and from related species by a unique combination of morphological characters, the breeding system, cardinal temperatures and growth rates. Four homothallic species, P. attenuata, P. flexuosa, P. formosa and P. intricata, were isolated from rhizosphere soil of healthy forests of Fagus hayatae, Quercus glandulifera, Q. tarokoensis, Castanopsis carlesii, Chamaecyparis formosensis and Araucaria cunninghamii. Two heterothallic species, P. xheterohybrida and P. xincrassata, were exclusively detected in three forest streams. All P. xincrassata isolates belonged to the A2 mating type while isolates of P. xheterohybrida represented both mating types with oospore abortion rates according to Mendelian ratios (4-33 %). Multiple heterozygous positions in their ITS, beta-tubulin and HSP90 gene sequences indicate that P. xheterohybrida, P. xincrassata and P. cambivora are interspecific hybrids. Consequently, P. cambivora is re-described as P. xcambivora without nomenclatural act. Pathogenicity trials on seedlings of Castanea sativa, Fagus sylvatica and Q. suber indicate that all six new species might pose a potential threat to European forests. PMID- 29151630 TI - Juglanconis gen. nov. on Juglandaceae, and the new family Juglanconidaceae (Diaporthales). AB - Molecular phylogenetic analyses of ITS-LSU rDNA sequence data demonstrate that Melanconis species occurring on Juglandaceae are phylogenetically distinct from Melanconis s.str., and therefore the new genus Juglanconis is described. Morphologically, the genus Juglanconis differs from Melanconis by light to dark brown conidia with irregular verrucae on the inner surface of the conidial wall, while in Melanconis s.str. they are smooth. Juglanconis forms a separate clade not affiliated with a described family of Diaporthales, and the family Juglanconidaceae is introduced to accommodate it. Data of macro- and microscopic morphology and phylogenetic multilocus analyses of partial nuSSU-ITS-LSU rDNA, cal, his, ms204, rpb1, rpb2, tef1 and tub2 sequences revealed four distinct species of Juglanconis. Comparison of the markers revealed that tef1 introns are the best performing markers for species delimitation, followed by cal, ms204 and tub2. The ITS, which is the primary barcoding locus for fungi, is amongst the poorest performing markers analysed, due to the comparatively low number of informative characters. Melanconium juglandinum (= Melanconis carthusiana), M. oblongum (= Melanconis juglandis) and M. pterocaryae are formally combined into Juglanconis, and J. appendiculata is described as a new species. Melanconium juglandinum and Melanconis carthusiana are neotypified and M. oblongum and Diaporthe juglandis are lectotypified. A short description and illustrations of the holotype of Melanconium ershadii from Pterocarya fraxinifolia are given, but based on morphology it is not considered to belong to Juglanconis. A key to all treated species of Juglanconis is provided. PMID- 29151631 TI - Phylogenetic relationships of eight new Dacrymycetes collected from New Zealand. AB - Dacrymycetes, sister to Agaricomycetes, is a noteworthy lineage for studying the evolution of wood-decaying basidiomycetes; however, its species diversity and phylogeny are largely unknown. Species of Dacrymycetes previously used in molecular phylogenetic analyses are mainly derived from the Northern Hemisphere, thus insufficient knowledge exists concerning the Southern Hemisphere lineages. In this study, we investigated the species diversity of Dacrymycetes in New Zealand. We found 11 previously described species, and eight new species which were described here: Calocera pedicellata, Dacrymyces longistipitatus, D. pachysporus, D. stenosporus, D. parastenosporus, D. cylindricus, D. citrinus, and D. cyrtosporus. These eight newly described species and seven of the known ones, namely, Calocera fusca, C. cf. guepinioides, C. lutea, Dacrymyces flabelliformis, D. intermedius, D. subantarcticensis, and Heterotextus miltinus, have rarely or never been recorded from the Northern Hemisphere. In a molecular-based phylogeny, these New Zealand strains were scattered throughout the Dacrymycetaceae clade. Sequences obtained from specimens morphologically matching C. guepinioides were separated into three distant clades. Because no obvious morphological differences could be discerned between the specimens in each clade and no sequence exists from the type specimen, a C. guepinioides s.str. clade could not be determined. This survey of dacrymycetous species in the Southern Hemisphere has increased taxon sampling for phylogenetic analyses that can serve as a basis for the construction of a stable classification of Dacrymycetes. PMID- 29151632 TI - Study in Agaricus subgenus Minores and allied clades reveals a new American subgenus and contrasting phylogenetic patterns in Europe and Greater Mekong Subregion. AB - Within Agaricus subg. Minores, A. sect. Minores remains a little-studied section due generally to its delicate sporocarps often lacking taxonomically relevant morphological characters. To reconstruct the section, using the recent taxonomic system based on divergence times, and to evaluate the species diversity of A. sect. Minores in the Greater Mekong Subregion, 165 specimens were incorporated in phylogenetic analyses. A dated tree based on nuclear ITS, LSU and tef1-alpha sequence data allowed us to better circumscribe A. subg. Minores and to propose a new subgenus, A. subg. Minoriopsis, which is only known from tropical and subtropical regions of the Americas. A larger tree based on ITS sequences indicated that, with 81 phylogenetic species, the reconstructed section Minores is now one of the largest sections in the genus. Within A. subg. Minores, a new section, A. sect. Leucocarpi, and eleven new species are described from the Greater Mekong Subregion. Thirty-eight species of A. sect. Minores from this region of Asia were distributed in multiple clades that successively diverged over the past 24 million years. In contrast, species reported from Europe mostly grouped in a single non-tropical clade, suggesting a major species diversification following the middle Miocene climatic optimum. PMID- 29151633 TI - The genus Elaphomyces (Ascomycota, Eurotiales): a ribosomal DNA-based phylogeny and revised systematics of European 'deer truffles'. AB - Elaphomyces ('deer truffles') is one of the most important ectomycorrhizal fungal genera in temperate and subarctic forest ecosystems, but also one of the least documented in public databases. The current systematics are mainly based on macromorphology, and is not significantly different from that proposed by Vittadini (1831). Within the 49 species recognised worldwide, 23 were originally described from Europe and 17 of these were described before the 20th century. Moreover, very recent phylogenetic treatments of the genus are mainly based on a few extra-European species and most common European species are still poorly documented. Based on an extensive taxonomic sampling mainly made in the biogeographically rich Cantabrian area (Spain), complemented with collections from France, Greece, Italy, Norway, Portugal and Sweden, all currently recognized species in Europe have been sequenced at the ITS and 28S of the rDNA. Combined phylogenetic analyses yielded molecular support to sections Elaphomyces and Ceratogaster (here emended), while a third, basal lineage encompasses the sections Malacodermei and Ascoscleroderma as well as the tropical genus Pseudotulostoma. Species limits are discussed and some taxa formerly proposed as genuine species based on morphology and biogeography are re-evaluated as varieties or forms. Spore size and ornamentation, features of the peridial surface, structure of the peridium, and the presence of mycelium patches attached to the peridial surface emerge as the most significant systematic characters. Four new species: E. barrioi, E. quercicola, E. roseolus and E. violaceoniger, one new variety: E. papillatus var. sulphureopallidus, and two new forms: E. granulatus forma pallidosporus and E. anthracinus forma talosporus are introduced, as well as four new combinations in the genus: E. muricatus var. reticulatus, E. muricatus var. variegatus, E. papillatus var. striatosporus and E. morettii var. cantabricus. Lectotypes and epitypes are designated for most recognised species. For systematic purposes, new infrageneric taxa are introduced: E. sect. Ascoscleroderma stat. nov., E. subsect. Sclerodermei stat. nov., E. subsect. Maculati subsect. nov., E. subsect. Muricati subsect. nov., and E. subsect. Papillati subsect. nov. Lastly, E.laevigatus, E. sapidus, E. sulphureopallidus and E. trappei are excluded from the genus and referred to Rhizopogon roseolus, Astraeus sapidus comb. nov., Astraeus hygrometricus and Terfezia trappei comb. nov. (syn.: Terfezia cistophila), respectively. PMID- 29151635 TI - Lower incidence of myocardial infarction after smoke-free legislation enforcement in Chile. AB - Objective: To evaluate the impact of a complete smoking ban in enclosed spaces on the incidence of acute myocardial infarction in Chile. Methods: The population based study involved residents of urban areas, where 80% of the Chilean population live, aged 20 years or older who had a myocardial infarction. Monthly myocardial infarction incidence and mortality rates at health-care facilities between January 2011 and December 2014 were derived from admission and mortality databases. Regression discontinuity methods were used to estimate the near immediate impact on disease incidence of enforcing smoke-free legislation in March 2013. The same analysis was performed for ischaemic stroke, degenerative disc disease and colon cancer. Data on the concentration of fine respirable particulates were included in an additional analysis of myocardial infarction incidence in the Santiago metropolitan area. Results: The enforcement of smoke free legislation was associated with an abrupt, near-immediate decline of 0.639 cases of myocardial infarction per 100 000 adults per month (95% confidence interval, CI: 0.242 to 1.036; relative decline: 7.8%). Similar declines were observed in men and women and in people aged over and under 70 years. However, enforcement of the legislation was not associated with a significant change in the rate of ischaemic stroke, degenerative disc disease or colon cancer. The abrupt decline in myocardial infarction incidence was also observed when data on fine respirable particulates were included in an analysis for Santiago. Conclusion: The enforcement of extensive smoke-free legislation in Chile was associated with an abrupt, near-immediate decline in the incidence of myocardial infarction. PMID- 29151636 TI - Bedaquiline: Fallible Hope Against Drug Resistant Tuberculosis. AB - Tuberculosis (TB) is a deadly bacterial infectious disease caused by intra cellular pathogen Mycobacterium tuberculosis (Mtb). There were an estimated 1.4 million TB deaths in 2015 and an additional 0.4 million deaths resulting from TB among individuals with HIV. Drug-discovery for its cure is very slow in comparison with the causative organism's fast pace of mutations conferring drug resistance. Moreover, the field of drug-discovery of anti-TB drugs is constantly being challenged by the drug resistant strains of Mtb. Several molecules/inhibitors are being tested across the pharmaceutical industry and research centres for their suitability as drug candidate. It takes immense effort, high costs and a whole lot of screening to bring a single molecule to the clinics for patient cure. In last 60 years, hundreds of molecules have been patented for their probable use to develop drug for treatment of TB. However, only one drug has been successfully approved that is bedaquiline (1-(6-bromo-2 methoxy-quinolin-3-yl)-4-dimethylamino-2-naphtalen-1-yl-1-phenyl-butan-2-ol). This is a brief review about bedaquiline (BDQ), the only drug in last 45 years approved for curing drug-resistant pulmonary TB, its development, action mechanism and development of resistance against it. PMID- 29151637 TI - Strategies to Improve Saccharomyces cerevisiae: Technological Advancements and Evolutionary Engineering. AB - Bakery industries are thriving to augment the diverse properties of Saccharomyces cerevisiae to increase its flavor, texture and nutritional parameters to attract the more consumers. The improved technologies adopted for quality improvement of baker's yeast are attracting the attention of industry and it is playing a pivotal role in redesigning the quality parameters. Modern yeast strain improvement tactics revolve around the use of several advanced technologies such as evolutionary engineering, systems biology, metabolic engineering, genome editing. The review mainly deals with the technologies for improving S. cerevisiae, with the objective of broadening the range of its industrial applications. PMID- 29151638 TI - Polyhydroxyalkanoate Production and Degradation Patterns in Bacillus Species. AB - Bacteria under stress conditions of excess of carbon (C) and limitations of nutrients divert its metabolism towards C storage as energy reservoir polyhydroxyalkanoate (PHA). Different Bacillus species-B. cereus and B. thuringiensis, were monitored to produce PHA from different C sources-glucose, crude glycerol and their combination at 37 degrees C for period up to 192 h. PHA production and its composition was found to vary with feed and bacterial strains. PHA production on crude glycerol continued to increase up to 120 h, reaching a maximum of 2725 mg/L with an effective yield of 71% of the dry cell mass. Depolymerization of PHA was observe to initiate after 96 h of incubation up to 192 h. PHA degradation products have been envisaged to be applied in medical field: tissue engineering, drug carriers, memory enhancers, antiosteoporosis, biodegradable implants. The PHA production and degradation cycle for 192 h has not been reported previously in literature. PMID- 29151634 TI - Fungal Planet description sheets: 558-624. AB - Novel species of fungi described in this study include those from various countries as follows: Australia: Banksiophoma australiensis (incl. Banksiophoma gen. nov.) on Banksia coccinea, Davidiellomycesaustraliensis (incl. Davidiellomyces gen. nov.) on Cyperaceae, Didymocyrtis banksiae on Banksia sessilis var. cygnorum, Disculoides calophyllae on Corymbia calophylla, Harknessia banksiae on Banksia sessilis, Harknessia banksiae-repens on Banksia repens, Harknessia banksiigena on Banksia sessilis var. cygnorum, Harknessia communis on Podocarpus sp., Harknessia platyphyllae on Eucalyptus platyphylla, Myrtacremonium eucalypti (incl. Myrtacremonium gen. nov.) on Eucalyptus globulus, Myrtapenidiella balenae on Eucalyptus sp., Myrtapenidiella eucalyptigena on Eucalyptus sp., Myrtapenidiella pleurocarpae on Eucalyptuspleurocarpa, Paraconiothyrium hakeae on Hakea sp., Paraphaeosphaeria xanthorrhoeae on Xanthorrhoea sp., Parateratosphaeria stirlingiae on Stirlingia sp., Perthomyces podocarpi (incl. Perthomyces gen. nov.) on Podocarpus sp., Readeriella ellipsoidea on Eucalyptus sp., Rosellinia australiensis on Banksia grandis, Tiarosporella corymbiae on Corymbia calophylla, Verrucoconiothyriumeucalyptigenum on Eucalyptus sp., Zasmidium commune on Xanthorrhoea sp., and Zasmidium podocarpi on Podocarpus sp. Brazil: Cyathus aurantogriseocarpus on decaying wood, Perenniporia brasiliensis on decayed wood, Perenniporia paraguyanensis on decayed wood, and Pseudocercospora leandrae-fragilis on Leandrafragilis.Chile: Phialocephala cladophialophoroides on human toe nail. Costa Rica: Psathyrella striatoannulata from soil. Czech Republic: Myotisia cremea (incl. Myotisia gen. nov.) on bat droppings. Ecuador: Humidicutis dictiocephala from soil, Hygrocybe macrosiparia from soil, Hygrocybe sangayensis from soil, and Polycephalomyces onorei on stem of Etlingera sp. France: Westerdykella centenaria from soil. Hungary: Tuber magentipunctatum from soil. India: Ganoderma mizoramense on decaying wood, Hodophilus indicus from soil, Keratinophyton turgidum in soil, and Russula arunii on Pterigota alata.Italy: Rhodocybe matesina from soil. Malaysia: Apoharknessia eucalyptorum, Harknessia malayensis, Harknessia pellitae, and Peyronellaea eucalypti on Eucalyptus pellita, Lectera capsici on Capsicum annuum, and Wallrothiella gmelinae on Gmelina arborea.Morocco: Neocordana musigena on Musa sp. New Zealand: Candida rongomai-pounamu on agaric mushroom surface, Candida vespimorsuum on cup fungus surface, Cylindrocladiella vitis on Vitis vinifera, Foliocryphia eucalyptorum on Eucalyptus sp., Ramularia vacciniicola on Vaccinium sp., and Rhodotorula ngohengohe on bird feather surface. Poland: Tolypocladium fumosum on a caterpillar case of unidentified Lepidoptera.Russia: Pholiotina longistipitata among moss. Spain: Coprinopsis pseudomarcescibilis from soil, Eremiomyces innocentii from soil, Gyroporus pseudocyanescens in humus, Inocybe parvicystis in humus, and Penicillium parvofructum from soil. Unknown origin: Paraphoma rhaphiolepidis on Rhaphiolepsis indica.USA: Acidiella americana from wall of a cooling tower, Neodactylaria obpyriformis (incl. Neodactylaria gen. nov.) from human bronchoalveolar lavage, and Saksenaea loutrophoriformis from human eye. Vietnam: Phytophthora mekongensis from Citrus grandis, and Phytophthora prodigiosa from Citrus grandis. Morphological and culture characteristics along with DNA barcodes are provided. PMID- 29151640 TI - Improved Sprouting and Growth of Mung Plants in Chromate Contaminated Soils Treated with Marine Strains of Staphylococcus Species. AB - Marine bacteria possess a wide variety of bioremediation potential which is beneficial environmentally and economically. In this study, bacterial isolates from marine waters were screened for tolerance and growth in high concentrations of chromate (Cr6+). Two isolates, capable of tolerating Cr6+ concentrations 300 ug mL-1 or higher, and found to completely reduce 20 ug mL-1 Cr6+ were grown in Cr6+ (50 and 100 mg kg-1) spiked garden soil. Notably, both facilitated normal germination and growth of mung (Vigna radiata) seeds, which could hardly germinate in Cr6+ spiked garden soil without either of these bacteria. In fact, large percent of mung seeds failed to sprout in the Cr6+ spiked garden soil and could not grow any further. Apparently, chromate detoxification by marine bacterial isolates and the ability of mung plants to deal with the reduced form appear to work complementarily. This study provides an insight into marine bacterial abilities with respect to chromium and potential applications in promoting growth of leguminous plants-similar to mung in particular-in Cr6+ contaminated soil. PMID- 29151639 TI - Efficient Using Durian Shell Hydrolysate as Low-Cost Substrate for Bacterial Cellulose Production by Gluconacetobacter xylinus. AB - Durian is one important tropical fruit with high nutritional value, but its shell is usually useless and considered as waste. To explore the efficient and high value utilization of this agricultural and food waste, in this study, durian shell was simply hydrolyzed by dilute sulfuric acid, and the durian shell hydrolysate after detoxification was used for bacterial cellulose (BC) production by Gluconacetobacter xylinus for the first time. BC was synthesized in static culture for 10 days and the highest BC yield (2.67 g/L) was obtained at the 8th day. The typical carbon sources in the substrate including glucose, xylose, formic acid, acetic acid, etc. can be utilized by G. xylinus. The highest chemical oxygen demand (COD) removal (16.40%) was obtained at the 8th day. The highest BC yield on COD consumption and the highest BC yield on sugar consumption were 93.51% and 22.98% (w/w), respectively, suggesting this is one efficient bioconversion for BC production. Durian shell hydrolysate showed small influence on the BC structure by comparison with the structure of BC generated in traditional Hestrin-Schramm medium detected by FE-SEM, FTIR, and XRD. Overall, this technology can both solve the issue of waste durian shell and produce valuable bio-polymer (BC). PMID- 29151641 TI - Foliar Treatment of Bacillus Methylotrophicus KE2 Reprograms Endogenous Functional Chemicals in Sesame to Improve Plant Health. AB - The present study was aimed to investigate the health of vegetative and reproductive parts of sesame plants during Bacillus methylotrophicus KE2 interaction by their pigments, sugars, organic acid, amino acids, hormones and antioxidant production analysis. In a green-house study, B. methylotrophicus KE2 was sprayed to sesame plants at late flowering stage. The bacterial treatment enhanced photosynthetic pigments of plants including pods than their controls. The shoots of plants had higher amount of sucrose, glucose, galactose, xylitol and malic acid, and while the pods of plants showed the more accumulation of sucrose, glucose, inulin and xylitol in bacterium treated plants. However, alanine, cysteine, valine, isoleucine, leucine, tyrosine, phenylalanine, arginine and proline content in shoots and cysteine in pods were increased by the effect of KE2 inoculation. Salicylic acid production was declined in shoots and increased in pods during bacterial exposure. In addition, abscisic acid concentration was lower in pods due to the effect of B. methylotrophicus KE2 in pods over controls. The total polyphenol synthesis was increased in shoots and pods of sesame plants by bacterial interaction. The results of this study revealed that foliar spray of B. methylotrophicus KE2 on sesame plants triggered the plant growth promoting and defense metabolites in vegetative and reproductive organs to improve the health status of sesame. PMID- 29151642 TI - Fusarium Infection Causes Phenolic Accumulations and Hormonal Disorders in Orobanche spp. AB - The physiological effects of Fusarium oxysporum on in-root parasitic weed, Orobanche spp. (broomrape) with references to change in plant hormones and secondary plant constituents were investigated. The levels of IAA, GA, ABA and JA in the experimental group were significantly lower than those in the control group, while the level of SA was higher in the experimental group. In secondary metabolic studies, the quantities of various phenols were measured in the two groups and catechin, syringic acid and p-coumaric acid amounts were significantly higher in the experimental group than in the control group, unlike gallic acid which have a lower amount. Consequently, in the light of all data, it was concluded that Fusarium oxysporum (1) causes heavy hormonal disorder, (2) triggered only SA-mediated defense and (3) induced intensively accumulation of phenolic substances in orobanche. Fusarium oxysporum causes lethal physiological damage on Orobanche spp. PMID- 29151643 TI - Cyanobacteria Nostoc Punctiforme from Abyssal Benthos of Lake Baikal: Unique Ecology and Metabolic Potential. AB - A strain of Nostoc punctiforme was isolated from the bottom sediments of the oil seep at Gorevoy Utes (Central Baikal) at a depth of 890 m. The Baikal strain is highly similar (98-99%) to the N. punctiforme CCAP 1453/9 strain and the typical N. punctiforme PCC 73103 strain isolated from soil ecotopes. Based on the analysis of functional genes and mass spectrometry data, we determined that the strain can produce bioactive peptides and polyketides, but does not produce known cyanobacterial toxins, saxitoxin or its analogs, or microcystins. The peptides aeruginosinamide, aeruginosin 606, aeruginosin 98-A, kasumigamide C, and microginin 91-D were recorded in the metabolic profile of the strain. The major ion found in the MALDI mass spectrum is most likely to be an ion of a polyketide substance with unknown function. PMID- 29151644 TI - Preparation, Characterization, and Antimicrobial Properties of Chitosan-Silver Nanocomposites Films Against Fish Pathogenic Bacteria and Fungi. AB - Abstract: Development of nanostructured films using natural polymers and metals has become a considerable interest in various biomedical applications. Objective of the present study was to develop silver nano particles (AgNPs) embedded chitosan films with antimicrobial properties. Based on the Ag content, two types of chitosan silver nano films, named as CAgNfs-12 (12 mM) and CAgNfs-52 (52 mM) were prepared and characterized. Field emission scanning electron microscope (FE SEM) images of two CAgNfs showed the circular AgNPs, which were uniformly embedded and distributed in the matrix of chitosan films. Antimicrobial experiment results clearly indicated that CAgNfs can inhibit the growth of fish pathogenic bacteria Vibrio (Allivibrio) salmonicida, V. tapetis, Edwardsiella tarda and fungi Fusarium oxysporum. Moreover, CAgNfs significantly reduced the experimentally exposed V. salmonicida levels in artificial seawater, suggesting that these CAgNfs could be used to develop antimicrobial filters/membranes for water purifying units to eliminate the pathogenic microbes. Graphical Abstract: PMID- 29151645 TI - Management of Staphylococcus Mediated Systemic Infection by Enhancing the Resurging Activity of Co-trimoxazole in Presence of Cryptdin-2. AB - Resurgence of sensitivity of the antibiotics, to which the pathogen had developed resistance in the past, requires special attention for strengthening the reservoir of antimicrobial compounds. Reports in the recent past have suggested that co-trimoxazole (COT) has regained its activity against methicillin resistant Staphylococcus aureus (MRSA). The present study exploited the use of COT in the presence of an antimicrobial peptide (AMP), cryptdin-2 (a murine Paneth cell alpha defensin), in order to reduce the selective pressure of the antibiotic on the pathogen. In vitro antibacterial activity and in vivo efficacy of the combination was ascertained against MRSA induced systemic infection using a murine model. Observations of the present study might help in restoring the regained activity of conventional antibiotics, such as COT, when used in combination with novel antimicrobial molecules like AMPs. This might prove as a viable strategy to eliminate the chances of re-occurrence of resistance due to their multi-prong targeting and synergistically combating infections caused by these resistant pathogens. PMID- 29151646 TI - Intracellular Synthesis of Gold Nanoparticles Using an Ectomycorrhizal Strain EM 1083 of Laccaria fraterna and Its Nanoanti-quorum Sensing Potential Against Pseudomonas aeruginosa. AB - In this research work different shapes and sizes of gold nanoparticles (AuNPs) were synthesized through an intracellular biogenic approach, exploiting the chloroauric acid reducing and Au0 stabilizing potential of Laccaria fraterna EM 1083 mycelia. The intracellularly synthesized AuNPs exhibits anti-quorum sensing inhibitory potential against Pseudomonas aeruginosa. The synthesized AuNPs were characterized using UV-visible spectroscopy; transmission electron microscopy, X ray diffraction, energy dispersive X-ray spectroscopy, and Fourier transform infrared spectroscopy. The characterization proved that the successful synthesis of highly stable crystalline AuNPs with various shapes. Here we tested inhibitory activity of AuNPs on QS-regulated biofilm development and pyocyanin production traits of P. aeruginosa. The qualitative and quantitative data demonstrated that AuNPs significantly inhibited the biofilm formation and pyocyanin production. In summary, our results signify the future use of intracellularly synthesized AuNPs in P. aeruginosa mediated diseases. PMID- 29151648 TI - Antimicrobial Efficacy of Methylated Lac Dye, an Anthraquinone Derivative. AB - A natural red dye which is produced by the tiny insects Kerria lacca while feeding on host trees is popularly known as lac dye. Lac dye is a mixture of at least five closely related pure compounds all being anthraquinone derivatives designated as laccaic acid A, B, C, D and E. Anthraquinones isolated from different natural sources and reported to have potent antimicrobial activity. The lac dye, which is also a mixture of anthraquinone derivatives, is expected to exhibit antifungal and antibacterial activity. Lac dye cannot be used as antibacterial and antifungal agent due to its low water solubility and high polarity. Therefore, it is modified into its methyl derivative to enhance its bio efficacy. Methylated lac dye is characterized with the help of TLC, UV-Vis spectroscopy and FT-IR, NMR analysis. An in vitro spore germination assay was carried out to evaluate the antifungal efficacy of methylated lac dye against some phytopathogenic fungi which commonly caused a various foliar diseases in crop plants viz., Alternaria solani, Curvularia lunata, Erysiphe pisi, Helminthosporium oryzae and Verticillium sp. Among the tested fungi, Verticillum sp. showed highest sensitivity, which showed 100% inhibition at 750 and 1000 ug/ml as compared to control. However, E. pisi an obligate parasite also showed varied sensitivity but at 1000 ug/ml showed 100% spore germination as compared to control. Methylated lac dye also showed strong antibacterial properties against Ralstonia solanacearum at very low concentration (40 and 50 ug/ml). Hence, lac dye may serve as potent antifungal and antibacterial agent in plant disease management. PMID- 29151647 TI - 7,10-Epoxyoctadeca-7,9-dienoic Acid: A Small Molecule Adjuvant That Potentiates beta-Lactam Antibiotics Against Multidrug-Resistant Staphylococcus aureus. AB - The emergence of methicillin-resistant Staphylococcus aureus (MRSA) infections with multi-drug resistance needs effective and alternative control strategies. In this study we investigated the adjuvant effect of a novel furan fatty acid, 7,10 epoxyoctadeca-7,9-dienoic acid (7,10-EODA) against multidrug-resistant S. aureus (MDRSA) strain 01ST001 by disc diffusion, checker board and time kill assays. Further the membrane targeting action of 7,10-EODA was investigated by spectroscopic and confocal microscopic studies. 7,10-EODA exerted synergistic activity along with beta-lactam antibiotics against all clinical MRSA strains, with a mean fractional inhibitory concentration index below 0.5. In time-kill kinetic study, combination of 7,10-EODA with oxacillin, ampicillin, and penicillin resulted in 3.8-4.2 log10 reduction in the viable counts of MDRSA 01ST001. Further, 7,10-EODA dose dependently altered the membrane integrity (p < 0.001) and increased the binding of fluorescent analog of penicillin, Bocillin-FL to the MDRSA cells. The membrane action of 7,10-EODA further facilitated the uptake of several other antibiotics in MDRSA. The results of the present study suggested that 7,10-EODA could be a novel antibiotic adjuvant, especially useful in repurposing beta-lactam antibiotics against multidrug-resistant MRSA. PMID- 29151649 TI - Role of the toxR Gene from Fish Pathogen Vibiro alginolyticus in the Physiology and Virulence. AB - A mutant strain of Vibiro alginolyticus with an in-frame deletion of the toxR gene was constructed to reveal the role of ToxR in the physiology and virulence of V. alginolyticus. The statistical analysis showed no significant difference in the growth ability, swarming motility, activity of extracellular protease and the virulence by injection (the value of LD50) between the wild-type and the toxR mutant. However, the deletion of toxR could decrease the level of biofilm formation. The comparative proteomic analysis demonstrated the deletion mutation of toxR could up-regulate the expression of glutamine synthetase and levansucrase, and down-regulate the expression of 10 proteins such as OmpU, DnaK, etc. These results suggest that ToxR may be involved in the early stages of infection by influencing colonization of the bacteria on the surface of the intestine through enhancing the biofilm information of V. alginolyticus via modulating the expression of glutamine synthetize, levansucrase and OmpU. PMID- 29151650 TI - Molecular Modeling of Cloned Bacillus subtilis Keratinase and Its Insinuation in Psoriasis Treatment Using Docking Studies. AB - Present study demonstrated the expression of cloned Bacillus subtilis RSE163 keratinase gene and in silico binding affinities of deduced protein with psoriasis topical drugs for systemic absorption and permeation through skin. The ker gene expressed in E. coli showed significantly higher keratinase activity 450 +/- 10.43 U representing 1342 bp nucleotides encoding 447 amino acids with molecular weight of 46 kDa. The modeled structure was validated using ramachandran's plot showing 305 residues (84.3%) in most favoured region. Docking studies using extra precision (XP) method of Glide showed optimum binding affinities with the drugs Acitretin (- 39.62 kcal/mol), Clobetasol propionate (- 37.90 kcal/mol), Fluticasone (- 38.53 kcal/mol), Desonide (- 32.23 kcal/mol), Anthralin (- 38.04 kcal/mol), Calcipotreine (- 21.55 kcal/mol) and Mometasone (- 28.40 kcal/mol) in comparison to other psoriasis drugs. The results can further be correlated with in vitro enzymatic experiments using keratinase as an effective drug mediator through skin to serve the unmet need of industries. PMID- 29151651 TI - RNA-Binding Domain is Necessary for PprM Function in Response to the Extreme Environmental Stress in Deinococcus radiodurans. AB - Deinococcus radiodurans was considered as one of the most radiation-resistant organisms on Earth because of its strong resistance to the damaging factors of both DNA and protein, including ionizing radiation, ultraviolet radiation, oxidants, and desiccation. PprM, as a bacterial cold shock protein homolog, was involved in the radiation resistance and oxidative stress response of D. radiodurans, but its potential mechanisms are poorly expounded. In this study, we found that PprM was highly conserved with the RNA-binding domain in Deinococcus genus through performing phylogenic analysis. Moreover, the paper presents the analysis on the tolerance of environmental stresses both in the wild-type and the pprM/pprM RBD mutant strains, demonstrating that pprM and RNA-binding domain disruptant strain were with higher sensitivity than the wild-type strain to cold stress, mitomycin C, UV radiation, and hydrogen peroxide. In the following step, the recombinant PprM was purified, with the finding that PprM was bound to the 5' untranslated region of its own mRNA by gel mobility shift assay in vitro. With all these findings taken into consideration, it was suggested that PprM act as a cold shock protein and its RNA-binding domain may be involved in reaction to the extreme environmental stress in D. radiodurans. PMID- 29151652 TI - Antimicrobial Efficacy of Synthetic Pyranochromenones and (Coumarinyloxy)acetamides. AB - Four (1, 2, 4 and 6) synthetic quaternary ammonium derivatives of pyranochromenones and (coumarinyloxy)acetamides were synthesized and investigated for their antimicrobial efficacy on MRSA (Methicillin-resistant Staphylococcus aureus), and multi-drug resistant Pseudomonas aeruginosa, Salmonella enteritidis and Mycobacterium tuberculosis H37Rv strain. One of the four compounds screened i.e. N,N,N-triethyl-10-((4,8,8-trimethyl-2-oxo-2,6,7,8-tetrahydropyrano[3,2 g]chromen-10-yl)oxy)decan-1-aminium bromide (1), demonstrated significant activity against S. aureus, P. aeruginosa and M. tuberculosis with MIC value of 16, 35, and 15.62 ug/ml respectively. The cytotoxicity evaluation of compound 1 on A549 cell lines showed it to be a safe antimicrobial molecule, TEM study suggested that the compound led to the rupture of the bacterial cell walls. PMID- 29151653 TI - The Relationship Between Agar Thickness and Antimicrobial Susceptibility Testing. AB - Antimicrobial susceptibility testing can be done using solid or liquid-based medium. Solid-based assays are easy and inexpensive; they are limited by not being as quantitative as liquid-based assays. Agar depth can influence the accuracy of plate-based assays and it is assumed the basis of this effect is antimicrobial agent diffusion. We tested this assumption by using ETEST(r) to quantitate the relationship between agar depth and minimum inhibitory concentration and zone of inhibition. PMID- 29151654 TI - Development and Evaluation of Simple Dot-Blot Assays for Rapid Detection of Staphylococcal Enterotoxin-A in Food. AB - The present study was aimed to develop and evaluate dot-blot assays for rapid detection of staphylococcal enterotoxin-A (SEA) in food. Dot blots were developed in two formats, indirect and sandwich utilizing mouse monoclonal anti-SEA and rabbit polyclonal anti-SEA antibodies. In indirect dot-blot format, recombinant SEA was directly coated on NCM dot-blot strip and detection was carried out by anti-SEA antibodies. In sandwich dot-blot format, SEA was trapped between anti SEA capture and detection antibodies. Both the dot-blot assays exhibited a sensitivity of ~48 ng ml-1 when tested in different food matrices. The developed assays were highly specific as no cross-reactivity was detected with other classical staphylococcal enterotoxins, toxigenic bacteria and foodborne pathogens. Sensitivity and specificity of developed indirect and sandwich dot blot assays with respect to PCR was found to be 100 and 99%, respectively. The results shows that the developed dot-blot assays can be used as rapid preliminary screening tests for detection of SEA in food or determining the toxigenic potential of staphylococci, especially in resource-limited settings. PMID- 29151655 TI - ASSESSING PARENTING AND FAMILY FUNCTIONING MEASURES FOR URBAN AMERICAN INDIANS. AB - Urban American Indian (AI) families often "live in two worlds," and widely used parenting measures may not adequately capture their parenting styles. Drawing from baseline surveys of AI parents living in 3 urban communities in Arizona (n = 606), this study examines the applicability of using 6 previously validated measures with urban AI parents: parent self-agency, parental supervision, positive parenting practices, discipline, family cohesion, and parent-adolescent conflict. A 4-step factor analytic sequential procedure was employed, and results indicate the only measure remaining as a single factor is discipline. The chi2 difference tests of the remaining 5 measures indicate multiple factors fit the data significantly better than the previously validated single factor. These findings indicate previously validated measures are not adequate holistic descriptions of the parenting and familial experiences of urban AIs. Understanding how urban AIs conceptualize parenting provides a foundation for strengthening urban AI families. PMID- 29151656 TI - Unmarried Mothers' Postnatal School Enrollment: The Role and Intersection of Demographic and Socioeconomic Characteristics. AB - Drawing from a theoretical model of educational decisions and intersectionality theory, this study examined demographic, socioeconomic, and public assistance characteristics that influence unmarried mothers' postnatal enrollment. Using the Fragile Families and Child Wellbeing Study (FFCWS), binomial and multinomial regression techniques were used to examine unmarried mothers' enrollment in their child's first nine years. Results showed unmarried mothers' educational commitment coupled with the influence of race and class indicate that they need additional opportunities to optimize their educations and job opportunities. Targeting outreach and enrollment assistance to underrepresented groups can reduce social-origin inequalities. Important directions for future research include understanding unmarried mothers' rationale for school enrollment and considering how race and class work in combination to support or deter enrollment. PMID- 29151657 TI - MWPCR: Multiscale Weighted Principal Component Regression for High-dimensional Prediction. AB - We propose a multiscale weighted principal component regression (MWPCR) framework for the use of high dimensional features with strong spatial features (e.g., smoothness and correlation) to predict an outcome variable, such as disease status. This development is motivated by identifying imaging biomarkers that could potentially aid detection, diagnosis, assessment of prognosis, prediction of response to treatment, and monitoring of disease status, among many others. The MWPCR can be regarded as a novel integration of principal components analysis (PCA), kernel methods, and regression models. In MWPCR, we introduce various weight matrices to prewhitten high dimensional feature vectors, perform matrix decomposition for both dimension reduction and feature extraction, and build a prediction model by using the extracted features. Examples of such weight matrices include an importance score weight matrix for the selection of individual features at each location and a spatial weight matrix for the incorporation of the spatial pattern of feature vectors. We integrate the importance score weights with the spatial weights in order to recover the low dimensional structure of high dimensional features. We demonstrate the utility of our methods through extensive simulations and real data analyses of the Alzheimer's disease neuroimaging initiative (ADNI) data set. PMID- 29151658 TI - Generalized Scalar-on-Image Regression Models via Total Variation. AB - The use of imaging markers to predict clinical outcomes can have a great impact in public health. The aim of this paper is to develop a class of generalized scalar-on-image regression models via total variation (GSIRM-TV), in the sense of generalized linear models, for scalar response and imaging predictor with the presence of scalar covariates. A key novelty of GSIRM-TV is that it is assumed that the slope function (or image) of GSIRM-TV belongs to the space of bounded total variation in order to explicitly account for the piecewise smooth nature of most imaging data. We develop an efficient penalized total variation optimization to estimate the unknown slope function and other parameters. We also establish nonasymptotic error bounds on the excess risk. These bounds are explicitly specified in terms of sample size, image size, and image smoothness. Our simulations demonstrate a superior performance of GSIRM-TV against many existing approaches. We apply GSIRM-TV to the analysis of hippocampus data obtained from the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset. PMID- 29151659 TI - Fabrication of Zr2WP2O12/ZrV0.6P1.4O7 composite with a nearly zero-thermal expansion property. AB - Sintered bodies of Zr2WP2O12 (ZWP) and ZrV0.6P1.4O7 (ZVP) were fabricated, and their linear thermal expansion coefficients (TEC) were found to be -2.92 * 10-6 and 3.27 * 10-6 degrees C-1, respectively, in the range 25-500 degrees C. In an attempt to fabricate composites with a zero-thermal-expansion property, sintered ZWP/ZVP composites with ZVP/ZWP volume ratios of 0.5/0.5, 0.53/0.47, 0.55/0.45, and 0.6/0.4 were fabricated. Scanning electron microscopy revealed that sintering of ZVP/ZWP composites progressed well compared with that of ZWP. A porous ZVP/ZWP composite with a relative density of ca. 83% was fabricated at a ZVP/ZWP volume ratio of 0.53/0.47. X-ray diffractometry and energy dispersive X-ray spectrometry clarified that the ZVP/ZWP composite mainly consisted of ZWP and ZVP grains. Thermomechanical analysis confirmed that the ZVP/ZWP composite exhibited very low thermal expansion with a slight hysteresis with a TEC of -0.29 * 10-7 degrees C 1 in the range 25-500 degrees C. PMID- 29151661 TI - Quasi-invariant Gaussian measures for the cubic fourth order nonlinear Schrodinger equation. AB - We consider the cubic fourth order nonlinear Schrodinger equation on the circle. In particular, we prove that the mean-zero Gaussian measures on Sobolev spaces [Formula: see text], [Formula: see text], are quasi-invariant under the flow. PMID- 29151660 TI - Neighbourhood Ethnic Density Effects on Behavioural and Cognitive Problems Among Young Racial/Ethnic Minority Children in the US and England: A Cross-National Comparison. AB - Studies on adult racial/ethnic minority populations show that the increased concentration of racial/ethnic minorities in a neighbourhood-a so-called ethnic density effect-is associated with improved health of racial/ethnic minority residents when adjusting for area deprivation. However, this literature has focused mainly on adult populations, individual racial/ethnic groups, and single countries, with no studies focusing on children of different racial/ethnic groups or comparing across nations. This study aims to compare neighbourhood ethnic density effects on young children's cognitive and behavioural outcomes in the US and in England. We used data from two nationally representative birth cohort studies, the US Early Childhood Longitudinal Study-Birth Cohort and the UK Millennium Cohort Study, to estimate the association between own ethnic density and behavioural and cognitive development at 5 years of age. Findings show substantial heterogeneity in ethnic density effects on child outcomes within and between the two countries, suggesting that ethnic density effects may reflect the wider social and economic context. We argue that researchers should take area deprivation into account when estimating ethnic density effects and when developing policy initiatives targeted at strengthening and improving the health and development of racial and ethnic minority children. PMID- 29151662 TI - Associations Between Economic Pressure and Diabetes Efficacy in Couples With Type 2 Diabetes. AB - Objective: The purpose of this study was to explore dyadic associations between economic pressure and diabetes self-efficacy via emotional distress in patients with type 2 diabetes and their partners. Background: Understanding how economic pressure is associated with successful diabetes management is an important area for research, as couples with type 2 diabetes can incur heavy economic pressures that could likely influence diabetes outcomes. Method: Data from 117 married couples were used to test actor-partner associations using moderated mediation analyses in a structural equation modeling framework. Problem-solving communication was tested as a possible moderator of the economic pressure emotional distress pathway. Results: Results revealed that greater patient economic pressure was associated with lower patient and spouse confidence in the patient's diabetes management ability through higher levels of patient emotional distress. The deleterious association between economic pressure and emotional distress was less pronounced when spouses reported more effective problem-solving communication. Conclusion: These results provide evidence that the economic pressure couples with type 2 diabetes face may reduce the patient and spouse's confidence in the patient's diabetes management ability. Implications: This study demonstrates the importance of couple's relationship processes in buffering the impact of economic pressure on diabetes management, providing a clear target for intervention and education efforts. PMID- 29151664 TI - Mild sp2Carbon-Oxygen Bond Activation by an Isolable Ruthenium(II) Bis(dinitrogen) Complex: Experiment and Theory. AB - The isolable ruthenium(II) bis(dinitrogen) complex [Ru(H)2(N2)2(PCy3)2] (1) reacts with aryl ethers (Ar-OR, R = Me and Ar) containing a ketone directing group to effect sp2C-O bond activation at temperatures below 40 degrees C. DFT studies support a low-energy Ru(II)/Ru(IV) pathway for C-O bond activation: oxidative addition of the C-O bond to Ru(II) occurs in an asynchronous manner with Ru-C bond formation preceding C-O bond breaking. Alternative pathways based on a Ru(0)/Ru(II) couple are competitive but less accessible due to the high energy of the Ru(0) precursors. Both experimentally and by DFT calculations, sp2C H bond activation is shown to be more facile than sp2C-O bond activation. The kinetic preference for C-H bond activation over C-O activation is attributed to unfavorable approach of the C-O bond toward the metal in the selectivity determining step of the reaction pathway. PMID- 29151665 TI - Near-infrared peptide-coated quantum dots for small animal imaging. AB - We have synthesized high quality type-II CdTe/CdSe near infrared quantum dots using successive ion layer adsorption and reaction chemistry. Transmission electron microscopy reveals that CdTe/CdSe can be synthesized layer by layer yielding quantum dots of narrow size distribution. Excitation and photoluminescence spectra reveal discrete type-II transitions, which correspond to energy lower that type-I bandgap. We have used a peptide coating technique on type-II and commercial near infrared quantum dots for delivery in live animals and cultured cells. PMID- 29151667 TI - Searching for the Golden Model of Education: Cross-National Analysis of Math Achievement. AB - We utilized four waves of TIMSS data in addition to the information we have collected on countries' educational systems to examine whether different degrees of standardization, differentiation, proportion of students in private schools and governmental spending on education influence students' math achievement, its variation and socioeconomic status (SES) gaps in math achievement. Findings: A higher level of standardization of educational systems was associated with higher average math achievement. Greater expenditure on education (as % of total government expenditure) was associated with a lower level of dispersion of math achievement and smaller SES gaps in math achievement. Wealthier countries exhibited higher average math achievement and a narrower variation. Higher income inequality (measured by Gini index) was associated with a lower average math achievement and larger SES gaps. Further, we found that higher level of standardization alleviates the negative effects of differentiation in the systems with more rigid tracking. PMID- 29151666 TI - Functional Connectivity Analysis in Resting State fMRI with Echo-State Networks and Non-Metric Clustering for Network Structure Recovery. AB - Echo state networks (ESN) are recurrent neural networks where the hidden layer is replaced with a fixed reservoir of neurons. Unlike feed-forward networks, neuron training in ESN is restricted to the output neurons alone thereby providing a computational advantage. We demonstrate the use of such ESNs in our mutual connectivity analysis (MCA) framework for recovering the primary motor cortex network associated with hand movement from resting state functional MRI (fMRI) data. Such a framework consists of two steps - (1) defining a pair-wise affinity matrix between different pixel time series within the brain to characterize network activity and (2) recovering network components from the affinity matrix with non-metric clustering. Here, ESNs are used to evaluate pair-wise cross estimation performance between pixel time series to create the affinity matrix, which is subsequently subject to non-metric clustering with the Louvain method. For comparison, the ground truth of the motor cortex network structure is established with a task-based fMRI sequence. Overlap between the primary motor cortex network recovered with our model free MCA approach and the ground truth was measured with the Dice coefficient. Our results show that network recovery with our proposed MCA approach is in close agreement with the ground truth. Such network recovery is achieved without requiring low-pass filtering of the time series ensembles prior to analysis, an fMRI preprocessing step that has courted controversy in recent years. Thus, we conclude our MCA framework can allow recovery and visualization of the underlying functionally connected networks in the brain on resting state fMRI. PMID- 29151668 TI - Bulging brains. AB - Brain swelling is a serious condition associated with an accumulation of fluid inside the brain that can be caused by trauma, stroke, infection, or tumors. It increases the pressure inside the skull and reduces blood and oxygen supply. To relieve the intracranial pressure, neurosurgeons remove part of the skull and allow the swollen brain to bulge outward, a procedure known as decompressive craniectomy. Decompressive craniectomy has been preformed for more than a century; yet, its effects on the swollen brain remain poorly understood. Here we characterize the deformation, strain, and stretch in bulging brains using the nonlinear field theories of mechanics. Our study shows that even small swelling volumes of 28 to 56 ml induce maximum principal strains in excess of 30%. For radially outward-pointing axons, we observe maximal normal stretches of 1.3 deep inside the bulge and maximal tangential stretches of 1.3 around the craniectomy edge. While the stretch magnitude varies with opening site and swelling region, our study suggests that the locations of maximum stretch are universally shared amongst all bulging brains. Our model has the potential to inform neurosurgeons and rationalize the shape and position of the skull opening, with the ultimate goal to reduce brain damage and improve the structural and functional outcomes of decompressive craniectomy in trauma patients. PMID- 29151669 TI - When Support Seeking Backfires: Co-Rumination, Excessive Reassurance Seeking, and Depressed Mood in the Daily Lives of Young Adults. AB - Research has linked depression to maladaptive variants of support seeking, including co-rumination (CR) and excessive reassurance seeking (ERS), which may contribute to symptom onset and maintenance. Although both CR and ERS are associated with depression, insufficient research has examined how daily behaviors and experiences interact with trait-level CR and ERS to predict daily mood. Fifty-one undergraduates, over-selected for internalizing symptoms, completed baseline assessments, followed by a 14-day daily diary assessing behaviors, stressors, and mood. Daily problem-related talk was associated with elevations in depressed mood for participants with high (but not low) trait CR, particularly for those with major depression. Trait ERS similarly moderated the association between daily reassurance seeking and depressed mood. CR, ERS, and daily reassurance seeking each predicted greater affective reactivity to daily stressors. Results align with daily processes hypothesized by CR and ERS models, and suggest that both constructs may be best understood within a diathesis-stress framework. PMID- 29151670 TI - Motivations and Consequences of Alcohol Use among Heavy Drinking Nonstudent Emerging Adults. AB - Research suggests that nonstudent emerging adults may be at elevated risk for alcohol-related problems in adulthood. The present study utilized a qualitative approach to broaden our understanding of the drinking-related perceptions and experiences of heavy drinking nonstudents, with the ultimate goal of generating meaningful knowledge that could aid intervention planning. Research aims were to identify nonstudent (1) drinking motivations and (2) drinking consequences. Eleven focus groups were conducted (n = 64 participants). Data analytic techniques were used to code transcripts and generate themes emerging from the group data. Analyses revealed three main themes emerged regarding nonstudent reasons for drinking (i.e., emotional, social, enhanced experiences). Four prominent themes were identified for drinking consequences (i.e., physical health, psychological health, risk-taking, life functioning). Our findings underscore several considerations related to intervening with this at-risk and understudied population. PMID- 29151671 TI - Do the Micronutrients Zinc and Magnesium Play a Role in Adult Depression? AB - Depression is a widespread disorder that affects more than 120 million people worldwide. The unsatisfactory clinical efficacy and adverse effects of antidepressant medication have prompted the search for novel treatments. Micronutrient deficiencies may play a role in the development of depression, and recent research studies have explored the use of micronutrient supplementation as an adjunct to the pharmacotherapy of this psychiatric illness. This article provides a review of the empirical evidence linking zinc and magnesium deficiency and depression, discusses possible mechanisms of action in the psychopathology and therapy of depression, and explores the nursing and registered dietitian implications of these findings. PMID- 29151672 TI - Development of a harmonized food grouping system for between-country comparisons in the TEDDY Study. AB - The Environmental Determinants of Diabetes in the Young (TEDDY) is an international study aiming to investigate associations between dietary and other environmental factors and the risk of developing islet autoimmunity and type 1 diabetes. Dietary intake was assessed using a 24-hour recall and repeated 3-day food records and analyzed using country-specific food composition databases (FCDBs) in Finland, Germany, Sweden, and the U.S. with respective in-house calculation programs. A food grouping harmonization process between four country specific FCDBs was conducted to evaluate and achieve comparability on food group definitions and quantification of food consumption across the countries. Systematic review revealed that the majority of existing food groups of the TEDDY FCDBs were not comparable. Therefore, a completely new classification system of 15 mutually exclusive main food groups (e.g. vegetables) and 89 subgroups (e.g. root vegetables, leafy vegetables) was developed. Foods and beverages were categorized into basic foods (single ingredient) and composite dishes (multiple ingredients). Composite dishes were broken down to ingredients using food composition data available in the FCDBs or generic recipes created for the harmonization effort. The daily consumption of every food group across FCDBs was quantified consistently as either raw or prepared weight depending on the food group to achieve maximal comparability. PMID- 29151673 TI - The Perfectly Matched Layer absorbing boundary for fluid-structure interactions using the Immersed Finite Element Method. AB - In this work, a non-reflective boundary condition, the Perfectly Matched Layer (PML) technique, is adapted and implemented in a fluid-structure interaction numerical framework to demonstrate that proper boundary conditions are not only necessary to capture correct wave propagations in a flow field, but also its interacted solid behavior and responses. While most research on the topics of the non-reflective boundary conditions are focused on fluids, little effort has been done in a fluid-structure interaction setting. In this study, the effectiveness of the PML is closely examined in both pure fluid and fluid-structure interaction settings upon incorporating the PML algorithm in a fully-coupled fluid-structure interaction framework, the Immersed Finite Element Method. The performance of the PML boundary condition is evaluated and compared to reference solutions with a variety of benchmark test cases including known and expected solutions of aeroacoustic wave propagation as well as vortex shedding and advection. The application of the PML in numerical simulations of fluid-structure interaction is then investigated to demonstrate the efficacy and necessity of such boundary treatment in order to capture the correct solid deformation and flow field without the requirement of a significantly large computational domain. PMID- 29151674 TI - Chemical Protection of Material Morphology: Robust and Gentle Gas-Phase Surface Functionalization of ZnO with Propiolic Acid. AB - Chemical functionalization of ZnO surface with an alkyne functional group was successfully achieved by exposing ZnO nanopowder to gas-phase propiolic acid in vacuum, which left the alkyne group available for subsequent chemical modification via the azide-alkyne cycloaddition "click" reaction with benzyl azide. The highly selective formation of a bidentate carboxylate linkage and the reaction of benzyl azide were confirmed by solid-state nuclear magnetic resonance spectroscopy, Fourier-transform infrared spectroscopy, and X-ray photoelectron spectroscopy. Most importantly, scanning electron microscopy revealed that the surface morphology was perfectly preserved by this gas-phase modification, as opposed to the alternative protocols based on liquid phase processing. This simple and precise design can serve as a universal method for the modular functionalization of zinc oxide surface following the initial surface preparation and be further applied to thin films, nanostructures, and powders, where preserving surface morphology during chemical modification is especially important. PMID- 29151675 TI - On the theoretical maximum achievable signal-to-noise ratio (SNR) of piezoelectric microphones. AB - A theoretical maximum achievable signal to noise ratio (SNR) for piezoelectric microphones is identified as a function of only microphone volume irrespective of architecture and construction details. For a given piezoelectric material, microphone SNR can be reduced to an expression containing only a dimensionless coupling coefficient and microphone volume. For a given material, the coupling coefficient has a theoretical upper bound defined by the most favorable deformation geometry. The ability to identify a theoretical maximum SNR as a function of only microphone size is surprising considering the numerous design variables and infinite design freedom afforded in the microphone design stage. PMID- 29151676 TI - Jim Hyde and the ENDOR Connection: A Personal Account. AB - In this minireview, we report on our year-long EPR work, such as electron-nuclear double resonance (ENDOR), pulse electron double resonance (PELDOR) and ELDOR detected NMR (EDNMR) at X-band and W-band microwave frequencies and magnetic fields. This report is dedicated to James S. Hyde and honors his pioneering contributions to the measurement of spin interactions in large (bio)molecules. From these interactions, detailed information is revealed on structure and dynamics of macromolecules embedded in liquid-solution or solid-state environments. New developments in pulsed microwave and sweepable cryomagnet technology as well as ultra-fast electronics for signal data handling and processing have pushed the limits of EPR spectroscopy and its multi-frequency extensions to new horizons concerning sensitivity of detection, selectivity of molecular interactions and time resolution. Among the most important advances is the upgrading of EPR to high magnetic fields, very much in analogy to what happened in NMR. The ongoing progress in EPR spectroscopy is exemplified by reviewing various multi-frequency electron-nuclear double-resonance experiments on organic radicals, light-generated donor-acceptor radical pairs in photosynthesis, and site-specifically nitroxide spin-labeled bacteriorhodopsin, the light-driven proton pump, as well as EDNMR and ENDOR on nitroxides. Signal and resolution enhancements are particularly spectacular for ENDOR, EDNMR and PELDOR on frozen-solution samples at high Zeeman fields. They provide orientation selection for disordered samples approaching single-crystal resolution at canonical g-tensor orientations-even for molecules with small g-anisotropies. Dramatic improvements of EPR detection sensitivity could be achieved, even for short-lived paramagnetic reaction intermediates. Thus, unique structural and dynamic information is revealed that can hardly be obtained by other analytical techniques. Micromolar concentrations of sample molecules have become sufficient to characterize stable and transient reaction intermediates of complex molecular systems-offering exciting applications for physicists, chemists, biochemists and molecular biologists. PMID- 29151677 TI - Uniform Field Re-entrant Cylindrical TE[Formula: see text] Cavity for Pulse Electron Paramagnetic Resonance Spectroscopy at Q-band. AB - Uniform field (UF) resonators create a region-of-interest, where the sample volume receives a homogeneous microwave magnetic field ([Formula: see text]) excitation. However, as the region-of-interest is increased, resonator efficiency is reduced. In this work, a new class of uniform field resonators is introduced: the uniform field re-entrant cylindrical TE[Formula: see text] cavity. Here, a UF cylindrical TE[Formula: see text] cavity is designed with re-entrant fins to increase the overall resonator efficiency to match the resonator efficiency maximum of a typical cylindrical TE[Formula: see text] cavity. The new UF re entrant cylindrical TE[Formula: see text] cavity is designed for Q-band (34 GHz) and is calculated to have the same electron paramagnetic resonance (EPR) signal intensity as a TE[Formula: see text] cavity, a 60% increase in average resonator efficiency [Formula: see text] over the sample, and has a [Formula: see text] profile that is 79.8% uniform over the entire sample volume (98% uniform over the region-of-interest). A new H-type T-junction waveguide coupler with inductive obstacles is introduced that increases the dynamic range of a movable short coupler while reducing the frequency shift by 43% during over-coupling. The resonator assembly is fabricated and tested both on the bench and with EPR experiments. This resonator provides a template to improve EPR spectroscopy for pulse experiments at high frequencies. PMID- 29151678 TI - A Pulse EPR 25 mT magnetometer with 10ppm resolution. AB - A magnetometer designed for permanent magnet manufacturing and operated around 25 mT with 10ppm absolute accuracy is described. The magnetometer uses pulse electron paramagnetic resonance (EPR) methodology. The use of a pulsed broadband acquisition allowed reliable measurements in the presence of the magnetic field gradient and in relatively inhomogeneous magnetic fields of un-shimmed magnets. PMID- 29151679 TI - Is it possible to implement a complex adaptive systems approach for marine systems? The experience of Italy and the Adriatic Sea. AB - *This paper evaluates the implementation of the MSFD in the Adriatic Sea.*The MSFD is the first policy for marine complex adaptive systems in the EU.*Ecological and jurisdictional boundaries overlap and cross-border cooperation is low.*Integrative assessments of marine systems may be impossible to achieve.*Relative isolation of theoretical approaches and management practices. PMID- 29151680 TI - Is Glaucoma a Neurodegeneration caused by Central Insulin Resistance: Diabetes Type 4? AB - How to cite this article: Dada T. Is Glaucoma a Neurodegeneration caused by Central Insulin Resistance: Diabetes Type 4? J Curr Glaucoma Pract 2017;11(3):77 79. PMID- 29151682 TI - Anterior Segment Morphology in Primary Angle Closure Glaucoma using Ultrasound Biomicroscopy. AB - Aim: To evaluate the configuration of the anterior chamber angle quantitatively and study the morphological changes in the eye with ultrasound biomicroscopy (UBM) in primary angle closure glaucoma (PACG) patients after laser peripheral iridotomy (LPI). Materials and methods: A total of 185 eyes of 185 PACG patients post-LPI and 126 eyes of 126 normal subjects were included in this prospective study. All subjects underwent complete ophthalmic evaluation, A-scan biometry, and UBM. The anterior segment and angle parameters were measured quantitatively and compared in both groups using Student's t-test. Results: The PACG patients had shorter axial length, shallower central anterior chamber depth anterior chamber depth (ACD), and anteriorly located lens when compared with normal subjects. Trabecular iris angle (TIA) was significantly narrow (5.73 +/- 7.76 degrees ) in patients with PACG when compared with normal subjects (23.75 +/- 9.38 degrees ). The angle opening distance at 500 pm from scleral spur (AOD 500), trabecular-ciliary process distance (TCPD), iris-ciliary process distance (ICPD), and iris-zonule distance (IZD) were significantly shorter in patients with PACG than in normal subjects (p < 0.0001). The iris lens angle (ILA), scleral-iris angle (SIA), and scleral-ciliary process angle (SCPA) were significantly narrower in patients with PACG than in normal subjects (p < 0.0001). The iris-lens contact distance (ILCD) was greater in PACG group than in normal (p = 0.001). Plateau iris was seen in 57/185 (30.8%) of the eyes. Anterior positioned ciliary processes were seen in 130/185 eyes (70.3%) of eyes. Conclusion: In PACG patients, persistent apposition angle closure is common even after LPI, which could be due to anterior rotation of ciliary body and plateau iris and overcrowding of anterior segment due to shorter axial length and relative anterior lens position.How to cite this article: Mansoori T, Balakrishna N. Anterior Segment Morphology in Primary Angle Closure Glaucoma using Ultrasound Biomicroscopy. J Curr Glaucoma Pract 2017;11(3):86-91. PMID- 29151681 TI - Incidence and Risk Factors of Early-onset Glaucoma following Pediatric Cataract Surgery in Egyptian Children: One-year Study. AB - Aim: To study the incidence and risk factors of glaucoma occurring within 1 year following pediatric cataract surgery in Egyptian children. Materials and methods: This is a prospective nonrandomized study conducted at Aburich Children's Hospital, over a period of 1 year on a cohort of Egyptian patients with congenital and infantile cataract. One hundred and fifty eyes of 88 patients were enrolled in this study. All the patients underwent anterior approach removal of lens matter, whereas primary intraocular lens (IOL) implantation was carried at the age of 1 and 2 years for unilateral and bilateral cases respectively. Intraocular pressure (IOP) was measured at 1 week, 1 month, 3 months, 6 months, 9 months, and 1 year. For those who developed glaucoma, time of diagnosis and associated risk factors were reported. Results: The incidence of glaucoma was 11.33% (17 of 150 eyes), while incidence of glaucoma suspect was 0.67% (1 of 150 eyes) in the first year following cataract surgery. The majority of the cases (66.7%) were discovered in the first 3 months postcataract surgery. Age at time of cataract surgery, the state of aphakia/pseudophakia, persistent fetal vasculature (PFV), and microphthalmia were not found to be significant predictors of early-onset glaucoma in our study. Conclusion: Aphakic glaucoma continues to be a devastating condition with high incidence during first year following cataract surgery. Clinical significance: Regular follow-up should start as early as possible following cataract surgery. Further prospective studies with larger study population are required.How to cite this article: Gawdat GI, Youssef MM, Bahgat NM, Elfayoumi DM, Eddin MAS. Incidence and Risk Factors of Early-onset Glaucoma following Pediatric Cataract Surgery in Egyptian Children: One-year Study. J Curr Glaucoma Pract 2017;11(3):80-85. PMID- 29151683 TI - Clinical Experience with the M4 Ahmed Glaucoma Drainage Implant. AB - Aim: To evaluate the safety and efficacy of the M4 (porous polyethylene plate) Ahmed Glaucoma Valve (AGV) drainage implant in a multicenter retrospective study. Materials and methods: A retrospective chart review of medical records of patients who had undergone the M4 Ahmed valve was performed from January 2013 to April 2015. The primary outcome measure was surgical failure defined as: Less than a 20% reduction in baseline intraocular pressure (IOP) to last follow-up visit, final IOP less than 5 mm Hg or greater than 18 mm Hg, reoperation for glaucoma, or loss of light perception vision. All eyes not meeting the above criteria were defined as success. Results: A total of 291 eyes met all study inclusion criteria. The average follow-up in the study was 6 months (+/-7.6 months) with 112 patients achieving 12-month follow-up (38.5%). 208 eyes (71.5%) met the study success criteria at final follow-up. No statistically significant spikes in postoperative IOP at 1 and 4 months were detected. The average preoperative IOP was 26.0 on an average of 2.8 medications. At 6 months, the average IOP dropped to 16.7 on 0.9 medications and stayed relatively stable at 15.8 on 1.2 medications at 12-month follow-up. Conclusion: The M4 valve appears to have less of a hypertensive phase compared with the other Ahmed class valves with a similar safety profile. While 71.5% success rate was achieved at final follow-up, the failure rate steadily increased over time. Clinical significance: While the M4 production has been discontinued, the porous design of the M4 may avoid a pressure spike in the Ahmed valve class and warrants future investigation for valve design.How to cite this article: Sluch I, Gudgel B, Dvorak J, Ahluwalia MA, Ding K, Vold S, Sarkisian S. Clinical Experience with the M4 Ahmed Glaucoma Drainage Implant. J Curr Glaucoma Pract 2017;11(3):92-96. PMID- 29151684 TI - Glaucoma Medication Preferences among Glaucoma Specialists in Mexico. AB - Aim: To determine the glaucoma specialists' preferences for the different brands of topical glaucoma medications available in Mexico. Materials and methods: A web based survey was sent to 150 board-certified glaucoma specialists in Mexico, with 14 questions related to brand preferences for all glaucoma medications available in Mexico. Participants were asked to select each glaucoma medication class by brand and to state the factors leading to their choice. Results: Data from 111 (74%) glaucoma specialists were collected. Imot (timolol 0.5%; Sophia, Mexico) was the preferred brand for the beta-blockers (BB) class by 71% (n = 79) of the participants. Azopt (brinzolamide 1%; Alcon Lab, US) was the preferred carbonic anhydrase inhibitor (CAI) by 54% (n = 60) of the glaucoma specialists. Lumigan (bimatoprost 0.01% and 0.03%; Allergan Inc., U.S.) was the first choice for the prostaglandin analogues (PGAs) in 62% (n = 70) of the answers. The most frequently prescribed alpha-agonist (AA) was Agglad (brimonidine 0.2%; Sophia Lab, Mexico) in 44% (n = 49) of the answers. Medication accessibility (31%), cost (29%), and recommended dose (23%) were the three main factors influencing the glaucoma specialists' preferences. Conclusion: Medication cost and accessibility, as well as posology, remain the main factors influencing brand preferences among glaucoma doctors. In our professional opinion, the therapeutic effect must be the leading factor when prescribing topical medications in the daily practice, so that patients receive the best treatment option. Clinical significance: This survey provides an understanding of the decision-making process when prescribing glaucoma medications by glaucoma specialists in a Latin American developing country. Ideally, patient treatment should be individualized and aimed to achieve the best results possible for their specific condition.How to cite this article: Lazcano-Gomez G, Alvarez-Ascencio D, Haro-Zuno C, Turati-Acosta M, Garcia-Huerta M, Jimenez-Arroyo J, Castaneda-Diez R, Castillejos-Chevez A, Gonzalez-Salinas R, Dominguez-Duenas F, Jimenez-Roman J. Glaucoma Medication Preferences among Glaucoma Specialists in Mexico. J Curr Glaucoma Pract 2017;11(3):97-100. PMID- 29151685 TI - Intraoperative Injection vs Sponge-applied Mitomycin C during Trabeculectomy: One year Study. AB - Aim: To determine the safety and efficacy of intraoperative injection of mitomycin C (MMC) against conventional sponge-applied MMC during trabeculectomy. Materials and methods: This study was a retrospective, comparative case series. Thirty eyes with primary open-angle glaucoma underwent consecutive trabeculectomies with MMC injection (injection group), and thirty eyes with sponge-applied MMC were as controls (sponge group). Data were collected preoperatively and postoperatively at 1 day, 1 week, 1 month, 3 months, 6 months, and 1 year after surgery. Demographic data, applanation intraocular pressure (IOP), best-corrected visual acuity (VA), number of glaucoma medications, postoperative interventions, postoperative complications, and number of visits within 3 months were recorded. In order to stratify data, proportion of eyes achieving >30% IOP reduction from baseline with or without glaucoma medications was calculated and defined as surgical success. Results: Mean IOP reduction at 1 year was significant in both the injection and sponge groups from baseline (46.8 and 37.8% respectively). The injection group had overall lower postoperative IOP and comparable complete treatment success, defined as achieving >30% IOP reduction without glaucoma medications (p = 0.941). The number of postoperative visits within 3 months and the proportion of eyes needing 5-fluorouracil (5-FU) intervention were significantly lower in the injection group (p = 0.03, p = 0.04 respectively). Conclusion: Injection of MMC was as safe and effective as sponge application with comparable estimated complete treatment success, less need for visits within 3 months, and 5-FU intervention. Clinical significance: Surgeons may consider intraopera-tive injection of MMC in appropriate patient cohorts given comparable safety and efficacy and several advantages over traditional sponge application. Further study in a prospective, larger, long-term manner is necessary to assess this modality.How to cite this article: Khouri AS, Huang G, Huang LY. Intraoperative Injection vs Sponge-applied Mitomycin C during Trabeculectomy: One-year Study. J Curr Glaucoma Pract 2017;11(3):101-106. PMID- 29151686 TI - Long-term Follow-up of Patients receiving Intraocular Pressure-lowering Medications as Cataract Surgery Candidates: A Case-control Study. AB - Aim: In this study, we reviewed demographics and biometric characteristics among patients receiving chronic beta-blockers and prostaglandins (PGs) for primary open-angle glaucoma. We compared the age at the time of cataract surgery in different patient groups and in a control group which was not under any medication. Materials and methods: Retrospective chart review of glau-comatous patients who underwent cataract extraction at the Department of Ophthalmology of the University Hospital of Heraklion, Crete, Greece, between January 1998 and December 2016 was done. Age at cataract surgery, axial length (AL), and preoperative and postoperative best-corrected visual acuities (BCVAs) were recorded. A cohort of patients without glaucoma who were operated for cataract extraction was also evaluated. Results: In all, 320 patients were reviewed. There were significant results in mean age difference between the beta-antagonist and the PG group [3.05 years, 95% confidence interval (CI) 1.54-4.57] and between the beta-antagonist group with the patients receiving a combined therapy (3.02 years, 95% CI 1.14-4.91). No significant difference was found between the PG and the combination group. All the three treated groups had a significant lower mean age than the control group at the time of cataract surgery. Conclusion: Based on our study, we concluded that there might be a possible association between chronic treatment with beta-antagonist agents and earlier cataract surgical time in the treated eye. Clinical significance: Intraocular pressure control is often usually achieved using ophthalmic agents. Their topical and systemic effects should be monitored precisely. Earlier cataract formation might be an important side effect which the physician has to keep in mind before choosing the suitable medication.How to cite this article: Bontzos G, Agiorgiotakis M, Detorakis ET. Long-term Follow-up of Patients receiving Intraocular Pressure-lowering Medications as Cataract Surgery Candidates: A Case-control Study. J Curr Glaucoma Pract 2017;11(3):107-112. PMID- 29151687 TI - Medium-term Anatomical Results of Laser Peripheral Iridoplasty: An Anterior Segment Optical Coherence Tomography Study. AB - Aim: To evaluate by anterior segment optical coherence tomography (AS-OCT) the medium-term (mean duration 3.2 years) anatomical changes in the anterior chamber angle (ACA) after laser peripheral iridoplasty. Materials and methods: This is a longitudinal, retrospective case series of 31 eyes of 31 patients with primary angle-closure suspicion, primary angle closure (PAC), or primary angle-closure glaucoma (PACG) who underwent laser peripheral iridoplasty. All patients had persistent iridotrabecular contact (ITC) despite the presence of a patent peripheral iridotomy (PI). An AS-OCT was performed in dark conditions before and after laser iridoplasty. Quadrants of ITC, intraocular pressure (IOP), and the AS OCT parameters of the temporal and nasal ACAs were measured and analyzed. Results: Prior to iridoplasty, the average number of quadrants of ITC was 3.3. At the first postiridoplasty visit (mean duration 6.8 weeks), this reduced to 1.7 quadrants but increased to 1.9 by the final follow-up visit (mean duration 3.2 years). Twenty-five patients (80.1%) had less ITC at the first postlaser visit increasing to 27 (87.1%) patients by the final visit. Two (6.5%) required a second iridoplasty, while 3 (9.7%) required cataract surgery. All parameters of angle width showed a statistically significant increase in magnitude. All patients maintained IOP >= 21 mm Hg throughout the follow-up period. Conclusion: Iridoplasty is a useful adjunct in widening the ACA, particularly in those with persistent angle closure after iridotomy but with no cataract. While not successful in all patients, it can act as a temporizing measure to widen the drainage angle until such time that cataract surgery can be performed. Clinical significance: Laser peripheral iridoplasty can be used as an adjunct in angle closure glaucoma patients with no cataract.How to cite this article: Hooshmand J, Leong JCY, O'Connor J, Ang GS, Wells AP. Medium-term Anatomical Results of Laser Peripheral Iridoplasty: An Anterior Segment Optical Coherence Tomography Study. J Curr Glaucoma Pract 2017;11(3):113-119. PMID- 29151688 TI - Schockmed Valve: A Novel Surgical Option for Uncontrolled Glaucoma in Eyes with Poor Conjunctiva and Encircling Bands. AB - : Surgical management of elevated intraocular pressure (IOP) in an eye with scarred conjunctiva, an encircling band, and silicone oil has limited options. By combining the flow restrictor of the Ahmed Glaucoma Valve (New World Medical, Rancho Cucamonga, California) and the capsule of the encircling band as a conduit for aqueous flow, immediate pressure reduction could theoretically be achieved in eyes with limited conjunctival mobilization. This is a description of a surgical technique in a case of a patient with multiple ocular surgeries with uncontrolled multimechanism glaucoma despite using all available topical and oral glaucoma medications. A combination of the Ahmed valve with a modification of the Schocket shunt technique was used in this case of an encircling band and poor conjunctiva. At 10-month follow-up, the patient maintains controlled pressures on dorzolamide timolol drops. The combined Ahmed-Schocket (or Schockmed) technique may be another surgical option for management of uncontrolled IOP in cases of scarred conjunctiva and encircling bands needing immediate pressure reduction. Schockmed valve: A novel surgical option for uncontrolled glaucoma in eyes with poor conjunctiva and encircling bands.How to cite this article: Fleischman D, Kim B. Schockmed Valve: A Novel Surgical Option for Uncontrolled Glaucoma in Eyes with Poor Conjunctiva and Encircling Bands. J Curr Glaucoma Pract 2017;11(3):120-124. PMID- 29151689 TI - Reabsorption of iron into acutely damaged rat liver: A role for ferritins. AB - AIM: To studied iron metabolism in liver, spleen, and serum after acute liver damage, in relation to surrogate markers for liver-damage and repair. METHODS: Rats received intraperitoneal injection of the hepatotoxin thioacetamide (TAA), and were sacrificed regularly between 1 and 96 h thereafter. Serum levels of transaminases and iron were measured using conventional laboratory assays. Liver tissue was used for conventional histology, immunohistology, and iron staining. The expression of acute-phase cytokines, ferritin light chain (FTL), and ferritin heavy chain (FTH) was investigated in the liver by qRT-PCR. Western blotting was used to investigate FTL and FTH in liver tissue and serum. Liver and spleen tissue was also used to determine iron concentrations. RESULTS: After a short initial decrease, iron serum concentrations increased in parallel with serum transaminase (aspartate aminotransferase and alanine aminotransferase) levels, which reached a maximum at 48 h, and decreased thereafter. Similarly, after 48 h a significant increase in FTL, and after 72h in FTH was detected in serum. While earliest morphological signs of inflammation in liver were visible after 6 h, increased expression of the two acute-phase cytokines IFN-gamma (1h) and IL-1beta (3h) was detectable earlier, with maximum values after 12-24 h. Iron concentrations in liver tissue increased steadily between 1 h and 48 h, and remained high at 96 h. In contrast, spleen iron concentrations remained unchanged until 48 h, and increased mildly thereafter (96 h). Although tissue iron staining was negative, hepatic FTL and FTH protein levels were strongly elevated. Our results reveal effects on hepatic iron concentrations after direct liver injury by TAA. The increase of liver iron concentrations may be due to the uptake of a significant proportion of the metal by healthy hepatocytes, and only to a minor extent by macrophages, as spleen iron concentrations do not increase in parallel. The temporary increase of iron, FTH and transaminases in serum is obviously due to their release by damaged hepatocytes. CONCLUSION: Increased liver iron levels may be the consequence of hepatocyte damage. Iron released into serum by damaged hepatocytes is obviously transported back and stored via ferritins. PMID- 29151690 TI - Region-dependent effects of diabetes and insulin-replacement on neuronal nitric oxide synthase- and heme oxygenase-immunoreactive submucous neurons. AB - AIM: To investigate the intestinal segment-specific effects of diabetes and insulin replacement on the density of different subpopulations of submucous neurons. METHODS: Ten weeks after the onset of type 1 diabetes samples were taken from the duodenum, ileum and colon of streptozotocin-induce diabetic, insulin treated diabetic and sex- and age-matched control rats. Whole-mount preparations of submucous plexus were prepared from the different gut segments for quantitative fluorescent immunohistochemistry. The following double immunostainings were performed: neuronal nitric oxide synthase (nNOS) and HuC/D, heme oxygenase (HO) 1 and peripherin, as well as HO2 and peripherin. The density of nNOS-, HO1- and HO2-immunoreactive (IR) neurons was determined as a percentage of the total number of submucous neurons. RESULTS: The total number of submucous neurons and the proportion of nNOS-, HO1- and HO2-IR subpopulations were not affected in the duodenal ganglia of control, diabetic and insulin-treated rats. While the total neuronal number did not change in either the ileum or the colon, the density of nitrergic neurons exhibited a 2- and 3-fold increase in the diabetic ileum and colon, respectively, which was further enhanced after insulin replacement. The presence of HO1- and HO2-IR submucous neurons was robust in the colon of controls (38.4%-50.8%), whereas it was significantly lower in the small intestinal segments (0.0%-4.2%, P < 0.0001). Under pathophysiological conditions the only alteration detected was an increase in the ileum and a decrease in the colon of the proportion of HO-IR neurons in insulin-treated diabetic animals. CONCLUSION: Diabetes and immediate insulin replacement induce the most pronounced region-specific alterations of nNOS-, HO1- and HO2-IR submucous neuronal density in the distal parts of the gut. PMID- 29151691 TI - Parallel mRNA, proteomics and miRNA expression analysis in cell line models of the intestine. AB - AIM: To identify miRNA-regulated proteins differentially expressed between Caco2 and HT-29: two principal cell line models of the intestine. METHODS: Exponentially growing Caco-2 and HT-29 cells were harvested and prepared for mRNA, miRNA and proteomic profiling. mRNA microarray profiling analysis was carried out using the Affymetrix GeneChip Human Gene 1.0 ST array. miRNA microarray profiling analysis was carried out using the Affymetrix Genechip miRNA 3.0 array. Quantitative Label-free LC-MS/MS proteomic analysis was performed using a Dionex Ultimate 3000 RSLCnano system coupled to a hybrid linear ion trap/Orbitrap mass spectrometer. Peptide identities were validated in Proteome Discoverer 2.1 and were subsequently imported into Progenesis QI software for further analysis. Hierarchical cluster analysis for all three parallel datasets (miRNA, proteomics, mRNA) was conducted in the R software environment using the Euclidean distance measure and Ward's clustering algorithm. The prediction of miRNA and oppositely correlated protein/mRNA interactions was performed using TargetScan 6.1. GO biological process, molecular function and cellular component enrichment analysis was carried out for the DE miRNA, protein and mRNA lists via the Pathway Studio 11.3 Web interface using their Mammalian database. RESULTS: Differential expression (DE) profiling comparing the intestinal cell lines HT-29 and Caco-2 identified 1795 Genes, 168 Proteins and 160 miRNAs as DE between the two cell lines. At the gene level, 1084 genes were upregulated and 711 were downregulated in the Caco-2 cell line relative to the HT-29 cell line. At the protein level, 57 proteins were found to be upregulated and 111 downregulated in the Caco-2 cell line relative to the HT-29 cell line. Finally, at the miRNAs level, 104 were upregulated and 56 downregulated in the Caco-2 cell line relative to the HT-29 cell line. Gene ontology (GO) analysis of the DE mRNA identified cell adhesion, migration and ECM organization, cellular lipid and cholesterol metabolic processes, small molecule transport and a range of responses to external stimuli, while similar analysis of the DE protein list identified gene expression/transcription, epigenetic mechanisms, DNA replication, differentiation and translation ontology categories. The DE protein and gene lists were found to share 15 biological processes including for example epithelial cell differentiation [P value <= 1.81613E-08 (protein list); P <= 0.000434311 (gene list)] and actin filament bundle assembly [P value <= 0.001582797 (protein list); P <= 0.002733714 (gene list)]. Analysis was conducted on the three data streams acquired in parallel to identify targets undergoing potential miRNA translational repression identified 34 proteins, whose respective mRNAs were detected but no change in expression was observed. Of these 34 proteins, 27 proteins downregulated in the Caco-2 cell line relative to the HT-29 cell line and predicted to be targeted by 19 unique anti-correlated/upregulated microRNAs and 7 proteins upregulated in the Caco-2 cell line relative to the HT-29 cell line and predicted to be targeted by 15 unique anti-correlated/downregulated microRNAs. CONCLUSION: This first study providing "tri-omics" analysis of the principal intestinal cell line models Caco-2 and HT-29 has identified 34 proteins potentially undergoing miRNA translational repression. PMID- 29151692 TI - Fecal calprotectin measurement is a marker of short-term clinical outcome and presence of mucosal healing in patients with inflammatory bowel disease. AB - AIM: To evaluate the utility of fecal calprotectin (FC) in predicting relapse and endoscopic activity during follow-up in an inflammatory bowel disease (IBD) cohort. METHODS: All FC measurements that were obtained during a 3-year period from patients with inflammatory bowel disease in clinical remission were identified. Data regarding the short-term (6 mo) course of the disease were extracted from the medical files. Exclusion criteria were defined as: (1) An established flare of the disease at the time of FC measurement, (2) Loss to follow up within 6 mo from baseline FC measurement, and, (3) Insufficient data on file. Statistical analysis was performed to evaluate whether baseline FC measurement could predict the short term clinical relapse and/or the presence of mucosal healing. RESULTS: We included 149 [Crohn's disease (CD) = 113, Ulcerative colitis (UC) = 36, male = 77] IBD patients in our study. Within the determined 6 month period post-FC measurement, 47 (31.5%) had a disease flare. Among 76 patients who underwent endoscopy, 39 (51.3%) had mucosal healing. Baseline FC concentrations were significantly higher in those who had clinical relapse compared to those who remained in remission during follow up (481.0 MUg/g, 286.0 600.0 vs 89.0, 36.0-180.8, P < 0.001). The significant predictive value of baseline median with IQR FC for clinical relapse was confirmed by multivariate Cox analysis [HR for 100MUg/g: 1.75 (95%CI: 1.28-2.39), P = 0.001]. Furthermore, lower FC baseline values significantly correlated to the presence of mucosal healing in endoscopy (69.0 MUg/g, 30.0-128.0 vs 481.0, 278.0-600.0, in those with mucosal inflammation, median with IQR, P < 0.001). We were able to extract cut off values for FC concentration with a high sensitivity and specificity for predicting clinical relapse (261 MUg/g with AUC = 0.901, sensitivity 87.2%, specificity 85.3%, P < 0.001) or mucosal healing (174 MUg/g with AUC = 0.956, sensitivity 91.9%, specificity 87.2%, P < 0.001). FC was better than CRP in predicting either outcome; nevertheless, having a pathological CRP (> 5 mg/L) in addition to the cut-offs for FC, significantly enhanced the specificity for predicting clinical relapse (95.1% from 85.3%) or endoscopic activity (100% from 87.2%). CONCLUSION: Serial FC measurements may be useful in monitoring IBD patients in remission, as FC appears to be a reliable predictor of short-term relapse and endoscopic activity. PMID- 29151693 TI - Endoscopic balloon dilation of Crohn's disease strictures-safety, efficacy and clinical impact. AB - AIM: To evaluate the incidence of anastomotic strictures after intestinal resection in Crohn's disease (CD), demonstrate long-term efficacy and safety of endoscopic balloon dilation (EBD) in CD strictures and its impact on the diagnosis of subclinical postoperative endoscopic recurrence. METHODS: Retrospective single tertiary center study based on prospectively collected data between 2010 and 2015 including anastomotic and non-anastomotic strictures. RESULTS: 29% of 162 CD patients included developed an anastomotic stricture. 43 patients with anastomotic strictures and 37 with non-anastomotic strictures underwent EBD; technical success was 97.7% and 100%, respectively, however, 63% and 41% needed repeat dilation during the 4.4-year follow-up. Longer periods between surgery and index colonoscopy and higher lactoferrin levels were associated with the presence of stricture after surgery. Calprotectin levels > 83.35 MUg/g and current or past history of smoking were associated with a shorter time until need for dilation (HR = 3.877, 95%CI: 1.480-10.152 and HR = 3.041, 95%CI: 1.213-7.627). Anastomotic strictures had a greater need for repeat dilation (63% vs 41%, P = 0.047). No differences were found between asymptomatic and symptomatic cohorts. Disease recurrence diagnosis was only possible after EBD in a third of patients. CONCLUSION: EBD is an effective and safe alternative to surgery, with a good short and long-term outcome, postponing or even avoiding further surgery. EBD may allow to diagnose disease recurrence in patients with no clinical signs/biomarkers of disease activity. PMID- 29151694 TI - Survival analysis based on human epidermal growth factor 2 status in stage II-III gastric cancer. AB - AIM: To investigate human epidermal growth factor 2 (HER2) overexpression and validate its prognostic effect in stage II-III gastric cancer. METHODS: We reviewed the data of patients who were diagnosed with gastric cancer between March 2008 and October 2013 at the Yonsei University Medical Center. Among these patients, 384 patients who met the inclusion criteria were analyzed retrospectively. RESULTS: Thirty-two (8.3%) of the 384 stage II-III gastric cancer patients exhibited HER2 overexpression. The median follow-up duration was 26.0 mo. HER2-negative patients had superior recurrence-free survival (RFS) compared to HER2-positive patients (HR = 0.52, 95%CI: 0.30-0.89; P = 0.015). The median overall survival (OS) was significantly prolonged in the HER2-negative group compared with the HER2-positive group (55.0 mo vs 38.0 mo, HR = 0.43, 95%CI: 0.21-0.88, P = 0.021). OS was also prolonged in HER2-negative patients who received adjuvant chemotherapy compared to HER2-positive patients (55.0 vs 38.0 mo, HR = 0.42, 95%CI: 0.18-1.00, P = 0.051). In patients who did not receive adjuvant chemotherapy, the median RFS was prolonged in the HER2-negative group compared to the HER2-positive group (not reached vs 12.0 mo, HR = 0.17, 95%CI: 0.06-0.49, P = 0.001). In a multivariate analysis, HER2 status (HR = 0.421, 95%CI: 0.206-0.861, P = 0.018) and Eastern Cooperative Oncology Group performance status (HR = 2.002, 95%CI: 1.530-2.618, P < 0.001) were independent predictors of OS. CONCLUSION: Our findings showed that HER2-positive patients had inferior OS and RFS. Stage II-III HER2-positive patients might be potential candidates for targeted therapies involving trastuzumab. PMID- 29151695 TI - Efficacy of postoperative adjuvant transcatheter arterial chemoembolization in hepatocellular carcinoma patients with microvascular invasion. AB - AIM: To investigate the efficacy and safety of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in preventing tumor recurrence and improving survival in Barcelona Clinic Liver Cancer (BCLC) early (A) and intermediate (B) stage hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). METHODS: A total of 519 BCLC A or B HCC patients treated by liver resection alone or followed by PA-TACE between January 2012 and December 2015 were studied retrospectively. Univariate and multivariate analyses were performed to investigate the risk factors for recurrence-free survival (RFS) and overall survival (OS). Multiple logistic regression was used to identify the clinicopathological characteristics associated with MVI. The rates of RFS and OS were compared among patients with or without MVI treated with liver resection alone or followed by PA-TACE. RESULTS: Univariate and multivariate analyses demonstrated that serum AFP level > 400 ng/mL, tumor size > 5 cm, tumor capsule invasion, MVI, and major hepatectomy were risk factors for poor OS. Tumor capsule invasion, MVI, tumor size > 5 cm, HBV-DNA copies > 1 x 104 IU/mL, and multinodularity were risk factors for poor RFS. Multiple logistic regression identified serum AFP level > 400 ng/mL, tumor size > 5 cm, and tumor capsule invasion as independent predictors of MVI. Both OS and DFS were significantly improved in patients with MVI who received PA-TACE as compared to those who underwent liver resection alone. Patients without MVI did not show a significant difference in OS and RFS between those treated by liver resection alone or followed by PA-TACE. CONCLUSION: PA-TACE is a safe adjuvant intervention and can efficiently prevent tumor recurrence and improve the survival of BCLC early- and intermediate-stage HCC patients with MVI. PMID- 29151696 TI - Value of gamma-glutamyltranspeptidase-to-platelet ratio in diagnosis of hepatic fibrosis in patients with chronic hepatitis B. AB - AIM: To investigate the value of the gamma-glutamyltraspeptidase (GGT)-to platelet (PLT) ratio (GPR) in the diagnosis of hepatic fibrosis in patients with chronic hepatitis B (CHB). METHODS: We included 390 untreated CHB patients in this study. The GPR, aspartate aminotransferase (AST)-to-PLT ratio index (APRI), and fibrosis-4 (FIB-4) of all patients were analysed to determine if these parameter were correlated with age, gender, medical history, liver function [total bilirubin (TBil), alanine aminotransferase (ALT), and AST], GGT, PLT count, or hepatic fibrosis stage. The GPR, APRI, and FIB-4, as well as the combination of the GPR and APRI or the GPR and FIB-4 were assessed in different cirrhosis stages using receiver operating characteristic (ROC) curve analysis to evaluate their value in diagnosing hepatic fibrosis in CHB patients. RESULTS: The GPR, APRI, and FIB-4 were not correlated with CHB patients' age, gender, or disease duration (P > 0.05), but all of these parameters were positively correlated with serum ALT, AST, GGT, and PLT count (P < 0.01). Additionally, the GPR, APRI, and FIB-4 were positively correlated with hepatic fibrosis (P < 0.01); the areas under the ROC curve for the GPR in F1, F2, F3, and F4 stages were 0.723, 0.741, 0.826, and 0.833, respectively, which were significantly higher than the respective values for the FIB-4 and APRI (F1: 0.581, 0.612; F2: 0.706, 0.711; F3: 0.73, 0.751; and F4: 0.799, 0.778). The respective diagnostic cut-off points for each stage were 0.402, 0.448, 0.548, and 0.833, respectively. The diagnostic sensitivity and specificity were, respectively, 88.8% and 87.5% in F1, 72.7% and 89.7% in F2, 81.3% and 98.6% in F3, and 80% and 97.4% in F4 when the GPR and APRI were connected in parallel; 86.6% and 90.2%, 78.4% and 96%, 78.6% and 97.4%, and 73.2% and 97.9%, respectively, when the GPR and APRI were connected in series; 80.2% and 89%, 65% and 89%, 70.3% and 98.5%, and 78.8% and 96.8%, respectively, when the GPR and FIB-4 were connected in parallel; and 83.6% and 87.9%, 76.8% and 96.6%, 72.7% and 98%, and 74.4% and 97.7%, respectively, when the GPR and FIB-4 were connected in series. CONCLUSION: The GPR, as a serum diagnostic index of liver fibrosis, is more accurate, sensitive, and easy to use than the FIB-4 and APRI, and the GPR can significantly improve the sensitivity and specificity of hepatic fibrosis diagnosis in CHB when combined with the FIB-4 or APRI. PMID- 29151697 TI - Anatomic isolated caudate lobectomy: Is it possible to establish a standard surgical flow? AB - AIM: To establish the surgical flow for anatomic isolated caudate lobe resection. METHODS: The study was approved by the ethics committee of the Second Affiliated Hospital Zhejiang University School of Medicine (SAHZU). From April 2004 to July 2014, 20 patients were enrolled who underwent anatomic isolated caudate lobectomy at SAHZU. Clinical and postoperative pathological data were analyzed. RESULTS: Of the total 20 cases, 4 received isolated complete caudate lobectomy (20%) and 16 received isolated partial caudate lobectomy (80%). There were 4 cases with the left approach (4/20, 20%), 6 cases with the right approach (6/20, 30%), 7 cases with the bilateral combined approach (7/20, 35%), 3 cases with the anterior approach (3/20, 15%), and the hanging maneuver was also combined in 2 cases. The median tumor size was 5.5 cm (2-12 cm). The median intra-operative blood loss was 600 mL (200-5700 mL). The median intra-operative blood transfusion volume was 250 mL (0-2400 mL). The median operation time was 255 min (110-510 min). The median post-operative hospital stay was 14 d (7-30 d). The 1- and 3-year survival rates for malignant tumor were 88.9% and 49.4%, respectively. CONCLUSION: Caudate lobectomy was a challenging procedure. It was demonstrated that anatomic isolated caudate lobectomy can be done safely and effectively. PMID- 29151698 TI - Circulating miRNAs as biomarkers for severe acute pancreatitis associated with acute lung injury. AB - AIM: To identify circulating micro (mi)RNAs as biological markers for prediction of severe acute pancreatitis (SAP) with acute lung injury (ALI). METHODS: Twenty four serum samples were respectively collected and classified as SAP associated with ALI and SAP without ALI, and the miRNA expression profiles were determined by microarray analysis. These miRNAs were validated by quantitative reverse transcription-polymerase chain reaction, and their putative targets were predicted by the online software TargetScan, miRanda and PicTar database. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (commonly known as KEGG) were used to predict their possible functions and pathways involved. RESULTS: We investigated 287 miRNAs based on microarray data analysis. Twelve miRNAs were differentially expressed in the patients with SAP with ALI and those with SAP without ALI. Hsa-miR-1260b, 762, 22-3p, 23b and 23a were differently up regulated and hsa-miR-550a*, 324-5p, 484, 331-3p, 140-3p, 342-3p and 150 were differently down-regulated in patients with SAP with ALI compared to those with SAP without ALI. In addition, 85 putative target genes of the significantly dysregulated miRNAs were found by TargetScan, miRanda and PicTar. Finally, GO and pathway network analysis showed that they were mainly enriched in signal transduction, metabolic processes, cytoplasm and cell membranes. CONCLUSION: This is the first study to identify 12 circulating miRNAs in patients with SAP with ALI, which may be biomarkers for prediction of ALI after SAP. PMID- 29151699 TI - Scoring systems for peptic ulcer bleeding: Which one to use? AB - AIM: To compare the Glasgow-Blatchford score (GBS), Rockall score (RS) and Baylor bleeding score (BBS) in predicting clinical outcomes and need for interventions in patients with bleeding peptic ulcers. METHODS: Between January 2008 and December 2013, 1012 consecutive patients admitted with peptic ulcer bleeding (PUB) were prospectively followed. The pre-endoscopic RS, BBS and GBS, as well as the post-endoscopic diagnostic scores (RS and BBS) were calculated for all patients according to their urgent upper endoscopy findings. Area under the receiver-operating characteristics (AUROC) curves were calculated for the prediction of lethal outcome, rebleeding, needs for blood transfusion and/or surgical intervention, and the optimal cutoff values were evaluated. RESULTS: PUB accounted for 41.9% of all upper gastrointestinal tract bleeding, 5.2% patients died and 5.4% patients underwent surgery. By comparing the AUROC curves of the aforementioned pre-endoscopic scores, the RS best predicted lethal outcome (AUROC 0.82 vs 0.67 vs 0.63, respectively), but the GBS best predicted need for hospital based intervention or 30-d mortality (AUROC 0.84 vs 0.57 vs 0.64), rebleeding (AUROC 0.75 vs 0.61 vs 0.53), need for blood transfusion (AUROC 0.83 vs 0.63 vs 0.58) and surgical intervention (0.82 vs 0.63 vs 0.52) The post-endoscopic RS was also better than the post-endoscopic BBS in predicting lethal outcome (AUROC 0.82 vs 0.69, respectively). CONCLUSION: The RS is the best predictor of mortality and the GBS is the best predictor of rebleeding, need for blood transfusion and/or surgical intervention in patients with PUB. There is no one 'perfect score' and we suggest that these two tests be used concomitantly. PMID- 29151701 TI - Clinical outcomes of transcatheter selective superior mesenteric artery urokinase infusion therapy vs transjugular intrahepatic portosystemic shunt in patients with cirrhosis and acute portal vein thrombosis. AB - AIM: To compare the outcomes of transcatheter superior mesenteric artery (SMA) urokinase infusion and transjugular intrahepatic portosystemic shunt (TIPS) for acute portal vein thrombosis (PVT) in cirrhosis. METHODS: From January 2013 to December 2014, patients with liver cirrhosis and acute symptomatic PVT who met the inclusion criteria were randomly assigned to either an SMA group or a TIPS group. The two groups accepted transcatheter selective SMA urokinase infusion therapy and TIPS, respectively. The total follow-up time was 24 mo. The primary outcome measure was the change in portal vein patency status which was evaluated by angio-computed tomography or Doppler ultrasound. Secondary outcomes were rebleeding and hepatic encephalopathy. RESULTS: A total of 40 patients were enrolled, with 20 assigned to the SMA group and 20 to the TIPS group. The symptoms of all patients in the two groups improved within 48 h. PVT was improved in 17 (85%) patients in the SMA group and 14 (70%) patients in the TIPS group. The main portal vein (MPV) thrombosis was significantly reduced in both groups (P < 0.001), and there was no significant difference between them (P = 0.304). In the SMA group, superior mesenteric vein (SMV) thrombosis and splenic vein (SV) thrombosis were significantly reduced (P = 0.048 and P = 0.02), which did not occur in the TIPS group. At 6-, 12-, and 24-mo follow-up, in the SMA group and the TIPS group, the cumulative rates free of the first episode of rebleeding were 80%, 65%, and 45% vs 90%, 80%, and 60%, respectively (P = 0.320); the cumulative rates free of the first episode of hepatic encephalopathy were 85%, 80%, and 65% vs 50%, 40%, and 35%, respectively (P = 0.022). CONCLUSION: Transcatheter selective SMA urokinase infusion and TIPS are safe and effective for acute symptomatic PVT in cirrhosis. PMID- 29151700 TI - Tenofovir vs lamivudine plus adefovir in chronic hepatitis B: TENOSIMP-B study. AB - AIM: To demonstrate the non-inferiority (15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate (TDF) vs the combination of lamivudine (LAM) plus adefovir dipivoxil (ADV) in the maintenance of virologic response in patients with chronic hepatitis B (CHB) and prior failure with LAM. METHODS: This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups (TDF and LAM+ADV) of adult patients with hepatitis B e antigen (HBeAg)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed. RESULTS: Forty-six patients were evaluated [median age: 55.4 years (30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA (HBV-DNA) remained undetectable, all patients remained HBeAg negative, and hepatitis B surface antigen (HBsAg) positive. Alanine aminotransferase (ALT) values at the end of the study were similar in the 2 groups (25.1 +/- 7.65, TDF vs 24.22 +/- 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects (AEs) (53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively (P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment (?4943 +/- 1059 vs ?5811 +/- 1538, respectively, P < 0.001). CONCLUSION: TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs. PMID- 29151702 TI - Extraordinary response of metastatic pancreatic cancer to apatinib after failed chemotherapy: A case report and literature review. AB - Chemotherapy has limited efficacy in the treatment of advanced and metastatic pancreatic cancer (PC), and has serious side effects. The development of novel effective agents, especially targeted therapy, is essential for patients with PC. We present a 58-year-old Chinese woman initially diagnosed with locally advanced PC. As the disease progressed to Stage IV, the patient was unable to tolerate chemotherapy after the fourth-line treatment. She was then treated with apatinib, a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 and achieved a progression-free-survival of 7 mo. All drug-related side effects were well controlled with medication. To the best of our knowledge, this is the first case of PC which responded to apatinib. Considering this remarkable response, apatinib may be a promising agent in the treatment of PC. We also reviewed the literature on chemotherapy and targeted therapy, especially the anti-angiogenesis therapy for patients with PC, and investigated the effect of apatinib in other solid tumors as well. PMID- 29151705 TI - [Formula: see text]-Contraction in terms of measure of noncompactness with application for nonlinear integral equations. AB - In this paper, some new generalization of Darbo's fixed point theorem is proved by using a [Formula: see text]-contraction in terms of a measure of noncompactness. Our result extends to obtaining a common fixed point for a pair of compatible mappings. The paper contains an application for nonlinear integral equations as well. PMID- 29151703 TI - 3D-printed "fistula stent" designed for management of enterocutaneous fistula: An advanced strategy. AB - Enterocutaneous fistulas (ECFs) are great challenges during the open abdomen. The loss of digestive juice, water-electrolyte imbalance and malnutrition are intractable issues during management of ECF. Techniques such as "fistula patch" and vacuum-assisted closure therapy have been applied to prevent contamination of open abdominal wounds by intestinal fistula drainage. However, failures are encountered due to high-output fistula and anatomical complexity. Here, we report 3D-printed patient-personalized fistula stent for ECF treatment based on 3D reconstruction of the fistula image. Subsequent follow-up demonstrated that this stent was well-implanted and effective to reduce the volume of enteric fistula effluent. PMID- 29151706 TI - Chebyshev type inequalities by means of copulas. AB - A copula is a function which joins (or 'couples') a bivariate distribution function to its marginal (one-dimensional) distribution functions. In this paper, we obtain Chebyshev type inequalities by utilising copulas. PMID- 29151704 TI - Polymeric Nanohybrids as a New Class of Therapeutic Biotransporters. AB - A possible solution to enhance existing drug and gene therapies is to develop hybrid nanocarriers capable of delivering therapeutic agents in a controlled and targeted manner. This goal can be achieved by designing nanohybrid systems, which combine organic or inorganic nanomaterials with biomacromolecules into a single composite. The unique combination of properties along with their facile fabrication enables the design of smart carriers for both drug and gene delivery. These hybrids can be further modified with cell targeting motifs to enhance their biological interactivity. In this Talents and Trends article, an overview of emerging nanohybrid-based technologies will be provided to highlight their potential use as innovative platforms for improved cancer therapies and new strategies in regenerative medicine. The clinical relevance of these systems will be reviewed to define the current challenges which still need to be addressed to allow these therapies to move from bench to bedside. PMID- 29151707 TI - Generalized matrix summability of a conjugate derived Fourier series. AB - The study of infinite matrices is important in the theory of summability and in approximation. In particular, Toeplitz matrices or regular matrices and almost regular matrices have been very useful in this context. In this paper, we propose to use a more general matrix method to obtain necessary and sufficient conditions to sum the conjugate derived Fourier series. PMID- 29151708 TI - Sharp bounds for a special quasi-arithmetic mean in terms of arithmetic and geometric means with two parameters. AB - In the article, we present the best possible parameters [Formula: see text] and [Formula: see text] on the interval [Formula: see text] such that the double inequality [Formula: see text] holds for any [Formula: see text] and all [Formula: see text] with [Formula: see text], where [Formula: see text], [Formula: see text] and [Formula: see text] are the arithmetic, geometric and special quasi-arithmetic means of a and b, respectively. PMID- 29151709 TI - Refinements and generalizations of some inequalities of Shafer-Fink's type for the inverse sine function. AB - In this paper, we give some sharper refinements and generalizations of inequalities related to Shafer-Fink's inequality for the inverse sine function stated in Theorems 1, 2, and 3 of Bercu (Math. Probl. Eng. 2017: Article ID 9237932, 2017). PMID- 29151711 TI - Beyond "Just Eat Less, Exercise More": Obesity Treatment in Patients With Type 2 Diabetes. PMID- 29151710 TI - Clinical Challenges With Concentrated Insulins: Setting the Record Straight. PMID- 29151712 TI - About Scott Kahan, MD, MPH: Guest Editor, Obesity Treatment in Patients With Type 2 Diabetes. PMID- 29151713 TI - Treatment of Obesity in Patients With Diabetes. AB - IN BRIEF More than 90% of patients with diabetes have overweight or obesity. Whereas weight gain and obesity worsen insulin resistance, weight loss slows the progression of diabetes complications. Given the elevated risk for diabetes complications in patients with obesity, clinicians must understand how to treat obesity in their patients with diabetes, including providing counseling and behavioral management, referral to weight loss programs, and medication management. This article summarizes guidelines for diagnosing and managing obesity in people with diabetes. PMID- 29151715 TI - Obesity Pharmacotherapy in Patients With Type 2 Diabetes. AB - IN BRIEF Patients with obesity and type 2 diabetes are key targets for weight loss. Given the lack of behavioral weight loss in most patients, obesity pharmacotherapy options should be considered in this patient population. This article reviews key pharmacotherapy options for patients with coexisting obesity and type 2 diabetes. Diabetes medications that are associated with weight gain should be avoided in these patients if possible. PMID- 29151714 TI - Multidisciplinary Team-Based Obesity Treatment in Patients With Diabetes: Current Practices and the State of the Science. AB - IN BRIEF Rates of obesity and diabetes are growing, as are their costs. Because the two diseases share many key determinants, the paradigms for their treatment overlap. For both, optimal treatment involves a multidisciplinary team following the Chronic Care Model of health care delivery. Combined treatment programs that include 1) a low-calorie diet individualized to patients' preferences, 2) structured exercise that is also tailored to each patient, and 3) psychotherapy induce the largest weight changes in patients with diabetes. Although diet alone can achieve weight loss, exercise and cognitive behavioral therapy components can enhance the effects of dietary modification. A multidisciplinary team that includes a physician with expertise in pharmacotherapy, a nurse and/or nurse practitioner, a dietitian, an exercise physiologist, and a psychologist can provide a comprehensive weight loss program combining the most effective interventions from each discipline. PMID- 29151716 TI - Endoscopic Medical Devices for Primary Obesity Treatment in Patients With Diabetes. AB - IN BRIEF Several new endoscopic bariatric therapies have been approved by the U.S. Food and Drug Administration for the treatment of obesity, with many more devices and procedures undergoing investigational studies. This article describes these devices and procedures and special considerations for their use in patients with diabetes. PMID- 29151718 TI - Achievement of Adequate Glycemic Control in Patients With Type 2 Diabetes and Comorbid Mental Health Conditions Treated in a Primary Care Setting. AB - Objective: This study investigated the association between the presence of a mental health condition (MHC) diagnosis and glycemic control in patients with type 2 diabetes in a primary care clinic network. Methods: This retrospective cross-sectional study compared adequate glycemic control (A1C <8.0%) in patients with type 2 diabetes with and without any MHC, as well as by MHC subtypes of depression or anxiety, bipolar or schizophrenia disorders, and substance use disorder. Results: Of 3,025 patients with type 2 diabetes, 721 (24%) had a diagnosis for one or more MHC. The majority (54.9%) were <65 years of age, female (54.9%), and Caucasian (74.5%). Mean A1C was statistically lower in the MHC cohort at 7.14 +/- 1.66% compared to 7.38 +/- 1.73% in the group without any MHC (P = 0.001). Furthermore, those with an MHC were more likely to attain adequate glycemic control than those without an MHC (odds ratio 1.27, 95% CI 1.01-1.59). Among patients with MHCs, similar rates of adequate glycemic control were seen between those with depression or anxiety and those with other MHCs. However, fewer patients with substance use disorder had adequate glycemic control compared to those without this condition (66.7 vs. 80.10%, P = 0.004). Conclusion: Patients with diabetes and MHCs had slightly better glycemic control than those without any MHC. However, the presence of substance use disorder may present more barriers to adequate glycemic control. Additional research is needed to identify barriers unique to each MHC to optimize diabetes management in this population. PMID- 29151719 TI - Reducing Social Distress for Chronic Disease Patients in Primary Care: An Intervention for Latino Type 2 Diabetes Patients Seen at Community Health Centers. AB - Background: Social and behavioral factors have important direct and indirect effects on chronic disease onset and progression. The U.S. health care system is beginning to focus on assessment and management of social and behavioral problems through federal mandates related to meaningful use of electronic health records and improved patient outcomes. Methods: We examined the clinical adoption of a 20 item screening tool to measure social distress focusing on type 2 diabetes. This Internet-based survey tool was embedded within a diabetes team care dashboard used to manage Latino patients with poorly controlled type 2 diabetes (n = 399) seen at urban safety-net clinics with referral as needed to clinical, community, and social services. Results: Results showed a high baseline prevalence of many of the 20 social distress issues assessed. The control group had a mean 6.8 +/- 4.3 items at baseline and 6.2 +/- 4.3 items at 6 months; the intervention group had a mean 7.2 +/- 4.5 items at baseline and 5.6 +/- 4.6 items at 6 months. The majority of participants (>90%) reported having one or more social distress issues during the previous week. Moreover, 11 of 20 social distress items were identified by >=30% of patients as being present. However, social distress was significantly reduced from our intervention based on a culturally sensitive team model focused on actively managing social distress issues compared to usual diabetes team care (P <0.01). Conclusion: Social distress issues are common but were significantly reduced with a 6-month diabetes team intervention involving initial screening followed by tailored diabetes education and referral to existing local services. PMID- 29151720 TI - Providing Lifelong Education and Support: Updates in the 2017 National Standards for Diabetes Self-Management Education and Support. PMID- 29151717 TI - Bariatric Surgery: A Perspective for Primary Care. AB - IN BRIEF Bariatric surgery is the most efficacious treatment for obesity, type 2 diabetes, and other obesity-related comorbidities. In this article, the authors review the current indications for bariatric surgery and discuss the most commonly performed procedures. They analyze medical outcomes of bariatric procedures by reviewing key prospective trials and discuss changes in physiology after these procedures. They conclude by discussing long-term management of bariatric patients by reviewing current guidelines for nutritional support and listing common complications related to these procedures. PMID- 29151722 TI - Perceptions of How the Transition From Home Life to College Life Affects Type 1 Diabetes Management. PMID- 29151724 TI - Preparation and Calibration of Carrier-Free 209Po Solution Standards. AB - Carrier-free 209Po solution standards have been prepared and calibrated. The standards, which will be disseminated by the National Institute of Standards and Technology as Standard Reference Material SRM 4326, consist of (5.1597 +/-0.0024) g of a solution of polonium in nominal 2 mol . L-1 hydrochloric acid (having a solution density of (1.031+/-0.004) g . mL-1 at 22 degrees C) that is contained in 5 mL flame-sealed borosilicate glass ampoules, and are certified to contain a 209Po alpha-particle emission rate concentration of (85.42+/-0.29) s-1 . g-1 (corresponding to a 209Po activity concentration of (85.83 +/-0.30) Bq . g-1) as of the reference time of 1200 EST 15 March 1994. The calibration was based on 4pialpha liquid scintillation (LS) measurements with two different LS counting systems and under wide variations in measurement and sample conditions. Confirmatory measurements by 2pialpha gas-flow proportional counting were also performed. The only known radionuclidic impurity, based on alpha- and photon emission spectrometry, is a trace quantity of 208Po. The 208Po to 209Po impurity ratio as of the reference time was 0.00124 +/-0.00020. All of the above cited uncertainty intervals correspond to a combined standard uncertainty multiplied by a coverage factor of k = 2. Although 209Po is nearly a pure alpha emitter with only a weak electron capture branch to 209Bi, LS measurements of the 209Po a decay are confounded by an a transition to a 2.3 keV ( Jpi= 1/2-) level in 205Pb which was previously unknown to be a delayed isomeric state. PMID- 29151723 TI - Home Environmental and Behavioral Risk Indices for Reading Achievement. AB - The goal of this study was to identify home environmental and temperament/behavior variables that best predict standardized reading comprehension scores among school-aged children. Data from 269 children aged 9-16 (M = 12.08; SD = 1.62) were used in discriminant function analyses to create the Home and Behavior indices. Family income was controlled in each index. The final Home and Behavior models each classified around 75% of cases correctly (reading comprehension at grade level vs. not). Each index was then used to predict other outcomes related to reading. Results showed that Home and/or Behavior accounted for 4-7% of the variance in reading fluency and spelling and 20-35% of the variance in parent-rated problems in math, social anxiety, and other dimensions. These metrics show promise as environmental and temperament/behavior risk scores that could be used to predict and potentially screen for further assessment of reading related problems. PMID- 29151725 TI - Spectral Radiance of a Large-Area Integrating Sphere Source. AB - The radiance and irradiance calibration of large field-of-view scanning and imaging radiometers for remote sensing and surveillance applications has resulted in the development of novel calibration techniques. One of these techniques is the employment of large-area integrating sphere sources as radiance or irradiance secondary standards. To assist the National Aeronautical and Space Administration's space based ozone measurement program, a commercially available large-area internally illuminated integrating sphere source's spectral radiance was characterized in the wavelength region from 230 nm to 400 nm at the National Institute of Standards and Technology. Spectral radiance determinations and spatial mappings of the source indicate that carefully designed large-area integrating sphere sources can be measured with a 1 % to 2 % expanded uncertainty (two standard deviation estimate) in the near ultraviolet with spatial nonuniformities of 0.6 % or smaller across a 20 cm diameter exit aperture. A method is proposed for the calculation of the final radiance uncertainties of the source which includes the field of view of the instrument being calibrated. PMID- 29151721 TI - 2017 National Standards for Diabetes Self-Management Education and Support. AB - This article was copublished in Diabetes Care 2017;40:1409-1419 and The Diabetes Educator 2017;43:449-464 and is reprinted with permission. The previous version of this article, also copublished in Diabetes Care and The Diabetes Educator, can be found at Diabetes Care 2012;35:2393-2401 (https://doi.org/10.2337/dc12-1707). PMID- 29151726 TI - Deposition of Diamond Films in a Closed Hot Filament CVD System. AB - A closed system hot filament chemical vapor deposition (CVD) reactor has been used to deposit diamond films on silicon substrates. A fixed charge of hydrogen gas is fed into the deposition system until the desired deposition pressure level is reached. A solid graphite cylindrical rod held above the tungsten filament was the carbon source. System parameters for diamond film growth have been determined. The diamond structure of the films has been verified by x-ray diffraction (XRD). Morphology typical of CVD diamond films has been observed in scanning electron microscopy (SEM). The quality of the diamond films has been evaluated by micro-Raman spectroscopy. PMID- 29151727 TI - Variances in the Measurement of Ceramic Powder Properties. AB - Variances in the measurement of properties used to characterize ceramic powders are discussed in the context of the International Energy Agency's study, Annex II, Subtask 2, which includes chemical and physical measurements for five powders: two grades of silicon nitride, and one grade each of silicon carbide, silicon, and zirconia. The analysis presented here includes results for 39 properties reported by 25 laboratories using approximately 700 samples of the powders. Measurement uncertainties are discussed in the contexts of measurement variations within given laboratories (within-laboratory variance, sometimes called repeatability), among different laboratories (between-laboratory variance, also called reproducibility), and among different measurement techniques (between methods variance). The analysis shows that the between-laboratory variance tends to be significantly greater than either the within-laboratory or the between methods variances. The implication of this result is that the most important improvements in powder characterization measurements may be achieved through the standardization of the measurement methodologies. PMID- 29151728 TI - On the Applications of Discontinuous Bessel Integrals to Chronoamperometry. AB - Discontinuous Bessel integrals are applied to a boundary value problem related to chronoamperometry, with zero concentration at the disk satisfied on the average and the zero flux at the shroud satisfied approximately only. Current functions are derived, series expansion at long time and asymptotic expansion at short times are given. Plots of numerical calculations of current functions are presented. PMID- 29151729 TI - Conference Report: THIRD INTERNATIONAL CONFERENCE ON INFORMATION AND KNOWLEDGE MANAGEMENT (CIKM-94) Gaithersburg, MD November 29-December 1, 1994. PMID- 29151730 TI - Conference Report: Federal Wireless Users' Forum Workshop Gaithersburg, MD June 7 9, 1994. PMID- 29151731 TI - Conference Report: Workshop on Water: its Measurement and Control in Vacuum Gaithersburg, MD May 23-25, 1994. PMID- 29151732 TI - Conference Report: Application Portability Profile and Open System Environment Users' Forum Gaithersburg, MD May 11-12, 1994. PMID- 29151733 TI - Low-Temperature Properties of Silver. AB - Pure silver is used extensively in the preparation of high-temperature superconductor wires, tapes, films, and other configurations in which the silver not only shields the superconducting material from the surrounding materials, but also provides a degree of flexibility and strain relief, as well as stabilization and low-resistance electrical contact. Silver is relatively expensive, but at this stage of superconductor development, its unique combination of properties seems to offer the only reasonable means of achieving usable lengths of conductor. In this role, the low-temperature physical (electrical, thermal, magnetic, optical) and mechanical properties of the silver all become important. Here we present a collection of properties data extracted from the cryogenic literature and, to the extent possible, selected for reliability. PMID- 29151734 TI - Mixing Plate-Like and Rod-Like Molecules With Solvent: A Test of Flory-Huggins Lattice Statistics. AB - Boehm and Martire have shown that the Flory-Huggins (FH) lattice model applied to mixtures of squares and rigid rods in solvent on a two dimensional lattice gives different results depending on whether rods or squares are placed first onto the lattice. This correct derivation places the validity of the FH model itself into question since the final result should be independent of the order of placement. An analysis of the FH model in terms of Poisson statistics suggests an alternative formula for the probability of successfully placing a rectangle into an area partially filled with other rectangles, which when incorporated into the FH counting procedure gives the exact thermodynamic result for the tiling of squares (i.e., no solvent and no rods). An attempt to solve the order of placement problem is made by solving the problem of one square plus any number of rods and then generalizing the statistics so that they are consistent with this result. Equations are given for squares plus rods plus solvent in both two and three dimensions. For plates plus solvent in three dimensions a purely entropy driven phase transition between an anisotropic layered phase and an isotropic phase is obtained. This transition is analogous to the isotropic to nematic liquid crystal phase transition in rigid rods. Our equations, when augmented by energy considerations, are useful for calculating the equilibrium properties of discotic systems, polymer-layered silicate composites, and the adsorption of plate like molecules onto surfaces. PMID- 29151735 TI - Determining the Magnetic Properties of 1 kg Mass Standards. AB - Magnetic interactions may lead to errors in precision mass metrology. An analytical description of such magnetic errors is presented in which the roles of both the volume magnetic susceptibility and permanent magnetization are discussed. The same formalism is then used to describe in detail the calibration and operation of a susceptometer developed at the Bureau International des Poids et Mesures (BIPM). The device has been optimized for the determination of the magnetic properties of 1 kg mass standards. PMID- 29151736 TI - Erratum: Determining the Magnetic Properties of 1 kg Mass Standards. AB - [This corrects the article on p. 209 in vol. 100.]. PMID- 29151737 TI - 1993 Intercomparison of Photometric Units Maintained at NIST (USA) and PTB (Germany). AB - A bilateral intercomparison of photometric units between NIST, USA and PTB, Germany has been conducted to update the knowledge of the relationship between the photometric units disseminated in each country. The luminous intensity unit (cd) and the luminous flux unit (lm) maintained at both laboratories are compared by circulating transfer standard lamps. Also, the photometric responsivity sv is compared by circulating a V(lambda)-corrected detector with a built-in current-to voltage converter. The results show that the difference of luminous intensity unit between NIST and PTB, (PTB-NIST)/NIST, is 0.2 % with a relative expanded uncertainty (coverage factor k = 2) of 0.24 %. The difference is reduced significantly from that at the 1985 CCPR intercomparison (0.9 %). The difference in luminous flux unit, (PTB - NIST)/NIST, is found to be 1.5 % with a relative expanded uncertainty (coverage factor k =2) of 0.15 %. The difference remained nearly the same as that at the 1985 intercomparison (1.6 %). These results agree with what is predicted from the history of maintaining the units at each laboratory. PMID- 29151738 TI - Determination of the Transmittance Uniformity of Optical Filter Standard Reference Materials. AB - An instrument based on a scientific grade charge-coupled device (CCD) camera system is performance-qualified to evaluate the transmittance homogeneity of solid optical filter standard reference materials. Measurement results are presented for the new instrument, and compared, where appropriate, with an older, scanning instrument, for a variety of filters spanning transmittances down to 0.01. The new instrument is found to give comparable results with the older instrument, with reduced random uncertainty and improved information content. PMID- 29151739 TI - Low-Frequency Model for Radio-Frequency Absorbers. AB - A simple model is developed to characterize the behavior of radio-frequency absorbers at low frequency. The absorber is represented by a flat, homogeneous, isotropic slab of lossy material, with effective constitutive parameters. These parameters are determined by a fit to measured data. Excellent fits are obtained in the two applications considered. The model is intended for use in the characterization of absorber-lined chambers at low frequency. It could also be used to predict the low-frequency performance of partially loaded shielded enclosures. PMID- 29151740 TI - Using Quantized Breakdown Voltage Signals to Determine the Maximum Electric Fields in a Quantum Hall Effect Sample. AB - We estimate the maximum values of the electric field across the width of a GaAs/AlGaAs heterostructure quantum Hall effect sample at several currents when the sample is in the breakdown regime. This estimate is accomplished by measuring the quantized longitudinal voltage drops along a length of the sample and then employing a quasielastic inter-Landau level scattering (QUILLS) model to calculate the electric field. We also present a pictorial description of how QUILLS transitions occurring between states distributed across the sample width can be detected as voltage signals along the sample length. PMID- 29151741 TI - High Accuracy Measurement of Aperture Area Relative to a Standard Known Aperture. AB - Precise knowledge of the area of apertures used in high precision radiometry is extremely important. A method is presented here for the determination of the area of round and irregularly shaped apertures by comparison to a standard aperture which has been measured by other means to high accuracy. The method presented here is quick and has no physical contact with the fragile edge of the aperture opening. Total flux transfer methods are used in the area determination with total relative standard uncertainty of 0.033 % for 2 mm to 25 mm mean diameter apertures not including the area uncertainty of the standard aperture used. Currently the relative standard uncertainty in the area measurement for the stadard aperture is 0.022 %. The worst case relative standard uncertainty of the transfer measurement is 0.04 % including the uncertainty of the standard aperture area. PMID- 29151742 TI - Letter to the Editor: New IUPAC guidelines for the reporting of stable hydrogen, carbon, and oxygen isotope-ratio data. PMID- 29151743 TI - QUEST FOR EXCELLENCE VII Washington, DC February 6-8, 1995. PMID- 29151744 TI - 17th NATIONAL COMPUTER SECURITY CONFERENCE Baltimore, MD October 11-14, 1994. PMID- 29151745 TI - The Gaseous Electronics Conference RF Reference Cell-An Introduction. AB - This paper provides an introduction to the Gaseous Electronics Conference (GEC) RF Reference Cell, and to the articles published in this Special Issue of the Journal of Research of the National Institute of Standards and Technology. A brief summary of the history and purpose of the Reference Cell concept is presented, and recent changes to the GEC Cell design are documented. The paper concludes with highlights of research performed on GEC Cells, and with an appendix of all known publications that present research performed on GEC Cells. PMID- 29151746 TI - Current and Voltage Measurements in the Gaseous Electronics Conference RF Reference Cell. AB - Measurements of the electrical characteristics of discharges in the Gaseous Electronics Conference Radio-Frequency Reference Cell are reviewed here. Topics include: common sources of error in the measurements; comparisons of current and voltage data among GEC cells; the effects of gas impurities, surface conditions and the external circuitry on the reproducibility of the electrical characteristics; and comparisons of current and voltage data with results of other measurements. PMID- 29151747 TI - Optical Emission Spectroscopy on the Gaseous Electronics Conference RF Reference Cell. AB - A summary of the experimental observations of the optical emission from the Gaseous Electronics Conference (GEC) rf Reference Cell plasma will be discussed. Spatially and temporally resolved results are provided for various reference and non-reference conditions, including etching type plasmas. These measurements provide a detailed description of the temporal evolution of optical emission from different excited atomic states within different atomic and ionic species, as well as their radial and axial distributions. Some of the measurements have been placed on a absolute radiometric scale to provide comparisons to model calculations. Spectral line profile measurements are also presented to provide some insight into the multi-component particle velocities present in such plasmas. PMID- 29151748 TI - Optical Diagnostics in the Gaseous Electronics Conference Reference Cell. AB - A number of laser-induced fluorescence and absorption spectroscopy studies have been conducted using Gaseous Electronics Conference Reference Cells. Laser induced fluorescence has been used to measure hydrogen atom densities, to measure argon metastable spatial profiles, to determine the sheath electric field, and to infer the electron density and temperature. Absorption spectroscopy, using lamp sources and diode lasers, has been used to measure metastable atom densities in helium and argon discharges and fluorocarbon densities in silicon etching discharges. The experimental techniques and sample results of these investigations are reviewed. PMID- 29151749 TI - Studies of Ion Kinetic-Energy Distributions in the Gaseous Electronics Conference RF Reference Cell. AB - A review is presented of kinetic-energy distribution measurements for ions striking grounded surfaces in a Gaseous Electronics Conference (GEC) rf Reference Cell. Two experimental arrangements that have been used to measure ion energies in the GEC Cell are described, and a comparison of their performance under different operating conditions is presented. Significant results from ion-energy analysis in the Reference Cell are highlighted, including evidence of effects due to surface conditions on ion sampling, verification of electrical behavior of the cell, inferences about ion-molecule reactions indicated by the shapes of measured ion kinetic-energy distributions (IEDs), and the use of measured IEDs for the validation of theoretical models. The paper concludes with a detailed study of IEDs measured for rf plasmas generated in mixtures of argon and oxygen, using both experimental arrangements. PMID- 29151750 TI - Microwave Diagnostic Results from the Gaseous Electronics Conference RF Reference Cell. AB - Electron density measurements with even the simplest microwave interferometry techniques can range over three to four orders of magnitude, can be responsive on time scales as fast as 50 ns, and are simple to obtain and interpret. Three groups have published electron density data taken in the Gaseous Electronics Conference (GEC) reference reactor using microwave interferometry. The agreement in the data from these groups at higher pressures is excellent especially when one considers that the GEC reactors involved have some key differences. These may have been the cause of some differences between the results obtained at low pressures, although, the manner in which the measurements were interpreted may also have contributed. The electron densities compare favorably in argon, helium, and nitrogen above 33.3 Pa (250 mTorr); but, the measurements tend to diverge some at 13.3 Pa (100 mTorr) and in 133 Pa helium above approximately 200 mA. It is speculated that the latter difference occurs as the discharges change from a bulk ionization or alpha-mode to a secondary electron emission or gamma-mode, and that this transition occurs at lower voltages and currents for reactors with aluminum electrodes than it does for those with stainless steel electrodes. In addition, time resolved electron densities are presented. There is agreement between time resolved measurements in the two reactors, in particular, the electron density in helium discharges is found to rise dramatically after the rf excitation is turned off while the electron densities in argon and nitrogen glows exhibit only slight increases. PMID- 29151751 TI - Langmuir Probe Measurements in the Gaseous Electronics Conference RF Reference Cell. AB - The use of a Langmuir probe system in two GEC cells is reviewed. The major problems associated with probe diagnostics in a GEC cell are outlined and discussed. While the data base is still insufficient to give definitive values for many parameters, a number of standard measurements are put forward. The plasma density in argon is 9*109 cm-3 (+/-20 %) at an applied rf voltage of 250 V (500 V peak to peak) and a gas pressure of 13.3 Pa (100 mTorr). The electron density scales linearly with applied voltage. The plasma to ground sheath resistance is shown to be very important with a value of 810 Omega in argon at a pressure of 13.3 Pa (100 mTorr) and discharge current of 0.1 A. The value of plasma to ground resistance scales inversely with discharge current and sublinear with pressure. Two standard features in the electron energy distribution function (EEDF) have been proposed as a test of the ability of a probe system to resolve features, first, the transition from a low temperature (<1 eV) bi-Maxwellian distribution to a Druyveysten distribution (3 eV) at 13.3 Pa (100 mTorr) in argon, and the "hole" in the EEDF at 2 eV to 4 eV in nitrogen plasmas. PMID- 29151752 TI - An Inductively Coupled Plasma Source for the Gaseous Electronics Conference RF Reference Cell. AB - In order to extend the operating range of the GEC RF Reference Cell, we developed an inductively coupled plasma source that replaced the standard parallel-plate upper-electrode assembly. Voltage and current probes, Langmuir probes, and an 80 GHz interferometer provided information on plasmas formed in argon, chlorine, and nitrogen at pressures from 0.1 Pa to 3 Pa. For powers deposited in the plasma from 20 W to 300 W, the source produced peak electron densities between 1010/cm3 and 1012/cm3 and electron temperatures near 4 eV. The electron density peaked on axis with typical full-width at half maximum of 7 cm to 9 cm. Discharges in chlorine and nitrogen had bimodal operation that was clearly evident from optical emission intensity. A dim mode occurred at low power and a bright mode at high power. The transition between modes had hysteresis. After many hours of high power operation, films formed on electrodes and walls of one Cell. These deposits affected the dim-to-bright mode transition, and also apparently caused generation of hot electrons and increased the plasma potential. PMID- 29151753 TI - Reactive Ion Etching in the Gaseous Electronics Conference RF Reference Cell. AB - This paper describes the results of using the GEC reference cell as a reactive ion etcher. Silicon wafers with layers of polysilicon and silicon dioxide on crystaline silicon patterned with photoresist have been investigated with fluorine and chlorine chemistries. Scanning electron microscopy (SEM), profilometry, and refraction techniques were used to determine the etch parameters such as etch rate, uniformity and selectivity. The discharges are in general monitored by measuring the optical emission spectroscopy and the bias voltages. For fluorine chemistries, etch rates ranged from 5 nm/min to 177 nm/min, and for chlorine chemistries, etch rates ranged from 25 nm/min to 90 nm/min. Depending upon the discharge and chemistry conditions, similar etch rates and etch patterns of different GEC cells were obtained. Etch rates and relative fluorine concentrations obtained from a commercial etcher were compared to the GEC reference cell and were found to be similar although the GEC cell generally gave lower etch rates than the commercial etcher. PMID- 29151754 TI - Dusty Plasma Studies in the Gaseous Electronics Conference Reference Cell. AB - Particle "dust" in processing plasmas is of critical concern to the semiconductor industry because of the threat particles pose to device yield. A number of important investigations into the formation, growth, charging, transport and consequences of particulate dust in plasmas have been made using the Gaseous Electronics Conference Reference Cell as the reactor test-bed. The greatest amount of work to date has been directed toward a better understanding of the role that electrostatic, ion drag, neutral fluid drag and gravitational forces play in governing the dynamic behavior of particle cloud motion. This has been accomplished by using laser light scattering (LLS) techniques to track the motion of suspended particle clouds in rf discharges. Also, statistical correlation's in the fluctuation of scattered laser light intensity [dynamic laser light scattering (DLLS)] can be used to determine information about particle size, motion, and growth dynamics. These results are reviewed, along with recent work demonstrating that charged dust particles in a plasma can form a strongly coupled Coulomb liquid or solid. New results from DLSS experiments performed in the Reference Cell are presented that show process-induced dust particles confined in an electrostatic trap exhibit low-frequency oscillatory motion consistent with charge density wave (CDW) motion predicted for strongly coupled Coulomb liquids. PMID- 29151755 TI - One-Dimensional Modeling Studies of the Gaseous Electronics Conference RF Reference Cell. AB - A review of the one-dimensional modeling studies in the literature of the Gaseous Electronics Conference (GEC) reference plasma reactor is presented. Most of the studies are based on the fluid model description of the discharge and some utilize hybrid fluid-kinetic schemes. Both models are discussed here briefly. The models provide a basic understanding of the discharge mechanisms and reproduce several critical discharge features observed experimentally. PMID- 29151756 TI - Two-Dimensional Self-Consistent Radio Frequency Plasma Simulations Relevant to the Gaseous Electronics Conference RF Reference Cell. AB - Over the past few years multidimensional self-consistent plasma simulations including complex chemistry have been developed which are promising tools for furthering our understanding of reactive gas plasmas and for reactor design and optimization. These simulations must be benchmarked against experimental data obtained in well-characterized systems such as the Gaseous Electronics Conference (GEC) reference cell. Two-dimensional simulations relevant to the GEC Cell are reviewed in this paper with emphasis on fluid simulations. Important features observed experimentally, such as off-axis maxima in the charge density and hot spots of metastable species density near the electrode edges in capacitively coupled GEC cells, have been captured by these simulations. PMID- 29151757 TI - Conference Report: FORTY-SEVENTH ANNUAL GASEOUS ELECTRONICS CONFERENCE Gaithersburg, MD October 18-21, 1994. PMID- 29151758 TI - Low Electrolytic Conductivity Standards. AB - Standards of low electrolytic conductivity were developed to satisfy the demands of the U.S. Navy and American industry for the measurement of high quality water. The criteria for the selection of appropriate solvent and solutes, based on the principles of equivalent conductivity and Onsager's limiting law, are described. Dilute solutions of potassium chloride and benzoic acid in 30 % n-propanol-water have been chosen as standards. The electrolytic conductivity of both sets of these solutions as a function of molality was determined. Solutions of potassium chloride and of benzoic acid are recommended for use as 5 MUS/cm, 10 MUS/cm, 15 MUS/cm, 20 MUS/cm, and 25 MUS/cm conductivity standards. Solutions prepared from potassium chloride in 30 % n-propanol-water have been certified as Standard Reference Materials (SRMs). SRM 3198 and SRM 3199 are certified nominally at 5 MUS/cm and 15 MUS/cm, respectively, at 25.000 degrees C. PMID- 29151759 TI - Potential and Current Distributions Calculated Across a Quantum Hall Effect Sample at Low and High Currents. AB - The potential and current distributions are calculated across the width of a quantum Hall effect sample for applied currents between 0 MUA and 225 MUA. For the first time, both a confining potential and a current-induced charge redistribution potential are used. The confining potential has a parabolic shape, and the charge-redistribution potential is logarithmic. The solution for the sum of the two types of potentials is unique at each current, with no free parameters. For example, the charge-depletion width of the confining potential is determined from a localization experiment by Choi, Tsui, and Alavi, and the spatial extent of the conducting two-dimensional electron gas across the sample width is obtained from the maximum electric field deduced from a high-current breakdown experiment by Cage and Lavine, and from the quantum Hall voltage. The spatial extent has realistic cut-off values at the sample sides; e.g., no current flows within 55 magnetic lengths of the sides for currents less than 215 MUA. The calculated potential distributions are in excellent agreement with contactless electro-optic effect laser beam measurements of Fontein et al. PMID- 29151760 TI - Microform Calibration Uncertainties of Rockwell Diamond Indenters. AB - National and international comparisons in Rockwell hardness tests show significant differences. Uncertainties in the geometry of the Rockwell diamond indenters are largely responsible for these differences. By using a stylus instrument, with a series of calibration and check standards, and calibration and uncertainty calculation procedures, we have calibrated the microform geometric parameters of Rockwell diamond indenters. These calibrations are traceable to fundamental standards. The expanded uncertainties (95 % level of confidence) are +/-0.3 MUm for the least-squares radius; +/-0.01 degrees for the cone angle; and +/-0.025 degrees for the holder axis alignment calibrations. Under ISO and NIST guidelines for expressing measurement uncertainties, the calibration and uncertainty calculation procedure, error sources, and uncertainty components are described, and the expanded uncertainties are calculated. The instrumentation and calibration procedure also allows the measurement of profile deviation from the least-squares radius and cone flank straightness. The surface roughness and the shape of the spherical tip of the diamond indenter can also be explored and quantified. Our calibration approach makes it possible to quantify the uncertainty, uniformity, and reproducibility of Rockwell diamond indenter microform geometry, as well as to unify the Rockwell hardness standards, through fundamental measurements rather than by performance comparisons. PMID- 29151761 TI - Performance Measures for Geometric Fitting in the NIST Algorithm Testing and Evaluation Program for Coordinate Measurement Systems. AB - The Algorithm Testing and Evaluation Program for Coordinate Measurement Systems (ATEP-CMS) is a Special Test Service offered under the NIST Calibration Program. ATEP-CMS evaluates the performance of geometric fitting software used in coordinate measurement systems. It is a Special Test because it is a new type of NIST service, experimental in nature and unsupported by historical data. This report documents and explains the rationale of the performance measures used in ATEP-CMS and analyzes the uncertainties of those measures. PMID- 29151762 TI - A Study on the Reuse of Plastic Concrete Using Extended Set-Retarding Admixtures. AB - The disposal of ready mixed concrete truck wash water and returned plastic concrete is a growing concern for the ready mixed concrete industry. Recently, extended set-retarding admixtures, or stabilizers, which slow or stop the hydration of portland cement have been introduced to the market. Treating truck wash-water or returned plastic concrete with stabilizing admixtures delays its setting and hardening, thereby facilitating the incorporation of these typically wasted materials in subsequent concrete batches. In a statistically designed experiment, the properties of blended concrete containing stabilized plastic concrete were evaluated. The variables in the study included (1) concrete age when stabilized, (2) stabilizer dosage, (3) holding period of the treated (stabilized) concrete prior to blending with fresh ingredients, and (4) amount of treated concrete in the blended batch. The setting time, strength, and drying shrinkage of the blended concretes were evaluated. For the conditions tested, batching 5 % treated concrete with fresh material did not have a significant effect on the setting time, strength, or drying shrinkage of the resulting blended concrete. Batching 50 % treated concrete with fresh materials had a significant effect on the setting characteristics of the blended cocnrete, which in turn affected the water demand to maintain slump. The data suggests that for a known set of conditions, the stabilizer dosage can be optimized within a relatively narrow range to produce desired setting characteristics. The strength and drying shrinkage of the blended concretes were essentially a function of the water content at different sampling ages and the relationship followed the general trend of control concrete. PMID- 29151763 TI - A Third Generation Water Bath Based Blackbody Source. AB - A third generation water bath based black-body source has been designed and constructed in the Radiometric Physics Division at the National Institute of Standards and Technology, Gaithersburg, MD. The goal of this work was to design a large aperture blackbody source with improved temporal stability and reproducibility compared with earlier designs, as well as improved ease of use. These blackbody sources operate in the 278 K to 353 K range with water temperature combined standard uncertainties of 3.5 mK to 7.8 mK. The calculated emissivity of these sources is 0.9997 with a relative standard uncertainty of 0.0003. With a 50 mm limiting aperture at the cavity; entrance, the emissivity increases to 0.99997. PMID- 29151764 TI - Conference Report: COMPASS '95 TENTH ANNUAL CONFERENCE ON COMPUTER ASSURANCE Gaithersburg, MD June 26-30, 1995. PMID- 29151765 TI - Calibration of Electret-Based Integral Radon Monitors Using NIST Polyethylene Encapsulated 226Ra/222Rn Emanation (PERE) Standards. AB - The recently developed 222Rn emanation standards that are based on polyethylene encapsulated 226Ra solutions were employed for a first field-measurement application test to demonstrate their efficacy in calibrating passive integral radon monitors. The performance of the capsules was evaluated with respect to the calibration needs of electret ionization chambers (E-PERM(r), Rad Elec Inc.). The encapsulated standards emanate well-characterized and known quantities of 222Rn, and were used in two different-sized, relatively-small, accumulation vessels (about 3.6 L and 10 L) which also contained the deployed electret monitors under test. Calculated integral 222Rn activities from the capsules over various accumulation times were compared to the averaged electret responses. Evaluations were made with four encapsulated standards ranging in 226Ra activity from approximately 15 Bq to 540 Bq (with 222Rn emanation fractions of 0.888); over accumulation times from 1 d to 33 d; and with four different types of E-PERM detectors that were independently calibrated. The ratio of the electret chamber response ERn to the integral 222Rn activity IRn was constant (within statistical variations) over the variables of the specific capsule used, the accumulation volume, accumulation time, and detector type. The results clearly demonstrated the practicality and suitability of the encapsulated standards for providing a simple and readily-available calibration for those measurement applications. However, the mean ratio ERn/IRn was approximately 0.91, suggesting a possible systematic bias in the extant E-PERM calibrations. This 9 % systematic difference was verified by an independent test of the E-PERM calibration based on measurements with the NIST radon-in-water standard generator. PMID- 29151766 TI - Microstructural Characterization of Cobalt-Tungsten Coated Graphite Fibers. AB - The present research concerns an electrodeposited cobalt-tungsten alloy coating on graphite fibers. Annealed and unannealed coated fibers were analyzed by scanning electron microscopy/energy dispersive x-ray spectroscopy (SEM/EDS), x ray diffraction (XRD), and transmission electron microscopy (TEM). The mole fraction of tungsten in the as-deposited cobalt-tungsten coating was found to be (7.10 +/- 0.82) %, and the crystalline lattice was determined to be hexagonal close-packed. Note: The uncertainties reported here are expanded uncertainties (i.e., 2 standard deviation estimates). After annealing at 1100 degrees C for 1.5 h, the lattice was found to be a cobalt-tungsten-carbon (Co-W-C) alloy with a face centered cubic lattice. The mole fraction of tungsten in the annealed coating was shown to be (5.30 +/- 0.66) %. XRD analysis revealed that the annealed coating contained regions having three slightly different lattice parameters. The lattice parameters in the three regions of the Co-W-C alloy coating corresponded to a mole fraction of carbon of 0.66 %, 0.40 %, and 0.19 % (+/- 0.18 %). These compositions are discussed with respect to the Co-W-C phase diagram. Various tungsten carbide species were identified in the coating and fiber, and a network of overlapping WC crystals was found at the coating-fiber interface. This network appeared to serve as a protective barrier to extend the lifetime of the fibers at elevated temperatures. PMID- 29151767 TI - On Using Collocation in Three Dimensions and Solving a Model Semiconductor Problem. AB - A research code has been written to solve an elliptic system of coupled nonlinear partial differential equations of conservation form on a rectangularly shaped three-dimensional domain. The code uses the method of collocation of Gauss points with tricubic Hermite piecewise continuous polynomial basis functions. The system of equations is solved by iteration. The system of nonlinear equations is linearized, and the system of linear equations is solved by iterative methods. When the matrix of the collocation equations is duly modified by using a scaled block-limited partial pivoting procedure of Gauss elimination, it is found that the rate of convergence of the iterative method is significantly improved and that a solution becomes possible. The code is used to solve Poisson's equation for a model semiconductor problem. The electric potential distribution is calculated in a metal-oxide-semiconductor structure that is important to the fabrication of electron devices. PMID- 29151768 TI - Precision Tests of a Quantum Hall Effect Device DC Equivalent Circuit Using Double-Series and Triple-Series Connections. AB - Precision tests verify the dc equivalent circuit used by Ricketts and Kemeny to describe a quantum Hall effect device in terms of electrical circuit elements. The tests employ the use of cryogenic current comparators and the double-series and triple-series connection techniques of Delahaye. Verification of the dc equivalent circuit in double-series and triple-series connections is a necessary step in developing the ac quantum Hall effect as an intrinsic standard of resistance. PMID- 29151769 TI - Analysis of the (5d2+5d6s)-5d6p Transition Arrays of Os VII and Ir VIII, and the 6s 2S-6p 2P Transitions of Ir IX. AB - The spectra of osmium and iridium were photographed in the 300 A to 1600 A region on a 3 m normal incidence spectrograph using a triggered spark source. The (5d2 + 5d6s)-5d6p transition arrays of Os VII and Ir VIII were analyzed. All levels of these three configurations in both spectra have been established. There are 77 lines in Os VII and 71 lines in Ir VIII classified. The parametric least squares fitting calculations are used to interpret both spectra. The 6s2S1/2-6p2P1/2,3/2 transitions in Ir IX have also been identified. PMID- 29151770 TI - Conference Report: APPLICATION PORTABILITY PROFILE AND OPEN SYSTEM ENVIRONMENT USER'S FORUM Gaithersburg, MD May 9-10, 1995. PMID- 29151771 TI - Conference Report: INTERNATIONAL WORKSHOP ON SEMICONDUCTOR CHARACTERIZATION: PRESENT STATUS AND FUTURE NEEDS Gaithersburg, MD January 30 - February 2, 1995. PMID- 29151772 TI - Conference Report: METROLOGY ISSUES IN TERAHERTZ PHYSICS AND TECHNOLOGY Gaithersburg, MD December 13, 1994 Report prepared by. PMID- 29151773 TI - Building the School Attendance Boundary Information System (SABINS): Collecting, Processing, and Modeling K to 12 Educational Geography. AB - The School Attendance Boundary Information System is a social science data infrastructure project that assembles, processes, and distributes spatial data delineating K through 12th grade school attendance boundaries for thousands of school districts in U.S. Although geography is a fundamental organizing feature of K to 12 education, until now school attendance boundary data have not been made readily available on a massive basis and in an easy-to-use format. The School Attendance Boundary Information System removes these barriers by linking spatial data delineating school attendance boundaries with tabular data describing the demographic characteristics of populations living within those boundaries. This paper explains why a comprehensive GIS database of K through 12 school attendance boundaries is valuable, how original spatial information delineating school attendance boundaries is collected from local agencies, and techniques for modeling and storing the data so they provide maximum flexibility to the user community. An important goal of this paper is to share the techniques used to assemble the SABINS database so that local and state agencies apply a standard set of procedures and models as they gather data for their regions. PMID- 29151774 TI - Inference in a survival cure model with mismeasured covariates using a simulation extrapolation approach. AB - In many situations in survival analysis, it may happen that a fraction of individuals will never experience the event of interest: they are considered to be cured. The promotion time cure model takes this into account. We consider the case where one or more explanatory variables in the model are subject to measurement error, which should be taken into account to avoid biased estimators. A general approach is the simulation-extrapolation algorithm, a method based on simulations which allows one to estimate the effect of measurement error on the bias of the estimators and to reduce this bias. We extend this approach to the promotion time cure model. We explain how the algorithm works, and we show that the proposed estimator is approximately consistent and asymptotically normally distributed, and that it performs well in finite samples. Finally, we analyse a database in cardiology: among the explanatory variables of interest is the ejection fraction, which is known to be measured with error. PMID- 29151776 TI - Mechanical Evaluation of Unobstructing Magnetic Microactuators for Implantable Ventricular Catheters. AB - Here, we report on the development and evaluation of novel unobstructing magnetic microactuators for maintaining the patency of implantable ventricular catheters used in hydrocephalus application. The treatment of hydrocephalus requires chronic implantation of a shunt system to divert excess cerebrospinal fluid from the brain. These shunt systems suffer from a high failure rate (>40%) within the first year of implantation, often due to biological accumulation. Previously, we have shown that magnetic microactuators can be used to remove biological blockage. The new cantilever-based magnetic microactuator presented in this paper improves upon the previous torsional design using a bimorph to induce a postrelease out-of-plane deflection that will prevent the device from occluding the pore at rest. The mechanical evaluations (i.e., postrelease deflection, static and dynamic responses) of fabricated devices are reported and compared with theoretical values. PMID- 29151775 TI - The application of antimicrobial photodynamic therapy (aPDT) in dentistry: a critical review. AB - In recent years there have been an increasing number of in vitro and in vivo studies that show positive results regarding antimicrobial photodynamic therapy (aPDT) used in dentistry. These include applications in periodontics, endodontics, and mucosal infections caused by bacteria present as biofilms. Antimicrobial photodynamic therapy is a therapy based on the combination of a non toxic photosensitizer (PS) and appropriate wavelength visible light, which in the presence of oxygen is activated to produce reactive oxygen species (ROS). ROS induce a series of photochemical and biological events that cause irreversible damage leading to the death of microorganisms. Many light-absorbing dyes have been mentioned as potential PS for aPDT and different wavelengths have been tested. However, there is no consensus on a standard protocol yet. Thus, the goal of this review was to summarize the results of research on aPDT in dentistry using the PubMed database focusing on recent studies of the effectiveness aPDT in decreasing microorganisms and microbial biofilms, and also to describe aPDT effects, mechanisms of action and applications. PMID- 29151777 TI - Multimodal Image Registration through Simultaneous Segmentation. AB - Multimodal image registration facilitates the combination of complementary information from images acquired with different modalities. Most existing methods require computation of the joint histogram of the images, while some perform joint segmentation and registration in alternate iterations. In this work, we introduce a new non-information-theoretical method for pairwise multimodal image registration, in which the error of segmentation - using both images - is considered as the registration cost function. We empirically evaluate our method via rigid registration of multi-contrast brain magnetic resonance images, and demonstrate an often higher registration accuracy in the results produced by the proposed technique, compared to those by several existing methods. PMID- 29151778 TI - IMPROVING MEDICAL EDUCATION: SIMULATING CHANGES IN PATIENT ANATOMY USING DYNAMIC HAPTIC FEEDBACK. AB - Virtual simulation is an emerging field in medical education. Research suggests that simulation reduces complication rates and improves learning gains for medical residents. One benefit of simulators is their allowance for more realistic and dynamic patient anatomies. While potentially useful throughout medical education, few studies have explored the impact of dynamic haptic simulators on medical training. In light of this research void, this study was developed to examine how a Dynamic-Haptic Robotic Trainer (DHRT) impacts medical student self-efficacy and skill gains compared to traditional simulators developed to train students in Internal Jugular Central Venous Catheter (IJ CVC) placement. The study was conducted with 18 third year medical students with no prior CVC insertion experience who underwent a pre-test, simulator training (manikin, robotic, or mixed) and post-test. The results revealed the DHRT as a useful method for training CVC skills and supports further research on dynamic haptic trainers in medical education. PMID- 29151779 TI - Integrating Motivational Interviewing and Brief Behavioral Activation Therapy: Theoretical and Practical Considerations. AB - Behavioral Activation and specifically the Brief Behavioral Activation Therapy for Depression (BATD) has a strong record of empirical support but its focus on practical out of session activation-based assignments can lead to poor levels of adherence if efforts to enhance motivation are not prioritized. Towards this end, this manuscript describes the assimilative integration of Motivational Interviewing (MI) and BATD to improve clinical outcomes by integrating MI's focus on building and maintaining motivation to change into BATD. The manuscript provides an overview of MI and BATD, theoretical issue raised in integrating the two approaches, and examples of how this integration results in a nondirective and motivation-focused approach to conducting BATD. PMID- 29151780 TI - Postsecondary Expectations of High-School Students With Autism Spectrum Disorders. AB - This study examined the perceptions of adulthood among 31 high school students with autism spectrum disorder (ASD). We had two research aims: (1) to report students' postsecondary expectations in terms of school, work, friendships and living arrangement and (2) to describe how our sample defined adulthood. To better compare our sample's criteria of adulthood to the criteria traditionally endorsed in secondary schools, we used a directed content analysis approach. Data were derived from a semi-structured interview that questioned students about friendships, activities and the transition to adulthood. The majority of students expected to attain traditional markers of adulthood after high school; however, for some the pathways to achieving these outcomes were narrowly defined and perceived as a rigid, linear process. Independence, maturity and personal responsibility were the most highly endorsed characteristics of adulthood, followed by chronological age and traditional markers. Implications for transition planning and adult services are discussed. PMID- 29151781 TI - Molecular Epidemiology of Extended-Spectrum beta-Lactamase-Producing Escherichia coli Pathotypes in Diarrheal Children from Low Socioeconomic Status Communities in Bihar, India: Emergence of the CTX-M Type. AB - Background: Childhood diarrheal diseases remain highly endemic in India, but the emergence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli among children with diarrhea in Bihar remains elusive. In this study, we determine and characterize ESBL-producing E coli pathotypes among hospitalized diarrheal preschool children living in low socioeconomic level communities in Bihar, India. Materials and methods: The stool samples were collected everyday throughout the year for 2 consecutive years. In our study, we collected stool samples randomly from every fifth patient. Stool samples were collected from a total of 633 randomly selected diarrheal children (age: 0-60 months) belonging to 17 communities and screened for identification of virulent diarrheagenic E coli (DEC) pathotype (viz, enteropathogenic E coli [EPEC], enteroaggregative E coli [EAEC], enterotoxigenic E coli [ETEC], enteroinvasive E coli [EIEC], and enterohemorrhagic E coli [EHEC]) by a multiplex polymerase chain reaction (PCR) assay. Furthermore, ESBLs were screened by conventional antibiotic resistance pattern testing and later characterized for the presence of beta-lactamase (bla) genes by PCR and DNA sequencing. Results: Diarrheagenic E coli was detected in 191 cases (30.2%) of the total 633 diarrheic children. Maximum occurrence of DEC was found in <=12 months age group (72.7%) with prevalence of the EAEC pathotype. Most isolates were resistant to ampicillin, ciprofloxacin, piperacillin, levofloxacin, ceftazidime, cefotaxime, ceftriaxone, and gentamicin, whereas over 96% of them were sensitive to amikacin. About 37.6% of total 191 DEC isolates were ESBL producers (n = 72), being prevalent among ETEC (n = 35; 18.32%), followed by EPEC (n = 21; 10.9%), EAEC (n = 13; 6.8%), and EIEC (n = 3; 1.57%). Interestingly, the commonest beta-lactamase was CTX-M type (blaCTX-M) in 86.1% (n = 62) of the ESBL isolates, followed by blaSHV (n = 49; 68%), blaTEM (n = 37; 51.8%), and blaOXA (n = 21; 29.1%) determinants. Resistance of ESBL isolates was mostly related to ampicillin (100%), ceftriaxone (98.1%), cefotaxime (92.4%), gentamicin (74.1%), and levofloxacin (73.2%), whereas best antimicrobial activities were observed for piperacillin-tazobactam, amikacin, meropenem, and imipenem. Conclusions: This study revealed that EAEC (72.1%) is the predominant pathotype in Bihar, significantly high in <=12 months age group children (P = .04). Moreover, the widespread prevalence of ESBLs in children, especially the CTX-M type, is of great concern, which requires monitoring of infection control measures through efficient antimicrobial management and detection of ESBL producing isolates. PMID- 29151782 TI - Salvage Low Dose Rate Brachytherapy For Recurrent Prostate Cancer After External Beam Radiotherapy: Results From A Single Institution With Focus On Toxicity And Functional Outcomes. AB - Background/aim: Low dose rate brachytherapy has been used as salvage therapy for locally recurrent prostate cancer (PC) after primary external beam radiation therapy (EBRT), along with surgery and cryotherapy. All these techniques, in particular, when applied to the whole gland, involve a relatively high risk of toxicity and may worsen the patient's quality of life. Our aim is to evaluate the results of whole-gland salvage brachytherapy (SBT) after primary EBRT in terms of toxicity, functional outcomes, and efficacy. Materials and methods: We retrospectively reviewed clinical data on 19 patients consecutively treated with SBT at our institution between June 2012 and November 2015. Local recurrences were identified with 11C-choline positron emission tomography/computed tomography and pelvic magnetic resonance imaging after biochemical recurrence according to Phoenix criteria (prostate-specific antigen nadir + 2). Low dose rate brachytherapy was performed by 125I permanent seeds implantation to the whole prostate gland, with a prescription dose of 130 Gy. At the time of SBT, only 2 patients were receiving androgen deprivation therapy. Acute and late toxicities were recorded using the CTCAE 4.0 scoring system. Quality of life was assessed using IPSS (International Prostate Symptoms Score) and IIEF (International Index of Erectile Function) questionnaires at baseline and 6, 12, and 24 months after SBT, and the respective mean values were compared using Student t test. Biochemical relapse-free survival (BRFS) was also calculated. Results: Median follow-up after SBT was 24 months. Of 19 patients, 2 patients experienced a G3 cystitis (10.2%) and 1 patient experienced a G4 proctitis (5.3%), respectively. Mean pre-SBT IPSS scores and 6, 12, and 24 months after SBT were 5.84, 10.22, 15.72, and 8.10, respectively. Mean pre-SBT IIEF scores and 6, 12, and 24 months after SBT were 8.42, 3.55, 7.89, and 6.40, respectively. At the time of analysis, only 2 patients showed a biochemical relapse (3-year BRFS 85.2%). The Student t test demonstrated a worsening of functional outcome 6 months and 1 year after treatment but a subsequent improvement 2 years after SBT. Conclusions: Salvage brachytherapy for recurrent PC after primary EBRT seems to be a feasible treatment for selected patients. Our series revealed a severe toxicity peak 6 months and 1 year after local re-treatment and then they decrease. Early BRFS rates are good. However, these are very preliminary results so further patient accrual, long-term follow-up, and prospective trials are needed in the future. PMID- 29151783 TI - Gastric microbiota: tracing the culprit. AB - The gastric environment has been long time considered bacteria-free, but the discovery of Helicobacter pylori (H. pylori) in 1982 superseded this conception. Over the last decades new diagnostic methods have been developed, starting with culture-dependent and advancing to culture-independent ones. These modern techniques provide new insight into the composition and influence of this ecosystem on the entire gastrointestinal tract. H. pylori is no longer considered the only microorganism in the stomach, other non-H. pylori microbial species may populate the same environment and exercise their role. Current knowledge suggests possible links of these bacteria with gastroduodenal diseases, such as peptic ulcer and gastric cancer but most of them need further scientific evidence. This review summarizes current information on these complex interrelations between gastric microbial communities and host in health and disease. PMID- 29151785 TI - Children's lifestyle behaviors in relation to anthropometric indices: a family practice study. AB - Introduction: Obesity prevention in children represents one of the main concerns in primary care. In order to develop into a healthy adult, the child has to follow a healthy lifestyle in all aspects: nutritional, behavioral, physical and recreational. Our main goal was to identify which habits may influence the children's somatic development. Method: Our study, performed in a family practice, consisted in a questionnaire regarding physical activity, diet and use of electronic devices.After obtaining the parent's and child's informed consent to participate in our cross-sectional study, 98 consecutive children aged 5-15 years, examined in the family practice, were enlisted. After collecting the answers, weight, height, waist circumference, wrist circumference, subscapular skinfold thickness were measured and body mass index was calculated. Results: The analysis of the relationship between the anthropometric data showed a significant difference between girls and boys only in respect of the wrist circumference. The groups performing daily household activities had a significantly increased weight, BMI, abdominal and wrist circumference. Participation in physical education classes in school was associated significantly only with the wrist circumference. Frequent change of the option for extracurricular sport showed a significant difference in weight, waist circumference, and wrist in favor of the group that practiced many sports. Fast food diet and the type of alimentary habits of the family (home cooked, pre-cooked, or ordered food) showed differences between medians of the anthropometric indices with higher values for those eating more frequently fast food or ordered food, yet without reaching statistical significance. Conclusion: Both girls and boys, in the presence of an unhealthy lifestyle (lack of recreational and educational physical activity, food habits, inappropriate time spent in front of a screen) had unfavorable adiposity indices. PMID- 29151784 TI - Molecular targeted treatment of metastatic colorectal cancer: the cardiovascular adverse effects of Bevacizumab and Cetuximab. AB - Novel emerging therapies have changed paradigms in metastatic colorectal cancer. The advantages of molecular targeted treatments, either the anti-angiogenic or the anti-epidermal growth factor receptor drugs, reside in the fact that while their specificity for the cancer cell is higher, their toxicity on normal tissues is significantly lower when compared to chemotherapy. But when it comes to their safety, especially from a cardiovascular point of view, they still need to pass the test of time and further prospective studies are needed. Clinical trial patients are very well selected with regards to comorbidities and therefore, they often differ from real-life patients. In order to maximize the benefits from these drugs, we need to better identify the population at risk, understand and early diagnose their on- and off-target adverse effects and to adequately choose the diagnostic tools; with a better prevention and early treatment, the quality and quantity of our patients' lives can be significantly improved. PMID- 29151786 TI - Concurrent middle and inferior meatus antrostomy for the treatment of maxillary mucoceles. AB - Background and aims: This study describes the technique of simultaneous middle and inferior antrostomy and outlines its usefulness in the management of maxillary mucoceles. Methods: This is a retrospective review of 12 consecutive patients with isolated maxillary mucocele operated on by means of middle and inferior antrostomy technique. We describe the clinical picture, details of the surgical technique and outcomes. Results: There were 7 males and 5 females with ages ranging from 20 years to 65 years (mean 42 years). One patient had past trauma to the face and one had a long history of chronic sinusitis. Eight patients had undergone multiple previous sinus operative procedures including Caldwell-Luc approach. All patients underwent middle and inferior antrostomy without complications. Follow-up was between 12 months and 60 months (mean 36 months) with no recurrences to date. Conclusion: In conclusion the results of our small series support the worth of using middle and inferior antrostomy when dealing with maxillary mucoceles. PMID- 29151787 TI - Infantile hemangiomas: a 7-year experience of a single-center. AB - Objectives: The aim of the study was to describe the historical and clinical characteristics of hemangiomas in a series of cases of our clinic. Methods: This is a retrospective study of 36 patients with infantile hemangiomas consulted in our clinic. Results: We had 14 multiple hemangiomas, and 1 kaposiform hemangioendothelioma. Almost two-thirds involved the cephalic extremity, and 76% of the cases were treated. Pregnancy risk factors included prematurity, low-birth weight and respiratory distress syndrome. Propranolol was used in 22 cases, followed by prednisone in 3 cases. Vincristine and interferon were used as associated therapies or as second line therapies. Two hemangiomas had complications, one ulceration and a Kasabach-Merritt syndrome. All the patients had a good evolution. Conclusions: Our study results regarding the involvement of pregnancy and birth risk factors in developing infantile hemangiomas is similar to literature data. The majority of patients had at least one risk factor suggesting that at least one trigger to develop an infantile hemangioma is necessary. Our study shows that the cephalic extremity is mostly involved, and because of its potential complications they are most likely to be treated. The study shows that propranolol is the leading treatment option with few and mild side effects. PMID- 29151788 TI - Attitudes toward mentally ill patients: a comparison between Romanian and international medical students. AB - Background: Stigmatizing attitudes to mental illness, and especially schizophrenia, are not limited to the general population but are also common among health professionals. Health professionals are in a position to model health related attitudes both in the general public and patients. Medical students are an interesting group to focus upon, since they are future health professionals and correcting stigmatizing attitudes is still possible during their educational curriculum. Methods: This study investigated the attitude toward mental illness in medical students at the Iuliu Hatieganu University of Medicine and Pharmacy. We surveyed first year students, since they have not yet received specific classes or internships in psychiatry; 322 students from the Romanian and English sections participated, representing a response rate of 94.7%. The questionnaire consisted of the Romanian and English versions of Link's Social Distance Scale towards people with mental illness scale. Results: Overall, medical students had a relatively negative attitude towards people with mental illness, with moderate social distance and stereotypical attitudes. The level of personal contact with people with mental illness was correlated with positive attitudes. International students had scored lower then Romanian students on social distance toward mentally ill patients. Conclusions: Medical education can play an important role in the attitudes of students toward mental illness. Medical students have stigmatizing attitudes about mentally ill patients. Personal contact with people suffering from mental illness might contribute to a positive attitude from the medical students toward mentally ill patients. PMID- 29151789 TI - Discriminative role of brachial artery Doppler parameters in correlation with hemodialysis arteriovenous fistula. AB - Purpose: The aim of this study was to evaluate the flow volume and resistive index parameters of the brachial artery in the functioning and dysfunctioning radiocephalic and brachiocephalic hemodialysis arteriovenous fistula (AVF). Methods: 82 patients were distributed into three groups according to their hemodialysis function - as normal function, decreased pump flow and increased venous pressure. Flow volumes and resistive indexes (RI) of the brachial artery of radiocephalic and brachiocephalic AVFs were measured by Doppler ultrasound. Flow parameters of the groups were compared. Results: A statistically significant difference was found between the normal and decreased pump flow groups in terms of flow volume and resistive index values. 770 ml/min flow volume of the brachial artery has a 94% sensitivity and 84% specificity and 0.52 value of RI has an 89% sensitivity and 88% specificity in the the differentiation of normal and decreased pump flow groups. Conclusion: Doppler parameters of the brachial artery such as flow volume and RI can provide valuable information about AVF function. PMID- 29151790 TI - Surgical scar endometriosis: a series of 14 patients and brief review of literature. AB - Background and aims: Endometriosis is a commonly encountered disorder in women of reproductive age, consisting of the presence of active ectopic endometrial tissue outside the endometrial cavity. Surgical scar endometriosis is a rare condition representing about 2% of all endometriosis cases. The purpose of this study was to assess the main characteristics, diagnostic tools and therapeutic options in abdominal wall endometriosis (AWE). Methods: We have reviewed a series of fourteen cases with histopathological confirmation of AWE that were managed in our institution. Results: The main characteristic of AWE were emphasized, showing that 78.57% of the patients had at least one previous caesarian section and that in only 57.14% of all cases an accurate diagnosis of AWE was established preoperatively. Conclusion: A direct relationship between gynecological and obstetrical surgery and AWE is well established and as the caesarian section rates increase constantly, the awareness regarding AWE should also be increased. PMID- 29151791 TI - Modern lymphatic dissection techniques for preventing post renal transplant lymphocele. AB - Background and aims: Development of a lymphocele is a well-known complication following kidney transplant. Among causative factors, recipient iliac lymphatics dissection plays an important role. Electrothermal bipolar sealing devices (LigaSureTM) have been shown to decrease lymphatic leakage in a number of instances. The aim of this study was to investigate whether the use of this device decreases post-operative lymphatic complications in kidney transplant. Methods: 48 patients admitted for renal transplant were included in the study. They were randomly assigned to either conventional ligation or LigaSureTM during lymphatic dissection. Results: One patient in the LigaSureTM arm and 5 patients in the conventional ligation arm developed lymphocele (p=0.04). Lymphatic drainage volumes were 99.8+/-39.87 ml in the LigaSure arm and 131.46+/-54.2 ml in the conventional ligation arm (p=0.02). Conclusion: Electrothermal bipolar sealing devices exhibit safety and efficiency when used in renal transplant lymphatic dissection. In the present study, this technique proved to be superior to conventional ligation in terms of post-operative lymphatic complications. PMID- 29151792 TI - Fluoxetine modulates sex steroid levels in vitro. AB - Background and aims: Selective serotonin reuptake inhibitors (SSRIs) are antidepressants increasingly prescribed against depression during and after pregnancy. However, these compounds cross the placenta and are found in breast milk, thus reaching, and possibly affecting, the fetus and infant during critical developmental stages. Fluoxetine (FLX), a widely used SSRI, can interfere with estrogen signaling, which is important for the development of female sex organs and certain brain areas, among others. Interference with estrogen signaling can take place on different levels, e.g., by affecting receptor activity or hormone levels. FLX has previously been shown to induce estrogen receptor-dependent transcription in vitro at high concentrations. In this study we set out to assess effects of FLX on estradiol levels in vitro. Methods: FLX was tested using the OECD recommended H295R model, a human adrenocortical carcinoma cell line that is able to produce all steroid hormones found in the gonads and adrenal glands, including estradiol and testosterone. H295R cells were incubated with different doses of FLX for 48h. Subsequently, concentrations of these two steroids were measured in cell culture medium after FLX exposure, using liquid chromatography coupled with tandem mass spectrometry. Aromatase mRNA expression was assessed using qPCR. Results: Fluoxetine significantly increased estradiol secretion in H295R cells after a 48h exposure at low, submicromolar concentrations, but showed no effects on testosterone levels or aromatase mRNA expression. Conclusion: Fluoxetine has the potential to interfere with estrogenic signaling by increasing estradiol secretion at low concentrations, which are relevant for fetal and adult human exposure. PMID- 29151793 TI - Plasma protein absolute quantification by nano-LC Q-TOF UDMSE for clinical biomarker verification. AB - Background and aims: Proteome-based biomarker studies are targeting proteins that could serve as diagnostic, prognosis, and prediction molecules. In the clinical routine, immunoassays are currently used for the absolute quantification of such biomarkers, with the major limitation that only one molecule can be targeted per assay. The aim of our study was to test a mass spectrometry based absolute quantification method for the verification of plasma protein sets which might serve as reliable biomarker panels for the clinical practice. Methods: Six EDTA plasma samples were analyzed after tryptic digestion using a high throughput data independent acquisition nano-LC Q-TOF UDMSE proteomics approach. Synthetic Escherichia coli standard peptides were spiked in each sample for the absolute quantification. Data analysis was performed using ProgenesisQI v2.0 software (Waters Corporation). Results: Our method ensured absolute quantification of 242 non redundant plasma proteins in a single run analysis. The dynamic range covered was 105. 86% were represented by classical plasma proteins. The overall median coefficient of variation was 0.36, while a set of 63 proteins was found to be highly stable. Absolute protein concentrations strongly correlated with values reviewed in the literature. Conclusions: Nano-LC Q-TOF UDMSE proteomic analysis can be used for a simple and rapid determination of absolute amounts of plasma proteins. A large number of plasma proteins could be analyzed, while a wide dynamic range was covered with low coefficient of variation at protein level. The method proved to be a reliable tool for the quantification of protein panel for biomarker verification in the clinical practice. PMID- 29151794 TI - Knowledge and practices of Indian dental students regarding the prescription of antibiotics and analgesics. AB - Background and aim: Making a diagnosis and prescribing medicine is the most important skill required by any doctor in the colleges, hospitals or clinical practice. Prescribing is the intervention that has the greatest influence on patients' health requiring complex series of sub-competencies like making a diagnosis, setting a therapeutic goal, choosing the approach, choosing the best drug, route and frequency of administration, duration of therapy, writing the prescription, patient information, monitoring drug effects and, lastly, review the prescription.The aim of this research is to assess the knowledge and practices of Indian dental students regarding the prescription of antibiotics and analgesics. Methods: A cross-sectional study was conducted among 870 Undergraduate and Post-graduate dental students of Udaipur city. A close ended, pretested questionnaire was administered to students. The data were analyzed using the student's t -test and one-way ANOVA with post hoc Bonferroni test. Results: A total of 870 students participated in the study. Most of them were females and were pursuing undergraduate studies. Post graduate students had greater medication prescription knowledge than the undergraduate students. Nevertheless, practice of medication prescription among these two was found adequate. Conclusion: Undergraduate dental students have lower knowledge about medication prescription as compared to post-graduate students. Also, knowledge of prescription of medicines in males were higher in comparison to females, though prescription practices of all the dental students was found almost similar. PMID- 29151795 TI - The influence of occlusal stabilization appliances on cervical dystonia symptoms. AB - Objectives: The aim of this study was to assess the therapeutic efficiency of the occlusal stabilization appliance (OSA) in patients with cervical dystonia (CD). Methods: The study included 11 patients aged between 29 and 80 years, 7 women and 4 men, diagnosed with primary CD. The patients underwent an extra- and intra-oral clinical examination, followed by para-clinical examinations, necessary for the specifications of the OSA. The following data were recorded: demographic parameters, CD duration, management of the disease, dental impression, recording of the centric relationship, recording of the position of the upper jaw with the facial bow. A standardized OSA was manufactured in a private dental laboratory. Patients received instructions for wearing the OSA for 24 hours. Patients filled a questionnaire designed by us, which evaluated the effects of wearing the OSA over a 24-hours period on the symptoms of CD: muscles contraction, pain, discomfort while walking, sleep quality, tremor. The patients kept the dental appliances, and after three months they completed the questionnaire one more time. Results: The OSA was applied on the lower arch in 3 (27.3%) patients and on the upper arch in 8 (72.7%) patients. The OSA wearing time for the first 24 h was on average 19.2+/-6 hours. Total relaxation of dystonic muscles was reported by 9 (81.8%) patients, while 2 (18.2%) patients related partial muscle relaxation. Seven (63.6%) patients reported a pain decrease. Increased comfort while walking was observed by 8 (72.7%) patients. Two (18.2%) patients described an increase of sleep quality. In two (18.2%) patients the tremor disappeared. All patients reported difficulties while eating and removed the OSA during meals. Patients who wore the OSA for more hours, experienced a pain decrease (p=0.08), an increase in sleep quality (p=0.1), the disappearance of the tremor (p=0.1). After three months, only seven patients continued to use the OSA. More patients described a pain decrease after three months (5 (71.4%) vs. 4 (57.1%); p=0.5), relaxation of dystonic muscles (7 (100%) vs. 6 (85.7%); p=0.3). Conclusions: The use of OSA might be beneficial in CD patients, as it reduced the dystonic symptoms, pain severity and improved the quality of sleep. PMID- 29151796 TI - Association of fragile X syndrome, Robertsonian translocation (13, 22) and autism in a child. AB - We describe the case of a 6-year-old boy with both fragile X syndrome and Robertsonian Translocation (45, XY, der (13; 22) (q10; q10)). This is the first reported case of a patient with fragile X syndrome with this Robertsonian translocation. Facial features and macroorchidism were consistent with fragile X syndrome. Cognitive impairment is more significant than in his sibling with fragile X syndrome, and the patient also has a prior diagnosis of autism spectrum disorder. We emphasize the challenges in his behavioral management and outline future directions for his management. PMID- 29151797 TI - Late onset of primary pulmonary primitive neuroectodermal tumor: a case report. AB - Lungs are one of most metastatic areas for primitive neuroectodermal tumor (PNET), however primary pulmonary PNET is extremely rare. Here we present a case of a 58-year-old male patient with a tumor in the right lung that originated from the lung but not from chest wall. Patient was diagnosed with PNET following histological and immunohistochemical examination of CT-guided percutaneous tru cut needle biopsy and no distant metastasis were detected in PET-CT scan. As advised recently in published literature, surgical resection following neoadjuvant chemotherapy protocol is preferred in the treatment of our patient as it has better success of complete resection leading to higher 5-year survival rates. Although primary pulmonary PNET is uncommon, it should be taken into account and complete surgical resection should be aimed as treatment to achieve higher survival rates. PMID- 29151798 TI - How to deal with penile carcinoma inguinal metastases invading femoral vessels. AB - Penile cancer accounts for 1-10% of men neoplastic diseases and 30-60% of patients have inguinal metastases at the time of diagnosis. Inguinal metastases of penile cancer with femoral vessel involvement could lead to vascular fistula and hemorrhagic shock. We present 3 consecutive patients with inguinal metastases of penile cancer complicated by infection and hemorrhage from femoral vessels invaded by the tumor. Simultaneous extra-anatomical axillo-femoral bypass graft, wide excision of tumor and groin defect reconstruction was used to achieve "tumor free" oncologic aim and to save the lower limb. We consider the extra-anatomic axillo-femoral bypass associated with wide inguinal tumor excision and defect covering a feasible surgical solution for improving the life quality and extend life expectancy in patients with lymph node metastasis of penile cancer complicated by necrosis, infection and femoral vessel involvement. PMID- 29151799 TI - Endodontic management of maxillary third molar with MB2 (Vertucci type IV) canal configuration diagnosed with Cone Beam Computed Tomography - a case report. AB - The endodontic treatment of maxillary third molar often poses a challenge even to an experienced endodontist because of their most posterior location in the dental arch, aberrant occlusal anatomy, abnormal root canal configuration and eruption patterns. Owing to these anatomical limitations, their extraction remains the treatment of choice for many clinicians. As we know, retaining every functional component of the dental arch is of prime importance in contemporary dental practice. This clinical case report aims to discuss the endodontic treatment of maxillary third molar with MB2 root canal separated throughout the length and exit at two separate apical foramina (Vertucci type IV) diagnosed with Cone Beam Computed Tomography (CBCT).. PMID- 29151800 TI - Hepatorenal syndrome: role of the transjugular intrahepatic stent shunt in real life practice. PMID- 29151801 TI - Formal and Informal Concrete Support and Discharge Disposition among Women in Substance Abuse Treatment in the U.S. AB - The purpose of this study is to examine the relative contribution and the relationships between formal (treatment related members) * informal (family members) concrete support and discharge disposition. A total of 172 women interviewed upon intake in one of 3 counties funded substance abuse treatment programs in Cleveland, Ohio. Hierarchical logistic regression was performed to assess the impact of formal concrete support and informal concrete support on the likelihood of a discharge disposition of completed treatment. Formal concrete support showed a statistically significant contribution to discharge disposition, while informal concrete support did not. Findings of this study highlight the importance of formal concrete support. Future research should continue to expand our knowledge of how support from formal treatment services interacts with support from informal (family) networks. PMID- 29151802 TI - Individual and household factors associated with incidences of village malaria in Xepon district, Savannakhet province, Lao PDR. AB - Background: In the Lao PDR, the incidence of malaria greatly differs among villages even within a subdistrict, and the reasons for this difference are poorly understood. The objective of this study was to identify differences in villagers' behavior and the household environment between villages with high incidences and those with low incidences of malaria in a rural district of the Lao PDR. Methods: A case-control study was conducted in Xepon district, Savannakhet province. Case villages were defined as those with a high incidence (> 10 cases per 1000 population per year), and control villages were those with a low incidence (0-10 cases per 1000 population per year). Data were collected from 178 households in the six case villages and six control villages between December 2016 and January 2017. The data collection consisted of an interview survey with the heads of households and an observational survey in and around the house. Logistic regression was used to assess the association between the case-control status and individual-level behavioral factors and household-level environmental factors adjusted for socio-demographic and economic factors. Results: Compared to the household members in the control villages, household members in the case villages were significantly more likely to work at night in the forest (adjusted odds ratio 1.95; 95% confidence interval 1.28 to 2.98) and more likely to sleep overnight in the forest (adjusted odds ratio 1.94; 95% confidence interval 1.13 to 3.33). Additionally, compared to the households in the control villages, households in the case villages were significantly more likely to have an open space on the house surface (adjusted odds ratio 3.64; 95% confidence interval 1.68 to 7.84). Conclusions: There were significant differences in nighttime working and sleeping behaviors in the forest and the presence of an open space on the house surface in the case versus control villages. These differences can partly explain the difference in the incidences of malaria among the villages. The Lao National Malaria Control Program should recommend that villagers use personal protection when working and sleeping in the forest and to reduce any open space on the house surfaces. PMID- 29151804 TI - Combining drought and submergence tolerance in rice: marker-assisted breeding and QTL combination effects. AB - TDK1 is a popular rice variety from the Lao PDR. Originally developed for irrigated conditions, this variety suffers a high decline in yield under drought conditions. Studies have identified three quantitative trait loci (QTLs) for grain yield under drought conditions, qDTY3.1 , qDTY6.1 , and qDTY6.2 , that show a high effect in the background of this variety. We report here the pyramiding of these three QTLs with SUB1 that provides 2-3 weeks of tolerance to complete submergence, with the aim to develop drought- and submergence-tolerant near isogenic lines (NILs) of TDK1. We used a tandem approach that combined marker assisted backcross breeding with phenotypic selection to develop NILs with high yield under drought stress and non-stress conditions and preferred grain quality. The effect of different QTL combinations on yield and yield-related traits under drought stress and non-stress conditions is also reported. Our results show qDTY3.1 to be the largest and most consistent QTL affecting yield under drought conditions, followed by qDTY6.1 and qDTY6.2 , respectively. QTL class analysis also showed that lines with a combination of qDTY3.1 and qDTY6.1 consistently showed a higher tolerance to drought than those in which one of these QTLs was missing. In countries such as Lao PDR, where large areas under rice cultivation suffer vegetative-stage submergence and reproductive-stage drought, these lines could ensure yield stability. These lines can also serve as valuable genetic material to be used for further breeding of high-yielding, drought- and submergence-tolerant varieties in local breeding programs. PMID- 29151805 TI - Transparency and cooperation in repeated dilemma games: a meta study. AB - We use data from experiments on finitely repeated dilemma games with fixed matching to investigate the effect of different types of information on cooperation. The data come from 71 studies using the voluntary contributions paradigm, covering 122 data points, and from 18 studies on decision-making in oligopoly, covering another 50 data points. We find similar effects in the two sets of experimental games. We find that transparency about what everyone in a group earns reduces contributions to the public good, as well as the degree of collusion in oligopoly markets. In contrast, transparency about choices tends to lead to an increase in contributions and collusion, although the size of this effect varies somewhat between the two settings. Our results are potentially useful for policy making, because they provide guidance on the type of information to target in order to stimulate or limit cooperation. PMID- 29151803 TI - Cognitive Consequences of Trilingualism. AB - Aims and Objectives: The objectives of the present research were to examine the cognitive consequences of trilingualism and explain them relative to the cognitive consequences of bilingualism. Approach: A comparison of cognitive abilities in trilinguals and bilinguals was conducted. In addition, we proposed a cognitive plasticity framework to account for cognitive differences and similarities between trilinguals and bilinguals. Data and Analysis: Three aspects of cognition were analyzed: (1) cognitive reserve in older adults, as measured by age of onset of Alzheimer's disease and mild cognitive impairment; (2) inhibitory control in children and younger adults, as measured by response times on behavioral Simon and flanker tasks; and (3) memory generalization in infants and toddlers, as measured by accuracy on behavioral deferred imitation tasks. Results were considered within a framework of cognitive plasticity, which took into account several factors that may affect plasticity, including the age of learning a third language and the extent to which additional cognitive resources are needed to learn the third language. Findings: A mixed pattern of results was observed. In some cases, such as cognitive reserve in older adults, trilinguals showed larger advantages than bilinguals. On other measures, for example inhibitory control in children and younger adults, trilinguals were found to exhibit the same advantages as bilinguals. In still other cases, like memory generalization in infants and toddlers, trilinguals did not demonstrate the advantages seen in bilinguals. Originality: This study is the first comprehensive analysis of how learning a third language affects the cognitive abilities that are modified by bilingual experience, and the first to propose a cognitive plasticity framework that can explain and predict trilingual-bilingual differences. Significance: This research shows that the cognitive consequences of trilingualism are not simply an extension of bilingualism's effects; rather, trilingualism has distinct consequences, with theoretical implications for our understanding of linguistic and cognitive processes and their plasticity, as well as applied-science implications for using second and third language learning in educational and rehabilitative contexts to foster successful cognitive development and aging. PMID- 29151806 TI - Externalities in appropriation: responses to probabilistic losses. AB - Using an appropriation game setting, we examine individual responses to changes in a groups' vulnerability to a probabilistic loss (L) of a public good. The probabilistic loss parameter entails losing 10, 50 or 90% of the value of the public good that is maintained through cooperation, where the likelihood of the loss decreases in total group cooperation. By design, the expected marginal net benefits to an individual and the expected harm to others depends endogenously on the individuals' expectations of group cooperation and exogenously on the magnitude of the loss parameter. We find that individual cooperation is greater when forecasts of total group cooperation are greater and where the magnitude of the probabilistic loss is larger. There is, however, an interesting asymmetry in responses by two subgroups. Subjects who are pessimistic regarding total group cooperation decrease cooperation the higher the magnitude of the probabilistic loss and their decisions are tied systematically to changes in their expectations of other's cooperation. On the other hand, subjects who are optimistic regarding total group cooperation are found to be more cooperative, but their decisions are not systematically tied to changes in expectations of others' cooperation. PMID- 29151807 TI - The effect of acute pain on risky and intertemporal choice. AB - Pain is a highly salient and attention-demanding experience that motivates people to act. We investigated the effect of pain on decision making by delivering acute thermal pain to participants' forearm while they made risky and intertemporal choices involving money. Participants (n = 107) were more risk seeking under pain than in a no-pain control condition when decisions involved gains but not when they involved equivalent losses. Pain also resulted in greater preference for immediate (smaller) over future (larger) monetary rewards. We interpret these results as a motivation to offset the aversive, pain-induced state, where monetary rewards become more appealing under pain than under no pain and when delivered sooner rather than later. Our findings add to the long-standing debate regarding the role of intuition and reflection in decision making. PMID- 29151808 TI - Constraining generalized non-local cosmology from Noether symmetries. AB - We study a generalized non-local theory of gravity which, in specific limits, can become either the curvature non-local or teleparallel non-local theory. Using the Noether symmetry approach, we find that the coupling functions coming from the non-local terms are constrained to be either exponential or linear in form. It is well known that in some non-local theories, a certain kind of exponential non local couplings is needed in order to achieve a renormalizable theory. In this paper, we explicitly show that this kind of coupling does not need to be introduced by hand, instead, it appears naturally from the symmetries of the Lagrangian in flat Friedmann-Robertson-Walker cosmology. Finally, we find de Sitter and power-law cosmological solutions for different non-local theories. The symmetries for the generalized non-local theory are also found and some cosmological solutions are also achieved using the full theory. PMID- 29151809 TI - Training Lay Interventionists to Support Tobacco Cessation among Teachers in India. AB - Despite the rapidly increasing burden of tobacco-related morbidity and mortality in low- and middle-income countries, tobacco control initiatives - especially cessation - receive little emphasis. This is true despite low-cost methods that have potential for widespread dissemination. The purpose of this paper is to provide a case study example of how lay interventionists may be trained and supported to facilitate tobacco use cessation, based on the successful Tobacco Free Teachers-Tobacco Free Society program (TFT-TFS) implemented in Bihar, India. This school-based program included multiple components, with lay interventionists having a crucial role. The lay interventionists included health educators and lead teachers, both of whom were selected based on formative research, underwent extensive training and received continuing support. We emphasized encouraging and supporting teachers to quit tobacco use and engaging both tobacco users and nonusers to create a supportive environment for cessation. We also stressed that neither the health educators nor lead teachers were being trained as counselors or as cessation experts. We focused on the importance of respecting teachers as individuals and identifying locally relevant methods of cessation. Although we cannot isolate the precise contribution of the lay interventionists to the successful TFT-TFS intervention, the abstinence findings in favor of the intervention at follow up are highly encouraging. Teachers have been neglected as lay interventionists for tobacco cessation despite the fact that they tend to be highly respected and credible. The approach used for TFT-TFS could be disseminable in multiple low- and middle-income country contexts through train the-trainer programs targeted to teachers. PMID- 29151810 TI - REAL-TIME SUBJECTIVE ASSESSMENT OF PSYCHOLOGICAL STRESS: ASSOCIATIONS WITH OBJECTIVELY-MEASURED PHYSICAL ACTIVITY LEVELS. AB - Psychosocial stress may be a factor in the link between physical activity and obesity. This study examines how the daily experience of psychosocial stress influences physical activity levels and weight status in adults. This study reports temporally ordered relationships between sedentary, light, and moderate to-vigorous physical activity levels and real-time reports of subjective psychosocial stress levels. Adults (n=105) wore an accelerometer and participated in an ecological momentary assessment (EMA) of stress by answering prompts on a mobile phone several times per day over 4 days. Subjective stress was negatively related to sedentary activity in the minutes immediately preceding and immediately following an EMA prompt. Light activity was positively associated with a subsequent EMA report of higher stress, but there were no observed associations between stress and moderate-to-vigorous activity. Real-time stress reports and accelerometer readings for the same 4-day period showed no association. Nor were there associations between real-time stress reports and weight status. PMID- 29151811 TI - Prophylactic plasma transfusion for patients undergoing non-cardiac surgery. AB - This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine the clinical effectiveness and safety of prophylactic plasma transfusion for people with confirmed or presumed coagulopathy requiring non-cardiac surgery. PMID- 29151812 TI - Prophylactic platelet transfusions prior to surgery for people with a low platelet count. AB - This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine the clinical effectiveness and safety of prophylactic platelet transfusions prior to surgery for people with a low platelet count or platelet dysfunction (inherited or acquired). PMID- 29151813 TI - Dietary energy density: Applying behavioural science to weight management. AB - Studies conducted by behavioural scientists show that energy density (kcal/g) provides effective guidance for healthy food choices to control intake and promote satiety. Energy density depends upon a number of dietary components, especially water (0 kcal/g) and fat (9 kcal/g). Increasing the proportion of water or water-rich ingredients, such as vegetables or fruit, lowers a food's energy density. A number of studies show that when the energy density of the diet is reduced, both adults and children spontaneously decrease their ad libitum energy intake. Other studies show that consuming a large volume of a low-energy dense food such as soup, salad, or fruit as a first course preload can enhance satiety and reduce overall energy intake at a meal. Current evidence suggests that energy density influences intake through a complex interplay of cognitive, sensory, gastrointestinal, hormonal and neural influences. Other studies that focus on practical applications show how the strategic incorporation of foods lower in energy density into the diet allows people to eat satisfying portions while improving dietary patterns. This review discusses studies that have led to greater understanding of the importance of energy density for food intake regulation and weight management. PMID- 29151815 TI - How should we evaluate research on counselling and the treatment of depression? A case study on how the National Institute for Health and Care Excellence's draft 2018 guideline for depression considered what counts as best evidence. AB - Background: Health guidelines are developed to improve patient care by ensuring the most recent and 'best available evidence' is used to guide treatment recommendations. The National Institute for Health and Care Excellence's (NICE's ) guideline development methodology acknowledges that evidence needed to answer one question (treatment efficacy) may be different from evidence needed to answer another (cost-effectiveness, treatment acceptability to patients). This review uses counselling in the treatment of depression as a case study, and interrogates the constructs of 'best' evidence and 'best' guideline methodologies. Method: The review comprises six sections: (i) implications of diverse definitions of counselling in research; (ii) research findings from meta-analyses and randomised controlled trials (RCTs); (iii) limitations to trials-based evidence; (iv) findings from large routine outcome datasets; (v) the inclusion of qualitative research that emphasises service-user voices; and (vi) conclusions and recommendations. Results: Research from meta-analyses and RCTs contained in the draft 2018 NICE Guideline is limited but positive in relation to the effectiveness of counselling in the treatment for depression. The weight of evidence suggests little, if any, advantage to cognitive behaviour therapy (CBT) over counselling once risk of bias and researcher allegiance are taken into account. A growing body of evidence from large NHS data sets also evidences that, for depression, counselling is as effective as CBT and cost-effective when delivered in NHS settings. Conclusion: Specifications in NICE's updated guideline procedures allow for data other than RCTs and meta-analyses to be included. Accordingly, there is a need to include large standardised collected data sets from routine practice as well as the voice of patients via high-quality qualitative research. PMID- 29151816 TI - Counselling professionals' awareness and understanding of female genital mutilation/cutting: Training needs for working therapeutically with survivors. AB - Background: There is a dearth of literature that has looked at the psychological impact of female genital mutilation/cutting (FGM/C), and little is known about the understanding and awareness of FGM/C amongst counselling professionals. Method: An online survey was completed by 2073 BACP members. The survey covered four broad themes: demographics; awareness and understanding of FGM/C; experience of working therapeutically with survivors; and FGM/C training. Descriptive and inferential analyses were undertaken on quantitative data, and thematic content analysis was undertaken on qualitative data. Results: Only a small proportion of respondents (10%) had knowingly worked with survivors of FGM/C. Overall, respondents lacked confidence in their awareness and understanding of FGM/C, including their safeguarding duties. Having cultural respect, knowledge and understanding was perceived as the most helpful factor when working with this client group. Less than a quarter of respondents had undertaken any training with regard to FGM/C, although the vast majority expressed a desire to do so. Discussion: This research has highlighted the importance of improving signposting to existing training and educational resources around FGM/C, as well as the need to develop new resources where appropriate. The importance of embedding cultural competency into core practitioner training, not just training specific to FGM/C, is paramount. PMID- 29151814 TI - De novo acute lymphoblastic leukemia-like disease of high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a case report and literature review. AB - Background: B-cell lymphomas harboring the 8q24/MYC plus 18q21/BCL2 translocations are now referred to as high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-MBR). Although HGBL-MBR is frequently found in cases with diffuse large B-cell lymphoma or Burkitt lymphoma-like B-cell lymphoma, acute lymphoblastic leukemia (ALL)-like disease of HGBL-MBR (AL-HGBL MBR) has been reported incidentally. Case presentation: A 69-year-old Japanese woman developed remittent fever and increasing systemic bone pain. The bone marrow examination revealed that more than 90% of nuclear cells were blastoid cells, which were positive for CD10, CD19, CD20, and surface IgMkappa and negative for terminal deoxynucleotidyl transferase (TdT). Cytogenetic studies confirmed that the patient had de novo AL-HGBL-MBR with the extra copies of MYC and loss of chromosome 17p. She showed resistance to chemoimmunotherapy and died seven months after the diagnosis. The literature review identified further 47 de novo AL-HGBL-MBR cases within the last 32 years. The median age was 61 years (range, 27 - 86); the male/female ratio was 2.0. Thirty-eight cases (79%) presented a clinical picture of ALL at diagnosis; 14 (36%) of 39 available cases showed central nervous system involvement. Loss of 17p and translocations at 2p12 13, 3q27, 9p13 were frequently observed as additional cytogenetic abnormalities. Although the median survival of 46 available cases was only five months (range, 0.1-18), rituximab use significantly improved the survival of AL-HGBL-MBR (log rank test, P = 0.0294). Conclusion: Our patient and most reported de novo AL-HGBL MBR cases showed resistance to conventional chemoimmunotherapy and disastrous consequences. AL-HGBL-MBL is a rare, but should be considered a distinct clinical condition in HGBL-MBR. Other therapeutic strategies, such as using inhibitors of MYC and BCL2, are needed to overcome the chemoresistance of AL-HGBL-MBR. PMID- 29151817 TI - MicroRNA-214-3p inhibits proliferation and cell cycle progression by targeting MELK in hepatocellular carcinoma and correlates cancer prognosis. AB - Background: MicroRNAs are considered as potential regulators in various biological pathways and contribute to the diagnosis and prognosis of cancers. MicroRNA-214-3p (miR-214-3p) was proved to be correlated with various cancers in recent studies. However, the biological functions of miR-214-3p in hepatocellular carcinoma (HCC) and its association with the prognosis of HCC after liver transplantation are still unevaluated. Here we intended to elucidate the functional implication of miR-214-3p in regulation of cell proliferation and apoptosis and its potential prediction of clinical prognosis of HCC patients. Methods: Expressions of miR-214-3p in 98 HCC patients and three HCC cell lines were detected by quantitative reverse transcription PCR (qRT-PCR) to explore the association of miR-214-3p expression and clinicopathological characteristics. The effects of miR-214-3p on cell proliferation and apoptosis were examined by proliferation and flow cytometry assay, respectively. The direct target gene of miR-214-3p was also detected by luciferase reporter assay. Results: The effects of miR-214-3p on cell proliferation and apoptosis were examined by proliferation and flow cytometry assay, respectively. The direct target gene of miR-214-3p was also detected by luciferase reporter assay. The results showed that miR-214-3p expression was downregulated in primary HCC samples compared with normal liver tissues, and was decreased in HCC recurrence species compared with non-recurrence controls (P = 0.001). Low miR-214-3p level was associated with poor overall survival (OS) (Log rank P = 0.003) and recurrence-free survival (RFS) (Log rank P = 0.007). Moreover, miR-214-3p precursor transfection resulted in decreased cell proliferation, cell cycle arrest at G1 phase, and enhanced cell apoptosis in HepG2 and HUH-7 cells. Further investigation showed that miR-214-3p could regulate its target gene maternal embryonic leucine zipper kinase (MELK) by directly binding to MELK-3'-UTR. Conclusions: miR-214-3p suppresses HCC progression by directly down-regulating MELK expression, indicating a potential therapeutic target for the treatment and prognosis of HCC patients. PMID- 29151818 TI - Lifetime cost-effectiveness analysis of intraoperative radiation therapy versus external beam radiation therapy for early stage breast cancer. AB - Background: To date no one has examined the quality of life and direct costs of care in treating early stage breast cancer with adjunct intraoperative radiation therapy (IORT) versus external beam radiation therapy (EBRT) over the life of the patient. As well no one has examined the effects of radiation exposure with both therapies on the longer term sequelae. The purpose of this analysis was to examine the cost-effectiveness of IORT vs. EBRT over the life of the patient. Methods: A Markov decision-analytic model evaluated these treatment strategies in terms of the direct costs in treating patients over their lifetime (including the downstream costs associated with radiation exposure) and the resultant quality of life of these patients. Medicare reimbursement amounts in treating patients were used for acute, steady state, recurrent cancer(s), and complications associated with radiation exposure. Quality adjusted life years (QALYs) derived from the medical literature were assessed with each of these states. Life expectancies as well were derived from the medical literature. Cost-effectiveness was evaluated for dominance and net monetary benefit [at a willingness to pay (WTP)] of $50,000/QALY. Sensitivity analysis was also performed. Results: IORT was the dominant (least costly with greater QALYs) versus EBRT: total costs over the life of the patient = $53,179 (IORT) vs. $63,828 (EBRT) and total QALYs: 17.86 (IORT) vs. 17.06 (EBRT). At a willingness to pay of $50,000 for each additional QALY, the net monetary benefit demonstrated that IORT was the most cost effective option: $839,815 vs. $789,092. The model was most sensitive to the probabilities of recurrent cancer and death for both IORT and EBRT. Conclusion: IORT is the more valuable (lower cost with improved QALYs) strategy for use in patients presenting with early stage ER+ breast cancer. It should be used preferentially in these patients. PMID- 29151820 TI - Name It! Store It! Protect It!: A Systems Approach to Managing Data in Research Core Facilities. AB - As the capabilities of technology increase, so do the production of data and the need for data management. The need for data storage at many academic institutions is increasing exponentially. Technology is expanding rapidly, and institutions are recognizing the need to incorporate data management that can be available for future data sharing as a critical component of institutional services. The establishment of a process to manage the surge in data storage is complex and often hindered by not having a plan. Simple file naming-nomenclature-is also becoming ever more important to leave an established understanding of the contents in a file. This is especially the case as research experiences turnover from research projects and personnel. The indexing of files consistently also helps to identify past work. Finally, the protection of the data contents is becoming increasing challenging. As the genomic field expands, and medicine becomes more personalized, the identification of methods to protect the contents of data in both short- and long-term storage needs to be established so as not to risk the potential of revealing identifiable information. This is often something we do not consider in a nonclinical research environment. The need for establishing basic guidelines for institutions is critical, as individual research laboratories are unable to handle the scope of data storage required for their own research. In addition to the immediate needs for establishing guidelines on data storage and file naming and how to protect information, the recognition of the need for specialized support for data management supporting research cores and laboratories at academic institutions is becoming a critical component of institutional services. Here, we outline some case studies and methods that you may be able to adopt at your own institution. PMID- 29151819 TI - Production of Monoclonal Antibodies against Human Trefoil Factor 3 and Development of a Modified-Sandwich ELISA for Detection of Trefoil Factor 3 Homodimer in Saliva. AB - Background: Human trefoil factor (TFF) peptides consist of three members: TFF1, TFF2 and TFF3. TFF3 is the most abundant TFF peptide in saliva. TFF3 homodimer was suggested to be involved in apoptosis inhibition and malignancy. Determination of TFF3 homodimer expression profiles in saliva may lead to new information about oral biology and diseases. The objective of this study was to generate monoclonal antibodies (mAbs) against TFF3 and apply the produced mAbs for the establishment of ELISA for quantification of dimeric TFF3 in saliva. Results: With our modified hybridoma technique, three hybridoma clones producing anti-TFF3 mAbs having IgG isotype were generated. The mAbs were specific for TFF3 with no cross-reactivity to other TFFs. Using the generated mAbs, a modified sandwich ELISA with high sensitivity for the quantification of dimeric TFF3 in saliva was developed. Using this ELISA, the amount of dimeric TFF3 in saliva could be measured. Conclusions: A modified-sandwich ELISA for the quantification of TFF3 dimeric form was established. The established ELISA will be a valuable tool for facilitating the investigation of the physiological roles and the diagnostic values of TFF3 in oral diseases. The concept of this modified-sandwich ELISA may be applied for the determination of other homodimeric peptides of interest. PMID- 29151821 TI - StreamQRE: Modular Specification and Efficient Evaluation of Quantitative Queries over Streaming Data. AB - Real-time decision making in emerging IoT applications typically relies on computing quantitative summaries of large data streams in an efficient and incremental manner. To simplify the task of programming the desired logic, we propose StreamQRE, which provides natural and high-level constructs for processing streaming data. Our language has a novel integration of linguistic constructs from two distinct programming paradigms: streaming extensions of relational query languages and quantitative extensions of regular expressions. The former allows the programmer to employ relational constructs to partition the input data by keys and to integrate data streams from different sources, while the latter can be used to exploit the logical hierarchy in the input stream for modular specifications. We first present the core language with a small set of combinators, formal semantics, and a decidable type system. We then show how to express a number of common patterns with illustrative examples. Our compilation algorithm translates the high-level query into a streaming algorithm with precise complexity bounds on per-item processing time and total memory footprint. We also show how to integrate approximation algorithms into our framework. We report on an implementation in Java, and evaluate it with respect to existing high performance engines for processing streaming data. Our experimental evaluation shows that (1) StreamQRE allows more natural and succinct specification of queries compared to existing frameworks, (2) the throughput of our implementation is higher than comparable systems (for example, two-to-four times greater than RxJava), and (3) the approximation algorithms supported by our implementation can lead to substantial memory savings. PMID- 29151822 TI - New Actuation Mechanism for Actively Cooled SMA Springs in a Neurosurgical Robot. AB - The paper presents the use of shape memory alloy (SMA) spring actuators with real time cooling to control the motion of the MINIR-II robot. A new actuation mechanism involving the passage of water as the cooling medium and air as the medium to drive out the water has been developed to facilitate real-time control of the springs. Control parameters, such as current, water flow rates, SMA pre displacement, and gauge pressure of the compressed air, are identified from the SMA thermal model and from the actuation mechanism. In depth modeling and characterization have been performed regarding these parameters to optimize the robot motion speed. Forced water cooling has also been compared with forced air cooling and proved to be the superior method to achieve higher robot speed. An improved robot design and an MRI-compatible experimental platform have been developed for the implementation of the actuation mechanism. PMID- 29151823 TI - Proteomic Changes Between Populus Allotriploids and Diploids Revealed Using an iTRAQ-based Quantitative Approach. AB - Background: Polyploid breeding is a powerful approach for Populus genetic improve ment because polyploid trees have valuable characteristics, including better timber quality and a higher degree of stress resistance compared with their full sib diploids. However, the genetic mech-anism underlying this phenomenon remains unknown. Objective: To better understand the proteomic changes between Populus allotriploids and diploids, we examined the proteomic profiles of allotriploid and diploid Populus by iTRAQ labeling coupled with two-dimensional liquid chromatography and MALDI-TOF/TOF mass spectrometry (MS). Method: iTRAQ labeling coupled with two-dimensional liquid chromatography and MALDI-TOF/TOF mass spectrometry (MS). Results: Between the Populus allotriploid and the full-sib diploid, 932 differentially expressed proteins (DEPs) were identified. These DEPs were primarily involved in stress, defense, transportation, transcriptional and/or translational modification, and energy production. The pathway analysis indi-cated that most of the DEPs were implicated in carbohydrate transport and metabolism, nitrogen me-tabolism and glycolysis, and the ribosome assembly pathway. These data suggest high protein di-vergence between Populus allotriploids and diploids, and rapid changes during hybridization. Conclusion: The results provide new data for further understanding of the mechanisms of polyploid trees that generally display increased height growth compared with their full-sib diploids. PMID- 29151824 TI - A real time metabolomic profiling approach to detecting fish fraud using rapid evaporative ionisation mass spectrometry. AB - Introduction: Fish fraud detection is mainly carried out using a genomic profiling approach requiring long and complex sample preparations and assay running times. Rapid evaporative ionisation mass spectrometry (REIMS) can circumvent these issues without sacrificing a loss in the quality of results. Objectives: To demonstrate that REIMS can be used as a fast profiling technique capable of achieving accurate species identification without the need for any sample preparation. Additionally, we wanted to demonstrate that other aspects of fish fraud other than speciation are detectable using REIMS. Methods: 478 samples of five different white fish species were subjected to REIMS analysis using an electrosurgical knife. Each sample was cut 8-12 times with each one lasting 3-5 s and chemometric models were generated based on the mass range m/z 600-950 of each sample. Results: The identification of 99 validation samples provided a 98.99% correct classification in which species identification was obtained near instantaneously (~ 2 s) unlike any other form of food fraud analysis. Significant time comparisons between REIMS and polymerase chain reaction (PCR) were observed when analysing 6 mislabelled samples demonstrating how REIMS can be used as a complimentary technique to detect fish fraud. Additionally, we have demonstrated that the catch method of fish products is capable of detection using REIMS, a concept never previously reported. Conclusions: REIMS has been proven to be an innovative technique to help aid the detection of fish fraud and has the potential to be utilised by fisheries to conduct their own quality control (QC) checks for fast accurate results. PMID- 29151825 TI - A network of helping: Generalized reciprocity and cooperative behavior in response to peer and staff affirmations and corrections among therapeutic community residents. AB - Background: Clinical theory in therapeutic communities (TCs) for substance abuse treatment emphasizes the importance of peer interactions in bringing about change. This implies that residents will respond in a more prosocial manner to peer versus staff intervention and that residents will interact in such a way as to maintain cooperation. Method: The data consist of electronic records of peer and staff affirmations and corrections at four corrections-based therapeutic community units. We treat the data as a directed social network of affirmations. We sampled 100 resident days from each unit (n = 400) and used a generalized linear mixed effects network time series model to analyze the predictors of sending and receiving affirmations and corrections. The model allowed us to control for characteristics of individuals as well as network-related dependencies. Results: Residents show generalized reciprocity following peer affirmations, but not following staff affirmations. Residents did not respond to peer corrections by increasing affirmations, but responded to staff corrections by decreasing affirmations. Residents directly reciprocated peer affirmations. Residents were more likely to affirm a peer whom they had recently corrected. Residents were homophilous with respect to race, age and program entry time. Conclusion: This analysis demonstrates that TC residents react more prosocially to behavioral intervention by peers than by staff. Further, the community exhibits generalized and direct reciprocity, mechanisms known to foster cooperation in groups. Multiple forms of homophily influence resident interactions. These findings validate TC clinical theory while suggesting paths to improved outcomes. PMID- 29151826 TI - Renal-Clearable PEGylated Porphyrin Nanoparticles for Image-guided Photodynamic Cancer Therapy. AB - Noninvasive dynamic positron emission tomography (PET) imaging was used to investigate the balance between renal clearance and tumor uptake behaviors of polyethylene glycol (PEG)-modified porphyrin nanoparticles (TCPP-PEG) with various molecular weights. TCPP-PEG10K nanoparticles with clearance behavior would be a good candidate for PET image-guided photodynamic therapy. PMID- 29151827 TI - Tumor necrosis factor-like weak inducer of apoptosis regulates quadriceps muscle atrophy and fiber-type alteration in a rat model of chronic obstructive pulmonary disease. AB - Background: In chronic obstructive pulmonary disease (COPD), weakness and muscle mass loss of the quadriceps muscle has been demonstrated to predict survival and mortality rates of patients. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), as a member of the TNF superfamily, has recently been identified as a key regulator of skeletal muscle wasting and metabolic dysfunction. So our aim was to study the role of TWEAK during quadriceps muscle atrophy and fiber-type transformation in COPD model rats and its possible pathway. Methods: Forty-four healthy male adult Wistar rats were randomly divided into two groups: A normal control group (n = 16) and a COPD model group (n = 28). The COPD group was exposed to cigarette smoke for 90 d and injected with porcine pancreatic elastase on day 15, whereas the control group was injected with saline alone. Following treatment, weights of the quadriceps muscles were measured and hematoxylin and eosin staining was performed to identify structural changes in lung and quadriceps muscle tissue. Immunohistochemical staining was also conducted to determine the localization of TWEAK, nuclear factor (NF)-kappaB, muscle ring finger (MuRF)-1 and proliferator-activated coactivator (PGC)-1a proteins in the quadriceps muscle, and western blotting was used to assess the level of protein expression. Results: Compared with controls, COPD model rats exhibited significantly lower quadriceps muscle weight (P < 0.05) accompanied by fiber atrophy and disordered fiber arrangement, a wide gap between adjacent muscle fibers, a significant reduction in nuclear number (P < 0.05) and an uneven size distribution. The proportion of fiber types was also significantly altered (P < 0.05). In addition, TWEAK expression in the quadriceps muscle of COPD model rats was significantly higher than that in control rats (P < 0.05), and was significantly associated with quadriceps atrophy and fiber-type alteration (P < 0.05). Levels of NF-kappaB, MuRF1 and PGC-1alpha expression also significantly differed between the two groups (P < 0.05). Conclusions: Collectively these data suggest that increased levels of TWEAK may lead to skeletal muscle atrophy and fiber-type alteration, which in turn may be associated with activation of the ubiquitin-proteasome pathway, involving NF-kappaB, MuRF1 and PGC-1alpha as potential regulatory factors. These preliminary results in rats suggest that TWEAK may be a therapeutic target for the treatment of muscle atrophy in COPD. PMID- 29151828 TI - Simulating colonic survival of probiotics in single-strain products compared to multi-strain products. AB - Background: Probiotic formulations can be single- or multi-strain. Commercially, multi-strain preparations have been suggested to have improved functionality over single-strain cultures. Probiotics are often tested as single-strain preparations but may subsequently be commercially formulated as multi-strain products. Objective: The aim of this study was to determine what happens at the site of action, the intestine, with probiotics as single- compared to multi-strain preparations. The human gastrointestinal tract contains a broad mixture of different microbes which may affect the survival of different probiotics in different ways. Design: The current study was performed to evaluate, in an in vitro colon simulation, whether probiotics influence each other's survival when they are taken as a combination of several strains (HOWARU Restore; Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, Bifidobacterium lactis Bl-04 and B. lactis Bi-07) compared to the strains as single preparations. Results: All strains could be detected after the colon simulations and there were no substantial differences in levels of the same strain when comparing single- and multi-strain products. Conclusions: It can be concluded that probiotics do not have an antagonistic effect on each other's survival when used in a multi-strain product compared to a single-strain product, at least within a microbiota in a simulated colonic environment. PMID- 29151829 TI - Validation of 'POIBA-How do we eat?' questionnaire in 9-10 years old schoolchildren. AB - Background: It is difficult to obtain good food reports with Food Frequency Questionnaires (FFQ) among children. In addition, validated questionnaires are scarce. Objective: The aim of this study was to validate the 'POIBA-How do we eat?' (POIBA-HDWE) FFQ and whether it could be administered to children under 10 years of age. Design: We validated the FFQ POIBA-HDWE as part of the Childhood Obesity Prevention Program (POIBA project) in Barcelona. Forty-two out of 63 primary school students (9-10 years old) answered three questionnaires: FFQ POBA HDWE; another questionnaire, 'POIBA-How do our children eat?' (POIBA-HDOCE), which was administered to the children's parents; and the 24-h recall computer program 'Young Adolescents' Nutrition Assessment on Computer' (YANA-C), which was used on three different days as a gold standard. We tested for correlations using the Spearman test for non-parametric variables. Results: We found low compliance with food recommendations (<50%). The POIBA-HDWE and POIBA-HDOCE questionnaires showed a moderate correlation for soft drinks (r = 0.49; p < 0.01), nuts (r = 0.59; p < 0.01), dairy products (r = 0.41; p < 0.01) and juices (r = 0.49; p < 0.01). There were moderate correlations between POIBA-HDWE and YANA-C for fried potatoes (r = 0.42; p = 0.01), dairy products (r = 0.53; p < 0.01), juices (r = 0.41; p < 0.01), and grains(r = 0.50; p < 0.01). Food frequency questions showed a homogeneity of 0.69, and a sensitivity of over 60% for all food items except chips (37.5%) and sweets (51.7%). Conclusions: The POIBA-HDWE FFQ showed moderate correlations with the gold standard, high sensitivity for most food types and acceptable internal consistency. It is an easy and affordable tool for recording food frequency in children under 10 years old. PMID- 29151830 TI - Antihypertensive properties of tilapia (Oreochromis spp.) frame and skin enzymatic protein hydrolysates. AB - Proteins from tilapia frame and skin can potentially be precursors of antihypertensive peptides according to the result of BIOPEP analyses. The aim was to generate peptides with inhibitory effects against angiotensin-converting enzyme (ACE) and renin from tilapia frame and skin protein isolates (FPI and SPI). The most active hydrolysate was then tested for blood pressure-lowering ability in spontaneously hypertensive rats (SHRs). Tilapia frame and skin protein hydrolysates (FPHs and SPHs) were respectively produced from FPI and SPI hydrolysis using pepsin, papain, or bromelain. The ACE-inhibitory activities of tilapia protein hydrolysates with varying degree of hydrolysis (DH) were evaluated. In order to enhance the activity, the hydrolysate was fractionated into four fractions (<1 kDa, 1-3 kDa, 3-5 kDa, and 5-10 kDa) and the one with the greatest ability to inhibit in vitro ACE and renin activities was subjected to oral administration (100 mg/kg body weight) to SHRs. Systolic and diastolic blood pressure (SBP and DBP), mean arterial pressure (MAP), and heart rates (HR) were subsequently measured within 24 h. The pepsin-hydrolyzed FPH (FPHPe) with the highest DH (23%) possessed the strongest ACE-inhibitory activity (IC50: 0.57 mg/mL). Its <1 kDa ultrafiltration fraction (FPHPe1) suppressed both ACE (IC50: 0.41 mg/mL) and renin activities more effectively than larger peptides. In addition, FPHPe1 significantly (p < 0.05) reduced SBP (maximum -33 mmHg), DBP (maximum -24 mmHg), MAP (maximum -28 mmHg), and HR (maximum -58 beats) in SHRs. FPHPe1 showed both in vitro and in vivo antihypertensive effects, which suggest tilapia processing coproducts may be valuable protein raw materials for producing antihypertensive peptides. PMID- 29151831 TI - A low proportion of malnourished patients receive nutrition treatment - results from nutritionDay. AB - NutritionDay is a yearly point-prevalence study of malnutrition in hospitals from more than 50 countries. The aim of the present study was to quantify the frequency of malnutrition and the proportion of malnourished patients receiving nutritional treatment in two university hospitals in Norway using data from nutritionDay. All units at Oslo University Hospital (OUH) and University Hospital of Northern Norway (UNN) were invited to participate in nutritionDay 2014, and 28 out of 85 eligible units agreed to take part. Malnutrition was diagnosed based on body mass index (BMI), weight reduction and food intake in the previous week, according to national guidelines and ESPEN criteria. Data from 488 patients were available, representing 90.1% of occupied beds in participating units. Thirty percent of the patients were diagnosed malnourished when national criteria were used, and only 41% of these patients received nutritional treatment. The estimated malnutrition rate was 11% when the ESPEN consensus criteria were used. Data on weight or height were frequently missing in the patient records, and BMI could only be calculated in two-thirds of the patients. The frequency of low BMI (<18.5 kg/m2) was only 5%. Involuntary weight loss was present in 37% of the patients, and 60% had eaten less than normal in the previous week. Oncology units had the highest frequency of patients with low BMI, and the highest weight loss and overall malnutrition rate. Surgery and geriatric units had the highest rate of patients with low food intake. In this study, nearly 60% of the malnourished patients did not receive any nutritional treatment, and this indicates a potential for improved nutritional care and cost savings. Low food intake and weight loss were frequent at these two Norwegian hospitals, and in line with previous reports from nutritionDay in other countries. PMID- 29151832 TI - Relationship between agricultural biodiversity and dietary diversity of children aged 6-36 months in rural areas of Northern Ghana. AB - In this study, we investigated the relationship between agricultural biodiversity and dietary diversity of children and whether factors such as economic access may affect this relationship. This paper is based on data collected in a baseline cross-sectional survey in November 2013.The study population comprising 1200 mother-child pairs was selected using a two-stage cluster sampling. Dietary diversity was defined as the number of food groups consumed 24 h prior to the assessment. The number of crop and livestock species produced on a farm was used as the measure of production diversity. Hierarchical regression analysis was used to identify predictors and test for interactions. Whereas the average production diversity score was 4.7 +/- 1.6, only 42.4% of households consumed at least four food groups out of seven over the preceding 24-h recall period. Agricultural biodiversity (i.e. variety of animals kept and food groups produced) associated positively with dietary diversity of children aged 6-36 months but the relationship was moderated by household socioeconomic status. The interaction term was also statistically significant [beta = -0.08 (95% CI: -0.05, -0.01, p = 0.001)]. Spearman correlation (rho) analysis showed that agricultural biodiversity was positively associated with individual dietary diversity of the child more among children of low socioeconomic status in rural households compared to children of high socioeconomic status (r = 0.93, p < 0.001 versus r = 0.08, p = 0.007). Socioeconomic status of the household also partially mediated the link between agricultural biodiversity and dietary diversity of a child's diet. The effect of increased agricultural biodiversity on dietary diversity was significantly higher in households of lower socioeconomic status. Therefore, improvement of agricultural biodiversity could be one of the best approaches for ensuring diverse diets especially for households of lower socioeconomic status in rural areas of Northern Ghana. PMID- 29151833 TI - Effect of ewe's (semi-skimmed and whole) and cow's milk yogurt consumption on the lipid profile of control subjects: a crossover study. AB - Yogurt is the most widely consumed fermented milk product worldwide. Studies have mainly used milk and dairy products from cow, which have a lower fat content than those from ewe and a different lipid profile. This study investigated the effect on the lipid profile of control subjects of three different set yogurts: (a) semi skimmed ewe's milk yogurt (2.8% milk fat); (b) whole ewe's milk yogurt (5.8 % milk fat); (c) cow's milk yogurt (3 % milk fat). A randomized crossover study included 30 healthy adults (16 women) to consume 250 g/yogurt/day during three consecutive 5-weeks periods separated by 4-week washouts. Blood samples were collected at the start and end of each period for the analysis of serum cholesterol (total, HDL-, LDL-) and triglycerides. We found no differences in the serum concentrations of lipid and lipoprotein fractions of the volunteers after the intake of any of the three types of yogurts. When the volunteers were grouped into two risk groups of risk according to their total cholesterol/HDL cholesterol ratio, the same differences between the groups in terms of the cholesterol (HDL-, LDL-) and triglyceride responses at baseline and after yogurt intake were found, with no effects due to the different types of yogurts. Moreover, we performed compositional analysis of the yogurts including determination of protein, fat, minerals and fatty acids (FA). Contents in protein, calcium, magnesium, non protein nitrogen and some FA (mainly short-chain-FA) were higher for ewe's than for cow's milk yogurt. n6-n3 ratio was lower in the ewe's milk yogurt. In conclusion, yogurt intake, from ewe's and cow's milk, at levels of consumption compatible with a varied diet, neither decreases nor increases plasma lipoprotein cholesterol levels in apparently healthy individuals. As ewe's milk yogurt has a high content of macro- and micronutrients, certain target populations could benefit from its consumption. PMID- 29151834 TI - Late introduction of fish and eggs is associated with increased risk of allergy development - results from the FARMFLORA birth cohort. AB - The prevalence of allergy is markedly low in children growing up on farms. An increasing number of studies indicate that the timing of food introduction may affect allergy development. We aimed to investigate if protection against allergy in farm environments may be mediated through differences in food-introduction practices between farm and non-farm families, using an explorative approach. Twenty-eight farm and 37 non-farm children were included in the FARMFLORA birth cohort. Practices of breastfeeding and introduction of formulas and complementary foods were collected by questionnaires at 6, 12, and 18 months of age. Allergy was diagnosed by pediatricians at 3 years of age. The only difference in food introduction practices observed between farm and non-farm children was an earlier introduction of nuts in farmers (median month: 11 [IQR: 8-6] in farmers, 15 [12 19] in non-farmers). One farm child (4%) and 10 non-farm children (27%) were allergic at 3 years of age. Lower risk of allergy development was associated with early exclusive breastfeeding (continuous variable; OR = 0.59, 95% CI: 0.39 0.89), but also having received eggs (OR = 0.08, 95% CI: 0.13-0.54) and fish (logistic regression not applicable, P = 0.01 in likelihood ratio testing [chi2]) at 10 months of age or earlier compared to later. Our results were not affected by reverse causation, as judged by a questionnaire sent to the families in retrospect. Timing of introduction of complementary foods is unlikely to contribute to the lower risk of allergy among farm children. Although early exclusive breastfeeding was associated with a lower rate of allergy development, postponed introduction of complementary foods might increase the risk of developing allergy. Owing to the limited sample size, our results are only indicative, but support prior findings. PMID- 29151835 TI - Opuntia humifusa modulates morphological changes characteristic of asthma via IL 4 and IL-13 in an asthma murine model. AB - Asthma is a chronic pulmonary disease that affects an estimated 235 million people worldwide, but asthma drugs have many adverse effects. Opuntia humifusa (eastern prickly pear) has been used as a food and traditional medicine worldwide; however, its anti-asthmatic effects have not been reported. We evaluated O. humifusa as a potential therapeutic or preventive component of anti asthmatic drugs. We divided ovalbumin-sensitized mice into the following groups: normal control, asthma-induced control, dexamethasone-treated group (positive control), 50 mg/kg O. humifusa-treated group, 100 mg/kg O. humifusa-treated group, and 500 mg/kg O. humifusa-treated group. Levels of Th1/Th2/Th17-related cytokines were evaluated using RT-PCR, ELISA, and immunohistochemistry. O. humifusa dose-dependently suppressed the morphological changes typically observed in asthma, such as goblet cell hyperplasia, inflammatory cell infiltration, mucous hypersecretion, and relative basement membrane thickening in the respiratory system. These results may be attributable to regulation of Th1-/Th2 /Th17-related factors, especially interleukin (IL)-4 and IL-13. We conclude that O. humifusa is a potential anti-asthmatic functional food. Abbreviations: O. humifusa: Opuntia humifusa; Th: helper T; RT-PCR: real-time polymerase chain reaction; ELISA: enzyme-linked immunosorbent assay; IL: interleukin; WHO: World Health Organization; IFN-gamma: interferon gamma; TNF-alpha: tumor necrosis factor-alpha; IgE: immunoglobulin E; CD: cluster of differentiation; OVA: ovalbumin; DEX: dexamethasone; BALF: bronchoalveolar fluid; H&E: hematoxylin and eosin; PAS: periodic acid-schiff; PBS: phosphate-buffered saline; BM: basement membrane; cDNA: complementary deoxyribonucleic acid; RNA: ribo nucleic acid; RIPA: radioimmunoprecipitation assay; IHC: immunohistochemistry; HPLC: high performance liquid chromatography; SD: standard deviation; WBC: white blood cells; APCs: antigen-presenting cells. PMID- 29151836 TI - Corrigendum: Induction of Monocyte Chemoattractant Proteins in Macrophages via the Production of Granulocyte/Macrophage Colony-Stimulating Factor by Breast Cancer Cells. AB - [This corrects the article on p. 2 in vol. 7, PMID: 26834744.]. PMID- 29151837 TI - Corrigendum: Immunoglobulin Fc Heterodimer Platform Technology: From Design to Applications in Therapeutic Antibodies and Proteins. AB - [This corrects the article on p. 394 in vol. 7, PMID: 27766096.]. PMID- 29151839 TI - Characteristics of the polarised off-body channel in indoor environments. AB - This paper addresses the depolarisation effect in off-body body area networks channels, based on measurements performed at 2.45 GHz in an indoor environment. Seven different scenarios, involving both static and dynamic users, were considered, taking a statistical perspective. The analysis of the cross polarisation discrimination is performed, as well as the analysis of path loss in co- and cross-polarised channels. Results show a strong dependence of the cross polarisation discrimination and of channel characteristics on the polarisation and propagation condition, i.e. line-of-sight (LoS), non-LoS or quasi-LoS. Distance, varied between 1 and 6 m in the considered scenarios, is observed to have very little impact on the cross-polarisation discrimination. In the considered dynamic scenario, the channel is characterised by lognormal distributed shadowing and Nakagami-distributed multipath fading. Parameters of the Nakagami distribution have essentially different values in the co- and cross polarised channels, showing a trend towards Rice in the former and Rayleigh in the latter. Based on results, a model is proposed for a dynamic off-body channel. PMID- 29151838 TI - Observation- and Model-Based Estimates of Particulate Dry Nitrogen Deposition to the Oceans. AB - Anthropogenic nitrogen (N) emissions to the atmosphere have increased significantly the deposition of nitrate (NO3-) and ammonium (NH4+) to the surface waters of the open ocean, with potential impacts on marine productivity and the global carbon cycle. Global-scale understanding of the impacts of N deposition to the oceans is reliant on our ability to produce and validate models of nitrogen emission, atmospheric chemistry, transport and deposition. In this work, ~2900 observations of aerosol NO3- and NH4+ concentrations, acquired from sampling aboard ships in the period 1995 - 2012, are used to assess the performance of modelled N concentration and deposition fields over the remote ocean. Three ocean regions (the eastern tropical North Atlantic, the northern Indian Ocean and northwest Pacific) were selected, in which the density and distribution of observational data were considered sufficient to provide effective comparison to model products. All of these study regions are affected by transport and deposition of mineral dust, which alters the deposition of N, due to uptake of nitrogen oxides (NOx) on mineral surfaces. Assessment of the impacts of atmospheric N deposition on the ocean requires atmospheric chemical transport models to report deposition fluxes, however these fluxes cannot be measured over the ocean. Modelling studies such as the Atmospheric Chemistry and Climate Model Intercomparison Project (ACCMIP), which only report deposition flux are therefore very difficult to validate for dry deposition. Here the available observational data were averaged over a 5 degrees * 5 degrees grid and compared to ACCMIP dry deposition fluxes (ModDep) of oxidised N (NOy) and reduced N (NHx) and to the following parameters from the TM4-ECPL (TM4) model: ModDep for NOy, NHx and particulate NO3- and NH4+, and surface-level particulate NO3- and NH4+ concentrations. As a model ensemble, ACCMIP can be expected to be more robust than TM4, while TM4 gives access to speciated parameters (NO3- and NH4+) that are more relevant to the observed parameters and which are not available in ACCMIP. Dry deposition fluxes (CalDep) were calculated from the observed concentrations using estimates of dry deposition velocities. Model - observation ratios, weighted by grid-cell area and numbers of observations, (RA,n) were used to assess the performance of the models. Comparison in the three study regions suggests that TM4 over-estimates NO3- concentrations (RA,n = 1.4 - 2.9) and under estimates NH4+ concentrations (RA,n = 0.5 - 0.7), with spatial distributions in the tropical Atlantic and northern Indian Ocean not being reproduced by the model. In the case of NH4+ in the Indian Ocean, this discrepancy was probably due to seasonal biases in the sampling. Similar patterns were observed in the various comparisons of CalDep to ModDep (RA,n = 0.6 - 2.6 for NO3-, 0.6 - 3.1 for NH4+). Values of RA,n for NHx CalDep - ModDep comparisons were approximately double the corresponding values for NH4+ CalDep - ModDep comparisons due to the significant fraction of gas-phase NH3 deposition incorporated in the TM4 and ACCMIP NHx model products. All of the comparisons suffered due to the scarcity of observational data and the large uncertainty in dry deposition velocities used to derive deposition fluxes from concentrations. These uncertainties have been a major limitation on estimates of the flux of material to the oceans for several decades. Recommendations are made for improvements in N deposition estimation through changes in observations, modelling and model - observation comparison procedures. Validation of modelled dry deposition requires effective comparisons to observable aerosol-phase species concentrations and this cannot be achieved if model products only report dry deposition flux over the ocean. PMID- 29151840 TI - Adherence with epinephrine autoinjector prescriptions in primary care. AB - Background: The aim of this study was to estimate primary adherence for epinephrine autoinjector (EA) prescriptions in primary care practices in Manitoba, Canada. Methods: A retrospective analysis of electronic medical record and administrative data was performed to determine primary adherence, defined as dispensation of a new EA prescription within 90 days of the date the prescription was written. Multivariable logistic regression models were used to test predictors of filling an EA prescription. Results: Of 1212 EA prescriptions written between 2012 and 2014, only 69.9% (N = 847) were filled. An increased number of prescriptions for non-EA mediations was associated with an increased odds ratio of not filling an EA prescription. Interpretation: This is the first study in Canada to examine adherence for EA prescriptions. The non-adherence rate identified is higher than rates previously reported in the literature, and indicates that many EA prescriptions for adults seen in primary care may never be filled. It also suggests that prescriptions of EAs for all patients at risk of anaphylaxis in community settings should consistently be accompanied by concise information about the importance of having the EA prescription filled and having the EA readily available. PMID- 29151841 TI - Microscope image based fully automated stomata detection and pore measurement method for grapevines. AB - Background: Stomatal behavior in grapevines has been identified as a good indicator of the water stress level and overall health of the plant. Microscope images are often used to analyze stomatal behavior in plants. However, most of the current approaches involve manual measurement of stomatal features. The main aim of this research is to develop a fully automated stomata detection and pore measurement method for grapevines, taking microscope images as the input. The proposed approach, which employs machine learning and image processing techniques, can outperform available manual and semi-automatic methods used to identify and estimate stomatal morphological features. Results: First, a cascade object detection learning algorithm is developed to correctly identify multiple stomata in a large microscopic image. Once the regions of interest which contain stomata are identified and extracted, a combination of image processing techniques are applied to estimate the pore dimensions of the stomata. The stomata detection approach was compared with an existing fully automated template matching technique and a semi-automatic maximum stable extremal regions approach, with the proposed method clearly surpassing the performance of the existing techniques with a precision of 91.68% and an F1-score of 0.85. Next, the morphological features of the detected stomata were measured. Contrary to existing approaches, the proposed image segmentation and skeletonization method allows us to estimate the pore dimensions even in cases where the stomatal pore boundary is only partially visible in the microscope image. A test conducted using 1267 images of stomata showed that the segmentation and skeletonization approach was able to correctly identify the stoma opening 86.27% of the time. Further comparisons made with manually traced stoma openings indicated that the proposed method is able to estimate stomata morphological features with accuracies of 89.03% for area, 94.06% for major axis length, 93.31% for minor axis length and 99.43% for eccentricity. Conclusions: The proposed fully automated solution for stomata detection and measurement is able to produce results far superior to existing automatic and semi-automatic methods. This method not only produces a low number of false positives in the stomata detection stage, it can also accurately estimate the pore dimensions of partially incomplete stomata images. In addition, it can process thousands of stomata in minutes, eliminating the need for researchers to manually measure stomata, thereby accelerating the process of analysing plant health. PMID- 29151842 TI - A "Do-It-Yourself" phenotyping system: measuring growth and morphology throughout the diel cycle in rosette shaped plants. AB - Background: Improvements in high-throughput phenotyping technologies are rapidly expanding the scope and capacity of plant biology studies to measure growth traits. Nevertheless, the costs of commercial phenotyping equipment and infrastructure remain prohibitively expensive for wide-scale uptake, while academic solutions can require significant local expertise. Here we present a low cost methodology for plant biologists to build their own phenotyping system for quantifying growth rates and phenotypic characteristics of Arabidopsis thaliana rosettes throughout the diel cycle. Results: We constructed an image capture system consisting of a near infra-red (NIR, 940 nm) LED panel with a mounted Raspberry Pi NoIR camera and developed a MatLab-based software module (iDIEL Plant) to characterise rosette expansion. Our software was able to accurately segment and characterise multiple rosettes within an image, regardless of plant arrangement or genotype, and batch process image sets. To further validate our system, wild-type Arabidopsis plants (Col-0) and two mutant lines with reduced Rubisco contents, pale leaves and slow growth phenotypes (1a3b and 1a2b) were grown on a single plant tray. Plants were imaged from 9 to 24 days after germination every 20 min throughout the 24 h light-dark growth cycle (i.e. the diel cycle). The resulting dataset provided a dynamic and uninterrupted characterisation of differences in rosette growth and expansion rates over time for the three lines tested. Conclusion: Our methodology offers a straightforward solution for setting up automated, scalable and low-cost phenotyping facilities in a wide range of lab environments that could greatly increase the processing power and scalability of Arabidopsis soil growth experiments. PMID- 29151843 TI - Acquiring and preprocessing leaf images for automated plant identification: understanding the tradeoff between effort and information gain. AB - Background: Automated species identification is a long term research subject. Contrary to flowers and fruits, leaves are available throughout most of the year. Offering margin and texture to characterize a species, they are the most studied organ for automated identification. Substantially matured machine learning techniques generate the need for more training data (aka leaf images). Researchers as well as enthusiasts miss guidance on how to acquire suitable training images in an efficient way. Methods: In this paper, we systematically study nine image types and three preprocessing strategies. Image types vary in terms of in-situ image recording conditions: perspective, illumination, and background, while the preprocessing strategies compare non-preprocessed, cropped, and segmented images to each other. Per image type-preprocessing combination, we also quantify the manual effort required for their implementation. We extract image features using a convolutional neural network, classify species using the resulting feature vectors and discuss classification accuracy in relation to the required effort per combination. Results: The most effective, non-destructive way to record herbaceous leaves is to take an image of the leaf's top side. We yield the highest classification accuracy using destructive back light images, i.e., holding the plucked leaf against the sky for image acquisition. Cropping the image to the leaf's boundary substantially improves accuracy, while precise segmentation yields similar accuracy at a substantially higher effort. The permanent use or disuse of a flash light has negligible effects. Imaging the typically stronger textured backside of a leaf does not result in higher accuracy, but notably increases the acquisition cost. Conclusions: In conclusion, the way in which leaf images are acquired and preprocessed does have a substantial effect on the accuracy of the classifier trained on them. For the first time, this study provides a systematic guideline allowing researchers to spend available acquisition resources wisely while yielding the optimal classification accuracy. PMID- 29151844 TI - PYM: a new, affordable, image-based method using a Raspberry Pi to phenotype plant leaf area in a wide diversity of environments. AB - Background: Plant science uses increasing amounts of phenotypic data to unravel the complex interactions between biological systems and their variable environments. Originally, phenotyping approaches were limited by manual, often destructive operations, causing large errors. Plant imaging emerged as a viable alternative allowing non-invasive and automated data acquisition. Several procedures based on image analysis were developed to monitor leaf growth as a major phenotyping target. However, in most proposals, a time-consuming parameterization of the analysis pipeline is required to handle variable conditions between images, particularly in the field due to unstable light and interferences with soil surface or weeds. To cope with these difficulties, we developed a low-cost, 2D imaging method, hereafter called PYM. The method is based on plant leaf ability to absorb blue light while reflecting infrared wavelengths. PYM consists of a Raspberry Pi computer equipped with an infrared camera and a blue filter and is associated with scripts that compute projected leaf area. This new method was tested on diverse species placed in contrasting conditions. Application to field conditions was evaluated on lettuces grown under photovoltaic panels. The objective was to look for possible acclimation of leaf expansion under photovoltaic panels to optimise the use of solar radiation per unit soil area. Results: The new PYM device proved to be efficient and accurate for screening leaf area of various species in wide ranges of environments. In the most challenging conditions that we tested, error on plant leaf area was reduced to 5% using PYM compared to 100% when using a recently published method. A high throughput phenotyping cart, holding 6 chained PYM devices, was designed to capture up to 2000 pictures of field-grown lettuce plants in less than 2 h. Automated analysis of image stacks of individual plants over their growth cycles revealed unexpected differences in leaf expansion rate between lettuces rows depending on their position below or between the photovoltaic panels. Conclusions: The imaging device described here has several benefits, such as affordability, low cost, reliability and flexibility for online analysis and storage. It should be easily appropriated and customized to meet the needs of various users. PMID- 29151845 TI - Measuring the compressive modulus of elasticity of pith-filled plant stems. AB - Background: The compressional modulus of elasticity is an important mechanical property for understanding stalk lodging, but this property is rarely available for thin-walled plant stems such as maize and sorghum because excised tissue samples from these plants are highly susceptible to buckling. The purpose of this study was to develop a testing protocol that provides accurate and reliable measurements of the compressive modulus of elasticity of the rind of pith-filled plant stems. The general approach was to relying upon standard methods and practices as much as possible, while developing new techniques as necessary. Results: Two methods were developed for measuring the compressional modulus of elasticity of pith-filled node-node specimens. Both methods had an average repeatability of +/- 4%. The use of natural plant morphology and architecture was used to avoid buckling failure. Both methods relied up on spherical compression platens to accommodate inaccuracies in sample preparation. The effect of sample position within the test fixture was quantified to ensure that sample placement did not introduce systematic errors. Conclusions: Reliable measurements of the compressive modulus of elasticity of pith-filled plant stems can be performed using the testing protocols presented in this study. Recommendations for future studies were also provided. PMID- 29151846 TI - Examining ethnic disparities in provider and parent in-session participation engagement. AB - Purpose: Well-documented ethnic disparities exist in the identification and provision of quality services among children receiving community-based mental health services. These disparities extend to parent treatment engagement, an important component of effective mental health services. Currently, little is known about differences in how providers support parents' participation in treatment and the degree to which parents actively participate in it. The purpose of this paper is to examine potential differences in both provider and parent in session participation behaviours. Design/methodology/approach: Participants included 17 providers providing standard community-based mental health treatment for 18 parent-child dyads, with 44 per cent of the dyads self-identifying as Hispanic/Latino. In-session participation was measured with the parent participation engagement in child psychotherapy and therapist alliance, collaboration, and empowerment strategies observational coding systems. Findings: Overall, results indicate significantly lower levels of parent participation behaviours among Hispanic/Latino families compared to their Non-Hispanic/Non Latino counterparts. No significant differences were seen in providers' in session behaviours to support parent participation across Hispanic/Latino and Non Hispanic/Non-Latino families. Research limitations/implications: These findings contribute to the literature on ethnic differences in parent treatment engagement by utilising measures of in-session provider and parent behaviours and suggest that further investigation is warranted to documenting and understanding ethnic disparities in parents' participation in community-based child mental health treatment. Originality/value: This paper contributes to the evaluation of differences in parent treatment engagement through demonstrating the utility of an in-session observational coding system as a measure of treatment engagement. PMID- 29151847 TI - Pediatric Traumatic Brain Injury: a 5-year descriptive study from the National Trauma Center in Qatar. AB - Background: The epidemiologic characteristics and outcomes of pediatric traumatic brain injury (pTBI) have not been adequately documented from the rapidly developing countries in the Arab Middle East. We aimed to describe the hospital based epidemiologic characteristics, injury mechanisms, clinical presentation, and outcomes of pTBI and analyze key characteristics and determinant of pTBI that could help to make recommendations for policies to improve their care. Methods: We conducted a retrospective observational study in a level 1 trauma center (2010 2014) for all pTBI patients. Data were analyzed and compared according to different patient age groups. Results: Out of 945 traumatic brain injury patients, 167 (17.7%) were <= 18 years old with a mean age of 10.6 +/- 5.9 and 81% were males. The rate of pTBI varied from 5 to 14 cases per 100,000 children per year. The most affected group was teenagers (15-18 years; 40%) followed by infants/toddlers (<= 4 years; 23%). Motor vehicle crash (MVC; 47.3%) was the most frequent mechanism of injury followed by falls (21.6%). MVC accounted for a high proportion of pTBI among teenagers (77.3%) and adolescents (10-14 years; 48.3%). Fall was a common cause of pTBI for infants/toddlers (51.3%) and 5-9 years old group (30.3%). The proportion of brain contusion was significantly higher in adolescents (61.5%) and teenagers (58.6%). Teenagers had higher mean Injury Severity Scoring of 24.2 +/- 9.8 and lower median (range) Glasgow Coma Scale of 3 (3-15) (P = 0.001 for all). The median ventilatory days and intensive care unit and hospital length of stay were significantly prolonged in the teenage group. Also, pTBI in teenage group showed higher association with pneumonia (46.4%) and sepsis (17.3%) than other age groups (P = 0.01). The overall mortality rate was 13% (n = 22); 11 died within the first 24 h, 7 died between the second and seventh day and 4 died one week post-admission. Among MVC victims, a decreasing trend of case fatality rate (CFR) was observed with age; teenagers had the highest CFR (85.7) followed by adolescents (75.0), young children (33.3), and infants/toddlers (12.5). Conclusions: This local experience to describe the burden of pTBI could be a basis to adopt and form an efficient, tailored strategy for safety in the pediatric population. PMID- 29151849 TI - The Stony Brook Temperament Study: Early Antecedents and Pathways to Emotional Disorders. AB - In this article, we summarize findings from the Stony Brook Temperament Study, which seeks to elucidate the early antecedents and pathways to later depressive and anxiety disorders. The study focuses on parents' internalizing disorders and children's early temperament as distal risk factors that operate, in part, through biobehavioral reward and threat systems. We summarize findings linking parents' emotional disorders and observations of children's early temperament to subsequent neural measures of children's affective processing. Next, we review findings showing that children's temperament and affective processing predict subsequent depression and anxiety. We also show that many of these associations are moderated by environmental factors, such as parenting and stress. Finally, we relate our findings to literature on the relationships of early temperament and affective processing to anxiety and depression in youth. PMID- 29151850 TI - Relationships between catastrophic thought, bodily sensations and physical symptoms. AB - Background: Researchers have recently begun to seek cognitive explanations for physical symptoms with no obvious biological cause. Concepts such as somatization, somatosensory amplification, and somatosensory catastrophizing have been invoked to explain these phenomena. Somatosensory amplification occurs when these bodily sensations become stronger and more painful. Somatosensory catastrophizing is the tendency to attribute these bodily sensations to unbearable functional modulation or as signs of serious illness. This causes the sufferer to pay excessive attention to these physical sensations. However, there is no scale for evaluating somatosensory catastrophizing, and there are no standard diagnostic criteria. There were two objectives for this study: to develop a scale for evaluating somatosensory catastrophizing and to investigate relationships between somatosensory amplification, somatosensory catastrophizing, and physical symptoms. Methods: In the first part of this study, in which we developed the scale, there were 231 student participants with an average age of 20.1 years. Of these, 57% of the participants were female. In the second part of the study, there were two groups of participants. The first group consisted of 158 non-patient subjects, 56% of whom were female, with an average age of 20.2 years. There were 33 outpatients receiving treatment for somatoform disorders in the second group. The average age of these participants, of whom 67% were female, was 48.8 years. The second part of the study was conducted using standardized self-rating questionnaires to assess somatosensory amplification and catastrophizing. Results: We developed a 27-item scale, which we have called the Somatosensory catastrophizing scale (SSCS). The SSCS assesses five key areas, and our analysis confirmed it to be valid and highly reliable. The scale identified that the patient group from the second part of the study scored more highly than the control group for both somatosensory amplification and catastrophizing. Additionally, the results of covariance structure analyses revealed a significant causal relationship of the form "somatosensory amplifcation" via "somatosensory catastrophizing" to "physical symptoms". This relationship held in both groups of participants. The key difference between the patient and non-patient groups was that somatosensory catastrophizing had a greater impact on the physical symptoms of the participants in the patient group. Conclusions: In this study, we developed the SSCS, which enables us to measure somatosensory catastrophizing empirically. We then clarified the relationship between somatosensory amplification, somatosensory catastrophizing, and physical symptoms. In the future, we expect to be able to apply our new understanding to developing intervention techniques to mitigate the physical symptoms caused by somatosensory catastrophizing. PMID- 29151848 TI - Developing and validating of Ramathibodi Appendicitis Score (RAMA-AS) for diagnosis of appendicitis in suspected appendicitis patients. AB - Background: Diagnosis of appendicitis is still clinically challenging where resources are limited. The purpose of this study was to develop and externally validate Ramathibodi Appendicitis Score (RAMA-AS) in aiding diagnosis of appendicitis. Methods: A two-phase cross-sectional study (i.e., derivation and validation) was conducted at Ramathibodi Hospital (for derivation) and at Thammasat University Hospital and Chaiyaphum Hospital (for validation). Patients with abdominal pain and suspected of having appendicitis were enrolled. Multiple logistic regression was applied to develop a parsimonious model. Calibration and discrimination performances were assessed. In addition, our RAMA-AS was compared with Alvarado's score performances using ROC curve analysis. Results: The RAMA-AS consisted of three domains with seven predictors including symptoms (i.e., progression of pain, aggravation of pain, and migration of pain), signs (i.e., fever and rebound tenderness), and laboratory tests (i.e., white blood cell count (WBC) and neutrophil). The model fitted well with data, and it performed better discrimination than the Alvarado score with C-statistics of 0.842 (95% CI 0.804, 0.881) versus 0.760 (0.710, 0.810). Internal validation by bootstrap yielded Sommer's D of 0.686 (0.608, 0.763) and C-statistics of 0.848 (0.846, 0.849). The C-statistics of two external validations were 0.853 (0.791, 0.915) and 0.813 (0.736, 0.892) with fair calibrations. Conclusion: RAMA-AS should be a useful tool for aiding diagnosis of appendicitis with good calibration and discrimination performances. PMID- 29151851 TI - Participation in mental healthcare: a qualitative meta-synthesis. AB - Background: Facilitation of service user participation in the co-production of mental healthcare planning and service delivery is an integral component of contemporary mental health policy and clinical guidelines. However, many service users continue to experience exclusion from the planning of their care. This review synthesizes qualitative research about participation in mental healthcare and articulates essential processes that enable service user participation in mental health care. Methods: Electronic databases were systematically searched. Studies were included if they were peer reviewed qualitative studies, published between 2000 and 2015, examining participation in mental health care. The Critical Appraisal Skills Program checklist was used to assess the quality of each included study. Constant comparison was used to identify similar constructs across several studies, which were then abstracted into thematic constructs. Results: The synthesis resulted in the identification of six principal themes, which articulate key processes that facilitate service user participation in mental healthcare. These themes included: exercising influence; tokenism; sharing knowledge; lacking capacity; respect; and empathy. Conclusions: This meta synthesis demonstrates that service user participation in mental healthcare remains a policy aspiration, which generally has not been translated into clinical practice. The continued lack of impact on policy on the delivery of mental healthcare suggests that change may have to be community driven. Systemic service user advocacy groups could contribute critically to promoting authentic service user participation in the co-production of mental health services. PMID- 29151852 TI - Ancient oncogenesis, infection and human evolution. AB - The recent discovery that malignant neoplastic lesions date back nearly 2 million years ago not only highlights the antiquity of cancer in the human lineage, but also provides remarkable insight into ancestral hominin disease pathology. Using these Early Pleistocene examples as a point of departure, we emphasize the prominent role of viral and bacterial pathogens in oncogenesis and evaluate the impact of pathogens on human evolutionary processes in Africa. In the Shakespearean vernacular "what's past is prologue," we highlight the significance of novel information derived from ancient pathogenic DNA. In particular, and given the temporal depth of human occupation in sub-Saharan Africa, it is emphasized that the region is ideally positioned to play a strategic role in the discovery of ancient pathogenic drivers of not only human mortality, but also human evolution. Ancient African pathogen genome data can provide novel revelations concerning human-pathogen coevolutionary processes, and such knowledge is essential for forecasting the ways in which emerging zoonotic and increasingly transmissible diseases might influence human demography and longevity in the future. PMID- 29151853 TI - In situ conservation-harnessing natural and human-derived evolutionary forces to ensure future crop adaptation. AB - Ensuring the availability of the broadest possible germplasm base for agriculture in the face of increasingly uncertain and variable patterns of biotic and abiotic change is fundamental for the world's future food supply. While ex situ conservation plays a major role in the conservation and availability of crop germplasm, it may be insufficient to ensure this. In situ conservation aims to maintain target species and the collective genotypes they represent under evolution. A major rationale for this view is based on the likelihood that continued exposure to changing selective forces will generate and favor new genetic variation and an increased likelihood that rare alleles that may be of value to future agriculture are maintained. However, the evidence that underpins this key rationale remains fragmented and has not been examined systematically, thereby decreasing the perceived value and support for in situ conservation for agriculture and food systems and limiting the conservation options available. This study reviews evidence regarding the likelihood and rate of evolutionary change in both biotic and abiotic traits for crops and their wild relatives, placing these processes in a realistic context in which smallholder farming operates and crop wild relatives continue to exist. It identifies areas of research that would contribute to a deeper understanding of these processes as the basis for making them more useful for future crop adaptation. PMID- 29151854 TI - Strong population structure deduced from genetics, otolith chemistry and parasite abundances explains vulnerability to localized fishery collapse in a large Sciaenid fish, Protonibea diacanthus. AB - As pressure on coastal marine resources is increasing globally, the need to quantitatively assess vulnerable fish stocks is crucial in order to avoid the ecological consequences of stock depletions. Species of Sciaenidae (croakers, drums) are important components of tropical and temperate fisheries and are especially vulnerable to exploitation. The black-spotted croaker, Protonibea diacanthus, is the only large sciaenid in coastal waters of northern Australia where it is targeted by commercial, recreational and indigenous fishers due to its food value and predictable aggregating behaviour. Localized declines in the abundance of this species have been observed, highlighting the urgent requirement by managers for information on fine- and broad-scale population connectivity. This study examined the population structure of P. diacanthus across north western Australia using three complementary methods: genetic variation in microsatellite markers, otolith elemental composition and parasite assemblage composition. The genetic analyses demonstrated that there were at least five genetically distinct populations across the study region, with gene flow most likely restricted by inshore biogeographic barriers such as the Dampier Peninsula. The otolith chemistry and parasite analyses also revealed strong spatial variation among locations within broad-scale regions, suggesting fine scale location fidelity within the lifetimes of individual fish. The complementarity of the three techniques elucidated patterns of connectivity over a range of spatial and temporal scales. We conclude that fisheries stock assessments and management are required at fine scales (100 s of km) to account for the restricted exchange among populations (stocks) and to prevent localized extirpations of this species. Realistic management arrangements may involve the successive closure and opening of fishing areas to reduce fishing pressure. PMID- 29151855 TI - Toward a mechanistic understanding of vulnerability to hook-and-line fishing: Boldness as the basic target of angling-induced selection. AB - In passively operated fishing gear, boldness-related behaviors should fundamentally affect the vulnerability of individual fish and thus be under fisheries selection. To test this hypothesis, we used juvenile common-garden reared carp (Cyprinus carpio) within a narrow size range to investigate the mechanistic basis of behavioral selection caused by angling. We focused on one key personality trait (i.e., boldness), measured in groups within ponds, two morphological traits (body shape and head shape), and one life-history trait (juvenile growth capacity) and studied mean standardized selection gradients caused by angling. Carp behavior was highly repeatable within ponds. In the short term, over seven days of fishing, total length, not boldness, was the main predictor of angling vulnerability. However, after 20 days of fishing, boldness turned out to be the main trait under selection, followed by juvenile growth rate, while morphological traits were only weakly related to angling vulnerability. In addition, we found juvenile growth rate to be moderately correlated with boldness. Hence, direct selection on boldness will also induce indirect selection on juvenile growth and vice versa, but given that the two traits are not perfectly correlated, independent evolution of both traits is also possible. Our study is among the first to mechanistically reveal that energy acquisition-related behaviors, and not growth rate per se, are key factors determining the probability of capture, and hence, behavioral traits appear to be the prime targets of angling selection. We predict an evolutionary response toward increased shyness in intensively angling-exploited fish stocks, possibly causing the emergence of a timidity syndrome. PMID- 29151856 TI - A pedigree-based experiment reveals variation in salinity and thermal tolerance in the salmon louse, Lepeophtheirus salmonis. AB - The salmon louse is a highly abundant ectoparasitic copepod of salmonids in the North Pacific and Atlantic. Widespread and rapid development of resistance to chemical agents used to delouse salmonids on marine farms is now threatening the continued development of the aquaculture industry and have served as a potent catalyst for the development of alternative pest management strategies. These include freshwater and warm-water treatments to which the louse is sensitive. However, given the well-documented evolutionary capacity of this species, the risk of developing tolerance towards these environmental treatments cannot be dismissed. Two common-garden experiments were performed using full-sibling families of lice identified by DNA parentage testing to investigate whether one of the fundamental premises for evolution, in this context genetic variation in the capacity of coping with fresh or warm water, exists within this species. Significant differences in survival were observed among families in both experiments, although for the salinity experiment, it was not possible to unequivocally disentangle background mortality from treatment-induced mortality. Thus, our data demonstrate genetic variation in tolerance of warm water and are suggestive of genetic variation in salinity tolerance. We conclude that extensive use of these environmental-based treatments to delouse salmonids on commercial farms may drive lice towards increased tolerance. PMID- 29151857 TI - Directional selection to improve the sterile insect technique: Survival and sexual performance of desiccation resistant Anastrepha ludens strains. AB - The sterile insect technique (SIT) is an effective, environmentally friendly method for insect control whose success depends on the sexual performance and survival of sterile males. These two parameters are influenced by environmental conditions of target areas, and releasing insects with a higher tolerance to stressful environments can improve SIT efficiency. Directional selection can be used to produce insect strains with higher tolerance to extreme environmental conditions, such as low humidity, for extended periods. We evaluated, under field cage conditions, the sexual competitiveness, sexual compatibility, and survival of strains of Anastrepha ludens (Loew) selected for desiccation resistance to determine the value of directional selection as a possible approach to enhance SIT efficiency. Fly strains (selected and unselected and those mass-reared) were exposed to stressful conditions of low humidity and food and water deprivation for 24 hr before test. As a control, mild conditions without the stressors were used. No differences in sexual competitiveness and sexual compatibility between selected, nonselected, and mass-reared strains were observed when previously exposed to mild conditions. Thus, selection for desiccation resistance does not modified negatively the sexual performance. However, when insects were exposed to stressful conditions, males of selected strains sexually outperform mass-reared males. Additionally, selected strains presented higher survival than mass-reared flies. The approach to integrate directional selection with other technologies in the SIT as well as the implications of using a desiccation-selected strain in the current pest management program is discussed. PMID- 29151858 TI - Effective population sizes of a major vector of human diseases, Aedes aegypti. AB - The effective population size (Ne ) is a fundamental parameter in population genetics that determines the relative strength of selection and random genetic drift, the effect of migration, levels of inbreeding, and linkage disequilibrium. In many cases where it has been estimated in animals, Ne is on the order of 10% 20% of the census size. In this study, we use 12 microsatellite markers and 14,888 single nucleotide polymorphisms (SNPs) to empirically estimate Ne in Aedes aegypti, the major vector of yellow fever, dengue, chikungunya, and Zika viruses. We used the method of temporal sampling to estimate Ne on a global dataset made up of 46 samples of Ae. aegypti that included multiple time points from 17 widely distributed geographic localities. Our Ne estimates for Ae. aegypti fell within a broad range (~25-3,000) and averaged between 400 and 600 across all localities and time points sampled. Adult census size (Nc) estimates for this species range between one and five thousand, so the Ne /Nc ratio is about the same as for most animals. These Ne values are lower than estimates available for other insects and have important implications for the design of genetic control strategies to reduce the impact of this species of mosquito on human health. PMID- 29151859 TI - Population genetic structure and connectivity of deep-sea stony corals (Order Scleractinia) in the New Zealand region: Implications for the conservation and management of vulnerable marine ecosystems. AB - Deep-sea stony corals, which can be fragile, long-lived, late to mature and habitat-forming, are defined as vulnerable marine ecosystem indicator taxa. Under United Nations resolutions, these corals require protection from human disturbance such as fishing. To better understand the vulnerability of stony corals (Goniocorella dumosa, Madrepora oculata, Solenosmilia variabilis) to disturbance within the New Zealand region and to guide marine protected area design, genetic structure and connectivity were determined using microsatellite loci and DNA sequencing. Analyses compared population genetic differentiation between two biogeographic provinces, amongst three subregions (north-central south) and amongst geomorphic features. Extensive population genetic differentiation was revealed by microsatellite variation, whilst DNA sequencing revealed very little differentiation. For G. dumosa, genetic differentiation existed amongst regions and geomorphic features, but not between provinces. For M. oculata, only a north-central-south regional structure was observed. For S. variabilis, genetic differentiation was observed between provinces, amongst regions and amongst geomorphic features. Populations on the Kermadec Ridge were genetically different from Chatham Rise populations for all three species. A significant isolation-by-depth pattern was observed for both marker types in G. dumosa and also in ITS of M. oculata. An isolation-by-distance pattern was revealed for microsatellite variation in S. variabilis. Medium to high levels of self-recruitment were detected in all geomorphic populations, and rates and routes of genetic connectivity were species-specific. These patterns of population genetic structure and connectivity at a range of spatial scales indicate that flexible spatial management approaches are required for the conservation of deep-sea corals around New Zealand. PMID- 29151860 TI - Dose-dependent selection drives lineage replacement during the experimental evolution of SDHI fungicide resistance in Zymoseptoria tritici. AB - Fungicide resistance is a constant threat to agricultural production worldwide. Molecular mechanisms of fungicide resistance have been studied extensively in the wheat pathogen Zymoseptoria tritici. However, less is known about the evolutionary processes driving resistance development. In vitro evolutionary studies give the opportunity to investigate this. Here, we examine the adaptation of Z. tritici to fluxapyroxad, a succinate dehydrogenase (Sdh) inhibitor. Replicate populations of Z. tritici derived from the sensitive isolate IPO323 were exposed to increasing concentrations of fluxapyroxad with or without UV mutagenesis. After ten increases in fungicide concentration, sensitivity had decreased dramatically, with replicate populations showing similar phenotypic trajectories. Sequencing the Sdh subunit B, C, and D encoding genes identified seven mutations associated with resistance to fluxapyroxad. Mutation frequency over time was measured with a pyrosequencing assay, revealing sequential lineage replacement in the UV-mutagenized populations but not in the untreated populations. Repeating selection from set time-points with different fungicide concentrations revealed that haplotype replacement of Sdh variants was driven by dose-dependent selection as fungicide concentration changed, and was not mutation limited. These findings suggest that fungicide field applications may select for highly insensitive Sdh variants with higher resistance factors if the fungicide concentration is increased to achieve a better disease control. However, in the absence or presence of lower fungicide concentrations, the spread of these strains might be restricted if the underlying Sdh mutations carry fitness penalties. PMID- 29151861 TI - Microgeographic differentiation in thermal performance curves between rural and urban populations of an aquatic insect. AB - The rapidly increasing rate of urbanization has a major impact on the ecology and evolution of species. While increased temperatures are a key aspect of urbanization ("urban heat islands"), we have very limited knowledge whether this generates differentiation in thermal responses between rural and urban populations. In a common garden experiment, we compared the thermal performance curves (TPCs) for growth rate and mortality in larvae of the damselfly Coenagrion puella from three urban and three rural populations. TPCs for growth rate shifted vertically, consistent with the faster-slower theoretical model whereby the cold adapted rural larvae grew faster than the warm-adapted urban larvae across temperatures. In line with costs of rapid growth, rural larvae showed lower survival than urban larvae across temperatures. The relatively lower temperatures hence expected shorter growing seasons in rural populations compared to the populations in the urban heat islands likely impose stronger time constraints to reach a certain developmental stage before winter, thereby selecting for faster growth rates. In addition, higher predation rates at higher temperature may have contributed to the growth rate differences between urban and rural ponds. A faster-slower differentiation in TPCs may be a widespread pattern along the urbanization gradient. The observed microgeographic differentiation in TPCs supports the view that urbanization may drive life-history evolution. Moreover, because of the urban heat island effect, urban environments have the potential to aid in developing predictions on the impact of climate change on rural populations. PMID- 29151862 TI - Profiling the immunome of little brown myotis provides a yardstick for measuring the genetic response to white-nose syndrome. AB - White-nose syndrome (WNS) has devastated populations of hibernating bats in eastern North America, leading to emergency conservation listings for several species including the previously ubiquitous little brown myotis (Myotis lucifugus). However, some bat populations near the epicenter of the WNS panzootic appear to be stabilizing after initial precipitous declines, which could reflect a selective immunogenetic sweep. To investigate the hypothesis that WNS exerts significant selection on the immunome of affected bat populations, we developed a novel, high-throughput sequence capture assay targeting 138 adaptive, intrinsic, and innate immunity genes of putative adaptive significance, as well as their respective regulatory regions (~370 kbp of genomic sequence/individual). We used the assay to explore baseline immunogenetic variation in M. lucifugus and to investigate whether particular immune genes/variants are associated with WNS susceptibility. We also used our assay to detect 1,038 putatively neutral single nucleotide polymorphisms and characterize contemporary population structure, providing context for the identification of local immunogenetic adaptation. Sequence capture provided a cost-effective, "all-in-one" assay to test for neutral genetic and immunogenetic structure and revealed fine-scale, baseline immunogenetic differentiation between sampling sites <600 km apart. We identified functional immunogenetic variants in M. lucifugus associated with WNS susceptibility. This study lays the foundations for future investigations of rangewide immunogenetic adaptation to WNS in M. lucifugus and provides a blueprint for studies of evolutionary rescue in other host-pathogen systems. PMID- 29151863 TI - A phylogenomic analysis of Marek's disease virus reveals independent paths to virulence in Eurasia and North America. AB - Virulence determines the impact a pathogen has on the fitness of its host, yet current understanding of the evolutionary origins and causes of virulence of many pathogens is surprisingly incomplete. Here, we explore the evolution of Marek's disease virus (MDV), a herpesvirus commonly afflicting chickens and rarely other avian species. The history of MDV in the 20th century represents an important case study in the evolution of virulence. The severity of MDV infection in chickens has been rising steadily since the adoption of intensive farming techniques and vaccination programs in the 1950s and 1970s, respectively. It has remained uncertain, however, which of these factors is causally more responsible for the observed increase in virulence of circulating viruses. We conducted a phylogenomic study to understand the evolution of MDV in the context of dramatic changes to poultry farming and disease control. Our analysis reveals evidence of geographical structuring of MDV strains, with reconstructions supporting the emergence of virulent viruses independently in North America and Eurasia. Of note, the emergence of virulent viruses appears to coincide approximately with the introduction of comprehensive vaccination on both continents. The time-dated phylogeny also indicated that MDV has a mean evolutionary rate of ~1.6 * 10-5 substitutions per site per year. An examination of gene-linked mutations did not identify a strong association between mutational variation and virulence phenotypes, indicating that MDV may evolve readily and rapidly under strong selective pressures and that multiple genotypic pathways may underlie virulence adaptation in MDV. PMID- 29151865 TI - Effect of cell cycle duration on somatic evolutionary dynamics. AB - Cellular checkpoints prevent damage and mutation accumulation in tissue cells. DNA repair is one mechanism that can be triggered by checkpoints and involves temporary cell cycle arrest and thus delayed reproduction. Repair-deficient cells avoid this delay, which has been argued to lead to a selective advantage in the presence of frequent damage. We investigate this hypothesis with stochastic modeling, using mathematical analysis and agent-based computations. We first model competition between two cell types: a cell population that enters temporary cell cycle arrest, corresponding to repair (referred to as arresting cells), and one that does not enter arrest (referred to as nonarresting cells). Although nonarresting cells are predicted to grow with a faster rate than arresting cells in isolation, this does not translate into a selective advantage in the model. Interestingly, the evolutionary properties of the nonarresting cells depend on the measure (or observable) of interest. When examining the average populations sizes in competition simulations, nonarresting and arresting cells display neutral dynamics. The fixation probability of nonarresting mutants, however, is lower than predicted for a neutral scenario, suggesting a selective disadvantage in this setting. For nonarresting cells to gain a selective advantage, additional mechanisms must be invoked in the model, such as small, repeated phases of tissue damage, each resulting in a brief period of regenerative growth. The same properties are observed in a more complex model where it is explicitly assumed that repair and temporary cell cycle arrest are dependent on the cell having sustained DNA damage, the rate of which can be varied. We conclude that repair deficient cells are not automatically advantageous in the presence of frequent DNA damage and that mechanisms beyond avoidance of cell cycle delay must be invoked to explain their emergence. PMID- 29151864 TI - Dissecting functional components of reproductive isolation among closely related sympatric species of the Anopheles gambiae complex. AB - Explaining how and why reproductive isolation evolves and determining which forms of reproductive isolation have the largest impact on the process of population divergence are major goals in the study of speciation. By studying recent adaptive radiations in incompletely isolated taxa, it is possible to identify barriers involved at early divergence before other confounding barriers emerge after speciation is complete. Sibling species of the Anopheles gambiae complex offer opportunities to provide insights into speciation mechanisms. Here, we studied patterns of reproductive isolation among three taxa, Anopheles coluzzii, An. gambiae s.s. and Anopheles arabiensis, to compare its strength at different spatial scales, to dissect the relative contribution of pre- versus postmating isolation, and to infer the involvement of ecological divergence on hybridization. Because F1 hybrids are viable, fertile and not uncommon, understanding the dynamics of hybridization in this trio of major malaria vectors has important implications for how adaptations arise and spread across the group, and in planning studies of the safety and efficacy of gene drive as a means of malaria control. We first performed a systematic review and meta-analysis of published surveys reporting on hybrid prevalence, showing strong reproductive isolation at a continental scale despite geographically restricted exceptions. Second, we exploited our own extensive field data sets collected at a regional scale in two contrasting environmental settings, to assess: (i) levels of premating isolation; (ii) spatio/temporal and frequency-dependent dynamics of hybridization, (iii) relationship between reproductive isolation and ecological divergence and (iv) hybrid viability penalty. Results are in accordance with ecological speciation theory predicting a positive association between the strength of reproductive isolation and degree of ecological divergence, and indicate that postmating isolation does contribute to reproductive isolation among these species. Specifically, only postmating isolation was positively associated with ecological divergence, whereas premating isolation was correlated with phylogenetic distance. PMID- 29151866 TI - Amphibian species traits, evolutionary history and environment predict Batrachochytrium dendrobatidis infection patterns, but not extinction risk. AB - The fungal pathogen Batrachochytrium dendrobatidis (B. dendrobatidis) has emerged as a major agent of amphibian extinction, requiring conservation intervention for many susceptible species. Identifying susceptible species is challenging, but many aspects of species biology are predicted to influence the evolution of host resistance, tolerance, or avoidance strategies towards disease. In turn, we may expect species exhibiting these distinct strategies to differ in their ability to survive epizootic disease outbreaks. Here, we test for phylogenetic and trait based patterns of B. dendrobatidis infection risk and infection intensity among 302 amphibian species by compiling a global data set of B. dendrobatidis infection surveys across 95 sites. We then use best-fit models that associate traits, taxonomy and environment with B. dendrobatidis infection risk and intensity to predict host disease mitigation strategies (tolerance, resistance, avoidance) for 122 Neotropical amphibian species that experienced epizootic B. dendrobatidis outbreaks, and noted species persistence or extinction from these events. Aspects of amphibian species life history, habitat use and climatic niche were consistently linked to variation in B. dendrobatidis infection patterns across sites around the world. However, predicted B. dendrobatidis infection risk and intensity based on site environment and species traits did not reveal a consistent pattern between the predicted host disease mitigation strategy and extinction outcome. This suggests that either tolerant or resistant species may have no advantage in ameliorating disease during epizootic events, or that other factors drive the persistence of amphibian populations during chytridiomycosis outbreaks. These results suggest that using a trait-based approach may allow us to identify species with resistance or tolerance to endemic B. dendrobatidis infections, but that this approach may be insufficient to ultimately identify species at risk of extinction from epizootics. PMID- 29151867 TI - Evolutionary toxicology: Toward a unified understanding of life's response to toxic chemicals. PMID- 29151868 TI - Evolutionary toxicology in an omics world. AB - Evolutionary toxicology is a young field that has grown rapidly in the past two decades. The potential of this field comes from the ability to link chemical contamination to multigenerational and population-wide effects in various species. The advancements and rapidly decreasing costs of -omic tools are improving the power and resolution of evolutionary toxicology studies. In this manuscript, we aim to address the trajectories and perspectives for conducting evolutionary toxicology studies with -omic approaches. We discuss the complementarity of using multiple -omic tools (genomics, eDNA, transcriptomics, proteomics, and metabolomics) for utility in understanding the toxicological relevance of adaptive responses in populations. In addition, we discuss phenotypic plasticity and its relevance to transcriptomic studies in toxicology. As evolutionary toxicology grows and expands its capacity to link toxicology with population-wide end points, we emphasize the applications of such studies in answering questions about ecological and population health, as well as future applicability to regulation. Thus, we aim to emphasize the enormous potential for evolutionary toxicology in an -omics world and give perspectives on the directions of future investigations. PMID- 29151870 TI - Elevated mitochondrial genome variation after 50 generations of radiation exposure in a wild rodent. AB - Currently, the effects of chronic, continuous low dose environmental irradiation on the mitochondrial genome of resident small mammals are unknown. Using the bank vole (Myodes glareolus) as a model system, we tested the hypothesis that approximately 50 generations of exposure to the Chernobyl environment has significantly altered genetic diversity of the mitochondrial genome. Using deep sequencing, we compared mitochondrial genomes from 131 individuals from reference sites with radioactive contamination comparable to that present in northern Ukraine before the 26 April 1986 meltdown, to populations where substantial fallout was deposited following the nuclear accident. Population genetic variables revealed significant differences among populations from contaminated and uncontaminated localities. Therefore, we rejected the null hypothesis of no significant genetic effect from 50 generations of exposure to the environment created by the Chernobyl meltdown. Samples from contaminated localities exhibited significantly higher numbers of haplotypes and polymorphic loci, elevated genetic diversity, and a significantly higher average number of substitutions per site across mitochondrial gene regions. Observed genetic variation was dominated by synonymous mutations, which may indicate a history of purify selection against nonsynonymous or insertion/deletion mutations. These significant differences were not attributable to sample size artifacts. The observed increase in mitochondrial genomic diversity in voles from radioactive sites is consistent with the possibility that chronic, continuous irradiation resulting from the Chernobyl disaster has produced an accelerated mutation rate in this species over the last 25 years. Our results, being the first to demonstrate this phenomenon in a wild mammalian species, are important for understanding genetic consequences of exposure to low-dose radiation sources. PMID- 29151871 TI - Genetic and epigenetic variation in Spartina alterniflora following the Deepwater Horizon oil spill. AB - Catastrophic events offer unique opportunities to study rapid population response to stress in natural settings. In concert with genetic variation, epigenetic mechanisms may allow populations to persist through severe environmental challenges. In 2010, the Deepwater Horizon oil spill devastated large portions of the coastline along the Gulf of Mexico. However, the foundational salt marsh grass, Spartina alterniflora, showed high resilience to this strong environmental disturbance. Following the spill, we simultaneously examined the genetic and epigenetic structure of recovering populations of S. alterniflora to oil exposure. We quantified genetic and DNA methylation variation using amplified fragment length polymorphism and methylation sensitive fragment length polymorphism (MS-AFLP) to test the hypothesis that response to oil exposure in S. alterniflora resulted in genetically and epigenetically based population differentiation. We found high genetic and epigenetic variation within and among sites and found significant genetic differentiation between contaminated and uncontaminated sites, which may reflect nonrandom mortality in response to oil exposure. Additionally, despite a lack of genomewide patterns in DNA methylation between contaminated and uncontaminated sites, we found five MS-AFLP loci (12% of polymorphic MS-AFLP loci) that were correlated with oil exposure. Overall, our findings support genetically based differentiation correlated with exposure to the oil spill in this system, but also suggest a potential role for epigenetic mechanisms in population differentiation. PMID- 29151872 TI - Evolved pesticide tolerance influences susceptibility to parasites in amphibians. AB - Because ecosystems throughout the globe are contaminated with pesticides, there is a need to understand how natural populations cope with pesticides and the implications for ecological interactions. From an evolutionary perspective, there is evidence that pesticide tolerance can be achieved via two mechanisms: selection for constitutive tolerance over multiple generations or by inducing tolerance within a single generation via phenotypic plasticity. While both mechanisms can allow organisms to persist in contaminated environments, they might result in different performance trade-offs including population susceptibility to parasites. We have identified 15 wood frog populations that exist along a gradient from close to agriculture and high, constitutive pesticide tolerance to far from agriculture and inducible pesticide tolerance. Using these populations, we investigated the relationship between evolutionary responses to the common insecticide carbaryl and host susceptibility to the trematode Echinoparyphium lineage 3 and ranavirus using laboratory exposure assays. For Echinoparyphium, we discovered that wood frog populations living closer to agriculture with high, constitutive tolerance experienced lower loads than populations living far from agriculture with inducible pesticide tolerance. For ranavirus, we found no relationship between the mechanism of evolved pesticide tolerance and survival, but populations living closer to agriculture with high, constitutive tolerance experienced higher viral loads than populations far from agriculture with inducible tolerance. Land use and mechanisms of evolved pesticide tolerance were associated with susceptibility to parasites, but the direction of the relationship is dependent on the type of parasite, underscoring the complexity between land use and disease outcomes. Collectively, our results demonstrate that evolved pesticide tolerance can indirectly influence host parasite interactions and underscores the importance of including evolutionary processes in ecotoxicological studies. PMID- 29151873 TI - Evolutionary responses to crude oil from the Deepwater Horizon oil spill by the copepod Eurytemora affinis. AB - The BP Deepwater Horizon Oil Disaster was the most catastrophic offshore oil spill in U.S. history, yet we still have a poor understanding of how organisms could evolve in response to the toxic effects of crude oil. This study offers a rare analysis of how fitness-related traits could evolve rapidly in response to crude oil toxicity. We examined evolutionary responses of populations of the common copepod Eurytemora affinis residing in the Gulf of Mexico, by comparing crude oil tolerance of populations collected before versus after the Deepwater Horizon oil spill of 2010. In addition, we imposed laboratory selection for crude oil tolerance for ~8 generations, using an E. affinis population collected from before the oil spill. We found evolutionary increases in crude oil tolerance in the wild population following the oil spill, relative to the population collected before the oil spill. The post-oil spill population showed increased survival and rapid development time in the presence of crude oil. In contrast, evolutionary responses following laboratory selection were less clear; though, development time from metamorphosis to adult in the presence of crude oil did become more rapid after selection. We did find that the wild population, used in both experiments, harbored significant genetic variation in crude oil tolerance, upon which selection could act. Thus, our study indicated that crude oil tolerance could evolve, but perhaps not on the relatively short time scale of the laboratory selection experiment. This study contributes novel insights into evolutionary responses to crude oil, in directly examining fitness-related traits before and after an oil spill, and in observing evolutionary responses following laboratory selection. PMID- 29151869 TI - When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations. AB - For most species, evolutionary adaptation is not expected to be sufficiently rapid to buffer the effects of human-mediated environmental changes, including environmental pollution. Here we review how key features of populations, the characteristics of environmental pollution, and the genetic architecture underlying adaptive traits, may interact to shape the likelihood of evolutionary rescue from pollution. Large populations of Atlantic killifish (Fundulus heteroclitus) persist in some of the most contaminated estuaries of the United States, and killifish studies have provided some of the first insights into the types of genomic changes that enable rapid evolutionary rescue from complexly degraded environments. We describe how selection by industrial pollutants and other stressors has acted on multiple populations of killifish and posit that extreme nucleotide diversity uniquely positions this species for successful evolutionary adaptation. Mechanistic studies have identified some of the genetic underpinnings of adaptation to a well-studied class of toxic pollutants; however, multiple genetic regions under selection in wild populations seem to reflect more complex responses to diverse native stressors and/or compensatory responses to primary adaptation. The discovery of these pollution-adapted killifish populations suggests that the evolutionary influence of anthropogenic stressors as selective agents occurs widely. Yet adaptation to chemical pollution in terrestrial and aquatic vertebrate wildlife may rarely be a successful "solution to pollution" because potentially adaptive phenotypes may be complex and incur fitness costs, and therefore be unlikely to evolve quickly enough, especially in species with small population sizes. PMID- 29151874 TI - Incorporating evolutionary insights to improve ecotoxicology for freshwater species. AB - Ecotoxicological studies have provided extensive insights into the lethal and sublethal effects of environmental contaminants. These insights are critical for environmental regulatory frameworks, which rely on knowledge of toxicity for developing policies to manage contaminants. While varied approaches have been applied to ecotoxicological questions, perspectives related to the evolutionary history of focal species or populations have received little consideration. Here, we evaluate chloride toxicity from the perspectives of both macroevolution and contemporary evolution. First, by mapping chloride toxicity values derived from the literature onto a phylogeny of macroinvertebrates, fish, and amphibians, we tested whether macroevolutionary relationships across species and taxa are predictive of chloride tolerance. Next, we conducted chloride exposure tests for two amphibian species to assess whether potential contemporary evolutionary change associated with environmental chloride contamination influences chloride tolerance across local populations. We show that explicitly evaluating both macroevolution and contemporary evolution can provide important and even qualitatively different insights from those obtained via traditional ecotoxicological studies. While macroevolutionary perspectives can help forecast toxicological end points for species with untested sensitivities, contemporary evolutionary perspectives demonstrate the need to consider the environmental context of exposed populations when measuring toxicity. Accounting for divergence among populations of interest can provide more accurate and relevant information related to the sensitivity of populations that may be evolving in response to selection from contaminant exposure. Our data show that approaches accounting for and specifically examining variation among natural populations should become standard practice in ecotoxicology. PMID- 29151876 TI - 'Comment on Saumitou et al. (2017): Elucidation of the genetic architecture of self-incompatibility in olive: evolutionary consequences and perspectives for orchard management'. AB - The new self-incompatibility system (SI) was presented by Saumitou-Laprade, Vernet, Vekemans et al. (2017). Evolutionary Applications based on 89 crosses between varieties in the olive tree. Four main points are not clear. We are examining here as follows: (i) the assertion that the self-incompatibility system is sporophytic was not sustained by pollen germination data; (ii) surprisingly, the new model does not explain that about one-third of pairwise combinations of olive varieties leads to asymmetric fruit setting; (iii) DNA preparation from one seed may contain two embryos, and thus, embryos should be separated before seed extraction; (iv) although effective self-fertility in olive varieties was reported by many studies, the DSI model fails to explain self-fertility in some olive varieties. Moreover, we cannot discuss result data, as science cannot be verified because variety names were encoded, this does not allow comparison of data with previous works. The DSI model on olive self-incompatibility should explain more features than the model based on four dominance levels shared by six S-alleles. Perspectives for orchard management based on this model may face serious limitations. An olive variety does not have a fifty percent chance of cross-incompatibility, but surely fewer, and thus, the sporophytic system limits fruit production. Evolutionary perspectives of self-incompatibility in Oleaceae should include data from the Jasmineae tribe that displays heterostyly SI. PMID- 29151875 TI - Adaptation costs to constant and alternating polluted environments. AB - Some populations quickly adapt to strong and novel selection pressures caused by anthropogenic stressors. However, this short-term evolutionary response to novel and harsh environmental conditions may lead to adaptation costs, and evaluating these costs is important if we want to understand the evolution of resistance to anthropogenic stressors. In this experimental evolution study, we exposed Caenorhabditis elegans populations to uranium (U populations), salt (NaCl populations) and alternating uranium/salt treatments (U/NaCl populations) and to a control environment (C populations), over 22 generations. In parallel, we ran common-garden and reciprocal-transplant experiments to assess the adaptive costs for populations that have evolved in the different environmental conditions. Our results showed rapid evolutionary changes in life history characteristics of populations exposed to the different pollution regimes. Furthermore, adaptive costs depended on the type of pollutant: pollution-adapted populations had lower fitness than C populations, when the populations were returned to their original environment. Fitness in uranium environments was lower for NaCl populations than for U populations. In contrast, fitness in salt environments was similar between U and NaCl populations. Moreover, fitness of U/NaCl populations showed similar or higher fitness in both the uranium and the salt environments compared to populations adapted to constant uranium or salt environments. Our results show that adaptive evolution to a particular stressor can lead to either adaptive costs or benefits once in contact with another stressor. Furthermore, we did not find any evidence that adaptation to alternating stressors was associated with additional adaption costs. This study highlights the need to incorporate adaptive cost assessments when undertaking ecological risk assessments of pollutants. PMID- 29151877 TI - Controlling for genetic identity of varieties, pollen contamination and stigma receptivity is essential to characterize the self-incompatibility system of Olea europaea L. AB - Berville et al. express concern about the existence of the diallelic self incompatibility (DSI) system in Olea europaea, mainly because our model does not account for results from previous studies from their group that claimed to have documented asymmetry of the incompatibility response in reciprocal crosses. In this answer to their comment, we present original results based on reciprocal stigma tests that contradict conclusions from these studies. We show that, in our hands, not a single case of asymmetry was confirmed, endorsing that symmetry of incompatibility reactions seems to be the rule in Olive. We discuss three important aspects that were not taken into account in the studies cited in their comments and that can explain the discrepancy: (i) the vast uncertainty around the actual genetic identity of vernacular varieties, (ii) the risk of massive contamination associated with the pollination protocols that they used and (iii) the importance of checking for stigma receptivity in controlled crosses. These studies were thus poorly genetically controlled, and we stand by our original conclusion that Olive tree exhibits DSI. PMID- 29151878 TI - Elucidation of the genetic architecture of self-incompatibility in olive: Evolutionary consequences and perspectives for orchard management. AB - The olive (Olea europaea L.) is a typical important perennial crop species for which the genetic determination and even functionality of self-incompatibility (SI) are still largely unresolved. It is still not known whether SI is under gametophytic or sporophytic genetic control, yet fruit production in orchards depends critically on successful ovule fertilization. We studied the genetic determination of SI in olive in light of recent discoveries in other genera of the Oleaceae family. Using intra- and interspecific stigma tests on 89 genotypes representative of species-wide olive diversity and the compatibility/incompatibility reactions of progeny plants from controlled crosses, we confirmed that O. europaea shares the same homomorphic diallelic self incompatibility (DSI) system as the one recently identified in Phillyrea angustifolia and Fraxinus ornus. SI is sporophytic in olive. The incompatibility response differs between the two SI groups in terms of how far pollen tubes grow before growth is arrested within stigma tissues. As a consequence of this DSI system, the chance of cross-incompatibility between pairs of varieties in an orchard is high (50%) and fruit production may be limited by the availability of compatible pollen. The discovery of the DSI system in O. europaea will undoubtedly offer opportunities to optimize fruit production. PMID- 29151879 TI - Parallel evolution of behaviour during independent host-shifts following maize introduction into Asia and Europe. AB - Maize was introduced into opposite sides of Eurasia 500 years ago, in Western Europe and in Asia. This caused two host-shifts in the phytophagous genus Ostrinia; O. nubilalis (the European corn borer; ECB) and O. furnacalis (the Asian corn borer; ACB) are now major pests of maize worldwide. They originated independently from Dicot-feeding ancestors, similar to O. scapulalis (the Adzuki bean borer; ABB). Unlike other host-plants, maize is yearly harvested, and harvesting practices impose severe mortality on larvae found above the cut-off line. Positive geotaxis in the ECB has been proposed as a behavioural adaptation to harvesting practices, allowing larvae to move below the cut-off line and thus escape harvest mortality. Here, we test whether the same behavioural adaptation evolved independently in Europe and in Asia. We sampled eight genetically differentiated ECB, ACB and ABB populations in France and China and monitored geotaxis through the entire larval development in artificial stacks mimicking maize stems. We find that all ECB and ACB populations show a similar tendency to move down during the latest larval stages, a behaviour not observed in any European or Asian ABB population. The behaviour is robustly expressed regardless of larval density, development mode or environmental conditions. Our results indicate that maize introduction triggered parallel behavioural adaptations in Europe and Asia, harvest selection presumably being the main driver. PMID- 29151880 TI - Invest more and die faster: The life history of a parasite on intensive farms. AB - Organisms are expected to respond to alterations in their survival by evolutionary changes in their life history traits. As agriculture and aquaculture have become increasingly intensive in the past decades, there has been growing interest in their evolutionary effects on the life histories of agri- and aquacultural pests, parasites, and pathogens. In this study, we used salmon lice (Lepeophtheirus salmonis) to explore how modern farming might have affected life history evolution in parasites. We infected salmon hosts with lice from either farmed or unfarmed locations, and monitored life history traits of those parasites in laboratory conditions. Our results show that compared to salmon lice from areas unaffected by salmon farming, those from farmed areas produced more eggs in their first clutch, and less eggs later on; they achieved higher infestation intensities in early adulthood, but suffered higher adult mortality. These results suggest that salmon lice on farms may have been selected for increased investment in early reproduction, at the expense of later fecundity and survival. This call for further empirical studies of the extent to which farming practices may alter the virulence of agricultural parasites. PMID- 29151881 TI - Genomic insights into adaptive divergence and speciation among malaria vectors of the Anopheles nili group. AB - Ongoing speciation in the most important African malaria vectors gives rise to cryptic populations, which differ remarkably in their behavior, ecology, and capacity to vector malaria parasites. Understanding the population structure and the drivers of genetic differentiation among mosquitoes is crucial for effective disease control because heterogeneity within vector species contributes to variability in malaria cases and allow fractions of populations to escape control efforts. To examine population structure and the potential impacts of recent large-scale control interventions, we have investigated the genomic patterns of differentiation in mosquitoes belonging to the Anopheles nili group-a large taxonomic group that diverged ~3 Myr ago. Using 4,343 single nucleotide polymorphisms (SNPs), we detected strong population structure characterized by high-FST values between multiple divergent populations adapted to different habitats within the Central African rainforest. Delineating the cryptic species within the Anopheles nili group is challenging due to incongruence between morphology, ribosomal DNA, and SNP markers consistent with incomplete lineage sorting and/or interspecific gene flow. A very high proportion of loci are fixed (FST = 1) within the genome of putative species, which suggests that ecological and/or reproductive barriers are maintained by strong selection on a substantial number of genes. PMID- 29151882 TI - Progression of phosphine resistance in susceptible Tribolium castaneum (Herbst) populations under different immigration regimes and selection pressures. AB - Insecticide resistance is an escalating global issue for a wide variety of agriculturally important pests. The genetic basis and biochemical mechanisms of resistance are well characterized in some systems, but little is known about the ecological aspects of insecticide resistance. We therefore designed a laboratory experiment to quantify the progression of phosphine resistance in Tribolium castaneum populations subject to different immigration regimes and selection pressures. Mated resistant females were added to originally susceptible populations under two distinct migration rates, and in addition, half of the populations in each migration treatment were exposed to selection pressures from phosphine fumigation. The progression of phosphine resistance was assessed by screening beetles for the resistance allele at rph2. Phosphine resistance increased slowly in the low migration treatment and in the absence of selection, as expected. But at the higher migration rate, the increase in frequency of the resistance allele was lower than predicted. These outcomes result from the high levels of polyandry known in T. castaneum females in the laboratory, because most of the Generation 1 offspring (86%) were heterozygous for the rph2 allele, probably because resistant immigrant females mated again on arrival. Phosphine resistance was not fixed by fumigation as predicted, perhaps because susceptible gametes and eggs survived fumigation within resistant females. In terms of phosphine resistance progression in populations exposed to selection, the effect of fumigation negated the difference in migration rates. These results demonstrate how species-specific traits relating to the mating system may shape the progression of insecticide resistance within populations, and they have broad implications for the management of phosphine resistance in T. castaneum in the field. We specify and discuss how these mating system attributes need to be accounted for when developing guidelines for resistance management. PMID- 29151883 TI - Speciation history of a species complex of Primulina eburnea (Gesneriaceae) from limestone karsts of southern China, a biodiversity hot spot. AB - Limestone karsts in southern China are characterized by high edaphic and topographic heterogeneity and host high levels of species richness and endemism. However, the evolutionary mechanisms for generating such biodiversity remain poorly understood. Here, we performed species delimitation, population genetic analyses, simulations of gene flow and analyses of floral morphological traits to infer the geographic history of speciation in a species complex of Primulina eburnea from limestone karsts of southern China. Using Bayesian species delimitation, we determined that there are seven distinct species that correspond well to the putative morphological species. Species tree reconstruction, Structure and Neighbor-Net analyses all recovered four lineages in agreement with currently species geographic boundaries. High levels of genetic differentiation were observed both within and among species. Isolation-migration coalescent analysis provides evidence for significant but low gene flow among species. Approximate Bayesian computation (ABC) analysis supports a scenario of historical gene flow rather than recent contemporary gene flow for most species divergences. Finally, we found no evidence of divergent selection contributing to population differentiation of a suite of flower traits. These results support the prevalence of allopatric speciation and highlight the role of geographic isolation in the diversification process. At small geographic scales, limited hybridization occurred in the past between proximate populations but did not eliminate species boundaries. We conclude that limited gene flow might have been the predominant evolutionary force in promoting population differentiation and speciation. PMID- 29151884 TI - A critical assessment of estimating census population size from genetic population size (or vice versa) in three fishes. AB - Technological and methodological advances have facilitated the use of genetic data to infer census population size (Nc) in natural populations, particularly where traditional mark-and-recapture is challenging. The effective number of breeders (Nb) describes how many adults effectively contribute to a cohort and is often correlated with Nc. Predicting Nc from Nb or vice versa in species with overlapping generations has important implications for conservation by permitting (i) estimation of the more difficult to quantify variable and (ii) inferences of Nb/Nc relationships in related species lacking data. We quantitatively synthesized Nb/Nc relationships in three salmonid fishes where sufficient data have recently accumulated. Mixed-effects models were analysed in which each variable was included as a dependent variable or predictor term (Nb from Nc and vice versa). Species-dependent Nb/Nc slope estimates were significantly positive in two of three species. Variation in species slopes was likely due to varying life histories and reinforce caution when inferring Nb/Nc from taxonomically related species. Models provided maximum probable estimates for Nb and Nc for two species. However, study, population and year effects explained substantial amounts of variation (39%-57%). Consequently, prediction intervals were wide and included or were close to zero for all population sizes and species; model predictive utility was limited. Cost-benefit trade-offs when estimating Nb and/or Nc were also discussed using a real-world system example. Our findings based on salmonids suggest that no short cuts currently exist when estimating population size and researchers should focus on quantifying the variable of interest or be aware of caveats when inferring the desired variable because of cost or logistics. We caution that the salmonid species examined share life-history traits that may obscure relationships between Nb and Nc. Sufficient data on other taxa were unavailable; additional research examining Nb/Nc relationships in species with potentially relevant life-history trait differences (e.g., differing survival curves) is needed. PMID- 29151885 TI - Treatment of old landfill leachate with high ammonium content using aerobic granular sludge. AB - Background: Aerobic granular sludge has become an attractive alternative to the conventional activated sludge due to its high settling velocity, compact structure, and higher tolerance to toxic substances and adverse conditions. Aerobic granular sludge process has been studied intensively in the treatment of municipal and industrial wastewater. However, information on leachate treatment using aerobic granular sludge is very limited. Methods: This study investigated the treatment performance of old landfill leachate with different levels of ammonium using two aerobic sequencing batch reactors (SBR): an activated sludge SBR (ASBR) and a granular sludge SBR (GSBR). Aerobic granules were successfully developed using old leachate with low ammonium concentration (136 mg L-1 NH4+-N). Results: The GSBR obtained a stable chemical oxygen demand (COD) removal of 70% after 15 days of operation; while the ASBR required a start-up of at least 30 days and obtained unstable COD removal varying from 38 to 70%. Ammonium concentration was gradually increased in both reactors. Increasing influent ammonium concentration to 225 mg L-1 N, the GSBR removed 73 +/- 8% of COD; while COD removal of the ASBR was 59 +/- 9%. The GSBR was also more efficient than the ASBR for nitrogen removal. The granular sludge could adapt to the increasing concentrations of ammonium, achieving 95 +/- 7% removal efficiency at a maximum influent concentration of 465 mg L-1 N. Ammonium removal of 96 +/- 5% was obtained by the ASBR when it was fed with a maximum of 217 mg L-1 NH4+-N. However, the ASBR was partially inhibited by free-ammonia and nitrite accumulation rate increased up to 85%. Free-nitrous acid and the low biodegradability of organic carbon were likely the main factors affecting phosphorus removal. Conclusion: The results from this research suggested that aerobic granular sludge have advantage over activated sludge in leachate treatment. PMID- 29151886 TI - Optogenetic regulation of artificial microRNA improves H2 production in green alga Chlamydomonas reinhardtii. AB - Background: Chlamydomonas reinhardtii is an ideal model organism not only for the study of basic metabolic processes in both plants and animals but also the production of biofuels including hydrogen. Transgenic analysis of C. reinhardtii is now well established and very convenient, but inducible exogenous gene expression systems remain under-studied. The most commonly used heat shock inducible system has serious effects on algal cell growth and is difficult and costly to control in large-scale culture. Previous studies of hydrogen photoproduction in Chlamydomonas also use this heat-inducible system to activate target gene transcription and hydrogen synthesis. Results: Here we describe a blue light-inducible system with which we achieved optogenetic regulation of target gene expression in C. reinhardtii. This light-inducible system was engineered in a photosynthetic organism for the first time. The photo-inducible heterodimerizing proteins CRY2 and CIB1 were fused to VP16 transcription activation domain and the GAL4 DNA-binding domain, respectively. This scheme allows for transcription activation of the target gene downstream of the activation sequence in response to blue light. Using this system, we successfully engineered blue light-inducible hydrogen-producing transgenic alga. The transgenic alga was cultured under red light and grew approximately normally until logarithmic phase. When illuminated with blue light, the transgenic alga expressed the artificial miRNA targeting photosynthetic system D1 protein, and altered hydrogen production was observed. Conclusions: The light-inducible system successfully activated the artificial miRNA and, consequently, regulation of its target gene under blue light. Moreover, hydrogen production was enhanced using this system, indicating a more convenient and efficient approach for gene expression regulation in large-scale microalgae cultivation. This optogenetic gene control system is a useful tool for gene regulation and also establishes a novel way to improve hydrogen production in green algae. PMID- 29151887 TI - An accurate description of Aspergillus niger organic acid batch fermentation through dynamic metabolic modelling. AB - Background: Aspergillus niger fermentation has provided the chief source of industrial citric acid for over 50 years. Traditional strain development of this organism was achieved through random mutagenesis, but advances in genomics have enabled the development of genome-scale metabolic modelling that can be used to make predictive improvements in fermentation performance. The parent citric acid producing strain of A. niger, ATCC 1015, has been described previously by a genome-scale metabolic model that encapsulates its response to ambient pH. Here, we report the development of a novel double optimisation modelling approach that generates time-dependent citric acid fermentation using dynamic flux balance analysis. Results: The output from this model shows a good match with empirical fermentation data. Our studies suggest that citric acid production commences upon a switch to phosphate-limited growth and this is validated by fitting to empirical data, which confirms the diauxic growth behaviour and the role of phosphate storage as polyphosphate. Conclusions: The calibrated time-course model reflects observed metabolic events and generates reliable in silico data for industrially relevant fermentative time series, and for the behaviour of engineered strains suggesting that our approach can be used as a powerful tool for predictive metabolic engineering. PMID- 29151888 TI - Enhancing biogas plant production using pig manure and corn silage by adding wheat straw processed with liquid hot water and steam explosion. AB - Background: Pig manure utilization and valorization is an important topic with tightening regulations focused on ecological and safety issues. By itself pig manure is a poor substrate for biogas production because of its excessive nitrogen content relative to available organic carbon. Such substrate is alkaline, and methanogenesis can be suppressed, and so additional substrates with high organic carbon must be added. The most promising is straw, which is available from adjacent biogas plant cultures. However, the abundant lignocellulosic biomass of wheat straw undergoes slow decomposition, and only a fraction of the chemical energy can be converted into biogas; thus economical methods for pretreatment increasing bioavailability are sought. Results: A method was investigated to increase the methane yield in a full-scale plant for co fermenting pig manure with corn silage, which was the default substrate in the original source reactors. Increased lignocellulosic bioavailability of wheat straw was achieved by combining liquid hot water (LHW) and steam explosion (SE). According to FT-IR analysis, the treatment resulted in hemicellulose hydrolysis, partial cellulose depolymerization, and lignin bond destruction. Low-mass polysaccharides (0.6 * 103 g mol-1) had significantly higher concentration in the leachate of LHW-SE wheat straw than raw wheat straw. The methanogenic potential was evaluated using inoculum from two different biogas plants to study the influence of microorganism consortia. The yield was 24-34% higher after the pretreatment process. In a full-scale biogas plant, the optimal conditions were ~ 165 degrees C, ~ 2.33 MPa, and 10 min in LHW and ~ 65 degrees C and ~ 0.1 MPa for SE. The processes did not generate detectable inhibitors according to GC-MS analysis, such as furfural and 5-hydroxymethylfurfural. Conclusions: The LHW-SE combined pretreatment process increases the bioavailability of carbohydrates from wheat straw. The LHW-SE treated wheat straw gave similar biogas yields to corn silage, thus enables at least partial replacement of corn silage and is good for diversification of substrates. Surprisingly, microorganisms consortia from other biogas plant fed with other substrates may have higher efficiency in utilization of tested substrate. Thus, methanogenic consortia may be considered in the process of optimization at industrial scale. The efficiency was calculated, and the LHW-SE may be profitable at full industrial scale and further optimization is proposed. PMID- 29151889 TI - Cell growth and lipid accumulation of a microalgal mutant Scenedesmus sp. Z-4 by combining light/dark cycle with temperature variation. AB - Background: The light/dark cycle is one of the most important factors affecting the microalgal growth and lipid accumulation. Biomass concentration and lipid productivity could be enhanced by optimization of light/dark cycles, and this is considered an effective control strategy for microalgal cultivation. Currently, most research on effects of light/dark cycles on algae is carried out under autotrophic conditions and little information is about the effects under mixotrophic cultivation. At the same time, many studies related to mixotrophic cultivation of microalgal strains, even at large scale, have been performed to obtain satisfactory biomass and lipid production. Therefore, it is necessary to investigate cellular metabolism under autotrophic and mixotrophic conditions at different light/dark cycles. Even though microalgal lipid production under optimal environmental factors has been reported by some researchers, the light/dark cycle and temperature are regarded as separate parameters in their studies. In practical cases, light/dark cycling and temperature variation during the day occur simultaneously. Therefore, studies about the combined effects of light/dark cycles and temperature variation on microalgal lipid production are of practical value, potentially providing significant guidelines for large-scale microalgal cultivation under natural conditions. Results: In this work, cell growth and lipid accumulation of an oleaginous microalgal mutant, Scenedesmus sp. Z-4, were investigated at five light/dark cycles (0 h/24 h, 8 h/16 h, 12 h/12 h, 16 h/8 h, and 24 h/0 h) in batch culture. The results showed that the optimal light/dark cycle was 12 h/12 h, when maximum lipid productivity rates of 56.8 and 182.6 mg L-1 day-1 were obtained under autotrophic and mixotrophic cultivation, respectively. Poor microalgal growth and lipid accumulation appeared in the light/dark cycles of 0 h/24 h and 24 h/0 h under autotrophic condition. Prolonging the light duration was unfavorable to the production of chlorophyll a and b, which was mainly due to photooxidation effect. Polysaccharide was converted into lipid and protein when the light irradiation time increased from 0 to 12 h; however, further increasing irradiation time had a negative effect on lipid accumulation. Due to the dependence of autotrophically cultured cells on light energy, the light/dark cycle has a more remarkable influence on cellular metabolism under autotrophic conditions. Furthermore, the combined effects of temperature variation and light/dark cycle of 12 h/12 h on cell growth and lipid accumulation of microalgal mutant Z-4 were investigated under mixotrophic cultivation, and the results showed that biomass was mainly produced at higher temperatures during the day, and a portion of biomass was converted into lipid under dark condition. Conclusions: The extension of irradiation time was beneficial to biomass accumulation, but not in favor of lipid production. Even though effects of light/dark cycles on autotrophic and mixotrophic cells were not exactly the same, the optimal lipid productivities of Scenedesmus sp. Z-4 under both cultivation conditions were achieved at the light/dark of 12 h/12 h. This may be attributed to its long-term acclimation in natural environment. By combining temperature variation with optimal light/dark cycle of 12 h/12 h, this study will be of great significance for practical microalgae-biodiesel production in the outdoor conditions. PMID- 29151890 TI - Techno-economic and resource analysis of hydroprocessed renewable jet fuel. AB - Background: Biomass-derived jet fuel is an alternative jet fuel (AJF) showing promise of reducing the dependence on fossil fuel and greenhouse gas emissions. Hydroprocessed esters and fatty acids (HEFA) concept is also known as one of the pathways for producing bio jet fuel. HEFA fuel was approved by the American Society for Testing and Materials in 2011, and can be blended up to 50% with conventional jet fuel. Since then, several HEFA economic and life-cycle assessments have been published in literature. However, there have been limited analyses on feedstock availability, composition, and their impact on hydrocarbon yield (particularly jet blendstock yield) and overall process economics. Results: This study examines over 20 oil feedstocks, their geographic distribution and production levels, oil yield, prices, and chemical composition. The results of our compositional analysis indicate that most oils contain mainly C16 and C18 fatty acids except pennycress, yellow grease, and mustard, which contain higher values and thus would require hydrocracking to improve jet fuel production. Coconut oil has a large content of shorter carbon fatty acids, making it a good feedstock candidate for renewable gasoline instead of jet substitutes' production. Techno-economic analysis (TEA) was performed for five selected oil feedstocks-camelina, pennycress, jatropha, castor bean, and yellow grease-using the HEFA process concept. Conclusion: The resource analysis indicates that oil crops currently grown in the United States (namely soybean) have relatively low oil yield when compared to oil crops grown in other parts of the world, such as palm, coconut, and jatropha. Also, non-terrestrial oil sources, such as animal fats and greases, have relatively lower prices than terrestrial oil crops. The minimum jet fuel selling price for these five resources ranges between $3.8 and $11.0 per gallon. The results of our TEA and resource studies indicate the key cost drivers for a biorefinery converting oil to jet hydrocarbons are as follows: oil price, conversion plant capacity, fatty acid profile, addition of hydrocracker, and type of hydroprocessing catalysts. PMID- 29151892 TI - Metrics to estimate differential co-expression networks. AB - Background: Detecting the differences in gene expression data is important for understanding the underlying molecular mechanisms. Although the differentially expressed genes are a large component, differences in correlation are becoming an interesting approach to achieving deeper insights. However, diverse metrics have been used to detect differential correlation, making selection and use of a single metric difficult. In addition, available implementations are metric specific, complicating their use in different contexts. Moreover, because the analyses in the literature have been performed on real data, there are uncertainties regarding the performance of metrics and procedures. Results: In this work, we compare four novel and two previously proposed metrics to detect differential correlations. We generated well-controlled datasets into which differences in correlations were carefully introduced by controlled multivariate normal correlation networks and addition of noise. The comparisons were performed on three datasets derived from real tumor data. Our results show that metrics differ in their detection performance and computational time. No single metric was the best in all datasets, but trends show that three metrics are highly correlated and are very good candidates for real data analysis. In contrast, other metrics proposed in the literature seem to show low performance and different detections. Overall, our results suggest that metrics that do not filter correlations perform better. We also show an additional analysis of TCGA breast cancer subtypes. Conclusions: We show a methodology to generate controlled datasets for the objective evaluation of differential correlation pipelines, and compare the performance of several metrics. We implemented in R a package called DifCoNet that can provide easy-to-use functions for differential correlation analyses. PMID- 29151891 TI - The exon junction complex factor Y14 is dynamic in the nucleus of the beetle Tribolium castaneum during late oogenesis. AB - Background: The oocyte chromosomes of the red flour beetle, Tribolium castaneum, are gathered into a knot, forming a karyosphere at the diplotene stage of meiotic prophase. Chromatin rearrangement, which is a characteristic feature of oocyte maturation, is well documented. The T. castaneum karyosphere is surrounded by a complex extrachromosomal structure termed the karyosphere capsule. The capsule contains the vast majority of oocyte RNA. We have previously shown using a BrUTP assay that oocyte chromosomes in T. castaneum maintain residual transcription up to the very end of oocyte maturation. Karyosphere transcription requires evidently not only transcription factors but also mRNA processing factors, including the components of the exon junction complex with its core component, the splicing factor Y14. We employed a gene engineering approach with injection of mRNA derived from the Myc-tagged Y14 plasmid-based construct in order to monitor the newly synthesized fusion protein in the oocyte nuclei. Results: Our preliminary data have been presented as a brief correspondence elsewhere. Here, we provide a full-length article including immunoelectron-microscopy localization data on Y14-Myc distribution in the nucleus of previtellogenic and vitellogenic oocytes. The injections of the fusion protein Y14-Myc mRNA into the oocytes showed a dynamic pattern of the protein distribution. At the previtellogenic stage, there are two main locations for the protein: SC35 domains (the analogues of interchromatin granule clusters or nuclear speckles) and the karyosphere capsule. At the vitellogenic stage, SC35 domains were devoid of labels, and Y14 Myc was found in the perichromatin region of the karyosphere, presumably at the places of residual transcription. We show that karyosphere formation is accompanied by the movement of a nuclear protein while the residual transcription occurs during genome inactivation. Conclusions: Our data indicate that the karyosphere capsule, being a destination site for a protein involved in mRNA splicing and export, is not only a specializes part of nuclear matrix separating the karyosphere from the products of chromosome activity, as believed previously, but represents a special nuclear compartment involved in the processes of gene expression in the case the karyosphere retains residual transcription activity. PMID- 29151893 TI - Defining the gap: a systematic review of the difference in rates of diabetes related foot complications in Aboriginal and Torres Strait Islander Australians and non-Indigenous Australians. AB - Background: The Aboriginal and Torres Strait Islander community has an increased risk of developing chronic illnesses including diabetes. Among people with diabetes, foot complications are common and make a significant contribution to the morbidity and mortality associated with this disease. The aim of this review was to systematically evaluate the literature comparing the rates of diabetes related foot complications in Aboriginal and Torres Strait Islander Australians to non-Indigenous Australians. Methods: MEDLINE, EMBASE, The Cochrane Library; PUBMED and CINAHL were searched from inception until August 2016. Inclusion criteria were: published cross-sectional or longitudinal studies reporting the prevalence of diabetes related foot complications in both a cohort of Aboriginal and Torres Strait Islander Australians and a cohort of one other Australian population of any age with diabetes. Risk of bias was assessed using the STROBE tool. Results: Eleven studies including a total of 157,892 participants were included. Studies were set in Queensland, the Northern Territory and Western Australia, primarily in rural and remote areas. Aboriginal and Torres Strait Islander Australians experienced substantially more diabetes related foot complications with the mean age up to 14 years younger than non-Indigenous Australians. Aboriginality was associated with increased risk of peripheral neuropathy, foot ulceration and amputation. In several studies, Aboriginal and Torres Strait Islander Australians accounted for the vast majority of diabetes related foot complications (up to 91%) while comprising only a small proportion of the regional population. Reporting quality as assessed with the STROBE tool showed underreporting of: methods, sample description and potential sources of bias. There are no data available for some Australian states and for specific types of diabetes related foot complications. Conclusions: Aboriginal and Torres Strait Islander Australians have a 3-6 fold increased likelihood of experiencing a diabetes related foot complication compared to non-Indigenous Australians. Evidence-based, culturally appropriate screening and intervention programs and improved access to effective health care services are required to prevent a widening of the gap in diabetes related foot complications between Aboriginal and Torres Strait Islander and non-Indigenous Australians. PMID- 29151894 TI - 'Fast cast' and 'needle Tenotomy' protocols with the Ponseti method to improve clubfoot management in Bangladesh. AB - Background: The management of congenital talipes equino varus (clubfoot deformity) has been transformed in the last 20 years as surgical correction has been replaced by the non-surgical Ponseti method. The Ponseti method, consists of corrective serial casting followed by maintenance bracing, and has been repeatedly demonstrated to give best results - regarded as the 'gold standard' treatment for paediatric clubfoot. Methods: To develop the study protocol Level 2 evidence was used to modify the corrective casting phase of the Ponseti method in children aged up to 12 months. Using Level 4 evidence, the percutaneous Achilles tenotomy (PAT) was performed using a 19-gauge needle instead of a scalpel blade, a technique found to reduce bleeding and scarring. Results: A total of 123 children participated in this study; 88 male, 35 female. Both feet were affected in 67 cases, left only in 22 cases, right only in 34 cases. Typical clubfeet were found in 112/123 cases, six atypical, five syndromic. The average age at first cast was 51 days (13-240 days).The average number of casts applied was five (2-10 casts). The average number of days between the first cast and brace was 37.8 days (10-122 days), including 21 days in a post-PAT cast. Hence, average time of corrective casts was 17 days.Parents preferred the reduced casting time, and were less concerned about unseen skin wounds.PAT was performed in 103/123 cases, using the needle technique. All post tenotomy casts were in situ for three weeks. Minor complications occurred in seven cases - four cases had skin lesions, three cases disrupted casting phase. At another site, 452 PAT were performed using the needle technique. Conclusions: The 'fast cast' protocol Ponseti casting was successfully used in infants aged less than 8 months. Extended manual manipulation of two minutes was the essential modification. Parents preferred the faster treatment phase, and ability to closer observe the foot and skin. The treating physiotherapists preferred the 'fast cast' protocol, achieving better correction with less complication. The needle technique for PAT is a further improvement for the Ponseti method. PMID- 29151895 TI - Toll-like receptor-4 differentially mediates intestinal and extra-intestinal immune responses upon multi-drug resistant Pseudomonas aeruginosa association of IL10-/- mice with chronic colitis. AB - Background: Infections with multi-drug resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (PA) have become a serious threat particularly in hospitalized patients with immunopathological co-morbidities. The well balanced interplay between immune cells, pattern recognition receptors such as Toll-like receptor (TLR)-4 sensing lipopolysaccharide from Gram-negative bacteria including PA, and evolving pathways is crucial to prevent the host from invading (opportunistic) pathogens. Information regarding the molecular mechanisms underlying the interactions between intestinal carriage of MDR PA and host immunity during chronic large intestinal inflammation is scarce, however. Methods and results: We therefore perorally challenged conventionally colonized TLR4 deficient IL10-/- mice and IL10-/- counterparts displaying comparably severe chronic colitis with a clinical MDR PA strain. PA could more sufficiently establish in the intestinal tract of TLR4-deficient IL10-/- mice until day 14 postinfection (p.i.), whereas within 48 h the majority of IL10-/- mice had already expelled the opportunistic pathogen from their guts. Intestinal colonization properties of PA in TLR4-deficient IL10-/- mice were associated with distinct genotype-dependent differences in gut microbiota compositions before challenge given that TLR4-deficient IL10-/- mice harbored more fecal enterobacteria and enterococci, but lower Clostridium/Eubacterium burdens. At day 14 p.i., PA-induced increases in colonic immune cells such as macrophages, monocytes and T-lymphocytes could be observed in TLR4-deficient IL10-/- mice, but not IL10-/- counterparts, that were accompanied by a more distinct secretion of IFN-gamma in the colon and TNF in the mesenteric lymph nodes (MLN) of the former as compared to the latter. Conversely, splenic TNF levels were lower in TLR4 deficient IL10-/- mice as compared to IL10-/- controls at day 14 p.i. Interestingly, more pronounced apoptotic responses could be assessed in colonic epithelia of PA-challenged IL10-/- mice only. This was paralleled by enhanced pro inflammatory cytokine secretion not only in the intestines, but also in extra intestinal compartments of IL10-/- mice as indicated by increased concentrations of nitric oxide in the colon, IFN-gamma in the MLN and IL-12p70 in the spleen at day 14 p.i. Conclusions: Under chronic intestinal inflammatory conditions including IL10-/- colitis MDR PA-association results in well-orchestrated TLR4 dependent immune responses both in intestinal and extra-intestinal compartments. Further studies should unravel the underlying molecular mechanisms in more detail. PMID- 29151897 TI - Community-acquired infection with hypervirulent Clostridium difficile isolates that carry different toxin and antibiotic resistance loci: a case report. AB - Background: Clostridium difficile infection (CDI) leads to the onset of antibiotic-associated diarrhea (AAD) and a wide range of gastrointestinal pathologies. Currently, CDI is one of the most important opportunistic infections at the intrahospital level and an exponential increase in community-acquired infections has been reported. Herein, we evaluated the relationships (at phylogenetic and genetic population structure levels), as well as the molecular toxigenic and antibiotic resistance profiles of a set of isolates established from a case of community acquired-CDI. Case presentation: A 30-year-old woman with no history of hospitalization who was exposed to antibiotics (ampicillin/sulbactam and metronidazole) after a cat-bite wound was presented. The patient had a continuous episode of diarrhea; a stool sample was then collected and community acquired-CDI was confirmed by molecular tests and in vitro culture. Seven isolates were established and subsequently subjected to: (i) Multilocus sequence typing, all isolates belonging to ST-1 (associated with hypervirulent strain (027/BI/NAP1); (ii) description of their toxigenic profile: two of the isolates (Gcol.49 and Gcol.91) were positive for the genes coding for the major toxins (tcdA and tcdB) and their negative regulator (tcdC). All isolates were positive for the cdtB gene encoding one of the binary toxin subunits, while only two (Gcol.51 and Gcol.52) were positive for cdtA; and (iii) identification of antibiotic resistance molecular markers, where there was no difference in gyrA or gyrB gene polymorphisms (related to quinolone resistance), but rather at loci presence/absence, being just one isolate negative, whereas the others showed a differential presence of the tet, ermB and Tn916 regions. The former was associated with resistance to tetracycline and the other two for erythromycin/clindamycin. Conclusions: This case represents the first report of community acquired-CDI in Colombia associated with hypervirulent strains and shows that isolates obtained from a single patient can carry different toxin and antibiotic resistance loci. PMID- 29151896 TI - Genotypic diversity, antimicrobial resistance and biofilm-forming abilities of Campylobacter isolated from chicken in Central China. AB - Background: Campylobacter is considered to be the leading cause of human bacterial gastroenteritis, of which poultry is the main reservoir. Campylobacter contaminated chicken products are a major cause of human Campylobacter infection. In this study, the prevalence of Campylobacter in chicken in central China was investigated, and the genotypic diversity, antimicrobial resistance and biofilm of these isolates were characterized. Results: A total of 206 Campylobacter isolates, including 166 C. jejuni and 40 C. coli, were isolated from chicken farms and live poultry markets in central China. Multilocus sequence typing and phylogenetic analysis showed that the Campylobacter isolates had diverse genetic backgrounds, which covered most of the dominant clone complexes (CCs) reported throughout China. The most prevalent CCs were CC-464, CC-1150, CC-353, and CC 828. All the isolates showed resistance to norfloxacin, ciprofloxacin and Cefazolin, and a prevalent resistance to fluoroquinolones, beta-lactams and tetracyclines was also observed. Among all the isolates, 133 strains showed the ability to form biofilm, thereinto, the isolates in two genetic branches, mainly including CC-21, CC-48, CC-677 and CC-45, showed a significantly lower ability to form biofilm than other genetic branches (p < 0.05). However, in general, the ability to form biofilm varied among different genetic branches, suggesting a complex genetic background to biofilm formation, but not only the genetic lineages. Compared with the strains unable to form biofilm, biofilm-producing strains possessed a significantly higher resistance to ampicillin, neomycin, sulfamethoxazole, amikacin, clindamycin and erythromycin (p < 0.05). Conclusions: To the best of our knowledge, this is the first report on the relationship of the genotypic diversity, antimicrobial resistance and biofilm-forming abilities of Campylobacter isolated from chicken in Central China, which showed the potential importance of biofilm in antimicrobial resistance. This study will help us better understand the epidemiology and antimicrobial resistance of Campylobacter. PMID- 29151898 TI - Validity of a continuous metabolic syndrome score as an index for modeling metabolic syndrome in children and adolescents: the CASPIAN-V study. AB - Background: The purpose of the present study was to assess the validity of continuous metabolic syndrome score (cMetS) for predicting metabolic syndrome (MetS) and to determine the cutoff values in a representative sample of Iranian children and adolescents. Methods: This national study was conducted among 3843 students, aged 7-18 years country during the fifth survey of a national school based surveillance program. The cMetS was computed by standardizing the residuals of waist circumference, mean arterial blood pressure, high-density lipoprotein cholesterol, triglycerides, and glucose by regressing them according to age and sex and aggregating them. The optimal cut-off points of cMetS for predicting MetS were determined by the receiver operation characteristic (ROC) curve analysis in different gender and age categories. Results: Totally, 3843 students (52.3% boys) with average age of 12.45 years were assessed. The mean of cMetS increased according to elevating the number of MetS components. The overall cMetS cut-off point was 1.76 (sensitivity 93% and specificity 82%) in total pediatrics. The area under the ROC curve was 94%. The values for boys and girls were 1.79 and 2.72, respectively. Conclusions: cMetS performed highly accurate in predicting pediatrics with MetS in all gender and age groups and it appears to be a valid index in children and adolescents. PMID- 29151899 TI - Globular domain structure and function of restriction-like-endonuclease LINEs: similarities to eukaryotic splicing factor Prp8. AB - Background: R2 elements are a clade of early branching Long Interspersed Elements (LINEs). LINEs are retrotransposable elements whose replication can have profound effects on the genomes in which they reside. No crystal or EM structures exist for the reverse transcriptase (RT) and linker regions of LINEs. Results: Using limited proteolysis as a probe for globular domain structure, we show that the protein encoded by the Bombyx mori R2 element has two major globular domains: (1) a small globular domain consisting of the N-terminal zinc finger and Myb motifs, and (2) a large globular domain consisting of the RT, linker, and type II restriction-like endonuclease (RLE). Further digestion of the large globular domain occurred within the RT. Mapping these RT cleavages onto an updated model of the R2Bm RT indicated that the thumb of the RT was largely protected from proteolytic cleavage. The crystal structure of the large globular domain of Prp8, a eukaryotic splicing factor, was a major template used in building the R2Bm RT model, particularly the thumb region. The large fragment of Prp8 consists not only of a RT similar to R2Bm, but also an RLE and a linker connecting the two regions. The linker sequences adjacent to the RLE in LINEs and Prp8 share a set of two important alpha-helices and a (presumptive) knuckle/betabetaalpha structural motif that are closely associated with the thumb. The RLEs of LINEs and Prp8 share a unique catalytic core residue spacing as well as other key residues. Conclusions: The protein encoded by RLE LINEs consists of two major globular domains. The larger of the two globular domain contains the RT, linker, and RLE and is similar to the large fragment of the spliceosomal protein Prp8. The similarities are suggestive of possible common ancestry. PMID- 29151900 TI - Examining Factors Associated With Nonadherence And Identifying Providers Caring For Nonadherent Subgroups. AB - Objectives: To examine racial/ethnic and regional differences in medication adherence in patients with diabetes taking oral anti-diabetic, anti-hypertensive, and cholesterol lowering medications and to identify the pharmacies and prescribers who serve these communities. Methods: Administrative claims data was analyzed for members enrolled in a large health plan in Hawaii (2008-2010) with diabetes mellitus who were taking three types of medications: 1) oral anti diabetic medications; 2) anti-hypertensive medications; 3) cholesterol lowering medications (n=5136). The primary outcome was medication adherence based on medication possession ratios. Multivariable logistic regression models were estimated to examine the association between race/ethnicity and region to adherence to each drug class separately, followed by non-adherence to all three. Covariates included age, gender, education level, chronic conditions, copayment level, and number of prescribers and pharmacies from which the patients received their medications. Key Findings: After adjustment for other factors, Filipinos [OR=0.58, 95%CI(0.45,0.74)], Native Hawaiians [OR=0.74, 95%CI(0.56,0.98)], and people of other race [OR=0.67, 95%CI(0.55,0.82)] were significantly less adherent to anti-diabetic and anti-hypertensive medications than Japanese. For cholesterol lowering medications, all racial and ethnic groups were significantly less adherent than Japanese, except mixed race. We also found that different racial/ethnic groups tended to use different pharmacies and prescribers, particularly in rural areas. Conclusion: Adherence differed by race/ethnicity as well as age and region. Qualitative research involving subgroups (e.g. Filipinos, Native Hawaiians, people under age 50) is needed to identify how to adapt and enhance the effects of interventions shown to be efficacious in prior studies. PMID- 29151902 TI - Coexistence of p210BCR-ABL and CBFbeta-MYH11 fusion genes in myeloid leukemia: A report of 4 cases. AB - Numerous acquired molecular and cytogenetic abnormalities are strongly associated with hematological malignancies. The breakpoint cluster region-ABL proto-oncogene 1 (BCR-ABL) rearrangement leads to a p210 chimeric protein in typical chronic myeloid leukemia (CML), whereas 17-25% of patients with acute lymphocytic leukemia and 0.9-3% patients with de novo acute myeloid leukemia (AML) carry a p190BCR-ABL fusion protein. Cases of patients with AML/CML carrying two specific primary molecular changes, BCR-ABL and core binding factor-beta-myosin heavy chain 11 (CBFbeta-MYH11) fusion genes have been rarely reported. The present study aimed to understand the nature and mechanism of this particular type of leukemia through case reports and literature review. A total of four patients who were diagnosed as AML/CML with BCR-ABL and CBFbeta-MYH11 fusion genes in the First Affiliated Hospital of Soochow University (Suzhou, China) between January 2004 and December 2012 were examined. Morphological analysis of bone marrow cells, flow cytometry, quantitative polymerase chain reaction of p210BCR-ABL and CBFbeta-MYH11 transcripts as well as cytogenetic and fluorescence in situ hybridization analyses were performed. A total of 4 patients who exhibited fusion of p210BCR-ABL and CBFbeta-MYH11 were identified. A single patient (case 1) was first diagnosed CML-acute phase (AP), which progressed rapidly to CML-blast crisis (BC), and three patients (cases 2, 3 and 4) were diagnosed with AML with bone marrow eosinophilia at first presentation with no evidence of previous onset of CML. All cases achieved remission following conventional chemotherapy/hematological stem cell transplantation combined with the inhibitor of tyrosine kinase (TKI) maintenance therapy. The patients with CML carrying and expressing BCR-ABL and CBFbeta-MYH11 fusion genes appeared more likely to rapidly progress to AP or BC. Therefore, the product of the CBFbeta-MYH11 fusion gene may serve an important role in the transformation of CML. The co-expression of p210BCR-ABL and CBFbeta-MYH11 fusion genes in myeloid leukemia may be a molecular event occurring not only during the development of CML, but also in AML. PMID- 29151901 TI - Surface acoustic wave devices for chemical sensing and microfluidics: A review and perspective. AB - Surface acoustic waves (SAWs), are electro-mechanical waves that form on the surface of piezoelectric crystals. Because they are easy to construct and operate, SAW devices have proven to be versatile and powerful platforms for either direct chemical sensing or for upstream microfluidic processing and sample preparation. This review summarizes recent advances in the development of SAW devices for chemical sensing and analysis. The use of SAW techniques for chemical detection in both gaseous and liquid media is discussed, as well as recent fabrication advances that are pointing the way for the next generation of SAW sensors. Similarly, applications and progress in using SAW devices as microfluidic platforms are covered, ranging from atomization and mixing to new approaches to lysing and cell adhesion studies. Finally, potential new directions and perspectives on the field as it moves forward are offered, with a specific focus on potential strategies for making SAW technologies for bioanalytical applications. PMID- 29151903 TI - Fusobacterium nucleatum in gastroenterological cancer: Evaluation of measurement methods using quantitative polymerase chain reaction and a literature review. AB - The human microbiome Fusobacterium nucleatum, which primarily inhabits the oral cavity, causes periodontal disease and has also been implicated in the development of colorectal cancer. However, whether F. nucleatum is present in other gastroenterological cancer tissues remains to be elucidated. The present study evaluated whether quantitative polymerase chain reaction (qPCR) assays were able to detect F. nucleatum DNA and measure the quantity of F. nucleatum DNA in esophageal, gastric, pancreatic and liver cancer tissues. The accuracy of the qPCR assay was determined from a calibration curve using DNA extracted from cells from the oral cavity. Formalin-fixed paraffin-embedded (FFPE) tumor tissues from 20 patients with gastroenterological [esophageal (squamous cell carcinoma), gastric, colorectal, pancreatic and liver] cancer and 20 matched normal tissues were evaluated for F. nucleatum DNA content. The cycle threshold values in the qPCR assay for F. nucleatum and solute carrier organic anion transporter family member 2A1 (reference sample) decreased linearly with the quantity of input DNA (r2>0.99). The F. nucleatum detection rate in esophageal, gastric and colorectal cancer tissues were 20% (4/20), 10% (2/20) and 45% (9/20), respectively. F. nucleatum was not detected in liver and pancreatic cancer tissues. The qPCR results from the frozen and FFPE tissues were consistent. Notably, F. nucleatum was detected at a higher level in superficial areas compared with the invasive areas. F. nucleatum in esophageal, gastric and colorectal cancer tissues was evaluated by qPCR using FFPE tissues. F. nucleatum may be involved in the development of esophageal, gastric and colorectal cancer. PMID- 29151904 TI - Inhibition of autophagy attenuated curcumol-induced apoptosis in MG-63 human osteosarcoma cells via Janus kinase signaling pathway. AB - The present study aimed to investigate whether autophagy was triggered by curcumol and to explore the association between autophagy and apoptosis of MG-63 cells and the underlying mechanism. MG-63 cells were cultured in vitro. An MTT assay was performed to evaluate the proliferation inhibition of the MG-63 osteosarcoma cell line by curcumol. Fluorescein isothiocyanate-Annexin V/propidium iodide staining flow cytometry was performed to analyze the apoptotic rate of cells. The morphological alterations of cell nuclei were evaluated by Hoechst 33258 viable cell staining. The effects of autophagy in cells was investigated by green fluorescent protein (GFP)-light chain 3 (LC3) transfection and using a fluorescence microscope. The expression levels of LC3II, LC3I and cleaved caspase-3 and Janus kinase (JNK) signaling pathway activation were determined by western blot analysis. Cell proliferation was inhibited by curcumol in a dose- and time-dependent manner. Curcumol induced apoptosis by the caspase dependent signaling pathway in MG-63 cells. The present study demonstrated that curcumol could induce autophagy of MG-63 cells, which was evaluated by transmission electron microscopy. Compared with the curcumol treatment alone group, the GFP-LC3-transfected green fluorescence plasmids and the LC3II/LC3I levels in cells of the curcumol and chloroquine (CQ) treatment group were upregulated, and the apoptotic ratio was downregulated following pretreatment with autophagy inhibitor CQ for 1 h. Furthermore, curcumol treatment induced phosphorylation of the JNK signaling pathway. Of note, pretreatment with the JNK inhibitor, SP600125, decreased the rates of autophagy and apoptosis, suggesting a crucial role served by the JNK signaling pathway in the activation of autophagy by curcumol. Taken together, the results of the present study suggested that activation of the JNK signaling pathway was involved in curcumol-induced autophagy. Curcumol is a novel drug for chemotherapeutic combination therapy. Curcumol demonstrated potential antitumor activities in MG-63 cells and may be used as a novel effective reagent in the treatment of osteosarcoma. PMID- 29151906 TI - HBME-1 expression in differentiated thyroid carcinoma and its correlation with the ultrasonic manifestation of thyroid. AB - We investigated expression of the protein human bone marrow endothelial cell marker-1 (HBME-1) in differentiated thyroid carcinoma tissues, and analyzed its correlation with ultrasonic manifestation of thyroid. The immunohistochemistry (IHC) staining method was used to measure the expression of HBME-1 in patient with nodular goiter (control group), papillary differentiated thyroid carcinoma (papillary carcinoma group) and follicular differentiated thyroid carcinoma (follicular carcinoma group) to investigate the differences in expression of HBME 1. We further analyzed the correlation of the expression of HBME-1 in the papillary carcinoma group and the follicular carcinoma group with ultrasonic manifestation of thyroid. In both the papillary carcinoma group and the follicular carcinoma group, the levels of HBME-1 in affected tissues and the IHS score of HBME-1 expression were higher than those in the control group (p<0.05). In the papillary carcinoma group, the mean IHS score of HBME-1 expression in affected tissues was higher than in the follicular carcinoma group (p<0.05). There were no statistically significant differences in comparison to HBME-1 expression in affected tissues between the papillary carcinoma group and the follicular carcinoma group (p>0.05). Between the papillary carcinoma group and the follicular carcinoma group, the differences in the comparison of the nodule diameter, echo, shape, boundary, calcification and blood flow signal were statistically significant (p<0.05), but incidence rate of enlargement of cervical lymph nodules between the groups were not statistically significant (p>0.05). Among patients in the papillary carcinoma group, the comparison of the nodule diameter, echo, shape, boundary, calcification and blood flow signal between the HBME-1-positive patients and the HBME-1-negative patients showed no statistical significance (p>0.05), but in the nodules of HBME-1-positive patients, the proportion of blood flow signal was higher than that in the nodules of HBME-1 negative patients. Among patients in the follicular carcinoma group, there was no statistically significant differences in the comparison of ultrasonic manifestation of thyroid (p>0.05). Therefore, there are difference in HBME-1 expression and ultrasonic manifestations of thyroid in patients with papillary carcinoma and follicular differentiated thyroid carcinoma. PMID- 29151905 TI - Stromal and intraepithelial tumor-infiltrating lymphocytes in colorectal carcinoma. AB - The local mechanisms of antitumor immune defense determine the development and organization of the tumor microenvironment, and the composition and relative proportions of the inflammatory cell population affect the quality and characteristics of the immune response. The aim of the present study was to conduct a quantitative morphological evaluation of two types of tumor infiltrating lymphocyte (TILs) populations, including those located in the stroma and intraepithelial cancer structures, in the invasive front and the center of the tumor in patients with colorectal cancer (CRC). The study included 160 patients with CRC who had undergone surgery. The tissue material was stained with hematoxylin and eosin, as used in routine histopathological diagnosis, and the two TIL populations were observed and counted with light microscopy. The relative extent of infiltration of stromal and intraepithelial TILs into the front and center of the primary tumors was similar. The extent of infiltration by stromal TILs was negatively correlated with the morphological features of tumor progression including the cancer infiltration of blood vessels (P=0.016), the invasion of lymph vessels (P=0.007), perineural invasion (P=0.036), lymph node involvement (P=0.047) and distant metastases (P=0.032). The infiltration by intraepithelial TILs was positively correlated with a desmoplastic reaction (P=0.002). Disease-free survival time was statistically shorter in patients without intraepithelial TILs in the center of the primary tumor mass (P=0.049; hazard ratio = 1.45). These results confirm that the infiltration of TILs into the invasive front and center of the tumor in patients with CRC serves an important role in the invasion and progression of the disease, and should be considered in routine histopathological examinations. PMID- 29151907 TI - The combination of anti-HBc and anti-HBs levels is a useful predictor of the development of chemotherapy-induced reactivation in lymphoma patients with resolved HBV infection. AB - Fatal chemotherapy-induced hepatitis B virus reactivation (HBV-R) is a well described serious complication observed in patients with lymphoma and resolved HBV infection. The aim of the present study was to determine the predictive factors of the development of chemotherapy-induced HBV-R. A total of 77 consecutive newly diagnosed patients with lymphoma and resolved HBV infection, who received chemotherapy from 2007 through 2015 were analysed retrospectively. Significant predictive factors associated with HBV-R were identified based on the data from these patients. Ten patients developed HBV-R during and following chemotherapy, and two of these 10 patients developed HBV-associated hepatitis flares. There was a significant negative correlation between anti-hepatitis B core (HBc) titres prior to chemotherapy and time to HBV-R (P=0.016, R=-0.732). Univariate and multivariate logistic regression analyses demonstrated that anti HBc and anti-hepatitis B surface (HBs) titres at baseline were significant predictive factors for HBV-R. In addition, patients with high anti-HBc titres at baseline (above 10 S/CO) were significantly more likely to experience HBV-R than patients with low anti-HBc and high anti-HBs titres (above 28 mIU/ml), who did not experience complete reactivation (P<0.0001). Furthermore, patients with low anti-HBs titres were significantly more likely to experience HBV-R than those with high anti-HBs titres (P=0.031). All HBV-R episodes among the patients with high anti-HBc titres occurred within 3 months following the initiation of chemotherapy. The combination of anti-HBc and anti-HBs titres, as opposed to either titre alone, at baseline in patients with lymphoma may serve as a surrogate marker for the occurrence of HBV-R under the influence of chemotherapy. PMID- 29151908 TI - Inhibition of prostate cancer cell growth in vivo with short hairpin RNA targeting SATB1. AB - Despite previous advances, the treatment options for prostate cancer remain limited. For the purposes of gene knockdown, the utility of RNA interference has been demonstrated and is considered to have therapeutic potential. In the present study, a short hairpin RNA (shRNA) was used to assess the effect of special AT rich sequence binding protein (SATB1) downregulation on the growth and metastatic potential of prostate cancer in xenograft nude mice. A plasmid carrying shRNA targeting SATB1, pSilencer-SATB1-shRNA, was successfully engineered. Using this plasmid, significant downregulation of SATB1 mRNA and protein expression in the DU145 prostate cancer cells was observed. pSilencer-SATB1-shRNA was demonstrated to be markedly efficacious against prostate cancer xenografts in nude mice. These results may lead to a novel method of improving gene therapy efficacy against prostate cancer via regulating the function of SATB1. PMID- 29151909 TI - BKM120 sensitizes C6 glioma cells to temozolomide via suppression of the PI3K/Akt/NF-kappaB/MGMT signaling pathway. AB - Glioblastoma is the most common type of malignant intracranial tumor in adults. Temozolomide (TMZ), as the first-line chemotherapy agent used in patients with glioblastoma, has demonstrated different effects in patients due to the expression of O6-methylguanine-DNA methyltransferase (MGMT) which is able to repair the DNA lesions induced by TMZ. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is over-activated in glioblastoma and has been revealed to be potentially implicated in resistance to TMZ. BKM120, a selective pan class I PI3K inhibitor, has been reported to facilitate apoptosis and reverse drug resistance in advanced solid tumors. The present study aims to investigate whether BKM120 is able to sensitize glioma cells to TMZ. C6 glioma cells were treated with BKM120 and/or TMZ for 12, 24 and 48 h, respectively. Cell Counting Kit-8 assays were performed to determine cell viability. The level of apoptosis was evaluated by Hoechst 33342 and TUNEL staining, and the levels of cleaved caspase-3 and Bcl-2-like protein 4 (Bax) expression was measured. Furthermore, the present study investigated the possible mechanism underlying BKM120 reverse chemoresistance to TMZ. The downstream targets of PI3K, including phosphorylated (p)-Akt, nuclear factor (NF)-B p65, were analyzed by western blotting. The MGMT transcription levels in monotherapy and combination therapy were demonstrated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The present study revealed that monotherapy treatments with either drug required a high concentration found reduction in cell viability. However, a low concentration of BKM120 inhibited the PI3K/Akt/NF-kappaB signaling pathway activity in glioma cells and significantly increased TMZ cytotoxicity. The coefficient of drug interaction was ~0.7. Results from the TUNEL assay, Hoechst 33342 staining and evaluation of the levels of cleaved caspase-3 and Bax expression also confirmed the finding that the combination treatment induced a higher level of apoptosis compared with the TMZ monotherapy. RT-qPCR demonstrated that the combination strategy reversed the TMZ-induced MGMT over-transcription. The reduction of NF-kappaB p65 in combination treatment supported the hypothesis that BKM120 may mediate MGMT transcription via inhibition of NF-kappaB p65. In conclusion, BKM120 and TMZ demonstrated strong synergistic cytotoxicity in C6 glioma cells. The BKM120-induced NF-kappaB p65 inhibition may be involved in the mediation of MGMT transcription to reverse TMZ-resistance in C6 glioma cells. PMID- 29151910 TI - Role and importance of the expression of transcription factor FOXC2 in cervical cancer. AB - The aim of the present study was to investigate the relationship between the expression of transcription factor forkhead box C2 (FOXC2) and the clinical features of cervical cancer. A total of 66 patients with cervical cancer, 42 patients with cervical intraepithelial neoplasia (CIN) and 25 patients with cervical inflammation were enrolled. The positive expression rates and expression levels of mRNA of FOXC2, E-cadherin, N-cadherin, vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1), Notch protein and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in cervical tissues were detected using immunohistochemistry and RT-PCR. The positive expression rates and expression levels of mRNA of FOXC2, N-cadherin, VEGF, SDF-1, Notch and LYVE-1 in cervical cancer were significantly higher than those in CIN, and those in the inflammatory tissues were the lowest, while the positive expression rate of E cadherin in cervical cancer was lower than that in CIN, and that in the inflammatory tissues was the highest (P<0.05). The positive expression rates of FOXC2, N-cadherin, VEGF, SDF-1, Notch and LYVE-1 in patients with cervical cancer [human papillomavirus (HPV) positive, squamous cell carcinoma, Stages III-IV, maximal diameter >=3.8 cm and low differentiation] were increased, and the positive expression rate of E-cadherin was decreased (P<0.05). Correlation analysis revealed that FOXC2 was positively correlated with the positive expression rates of N-cadherin, VEGF, SDF-1, Notch and LYVE-1, and negatively correlated with E-cadherin (P<0.05). In conclusion, the high expression of FOXC2 is correlated with the HPV infection, pathological pattern, clinical stage, tumor diameter and differentiation grade of cervical cancer, which may be involved in the epithelial-mesenchymal transition, vascular and matrix formation, Notch signaling pathway and lymphangiogenesis. PMID- 29151911 TI - Multiple pulmonary metastases with halo-sign from malignant mixed Mullerian tumors. AB - The lungs are one of the most common organs to which cancer metastasizes, but are a location not common for uterine sarcoma. A malignant mixed Mullerian tumor (MMMT) of the uterus is an extremely rare and aggressive sarcoma, characterized by a mixture of epithelial and mesenchymal components. There are few reports regarding the pulmonary metastasis from MMMTs. The present study presents the case of a 58-year-old woman with hemoptysis and post-menopausal vaginal bleeding. The woman was initially diagnosed with invasive aspergillosis based on a chest computed tomography (CT) scan showing multiple pulmonary nodular opacities surrounded by a ground-glass attenuation halo (halo-sign). Diagnostic curettage and a percutaneous CT-guided lung biopsy were conducted for the pathological diagnosis. Finally, the diagnosis was confirmed as MMMT with lung metastasis based on the histopathological examination of cervical canals, uterus and lung specimens, which showed a mixture of carcinomatous and sarcomatous elements, and morphology exhibiting hyperchromatic nuclei and necrosis. Immunohistochemical staining was positive for vimentin, focally positive for p16, and negative for napsin, cytokeratin 7 (CK7), CK20, carcinoembryonic antigen, carbohydrate antigen 125, homeobox protein CDX2 and villin in the lung specimens. This case highlights that pulmonary metastatic tumor from uterine sarcoma can present as halo-sign, which is commonly observed in pulmonary aspergillosis. Therefore, it needs to be considered in the differential diagnosis of such lesions, and pathological confirmation is required. PMID- 29151912 TI - Duodenal angiomyolipoma with multiple systemic vascular malformations and aneurysms: A case report and literature review. AB - Angiomyolipomas (AMLs) are barely benign mesenchymal tumors that usually occur in the kidneys and may be associated with tuberous sclerosis complex (TSC). Extrarenal AMLs are markedly rare and infrequently observed in the duodenum. In the present case report, a 22-year-old female patient with duodenal AMLs presenting multiple systemic vascular malformations and aneurysms is described. The patient had a medical history of aneurysm rupture of the right subclavian artery and no other manifestation of TSC. Surgical intervention was performed. Following complete tumor resection, the patient declined to be treated further for vascular lesions. Pathological and immunohistochemical examination confirmed the diagnosis of duodenal AMLs. No tumor recurrence or progression of the vascular lesions was observed within 24 months of follow-up. This case report demonstrates the scarcity of duodenal AMLs with multiple systemic vascular malformations and aneurysms, which may be associated with novel gene mutations or TSC; however, further verification by gene sequencing is required. PMID- 29151913 TI - Expression of NF-kappaB and PTEN in osteosarcoma and its clinical significance. AB - We investigated the role of nuclear factor-kappaB (NF-kappaB) and phosphatase and tensin homolog deleted in chromosome 10 (PTEN) in the pathogenesis of osteosarcoma and its relationship with prognosis. Immunohistochemical method was used to detect the expression of NF-kappaB and PTEN in osteosarcoma and adjacent tissues. RT-PCR was used to detect the expression of NF-kappaB and PTEN mRNA in osteosarcoma and adjacent tissues. Western blotting was used to detect the expression of NF-kappaB and PTEN in osteosarcoma and adjacent tissues and compare their differences. The expression of NF-kappaB and PTEN was detected in osteosarcoma and adjacent tissues. The positive rate of NF-kappaB was 75.3 and 32.9%, respectively; while the positive rate of PTEN was 67.1 and 90.4%, respectively. The positive expression of NF-kappaB and PTEN was statistically significant. There was a negative correlation between NF-kappaB and PTEN expression (r=-0.502, p<0.05). The positive and negative expression of NF-kappaB and PTEN was statistically significant for the five-year survival (p<0.05). At gene and protein level, osteosarcoma tissues had higher expression of NF-kappaB, and lower expression of PTEN, which was significantly different from the adjacent tissues. In osteosarcoma, NF-kappaB is highly expressed, but PTEN is expressed at low level, and the two are negatively correlated. This is of great significance for the early diagnosis of osteosarcoma and prognosis. PMID- 29151914 TI - A correlation analysis between tumor imaging changes and p-AKT and HSP70 expression in tumor cells after osteosarcoma chemotherapy. AB - This study sought to investigate osteosarcoma property changes after neoadjuvant chemotherapy and to analyze any correlation between changes with phospho-AKT (p AKT) and heat shock protein 70 (HSP70) expression in osteosarcoma cells. Thirty patients with osteosarcoma treated at Liaocheng People's Hospital between January and October, 2016 were given an imaging examination before and after neoadjuvant chemotherapy to examine osteosarcoma tumor properties, with images scored. Immunohistochemistry was used to determine p-AKT and HSP70 expression levels, as well as tumor cell necrosis rate (TCNR), in specimens obtained before and after chemotherapy. The correlation between the imaging changes of osteosarcoma after chemotherapy and the expressions of p-AKT and HSP70 in tumor cells. Compared with pre-chemotherapy, the imaging scores of the 30 patients significantly increased after chemotherapy (P<0.05). The radiographic score of the TCNR >=90% group was 11.3+/-0.5, which was significantly higher than that of the TCNR <90% group (8.7+/-0.3, P<0.05). p-AKT expression in osteosarcoma cells was found in 13.3% of samples (4/30 cases) after chemotherapy, which was significantly lower than prior to chemotherapy (73.3%, 22/30 cases, P<0.05). After chemotherapy, HSP70 expression in osteosarcoma cells was found in 6.7% of samples (2/30 cases), which was significantly lower than prior to chemotherapy (83.3%, 25/30 cases, P<0.05). p-AKT and HSP70 expression levels were found to be correlated with TCNR after chemotherapy (P<0.05). After chemotherapy, p-AKT and HSP70 expression levels demonstrated a positive correlation with TCNR. Tumor property changes, as uncovered by imaging, were significantly inversely correlated with tumor cell p AKT and HSP70 expression after chemotherapy. Therefore, osteosarcoma properties, as determined through X-ray imaging, were closely related to p-AKT and HSP70 expression in osteosarcoma cells after neoadjuvant chemotherapy. The effect of chemotherapy can be evaluated by observing the above examination results. PMID- 29151915 TI - Phloretin induces apoptosis of human esophageal cancer via a mitochondria dependent pathway. AB - 2,4,6-trihydroxy-3-(4-hydroxyphenyl)-propiophenone (phloretin) is found in apple tree leaves and the Manchurian apricot, and is a potent compound that exhibits anti-inflammatory, antioxidant and antitumor activities. However, the effect of phloretin on esophageal cancer cells is not well-defined. The present study aimed to examine whether and how phloretin induced apoptosis in human esophageal cancer cells. EC-109 cells were cultured in Dulbecco's modified Eagle's medium and incubated with 60, 70, 80, 90 and 100 ug/ml phloretin for 6, 12, 24 and 48 h. Cell proliferation was measured by an MTT assay. Cell apoptosis rate was measured using flow cytometric analysis subsequent to propidium iodide (PI) staining. The protein expression levels were determined by western blot analysis. It was found that phloretin significantly decreased viable cell numbers in a dose- and time dependent manner and induced apoptosis in EC-109 cells. Additionally, phloretin exhibited potent anticancer activity in vitro, as evidenced by the downregulation of the anti-apoptosis-associated molecule B-cell lymphoma 2 (bcl-2) and an increase in the levels of the apoptosis-associated molecules bcl-2-like protein 4 and tumor protein p53. Phloretin treatment also affected the expression of apoptotic protease activating factor-1, the protein product of the direct binding of the inhibitor of apoptosis protein with low PI to the X-linked inhibitor of apoptosis protein. The present results indicated that phloretin may inhibit EC 109 cell growth by inducing apoptosis, which may be mediated through a mitochondria-dependent pathway. PMID- 29151916 TI - Early changes in the apparent diffusion coefficient and MMP-9 expression of a cervical carcinoma U14 allograft model following irradiation. AB - A cervical carcinoma allograft model was designed to assess the correlation between early changes in the apparent diffusion coefficient (ADC) values on diffusion-weighted magnetic resonance imaging (DW-MRI) and the expression of matrix metalloproteinase-9 (MMP-9) in tumors. BALB/c mice with U14 tumor allografts on the right rear flank were irradiated with a single 20 Gy dose. All tumor-bearing mice were subjected to DW-MRI, followed by calculation of the ADC values and characterization of the T1 and T2 relaxation time constants. Pre- and post-irradiation ADC values were compared with the tumor volume, and the immunohistochemical staining of MMP-9 and hematoxylin-eosin (HE) staining of tumor allografts. However, no correlations between the pre-treatment ADC values and changes in tumor volumes following irradiation were observed. Notably, the mean ADC value was significantly higher in the irradiated tumors (0.756+/ 0.102*10-3 mm2/sec) as compared with those in the untreated tumors (0.501+/ 0.052*10-3 mm2/sec; P=0.002; r=0.682). Additionally, immunohistochemical staining demonstrated that MMP-9 expression in the irradiated tumors was significantly increased. The mean ADC value was significantly higher in the irradiated tumors with high MMP-9 expression levels (0.815+/-0.112*10-3 mm2/sec), as compared with in the untreated tumors with low MMP-9 expression levels (0.631+/-0.068*10-3 mm2/sec). Quantitative analysis determined that the ADC values were correlated with MMP-9 expression (r=0.752; P=0.003). Combined, these results suggest that radiation-induced increases in MMP-9 expression levels may be responsible for early changes in the mean ADC value and the response to irradiation in cervical carcinoma. PMID- 29151917 TI - Downregulation of lipolysis-stimulated lipoprotein receptor promotes cell invasion via claudin-1-mediated matrix metalloproteinases in human endometrial cancer. AB - Lipolysis-stimulated lipoprotein receptor (LSR) is a novel molecule present at tricellular contacts which recruits tricellulin (TRIC), a molecular component of tricellular tight junctions (tTJs). LSR and TRIC are colocalized with the bicellular tight junction (bTJ) protein claudin (CLDN)-1-based tight junction strands at tricellular corners. Knockdown of LSR in normal epithelial cells affects tTJ formation and the epithelial barrier function. In cancer cells knockdown of LSR has been demonstrated to increase cell invasion. However, the detailed mechanisms of how the downregulation of LSR enhances cell invasion in cancer remain unclear. In the present study, knockdown of LSR by small interfering RNA (siRNA) in Sawano human endometrial adenocarcinoma cells induced cell invasion. In LSR-knockdown Sawano cells, upregulation of CLDN-1 protein, which contributes to the cell invasion via matrix metalloproteinases (MMPs), was observed compared with the control group by western blotting and immunostaining. Knockdown of LSR significantly induced Sp1 transcription factor activity in the CLDN-1 promoter region. In LSR-knockdown Sawano cells, DNA microarray analysis demonstrated that MMP-1, MMP-2 and MMP-10 mRNA levels were increased, and the protein levels of membrane-type 1-MMP, MMP-2, MMP-9 and MMP-10 were shown to be increased on western blots. Knockdown of CLDN-1 with siRNA prevented the upregulation of cell invasion induced by the knockdown of LSR in Sawano cells. On the invasive front of human endometrial carcinoma tissue samples, a decrease in LSR and increase in CLDN-1 protein levels were observed using immunohistochemical methods. In conclusion, the results indicate that the downregulation of LSR promotes cell invasion of human endometrial cancer via CLDN-1 mediation of MMPs. This mechanism is important for studying the association of tTJs with the cellular invasion of cancer. PMID- 29151918 TI - Engrailed-2 promoter hyper-methylation is associated with its downregulation in clear cell renal cell carcinoma. AB - In a previous study by the present authors, it was identified that the expression of engrailed-2 (EN2) gene was downregulated in clear cell renal cell carcinoma (cc-RCC). The aim of the present study was to determine whether aberrant methylation was the mechanism underlying the silencing of EN2 gene in cc-RCC. A total of forty paired cc-RCC tissues, four cc-RCC cell lines and one normal human proximal tubule epithelial cell line were evaluated for EN2 gene methylation status using methylation-specific polymerase chain reaction (PCR). Following treatment with 5-Aza-dc, reverse transcription-quantitative PCR and western blot analysis were performed to examine the expression of EN2. Furthermore, cell proliferation, apoptosis and invasion assays were conducted to analyze the inhibitory effects of EN2 re-expression in 786-O cells. The results of the present study demonstrated that hyper-methylation of EN2 was identified in 12/40 cc-RCC tissues and all cc-RCC cell lines. The methylation status of the EN2 gene was revealed to be associated with histological grade and tumor size in cc-RCC. Following 5-Aza-dc treatment, demethylation of the EN2 gene was identified in 786 O cells, in conjunction with EN2 re-expression. Furthermore, re-activation of the EN2 gene markedly inhibited the proliferative and invasive capacities of cc-RCC. The results of the present study demonstrated that the EN2 gene promoter was hyper-methylated in cc-RCC, which may underlie the silencing of the EN2 gene in cc-RCC. PMID- 29151919 TI - miR-21 is involved in transforming growth factor beta1-induced chemoresistance and invasion by targeting PTEN in breast cancer. AB - Transforming growth factor beta1 (TGF-beta1) has been associated with poor outcomes in patients with breast cancer. However, the functions and underlying molecular mechanisms of TGF-beta1 in breast cancer remain unknown. Therefore, the present study aimed to identify the effects of components of the TGF beta/microRNA (miR-)21/phosphatase and tensin homolog (PTEN) signaling axis in breast cancer. TGF-beta1 was identified to upregulate the expression of miR-21, and miR-21 was demonstrated to be significantly upregulated in breast cancer tissues compared with benign proliferative breast disease. In addition, the expression of miR-21 was significantly associated with increased TGF-beta1 and clinical characteristics in patients, including tumor grade and lymph node metastasis (all P<0.05). Furthermore, in the breast cancer MCF-7 cell line, TGF beta1 was revealed to induce the expression of miR-21 in a dose- and time dependent manner. The results of the present study additionally demonstrated that increased miR-21, in response to TGF-beta1 signaling, was associated with tumor invasion and chemoresistance in vitro. In addition, suppression of PTEN was mediated by TGF-beta1-induced expression of miR-21 in breast cancer cells and using a miR-21 inhibitor revitalized the expression of PTEN. The results of the present study explored the functions of TGF-beta1-stimulated expression of miR-21 to suppress the PTEN axis, which promotes breast cancer progression and chemoresistance. PMID- 29151920 TI - Viscoelasticity of amyloid plaques in transgenic mouse brain studied by Brillouin microspectroscopy and correlative Raman analysis. AB - Amyloidopathy is one of the most prominent hallmarks of Alzheimer's disease (AD), the leading cause of dementia worldwide, and is characterized by the accumulation of amyloid plaques in the brain parenchyma. The plaques consist of abnormal deposits mainly composed of an aggregation-prone protein fragment, beta-amyloid 1 40/1-42, into the extracellular matrix. Brillouin microspectroscopy is an all optical contactless technique that is based on the interaction between visible light and longitudinal acoustic waves or phonons, giving access to the viscoelasticity of a sample on a subcellular scale. Here, we describe the first application of micromechanical mapping based on Brillouin scattering spectroscopy to probe the stiffness of individual amyloid plaques in the hippocampal part of the brain of a beta-amyloid overexpressing transgenic mouse. Correlative analysis based on Brillouin and Raman microspectroscopy showed that amyloid plaques have a complex structure with a rigid core of beta-pleated sheet conformation (beta amyloid) protein surrounded by a softer ring-shaped region richer in lipids and other protein conformations. These preliminary results give a new insight into the plaque biophysics and biomechanics, and a valuable contrast mechanism for the study and diagnosis of amyloidopathy. PMID- 29151922 TI - Clinicopathological Characteristics and Prognostic Value of Signet Ring Cells in Gastric Carcinoma: A Meta-Analysis. AB - Background and Objectives: Previous studies of the prognostic value of the signet ring cell (SRC) type have yielded inconsistent results. Therefore, the aim of the present meta-analysis is to explore the clinicopathological characteristics and prognostic value of SRCs. Methods: Relevant articles that compared SRC and non SRC type in PubMed and Web of Science were comprehensively searched. Then, a meta analysis was performed. Results: A total of 19 studies including 35947 cases were analyzed. Compared with non-SRC patients, SRC patients tended to be younger (WMD: -3.88, P=0.001) and predominantly female (OR: 1.60, P<0.001). Additionally, SRC patients exhibited less upper third tumor location (OR: 0.62, P<0.001) and less frequent hematogenous metastasis (OR: 0.41, P<0.001). There was no difference in overall survival (OS) between SRC and non-SRC patients in the total population (HR: 1.02, P=0.830). Early gastric cancer with SRCs was associated with better OS (HR: 0.57, P=0.002), while advanced gastric cancer with non-SRCs was associated with a worse prognosis (HR: 1.17, P<0.001). Conclusions: This meta-analysis revealed that SRC tends to affect young females and tends to be located in the middle and lower third of the stomach. Early SRCs are associated with better prognoses, while advanced SRCs are associated with worse prognoses. PMID- 29151923 TI - p300 Knockout Promotes Butyrate Resistance. AB - Dietary fiber is linked to a reduced risk of colorectal cancer (CRC), and this protective activity is likely due to its fermentation product, butyrate. Dependent upon the hyperactivation of Wnt signaling, butyrate represses CRC cell growth and induces apoptosis. However, resistance to butyrate activity may allow for CRC development even in the context of relatively high fiber intake. We have previously determined that CRC cells resistant to butyrate are deficient in p300 expression. The histone acetylase p300 influences colonic cell signaling and physiology through effects on Wnt signaling. In this short research communication, we report that p300 knockout CRC cells exhibit butyrate resistance, and the re-introduction of p300 expression in p300 knockout CRC cells restores butyrate sensitivity. Microarray data on gene expression associated with butyrate sensitivity are presented and discussed. PMID- 29151921 TI - Linking Gut Microbiota to Colorectal Cancer. AB - Pre-clinical and clinical data produce mounting evidence that the microbiota is strongly associated with colorectal carcinogenesis. Dysbiosis may change the course of carcinogenesis as microbial actions seem to impact genetic and epigenetic alterations leading to dysplasia, clonal expansion and malignant transformation. Initiation and promotion of colorectal cancer may result from direct bacterial actions, bacterial metabolites and inflammatory pathways. Newer aspects of microbiota and colorectal cancer include quorum sensing, biofilm formation, sidedness and effects/countereffects of microbiota and probiotics on chemotherapy. In the future, targeting the microbiota will probably be a powerful weapon in the battle against CRC as gut microbiology, genomics and metabolomics promise to uncover important linkages between microbiota and intestinal health. PMID- 29151924 TI - The Effect of CA125 Nadir Level on Survival of Advanced-Stage Epithelial Ovarian Carcinoma after Interval Debulking Surgery. AB - Purpose. The study aims at investigating the most reliable CA125-related factors in terms of predicting survival outcomes in advanced-stage epithelial ovarian carcinoma (EOC) patients received neoadjuvant chemotherapy (NAC). Methods. The EOC patients treated with NAC at Peking Union Medical College Hospital by a single gynecological oncology team were enrolled for the retrospective study. The CA125-related variables were categorized into four groups: normalizations, nadirs, half-life and percentage reductions. Associations of these variables with progress-free survival (PFS) and overall survival (OS) were evaluated. Results. Of the 101 patients included, 81 patients (80.2%) had progressed, and 51 patients (50.5%) had died of the disease progression. Univariate analysis showed that the CA125 nadir, reduction after the first, second and third postoperative chemotherapy cycles, and time to normalization were significantly (P<0.05) associated with PFS. The CA125 nadir, reduction after the first, second and third postoperative chemotherapy cycles were significantly (P<0.05) associated with OS. In the multivariate analysis, the CA125 nadir value was the most significant factor for PFS and OS, using the CA125 median level 13 U/ml as a cutoff value. Conclusions. Our study suggests that the CA125 nadir value is the most reliable prognostic factor to predict PFS and OS in advanced EOC patients treated with NAC. This information is important in patient counseling and creating individualized follow-up plans. PMID- 29151925 TI - Phycocyanin: A Potential Drug for Cancer Treatment. AB - Phycocyanin isolated from marine organisms has the characteristics of high efficiency and low toxicity, and it can be used as a functional food. It has been reported that phycocyanin has anti-oxidative function, anti-inflammatory activity, anti-cancer function, immune enhancement function, liver and kidney protection pharmacological effects. Thus, phycocyanin has an important development and utilization as a potential drug, and phycocyanin has become a new hot spot in the field of drug research. So far, there are more and more studies have shown that phycocyanin has the anti-cancer effect, which can block the proliferation of cancer cells and kill cancer cells. Phycocyanin exerts anti cancer activity by blocking tumor cell cell cycle, inducing tumor cell apoptosis and autophagy, thereby phycocyanin can serve as a promising anti-cancer agent. This review discusses the therapeutic use of phycocyanin and focuses on the latest advances of phycocyanin as a promising anti-cancer drug. PMID- 29151927 TI - Comparative Outcomes of Induction Chemotherapy Followed By Definitive Chemoradiotherapy versus Chemoradiotherapy Alone In Esophageal Squamous Cell Carcinoma. AB - Purpose: To compare the clinical outcomes of induction chemotherapy (IC) followed by chemoradiotherapy (CRT) versus chemoradiotherapy alone in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Patients and methods: Between 2002 and 2015, 267 ESCC patients who received definitive CRT with docetaxel and cisplatin were enrolled in this study. Through a matched case control study, 85 patients receiving IC before CRT were matched 1:1 to patients who received CRT alone, according to age, gender, performance status, tumor location, tumor length, and pretreatment TNM stage. Results: The median overall survival (OS) in the IC group was significantly better than that in the CRT group (26.0 vs. 22.0 months), with 3-year OS rates of 30.6% vs. 25.9%, respectively (P = 0.028). However, IC plus CRT was associated with a significantly higher rate of grade 3-4 leukopenia than CRT alone (P = 0.048). The overall clinical response rate was 50.6% after IC in the IC group. The IC responder group showed significantly more favorable OS (P=0.002) and progression-free survival (P=0.001) compared with the IC non-responder group and the CRT group. Multivariate analysis revealed that age >= 60 (P = 0.003) and the addition of IC (P=0.016) were independent prognostic factors that affected survival positively. Conclusions: The addition of IC before CRT yielded satisfactory clinical outcomes and manageable toxicities. The combination of IC with CRT might be a promising treatment strategy to further improve systemic control and survival in ESCC. Prospective randomized trials are required to confirm the role of IC. PMID- 29151926 TI - The Glycolytic Switch in Tumors: How Many Players Are Involved? AB - Reprogramming of cellular metabolism is a hallmark of cancers. Cancer cells more readily use glycolysis, an inefficient metabolic pathway for energy metabolism, even when sufficient oxygen is available. This reliance on aerobic glycolysis is called the Warburg effect, and promotes tumorigenesis and malignancy progression. The mechanisms of the glycolytic shift in tumors are not fully understood. Growing evidence demonstrates that many signal molecules, including oncogenes and tumor suppressors, are involved in the process, but how oncogenic signals attenuate mitochondrial function and promote the switch to glycolysis remains unclear. Here, we summarize the current information on several main mediators and discuss their possible mechanisms for triggering the Warburg effect. PMID- 29151928 TI - Serum Pre-Albumin Predicts the Clinical Outcome in Metastatic Castration Resistant Prostate Cancer Patients Treated With Abiraterone. AB - Objective To determine the prognostic utility of serum pre-albumin in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone (AA). Patients and Methods 112 chemotherapy pretreated or chemotherapy-naive patients were scheduled for systemic treatment with AA. Serum pre-albumin levels were measured before and after 3 months of AA treatment. Univariate and multivariate analyses were performed to determine prognostic factors that were associated with PSA progression-free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS). The Harrell concordance index with variables only or combined pre-albumin data were used to evaluate the prognostic accuracy. Results The group of patients with baseline pre-albumin value >=20mg/dL had a longer OS, PSA-PFS, rPFS than those with pre-albumin value <20mg/dL. Based on the values of pre-albumin before and after 3 months of AA treatment, we divided these patients into 4 groups: high-high, high-low, low-high and low-low group. High- high group showed a significantly better OS, PSA-PFS, rPFS than other 3 groups. In multivariate analysis, low pre-albumin level remained significant predictors of OS (HR, 13.2; P<0.001), rPFS (HR, 3.7; P=0.003) and PSA-PFS (HR, 8.7; P<0.001). The estimated c-index of the multivariate model for OS increased from 0.814 without pre-albumin to 0.845 when pre-albumin added. Conclusion Low pretreatment serum pre-albumin is a negative independent prognosticator of survival outcomes in mCRPC treated with AA and also increases the accuracy of established prognostic model. Serial pre-albumin evaluation might help clinicians guide clinical treatment of mCRPC patients. PMID- 29151929 TI - Identification of circular RNA signature in bladder cancer. AB - Circular RNA (circRNA) comprises a class of endogenous species of RNA consisting of a circular loop that is crucial for genetic and epigenetic regulation. The significance of circRNA in bladder cancer (BCa) remains to be investigated. Here we performed genome-wide circRNA analysis of 5 paired tumour and adjacent normal tissue samples from BCa patients via next generation sequencing (NGS) technology. Next we confirmed NGS data in a separate set of 32 paired BCa samples using quantitative real-time reverse transcription polymerase chain reaction. The results showed that circRNA profile presented a total of 88,732 circRNA in BCa samples. Among them, 14 were upregulated and 42 were downregulated with q-values of <0.001 and fold changes of >=2 or <=0.5. The expression level changes of hsa_circ_0091017 and hsa_circ_0002024 in the 32 paired samples were in accord with NGS data. In conclusion, we identified a set of circRNAs that are potentially implicated in the tumorigenesis of BCa and could serve as novel diagnostic markers for BCa. PMID- 29151930 TI - Overexpression of PTK6 predicts poor prognosis in bladder cancer patients. AB - Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase and works as an oncogene in various cancers. Recently, PTK6 has been used as a therapeutic target for breast cancer patients in a clinical study. However, the prognostic value of PTK6 in bladder cancer (BC) remains vague. Therefore, we retrieved 3 independent investigations of Oncomine database and found that PTK6 is highly expressed in BC tissues compared with corresponding normal controls. Similar results were also observed in clinical specimens at both mRNA and protein levels. Immunohistochemical analysis indicated that PTK6 overexpression was highly related to the T classification, N classification, grade, recurrence, and poor prognosis of BC patients. Furthermore, we demonstrated that when PTK6 expression was knocked down by siRNAs, cell proliferation and migration were considerably inhibited in BC cell lines T24 and EJ. By these approaches, we are intended to elucidate PTK6 may be a reliable therapeutic target in BC and might benefit from PTK6 inhibitors in the future. PMID- 29151931 TI - Prognostic Value of Clinical and Pathological Features in Chinese Patients with Chromophobe Renal Cell Carcinoma: A 10-Year Single-Center Study. AB - Objective: To evaluate the prognostic significance of clinicopathological features in a large series of Chinese patients with chromophobe renal cell carcinoma (RCC). Materials and Methods: Patients with chromophobe RCC who were treated surgically for renal masses at Chinese PLA General Hospital from 2006 to 2015 were identified. Tissue slides were reviewed to verify diagnoses and collect clinicopathological variables. Cox proportional hazard regression models and the Kaplan-Meier method were performed to evaluate the significance of clinicopathological variables on survival outcomes. Results: A total of 209 patients with chromophobe RCC were enrolled in this study. There were only 13 cancer-specific events, which included 7 local recurrences and 6 metastases. The estimated 5-year and 10-year disease-free survival (DFS) rates were 92.4% and 83.1%, respectively. Univariate analysis indicated that tumor size, 2010 AJCC TNM stage, grade, sarcomatoid differentiation and urinary collecting system invasion were correlated with poor DFS. Multivariate analysis revealed that tumor size, 2010 AJCC TNM stage and grade were independent predictors of DFS. Conclusions: According to this long-term follow-up on a large number of Chinese patients, we found that chromophobe RCC was associated with a very low rate of cancer-specific events (6.2%) and has a better prognosis than clear cell RCC. Tumor size, 2010 AJCC TNM stage and grade were independent prognostic factors in Chinese patients with chromophobe RCC. The presence of these features in a nephrectomy specimen with chromophobe RCC warrants more active surveillance. PMID- 29151932 TI - Restoration of KLF4 Inhibits Invasion and Metastases of Lung Adenocarcinoma through Suppressing MMP2. AB - BACKGROUND: KLF4 is a zin-finger transcription factor that plays roles in differentiation, development, and proliferation. Recent studies show that KLF4 is involved in tumorigenesis and somatic cells reprogramming. Metastasis is the primary cause of death in patients with lung cancer, and its biological mechanisms are poorly understood. GOALS: In this study, we aim to explore the expression pattern and biological function of KLF4 in lung adenocarcinoma. METHODS: We determined KLF4 in lung adenocarcinoma tissue and cell lines, using immunohistochemistry and western blotting. And we further analyzed the correlation between KLF4 expression and clinicopathologic parameters. We restored KLF4 expression and studied its effect on lung adenocarcinoma cells in vivo and in vitro. Luciferase assay was used to study impact of KLF4 on activity of MMP2 promoter. RESULTS: KLF4 is dramatically down-regulated in lung adenocarcinoma tissue and cell lines. Promoter methylation contributes to the down-regulation of KLF4. Down-regulation of KLF4 in lung adenocarcinoma tissue is significantly associated with reduced survival time. Restoration of KLF4 inhibits migration and invasion of lung adenocarcinoma cells in vitro. Metastases to lungs significantly decrease in mice intravenously injected with tumor cells overexpressing KLF4. KLF4 inhibits invasion and metastasis via suppressing MMP2 promoter activity. CONCLUSION: The ability of KLF4 to inhibit migration, invasion, and metastasis of lung tumor cells indicates a potential role of KLF4 as therapeutic target in lung adenocarcinoma. KLF4 might be utilized as a favorable biomarker for prognosis of lung adenocarcinoma patients. PMID- 29151933 TI - Expression of ARID1B Is Associated With Poor Outcomes and Predicts the Benefit from Adjuvant Chemotherapy in Bladder Urothelial Carcinoma. AB - Background ARID1B, which exists as a mutually exclusive isoform with ARID1A in the SWI/SNF chromatin remodeling complex, has been recently identified as a major mutant gene in a wide variety of cancers. The present study aimed to determine the association between ARID1B expression and outcomes, as well as the benefit from adjuvant chemotherapy in patients with bladder cancer. Methods Tissue microarrays of 143 consecutively recruited patients with bladder cancer from our center were created. Immunohistochemistry was performed to assess the expression of ARID1B and its association with outcomes. Clinicopathological factors were also evaluated. Results ARID1B expression was significantly associated with tumor size (P=0.015), T stage (P=0.027), lymph node status (P=0.030), TNM stage (P=0.040), overall survival (P<0.001), and progression-free survival (P=0.043). Furthermore, high expression of ARID1B was an independent indicator of poor OS (P=0.022). The prognostic model containing ARID1B showed a better predictive accuracy than the bench models. Most importantly, the benefit of adjuvant chemotherapy observed in patients with low ARID1B expression was superior to that observed in patients with high ARID1B expression. Conclusions Our study suggests that ARID1B can serve as a prognostic biomarker of bladder urothelial carcinoma. Additionally, ARID1B might be a predictive marker for selecting patients for adjuvant chemotherapy in the high-risk subgroup. PMID- 29151934 TI - Development and Validation of a Nomogram to Predict the Benefit of Adjuvant Radiotherapy for Patients with Resected Gastric Cancer. AB - Background: The US guidelines for gastric cancer (GC) recommend adjuvant radiotherapy (ART) combined with 5-fluorouracil as a standard treatment for patients with resected locally advanced GC. However, patient selection criteria for optimizing the use of adjuvant therapies are lacking. In this study, we developed and validated a nomogram to predict the individualized overall survival (OS) benefit of ART among patients with resected >=stage IB GC. Patients and Methods: The 2002-2006 Surveillance, Epidemiology, and End Results (SEER) data of 5,206 patients with resected GC were used as a training set for the development of a nomogram. The 2007-2008 SEER data of 1,986 patients with resected GC were used as validation data. Results: In the multivariate analysis weighted by inverse propensity score, the efficacy of ART varied by the ratio of positive to examined nodes (Pinteraction <0.01). The magnitude of this difference was included in the nomogram with associated prognosticators to predict the 3- and 5 year OS with and without ART. The nomogram showed significant prognostic superiority to the 8th TNM staging in the training set (Concordance index, 0.68 versus 0.65; P<0.01) and the validation set (Concordance index, 0.68 versus 0.64; P<0.01). Moreover, the calibration was accurate, and the actual efficacy of ART was positively correlated with the nomogram-estimated survival benefit from ART (Pinteraction <0.01 and Pinteraction =0.02 in the training set and the validation set, respectively). Conclusion: The nomogram can aid individualized clinical decision making by estimating the 3- and 5-year OS and potential benefits of ART among patients with resected GC. PMID- 29151935 TI - Comparison of Combined Transcatheter Arterial Chemoembolization and CT-guided Radiofrequency Ablation with Surgical Resection in Patients with Hepatocellular Carcinoma within the Up-to-seven Criteria: A Multicenter Case-matched Study. AB - Background & Aims: We compared the efficacy of transcatheter arterial chemoembolization (TACE) in combination with CT-guided radiofrequency ablation (RFA) with that of surgical resection (SR) in patients with hepatocellular carcinoma (HCC) within the up-to-seven criteria. Methods: From January 2004 to December 2014, 420 multicenter consecutive patients with HCC who conformed to the up-to-seven criteria and initially received either TACE plus CT-guided RFA (TACE RFA) or SR were enrolled. A matched cohort composed of 206 patients was selected after adjustment with propensity score matching. The overall survival (OS) of each patient was calculated with the Kaplan-Meier method and compared by the log rank test. Results: The median OS and 1-, 3-, and 5-year survival rates were 56.0 months, 96.1%, 76.7% and 41.3% in the TACE-RFA group and 58.0 months, 96.1%, 86.4% and 46.2% in the SR group, respectively. There was no significant difference in OS between the two groups (P = 0.138). For patients with HCC beyond the Milan criteria, TACE-RFA provided a longer median OS than SR (52.0 vs 45.0 months, P = 0.023). Conclusions: Treatment by TACE-RFA conferred an OS rate comparable with that of SR in patients within the up-to-seven criteria. For patients with HCC between the Milan and the up-to-seven criteria, TACE-RFA might be superior to SR for survival prolongation. PMID- 29151936 TI - Multiple guided technologies based on radial probe endobronchial ultrasound for the diagnosis of solitary peripheral pulmonary lesions: a single-center study. AB - Objective To evaluate the value of multiple guided technologies based on radial probe endobronchial ultrasound (R-EBUS) in the application of the diagnosis of solitary pulmonary peripheral lesions (PPLs). Methods Analysis of diagnostic yield in 4 groups patients with different combined multiple guided technologies based on R-EBUS, 94 patients with 94 solitary PPLs from Mar, 2013 to Nov, 2014 in Changhai Hospital. Results The overall diagnostic yield was 75% (70/94), the diagnostic yield of Group A (R-EBUS) was 62%(16/26), Group B (R-EBUS with guided sheath, EBUS-GS) was 76% (34/45), Group C (EBUS-GS with fluoroscopy) was 82% (9/11), Group D (virtual bronchoscopic navigation guided EBUS-GS with fluoroscopy) was 92% (11/12). The overall histopathological diagnostic yield was 56% (53/94. Better histopathological diagnostic yield was associated with application of multiple guided technologies based on EBUS-GS, lesions located in non-lower lobes, lesion's diameter > 2cm, radial probe within the lesions and lidocaine nebulization combined with intravenous anesthesia. There were no severe complications in all the 94 cases. A ultrasonic radial probe was broken when exploring a lesion located in the apical-posterior segment of left upper lobe. Conclusion Multiple guided technologies based on R-EBUS were safe and effective in the diagnosis of solitary PPLs. In practice, the diagnosis yield improved with the application of forcep biopsies combined with bronchial brushing and washing. PMID- 29151937 TI - Combination of plasma HA and circulating M2-like monocytes may serve as a diagnostic marker for breast cancer. AB - Background: Breast cancer (BC)-derived hyaluronan (HA) can induce the formation of M2-like tumor-associated macrophages (TAMs) in tumor context. However, little is known about the correlation between circulating M2-like monocytes and plasma HA in BC patients. This study focused on evaluating the relationship between circulating M2-like monocytes and plasma HA, and further appraised the diagnostic value of them in BC. Methods: The expression of M2-like TAMs and HA was determined in pathological tissues by immunohistochemistry. Flow cytometry was used to detect the levels of circulating CD14+CD204+ M2-like monocytes in 81 BC patients, 45 patients with breast benign diseases, and 46 healthy subjects. The levels of HA, CEA, and CA15-3 were measured in plasma samples using chemiluminescence method. Results: M2-like TAMs and HA expressions were elevated in BC tissues compared with benign tissues. In correspondence, the frequency of circulating CD14+CD204+ M2-like monocytes and the plasma HA levels were significantly higher in patients with BC than those in control groups. Importantly, there was a positive correlation between circulating M2-like monocytes and the plasma HA (Spearman r = 0.404, p < 0.001). Area under receiver operating characteristic curve (ROC) for the combination of circulating M2-like monocytes and HA was 0.899 (95% CI: 0.853-0.946), which was higher than the panel of CEA and CA15-3. Conclusions: The frequency of circulating CD14+CD204+ M2-like monocytes was positively correlated to plasma HA levels. The combination of circulating CD14+CD204+ M2-like monocytes and plasma HA could provide considerable diagnostic value in BC. PMID- 29151938 TI - Comparison of HER2 and Lauren Classification between Biopsy and Surgical Resection Samples, Primary and Metastatic Samples of Gastric Cancer. AB - Purpose: Patients with advanced or metastatic adenocarcinoma of the stomach or esophagogastric junction for whom trastuzumab therapy is being considered, assessment for tumor human epidermal growth factor receptor-2 (HER2) status is necessary. Can the HER2 status and Lauren classification of the biopsy sample truly represent the HER2 status in the gastric cancer? Methods: Formalin-fixed, paraffin-embedded sections of 116 pair surgically resected and biopsy specimens as well as 80 pair primary and metastatic lesions of gastric cancer patients were analyzed. Protein expression was assessed using immunohistochemistry (IHC) and graded by the modified scoring criteria for gastric cancer. Gene amplification was evaluated by fluorescence in situ hybridization (FISH) in IHC 2+ cases. Results: The positive rate of HER2 was 11.2% in both surgical and biopsy samples. The consistent rate of HER2 expression was 91.4% (106/116) between biopsy and surgical samples, P=0.666. The positive rate of HER2 was 20.5% in primary and 15.9% in metastatic samples, P=0.1876. The consistent rate of HER2 expression was 90.9% (40/44) between primary and metastatic samples, P=0.580. The consistent rate of Lauren classification was 64.7% (75/116) between biopsy and surgical sample, and 92.5% (74/80) between primary and metastatic samples. Discussion: For gastric cancer, HER2 expression and Lauren classification were highly homogenous in biopsy and surgical samples, primary and their corresponding metastatic samples. The high concordance observed between these two cohorts indicated that the HER2 examination and Lauren classification of biopsy samples from the primary tumor could well represent the metastatic lesions of the patients. PMID- 29151939 TI - Clinical Impact of microRNAs Associated With Cancer Stem Cells as a Prognostic Factor in Ovarian Carcinoma. AB - Background: Ovarian carcinoma is a highly lethal gynecological malignancy due to its frequent relapses and adoption of chemoresistance. To develop new biomarkers for disease progression in ovarian carcinoma, CSCs, which are considered to contribute to disease relapse and metastasis, were isolated from human ovarian carcinoma tissues, and differentially expressed microRNAs (miRNAs) in CSCs were identified and assessed the clinical implication of expression of these miRNAs. Methods: Primary cancer cells derived from human ovarian carcinomas were cultured and spheroid-forming cells (SFCs) were isolated. Profiles of miRNA expression in CSC-like SFCs were identified by miRNA microarray and the results were validated by quantitative real-time RT-PCR (qRT-PCR). We also assessed the correlations between miRNA expression levels and clinicopathological parameters in ovarian carcinomas. Results: Five miRNAs (miR-5703, miR-630, miR-1246, miR-424-5p, and miR-320b) were significantly dysregulated in CSC-like SFCs compared with primary cancer cells. The qRT-PCR showed that miR-5703 and miR-1246 expression was significantly higher in ovarian cancer cells than in normal control cells, whereas the miR-424-5p level was significantly lower. Decreased expression of miR 424-5p was significantly associated with distant metastasis in high stage (stage IIII & IV) carcinomas (35.5% vs. 72.2%, respectively, p=0.013) Conclusion: Taken together, miR-5703, miR-630, miR-1246, miR-424-5p, and miR-320b are useful markers for enriching ovarian CSCs. Decreased expression of miR-424-5p in ovarian carcinoma might be a putative biomarker for distant metastasis in ovarian carcinoma. PMID- 29151940 TI - Loss of LKB1 Expression Decreases the Survival and Promotes Laryngeal Cancer Metastasis. AB - Background: Given recent results indicating that diminished LKB1 expression in laryngeal cancer correlates with shorter survival. We aim to perform an analysis estimate the role of decreased liver kinase B1(LKB1) and in the prognostication of human laryngeal squamous cell carcinoma (LSCC). Methods: We conducted a retrospective study and evaluate the expression of LKB1 and p16INK4a (p16) in 208 clinical advanced-stage LSCC tissue samples by using immunohistochemistry. The specimens were received at Sun Yat-sen University Cancer Center (Guangzhou, China). To evaluate the independent prognostic relevance of LKB1, univariate and multivariate Cox regression models were used, overall survival (OS) and distant metastasis-free survival (DMFS) were compared using the Kaplan-Meier method. Results: Immunohistochemical analyses revealed that 80/208 (38.5%) of the LSCC tissue samples expressed high LKB1. Low LKB1 expression was associated with a significantly shorter OS and DMFS than high LKB1 expression (P = 0.041 and 0.028, respectively; log-rank test), and there was a poorer OS in the p16-positive than p16-negative group. In the subgroup stratified by p16 status, the shorter OS were also seen with low LKB1 expression. Multivariate survival analysis indicated that high LKB1 expression was an independent prognostic factor for OS (hazard ratio [HR]: 1.628, 95% confidence interval [CI]: 1.060-2.500, P = 0.026) and DMFS (HR: 2.182, 95% CI: 1.069-4.456, P = 0.032). Conclusions: Our data indicated that low expression of LKB1 was significantly associated with poor prognosis and it may represent a marker of tumor metastasis in patients with LSCC. When combined with p16, LKB1 was also of prognostic value. PMID- 29151941 TI - ZEB1 Promotes Oxaliplatin Resistance through the Induction of Epithelial - Mesenchymal Transition in Colon Cancer Cells. AB - Background: Oxaliplatin (OXA) chemotherapy is widely used in the clinical treatment of colon cancer. However, chemo-resistance is still a barrier to effective chemotherapy in cases of colon cancer. Accumulated evidence suggests that the epithelial mesenchymal transition (EMT) may be a critical factor in chemo-sensitivity. The present study investigated the effects of Zinc finger E box binding homeobox 1 (ZEB1) on OXA-sensitivity in colon cancer cells. Method: ZEB1expression and its correlation with clinicopathological characteristics were analyzed using tumor tissue from an independent cohort consisting of 118 colon cancer (CC) patients who receiving OXA-based chemotherapy. ZEB1 modulation of OXA sensitivity in colon cancer cells was investigated in a OXA-resistant subline of HCT116/OXA cells and the parental colon cancer cell line: HCT116. A CCK8 assay was carried out to determine OXA-sensitivity. qRT-PCR, Western blot, Scratch wound healing and transwell assays were used to determine EMT phenotype of colon cells. ZEB1 knockdown using small interfering RNA (siRNA) was used to determine the ZEB1 contribution to OXA-sensitivity in vitro and in vivo (in a nude mice xenograft model). Result: ZEB1 expression was significantly increased in colon tumor tissue, and was correlated with lymph node metastasis and the depth of invasion. Compared with the parental colon cancer cells (HCT116), HCT116/OXA cells exhibited an EMT phenotype characterized by up-regulated expression of ZEB1, Vimentin, MMP2 and MMP9, but down-regulated expression of E-cadherin. Transfection of Si-ZEB1 into HCT116/OXA cells significantly reversed the EMT phenotype and enhanced OXA-sensitivity in vitro and in vivo. Conclusion: HCT116/OXA cells acquired an EMT phenotype. ZEB1 knockdown effectively restored OXA-sensitivity by reversing EMT. ZEB1 is a potential therapeutic target for the prevention of OXA-resistance in colon cancer. PMID- 29151942 TI - Gender-related Outcome in Bladder Cancer Patients undergoing Radical Cystectomy. AB - Background: The impact of gender on oncological outcome after radical cystectomy (RC) is not fully understood yet. The aim of the study was to evaluate gender related differences in histopathological parameters and prognosis of patients with bladder cancer undergoing RC. Methods: A retrospective analysis of a 10-year single-center cystectomy database was performed. Kaplan-Meier survival and Cox regression analyses with sex-specific interactions were performed to determine the impact of gender on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS), in addition to established clinicopathological factors. Results: 259 patients (212 [81.8%] men and 47 [18.2%] women) were enrolled. Although women had a greater propensity for extravesical (>=pT3) disease (53.2% vs. 33.9%, p=0.03) and heterotopic urinary diversion (72.3% vs. 49.5%, p=0.006), gender did not independently predict RFS, CSS or OS on multivariate analysis. Extravesical tumor disease was the sole independent predictor concerning RFS (hazard ratio [HR]=4.70; p<0.001), CCS (HR=2.77; p=0.013), and OS (HR=1.93; p=0.041). Orthotopic urinary diversion (HR=0.36; p=0.002) had an independent effect only on RFS. Rates of 5-year RFS (73.7% vs. 48.3%; p=0.001), CSS (72.5% vs. 44.9%; p<0.001) and OS (62.6% vs. 37.8%; p<0.001) were higher in orthotopic versus heterotopic diversions. Conclusion: In our series, women presented with more advanced tumors and higher rates of heterotopic urinary diversions, but their survival outcome was not significantly inferior to that of men. Extravesical disease was independently related to poorer survival after RC. PMID- 29151943 TI - Total mesopancreas excision for the treatment of pancreatic head cancer. AB - Mesopancreas is a controversial structure. This study aimed to explore the anatomical characteristics of the mesopancreas, define the range of the total mesopancreas excision (TMpE), and evaluate the feasibility, safety and effectivity of TMpE in the treatment of pancreatic head cancer. The clinical and pathological data of 58 consecutive patients undergoing TMpE for pancreatic head carcinoma from January 2013 to December 2015 were analyzed prospectively. The perioperative morbidity, mortality and clinical outcomes of patients undergoing TMpE were compared with the patients undergoing conventional pancreaticoduodenectomy. The mesopancreas was located in the retropancreatic area, extending from the head, neck, and uncinated process of pancreas to the aorto-caval groove, in which there were loose areolar tissue, adipose tissue, nerve plexus, lymphatic and capillaries. We observed significantly higher R0 rate (94.8% vs. 81.4%, P=0.035), more lymph nodes (16.2 vs. 11.4, P=0.000), lower total and local recurrence rate (half-year local recurrence rate 7.8% vs. 23.7%, P=0.036, one-year 18.2% vs. 39.5%, P=0.018) and longer disease-free survival (16.9 vs. 13.4 months, P=0.044) in TMpE group than in control group. In conclusion, mesopancreas is different from mesorectum because there is no fascial envelop or anatomical boundary in this area. TMpE could be safely and feasibly performed for the treatment of pancreatic head cancer to increase the R0 resection rate and improve the clinical outcomes. PMID- 29151944 TI - DNA Methylation Analysis of the SHOX2 and RASSF1A Panel in Bronchoalveolar Lavage Fluid for Lung Cancer Diagnosis. AB - Introduction: Currently the majority of lung cancer patients are diagnosed as advanced diseases for no sensitive and specific biomarkers exist, noninvasive biomarkers with high sensitivity and specificity are urgently needed in lung cancer diagnosis. Bronchoscopy is a standard procedure of the diagnostic work-up of patients with suspected lung cancer despite of the limited diagnostic accuracy. Besides, epigenetic changes through DNA methylation play an important role in tumorigenesis. Thus, we examined the aberrant methylation of the SHOX2 and RASSF1A in bronchoalveolar lavage fluid (BALF) in comparing with conventional cytology examination and serum CEA in order to evaluate the new diagnostic method. Patients and Methods: BALF and serum samples were collected from 322 patients at the time of diagnosis, 284 of them were pathologically confirmed lung cancer, 35 were benign lung diseases and 3 were malignancies in other systems. For all of the 322 patients, the methylation status of the SHOX2 and RASSF1A gene were detected by a new RT-PCR platform and then confirmed by sanger sequencing. Serum CEA were detected using electrochemiluminescence immunoassay. Results: Profiling data showed the consistency of RT-PCR and sanger sequencing in detecting the methylation of the SHOX2 and RASSF1A. Besides, the combination of SHOX2 and RASSF1A methylation in BALF yielded a diagnostic sensitivity of 81.0% and specificity of 97.4%. When compared with established cytology examination (sensitivity: 68.3%, specificity: 97.4%) and serum biomarker carcinoembryonic antigen (CEA) (sensitivity: 30.6%, specificity: 100.0%), the SHOX2 and RASSF1A methylation panel showed the highest diagnostic efficiency. Notably, the combination of cytology and the SHOX2 and RASSF1A methylation panel could significantly improve the diagnostic efficacy. Conclusion: The methylation analysis of the SHOX2 and RASSF1A panel in BALF with RT-PCR achieved a satisfactory sensitivity and specificity in lung cancer diagnosis, especially in an early stage. It could be used as a promising noninvasive biomarker for auxiliary diagnosis of lung cancer. PMID- 29151945 TI - Clinicopathological Characteristics and Prognosis of Ossifying Fibroma in the Jaws of Children: A Retrospective Study. AB - BACKGROUND: Ossifying fibroma in the jaws is a benign tumor and easily recurs in children, of which the treatment methods and prognosis still remain controversial. In this study, we aimed to review the clinicopathological characteristics, treatment, and prognosis of ossifying fibroma in the jaws of children, and offer recommendations for clinical decision-making. METHODS: A retrospective study was carried out on patients below the age of 18 years with ossifying fibroma in the jaws. Patients with complete clinical, pathological, and radiological records were included and followed-up. RESULTS: Sixty-three cases were collected with a preliminary search. After screening, fifty patients were included for general information analysis, of which forty-two patients were included in the recurrence analysis. Twelve patients showed a relapse, with a recurrence rate of 28.6% (12/42). The recurrence rates in cases with different surgical approaches and different X-ray boundaries were statistically different. Besides, twenty-three patients underwent reconstruction by free tissue grafting and the success rate was 96% (22/23). CONCLUSIONS: There was significant difference in the recurrence rates among different X-ray manifestations and surgical methods. An extended resection and reconstruction with free tissue grafting was a reliable method with a 96% success rate. PMID- 29151946 TI - Gene Expression Profiling Reveals Novel Candidate Markers of Ovarian Carcinoma Intraperitoneal Metastasis. AB - Epithelial ovarian cancer (EOC) has the highest mortality among gynecological carcinomas. The lack of specific markers for prognostic determination of EOC progression hinders the search for novel effective therapies. The aim of the present study was (i) to explore differences in expressions of ATP-binding cassette (ABC) and solute carrier (SLC) transporter genes, genes associated with drug metabolism and cell cycle regulation between control ovarian tissues (n = 14), primary EOCs (n = 44) and intraperitoneal metastases (n = 29); (ii) to investigate associations of gene expression levels with prognosis of patients with intraperitoneal metastases. In all tissue samples, transcript levels of the above target genes were assessed using quantitative real-time PCR. Gene expression levels were compared between particular tissue types and evaluated with regard to progression-free survival (PFS) and drug-resistance status of patients with metastases. Gene expression of ABCA7 significantly increased and that of ESR2 decreased in the order control ovarian tissues - primary EOCs - metastases. High expressions of ABCA2/8/9/10, ABCB1, ABCC9, ABCG2, ATP7A, SLC16A14, and SOD3 genes were significantly associated with longer progression free survival of patients. In intraperitoneal metastases, expression of all of these genes highly correlated and indicated prognostic profile. Transporters from the ABCA family, ABCG2, and ESR2 are involved mainly in lipid metabolism, membrane transport, and cell proliferation. These processes are thus probably the most important for EOC progression. Based on these results, we have proposed novel markers of ovarian carcinoma progression and metastatic spread which might be potentially useful as therapeutic targets. Their significance should be further explored on a larger independent set of patients. PMID- 29151947 TI - Diagnostic Accuracy of a CA125-Based Biomarker Panel in Patients with Pancreatic Cancer: A Systematic Review and Meta-Analysis. AB - Background: Increasing evidence from recent studies has revealed the association of CA125 with the diagnosis of pancreatic cancer, but inconsistent findings have been reported. We aimed to evaluate the diagnostic value of a serum CA125-based diagnostic panel in predicting malignant pancreatic cancer. Materials and Methods: We searched EMBASE, MEDLINE and Web of Science for relevant articles from inception to October 2016. Methodological quality was evaluated using the Quality Assessment of Comparative Diagnostic Accuracy Studies (QUADAS-2) checklist. The performance characteristics were pooled using random-effects models. The statistical analysis was performed using Meta-Disc 1.4 and Stata Version 12.0 software. Results: A total of 1235 participants pooled from 8 eligible studies were included in the meta-analysis to evaluate the accuracy of tumor predictors for the diagnosis of pancreatic cancer. The pooling accuracy analysis of CA125 alone indicated that the pooled sensitivity was 0.59 (95% CI: 0.54-0.62) and the specificity was 0.78 (95% CI: 0.75-0.82), whereas the serum CA125-based diagnostic panel had a pooled sensitivity of 0.47 (95% CI 0.47-0.51) and a specificity of 0.88 (95% CI 0.86-0.90). Furthermore, the AUC and Q-value of the CA125-based diagnostic panel were 0.89 and 0.82, respectively, which indicated that the CA125-based panel is superior to CA125 or CA19-9 alone in diagnosing pancreatic cancer. No obvious publication bias was found. Conclusions: In summary, a CA125-based diagnostic panel is better at diagnosing pancreatic cancer than a test using CA125 or CA19-9 alone. Further studies should be performed to confirm our conclusion. PMID- 29151948 TI - High Intratumoral Expression of Tetranectin Associates with Poor Prognosis of Patients with Gastric Cancer after Gastrectomy. AB - Tetranectin, encoded by the clec3b gene, is a plasminogen kringle-4 binding protein that can be detected in the plasma and the extracellular matrix. In malignancies, tetranectin is thought to enhance proteolytic processes enabling tumor cells to invade and metastasize. Nevertheless, the prognostic value of tetranectin in gastric cancer remains elusive. In this study, we found the expression of tetranectin was decreased in gastric cancer. High intratumoral tetranectin level was positively associated with tumor invasion (P = 0.013), lymph node metastasis (P = 0.005), advanced TNM stage (P = 0.003) and shorter overall survival (OS) (P < 0.001) for patients with gastric cancer. Tetranectin expression was identified as an independent prognostic factor for poor OS, and combining tetranectin expression with other independent prognostic factors generated a predictive nomogram, which showed better prognostic efficiency for OS in patients with gastric cancer. In summary, our study suggests that intratumoral tetranectin is a potential independent unfavorable prognostic biomarker for OS of patients with gastric cancer after gastrectomy. PMID- 29151949 TI - Cerebrospinal Fluid Proteins Identification Facilitates the Differential Diagnosis of Central Nervous System Diffuse Large B Cell Lymphoma. AB - Background: Diagnosis of central nervous system (CNS) lymphoma remains a challenge. This study aimed to identify cerebrospinal fluid (CSF) proteins that distinguish patients with and without CNS lymphoma. Methods: We used one dimensional SDS-polyacrylamide gel electrophoresis coupled with liquid chromatography- electrospray ionization-quadrupole-time of flight-mass spectrometry (LC-ESI-Q-TOF MS) to identify CSF proteins in CNS diffuse large B cell lymphoma (DLBCL) patients and controls. Results: Approximately 166 CSF proteins were identified, 12 for the first time in the CSF of lymphoma patients. Three proteins with significantly increased expression in CNS lymphoma patients compared with controls - haemopexin, apolipoprotein A1, and transferrin were verified by immunohistochemistry, and found to be strongly expressed in CNS DLBCL and nodal DLBCL. These proteins were found to be localized in the cytoplasm of a human DLBCL cell line by indirect immunofluorescence. ELISA confirmed expression at higher concentrations in the CSF of CNS lymphoma patients. CSF haemopexin, apolipoprotein A1, and transferrin concentrations were detected in CNS lymphoma patients and had diagnostic sensitivities of 80%, 83%, and 70%, and specificities of 75%, 89%, and 90%, respectively. Conclusion: Our study suggests that CSF proteins may be potential diagnostic biomarker for CNS lymphoma, especially for patients in which imaging and cytology do not provide a clear diagnosis. PMID- 29151950 TI - MCMs expression in lung cancer: implication of prognostic significance. AB - Minichromosome Maintenance (MCM) proteins play essential roles in various cancers. We previously reported that MCM7 could be a prognostic biomarker in non small cell lung cancer (NSCLC). The purpose of current study is to explore roles of other MCM proteins in NSCLC and their correlation with clinico-pathologic parameters of NSCLC patients. We evaluated the expression of MCM2, MCM5 and MCM6 immunohistochemically in 571 primary NSCLC samples. High expression of MCM2, MCM5 and MCM6 was detected in 42.2%, 38.3% and 52.9% of tumor tissues, respectively. The expression of MCM2, MCM5 and MCM6 was significantly associated with gender (P = 0.00004, 0.00004, 0.008), tumor type (P < 0.00001, < 0.00001, 0.00001) and smoking history (P = 0.009, 0.00043, 0.002). MCM2 and MCM5 were detected more in central-type lung cancer (P< 0.006, 0.016). Higher labeling index (LI) of MCM2 was observed more frequently in aged patients (P = 0.023) and in those at later stage (P = 0.001). Higher MCM5 LIs was detected more in patients with distant metastasis (P = 0.008). Kaplan-Meier curves indicated that early-stage (stage I/II) patients with higher MCM2 LIs had a poorer OS compared to those with lower LIs (P = 0.021). And lung squamous cell carcinoma (SCC) patients presenting high MCM5 expression had shorter OS (P = 0.015). Multivariate Cox regression analysis showed that MCM5 was an independent prognostic indicator (P = 0.035, HR = 1.586, 95%CI: 1.032-2.437). We reported for the first time that higher MCM5 LIs could be an independent adverse prognostic biomarker for SCC patients. PMID- 29151951 TI - Potential synergistic effect of phosphodiesterase inhibitors with chemotherapy in lung cancer. AB - Purpose: Lung cancer remains the leading cause of cancer-related deaths worldwide and novel therapeutic approaches targeting crucial pathways are urgently needed to improve its treatment. Differentiation-based therapeutics (Methylxanthines) and phosphodiesterase inhibitors (type 4 and 5), have been implicated in cancer treatment. Our objectives were to capture any potential anti-tumor effect of these drug combinations with chemotherapeutic agents in vitro. Methods: Theophylline as Methylxanthines, Roflumilast as phosphodiesterase type 4 (PDE4) inhibitor and Sildenafil as phosphodiesterase type 5 (PDE5) inhibitor are the drugs that we combined with the chemotherapeutic agents (Docetaxel, Cisplatin and Carboplatin) in vitro. Lung cancer cell lines (NCI-H1048-Small cell lung cancer SCLC, A549- Non-small cell lung cancer-NSCLC) were purchased from ATCC LGC Standards. At indicated time-point, following 24h and 48h incubation, cell viability and apoptosis were measured with Annexin V staining by flow cytometry. Statistical analysis was performed by GraphPad Prism. Results: In SCLC, following 48h incubation, platinum combinations of carboplatin with roflumilast and sildenafil (p<0.001) and carboplatin with theophylline and sildenafil showed increased apoptosis when compared to carboplatin alone. Concerning the combinations of cisplatin, when combined with roflumilast, theophylline and sildenafil appeared with increased apoptosis of that alone (p<0.001, 24h and 48h incubation). In NSCLC, the 24h incubation was not enough to induce satisfactory apoptosis, except for the combination of cisplatin with roflumilast and theophylline (p<0.05) when compared to cisplatin alone. However, following 48h incubation, carboplatin plus sildenafil, carboplatin plus sildenafil, theophylline and roflumilast showed more cytotoxicity when compared to carboplatin alone (p<0.001). Docetaxel combinations showed no statistically significant results. Conclusion: The synergistic effect of PDE inhibitors with platinum-based agents has been demonstrated in lung cancer. Our suggestion is that these combinations could be used as additive and maintenance treatment in combination to antineoplastic agents in lung cancer patients. PMID- 29151952 TI - A Phase II Randomized Controlled Trial: Definitive Concurrent Chemoradiotherapy with Docetaxel Plus Cisplatin versus 5-Fluorouracil plus Cisplatin in Patients with Oesophageal Squamous Cell Carcinoma. AB - Purpose: To evaluate the efficacy and toxicity of definitive concurrent chemoradiotherapy (CCRT) with docetaxel plus cisplatin (DP regimen) versus 5 fluorouracil plus cisplatin (PF regimen) in patients with oesophageal squamous cell carcinoma (ESCC). Patients and Methods: In this phase II randomized controlled trial, eighty-six patients with clinical stage II - IVa ESCC were randomized to receive radiotherapy concurrently with two cycles of the PF or DP regimen at 3-week intervals. The primary endpoint was overall survival (OS). The secondary end points included the overall response rate (ORR), progression-free survival (PFS) and treatment-related toxicities. Results: The ORRs were 84.4% in the DP group and 87.3% in the PF group (P = 0.653). After a median follow-up time of 25.1 months, the 1- and 2-year OS rates were 93.7% and 86.2% for the PF group and 87.3% and 69.1% for the DP group, respectively (P = 0.364). The 1- and 2-year PFS rates were 77.4% and 55.0% for the PF group and 78.8% and 69.4% for the DP group, respectively (P = 0.845). Grade 3/4 leukocytopenia/neutropenia (68.9% vs. 19.5%, P < 0.001) was significantly more common in the DP group. Conclusion: The treatment response, OS and PFS associated with using CCRT with the DP regimen were not superior to those associated with using CCRT with the PF regimen as a first-line treatment in patients with ESCC. Additionally, the DP regimen was associated with more severe haematological toxicities. This trial has been registered with the US National Institute of Health (clinicaltrials.gov, Identifier NCT 02969473). PMID- 29151953 TI - Pancreatic Cancer in Lynch Syndrome Patients. AB - Although colorectal cancer (CRC) is the most common cancer type in Lynch syndrome (LS) families, patients have also increased lifetime risk of other types of tumors. The accumulated risk of pancreatic cancer (PC) in LS patients is around 3.7% and developed tumors often present a characteristically medullary appearance with prominent lymphocytic infiltration. LS patients are considered in high risk for PC development as they present 8.6-fold increase compared with the general population. Here we review PC cases reported in LS patients and current management guidelines. Literature data show that LS is clearly associated with PC and recent publications also demonstrated a connection with pancreatic neoplasic precursor lesions such as intraductal papillary mucinous neoplasms (IPMN) in these patients. While screening techniques are well established for CRC detection, clear strategies are not yet uniform for PC. Magnetic resonance imaging (MRI) and/or endoscopic ultrasound every 1-2 years in MMR mutation carriers with PC in a first or second-degree relative is recommended. Better pancreatic cancer detection strategies should be urgently defined due to the importance of early diagnosis in this disease. PMID- 29151954 TI - Cpt1c regulated by AMPK promotes papillary thyroid carcinomas cells survival under metabolic stress conditions. AB - Background: Cancer cells have to take metabolic transformation in tumor progression when facing need of increased energy and adequate vascularization. However, molecular mechanism is not fully known. In this study, we showed that expression of carnitine palmitoyltransferase 1C (Cpt1c), as a member of the gate keeper enzymes , which transferring long-chain fatty acids into mitochondria to further oxidation, which is regulated by AMPK promotes papillary thyroid carcinomas cells survival under metabolic stress conditions. Methods: Firstly, we used qRT-PCR to detect expression of Cpt1c in papillary thyroid carcinomas tissues compared with paired normal tissues. Secondly, to evaluate whether Cpt1c is induced under metabolic stress, models of hypoxia (0.2% oxygen) and glucose deprivation for cultured papillary thyroid carcinomas cells were established. Lastly, KTC-1 cells were treated with AICAR (as an agonist of AMPK) and Compound C (as an inhibitor of AMPK) to investigate the correlation of AMPK activity with Cpt1c expression under metabolic stress. Results: Cpt1c is higher in papillary thyroid carcinomas tissues compared with paired normal tissues. Furthermore, Cpt1c up-regulation promotes cancer cell growth and metastasis. In addition, the results showed that Cpt1c expression is induced by metabolic stress, including hypoxia and low glucose treatment. Consistently, Cpt1c can protect cells from cancer cells death caused by hypoxia and low glucose. Lastly, Cpt1c expression is regulated by AMPK activity. Conclusion: Here we describe that induction of Cpt1c expression facing metabolic stress in papillary thyroid carcinomas is at least partly regulated by AMPK activity and ultimately contribute to development and progression of papillary thyroid carcinomas. PMID- 29151955 TI - Continuation of Tyrosine Kinase Inhibitor is Associated with Survival Benefit in NSCLC Patients with Exon 19 Deletion after Solitary Progression. AB - INTRODUCTION: The benefit and selection criteria of continuing tyrosine kinase inhibitor (TKI) after secondary resistance in non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutation remain largely unknown. This study was designed to investigate the role and predictive factors of TKI continuation in patients with solitary progression. METHODS: We retrospectively analyzed NSCLCs treated with first generation of TKI from June 2009 to October 2014 in our cancer center. Number of progressive lesions upon first progression was recorded per RECIST v1.1. RESULTS: Sixty-one of 144 (42.4%) patients progressed with one lesion. Postprogression TKI use information was available in 58 patients. No brain metastases and stable disease compared to immediate prior scans were associated continued TKI. In the whole cohort, TKI as the first line treatment was found to be associated with longer postprogression survival, but TKI continuation was not. In patients with exon 19 deletion, TKI continuation compared to discontinuation was significantly associated with longer postprogression survival (32.0 months, 95% CI: 20.8 - 43.3 vs. 15.6 months, 95% CI: 7.3 - 23.8, p=0.013). This difference was not observed in L858R mutation. Exon 19 deletion patients had longer time to TKI cessation after progression (13.7 months, 95% CI: 4.5-22.9 vs. 5.6 months in L858R, 95% CI: 0.0-11.9, p = 0.047). CONCLUSIONS: TKI continuation may prolong survival of NSCLCs with exon 19 deletion rather than L858R. Further studies are required to validate this finding. PMID- 29151956 TI - Strategies for Bispecific Single Chain Antibody in Cancer Immunotherapy. AB - Genetic engineering has resulted in more than 50 recombinant bispecific antibody formats over the past two decades. Bispecific scFv antibodies represent a successful and promising immunotherapy platform that retargets cytotoxic T cells to tumor cells, with one scFv directed to tumor-associated antigens and the other to T cells. Based on this antibody construct, strategies for both specific tumor targeting and T cell activation are reviewed here. Three distinct types of tumor antigens are considered to optimize specificity and safety in bispecific scFv based treatment: cancer-testis antigens, neo-antigens and virus-associated antigens. In terms of T cell activation, although CD3 has been widely applied in bispecific scFvs being developed, CD28 and CD137 among co-stimulatory signals are also ideal candidates to be evaluated. Besides, LIGHT and HIV-Tat101 have drawn much attention as their potential roles in modulating antitumor responses. PMID- 29151957 TI - Curcumin Enhances the Anticancer Effect Of 5-fluorouracil against Gastric Cancer through Down-Regulation of COX-2 and NF- kappaB Signaling Pathways. AB - Background: 5-fluorouracil (5-FU) is one of the most commonly used first-line anticancer drugs to treat gastric cancer in clinical practice. However, severe adverse events such as gastrointestinal toxicity and bone marrow suppression limit its clinical application. Combination chemotherapy to combine two or more anticancer drugs with different mechanistic action is an effective anticancer strategy against gastric cancer. Therefore, we studied the anticancer effect of the combination of 5-FU with curcumin against gastric cancer MKN45 and AGS cells (normal gastric mucosal GES-1 cells as control) and associated molecular mechanisms. Methods: Cytotoxicity of 5-FU and curcumin alone or in combination was evaluated in MKN45, AGS and GES cells by MTT assay. The protein expressions of COX-2 and NF-kappaB were evaluated in MKN45 cells by Western blotting analysis. In addition, antitumor activity of 5-FU and curcumin alone or in combination was evaluated in nude mice bearing MKN45 tumor xenografts in vivo. Results: The combination of 5-FU and curcumin (2:1, mol/mol) showed 2.2-, 3.5 fold and 2.3-, 3.9-fold enhanced cytotoxic effect compared to 5-FU or curcumin alone and generated synergistic effect at the concentration of 5-FU (>4.09 and >5.71 MUmol/l) and curcumin (>2.05 and > 2.86 MUmol/l) in MKN45 cells for 48 h and 72 h exposures, respectively. The combination of 5-FU and curcumin also potentiated cytotoxicity in AGS cells compared to 5-FU or curcumin alone but the effect was moderate. However, the cytotoxicity of 5-FU and curcumin alone or in combination was much less in GES-1 cells. Furthermore, the protein expressions of COX-2 and NF-kappaB in MKN45 cells were decreased by 44.79% and 37.67%, 47.17% and 48.21%, 60.21% and 62.44%, respectively, after treatment of curcumin (25 MUmol/l) and 5-FU (50 MUmol/l) alone or in combination for 48 h. Curcumin also enhanced the anticancer activity of 5-FU without increasing toxicity in nude mice bearing MKN45 tumor xenografts in vivo. Conclusions: Curcumin enhances the anticancer effect of 5-FU against gastric cancer in vitro and in vivo. The possible molecular mechanism may be, at least in part, related to down-regulation of COX-2 and NF-kappaB pathways. PMID- 29151958 TI - Santamarine Inhibits NF-kB and STAT3 Activation and Induces Apoptosis in HepG2 Liver Cancer Cells via Oxidative Stress. AB - Sesquiterpene lactones have long been used in traditional Chinese medicines to treat inflammatory diseases. Recently, sesquiterpene lactone family compounds have been recognized as potential anticancer agents. Thus, it is necessary to explore new sesquiterpene lactones and their antitumor mechanism for cancer treatments. In the present study, we have explored the potential anti-cancer activity of a novel sesquiterpene lactone compound "santamarine" (STM) in HepG2 cells. It inhibited proliferation and induced apoptosis dose-dependently with IC50 ~ 70 MUM. Induction of apoptosis was found to be linked with increased reactive oxygen species (ROS) generation, decreased activity of thioredoxin reductase (TrxR), glutathione (GSH) depletion, mitochondrial membrane potential (DeltaPsim) dissipation, Bcl-2 family proteins modulation, cytochrome c release, caspases-9, -8 and -3 activation and PARP cleavage. Further mechanistic study demonstrated that STM inhibited the constitutive and TNF-alpha-induced translocation of NF-kB into nucleus by decreasing phosphorylation of IkB-alpha. Moreover, STM inhibited STAT3 activation by decreasing phosphorylation at tyrosine705. NAC pretreatment reversed the effect of STM-mediated cell death, NF kB inhibition and blockage of STAT3 activity, indicating the involvement of oxidative stress in STM-mediated anticancer activity. Further studies are needed to explore the exact molecular mechanism of STM-induced apoptosis to develop it into a lead for treatment of liver cancer in future. PMID- 29151959 TI - Survival and Toxicities of IMRT Based on the RTOG Protocols in Patients with Nasopharyngeal Carcinoma from the Endemic Regions of China. AB - Background: This study evaluated the survival outcomes and toxicities of intensity-modulated radiation therapy (IMRT) based on the RTOG 0225/0615 RT protocols in patients with nasopharyngeal carcinoma (NPC) from a region of China where this tumor type is endemic. Methods: A total of 455 patients with non metastatic, histologically-confirmed NPC were retrospectively reviewed. All patients were treated by IMRT using the RTOG 0225/0615 RT protocols; 91.1% (288/316) of patients with stage III-IVb NPC received concurrent chemotherapy +/- induction chemotherapy or adjuvant chemotherapy. Results: Estimated four-year overall survival (OS), failure free survival (FFS), local relapse free survival (LRFS), regional relapse free survival (RRFS) and distant metastasis free survival (DMFS) were 83.8%, 80.5%, 94.3%, 96.7% and 85.8%, respectively. T and N category were significant prognostic factors for OS, FFS, RRFS and DMFS; and T category, for LRFS. In-field failure was the major loco-regional failure pattern. During RT, 206 (45.3%) patients experienced acute grade 3-4 toxicities. The most common acute toxicity was mucositis; 124 (27.2%) patients experienced grade 3-4 mucositis; 46 (10.1%) experienced serious late toxicities. The most common late toxicity was MRI-detected radiation-induced temporal lobe necrosis (6.8%). Conclusions: The RTOG IMRT protocols are feasible for patients with NPC from the endemic regions of China. PMID- 29151960 TI - R.E.N.A.L. Nephrometry Score: A Preoperative Risk Factor Predicting the Fuhrman Grade of Clear-Cell Renal Carcinoma. AB - Objective: The purpose of this study was to evaluate the efficacy and feasibility of the R.E.N.A.L. Nephrometry Score to postoperatively predict high-grade clear cell renal carcinoma (ccRCC). Methods: The study included 288 patients diagnosed with ccRCC who had complete CT/CTA data and R.E.N.A.L. Nephrometry Scores and underwent renal surgery at our center between January 2012 and December 2015. The relationship between the pathological grade of renal masses and R.E.N.A.L. Nephrometry Score was evaluated. Results: Univariate analysis indicated that diagnostic modality, cystic necrosis, enlargement of the regional lymph node, distant metastasis, clinical T stage, TNM stage, surgical modality, tumor size, nearness of the tumor to the collecting system or sinus, total Nephrometry Score and individual anatomic descriptor components were significantly associated with postoperative tumor grade (P < 0.05). Multivariate analysis showed that tumor size, the maximal diameter (R score), exophytic/endophytic properties (E score) and the location relative to the polar lines (L score) were independent prognostic factors to preoperatively predicting ccRCC pathological grade. The areas under the ROC curve with respect to the multi-parameter regression model (0.935, 95%CI: 0.904-0.966), tumor size (0.901, 95%CI: 0.866-0.937), R score (0.868, 95%CI: 0.825-0.911), E score (0.511, 95%CI: 0.442-0.581) and L score (0.842, 95%CI: 0.791-0.892) were calculated and compared. Conclusion: Tumor size, as well as R, E, and L scores were independent prognostic factors for high-grade pathology. Lager tumor sizes and higher R, E and L scores were more likely to be associated with high-grade pathological outcomes. Thus, the R.E.N.A.L. Score is of practical significance in facilitating urologists to make therapeutic decisions. PMID- 29151961 TI - Galectin-1 promotes tumor progression via NF-kappaB signaling pathway in epithelial ovarian cancer. AB - Purpose: We previously reported that Galectin-1 (Gal-1) played a role in epithelial ovarian cancer (EOC) progression. In this study, we aimed to further investigate the association between Gal-1 expression and prognosis in EOC patients and tried to reveal some novel potential mechanisms of Gal-1 in EOC invasion and migration. Materials and Methods: Gal-1 and nucleus NF-kappaBp65 expression in 109 human epithelial ovarian cancer tissue specimens were evaluated by immunohistochemistry. The Cox model and survival curves were used to investigate the effect of Gal-1 on EOC prognosis. Correlation between Gal-1 expression and NF-kappaB activation in EOC patients was also analyzed. In vitro experiments were further performed to reveal the function and mechanisms of Gal-1 in invasion and migration of EOC cells. Results: Expression level of Gal-1 in EOC tissue was an independent prognostic factor on overall survival (p<0.05) and progression-free survival (p<0.05). Patients with high Galectin-1 expression had shorter overall survival (OS, p<0.05)) and progression-free survival (PFS, p<0.05). Immunohistochemistry revealed that expression of Gal-1 was positively associated with activation of NF-kappaBp65 in EOC tissues (Kappa coefficient=0.458, p<0.001). Patients with tumors concomitantly co-over expressing Gal-1 and NF-kappaBp65 had the worse OS (p<0.001) and PFS (p<0.001). The abilities of migration and invasion for EOC cells were significantly reduced after Gal-1 knocked-down in human EOC cell line HO8910, which was accompanied with the suppression of NF-kappab pathway activation and with the matrix metalloproteinase-2 and matrix metalloproteinase-9 down-regulation. Conclusions: Our results suggest that Gal-1 is associated with poor outcome in EOC and Galectin-1 promotes tumor progression via NF-kappaB pathway activation in EOC. PMID- 29151962 TI - Insufficient Radiofrequency Ablation Treated Hepatocellular Carcinoma Cells Promote Metastasis by Up-Regulation ITGB3. AB - Radiofrequency ablation (RFA) is one of the standards of care for early stage hepatocellular carcinoma (HCC). However, rapid progression of residual tumor after RFA has been confirmed. The aim of this study was to investigate the underlying mechanism of this phenomenon. Human HCC cell lines HCCLM3 and HepG2 were employed to establish insufficient RFA models in vivo and in vitro, respectively. The effects of insufficient RFA on metastatic potential of residual tumors were evaluated. The molecular changes after insufficient RFA were evaluated by PCR array, western blot, immunofluorescence, and immunohistochemistry. Results showed that insufficient RFA significantly promoted lung and intrahepatic residual tumor cells in vivo, and heat intervention promoted migration and invasion of hepatoma cells in vitro. PCR array revealed that the expression of integrin beta3 (ITGB3) and MMP2 were up-regulated in the residual tumors of HCCLM3 xenograft model. The up-regulation of ITGB3 was confirmed by qRT-PCR, Western blot and immunohistochemistry. Knockdown ITGB3 expression in HCCLM3 cells by shRNA significantly lowered the pro-metastatic effects of insufficient RFA. Mechanism studies indicated that ITGB3 mediated the expression of MMP2 by activing FAK/PI3K/AKT signaling pathway. The up-regulation of ITGB3 contributed to enhanced metastatic potential of residual cancer in HCCLM3 model after insufficient RFA. Targeting ITGB3 expression may further improve the clinical effects of RFA. PMID- 29151963 TI - A nomogram based on phosphorylated AKT1 for predicting locoregional recurrence in patients with oesophageal squamous cell carcinoma. AB - Background: The AKT signalling pathway controls survival and growth in many malignant tumours. However, the prognostic value of phosphorylated AKT1 (p-AKT1) for locoregional-progression free survival (LPFS) in oesophageal squamous cell carcinoma (ESCC) has not been established. Our aim was to develop a nomogram to predict local recurrence using p-AKT1 and main clinical characteristics in patients with thoracic ESCC undergoing radical three-field lymph node dissection. Methods: Immunohistochemistry was performed to examine p-AKT1 expression in 181 thoracic ESCC patients. The Kaplan-Meier method was used to calculate LPFS. Cox regression analysis was also performed to evaluate prognostic factors. A nomogram comprising biological and clinical factors was established to predict LPFS. Results: The 5-year LPFS rate was 63.9%. Multivariate analysis revealed that expression of p-AKT1 (p<0.001), pathologic N category (p=0.004) and number of lymph nodes retrieved (p=0.001) were independent prognostic factors for LPFS. Increased expression of p-AKT1 was associated with decreased LPFS in patients with ESCC. In addition, a nomogram was established based on all significant independent factors for locoregional recurrence risk. Harrell's c-index for predicting LPFS was 0.78. Conclusion: Activation of AKT1 was associated with poor locoregional control in ESCC patients. The nomogram, based on p-AKT1 expression and clinically significant parameters, could be used as an accurate stratification model for predicting locoregional recurrence in patients with ESCC after radical resection. PMID- 29151964 TI - ITGBL1 Predicts a Poor Prognosis and Correlates EMT Phenotype in Gastric Cancer. AB - Integrin, beta-like 1 (ITGBL1), a beta-integrin-related extracellular matrix protein, was found more commonly up-regulated in gastric cancer (GC) by screening and analyzing Gene Expression Omnibus (GEO) and Oncomine databases, reminding us to explore its prognostic significance in GC. In our current study, we observed that ITGBL1 expression was significantly up-regulated in GC compared with normal controls in clinical specimens. In addition, elevated ITGBL1 expression was positively correlated with patients' tumor-node-metastasis (TNM) stage and distant metastasis. Kaplan-Meier analysis indicated that high ITGBL1 expression was significantly associated with shorter survival times in GC patients. Multivariate Cox regression analysis confirmed ITGBL1 expression as an independent prognostic factor in GC. Gene set enrichment analysis (GSEA) of multiple GEO datasets revealed a close relationship between ITGBL1 expression and the KRAS/epithelial-mesenchymal transition (EMT) signaling pathway. In conclusion, these data provide evidences that ITGBL1 is a potential predictor and may be involved in cancer cell invasion and metastasis via inducing EMT, and the ITGBL1-related pathways may represent a novel therapeutic strategy for treatment of GC. PMID- 29151965 TI - Combined Inhibitions of Glycolysis and AKT/autophagy Can Overcome Resistance to EGFR-targeted Therapy of Lung Cancer. AB - Efficacy of EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, to treat human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR is not persistent due to drug resistance. Reprogramming in energy (especially glucose) metabolism plays an important role in development and progression of acquired resistance in cancer cells. We hypothesize that glucose metabolism in EGFR-TKI sensitive HCC827 cells and erlotinib-resistant sub-line of HCC827 (which we name it as erlotinib-resistant 6, ER6 cells in this study) is different and targeting glucose metabolism might be a treatment strategy for erlotinib-resistant NSCLCs. In this study, we found increased glucose uptakes, significant increase in glycolysis rate and overexpression of glucose transporter 1 in ER6 cells compared to its parental cells HCC827. We also found AKT and autophagy of ER6 cells were more activated than HCC827 cells after glucose starvation. Combining glucose deprivation and AKT or autophagy inhibitor could synergize and overcome the acquired resistance against EGFR-targeted therapy for NSCLCs. Our data suggest that the combinations of inhibitors of AKT or autophagy together with glucose deprivation could be novel treatment strategies for NSCLC with acquired resistance to targeted therapy. PMID- 29151966 TI - Polymorphisms of CCNB1 Associated With the Clinical Outcomes of Platinum-Based Chemotherapy in Chinese NSCLC Patients. AB - As a crucial cell cycle regulator and G2/M phase promotor, CCNB1 played an essential role in progression of chemotherapy related cell death. Platinum-based chemotherapy is still the first-line chemotherapy regimen for most advanced NSCLC patients. We aim to investigate the correlation of CCNB1 polymorphisms to the efficiency of platinum-based chemotherapy in Chinese advanced NSCLC patients. We enrolled 972 patients with advanced NSCLC, and extracted DNA from their peripheral blood for genotyping CCNB1 four tagSNPs which selected from the Hapmap database. We analyzed the association of CCNB1 four tagSNPs with efficiency of platinum-based chemotherapy. We found that rs2069429 and rs2069433 of CCNB1 were associated with the OS of advanced NSCLC patients. Patients with GG genotype of rs2069429 had longer OS than non-GG patients (HR=0.81, 95%CI=0.68-0.95, p=0.009); and patients with AA genotype of rs2069433 had longer OS than non-AA patients (HR=0.78, 95%CI=0.61-0.98, p=0.036). And the haplotype GAAA of CCNB1 was a putative factor in subgroup patients with clinical stage IV. The association of CCNB1 polymorphisms and toxicities after platinum-based chemotherapy was assessed. Rs2069433 and rs350104 were related with gastrointestinal toxicity of platinum-based chemotherapy. The patients with GG genotype of rs2069433 (p=0.013) and/or non-GG genotype of rs350104 (p=0.042) may have a severe gastrointestinal toxicity after chemotherapy, and then clinician may can reduce the dosage of chemotherapy agents to avoid sever toxicities in these patients. In summary, CCNB1 polymorphisms may contribute to the clinical efficiency of platinum-based chemotherapy in advanced NSCLC patients, and it is helpful for the personalized treatment. PMID- 29151967 TI - New Clinical Features and Dosimetric Predictor Identification for Symptomatic Radiation Pneumonitis after Tangential Irradiation in Breast Cancer Patients. AB - Background: Tangential irradiation is the most popular postoperative radiotherapy technique for breast cancer. However, irradiation has been related to symptomatic radiation pneumonitis (SRP), which decreases the quality of life of patients. This study investigated the clinical features and dosimetric parameters related to SRP of the ipsilateral lung to identify risk factors for SRP in breast cancer patients after three-dimensional conformal radiation therapy (3D-CRT) with tangential fields. Material and Methods: A total of 515 breast cancer patients were evaluated and divided into two groups: the local-regional irradiation group (259 patients) and the simple local irradiation group (256 patients). Clinical symptoms were registered and patient data collected. The relationship between the incidence of SRP and dosimetric parameters for the ipsilateral lung was assessed within 6 months after 3D-CRT. Dosimetric parameters were compared using t tests. The dosimetric predictors for SRP were estimated using a logistic regression model and receiver operating characteristic curve analysis. Results: In total, 19 patients (3.7%) developed grade 2 SRP. In the local-regional irradiation group, the probability of SRP in the lung body was greater than that in the lung apex (3.9% vs. 1.5%). V20 and V30 were independent predictors for SRP in the local regional irradiation group (odds ratio = 1.152 and 1.439, both p = 0.030), whereas only V20 was an independent predictor of SRP in the simple local irradiation group (odds ratio = 1.351, p = 0.001). With 39.8% as the optimal threshold for V20 and 25.7% for V30 for local-regional irradiation, SRP could be predicted with an accuracy of 80.3% and 79.9%, a sensitivity of 61.5% and 69.2%, and a specificity of 81.3% and 80.5%, respectively. With 20.2% as the optimal V20 threshold for simple local irradiation, SRP could be predicted with an accuracy of 88.7%, a sensitivity of 83.3% and a specificity of 89.6%. Conclusions: SRP has become a rare complication with mild symptoms and occurs mainly in the lung body. V20 and V30 may be useful dosimetric predictors to evaluate SRP risk of the ipsilateral lung in breast cancer. PMID- 29151969 TI - Overexpression of SMOC2 Attenuates the Tumorigenicity of Hepatocellular Carcinoma Cells and Is Associated With a Positive Postoperative Prognosis in Human Hepatocellular Carcinoma. AB - Secreted modular calcium binding protein-2 (SMOC2), a recently identified matricellular protein that belongs to the SPARC protein family, has been reported to be downregulated in various cancers. The purpose of this study was to investigate the clinical significance and biological function of SMOC2 in human hepatocellular carcinoma. Real-time quantitative PCR and western blotting analyses revealed that SMOC2 mRNA and protein levels were significantly downregulated in human HCC tissues compared to the matched adjacent normal tissues. Clinicopathological analysis indicated that SMOC2 expression was significantly associated with tumor size, number of tumors, tumor-node-metastasis (TNM) stage and distant metastasis. Kaplan-Meier survival analysis showed that high tumor SMOC2 expression was associated with improved overall survival and disease-free survival in patients with HCC. Functional analyses (cell proliferation and colony formation assays, cell migration and invasion assays, cell cycle and apoptosis assays) demonstrated that stable overexpression of SMOC2 using a lentiviral vector significantly inhibited cell proliferation, colony formation, migration and invasion, and induced G0/G1 phase arrest in HCC cells in vitro. In addition, experiments with a mouse model revealed the suppressed effect of SMOC2 on HCC tumorigenicity and metastases in vivo. These results suggest that SMOC2 functions as a tumor suppressor during the development of HCC and may represent an effective prognostic factor and novel therapeutic target for HCC. PMID- 29151968 TI - LncRNA MALAT1 Inhibits Apoptosis and Promotes Invasion by Antagonizing miR-125b in Bladder Cancer Cells. AB - Accumulating evidences suggest that longnon-coding RNAs (lncRNAs) play functional roles in development of different cancers, including cancer initiation and progression. Metastasis associated lung adenocarcinoma transcript 1(MALAT1) is a well-known lncRNA which was previously shown to be a direct target of miR-125b in bladder cancer (BCa) and to promote cancer progression and invasion. However, little is known whether MALAT1 can also target miR-125b. In the present study, using CRISPR-based technologies and qRT-PCR, we show that MALAT1 is capable of suppressing mature miR-125b and increasing the expression of its target genes (Bcl-2 and MMP-13), but has no effect on pri-miR-125b and pre-miR-125b. We observe that the biotin-labeled MALAT1-RNA probe is able to pull down Ago2 and miR-125b and that the negative regulation of miR-125b by MALAT1 is dependent on Ago2. Importantly, the results of flow cytometry assay and transwell assay reveal that the MALAT1-mediated cancer progression is in part due to specific suppression of miR-125b and activation of its two target genes. All together, these data suggest that the "MALAT1-miR-125b-Bcl-2 / MMP-13" axis plays an important role in the progression of BCa, thereby may provide a potential therapeutic strategy for the treatment of human BCa. PMID- 29151970 TI - Ki67 Proliferation Index as a Histopathological Predictive and Prognostic Parameter of Oral Mucosal Melanoma in Patients without Distant Metastases. AB - Background: To investigate the relationship between clinical and histopathological characteristics and overall survival of patients with oral mucosal melanoma (OMM) without distal metastasis in order to provide predictive prognostic information of OMM. Methods: Ki67 expression was assessed by immunohistochemistry in 123 patients with OMM without distant metastases. The associations between Ki67 expression and clinical features and overall survival (OS) of patients were statistically analyzed. The Ki67 levels of the primary and recurrent lesions from 14 OMM patients were compared. Results: Univariate analysis showed that tumor type and cervical lymph node (CLN) status, as well as Ki67 expression, were all correlated with survival. Cox proportional hazards regression analysis identified Ki67 expression and CLN status as independent prognostic factors in OMM patients. Further, we found that Ki67 expression was associated with clinical tumor type of OMM. Moreover, with a cut-off point of 20%, patients with lower Ki67 scores showed a survival advantage over those with higher Ki67 scores. Conclusions: Ki67 expression may be a useful pathological predictor of survival of OMM patients without distant metastases. PMID- 29151971 TI - The Predictive and Prognostic Role of Stromal Tumor-infiltrating Lymphocytes in HER2-positive Breast Cancer with Trastuzumab-based Treatment: a Meta-analysis and Systematic Review. AB - Background Tumor-infiltrating lymphocytes (TILs) are white blood cells that have left the bloodstream and migrated into a tumor, involving in the prognosis of breast cancer (BC) patients. Published studies reported the value of TILs in patients with HER2-positive receiving trastuzumab-based treatment. However, the results obtained remain controversial. Here, we conducted this study to explore the predictive and prognostic role of TILs for HER2-positive BC patients receiving trastuzumab therapies. Method To identify the related published studies, a comprehensive literature search dating up to July 2017 was performed in the databases of PubMed, PMC, Web of Science and China National Knowledge Infrastructure (CNKI) according to predefined selection criteria. The pathologic complete response (pCR) and survival outcome of patients were measured by odds ratio (OR) and hazard ratio (HR) with corresponding 95% confidence interval (95% CI), respectively. The association between TILs and trastuzumab benefit was analyzed by using STATA version 11.0. Result Eleven eligible studies comprising 3228 patients were identified in the present study. The pooled results showed that high level of TILs was associated with a significantly improved pCR rate (OR = 1.32; 95% CI = 1.10-1.60) and longer survival (HR = 0.97; 95% CI = 0.96-0.99), particularly in the subgroups of retrospective study design and 10% INC cut-off value. Moreover, stratified analysis revealed that elevated TILs was a predictor of higher pCR rate in the Asian population and improved survival in the subgroups of Caucasian population and multivariate analysis. Conclusion This meta-analysis indicated that the level of stromal TILs was an independent predictive and prognostic marker for better outcome in HER2-positive BC patients receiving trastuzumab-based treatment. High level of TILs was significantly associated with trastuzumab benefit. PMID- 29151972 TI - Comparable Survival between Additional Radiotherapy and Local Surgery in Occult Breast Cancer after Axillary Lymph Node Dissection: A Population-based Analysis. AB - Purpose: To investigate the clinical value of additional local treatment strategies in occult breast cancer (OBC) after axillary lymph node dissection (ALND). Methods: Patients diagnosed with OBC between 1990 and 2013 were included from the Surveillance, Epidemiology, and End Results registry database. The significant risk factors of cause-specific survival (CSS) and overall survival (OS) were identified using univariate and multivariate Cox regression analyses. Results: We identified 980 patients, including 219 (22.3%), 252 (25.7%), 263 (26.8%), and 246 (25.1%) of patients underwent ALND, ALND + radiotherapy (RT), ALND + surgery (S) (mastectomy or breast-conserving surgery), and ALND + S + RT, respectively. Patients with younger age, diagnosed before 2000, advanced nodal stage, ER-negative disease, and PR-negative disease were more likely to undergo additional local treatment compared with ALND only. The 10-year rate CSS of the ALND only group was 57.2%, while that of the ALND + RT, ALND + S, and ALND + S + RT groups was 78.0%, 81.0%, and 71.5%, respectively (p < 0.001). The 10-year OS rate in the ALND only, ALND + RT, ALND + S, and ALND + S + RT groups was 46.0%, 69.5%, 66.1%, and 67.0%, respectively (p < 0.001). Multivariate analysis indicated that older age, advanced nodal stage, and ALND only were independent risk factors for decreased CSS and OS. CSS and OS among the groups including ALND + RT, ALND + S, and ALND + S + RT were not significantly different. Conclusions: Additional local treatment (local surgery or RT) improves survival outcomes compared with ALND only in OBC after ALND. ALND + RT may be the optimal local treatment for OBC due to no different in survival outcomes and cosmesis is better. PMID- 29151973 TI - Roles of microRNAs in the resistance to platinum based chemotherapy in the non small cell lung cancer. AB - Platinum-based adjuvant chemotherapy improves survival among patients with lung tumors, in particular non-small cell lung cancer (NSCLC). But the predicament of drug resistance in NSCLC patients is frustrating us. The profiles of microRNAs are different between platinum chemotherapy resistant and sensitive NSCLC cells. Researches regarding microRNAs and their targets, in platinum drug resistant cases, illuminate novel ideals for platinum-based chemotherapy for NSCLC patients. Therefore, in this review we will focus on three aspects: Epithelial mesenchymal transition (EMT), cell proliferation and apoptosis, and the roles of microRNAs in cisplatin (CDDP) and carboplatin (CBP) resistance. PMID- 29151974 TI - Preoperative Albumin-Bilirubin Score for Postoperative Solitary Hepatocellular Carcinoma within the Milan Criteria and Child-Pugh A Cirrhosis. AB - Surgical resection remains the initial treatment of choice for the majority of early stage hepatocellular carcinoma (HCC) patients. Although the factors that influence the prognosis of postoperative HCC patients have been well elucidated, there are a limited number of simple, objective, and distinct methods for estimating survival for postoperative patients with solitary HCC within the Milan criteria and Child-Pugh (C-P) A cirrhosis. The Albumin-Bilirubin (ALBI) score is a new evidence-based approach to assess liver function. The ALBI score eliminates subjective variables, such as ascites and encephalopathy which are the requirements for the conventional C-P grading system. This study enrolled 654 patients to determine whether the ALBI score can predict the outcomes of postoperative solitary HCC patients within the Milan criteria and C-P A cirrhosis. Our results showed the ALBI score significantly influenced the overall survival and cumulative recurrence rates. Furthermore, the ALBI score was significantly related to the degree of liver cirrhosis and serum gamma-glutamyl transpeptidase (GGT) concentration in solitary HCC cases within the Milan criteria and C-P A cirrhosis. Additionally, the combination of the ALBI score and serum GGT concentration contributed to the prognosis prediction in this cohort. In conclusion, we externally validated the ALBI grade as a novel biomarker to predict prognosis for solitary HCC within the Milan Criteria and C-P A cirrhosis. PMID- 29151975 TI - Clinical Significance of CD163+ and CD68+ Tumor-associated Macrophages in High risk HPV-related Cervical Cancer. AB - Objective. To explore the influence of M2-polarized tumor-associated macrophages (TAMs) on high-risk human papillomavirus (hr-HPV)-related cervical carcinogenesis and metastasis. Methods. CD68+ and CD163+ macrophages were examined immunohistochemically in a series of 130 samples, including 26 cases of normal cervical tissues, 59 cases of cervical intraepithelial neoplasia (CIN), and 45 cases of squamous cell carcinoma (SCC), and the results were statistically analyzed. The macrophage count was corrected for the epithelial and stromal compartments respectively. Clinical data were also obtained. Results. High counts of CD68+ and CD163+ macrophages were associated with hr-HPV infection (both p < 0.05) and positively correlated with cervical carcinogenesis (Spearman's rho = 0.478, p = 0.000; Spearman's rho = 0.676, p =0.000, respectively). The immunostaining pattern of CD163 exhibited clearer background than that of CD68. CD163+ macrophages showed a more obviously increasing migration into the epithelium along with the progression of CIN to invasive cancer. Notably, a high index of CD163+ macrophages was significantly associated with higher FIGO stages (p = 0.009) and lymph node metastasis (p = 0.012), but a similar finding was not found for CD68+ macrophages (p = 0.067, p = 0.079, respectively). Conclusions. Our study supported a critical role of TAMs as a prospective predictor for hr-HPV related cervical carcinogenesis. CD163, as a promising TAMs marker, is superior to CD68 for predicting the malignant transformation and metastatic potential of cervical cancer. PMID- 29151976 TI - Aqueous Huaier Extract Suppresses Gastric Cancer Metastasis and Epithelial to Mesenchymal Transition by Targeting Twist. AB - Trametes robiniophila Murr. (Huaier) is a widely used anti-cancer agent in China. Strong evidence for the anti-proliferative activity of Huaier has been reported; however, its anti-metastatic potential against gastric cancer (GC) as well as its underlying mechanism of action are unknown. Here, we show that treatment with an aqueous Huaier extract over a range of concentrations significantly suppressed both the invasiveness and migratory ability of GC cells. Huaier could also partly reverse the epithelial-mesenchymal transition (EMT), as characterized by increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin. In addition, Huaier-treated cells expressed lower levels of Twist compared to untreated controls, and overexpression of Twist via transfection could partially abolish the anti metastatic activity of Huaier. Furthermore, elevated Twist expression was correlated with an advanced TNM stage, a high rate of lymph node metastasis, and reduced disease-free survival in GC patients. These findings reveal a novel anti metastatic mechanism for Huaier, which inhibits the EMT by targeting Twist, suggesting its potential application against a GC relapse. PMID- 29151977 TI - PFKFB3 promotes proliferation, migration and angiogenesis in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a squamous epithelial cancer, arising from the nasopharynx epithelium. It has high morbidity and mortality. PFKFB3 as a glycolytic activator has been implicated in the progression of multiple types of tumor. PFKFB3 can be contributed to the progression and metastasis of cancer. However, whether PFKFB3 is associated with the progression of NPC remains unknown. We postulated that PFKFB3 promotes proliferation, migration and angiogenesis in nasopharyngeal carcinoma. In this study, we found that PFKFB3 was significantly up-regulated in NPC tissues and cell lines compared with normal control. Our study proved that PFKFB3 can regulate the proliferation, metastasis and apoptosis of NPC. By the way, the NPC-derived exosomes come from and CNE2 derived exosomes are enriched in PFKFB3. The enrichment of PFKFB3 played a crucial functional role in promotes HUVECs proliferation, migration and angiogenesis. And tumor angiogenesis is closely related to the proliferation and metastasis of tumor. In conclusion, our findings demonstrate that PFKFB3 could act not only as a clinical biomarker for angiogenesis but also as a therapeutic target to overcome angiogenesis, enhancing the clinical benefits of angiogenesis therapy in NPC patients. PMID- 29151978 TI - Overexpression of alpha-sma-positive fibroblasts (CAFs) in Nasopharyngeal Carcinoma Predicts Poor Prognosis. AB - Purpose: The aim of this study is to investigate the differential expression of alpha-sma-positive fibroblasts (CAFs) in nasopharyngeal carcinomas (NPCs), nasopharyngitis, metastatic tissues of NPCs and its prognostic value in NPCs. Methods: The expression of alpha-sma-labeled CAFs in 85 NPCs, 32 nasopharyngitis and 12 metastatic tissues of NPCs was detected by immunohistochemical method. The relationship between CAFs and clinicopathological parameters of NPCs was analyzed. Results: The high density of CAFs in the NPCs, nasopharyngitis and metastatic tissues of NPCs group were 41.2% (35/85), 6.2% (2/32) and 83.3% (10/12), and a significant difference was showed among these three groups (P<0.05). Chi-square test showed that there was no significant correlation between the density of CAFs and gender, age, N stage, treatment (P>0.05), but closely correlated with T stage and relapse (P<0.05). Kaplan-Meier survival analysis showed that the mean overall survival of high-density and low-density CAFs was 86.8 months and 127.0 months, respectively. Correspondingly, the 5-year survival rates were 57.1% (20/35) and 90.0% (45/50), and there were inversely statistical differences between two groups (P<0.05). Cox multivariate analysis showed that the density of CAFs could be used as an independent prognostic factor for the survival of NPC patients (P<0.05). Conclusions: The density of CAFs could be closely related to the metastasis of NPCs, and also is an efficient prediction factor of poor survival in patients with NPCs. PMID- 29151979 TI - Effects of Triple Effective RNA (teRNA) on the Inhibition of Hepatocellular Carcinoma Cells. AB - The occurrence and development of hepatocellular carcinoma (HCC) is a complicate process involved in genetic mutation and epigenetic regulation. Successful HCC therapy needs multi-targets be involved. The aim of this study was to provide a triple effective RNA (teRNA) which composed of the specific siRNAs targeting NET 1 and VEGF and dsRNA activating TLR3, and explored its anti-HCC roles and mechanism. Real-time quantitative PCR (RT-qPCR), Western blot, immunofluorescence staining, MTT, Annexin V-FITC flow cytometry, Transwell and in-vitro Angiogenesis assay were used to measure the cell biological functions and protein expression analysis. Furthermore in in-vivo mouse model, teRNA inhibited tumor growth were detected by immunohistochemistry and TUNEL assay. Results showed that the proliferation, migration and angiogenesis of HCC cells were inhibited by teRNA effectively, the cell apoptosis also was induced, and further tumor growth was suppressed in-vivo. The gene silencing mechanism of teRNA was in an Ago2 dependent manner with no interferon response. The study suggests that NET-1, VEGF and TLR3 might be better targets for HCC treatment and combined these targets in form of a multi-target small RNA, teRNA could be a stagey for the development of anti-HCC drugs. PMID- 29151980 TI - Synbiotic effects of beta-glucans from cauliflower mushroom and Lactobacillus fermentum on metabolic changes and gut microbiome in estrogen-deficient rats. AB - Background: We investigated whether the long-term consumption of a symbiotic formulation with Lactobacillus fermentum (probiotic) and beta-glucan from cauliflower mushroom (prebiotic) would delay the progression of post-menopausal symptoms in ovariectomized (OVX) rats and explored their mechanisms of action, including changes in gut microbiota. Methods: OVX rats were fed with high-fat diets containing 1% dextrin (control), 1% lyophilized cauliflower mushroom extract (CFM), 0.1% L. fermentum JS (LFE), 1% CFM plus 0.1% LFE (CFLF), or 30 MUg 17beta-estradiol/kg body weight (positive-control) for 8 weeks. Results: CFM contained 95.8% beta-glucans. OVX increased the ratio of Firmicutes and Bacteroidetes in the large intestines. Only CFLF lowered tail skin temperature without increasing serum 17beta-estradiol and uterine index. Visceral fat mass was lower in CFLF and positive-control groups by increasing daily energy expenditure and fat oxidation. Dyslipidemia induced by OVX was improved by CFM and CFLF as much as in the positive-control group. Homeostasis model assessment estimate of insulin resistance was lower in CFLF than in the positive-control. Hepatic insulin signaling (pAkt?GSK-3beta) was potentiated in the ascending order of the control, LFE, CFM, CFLF, and positive-control. AMPK phosphorylation showed similar patterns of hepatic insulin signaling but LFE increased it more than CFM. The changes in gut microbiota were prevented by CFLF in OVX rats, and the ratio of Firmicutes and Bacteroidetes in the CFLF was similar to the positive-control group. Conclusion: OVX changed gut microbiota and was associated with menopausal symptoms; however, the synbiotics, CFM and LFE, prevented menopausal symptoms and improved the gut microbiota in estrogen-deficient rats. PMID- 29151981 TI - Cellular Uptake of Plain and SPION-Modified Microbubbles for Potential Use in Molecular Imaging. AB - Introduction: Both diagnostic ultrasound (US) and magnetic resonance imaging (MRI) accuracy can be improved by using contrast enhancement. For US gas-filled microbubbles (MBs) or silica nanoparticles (SiNPs), and for MRI superparamagnetic or paramagnetic agents, contribute to this. However, interactions of MBs with the vascular wall and cells are not fully known for all contrast media. Methods: We studied the in vitro interactions between three types of non-targeted air-filled MBs with a polyvinyl-alcohol shell and murine macrophages or endothelial cells. The three MB types were plain MBs and two types that were labelled (internally and externally) with superparamagnetic iron oxide nanoparticles (SPIONs) for US/MRI bimodality. Cells were incubated with MBs and imaged by microscopy to evaluate uptake and adhesion. Interactions were quantified and the MB internalization was confirmed by fluorescence quenching of non-internalized MBs. Results: Macrophages internalized each MB type within different time frames: plain MBs 6 h, externally labelled MBs 25 min and internally labelled MBs 2 h. An average of 0.14 externally labelled MBs per cell were internalized after 30 min and 1.34 after 2 h; which was 113% more MBs than the number of internalized internally labelled MBs. The macrophages engulfed these three differently modified new MBs at various rate, whereas endothelial cells did not engulf MBs. Conclusions: Polyvinyl-alcohol MBs are not taken up by endothelial cells. The MB uptake by macrophages is promoted by SPION labelling, in particular external such, which may be important for macrophage targeting. PMID- 29151983 TI - Moving Beyond "China in Africa": Insights from Zambian Immigration Data. AB - China's growing presence in Africa is not news: the expansion of bilateral trade and investment ties has garnered intense media and political focus over the past decade. However, less is known about the people accompanying these increasingly intensive flows of goods and capital. This paper focuses on Zambia, drawing on multiple primary datasets to shed light on both the scale and nature of Chinese migration to the continent. Two years of Department of Immigration employment permit data serve as the basis for the first quantitative analysis of the "Chinese" in "Africa," illuminating the increasing diversity of this population flow. While the growing Chinese presence in Africa is often viewed as a coherent neocolonialist strategy planned and implemented by the Chinese state, this paper demonstrates that it is in fact typified by a multitude of both public and private actors with independent motives. PMID- 29151982 TI - The Effect of Low-Magnitude Low-Frequency Vibrations (LMLF) on Osteogenic Differentiation Potential of Human Adipose Derived Mesenchymal Stem Cells. AB - Introduction: In the current study, we investigated the effect of low magnitude, low frequency (LMLF) mechanical vibrations on the osteogenic differentiation potential of human adipose derived mesenchymal stem cells (hASC), taken from elderly patients. Methods: During 21 days in osteogenic culture medium, cells were periodically exposed to three different frequencies (25, 35 and 45 Hz) of continuous sinusoidal oscillation, using a vibration generator. We measured cell proliferation, cell morphology, calcium and phosphorus deposition using Almar Blue assay, fluorescence microscopy, scanning electron microscopy, and a EDX detector, respectively. Osteogenic differentiation was measured by assessing protein and mRNA levels. Osteogenesis was confirmed by detection of specific markers with alkaline phosphatase and enzyme-linked immunosorbent assays for: bone morphogenetic protein 2 (BMP-2), osteocalcin (OCL) and osteopontin (OPN). Results: We found that 25 Hz vibrations had the greatest impact on hASC morphology, ultrastructure, and proliferation. We observed the formation of osteocyte- and hydroxyapatite-like structures, an increased quantity of calcium and phosphorus deposits, and increased differentiation in the stimulated groups. Conclusions: Our findings suggest that LMLF vibrations could be used to enhance cell-based therapies for treatment of bone deficits, particularly in elderly patients, where the need is greatest. PMID- 29151984 TI - Hepatic and Aortic Arch Expression and Serum Levels of Syndecan-1 in ApoE-/- Mice. AB - Background: Heparan sulfate proteoglycan (HSPG) syndecan-1 (Sdc1) acts as a receptor for triglyceride-rich lipoproteins (TRLs), growth factors, chemokines and enzymes. Due to the disordered structure, its function is as diverse as its ligands. In this paper, we have analyzed hepatic and aortic arch expression of Sdc1 in ApoE-/- mice and examined their association with biochemical changes in plasma during the atheroma formation. Methods: ApoE knockout (ApoE-/-) mice as a model of atherosclerosis were used. Plasma chemistry parameters were estimated by automatic biochemical analyzer. The ELISA test was used to detect soluble Sdc1. The mRNA level of syndecan-1 in liver cells and aortic arch was determined by real time PCR. Results: The Sdc1 mRNA level in liver cells was 1.5-2.5 times higher in ApoE-/- mice compared to the wild-type species and increased with age, whereas it remained at the same level in wild-type mice upon aging. Furthermore, the plasma cholesterol level was 4-6 times higher in ApoE-/- mice compared to the wild type; in contrast, triglyceride (TG) remained at the same level. Simultaneously, the expression of Sdc1 in the aortic arch of ApoE-/- mice decreases with age; however, it increases in wild-type mice of the same age. We determined that the Sdc1 mRNA expression in liver cells is significantly higher compared to the cells of aortic arch. In addition, our research demonstrated that the level of soluble Sdc1 slightly increased with age and did not depend on mouse genotype; yet, the total amount of soluble Sdc1 was higher in ApoE-/- mice. Conclusion: Our data suggest that the level of soluble Sdc1 in serum of mice can be associated with chronic inflammation. In addition, we hypothesized that a compensatory increase in the Sdc1 expression in ApoE-/- mice may prevent accumulation of triglycerides in serum, yet having no effect on cholesterol accumulation. PMID- 29151985 TI - Synthesis and Anticancer Evaluation of Some New 3-Benzyl-4,8-Dimethylbenzopyrone Derivatives. AB - Introduction: New benzopyrone derivatives such as Schiff's like compounds, acetohydrazides or substituted with oxadiazole or pyrazole heterocycles were synthesized from parent acid hydrazide compound 3. Methods and Materials: Structures of the synthesized compounds were elucidated using IR, NMR and mass spectroscopy. All the synthesized derivatives were selected by National Cancer Institute (NCI), Bethesda, and evaluated for their in vitro anticancer activity in the full NCI 60 cell lines panel assay. Results and Conclusion: Schiffs like compounds 4a, b and c were found to have good growth inhibition % against numerous cell lines that belong mainly to leukemia, non-small cell lung, CNS and breast Cancer subpanels. PMID- 29151986 TI - Pyrrolyl Pyrazoline Carbaldehydes as Enoyl-ACP Reductase Inhibitors: Design, Synthesis and Antitubercular Activity. AB - Introduction: In efforts to develop new antitubercular (anti-TB) compounds, herein we describe cytotoxic evaluation of 15 newly synthesized pyrrolyl pyrazoline carbaldehydes. Method & Materials: Surflex-Docking method was used to study binding modes of the compounds at the active site of the enzyme enoyl ACP reductase from Mycobacterium tuberculosis (M. tuberculosis), which plays an important role in FAS-II biosynthetic pathway of M. tuberculosis and also it is an important target for designing novel anti-TB agents. Results: Among the synthesized compounds, compounds 4g and 4i showed H-bonding interactions with MET98, TYR158 and co-factor NAD+, all of which fitted well within the binding pocket of InhA. Also, these compounds have shown the same type of interaction as that of 4TZK ligand. The compounds were further evaluated for preliminary anti-TB activities against M. tuberculosis H37Rv strain. Conclusion: Some compounds were also screened for their mammalian cell toxicity using human lung cancer cell-line (A549) that was found to be nontoxic. PMID- 29151987 TI - A Review on the Modification of Polysaccharide Through Graft Copolymerization for Various Potential Applications. AB - Introduction: Graft copolymerization is one of the most promising technique uses to modify the properties of naturally available polymers with a minimum loss in their native characteristics. Methods and Materials: Graft copolymerization is a very significant technique to add hybrid properties in backbone of polymers. The grafting generally initiated through the formation of free radical centers on the polymer backbone as well as monomer. Results: Grafted polysaccharides have various applications in different important scientific areas such as drug delivery, pharmaceutical field, plastic industry, waste water treatment, tannery effluent treatment, textile industry, agriculture area, etc. all of this fascinated us to summarize the major research articles over the last two decades outlining different methods of grafting, surface modification, graft copolymerization of synthetic and natural polymers. Conclusion: Various redox initiator systems viz. Ceric ammonium nitrate, per sulfate, Irradiation, FAS H2O2etc. is also explored for grafting of vinyl through conventional and non conventional techniques. PMID- 29151988 TI - Lumbar Spinal Angiolipoma with Expanding Left Neural Foramen Mimicking Lumbar Schwannoma; Case Report and Review of The Literature. AB - Aim: To describe a patient with lumbar angiolipoma mimicking schwannoma in the posterolateral side of the spinal canal with expansion of the left lumbar foramen and to discuss the clinical, radiologic, and surgical features of these lesions with literature. Methods: Without language restriction in this paper, the electronic databases; The Cochrane Collaboration the Cochrane, The Cochrane Library (Issue 2 of 12, Feb. 2011), ProQuest, US National Library of Medicine, National Institutes of Health (NLM) and PubMed dating from 1966 September to January Week 2 2017, were searched for comparative experimental studies using the terms: "OR", "AND". On-line literature searches were conducted using the key words "lumbar angiolipoma", "schwannoma ", "spinal angiolipoma", "spinal cord", and "spinal canal". We compared this research with our patient. Results: Bilateral L2 total laminectomy, excision of the tumors and bilateral L2-L3 transpedicular stabilization were performed, and complaints improved prominently. Pathological examination was reported as angiolipoma. Conclusion: The research shows that a probable diagnosis in such tumor cases could be made by sufficient pre-op scanning before surgical operations and although angiolipoma has been rarely seen in lumbar posterolateral space, it can be seen in lumbar region and mimic schwannoma as producing symptoms and signs of spinal cord and nerve root compression. PMID- 29151989 TI - Human Induced Pluripotent Stem Cells and the Modelling of Alzheimer's Disease: The Human Brain Outside the Dish. AB - Background: Neurodegenerative diseases like Alzheimer's Disease (AD) are a global health issue primarily in the elderly. Although AD has been investigated using primary cultures, animal models and post-mortem human brain tissues, there are currently no effective treatments. Summary: With the advent of induced pluripotent stem cells (iPSCs) reprogrammed from fully differentiated adult cells such as skin fibroblasts, newer opportunities have arisen to study the pathophysiology of many diseases in more depth. It is envisioned that iPSCs could be used as a powerful tool for neurodegenerative disease modelling and eventually be an unlimited source for cell replacement therapy. This paper provides an overview of; the contribution of iPSCs towards modeling and understanding AD pathogenesis, the novel human/mouse chimeric models in elucidating current AD pathogenesis hypotheses, the possible use of iPSCs in drug screening, and perspectives on possible future directions. Key messages: Human/mouse chimeric models using iPSCs to study AD offer much promise in better replicating AD pathology and can be further exploited to elucidate disease pathogenesis with regards to the neuroinflammation hypothesis of AD. PMID- 29151990 TI - Robot-Embodied Neuronal Networks as an Interactive Model of Learning. AB - Background and Objective: The reductionist approach of neuronal cell culture has been useful for analyses of synaptic signaling. Murine cortical neurons in culture spontaneously form an ex vivo network capable of transmitting complex signals, and have been useful for analyses of several fundamental aspects of neuronal development hitherto difficult to clarify in situ. However, these networks lack the ability to receive and respond to sensory input from the environment as do neurons in vivo. Establishment of these networks in culture chambers containing multi-electrode arrays allows recording of synaptic activity as well as stimulation. Method: This article describes the embodiment of ex vivo neuronal networks neurons in a closed-loop cybernetic system, consisting of digitized video signals as sensory input and a robot arm as motor output. Results: In this system, the neuronal network essentially functions as a simple central nervous system. This embodied network displays the ability to track a target in a naturalistic environment. These findings underscore that ex vivo neuronal networks can respond to sensory input and direct motor output. Conclusion: These analyses may contribute to optimization of neuronal-computer interfaces for perceptive and locomotive prosthetic applications. Ex vivo networks display critical alterations in signal patterns following treatment with subcytotoxic concentrations of amyloid-beta. Future studies including comparison of tracking accuracy of embodied networks prepared from mice harboring key mutations with those from normal mice, accompanied with exposure to Abeta and/or other neurotoxins, may provide a useful model system for monitoring subtle impairment of neuronal function as well as normal and abnormal development. PMID- 29151991 TI - Experiences from the Merger of Clinics in the Swedish Public Dental Service - the Employee Perspective. AB - Objectives: The purpose of this study was to investigate the experiences of employees regarding the merger of clinics within the Public Dental Service (PDS), Vastra Gotaland Region, Sweden. Methods: Employees (dentists, dental hygienists, dental nurses) affected by both administrative and geographical mergers of dental clinics answered a web-based survey about experiences and effects of the merger process (n = 99, 47%). The Swedish short-form version of "The Nordic Questionnaire for Psychological and Social Factors at Work" (QPSNordic), the QPSNordic-34+ was used. Chi-squared tests and logistic regression analyses were used. Results: Two thirds of the participants were aged >= 50 years. The respondents stated that the reasons for the merger were often made clear (78%). Satisfaction with and involvement in the merger process received lower scores (45%). Work was often perceived as stressful, irrespective of the merger. Job demands and engagement scored positively, but control at work was given a low score (one fifth stated fairly high or high control). Dentists (OR 5.9; 95%, CI 1.1-32.3), but not dental hygienists (OR 2.8; 95%, CI 0.9-9.0), indicated stress significantly more often than dental nurses (reference) (adjusted for age and gender). Conclusion: Employees in the Public Dental Service (PDS) in a Swedish region had mainly positive experiences after the merger of clinics; however, their involvement in the process was low. Work demands were perceived as high. These findings should be considered when planning mergers in dental organizations. PMID- 29151992 TI - Aerococcus urinae and Aerococcus sanguinicola: Susceptibility Testing of 120 Isolates to Six Antimicrobial Agents Using Disk Diffusion (EUCAST), Etest, and Broth Microdilution Techniques. AB - Background: Aerococcus urinae and Aerococcus sanguinicola are relatively newcomers and emerging organisms in clinical and microbiological practice. Both species have worldwide been associated with urinary tract infections. More rarely cases of bacteremia/septicemia and infective endocarditis have been reported. Treatment options are therefore important. Just recently, European recommendations on susceptibility testing and interpretive criteria have been released. Objective: In this investigation 120 A. urinae and A. sanguinicola isolates were tested for susceptibility to six antimicrobial agents: Penicillin, cefotaxime, meropenem, vancomycin, linezolid, and rifampicin. Methods: Three susceptibility testing methods were used; disk diffusion according to The European Committee on Antimicrobial Susceptibility Testing (EUCAST) standardized disk diffusion methodology and MIC determination with Etest and broth microdilution (BMD). All testing was performed with EUCAST media for fastidious organisms. Results: Data obtained in this study were part of the background data for establishing EUCAST breakpoints. MIC values obtained by Etest and BMD were well correlated with disk diffusion results. Conclusion: All isolates were found susceptible to all six antimicrobial agents: penicillin, cefotaxime, meropenem, vancomycin, linezolid, and rifampicin. PMID- 29151993 TI - Antibiotic Based Phenotype and Hospital Admission Profile are the Most Likely Predictors of Genotyping Classification of MRSA. AB - Background: Methicillin-resistant Staphylococcus aureus (MRSA) infection is associated with increased morbidity, mortality, and financial burdens. Phenotyping methods are used to classify MRSA as either health care MRSA (HA MRSA) or community-associated MRSA (CA-MRSA). Recent studies suggested the phenotyping methods are not always reliable, based on a lack of concordance with genotyping results. Objective: In this study, concordance of classification methods based on clinical characteristics or antibiotic susceptibility compared to the gold standard genotyping was assessed in the classification of MRSA. Methods: We compared the genotypes and phenotypes of MRSA in 133 samples taken from patients in Saudi Arabia. Statistical analyses included concordance, specificity and sensitivity, and logistic regression modeling. Results: There was fair a definite agreement between the health care risk and infection type methods (p < .001), but no statistically significant agreement between the susceptibility pattern and health care risk methods (p = 243), and between susceptibility pattern and infection type methods (p = .919). Reduced multiple regression modelling suggested the potential of a phenotyping-based method of antibiotic susceptibility pattern (OR = 15.47, p < .001) in conjunction with hospital admission profile(OR = 2.87, p = .008) to accurately identify MRSA as HA-MRSA and CA-MRSA. Conclusion: The use of a standardized phenotyping technique, using susceptibility pattern and hospital admission profiles to classify MRSA infections as either HA-MRSA or CA-MRSA, would facilitate diagnosis, infection control efforts, prevention, and assignment of appropriate therapies. The ability to use phenotyping in the classification of these strains would improve efforts to contend with this adept and evolving bacterial organism. PMID- 29151994 TI - Antimicrobial Activity of Cultivable Endophytic Fungi Associated with Hancornia Speciosa Gomes Bark. AB - Introduction: In this study, we evaluated the antimicrobial potential of cultivable endophytic fungi associated with Hancornia speciosa Gomes stem bark. Methods and Materials: Plant samples were collected in rainy (July 2010) and dry (January 2011) seasons. In total, 116 endophytic fungi strains were isolated from 90 fragments (64.4% frequency of colonization). Higher fungi frequency was observed in the rainy season (84.4%). The strains were grouped into 14 species; the most frequent were Phoma cava (13.8%), Colletotrichum gloeosporioides (12.1%), and Lasiodiplodia theobromae (11.2%). Fungal diversity was similar in both the seasons. Among the 116 strains, 39 (33.6%) showed antimicrobial activity in preliminary screening. The ten most active isolates were subjected to semi solid fermentation using rice or corn as substrates. Methanolic extracts were obtained from each fermentation medium and the minimum inhibitory (MIC) and minimum microbicide concentrations (MMC) were determined. Results: The best antimicrobial results (MIC < 100 ug/mL) were observed for fungi strains grown in rice medium: Aspergillus niger FHS061 against Proteus mirabilis (MIC = 19 ug/mL) and Staphylococcus aureus (MIC = 39 ug/mL). These strains also showed good results when cultivated in corn medium against P. mirabilis (MIC = 78 ug/mL). Conclusion: Thus, the stem bark of H. speciosa harbors diverse endophytic fungi with antimicrobial potential. PMID- 29151995 TI - The Molecular Study of Antibiotic Resistance to Quinolones in Salmonella enterica Strains Isolated in Tehran, Iran. AB - Introduction: Salmonella is known as one of the most important causes of gastrointestinal disease in the world. Quinolones and fluoroquinolones are used successfully in the treatment of salmonellosis particularly for infections that have become resistant to several antibiotics. But non-susceptible isolates to quinolones have been reported in several countries. The data are limited about the prevalence of quinolone-resistant isolates in our country. Therefore, this study investigated the plasmid-mediated quinolone resistance genes in Salmonella enterica isolated in Children's Medical Center in Tehran during 2014-2015. Methods and Materials: Salmonella isolates were isolated and identified using standard microbiological methods. Antibiotic susceptibility testing and screening of Salmonella strains resistant to quinolones were performed according to the CLSI guidelines. The molecular investigation was done using specific primers for detection of qnr genes including: qnrA, qnrB and qnrS, by polymerase chain reaction. Results: Overall, 92 (66.6%) strains were resistant to nalidixic acid. None of the strains showed resistance to ciprofloxacin. Out of the 92 nalidixic acid resistant strains, 52 (56.52%) harbored qnrS genes, 15 strains (16.30%) had both qnrA and qnrS genes. Two (1.1%) isolates were positive for qnrB gene. Twenty four (26.08%) nalidixic acid resistant isolates did not have any qnr qens. Conclusion: The results of this study show high prevalence of resistance to nalidixic and qnr genes in Salmonella isolates. Plasmid nature of this type of resistance poses an increased risk of dissemination of quinolone resistance between Salmonella and non-Salmonella isolates circulating in hospitals environments. PMID- 29151996 TI - Co-Occurrence of Plasmid-Mediated AmpC beta-Lactamase Activity Among Klebsiella pneumoniae and Escherichia Coli. AB - Introduction: Extended-spectrum beta-lactamases (ESBLs), including the AmpC type, are important mechanisms of resistance among Klebsiella pneumoniae and Escherichia coli isolates. Objective: The aim of the study was to investigate the occurrence of AmpC-type beta-lactamase producers isolated from two hospitals in Tripoli, Libya. Methods: All clinical isolates (76 K. pneumoniae and 75 E. coli) collected over two years (2013-2014) were evaluated for susceptibility to a panel of antimicrobials and were analyzed phenotypically for the ESBL and AmpC phenotype using E-test and ESBL and AmpC screen disc test. Both ESBL and AmpC positive isolates were then screened for the presence of genes encoding plasmid mediated AmpC beta-lactamases by polymerase chain reaction (PCR). Results: Of the K. pneumoniae and E. coli tested, 75% and 16% were resistant to gentamicin, 74% and 1.3% to imipenem, 71% and 12% to cefoxitin, 80% and 12% to cefepime, 69% and 22.6% to ciprofloxacin, respectively. None of the E. coli isolates were multidrug resistant compared with K. pneumoniae (65.8%). K. pneumoniae ESBL producers were significantly higher (85.5%) compared with (17.3%) E. coli isolates (P <0.0001, OR=4.93). Plasmid-mediated AmpC genes were detected in 7.9% of K. pneumoniae, and 4% E. coli isolates. There was low agreement between phenotypic and genotypic methods, phenotypic testing underestimated detection of AmpC enzyme and did not correlate well with molecular results. The gene encoding CMY enzyme was the most prevalent (66.6%) of AmpC positive isolates followed by MOX, DHA and EBC. Only one AmpC gene was detected in 5/9 isolates, i.e, blaCMY (n=3), blaMOX (n=1), blaDHA (n=1). However, co-occurrence of AmpC genes were evident in 3/9 isolates with the following distribution: blaCMY and blaEBC (n=1), and blaCMY and blaMOX (n=2). Neither blaFOX nor blaACC was detected in all tested isolates. All AmpC positive strains were resistant to cefoxitin and isolated from patients admitted to intensive care units. Conclusion: Further studies are needed for detection of other AmpC variant enzyme production among such isolates. Continued surveillance and judicious antibiotic usage together with the implementation of efficient infection control measures are absolutely required. PMID- 29151997 TI - Genetic Investigation of Beta-Lactam Associated Antibiotic Resistance Among Escherichia Coli Strains Isolated from Water Sources. AB - Background: Antimicrobial resistance is an important factor threatening human health. It is widely accepted that antibiotic resistant bacteria such as Escherichia coli (E. coli) released from humans and animals into the water sources, can introduce their resistance genes into the natural bacterial community. Objective: The aim of this study was to investigate the prevalence of blaTEM, blaCTX, blaSHV, blaOXA and blaVEB associated-antibiotic resistance among E. coli bacteria isolated from different water resources in Iran. Methods: The study contained all E. coli strains segregated from different surface water sources. The Kirby-Bauer method and combined discs method was determined in this study for testing antimicrobial susceptibility and strains that produced Extended Spectrum Beta Lactamases (ESBL), respectively. DNA extraction kit was applied for genomic and plasmid DNA derivation. Finally the frequency of resistant genes including blaTEM, blaCTX, blaSHV, blaOXA and blaVEB in ESBL producing isolates were studied by PCR. Results: One hundred E. coli strains were isolated and entered in the study. The highest antibiotic resistance was observed on clindamycin (96%). Moreover, 38.5% isolates were ESBL producers. The frequency of different ESBLs genes were 37%, 27%, 27%, and 25% for blaTEM, blaCTX, blaSHV, and blaOXA , respectively. The blaVEB wasn't found in any isolates. Conclusion: The study revealed a high prevalence of CTX-M, TEM, SHV and OXA genes among E. coli strains in surface water resources. In conclusion, these results raised a concern regarding the presence and distribution of these threatening factors in surface water sources and its subsequent outcomes. PMID- 29151998 TI - Hallux Osteoid Osteoma: A Case Report and Literature Review. AB - Osteoid osteoma is a benign bone tumour that mostly affects males in the second and third decade of their life. The lesion mainly occurs in long bones, usually in the femur and tibia, causing severe localized pain that is worse at night and responds to nonsteroidal anti-inflammatory drugs (NSAIDs). Diagnosis is usually made on the basis of history and radiographic findings. However, in more unusual locations as the hand and foot, diagnostic issues can arise. Treatment often includes complete removal of the tumor. We present a 22 year old male with osteoid osteoma involving the distal phalanx of the hallux. To our knowledge very few cases of great toe osteoid osteoma have been reported in the literature. PMID- 29151999 TI - Mid-Term Outcomes After Open Reduction Internal Fixation of Proximal Interphalangeal Joint Dorsal Fracture-Dislocations Through a Volar, Shotgun Approach and a Review of the Literature. AB - Background: Proximal interphalangeal (PIP) fracture dislocations remain a complex injury pattern to treat. There are several treatment methods available aimed to restore stability, preserve range of motion, and reconstitute the articular surface. This study looked at the mid-term clinical and radiographic results of open reduction internal fixation through a shotgun approach of comminuted PIP fracture dislocations. Methods: A retrospective review was conducted of all PIP fracture dislocations treated through a volar, shotgun approach at a single institution over a 15-year period. Patients identified were contacted and asked to return to the office for clinical and radiographic evaluation. Patient reported outcomes were assessed with the Michigan hand questionnaire (MHQ) and visual analog scale (VAS) for pain. Results: 5 patients returned to the office for further evaluation with average follow-up of 69 months (range, 33-133 months). 3 patients were found to have post traumatic arthritis on radiographs. 1 case had recurrent instability and one case had a deep infection, both necessitating further surgical intervention. Average PIP arc of motion was found to be 79 degrees . Average VAS score of 0 and MHQ result of 95 (out of a possible score of 100) indicating no residual pain and excellent functionality of the affected hand. Conclusion: Open reduction internal fixation of comminuted PIP fracture dislocations utilizing the volar, shotgun approach provides excellent mid-term functional results despite the high incidence of post traumatic arthritis. PMID- 29152000 TI - Muscle Weakness in the Empty and Full Can Tests Cannot Differentiate Rotator Cuff Tear from Cervical Spondylotic Amyotrophy: Pain Provocation is a Useful Finding. AB - Purpose: Rotator cuff tears and cervical spondylotic amyotrophy (CSA) are often confused as the main symptom in those with difficulty in shoulder elevation. Empty and full can tests are frequently used for the clinical diagnosis of rotator cuff tears. The aim of the present study was to investigate whether the empty and full can test results can help differentiate rotator cuff tears from CSA. Methods: Twenty-seven consecutive patients with rotator cuff tears and 25 with CSA were enrolled. We prospectively performed empty and full can tests in patients with rotator cuff tears and CSA. The following signs were considered positive: (a) muscle weakness during the empty can test, (b) muscle weakness during the full can test, (c) pain provocation during the empty can test, and (d) pain provocation during the full can test. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of rotator cuff tears for each positive finding. Results: The sensitivity and specificity of each index were as follows (sensitivity, specificity, PPV, NPV): (a) 77.8%, 0%, 45.7%, 0%; (b) 66.7%, 4.0%, 42.9%, 10.0%; (c) 88.9%, 96.0%, 96.0%, 88.9%; and (d) 74.1%, 96.0%, 95.2%, 77.4%. There were significant differences for each index. Conclusion: Muscle weakness during the empty and full can tests was not useful in differentiating rotator cuff tears from CSA because of low specificity and PPV. However, pain provocation was useful in differentiating these two conditions because of high specificity and PPV. PMID- 29152001 TI - Total Knee Arthroplasty In Patients With Parkinson's Disease- A Critical Analysis of Available Evidence. AB - Background: In this era of modern medicine, there is an increase in life expectancy and thereby an ageing population. Among this group one of the most common neurological disorder is Parkinson disease and one of the most common operation done in elderly population is a total joint arthroplasty. But total joint arthroplasty in Parkinson disease is a relatively uncommon entity. There is sparse literature available with regards to total knee arthroplasty (TKA) in Parkinson disease. This review focusses on the necessity, complications and previous experiences on TKA in PD based on the literature available. Method: The review was conducted after a series of advanced search in the following medical databases; Pub med, Biomed central, Cochrane and Google scholar for articles related to total knee replacement in patients with Parkinson's disease. The following keywords were used; Total knee arthroplasty, Parkinson's disease, Hoehn and Yahr, Flexion Contracture. Results: The review indicates that the functional outcome is comparable to that of controls in immediate post-operative phase, one year and three-year phase, but the long term functional outcome seems to deteriorate significantly. Conclusion: Total knee arthroplasty can serve as an effective tool in alleviating pain in short term as well as long term periods, whereas the functional outcome seems to deteriorate post operatively on a long term basis. Nevertheless, TKA in PD is a challenging situation, thereby necessitating a holistic approach with the efforts from various specialists needed at each stage to ensure a successful operation. PMID- 29152002 TI - Cadaveric Anatomical Study of Sural Nerve: Where is The Safe Area for Endoscopic Gastrocnemius Recession? AB - Purpose: To ascertain in cadavers where the sural nerve crosses the gastro-soleus complex and where the gastrocnemius tendon merges with the Achilles tendon in relation to the calcaneal tuberosities. Methods: Twelve cadaveric lower limbs (6 right and 6 left) were dissected. The distances between the calcaneal tuberosities and the lateral border of the Achilles tendon where the sural nerve crosses from medial to lateral, as well as to the gastrocnemius tendon insertion into the Achilles tendon, were measured. Results: The mean and median longitudinal distances from the calcaneal tuberosity to where the sural nerve crosses the lateral border of the Achilles tendon are 9.9cm and 10cm respectively (range 7cm to 14cm). The mean and median longitudinal distances from the calcaneal tuberosity to where the gastrocnemius tendon inserts into the Achilles tendon are 19.9cm and 18.5cm (range 17cm to 25cm) respectively. Conclusion: It is generally safe to place the posterolateral incision more than 14cm above the calcaneal tuberosity to avoid the sural nerve if surgeons plan to use a posterolateral incision for endoscopic recession. The distance between the calcaneal tuberosity to the gastrocnemius tendon insertion into the Achilles tendon is too highly variable to be used as a landmark for locating the gastrocnemius insertion. PMID- 29152003 TI - Shoulder Prosthesis. PMID- 29152004 TI - Shoulder Arthroplasty: Historical Considerations. AB - Background: The first articular metal prosthesis was implanted in the shoulder more than 120 years ago. The aim of this paper is to report shoulder arthroplasty evolution during this time thru the literature of the twentieth century. Methods: A literature review was performed selecting the founding papers about shoulder arthroplasty. Results: After being almost forgotten during the first part of the 20th century, various implants were introduced in the 1950s with Charles Neer as a leader. The reverse concept appeared in the 1970s and knew many failures before Grammont's design. Conclusion: After many unfortunate trials, the shoulder prosthesis is now widely disseminated with products of many companies. PMID- 29152005 TI - Humeral Head Replacement and Reverse Shoulder Arthroplasty for the Treatment of Proximal Humerus Fracturesm. AB - Acute proximal humeral fractures in the elderly are generally treated non operatively if alignment is acceptable and in stable fracture patterns. When operative treatment is indicated, surgical fixation is often difficult or impossible to obtain. Hemiarthroplasty has long been the standard of care. However, with its reliance on tuberosity healing, functional outcomes and patient satisfaction are often poor. Reverse shoulder arthroplasty has emerged as a new technology for treating proximal humeral fractures but the indications for its use remain uncertain. While not conclusive, the evidence suggests that reverse shoulder arthroplasty yields more consistent results, with improved forward elevation and higher functional outcome scores. The primary advantages of hemiarthroplasty are improved shoulder rotation and shorter operative time. Complication rates do not vary significantly between the two options. Although higher quality trials are needed to further define the role of reverse shoulder arthroplasty, current evidence suggests that this is a reasonable option for surgeons who are highly familiar with its use. PMID- 29152006 TI - Anatomic Shoulder Arthroplasty: Technical Considerations. AB - Osteoarthritis of the shoulder is a common condition in the aging population, and it can have profound effects on patients' quality of life. The anatomic total shoulder arthroplasty is a well-described treatment modality resulting generally excellent outcomes. The objective of this review is to discuss the technical aspects of primary anatomic total shoulder arthroplasty, and to provide a framework to follow to achieve a successful surgical result. The topics covered include preoperative planning, surgical considerations, and approaches, humeral preparation, glenoid bone loss and the emerging concept of using the reverse total shoulder arthroplasty for the type B2 glenoid. PMID- 29152007 TI - Shoulder Arthroplasty Imaging: What's New. AB - Background: Shoulder arthroplasty, in its different forms (hemiarthroplasty, total shoulder arthroplasty and reverse total shoulder arthroplasty) has transformed the clinical outcomes of shoulder disorders. Improvement of general clinical outcome is the result of stronger adequacy of the treatment to the diagnosis, enhanced surgical techniques, specific implanted materials, and more accurate follow up. Imaging is an important tool in each step of these processes. Method: This article is a review article declining recent imaging processes for shoulder arthroplasty. Results: Shoulder imaging is important for shoulder arthroplasty pre-operative planning but also for post-operative monitoring of the prosthesis and this article has a focus on the validity of plain radiographs for detecting radiolucent line and on new Computed Tomography scan method established to eliminate the prosthesis metallic artefacts that obscure the component fixation visualisation. Conclusion: Number of shoulder arthroplasties implanted have grown up rapidly for the past decade, leading to an increase in the number of complications. In parallel, new imaging system have been established to monitor these complications, especially component loosening. PMID- 29152008 TI - Short, Medium and Long Term Complications After Total Anatomical Shoulder Arthroplasty. AB - Total shoulder arthroplasty (TSA) is an effective approach for the treatment of a variety of clinical conditions affecting the shoulder, including osteoarthritis, inflammatory arthritis and osteonecrosis, and the number of TSA implanted has grown exponentially over the past decade. This review gives an update of the major complications, mainly infections, instability and loosening, encountered after TSA, based on a corpus of recent publications and a dynamic approach: The review focuses on the causes of glenoid loosening, which account for 80% of the complication, and underlines the importance of glenoid positioning in the recovery of early shouder function and in the long term survival rate of TSA. PMID- 29152009 TI - Constituents of Nelumbo nucifera leaves and their antimalarial and antifungal activity. AB - From the leaves of Nelumbo nucifera (an aquatic plant), one new compound, 24(R) ethylcholest-6-ene-5alpha-ol-3-O-beta-D-glucopyranoside (1), along with 11 known metabolites (2-12), were isolated and identified by spectroscopic methods including 1D- and 2D NMR. Antifungal activity for (R)-roemerine (3) (IC50/MIC = 4.5/10 MUg/mL against Candida albicans) and antimalarial activity for (R) roemerine (3) and N-methylasimilobine (5) (IC50 = 0.2 and 4.8 MUg/mL for the D6 clone, respectively, and 0.4 and 4.8 MUg/mL for the W2 clone, respectively) was observed. None of the compounds were cytotoxic to Vero cells up to a concentration of 23.8 MUg/mL. NMR data for 10-eicosanol (7) and 7,11,15-trimethyl 2-hexadecanone (10) are presented for the first time. An analysis of the structure-activity relationship shows that the substituents in position C-1 and C 2 of aporphine alkaloids are crucial for the antimalarial activity. PMID- 29152010 TI - A Summary of a Cochrane Review: Music interventions for acquired brain injury. PMID- 29152011 TI - Massively parallel simulations of hemodynamics in the primary large arteries of the human vasculature. AB - We present a computational model of three-dimensional and unsteady hemodynamics within the primary large arteries in the human on 1,572,864 cores of the IBM Blue Gene/Q. Models of large regions of the circulatory system are needed to study the impact of local factors on global hemodynamics and to inform next generation drug delivery mechanisms. The HARVEY code successfully addresses key challenges that can hinder effective solution of image-based hemodynamics on contemporary supercomputers, such as limited memory capacity and bandwidth, flexible load balancing, and scalability. This work is the first demonstration of large fluid dynamics simulations of the aortofemoral region of the circulatory system at resolutions as small as 10 MUm. PMID- 29152013 TI - Energy conversion in magneto-rheological elastomers. AB - Magneto-rheological (MR) elastomers contain micro-/nano-sized ferromagnetic particles dispersed in a soft elastomer matrix, and their rheological properties (storage and loss moduli) exhibit a significant dependence on the application of a magnetic field (namely MR effect). Conversely, it is reported in this work that this multiphysics coupling is associated with an inverse effect (i.e. the dependence of the magnetic properties on mechanical strain), denoted as the pseudo-Villari effect. MR elastomers based on soft and hard silicone rubber matrices and carbonyl iron particles were fabricated and characterized. The pseudo-Villari effect was experimentally quantified: a shear strain of 50 % induces magnetic induction field variations up to 10 mT on anisotropic MR elastomer samples, when placed in a 0.2 T applied field, which might theoretically lead to potential energy conversion density in the mJ cm-3 order of magnitude. In case of anisotropic MR elastomers, the absolute variation of stiffness as a function of applied magnetic field is rather independent of matrix properties. Similarly, the pseudo-Villari effect is found to be independent to the stiffness, thus broadening the adaptability of the materials to sensing and energy harvesting target applications. The potential of the pseudo-Villari effect for energy harvesting applications is finally briefly discussed. PMID- 29152012 TI - Machine learning reveals orbital interaction in materials. AB - We propose a novel representation of materials named an 'orbital-field matrix (OFM)', which is based on the distribution of valence shell electrons. We demonstrate that this new representation can be highly useful in mining material data. Experimental investigation shows that the formation energies of crystalline materials, atomization energies of molecular materials, and local magnetic moments of the constituent atoms in bimetal alloys of lanthanide metal and transition-metal can be predicted with high accuracy using the OFM. Knowledge regarding the role of the coordination numbers of the transition-metal and lanthanide elements in determining the local magnetic moments of the transition metal sites can be acquired directly from decision tree regression analyses using the OFM. PMID- 29152015 TI - Laser synthesized TiO2-based nanoparticles and their efficiency in the photocatalytic degradation of linear carboxylic acids. AB - Titanium dioxide nanoparticles were synthesized by laser pyrolysis, their surface and electronic properties were modified by gold and/or nitrogen. These materials were characterized by different techniques like X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and electron paramagnetic resonance (EPR). Time resolved conductivity (TRMC) was used to study the charge separation of electron/hole pairs. Altogether (XPS, EPR, TRMC), the physicochemical characterizations are well correlated with chemical photoactivity of the different samples. Their photocatalytic activity was evaluated for the degradation of linear carboxylic acids (C2-C3) under UV and visible illumination. The decomposition rate of acids was measured, it shows that the modification with gold increases the photoactivity while the presence of nitrogen slows down the process. Such observations are in good agreement with evolution of TRMC signals. A degradation pathway has been determined by identification of intermediate products by chromatography and EPR, results show different intermediate species. In particular EPR confirms the presence of NO2- paramagnetic centers and shows two novel N centered paramagnetic centers. A decrease of the degradation rate is observed with increase of carboxylic acid chain length. PMID- 29152014 TI - Recent progress in boron nanomaterials. AB - Various types of zero, one, and two-dimensional boron nanomaterials such as nanoclusters, nanowires, nanotubes, nanobelts, nanoribbons, nanosheets, and monolayer crystalline sheets named borophene have been experimentally synthesized and identified in the last 20 years. Owing to their low dimensionality, boron nanomaterials have different bonding configurations from those of three dimensional bulk boron crystals composed of icosahedra or icosahedral fragments. The resulting intriguing physical and chemical properties of boron nanomaterials are fascinating from the viewpoint of material science. Moreover, the wide variety of boron nanomaterials themselves could be the building blocks for combining with other existing nanomaterials, molecules, atoms, and/or ions to design and create materials with new functionalities and properties. Here, the progress of the boron nanomaterials is reviewed and perspectives and future directions are described. PMID- 29152016 TI - Membrane thinning for efficient CO2 capture. AB - Enhancing the fluxes in gas separation membranes is required for utilizing the membranes on a mass scale for CO2 capture. Membrane thinning is one of the most promising approaches to achieve high fluxes. In addition, sophisticated molecular transport across membranes can boost gas separation performance. In this review, we attempt to summarize the current state of CO2 separation membranes, especially from the viewpoint of thinning the selective layers and the membrane itself. The gas permeation behavior of membranes with ultimate thicknesses and their future directions are discussed. PMID- 29152018 TI - Grain growth prediction based on data assimilation by implementing 4DVar on multi phase-field model. AB - We propose a method to predict grain growth based on data assimilation by using a four-dimensional variational method (4DVar). When implemented on a multi-phase field model, the proposed method allows us to calculate the predicted grain structures and uncertainties in them that depend on the quality and quantity of the observational data. We confirm through numerical tests involving synthetic data that the proposed method correctly reproduces the true phase-field assumed in advance. Furthermore, it successfully quantifies uncertainties in the predicted grain structures, where such uncertainty quantifications provide valuable information to optimize the experimental design. PMID- 29152017 TI - Manipulating mammalian cell morphologies using chemical-mechanical polished integrated circuit chips. AB - Tungsten chemical-mechanical polished integrated circuits were used to study the alignment and immobilization of mammalian (Vero) cells. These devices consist of blanket silicon oxide thin films embedded with micro- and nano-meter scale tungsten metal line structures on the surface. The final surfaces are extremely flat and smooth across the entire substrate, with a roughness in the order of nanometers. Vero cells were deposited on the surface and allowed to adhere. Microscopy examinations revealed that cells have a strong preference to adhere to tungsten over silicon oxide surfaces with up to 99% of cells adhering to the tungsten portion of the surface. Cells self-aligned and elongated into long threads to maximize contact with isolated tungsten lines as thin as 180 nm. The orientation of the Vero cells showed sensitivity to the tungsten line geometric parameters, such as line width and spacing. Up to 93% of cells on 10 MUm wide comb structures were aligned within +/- 20 degrees of the metal line axis. In contrast, only ~22% of cells incubated on 0.18 MUm comb patterned tungsten lines were oriented within the same angular interval. This phenomenon is explained using a simple model describing cellular geometry as a function of pattern width and spacing, which showed that cells will rearrange their morphology to maximize their contact to the embedded tungsten. Finally, it was discovered that the materials could be reused after cleaning the surfaces, while maintaining cell alignment capability. PMID- 29152019 TI - Mechanistic investigation of the formation of H2 from HCOOH with a dinuclear Ru model complex for formate hydrogen lyase. AB - We report the mechanistic investigation of catalytic H2 evolution from formic acid in water using a formate-bridged dinuclear Ru complex as a formate hydrogen lyase model. The mechanistic study is based on isotope-labeling experiments involving hydrogen isotope exchange reaction. PMID- 29152020 TI - Thermal conductivity analysis and applications of nanocellulose materials. AB - In this review, we summarize the recent progress in thermal conductivity analysis of nanocellulose materials called cellulose nanopapers, and compare them with polymeric materials, including neat polymers, composites, and traditional paper. It is important to individually measure the in-plane and through-plane heat conducting properties of two-dimensional planar materials, so steady-state and non-equilibrium methods, in particular the laser spot periodic heating radiation thermometry method, are reviewed. The structural dependency of cellulose nanopaper on thermal conduction is described in terms of the crystallite size effect, fibre orientation, and interfacial thermal resistance between fibres and small pores. The novel applications of cellulose as thermally conductive transparent materials and thermal-guiding materials are also discussed. PMID- 29152021 TI - Forging property, processing map, and mesoscale microstructural evolution modeling of a Ti-17 alloy with a lamellar (alpha+beta) starting microstructure. AB - This work identifies microstructural conversion mechanisms during hot deformation (at temperatures ranging from 750 degrees C to 1050 degrees C and strain rates ranging from 10-3 s-1 to 1 s-1) of a Ti-5Al-2Sn-2Zr-4Mo-4Cr (Ti-17) alloy with a lamellar starting microstructure and establishes constitutive formulae for predicting the microstructural evolution using finite-element analysis. In the alpha phase, lamellae kinking is the dominant mode in the higher strain rate region and dynamic globularization frequently occurs at higher temperatures. In the beta phase, continuous dynamic recrystallization is the dominant mode below the transition temperature, Tbeta (880~890 degrees C). Dynamic recovery tends to be more active at conditions of lower strain rates and higher temperatures. At temperatures above Tbeta , continuous dynamic recrystallization of the beta phase frequently occurs, especially in the lower strain rate region. A set of constitutive equations modeling the microstructural evolution and processing map characteristic are established by optimizing the experimental data and were later implemented in the DEFORM-3D software package. There is a satisfactory agreement between the experimental and simulated results, indicating that the established series of constitutive models can be used to reliably predict the properties of a Ti-17 alloy after forging in the (alpha+beta) region. PMID- 29152022 TI - Proteomic Approach for Extracting Cytoplasmic Proteins from Streptococcus sanguinis using Mass Spectrometry. AB - Streptococcus sanguinis is a commensal and early colonizer of oral cavity as well as an opportunistic pathogen of infectious endocarditis. Extracting the soluble proteome of this bacterium provides deep insights about the physiological dynamic changes under different growth and stress conditions, thus defining "proteomic signatures" as targets for therapeutic intervention. In this protocol, we describe an experimentally verified approach to extract maximal cytoplasmic proteins from Streptococcus sanguinis SK36 strain. A combination of procedures was adopted that broke the thick cell wall barrier and minimized denaturation of the intracellular proteome, using optimized buffers and a sonication step. Extracted proteome was quantitated using Pierce BCA Protein Quantitation assay and protein bands were macroscopically assessed by Coomassie Blue staining. Finally, a high resolution detection of the extracted proteins was conducted through Synapt G2Si mass spectrometer, followed by label-free relative quantification via Progenesis QI. In conclusion, this pipeline for proteomic extraction and analysis of soluble proteins provides a fundamental tool in deciphering the biological complexity of Streptococcus sanguinis. PMID- 29152023 TI - Role of Social Knowledge Networking technology in facilitating meaningful use of Electronic Health Record medication reconciliation. AB - Despite the federal policy impetus towards EHR Medication Reconciliation, hospital adherence has lagged for one chief reason; low physician engagement, which in turn emanates from lack of consensus in regard to which physician is responsible for managing a patient's medication list, and the importance of medication reconciliation as a tool for improving patient safety and quality of care. The Technology-in-Practice (TIP) framework stresses the role of human action in enacting structures of technology use or "technologies-in-practice." Applying the TIP framework to the EHR Medication Reconciliation context, helps frame the problem as one of low physician engagement in performing EHR Medication Reconciliation, translating to limited-use-EHR-in-practice. Concurrently, the problem suggests a hierarchical network structure, reflecting limited communication among hospital administrators and clinical providers on the importance of EHR Medication Reconciliation in improving patient safety. Integrating the TIP literature with the more recent knowledge-in-Practice (KIP) literature suggests that EHR-in-practice could be transformed from "limited use" to "meaningful use" through the use of Social Knowledge Networking (SKN) Technology to create new social network structures, and enable engagement, learning, and practice change. Correspondingly, the objectives of this paper are to: 1) Conduct a narrative review of the literature on "technology use," to understand how technologies-in-practice may be transformed from limited use to meaningful use; 2) Conduct a narrative review of the literature on "organizational change implementation," to understand how changes in technology use could be successfully implemented and sustained in a healthcare organizational context; and 3) Apply lessons learned from the narrative literature reviews to identify strategies for the meaningful use and successful implementation of EHR Medication Reconciliation technology. PMID- 29152024 TI - Direct measurement of the mechanism by which magnesium specifically modifies the mechanical properties of DNA. AB - We examine the effect of physiological cations Na+, K+, Mg2+, and Ca2+ on the mechanical properties of bundles of lambda-phage DNA using silicon nanotweezers (SNTs). Integrating SNTs with a microfluidic device allows us to perform titration experiments while measuring the effect in real-time. The results show that only for Mg2+ and in particular, at the intra-nuclear concentration (100 mM), the interaction occurs. PMID- 29152026 TI - Particle separation by phase modulated surface acoustic waves. AB - High efficiency isolation of cells or particles from a heterogeneous mixture is a critical processing step in lab-on-a-chip devices. Acoustic techniques offer contactless and label-free manipulation, preserve viability of biological cells, and provide versatility as the applied electrical signal can be adapted to various scenarios. Conventional acoustic separation methods use time-of-flight and achieve separation up to distances of quarter wavelength with limited separation power due to slow gradients in the force. The method proposed here allows separation by half of the wavelength and can be extended by repeating the modulation pattern and can ensure maximum force acting on the particles. In this work, we propose an optimised phase modulation scheme for particle separation in a surface acoustic wave microfluidic device. An expression for the acoustic radiation force arising from the interaction between acoustic waves in the fluid was derived. We demonstrated, for the first time, that the expression of the acoustic radiation force differs in surface acoustic wave and bulk devices, due to the presence of a geometric scaling factor. Two phase modulation schemes are investigated theoretically and experimentally. Theoretical findings were experimentally validated for different mixtures of polystyrene particles confirming that the method offers high selectivity. A Monte-Carlo simulation enabled us to assess performance in real situations, including the effects of particle size variation and non-uniform acoustic field on sorting efficiency and purity, validating the ability to separate particles with high purity and high resolution. PMID- 29152025 TI - Advances in microfluidic devices made from thermoplastics used in cell biology and analyses. AB - Silicon and glass were the main fabrication materials of microfluidic devices, however, plastics are on the rise in the past few years. Thermoplastic materials have recently been used to fabricate microfluidic platforms to perform experiments on cellular studies or environmental monitoring, with low cost disposable devices. This review describes the present state of the development and applications of microfluidic systems used in cell biology and analyses since the year 2000. Cultivation, separation/isolation, detection and analysis, and reaction studies are extensively discussed, considering only microorganisms (bacteria, yeast, fungi, zebra fish, etc.) and mammalian cell related studies in the microfluidic platforms. The advantages/disadvantages, fabrication methods, dimensions, and the purpose of creating the desired system are explained in detail. An important conclusion of this review is that these microfluidic platforms are still open for research and development, and solutions need to be found for each case separately. PMID- 29152027 TI - Design considerations for open-well microfluidic platforms for hypoxic cell studies. AB - Regions of hypoxia are common in solid tumors and are associated with enhanced malignancy, metastasis, and chemo/radio resistance. Real-time hypoxic cellular experimentation is challenging due to the constant need for oxygen control. Most microfluidic platforms developed thus far for hypoxic cell studies are burdened by complex design parameters and are difficult to use for uninitiated investigators. However, open-well microfluidic platforms enable short and long term hypoxic cell studies with an ease of use workflow. Specifically, open-well platforms enable manipulation and addition of cells, media, and reagents using a micropipette for hypoxic cell studies in tunable dissolved oxygen concentrations as low 0.3 mg/l. We analyzed design considerations for open-well microfluidic platforms such as media height, membrane thickness, and impermeable barriers to determine their effects on the amount of dissolved oxygen within the platform. The oxygen concentration was determined by experimental measurements and computational simulations. To examine cell behavior under controlled oxygen conditions, hypoxia-induced changes to hypoxia inducible factor activity and the mitochondrial redox environment were studied. A fluorescent reporter construct was used to monitor the stabilization of hypoxia inducible factors 1alpha and 2alpha throughout chronic hypoxia. Reporter construct fluorescence intensity inversely correlated with dissolved oxygen in the medium, as expected. Additionally, the glutathione redox poise of the mitochondrial matrix in living cancer cells was monitored throughout acute hypoxia with a genetically encoded redox probe and was observed to undergo a reductive response to hypoxia. Overall, these studies validate an easy to use open-well platform suitable for studying complex cell behaviors in hypoxia. PMID- 29152028 TI - A fast and efficient size separation method for haploid embryonic stem cells. AB - Hemizygous mutations introduced in haploid genomes can directly expose a phenotype, thus facilitating gene function analysis and forward genetic screening. Recently, mammalian haploid cells could be derived from mouse, rat, monkey, and human embryos and have been applied to screens of cellular mechanisms including cell signaling, pathogen host factors, and developmental pathways. Notably, haploid cell cultures have an intrinsic tendency for diploidization and, thus, require periodic cell sorting. Here, we report a method for rapid purification of haploid mouse embryonic stem cells from mixed cell populations with high viability and yield. Our method uses membranes with micrometer pores for force-free separation and facilitates enrichment of haploid cells without flow cytometry. The separation method simplifies maintaining haploid cell cultures and has further applications in establishing haploid cell lines from embryos and isolating cell cycle phases of mammalian cells. PMID- 29152029 TI - Portable detection of trace metals in airborne particulates and sediments via MUPADs and smartphone. AB - Particulate matter (PM), a key indicator of air pollution by natural and anthropogenic activities, contributes to a wide spectrum of diseases that lead to a shortening of life expectancy. It has been recognized that trace metals in airborne PM are highly toxic and can be correlated with lesion in respiratory, gastrointestinal, immunological, and hematological systems. Traditional methods for trace metal assay require sophisticated instrumentations and highly trained operators in centralized laboratories. In this work, by integrating the technologies of microfluidic paper-based analytical devices, additive manufacturing, smartphone, and colorimetric sensing, we developed the first smartphone based paper microfluidic platform for portable, disposable, and quantitative measurements of cobalt (Co), copper (Cu), and iron (Fe) in ambient air and street sediments. On a single A4-sized paper, 48 devices were fabricated in under 30 s with a total cost of ~$1.9. On each device, 12 reaction units were patterned and used for colorimetric tests. Particulate samples from urban ambient air and street sediments were collected, processed, and analyzed. Signals of the on-chip complexation product were recorded using a smartphone camera and processed by a self-developed app on an iOS system. For precisely controlling the object distance, chip position, and luminance, a hand-held 3D cellphone housing was designed and printed. The detection limits of Co, Cu, and Fe were determined to be 8.2, 45.8, and 186.0 ng, while the linear dynamic ranges were calculated to be 8.2-81.6, 45.8-4.58 * 102, and 1.86 * 102-1.86 * 103 ng, representing a practically relevant device performance with a significant reduction in the detection cost and time consumption. Trace metals in ambient air and sediments of two cities in China have been quantified portably, thus demonstrating the utility of our system in improving strategies for air pollution control in low-resource settings. PMID- 29152030 TI - Yeast cell fractionation by morphology in dilute ferrofluids. AB - Morphology is an important particle (both biological and synthetic) property and potentially a useful marker for label-free particle separation. We present in this work a continuous-flow morphology-based fractionation of a heterogeneous mixture of drug-treated yeast cells in dilute ferrofluids. Such a diamagnetic cell separation technique utilizes the negative magnetophoretic motion to direct pre-focused yeast cells to morphology-dependent streamlines in a laminar flow. The separation performance is evaluated by comparing the exiting positions of the four classified groups of yeast cells: Singles, Doubles, Triples, and Others. We also develop a three-dimensional numerical model to simulate the separation process by the use of the experimentally determined correction factor for each group of non-spherical cells. The determining factors in this separation are studied both experimentally and numerically, the results of which show a reasonable agreement. PMID- 29152032 TI - LATENT CLASS MODELING USING MATRIX COVARIATES WITH APPLICATION TO IDENTIFYING EARLY PLACEBO RESPONDERS BASED ON EEG SIGNALS. AB - Latent class models are widely used to identify unobserved subgroups (i.e., latent classes) based upon one or more manifest variables. The probability of belonging to each subgroup is typically modeled as a function of a set of measured covariates. In this paper, we extend existing latent class models to incorporate matrix covariates. This research is motivated by a randomized placebo controlled depression clinical trial. One study goal is to identify a subgroup of subjects who experience symptoms improvement early on during antidepressant treatment, which is considered to be an indication of a placebo rather than a true pharmacological response. We want to relate the likelihood of belonging to this subgroup of early responders to baseline electroencephalography (EEG) measurement that takes the form of a matrix. The proposed method is built upon a low rank Candecomp/Parafac (CP) decomposition of the target coefficient matrix through low-dimensional latent variables, which effectively reduces the model dimensionality. We adopt a Bayesian hierarchical modeling approach to estimate the latent variables, which allows a flexible way to incorporate prior knowledge about covariate effect heterogeneity and offers a data-driven method of regularization. Simulation studies suggest that the proposed method is robust against potentially misspecified rank in the CP decomposition. With the motivating example we show how the proposed method can be applied to extract valuable information from baseline EEG measurements that explains the likelihood of belonging to the early responder subgroup, helping to identify placebo responders and suggesting new targets for the study of placebo response. PMID- 29152031 TI - Examining the Relationship between Online Social Capital and eHealth Literacy: Implications for Instagram Use for Chronic Disease Prevention among College Students. AB - Background: College students actively seek online health information and use Instagram, an image- and video-based social networking website, to build social networks grounded in trust and behavioral norms (social capital), which have the potential to prevent chronic disease. Purpose: This study aimed to: (1) examine how intensity of Instagram use moderates the relationship between eHealth Literacy and online social capital in college students, and (2) discuss how Instagram can be used as a social awareness platform for chronic disease prevention among college students. Methods: Hierarchical regression analyses were conducted to analyze web-based survey data from a random sample of college students (N=327). Results: Online bridging social capital was associated with greater eHealth Literacy (P<.05) and intensity of Instagram use (P<.001), when controlling for socio-demographic variables. The relationship between eHealth Literacy and online bridging social capital was strongest among respondents' with average (P<.01) and high (P<.01) intensity Instagram use, as compared to low Instagram intensity. Discussion: High intensity of Instagram may strengthen college students' low eHealth Literacy, especially when interacting with heterogeneous connections with weaker ties. Translation to Health Education Practice: Health education specialists should continue to explore how college students' intensity of Instagram use can be strengthened to build bridging online social capital, and ultimately prevent chronic disease. PMID- 29152033 TI - Role of Metal Lattice Expansion and Molecular pi-Conjugation for the Magnetic Hardening at Cu-Organics Interfaces. AB - Magnetic hardening and generation of room-temperature ferromagnetism at the interface between originally nonmagnetic transition metals and pi-conjugated organics is understood to be promoted by interplay between interfacial charge transfer and relaxation-induced distortion of the metal lattice. The relative importance of the two contributions for magnetic hardening of the metal remains unquantified. Here, we disentangle their role via density functional theory simulation of several models of interfaces between Cu and polymers of different steric hindrance, pi-conjugation, and electron-accepting properties: polyethylene, polyacetylene, polyethylene terephthalate, and polyurethane. In the absence of charge transfer, expansion and compression of the Cu face-centered cubic lattice is computed to lead to magnetic hardening and softening, respectively. Contrary to expectations based on the extent of pi-conjugation on the organic and resulting charge transfer, the computed magnetic hardening is largest for Cu interfaced with polyethylene and smallest for the Cu-polyacetylene systems as a result of a differently favorable rehybridization leading to different enhancement of exchange interactions and density of states at the Fermi level. It thus transpires that neither the presence of molecular pi-conjugation nor substantial charge transfer may be strictly needed for magnetic hardening of Cu-substrates, widening the range of organics of potential interest for enhancement of emergent magnetism at metal-organic interfaces. PMID- 29152035 TI - Direct Visualization of Au Atoms Bound to TiO2(110) O-Vacancies. AB - Au nanoparticles supported on reducible metal oxide surfaces are known to be active catalysts for a number of reactions including CO oxidation and hydrogen production. The exact choice of a metal oxide support has been shown to have a marked impact on activity, suggesting that interactions between Au and the support play a key role in catalysis. For TiO2, a model substrate for Au catalysis, it had been thought that bridging oxygen vacancies are involved in binding Au atoms to the (110) surface based on indirect evidence. However, a recent scanning transmission electron microscopy study of single Pt atoms on TiO2(110) suggests that subsurface vacancies are more important. To clarify the role of bridging or subsurface vacancies we employ scanning tunneling microscopy to determine the bonding site of single Au atoms on TiO2(110). Using in situ deposition as well as a manipulation method, we provide definitive evidence that the bonding site is atop surface oxygen vacancies. PMID- 29152034 TI - Orientation-Dependent Work-Function Modification Using Substituted Pyrene-Based Acceptors. AB - The adsorption of molecular acceptors is a viable method for tuning the work function of metal electrodes. This, in turn, enables adjusting charge injection barriers between the electrode and organic semiconductors. Here, we demonstrate the potential of pyrene-tetraone (PyT) and its derivatives dibromopyrene-tetraone (Br-PyT) and dinitropyrene-tetraone (NO2-PyT) for modifying the electronic properties of Au(111) and Ag(111) surfaces. The systems are investigated by complementary theoretical and experimental approaches, including photoelectron spectroscopy, the X-ray standing wave technique, and density functional theory simulations. For some of the investigated interfaces the trends expected for Fermi-level pinning are observed, i.e., an increase of the metal work function along with increasing molecular electron affinity and the same work function for Au and Ag with monolayer acceptor coverage. Substantial deviations are, however, found for Br-PyT/Ag(111) and NO2-PyT/Ag(111), where in the latter case an adsorption-induced work function increase of as much as 1.6 eV is observed. This behavior is explained as arising from a face-on to edge-on reorientation of molecules in the monolayer. Our calculations show that for an edge-on orientation much larger work-function changes can be expected despite the prevalence of Fermi level pinning. This is primarily ascribed to a change of the electron affinity of the adsorbate layer that results from a change of the molecular orientation. This work provides a comprehensive understanding of how changing the molecular electron affinity as well as the adsorbate structure impacts the electronic properties of electrodes. PMID- 29152036 TI - Case Study Quasi-Qualitative Analysis of Peer Group Supervision of a Child Trauma Recovery Program in Occupied Palestine. AB - This case study explores the impact of peer group supervision (PGS) for counselors delivering Teaching Recovery Techniques (TRT), a group psycho-social program for traumatized adolescents. Interviews were conducted with seven school counselors, from villages near East Jerusalem in occupied Palestine; a skilled supervisor; and an international trainer. A quasi-qualitative analysis was conducted to quantify responses and themes along with a measure of inter-rater reliability. Participants reported that even in a context of military violence, PGS provided a reflective process inclusive of formative, normative and restorative functions. Locally available PGS was viewed as essential within a geographically fragmented context. Counselors' reported PGS led to a trusting environment in contrast to military practices and gender norms. War stressors and lack of Training of Trainers led to low counselor confidence in training others in TRT. PGS and Trainer of Trainers were recommended as core aspects of program delivery and to support training of colleagues. PMID- 29152037 TI - Complete genome sequence of Pseudomonas corrugata strain RM1-1-4, a stress protecting agent from the rhizosphere of an oilseed rape bait plant. AB - 10.1601/nm.2592 strain RM1-1-4 is a rhizosphere colonizer of oilseed rape. A previous study has shown that this motile, Gram-negative, non-sporulating bacterium is an effective stress protecting and biocontrol agent, which protects their hosts against abiotic and biotic stresses. Here, we announce and describe the complete genome sequence of P. corrugata RM1-1-4 consisting of a single 6.1 Mb circular chromosome that encodes 5189 protein coding genes and 85 RNA-only encoding genes. Genome analysis revealed genes predicting functions such as detoxifying mechanisms, stress inhibitors, exoproteases, lipoproteins or volatile components as well as rhizobactin siderophores and spermidine. Further analysis of its genome will help to identify traits promising for stress protection, biocontrol and plant growth promotion properties. PMID- 29152038 TI - Associations Between Interoceptive Cognition and Age in Autism Spectrum Disorder and Typical Development. AB - Interoceptive awareness is linked to emotional and social cognition, which are impaired in individuals with autism spectrum disorder (ASD). It is unknown how this ability is associated with age in either typical or atypical development. We used a standard test of interoceptive accuracy (IA) to investigate these questions in children and adults with and without ASD. Perceived number of heartbeats over 4 time intervals was compared with actual heart rate to determine IA. Effects of group, age, IQ, heart rate, and mental counting ability on accuracy were assessed using multiple regression. Post hoc correlations were performed to clarify significant interactions. Age was unrelated to IA in both groups when IQ >=115. When IQ <115, this relationship was positive in typical development and negative in ASD. These results suggest that cognitive ability moderates the effect of age on IA differently in autism and typical development. PMID- 29152039 TI - Hepatic hydrothorax: An update and review of the literature. AB - This review considers the modern concepts of pathogenesis, diagnostic methods, and treatment principles of hepatic hydrothorax (HH). HH is the excessive (> 500 mL) accumulation of transudate in the pleural cavity in patients with decompensated liver cirrhosis but without cardiopulmonary and pleural diseases. It causes respiratory failure which aggravates the clinical course of liver cirrhosis, and the emergence of spontaneous bacterial pleural empyema may be the cause of death. The information was collected from the PubMed database, the Google Scholar retrieval system, the Cochrane reviews, and the reference lists from relevant publications for 1994-2016 using the keywords: "liver cirrhosis", "portal hypertension", "hepatic hydrothorax", "pathogenesis", "diagnostics", and "treatment". To limit the scope of this review, only articles dealing with uncomplicated hydrothorax in patients with liver cirrhosis were included. The analysis of the data showed that despite the progress of modern hepatology, the presence of HH is associated with poor prognosis and high mortality. Most patients suffering from it are candidates for orthotopic liver transplantation. In routine clinical practice, stratification of the risk for an adverse outcome and the subsequent determination of individual therapeutic strategies may be the keys to the successful management of the patient's condition. The development of pathogenetic pharmacotherapy and optimization of minimally invasive treatment will improve the quality of life and increase the survival rate among patients with HH. PMID- 29152040 TI - Ayurvedic drug induced liver injury. AB - Drug induced liver injury is responsible for 50% of acute liver failure in developed countries. Ayurvedic and homeopathic medicine have been linked to liver injury. This case describes the first documented case of Punarnava mandur and Kanchnar guggulu causing drug induced liver injury. Drug induced liver injury may be difficult to diagnosis, but use of multi-modalities tools including the ACG algorithms, causative assessment scales, histological findings, and imaging, is recommended. Advanced imaging, such as magnetic resonance cholangiopancreatography, may possibly have a greater role than previously reported in literature. PMID- 29152041 TI - Selective Estrogen Receptor Degraders (SERDs): A Promising Treatment to Overcome Resistance to Endocrine Therapy in ERalpha-Positive Breast Cancer. PMID- 29152042 TI - Selective Inhibitors of Phosphodiesterase 4B (PDE-4B) May Provide a Better Treatment for CNS, Metabolic, Autoimmune, and Inflammatory Diseases. PMID- 29152043 TI - Lysine-Specific Demethylase 1 (LSD1) Inhibitors as Potential Treatment for Different Types of Cancers. PMID- 29152044 TI - Structure-Based Discovery of Thiosemicarbazone Metalloproteinase Inhibitors for Hemorrhage Treatment in Snakebites. AB - The venoms of snakes are composed by many toxins, which are responsible for various toxic effects including intense pain, bleeding disorders, and local tissue damage caused by hemorrhage and necrosis. The snake venom metalloproteinases (SVMPs) are proteolytic zinc-dependent enzymes acting in different hemostatic mechanisms. In this work, a structure-based molecular modeling strategy was used for the rational design, by means of a homology 3D model of an SVMP isolated from Bothrops pauloensis venom (BpMP-I), followed by synthesis and in vitro evaluation of new thiosemicarbazones as the first inhibitors of the B. pauloensis SVMP. Besides being effective for the SVMP inhibition, two molecules were shown to be effective also in vivo, inhibiting hemorrhage caused by the B. pauloensis whole venom. Docking studies on metalloproteinases from other snake species suggest that the thiosemicarbazones activity is not confined to BpMP-I, but seems to be a common feature of metzincins. PMID- 29152045 TI - Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a serious and deadly disease for which treatment options are limited. The recent approval of antifibrosis agent nintedanib represents one of the first therapeutic approaches for the treatment of IPF. Here, we report novel indolinone-based multikinase inhibitors that target angiogenesis and fibrosis pathways and may serve as potential therapeutics for IPF. KBP-7018 is a novel, tyrosine kinase-selective inhibitor with potent effects on three fibrotic kinases (c-KIT, PDGFR, and RET). The pharmacokinetics (PK) properties of KBP-7018 were favorable in mice, rats, and dogs. In a bleomycin (BLM)-induced mouse pulmonary fibrosis model, 10, 30, and 100 mg/kg daily doses (q.d.) of KBP-7018 improved the 28-day survival rate in a dose-dependent manner. The improved efficacy of KBP-7018 compared to nintedanib provided a certain level of chemical validation for the involvement of PDGFR, c-KIT, and RET in IPF. Thus, KBP-7018 represents a novel multikinase inhibitor with differentiated activity, highly enhanced selectivity, and acceptable PK profiles that will enter phase I clinical trials. PMID- 29152046 TI - Design and Synthesis of N1-Modified Imidazoquinoline Agonists for Selective Activation of Toll-like Receptors 7 and 8. AB - A series of N1-modified imidazoquinolines were synthesized and screened for Toll like receptors (TLR) 7 and 8 activities to identify recognition elements that confer high affinity binding and selectivity. These receptors are key targets in the development of immunomodulatory agents that signal the NF-kappaB mediated transcription of pro-inflammatory chemokines and cytokines. Results are presented showing both TLR7/8 activations are highly correlated to N1-substitution, with TLR8 selectivity achieved through inclusion of an ethyl-, propyl-, or butylamino group at this position. While the structure-activity relationship analysis indicates TLR7 activity is less sensitive to N1-modification, extension of the aminoalkyl chain length to pentyl and p-methylbenzyl elicited high affinity TLR7 binding. Cytokine profiles are also reported that show the pure TLR8 agonist [4 amino-2-butyl-1-(2-aminoethyl)-7-methoxycarbonyl-1H-imidazo[4,5-c]quinoline] induces higher levels of IL-1beta, IL-12, and IFNgamma when compared with TLR7 selective or mixed TLR7/8 agonists. The results are consistent with previous work suggesting TLR8 agonists are Th1 polarizing and may help promote cell-mediated immunity. PMID- 29152047 TI - Design, Synthesis, and Antibacterial Evaluation of Oxazolidinones with Fused Heterocyclic C-Ring Substructure. AB - A series of novel oxazolidinone antibacterials with diverse fused heteroaryl C rings bearing hydrogen bond donor and hydrogen bond acceptor functionalities were designed and synthesized. The compound with benzoxazinone C-ring substructure (8c) exhibited superior activity compared to linezolid against a panel of Gram positive and Gram-negative bacteria. Structural modifications at C5-side chain of 8c resulted in identification of several potent compounds (12a, 12b, 12g, and 12h). Selected compounds 8c and 12a showed very good microsomal stability and no CYP450 liability, thus clearing preliminary safety hurdles. A docking model of 12a binding to 23S rRNA suggested that the increased potency of 12a is due to additional ligand-receptor interaction. PMID- 29152048 TI - Structure-Based Design and Synthesis of New Estrane-Pyridine Derivatives as Cytochrome P450 (CYP) 1B1 Inhibitors. AB - Inhibition of cytochrome P450 (CYP) 1B1 is a promising therapeutic strategy, as such an inhibitor could modulate the bioactivation of procarcinogens while reducing drug resistance. Based on docking studies, the synthesis of 12 estra 1,3,5(10)-triene derivatives containing a pyridin-3-/4-yl moiety at position C2, C3, or C4 was performed, and we measured their inhibitory activity on CYP1B1 using the ethoxyresorufin-O-deethylase (EROD) assay. The position of the nitrogen atom in the aromatic ring has little influence on their inhibition potency, but compounds with a pyridinyl at C2 of the steroid nucleus are more potent CYP1B1 inhibitors than those with a pyridinyl at C3 or C4. Estradiol derivatives (OH at C17beta) are also 10-fold more potent inhibitors than estrone derivatives (carbonyl at C17). Thus, 2-(pyridin-3-yl)-estradiol (4a) is the best CYP1B1 inhibitor (IC50 = 0.011 MUM) from this series of compounds, and the best steroid inhibitor reported until now. It is also 7.5-fold more potent than the well-known nonsteroidal CYP1B1 inhibitor alpha-naphthoflavone (IC50 = 0.083 MUM). PMID- 29152049 TI - Indolylalkyltriphenylphosphonium Analogues Are Membrane-Depolarizing Mycobactericidal Agents. AB - Agents that selectively target the mycobacterial membrane could potentially shorten treatment time for tuberculosis, reduce relapse, and curtail emergence of resistant strains. The lipophilicity and extensive charge-delocalized state of the triphenylphosphonium cation strongly favor accumulation within bacterial membranes. Here, we explored the antimycobacterial activities and membrane targeting properties of indolylalkyltriphenylphosphonium analogues. The most active analogues preferentially inhibited growth of Mycobacterium tuberculosis H37Rv (MIC50 2-4 MUM) and were bactericidal against Mycobacterium bovis BCG (MBC99 3 MUM). In spite of their propensity to accumulate within membranes, we found no evidence that these compounds permeabilized mycobacterial membranes or induced cell-envelope stress. Our investigations indicated that their bacterical effects stem from sustained depolarization of mycobacterial membranes and ensuing disruptive effects on electron transfer and cell division. PMID- 29152050 TI - Consequences of Depsipeptide Substitution on the ClpP Activation Activity of Antibacterial Acyldepsipeptides. AB - The acyldepsipeptide (ADEP) antibiotics operate through a clinically unexploited mechanism of action and thus have attracted attention from several antibacterial development groups. The ADEP scaffold is synthetically tractable, and deep-seated modifications have produced extremely potent antibacterial leads against Gram positive pathogens. Although newly identified ADEP analogs demonstrate remarkable antibacterial activity against bacterial isolates and in mouse models of bacterial infections, stability issues pertaining to the depsipeptide core remain. To date, no study has been reported on the natural ADEP scaffold that evaluates the sole importance of the macrocyclic linkage on target engagement, molecular conformation, and bioactivity. To address this gap in ADEP structure activity relationships, we synthesized three ADEP analogs that only differ in the linkage motif (i.e., ester, amide, and N-methyl amide) and provide a side-by-side comparison of conformational behavior and biological activity. We demonstrate that while replacement of the naturally occurring ester linkage with a secondary amide maintains in vitro biochemical activity, this simple substitution results in a significant drop in whole-cell activity. This study provides direct evidence that ester to amide linkage substitution is unlikely to provide a reasonable solution for ADEP instability. PMID- 29152051 TI - chi-Space Screening of Dermorphin-Based Tetrapeptides through Use of Constrained Arylazepinone and Quinolinone Scaffolds. AB - Herein, the synthesis of novel conformationally constrained amino acids, 4-amino 8-bromo-2-benzazepin-3-one (8-Br-Aba), 3-amino-3,4-dihydroquinolin-2-one, and regioisomeric 4-amino-naphthoazepinones (1- and 2-Ana), is described. Introduction of these constricted scaffolds into the N-terminal tetrapeptide of dermorphin (i.e., H-Tyr-d-Ala-Phe-Gly-NH2) induced significant shifts in binding affinity, selectivity, and in vitro activity at the MU- and delta-opioid receptors (MOP and DOP, respectively). A reported constrained MU-/delta-opioid lead tetrapeptide H-Dmt-d-Arg-Aba-Gly-NH2 was modified through application of various constrained building blocks to identify optimal spatial orientations in view of activity at the opioid receptors. Interestingly, when the aromatic moieties were turned toward the C-terminus of the peptide sequences, (partial) (ant)agonism at MOP and weak (ant)agonism at DOP were noticed, whereas the incorporation of the 1-Ana residue led toward balanced low nanomolar MOP/DOP binding and in vitro agonism. PMID- 29152052 TI - Discovery of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 NNRTIs Targeting the Tolerant Region I of NNIBP. AB - Our previous studies led us to conclude that thiophene[3,2-d]pyrimidine is a promising scaffold for diarylpyrimidine (DAPY)-type anti-HIV agents with potent activity against resistance-associated human immunodeficiency virus (HIV) variants (J. Med. Chem. 2016, 59, 7991-8007; J. Med. Chem. 2017, 60, 4424-4443). In the present study, we designed and synthesized a series of thiophenepyrimidine derivatives with various substituents in the right wing region of the structure with the aim of developing new interactions with the tolerant region I of the binding pocket of the HIV-1 non-nucleoside reverse transcriptase (NNRTI), and we evaluated their activity against a panel of mutant HIV-1 strains. All the derivatives exhibited moderate to excellent potency against wild-type (WT) HIV-1 in MT-4 cells. Among them, sulfonamide compounds 9b and 9d were single-figure nanomolar inhibitors with EC50 values of 9.2 and 7.1 nM, respectively. Indeed, 9a and 9d were effective against the whole viral panel except RES056. Notably, both compounds showed potent antiviral activity against K103N (EC50 = 0.032 and 0.070 MUM) and E138K (EC50 = 0.035 and 0.045 MUM, respectively). Furthermore, 9a and 9d exhibited high affinity for WT HIV-1 RT (IC50 = 1.041 and 1.138 MUM, respectively) and acted as classical NNRT inhibitors (NNRTIs). These results are expected to be helpful in the design of thiophenepyrimidine-based NNRTIs with more potent activity against HIV strains with RT mutations. PMID- 29152053 TI - Benzoxaboroles as Efficient Inhibitors of the beta-Carbonic Anhydrases from Pathogenic Fungi: Activity and Modeling Study. AB - A series of 6-substituted benzoxaboroles were investigated as inhibitors of the beta-class carbonic anhydrase from three pathogenic fungi (Cryptococcus neoformans, Candida glabrata, and Malassezia globosa). Independently from the nature of the substituents on the phenyl of the urea/thiourea group, all reported derivatives showed nanomolar inhibitory activities against Can2 and CgNce103 vs micromolar inhibition against MgCA. Selectivity over human CA I and CA II was noticed. The observed structure-activity relationship trends have been rationalized by modeling study of selected compounds into the active site of Can2 and MgCA. The present letter demonstrates that benzoxaborole chemotype may offer interesting opportunities for the inhibition of beta-CA from pathogenic fungi and for the development of antifungal agents with a new mechanism of action. PMID- 29152054 TI - Structure Optimization of Aloperine Derivatives as HIV-1 Entry Inhibitors. AB - As a step toward developing novel anti-HIV agents, we have identified a class of quinolizidines, including aloperine, that inhibit HIV at 1-5 MUM by blocking viral entry. In this study, we have optimized the structure of aloperine and derived compounds with markedly improved activity. Our structural optimization has yielded an aloperine derivative 19 with approximately a 15-fold increase in anti-HIV-1 activity. Our mechanism of action study reveals that compound 19 does not inhibit binding of HIV-1 to receptors but arrests the virus from fusion with the membrane. Binding of the compound to HIV-1gp120 might be responsible for its anti-HIV-1 entry activity. PMID- 29152055 TI - Correction to "Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors". AB - [This corrects the article DOI: 10.1021/acsmedchemlett.6b00464.]. PMID- 29152056 TI - Distant metastasis is a critical mode of failure for patients with localized major salivary gland tumors treated with surgery and radiation. AB - Objectives: Excellent local-regional control can be achieved for major salivary gland tumors treated with surgery and post-operative radiotherapy. We evaluated the cumulative incidence and predictors of distant metastasis in high-risk major salivary gland tumors. Methods: Between 1990 and 2011, 200 patients with major salivary gland tumors received post-operative radiotherapy at our center. The patients' median age was 60 years. Patients had primary tumors of the parotid gland (84%), submandibular (16%), and one sublingual gland. Among the patients, 34% had T3-T4 tumors, 32% had nodal involvement. Other high-risk features included close/positive margins and high grade tumors. The median RT dose was 63 Gy. Results: With a median follow-up of 50 months, the 5-year local control and regional control were 88% and 94%, respectively. The 5-year freedom from distant metastasis was 73%. The median overall survival was 14.6 years corresponding to a 5 and 10-year overall survival of 77% and 59%, respectively. T category and nodal involvement were independent predictors of distant metastasis. Nodal involvement was also an independent predictor of overall survival. Conclusions: Distant relapse was the predominant mode of failure despite excellent local-regional control in high-risk major salivary gland tumors. Both advanced T category and nodal involvement were independent predictors of distant metastasis. More effective systemic therapy is needed to combat distant relapse. PMID- 29152057 TI - Maintenance and repair of an aging life cycle. PMID- 29152058 TI - Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy. AB - Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment. PMID- 29152059 TI - GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways. AB - Available therapeutic options for advanced B cell precursor acute lymphoblastic leukemia (pre-B ALL) are limited. Many lead to neutropenia, leaving patients at risk of life-threatening infections and result in bad outcomes. New treatment options are needed to improve overall survival. We previously showed that GZD824, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells and tumor models. Here, we show that GZD824 decreases cell viability, induces cell-cycle arrest, and causes apoptosis in pre-B ALL cells. Furthermore, Ph- pre-B ALL cells were more sensitive to GZD824 than Ph+ pre-B ALL cells. GZD824 consistently reduced tumor loads in Ph- pre-B ALL xenografts but failed to suppress Ph+ pre-B ALL xenografts. GZD824 decreased phosphorylation of SRC kinase, STAT3, RB and C myc. It also downregulated the expression of BCL-XL, CCND1 and CDK4 and upregulated expression of CCKN1A. Expression of IRS1 was decreased in GZD824 treated pre-B ALL cells, blocking the PI3K/AKT pathway. These data demonstrate that GZD824 suppresses pre-B ALL cells through inhibition of the SRC kinase and PI3K/AKT pathways and may be a potential therapeutic agent for the management of pre-B ALL. PMID- 29152060 TI - Inhibition of CHK1 sensitizes Ewing sarcoma cells to the ribonucleotide reductase inhibitor gemcitabine. AB - Ewing sarcoma is a bone and soft tissue sarcoma that occurs in children and young adults. The EWS-FLI1 gene fusion is the driver mutation in most Ewing sarcoma tumors and functions, in part, as an aberrant transcription factor. We recently identified that Ewing sarcoma cells are sensitive to inhibition of ribonucleotide reductase (RNR), which catalyzes the formation of deoxyribonucleotides from ribonucleotides. In this report, we show that Ewing sarcoma cells are sensitive to treatment with clofarabine, which is a nucleoside analogue and allosteric inhibitor of RNR. However, clofarabine is a reversible inhibitor of RNR and we found that the effect of clofarabine is limited when using a short (6-hour) drug treatment. Gemcitabine, on the other hand, is an irreversible inhibitor of the RRM1 subunit of RNR and this drug induces apoptosis in Ewing sarcoma cells when used in both 6-hour and longer drug treatments. Treatment of Ewing sarcoma cells with gemcitabine also results in activation of checkpoint kinase 1 (CHK1), which is a critical mediator of cell survival in the setting of impaired DNA replication. Notably, inhibition of CHK1 function in Ewing sarcoma cells using a small-molecule CHK1 inhibitor, or siRNA knockdown, in combination with gemcitabine results in increased toxicity both in vitro and in vivo in a mouse xenograft experiment. Overall, our results provide insight into Ewing sarcoma biology and identify a candidate therapeutic target, and drug combination, in Ewing sarcoma. PMID- 29152061 TI - EPMDA: an expression-profile based computational model for microRNA-disease association prediction. AB - MicroRNA has become a new star molecule for understanding multiple biological processes and the mechanism of various complex human diseases. Even though a number of computational models have been proposed for predicting the association between microRNAs and various human diseases, most of them are mainly based on microRNA functional similarity and heterogeneous biological networks which suffer from inevitable computational error and bias. In this work, considering the limitation of information resource used by existing methods, we proposed EPMDA model which is the first computational method using the expression profiles of microRNAs to predict the most potential microRNAs associated with various diseases. Based on the dataset constructed from HMDD v2.0 database, EPMDA obtained AUCs of 0.8945 and 0.8917 based on the leave-one-out and 5-fold cross validation, respectively. Furthermore, EPMDA was applied to two important human diseases. As a result, 80% and 88% microRNAs in the top-25 lists of Colon Neoplasms and Kidney Neoplasms were confirmed by other databases. The performance comparison of EPMDA with existing prediction models and classical algorithms also demonstrated the reliable prediction ability of EPMDA. It is anticipated that EPMDA can be used as an effective computational tool for future biomedical researches. PMID- 29152062 TI - Rapamycin sensitizes cancer cells to growth inhibition by the PARP inhibitor olaparib. AB - Poly (ADP-ribose) polymerase inhibitors (PARPi) have been developed and tested in a context of combining it with double-stranded (ds) DNA repair defects or inhibitors, as PARP inhibitor impairs single-stranded (ss) DNA break repair, resulting in the activation of the dsDNA break repair machinery. Rapamycin has been widely prescribed for more than a decade and recent studies have revealed that it may inhibit dsDNA break repair. The combination of the PARP inhibitor olaparib and rapamycin synergistically inhibited cell proliferation in non-small cell lung cancer (NSCLC) cells, and even in triple negative breast cancer (TNBC) cells with BRCA1 mutations. Rad51, which forms a polymer on ssDNA upon dsDNA breaks, plays an essential role in homologous recombination. Olaparib induced Rad51 focus formation, while rapamycin successfully inhibited it both in vivo and in vitro, suggesting that this combination worked through the blocking of both ssDNA break repair and dsDNA break repair; hence the cells cannot go through the G2/M checkpoint. The protein level of PARP was a predictive marker for both PAR activity and Rad51 focus formation in this combination. Collectively, these data suggest that this combination could have therapeutic potential in the treatment of cancer with high PARP expression, or in combination with cytotoxic chemotherapy or radiotherapy. PMID- 29152063 TI - Acquisition of an oncogenic fusion protein is sufficient to globally alter the landscape of miRNA expression to inhibit myogenic differentiation. AB - The differentiation status of tumors is used as a prognostic indicator, with tumors comprised of less differentiated cells exhibiting higher levels of aggressiveness that correlate with a poor prognosis. Although oncogenes contribute to blocking differentiation, it is not clear how they globally alter miRNA expression during differentiation to achieve this result. The pediatric sarcoma Alveolar Rhabdomyosarcoma, which is primarily characterized by the expression of the PAX3-FOXO1 oncogenic fusion protein, consists of undifferentiated muscle cells. However, it is unclear what role PAX3-FOXO1 plays in promoting the undifferentiated state. We demonstrate that expression of PAX3 FOXO1 globally alters the expression of over 80 individual miRNA during early myogenic differentiation, resulting in three primary effects: 1) inhibition of the expression of 51 miRNA essential for promoting myogenesis, 2) promoting the aberrant expression of 43 miRNA not normally expressed during myogenesis, and 3) altering the expression pattern of 39 additional miRNA. Combined, these changes are predicted to have an overall negative effect on myogenic differentiation. This is one of the first studies describing how an oncogene globally alters miRNA expression to block differentiation and has clinical implications for the development of much needed multi-faceted tumor-specific therapeutic regimens. PMID- 29152065 TI - Kahweol decreases hepatic fibrosis by inhibiting the expression of connective tissue growth factor via the transforming growth factor-beta signaling pathway. AB - Kahweol is a diterpene molecule found in Coffea Arabica beans. Previous studies have shown that coffee reduces liver fibrosis, but it is not clear which component of coffee has the protective effect. In this study, we examined whether kahweol has a protective effect on hepatic fibrosis in vivo and in vitro. Kahweol decreased hepatic fibrosis by inhibiting connective tissue growth factor (CTGF) expression in thioacetamide (TAA)-treated mice. The expression of phospho-Smad3, signal transducer and activator of transcription 3 (STAT3), extracellular signal regulated kinases (ERK), and c-Jun N-terminal protein kinase (JNK) increased in the livers of TAA-treated mice and decreased in the kahweol-treated group. Kahweol significantly decreased the expression of transforming growth factor beta (TGF-beta)-stimulated type I collagen and CTGF expression in vitro. In addition, kahweol significantly decreased the expression of Smad3, STAT3, ERK and JNK, which are involved in the induction of CTGF expression by TGF-beta in hepatocytes, but not in HSCs. These results suggest that kahweol may be a new candidate for treatment of liver fibrosis. PMID- 29152064 TI - Development of a population-based cancer case-control study in southern china. AB - With its population of over 1.3 billion persons, China offers abundant opportunities to discover causes of disease. However, few rigorous population based case-control studies have as yet been conducted in mainland China. We conducted a population-based case-control study of nasopharyngeal carcinoma in Guangdong Province and Guangxi Autonomous Region. We collected questionnaires and biospecimens from incident cases recruited between March 2010 and December 2013, and population-based controls between November 2010 and November 2014. Preparatory activities prior to subject enrollment required approximately 18 months. We enrolled a total of 2554 NPC cases and 2648 controls. Among all identified cases, 83.8% participated. For the participating cases, the median time between diagnosis and interview was 2 days. Among all contacted controls, 82.7% participated. From the enrolled cases, we collected 2518 blood specimens (provided by 98.6% of eligible cases), 2350 saliva specimens (92.0%), 2514 hair specimens (98.4%), and 2507 toenail/fingernail specimens (98.2%). From the enrolled controls, we collected 2416 blood specimens (91.2%), 2505 saliva specimens (94.6%), 2517 hair specimens (95.1%), and 2514 toenail/fingernail specimens (94.9%). We demonstrate that population-based epidemiologic research can successfully be conducted in southern China. The study protocols, databases, and biobank will serve as an extraordinarily valuable resource for testing future etiologic hypotheses. PMID- 29152066 TI - Identification and validation of FGFR2 peptide for detection of early Barrett's neoplasia. AB - The incidence of esophageal adenocarcinoma (EAC) is rising rapidly, and early detection within the precursor state of Barrett's esophagus (BE) is challenged by flat premalignant lesions that are difficult detect with conventional endoscopic surveillance. Overexpression of cell surface fibroblast growth factor receptor 2 (FGFR2) is an early event in progression of BE to EAC, and is a promising imaging target. We used phage display to identify the peptide SRRPASFRTARE that binds specifically to the extracellular domain of FGFR2. We labeled this peptide with a near-infrared fluorophore Cy5.5, and validated the specific binding to FGFR2 overexpressed in cells in vitro. We found high affinity kd = 68 nM and rapid binding k = 0.16 min-1 (6.2 min). In human esophageal specimens, we found significantly greater peptide binding to high-grade dysplasia (HGD) versus either BE or normal squamous epithelium, and good correlation with anti-FGFR2 antibody. We also observed significantly greater peptide binding to excised specimens of esophageal squamous cell carcinoma and gastric cancer compared to normal mucosa. These results demonstrate potential for this FGFR2 peptide to be used as a clinical imaging agent to guide tissue biopsy and improve methods for early detection of EAC and potentially other epithelial-derived cancers. PMID- 29152067 TI - Propoxur enhances MMP-2 expression and the corresponding invasion of human breast cancer cells via the ERK/Nrf2 signaling pathway. AB - Propoxur is considered a prime etiological suspect of increasing tumor incidence, but the role is still undefined. In this study, two human breast cancer cells lines, MCF-7 and MDA-MB-231 cells, were used as cell models. Cells were respectively treated with 0, 0.01, 1, or 100 MUM propoxur. PD98059, a MEK inhibitor, was administered to block the ERK/MAPK pathway. Migration and reactive oxygen species were measured by wound healing and Transwell assays, and flow cytometry. Protein expression and subcellular location were detected by western blotting and immunofluorescence staining, respectively. Results showed that propoxur treatment enhanced cell migration and invasion in a dose-dependent manner, while MMP-2 expression, but not MMP-9, was significantly increased in two cell lines. Meanwhile, the treatment increased intracellular reactive oxygen species, Nrf2 expression and nuclear translocation, and ERK1/2 phosphorylation. Inversely, inhibition of ERK1/2 activation with PD98059 significantly attenuated propoxur-induced Nrf2 expression and nuclear translocation. Moreover, PD98059 suppressed propoxur-induced cell migration and invasion, and MMP-2 overexpression. Collectively, these results indicate that propoxur can trigger reactive oxygen species overproduction, further promoting breast cancer cell migration and invasion by regulating the ERK/Nrf2 signaling pathways. PMID- 29152068 TI - Age-associated and therapy-induced alterations in the cellular microenvironment of experimental gliomas. AB - The poor prognosis associated with advanced age in patients with glioblastoma remains poorly understood. Glioblastoma in the elderly has been particularly associated with vascular endothelial growth factor (VEGF)-dependent angiogenesis, and early uncontrolled studies suggested that the anti-angiogenic agent bevacizumab (BEV), an antibody to VEGF, might be preferentially active in this patient population. Accordingly, we explored host age-dependent differences in survival and benefit from radiotherapy (RT) or BEV in syngeneic mouse glioma models. Survival was inferior in older mice in the SMA-540 and and less so in SMA 560, but not in the SMA-497 or GL-261 models. Detailed flow cytometric studies revealed increased myeloid and decreased effector T cell population frequencies in SMA-540 tumors of old compared to young mice, but no such difference in the SMA-497 model. Bone marrow transplantation (BMT) from young to old mice had no effect, whereas survival was reduced with BMT from old to young mice. BEV significantly decreased vessel densities in gliomas of old, but not young mice. Accordingly, old, but not young SMA-540 tumor-bearing mice benefited from BEV alone or in combination with RT. End-stage tumors of old BEV- and BEV/RT-treated mice exhibited increased infiltration of T helper and cytotoxic T cells compared to tumors of young mice. The SMA-540 model may provide a valuable tool to evaluate the influence of host age on glioblastoma progression and treatment response. The biological host factors that modulate glioma growth in old as opposed to young mice remain to be identified. PMID- 29152069 TI - The transcriptional coregulator NAB2 is a target gene for the Wilms' tumor gene 1 protein (WT1) in leukemic cells. AB - The Wilms' tumor gene 1 (WT1) is recurrently mutated in acute myeloid leukemia. Mutations and high expression of WT1 associate with a poor prognosis. In mice, WT1 cooperates with the RUNX1/RUNX1T1 (AML1/ETO) fusion gene in the induction of acute leukemia, further emphasizing a role for WT1 in leukemia development. Molecular mechanisms for WT1 are, however, incompletely understood. Here, we identify the transcriptional coregulator NAB2 as a target gene of WT1. Analysis of gene expression profiles of leukemic samples revealed a positive correlation between the expression of WT1 and NAB2, as well as a non-zero partial correlation. Overexpression of WT1 in hematopoietic cells resulted in increased NAB2 levels, while suppression of WT1 decreased NAB2 expression. WT1 bound and transactivated the proximal NAB2 promoter, as shown by ChIP and reporter experiments, respectively. ChIP experiments also revealed that WT1 can recruit NAB2 to the IRF8 promoter, thus modulating the transcriptional activity of WT1, as shown by reporter experiments. Our results implicate NAB2 as a previously unreported target gene of WT1 and that NAB2 acts as a transcriptional cofactor of WT1. PMID- 29152070 TI - The role of BRCA status on prognosis in patients with triple-negative breast cancer. AB - Studies have showed that dysfunction in the breast cancer susceptibility gene (BRCA) is associated with triple-negative breast cancer (TNBC); however, its effect on patient survival remains controversial. We investigated the distribution of BRCA1/2 mutations in unselected Chinese patients with TNBC and explored their roles in prognosis. Then a systematic review and meta-analysis were performed to evaluate the prognostic role of BRCA dysfunction, including BRCA1/2 germline/somatic mutations, BRCA1 promoter methylation, and low BRCA1 protein expression in TNBC patients. Pooled hazard ratios with 95% confidence intervals were estimated to determine the association between BRCA dysfunction and survival. Our results showed a high frequency of BRCA1/2 mutations, especially germline BRCA1 variants, were associated with bilateral breast cancer. Although no correlations were found between BRCA1/2 mutations and recurrence-free survival (RFS) or overall survival (OS). In the meta-analysis, patients with BRCA1 promoter methylation showed poor OS. However, there was a favorable impact on disease free survival (DFS) for TNBC patients with BRCA1 promoter methylation when received adjuvant-chemotherapy. In conclusion, BRCA1/2 mutations were associated with bilateral breast cancer and BRCA1 promoter methylation may have a prognostic effect on TNBC. PMID- 29152071 TI - Outcomes of phase I clinical trials for patients with advanced pancreatic cancer: update of the MD Anderson Cancer Center experience. AB - Background: In 2011, we reported the outcomes of pancreatic cancer (PC) patients enrolled in phase I trials at our institution from 2004 through 2009. At the time, gemcitabine and erlotinib were the only Food and Drug Administration approved drugs for PC and median overall survival (OS) from consultation in the phase I clinic was 5 months. We sought to determine the impact of novel therapeutics on PC patients in phase I trials. Methods: We reviewed records of PC patients treated in phase I trials at our institution from January 2009 through December 2014. Survival was analyzed using the Kaplan-Meier method. Results: Ninety-five patients were identified. The median age was 61 years (range, 40-84), 59% were men, and 41% had stage IV disease. The median OS from consultation in the phase I clinic was 5.8 months (95% confidence interval [CI], 4.5-6.8), and the 1-year OS rate was 9% (95% CI, 4%-17%). Three patients had partial responses and 18 had stable disease >= 4 months. Conclusion: We observed no improvement in OS between PC patients enrolled in phase I trials in 2004-2009 and 2009-2015. To substantially improve OS in this challenging disease, improved patient selection and science-driven, innovative trial designs will be key. PMID- 29152072 TI - Platelet derived TGF-beta promotes cervical carcinoma cell growth by suppressing KLF6 expression. AB - Platelets in the primary tumor microenvironment play crucial roles in regulating tumor growth, metastasis, and angiogenesis, but the underlying mechanisms are unclear. Here, we show that platelet releasates exhibited a proliferative effect on HeLa cells, and this effect correlated with a reduction of KLF6 expression. After incubation with either washed human platelets or collagen-related peptide (CRP) activated platelet releasates, expression of KLF6 in the HeLa cervical tumor cell line was markedly reduced. However, no significant difference was observed between control HeLa cells and HeLa cells incubated with resuspended activated platelet pellet. Moreover, the platelets' promoting effect on HeLa cell growth was significantly abolished in KLF6 silenced HeLa cells. In addition, blocking TGF-beta signaling with SB431542, a TGF-beta receptor inhibitor, also counteracted the effect of platelets on proliferation and KLF6 expression in HeLa cells. From these findings, we conclude that platelet derived TGF-beta promotes proliferation of HeLa cells by decreasing the expression of KLF6. The discovery that KLF6 is a key target of platelet-derived TGF-beta signaling in HeLa cells identifies a potential new therapeutic target for the prevention and treatment of cervical carcinoma. PMID- 29152073 TI - Molecular diagnosis of citrin deficiency in an infant with intrahepatic cholestasis: identification of a 21.7kb gross deletion that completely silences the transcriptional and translational expression of the affected SLC25A13 allele. AB - Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) arises from biallelic SLC25A13 mutations, and SLC25A13 analysis provides reliable evidences for NICCD definite diagnosis. However, novel large insertions/deletions in this gene could not be detected just by conventional DNA analysis. This study aimed to explore definite diagnostic evidences for an infant highly-suspected to have NICCD. Prevalent mutation screening and Sanger sequencing of SLC25A13 gene just revealed a paternally-inherited mutation c.851_854del4. Nevertheless, neither citrin protein nor SLC25A13 transcripts of maternal origin could be detected on Western blotting and cDNA cloning analysis, respectively. On this basis, the hidden maternal mutation was precisely positioned using SNP analysis and semi quantitative PCR, and finally identified as a novel large deletion c. 3251_c.15+18443del21709bp, which involved the SLC25A13 promoter region and the entire exon 1 where locates the translation initiation codon. Hence, NICCD was definitely diagnosed in the infant. To the best of our knowledge, the novel gross deletion, which silenced the transcriptional and translational expression of the affected SLC25A13 allele, is the hitherto largest deletion in SLC25A13 mutation spectrum. The Western blotting approach using mitochondrial protein extracted from expanded peripheral blood lymphocytes, of particular note, might be a new minimally-invasive and more-feasible molecular tool for NICCD diagnosis. PMID- 29152075 TI - A novel multikinase inhibitor R8 exhibits potent inhibition on cancer cells through both apoptosis and autophagic cell death. AB - Chemotherapy is an important treatment for cancer patients, especially for those with unresectable lesions. Targeted therapy of cancer by specific inhibition of aberrant tyrosine kinase activities in cancer cells with chemically synthesized tyrosine kinase inhibitors (TKIs), shows better responses while less side effects than traditional chemotherapeutic drugs. It is common that cancer cells often exhibit deregulation of several tyrosine kinases simultaneously, multikinase TKIs (MKIs) therefore have greater advantages over single-target TKIs. Currently more MKIs are under developing for better efficacy for different types of cancer. In the present work, we evaluated the in vitro therapeutic potential of a novel MKI, namely R8, with comparison to the clinically available MKI Sunitinib. Results showed that R8 has stronger inhibition on six different types of cancer cell lines with lower IC50 than Sunitinib does. Cell cycle analysis showed that R8 induced significant G0/G1 arrest phase of lung cancer A549 and NCI-H226 cells. The inhibition was also confirmed by colony formation and migration assays in both lung cancer cell lines in a dose-dependent manner. R8 could significantly inhibit the phosphorylation of multiple receptor tyrosine kinases (RTKs) included PDGFRbeta, VEGFR2, EGFR and C-Kit, leading to the down-regulation of PI3K-Akt mTOR signaling. Further analysis revealed that R8 treatment induced more significant apoptosis than Sunitinib did, which might be the consequence of the autophagic cell death. In conclusion, this work suggested R8 to be a promising novel anticancer MKI, and provided the basis for further in vivo investigation on its potential in treatment of lung cancer. PMID- 29152074 TI - Vanillic acid attenuates testosterone-induced benign prostatic hyperplasia in rats and inhibits proliferation of prostatic epithelial cells. AB - Benign prostatic hyperplasia (BPH) is a common disease in the male population, especially in elderly men. Vanillic acid (VA), a dihydroxybenzoic derivative used as a flavoring agent, is reported to have an anti-inflammatory effect. However, there are no reports of its effects on BPH to date. BPH was induced with a pre-4 week treatment of daily subcutaneous injections of testosterone propionate (TP), and the normal control group received injections of ethanol with corn oil instead. Six weeks of further injections were done with (a) ethanol with corn oil, (b) TP only, (c) TP + finasteride, and (d) TP + VA. Finasteride was used as a positive control group. VA had protective effects on the TP-induced BPH. In the VA treatment group, the prostate weight was reduced, and the histological changes including the epithelial thickness and lumen area were restored like in the normal control group. Furthermore, in the VA treatment group, two proliferation related factors, high molecular weight cytokeratin 34betaE12 and alpha smooth muscle actin, were significantly down-regulated compared to the TP-induced BPH group. The expressions of dihydrotestosterone and 5alpha-reductase, the most crucial factors in BPH development, were suppressed by VA treatment. Expressions of the androgen receptor, estrogen receptor alpha and steroid receptor coactivator 1 were also significantly inhibited by VA compared to the TP-induced BPH group. In addition, we established an in vitro model for BPH by treating a normal human prostatic epithelial cell line RWPE-1 with TP. VA successfully inhibited proliferation and BPH-related factors in a concentration-dependent manner in this newly established model. These results suggest a new and potential pharmaceutical therapy of VA in the treatment of BPH. PMID- 29152076 TI - Profiling tumour heterogeneity through circulating tumour DNA in patients with pancreatic cancer. AB - The majority of pancreatic ductal adenocarcinomas (PDAC) are diagnosed late so that surgery is rarely curative. Earlier detection could significantly increase the likelihood of successful treatment and improve survival. The aim of the study was to provide proof of principle that point mutations in key cancer genes can be identified by sequencing circulating free DNA (cfDNA) and that this could be used to detect early PDACs and potentially, premalignant lesions, to help target early effective treatment. Targeted next generation sequencing (tNGS) analysis of mutation hotspots in 50 cancer genes was conducted in 26 patients with PDAC, 14 patients with chronic pancreatitis (CP) and 12 healthy controls with KRAS status validated by digital droplet PCR. A higher median level of total cfDNA was observed in patients with PDAC (585 ng/ml) compared to either patients with CP (300 ng/ml) or healthy controls (175 ng/ml). PDAC tissue showed wide mutational heterogeneity, whereas KRAS was the most commonly mutated gene in cfDNA of patients with PDAC and was significantly associated with a poor disease specific survival (p=0.018). This study demonstrates that tNGS of cfDNA is feasible to characterise the circulating genomic profile in PDAC and that driver mutations in KRAS have prognostic value but cannot currently be used to detect early emergence of disease. Importantly, monitoring total cfDNA levels may have utility in individuals "at risk" and warrants further investigation. PMID- 29152077 TI - Concordance of programmed death-ligand 1 expression between primary and metastatic non-small cell lung cancer by immunohistochemistry and RNA in situ hybridization. AB - We investigated the concordance of programmed death-ligand 1 (PD-L1) expression between primary cancer at initial diagnosis and metastasis at recurrence in resected non-small cell lung cancer (NSCLC). PD-L1 expression was evaluated using the SP142 assay in 37 NSCLC patients with paired primary lung cancer and surgically resected metastases at recurrence. PD-L1 positivity was defined as immunohistochemistry (IHC) and also evaluated by RNA in situ hybridization (RISH). The concordance rate of PD-L1 between primaries and metastases and correlation with clinicopathological factors were analyzed. PD-L1 expression was higher in squamous cell carcinoma, wild-type EGFR, and smokers than in non squamous carcinoma, mutant EGFR, and never smokers, respectively. PD-L1 positivity was observed in 18.9% of primaries and 21.6% of metastases. IHC demonstrated 78.4% concordance of PD-L1 positivity between primary and metastatic cancers. In 10.8% of cases, PD-L1 positivity was higher in primaries than in metastases, and vice versa in the remaining 10.8%. By PD-L1 RISH, 35.1% of primaries and 27.0% of metastases demonstrated PD-L1 positivity. There was 62.2% concordance in PD-L1 by RISH between the primaries and metastases. Our results thus highlight the clinical importance of replacing metastases with primary archival tissue, particularly when re-biopsy is difficult at recurrence. PMID- 29152078 TI - CD163 as a novel target gene of STAT3 is a potential therapeutic target for gastric cancer. AB - CD163 is a member of the scavenger receptor cysteine-rich superfamily, and has been widely used to identify M2 type macrophage. However, the expression of CD163 in gastric cancer and its regulatory mechanism are still unclear. Here we show that CD163 is elevated in gastric cancer tissues. High expression of CD163 is a potential indicator to evaluate the status of tumor associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and cancer associated fibroblasts (Cafs). Besides, more CD163 positive macrophages and CD163 expressing gastric cancer cells are associated with tumor invasion and poor prognosis. Knocking-down CD163 in cancer cells could inhibit tumor growth in vivo. We also find various immune molecules which are correlated with CD163 in gastric cancer tissues and cell lines have positive staining in the cancer cells of clinical sample. Finally, we confirm CD163 is a novel target gene of STAT3 (signal transducer and activator of transcription 3) in gastric cancer. Our data indicate that CD163 may be a potential poor prognostic marker and therapeutic target for gastric cancer. PMID- 29152079 TI - An analysis of the gene interaction networks identifying the role of PARP1 in metastasis of non-small cell lung cancer. AB - Background and Objective: Though there were many researches about the effects of cancer cells on non-small cell lung cancer (NSCLC) currently, it has been rarely reported completed oncogene and its mechanism in tumors by far. Here, we used biological methods with known oncogene of NSCLC to find new oncogene and explore its functionary mechanism in NSCLC. Methods: The study firstly built NSCLC genetic interaction network based on bioinformatics methods and then combined shortest path algorithm with significance test to confirmed core genes that were closely involved with given genes; real-time qPCR was conducted to detect expression levels between patients with NSCLC and normal people; additionally, detection of PARP1's role in migration and invasion was performed by trans-well assays and wound-healing. Results: Through gene interaction network, it was found that, core genes like PARP1, EGFR and ALK had a direct interaction. TCGA database showed that PARP1 presented strong expression in NSCLC and the expression level of metastatic NSCLC was significantly higher than that of non-metastatic NSCLC. Cell migration of NSCLC in accordance to the scratch test was suppressed by PARP1 silence but stimulated noticeably by PARP1 overexpression. According to Kaplan meier survival curve, the higher PARP1 expression, the poorer patient survival rate and prognosis. Thus, PARP1 expression had a negative correction with patient survival rate and prognosis. Conclusion: New oncogene PARP1 was found from known NSCLC oncogene in terms of gene interaction network, demonstrating PARP1's impact on NSCLC cell migration. PMID- 29152080 TI - Vincristine liposomes with smaller particle size have stronger diffusion ability in tumor and improve tumor accumulation of vincristine significantly. AB - The passive targeting is the premise of active targeting that could make nanocarrier detained in tumor tissue. The particle size is the most important factor that influences the diffusion and distribution of nanoparticle both in vivo and in vitro. In order to investigate the relationship between particle size and diffusion ability, two kinds of liposome loaded with Vincristine (VCR-Lip) were prepared. The diffusion behavior of VCR-Lip with different particle size and free VCR was compared through diffusion stability study. The diffusion ability from 12-well culture plate to Millipore transwell of each formulation reflected on HepG-2 cytotoxicity results. Different cell placement methods and drug adding positions were used to study the VCR-Lip diffusion behaviors, which influenced the apoptosis of HepG-2 cell. The different cell uptake of Nile red-Lip and free Nile red was compared when changed the adding way of fluorescent fluorescein. To study the penetration ability in HepG-2 tumor spheroids, we constructed 30 nm and 100 nm Cy5.5-Lip to compare with free Cy5.5. Then the anti-tumor effect, tissue distribution of free VCR injection, 30 nm and 100 nm VCR-Lip were further investigated on the HepG-2 tumor bearing nude mice. The results of these study showed that the diffusion ability of free drug and fluorescent fluorescein was remarkable stronger than which encapsulated in liposomes. Moreover, diffusion ability of smaller liposome was stronger than larger one. In this way, 30 nm liposome had not only faster and stronger tumor distribution than 100 nm liposome, but also higher tumor drug accumulation than free drug as well. Our study provided a new thinking to improve the targeting efficiency of nano drug delivery system, no matter passive or active targeting. PMID- 29152081 TI - Identification of lung adenocarcinoma specific dysregulated genes with diagnostic and prognostic value across 27 TCGA cancer types. AB - As the most common histologic subtype of lung cancer, lung adenocarcinoma (LUAD) contributes to a majority of cancer-related deaths worldwide annually. In order to find specific biomarkers of LUAD that are able to distinguish LUAD from other types of cancer so as to improve the early diagnostic and prognostic power in LUAD, we analyzed 10098 tumor tissue samples across 27 TCGA cancer types and identified 112 specific expressed genes in LUAD. Meantime, 8240 LUAD dysregulated genes in tumor and normal samples were identified. Combining with the results of specific expressed genes and dysregulated genes in LUAD, we found there were 70 specific dysregulated genes in LUAD (LUAD-SDGs). Then ROC curve revealed six LUAD SDGs that may be of strong diagnostic value to predict the existence of cancer (area under curve[AUC] > 95%). Kaplan-Meier survival analysis was performed to identify 6 LUAD-SDGs associated with patients' prognosis (P-values < 0.001). Multivariate Cox proportional hazards regression was employed to demonstrate that the six LUAD-SDGs were independent prognostic factors. Then, we used the six overall survival (OS)-related LUAD-SDGs constructing a six-gene signature. Multivariate Cox regression analysis suggested that the six-gene signature was an independent prognostic factor of other clinical variables (hazard ratio [HR] = 1.5098, 95%CI = 1.2996-1.7538, P < 0.0001). Based on our findings, we first presented the LUAD-SDGs for LUAD diagnosis and prognosis. Our results may provide efficient biomarkers to clinical diagnostic and prognostic evaluation in LUAD. PMID- 29152082 TI - Panbinostat decreases cFLIP and enhances killing of cancer cells by immunotoxin LMB-100 by stimulating the extrinsic apoptotic pathway. AB - LMB-100 (RG7787) is a recombinant immunotoxin, which kills mesothelin-expressing cancer cells and now being evaluated in phase 1 trials. To enhance the anti-tumor activity of LMB-100, we have searched for agents, already approved for cancer therapy, that can be combined with LMB-100 to increase its efficacy. Panbinostat is a pan-histone deacetylase inhibitor that is used to treat multiple myeloma. We incubated different types of cancer cells with panbinostat and LMB-100 and found that they interacted synergistically to cause cell death. We found that panbinostat and the combination increased levels of mRNAs encoding TNF/TNFR family members, as well as BNIP3L and CASP-9, and markedly decreased mRNA levels for c-FLIP and BID. Western blots confirmed a fall in levels of cFLIP protein and a rise in BNIP3L and caspase-9. The combination also increased levels of cleaved BID (t-BID), cleaved-capsase-3 and -8 and PARP. To assess the importance of the fall in cFLIP levels, we treated cells with the cFLIP inhibitor, Rocaglamide, and found it also enhanced killing of tumor cells by LMB-100. LMB-100, which activates the intrinsic pathway of apoptosis, and panbinostat, which activates the extrinsic pathway, work in a synergistic manner to kill cancer cell lines. PMID- 29152083 TI - Programmed cell death 1 expression is associated with inferior survival in patients with primary central nervous system lymphoma. AB - Programmed cell death 1 (PD-1) and its ligands PD-L1/PD-L2 have been shown to mediate immune evasion in various cancers, but their prognostic implications in patients with primary central nervous system lymphoma (PCNSL) are poorly understood. Therefore, we analyzed 76 PCNSL patients at initial diagnosis who were treated homogenously with high-dose methotrexate-based chemotherapy, and evaluated the prognostic roles of high immunohistochemical PD-1, PD-L1, and PD-L2 expression. The cut-off values for high PD-1 (>= 70 cells/high power field [HPF]), PD-L1 (>= 100 cells/HPF), and PD-L2 (>= 100 cells/HPF) were determined by the area under the receiver operating characteristic curve. Expression of PD-1, PD-L1, and PD-L2 was high in 7.9%, 13.2%, and 42.1% patients, respectively. High PD-1, (P = 0.007) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic scoring (P = 0.019) were independently associated with inferior overall survival on multivariate analysis. High PD-1 also remained an independent prognostic factor for inferior progression-free survival (P = 0.028), as did MSKCC prognostic scoring (P = 0.041) on multivariate analysis. However, there were no differences in survival according to the expression levels of PD-L1/PD-L2 in PCNSL tumor microenvironment. Our results suggest that PD-1 may be considered a biomarker and potential therapeutic target in PCNSL. PMID- 29152084 TI - The stromal morphological changes for differential diagnosis of uninodular high grade dysplastic nodule and well-differentiated small hepatocellular carcinoma. AB - Aim: The stromal invasion has been regarded as the most valuable clue to distinguish high-grade dysplastic nodules (HGDNs) and well-differentiated small hepatocellular carcinomas (WD-SHCCs). The purposes of this study are to explore the stromal morphological changes for the differential diagnosis of these two equivocal lesions. Results: Based on the systemic studies of histological characteristics of HGDNs and WD-SHCCs, the stromal morphological changes, including sinusoid capillarization, ductular reaction and solitary artery, were performed to make a differential diagnosis between them. Separately, the solitary artery had the best sensitivity (93.75%) and accuracy (88.89%), and the sinusoid capillarization had the best specificity of 90.32%. On the whole, when at least 2 stromal morphological changes were abnormal, no matter what combination, the diagnostic performance was favorable and optimal with the highest accuracy of 92.06%, balancing the sensitivity (93.75%) and specificity (90.32%). The diagnostic performances were prior to the classical immunohistochemical panel comprising heat shock protein 70, glypican 3 and glutamine synthetase with the best sensitivity, specificity and accuracy of 62.50%, 80.65% and 71.43%, respectively. Materials and Methods: A retrospective case-control study was conducted on 63 patients who underwent partial hepatectomy for uninodular HGDNs or WD-SHCCs at the Eastern Hepatobiliary Surgery Hospital from 2005 to 2015. Conclusions: The stromal morphological changes, containing sinusoid capillarization, ductular reaction and solitary artery could provide a more considerable diagnostic and differential diagnostic performance between HGDNs and WD-SHCCs. And they should be the key points during the histopathological diagnosis. PMID- 29152085 TI - The effect of human chorionic gonadotrophin contained in human menopausal gonadotropin on the clinical outcomes during progestin-primed ovarian stimulation. AB - Progestin-primed ovarian stimulation (PPOS) protocol has recently been demonstrated to be an novel regimen for preventing premature LH surges during controlled ovarian hyperstimulation (COH) in combination with frozen-thawed embryo transfer (FET). Our prospective controlled study was to explore the effect of human chorionic gonadotropin (hCG) contained in human menopausal gonadotropin (hMG) on the clinical outcomes in normalovulatory women undergoing COH with PPOS. A total of 180 patients were allocated into three groups according to the gonadotropin (Gn) used: group A (human menopausal gonadotropin, hMG-A), group B (hMG-B) or group C (follicle stimulating hormone, FSH). The primary outcome measured was the number of oocytes retrieved. The number of oocytes retrieved in group A B C was 10.72+/-5.78 11.33+/-5.19and13.38+/-8.97, respectively, with no statistic significance (p>0.05). Other embryological indicators were also similar (p>0.05). The concentration of serum and urinary beta-hCG on the trigger day in group A and B were not associated with embryo results (p>0.05). There was no significant differences in the clinical pregnancy rate (41.67% vs. 51.56% vs. 39.51%, p>0.05) and implantation rate (31.58%vs. 34.75%vs.25.33%) after FET among the three groups. Thus the clinical characteristics were not affected by the hCG contained in hMG in normalovulatory women treated with PPOS. PMID- 29152086 TI - COX-2/sEH dual inhibitor PTUPB suppresses glioblastoma growth by targeting epidermal growth factor receptor and hyaluronan mediated motility receptor. AB - Aims: Cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) dual inhibitor, PTUPB, has been demonstrated to inhibit angiogenesis, primary tumor growth and metastasis. The aim of this study is to investigate the effects of PTUPB on glioblastoma cells and xenograft model. Results: We show here that PTUPB inhibits glioblastoma cell proliferation and G1 phase cell cycle arrest in vitro, and suppresses the tumor growth and angiogenesis in vivo. The expression and activation of epidermal growth factor receptor (EGFR) and its downstream kinases, ERK1/2 and AKT, are reduced by PTUPB, indicating that the EGF/EGFR signaling pathway is a potential target. Moreover, PTUPB dramatically suppresses expression of hyaluronan mediated motility receptor (HMMR) in the glioblastoma cell lines and xenograft mouse model, suggesting that the HMMR is the other potential target. Materials and Methods: Cellular immunofluorescence assays were used for cell staining of actin fibers and HMMR. CCK-8 kit was used for cell proliferation assay. Cell-cycle analysis was performed by flow cytometry. Quantitative real time PCR assay was performed to test mRNA level. Western blot analysis was used to test protein expression. Immunohistochemical staining assay was used for xenograft tumor tissue staining of Ki-67, CD31 and HMMR. The SPSS version 17.0 software was applied for statistical analysis. Conclusions: Our data demonstrate that PTUPB is a potential therapeutic agent to treat glioblastomas. PMID- 29152087 TI - Specific role of RhoC in tumor invasion and metastasis. AB - Rho GTPases are regulators of many cellular functions and are often dysregulated in cancer. However, the precise role of Rho proteins for tumor development is not well understood. In breast cancer, overexpression of RhoC is linked with poor prognosis. Here, we aim to compare the function of RhoC and its homolog family member RhoA in breast cancer progression. We established stable breast epithelial cell lines with inducible expression of RhoA and RhoC, respectively. Moreover, we made use of Rho-activating bacterial toxins (Cytotoxic Necrotizing Factors) to stimulate the endogenous pool of Rho GTPases in benign breast epithelial cells and simultaneously knocked down specific Rho proteins. Whereas activation of Rho GTPases was sufficient to induce an invasive phenotype in three-dimensional culture systems, overexpression of RhoA or RhoC were not. However, RhoC but not RhoA was required for invasion, whereas RhoA and RhoC equally regulated proliferation. We further identified downstream target genes of RhoC involved in invasion and identified PTGS2 (COX-2) being preferentially upregulated by RhoC. Consistently, the COX-2 inhibitor Celecoxib blocked the invasive phenotype induced by the Rho-activating toxins. PMID- 29152089 TI - High glucose downregulates myocardin expression in rat glomerular mesangial cells via the ERK signaling pathway. AB - Mesangial cells (MCs), which are vascular smooth muscle-derived cells, occupy the central position in the glomerulus. Diabetic nephropathy (DN) is one of the most common diabetes complications and is likely attributed to the loss of MC contractility. Myocardin stimulates downstream vascular smooth muscle genes and regulates the contractility of vascular smooth muscle cells. Therefore, we hypothesized that myocardin is expressed in MCs and that high glucose is involved in the regulation of myocardin and downstream contractile genes in the context of DN. Confocal microscopy revealed that myocardin is expressed in rat MCs. Western blot and RT-qPCR analyses showed that treatment with 30 mM D-glucose significantly downregulated the mRNA and protein levels of myocardin and downstream SM alpha-actin. As an isotonic contrast, 30 mM mannitol did not affect myocardin mRNA levels but did downregulate myocardin protein levels. Treatment with 30 mM mannitol also downregulated SM alpha-actin mRNA and protein levels. Conversely, as another isotonic contrast, 30 mM L-glucose also had no effect on myocardin and SM alpha-actin expression in MCs. The extracellular signal regulated kinase (ERK) pathway was activated by treatment with 30 mM D-glucose or mannitol, while specific inhibitors of the ERK pathway (PD98059) compromised the downregulation of myocardin and SM alpha-actin triggered by high glucose or mannitol. Thus we revealed that myocardin is expressed in MCs and that high glucose downregulates myocardin expression and downstream contractile protein SM alpha-actin via the ERK pathway. Our results suggest a novel mechanism for high glucose inhibition of MC contraction, which contributes to DN pathogenesis. PMID- 29152088 TI - Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells. AB - Evidence suggests that nonsteroidal anti-inflammatory drug aspirin (acetylsalicylic acid) may improve patient survival in PIK3CA-mutant colorectal carcinoma, but not in PIK3CA-wild-type carcinoma. However, whether aspirin directly influences the viability of PIK3CA-mutant colon cancer cells is poorly understood. We conducted in vitro experiments to test our hypothesis that the anti-proliferative activity of aspirin might be stronger for PIK3CA-mutant colon cancer cells than for PIK3CA-wild-type colon cancer cells. We measured the anti proliferative effect of aspirin at physiologic concentrations in seven PIK3CA mutant and six PIK3CA-wild-type human colon cancer cell lines. After exposure to aspirin, the apoptotic index and cell cycle phase of colon cancer cells were assessed. In addition, the effect of aspirin was examined in parental SW48 cells and SW48 cell clones with individual knock-in PIK3CA mutations of either c.3140A>G (p.H1047R) or c.1633G>A (p.E545K). Aspirin induced greater dose dependent loss of cell viability in PIK3CA-mutant cells than in PIK3CA-wild-type cells after treatment for 48 and 72 hours. Aspirin treatment also led to higher proportions of apoptotic cells and G0/G1 phase arrest in PIK3CA-mutant cells than in PIK3CA-wild-type cells. Aspirin treatment of isogenic SW48 cells carrying a PIK3CA mutation, either c.3140A>G (p.H1047R) or c.1633G>A (p. E545K), resulted in a more significant loss of cell viability compared to wild-type controls. Our findings indicate that aspirin causes cell cycle arrest, induces apoptosis, and leads to loss of cell viability more profoundly in PIK3CA-mutated colon cancer cells than in PIK3CA-wild-type colon cancer cells. These findings support the use of aspirin to treat patients with PIK3CA-mutant colon cancer. PMID- 29152090 TI - Gynostemma pentaphyllum saponins attenuate inflammation in vitro and in vivo by inhibition of NF-kappaB and STAT3 signaling. AB - Recent advances in the development of anti-inflammatory agents have improved their therapeutic outcome in inflammatory bowel disease (IBD), however, the presence of side effects and limited effectiveness hinder their widespread use. Therefore, novel compounds with strong anti-inflammatory efficacy are still required. In this study, we investigated the anti-inflammatory effect and potential mechanisms of Gynostemma pentaphyllum (Thunb.) Makino saponins (GpS), a major component of the herbal medicine widely used in Asian countries. In in vitro studies, we demonstrated that GpS dose dependently suppressed activation of macrophages, one of the main effectors in IBD. GpS also suppressed cytokine production and the activation of NF-kappaB and STAT3 signaling in lipopolysaccharide-induced macrophages, without affecting their viability. Further in vivo studies demonstrated that GpS could ameliorate the weight loss, increased disease activity index, colon shortening and histological damage associated with dextran sulfate sodium (DSS)-induced colitis in mice. In agreement with results from our in vitro experiments, GpS suppressed cytokine production and activation of NF-kappaB and STAT3 signaling in the colons of DSS induced mice. In this study, we present for the first time, evidence of the therapeutic effect of GpS in IBD, highlighting its potential as an effective therapeutic against the disease. PMID- 29152091 TI - Fibroblast growth factor-2-mediated protection of cardiomyocytes from the toxic effects of doxorubicin requires the mTOR/Nrf-2/HO-1 pathway. AB - Background: Cardiotoxic side effects impose limits to the use of anti-tumour chemotherapeutic drugs such as doxorubicin (Dox). There is a need for cardioprotective strategies to prevent the multiple deleterious effects of Dox. Here, we examined the ability of administered fibroblast growth factor-2 (FGF-2), a cardioprotective protein that is synthesized as high and low molecular weight (Hi-, Lo-FGF-2) isoforms, to prevent Dox-induced: oxidative stress; cell death; lysosome dysregulation; and inactivation of potent endogenous protective pathways, such as the anti-oxidant/detoxification nuclear factor erythroid-2 related factor (Nrf-2), heme oxygenase-1 (HO-1) axis. Methods and Results: Brief pre-incubation of neonatal rat cardiomyocyte cultures with either Hi- or Lo-FGF-2 reduced the Dox-induced: oxidative stress; apoptotic/necrotic cell death; lysosomal dysregulation; decrease in active mammalian target of Rapamycin (mTOR). FGF-2 isoforms prevented the Dox-induced downregulation of Nrf-2, and promoted robust increases in the Nrf-2-downstream targets including the cardioprotective protein HO-1, and p62/SQSTM1, a multifunctional scaffold protein involved in autophagy. Chloroquine, an autophagic flux inhibitor, caused a further increase in p62/SQSTM1, indicating intact autophagic flux in the FGF-2-treated groups. A selective inhibitor for HO-1, Tin-Protoporphyrin, prevented the FGF-2 protection against cell death. The mTOR inhibitor Rapamycin prevented FGF-2 protection, and blocked the FGF-2 effects on Nrf-2, HO-1 and p62/SQSTM1. Conclusions: In an acute setting Hi- or Lo-FGF-2 protect cardiomyocytes against multiple Dox-induced deleterious effects, by a mechanism dependent on preservation of mTOR activity, Nrf-2 levels, and the upregulation of HO-1. Preservation/activation of endogenous anti-oxidant/detoxification defences by FGF-2 is a desirable property in the setting of Dox-cardiotoxicity. PMID- 29152092 TI - The long non-coding RNA PARTICLE is associated with WWOX and the absence of FRA16D breakage in osteosarcoma patients. AB - Breakage of the fragile site FRA16D disrupts the WWOX (WW Domain Containing Oxidoreductase) tumor suppressor gene in osteosarcoma. However, the frequency of breakage is not sufficient to explain the rate of WWOX loss in pathogenesis. The involvement of non-coding RNA transcripts is proposed due to their accumulation at fragile sites, where they are advocated to influence specific chromosomal regions associated with malignancy. The long ncRNA PARTICLE (promoter of MAT2A antisense radiation-induced circulating long non-coding RNA) is transiently elevated in response to irradiation and influences epigenetic silencing modification within WWOX. It now emerges that elevated PARTICLE levels are significantly associated with FRA16D non-breakage in OS patients. Although not associated with overall survival, high PARTICLE levels were found to be significantly linked to metastasis free outcome. The transcription of both PARTICLE and WWOX are transiently responsive to exposure to low doses of radiation in osteosarcoma cell lines. Herein, a relationship between WWOX and PARTICLE transcription is suggested in human osteosarcoma cell lines representing alternative genetic backgrounds. PARTICLE over-expression ameliorated WWOX promoter activity in U2OS harboring FRA16D non-breakage. It can be concluded that the lncRNA PARTICLE influences the WWOX tumor suppressor and in the absence of WWOX FRA16D breakage, it is associated with OS metastasis-free survival. PMID- 29152093 TI - The role of weekly nanoparticle albumin bound paclitaxel monotherapy as second line or later treatment for advanced NSCLC in China. AB - For patients with pretreated advanced non-small cell lung cancer (NSCLC), more effective treatments are unmet. We conducted a study to explore the optimal treatment schedule of nanoparticle albumin bound paclitaxel (Nab-PTX) as a second line or later treatment for advanced NSCLC patients in China. Ninety-eight patients, who had experienced failure of prior treatment and received Nab-PTX monotherapy (130 mg/m2) on days 1, 8 of a 21-day cycle were included. The median progression-free survival (PFS) and overall survival (OS) were 4.34 months (95% confidence interval [CI] 3.508 to 5.165 months) and 11.73 months (95% CI 9.211 to 14.247 months), respectively. The objective responses rate (ORR) and disease control rate (DCR) were 22.4% and 74.5%. Prior treatment with taxane and line of therapy did not influence the efficacy of Nab-PTX. The main grade 3 to 4 toxicities were neutropenia (25.5%) and leukopenia (12.4%). Furthermore, 24 cases offered samples to assess secreted protein acidic and rich in cysteine (SPARC) expression. No statistical difference was observed in treatment efficacy between SPARC expression-negative and positive. The findings suggest that weekly Nab-PTX monotherapy is effective and well tolerated for patients with pretreated advanced NSCLC, regardless of prior taxane exposure or line of therapy. PMID- 29152095 TI - TIPE2 expression is increased in peripheral blood mononuclear cells from patients with rheumatoid arthritis. AB - We investigated the changes in mRNA and protein expression of tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) and PEST-containing nuclear protein (PCNP) in peripheral blood lymphocytes from 54 patients with rheumatoid arthritis (RA) and the spleens of model mice with collagen-induced arthritis (CIA) to generate new ideas for clinical diagnosis and treatment. Expression levels of both TIPE2 and PCNP were higher in RA patients and CIA mice than in their respective controls. They were also higher in the 32 patients with active RA than in the 22 with inactive RA (P < 0.001 for both). After comprehensively treating patients with active RA with anti-inflammatory and antirheumatic drugs for 6 months, they were stable, and there was no difference in TIPE2 levels between the treated patients and those with inactive RA (P = 0.85). In addition, TIPE2 mRNA levels in peripheral blood correlated positively with PCNP (R2 = 0.744, P = 0.001). The DAS28 score correlated positively with peripheral blood TIPE2 levels in the RA patients (R2 = 0.945, P = 0.001). These findings suggest TIPE2 expression increases with the severity of RA. PMID- 29152094 TI - Xenotransplantation of pediatric low grade gliomas confirms the enrichment of BRAF V600E mutation and preservation of CDKN2A deletion in a novel orthotopic xenograft mouse model of progressive pleomorphic xanthoastrocytoma. AB - To identify cellular and molecular changes that driver pediatric low grade glioma (PLGG) progression, we analyzed putative cancer stem cells (CSCs) and evaluated key biological changes in a novel and progressive patient-derived orthotopic xenograft (PDOX) mouse model. Flow cytometric analysis of 22 PLGGs detected CD133+ (<1.5%) and CD15+ (20.7 +/- 28.9%) cells, and direct intra-cranial implantation of 25 PLGGs led to the development of 1 PDOX model from a grade II pleomorphic xanthoastrocytoma (PXA). While CSC levels did not correlate with patient tumor progression, neurosphere formation and in vivo tumorigenicity, the PDOX model, IC-3635PXA, reproduced key histological features of the original tumor. Similar to the patient tumor that progressed and recurred, IC-3635PXA also progressed during serial in vivo subtransplantations (4 passages), exhibiting increased tumor take rate, elevated proliferation, loss of mature glial marker (GFAP), accumulation of GFAP-/Vimentin+ cells, enhanced local invasion, distant perivascular migration, and prominent reactive gliosis in normal mouse brains. Molecularly, xenograft cells with homozygous deletion of CDKN2A shifted from disomy chromosome 9 to trisomy chromosome 9; and BRAF V600E mutation allele frequency increased (from 28% in patient tumor to 67% in passage III xenografts). In vitro drug screening identified 2/7 BRAF V600E inhibitors and 2/9 BRAF inhibitors that suppressed cell proliferation. In summary, we showed that PLGG tumorigenicity was low despite the presence of putative CSCs, and our data supported GFAP-/Vimentin+ cells, CDKN2A homozygous deletion in trisomy chromosome 9 cells, and BRAF V600E mutation as candidate drivers of tumor progression in the PXA xenografts. PMID- 29152096 TI - The non-canonical ubiquitin activating enzyme UBA6 suppresses epithelial mesenchymal transition of mammary epithelial cells. AB - Ubiquitination plays critical roles in the regulation of oncoproteins and tumor suppressors during carcinogenesis. The two ubiquitin activating enzymes (E1) in human genome, UBA1 and UBA6, initiate ubiquitination by ATP-dependent activation of ubiquitin. Recent evidence suggests that UBA1 and UBA6 play partially overlapped yet distinct roles in controlling the proteome. Here we demonstrate that ubiquitination pathways initiated specifically by UBA6 set a suppressive barrier against critical steps of mammary carcinogenesis such as loss of polarity, anoikis resistance and epithelial-mesenchymal transition (EMT). Mammary epithelial MCF-10A cells expressing shRNA against UBA6 fail in establishing cell cycle arrest in response to detachment from extracellular matrix, confluency with fully engaged cell-cell contact or growth factor deprivation. Moreover, UBA6 deficient MCF-10A cells undergo spontaneous EMT under growth factor deprivation and exhibit accelerated kinetics of TGF-beta-induced EMT. The Rho-GTPase CDC42 is one of the specific targets of UBA6-initiated ubiquitination and plays a key role in the function of UBA6 in controlling epithelial homeostasis, since a CDC42 inhibitor, ML141, rescues UBA6-deficient cells from the EMT phenotype. Immunohistochemical analysis of human breast cancer tissues demonstrates that 38% of invasive carcinomas express low or undetectable expression of UBA6, suggesting that downregulation of this non-canonical E1 plays a role in breast cancer development. PMID- 29152098 TI - Toxic metabolites, Sertoli cells and Y chromosome related genes are potentially linked to the reproductive toxicity induced by mequindox. AB - Mequindox (MEQ) is a relatively new synthetic antibacterial agent widely applied in China since the 1980s. However, its reproductive toxicity has not been adequately performed. In the present study, four groups of male Kunming mice (10 mice/group) were fed diets containing MEQ (0, 25, 55 and 110 mg/kg in the diet) for up to 18 months. The results show that M4 could pass through the blood-testis barrier (BTB), and demonstrate that Sertoli cells (SCs) are the main toxic target for MEQ to induce spermatogenesis deficiency. Furthermore, adrenal toxicity, adverse effects on the hypothalamic-pituitary-testicular axis (HPTA) and Leydig cells, as well as the expression of genes related to steroid biosynthesis and cholesterol transport, were responsible for the alterations in sex hormones in the serum of male mice after exposure to MEQ. Additionally, the changed levels of Y chromosome microdeletion related genes, such as DDX3Y, HSF2, Sly and Ssty2 in the testis might be a mechanism for the inhibition of spermatogenesis induced by MEQ. The present study illustrates for the first time the toxic metabolites of MEQ in testis of mice, and suggests that SCs, sex hormones and Y chromosome microdeletion genes are involved in reproductive toxicity mediated by MEQ in vivo. PMID- 29152099 TI - S149R, a novel mutation in the ABCD1 gene causing X-linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. It is a heterogeneous disorder caused by mutations in the ATP-binding cassette protein subfamily D1 (ABCD1) gene, encoding the peroxisomal membrane protein ALDP, which is involved in the transmembrane transport of very long-chain fatty acids. For the first time, we report a case of olivopontocerebellar X-ALD on the Chinese mainland. In this study, a novel mutation (c.447T>A; p.S149R) in ABCD1 was detected in a patient diagnosed with X-ALD. The mutant amino acid is well conserved among species. Bioinformatics analysis predicted the substitution to be deleterious and to cause structural changes in the adrenoleukodystrophy protein. Immunofluorescence showed an altered subcellular localization of the S149R mutant protein, which may lead to defects in the degradation of very long chain fatty acids in peroxisomes. We therefore suggest that the novel mutation, which alters ALDP structure, subcellular distribution and function, is responsible for X-ALD. PMID- 29152097 TI - Identifying and analyzing different cancer subtypes using RNA-seq data of blood platelets. AB - Detection and diagnosis of cancer are especially important for early prevention and effective treatments. Traditional methods of cancer detection are usually time-consuming and expensive. Liquid biopsy, a newly proposed noninvasive detection approach, can promote the accuracy and decrease the cost of detection according to a personalized expression profile. However, few studies have been performed to analyze this type of data, which can promote more effective methods for detection of different cancer subtypes. In this study, we applied some reliable machine learning algorithms to analyze data retrieved from patients who had one of six cancer subtypes (breast cancer, colorectal cancer, glioblastoma, hepatobiliary cancer, lung cancer and pancreatic cancer) as well as healthy persons. Quantitative gene expression profiles were used to encode each sample. Then, they were analyzed by the maximum relevance minimum redundancy method. Two feature lists were obtained in which genes were ranked rigorously. The incremental feature selection method was applied to the mRMR feature list to extract the optimal feature subset, which can be used in the support vector machine algorithm to determine the best performance for the detection of cancer subtypes and healthy controls. The ten-fold cross-validation for the constructed optimal classification model yielded an overall accuracy of 0.751. On the other hand, we extracted the top eighteen features (genes), including TTN, RHOH, RPS20, TRBC2, in another feature list, the MaxRel feature list, and performed a detailed analysis of them. The results indicated that these genes could be important biomarkers for discriminating different cancer subtypes and healthy controls. PMID- 29152100 TI - Differential regulation of mRNAs and lncRNAs related to lipid metabolism in two pig breeds. AB - Long non-coding RNAs (lncRNAs) can regulate lipid metabolism and adipogenesis. However, there is little research on the role of lncRNAs in fat deposition in pig. In this study, RNA-seq technology was used to analyze the gene expression profiles of subcutaneous adipose tissue in Laiwu (LW) and Large White (LY) pigs. Then, key lncRNAs and genes associated with lipid metabolism and adipogenic differentiation were identified. Fifty four lncRNAs and 482 known mRNAs were differentially expressed in the two pig breeds. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses revealed that differentially expressed genes and the target genes of differentially expressed lncRNAs were significantly enriched in PPAR signaling pathway and biological processes including fat cell differentiation and fatty acid metabolism. Key lncRNAs might regulate adipogenic differentiation and fatty acid metabolism by regulating genes involved in above signaling pathway and biological processes. Specifically, XLOC_014379, XLOC_011279, XLOC_064871, XLOC_019518 and XLOC_013639 might target SCD, LPIN1, TRIB3, EGR2 and FABP3, respectively, and then play critical regulatory role. These results are useful for understanding fat deposition in pig, breeding livestock with high quality meat, and preventing and treating lipid metabolic disease. PMID- 29152101 TI - Functional network analysis of gene-phenotype connectivity associated with temozolomide. AB - Rationale: Glioma has a poor survival rate in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for treating glioma, but TMZ treatment consistently leads to high resistance. Aim: To investigate the underlying mechanisms of TMZ action with new therapeutic regimens in glioma. Methods and results: The biological effects of TMZ mainly depend on the three following DNA repair systems: methylguanine methyltransferase (MGMT), mismatch repair (MMR) and base excision repair (BER). Based on related genes in these three systems, web-based tools containing data compiled from open-source databases, including DrugBank, STRING, WebGestalt and ClueGO, were queried, and five common genes along with the top fifteen pathways, including the glioma pathway, were identified. A genomic analysis of the six genes identified in the glioma pathway by cBioPortal indicated that TMZ might exert biological effects via interaction with the tumor protein P53(TP53) signaling axis. Finally, a survival analysis with the six genes in glioma cases (low-grade glioma and glioblastoma multiforme) was conducted using OncoLnc, which might provide directions for the future exploration of prognosis in glioma. Conclusions: This study indicates that a functional network analysis resembles a "BioGPS", with the ability to draw a web-based scientific map that can productively and cost effectively associate TMZ with its primary and secondary biological targets. PMID- 29152102 TI - L1 cell adhesion molecule (L1CAM) is a strong predictor for locoregional recurrences in cervical cancer. AB - Background: L1 cell adhesion molecule (L1CAM) has been shown to be a prognostic marker in various cancer types, and has been suggested to play a role in epithelial mesenchymal transition (EMT). Here, we determined the prognostic significance of L1CAM in cervical cancer and its association with vimentin expression on tumor cells, indicative of EMT. Methods: Formalin-fixed, paraffin embedded primary tumor samples from 372 cervical cancer patients were collected for immunohistochemical analysis of L1CAM expression. In 109 FFPE specimens, the percentage of vimentin expressing tumor cells was determined by flow cytometry. Results: Positive L1CAM expression (>=10% of tumor cells) was associated with disease-free survival, validated using RNAseq TCGA data. L1CAM expression was independently associated with locoregional recurrence-free survival (hazard ratio 2.62, 95% CI 1.33 - 5.17, P = 0.006), and strongly associated with percentage of vimentin expressing tumor cells (P = 0.003). Expression of both L1CAM and vimentin indicated a subgroup with the highest risk of recurrence (hazard ratio 3.15, 95% CI 1.25 - 7.92, P = 0.015). Conclusion: L1CAM might be a promising new prognostic marker for locoregional recurrences in cervical cancer, and its association with vimentin expression suggests that L1CAM might affect tumor aggressiveness, possibly through EMT. PMID- 29152103 TI - Myxinidin2 and myxinidin3 suppress inflammatory responses through STAT3 and MAPKs to promote wound healing. AB - Skin wounds are continuously exposed to bacteria and can easily become infected. Infected wounds require antibiotic treatment, and infections caused by drug resistant bacteria are an important public health problem. Antimicrobial peptides have broad-spectrum antibacterial activity, induce little or no drug resistance and may be suitable for treating skin infections caused by drug-resistant bacteria. We previously reported the design and function of myxinidin and myxinidin analogues. Here we showed that myxinidin2 and myxinidin3 exhibit antimicrobial and anti-biofilm activities against antibiotic-resistant Staphylococcus aureus, Acinetobacter baumannii, and Pseudomonas aeruginosa in high salt environments and in gelatin. Moreover, these peptides facilitated infected wound healing by decreasing inflammation through suppression of IL-6, IL 8, and TNF-alpha and regulation of downstream mediators such as STAT3, p38, JNK, and EGFR. In a mouse skin wound model infected with antibiotic-resistant bacteria, myxinidin2 and myxinidin3 eliminated the infection and enhanced wound healing. We therefore propose the use of these peptides for treating infected wounds and burns. PMID- 29152104 TI - A developed model of cancer patients participation in intravenous chemotherapy safety. AB - How to reduce intravenous chemotherapy-related adverse reactions of cancer patients is one focus of clinical work. Nowadays, patient for patient safety (PFPS) is an important component of hospital safety management and can contribute to a reduction in the rate of adverse events following intravenous chemotherapy of cancer patients. To guide and evaluate cancer patients participate in intravenous chemotherapy, we explored a scientific and practical model of cancer patients participation in intravenous chemotherapy safety. which can also guide nurse practitioners (NPs) practice. Based on a literature review and analysis of chemotherapy-associated adverse events from two large comprehensive hospitals, combined with the existing strategies for PFPS, the model of cancer patients participation in intravenous chemotherapy safety was drafted. Then we conducted two rounds of the Delphi-method questionnaire to revise the model. The two rounds Delphi questionnaire survey had a response rate of 82.36%. The authoritative coefficient was 0.87 and the coordination coefficients were 0.165 and 0.214, respectively. The proposed safety model included 3 first-order indicators, 8 second-order indicators, and 41 third-order indicators, including content of patients participation, responsibilities of medical personnel to assist cancer patients participation, and suggestions for guaranteeing implementation. Many NPs practice in a medical setting where cancer patients for patient safety behavior are blurred. The model of cancer patients participation in intravenous chemotherapy safety can guide NPs in their practice of promoting PFPS among cancer patients intravenous chemotherapy. PMID- 29152105 TI - Necdin modulates leukemia-initiating cell quiescence and chemotherapy response. AB - Acute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear. In this study, we utilized two well-established murine models of human AML induced by MLL-AF9 or AML1-ETO9a to determine the role of Necdin in leukemogenesis. We found that loss of Necdin decreased the number of functional LICs and enhanced myeloid differentiation in vivo, leading to delayed development of leukemia induced by MLL-AF9. Importantly, Necdin null LICs expressing MLL-AF9 were less quiescent than wild-type LICs. Further, loss of Necdin enhanced the response of MLL-AF9+ leukemia cells to chemotherapy treatment, manifested by decreased viability and enhanced apoptosis. We observed decreased expression of Bcl2 and increased expression of p53 and its target gene Bax in Necdin null leukemia cells following chemotherapy treatment, indicating that p53-dependent apoptotic pathways may be activated in the absence of Necdin. In addition, we found that loss of Necdin decreased the engraftment of AML1-ETO9a+ hematopoietic stem and progenitor cells in transplantation assays. However, Necdin-deficiency did not affect the response of AML1-ETO9a+ hematopoietic cells to chemotherapy treatment. Thus, Necdin regulates leukemia initiating cell quiescence and chemotherapy response in a context-dependent manner. Our findings suggest that pharmacological inhibition of Necdin may hold potential as a novel therapy for leukemia patients with MLL translocations. PMID- 29152106 TI - Disrupting glucose-6-phosphate isomerase fully suppresses the "Warburg effect" and activates OXPHOS with minimal impact on tumor growth except in hypoxia. AB - As Otto Warburg first observed, cancer cells largely favor fermentative glycolysis for growth even under aerobic conditions. This energy paradox also extends to rapidly growing normal cells indicating that glycolysis is optimal for fast growth and biomass production. Here we further explored this concept by genetic ablation of fermentative glycolysis in two fast growing cancer cell lines: human colon adenocarcinoma LS174T and B16 mouse melanoma. We disrupted the upstream glycolytic enzyme, glucose-6-phosphate isomerase (GPI), to allow cells to re-route glucose-6-phosphate flux into the pentose-phosphate branch. Indeed, GPI-KO severely reduced glucose consumption and suppressed lactic acid secretion, which reprogrammed these cells to rely on oxidative phosphorylation and mitochondrial ATP production to maintain viability. In contrast to previous pharmacological inhibition of glycolysis that suppressed tumor growth, GPI-KO surprisingly demonstrated only a moderate impact on normoxic cell growth. However, hypoxic (1% O2) cell growth was severely restricted. Despite in vitro growth restriction under hypoxia, tumor growth rates in vivo were reduced less than 2-fold for both GPI-KO cancer cell lines. Combined our results indicate that exclusive use of oxidative metabolism has the capacity to provide metabolic precursors for biomass synthesis and fast growth. This work and others clearly indicate that metabolic cancer cell plasticity poses a strong limitation to anticancer strategies. PMID- 29152107 TI - Neoadjuvant olaparib targets hypoxia to improve radioresponse in a homologous recombination-proficient breast cancer model. AB - Clinical trials are studying the benefits of combining the PARP-1 inhibitor olaparib with chemotherapy and radiotherapy treatment in a variety of cancer increasing the therapeutic ratio for olaparib may come from its ability to modify the tumour microenvironment by targeting homologous recombination-deficient, hypoxic tumour clonogens, and/or increasing tumour-associated vasodilation to improve oxygenation. Herein, we investigated the effect of prolonged neoadjuvant exposure to olaparib on the tumor microenvironment using a genetically-engineered mouse p53-/- syngeneic breast cancer model, which is proficient in homology directed DNA repair. We observed increased in vivo growth delay and decreased ex vivo clonogenic survival following pre-treatment with olaparib 50 mg/kg bid Olaparib for 7 days ending 48 hours prior to a radiation dose of 12Gy. This increased in vivo radioresponse was associated with a decreased hypoxic fraction. This study suggests that the radiation response in patients can be improved with limited toxicity if olaparib is given in a purely neoadjuvant setting to modify the tumor microenviroment prior to the start of the radiotherapy treatment. Consequently a significant gain can be achieved in therapeutic window and clinical studies are needed to confirm this preclinical data. PMID- 29152108 TI - MicroRNA-31 suppresses the self-renewal capability of alpha2delta1+ liver tumor initiating cells by targeting ISL1. AB - Accumulating evidence demonstrates that miRNAs, a class of small non-coding RNAs, are involved in the regulation of tumor-initiating cells (TICs) which are considered to be the origin of cancer development according to the cancer stem cell hypothesis. We have previously identified that miR-31 may play suppressive roles in alpha2delta1+ hepatocellular carcinoma (HCC) TICs. Here, we confirm that the expression of miR-31 is significantly downregulated in alpha2delta1+ HCC TICs. Overexpression of miR-31 in alpha2delta1+ HCC TICs results in significant suppression of the self-renewal and tumorigenicity abilities of these cells. Conversely, knockdown the expression of miR-31 in PLC/PRF/5 cells is able to reprogram them into TICs with stem cell-like properties. Furthermore, the expression of ISL LIM Homeobox 1(ISL1), a transcription factor involved in recognition of undifferentiated cardiac progenitors, is negatively regulated by miR-31, and the luciferase reporters' activities with the 3'-UTRs of ISL1 are inhibited significantly by miR-31. Collectively, our results suggest that miR-31 can negatively regulate the self-renewal ability of alpha2delta1+ liver TICs via silencing ISL1. PMID- 29152109 TI - Sevoflurane preconditioning ameliorates traumatic spinal cord injury through caveolin-3-dependent cyclooxygenase-2 inhibition. AB - Acute traumatic spinal cord injury (tSCI) results in a lifetime of paralysis associated with a host of medical complications. The developing secondary complications of tSCI may result in further chronic neurodegenerative diseases. Sevoflurane preconditioning (SF-PreCon) has shown guaranteed protective effects in myocardial or cerebral ischemic/reperfusion injury. However, the role of SF PreCon in tSCI still remains to be elucidated. Here, we found that SF-PreCon ameliorated the developing secondary complications through reducing the apoptosis rate and the secretion of inflammatory cytokines in injured spinal cord tissues, and therefore enhancing the recovery after tSCI. Notably, we demonstrated that SF PreCon ameliorates tSCI through inhibiting Cycloxygenase-2 (COX-2). Importantly, we verified that SF-PreCon inhibits the expression of COX-2 and reduces the apoptosis rate after tSCI via the induction of Caveolin-3 (Cav-3). Taken together, our results suggest that SF-PreCon ameliorates tSCI via Cav-3-dependent COX-2 inhibition and provide an economical and practical method against the secondary injury after tSCI. PMID- 29152110 TI - Comparison of the effect of spinal anesthesia and general anesthesia on 5-year tumor recurrence rates after transurethral resection of bladder tumors. AB - Non-muscle invasive bladder tumors are early-stage tumors with high recurrence rates. Transurethral resection of bladder tumor (TURB) is performed under spinal or general anesthesia; however, the effect of the two anesthetic techniques on non-muscle invasive bladder tumor recurrence is unknown. Thus, we compared their effects on tumor recurrence rates five years after TURB. Data from 876 patients who underwent TURB from 2000 to 2007 was reviewed. Patients received spinal or general anesthesia based on their choice or the clinician's preference. Tumor recurrence five years after TURB was assessed using multivariate Cox regression model, propensity score analysis (matching and inverse probability of treatment weighting), and Kaplan-Meier method. The five-year tumor recurrence rate after TURB was 42% and 53% for spinal and general anesthesia groups, respectively (P = 0.013). Hazard ratios for tumor recurrence in the spinal anesthesia group compared to that in the general anesthesia group were 0.619 (P <0.001), 0.642 (P = 0.001), and 0.636 (P <0.001) in the Cox regression model, Cox regression model with propensity score matching, and adjusted analysis with inverse probability of treatment weighting, respectively. The five-year tumor recurrence rate was significantly lower in the spinal anesthesia group than in the general anesthesia group in both the unadjusted (P = 0.002) and adjusted Kaplan-Meier curves (P <0.001). Therefore, spinal anesthesia for non-muscle invasive bladder tumor resection was associated with a lower five-year tumor recurrence rate than general anesthesia. This finding provides useful information for an appropriate selection of anesthetic technique for TURB. PMID- 29152111 TI - Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer. AB - Reactive oxygen species (ROS) production induced by taxanes in cancer cells may influence the taxane-induced cell death or the drug resistance. We investigated the correlation between the cytotoxic effect of taxanes and ROS production in human castration-resistant prostate cancer (CRPC) cell lines. Three human prostate cancer cell lines were treated with increasing concentrations of docetaxel or cabazitaxel in vitro. Cabazitaxel showed significantly higher cytotoxic efficacy than docetaxel in human CRPC cells, accompanied by elevated ROS production detected by FACS analysis. To investigate whether cabazitaxel mediated cell death was caused by the ROS generation induced by cabazitaxel, we treated CRPC cells in the presence of antioxidant NAC. NAC reduced the cytotoxic effect induced by cabazitaxel. We found that ROS elimination by Sestrin-3 (SESN3) was significantly inhibited by cabazitaxel, but not by docetaxel. These results indicate higher sensitivity of human CRPC to cabazitaxel compared to docetaxel involves ROS production through inhibiting the expression of antioxidant enzyme SESN3. PMID- 29152112 TI - Capsaicin exerts synergistic antitumor effect with sorafenib in hepatocellular carcinoma cells through AMPK activation. AB - In this study, we investigated the antitumoral effects of combined treatment using sorafenib and capsaicin in hepatocellular carcinoma (HCC) cells. Here we showed that the combination of the two drugs had a much stronger inhibitory effect on both HepG2 and Huh-7 human HCC cells growth than either drug alone. The isobolograms demonstrated that the combinations investigated in this study produced a synergistic interaction. In the combination treatment using capsaicin and sorafenib, increased apoptosis, followed by the activation of caspase-9 and PARP, was observed. In addition, the present study demonstrated that sorafenib treatment induces activation of Akt, probably as a mechanism of resistance, whereas capsaicin inhibits Akt providing a possible pathway whereby capsaicin sensitizes to sorafenib in HCC cells. Moreover, capsaicin singly and the combination of capsaicin and sorafenib induce AMPK activation and Acetyl CoA carboxylase phosphorylation in HCC cells. Knocking down of AMPK by selective siRNA abrogates capsaicin-induced Akt inhibition, suggesting the involvement of AMPK in the antiproliferative effect. In vivo experiments further showed that that the anti-tumor effect of sorafenib was enhanced by its combination with 2.5 mg/Kg of capsaicin. Overall, these results show that combined treatment with capsaicin and sorafenib might improve sorafenib sensitivity and therefore it represents a promising and attractive strategy for the treatment of HCC. PMID- 29152113 TI - The prognostic significance of MCL1 copy number gain in esophageal squamous cell carcinoma. AB - Background: MCL1 copy number variations have been reported to be associated with cancer prognosis in several cancers. However, the role of MCL1 gain has not yet been determined in esophageal squamous cell carcinomas (ESCC). Methods: Fluorescence in situ hybridization (FISH) for MCL1 was performed on 262 ESCC samples using tissue microarray (TMA). Results: The median age of ESCC patients was 62 years (range 37-83), with frequencies between women (16.4%) and men (83.6%). Of the 262 tumors, 77 tumors (29.4%) had high MCL1 gain. In the multivariate analysis, lymph node metastasis (HR: 3.236, P<0.001 for DFS; HR: 3.501, P<0.001 for OS) and clinical stage (HR: 3.388, P<0.001 for DFS; HR: 3.616, P<0.001 for OS) were identified as independent worse prognostic factors. Interestingly, among patients without lymph node metastasis or stage I-II patients, high MCL1 gain was associated with better DFS (P=0.009 or 0.046) and OS (P=0.014 or 0.069) after disease free survival time was more than or equal to 12 months. Reversely, among patients with lymph node metastasis or stage III-IVa patients, high MCL1 gain was associated with poorer DFS (P=0.007 or 0.021) and OS (P=0.029 or 0.068) after disease free survival time was more than or equal to 29 months. Conclusion: We observed that high MCL1 gain had bidirectional prognostic significance in ESCC patients with different lymph node status or clinical stage. These findings might provide the useful way of detailed risk stratification in patients with ESCC, and an insight into pathogenesis and mechanism of progression in ESCC. PMID- 29152114 TI - Comparison of isolation platforms for detection of circulating renal cell carcinoma cells. AB - Background: Analysis of circulating tumor cells (CTCs) has progressed in several tumor entities. However, little is known about CTCs in clear cell renal cell carcinoma (ccRCC) patients. Aim of our studies was to build a stable in vitro fundament for isolation of CTCs in ccRCC. Methods: We compared the analytical performance of different CTC isolation methods with regard to yield and purity: EpCAM based enrichment, leukocyte depletion and size based enrichment. EpCAM and cytokeratin 8 (KRT8) as biomarker for CTCs expression were evaluated in ccRCC cell lines as well as clinical samples. Results: While the EpCAM based approach failed to successfully isolate tumor cells, CD45 based approaches showed intermediate recovery rates. The cell-size based Parsortix system showed highest recovery rates. EpCAM expression was low or absent in most cell lines as well as in clinical samples, whereas KRT8 was detected as a potential biomarker in ccRCC. Conclusion: EpCAM based approaches might miss a high number of CTCs due to low or absent expression of EpCAM in ccRCC, as shown in cell lines as well as in patient samples. We identified the cell-sized based, label independent Parsortix system to be the most effective recovery system for ccRCC CTCs. PMID- 29152115 TI - HDAC-4 regulates claudin-2 expression in EGFR-ERK1/2 dependent manner to regulate colonic epithelial cell differentiation. AB - In normal colon, claudin-2 expression is restricted to the crypt bottom containing the undifferentiated and proliferative colonocytes. Claudin-2 expression is also upregulated in colorectal cancer (CRC) and promotes carcinogenesis. However, cellular mechanism/s regulated by increased claudin-2 expression during the CRC and mechanism/s regulating this increase remain poorly understood. Epigenetic mechanisms help regulate expression of cancer-associated genes and inhibition of Histone Deacetylases (HDACs) induces cell cycle arrest and differentiation. Accordingly, based on a comprehensive in vitro and in vivo analysis we here report that Histone Deacetylases regulate claudin-2 expression in causal association with colonocyte dedifferentiation to promote CRC. Detailed differentiation analyses using colon cancer cells demonstrated inverse association between claudin-2 expression and epithelial differentiation. Genetic manipulation studies revealed the causal role of HDAC-4 in regulating claudin-2 expression during this process. Further analysis identified transcriptional regulation as the underlying mechanism, which was dependent on HDAC-4 dependent modulation of the EGFR-ERK1/2 signaling. Accordingly, colon tumors demonstrated marked upregulation of the HDAC-4/ERK1/2/Claudin-2 signaling. Taken together, we demonstrate a novel role for HDAC-4/EGFR/ERK1/2 signaling in regulating claudin-2 expression to modulate colonocyte differentiation. These findings are of clinical significance and highlight epigenetic regulation as potential mechanism to regulate claudin-2 expression during mucosal pathologies including CRC. PMID- 29152116 TI - microRNA-526b servers as a prognostic factor and exhibits tumor suppressive property by targeting Sirtuin 7 in hepatocellular carcinoma. AB - Recent studies have reported that microRNA-526b (miR-526b) is implicated in the growth and metastasis of cancer cells. However, the clinical significance of miR 526b and its role as well as underlying mechanisms are largely unknown in hepatocellular carcinoma (HCC). Here, we detected miR-526b expression difference between HCC and matched nontumor tissues with qRT-PCR. We found that miR-526b displayed lower expression in HCC patient tissues and cells. Clinical analysis revealed that low miR-526b expression correlated with large tumor size, venous infiltration, advanced tumor-node-metastasis (TNM) stage. Furthermore, miR-526b underexpression independently predicted poor prognosis of HCC patients. Functionally, we demonstrated that miR-526b inhibited proliferation, migration and invasion of HCC cells in vitro. Moreover, miR-526b overexpression restrained the tumor growth and pulmonary metastasis in vivo. Mechanistically, we proved that miR-526b could directly bind to 3'UTR of sirtuin 7 (SIRT7) mRNA and repressed its expression. miR-526b and SIRT7 showed a negative correlation in HCC tissues. More importantly, up-regulating SIRT7 expression antagonized miR-526b inhibited proliferation, migration and invasion in SMMC-7721 cells. Furthermore, miR-526b suppressed epithelial-to-mesenchymal transition (EMT) of HCC cells. Immunoblotting analysis indicated that miR-526b reduced the levels of phosphorylated ERK (p-ERK), c-Myc, Cyclin D1, c-Jun, SNAIL and SLUG in HCC cells. SIRT7 restoration promoted phosphorylation of ERK and EMT in miR-526b overexpressing SMMC-7721 cells. Taken together, this is the first time we demonstrated that miR-526b might function as a prognostic biomarker and suppressed SIRT7 expression, and subsequently led to the growth and metastasis of HCC. Our findings provide miR-526b/SIRT7 axis as a promising drug target for HCC. PMID- 29152117 TI - FGF5 is expressed in melanoma and enhances malignancy in vitro and in vivo. AB - Although FGF5 mRNA was previously found expressed in some melanoma cell lines in contrast to normal human melanocytes, neither its contribution to melanoma growth nor its expression in melanoma tissue has been investigated. Here we demonstrate that ectopic overexpression of FGF5 in human melanoma cells with low endogenous FGF5 expression increased clonogenicity and invasion but not short-term growth in vitro. Silencing of FGF5 in melanoma cells with high endogenous FGF5 expression had the opposite effect on clonogenicity. FGF overexpression led to increased signaling along the MAPK and NFAT axis but had no effect on STAT3 signaling. In an in vivo experiment in immunocompromised mice, human melanoma xenografts overexpressing FGF5 showed enhanced tumor growth, a higher Ki-67 proliferation index, decreased apoptosis and enhanced angiogenesis. Immunohistochemistry performed on a tissue microarray demonstrated FGF5 protein expression in more than 50% of samples of melanoma and benign nevi. These data suggest that FGF5 has oncogenic potential in melanoma cells and contributes to melanoma growth in a subset of patients. This highlights the importance of further evaluating FGF5 as potential biomarker and therapy target in melanoma. PMID- 29152118 TI - Sensitization of neuroblastoma for vincristine-induced apoptosis by Smac mimetic LCL161 is attended by G2 cell cycle arrest but is independent of NFkappaB, RIP1 and TNF-alpha. AB - We demonstrated sensitization for chemotherapy by Smac mimetic (SM) LCL161, a potent antagonist of inhibitor of apoptosis proteins (IAP), in neuroblastoma (NB). Vinca alkaloids, particularly vincristine (VCR), displayed the strongest impact on inhibition of proliferation and apoptosis induction in combination with LCL161. The underlying signaling pathways remain elusive, though. LCL161 induces a quick degradation of cellular IAP 1 (cIAP-1). Combination of LCL161 with VCR had only marginal effects on X-linked IAP (XIAP) protein expression. Cell death is accompanied by activation of intrinsic (caspase-9 and MMP) and extrinsic (caspase-8) pathways of apoptosis, repression of migratory potential and cell cycle arrest in G2 phase. LCL161-induced cIAP degradation leads to activation of non-canonical and blockade of canonical NF-kappaB pathways but not induction of apoptosis. Surprisingly NF-kappaB and TNF-alpha signaling is negligible for VCR- and VCR/LCL161-induced apoptosis since chemical inhibition of NF-kappaB using BAY 7085 and PBS-1086, as well as application of TNF-alpha blocking antibody Humira (adalimumab) has no relevant effect on cell death. Recently formation of a TNF alpha-independent complex (ripoptosome) consisting of RIP1, FADD and caspase-8 following IAP inhibition by SM has been described. However, targeting of RIP1 by Necrostatin was not sufficient to influence apoptosis induced by VCR/LCL161. PMID- 29152119 TI - A genome-wide comprehensively analyses of long noncoding RNA profiling and metastasis associated lncRNAs in renal cell carcinoma. AB - Recently, a growing number of studies have indicated that long noncoding RNAs (lncRNAs) are emerging as new critical regulators of tumorigenesis and prognostic markers in multiple cancers. However, the expression pattern of lncRNAs and their contributions in renal cell carcinoma (RCC) remains poorly understood. In this study, we performed a genome-wide comprehensively analysis of lncRNAs profiling and clinical relevance to provide valuable lncRNA candidates for the further study in RCC. RCC and non-tumor tissues RNA sequencing data, and microarray data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), then, these data were annotated and analyzed to find dysregulated lncRNAs in RCC. We identified that hundreds of lncRNAs were differentially expressed in RCC tissues compared with normal tissues, and genomic variation analyses revealed that copy number amplification or deletion happened in some of these lncRNAs genome loci. Moreover, lots of lncRNAs expression levels are significantly associated RCC patients overall survival time, such as PVT1 and DUXAP8. Finally, we identified some novel metastasis associated lncRNAs in RCC (such as DUXAP8) by analyzing lncRNAs profiling in the RCC tissues from patients with metastasis compared with the primary RCC tissues without metastasis; knockdown of DUXAP8 could impair RCC cells invasive ability in vitro. Overall, our findings illuminate a lot of lncRNAs are aberrantly expressed in RCC that may offer useful resource for identification novel prognostic markers in this disease. PMID- 29152120 TI - Hierarchical clustering analysis identifies metastatic colorectal cancers patients with more aggressive phenotype. AB - A large percentage of metastatic colorectal cancer (mCRC) patients presents metastasis at the time of diagnosis. In the last years, great efforts have been made in the treatment of these patients with the identification of different phenotypes playing a key role in the definition of new systemic therapies. Unsupervised hierarchical clustering analysis (HCA) was performed considering the clinicopathological characteristics of 51 mCRCs. Using immunohistochemistry on tissue microarrays, we assessed the expression of beta-catenin, NHERF1, RASSF1A, TWIST1, HIF-1alpha proteins in tumors and paired liver metastases. We also analyzed RASSF1A methylation status on the samples of the same patients. HCA distinguished Group 1 and Group 2 characterized by different clinicopathological features. Group 1 was characterized by higher number of positive lymph nodes (p=0.0139), poorly differentiated grade (p<0.0001) and high extent of tumor spread (p=0.0053) showing a more aggressive phenotype compared to Group 2. In both Groups, we found a common "basal" condition with a higher level of nuclear TWIST1 (p<0.0001 and cytoplasmic beta-catenin (p<0.0001) in tumors than in paired liver metastases. Furthermore, the Group 1 was also characterized by RASSF1A hypermethylation (p<0.0001) and nuclear HIF-1alpha overexpression (p=0.0354) in paired liver metastases than in tumors. In conclusion, HCA identifies mCRC patients with a more aggressive phenotype. Moroever, our results support the important contribution to the progression of the disease of RASSF1A methylation and the oncogenic role of HIF-1alpha in these patients. These evidences, should provide relevant information concerning the biology of this tumor and, as a consequence, potential new systemic therapeutic approaches. PMID- 29152121 TI - Longitudinal evaluation of myocardial glucose metabolism and contractile function in obese type 2 diabetic db/db mice using small-animal dynamic 18F-FDG PET and echocardiography. AB - The aim was to evaluate sequential changes of myocardial glucose utilization and LV systolic function in db/db mice. Eight db/db and eight wild-type mice underwent plasma substrate analysis and dynamic 18F-FDG PET at week 8 (W8), W10, W12, W14, and W16. 18F-FDG uptake constant Ki and the rate of myocardial glucose uptake (MRGlu) were derived via Patlak graphic analysis. Another 8 db/db and 8 wild-type mice received echocardiography at W8, W12, and W16 and LV structure and function were measured. The db/db mice showed increased weights and glucose levels as they aged. The index of homeostasis model assessment-estimated insulin resistance, insulin, and free fatty acid concentrations were higher in db/db mice compared with wild-type. MRGlu of db/db mice across all time points was markedly higher than that of wild-type. An age-dependent elevation of MRGlu was observed in db/db mice. Ki and MRGlu of db/db mice showed negative correlation with triglyceride levels. When two groups were pooled together, Ki and MRGlu were significantly proportional to glucose levels. No significant difference in LV structure and function was noted between db/db and control mice. In conclusion, we demonstrated altered myocardial glucose utilization preceding the onset of LV systolic dysfunction in db/db mice. PMID- 29152122 TI - Cisplatin radiosensitizes radioresistant human mesenchymal stem cells. AB - Cisplatin-based chemo-radiotherapy is widely used to treat cancers with often severe therapy-associated late toxicities. While mesenchymal stem cells (MSCs) were shown to aid regeneration of cisplatin- or radiation-induced tissue lesions, the effect of the combined treatment on the stem cells remains unknown. Here we demonstrate that cisplatin treatment radiosensitized human bone marrow-derived MSCs in a dose-dependent manner and increased levels of radiation-induced apoptosis. However, the defining stem cell properties of MSCs remained largely intact after cisplatin-based chemo-radiation, and stem cell motility, adhesion, surface marker expression and the characteristic differentiation potential were not significantly influenced. The increased cisplatin-mediated radiosensitivity was associated with a cell cycle shift of MSCs towards the radiosensitive G2/M phase and increased residual DNA double-strand breaks. These data demonstrate for the first time a dose-dependent radiosensitization effect of MSCs by cisplatin. Clinically, the observed increase in radiation sensitivity and subsequent loss of regenerative MSCs may contribute to the often severe late toxicities observed after cisplatin-based chemo-radiotherapy in cancer patients. PMID- 29152123 TI - MSC-derived cytokines repair radiation-induced intra-villi microvascular injury. AB - Microvascular injury initiates the pathogenesis of radiation enteropathy. As previously demonstrated, the secretome from mesenchymal stem cells contains various angiogenic cytokines that exhibited therapeutic potential for ischemic lesions. As such, the present study aimed to investigate whether cytokines derived from mesenchymal stem cells can repair endothelial injuries from irradiated intestine. Here, serum-free medium was conditioned by human adipose derived mesenchymal stem cells, and we found that there were several angiogenic cytokines in the medium, including IL-8, angiogenin, HGF and VEGF. This medium promoted the formation of tubules between human umbilical cord vein endothelial cells and protected these cells against radiation-induced apoptosis in vitro. Likewise, our in vivo results revealed that repeated injections of mesenchymal stem cell-conditioned medium could accelerate the recovery of irradiated mice by reducing the serum levels of pro-inflammatory cytokines, including IL-1alpha, IL 6 and TNF-alpha, and promoting intra-villi angiogenesis. Herein, intervention by conditioned medium could increase the number of circulating endothelial progenitors, whereas neutralizing SDF-1alpha and/or inhibiting PI3K would hamper the recruitment of endothelial progenitors to the injured sites. Such results suggested that SDF-1alpha and PI3K-mediated phosphorylation were required for intra-villi angiogenesis. To illustrate this, we found that conditioned medium enabled endothelial cells to increase intracellular levels of phosphorylated Akt Ser473, both under irradiated and steady state conditions, and to up-regulate the expression of the CXCR4 and CXCR7 genes. Collectively, the present results revealed the therapeutic effects of mesenchymal stem cell-derived cytokines on microvascular injury of irradiated intestine. PMID- 29152124 TI - Identification of a sixteen-microRNA signature as prognostic biomarker for stage II and III colon cancer. AB - Despite advances in colon cancer research and novel therapies, high risk of recurrence remains a major challenge. This study reports miRNA expression profiling as a biomarker for the prognosis of TNM stage II and III colon cancer. Fresh frozen biopsies from the study cohort (N=111) were analyzed for miRNA by RT qPCR and LASSO regression analysis was used to build a classifier of miRNAs. The prognostic accuracy was tested and the classifier was validated in an independent colon cohort (TCGA-COAD, N=209). The LASSO regression analysis identified a 16 miRNA signature including miR-143-5p, miR-27a-3p, miR-31-5p, miR-181a-5p, miR-30b 5p, miR-30d-5p, miR-146a-5p, miR-23a-3p, miR-150-5p, miR-210-3p, miR-25-3p, miR 196a-5p, miR-148a-3p, miR-222-3p, miR-30c-5p and miR-223-3p. A low 16-miRNA signature was associated with better 5-year disease-free survival (DFS) in the study cohort than a high signature (93 % versus 58 %; p< 0.001). The signature was an independent prognostic factor for better 5-year DFS in multivariate analyses (HR 21.4; 95% CI: 4.21-108.7; p< 0.001). The results in the validation cohort were consistent with the study cohort in univariate (77 % versus 65 %; p= 0.045) and multivariate analyses (HR 2.0; 95% CI: 1.04-3.89; p=0.039). We identified a 16-miRNA signature as a reliable prognostic biomarker for classification of colon cancer stage II and III patients into groups with low and high risk for recurrence. PMID- 29152125 TI - CD49b inhibits osteogenic differentiation and plays an important role in osteosarcoma progression. AB - Osteosarcoma is a cancer whose cell of origin lies in the differentiation pathway between the mesenchymal stem cell (MSC) and the osteoblast (OB). In this study, we sought to determine if surface markers associated with osteoblastic differentiation are involved in osteosarcoma progression. cDNA expression arrays were performed on MSCs and osteoblasts to identify differentially expressed genes. The specificity of candidate genes for osteoblast differentiation was assessed through time course experiments in differentiation media with confirmation utilizing CD49b transfected MSCs. In addition, CD49b was transfected into osteosarcoma cell lines to determine its impact on cell proliferation, motility, and invasion. Finally, the expression of CD49b was assessed in osteosarcoma patient samples and correlated with survival outcomes. cDNA expression arrays identified a list of genes differentially expressed between MSCs and osteoblasts with a subset of those genes encoding cell surface proteins. Three genes were selected for further analysis, based on qPCR validation, but only CD49b was selective for osteoblastic differentiation. Forced expression of CD49b in MSCs led to delayed osteoblastic differentiation. Down-regulation of CD49b expression in osteosarcoma cell lines resulted in inhibition of their migration and invasion capacity. CD49b expression in osteosarcoma patients was associated with presence of metastases and inferior 5 year overall survival (31.4% vs. 57.4%, p=0.03). Surface proteins involved in osteosarcoma cell differentiation, such as CD49b, have the potential to serve as prognostic biomarkers, and may lead to the identification of new therapeutic targets. PMID- 29152126 TI - Extracellular ATP, as an energy and phosphorylating molecule, induces different types of drug resistances in cancer cells through ATP internalization and intracellular ATP level increase. AB - Cancer cells are able to uptake extracellular ATP (eATP) via macropinocytosis to elevate intracellular ATP (iATP) levels, enhancing their survival in drug treatment. However, the involved drug resistance mechanisms are unknown. Here we investigated the roles of eATP as either an energy or a phosphorylating molecule in general drug resistance mediated by ATP internalization and iATP elevation. We report that eATP increased iATP levels and promoted drug resistance to various tyrosine kinase inhibitors (TKIs) and chemo-drugs in human cancer cell lines of five cancer types. In A549 lung cancer cells, the resistance was downregulated by macropinocytosis inhibition or siRNA knockdown of PAK1, an essential macropinocytosis enzyme. The elevated iATP upregulated the efflux activity of ABC transporters in A549 and SK-Hep-1 cells as well as phosphorylation of PDGFRalpha and proteins in the PDGFR-mediated Akt-mTOR and Raf-MEK signaling pathways in A549 cells. Similar phosphorylation upregulations were found in A549 tumors. These results demonstrate that eATP induces different types of drug resistance by eATP internalization and iATP elevation, implicating the ATP-rich tumor microenvironment in cancer drug resistance, expanding our understanding of the roles of eATP in the Warburg effect and offering new anticancer drug resistance targets. PMID- 29152127 TI - Minocycline treatment increases resistance to oxidative stress and extends lifespan in Drosophila via FOXO. AB - Minocycline is a semi-synthetic tetracycline derivative antibiotic that has received increasing attention for its non-antibiotic properties, mainly anti inflammatory, tumor-suppressive, and neuroprotective effects. Drosophila is a widely used genetically tractable model organism for studying organismal aging by virtue of its short lifespan and ease of cultivation. In this study, we examined the effects of minocycline on Drosophila lifespan and its associated traits. Minocycline-supplemented food significantly extended lifespan in both Canton S and w1118 Drosophila strains. The drug-induced lifespan extension was not associated with reduced dietary intake or reduced female fecundity, but rather with increased resistance to an oxidative stressor (hydrogen peroxide). Notably, minocycline's effects on lifespan and resistance to oxidative stress were largely abrogated in Forkhead box O (FOXO) null mutant, and the drug treatment increased the activity of FOXO. These results may further our understanding of minocycline's beneficial effects against several age-associated deteriorations observed in animal models. PMID- 29152128 TI - Modulation of cabozantinib efficacy by the prostate tumor microenvironment. AB - The tumor microenvironment (TME) is increasingly recognized as the arbiter of metastatic progression and drug resistance in advanced prostate cancer (PCa). Cabozantinib is a potent tyrosine kinase inhibitor (TKI) with reported biological activity in the PCa epithelia, but failed to provide an overall survival benefit in phase 3 clinical trials. However, the promising biologic efficacy of the drug in early trials warranted a better understanding of the mechanism of action, with the goal of improving patient selection for TKI-based therapy such as cabozantinib. We found a 100-fold lower cabozantinib IC50 in macrophages, PCa associated fibroblasts, and bone marrow fibroblasts compared to PCa epithelia. In PCa mouse models, pre-treatment with cabozantinib potentiated osseous and visceral tumor engraftment, suggesting a pro-tumorigenic host response to the drug. We further found that the host effects of cabozantinib impacted bone turnover, but not necessarily tumor expansion. Cabozantinib affected M1 macrophage polarization in mice. Analogously, circulating monocytes from PCa patients treated with cabozantinib, demonstrated a striking correlation of monocyte reprograming with therapeutic bone responsivity, to support patient selection at early stages of treatment. Thus, a re-evaluation of TKI-based therapeutic strategies in PCa can be considered for suitable patient populations based on TME responses. PMID- 29152129 TI - Protective effect of dehydroandrographolide on obstructive cholestasis in bile duct-ligated mice. AB - Background: Dehydroandrographolide (DA) is the main contributor to the therapeutic properties of the medicinal plant Andrographis paniculata (AP). However, it is unknown whether DA has a hepatoprotective effect on obstructive cholestasis in mice and humans. Methods: We administered DA to mice for 5 days prior to bile duct ligation (BDL) and for the 7 days. Liver function markers, liver histology and necrosis, compensatory responses of hepatocytes, liver fibrosis and the expression of hepatic fibrogenesis markers were evaluated in BDL mice and/or human LX-2 cells. Results: Mice treated with DA demonstrated lower levels of serum alanine transarninase (ALT), milder liver damage, liver necrosis and fibrosis formation than in vehicle control with carboxymethylcellulose (CMC) mice after BDL. DA treatment also enhanced the Mrp3 expression of hepatocytes but not Mrp4 following BDL. Further, DA treatment in BDL mice significantly reduced liver mRNA and/or protein expression of Tgf-beta, Col1a1, alpha-Sma and Mmp2. This result was also supported by hydroxyproline analysis. The molecular mechanisms of DA treatment were also assessed in human hepatic stellate cell line (LX-2 cell). DA treatment significantly inhibited Tgf-beta-induced Col1a1, Mmp2 and alpha-Sma expression in human LX-2 cells. These data suggested that DA treatment reduced liver damage through development of a hepatic adaptive response and inhibition of the activation of HSCs, which led to a reduction in liver fibrosis formation in BDL mice. Conclusions: DA treatment protected against liver damage and fibrosis following BDL and might be an effective therapy for extrahepatic cholestasis due to bile duct obstruction. PMID- 29152130 TI - The association between polymorphisms in microRNA genes and cervical cancer in a Chinese Han population. AB - Several studies have confirmed the crucial roles of microRNAs (miRNAs) in cancer occurrence. In addition, single nucleotide polymorphisms (SNPs) in miRNA genes have been associated with various cancers. The aim of the present study was to investigate the association of SNPs in miRNA genes with cervical intraepithelial neoplasia (CIN) and cervical cancer in a Chinese Han population. We searched SNPs in nineteen miRNAs by sequencing healthy individuals (n=50). Then, a total of 400 patients with CIN, 609 patients with cervical cancer and 583 healthy individuals were recruited to genotype the SNPs using a Taqman assay. The results showed that only five of the nineteen miRNAs had SNPs (rs11134527 in pri-miR-218-2; rs74693964 in pri-miR-145; rs6062251 in pri-miR-133a2; rs531564 in pri-miR-124-1; and rs1834306 in pri-miR-100) in this Chinese Han population. The frequency of the rs11134527A allele was significantly higher in the control group than in CIN and cervical cancer groups (P=0.011 and 0.035, respectively). The frequency of the rs531564G allele was higher in the CIN and control groups than in the cervical cancer group (P=0.019 and 0.017, respectively). These results indicated that rs11134527 in pri-miR-218-2 and rs531564 in pri-miR-124-1 could be associated with CIN and cervical cancer in the Chinese Han population. PMID- 29152132 TI - High BAALC copy numbers in peripheral blood prior to allogeneic transplantation predict early relapse in acute myeloid leukemia patients. AB - High BAALC expression levels at acute myeloid leukemia diagnosis have been linked to adverse outcomes. Recent data indicate that high BAALC expression levels may also be used as marker for residual disease following acute myeloid leukemia treatment. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment for acute myeloid leukemia patients. However, disease recurrence remains a major clinical challenge and identification of high-risk patients prior to HSCT is crucial to improve outcomes. We performed absolute quantification of BAALC copy numbers in peripheral blood prior (median 7 days) to HSCT in complete remission (CR) or CR with incomplete peripheral recovery in 82 acute myeloid leukemia patients using digital droplet PCR (ddPCR) technology. An optimal cut-off of 0.14 BAALC/ABL1 copy numbers was determined and applied to define patients with high or low BAALC/ABL1 copy numbers. High pre-HSCT BAALC/ABL1 copy numbers significantly associated with higher cumulative incidence of relapse and shorter overall survival in univariable and multivariable models. Patients with high pre-HSCT BAALC/ABL1 copy numbers were more likely to experience relapse within 100 days after HSCT. Evaluation of pre-HSCT BAALC/ABL1 copy numbers in peripheral blood by ddPCR represents a feasible and rapid way to identify acute myeloid leukemia patients at high risk of early relapse after HSCT. The prognostic impact was also observed independently of other known clinical, genetic, and molecular prognosticators. In the future, prospective studies should evaluate whether acute myeloid leukemia patients with high pre HSCT BAALC/ABL1 copy numbers benefit from additional treatment before or early intervention after HSCT. PMID- 29152131 TI - MicroRNA-130b attenuates dexamethasone-induced increase of lipid accumulation in porcine preadipocytes by suppressing PPAR-gamma expression. AB - In this study, two experiments were conducted to determine the role of miR-130b in dexamethasone (DEX)-induced lipid accumulation. Porcine preadipocytes were treated with 10-6 M DEX for 48 h to investigate effects of DEX in lipid accumulation. Next, in order to illustrate the regulatory role of miR-130b on lipid accumulation induced by DEX, miRNA scrambled control (miR-SC), miR-130b overexpression plasmid and miR-130b inhibitor were respectively transfected into porcine preadipocytes at 24 h before DEX treatment for 48 h (miR-SC-DEX, miR-130b DEX and miR-130b-inhibitor-DEX). Results showed that 10-6 M DEX significantly increased TG concentration and expression of miR-130b as well as its target gene peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Dual-luciferase reporter assays indicated that PPAR-gamma expression was negatively regulated by miR-130b, while this effect was abolished with cotransfection of miR-130b and miR 130b inhibitor. In addition, miR-130b-DEX did not change cell proliferation but significantly decreased TG concentration and PPAR-gamma expression compared to miR-SC-DEX cells, while miR-130b-inhibitor-DEX cells presented opposite results. Furthermore, miR-130b-DEX significantly reduced expression of PPAR-gamma downstream factor perilipin 1 as well as adipogenesis genes fatty acid synthase, acetyl coenzyme A carboxylase, 11beta hydroxysteroid dehydrogenase type 1 and fat mass and obesity-associated gene, whereas expression as well as enzyme activity of adipose triglyceride lipase and hormone-sensitive lipase were greatly increased. Overall, these results clarified the role of miR-130b in DEX-induced increase of lipid accumulation in porcine preadipocytes, suggesting that miR-130b might be deemed as a novel potential therapeutic target for DEX-induced increase of lipid accumulation, and consequently provide new insights in obesity control. PMID- 29152133 TI - Prognostic significance of XRCC4 expression in hepatocellular carcinoma. AB - Background: Our previous investigations have shown that the variants of X-ray repair complementing 4 (XRCC4) may be involved in hepatocellular carcinoma (hepatocarcinoma) tumorigenesis. This study aimed to investigate the possible prognostic significance of XRCC4 expression for hepatocarcinoma patients and possible value for the selection of transarterial chemoembolization (TACE) treatment. Materials and Methods: We conducted a hospital-based retrospective analysis (including 421 hepatocarcinoma cases) to analyze the effects of XRCC4 on hepatocarcinoma prognosis and TACE. The levels of XRCC4 expression were tested using immunohistochemistry. The sensitivity of cancer cells to anti-cancer drug doxorubicin was evaluated using the half-maximal inhibitory concentration (IC50). Results: XRCC4 expression was significantly correlated with pathological features including tumor stage, liver cirrhosis, and micro-vessel density. XRCC4 expression was an independent prognostic factor of hepatocarcinoma, and TACE treatments had no effects on prognosis of hepatocarcinoma patients with high XRCC4 expression. More intriguingly, TACE improved the prognosis of hepatocarcinoma patients with low XRCC4 expression. Functionally, XRCC4 overexpression increased while XRCC4 knockdown reduced the IC50 of cancer cells to doxorubicin. Conclusions: These results suggest that XRCC4 may be an independent prognostic factor for hepatocarcinoma patients, and that decreasing XRCC4 expression may be beneficial for post-operative adjuvant TACE treatment in hepatocarcinoma. PMID- 29152134 TI - Combined neutrophil-platelet score and hemoglobin level predict survival in esophageal squamous cell carcinoma patients treated with chemoradiotherapy. AB - Systemic inflammation and hematological markers have prognostic value in patients with esophageal squamous cell carcinoma (ESCC). The objective of this study was to evaluate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), combined neutrophil-platelet (CNP) score, and hemoglobin (Hb) to inform treatment decisions and predict outcomes in patients with locally advanced ESCC treated with chemoradiotherapy (CRT). A total of 168 patients with locally advanced ESCC were retrospectively evaluated. Patients were stratified by marker value using a receiver operating characteristic curve analysis to determine the cutoff point. Logistic regression was used to identify markers associated with sensitivity to treatment. Overall survival (OS) was calculated by the Kaplan Meier method. Multivariate Cox logistic regression modeling was used to assess the influences of OS. Smoking history, tumour site, clinical stage, NLR, PLR, CNP, and Hb (p <= 0.05) were associated with the sensitivity to therapy. In multivariate analysis, a high CNP score was independently associated with poor treatment sensitivity (OR = 2.066, p = 0.021). Univariate analysis revealed that PLR, CNP, and Hb levels were associated with OS, and Cox multivariate analysis found that CNP (HR = 1.47, p = 0.027) and Hb level (HR = 0.44, p = 0.007) were independent predictors of OS. In conclusion, CNP and Hb are inexpensive and universally available prognostic markers in patients with locally advanced ESCC patients. CNP score is a systemic inflammatory marker that predicted sensitivity to CRT. PMID- 29152135 TI - Evaluation of pre-analytical conditions and comparison of the performance of several digital PCR assays for the detection of major EGFR mutations in circulating DNA from non-small cell lung cancers: the CIRCAN_0 study. AB - Non invasive somatic detection assays are suitable for repetitive tumor characterization or for detecting the appearance of somatic resistance during lung cancer. Molecular diagnosis based on circulating free DNA (cfDNA) offers the opportunity to track the genomic evolution of the tumor, and was chosen to assess the molecular profile of several EGFR alterations, including deletions in exon 19 (delEX19), the L858R substitution on exon 21 and the EGFR resistance mutation T790M on exon 20. Our study aimed at determining optimal pre-analytical conditions and EGFR mutation detection assays for analyzing cfDNA using the picoliter-droplet digital polymerase chain reaction (ddPCR) assay. Within the framework of the CIRCAN project set-up at the Lyon University Hospital, plasma samples were collected to establish a pre-analytical and analytical workflow of cfDNA analysis. We evaluated all of the steps from blood sampling to mutation detection output, including shipping conditions (4H versus 24H in EDTA tubes), the reproducibility of cfDNA extraction, the specificity/sensitivity of ddPCR (using external controls), and the comparison of different PCR assays for the detection of the three most important EGFR hotspots, which highlighted the increased sensitivity of our in-house primers/probes. Hence, we have described a new protocol facilitating the molecular detection of somatic mutations in cancer patients from liquid biopsies, improving their diagnosis and introducing a less traumatic monitoring system during tumor progression. PMID- 29152136 TI - Postnatal calpain inhibition elicits cerebellar cell death and motor dysfunction. AB - Calpain-1 deletion elicits neurodevelopmental disorders, such as ataxia. However, the function of calpain in postnatal neurodevelopment and its mechanisms remain unknown. In this study, we revealed that postnatal intraperitoneal injection of various calpain inhibitors attenuated cerebellar cytosolic calpain activity. Moreover, postnatal application of calpeptin (2 mg/kg) apparently reduced spectrin breakdown, promoted suprachiasmatic nucleus circadian oscillatory protein (SCOP) accumulation in cerebellar tissue. In addition, application of calpeptin decreased phosphorylated protein kinase B (p-AKT) level (p<0.05), as well as total AKT level (p<0.05). We also evidenced that administration of calpeptin obviously increased phosphorylation of mammalian target of rapamycin (p mTor) (p<0.01). Apoptosis of granular cells and activation of caspase-3 (p<0.01) were facilitated after calpain inhibition. Importantly, cell numbers of granular cells were reduced and motor function was remarkably impaired in 4-month-old rats receiving postnatal calpain inhibition. Taken together, our data implicated that calpain activity in the postnatal period was critical for the cerebellar development. Postnatal calpain inhibition causes cerebellar granular cell apoptosis and motor dysfunction, likely through SCOP/AKT and p-mTor signaling pathways. PMID- 29152137 TI - Emodin and rhein decrease levels of hypoxia-inducible factor-1alpha in human pancreatic cancer cells and attenuate cancer cachexia in athymic mice carrying these cells. AB - The transcription factor hypoxia-inducible factor-1 (HIF-1) consists of oxygen sensitive HIF-1alpha and constitutive HIF-1beta. HIF-1alpha is undetectable in normal cells, but cancer cells frequently express HIF-1alpha to support their growth, angiogenesis, and high glycolysis (also known as the Warburg effect). The Warburg effect in cancer cells increases energy expenditure and thus participates in cancer-induced metabolic disorder, cancer cachexia. In the present study, we investigated whether two components of Rheum palmatum, emodin and rhein, inhibited HIF-1alpha expression in human pancreatic cancer cells and whether the inhibiting effect, if any, attenuated cancer cachexia. Using Western blotting, we demonstrated that emodin and rhein decreased HIF-1alpha expression in MiaPaCa2 and four other human pancreatic cancer cell lines. We also examined HIF-1alpha expression when MiaPaCa2 cells were exposed to PX-478, noscapine, and phenethyl isothiocyanate, as these compounds were known to inhibit HIF-1alpha expression in different cancer cells. PX-478 and noscapine inhibited HIF-1alpha expression to a less extent than emodin and rhein, and phenethyl isothiocyanate did not inhibit HIF-1alpha expression in tested concentrations. We obtained evidence that emodin and rhein decreased HIF-1alpha by decreasing its biosynthesis but not gene transcription or protein stability. When MiaPaCa2 cells were implanted in athymic mice, emodin and rhein inhibited cancer-cell growth and HIF-1alpha expression. In these athymic mice, emodin and rhein also attenuated two pathological constituents of cancer cachexia, namely high hepatic gluconeogenesis and skeletal muscle proteolysis. In conclusion, emodin and rhein decrease pancreatic cancer cell's growth and HIF-1alpha expression and attenuate cancer cachexia in the athymic mice carrying the cancer cells. PMID- 29152138 TI - The hOCT1 and ABCB1 polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia. AB - First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of hOCT1 (rs683369 [c.480C>G]) and ABCB1 (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, hOCT1 and ABCB1 polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, in contrast to data obtained in patients treated with imatinib, hOCT1 and ABCB1 polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy. PMID- 29152139 TI - IGF1 gene polymorphisms associated with diabetic retinopathy risk in Chinese Han population. AB - Objective: This study aimed to explore the association of insulin-like growth factor 1 gene (IGF1) polymorphisms with diabetic retinopathy (DR) in a Chinese Han population. Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping. Genotype frequencies were compared by chi-square test. Odds ratio (OR) with 95% confidence interval (95%CI) was calculated to express the risk intensity of DR. Linkage disequilibrium between IGF1 polymorphisms was analyzed by Haploview. Serum IGF1 concentration was measured by enzyme-linked immunosorbent assays (ELISA) and assessed by student's t test. Results: AG genotype of rs6218 and TT genotype of rs35767 were significantly associated with the elevated risk of DR (rs6218: OR=1.77, P=0.04; rs35767: OR=2.32, P=0.03) and type II diabetes mellitus (T2DM) (rs6218: OR=1.92, P=0.00. rs35767: OR=2.29, P=0.02). Only T allele of rs35767 significantly increased the risk of DR (OR=1.45, P=0.04), however, rs6218 (OR=1.92, P=0.00), rs35767 (OR=0.02, P=0.02) and rs5742612 (OR=2.21, P=0.04) showed obvious association with T2DM. Haplotypes were only associated with T2DM, but not DR. Minor allele homozygote of rs35767 was obviously correlated with serum IGF1 level. Conclusion: IGF1 rs6218 and rs35767 polymorphisms contribute to the risk of DR. IGF1 rs35767 polymorphism may participate in the regulation of serum IGF1 concentration in DR. PMID- 29152140 TI - Inhibition of IL-8-mediated endothelial adhesion, VSMCs proliferation and migration by siRNA-TMEM98 suggests TMEM98's emerging role in atherosclerosis. AB - Transmembrane protein 98 (TMEM98), known as a novel gene related to lung cancer, hepatocellular carcinoma, differentiation of T helper 1 cells and normal eye development, has no defined role reported in terms of atherosclerosis (AS). To investigate the potential involvement of TMEM98 during AS processes, its obvious secretion and expression has been initially characterized in hyperlipidemia patients' serum and AS mice's serum respectively. We then explored the possible role of TMEM98 in the pathogenesis of AS in vitro. IL-8, a pro-atherogenesis cytokine, was used to induce the expression of TMEM98 in both endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Collectively, TMEM98 expression significantly increased in ECs and VSMCs, both induced by IL-8. Additionally, the adhesion ability of monocytes to ECs as well as the proliferation and migration of VSMCs were all decreased after siRNA-TMEM98 treatment. Furthermore, siRNA TMEM98 dramatically inhibited the expression of ICAM-1 in ECs and the expression of p-AKT, p-GSK3beta and Cyclin D1 from VSMCs, and AKT agonist partially restored the proliferation and migration of VSMC after siRNA-TMEM98 treatment. Taken together, siRNA-TMEM98 inhibits IL-8 mediated EC adhesion by down-regulating the expression of ICAM-1. Additionally, it also hinders the proliferation and migration of VSMCs through suppressing the AKT/GSK3beta/Cyclin D1 signaling pathway. Our study provides sufficient evidence to support that TMEM98 could be a novel gene associated with AS for the first time. PMID- 29152142 TI - Antiproliferative and apoptotic effects of xanthohumol in cholangiocarcinoma. AB - Cholangiocarcinoma remains the second most prevalent hepatic neoplasm in the United States with a 5-year survival rate of less than 10%. Currently, no systemic therapy has demonstrated efficacy. Therefore, an urgent need for the identification of molecularly targeted compound(s) remains. The Notch signaling pathway has been shown to be dysregulated in cholangiocarcinoma, exhibiting hyperactivity while also possibly mediating chemotherapeutic resistance. We analyzed the effects of xanthohumol, a prenylated chalcone, on cholangiocarcinoma proliferation utilizing human cholangiocarcinoma cell lines CCLP1, SG-231 and CC SW-1 while gaining insight into the associated mechanism. Xanthohumol potently reduced cellular proliferation, colony formation, and cell confluency in all three cell lines. Xanthohumol induced cell cycle arrest as well as apoptosis through the reduction of cell cycle regulatory proteins as well as an increase in pro-apoptotic markers (cleaved poly ADP ribose polymerase, cleaved caspase-3) and a decrease in anti-apoptotic markers (X-linked inhibitor of apoptosis and survivin). At the molecular level, xanthohumol reduced Notch1 and AKT expression in a step-wise and time-dependent fashion, with Notch1 reductions preceding AKT. Additionally, xanthohumol reduced cholangiocarcinoma growth in both CCLP-1 and SG 231 derived mice xenografts. In summary, we show that xanthohumol significantly reduced cholangiocarcinoma growth through the Notch1/AKT signaling axis. Furthermore, known pharmacokinetics and bioavailability of XN supports continued development of treatment for cholangiocarcinoma. PMID- 29152141 TI - Notch1 ablation radiosensitizes glioblastoma cells. AB - Broad specific Notch1 inhibitors suppress glioblastoma multiforme (GBM) growth but have significant gastrointestinal toxicities. Here, we examined Notch1 expression in GBM tissue specimens and its correlation with the overall survival (OS) of GBM patients. Furthermore, using the CRISPR/Cas9 system, we investigated the effects of Notch1 downregulation on clonogenic growth and angiogenesis of GBM cells and xenografts. Immunohistochemistry showed positive Notch1 expression in 71% (49/69) of GBM tissues. Our multivariate Cox regression analysis further revealed that Notch1 expression was an independent adverse prognostic factor for OS. Notch1 downregulation suppressed the growth of GBM cells U87MG and U251. The mean duration to reach 6 x the starting volume was 18.3 days for xenografts with Notch1 downregulation and 13.4 days for the control xenografts. Immunofluorescent staining further disclosed that Notch1 downregulation markedly increased the number of gammaH2AX foci and radiosensitized GBM cells. Notch1 downregulation also impaired angiogenesis and attenuated VEGF and hypoxic response to irradiation in xenografts. In conclusion, Notch1 ablation inhibited GBM cell proliferation and neovascularization and radiosensitized GBM cells and xenografts, suggesting a pivotal role of Notch1 in tumor growth, angiogenesis, and radioresistance in GBM. PMID- 29152143 TI - Therapeutic hexapeptide (PGPIPN) prevents and cures alcoholic fatty liver disease by affecting the expressions of genes related with lipid metabolism and oxidative stress. AB - PGPIPN is a therapeutic hexapeptide derived from bovine beta-casein. Here we investigated the role and mechanism of this peptide on alcoholic fatty liver disease (AFLD). We took human hepatic cell line LO2 and hepatocellular carcinoma cell line HepG2 to establish the models of steatosis hepatocyte induced by alcohol, taken PGPIPN as pharmacological intervention. And we also established the model of AFLD mice, taken PGPIPN as therapeutic drug and glutathione (GSH) as positive control. We assayed the biochemical materials related to liver injury, lipid metabolism and oxidation, and observed morphology change and fat accumulation of hepatocyte. The gene expressions and/or activities related to liver injury, lipid metabolism and oxidation, such as ACC, PPAR-gamma, CHOP and Caspase-3, were assessed by real time PCR and western blot. Our results showed PGPIPN alleviated hepatic steatosis in both model cells and AFLD model mice. PGPIPN can effectively reduce the lipid accumulation and oxidative stress of hepatocyte in a dose-dependent manner. PGPIPN alleviated alcohol-induced cell steatosis and injuries by regulating the gene expressions and/or activities of ACC, PPAR-gamma, CHOP and Caspase-3. Our results demonstrated PGPIPN had the protective and therapeutic effect on AFLD, which may serve as a potential therapeutic agent for AFLD. PMID- 29152144 TI - Tissue-type plasminogen activator modulates macrophage M2 to M1 phenotypic change through annexin A2-mediated NF-kappaB pathway. AB - Macrophage accumulation is one of the hallmarks of progressive kidney disease. In response to injury, macrophages undergo a phenotypic polarization to become two functionally distinct subsets: M1 and M2 macrophages. Macrophage polarization is a dynamic process, and recent work indicates that macrophages, in response to kidney injury, can shift their polarity. However, the underlying mechanisms remain largely unknown. Tissue-type plasminogen activator (tPA), a protease up regulated in the chronically injured kidneys, has been shown to preferably promote M1 macrophage accumulation and renal inflammation. We hypothesized that tPA may be an endogenous factor that modulates macrophage M2 to M1 phenotypic change contributing to the accumulation of M1 macrophages in the injured kidneys. It was found that obstruction-induced renal M1 chemokine expression was alleviated in tPA knockout mice, and these knockout mice displayed increased M2 markers. In vitro, resting J774 macrophages were treated with IL-4 to induce M2 phenotype as indicated by de novo expression of arginase 1, Ym1, and IL-10, as well as suppression of iNOS, TNF-alpha, and IL-1beta. Intriguingly, these IL-4 induced M2 macrophages, after tPA treatment, not only lost their M2 markers such as arginase 1, Ym1, and IL-10, but also displayed increased M1 chemokines including iNOS, TNF-alpha, and IL-1beta. Possible endotoxin contamination was also excluded as heat-inactivated tPA lost its effect. Additionally, tPA-mediated macrophage M2 to M1 phenotypic change required its receptor annexin A2, and SN50, a specific NF-kappaB inhibitor, abolished tPA's effect. Thus, it's clear that tPA promotes macrophage M2 to M1 phenotypic change through annexin A2-mediated NF kappaB pathway. PMID- 29152145 TI - GFAPdelta/GFAPalpha ratio directs astrocytoma gene expression towards a more malignant profile. AB - Astrocytomas are the most common malignant brain tumours and are to date incurable. It is unclear how astrocytomas progress into higher malignant grades. The intermediate filament cytoskeleton is emerging as an important regulator of malignancy in several tumours. The majority of the astrocytomas express the intermediate filament protein Glial Fibrillary Acidic Protein (GFAP). Several GFAP splice variants have been identified and the main variants expressed in human astrocytoma are the GFAPalpha and GFAPdelta isoforms. Here we show a significant downregulation of GFAPalpha in grade IV astrocytoma compared to grade II and III, resulting in an increased GFAPdelta/alpha ratio. Mimicking this increase in GFAPdelta/alpha ratio in astrocytoma cell lines and comparing the subsequent transcriptomic changes with the changes in the patient tumours, we have identified a set of GFAPdelta/alpha ratio-regulated high-malignant and low malignant genes. These genes are involved in cell proliferation and protein phosphorylation, and their expression correlated with patient survival. We additionally show that changing the ratio of GFAPdelta/alpha, by targeting GFAP expression, affected expression of high-malignant genes. Our data imply that regulating GFAP expression and splicing are novel therapeutic targets that need to be considered as a treatment for astrocytoma. PMID- 29152146 TI - Breast tissue, oral and urinary microbiomes in breast cancer. AB - It has long been proposed that the gut microbiome contributes to breast carcinogenesis by modifying systemic estrogen levels. This is often cited as a possible mechanism linking breast cancer and high-fat, low-fiber diets as well as antibiotic exposure, associations previously identified in population-based studies. More recently, a distinct microbiome has been identified within breast milk and tissue, but few studies have characterized differences in the breast tissue microbiota of patients with and without cancer, and none have investigated distant body-site microbiomes outside of the gut. We hypothesize that cancerous breast tissue is associated with a microbiomic profile distinct from that of benign breast tissue, and that microbiomes of more distant sites, the oral cavity and urinary tract, will reflect dysbiosis as well. Fifty-seven women with invasive breast cancer undergoing mastectomy and 21 healthy women undergoing cosmetic breast surgery were enrolled. The bacterial 16S rRNA gene was amplified from urine, oral rinse and surgically collected breast tissue, sequenced, and processed through a QIIME-based bioinformatics pipeline. Cancer patient breast tissue microbiomes clustered significantly differently from non-cancer patients (p=0.03), largely driven by decreased relative abundance of Methylobacterium in cancer patients (median 0.10 vs. 0.24, p=0.03). There were no significant differences in oral rinse samples. Differences in urinary microbiomes were largely explained by menopausal status, with peri/postmenopausal women showing decreased levels of Lactobacillus. Independent of menopausal status, however, cancer patients had increased levels of gram-positive organisms including Corynebacterium (p<0.01), Staphylococcus (p=0.02), Actinomyces (p<0.01), and Propionibacteriaceae (p<0.01). Our observations suggest that the local breast microbiota differ in patients with and without breast cancer. Cancer patient urinary microbiomes were characterized by increased levels of gram-positive organisms in this study, but need to be further studied in larger cohorts. PMID- 29152147 TI - MicroRNA-370 inhibits the growth and metastasis of lung cancer by down-regulating epidermal growth factor receptor expression. AB - Abnormal microRNA-370 (miR-370) expression has been frequently reported in several types of cancers, including lung cancer. However, the role and molecular mechanisms of miR-370 in regulating the growth and metastasis of lung cancer have not been clarified. Here, we show higher levels of epidermal growth factor receptor (EGFR), but lower levels of miR-370 expression in most human lung cancer cells and non-tumor cells. Induction of miR-370 over-expression significantly reduced the levels of EGFR expression and the EGFR 3'untranslated region (UTR) regulated luciferase activity in XWLC-05 and H157 cells, suggesting that miR-370 may bind to the 3'UTR of EGFR mRNA. Compared with the control cells, induction of miR370 overexpression significantly inhibited the proliferation, clone formation capacity, migration and invasion of XWLC-05 and H157 cells while miR-370 inhibitor over-expression enhanced their tumor behaviors in vitro. Furthermore, miR-370 over-expression down-regulated the EGFR and hypoxia-inducible factor (HIF)-1alpha expression, and attenuated the extracellular single-regulated kinase (ERK)1/2 and AKT phosphorylation in XWLC-05 and H157 cells. In contrast, miR370 inhibitor over-expression increased the EGFR and HIF-1alpha expression as well as the ERK1/2 and AKT phosphorylation in XWLC-05 and H157 cells. Moreover, miR-370 over-expression significantly reduced the levels of EGFR and CD31 expression and inhibited the growth and lung metastasis of xenograft NSCLC tumors in mice. Our study indicates that miR-370 may bind to the 3'UTR of EGFR to inhibit EGFR expression and the growth, angiogenesis and metastasis of non-small cell lung cancer by down-regulating the ERK1/2 and AKT signaling. PMID- 29152148 TI - COX-2 expression in ovarian cancer: an updated meta-analysis. AB - The prognostic role of COX-2 expression in ovarian cancer patients has been studied for years, while results remain controversial. Thus we performed a meta analysis to evaluate the prognostic impact of COX-2 expression on survival of ovarian cancer patients. The databases PubMed, Embase and CNKI were searched. Summary hazard ratio (HR) and 95% confidence intervals (CIs) were calculated to analyze the correlations between COX-2 expression and overall survival (OS), and disease-free survival (DFS). A total of 1,867 patients from 18 studies were enrolled in the final analysis. The results showed that patients with higher COX 2 expression had a poor OS (HR: 1.48; 95% CI: 1.19-1.85) and DFS (HR: 1.81, 95% CI: 1.28-2.55). Subgroup analysis showed that there had significant associations between COX-2 expression and survival rate in most of the subgroups. Furthermore, there were significant associations between COX-2 expression and several clinical parameters such as FIGO stage, histological type and age. These results showed the patients with higher COX-2 expression had a significantly poorer survival rate, COX-2 expression had the potential to be a prognostic marker of ovarian cancer. PMID- 29152149 TI - The long non-coding RNA CRNDE acts as a ceRNA and promotes glioma malignancy by preventing miR-136-5p-mediated downregulation of Bcl-2 and Wnt2. AB - The colorectal neoplasia differentially expressed (CRNDE) gene encodes a long non coding RNA (lncRNA) that is the most unregulated among 129 lncRNAs differentially expressed in gliomas. In this study, we confirmed high CRNDE expression in clinical glioma specimens and observed through experiments in human glioma cell lines a novel molecular mechanism by which CRNDE may contribute to glioma pathogenesis. By inducing or silencing CRNDE expression, we detected a positive correlation between CRNDE levels and the proliferative, migratory, and invasive capacities of glioma cells, which were concomitant with a decreased apoptosis rate. Our experiments also suggest that these effects are mediated by downregulation of miR-136-5p, which correlated with the glioma WHO grade. Based on predicted CRNDE/miR-136-5p/mRNA interactions, both the mRNA and protein expression analyses suggested that miR-136-5p-mediated repression of Bcl-2 and Wnt2 underlies the pro-tumoral actions of CRNDE. We therefore propose that CRNDE functions as a competing endogenous RNA (ceRNA) that binds to and negatively regulates miR-136-5p, thereby protecting Bcl-2 and Wnt2 from miR-136-5p-mediated inhibition in glioma. PMID- 29152150 TI - Meta-analysis of the association between NLRP1 polymorphisms and the susceptibility to vitiligo and associated autoimmune diseases. AB - Genetic variants are linked to vitiligo and associated autoimmune diseases. We performed a meta-analysis to evaluate the effects of the rs12150220, rs2670660, and rs6502867 polymorphisms within the human NLR Family Pyrin Domain Containing 1 (NLRP1) gene. We initially identified 1,306 candidate articles through literature searches of Pubmed, WOS, Embase, CNKI, WANFANGI, Ovid, Scopus, and Cochrane in July 2017. After strict screening, we included 19 eligible case-control studies, and analyzed the data using Stata/SE 12.0 software. No difference between vitiligo cases and controls was detected for NLRP1 rs12150220, rs2670660, or rs6502867 under most genetic models [Passociation (P value of association test) > 0.05). With regard to vitiligo-associated autoimmune diseases, like Addison's disease, type 1 diabetes, or systemic lupus erythematosus, a decreased risk was detected for rs12150220 in the Caucasian subgroup under all models [Passociation < 0.05, odds ratio (OR) < 1]. No relationships were observed for other polymorphisms, including rs2670660, rs6502867, and the "A-A, G-T, G-A, A-T" haplotypes of rs2670660/rs12150220 (Passociation > 0.05). This meta-analysis demonstrates that within the Caucasian population, the NLRP1 rs12150220 polymorphism may correlate with a decreased risk of vitiligo-associated autoimmune diseases, especially autoimmune Addison's disease, type 1 diabetes, or systemic lupus erythematosus. PMID- 29152151 TI - Aliskiren for heart failure: a systematic review and meta-analysis of randomized controlled trials. AB - Objective: To systematically review and synthesize the currently available evidence of aliskiren for the treatment of heart failure. Materials and Methods: We systematically searched the Cochrane, Embase and PubMed databases to identify the randomized controlled trials (RCT) on the effects of aliskiren on heart failure. Data were synthesized with random effects model and presented in forest plot. Publication bias was evaluated with funnel plot. Heterogeneity was evaluated with Begg's test and Egger's test. Results: Of 124 studies, 6 RCT of 9845 heart failure patients were included for meta-analysis, including 3727 patients receiving aliskiren. Compared with the controls, aliskiren did not significantly reduce the all-cause mortality (1.02 [0.91-1.14], I2 = 0%) or cardiovascular mortality (1.02 [0.88-1.17], I2 = 7.3%) of heart failure patients. Total adverse events, renal dysfunction, hypotension and hyperkalaemia were not significantly different between the aliskiren group and control group. Begg's test and Egger's test indicated low heterogeneity. Funnel plots indicated low publication bias. Conclusions: Aliskiren, either used alone or combined with standard medical therapy, does not significantly reduce the all-cause mortality or cardiovascular mortality of heart failure patients. Although aliskiren does not cause statistically higher adverse events, its adverse events may not be neglected. PMID- 29152152 TI - Association of genetic variations in the lipid regulatory pathway genes FBXW7 and SREBPs with coronary artery disease among Han Chinese and Uygur Chinese populations in Xinjiang, China. AB - Background: Hyperlipidemia is a major risk factor for coronary artery disease (CAD). The current study was designed to explore the possible correlation between single nucleotide polymorphisms (SNPs) in the lipid homeostasis regulatory genes F-box and WD repeat domain-containing 7 (FBXW7) and sterol regulatory element binding proteins (SREBPs) with CAD among Han Chinese and Uygur Chinese populations in Xinjiang, China. Results: In the Uygur Chinese population, rs9902941 in SREBP-1 and rs10033601 in FBXW7 were found to be associated with CAD in a recessive model (TT vs. CT + CC, P = 0.032; GG vs. AG + AA, P = 0.010, respectively), and rs7288536 in SREBP-2 was found to be associated with CAD in an additive model (CT vs. CC + TT, P = 0.045). The difference was statistically significant in the Uygur Chinese population after multivariate adjustments [Odds ratio (OR) = 1.803, 95% confidence interval (CI): 1.036~3.137, P = 0.037; OR = 1.628, 95% CI: 1.080~2.454, P = 0.020; OR = 1.368; and 95% CI: 1.018~1.837, P = 0.037, respectively]. There were also significant interactions between the above mentioned models in the Uygur Chinese population. However, these relationships were not observed before or after multivariate adjustment in the Han Chinese population. Materials and Methods: A total of 1,312 Han Chinese (650 CAD patients and 662 controls) and 834 Uygur Chinese (414 CAD patients and 420 controls) were enrolled in this case-control study. Three SNPs (rs9902941 in SREBP-1, rs7288536 in SREBP-2 and rs10033601 in FBXW7) were selected and genotyped using the improved multiplex ligase detection reaction (iMLDR) method. Conclusions: The results of this study indicate that variations in the lipid regulatory pathway genes FBXW7 and SREBPs (rs9902941 in SREBP-1, rs7288536 in SREBP-2 and rs10033601 in FBXW7) are associated with CAD in the Uygur Chinese population in Xinjiang, China. PMID- 29152153 TI - Molecular determinants of prostate cancer metastasis. AB - Metastatic cancer remains largely incurable and fatal. The general course of cancer, from the initiation of primary tumor formation and progression to metastasis, is a multistep process wherein tumor cells at each step must display specific phenotypic features. Distinctive capabilities required for primary tumor initiation and growth form the foundation, and sometimes may remain critical, for subsequent metastases. These phenotypic features must remain easily malleable during the acquisition of additional capabilities unique and essential to the metastatic process such as dissemination to distant tissues wherein tumor cells interact with foreign microenvironments. Thus, the metastatic phenotype is a culmination of multiple genetic and epigenetic alterations and subsequent selection for favorable traits under the pressure of ever-changing tumor microenvironments. Although our understanding of the molecular programs that drive cancer metastasis are incomplete, increasing evidence suggests that successful metastatic colonization relies on the dissemination of cancer stem cells (CSCs) with tumor-regenerating capacity and adaptive programs for survival in distant organs. In the past 2-3 years, a myriad of novel molecular regulators and determinants of prostate cancer metastasis have been reported, and in this Perspective, we comprehensively review this body of literature and summarize recent findings regarding cell autonomous molecular mechanisms critical for prostate cancer metastasis. PMID- 29152154 TI - Cortactin in cancer cell migration and invasion. AB - Cortactin, a substrate of sarcoma (Src) kinases, is an actin-binding protein that is involved in cytoskeletal regulation, and is frequently overexpressed in cancer cells. Binding to the actin related protein 2/3 (Arp2/3) complex stimulates cortactin activity, which promotes F-actin nucleation and assembly. Cortactin promotes cancer cell migration and invasion, and plays a pivotal role in invadopodia formation and extra cellular matrix degradation. Overexpression of cortactin, by amplification of the chromosomal band 11q13, increases tumor aggressiveness. In this review, we report on the current knowledge and potential mechanisms of action of cortactin as a critical mediator of cancer cell migration and invasion. PMID- 29152155 TI - Chibby 1: a new component of beta-catenin-signaling in chronic myeloid leukemia. AB - Chibby 1 (CBY1) is a small and evolutionarily conserved protein, which act as beta-catenin antagonist. CBY1 is encoded by C22orf2 (22q13.1) Its antagonistic function on beta-catenin involves the direct interaction with: The C-terminal activation domain of beta-catenin, which hinders beta-catenin binding with Tcf/Lef transcription factors hence repressing beta-catenin transcriptional activation. 14-3-3 scaffolding proteins (sigma or xi), which drive CBY1 nuclear export into a stable tripartite complex with beta-catenin. The relative proximity of C22orf2 gene encoding for CBY1 to the BCR breakpoint on chromosome 22q11, whose translocation and rearrangement with the c-ABL is the causative event of chronic myeloid leukemia (CML), suggested that gene haploinsufficiency may play a role in the disease pathogenesis and progression. We found CBY1 down-modulation associated with the BCR-ABL1, promoted by transcriptional mechanisms (promoter hyper-methylation) and post-transcriptional events, addressing the protein towards proteasome-dependent degradation through SUMOylation. CBY1 reduced expression in clonal progenitors and, more importantly, in leukemic stem cells (LSC), is contingent upon the tyrosine kinase (TK) activity of BCR-ABL1 fusion protein. Accordingly, its induction by Imatinib (IM) and second generation TK inhibitors contributes to beta-catenin inactivation through multiple events encompassing the activation of endoplasmic reticulum (ER) stress-associated unfolded protein response (UPR) and autophagy, eventually leading to apoptotic death. These findings support the advantage of combined regimens including drugs targeting DNA epigenetics and/or proteasome to eradicate the BCR-ABL1+ hematopoiesis. PMID- 29152156 TI - Revisiting the linkage between ethnomedical use and development of new medicines: A novel plant collection strategy towards the discovery of anticancer agents. AB - The Vietnam-Laos International Cooperative Biodiversity Group (ICBG) based at the University of Illinois at Chicago (UIC) catalyzed a country-wide network of medicinal plant preserves (MPP) and medicinal biodiversity preserves (MBP) now established in ten provinces of the Lao People's Democratic Republic (Lao PDR), which are relied upon as protected sources of ethnomedicines for local villagers and traditional healers. In collaboration with the Lao PDR's Institute of Traditional Medicine (ITM), our ongoing P01 Program Project (Ohio State University) examined the anticancer bioprospecting potential for two of the most exhaustively inventoried of these sites: the Bolikhamxay MPP and the Xiengkhouang MBP. Guided by prior voucher specimens sourced from these preserves with an overwhelming emphasis on plants employed in traditional medicine, 201 distinct samples from 96 species were collected along with proper herbarium documentation. Aliquots of these plant samples were extracted in azeotropic ethanol and evaporated to dryness for initial biological evaluation. In six samples from six different species (2.99% of the collected samples, 6.25% of taxa) it was observed that extracts exhibited notable cytotoxicity against HT-29 colon adenocarcinoma cells. The wisdom behind the utilization of HT-29 cells in this preliminary biological screen is discussed. Furthermore, comparison of screening results based on longstanding considerations and ideological underpinnings of ethnobotanical vs. "random" biodiversity-based collection approaches is detailed herein. The results of this interdisciplinary study support the hypothesis that, by privileging the initial sample set in terms of human safety and pharmacological activity, ethnobotanically driven collection for biological screening efforts can produce leads unprecedented by the strict traditional usages of plants. PMID- 29152158 TI - Systematic search of Bayesian statistics in the field of psychotraumatology. PMID- 29152157 TI - A dysbiotic mycobiome dominated by Candida albicans is identified within oral squamous-cell carcinomas. AB - The aim of this study was to characterize the mycobiome associated with oral squamous-cell carcinoma (OSCC). DNA was extracted from 52 tissue biopsies (cases: 25 OSCC; controls: 27 intra-oral fibro-epithelial polyps [FEP]) and sequenced for the fungal internal transcribed spacer 2 region using IlluminaTM 2 x300bp chemistry. Merged reads were classified to species level using a BLASTN-algorithm with UNITE's named species sequences as reference. Downstream analyses were performed using QIIMETM and linear discriminant analysis effect size. A total of 364 species representing 160 genera and two phyla (Ascomycota and Basidiomycota) were identified, with Candida and Malassezia making up 48% and 11% of the average mycobiome, respectively. However, only five species and four genera were detected in >=50% of the samples. The species richness and diversity were significantly lower in OSCC. Genera Candida, Hannaella, and Gibberella were overrepresented in OSCC; Alternaria and Trametes were more abundant in FEP. Species-wise, Candida albicans, Candida etchellsii, and a Hannaella luteola-like species were enriched in OSCC, while aHanseniaspora uvarum-like species, Malassezia restricta, and Aspergillus tamarii were the most significantly abundant in FEP. In conclusion, a dysbiotic mycobiome dominated by C. albicans was found in association with OSCC, a finding worth further investigation. PMID- 29152159 TI - Tetris and Word games lead to fewer intrusive memories when applied several days after analogue trauma. AB - Background: Intrusive trauma memories are a key symptom of posttraumatic stress disorder (PTSD), so disrupting their recurrence is highly important. Intrusion development was hindered by visuospatial interventions administered up to 24 hours after analogue trauma. It is unknown whether interventions can be applied later, and whether modality or working-memory load are crucial factors. Objectives: This study tested: (1) whether a visuospatial task would lead to fewer intrusions compared to a reactivation-only group when applied after memory reactivation four days after analogue trauma exposure (extended replication), (2) whether both tasks (i.e. one aimed to be visuospatial, one more verbal) would lead to fewer intrusions than the reactivation-only group (intervention effect), and (3) whether supposed task modality (visuospatial or verbal) is a critical component (modality effect). Method: Fifty-four participants were randomly assigned to reactivation+Tetris (visuospatial), reactivation+Word games (verbal), or reactivation-only (no task). They watched an aversive film (day 0) and recorded intrusive memories of the film in diary A. On day 4, memory was reactivated, after which participants played Tetris, Word games, or had no task for 10 minutes. They then kept a second diary (B). Informative hypotheses were evaluated using Bayes factors. Results: Reactivation+Tetris and reactivation+Word games resulted in relatively fewer intrusions from the last day of diary A to the first day of diary B than reactivation-only (objective 1 and 2). Thus, both tasks were effective even when applied days after analogue trauma. Reactivation-only was not effective. Reactivation+Word games appeared to result in fewer intrusions than reactivation+Tetris (objective 3; modality effect), but this evidence was weak. Explorative analyses showed that Word games were more difficult than Tetris. Conclusions: Applying a task four days after the trauma film (during memory reconsolidation) was effective. The modality versus working-memory load issue is inconclusive. PMID- 29152160 TI - Traumatized refugees: identifying needs and facing challenges for mental health care. AB - In the past few years the number of refugees worldwide has increased dramatically. Many of them were traumatized in their homelands due to violent conflict or persecution, as well as during their flight, and are confronted with ongoing stressors in the exile countries. In order to contribute to enhancing the clinical knowledge, this special issue of the European Journal of Psychotraumatology focuses on traumatized refugees. It includes three review articles as well as four original articles on the mental health burden, screening instruments and interventions in different groups of refugees. The articles published in this special issue focus on important aspects of better understanding the needs of traumatized refugees, as well as on identifying and offering appropriate mental health care for this population. Future research recommendations are provided in the hope to contribute to improving mental health care strategies of this still underserved population. PMID- 29152161 TI - The hidden wounds of childhood trauma. PMID- 29152163 TI - Effect of aging and lifestyle on photoreceptors and retinal pigment epithelium: cross-sectional study in a healthy Danish population. AB - Photoreceptors and their supporting retinal pigment epithelium constitute the key functional parts of the retina. Here, a study was undertaken to show how aging and lifestyle factors affect the photoreceptor layer and the retinal pigment epithelium and Bruch's membrane complex (RPE-BM) in vivo in a healthy Danish population using spectral-domain optical coherence tomography. This was a cross sectional study of healthy humans aged >=50 years. All participants were interviewed for medical history and lifestyle factors. Maculae of all participants were scanned using spectral-domain optical coherence tomography. The thickness of the photoreceptor layer and the RPE-BM was measured on one eye from each participant. In 150 eyes of 150 participants, it was found that aging was associated with a decrease in the thickness of the photoreceptor layer (-0.143 MUm/year, P = 0.031) and an increase in the thickness of the RPE-BM layer (0.100 MUm/year, P = 0.029) at the foveal minimum. Regarding lifestyle factors, alcohol intake or BMI were not associated with any significant trend, but physical inactivity and smoking had effects on the photoreceptor layer (decreased thickness) and the RPE-BM layer (increased thickness) indicating an accelerated aging process of the macula. Taken together, aging affects photoreceptors and the RPE-BM, and these aging trends are accelerated in smokers and the physically inactive. PMID- 29152162 TI - Evaluation and optimization of microbial DNA extraction from fecal samples of wild Antarctic bird species. AB - Introduction: Advances in the development of nucleic acid-based methods have dramatically facilitated studies of host-microbial interactions. Fecal DNA analysis can provide information about the host's microbiota and gastrointestinal pathogen burden. Numerous studies have been conducted in mammals, yet birds are less well studied. Avian fecal DNA extraction has proved challenging, partly due to the mixture of fecal and urinary excretions and the deficiency of optimized protocols. This study presents an evaluation of the performance in avian fecal DNA extraction of six commercial kits from different bird species, focusing on penguins. Material and methods: Six DNA extraction kits were first tested according to the manufacturers' instructions using mallard feces. The kit giving the highest DNA yield was selected for further optimization and evaluation using Antarctic bird feces. Results: Penguin feces constitute a challenging sample type: most of the DNA extraction kits failed to yield acceptable amounts of DNA. The QIAamp cador Pathogen kit (Qiagen) performed the best in the initial investigation. Further optimization of the protocol resulted in good yields of high-quality DNA from seven bird species of different avian orders. Conclusion: This study presents an optimized approach to DNA extraction from challenging avian fecal samples. PMID- 29152164 TI - Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly. AB - Background: Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype. Methods: Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses. Results: Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis. Conclusions: Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated. PMID- 29152166 TI - A retrospective cohort study of treatment patterns among patients with metastatic soft tissue sarcoma in the US. AB - Background: Since treatment patterns in metastatic soft tissue sarcoma (mSTS) have not been studied subsequent to US approval of pazopanib in 2012, this study sought to examine mSTS treatment patterns by line of therapy, including regimen and duration of therapy. Methods: This retrospective study employed administrative claims from a large US health plan from 1/2006-9/2015. Adult mSTS patients were required to have an NCCN-recommended therapy and be continuously enrolled in the health plan during the study period. The most frequent regimens for distinct lines of therapy (LOT) were assessed. Sensitivity analyses evaluated changes to study findings using two alternate medical and pharmacy claims diagnostic algorithms to define the STS study population. Results: Among 555 patients with mSTS, mean age was 59 years and 54% were male. During the study period, 41% of patients initiated >= 2 LOTs; 16% had >= 3 LOTs and 5% had >= 4 LOTs. Docetaxel + gemcitabine was most common in LOT1, pazopanib in LOT2 and LOT3, and doxorubicin in LOT4. The five most common LOT1 regimens represented 53% of patients; among the remaining 47%, the most common regimen represented < 6% of patients. Among patients with pazopanib in LOT2 and LOT3, the most common prior regimen was docetaxel + gemcitabine (47% and 30% respectively). Kaplan-Meier estimation of median treatment duration overall for LOT1 was 3.5 months, while for LOT2 and LOT3, median treatment duration was 2.9 and 3.3 months, respectively. For both sensitivity analyses, patient demographic and clinical characteristics were similar to the original study population, and the five most frequently used regimens in LOT1 and LOT2 were similar among the three populations regardless of the population selection criteria employed. Conclusion: Choice of regimen by LOT among patients with mSTS is varied; < 65% of patients in any LOT received the five most common regimens. Pazopanib, the only approved targeted therapy, is primarily used in second and later lines of therapy and is mostly given post docetaxel + gemcitabine. PMID- 29152165 TI - Specificity of executive function and theory of mind performance in relation to attention-deficit/hyperactivity symptoms in autism spectrum disorders. AB - Background: Individuals with autism spectrum disorder (ASD) frequently demonstrate symptoms of attention-deficit/hyperactivity disorder (ADHD). Previous findings in children with ASD have suggested that these symptoms are associated with an impairment in executive function (EF) abilities. However, studies rarely considered this association within a single framework that controls for other related factors such as Theory of Mind (ToM) abilities and ASD symptoms. Methods: We used structural equation modeling to explore the relations among EF, ToM, and symptoms of ASD and ADHD, using data from a population-based sample of 100 adolescents with ASD and full-scale IQ >= 50 (the Special Needs and Autism Project (SNAP) cohort). The study used a multi-measure and multi-informant approach, where performance of inhibition, planning, switching, and working memory tasks indexed EF and performance on tasks involving mentalizing indexed ToM. Measures of ASD and ADHD symptoms included parent and teacher reports and direct observation of the children. Shared source of symptom reporting was accounted for with a parental rating latent factor indexed by symptom measures reported by parents. Results: Impairments in EF abilities were specifically associated with ADHD symptoms while impaired ToM was specifically associated with ASD symptoms, when accounting for the associations of each cognitive domain with the other factors. ASD and ADHD symptom latent factors were also correlated, but this association became nonsignificant once the shared source of reporting from parents was accounted for and within a model that also controlled for the correlated pathway between EF and ToM factors. The specific relations between the cognitive domains and behavioral symptoms remained even after controlling for IQ. Conclusions: In this ASD sample, symptoms of ADHD and ASD are underpinned by separate cognitive domains. The association between EF and ToM impairments is a likely partial explanation for the co-occurrence of ADHD symptoms in ASD, but the role of shared reporting effects is also important and supports the inclusion of independent informants and objective measures in future research. PMID- 29152167 TI - Differences in medication adherence are associated with beliefs about medicines in asthma and COPD. AB - Adherence to medication is crucial for achieving treatment control in chronic obstructive lung diseases. This study refers to the "necessity-concerns framework" and examines the associations between beliefs about medicines and self reported medication adherence in people with chronic obstructive lung disease. 402 patients (196 with asthma, 206 with COPD) participated in the study and completed a questionnaire comprising the "Beliefs about Medicines-Questionnaire" (BMQ) and the "Medication Adherence Report Scale" (MARS). Multivariable logistic regression analyses with the BMQ-subscales as explanatory and the dichotomized MARS-score as dependent variable were computed for the asthma and the COPD sample, respectively, and adjusted for potentially confounding variables. 19% of asthma patients and 34% of COPD patients were completely adherent to their prescribed medication. While specific beliefs about the necessity of medicines were positively associated with medication adherence both in patients with asthma and with COPD, general beliefs about harm and overuse of medicines by doctors were negatively associated with medication adherence only among patients with asthma. The findings of this study suggest that patients' specific beliefs about the necessity of medicines represent an important modifiable target for improving patient-doctor consultations when prescribing medicines. PMID- 29152168 TI - Pollination by the locally endangered island flying fox (Pteropus hypomelanus) enhances fruit production of the economically important durian (Durio zibethinus). AB - Fruit bats provide valuable pollination services to humans through a unique coevolutionary relationship with chiropterophilous plants. However, chiropterophily in the Old World and the pollination roles of large bats, such as flying foxes (Pteropus spp., Acerodon spp., Desmalopex spp.), are still poorly understood and require further elucidation. Efforts to protect these bats have been hampered by a lack of basic quantitative information on their role as ecosystem service providers. Here, we investigate the role of the locally endangered island flying fox Pteropus hypomelanus in the pollination ecology of durian (Durio zibethinus), an economically important crop in Southeast Asia. On Tioman Island, Peninsular Malaysia, we deployed 19 stations of paired infrared camera and video traps across varying heights at four individual flowering trees in a durian orchard. We detected at least nine species of animal visitors, but only bats had mutualistic interactions with durian flowers. There was a clear vertical stratification in the feeding niches of flying foxes and nectar bats, with flying foxes feeding at greater heights in the trees. Flying foxes had a positive effect on mature fruit set and therefore serve as important pollinators for durian trees. As such, semi-wild durian trees-particularly tall ones-may be dependent on flying foxes for enhancing reproductive success. Our study is the first to quantify the role of flying foxes in durian pollination, demonstrating that these giant fruit bats may have far more important ecological, evolutionary, and economic roles than previously thought. This has important implications and can aid efforts to promote flying fox conservation, especially in Southeast Asian countries. PMID- 29152169 TI - Land use types influenced avian assemblage structure in a forest-agriculture landscape in Ghana. AB - The conservation of biodiversity within tropical forest regions does not lie only in the maintenance of natural forest areas, but on conservation strategies directed toward agricultural land types within which they are embedded. This study investigated variations in bird assemblages of different functional groups of forest-dependent birds in three agricultural land types, relative to distance from the interior of 34 tropical forest patches of varying sizes. Point counts were used to sample birds at each study site visited. Data from counts were used to estimate species richness, species evenness, and Simpson's diversity of birds. Mean species richness, evenness, and diversity were modeled as responses and as a function of agricultural land type, distance from the forest interior and three site-scale vegetation covariates (density of large trees, fruiting trees, and patch size) using generalized linear mixed-effect models. Mean observed species richness of birds varied significantly within habitat types. Mean observed species richness was highest in forest interior sites while sites located in farm centers recorded the lowest mean species richness. Species richness of forest specialists was strongly influenced by the type of agricultural land use. Fallow lands, density of large trees, and patch size strongly positively influenced forest specialists. Insectivorous and frugivorous birds were more species-rich in fallow lands while monoculture plantations favored nectarivorous birds. Our results suggest that poor agricultural practices can lead to population declines of forest-dependent birds particularly specialist species. Conservation actions should include proper land use management that ensures heterogeneity through retention of native tree species on farms in tropical forest-agriculture landscapes. PMID- 29152170 TI - Responses of two marine top predators to an offshore wind farm. AB - Quantifying the likely effects of offshore wind farms on wildlife is fundamental before permission for development can be granted by any Determining Authority. The effects on marine top predators from displacement from important habitat are key concerns during offshore wind farm construction and operation. In this respect, we present evidence for no significant displacement from a UK offshore wind farm for two broadly distributed species of conservation concern: common guillemot (Uria aalge) and harbor porpoise (Phocoena phocoena). Data were collected during boat-based line transect surveys across a 360 km2 study area that included the Robin Rigg offshore wind farm. Surveys were conducted over 10 years across the preconstruction, construction, and operational phases of the development. Changes in guillemot and harbor porpoise abundance and distribution in response to offshore wind farm construction and operation were estimated using generalized mixed models to test for evidence of displacement. Both common guillemot and harbor porpoise were present across the Robin Rigg study area throughout all three development phases. There was a significant reduction in relative harbor porpoise abundance both within and surrounding the Robin Rigg offshore wind farm during construction, but no significant difference was detected between the preconstruction and operational phases. Relative common guillemot abundance remained similar within the Robin Rigg offshore wind farm across all development phases. Offshore wind farms have the potential to negatively affect wildlife, but further evidence regarding the magnitude of effect is needed. The empirical data presented here for two marine top predators provide a valuable addition to the evidence base, allowing future decision making to be improved by reducing the uncertainty of displacement effects and increasing the accuracy of impact assessments. PMID- 29152171 TI - Plant-facilitated effects of exotic earthworm Pontoscolex corethrurus on the soil carbon and nitrogen dynamics and soil microbial community in a subtropical field ecosystem. AB - Earthworms and plants greatly affect belowground properties; however, their combined effects are more attractive based on the ecosystem scale in the field condition. To address this point, we manipulated earthworms (exotic endogeic species Pontoscolex corethrurus) and plants (living plants [native tree species Evodia lepta] and artificial plants) to investigate their combined effects on soil microorganisms, soil nutrients, and soil respiration in a subtropical forest. The manipulation of artificial plants aimed to simulate the physical effects of plants (e.g., shading and interception of water) such that the biological effects of plants could be evaluated separately. We found that relative to the controls, living plants but not artificial plants significantly increased the ratio of fungal to bacterial phospholipid fatty acids (PLFAs) and fungal PLFAs. Furthermore, earthworms plus living plants significantly increased the soil respiration and decreased the soil NH 4+-N, which indicates that the earthworm effects on the associated carbon, and nitrogen processes were greatly affected by living plants. The permutational multivariate analysis of variance results also indicated that living plants but not earthworms or artificial plants significantly changed the soil microbial community. Our results suggest that the effects of plants on soil microbes and associated soil properties in this study were largely explained by their biological rather than their physical effects. PMID- 29152172 TI - A quadratic correlation between long-term mean group size and group density in a cooperatively breeding passerine. AB - Both mean group size (MGS) and mean group density (MGD) are critical indices to characterize a population of cooperatively breeding birds. When a population reaches its carrying capacity, both long-term MGS and long-term MGD will remain relatively stable. However, there has been little study of how these two variables relate. The Masked laughingthrush Garrulax perspicillatus is a cooperatively breeding bird living in fragmented habitats. During 2010 and 2012 2016, we used song playback to observe and confirm the group sizes and territory ranges of the birds and the data of bird presence to determine habitat suitability. By grouping the nearest territories according to their geographical coordinates, we divided the whole study area into 12 subareas and the whole population into 12 subpopulations. Then, we calculated both MGS and MGD for different time durations for each subpopulation. Finally, using MGD as independent variable and MGS as the dependent variable, we explored the correlations between MGS and MGD by fitting quadratic functions and modeling quadratic regression. Both MGS and MGD were averaged for different time durations and were cross-related. Our results show that the MGS for more than 2 years significantly correlated with MGD for more than 3 years in a reverse parabolic shape, differing from that of short-term effects. Our findings suggest that long term MGD is a better predictor of long-term habitat quality and that long-term MGS is determined by long-term habitat quality in Masked Laughingthrushes. Based on above findings, we can infer that: (1) Long-term habitat quality determines the long-term MGS, but it sets no prerequisite for the status and source of group members; (2) Long-term MGS in certain populations is adapted to the corresponding level of long-term habitat quality, it facilitates us to predict the helper effects on current or future survival or reproduction in different situations. These findings and inferences are both helpful for us to understand the evolution of cooperative breeding. PMID- 29152173 TI - State-space mark-recapture estimates reveal a recent decline in abundance of North Atlantic right whales. AB - North Atlantic right whales (Eubalaena glacialis Muller 1776) present an interesting problem for abundance and trend estimation in marine wildlife conservation. They are long lived, individually identifiable, highly mobile, and one of the rarest of cetaceans. Individuals are annually resighted at different rates, primarily due to varying stay durations among several principal habitats within a large geographic range. To date, characterizations of abundance have been produced that use simple accounting procedures with differing assumptions about mortality. To better characterize changing abundance of North Atlantic right whales between 1990 and 2015, we adapted a state-space formulation with Jolly-Seber assumptions about population entry (birth and immigration) to individual resighting histories and fit it using empirical Bayes methodology. This hierarchical model included accommodation for the effect of the substantial individual capture heterogeneity. Estimates from this approach were only slightly higher than published accounting procedures, except for the most recent years (when recapture rates had declined substantially). North Atlantic right whales' abundance increased at about 2.8% per annum from median point estimates of 270 individuals in 1990 to 483 in 2010, and then declined to 2015, when the final estimate was 458 individuals (95% credible intervals 444-471). The probability that the population's trajectory post-2010 was a decline was estimated at 99.99%. Of special concern was the finding that reduced survival rates of adult females relative to adult males have produced diverging abundance trends between sexes. Despite constraints in recent years, both biological (whales' distribution changing) and logistical (fewer resources available to collect individual photo identifications), it is still possible to detect this relatively recent, small change in the population's trajectory. This is thanks to the massive dataset of individual North Atlantic right whale identifications accrued over the past three decades. Photo-identification data provide biological information that allows more informed inference on the status of this species. PMID- 29152174 TI - Tree diversity drives diversity of arthropod herbivores, but successional stage mediates detritivores. AB - The high tree diversity of subtropical forests is linked to the biodiversity of other trophic levels. Disentangling the effects of tree species richness and composition, forest age, and stand structure on higher trophic levels in a forest landscape is important for understanding the factors that promote biodiversity and ecosystem functioning. Using a plot network spanning gradients of tree diversity and secondary succession in subtropical forest, we tested the effects of tree community characteristics (species richness and composition) and forest succession (stand age) on arthropod community characteristics (morphotype diversity, abundance and composition) of four arthropod functional groups. We posit that these gradients differentially affect the arthropod functional groups, which mediates the diversity, composition, and abundance of arthropods in subtropical forests. We found that herbivore richness was positively related to tree species richness. Furthermore, the composition of herbivore communities was associated with tree species composition. In contrast, detritivore richness and composition was associated with stand age instead of tree diversity. Predator and pollinator richness and abundance were not strongly related to either gradient, although positive trends with tree species richness were found for predators. The weaker effect of tree diversity on predators suggests a cascading diversity effect from trees to herbivores to predators. Our results suggest that arthropod diversity in a subtropical forest reflects the net outcome of complex interactions among variables associated with tree diversity and stand age. Despite this complexity, there are clear linkages between the overall richness and composition of tree and arthropod communities, in particular herbivores, demonstrating that these trophic levels directly impact each other. PMID- 29152175 TI - Divergent scaling of respiration rates to nitrogen and phosphorus across four woody seedlings between different growing seasons. AB - Empirical studies indicate that the exponents governing the scaling of plant respiration rates (R) with respect to biomass (M) numerically vary between three fourth for adult plants and 1.0 for seedlings and saplings and are affected by nitrogen (N) and phosphorus (P) content. However, whether the scaling of R with respect to M (or N and P) varies among different phylogenetic groups (e.g., gymnosperms vs. angiosperms) or during the growing and dormant seasons remains unclear. We measured the whole-plant R and M, and N and P content of the seedlings of four woody species during the growing season (early October) and the dormant season (January). The data show that (i) the scaling exponents of R versus M, R versus N, and R versus P differed significantly among the four species, but (ii), not between the growing and dormant seasons for each of the four species, although (iii) the normalization constants governing the scaling relationships were numerically greater for the growing season compared to the dormant season. In addition, (iv) the scaling exponents of R versus M, R versus N, and R versus P were numerically larger for the two angiosperm species compared to those of the two gymnosperm species, (v) the interspecific scaling exponents for the four species were greater during the growing season than in the dormant season, and (vi), interspecifically, P scaled nearly isometric with N content. Those findings indicate that the metabolic scaling relationships among R, M, N, and P manifest seasonal variation and differ between angiosperm and gymnosperm species, that is, there is no single, canonical scaling exponent for the seedlings of woody species. PMID- 29152176 TI - Phytophagous insect oviposition shifts in response to probability of flower abortion owing to the presence of basal fruits. AB - Phytophagous insects use a wide range of indicators or associated cues to avoid laying eggs in sites where offspring survival is low. For insects that lay eggs in flowers, these unsuitable sites may be created by the host plant's resource allocation to flowers. In the sequentially flowering host plant, Yucca glauca, late-opening distal flowers are more likely to be aborted in the presence of already-initiated basal fruits because they are strong resource sinks. If flowers are aborted, all eggs of the phytophagous insect, Tegeticula yuccasella, within the flower die. We used the phytophagous insect T. yuccasella that lays eggs in and pollinates host plant Y. glauca flowers to test the hypothesis that phytophagous insect females are less likely to invest eggs in host plant flowers if basal fruits are present because they are more likely to be aborted. We also investigated potential predictors of arrival of T. yuccasella at inflorescences at the onset of flowering. These factors may influence a phytophagous insect's decisions to select oviposition sites. We carried out a behavioral experiment using wild-caught T. yuccasella females on manipulated inflorescences with distal flowers with basal fruits and without fruits. As potential predictors of T. yuccasella arriving at inflorescences, we used floral display size and day of onset of flowering. In support of our hypothesis, our experimental results showed that T. yuccasella was significantly less likely to oviposit in distal flowers on inflorescences with basal fruits. We also found that T. yuccasella arrival was higher at inflorescences with larger floral display size and earlier in the flowering season. These findings uncover a novel indicator of unsuitable oviposition sites-the presence of basal fruits, that phytophagous insects use to make oviposition decisions. Further, our study contributes to the growing body of evidence that shows that females prefer sites that increase the probability of survival of their offspring. PMID- 29152177 TI - Maternal effects in vulnerability to eye-parasites and correlations between behavior and parasitism in juvenile Arctic charr. AB - Hatchery-reared fish show high mortalities after release to the wild environment. Explanations for this include potentially predetermined genetics, behavioral, and physiological acclimation to fish farm environments, and increased vulnerability to predation and parasitism in the wild. We studied vulnerability to Diplostomum spp. parasites (load of eye flukes in the lenses), immune defense (relative spleen size) and antipredator behaviors (approaches toward predator odor, freezing, and swimming activity) in hatchery-reared juvenile Arctic charr (Salvelinus alpinus) using a nested mating design. Fish were exposed to eye-fluke larvae via the incoming water at the hatchery. Fish size was positively associated with parasite load, but we did not find any relationship between relative spleen size and parasitism. The offspring of different females showed significant variation in their parasite load within sires, implying a dam effect in the vulnerability to parasites. However, the family background did not have any effect on spleen size. In the mean sire level over dams, the fish from the bolder (actively swimming) families in the predator trials suffered higher loads of eye flukes than those from more cautiously behaving families. Thus, the results indicate potentially maternally inherited differences in vulnerability to eye-fluke parasites, and that the vulnerability to parasites and behavioral activity are positively associated with each other at the sire level. This could lead to artificial and unintentional selection for increased vulnerability to both parasitism and predation if these traits are favored in fish farm environments. PMID- 29152178 TI - The genetics of phenotypic plasticity. XV. Genetic assimilation, the Baldwin effect, and evolutionary rescue. AB - We used an individual-based simulation model to examine the role of phenotypic plasticity on persistence and adaptation to two patterns of environmental variation, a single, abrupt step change and continual, linear change. Our model tested the assumptions and predictions of the theory of genetic assimilation, explored the evolutionary dynamics of the Baldwin effect, and provided expectations for the evolutionary response to climate change. We found that genetic assimilation as originally postulated is not likely to occur because the replacement of plasticity by fixed genetic effects takes much longer than the environment is likely to remain stable. On the other hand, trait plasticity as an enhancement to continual evolutionary change may be an important evolutionary mechanism as long as plasticity has little or no costs. Whether or not plasticity helps or hinders evolutionary rescue following a step change in the environment depends on whether plasticity is costly. For linear environmental change, noncostly plasticity always decreases extinction rates, while costly plasticity can create a fitness drag and increase the chance of extinction. Thus, with changing climates plasticity can enhance adaptation and prevent extinction under some conditions, but not others. PMID- 29152179 TI - Flight is the key to postprandial blood glucose balance in the fruit bats Eonycteris spelaea and Cynopterus sphinx. AB - Excessive sugar consumption could lead to high blood glucose levels that are harmful to mammalian health and life. Despite consuming large amounts of sugar rich food, fruit bats have a longer lifespan, raising the question of how these bats overcome potential hyperglycemia. We investigated the change of blood glucose level in nectar-feeding bats (Eonycteris spelaea) and fruit-eating bats (Cynopterus sphinx) via adjusting their sugar intake and time of flight. We found that the maximum blood glucose level of C. sphinx was higher than 24 mmol/L that is considered to be pathological in other mammals. After C. sphinx bats spent approximately 75% of their time to fly, their blood glucose levels dropped markedly, and the blood glucose of E. spelaea fell to the fast levels after they spent 70% time of fly. Thus, the level of blood glucose elevated with the quantity of sugar intake but declined with the time of flight. Our results indicate that high-intensive flight is a key regulator for blood glucose homeostasis during foraging. High-intensive flight may confer benefits to the fruit bats in foraging success and behavioral interactions and increases the efficiency of pollen and seed disposal mediated by bats. PMID- 29152180 TI - Varying congruence among spatial patterns of vascular plants and vertebrates based on habitat groups. AB - Proxies are adopted to represent biodiversity patterns due to inadequate information for all taxa. Despite the wide use of proxies, their efficacy remains unclear. Previous analyses focused on overall species richness for fewer groups, affecting the generality and depth of inference. Biological taxa often exhibit very different habitat preferences. Habitat groupings may be an appropriate approach to advancing the study of richness patterns. Diverse geographical patterns of species richness and their potential mechanisms were then examined for habitat groups. We used a database of the spatial distribution of 32,824 species of mammals, birds, reptiles, amphibians and plants from 2,376 counties across China, divided the five taxa into 30 habitat groups, calculated Spearman correlations of species richness among taxa and habitat groups, and tested five hypotheses about richness patterns using multivariate models. We identified one major group [i.e., forest- and shrub-dependent (FS) groups], and some minor groups such as grassland-dependent vertebrates and desert-dependent vertebrates. There were mostly high or moderate correlations among FS groups, but mostly low or moderate correlations among other habitat groups. The prominent variables differed among habitat groups of the same taxon, such as birds and reptiles. The sets of predictors were also different within the same habitat, such as forests, grasslands, and deserts. Average correlations among the same habitat groups of vertebrates and among habitat groups of a single taxon were low or moderate, except correlations among FS groups. The sets of prominent variables of species richness differed strongly among habitat groups, although elevation range was the most important variable for most FS groups. The ecological and evolutionary processes that underpin richness patterns might be disparate among different habitat groups. Appropriate groupings based on habitats could reveal important patterns of richness gradients and valuable biodiversity components. PMID- 29152181 TI - Projecting species' vulnerability to climate change: Which uncertainty sources matter most and extrapolate best? AB - Species distribution models (SDMs) are commonly used to assess potential climate change impacts on biodiversity, but several critical methodological decisions are often made arbitrarily. We compare variability arising from these decisions to the uncertainty in future climate change itself. We also test whether certain choices offer improved skill for extrapolating to a changed climate and whether internal cross-validation skill indicates extrapolative skill. We compared projected vulnerability for 29 wetland-dependent bird species breeding in the climatically dynamic Prairie Pothole Region, USA. For each species we built 1,080 SDMs to represent a unique combination of: future climate, class of climate covariates, collinearity level, and thresholding procedure. We examined the variation in projected vulnerability attributed to each uncertainty source. To assess extrapolation skill under a changed climate, we compared model predictions with observations from historic drought years. Uncertainty in projected vulnerability was substantial, and the largest source was that of future climate change. Large uncertainty was also attributed to climate covariate class with hydrological covariates projecting half the range loss of bioclimatic covariates or other summaries of temperature and precipitation. We found that choices based on performance in cross-validation improved skill in extrapolation. Qualitative rankings were also highly uncertain. Given uncertainty in projected vulnerability and resulting uncertainty in rankings used for conservation prioritization, a number of considerations appear critical for using bioclimatic SDMs to inform climate change mitigation strategies. Our results emphasize explicitly selecting climate summaries that most closely represent processes likely to underlie ecological response to climate change. For example, hydrological covariates projected substantially reduced vulnerability, highlighting the importance of considering whether water availability may be a more proximal driver than precipitation. However, because cross-validation results were correlated with extrapolation results, the use of cross-validation performance metrics to guide modeling choices where knowledge is limited was supported. PMID- 29152182 TI - Selective regimes and functional anatomy in the mustelid forelimb: Diversification toward specializations for climbing, digging, and swimming. AB - Anatomical traits associated with locomotion often exhibit specializations for ecological niche, suggesting that locomotor specializations may constitute selective regimes acting on limb skeletal traits. To test this, I sampled 42 species of Mustelidae, encompassing climbing, digging, and swimming specialists, and determined whether trait variation reflects locomotor specialization by performing a principal components analysis on 14 forelimb traits. In addition to Brownian motion models, three Ornstein-Uhlenbeck models of selective regimes were applied to PC scores describing trait variation among mustelids: one without a priori defined phenotypic optima, one with optima based upon locomotor habit, and one with a single phenotypic optimum. PC1, which explained 43.8% of trait variance, represented a trade-off in long bone gracility and deltoid ridge length vs. long robustness and olecranon process length and distinguished between climbing specialists and remaining mustelids. PC2, which explained 17.4% of trait variance, primarily distinguished the sea otter from other mustelids. Best fitting trait diversification models are selective regimes differentiating between scansorial and nonscansorial mustelids (PC1) and selective regimes distinguishing the sea otter and steppe polecat from remaining mustelids (PC2). Phylogenetic half-life values relative to branch lengths suggest that, in spite of a strong rate of adaptation, there is still the influence of past trait values. However, simulations of likelihood ratios suggest that the best fitting models are not fully adequate to explain morphological diversification within extant mustelids. PMID- 29152183 TI - Genetic mating system and mate selection in smallmouth bass. AB - Mating systems are an important factor influencing the variance in reproductive success among individuals within natural populations and thus have important ecological and evolutionary implications. We used molecular pedigree reconstruction techniques with microsatellite DNA data to characterize the genetic mating system and mate selection in adult smallmouth bass spawning in Lake Opeongo. The genetic mating system of smallmouth bass in this system can be characterized as predominantly monogamous with a low rate of polygynandry particularly among larger individuals. Iteroparous individuals showed a complete absence of interannual mate fidelity, presumably due to the low annual return rate of spawning adults. Within a season, individuals from both sexes pursued additional mating opportunities with males showing greater variance in mate number than females. Female mate selection appeared to be largely random with little evidence for elevated levels of inbreeding in this population. Multiple mating females pursued additional males to whom they were less related than the first male with which they spawned within a given season, however, this pattern varied among years. The mating pattern observed in this population would likely limit the strength of sexual selection and thus could account for the lack of sexual dimorphism and the absence of alternative reproductive tactics in this species. PMID- 29152184 TI - Last and corresponding authorship practices in ecology. AB - Authorship is intended to convey information regarding credit and responsibility for manuscripts. However, while there is general agreement within ecology that the first author is the person who contributed the most to a particular project, there is less agreement regarding whether being last author is a position of significance and regarding what is indicated by someone being the corresponding author on a manuscript. Using an analysis of papers published in American Naturalist, Ecology, Evolution, and Oikos, I found that: (1) the number of authors on papers is increasing over time; (2) the proportion of first authors as corresponding author has increased over time, as has the proportion of last authors as corresponding author; (3) 84% of papers published in 2016 had the first author as corresponding author; and (4) geographic regions differed in the likelihood of having the first (or last) author as corresponding author. I also carried out an online survey to better understand views on last and corresponding authorship. This survey revealed that most ecologists view the last author as the "senior" author on a paper (i.e., the person who runs the research group in which most of the work was carried out), and most ecologists view the corresponding author as the person taking full responsibility for a paper. However, there was substantial variation in views on authorship, especially corresponding authorship. Given these results, I suggest that discussions of authorship have as their starting point that the first author will be corresponding author and the senior author will be last author. I also suggest ways of deciding author order in cases where two senior authors contributed equally. PMID- 29152185 TI - Naming diversity in an evolutionary context: Phylogenetic definitions of the Roucela clade (Campanulaceae/Campanuloideae) and the cryptic taxa within. AB - In recent times, evolution has become a central tenet of taxonomy, but nomenclature has consistently been decoupled from the tree-thinking process, often leading to significant issues in reconciling traditional (Linnaean) names with clades in the Tree of Life. Recent evolutionary studies on the Roucela clade, a group of endemic plants found in the Mediterranean Basin, motivated the establishment of phylogenetic concepts to formally anchor clade names on the Campanuloideae (Campanulaceae) tree. These concepts facilitate communication of clades that approximate traditionally defined groups, in addition to naming newly discovered cryptic diversity in a phylogenetic framework. PMID- 29152186 TI - Cumulative effects of climate and landscape change drive spatial distribution of Rocky Mountain wolverine (Gulo gulo L.). AB - Contemporary landscapes are subject to a multitude of human-derived stressors. Effects of such stressors are increasingly realized by population declines and large-scale extirpation of taxa worldwide. Most notably, cumulative effects of climate and landscape change can limit species' local adaptation and dispersal capabilities, thereby reducing realized niche space and range extent. Resolving the cumulative effects of multiple stressors on species persistence is a pressing challenge in ecology, especially for declining species. For example, wolverines (Gulo gulo L.) persist on only 40% of their historic North American range. While climate change has been shown to be a mechanism of range retractions, anthropogenic landscape disturbance has been recently implicated. We hypothesized these two interact to effect declines. We surveyed wolverine occurrence using camera trapping and genetic tagging at 104 sites at the wolverine range edge, spanning a 15,000 km2 gradient of climate, topographic, anthropogenic, and biotic variables. We used occupancy and generalized linear models to disentangle the factors explaining wolverine distribution. Persistent spring snow pack-expected to decrease with climate change-was a significant predictor, but so was anthropogenic landscape change. Canid mesocarnivores, which we hypothesize are competitors supported by anthropogenic landscape change, had comparatively weaker effect. Wolverine population declines and range shifts likely result from climate change and landscape change operating in tandem. We contend that similar results are likely for many species and that research that simultaneously examines climate change, landscape change, and the biotic landscape is warranted. Ecology research and species conservation plans that address these interactions are more likely to meet their objectives. PMID- 29152187 TI - Genetic diversity, population structure, and traditional culture of Camellia reticulata. AB - Camellia reticulata is an arbor tree that has been cultivated in southwestern China by various sociolinguistic groups for esthetic purposes as well as to derive an edible seed oil. This study examined the influence of management, socio economic factors, and religion on the genetic diversity patterns of Camellia reticulata utilizing a combination of ethnobotanical and molecular genetic approaches. Semi-structured interviews and key informant interviews were carried out with local communities in China's Yunnan Province. We collected plant material (n = 190 individuals) from five populations at study sites using single dose AFLP markers in order to access the genetic diversity within and between populations. A total of 387 DNA fragments were produced by four AFLP primer sets. All DNA fragments were found to be polymorphic (100%). A relatively high level of genetic diversity was revealed in C. reticulata samples at both the species (Hsp = 0.3397, Isp = 0.5236) and population (percentage of polymorphic loci = 85.63%, Hpop = 0.2937, Ipop = 0.4421) levels. Findings further revealed a relatively high degree of genetic diversity within C. reticulata populations (Analysis of Molecular Variance = 96.31%). The higher genetic diversity within populations than among populations of C. reticulata from different geographies is likely due to the cultural and social influences associated with its long cultivation history for esthetic and culinary purposes by diverse sociolinguistic groups. This study highlights the influence of human management, socio-economic factors, and other cultural variables on the genetic and morphological diversity of C. reticulata at a regional level. Findings emphasize the important role of traditional culture on the conservation and utilization of plant genetic diversity. PMID- 29152188 TI - Prey use by dingoes in a contested landscape: Ecosystem service provider or biodiversity threat? AB - In Australia, dingoes (Canis lupus dingo) have been implicated in the decline and extinction of a number of vertebrate species. The lowland Wet Tropics of Queensland, Australia is a biologically rich area with many species of rainforest restricted vertebrates that could be threatened by dingoes; however, the ecological impacts of dingoes in this region are poorly understood. We determined the potential threat posed by dingoes to native vertebrates in the lowland Wet Tropics using dingo scat/stomach content and stable isotope analyses of hair from dingoes and potential prey species. Common mammals dominated dingo diets. We found no evidence of predation on threatened taxa or rainforest specialists within our study areas. The most significant prey species were northern brown bandicoots (Isoodon macrourus), canefield rats (Rattus sordidus), and agile wallabies (Macropus agilis). All are common species associated with relatively open grass/woodland habitats. Stable isotope analysis suggested that prey species sourced their nutrients primarily from open habitats and that prey choice, as identified by scat/stomach analysis alone, was a poor indicator of primary foraging habitats. In general, we find that prey use by dingoes in the lowland Wet Tropics does not pose a major threat to native and/or threatened fauna, including rainforest specialists. In fact, our results suggest that dingo predation on "pest" species may represent an important ecological service that outweighs potential biodiversity threats. A more targeted approach to managing wild canids is needed if the ecosystem services they provide in these contested landscapes are to be maintained, while simultaneously avoiding negative conservation or economic impacts. PMID- 29152189 TI - Intraspecific trait variation can weaken interspecific trait correlations when assessing the whole-plant economic spectrum. AB - The worldwide plant economic spectrum hypothesis predicts that leaf, stem, and root traits are correlated across vascular plant species because carbon gain depends on leaves being adequately supplied with water and nutrients, and because construction of each organ involves a trade-off between performance and persistence. Despite its logical and intuitive appeal, this hypothesis has received mixed empirical support. If traits within species diverge in their responses to an environmental gradient, then interspecific trait correlations could be weakened when measured in natural ecosystems. To test this prediction, we measured relative growth rates (RGR) and seven functional traits that have been shown to be related to fluxes of water, nutrients, and carbon across 56 functionally diverse tree species on (1) juveniles in a controlled environment, (2) juveniles in forest understories, and (3) mature trees in forests. Leaf, stem, and fine root traits of juveniles grown in a controlled environment were closely correlated with each other, and with RGR. Remarkably, the seven leaf, stem, and fine root tissue traits spanned a single dimension of variation when measured in the controlled environment. Forest-grown juveniles expressed lower leaf mass per area, but higher wood and fine root tissue density, than greenhouse grown juveniles. Traits and growth rates were decoupled in forest-grown juveniles and mature trees. Our results indicate that constraints exist on the covariation, not just the variation, among vegetative plant organs; however, divergent responses of traits within species to environmental gradients can mask interspecific trait correlations in natural environments. Correlations among organs and relationships between traits and RGR were strong when plants were compared in a standardized environment. Our results may reconcile the discrepancies seen among studies, by showing that if traits and growth rates of species are compared across varied environments, then the interorgan trait correlations observed in controlled conditions can weaken or disappear. PMID- 29152190 TI - Sex and weaponry: The distribution of toxin-storage glands on the bodies of male and female cane toads (Rhinella marina). AB - The parotoid macroglands of bufonid anurans store (and can expel) large volumes of toxic secretions and have attracted detailed research. However, toxins also are stored in smaller glands that are distributed on the limbs and dorsal surface of the body. Female and male cane toads (Rhinella marina) differ in the location of toxin-storage glands and the extent of glandular structures. Female toads store a larger proportion of their toxins in the parotoids than males as well as (to a lesser extent) in smaller glands on the forelimbs. Males have smaller and more elongate parotoids than females, but glands cover more of the skin surface on their limbs (especially hindlimbs) and dorsal surface. The delay to toxin exudation in response to electrostimulation varied among glands in various parts of the body, and did so differently in males than in females. The spatial distribution of toxin glands differs between the sexes even in toads that have been raised under standardized conditions in captivity; hence, the sexual dimorphism is due to heritable factors rather than developmentally plastic responses to ecological (e.g., habitat, predation risk) differences between the sexes. The selective advantages of this sexual dimorphism remain unclear. A priori, we might expect to see toxin widely dispersed across any part of the body likely to be contacted by a predator; and a wide distribution also would be expected if the gland secretions have other (e.g., male-male rivalry) functions. Why, then, is toxin concentrated in the parotoids, especially in female toads? That concentration may enhance the effectiveness of frontal displays to deter predation and also may facilitate the transfer of stored toxins to eggs. PMID- 29152191 TI - The effect of temperature on male mating signals and female choice in the red mason bee, Osmia bicornis (L.). AB - Climate change and the resulting changes in air temperature are known to have a major influence on most animals, especially poikilothermic insects, because they depend on the high enough temperatures to function. Previous studies have shown that various signals can be affected by changes in temperature. However, research into the effect of temperature on mating signals and subsequently communication between mates and on female choice is still rare. In the red mason bee, Osmia bicornis, which emerges early in spring and is therefore subject to extensive temperature changes, females choose suitable males based on, among other criteria, their thorax vibrations and odor. So far there has been no research into the effect of temperature changes on these signals. We therefore investigated whether the environmental temperature has an influence on the male's mating signals by measuring vibrations using a laser vibrometer and collecting male and female odor at different temperatures. Furthermore, we performed behavioral experiments in order to show whether there is an effect of temperature induced changes and female choice. Our results showed that rejected males differed in their vibrations between the two temperature settings but accepted ones did not. Temperature changes therefore seem to have a stronger effect on those males that are rejected by the females, whereas the accepted males are the ones that can produce desirable signals despite temperature fluctuations. Furthermore, we found that the differences in odor profiles were greater between temperature settings than between the sexes and that females change their preference for odor with temperature. We conclude that temperature strongly influences the male mating signals and therefore may have a major impact on sexual selection in this species. This is an important aspect to consider, not only in future studies on mating behavior, but also in view of our ever raising temperatures. PMID- 29152192 TI - Close and distant: Contrasting the metabolism of two closely related subspecies of Scots pine under the effects of folivory and summer drought. AB - Metabolomes, as chemical phenotypes of organisms, are likely not only shaped by the environment but also by common ancestry. If this is the case, we expect that closely related species of pines will tend to reach similar metabolomic solutions to the same environmental stressors. We examined the metabolomes of two sympatric subspecies of Pinus sylvestris in Sierra Nevada (southern Iberian Peninsula), in summer and winter and exposed to folivory by the pine processionary moth. The overall metabolomes differed between the subspecies but both tended to respond more similarly to folivory. The metabolomes of the subspecies were more dissimilar in summer than in winter, and iberica trees had higher concentrations of metabolites directly related to drought stress. Our results are consistent with the notion that certain plant metabolic responses associated with folivory have been phylogenetically conserved. The larger divergence between subspecies metabolomes in summer is likely due to the warmer and drier conditions that the northern iberica subspecies experience in Sierra Nevada. Our results provide crucial insights into how iberica populations would respond to the predicted conditions of climate change under an increased defoliation in the Mediterranean Basin. PMID- 29152193 TI - Using pentosidine and hydroxyproline to predict age and sex in an avian species. AB - All living organisms are subject to senescence accompanied by progressive and irreversible physiological changes. The error damage and cross-linking theories suggest that cells and tissues are damaged by an accumulation of cross-linked proteins, slowing down bodily processes and resulting in aging. A major category of these cross-linked proteins are compounds called advanced glycation end products (AGEs). We investigated the relationship between accumulation of the AGE, pentosidine (Ps), and hydroxyproline (HYP) a post-translationally modified amino acid, with age, sex, and breeding status (breeder/nonbreeder) from skin samples of known age (i.e., banded as fledglings), free-ranging Double-crested Cormorants (Phalacrocorax auritus, Lesson 1831). We developed multivariate models and evaluated the predictive capability of our models for determining age and breeding versus nonbreeding birds. We found significant relationships with Ps and HYP concentration and age, and Ps concentration and sex. Based on our two-class model using Ps and HYP as explanatory variables, we were able to accurately determine whether a cormorant was a breeder or nonbreeder in 83.5% of modeled classifications. Our data indicate that Ps and HYP concentrations can be used to determine breeding status of cormorants and potentially age of cormorants although sex-specific models may be necessary. Although the accumulation of Ps explained the greatest amount of variance in breeding status and age, importantly, Ps covaried with HYP and combined improved prediction of these demographics in cormorants. Our data support the error damage and cross-linking theories of aging. Both Ps and HYP increase predictably in cormorants and are predictive of age and breeding status. Given the ubiquity of these biomarkers across taxa, their use in estimating demographic characteristics of animals could provide a powerful tool in animal ecology, conservation, and management. PMID- 29152194 TI - Seasonal variation in daily patterns of social contacts in the European badger Meles meles. AB - Social interactions among hosts influence the persistence and spread of infectious pathogens. Daily and seasonal variation in the frequency and type of social interactions will play an important role in disease epidemiology and, alongside other factors, may have an influence on wider disease dynamics by causing seasonal forcing of infection, especially if the seasonal variation experienced by a population is considerable. We explored temporal variation in within-group contacts in a high-density population of European badgers Meles meles naturally infected with Mycobacterium bovis (the causative agent of bovine tuberculosis). Summer contacts were more likely and of longer duration during the daytime, while the frequency and duration of winter contacts did not differ between day and night. In spring and autumn, within-group contacts peaked at dawn and dusk, corresponding with when they were of shortest duration with reduced potential for aerosol transmission of pathogens. Summer and winter could be critical for transmission of M. bovis in badgers, due to the high frequency and duration of contacts during resting periods, and we discuss the links between this result and empirical disease data. This study reveals clear seasonality in daily patterns of contact frequency and duration in species living in stable social groups, suggesting that changes in social contacts could drive seasonal forcing of infection in wildlife populations even when the number of individuals interacting remains similar. PMID- 29152195 TI - Microsite and elevation zone effects on seed pilferage, germination, and seedling survival during early whitebark pine recruitment. AB - Tree recruitment is a spatially structured process that may undergo change over time because of variation in postdispersal processes. We examined seed pilferage, seed germination, and seedling survival in whitebark pine to determine whether 1) microsite type alters the initial spatial pattern of seed caches, 2) higher abiotic stress (i.e. higher elevations) exacerbates spatial distribution changes, and 3) these postdispersal processes are spatially clustered. At two study areas, we created a seed distribution pattern by burying seed caches in microsite types frequently used by whitebark pine's avian seed disperser (Clark's nutcracker) in upper subalpine forest and at treeline, the latter characterized by high abiotic environmental stress. We monitored caches for two years for pilferage, germination, and seedling survival. Odds of pilferage (both study areas), germination (northern study area), and survival (southern study area) were higher at treeline relative to subalpine forest. At the southern study area, we found higher odds of 1) pilferage near rocks and trees relative to no object in subalpine forest, 2) germination near rocks relative to trees within both elevation zones, and 3) seedling survival near rocks and trees relative to no object at treeline. No microsite effects were detected at the northern study area. Findings indicated that the microsite distribution of seed caches changes with seed/seedling stage. Higher odds of seedling survival near rocks and trees were observed at treeline, suggesting abiotic stress may limit safe site availability, thereby shifting the spatial distribution toward protective microsites. Higher odds of pilferage at treeline, however, suggest rodents may limit treeline recruitment. Further, odds of pilferage were higher near rocks and trees relative to no object in subalpine forest but did not differ among microsites at treeline, suggesting pilferage can modulate the spatial structure of regeneration, a finding supported by limited clustering of postdispersal processes. PMID- 29152196 TI - Influences of population pressure change on vegetation greenness in China's mountainous areas. AB - Mountainous areas in China account for two-thirds of the total land area. Due to rapid urbanization, rural population emigration in China's mountainous areas is very significant. This raises the question to which degree such population emigration influences the vegetation greenness in these areas. In this study, 9,753 sample areas (each sample measured about 64 square kilometers) were randomly selected, and the influences of population emigration (population pressure change) on vegetation greenness during 2000-2010 were quantitatively expressed by the multivariate linear regression (MLR) model, using census data under the condition of controlling the natural elements such as climatic and landform factors. The results indicate that the vegetation index in the past 10 years has presented an increasing overall trend, albeit with local decrease in some regions. The combined area of the regions with improved vegetation accounted for 81.7% of the total mountainous areas in China. From 2000 to 2010, the rural population significantly decreased, with most significant decreases in the northern and central areas (17.2% and 16.8%, respectively). In China's mountainous areas and in most of the subregions, population emigration has significant impacts on vegetation change. In different subregions, population decrease differently influenced vegetation greenness, and the marginal effect of population decrease on vegetation change presented obvious differences from north to south. In the southwest, on the premise of controlling other factors, a population decrease by one unit could increase the slope of vegetation change by 16.4%; in contrast, in the southeastern, northern, northeastern, and central area, the proportion was about 15.5%, 10.6%, 9.7%, and 7.5%, respectively, for improving the trend of NDVI variation. PMID- 29152197 TI - Selection of reference genes for qRT-PCR and expression analysis of high-altitude related genes in grassland caterpillars (Lepidoptera: Erebidae: Gynaephora) along an altitude gradient. AB - Changes in gene expression patterns can reflect the adaptation of organisms to divergent environments. Quantitative real-time PCR (qRT-PCR) is an important tool for ecological adaptation studies at the gene expression level. The quality of the results of qRT-PCR analysis largely depends on the availability of reliable reference genes (RGs). To date, reliable RGs have not been determined for adaptive evolution studies in insects using a standard approach. Here, we evaluated the reliability of 17 candidate RGs for five Gynaephora populations inhabiting various altitudes of the Tibetan Plateau (TP) using four independent (geNorm, NormFinder, BestKeeper, and the deltaCt method) and one comprehensive (RefFinder) algorithms. Our results showed that EF1-alpha, RPS15, and RPS13 were the top three most suitable RGs, and a combination of these three RGs was the most optimal for normalization. Conversely, RPS2,ACT, and RPL27 were the most unstable RGs. The expression profiles of two target genes (HSP70 and HSP90) were used to confirm the reliability of the chosen RGs. Additionally, the expression patterns of four other genes (GPI,HIF1A,HSP20, and USP) associated with adaptation to extreme environments were assessed to explore the adaptive mechanisms of TP Gynaephora species to divergent environments. Each of these six target genes showed discrepant expression patterns among the five populations, suggesting that the observed expression differences may be associated with the local adaptation of Gynaephora to divergent altitudinal environments. This study is a useful resource for studying the adaptive evolution of TP Gynaephora to divergent environments using qRT-PCR, and it also acts as a guide for selecting suitable RGs for ecological and evolutionary studies in insects. PMID- 29152198 TI - Trading heat and hops for water: Dehydration effects on locomotor performance, thermal limits, and thermoregulatory behavior of a terrestrial toad. AB - Due to their highly permeable skin and ectothermy, terrestrial amphibians are challenged by compromises between water balance and body temperature regulation. The way in which such compromises are accommodated, under a range of temperatures and dehydration levels, impacts importantly the behavior and ecology of amphibians. Thus, using the terrestrial toad Rhinella schneideri as a model organism, the goals of this study were twofold. First, we determined how the thermal sensitivity of a centrally relevant trait-locomotion-was affected by dehydration. Secondly, we examined the effects of the same levels of dehydration on thermal preference and thermal tolerance. As dehydration becomes more severe, the optimal temperature for locomotor performance was lowered and performance breadth narrower. Similarly, dehydration was accompanied by a decrease in the thermal tolerance range. Such a decrease was caused by both an increase in the critical minimal temperature and a decrease in the thermal maximal temperature, with the latter changing more markedly. In general, our results show that the negative effects of dehydration on behavioral performance and thermal tolerance are, at least partially, counteracted by concurrent adjustments in thermal preference. We discuss some of the potential implications of this observation for the conservation of anuran amphibians. PMID- 29152199 TI - Effect of pollen and resource limitation on reproduction of Zygophyllum xanthoxylum in fragmented habitats. AB - Limitations on pollen and resources may significantly affect plant reproduction in fragmented habitats. In this study, phenology and pollinator frequency and activity were investigated to estimate the role of pollinators in Zygophyllum xanthoxylum reproduction, and this species is ecologically important in northwest China. In addition, the relative impact of restrictive amounts of pollen and resources on the seed set per flower was evaluated. It was found that adding pollen boosted the size of the seed set per flower, but had no significant effect on the number of flowers. By contrast, the addition of resources increased flower numbers as well as had a slight impact on the seed set per flower. These results indicate the amount of available pollen is a limiting factor for reproductive success. Moreover, Apis mellifera was identified as the most effective pollinator of Z. xanthoxylum, and there were more overall pollinators and visitations in the control than in the fragmented habitats. Furthermore, the limitations in pollen were more restrictive in the fragmented area than in the control. This was due to increased pollinator visitations in the control that could ameliorate the effects of lower pollen levels. When there is a limited availability of suitable pollinators, self-pollination is critical in fragmented habitats. Z. xanthoxylum has reproductive strategies that aid in adapting to harsh environments, including protogyny and delayed selfing. PMID- 29152200 TI - Resource partitioning facilitates coexistence in sympatric cetaceans in the California Current. AB - Resource partitioning is an important process driving habitat use and foraging strategies in sympatric species that potentially compete. Differences in foraging behavior are hypothesized to contribute to species coexistence by facilitating resource partitioning, but little is known on the multiple mechanisms for partitioning that may occur simultaneously. Studies are further limited in the marine environment, where the spatial and temporal distribution of resources is highly dynamic and subsequently difficult to quantify. We investigated potential pathways by which foraging behavior may facilitate resource partitioning in two of the largest co-occurring and closely related species on Earth, blue (Balaenoptera musculus) and humpback (Megaptera novaeangliae) whales. We integrated multiple long-term datasets (line-transect surveys, whale-watching records, net sampling, stable isotope analysis, and remote-sensing of oceanographic parameters) to compare the diet, phenology, and distribution of the two species during their foraging periods in the highly productive waters of Monterey Bay, California, USA within the California Current Ecosystem. Our long term study reveals that blue and humpback whales likely facilitate sympatry by partitioning their foraging along three axes: trophic, temporal, and spatial. Blue whales were specialists foraging on krill, predictably targeting a seasonal peak in krill abundance, were present in the bay for an average of 4.7 months, and were spatially restricted at the continental shelf break. In contrast, humpback whales were generalists apparently feeding on a mixed diet of krill and fishes depending on relative abundances, were present in the bay for a more extended period (average of 6.6 months), and had a broader spatial distribution at the shelf break and inshore. Ultimately, competition for common resources can lead to behavioral, morphological, and physiological character displacement between sympatric species. Understanding the mechanisms for species coexistence is both fundamental to maintaining biodiverse ecosystems, and provides insight into the evolutionary drivers of morphological differences in closely related species. PMID- 29152201 TI - The natural selection of metabolism and mass selects lifeforms from viruses to multicellular animals. AB - I show that the natural selection of metabolism and mass can select for the major life-history and allometric transitions that define lifeforms from viruses, over prokaryotes and larger unicells, to multicellular animals. The proposed selection is driven by a mass-specific metabolism that is selected as the pace of the resource handling that generates net energy for self-replication. An initial selection of mass is given by a dependence of mass-specific metabolism on mass in replicators that are close to a lower size limit. A sublinear maximum dependence selects for virus-like replicators, with no intrinsic metabolism, no cell, and practically no mass. A superlinear dependence selects for prokaryote-like self replicating cells, with asexual reproduction and incomplete metabolic pathways. These self-replicators have selection for increased net energy, and this generates a gradual unfolding of population-dynamic feed-back selection from interactive competition. The incomplete feed-back selects for larger unicells with more developed metabolic pathways, and the completely developed feed-back for multicellular animals with sexual reproduction. This model unifies the natural selection of lifeforms from viruses to multicellular animals, and it provides a parsimonious explanation where allometries and major life histories evolve from the natural selection of metabolism and mass. PMID- 29152202 TI - Assessing the potential of translocating vulnerable forest birds by searching for novel and enduring climatic ranges. AB - Hawaiian forest birds are imperiled, with fewer than half the original >40 species remaining extant. Recent studies document ongoing rapid population decline and project complete climate-based range losses for the critically endangered Kaua'i endemics 'akeke'e (Loxops caeruleirostris) and 'akikiki (Oreomystis bairdi) by end-of-century due to projected warming. Climate change facilitates the upward expansion of avian malaria into native high elevation forests where disease was historically absent. While intensified conservation efforts attempt to safeguard these species and their habitats, the magnitude of potential loss and the urgency of this situation require all conservation options to be seriously considered. One option for Kaua'i endemics is translocation to islands with higher elevation habitats. We explored the feasibility of interisland translocation by projecting baseline and future climate-based ranges of 'akeke'e and 'akikiki across the Hawaiian archipelago. For islands where compatible climates for these species were projected to endure through end-of century, an additional climatic niche overlap analysis compares the spatial overlap between Kaua'i endemics and current native species on prospective destination islands. Suitable climate-based ranges exist on Maui and Hawai'i for these Kaua'i endemics that offer climatically distinct areas compared to niche distributions of destination island endemics. While we recognize that any decision to translocate birds will include assessing numerous additional social, political, and biological factors, our focus on locations of enduring and ecologically compatible climate-based ranges represents the first step to evaluate this potential conservation option. Our approach considering baseline and future distributions of species with climatic niche overlap metrics to identify undesirable range overlap provides a method that can be utilized for other climate-vulnerable species with disjointed compatible environments beyond their native range. PMID- 29152203 TI - Pyric-carnivory: Raptor use of prescribed fires. AB - Fire is a process that shaped and maintained most terrestrial ecosystems worldwide. Changes in land use and patterns of human settlement have altered fire regimes and led to fire suppression resulting in numerous undesirable consequences spanning individual species and entire ecosystems. Many obvious and direct consequences of fire suppression have been well studied, but several, albeit less obvious, costs of alteration to fire regimes on wildlife are unknown. One such phenomenon is the response of carnivores to fire events-something we refer to as pyric-carnivory. To investigate the prevalence of pyric-carnivory in raptors, we monitored 25 prescribed fires occurring during two different seasons and across two different locations in tallgrass prairie of the central United States. We used paired point counts occurring before and during prescribed fires to quantify the use of fires by raptors. We found a strong attraction to fires with average maximum abundance nearly seven times greater during fires than prior to ignitions (before: x- = 2.90, SE = 0.42; during: x- = 20.20; SE = 3.29) and an average difference between fire events and immediately before fires of 15.2 (+/ 2.69) raptors. This result was driven by Swainson's hawks (Buteo swainsoni), which were the most abundant (n = 346) of the nine species we observed using fires. Our results illustrate the importance of fire as integral disturbance process that effects wildlife behavior through multiple mechanisms that are often overshadowed by the predominant view of fire as a tool used for vegetation management. PMID- 29152204 TI - Prozac in the water: Chronic fluoxetine exposure and predation risk interact to shape behaviors in an estuarine crab. AB - Predators exert considerable top-down pressure on ecosystems by directly consuming prey or indirectly influencing their foraging behaviors and habitat use. Prey is, therefore, forced to balance predation risk with resource reward. A growing list of anthropogenic stressors such as rising temperatures and ocean acidification has been shown to influence prey risk behaviors and subsequently alter important ecosystem processes. Yet, limited attention has been paid to the effects of chronic pharmaceutical exposure on risk behavior or as an ecological stressor, despite widespread detection and persistence of these contaminants in aquatic environments. In the laboratory, we simulated estuarine conditions of the shore crab, Hemigrapsus oregonensis, and investigated whether chronic exposure (60 days) to field-detected concentrations (0, 3, and 30 ng/L) of the antidepressant fluoxetine affected diurnal and nocturnal risk behaviors in the presence of a predator, Cancer productus. We found that exposure to fluoxetine influenced both diurnal and nocturnal prey risk behaviors by increasing foraging and locomotor activity in the presence of predators, particularly during the day when these crabs normally stay hidden. Crabs exposed to fluoxetine were also more aggressive, with a higher frequency of agonistic interactions and increased mortality due to conflicts with conspecifics. These results suggest that exposure to field-detected concentrations of fluoxetine may alter the trade-off between resource acquisition and predation risk among crabs in estuaries. This fills an important data gap, highlighting how intra- and interspecific behaviors are altered by exposure to field concentrations of pharmaceuticals; such data more explicitly identify potential ecological impacts of emerging contaminants on aquatic ecosystems and can aid water quality management. PMID- 29152205 TI - Genetic structure and demographic history of Lymantria dispar (Linnaeus, 1758) (Lepidoptera: Erebidae) in its area of origin and adjacent areas. AB - We analyzed the population genetic structure and demographic history of 20 Lymantria dispar populations from Far East Asia using microsatellite loci and mitochondrial genes. In the microsatellite analysis, the genetic distances based on pairwise FST values ranged from 0.0087 to 0.1171. A NeighborNet network based on pairwise FST genetic distances showed that the 20 regional populations were divided into five groups. Bayesian clustering analysis (K = 3) demonstrated the same groupings. The populations in the Korean Peninsula and adjacent regions, in particular, showed a mixed genetic pattern. In the mitochondrial genetic analysis based on 98 haplotypes, the median-joining network exhibited a star shape that was focused on three high-frequency haplotypes (Haplotype 1: central Korea and adjacent regions, Group 1; Haplotype 37: southern Korea, Group 2; and Haplotype 90: Hokkaido area, Group 3) connected by low-frequency haplotypes. The mismatch distribution dividing the three groups was unimodal. In the neutral test, Tajima's D and Fu's FS tests were negative. We can thus infer that the Far East Asian populations of L. dispar underwent a sudden population expansion. Based on the age expansion parameter, the expansion time was inferred to be approximately 53,652 years before present (ybp) for Group 1, approximately 65,043 ybp for Group 2, and approximately 76,086 ybp for Group 3. We propose that the mixed genetic pattern of the inland populations of Far East Asia is due to these expansions and that the inland populations of the region should be treated as valid subspecies that are distinguishable from other subspecies by genetic traits. PMID- 29152206 TI - Global population structure and adaptive evolution of aflatoxin-producing fungi. AB - Aflatoxins produced by several species in Aspergillus section Flavi are a significant problem in agriculture and a continuous threat to human health. To provide insights into the biology and global population structure of species in section Flavi, a total of 1,304 isolates were sampled across six species (A. flavus, A. parasiticus, A. nomius, A. caelatus, A. tamarii, and A. alliaceus) from single fields in major peanut-growing regions in Georgia (USA), Australia, Argentina, India, and Benin (Africa). We inferred maximum-likelihood phylogenies for six loci, both combined and separately, including two aflatoxin cluster regions (aflM/alfN and aflW/aflX) and four noncluster regions (amdS, trpC, mfs and MAT), to examine population structure and history. We also employed principal component and STRUCTURE analysis to identify genetic clusters and their associations with six different categories (geography, species, precipitation, temperature, aflatoxin chemotype profile, and mating type). Overall, seven distinct genetic clusters were inferred, some of which were more strongly structured by G chemotype diversity than geography. Populations of A. flavus S in Benin were genetically distinct from all other section Flavi species for the loci examined, which suggests genetic isolation. Evidence of trans-speciation within two noncluster regions, whereby A. flavus SBG strains from Australia share haplotypes with either A. flavus or A. parasiticus, was observed. Finally, while clay soil and precipitation may influence species richness in Aspergillus section Flavi, other region-specific environmental and genetic parameters must also be considered. PMID- 29152207 TI - Endotracheal intubation in patients with difficult airway: using laryngeal mask airway with bougie versus video laryngoscopy. AB - Airway management is essential for safe anesthesia and endotracheal intubation is the most important procedure by which critically ill patients can be better managed, especially if done quickly and successfully. This study aimed to compare the techniques of intubation through laryngeal mask airway (LMA) using a bougie versus video laryngoscopy (VL) regarding to intubation success and the quality of intubation indices in patients with difficult airways. This randomized clinical trial was performed on 96 patients aged 16-76 years with Mallampati class 3 or 4 who underwent elective surgery. Once the demographics were recorded, patients were randomly divided into two groups and the first group intubated with VL, and the second group intubated through laryngeal mask using a bougie. Then vital signs, arterial oxygen saturation, the time required for successful intubation, and ease of intubation were recorded. Here t-tests, chi-square, Fisher exact tests, and analysis of variance for repeated measurement were used to analyze the data in SPSS software. The overall success rates of intubation in VL and LMA groups were 46 (96%) and 44 (92%), respectively. The mean duration of intubation for the LMA and VL groups was 18.70 +/- 6.73 and 14.21 +/- 4.14 seconds, respectively (P < 0.001). Moreover, visual analogue scale score for pain in throat was significantly lower in VL group than LMA (1.65 +/- 0.76 vs. 1.33 +/- 0.52). Moreover, easy intubation in bougie group was 50%, while the easy intubation in VL was 73% (P = 0.023). In addition, incidence of cough was 31% in the LMA with bougie group and 9% in VL group (P = 0.005). The VL technique is an easier method and has a shorter intubation time than LMA using bougie, and causes a lower incidence of coughing, laryngospasm in patients that need intubation. Moreover, cough and discomfort in the throat tend to be less in VL, and the LMA could be used as replacement of VL in hard situations. PMID- 29152208 TI - Correction: Argon attenuates the emergence of secondary injury after traumatic brain injury within a 2-hour incubation period compared to desflurane: an in vitro study. AB - [This corrects the article on p. 93 in vol. 7, PMID: 28744361.]. PMID- 29152210 TI - A method for calculating the gas volume proportions and inhalation temperature of inert gas mixtures allowing reaching normothermic or hypothermic target body temperature in the awake rat. AB - The noble gases xenon (Xe) and helium (He) are known to possess neuroprotective properties. Xe is considered the golden standard neuroprotective gas. However, Xe has a higher molecular weight and lower thermal conductivity and specific heat than those of nitrogen, the main diluent of oxygen (O2) in air, conditions that could impair or at least reduce the intrinsic neuroprotective properties of Xe by increasing the critical care patient's respiratory workload and body temperature. In contrast, He has a lower molecular weight and higher thermal conductivity and specific heat than those of nitrogen, but is unfortunately far less potent than Xe at providing neuroprotection. Therefore, combining Xe with He could allow obtaining, depending on the gas inhalation temperature and composition, gas mixtures with neutral or hypothermic properties, the latter being advantageous in term of neuroprotection. However, calculating the thermal properties of a mixture, whatever the substances - gases, metals, rubbers, etc. - is not trivial. To answer this question, we provide a graphical method to assess the volume proportions of Xe, He and O2 that a gas mixture should contain, and the inhalation temperature to which it should be administered to allow a clinician to maintain the patient at a target body temperature. PMID- 29152209 TI - Case control study: hyperbaric oxygen treatment of mild traumatic brain injury persistent post-concussion syndrome and post-traumatic stress disorder. AB - Mild traumatic brain injury (TBI) persistent post-concussion syndrome (PPCS) and post-traumatic stress disorder (PTSD) are epidemic in United States Iraq and Afghanistan War veterans. Treatment of the combined diagnoses is limited. The aim of this study is to assess safety, feasibility, and effectiveness of hyperbaric oxygen treatments (HBOT) for mild TBI PPCS and PTSD. Thirty military subjects aged 18-65 with PPCS with or without PTSD and from one or more blast-induced mild moderate traumatic brain injuries that were a minimum of 1 year old and occurred after 9/11/2001 were studied. The measures included symptom lists, physical exam, neuropsychological and psychological testing on 29 subjects (1 dropout) and SPECT brain imaging pre and post HBOT. Comparison was made using SPECT imaging on 29 matched Controls. Side effects (30 subjects) experienced due to the HBOT: reversible middle ear barotrauma (n = 6), transient deterioration in symptoms (n = 7), reversible bronchospasm (n = 1), and increased anxiety (n = 2; not related to confinement); unrelated to HBOT: ureterolithiasis (n = 1), chest pain (n = 2). Significant improvement (29 subjects) was seen in neurological exam, symptoms, intelligence quotient, memory, measures of attention, dominant hand motor speed and dexterity, quality of life, general anxiety, PTSD, depression (including reduction in suicidal ideation), and reduced psychoactive medication usage. At 6 month follow-up subjects reported further symptomatic improvement. Compared to Controls the subjects' SPECT was significantly abnormal, significantly improved after 1 and 40 treatments, and became statistically indistinguishable from Controls in 75% of abnormal areas. HBOT was found to be safe and significantly effective for veterans with mild to moderate TBI PPCS with PTSD in all four outcome domains: clinical medicine, neuropsychology, psychology, and SPECT imaging. Veterans also experienced a significant reduction in suicidal ideation and reduction in psychoactive medication use. PMID- 29152211 TI - Xenon-helium gas mixture at equimolar concentration of 37.5% protects against oxygen and glucose deprivation-induced injury and inhibits tissue plasminogen activator. AB - Xenon (Xe) is considered to be the golden standard neuroprotective gas. However, Xe has a higher molecular weight and lower thermal conductivity and specific heat than those of nitrogen, the main diluent of oxygen in air. These physical characteristics could impair or at least reduce the intrinsic neuroprotective action of Xe by increasing the patient's respiratory workload and body temperature. In contrast, helium (He) is a cost-efficient gas with a lower molecular weight and higher thermal conductivity and specific heat than those of nitrogen, but is far less potent than Xe. In this study, we hypothesized that mixing Xe and He could allow obtaining a neuroprotective gas mixture with advantageously reduced molecular weight and increased thermal conductivity. We found that Xe and He at the equimolar concentration of 37.5% reduced oxygen glucose deprivation-induced increase in lactate dehydrogenase in brain slices, an ex vivo model of acute ischemic stroke. These results together with the effects of Xe-He on the thrombolytic efficiency of tissue plasminogen activator are discussed. PMID- 29152212 TI - Sevoflurane and renal function: a meta-analysis of randomized trials. AB - Objective: This study aims to describe the overall cumulative effect of sevoflurane on kidney function in healthy patients in terms of mean plasma creatinine, blood urea nitrogen (BUN), creatinine clearance, urinary protein, and glucose excretion at 24 and 72 hours post-anesthesia. Data retrieval: A systematic literature search using MEDLINE and EMBASE as primary search engines was conducted. Articles, relevant abstracts, and citations dated January 1, 1995 to June 30, 2016 were retrieved. Data selection: Search terms included the pharmacological generic name sevoflurane. Search was expanded using the terms "renal function" OR "kidney" function AND "creatinine" OR "blood urea nitrogen" OR "creatinine clearance" OR "proteinuria" OR "glucosuria" OR "nephrotoxicity." Limitations included randomized controlled trial, humans, and ages 19 and above, to include English and non-English text formats. All bibliographic indices for the relevant journals identified were also searched and collated according to relevance. Main outcome measures: Changes in serum/plasma creatinine, BUN, urinary protein, and glucose excretion of sevoflurane at 24 and 72-hours were determined. Results: Six relevant studies were qualified by both the inclusion criteria and inclusion dates. This review consists of 873 patients, 65% are males and 35% are females, with mean age of 56 +/- 3 years. Sevoflurane was compared to isoflurane with regard to its nephrotoxic potential. Analyses on the effects of sevoflurane were performed on serum/plasma creatinine, BUN, urinary protein, and glucose excretion at 24 and 72 hours which showed no statistical difference between sevoflurane and isoflurane. Conclusion: In an apparently healthy adult without coexisting renal disorder, sevoflurane does not produce elevations in creatinine and BUN above the established upper limit of the reference range. PMID- 29152213 TI - The role of nitric oxide in stroke. AB - Stroke is considered to be an acute cerebrovascular disease, including ischemic stroke and hemorrhagic stroke. The high incidence and poor prognosis of stroke suggest that it is a highly disabling and highly lethal disease which can pose a serious threat to human health. Nitric oxide (NO), a common gas in nature, which is often thought as a toxic gas, because of its intimate relationship with the pathological processes of many diseases, especially in the regulation of blood flow and cell inflammation. However, recent years have witnessed an increased interest that NO plays a significant and positive role in stroke as an essential gas signal molecule. In view of the fact that the neuroprotective effect of NO is closely related to its concentration, cell type and time, only in the appropriate circumstances can NO play a protective effect. The purpose of this review is to summarize the roles of NO in ischemic stroke and hemorrhagic stroke. PMID- 29152214 TI - Anesthetic effects on autophagy. AB - Anesthetic agents provide patient comfort and optimize conditions for surgical and procedural interventions. These agents have been shown to modulate autophagy, which is a cellular mechanism that maintains tissue homeostasis by degrading and recycling excess, aged, or dysfunctional proteins. However, it is not always clear if upregulated autophagy is beneficial or harmful. This review assesses the anesthetic effects on autophagy. In the vast majority of studies, anesthetic modulation of autophagy is beneficial for cell survival. PMID- 29152216 TI - Macrophage polarization is related to the pathogenesis of decompression induced lung injury. AB - Studies have shown that blood bubbles may be detectable and there is ultrasonic evidence of acute interstitial lung edema even after diving without protocol violation. Macrophages play a central role in the inflammation, and macrophage polarization is closely related to the pathogenesis some lung diseases. Available findings indicate that decompression may induce the production of pro inflammatory cytokines, chemokines, and adhesion molecules in the blood and tissues, which are associated with the macrophage polarization, and hyperbaric treatment may exert therapeutic effects on decompression related diseases via regulating these factors. Thus, we hypothesize that the polarization of circulating and/or resident macrophages is involved in the pathogenesis of decompression induced lung injury. PMID- 29152215 TI - Ozone therapy: an overview of pharmacodynamics, current research, and clinical utility. AB - The use of ozone (O3) gas as a therapy in alternative medicine has attracted skepticism due to its unstable molecular structure. However, copious volumes of research have provided evidence that O3's dynamic resonance structures facilitate physiological interactions useful in treating a myriad of pathologies. Specifically, O3 therapy induces moderate oxidative stress when interacting with lipids. This interaction increases endogenous production of antioxidants, local perfusion, and oxygen delivery, as well as enhances immune responses. We have conducted a comprehensive review of O3 therapy, investigating its contraindications, routes and concentrations of administration, mechanisms of action, disinfectant properties in various microorganisms, and its medicinal use in different pathologies. We explore the therapeutic value of O3 in pathologies of the cardiovascular system, gastrointestinal tract, genitourinary system, central nervous system, head and neck, musculoskeletal, subcutaneous tissue, and peripheral vascular disease. Despite compelling evidence, further studies are essential to mark it as a viable and quintessential treatment option in medicine. PMID- 29152217 TI - Anesthetic-induced developmental neurotoxicity: causes, prospective studies and possible interventions. PMID- 29152218 TI - Recent advances in understanding/managing type 2 diabetes mellitus. AB - The treatment of type 2 diabetes mellitus has evolved in the present century toward safer and maybe more effective drugs, which in some cases can also reduce the risk of cardiovascular and renal outcomes. Nevertheless, we still need better strategies to reduce excess body weight in order to achieve diabetes remission, which is now a feasible target, as has been demonstrated with bariatric surgery. This review focuses on the significant advances in the management of blood glucose in type 2 diabetes mellitus, including the current understanding of the mechanisms of drug action but keeping in mind that the treatment of the disease is multifactorial. PMID- 29152220 TI - Preference and willingness to pay for nutritional counseling services in urban Hanoi. AB - Background: Despite substantial achievement in reducing malnutrition rates in Vietnam, there has been an increasing rate of overweight individuals in urban areas, which may result in a high burden of non-communicable diseases. Nutritional counseling clinics have been introduced in several settings; however, little is known about the preference for this service among urban clients. This study aimed to assess the preference and willingness to pay (WTP) for nutritional counseling services among urban clients. Methods: We interviewed 429 clients who attended Hanoi Medical University Nutritional Counseling Clinic (Hanoi, Vietnam). WTP was determined using double-bounded dichotomous-choice questions and open ended questions. Results: In total, 78.6% respondents were willing to use nutritional counseling services. The mean amount of WTP for one-time service and one-year package was 96,100VND (~$4.3) and 946,400VND (~$41.9), respectively. Clients' willingness to use the service was higher among females, those seeking counseling for elderly people and those who preferred face-to-face counseling services (p<0.05). WTP was higher among those who were over 35 years old, those seeking services for the elderly people, those having poor nutritional status, and those having under-6 year old children (p<0.05). Conclusions: The preference and WTP for nutritional counseling services in urban Hanoi were relatively high. Scaling up this service is necessary to actively prevent and control the spread of non-communicable diseases. PMID- 29152221 TI - PubRunner: A light-weight framework for updating text mining results. AB - Biomedical text mining promises to assist biologists in quickly navigating the combined knowledge in their domain. This would allow improved understanding of the complex interactions within biological systems and faster hypothesis generation. New biomedical research articles are published daily and text mining tools are only as good as the corpus from which they work. Many text mining tools are underused because their results are static and do not reflect the constantly expanding knowledge in the field. In order for biomedical text mining to become an indispensable tool used by researchers, this problem must be addressed. To this end, we present PubRunner, a framework for regularly running text mining tools on the latest publications. PubRunner is lightweight, simple to use, and can be integrated with an existing text mining tool. The workflow involves downloading the latest abstracts from PubMed, executing a user-defined tool, pushing the resulting data to a public FTP, and publicizing the location of these results on the public PubRunner website. This shows a proof of concept that we hope will encourage text mining developers to build tools that truly will aid biologists in exploring the latest publications. PMID- 29152222 TI - Preprocessed Consortium for Neuropsychiatric Phenomics dataset. AB - Here we present preprocessed MRI data of 265 participants from the Consortium for Neuropsychiatric Phenomics (CNP) dataset. The preprocessed dataset includes minimally preprocessed data in the native, MNI and surface spaces accompanied with potential confound regressors, tissue probability masks, brain masks and transformations. In addition the preprocessed dataset includes unthresholded group level and single subject statistical maps from all tasks included in the original dataset. We hope that availability of this dataset will greatly accelerate research. PMID- 29043062 TI - The future of metabolomics in ELIXIR. AB - Metabolomics, the youngest of the major omics technologies, is supported by an active community of researchers and infrastructure developers across Europe. To coordinate and focus efforts around infrastructure building for metabolomics within Europe, a workshop on the "Future of metabolomics in ELIXIR" was organised at Frankfurt Airport in Germany. This one-day strategic workshop involved representatives of ELIXIR Nodes, members of the PhenoMeNal consortium developing an e-infrastructure that supports workflow-based metabolomics analysis pipelines, and experts from the international metabolomics community. The workshop established metabolite identification as the critical area, where a maximal impact of computational metabolomics and data management on other fields could be achieved. In particular, the existing four ELIXIR Use Cases, where the metabolomics community - both industry and academia - would benefit most, and which could be exhaustively mapped onto the current five ELIXIR Platforms were discussed. This opinion article is a call for support for a new ELIXIR metabolomics Use Case, which aligns with and complements the existing and planned ELIXIR Platforms and Use Cases. PMID- 29152223 TI - Stage 1 Registered Report: Effect of deficient phagocytosis on neuronal survival and neurological outcome after temporary middle cerebral artery occlusion (tMCAo). AB - Stroke is a major cause of death and disability worldwide. In addition to neuronal death resulting directly from energy depletion due to lack of blood supply, inflammation and microglial activation following ischemic brain injury has been increasingly recognized to be a key contributor to the pathophysiology of cerebrovascular disease. However, our understanding of the cross talk between the ischemic brain and the immune system is limited. Recently, we demonstrated that following focal ischemia, death of mature viable neurons can be executed through phagocytosis by microglial cells or recruited macrophages, i.e. through phagoptosis. It was shown that inhibition of phagocytic signaling pathways following endothelin-1 induced focal cerebral ischemia leads to increased neuronal survival and neurological recovery. This suggests that inhibition of specific phagocytic pathways may prevent neuronal death during cerebral ischemia. To further explore this potential therapeutic target, we propose to assess the role of phagocytosis in an established model of temporary (45min) middle cerebral artery occlusion, and to evaluate neuronal survival and neurological recovery in mice with deficient phagocytosis. PMID- 29152224 TI - Recent insights into PERK-dependent signaling from the stressed endoplasmic reticulum. AB - The unfolded protein response (UPR) is an evolutionarily conserved stress response to intra- and extracellular conditions that disrupt endoplasmic reticulum (ER) protein-folding capacity. The UPR is engaged by a variety of disease conditions, including most cancers as well as both metabolic and neurodegenerative disorders. Three transmembrane transducers-PERK, IRE1, and ATF6 are responsible for activating downstream signaling pathways that mediate the UPR and subsequent stress response pathways. PERK, an ER resident transmembrane protein kinase, initiates both pro-apoptotic and pro-survival signaling pathways. In the context of neoplasia, PERK and its downstream targets alter gene expression that can be both pro- and anti-tumorigenic. In this review, we discuss recent advances in understanding how canonical and non-canonical PERK-mediated signaling pathways influence cell fate, tumor progression, and tumor suppression and avenues for therapeutic intervention. PMID- 29152225 TI - Leaders in collective migration: are front cells really endowed with a particular set of skills? AB - Collective cell migration is the coordinated movement emerging from the interaction of at least two cells. In multicellular organisms, collective cell migration is ubiquitous. During development, embryonic cells often travel in numbers, whereas in adults, epithelial cells close wounds collectively. There is often a division of labour and two categories of cells have been proposed: leaders and followers. These two terms imply that followers are subordinated to leaders whose proposed broad range of actions significantly biases the direction of the group of cells towards a specific target. These two terms are also tied to topology. Leaders are at the front while followers are located behind them. Here, we review recent work on some of the main experimental models for collective cell migration, concluding that leader-follower terminology may not be the most appropriate. It appears that not all collectively migrating groups are driven by cells located at the front. Moreover, the qualities that define leaders (pathfinding, traction forces and matrix remodelling) are not specific to front cells. These observations indicate that the terms leaders and followers are not suited to every case. We think that it would be more accurate to dissociate the function of a cell from its position in the group. The position of cells can be precisely defined with respect to the direction of movement by purely topological terms such as "front" or "rear" cells. In addition, we propose the more ample and strictly functional definition of "steering cells" which are able to determine the directionality of movement for the entire group. In this context, a leader cell represents only a specific case in which a steering cell is positioned at the front of the group. PMID- 29152226 TI - An overview of the cutaneous porphyrias. AB - This is an overview of the cutaneous porphyrias. It is a narrative review based on the published literature and my personal experience; it is not based on a formal systematic search of the literature. The cutaneous porphyrias are a diverse group of conditions due to inherited or acquired enzyme defects in the porphyrin-haem biosynthetic pathway. All the cutaneous porphyrias can have (either as a consequence of the porphyria or as part of the cause of the porphyria) involvement of other organs as well as the skin. The single commonest cutaneous porphyria in most parts of the world is acquired porphyria cutanea tarda, which is usually due to chronic liver disease and liver iron overload. The next most common cutaneous porphyria, erythropoietic protoporphyria, is an inherited disorder in which the accumulation of bile-excreted protoporphyrin can cause gallstones and, rarely, liver disease. Some of the porphyrias that cause blistering (usually bullae) and fragility (clinically and histologically identical to porphyria cutanea tarda) can also be associated with acute neurovisceral porphyria attacks, particularly variegate porphyria and hereditary coproporphyria. Management of porphyria cutanea tarda mainly consists of visible light photoprotection measures while awaiting the effects of treating the underlying liver disease (if possible) and treatments to reduce serum iron and porphyrin levels. In erythropoietic protoporphyria, the underlying cause can be resolved only with a bone marrow transplant (which is rarely justifiable in this condition), so management consists particularly of visible-light photoprotection and, in some countries, narrowband ultraviolet B phototherapy. Afamelanotide is a promising and newly available treatment for erythropoietic protoporphyria and has been approved in Europe since 2014. PMID- 29152227 TI - Promising neuroprotective strategies for traumatic spinal cord injury with a focus on the differential effects among anatomical levels of injury. AB - Traumatic spinal cord injury (SCI) is a devastating condition of motor, sensory, and autonomic dysfunction. The significant cost associated with the management and lifetime care of patients with SCI also presents a major economic burden. For these reasons, there is a need to develop and translate strategies that can improve outcomes following SCI. Given the challenges in achieving regeneration of the injured spinal cord, neuroprotection has been at the forefront of clinical translation. Yet, despite many preclinical advances, there has been limited translation into the clinic apart from methylprednisolone (which remains controversial), hypertensive therapy to maintain spinal cord perfusion, and early decompressive surgery. While there are several factors related to the limited translational success, including the clinical and mechanistic heterogeneity of human SCI, the misalignment between animal models of SCI and clinical reality continues to be an important factor. Whereas most clinical cases are at the cervical level, only a small fraction of preclinical research is conducted in cervical models of SCI. Therefore, this review highlights the most promising neuroprotective and neural reparative therapeutic strategies undergoing clinical assessment, including riluzole, hypothermia, granulocyte colony-stimulating factor, glibenclamide, minocycline, Cethrin (VX-210), and anti-Nogo-A antibody, and emphasizes their efficacy in relation to the anatomical level of injury. Our hope is that more basic research will be conducted in clinically relevant cervical SCI models in order to expedite the transition of important laboratory discoveries into meaningful treatment options for patients with SCI. PMID- 29152228 TI - CD1: From Molecules to Diseases. AB - The human cluster of differentiation (CD)1 system for antigen display is comprised of four types of antigen-presenting molecules, each with a distinct functional niche: CD1a, CD1b, CD1c, and CD1d. Whereas CD1 proteins were thought solely to influence T-cell responses through display of amphipathic lipids, recent studies emphasize the role of direct contacts between the T-cell receptor and CD1 itself. Moving from molecules to diseases, new research approaches emphasize human CD1-transgenic mouse models and the study of human polyclonal T cells in vivo or ex vivo in disease states. Whereas the high genetic diversity of major histocompatibility complex (MHC)-encoded antigen-presenting molecules provides a major hurdle for designing antigens that activate T cells in all humans, the simple population genetics of the CD1 system offers the prospect of discovering or designing broadly acting immunomodulatory agents. PMID- 29152229 TI - Ticking time bombs: connections between circadian clocks and cancer. AB - Connections between mammalian circadian and cell division cycles have been postulated since the early 20th century, and epidemiological and genetic studies have linked disruption of circadian clock function to increased risk of several types of cancer. In the past decade, it has become clear that circadian clock components influence cell growth and transformation in a cell-autonomous manner. Furthermore, several molecular mechanistic connections have been described in which clock proteins participate in sensing DNA damage, modulating DNA repair, and influencing the ubiquitination and degradation of key players in oncogenesis (c-MYC) and tumor suppression (p53). PMID- 29152231 TI - Does penile rehabilitation have a role in the treatment of erectile dysfunction following radical prostatectomy? AB - In men undergoing radical treatment for prostate cancer, erectile function is one of the most important health-related quality-of-life outcomes influencing patient choice in treatment. Penile rehabilitation has emerged as a therapeutic measure to prevent erectile dysfunction and expedite return of erectile function after radical prostatectomy. Penile rehabilitation involves a program designed to increase the likelihood of return to baseline-level erectile function, as opposed to treatment, which implies the therapeutic treatment of symptoms, a key component of post-radical prostatectomy management. Several pathological theories form the basis for rehabilitation, and a plethora of treatments are currently in widespread use. However, whilst there is some evidence supporting the concept of penile rehabilitation from animal studies, randomised controlled trials are contradictory in outcomes. Similarly, urological guidelines are conflicted in terms of recommendations. Furthermore, it is clear that in spite of the lack of evidence for the role of penile rehabilitation, many urologists continue to employ some form of rehabilitation in their patients after radical prostatectomy. This is a significant burden to health resources in public-funded health economies, and no effective cost-benefit analysis has been undertaken to support this practice. Thus, further research is warranted to provide both scientific and clinical evidence for this contemporary practice and the development of preventative strategies in treating erectile dysfunction after radical prostatectomy. PMID- 29152233 TI - Inappropriate use of antibiotics among communities of Gondar town, Ethiopia: a threat to the development of antimicrobial resistance. AB - Background: The emergence of antimicrobial resistance, the main cause of morbidity and mortality from otherwise treatable infections, is largely attributed to the inappropriate use of antimicrobials. However, data on the extent of inappropriate use of antibiotics in the community is scarce in Ethiopia. The aim of present study is to document the extent of inappropriate use of antibiotics and its associated factors among the communities of Gondar, Northwest Ethiopia. Methods: A community based cross-sectional survey was conducted on a total of 650 participants in Gondar town, northwest Ethiopia from December 1, 2016 to January 30, 2017. Descriptive statistics, univariate and multivariate logistic regression analysis were also performed to express different variables and to examine factors associated with inappropriate use of antibiotics. Results: According to the finding of our study, 315 (48.5%) of the participants took antibiotics in the past 1 year, of which 115 (35.9%) of them used inappropriately. Amoxicillin (72%) was the most commonly utilized antibiotics and respiratory tract infection (40.9%) was the most common disease condition to which antibiotics had been sought. About 36.8% of the respondents got antibiotics from community drug retail outlets without a prescription and 67.9% of respondents had discontinued the use of antibiotics once their symptoms subside. Low educational status (AOR = 5.01, 95% CI = 2.62-9.34), being employed (AOR = 2.12, 95% CI = 1.81-7.29) and unsatisfied with health care services provided (AOR = 5.41, 95% CI = 2.71-14.21) were found to be strong predictors of inappropriate use of antibiotics use among the community. Conclusion: Inappropriate use of antibiotics was found to be considerably high in the communities of Gondar, northwest Ethiopia. Taking into consideration the heightened importance of comprehensive knowledge in the rational use of antibiotics, different stakeholders working in the public health sectors should provide a comprehensive and customized education to the public so as to improve their knowledge about antibiotics. It is also essential to adopt a strong and explicit line of actions towards the accessibility of antibiotics without a valid prescription in community medicine retail outlets. PMID- 29152234 TI - Comparison of measured and predicted energy density of an oral care chew for dogs. AB - The dog chew studied here is a starch-based, twin-screw cooker extruded dog care and treat (C&T) product with oral health benefits. The manufacturing process and nutrient profile of such products are markedly different from those of main meal pet foods. Predicted metabolisable energy (PME) in pet food is calculated using equations derived from main meal feeding studies so it is unclear whether these equations can be applied to C&T products. The present study aimed to directly measure metabolisable energy (ME) content of the dog chew in dogs and compare with calculated PME. A batch of dog chews was manufactured and the product rendered micronutrient complete to allow solus feeding. Following a 3 d standard diet pre-feed phase, the test product was fed solus to a panel of seven adult dogs for a period of 8 d. Dietary intake was recorded daily and faecal matter collected for the last 5 d. Test product and pooled faecal samples were analysed for proximate nutrients, and digestibility coefficients were calculated as the difference in intake and faecal excretion (7-11 d). Digestible energy was converted to ME by correcting for energy losses in urine. PME was calculated using proximate analysis and modified Atwater factors according to National Research Council 2006. The results showed close agreement between actual ME (1272 (sd 12.1) kJ/100 g) and calculated PME (1268 (sd 12.6) kJ/100 g), indicating transferability of the NRC 2006 PME equations to the dog chew tested here. PMID- 29152230 TI - Rare fungal infectious agents: a lurking enemy. AB - In the expanding population of immunocompromised patients and those treated in intensive care units, rare fungal infectious agents have emerged as important pathogens, causing invasive infections associated with high morbidity and mortality. These infections may present either as de novo or as breakthrough invasive infections in high-risk patients with hematologic malignancies receiving prophylactic or empirical antifungal therapy or in patients with central venous catheters. Diagnosis and treatment are challenging. Physicians should have a high index of suspicion because early diagnosis is of paramount importance. Conventional diagnostic methods such as cultures and histopathology are still essential, but rapid and more specific molecular techniques for both detection and identification of the infecting pathogens are being developed and hopefully will lead to early targeted treatment. The management of invasive fungal infections is multimodal. Reversal of risk factors, if feasible, should be attempted. Surgical debridement is recommended in localized mold infections. The efficacy of various antifungal drugs is not uniform. Amphotericin B is active against most yeasts, except Trichosporon, as well as against Mucorales, Fusarium, and some species of Paecilomyces and dimorphic fungi. The use of voriconazole is suggested for the treatment of trichosporonosis and scedosporiosis. Combination treatment, though recommended as salvage therapy in some infections, is controversial in most cases. Despite the use of available antifungals, mortality remains high. The optimization of molecular-based techniques, with expansion of reference libraries and the possibility for direct detection of resistance mechanisms, is awaited with great interest in the near future. Further research is necessary, however, in order to find the best ways to confront and destroy these lurking enemies. PMID- 29152232 TI - Recent therapeutic advances in chronic lymphocytic leukemia. AB - The last several years have witnessed a paradigm shift in the management of patients with chronic lymphocytic leukemia (CLL). The course of this very heterogeneous disease, traditionally treated with chemotherapeutic agents usually in combination with rituximab, typically has been characterized by remissions and relapses, and survival times vary greatly, depending on intrinsic biological attributes of the leukemia. The developments of the last few years have been transformative, ushering in an era of novel, molecularly targeted therapies, made possible by extensive efforts to elucidate the biology of the disease that predated the new targeted drugs. Thus, successful therapeutic targeting of the B cell receptor signaling pathway and of the Bcl-2 anti-apoptotic protein with small molecules has now made chemotherapy-free approaches possible, hopefully mitigating the risk of development of therapy-related myeloid neoplasms and making eventual cure of CLL with the use of optimal drug combinations a realistic goal. Most importantly, these therapies have demonstrated unprecedented efficacy in patients with deletion 17p/TP53 mutation, a subset that historically has been very difficult to treat. However, as we gain more experience with the newer agents, unique safety concerns and resistance mechanisms have emerged, as has the issue of cost, as these expensive drugs are currently administered indefinitely. Accordingly, novel laboratory-based strategies and clinical trial designs are being explored to address these issues. The availability of whole exome/genome sequencing has given us profound insights into the mutational landscape of CLL. In this article, we highlight some of the most impactful advances since this topic was last reviewed in this journal. PMID- 29152235 TI - Serum 25-hydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3 concentrations in adult dogs are more substantially increased by oral supplementation of 25 hydroxyvitamin D3 than by vitamin D3. AB - We previously found a weak response in serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations when dogs were supplemented with oral vitamin D3 (D3). In the present study, we determined the relative potency of oral 25(OH)D3 compared with D3 for increasing vitamin D status in dogs with low serum 25(OH)D concentrations. Four male and three female, 4-year-old, intact, lean, genetically related, Chinese-crested/beagle dogs were studied in a randomised, single cross-over trial. After feeding a low-vitamin D diet (<4 IU/100 g) for 30 d, four dogs received daily D3 supplementation at 2.3 ug/kg body weight0.75, while three dogs received a molar equivalency as 25(OH)D3. The supplements, dissolved in ethanol, were applied to a commercial treat for consumption. Serum 25(OH)D3 and 24R,25 dihydroxyvitamin D3 (24R,25(OH)2D3) were analysed weekly using a validated HPLC method. Both supplementations increased (P <= 0.01) serum 25(OH)D3 concentrations. However, oral 25(OH)D3 resulted in greater (P < 0.0001) concentrations than D3 by week 1, with a difference of 173 % (P < 0.0001) by week 2. The supplementation period was limited to 14 d after serum 25(OH)D3 concentrations were not appearing to plateau. Thereafter, a washout period of 1 month separated the cross-over. Following 25(OH)D3, but not D3 supplementation, serum 24R,25(OH)2D3 concentrations increased (P <= 0.02), 3 to 5 weeks after initiating supplementation. Vitamin D status, as indicated by serum 25(OH)D3 and 24R,25(OH)2D3 concentrations, is more rapidly and efficiently increased in adult dogs by oral supplementation of 25(OH)D3 than D3. PMID- 29152237 TI - Analysis of recipes of home-prepared diets for dogs and cats published in Portuguese. AB - The present study evaluated recipes of home-prepared diets for dogs and cats published in Portuguese. A total of 106 diets were evaluated: eighty for dogs, twenty-four for cats and two intended for both species. A commercial software package was used to analyse the diets, and an ingredient chemical composition database was built based on the Brazilian Tables of Food Composition and United States Department of Agriculture Nutrient Database. The estimated chemical composition of each recipe was compared with the Nutritional Guidelines for Complete and Complementary Pet Food for Cats and Dogs (Federation Europeenne de L'industrie des Aliments Pour Animaux Familiers; FEDIAF, 2014) recommendations for maintenance (as units/MJ). Most recipes (48 %) had no precise determination of ingredients and quantities. All diets had at least one nutrient below the recommendations, and all investigated nutrients were deficient in at least one diet. The most frequent nutrients below recommendation were: Fe (68.3 % of the recipes for dogs; 100 % of the recipes for cats); vitamin E (82.9 % of the dog recipes; 84.6 % of the cat recipes); Zn (75.6 % for dogs; 88.4 % for cats); Ca (73.2 % for dogs; 73 % for cats); Cu (85.4 % for dogs; 69.2 % for cats); choline (85.4 % for dogs; 69.2 % for cats); riboflavin (65.8 % for dogs; 11.5 % for cats); thiamine (39 % for dogs; 80.7 % for cats); and vitamin B12 (61 % for dogs; 34.6 % for cats). These recipes may potentially expose animals to nutritional deficiencies, and it is important to inform the owners of the risks of providing home-prepared diets. Better training of professionals that intend to prescribe home-prepared diets is advisable. PMID- 29152236 TI - Low levels of very-long-chain n-3 PUFA in Atlantic salmon (Salmo salar) diet reduce fish robustness under challenging conditions in sea cages. AB - The present study aimed to determine the minimum requirements of the essential n 3 fatty acids EPA and DHA in Atlantic salmon (Salmo salar) that can secure their health under challenging conditions in sea cages. Individually tagged Atlantic salmon were fed 2, 10 and 17 g/kg of EPA + DHA from 400 g until slaughter size (about 3.5 kg). The experimental fish reared in sea cages were subjected to the challenging conditions typically experienced under commercial production. Salmon receiving the lowest EPA + DHA levels showed lower growth rates in the earlier life stages, but no significant difference in final weights at slaughter. The fatty acid composition of various tissues and organs had remarkably changed. The decreased EPA + DHA in the different tissue membrane phospholipids were typically replaced by pro-inflammatory n-6 fatty acids, most markedly in the skin. The EPA + DHA levels were maintained at a higher level in the liver and erythrocytes than in the muscle, intestine and skin. After delousing at high water temperatures, the mortality rates were 63, 52 and 16 % in the salmon fed 2, 10 and 17 g/kg EPA + DHA. Low EPA + DHA levels also increased the liver, intestinal and visceral fat amount, reduced intervertebral space and caused mid-intestinal hyper vacuolisation. Thus, 10 g/kg EPA + DHA in the Atlantic salmon diet, a level previously regarded as sufficient, was found to be too low to maintain fish health under demanding environmental conditions in sea cages. PMID- 29152238 TI - Identifying the metabolomic fingerprint of high and low flavonoid consumers. AB - High flavonoid consumption can improve vascular health. Exploring flavonoid metabolome relationships in population-based settings is challenging, as: (i) there are numerous confounders of the flavonoid-metabolome relationship; and (ii) the set of dependent metabolite variables are inter-related, highly variable and multidimensional. The Metabolite Fingerprint Score has been developed as a means of approaching such data. This study aims to compare its performance with that of more traditional methods, in identifying the metabolomic fingerprint of high and low flavonoid consumers. This study did not aim to identify biomarkers of intake, but rather to explore how systemic metabolism differs in high and low flavonoid consumers. Using liquid chromatography-tandem MS, 174 circulating plasma metabolites were profiled in 584 men and women who had complete flavonoid intake assessment. Participants were randomised to one of two datasets: (a) training dataset, to determine the models for the discrimination variables (n 399); and (b) validation dataset, to test the capacity of the variables to differentiate higher from lower total flavonoid consumers (n 185). The stepwise and full canonical variables did not discriminate in the validation dataset. The Metabolite Fingerprint Score successfully identified a unique pattern of metabolites that discriminated high from low flavonoid consumers in the validation dataset in a multivariate-adjusted setting, and provides insight into the relationship of flavonoids with systemic lipid metabolism. Given increasing use of metabolomics data in dietary association studies, and the difficulty in validating findings using untargeted metabolomics, this paper is of timely importance to the field of nutrition. However, further validation studies are required. PMID- 29152239 TI - Effects of dietary supplementation with a mixed blueberry and grape extract on working memory in aged beagle dogs. AB - Cellular oxidative damage is thought to be one of the key mechanisms underlying age-related cognitive impairment in dogs. Several nutritional interventions to limit cognitive decline are reported in the literature. To our knowledge, the association of grape and blueberry extracts has never been tested in aged dogs. Our objective was to evaluate the effect of a polyphenol-rich extract from grape and blueberry (PEGB) on oxidative status and cognitive performances in aged dogs. A total of thirty-five beagle dogs (aged 8.0-14.5 years) were fed a basal diet with PEGB at either 0 parts per million (ppm) (n 11; control), 240 ppm (n 12; PEGB1) or 480 ppm (n 12; PEGB2) for 75 d. To investigate the effects of PEGB supplementation on cognition and oxidative status, a delayed non-matching to position (DNMP) test and RT-PCR on genes involved in oxidative stress were evaluated. The dogs fed PEGB1 showed a higher superoxide dismutase mRNA expression compared with dogs fed PEGB2 (P = 0.042) and with the control group (P = 0.014). Moreover, the dogs fed PEGB2 showed higher nuclear factor-like 2 (Nrf2) mRNA expression compared with the dogs fed PEGB1 (P = 0.027). Concerning the DNMP test, the proportion of dogs showing cognitive improvements relative to their baseline level was significantly higher in dogs fed the PEGB, regardless of the dosage, than in dogs receiving no supplementation (P = 0.030). The results obtained in the DNMP test suggested a potential benefit of the PEGB on working memory. However, this hypothesis should be further investigated to confirm this cognitive effect. PMID- 29152240 TI - Nutrient digestibility, hindgut metabolites and antioxidant status of dogs supplemented with pomegranate peel extract. AB - The present study assessed the effect of dietary supplementation of pomegranate peel (methanolic) extract (PPE) on the nutrient digestibility, faecal fermentative metabolites and antioxidant status of dogs. Six medium-sized dogs of mixed breeds were allocated to two groups in a replicated cross-over design and fed a basal diet with and without supplementation of PPE at 50 mg/kg body weight. Each of the experimental periods consisted of 30 d, with a 21 d washout period in between. Results indicated that PPE supplementation led to no significant changes in nutrient digestibility except a trend of improvement (P = 0.070) in crude fibre digestibility. PPE supplementation significantly (P < 0.001) influenced faecal pH, ammonia and lactate production, indicative of positive effects of PPE polyphenols. PPE supplementation further increased faecal SCFA concentration accompanied by a reduction (P < 0.01) in branched-chain fatty acids. PPE supplementation also improved (P < 0.05) indices of erythrocytic antioxidants, namely reduced glutathione, catalase, glutathione peroxidase and glutathione S transferase together with an improvement in lipid peroxidation. Overall, it can be concluded that dietary supplementation with PPE at 50 mg/kg body weight had a positive impact on hindgut fermentation and antioxidant status in dogs, thereby demonstrating its potential as a gut health-promoting nutraceutical. PMID- 29152241 TI - Effects of matrix on plasma levels of EPA and DHA in dogs. AB - EPA and DHA are often used in veterinary medicine due to their beneficial effects for several medical conditions such as osteoarthritis. EPA and DHA are administered to dogs through different matrices. The aim of the present study was to determine the effects on the plasma levels in dogs caused by various matrices for EPA and DHA administration. In this study, three different n-3 PUFA formulations were used: soft chew tablet (CCx); liquid fish oil (LFO); and enriched kibbles (EK). The formulations were administered single-dose and compared in a randomised, cross-over designed study with a 1-week wash-out period. Several variables were observed after the administration of these formulations in thirteen dogs: the NEFA plasma concentration, the AUC for 1 d (AUC0-24 h), and maximum plasma concentration for both EPA and DHA. All plasma fatty acid levels reached baseline levels within 72 h. CCx (median = 2.987) had a significantly lower AUC0-24 h for EPA compared with LFO (median = 5.647, P = 0.043) and EK (median = 5.119, P = 0.032) (F2,22 = 4.637, P = 0.021). CCx (median = 2.471) AUC0-24 h for DHA was significantly lower compared with LFO (median = 4.837, Z = -2.56, P = 0.011) and EK (median = 4.413, Z = -2.59, P = 0.01). EPA and DHA plasma levels were affected by matrix, as with the CCx, the AUC0-24 h of EPA and DHA were both lower compared with LFO and EK. The effect of matrix on bioavailability is important for product development as well as for clinical trials studying effects of EPA and DHA. PMID- 29152242 TI - Comparative assessment of canine-origin Lactobacillus johnsonii CPN23 and dairy origin Lactobacillus acidophillus NCDC 15 for nutrient digestibility, faecal fermentative metabolites and selected gut health indices in dogs. AB - The present experiment was undertaken to validate a probiotic of canine origin for its potential use in dogs. A total of fifteen adult female Labrador dogs were allocated to three equal groups and fed a basal diet without probiotic (control) or with probiotic of either canine (Lactobacillus johnsonii CPN23; cPRO) or dairy (L. acidophilus NCDC 15; dPRO) origin for 9 weeks. The digestibility of most macronutrients remained similar among the groups; however, fibre digestibility was improved (P = 0.034) in dogs receiving cPRO. The faecal fermentative metabolites ammonia (P < 0.05) and lactate (P = 0.094) were altered favourably, indicating a positive influence of both probiotics. Faecal concentrations of acetate, propionate and butyrate were increased (P < 0.01) in both probiotic groups. However, improvements were higher in cPRO v. dPRO. The delayed-type hypersensitivity reaction to intradermal inoculation of phytohaemagglutinin-P was higher (P = 0.053) in cPRO as compared with control. The antibody response to sheep erythrocytes was, however, similar across the three groups. Overall, in dogs, the canine-origin probiotic was superior when compared with the dairy origin probiotic. PMID- 29152243 TI - Effect of pomegranate extract on blood pressure and anthropometry in adults: a double-blind placebo-controlled randomised clinical trial. AB - Pomegranate (Punica granatum), a polyphenol-rich fruit, has been suggested to reduce cardiovascular risk due to its antioxidant properties. Hypertension and obesity are the most preventable cardiovascular risk factors. Few studies on blood pressure and/or body-weight status have been conducted in human subjects. Previous investigations have tended to focus on pomegranate juice. The aim of the present study was to investigate the effect of pomegranate extract (PE) on blood pressure and anthropometric measures in adults with no symptomatic disease. A total of fifty-five participants enrolled in a randomised double-blinded placebo controlled clinical trial where they were assigned to either PE capsules or placebo capsules for 8 weeks. Blood pressure, body weight, waist circumference, waist:hip ratio (WHR) and body composition (lean body mass, body fat) were measured at baseline, week 4 and week 8. Results showed a significant decrease in diastolic blood pressure after 8 weeks (by 2.79 (sd 5.32) mmHg; P < 0.05), while the decrease in systolic blood pressure did not reach statistical significance (2.57 (sd 7.4) mmHg; P > 0.05). Body fat percentage, lean body mass, waist circumference and WHR did not significantly differ between groups at the end of the intervention. Results suggest that PE may reduce blood pressure and possibly prevent hypertension in the normotensive population. Further large trials are required to elucidate this effect. PMID- 29152244 TI - Effect of dietary protein intake on the body composition and metabolic parameters of neutered dogs. AB - Neutering is a common veterinary recommendation and is often associated with obesity development. Thus, the aim of the present study was to evaluate the effects of two different amounts of protein intake by neutered dogs regarding maintenance energy requirement (MER), body composition, and biochemical and hormonal parameters. A total of fourteen healthy adult dogs were fed either a diet containing 59.7 g protein/1000 kcal (4184 kJ) (P60) or a diet with 94.0 g protein/1000 kcal (4184 kJ) (P94) for 26 weeks after neutering to maintain their body weight prior to neutering. A mixed model was fitted to verify diet, time and diet * time interaction effects on biochemical parameters, serum concentrations of insulin, glucagon, leptin and insulin-like growth factor-1 (IGF-1). MER and the body composition data were evaluated within diets (paired t test) and within times (unpaired t test). A time effect was found for fructosamine, TAG, total lipids and IGF-1 serum concentrations. The diet * time interaction was significant for glucagon (P < 0.05). No differences between diets in the MER within each time were found. However, there was a reduction in the MER of dogs fed the P60 diet 26 weeks after neutering (P = 0.042). The fat body mass of dogs fed the P60 diet increased (P < 0.05) after neutering, even without a body-weight change. Some of the biochemical parameters changed over time, but all remained within the normal range. For the period evaluated in the present study, a diet with 94.0 g of protein/1000 kcal (4184 kJ) metabolisable energy seems to be a beneficial nutritional strategy to maintain the MER and the body composition of dogs after neutering. PMID- 29152246 TI - The effect of reducing energy density, via the addition of water to dry diet, on body weight and activity in dogs. AB - Approximately 40 % of pet dogs are estimated to be overweight and this is associated with health conditions significantly reducing life span and quality. In cats, dietary energy dilution has been reported to increase activity levels and aid healthy body-weight maintenance. Our aim was to investigate this in dogs. For 28 d, a complete and balanced standard dry diet, hydrated to a total moisture content (TMC) of 72 %, was offered to forty-six dogs at individual maintenance energy requirements (MER). Intake, body weight and activity were measured. For the following 28 d, the dry diet was offered at 200 % of MER with or without hydration (7.6 or 72 % TMC) and measurements repeated. When offered diets in excess, body weight increased significantly faster (19.3 g/d) with the hydrated diet (P = 0.001), but activity levels did not change from baseline (P = 0.392), while activity reduced significantly with the dry diet (about 15 %; P < 0.001). Dogs completely compensated for the reduction of dietary energy content, indicating that this is not a useful strategy for maintaining body weight when offered excess food. PMID- 29152245 TI - Metabolic syndrome and inflammation in adipose tissue occur at different times in animals submitted to a high-sugar/fat diet. AB - Obesity is associated with low-grade inflammation, triggered in adipose tissue, which may occur due to an excess of SFA from the diet that can be recognised by Toll-like receptor-4. This condition is involved in the development of components of the metabolic syndrome associated with obesity, especially insulin resistance. The aim of the study was to evaluate the manifestation of the metabolic syndrome and adipose tissue inflammation as a function of the period of time in which rats were submitted to a high-sugar/fat diet (HSF). Male Wistar rats were divided into six groups to receive the control diet (C) or the HSF for 6, 12 or 24 weeks. HSF increased the adiposity index in all HSF groups compared with the C group. HSF was associated with higher plasma TAG, glucose, insulin and leptin levels. Homeostasis model assessment increased in HSF compared with C rats at 24 weeks. Both TNF-alpha and IL-6 were elevated in the epididymal adipose tissue of HSF rats at 24 weeks compared with HSF at 6 weeks and C at 24 weeks. Only the HSF group at 24 weeks showed increased expression of both Toll-like receptor-4 and NF kappaB. More inflammatory cells were found in the HSF group at 24 weeks. We can conclude that the metabolic syndrome occurs independently of the inflammatory response in adipose tissue and that inflammation is associated with hypertrophy of adipocytes, which varies according to duration of exposure to the HSF. PMID- 29152247 TI - Effects of different protein sources on fermentation metabolites and nutrient digestibility of brachycephalic dogs. AB - Benefits to microbial fermentation in the colon and as a consequence less flatulence can be promoted for the health of adult dogs according to the amount and protein source. The present study evaluated different protein sources in dry food for brachycephalic dogs regarding microbial fermentation and nutrient digestibility. Four dry dog foods with similar protein content were formulated for adult maintenance: poultry meal (PM) diet; wheat gluten (WG) diet; PM + WG diet; and PM + WG + hydrolysed protein (HP) diet. Eight French bulldog adult dogs were arranged in a 4 * 4 Latin square design during the 28 d trial. Fresh faeces were collected for assessment of nutrient digestibility and analyses of faecal pH, SCFA, biogenic amines, ammonia and lactate. Means were compared by the PROC MIXED procedure of SAS and by Tukey's test, considering P <= 0.05. The animals fed the WG and PM + WG diets showed higher digestibility for DM (P < 0.05), organic matter (P < 0.05), crude protein (P < 0.001) and lower faeces production (P < 0.02) than the PM and PM + WG + HP diets. Feeding diet PM + WG + HP resulted in lower faecal score and pH (P < 0.05) compared with other diets. Concentrations of fermentation metabolites were not statistically significantly different among diets. In conclusion, WG alone or in combination with PM improved protein and DM digestibility. Fermentation products were not affected by protein source. PMID- 29152248 TI - Nutritional management of search and rescue dogs. AB - Dogs used for search and rescue (SAR) may experience continuous micro-traumas that predispose them to skeletal disorders. The aim of the present study was to evaluate the effect of diet on osteo-articular apparatus in healthy SAR dogs. A total of sixteen SAR dogs were divided into two groups (low supplementation (LS) and high supplementation (HS)) and were fed for 3 months with two experimental diets, characterised by the same protein and energy density, but different in n-3 PUFA (6.2 v. 8.4 % of metabolisable energy), chondroitin sulfate (219.8 v. 989.0 mg/kg DM) and glucosamine (769.2 v. 1318.7 mg/kg DM) in the LS and HS groups, respectively. At recruitment all dogs showed no joint inflammation signs, except four that showed mild symptoms. Haematology and serum biochemistry were performed every 30 d. Joint status was scored by physical and lameness evaluations. The sampling effect analysis showed potential beneficial effects by a decrease in a specific marker of membrane integrity (creatine kinase; CK). Comparing groups, glucose was significantly higher and CK was significantly lower in the HS group; however, in both cases the levels of these parameters fell in the normal range. At the end of the experiment, erythrocytes, Hb and packed cell volume were significantly higher in the HS compared with the LS group. These could result in an improvement in dogs' performance, even if this aspect was not investigated in the present study. Concerning joint evaluation (pain on manipulation, lameness and range of motion), no statistically significant differences were detected between the groups and within the experimental period. PMID- 29152249 TI - A survey of feeding, activity, supplement use and energy consumption in North American agility dogs. AB - A survey was designed and administered at eighteen agility competitions across the Northeast and Midwest USA in 2015 to obtain information regarding competition level, training, feeding practices, owner-reported weight, body condition score (BCS) and supplement use. Average energy intake per d from reported consumption was assessed for all dogs in ideal body condition based on manufacturers' or US Department of Agriculture database information. To assess the respective parameters across competition levels (novice, open, master/elite), non-parametric or parametric ANOVA or chi2 was used to determine significance. There were 494 respondents with usable data. Results showed that approximately 99 % of respondents used treats and 62 % utilised supplements. Of the respondents, 61 % fed primarily commercial dry food. Approximately 25 % of owners fed foods other than commercial dry (i.e. raw/home-prepared or freeze-dried). This 25 % of non traditional diets included: 11 % home-prepared raw/cooked diets, 11 % commercial raw/cooked diets, and the remaining 3 % were fed commercial freeze-dried raw products. The remaining 14 % fed a mix of commercial dry food and raw/home-cooked blend. Average BCS was 4.7 (sd 1.1). Mean energy consumption of 238 dogs (BCS 4 5/9) was 444 (sd 138) kJ/kg body weight0.75 per d (106 (sd 33) kcal/kg body weight0.75 per d), with no significant differences observed between dogs at different levels of competition. The mean percentage of energy from treats was 15.1 (sd 12.7) % of overall energy consumption. PMID- 29152250 TI - Development and evaluation of a concise food list for use in a web-based 24-h dietary recall tool. AB - Foodbook24 is a self-administered web-based 24-h dietary recall tool developed to assess food and nutrient intakes of Irish adults. This paper describes the first step undertaken in developing Foodbook24 which was to limit participant burden by establishing a concise list of food items for inclusion in the tool. The aim of the present study was to evaluate whether using a concise food list (as opposed to an extensive list) with generic composition data would influence the estimates of nutrient intakes in a nationally representative sample of Irish adults. A 2319 item food list generated from the Irish National Adult Nutrition Survey (NANS) (2008-2010) (n 1500) was used as the basis for a shortened food list for integration into the tool. Foods similar in nutritional composition were recoded with a generic type food code to produce a concise list of 751 food codes. The concise food list was applied to the NANS food consumption dataset and intake estimates of thirty-five nutrients were compared with estimates derived using the original extensive list. Small differences in nutrient intakes (<6 %) with limited effect size (Cohen's d < 0.1) were observed between estimates from both food lists. The concise food list showed strong positive correlations (rs 0.9 1.0, n 1500, P < 0.001) and a high level of agreement with the extensive list (80 97 % of nutrient intakes classified into the same tertile; >90% of intakes similarly categorised according to dietary reference values). This indicates that a concise food list is suitable for use in a web-based 24-h dietary recall tool for Irish adults. PMID- 29152251 TI - Oxygen - the forgotten nutrient. AB - O2 is essential for the maintenance and growth of aerobic animals, similar to the essentiality of what are classically considered nutrients. Nevertheless, O2 is not customarily regarded as a nutrient, this reflecting the route by which it enters the body - through the lungs or gills in vertebrates, rather than via the mouth and gastrointestinal tract. A relative deficiency of O2 occurs at high altitudes and during deep-sea diving, to which distinct adaptations occur. Deficiency is also evident in lung diseases such as emphysema. Without O2, mitochondrial respiration and oxidative phosphorylation cannot take place. At a molecular level, cells adapt to O2 deficiency by switching from oxidative metabolism to anaerobic glycolysis and there are changes in the expression of a multiplicity of genes, driven by hypoxia-sensitive transcription factors, particularly hypoxia-inducible factor-1. It is argued that O2 should be fully included within the remit of nutritional science alongside the other essential macronutrients. PMID- 29152252 TI - Effect of fish oil and vitamin E on sperm lipid peroxidation in dogs. AB - The objective was to evaluate the effects of dietary fish oil (FO) and vitamin E (VE) supplementation on sperm sensitivity to lipid peroxidation (LP) in dogs. Using an incomplete replicate 3 * 3 Latin square design, five dogs were allocated into three groups. One of the squares was incomplete and had two dogs that were used with three treatments. The dogs were assigned to three different treatments, fed a control diet of balanced commercial food (control group; CG), control diet supplemented with 54 mg FO/kg body weight0.75 per d (FO group; FG) and FO plus 400 mg VE per d (FO and VE group; FEG) for 60 d. Semen samples were collected on days 0 and 60 and divided into two halves, peroxidised and control, with or without ascorbate-Fe2+, respectively. LP was measured in both halves by chemiluminescence as counts per min/mg protein. Fatty acid profile was determined by GC. Data were analysed using the mixed procedure (SAS). On day 0, LP increased in all groups in the peroxidised samples (P < 0.05). However, on day 60 LP decreased in peroxidised samples of both the FG and FEG (P < 0.05), but there were no differences between the FG and FEG (P > 0.1). Additionally, on day 60 total n-3 was higher in the FG and FEG compared with the CG (P < 0.05). Supplementation with FO alone or together with VE decreased LP in peroxidised samples. These results could indicate a protective effect of n-3 on sperm. More studies are needed to understand the mechanism whereby FO and/or FO plus VE decrease LP in dogs' sperm. PMID- 29152253 TI - Evaluation of dietary intake assessed by the Dutch self-administered web-based dietary 24-h recall tool (Compl-eatTM) against interviewer-administered telephone based 24-h recalls. AB - Self-administered web-based 24-h dietary recalls (24 hR) may save a lot of time and money as compared with interviewer-administered telephone-based 24 hR interviews and may therefore be useful in large-scale studies. Within the Nutrition Questionnaires plus (NQplus) study, the web-based 24 hR tool Compl eatTM was developed to assess Dutch participants' dietary intake. The aim of the present study was to evaluate the performance of this tool against the interviewer-administered telephone-based 24 hR method. A subgroup of participants of the NQplus study (20-70 years, n 514) completed three self-administered web based 24 hR and three telephone 24 hR interviews administered by a dietitian over a 1-year period. Compl-eatTM as well as the dietitians guided the participants to report all foods consumed the previous day. Compl-eatTM on average underestimated the intake of energy by 8 %, of macronutrients by 10 % and of micronutrients by 13 % as compared with telephone recalls. The agreement between both methods, estimated using Lin's concordance coefficients (LCC), ranged from 0.15 for vitamin B1 to 0.70 for alcohol intake (mean LCC 0.38). The lower estimations by Compl-eatTM can be explained by a lower number of total reported foods and lower estimated intakes of the food groups, fats, oils and savoury sauces, sugar and confectionery, dairy and cheese. The performance of the tool may be improved by, for example, adding an option to automatically select frequently used foods and including more recall cues. We conclude that Compl-eatTM may be a useful tool in large-scale Dutch studies after suggested improvements have been implemented and evaluated. PMID- 29152255 TI - Effects of monobutyrin and tributyrin on liver lipid profile, caecal microbiota composition and SCFA in high-fat diet-fed rats. AB - Butyric acid has been shown to have suppressive effects on inflammation and diseases related to the intestinal tract. The aim of the present study was to investigate whether supplementation of two glycerol esters, monobutyrin (MB) and tributyrin (TB), would reach the hindgut of rats, thus having an effect on the caecal profile of SCFA, microbiota composition and some risk markers associated with chronic inflammation. For this purpose, rats were fed high-fat diets after adding MB (1 and 5 g/kg) and TB (5 g/kg) to a diet without any supplementation (high-fat control; HFC). A low-fat (LF) diet was also included. In the liver, total cholesterol concentrations, LDL-cholesterol concentrations, LDL:HDL ratio, and succinic acid concentrations were reduced in rats given the MB and TB (5 g/kg) diets, compared with the group fed the HFC diet. These effects were more pronounced in MB than TB groups as also expressed by down-regulation of the gene Cyp8b1. The composition of the caecal microbiota in rats fed MB and TB was separated from the group fed the HFC diet, and also the LF diet, as evidenced by the absence of the phylum TM7 and reduced abundance of the genera Dorea (similar to LF-fed rats) and rc4-4. Notably, the caecal abundance of Mucispirillum was markedly increased in the MB group compared with the HFC group. The results suggest that dietary supplementation of MB and TB can be used to counteract disturbances associated with a HFC diet, by altering the gut microbiota, and decreasing liver lipids and succinic acid concentrations. PMID- 29152254 TI - Calcium intake and the associations with faecal fat and energy excretion, and lipid profile in a free-living population. AB - The aim of the present study was to investigate the associations between the habitual Ca intake and faecal fat and energy excretion as well as blood lipid profile in free-living normal-weight and overweight individuals. The participants were enrolled for an 8-d period where data from a 7-d diet registration (days 1 7), a 5-d faeces collection (days 3-7), a 2-d urine collection (days 5-7), and anthropometric measurements and a fasting blood sample (day 8) were collected. Analyses showed that dietary Ca intake (g/10 MJ per d) was positively associated with excretion of faecal fat (P = 0.004) and energy (P = 0.031) when adjusted for BMI, age, sex and intake of Ca-containing supplements. However, after adjustment for intake of fibre, the effect of Ca intake disappeared. Nevertheless, total cholesterol (CHOL) and LDL-CHOL concentrations were associated negatively with Ca intake (beta -0.62 (95 % CI -0.96, -0.28) mmol/l, P < 0.001, and beta -0.49 (95 % CI -0.78, -0.20) mmol/l, P = 0.001, respectively, per 1000 mg/10 MJ per d increase in Ca intake). In conclusion, incorporation of Ca-rich food products in a habitual diet was associated with reduced total CHOL and LDL-CHOL concentrations, which may lower the risk of CVD in the long term. PMID- 29152256 TI - Consumption of kiwifruit capsules increases Faecalibacterium prausnitzii abundance in functionally constipated individuals: a randomised controlled human trial. AB - This study investigated the impact of ACTAZINTM green (2400 and 600 mg) and LivauxTM (2400 mg) gold kiwifruit supplements on faecal microbial composition and metabolites in healthy and functionally constipated (FC) participants. The participants were recruited into the healthy group (n 20; one of whom did not complete the study) and the FC group (n 9), each of whom consumed all the treatments and a placebo (isomalt) for 4 weeks in a randomised cross-over design interspersed with 2-week washout periods. Modification of faecal microbiota composition and metabolism was determined by 16S rRNA gene sequencing and GC, and colonic pH was calculated using SmartPill(r) wireless motility capsules. A total of thirty-two taxa were measured at greater than 1 % abundance in at least one sample, ten of which differed significantly between the baseline healthy and FC groups. Specifically, Bacteroidales and Roseburia spp. were significantly more abundant (P < 0.05) in the healthy group and taxa including Ruminococcaceae, Dorea spp. and Akkermansia spp. were significantly more abundant (P < 0.05) in the FC group. In the FC group, Faecalibacterium prausnitzii abundance significantly increased (P = 0.024) from 3.4 to 7.0 % following LivauxTM supplementation, with eight of the nine participants showing a net increase. Lower proportions of F. prausnitzii are often associated with gastrointestinal disorders. The discovery that LivauxTM supplementation increased F. prausnitzii abundance offers a potential strategy for improving gut microbiota composition, as F. prausnitzii is a butyrate producer and has also been shown to exert anti inflammatory effects in many studies. PMID- 29152257 TI - A new model for evaluating maintenance energy requirements in dogs: allometric equation from 319 pet dogs. AB - Reports concerning maintenance energy requirements (MER) in dogs are common but most of the data cover laboratory or utility dogs. This study establishes those of healthy adult pet dogs and the factors which cause these energy requirements to vary. Within the framework of a nutrition teaching exercise, each student followed a pet from his entourage and gathered accurate records of its feeding habits. Data have been restricted to healthy adult dogs with an ideal body weight (BW) which did not vary more than 5 % during the study period. A total of 319 eligible records were analysed using multiple linear regression. Variation factors such as ownership, breed, sex and neutered status, bedding location, temperament and feeding habits were then analysed individually using a non parametric model. Two models result from this study, one excluding age (r2 0.813) and a more accurate one which takes into consideration the age in years (r2 0.816). The second model was assessed with the main variation factors and shows that: MER (kcal) = k1 * k2 * k3 * k4 * k5 * 128 * BW0.740 * age-0.050/d (r2 0.836), with k1 the effect of the breed, k2 the effect of sex and neutered status, k3 the effect of bedding location, k4 the effect of temperament and k5 the effect of the type of feed. The resulting model is very similar to the recommendations made by the National Research Council (2006) but a greater accuracy was obtained using age raised to a negative power, as demonstrated in human nutrition. PMID- 29152258 TI - In vitro screening of neuroprotective activity of Indian medicinal plant Withania somnifera. AB - Canine cognitive dysfunction (CCD) is an age-dependent neurodegenerative condition characterised by changes in decline in learning and memory patterns. The neurodegenerative features of CCD in ageing dogs and cats are similar to human ageing and Alzheimer's disease (AD). Discovering neuroprotective disease modifying therapies against CCD and AD is a major challenge. Strong evidence supports the role of amyloid beta peptide deposition and oxidative stress in the pathophysiology of CCD and AD. In both the human and canine brain, oxidative damage progressively increases with age. Dietary antioxidants from natural sources hold a great promise in halting the progression of CCD and AD. Withania somnifera (WS), an Ayurvedic tonic medicine, also known as 'Indian ginseng' or ashwagandha has a long history of use in memory-enhancing therapy but there is a dearth of studies on its neuroprotective effects. The objective of this study was to investigate whether WS extract can protect against Abeta peptide- and acrolein induced toxicity. We demonstrated that treatment with WS extract significantly protected the human neuroblastoma cell line SK-N-SH against Abeta peptide and acrolein in various cell survival assays. Furthermore, treatment with WS extract significantly reduced the generation of reactive oxygen species in SK-N-SH cells. Finally, our results showed that WS extract is also a potent inhibitor of acetylcholinesterase activity. Thus, our initial findings indicate that WS extract may act as an antioxidant and cholinergic modulator and may have beneficial effects in CCD and AD therapy. PMID- 29152259 TI - Prevalence of malnutrition and risk of undernutrition in hospitalised children with liver disease. AB - Nutritional status of 380 hospitalised children aged from 1 month to 5 years with liver disease was evaluated in a single paediatric centre. The total prevalence of stunting (height-for-age Z (HAZ) < -2), underweight (weight-for-age Z (WAZ) < 2) and wasting (weight-for-height Z < -2) was 9.8, 9.0 and 7.9 %, respectively. The overall nutritional risk (-2 <= Z < -1) of stunting, underweight and wasting was 11.8, 12.9 and 12.6 %. The prevalence of undernutrition was significantly higher in children with cholestasis than children without cholestasis (stunting, 17.5 %/4.4 %, P < 0.001, and underweight, 14.9 %/4.9 %, P < 0.001). HAZ and WAZ scores were significantly higher in children without cholestasis than children with cholestasis (0.58 (sd 1.59)/-0.68 (sd 1.99), P < 0.001, and 0.37 (sd 1.35)/ 0.47 (sd 1.75), P < 0.001). Further multivariate logistic regression analysis strengthened the evidence that cholestasis was significantly associated with undernutrition of stunting (OR = 4.18, P = 0.002) and underweight (OR = 3.26, P = 0.008), and suggested that the prevalence of stunting caused by infection was lower than other aetiologies in hospitalised children with liver disease (OR = 0.10, P = 0.002). We concluded that a high prevalence of malnutrition and risk of undernutrition presents in hospitalised young children with liver disease, especially in children with cholestasis. Nutrition assessment is recommended for hospitalised children with liver disease. PMID- 29152260 TI - Improving estimates of the burden of severe acute malnutrition and predictions of caseload for programs treating severe acute malnutrition: experiences from Nigeria. AB - Background: The burden of severe acute malnutrition (SAM) is estimated using unadjusted prevalence estimates. SAM is an acute condition and many children with SAM will either recover or die within a few weeks. Estimating SAM burden using unadjusted prevalence estimates results in significant underestimation. This has a negative impact on allocation of resources for the prevention and treatment of SAM. A simple method for adjusting prevalence estimates intended to improve the accuracy of burden estimates and caseload predictions has been proposed. This method employs an incidence correction factor. Application of this method using the globally recommended incidence correction factor has led to programs underestimating burden and caseload in some settings. Methods: A method for estimating a locally appropriate incidence correction factor from prevalence, population size, program caseload, and program coverage was developed and tested using data from the Nigerian national SAM treatment program. Results: Applying the developed method resulted in errors in caseload prediction of about 10%. This is a considerable improvement upon the current method, which resulted in a 79.5% underestimate. Methods for improving the precision of estimates are proposed. Conclusions: It is possible to considerably improve predictions of caseload by applying a simple model to data that are readily available to program managers. This implies that more accurate estimates of burden may also be made using the same methods and data. PMID- 29152262 TI - Prosthetic rehabilitation of edentulous hemimandibulectomy patient: a clinical report. AB - Surgical resection of mandible causes deviation of mandible toward affected side, resulting in loss of occlusal contact. This article presents twin rows of nonanatomic teeth on the untreated side of maxillary complete denture. The palatal row helps in mastication, whereas the buccal row supports the cheeks and improves the aesthetics. PMID- 29152261 TI - COPD management as a model for all chronic respiratory conditions: report of the 4th Consensus Conference in Respiratory Medicine. AB - Background: Non-communicable diseases (NCDs) kill 40 million people each year. The management of chronic respiratory NCDs such as chronic obstructive pulmonary disease (COPD) is particularly critical in Italy, where they are widespread and represent a heavy burden on healthcare resources. It is thus important to redefine the role and responsibility of respiratory specialists and their scientific societies, together with that of the whole healthcare system, in order to create a sustainable management of COPD, which could become a model for other chronic respiratory conditions. Methods: These issues were divided into four main topics (Training, Organization, Responsibilities, and Sustainability) and discussed at a Consensus Conference promoted by the Research Center of the Italian Respiratory Society held in Rome, Italy, 3-4 November 2016. Results and conclusions: Regarding training, important inadequacies emerged regarding specialist training - both the duration of practical training courses and teaching about chronic diseases like COPD. A better integration between university and teaching hospitals would improve the quality of specialization. A better organizational integration between hospital and specialists/general practitioners (GPs) in the local community is essential to improve the diagnostic and therapeutic pathways for chronic respiratory patients. Improving the care pathways is the joint responsibility of respiratory specialists, GPs, patients and their caregivers, and the healthcare system. The sustainability of the entire system depends on a better organization of the diagnostic-therapeutic pathways, in which also other stakeholders such as pharmacists and pharmaceutical companies can play an important role. PMID- 29152263 TI - Late-onset hemophagocytic lymphohistiocytosis with neurological presentation. AB - Missense mutations in genes involved in familial hemophagocytic lymphohistiocytosis can delay the onset of this life-threatening disease. In children and adults, early recognition of aspecific features as neurological symptoms is crucial as urgent treatment is required. PMID- 29152264 TI - Live-attenuated vaccines in a cryopyrin-associated periodic syndrome patient receiving canakinumab treatment during infancy. AB - We successfully immunized the neonatal-onset multisystem inflammatory disease (NOMID) patient with live-attenuated vaccines for measles, rubella, varicella, and mumps and achieved sufficient antibody titer under canakinumab therapy without complications. PMID- 29152266 TI - Vaccine-associated measles in an immunocompetent child. AB - We present a rare case of vaccine-associated measles infection in an immunocompetent, HIV-negative patient in the United States. This case depicts the impressive rash our patient manifested and highlights the importance of reviewing public health interventions to determine epidemiological links in geographical areas with low incidence of measles. PMID- 29152265 TI - Hemophagocytic syndrome in pregnancy: case report, diagnosis, treatment, and prognosis. AB - Diagnosis of hemophagocytic syndrome remains a challenge in particular during pregnancy. Concomitant presence of clinical and biological signs, for example, fever, pancytopenia, hyperferritinemia, and hypertriglyceridemia, should alert clinicians to suspect HPS and proceed to prompt treatments. PMID- 29152267 TI - Acromegaly and Cushing's syndrome caused by a neuroendocrine tumor arising within a sacrococcygeal teratoma. AB - A 60-year-old man with a pre-existing stable sacrococcygeal teratoma developed acromegaly, ectopic Cushing's syndrome, and 5HIAA secretion. To our knowledge, this represents the first reported case of ACTH and serotonin secretion, and likely GHRH or GH cosecretion, from a sacrococcygeal teratoma in an adult. PMID- 29152268 TI - Dextrocardia with asymptomatic right atrial appendage aneurysm: a case report. AB - Right atrial appendage aneurysm (RAAA) is rarely encountered with variable intracardiac anatomy. We report a case of asymptomatic RAAA in a patient with dextrocardia and anomalous origin of RCA from left coronary sinus which was treated successfully by CABG and the aneurysm was completely excised. PMID- 29152269 TI - Leptospirosis presenting as acute acalculous cholecystitis. AB - Leptospirosis is the commonest zoonotic infection worldwide but is vastly underreported and extremely heterogeneous in its presentation. Acalculous cholecystitis is an under recognized presentation of acute leptospirosis. In the appropriate clinical context, with a clear exposure history, recognition of this association presents a unifying diagnosis and limits unnecessary surgical interventions. PMID- 29152270 TI - Complete remission of chemo-refractory multiple-metastatic upper tract urothelial carcinoma by autologous formalin-fixed tumor vaccine. AB - A patient with chemo-refractory multiple-metastatic upper tract urothelial carcinoma (UTUC) treated by monotherapy with autologous formalin-fixed tumor vaccine (AFTV) resulted in complete remission of the lung and para-aortic lymph node metastases (ongoing >3 years after AFTV). The tumor was immunohistologically negative for PD-L1. AFTV will be an attractive treatment option. PMID- 29152271 TI - c.464A>G variation in the GJB2 gene is detected in a Han Chinese family. AB - We report two heterozygous carriers of c.464A>G variation in the GJB2 gene in a Chinese pedigree. The proband with hearing loss most likely inherited the c.464A>G variation from his mother who also carries heterozygous c.79G>A variation and has normal hearing. The pathological significance of c.464A>G variation remains to be determined. PMID- 29152272 TI - Rare behavior of follicular variant of papillary thyroid cancer. AB - Follicular variant of papillary thyroid cancer typically favors nodal spread. We report a case with hematogenous spread including multi-organ involvement and describe our staged management approach. This is the first case to report follicular variant of papillary thyroid cancer with simultaneous adrenal and renal involvement. PMID- 29152273 TI - Orbital pseudotumor as a result of chronic sinusitis in an HIV-positive patient. AB - Orbital inflammatory pseudotumor is an infrequent lesion that may mimic malignancy and may be associated with autoimmune disease. Orbital pseudotumor is in the differential in any patient with an orbital mass, especially in the setting of chronic infection or immunosuppression. This HIV-positive patient presented with chronic sinusitis and orbital pseudotumor. PMID- 29152274 TI - A case of successful bystander cardiopulmonary resuscitation of an adult with Bland-White-Garland syndrome. AB - In Japan and worldwide, the increase in educational interventions about resuscitation training significantly increases favorable neurological survival in out-of-hospital cardiopulmonary arrest cases treated with bystander cardiopulmonary resuscitation (BCPR) each year. This case with Bland-White Garland syndrome having high-quality BCPR by nurses demonstrates the importance of education about BCPR. PMID- 29152275 TI - Isolated myeloid sarcoma as the first manifestation of acute myeloid leukemia: a case study. AB - This case report brings awareness to the diverse extramedullary manifestations of isolated myeloid sarcoma, as well as the importance and difficulties that are associated with establishing a rapid diagnosis and initiating treatment. PMID- 29152276 TI - Percutaneous mitral valve repair with the MitraClip NTTM system in a patient presenting with prolonged cardiogenic shock. AB - The MitraClip NTTM system for the treatment of severe mitral valve regurgitation is effective and safe - even for patients suffering from cardiogenic shock. The use of an intra-aortic balloon pump expands the range of possible applications to this particular group of challenging patients. PMID- 29152277 TI - Uveal myxoid leiomyosarcoma in a horse. AB - A uveal leiomyosarcoma of a horse is reported. There are few published reports of intraocular tumors in horses. Intraocular tumors challenge animal welfare by causing uveitis, glaucoma, and loss of vision. Knowledge regarding treatment of intraocular tumors with globe preservation is sparse, and further investigations on this topic are required. PMID- 29152278 TI - Late diagnosis of systemic lupus erythematosus and antiphospholipid syndrome in an older woman with psychosis: a case report and review of the literature. AB - In older adults with first-time psychiatric manifestations, physical disorders such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) must be considered, even in patients with cognitive dysfunction and/or dementia. Here, we describe the case of a 77-year-old woman with psychosis who was later diagnosed with SLE and APS. PMID- 29152279 TI - Partial left superior pulmonary vein potential elimination by an inferior ganglionated plexus ablation. AB - Ganglionated plexus (GP) plays an important role in the initiation and maintenance of atrial fibrillation (AF). The GP ablation has been found to be effective for AF treatment. In this case, we reported an AF case in which the pulmonary vein (PV) potentials of the anterior region of the left superior PV were eliminated by an inferior right GP ablation. PMID- 29152280 TI - Mycoplasma pneumoniae-associated encephalitis complicated by cerebral salt wasting syndrome. AB - Cerebral salt wasting syndrome can occur in children with encephalitis. Clinicians should be aware of hyponatremia in patients who develop polyuria with the signs of dehydration and deteriorated consciousness. Furthermore, patients who present with status epilepticus or who are suspected to have high intracranial pressure may have an increased risk of cerebral salt wasting syndrome. PMID- 29152281 TI - Catheter ablation of typical atrial flutter with the superior approach in a patient with inferior vena cava interruption. AB - Inferior vena cava (IVC) interruption is a rare condition that might pose difficulties during typical flutter ablation. When azygos vein continuation is present ablation via the femoral route could be performed. In the absence of azygos vein continuation, typical atrial flutter ablation via a superior approach from the SVC is feasible. PMID- 29152282 TI - Incarcerated giant uterine leiomyoma within an incisional hernia: a case report. AB - Uterine leiomyomas presenting as incarcerated or strangulated hernias in surgical emergencies are extremely rare and should be considered in the differential diagnosis in patients with known uterine fibroids and an irreducible ventral abdominal wall hernia. Detailed history and multidisciplinary approach optimize the diagnosis and decision making toward surgical treatment. PMID- 29152283 TI - The extra-anatomical jump graft reconstruction of the right hepatic artery after resection of a biliary tract malignancy with a common hepatic artery aneurysm: a case report. AB - Performing resection of a biliary tract malignancy with a hepatic artery aneurysm is very challenging. Resection of the extrahepatic bile duct and extra-anatomical reconstruction can be successfully performed using free radial artery autografts from the aorta to the right hepatic artery. Hepatic artery thrombosis can be prevented with intimal preservation. PMID- 29152284 TI - Recurrent TransIent Perivascular Inflammation of the Carotid artery syndrome with temporary carotid plaque on ultrasonography: a case report. AB - TransIent Perivascular Inflammation of the Carotid artery (TIPIC) syndrome is a rare syndrome with an unknown cause that is characterized by unilateral neck pain. Its existence as a pathological entity was controversial. We describe a 44 year-old male presenting with a 10-day history of right neck pain diagnosed recurrent TIPIC syndrome with temporary carotid plaque followed by ultrasonography. PMID- 29152285 TI - Mexican case report of a never-treated Laron syndrome patient evolving to metabolic syndrome, type 2 diabetes, and stroke. AB - Glucose and lipid profile together with blood pressure should always be considered for low sera-IGF-1 patients. Even when adulthood is reached, IGF-1 therapy in these patients should be pursued as metabolic and protective cellular effects could be triggered. Real incidence of growth hormone insensitivity is still to be uncovered. PMID- 29152286 TI - Bony spicules trapped in peri-implant soft tissue: a common unrecognized finding. AB - According to the study, there were unexpected tiny bone spicules being inspected in peri-implant soft tissue. These displaced autogenous bone chips were probably presented when preparing implant sites. The displaced bone spicules seemed not induced significant inflammatory reactions; on contrary, defects of specimens and dissolving bone spicules pictures were demonstrated. PMID- 29152287 TI - Acute drop of platelets in metastatic colon cancer. AB - Oxaliplatin is a platinum commonly used in the treatment of metastatic colon cancer. It can cause thrombocytopenia through different mechanism. Sudden isolated drop in platelets should raise the concern for oxaliplatin immune induced thrombocytopenia and abrupt discontinuation of the drug. Patients should not be rechallenged with oxaliplatin once diagnosis of OIIT is confirmed. PMID- 29152288 TI - Small bowel stenosis following blunt abdominal trauma: a case report. AB - Blunt abdominal trauma is a rare case of intestinal obstruction, and only few cases have been reported in the world literature. Stenotic intestinal obstruction following blunt abdominal trauma is a very rare complication. This case highlights the need for clinical suspicion serial clinical assessment and radiological evaluation and the need for early surgery in patients presenting with abdominal symptoms following blunt abdominal trauma. PMID- 29152289 TI - Chronic cluster-like headache in a patient with a macroprolactinoma presenting with falsely low prolactin levels: bromocriptine versus cabergoline? AB - Cluster-like headache may be associated with pituitary tumors, mostly prolactinomas. Pituitary imaging and prolactin measurement should be assessed in patients presenting with cluster-like headaches with atypical features or unsatisfactory response to treatment. Furthermore, large pituitary adenomas with moderate increase in prolactin levels should prompt prolactin dilutions to avoid "hook effect". PMID- 29152290 TI - Promyelocytic sarcoma of the right humerus: an unusual clinical presentation with unique diagnostic and treatment considerations. AB - Promyelocytic leukemia is a known medical emergency and requires rapid diagnosis and expedient therapy with differentiating agents. We present an unusual case in which the diagnosis is based on a fine needle aspirate of a humeral mass. Despite lack of systemic involvement, the sarcoma responded to traditional differentiation agents. PMID- 29152291 TI - Spontaneous cholecystocolic fistula: an uncommon complication of chronic cholecystitis. AB - Cholecystocolic fistula, a rare complication of long-standing gallstone disease, is a diagnostic challenge owing to nonspecific clinical presentation and lack of accurate preprocedural diagnostic modalities. In case of incidental discovery of the fistula during the surgical procedure, excision of the fistula with repair of the colonic defect is imperative. PMID- 29152292 TI - Concomitant occurrence of primary hyperparathyroidism (PHPT) due to mediastinal parathyroid adenoma and sublingual thyroid gland: the role of parathyroid technetium-99m-MIBI scintigraphy. AB - The concomitant appearance of a sublingual thyroid and primary hyperparathyroidism due to parathyroid mediastinal adenoma is not common. This co occurrence can lead to a misdiagnosis by morphological imaging methods alone. This case emphasizes the role of 99mTc-MIBI scintigraphy in the detection of parathyroid ectopic adenoma in a patient with an ectopic thyroid gland. This more accurate location of parathyroid scintigraphy is of great benefit to the surgeon for surgical excision. PMID- 29152293 TI - Allogeneic hematopoietic cell transplantation in an adult patient with Glanzmann thrombasthenia. AB - Glanzmann thrombasthenia is a rare bleeding disorder that can present life threatening bleeding. Our patients develop antiplatelet antibodies that become refractory to any pharmacological treatment. Allogeneic hematopoietic stem-cell transplantation is the only currently curative procedure, but has major risks mainly in adult; indeed, our patient died. PMID- 29152294 TI - Awake tracheotomy in a patient with stridor and dyspnoea caused by a sizeable malignant thyroid tumor: a case report and short review of the literature. AB - Individual airway management is mandatory in patients with large goiters undergoing thyroid surgery. Preoperative endoscopic airway evaluation and imaging studies can support clinical decision making. Awake tracheotomy can be an effective and reasonable airway management strategy in such patients. PMID- 29152295 TI - Pneumatosis cystoides intestinalis: lung window setting on CT. AB - Pneumatosis cystoides intestinalis is a rare and often presents nonspecific symptoms. In this case, CT imaging revealed air collection within the wall of the ileum, which was more clearly defined using the lung window setting. When we consider pneumatosis cystoides intestinalis, we should evaluate CT using the lung window setting. PMID- 29152296 TI - Catheter-related right atrial thrombus in sickle cell disease. AB - Catheter-related right atrial thrombus (CRAT) can occur in patients with sickle cell disease, particularly if additional risk factors for thrombosis are present. Cardiac MRI may differentiate thrombi from other types of atrial masses. Treatment should include anticoagulation and the timing of catheter removal should balance the potential risk of embolization. PMID- 29152297 TI - Sudden swelling and redness of the toe. AB - The presence of history of redness and swelling of toe in an infant without history of trauma is typical of hair threat tourniquet syndrome. The treatment simply involves incision and removal of hair fibers. Physicians should be aware of this syndrome because early diagnosis and treatment avoid serious complications. PMID- 29152298 TI - Medullary nephrocalcinosis in idiopathic hypercalciuria. AB - Idiopathic hypercalciuria is a metabolic abnormality characterized by excessive calcium excretion in the urine with normal serum calcium levels and is a common risk factor for formation of kidney stones and/or nephrocalcinosis. These patients benefit from a normal-calcium, reduced-animal protein, and low-salt diet, along with a thiazide diuretic. PMID- 29152299 TI - Gastrointestinal stromal tumor: an incidental finding during laparoscopic bariatric surgery. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Lack of clinical symptoms and findings on preoperative upper endoscopy makes its diagnosis difficult in bariatric patients. A laparoscopic resection of the gastric GIST during bariatric surgery is associated with good long-term prognosis. PMID- 29152300 TI - Gastric trichobezoar. AB - Trichobezoar is a rare gastrointestinal pathology, but should be considered in patients with abdominal mass and previous history of trichophagia. In physical examination, it is important to verify signs of alopecia. Minimally invasive surgery is a secure method to remove the specimen from the stomach. PMID- 29152301 TI - Persistence of bone voids after calcaneal bone-graft harvest. AB - Objectives: The complications associated with iliac crest bone-graft harvest have resulted in the development of alternative harvest sites. Lower extremity alternative sites that have been reported for foot and ankle procedures include greater trochanter, proximal tibia, distal tibia, and calcaneus. These sites have been studied in terms of complications, postoperative pain, and quality of the harvested bone. The long-term effect of the harvest on the bone of the calcaneus has not been reported. Methods: Case report on incidental CT imaging 4 years after bone graft harvest from the calcaneus. Results: This case demonstrates the failure of the calcaneal trabecular bone to regenerate after harvesting cancellous bone graft for foot fusion procedure. Conclusions: The calcaneal graft site should not be used for a repeat bone-graft harvest without advanced imaging to confirm reconstitution of the harvest bed. PMID- 29152302 TI - Surgical management of extensive hypertrophic scarring of the halluces secondary to a decade of untreated onychocryptosis: An illustrative case report. AB - Extensive hypertrophic scarring of the halluces secondary to chronic onychocryptosis is a rare condition, which causes significant physical and psychosocial effects. In this case, a 31-year-old male developed large lesions on both great toes after he delayed treatment of chronic hallucal onychocryptosis for over a decade. Current treatment options for hypertrophic and keloid lesions in the foot and ankle vary considerably and differentiation is critical for appropriate treatment planning. In this case, surgical excision with total matrixectomy (modified Zadik-Syme) was considered optimal management. Histopathology testing confirmed the diagnosis of irritated hypertrophic scar secondary to onychocryptosis. The patient was monitored closely and at 3 months post-operatively, the incisional scars exhibited progressive maturation, and there was no recurrence of the lesions and no nail regrowth. Furthermore, the halluces were only marginally shorter providing good function and cosmesis. At the long-term follow-up consultation (5.5 years), the patient indicated complete satisfaction and had returned to regular footwear and social activities. Chronic onychocryptosis can trigger and facilitate proliferation of large benign keloid like fibrous lesions; excision with total matrixectomy can provide an excellent long-term outcome. PMID- 29152303 TI - Multiple ultrasound cavitation-enabled treatments for myocardial reduction. AB - Background: Ultrasound myocardial cavitation enabled treatment (MCET) is an image guided method for tissue reduction. In this study, a strategy of fractionated (multiple) treatments was tested for efficacy. Methods: Dahl SS rats were anesthetized and prepared for treatment with a focused ultrasound transducer in a warm water bath. Aiming at the anterior left ventricular wall was facilitated by imaging with a 10 MHz phased array (10S, GE Vivid 7, GE Vingmed Ultrasound, Horten, Norway). MCET was accomplished at 1.5 MHz by pulse bursts of 4 MPa peak rarefactional pressure amplitude, which were intermittently triggered 1:8 from the ECG during infusion of a microbubble suspension for cavitation nucleation. Test groups were sham, a 200 s treatment, three 200 s treatments a week apart, and a 600 s treatment. Treatment outcome was observed by plasma troponin after 4 h, echocardiographic monitoring and histology at 6 wk. Results: The impacts of the fractionated treatments summed to approximately the same as the long treatment; e. g. the troponin result was 10.5 +/- 3.2 for 200 s, 22.7 +/- 5.4 (p < 0.001) for the summed fractionated treatments and 29.9 +/- 6.4 for 600 s (p = 0.06 relative to the summed fractionated). While wall thickness was not reduced for the fractionated treatment, tissue strain was reduced by 35% in the target area relative sham (p < 0.001). Conclusion: The ability to fractionate treatment may be advantageous for optimizing patient outcome relative to all-or nothing therapy by surgical myectomy or alcohol ablation. PMID- 29152304 TI - In situ protein-templated porous protein-hydroxylapatite nanocomposite microspheres for pH-dependent sustained anticancer drug release. AB - Silk sericin, a water-soluble glue-like protein, is extensively used as a biomaterial due to its biocompatibility, hydrophilicity, biodegradability, and adequate resource. In addition, hydroxyapatite-based drug carriers are functionally efficient for drug or gene delivery due to their biodegradability, biocompatibility and easy metabolism in vivo. Herein, for the first time, this study used sericin, from a wild silkworm called Antheraea pernyi (A. pernyi), as a template to nucleate hydroxylapatite (HAp) nano-needles and form porous sericin HAp nanocomposite microspheres as an anticancer drug carrier. Specifically, A. pernyi sericin (AS) was incubated in 1.5* simulated body fluid to induce the formation of porous AS/HAp microspheres in situ. Doxorubicin (DOX) loading and release assays proved that the microspheres exhibited pH-dependent controlled and sustained release of DOX. In particular, the microspheres can selectively release DOX at a higher rate at the acidic conditions typical for tumor microenvironment than at the physiological conditions typical for normal tissues, which will potentially reduce the side effect of the cancer drugs in normal tissues. Cancer cell toxicity assay, cancer cell imaging and intracellular DOX distribution assay provided further evidence to support the pH-dependent controlled and sustained release of DOX to cancer cells from the microspheres. Our work has demonstrated a biomimetic strategy for the design and synthesis of silk protein-based drug carriers that can be potentially employed in drug delivery and regenerative medicine. PMID- 29152305 TI - Critical appraisal of the role of serum albumin in cardiovascular disease. AB - Concentration of serum albumin (SA), a multifunctional circulatory protein, is influenced by several factors, including its synthesis rate, catabolism rate, extravascular distribution, and exogenous loss. Moreover, both nutritional status and systemic inflammation affect the synthesis of SA. Determining SA concentration aids in risk prediction in various clinical settings. It is of interest to understand the prognostic value of SA in the full spectrum of cardiovascular disease (CVD) in the era of newly developed pharmacological and interventional treatments. Proper interpretation of SA in addition to established risk factors potentially provides a better risk discrimination and thereby presents an option to modify therapeutic strategies accordingly. In this narrative review, we summarize the basic features of SA and its associated physiological functions contributing to its prognostic impacts on CVD. Finally, we discuss the prognostic role of SA in CVDs based on existing evidence. PMID- 29152306 TI - Evaluation of two high-throughput proteomic technologies for plasma biomarker discovery in immunotherapy-treated melanoma patients. AB - Background: Selective kinase and immune checkpoint inhibitors, and their combinations, have significantly improved the survival of patients with advanced metastatic melanoma. Not all patients will respond to treatment however, and some patients will present with significant toxicities. Hence, the identification of biomarkers is critical for the selection and management of patients receiving treatment. Biomarker discovery often involves proteomic techniques that simultaneously profile multiple proteins but few studies have compared these platforms. Methods: In this study, we used the multiplex bead-based Eve Technologies Discovery assay and the aptamer-based SomaLogic SOMAscan assay to identify circulating proteins predictive of response to immunotherapy in melanoma patients treated with combination immune checkpoint inhibitors. Expression of four plasma proteins were further validated using the bead-based Millipore Milliplex assay. Results: Both the Discovery and the SOMAscan assays detected circulating plasma proteins in immunotherapy-treated melanoma patients. However, these widely used assays showed limited correlation in relative protein quantification, due to differences in specificity and the dynamic range of protein detection. Protein data derived from the Discovery and Milliplex bead based assays were highly correlated. Conclusions: Our study highlights significant limitations imposed by inconsistent sensitivity and specificity due to differences in the detection antibodies or aptamers of these widespread biomarker discovery approaches. Our findings emphasize the need to improve these technologies for the accurate identification of biomarkers. PMID- 29152307 TI - Coagulation profile of Sudanese children with homozygous sickle cell disease and the effect of treatment with omega-3 fatty acid on the coagulation parameters. AB - Background: It has been reported that patients with SCD do have an abnormal coagulation profile. Coagulopathy is thought to be one of the key factors that contribute to the vaso-occlusive crisis that characterises sickle cell disease (SCD). In this study, we investigated whether Sudanese sickle cell patients have an abnormal coagulation profile. In addition, the effect of treatment with either omega-3 fatty acids or hydroxyurea on coagulation profile was assessed. Methods: Homozygous SCD patients untreated (n = 52), omega-3 treated (n = 44), hydroxyurea (HU) treated (n = 8) and healthy (HbAA) controls (n = 52) matched for age (4-20 years), gender and socioeconomic status were enrolled. Patients on omega-3 fatty acids, according to age, received one to four capsules containing 277.8 mg DHA and 39.0 mg eicosapentnoic. Patients on Hydroxyurea were in on dosage more than 20 mg/kg/day. The steady state levels of the coagulation parameters and the effect of the treatments with either HU or omega-3 fatty acids on markers of coagulation were investigated. Results: Compared to the healthy controls, treated and untreated HbSS patients had lower hemoglobin, plasma Protein C, proteins S and higher white blood cell count (WBC), platelets count (PLTs) and plasma D dimer levels,(p < 0.05). In comparison to untreated HbSS, treatment with neither omega-3 nor HU had effect on the WBC, plasma proteins C and S, (p > 0.05). HU treated group had a lower PLTs count compared to HbSS untreated group (p < 0.5). The prothrombin and activated partial thromboplastin times and international normalized ratio (INR) of untreated patients are significantly higher than n-3 treated, HU-treated patients and health controls, (p < 0.05). Patients treated with omega-3 had lowered D-dimer levels in comparison to HU-treated and untreated HbSS patients, (p < 0.001). Conclusion: This study provides evidence that Sudanes patients have abnormal coagulation profile and treatment with either HU or omega 3 fatty acids might partially ameliorate SCD-associated chronic coagulopathic state. PMID- 29152308 TI - Emergency blood transfusion practices among anaemic children presenting to an urban emergency department of a tertiary hospital in Tanzania. AB - Background: Severe anaemia contributes significantly to mortality, especially in children under 5 years of age. Timely blood transfusion is known to improve outcomes. We investigated the magnitude of anaemia and emergency blood transfusion practices amongst children under 5 years presenting to the Emergency Department (ED) of Muhimbili National Hospital (MNH) in Tanzania. Methods: This prospective observational study enrolled children under 5 years old with anaemia, over a 7-week period in August and September of 2015. Anaemia was defined as haemoglobin of <11 g/dL. Demographics, anaemia severity, indications for transfusion, receipt of blood, and door to transfusion time were abstracted from the charts using a standardized data entry form. Anaemia was categorized as severe (Hb <7 g/dL), moderate (Hb 7-9.9 g/dL) or mild (Hb 10-10.9 g/dL). Results: We screened 777 children, of whom 426 (55%) had haemoglobin testing. Test results were available for 388/426 (91%), 266 (69%) of whom had anaemia. Complete data were available for 257 anaemic children, including 42% (n = 108) with severe anaemia, 40% (n = 102) with moderate anaemia and 18% (n = 47) with mild anaemia. Forty-nine percent of children with anaemia (n = 125) had indications for blood transfusion, but only 23% (29/125) were transfused in the ED. Among the non transfused, the provider did not identify anaemia in 42% (n = 40), blood was not ordered in 28% (n = 27), and blood was ordered, but not available in 30% (n = 29). The median time to transfusion was 7.8 (interquartile range: 1.9) hours. Mortality was higher for the children with severe anemia who were not transfused as compared with those with severe anaemia who were transfused (29% vs 10%, p = 0.03). Conclusion: The burden of anaemia is high among children under 5 presenting to EMD-MNH. Less than a quarter of children with indications for transfusion receive it in the EMD, the median time to transfusion is nearly 8 h, and those not transfused have nearly a 3-fold higher mortality. Future quality improvement and research efforts should focus on eliminating barriers to timely blood transfusion. PMID- 29152309 TI - Reticulocytosis in screen-printing workers exposed to 2-butoxyethanol and 2 ethoxyethanol. AB - Background: Studies on the hematologic toxicity of ethylene glycol ethers in humans are limited. Therefore, the aim of this study was to examine the association between exposure to solvents (containing 2-butoxyethanol and 2 ethoxyethanol) and hematological effects. Methods: Thirty-four screen-printing workers who were exposed to 2-butoxyethanol and 2-ethoxyethanol and 37 non exposed clerical workers were selected using data from the health care facilities that provided regular health screening services. Student's t-tests and Pearson's chi-square tests were used to compare differences in hematological parameters between the exposed and the control groups. A multivariate analysis was performed using the multiple logistic regression models to adjust for other variables. Results: The chi-square test showed the reticulocyte percentages and corrected reticulocyte counts to be significantly higher in the exposed group. The t-tests showed a significant increase in white blood cell counts, reticulocyte percentages, and corrected reticulocyte count (i.e., reticulocyte index) in the exposed group, with p-values of 0.002, 0.004, and 0.002, respectively. Multivariate analysis showed the odds ratio for the corrected reticulocyte counts to be 16.30 for the exposed group, when compared with that of the control group. Conclusions: Exposure to 2-butoxyethanol and 2-ethoxyethanol was significantly associated with reticulocytosis, necessitating the implementation of preventive measures for workers prone to occupational exposure to ethylene glycol ethers. PMID- 29152311 TI - Associations of out of school physical activity, sedentary lifestyle and socioeconomic status with weight status and adiposity of Cameroon children. AB - Background: Low physical activity and a sedentary lifestyle are contributing to overweight/obesity in children. This study aims to explore relationships between out of school physical activity, sedentary lifestyle and socioeconomic status indicators with children's weight status and adiposity. Methods: Five hundred twenty-two children of ages 5 to 12 years were randomly selected in a school based cross sectional study in Bamenda, Cameroon. Weight and height were measured and BMI calculated. These variables were standardized for age and gender. Socioeconomic variables and proxy measures of physical activity and sedentary lifestyle of children were reported by parents using a structured questionnaire. Bivariate and multivariable logistic regression was used to calculate odds ratios.Quantile regression was used to compare median values of triceps skinfold thickness across the different factors. Results: In bivariate analysis, physical activity > 4 - 7 times/week was significantly (p = 0.010) associated with a lower prevalence (5.9%) of overweight/obesity. In multivariable analysis, physical activity > twice a week (OR 0.1, 95% CI 0.05 - 0.3), sedentary lifestyle > 3 h/day (OR 2.4, 95% CI 1.2 - 4.3) and being in the high occupation class (OR 4.3, 95% CI 2.2 - 8.1) independently predicted overweight/obesity. With quantile regression, physical activity > 4 - 7 times/week was significantly (p = 0.023) associated with a 1.36 mm decrease in median triceps skinfold thickness, while sedentary lifestyle (> 3 h/day) (p = 0.026) and being in the high occupation class (p = 0.007) were significantly associated with a 1.37 mm and 1.86 mm increase in median triceps skinfold thickness respectively. Conclusion: Physical activity is inversely related to BMI-defined overweight/obesity and triceps skinfold thickness. Also, a high sedentary lifestyle and a high occupation class were associated with overweight/obesity and had the largest significant relationship with triceps skinfold thickness. There is need to objectively assess physical activity and sedentary lifestyle in our setting, in and out of school. Also longitudinal studies are warranted to understand the influence of cultural and behavioral drivers of physical activity and sedentary lifestyle. PMID- 29152312 TI - A 4-year study of the proportional distribution of male reproductive organ abnormalities in cattle slaughtered at Nyagatare abattoir, Eastern Rwanda. AB - Male reproductive performance has more impact on overall herd productivity than in the female. In order to assess herd productivity in cattle in Nyagatare, Eastern Rwanda, the proportional distribution of male reproductive organ abnormalities was investigated in 3087 bulls slaughtered over a 4-year period. The aim of the study was to investigate the proportional distribution of male reproductive organ abnormalities in exotic and indigenous bulls slaughtered over a 4-year period at Nyagatare abattoir in Eastern Rwanda. Positioning of the testicles was observed and recorded as the animals were assembled before slaughter. After slaughter, the internal and external reproductive organs of all bulls were removed, labelled and analysed for pathology. Significantly more indigenous (79.01%) than exotic (20.99%) animals were slaughtered (P < 0.05; N = 3 087). Overall occurrence of abnormalities was significantly higher in exotic (20.83%) than in indigenous (10.33%) animals (P < 0.05). Overall, abnormal location of testicles was the most common abnormality (4.08%) followed by abnormal prepuce and penis (2.33%), orchitis (1.94%), enlarged vesicular gland (0.91%), scrotal hernia (0.87%), unilateral cryptorchidism (0.81%), testicular hypoplasia (0.81%) and hydrocoele (0.78%). Abnormal location of testicles, abnormal prepuce and penis, orchitis, testicular hypoplasia and enlarged vesicular glands had significantly higher prevalence in exotic animals than in indigenous animals (P < 0.05). There was no significant difference in the prevalence of unilateral cryptorchidism, hydrocoele and scrotal hernia between the exotic and indigenous breeds. The encountered reproductive abnormalities result in poor herd fertility manifesting as low first-service conception rates, prolonged breeding seasons and reduced weaning weights accompanied by inevitable financial losses in beef production. The observed high proportion of male reproductive abnormalities in exotic breeds might offset the professed benefits from introduction of these exotic breeds with the aim of improving productivity. PMID- 29152310 TI - Genome resequencing and transcriptome profiling reveal structural diversity and expression patterns of constitutive disease resistance genes in Huanglongbing tolerant Poncirus trifoliata and its hybrids. AB - Huanglongbing (HLB) is the most destructive bacterial disease of citrus worldwide. While most citrus varieties are susceptible to HLB, Poncirus trifoliata, a close relative of Citrus, and some of its hybrids with Citrus are tolerant to HLB. No specific HLB tolerance genes have been identified in P. trifoliata but recent studies have shown that constitutive disease resistance (CDR) genes were expressed at much higher levels in HLB-tolerant Poncirus hybrids and the expression of CDR genes was modulated by Candidatus Liberibacter asiaticus (CLas), the pathogen of HLB. The current study was undertaken to mine and characterize the CDR gene family in Citrus and Poncirus and to understand its association with HLB tolerance in Poncirus. We identified 17 CDR genes in two citrus genomes, deduced their structures, and investigated their phylogenetic relationships. We revealed that the expansion of the CDR family in Citrus seems to be due to segmental and tandem duplication events. Through genome resequencing and transcriptome sequencing, we identified eight CDR genes in the Poncirus genome (PtCDR1-PtCDR8). The number of SNPs was the highest in PtCDR2 and the lowest in PtCDR7. Most of the deletion and insertion events were observed in the UTR regions of Citrus and Poncirus CDR genes. PtCDR2 and PtCDR8 were in abundance in the leaf transcriptomes of two HLB-tolerant Poncirus genotypes and were also upregulated in HLB-tolerant, Poncirus hybrids as revealed by real-time PCR analysis. These two CDR genes seem to be good candidate genes for future studies of their role in citrus-CLas interactions. PMID- 29152313 TI - Pharmacokinetic profile and partitioning in red blood cells of romifidine after single intravenous administration in the horse. AB - The aims of this study were to assess the plasma concentrations of romifidine in horses after intravenous injection, to evaluate the red blood cell (RBC) partitioning of the anaesthetic drug, and to improve knowledge regarding its sedative effect in horses describing the pharmacokinetic model. Eight adult Standardbred horses received a single bolus of romifidine at a dosage of 100 MUg/kg. Blood samples (5 mL) were collected immediately before romifidine administration (t0), and at 2, 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 min after injection. A sedation score was recorded at the same time. The romifidine concentrations in plasma and red blood cells were determined by high performance liquid chromatography (HPLC). The plasma and red blood cell concentrations were correlated with the sedation at each time point. Romifidine produced a satisfactory level of sedation in all animals. The sedation was detectable in all horses for up to 105 min. All the animals returned to normal without any behavioural changes at 180 min. The romifidine concentrations in the red blood cells were significantly higher (P < 0.01) at all time points than those in the plasma. The T1/2beta was 148.67 +/- 61.59 min and body clearance was 22.55 +/- 6.67 mL/kg per min. The results showed that after a single bolus administration of romifidine, a partitioning in the RBCs was detected. PMID- 29152314 TI - Seroprevalence of West Nile virus in horses in different Moroccan regions. AB - West Nile virus-associated disease is one of the most widespread vector-borne diseases in the world. In Morocco, the first cases were reported in horses in 1996 and the disease re-emerged in 2003 and in 2010. The objective of this work was to study the epidemiological situation of WNV-associated infection in Morocco, by quantifying the seroprevalence of anti-WNV IgM and IgG antibodies in horses in different bioclimatic regions-zones of Morocco in 2011. During the months of May, June and July 2011, 840 serum samples were collected from horses in four regions characterized by different environmental and climatic features such as altitude, temperature and precipitation. These environmental-climatic regions are: the Atlantic plateaus of the Gharb and pre-Rif region, the North Atlasic plains and plateaus region, the Atlas Mountains and pre-Atlas region and the plains and plateaus of the Oriental region. All samples were tested for the anti-WNV IgG antibodies by ELISA and positive sera were confirmed by virus neutralization (VN). An anti-WNV antibody prevalence map was developed. A total of 261 samples (31%) were found positive by both techniques. The prevalence of the infection was higher in the Atlantic plateaus of the Gharb and pre-Rif region, in the northern part of the country. Available data concerning the previous WNV-associated disease outbreaks in Morocco and the preliminary results of this serological survey suggest that the Moroccan northwest is the region at highest risk for WNV circulation. In this region, the climate is more humid with higher rainfall than other regions and milder winter temperatures exist. In the same area, the presence of migratory bird settlements may affect the risk of virus introduction and amplification. PMID- 29152315 TI - A pilot survey of farm animal welfare in Serbia, a country preparing for EU accession. AB - The selection and field application of animal-based welfare measures for pigs, sheep, dairy cows and broilers was the first step towards the future development of welfare improvement schemes for Serbia - a country that is applying for EU accession. The aim of this pilot study was to: (1) test the feasibility of a protocol for monitoring farm animal welfare in Serbia, (2) ascertain preliminary data on animal-based outcomes of farm welfare and (3) gain insight into Serbian farmers' understanding of animal welfare as part of a wider project working towards inclusion of animal-based assessments in a 'higher welfare' voluntary assurance scheme. This study encompasses the first national survey of farm animal welfare in which animal-based outcomes were tested on 105 farms by a total of ten trained assessors. Data on the views and aspirations of the farmers from these 105 farms were also systematically gathered during face-to-face interviews. Existing animal-based measures for pigs, sheep, dairy cows and broilers that have been successfully applied and identified as valid, reliable and feasible measures in other countries, were found to be largely transferable. However, some on-farm protocols, previously used in other countries, had to be shortened for logistical reasons when used in Serbia. Our findings suggest that further refinement may be needed in order to allow local application of all measures. While the term 'animal welfare' has only recently been introduced into the Serbian language, seventy-three percent of farmers had heard of it. Overall, few positive associations were found between farmer satisfaction with animals' living conditions and animal-based data. Many farmers had aspirations to develop and expand their farms, which may potentially enhance animal welfare, but these farmers identified that financial and technical advice and support would be needed in order to achieve these goals. PMID- 29152316 TI - Seroepidemiology and assessment of risk factors for the spread of avian influenza in birds in two Nigerian states. AB - Despite modified stamping out eradication policy adopted in Nigeria, there was resurgence in 2015 of highly pathogenic avian influenza (HPAI) H5N1 with greater infectivity. A survey of the risk of spread of HPAI in two HPAI-infected and uninfected Nigerian states were studied. A cross-sectional study to detect avian influenza (AI) H5 antibodies was conducted using haemagglutination inhibition (HI) test and enzyme-linked immunosorbent assay (ELISA). A total of 950 birds' sera were tested for AI H5 antibodies. Questionnaires were also administered to evaluate risks of AI spread in two states of Nigeria in 2013. AI H5 seroprevalence of 3% and 5% were obtained in Bauchi and Gombe states, respectively. Free flying and captive wild birds had 15% and 11% seroprevalence, respectively. Ninety-two per cent AI awareness and 90% preparedness to report outbreaks of poultry diseases were recorded. Veterinary personnel, radio and television contributed 87% to HPAI awareness. Of the 10 risk categories evaluated, Gombe state had 3 moderate and 1 high risk of AI virus spread. Bauchi state recorded 5 moderate and 1 high risk of AI virus spread. Chi-square analysis showed associations of altitude, temperature, rainfall and presence of live bird markets (LBMs) (P < 0.05) to AI seroprevalence. Odds ratio at 95% CI (1.313 6.333) indicated LBMs presence to be three times more likely to influence AI occurrence. HPAI H5N1 resurged in many states and occurred for the first time in Gombe state in 2015. Veterinary personnel, radio and television may be reliable in changing farmers' attitudes to adopt good biosecurity practices. PMID- 29152317 TI - Bone marrow-derived multipotent mesenchymal stromal cells from horses after euthanasia. AB - Allogeneic equine multipotent mesenchymal stromal cells (eMSCs) have been proposed for use in regenerative therapies in veterinary medicine. A source of allogeneic eMSCs might be the bone marrow from euthanized horses. The purpose of this study was to compare in vitro characteristics of equine bone marrow derived eMSC (eBM-MSCs) from euthanized horses (eut-MSCs) and from narcotized horses (nar MSCs). Eut-MSCs and nar-MSCs showed typical eMSC marker profiles (positive: CD44, CD90; negative: CD11a/CD18 and MHCII) and possessed tri-lineage differentiation characteristics. Although CD105 and MHCI expression varied, no differences were detected between eut-MSCs and nar-MSCs. Proliferation characteristics did not differ between eut-MSCs and nar-MSCs, but age dependent decrease in proliferation and increase in MHCI expression was detected. These results suggest the possible use of eut-MSCs for therapeutic applications and production of commercial available eBM-MSC products. PMID- 29152318 TI - Gut microbiota composition may relate to weight loss rate in obese pet dogs. AB - Obese dogs seem to have a different gut microbiome (GM) composition compared to lean dogs, and in humans, GM composition may negatively impact the ability to lose weight in some individuals. The purpose of this study was to investigate the interaction between exercise, weight-loss and the composition of GM in dogs. Eighteen obese pet dogs were recruited for a 12-week weight-loss intervention. All dogs were fed restrictively with a commercial high-protein/high-fibre dry diet, and eight of these dogs were enrolled in an exercise program in addition to the diet intervention. Faecal samples were collected and the dogs were weighed at week 0, week 6 and week 12. GM composition was determined using MiSeq-based tag encoded 16S rRNA gene high-throughput amplicon sequencing, and concentrations of short chain fatty acids (SCFA) by gas-liquid chromatography. Total weight loss, food allowance and GM were not changed by exercise inclusion. However, Megamonas abundance negatively correlated with weight loss rate and Ruminococcaceae relative abundance was lower at 12 weeks in dogs with a faster weight loss rate (>=1% per week) compared with slower weight loss rate (<1% per week) independent of exercise. Acetic and propionic acid concentrations decreased in the dogs with a faster weight loss rate. Members of Megamonas and Ruminococcaceae produce acetic and propionic acids and we therefore interpret that having a GM that favour SCFA production may negatively affect weight loss rate in dogs. Weight loss rate in dogs may be related to the composition of the GM and its production of metabolites. PMID- 29152319 TI - The effect of sodium bicarbonate and validation of beckman coulter AU680 analyzers for measuring total carbon dioxide (TCO2) concentrations in horse serum. AB - This study evaluated the usage of Beckman Coulter AU680 analyzers for measurement of TCO 2 in horse serum, and the effect of sodium bicarbonate administrations on serum TCO 2 levels in resting horses. Treatment of horses with sodium bicarbonate did not result in any adverse events. Mean TCO 2 concentration was significantly higher from 1 to 8 h in the sodium bicarbonate-treated horses compared to the untreated controls. Within an hour, administration of sodium bicarbonate increased the TCO 2 level from 31.5 +/- -2.5 (SD) to 34.0 +/- 2.65 (SD) mmol/L and at 2-8 h post-administration, the TCO 2 level was above the 36 mmol/L cut-off level. In all quality control analysis of Australian standard by Beckman Coulter AU680 analyzer, the instrument slightly over estimated the TCO 2 level but the values were in close agreement with mean TCO 2 level being 38.03 with +/- 0.87 mmol/L (SD). Expanded uncertainty was calculated using different levels of confidence interval. Based on 99.5% confidence interval using 0.805% expanded uncertainty using mean measured concentration of 38.05 mmol/L, it was estimated that any race samples TCO 2 level higher than 38.5 mmol/L will be indicative of sodium bicarbonate administration using Beckman Coulter AU680 analyzer in Louisiana. PMID- 29152320 TI - Intramuscular progesterone (Gestone) versus vaginal progesterone suppository (Cyclogest) for luteal phase support in cycles of in vitro fertilization-embryo transfer: patient preference and drug efficacy. AB - Background: The requirement for luteal phase support (LPS) in stimulated IVF cycles is well established, however drug choice, and route of administration and duration of use are not. This report evaluates patients' preference and satisfaction by using either vaginal or intramuscular (IM) progesterone (P) supplementation for luteal phase support after in vitro fertilization and embryo transfer (IVF-ET). Methods: It is a prospective cohort study done in a reproductive and infertility unit in a tertiary care hospital from March 2013 through February 2015 for four hundred and nine patients undergoing IVF-ET. Patients were allowed to choose either vaginal or IM P for LPS. Patient preference and satisfaction, as well as differences in clinical pregnancy rates between the two groups were assessed at one or two time points throughout the study. Results: There were no statistically significant differences in the patients' characteristics and clinical outcomes between the two groups. There were 88 pregnancies (38.8%) among patients treated with vaginal p and 62 pregnancies (34%) among IM P patients. Average satisfaction score at the pregnancy test and ultrasound (U/S) visits was similar between both groups. Conclusions: Patients' satisfaction and pregnancy rates were similar between vaginal and IM P supplementation. PMID- 29152321 TI - Impact of the number of repeated inhalations and patient characteristics on the residual amount of inhaled laninamivir octanoate hydrate dry powder in pediatric patients with influenza. AB - Background: A dry powder inhaled formulation is used for the anti-influenza drug laninamivir octanoate hydrate (laninamivir). Although two successive inhalations (puffs) are recommended to minimize residual amounts of active ingredients, previous reports suggest that pediatric patients with low peak inspiratory flow are unable to inhale the active ingredient adequately. In the present study, we prospectively investigated the appropriate number of repeated inhalations of laninamivir dry powder and factors influencing the residual amount of ingredients in pediatric patients with influenza. Methods: The study enrolled 64 patients receiving laninamivir dry powder inhaler (Inavir(r)) between January and March 2016 at Tsu emergency medical center/pediatric clinic and dental clinic. All patients enrolled used a laninamivir dry powder inhaler in four repeated inhalations, as instructed by a pharmacist. The residual amount of laninamivir dry powder was calculated by measuring the device weight before and after each inhalation and a residual amount of >20% was defined as an unsuccessful inhalation. Results: The inadequate inhalation rate after two successive inhalations was 45%, and it decreased as number of inhalation repeats increased, reaching 23% after four successive inhalations. Peak inspiratory flow in patients with inadequate inhalation was significantly lower than that in patients with adequate inhalation, for all numbers of inhalation repeats analyzed. Receiver operating characteristic analyses indicated peak inspiratory flow cut-off values of 140, 120, 100, and 100 L/min at 1-4 successive inhalations, respectively. Conclusions: The present findings suggest that a proportion of patients with low peak inspiratory flow were unable to inhale the active ingredient adequately when laninamivir dry powder inhaler was administered as two successive inhalations, as recommended in the instruction manual. Three or four repeated inhalations of laninamivir dry powder inhaler should be administered to pediatric patients with low peak inspiratory flow. PMID- 29152324 TI - A field efficacy and safety trial in the Netherlands in pigs vaccinated at 3 weeks of age with a ready-to-use porcine circovirus type 2 and Mycoplasma hyopneumoniae combined vaccine. AB - Background: Respiratory diseases impair the health and welfare of growing pigs and impacts farmers' gains worldwide. Their control through a preventative medical approach has to be tailored according to the pathogens identified at farm level. In the Netherlands, several studies have emphasized the prominent role of Mycoplasma hyopneumoniae, Porcine Circovirus type 2 and Porcine Reproductive and Respiratory Syndrome Virus in such respiratory conditions. Further to the arrival on the Dutch market of the first commercially available bivalent vaccine against PCV2 and M. hyopneumoniae, Porcilis(r) PCV M. Hyo, a trial was designed to evaluate its safety and efficacy under local field conditions. Material and methods: In a conventional farrow-to-finish 170-sow farm with a history of respiratory diseases and demonstrated circulation of both M. hyopneumoniae and PCV2, 812 piglets were randomised and included at weaning in either of the three following groups: PCVM (vaccinated with Porcilis(r) PCV M. Hyo), FLEX (vaccinated with CircoFLEX(r) and MycoFLEX(r)) or NC (negative control, injected with placebo). Piglets were vaccinated at 3 weeks of age (day 0) and a subset was bled and weighed at regular intervals up to slaughter. Lung slaughter checks were only performed on 64% of the pigs included on day 0. Results and implication: No side effect of injection was observed in any of the three groups. Average daily weight gain was improved in both vaccinated groups as compared to the NC group, over the finishing period as well as from wean-to-finish. The PCVM group had a significantly lower PCV2 viremia area under the curve than the two other groups, and a significant reduction in the severity of the pneumonia-like lesions was observed at slaughter in the pigs of the PCVM group. A conservative estimate of the economic benefit of that vaccine was 2.84 ? per finisher. This trial confirms that the vaccine is efficacious against the health and growth effects of PCV2 and M. hyopneumoniae, of practical advantage (single injection of a bivalent product) and well tolerated. PMID- 29152323 TI - New melanocortin-like peptide of E. coli can suppress inflammation via the mammalian melanocortin-1 receptor (MC1R): possible endocrine-like function for microbes of the gut. AB - E. coli releases a 33 amino acid peptide melanocortin-like peptide of E. coli (MECO-1) that is identical to the C-terminus of the E. coli elongation factor-G (EF-G) and has interesting similarities to two prominent mammalian melanocortin hormones, alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropin (ACTH). Note that MECO-1 lacks HFRW, the common pharmacophore of the known mammalian melanocortin peptides. MECO-1 and the two hormones were equally effective in severely blunting release of cytokines (HMGB1 and TNF) from macrophage-like cells in response to (i) endotoxin (lipopolysaccharide) or (ii) pro-inflammatory cytokine HMGB-1. The in vitro anti-inflammatoty effects of MECO 1 and of alpha-MSH were abrogated by (i) antibody against melanocortin-1 receptor (MC1R) and by (ii) agouti, an endogenous inverse agonist of MC1R. In vivo MECO-1 was even more potent than alpha-MSH in rescuing mice from death due to (i) lethal doses of LPS endotoxin or (ii) cecal ligation and puncture, models of sterile and infectious sepsis, respectively. PMID- 29152322 TI - Choosing a culture medium for SCNT and iSCNT reconstructed embryos: from domestic to wildlife species. AB - Over the past decades, in vitro culture media have been developed to successfully support IVF embryo growth in a variety of species. Advanced reproductive technologies, such as somatic cell nuclear transfer (SCNT), challenge us with a new type of embryo, with special nutritional requirements and altered physiology under in vitro conditions. Numerous studies have successfully reconstructed cloned embryos of domestic animals for biomedical research and livestock production. However, studies evaluating suitable culture conditions for SCNT embryos in wildlife species are scarce (for both intra- and interspecies SCNT). Most of the existing studies derive from previous IVF work done in conventional domestic species. Extrapolation to non-domestic species presents significant challenges since we lack information on reproductive processes and embryo development in most wildlife species. Given the challenges in adapting culture media and conditions from IVF to SCNT embryos, developmental competence of SCNT embryos remains low. This review summarizes research efforts to tailor culture media to SCNT embryos and explore the different outcomes in diverse species. It will also consider how these culture media protocols have been extrapolated to wildlife species, most particularly using SCNT as a cutting-edge technical resource to assist in the preservation of endangered species. PMID- 29152325 TI - Changes of intestinal microbiota composition and diversity in very low birth weight infants related to strategies of NEC prophylaxis: protocol for an observational multicentre pilot study. AB - Background: At the Division of Neonatology, Department of Paediatrics, Medical University Graz, a unique regimen of necrotizing enterocolitis (NEC) prophylaxis in preterm infants showing a < 1500 g birth weight (i.e. very low birth weight, VLBW) is used. The regimen includes oral antibiotic and antifungal therapy and probiotic preparations as well as a standardised feeding regimen. The incidence of NEC in preterm infants treated by this regimen has been shown to be lower, reflecting 0.7% when treatment was initiated on the first day of life, compared to international incidence rates (5.1%). However, the impact of the prophylaxis regimen on the intestinal microbiome is yet unknown. Methods: We here report the protocol of an observational multicentre STROBE compliant pilot study in VLBW preterm infants. Research will compare three groups as defined by different NEC prophylaxis regimens. Each centre will provide 20 infants. Stool samples will be collected every 2 days throughout the first 2 weeks of life. Samples will be stored at - 80 degrees C until 16S-rRNA sequencing. 16S-rRNA genes will be amplified using suitable primers (specific for bacteria, fungi and archaea) and prepared for MiSeq Sequencing. Analyses will be performed using public analysis pipelines, such as Mothur and Qiime, thus allowing an analysis of high-throughput community sequencing data. Abundance and composition changes in intestinal microbiota will be compared between the groups throughout the first 2 weeks of life. Discussion: Different surroundings at the three participating study centres, including contacts to care takers and parents, as well as feeding or medication all might influence intestinal microbiota composition and abundance. In the planned sequel study, this should be kept in mind and a more standardised process ought to be established. However, the results obtained from the presented pilot study will display the burden of bias and help to establish a more strict protocol for the future. Trial registration: Trial has been registered with the German Registry for Clinical Trials (registry ID DRKS00009290). PMID- 29152328 TI - Corrigendum. AB - [This corrects the article DOI: 10.4155/fsoa-2016-0066.]. PMID- 29152326 TI - Development of a communication aid for explaining hypertrophic cardiomyopathy genetic test results. AB - Background: Large gene panels are now commonplace for hypertrophic cardiomyopathy (HCM), increasing the yield of uncertain genetic findings. Few resources exist which aim to facilitate communication of HCM genetic test results. We sought to develop, pilot, and refine a communication aid for probands receiving HCM genetic test results. Methods: Development was a multi-step process involving expertise of a multidisciplinary team, literature review, and empirical experience. The aid went through an iterative revision process throughout the piloting phase to incorporate feedback. HCM probands attending a specialized multidisciplinary HCM clinic, aged >= 18 years and genetic test results available for disclosure between May and August 2016, or recently received their gene results (January April 2015) were eligible. A purposive sampling strategy was employed, recruiting those attending clinic during the study period or those who could attend without difficulty. Results: We developed and pilot tested a genetic counsellor-led communication aid. Based on clinical expertise, the aid addresses (a) what genetic testing is, (b) implications for the patient, (c) reasoning for variant classification, and (d) implications for the family. Pilot data were sought to assess knowledge, feasibility, and acceptability using a self-report survey 2 weeks post-intervention. Twelve of 13 participants completed the follow-up questionnaire. Participants valued the individualised nature of the aid, recommended use of the aid, and indicated genetic knowledge, and family communication was better facilitated. Iterative modification of images helped to more simply depict important genetic concepts. Conclusions: We have developed a tool that is feasible, acceptable, and helpful to patients receiving genetic results. This is an important first step, and trial of the aid to assess effectiveness compared to usual care will follow. PMID- 29152327 TI - Proangiogenic alginate-g-pyrrole hydrogel with decoupled control of mechanical rigidity and electrically conductivity. AB - Background: An electrically conductive hydrogel has emerged to regulate cellular secretion activities with electrical stimulation. However, the electrical conductivity of typical hydrogel systems decreases with increasing elastic modulus of the hydrogels because of decreased transport of ions through a polymeric cross-linked mesh. Method: This study hypothesized that the inverse dependency between electrical conductivity and elastic modulus would be made through the cross-linking of conductive monomer-units conjugated to a hydrophilic polymeric backbone. This hypothesis was examined through the cross-linking of pyrrole groups that were conjugated to an alginate backbone, termed alginate-g pyrrole. Results: Hydrogels with increased degrees of pyrrole substitution exhibited a simultaneous increase in the gels mechanical rigidity and electrical conductivity. The resulting hydrogel could control the adhesion and vascular endothelial growth factor secretion of cells via applied electrical stimulation. Conclusions: This material design principle will be broadly useful to fabricating materials used for various actuation, cell culture, and biomedical applications. PMID- 29152329 TI - Patient-physician collaboration in rheumatology: a necessity. AB - Over the past few decades, there has been significant and impressive progress in the understanding and management of rheumatic diseases. One of the key reasons for succeeding in making this progress has been the increasingly stronger partnership between physicians and patients, setting a milestone in patient care. In this viewpoint, we discuss the recent evolution of the physician-patient relationship over time in Europe, reflecting on the 'journey' from behind the clinic walls through to clinical and research collaborations at national and international level and the birth of healthcare professional and 'rheumatic' patient organisations. The role of expert patients and patient advocates in clinical and scientific committees now represents a core part of the decision making process. In more recent years and following the recognition that the young patients, physicians and academics have a voice and needs of their own, including the need to be educated and instructed, has encouraged the establishment of youth organisations, enabling change and innovation to take place at a uniquely different level. PMID- 29152330 TI - Research Involvement and Engagement: reflections so far and future directions. AB - Plain English summary: Two years ago we launched Research Involvement and Engagement (RIE) as an interdisciplinary co-produced journal, focusing on patient and wider involvement and engagement in all stages of health and social care research. In this Editorial we reflect on progress and consider future directions. Now indexed in PubMed Central, RIE's prime objective is to publish papers that report public involvement in enough depth to generate a sound and robust evidence base, from which others can draw to develop best practice. Our open access publishing enables anyone who wants to read a paper to access it free of charge, a powerful way of making research more open and more democratic, with RIE a key part of this slow but necessary revolution. While we have made progress, there is still a long way to go to embed involvement and engagement as normal within research practice. Publishers and funders have a vital role to play in changing research so the co-production of knowledge becomes the norm. In this Editorial we highlight key areas that we need to develop to strengthen involvement and engagement. We draw strength from knowing we are not alone in this journey. Our Editorial Board, our authors, our reviewers, and you dear readers, are all companions on this journey, making a wide range of contributions that help us move forward, slowly but surely. Abstract: Two years ago we launched Research Involvement and Engagement (RIE) as an interdisciplinary co-produced journal, focusing on patient and wider involvement and engagement in all stages of health and social care research. In this Editorial we reflect on progress and consider future directions. Now indexed in PubMed Central, RIE's prime objective is to publish papers that report public involvement in enough depth to generate a sound and robust evidence base, from which others can draw to develop best practice. Our open access publishing enables anyone who wants to read a paper to access it free of charge, a powerful way of making research more open and more democratic, with RIE a key part of this slow but necessary revolution. While we have made progress, there is still a long way to go to embed involvement and engagement as normal within research practice. Publishers and funders have a vital role to play in changing research so the co-production of knowledge becomes the norm. In this Editorial we highlight key areas that we need to develop to strengthen involvement and engagement. We draw strength from knowing we are not alone in this journey. Our Editorial Board, our authors, our reviewers, and you dear readers, are all companions on this journey, making a wide range of contributions that help us move forward, slowly but surely. PMID- 29152331 TI - Cost-effectiveness of massively parallel sequencing for diagnosis of paediatric muscle diseases. AB - Childhood-onset muscle disorders are genetically heterogeneous. Diagnostic workup has traditionally included muscle biopsy, protein-based studies of muscle specimens, and candidate gene sequencing. High throughput or massively parallel sequencing is transforming the approach to diagnosis of rare diseases; however, evidence for cost-effectiveness is lacking. Patients presenting with suspected congenital muscular dystrophy or nemaline myopathy were ascertained over a 15 year period. Patients were investigated using traditional diagnostic approaches. Undiagnosed patients were investigated using either massively parallel sequencing of a panel of neuromuscular disease genes panel, or whole exome sequencing. Cost data were collected for all diagnostic investigations. The diagnostic yield and cost effectiveness of a molecular approach to diagnosis, prior to muscle biopsy, were compared with the traditional approach. Fifty-six patients were analysed. Compared with the traditional invasive muscle biopsy approach, both the neuromuscular disease panel and whole exome sequencing had significantly increased diagnostic yields (from 46 to 75% for the neuromuscular disease panel, and 79% for whole exome sequencing), and reduced the cost per diagnosis from USD$16,495 (95% CI: $12,413-$22,994) to USD$3706 (95% CI: $3086-$4453) for the neuromuscular disease panel and USD $5646 (95% CI: $4501-$7078) for whole exome sequencing. The neuromuscular disease panel was the most cost-effective, saving USD$17,075 (95% CI: $10,654-$30,064) per additional diagnosis, over the traditional diagnostic pathway. Whole exome sequencing saved USD$10,024 (95% CI: $5795-$17,135) per additional diagnosis. This study demonstrates the cost effectiveness of investigation using massively parallel sequencing technologies in paediatric muscle disease. The findings emphasise the value of implementing these technologies in clinical practice, with particular application for diagnosis of Mendelian diseases, and provide evidence crucial for government subsidy and equitable access. PMID- 29152332 TI - Crystal structure of poly[di-aqua-bis-(MU5-benzene-1,3-di-carboxyl-ato)(N,N-di methyl-formamide)-cadmium(II)disodium(I)]. AB - The title compound, [CdNa2(C8H4O4)2(C3H7NO)(H2O)2] n or [CdNa2(1,3 bdc)2(DMF)(H2O)2] n , is a new CdII-NaI heterobimetallic coordination polymer. The asymmetric unit consists of one CdII atom, two NaI atoms, two 1,3-bdc ligands, two coordinated water mol-ecules and one coordinated DMF mol-ecule. The CdII atom exhibits a seven-coordinate geometry, while the NaI atoms can be considered to be penta-coordinate. The metal ions and their symmetry-related equivalents are connected via chelating-bridging carboxyl-ate groups of the 1,3 bdc ligands to generate a three-dimensional framework. In the crystal, there are classical O-H?O hydrogen bonds involving the coordinated water mol-ecules and the 1,3-bdc carboxyl-ate groups and pi-pi stacking between the benzene rings of the 1,3-bdc ligands present within the frameworks. PMID- 29152333 TI - Crystal structure of an ep-oxy-sterol: 9alpha,11alpha-ep-oxy-5alpha-cholest-7-ene 3beta,5,6alpha-triol 3,6-di-acetate. AB - The title compound, C31H48O6, is a polyoxygenated ep-oxy steroid obtained by a multi-step synthesis involving oxidation of 7-de-hydro-cholesterol. It crystallizes in the P212121 space group; however, the absolute structure of the molecule in the crystal could not be determined by resonant scattering. The configuration at the C5 and C6 positions is in both cases of the alpha-type, as is that of the C atoms of the ep-oxy ring. Mol-ecules in the crystal form chains parallel to the b axis by hydrogen bonding between O-H donors and carbonyl O-atom acceptors. Some atoms of the alkyl chain are disordered over two orientations, with a refined occupancy ratio of 0.511 (10):0.489 (10). PMID- 29152334 TI - 1-{(E)-[(2E)-3-(4-Meth-oxy-phen-yl)-1-phenyl-prop-2-en-1-yl-idene]amino}-3-phenyl urea: crystal structure and Hirshfeld surface analysis. AB - The title compound, C23H21N3O2, is constructed about an almost planar disubstituted amino-urea residue (r.m.s. deviation = 0.0201 A), which features an intra-molecular amine-N-H?N(imine) hydrogen bond. In the 'all-trans' chain connecting this to the terminal meth-oxy-benzene residue, the conformation about each of the imine and ethyl-ene double bonds is E. In the crystal, amide-N H?O(carbon-yl) hydrogen bonds connect centrosymmetrically related mol-ecules into dimeric aggregates, which also incorporate ethyl-ene-C-H?O(amide) inter-actions. The dimers are linked by amine-phenyl-C-H?pi(imine-phen-yl) and meth-oxy-benzene C-H?pi(amine-phen-yl) inter-actions to generate a three-dimensional network. The importance of C-H?pi inter-actions in the mol-ecular packing is reflected in the relatively high contributions made by C?H/H?C contacts to the Hirshfeld surface, i.e. 31.6%. PMID- 29152335 TI - Synthesis and crystal structure of [Pd{C6H4(CH2NHCH2Ph)-2-kappa2C,N}(MU-I)]2. AB - The binuclear title complex, di-MU-iodido-bis(-{2-[(benzylamino-kappaN)meth yl]phenyl-kappaC1}palladium(II)), [Pd2I2(C14H14N)2], was prepared by reaction of [Pd{C6H4(CH2NHCH2Ph)-2}(MU-OAc)]2 with NaI. It crystallizes with one discrete mol ecule in the asymmetric unit. The mol-ecule presents an iodide-bridged dimeric structure with a cisoid arrangement with respect to the C,N-cyclo-palladated ligands. Both PdII atoms have a slightly distorted square-planar coordination environment. Weak inter-molecular contacts of the type C-H?Pd seem to have a significant influence on the arrangement of the mol-ecules along the b axis in the crystal. PMID- 29152336 TI - Structural characterization of two solvates of a luminescent copper(II) bis (pyridine)-substituted benzimidazole complex. AB - Copper(II) complexes of benzimidazole are known to exhibit biological activity that makes them of inter-est for chemotherapeutic and other pharmaceutical uses. The complex bis-(acetato-kappaO){5,6-dimethyl-2-(pyridin-2-yl)-1-[(pyridin-2 yl)meth-yl]-1H-benzimidazole-kappa2N2,N3}copper(II), has been prepared. The absorption spectrum has features attributed to intra-ligand and ligand-field transitions and the complex exhibits ligand-centered room-temperature luminescence in solution. The aceto-nitrile monosolvate, [Cu(C2H3O2)2(C20H18N4)].C2H3N (1), and the ethanol hemisolvate, [Cu(C2H3O2)2(C20H18N4)].0.5C2H6O (2), have been structurally characterized. Compound 2 has two copper(II) complexes in the asymmetric unit. In both 1 and 2, distorted square-planar N2O2 coordination geometries are observed and the Cu N(Im) bond distance is slightly shorter than the Cu-N(py) bond distance. Inter molecular pi-pi inter-actions are found in 1 and 2. A weak C-H?pi inter-action is observed in 1. PMID- 29152337 TI - Crystal structure and features of 3',8-di-benzyl-idene-4a,5,6,7,8,8a-hexa-hydro 2'H-spiro-[chromene-2,1'-cyclo-hexa-n]-2'-one. AB - The synthesis and crystal structure of the title compound, C28H28O2, are reported. The C=C-C-C torsion angles in the phenyl-methyl-idene units are 166.6 (3) and -48.0 (4) degrees . In the crystal, mol-ecules form a three-dimensional network by means of weak C-H?O hydrogen bonds. The most important contributions to the crystal structure are the H?H inter-actions (68.8%), while the H?O contacts account for 4.5%. PMID- 29152338 TI - Crystal structure of methyl (Z)-2-[(Z)-3-methyl-2-({(E)-1-[(R*)-4-methyl-cyclo hex-3-en-1-yl]ethyl-idene}hydrazinyl-idene)-4-oxo-thia-zolidin-5-yl idene]acetate. AB - The new title 4-thia-zolidinone derivative, C16H21N3O3S, was obtained from the cyclization reaction of 4-methyl-3-thio-semicarbazone and dimethyl acetyl-enedi carboxyl-ate (DMAD). The cyclo-hexyl-idene ring has an envelope conformation with the stereogenic centre C atom as the flap. Its mean plane makes a dihedral angle of 56.23 (9) degrees with the thia-zolidine ring mean plane. In the crystal, mol ecules are linked by C-H?O hydrogen bonds forming chains propagating in the [001] direction. Within the chains there are offset pi-pi inter-actions between the thia-zolidine rings of inversion-related mol-ecules [centroid-centroid distance = 3.703 (1) A]. The chains are linked by further C-H?O hydrogen bonds, forming slabs parallel to the ac plane. PMID- 29152339 TI - Stoichiometric and polymorphic salts of hexa-methyl-ene-tetra-minium and 2-chloro 4-nitro-benzoate. AB - Four mol-ecular salts made from hexa-methyl-ene-tetra-minium and 2-chloro-4-nitro benzoate have been synthesized and are reported, namely ammonium hexa-methyl-ene tetra-minium bis-(2-chloro-4-nitro-benzoate), NH4+.C6H13N4+.2C7H3ClNO4-, (I), hexa-methyl-ene-tetra-minium hydrogen bis-(2-chloro-4-nitro-benzoate), 0.5C6H13N4+.C7H3.50ClNO4-, (II), hexa-methyl-ene-tetra-minium 2-chloro-4-nitro benzoate, C6H13N4+.C7H3ClNO4-, (IIIa) and (IIIb). All four mol-ecular salts show N+-H?O- hydrogen bonding. Salt (I) crystallized out with an NH4+ counter-ion which came from decomposition of 50% of the hexa-methyl-ene-tetra-minium cation in solution. (II) shows an unusual asymmetric unit, with both a hexa-methyl-ene tetra-minium cation and a partially deproton-ated 2-chloro-4-nitro-benzoate anion. Salts (IIIa) and (IIIb) are polymorphs of each other. This work shows that hexamethylenetetramine only protonates once, even in the presence of excess acid. PMID- 29152340 TI - Crystal structures and Hirshfeld surfaces of differently substituted (E)-N' benzyl-idene-N-methyl-2-(thio-phen-2-yl)acetohydrazides. AB - The syntheses and crystal structures of (E)-N'-(3-cyano-benzyl-idene)-N-methyl-2 (thio-phen-2-yl)acetohydrazide, C15H13N3OS, (I), and (E)-N'-(4-meth-oxy-benzyl idene)-N-methyl-2-(thio-phen-2-yl)acetohydrazide, C15H16N2O2S, (II), with different substituents in the meta and para position of the benzene ring are described. Compounds (I) and (II) both crystallize with two mol-ecules in the asymmetric unit, with generally similar conformations [r.m.s. overlay fits for (I) and (II) of 0.334 and 0.280 A, respectively] that approximate to L-shapes. The thio-phene rings in (I) are well ordered, whereas those in (II) exhibit 'flip' rotational disorder [occupancies 0.662 (2) and 0.338 (2) for mol-ecule 1, and 0.549 (3) and 0.451 (3) for mol-ecule 2]. The packing for (I) features short C-H?O inter-actions arising from the C-H grouping adjacent to the cyanide group and C-H?Nc (c = cyanide) links arising from the methine groups to generate [110] double chains. Weak C-H?pi inter-actions inter-link the chains into a three dimensional network. The packing for (II) features numerous C-H?O and C-H?pi inter-actions arising from different donor groups to generate a three-dimensional network. Hirshfeld fingerprint plots indicate significant differences in the percentage contact surfaces for (I) and (II). PMID- 29152341 TI - Crystal structure of (4,4'-bipyridyl-kappaN)bis-[N-(2-hydroxy-ethyl)-N-iso-propyl dithio-carbamato-kappa2S,S']zinc(II)-4,4'-bipyridyl (2/1) and its isostructural cadmium(II) analogue. AB - The title structures, [M(C6H12NOS2)2(C10H8N2)].0.5C10H8N2, for M = Zn, (I), and Cd, (II), feature terminally bound 4,4'-bipyridyl ligands and non-coordinating 4,4'-bi-pyridyl mol-ecules, with the latter disposed about a centre of inversion. The coordination geometry about the metal atom is defined by two non symmetrically chelating di-thio-carbamate ligands and a pyridyl N atom. The NS4 donor sets are distorted but, approximate to trigonal bipyramidal in each case. In the crystal, hy-droxy-O-H?O(hy-droxy) and hy-droxy-O-H?N(pyrid-yl) hydrogen bonds between the zinc-containing mol-ecules lead to a supra-molecular layer parallel to (100). The three-dimensional architecture arises as the layers are linked via methine-C-H?S, pyridyl-C-H?O(hy-droxy) and pi-pi [inter-centroid distance between coordinated pyridyl rings = 3.6246 (18) A] inter-actions. Channels along the c-axis direction are occupied by the non-coordinating 4,4' bipyridine mol-ecules, which are held in place by C-H?pi(chelate ring) contacts. PMID- 29152342 TI - Green synthesis and crystal structure of 3-(benzo-thia-zol-2-yl)thio-phene. AB - The title compound, C11H7NS2, was prepared in high yield (87%) using a solvent free microwave-assisted synthesis. The structure shows whole-mol-ecule disorder with occupancies for two orientations (A and B) of 0.4884 (10) and 0.5116 (10), respectively. The thio-phene and benzo-thia-zole rings are almost planar and make dihedral angles of 10.02 (18) and 12.54 (19) degrees for orientations A and B, respectively. Slipped pi-pi stacking between the aromatic rings, together with C H?pi, C-H?S and C-H?N inter-actions, result in a herringbone motif in the crystal packing. PMID- 29152343 TI - [MU2-Bis(di-phenyl-phosphan-yl)hexa-ne]bis-[undeca-carbonyl-triangulo triruthenium(3 Ru-Ru)] hexane monosolvate: crystal structure and Hirshfeld surface analysis. AB - In the title cluster complex hexane solvate, [Ru6(C30H32P2)(CO)22].C6H14, two Ru3(CO)11 fragments are linked by a Ph2P(CH2)6PPh2 bridge with the P atoms equatorially disposed with respect to the Ru3 triangle in each case; the hexane solvent mol-ecule is statistically disordered. The Ru?Ru distances span a relatively narrow range, i.e. 2.8378 (4) to 2.8644 (4) A. The hexyl chain within the bridge has an all-trans conformation. In the mol-ecular packing, C-H?O inter actions between cluster mol-ecules, and between cluster and hexane solvent mol ecules lead to a three-dimensional architecture. In addition, there are a large number of C=O?pi(arene) inter-actions in the crystal. The importance of the carbonyl groups in establishing the packing is emphasized by the contribution of 53.4% to the Hirshfeld surface by O?H/H?O contacts. PMID- 29152344 TI - Crystal structure of akuammicine, an indole alkaloid from Catharanthus roseus. AB - The title compound, C20H22N2O2, an alkaloid isolated from the Madagascar periwinkle, crystallizes in P1 with two independent but closely similar mol ecules in the unit cell. The mol-ecules are linked into pairs by two N-H?O=C hydrogen bonds. The absolute configuration was confirmed by anomalous dispersion effects as S at the 3 and 15 positions, and R at the 7 position. PMID- 29152345 TI - 4-(4-Hy-droxy-phenyl)-2,2,4-trimethyl-7,8-benzo-thia-chroman, a fused-ring counterpart of thia-Dianin's compound. AB - The title compound, C22H22OS [systematic name: 4-(1,3,3-trimethyl-2,3-di-hydro-1H 4-thia-phenanthren-1-yl)phenol], crystallizes unsolvated from nitro-methane as colourless prisms (m.p. 425-427 K) in the polar monoclinic space group Ia with Z' = 2 (mol-ecules A and B). Both independent mol-ecules possess a very similar proximal conformation, this referring to the juxtaposition of the 4-hy-droxy phenyl substituent with respect to the syn-related methyl group. In the crystal, mol-ecule A is linked to mol-ecule B by an O-H?O hydrogen bond. In turn, mol ecule B exhibits a weak O-H?pi inter-action with the phenolic group of mol-ecule A related by a-glide symmetry. Together, these lead to [100] chains. PMID- 29152346 TI - Crystal structure of (Z)-N-benzyl-idene-1-phenyl-methanamine oxide hydrogen peroxide monosolvate. AB - The title adduct, C14H13NO.H2O2, consists of (Z)-N-benzyl-idene-1-phenyl methanamine oxide and hydrogen peroxide mol-ecules in a 1:1 ratio. The organic coformer adopts a skew geometry with an inter-aryl-ring dihedral angle of 81.9 (2) degrees . In the crystal, the organic and peroxide mol-ecules are linked through both peroxide O-H donor groups to oxide O-atom acceptors, giving one dimensional chains extending along the b axis. Present also are weak inter molecular C-H?O hydrogen-bonding inter-actions. PMID- 29152347 TI - Hybrid organic-inorganic crystal structure of 4-(di-methyl-amino)-pyridinium di methyl-ammonium tetra-chlorido-lead(II). AB - The title compound, (C2H8N)(C7H11N2)[PbCl4], is a hybrid organic-inorganic material. It crystallizes in the space group C2/c and contains one half of a mol ecule of lead chloride, 4-(di-methyl-amino)-pyridinium, and di-methyl-ammonium in the asymmetric unit. The crystal structure exhibits chains of lead chloride capped by 4-(di-methyl-amino)-pyridinium and di-methyl-ammoium by hydrogen bonding. This creates a one-dimensional zipper-like structure down the a axis. The crystal structure is examined and compared to a similar structure containing lead chloride and di-methyl-benzene-1,4-diaminium. PMID- 29152348 TI - Zwitterionic 1-{(1E)-[(4-hy-droxy-phen-yl)iminio]meth-yl}naphthalen-2-olate: crystal structure and Hirshfeld surface analysis. AB - The title zwitterion, C17H13NO2 (systematic name: 1-{(1E)-[(4-hy-droxy-phen yl)iminium-yl]meth-yl}naphthalen-2-olate), features an intra-molecular charge assisted N+-H?O- hydrogen bond. A twist in the mol-ecule is evident around the N C(hy-droxy-benzene) bond [C-N-C-C torsion angle = 39.42 (8) degrees ] and is reflected in the dihedral angle of 39.42 (8) degrees formed between the aromatic regions of the mol-ecule. In the crystal, zigzag supra-molecular chains along the a axis are formed by charge-assisted hy-droxy-O-H?O(phenoxide) hydrogen bonding. These are connected into a layer in the ab plane by charge-assisted hy-droxy benzene-C-H?O(phenoxide) inter-actions and pi-pi contacts [inter-centroid distance between naphthyl-C6 rings = 3.4905 (12) A]. Layers stack along the c axis with no specific inter-actions between them. The Hirshfeld surface analysis points to the significance C?H contacts between layers. PMID- 29152349 TI - Crystal structure of {2,6-bis-[(di-methyl-amino)-meth-yl]phenyl kappa3N,C1,N'}(bromido/chlorido)-mercury(II). AB - In the mol-ecular structure of the title compound, {2,6-bis-[(di-methyl-amino) meth-yl]phenyl-kappa3N,C1,N'}[bromido/chlorido-(0.30/0.70)]mercury(II)-{2,6-bis [(di-methyl-amino)-meth-yl]phenyl-kappa3N,C1,N'}[bromido/chlorido-(0.24/0.76)]mer cury(II) (1/1), [HgBr0.30Cl0.70(C12H19N2)].[HgBr0.24Cl0.76(C12H19N2)], there are two mol-ecules in the asymmetric unit of formula LHgX {L = 2,6-bis-[(di-methyl amino)-meth-yl]phenyl and X = Cl/Br}. In each mol-ecule, the halide site is mixed Cl/Br, with occupancies of 0.699 (7):0.301 (7) and 0.763 (7):0.237 (7), respectively. The two mol-ecules are linked into dimers by a combination of Hg?Hg [Hg?Hg = 3.6153 (3) A] and C-H?Cl and C-H?pi inter-actions. PMID- 29152350 TI - Crystal structure of (E)-4-methyl-N-{2-[2-(4-nitro-benzyl-idene)hydrazin-1-yl]-2 oxoeth-yl}benzene-sulfonamide N,N-di-methyl-formamide monosolvate. AB - The mol-ecule of the title Schiff base compound, C16H16N4O5S.C3H7NO, displays a trans conformation with respect to the C=N double bond. The C-N and N-N bonds are relatively short compared to their normal bond lengths, indicating some degree of delocalization in the mol-ecule. The mol-ecule is bent at the S atom, with an S-N C-C torsion angle of 164.48 (11) degrees . The dihedral angle between the two aromatic rings is 84.594 (7) degrees . Inter-molecular N-H?O and C -H?O hydrogen bonds connect centrosymmetrically related mol-ecules into dimers forming rings of R33(11) and R22(10) graph-set motif stacked along the a axis into a columnar arrangement. The mol-ecular columns are further linked into a three-dimensional network by C-H?pi inter-actions. PMID- 29152351 TI - Synthesis and crystal structures of two purpurin derivatives: 1,4-dihy-droxy-2 propoxyanthra-quinone and 2-but-oxy-1,4-di-hydroxy-anthra-quinone. AB - The title compounds were obtained by deprotonation of 1,2,4-tri-hydroxy-anthra quinone (purpurin) using sodium hydride followed by reaction with either 1-bromo propane or 1-bromo-butane. 1,4-Dihy-droxy-2-propoxyanthra-quinone crystallizes as a 1:1 solvate from aceto-nitrile, C17H14O5.CH3CN. The anthra-quinone core of the mol-ecule is essentially planar and both hy-droxy groups participate in intra molecular O-H?O (carbon-yl) hydrogen bonds. The propyl chain is angled slightly above the plane of the anthra-quinone moiety with a maximum deviation of 0.247 (2) A above the plane for the terminal carbon atom. In contrast, 2-but-oxy-1,4-di hydroxy-anthra-quinone, C18H16O5, crystallizes from nitro-methane with two independent mol-ecules in the asymmetric unit. The anthra-quinone core of each independent mol-ecule is essentially planar and both hy-droxy groups on both mol ecules participate in intra-molecular O-H?O(carbon-yl) hydrogen bonds. The butyl chain in one mol-ecule is also angled slightly above the plane of the anthra quinone moiety, with a maximum deviation of 0.833 (5) A above the plane for the terminal carbon atom. In contrast, the butyl group on the second mol-ecule is twisted out of the plane of the anthra-quinone core with a torsion angle of 65.1 (3) degrees , resulting in a maximum deviation of 1.631 (5) A above the plane for the terminal carbon atom. PMID- 29152352 TI - Crystal structure of the co-crystalline adduct 1,3,6,8-tetra-aza-tri-cyclo [4.4.1.13,8]dodecane (TATD)-4-iodo-phenol (1/2): supra-molecular assembly mediated by halogen and hydrogen bonding. AB - The asymmetric unit of the title co-crystalline adduct, 1,3,6,8-tetra-aza-tri cyclo[4.4.1.13,8]dodecane (TATD)-4-iodo-phenol (1/2), C8H16N4.2C6H5IO, comprises a half mol-ecule of the aminal cage polyamine plus a 4-iodo-phenol mol-ecule. A twofold rotation axis generates the other half of the adduct. The components are linked by two inter-molecular O-H?N hydrogen bonds. The adducts are further linked into a three-dimensional framework structure by a combination of N?I halogen bonds and weak non-conventional C-H?O and C-H?I hydrogen bonds. PMID- 29152353 TI - Crystal structure of a CoII coordination polymer with a dipyridyl ligand: catena poly[[bis-(nitrato-kappa2O,O')cobalt(II)]-MU-N-(pyridin-2-ylmeth-yl)pyridine-3 amine-kappa3N,N':N'']. AB - The asymmetric unit of the title compound, [Co(NO3)2L] n , L = N-(pyridine-2 ylmeth-yl)pyridine-3-amine (C11H11N3), contains one CoII centre, two nitrate anions and one L ligand in which the Cpy-C-N-Cpy moiety adopts a trans conformation with a torsion angle of -173.1 (3) A. The coordination geometry of the CoII atom is a distorted penta-gonal bipyramid. One amine N atom from the L ligand and four O atoms from two eta2-nitrato ligands form the basal plane and two pyridyl N atoms from two symmetry-related L ligands occupy the apical positions [N-Co-N = 171.86 (11) degrees ]. The displacement of the central CoII atom from the basal plane (r.m.s. deviation = 0.085 A) is 0.1491 (12) A. Each bidentate nitrate group is bonded asymmetrically to the cobalt atom in an chelating fashion. The CoII ions are linked by the L ligands to form a zigzag chain propagating along the c-axis direction. Within the zigzag chain, C-H?O hydrogen bonds between the ligands and the nitrate anions are observed. Adjacent zigzag chains are connected via inter-molecular pi-pi stacking inter-actions [centroid-to-centroid distance = 3.844 (2) A] between the pyridine rings together with N/C-H?O hydrogen bonds. PMID- 29152354 TI - Crystal structure of a looped-chain CoII coordination polymer: catena-poly[[bis (nitrato-kappaO)cobalt(II)]bis-[MU-bis-(pyridin-3-ylmeth-yl)sulfane-kappa2N:N']]. AB - The asymmetric unit of the title compound, [Co(NO3)2(C12H12N2S)2] n , contains a bis-(pyridin-3-ylmeth-yl)sulfane (L) ligand, an NO3- anion and half a CoII cation, which lies on an inversion centre. The CoII cation is six-coordinated, being bound to four pyridine N atoms from four symmetry-related L ligands. The remaining coordination sites are occupied by two O atoms from two symmetry related nitrate anions in a monodentate manner. Thus, the CoII centre adopts a distorted octa-hedral geometry. Two symmetry-related L ligands are connected by two symmetry-related CoII cations, forming a 20-membered cyclic dimer, in which the CoII atoms are separated by 10.2922 (7) A. The cyclic dimers are connected to each other by sharing CoII atoms, giving rise to the formation of an infinite looped chain propagating along the [101] direction. Inter-molecular C-H?pi (H?ring centroid = 2.89 A) inter-actions between one pair of corresponding L ligands and C-H?O hydrogen bonds between the L ligands and the nitrate anions occur in the looped chain. In the crystal, adjacent looped chains are connected by inter-molecular pi-pi stacking inter-actions [centroid-to-centroid distance = 3.8859 (14) A] and C-H?pi hydrogen bonds (H?ring centroid = 2.65 A), leading to the formation of layers parallel to (101). These layers are further connected through C-H?O hydrogen bonds between the layers, resulting in the formation of a three-dimensional supra-molecular architecture. PMID- 29152355 TI - Synthesis and crystal structure of bis-(1H-benzo[d][1,2,3]triazole-kappaN2){2,2' [N-(phenyl-phospho-r-yl-methyl-kappaO)aza-nedi-yl]di-acetato kappa3O,N,O'}cobalt(II)-1H-benzo[d][1,2,3]triazole (1/1). AB - In the title compound, [Co(C11H12NO6P)(C6H5N3)2].C6H5N3, the 2,2'-[N-(phenyl phospho-rylmethyl-kappaO)aza-nedi-yl]di-acetate dianion N,O,O',O''-chelates the CoII cation and two 1H-benzo[d][1,2,3]triazole mol-ecules coordinate to the CoII cation to complete the slightly distorted octa-hedral coordination. In the crystal, classical O-H?O, N-H?O hydrogen bonds and weak C-H?N hydrogen bonds link the mol-ecules into a three-dimensional supra-molecular architecture. pi-pi stacking between the triazole and benzene rings and between the benzene rings is also observed in the crystal. PMID- 29152356 TI - Crystal structure of aqua-(perchlorato)bis-[MU-(E)-2-({[2-(pyridin-2-yl)eth yl]imino}-meth-yl)phenolato-kappa4N,N',O:O]dicopper(II) perchlorate. AB - The title compound, [Cu2(ClO4)(C14H13N2O)2(H2O)]ClO4, crystallizes as an unsymmetrical dinuclear cation bridged by the phen-oxy O atoms with one CuII atom coordinated by a water mol-ecule and the other by a perchlorate anion, thus making both CuII atoms five-coordinate, and with a further perchlorate anion present for charge balance. A long inter-action [2.9893 (5) A] between one of the two CuII atoms and an O atom of the perchlorate counter-ion links the cations and anions into linear chains along the a-axis direction. In addition, the water H atoms link with the perchlorate counter-ion. These inter-actions, along with numerous C-H?O inter-actions between the tetra-hedral perchlorate anions, link the ions into a complex three-dimensional array. One of the perchlorate anions is disordered over two conformations with occupancies of 0.586 (4) and 0.414 (4). PMID- 29152357 TI - Crystal structure of (1R,5S)-endo-(8-methyl-8-azoniabi-cyclo-[3.2.1]oct-3 yl)ammonium aqua-tri-chlorido-nitratocopper(II). AB - The structure of a salt of diprotonated endo-3-amino-tropane crystallized with a copper(II) anionic cluster is reported, viz. (C8H18N2)[CuCl3(NO3)(H2O)]. Neither ion in the salt has been structurally characterized previously. In the crystal, the ions pack together to form a three-dimensional structure held together by a network of inter-molecular N-H?O, O-H?Cl and N-H?Cl hydrogen-bonding inter actions. Selective crystallization of the title compound can be considered as a simple method for the separation of the exo and endo isomers of 3-amino-tropane. PMID- 29152358 TI - 4-Benzyl-1-(4-nitro-phen-yl)-1H-1,2,3-triazole: crystal structure and Hirshfeld analysis. AB - The mol-ecule in the title compound, C15H12N4O2, has a twisted L-shape with the dihedral angle between the aromatic rings of the N-bound benzene and C-bound benzyl groups being 70.60 (9) degrees . The nitro group is co-planar with the benzene ring to which it is connected [C-C-N-O torsion angle = 0.4 (3) degrees ]. The three-dimensional packing is stabilized by a combination of methyl-ene-C H?O(nitro), methyl-ene-C-H?pi(phen-yl), phenyl-C-H?pi(triazol-yl) and nitro O?pi(nitro-benzene) inter-actions, along with weak pi(triazol-yl) pi(nitrobenzene) contacts [inter-centroid distance = 3.8386 (10) A]. The importance of the specified inter-molecular contacts has been verified by an analysis of the calculated Hirshfeld surface. PMID- 29152359 TI - Crystal structure of bis[bis(4-azaniumylphenyl) sulfone] tetranitrate monohydrate. AB - In the title compound, the hydrated tetra-(nitrate) salt of dapsone (4,4'-di amino-diphenyl-sulfone), 2C12H14N2O2S2+.4NO3-.H2O {alternative name: bis[bis (4,4'-di-aza-niumylphen-yl) sulfone] tetra-nitrate monohydrate}, the cations are conformationally similar, with comparable dihedral angles between the two benzene rings in each of 70.03 (18) and 69.69 (19) degrees . In the crystal, mixed cation anion-water mol-ecule layers lying parallel to the (001) plane are formed through N-H?O, O-H?O and C-H?O hydrogen-bonding inter-actions and these layers are further extended into an overall three-dimensional supra-molecular network structure. Inter-ring pi-pi inter-actions are also present [minimum ring centroid separation = 3.693 (3) A]. PMID- 29152360 TI - The crystal structures of two isomers of 5-(phenyl-iso-thia-zol-yl)-1,3,4-oxa thia-zol-2-one. AB - The syntheses and crystal structures of two isomers of phenyl iso-thia-zolyl oxa thia-zolone, C11H6N2O2S2, are described [systematic names: 5-(3-phenyl-iso-thia zol-5-yl)-1,3,4-oxa-thia-zol-2-one, (I), and 5-(3-phenyl-iso-thia-zol-4-yl)-1,3,4 oxa-thia-zol-2-one, (II)]. There are two almost planar (r.m.s. deviations = 0.032 and 0.063 A) mol-ecules of isomer (I) in the asymmetric unit, which form centrosymmetric tetra-mers linked by strong S?N [3.072 (2) A] and S?O contacts [3.089 (1) A]. The tetra-mers are pi-stacked parallel to the a-axis direction. The single mol-ecule in the asymmetric unit of isomer (II) is twisted into a non planar conformation by steric repulsion [dihedral angles between the central iso thia-zolyl ring and the pendant oxa-thia-zolone and phenyl rings are 13.27 (6) and 61.18 (7) degrees , respectively], which disrupts the pi-conjugation between the heteroaromatic iso-thia-zoloyl ring and the non-aromatic oxa-thia-zolone heterocycle. In the crystal of isomer (II), the strong S?O [3.020 (1) A] and S?C contacts [3.299 (2) A] and the non-planar structure of the mol-ecule lead to a form of pi-stacking not observed in isomer (I) or other oxa-thia-zolone derivatives. PMID- 29152361 TI - A new approach to alkaloid-like systems: synthesis and crystal structure of 1-(2 acetyl-11-meth-oxy-5,6-di-hydro-[1,3]dioxolo[4,5-g]pyrrolo-[2,1-a]isoquinolin-1 yl)propan-2-one. AB - The title compound, C19H19NO5, (I), is the product of a domino reaction between cotarnine chloride and acetyl-acetylene catalysed by copper(I) iodide. The mol ecule of (I) comprises a fused tetra-cyclic system containing two terminal five membered rings (pyrrole and 1,3-dioxole) and two central six-membered rings (di hydro-pyridine and benzene). The five-membered 1,3-dioxole ring has an envelope conformation and the central six-membered di-hydro-pyridine ring adopts a twist boat conformation. The acyl substituent is almost coplanar with the pyrrole ring, whereas the meth-oxy substituent is twisted by 27.93 (16) degrees relative to the benzene ring. The 2-oxopropan-1-yl substituent is roughly perpendicular to the pyrrole ring. In the crystal, mol-ecules are stacked along the a-axis direction; the stacks are linked by weak C-H?O hydrogen bonds into puckered layers lying parallel to (001). PMID- 29152362 TI - Crystal structure of 2,4,6-tri-methyl-benzoic anhydride. AB - The title compound, C20H22O3, was formed in the reaction between 2,4,6-tri-methyl benzoic acid and N,N-diiso-propyl-ethyl-amine in the presence of 1,3-di-chloro 1,3-bis-(di-methyl-amino)-propenium hydrogen dichloride, and was recrystallized from diethyl ether solution. It is the first exclusively alkyl-substituted benzoic anhydride to have been structurally characterized. The asymmetric unit consists of a half mol-ecule, the other half of which is generated by twofold rotation symmetry; the dihedral angle between the symmetry-related aromatic rings is 54.97 (3) degrees . The geometric parameters of the aromatic ring are typical of those for 2,4,6-tri-methyl-phenyl substituted groups. The C=O and C-O bond lengths are 1.1934 (12) and 1.3958 (11) A, respectively, and the angle between these three atoms (O=C-O) is 121.24 (9) degrees . In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds and C-H?pi inter-actions. The packing features wavy chains that extend parallel to [001]. PMID- 29152363 TI - A new lanthanum(III) complex containing acetyl-acetone and 1H-imidazole. AB - In the title complex, di-aqua-(1H-imidazole-kappaN3)(nitrato-kappa2O,O')bis-(4 oxo-pent-2-en-2-olato-kappa2O,O')lanthanum(III), [La(C5H7O2)2(NO3)(C3H4N2)(H2O)2], the La atom is coordinated by eight O atoms of two acetyl-acetonate (acac) anions acting as bidentate ligands, two water mol ecule as monodentate ligands, one nitrate anions as a bidentate ligand and one N atom of an imidazolate (ImH) molecule as a monodentate ligand. Thus, the coordination number of the La atom is nine in a monocapped square anti-prismatic polyhedron. There are three types of inter-molecular hydrogen bonds between ligands, the first involving nitrate-water O?H-O inter-actions running along the [001] direction, the second involving acac-water O?H-O inter-actions along the [010] direction and the third involving an Im-nitrate N-H?O inter-action along the [100] direction (five inter-actions of this type). Thus, an overall one dimensional network structure is generated. The mol-ecular plane of an ImH molecule is almost parallel to that of a nitrate ligand, making an angle of only 6.04 (12) degrees . Inter-estingly, the ImH plane is nearly perpendicular to the planes of two neighbouring acac ligands. PMID- 29152364 TI - A 2:1 co-crystal of 3,5-di-bromo-4-cyano-benzoic acid and anthracene. AB - The title co-crystal, C8H3Br2NO2.0.5C14H10, was self-assembled from a 2:1 mixture of the components in slowly evaporating di-chloro-methane. The mol-ecules adopt a sheet structure parallel to (1-12) in which carb-oxy hydrogen-bonded dimers and anthracene mol-ecules stagger in both dimensions. Within the sheets, six individual cyano acid mol-ecules surround each anthracene mol-ecule. Cyano acid mol-ecules form one of the two possible R22(10) rings between neighboring cyano and bromo groups. Compared to the di-chloro analog [Britton (2012 ?). J. Chem. Crystallogr.42, 851-855], the dihedral angle between the best-fit planes of acid and anthracene mol-ecules has decreased from 7.1 to 0.9 (2) degrees . PMID- 29152365 TI - Crystal structure and Hirshfield analysis of the 4-(di-methyl-amino)-pyridine adduct of 4-meth-oxy-phenyl-borane. AB - The title compound [systematic name: 4-(di-methyl-amino)-pyridine-4-meth-oxy phenyl-borane (1/1)], C14H19BN2O, contains two independent mol-ecules in the asymmetric unit. Both molecules exhibit coplanar, mostly sp2-hybridized meth-oxy and di-methyl-amino substituents on their respective aromatic rings, consistent with pi-donation into the aromatic systems. The B-H groups exhibit an intra molecular close contact with a C-H group of the pyridine ring, which may be evidence of electrostatic attraction between the hydridic B-H and the electropositive aromatic C-H. There appears to be weak C-H?pi(arene) inter actions between two of the H atoms of an amino-methyl group and the meth-oxy substituted benzene ring of the other independent mol-ecule, and another C-H?pi (arene) inter-action between one of the pyridine ring H atoms and the same benzene ring. PMID- 29152366 TI - Crystal structure of 4,6-dimethyl-2-{[3,4,5-trihy-droxy-6-(hy-droxy-meth-yl)tetra hydro-2H-pyran-2-yl]sulfan-yl}nicotino-nitrile. AB - In the title compound, C14H18N2O5S, the C-S bond lengths are unequal, with S Cglucose = 1.8016 (15) A and S-Cpyrid-yl = 1.7723 (13) A. The hydro-philic glucose residues lie in the regions z ? 0.25 and 0.75. Four classical hydrogen bonds link the mol-ecules to form layers parallel to the ab plane, from which the pyridyl rings project; pyridyl ring stacking parallel to the a axis links adjacent layers. PMID- 29152367 TI - Crystal structure of poly[tetra-MU-cyanido-ethanol-bis(2-iodo-pyrazine) digold(I)iron(II)]. AB - In the title polymeric complex, [Au2Fe(CN)4(C4H3IN2)2(C2H6O)] n , the FeII cation is coordinated by two iodo-pyrazine mol-ecules, one ethanol mol-ecule and three di-cyano-aurate anions in a distorted N5O octa-hedral geometry. In the crystal, the di-cyano-aurate anions bridge the FeII cations to form polymeric chains propagating along the b-axis direction. Stabilization of the crystal structure is provided by O-H?N hydrogen bonds and pi-pi stacking between parallel iodo pyrazine rings of neighbouring chains, the centroid-centroid distances being 3.654 (10) and 3.658 (9) A. PMID- 29152368 TI - Synthesis, crystal structure and Hirshfeld surface analysis of a polymeric bis muthate(III) halide complex, (C6H6N3)2[BiCl5].2H2O. AB - The synthesis and the crystal structure of a new halide-bridged polymer, namely catena-poly[bis-(1,2,3-benzotriazolium) [[tetra-chlorido-bis-muth(III)]-MU chlorido] dihydrate], {(C6H6N3)2[BiCl5].2H2O} n are reported. The structure comprises polyanionic zigzag chains of formula [(BiCl5)2-] n running along the c axis direction. The 1,2,3-benzotriazolium cations are linked between these polymer chains, via the water mol-ecules, giving rise to left- and right-handed helical chains. Hirshfeld surface analysis and fingerprint plots were used to decode the inter-molecular inter-actions in the crystal network and determine the contribution of the component units for the construction of the three-dimensional architecture. PMID- 29152369 TI - Crystal structure of tetra-iso-butyl-thiuram di-sulfide. AB - Tetra-kis(2-methyl-prop-yl)thio-per-oxy-dicarbonic di-amide, or tetra-iso-butyl thiuram di-sulfide, C18H36N2S4, crystallizes in a general position in the triclinic space group P-1 but shows pseudo-C2 symmetry about the di-sulfide bond. The C-S-S-C torsion angle [-85.81 (2) degrees ] and the dihedral angle between the two NCS2 mean planes [85.91 (5) degrees ] are within the range observed for this compound type. Multiple intra- and inter-molecular S?H-C close contacts appear to play a role in assisting the specific conformation of the pendant isobutyl groups and the packing arrangement of mol-ecules within the cell. Tetra iso-butyl-thiuram di-sulfide mol-ecules of one optical configuration form sheets in the plane of the a and b axes. Inversion centers exist between adjoining sheets, which stack along the c axis and alternate in the handedness of their constituent mol-ecules. PMID- 29152370 TI - Unusual thermolysis of aza-cyclic allene under microwave conditions: crystal structure of (3RS,3aSR,8RS,8aRS)-methyl 5,6-dimeth-oxy-3a,10-dimethyl-1-phenyl 3,3a,8,8a-tetra-hydro-3,8-(epimino-methano)-cyclo-penta-[a]indene-2-carboxyl-ate from synchrotron X-ray diffraction. AB - The title compound, C25H27NO4 (I), the product of the unusual thermolysis of aza cyclic allene methyl 10,11-dimeth-oxy-3,8-dimethyl-6-phenyl-3-aza-benzo[d]cyclo deca-4,6,7-triene-5-carboxyl-ate, represents a bicyclic heterosystem and crystallizes in the monoclinic space group P21/c with three crystallographically independent mol-ecules in the unit cell. These independent mol-ecules adopt very similar geometries and differ only in the conformations of the two meth-oxy substituents on the benzene ring. In two of the three independent mol-ecules, both meth-oxy groups are almost coplanar with the benzene ring [the C-C-O-Me torsion angles are 10.8 (2), 12.3 (2), 9.1 (2) and 13.6 (3) degrees ], whereas in the third mol-ecule, one of the meth-oxy groups is practically coplanar to and the other meth-oxy group is roughly perpendicular to the benzene ring, the C-C-O Me torsion angles being 14.1 (2) and 76.5 (2) degrees . The mol-ecule of (I) comprises a fused tetra-cyclic system containing two five-membered rings (cyclo pentenes) and two six-membered rings (piperidine and benzene). The five-membered rings have the usual envelope conformation, with the methyl-subsituted C atom as the flap in each molecule, and the six-membered piperidine ring has a chair conformation. The methyl substituent at the N atom occupies the sterically favourable equatorial position. The carboxyl-ate group lies almost within the basal plane of the parent cyclo-pentene ring [making dihedral angle of 11.68 (8), 18.94 (9) and 15.16 (9) degrees in the three independent mol-ecules], while the phenyl substituent is twisted by 48.26 (6), 42.04 (6) and 41.28 (6) degrees (for the three independent mol-ecules) relative to this plane. In the crystal, mol ecules of (I) form stacks along the b-axis direction. The mol-ecules are arranged at van der Waals distances. PMID- 29152371 TI - Crystal structures of the solid solutions Na3Zn0.912Cd0.088B5O10 and Na3Zn0.845Mg0.155B5O10. AB - Two new penta-borates, tris-odium zinc cadmium penta-borate, Na3Zn0.912Cd0.088B5O10, and tris-odium zinc magnesium penta-borate, Na3Zn0.845Mg0.155B5O10, have been synthesized by high-temperature solution reactions at 1023 K. Their crystal structures were determined by single-crystal X ray diffraction. Both solid solutions crystallize in the ortho-rhom-bic form of the parent compound Na3ZnB5O10 (space group type Pbca, Z = 8) and contain the double ring [B5O10]5- anion composed of one BO4 tetra-hedron and four BO3 triangles as the basic structural motif. The anions are bridged by tetra-hedrally coordinated and occupationally disordered M2+ (M = Zn/Cd, Zn/Mg) cations via common O atoms to form [MB5O10] n3n- layers. The intra-layer inter-secting channels and the inter-layer voids are occupied by Na+ cations to balance the charge. PMID- 29152372 TI - Synthesis and crystal structure of a two-dimensional CoII coordination polymer: poly[(MU3-3-carb-oxy-benzoato)[MU2-5-(pyridin-4-yl)-1H,2'H-3,3'-bi[1,2,4 triazole]]cobalt(II)]. AB - In the title compound, [Co(C8H5O4)(C9H6N7)] n , the divalent CoII atom is six coordinated to three N atoms from two symmetrical 5-(pyridin-4-yl)-1H,2'H-3,3' bi[1,2,4-triazole] (H2pyttz) ligands and three O atoms from three symmetrical 3 carb-oxy-benzoate (Hbdic) ligands, leading to a distorted {CoN3O3} octa-hedral coordination environment. Two CoII cations are linked by four bridging carboxyl ate groups to generate a dinuclear [Co2(CO2)4] unit. The dinuclear units are further connected into a chain along [010] via the Hbdic ligands. The other infinite chain, along [100], is formed through the H2pyttz ligands. Finally, the two kinds of chains are cross-linked, by sharing the CoII cations, into a two dimensional network. In the crystal, adjacent layers are further linked by O-H?N hydrogen bonds into a three-dimensional framework. PMID- 29152373 TI - A two-dimensional copper(I) coordination polymer based on 1-[2-(cyclo-hexyl sulfan-yl)eth-yl]pyridin-2(1H)-one. AB - The reaction of copper(I) iodide with 1-[2-(cyclo-hexyl-sulfan-yl)eth-yl]pyridin 2(1H)-one (L, C13H19NOS) in aceto-nitrile/di-chloro-methane results in a crystalline coordination polymer, namely poly[bis-{MU2-1-[2-(cyclo-hexyl-sulfan yl)eth-yl]pyridin-2(1H)-one}tetra-MU3-iodido-tetra-copper(I)], [Cu4I4L2] n . The asymmetric unit comprises two ligand mol-ecules, four copper(I) ions and four iodide ions. Inter-estingly, the O atoms are bound to the soft copper(I) ions. The stair-step clusters of Cu and I atoms in the asymmetric unit are linked repeatedly, giving rise to infinite chains along [100]. Neighbouring infinite chains are linked through the L mol-ecules, forming a two-dimensional brick-wall structure. These two-dimensional networks are stacked alternately along [001]. Additionally, there are inter-molecular C-H?I hydrogen bonds and C-H?pi inter actions between the ligands. PMID- 29152374 TI - Crystal structure of bis-(pyridine-4-carbo-thio-amide-kappaN1)bis-(thio-cyanato kappaN)cobalt(II) methanol monosolvate. AB - The asymmetric unit of the title compound, [Co(NCS)2(C6H6NS)4].CH3OH, consists of one cobalt(II) cation, two thio-cyanate anions, four pyridine-4-carbo-thio-amide ligands and one methanol mol-ecule that are located in general positions. The CoII cations are coordinated by two terminal N-bonding thio-cyanate anions and four N-bonding pyridine-4-carbo-thio-amide ligands, resulting in discrete and slightly distorted octa-hedral complexes. These complexes are linked into a three dimensional network via inter-molecular N-H?S hydrogen bonding between the amino H atoms and the thio-cyanate and pyridine-4-carbo-thio-amide S atoms. From this arrangement, channels are formed in which the methanol solvate mol-ecules are embedded and linked to the host structure by inter-molecular O-H?S and N-H?O hydrogen bonding. PMID- 29152375 TI - Crystal structure of diethyl 3,3'-[(2-fluoro-phen-yl)methyl-idene]bis-(1H-indole 2-carboxyl-ate). AB - In the title compound, C29H25FN2O4, the mean planes of the two indole ring systems (r.m.s. deviations = 0.1392 and 0.0115 A) are approximately perpendicular to one another, subtending a dihedral angle of 86.0 (5) degrees ; the benzene ring is twisted with respect to the mean planes of the two indole ring systems by 83.3 (2) and 88.1 (4) degrees , respectively. In the crystal, pairs of N-H?O hydrogen bonds link the mol-ecules into centrosymmetric dimers, which are further linked by N-H?O hydrogen bonds into supra-molecular chains propagating along the [101] direction. PMID- 29152376 TI - Crystal structure of 2,3,5,6-tetra-kis-(pyridin-2-yl)pyrazine hydrogen peroxide 4.75-solvate. AB - The structure of the title co-crystal, C24H16N6.4.75H2O2, consists of a 2,3,5,6 tetra-kis-(pyridin-2-yl)pyrazine coformer and hydrogen peroxide solvent mol ecules in an overall ratio of 1:4.75. Three of the six H2O2 mol-ecules modelled in the structure were found to be cross-orientationally disordered over two positions with occupancy ratios 0.846 (9):0.154 (9), 0.75 (2):0.25 (2), and 0.891 (9):0.109 (9). In the crystal, all of the peroxide mol-ecules are linked into hydrogen-bonded chains that propagate parallel to the a axis. These chains are further linked by O-H?N hydrogen bonds to the pyridine groups of the main mol ecule. PMID- 29152377 TI - Crystal structure of bis(MU2-4-bromo-2-[({2-[({2-[(5-bromo-2 oxidobenzylidene)amino]ethyl}sulfanyl)sulfonyl]ethyl}imino)methyl]phenolato)dicop er(II) dimethylformamide disolvate. AB - The title dinuclear copper(II) complex [Cu2(C18H16Br2N2O4S2)2] was prepared by direct synthesis of a dianionic Schiff base derived from 5-bromo-salicyl-aldehyde and cyste-amine. The discrete mol-ecules lie across inversion centers and crystallize with two di-methyl-formamide (DMF) mol-ecules of crystallization. The unique CuII ion is four-coordinated by two tetra-dentate Schiff base ligands in a distorted square-planar N2O2 environment. In the crystal, short inter-molecular S?Br contacts, weak C-H?O hydrogen bonds and intra- and inter-molecular pi-pi stacking inter-actions between rings of the ligand link the components into a two dimensional network parallel to (010). PMID- 29152379 TI - Interplay of neuronal and non-neuronal genes regulates intestinal DAF-16-mediated immune response during Fusarium infection of Caenorhabditis elegans. AB - Although precisely controlled innate immune response is governed by conserved cellular events in phylogenetically diverse hosts, the underlying molecular mechanisms by which this process is regulated against a multi-host pathogen remain unknown. Fusarium oxysporum is a model multi-host pathogen, known to be associated with neuronal stress in humans and vascular wilt in plants. The interaction between innate immune and neuronal pathways is the basis of many diverse biological responses. How these processes are coordinated in response to fungal disease is not well understood. Here, we show that F. oxysporum f. sp. ciceri causes neuronal stress and intestinal disintegration, ultimately leading to the death of Caenorhabditis elegans. To explore the regulatory framework of Fusarium-associated disease, we analysed the gene expression during infection, integrated temporal gene expression, and network analysis with genetic inactivation data in Caenorhabditis elegans. We identified 1024 genes showing significant changes in expression (corrected P-values <0.05) in response to Fusarium infection. Co-expression network analysis of our data identified prognostic genes related to disease progression. These genes were dynamically expressed in various neuronal and non-neuronal tissues exhibiting diverse biological functions, including cellular homeostasis, organ patterning, stress response, and lipid metabolism. The RNA-seq analysis further identified shared and unique signalling pathways regulated by DAF-16/FOXO and SIR-2.1 linking neuronal stress, which facilitates negative regulation of intestinal innate immunity. Genetic analysis revealed that GCY-5 in ASE functions upstream of DAF 16, whereas ASI-specific SRD-1 regulates behavioural immunity. Overall, our results indicate that a ubiquitous response occurs during Fusarium infection mediated by highly conserved regulatory components and pathways, which can be exploited further for the identification of disease-responsive genes conserved among animals and plants. Finally, this study provided a novel insight into cross species immune signalling and may facilitate the discovery of cellular therapeutic targets for Fusarium-associated disease. PMID- 29152378 TI - Zinc-finger proteins in health and disease. AB - Zinc-finger proteins (ZNFs) are one of the most abundant groups of proteins and have a wide range of molecular functions. Given the wide variety of zinc-finger domains, ZNFs are able to interact with DNA, RNA, PAR (poly-ADP-ribose) and other proteins. Thus, ZNFs are involved in the regulation of several cellular processes. In fact, ZNFs are implicated in transcriptional regulation, ubiquitin mediated protein degradation, signal transduction, actin targeting, DNA repair, cell migration, and numerous other processes. The aim of this review is to provide a comprehensive summary of the current state of knowledge of this class of proteins. Firstly, we describe the actual classification of ZNFs, their structure and functions. Secondly, we focus on the biological role of ZNFs in the development of organisms under normal physiological and pathological conditions. PMID- 29152380 TI - Wide-field three-photon excitation in biological samples. AB - Three-photon wide-field depth-resolved excitation is used to overcome some of the limitations in conventional point-scanning two- and three-photon microscopy. Excitation of chromophores as diverse as channelrhodopsins and quantum dots is shown, and a penetration depth of more than 700 MUm into fixed scattering brain tissue is achieved, approximately twice as deep as that achieved using two-photon wide-field excitation. Compatibility with live animal experiments is confirmed by imaging the cerebral vasculature of an anesthetized mouse; a complete focal stack was obtained without any evidence of photodamage. As an additional validation of the utility of wide-field three-photon excitation, functional excitation is demonstrated by performing three-photon optogenetic stimulation of cultured mouse hippocampal neurons expressing a channelrhodopsin; action potentials could reliably be excited without causing photodamage. PMID- 29152381 TI - Selective deletion of the soluble Colony-Stimulating Factor 1 isoform in vivo prevents estrogen-deficiency bone loss in mice. AB - Neutralizing CSF1 in vivo completely prevents ovariectomy (OVX)-induced bone loss in mice. There are two isoforms of CSF1, soluble (sCSF1), and membrane-bound (mCSF1), but their individual biological functions are unclear. It had been previously reported that mCSF1 knockout (K/O) and wild type (Wt) female mice experience the same degree of bone loss following OVX. In Wt mice the expression of sCSF1 was elevated fourfold in skeletal tissue following OVX while expression of mCSF1 was unchanged. To examine the role of sCSF1 in OVX-induced bone loss, mice were engineered in which sCSF1 was not expressed but expression of mCSF1 was unaffected (sCSF1 K/O). Isoform-specific reverse transcription PCR confirmed the absence of transcripts for sCSF1 in bone tissue isolated from these animals and no circulating CSF1 was detected by ELISA. Surprisingly, there were no significant differences in bone mineral density (BMD) between sCSF1 K/O mice and Wt controls as assessed by dual-energy X-ray absorptiometry and micro-CT. However, one month after OVX, femoral, spinal and total BMD had declined by 11.2%, 8.9%, and 8.7% respectively in OVX-Wt animals as compared to Sham-OVX. In contrast OVX sCSF1 K/O mice showed changes of +0.1%, -2.4%, and +2.3% at the same 3 sites compared to Sham-OVX sCSF1 K/O mice. These data indicate important non redundant functions for the two isoforms of CSF1 and suggest that sCSF1, but not mCSF1, plays a key role in estrogen-deficiency bone loss. PMID- 29152383 TI - JADPRO Live at APSHO 2015: Focus on Education and Collaboration. PMID- 29152384 TI - Biosimilars: Beginning a Conversation. PMID- 29152382 TI - Why sex differences in schizophrenia? AB - Clinical observation shows that men and women are different in prevalence, symptoms, and responses to treatment of several psychiatric disorders, including schizophrenia. While the etiology of gender differences in schizophrenia is only partially understood, recent genetic studies suggest significant sex-specific pathways in the schizophrenia between men and women. More research is needed to understand the causal roles of sex differences in schizophrenia in order to ultimately develop sex-specific treatment of this serious mental illness. In the present review, we will outline the current evidence on the sex-related factors interaction with disease onset, symptoms and treatment of schizophrenia, and discuss the potential molecular mechanisms that may mediate their cooperative actions in schizophrenia pathogenesis. PMID- 29152385 TI - Revolution at the Corner Drugstore. PMID- 29152386 TI - Getting Familiar With Biosimilars. PMID- 29152387 TI - 2015 Review of Newly Approved Oncologic Therapies. PMID- 29152388 TI - Ovarian Cancer: Current Treatment and Patient Management. PMID- 29152389 TI - Collaborative Practice in the Management of Neuroendocrine Tumors. PMID- 29152390 TI - Patients Living Longer With Metastatic Colorectal Cancer. PMID- 29152391 TI - Evolving Paradigms in Melanoma Therapy. PMID- 29152392 TI - New Agents for the Management of Advanced HER2-Positive Breast Cancer. PMID- 29152393 TI - Navigating the Landscape of Molecular Testing and Targeted Treatment of Non-Small Cell Lung Cancer. PMID- 29152394 TI - Immunotherapy and the Treatment of Non-Small Cell Lung Cancer. PMID- 29152395 TI - What Radiation Oncology Wants Medical Oncology to Know. PMID- 29152396 TI - Diagnostic Radiology: What the Advanced Practitioner Needs to Know. PMID- 29152397 TI - Risk-Stratified Treatment in Chronic Lymphocytic Leukemia. PMID- 29152398 TI - Risk Stratification in Multiple Myeloma: Putting the Pieces Together. PMID- 29152399 TI - Outpatient Management of the Hematopoietic Stem Cell Transplant Patient. PMID- 29152400 TI - Diagnosis and Treatment of Benign Bleeding Disorders. PMID- 29152401 TI - Management of Dermatologic Toxicities Associated With Targeted Therapy. PMID- 29152402 TI - Management of Weight Loss in People With Cancer. PMID- 29152403 TI - The Role of Exercise and Rehabilitation in the Cancer Care Plan. PMID- 29152404 TI - Incorporating a Survivorship Clinic Into Practice. PMID- 29152406 TI - Protozoan parasites in irritable bowel syndrome: A case-control study. AB - AIM: To investigate the putative role of protozoan parasites in the development of irritable bowel syndrome (IBS). METHODS: The study included 109 IBS consecutive adult patients fulfilling the Rome III criteria and 100 healthy control subjects. All study subjects filled a structured questionnaire, which covered demographic information and clinical data. Fresh stool samples were collected from patients and control subjects and processed within less than 2 h of collection. Iodine wet mounts and Trichrome stained smears prepared from fresh stool and sediment concentrate were microscopically examined for parasites. Blastocystis DNA was detected by polymerase chain reaction, and Cryptosporidium antigens were detected by ELISA. RESULTS: A total of 109 IBS patients (31 males, 78 females) with a mean age +/- SD of 27.25 +/- 11.58 years (range: 16 -60 years) were enrolled in the study. The main IBS subtype based on the symptoms of these patients was constipation-predominant (88.7% of patients). A hundred healthy subjects (30 males, 70 females) with a mean +/- SD age of 25.0 +/- 9.13 years (range 18-66 years) were recruited as controls. In the IBS patients, Blastocystis DNA was detected in 25.7%, Cryptosporidium oocysts were observed in 9.2%, and Giardia cysts were observed in 11%. In the control subjects, Blastocystis, Cryptosporidium and Giardia were detected in 9%, 0%, and 1%, respectively. The difference in the presence of Blastocystis (P = 0.0034), Cryptosporidium (P = 0.0003), and Giardia (P = 0.0029) between IBS patients and controls was statistically significant by all methods used in this study. CONCLUSION: Prevalence of Blastocystis, Cryptosporidium and Giardia is higher in IBS patients than in controls. These parasites are likely to have a role in the pathogenesis of IBS. PMID- 29152405 TI - Association of miR-146 rs2910164, miR-196a rs11614913, miR-221 rs113054794 and miR-224 rs188519172 polymorphisms with anti-TNF treatment response in a Greek population with Crohn's disease. AB - AIM: To investigate the correlation between rs2910164, rs11 614913, rs113054794, and rs188519172 polymorphisms and response to anti-TNF treatment in patients with Crohn's disease (CD). METHODS: One hundred seven patients with CD based on standard clinical, endoscopic, radiological, and pathological criteria were included in the study. They all received infliximab or adalimumab intravenously or subcutaneously at standard induction doses as per international guidelines. Clinical and biochemical response was assessed using the Harvey-Bradshaw index and CRP levels respectively. Endoscopic response was evaluated by ileocolonoscopy at week 12-20 of therapy. The changes in endoscopic appearance compared to baseline were classified into four categories, and patients were classified as responders and non-responders. Whole peripheral blood was extracted and genotyping was performed by PCR. RESULTS: One hundred and seven patients were included in the study. Seventy two (67.3%) patients were classified as complete responders, 22 (20.5%) as partial while 13 (12.1%) were primary non-responders. No correlation was detected between response to anti-TNF agents and patients' characteristics such as gender, age and disease duration while clinical and biochemical indexes used were associated with endoscopic response. Concerning prevalence of rs2910164, rs11614913, and rs188519172 polymorphisms of miR-146, miR-196a and miR-224 respectively no statistically important difference was found between complete, partial, and non-responders to anti-TNF treatment. Actually CC genotype of rs2910164 was not detected in any patient. Regarding rs113054794 of miR-221, normal CC genotype was the only one detected in all studied patients, suggesting this polymorphism is highly rare in the studied population. CONCLUSION: No correlation is detected between studied polymorphisms and patients' response to anti-TNF treatment. Polymorphism rs113054794 is not detected in our population. PMID- 29152407 TI - Fecal microbiota transplantation against irritable bowel syndrome? Rigorous randomized clinical trials are required. AB - Halkjaer et al searched systematically nine articles including 48 patients, and concluded that fecal microbiota transplantation (FMT) can be an ideal treatment option for irritable bowel syndrome (IBS) subjects. Regardless of the few successes in current traditional therapies (change in diet, herbal medicine and antibiotics) in IBS, a sharp increase in interests in the FMT option has been reported in the current century. However, there is a long list of unclear issues concerning the application of FMT for the treatment of IBS. Route of delivery and optimum dosage are the major concerns to consider before using in clinical practice. PMID- 29152409 TI - Long-adapter single-strand oligonucleotide probes for the massively multiplexed cloning of kilobase genome regions. AB - As the catalogue of sequenced genomes and metagenomes continues to grow, massively parallel approaches for the comprehensive and functional analysis of gene products and regulatory elements are becoming increasingly valuable. Current strategies to synthesize or clone complex libraries of DNA sequences are limited by the length of the DNA targets, throughput and cost. Here, we show that long adapter single-strand oligonucleotide (LASSO) probes can capture and clone thousands of kilobase DNA fragments in a single reaction. As a proof-of principle, we simultaneously cloned >3,000 bacterial open reading frames (ORFs) from E. coli genomic DNA (spanning 400-5,000 bp targets). Targets were enriched up to a median of ~60-fold compared to non-targeted genomic regions. At a cutoff of 3 times the median non-target reads per kilobase of genetic element per million reads, ~75% of the targeted ORFs were successfully captured. We also show that LASSO probes can clone human ORFs from complementary DNA, and an ORF library from a human-microbiome sample. LASSO probes could be used for the preparation of long-read sequencing libraries and for massively multiplexed cloning. PMID- 29152408 TI - Ethical Considerations in Deep Brain Stimulation for the Treatment of Addiction and Overeating Associated With Obesity. AB - The success of deep brain stimulation (DBS) for movement disorders and the improved understanding of the neurobiologic and neuroanatomic bases of psychiatric diseases have led to proposals to expand current DBS applications. Recent preclinical and clinical work with Alzheimer's disease and obsessive compulsive disorder, for example, supports the safety of stimulating regions in the hypothalamus and nucleus accumbens in humans. These regions are known to be involved in addiction and overeating associated with obesity. However, the use of DBS targeting these areas as a treatment modality raises common ethical considerations, which include informed consent, coercion, enhancement, threat to personhood, and manipulation of the reward center. Pilot studies for both of these conditions are currently investigational. If these studies show promise, then there is a need to address the ethical concerns related to the initiation of clinical trials including the reliability of preclinical evidence, patient selection, study design, compensation for participation and injury, cost effectiveness, and the need for long-term follow-up. Multidisciplinary teams are necessary for the ethical execution of such studies. In addition to establishing safety and efficacy, the consideration of these ethical issues is vital to the adoption of DBS as a treatment for these conditions. We offer suggestions about the pursuit of future clinical trials of DBS for the treatment of addiction and overeating associated with obesity and provide a framework for addressing ethical concerns related to treatment. PMID- 29152411 TI - Asymmetric and Symmetric Unbiased Image Registration: Statistical Assessment of Performance. AB - Measures of brain changes can be computed from sequential MRI scans, providing valuable information on disease progression for neuroscientific studies and clinical trials. Tensor-based morphometry (TBM) creates maps of these brain changes, visualizing the 3D profile and rates of tissue growth or atrophy. In this paper, we examine the power of different nonrigid registration models to detect changes in TBM, and their stability when no real changes are present. Specifically, we investigate an asymmetric version of a recently proposed unbiased registration method, using mutual information as the matching criterion. We compare matching functionals (sum of squared differences and mutual information), as well as large deformation registration schemes (viscous fluid registration versus symmetric and asymmetric unbiased registration) for detecting changes in serial MRI scans of 10 elderly normal subjects and 10 patients with Alzheimer's Disease scanned at 2-week and 1-year intervals. We demonstrated that the unbiased methods, both symmetric and asymmetric, have higher reproducibility. The unbiased methods were also less likely to detect changes in the absence of any real physiological change. Moreover, they measured biological deformations more accurately by penalizing bias in the corresponding statistical maps. PMID- 29152413 TI - Confocal Vessel Structure Segmentation with Optimized Feature Bank and Random Forests. AB - In this paper, we consider confocal microscopy based vessel segmentation with optimized features and random forest classification. By utilizing multi-scale vessel-specific features tuned to capture curvilinear structures such as Frobenius norm of the Hessian eigenvalues, Laplacian of Gaussians (LoG), oriented second derivative, line detector and intensity masked with LoG scale map. we obtain better segmentation results in challenging imaging conditions. We obtain binary segmentations using random forest classifier trained on physiologists marked ground-truth. Experimental results on mice dura mater confocal microscopy vessel segmentations indicate that we obtain better results compared to global segmentation approaches. PMID- 29152412 TI - Histomorphological responses after therapy with pegylated interferon alpha-2a in patients with essential thrombocythemia (ET) and polycythemia vera (PV). AB - Background: Pegylated interferon alfa-2a (PEG-IFN-alpha-2a) is a potent immunomodulating agent capable of inducing high rate of hematologic and even complete molecular remission in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We recently reported results of a phase 2 trial of PEG IFN-alpha-2a in 83 patients with ET and PV after a median follow-up of 83 months. Here we report an analysis of bone marrow (BM) responses in these patients. Methods: Among 83 patients, 58 (70%, PV 25, ET 31) had evaluable BM samples. BM responses and fibrosis grading were defined according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment, and the European Consensus on grading of BM fibrosis, respectively. BM was assessed prior to enrollment, and every 6-24 months while on therapy in all patients, and after therapy discontinuation in some patients. Results: The median age of analyzed 58 patients was 52 years, and 29% were males. After a median follow-up of 84 months, 32 patients are still on study. Hematologic (HR) and molecular responses (MR) were seen in 93 and 69% patients, respectively. Twenty-nine patients (50%) had a BM response, including 13 (22%) with a complete BM response (BM-CR). Moreover, 13 patients (22%) have experienced complete resolution of bone marrow reticulin fibrosis. Patients with BM response had higher duration of HR and MR, and lower discontinuation rate. Furthermore, patients with BM-CR had a higher probability of complete MR. The median duration of BM-CR was 30 months, and 9 patients have maintained their BM-CR (69%), including five who have maintained their response after discontinuation of therapy. Despite this observation, the pattern of HR, MR and BM response, their durability and interrelation was heterogeneous. Conclusions: Our results show the ability of PEG-IFN-alpha-2a to induce complete BM responses in a subset of ET and PV patients, but its correlation with durable clinically relevant treatment benefit warrants further investigation. Trial registration This study is registered with ClinicalTrials.gov (NCT00452023), and is ongoing but not enrolling new patients. PMID- 29152410 TI - Ultrasound-triggered local anaesthesia. AB - On-demand relief of local pain would allow patients to control the timing, intensity and duration of nerve block in a safe and non-invasive manner. Ultrasound would be a suitable trigger for such a system, as it is in common clinical use and can penetrate deeply into the body. Here, we demonstrate that ultrasound-triggered delivery of an anaesthetic from liposomes allows the timing, intensity and duration of nerve block to be controlled by ultrasound parameters. On insonation, the encapsulated sonosensitizer protoporphyrin IX produces reactive oxygen species that react with the liposomal membrane, leading to the release of the potent local anaesthetic tetrodotoxin. We also show repeatable ultrasound-triggered nerve blocks in vivo, with nerve-block duration depending on the extent and intensity of insonation. We did not detect any systemic toxicity, and tissue reaction was benign in all groups. On-demand, personalized local anaesthesia could be beneficial for the managing of relatively localized pain states, and potentially minimize opioid use. PMID- 29152414 TI - Vegetation structure of plantain-based agrosystems determines numerical dominance in community of ground-dwelling ants. AB - In tropics, ants can represent an important part of animal biomass and are known to be involved in ecosystem services, such as pest regulation. Understanding the mechanisms underlying the structuring of local ant communities is therefore important in agroecology. In the humid tropics of Africa, plantains are cropped in association with many other annual and perennial crops. Such agrosystems differ greatly in vegetation diversity and structure and are well-suited for studying how habitat-related factors affect the ant community. We analysed abundance data for the six numerically dominant ant taxa in 500 subplots located in 20 diversified, plantain-based fields. We found that the density of crops with foliage at intermediate and high canopy strata determined the numerical dominance of species. We found no relationship between the numerical dominance of each ant taxon with the crop diversity. Our results indicate that the manipulation of the densities of crops with leaves in the intermediate and high strata may help maintain the coexistence of ant species by providing different habitat patches. Further research in such agrosystems should be performed to assess if the effect of vegetation structure on ant abundance could result in efficient pest regulation. PMID- 29152415 TI - Character drawing style in cartoons on empathy induction: an eye-tracking and EEG study. AB - In its most basic form, empathy refers to the ability to understand another person's feelings and emotions, representing an essential component of human social interaction. Owing to an increase in the use of mass media, which is used to distribute high levels of empathy-inducing content, media plays a key role in individual and social empathy induction. We investigated empathy induction in cartoons using eye movement, EEG and behavioral measures to explore whether empathy factors correlate with character drawing styles. Two different types of empathy-inducing cartoons that consisted of three stages and had the same story plot were used. One had an iconic style, while the other was realistic style. Fifty participants were divided into two groups corresponding to the individual cartoon drawing styles and were presented with only one type of drawing style. We found that there were no significant differences of empathy factors between iconic and realistic style. However, the Induced Empathy Score (IES) had a close relationship with subsequent attentional processing (total fixation length for gaze duration). Furthermore, iconic style suppressed the fronto-central area more than realistic style in the gamma power band. These results suggest that iconic cartoons have the advantage of abstraction during empathy induction, because the iconic cartoons induced the same level of empathy as realistic cartoons while using the same story plot (top-down process), even though lesser time and effort were required by the cartoon artist to draw them. This also means that the top down process (story plot) is more important than the bottom-up process (drawing style) in empathy induction when viewing cartoons. PMID- 29152416 TI - Microbial agents in macroscopically healthy mammary gland tissues of small ruminants. AB - Background: Health of mammary glands is fundamental for milk and dairy products hygiene and quality, with huge impacts on consumers welfare. Methods: This study aims to investigate the microbial agents (bacteria, fungi and lentiviruses) isolated from 89 macroscopically healthy udders of regularly slaughtered small ruminants (41 sheep, 48 goats), also correlating their presence with the histological findings. Multinomial logistic regression was applied to evaluate the association between lesions and positivity for different microbial isolates, animal age and bacteria. Results: Twenty-five samples were microbiologically negative; 138 different bacteria were isolated in 64 positive udders. Coagulase negative staphylococci were the most prevalent bacteria isolated (46.42%), followed by environmental opportunists (34.76%), others (10.14%) and pathogens (8.68%). Most mammary glands showed coinfections (75%). Lentiviruses were detected in 39.3% of samples. Histologically, chronic non-suppurative mastitis was observed in 45/89 glands, followed by chronic mixed mastitis (12/89) and acute suppurative mastitis (4/89). Only 28 udders were normal. Histological lesions were significantly associated with the animal species and lentiviruses and coagulase-negative staphylococci infections. Goats had significantly higher risk to show chronic mixed mastitis compared to sheep. Goats showed a significantly lower risk (OR = 0.26; 95% CI [0.06-0.71]) of being infected by environmental opportunists compared to sheep, but higher risk (OR = 10.87; 95% CI [3.69-37.77]) of being infected with lentiviruses. Discussion: The results of the present study suggest that macroscopically healthy glands of small ruminants could act as a reservoir of microbial agents for susceptible animals, representing a potential risk factor for the widespread of acute or chronic infection in the flock. PMID- 29152417 TI - Assessing Mongolian gerbil emotional behavior: effects of two shock intensities and response-independent shocks during an extended inhibitory-avoidance task. AB - Despite step-down inhibitory avoidance procedures that have been widely implemented in rats and mice to study learning and emotion phenomena, performance of other species in these tasks has received less attention. The case of the Mongolian gerbil is of relevance considering the discrepancies in the parameters of the step-down protocols implemented, especially the wide range of foot-shock intensities (i.e., 0.4-4.0 mA), and the lack of information on long-term performance, extinction effects, and behavioral patterning during these tasks. Experiment 1 aimed to (a) characterize gerbils' acquisition, extinction, and steady-state performance during a multisession (i.e., extended) step-down protocol adapted for implementation in a commercially-available behavioral package (Video Fear Conditioning System-MED Associates Fairfax, VT, USA), and (b) compare gerbils' performance in this task with two shock intensities - 0.5 vs. 1.0 mA-considered in the low-to-mid range. Results indicated that the 1.0 mA protocol produced more reliable and clear evidence of avoidance learning, extinction, and reacquisition in terms of increments in freezing and on-platform time as well as suppression of platform descent. Experiment 2 aimed to (a) assess whether an alternate protocol consisting of a random delivery of foot shocks could replicate the effects of Experiment 1 and (b) characterize gerbils' exploratory behavior during the step-down task (jumping, digging, rearing, and probing). Random shocks did not reproduce the effects observed with the first protocol. The data also indicated that a change from random to response-dependent shocks affects (a) the length of each visit to the platform, but not the frequency of platform descends or freezing time, and (b) the patterns of exploratory behavior, namely, suppression of digging and rearing, as well as increments in probing and jumping. Overall, the study demonstrated the feasibility of the extended step-down protocol for studying steady performance, extinction, and reacquisition of avoidance behavior in gerbils, which could be easily implemented in a commercially available system. The observation that 1.0 mA shocks produced a clear and consistent avoidance behavior suggests that implementation of higher intensities is unnecessary for reproducing aversive conditioning effects in this species. The observed patterning of freezing, platform descents, and exploratory responses produced by the change from random to periodic shocks may relate to the active defensive system of the gerbil. Of special interest is the probing behavior, which could be interpreted as risk assessment and has not been reported in other rodent species exposed to step-down and similar tasks. PMID- 29152419 TI - Supradapedon revisited: geological explorations in the Triassic of southern Tanzania. AB - The upper Triassic deposits of the Selous Basin in south Tanzania have not been prospected for fossil tetrapods since the middle of last century, when Gordon M. Stockley collected two rhynchosaur bone fragments from the so called "Tunduru beds". Here we present the results of a field trip conducted in July 2015 to the vicinities of Tunduru and Msamara, Ruvuma Region, Tanzania, in search for similar remains. Even if unsuccessful in terms of fossil discoveries, the geological mapping conducted during the trip improved our knowledge of the deposition systems of the southern margin of the Selous Basin during the Triassic, allowing tentative correlations to its central part and to neighbouring basins. Moreover, we reviewed the fossil material previously collected by Gordon M. Stockley, confirming that the remains correspond to a valid species, Supradapedon stockleyi, which was incorporated into a comprehensive phylogeny of rhynchosaurs and found to represent an Hyperodapedontinae with a set of mostly plesiomorphic traits for the group. Data gathered form the revision and phylogenetic placement of Su. stockleyi helps understanding the acquisition of the typical dental traits of Late Triassic rhynchosaurs, corroborating the potential of hyperodapedontines as index fossils of the Carnian-earliest Norian. PMID- 29152418 TI - Generation and characterization of cross neutralizing human monoclonal antibody against 4 serotypes of dengue virus without enhancing activity. AB - Background: Dengue disease is a leading cause of illness and death in the tropics and subtropics. Most severe cases occur among patients secondarily infected with a different dengue virus (DENV) serotype compared with that from the first infection, resulting in antibody-dependent enhancement activity (ADE). Our previous study generated the neutralizing human monoclonal antibody, D23-1B3B9 (B3B9), targeting the first domain II of E protein, which showed strong neutralizing activity (NT) against all four DENV serotypes. However, at sub neutralizing concentrations, it showed ADE activity in vitro. Methods: In this study, we constructed a new expression plasmid using the existing IgG heavy chain plasmid as a template for Fc modification at position N297Q by site-directed mutagenesis. The resulting plasmid was then co-transfected with a light chain plasmid to produce full recombinant IgG (rIgG) in mammalian cells (N297Q-B3B9). This rIgG was characterized for neutralizing and enhancing activity by using different FcgammaR bearing cells. To produce sufficient quantities of B3B9 rIgG for further characterization, CHO-K1 cells stably secreting N297Q-B3B9 rIgG were then established. Results: The generated N297Q-B3B9 rIgG which targets the conserved N-terminal fusion loop of DENV envelope protein showed the same cross neutralizing activity to all four DENV serotypes as those of wild type rIgG. In both FcgammaRI- and RII-bearing THP-1 cells and FcgammaRII-bearing K562 cells, N297Q-B3B9 rIgG lacked ADE activity against all DENV serotypes at sub neutralizing concentrations. Fortunately, the N297Q-B3B9 rIgG secreted from stable cells showed the same patterns of NT and ADE activities as those of the N297Q-B3B9 rIgG obtained from transient expression against DENV2. Thus, the CHO K1 stably expressing N297Q-B3B9 HuMAb can be developed as high producer stable cells and used to produce sufficient amounts of antibody for further characterization as a promising dengue therapeutic candidate. Discussion: Human monoclonal antibody, targeted to fusion loop of envelope domainII (EDII), was generated and showed cross-neutralizing activity to 4 serotypes of DENV, but did not cause any viral enhancement activity in vitro. This HuMAb could be further developed as therapeutic candidates. PMID- 29152420 TI - Treatment Planning for Self-Shielded Radiosurgery. AB - A five degree of freedom, robotic, radiosurgical system dedicated to the brain is currently under development. In the proposed design, the machine is entirely self shielded. The main advantage of a self-shielded system is the simplification of the system's installation, which can reduce the cost of radiosurgery. In this way, more patients can benefit from this minimally invasive and highly effective type of procedure. For technical reasons, space inside the shielded region is limited, which leads to constraints on the design. Here, two axes of rotation move a 3-megavolt linear accelerator around the patient's head at a source axis distance of 400 millimeters (mm), while the integrated patient table is characterized by two additional rotational, and one translational, degrees of freedom. Eight cone collimators of different diameters are available. The system can change the collimator automatically during treatment, using a collimator wheel. Since the linear accelerator can only move with two rotational axes, it is not possible to reposition the beam translationally (as it is in six degrees of freedom robotic radiosurgery). To achieve translational repositioning, it is necessary to move the patient couch. Thus, translational repositioning must be kept to a minimum during treatment. Our goal in this contribution is a preliminary investigation of dose distributions attainable with this type of design. Thus, we do not intend to design and evaluate the treatment planning system itself, but rather to establish that appropriate dose distributions can be achieved with this design under realistic clinical circumstances. Our simulation suggests that dose gradients and conformity for complex target shapes, corresponding to state-of-the-art systems, can be achieved with this construction, although a detailed evaluation of the system itself would be needed in the future. PMID- 29152421 TI - Severe Acute Respiratory Distress Syndrome after Laparoscopic Appendectomy in a Young Adult. AB - Severe acute respiratory distress syndrome after laparoscopic appendectomy for acute appendicitis in a young adult is an uncommon complication. We describe the case of a 25-year-old male who developed severe acute respiratory distress syndrome after an uneventful laparoscopic appendectomy for a perforated appendix, requiring mechanical ventilation in the intensive care unit. PMID- 29152422 TI - Suicide and Its Legal Implications in Pakistan: A Literature Review. AB - In recent decades, great strides have been made in understanding the science of suicide. Thus, it is imperative that Pakistani legal systems bridge the gap between Pakistani law and science. For instance, recent discoveries in public health, psychology, and neurobiology have shaped the etiological model of suicidal behavior and highlighted the high preponderance of certain psychiatric patients towards suicide. We present here a brief overview of psychiatric evidence implicated in suicides to better inform the Pakistani legal system of advances in the psychiatric literature. PMID- 29152423 TI - Foodborne Botulism, I Only Had Nacho Cheese: A Case Report. AB - A 32-year-old female presented to the emergency department with complaints of diplopia, followed by dyspnea, chest tightness, congestion, and dysphagia. The patient was resuscitated and initial investigations were done. Within a few hours of the admission, she started developing signs of respiratory failure and was intubated and placed on the mechanical ventilator. The patient denied any ingestion of exotic food, shellfish, raw meat, or raw fish. The patient also denied traveling to any exotic place or recent camping trips. The edrophonium tensilon test and lumbar puncture came out to be negative. The botulinum toxin test was positive, the patient was started on botulinum antitoxin, and the rest of symptomatic treatment was continued. The Centre for Disease Control (CDC) tracked the events related to the presentation and found she had eaten nacho cheese from a gas station the day before the appearance of the symptoms. A total of 10 cases were associated with this source within days and one death was reported. PMID- 29152424 TI - Acquired Acrodermatitis Enteropathica: A Case Study. AB - We present a case of severe acquired acrodermatitis enteropathica in a vegan adult female with multiple underlying comorbidities. Acquired acrodermatitis enteropathica or zinc-deficiency dermatitis is the most common diagnosis than many practitioners realize with up to 10% of the patients in developed nations with the risk of zinc deficiency. The condition can be difficult to diagnose due to many similarly-presenting conditions. Furthermore, comorbid conditions in the patients can serve as confounders to the diagnosis. The symptoms are often extremely distressing for the patients, though the treatment is simple and clinical improvement occurs rapidly with appropriate care. We recommend a high index of suspicion to practitioners as well as a low-threshold for initiating treatment in the patients with any clinical symptoms of the condition. PMID- 29152425 TI - Stereotactic Body Radiotherapy for Low-Risk Prostate Cancer: A Ten-Year Analysis. AB - Objective This study represents the first 10 year analysis of the efficacy and toxicity of stereotactic body radiotherapy (SBRT) in the treatment of early low risk prostate cancer. Materials and methods Two hundred and thirty males were treated with Cyberknife SBRT to a dose of 35 Gray (Gy) or 36.25 Gy in five consecutive days. All patients had a Gleason score of six and a PSA < 10ng/ml. Median follow-up is nine years. The median age was 69.5 years and median prostate specific antigen (PSA) was 5.6ng/ml. The treatment was delivered with homogeneous planning with a dose prescription of 82-87% of the maximum dose to cover the planning target volume (PTV). Results Ten-year biochemical disease free survival was 93% with either dose. Local control was 98.4%. Median prostate specific antigen (PSA) dropped to 0.1 by five years and has remained there. Toxicity was mild with 10% of patients having Grade two-three late urinary toxicity and 4% having the late grade two rectal toxicity. Mean Expanded Prostate Cancer Index Composite (EPIC) Quality of Life (QOL) scores declined initially for bowel and urinary domains, but recovered to baseline, where they remain. EPIC sexual scores have declined by 40%. Discussion/Conclusions Stereotactic body radiotherapy to a dose of 35 Gy-36.25 Gy is an effective treatment for early low-risk prostate cancer, with acceptably low toxicity. There appears to be no benefit to increasing the dose beyond 35 Gy. Ten-year biochemical disease free survival appears to be higher than with standard intensity modulated radiotherapy (IMRT). PMID- 29152426 TI - An Overview of Infant Mortality Trends in Qatar from 2004 to 2014. AB - Background Infant mortality is an important health indicator that estimates population well-being. Infant mortality has declined globally but is still a major public health challenge. This article provides the characteristics, causes, burden, and trends of infant mortality in Qatar. Methods Frequencies, percentages, and rates were calculated using data from birth-death registries over 2004-2014 to describe infant mortality by nationality, gender, and age group. We calculated the relative risks of the top causes of infant mortality among subgroups according to the 10th Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10, Version 2016). Results During 2004-2014, 204,224 live births and 1,505 infant deaths were recorded. The infant mortality rate (IMR) averaged 7.4/1000 live births (males 8.1, females 6.6, non-Qataris 7.7, and Qataris 6.8). IMR declined 20% from 2004 to 2014. The decline in IMR was significant for the overall population of infants (p=0.006), male infants (p=0.04), females (p=0.006), and for non-Qatari males (p=0.007) and non-Qatari females (p=0.007). The leading causes of infant mortality were congenital malformations (all types) (34.5%), low birth weight (LBW) (27%), and respiratory distress of newborns (2.8%). Male infants had a higher risk of mortality than female infants due to a congenital malformation of lungs (p=0.02), other congenital malformations, not elsewhere classified (p=0.01), and cardiovascular disorders (p=0.05). Conclusion The study shows that infant mortality among male infants is high due to the top infant mortality related disorders, and male infants have a higher risk of mortality than female infants. PMID- 29152427 TI - Dramatic Response of a Large Sacral Chordoma to Intensity Modulated Proton Beam Therapy. AB - Sacral chordomas are slow-growing, indolent, and locally invasive tumors that typically present with pain and neurologic dysfunction. Wide en-bloc surgical excision is the primary treatment, but achieving adequate margins is difficult and surgery is often associated with significant morbidity. Adjuvant radiation therapy (RT) is utilized to decrease the risk of local recurrence or as definitive treatment for nonsurgical candidates. Although chordomas are considered to be relatively radioresistant tumors, several studies have demonstrated tumor response to high-dose proton therapy. Here, we present a patient with a large sacral chordoma who underwent definitive treatment with intensity-modulated proton therapy (IMPT). PMID- 29152428 TI - A Case of Radiation Recall Dermatitis of Scalp in Acute Lymphoblastic Leukemia After Prophylactic Cranial Radiotherapy. AB - The radiation recall dermatitis (RRD) phenomenon is defined as the "recalling" of the skin following the administration of drugs; this induces a response or flare like reaction over the skin that is exposed to radiation. In this case report, a young female developed RRD on Day 18 after the completion of cranial radiotherapy, that is, four days after the restart of the chemotherapy with doxorubicin. It is a self-limiting condition with supportive care as the treatment. When encountered in hematological malignancies, undue treatment breaks can delay definitive treatment and can eventually cause a relapse. PMID- 29152429 TI - Refining Surgical Corridors with Whole Brain Tractography: A Case Series. AB - Recent advancements in automated diffusion tensor imaging (DTI) and whole brain tractography (WBT) may be of great use to the neurosurgeon in selecting surgical corridors that can minimize disruption of surrounding white matter tracts. This is especially important in cases where the lesion displaces white matter tracts and traditional operative approaches may inadvertently violate these fibers. Here, we present automated DTI seeding and WBT as a practical and efficient means for preoperative surgical planning, in an effort to spare white matter tracts that may be displaced by a variety of lesions and may be vulnerable during surgery. We retrospectively reviewed the records of seven patients with various intracranial lesions, who underwent preoperative magnetic resonance imaging (MRI) with automated DTI analysis. These images were used to guide operative planning so that we could select white matter corridors that would allow for minimal damage to vulnerable fiber tracts. The patients had various pathologies, ranging from neoplasms to intracranial hemorrhage, in a number of different intracranial locations. All the patients underwent preoperative intracranial imaging with post processing of these images to generate white matter tracts. These images were then used to design an appropriate surgical approach that would minimize injury to white matter tracts. For the patients with neoplasms, all were totally or near totally resected with a stability of symptoms postoperatively. In the case of the patient with intracranial hemorrhage, the hematoma was evacuated, with significant improvement in the postoperative period. Automated DTI seeding and WBT, which have become increasingly prevalent in recent years, can be of significant use to the neurosurgeon for preoperative planning. Their application is especially important in cases where white matter tracts are displaced by the lesion in question and are put at risk of injury during surgery. Using WBT to design customized surgical approaches appropriate to the case at hand can be of immense value in preserving these white matter tracts, minimizing postoperative deficits, and improving surgical outcomes. Further studies are needed to validate these results and better define their applicability to other regions and pathologies. PMID- 29152430 TI - A Dosimetric Comparison of Intensity-Modulated Proton Therapy, Volumetric Modulated Arc Therapy, and 4pi Non-Coplanar Intensity-Modulated Radiation Therapy for a Patient with Parameningeal Rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and manifests as two major histological subtypes: embryonal and alveolar. The five year local failure rate for RMS at parameningeal sites (middle ear, mastoid region, nasal cavity, etc.) is around 17% despite multiple Intergroup Rhabdomyosarcoma Study Group (IRS) trials conducted to determine the optimal radiation treatment regimen. This case report explores the use of intensity modulated proton therapy (IMPT) for a 10-year-old child who presented with left eye irritation, facial pain, and headaches and was found to have an alveolar parameningeal rhabdomyosarcoma. He received systemic therapy as well as radiation therapy to 5,640 cGy and 4,320 cGy over 24 fractions, prescribed for gross tumor extension and adjacent high-risk involved sites, respectively, via simultaneous integrated boost. Approximately two years following treatment, the patient has had no recurrence of his RMS with no distant metastases. In addition, his presenting symptom of left eye irritation has improved. His only side effect from radiation at this point is short stature, possibly due to growth hormone deficiency. The patient's IMPT plan was compared with volumetric-modulated arc therapy (VMAT) and 4pi non-coplanar intensity-modulated radiation therapy (IMRT) plans, and comparisons of isodose lines show decreased dose to the distal brain tissue with preserved target conformality by IMPT. IMPT also allowed for increased sparing of the patient's retina, lens, and lacrimal gland. All radiation plans achieved conformal dose coverage to the planning/scanning target volumes, while the IMPT plan is potentially better at sparing the patient from developing long-term optic apparatus side effects and neurocognitive defects. In this case, IMPT is comparable, if not favorable, when long-term side effects can be reduced while maintaining dose conformality and local control. PMID- 29152431 TI - Intensity Modulated Proton Therapy with Advanced Planning Techniques in a Challenging Hepatocellular Carcinoma Patient. AB - The use of radiation therapy has been increasing over recent years for the treatment of hepatocellular carcinoma (HCC). Proton beam therapy (PBT) has emerged as a promising treatment option for HCC patients due to its dosimetric advantages of sparing more normal liver tissue from radiation at low to moderate doses compared to photon-based treatments while still delivering high doses of radiation to tumors. The PBT therapy may be particularly beneficial in high-risk HCC cirrhotic patients with large, bulky tumors and/or vascular invasion complicated by surrounding perfusion abnormalities. We present a case of a 62 year-old male with an unresectable 13 cm diffusely infiltrative HCC tumor with main portal vein invasion and elevated alpha-feta protein (AFP) of 37,200 that was intolerant of standard sorafenib treatment. He was treated with hypofractionated PBT to 67.5 GyE in 15 fractions using a novel combination of simultaneously integrated boost intensity modulated proton therapy (SIB-IMPT), breath hold technique, and functional liver imaging with technetium-99m [99mTc] sulfur colloid single-photon emission computed tomography (SPECT/CT) to assist in the differentiation of tumor and normal liver. He had a complete radiographic and biochemical response by AFP normalization by seven months post-treatment without evidence of radiation hepatotoxicity. PMID- 29152432 TI - Acute Changes in Mentation in a Patient with Hepatic Cirrhosis Treated with High Doses of Dexamethasone. AB - Despite the anti-inflammatory benefits of steroids in the management of multiple medical conditions, they are associated with undesired metabolic and psychiatric side effects. We present a case of a 57-year-old Hispanic man with hepatic cirrhosis due to hepatitis C and no past medical history of psychiatric illnesses who became delirious after treatment with high doses of intravenous Dexamethasone. The patient presented to Larkin Community Hospital, USA with complaints of lower back pain requiring treatment with steroids for severe lumbar central canal stenosis. After three days of treatment, the patient became disoriented to time and place, grossly psychotic with auditory hallucinations and disorganized behavior, manic, aggressive, combative, restless, hard to redirect, and unable to follow commands. He met the criteria for a diagnosis of substance induced psychotic disorder according to Diagnostic and Statistical Manual of Mental Disorders (DSM) V. Furthermore, the patient had worsening hepatic profile, a high ammonia level of 125 umol/L, and clinical findings consistent with West Haven classification grade 2 encephalopathy. Head computed tomography (CT) scan was normal. He was treated with discontinuation of steroids, lactulose, and Haloperidol returning to baseline mental status after 48 hours. The patient's hospitalization was complicated with a prolonged hospital stay after lumbar surgery. This case illustrates that treatment with high doses of Dexamethasone in a patient with hepatic cirrhosis can cause acute changes in mental status by (i) inducing delirium, and (ii) precipitating hepatic encephalopathy. PMID- 29152433 TI - To Dab or Not to Dab: Rising Concerns Regarding the Toxicity of Cannabis Concentrates. AB - Cannabis use is steadily rising in the United States. As the popularity of marijuana rises, new varieties of cannabis-related products are becoming available. Dabs are cannabis concentrates gaining notoriety for their significant amounts of tetrahydrocannabinol (THC) that are ultimately vaporized and inhaled for their effect. Herein, we provide an overview of recent cases of dabbing to bring awareness to the clinicians, of the significant adverse effects associated with dabs including psychosis, neurotoxicity, and cardiotoxicity. PMID- 29152434 TI - Characterization of Eyeball Loss in Four Cities of Colombia. AB - PURPOSE: Describe the socio-demographic characteristics of anophthalmic patients examined at specialized centers of four cities in Colombia to know the different causes of eyeball loss. METHOD: A transversal retrospective study was done of 511 medical records from the specialized practices of four cities in Colombia. Socio demographic data of patients who were seen between January 2011 and December 2013 were compiled. SOFA Statistics software v1.4.6 was used for this analysis. An analysis throughout the measures of central tendency for numerical variables was developed, and the descriptive statistics were used for the categorical variables. RESULTS: Almost 63% of the data belonged to male patients. Eyeball loss was more frequent in patients over 40 years of age. Fifty-one percent of the patients suffered eyeball loss due to traumatic causes, 40.2% due to pathological causes, and 4.6% due to congenital anomalies. The most frequent specific causes were glaucoma (19%), ocular cancer (15.4%), and home accidents (11,2%). Around 60% of the anophthalmic patients belonged to low socioeconomic level. CONCLUSIONS: It is important to highlight that more than half of the analyzed anophthalmia cases originated in some type of trauma; this means that they could be considered potentially avoidable losses. Complications deriving from glaucoma became the most frequent cause of anophthalmia in the pathological origin group, which suggests a reflection regarding the strategies of early detection of the disease and access to proper treatment. It is also showed the need to develop an efficient system to manage information. PMID- 29152435 TI - A Full-Blown Case of Bronchiectasis: Kartagener Syndrome Without Infertility Diagnosed Later in Life. AB - Kartagener syndrome (KS) is a rare autosomal recessive genetic ciliary disorder characterized by situs inversus, chronic sinusitis, bronchiectasis, and infertility. KS is associated with ultrastructural anomalies of the cilia in epithelial cells covering the upper and lower respiratory tracts and spermatozoa flagella. This case describes a patient with KS with situs inversus and sudden onset bronchiectasis with a sharp decline in respiratory function presenting later in life but without sinusitis or infertility. PMID- 29152436 TI - On the Horizon: The Synthetic Opioid U-49900. AB - Synthetic opioid use continues to be a problem in the United States. New designer opioids continue to be released as "research chemicals" by vendors, leading to widespread use and potentially devastating consequences. U-49900 is a new synthetic opioid with limited clinical data available. Herein, we provide an overview of U-49900, the anecdotal accounts of U-49900 use that clinicians need to be made aware of, and a call for the federal government to take immediate action in curtailing the use of U-49900. PMID- 29152437 TI - Iatrogenic Circumflex Artery Stenosis Following Mitral Valve Repair. AB - Injury of the left circumflex coronary artery is a potentially serious complication of mitral valve surgery due to the proximity of the vessel to the posterior segment of the mitral annulus. Suture-related distortion of the artery with partial or subtotal occlusion is the most commonly implicated mechanism. Herein, we present a case of symptomatic iatrogenic circumflex coronary artery stenosis following mitral valve annuloplasty for degenerative mitral valve regurgitation. PMID- 29152438 TI - Barriers to Timely Completion of Radiation Therapy in Patients with Cervical Cancer in an Urban Tertiary Care Center. AB - Background In 2017, there will be an estimated 12,820 women diagnosed with cervical cancer in the United States, causing an estimation of 4,210 deaths. Among U.S. women, there is a 33% greater incidence and 71% higher cervical cancer mortality in high-poverty counties when compared to low-income counties [1]. In those dispositioned to chemoradiation, treatment time of less than eight weeks is associated with compromised pelvic control. We sought to identify patient or disease characteristics and socioeconomic or psychosocial barriers that contribute to delays in treatment completion in order to formulate new policies to address these needs. Methods Cervical cancer patients treated with primary chemoradiation through the University of Maryland from 2011-2016 were identified retrospectively. Patients were placed in one of two groups: those who completed radiation treatment within 56 days, and those who failed to complete treatment within 56 days. Time to completion of radiation therapy was evaluated in relation to patient and disease variables. Results Forty-three patients with sufficient information for inclusion were identified. The median age was 51 years. Ten patients were stage I at diagnosis (23.3%), 16 were stage II (37.2%), 11 were stage III (25.5%) and six were stage IV (14%). Histopathology revealed squamous cell carcinoma in 37 patients (86%), adenocarcinoma in three patients (7%), mixed histology in two patients (4.7%), and neuroendocrine histology in one patient (2.3%). Twenty patients (46.5%) completed treatment within the recommended timeframe of 56 days while 23 patients (53.5%) did not. The most common reasons for a protracted treatment, or failure to complete the prescribed treatment were non-compliance/psychosocial factors (10 patients, 43.5%). Age, race, primary language, marital status, insurance, employment status, HIV status, mental health, substance abuse, tobacco use, stage at diagnosis, performance status at diagnosis, BMI (body mass index, kg/m2) at diagnosis, and income by zip code were not significantly associated with protracted treatment. The distance to treatment center was a significant factor (p=0.07); patients who lived closest to the treatment center were least likely to complete RT in the designated time frame. This is most likely due to the location of the treatment center, which is in the heart of an urban, low socioeconomic area. Conclusions More than half of all cervical cancer patients presenting to an urban tertiary care center do not complete chemoradiation therapy in the recommended timeframe. Underlying psychosocial factors are prominent. The role for patient navigation in this vulnerable population must be investigated. PMID- 29152439 TI - Anterior Cruciate Ligament Ganglion Cyst and Mucoid Degeneration: A Review. AB - Mucoid degeneration and ganglion cyst are two distinct non-traumatic lesions of the anterior cruciate ligament (ACL) that most commonly occur discretely but occasionally coexist. They are relatively uncommon, and their exact aetiopathogenesis is still not clear. ACL ganglion cyst occurs more frequently among relatively younger patients compared to mucoid degeneration. They could be asymptomatic and discovered incidentally while evaluating the knee for other pathologies. Symptomatic cases of the two conditions present with nonspecific chronic pain, painful limitation of terminal flexion and extension, and mechanical block (among other symptoms), similar to that of other internal derangement pathologies of the knee. Magnetic resonance imaging is the investigation of choice, and diagnostic criteria are defined. Arthroscopic management of these conditions efficiently provides an improvement in symptoms without instability. Computed tomography scan guided aspiration is also useful in selected cases of ACL ganglion cyst. ACL ganglion cyst and mucoid degeneration should be considered in the differential diagnosis of chronic knee pain and stiffness of unspecified etiology. PMID- 29152440 TI - Risperidone-Induced Amenorrhea in Floridly Psychotic Female. AB - Despite the high prevalence of hyperprolactinemia in patients receiving antipsychotic medications, its side effects are often neglected. In patients receiving risperidone, the incidence of menstrual abnormalities is relatively small. Our patient was a 44-year-old, Haitian female whose total course of hospitalization was nine months, during most of which she remained floridly psychotic with low cognitive function with waxing and waning symptoms. She developed hyperprolactinemia and amenorrhea on risperidone. She was treated and discharged to the state mental hospital. Menstrual abnormalities cause psychological distress in women. In women, hyperprolactinemia can cause sexual and reproductive dysfunction. Chronic hyperprolactinemia can predispose to osteoporosis and cardiovascular disease. Clinicians should be vigilant about the consequences when prescribing medications for women, particularly those suffering from a psychotic disorder. PMID- 29152441 TI - Trabecular Variant Juvenile Ossifying Fibroma of the Maxilla. AB - Juvenile ossifying fibroma (JOF) is a benign, bone-forming neoplasm occurring primarily in children and adolescents. JOF is an aggressive variant of ossifying fibroma of the jaw with a variable clinical behavior and a high tendency for recurrence. Early detection and prompt treatment are required to treat JOF successfully. This case report describes JOF in a 13-year-old girl presenting with a year-long, gradually progressive swelling on the right side of her face with typical clinical, radiological, and histopathological features. PMID- 29152442 TI - Combination Intensity Modulated Proton Therapy and Passive Scatter Boost for Rapidly Progressing Nasal Cavity Squamous Cell Carcinoma. AB - Cancers of the nasal cavity and septum are associated with poor prognosis and are usually treated with surgery followed by post-operative radiotherapy with or without concurrent chemotherapy. Definitive radiotherapy is used in cases where the tumor is unresectable, patient is unfit for surgery, and/or the patient declines surgical intervention. Here, we present a case of a patient, who for non medical reasons, opted to have non-surgical management of his rapidly progressing nasal cavity tumor. He was successfully treated with concurrent chemoradiotherapy utilizing a combination of intensity modulated proton therapy (IMPT) with passive scatter boost to reduce dose to the adjacent critical neural structures. Post treatment clinical examination and imaging demonstrated complete clinical and metabolic response at the primary site and neck. This case highlights the use of IMPT and passive scatter boost in combination to achieve delivery of therapeutic dose to nasal cavity tumor and neck whilst limiting dose to numerous adjacent organs-at-risk. PMID- 29152443 TI - Psychiatric Comorbidities and Outcomes in Epilepsy Patients: An Insight from a Nationwide Inpatient Analysis in the United States. AB - Background Psychiatric comorbidities in epilepsy impose significant burdens on patients and their families. It affects their quality of life and medical care and results in cost increases. This study reports the impact of various psychiatric comorbidities in epilepsy patients regarding hospital outcomes and in hospital mortality. Methods We used the Nationwide Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project (HCUP) from years 2013-2014. We identified epilepsy as the primary diagnosis and psychiatric comorbidities, namely, alcohol abuse, depression, drug abuse, and psychosis, using validated International Classification of Diseases, 9th Revision, Clinical Modification (ICD--9--CM) codes. The differences in comorbidities were quantified using chi square (chi2) tests and the multinomial logistic regression model was used to quantify associations among comorbidities using the adjusted Odds Ratio (aOR). Results We analyzed 397,440 hospitalizations with epilepsy as the primary diagnosis. The most prevalent psychiatric comorbidities present in epilepsy were depression (13%) followed by psychosis (10.4%). The risk of inpatient death was only seen in epilepsy with comorbid alcohol abuse (aOR 1.164; 95%CI 1.043 - 1.300; p-value =0.007). Epilepsy with comorbid depression (aOR 1.473; 95% CI 1.391 - 1.559; p-value <0.001) was associated with a higher risk of a length of stay of more than three days (median), followed by comorbid psychosis (aOR 1.290; 95% CI 1.258 - 1.322; p-value <0.001). Epilepsy with comorbid depression (aOR 1.242; 95% CI 1.172 - 1.317; p-value <0.001) was associated with a higher risk of inpatient total charge of more than $21,000 (median), followed by comorbid psychosis (aOR 1.071; 95% CI 1.045 - 1.098; p-value <0.001). Conclusion Psychiatric comorbidities are influential factors that must be considered in models of Health-Related Quality of Life (HRQOL) in epilepsy. Further, efforts to improve HRQOL and reduce the burden of epilepsy require greater emphasis on the early diagnosis and treatment of comorbid psychopathology. PMID- 29152444 TI - Excellent Pathologic Response and Atypical Clinical Course of High-Grade Extremity Sarcoma to Neoadjuvant Pencil Beam Scanning Proton Therapy. AB - Neoadjuvant radiation therapy, followed by definitive surgical resection, remains the standard of care for resectable high-grade and unresectable soft tissue sarcomas. Proton therapy offers the promise of highly conformal dose distributions with improved sparing of neighboring normal tissues as compared with conformal and intensity modulated photon techniques. It is unclear whether proton therapy may offer an improved tumoral response, especially with dose escalation, in this relatively radio-insensitive tumor type. We, herein, present a patient with an excellent pathologic response to preoperative pencil beam scanning proton therapy despite a complex treatment course. PMID- 29152445 TI - Anatomical Study and Comprehensive Review of the Incisivus Labii Superioris Muscle: Application to Lip and Cosmetic Surgery. AB - Objectives The incisivus labii superioris muscle, which originates from the floor of the incisive fossa of the maxilla, has previously been described, it is not well understood. The purpose of this study was to investigate the incisivus labii superioris muscle with detailed dissection. Methods Twenty-six halves from thirteen fresh frozen cadaveric Caucasian heads were used in this study. First, the incisivus labii superioris muscle was dissected to reveal its origin and insertion, and its relationship to other mimetic muscles. Secondly, the distance from the midline to the innermost part of the bony attachment of the muscle was measured. The literature describing the incisivus labii superioris muscle was reviewed. Results The incisivus labii superioris muscle consisted of two parts, inferior and superior. The former merged into the orbicularis oris and the latter into the nasalis. The mean distance from the midline to the innermost part of the bony attachment of the incisivus labii superioris muscle was 4.8 +/- 1.7 mm on the right side and 4.9 +/-1.7 mm on the left. Conclusions The results of the present study suggest that the inferior part of the incisivus labii superioris should be considered as an accessory muscle of the orbicularis oris complex, and the superior part is the nasalis muscle. PMID- 29152446 TI - SGK1 (glucose transport), dishevelled2 (wnt signaling), LC3/p62 (autophagy) and p53 (apoptosis) proteins are unaltered in Lafora disease. AB - Glycogen forms through the concerted actions of glycogen synthase (GS) which elongates glycogen strands, and glycogen branching enzyme (GBE). Lafora disease (LD) is a fatal neurodegenerative epilepsy that results from neuronal accumulation of hyperphosphorylated glycogen with excessively long strands (called polyglucosans). There is no GBE deficiency in LD. Instead, the disease is caused by loss-of-function mutations in the EPM2A or EPM2B genes, encoding, respectively, a phosphatase, laforin, and an E3 ubiquiting ligase, malin. A number of experimentally derived hypotheses have been published to explain LD, including: The SGK1 hypothesis - Phosphorylated SGK1 (pSGK1) raises cellular glucose uptake and levels, which would activate GS. Based on observing increased pSGK1 in LD mice it was proposed that raised pSGK1 leads to polyglucosan generation through GS hyperactivation. The Dishevelled2 hypothesis - Downregulating malin in cell culture was reported to increase levels of dishevelled2, which through the wnt/glycogen synthase kinase-3 pathway would likewise overactivate GS. The Autophagic defect hypothesis - Polyglucosans may be natural byproducts of normal glycogen metabolism. LD mice were reported to be autophagy-defective. LD would arise from failed autophagy leading to failed polyglucosan clearance. Finally, the p53 hypothesis - laforin and malin were reported to downregulate p53, their absence leading to increased p53, which would activate apoptosis, leading to the neurodegeneration of LD. In the present work we repeat key experiments that underlie these four hypotheses. We are unable to confirm increased pSGK1, dishevelled2, or p53 in LD mice, nor the reported autophagic defects. Our work does not support the above hypotheses in understanding this unique and severe form of epilepsy. PMID- 29152448 TI - Vision-assisted micromanipulation using closed-loop actuation of multiple microrobots. AB - Accurate control and precise positioning of opto-thermocapillary flow-addressed bubble microrobots are necessary for micromanipulation. In addition, micromanipulation using the simultaneous actuation of multiple microrobots requires a robust control system to enable independent motion. This paper demonstrates a hybrid closed-loop vision-assisted control system capable of actuating multiple microrobots simultaneously and positioning them at precise locations relative to micro-objects under manipulation. A vision-assisted grasp planning application was developed and used to calculate the necessary trajectories of the microrobots to form cages around micro-objects. The location of the microrobots and the micro-objects was detected at the caging locations using a particle-tracking application that used image feedback for precise positioning. The closed-loop image feedback information enabled the position update of the microrobots, allowing them to precisely follow the trajectory and caging locations calculated by the grasp-planning application. Four microrobots were assigned to cage a star-shaped micro-object using the closed-loop control system. Once caged, the micro-object was transported to a location within the workspace and uncaged, demonstrating the micromanipulation task. This microrobotic system is well suited for the micromanipulation of single cells. PMID- 29152447 TI - Nanostructured porous graphene and its composites for energy storage applications. AB - Graphene, 2D atomic-layer of sp2 carbon, has attracted a great deal of interest for use in solar cells, LEDs, electronic skin, touchscreens, energy storage devices, and microelectronics. This is due to excellent properties of graphene, such as a high theoretical surface area, electrical conductivity, and mechanical strength. The fundamental structure of graphene is also manipulatable, allowing for the formation of an even more extraordinary material, porous graphene. Porous graphene structures can be categorized as microporous, mesoporous, or macroporous depending on the pore size, all with their own unique advantages. These characteristics of graphene, which are further explained in this paper, may be the key to greatly improving a wide range of applications in energy storage systems. PMID- 29152449 TI - A new multiple robot path planning algorithm: dynamic distributed particle swarm optimization. AB - Multiple robot systems have become a major study concern in the field of robotic research. Their control becomes unreliable and even infeasible if the number of robots increases. In this paper, a new dynamic distributed particle swarm optimization (D2PSO) algorithm is proposed for trajectory path planning of multiple robots in order to find collision-free optimal path for each robot in the environment. The proposed approach consists in calculating two local optima detectors, LODpBest and LODgBest. Particles which are unable to improve their personal best and global best for predefined number of successive iterations would be replaced with restructured ones. Stagnation and local optima problems would be avoided by adding diversity to the population, without losing the fast convergence characteristic of PSO. Experiments with multiple robots are provided and proved effectiveness of such approach compared with the distributed PSO. PMID- 29152450 TI - Studying slippage on pushing applications with snake robots. AB - In this paper, a framework for analyzing the motion resulting from the interaction between a snake robot and an object is shown. Metrics are derived to study the motion of the object and robot, showing that the addition of passive wheels to the snake robot helps to minimize slippage. However, the passive wheels do not have a significant impact on the force exerted onto the object. This puts snake robots in a similar framework as robotic arms, while considering special properties exclusive to snake robots (e.g., lack of a fixed-base, interaction with the environment through friction). It is also shown that the configuration (shape) of the snake robot, parameterized with the polar coordinates of the robot's COM, plays an important role in the interaction with the object. Two examples, a snake robot with two joints and another with three joints, are studied to show the applicability of the model. PMID- 29152451 TI - Comparison of different soft grippers for lunch box packaging. AB - Automating the lunch box packaging is a challenging task due to the high deformability and large individual differences in shape and physical property of food materials. Soft robotic grippers showed potentials to perform such tasks. In this paper, we presented four pneumatic soft actuators made of different materials and different fabrication methods and compared their performances through a series of tests. We found that the actuators fabricated by 3D printing showed better linearity and less individual differences, but showed low durability compared to actuators fabricated by traditional casting process. Robotic grippers were assembled using the soft actuators, and grasping tests were performed on soft paper containers filled with food materials. Results suggested that grippers with softer actuators required lower air pressure to lift up the same weight and generated less deformation on the soft container. The actuator made of casting process with Dragon Skin 10 material lifted the most weight among different actuators. PMID- 29152452 TI - A comparison study of adaptive scale estimation in correlation filter-based visual tracking methods. AB - Recently, discriminative correlation filter-based method becomes one of the popular directions in the field of visual tracking because of its computational efficiency and excellent performance, which make it especially suitable for real time application. Most of them are focused only on the transition estimation. However, accurate scale estimation of the target plays a very important role in long-term tracking task and is still a challenging problem. The principle of CF based visual tracking is introduced first. The approaches of adaptive scale estimation in correlation filter-based visual tracking methods are summarized in this paper, and their performances are analyzed by experiment comparison. The works here can provide a better understanding on the scale estimation problem for correlation filter-based visual tracking. Furthermore, maybe with the same strategy, other factors in visual tracking, such as appearance variation, can be integrated into the framework to improve the performance of correlation filter based method. PMID- 29152453 TI - Targeting the Stem Cell Properties of Adult Breast Cancer Cells: Using Combinatorial Strategies to Overcome Drug Resistance. AB - Purpose of review: Cancer is a major public health problem worldwide. In aggressive cancers, which are heterogeneous in nature, there exists a paucity of targetable molecules that can be used to predict outcome and response to therapy in patients, especially those in the high risk category with a propensity to relapse following chemotherapy. This review addresses the challenges pertinent to treating aggressive cancer cells with inherent stem cell properties, with a special focus on triple-negative breast cancer (TNBC). Recent findings: Plasticity underlies the cancer stem cell (CSC) phenotype in aggressive cancers like TNBC. Progenitors and CSCs implement similar signaling pathways to sustain growth, and the convergence of embryonic and tumorigenic signaling pathways has led to the discovery of novel oncofetal targets, rigorously regulated during normal development, but aberrantly reactivated in aggressive forms of cancer. Summary: Translational studies have shown that Nodal, an embryonic morphogen, is reactivated in aggressive cancers, but not in normal tissues, and underlies tumor growth, invasion, metastasis and drug resistance. Front-line therapies do not inhibit Nodal, but when a combinatorial approach is used with an agent such as doxorubicin followed by anti-Nodal antibody therapy, significant decreases in cell growth and viability occur. These findings are of special interest in the development of new therapeutic interventions that target the stem cell properties of cancer cells to overcome drug resistance and metastasis. PMID- 29152455 TI - Surveying immigrants in Southern Europe: Spanish and Italian strategies in comparative perspective. AB - Italy and Spain, as countries of recent immigration and high irregularity rates, have struggled to adapt their statistical system, especially their population registers, to adequately reflect the presence of an increasing number of immigrants in their territory. The population registers of the two countries have adapted differently to these changing realities: Spain introduced significant improvements in Padron which have increased its coverage and accuracy. This is still not the case in Italy, making it necessary to resort to non-random sampling methods. The paper discusses the methodological implications of these differences and evaluates different methodological solutions based on both random and non random sampling methods in both countries. PMID- 29152454 TI - Recent Advances in Retinal Stem Cell Therapy. AB - Purpose of review: Progress in stem cell research for blinding diseases over the past decade is now being applied to patients with retinal degenerative diseases and soon perhaps, glaucoma. However, the field still has much to learn about the conversion of stem cells into various retinal cell types, and the potential delivery methods that will be required to optimize the clinical efficacy of stem cells delivered into the eye. Recent findings: Recent groundbreaking human clinical trials have demonstrated both the opportunities and current limitations of stem cell transplantation for retinal diseases. New progress in developing in vitro retinal organoids, coupled with the maturation of bio-printing technology, and non-invasive high-resolution imaging have created new possibilities for repairing and regenerating the diseased retina and rigorously validating its clinical impact in vivo. Summary: While promising progress is being made, meticulous clinical trials with cells derived using good manufacturing practice, novel surgical methods, and improved methods to derive all of the neuronal cell types present in the retina will be indispensable for developing stem cell transplantation as a paradigm shift for the treatment of blinding diseases. PMID- 29152456 TI - Disorders of branched chain amino acid metabolism. AB - The three essential branched-chain amino acids (BCAAs), leucine, isoleucine and valine, share the first enzymatic steps in their metabolic pathways, including a reversible transamination followed by an irreversible oxidative decarboxylation to coenzyme-A derivatives. The respective oxidative pathways subsequently diverge and at the final steps yield acetyl- and/or propionyl-CoA that enter the Krebs cycle. Many disorders in these pathways are diagnosed through expanded newborn screening by tandem mass spectrometry. Maple syrup urine disease (MSUD) is the only disorder of the group that is associated with elevated body fluid levels of the BCAAs. Due to the irreversible oxidative decarboxylation step distal enzymatic blocks in the pathways do not result in the accumulation of amino acids, but rather to CoA-activated small carboxylic acids identified by gas chromatography mass spectrometry analysis of urine and are therefore classified as organic acidurias. Disorders in these pathways can present with a neonatal onset severe-, or chronic intermittent- or progressive forms. Metabolic instability and increased morbidity and mortality are shared between inborn errors in the BCAA pathways, while treatment options remain limited, comprised mainly of dietary management and in some cases solid organ transplantation. PMID- 29152459 TI - Marking 15 years of the Genetic and Rare Diseases Information Center. AB - BACKGROUND: The Genetic and Rare Diseases Information Center (GARD), a program of the National Center for Advancing Translational Sciences, was established in 2002 to assist the public in finding reliable, timely, and easy-to-understand information about genetic and/or rare diseases in English or Spanish. OBJECTIVE: A review of longitudinal data on GARD inquiries from 2002 to 2016 and assessment of the results of two user satisfaction surveys were conducted to understand the demographics and needs of GARD customers over time. METHODS: Since 2002, GARD has collected anonymized data while responding to questions received via e-mail, website, telephone, fax, letter, or TTY. Between 2002 and 2016 GARD received a total of 60,106 inquiries. User satisfaction surveys were conducted in 2006 and 2014, in which users self-selected to participate. RESULTS: The annual number of inquiries has risen steadily since 2002. Inquiries are overwhelmingly from educated female patients, family, and friends seeking disease-specific information, treatment options, referrals, and research studies. Most users report satisfaction with the experience. CONCLUSIONS: Rare disease patients and their families face challenges in finding information about their symptoms or diagnosis, prognosis, treatment options, significance for family members, and research opportunities. Lack of available clinical expertise can leave patients, their family, and friends with little choice but to become knowledgeable on their own. GARD fills a critical need by providing the public with vetted, evidence based information that empowers people to engage in their own health care and seek research studies of relevance. PMID- 29152460 TI - Bisphenol S impairs blood functions and induces cardiovascular risks in rats. AB - Bisphenol S (BPS) is an industrial chemical which is recently used to replace the potentially toxic Bisphenol A (BPA) in making polycarbonate plastics, epoxy resins and thermal receipt papers. The probable toxic effects of BPS on the functions of haemopoietic and cardiovascular systems have not been reported till to date. We report here that BPS depresses haematological functions and induces cardiovascular risks in rat. Adult male albino rats of Sprague-Dawley strain were given BPS at a dose level of 30, 60 and 120 mg/kg BW/day respectively for 30 days. Red blood cell (RBC) count, white blood cell (WBC) count, Hb concentration, and clotting time have been shown to be significantly (*P < 0.05) reduced in a dose dependent manner in all exposed groups of rats comparing to the control. It has also been shown that BPS increases total serum glucose and protein concentration in the exposed groups of rats. We have observed that BPS increases serum total cholesterol, triglyceride, glycerol free triglyceride, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) concentration, whereas high density lipoprotein (HDL) concentration has been found to be reduced in the exposed groups. BPS significantly increases serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities dose dependently. Moreover, serum calcium, bilirubin and urea concentration have been observed to be increased in all exposed groups. In conclusion, BPS probably impairs the functions of blood and promotes cardiovascular risks in rats. PMID- 29152462 TI - Dietary intake of heavy metals from eight highly consumed species of cultured fish and possible human health risk implications in Bangladesh. AB - Concentrations of five heavy metals (Pb, Cd, Cr, As and Hg) in eight highly consumed cultured fish species (Labeo rohita, Clarias gariepinus, Hypophthalmichthys molitrix, Cyprinus capio, Puntius sarana, Oreochromis mossambicus, Pangasius pangasius and Anabas testudineus) collected from four wholesale markets of Dhaka city, Bangladesh (Karwan Bazar, Mohammadpur Town Hall, Newmarket and Mirpur-1) were measured using atomic absorption spectrometry (AAS) in order to evaluate the potential human health risks from the consumption of fish. The estimated daily intake (EDI) of all the studied heavy metals calculated on the basis of mean fish consumption of 49.5 g person-1 d-1 by Bangladeshi households indicated that no risk to people's health with respect to the EDI of investigated heavy metals through the consumption of the fish samples. From the human health point of view, the estimation of non-carcinogenic risk indicated that intake of individual heavy metal through the consumption of fish was safe for human health, whereas, consumption of combined heavy metals suggested potential health risk to highly exposed consumers. However, the estimation of carcinogenic risk of arsenic due to the consumption of fish indicated that consumers remain at risk of cancer. PMID- 29152457 TI - Peroxisome biogenesis disorders. PMID- 29152461 TI - Use of Toll-like receptor assays for the detection of bacterial contaminations in icodextrin batches released for peritoneal dialysis. AB - Icodextrin is a starch derivative used for preparing solutions of peritoneal dialysis. Unfortunately, peptidoglycans (PGN) and lipopolysaccharides (LPS) have been reported to contaminate certain icodextrin batches and to contribute to the development of sterile peritonitis. The decision of selecting or rejecting icodextrin batches is however difficult, because of limitations in the detection of these bacterial contaminants. Besides monocyte activation tests of cytokine release, a number of bio-assays using stably TLR-transfected cell lines have been developed. Here, we compared the efficacy of TLR2- and TLR4-transfected cells to detect bacterial contamination with the responses of monocytes exposed to the same icodextrin samples. In contrast to monocyte models of cytokine release, we found that TLR2- and TLR4-transfected cell lines are highly sensitive to detect little PGN and LPS contaminations in the presence of icodextrin. With the intent to increase PGN reactivity, mutanolysin was used to generate soluble fragments in icodextrin samples. We found that such an enzymatic treatment led to an enhanced response of TLR2-transfected cells, even though parental icodextrin samples were poorly reactive. Altogether, these findings indicate that the use of TLR2- and TLR4-transfected cell lines is a valuable approach for helping to the decision of selecting icodextrin batches for peritoneal dialysis. PMID- 29152463 TI - Acute oral toxicity evaluation of aqueous ethanolic extract of Saccharum munja Roxb. roots in albino mice as per OECD 425 TG. AB - Background: S. munja roots have been used in ethno medicines for the treatment of different ailments. Despite its beneficial uses no studies on its toxicity potential have been reported. Objective: The study was designed to evaluate acute toxic potential of aqueous ethanolic extract of S. munja roots according to OECD TG No. 425. Material and methods: Female mice were divided into two groups (n = 5). One group served as control while the other as treated group that received 2000 mg/kg b.w. of S. munja roots ethanolic extract orally. Then both groups were observed for 14 days. Then the blood samples were collected by cardiac puncture, under chloroform general anesthesia and were subjected to hematological and biochemical analyses. The vital organs of anesthetized animals were preserved for histopathological examination. Results: The the data revealed that LD50 of the extract was greater than 2000 mg/kg b.w. There was no significant alteration found in body weight and organ to body mass index. In comparison with control group, there was significant increase in levels of ALT, AST, total proteins, globulin levels, serum urea, cholesterol, triglycerides, LDL, platelet count, MCV, MCH, WBC count and lymphocytes whereas ALP and MCHC levels were reduced significantly. Conclusions: From the data obtained in this study, It can be concluded that though LD50 is greater than 2000 mg/kg b.w. but moderate toxicity signs appeared in liver, kidney, lipid profile and CBC also showed blood dyscresias at limit dose. PMID- 29152464 TI - Intensivist-based deep sedation using propofol for pediatric outpatient flexible bronchoscopy. AB - AIM: To evaluate the safety and efficacy of sedating pediatric patients for outpatient flexible bronchoscopy. METHODS: A retrospective chart review was conducted for all children, age 17 years or under who underwent flexible bronchoscopy under deep sedation in an outpatient hospital-based setting. Two sedation regimens were used; propofol only or ketamine prior to propofol. Patients were divided into three age groups; infants (less than 12 mo), toddlers (1-3 years) and children (4-17 years). Demographics, indication for bronchoscopy, sedative dosing, sedation and recovery time and adverse events were reviewed. RESULTS: Of the total 458 bronchoscopies performed, propofol only regimen was used in 337 (74%) while propofol and ketamine was used in 121 (26%). About 99% of the procedures were successfully completed. Children in the propofol + ketamine group tend to be younger and have lower weight compared to the propofol only group. Adverse events including transient hypoxemia and hypotension occurred in 8% and 24% respectively. Median procedure time was 10 min while the median discharge time was 35 min. There were no differences in the indication of the procedure, propofol dose, procedure or recovery time in either sedative regimen. When compared to other age groups, infants had a higher incidence of hypoxemia. CONCLUSION: Children can be effectively sedated for outpatient flexible bronchoscopy with high rate of success. This procedure should be performed under vigilance of highly trained providers. PMID- 29152458 TI - Lysosomal storage diseases. AB - Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively. PMID- 29152465 TI - Reproducibility of diaphragm thickness measurements by ultrasonography in patients on mechanical ventilation. AB - AIM: To prospectively evaluate the reproducibility of diaphragm thickness measurement by ultrasonography at the bedside by critical care physicians in patients on invasive mechanical ventilation. METHODS: In a prospective observational study of 64 invasively ventilated patients, diaphragmatic thickness measurement was taken by 2 different observers at the same site. Three measurements were taken by each observer and averaged. The intraobserver and interobserver variability was assessed by estimation of intraclass correlation coefficient. The limits of agreement were plotted as the difference between two observations against the average of the two observations in Bland and Altman analysis. RESULTS: The mean diaphragm thickness at the functional residual capacity was 2.29 +/- 0.4 mm and the lower limit of the normal, i.e., the 5th percentile was 1.7 mm (95%CI: 1.6-1.8). The intraclass correlation coefficient for intraobserver variability was 0.986 (95%CI: 0.979-0.991) with a P value of < 0.001. The intraclass correlation coefficient for interobserver variability was 0.987 (95%CI: 0.949-0.997) with a P value of < 0.001. In Bland and Altman analysis, both intraobserver and interobserver measurements showed high limits of agreement. CONCLUSION: Our study demonstrates that the measurement of diaphragm thickness by ultrasound can be accurately performed by critical care physicians with high degree of reproducibility in patients on mechanical ventilation. PMID- 29152466 TI - A Less Invasive Strategy for Ruptured Cerebral Aneurysms with Intracerebral Hematomas: Endovascular Coil Embolization Followed by Stereotactic Aspiration of Hematomas Using Urokinase. AB - Objective: Aneurysm clipping and simultaneous hematoma evacuation through open craniotomy is traditionally recommended for ruptured cerebral aneurysms accompanied by intracerebral or intrasylvian hemorrhages. We report our experience of adapting a less invasive treatment strategy in poor-grade patients with intracerebral or intrasylvian hemorrhages associated with ruptured cerebral aneurysms, where the associated ruptured cerebral aneurysms were managed by endovascular coil embolization, followed by stereotactic aspiration of hematomas (SRH) using urokinase. Materials and Methods: We retrospectively analyzed 112 patients with ruptured cerebral aneurysms. There were accompanying intracerebral or intrasylvian hemorrhages in 36 patients (32.1%). The most common site for these ruptured aneurysms was the middle cerebral artery (MCA) (n = 15; 41.6%). Endovascular coil embolization followed by SRH using urokinase was performed in 9 patients (25%). Results: In these 9 patients, the most common site of aneurysms was the MCA (n = 3; 33.4%); the hematoma volume ranged from 19.24 to 61.68 mL. Four patients who were World Federation of Neurological Surgeons (WFNS) grade-IV on admission, achieved favorable outcomes (Glasgow Outcome Score [GOS] 4 or 5) at 6-months postoperatively. In the five patients who were WFNS grade-V on admission, one achieved a favorable outcome, whereas 4 achieved GOS scores of 2 or 3, 6-months postoperatively. There was no mortality. Conclusion: If immediate hematoma evacuation is not mandated by clinical or radiological signs of brain herniation, a less invasive strategy, such as endovascular coil embolization followed by SRH using urokinase, may be a good alternative in poor-grade patients with intracerebral or intrasylvian hemorrhages associated with ruptured cerebral aneurysms. PMID- 29152467 TI - An Unruptured Anterior Communicating Artery Aneurysm Presenting with Left Homonymous Hemianopsia: A Case Report. AB - Unruptured cerebral aneurysms sometimes present with visual symptomsdue to compression of the visual pathways. However, until now, unruptured anterior communicating artery (ACoA) aneurysms presenting visual field defects have been extremely rare. The authors report the case of a 51-year-old woman who presented with left homonymous hemianopsia. Radiological findings demonstrated an ACoA aneurysm filled with thrombus, that was compressing the optic chiasm and post chiasmal tract. The patient underwent clipping of the aneurysm, which resolved the visual field defect. In cases of visual field defects, an ACoA aneurysm should be included in the differential diagnosis. PMID- 29152468 TI - Dual Mechanical Thrombectomy for Recanalization of a Resistant Acute Posterior Circulation Stroke. AB - A 71-year-old man with acute basilar artery occlusion was referred for endovascular treatment 6 hours after the onset of stroke with a Glasgow Coma Score of 3 and National Institutes of Health Stroke Scale of 27. A cerebral arteriogram revealed occlusion of the left vertebral artery proximally and thromboembolic occlusion of the basilar tip. Direct aspiration and mechanical thrombectomy with various stent retrievers failed to reconstitute arterial flow in the basilar artery. Thrombolysis in cerebral infarction 2b recanalization was achieved only after placement of double Catch Mini stent retrievers through 2 microcatheters, on both side branches of the basilar bifurcation in a kissing fashion and retrieving them simultaneously. It was possible to perform this maneuver through a single distal access catheter without any complications. On follow-up the patient awakened and was able to follow commands on his right side. To our knowledge, dual mechanical thrombectomy with stent retrievers has not been reported in the posterior circulation previously. This technique may be useful in retrieving thrombi located at major intracranial bifurcations of the posterior circulation which do not recanalize with standard mechanical thrombectomy procedures. Although bilateral access to the basilar artery through both vertebral arteries is an advantage in posterior circulation for this technique, dual mechanical thrombectomy can also be performed through a unilateral access. PMID- 29152469 TI - Eyebrow Incision for Surgical Evacuation of a Lobar Intracerebral Hematoma with a Novel Endoport System. AB - Large lobar intracerebral hemorrhages (ICHs) can cause rapid neurological deterioration, and affected patients have low rates of survival and functional independence. Currently, the role of surgical intervention in the management patients with lobar ICHs is controversial. Minimally invasive technologies have been developed which may potentially decrease the operative morbidity of ICH surgery. The aim of this case report is to describe the technical aspects of the use of a novel minimally invasive endoport system, the BrainPath (NICO, Indianapolis, IN, USA), through an eyebrow incision for evacuation of a large lobar hematoma. An 84-year-old female presented with a left frontal ICH, measuring 7.5 cm in maximal diameter and 81 cm3 in volume, secondary to cerebral amyloid angiopathy. Through a left eyebrow incision, a miniature modified orbitozygomatic craniotomy was performed, which allowed endoport cannulation of the hematoma from a lateral subfrontal cortical entry point. Endoport-assisted hematoma evacuation resulted in nearly 90% volume reduction and improvement of the patient's functional status at clinical follow-up. We found that minimally invasive endoport technology can be employed in conjunction with conventional neurosurgical skull base principles to achieve safe and effective evacuation of large lobar hematomas in carefully selected patients. PMID- 29152470 TI - Fluoroscopy-guided Combined (Surgical/Endovascular) Treatment of Dural Arteriovenous Fistula. AB - For dural arteriovenous fistula (DAVF), when the usual endovascular or neurosurgical approaches are difficult to treat, multi-modal treatment can be helpful. We present a case of a 71-year-old woman with DAVF, who presented with an intracerebral haemorrhage. Digital subtraction angiography revealed a DAVF of the transverse sinus, with cortical venous reflux. Transvenous and transarterial approaches for coil embolization failed. In the operating room, a small craniotomy was performed, and coil embolization was done under fluoroscopy. Transcranial venous embolization might be a useful method to occlude DAVF in a case that is difficult to access by usual surgical or endovascular approaches. PMID- 29152471 TI - Internal Carotid Artery Dissection in Brazilian Jiu-Jitsu. AB - Carotid artery dissection is a significant cause of stroke in young patients. It may be asymptomatic and go undiagnosed, or minimal transient manifestations may follow, commanding a higher index of suspicion than ordinarily exists to avoid misdiagnosis. Reported herein is a 27-year-old man who suffered extracranial internal carotid artery dissection while practicing a Brazilian Jiu-Jitsu submission maneuver. The patient's condition suddenly deteriorated one week later due to distal embolization and stroke. Despite endovascular treatment, with stenting of the cervical carotid artery, neurologic deficits remained. Of note, the objective in martial arts, which is to kill or incapacitate, has yet to be fully tempered in transitioning to sport. Brazilian Jiu-jitsu, a relatively new and fast-growing form of martial art, places emphasis on submission maneuvers. Related injuries are not common knowledge and are poorly described in the literature. This account is intended to shed light on the risk of this discipline. Through education and improved supervision, vascular injuries of this nature and the potentially lethal or disabling consequences may thus be prevented in young athletes. PMID- 29152472 TI - Intraoperative Common Carotid Artery Injury during Ventriculoperitoneal Shunt Surgery. AB - There are a number of complications associated with ventriculoperitoneal shunt (VPS) surgery. The authors present a rare case of iatrogenic common carotid artery injury during VPS surgery. PMID- 29152473 TI - Kissing Aneurysms at Fenestrated Proximal Basilar Artery: Double-barrel Stent assisted Coiling Using Dual Closed-cell Stents. AB - Kissing aneurysms associated with a proximal basilar artery fenestration are an exceedingly rare and unique therapeutic challenge due to anatomical complexity. This report describes double-barrel stent-assisted technique with dual closed cell stents for the successful endovascular coiling of kissing aneurysms from a proximal basilar artery fenestration. PMID- 29152474 TI - Simultaneous Onset of Ischemic and Hemorrhagic Stroke Due To Intracranial Artery Dissection. AB - Intracranial dissections commonly present as ischemic stroke and as hemorrhagic stroke. In general, while either ischemic stroke or hemorrhagic stroke may develop, the simultaneous onset of both may also occasionally occur. In this report, we present a case of simultaneous development of ischemic stroke and hemorrhagic stroke due to an intracranial artery dissection. PMID- 29152475 TI - Use of robotics in liver donor right hepatectomy. AB - Liver transplantation is the best solution for end stage liver disease, and has been widely accepted and rapidly developed in the past decades. Along with the improved outcomes of liver transplantation, living-related donor transplantation has been conducted to overcome the shortage of the deceased donor. The most important aspects of the living-related liver transplantation are donor safety and fast recovery after graft procurement. Meanwhile, the rapid progress of minimally invasive surgery (MIS) in general surgery has generated heated debate regarding the appropriateness of MIS in living-related donor graft hepatectomy. Technical innovations and instrument enhancements have been allowing recruitment of more potential candidates through smaller wounds and better surgical experience. Although MIS has been documented with safety and feasibility in complex liver surgery, the progress is slow in regard to the application of MIS in donor graft hepatectomy. Pioneer surgeons have devoted themselves to develop the pure MIS approach for the liver donor surgery, but the steep learning curve for pure MIS major hepatectomy remains a major barrier for wide adoption. The introduction of robotic system may lower the barrier for entry for practice into MIS donor hepatectomy. PMID- 29152477 TI - Robotic transduodenal excision of ampullary tumour. AB - Ampullary tumours are uncommon lesions with potential risk of malignancy. The management is excision by either endoscopic ampullectomy, pancreaticoduodenectomy or transduodenal excision. Endoscopic ampullectomy offers a less invasive approach, whereas pancreaticoduodenectomy allows radical excision of the tumour. They both carry their own limitations. Transduodenal excision of ampullary tumour offers significantly lower risks with low recurrence rate, and can be offered for benign or early grade tumours. Limited cases of laparoscopic transduodenal excision of ampullary tumours were reported in the literature, probably due to the technical difficulties in performing the operation, especially during the reconstruction of the pancreaticobiliary ducts with the laparoscopic approach. In the era with robotic surgical systems, the technical demanding procedures are greatly facilitated. Hence, we are writing to report a case of transduodenal excision of ampullary tumour with the robot assisted laparoscopic approach. PMID- 29152476 TI - Early recovery pathway for hepatectomy: data-driven liver resection care and recovery. AB - In recent years, great progress has been made toward safer hepatobiliary surgical interventions. This has resulted in more widely available treatments for patients who in the past were ineligible for curative resection of primary liver tumors, liver metastases, and advanced biliary tumors. However, the rise in procedures has seen increasingly heterogeneous perioperative management, yielding strikingly disparate outcomes. A number of groups have attempted to standardize perioperative care in an effort to create enhanced recovery pathways (ERPs) and provide clinicians with a dependable roadmap to success following hepatectomy. In the future, each aspect of perioperative care could be pre-ordained with emphasis on nutrition, anesthesia, prophylaxis, use of surgical drains, post-operative fluid and electrolyte management, and contact with physician extenders following discharge. This article reviews the data behind ERPs preceding and following hepatectomy. It includes primary data justifying practices in post-hepatectomy support. It also touches on the benefits of minimally invasive hepatectomy and offers future directions for research in peri-hepatectomy ERPs. Overall, this article seeks to formulate a pathway for practice based on data, with enough details to allow creation of rational order sets for efficient and superior practice. PMID- 29152479 TI - Appropriate surgical therapy for patients with hepatocellular carcinoma beyond Milan criteria. PMID- 29152478 TI - Changes in dietary patterns and body composition within 12 months of liver transplantation. AB - Background: Cardiometabolic risk factors are increasing in liver transplant recipients (LTR). Influencing dietary factors have not been assessed. The aim of this observational study was to assess changes in weight, metabolic function, dietary intake and eating behaviours in the first year after orthotopic liver transplantation (OLT). Methods: Consecutive recruitment of 17 patients (14 males) awaiting OLT at a single tertiary hospital. Dietary intake, food behaviours and anthropometry were recorded at baseline, and 6 and 12 months post-transplant. Results: By 12 months, patients had gained on average 7.3% of body weight. The prevalence of overweight or obesity increased from baseline 53% to 77% (P=0.001). By 6 months, 65% (n=11/17) of patients had altered glucose metabolism. Dietary intake was consistent with a Western-style dietary pattern with high saturated fat. Over half of the patients (69%, n=11/16) reported low to no depressive feelings and rated their self-esteem as good (53%, n=9/16). The Power of Food Scale increased between pre and post-transplant, indicating a stronger appetitive drive. Conclusions: Weight gain occurs early post-transplant, with significant metabolic dysfunction present within 6 months, however is not associated with significant psychological distress. Early dietary intervention designed to limit weight gain and target cardiometabolic health is recommended for this unique patient population. PMID- 29152480 TI - Expanding the boundaries of Milan. PMID- 29152481 TI - Liver transplantation for the solitary intrahepatic cholangiocarcinoma less than 2 cm in diameter. PMID- 29152482 TI - Should we expand liver transplant criteria to cirrhotic patients with intrahepatic cholangiocarcinoma? PMID- 29152483 TI - Expanding transplantation of patients with a liver cancer without harming allocation: a priority in the era of scarce donation. PMID- 29152484 TI - Searching the ideal hepatocellular carcinoma patient for liver transplantation: are the Toronto criteria a step in the right direction? PMID- 29152485 TI - Patient-derived xenografts, a multi-faceted in vivo model enlightening research on rare liver cancer biology. PMID- 29152486 TI - Avatars to personalized medicine: of mice and men. PMID- 29152487 TI - Clinical patterns of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD): a multicenter prospective study. PMID- 29152488 TI - NAFLD-which patients should have hepatocellular carcinoma surveillance? PMID- 29152489 TI - Laparoscopic liver resection in the treatment of HCC with liver cirrhosis: would it provide superiority to conventional open hepatectomy? PMID- 29152490 TI - Implementing genetic screening for the management of hepatic disease. PMID- 29152491 TI - Acute on chronic pancreatitis in a young female. PMID- 29152492 TI - Prof. Tilman Sauerbruch: patients with HCC may be benefit from statins. PMID- 29152493 TI - A pilot study evaluating biomarker development for drug-induced chronic eczematous eruptions of aging individuals. AB - Background: Identifying the drug(s) responsible for drug-induced chronic eczematous eruptions of aging individuals (CEEA) is a clinical challenge in patients on multiple medications. Reliable in vitro testing methods and biomarkers are needed to identify the causative agent and allow simultaneous assessment of T-cell responses to multiple drugs being taken concurrently. This study examined the feasibility of using in vitro, drug-specific T cell activation responses as a biomarker for drug-induced CEEA. Methods: This was a single center, proof-of-concept pilot study at the University of Utah Hospital, Salt Lake City, Utah. Eight aging study subjects having a history suggestive of chronic eczematous drug eruptions suspected to have resulted from calcium channel blocker (CCB) and/or hydrochlorothiazide (HCTZ) hypersensitivity plus three matched aging control subjects were identified. Drug patch testing for CCB and/or HCTZ, in vitro drug antigen-induced lymphocyte proliferation assays, and multianalyte-determined cytokine release assays were performed before and after HCTZ and/or CCB incubation. Results: All study and control subject blood samples tested failed to demonstrate detectable enhanced lymphocyte proliferation or cytokine release to in vitro CCBs or HCTZ challenge when tested with a fairly wide range of drug concentrations. Additionally, none of the enrolled patients developed a positive patch test to CCBs and/or HCTZ. Conclusions: This pilot study aimed to correlate in vitro drug-induced T lymphocyte transformation and cytokine production with the presence of drug-induced CEEA. Failure to identify T cell proliferative responses to CCB drug antigens in our in vitro studies could have, in part, resulted from a pharmacologic inhibiting effect of CCB on T cell activation. PMID- 29152494 TI - D-dimer level is related to the prognosis of patients with small cell lung cancer. AB - Background: Although the significance of D-dimer in cancer patients has been extensively studied and plasma D-dimer levels have been reported to be abnormally high in certain types of lung cancer patients, its prognostic value for small cell lung cancer (SCLC) remains largely unknown. Methods: One hundred and seven newly diagnosed SCLC patients were enrolled in this study. Variables including the clinical features, pre-treatment levels of D-dimer, serum neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) were extracted. The correlations between D-dimer levels and prognosis of the patient were analysed with Kaplan-Meier survival analysis. Results: Plasma D-dimer levels were elevated in 57.01% of patients. Patients with extensive stage disease had higher D-dimer levels compared with those at limited stage. D-dimer levels were positively correlated with NSE and CEA levels. The elevated D-dimer levels were significantly associated with the SCLC-related mortality. Patients with elevated D-dimer levels had a shorter median survival time than those with normal levels, and a significant difference existed between the two groups. Conclusions: Increased D-dimer levels suggested a shorter survival time in SCLC patients. Pre treatment D-dimer level is useful in estimating the prognosis of patients with SCLC. PMID- 29152495 TI - Midterm outcomes of titanium modular femoral necks in total hip arthroplasty. AB - Background: Modular femoral necks present surgical and biomechanical advantages in total hip arthroplasty (THA), but their benefits remain controversial due to risks of corrosion and fracture at the additional junction. This study aimed to report 10-year survival and clinical outcomes of a titanium femoral stem with a titanium modular neck in consecutive series. Methods: The authors reviewed the records of 97 patients (99 THAs) using uncemented modular stem and ceramic-on ceramic acetabular components. Patients were evaluated at minimum follow-up of 5 years using the Harris Hip Score (HHS) and Postel Merle-D'Aubigne score (PMA). Survival was calculated using the Kaplan-Meier (KM) method with any reoperation or revision as endpoint. Results: From the original cohort, 14 patients died, 6 were lost to follow-up, and 5 had revision operations with exchange of the femoral stem. The KM survival at 10 years was 94.2% (CI, 86.5-97.5). Clinical assessment was performed on 67 of the 72 patients (69 of the 74 hips) presently living with their original THA components. At mean follow-up of 9.4+/-1.0 years (median, 10; range, 5-11), the HHS was 93.6+/-8.2 and the PMA score 17.0+/-1.6. The X-rays revealed no signs of adverse reactions or bone loss. Conclusions: The uncemented titanium hip stem with modular titanium neck provided a satisfactory 10-year survival and clinical outcomes. Neck modularity enabled restoration of patient-specific femoral offset and limb length thanks to five possible neck configurations, though greater follow up is required to confirm the long-term benefits and safety of this design concept. PMID- 29152496 TI - Case management: an up-to-date review of literature and a proposal of a county utilization. AB - The current phase of development of health services is characterised by multiple changes that affect the organisational models of primary production lines (hospital, clinics, etc.) and the method of use by users. The clinical governance is a "strategy by which healthcare organisations are responsible for continuous improvement in the quality of services and achievement-maintaining high professional standards, stimulating the creation of an environment that fosters professional excellence". In this perspective of clinical governance, the role of the case manager with its clinical and managerial and financial skills becomes a key figure to ensure quality as a set of aspects of efficiency, effectiveness, safety, appropriateness, participation and equity. Case management fits perfectly in the context of assistance, to promote an increased quality of care, resulting in improved life, through coordination, integrating different professional contributions and ensuring continuity of care through all stages of treatment. In conclusion, preliminary results indicate that the increase of this organisation could be more functionally to reduce some team's gap. PMID- 29152497 TI - Molecular analysis driven video-assisted thoracic surgery resections in bilateral synchronous lung cancers: from the test tube to the operatory room. AB - Synchronous cancers are not such rare clinical conditions. Nevertheless, even after the 8th edition of the TNM classification of the lung cancer, the surgical approach for patients presenting with synchronous bilateral lung cancer is still under debate. The resection of both lesions in the case of synchronous bilateral lung cancer is reasonable, but, on the other hand, is the lobectomy the correct choice in the event of the single primary with a contralateral metastatic lesion? In this case report, we describe how the molecular analysis and the detection of the EGFR, KRAS and TP53 mutations in both tumours have determined in a patient the two tumours as primary and both the right surgical approach. We also discuss how molecular analysis found differences in all the three genes examined in the two lesions and allowed to exclude the clonal nature of the two tumours. In conclusion, genetic studies help to offer a more radical surgical treatment to this patient. PMID- 29152498 TI - Extracorporeal life support in preoperative and postoperative heart transplant management. AB - Increased experience with extracorporeal life support (ECLS) as a mode of cardiac support has expanded its use to diverse patient populations including patients requiring a bridge to heart transplantation and patients requiring posttransplant support for primary graft dysfunction (PGD). The use of ECLS is associated with acceptable outcomes in well-selected patients. While outcomes with the use of extracorporeal membrane oxygenation (ECMO) as a bridge to heart transplant have been variable, several series have confirmed the safe use of ECLS to stabilize patients prior to left ventricular assist device (LVAD) implantation. These patients are then considered later, when in stable condition, for heart transplant. When ECLS is used prior to heart transplant, mortality is greatest during the first 6 months posttransplant. Patients who are alive 6 months after transplant appear to have similar survival rates as patients who were not supported with ECLS prior to transplant. ECLS support is a reliable therapeutic option for severe PGD and early graft failure after heart transplantation. In patients who require support for severe PGD, venoarterial-ECMO appears to result in better clinical outcomes than LVAD support. ECLS use for PGD after heart transplant continues to be the first line of support. Further studies are necessary to understand the optimal role of ECLS in heart transplantation. PMID- 29152499 TI - Integrating surgery and genetic testing for the modern surgeon. AB - The field of cancer genetics is rapidly evolving and several genetic mutations have been identified in hereditary cancer syndromes. These mutations can be diagnosed via routine genetic testing allowing prompt intervention. This is especially true for certain variants of colorectal, breast, and thyroid cancers where genetic testing may guide surgical therapy. Ultimately, surgical intervention may drastically diminish disease manifestation or progression in individuals deemed as high-risk based on their genetic makeup. Understanding the concepts of gene-based testing and integrating into current surgical practice is crucial. This review addresses common genetic syndromes, tests, and interventions salient to the current surgeon. PMID- 29152500 TI - Application of 3D technology and printing for femoral derotation osteotomy: case and technical report. AB - In some surgical techniques like femoral derotation osteotomy, accuracy is a key factor that often is not optimal because of the lack of appropriate technology. 3D printing is emerging in many professional areas and its use in the medical field may enhance the results of certain surgeries. This case describes a patient who underwent an intramedullary nail fixation to treat a femoral shaft fracture. After nine months, the patient presented hip pain and "in toe" walking caused by a malrotation produced during the surgery. To address the consequent femoral derotation osteotomy, 3D technology was used throughout the whole process. A 3D model of the patient's femur was created to conduct a real and accuracy assessment of femoral anteversion. Then, a customized surgical guide was designed and printed to ensure the proper alignment during surgery. Given the success of this surgery, 3D printing can be considered a quick and inexpensive tool to improve surgical results. PMID- 29152501 TI - Myocardial bridging with left ventricular hypertrophy presenting as Wellens pattern. AB - The course of epicardial coronary arteries into a muscular tunnel under a bridge of myocardium is known as myocardial bridging (MB). This could be a benign anomaly, nevertheless, it could have a great impact on the quality of life in the setting of severe anginal symptoms. The clinical presentation and diagnosis could be challenging in those patients. The treatment options start from simple medical therapy to surgical intervention in refractory cases, the role of percutaneous coronary intervention (PCI) is limited in MB. We are describing a case of severe MB presenting as Wellens pattern with underlying left ventricular hypertrophy (LVH). PMID- 29152502 TI - Target-specific deep brain stimulation of the ventral capsule/ventral striatum for the treatment of neuropsychiatric disease. AB - Deep brain stimulation (DBS) is a well-established therapy for Parkinson's disease and other movement disorders. An accumulating body of evidence supports the extension of DBS application for the treatment of refractory psychiatric disorders. The ventral capsule/ventral striatum (VC/VS) is the most common anatomical target for obsessive-compulsive disorder (OCD), addiction, and depression. However, no specific electrode is available for the clinical targeting of these areas for DBS. According to the anatomical features of the VC/VS, a novel electrode was developed for simultaneous and independently programmed stimulation of the nucleus accumbens (NAc) and the anterior limb of the internal capsule (ALIC). This VC/VS-specific electrode has the potential to enhance stimulus intensity, provide independent and flexible target stimulation. PMID- 29152503 TI - Nomogram for survival analysis in the presence of competing risks. AB - Clinical research usually involves time-to-event survival analysis, in which the presence of a competing event is prevalent. It is acceptable to use the conventional Cox proportional hazard regression to model cause-specific hazard. However, this cause-specific hazard cannot directly translate to the cumulative incidence function, and the latter is usually clinically relevant. The subdistribution hazard regression directly quantifies the impact of covariates on the cumulative incidence. When estimating the subdistribution hazard, subjects experiencing competing event continue to contribute to the risk set, and censoring weights are assigned to them after the competing event time. The weights are the conditional probability that a subject remains uncensored, and can be modelled to depend on the covariates of a subject. The first option to perform regression on the subdistribution hazard was the crr() function in the cmprsk package. However, it is not straightforward to draw a nomogram, which is a user-friendly tool for risk prediction, with the crr() function. To overcome this problem, we show an alternative method to use a nomogram function based on result of subdistribution hazard modeling. PMID- 29152504 TI - Hypertension highlights during 2016. PMID- 29152505 TI - Reduction in dietary sodium improves blood pressure and reduces cardiovascular events and mortality. PMID- 29152506 TI - Selecting high-risk individuals for lung cancer screening; the use of risk prediction models vs. simplified eligibility criteria. PMID- 29152507 TI - Editorial on "Genesis on diamonds II: contact with diamond enhances human sperm performance by 300%". PMID- 29152508 TI - Challenges of interpreting patient reported outcomes from clinical trials. PMID- 29152509 TI - Of diamond surfaces, red light photobiomodulation and fertility: lessons from the laboratory. PMID- 29152510 TI - An interesting approach for the diagnosis of hepatic fibrosis: Wang et al., "A combined use of intravoxel incoherent motion MRI parameters can differentiate early-stage hepatitis-b fibrotic livers from healthy livers". PMID- 29152511 TI - Treatment recommendations for stage I non-small cell lung cancer: does patient preference matter? PMID- 29152512 TI - Balanced crystalloids for the critically ill: knowledge on the rise but confusion still reigns! PMID- 29152513 TI - Potential benefits of large database analysis. PMID- 29152514 TI - Open thoracoabdominal aortic aneurysm repair in expert hands: "all roads lead to Rome". PMID- 29152515 TI - Should copyright be transferred before a manuscript is accepted? AB - Academic journals that undergo a process of academic scrutiny often pass a stage of peer review and subsequent editorial approval. In a process that can take weeks or months (in some cases, even years), an author aims to satisfy the requirements of peer reviewer and editorial scrutiny that would merit publication of their work. It is customary to, in traditional, non-open access journals, to then sign over copyright to the publisher, upon which the publisher then issues a proof, and the manuscript is then published. Even though it is obvious that an author would not submit to a journal with the objective of having it rejected, the issue of the timing of copyright transfer is one which does not appear to have been discussed in the literature, possibly because the order of transfer, i.e., after acceptance of a paper for publication, seems naturally logical. With the modernization of online submission systems, the transfer of copyright tends to occur online, after acceptance. However, on occasion, some journals request the transfer of copyright before peer review and editorial processing occurs, i.e., upon the act of submission. This letter examines three cases of Springer Nature plant science journals that demand the transfer of copyright to the journal's society upon submission, in direct violation of their instructions for authors. Authors have no right to challenge this discrepancy, nor can they complete submission in accordance with the instructions for authors because they are forced to submit copyright upon submission. Not only does transfer of copyright at such an early stage of the publishing process constitute a waste of authors' time-a precious commodity in a cut-throat field of science-in the three cases indicated in this paper, they may constitute a violation of authors' rights. The ethics of this request by the journals and publisher need to be debated. PMID- 29152516 TI - How do I write a scientific article?-A personal perspective. AB - Scientific writing is not an easy task. Although there is no single and universally agreed strategy for assembling a successful scientific article, it is undeniable that some basic notions, gathered after decades of experience, may help increasing the chance of acceptance of a scientific manuscript. Therefore, the purpose of this article is to present a personal and arbitrary perspective on how to write a scientific article, entailing a tentative flowchart and a checklist describing the most important aspects characterizing each section of the manuscript. The final suggestion, which can be summarized in one simple and straightforward concept, is that you should always remember that a scientific article is meant to be read by others (i.e., referees and readers) and not by yourself. PMID- 29152517 TI - On the article "prospective study of quality of life after lung cancer resection". PMID- 29152518 TI - Follow-up in patients with a burn-related emergency department visit: a feasibility study. AB - Background: Data on epidemiology, costs, and outcomes of burn-related injuries presenting at emergency departments (EDs) are scarce. To obtain such information, a questionnaire study with an adequate response rate is imperative. There is evidence that optimized strategies can increase patient participation. However, it is unclear whether this applies to burn patients in an ED setting. The objective of this feasibility study was to optimize and evaluate patient recruitment strategy and follow-up methods in patients with burn injuries presenting at EDs. Methods: In a prospective cohort study with a 6-month follow up, patients with burn-related injuries attending two large EDs during a 3-month study period were included. Eligible patients were quasi-randomly allocated to a standard or optimized recruitment strategy by week of the ED visit. The standard recruitment strategy consisted of an invitation letter to participate, an informed consent form, a questionnaire, and a franked return envelope. The optimized recruitment strategy was complemented by a stamped returned envelope, monetary incentive, sending a second copy of the questionnaire, and a reminder by telephone in non-responders. Response rates were calculated, and questionnaires were used to assess treatment, costs, and health-related quality of life. Results: A total of 87 patients were included of which 85 were eligible for the follow-up study. There was a higher response rate at 2 months in the optimized versus the standard recruitment strategy (43.6% vs. 20.0%; OR = 3.1 (95% CI 1.1 8.8)), although overall response is low. Non-response analyses showed no significant differences in patient, burn injury or treatment characteristics between responders versus non-responders. Conclusions: This study demonstrated that response rates can be increased with an optimized, but more labor-intensive recruitment strategy, although further optimization of recruitment and follow-up is needed. It is feasible to assess epidemiology, treatment, and costs after burn related ED contacts. PMID- 29152519 TI - Primary Carcinosarcoma of the Pancreas With CD10-Positive Sarcoma Component. AB - Carcinosarcomas of the pancreas are rare entities with a dismal prognosis. We report a rare case of pancreatic carcinosarcoma in a 49-year-old African American female who underwent a total abdominal hysterectomy with right salpingo oophorectomy and exploration of the pancreatic mass. The surgery revealed a sclerotic mass in the body and tail of the pancreas that was surgically unresectable, and a pancreatic biopsy confirmed the pathology of pancreatic carcinosarcoma. Histologically, the lesion showed a high-grade spindle cell sarcoma and adjacent moderately differentiated adenocarcinoma. On immunohistochemical examination, the carcinomatous component was positive for epithelial markers, and the sarcomatous component was focally positive for SMA and desmin. In addition, the sarcomatous component showed diffuse immunoreactivity for CD10 with a surrounding myofibroblastic proliferation. Reports have associated expression of CD10 in pancreatic stellate cells with increased tumor aggressiveness. In this article, we report a case of pancreatic carcinosarcoma that shows sarcomatous CD10 immunoexpression with higher Ki67 labeling in the sarcoma than the carcinoma raising the question if the sarcomatous component could be potentiating the aggressiveness of the carcinomatous component. PMID- 29152520 TI - A Case of Escherichia coli Hemolytic Uremic Syndrome in a 10-Year-Old Male With Severe Neurologic Involvement Successfully Treated With Eculizumab. AB - Hemolytic uremic syndrome (HUS) can be classified as typical and atypical, and the treatment recommendations currently differ between the 2 types. Eculizumab is recommended as first-line treatment for atypical HUS; however, its use in typical HUS has been controversial. We report a case of a 10-year-old male with severe neurologic impairment who was successfully treated with eculizumab, which was started 4 days after onset of neurologic symptoms. Our case supports the use of eculizumab in typical HUS with neurologic involvement, even when given later in the course, as the pathophysiology of typical HUS has been shown to involve activation of the complement pathway, similar to atypical HUS. Further studies are required to establish the efficacy and duration of eculizumab use in this patient population. PMID- 29152521 TI - Isokinetic Strength Deficit 6 Months After Adductor Canal Blockade for Anterior Cruciate Ligament Reconstruction. AB - Background: Recent evidence shows a delayed return to sport in children and delayed quadriceps recovery in both adults and children who have undergone anterior cruciate ligament (ACL) reconstruction with concomitant femoral nerve blockade (FNB) compared with those who had no blockade. We evaluated the use of adductor canal blockade (ACB), as an alternative to FNB, at the time of ACL reconstruction. Hypothesis: Patients who receive ACB will have greater isokinetic strength at 6 months postoperative compared with patients who receive FNB at the time of ACL reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective record review was performed at a single academic medical center to identify all patients aged >=16 years who had undergone ACL reconstruction with blockade between January 2010 and January 2015. Exclusion criteria included (1) non-sports medicine fellowship-trained surgeon performing the procedure, (2) continuous nerve catheter or concurrent epidural used, (3) revision ACL reconstruction or multiligament reconstruction as the index procedure, (4) previous contralateral ACL reconstruction, (5) concurrent microfracture, and (6) additional surgery within the 6-month outcome period that affected recovery. Isokinetic strength testing was performed using a computerized dynamometer, measuring total work at fast speed and peak torque at slow speed at 6 months; results were evaluated as a percentage of the nonoperative side. Multivariate regression analysis was used to evaluate the effect of block type on isokinetic strength outcome variables, controlling for age, sex, body mass index, graft type, and surgeon. Results: There were 230 patients receiving FNB and 30 patients receiving ACB included in the study. The multivariate regression analysis identified a greater side-to-side deficit in extension total work for the ACB group compared with the FNB group (P = .040), after controlling for age, sex, body mass index, graft type, and surgeon. Conclusion: Compared with FNB, ACB for ACL reconstruction is associated with a persistent fast-activation isokinetic strength deficit at 6 months after surgery. This is the first study to compare FNB to ACB, and results are concerning for patients planning an early return to sport. PMID- 29152522 TI - Bone-Patellar Tendon-Bone Versus Hamstring Tendon Autografts for Primary Anterior Cruciate Ligament Reconstruction: A Systematic Review of Overlapping Meta analyses. AB - Background: Previous meta-analyses have compared bone-patellar tendon-bone (BPTB) with hamstring tendon (HT) autografts for primary anterior cruciate ligament reconstruction (ACLR). Purpose: To conduct a systematic review of overlapping meta-analyses comparing BPTB with HT autografts for ACLR to determine which meta analyses provide the best available evidence. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review was performed by searching the PubMed and Cochrane Library databases. Search words included "anterior cruciate ligament" AND "patellar tendon" AND "hamstring tendon" AND "meta-analysis." Results were reviewed to determine study eligibility. Patient outcomes and postoperative complications were extracted from the included meta-analyses. Meta analysis quality was assessed using the Oxman-Guyatt and Quality of Reporting of Meta-analyses (QUOROM) scores. The Jadad decision algorithm was then utilized to determine which meta-analyses provided the best level of evidence. Results: Sixteen meta-analyses containing an average of 1396 patients met the eligibility criteria. Most studies found BPTB autografts to provide superior stability but more postoperative complications, such as anterior knee pain and kneeling pain. Studies by Gabler et al (2016), Mohtadi et al (2011), and Xie et al (2015) received the highest Oxman-Guyatt and QUOROM scores, and therefore, these meta analyses proved to provide the highest level of evidence. Additionally, Xie et al was selected as the highest-quality study in this systematic review based on the Jadad decision algorithm. Conclusion: The current best evidence suggests that ACLR with BPTB autografts provides superior static knee stability and that there are fewer postoperative complications in ACLR with HT autografts. PMID- 29152524 TI - Young Adult Perceptions Surrounding Hookah Use. AB - Objective: We aimed to improve understanding of young adults' perceptions and interpretations of the contexts surrounding use. Methods: We conducted focus groups with young adult hookah users (ages 18-28) to examine hookah-use experiences and risk perceptions. Results: Two dominant themes that emerged from the discussions were the social aspects of use (eg, "ending up" at a hookah cafe while out with friends), and the mental and physiological reactions to use (eg, relaxation and a "high" feeling). Participants often argued that because they only used hookah every few weeks, hookah use was much less dangerous than cigarette use. Conclusions: Findings suggest that hookah research should account for heuristic processing and point to several areas where better health communication and stricter regulatory policies are needed. PMID- 29152525 TI - Do you what I say? People reconstruct the syntax of anomalous utterances. AB - We frequently experience and successfully process anomalous utterances. Here we examine whether people do this by 'correcting' syntactic anomalies to yield well formed representations. In two structural priming experiments, participants' syntactic choices in picture description were influenced as strongly by previously comprehended anomalous (missing-verb) prime sentences as by well formed prime sentences. Our results suggest that comprehenders can reconstruct the constituent structure of anomalous utterances - even when such utterances lack a major structural component such as the verb. These results also imply that structural alignment in dialogue is unaffected if one interlocutor produces anomalous utterances. PMID- 29152526 TI - Building Classification Models with Combined Biomarker Tests: Application to Early Detection of Liver Cancer. AB - Early detection of hepatocellular carcinoma (HCC) is critical for the effective treatment. Alpha fetoprotein (AFP) serum level is currently used for HCC screening, but the cutoff of the AFP test has limited sensitivity (~50%), indicating a high false negative rate. We have successfully demonstrated that cancer derived DNA biomarkers can be detected in urine of patients with cancer and can be used for the early detection of cancer (Jain et al., 2015; Lin et al., 2011; Song et al., 2012; Su, Lin, Song, & Jain, 2014; Su, Wang, Norton, Brenner, & Block, 2008). By combining urine biomarkers (uBMK) values and serum AFP (sAFP) level, a new classification model has been proposed for more efficient HCC screening. Several criterions have been discussed to optimal the cutoff for uBMK score and sAFP score. A joint distribution of sAFP and uBMK with point mass has been fitted using maximum likelihood method. Numerical results show that the sAFP data and uBMK data are very well described by proposed model. A tree-structured sequential test can be optimized by selecting the cutoffs. Bootstrap simulations also show the robust classification results with the optimal cutoff. PMID- 29152527 TI - Novel LRPPRC Mutation in a Boy With Mild Leigh Syndrome, French-Canadian Type Outside of Quebec. AB - Background: Leigh syndrome, French-Canadian type is unique to patients from a genetic isolate in the Saguenay-Lac-Saint-Jean region of Quebec. It has also been recently described in 10 patients with LRPPRC mutation outside of Quebec. It is an autosomal recessive genetic disorder with fatal metabolic crisis and severe neurological morbidity in infancy caused by LRPPRC mutation. Methods and Results: The authors report a boy with a novel LRPPRC compound heterozygous missense mutations c.3130C>T, c.3430C>T, and c.4078G>A found on whole-exome sequencing which correlated with isolated cytochrome c-oxidase deficiency found in skeletal muscle. Conclusion: LRPPRC mutation is a rare cause of cytochrome c-oxidase deficient form of Leigh syndrome outside of Quebec. Our patient broadens the spectrum of phenotypes of Leigh syndrome, French-Canadian type. LRPPRC mutation should be considered in children with early childhood neurodegenerative disorder, even in the absence of metabolic crisis. Early evaluation with whole-exome sequencing is useful for early diagnosis and for genetic counseling. PMID- 29152523 TI - Workshops of the Sixth International Brain-Computer Interface Meeting: brain computer interfaces past, present, and future. AB - The Sixth International Brain-Computer Interface (BCI) Meeting was held 30 May-3 June 2016 at the Asilomar Conference Grounds, Pacific Grove, California, USA. The conference included 28 workshops covering topics in BCI and brain-machine interface research. Topics included BCI for specific populations or applications, advancing BCI research through use of specific signals or technological advances, and translational and commercial issues to bring both implanted and non-invasive BCIs to market. BCI research is growing and expanding in the breadth of its applications, the depth of knowledge it can produce, and the practical benefit it can provide both for those with physical impairments and the general public. Here we provide summaries of each workshop, illustrating the breadth and depth of BCI research and highlighting important issues and calls for action to support future research and development. PMID- 29152528 TI - X-Linked Lissencephaly With Absent Corpus Callosum and Abnormal Genitalia: An Evolving Multisystem Syndrome With Severe Congenital Intestinal Diarrhea Disease. AB - X-linked lissencephaly with abnormal genitalia is a rare and devastating syndrome. The authors present an infant with a multisystem phenotype where the intestinal manifestations were as life limiting as the central nervous system features. Severe chronic diarrhea resulted in failure to thrive, dehydration, electrolyte derangements, long-term hospitalization, and prompted transition to palliative care. Other multisystem manifestations included megacolon, colitis, pancreatic insufficiency hypothalamic dysfunction, hypothyroidism, and hypophosphatasia. A novel aristaless-related homeobox gene mutation, c.1136G>T/p.R379L, was identified. This case contributes to the clinical, histological, and molecular understanding of the multisystem nature of this disorder, especially the role of ARX in the development of the enteroendocrine system. PMID- 29152529 TI - Special Section Guest Editorial: Publisher's Note: Functional Near Infrared Spectroscopy, Part 2. AB - This article introduces the second part of the Neurophotonics Special Section on Functional Near Infrared Spectroscopy. PMID- 29152530 TI - Neurofeedback-induced facilitation of the supplementary motor area affects postural stability. AB - Near-infrared spectroscopy-mediated neurofeedback (NIRS-NFB) is a promising therapeutic intervention for patients with neurological diseases. Studies have shown that NIRS-NFB can facilitate task-related cortical activation and induce task-specific behavioral changes. These findings indicate that the effect of neuromodulation depends on local cortical function. However, when the target cortical region has multiple functions, our understanding of the effects is less clear. This is true in the supplementary motor area (SMA), which is involved both in postural control and upper-limb movement. To address this issue, we investigated the facilitatory effect of NIRS SMA neurofeedback on cortical activity and behavior, without any specific task. Twenty healthy individuals participated in real and sham neurofeedback. Balance and hand dexterity were assessed before and after each NIRS-NFB session. We found a significant interaction between assessment periods (pre/post) and condition (real/sham) with respect to balance as assessed by the center of the pressure path length but not for hand dexterity as assessed by the 9-hole peg test. SMA activity only increased during real neurofeedback. Our findings indicate that NIRS-NFB itself has the potential to modulate focal cortical activation, and we suggest that it be considered a therapy to facilitate the SMA for patients with postural impairment. PMID- 29152531 TI - Erratum: Publisher's note: Restoring vision in mice with retinal degeneration using multicharacteristic opsin. AB - [This corrects the article DOI: 10.1117/1.NPh.4.4.041412.]. PMID- 29152532 TI - H-scan sensitivity to scattering size. AB - In the H-scan analysis and display, visualization of different scattering sizes and types is enabled by a matched filter approach involving different orders of Gaussian weighted Hermite functions. An important question with respect to clinical applications involves the change in H-scan outputs with respect to small changes in scatterer sizes. The sensitivity of H-scan outputs is analyzed using the theory of backscatter from a compressible sphere. Experimental corroboration is established using mono dispersed spherical scatterers in phantoms. With a 6 MHz center frequency broadband transducer, it is possible to visualize changes in scattering size in the order of 10 to [Formula: see text] in phantoms and also changes in ex vivo bovine liver tissue due to edema caused by hypotonic perfusion. PMID- 29152533 TI - Automatic psoriasis lesion segmentation in two-dimensional skin images using multiscale superpixel clustering. AB - Psoriasis is a chronic skin disease that is assessed visually by dermatologists. The Psoriasis Area and Severity Index (PASI) is the current gold standard used to measure lesion severity by evaluating four parameters, namely, area, erythema, scaliness, and thickness. In this context, psoriasis skin lesion segmentation is required as the basis for PASI scoring. An automatic lesion segmentation method by leveraging multiscale superpixels and [Formula: see text]-means clustering is outlined. Specifically, we apply a superpixel segmentation strategy on CIE [Formula: see text] color space using different scales. Also, we suppress the superpixels that belong to nonskin areas. Once similar regions on different scales are obtained, the [Formula: see text]-means algorithm is used to cluster each superpixel scale separately into normal and lesion skin areas. Features from both [Formula: see text] and [Formula: see text] color bands are used in the clustering process. Furthermore, majority voting is performed to fuse the segmentation results from different scales to obtain the final output. The proposed method is extensively evaluated on a set of 457 psoriasis digital images, acquired from the Royal Melbourne Hospital, Melbourne, Australia. Experimental results have shown evidence that the method is very effective and efficient, even when applied to images containing hairy skin and diverse lesion size, shape, and severity. It has also been ascertained that CIE-[Formula: see text] outperforms other color spaces for psoriasis lesion analysis and segmentation. In addition, we use three evaluation metrics, namely, Dice coefficient, Jaccard index, and pixel accuracy where scores of 0.783%, 0.698%, and 86.99% have been achieved by the proposed method for the three metrics, respectively. Finally, compared with existing methods that employ either skin decomposition and support vector machine classifier or Euclidean distance in the hue-chrome plane, our multiscale superpixel-based method achieves markedly better performance with at least 20% accuracy enhancement. PMID- 29152534 TI - Automated mediastinal lymph node detection from CT volumes based on intensity targeted radial structure tensor analysis. AB - This paper presents a local intensity structure analysis based on an intensity targeted radial structure tensor (ITRST) and the blob-like structure enhancement filter based on it (ITRST filter) for the mediastinal lymph node detection algorithm from chest computed tomography (CT) volumes. Although the filter based on radial structure tensor analysis (RST filter) based on conventional RST analysis can be utilized to detect lymph nodes, some lymph nodes adjacent to regions with extremely high or low intensities cannot be detected. Therefore, we propose the ITRST filter, which integrates the prior knowledge on detection target intensity range into the RST filter. Our lymph node detection algorithm consists of two steps: (1) obtaining candidate regions using the ITRST filter and (2) removing false positives (FPs) using the support vector machine classifier. We evaluated lymph node detection performance of the ITRST filter on 47 contrast enhanced chest CT volumes and compared it with the RST and Hessian filters. The detection rate of the ITRST filter was 84.2% with 9.1 FPs/volume for lymph nodes whose short axis was at least 10 mm, which outperformed the RST and Hessian filters. PMID- 29152535 TI - Time zero determination for FEL pump-probe studies based on ultrafast melting of bismuth. AB - A common challenge for pump-probe studies of structural dynamics at X-ray free electron lasers (XFELs) is the determination of time zero (T0)-the time an optical pulse (e.g., an optical laser) arrives coincidently with the probe pulse (e.g., a XFEL pulse) at the sample position. In some cases, T0 might be extracted from the structural dynamics of the sample's observed response itself, but generally, an independent robust method is required or would be superior to the inferred determination of T0. In this paper, we present how the structural dynamics in ultrafast melting of bismuth can be exploited for a quickly performed, reliable and accurate determination of T0 with a precision below 20 fs and an overall experimental accuracy of 50 fs to 150 fs (estimated). Our approach is potentially useful and applicable for fixed-target XFEL experiments, such as serial femtosecond crystallography, utilizing an optical pump pulse in the ultraviolet to near infrared spectral range and a pixelated 2D photon detector for recording crystallographic diffraction patterns in transmission geometry. In comparison to many other suitable approaches, our method is fairly independent of the pumping wavelength (UV-IR) as well as of the X-ray energy and offers a favorable signal contrast. The technique is exploitable not only for the determination of temporal characteristics of the experiment at the interaction point but also for investigating important conditions affecting experimental control such as spatial overlap and beam spot sizes. PMID- 29152537 TI - Halfhearted Action and Control. AB - Some of the things we do intentionally we do halfheartedly. I develop and defend an account of halfheartedness with respect to action on which one is halfhearted with respect to an action A if one's overall motivation to A is weak. This requires getting clear on what it is to have some level of overall motivation with respect to an action, and on what it means to say one's overall motivation is weak or strong. After developing this account, I defend the claim that one key functional expression of halfhearted action is the possession of impaired control over the action in question. Finally, I elucidate a puzzle that sometimes arises with respect to halfhearted action. The puzzle arises when an agent's commitment in acting conflicts with an agent's acceptance of poor performance. PMID- 29152536 TI - Breast Cancer Symptom Clusters Derived from Social Media and Research Study Data Using Improved K-Medoid Clustering. AB - Most cancer patients, including patients with breast cancer, experience multiple symptoms simultaneously while receiving active treatment. Some symptoms tend to occur together and may be related, such as hot flashes and night sweats. Co occurring symptoms may have a multiplicative effect on patients' functioning, mental health, and quality of life. Symptom clusters in the context of oncology were originally described as groups of three or more related symptoms. Some authors have suggested symptom clusters may have practical applications, such as the formulation of more effective therapeutic interventions that address the combined effects of symptoms rather than treating each symptom separately. Most studies that have sought to identify clusters in breast cancer survivors have relied on traditional research studies. Social media, such as online health related forums, contain a bevy of user-generated content in the form of threads and posts, and could be used as a data source to identify and characterize symptom clusters among cancer patients. The present study seeks to determine patterns of symptom clusters in breast cancer survivors derived from both social media and research study data using improved K-Medoid clustering. A total of 50,426 publicly available messages were collected from Medhelp.com and 653 questionnaires were collected as part of a research study. The network of symptoms built from social media was sparse compared to that of the research study data, making the social media data easier to partition. The proposed revised K-Medoid clustering helps to improve the clustering performance by re assigning some of the negative-ASW (average silhouette width) symptoms to other clusters after initial K-Medoid clustering. This retains an overall non decreasing ASW and avoids the problem of trapping in local optima. The overall ASW, individual ASW, and improved interpretation of the final clustering solution suggest improvement. The clustering results suggest that some symptom clusters are consistent across social media data and clinical data, such as gastrointestinal (GI) related symptoms, menopausal symptoms, mood-change symptoms, cognitive impairment and pain-related symptoms. We recommend an integrative approach taking advantage of both data sources. Social media data could provide context for the interpretation of clustering results derived from research study data, while research study data could compensate for the risk of lower precision and recall found using social media data. PMID- 29152538 TI - Isolation of Primary Human Skeletal Muscle Cells. AB - Primary myoblast culture is a valuable tool in research of muscle disease, pathophysiology, and pharmacology. This protocol describes techniques for dissociation of cells from human skeletal muscle biopsies and enrichment for a highly myogenic population by fluorescence-activated cell sorting (FACS). We also describe methods for assessing myogenicity and population expansion for subsequent in vitro study. PMID- 29152539 TI - Early mobilizing and dangling of the lower leg after one-stage reconstruction of Achilles tendon and overlying tissue defect using an anterolateral thigh flap with vascularized fascia lata. AB - We have treated two patients who had an Achilles tendon and overlying tissue defect using an anterolateral thigh flap with fascia lata. Postoperatively, skeletal suspension of the affected leg and intra-arterial heparin infusion were performed for seven days. Six weeks postoperatively, the patients could walk again. PMID- 29152540 TI - If You Build It, Who Will Come? A Description of User Characteristics and Experiences With the McMaster Optimal Aging Portal. AB - Objectives: The McMaster Optimal Aging Portal (the Portal) aims to increase access to evidence-based health information. We would now like to understand who uses the Portal, why, and for what, and elicit feedback and suggestions for future initiatives. Methods: An online survey of users collected data on demographics, eHealth literacy, Internet use, information-seeking behavior, site acceptability and perceived impact on health behaviors, participant satisfaction, and suggestions for improvements using mixed methods. Results: Participants (n = 163, age 69.8 +/- 8.6 years) were predominantly female (76%), married (67%), retired (80%), and well-educated with very good/excellent health (55%). The Portal was easy to use (83%) and relevant (80%), with 68% intending to, and 48% having changed behavior after using the Portal. A number of suggestions for improvement were obtained. Discussion: A better understanding of users' characteristics, needs, and preferences will allow us to improve content, target groups who are not engaging with the Portal, and plan future directions. PMID- 29152541 TI - Missing the Mark? A Two Time Point Cohort Study Estimating Intestinal Parasite Prevalence in Informal Settlements in Lima, Peru. AB - Objectives: The World Health Organization's (WHO) recommendations list Peru as potentially needing prevention of soil-transmitted helminthiasis (STH). Prevalence of STH varies regionally and remains understudied in the newest informal settlements of the capital city, Lima. The purpose of this study was to evaluate the need for Mass Drug Administration (MDA) of antiparasitic drugs in the newest informal settlements of Lima. The aim of this study was to estimate the season-specific prevalence of STH to determine if these prevalence estimates met the WHO threshold for MDA in 3 informal settlements. Methods: A 2 time point cohort study was conducted among a sample of 140 children aged 1 to 10 years living in 3 purposively sampled informal settlements of Lima, Peru. Children were asked to provide 2 stool samples that were analyzed with the spontaneous sedimentation in tube technique. The season-specific prevalence proportions of MDA-targeted STH were estimated using a hidden (latent) Markov modeling approach to adjust for repeated measurements over the 2 seasons and the imperfect validity of the screening tests. Results: The prevalence of MDA targeted STH was low at 2.2% (95% confidence interval = 0.3% to 6%) and 3.8% (95% confidence interval = 0.7% to 9.3%) among children sampled in the summer and winter months, respectively, when using the most conservative estimate of test sensitivity. These estimates were below the WHO threshold for MDA (20%). Conclusions: Empiric treatment for STH by organizations active in the newest informal settlements is not supported by the data and could contribute to unnecessary medication exposures and poor allocation of resources. PMID- 29152542 TI - Prescribing Outdoor Physical Activity to Children: Health Care Providers' Perspectives. AB - Little evidence exists on health care provider (HCP) prescriptions for children's outdoor physical activity (PA). Semistructured interviews were conducted with 15 children's HCPs to explore perspectives on outdoor PA prescription programs for children and barriers to implementation. Thematic analytic techniques were used to analyze the data. Most participants reported an awareness of health benefits to children being in the outdoors. Ten themes emerged from the data related to 3 thematic categories: (1) current strategies that HCPs are using to promote PA among children, (2) barriers that HCPs see to prescribing outdoor PA, and (3) potential strategies for promoting outdoor PA among children. Assessment of the local outdoor PA environment and resource development must be done prior to a prescription program. HCPs should be skilled in conducting conversations and setting goals related to outdoor PA tailored to the patient. Developing a system for follow-up with patients on established goals should also be included. PMID- 29152543 TI - Disease Knowledge, Illness Perceptions, and Quality of Life in Adolescents With Sickle Cell Disease: Is There a Link? AB - Disease knowledge, illness perceptions, and quality of life (QOL) were examined in 150 adolescents (mean age = 16.1 years, SD = 1.9; 49.3% males) with sickle cell disease (SCD). Females had higher knowledge (P = .004), lower QOL (P = .02), and perceived their illness to be more unpredictable (P = .03). Those with more severe disease perceived their illness to be unpredictable with worse outcomes. Those with higher knowledge scores perceived their illness to be chronic, made more sense of their illness, and perceived greater personal and treatment control. Final hierarchical regression model showed that secondary education as compared to primary education level (P < .001) was positively correlated whereas disease severity (P < .001), perceived unpredictability (P = .024), and negative emotions (P < .001) were negatively correlated with QOL. Health practitioners should assess adolescents' illness perceptions and encouraging continuing schooling and addressing emotional/psychological problems could improve their QOL. PMID- 29152544 TI - Determinants and Outcome of Metabolic Acidosis in Diarrheal Children Under 5 Years of Age in an Urban Critical Care Ward in Bangladesh. AB - We evaluated the independent determinants and outcome of metabolic acidosis in diarrheal children. Children under 5 years of age admitted with diarrhea and severe respiratory distress in the critical care ward at Dhaka Hospital of icddr,b (International Centre for Diarrhoeal Disease Research, Bangladesh) from April 2010 to April 2014 who had their reports of arterial blood gas analyses were enrolled in the study. We compared clinical and laboratory characteristics between the study children with (cases = 74) and without metabolic acidosis (controls = 65). Metabolic acidosis was defined if pH < 7.35 and HCO3 < 22 mmol/L in ABG. Cases had higher mortality (53% vs 29%, P = .01) compared to controls. After adjustment of potential confounders, for instance, hypokalemia and dehydration, the cases were independently associated with severe sepsis and raised serum creatinine (for both P < .05). Thus, early identification of these features of metabolic acidosis in diarrheal children may help clinicians to have prompt management that may further help reduce mortality in such children especially in resource-limited settings. PMID- 29152545 TI - Joint Reconstruction of Absorbed Optical Energy Density and Sound Speed Distributions in Photoacoustic Computed Tomography: A Numerical Investigation. AB - Photoacoustic computed tomography (PACT) is a rapidly emerging bioimaging modality that seeks to reconstruct an estimate of the absorbed optical energy density within an object. Conventional PACT image reconstruction methods assume a constant speed-of-sound (SOS), which can result in image artifacts when acoustic aberrations are significant. It has been demonstrated that incorporating knowledge of an object's SOS distribution into a PACT image reconstruction method can improve image quality. However, in many cases, the SOS distribution cannot be accurately and/or conveniently estimated prior to the PACT experiment. Because variations in the SOS distribution induce aberrations in the measured photoacoustic wavefields, certain information regarding an object's SOS distribution is encoded in the PACT measurement data. Based on this observation, a joint reconstruction (JR) problem has been proposed in which the SOS distribution is concurrently estimated along with the sought-after absorbed optical energy density from the photoacoustic measurement data. A broad understanding of the extent to which the JR problem can be accurately and reliably solved has not been reported. In this work, a series of numerical experiments is described that elucidate some important properties of the JR problem that pertain to its practical feasibility. To accomplish this, an optimization-based formulation of the JR problem is developed that yields a non linear iterative algorithm that alternatively updates the two image estimates. Heuristic analytic insights into the reconstruction problem are also provided. These results confirm the ill-conditioned nature of the joint reconstruction problem that will present significant challenges for practical applications. PMID- 29152546 TI - Advances in Behavioral Laboratory Methods that Inform Tobacco Regulatory Science: A TCORS Working Group Special Issue. AB - Objective: The 2009 Family Smoking Prevention and Tobacco Control Act (TCA) created unprecented enabling conditions for establishing national regulatory policy that reduces the burden of public health and societal problems associated with tobacco product use. The Center for Tobacco Products (CTP), created by the FDA to implement the TCA, developed a first-of-its-kind FDA/National Institutes of Health (NIH) collaborative program to fund Tobacco Centers of Regulatory Science (TCORS). Methods: To assist the TCORS with addressing research priorites, working groups (WGs) comprised of FDA-CTP liasions and TCORS investigators were formed. Under the direction of the Center for Evaluation and Coordination of Trainin and Research (CECTR), the TCORS WGs seek to develop tangible work products in their respective areas of focus. Results: The focus of the behavioral pharmacology WG evolved from publishing a narrow paper on behavioral methods in electronic cigarette research to a collection of papers on advances in behavioral laboratory methods that may inform tobacco regulatory science. Conclusion: This Special Issue contains articles that address all of the CTP research priorities and demonstrates how advances in behavioral laboratory methods made by TCORS investigators can inform FDA efforst to regulate tobacco products. PMID- 29152547 TI - Evidence of Atypical Recurrences After Robot-Assisted Radical Cystectomy: A Comprehensive Review of the Literature. AB - Robot-assisted radical cystectomy (RARC) has seen remarkable growth in the last decade. Despite a low level of evidence, numerous publications reporting on outcomes after RARC are now available. While definitive data on the long-term oncologic safety and efficacy of this technique are still lacking, similar oncological and functional outcomes compared to open radical cystectomy (ORC) have been reported. Several studies have also reported on atypical recurrences after RARC, including peritoneal carcinomatosis, extra-pelvic lymph node metastasis and port-site metastasis. While distant metastases overall do not appear to be affected by technique, it is possible that RARC may be associated with an increased risk of some atypical recurrences and this should be prospectively studied in RARC. However, atypical recurrences are rare events and are infrequent in their description. To date, there is no convincing evidence that, in the hands of equally experienced surgeons who treat bladder cancer routinely, a skillfully performed RARC is less oncologically efficacious than a skillfully performed ORC. PMID- 29152548 TI - Quantitative Assessment of Heterogeneity in Bladder Tumor MRI Diffusivity: Can Response be Predicted Prior to Neoadjuvant Chemotherapy? AB - Background: It is a critical unmet need to predict chemosensitivity in muscle invasive bladder cancer patients who receive neoadjuvant chemotherapy (NAC). Quantification of tumor heterogeneity has been shown to be useful in the assessment of therapeutic response. Apparent diffusion coefficient (ADC) is derived from diffusion weighted MRI (DWI) to quantify the water diffusivity which characterizes micro-cellularity in tumor tissues. Objective: The aim of this study is to assess if a quantitative measurement of ADC heterogeneity in bladder tumors can be a predictor of therapeutic response to NAC. Materials and Methods: Twenty patients with pT2 bladder cancer have been included in this study. Patient MRI was performed on a 3T system with DWI prior to NAC. Regions of interest (ROIs) were placed over the whole tumor volume on ADC maps to acquire a data matrix of voxel-wise ADC values for each patient. We performed histogram analysis on each ADC data matrix to calculate uniformity (U) and entropy (E). These quantities were subsequently correlated with the patient's response to chemotherapy. Statistical significance was found with P < 0.05. Results: Fifteen patients were categorized as responders, and five as non-responders. The data showed that tumors of responders were significantly higher in U (P = 0.01) and lower in E (P < 0.01) than non-responders. This finding indicates that resistant tumors were more heterogeneous in their spatial distribution of ADC values. While this difference in ADC heterogeneity was not always visually recognizable, it could be quantified by the data analytics. Conclusions: This study demonstrates that the quantitative readout of tumor heterogeneity in micro-cellularity is associated with the patient's defined response to chemotherapy. Quantification of tumor ADC heterogeneity may provide useful information to enable the prediction of chemotherapeutic response prior to the treatment to improve patient outcomes. PMID- 29152549 TI - Systematic Review and Meta-Analysis on the Efficacy of Chemotherapy with Transurethral Resection of Bladder Tumors as Definitive Therapy for Muscle Invasive Bladder Cancer. AB - Background: Bladder-sparing treatment of muscle invasive bladder cancer (MIBC) with systemic chemotherapy plus transurethral resection of bladder tumors (TURBT) is increasingly seen in the literature -both in case series and subanalyses of patients who opt out of or are unfit for radical cystectomy (RC). Survival outcomes among these patients are often impressive, but these are typically small retrospective studies from single institutions and therefore of limited clinical value. Objectives: Our aim is to summarize the literature regarding definitive treatment of MIBC with systemic chemotherapy plus TURBT and provide a meta analysis of survival outcomes for patients who received this treatment. Methods: A systematic literature search was performed consistent with the Prisma statement to identify publications reporting the outcomes of patients treated with TURBT and systemic chemotherapy as definitive treatment for locally confined MIBC. Identified studies were screened in a two-stage process: first by title and abstract; then by full-text reading. 18 publications (518 patients) were included in the qualitative systematic review and 10 publications (266 patients) were included in the meta-analysis. The primary objective was overall survival (OS). Results: Overall survival ranged from 20% to 87.5% across studies at median follow-up ranging 4 to 120 months. 5-year survival rate for all patients included in the meta-analysis was estimated to be 72% [95% CI: 64%, 82%]. Conclusions: Definitive treatment with systemic chemotherapy plus TURBT can lead to favorable survival outcomes in select patients. Further study to improve patient selection for this method of treatment is needed. PMID- 29152550 TI - Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer. AB - Background: Urothelial bladder cancer (UBC) is a highly prevalent disease in North America, however its optimal management remains elusive. The contribution of B cell associated responses is poorly understood in bladder cancer. Lymphoid neogenesis is a hallmark of an active immune response at tumor sites that sometimes leads to formation of tertiary lymphoid structures (TLS) that resemble germinal centers formed in secondary lymphoid organs. Objective: This study was conducted with an aim to investigate the presence and characteristics of TLS in UBC with a focus to compare and contrast the TLS formation in treatment naive low grade non-muscle invasive (NMIBC) and muscle invasive bladder cancers (MIBC). Methods: The study cohort consisted of transurethral bladder resection tumour (TURBT) specimens from 28 patients. Sections showing lymphoid aggregates in hematoxylin and eosin (H&E) stained TURBT specimens were further subjected to multi-color immunohistochemistry using immune cell markers specific to CD20+ B cells, CD3+ and CD8+ T cells, PNAd+ high endothelial venules, CD208+ mature dendritic cells, CD21+ follicular dendritic cells to confirm the hallmarks of classical germinal centers. Results: Our pilot study investigating the presence of TLS in bladder cancer patients is the first to demonstrate that well-formed TLS are more common in aggressive high grade MIBC tumors compared to low grade NIMBC. Conclusions: These novel findings suggest B cell mediated anti-tumour humoral immune responses in bladder cancer progression. PMID- 29152552 TI - Chemotherapy Versus Chemoradiation for Node-Positive Bladder Cancer: Practice Patterns and Outcomes from the National Cancer Data Base. AB - Background: Management of clinically node-positive bladder cancer (cN+ BC) is poorly defined; national guidelines recommend chemotherapy (CT) alone or chemoradiation (CRT). Objective: Using a large, contemporary dataset, we evaluated national practice patterns and outcomes of CT versus CRT to elucidate the optimal therapy for this patient population. Methods: The National Cancer Data Base (NCDB) was queried (2004-2013) for patients diagnosed with cTanyN1-3M0 BC. Patients were divided into two groups: CT alone or CRT. Statistics included multivariable logistic regression to determine factors predictive of receiving additional radiotherapy, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS. Propensity score matching was performed to assess groups in a balanced manner while reducing indication biases. Results: Of 1,783 total patients, 1,388 (77.8%) underwent CT alone, and 395 (22.2%) CRT. Although patients receiving CRT tended to be of higher socioeconomic status, they were more likely older (p = 0.053), higher T stage, N1 (versus N2) disease, squamous histology, and treated at a non academic center (p < 0.05). Median overall survival (OS) was 19.0 months and 13.8 months (p < 0.001) for patients receiving CRT or CT, respectively. On Cox multivariate analysis, receipt of CRT was independently associated with improved survival (p < 0.001). Outcome improvements with CRT persisted on evaluation of propensity-matched populations (p < 0.001). Conclusions: CRT is underutilized in the United States for cN+ BC but is independently associated with improved survival despite being preferentially administered to a somewhat higher-risk population. PMID- 29152551 TI - Bladder Cancer Recovery Pathways: A Systematic Review. AB - Background: Enhanced recovery pathways, also known as fast-track protocols, have been adopted since the early 2000s by various surgical specialties with the goal of improving patient outcomes and reducing the cost burden of major surgery on the health care system. Objective: To review the scientific literature on the origin of enhanced recovery pathways, track the contemporary utilization of such practices for patients undergoing radical cystectomy, and analyze the available data regarding their effect on morbidity, mortality, and treatment cost. Methods: A literature search of multiple electronic databases was undertaken. Manuscripts including patients undergoing radical cystectomy were chosen based on predefined criteria with an emphasis on randomized controlled trials and cohort studies. Strength of evidence for each study that met inclusion criteria was assessed based on the risk of bias, consistency, directness, and precision. Results: Database searches resulted in 1,236 potentially relevant articles. A total of 485 articles were selected for full-text dual review and 106 studies in 52 publications met the inclusion criteria. Conclusion: The utilization of enhanced recovery pathways with the goal of improving overall patient morbidity and mortality is well supported in the literature, however standardization of implementation and adherence across institutions is lacking, and their direct efficacy on reducing preventable treatment related expenditures is unconfirmed. PMID- 29152553 TI - Oncological Outcomes of Sequential Intravesical Gemcitabine and Docetaxel in Patients with Non-Muscle Invasive Bladder Cancer. AB - Background: Bacillus Calmette-Guerin (BCG) unresponsive/relapsing patients with non-muscle invasive bladder cancer (NMIBC) who prefer bladder preservation over radical cystectomy (RC) or those who do not qualify for surgery may be offered intravesical therapies. Gemcitabine (GEM) combined with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH). Objective: To evaluate experience with GEM/DOCE, to confirm safety of the regimen, to identify populations that may benefit most, and to consider the appropriate endpoints for judging efficacy of second line therapies. Methods: Thirty-three patients who received full induction GEM/DOCE since 2011, per the protocol adapted from U. Iowa, were identified and characterized. Multivariable logistic regression was used to determine factors associated with recurrence. Cox proportional hazard models evaluated risk factors for disease-free survival (DFS) and high-grade recurrence-free survival (HG-RFS). Results: There were no serious adverse effects of therapy. Across all patients, median follow-up time was 18.6 months with a median DFS of 6.5 months, 42% 1 year, and 24% 2-year DFS. Median HG-RFS was 17.1 months with 56% 1-year and 42% 2 year HG-RFS. Among patients initially presenting with HG-NMIBC, 46% (13/28) had HG recurrence. BCG unresponsive/relapsing patients (N = 25) displayed 49% 1-year HG-RFS and 34% 2-year HG-RFS. In total, there were 5 LG and 16 HG recurrences, with 5 progressions and 8 cystectomies among these. Conclusions: GEM/DOCE is a well-tolerated therapy that deserves further study as an alternative to immediate RC for highly selected patients with HG-NMIBC. BCG naive patients responded more effectively than BCG unresponsive/relapsing patients. As anticipated, GEM/DOCE efficacy was improved for HG only patients. PMID- 29152554 TI - Prevalence of Clostridium Difficile Infection in Patients After Radical Cystectomy and Neoadjuvant Chemotherapy. AB - Background and Objectives: Clostridium Difficile is the most common cause of nosocomial infectious diarrhea. This study evaluates the prevalence and predictors of Clostridium Difficile infections in patients undergoing radical cystectomy with or without neoadjuvant chemotherapy. Methods: Retrospective chart review was performed of all patients undergoing cystectomy and urinary diversion at a single institution from 2011-2017. Infection was documented in all cases with testing for Clostridium Difficile polymerase chain reaction toxin B. Patient and disease related factors were compared for those who received neoadjuvant chemotherapy vs. those who did not in order to identify potential risk factors associated with C. Difficile infections. Chi squared test and logistic regression analysis were used to determine statistical significance. Results: Of 350 patients who underwent cystectomy, 41 (11.7%) developed Clostridium Difficile in the 30 day post-operative period. The prevalence of C. Difficile infection was higher amongst the patients undergoing cystectomy compared to the non-cystectomy admissions at our hospital (11.7 vs. 2.9%). Incidence was not significantly different among those who underwent cystectomy for bladder cancer versus those who underwent the procedure for other reasons. Median time to diagnosis was 6 days (range 3-28 days). The prevalence of C. Diff infections was not significantly different among those who received neoadjuvant chemotherapy vs. those who did not (11% vs. 10.4% p = 0.72). A significant association between C. Difficile infection was not seen with proton pump inhibitor use (p = 0.48), patient BMI (p = 0.67), chemotherapeutic regimen (p = 0.94), individual surgeon (p = 0.54), type of urinary diversion (0.41), or peri-operative antibiotic redosing (p = 0.26). Conclusions: Clostridium Difficile infection has a higher prevalence in patients undergoing cystectomy. No significant association between prevalence and exposure to neoadjuvant chemotherapy was seen. PMID- 29152555 TI - Challenging Cases in Urothelial Cancer. PMID- 29152556 TI - Bladder Sparing Therapy for BCG Failures - I - Intravesical Immunotherapy. PMID- 29152557 TI - Clinical Trials Corner. PMID- 29152558 TI - Erratum: Author Correction: Using a smartphone-based self-management platform to support medication adherence and clinical consultation in Parkinson's disease. AB - [This corrects the article DOI: 10.1038/s41531-016-0003-z.]. PMID- 29152559 TI - Fasciola hepatica ESPs Could Indistinctly Activate or Block Multiple Toll-Like Receptors in a Human Monocyte Cell Line. AB - Fasciola hepatica is a parasitic helminth that induces Th2/Treg responses in its mammalian host. Some reports have suggested that ESPs achieve these polarized immune responses by delaying the activation of dendritic cells and macrophages during the early stages of innate immunity, a process that is mediated by TLR4. The present study aimed to investigate whether TLRs other than TLR4 could also be targeted by F. hepatica ESPs. To achieve this aim a screening system was optimized using THP1-Blue CD14 cells. ESPs were first separated based on their molecular weight and according their net charge by ion exchange chromatography (IEC). Results demonstrated that F. hepatica ESPs mainly cathepsin, serpin and endopin are capable of activating TLR2, TLR4, TLR8 and likely also TLR5 and TLR6. In contrast, fatty acid binding protein strongly suppressed the stimulation induced by various TLR-ligands. Further studies are needed to understand how these apparent contradictory effects of molecules of the same protein mix complement each other in the context of an active infection resulting in the polarized Th2-immune response that characterize F. hepatica infections. PMID- 29152561 TI - Targeted Modulation of Tropoelastin Structure and Assembly. AB - Tropoelastin, as the monomer unit of elastin, assembles into elastic fibers that impart strength and resilience to elastic tissues. Tropoelastin is also widely used to manufacture versatile materials with specific mechanical and biological properties. The assembly of tropoelastin into elastic fibers or biomaterials is crucially influenced by key submolecular regions and specific residues within these domains. In this work, we identify the functional contributions of two rarely occurring negatively charged residues, glutamate 345 in domain 19 and glutamate 414 in domain 21, in jointly maintaining the native conformation of the tropoelastin hinge, bridge and foot regions. Alanine substitution of E345 and/or E414 variably alters the positioning and interactive accessibility of these regions, as illustrated by nanostructural studies and detected by antibody and cell probes. These structural changes are associated with a lower propensity for monomer coacervation, cross-linking into morphologically and functionally atypical hydrogels, and markedly impaired and abnormal elastic fiber formation. Our work indicates the crucial significance of both E345 and E414 residues in modulating specific local structure and higher-order assembly of human tropoelastin. PMID- 29152562 TI - Fast Dissolving Dendrimer Nanofiber Mats as Alternative to Eye Drops for More Efficient Antiglaucoma Drug Delivery. AB - Polyamidoamine (PAMAM) dendrimers have been investigated as a potential platform for a number of ocular drugs, but only in aqueous solution. In this work we have developed fast dissolving dendrimer-based nanofibers (DNF) as a topical delivery vehicle for the glaucoma drug brimonidine tartrate (BT). The safety and drug release kinetics of these nanofiber mats were evaluated in vitro and in vivo. DNF caused no toxicity at therapeutic levels in cultured cells or ocular irritation in animal tests using a normotensive rat model. Intra-ocular pressure response was equivalent between DNF and BT solution in a single dose test, but DNF showed improved efficacy with daily dosing over a 3-week test period. This study indicates electrospun dendrimer nanofibers are a viable alternative to aqueous solutions as a more efficient method of administering antiglaucoma drug topically. PMID- 29152560 TI - Effects of Inflammation on Multiscale Biomechanical Properties of Cartilaginous Cells and Tissues. AB - Cells within cartilaginous tissues are mechanosensitive and thus require mechanical loading for regulation of tissue homeostasis and metabolism. Mechanical loading plays critical roles in cell differentiation, proliferation, biosynthesis, and homeostasis. Inflammation is an important event occurring during multiple processes, such as aging, injury, and disease. Inflammation has significant effects on biological processes as well as mechanical function of cells and tissues. These effects are highly dependent on cell/tissue type, timing, and magnitude. In this review, we summarize key findings pertaining to effects of inflammation on multiscale mechanical properties at subcellular, cellular, and tissue level in cartilaginous tissues, including alterations in mechanotransduction and mechanosensitivity. The emphasis is on articular cartilage and the intervertebral disc, which are impacted by inflammatory insults during degenerative conditions such as osteoarthritis, joint pain, and back pain. To recapitulate the pro-inflammatory cascades that occur in vivo, different inflammatory stimuli have been used for in vitro and in situ studies, including tumor necrosis factor (TNF), various interleukins (IL), and lipopolysaccharide (LPS). Therefore, this review will focus on the effects of these stimuli because they are the best studied pro-inflammatory cytokines in cartilaginous tissues. Understanding the current state of the field of inflammation and cell/tissue biomechanics may potentially identify future directions for novel and translational therapeutics with multiscale biomechanical considerations. PMID- 29152563 TI - Integrated radiomic framework for breast cancer and tumor biology using advanced machine learning and multiparametric MRI. AB - Radiomics deals with the high throughput extraction of quantitative textural information from radiological images that not visually perceivable by radiologists. However, the biological correlation between radiomic features and different tissues of interest has not been established. To that end, we present the radiomic feature mapping framework to generate radiomic MRI texture image representations called the radiomic feature maps (RFM) and correlate the RFMs with quantitative texture values, breast tissue biology using quantitative MRI and classify benign from malignant tumors. We tested our radiomic feature mapping framework on a retrospective cohort of 124 patients (26 benign and 98 malignant) who underwent multiparametric breast MR imaging at 3 T. The MRI parameters used were T1-weighted imaging, T2-weighted imaging, dynamic contrast enhanced MRI (DCE MRI) and diffusion weighted imaging (DWI). The RFMs were computed by convolving MRI images with statistical filters based on first order statistics and gray level co-occurrence matrix features. Malignant lesions demonstrated significantly higher entropy on both post contrast DCE-MRI (Benign-DCE entropy: 5.72 +/- 0.12, Malignant-DCE entropy: 6.29 +/- 0.06, p = 0.0002) and apparent diffusion coefficient (ADC) maps as compared to benign lesions (Benign-ADC entropy: 5.65 +/ 0.15, Malignant ADC entropy: 6.20 +/- 0.07, p = 0.002). There was no significant difference between glandular tissue entropy values in the two groups. Furthermore, the RFMs from DCE-MRI and DWI demonstrated significantly different RFM curves for benign and malignant lesions indicating their correlation to tumor vascular and cellular heterogeneity respectively. There were significant differences in the quantitative MRI metrics of ADC and perfusion. The multiview IsoSVM model classified benign and malignant breast tumors with sensitivity and specificity of 93 and 85%, respectively, with an AUC of 0.91. PMID- 29152564 TI - Authorship and contribution disclosures. AB - Most scientific research is performed by teams, and for a long time, observers have inferred individual team members' contributions by interpreting author order on published articles. In response to increasing concerns about this approach, journals are adopting policies that require the disclosure of individual authors' contributions. However, it is not clear whether and how these disclosures improve upon the conventional approach. Moreover, there is little evidence on how contribution statements are written and how they are used by readers. We begin to address these questions in two studies. Guided by a conceptual model, Study 1 examines the relationship between author order and contribution statements on more than 12,000 articles to understand what information is provided by each. This analysis quantifies the risk of error when inferring contributions from author order and shows how this risk increases with team size and for certain types of authors. At the same time, the analysis suggests that some components of the value of contributions are reflected in author order but not in currently used contribution statements. Complementing the bibliometric analysis, Study 2 analyzes survey data from more than 6000 corresponding authors to examine how contribution statements are written and used. This analysis highlights important differences between fields and between senior versus junior scientists, as well as strongly diverging views about the benefits and limitations of contribution statements. On the basis of both studies, we highlight important avenues for future research and consider implications for a broad range of stakeholders. PMID- 29152565 TI - Should coastal planners have concern over where land ice is melting? AB - There is a general consensus among Earth scientists that melting of land ice greatly contributes to sea-level rise (SLR) and that future warming will exacerbate the risks posed to human civilization. As land ice is lost to the oceans, both the Earth's gravitational and rotational potentials are perturbed, resulting in strong spatial patterns in SLR, termed sea-level fingerprints. We lack robust forecasting models for future ice changes, which diminishes our ability to use these fingerprints to accurately predict local sea-level (LSL) changes. We exploit an advanced mathematical property of adjoint systems and determine the exact gradient of sea-level fingerprints with respect to local variations in the ice thickness of all of the world's ice drainage systems. By exhaustively mapping these fingerprint gradients, we form a new diagnosis tool, henceforth referred to as gradient fingerprint mapping (GFM), that readily allows for improved assessments of future coastal inundation or emergence. We demonstrate that for Antarctica and Greenland, changes in the predictions of inundation at major port cities depend on the location of the drainage system. For example, in London, GFM shows LSL that is significantly affected by changes on the western part of the Greenland Ice Sheet (GrIS), whereas in New York, LSL change predictions are greatly sensitive to changes in the northeastern portions of the GrIS. We apply GFM to 293 major port cities to allow coastal planners to readily calculate LSL change as more reliable predictions of cryospheric mass changes become available. PMID- 29152566 TI - Radiocarbon chronology of Manot Cave, Israel and Upper Paleolithic dispersals. AB - The timing of archeological industries in the Levant is central for understanding the spread of modern humans with Upper Paleolithic traditions. We report a high resolution radiocarbon chronology for Early Upper Paleolithic industries (Early Ahmarian and Levantine Aurignacian) from the newly excavated site of Manot Cave, Israel. The dates confirm that the Early Ahmarian industry was present by 46,000 calibrated years before the present (cal BP), and the Levantine Aurignacian occurred at least between 38,000 and 34,000 cal BP. This timing is consistent with proposed migrations or technological diffusions between the Near East and Europe. Specifically, the Ahmarian could have led to the development of the Protoaurignacian in Europe, and the Aurignacian in Europe could have spread back to the Near East as the Levantine Aurignacian. PMID- 29152567 TI - Scanning wave photopolymerization enables dye-free alignment patterning of liquid crystals. AB - Hierarchical control of two-dimensional (2D) molecular alignment patterns over large areas is essential for designing high-functional organic materials and devices. However, even by the most powerful current methods, dye molecules that discolor and destabilize the materials need to be doped in, complicating the process. We present a dye-free alignment patterning technique, based on a scanning wave photopolymerization (SWaP) concept, that achieves a spatial light triggered mass flow to direct molecular order using scanning light to propagate the wavefront. This enables one to generate macroscopic, arbitrary 2D alignment patterns in a wide variety of optically transparent polymer films from various polymerizable mesogens with sufficiently high birefringence (>0.1) merely by single-step photopolymerization, without alignment layers or polarized light sources. A set of 150,000 arrays of a radial alignment pattern with a size of 27.4 MUm * 27.4 MUm were successfully inscribed by SWaP, in which each individual pattern is smaller by a factor of 104 than that achievable by conventional photoalignment methods. This dye-free inscription of microscopic, complex alignment patterns over large areas provides a new pathway for designing higher performance optical and mechanical devices. PMID- 29152568 TI - Moire excitons: From programmable quantum emitter arrays to spin-orbit-coupled artificial lattices. AB - Highly uniform and ordered nanodot arrays are crucial for high-performance quantum optoelectronics, including new semiconductor lasers and single-photon emitters, and for synthesizing artificial lattices of interacting quasiparticles toward quantum information processing and simulation of many-body physics. Van der Waals heterostructures of two-dimensional semiconductors are naturally endowed with an ordered nanoscale landscape, that is, the moire pattern that laterally modulates electronic and topographic structures. We find that these moire effects realize superstructures of nanodot confinements for long-lived interlayer excitons, which can be either electrically or strain tuned from perfect arrays of quantum emitters to excitonic superlattices with giant spin orbit coupling (SOC). Besides the wide-range tuning of emission wavelength, the electric field can also invert the spin optical selection rule of the emitter arrays. This unprecedented control arises from the gauge structure imprinted on exciton wave functions by the moire, which underlies the SOC when hopping couples nanodots into superlattices. We show that the moire hosts complex hopping honeycomb superlattices, where exciton bands feature a Dirac node and two Weyl nodes, connected by spin-momentum-locked topological edge modes. PMID- 29152569 TI - Vocalizing in chimpanzees is influenced by social-cognitive processes. AB - Adjusting communication to take into account information available to one's audience is routine in humans but is assumed absent in other animals, representing a recent development on the lineage leading to humans. This assumption may be premature. Recent studies show changes in primate alarm signaling to threats according to the receivers' risk. However, a classic problem in these and other perspective-taking studies is discerning whether signalers understand the receivers' mental states or simply are responding to their behavior. We designed experiments to exclude concurrent reading of the receivers' behavior by simulating receivers using prerecorded calls of other group members. Specifically, we tested whether wild chimpanzees emitted differing signals in response to a snake model when simulated receivers previously emitted either snake-related calls (indicating knowledge) or acoustically similar non-snake related calls (indicating ignorance). Signalers showed more vocal and nonvocal signaling and receiver-directed monitoring when simulated receivers had emitted non-snake-related calls. Results were not explained by signaler arousal nor by receiver identity. We conclude that chimpanzees are aware enough of another's perspective to target information toward ignorant group members, suggesting that the integration of signaling and social cognition systems was already emerging in early hominoid lineages before the advent of more language-specific features, such as syntax. PMID- 29152570 TI - The Mediterranean Overflow in the Gulf of Cadiz: A rugged journey. AB - The pathways and transformations of dense water overflows, which depend on small scale interactions between flow dynamics and erosional-depositional processes, are a central piece in the ocean's large-scale circulation. A novel, high resolution current and hydrographic data set highlights the intricate pathway travelled by the saline Mediterranean Overflow as it enters the Atlantic. Interaction with the topography constraints its spreading. Over the initial 200 km west of the Gibraltar gateway, distinct channels separate the initial gravity current into several plunging branches depth-sorted by density. Shallow branches follow the upper slope and eventually detach as buoyant plumes. Deeper branches occupy mid slope channels and coalesce upon reaching a diapiric ridge. A still deeper branch, guided by a lower channel wall marked by transverse furrows, experiences small-scale overflows which travel downslope to settle at mid-depths. The Mediterranean salt flux into the Atlantic has implications for the buoyancy balance in the North Atlantic. Observations on how this flux enters at different depth levels are key to accurately measuring and understanding the role of Mediterranean Outflow in future climate scenarios. PMID- 29152571 TI - Structural water as an essential comonomer in supramolecular polymerization. AB - Although the concept of structural water that is bound inside hydrophobic pockets and helps to stabilize protein structures is well established, water has rarely found a similar role in supramolecular polymers. Water is often used as a solvent for supramolecular polymerization, however without taking the role of a comonomer for the supramolecular polymer structure. We report a low-molecular weight monomer whose supramolecular polymerization is triggered by the incorporation of water. The presence of water molecules as comonomers is essential to the polymerization process. The supramolecular polymeric material exhibits strong adhesion to surfaces, such as glass and paper. It can be used as a water activated glue, which can be released at higher temperatures and reused many times without losing its performance. PMID- 29152573 TI - Self-organization of helium precipitates into elongated channels within metal nanolayers. AB - Material degradation due to precipitation of implanted helium (He) is a key concern in nuclear energy. Decades of research have mapped out the fate of He precipitates in metals, from nucleation and growth of equiaxed bubbles and voids to formation and bursting of surface blisters. By contrast, we show that He precipitates confined within nanoscale metal layers depart from their classical growth trajectories: They self-organize into elongated channels. These channels form via templated nucleation of He precipitates along layer surfaces followed by their growth and spontaneous coalescence into stable precipitate lines. The total line length and connectivity increases with the amount of implanted He, indicating that these channels ultimately interconnect into percolating "vascular" networks. Vascularized metal composites promise a transformative solution to He-induced damage by enabling in operando outgassing of He and other impurities while maintaining material integrity. PMID- 29152572 TI - A null mutation in SERPINE1 protects against biological aging in humans. AB - Plasminogen activator inhibitor-1 (PAI-1) has been shown to be a key component of the senescence-related secretome and a direct mediator of cellular senescence. In murine models of accelerated aging, genetic deficiency and targeted inhibition of PAI-1 protect against aging-like pathology and prolong life span. However, the role of PAI-1 in human longevity remains unclear. We hypothesized that a rare loss-of-function mutation in SERPINE1 (c.699_700dupTA), which encodes PAI-1, could play a role in longevity and metabolism in humans. We studied 177 members of the Berne Amish community, which included 43 carriers of the null SERPINE1 mutation. Heterozygosity was associated with significantly longer leukocyte telomere length, lower fasting insulin levels, and lower prevalence of diabetes mellitus. In the extended Amish kindred, carriers of the null SERPINE1 allele had a longer life span. Our study indicates a causal effect of PAI-1 on human longevity, which may be mediated by alterations in metabolism. Our findings demonstrate the utility of studying loss-of-function mutations in populations with geographic and genetic isolation and shed light on a novel therapeutic target for aging. PMID- 29152575 TI - Advances in neuroscience. PMID- 29152574 TI - Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) has caused human respiratory infections with a high case fatality rate since 2012. However, the mode of virus transmission is not well understood. The findings of epidemiological and virological studies prompted us to hypothesize that the human gastrointestinal tract could serve as an alternative route to acquire MERS-CoV infection. We demonstrated that human primary intestinal epithelial cells, small intestine explants, and intestinal organoids were highly susceptible to MERS-CoV and can sustain robust viral replication. We also identified the evidence of enteric MERS-CoV infection in the stool specimen of a clinical patient. MERS-CoV was considerably resistant to fed-state gastrointestinal fluids but less tolerant to highly acidic fasted-state gastric fluid. In polarized Caco-2 cells cultured in Transwell inserts, apical MERS-CoV inoculation was more effective in establishing infection than basolateral inoculation. Notably, direct intragastric inoculation of MERS-CoV caused a lethal infection in human DPP4 transgenic mice. Histological examination revealed MERS-CoV enteric infection in all inoculated mice, as shown by the presence of virus-positive cells, progressive inflammation, and epithelial degeneration in small intestines, which were exaggerated in the mice pretreated with the proton pump inhibitor pantoprazole. With the progression of the enteric infection, inflammation, virus-positive cells, and live viruses emerged in the lung tissues, indicating the development of sequential respiratory infection. Taken together, these data suggest that the human intestinal tract may serve as an alternative infection route for MERS-CoV. PMID- 29152576 TI - Meningococcal Antigen Typing System (MATS)-Based Neisseria meningitidis Serogroup B Coverage Prediction for the MenB-4C Vaccine in the United States. AB - Neisseria meningitidis is the most common cause of bacterial meningitis in children and young adults worldwide. A 4-component vaccine against N. meningitidis serogroup B (MenB) disease (MenB-4C [Bexsero]; GSK) combining factor H binding protein (fHBP), neisserial heparin binding protein (NHBA), neisserial adhesin A (NadA), and PorA-containing outer membrane vesicles was recently approved for use in the United States and other countries worldwide. Because the public health impact of MenB-4C in the United States is unclear, we used the meningococcal antigen typing system (MATS) to assess the strain coverage in a panel of strains representative of serogroup B (NmB) disease in the United States. MATS data correlate with killing in the human complement serum bactericidal assay (hSBA) and predict the susceptibility of NmB strains to killing in the hSBA, the accepted correlate of protection for MenB-4C vaccine. A panel of 442 NmB United States clinical isolates (collected in 2000 to 2008) whose data were down weighted with respect to the Oregon outbreak was selected from the Active Bacterial Core Surveillance (ABCs; CDC, Atlanta, GA) laboratory. MATS results examined to determine strain coverage were linked to multilocus sequence typing and antigen sequence data. MATS predicted that 91% (95% confidence interval [CI95], 72% to 96%) of the NmB strains causing disease in the United States would be covered by the MenB-4C vaccine, with the estimated coverage ranging from 88% to 97% by year with no detectable temporal trend. More than half of the covered strains could be targeted by two or more antigens. NHBA conferred coverage to 83% (CI95, 45% to 93%) of the strains, followed by factor H binding protein (fHbp), which conferred coverage to 53% (CI95, 46% to 57%); PorA, which conferred coverage to 5.9%; and NadA, which conferred coverage to 2.5% (CI95, 1.1% to 5.2%). Two major clonal complexes (CC32 and CC41/44) had 99% strain coverage. The most frequent MATS phenotypes (39%) were fHbp and NHBA double positives. MATS predicts over 90% MenB-4C strain coverage in the United States, and the prediction is stable in time and consistent among bacterial genotypes. IMPORTANCE The meningococcal antigen typing system (MATS) is an enzyme linked immunosorbent assay (ELISA)-based system that assesses the levels of expression and immune reactivity of the three recombinant MenB-4C antigens and, in conjunction with PorA variable 2 (VR2) sequencing, provides an estimate of the susceptibility of NmB isolates to killing by MenB-4C-induced antibodies. MATS assays or similar antigen phenotype analyses assume importance under conditions in which analyses of vaccine coverage predictions are not feasible with existing strategies, including large efficacy trials or functional antibody screening of an exhaustive strain panel. MATS screening of a panel of NmB U.S. isolates (n = 442) predicts high MenB-4C vaccine coverage in the United States. PMID- 29152577 TI - Pseudomonas aeruginosa Contact-Dependent Growth Inhibition Plays Dual Role in Host-Pathogen Interactions. AB - Microorganisms exist in a diverse ecosystem and have evolved many different mechanisms for sensing and influencing the polymicrobial environment around them, utilizing both diffusible and contact-dependent signals. Contact-dependent growth inhibition (CDI) is one such communication system employed by Gram-negative bacteria. In addition to CDI mediation of growth inhibition, recent studies have demonstrated CDI-mediated control of communal behaviors such as biofilm formation. We postulated that CDI may therefore play an active role in host pathogen interactions, allowing invading strains to establish themselves at polymicrobial mucosal interfaces through competitive interactions while simultaneously facilitating pathogenic capabilities via CDI-mediated signaling. Here, we show that Pseudomonas aeruginosa produces two CDI systems capable of mediating competition under conditions of growth on a surface or in liquid. Furthermore, we demonstrated a novel role for these systems in contributing to virulence in acute infection models, likely via posttranscriptional regulation of beneficial behaviors. While we did not observe any role for the P. aeruginosa CDI systems in biofilm biogenesis, we did identify for the first time robust CDI mediated competition during interaction with a mammalian host using a model of chronic respiratory tract infection, as well as evidence that CDI expression is maintained in chronic lung infections. These findings reveal a previously unappreciated role for CDI in host-pathogen interactions and emphasize their importance during infection. IMPORTANCE How bacteria compete and communicate with each other is an increasingly recognized aspect of microbial pathogenesis with a major impact on disease outcomes. Gram-negative bacteria have recently been shown to employ a contact-dependent toxin-antitoxin system to achieve both competition and regulation of their physiology. Here, we show that this system is vital for virulence in acute infection as well as for establishment of chronic infection in the multidrug-resistant pathogen Pseudomonas aeruginosa. Greater understanding of the mechanisms underlying bacterial virulence and infection is important for the development of effective therapeutics in the era of increasing antimicrobial resistance. PMID- 29152578 TI - Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis. AB - Coronaviruses (CoVs) encode a mixture of highly conserved and novel genes, as well as genetic elements necessary for infection and pathogenesis, raising the possibility of common targets for attenuation and therapeutic design. In this study, we focused on highly conserved nonstructural protein 16 (NSP16), a viral 2'O-methyltransferase (2'O-MTase) that encodes critical functions in immune modulation and infection. Using reverse genetics, we disrupted a key motif in the conserved KDKE motif of Middle East respiratory syndrome CoV (MERS-CoV) NSP16 (D130A) and evaluated the effect on viral infection and pathogenesis. While the absence of 2'O-MTase activity had only a marginal impact on propagation and replication in Vero cells, dNSP16 mutant MERS-CoV demonstrated significant attenuation relative to the control both in primary human airway cell cultures and in vivo. Further examination indicated that dNSP16 mutant MERS-CoV had a type I interferon (IFN)-based attenuation and was partially restored in the absence of molecules of IFN-induced proteins with tetratricopeptide repeats. Importantly, the robust attenuation permitted the use of dNSP16 mutant MERS-CoV as a live attenuated vaccine platform protecting from a challenge with a mouse-adapted MERS CoV strain. These studies demonstrate the importance of the conserved 2'O-MTase activity for CoV pathogenesis and highlight NSP16 as a conserved universal target for rapid live attenuated vaccine design in an expanding CoV outbreak setting. IMPORTANCE Coronavirus (CoV) emergence in both humans and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of severe acute respiratory syndrome CoV (SARS-CoV), MERS-CoV, porcine epidemic diarrhea virus, and swine delta CoV in the 21st century. These studies describe an approach that effectively targets the highly conserved 2'O-MTase activity of CoVs for attenuation. With clear understanding of the IFN/IFIT (IFN-induced proteins with tetratricopeptide repeats)-based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform, as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-CoV functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2'O-MTase function across CoVs. PMID- 29152579 TI - Streptococcus pneumoniae TIGR4 Phase-Locked Opacity Variants Differ in Virulence Phenotypes. AB - Streptococcus pneumoniae (pneumococcus) is a leading human pathogen that can cause serious localized and invasive diseases. Pneumococci can undergo a spontaneous and reversible phase variation that is reflected in colony opacity and which allows the population to adapt to different host environments. Generally, transparent variants are adapted for nasopharyngeal colonization, whereas opaque variants are associated with invasive disease. In recent work, colony phase variation was shown to occur by means of recombination events to generate multiple alleles of the hsdS targeting domain of a DNA methylase complex, which mediates epigenetic changes in gene expression. A panel of isogenic strains were created in the well-studied S. pneumoniae TIGR4 background that are "locked" in the transparent (n = 4) or opaque (n = 2) colony phenotype. The strains had significant differences in colony size which were stable over multiple passages in vitro and in vivo. While there were no significant differences in adherence for the phase-locked mutant strains to immortalized epithelial cells, biofilm formation and viability were reduced for the opaque variants in static assays. Nasopharyngeal colonization was stable for all strains, but the mortality rates differed between them. Transcript profiling by transcriptome sequencing (RNA-seq) analyses revealed that the expression levels of certain virulence factors were increased in a phase-specific manner. As epigenetic regulation of phase variation (often referred to as "phasevarion") is emerging as a common theme for mucosal pathogens, these results serve as a model for future studies of host-pathogen interactions. IMPORTANCE A growing number of bacterial species undergo epigenetic phase variation due to variable expression or specificity of DNA-modifying enzymes. For pneumococci, this phase variation has long been appreciated as being revealed by changes in colony opacity, which are reflected in changes in expression or accessibility of factors on the bacterial surface. Recent work showed that recombination-generated variation in alleles of the HsdS DNA methylase specificity subunit mediated pneumococcal phase variation. We generated phase-locked populations of S. pneumoniae TIGR4 expressing a single nonvariant hsdS allele and observed significant differences in gene expression and virulence. These results highlight the importance of focused pathogenesis studies within specific phase types. Moreover, the generation of single-allele hsdS constructs will greatly facilitate such studies. PMID- 29152580 TI - Chromosomal Targeting by the Type III-A CRISPR-Cas System Can Reshape Genomes in Staphylococcus aureus. AB - CRISPR-Cas (clustered regularly interspaced short palindromic repeat [CRISPR] CRISPR-associated protein [Cas]) systems can provide protection against invading genetic elements by using CRISPR RNAs (crRNAs) as a guide to locate and degrade the target DNA. CRISPR-Cas systems have been classified into two classes and five types according to the content of cas genes. Previous studies have indicated that CRISPR-Cas systems can avoid viral infection and block plasmid transfer. Here we show that chromosomal targeting by the Staphylococcus aureus type III-A CRISPR Cas system can drive large-scale genome deletion and alteration within integrated staphylococcal cassette chromosome mec (SCCmec). The targeting activity of the CRISPR-Cas system is associated with the complementarity between crRNAs and protospacers, and 10- to 13-nucleotide truncations of spacers partially block CRISPR attack and more than 13-nucleotide truncation can fully abolish targeting, suggesting that a minimal length is required to license cleavage. Avoiding base pairings in the upstream region of protospacers is also necessary for CRISPR targeting. Successive trinucleotide complementarity between the 5' tag of crRNAs and protospacers can disrupt targeting. Our findings reveal that type III-A CRISPR-Cas systems can modulate bacterial genome stability and may serve as a high-efficiency tool for deleting resistance or virulence genes in bacteria. IMPORTANCEStaphylococcus aureus is a pathogen that can cause a wide range of infections in humans. Studies have suggested that CRISPR-Cas systems can drive the loss of integrated mobile genetic elements (MGEs) by chromosomal targeting. Here we demonstrate that CRISPR-mediated cleavage contributes to the partial deletion of integrated SCCmec in methicillin-resistant S. aureus (MRSA), which provides a strategy for the treatment of MRSA infections. The spacer within artificial CRISPR arrays should contain more than 25 nucleotides for immunity, and consecutive trinucleotide pairings between a selected target and the 5' tag of crRNA can block targeting. These findings add to our understanding of the molecular mechanisms of the type III-A CRISPR-Cas system and provide a novel strategy for the exploitation of engineered CRISPR immunity against integrated MGEs in bacteria for clinical and industrial applications. PMID- 29152581 TI - The Candida albicans TOR-Activating GTPases Gtr1 and Rhb1 Coregulate Starvation Responses and Biofilm Formation. AB - Target of rapamycin complex 1 (TORC1) is an essential regulator of metabolism in eukaryotic cells and in the fungal pathogen Candida albicans regulates morphogenesis and nitrogen acquisition. Gtr1 encodes a highly conserved GTPase that in Saccharomyces cerevisiae regulates nitrogen sensing and TORC1 activation. Here, we characterize the role of C. albicans GTR1 in TORC1 activation and compare it with the previously characterized GTPase Rhb1. A homozygous gtr1/gtr1 mutant exhibited impaired TORC1-mediated phosphorylation of ribosomal protein S6 and increased susceptibility to rapamycin. Overexpression of GTR1 impaired nitrogen starvation-induced filamentous growth, MEP2 expression, and growth in bovine serum albumin as the sole nitrogen source. Both GTR1 and RHB1 were shown to regulate genes involved in ribosome biogenesis, amino acid biosynthesis, and expression of biofilm growth-induced genes. The rhb1/rhb1 mutant exhibited a different pattern of expression of Sko1-regulated genes and increased susceptibility to Congo red and calcofluor white. The homozygous gtr1/gtr1 mutant exhibited enhanced flocculation phenotypes and, similar to the rhb1/rhb1 mutant, exhibited enhanced biofilm formation on plastic surfaces. In summary, Gtr1 and Rhb1 link nutrient sensing and biofilm formation and this connectivity may have evolved to enhance the competitiveness of C. albicans in niches where there is intense competition with other microbes for space and nutrients. IMPORTANCECandida albicans is the major fungal pathogen of humans and is responsible for a wide range of infections, including life-threatening systemic infections in susceptible hosts. Target of rapamycin complex 1 (TORC1) is an essential regulator of metabolism in this fungus, and components of this complex are under increased investigation as targets for new antifungal drugs. The present study characterized the role of GTR1, encoding a putative GTPase, in TORC1 activation. This study shows that GTR1 encodes a protein required for activation of TORC1 activity in response to amino acids and regulation of nitrogen starvation responses. GTR1 mutants show increased cell-cell adhesion and biofilm formation and increased expression of genes involved in these processes. This study demonstrates that starvation responses and biofilm formation are coregulated by GTR1 and suggests that these responses are linked to compete with the microbiome for space and nutrients. PMID- 29152582 TI - The Genomic Landscape of the Fungus-Specific SWI/SNF Complex Subunit, Snf6, in Candida albicans. AB - SWI/SNF is an ATP-dependent chromatin-remodeling complex that is required for the regulation of gene expression in eukaryotes. While most of the fungal SWI/SNF components are evolutionarily conserved with those of the metazoan SWI/SNF, subunits such as Snf6 are specific to certain fungi and thus represent potential antifungal targets. We have characterized the role of the Snf6 protein in Candida albicans. Our data showed that although there was low conservation of its protein sequence with other fungal orthologs, Snf6 was copurified with bona fide SWI/SNF complex subunits. The role of Snf6 in C. albicans was investigated by determining its genome-wide occupancy using chromatin immunoprecipitation coupled to tiling arrays in addition to transcriptional profiling of the snf6 conditional mutant. Snf6 directs targets that were enriched in functions related to carbohydrate and amino acid metabolic circuits, to cellular transport, and to heat stress responses. Under hypha-promoting conditions, Snf6 expanded its set of targets to include promoters of genes related to respiration, ribosome biogenesis, mating, and vesicle transport. In accordance with the genomic occupancy data, an snf6 doxycycline-repressible mutant exhibited growth defects in response to heat stress and also when grown in the presence of different fermentable and nonfermentable carbon sources. Snf6 was also required to differentiate invasive hyphae in response to different cues. This study represents the first comprehensive characterization, at the genomic level, of the role of SWI/SNF in the pathogenic yeast C. albicans and uncovers functions that are essential for fungal morphogenesis and metabolic flexibility. IMPORTANCECandida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections in immunosuppressed patients. Current therapeutics include a limited number of molecules that suffer from limitations, including growing clinical resistance and toxicity. New molecules are being clinically investigated; however, the majority of these potential antifungals target the same processes as do the standard antifungals and might confront the same problems of toxicity and loss of efficiency due to the common resistance mechanisms. Here, we characterized the role of Snf6, a fungus-specific subunit of the chromatin-remodeling complex SWI/SNF. Our genomic and phenotypic data demonstrated a central role of Snf6 in biological processes that are critical for a fungal pathogen to colonize its host and cause disease, suggesting Snf6 as a possible antifungal target. PMID- 29152583 TI - Inhibition of Retrograde Transport Limits Polyomavirus Infection In Vivo. AB - Polyomaviruses (PyVs) silently infect most humans, but they can cause life threatening diseases in immunocompromised individuals. The JC polyomavirus (JCPyV) induces progressive multifocal leukoencephalopathy, a severe demyelinating disease in multiple sclerosis patients receiving immunomodulatory therapy, and BK polyomavirus (BKPyV)-associated nephropathy is a major cause of kidney allograft failure. No effective anti-PyV agents are available. Several compounds have been reported to possess anti-PyV activity in vitro, but none have shown efficacy in clinical trials. Productive PyV infection involves usurping the cellular retrograde vesicular transport pathway to enable endocytosed virions to navigate to the endoplasmic reticulum where virion uncoating begins. Compounds inhibiting this pathway have been shown to reduce infection by simian virus 40 (SV40), JCPyV, and BKPyV in tissue culture. In this study, we investigated the potential of Retro-2.1, a retrograde transport inhibitor, to limit infection by mouse polyomavirus (MuPyV) in vivo. We found that Retro-2.1 significantly reduced MuPyV levels in the kidney during acute infection without affecting renal function or the MuPyV-specific CD8 T cell response. To approximate the clinical setting of PyV resurgence in immunocompromised hosts, we showed that antibody mediated depletion of T cells in persistently infected mice elevated MuPyV levels in the kidney and that Retro-2.1 blunted this increase in virus levels. In summary, these data indicate that inhibition of retrograde vesicular transport in vivo controls infection in a natural PyV mouse model and supports development of these compounds as potential therapeutic agents for individuals at risk for human PyV-associated diseases. IMPORTANCE PyVs can cause significant morbidity and mortality in immunocompromised individuals. No clinically efficacious anti-PyV therapeutic agents are available. A recently identified inhibitor of retrograde transport, Retro-2cycl, blocks movement of PyV virion-containing vesicles from early endosomes to the endoplasmic reticulum, an early step in the PyV life cycle. Retro-2cycl and its derivatives have been shown to inhibit infection by human PyVs in tissue culture. Here, we demonstrate that a derivative of Retro 2cycl, Retro-2.1, reduces infection by MuPyV in the kidneys of acutely infected mice. Mimicking the common clinical scenario of PyV resurgence, we further show that MuPyV levels increase in the kidneys of immunocompromised, persistently infected mice and that this increase is inhibited by Retro-2.1. These data provide the first evidence for control of a natural PyV infection in vivo by administration of an inhibitor of retrograde transport. PMID- 29152584 TI - Large-Scale Bioinformatics Analysis of Bacillus Genomes Uncovers Conserved Roles of Natural Products in Bacterial Physiology. AB - Bacteria possess an amazing capacity to synthesize a diverse range of structurally complex, bioactive natural products known as specialized (or secondary) metabolites. Many of these specialized metabolites are used as clinical therapeutics, while others have important ecological roles in microbial communities. The biosynthetic gene clusters (BGCs) that generate these metabolites can be identified in bacterial genome sequences using their highly conserved genetic features. We analyzed an unprecedented 1,566 bacterial genomes from Bacillus species and identified nearly 20,000 BGCs. By comparing these BGCs to one another as well as a curated set of known specialized metabolite BGCs, we discovered that the majority of Bacillus natural products are comprised of a small set of highly conserved, well-distributed, known natural product compounds. Most of these metabolites have important roles influencing the physiology and development of Bacillus species. We identified, in addition to these characterized compounds, many unique, weakly conserved BGCs scattered across the genus that are predicted to encode unknown natural products. Many of these "singleton" BGCs appear to have been acquired via horizontal gene transfer. Based on this large-scale characterization of metabolite production in the Bacilli, we go on to connect the alkylpyrones, natural products that are highly conserved but previously biologically uncharacterized, to a role in Bacillus physiology: inhibiting spore development. IMPORTANCEBacilli are capable of producing a diverse array of specialized metabolites, many of which have gained attention for their roles as signals that affect bacterial physiology and development. Up to this point, however, the Bacillus genus's metabolic capacity has been underexplored. We undertook a deep genomic analysis of 1,566 Bacillus genomes to understand the full spectrum of metabolites that this bacterial group can make. We discovered that the majority of the specialized metabolites produced by Bacillus species are highly conserved, known compounds with important signaling roles in the physiology and development of this bacterium. Additionally, there is significant unique biosynthetic machinery distributed across the genus that might lead to new, unknown metabolites with diverse biological functions. Inspired by the findings of our genomic analysis, we speculate that the highly conserved alkylpyrones might have an important biological activity within this genus. We go on to validate this prediction by demonstrating that these natural products are developmental signals in Bacillus and act by inhibiting sporulation. PMID- 29152585 TI - Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling. AB - Cohabitation of microbial communities with the host enables the formation of a symbiotic relationship that maintains homeostasis in the gut and beyond. One prevailing model suggests that this relationship relies on the capacity of host cells and tissues to remain tolerant to the strong immune stimulation generated by the microbiota such as the activation of Toll-like receptor 4 (TLR4) pathways by lipopolysaccharide (LPS). Indeed, gut microbial LPS is thought to be one of the most potent activators of innate immune signaling and an important mediator of the microbiome's influence on host physiology. In this study, we performed computational and experimental analyses of healthy human fecal samples to examine the TLR4 signaling capacity of the gut microbiota. These analyses revealed that an immunoinhibitory activity of LPS, conserved across the members of the order Bacteroidales and derived from an underacylated structural feature, silences TLR4 signaling for the entire consortium of organisms inhabiting the human gut. Comparative analysis of metagenomic data from the Human Microbiome Project and healthy-donor samples indicates that immune silencing via LPS is a microbe intrinsic feature in all healthy adults. These findings challenge the current belief that robust TLR4 signaling is a feature of the microbiome and demonstrate that microbiome-derived LPS has the ability to facilitate host tolerance of gut microbes. These findings have broad implications for how we model host-microbe interactions and for our understanding of microbiome-linked disease. IMPORTANCE While the ability for humans to host a complex microbial ecosystem is an essential property of life, the mechanisms allowing for immune tolerance of such a large microbial load are not completely understood and are currently the focus of intense research. This study shows that an important proinflammatory pathway that is commonly triggered by pathogenic bacteria upon interaction with the host is, in fact, actively repressed by the bacteria of the gut microbiome, supporting the idea that beneficial microbes themselves contribute to the immune tolerance in support of homeostasis. These findings are important for two reasons. First, many currently assume that proinflammatory signaling by lipopolysaccharide is a fundamental feature of the gut flora. This assumption influences greatly how host microbiome interactions are theoretically modeled but also how they are experimentally studied, by using robust TLR signaling conditions to simulate commensals. Second, elucidation of the mechanisms that support host-microbe tolerance is key to the development of therapeutics for both intestinal and systemic inflammatory disorders. PMID- 29152586 TI - Genomic, Transcriptomic, and Phenotypic Analyses of Neisseria meningitidis Isolates from Disease Patients and Their Household Contacts. AB - Neisseria meningitidis (meningococcus) can cause meningococcal disease, a rapidly progressing and often fatal disease that can occur in previously healthy children. Meningococci are found in healthy carriers, where they reside in the nasopharynx as commensals. While carriage is relatively common, invasive disease, associated with hypervirulent strains, is a comparatively rare event. The basis of increased virulence in some strains is not well understood. New Zealand suffered a protracted meningococcal disease epidemic, from 1991 to 2008. During this time, a household carriage study was carried out in Auckland: household contacts of index meningococcal disease patients were swabbed for isolation of carriage strains. In many households, healthy carriers harbored strains identical, as determined by laboratory typing, to the ones infecting the associated patient. We carried out more-detailed analyses of carriage and disease isolates from a select number of households. We found that isolates, although indistinguishable by laboratory typing methods and likely closely related, had many differences. We identified multiple genome variants and transcriptional differences between isolates. These studies enabled the identification of two new phase-variable genes. We also found that several carriage strains had lost their type IV pili and that this loss correlated with reduced tumor necrosis factor alpha (TNF-alpha) expression when cultured with epithelial cells. While nonpiliated meningococcal isolates have been previously found in carriage strains, this is the first evidence of an association between type IV pili from meningococci and a proinflammatory epithelial response. We also identified potentially important metabolic differences between carriage and disease isolates, including the sulfate assimilation pathway. IMPORTANCENeisseria meningitidis causes meningococcal disease but is frequently carried in the throats of healthy individuals; the factors that determine whether invasive disease develops are not completely understood. We carried out detailed studies of isolates, collected from patients and their household contacts, to identify differences between commensal throat isolates and those that caused invasive disease. Though isolates were identical by laboratory typing methods, we uncovered many differences in their genomes, in gene expression, and in their interactions with host cells. In particular, we found that several carriage isolates had lost their type IV pili, a surprising finding since pili are often described as essential for colonization. However, loss of type IV pili correlated with reduced secretion of a proinflammatory cytokine, TNF-alpha, when meningococci were cocultured with human bronchial epithelial cells; hence, the loss of pili could provide an advantage to meningococci, by resulting in a dampened localized host immune response. PMID- 29152587 TI - A Synthetic Community System for Probing Microbial Interactions Driven by Exometabolites. AB - Though most microorganisms live within a community, we have modest knowledge about microbial interactions and their implications for community properties and ecosystem functions. To advance understanding of microbial interactions, we describe a straightforward synthetic community system that can be used to interrogate exometabolite interactions among microorganisms. The filter plate system (also known as the Transwell system) physically separates microbial populations, but allows for chemical interactions via a shared medium reservoir. Exometabolites, including small molecules, extracellular enzymes, and antibiotics, are assayed from the reservoir using sensitive mass spectrometry. Community member outcomes, such as growth, productivity, and gene regulation, can be determined using flow cytometry, biomass measurements, and transcript analyses, respectively. The synthetic community design allows for determination of the consequences of microbiome diversity for emergent community properties and for functional changes over time or after perturbation. Because it is versatile, scalable, and accessible, this synthetic community system has the potential to practically advance knowledge of microbial interactions that occur within both natural and artificial communities. IMPORTANCE Understanding microbial interactions is a fundamental objective in microbiology and ecology. The synthetic community system described here can set into motion a range of research to investigate how the diversity of a microbiome and interactions among its members impact its function, where function can be measured as exometabolites. The system allows for community exometabolite profiling to be coupled with genome mining, transcript analysis, and measurements of member productivity and population size. It can also facilitate discovery of natural products that are only produced within microbial consortia. Thus, this synthetic community system has utility to address fundamental questions about a diversity of possible microbial interactions that occur in both natural and engineered ecosystems. PMID- 29152588 TI - The Delivery Science Rapid Analysis Program: A Research and Operational Partnership at Kaiser Permanente Northern California. AB - Introduction: Health care researchers and delivery system leaders share a common mission to improve health care quality and outcomes. However, differing timelines, incentives, and priorities are often a barrier to research and operational partnerships. In addition, few funding mechanisms exist to generate and solicit analytic questions that are of interest to both research and to operations within health care settings, and provide rapid results that can be used to improve practice and outcomes. Methods: The Delivery Science Rapid Analysis Program (RAP) was formed in 2013 within the Kaiser Permanente Northern California Division of Research, sponsored by The Permanente Medical Group. A Steering Committee consisting of both researchers and clinical leaders solicits and reviews proposals for rapid analytic projects that will use existing data and are feasible within 6 months and with up to $30,000 (approximately 25-50% full time equivalent) of programmer/analyst effort. Review criteria include the importance of the analytic question for both research and operations, and the potential for the project to have a significant impact on care delivery within 12 months of completion. Results: The RAP funded 5 research and operational analytic projects between 2013 and 2017. These projects spanned a wide range of clinical areas, including lupus, pediatric obesity, diabetes, e-cigarette use, and hypertension. The hypertension RAP project, which focused on optimizing thiazide prescribing in Black/African-American patients with hypertension, led to new insights that inform an equitable care quality metric designed to reduce blood pressure control disparities throughout the KPNC region. Conclusions: Programs that actively encourage research and operational analytic partnerships have significant potential to improve care, enhance research collaborations, and contribute to the building and sustaining of learning health care systems. PMID- 29152589 TI - The Argentina Premature Asthma and Respiratory Team (APART): objectives, design, and recruitment results of a prospective cohort study of viruses and wheezing in very low birth weight infants. AB - Background: Asthma and wheezing account for a substantial disease burden around the world. Very low birth weight (VLBW, <1500 grams) infants are at an increased risk for the development of severe acute respiratory illness (ARI) and recurrent wheeze/asthma. The role of respiratory viruses in asthma predisposition in premature infants is not well understood. Preliminary evidence suggests that infection with human rhinovirus (RV) early in life may contribute to greater burden of asthma later in life. Methods: A prospective cohort study of premature VLBW infants from Buenos Aires, Argentina, was enrolled year-round during a three year period in the neonatal intensive care unit and followed during every ARI and with monthly well visits during the first year of life. Longitudinal follow-up up until age five years is ongoing. Results: This report describes the objectives, design, and recruitment results of this prospective cohort. Two hundred and five patients were enrolled from August 2011 through January 2014, and follow-up is ongoing. A total of 319 ARI episodes were observed from August 2011 to July 2014, and 910 well visits occurred during this time period. Conclusions: The Argentina Premature Asthma and Respiratory Team (APART) is a unique cohort consisting of over 200 patients and over 1200 specimens who have been and will continue to be followed intensively from NICU discharge to capture baseline risk factors and every ARI, with interceding well visits during the first year of life, as well as longitudinal follow-up to age 5 years for asthma and atopy outcomes. PMID- 29152590 TI - Introversion, the prevalent trait of adolescents with idiopathic scoliosis: an observational study. AB - Background: A large number of studies about adolescents with idiopathic scoliosis focus on health-related quality of life (HRQOL). However, only a few articles aim at evaluating the personality of these patients. Therefore, the purpose of the present research is to assess the personality traits of adolescents with idiopathic scoliosis and their relationship with HRQOL.Our hypothesis is that adolescents with idiopathic scoliosis present the principal personality trait of introversion, defined as self-reliance and inhibition in social relationships. Methods: This was a cross-sectional study. The examined group consisted of 43 patients (only 4 boys), mean age = 14.3 (SD = 2.23). On the day of the visit, HRQOL tools (Scoliosis Research Society-22 Questionnaire (SRS-22) and Trunk Appearance Perception Scale (TAPS)) and a personality test (16 Personality Factors-Adolescent Personality Questionnaire (16PF-APQ)) were completed; in addition, a posterior-anterior radiography was performed. Correlations among demographic and medical data and HRQOL and personality tests were assessed. Results: Results for SRS-22 were as follows: Function 4.5 (SD = .4), Pain 4.3 (SD = .5), Self-image 3.6 (SD = .7), Mental Health 3.8. (SD = .7), and Subtotal 4.2 (SD = .7). Mean TAPS was 3.5 (SD = .6).In personality, the lowest values were assessed for Extroversion (M = 29.4, SD = 24.7) and Self-reliance (M = 71, SD = 25.3).Independence was negatively related to Self-image (r = -.51), Mental Health (r = -.54), and Subtotal SRS-22 (r = -.60) (p < .01). Conclusions: Adolescents with idiopathic scoliosis presented a common style of personality, characterized by social inhibition (introversion), preference for staying alone, and being self sufficient (self-reliance).Specific programs in promoting social abilities may help adolescent patients with idiopathic scoliosis in finding a way to express themselves and to become more sociable. Correlational studies between personality and HRQOL need to be performed to better understand these issues. PMID- 29152591 TI - The idiosyncratic nature of confidence. AB - Confidence is the 'feeling of knowing' that accompanies decision making. Bayesian theory proposes that confidence is a function solely of the perceived probability of being correct. Empirical research has suggested, however, that different individuals may perform different computations to estimate confidence from uncertain evidence. To test this hypothesis, we collected confidence reports in a task where subjects made categorical decisions about the mean of a sequence. We found that for most individuals, confidence did indeed reflect the perceived probability of being correct. However, in approximately half of them, confidence also reflected a different probabilistic quantity: the perceived uncertainty in the estimated variable. We found that the contribution of both quantities was stable over weeks. We also observed that the influence of the perceived probability of being correct was stable across two tasks, one perceptual and one cognitive. Overall, our findings provide a computational interpretation of individual differences in human confidence. PMID- 29152592 TI - Revisiting the IGF-1R as a breast cancer target. AB - The type I insulin-like growth factor-1 receptor is a well-described target in breast cancer and multiple clinical trials examining insulin-like growth factor-1 receptor have been completed. Unfortunately, monoclonal antibodies and tyrosine kinase inhibitors targeting insulin-like growth factor-1 receptor failed in phase III breast clinical trials for several reasons. First, insulin-like growth factor 1 receptor antibody therapy resulted in hyperglycemia and metabolic syndrome most likely due to disruption of insulin-like growth factor-1 homeostasis and subsequent growth hormone elevation. Growth hormone elevation induces insulin resistance, hence a subsequent elevation of insulin and the potential for activation of insulin receptor. Second, the insulin-like growth factor-1 receptor and insulin receptor are highly homologous in amino acid sequence, structure, and function. These two receptors bind insulin, insulin-like growth factor-1 and insulin-like growth factor-2, to regulate glucose uptake and other cellular functions. Hybrid receptors composed of one chain of insulin-like growth factor-1 receptor and insulin receptor also participate in signaling. Third, since all the monoclonal antibodies were specific for insulin-like growth factor-1 receptor, any pathophysiologic role for insulin receptor was not inhibited. While the insulin-like growth factor-1 receptor tyrosine kinase inhibitors effectively inhibited both insulin-like growth factor-1 receptor and insulin receptor, these drugs are not being further developed likely due to their metabolic toxicities. Insulin-like growth factor-1/2 neutralizing antibodies are still being studied in early phase clinical trials. Perhaps a more comprehensive strategy of targeting the insulin-like growth factor-1 receptor network would be successful. For example, targeting receptor, ligand and downstream signaling molecules such as phosphatidylinositol 3'-kinase or particularly the insulin receptor substrate adapter proteins might result in a complete blockade of insulin-like growth factor-1 receptor/insulin receptor biological functions. PMID- 29152593 TI - Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma. AB - The advent of genomics has led to the identification of specific "driver" mutations in oncogenic kinases, and the development of targeted small molecule inhibitors to block their tumor-driving functions. These specific inhibitors have been a clinical success, and often significantly prolong the lives of individuals with cancer. Inevitably, however, the treated tumors recur as resistance to these targeted therapies develops. Here, we review the major mechanisms by which a cancer cell can evade targeted therapy, focusing on mechanisms of resistance to kinase inhibitors in lung cancer. We discuss the promising concept of rational upfront polytherapy in lung cancer, which involves concurrently targeting multiple proteins in critical signaling pathways in a cancer cell to prevent or delay resistance. PMID- 29152594 TI - " Blaming, shaming, humiliation": Stigmatising medical interactions among people with non-epileptic seizures. AB - Background: People with non-epileptic seizures (NES) describe challenging relationships with health professionals, and explain negative interactions as common and expected. Despite these difficulties, little is known about how people with NES experience difficult healthcare encounters. Methods: Using a thematic discourse analysis approach, we analysed the free-text survey responses of 135 people with NES and asked: what kind of challenges do people living with this condition encounter when interacting with health professionals, and how do they experience the consequences of difficult interactions? We explore their experiences by interpreting the latent meaning of participants' texts from a social-constructionist perspective on health and illness. Results: The overarching narrative depicts a fundamental breakdown in patient-provider relationships. According to our data, the negative experiences of study participants emerge from more than practitioners' lack of awareness of NES and access to information about the condition - to the extent that it is available. In examining the challenges people with NES encounter when interacting with health professionals, their main experiences centre on blame and humiliation. When exploring their experiences, theories of stigma serve as a useful theoretical framework. Conclusions: Normative judgements arising from psychogenic understandings of NES are stigmatising and restrict professional displays of respectful (patient-centred) care. Those with the condition depict being negatively stereotyped, illegitimated and held morally culpable by health professionals. Perceived to lack medical, moral and credible status, participants describe practitioners who treat them with disrespect, and some recount conduct that defies all ethical and professional obligations and standards. These encounters can have wide-ranging adverse consequences for patients: emotionally, physically, and for their future healthcare. The quality of healthcare interactions for people with NES requires urgent improvements. In addition to increased awareness of the condition, practitioners need to be conscious of making and acting on adverse moral appraisals when interacting with this patient group. PMID- 29152595 TI - Identification of Equid herpesvirus 2 in tissue-engineered equine tendon. AB - Background: Incidental findings of virus-like particles were identified following electron microscopy of tissue-engineered tendon constructs (TETC) derived from equine tenocytes. We set out to determine the nature of these particles, as there are few studies which identify virus in tendons per se, and their presence could have implications for tissue-engineering using allogenic grafts. Methods: Virus particles were identified in electron microscopy of TETCs. Virion morphology was used to initially hypothesise the virus identity. Next generation sequencing was implemented to identify the virus. A pan herpesvirus PCR was used to validate the RNASeq findings using an independent platform. Histological analysis and biochemical analysis was undertaken on the TETCs. Results: Morphological features suggested the virus to be either a retrovirus or herpesvirus. Subsequent next generation sequencing mapped reads to Equid herpesvirus 2 (EHV2). Histological examination and biochemical testing for collagen content revealed no significant differences between virally affected TETCs and non-affected TETCs. An independent set of equine superficial digital flexor tendon tissue (n=10) examined using designed primers for specific EHV2 contigs identified at sequencing were negative. These data suggest that EHV is resident in some equine tendon. Conclusions: EHV2 was demonstrated in equine tenocytes for the first time; likely from in vivo infection. The presence of EHV2 could have implications to both tissue-engineering and tendinopathy. PMID- 29152596 TI - Estimating the number of cases of podoconiosis in Ethiopia using geostatistical methods. AB - BACKGROUND: In 2011, the World Health Organization recognized podoconiosis as one of the neglected tropical diseases. Nonetheless, the number of people with podoconiosis and the geographical distribution of the disease is poorly understood. Based on a nationwide mapping survey and geostatistical modelling, we predict the prevalence of podoconiosis and estimate the number of cases across Ethiopia. METHODS: We used nationwide data collected in Ethiopia between 2008 and 2013. Data were available for 141,238 individuals from 1,442 villages in 775 districts from all nine regional states and two city administrations. We developed a geostatistical model of podoconiosis prevalence among adults (individuals aged 15 years or above), by combining environmental factors. The number of people with podoconiosis was then estimated using a gridded map of adult population density for 2015. RESULTS: Podoconiosis is endemic in 345 districts in Ethiopia: 144 in Oromia, 128 in Southern Nations, Nationalities and People's [SNNP], 64 in Amhara, 4 in Benishangul Gumuz, 4 in Tigray and 1 in Somali Regional State. Nationally, our estimates suggest that 1,537,963 adults (95% confidence intervals, 290,923-4,577,031 adults) were living with podoconiosis in 2015. Three regions (SNNP, Oromia and Amhara) contributed 99% of the cases. The highest proportion of individuals with podoconiosis resided in the SNNP (39%), while 32% and 29% of people with podoconiosis resided in Oromia and Amhara Regional States, respectively. Tigray and Benishangul Gumuz Regional States bore lower burdens, and in the remaining regions, podoconiosis was almost non-existent. Discussion: The estimates of podoconiosis cases presented here based upon the combination of currently available epidemiological data and a robust modelling approach clearly show that podoconiosis is highly endemic in Ethiopia. Given the presence of low cost prevention, and morbidity management and disability prevention services, it is our collective responsibility to scale-up interventions rapidly. PMID- 29152597 TI - Identification of Spiroplasmainsolitum symbionts in Anopheles gambiae. AB - Background: Insect symbionts have the potential to block the transmission of vector-borne diseases by their hosts. The advancement of a symbiont-based transmission blocking strategy for malaria requires the identification and study of Anopheles symbionts. Methods: High throughput 16S amplicon sequencing was used to profile the bacteria associated with Anopheles gambiae sensu lato and identify potential symbionts. The polymerase chain reaction (PCR) with specific primers were subsequently used to monitor symbiont prevalence in field populations, as well as symbiont transmission patterns. Results: We report the discovery of the bacterial symbiont, Spiroplasma, in Anopheles gambiae in Kenya. We determine that geographically dispersed Anopheles gambiae populations in Kenya are infected with Spiroplasma at low prevalence levels. Molecular phylogenetics indicates that this Anopheles gambiae associated Spiroplasma is a member of the insolitum clade. We demonstrate that this symbiont is stably maternally transmitted across at least two generations and does not significantly affect the fecundity or egg to adult survival of its host. Conclusions: In diverse insect species, Spiroplasma has been found to render their host resistant to infection by pathogens. The identification of a maternally transmitted strain of Spiroplasma in Anopheles gambiae may therefore open new lines of investigation for the development of symbiont-based strategies for blocking malaria transmission. PMID- 29152598 TI - Study protocol: A Randomized Controlled Trial of a Comprehensive Breast Cancer Treatment Patient Decision Tool (iCanDecide). AB - Background: Patients newly diagnosed with breast cancer face a series of complex decisions regarding locoregional and systemic treatment. There is a need to improve the quality of locoregional and systemic decisions for breast cancer patients, and to help patients understand the role of evaluative tests in this decision process. We are now conducting a randomized controlled trial (RCT) of an online decision tool-called iCanDecide, which we expect will help patients with these difficult decisions. Furthermore, the results of this RCT will be highly relevant to future breast cancer patients making these decisions and to their clinicians. Methods: This is a two-arm randomized controlled trial with the target of 222 participants per arm. Participants are recruited from 25 surgical practices (total 40 surgeons) and 2 medical oncology practices (total 2 oncologists) in Michigan, Georgia, Tennessee, and California. Participants are newly-diagnosed female breast cancer patients between 21 and 84 years, with stage I-II invasive breast cancer or ductal carcinoma in situ (DCIS) and who are eligible for and considering either mastectomy or lumpectomy with radiation, and who may be eligible for adjuvant systemic treatment.The RCT tests an interactive, tailored website, called iCanDecide (intervention arm), compared to a static version of the website (control arm). The static control arm is designed to include the same basic content as the intervention version, but without tailoring and interactive features. The primary outcome includes the rate of making a high quality decision. The hypothesis is that patients randomized to the interactive version of iCanDecide will have higher rates of high quality decisions (informed and values-concordant), and will appraise their decision-making process more positively, for both surgical and systemic treatment. Discussion: The goal of this study is to evaluate the impact of the iCanDecide interactive website on decision-making for locoregional and systemic breast cancer treatments. The results of this study will be important for future breast cancer patients and their clinicians as we determine how to better individualize decision making across this complex treatment landscape. PMID- 29152599 TI - A Novel clinical sign in Intraocular Tuberculosis: Active chorioretinitis within chorioretinal atrophy. AB - Purpose: To report a novel clinical sign in patients with intraocular tuberculosis. The current study is an observational consecutive case series of patients diagnosed with intraocular tuberculosis managed at a tertiary eye care centre from June 1, 2012 to December 31, 2015. Observations: The diagnosis of intraocular tuberculosis was made in 6 patients based on ocular features suggestive of tuberculosis along with a positive tuberculin skin testing and chest X-ray consistent with tuberculosis. All patients presented with decreased visual acuity ranging from 20/25 to 20/400, anterior chamber reaction, vitritis, multifocal choroiditis and vasculitis. All patients had an area of active chorioretinitis within the zone of pre-existing chorioretinal atrophy, apart from various other signs suggestive of intraocular inflammation. All patients were started on anti-tubercular therapy for a period of 9 months alone or in combination with oral corticosteroids tapered over 3-4 months. A prompt response to the treatment with resolution of chorioretinitis within the chorioretinal atrophy occurred in all patients. In addition, there was resolution of vitritis and improvement in the visual acuity ranging from 20/20 to 20/40 at last follow up. Conclusions and Importance: Active chorioretinitis within an area of chorioretinal atrophy is a novel clinical sign that may indicate intraocular tuberculosis. PMID- 29152600 TI - Role of epinephrine and extracorporeal membrane oxygenation in the management of ischemic refractory ventricular fibrillation: a randomized trial in pigs. AB - xtracorporeal membrane oxygenation (ECMO) is used in cardiopulmonary resuscitation (CPR) of refractory cardiac arrest. We used a 2*2 study design to compare ECMO versus CPR and epinephrine versus placebo in a porcine model of ischemic refractory ventricular fibrillation (VF). Pigs underwent 5 minutes of untreated VF, 10 minutes of CPR, and were randomized to receive epinephrine versus placebo for another 35 minutes. Animals were further randomized to LAD reperfusion at minute 45 with ongoing CPR versus veno-arterial ECMO cannulation at minute 45 of CPR and subsequent LAD reperfusion. Four-hour survival was improved with ECMO while epinephrine showed no effect. PMID- 29152601 TI - A novel approach to analyzing lung cancer mortality disparities: Using the exposome and a graph-theoretical toolchain. AB - Objectives: The aim is to identify exposures associated with lung cancer mortality and mortality disparities by race and gender using an exposome database coupled to a graph theoretical toolchain. Methods: Graph theoretical algorithms were employed to extract paracliques from correlation graphs using associations between 2162 environmental exposures and lung cancer mortality rates in 2067 counties, with clique doubling applied to compute an absolute threshold of significance. Factor analysis and multiple linear regressions then were used to analyze differences in exposures associated with lung cancer mortality and mortality disparities by race and gender. Results: While cigarette consumption was highly correlated with rates of lung cancer mortality for both white men and women, previously unidentified novel exposures were more closely associated with lung cancer mortality and mortality disparities for blacks, particularly black women. Conclusions: Exposures beyond smoking moderate lung cancer mortality and mortality disparities by race and gender. Policy Implications: An exposome approach and database coupled with scalable combinatorial analytics provides a powerful new approach for analyzing relationships between multiple environmental exposures, pathways and health outcomes. An assessment of multiple exposures is needed to appropriately translate research findings into environmental public health practice and policy. PMID- 29152602 TI - Shortened Penetratin Cell-Penetrating Peptide Is Insufficient for Cytosolic Delivery of a Grb7 Targeting Peptide. AB - Delivery across the cell membrane is of critical importance for the development of therapeutics targeting intracellular proteins. The use of cell-penetrating peptides (CPPs), such as Penetratin (P16), has facilitated the delivery of otherwise cell-impermeable molecules allowing them to carry out their biological function. A truncated form of Penetratin (RRMKWKK) has been previously described as the minimal Penetratin sequence that is required for translocation across the cell membrane. Here, we performed a detailed comparison of cellular uptake by Penetratin (P16) and the truncated Penetratin peptide (P7), including their ability to deliver G7-18NATE, a cyclic peptide targeting the cytosolic cancer target Grb7-adapter protein into cells. We identified that both P16 and P7 were internalized by cells to comparable levels; however, only P16 was effective in delivering G7-18NATE to produce a biological response. Live-cell imaging of fluorescein isothiocyanate-labeled peptides suggested that while P7 may be taken up into cells, it does not gain access to the cytosolic compartment. Thus, this study has identified that the P7 peptide is a poor CPP for the delivery of G7 18NATE and may also be insufficient for the intracellular delivery of other bioactive molecules. PMID- 29152603 TI - Investigation into the fungal diversity within different regions of the gastrointestinal tract of Panaque nigrolineatus, a wood-eating fish. AB - The Amazonian catfish, Panaque nigrolineatus have several physiological adaptions enabling the scraping and consumption of wood (xylivory), facilitating a detritivorous dietary strategy. Composed of lignocellulose, wood is a difficult substrate to degrade and as yet, it is unclear whether the fish obtains any direct nutritional benefits from wood ingestion and degradation. However, there are numerous systems that rely on microbial symbioses to provide energy and other nutritional benefits for host organisms via lignocellulose decomposition. While previous studies on the microbial community of P. nigrolineatus have focused upon the bacterial population, the role of fungi in lignocellulose degradation in the fish has not yet been examined. This study describes the detection of fungi within the fish gastrointestinal tract. Using next generation sequencing, the effects of diet on enteric fungal populations were examined in each gastrointestinal tract region. Fungal species were found to vary in different regions of the gastrointestinal tract as a function of diet. This study is the first to examine the fungal community in a xylivorous fish and results support the hypothesis that diet influences fungal distribution and diversity within the gastrointestinal tract of P. nigrolineatus. PMID- 29152604 TI - Crosstalk of LKB1- and PTEN-regulated signals in liver morphogenesis and tumor development. AB - : Liver kinase B 1 (LKB1 or STK11) and PTEN (phosphatase and tensin homologue deleted on chromosome 10) are two tumor suppressors that regulate the mTOR signaling pathway. Deletion studies show that loss of either Lkb1 (Lkb+/- ) or Pten (PtenloxP/loxP; Alb-Cre+ ) leads to liver injury and development of hepatocarcinoma. In this study, we investigated the crosstalk of LKB1 and PTEN loss during tumorigenesis and liver development. We show here that haplo insufficiency of Lkb1 in the liver leads to advanced tumor development in the Pten null mice (PtenloxP/loxP; LkbloxP/+; Alb-Cre+ ). Our analysis shows that LKB1 and PTEN interacted with each other in their regulation of fatty acid synthase as well as p21 expression. The combined loss of LKB1 and PTEN (PtenloxP/loxP; LkbloxP/loxP; Alb-Cre+ ) also led to the inability to form zonal structures in the liver. The lack of metabolic zonal structures is consistent with the inability of the livers to store glycogen as well as elevated plasma bilirubin and alanine aminotransferase (ALT), indicative of liver dysfunction. These structural and functional defects are associated with cytoplasm distribution of a canalicular membrane protein MRP2 (multidrug resistant protein 2) which is responsible for clearing bilirubin. This observed regulation of MRP2 by LKB1 likely contributed to the lack of cellular polarity and the early lethality phenotype associated with homozygous loss of Lkb1 alone or in combination with Pten. Finally, Pten deletion does not rescue the precocious ductal plate formation reported for Lkb1 deleted livers. CONCLUSION: Our study dissected the functional and molecular crosstalk of PTEN and LKB1 and elucidate key molecular targets for such interaction. PMID- 29152605 TI - Hepatic Natural Killer T-cell and CD8+ T-cell Signatures in Mice with Nonalcoholic Steatohepatitis. AB - : Hepatic inflammation is a key pathological feature of Nonalcoholic Steatohepatitis (NASH). Natural Killer T-cells (NKT) and CD8+ T-cells are known to play an important role in obesity related adipose tissue inflammation. We hypothesized that these same inflammatory phenotypes would be present in progressive NASH. We used a previously established high fat high carbohydrate (HFHC) murine obesogenic diet model of progressive NASH to investigate the role of NKT cells and CD8+ T-cells in C57Bl6/J mice. Further, to better understand the impact of these cell populations; CD1d-deficient and CD8+ T-cell depleted mice were subjected to HFHC diet for 16 weeks. C57Bl6/J mice fed HFHC diet had increased body weight, liver triglyceride content, serum alanine aminotransferase (ALT) levels and increased NKT cells and CD8+ T-cells infiltration in the liver. In addition human liver sections from patients with NASH showed increased CD8+ T cells. In comparison, CD1d-deficient and CD8-T cell depleted mice fed HFHC had lower hepatic triglyceride content, lower ALT levels, as well reduced alpha smooth muscle actin (alphaSMA), collagen type 1 alpha 1 (Col1a1), collagen type 1 alpha 2 (Col1a2) mRNA expression, lower activated resident macrophages and infiltrating macrophages and improved NAFLD activity scores. Further, while CD1d deficient mice were protected against weight gain on the HFHC diet, CD8 T-cell depleted mice gained weight on the HFHC diet. Conclusion: We found that NASH has an immunological signature that includes hepatic infiltrating NKT and CD8+ T Cells. Depletion of these cells resulted in reduced NASH progression and thus presents novel therapeutic avenues for the treatment of NASH. PMID- 29152606 TI - Ethanol-induced steatosis involves impairment of lipophagy, associated with reduced Dynamin2 activity. AB - Background: Lipid droplets (LDs), the organelles central to alcoholic steatosis, are broken down by lipophagy, a specialized form of autophagy. Here, we hypothesize that ethanol administration retards lipophagy by down-regulating Dynamin 2 (Dyn2), a protein that facilitates lysosome re-formation, contributing to hepatocellular steatosis. Methods: Primary hepatocytes were isolated from male Wistar rats fed Lieber-DeCarli control or EtOH liquid diets for 6-8 wk. Hepatocytes were incubated in complete medium (fed) or nutrient-free medium (fasting) with or without the Dyn2 inhibitor Dynasore or the Src inhibitor SU6656. Phosphorylated (active) forms of Src and Dyn2, and markers of autophagy were quantified by Western Blot. Co-localization of LDs-with autophagic machinery was determined by confocal microscopy. Results: In hepatocytes from pair-fed rats, LD breakdown was accelerated during fasting, as judged by smaller LDs and lower TG content when compared to hepatocytes in complete media. Fasting-induced TG loss in control hepatocytes was significantly blocked by either SU6656 or Dynasore. Compared to controls, hepatocytes from EtOH-fed rats had 66% and 40% lower content of pSrc and pDyn2, respectively, coupled with lower rate of fasting induced TG loss. This slower rate of fasting-induced TG loss was blocked in cells co-incubated with Dynasore. Microscopic examination of EtOH-fed rat hepatocytes revealed increased co-localization of the autophagosome marker LC3 on LDs with a concomitant decrease in lysosome marker LAMP1. Whole livers and LD fractions of EtOH-fed rats exhibited simultaneous increase in LC3II and p62 over that of controls, indicating a block in lipophagy. Conclusion: Chronic ethanol administration slowed the rate of hepatocyte lipophagy, owing in part to lower levels of phosphorylated Src kinase available to activate its substrate, Dyn2, thereby causing depletion of lysosomes for LD breakdown. PMID- 29152607 TI - Use of post-acute care after hospital discharge in urban and rural hospitals. AB - Objectives: Geographic variation in the use of post-acute care (PAC - skilled nursing facility and home health care) after hospital discharge is substantial, but reasons for this remain largely unexplored. PAC use in urban hospitals compared to rural hospitals may be one key contributor. We aimed to describe PAC use, explore substitution of one type of PAC for another, and identify how PAC use varies by diagnosis in urban and rural settings. Study Design: Secondary analysis of the 2012 National Inpatient Sample including adult discharges to PAC after a hospitalization. Methods: We adjusted for differences in patient demographics, comorbidities, hospital care provided, and hospital information, comparing use of PAC in urban and rural settings in multivariable logistic regression. Results: Rural patients discharged from rural hospitals constituted 188,137 (12.1%) of the 1.56 million discharges in the sample. Rural discharges received less home health care (0.85; 0.80-0.90) than urban discharges, resulting in less rural PAC use overall (0.95; 0.91-0.99). Rural discharges received more overall PAC for stroke (OR 1.11; 95% CI 1.03-1.19) and less PAC for sepsis (0.92; 0.86-0.98), hip fracture (0.82; 0.70-0.96), and elective joint arthroplasty, where rural discharges had 41% lower odds of receiving PAC (0.59; 0.49-0.71). Conclusions: The striking differences in receipt of post-acute care in urban and rural patients may constitute a disparity. Evaluation of costs and outcomes of PAC use in these settings is urgently needed as Medicare expands bundled payments for this care. PMID- 29152608 TI - Galectin-3 and Venous Thromboembolism Incidence: the Atherosclerosis Risk in Communities (ARIC) Study. AB - Background: The inflammatory biomarker galectin-3 contributes to pathologic conditions such as heart failure and stimulates murine thrombogenesis. Its association with venous thromboembolism (VTE) has been sparsely studied. Objectives: To assess the prospective association of plasma galectin-3 and the LGALS3 rs4644 SNP with VTE incidence. Methods: We measured plasma galectin-3 in 9,916 participants in the Atherosclerosis Risk in Communities (ARIC) study cohort in 1996 - 1998 and identified VTEs through 2013. Using Cox regression, we estimated the hazard ratio associating galectin-3 with incident VTE over a median of 13.9 years. Replication was sought in the Cardiovascular Health Study (CHS). Results: ARIC included 21.8% blacks and 56.2% females with mean baseline age of 62.7 years. The incidence rate of VTE (n=389 events) increased across quintiles of galectin-3, with hazard ratios (95% CI) of 1 (reference), 1.13 (0.80 - 1.61), 1.00 (0.70 - 1.43), 1.36 (0.96 - 1.91), and 1.55 (1.09 - 2.19) (p-trend = 0.005), adjusted for age, sex, race, body mass index, diabetes status, and renal function. Results did not replicate in the CHS (124 VTE), but meta-analysis of both studies yielded a pooled hazard ratio (95% CI) for 1 SD increment in log galectin-3 of 1.10 (1.00 - 1.22). In ARIC, the C allele of rs4644 in the LGALS3 gene was associated with higher galectin-3 level, and in whites, with an increased rate of VTE. Conclusion: Galectin-3 levels were associated positively with VTE incidence. PMID- 29152609 TI - Matricial Wasserstein-1 Distance. AB - We propose an extension of the Wasserstein 1-metric (W1) for density matrices, matrix-valued density measures, and an unbalanced interpretation of mass transport. We use duality theory and, in particular, a "dual of the dual" formulation of W1. This matrix analogue of the Earth Mover's Distance has several attractive features including ease of computation. PMID- 29152610 TI - Mutations in Coagulation Factor VIII Are Associated with More Favorable Outcome in Patients with Cutaneous Melanoma. AB - Coagulation factor VIII (FVIII), von Willebrand factor (VWF), and ADAMTS13 play an important role in regulation of normal hemostasis. However, little is known about their roles in patients with malignancy, particularly with cutaneous melanoma. Whole genome sequencing data are available for 25,719 cases in 126 cancer genomic studies for analysis. All sequencing data and corresponding pathology findings were obtained from The Cancer Genome Atlas. The cBioportal bioinformatics tools were used for the data analysis. Our results demonstrated that mutations in genes encoding FVIII, VWF, and ADAMTS13 were reported in 92 of 126 cancer genomic studies and high mutation rates in these three genes were observed in patients with cutaneous melanoma from three independent studies. Moreover, high mutation rates in FVIII, VWF, and ADAMTS13 were also found in patients with diffuse large B cell lymphoma (22.9%), lung small cell carcinoma (20.7%), and colon adenocarcinoma (19.4%). Among 366 melanoma cases from TCGA provisional, the somatic mutation rates of FVIII, VWF and ADAMTS13 in tumor cells were 15%, 14%, and 5%, respectively. There was a strong tendency for coexisting mutations of FVIII, VWF, and ADAMTS13. Kaplan-Meier survival analysis demonstrated that melanoma patients with FVIII mutations had a more favorable overall survival rate than those without FVIII mutations (p=0.02). These findings suggest for the first time that the FVIII mutation burden may have a prognostic value for patients with cutaneous melanoma. Further studies are warranted to delineate the molecular mechanisms underlying the favorable prognosis associated with FVIII mutations. PMID- 29152611 TI - Nur77 Is Upregulated in B-1a Cells by Chronic Self-Antigen Stimulation and Limits Generation of Natural IgM Plasma Cells. AB - B-1a cells are a unique population of innate-like B cells with a highly restricted and self-reactive BCR repertoire. Preimmune "natural" IgM produced by B-1a-derived plasma cells is essential for homeostatic clearance of cellular debris and forms a primary layer of protection against infection. In this study, we take advantage of a fluorescent reporter of BCR signaling to show that expression of the orphan nuclear hormone receptor Nur77 is upregulated under steady-state conditions in self-reactive B-1a cells in response to chronic Ag stimulation. Nur77-deficient mice exhibit elevated natural serum IgM (but not IgG) and marked expansion of IgM plasma cells of B-1a origin. Moreover, we show that Nur77 restrains the turnover of B-1a cells and the accumulation of immature IgM plasma cells. Thus, we identify a new critical negative-regulatory pathway that serves to maintain B-1a cells in a quiescent state in the face of chronic endogenous Ag stimulation. PMID- 29152612 TI - Genome-wide compatible SNP intervals and their properties. AB - Intraspecific genomes can be subdivided into blocks with limited diversity. Understanding the distribution and structure of these blocks will help to unravel many biological problems including the identification of genes associated with complex diseases, finding the ancestral origins of a given population, and localizing regions of historical recombination, gene conversion, and homoplasy. We present methods for partitioning a genome into blocks for which there are no apparent recombinations, thus providing parsimonious sets of compatible genome intervals based on the four-gamete test. Our contribution is a thorough analysis of the problem of dividing a genome into compatible intervals, in terms of its computational complexity, and by providing an achievable lower-bound on the minimal number of intervals required to cover an entire data set. In general, such minimal interval partitions are not unique. However, we identify properties that are common to every possible solution. We also define the notion of an interval set that achieves the interval lower-bound, yet maximizes interval overlap. We demonstrate algorithms for partitioning both haplotype data from inbred mice as well as outbred heterozygous genotype data using extensions of the standard four-gamete test. These methods allow our algorithms to be applied to a wide range of genomic data sets. PMID- 29152613 TI - Commentary: Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis. PMID- 29152614 TI - Ataxia-Telangiectasia Mutated Kinase: Role in Myocardial Remodeling. AB - Ataxia-telangiectasia mutated kinase (ATM) is a serine/threonine kinase. Mutations in the ATM gene cause a rare autosomal multisystemic disease known as Ataxia-telangiectasia (AT). Individuals with mutations in both copies of the ATM gene suffer from increased susceptibility to ionizing radiation, predisposition to cancer, insulin resistance, immune deficiency, and premature aging. Patients with one mutated allele make-up ~1.4 to 2% of the general population. These individuals are spared from most of the symptoms of the disease. However, they are predisposed to developing cancer or ischemic heart disease, and die 7-8 years earlier than the non-carriers. DNA double-strand breaks activate ATM, and active ATM is known to phosphorylate an extensive array of proteins involved in cell cycle arrest, DNA repair, and apoptosis. The importance of ATM in the regulation of DNA damage response signaling is fairly well-established. This review summarizes the role of ATM in the heart, specifically in cardiac remodeling following beta-adrenergic receptor stimulation and myocardial infarction. PMID- 29152615 TI - SCID pigs: An emerging large animal NK model. AB - Severe Combined ImmunoDeficiency (SCID) is defined as the lack or impairment of an adaptive immune system. Although SCID phenotypes are characteristically absent of T and B cells, many such SCID cellular profiles include the presence of NK cells. In human SCID patients, functional NK cells may impact the engraftment success of life saving procedures such as bone marrow transplantation. However, in animal models, a T cell-, B cell-, NK cell+ environment provides a valuable tool for asking specific questions about the extent of the innate immune system function as well as emerging NK targeted therapies against cancer. Physiologically and immunologically the pig is more similar to the human than common rodent research animals. This review discusses why the T- B- NK+ SCID pig may offer a more relevant model for development of human SCID patient therapies as well as provide an opportunity for systematic exploration of the role of NK cells in artiodactyl immunity. PMID- 29152616 TI - Evaluation of the 129I Half-Life Value Through Analyses of Primitive Meteorites. AB - The preserved record of decay of now-extinct 129I into 129Xe forms the basis of the I-Xe chronometer. Comparison of the high precision I-Xe and Pb-Pb ages of chondrules and pure mineral phases separated from eight meteorites suggests the 17.5 / 14.6 Ma range for the 129I half-life, assuming that the 235U and 238U half lives are correct. The mean value of 16 Ma indicates that the 15.7 Ma half-life of 129I used here for the I-Xe age calculations is most probably correct. Since the 129I half-life value only affects the relative I-Xe ages, the few Ma relative to the Shallowater standard, the absolute I-Xe ages are almost immune to this uncertainty in the 129I half-life. PMID- 29152618 TI - Effect of Mechanical Fatigue on the Bond Between Zirconia and Composite Cement. AB - PURPOSE: To examine the effect of mechanical fatigue on the bond strength of resin composite cemented to silica-coated yttria-tetragonal zirconia polycrystal ceramic (Y-TZP). MATERIALS AND METHODS: Ten Y-TZP blocks were polished down to 600-grit silicon carbide paper. Specimens were silica coated by airborne-particle abrasion with 30-MUm silica-modified Al2O3 particles. Blocks were cleaned in an ultrasonic bath, and a dental adhesive was applied and light cured for 20 s. Pre cured composite blocks were luted to treated Y-TZP surfaces with a dual-curing resin cement. Half of the samples (n = 5) were subjected to mechanical fatigue before trimming (fatigue group) and the other half tested 24 h after bonding procedures (control group). Forty-five beam-shaped samples with an approximately 1 mm2 cross-sectional area were prepared for each group and tested in microtensile mode at 0.5 mm/min. Fractographic analysis was performed by optical and scanning electron microscopy. Only specimens that failed at the interface area were considered for statistical analysis. Weibull distribution (95% confidence bounds) was used to determine the characteristic strength (sigma0 in MPa) and Weibull modulus (m) for each group. Probability of survival was calculated over the range of loads until specimens failed. RESULTS: The control group showed sigma0 = 45.91 MPa and m = 7.98, and the fatigue group sigma0 = 43.94 MPa and m = 6.44 (p > 0.05). The probability of survival did not differ significantly between groups. CONCLUSIONS: Fatigue did not affect the bond strength between silica-treated Y-TZP intaglio surfaces and composite cement under these experimental conditions. PMID- 29152617 TI - Bacopa monnieri protects SH-SY5Y cells against tert-Butyl hydroperoxide-induced cell death via the ERK and PI3K pathways. AB - Objective: Oxidative stress plays an important role in the pathological processes of various neurodegenerative diseases. Bacopa monnieri (BM) has a potent antioxidant property. Therefore, the purpose of this study was to evaluate the neuroprotective potential of BM against SH-SY5Y neuroblastoma cell death induced by the pro-oxidant insult, tert-Butyl hydroperoxide (TBHP), and to identify possible mechanisms related to its neuroprotective action. Methods: The neuroprotective effect of BM was evaluated by the degree of protection against TBHP-induced cell death in human SH-SY5Y cells that was measured by calcein-AM assay. ERK1/2 and Akt phosphorylation was evaluated by immunoblotting. Results: We found that BM exhibited protection against TBHP-mediated cytotoxicity. The neuroprotective effect of BM was abolished in the presence of either ERK1/2 or PI3K inhibitors. In addition, western blotting with anti-phospho-ERK1/2 and anti phospho-Akt antibodies showed that BM increased both ERK1/2 and Akt phosphorylation. Conclusion: These results suggest that BM by activation of ERK/MAPK and PI3K/Akt signaling pathways protects SH-SY5Y cells from TBHP-induced cell death. PMID- 29152619 TI - Dentin uTBS and Hardness of Bulk-fill and Conventional Composites Placed in a Box shaped Cavity Preparation. AB - PURPOSE: To compare the dentin microtensile bond strength (uTBS) and the Knoop hardness of bulk-fill and conventional restorative composites in box-shaped Class I cavities using different insertion techniques. MATERIALS AND METHODS: Forty box shaped Class I preparatons 4 mm deep were performed in the pulp chamber of sound human third molars. The restorations were made using either a conventional microhybrid (Z250, 3M ESPE) or bulk-fill (Tetric EvoCeram Bulk-fill, TCBF) composite using two incremental thicknesses: 2 mm or 4 mm (n = 10). After 24-h water storage, the restorations were sectioned. The first slice (0.7 mm thick) taken from a proximal surface was submitted to the Knoop hardness (KHN) test at five depths from the occlusal cavosurface to the pulpal line angle. Sticks were fabricated from the remaining sections and tested for dentin microtensile bond strength (uTBS). Means were analyzed using two-way ANOVA and Tukey's test (p < 0.05). RESULTS: Higher (p < 0.05) uTBS resulted when both composites were restored with 2-mm increments, with no significant difference between materials (p > 0.05). Higher (p < 0.05) KHN means were found when 2-mm increments were used, with no significant differences (p > 0.05) between the materials. When the teeth were restored with one bulk increment (4 mm), the deeper layers presented lower KHN means (p < 0.05) starting at 2 mm for Z250 and 3 mm for TCBF. CONCLUSION: The 2-mm increment restorations in box-shaped cavities yielded higher uTBS and microhardness for conventional and bulk-fill composites. PMID- 29152620 TI - Efficacy of a Universal Adhesive in the Bond Strength of Composite Cements to Polymer-infiltrated Ceramic. AB - PURPOSE: To investigate the effect of a universal adhesive on the bond strength of composite cements to a polymer-infiltrated ceramic network. MATERIALS AND METHODS: Shear bond strength to a polymer-infiltrated ceramic network (Vita Enamic) and to its polymer and ceramic components was assessed on polished surfaces using either a conventional dual-curing resin (RelyX Ultimate) or self adhesive composite cement (RelyX Unicem 2 Automix). Substrate surfaces were either not pretreated or a silane coupling agent (Vitasil), a universal adhesive (Scotchbond Universal Adhesive), or both were applied. Further, the shear bond strength to polymer-infiltrated ceramic network was evaluated after etching with 5% hydrofluoric acid (Vita Ceramics Etch) of 0, 15, 30, 60 or 120 s without or with application of silane, universal adhesive, or both (n = 10). Statistical analysis was performed using the Kruskal-Wallis test (p < 0.05) followed by post hoc comparisons with Bonferroni correction. RESULTS: No bond (0 MPa) was formed to the polished polymer-infiltrated ceramic network or to its components for either cement. Application of silane resulted in low mean bond strengths (4 to 5 MPa) to the ceramic. The universal adhesive bonded mainly to the polymer part of the polymer-infiltrated ceramic network. The best bonding performance for both cements was achieved when silane and universal adhesive were applied on the polymer-infiltrated ceramic network. Etching for 30 s or 60 s resulted in the highest mean shear bond strengths for all pretreatment groups (p < 0.05). CONCLUSION: The best bonding performance of the self-adhesive dual-curing composite cement RelyX Unicem 2 Automix was found on the HF-etched polymer infiltrated ceramic network. The conventional dual-curing composite cement RelyX Ultimate with Scotchbond Universal Adhesive may bond chemically to the polymer part of the polymer-infiltrated ceramic network. To achieve the highest bond strengths for both cements, the polymer-infiltrated ceramic network should be etched for 30 to 60 s, followed by the application of silane and universal adhesive. PMID- 29152621 TI - Improvement in the Bonding of Y-TZP by Room-temperature Ultrasonic HF Etching. AB - PURPOSE: To investigate the effects of room-temperature etching with hydrofluoric acid (HF) in the presence and absence of ultrasonic irradiation on the bonding of yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) to resin. MATERIALS AND METHODS: Y-TZP specimens were etched with 40% HF at room temperature for different time periods (2, 5, 10, 15, 30, 60, and 90 min) with and without ultrasonic exposure. The surface roughness, micromorphology, dimensions, and phases of the treated Y-TZP specimens were evaluated by atomic force microscopy (AFM), scanning electron microscopy (SEM), digital caliper measurement, and x-ray diffraction, respectively. The HF etching conditions that resulted in the most drastic Y-TZP surface morphology and highest roughness values were used to prepare specimens for shear bond strength (SBS) testing; the effect of thermocycling on SBS was also examined. Alumina-sandblasted Y-TZP specimens were used as the control. RESULTS: The Y-TZP surfaces etched with HF without ultrasonic exposure for 30, 60, and 90 min and those surfaces ultrasonically etched with HF for 10 and 15 min were severely etched, although their dimensions were not changed by etching. Monoclinic-phase zirconia was observed only in the alumina-sandblasted Y-TZP specimens. Surface roughening from HF etching for 30 min and ultrasonic etching for 10 min resulted in higher mean SBS compared to roughening with alumina sandblasting. CONCLUSION: Ultrasonic etching with 40% HF at room temperature for 10 min may be used as an alternative roughening method for improving the bonding of Y-TZP. PMID- 29152622 TI - The Effect of Enamel Sandblasting on Enhancing Bond Strength of Orthodontic Brackets: A Systematic Review and Meta-analysis. AB - PURPOSE: To critically appraise the evidence regarding the effect of enamel sandblasting on the bond strength of orthodontic brackets on either the labial or lingual tooth surface. MATERIALS AND METHODS: An electronic database search of published and unpublished literature was performed. Search terms included sandblasting, enamel abrasion, tooth surface, bond strength, bond failure, and adhesive remnant; data were extracted in standardized piloted forms. Risk of bias was assessed using the Cochrane risk of bias tool, adapted for in vitro studies where necessary. RESULTS: Of the 81 articles initially retrieved, 13 were eligible for inclusion in the systematic review. All of the latter were in vitro studies with unclear risk of bias primarily due to unclear reporting of blinding of outcome assessors. Eight studies assessed the combined effect of enamel sandblasting and etching, while only five evaluated the isolated effect of sandblasting on the buccal enamel surface. In view of the apparently heterogeneous study settings, intervention protocols, specimen preparation and storage sequences, only two studies were deemed eligible for quantitative synthesis. Random effects meta-analysis revealed no evidence to support sandblasting prior to etching over etching alone with regard to shear bond strength of orthodontic brackets bonded in vitro to lingual enamel surfaces of extracted premolars (standardized mean difference: 0.36; 95% CI: -0.21, 0.94; p = 0.22). CONCLUSIONS: The findings of the present study cannot support lingual enamel sandblasting prior to etching for augmentation of the bond strength of orthodontic brackets. PMID- 29152623 TI - Margin Integrity of Conservative Composite Restorations after Resin Infiltration of Demineralized Enamel. AB - PURPOSE: To investigate the influence of pretreating demineralized enamel with a caries infiltrant on the margin integrity of Class V composite restorations bonded with different adhesives. MATERIALS AND METHODS: A total of 60 specimens from bovine incisors were demineralized (21 days, acid buffer, pH 4.95) to create artificial enamel lesions, and circular Class V cavities were prepared. Cavities of half of the specimens were treated with either an unfilled etch-and-rinse adhesive (Syntac Classic; Ivoclar Vivadent), a filled etch-and-rinse adhesive (Optibond FL; Kerr), or a self-etch adhesive (iBond Self Etch; Heraeus Kulzer) (n = 10 per group). Demineralized enamel of the other half of the specimens was pretreated with a caries infiltrant (Icon; DMG) prior to adhesive application. All cavities were restored with a nanofilled composite material and thermocycled (5000*, 5 degrees C-55 degrees C). Margin integrity was evaluated using scanning electron microscopy, and the percentage of continuous margin was statistically analyzed (p < 0.05). RESULTS: The significantly highest margin integrity was observed for Optibond FL, whether or not demineralized enamel was pretreated with the infiltrant. Pretreatment of demineralized enamel with the infiltrant resulted in a significant increase in margin integrity when the unfilled etch-and-rinse adhesive (Syntac Classic) or the self-etch adhesive (iBond Self Etch) was subsequently applied, but showed no significant improvement in combination with the filled etch-and-rinse adhesive (Optibond FL). CONCLUSION: Application of a caries infiltrant can improve margin integrity of composite fillings in demineralized enamel when used in combination with the examined self-etch and unfilled adhesives. PMID- 29152624 TI - Preparation of Fe-MOFs by microwave-assisted ball milling for reducing Cr(vi) in wastewater. AB - Fe-Based metal-organic frameworks (Fe-MOFs) were prepared with trimesic acid and FeSO4.7H2O via a microwave-assisted ball milling approach. The structure and thermal stability of the as-prepared Fe-MOFs were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectrometry (FTIR), X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA). When used to degrade 20 mg L-1 hexavalent chromium in aqueous solution, the Fe-MOFs were found to completely reduce a 100 mL solution within 120 min under natural light and a 400 mL solution within 90 min under Xe lamp irradiation. Under natural sunlight, 98% of the Cr(vi) was removed from a 40 mL solution after 40 min. PMID- 29152625 TI - An ionic liquid-based extraction system using diglycolamide functionalized macrocyclic platforms for the extraction and recovery of lanthanides. AB - Solvent extraction of lanthanides Ln(iii) (La, Eu and Yb) with resorcin[4]arene cavitand-triazole-DODGA (CR4-TZ-DODGA) and t-butylcalix[4]arene-triazole-DODGA (C4-TZ-DODGA) has been studied in a room temperature ionic liquid (RTIL), N-octyl N-ethylpiperidinium bis(trifluoromethylsulfonyl)imide ([EOPip]NTf2). The two macrocyclic platforms were functionalized with four diglycolamide (DGA) moieties thanks to a click reaction and fully characterized by NMR and MS analysis. The effects of acidity as well as the concentration of the ligands were investigated on the extraction and separation properties. The parameters of the extraction processes were determined by the slope method and thermodynamic studies. For both ligands, the extraction efficiency changes along the lanthanoid series with selectivity toward Yb(iii) in regard to La(iii) and Eu(iii). The selective extraction and recovery of lanthanides from a simulated leaching solution of a Nd/Fe/B/Dy magnet has also been investigated. PMID- 29152626 TI - Specific recognition of Cr3+ under physiological conditions by allyl substituted appendage rhodamine and its cell-imaging studies. AB - An allyloxynitrophenylimio-propylhydroxyl appended rhodamine (RD-3) specifically recognises Cr3+ in aqueous buffer medium at pH 7.4. The visible light excitable reagent (lambdaex 505 nm) on selective binding to Cr3+ exhibited a strong fluorescence turn-on response with powerful emission at 557 nm and the tail of this luminescence band is extended to ~650 nm. Interference studies confirm that other metal ions (27 ions) do not hamper the detection process of Cr3+. The sensing mechanism is studied by absorption, fluorescence, Job's plot, and 1H NMR titration studies. The detection limit is as low as 33 nM. The practical applicability of RD-3 is examined for imaging Cr(iii) ions in HCT116 (human colorectal carcinoma) cells. PMID- 29152627 TI - Direct estimation of the transfer integral for photoinduced electron transfer from TD DFT calculations. AB - The rate of photoinduced ET in molecular systems is controlled by electronic coupling of the locally excited and charge transfer states. We generalize the Bixon-Jortner-Verhoeven expression for electronic coupling to systems with a small energy gap and derive the transfer integral for charge separation in two model heterojunctions using the excitation energies and oscillator strengths computed with TD DFT. The estimated couplings are in good agreement with the reference values. PMID- 29152628 TI - Highly efficient gas-phase reactivity of protonated pyridine radicals with propene. AB - Small nitrogen containing heteroaromatics are fundamental building blocks for many biological molecules, including the DNA nucleotides. Pyridine, as a prototypical N-heteroaromatic, has been implicated in the chemical evolution of many extraterrestrial environments, including the atmosphere of Titan. This paper reports on the gas-phase ion-molecule reactions of the three dehydro-N-pyridinium radical cation isomers with propene. Photodissociation ion-trap mass spectrometry experiments are used to measure product branching ratios and reaction kinetics. Reaction efficiencies for 2-dehydro-N-pyridinium, 3-dehydro-N-pyridinium and 4 dehydro-N-pyridinium with propene are 70%, 47% and 41%, respectively. The m/z 106 channel is the major product channel across all cases and assigned 2-, 3-, and 4 vinylpyridinium for each reaction. The m/z 93 channel is also significant and assigned the 2-, 3-, and 4-N-protonated-picolyl radical cation for each case. H Abstraction from propene is not competitive under experimental conditions. Potential energy schemes, at the M06-2X/6-31(2df,p) level of theory and basis set, are described to assist in rationalising observed product branching ratios and elucidating possible reaction mechanisms. Reaction barriers to the production of vinylpyridinium (m/z 106) + CH3 are the lowest identified for the 3- and 4 dehydro-N-pyridinium reactions, in support of the observed dominance of the m/z 106 ion signal. Ethylene loss via ring-mediated H-transfer along the propyl group is found to be the lowest energy pathway for the 2-dehydro-N-pyridinium reaction, suggesting a preference toward m/z 93 (N-protonated-picolyl radical cation) over the experimentally observed products. Entropic bottle-necks along the m/z 93 pathway however, associated with ring-mediated H-atom transfer, are responsible for the dominance of m/z 106 in the 2-dehydro-N-pyridinium + propene reaction. For all three isomers, computed barriers for all observed reaction channels were below the entrance channel, suggesting these reactions can contribute to molecular weight growth in extraterrestrial environments with accelerated reaction rates in low temperature regions of space. PMID- 29152629 TI - Nanocrystalline LaOx/NiO composite as high performance electrodes for supercapacitors. AB - Nanocrystalline LaOx/NiO composite electrodes were synthesized via two types of facile cathodic electrodeposition methods onto nickel foam followed by thermal annealing without any binders. Scanning electron microscopy and transmission electron microscopy investigation revealed that LaOx nanocrystalline particles with an average diameter of 50 nm are uniformly distributed in the NiO layer or alternately deposited with the NiO layer onto the substrate. It is speculated that LaOx particles can participate in the faradaic reaction directly and offer more redox sites. Besides this, the unique Ni/La layered structure facilitates the diffusion of ions and retards the electrode polarization, thus leading to a better rate capability and cycling stability of NiO. As a result, the obtained electrodes display very competitive electrochemical performance (a specific capacitance of 1238 F g-1 at a current density of 0.5 A g-1, excellent rate capability of 86% of the original capacitance at 10 A g-1 and excellent cycling stability of 93% capacitance after 10 000 cycles). In addition, asymmetric coin devices were assembled using LaOx/NiO as the positive electrode and active carbon as the negative electrode. The assembled asymmetric devices demonstrate a high energy density of 13.12 W h kg-1 at a power density of 90.72 W kg-1. PMID- 29152630 TI - Noise and diffusion of a vibrated self-propelled granular particle. AB - Granular materials are an important physical realization of active matter. In vibration-fluidized granular matter, both diffusion and self-propulsion derive from the same collisional forcing, unlike many other active systems where there is a clean separation between the origin of single-particle mobility and the coupling to noise. Here we present experimental studies of single-particle motion in a vibrated granular monolayer, along with theoretical analysis that compares grain motion at short and long time scales to the assumptions and predictions, respectively, of the active Brownian particle (ABP) model. Our results show that despite the unique relation between noise and propulsion, a variety of granular particles are correctly described by the ABP model. Additionally, our scheme of analysis for validating the inputs and outputs of the model can be applied to other granular and non-granular active systems. PMID- 29152631 TI - Mask-free fabrication of a versatile microwell chip for multidimensional cellular analysis and drug screening. AB - Cells are frequently studied because they are basic structural, functional, and biological units of living organisms. Extracting features from cellular behaviors can facilitate decision making in medical diagnoses and represents an important aspect in the development of biomedical engineering. Previous studies have just focused on either the individual cell or cell clusters separately, which leads to a great lack of information. Microwell technologies could address the challenges of in vitro cellular studies, from individual cell studies to 3D functional assays, by providing more information from smaller sample volumes and enabling the incorporation of low-cost high-throughput assays in the drug discovery process. To this end, the present study describes an easy-to-use method for fabricating a versatile microwell chip that utilizes a digital micro-mirror device printing system, and the chip can be employed in multidimensional cellular analysis, ranging from the single cell to the 3D spheroid level. The microwell manufacturing process, using a digital mask in place of a conventional physical mask, is based on shadowed light and is full of flexibility. Three different dimensions (single cell (1D), cell monolayer (2D) and cell spheroid (3D)) of one cell type can be formed using a microwell array and the analyses of biological characteristics are achieved separately. Single cells and cell clusters can be controlled via customized geometries of microfabricated selectively adhesive poly(ethylene glycol) diacrylate (PEGDA) wells. The effects of shape on cellular growth and hybrid tissue layers were investigated by peeling off the microwells. Furthermore, 3D multicellular spheroids were successfully established in a controllable and high-throughput format. Preclinical drug screening was investigated and distinct differences were observed in the tolerance response to drug testing between the 2D and 3D conditions. The study results further demonstrate that the high-density microwell chip is an easy-to-use multidimensional cellular analysis and rapid drug screening technique, and it could be easily adapted for a wide range of biological research applications. PMID- 29152632 TI - A combination of quercetin and resveratrol reduces obesity in high-fat diet-fed rats by modulation of gut microbiota. AB - Resveratrol and quercetin, widely found in foods and vegetables, are plant polyphenols reported to have a wide range of biological activities. Despite their limited bioavailabilities, both resveratrol and quercetin are known to exhibit anti-inflammation and anti-obesity effects. We hypothesized that gut microbiota may be a potential target for resveratrol and quercetin to prevent the development of obesity. The aim of this research was to confirm whether a combination of quercetin and resveratrol (CQR) could restore the gut microbiota dysbiosis induced by a high-fat diet (HFD). In this study, Wistar rats were divided into three groups: a normal diet (ND) group, a HFD group and a CQR group. The CQR group was treated with a HFD and administered with a combination of quercetin [30 mg per kg body weight (BW) per day] and resveratrol [15 mg per kg body weight (BW) per day] by oral gavage. At the end of 10 weeks, CQR reduced the body weight gain and visceral (epididymal, perirenal) adipose tissue weight. Moreover, CQR also reduced serum lipids, attenuated serum inflammatory markers [interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1] and reversed serum biochemical parameters (adiponectin, insulin, leptin, etc.). Importantly, our results demonstrated that CQR could modulate the gut microbiota composition. 16S rRNA gene sequencing revealed that CQR had an impact on gut microbiota, decreasing Firmicutes (P < 0.05) and the proportion of Firmicutes to Bacteroidetes (P = 0.052). CQR also significantly inhibited the relative abundance of Desulfovibrionaceae (P < 0.01), Acidaminococcaceae (P < 0.05), Coriobacteriaceae (P < 0.05), Bilophila (P < 0.05), Lachnospiraceae (P < 0.05) and its genus Lachnoclostridium (P < 0.001), which were reported to be potentially related to diet-induced obesity. Moreover, compared with the HFD group, the relative abundance of Bacteroidales_S24-7_group (P < 0.01), Christensenellaceae (P < 0.001), Akkermansia (P < 0.01), Ruminococcaceae (P < 0.01) and its genera Ruminococcaceae_UCG-014 (P < 0.01), and Ruminococcaceae_UCG 005 (P < 0.01), which were reported to have an effect of relieving HFD-induced obesity, was markedly increased in the CQR group. Overall, these results indicated that administration of CQR may have beneficial effects on ameliorating HFD-induced obesity and reducing HFD-induced gut microbiota dysbiosis. PMID- 29152633 TI - Conformational collapse of spherical poly(N-isopropylacrylamide) brushes under the constraint of bound micelles. AB - In this paper, we investigate the micelle (charge)-constrained collapse of a spherical poly(N-isopropylacrylamide) (PNIPAM) brush. The system is an example of the transition of a short-length neutral polymer from a stretched state to a folded state under the constraint of long-range electrostatic repulsion. The collapsed state is described as an anisotropic globule comprising a cascade of rod-like or hairpin bundles. A critical aggregation number of bound micelles is obtained to distinguish the charge-induced deformation of the globule, which provides a guideline to characterize globule dimensions under different strengths of electrostatic interaction. The volume of the constrained globule is controlled by two length scales, i.e., the Bjerrum length lB and the persistence length lp*, as well as the aggregation number Zm. The increase of the number density from a constrained globule to a conventional globule is a first-order transition. Excluded volume parameters are depicted by a mean-field model which reconciles the expansion of the PNIPAM-micelle complex with the collapse of the micelle constrained PNIPAM string. Calculated heights of the spherical PNIPAM brush utilizing the model are overall in agreement with those obtained from our experiments. Using the experimental data, we implement a pragmatic analysis for the monomer density and the corresponding osmotic pressure. The profiles obtained manifest all the features predicted by the self-consistent field theory. Our results rationalize the experimental observation concerning the weak collapse associated with a loose packing density and quantitatively reveal the synergistic effect of control parameters such as the solvent quality and the number of bound micelles within the fundamental framework of polymer brushes. PMID- 29152634 TI - Effects of ionic liquids on the nanoscopic dynamics and phase behaviour of a phosphatidylcholine membrane. AB - Ionic liquids (ILs) are potential candidates for new antimicrobials due to their tunable antibacterial and antifungal properties that are required to keep pace with the growing challenge of bacterial resistance. To a great extent their antimicrobial actions are related to the interactions of ILs with cell membranes. Here, we report the effects of ILs on the nanoscopic dynamics and phase behaviour of a dimyristoylphosphatidylcholine (DMPC) membrane, a model cell membrane, as studied using neutron scattering techniques. Two prototypical imidazolium-based ILs 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM[BF4]) and 1-decyl-3 methylimidazolium tetrafluoroborate (DMIM[BF4]), which differ only in terms of the alkyl chain length of cations, have been used for the present study. Fixed Elastic Window Scan (FEWS) shows that the incorporation of ILs affects the phase behaviour of the phospholipid membrane significantly and the transition from a solid gel to a fluid phase shifts to lower temperature. This is found to be consistent with our differential scanning calorimetry measurements. DMIM[BF4], which has a longer alkyl chain cation, affects the phase behaviour more strongly in comparison to BMIM[BF4]. The pressure-area isotherms of the DMPC monolayer measured at the air-water interface show that in the presence of ILs, isotherms shift towards higher area-per lipid molecule. DMIM[BF4] is found to shift the isotherm to a greater extent compared to BMIM[BF4]. Quasielastic neutron scattering (QENS) data show that both ILs act as a plasticizer, which enhances the fluidity of the membrane. DMIM[BF4] is found to be a stronger plasticizing agent in comparison to BMIM[BF4] that has a cation with a shorter alkyl chain. The incorporation of DMIM[BF4] enhances not only the long range lateral motion but also the localised internal motion of the lipids. On the other hand, BMIM[BF4] acts weakly in comparison to DMIM[BF4] and mainly alters the localised internal motion of the lipids. Any subtle change in the dynamical properties of the membrane can profoundly affect the stability of the cell. Hence, the dominant effect of the IL with the longer chain length on the dynamics of the phospholipid membrane might be correlated with its cytotoxic activity. QENS data analysis has provided a quantitative description of the effects of the two imidazolium-based ILs on the dynamical and phase behaviour of the model cell membrane, which is essential for a detailed understanding of their action mechanism. PMID- 29152635 TI - Profiling polyphenol composition by HPLC-DAD-ESI/MSn and the antibacterial activity of infusion preparations obtained from four medicinal plants. AB - The infusions of Thymus pallescens Noe, Saccocalyx satureioides Coss. et Dur., Ptychotis verticillata Briq. and Limoniastrum guyonianum Boiss. have been used as medicinal remedies for many diseases in Algerian folk medicine. These species have also been well documented as rich sources of phytochemicals, such as phenolic compounds with wide diversified chemical structures, which exhibit far ranging biological activities. Thus, the phenolic compound profile of the aqueous extracts, obtained by infusing, of the mentioned species was obtained by HPLC-DAD ESI/MS, and their antibacterial activity was evaluated against clinical isolates. Several phenolic acids were identified and quantified, particularly caffeic acid derivatives along with glycosylated flavonoids. T. pallescens and S. satureioides contain 13 phenolic compounds, where rosmarinic acid was the most abundant phenolic acid present, while L. guyonianum presented myricetin-3-O-glucoside and myricetin-O-rhamnoside as the main compounds among the eight detected molecules. P. verticillata presented a profile of ten phenolic compounds, where 5-O caffeoylquinic acid was the most abundant phenolic acid, followed by the flavone luteolin-3-O-glucoside. The antibacterial activity of the infusions ranged between 2.5 and 20 mg mL-1 (MIC values), and L. guyonianum showed the highest activity against all of the tested bacteria, Staphylococcus aureus and Pseudomonas aeruginosa being the most sensitive and resistant strains, respectively. Thus, the studied plant species are sources of natural antibacterial substances that can be used to fight against pathogenic microorganisms. PMID- 29152636 TI - A universal genotyping-microarray constructed by ligating a universal fluorescence-probe with SNP-encoded flaps cleaved from multiplex invasive reactions. AB - To achieve a microarray universal to any SNP, we proposed a new way to construct a genotyping-microarray by ligating a universal fluorescence-probe with SNP encoded flaps cleaved from invasive reactions on a slide surface. Our proposed microarray is labor-saving and cost-saving in setting up a new experiment for genotyping multiple SNPs, which is related to personalized medicine. PMID- 29152638 TI - Charge doping in graphene on thermodynamically preferred BiFeO3(0001) polar surfaces. AB - For graphene/ferroelectric hybrid structures, the atomistic and electronic details of the interfaces are of crucial importance for charge doping in graphene. In this paper, we choose thermodynamically stable BiFeO3(0001) surfaces to explore the adsorption behavior and charge doping effect in a graphene/BiFeO3 system. By performing first-principles calculations, we find that both the adsorption behavior and charge doping effect show distinct characteristics for graphene adsorbed on the oppositely polarized BiFeO3(0001) surfaces. We predict that n-type doping and p-type charge doping occur in graphene on the positive and negative BiFeO3(0001) surfaces, respectively. The carrier density is estimated to be 1013 cm-2 orders of magnitude. Our results reveal that the graphene/BiFeO3 hybrid system is an intriguing candidate to make graphene-based field-effect transistors, whose p-n junctions can be made by patterning the domain structure of the BiFeO3 substrate. Moreover, the graphene/BFO hybrid structure may display an outstanding photovoltaic effect due to the combination of the bulk photovoltaic effect of the BFO substrate and the optical transparency of the graphene electrode. PMID- 29152642 TI - Variability of characteristics of cranial projectile trauma in skeletal material. AB - ABSTRACT: In cranial firearm trauma, where soft tissues have decomposed, determining the manner of death can pose difficultly for a forensic anthropologist. Detailed analysis of skeletal wounds may lead to reconstruction of the events surrounding death, however considerable research has been conducted on soft tissue details and less has focused on skeletal wounds alone. Macroscopic descriptive observations were carried out on thirteen skulls from the Hamman-Todd Human Osteological Collection at the Cleveland Museum of Natural History, Ohio which had documented cranial projectile trauma to analyse wound location, shape, size, beveling and projectile paths. This sample of skeletons provides a non arbitrary selection of individuals which were unclaimed bodies from a disturbed social environment. Nine entry wounds were located on the right side of the skull, 3 located on left side of skull and one had entry under the right side of the skull. Entry wounds were often oval or round in shape. Exit wounds were not present in all cases; however, when present they were of irregular shape. Radiating fractures occurred in 8 entry wounds and 8 exit wounds. Concentric fractures accompanied 3 exit wounds. Three entry wounds had clear internal beveling. Three cases had exit wounds with external beveling. One showed signs of combination beveling on the entry wound. Beveling, if present, can lead to identifying the entry/exit wound. Radiating fractures form when the intracranial pressure is too great and if the pressure is not relieved, concentric fractures form secondarily. Based on the characteristics of the cranial projectile trauma one can suggest manner of death, however, it is not possible to reach a firm decision. PMID- 29152643 TI - Differences in tibial shape among the Prehispanic inhabitants from Gomera, Punta Azul (El Hierro), and Gran Canaria (Canary Islands). AB - ABSTRACT: The Canary Archipelago was colonized by North African Berbers who arrived at the Islands in the first millenium BC. Although it was classically considered that the prehispanic population was more or less uniform, recent genetic analysis has disclosed that some differences did exist between inhabitants of the different islands. From pure anthropometrical point of view, detailed inspection of some bones such as tibiae of prehispanic inhabitants of different islands allow the detection of some differences in tibial shape, especially regarding the relative size of both the proximal and distal thirds of these bones. On this basis, we have elaborated and calculated several indexes combining distal and proximal breadth measurements that define the global shape of the tibia. We have compared these indexes among the prehispanic population of the three islands for which sex has been accurately established. Both men and women from La Gomera, and, especially, from El Hierro, showed thicker distal ends of the tibiae with respect to proximal ones, in contrast with the population of Gran Canaria. In addition, differences among male and female tibiae were more marked among the population of Gran Canaria than among those of Gomera and El Hierro. Differences in these indexes could point either to differences in genetical background or to differences in activity. Compared with single anthropometric measurements, these indices separate better the population of the different islands. Just the opposite was observed when logistic regression analysis was used to analyse differences in sex. PMID- 29152644 TI - HMGA1 participates in MHCC97H cell proliferation and invasion through the ILK/Akt/GSK3beta signaling pathway. AB - Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality, and the prognosis of HCC patients is unsatisfactory. It is known that the occurrence and development of HCC involves numerous genes, as well as various steps and stages in the pathological process. High mobility group AT-hook 1 (HMGA1) and integrin-linked kinase (ILK) may be overexpressed in HCC and may serve important roles in the development of cancer; however, the relationship between HMGA1 and ILK in HCC has not been examined. The present study demonstrated that inhibition of HMGA1 expression significantly decreased the levels of expression of ILK and the downstream elements phosphorylated (p)-Akt, p glycogen synthase kinase 3beta (GSK3beta), matrix metalloproteinase (MMP)2, MMP9, CyclinD1 and c-Myc. Transfection with an ILK expression vector was able to recover the decreased expression of these downstream genes, and affected cell proliferation and apoptosis. In addition, results from Transwell and wound healing experiments indicated that HMGA1 participates cell invasion and migration through the ILK/Akt/GSK3beta pathway. The present study aimed to improve our understanding about the regulatory pathway involved in HCC and provides the basis for exploring HMGA1 inhibition as a therapy for patients with HCC and a new treatment strategy to prevent the development of HCC. PMID- 29152645 TI - miR-214 promotes periodontal ligament stem cell osteoblastic differentiation by modulating Wnt/beta-catenin signaling. AB - The canonical Wnt/beta-catenin signaling is important in the differentiation of human mesenchymal stem cells into osteoblasts. Accumulating evidence suggests that the expression of beta-catenin is, in part, regulated by specific microRNAs (miRNAs). The aim of the present study was to investigate the putative roles of miRNAs in osteoblast differentiation. Polymerase chain reaction (PCR) arrays were used to identify miRNAs that were differentially expressed between differentiated and non-differentiated periodontal ligament stem cells (PDLSCs), and reverse transcription-quantitative PCR (RT-qPCR) was used for validation. Since miR-214 was revealed to be significantly downregulated during PDLSC differentiation, its function was further investigated via silencing and overexpression. In addition, osteogenic differentiation of PDLSCs was evaluated at 10 and 21 days following induction, using Alizarin red staining and RT-qPCR analysis for mRNA expression levels of the osteogenic differentiation markers alkaline phosphatase (ALP), osteocalcin and bone sialoprotein. Furthermore, the potential target genes of miR 214 were investigated using a dual-luciferase reporter assay, RT-qPCR and western blot analysis, whereas a TOPflash/FOPflash reporter plasmid system followed by a luciferase assay was used to examine the effects of miR-214 on Wnt/beta-catenin signaling. The present results demonstrated that miR-214 was significantly downregulated during the osteoblastic differentiation of PDLSCs. Notably, its overexpression inhibited PDLSC differentiation, whereas its knockdown promoted PDLSC differentiation, as revealed by alterations in mRNA expression of osteoblast-specific genes and ALP. In addition, miR-214 was demonstrated to directly interact with the 3'-untranslated region of the beta-catenin gene CTNNB1, and suppressed Wnt/beta-catenin signaling through the inhibition of beta catenin. The results of the present study suggested that miR-214 may participate in the regulation of the Wnt/beta-catenin signaling pathway, and may have potential as a candidate target for the development of preventive or therapeutic agents for the treatment of patients with osteogenic disorders. PMID- 29152646 TI - Naringin protects myocardial cells from doxorubicin-induced apoptosis partially by inhibiting the p38MAPK pathway. AB - Doxorubicin (DOX) has been widely used to treat cancers as a first-line antitumor drug. However, it causes severe, irreversible, dose-dependent cardiotoxicity. To evaluate the protective effects of naringin (NRG) on cardiotoxicity, the authors investigated the molecular mechanism of the p38MAPK signaling pathway. H9c2 cells were treated for 24 h by using 5 umol/l DOX without or with being pretreated by 1 uM NRG for 150 min or by 3 uM SB203580 for 60 min. Cell viability was detected by cell counting kit-8 assay. Intracellular reactive oxygen species (ROS) levels were detected based on the oxidative conversion of 2',7'-dichlorfluorescein diacetate (cell-permeable) to dichlorofluorescein (fluorescent). The expression of p38MAPK was determined by western blotting. The expression level of p-p38MAPK in H9c2 cells, which was significantly increased by exposure to 5 uM DOX for 60 min (P<0.01), was significantly decreased by pretreatment with 1 uM NRG for 150 min beforehand (P<0.01). The viability of H9c2 cells pretreated for 150 min with 1 uM NRG was significantly enhanced compared with that using DOX directly (P<0.01). Intracellular ROS levels were significantly reduced by being pretreated with 1 uM NRG for 150 min or with 3 uM SB203580 for 60 min before the cells were exposed to 5 uM DOX. Collectively, NRG protected H9c2 cells against the cardiotoxicity induced by DOX through suppressing the expression and activity of the p38MAPK pathway. The findings provided valuable evidence for the possible use of NRG to relieve DOX-induced cardiotoxicity. PMID- 29152647 TI - Cryptotanshinone exhibits therapeutical effects on cerebral stroke through the PI3K/AKT-eNOS signaling pathway. AB - Cerebral stroke is a kind of acute cerebrovascular disease with high incidence, morbidity and disability. Treatments against various types of cerebral stroke are limited at preventive measurements due to the lack of effective therapeutic method. The present study aimed to investigate the protective effect of cryptotanshinone (CPT) on cerebral stroke, and investigate the possible mechanism involved in order to develop a novel therapy against stoke. The phosphoinositide 3-kinase membrane translocation of cerebral stroke rats pretreated with CPT at various concentrations were measured, as well as the phosphorylation of protein kinase B (AKT) and endothelial nitric oxide synthase (eNOS). Additionally, the expression level of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and vascular endothelial growth factor were also assessed using western blotting and reverse transcription-quantitative polymerase chain reaction. Furthermore, biochemical tests were used to measure the activity of superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) in both the cerebral cortex and peripheral blood. As a result, CPT-pretreated rats presented declined phosphoinositide 3-kinase (PI3K) and AKT expression levels, indicating that the PI3K/AKT signaling pathway was inhibited. Increased Bcl-2 and NO levels in both the cerebral cortex and peripheral blood demonstrated the anti-apoptosis and blood vessel protection effect of CPT. Furthermore, increased SOD activity and declined MDA levels demonstrated suppressed lipid peroxidation. In conclusion, CPT exhibited a protective effect against cerebral stroke through inhibition of the PI3K/AKT-eNOS signaling pathway. These results suggested the potential of CPT as a promising agent in the treatment of cerebral stroke. PMID- 29152648 TI - Melatonin inhibits colon cancer RKO cell migration by downregulating Rho associated protein kinase expression via the p38/MAPK signaling pathway. AB - Melatonin is predominately produced and secreted by the pineal gland, and inhibits cell growth in various cancer cell lines such as colorectal cancer. However, the precise mechanisms involved have not been fully elucidated. In the present study, the potential molecular mechanism underlying the efficacy of melatonin on migration in RKO colon cancer cells was investigated. The effects of melatonin and H-1152, a selective inhibitor of Rho-associated protein kinase (ROCK), on the migration of RKO cells were analyzed by an in vitro wound healing assay. The localization of zonula occludens-1 (ZO-1) and occludin were observed by immunofluorescence. Reverse transcription-quantitative polymerase chain reaction (qPCR) was performed to analyze the relative mRNA levels of ROCK, ZO-1 and occludin. In addition, western blot analysis was implemented to examine the expression of ROCK, phospho (p)-myosin phosphatase targeting subunit 1 (MYPT1), p myosin light chains (MLC) and p-p38. The results revealed that the expression levels of ROCK2, p-MYPT1 and p-MLC in RKO cells were decreased, and the membrane protein expression of ZO-1 and occludin increased when the cells were treated with melatonin. qPCR demonstrated that melatonin downregulated ROCK2 gene expression, and upregulated the expression of the ZO-1 and occludin genes. The levels of ZO-1 and occludin localized in the tight junctions were markedly increased in the immunofluorescence assay. In addition, the phosphorylation levels of p38 were reduced when the cells were treated with melatonin, and treatment with H-1152 downregulated p38 phosphorylation. The results indicated that melatonin may inhibit the migration of RKO colon cancer cells by downregulating ROCK expression via the p38/mitogen-activated protein kinase signaling pathway. PMID- 29152649 TI - Identification of key genes in glioma CpG island methylator phenotype via network analysis of gene expression data. AB - Gene expression data were analysed using bioinformatic tools to demonstrate molecular mechanisms underlying the glioma CpG island methylator phenotype (CIMP). A gene expression data set (accession no. GSE30336) was downloaded from Gene Expression Omnibus, including 36 CIMP+ and 16 CIMP- glioma samples. Differential analysis was performed for CIMP+ vs. CIMP- samples using the limma package in R. Functional enrichment analysis was subsequently conducted for differentially expressed genes (DEGs) using Database for Annotation, Visualization and Integration Discovery. Protein-protein interaction (PPI) networks were constructed for upregulated and downregulated genes with information from STRING. MicroRNAs (miRNAs) targeting DEGs were also predicted using WebGestalt. A total of 439 DEGs were identified, including 214 upregulated and 198 downregulated genes. The upregulated genes were involved in extracellular matrix organisation, defence and immune response, collagen fibril organisation and regulation of cell motion and the downregulated genes in cell adhesion, sensory organ development, regulation of system process, neuron differentiation and membrane organisation. A PPI network containing 134 nodes and 314 edges was constructed from the upregulated genes, whereas a PPI network consisting of 85 nodes and 80 edges was obtained from the downregulated genes. miRNAs regulating upregulated and downregulated genes were predicted, including miRNA-124a and miRNA-34a. Numerous key genes associated with glioma CIMP were identified in the present study. These findings may advance the understanding of glioma and facilitate the development of appropriate therapies. PMID- 29152651 TI - Age-related differences in serum MFG-E8, TGF-beta1 and correlation to the severity of atherosclerosis determined by ultrasound. AB - Atherosclerosis (AS) is an age-related inflammatory disease. Globule-epidermal growth factor-8 (MFG-E8) and transforming growth factor-beta1 (TGF-beta1) are involved in the pathogenesis of AS. However, age-related changes in circulating levels of MFG-E8 and TGF-beta1, and their correlation with the severity of AS is not well-characterized. In this study, we investigated age-related changes in serum levels of MFG-E8, TGF-beta1 and examined their association with the severity of AS. Sixty healthy volunteers were divided into young, middle-age and old-age groups. In addition, carotid ultrasound examination was performed to assess the intima-media thickness (IMT) of carotid artery. Sixty-seven patients with carotid AS and 30 age-matched healthy persons were divided into IMT increased group, plaque group and control group. Serum levels of MFG-E8, TGF beta1, tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 were measured in all subjects. A positive association between serum MFG-E8 levels and age was observed in healthy volunteers, while a significant negative association was observed between TGF-beta1 levels and age. Serum levels of MFG-E8 and TNF-alpha showed a positive correlation while those of TGF-beta1 showed a negative correlation with Crouse scores for carotid artery IMT (P<0.05 for both). Both MFG-E8 and TGF-beta1 were age-related inflammatory factors. MFG E8 showed a positive correlation, while TGF-beta1 showed a negative correlation with the severity of AS. Our findings suggest that both MFG-E8 and TGF-beta1 are age-related inflammatory factors and are related to the degree of AS. In conclusion, both MFG-E8 and TGF-beta1 may serve as potential markers of the severity of AS. PMID- 29152650 TI - Semi-random mutagenesis profile of BCR-ABL during imatinib resistance acquirement in K562 cells. AB - Although imatinib is effective in chronic myeloid leukemia treatment, imatinib resistance due to the T315I mutation and/or other mutations is a challenge to be overcome. However, how DNA mutation occurs, particularly the T315I mutation, remains unclear. In the current study, the mutagenesis of BCR-ABL was analyzed via focusing on the process of drug resistance, rather than the final results. Clone sequencing of the BCR-ABL gene and other control genes was applied in two imatinib-resistant cell models. The results have indicated that imatinib actively and selectively causes sporadic mutations in the BCR-ABL gene, however not in the control genes. The majority of the mutations of BCR-ABL were not the clinically observed T315I mutation, suggesting that the T315I mutation may be due to clonal expansion of cells with survival advantages. Taken together, the results of the current study elucidated the mutagenesis process during drug resistance and thus aids in the management of chemotherapy. PMID- 29152652 TI - Effect of Wnt1 and Wnt5a on the development of dopaminergic neurons, and toxicity induced by combined exposure to paraquat and maneb during gestation and lactation. AB - Paraquat (PQ) and maneb (MB) are widely used herbicides. Wingless (Wnt) proteins serve a role in the development and differentiation of dopaminergic neurons. Previous studies demonstrated that combined exposure to PQ and MB damages dopaminergic neurons in the midbrain. Effects of PQ and MB exposure on midbrain Wnt proteins have also been previously reported. In the present study, from the 5th day of gestation to weaning of the offspring, pregnant Sprague-Dawley rats were administrated saline, or PQ and MB at two different doses: high, 15 mg/kg body weight PQ + 45 mg/kg body weight MB; or low, 10 mg/kg body weight PQ + 30 mg/kg body weight MB. Dopamine content in the striatum was examined by high performance liquid chromatography with a fluorescence detector and mRNA and protein expression of Wnt1, Wnt5a, nuclear receptor related factor 1 (Nurr1) and tyrosine hydroxylase (TH) in the midbrain was examined by reverse transcription quantitative polymerase chain reaction and western blotting. Combined exposure to PQ and MB during development decreased mRNA and protein expression of Wnt1, TH and Nurr1 and increased expression of Wnt5a in the offspring. PMID- 29152654 TI - Nephrin loss is reduced by grape seed proanthocyanidins in the experimental diabetic nephropathy rat model. AB - Diabetic nephropathy (DN) is one of the major causes of end-stage renal failure. Grape seed proanthocyanidin extracts (GSPE) are known to act as antioxidants. The current study aimed to determine the effects of GSPE on the streptozotocin (STZ) induced diabetic rat model and to explore the underlying mechanism of its action. Wistar rats were induced into a diabetic state by injection of STZ and were treated with 250 mg.kg-1.day-1 GSPE for 24 weeks. Kidney samples were collected for observation of renal pathological changes by light microscope (periodic acid Schiff staining) and electron microscopy. Reverse transcription-polymerase chain reaction, western blotting, and immunohistochemical staining were used to detect the mRNA and protein expression of the receptor for advanced glycation end products (RAGE), nephrin and podocin. The results indicated that diabetic rats treated with GSPE had markedly reduced Ccr, urinary albumin excretion, ratio of kidney weight to body weight, AGEs and ECM accumulation (P<0.01) compared with that in the diabetic rats. GSPE treatment can also reverse the renal pathological damage in diabetic rats. Further results indicated that GSPE treatment significantly decreased the RAGE expression level (P<0.01), and significantly increased the expression level of nephrin in the kidney and glomeruli of diabetic rats (P<0.01). However, no significant differences were identified in the expression of podocin following GSPE treatment (P>0.05). In conclusion, the results demonstrated that GSPE exerts a reno-protective effect by decreasing urinary albumin excretion and reversing renal pathological damage in diabetic rats. The underlying mechanism of GSPE activity is associated with the decreased expression of the AGEs/RAGE axis and the increased expression of nephrin in diabetic rats. PMID- 29152653 TI - Elaidic acid induces cell apoptosis through induction of ROS accumulation and endoplasmic reticulum stress in SH-SY5Y cells. AB - Elaidic acid, which is a major trans fatty acid, has been reported to be involved in neurotoxicity; however, the underlying molecular mechanisms underlying its neurotoxic effects remain largely unknown. Therefore, the present study aimed to investigate the potential mechanisms underlying elaidic acid-induced neuronal damage in vitro. The SH-SY5Y neuroblastoma cell line was used as a model in the present study. Following treatment of cells with various concentrations of elaidic acid or with vehicle for 24 h, cell viability was measured using the MTT assay. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) release were measured using flow cytometry. Cell apoptosis was measured by Annexin V-fluorescein isothiocyanate/propidium iodide double staining, and cellular redox status was determined using ELISA analysis. Furthermore, western blotting was used to detect the protein expression levels of factors associated with oxidative damage and components of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) signaling pathways. The results demonstrated that elaidic acid treatment inhibited cell viability, elevated cell apoptosis and resulted in a loss of MMP. In addition, elaidic acid induced marked alterations in cellular redox status. Treatment with high doses of elaidic acid treatment also enhanced the release of ROS, and upregulated lipid peroxide and malondialdehyde levels; however, it reduced superoxide dismutase and glutathione peroxidase activities. Furthermore, elaidic acid resulted in upregulation of nuclear factor erythroid 2-related factor 2 and downregulation of heme oxygenase 1, which are two key antioxidative factors. Elaidic acid treatment also induced or inhibited the expression of numerous ER stress/UPR-associated molecules. It induced glucose-regulated protein 78 (GRP78) expression, whereas the expression levels of activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP) were upregulated and then downregulated following treatment with various doses of elaidic acid. These results indicated that elaidic acid inhibited SH-SY5Y cell growth and induced apoptosis by enhancing oxidative stress and activating the ER stress/UPR signaling pathway and the GRP78/ATF4/CHOP pathway. PMID- 29152655 TI - TGF-beta1 expression in adults with non-traumatic osteonecrosis of the femoral head. AB - Non-traumatic osteonecrosis of the femoral head (NONFH) is a common clinical osteoarthropathy. The present study aimed to investigate the association between transforming growth factor beta1 (TGF-beta1) and NONFH. Femoral head specimens were collected from patients with NONFH. Patients with traumatic osteonecrosis served as the control. Hematoxylin and eosin (H&E) staining was used to visualize the bone tissue architecture. Immunohistochemistry and densitometry were performed to quantify TGF-beta1 expression in tissues. Flow cytometry was used to detect cluster of differentiation (CD)3+, CD4+ and CD8+ cells, and the ratio of CD4+ to CD8+ T cells in the peripheral blood. H&E staining revealed osteonecrosis, disintegration of osteocytes with karyopyknosis and karyorrhexis, loss of osteocyte lacunae, aberrantly arranged circumferential lamellae, as well as dissolution of the lamellae and subtle osteogenesis in the experimental group, as opposed to the control group. Immunohistochemistry revealed that the expression of TGF-beta1 was significantly reduced in the experimental group (P<0.01). Further, the NONFH group had a decrease in the CD3+ and CD4+ cell populations (P<0.05 and P<0.01, respectively), an increase in the CD8+ cell population (P<0.05), as well as a reduction in the ratio of CD4+ to CD8+ cells (P<0.01). The present study indicated that TGF-beta1 expression was reduced in NONFH. This was associated with impaired repairing capacity of the femoral head and dysregulated subsets of T-lymphocytes and possible immune functions. PMID- 29152656 TI - miR-320a modulates cell growth and chemosensitivity via regulating ADAM10 in gastric cancer. AB - MicroRNAs (miRNAs) may function as tumor suppressor or onco-miRNAs and have critical roles in the pathogenesis of gastric cancer (GC). The exact function and mechanism of miRNA (miR)-320a in GC remains to be elucidated. The present study performed gain- and loss-of-function analyses by transfecting cells with mimics or inhibitors and subsequently performing colony formation, proliferation and cisplatin-sensitivity assays. Additionally, in vivo xenograft models were also performed. Bioinformatics algorithms, luciferase reporter activity assay and western blotting were used to predict the potential target of miR-320a. Additionally, the effect of knockdown or overexpression of ADAM metallopeptidase domain 10 (ADAM10) on cell growth and chemosensitivity was examined. The expression of miR-320a and ADAM10 was also determined in primary tumors. The present study revealed that the expression of miR-320a was reduced in GC cells and ectopic miR-320a expression significantly inhibited cell growth in vitro and in vivo and enhanced the sensitivity of GC cells to cisplatin. ADAM10 was a direct target of miR-320a in GC. Knockdown of ADAM10 attenuated the proliferative ability of GC cells, and increased the sensitivity of GC cells to cisplatin. The upregulated ADAM10 accelerated cell growth rate and reduced the cisplatin sensitivity of cells. Clinically, a significantly negative correlation was identified between the expression of miR-320a and mRNA levels of ADAM10 in tumors. The findings of the present study suggested that miR-320a may function as a tumor suppressor in GC progression and potential therapeutic strategies for GC may be based on the miR-320a/ADAM10 axis. PMID- 29152657 TI - Dihydroartemisinin treatment exhibits antitumor effects in glioma cells through induction of apoptosis. AB - The present study aimed to investigate the effect of dihydroartemisinin on the proliferation of chemotherapy-resistant C6 rat glioma cells. The results revealed that incubation of C6 glioma cells with a range of dihydroartemisinin concentrations for 48 h led to a significant (P<0.02) reduction in the cell number. There was a -0.8-fold reduction in the cell count following treatment with 20 uM dihydroartemisinin when compared with the control cultures. Analysis of DNA synthesis using bromodeoxyuridine (BrdU) staining demonstrated a reduction in the BrdU-labeling index (LI) following treatment with 20 uM dihydroartemisinin. There was a 6-fold reduction in the BrdU-LI compared with the control cultures. Incubation of the C6 glioma cells with dihydroartemisinin led to a concentration dependent reduction in the level of cyclic adenosine 3',5' monophosphate following 48 h. The percentage of apoptotic cells in the cultures incubated with 20 uM dihydroartemisinin was 54.78% compared with 2.57% in the control cultures. Incubation of the C6 glioma cells with dihydroartemisinin for 48 h led to a reduction in the percentage of cells in G2/M phase with an increase in G0/G1 phase. The control cells exhibited spindle-shaped morphology and were actively undergoing mitosis following 48 h of culture. The morphological characteristics of the cells treated with dihydroartemisinin were demonstrated to be round with small surface projections. Therefore, treatment of glioma cells with dihydroartemisinin exhibited an antitumor effect by the induction of apoptosis. Therefore, dihydroartemisinin should be evaluated further in the animal models for the treatment of glioma. PMID- 29152658 TI - Hepatic differentiation of mouse bone marrow-derived mesenchymal stem cells using a novel 3D culture system. AB - The development of novel culture systems that mimic the in vivo microenvironment may be beneficial for inducing the differentiation of stem cells and promoting liver function. In the present study, spheroid cultures and decellularized liver scaffolds (DLSs) were utilized to obtain differentiated hepatocyte-like cells. Mouse bone marrow (BM)-derived mesenchymal stem cells (MSCs) self-aggregated into spheroids under low-attachment conditions and implanted into the DLSs via a negative pressure suction device. The Albp-ZsGreen adenoviral vector was utilized for real-time monitoring of hepatocyte-like cell differentiation. To detect the differentiation stages of the MSCs, immunostaining of hepatocyte markers and functional analysis was performed. Compared with traditional 2D monolayer induction, mouse BM-MSCs spheroids and DLSs in 3D culture generated greater yields of mature, differentiated hepatocytes. In conclusion, this 3D culture system may provide a strategy for generating hepatocyte-like cells for portable liver micro-organs, and aid clinical hepatocyte transplantation and liver tissue engineering. PMID- 29152659 TI - MicroRNA-216b inhibits cell proliferation and invasion in glioma by directly targeting metadherin. AB - Glioma is a well-known aggressive and malignant brain tumor, and accounts for ~30% of all brain and central nervous system tumors. A number of studies have indicated that the abnormal expression of specific microRNAs (miR) serves vital roles in the tumorigenesis and tumor development of human cancer, including glioma. miR-216b has been studied in a number of types of cancer. However, the expression pattern, molecular function and underlying mechanisms of miR-216b in glioma remain unclear. In the present study, it was demonstrated that the level of miR-216b was significantly decreased in glioma tissues and cell lines compared with matched normal tissues and primary normal human astrocytes. The reduced miR 216b expression level was correlated with the Karnofsky Performance Score and the World Health Organization grade of gliomas. Upregulation of miR-216b repressed cell proliferation and invasion in glioma. Additionally, metadherin (MTDH) was identified as a direct target gene of miR-216b in glioma. MTDH expression was demonstrated to be significantly upregulated and inversely associated with miR 216b expression in glioma specimens. MTDH knockdowns could simulate the cellular conditions induced by miR-216b overexpression in glioma cells. In addition, miR 216b regulated phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual specificity protein phosphatase PTEN/protein kinase B signaling pathways in glioma. These results suggested that miR-216b acted as a tumor suppressor in glioma by directly targeting MTDH and that the miR-216b/MTDH axis may be an effective therapeutic target for the treatment of patients with this disease. PMID- 29152661 TI - Apolipoprotein status in type 2 diabetes mellitus and its complications (Review). AB - Dyslipidaemia in type 2 diabetes mellitus (T2DM) is characterized by high plasma triglyceride concentrations, reduced high-density lipoprotein concentrations and increased small density low-density lipoprotein concentrations. Dyslipidaemia may lead to cardiovascular disease (CVD) and other complications. Apolipoproteins mainly comprise six species, apolipoprotein (apo)A, apoB, apoC, apoD, apoE and apoM, which are important components of plasma lipoproteins that carry lipids and stabilize the structure of lipoproteins. Complex metabolic disorders of apolipoproteins are present in T2DM, such as high plasma apoB, apoC-II, apoC-III and apoE concentrations, and low plasma apoA-I and apoM concentrations, which are associated with dyslipidaemia and interrelated complications. Plasma concentrations of some apolipoproteins are also altered in T2DM with CVD or other complications. Several apolipoprotein polymorphisms are associated with diabetes susceptibility and/or lipid metabolism. The present review described the metabolic disorders of apolipoproteins in T2DM and its complications, and the relationship between each major apolipoprotein and T2DM, as well as the effects of apolipoprotein polymorphisms on diabetic susceptibility. PMID- 29152662 TI - Oxymatrine induces nasopharyngeal cancer cell death through inhibition of PI3K/AKT and NF-kappaB pathways. AB - Oxymatrine may inhibit tumor cell proliferation, induce cell cycle arrest, promote apoptosis, induce tumor cell differentiation and fight against tumor angiogenesis, as well as inhibit tumor invasion and metastasis. The present study aimed to investigate the anticancer effects of oxymatrine on nasopharyngeal cancer (NPC) cell death, and the underlying molecular mechanisms of these effects. NPC HK-1 cells were incubated overnight and treated with oxymatrine (0, 2, 4, 6 and 8 mg/ml) for 1, 2 or 3 days. The results demonstrated that oxymatrine significantly inhibited NPC cell proliferation in a time- and dose-dependent manner. Oxymatrine treatment also induced apoptosis, induced the activities of caspase-3 and caspase-9, promoted p53 and Bax protein expression, and suppressed cyclin D protein expression in these cells. The protein expression levels of phosphoinositide 3 kinase (PI3K), phosphorylated (p)-AKT, p-mammalian target of rapamycin, p-p70 ribosomal protein S6 kinase and nuclear factor (NF)-kappaB were significantly downregulated by oxymatrine treatment. In conclusion, results from the present study suggested that oxymatrine may induce NPC cell death through the inhibition of PI3K/AKT and NF-kappaB signaling pathways. PMID- 29152660 TI - Therapeutic effects of STAT3 inhibition by nifuroxazide on murine acute graft graft-vs.-host disease: Old drug, new use. AB - Graft-vs.-host disease (GvHD) is a major and lethal complication of allogeneic bone marrow transplantation (allo-BMT). Although great development has been made, the treatment progress of this disorder is slow. Research has illustrated that STAT3 was critical for T cell alloactivation in GvHD. In the present study, the authors hypothesized that nifuroxazide, as the STAT3 inhibitor, treatment may attenuate the development of acute GvHD (aGvHD). The results demonstrated that nifuroxazide suppressed the development of aGvHD and significantly delayed aGvHD induced lethality. Mice receiving nifuroxazide had mostly normal-appearing skin with minimal focal ulceration, mild edema and congestion in the liver, and a less pronounced villus injury and less inflammatory infiltrate in the small intestine. Treatment with nifuroxazide inhibited the activation of STAT3, resulting in the regulation of the CD4+ T cells and CD4+CD25+ T cells and reduction of interferon gamma and tumor necrosis factor-alpha levels. In conclusion, nifuroxazide may be efficacious for post-transplant of GvHD, providing a potent drug for use as a prophylactic or as a second-line therapy for aGvHD in clinical trials. PMID- 29152663 TI - MicroRNA-137 has a suppressive role in liver cancer via targeting EZH2. AB - A variety of microRNAs (miRs) have been demonstrated to be associated with the development and malignant progression of human cancer; however, the regulatory mechanism of miR-137 underlying hepatocellular carcinoma (HCC) growth and metastasis still remains to be fully revealed. In the present study, reverse transcription-quantitative polymerase chain reaction and western blot were used to examine mRNA and protein expression. MTT assay, wound healing assay and Transwell assay were performed to determine cell proliferation, migration and invasion. Luciferase reporter assay was conducted to confirm the targeting relationship. miR-137 was significantly downregulated in HCC tissues compared to adjacent normal tissues. Low expression of miR-137 was significantly associated with lymph node metastasis, vein invasion, advanced clinical stage and poor prognosis in HCC. In addition, miR-137 was also downregulated in several liver cancer cell lines compared with normal liver epithelial cells. Overexpression of miR-137 led to a significant reduction in cell proliferation, migration and invasion of HepG2 cells. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) was further identified as a direct target gene of miR-137, and the protein expression of EZH2 was negatively regulated by miR-137 in HepG2 cells. Additionally, EZH2 was significantly upregulated in HCC tissues and liver cancer cell lines. Furthermore, overexpression of EZH2 significantly eliminated the inhibitory effects of miR-137 on the malignant phenotypes of HepG2 cells. Therefore, the findings suggest that miR-137 may have a suppressive role in HCC growth and metastasis via targeting EZH2. PMID- 29152664 TI - Tumor suppressive role of miR-194-5p in glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is defined by the World Health Organization as the most aggressive form of grade IV glioma, characterized by unrestrained cellular proliferation. microRNAs (miRs) serve important roles in the pathogenesis of GBM. However, the function of miR-194-5p in GBM remains unknown. In the present study, the miR-194-5p levels in GBM tissues and cells were evaluated using the reverse transcription-quantitative polymerase chain reaction. Cellular proliferation was tested by MTT analysis. Cellular apoptosis was analyzed by fluorescence-activated cell sorting. The protein level of insulin-like growth factor 1 receptor, the target gene of miR-194-5p, was evaluated by western blotting. The interaction between miR-194-5p and the target gene was confirmed by the dual-luciferase reporter assay. It was demonstrated that miR-194-5p inhibited cell growth and promoted apoptosis. In conclusion, the results of the present study indicated the tumor suppressive role of miR-194-5p. PMID- 29152666 TI - Neuroanatomical background and functional considerations for stereotactic interventions in the H fields of Forel. AB - The H fields of Forel constitute an intricate neuroanatomical structure that occupies a central position within the posterior subthalamus. Anatomically, it features a dense concentration of fiber bundles including corticofugal, pallidothalamic, cerebellothalamic and other projections that connect functionally relevant areas of the brain. Functionally, the fields of Forel are embedded within the cortico-striato-thalamo-cortical circuit and constitute the main link between the striatopallidal system and the thalamocortical network. Given the current understanding of basal ganglia involvement in movement disorders and neuropsychiatric disease we sought to investigate the H fields of Forel as a potential target in stereotactic functional neurosurgery. Although historically recognized in the treatment of movement disorders, behavioral disorders and epilepsy, the significance of the H fields is considerably diminished today receiving only little attention. Owing to the current lack of reviews addressing the anatomical and functional organization of Forel's fields, we aim to deliver an up-to-date overview of the H fields in this paper. We investigate the complex neuroanatomy and describe the passage of the various fiber systems that course through the posterior subthalamus. We revise the role of Forel's fields in the current context of our understanding of cortico-basal ganglia circuitry and discuss the historic relevance of Forel's fields during the lesional era. Finally, we provide an outlook regarding the potential of deep brain stimulation in close proximity and within the H fields of Forel. PMID- 29152665 TI - Effects of WD-3 on tumor growth and the expression of integrin alphavbeta3 and ERK1/2 in mice bearing human gastric cancer using the 18F-RGD PET/CT imaging system. AB - Activation of the vitronectin receptor alphavbeta3 and the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 are critical events during tumor development and progression. The aim of the present study was to investigate the effects of WD-3, a formula used in traditional Chinese medicine, on integrin alphavbeta3 and ERK1/2 expression in vivo using a nude mouse-human gastric cancer xenograft model combined with non-invasive, real-time 18F-Arg-Gly-Asp (RGD) positron emission tomography (PET)/computerized tomography (CT) imaging methods. SGC-7901 human gastric cancer cells were subcutaneously injected into BALB/c nude mice. Following tumor development, animals were randomly assigned into the following 4 groups (n=6 mice/group): Control group (CG), Chinese medicine group (CMG), Western medicine group (WMG) and Chinese and Western medicine combination group (CMG + WMG). Mice in the CG and CMG received daily intragastric injections of 0.5 ml saline and 0.5 ml WD-3, respectively. Mice in the WMG received an intravenous injection of albumin-bound paclitaxel (25 mg/kg) on days 0, 2 and 4 Mice in the CMG + WMG received combination therapy of WD-3 and albumin-bound paclitaxel. Tumor growth was monitored using standard caliper technique and via PET imaging. 18F-RGD PET/CT analysis was performed on days 3, 7, 18 and 24 following drug administration. Radioactivity uptake was measured and expressed as the percentage of injected dose (ID) per tissue weight (%ID/g) and the standardized uptake value (SUV). Animals were sacrificed at 30 days following treatment and tumor weight was measured. Immunohistochemistry was used to detect the expression of phosphorylated (p)-ERK1/2 protein in tumor tissue samples. No statistically significant differences were observed in %ID/g and SUV among the various groups prior to treatment. At the end of treatment, mice in the CMG, WMG and CMG + WMG exhibited significantly reduced tumor mass when compared with mice in the CG. In addition, mice in the CMG and CMG + WMG demonstrated reduced %ID/g and SUV when compared with mice in the CG. Conversely, mice in the WMG exhibited no significant difference in %ID/g and SUV compared with the CG. Furthermore, p ERK1/2 expression was significantly reduced in mice from all treatment groups when compared with those in the CG. The results of the present study suggest that the traditional Chinese formula WD-3 may inhibit gastric tumor growth, potentially via the downregulation of integrin alphavbeta3 and the inhibition of ERK1/2 phosphorylation in vivo. PMID- 29152667 TI - Correction to: Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis. AB - On page 4 of the original version of this article, the text "Eight (29%) of the patients had significant FDG-avid disease (i.e. with intensity above liver parenchyma) prior to treatment" needs to be corrected. PMID- 29152668 TI - The role of astrocytic calcium and TRPV4 channels in neurovascular coupling. AB - Neuronal activity evokes a localised change in cerebral blood flow in a response known as neurovascular coupling (NVC). Although NVC has been widely studied the exact mechanisms that mediate this response remain unclear; in particular the role of astrocytic calcium is controversial. Mathematical modelling can be a useful tool for investigating the contribution of various signalling pathways towards NVC and for analysing the underlying cellular mechanisms. The lumped parameter model of a neurovascular unit with both potassium and nitric oxide (NO) signalling pathways and comprised of neurons, astrocytes, and vascular cells has been extended to include the glutamate induced astrocytic calcium pathway with epoxyeicosatrienoic acid (EET) signalling and the stretch dependent TRPV4 calcium channel on the astrocytic endfoot. Results show that the potassium pathway governs the fast onset of vasodilation while the NO pathway has a delayed response, maintaining dilation longer following neuronal stimulation. Increases in astrocytic calcium concentration via the calcium signalling pathway and/or TRPV4 channel to levels consistent with experimental data are insufficient for inducing either vasodilation or constriction, in contrast to a number of experimental results. It is shown that the astrocyte must depolarise in order to produce a significant potassium flux through the astrocytic BK channel. However astrocytic calcium is shown to strengthen potassium induced NVC by opening the BK channel further, consequently allowing more potassium into the perivascular space. The overall effect is vasodilation with a higher maximal vessel radius. PMID- 29152669 TI - Brief Report: Bullying and Anxiety in High-Functioning Adolescents with ASD. AB - Youth with ASD are more likely to experience bullying than their typically developing peers. This risk has not been studied in youth with ASD transitioning to college. We examined the occurrence of bullying in 35 high functioning youth with ASD who were preparing to attend college. We also examined youth anxiety and ASD symptoms. Fifty-one percent of the sample reported being recent victims of bullying; 31% of parents reported their child was a victim of bullying. Parent report of bullying correlated significantly with ratings of youth social anxiety symptoms. These findings suggest that bullying is an issue of concern for higher functioning, older adolescents with ASD, and that their own reports may be particularly important in identifying its occurrence. PMID- 29152670 TI - Double Voicing and Personhood in Collaborative Life Writing about Autism: the Transformative Narrative of Carly's Voice. AB - Collaborative memoirs by co-writers with and without autism can enable the productive interaction of the voices of the writers in ways that can empower rather than exploit the disabled subject. Carly's Voice, co-written by Arthur Fleischmann and his autistic daughter Carly, demonstrates the capacity for such life narratives to facilitate the relational interaction between writers in the negotiation of understandings of disability. Though the text begins by focusing on the limitations of life with autism, it develops into a collaboration which helps both writers move toward new ways of understanding disability and their own and one another's life stories. PMID- 29152671 TI - Comparative Transcriptome Analysis Provides Insights into Differentially Expressed Genes and Long Non-Coding RNAs between Ovary and Testis of the Mud Crab (Scylla paramamosain). AB - The molecular mechanism underlying sex determination and gonadal differentiation of the mud crab (Scylla paramamosain) has received considerable attention, due to the remarkably biological and economic differences between sexes. However, sex biased genes, especially non-coding genes, which account for these differences, remain elusive in this crustacean species. In this study, the first de novo gonad transcriptome sequencing was performed to identify both differentially expressed genes and long non-coding RNAs (lncRNAs) between male and female S. paramamosain by using Illumina Hiseq2500. A total of 79,282,758 and 79,854,234 reads were generated from ovarian and testicular cDNA libraries, respectively. After filtrating and de novo assembly, 262,688 unigenes were produced from both libraries. Of these unigenes, 41,125 were annotated with known protein sequences in public databases. Homologous genes involved in sex determination and gonadal development pathways (Sxl-Tra/Tra-2-Dsx/Fru, Wnt4, thyroid hormone synthesis pathway, etc.) were identified. Three hundred and sixteen differentially expressed unigenes were further identified between both transcriptomes. Meanwhile, a total of 233,078 putative lncRNAs were predicted. Of these lncRNAs, 147 were differentially expressed between sexes. qRT-PCR results showed that nine lncRNAs negatively regulated the expression of eight genes, suggesting a potential role in sex differentiation. These findings will provide fundamental resources for further investigation on sex differentiation and regulatory mechanism in crustaceans. PMID- 29152672 TI - Effectiveness of biosimilar filgrastim vs. original granulocyte colony stimulating factors in febrile neutropenia prevention in breast cancer patients. AB - PURPOSE: The purpose of this study is to describe the effectiveness of biosimilar filgrastim and original granulocyte colony-stimulating factors (G-CSFs), lenograstim and pegfilgrastim, in febrile neutropenia (FN) prevention in breast cancer patients receiving docetaxel/doxorubicin/cyclophosphamide (TAC) as adjuvant/neoadjuvant treatment and to analyze their treatment patterns. METHODS: A pharmacoepidemiology cohort study was developed in a university hospital (with 23 healthcare centers) with retrospective data collection (2012-2014). Effectiveness of G-CSFs was assessed by the FN incidence. Other parameters analyzed were as follows: moderate and severe neutropenia incidence, neutropenia related hospitalizations, dosage, and duration. Data was analyzed using each cycle as a unit of analysis. RESULTS: We identified 98 patients representing 518 chemotherapy cycles, 215 with original G-CSFs (35 lenograstim and 180 pegfilgrastim) and 303 with biosimilar filgrastim. The FN incidence was similar in both groups (3.7% original vs. 3.3% biosimilar; p = 0.79). No statistically significant differences were found in moderate and severe neutropenia incidence (4.7 vs. 6.3%; p = 0.43) or neutropenia-related hospitalizations (3.3 vs. 3.6%; p = 0.19). When the three drugs were evaluated separately, a higher FN incidence was observed with lenograstim than with pegfilgratim or biosimilar (p = 0.024). The dosage and duration of biosimilar were lower than lenograstim (4.9 vs. 5.7 MUg/kg/day; 5 vs. 7 days; p < 0.001). CONCLUSION: An abbreviated 5-day course of biosimilar filgrastim provided optimal primary prophylaxis against FN post chemotherapy TAC in patients with breast cancer. The clinical relevance of the highest FN incidence in the lenograstim cohort needs further attention. PMID- 29152674 TI - Progress and promise for the MDMA drug development program. AB - Pharmacotherapy is often used to target symptoms of posttraumatic stress disorder (PTSD), but does not provide definitive treatment, and side effects of daily medication are often problematic. Trauma-focused psychotherapies are more likely than drug treatment to achieve PTSD remission, but have high dropout rates and ineffective for a large percentage of patients. Therefore, research into drugs that might increase the effectiveness of psychotherapy is a logical avenue of investigation. The most promising drug studied as a catalyst to psychotherapy for PTSD thus far is 3,4-methylenedioxymethamphetamine (MDMA), commonly known as the recreational drug "Ecstasy." MDMA stimulates the release of hormones and neurochemicals that affect key brain areas for emotion and memory processing. A series of recently completed phase 2 clinical trials of MDMA-assisted psychotherapy for treatment of PTSD show favorable safety outcomes and large effect sizes that warrant expansion into multi-site phase 3 trials, set to commence in 2018. The nonprofit sponsor of the MDMA drug development program, the Multidisciplinary Association for Psychedelic Studies (MAPS), is supporting these trials to explore whether MDMA, administered on only a few occasions, can increase the effectiveness of psychotherapy. Brain imaging techniques and animal models of fear extinction are elucidating neural mechanisms underlying the robust effects of MDMA on psychological processing; however, much remains to be learned about the complexities of MDMA effects as well as the complexities of PTSD itself. PMID- 29152675 TI - A randomized double-blind placebo-controlled trial of vitamin D supplementation in juvenile-onset systemic lupus erythematosus: positive effect on trabecular microarchitecture using HR-pQCT. AB - : In this randomized double-blind placebo-controlled 24-week trial, cholecalciferol supplementation at 50,000 IU/week effectively improved bone microarchitecture parameters in juvenile-onset systemic lupus erythematosus (JoSLE) patients, as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at tibia site. An increase in the trabecular number and a decrease in the trabecular separation were observed, suggesting that vitamin D supplementation may be recommended for JoSLE patients with its deficiency. INTRODUCTION: Vitamin D has an important effect on bone but there are no trials that directly address the boosting of serum levels of 25-hydroxyvitamin D (25OHD) in bone microarchitecture in JoSLE patients. The aim of this study was to evaluate the effect of vitamin D supplementation on bone microarchitecture parameters using HR-pQCT in JoSLE patients. METHODS: This study was a randomized double-blind placebo-controlled 24-week trial. Forty female JoSLE patients were randomized (1:1) to receive oral cholecalciferol at 50,000 IU/week (JoSLE-VitD) or placebo (JoSLE-PL). The medications remained stable throughout the study. Serum levels of 25OHD were measured using a radioimmunoassay. The bone microarchitecture and volumetric bone density were analyzed using HR-pQCT at tibia site. RESULTS: At baseline, the groups were similar with respect to their age, body mass index, organ involvement, glucocorticoid dose, immunosuppressant use, serum 25OHD levels, and HR-pQCT parameters. After 24 weeks, higher 25OHD levels were observed in the JoSLE-VitD group compared to the JoSLE-PL group [31.3 (8.6) vs. 16.5 (5.8) ng/mL, p < 0.001]. An increase in the trabecular number [?Tb.N 0.16 (0.24) vs. 0.03 (0.19) 1/mm, p = 0.024] and a decrease in the trabecular separation [?ThSp -0.045 (0.067) vs. 0.001 (0.009) mm, p = 0.017] were found in the JoSLE-VitD group compared to the JoSLE-PL group at tibia site. No differences were observed in other structural parameters [trabecular (Tb.Th) or cortical thickness (Ct.Th)], volumetric bone mineral densities, cortical porosity, and biomechanical parameters (p > 0.05). CONCLUSION: This study suggests that cholecalciferol supplementation for 24 weeks effectively improved the bone microarchitecture parameters, mainly the trabecular number, in JoSLE patients. TRIAL REGISTRATION: NCT01892748. PMID- 29152673 TI - Approach to hyponatremia according to the clinical setting: Consensus statement from the Italian Society of Endocrinology (SIE), Italian Society of Nephrology (SIN), and Italian Association of Medical Oncology (AIOM). PMID- 29152676 TI - Coraliitalea coralii gen. nov., sp. nov., a Marine Bacterium of the Family Flavobacteriaceae Isolated from the Hard Coral Galaxea fascicularis. AB - A polyphasic taxonomic study was performed on a novel strain designated as 04OKA 3-121T, which was isolated from the hard coral Galaxea fascicularis L. collected at Akajima, Okinawa, Japan. These bacterial cells were observed to be pale yellow, Gram-stain-negative, strictly aerobic, chemoheterotrophic, non-spore forming, non-motile, and rod-shaped. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that the novel marine isolate is affiliated with the family Flavobacteriaceae of the phylum Bacteroidetes and that it shared the highest (93.6%) sequence similarity with Pseudozobellia thermophila KMM 3531T. The strain could be phenotypically differentiated from related members of the family Flavobacteriaceae. Major fatty acids of strain 04OKA-3-121T were iso C15:0, iso-C15:1 G, and C16:1 omega7c and/or C16:1 omega6c. The DNA G + C content of the strain was determined to be 38.8 mol% and the major respiratory quinone was identified as menaquinone 6 (MK-6). Strain 04OKA-3-121T had phosphatidylethanolamine, two unidentified aminolipids, and eight unidentified lipids as polar lipids. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, the strain is considered to represent a novel genus in the family Flavobacteriaceae, for which the name Coraliitalea coralii gen. nov., sp. nov. is proposed. The type strain of C. coralii gen. nov., sp. nov. is 04OKA-3-121T (= KCTC 52378T = NBRC 112329T). PMID- 29152677 TI - ADHD and Anxiety: Clinical Significance and Treatment Implications. AB - In comparison to the DSM formulation of ADHD, we have proposed that ADHD in adults should be divided into Inattentive and Emotional Dysregulation Presentations. Under both systems, there is potential overlap with generalized anxiety disorder (GAD). We compared data from four distinct populations: ADHD clinical trials, GAD clinical trials, an ADHD clinic, and a forensic clinic. Approximately 25% of patients in each population had comorbid ADHD and anxiety. Comorbid subjects reported more childhood ADHD symptoms and higher scores on ADHD scales and were more likely to fit criteria for ADHD Emotional Dysregulation Presentation or DSM-IV combined type. Comorbid subjects did not drop out at a higher rate and showed significant drug-placebo differences on ADHD symptoms, including Emotional Dysregulation. Conversely, although symptoms of anxiety decreased, there was no drug-placebo difference in improvement. PMID- 29152678 TI - First-year results of an antibiotic stewardship program in a Greek tertiary care hospital. AB - The aim of this study was to investigate the effect of the implementation of an antibiotic stewardship program (ASP) on antibiotic consumption in our 428-bed hospital. The Infection Control Committee implemented an ASP beginning in January 2016, aiming to reduce inappropriate antibiotic use through improved prescribing practices. The ASP included both pre-authorization and prospective audit and feedback strategies. We collected pharmacy and hospital data for the years 2015 (pre-intervention) and 2016 (post-intervention). Consumption data were expressed as daily defined doses (DDDs) per 100 patient-days (PD) and the significance of the differences between 2015 and 2016 was assessed by paired t-test. Antibiotic resistance rates for the most important hospital pathogens were monitored for 2015-2016. The ASP effectively reduced consumption of most antimicrobials; total antibiotic use decreased by 16.7% (from 104.3 in 2015 to 86.9 DDDs/100 patient days in 2016, p < 0.001) owing to reduction of 19.1% for non-restricted and 13.8% for restricted antibiotics. Important restricted antimicrobials, such as colistin, carbapenems, quinolones and tigecycline showed significantly decreased usage post-intervention. Significant changes in the resistance rates were not observed, except a decreasing trend for colistin and tigecycline (Acinetobacter baumannii and Klebsiella pneumoniae) and also vancomycin (enterococci). The ASP was successful in terms of reducing the antibiotic consumption for the first year of its implementation. Interestingly, antimicrobials requiring pre-authorization exhibited a lower reduction than other antibiotics. Potential effects of the ASP in reducing resistance rates remain to be shown. PMID- 29152679 TI - A comparative study of cone beam computed tomography and conventional radiography in diagnosing the extent of root resorptions. AB - BACKGROUND: Root resorptions are assessed and diagnosed using different radiographical techniques. A comparison of the ability to assess resorptions on two-dimensional (2D) and three-dimensional (3D) radiographs is, hitherto, lacking. The aims of this study were to evaluate the accuracy of 2D (periapical radiographs, PA and panoramic radiograph, PAN) and 3D (cone beam computed tomography, CBCT) radiographic techniques in measuring slanted root resorptions compared to the true resorptions, a histological gold standard, in addition to a comparison of all the radiographic techniques to each other. METHODS: Radiographs (CBCT, PA, and PAN), in addition to histological sections, of extracted deciduous canines from thirty-four patients were analyzed. Linear measurements of the most and least resorbed side of the root, i.e., "slanted" resorptions, were measured using an analyzing software (Facad (r)). For classification of slanted root resorptions, a modified Malmgren index was used. RESULTS: PAN underestimated the root length on both the least and most resorbed side. Small resorptions, i.e., low modified Malmgren scores, were more difficult to record and were only assessed accurately using CBCT. The root resorption scores were underestimated using PA and PAN. In assessment of linear measures, PAN differed significantly from both CBCT and PA. CONCLUSIONS: CBCT is the most accurate technique when measuring and scoring slanted root resorptions. PMID- 29152680 TI - Restless legs syndrome and sleep quality among adult sickle cell disease patients. AB - OBJECTIVE: The purpose of this study is to determine and compare the prevalence of restless legs syndrome (RLS) between adult patients with sickle cell disease (SCD) and non-SCD anemia. METHODS: This cross-sectional study was conducted from December 2013 to July 2014. Patients with SCD and non-SCD anemia were recruited from a hematology clinic at a large university hospital. Patients with secondary RLS were excluded. Data were collected on demographic features, clinical evaluations, laboratory tests, sleep quality using the Pittsburgh Sleep Quality Index, RLS symptoms using the International Restless Legs Syndrome Study Group Criteria, severity of RLS using the International Restless Leg Syndrome Rating Scale, and daytime sleepiness using the Epworth Sleepiness Scale. RESULTS: The study sample consisted of 44 patients with SCD and 45 with non-SCD anemia. The two groups were comparable in age, gender, body mass index, smoking habit, and comorbidities. Poor sleep quality was found in 63% of the SCD group compared to 53% of the non-SCD group. The prevalence of RLS among SCD group and non-SCD group was 13.6% (6/44) and 8.8% (4/45), respectively. These differences, however, were not statistically significant, p > 0.05. Excessive daytime sleepiness was also similar in both groups, with the rate being 20.5 and 17.8% in the SCD and non-SCD groups, respectively. CONCLUSION: Our study revealed that poor sleep quality and RLS were both common among adult patients with SCD; however, they did not differ significantly from patients with non-SCD anemia. PMID- 29152681 TI - Trichothecenes: immunomodulatory effects, mechanisms, and anti-cancer potential. AB - Paradoxically, trichothecenes have both immunosuppressive and immunostimulatory effects. The underlying mechanisms have not been fully explored. Early studies show that dose, exposure timing, and the time at which immune function is assessed influence whether trichothecenes act in an immunosuppressive or immunostimulatory fashion. Recent studies suggest that the immunomodulatory function of trichothecenes is also actively shaped by competing cell-survival and death-signaling pathways. Autophagy may also promote trichothecene immunosuppression, although the mechanism may be complicated. Moreover, trichothecenes may generate an "immune evasion" milieu that allows pathogens to escape host and vaccine immune defenses. Some trichothecenes, especially macrocyclic trichothecenes, also potently kill cancer cells. T-2 toxin conjugated with anti-cancer monoclonal antibodies significantly suppresses the growth of thymoma EL-4 cells and colon cancer cells. The type B trichothecene diacetoxyscirpenol specifically inhibits the tumor-promoting factor HIF-1 in cancer cells under hypoxic conditions. Trichothecin markedly inhibits the growth of multiple cancer cells with constitutively activated NF-kappaB. The type D macrocyclic toxin Verrucarin A is also a promising therapeutic candidate for leukemia, breast cancer, prostate cancer, and pancreatic cancer. The anti-cancer activities of trichothecenes have not been comprehensively summarized. Here, we first summarize the data on the immunomodulatory effects of trichothecenes and discuss recent studies that shed light on the underlying cellular and molecular mechanisms. These mechanisms include autophagy and major signaling pathways and their crosstalk. Second, the anti-cancer potential of trichothecenes and the underlying mechanisms will be discussed. We hope that this review will show how trichothecene bioactivities can be exploited to generate therapies against pathogens and cancer. PMID- 29152682 TI - Estrogenicity of halogenated bisphenol A: in vitro and in silico investigations. AB - The binding interactions of bisphenol A (BPA) and its halogenated derivatives (halogenated BPAs) to human estrogen receptor alpha ligand binding domain (hERalpha-LBD) was investigated using a combined in vitro and in silico approach. First, the recombinant hERalpha-LBD was prepared as a soluble protein in Escherichia coli BL21(DE3)pLysS. A native fluorescent phytoestrogen, coumestrol, was employed as tracer for the fluorescence polarization assay. The results of the in vitro binding assay showed that bisphenol compounds could bind to hERalpha LBD as the affinity ligands. All the tested halogenated BPAs exhibited weaker receptor binding than BPA, which might be explained by the steric effect of substituents. Molecular docking studies elucidated that the halogenated BPAs adopted different conformations in the flexible hydrophobic ligand binding pocket (LBP), which is mainly dependent on their distinct halogenation patterns. The compounds with halogen substituents on the phenolic rings and on the bridging alkyl moiety acted as agonists and antagonists for hERalpha, respectively. Interestingly, all the compounds in the agonist conformation of hERalpha formed a hydrogen bond with His524, while the compounds in the antagonist conformation formed a hydrogen bond with Thr347. These docking results suggested a pivotal role of His524/Thr347 in maintaining the hERalpha structure in the biologically active agonist/antagonist conformation. Comparison of the calculated binding energies vs. experimental binding affinities yielded a good correlation, which might be applicable for the structure-based design of novel bisphenol compounds with reduced toxicities and for environmental risk assessment. In addition, based on hERalpha-LBD as a recognition element, the proposed fluorescence polarization assay may offer an alternative to chromatographic techniques for the multi residue determination of bisphenol compounds. PMID- 29152683 TI - Newer Development in Immunization Practices. PMID- 29152684 TI - Infantile Systemic Lupus Erythematosus with Cerebral Calcification and Delayed Development. PMID- 29152685 TI - Cerebral Palsy: An Overview. AB - Cerebral palsy (CP) is a neurodevelopmental disorder characterized by abnormalities of muscle tone, movement and motor skills, and is attributed to injury to the developing brain. The clinical features of this entity evolve over time and the specific CP syndrome may be recognizable only after 3-5 y of age; although suggestive signs and symptoms may be present at an earlier age. The management involves neurological rehabilitation (addressing muscle tonal abnormalities, and devising physical and occupational therapies) and diagnosis and management of co-morbidities (including epilepsy, impairment of cognition, vision, hearing, and disturbances of growth and gastrointestinal function). The management, therefore, is multidisciplinary involving the treating physician working with a team of rehabilitation-, orthopedic-, psychologic-, and social care- providers. PMID- 29152686 TI - Tetralogy of Fallot with Restrictive Ventricular Septal Defect. PMID- 29152687 TI - Utility of Low Fidelity Manikins for Learning High Quality Chest Compressions. AB - OBJECTIVES: Primarily, to measure the adequacy of chest compression depth after training on low fidelity manikins and secondarily to assess the comparative experience of the learners on high fidelity and low fidelity simulators. METHODS: An observational cohort study in which seventy-two first year postgraduate students underwent a Basic Life Support (BLS) workshop conducted by AHA accredited BLS trainers and they were then required to perform on a high fidelity manikin to objectively record the quality of their performance. RESULTS: There were 34 (47.22%) male and 38 (52.77%) female participants. CPR skills, as judged by checklist of sequential actions and visual inspection during the BLS training on low fidelity simulators (LFS) were correctly performed by majority (95.89%) participants. However, none of the participants could achieve the recommended depth for high quality chest compressions. The participants' perception of degree of realism and their practical experience on both the types of manikins were similar. CONCLUSIONS: Low fidelity manikins are useful for training CPR in sequential manner but fail to impart quality of chest compressions as per AHA recommendations. PMID- 29152688 TI - Serum Zinc Levels as a Predictor of Severity of Acute Diarrhea. AB - OBJECTIVE: To determine relationship between serum zinc levels and severity of diarrhea as determined by hydration status, duration of diarrhea and requirement for hospitalization. Also, to compare serum zinc levels in relation to rotavirus status. METHODS: A prospective observational study which included 254 children aged 6 mo to 5 y with diarrhea was conducted. RESULTS: Serum zinc levels could be estimated in 198 children. Median (IQR) serum zinc levels of study population were 73.5 (59.11-92.86)MUg/dl. Median (IQR) of serum zinc levels in children with dehydration and without dehydration were 69.64 (54.57-81.62) and 82.86 (64.1 103.48) MUg/dl respectively (p < 0.001). Median (IQR) of serum zinc levels in hospitalised and non-hospitalished children were 63.28 (51.81-85.37) and 74.86 (61.75-95.78) MUg/dl, respectively (p 0.013). Median (IQR) of total duration of diarrhea was 4.8 (3.5-6.0) d and it did not correlate with serum zinc levels. Median (IQR) of serum zinc levels in children, with rotavirus diarrhea was 66.8 (49.7-82.48) and non-rotavirus diarrhea was 80.0 (62.42-100.12) MUg/dl (p < 0.001). CONCLUSIONS: Children with dehydration and those with rotavirus diarrhea tend to have significantly lower serum zinc levels. Hospitalized children also have lower serum zinc levels than non-hospitalized children. Duration of diarrhea does not relate with serum zinc levels. PMID- 29152689 TI - Role of WNT signaling in epididymal sperm maturation. AB - PURPOSE: Spermatozoa maturation, a process required for spermatozoa to acquire progressive motility and the ability to fertilize ova, primarily occurs in the caput and corpus of the epididymis. Despite considerable efforts, the factor(s) promoting epididymal sperm maturation remains unclear. Recently, WNT signaling has been implicated in epididymal sperm maturation. METHODS: To further investigate WNT signaling function in epididymal sperm maturation, we generated Wntless conditional knockout mice (Wls cKO), Wls flox/flox ; Lcn5-Cre. RESULTS: In these mice, WNTLESS (WLS), a conserved membrane protein required for all WNT protein secretion, was specifically disrupted in the principal cells of the caput epididymidis. Immunoblot analysis showed that WLS was significantly reduced in the caput epididymidis of Wls cKO mice. In the caput epididymidis of Wls cKO mice, WNT 10A and WNT 2b, which are typically secreted by the principal cells of the caput epididymis, were not secreted. Interestingly, sperm motility analysis showed that the WLS deficiency in the caput epididymidis had no effect on sperm motility. Moreover, fertility tests showed that Wls cKO male mice had normal fertility. CONCLUSION: These results indicate that the disruption of WLS in principal cells of the caput epididymidis inhibits WNT protein secretion but has no effect on sperm motility and male fertility, suggesting that WNT signaling in the caput epididymidis may be dispensable for epididymal sperm maturation in mice. PMID- 29152690 TI - Seasonal analysis and acaricidal activity of the thymol-type essential oil of Ocimum gratissimum and its major constituents against Rhipicephalus microplus (Acari: Ixodidae). AB - The tick Rhipicephalus microplus affects cattle health, with production loss in tropical and subtropical regions. Moreover, the use of commercial acaricides has been reduced due to the resistance of this parasite. Although alternatives such as plant bioactive molecules have been sought, essential oils present variations in their chemical constituents due to environmental factors, which can interfere with their acaricidal activity. The objective of the present study was to evaluate the seasonal influence of the essential oil of Ocimum gratissimum and its major constituents on acaricidal activity against R. microplus larvae. A high yield essential oil of O. gratissimum and its major constituents were used, and a plant with a thymol-type oil was selected for seasonal analysis and acaricidal activity against R. microplus. Gas chromatography (GC) and GC-mass spectrometry (MS) were employed to identify 31 oil constituents (average yield of 6.26%). The main compounds were found to be thymol (33.4 to 47.9%), gamma-terpinene (26.2 to 36.8%), and p-cymene (4.3 to 17.0%). Concerning acaricidal activity, the December (LC50 0.84 mg/mL) and September (LC50 1.58 mg/mL) oils obtained in the dry season were the most active, and assays performed with commercial standards revealed LC50 values of p-cymene, thymol, and gamma-terpinene of 1.41, 1.81, and 3.08 mg/mL, respectively. Overall, lower acaricidal activities were found for oils produced from plants harvested in the rainy season. The results showed that seasonal variation in the chemical composition of the O. gratissimum essential oil influences its acaricidal activity. The seasonal variations in the thymol type essential oil of O. gratissimum can represent an important strategy for the control of R. microplus. PMID- 29152692 TI - Left frontoparietal network activity is modulated by drug stimuli in cocaine addiction. AB - Cocaine addicts present reduced activity in the left frontoparietal network, a brain network associated with cognitive control, during the processing of non drug reward related stimuli (Costumero et al., Addiction Biology 22:479-489, 2015). However, the involvement of this network in drug-related stimuli processing remains unclear. Here, fifteen cocaine-dependent men and fifteen healthy matched controls viewed cocaine-related, erotic, aversive, and neutral pictures during an fMRI session. Group independent component analysis was then performed to investigate how functional networks were modulated by the different emotional images. The results showed that the cocaine-dependent group showed stronger left frontoparietal network activity during the processing of cocaine related pictures than the control group. Furthermore, the activity of this network during cocaine image processing was positively associated with the years of cocaine use in addicted subjects. In conclusion, our results indicate that the left frontoparietal network is affected in cocaine-dependent men, and may be related to the cognitive control deficits shown in addiction. PMID- 29152693 TI - Synthesis of 2-Ethylhexyl Palmitate Catalyzed by Enzyme Under Microwave. AB - 2-Ethylhexyl palmitate has been prepared in organic solvents catalyzed by an immobilized lipase QLM. Microwave irradiation was used to improve the enzyme activity and shorten the reaction time. The reaction conditions under microwave have been optimized. Compared with that of the free QLM under classical heating, the immobilized QLM under microwave exhibited higher enzyme activity and the conversion could achieve 99% in about 3.0 h. Furthermore, the immobilized QLM displayed excellent reusability under microwave irradiation. PMID- 29152694 TI - RNA-Seq Analysis of Antibiotic-Producing Bacillus subtilis SC-8 Reveals a Role for Small Peptides in Controlling PapR Signaling. AB - Bacillus subtilis SC-8 (BSSC8) shows a narrow antimicrobial activity against the Bacillus cereus group. Previously, B. cereus-derived PapR as a signal peptide to stimulate PlcR, which plays a significant role in regulating the transcription of virulence factors, was assumed to stimulate antibiotic production in BSSC8. To better understand the functional role of PapR in the antibiotic production of BSSC8 and the interspecies interaction, the global transcriptomic profiling of BSSC8 was investigated using RNA-Seq in this study. Small peptides derived from B. cereus wild type (WTBC) and a papR-deleted mutant strain (MTBC) were individually supplied to BSSC8 cultures, and changes in global transcription levels were compared by RNA-Seq. In the presence of WTBC small peptides, more genes (80.9%) were significantly upregulated than in cells exposed to MTBC small peptides. Specifically, 48.8 and 83.4% of genes involved in glycolysis and the TCA cycle, respectively, showed changes in transcription levels in response to small peptides from both strains. Of the genes showing the alterations, 35.0% (glycolysis) and 60.0% (TCA cycle) of transcripts were significantly regulated only in response to WTBC-derived small peptides. Furthermore, the expression of biosynthetic genes encoding several known antibiotics in BSSC8 was further decreased in response to WTBC small peptides. PMID- 29152691 TI - Strategies for the control of Rhipicephalus microplus ticks in a world of conventional acaricide and macrocyclic lactone resistance. AB - Infestations with the cattle tick, Rhipicephalus microplus, constitute the most important ectoparasite problem for cattle production in tropical and subtropical regions worldwide, resulting in major economic losses. The control of R. microplus is mostly based on the use of conventional acaricides and macrocyclic lactones. However, the intensive use of such compounds has resulted in tick populations that exhibit resistance to all major acaricide chemical classes. Consequently, there is a need for the development of alternative approaches, possibly including the use of animal husbandry practices, synergized pesticides, rotation of acaricides, pesticide mixture formulations, manual removal of ticks, selection for host resistance, nutritional management, release of sterile male hybrids, environmental management, plant species that are unfavourable to ticks, pasture management, plant extracts, essential oils and vaccination. Integrated tick management consists of the systematic combination of at least two control technologies aiming to reduce selection pressure in favour of acaricide-resistant individuals, while maintaining adequate levels of animal production. The purpose of this paper is to present a current review on conventional acaricide and macrocyclic lactone resistance for better understanding and control of resistant ticks with particular emphasis on R. microplus on cattle. PMID- 29152695 TI - Chitosan-Based Surface Molecularly Imprinted Polymer Microspheres for Sustained Release of Sinomenine Hydrochloride in Aqueous Media. AB - The surface molecular imprinting technique has been proposed as a prospective strategy for template molecule recognition and separation by devising the recognition sites on the surface of imprinted materials. The purpose of this study was to establish a novel drug delivery system which was developed by surface molecular imprinting method using beta-cyclodextrin (beta-CD)-grafted chitosan (CS) (CS-g-beta-CD) microspheres as matrix and sinomenine hydrochloride (SM) as the template molecule. By adjusting the amount of functional monomer and cross-linking agent, we got the more excellent adsorption of CS-g-beta-CD molecularly imprinted polymers (MIPs-CS-g-beta-CD). When the amount of functional monomer was 6 mmol and cross-linking agent was 20 mmol, the maximum binding capacity of MIPs and non-imprinted polymers (NIPs) was 55.9 mg/g and 37.2 mg/g, respectively. The results indicated that the recognition of SM with MIPs was superior to NIPs. The adsorption isotherms of MIPs-CS-g-beta-CD indicated that the adsorption behavior fitted better to the Langmuir model, which showed that the adsorption process of polymer was monomolecular layer. In in vitro drug release studies, the accumulative release amount of MIPs-CS-g-beta-CD was up to 78% within 24 h. MIPs exhibited an excellent controlled SM release profile without burst release and the mechanism of SM release was shown to conform to non Fick diffusion. Therefore, MIPs-CS-g-beta-CD were successfully applied to extraction of SM and used as the materials for drug delivery system. PMID- 29152696 TI - Degradation of the earthy and musty odorant 2,4,6-tricholoroanisole by persulfate activated with iron of different valences. AB - 2,4,6-Trichloroanisole (TCA) is an odorous compound that is often detected in tap water and is difficult to be removed via water treatment. In this study, the transformation efficiency of TCA in the presence of persulfate (PS) activated by iron (Fe2+, Fe0, and Fe3+) was investigated for the first time. The effects of the activator dosage, oxidant dosage, pH, dosing method, chelating agents, humic acid, and temperature were evaluated. The degradation rate of TCA increased with increasing PS dosages (0.12-0.48 mM) and initial Fe2+ concentrations (0.12-0.96 mM), while it decreased with higher Fe2+ concentrations. Fe2+/PS and Fe0/PS systems achieved their best TCA removal efficiency at pH 7 and 2.5, respectively. According to the results of electron paramagnetic resonance (EPR), the contribution of SO4-* to TCA degradation was much higher than that of *OH. Gradual addition of Fe2+ improved TCA degradation compared to single addition. Citric acid (CA) promoted TCA degradation under Fe2+/PS at the beginning of the reaction, but inhibited it after 10 min. Ethylenediaminetetraacetic acid (EDTA) improved the TCA removal rate with an EDTA/Fe2+ molar ratio of 0.5:1, while it decreased it at higher EDTA/Fe2+ molar ratios. Oxalic acid (OA) negatively affected TCA degradation with increasing OA/Fe2+ molar ratios. Among all of the chelating agents, only CA increased TCA degradation by Fe0/PS. Humic acid promoted TCA degradation by Fe2+/PS at the proper dosage (1 mg/L). Under our specific conditions and over the temperature ranging from 10 to 25 degrees C, no change was observed in the reaction kinetics. It was found that 2,4,6 trichlorophenol (TCP) was the only detected oxidation product. The presence of an Fe2+-Fe3+ redox cycle in iron-activated PS systems was confirmed by TCA degradation under the Fe3+/PS system. PMID- 29152698 TI - Characterization and valorization of biomass char: a comparison with biomass ash. AB - Organic matter derived from living, or recently living plant and animal, which can be used as fuel is called as biomass. It includes wood and agricultural waste such as dead plant etc. In India, majority of population depends largely upon agriculture as their primary source of income. Following every harvest, a huge amount of biomass is generated. It is mostly discarded as "agro waste"; however, recently, several uses of biomass and its derivatives have been reported. Thermochemical processing of biomass in absence of oxygen produces biomass char and flue gases which are of economic importance. However, it is necessary to characterize the physical and chemical properties of these components so as to utilize their potential benefit to the fullest. In this study, six different biomass remains that include mustard plant, groundnut plant, cotton plant, wheat plant, pigeon peas, and groundnut shell were pyrolyzed at 650 degrees C, in vertical downdraft fixed-bed biomass reactor. The flue gases were characterized in detail by gas chromatography. X-ray fluorescence, proximate, and ultimate analyses were performed on all BMC (biomass char) samples, and properties such as porosity, particle density, bulk density, point of zero charge, surface pH, surface charges, water-absorption capacity, and BET surface area were determined. SEM and FTIR were also carried out on all BMC samples. Our results showed that the surface area of biomass char varies from 38 to 138 m2/g. The solution pH for all BMC exceeds 8.6, thus confirmed the alkaline nature. Comparison between combustion products produced in the presence (biomass ash) and absence of oxygen (biomass char) is presented. BMC finds applications in agriculture, soil neutralizer, adsorbent, and soil additive. They have high amount of carbon and can act as a rich carbon source for the soil. Flue gases released contain methane and hydrogen which can also improve economic value for the char formation process. PMID- 29152697 TI - A novel process for CO2 capture by using sodium metaborate. Part I: effects of calcination. AB - This paper presents a comprehensive study on the carbonation of sodium metaborate (NaBO2) and the synthesis of high added value chemicals via NaBO2 and carbon dioxide (CO2). Carbon dioxide (CO2) is a greenhouse gas and NaBO2 is a by-product of sodium borohydride (NaBH4) hydrolysis reaction to produce H2. Therefore their transformation into commercial chemicals is quite important in order to provide a mutual benefit to global warming issue and hydrogen economy. In the presented study, reaction parameters such as hydration factor, furnace type, calcination temperature, and environment are investigated at different levels and optimized. The effects of those key parameters on CO2 fixation yield are discussed. It is found that 400 degrees C is a key temperature for dehydration and reaction steps. Both dehydrated NaBO2 is obtained and maximum carbonation conversion is reached at 400 degrees C. Moreover, at relatively low temperatures (below 400 degrees C), a new reaction pathway is proposed and proved by thermodynamic calculations. Structural properties of NaBO2 are exhibited differences regard to thermal exposure and the conversion is strictly related to the structural properties. PMID- 29152699 TI - Comparative analysis of the protective effects of curcumin and N-acetyl cysteine against paracetamol-induced hepatic, renal, and testicular toxicity in Wistar rats. AB - This study aimed to investigate the possible protective role of curcumin (CUR) vs. N-acetyl cysteine (NAC) against paracetamol (PCM)-induced oxidative damage and impairment of liver, kidney, and testicular functions, as well as hematotoxicity, in albino rats. A large single dose of PCM induced lipid peroxidation along with a significant decline in glutathione content and catalase activity in the liver, kidneys, and testicles. The apparent oxidative damage was associated with evident hepatic, renal, and testicular dysfunction, which was confirmed in histopathological lesions, and increased serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities. PCM decreased serum total protein, albumin, and globulin contents; increased bilirubin, urea, and creatinine contents; and induced hematotoxicity. PCM also reduced the sperm cell count, sperm motility, and alive sperm rate and increased the sperm abnormality rate. Pretreatment of PCM-intoxicated animals with CUR or NAC substantially alleviated the increase in malondialdehyde and maintained the antioxidants at control levels. These pretreatments also minimized liver, kidney, and testicular histopathological changes and normalized their functions. CUR similarly mitigated the PCM hemato- and hepatotoxicity compared with NAC. However, it exhibited a pronounced nephroprotection, rather than reproductive protection as did NAC. Our findings demonstrate that a large single dose of PCM is not only associated with hepatotoxicity but also nephrotoxicity and reproductive toxicity. Both CUR and NAC administration provided substantial organ protection with pronounced efficacy against PCM nephrotoxicity with CUR and reproductive toxicity with NAC, which was possibly mediated through their antioxidant activities, as well as their specific characteristics. PMID- 29152701 TI - Risk communication by health professionals: an analysis of press releases drafted by Italian veterinarians. AB - The aim of this study is to analyse and evaluate the knowledge concerning risk communication acquired by veterinarians during a national training course. The study analyses 694 press releases written during the training course. Textual variables and indexes were considered to identify the linguistic structures used by veterinarians. At first, the analysis of press releases focused on the descriptive demographic variables, then stylistic and editorial variables were considered, and finally a lexicographic analysis was performed on the textual variables. The texts were found to have a moderate level of readability due to the use of scientific and technical terms. This study shows the need to improve training activities to develop effective risk communication, especially in terms of the language used, in order to facilitate interactions among veterinarians, mass media, and citizens. PMID- 29152700 TI - The micronucleus test for the oral mucosa: global trends and new questions. AB - This study reviews global trends in the publication of papers on the micronucleus test of the exfoliated cells of the oral mucosa in mammals as an approach for environmental biomonitoring. This test has been widely used due to its precision for the detection of chromosome damage. Our temporal analysis showed a significant increase (p < 0.05) in the publication of papers on the oral mucosa over the past 33 years. Brazil was the country that published most papers (24% of the total), followed by India (16%), the USA (10%), Mexico (7%), and Turkey (6%). A further 30 countries contributed the other 37% of the papers. Overall, 99% of the micronucleus studies involved human subjects, and only 1% involved other mammals. As many wild mammals are subject to the same environmental pressures as humans, in particular chemical pollution, it seems likely that many species are equally susceptible to genotoxicogical damage. We emphasize the importance of applying this technique to the analysis of the oral mucosa of wild mammals, as well as the evaluation of its effectiveness, as observed in humans, and the expansion of the available approaches to the monitoring of environmental quality. PMID- 29152702 TI - A new supporting tool for pig handling in the breeding-slaughterhouse production chain. AB - This paper focuses on a research concerning the operational management of the pig handling phase, during the period of breeding and before slaughtering. Given the behaviour of these animals during transfers, a particular tool has been designed to manage them in this phase. A total number of 48 animals, divided in 4 groups, were moved without use of the tool (control groups) and by using the tool described in this article. The time required by the control groups to leave the pen ranges from 21 to 125 seconds; while, when the proposed tool was used, the time for the movement of the animals ranged between 10 and 17 seconds. In particular, in the groups where the tool was deployed the 'waiting phase' (before the first animal goes out) lasted less than half of the time of the 'waiting phase' of the control group, thus showing a minimization of the effects of the 'panic phenomenon' among the animals. Thus, the studied device can be considered as valid guide technique, both for the quick exit of the first animal and for those that follow. Once the row has been formed, the animals continue neatly to leave the box. This study also shows that this solution can also be considered appropriate for reducing the identified critical issues in the traditional handling. The need of only 1 worker to move the group of pigs is important to achieve economic saving. The deployment of this tool, thus, make possible to consider the movement of animals no longer a 'critical stage', but as a routine step of the production cycle of pork's meat. PMID- 29152703 TI - Multiplex PCR to detect bacteriophages from natural whey cultures of buffalo milk and characterisation of two phages active against Lactococcus lactis, PhiApr-1 and PhiApr-2. AB - This work investigated bacteriophage induced starter failures in artisanal buffalo Mozzarella production plants in Southern Italy. Two hundred and ten samples of whey starter cultures were screened for bacteriophage infection. Multiplex polymerase chain reaction (PCR) revealed phage infection in 28.56% of samples, all showing acidification problems during cheese making. Based on DNA sequences, bacteriophages for Lactococcus lactis (L. lactis), Lactobacillus delbruekii (L. delbruekii) and Streptococcus thermophilus (S. thermophilus) were detected. Two phages active against L. lactis, PhiApr-1 and PhiApr-2, were isolated and characterised. The genomes, approximately 31.4 kb and 31 kb for PhiApr-1 and PhiApr-2 respectively, consisted of double-stranded linear DNA with pac-type system. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) showed one major structural protein of approximately 32.5 kDa and several minor proteins. This is the first report of phage isolation in buffalo milk and of the use of multiplex PCR to screen and study the diversity of phages against Lactic Acid Bacteria (LAB) strains in artisanal Water Buffalo Mozzarella starters. PMID- 29152704 TI - West Nile disease in Tunisia: an overview of 60 years. AB - West Nile virus (WNV) is an arthropod borne virus of public health importance. The virus is a member of the genus Flavivirus and belongs to the Japanese encephalitis virus (JEV) antigenic complex under the Flaviviridae family. The WNV is continuously spreading across Tunisia especially in the coastal and Southern area of the country. The first human West Nile disease (WND) epidemic in Tunisia occurred in 1997, since then, the quantity and the extension of spillover effects increased constantly. However, the existing knowledge of factors triggering such events continues to be rather poor. The last epidemic WNV human meningitis and meningoencephalitis recorded in 2012, with 86 cases and 6 deaths, confirmed the failure of the current system in predicting new cases. This review, based on analysis of scientific papers published between 1970 and 2015, summarises the state of knowledge on WNV in Tunisia and highlights the existing knowledge and research gaps that need to be addressed. PMID- 29152705 TI - An epidemological study on Peste des petits ruminants in Tripoli Region, Lybia. AB - A cross-sectional study was conducted in Libya in 7 areas of Tripoli to determine the seroprevalence of Peste des Petits Ruminants (PPR) Virus (PPRV) in small ruminants (sheep and goats) between June and August 2013, and to identify the potential risk factors associated with the infection. The study involved 10% of small ruminant herds with >=50 animals in the Tripoli region. They were selected randomly (15 herds), and 35 to 58 samples, depending on its size, were collected from each selected herd. Seven-hundred and twenty-one serum samples from unvaccinated animals (601 of sheep and 120 of goats) were collected and then tested using cELISA commercial kit in the National Center of Animal Health Laboratory in Tripoli, Libya. The overall seroprevalence was 46.7% [(sheep 44.3% (266/601) and goats 59.2% (71/120)]. Mean within-herd prevalence was 48.5% (95% CI: 32.1% - 64.8%), and the herd prevalence was 93.3% (14/15). Various risk factors at the animal and herd levels were analysed by multivariable logistic regression model (forward stepwise). The results identified breed, source of animal, and region as significant risk factors (p< 0.05). As for the source of new animal to the farm, PPRV seroprevalence was highest in illegally imported animals (90.9%), followed by the seroprevalence in animal legitimately acquired (55.8%), and by the seroprevalence in animals belonging to the same herd (4.7%). The seroprevalence among breeds was 69.5% (228/328) in illegally imported animals, whereas 27.7% (109/393) was found to be in local breed. Seroprevalence in the areas considered in this study was higher (66.2%) in Al-Mashroa area followed by Ein-zara (57.8%), Arada (50%), Ben-Own (47%), AL-Naem (37.5), Ber Alalem (24.5) and in Tajora (0%). The results indicated that PPRV virus was actively circulating in Tripoli regions and that the illegal importing of animals was the main source of spreading PPR in Tripoli regions, showing that better efforts should be made to raise public awareness with respect to biosecurity. PMID- 29152706 TI - The impact of captivity on some haematological parameters of griffon vultures (Gyps fulvus). AB - Haematological analysis is an essential field of veterinary medicine that provides inexpensive and reliable support to determinate animal health. The knowledge of how different factors affect the normal mean values of blood parameters is key to understand and improve animal health. In order to investigate how captivity can affect the haematological profile of birds of prey, the erythrocyte count, haemoglobin concentration, haematocrit, mean corpuscular volume, total leukocytes count of 123 griffon vultures (Gyps fulvus) were analysed. The birds were divided into 4 groups according to their life conditions: a control group of free-living griffons, 2 semi-captive groups held in an aviary for 15 and 30 days respectively, representing short-term captivity, and a captive group that had lived in cage for about 2 years. Our results showed that long-term captivity could influence haematocrit value and haemoglobin concentration. Furthermore, discriminant analysis highlighted significant separation between the captive birds on one hand and the control group and the semi-captive birds on the other. Instead, short-term captivity did not seem to affect prominently haemocytometric profile. PMID- 29152707 TI - Ethylene glycol toxicity: a retrospective pathological study in cats. AB - Ethylene glycol (EG) is a well known toxic compound, the assumption of which can be fatal to pet animals as well as to humans. Limited information is available on the pathological features of EG poisoning in pet animals, with special emphasis on cats. Twenty-five cats with histologically confirmed EG intoxication were retrospectively investigated, in order to define more precisely the gross pathological findings and improve the diagnostic process. Furthermore, a brief comparison with the lesions reported in EG-poisoned human patients and dogs was also made. PMID- 29152708 TI - Influence of sex on activated partial thromboplastin time (aPTT) and prothrombin time (PT) in sheep. AB - Haemostasis is a physiological process that prevents excessive blood loss. In laboratory, the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are used to examine clotting systems. However, the influence of sex on PT and aPTT values is unknown. The present work aimed to determine the values for PT and aPTT in adult sheep and to evaluate their dependence on the sex of the animal. Blood samples were collected from 40 adults (1-6 years old) of mixed breed sheep (20 males and 20 females) via jugular venepuncture conducted using vacuum tubes containing 3.8% sodium citrate as an anticoagulant. PT and aPTT were determined by visual detection of clot formation. The mean PT and aPTT values for all sheep were 7.71 +/- 0.87 s and 35.7 +/- 3.57 s, respectively. The aPTT values showed a significant difference (P = 0.0013) between male and female samples, while the difference in PT values was not significant (P = 0.0565). Thus, the animal sex influences the function of the plasma blood-clotting system in sheep. In contrast with table 1 data, in particular, aPTT values are significantly higher in female sheep than in males. PMID- 29152709 TI - Perioperative gastrointestinal problems in the ICU. AB - Gastrointestinal (GI) problems after surgery are common and are not limited to patients undergoing abdominal surgery. GI function is complicated to monitor and is not included in organ dysfunction scores widely used in the ICUs. In most cases, it recovers after surgery, if systemic and local inflammation and perfusion improve, gut oedema resolves, and analgosedation is reduced. However, perioperative GI problems may have severe consequences and increase the risk of death if not recognized and managed in a timely manner. Careful risk evaluation followed by a complex structured assessment and appropriate management of GI symptoms should minimize the potentially severe consequences and thereby possibly improve outcome. In the current review, we summarize common non-specific perioperative GI problems and some specific surgery-related abdominal problems, address identification of patients at risk of GI problems, and give suggestions for perioperative GI management. PMID- 29152710 TI - The black box revelation: monitoring gastrointestinal function. AB - The gastrointestinal tract comprises diverse functions. Despite recent developments in technology and science, there is no single and universal tool to monitor GI function in intensive care unit (ICU) patients. Clinical evaluation is complex and has a low sensitivity to diagnose pathological processes in the abdomen. We performed a MEDLINE and Pubmed search connecting abdominal assessment and critical care. Based on these findings we defined the following major categories of monitoring and diagnostic measures: clinical investigation; assessment of motility and digestive function; microbiome monitoring; perfusion monitoring; laboratory biomarkers and hormonal function; intra-abdominal pressure measurement; and imaging techniques. Only a few of these monitoring and assessment tools have found their way into clinical practice, as most of them have one or more significant objections preventing broad implementation in daily clinical practice. Further research should be directed to reaffirm and define the use of current techniques to ascertain their validity and usefulness to monitor gastrointestinal function in ICU patients. PMID- 29152712 TI - Correction. PMID- 29152711 TI - The burst-phase folding intermediate of ribonuclease H changes conformation over evolutionary history. AB - The amino acid sequence encodes the energy landscape of a protein. Therefore, we expect evolutionary mutations to change features of the protein energy landscape, including the conformations adopted by a polypeptide as it folds to its native state. Ribonucleases H (RNase H) from Escherichia coli and Thermus thermophilus both fold via a partially folded intermediate in which the core region of the protein (helices A-D and strands 4-5) is structured. Strand 1, however, uniquely contributes to the T. thermophilus RNase H folding intermediate (Icore+1 ), but not the E. coli RNase H intermediate (Icore ) (Rosen & Marqusee, PLoS One 2015). We explore the origin of this difference by characterizing the folding intermediate of seven ancestral RNases H spanning the evolutionary history of these two homologs. Using fragment models with or without strand 1 and FRET probes to characterize the folding intermediate of each ancestor, we find a distinct evolutionary trend across the family-the involvement of strand 1 in the folding intermediate is an ancestral feature that is maintained in the thermophilic lineage and is gradually lost in the mesophilic lineage. Evolutionary sequence changes indeed modulate the conformations present on the folding landscape and altered the folding trajectory of RNase H. PMID- 29152713 TI - Verbal and action-based measures of kindergartners' SFON and their associations with number-related utterances during picture book reading. AB - BACKGROUND: Young children's spontaneous focusing on numerosity (SFON) as measured by experimental tasks is related to their mathematics achievement. This association is hypothetically explained by children's self-initiated practice in number recognition during everyday activities. As such, experimentally measured SFON should be associated with SFON exhibited during everyday activities and play. However, prior studies investigating this assumed association provided inconsistent findings. AIMS: We aimed to address this issue by investigating the association between kindergartners' SFON as measured by two different experimental tasks and the frequency of their number-related utterances during a typical picture book reading activity. SAMPLE: Participants were 65 4- to 6-year olds in kindergarten (before the start of formal education). METHODS: Kindergartners individually participated in two sessions. First, they completed an action-based SFON Imitation task and a verbal SFON Picture task, with a short visuo-motor task in between. Next, children were invited to spontaneously comment on the pictures of a picture book during a typical picture book reading activity. RESULTS: Results revealed a positive association between children's SFON as measured by the Picture task and the frequency of their number-related utterances during typical picture book reading, but no such association for the Imitation task. CONCLUSIONS: Our findings indicate that children with higher SFON as measured by a verbal experimental task also tend to focus more frequently on number during verbal everyday activities, such as picture book reading. In view of the divergent associations between our SFON measures under study with everyday number activities, the current data suggest that SFON may not be a unitary construct and/or might be task-dependent. PMID- 29152714 TI - Scaffolding as a key role for teaching assistants: Perceptions of their pedagogical strategies. AB - BACKGROUND: Inclusive education policies have led to a worldwide increase in the number of teaching assistants (TAs) working in mainstream schools. TAs have a large amount of responsibility for supporting children with special educational needs and disabilities (SEND), a role which by default has become instructional in practice, and for which training and preparation are rarely adequate. While there is some research into the nature of TAs' interactions with pupils and the strategies they use which are helpful for children's learning, TAs' perspectives on their own classroom practice have yet to be explored. AIMS: To explore TAs' perceptions about their use of inclusive pedagogical strategies. SAMPLE: The study involved eleven TAs in two mainstream primary schools. METHODS: The TAs were interviewed face to face to explore their views about inclusive pedagogical strategies. The data were analysed using thematic analysis. RESULTS: TAs were clear about the strategies they use to offer emotional and relational support to children. There were some gaps, however, in their knowledge about how children learn, specifically in terms of transferring responsibility for learning onto children. CONCLUSION: The study advances understanding of scaffolding from a TA perspective and highlights the importance of training TAs in scaffolding theory. PMID- 29152715 TI - Erratum: Resolving relationships between several Neolithic and Mesolithic populations in Northern Eurasia using geometric morphometrics; 164:163-183. Ekaterina Stansfield (Bulygina), Anna Rasskasova, Natalia Berezina and Andrei D. Soficaru. DOI: 10.1002/ajpa.23264. PMID- 29152716 TI - ERPs reveal weaker effects of spelling on auditory rhyme decisions in children than in adults. AB - A classic finding in psycholinguistics is that orthographic form influences the processing of auditory words. The aim of the present study was to examine how reading experience changes this effect. Specifically, we tested the prediction that top-down visual modulation of spoken word recognition is reduced in children compared to adults, owing to their reduced experience with print. Event-related potentials (ERPs) were measured as 8-10-year-old children and adults made rhyme decisions about spoken word pairs that were either orthographically similar or dissimilar. When orthography did not conflict (e.g., throat-boat), both age groups demonstrated a robust rhyme effect marked by greater N400 to no-rhyme versus rhyme trials. For rhyming trials that differed in orthography (e.g., vote boat) and non-rhyming trials that shared orthography (e.g., warm-farm), adults showed more interference than children. Differences in orthographic interference suggest an extended developmental schedule for top-down mechanisms in speech recognition. PMID- 29152717 TI - Anti-desmogleins autoantibodies detected by ELISA and blotting in bullous pemphigoid: what do they mean? PMID- 29152718 TI - An extension of a multicenter, randomized, split-face clinical trial evaluating the efficacy and safety of chromophore gel-assisted blue light phototherapy for the treatment of acne. AB - A variety of laser/light-based devices have been reported to be effective for the treatment of acne, yet no long-term data on efficacy and safety have been published. A first 12-week clinical trial ("Main trial") recently demonstrated that the KLOX BioPhotonic System, an LED blue light device using photo-converter chromophores, can significantly improve moderate and severe facial acne vulgaris with an excellent safety profile. This Extension trial followed the Main trial, using the same BioPhotonic System, with the same dose and instructions for use, on patients having already completed treatment in the Main trial. Main objectives of this open-label long-term extension 12-week study were to evaluate the efficacy of the KLOX BioPhotonic System on the untreated hemiface during the Main trial, as well as the duration of response on the hemiface treated during the first 12-week Main trial. Despite their young age (mean age: 21.6 years) and their 12-week participation in the Main trial, 49 (54.4%) of the total number of patients who participated in the Main trial enrolled in this additional 12-week Extension trial. Baseline grading of acne was performed with the Investigator's Global Assessment (IGA) scale. For each patient, the hemiface randomly selected as a control during the Main trial received 6 weeks of treatment (twice weekly) and was then followed up for an additional 6 weeks. The first hemiface treated in the Main trial was consequently observed throughout the Extension trial, allowing for a further 12-week assessment of outcomes (total 24 weeks). In light of an additional 12 weeks of treatment on the contralateral face, the patient compliance rate was excellent, with 91.9% of the total number of patients receiving at least 80% of the treatments. Patients with a baseline IGA grade of 2 (mild) on the treated hemiface demonstrated a success rate of 58.3 and 66.7% at weeks 6 and 12, respectively. At these same time points, subjects with a baseline IGA grade of 3 (moderate) demonstrated a success rate of 81.8 and 90.0%. Patients with a baseline IGA grade of 4 (severe) demonstrated a success rate of 100% at both week 6 and week 12. When evaluating the originally treated hemifaces from the Main trial, the rate of return to baseline at 24 weeks was calculated to be 15.5%. This latter outcome confirmed the long duration of effect following treatment. The patient safety profile was also excellent, with very few related adverse events. The BioPhotonic System, which is comprised of LED blue light phototherapy and photo-converter chromophores, provides long-term efficacy and safety in the treatment of acne vulgaris, with a rate of compliance above what is generally observed in a young population of patients suffering from acne vulgaris, especially in light of sequential enrollment in a study treating one hemiface. PMID- 29152719 TI - Course and predictors of post-traumatic stress disorder in a cohort of psychologically distressed patients with cancer: A 4-year follow-up study. AB - BACKGROUND: Scant evidence exists on the long-term course of cancer-related post traumatic stress disorder (PTSD). This is among the few studies worldwide, and the first in the South-East Asian region, to prospectively evaluate PTSD in patients with cancer using gold-standard clinical interviews. The objective of the study was to assess the course and predictors of PTSD in adult patients with cancer in a South-East Asian population. METHODS: A prospective, longitudinal study was conducted in a cohort of 469 consecutively recruited patients (aged >=18 years) with various cancer types within 1 month of diagnosis at a single oncology referral center. Only patients who had significant psychological distress (Hospital Anxiety and Depression Scale total cutoff score >=16) underwent the PTSD module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (SCID) at at 6-months follow-up. All patients completed the SCID at the 4-year follow-up assessment regardless of their initial Hospital Anxiety and Depression Scale score. RESULTS: In an analysis combining patients who had both full and subsyndromal PTSD, there was a 21.7% incidence of PTSD at the 6-month follow-up assessment (n = 44 of 203 SCID-interviewed patients), with rates dropping to 6.1% at the 4-year follow-up assessment (n = 15 of 245 SCID-interviewed patients). Patients with breast cancer (compared with those who had other types of cancer) were 3.68 times less likely to develop PTSD at 6-months, but not at 4-years follow-up. CONCLUSIONS: The overall rates of PTSD decreased with time, but one third of patients (34.1%) who were initially diagnosed had persistent or worsening PTSD 4 years later. There is a need for early identification of this subset of patients who have cancer with PTSD to design risk-targeted interventions. Cancer 2018;124:406-16. (c) 2017 American Cancer Society. PMID- 29152720 TI - Secondary erythromelalgia: a tryptophan dietary supplement-induced case associated with elevated 5-hydroxyindoleacetic acid (5HIAA) urinary levels. PMID- 29152721 TI - Perspectives on the Current State of the Biosimilar Regulatory Pathway in the United States. AB - The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) created an abbreviated licensure pathway in the United States that allows for the development and approval of biologic products shown to be biosimilar to or interchangeable with a US Food and Drug Administration (FDA)-licensed reference product (Table 1). Here we discuss implementation of the US biosimilar approval pathway and the role of various types of data, including clinical pharmacology data, in biosimilar development. PMID- 29152722 TI - Polymorphous presentation of subcutaneous phaeohyphomycosis: a rare occurrence. PMID- 29152723 TI - Changing practices of hair relaxer use among black women in the United States. PMID- 29152724 TI - Syringe lubricant and adverse reactions. PMID- 29152725 TI - Regressed melanocytic nevi secondary to pembrolizumab therapy: an emerging melanocytic dermatologic effect from immune checkpoint antibody blockade. AB - BACKGROUND: Immune checkpoint antibody blockade is an emerging therapeutic option for treating certain cancers including melanoma. This therapy is associated with dermatologic and systemic toxicities, some of which are more severe than others and may require withholding therapy. CASE REPORTS: We report two patients with melanocytic nevi that regressed with pembrolizumab therapy. The first patient had stage IV BRAF K601E/L584F mutant melanoma that developed a regressed melanocytic nevus while being treated with pembrolizumab. The second patient had stage III BRAF V600R mutant melanoma that was treated with pembrolizumab and dabrafenib, and also developed a regressed melanocytic nevus. Both patients had good response to therapy and stable disease at 8 and 12 months of treatment, respectively. RESULTS: Regressed melanocytic nevi were observed in both patients treated with pembrolizumab for advance-stage melanoma. Immunohistochemical analysis of a regressed melanocytic nevus was associated with an inflammatory infiltrate rich in CD8+ T cells and CD163+, CD11c+ histiocytes. CONCLUSION: Regressed melanocytic nevi are an emerging dermatologic effect from pembrolizumab therapy. PMID- 29152726 TI - Autoantibodies to full body vascular cell junctions colocalize with MYZAP, ARVCF, desmoplakins I and II and p0071 in endemic pemphigus in Colombia, South America. AB - BACKGROUND: We previously described a new variant of endemic pemphigus foliaceus in El Bagre, Colombia (El Bagre-EPF). METHODS: Here we aimed to investigate disease autoreactivity to vessels in all body organs/systems. We compared 57 patients and 57 controls from the endemic area, matched by demographics, age, sex, and work activity. We performed immunofluorescence, immunohistochemistry, confocal microscopy, immunoblotting, indirect immune electron microscopy studies, and autometallographic studies. We performed ultrasonography on large patient arteries, investigating for vascular anomalies. In addition, we reviewed autopsies on seven patients who died affected by El Bagre-EPF. We immunoadsorbed any positive vessel immunofluorescence with desmoglein (Dsg1), investigating for new autoantigens. RESULTS: Overall, 57/57 patients affected by El Bagre-EPF displayed autoantibodies to vessels in all the organs/systems of the body via all methods (P < 0.01). The autoreactivity was polyclonal, and the patient's antibodies colocalized with commercial antibodies to desmoplakins I and II, p0071, ARVCF, and MYZAP (all from Progen Biotechnik, Germany; P < 0.01; all present at cell junctions). Immunoadsorption with Dsg1 on positive vessel immunofluorescence showed that the immune response against the vessels was directed against non-Dsg1 antigen(s). Autometallographic studies showed deposits of metals and metalloids in vessel cell junctions and in erythrocytes of 85% of patients (P < 0.01). CONCLUSIONS: Immune response to these vascular antigens is likely altering endothelial cells and vessel shapes, thus disturbing hemodynamic flow. The flow alterations likely lead to inflammation and may play a role in the atherogenesis often seen in these patients. PMID- 29152727 TI - Human papillomavirus-associated cutaneous disease burden in human immunodeficiency virus (HIV)-positive patients: the role of human papillomavirus vaccination and a review of the literature. AB - Human papillomavirus (HPV) infection is related to the development of cutaneous squamous cell carcinoma, oropharyngeal carcinoma, and anogenital malignancies. Patients infected with human immunodeficiency virus (HIV) have impaired cell mediated immunity, placing them at risk for more prolonged infection with a greater likelihood of disease expression. This presents important implications for screening and treatment of HPV in the HIV patient population. The use of prophylactic vaccines directed against HPV has been a promising clinical development, though the immunogenicity of these vaccines in the immunocompromised host and in patients with previously established HPV infections has not been well established. In this review, we describe the pathogenesis and epidemiology of HPV related cutaneous malignancies in patients with HIV. We outline the current guidelines and recent advances in the field of HPV vaccination. It is our hope that increasing awareness of the HPV-related HIV comorbidities will lead to developments in preventative medicine capable of reducing the burden of these diseases. We recognize the importance of prevention as a primary defense against disease and hope that this article organizes and disseminates recent findings in the field of HPV-associated comorbidities in the HIV population. PMID- 29152728 TI - The "Duvic regimen" for erythrodermic flares secondary to Staphylococcus aureus in mycosis fungoides and Sezary syndrome. PMID- 29152729 TI - Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. AB - The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase (DPYD) genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5-fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost-effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC(r) ) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/). PMID- 29152731 TI - Decision-making under risk of gain in young children and mangabey monkeys. AB - In contrast to human adults, risk proneness in the gain domain is usually observed in both young children and non-human primates. It is currently unclear what mechanism might be underlying such economic preferences. We investigated decision-making under risk of gain in toddlers and monkeys. The choices of 2.5 year-old children and red-capped mangabeys (Cercocebus torquatus torquatus) were examined in a gambling task for food reward in which participants have to choose between two options, a secure option and a risky option. In contrast to monkeys, toddlers showed a strong preference for the risky option over the safe option. In order to test the hypothesis that risky choices in participants reflect inhibitory control difficulties, toddlers and mangabeys were presented in Experiment 2 with a situation analogous to that used in Experiment 1 except for the fact that the opaque cover under which was placed the secure option was replaced by a transparent cover. In this second experiment, toddlers continued to show a preference for the risky option over the safe option. In contrast, mangabeys showed a preference for the safe option over the risky option in Trial 1 but they shifted their economic preferences in Trial 2. We argue that decision making strategies under risk of gain in both toddlers and mangabeys (a) do not reflect poor behavioral control and (b) are not reducible to perception-action couplings. PMID- 29152730 TI - Development of behavioral responses to thermal challenges. AB - Body temperature regulation involves the development of responses to cold and warm challenges. Matching our understanding of the development of body temperature regulation to warm challenges with that of cold challenges will enhance our understanding of the ontogeny of thermoregulation and reveal different adaptive specializations. Warm and cold thermoregulation are important processes, and they include direct thermal effects on offspring, as well as indirect effects on them, such as those imposed by thermally associated alterations of maternal behavior. The present paper is a selective review of the existing literature and a report of some new empirical data, aimed at processes of mammalian development, especially those affecting behavior. We briefly discuss the development of body temperature regulation in rats and mice, and thermal aspects of maternal behavior with emphasis on responses to high temperatures. The new data extend previous analyses of individual and group responses in developing rodents to warm and cool ambient temperatures. This literature not only reveals a variety of adaptive specializations during development, but it points to the earlier appearance in young mammals of abilities to combat heat loss, relative to protections from hyperthermia. These relative developmental delays in compensatory defenses to heating appear to render young mammals especially vulnerable to environmental warming. We describe cascading consequences of warming-effects that illustrate interactions across levels of physiological, neural, and behavioral development. PMID- 29152732 TI - In-home salivary melatonin collection: Methodology for children and adolescents. AB - In-home salivary collection quality and adherence to a prescribed collection methodology for evaluation of dim light melatonin onset (DLMO) is unknown in children. Primary aims of this study were to 1) describe a novel family centered methodology for in-home salivary collection; 2) determine the acceptance and feasibility of this methodology; 3) measure adherence to collection instructions; and 4) identify patterns between participants' age and quality of samples collected. After receiving instructional handouts from the study team, families utilized in-home salivary melatonin collection. Participants (N = 64) included 39 children (21 female, mean age 9.5 +/- 1.61 years) and 25 adolescents (11 female, mean age 15.9 +/- 2.12 years) with craniopharyngioma. Participants were 90% adherent to collection schedule, and 89% of the samples collected were of sufficient quantity and quality, with no differences found between age (child vs. adolescent) and melatonin sample quantity and quality. In-home saliva collection provides an acceptable and feasible method to collect salivary melatonin and biomarkers in children and adolescents. PMID- 29152733 TI - Factorial and convergent validity of the Youth Psychopathic Traits Inventory Short Version in Ghana. AB - Studies have shown the existence of psychopathy construct in Western cultures. However, there is a general lack of research on this topical issue in non-Western countries, specifically sub-Saharan Africa. Consequently, this study investigated the factorial and convergent validity of the Youth Psychopathic Traits Inventory Short Version (YPI-S) in 327 adolescents in Ghana. Confirmatory factor analysis supported a three-factor structure (interpersonal, behavioural and affective) of psychopathy that was invariant across gender. These results were replicated in a cross-validation sample comprising 363 adolescents. The YPI-S factors correlated significantly and positively with reactive and proactive aggression, thus bolstering its construct validity. The YPI-S and Big-Five domains were related differently, and where significant correlations were observed, their directions generally confirmed and extended previous studies. All in all, the result generally suggested the existence of psychopathy construct among Ghanaian youth which can be described along interpersonal, affective and behavioural domains. However, the alterations made to the YPI-S, coupled with its relatively low factor loadings and internal consistency largely, indicate cultural influences on the assessment of cross-cultural traits. This study illuminated the problem of exporting Western-based measures and their findings to non-Western contexts. PMID- 29152734 TI - Access to diagnostic and therapeutic facilities for psychogenic nonepileptic seizures: An international survey by the ILAE PNES Task Force. AB - OBJECTIVE: Studies from a small number of countries suggest that patients with psychogenic nonepileptic seizures (PNES) have limited access to diagnostic and treatment services. The PNES Task Force of the International League Against Epilepsy (ILAE) carried out 2 surveys to explore the diagnosis and treatment of PNES around the world. METHODS: A short survey (8 questions) was sent to all 114 chapters of the ILAE. A longer survey (36 questions) was completed by healthcare professionals who see patients with seizures. Questions were separated into 5 sections: professional role, diagnostic methods, management, etiology, and access to health care. RESULTS: Responses were received from 63 different countries. The short survey was completed by 48 ILAE chapters, and the long survey by 1098 health professionals from 28 countries. PNES were recognized as a diagnostic and therapeutic problem in all countries. Trauma and mental health issues were most commonly recognized as etiologic factors. There was a clear relationship between income and access to diagnostic tests and expertise. Psychological therapy was most commonly considered the treatment of choice. Although financial difficulties were the most commonly reported problem with service access in low-income countries, in all countries stigma, lack of popular awareness, and lack of information posed challenges. SIGNIFICANCE: This global provider survey demonstrates that PNES are a health problem around the world. Health care for PNES could be improved with better education of healthcare professionals, the development of reliable and simple diagnostic procedures that do not rely on costly tests, and the provision of accessible information. PMID- 29152735 TI - 6 Hz corneal kindling in mice triggers neurobehavioral comorbidities accompanied by relevant changes in c-Fos immunoreactivity throughout the brain. AB - OBJECTIVE: Besides seizures, patients with epilepsy are affected by a variety of cognitive and psychiatric comorbidities that further impair their quality of life. The present study provides an in-depth characterization of the behavioral alterations induced by 6 Hz corneal kindling. Furthermore, we correlate these behavioral changes to alterations in c-Fos protein expression throughout the brain following kindling. METHODS: Adolescent male Naval Medical Research Institute (NMRI) mice were kindled via repetitive subconvulsive 6 Hz corneal stimulations until they reached the fully kindled state (defined as 10 consecutive generalized seizures). Afterwards we performed an elaborate battery of behavioral tests and we evaluated c-Fos expression throughout the brain using immunohistochemistry. RESULTS: Fully kindled mice display an abnormal behavioral phenotype, characterized by basal and amphetamine-induced hyperlocomotion, anhedonia, social withdrawal, and deficits in short- and long-term memory. Moreover, 6 Hz corneal kindling enhances c-Fos immunoreactivity in the visual, parahippocampal, and motor cortices and the limbic system, whereas c-Fos+ cells are decreased in the orbital cortex of fully kindled mice. SIGNIFICANCE: The behavioral outcomes of 6 Hz corneal kindling cluster into 3 main categories: positive symptoms, negative symptoms, and cognitive impairment. These symptoms are accompanied by c-Fos activation in relevant brain regions once the fully kindled state is established. Based on the face validity of this model, we speculate that 6 Hz corneal kindling can be used to model not only pharmacoresistant limbic seizures, but also several neurobehavioral comorbidities that affect patients with epilepsy. PMID- 29152736 TI - Protein deficiency decreases stereotypic behavior frequency and prevalence and activity in the striped mouse Rhabdomys dilectus chakae. AB - Diverse motivational triggers, including diet, elicit stereotypic behavior. We investigated whether diets comprised of different protein levels but similar levels of energy were associated with the occurrence of locomotor stereotypies in the striped mouse Rhabdomys dilectus chakae. In a first experiment, 20 stereotypic and 20 non-stereotypic (10 subjects per sex and per group) juvenile (40 days old) subjects were placed on baseline (BP), high (HP) or low protein (LP) diet treatments (120 subjects in total). All subjects initially identified as stereotypic displayed stereotypic behavior in the BP and HP treatments on Days 60-63 and Days 80-83 compared to 35% and 12.5% of LP subjects, respectively. Moreover, LP subjects displayed lower levels of activity and stereotypic behavior than BP and HP subjects. Those identified as non-stereotypic never displayed stereotypy. In a second experiment, 48 individuals, bred and reared on LP and whose parents were stereotypic, were assigned to either HP (13 males, 12 females) or LP (12 males, 11 females) treatments at 50 days of age for 30 days. Stereotypy was three times less likely to occur in the LP than the HP treatment, and activity was greater in LP-HP individuals than LP-LP individuals. In both experiments, LP individuals had the lowest body mass. Striped mice adjusted their behaviors in response to dietary protein levels. Protein deficiency reduced activity and stereotypic behavior and prevalence, possibly related to an energy or neurological deficit. PMID- 29152737 TI - Molecular mechanisms of drug resistance in ovarian cancer. AB - Ovarian cancer is the most lethal malignancy among the gynecological cancers, with a 5-year survival rate, mainly due to being diagnosed at advanced stages, recurrence and resistance to the current chemotherapeutic agents. Drug resistance is a complex phenomenon and the number of known involved genes and cross-talks between signaling pathways in this process is growing rapidly. Thus, discovering and understanding the underlying molecular mechanisms involved in chemo resistance are crucial for management of treatment and identifying novel and effective drug targets as well as drug discovery to improve therapeutic outcomes. In this review, the major and recently identified molecular mechanisms of drug resistance in ovarian cancer from relevant literature have been investigated. In the final section of the paper, new approaches for studying detailed mechanisms of chemo-resistance have been briefly discussed. PMID- 29152738 TI - When should you perform injection medialization for pediatric unilateral vocal fold immobility? PMID- 29152739 TI - First bite syndrome following transcervical arterial ligation after transoral robotic surgery. AB - OBJECTIVE: To assess the incidence of first bite syndrome (FBS) in transoral robotic surgical (TORS) patients undergoing transcervical arterial ligation. METHODS: Retrospective case series of all patients diagnosed with FBS following prophylactic transcervical arterial ligation of branches of the external carotid system between March 2010 and December 2016 at a single academic center. RESULTS: Six patients with FBS after TORS with transcervical arterial ligation were evaluated, representing 7% of all patients who underwent neck dissection with concomitant transcervical arterial ligation (6 of 83). Median presentation of FBS was 63 days, with an average duration of 66 days. Treatment ranged from observation to botulinum toxin injection. CONCLUSION: Patients who undergo transcervical arterial ligation to minimize bleeding complications following TORS are at risk of developing first bite syndrome. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1589-1593, 2018. PMID- 29152740 TI - Microwave as a rapid cooking method for beef tenderness evaluation. AB - : Semitendinosus (ST) muscle steaks were grouped according to three locations (proximal, middle, and distal end), grilled to endpoint temperature of 71C or cooked for 20, 30, 40, 50, or 60 s in a microwave oven (Mw). The location did not affect (p > .05) the cooking loss (CL) or shear force (SF) values. The CL increased (p < .05) with longer microwave cooking times, but only the Mw40 samples did not differ (p > .05) from the grill samples. None of the microwaves' SF values were different (p > .05) from the grill values, with treatments Mw30 to Mw50 showing moderate repeatability (R = 0.51-0.60) and Mw30 and Mw60 showing higher correlations (r > .71) with grill values. Cooking beef strips with a microwave is a potential method for tenderness evaluation, but requires additional study to evaluate and optimize this application in different muscles and for comparison to sensorial data. PRACTICAL APPLICATIONS: The work was intended to evaluate the possibility of using a microwave oven for cooking meat to be used in objective measurement protocols for meat tenderness and to optimize the conditions for this purpose. The use of a standardized microwave procedure allows a dramatic reduction in analysis time and may reduce error variance due to nonuniform cooking procedures. PMID- 29152741 TI - NEAT1 acts as an inducer of cancer stem cell-like phenotypes in NSCLC by inhibiting EGCG-upregulated CTR1. AB - Long non-coding RNAs (lncRNAs) play significant roles in the pathogenesis of various cancers, including lung cancer. In this study, we aimed to investigate the biological function of lncRNA nuclear enriched abundant transcript 1 (NEAT1) in cancer stem cells (CSCs). CSCs have been suggested as the main cause of tumor metastasis, tumor recurrence, and chemotherapy resistance. The copper transporter 1 (CTR1) has been the focus of many recent studies because of its correlation with cisplatin (CDDP) resistance. So far, the mechanism of how NEAT1 regulates CSCs in NSCLC remains unknown. In the current study, lung cancer stem cells were enriched from the parental NSCLC cells. We observed that NEAT1 was up-regulated while copper transporter 1 (CTR1) was down-regulated in the enriched NSCLC cancer stem cells. Knockdown of NEAT1 was able to decrease the CSC-like properties in NSCLC cells, while over-expression of NEAT1 could contribute to the stemness respectively. Meanwhile, appropriate doses of EGCG restrained the stemness triggered by over-expressing NEAT1 via inducing CTR1 expression. Wnt signal pathway and epithelial-to-mesenchymal transition (EMT) process were involved in NEAT1-induced CSCs in NSCLC. These findings may suggest a novel role of NEAT1 for NSCLC treatment. PMID- 29152742 TI - Presbyopia monovision correction and cortical adaptation. PMID- 29152743 TI - Author's reply to: Prognosis of sentinel lymph node biopsy in patients with thick melanoma by a propensity score matching prospective study. PMID- 29152744 TI - Hirano's cover-body model and its unique laryngeal postures revisited. AB - OBJECTIVES/HYPOTHESIS: In 1974, Minoru Hirano proposed his theory of voice production that is now known as the cover-body theory. He described the thyroarytenoid (TA) and cricothyroid (CT) muscles as the major determinants of vocal fold shape and stiffness, and theorized four typical laryngeal configurations resulting from unique TA/CT activations, with implications for the resulting voice quality. In this study, we directly observed the vocal fold medial surface shape under Hirano's unique TA/CT activation conditions to obtain a three-dimensional (3D) understanding of these laryngeal configurations during muscle activation. STUDY DESIGN: In vivo canine hemilarynx model. METHODS: Flesh points were marked along the medial surface of the vocal fold. Selective TA and CT activation were performed via respective laryngeal nerves. 3D reconstructions of the vocal fold medial surface were derived using digital image correlation. RESULTS: Low level TA and CT activation yielded anteroposterior lengthening and vertical thinning of the vocal fold. When TA activation is far greater than CT, the vocal fold shortens and thickens. With slightly greater TA than CT, activation the vocal length is maintained on average, whereas its vertical thickness decreases. With CT far greater than TA activation, the vocal fold lengthens and thins. In all conditions, glottal contour changes remained minimal. CONCLUSIONS: Analysis of the 3D geometry of the vocal fold medial surface under Hirano's four typical laryngeal configurations revealed that the key geometric changes during TA/CT interactions lie within the anteroposterior length and the vertical thickness of the vocal fold. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:1412-1418, 2018. PMID- 29152745 TI - Impact of an oral appliance on obstructive sleep apnea severity, quality of life, and biomarkers. AB - OBJECTIVE/HYPOTHESIS: To investigate outcomes including efficacy, quality of life, and levels of inflammatory markers of a mandibular advancement device (MAD) for moderate-to-severe obstructive sleep apnea (OSA). STUDY DESIGN: Case-control study. METHODS: Patients with apnea-hypopnea index (AHI) >= 15/hr who only accepted MAD therapy (study group) or who refused any treatment (control group) were recruited. At baseline and at 6 months, polysomnography, Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), C-reactive protein (CRP), interleukin 1beta, interleukin 6, and tumor necrosis factor alpha (TNF-alpha) were assessed in both groups. RESULTS: At baseline, the study group (n = 30) showed a higher percentage of rapid eye movement sleep and higher CRP levels (P < .05) than the control group (n = 10). At 6 months, the MAD significantly improved AHI and lowest oxygen saturation (P < .01), non-rapid eye movement (N)1 and N3 sleep stages (P < .05), ESS score (P < .05), FOSQ total score (P < .01), interleukin 1beta (P < .05), and TNF-alpha (P < .01) compared with the untreated group. In the overall, moderate, and severe OSA groups, 63.3%, 75%, and 50%, respectively, achieved at least good response. CONCLUSIONS: Use of a MAD significantly improved polysomnographic parameters, quality of life, and some inflammatory markers (CRP, IL-beta, and TNF-alpha) in a significant proportion of patients with moderate OSA and in some patients with severe OSA. Hence, a MAD may be a viable alternative therapy in patients with moderate-to severe OSA who refuse continuous positive airway pressure. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:1720-1726, 2018. PMID- 29152746 TI - Referral patterns from emergency department to otolaryngology clinic. AB - OBJECTIVES/HYPOTHESIS: Patients who present to the emergency department (ED) with various otolaryngologic disorders are frequently referred to an otolaryngologist for follow-up care. Our aim was to further characterize this group as it has not been well described in the literature. STUDY DESIGN: Cross-sectional retrospective study. METHODS: We reviewed the charts of patients seen during an 18-month period in an urban public hospital trauma center adult ED and referred to an otolaryngology clinic for follow-up care. RESULTS: Seven hundred thirty eight patients were seen and referred; the most common diagnoses made by ED providers were peripheral vertigo (12%), otitis externa (8%), and nasal fractures (8%). Nine percent of patients were evaluated during their ED visit by an otolaryngology provider. Three hundred seventy-two (50%) patients returned for their otolaryngology clinic visit; facial trauma patients were least likely to return. The most common diagnoses made by otolaryngology providers were otitis externa (12%), peripheral vertigo (12%), and nasal fractures (7%). There was 50% concordance between patients' diagnoses made by ED and otolaryngology providers. The most common differences were otitis media versus otitis externa (10%) and acute pharyngitis versus laryngopharyngeal reflux (8%). During 37% of follow-up visits, an in-office procedure was performed, most commonly flexible fiberoptic laryngoscopy, cerumen removal, and nasal endoscopy. CONCLUSIONS: Our analysis reports comprehensive characteristics of this referral group, identifying potential areas for improvement in patient management, resident education and efficiency. Otolaryngologists covering EDs should be familiar with this population in terms of types of cases that may affect their practices. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1062-1067, 2018. PMID- 29152747 TI - Genetic structure and evidence of anthropogenic effects on wild populations of two Neotropical catfishes: baselines for conservation. AB - Genetic diversity and structure of Pseudoplatystoma corruscans and P. reticulatum, large migratory South America catfishes, where overfishing and the construction of numerous dams in their feeding and reproducing areas are affecting their migratory processes negatively, were studied using microsatellites in samples from Paraguay (that comprises the Pantanal biome), and the upper and lower Parana Basins. Genetic diversity was in accordance to that observed for other large migratory fishes, but the most geographically isolated populations of P. reticulatum and those P. corruscans subject to anthropogenic effects (stocking and dams) showed lower genetic diversity and evidences of bottlenecks compatible with low effective population size. Pseudoplatystoma reticulatum presented subtle genetic differentiation within the Paraguay area, especially between the edges of its distribution. Pseudoplatystoma corruscans, in this same area, presented a quite homogeneous but significant genetic break between the Paraguay and upper Parana populations, apparently resulting from natural and historical isolation between the basins until recently. These data demonstrates that, although these Pseudoplatystoma spp. are abundant in the Pantanal area, anthropogenic events are leading to negative effects on their populations, particularly in the upper Parana Basin. Genetic differentiation observed along each species distribution demands conservation actions to preserve each population's biodiversity. These results represent important genetic information using new microsatellite markers and the first genetic study of P. reticulatum covering this area of its native distribution. Data may also contribute to a better understanding of species migration patterns and to be used as a baseline for proper management. PMID- 29152748 TI - Comparison of pediatric adenoidectomy techniques. AB - OBJECTIVES: Evaluate the effects of electrocautery, microdebrider, and coblation techniques on outpatient pediatric adenoidectomy costs and complications. STUDY DESIGN: Observational retrospective cohort study. METHODS: An observational cohort study was performed in a multihospital network using a standardized accounting system. Children < 18 years of age who underwent outpatient adenoidectomy were included from January 2008 to September 2015. Cases with additional procedures were excluded. The cohorts were divided into children who underwent electrocautery, microdebrider, or coblator adenoidectomy. Data regarding costs, postoperative complications, and revision surgeries were analyzed. RESULTS: A total of 1,065 cases of adenoidectomy were performed with electrocautery (34.9%), microdebrider (26.1%), and coblation (39.0%). There was an increased after direct cost associated with the microdebrider, $833 (standard deviation [SD] $363) and the coblator, $797 (SD $262) compared to the electrocautery, $597 (SD $361) (P < 0.0001). There was a greater overall operating room (OR) time associated with use of the microdebrider (mean 28.7, SD 11.0 minutes) compared with both the electrocautery (mean 24.7, SD 8.1 minutes) and coblator (mean 26.2, SD 9.8 minutes) (P < 0.0001). No significant difference was found with regard to complication rates. The incidence of repeat adenoidectomies was significantly greater for microdebrider (9.7%) compared to electrocautery (2.7%; P = 0.0002) and coblator (5.3%; P = 0.0336) techniques. CONCLUSION: These results suggest that adenoidectomy with electrocautery is significantly less expensive than microdebrider and coblator, with no differences in complication rates or surgical times among the techniques. Microdebrider adenoidectomy was associated with a longer overall OR time and a higher rate of adenoid regrowth, requiring revision surgery. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:745-749, 2018. PMID- 29152749 TI - Effect of topical nasal anesthetic on swallowing in healthy adults: A double blind, high-resolution manometry study. AB - OBJECTIVE: Topical nasal anesthetic (TNA) is used when evaluating pharyngeal swallowing with high-resolution manometry (HRM). It is unclear if desensitizing the nasal mucosa improves procedure tolerability or affects pharyngeal pressure. This study evaluated the effects of TNA on comfort and pharyngeal pressure using HRM. METHODS: A double-blinded study was conducted with 20 healthy participants ( x- = 27 years). Participants performed five saliva and five 10-mL swallows during two exams with ManoScan HRM ESO catheter (Medtronic, Minneapolis, MN) randomized under placebo (nonanesthetic lubricant) and anesthetized (0.4 mL of 2% viscous lidocaine hydrochloride) conditions. Comfort was rated using a 100-mm visual analog scale (VAS). Pharyngeal HRM amplitude and timing were analyzed. RESULTS: VAS ratings were similar under placebo (mean = 38.4, standard deviation [SD] = 19.92) and TNA conditions (mean = 33.78, SD = 18.9), with no significant differences between placebo and anesthetized conditions (t[19] = 1.23, P = 0.23) or tolerability at first and second procedure (t[19] = 1.38, P = 0.18). Lower maximum and mean pharyngeal pressure were found for the TNA condition when compared to placebo (dry: maximum [-15.45 mmHg, standard error (SE) = 5.06 mmHg, P = 0.021]; mean [-5.22 mmHg, SE = 1.58 mmHg, P = 0.005]), and (liquid: maximum [ 14.79 mmHg, SE = 5.01 mmHg, P = 0.010]; mean [-2.79 mmHg, SE = 1.99 mmHg, P = 0.008]). CONCLUSION: This double-blind, randomized study is the first to investigate effects of TNA on tolerability and pharyngeal pressure using HRM. Results indicate TNA offered no significant difference in procedure comfort while affecting the magnitude of pharyngeal swallowing. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1335-1339, 2018. PMID- 29152750 TI - Avoiding being dragged away: finding egg cases of Schroederichthys bivius (Chondrichthyes: Scyliorhinidae) associated with benthic invertebrates. AB - Egg cases of the narrowmouthed catshark Schroederichthys bivius were recorded entangled with sponges, corals and tubeworms at different sites in the south-west Atlantic Ocean. This work sheds light on the importance of benthic invertebrates in the life cycle of oviparous chondrichthyan species. PMID- 29152751 TI - Healthcare disparities in pediatric otolaryngology: A systematic review. AB - OBJECTIVES: Multiple studies have reported healthcare disparities in particular settings and conditions within pediatric otolaryngology, but a systematic examination of the breadth of the problem within the field is lacking. This study's objectives are to synthesize the available evidence regarding healthcare disparities in pediatric otolaryngology, highlight recurrent themes with respect to etiologies and manifestations, and demonstrate potential impacts from patient and provider standpoints. METHODS: A qualitative systematic review of the PubMed, Ovid, and Cochrane databases for articles focusing on racial, ethnic, or socioeconomic disparities related to pediatric otolaryngology conditions or settings was conducted. United States-based studies of any design or publication date with analysis of children 0 to 18 years old were included. RESULTS: Of 711 abstracts identified, 39 met inclusion criteria. Manual review of references from these articles yielded 22 additional studies, for a total of 61. Disparities were identified in nearly every subspecialty within pediatric otolaryngology, with otologic conditions the most frequently studied (33 of 61). The most commonly cited disparities involved low socioeconomic status (25 of 61), inadequate insurance (23 of 61), nonwhite race (21 of 61), and barriers to accessing care (21 of 61). Only six articles found no disparities regarding the condition examined in their study. CONCLUSION: Through a variety of study topics, designs, and settings, a growing body of literature documents disparities across the spectrum of pediatric otolaryngology care. The etiologies and manifestations of such disparities are myriad. This evidence suggests the need for interventions to address these disparities at various professional and institutional levels, ideally with methodological rigor to assess the effectiveness of such interventions. Laryngoscope, 128:1699-1713, 2018. PMID- 29152752 TI - Nasoseptal flap closure of the eustachian tube for recalcitrant cerebrospinal fluid rhinorrhea. PMID- 29152753 TI - The hospital otolaryngologist: The louisiana state university experience. AB - OBJECTIVES/HYPOTHESIS: To describe the implementation and impact of a hospital otolaryngologist in an academic medical center setting. Our hypothesis was that the hospital otolaryngologist would increase productivity of the Louisiana State University (LSU) faculty otolaryngologists and provide more timely access to inpatient otolaryngology services. STUDY DESIGN: Retrospective clinical and administrative database review. METHODS: A comparative database review was performed with data from the year predating the initiation of the hospitalist program (2013) to the first full year after initiation of the program (2014). A clinical database review including diagnoses and procedures was also performed. RESULTS: Overall outpatient clinic relative value units for the aggregated LSU faculty increased 16% (despite the fact that the direct outpatient contribution of the hospital otolaryngologist was negligible). Overall capture of inpatient consult codes increased 128%. The hospital otolaryngologist was responsible for 84.5% of inpatient consult codes. There was a 100% increase in outpatient consult codes for the LSU faculty, of which <1% was attributed to the otolaryngology hospitalist. No significant impact was seen on length of stay over the study interval. Clinical database review of the first 2 years of the program showed 3,707 total encounters with postoperative encounters the most common. Four hundred fifty-four inpatient procedures were logged. The most common surgical procedure was tracheostomy. CONCLUSIONS: The otolaryngology hospitalist program is a viable clinical and economic model. LEVEL OF EVIDENCE: NA Laryngoscope, 1851 1857, 2018. PMID- 29152754 TI - Easy insertion into the duct: The use of an angiocatheter as a sialendoscopy applicator. PMID- 29152755 TI - Interviewing intoxicated witnesses: Memory performance in theory and practice. AB - Memory encoding and recall involving complex, effortful cognitive processes are impaired by alcohol primarily due to impairment of a select few, but crucial, cortical areas. This review shows how alcohol affects some, but not all, aspects of eyewitnesses' oral free recall performance. The principal results, so far, are that: a) free recall reports by intoxicated witnesses (at the investigated BAC levels) may contain less, but as accurate, information as reports by sober witnesses; b) immediate reports given by intoxicated witnesses may yield more information compared to reports by sober witnesses given after a one week delay; c) an immediate interview may enhance both intoxicated and sober witnesses' ability to report information in a later interview; and d) reminiscence seems to occur over repeated interviews and the new information seems to be as accurate as the previously reported information. Based on this, recommendations are given for future research to enhance understanding of the multifaceted impact of alcohol on witnesses' oral free recall of violent crimes. PMID- 29152757 TI - Measuring automatic value orientations: The Achievement-Benevolence Implicit Association Test. AB - The construct and criterion validity of an Implicit Association Test designed to rate the importance ascribed to Achievement-Benevolence oriented goals (AB-IAT) according to Schwartz's model were investigated. In a first study (N = 113), the AB-IAT and three other value-IATs (Power-Universalism, Security-Self-direction, and Tradition-Stimulation) were administered along with the corresponding self report scales. The AB-IAT showed the following: (1) an adequate internal consistency; (2) a small correlation and a different pattern of means with respect to the corresponding self-report scale; (3) a pattern of correlations with the other value-IATs that is consistent with Schwartz's model. In a second study (N = 99), results showed that (1) in contrast to self-report measures of values, the AB-IAT appeared unrelated to social desirability; (2) the AB-IAT was significantly correlated with an actual behaviour expressing Benevolence values; (3) in accordance with a double dissociation pattern of prediction, implicit and explicit values are best predictors of actual and self-rated behaviours, respectively. Overall, results of the studies support the construct and criterion validity of the AB-IAT. Moreover, they provide a first support for the generalizability of Schwartz's model in the realm of implicit social cognition, and for the applicability of dual-process models in value research. PMID- 29152756 TI - beta-catenin deficiency in hepatocytes aggravates hepatocarcinogenesis driven by oncogenic beta-catenin and MET. AB - : Both activating and inactivating mutations in catenin beta1 (ctnnb1), which encodes beta-catenin, have been implicated in liver tumorigenesis in humans and mice, although the underlying mechanisms are not fully understood. Herein, we show that deletion of endogenous beta-catenin in hepatocytes aggravated hepatocellular carcinoma (HCC) development driven by an oncogenic version of beta catenin (CAT) in combination with the hepatocyte growth factor receptor MET proto oncogene receptor tyrosine kinase (MET). Although the mitogenic signaling and cell cycle progression was modestly impaired after CAT/MET transfection, the beta catenin-deficient livers displayed changes in transcriptomes, increased DNA damage response, expanded Sox9+ cells, and up-regulation of protumorigenic cytokines, including interleukin-6 and transforming growth factor beta1. These events eventually exacerbated CAT/MET-driven hepatocarcinogenesis in beta-catenin deficient livers, featured by up-regulation of extracellular signal-regulated kinase (Erk), protein kinase B (Akt), and Wnt/beta-catenin signaling and cyclin D1 expression. The resultant mouse tumors showed similar transcriptomes to human HCC samples with concomitant CTNNB1 mutations and MET overexpression. CONCLUSION: These data argue that while dominantly activating mutants of beta-catenin are oncogenic, inhibiting the oncogenic signaling pathway generates a pro-oncogenic microenvironment that may facilitate HCC recurrence following a targeted therapy of the primary tumor. An effective therapeutic strategy must require disruption of the oncogenic signaling in tumor cells and suppression of the secondary tumor promoting stromal effects in the liver microenvironment. (Hepatology 2018;67:1807 1822). PMID- 29152758 TI - The role of genetics in hepatic fibrosis among hepatitis C virus patients. PMID- 29152759 TI - Retrieval of Adult Patients on Extracorporeal Membrane Oxygenation by an Intensive Care Physician Model. AB - The optimal staffing model during the inter-hospital transfer of patients on extracorporeal membrane oxygenation (ECMO) is not known. We report the complications and outcomes of patients who were commenced on ECMO at a referring hospital by intensive care physicians and compare these findings with patients who had ECMO established at an ECMO center in Australia. This was a single center, retrospective observational study based on a prospectively collected ECMO database from Melbourne, Australia. Patients with severe cardiac and/or respiratory failure failing conventional supportive treatment between 2007-2013 were placed on ECMO via a physician-led model of ECMO retrieval, including two intensivists in a four person team, using percutaneous ECMO cannulation. Patients (198) underwent ECMO over the study period, of which 31% were retrieved. Veno venous (VV)-ECMO and veno-arterial (VA)-ECMO accounted for 27 and 73% respectively. The VA-ECMO patients had more intra-transport interventions compared with VV-ECMO transported patients, but none resulting in serious morbidity or death. There was no overall difference in survival at 6 months between retrieved and ECMO center patients: VV-ECMO (75 vs. 70%, P = 0.690) versus VA-ECMO (70 vs. 68%, P = 1.000). An intensive care physician-led team was able to safely place all critically ill patients on ECMO and retrieve them to an ECMO center. This may be an appropriate staffing model for ECMO retrieval. PMID- 29152760 TI - The national landscape of unplanned 30-day readmissions after total laryngectomy. AB - OBJECTIVES/HYPOTHESIS: Examine rates of readmission after total laryngectomy and determine primary etiologies, timing, and risk factors for unplanned readmission. STUDY DESIGN: Retrospective cohort study. METHODS: The Nationwide Readmissions Database was queried for patients who underwent total laryngectomy between January 2013 and November 2013. Patient-, procedure-, admission-, and institution level characteristics were compared for patients with and without unplanned 30 day readmission. Outcomes of interest included rates, etiology, and timing of readmission. Multivariate logistic regression was used to identify predictors of 30-day readmission. RESULTS: There were 2,931 total laryngectomies performed in 2013 with an unplanned readmission rate of 17.5%. Postoperative fistula accounted for 13.7% of readmissions. The odds of readmission were elevated for patients undergoing concurrent procedures, including primary tracheoesophageal fistulization (adjusted odds ratio [aOR]: 2.44, 95% confidence interval [CI]: 1.15-5.18, P = .02) and/or pedicle graft or flap procedures (aOR: 1.73, 95% CI: 1.13-2.66, P = .01). Additionally, patients with comorbid coagulopathy (aOR: 3.04, 95% CI: 1.13-8.22, P = .03), liver disease (aOR: 2.48, 95% CI: 1.08-5.71, P = .03), and valvular heart disease (aOR: 3.18, 95% CI: 1.20-8.41, P = .02) had increased risk for unplanned 30-day readmission. Private insurance and longer lengths of stay were associated with decreased odds of readmission. CONCLUSIONS: Nearly one-fifth of total laryngectomy patients are readmitted to the hospital within 30 days of discharge. Risk factors identified in this nationally representative cohort should be carefully considered during the postoperative period to reduce preventable readmissions after total laryngectomy. LEVEL OF EVIDENCE: 2c Laryngoscope, 1842-1850, 2018. PMID- 29152761 TI - Loneliness and acute stress reactivity: A systematic review of psychophysiological studies. AB - Physiological reactivity to acute stress has been proposed as a potential biological mechanism by which loneliness may lead to negative health outcomes such as cardiovascular disease. This review was conducted to investigate the association between loneliness and physiological responses to acute stress. A series of electronic databases were systematically searched (PsycARTICLES, PsycINFO, Medline, CINAHL Plus, EBSCOhost, PubMed, SCOPUS, Web of Science, Science Direct) for relevant studies, published up to October 2016. Eleven studies were included in the review. Overall, the majority of studies reported positive associations between loneliness and acute stress responses, such that higher levels of loneliness were predictive of exaggerated physiological reactions. However, in a few studies, loneliness was also linked with decreased stress responses for particular physiological outcomes, indicating the possible existence of blunted relationships. There was no clear pattern suggesting any sex or stressor-based differences in these associations. The available evidence supports a link between loneliness and atypical physiological reactivity to acute stress. A key finding of this review was that greater levels of loneliness are associated with exaggerated blood pressure and inflammatory reactivity to acute stress. However, there was some indication that loneliness may also be related to blunted cardiac, cortisol, and immune responses. Overall, this suggests that stress reactivity could be one of the biological mechanisms through which loneliness impacts upon health. PMID- 29152762 TI - Optimizing lonafarnib treatment for the management of chronic delta hepatitis: The LOWR HDV-1 study. AB - : In a proof-of-concept (POC) study, the oral prenylation inhibitor, lonafarnib (LNF), decreased hepatitis D virus (HDV) RNA during 4 weeks of treatment. Here, we explored optimal LNF regimens. Fifteen patients (five groups; 3 per group) completed dosing as follows: (1) LNF 200 mg twice-daily (BID; 12 weeks); (2) LNF 300 mg BID (12 weeks); (3) LNF 100 mg thrice-daily (5 weeks); (4) LNF 100 mg BID + pegylated interferon alfa (PEG-IFNalpha) 180 MUg once-weekly (QW; 8 weeks); and (5) LNF 100 mg BID + ritonavir (RTV) 100 mg once-daily (QD; 8 weeks). Tolerability and efficacy were assessed. Higher LNF monotherapy doses had greater decreases in HDV viral load than achieved in the original POC study. However, this was associated with increased gastrointestinal adverse events. Addition of RTV 100 mg QD to a LNF 100 mg BID regimen yielded better antiviral responses than LNF 300 mg BID monotherapy and with less side effects. A similar improvement was observed with LNF 100 mg BID + PEG-IFNalpha 180 MUg QW. Two of 6 patients who received 12 weeks of LNF experienced transient posttreatment alanine aminotransferase (ALT) increases resulting in HDV-RNA negativity and ALT normalization. CONCLUSION: The cytochrome P450 3A4 inhibitor, RTV, allows a lower LNF dose to be used while achieving higher levels of postabsorption LNF, yielding better antiviral responses and tolerability. In addition, combining LNF with PEG IFNalpha achieved more substantial and rapid HDV-RNA reduction, compared to historical responses with PEG-IFNalpha alone. Twelve weeks of LNF can result in posttreatment HDV-RNA negativity in some patients, which we speculate results from restoring favorable immune responses. These results support further development of LNF with RTV boosting and exploration of the combination of LNF with PEG-IFN. (Hepatology 2018;67:1224-1236). PMID- 29152765 TI - Mesenchymal stromal cells in treatment of acute-on-chronic liver failure. PMID- 29152764 TI - Comparative transcriptome analysis of the calcium signaling and expression analysis of sodium/calcium exchanger in Aspergillus cristatus. AB - Aspergillus cristatus develops into various stages under different Na concentrations: the sexual stage in 0.5 M NaCl and asexual development stage in 3 M NaCl. In order to explore whether the Ca2+ signaling pathway in A. cristatus responded to the changes in the salt stress, we analyzed the gene expression levels in A. cristatus respectively cultured in 0.5 M NaCl and 3 M NaCl. According to the BLAST analysis results, we identified 25 Ca2+ -signaling proteins in A. cristatus. The expression levels of most genes involved in the Ca2+ -signaling pathway in A. cristatus cultured in different salt concentrations showed significant differences, indicating that the Ca2+ signaling pathway was involved in the response to the changes in the salt stress. In yeasts, only calcium ion influx proteins were reported to be involved in the response to the changes in the salt stress. So far, the protein for the exchanger of calcium/sodium ions has not been reported. Therefore, we obtained the sodium/calcium exchanger (termed NCX) proteins from the KEGG Database. The ncx gene of A. cristatus was cloned and characterized. The full length of ncx gene is 3055 bp, including a 2994-bp open reading frame encoding 994 amino acids. The expression levels of ncx in the sexual development stage and asexual development stage were respectively ~8.94 times and ~2.57 times of that in the hyphal formation stage. Therefore, we suggested that ncx gene was up-regulated to resist the sodium stress. The study results provide the basis for further exploring the Ca2+ -signaling mechanism and ion exchanger mechanism. PMID- 29152763 TI - Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: Results from two prospective cohort studies. AB - : Type 2 diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). However, it is unknown whether T2D duration or additional metabolic comorbidities further contribute to HCC risk. From the Nurses' Health Study (NHS), 120,826 women were enrolled in 1980, and from the Health Professionals Follow-up Study (HPFS), 50,284 men were enrolled in 1986 and followed through 2012. Physician diagnosed T2D was ascertained at baseline and updated biennially. Cox proportional hazards regression models were used to calculate age- and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident HCC. Over 32 years of follow-up (4,488,410 person-years), we documented 112 cases of HCC (69 women, 43 men). T2D was associated with an increased HCC risk (multivariable HR, 4.59; 95% CI, 2.98-7.07), as was an increasing T2D duration (Ptrend < 0.001). Compared to nondiabetics, the multivariable HRs for HCC were 2.96 (95% CI, 1.57-5.60) for 0-<2 years; 6.08 (95% CI, 2.96-12.50) for 2 <10 years; and 7.52 (95% CI, 3.88-14.58) for >=10 years. Increasing number of metabolic comorbidities (T2D, obesity, hypertension, and dyslipidemia) was associated with increased HCC risk (Ptrend < 0.001); compared to individuals without metabolic comorbidity, those with four metabolic comorbidities had an 8.1 fold increased HCC risk (95% CI, 2.48-26.7). In T2D, neither insulin use nor oral hypoglycemic use was significantly associated with HCC risk (HR, 2.04 [95% CI, 0.69-6.09] and HR, 1.45 [95% CI, 0.69-3.07], respectively). CONCLUSION: T2D is independently associated with increased risk for HCC in two prospective cohorts of U.S. men and women. This risk is enhanced with prolonged diabetes duration and with comorbid metabolic conditions, suggesting the importance of insulin resistance in the pathogenesis of HCC. (Hepatology 2018;67:1797-1806). PMID- 29152766 TI - Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: More details, more significance. PMID- 29152767 TI - Development and validation of a primary sclerosing cholangitis-specific patient reported outcomes instrument: The PSC PRO. AB - : Primary sclerosing cholangitis (PSC) is a chronic liver disease associated with inflammation and biliary fibrosis that leads to cholangitis, cirrhosis, and impaired quality of life. Our objective was to develop and validate a PSC specific patient-reported outcome (PRO) instrument. We developed a 42-item PSC PRO instrument that contains two modules (Symptoms and Impact of Symptoms) and conducted an external validation. Reliability and validity were evaluated using clinical data and a battery of other validated instruments. Test-retest reliability was assessed in a subgroup of patients who repeated the PSC PRO after the first administration. One hundred two PSC subjects (44 +/- 13 years; 32% male, 74% employed, 39% with cirrhosis, 14% with a history of decompensated cirrhosis, 38% history of depression, and 68% with inflammatory bowel disease [IBD]) completed PSC PRO and other PRO instruments (Short Form 36 V2 [SF-36], Chronic Liver Disease Questionnaire [CLDQ], Primary Biliary Cholangitis - 40 [PBC 40], and five dimensions [5-D Itch]). PSC PRO demonstrated excellent internal consistency (Cronbach alphas, 0.84-0.94) and discriminant validity (41 of 42 items had the highest correlations with their own domains). There were good correlations between PSC PRO domains and relevant domains of SF-36, CLDQ, and PBC 40 (R = 0.69-0.90; all P < 0.0001), but lower (R = 0.31-0.60; P < 0.001) with 5-D Itch. Construct validity showed that PSC PRO can differentiate patients according to the presence and severity of cirrhosis and history of depression (P < 0.05), but not by IBD (P > 0.05). Test-retest reliability was assessed in 53 subjects who repeated PSC PRO within a median (interquartile range) of 37 (27-47) days. There was excellent reliability for most domains with intraclass correlations (0.71-0.88; all P < 0.001). CONCLUSION: PSC PRO is a self-administered disease specific instrument developed according to U.S. Food and Drug Administration guidelines. This preliminary validation study suggests good psychometric properties. Further validation of the instrument in a larger and more diverse sample of PSC patients is needed. (Hepatology 2018;68:155-165). PMID- 29152768 TI - The distribution of calbindinD-28k and parvalbumin immunoreactive neurons in the somatosensory area of the pigeon pallium. AB - GABAergic interneurons regulate the degree of glutamatergic excitation and output of projection neurons. In this study, we investigated the distribution of calbindinD-28k (CB) and parvalbumin (PV) in the somatosensory area of the pigeon pallium using immunohistochemical method. Our results show that anatomical structures of the somatosensory area of the pigeon pallium consisted of several subdivisions including the hyperpallium, intercalated hyperpallium, mesopallium, nidopallium and basorostralis. Neuronal density was significantly higher in the intercalated hyperpallium and basorostralis than that in the other subdivisions. The density of the CB immunoreactive neurons was generally similar in all the subdivisions; however, the density of PV immunoreactive neurons was particularly prominent in the basorostralis compared with that in the other subdivisions. In addition, the mean proportion of PV immunoreactive neurons to total neurons was higher than that in the CB immunoreactive neurons in all the subdivisions. In brief, our present study shows that PV immunoreactive neurons in the somatosensory area of the pigeon pallium were significantly abundant compared with CB immunoreactive neurons. This finding needs more studies regarding CB- and PV-related functions in the somatosensory area of the avian pallium. PMID- 29152769 TI - Sofosbuvir, pegylated interferon, and ribavirin for retreatment of hepatitis C virus genotype 1b following sofosbuvir and ledipasvir failure. PMID- 29152770 TI - Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness. AB - : The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the basolateral cell polarity complex protein scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison with HCC cells stably expressing wild-type Scrib (ScribWT ), mutated Scrib with enforced cytoplasmic enrichment (ScribP305L ) induced AKT signaling through the destabilization of phosphatase and tensin homolog (PTEN) and PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1). Cytoplasmic ScribP305L stimulated a gene signature and a phenotype characteristic for epithelial to mesenchymal transition (EMT) and HCC cell invasiveness. ScribP305L -dependent invasion was mediated by the activator protein 1 (AP-1) constituents ATF2 and JunB through induction of paracrine-acting secreted protein acidic and cysteine rich (SPARC). Coexpression of ScribP305L and the oncogene c-MYC through hydrodynamic gene delivery in mouse livers promoted tumor formation and increased abundance of pAKT, pATF2, and SPARC in comparison with controls. Finally, cytoplasmic Scrib localization correlated with AKT and ATF2 phosphorylation in human HCC tissues, and the ScribP305L -dependent gene signature was enriched in cancer patients with poor prognosis. CONCLUSION: Perturbation of hepatocellular polarity due to overexpression and cytoplasmic enrichment of Scrib supports tumor initiation and HCC cell dissemination through specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patients with higher risk for the development of metastasis. (Hepatology 2018;67:1842-1856). PMID- 29152771 TI - Prevalence of hearing loss among noise-exposed workers within the agriculture, forestry, fishing, and hunting sector, 2003-2012. AB - BACKGROUND: The purpose of this study was to estimate the prevalence of hearing loss among noise-exposed US workers within the Agriculture, Forestry, Fishing, and Hunting (AFFH) sector. METHODS: Audiograms for 1.4 million workers (17 299 within AFFH) from 2003 to 2012 were examined. Prevalence, and the adjusted risk for hearing loss as compared with the reference industry (Couriers and Messengers), were estimated. RESULTS: The overall AFFH sector prevalence was 15% compared to 19% for all industries combined, but many of the AFFH sub-sectors exceeded the overall prevalence. Forestry sub-sector prevalences were highest with Forest Nurseries and Gathering of Forest Products at 36% and Timber Tract Operations at 22%. The Aquaculture sub-sector had the highest adjusted risk of all AFFH sub-sectors (PR = 1.70; CI = 1.42-2.04). CONCLUSIONS: High risk industries within the AFFH sector need continued hearing conservation efforts. Barriers to hearing loss prevention and early detection of hearing loss need to be recognized and addressed. PMID- 29152772 TI - Papillary architecture of the lingual surface in the puma (Puma concolor). AB - This research presents the first anatomical description of the tongue and lingual papillae of the mountain lion (puma). The tongues of three adult male pumas were used in this study. The tongues were dissected and studied firstly by gross and stereomicroscopy. Samples of each part were processed by study with scanning electron microscopy. The margins of the lingual apex were surrounded by numerous filiform papillae, which had a bulky papillary body and a bifurcated tip. On the dorsal surface of the lingual apex, filiform papillae were remarkably pointed and had many secondary projections, which emerged from the base of the main papilla. In the rostral half of the lingual body, filiform papillae were longer, cylindrical and had blunt tips. On the caudal half of the lingual body, filiform papillae gave place to conical ones exhibiting a pointed tip. The fungiform papillae were scattered on the whole dorsal surface of the tongue. On each lateral half of the tongue, four circumvallate papillae were observed and each circumvallate papilla was surrounded by thick and horseshoe-like annular pad, which were composed by pointed conical papillae on the caudal border of the lingual body. The dorsal surface of the circumvallate papilla was covered by many finger-like protrusion, and the tip of each protrusion had a central orifice. Anatomical distribution of lingual papillae was different to other carnivores and represents the adaptation to the feeding habits of this mammal. General morphology of the lingual structures was similar to those of the tiger. PMID- 29152773 TI - Categorization of the pelvic limb standing posture in nine breeds of dogs. AB - The objective of the study was to categorize objectively nine breeds of healthy dogs according to pelvic limb standing posture. A total of 135 dogs from different breeds were used and the standing angles of the hip, stifle, and tarsal joints, together with the percentages of the greater trochanter, patella and tuber calcanei heights, with respect to crista iliaca height, were used as discriminant variables for the categorization of pelvic limb posture. All included breeds were allocated to three groups of the standing pelvic limb posture. The best discriminant variables between the three groups were the percentage of patellar height, and the standing angles of the stifle and tarsal joints. German shepherds, Anatolian shepherds, golden retrievers, Rottweilers, Belgian Malinois and Dobermann pinschers were well separated between 89% and 100% success rate for the categorization. The minimal success rate was determined in Berner sennenhunds as the ratio of 75%. It was also determined that Dobermann pinschers had the straightest pelvic limbs, while German shepherds had the most angulated pelvic limbs. Further studies are required to document the impact of postural differences in active and passive structure diseases of the locomotor system of the pelvic limb among dog breeds. PMID- 29152774 TI - Knowledge of Safety, Training, and Practice of Neonatal Cranial Ultrasound: A Survey of Operators. AB - OBJECTIVES: Ultrasound can lead to thermal and mechanical effects in interrogated tissues. This possibility suggests a potential risk during neonatal cranial ultrasound examinations. The aim of this study was to explore safety knowledge and training of neonatal cranial ultrasound among Australian operators who routinely perform these scans. METHODS: An online survey was administered on biosafety and training in neonatal cranial ultrasound, targeting all relevant professionals who can perform neonatal cranial ultrasound examinations in Australia: namely, radiologists, neonatologists, sonographers, and pediatricians. The survey was conducted between November 2013 and May 2014. RESULTS: A total of 282 responses were received. Twenty of 208 (10%) answered all ultrasound biosafety questions correctly, and 49 of 169 (29%) correctly defined the thermal index. Two-thirds (134 of 214 [63%]) of respondents failed to recognize that reducing the overall scanning time is the most effective method of reducing the total power exposure. Only 13% (31 of 237) indicated that a predetermined fixed period of training or that a specified minimum number of supervised scans was used during training. The reported number of supervised scans during training was highly variable. Almost half of the participants (82 of 181 [45%]) stated that they had received supervision for 10 to 50 scans (median, 20 scans). CONCLUSIONS: There is a need to educate operators on biosafety issues and approaches to minimize power outputs and reduce the overall duration of cranial ultrasound scans. Development of standardized training requirements may be warranted. PMID- 29152775 TI - New insights into diagnosis and therapeutic options for proliferative hepatoblastoma. AB - : Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70%-80% of patients. However, some important challenges remain in diagnosing high-risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of HB tumors have been described, C1 and C2, with C2 being the subgroup with the poorest prognosis, a more advanced tumor stage, and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed, but it has not been transferred into clinical routine. To address these issues, we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A, and C2B, identifiable by a concise four-gene signature: hydroxysteroid 17-beta dehydrogenase 6, integrin alpha 6, topoisomerase 2-alpha, and vimentin, with topoisomerase 2-alpha being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by quantitative RT-PCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in the Fanconi anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, a Food and Drug Administration-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway-associated double-strand DNA repair, and significantly impedes HB growth in vivo. CONCLUSION: The highly proliferating C2A subtype is characterized by topoisomerase 2-alpha gene up-regulation and FA pathway activation, and the HB therapeutic arsenal could include bortezomib for the treatment of patients with the most aggressive tumors. (Hepatology 2018;68:89 102). PMID- 29152776 TI - Sparse boosting for high-dimensional survival data with varying coefficients. AB - Motivated by high-throughput profiling studies in biomedical research, variable selection methods have been a focus for biostatisticians. In this paper, we consider semiparametric varying-coefficient accelerated failure time models for right censored survival data with high-dimensional covariates. Instead of adopting the traditional regularization approaches, we offer a novel sparse boosting (SparseL2 Boosting) algorithm to conduct model-based prediction and variable selection. One main advantage of this new method is that we do not need to perform the time-consuming selection of tuning parameters. Extensive simulations are conducted to examine the performance of our sparse boosting feature selection techniques. We further illustrate our methods using a lung cancer data analysis. PMID- 29152777 TI - Evidence synthesis from aggregate recurrent event data for clinical trial design and analysis. AB - Information from historical trials is important for the design, interim monitoring, analysis, and interpretation of clinical trials. Meta-analytic models can be used to synthesize the evidence from historical data, which are often only available in aggregate form. We consider evidence synthesis methods for trials with recurrent event endpoints, which are common in many therapeutic areas. Such endpoints are typically analyzed by negative binomial regression. However, the individual patient data necessary to fit such a model are usually unavailable for historical trials reported in the medical literature. We describe approaches for back-calculating model parameter estimates and their standard errors from available summary statistics with various techniques, including approximate Bayesian computation. We propose to use a quadratic approximation to the log likelihood for each historical trial based on 2 independent terms for the log mean rate and the log of the dispersion parameter. A Bayesian hierarchical meta analysis model then provides the posterior predictive distribution for these parameters. Simulations show this approach with back-calculated parameter estimates results in very similar inference as using parameter estimates from individual patient data as an input. We illustrate how to design and analyze a new randomized placebo-controlled exacerbation trial in severe eosinophilic asthma using data from 11 historical trials. PMID- 29152778 TI - Hepatocellular carcinoma with hepatic vein invasion should not be considered a contraindication for liver resection. PMID- 29152779 TI - Morphogenesis of lingual papillae of one-humped camel (Camelus dromedarius) during prenatal life: A light and scanning electron microscopic study. AB - This study was made on 24 camel fetuses of crown-rump vertebral length (CVRL) ranging from 10.5 cm to 105 cm CVRL (94-352 days old). These camel fetuses were classified into three groups representing the three trimesters of prenatal life. During the first trimester (94-142 days), lingual papillae (circumvallate and lentiform papillae) were demonstrated on the lingual root, but lingual body and the apex were almost free of papillae except for some scattered epithelial projections especially near the lateral borders of the body. In the second trimester (152-229 days), the lentiform papillae covered the entire root of the tongue except for areas occupied by the circumvallate papillae. Taste buds with clear pores were observed for the first time in areas between the circumvallate gustatory furrow and surface epithelium of the tongue. In addition, short numerous filiform papillae were observed on the rostral part of the lingual body and the lateral parts of the apex. Fungiform papillae, however, were demonstrated amidst the filiform papillae. In this trimester, taste buds were also seen on the top of the fungiform papillae. In the third trimester (256-352 days), all lingual papillae were clearly demonstrated on the dorsum of the root, body and apex of the tongue. Both types of gustatory papillae (circumvallate and fungiform) had well-developed taste buds. Mechanical papillae (filiform and lentiform) were well developed. Lentiform papillae occupied most of the dorsal aspect of the Torus linguae; they were larger in size with semicircular apices. Filiform papillae, however, were numerous and demonstrated heavily on the lateral and rostral parts of the body as well as on the apex of the tongue. PMID- 29152780 TI - 6-Nitroazolo[1,5-a]pyrimidin-7(4H)-ones as Antidiabetic Agents. AB - Prevention of the formation of advanced glycation end-products (AGEs) is a reliable approach to achieve control over hyperglycemia and the associated pathogenesis of diabetic vascular complications. In these terms, new synthetic approaches to 6-nitroazolo[1,5-a]pyrimidines have been developed on the basis of the promising antiglycation activity of their structural analogues, such as azolo[5,1-c][1,2,4]triazine-4(1H)-ones. A number of nitroazolopyrimidines were obtained by using nitration, chlorodeoxygenation, and amination reactions, and their antidiabetic properties were elucidated in vitro. It was shown that triazolo[1,5-a]pyrimidine-7(4H)-ones exhibit a higher antiglycation activity than the corresponding 7-alkylamino analogs and aminoguanidine, as the reference compound. It is suggested that this kind of activity can be associated with the chelating properties possessed by the synthesized 6-nitro-7-oxoderivatives. Furthermore, the compounds obtained were tested for their inhibitory activity against dipeptidyl peptidase 4 (DPP4), glycogen phosphorylase, and alpha glucosidase in vitro, but their activities proved to be significantly inferior to those of the reference compounds. PMID- 29152783 TI - Comparison of sub- versus suprafascially raised anterolateral thigh free flaps with regard to donor-site morbidity, function and aesthetics. AB - BACKGROUND: Although the anterolateral thigh flap (ALT) is one of the most frequently applied free flaps in plastic surgery, it remains controversial if the flap should be raised in a sub- or suprafascial plane. The purpose of this study was to compare both harvest techniques regarding donor-site morbidity and outcomes. METHODS: We included 40 pair-matched patients, of whom 20 received a fasciocutaneous and 20 an adipocutaneous ALT free flap for extremity reconstruction. Patients were matched for age (+/-5 years), sex and affected extremity. Chart review focused on co-morbidities, flap dimensions, course of perforator(s), postoperative complications, and surgery time. Follow-up included sensation, range of motion, and muscle strength at the donor-site. In addition, patients rated the aesthetic and functional outcome on a scale from 1 to 6 and completed a Quality of Life 36-item Short-Form Health Survey (SF-36) as well as the lower extremity functional scale (LEFS) questionnaire. RESULTS: Chart review did not reveal any significant differences among study groups. Follow-up indicated better sensory outcomes after subfascial flap elevation, but without statistical significance. Range of motion and muscle strength were not impaired in any patient. Neither patients' ratings regarding aesthetic and functional outcomes nor scores of the SF-36 or LEFS differed significantly among study groups. CONCLUSION: Sub- or suprafascial harvest of the ALT free flap for extremity reconstruction does not impact donor-site morbidity or complications. PMID- 29152782 TI - Oestradiol-17beta is a local factor inducing the early stage of spermatogenesis in mouse testes. AB - This study was undertaken to elucidate the effect of testicular oestradiol-17beta (E2 ) on spermatogenesis. Spermatogonial development and spermatogenic gene expression in testicular germ cells were investigated using an in vitro culture system supplemented with E2 . E2 stimulated spermatocytogenic development of cultured testicular germ cells regardless of the addition of follicle-stimulating hormone and testosterone to the culture medium. E2 also induced the expression of genes encoding synaptonemal complex protein 1 and protamine 1, proteins required for spermatogenesis. In conclusion, the results of this study suggest that E2 is a spermatocytogenic factor that acts via the stimulation of spermatogenic gene expression. PMID- 29152784 TI - Workplace violence injury in 106 US hospitals participating in the Occupational Health Safety Network (OHSN), 2012-2015. AB - BACKGROUND: Workplace violence is a substantial occupational hazard for healthcare workers in the United States. METHODS: We analyzed workplace violence injury surveillance data submitted by hospitals participating in the Occupational Health Safety Network (OHSN) from 2012 to 2015. RESULTS: Data were frequently missing for several important variables. Nursing assistants (14.89, 95%CI 10.12 21.91) and nurses (8.05, 95%CI 6.14-10.55) had the highest crude workplace violence injury rates per 1000 full-time equivalent (FTE) workers. Nursing assistants' (IRR 2.82, 95%CI 2.36-3.36) and nurses' (IRR 1.70, 95%CI 1.45-1.99) adjusted workplace violence injury rates were significantly higher than those of non-patient care personnel. On average, the overall rate of workplace violence injury among OHSN-participating hospitals increased by 23% annually during the study period. CONCLUSION: Improved data collection is needed for OHSN to realize its full potential. Workplace violence is a serious, increasingly common problem in OHSN-participating hospitals. Nursing assistants and nurses have the highest injury risk. PMID- 29152781 TI - Glecaprevir/Pibrentasvir in patients with hepatitis C virus genotype 1 or 4 and past direct-acting antiviral treatment failure. AB - : Patients with hepatitis C virus (HCV) who have virological failure (VF) after treatment containing a nonstructural protein 5A (NS5A) inhibitor have limited retreatment options. MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and past VF on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virological response (SVR) at 12 weeks posttreatment (SVR12). Among 91 patients treated, 87 had GT1 and 4 had GT4 infection. SVR12 was achieved by 89% (39 of 44) and 91% (43 of 47) of patients who received 12 and 16 weeks of G/P, respectively. Virological relapse occurred in 9% (4 of 44) of patients treated with 12 weeks of G/P; there were no relapses with 16 weeks of treatment. Past treatment history with one class of inhibitor (protease or NS5A) had no impact on SVR12, whereas past treatment with both classes of inhibitors was associated with lower SVR12 rate. The most common adverse event (AE) was headache (>=10% of patients), and there were no serious AEs assessed as related to study drugs or AEs leading to discontinuation. CONCLUSION: Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and past failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors. (Hepatology 2018;67:1253-1260). PMID- 29152785 TI - Ultrastructure of plasma cells in harderian gland of laying hens. AB - Ultrastructure of plasma cells in Harderian gland was investigated using the transmission electron microscopy. For this research, we examined the glands of 32 laying hens collected at 1, 7, 20 and 40 days and 4, 6, 8 and 12 months of the birds' ages. The research showed that the stroma of the gland contains a large number of lymphocytes and plasma cells. Most of the plasma cells are mature, but morphologically do not show productive activity. Only some individual plasma cells, situated under the secretory epithelium of primary and secondary ducts, have extremely dilated cisternae of rough endoplasmic reticulum which contain moderately dense, granular material. The morphology of these cells indicates that they are in active stage of immunoglobulin production. Also, we identified plasma cells with two types of Russell bodies. One type of these bodies was small, round or oval, while the other had irregular, angular shape. It was noted that one plasma cell never contains both type of Russell bodies at the same time. These cells were often affected by apoptosis. Among them, in deeper part of the stroma, were situated the small plasmablast cells. PMID- 29152786 TI - Neurocognitive performance after PCSK9 inhibitor therapy: Current state of the evidence. PMID- 29152787 TI - An oral hygiene protocol improves oral health for patients in inpatient stroke rehabilitation. AB - THE OBJECTIVE: To determine whether a simple oral hygiene protocol improves the oral health of inpatients in stroke rehabilitation. THE BACKGROUND DATA DISCUSSING THE PRESENT STATUS OF THE FIELD: Poor oral health can lead to serious complications, such as pneumonia. The comorbidities associated with stroke, such as dysphagia, hemiparesis and cognitive impairment, can further impede independent oral care. International stroke guidelines recommend routine oral care but stop short of detailing specific regimes. MATERIALS AND METHODS: The oral health assessment tool (OHAT) was conducted by speech-language pathologists with 100 patients with and without dysphagia in three metropolitan inpatient stroke rehabilitation facilities. A simple nurse-led oral hygiene regime was then implemented with all participants, which included twice daily tooth brushing and mouth rinsing after lunch, and oral health was measured again one week later. RESULTS: Initially, dysphagia was negatively associated with OHAT scores, and independence for oral hygiene was positively associated with oral health. After one week of a simple oral hygiene regime, the OHAT scores available for 89 participants indicated an improvement on average for all participants. In particular, 59% of participants with dysphagia had an improvement of 1 or more points. None of the participants developed pneumonia. CONCLUSION: A simple, inexpensive oral hygiene regime resulted in positive outcomes for patients with and without dysphagia in inpatient stroke rehabilitation settings. Oral health assessments and oral hygiene regimes that are simple to implement by the interdisciplinary team can be incorporated into standard stroke care with positive effect. PMID- 29152788 TI - Fibroelastoma of the aortic valve. PMID- 29152789 TI - Automatic differential analysis of NMR experiments in complex samples. AB - Liquid state nuclear magnetic resonance (NMR) is a powerful tool for the analysis of complex mixtures of unknown molecules. This capacity has been used in many analytical approaches: metabolomics, identification of active compounds in natural extracts, and characterization of species, and such studies require the acquisition of many diverse NMR measurements on series of samples. Although acquisition can easily be performed automatically, the number of NMR experiments involved in these studies increases very rapidly, and this data avalanche requires to resort to automatic processing and analysis. We present here a program that allows the autonomous, unsupervised processing of a large corpus of 1D, 2D, and diffusion-ordered spectroscopy experiments from a series of samples acquired in different conditions. The program provides all the signal processing steps, as well as peak-picking and bucketing of 1D and 2D spectra, the program and its components are fully available. In an experiment mimicking the search of a bioactive species in a natural extract, we use it for the automatic detection of small amounts of artemisinin added to a series of plant extracts and for the generation of the spectral fingerprint of this molecule. This program called Plasmodesma is a novel tool that should be useful to decipher complex mixtures, particularly in the discovery of biologically active natural products from plants extracts but can also in drug discovery or metabolomics studies. PMID- 29152790 TI - Exploring the Reactivity of Trifluoromethyl Tolueneselenosulfonate with Alkynes under Copper Catalysis. AB - The direct fluoroalkylselenolation of terminal alkynes is reported herein involving shelf stable electrophilic reagents TsSeRF . The use of these reagents allows for the first time performing the reaction under catalytic conditions (copper/ligand). Moreover, the presence of oxygen directing groups allows the selective addition of the reagents to alkynes, therefore yielding a new family of vinyl sulfones. PMID- 29152791 TI - Interleukin-17 alters the biology of many cell types involved in the genesis of psoriasis, systemic inflammation and associated comorbidities. AB - Psoriasis is a chronic, immune-mediated, systemic inflammatory disease that is defined by a characteristic skin reaction produced when elevated levels of inflammatory cytokines such as interleukin (IL)-17 alter the growth and differentiation of skin cells. The pathogenesis of comorbid conditions associated with psoriasis, including psoriatic arthritis, cardiovascular disease, obesity, metabolic syndrome, liver disorders, renal disease and depression, is also largely affected by inflammation. In this review, we examine the effect of IL-17 on the inflammatory pathways in a variety of different cell types, including keratinocytes, as well as epithelial cells of the colon, kidney, gut and liver. Additionally, we investigate the role of IL-17 in mediating the psoriasis associated comorbidities detailed above. PMID- 29152793 TI - Effects of dietary tryptophan levels on performance and biochemical variables of plasma and intestinal mucosa in yellow-feathered broiler breeders. AB - The effects of dietary tryptophan (Trp) levels on performance and biochemical variables of plasma and intestinal mucosa in broiler breeder hens were investigated in this study. A total of 780 Lingnan yellow-feathered broiler breeder hens were randomly assigned in one of five dietary treatments with six replicates per treatment (26 birds per replicate). The breeder hens were fed either the basal diet (0.11% Trp) or the basal diet supplemented to 0.15%, 0.19%, 0.23% and 0.27% Trp, from 197 to 259 days of age. Graded levels of Trp from 0.11% to 0.27% in the diet produced quadratic (p < .05) responses in laying rate, average daily egg production, and feed conversion ratio, and quadratic (p < .01) responses in total large follicle weight and average large follicle weight. An increase in fertilization rate of total eggs was observed in breeders fed 0.27% Trp, and hatchability was higher in breeders fed 0.23% and 0.27% Trp than with 0.19% Trp (p < .05). The content of uric acid N decreased with 0.15% and 0.23% dietary Trp (p < .05). The content of GSH and the GSH-to-GSSG ratio in plasma were reduced by 0.15%, 0.19% and 0.27% Trp diets (p < .05). A higher activity of GST in plasma was observed with 0.15% Trp in relation to 0.23% and 0.27% Trp (p < .05). The activity of Na+ -K+ -ATPase of plasma in birds fed 0.27% Trp was lower than in those fed 0.15% Trp and the control birds (p < .05). There were significant influences of dietary Trp levels on S6K1, B0 AT1, Nrf2, TLR4, TNF alpha and IL-6 transcripts of ileal mucosa (p < .05). The optimal dietary Trp level was 0.203% or 254 mg per hen per day, for Chinese yellow-feathered broiler breeder hens aged from 197 to 259 days. PMID- 29152794 TI - Highly Sustainable Zinc Anodes for a Rechargeable Hybrid Aqueous Battery. AB - The synthesis of novel zinc electrodes has been successfully implemented by using the electroplating method with the aid of inorganic additives in the electroplating solution. The selected inorganic additives are indium sulfate, tin oxide, and boric acid. From X-ray diffraction results, these synthesized zinc electrodes prefer (002) and/or (103) crystallographic orientations, representing basal morphology and high resistance to dendrite growth. The corrosion rates of these electroplated zinc samples decrease as much as 11 times smaller than the corrosion rate on zinc foil when the zinc materials are in contact with the aqueous electrolyte of a rechargeable hybrid aqueous battery (ReHAB). The ReHABs employing these anodes exhibit up to a threefold decrease in float charge current density after a seven-day constant-voltage charging at 2.1 V versus Zn2+ /Zn. Furthermore, the capacity retention is up to 15 % higher than the performance of battery containing commercial Zn after 1000 cycles of charge-discharge. The significant advancements are attributed to the careful preparation of the anode, which contains appropriate crystallographic orientation and morphology. PMID- 29152792 TI - Novel technique using a non-tip and short-wire papillotome for biliary cannulation of intradiverticular papilla in patients with Roux-en-Y anastomosis. PMID- 29152795 TI - Influence of Radiation on the Properties and the Stability of Hybrid Perovskites. AB - Organic-inorganic perovskites are well suited for optoelectronic applications. In particular, perovskite single and perovskite tandem solar cells with silicon are close to their market entry. Despite their swift rise in efficiency to more than 21%, solar cell lifetimes are way below the needed 25 years. In fact, comparison of the time when the device performance has degraded to 80% of its initial value (T80 lifetime) of numerous solar cells throughout the literature reveals a strongly reduced stability under illumination. Herein, the various detrimental effects are discussed. Most notably, moisture- and heat-related degradation can be mitigated easily by now. Recently, however, several photoinduced degradation mechanisms have been observed. Under illumination, mixed perovskites tend to phase segregate, while, further, oxygen catalyzes deprotonation of the organic cations. Additionally, during illumination photogenerated charge can be trapped in the N?H antibonding orbitals causing dissociation of the organic cation. On the other hand, organic-inorganic perovskites exhibit a high radiation hardness that is superior to crystalline silicon. Here, the proposed degradation mechanisms reported in the literature are thoroughly reviewed and the microscopic mechanisms and their implications for solar cells are discussed. PMID- 29152796 TI - The genetic basis of seborrhoeic dermatitis: a review. AB - Seborrhoeic Dermatitis (SD) is a common inflammatory skin disease that presents as itchy, flaking skin in the seborrhoeic areas. Various environmental and intrinsic factors have been identified as predisposing factors for SD, but its aetiology remains poorly understood. Although it was recognized that genetic factors play a role in SD aetiology, there have not been studies that systematically review the literature specifically for causal mutations or protein deficiencies in SD. In this review, we searched various databases for gene mutations and protein deficiencies that cause SD or SD-like phenotype in humans and experimental animals, and summarize 11 gene mutations or protein deficiencies that were described in the literature. Most of the encoded proteins play a role either in the immune response (ACT1, C5, IKBKG/NEMO, STK4, 2C TCR) or epidermal differentiation (ZNF750, MPZL3). Understanding the genetic basis of SD can impart knowledge of the pathobiology of the disease and help identify novel therapeutic targets. PMID- 29152797 TI - Oxidative stress does not influence local sweat rate during high-intensity exercise. AB - NEW FINDINGS: What is the central question of this study? We evaluated whether oxidative stress attenuates the contribution of nitric oxide to sweating during high-intensity exercise. What is the main finding and its importance? In contrast to our previous report of an oxidative stress-mediated reduction in nitric oxide dependent cutaneous vasodilatation in this cohort during intense exercise, we demonstrated no influence of local ascorbate administration on the sweating response during moderate- (~51% peak oxygen uptake) or high-intensity exercise (~72% peak oxygen uptake). These new findings provide important mechanistic insight into how exercise-induced oxidative stress impacts sudomotor activity. Nitric oxide (NO)-dependent sweating is diminished during high- but not moderate intensity exercise. We evaluated whether this impairment stems from increased oxidative stress during high-intensity exercise. On two separate days, 11 young (24 +/- 4 years) men cycled in the heat (35 degrees C) at a moderate [500 W; 52 +/- 6% peak oxygen uptake (VO2 peak )] or high (700 W; 71 +/- 5% VO2 peak ) rate of metabolic heat production. Each session included two 30 min exercise bouts separated by a 20 min recovery period. Local sweat rate was monitored at four forearm skin sites continuously perfused via intradermal microdialysis with the following: (i) lactated Ringer solution (Control); (ii) 10 mm ascorbate (Ascorbate; non-selective antioxidant); (iii) 10 mm NG -nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor); or (iv) 10 mm ascorbate plus 10 mm l-NAME (Ascorbate + l-NAME). During moderate exercise, sweat rate was attenuated at the l-NAME and Ascorbate + l-NAME sites (both ~1.0 mg min-1 cm-2 ; all P < 0.05) but not at the Ascorbate site (~1.1 mg min-1 cm-2 ; both P >= 0.28) in comparison to the Control site (~1.1 mg min-1 cm-2 ). However, no differences were observed between treatment sites (~1.4 mg min-1 cm-2 ; P = 0.75) during high-intensity exercise. We conclude that diminished NO-dependent sweating during intense exercise occurs independent of oxidative stress. PMID- 29152798 TI - Atomic force microscopy for biomechanical and structural analysis of human dermis: A complementary tool for medical diagnosis and therapy monitoring. AB - Skin mechanical properties are usually measured considering the entire skin thickness and very little is known about the mechanical behaviour of individual skin layers. We propose atomic force microscopy (AFM) as a tool to quantify nanoscale changes in the biomechanical properties and ultrastructure of human papillary dermis exposed to different mechanical and physical stimuli. Samples from 3 human skin biopsies were studied: one stretched by obesity, one subjected to a high level of sun exposure and normal skin as control. Slices of the papillary dermis layer were harvested at controlled depths from each skin biopsy and 25 MUm2 areas of each slice were imaged and D-periodicity of collagen fibres measured by AFM, together with their stiffness. Standard histological analysis was also carried out to correlate biochemical properties and their distribution with stiffness and topography. We obtained similar stiffness values between the sample affected by obesity and the control sample at any depth level into the dermis, while the sun-exposed sample presented a significantly lower stiffness. Additionally, all samples presented an increase in the stiffness at higher depths into the papillary dermis layer. Collagen fibres close to the epidermis of sample affected either by obesity and sun exposure-the former even more than the latter are thicker and present a larger D-period than those in the control sample. Our results open the possibility to use structural and mechanical analysis based on AFM as a complementary tool for medical diagnosis and therapy monitoring. PMID- 29152801 TI - ERRATUM. PMID- 29152800 TI - Authors' Response. PMID- 29152799 TI - Molecular basis for the differential expression of the global regulator VieA in Vibrio cholerae biotypes directed by H-NS, LeuO and quorum sensing. AB - VieA is a cyclic diguanylate phosphodiesterase that modulates biofilm development and motility in Vibrio cholerae O1 of the classical biotype. vieA is part of an operon encoding the VieSAB signal transduction pathway that is nearly silent in V. cholerae of the El Tor biotype. A DNA pull-down assay for proteins interacting with the vieSAB promoter identified the LysR-type regulator LeuO. We show that in classical biotype V. cholerae, LeuO cooperates with the nucleoid-associated protein H-NS to repress vieSAB transcription. LeuO and H-NS interacted with the vieSAB promoter of both biotypes with similar affinities and protected overlapping DNA sequences. H-NS was expressed at similar levels in both cholera biotypes. In contrast, El Tor biotype strains expressed negligible LeuO under identical conditions. In El Tor biotype vibrios, transcription of vieSAB is repressed by the quorum sensing regulator HapR, which is absent in classical biotype strains. Restoring HapR expression in classical biotype V. cholerae repressed vieSAB transcription by binding to its promoter. We propose that double locking of the vieSAB promoter by H-NS and HapR in the El Tor biotype prior to the cessation of exponential growth results in a more pronounced decline in VieA specific activity compared to the classical biotype. PMID- 29152803 TI - Commentary on: Gibbons J, Mojica A, Peele M. Human electrical muscular incapacitation and effects on QTc interval. J Forensic Sci https://doi.org/10.1111/1556-4029.13490. Epub 2017 April 17. PMID- 29152804 TI - Authors' Response. PMID- 29152805 TI - Commentary on: Schuman MJ, Hutchins KD. Severe retinal hemorrhages with retinoschisis in infants are not pathognomonic for abusive head trauma. J Forensic Sci 2017;62(3):807-11. PMID- 29152806 TI - Nanomorphology Effects in Semiconductors with Native Ferromagnetism: Hierarchical Europium (II) Oxide Tubes Prepared via a Topotactic Nanostructure Transition. AB - Semiconductors with native ferromagnetism barely exist and defined nanostructures are almost unknown. This lack impedes the exploration of a new class of materials characterized by a direct combination of effects on the electronic system caused by quantum confinement effects with magnetism. A good example is EuO for which currently no reliable routes for nanoparticle synthesis can be established. Bottom-up approaches applicable to other oxides fail because of the labile oxidation state +II. Instead of targeting a direct synthesis, the two steps "structure control" and "chemical transformation"-are separated. The generation of a transitional, hybrid nanophase is followed by its conversion into EuO under full conservation of all morphological features. Hierarchical EuO materials are now accessible in the shape of oriented nanodisks stacked to tubular particles. Magnetically, the coupling of either vortex or onion states has been found. An unexpected temperature dependence is governed by thermally activated transitions between these states. PMID- 29152807 TI - Looking to the future-more concern than optimism that cryptomarkets will reduce drug-related harms. PMID- 29152808 TI - Observational safety study of specific outcomes after trivalent cell culture seasonal influenza vaccination (Optaflu(r) ) among adults in THIN database of electronic UK primary healthcare records. AB - PURPOSE: To investigate the safety of trivalent seasonal influenza vaccine (TIVc) (Optaflu(r) ), the first cell culture seasonal trivalent influenza vaccine available in Europe. METHODS: Codes and unstructured text in adult electronic healthcare records (The Health Improvement Network) were searched for a TIVc brand name or batch number and possible outcomes within a 3 month pre- to 6 month post-TIVc exposure study period (2012-2015). The outcomes were severe allergic reactions, Bell's palsy, convulsions, demyelination, paresthesia, noninfectious encephalitis, neuritis (optic and brachial), vasculitis, inflammatory bowel disease, and thrombocytopenia. Risk periods were defined based on biologically plausible time frame postvaccination when an outcome caused by the vaccine might be expected to occur. Possible outcomes were adjudicated against outcome specific case definitions and a date of onset assigned by using electronic and other medical records. Observed (risk period) to expected (outside risk and preexposure periods) rate ratios, postexposure incidence, and plots of time from exposure to outcome were reported. RESULTS: Sixteen of 1011 events from 4578 exposures fulfilled a primary case definition and had a date of onset during the study period. Three were in observed time. The observed-to-expected rate ratios were (3.3, 95% CI 0.3, 31.7) for convulsions and (1.5, 95% CI 0.2, 14.9) for thrombocytopenia with 1 outcome each in observed time. There was 1 incident inflammatory bowel disease in observed, but none in expected, time. CONCLUSION: The small sample size restricts interpretation; however, no hypothesis of an increased risk of a study outcome was generated. Adjudication of events against case definitions to reduce misclassification of onset and outcomes allowed use of precise risk periods. KEY POINTS This observational study did not generate a hypothesis of an association between the first cell-culture seasonal influenza vaccination available in the European Union and any of the study outcomes (severe allergic reactions, Bell's palsy, convulsions, demyelination, paresthesia, noninfectious encephalitis, neuritis [optic and brachial], vasculitis, inflammatory bowel disease [IBD], and thrombocytopenia). The small sample size limits interpretation of the results. The review of each possible outcome identified from electronic healthcare records against case definitions was included to minimize misclassification of time and outcomes and allow the use of precise risk-periods in an observed-to-expected within cohort analysis. Plots of time from exposure to outcome were included to assess the risk windows. PMID- 29152809 TI - The harm reduction impact of cryptomarkets: inequality and opportunity. PMID- 29152810 TI - Applying recommended evidence standards to understand the impact of e-cigarettes on youth smoking and reporting of weak scientific evidence. PMID- 29152811 TI - A Latent Class Analysis of Online Sexual Experiences and Offline Sexual Behaviors Among Female Adolescents. AB - This study used latent class analysis to identify patterns (i.e., classes) across a broad range of online sexual experiences among female adolescents (n = 312) and to explore offline sexual behavior and substance use correlates of as well as maltreatment differences in class membership. The following four classes were identified: Online Abstinent, Online Inclusive, Attractors, and Seekers. Maltreated female adolescents were more likely to be members of the Online Inclusive class and less likely to be members of the Online Abstinent class than nonmaltreated female adolescents. Offline sexual behaviors and substance use differentially predicted class membership. These results suggest online sexual experiences vary greatly and should not be aggregated together as a global risk factor for all female adolescents. PMID- 29152812 TI - Focus on cryptomarkets and online reviews too narrow to debate harms of drugs bought online. PMID- 29152813 TI - Replication of a Modified Factor Structure for the Eating Disorder Examination Questionnaire: Extension to Clinical Eating Disorder and Non-clinical Samples in Portugal. AB - Psychometric investigations of the Eating Disorder Examination-Questionnaire (EDE Q) have generally not supported the original scale structure. The present study tested an alternative brief factor structure in two large Portuguese samples: (1) a non-clinical sample of N = 4117 female students and (2) a treatment-seeking sample of N = 609 patients diagnosed with eating disorders. Confirmatory factor analysis revealed a poor fit for the original EDE-Q structure in both the non clinical and the clinical samples but revealed a good fit for the alternative 7 item 3-factor structure (dietary restraint, shape/weight overvaluation and body dissatisfaction). Factor loadings were invariant across samples and across the different specific eating disorder diagnoses in the clinical sample. These confirmatory factor analysis findings, which replicate findings from studies with diverse predominately overweight/obese samples, supported a modified 7-item, 3 factor structure for the EDE-Q. The reliable findings across different non clinical and clinical eating disorder groups provide confidence regarding the potential utility of this brief version. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 29152814 TI - Depression, young age, chronic marijuana use, and interepisodic symptoms predict psychological distress in patients with cyclic vomiting syndrome. AB - BACKGROUND: Cyclic vomiting syndrome (CVS) is often triggered by stress. Patients report high degrees of psychological distress due to CVS, but there is limited data on factors associated with psychological distress. We sought to determine the degree of psychological distress and its correlation with clinical characteristics in CVS. METHODS: The Brief Symptom Inventory (BSI), a validated tool to determine psychological distress, was administered prospectively to patients. The control population consisted of 719 normal subjects. Student's t test was used to compare means, and logistic regression analysis was performed to identify predictors of a GSI score >=63, indicating high degrees of psychological distress. Scores for the regression predictors were calculated using the maximum likelihood estimate for the logistic regression model and was called the DAME score (depression, age 25-35, chronic marijuana use, and interepisodic GI symptoms). KEY RESULTS: Of 87 patients, 60% were female, 92% were caucasian, and mean age was 37 years. Forty-one percent of patients had high degrees of psychological distress with the highest scores for somatization. Independent predictors of psychological distress included depression, young age (25-35 years), chronic marijuana use, and interepisodic dyspepsia (called the DAME score). A score of >=7 accurately predicted psychological distress in >88% of patients. CONCLUSIONS & INFERENCES: Psychological distress is common in CVS and can be predicted accurately using our proposed DAME score. Whether psychological distress is a cause or an effect of CVS needs to be determined. Addressing psychological distress can potentially improve overall healthcare outcomes in CVS. PMID- 29152815 TI - Harder, better, faster ... Yet stronger? Working conditions and self-declaration of chronic diseases. AB - The role played by working conditions in worker health status has been widely acknowledged in the literature in general but has received less attention in economics, due to the inherent statistical biases and lack of data available to determine the role of simultaneous and chronic exposures. This study aims to estimate the causal impact of detrimental working conditions on the self declaration of chronic diseases in France. Using a rebuilt retrospective lifelong panel and defining indicators for physical and psychosocial strains, I implement a mixed econometric strategy that relies on difference-in-differences and matching methods to take into account for selection biases as well as unobserved heterogeneity. For men and women, I find deleterious effects of both types of working conditions on the declaration of chronic diseases after exposure, with varying patterns of impacts according to the nature and magnitude of the strains. These results provide insights into the debate on legal retirement age postponement and justify not only policies being enacted early in individuals' careers in order to prevent subsequent midcareer health repercussions, but also schemes that are more focused on psychosocial risk factors. PMID- 29152816 TI - Body image dissatisfaction in patients undergoing breast reconstruction: Examining the roles of breast symmetry and appearance investment. AB - OBJECTIVE: Reconstruction as part of treatment for breast cancer is aimed at mitigating body image concerns after mastectomy. Although algorithms have been developed to objectively assess breast reconstruction outcomes, associations between objectively quantified breast aesthetic appearance and patient-reported body image outcomes have not been examined. Further, the role of appearance investment in explaining a patient's body image is not well understood. We investigated the extent to which objectively quantified breast symmetry and patient-reported appearance investment were associated with body image dissatisfaction in patients undergoing cancer-related breast reconstruction. METHODS: Breast cancer patients in different stages of reconstruction (n = 190) completed self-report measures of appearance investment and body image dissatisfaction. Vertical extent and horizontal extent symmetry values, which are indicators of breast symmetry, were calculated from clinical photographs. Associations among breast symmetry, appearance investment, body image dissatisfaction, and patient clinical factors were examined. Multi-variable regression was used to evaluate the extent to which symmetry and appearance investment were associated with body image dissatisfaction. RESULTS: Vertical extent symmetry, but not horizontal extent symmetry, was associated with body image dissatisfaction. Decreased vertical extent symmetry (beta = -.19, P < .05) and increased appearance investment (beta = .45, P < .001) were significantly associated with greater body image dissatisfaction while controlling for clinical factors. CONCLUSIONS: Breast symmetry and patient appearance investment both significantly contribute to an understanding of patient-reported body image satisfaction during breast reconstruction treatment. PMID- 29152817 TI - How complex should models be? Comparing correlative and mechanistic range dynamics models. AB - Criticism has been levelled at climate-change-induced forecasts of species range shifts that do not account explicitly for complex population dynamics. The relative importance of such dynamics under climate change is, however, undetermined because direct tests comparing the performance of demographic models vs. simpler ecological niche models are still lacking owing to difficulties in evaluating forecasts using real-world data. We provide the first comparison of the skill of coupled ecological-niche-population models and ecological niche models in predicting documented shifts in the ranges of 20 British breeding bird species across a 40-year period. Forecasts from models calibrated with data centred on 1970 were evaluated using data centred on 2010. We found that more complex coupled ecological-niche-population models (that account for dispersal and metapopulation dynamics) tend to have higher predictive accuracy in forecasting species range shifts than structurally simpler models that only account for variation in climate. However, these better forecasts are achieved only if ecological responses to climate change are simulated without static snapshots of historic land use, taken at a single point in time. In contrast, including both static land use and dynamic climate variables in simpler ecological niche models improve forecasts of observed range shifts. Despite being less skilful at predicting range changes at the grid-cell level, ecological niche models do as well, or better, than more complex models at predicting the magnitude of relative change in range size. Therefore, ecological niche models can provide a reasonable first approximation of the magnitude of species' potential range shifts, especially when more detailed data are lacking on dispersal dynamics, demographic processes underpinning population performance, and change in land cover. PMID- 29152818 TI - Electrical Stimulation of Dorsal Root Ganglion in the Context of Pain: A Systematic Review of In Vitro and In Vivo Animal Model Studies. AB - OBJECTIVE: Dorsal root ganglion (DRG) has recently emerged as an attractive target for neuromodulation therapy since primary sensory neurons and their soma in DRGs are important sites for pathophysiologic changes that lead to neuropathic pain. Our aim was to create evidence synthesis about the effects of electrical stimulation of DRG in the context of pain from in vitro and in vivo animal models, analyze methodology and quality of studies in the field. METHODS: For conducting systematic review we searched three data bases: MEDLINE, Embase and Web of Science. The quality of included studies was assessed with the Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool for animal studies. The study was registered in the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies data base. RESULTS: We included six in vitro and eight in vivo animal studies. All included in vitro studies combined neurostimulation with substances or drugs and reported an improvement in pain-related parameters due to neurostimulation. Among in vivo studies, six used pulsed radiofrequency, while two used electrical field stimulation. All in vivo studies reported improvement in pain-related behavior following stimulation. Meta-analysis was not possible because of heterogeneity and missing data. The quality of included studies was suboptimal since all had an unclear risk of bias in multiple domains. CONCLUSIONS: Limited data from in vitro and in vivo animal studies indicate that electrical stimulation of DRG has a positive therapeutic effect in the context of pain-related outcomes. Further studies with a standardized methodological approach and outcomes will provide useful information about electrical stimulation of DRG in animal models. PMID- 29152819 TI - The application of systems thinking concepts, methods, and tools to global health practices: An analysis of case studies. AB - OBJECTIVES: This review of systems thinking (ST) case studies seeks to compile and analyse cases from ST literature and provide practitioners with a reference for ST in health practice. Particular attention was given to (1) reviewing the frequency and use of key ST terms, methods, and tools in the context of health, and (2) extracting and analysing longitudinal themes across cases. METHODS: A systematic search of databases was conducted, and a total of 36 case studies were identified. A combination of integrative and inductive qualitative approaches to analysis was used. RESULTS: Most cases identified took place in high-income countries and applied ST retrospectively. The most commonly used ST terms were agent/stakeholder/actor (n = 29), interdependent/interconnected (n = 28), emergence (n = 26), and adaptability/adaptation (n = 26). Common ST methods and tools were largely underutilized. Social network analysis was the most commonly used method (n = 4), and innovation or change management history was the most frequently used tool (n = 11). Four overarching themes were identified; the importance of the interdependent and interconnected nature of a health system, characteristics of leaders in a complex adaptive system, the benefits of using ST, and barriers to implementing ST. CONCLUSIONS: This review revealed that while much has been written about the potential benefits of applying ST to health, it has yet to completely transition from theory to practice. There is however evidence of the practical use of an ST lens as well as specific methods and tools. With clear examples of ST applications, the global health community will be better equipped to understand and address key health challenges. PMID- 29152820 TI - Positive Peer Association Among Black American Youth and the Roles of Ethnic Identity and Gender. AB - The study examined whether peer association, a subtype of peer influence that involves the indirect modeling of behaviors, can promote positive development among Black American adolescents living in high-risk neighborhoods. Data were collected during a three-year longitudinal study from a sample of 316 Black American adolescents (M = 11.65 years). As positive peer association increased over time, youth experienced an increase in self-esteem, school connectedness, paternal and maternal closeness, and a decrease in supportive beliefs about aggression. Additionally, lower ethnic identity appeared to account for why some youth experienced a sharper increase in maternal and paternal closeness as positive peer association increased. Future interventions should consider harnessing the ability of prosocial peers to foster healthy development. PMID- 29152821 TI - Skin care products can aggravate epidermal function: studies in a murine model suggest a pathogenic role in sensitive skin. AB - BACKGROUND: Sensitive skin is defined as a spectrum of unpleasant sensations in response to a variety of stimuli. However, only some skin care products provoke cutaneous symptoms in individuals with sensitive skin. Hence, it would be useful to identify products that could provoke cutaneous symptoms in individuals with sensitive skin. OBJECTIVE: To assess whether vehicles, as well as certain branded skin care products, can alter epidermal function following topical applications to normal mouse skin. METHODS: Following topical applications of individual vehicle or skin care product to C57BL/6J mice twice daily for 4 days, transepidermal water loss (TEWL) rates, stratum corneum (SC) hydration and skin surface pH were measured on treated versus untreated mouse skin with an MPA5 device and pH 900 pH meter. RESULTS: Our results show that all tested products induced abnormalities in epidermal functions of varying severity, including elevations in TEWL and skin surface pH, and reduced SC hydration. CONCLUSIONS: Our results suggest that mice can serve as a predictive model that could be used to evaluate the potential safety of skin care products in humans with sensitive skin. PMID- 29152822 TI - Thoracic endovascular repair versus medical management for acute uncomplicated type B aortic dissection. AB - BACKGROUND: Current treatment options and outcomes for acute uncomplicated thoracic Type-B aortic dissection (TBAD) remain unclear between medical management (MED) and thoracic endovascular aortic repair (TEVAR). In this study we aim to compare both strategies in terms of all-cause mortality, aortic dilation, and aortic rupture. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were queried from January 1990 through March 2017. Only studies comparing TEVAR to MED for acute uncomplicated TBAD were included. Random-effects meta-analysis was used to pool outcomes across studies. Study outcomes included short (1 month), intermediate (1 year), and mid-term (2-5 year) all-cause mortality. Additional outcomes included aortic dilation and rupture at 1 year. RESULTS: A total of 1,960 patients (64.3 years; 75.8% male) were included from six studies (one prospective and five retrospective). No difference was observed in short-term (odd ratio [OR] 0.73 with 95% confidence interval [CI] 0.47 to 1.12, P = 0.15), intermediate (OR 0.99 with 95% CI 0.56 to 1.73, P = 0.96), or mid-term all-cause mortality (OR 1.12 with 95% CI 0.54 to 2.32, P = 0.75). No difference in aortic dilation with either modality was noted at 1-year (OR 1.11 with 95% CI 0.76 to 1.64, P = 0.59). TEVAR was associated with a significantly lower 1-year risk of aortic rupture (OR 2.49 with 95% CI 1.23 to 5.06, P = 0.01). CONCLUSION: There were no short, intermediate, or mid-term differences in mortality between TEVAR or MED in patients with acute uncomplicated TBAD. Although the dilation rate was similar between both groups, TEVAR was associated with lower likelihood of aortic rupture at 1 year. PMID- 29152823 TI - Monopolar radiofrequency treatment in Asian skin: An update. PMID- 29152824 TI - Can Nomograms Predict Preoperative Axillary Lymph Node Metastasis in Patients With Breast Cancer to Guide Second Look Ultrasonography? AB - OBJECTIVES: The low sensitivity of ultrasonography (US) for diagnosing axillary lymph node metastasis in patients with breast cancer has led to the development of multiple tools in an attempt to increase preoperative sensitivity, including second-look US. We compared axillary lymph node metastasis predictor scores with postsurgical findings, using the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY) and Evidencio (www.evidencio.com) nomograms: 2 freely available online predictor tools. METHODS: We retrospectively evaluated 450 patients with breast cancer and analyzed data from 194 patients. Sonograms were evaluated to measure lymph node cortical thickness, transverse diameter, and hilum status. Patients were divided into 3 groups: namely 0, 1, and 2 based on the number of postoperative positive nodes (0, 1 and >=2, respectively). One-way analysis of variance was used to analyze the differences in mean scores across the 3 nodal groups for both nomograms. P < .05 was considered statistically significant. RESULTS: There were significant differences in mean scores across the 3 nodal groups when using MSKCC (P < .001) as well as Evidencio (P < .001). However, there was an overlap of scores across the 3 groups; thus, mutually exclusive values were not obtained. A strong positive correlation was found between MSKCC and Evidencio (P < 0.001). Tumor size and the presence of lymphovascular invasion were significantly associated with axillary nodal disease (P < .001; P = .003, respectively). CONCLUSIONS: The use of nomograms to predict axillary nodal involvement in patients with breast cancer can guide discussions, but in their present state, these scores cannot guide clinical decisions or direct second-look US of axilla. PMID- 29152826 TI - Synthesis and Reactivity of Nickel-Stabilised MU2 :eta2 ,eta2 -P2 , As2 and PAs Units. AB - The reactivity of two paramagnetic nickel(I) compounds, CpNi(NHC) (where Cp=cyclopentadienyl; NHC=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) or 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr)), towards [Na(dioxane)x ][PnCO] (Pn=P, As) is described. These reactions afford symmetric bimetallic compounds (MU2 :eta2 ,eta2 -Pn2 ){Ni(NHC)(CO)}2 . Several novel intermediates en route to such species are identified and characterised, including a compound containing the PCO- anion in an unprecedented MU2 :eta2 ,eta2 -binding mode. Ultimately, on treatment of the (MU2 :eta2 ,eta2 -Pn2 ){Ni(IMes)(CO)}2 compounds with carbon monoxide, the Pn2 units can be released, affording P4 in the case of the phosphorus-containing species, and elemental arsenic in the case of (MU2 :eta2 ,eta2 -As2 ){Ni(IMes)(CO)}2 . PMID- 29152827 TI - Abstracts of the 26th Malaysian Urological Conference MUC 2017, Malaysia, 24-26 November 2017. PMID- 29152825 TI - Feasibility Study Combining Art Therapy or Cognitive Remediation Therapy with Family-based Treatment for Adolescent Anorexia Nervosa. AB - Adolescents with anorexia nervosa who have obsessive-compulsive (OC) features respond poorly to family-based treatment (FBT). This study evaluated the feasibility of combining FBT with either cognitive remediation therapy (CRT) or art therapy (AT) to improve treatment response in this at-risk group. Thirty adolescents with anorexia nervosa and OC features were randomized to 15 sessions of FBT + CRT or AT. Recruitment rate was 1 per month, and treatment attrition was 16.6% with no differences between groups. Suitability, expectancy and therapeutic relationships were acceptable for both combinations. Correlations between changes in OC traits and changes in cognitive inefficiencies were found for both combinations. Moderate changes in cognitive inefficiencies were found in both groups but were larger in the FBT + AT combination. This study suggests that an RCT for poor responders to FBT because of OC traits combining FBT with either CRT or AT is feasible to conduct. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 29152829 TI - Procedural trends, outcomes, and readmission rates pre-and post-FDA approval for MitraClip from the National Readmission Database (2013-14). AB - BACKGROUND: There are sparse clinical data on the procedural trends, outcomes and readmission rates following FDA approval and expansion of Transcatheter mitral valve repair/MitraClip(r) . Whether a complex new technology can be disseminated safely and quickly is controversial. METHODS: The study cohort was derived from the National Readmission Data (NRD) 2013-14. MitraClip(r) was identified using appropriate International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. The primary outcome was a composite of in-hospital mortality + procedural complications. Secondary outcome included 30-day readmissions. Hierarchical two level logistic models were used to evaluate study outcomes. RESULTS: Our analysis included 2003 MitraClip(r) procedures. Overall in hospital mortality was 3.9%. As expected, there was a significant increase in procedural volume post-FDA approval. Importantly, a corresponding downward trend in mortality and procedural complications was observed. Significant predictors of in-hospital mortality and procedural complications included the use of vasopressors (P <0.001) and hemodynamic support (P < 0.001). Higher hospital volume (>=10 MitraClips/year) was associated with lower in-hospital mortality and complications (P = 0.02). There were 304 (15.1%) 30-day readmissions, with heart failure being the most common cause of readmission. Elective procedures had lower in-hospital mortality (P < 0.001) and lower readmission rates (P = 0.011) compared with nonelective procedures. CONCLUSION: A significant increase in MitraClip(r) procedural volumes occurred post-FDA approval. Overall morbidity and mortality were low and trended downwards. Hospital procedure volume >=10 cases were associated with lower mortality and overall complication rates. These data suggest a successful roll out of a very complex novel structural heart procedure. PMID- 29152828 TI - Efficacy and safety of 12 weeks of elbasvir +/- grazoprevir +/- ribavirin in participants with hepatitis C virus genotype 2, 4, 5 or 6 infection: The C-SCAPE study. AB - People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group. The aim of the phase 2 C-SCAPE study was to evaluate elbasvir/grazoprevir (EBR/GZR), with or without ribavirin (RBV), in participants with HCV genotype 2, 4, 5 or 6 infection. This was a part randomised, open-label, parallel-group study (NCT01932762; PN047-03) of treatment-naive, noncirrhotic participants. Participants with HCV genotype 2 infection received GZR 100 mg + RBV +/- EBR 50 mg for 12 weeks and those with genotype 4, 5 or 6 infection were randomized to receive EBR/GZR +/- RBV for 12 weeks. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12; HCV RNA <25 IU/mL). Among participants with genotype 2 infection, SVR12 was achieved by 80% (24/30) of those receiving EBR/GZR + RBV and 73% (19/26) of those receiving GZR + RBV. SVR rates were high in participants with HCV genotype 4 infection receiving EBR/GZR with and without RBV (100% [10/10] and 90% [9/10]; respectively). In contrast, the addition of RBV to EBR/GZR appeared to increase SVR12 in participants with genotype 5 infection (EBR/GZR, 25%; EBR/GZR + RBV 100% [4/4]). In participants with genotype 6 infection, SVR12 was 75% (3/4) in both those receiving EBR/GZR and those receiving EBR/GZR + RBV. The safety profile was similar across treatment arms, with adverse events tending to occur more frequently among participants receiving RBV. In conclusion, these data support the inclusion of participants with genotype 4 or 6 infection in the EBR/GZR phase 3 studies. EBR/GZR +/- RBV was unsatisfactory for participants with genotype 2 or 5 infection. PMID- 29152830 TI - In response to: Metformin for the management of peri-operative hyperglycaemia. PMID- 29152831 TI - Laser treatment of cutaneous angiokeratomas: A systematic review. AB - Angiokeratomas can present therapeutic challenges, especially in cases of extensive lesions, where traditional surgical methods carry high risks of scarring and hemorrhage. Argon, pulsed dye (PDL), neodymium-doped yttrium aluminum garnet (Nd:YAG), copper vapor, potassium titanyl phosphate, carbon dioxide, and erbium-doped yttrium aluminum garnet (Er:YAG) lasers have emerged as alternative options. To review the use and efficacy of lasers in treating angiokeratomas. A PubMed search identified randomized clinical trials, cohort studies, case series, and case reports involving laser treatment of cutaneous angiokeratomas. Twenty-five studies were included. Quality ratings were assigned using the Oxford Centre for Evidence-Based Medicine scheme. Several laser modalities are effective in treating multiple variants of angiokeratomas. Vascular lasers like PDL, Nd:YAG, and argon are the most studied and of these, PDL offers the safest side effect profile. Nd:YAG may be more effective for hyperkeratotic angiokeratomas. Combination treatment with multiple laser modalities has also demonstrated some success. Lasers are a promising treatment option for angiokeratomas, but current use is limited by the lack of treatment guidelines. There are limited high quality studies comparing laser treatments to each other and to non-laser options. Additional studies are needed to establish guidelines and to optimize laser parameters. PMID- 29152832 TI - Mono- and Bis(imidazolidinium ethynyl) Cations and Reduction of the Latter To Give an Extended Bis-1,4-([3]Cumulene)-p-carboquinoid System. AB - An extended pi-system containing two [3]cumulene fragments separated by a p carboquinoid and stabilized by two capping N-heterocyclic carbenes (NHCs) has been prepared. Mono- and bis(imidazolidinium ethynyl) cations have also been synthesized from the reaction of an NHC with phenylethynyl bromide or 1,4 bis(bromoethynyl)benzene. Cyclic voltammetry coupled with synthetic and structural studies showed that the dication is readily reduced to a neutral, singlet bis-1,4-([3]cumulene)-p-carboquinoid as a result of the pi-accepting properties of the capping NHCs. PMID- 29152833 TI - Training therapists to work with people with intellectual disability in Improving Access to Psychological Therapies (IAPT) services. AB - BACKGROUND: Current policy in the England suggests that people with intellectual disabilities should, where possible, access mainstream mental health services; this should include access to mainstream therapy services. It is likely that mainstream therapists will need training and support to work with people with intellectual disabilities. METHOD: Sixty-eight therapists working in an English Improving Access to Psychological Therapies (IAPT) service received one- or 2-day training on working with people with intellectual disabilities. Measures of confidence, general therapeutic self-efficacy and attitudes to people with intellectual disabilities' use of mainstream mental health services were completed pre-training, post-training and at 3-month follow-up; at which time, 12 participants were interviewed about the impact of the training on their practice. RESULTS: There was a significant positive change in all measures immediately post training which was maintained at 3-month follow-up. CONCLUSIONS: Training considerations for mainstream therapists who may work with people with intellectual disabilities are discussed. PMID- 29152834 TI - Retrospective analysis of factors affecting clinical outcome following CHOP-based chemotherapy in dogs with primary nodal diffuse large B-cell lymphoma. AB - Numerous factors are known to affect the prognosis of dogs with chemotherapy treated lymphomas. However, prognostic factors for dogs with specific subtypes of lymphoma are less clearly defined. The objective of this study was to identify prognostic factors for dogs receiving CHOP-based chemotherapy for primary nodal diffuse large B-cell lymphoma (DLBCL). Medical records of dogs treated for DLBCL at the Purdue Veterinary Teaching Hospital (PUVTH) from 2006 to 2016 were reviewed. Factors potentially related to prognosis were analysed using multivariable statistical methods. Ninety-eight dogs were included in the study. Best overall response to chemotherapy was complete remission in 80 dogs (81.6%) and partial remission in 18 dogs (18.4%). Median progression-free survival (PFS) for the entire population was 252 days (range 19-1068). Factors significantly associated with achieving partial (rather than complete) remission following CHOP included presence of thrombocytopenia at diagnosis (OR 6.88; 95% CI 1.98-23.93; P = .002), baseline serum globulin concentration (OR 2.63; 95% CI 1.03-6.75; P = .044), and age at diagnosis (OR 1.36; 95% CI 1.08-1.71; P = .009). Factors significantly associated with PFS in the lowest quartile (<=93 days) included presence of thrombocytopenia at diagnosis (OR 8.72; 95% CI 1.54-49.33; P = .014), age at diagnosis (OR 1.47; 95% CI 1.12-1.94; P = .005), and baseline neutrophil count (OR 1.18; 95% CI 1.02-1.37; P = .025). Presence of thrombocytopenia, greater age, higher neutrophil count, and higher serum globulin concentration all may be associated with a particularly poor outcome in dogs receiving CHOP-based chemotherapy for DLBCL. PMID- 29152835 TI - Intra- and inter-fractional liver and lung tumor motions treated with SBRT under active breathing control. AB - PURPOSE: To assess intra- and inter-fractional motions of liver and lung tumors using active breathing control (ABC). METHODS AND MATERIALS: Nineteen patients with liver cancer and 15 patients with lung cancer treated with stereotactic body radiotherapy (SBRT) were included in this retrospective study. All patients received a series of three CTs at simulation to test breath-hold reproducibility. The centroids of the whole livers and of the lung tumors from the three CTs were compared to assess intra-fraction variability. For 15 patients (8 liver, 7 lung), ABC-gated kilovoltage cone-beam CTs (kV-CBCTs) were acquired prior to each treatment, and the centroids of the whole livers and of the lung tumors were also compared to those in the planning CTs to assess inter-fraction variability. RESULTS: Liver intra-fractional systematic/random errors were 0.75/0.39 mm, 1.36/0.97 mm, and 1.55/1.41 mm at medial-lateral (ML), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. Lung intra-fractional systematic/random errors were 0.71/0.54 mm (ML), 1.45/1.10 mm (AP), and 3.95/1.93 mm (SI), respectively. Substantial intra-fraction motions (>3 mm) were observed in 26.3% of liver cancer patients and in 46.7% of lung cancer patients. For both liver and lung tumors, most inter-fractional systematic and random errors were larger than the corresponding intra-fractional errors. However, these inter fractional errors were mostly corrected by the treatment team prior to each treatment based on kV CBCT-guided soft tissue alignment, thereby eliminating their effects on the treatment planning margins. CONCLUSIONS: Intra-fractional motion is the key to determine the planning margins since inter-fractional motion can be compensated based on daily gated soft tissue imaging guidance of CBCT. Patient-specific treatment planning margins instead of recipe-based margins were suggested, which can benefit mostly for the patients with small intra-fractional motions. PMID- 29152836 TI - Modulation of fatty acid metabolism and immune suppression are features of in vitro tumour sphere formation in ontogenetically distinct dog cancers. AB - Non-adherent, 3-dimensional sphere formation is used as an in vitro surrogate to evaluate cellular potential for tumour initiation and self-renewal. To determine if a shared molecular program underlies the capacity for sphere formation by cells originating from diverse tumour types, we characterized molecular and functional properties of 10 independent cell lines derived from 3 ontogenetically distinct dog cancers: hemangiosarcoma, osteosarcoma and glial brain tumours. Genome-wide gene expression profiling identified tumour-of-origin-dependent patterns of adjustment to sphere formation in a uniform culture condition. However, expression of the stem/progenitor markers CD34 and CD117, resistance to cytotoxic drugs and dye efflux (side population assays) showed no association with these gene expression profiles. Instead, primary sphere-forming capacity was inversely correlated with the ability to reform secondary spheres, regardless of tumour ontogeny. Primary sphere formation seemed to be proportional to the number of pre-existing cells with sphere-forming capacity in the cell lines. Cell lines where secondary sphere formation was more proficient than primary sphere formation showed enrichment of genes involved in fatty acid synthesis and immunosuppressive cytokines. In contrast, cell lines where secondary sphere formation was approximately equivalent to or less proficient than primary sphere formation showed upregulation of CD40 and enrichment of genes involved in fatty acid oxidation. Our data suggest that in vitro sphere formation is associated with upregulation of gene clusters involved in metabolic and immunosuppressive functions, which might be necessary for self-renewal and for tumour initiation and/or tumour propagation in vivo. PMID- 29152837 TI - Effect of nanoliposomes containing Zataria multiflora Boiss. essential oil on gene expression of Shiga toxin 2 in Escherichia coli O157:H7. AB - AIMS: Enterohaemorrhagic Escherichia coli serotype O157:H7 as a major human pathogen is responsible for food borne outbreaks, bloody diarrhoea, haemorrhagic colitis and haemolytic uraemic syndrome and even death. In this study, the antibacterial activity of the Zataria multiflora essential oil (ZMEO) and nanoliposome-encapsulated ZMEO was evaluated on the pathogenicity of E. coli O157:H7. METHODS AND RESULTS: The minimum inhibitory concentrations (MIC) of essential oil (EO) were determined against the bacterium before and after encapsulation into nanoliposome. Then, the effect of subinhibitory concentrations was evaluated on Shiga toxin 2 (Stx2) production. The effect of free and nanoliposomal EO was also studied on the gene expression of Stx2 by real-time PCR. It was found that inhibitory activity of EO was improved after incorporation into nanoliposomes (P < 0.05). The MIC of free EO against E. coli O157:H7 was 0.03% (v/v), while this value decreased to 0.015%, after encapsulation of EO into nanoliposomes. Furthermore, subinhibitory concentrations of liposomal EO (50 and 75% MIC) had significantly higher inhibitory effect on Stx2 titre than its free form (P < 0.05). Sub-MICs of nanoencapsulated EO also showed a better activity in reduction of Stx2A gene expression than free EO. Using 75% MIC of nanoliposomal EO, the relative transcriptional level of Stx2A gene was decreased from 0.721 to 0.646. CONCLUSIONS: The findings of present study suggest that application of nanoliposomes can improve the antibacterial effect of EOs like ZMEO. SIGNIFICANCE AND IMPACT OF THE STUDY: Due to the enhancement of antimicrobial activity, nanoencapsulation of plant EOs and extracts may increase their commercial application not only in food area but also in the pharmaceutics, cosmetics and health products. PMID- 29152838 TI - Commissioning of the world's first compact pencil-beam scanning proton therapy system. AB - This paper summarizes clinical commissioning of the world's first commercial, clinically utilized installation of a compact, image-guided, pencil-beam scanning, intensity-modulated proton therapy system, the IBA Proteus(r) ONE, at the Willis-Knighton Cancer Center (WKCC) in Shreveport, LA. The Proteus(r) ONE is a single-room, compact-gantry system employing a cyclotron-generated proton beam with image guidance via cone-beam CT as well as stereoscopic orthogonal and oblique planar kV imaging. Coupling 220 degrees of gantry rotation with a 6D robotic couch capable of in plane patient rotations of over 180 degrees degrees allows for 360 degrees of treatment access. Along with general machine characterization, system commissioning required: (a) characterization and calibration of the proton beam, (b) treatment planning system commissioning including CT-to-density curve determination, (c) image guidance system commissioning, and (d) safety verification (interlocks and radiation survey). System readiness for patient treatment was validated by irradiating calibration TLDs as well as prostate, head, and lung phantoms from the Imaging and Radiation Oncology Core (IROC), Houston. These results confirmed safe and accurate machine functionality suitable for patient treatment. WKCC also successfully completed an on-site dosimetry review by an independent team of IROC physicists that corroborated accurate Proteus(r) ONE dosimetry. PMID- 29152841 TI - Adjusting for heterogeneity of experimental data in genetic evaluation of dry matter intake in dairy cattle. AB - The objectives of the present study were (i) to find the best fitted model for repeatedly measured daily dry matter intake (DMI) data obtained from different herds and experiments across lactations and (ii) to get better estimates of the genetic parameters and better genetic evaluations. After editing, there were 572,512 daily DMI records of 3,495 animals (Holstein cows) from 11 different herds across 13 lactations and the animals were under 110 different nutritional experiments. The fitted model for this data set was a univariate repeated-measure animal model (called model 1) in which additive genetic and permanent environmental (within and across lactations) effects were fitted as random. Model 1 was fitted as two distinct models (called models 2 and 3) based on alternative fixed effect corrections. For unscaled data, each model (models 2 and 3) was fitted as a homoscedastic (HOM) model first and then as a heteroscedastic (HET) model. Then, data were scaled by multiplying with particular herd-scaling factors, which were calculated by accounting for heterogeneity of phenotypic within-herd variances. Models were selected based on cross-validation and prediction accuracy results. Scaling factors were re-estimated to determine the effectiveness of accounting for herd heterogeneity. Variance components and respective heritability and repeatability were estimated based on a pedigree based relationship matrix. Results indicated that the model fitted for scaled data showed better fit than the models (HOM or HET) fitted for unscaled data. The heritability estimates of the models 2 and 3 fitted for scaled data were 0.30 and 0.08, respectively. The repeatability estimates of the model fitted for scaled data ranged from 0.51 to 0.63. The re-estimated scaling factor after accounting for heterogeneity of residual variances was close to 1.0, indicating the stabilization of residual variances and herd accounted for most of the heterogeneity. The rank correlation of EBVs between scaled and unscaled data ranged from 0.96 to 0.97. PMID- 29152839 TI - Beta-cell sensitivity to glucose is impaired after gastric bypass surgery. AB - AIMS: Patients who have undergone Roux-en-Y gastric bypass surgery (GB) have exaggerated postprandial insulin secretion, which has been attributed to increased meal glucose appearance and enhanced incretin effect. Here, we sought to determine beta-cell glucose sensitivity in the absence of meal stimulation and insulinotropic gut factors. MATERIALS AND METHODS: A total of 12 non-diabetic subjects with prior GB, and 7 matched non-surgical control subjects with normal glucose tolerance were studied. Blood glucose and insulin secretion rates were measured during a graded glucose infusion at increasing and then decreasing rates. Insulin sensitivity (SI ) and glucose effectiveness (SG ) were determined by the minimal model. RESULTS: GB subjects had SI comparable to that of control subjects. GB subjects had relative hyperglycaemia during the highest dose of glucose infusion associated with significantly reduced beta-cell glucose sensitivity throughout both step-up (GB: 34 +/- 6, CN: 82 +/- 9 pmol min-1 mM-1 L, P < .0001) and step-down (GB: 31 +/- 6, CN: 74 +/- 9 pmol min-1 mM-1 L, P < .0001) phases of the glucose infusion. GB subjects also had reduced SG (GB: 0.04 +/- 0.00, CN: 0.07 +/- 0.01 min-1 , P = .004). CONCLUSION: In the absence of enteric stimuli, beta-cell sensitivity to changes in glycaemia is blunted among individuals with GB, indicating a significant shift in a fundamental property of beta-cell function several years after surgery. PMID- 29152840 TI - On the use of bolus for pacemaker dose measurement and reduction in radiation therapy. AB - Special attention is required in planning and administering radiation therapy to patients with cardiac implantable electronic devices (CIEDs), such as pacemaker and defibrillator. The range of dose to CIEDs that can induce malfunction is large among CIEDs. Clinically significant defects have been reported at dose as low as 0.15 Gy. Therefore, accurate estimation of dose to CIED and dose reduction are both important even if the dose is expected to be less than the often-used 2 Gy limit. We investigated the use of bolus in in vivo dosimetry for CIEDs. Solid water phantom measurements of out-of-field dose for a 6-MV beam were performed using parallel plate chamber with and without 1- to 2-cm bolus covering the chamber. In vivo dosimetry at skin surface above the CIED was performed with and without bolus covering the CIED for three patients with the CIED <5 cm from the field edge. Chamber measured dose at depth ~0.5-1.5 cm below the skin surface, where the CIED is normally located, was reduced by ~7-48% with bolus. The dose reduction became smaller at deeper depths and with smaller field size. In vivo dosimetry at skin surface also indicated ~20%-60% lower dose when using bolus for the three patients. The dose measured with bolus more accurately reflects the dose to CIED and is less affected by contaminant electrons and linac head scatter. In general, the treatment planning system (TPS) calculation underestimated the dose to CIED, but it predicts the CIED dose more accurately when bolus is used. We recommend the use of 1- to 2-cm bolus to cover the CIED during in vivo CIED dose measurements for more accurate CIED dose estimation. If the CIED is placed <2 cm in depth and its dose is mainly from anterior beams, we recommend using the bolus during the entire course of radiation delivery to reduce the dose to CIED. PMID- 29152842 TI - Cross-sectional survey of patients' need for information and support with medicines after discharge from hospital. AB - BACKGROUND: Most patients experience changes to prescribed medicines during a hospital stay. Ensuring they understand such changes is important for preventing adverse events post-discharge and optimising patient understanding. However, little work has explored the information that patients receive about medicines or their perceived needs for information and support after discharge. OBJECTIVES: To determine information that hospital inpatients who experience medicine changes receive about their medicines during admission and their needs and preferences for, and use of, post-discharge support. METHODS: Cross-sectional survey with adult medical inpatients experiencing medicine changes in six English hospitals, with telephone follow-up 2-3 weeks post-discharge. KEY FINDINGS: A total of 444 inpatients completed surveys, and 99 of these were followed up post-discharge. Of the 444, 44 (10%) were unaware of changes to medicines and 65 (16%) did not recall discussing them with a health professional, but 305 (77%) reported understanding the changes. Type of information provided and patients' perceived need for post-discharge support differed between hospitals. Information about changes was most frequently provided by consultant medical staff (157; 39%) with pharmacists providing information least often (71; 17%). One third of patients surveyed considered community pharmacists as potential sources of information about medicines and associated support post-discharge. Post-discharge, just 5% had spoken to a pharmacist, although 35% reported medicine-related problems. CONCLUSION: In north-west England, patient inclusion in treatment decisions could be improved, but provision of information prior to discharge is reasonable. There is scope to develop hospital and community pharmacists' role in medicine optimisation to maximise safety and effectiveness of care. PMID- 29152844 TI - Faecal microbiota in dogs with multicentric lymphoma. AB - Malignant lymphoma B-cell type is the most common canine haematopoietic malignancy. Changes in intestinal microbiota have been implicated in few types of cancer in humans. The aim of this prospective and case-control study was to determine differences in faecal microbiota between healthy control dogs and dogs with multicentric lymphoma. Twelve dogs affected by multicentric, B-cell, stage III-IV lymphoma, and 21 healthy dogs were enrolled in the study. For each dog, faecal samples were analysed by Illumina sequencing of 16S rRNA genes and quantitative PCR (qPCR) for selected bacterial groups. Alpha diversity was significant lower in lymphoma dogs. Principal coordinate analysis plots showed different microbial clustering (P = .001) and linear discriminant analysis effect size revealed 28 differentially abundant bacterial groups in lymphoma and control dogs. The qPCR analysis showed significant lower abundance of Faecalibacterium spp. (q < .001), Fusobacterium spp. (q = .032), and Turicibacter spp. (q = .043) in dogs with lymphoma compared with control dogs. On the contrary, Streptococcus spp. was significantly higher in dogs with lymphoma (q = .041). The dysbiosis index was significantly higher (P < .0001) in dogs with lymphoma. In conclusion, both sequencing and qPCR analyses provided a global overview of faecal microbial communities and showed significant differences in the microbial communities of dogs presenting with multicentric lymphoma compared with healthy control dogs. PMID- 29152846 TI - On the gEUD biological optimization objective for organs at risk in Photon Optimizer of Eclipse treatment planning system. AB - Inverse planning optimization using biologically based objectives is becoming part of the intensity modulated optimization process. The performances and efficacy of the biologically based gEUD (generalized Equivalent Uniform Dose) objective implemented in the Photon Optimizer (PO) of Varian Eclipse treatment planning system have been here analyzed. gEUD is associated with the parameter a that accounts for the seriality of a structure, being higher for more serial organs. The PO was used to optimize volumetric modulated arc therapy (VMAT) plans on a virtual homogeneous cylindrical phantom presenting a target and an organ at risk (OAR). The OAR was placed at 4 mm, 1 and 2 cm distance, or cropped at 0, 2 and 4 mm from the target. Homogeneous target dose of 60 Gy in 20 fractions was requested with physical dose-volume objectives, while OAR dose was minimized with the upper gEUD objective. The gEUD specific a parameter was varied from 0.1 to 40 to assess its impact to OAR sparing and target coverage. Actual head and neck and prostate cases, with one parotid and the rectum as test OAR, were also analyzed to translate the results in the more complex clinical environment. Increasing the a parameter value in the gEUD objective, the optimization achieved lower volumes of the OAR which received the highest dose levels. The maximum dose in the OAR was minimized well with a values up to 20, while further increase of a to 40 did not further improve the result. The OAR mean dose was reduced for the OAR located at 1 and 2 cm distance from the target, enforced with increasing a. For cropped OARs, a mean dose reduction was achieved for a values up to 3-5, but mean dose increased for higher a values. The optimal choice of the parameter a depends on the mutual OAR and target position, and seriality of the organ. Today no significant compendium of clinical and biological specific a and gEUD values are available for a wide range of OARs. PMID- 29152845 TI - Association of IMMP2L deletions with autism spectrum disorder: A trio family study and meta-analysis. AB - IMMP2L, the gene encoding the inner mitochondrial membrane peptidase subunit 2 like protein, has been reported as a candidate gene for Tourette syndrome, autism spectrum disorder (ASD) and additional neurodevelopmental disorders. Here we genotyped 100 trio families with an index proband with autism spectrum disorder in Han Chinese population and found three cases with rare exonic IMMP2L deletions. We have conducted a comprehensive meta-analysis to quantify the association of IMMP2L deletions with ASD using 5,568 cases and 10,279 controls. While the IMMP2L deletions carried non-recurrent breakpoints, in contrast to previous reports, our meta-analysis found no evidence of association (P > 0.05) between IMMP2L deletions and ASD. We also observed common exonic deletions impacting IMMP2L in a separate control (5,971 samples) cohort where subjects were screened for psychiatric conditions. This is the first systematic review and meta analysis regarding the effect of IMMP2L deletions on ASD, but further investigations in different populations, especially Chinese population may be still needed to confirm our results. PMID- 29152847 TI - A case study in identifying targeted patients population in major depressive disorder by enhanced enrichment design. AB - Despite advances in clinical trial design, failure rates near 80% in phase 2 and 50% in phase 3 have recently been reported. The challenges to successful drug development are particularly acute in central nervous system trials such as for pain, schizophrenia, mania, and depression because high-placebo response rates lessen assay sensitivity, diminish estimated treatment effect sizes, and thereby decrease statistical power. This paper addresses the importance of rigorous patient selection in major depressive disorder trials through an enhanced enrichment paradigm. This approach led to a redefinition of an ongoing, blinded phase 3 trial algorithm for patient inclusion (1) to eliminate further randomization of transient placebo responders and (2) to exclude previously randomized transient responders from the primary analysis of the double blind phase of the trial. It is illustrated for a case study for the comparison between brexpiprazole + antidepressant therapy and placebo + antidepressant therapy. Analysis of the primary endpoint showed that efficacy of brexpiprazole versus placebo could not be established statistically if the original algorithm for identification of placebo responders was used, but the enhanced enrichment approach did statistically demonstrate efficacy. Additionally, the enhanced enrichment approach identified a target population with a clinically meaningful treatment effect. Through its successful identification of a target population, the innovative enhanced enrichment approach enabled the demonstration of a positive treatment effect in a very challenging area of depression research. PMID- 29152848 TI - Skin care and cosmeceuticals: Attitudes and trends among trainees and educators. AB - INTRODUCTION: Patients often seek skin care recommendations from their dermatologist. The objective of this study was to determine the degree of education dermatology residents receive on skin care and cosmeceutical products, the source of education, and the attitude of trainees and their educators toward skin care and cosmeceuticals. METHODS: A cross-sectional survey of dermatology residents and faculty via an online survey administered June 2015 and August 2015, respectively. RESULTS: In total, 104 dermatology residents and 50 dermatology faculty members completed the survey. Among the dermatology residents and faculty, equal distribution was represented across the country. The majority of residents and faculty (62% and 69%, respectively) report discussing skin care with up to 25% of their patients. Among resident participants, 76.5% "agree or strongly agree" that skin care and cosmeceutical education should be part of their education and the majority of residents (74.5%) report their education has been "too little or nonexistent" during residency. In contrast, the majority of the faculty (60%) reports their resident education is "just the right amount or too much" (P < .001). CONCLUSIONS: Skin care and cosmeceutical recommendations are often discussed in dermatology visits. Dermatology residents feel that education on these products should be a part of their residency training. PMID- 29152849 TI - High-Performance Aqueous Zinc-Ion Battery Based on Layered H2 V3 O8 Nanowire Cathode. AB - Rechargeable aqueous zinc-ion batteries have offered an alternative for large scale energy storage owing to their low cost and material abundance. However, developing suitable cathode materials with excellent performance remains great challenges, resulting from the high polarization of zinc ion. In this work, an aqueous zinc-ion battery is designed and constructed based on H2 V3 O8 nanowire cathode, Zn(CF3 SO3 )2 aqueous electrolyte, and zinc anode, which exhibits the capacity of 423.8 mA h g-1 at 0.1 A g-1 , and excellent cycling stability with a capacity retention of 94.3% over 1000 cycles. The remarkable electrochemical performance is attributed to the layered structure of H2 V3 O8 with large interlayer spacing, which enables the intercalation/de-intercalation of zinc ions with a slight change of the structure. The results demonstrate that exploration of the materials with large interlayer spacing is an effective strategy for improving electrochemical stability of electrodes for aqueous Zn ion batteries. PMID- 29152851 TI - Harold Ross Roberts, M.D: inspirational mentor, consummate physician, superb scientist (1930-2017). PMID- 29152850 TI - Estimation of minimal disease prevalence from population genomic data: Application to primary familial brain calcification. AB - Primary Familial Brain Calcification (PFBC) is a rare calcifying disorder of the brain with autosomal dominant inheritance, of unknown prevalence. Four causal genes have been identified so far: SLC20A2, PDGFB, PDGFRB, and XPR1, with pathogenic, probably pathogenic or missense variants of unknown significance found in 27.7% probands in the French PFBC series. Estimating PFBC prevalence from a clinical input is arduous due to a large diversity of symptoms and ages of onset and to incomplete clinical penetrance. Abnormal calcifications on CT scan can be used as a reliable diagnostic biomarker whatever the clinical status, but differential diagnoses should be ruled out including the challenging exclusion of common basal ganglia calcifications. Our primary aim was to estimate the minimal prevalence of PFBC due to a variant in one of the known genes. We extracted variants from the four known genes present in the gnomAD database gathering genomic data from 138,632 individuals. We interpreted all variants based on their predicted effect, their frequency, and previous studies on PFBC patients. Using the most conservative estimate, the minimal prevalence of PFBC related to a variant in one of the four known genes was 4.5 p. 10,000 (95%CI [3.4-5.5] p. 10,000). We then used variant detection rates in patients to extrapolate an overall minimal prevalence of PFBC to 2.1 p. 1,000 (95%CI [1.9-2.4] p. 1,000). The population-based genomic analysis indicates that PFBC is not an exceptionally rare disorder, still underestimated and underdiagnosed. PMID- 29152852 TI - Should I stay or should I go? Hospital emergency department waiting times and demand. AB - In the absence of the price mechanism, hospital emergency departments rely on waiting times, alongside prioritisation mechanisms, to restrain demand and clear the market. This paper estimates by how much the number of treatments demanded is reduced by a higher waiting time. I use variation in waiting times for low urgency patients caused by rare and resource-intensive high-urgency patients to estimate the relationship. I find that when waiting times are higher, more low urgency patients are deterred from treatment and leave the hospital during the waiting period without being treated. The waiting time elasticity of demand for low-urgency patients is approximately -0.25 and is highest for the lowest-urgency patients. PMID- 29152853 TI - Development of the Self-Regulated Learning Scale in Clinical Nursing Practice for nursing students: Consideration of its reliability and validity. AB - AIM: This study aimed to develop the Self-Regulated Learning Scale in Clinical Nursing Practice (SRLS-CNP) for the assessment of nursing students and to validate it. METHODS: Questionnaires, including the SRLS-CNP item pool, were sent to 766 students in the second-to-fourth grades of nursing universities in Japan. The analysis involved an exploratory factor analysis, Cronbach's alpha, confirmatory factor analysis, and calculation of the Spearman's rank correlation coefficient. In order to confirm stability, 198 students underwent test-retest reliability. RESULTS: Responses were received from 437 students (return rate: 57.0%); the data of 376 students (valid response rate: 86.0%) were analyzed. Following the factor analysis, the SRLS-CNP was divided into the motivation subscale (two factors, seven items) and learning strategies subscale (three factors, nine items). The motivation subscale items were termed "intrinsic motivation" and "achievement motivation." The learning strategies subscale items were termed "synthesized knowledge and nursing skills," "multidimensional thinking," and "effort control." The Cronbach's alpha for the SRLS-CNP was 0.853. The verification model in the confirmatory factor analysis showed good conformance; a strong positive correlation was evident between the motivation subscale and the learning strategy subscale. The correlation coefficient for test retest reliability was 0.77. CONCLUSION: As shown by its Cronbach's alpha coefficient, test-retest reliability results, and content, criterion-related, and construct validity, the SRLS-CNP was found to have good reliability and validity. PMID- 29152854 TI - An Approach to Incorporate Multi-Enzyme Digestion into C-TAILS for C-Terminomics Studies. AB - Protein C-termini study is still a challenging task and far behind its counterpart, N-termini study. MS based C-terminomics study is often hampered by the low ionization efficiency of C-terminal peptides and the lack of efficient enrichment methods. We previously optimized the C-terminal amine-based isotope labeling of substrates (C-TAILS) method and identified 369 genuine protein C termini in Escherichia coli. A key limitation of C-TAILS is that the prior protection of amines and carboxylic groups at protein level makes Arg-C as the only specific enzyme in practice. Herein, we report an approach combining multi enzyme digestion and C-TAILS, which significantly increases the identification rate of C-terminal peptides and consequently improves the applicability of C TAILS in biological studies. We carry out a systematic study and confirm that the omission of the prior amine protection at protein level has a negligible influence and allows the application of multi-enzyme digestion. We successfully apply five different enzyme digestions to C-TAILS, including trypsin, Arg-C, Lys C, Lys-N, and Lysarginase. As a result, we identify a total of 722 protein C termini in E. coli, which is at least 66% more than the results using any single enzyme. Moreover, the favored enzyme and enzyme combination are discovered. Data are available via ProteomeXchange with identifier PXD004275. PMID- 29152855 TI - Kinase interest you in treating incubated cocaine-craving? A hypothetical model for treatment intervention during protracted withdrawal from cocaine. AB - A diagnostic criterion for drug addiction, persistent drug-craving continues to be the most treatment-resistant aspect of addiction that maintains the chronic, relapsing, nature of this disease. Despite the high prevalence of psychomotor stimulant addiction, there currently exists no FDA-approved medication for craving reduction. In good part, this reflects our lack of understanding of the neurobiological underpinnings of drug-craving. In humans, cue-elicited drug craving is associated with the hyperexcitability of prefrontal cortical regions. Rodent models of cocaine addiction indicate that a history of excessive cocaine taking impacts excitatory glutamate signaling within the prefrontal cortex to drive drug-seeking behavior during protracted withdrawal. This review summarizes evidence that the capacity of cocaine-associated cues to augment craving in highly drug-experienced rats relates to a withdrawal-dependent incubation of glutamate release within prelimbic cortex. We discuss how stimulation of mGlu1/5 receptors increases the activational state of both canonical and noncanonical intracellular signaling pathways and present a theoretical molecular model in which the activation of several kinase effectors, including protein kinase C, extracellular signal-regulated kinase and phosphoinositide 3-kinase (PI3K) might lead to receptor desensitization to account for persistent cocaine-craving during protracted withdrawal. Finally, this review discusses the potential for existing, FDA-approved, pharmacotherapeutic agents that target kinase function as a novel approach to craving intervention in cocaine addiction. PMID- 29152856 TI - Treatment-associated symptoms and coping of postoperative patients with lung cancer in Japan: Development of a model of factors influencing hope. AB - AIM: Postoperative patients with lung cancer have a high recurrence rate and poor prognosis; hence, it was aimed to identify the factors affecting hope to develop a care-oriented perspective that focuses on the levels of hope of postoperative patients with lung cancer. METHODS: In the study, postoperative patients with lung cancer were included and data were collected for treatment-related symptoms, coping, and support-related factors as the primary variables. The Herth Hope Index, Quality of Life Questionnaire Lung Cancer Module of the European Organization for Research and Treatment of Cancer, Japanese version of the Coping Inventory for Stressful Situations, and Social Support Scale for Cancer Patients were used. RESULTS: For the 82 patients that were included in this study, 55% of the variance in the level of hope was explained by using a model that included the following: (i) symptoms of dyspnea, sore mouth, and chest pain; (ii) support, including satisfaction with postoperative symptom control by healthcare providers, satisfaction with the amount of information provided by healthcare providers, and the level of trust in the nurses during treatment and recovery; and (iii) task-oriented and social diversion coping behaviors. CONCLUSION: As a result of this study, the support-related factors had no direct influence on hope, but they did have a significantly negative influence on the treatment related symptoms, with improved symptoms also influencing hope. PMID- 29152857 TI - Rapid analysis of traditional Chinese medicine Pinellia ternata by microchip electrophoresis with electrochemical detection. AB - Traditional Chinese herbal medicine has long enjoyed the reputation of the world's most advanced system of natural medicine. Pinellia ternata is one of the most commonly used herbs in the traditional Chinese medical science. In this study, five representative ingredients of Pinellia ternata guanosine, methionine, glycine, 3,4-dihydroxybenzaldehyde, and homogentisic acid, were assayed using simple derivatization procedures. Under optimized experimental condition, five analytes in Pinellia ternata were rapidly separated and detected using microchip electrophoresis, affording the benefits of speed, minimal sample requirements, and sensitive on-the-chip electrochemical detection, in 5 min with linearity over a concentration of 20-500 MUM (R2 = 0.994) with nearly complete recovery (95.6 98.5%). PMID- 29152858 TI - In Vitro Evaluation of Anti-Aggregation and Degradation Behavior of PEGylated Polymeric Nanogels under In Vivo Like Conditions. AB - The in vivo stability and biodegradability of nanocarriers crucially determine therapeutic efficacy as well as safety when used for drug delivery. This study aims to evaluate optimized in vitro techniques predictive for in vivo nanocarrier behavior. Polymeric biodegradable nanogels based on hydroxyethyl methacrylamide oligoglycolates-derivatized poly(hydroxyethyl methacrylamide-co-N-(2 azidoethyl)methacrylamide) and with various degrees of PEGylation and crosslinking densities are prepared. Three techniques are chosen and refined for specific in vitro evaluation of the nanocarrier performance: (1) fluorescence single particle tracking (fSPT) to study the stability of nanogels in human plasma, (2) tangential flow filtration (TFF) to study the degradation and filtration of nanogel degradation products, and (3) fluorescence fluctuation spectroscopy (FFS) to evaluate and compare the degradation behavior of nanogels in buffer and plasma. fSPT results demonstrate that nanogels with highest PEGylation content show the least aggregation. The TFF results reveal that nanogels with higher crosslink density have slower degradation and removal by filtration. FFS results indicate a similar degradation behavior in human plasma as compared to that in phosphate buffered saline. In conclusion, three methods can be used to compare and select the optimal nanogel composition, and these methods hold potential to predict the in vivo performance of nanocarriers. PMID- 29152859 TI - Deletion of the EGF receptor in vascular smooth muscle cells prevents chronic angiotensin II-induced arterial wall stiffening and media thickening. AB - AIM: In vivo vascular smooth muscle cell (VSMC) EGF receptor (EGFR) contributes to acute angiotensin II (AII) effects on vascular tone and blood pressure. The ubiquitously expressed EGFR has been implicated in vascular remodelling preceding end-organ damage by pharmacological inhibition, and AII signalling in cultured vascular cells is partly EGFR-dependent. However, the role of VSMC-EGFR in vivo during AII-induced pathophysiological processes is not known. METHODS: This study assesses the in vivo relevance of VSMC-EGFR during chronic AII challenge without further stressors, using a mouse model with inducible, VSMC-specific EGFR knock out (VSMC-EGFR-KO). In these mice functional and structural vascular, renal and cardiac effects or biomarkers were investigated in vivo and ex vivo. RESULTS: Vascular smooth muscle cell-EGFR-KO prevented AII-induced media hypertrophy of mesenteric arteries, renal arterioles and the aorta, VSMC ERK1/2-phosphorylation as well as the impairment of vascular compliance. Furthermore, induction of vascular fibrosis, creatinineamia, renal interstitial fibrosis as well as the increase in fractional water excretion was prevented. AII-induced increase in systolic blood pressure was mitigated. By contrast, endothelial dysfunction, induction of vascular inflammatory marker mRNA and albuminuria were not inhibited. Cardiac and cardiomyocyte hypertrophy were also not prevented by VSMC EGFR-KO. CONCLUSION: Vascular smooth muscle cell-EGFRs are relevant for pathological AII action in vivo. Our data show in vivo and ex vivo the necessity of VSMC-EGFR for AII-induced structural and functional vascular remodelling, not including endothelial dysfunction. Hereby, VSMC-EGFR gains importance for complete AII-induced renal end-organ damage succeeding vascular remodelling. PMID- 29152860 TI - "Pretty Pressure" From Peers, Parents, and the Media: A Longitudinal Study of Appearance-Based Rejection Sensitivity. AB - Drawing from the tripartite sociocultural model of body image, the researchers examined whether direct messages and modeling from peers, parents, and media were concurrently and prospectively associated with appearance-based rejection sensitivity (appearance-RS) in young adolescents (Mage = 12.0 years). Appearance RS was higher among those who concurrently reported more appearance-related teasing and pressure by peers, more parent teasing, and greater acceptance of media appearance ideals. In prospective analyses, greater increases in appearance RS over 1 year were found for adolescents who perceived higher levels of parental appearance-related teasing and negative attitudes about their own appearance. Moderation analyses indicated the positive prospective association between parental negative appearance attitudes and appearance-RS was found in younger but not older participants. Gender did not moderate associations. PMID- 29152861 TI - Reward Seeking and Cognitive Control: Using the Dual Systems Model to Predict Adolescent Sexual Behavior. AB - Research has provided support for the dual systems model of adolescent risk taking, but the model has rarely been applied to sexual behavior. Using data from the NICHD SECCYD (N = 958; Mage = 15.07, SD = 0.18), this study examined the effects of cognitive control, reward seeking, and their interaction on sexual behavior. Results of structural equation models revealed that performance on behavioral tasks assessing reward seeking and cognitive control uniquely predicted sexual intercourse, but the interaction between them was not significant. For oral sex, only cognitive control was a significant predictor. The findings provide additional support for the dual systems model, and suggest that reward seeking and cognitive control make unique contributions to adolescent sexual behavior. PMID- 29152862 TI - Relational-Interdependent Self-Construal and Gender Predicting Blood Pressure Reactivity and Recovery From Stress in Early Adolescence. AB - This study investigated the association between relational-interdependent self construals (relational interdependence) and blood pressure reactivity and recovery from two types of peer stressors (i.e., relational and instrumental) and gender as a moderator of this association. One hundred and ninety-six early adolescents (M = 10.11 years) reported their relational interdependence and participated in a laboratory stress protocol in which their systolic and diastolic blood pressures before, during, and after experiencing peer stressors were assessed. Results indicated that for males only, those with high relational interdependence showed greater systolic blood pressure reactivity and, at a trend level, impaired recovery from instrumental stressors; females with high relational interdependence showed greater diastolic blood pressure reactivity to relational stressors. PMID- 29152864 TI - The Effect of Active and Passive Peer Discouragement on Adolescent Risk taking: An Experimental Study. AB - This experiment investigated the effect of peer discouragement on adolescent risk taking. Overall, 269 Dutch adolescents aged 11-15 years completed a risk taking computer task in the presence of an e-confederate who demonstrated very little risk taking (passive peer discouragement) and/or sent risk-discouraging messages to participants (active peer discouragement). The results showed that, compared to a situation with no peer discouragement, adolescents took significantly less risk only when they encountered a combination of active and passive peer discouragement; hence, when peers practiced what they preached. No gender differences were found in the effect of passive and active peer discouragement on risk taking. The results showed that digital peer messages play a promising role in diminishing adolescent risk taking. PMID- 29152863 TI - Using an Acculturation-Stress-Resilience Framework to Explore Latent Profiles of Latina/o Language Brokers. AB - With survey data from 243 Latina/o early adolescent language brokers, latent profile analyses were conducted to identify different types (i.e., profiles) of brokers. Profiles were based on how often Latina/o early adolescents brokered for family members, as well as their levels of family-based acculturation stress, negative brokering beliefs, parentification, and positive brokering beliefs. Three brokering profiles emerged: (1) infrequent-ambivalents, (2) occasional moderates, and (3) parentified-endorsers. Profile membership was significantly predicted by ethnic identification and brokering in a medical context. Respect, brokering at school, and brokering at home did not significantly predict profile membership. In addition, parentified-endorsers had more frequent perceived ethnic/racial discrimination and depressive symptoms than other profiles. In contrast, infrequent-ambivalents engaged in risky behaviors less frequently than other profiles. PMID- 29152865 TI - Adolescent Offenders' Qualitative Reflections on Desistance From Crime. AB - Although many young offenders desist from crime during adolescence, little is known about this process. This study used a qualitative approach to elucidate adolescent offenders' experiences in desisting from crime. Thirty-nine male adolescent offenders (Mage = 16.59 years) participated in a semistructured interview about the desistance process. One of four themes characterized adolescents' reflections on their own desistance: having a psychological reorientation, reacting to consequences, persisting, or being in the wrong place at the wrong time. Adolescents discussed five agentic moves they make to facilitate desistance: seeking and maintaining supportive relationships, navigating peer groups, working toward long-term goals, structuring time, and finding sanctuaries from the outside. These findings highlight adolescents' strengths, resources, and active role in desisting from crime. PMID- 29152866 TI - Student-Perceived Mothers' and Fathers' Beliefs, Mathematics and English Motivations, and Career Choices. AB - According to Eccles and Jacobs' (1986) parent socialization model, parents' gendered ability and value beliefs influence girls' and boys' interpretations of those beliefs, and hence students' domain-specific valuing of tasks and competence beliefs and subsequent career plans. Studies have rarely analyzed how both student-perceived mothers' and fathers' beliefs affect girls' and boys' task values, success expectancies, and career plans across domains. This study analyzed survey data of 459 students (262 boys) assessed through Grades 9, 10, and 11 from three coeducational secondary schools in Sydney, Australia. Longitudinal structural equation models revealed gendered value transmission pathways for girls in mathematics. Although mathematics test scores did not vary statistically significantly, girls reported statistically significantly lower mothers' ability beliefs for them in mathematics than boys at Time 1, which led to their statistically significantly lower mathematics intrinsic value at Time 2 and mathematics-related career plans at Time 3. Such gendered pathways did not occur in English. Matched same-gender effects and gendered pathways in parent socialization processes were evident; perceived mothers' value beliefs were more strongly related to girls' than boys' importance values in English. Student perceived fathers' ability beliefs positively predicted boys', not girls', importance value in mathematics. Implications for educational practice emphasize the need to target girls' and boys' interest when aiming to enhance their mathematical career motivations. PMID- 29152867 TI - Profiles of Emotion Deficits and Adolescent Nonsuicidal Self-Injury in an Inpatient Sample. AB - This study examined profiles of specific emotion deficits, including poor emotion awareness, reluctance to express emotion, sadness inhibition and dysregulation, and anger inhibition and dysregulation. Self-report questionnaires assessed adolescents' emotion skills and nonsuicidal self-injury (NSSI) engagement, frequency, severity, methods, and age of onset. Latent profile analysis yielded a three-profile solution: Low Deficit (LD; n = 49), Unaware/Anger Dysregulated (UAD; n = 24), and Anger Inhibited (AI; n = 20) profiles. Adolescents in the UAD profile were more likely to engage in NSSI, displayed a higher NSSI frequency, and reported a higher number of NSSI methods when compared to adolescents in the LD profile. No links emerged for NSSI severity or age of onset. PMID- 29152868 TI - Trends in Parental Monitoring and Knowledge Over Time Between Sexual Minority and Heterosexual Girls. AB - This study assessed whether trajectories of parental monitoring components were different for sexual minority girls (SMGs) compared to heterosexual girls. We recruited 14-19-year-old girls from two adolescent medicine clinics. We estimated growth curve models to compare how components of parental monitoring-adolescent disclosure, parental solicitation, and parental knowledge-changed over 2 years for SMGs and heterosexual girls. SMGs and heterosexual girls had similar trajectory slopes and quadratic forms of adolescent disclosure, but SMGs had consistently lower adolescent disclosure scores. Parental knowledge trajectories indicated differential intercepts and slopes for SMGs compared to heterosexual girls, suggesting potential higher risk for maladaptive behaviors. Results of this study suggest that parental monitoring may operate differently over time for SMGs compared to heterosexual girls. PMID- 29152869 TI - Linking Magazine Exposure to Social Appearance Anxiety: The Role of Appearance Norms in Early Adolescence. AB - Early adolescents (N = 1,591; Mage = 11.698; SD = 0.892) participated in a two wave panel study (6-month interval) to examine the longitudinal association between appearance-focused magazine exposure and social appearance anxiety. We revealed that magazine exposure positively correlated with the internalization of appearance ideals and the attribution of social rewards to attractiveness which, in turn, related to social appearance anxiety. Internalization and attribution of social rewards formed a reinforcing spiral; once internalized, early adolescents associate positive things with appearance ideals (e.g., peer acceptance) and the perception of rewards increases early adolescents' inclination to internalize ideals. Given the adverse consequences of social appearance anxiety, the findings warrant research on the role of media in the occurrence of social appearance anxiety. PMID- 29152870 TI - Social Support and Academic Engagement Among Reconnected Youth: Adverse Life Experiences as a Moderator. AB - Using motivational theories of engagement and adopting a multidimensional perspective of academic engagement, the authors investigate the associations among teacher and parent support, students' academic self-efficacy, and academic engagement among a sample of reconnected youth who have returned to academic pursuit after dropping out (N = 938, mean age = 16.50, SD = 1.78). In addition, they examine how youth's adverse life experiences moderate the pathways in this model, an analysis notably missing from much of the academic engagement literature. They find that students' academic self-efficacy mediates parent and teacher support and youth academic engagement. Moreover, participants' adverse life experiences moderate the connections among perceived support from parents, academic self-efficacy, and academic engagement. Implications for practice and future directions are discussed. PMID- 29152871 TI - An Explanatory Model of Dating Violence Risk Factors in Spanish Adolescents. AB - Dating violence is a serious public health issue that needs further understanding in terms of risk factors that may be involved in it. The main goal of this study was to test a mediational model of dating violence risk factors. The sample was composed of 477 secondary and college students from Spain (59% females). A dynamic developmental explanatory model considering aggressiveness, insecure attachment, interparental conflict, and peer dating violence was tested using a multigroup structural equation model. Aggressiveness partially mediated the relation between anxious attachment and dating violence and fully mediated the association between interparental conflict resolution and dating violence. Furthermore, perceived peer dating violence was a direct predictor of dating violence. Implications for prevention and intervention plans are discussed. PMID- 29152872 TI - Authority, Autonomy, and Deception: Evaluating the Legitimacy of Parental Authority and Adolescent Deceit. AB - This research examined adolescents' judgments about lying to avoid parental control over different types of activities. Participants (N = 66, Mage = 16.38, 73% European American) were interviewed about hypothetical situations describing adolescents who defied parental directives and lied about their defiance. Judgments about the legitimacy of parents' directives and protagonists' deception differed by types of parent relationship with adolescents (mutual or unilateral). Directives were least accepted, and deception was most accepted, in the context of unilateral relationships. Judgments also differed by domain of the action (personal, prudential, or conventional). Participants were least accepting of parental directives, and most accepting of deception about personal activities. Findings indicate that adolescents value honesty and parental authority, but sometimes give priority to concerns with autonomy and mutuality. PMID- 29152873 TI - Exclusive Synthesis of Poly(3-hexylthiophene) with an Ethynyl Group at Only One End for Effective Block Copolymerization. AB - Well-controlled synthesis of ethynyl-functionalized poly(3-hexylthiophene) (P3HT) is crucial for preparation of block copolymers containing the P3HT segment by means of click coupling reaction. A well-known chain end modification method, in which Kumada-Tamao catalyst-transfer polymerization is quenched with ethynylmagnesium chloride, under various conditions is re-examined, but in all cases not only P3HT with an ethynyl group at one end but also P3HT di-ethynylated at both ends is obtained. Accordingly, Sonogashira coupling reaction of P3HT having H/Br ends with trimethylsilylacetylene is tried, followed by removal of the trimethylsilyl group, and it is found that this protocol affords exclusively P3HT with an ethynyl group at one end. This post end-modification method is applied to the synthesis of an amphiphilic diblock copolymer of P3HT and poly(2 ethyl-2-oxazoline) (PEtOx) by means of click reaction between ethynylated P3HT and PEtOx with an azide group at one end, and the product is confirmed to be free from contamination with triblock copolymer. Micellization of this block copolymer is confirmed in tetrahydrofuran (THF)/water and THF/methanol mixtures. PMID- 29152874 TI - Concordance and correlation of activity indices in patients with rheumatoid arthritis in northwestern Colombia: A cross-sectional study. AB - AIM: To determine the correlation and concordance between different clinimetric scores in patients with rheumatoid arthritis in two high-complexity reference centers in northwestern Colombia. METHOD: A cross-sectional study in adults diagnosed with rheumatoid arthritis was conducted according to the 2010 American College of Rheumatology and European League Against Rheumatism Classification Criteria, between January and June, 2013. The correlation was evaluated using Spearman's correlation coefficient, and concordance with quadratic weighted kappa with the respective confidence intervals, for which patients were classified into different categories of disease activity. RESULTS: One hundred patients were included, of whom 83% were women; 58 and 75% received methotrexate and glucocorticoids, respectively. Most individuals were in remission or low activity. High correlations between Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS28-ESR) values with DAS28 C-reactive protein and Simple Disease Activity Index (SDAI) with Clinical Disease Activity Index (P < 0.0001; r = 0.82 and r = 0.86, respectively) were observed; likewise, the scores obtained with different indices correlated well with gold standard values for remission (SDAI), where the correlation with DAS28-ESR was slightly lower. Excellent concordance among all clinimetric scores was observed, although it was lower among DAS28-ESR and SDAI. CONCLUSION: Clinimetric indices had high concordance and correlation, especially for rheumatoid arthritis patients in remission or low disease activity, without being interchangeable among them. PMID- 29152875 TI - Effectiveness of the teach-back method for improving the health literacy of senior citizens in nursing homes. AB - AIM: To explore the effectiveness of the teach-back method for improving the health literacy of older adults in nursing homes in Urumqi, the capital of Xinjiang, China. METHODS: Among the 27 registered nursing homes, 10 were selected randomly by size and divided into the intervention and control groups. A total of 127 older adults in the intervention group and 136 in the control group met the inclusion criteria. The intervention and control groups were educated by using the teach-back and traditional methods, respectively, in this 6 month study. The Chinese Citizen Health Literacy Questionnaire was used to evaluate the effects of the interventions. RESULTS: Pre-intervention, the health literacy level of the cohorts was relatively low. Postintervention, the total health literacy score of the intervention group increased, while the total health literacy score of the control group had increased to a lesser extent. The total and four-dimension scores of the two groups were statistically significant. The intergroup difference in the two groups, and the intervention group's total health literacy score and each dimension score were higher than in the control group; these differences were statistically significant . CONCLUSIONS: The teach-back method can improve the health literacy level of older adults through short-term educational intervention. The teach-back method should be adopted by more healthcare providers and applied to improve the health literacy education of older adults. PMID- 29152876 TI - Refining Transcriptome Gene Catalogs by MS-Validation of Expressed Proteins. AB - Protein sequence identification by tandem mass spectroscopy (LC-MS/MS) identifies thousands of protein sequences even in complex mixtures, and provides valuable insight into the biological functions of different cells. For non-model organisms, transcriptomes are generally used to allow peptide identification, an important addition to their use as a gene catalog allowing the potential metabolic activities of cells to be determined. We used LC-MS/MS data to identify which of the six possible reading frames in the transcriptome was actually used by the cell to make protein, and asked whether this would have an impact on downstream analyses using the dataset. We combined results from several LC-MS/MS experiments designed to identify peptide sequences in extracts from the dinoflagellate Lingulodinium polyedra using a 74 655-sequence transcriptome. We compiled a list of 6628 translated nucleic acid sequences that contained the ensemble of peptide matches (termed MS-validated sequences) and assessed the similarity in downstream analyses between this data set and the 6628 nucleic acid sequences from which they were derived. When compared with BLASTx analyses of the DNA sequences, the MS-validated protein-sequences-analyzed using BLASTp showed differences in gene ontology, had more identified BLAST hits, and contained more KEGG pathway enzymes. The MS-validated protein sequences also differ from datasets containing longest open reading frame (ORF) protein sequences. We also note a poor correlation between the levels of protein and mRNA abundance, a comparison not previously performed for dinoflagellates. The differences observed between analyses of MS-validated protein sequence and nucleic acid sequence datasets suggest use of the former may provide a more accurate representation of cellular capacity than the latter. Developing MS-validated protein sequence datasets may also speed interpretation of MS-MS spectra in bottom up proteomics experiments. PMID- 29152877 TI - Rapid risk assessment during the early weeks of the 2015-2016 influenza season in Ukraine. AB - BACKGROUND: Several eastern European countries reported a severe influenza season to the World Health Organization (WHO) during late 2015. A country-specific rapid risk assessment for Ukraine was conducted to assess the season's severity and inform public health action. METHODS: The exposure and hazard were assessed using acute respiratory infection (ARI), severe acute respiratory infection (SARI), laboratory surveillance, virological and vaccine data from weeks 40/2015 to 7/2016 with comparison to 4 previous seasons to describe the influenza season start (5-week consecutive increase in ARI or SARI), predominant virus types, geographical spread and affected age groups. RESULTS: The exposure was characterised by an earlier and steeper increase in SARI (week 1/2016) and ARI (week 2/2016) compared to the previous 4 seasons. Transmission was across Ukraine with an increase in ARI and SARI cases aged 30-64 years compared to 2014/15. Laboratory-confirmed deaths increased from 11 in 2014/2015 to 342 in 2015/2016; the majority were 30-64 years old and unvaccinated; and 63.5% had underlying conditions. Total population vaccination coverage was 0.3%. The hazard assessment found influenza virus A(H1N1)pdm09 accounted for >95% of viruses detected. Ukrainian virus strains (n = 62) were antigenically similar to vaccine strains and susceptible to neuraminidase inhibitors. CONCLUSIONS: The first weeks of the 2015/16 influenza season were more severe than previous seasons, with an earlier and steeper increase in severe cases and deaths, particularly in younger adults. Influenza A(H1N1)pdm09 was the predominant strain and was closely related to the seasonal vaccine strain with no evidence of resistance to antiviral drugs. PMID- 29152878 TI - Potency determination of inactivated H7 influenza vaccines using monoclonal antibody-based ELISA and biolayer interferometry assays. AB - BACKGROUND: The single radial immunodiffusion (SRID) assay, the accepted method for determining potency of inactivated influenza vaccines, measures an immunogenic form of the influenza hemagglutinin. Nevertheless, alternative methods for measuring vaccine potency have been explored to address some of the weaknesses of the SRID assay, including limited sensitivity and the requirement for large amounts of standardized reagents. Monoclonal antibody (mAb)-based potency assays also have the ability to detect and measure relevant immunogenic forms of HA. OBJECTIVES: The objective of this study was to continue evaluation of mAb-based alternative methods for measuring the potency of inactivated influenza vaccines, focusing on A(H7N9) pandemic influenza vaccines. METHODS: Several murine mAbs that recognize different epitopes on the H7 hemagglutinin (HA) were identified and characterized. These mAbs were evaluated in both a mAb capture ELISA and a mAb-based biolayer interferometry (BLI) assay. RESULTS: Results indicated that potency of inactivated A(H7N9) vaccines, including vaccine samples that were stressed by heat treatment, measured by either alternative method correlated well with potency determined by the traditional SRID potency assay. CONCLUSIONS: The availability of multiple H7 mAbs, directed to different HA epitopes, provides needed redundancy in the potency analysis as A(H7N9) viruses continue to evolve antigenically and suggests the importance of having a broad, well-characterized panel of mAbs available for development of vaccines against influenza strains with pandemic potential. In addition, the results highlight the potential of mAb-based platform such as ELISA and BLI for development as alternative methods for determining the potency of inactivated influenza vaccines. PMID- 29152879 TI - Y RNA derived small RNAs in Sjogren's syndrome: Candidate biomarkers? AB - Anti-Ro and anti-La antibodies are important in pathogenesis and diagnosis of Sjogren's syndrome (SS). Ro60, Ro52 and La are RNA binding proteins of Y RNA, which were discovered more than three decades ago. Significance of Y RNA is not appreciated as much as Ro and La in SS. It can be hypothesised that 5'-YsRNA, short fragment derived from Y RNA may be recognized by TLR7 in pDC, which induces type I interferon signature in SS. New genomics tools, namely RNA seq, enables assay of 5'-YsRNA in blood. 5'-YsRNA has the potential to be a novel biomarker of SS. PMID- 29152880 TI - Enantioselective Synthesis of Chromenes via a Palladium-Catalyzed Asymmetric Redox-Relay Heck Reaction. AB - A palladium-catalyzed asymmetric redox-relay Heck reaction of 4H-chromenes and arylboronic acids has been successfully developed. The reaction proceeded in moderate to good yields with good to high enantioselectivities. The resulting product is an advanced intermediate of bio-active compound BW683C. PMID- 29152881 TI - Spontaneous perirenal hemorrhage in hemodialysis patient treated with selective embolization: A case series and review of the literature. AB - INTRODUCTION: Spontaneous perirenal hemorrhage (SPH) or Wunderlich syndrome, is a rare but potentially life-threatening condition. It is characterized by an unexpected bleeding in the kidneys and usually presents as an abdominal pain. Angiography and more recently selective renal arterial embolization are emerging as effective modalities for the diagnosis and treatment of SPH. In this article, we report a total of three cases of SPH in hemodialysis (HD) patients. METHODS: This is the experience of diagnosis and treatment of SPH in HD patients. FINDINGS: All three were female, between 37 and 54 years of age and were undergoing HD for end stage renal disease (ESRD). Two of patients presented with left flank or abdominal pain after termination of HD therapy, while the third patient presented with left abdominal pain during the dialysis session. All patients received anti-coagulation therapy for HD, but no abnormal levels of coagulation index were found. These patients were diagnosed using CT and two of them were diagnosed with acquired cystic kidney disease (ACKD). Selective renal arterial embolization was performed in the case of active bleeding. DISCUSSION: We are aware that HD patients have elevated risk of bleeding related complications, additionally the presence of an acute abdominal pain increases the suspicion of SPH as a possible cause. ACKD can be considered one of the possible risk factors for SPH in long-term HD patients. Interventional treatment for kidney injury is useful and safe for active bleeding in most cases. PMID- 29152882 TI - Kawasaki disease - a parent's perspective. PMID- 29152883 TI - Preemption in Singular Causation Judgments: A Computational Model. AB - Causal queries about singular cases are ubiquitous, yet the question of how we assess whether a particular outcome was actually caused by a specific potential cause turns out to be difficult to answer. Relying on the causal power framework (Cheng, ), Cheng and Novick () proposed a model of causal attribution intended to help answer this question. We challenge this model, both conceptually and empirically. We argue that the central problem of this model is that it treats causal powers that are probabilistically sufficient to generate the effect on a particular occasion as actual causes of the effect, and thus neglects that sufficient causal powers can be preempted in their efficacy. Also, the model does not take into account that reasoners incorporate uncertainty about the underlying general causal structure and strength of causes when making causal inferences. We propose a new measure of causal attribution and embed it into the structure induction model of singular causation (SISC; Stephan & Waldmann, ). Two experiments support the model. PMID- 29152884 TI - Economic impacts of avian influenza outbreaks in Kerala, India. AB - This study assessed the short-run impact to poultry farmers, duck hatcheries, control costs, compensation paid to stakeholders (transfer payments) and market reactions on own and substitute product prices and backwater tourism (boat operators) due to avian influenza (AI) outbreaks in Kuttanad region of Kerala, India, during 2014. The primary data from 91 poultry farms (duck farms, broiler chicken and backyard poultry), four hatcheries and 90 backwater boat owners were collected through pre-tested schedules. The secondary data on transfer payments and expenditure incurred to control AI were collected from developmental departments and were analysed. The estimated loss (culling live birds, eggs and feed destruction) per duck farm was USD 9,181, USD 3,889 and USD 156 in case of commercial farms reared for meat, dual-purpose and backyard farms, respectively. The loss incurred by small-scale broiler and backyard poultry farms was USD 453 and USD 40, respectively. The loss incurred by large and small duck hatcheries was USD 11,963 and USD 5,790, respectively, due to culling of hatchlings, young birds and destroying eggs. The government invested USD 744,890 to contain the disease spread through massive culling, surveillance and monitoring of poultry and humans due to zoonotic nature of the disease. A sharp market reaction on own and substitute product prices and eight weeks' time lag in price recovery was observed. The consequential impact on tourism especially for the backwater boat operators amounted to a loss of USD 2,280/boat due to fall in tourist inflow. Since, control measures are post-incidence, it is necessary to adopt appropriate preventive bio-security measures at the farm level besides periodical screening of domestic birds in migratory birds' flyway locations like Kuttanad to reduce the AI burden on various stakeholders including government. PMID- 29152885 TI - Addressing Weight Stigma and Opening Doors for a Patient-Centered Approach to Childhood Obesity. PMID- 29152886 TI - A Contrast-Based Computational Model of Surprise and Its Applications. AB - We review our work on a contrast-based computational model of surprise and its applications. The review is contextualized within related research from psychology, philosophy, and particularly artificial intelligence. Influenced by psychological theories of surprise, the model assumes that surprise-eliciting events initiate a series of cognitive processes that begin with the appraisal of the event as unexpected, continue with the interruption of ongoing activity and the focusing of attention on the unexpected event, and culminate in the analysis and evaluation of the event and the revision of beliefs. It is assumed that the intensity of surprise elicited by an event is a nonlinear function of the difference or contrast between the subjective probability of the event and that of the most probable alternative event (which is usually the expected event); and that the agent's behavior is partly controlled by actual and anticipated surprise. We describe applications of artificial agents that incorporate the proposed surprise model in three domains: the exploration of unknown environments, creativity, and intelligent transportation systems. These applications demonstrate the importance of surprise for decision making, active learning, creative reasoning, and selective attention. PMID- 29152887 TI - Association between maternal sleep practices and late stillbirth - findings from a stillbirth case-control study. AB - OBJECTIVE: To report maternal sleep practices in women who experienced a stillbirth compared with controls with ongoing live pregnancies at similar gestation. DESIGN: Prospective case-control study. SETTING: Forty-one maternity units in the United Kingdom. POPULATION: Women who had a stillbirth after >= 28 weeks' gestation (n = 291) and women with an ongoing pregnancy at the time of interview (n = 733). METHODS: Data were collected using an interviewer administered questionnaire that included questions on maternal sleep practices before pregnancy, in the four weeks prior to, and on the night before the interview/stillbirth. MAIN OUTCOME MEASURES: Maternal sleep practices during pregnancy. RESULTS: In multivariable analysis, supine going-to-sleep position the night before stillbirth had a 2.3-fold increased risk of late stillbirth [adjusted Odds Ratio (aOR) 2.31, 95% CI 1.04-5.11] compared with the left side. In addition, women who had a stillbirth were more likely to report sleep duration less than 5.5 hours on the night before stillbirth (aOR 1.83, 95% CI 1.24-2.68), getting up to the toilet once or less (aOR 2.81, 95% CI 1.85-4.26), and a daytime nap every day (aOR 2.22, 95% CI 1.26-3.94). No interaction was detected between supine going-to-sleep position and a small-for-gestational-age infant, maternal body mass index, or gestational age. The population-attributable risk for supine going-to-sleep position was 3.7% (95% CI 0.5-9.2). CONCLUSIONS: This study confirms that supine going-to-sleep position is associated with late stillbirth. Further work is required to determine whether intervention(s) can decrease the frequency of supine going-to-sleep position and the incidence of late stillbirth. TWEETABLE ABSTRACT: Supine going-to-sleep position is associated with 2.3* increased risk of stillbirth after 28 weeks' gestation. PLAIN LANGUAGE SUMMARY: Stillbirth, the death of a baby before birth, is a tragedy for mothers and families. One approach to reduce stillbirths is to identify factors that are associated with stillbirth. There are few risk factors for stillbirth that can be easily changed, but this study is looking at identifying how mothers may be able to reduce their risk. In this study, we interviewed 291 women who had a stillbirth and 733 women who had a live-born baby from 41 maternity units throughout the UK. The mothers who had a stillbirth were interviewed as soon as practical after their baby died. Mothers who had a live birth were interviewed during their pregnancies at the same times in pregnancy as when the stillbirths occurred. We did not interview mothers who had twins or who had a baby with a major abnormality. Mothers who went to sleep on their back had at least twice the risk of stillbirth compared with mothers who went to sleep on their left-hand side. This study suggests that 3.7% of stillbirths after 28 weeks of pregnancy were linked with going to sleep lying on the back. This study also shows that the link between going-to-sleep position and late stillbirth was not affected by the duration of pregnancy after 28 weeks, the size of the baby, or the mother's weight. Women who got up to the toilet once or more at night had a reduced risk of stillbirth. This is the largest of four similar studies that have all shown the same link between the position in which a mother goes to sleep and stillbirth after 28 weeks of pregnancy. Further studies are needed to see whether women can easily change their sleep position in late pregnancy and whether changing the position a mother goes to sleep in reduces stillbirth. PMID- 29152888 TI - The sensitivity of breeding songbirds to changes in seasonal timing is linked to population change but cannot be directly attributed to the effects of trophic asynchrony on productivity. AB - A consequence of climate change has been an advance in the timing of seasonal events. Differences in the rate of advance between trophic levels may result in predators becoming mismatched with prey availability, reducing fitness and potentially driving population declines. Such "trophic asynchrony" is hypothesized to have contributed to recent population declines of long-distance migratory birds in particular. Using spatially extensive survey data from 1983 to 2010 to estimate variation in spring phenology from 280 plant and insect species and the egg-laying phenology of 21 British songbird species, we explored the effects of trophic asynchrony on avian population trends and potential underlying demographic mechanisms. Species which advanced their laying dates least over the last three decades, and were therefore at greatest risk of asynchrony, exhibited the most negative population trends. We expressed asynchrony as the annual variation in bird phenology relative to spring phenology, and related asynchrony to annual avian productivity. In warmer springs, birds were more asynchronous, but productivity was only marginally reduced; long-distance migrants, short distance migrants and resident bird species all exhibited effects of similar magnitude. Long-term population, but not productivity, declines were greatest among those species whose annual productivity was most greatly reduced by asynchrony. This suggests that population change is not mechanistically driven by the negative effects of asynchrony on productivity. The apparent effects of asynchrony on population trends are therefore either more likely to be strongly expressed via other demographic pathways, or alternatively, are a surrogate for species' sensitivity to other environmental pressures which are the ultimate cause of decline. PMID- 29152889 TI - Systemic use of antibiotics and risk of diabetes in adults: A nested case-control study of Alberta's Tomorrow Project. AB - AIMS: Previous observational studies using administrative health records have suggested an increased risk of diabetes with use of antibiotics. However, unmeasured confounding factors may explain these results. This study characterized the association between systemic use of antibiotics and risk of diabetes in a cohort of adults in Canada, accounting for both clinical and self reported disease risk factors. MATERIALS AND METHODS: In this nested case-control study, we used data from Alberta's Tomorrow Project (ATP), a longitudinal cohort study in Canada, and the linked administrative health records (2000-2015). Incident cases of diabetes were matched with up to 8 age and sex-matched controls per case. Conditional logistic regression was used to examine the association between antibiotic exposures and incident diabetes after sequentially adjusting for important clinical and lifestyle factors. RESULTS: This study included 1676 cases of diabetes and 13 401 controls. Although 17.9% of cases received more than 5 courses of antibiotics, compared to 13.8% of controls (P < .0001), the association between antibiotic use and risk of diabetes was progressively reduced as important clinical and lifestyle factors were accounted for. In fully adjusted models, compared to participants with 0 to 1 courses of antibiotics, participants receiving more antibiotics had no increased risk of diabetes [Odds Ratio, 0.97 (0.83-1.13) for 2 to 4 courses and 0.98 (0.82-1.18) for >=5 courses]. CONCLUSIONS: After adjustment for clinical and difficult-to-capture lifestyle data, we found no association between systemic use of antibiotics and risk of diabetes. Our results suggest that those positive associations observed in previous studies using only administrative records might have been confounded. PMID- 29152890 TI - Influenza-associated severe acute respiratory infections in 2 sentinel sites in Lebanon-September 2015 to August 2016. AB - BACKGROUND: Given the sparse information on the burden of influenza in Lebanon, the Ministry of Public Health established a sentinel surveillance for severe acute respiratory infections (SARI) to identify the attribution of influenza to reported cases. We aim to highlight the proportion of influenza-associated SARI from September 1st, 2015 to August 31st, 2016 in 2 Lebanese hospitals. METHODS: The study was conducted in 2 sentinel sites located in Beirut suburbs and southern province of Lebanon. WHO's 2011 standardized SARI case definition was used. Data from September 1, 2015 to August 31, 2016 were reviewed, and all-cause hospital admission numbers were obtained. Nasopharyngeal swabs were collected and tested by RT-PCR. Descriptive and bivariate analyses were conducted using STATA 13. RESULTS: The 2 sentinel sites reported 746 SARI cases during the studied time frame: 467 from the southern province site and 279 from the Beirut suburbs site. SARI reports peaked between January and March 2016. All, except 4, cases were sampled, and a co-dominance of influenza B (43%) and influenza A (H1N1) (41%) was evident. A high proportion of cases was reported in children <2 years 274 (37%). The proportional contribution of influenza-associated SARI to all-cause hospital admissions was high in children <2 years in the south (4.5% [95% CI: 3.1-6.5]) and in children <5 years in Beirut (0.7% [95% CI: 0.6-0.8]). CONCLUSION: This is the first study to highlight the proportion of influenza-associated SARI in 2 hospitals in Lebanon. The findings will be beneficial for supporting respiratory prevention and immunization program policies. PMID- 29152891 TI - Factors related to quality of life among older adults in Bangladesh: A cross sectional survey. AB - This cross-sectional design study aimed to describe quality of life and examine factors related to quality of life among older adults in Bangladesh. Convenience sampling was used to recruit 280 older adults from ten villages in two southern districts. The results demonstrate that the majority of the participants reported an overall moderate score of quality of life. Moreover, participants' sleep problems, depression, religiosity, and activities of daily living were negatively correlated with quality of life whereas social support and health service availability were positively correlated with quality of life. Implementing intervention programs upon the significant related factors to improve older adults' quality of life is recommended. PMID- 29152892 TI - Pyran-Bridged Indacenodithiophene as a Building Block for Constructing Efficient A-D-A-Type Nonfullerene Acceptors for Polymer Solar Cells. AB - In recent years, nonfullerene acceptors have attracted much attention, owing to their great potential for use in high-performance polymer solar cells.The ladder type building block, pyran-bridged indacenodithiophene (PDT), was used for constructing A-D-A nonfullerene acceptors through introduction of oxygen atoms into an indacenodithiophene (IDT) unit. The synthesis of PDT is accomplished by a BBr3 -mediated tandem cyclization-deprotection reaction to construct the pyran ring. Hence, molecular acceptor PTIC was synthesized and used in a polymer solar cell device. Compared to the IDT-based acceptor, PTIC exhibits higher HOMO levels and wider optical band gap at 550-800 nm. Devices fabricated with poly[(2,6-(4,8 bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene)-co-(1,3-di(5 thiophene-2-yl)-5,7-bis(2-ethylhexyl)-benzo[1,2-c:4,5-c']dithiophene-4,8-dione)] (PBDB-T):PTIC as the active layer give a power conversion efficiency (PCE) of 7.66 %. PMID- 29152893 TI - Characterization of the novel HLA-B*48:43 allele by sequencing-based typing. AB - HLA-B*48:43 differs from HLA-B*48:01:01:01 by two nucleotide substitutions at positions 981 and 986. PMID- 29152894 TI - Toward a comprehensive, theoretical model of compassion fatigue: An integrative literature review. AB - This study was an integrative literature review in relation to compassion fatigue models, appraising these models, and developing a comprehensive theoretical model of compassion fatigue. A systematic search on PubMed, EbscoHost (Academic Search Premier, E-Journals, Medline, PsycINFO, Health Source Nursing/Academic Edition, CINAHL, MasterFILE Premier and Health Source Consumer Edition), gray literature, and manual searches of included reference lists was conducted in 2016. The studies (n = 11) were analyzed, and the strengths and limitations of the compassion fatigue models identified. We further built on these models through the application of the conservation of resources theory and the social neuroscience of empathy. The compassion fatigue model shows that it is not empathy that puts nurses at risk of developing compassion fatigue, but rather a lack of resources, inadequate positive feedback, and the nurse's response to personal distress. By acting on these three aspects, the risk of developing compassion fatigue can be addressed, which could improve the retention of a compassionate and committed nurse workforce. PMID- 29152895 TI - Survey of financial burden of families in the U.S. with children using home mechanical ventilation. AB - AIM: To describe and quantify the out-of-pocket expenses, employment loss, and other financial impact related to caring for a child using home mechanical ventilation (HMV). METHOD: We conducted a cross-sectional survey of U.S. families with children who used HMV. Eligible participants were invited to complete a questionnaire addressing household and child characteristics, out-of-pocket expenses, employment loss/reduction, and financial stress. Participants were recruited with the help of three national patient registries. RESULTS: Two hundred twenty-six participants from 32 states (152 with children who used invasive ventilation and 74 with children who used noninvasive ventilation) completed the questionnaire. Participants' median reported yearly household income was $90 000 (IQR 70 000-150 000). The median amount paid in out-of-pocket expenses in the previous 3 months to care for their child using HMV totaled $3899 (IQR $2900-4550). Reported levels of financial stress decreased as income increased; 37-60% of participants, depending on income quintile, reported moderate financial stress with "some" of that stress due to their out-of-pocket expenses. A substantial majority reported one or more household members stopped or reduced work and took unpaid weeks off of work to care for their child. CONCLUSION: The financial impact of caring for a child using HMV is considerable for some families. Providers need to understand these financial burdens and should inform families of them to help families anticipate and plan for them. PMID- 29152896 TI - Trimetazidine restores the positive adaptation to exercise training by mitigating statin-induced skeletal muscle injury. AB - BACKGROUND: Exercise rehabilitation is demonstrated to improve the prognosis of patients with coronary heart disease (CHD). Statins, as the key medicine to lower cholesterol in CHD, result in skeletal muscle injury and impair exercise training adaptation. Energy metabolism dysfunction is identified as the potential mechanism underlying statin-induced skeletal muscle injury. In this study, we investigated the effects of the metabolic modulator trimetazidine on skeletal muscle energy metabolism and statin-associated exercise intolerance. METHODS: High-fat fed apolipoprotein E knockout (ApoE-/- ) mice were given aerobic exercise and administrated simvastatin, trimetazidine, or simvastatin plus trimetazidine by gavage. Exercise capacity was evaluated at the end of the treatment by hanging grid test, forelimb grip strength, and running tolerance test. Plasma glucose, lipid, and creatine kinase concentrations were measured at the end of the treatment. After sacrifice, gastrocnemii were stored for assessment of muscle morphology and fibre type. Energy metabolism was estimated by plasma lactic acid concentration, ragged red fibres, and glycogen stores. Activities of mitochondrial complex III, citrate synthase activity, and membrane potential were measured to assess mitochondrial function. Oxidative stress was also evaluated by superoxide in mitochondria, superoxide dismutase activity, and glutathione redox state. RESULTS: In high-fat fed ApoE-/- mice, exercise training had no effect on lipid concentrations. Lower lipid concentrations with increased creatine kinase were observed with additional simvastatin treatment. Exercise capacity increased significantly in response to exercise training alone but was blunted by the addition of simvastatin. Similarly, cross-sectional area of muscle fibres and the proportion of slow-twitch fibres increased in the exercise group but decreased in the simvastatin plus exercise group. Additionally, simvastatin increased centronucleated fibres and induced energy metabolism dysfunction by inhibiting complex III activity and thus promoted oxidative stress in gastrocnemius. We demonstrated that trimetazidine could reverse simvastatin induced exercise intolerance and muscle damages. We also found the ability of trimetazidine in restoration of muscle fibre hypertrophy and facilitating fast-to slow type shift. The energy metabolism dysfunction and oxidative stress in gastrocnemii were rescued by trimetazidine. CONCLUSIONS: Trimetazidine alleviated statin-related skeletal muscle injury by restoration of oxidative phenotype and increasing fibre cross-sectional areas in response to exercise training. Correspondingly, the exercise training adaptation were improved in high-fat fed ApoE-/- mice. Moreover, trimetazidine is able to exert its positive effects without affecting the beneficial lipid-lowering properties of the statins. Thus, trimetazidine could be prescribed to remedy the undesirable statins-induced exercise intolerance during cardiac rehabilitation in patients with CHD. PMID- 29152897 TI - Screening and identification of alpha-glucosidase inhibitors from Shenqi Jiangtang Granule by ultrafiltration liquid chromatography and mass spectrometry. AB - Shenqi Jiangtang Granule, a well-known traditional Chinese herbal preparation, has been widely used for the treatment of type II diabetes mellitus. In this work, an ultrafiltration liquid chromatography with quadrupole time-of-flight mass spectrometry method was proposed for the rapid identification of bioactive ingredients from Shenqi Jiangtang Granule using alpha-glucosidase as an example. First, the chemical profile of this preparation was clarified, including 37 saponins, 17 flavonoids, 37 lignans, and seven other compounds. After incubation with alpha-glucosidase in vitro, the methanol extract with an IC50 value of 0.19 mg/mL exhibited significant inhibitory activity. Then, 18 specific binding peaks were screened, and 15 peaks were identified. Among these, ten compounds were reported to have potential alpha-glucosidase inhibitory activity for the first time. Subsequently, the inhibitory activities of these active compounds were evaluated by ultraviolet spectrophotometry with p-nitrophenyl alpha-d glucopyranoside as a substrate. As a result, gomisin J and gomisin D exhibited stronger alpha-glucosidase inhibitory activities than other active compounds with IC50 values of 77.69 and 133.85 MUM, respectively. The results demonstrated that the integrated ultrafiltration liquid chromatography with mass spectrometry method was an effective and powerful tool for the discovery of active ingredients in Shenqi Jiangtang Granule. PMID- 29152898 TI - Tolerance levels of CT number to electron density table for photon beam in radiotherapy treatment planning system. AB - The accuracy of computed tomography number to electron density (CT-ED) calibration is a key component for dose calculations in an inhomogeneous medium. In a previous work, it was shown that the tolerance levels of CT-ED calibration became stricter with an increase in tissue thickness and decrease in the effective energy of a photon beam. For the last decade, a low effective energy photon beam (e.g., flattening-filter-free (FFF)) has been used in clinical sites. However, its tolerance level has not been established yet. We established a relative electron density (ED) tolerance level for each tissue type with an FFF beam. The tolerance levels were calculated using the tissue maximum ratio (TMR) and each corresponding maximum tissue thickness. To determine the relative ED tolerance level, TMR data from a Varian accelerator and the adult reference computational phantom data in the International Commission on Radiological Protection publication 110 (ICRP-110 phantom) were used in this study. The 52 tissue components of the ICRP-110 phantom were classified by mass density as five tissues groups including lung, adipose/muscle, cartilage/spongy-bone, cortical bone, and tooth tissue. In addition, the relative ED tolerance level of each tissue group was calculated when the relative dose error to local dose reached 2%. The relative ED tolerances of a 6 MVFFF beam for lung, adipose/muscle, and cartilage/spongy-bone were +/-0.044, +/-0.022, and +/-0.044, respectively. The thicknesses of the cortical bone and tooth groups were too small to define the tolerance levels. Because the tolerance levels of CT-ED calibration are stricter with a decrease in the effective energy of the photon beam, the tolerance levels are determined by the lowest effective energy in useable beams for radiotherapy treatment planning systems. PMID- 29152899 TI - Lung function after extremely preterm birth-A population-based cohort study (EXPRESS). AB - BACKGROUND AND OBJECTIVES: Follow-up studies of children and young adults born very-to-moderately preterm show persistent and significant lung function deficits. The aim of the study was to determine lung function and airway mechanics in school-aged children born in 2004 to 2007 and extremely preterm (after 22-26 weeks of gestation). METHODS: In a population-based cohort of children born extremely preterm and controls born at term (n = 350), follow-up at 61/2-years-of-age was performed using spirometry and impulse oscillometry. Associations to gestational age, smallness for gestational age (SGA), and bronchopulmonary dysplasia (BPD) were assessed. RESULTS: Children born extremely preterm had lower forced vital capacity (FVC, z-score: -0.7, 95%CI: -1.0;-0.4), forced expiratory volume (FEV1 , z-score: -1.1, 95%CI: -1.4; -0.8), higher frequency-dependence of resistance (R5-20 , 0.09, 95%CI: 0.05; 0.12 kPa . L-1 . s-1 ) and larger area under the reactance curve (AX, 0.78, 95%CI: 0.49; 1.07 kPa . L-1 ) than controls. In children born at 22-24 weeks of gestation, 24% had FVC and 44% had FEV1 below the lower limit of normal. SGA and severe BPD only marginally contributed to pulmonary outcomes. Asthma-like disease was reported in 40% of extremely preterm children and 15% of controls. CONCLUSION: Many children born extremely preterm have altered airway mechanics and significant obstructive reduction in lung function. This warrants consideration for treatment and continued follow-up. PMID- 29152901 TI - Broad spectrum of neuropsychiatric phenotypes associated with white matter disease in PTEN hamartoma tumor syndrome. AB - White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN-related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals. PMID- 29152902 TI - The genetics of human personality. AB - Personality traits are the relatively enduring patterns of thoughts, feelings and behaviors that reflect the tendency to respond in certain ways under certain circumstances. Twin and family studies have showed that personality traits are moderately heritable, and can predict various lifetime outcomes, including psychopathology. The Research Domain Criteria characterizes psychiatric diseases as extremes of normal tendencies, including specific personality traits. This implies that heritable variation in personality traits, such as neuroticism, would share a common genetic basis with psychiatric diseases, such as major depressive disorder. Despite considerable efforts over the past several decades, the genetic variants that influence personality are only beginning to be identified. We review these recent and increasingly rapid developments, which focus on the assessment of personality via several commonly used personality questionnaires in healthy human subjects. Study designs covered include twin, linkage, candidate gene association studies, genome-wide association studies and polygenic analyses. Findings from genetic studies of personality have furthered our understanding about the genetic etiology of personality, which, like neuropsychiatric diseases themselves, is highly polygenic. Polygenic analyses have showed genetic correlations between personality and psychopathology, confirming that genetic studies of personality can help to elucidate the etiology of several neuropsychiatric diseases. PMID- 29152903 TI - Reproductive endocrine phenotypes relating to CHD7 mutations in humans. AB - Mutations in the gene CHD7 cause CHARGE syndrome, a rare multi-organ syndromic disorder. Gonadal defects are common in individuals with CHARGE syndrome (seen in ~60-80% of cases) and represent the letter "G" in the CHARGE syndrome acronym. The gonadal defect in CHARGE syndrome results from congenital deficiency of the hypothalamic hormone Gonadotropin-releasing hormone (GnRH), which manifests clinically as pubertal failure and infertility, and biochemically as hypogonadotropic hypogonadism (low sex steroid hormone levels with inappropriately normal or low gonadotropin levels). In addition to the gonadal endocrine abnormalities, in a small minority of individuals with CHARGE, additional endocrine defects including growth hormone deficiency, multiple pituitary hormone deficits and primary hypothyroidism may also be seen. CHD7 mutations disrupt the targeting of olfactory axons and the migration of GnRH synthesizing neurons during embryonic development, resulting in congenital idiopathic hypogonadotropic hypogonadism (IHH) and anosmia (or hyposmia), two features that define human Kallmann syndrome. Since Kallmann syndrome is one of the constituent phenotypes within CHARGE, recent studies have investigated the role of CHD7 mutations in individuals with IHH and established that deleterious missense mutations in CHD7 are associated with Kallmann syndrome as well as normosmic form of IHH. These missense mutations affect the ATPase and nucleosome remodeling activities of the CHD7 protein. These observations suggest that CHD7 protein function is critical for the ontogeny of GnRH neurons and neuroendocrine regulation of GnRH secretion. PMID- 29152904 TI - Creating Time: Social Collaboration in Music Improvisation. AB - Musical collaboration emerges from the complex interaction of environmental and informational constraints, including those of the instruments and the performance context. Music improvisation in particular is more like everyday interaction in that dynamics emerge spontaneously without a rehearsed score or script. We examined how the structure of the musical context affords and shapes interactions between improvising musicians. Six pairs of professional piano players improvised with two different backing tracks while we recorded both the music produced and the movements of their heads, left arms, and right arms. The backing tracks varied in rhythmic and harmonic information, from a chord progression to a continuous drone. Differences in movement coordination and playing behavior were evaluated using the mathematical tools of complex dynamical systems, with the aim of uncovering the multiscale dynamics that characterize musical collaboration. Collectively, the findings indicated that each backing track afforded the emergence of different patterns of coordination with respect to how the musicians played together, how they moved together, as well as their experience collaborating with each other. Additionally, listeners' experiences of the music when rating audio recordings of the improvised performances were related to the way the musicians coordinated both their playing behavior and their bodily movements. Accordingly, the study revealed how complex dynamical systems methods (namely recurrence analysis) can capture the turn-taking dynamics that characterized both the social exchange of the music improvisation and the sounds of collaboration more generally. The study also demonstrated how musical improvisation provides a way of understanding how social interaction emerges from the structure of the behavioral task context. PMID- 29152906 TI - Short-term outcomes following implementation of a dedicated young adult congenital heart disease transition program. AB - OBJECTIVE: Transition from pediatric to adult care is a critical time for patients with congenital heart disease. Lapses in care can lead to poor outcomes, including increased mortality. Formal transition clinics have been implemented to improve success of transferring care from pediatric to adult providers; however, data regarding outcomes remain limited. We sought to evaluate outcomes of transfer within a dedicated transition clinic for young adult patients with congenital heart disease. DESIGN, SETTING, AND PATIENTS: We performed a retrospective analysis of all 73 patients seen in a dedicated young adult congenital heart disease transition clinic from January 2012 to December 2015 within a single academic institution that delivered pediatric and adult care at separate children's and adult hospitals, respectively. INTERVENTION AND OUTCOME MEASURES: Demographic characteristics including congenital heart disease severity, gender, age, presence of comorbidities, presence of cardiac implantable electronic devices, and type of insurance were correlated to success of transfer. Rate of successful transfer was evaluated, and multivariate analysis was performed to determine which demographic variables were favorably associated with transfer. RESULTS: Thirty-nine percent of patients successfully transferred from pediatric to adult services during the study period. Severe congenital heart disease (OR 4.44, 95% CI 1.25-15.79, P = .02) and presence of a cardiac implantable electronic device (OR 4.93, 95% CI 1.18-20.58, P = .03) correlated with transfer. Trends favoring successful transfer with presence of comorbidities and private insurance were also noted. CONCLUSIONS: Despite a dedicated transition clinic, successful transfer rates remained relatively low though comparable to previously published rates. Severity of disease and presence of implantable devices correlated with successful transfer. Other obstacles to transfer remain and require combined efforts from pediatric and adult care systems, insurance carriers, and policy makers to improve transfer outcomes. PMID- 29152907 TI - Hierarchical Multicomponent Inorganic Metamaterials: Intrinsically Driven Self Assembly at the Nanoscale. AB - Increasingly intricate in their composition and structural organization, hierarchical multicomponent metamaterials with nonlinear spatially reconfigurable functionalities challenge the intrinsic constraints of natural materials, revealing tremendous potential for the advancement of biochemistry, nanophotonics, and medicine. Recent breakthroughs in high-resolution nanofabrication utilizing ultranarrow, precisely controlled ion or laser beams have enabled assembly of architectures of unprecedented structural and functional complexity, yet costly, time- and energy-consuming high-resolution sequential techniques do not operate effectively at industry-required scale. Inspired by the fictional Baron Munchausen's fruitless attempt to pull himself up, it is demonstrated that metamaterials can undergo intrinsically driven self-assembly, metaphorically pulling themselves up into existence. These internal drivers hold a key to unlocking the potential of metamaterials and mapping a new direction for the large-area, cost-efficient self-organized fabrication of practical devices. A systematic exploration of these efforts is presently missing, and the driving forces governing the intrinsically driven self-assembly are yet to be fully understood. Here, recent progress in the self-organized formation and self propelled growth of complex hierarchical multicomponent metamaterials is reviewed, with emphasis on key principles, salient features, and potential limitations of this family of approaches. Special stress is placed on self assembly driven by plasma, current in liquid, ultrasonic, and similar highly energetic effects, which enable self-directed formation of metamaterials with unique properties and structures. PMID- 29152908 TI - The genetics of Kawasaki disease. AB - Kawasaki disease (KD) is a complex disorder which affects genetically susceptible infants and children. Several susceptibility genes (e.g., ITPKC, CASP3, CD40 and ORAI) and chromosomal regions have been identified through genome-wide association and genome-wide linkage studies to have association with KD. Knowledge of susceptibility genes involved in the pathogenesis of KD may provide new insights into diagnosis and treatment of this condition. However, there is much that we still do not know about the genetic basis of KD. PMID- 29152905 TI - The GAIT translational control system. AB - The interferon (IFN)-gamma-activated inhibitor of translation (GAIT) system directs transcript-selective translational control of functionally related genes. In myeloid cells, IFN-gamma induces formation of a multiprotein GAIT complex that binds structural GAIT elements in the 3'-untranslated regions (UTRs) of multiple inflammation-related mRNAs, including ceruloplasmin and VEGF-A, and represses their translation. The human GAIT complex is a heterotetramer containing glutamyl prolyl tRNA synthetase (EPRS), NS1-associated protein 1 (NSAP1), ribosomal protein L13a (L13a), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). A network of IFN-gamma-stimulated kinases regulates recruitment and assembly of GAIT complex constituents. Activation of cyclin-dependent kinase 5 (Cdk5), mammalian target of rapamycin complex 1 (mTORC1), and S6K1 kinases induces EPRS release from its parental multiaminoacyl tRNA synthetase complex to join NSAP1 in a 'pre-GAIT' complex. Subsequently, the DAPK-ZIPK kinase axis phosphorylates L13a, inducing release from the 60S ribosomal subunit and binding to GAPDH. The subcomplexes join to form the functional GAIT complex. Each constituent has a distinct role in the GAIT system. EPRS binds the GAIT element in target mRNAs, NSAP1 negatively regulates mRNA binding, L13a binds eIF4G to block ribosome recruitment, and GAPDH shields L13a from proteasomal degradation. The GAIT system is susceptible to genetic and condition-specific regulation. An N-terminus EPRS truncate is a dominant-negative inhibitor ensuring a 'translational trickle' of target transcripts. Also, hypoxia and oxidatively modified lipoproteins regulate GAIT activity. Mouse models exhibiting absent or genetically modified GAIT complex constituents are beginning to elucidate the physiological role of the GAIT system, particularly in the resolution of chronic inflammation. Finally, GAIT-like systems in proto-chordates suggests an evolutionarily conserved role of the pathway in innate immunity. WIREs RNA 2018, 9:e1441. doi: 10.1002/wrna.1441 This article is categorized under: Translation > Translation Regulation RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes Regulatory RNAs/RNAi/Riboswitches > Riboswitches. PMID- 29152909 TI - History of the worldwide emergence of Kawasaki disease. AB - Dr. Kawasaki saw his first case of the disease that would come to bear his name in 1961. His meticulous description of the clinical syndrome persists as the case definition to the present day. This review chronicles the emergence and recognition of Kawasaki disease in Asia and Western countries and articulates the old disease/new disease controversy. PMID- 29152910 TI - Treating amblyopia in adults with prosthetic occluding contact lenses. AB - PURPOSE: To investigate the feasibility, effectiveness and acceptability of using prosthetic occluding contact lenses (OCLs) to treat moderate amblyopia in adults and of the role of the multifocal visual evoked potential (mfVEP) as a predictor of postamblyopic therapy. METHODS: A comparative, prospective, interventional, case series pilot study with amblyopic adults (mean age: 40 years, range 20-50 years) allocated into two intervention groups: eye patching and OCL. The primary outcome variable was logarithm of the minimum angle of resolution (logMAR) best corrected visual acuity (BCVA), and secondary outcomes were mfVEP amplitude and latency and patients' health-related quality of life National Eye Institute Visual Function Questionnaire (NEI VFQ-25). RESULTS: Significant improvements in pre- to postamblyopic therapy BCVA were seen at 1.5 months in the OCL group [0.29 logMAR, 95% confidence interval (CI): 0.10-0.47 versus 0.11 logMAR, 95% CI: 0.02 0.19; p < 0.001] and eye patching group (0.29 logMAR, 95% CI: 0.17-0.40 versus 0.18 logMAR, 95% CI: 0.12-0.23; p < 0.01). Post-treatment BCVA was inversely related to age (R: 0.009, 95% CI: -0.02 to -0.001; p = 0.04) and the presence of strabismus (R: -0.3, 95% CI: -0.434 to -0.17; p = 0.001). No significant changes in the number and size of the abnormal mfVEP amplitude and latency defects were observed after occlusion. The NEI VFQ-25 composite score showed significant improvement in the OCL users at 12 months compared to eye patching. CONCLUSION: Significant vision improvement can be achieved, making occlusion with OCLs an effective and more acceptable therapy for adults with amblyopia. PMID- 29152911 TI - Optimizing performance of semi-continuous cell culture in an ambr15TM microbioreactor using dynamic flux balance modeling. AB - The ambr bioreactors are single-use microbioreactors for cell line development and process optimization. With operating conditions for large-scale biopharmaceutical production properly scaled down, microbioreactors such as the ambr15TM can potentially be used to predict the effect of process changes such as modified media or different cell lines. While there have been some recent studies evaluating the ambr15TM technology as a scale-down model for fed-batch operations, little has been reported for semi-continuous or continuous operation. Gassing rates and dilution rates in the ambr15TM were varied in this study to attempt to replicate performance of a perfusion process at the 5 L scale. At both scales, changes to metabolite production and consumption, and cell growth rate and therapeutic protein production were measured. Conditions were identified in the ambr15TM bioreactor that produced metabolic shifts and specific metabolic and protein production rates that are characteristic of the corresponding 5 L perfusion process. A dynamic flux balance (DFB) model was employed to understand and predict the metabolic changes observed. The DFB model predicted trends observed experimentally, including lower specific glucose consumption and a switch from lactate production to consumption when dissolved CO2 was maintained at higher levels in the broth. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:420-431, 2018. PMID- 29152912 TI - Physiological and anatomical dead space in mechanically ventilated newborn infants. AB - OBJECTIVES: To compare the anatomical (VD-Ana ) and alveolar dead space (VD-Alv ) in term and prematurely born infants and identify the clinical determinants of those indices. WORKING HYPOTHESIS: VD-Ana and VD-Alv will be higher in prematurely born compared to term born infants. STUDY DESIGN: Retrospective analysis of data collected at King's College Hospital NHS Foundation Trust, London, UK. PATIENT SELECTION: Fifty-six infants (11 term, 45 preterm) were studied at a median age of 8 (IQR 2-33) days. METHODOLOGY: VD-Ana was determined using Fowler's method of volumetric capnography. VD-Alv was determined by subtracting VD-Ana from the physiological dead space which was determined by the Bohr-Enghoff equation. VD-Ana and VD-Alv were related to body weight at the time of study. RESULTS: The median VD-Ana /kg was higher in prematurely born infants [3.7 (IQR: 3.0-4.5) mL/kg] compared to term infants [2.4 (IQR: 1.9-2.9) mL/kg, adjusted P = 0.001]. The median VD-Alv /kg was not higher in prematurely born infants [0.3 (IQR: 0.1-0.5)] compared to term infants [0.1 (IQR: 0.0-0.2) mL/kg] after adjusting for differences in respiratory rate and days of ventilation (P = 0.482). VD-Ana /kg was related to postmenstrual age (r = -0.388, P < 0.001), birth weight (r = -0.397, P < 0.001), and weight at measurement (r = -0.476, P < 0.001). VD-Alv /kg was related to postmenstrual age (r = -0.254, P < 0.001), birth weight (r = -0.291, P = 0.002), and weight at measurement (r = -0.281, P = 0.003) and related to days of ventilation (r = 0.194, P = 0.044). CONCLUSIONS: VD Ana /kg and VD-Alv /kg increased with decreasing weight and gestation. VD-Alv was higher in infants that have undergone prolonged mechanical ventilation. PMID- 29152913 TI - The Relationship of Socioeconomic Status with Body Mass Index Depends on the Socioeconomic Measure Used. AB - OBJECTIVE: The association between socioeconomic status (SES) and body mass index (BMI) in middle-income countries is mixed. Heterogeneity in SES indicators used could explain some differences. This study aimed to identify SES indicators consistently associated with BMI in Mexican adults in 2006, 2012, and 2016. METHODS: Data were obtained from the Mexican National Health and Nutrition Surveys of 2006, 2012, and 2016, including adults 20 to 59 years old. Given expected differences by sex, sex-stratified linear regression models were fitted for each survey. Age-adjusted and multivariate models were fit by using seven noncollinear SES indicators. RESULTS: In age-adjusted models, most SES indicators were associated with a higher BMI in men; mixed associations were found for women. In multivariate models, living in urban areas was associated with a higher BMI for both men and women in 2006 and 2012. Across all surveys, education was associated with a lower BMI in women, while household assets were associated with a higher BMI in men. CONCLUSIONS: The association between SES indicators and BMI is complex. Differences by sex need to be explicitly recognized when modeling this association. Approaches that rely on a single indicator could be confounded by other SES indicators. Adjusted models show the specific SES attributes that may influence BMI. PMID- 29152914 TI - Self-Assembled 3D Helical Hollow Superstructures with Enhanced Microwave Absorption Properties. AB - Helical structures at different scales endow functional materials with special optical, electrical, and magnetic properties. However, methods for constructing and regulating single-handed helicity, particularly complex 3D hierarchical structures, remain limited. In this study, co-self-assembly process combined with emulsion droplets is used to produce the various well-defined 3D hollow superstructures of conducting polyaniline (PANI) with single-handed helicity. The chirality of PANI is induced using enantiomeric r- or s-camphorsulfonic acid as a dopant; the chirality of the dopant is then transferred to the supramolecular chirality of PANI assemblies and consequently to the helicity of 3D superstructures by incorporating emulsion droplets to serve collectively as soft templates. The twisting and anisotropism of these superstructures vary with the enhancement of the supramolecular chirality and result in the transformation of their morphologies from seashell-like to spindle-like and their cavity becoming more slender than their original shape. Due to the supramolecular chirality and hierarchical characteristics of these superstructures, enhanced microwave absorption performance is observed under a filler content of as low as 20 wt%, suggesting their promising application as microwave absorbers. PMID- 29152915 TI - Standing out from the crowd: Spotting your targets in a mixed plankton sample. AB - The diversity of marine organisms is staggering, and this fact is readily appreciated by microscopic examination of the contents of a plankton net after a short tow across the ocean surface. Although this diversity is beautiful, it can present a significant problem for those seeking to extract information about a single species of interest. Enumeration of the eggs and larvae of a specific target species can provide a quantitative window into reproductive dynamics that are of great use for fisheries stock assessment and management. But how do you efficiently sort through the mass of plankton and identify target species' eggs and larvae that may be morphologically indistinguishable from those of a number of other local species? In this issue of Molecular Ecology Resources, Oxley et al. () describe an innovative in situ hybridization (ISH) approach that successfully solves this important problem and opens an exciting new avenue to ichthyoplankton analysis that may be widely adopted by both fish ecologists and fisheries managers. PMID- 29152916 TI - Serum and urine metabolomics study reveals a distinct diagnostic model for cancer cachexia. AB - BACKGROUND: Cachexia is a multifactorial metabolic syndrome with high morbidity and mortality in patients with advanced cancer. The diagnosis of cancer cachexia depends on objective measures of clinical symptoms and a history of weight loss, which lag behind disease progression and have limited utility for the early diagnosis of cancer cachexia. In this study, we performed a nuclear magnetic resonance-based metabolomics analysis to reveal the metabolic profile of cancer cachexia and establish a diagnostic model. METHODS: Eighty-four cancer cachexia patients, 33 pre-cachectic patients, 105 weight-stable cancer patients, and 74 healthy controls were included in the training and validation sets. Comparative analysis was used to elucidate the distinct metabolites of cancer cachexia, while metabolic pathway analysis was employed to elucidate reprogramming pathways. Random forest, logistic regression, and receiver operating characteristic analyses were used to select and validate the biomarker metabolites and establish a diagnostic model. RESULTS: Forty-six cancer cachexia patients, 22 pre-cachectic patients, 68 weight-stable cancer patients, and 48 healthy controls were included in the training set, and 38 cancer cachexia patients, 11 pre-cachectic patients, 37 weight-stable cancer patients, and 26 healthy controls were included in the validation set. All four groups were age-matched and sex-matched in the training set. Metabolomics analysis showed a clear separation of the four groups. Overall, 45 metabolites and 18 metabolic pathways were associated with cancer cachexia. Using random forest analysis, 15 of these metabolites were identified as highly discriminating between disease states. Logistic regression and receiver operating characteristic analyses were used to create a distinct diagnostic model with an area under the curve of 0.991 based on three metabolites. The diagnostic equation was Logit(P) = -400.53 - 481.88 * log(Carnosine) -239.02 * log(Leucine) + 383.92 * log(Phenyl acetate), and the result showed 94.64% accuracy in the validation set. CONCLUSIONS: This metabolomics study revealed a distinct metabolic profile of cancer cachexia and established and validated a diagnostic model. This research provided a feasible diagnostic tool for identifying at-risk populations through the detection of serum metabolites. PMID- 29152917 TI - The distribution of the DRB4*01:03:01:02N null allele in HLA-DRB1~DQB1 haplotypes in the Croatian population. AB - The aim of the present study was to investigate frequency and haplotype distribution of DRB4 alleles in the Croatian population. The investigated sample consisted of 288 cadaveric donor samples positive for one of the DR53 alleles. HLA-A, -B, -C, -DRB1, and -DQB1 typing was performed using the polymerase chain reaction-sequence specific primers (PCR-SSP) low resolution method, while HLA DRB4 and selected HLA class II specificities typing was performed using PCR-SSP at the allelic level. Three different DRB4 alleles were observed among DRB1*04 samples; DRB4*01:02 (2.38%), DRB4*01:03 (91.27%), and DRB4*01:03:01:02N (6.35%). The DRB4*01:03:01:02N allele was predominantly observed among DRB1*04:02-positive samples, while DRB4*01:02 and DRB4*01:03 alleles did not associate preferably with any of the DRB1*04 subtypes. Among DRB1*04~DRB4~DQB1 haplotypes, the predominant DQB1 allele was DQB1*03:02 (69.94%). Seven different DRB4 alleles were found among DRB1*07:01-positive samples. The analysis of DRB1*07~DRB4~DQB1 haplotypes showed that DRB4*01:03 was found in the majority of HLA DRB1*07:01~DQB1*02:02 (49.09%) haplotypes while DRB1*07:01~DQB1*03:03 haplotypes carried the DRB4*01:03:01:02N allele almost exclusively (98.21%). Among six DRB1*09:01-positive samples, HLA-DRB1*09:01~DRB4*01:03~DQB1*03:03 was the only detected haplotype. The extended haplotype analysis showed a high frequency of HLA-B*15(B62)~C*03(Cw9)~DRB1*04:02~DRB4*01:03:01:02N~DQB1*03:02 and HLA B*57~C*06~DRB1*07:01~DRB4*01:03:01:02N~DQB1*03:03 haplotypes. In conclusion, the data presented in this study should prompt other population studies focused on DRB3/4/5 genes and be used as a basis for future investigations of the clinical relevance of these genes in transplantation setting. PMID- 29152918 TI - Cosmeceutical effect of ethyl acetate fraction of Kombucha tea by intradermal administration in the skin of aged mice. AB - BACKGROUND/PURPOSE: Natural ingredients have been always an interesting approach to prolong youthful appearance of skin. One of the natural compounds is Kombucha tea (KT), which has been mainly used as an energy drink in Asian countries for a long time. Previous reports indicated that it has pharmaceutical and favorable wound repairing effects. The beneficial properties of KT are thought to be mainly due to the presence of fermentation products such as flavonoids and other polyphenols with inhibition of hydrolytic and oxidative enzymes and anti inflammatory effects. These properties prompted us to study the anti-aging potential of KT and investigate its effective fraction in aged mice, METHODS: Kombucha tea was fractionated into chloroform, butanol, and ethyl acetate, and flavonoid content was determined. Young and old mice were used as control. KT ethyl acetate fraction (KEAf), which had the highest flavonoid content, was intradermally administered to old mice. RESULTS: Administration of KEAf significantly increased the collagen content, NAD+ /NADH level, and concomitantly improved skin connective tissue abnormalities in the aged skin. No sensitivity or irritation was observed. CONCLUSION: This finding suggested that KEAf can be a suitable candidate as a cosmetic product to improve aging-related skin abnormalities and regeneration of aged skin. PMID- 29152919 TI - Characterisation of the novel HLA-G null allele, HLA-G*01:21N, in Finnish individuals. AB - We identified the novel HLA-G*01:21N null allele in Finnish Caucasian individuals. PMID- 29152920 TI - Using State Birth Defects Registries to Evaluate Regional Critical Congenital Heart Disease Newborn Screening. AB - BACKGROUND: Most states have now passed legislation mandating pulse oximetry for all newborns, or have promulgated regulations or guidelines to encourage use of routine pulse oximetry. State-based birth defects registries may be well positioned to track and evaluate critical congenital heart disease (CCHD) screening coverage and outcomes. This purpose of this study was to determine: (1) the proportion of cases detected by screening, (2) health services use by children with CCHDs during the first year of life, and (3) mortality outcomes. METHODS: Records of children born in 2012 to 2013 with any of seven CCHD lesions were identified in New England birth defects databases. Information was abstracted from each child's medical record. Descriptive statistics were used to report results. RESULTS: From nearly 160,000 live births, 208 CCHD diagnoses were noted in the records of 157 children. Screening was noted in 67% of records of confirmed cases of CCHDs. Data completeness varied by state; for example, information was available regarding prenatal diagnosis in 91% of records and age at first surgery in 85% among states with active surveillance compared with 35% and 75%, respectively, with passive surveillance. Documentation of screening results in medical records was inconsistent. The one year survival was 85% (77/91). CONCLUSION: Birth defects surveillance systems can provide information on outcomes for infants with CCHDs. However, information varies by surveillance method and by hospital practices. Engaging hospitals in standardizing recording procedures and enhancing training and quality control could increase the value of birth defects registries records in assessing outcomes for children identified through CCHD screening. Birth Defects Research 109:1414-1422, 2017.(c) 2017 Wiley Periodicals, Inc. PMID- 29152922 TI - Population-based birth defects surveillance: Challenges, opportunities, and recent developments. PMID- 29152921 TI - Proximity to Pediatric Cardiac Surgical Care among Adolescents with Congenital Heart Defects in 11 New York Counties. AB - BACKGROUND: Many individuals with congenital heart defects (CHDs) discontinue cardiac care in adolescence, putting them at risk of adverse health outcomes. Because geographic barriers may contribute to cessation of care, we sought to characterize geographic access to comprehensive cardiac care among adolescents with CHDs. METHODS: Using a population-based, 11-county surveillance system of CHDs in New York, we characterized proximity to the nearest pediatric cardiac surgical care center among adolescents aged 11 to 19 years with CHDs. Residential addresses were extracted from surveillance records documenting 2008 to 2010 healthcare encounters. Addresses were geocoded using ArcGIS and the New York State Street and Address Maintenance Program, a statewide address point database. One-way drive and public transit time from residence to nearest center were calculated using R packages gmapsdistance and rgeos with the Google Maps Distance Matrix application programming interface. A marginal model was constructed to identify predictors associated with one-way travel time. RESULTS: We identified 2522 adolescents with 3058 corresponding residential addresses and 12 pediatric cardiac surgical care centers. The median drive time from residence to nearest center was 18.3 min, and drive time was 30 min or less for 2475 (80.9%) addresses. Predicted drive time was longest for rural western addresses in high poverty census tracts (68.7 min). Public transit was available for most residences in urban areas but for few in rural areas. CONCLUSION: We identified areas with geographic barriers to surgical care. Future research is needed to determine how these barriers influence continuity of care among adolescents with CHDs. Birth Defects Research 109:1494-1503, 2017.(c) 2017 Wiley Periodicals, Inc. PMID- 29152923 TI - Editorial In Bed with The Devil: Recognizing Human Teratogenic Exposures. PMID- 29152925 TI - Detection of a novel HLA-DRB1*12 variant, HLA-DRB1*12:68, in a Taiwanese individual. AB - One nucleotide substitution at residue 628 of HLA-DRB1*12:01:01:01 results in a novel allele, HLA-DRB1*12:68. PMID- 29152924 TI - Population-based birth defects data in the United States, 2010-2014: A focus on gastrointestinal defects. AB - BACKGROUND: Gastrointestinal defects are a phenotypically and etiologically diverse group of malformations. Despite their combined prevalence and clinical impact, little is known about the epidemiology of these birth defects. Therefore, the objective of the 2017 National Birth Defects Prevention Network (NBDPN) data brief was to better describe the occurrence of gastrointestinal defects. METHODS: As part of the 2017 NBDPN annual report, 28 state programs provided additional data on gastrointestinal defects for the period 2010-2014. Counts and prevalence estimates (per 10,000 live births) were calculated overall and by demographic characteristics for (1) biliary atresia; (2) esophageal atresia/tracheoesophageal fistula; (3) rectal and large intestinal atresia/stenosis; and (4) small intestinal atresia/stenosis. Additionally, we explored the frequency of these malformations co-occurring with other structural birth defects. RESULTS: Pooling data from all participating registries, the prevalence estimates were: 0.7 per 10,000 live births for biliary atresia (713 cases); 2.3 per 10,000 live births for esophageal atresia/tracheoesophageal fistula (2,472 cases); 4.2 per 10,000 live births for rectal and large intestinal atresia/stenosis (4,334 cases); and 3.4 per 10,000 live births for small intestinal atresia/stenosis (3,388 cases). Findings related to co-occurring birth defects were especially notable for esophageal atresia/tracheoesophageal fistula, rectal and large intestinal atresia/stenosis, and small intestinal atresia/stenosis, where the median percentage of non-isolated cases was 53.9%, 45.5%, and 50.6%, respectively. CONCLUSIONS: These population-based prevalence estimates confirm some previous studies, and provide a foundation for future epidemiologic studies of gastrointestinal defects. Exploring the genetic and environmental determinants of these malformations may yield new clues into their etiologies. PMID- 29152926 TI - Nomenclature for factors of the HLA system, update July 2017. PMID- 29152927 TI - Nomenclature for factors of the HLA system, update September 2017. PMID- 29152928 TI - Nomenclature for factors of the HLA system, update August 2017. PMID- 29152929 TI - The role of echocardiography in Kawasaki disease. AB - Kawasaki disease (KD) is an acute, self-limited vasculitis affecting young children. It can result in coronary artery abnormalities in a significant proportion of patients, especially if the diagnosis is missed or treatment gets delayed. Echocardiography is the imaging modality of choice for detection of coronary artery abnormalities and assessment of myocardial function. It is also useful for characterization and risk stratification of patients with KD. Echocardiography should be performed at the time of diagnosis and then again at 1 2 weeks and 4-6 weeks after treatment, for uncomplicated cases who do not have significant coronary artery involvement. Use of a standardized imaging protocol is necessary to detect and characterize coronary artery abnormalities, including standardization of measurements (Z scores). For patients with evolving abnormalities, more frequent assessment is necessary in order to detect thromboses in aneurysms. Long-term prognosis and management is dependent on both the maximal and current Z scores of aneurysms. Patients with large or giant aneurysms (i.e., Z score >= 10) are at the highest risk of both thrombosis and stenosis. Such patients need careful follow-up for subsequent cardiovascular events. Many of them would be candidates for advanced cardiovascular imaging and may require revascularization therapy. Serial echocardiography plays a key role in surveillance. In addition, stress echocardiography has proven useful as a modality to assess for inducible myocardial ischemia. Intravascular ultrasound has been recommended for functional and structural assessment of coronary arteries in children with KD. PMID- 29152930 TI - The search for perfect supraglottic airway device: but I still haven't found what I am looking for. PMID- 29152931 TI - Can red blood cell distribution width predict outcome after cardiac arrest? AB - BACKGROUND: In critically ill patients, high red blood cell distribution width (RDW) values have been associated with increased hospital mortality, but there are no data on the impact of RDW on outcomes of patients resuscitated from cardiac arrest (CA). The aim of this study was to investigate the relationship between RDW and long-term neurologic outcome in CA survivors. METHODS: We performed a retrospective analysis of an institutional database including all unconscious adult patients admitted to the intensive care unit (ICU) after non traumatic CA between January 2007 and January 2015. Patients who survived <24 hours were excluded. The RDW (normal values 10.9-13.4%) was obtained daily from the day of admission to day 3. Patients with a cerebral performance category (CPC) score of 3-5 at 3 months were considered to have an unfavourable neurological outcome. RESULTS: Three hundred and ninety patients were included. The ICU mortality rate was 56% (N.=220) and 64% of patients (N.=251) had an unfavorable 3-month neurological outcome. The median RDW on the day of admission was 14% (13.0-15.2%) and remained stable over the observation period. Two hundred and forty-five patients (63%) had a high RDW (>13.4%) on admission. In multivariable logistic regression analysis, older age, absence of bystander cardiopulmonary resuscitation (CPR), a non-cardiac etiology of the arrest, a non shockable initial rhythm, high adrenaline dose during CPR and high admission RDW levels were independently associated with an unfavorable outcome at 3 months. CONCLUSIONS: High RDW values are associated with poor neurological outcome among CA survivors. PMID- 29152932 TI - Screening with oro-rectal surveillance swab in an Italian ICU: epidemiological and medico-legal aspects. PMID- 29152933 TI - Ventilator-induced lung injury: does it occur in children? AB - Mechanical ventilation is one of the most practiced interventions in the pediatric intensive care unit (PICU). Although unmistakable life-saving, it can also injury the lung, a process coined ventilator induced lung injury (VILI). To date, almost all of our knowledge VILI has been obtained from studies in adults or experimental studies mimicking the adult critical care situation. This leaves the question if VILI is of importance in the pediatric context. Pediatric clinical studies did not confirm an association between large tidal volume (Vt) and adverse outcome. In fact, the opposite has been shown. These same studies did show an association between high pressures and adverse outcome. Experimental data showed that the use of large, supraphysiologic Vt resulted in less inflammation and injury in pediatric animal models compared to adult models, suggesting an age related susceptibility to VILI. However, the question whether or not there is an age-related susceptibility to VILI remains puzzling and unanswered. It is remarkable that one of the most practiced interventions such as pediatric MV is hardly supported by any scientific evidence but rather based on personal experience and data from adults. This signifies the need for clinical and experimental studies in order to better understand the use and effects of MV in pediatric patients with or without lung injury. PMID- 29152934 TI - A prospective, randomized trial of the Ambu AuraGainTM laryngeal mask versus the LMA(r) protector airway in paralyzed, anesthetized adult men. AB - BACKGROUND: We hypothesize that oropharyngeal leak pressures differ between the LMA(r) ProtectorTM and the AuraGainTM, two novel supraglottic airway devices offering the possibility of intubation. METHODS: Ninety-eight male patients ASAI II were randomly assigned to the AuraGainTM or ProtectorTM group. Oropharyngeal leak pressure was measured by incrementing cuff volume in 10 mL steps from 10 mL to 40 mL. The primary outcome was oropharyngeal leak pressure at 40 mL cuff volume. Secondary parameters such as transdevice intubation success, intubation time, the number of intubation attempts, and resistance during advancement of the endotracheal tube were determined. RESULTS: Mean (SD) oropharyngeal leak pressures at cuff volume of 40 mL was 30.1 (6) cmH2O for the AuraGainTM and 28.2 (7) cmH2O for the LMA ProtectorTM (P=0.142). The mean intracuff pressure for the AuraGainTM was 154 (41) cmH2O and 200 (43) cmH2O for the LMA Protector (P<=0.001). The number of attempts to insert the laryngeal mask was higher for the AuraGainTM group (P=0.002). Intubation time was lower in the AuraGainTM group (15.7 s vs. 18.5 s [ProtectorTM group]; P=0.004), and less resistance in advancing the tracheal tube through the AuraGainTM compared to LMA ProtectorTM device (P<0.001). There were no differences in fiberoptic placement of the endotracheal tube, the number of intubation attempts or postoperative morbidity between the groups. CONCLUSIONS: Because of the higher success rate in first time insertion of the laryngeal mask and the gastric tube, respectively, as well as the lower resistance to insertion of the endotracheal tube we conclude a possible easier handling of the AuraGainTM in anesthetized male patients. PMID- 29152935 TI - Heterogenic control groups in randomized, controlled, analgesic trials of total hip and knee arthroplasty. AB - INTRODUCTION: Postoperative analgesic interventions are often tested adjunct to basic non-opioid analgesics in randomized controlled trials (RCTs). Consequently, treatment in control groups, and possible assay sensitivity, differs between trials. We hypothesized that postoperative opioid requirements and pain intensities vary between different control groups in analgesic trials. EVIDENCE ACQUISITION: Control groups from RCTs investigating analgesic interventions after total hip and knee arthroplasty were categorized based on standardized basic analgesic treatment. Morphine consumption 0 to 24 hours postoperatively, and resting pain scores at 6 and 24 hours for subgroups of basic treatments, were compared with ANOVA. In an additional analysis, we compared pain and opioid requirements in trials where a non-steroidal anti-inflammatory drug (NSAID) was administered as an intervention with trial where NSAID was administered in a control group. EVIDENCE SYNTHESIS: We included 171 RCTs employing 28 different control groups with large variability in pain scores and opioid requirements. Four types of control groups (comprising 78 trials) were eligible for subgroup comparisons. These subgroups received "opioid" alone, "NSAID + opioid", "acetaminophen + opioid", or "NSAID + acetaminophen + opioid", respectively. Morphine consumption and pain scores varied substantially between these groups, with no consistent superior efficacy in any subgroup. Additionally, trials administering NSAID as an intervention demonstrated lower pain scores and opioid requirements than trials where NSAID was administered in a control group. CONCLUSIONS: Analgesic treatment in RCT control groups varies considerably. Control groups receiving various combinations of opioid, NSAID and acetaminophen did not differ consistently in pain and opioid requirements. Pain and opioid requirements were lower in trials administering NSAID as an intervention compared with trials administering NSAID in a control group. PMID- 29152936 TI - Gastric ultrasound to guide anesthetic management in elective surgical patients non-compliant with fasting instructions: a retrospective cohort study. AB - BACKGROUND: Perioperative aspiration leads to significant morbidity and mortality. Standard fasting periods are used to ensure an empty stomach in patients. Anesthesiologists are frequently confronted with cases of dubious adherence to these guidelines. Point-of-care gastric ultrasound is a diagnostic tool that offers information on the type and volume of gastric contents. METHODS: We performed a retrospective analysis of a departmental database containing clinical and sonographic information on elective surgical patients who had been non-compliant to the fasting guidelines. Primary outcome was the incidence of changes in aspiration risk stratification and anesthetic management when a point of-care gastric ultrasound examination was added to a standard history-based clinical assessment. Secondary outcomes included type of changes (timing of the surgical procedure or change in anesthetic technique) and the incidence of aspiration. Differences in the management plan (history-based versus gastric ultrasound) were tested with McNemar-Bowker's Exact Test of symmetry. RESULTS: Thirty-seven patients met the inclusion criteria. Aspiration risk assessment and anesthetic management changed in 24 cases (64.9%) following gastric ultrasound. Additionally, there was a non-significant difference in the distribution of the pre- and post-test changes in timing (delay, cancel, proceed) (P=0.074) with a trend towards a lower number of surgical cancellations and a higher number of proceeds. No aspirations were documented. CONCLUSIONS: This retrospective study suggests that gastric ultrasound may be a useful diagnostic addition to standard patient assessment in cases of non-compliance to fasting guidelines. It allows to personalize aspiration risk assessment and to tailor anesthetic management to the individual patient. PMID- 29152937 TI - Thyroid surgery under bilateral superficial cervical block and hypnosis. PMID- 29152938 TI - A case of ultrasound-guided Serratus Plane block for postoperative analgesia in video-assisted thoracoscopic lobectomy in a patient with previous axillary dissection surgery. PMID- 29152939 TI - Right patient selection and management in veno-venous extracorporeal carbon dioxide removal. PMID- 29152940 TI - Light curing may not be as simple as it seems - again! PMID- 29152941 TI - The histopathological and stereological assessment of the effect of topically administered leptin on cerebral vasospasm in an experimental subarachnoid hemorrhage model AB - Background/aim: Cerebral vasospasm is a term that refers to prolonged, slowly progressing but reversible pathological narrowing of cerebral arteries occurring several days after subarachnoid hemorrhage (SAH), usually accompanied by a decrease in perfusion distal to the affected artery. Leptin is an endogenous polypeptide hormone that can be carried freely and bound to protein in the blood. Materials and methods: We investigated the superiority of topical application of leptin that may make a contribution to the development of new treatment modalities for unconscious patients in brain injury intensive care units and its preventive effect, which is considered to have multifactorial pathogenesis on cerebral vasospasm occurring after SAH via stereological studies of the basilar artery. Results: When mean serum leptin levels of the groups were compared, statistically significant differences were observed between the control and topical leptin-treated groups in favor of the treated groups with respect to serum leptin levels (P < 0.05). In the topical leptin-applied group, a significant difference in favor of vasodilatation was observed in the measurements of the basilar artery luminal area (P < 0.05). Conclusion: In accordance with the results, the topical administration of leptin can be used in the prevention of vasospasm, especially in unconscious patients with subarachnoid hemorrhage. PMID- 29152942 TI - Effects of positive end-expiratory pressure on intracranial pressure during pneumoperitoneum and Trendelenburg position in a porcine mode AB - Background/aim: This study was undertaken to evaluate the effects of positive end expiratory pressure (PEEP) levels on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) and to determine the appropriate PEEP level during steep Trendelenburg position combined with pneumoperitoneum.Materials and methods: Ten pigs were included in this study. Pneumoperitoneum and Trendelenburg position were maintained and PEEP titration was initiated. Arterial pressure, heart rate, arterial blood gas, ICP, and CPP were recorded at the following time points: baseline (T0), 30 min after positioning and pneumoperitoneum (T1), PEEP 5 (T2), PEEP 10 (T3), PEEP 15 (T4), and PEEP 20 (T5).Results: MAP significantly increased at T1 compared to T0 and decreased at T4 and T5 compared to T1. ICP was 9.5 mmHg and CPP was 69.3 mmHg at T0. CO2 insufflation and steep Trendelenburg position did not cause any significant difference in ICP and CPP. ICP increased and CPP decreased significantly at T4 and T5 compared to both T0 and T1. PaO2 and PaO2/FiO2 decreased significantly at T1 and T2 compared to T0, while both increased significantly at T3, T4, and T5 compared to T1.Conclusion: PEEP of 10 cmH2O was effective for providing oxygenation while preserving hemodynamic stability, ICP, and CPP in this model. PMID- 29152943 TI - Winnie-the-Pooh and the Royal College of Surgeons. PMID- 29152944 TI - Combined oral supplementation of chromium picolinate, docosahexaenoic acid, and boron enhances neuroprotection in rats fed a high-fat diet AB - Background/aim: A novel complex of a nutritional supplement (CDB) contains chromium picolinate (CrPic), phosphatidylserine (PS), docosahexaenoic acid (DHA), and boron (B). The present study aimed to investigate the effects of CDB on the metabolic profile and memory acquisition in rats fed a high-fat diet (HFD). Materials and methods: Male Wistar rats were divided into six groups and received either a regular diet or HFD supplemented with or without different levels of CDB (0, 11, or 22 mg/kg BW). Results: Rats fed the HFD had greater glucose, insulin, lipid profile, and serum malondialdehyde concentrations, but lower serotonin and tryptophan in the serum and brain and lower Cr concentrations in serum, kidney, brain, and liver (P < 0.0001). CDB complex supplementation reversed all the effects, and the reversal effect was more pronounced with HFD for some parameters. Latency was less (P < 0.05) but probe was greater (P < 0.0001) for rats fed a regular diet. Increasing CDB complex levels in the diets resulted in a linear decrease in latency (P < 0.0002) but a linear increase in probe (P < 0.0002). Conclusion: Findings of the present work indicate that the CDB complex could be considered as an alternative treatment for preventing certain metabolic diseases and improving neurological functions, such as learning and memory. PMID- 29152945 TI - DNA methylation of the prestin gene and outer hair cell electromotileresponse of the cochlea in salicylate administration AB - Background/aim: Activity of the prestin gene may have a role in the pathogenesis of salicylate-induced ototoxicity. We investigated DNA methylation for prestin gene exon 1 in salicylate-injected guinea pigs.Materials and methods: Fifteen guinea pigs (30 ears) underwent audiological evaluation including 1000 Hz probe tone tympanometry and a distortion product otoacoustic emission (DPOAE) test. The animals were randomly divided into three groups. Groups 2 (8 ears) and 3 (14 ears) were injected with intramuscular saline and sodium salicylate (200 mg/kg), respectively twice daily for 2 weeks. Group 1 (8 ears) received no injection. DPOAE measurements were performed at baseline; after 1, 2, 4, and 8 h (acute effect); and after 1 and 2 weeks (chronic effect). After audiological measurements, the animals were sacrificed for DNA isolation.Results: While a significant decrease (P < 0.01) was found for the acute effect in all frequencies in Group 3 according to baseline measurements, there was no difference in terms of chronic effect. DNA methylation increased during the acute phase of salicylate administration, whereas it returned to initial levels during the chronic phase.Conclusion: Salicylate-induced changes in DPOAE responses may be related to prestin-gene methylation. These results may have important implications for salicylate ototoxicity. PMID- 29152946 TI - The effects of mesenchymal stem cells on the structure and contractile force of the carotid artery in a rat aneurysm model AB - Background/aim: An aneurysm is a pathological enlargement of an artery characterized by the thinning of the elastic fiber layer in the tunica media. Because the aneuritic artery wall is weakened, these vessels can rupture and cause serious bleeding. Surgical methods are often used for the treatment of aneurysms. However, cell-based therapies are less invasive and potentially safer alternatives. In this study, the therapeutic efficacy of rat adipose tissue derived mesenchymal stem cells (MSCs) was investigated in a new carotid artery aneurysm model.Materials and methods: Arteries were pretreated with elastase to create aneurysms. Gelatin matrices containing MSCs were applied to the outer surface of the elastase-treated carotid artery sections.Results: Healing of the aneuritic arteries for which MSC applications were performed was significantly better than in the aneuritic group. The histological structure of the vessels was largely reconstituted, and the contractile force of the MSC-treated group was similar to the untreated healthy group.Conclusions: Application of MSCs facilitates the healing of aneurysms. Hereby, MSC application could be a promising approach for clinical applications after further validation processes are concluded. PMID- 29152947 TI - Dental Trauma Part 1- Acute Management of Luxation/Displacement Injuries. AB - Fortunately, traumatic dental injuries are a relatively uncommon occurrence in general dental practice. However, when they do present, timely diagnosis and treatment of such injuries is essential to maximize the chance of a successful outcome. This is the first part of a two-part series on traumatic dental injuries that are commonly encountered in the clinical setting. Part one will cover acute management of luxation/displacement injuries that primarily affect the supporting structures of the tooth, while part two will cover the management of fracture injuries associated with teeth and the alveolar bone. Clinical relevance: A simple, step-by-step approach in the diagnosis and clinical management of acute luxation/displacement injuries should be part of a dental clinician's knowledge. PMID- 29152948 TI - Exogenous erythropoietin aggravates retinal neovascularizationin a murine model of proliferative retinopathy AB - Background/aim: Erythropoietin (EPO) has been proven recently to be a critical mediator in retinal neovascularization (RNV). Previous studies have indicated that the use of recombinant human EPO (rEPO) is a high risk factor in the development of retinopathy of prematurity. In this study, we aimed to investigate the effect of rEPO administration on RNV and its underlying mechanism in a mouse model of oxygen-induced retinopathy (OIR). Materials and methods: A murine model of OIR was used to generate RNV. After daily intraperitoneal injection of rEPO from postnatal day 12 (P12), mice were euthanized at P17. Whole-mount retina staining was used to indicate the nonperfused area and neovascularization tufts. Preretinal neovascular cells were calculated through hematoxylin and eosin staining. The expression levels of vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) were detected via western blot analysis. Results: We found that injection of rEPO promoted the severity of RNV. The areas of neovascular tufts and preretinal neovascular cells were increased after administration of rEPO. When mice were injected with rEPO, a dose-dependent upregulation in VEGF and iNOS was observed. Conclusion: The study indicates the proangiogenic role of EPO, suggesting that rEPO contributes to the pathogenesis of RNV. PMID- 29152949 TI - Effects of valproic acid on sympathetic activity and left ventricularmyocardial remodelling in rats during pressure overload AB - Background/aim: Pressure overload induces cardiac remodelling and results in heart failure. Enhanced sympathetic outflow participates in the development of cardiac remodelling for the duration of pressure overload as an independent factor. Valproic acid has recently been shown to reduce neuronal injury and have antiinflammatory and antiapoptotic effects as a histone deacetylase inhibitor. We speculate that the drug plays a specific role in alleviating cardiac remodelling by inhibiting sympathetic activity. Materials and methods: Surgery of partial abdominal aortic constriction was performed on male Sprague-Dawley rats. After 4 weeks, animal models of pressure overload were validated and then valproic acid (300 mg/kg) was administrated to rats once a day for the next 4 weeks. Experimental parameters were detected 4 weeks after validation. Results: The administration of valproic acid alleviated cardiomyocyte hypertrophy, myocardial interstitial fibrosis and left ventricular diastolic dysfunction caused by partial abdominal aortic constriction. Valproic acid reduced the levels of plasma and local norepinephrine, augmented concentrations of hypothalamic gamma aminobutyric acid, and had no side effects on the hepatic and renal function of the animals. Conclusion: These results suggest that valproic acid may be a safe and effective therapeutic strategy for the inhibition of sympathetic outflow and cardiac remodelling. PMID- 29152950 TI - Investigation of class-d beta-lactamases causing carbapenem resistance in clinical Acinetobacter baumannii isolates AB - Background/aim: Acinetobacter baumannii is an important causative agent of nosocomial infections, and carbapenems have been frequently used in the treatment of these infections. This study was designed to investigate the prevalence of primary carbapenem hydrolyzing oxacillinase (CHO) types in clinical A. bumannii strains. Materials and methods: Minimum inhibitory concentration (MIC) values of 76 imipenem nonsusceptible A. baumannii strains, isolated from a tertiary care hospital, were determined by microdilution method. The clonal relationship of the isolates was analyzed with enterobacterial repetitive intergenic consensus (ERIC) PCR, and the presence of CHO major groups (OXA-23; OXA-24, OXA-51, and OXA-58 groups) was investigated with multiplex PCR. Results: According to the ERIC-PCR patterns, the isolates were distributed in 13 different clones, the largest of which had 40 members. blaOXA-51-group was detected in representatives of all clones, whereas blaOXA-23-group was detected in representatives of all but two small clones. Additionally, the presence of blaOXA-58-group was discovered in the members of two small clones, whereas blaOXA-24-group was not encountered in any of the examined strains. Conclusion: Molecular fingerprinting revealed that most imipenem-resistant A. baumannii strains were clonally related. blaOXA-23-group and blaOXA-51-group were mostly responsible for the imipenem resistance of the examined A. baumannii strains. PMID- 29152951 TI - Lipid emulsion and verapamil toxicity PMID- 29152952 TI - Lack of MIR143, MIR145, MIR184, MIR1224, and MIR29b1 mutations in keratoconus pathogenesis PMID- 29152953 TI - The Use of 3D Metal Printing (Direct Metal Laser Sintering) in Removable Prosthodontics. AB - The use of 3D printing is expanding and it is envisaged that it will have an increasing presence within dentistry. Having an appreciation and understanding of such technology is therefore paramount. It is currently used to produce a variety of dental objects/prostheses. This paper briefly looks at 3D printing in dentistry and specifically describes the use of the direct metal laser sintering 3D printing technique in the production of cobalt chromium removable prosthesis frameworks. Clinical relevance: Understanding the different technologies that can and are being used within the dental field is important, particularly as it is a rapidly changing field. Having an understanding of such technologies will allow practitioners to utilize such technologies appropriately in the management of their patients. PMID- 29152954 TI - Hypersensitivity to Dental Composites and Resin-Bonding Agents. AB - Adverse reactions to dental materials are not an uncommon occurrence, although hypersensitivity has gained much renewed interest in light of public concerns over the safety of dental materials. Hypersensitivity can affect both patients and dental professionals and may manifest as either allergic contact dermatitis or stomatitis. Methacrylic monomers, such as MMA, EGDMA, TEGDMA and Bis-GMA, have been documented as causative allergens, however, little has been documented on the risk of such monomers in composites and bonding agents. The purpose of this article is to examine the current evidence and aspects of hypersensitivity to resin composites and bonding systems that are relevant within a dental setting. Clinical relevance: In the dental profession, dental materials have historically been documented as a cause of hypersensitivity. However, there remains little recent evidence on such reactions. The aims of this article are to highlight both the risk of hypersensitivity to dental composites and resin-bonding agents and the importance of reporting adverse reactions appropriately. PMID- 29152955 TI - Primary Extranodal Non-Hodgkin Lymphoma in the Infra-Orbital Region - A Diagnostic Challenge. AB - Lymphomas within the head and neck region (HNR) are relatively uncommon; however, they can mimic common odontogenic conditions leading to diagnostic delays and subsequently the implementation of treatment. We report a case of a chronic infra orbital swelling which, following excision, was diagnosed as an extranodal low grade Non-Hodgkin lymphoma. This paper explains the mode of presentation of extranodal lymphomas in the HNR, so that dental practitioners may consider it as a potential diagnosis when presented with a lump in the HNR. Clinical relevance: Extranodal lymphomas presenting within the head and neck region can have a multitude of clinical presentations, which may often resemble odontogenic conditions. This can cause confusion, resulting in diagnostic delays and treatment. This case highlights the importance of being aware of the features of extranodal lymphoma in the head and neck region, and the diagnostic challenges that may be encountered. PMID- 29152956 TI - Blood Tests for People with Severe Learning Disabilities Receiving Dental Treatment under General Anaesthesia. AB - People with learning disabilities (LDs) have poorer health than their non disabled peers due to failures in reasonable adjustments. One hundred patients with severe LD and challenging behaviour attended for dental treatment under GA, during which routine blood testing was provided. Communication with general medical practitioners (GMPs) and blood test results were evaluated, showing poor communication with GMPs and significant undiagnosed disease among this group. Blood tests generate similar costs in primary and secondary care but a holistic approach to care under GA reduces expenses brought by lost clinical time and resources due to complex behaviours in an out-patient setting. Clinical relevance: This article discusses a holistic approach to healthcare for people with severe LD, including patient outcomes, financial and resource implications, and offers practical guidance on venepuncture technique, which is relevant to many aspects of both community and hospital dental practice. PMID- 29152957 TI - Vascular Lesions of the Head and Oral Cavity - Diagnosis and Management. AB - Vascular anomalies constitute a diffuse group of conditions which can range in their significance from being completely harmless and of little clinical relevance to being potentially life threatening. It is important that dentists have a good understanding of these conditions so that the risk of potential complications of dental treatment in affected patients is reduced as much as possible. This article focuses on the pathogenesis, diagnosis and treatment of these conditions, with explanation on their relevance to the practising dentist. Clinical relevance: The paper describes several vascular anomalies that may be encountered in clinical practice with information that is relevant to their diagnosis and management. PMID- 29152958 TI - Relating Aesthetics to Clinical Need: Improved Aesthetics of an Ill-Fitting Crown and Anterior Toothwear. AB - This case report presents a case in which a patient attended because of the poor appearance of an anterior crown, but she was unaware that she had a number of teeth affected by toothwear. Clinical relevance: The quest for aesthetic improvement may be a reason for a patient presenting for dental treatment. PMID- 29152959 TI - Sore or Swollen Lips Part 1- Causes and Diagnosis. AB - This series of three papers reviews the causes, diagnosis and differential diagnosis, and outlines the management of sore and/or swollen lips. Clinical relevance: Sore and/or swollen lips are not uncommon, often have a local cause but may reflect a systemic disease. This first part of a series of three papers reviews their causes and diagnosis alphabetically, for ease of reference. PMID- 29152960 TI - Dental Anxiety- Understanding is the Key to Effective Management. AB - Dental anxiety (DA) is a common problem; the latest Adult Dental Health Survey (UK) reported nearly half of the adult population experienced anxiety when visiting the dentist. Given individual differences in the experience of dental anxiety, it is important for the dentist to understand its development, detection and management. This article aims to provide an overview of the main psychological theories to explain the development of dental anxiety (behavioural, psychoanalytical and cognitive), as well as an overview of anxiety detection and management techniques from a psychological perspective. Clinical relevance: Dental anxiety is a common barrier to oral healthcare, with nearly half of the UK population affected. By understanding its causes, effective management can reduce anxiety, and therefore barriers to achieving high standards of oral health can be overcome. PMID- 29152961 TI - Noting personal, It's just business'. PMID- 29152962 TI - A case report of an unusual presentation of a keratocystic odontogenic tumour in the anterior mandible. PMID- 29152963 TI - Dear editor. PMID- 29152965 TI - Technique Tips - A Simplified Technique of Fabricating Foldable Mandibular Complete Denture using a Custom-Made Hinge Assembly. PMID- 29152964 TI - Clinical Challenges Q&A 25. White Gingivae. PMID- 29152966 TI - The knowledge and high seroprevalence of hepatitis A in a high-risk group (agricultural reproductive-aged women) in the southeastern region of Turkey AB - Background/aim: The aim of this study was to determine the seroprevalence of antihepatitis A virus (HAV), risk factors, and the knowledge of female farm workers living in the Southeastern Anatolia Region (SAR) of Turkey. Materials and methods: This representative cross-sectional survey was conducted between January and April of 2013 in the SAR. A total of 705 reproductive-aged women were randomly selected by clustering method using Epi Info software. The sera were analyzed for anti-HAV antibodies using ELISA. Sociodemographic information and the knowledge of female farm workers regarding hepatitis A were collected using a questionnaire. Results: Of the female farm workers, 99.1% were seropositive for anti-HAV. The anti-HAV seroprevalence was significantly higher in the adults than in the adolescents (P < 0.05). Of the participants, 64.5% had 7 or more family members, 58.4% had 5 or more pregnancies, 68.1% were illiterate, 65.2% were family farmers, 90.6% were poor, 71.9% used unsafe water, 58.9% had toilets outside, and 68% had no knowledge about hepatitis A. Conclusion: Turkey is considered to have high endemicity and female farm workers are considered a high risk group for hepatitis A. This high HAV exposure might be reduced with vaccination, as well as improvements in sanitation, living conditions, health care utilization, safer drinking water, and health education. PMID- 29152967 TI - Chemokine CXCR-4 and cyclooxygenase-2 in the pathogenesis of pterygium AB - Background/aim: This study aimed to investigate the expression of chemokine receptor 4 (CXCR-4) and cyclooxygenase-2 (COX-2) in the epithelium and stroma of pterygium tissue in comparison with healthy conjunctiva. Materials and methods: The expression of CXCR4 and COX-2 was investigated by immunohistochemistry in the epithelium and stroma of the pterygium tissue of 29 eyes and compared with healthy conjunctival tissues. The correlation between CXCR4 and COX-2 expression as well as the correlation of these markers with the area of pterygium were evaluated statistically. Results: COX-2 staining scores were 1.75 +/- 0.63 in the epithelium and 1.20 +/- 0.62 in the stroma of the pterygium tissue. Mean CXCR-4 staining in the epithelium was 0.069 +/- 0.37, whereas it was 5.0 +/- 2.84 cells in the stroma. There was almost no staining of COX-2 and CXCR4 in the control samples. There was a strong positive correlation between the expression of CXCR-4 and COX-2 in the stroma of the pterygium. Conclusion: CXCR-4 and COX-2 may play important roles in the pathogenesis of pterygium. PMID- 29152968 TI - Natural Carbonized Sugar as a Low-Temperature Ammonia Sensor Material: Experimental, Theoretical, and Computational Studies. AB - Carbonized sugar (CS) has been synthesized via microwave-assisted carbonization of market-quality tabletop sugar bearing in mind the advantages of this synthesis method, such as being useful, cost-effective, and eco-friendly. The as-prepared CS has been characterized for its morphology, phase purity, type of porosity, pore-size distribution, and so on. The gas-sensing properties of CS for various oxidizing and reducing gases are demonstrated at ambient temperature, where we observe good selectivity toward liquid ammonia among other gases. The highest ammonia response (50%) of a CS-based sensor was noted at 80 degrees C for 100 ppm concentration. The response and recovery times of the CS sensor are 180 and 216 s, respectively. This unveiling ammonia-sensing study is explored through a plausible theoretical mechanism, which is further well-supported by computational modeling performed using density function theory. The effect of relative humidity on the CS sensor has also been studied at ambient temperature, which demonstrated that the minimum and maximum (20-100%) relative humidity values revealed 16 and 62% response, respectively. PMID- 29152969 TI - syn-Fluoro- and -Oxy-trifluoromethylation of Arylacetylenes. AB - One-step concurrent fluoro-trifluoromethylation across the triple bond of arylacetylenes in a syn mode is enabled by the collaboration of (phen)CuIII(CF3)3 and CsF that produces chemo-, regio-, and stereoselectively (Z)-alpha-fluoro-beta CF3 styrenes. This method can be extended to achieve syn-oxy-trifluoromethylation and syn-aryl-trifluoromethylation of alkynes using phenoxides, alkoxides, or phenylboronic acid in place of CsF. It opens up new opportunities for preparing various functionalized trifluoromethylated Z-alkenes and demonstrates the potential of Cu(III)-CF3 complexes in organic synthesis. PMID- 29152970 TI - Pd-Catalyzed Enantio- and Regioselective Formation of Allylic Aryl Ethers. AB - A general methodology for the synthesis of enantioenriched tertiary allylic aryl ethers through Pd-catalyzed decarboxylative reactions of vinyl cyclic carbonates and phenols is presented. Switching of the regioselectivity toward the formation of linear products by a judicious choice of the ligand is also reported. PMID- 29152971 TI - A Cascade Dehydrogenative Cross-Coupling/Annulation Reaction of Benzamides with beta-Keto Esters for the Synthesis of Isoquinolinone Derivatives. AB - A novel cascade DCC/annulation reaction of N-alkoxybenzamides with beta-keto esters has been developed for the synthesis of isoquinolinone derivatives under palladium catalysis. A plausible mechanism involving alpha-C(sp2)-H activation and a Pd(II)/Pd(IV) catalytic cycle is also proposed. PMID- 29152972 TI - Defect Engineering in MoSe2 for the Hydrogen Evolution Reaction: From Point Defects to Edges. AB - Superior catalytic activity and high chemical stability of inexpensive electrocatalysts for the hydrogen evolution reaction (HER) are crucial to the large-scale production of hydrogen from water. The nonprecious two-dimensional MoSe2 materials emerge as a potential candidate, and the improvement of their catalytic activity depends on the optimization of active reaction sites at both the edges and the basal plane. Herein, the structural stability, electrocatalytic activity, and HER mechanisms on a series of MoSe2 catalytic structures including of point defects, holes, and edges have been explored by using first-principles calculations. Our calculated results demonstrate that thermodynamically stable defects (e.g., VSe, VSe2, SeMo, and VMo3Se2) and edges (e.g., Mo-R and Se-R) in MoSe2 are very similar to the case of MoS2, but their HER activity is higher than that of the corresponding structures in MoS2, which is in good agreement with experimental observations. Furthermore, a Fermi-abundance model is proposed to explain the fundamental correlation between the HER activity of various MoSe2 catalysts and their intrinsic electronic structures, and this model is also applicable for assessing the HER activity of other types of catalysts, such as MoS2 and Pt. Moreover, two different HER mechanisms have been revealed in the MoSe2 catalytic structures: the Volmer-Tafel mechanism is preferred for the VSe and VSe2 structures, whereas the Volmer-Heyrovsky mechanism is more favorable for other MoSe2 catalytic structures. The present work suggests that MoSe2 with appropriate defects and edges is able to compete against the Pt-based catalysts and also opens a route to design highly active electrocatalysts for the HER. PMID- 29152973 TI - Epidermal Microfluidic Electrochemical Detection System: Enhanced Sweat Sampling and Metabolite Detection. AB - Despite tremendous recent efforts, noninvasive sweat monitoring is still far from delivering its early analytical promise. Here, we describe a flexible epidermal microfluidic detection platform fabricated through hybridization of lithographic and screen-printed technologies, for efficient and fast sweat sampling and continuous, real-time electrochemical monitoring of glucose and lactate levels. This soft, skin-mounted device judiciously merges lab-on-a-chip and electrochemical detection technologies, integrated with a miniaturized flexible electronic board for real-time wireless data transmission to a mobile device. Modeling of the device design and sweat flow conditions allowed optimization of the sampling process and the microchannel layout for achieving attractive fluid dynamics and rapid filling of the detection reservoir (within 8 min from starting exercise). The wearable microdevice thus enabled efficient natural sweat pumping to the electrochemical detection chamber containing the enzyme-modified electrode transducers. The fabricated device can be easily mounted on the epidermis without hindrance to the wearer and displays resiliency against continuous mechanical deformation expected from such epidermal wear. Amperometric biosensing of lactate and glucose from the rapidly generated sweat, using the corresponding immobilized oxidase enzymes, was wirelessly monitored during cycling activity of different healthy subjects. This ability to monitor sweat glucose levels introduces new possibilities for effective diabetes management, while similar lactate monitoring paves the way for new wearable fitness applications. The new epidermal microfluidic electrochemical detection strategy represents an attractive alternative to recently reported colorimetric sweat-monitoring methods, and hence holds considerable promise for practical fitness or health monitoring applications. PMID- 29152974 TI - Biocompatible Copper Oxide Nanoparticle Composites from Cellulose and Chitosan: Facile Synthesis, Unique Structure, and Antimicrobial Activity. AB - Copper in various forms has been known to have bactericidal activity. Challenges to its application include preventing mobilization of the copper, to both extend activity and avoid toxicity, and bioincompatibility of many candidate substrates for copper immobilization. Using a simple ionic liquid, butylmethylimmidazolium chloride as the solvent, we developed a facile and green method to synthesize biocompatible composites containing copper oxide nanoparticles (CuONPs) from cellulose (CEL) and chitosan (CS) or CEL and keratin (KER). Spectroscopy and imaging results indicate that CEL, CS, and KER remained chemically intact and were homogeneously distributed in the composites with CuONPs with size of 22 +/- 1 nm. Electron paramagnetic resonance (EPR) suggests that some 25% of the EPR detectable Cu(II) is present as a monomeric species, chemically anchored to the substrate by two or more nitrogen atoms, and, further, adopts a unique spatially oriented conformation when incorporated into the [CEL + CS] composite but not in the [CEL + KER] composite. The remaining 75% of EPR-detectable Cu(II) exhibited extensive spin-spin interactions, consistent with Cu(II) aggregates and Cu(II) on the surface of CuONPs. At higher levels of added copper (>59 nmol/mg), the additional copper was EPR-silent, suggesting an additional phase in larger CuONPs, in which S > 0 spin states are either thermally inaccessible or very fast relaxing. These data suggest that Cu(II) initially binds substrate via nitrogen atoms, from which CuONPs develop through aggregation of copper. The composites exhibited excellent antimicrobial activity against a wide range of bacteria and fungi, including methicillin-resistant Staphylococcus aureus; vancomycin resistant Enterococcus; and highly resistant Escherichia coli, Streptococcus agalactiae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Candida albicans. Expectedly, the antibacterial activity was found to be correlated with the CuONPs content in the composites. More importantly, at CuONP concentration of 35 nmol/mg or lower, bactericidal activity of the composite was complemented by its biocompatibility with human fibroblasts. PMID- 29152975 TI - Divergent Synthesis of Fused Tricyclic Compounds via a Tandem Reaction from Alkynyl-cyclohexadienones and Diazoesters. AB - A distinct one-pot protocol toward several types of fused tricyclic scaffolds has been developed, by employing diazoesters and alkynyl-cyclohexadienones as starting materials, enabling rapid construction of diverse tricyclic compounds with multiple bonds formation in an operationally simple procedure. Typically, this controlled tandem sequence showcases the in situ formation of tetrasubstituted allenoates, an unprecedented anion-triggered annulation, and oxidative aromatization. PMID- 29152976 TI - Unmasking Amides: Ruthenium-Catalyzed Protodecarbonylation of N-Substituted Phthalimide Derivatives. AB - The unprecedented transformation of a wide range of synthetically appealing phthalimides into amides in a single-step operation has been achieved in high yields and short reaction times using a ruthenium catalyst. Mechanistic studies revealed a unique, homogeneous pathway involving five-membered ring opening and CO2 release with water being the source of protons. PMID- 29152977 TI - Local Disorder and Tunable Luminescence in Sr1-x/2Al2-xSixO4 (0.2 <= x <= 0.5) Transparent Ceramics. AB - Eu-doped Sr1-x/2Al2-xSixO4 (x = 0.2, 0.4, and 0.5) transparent ceramics have been synthesized by full and congruent crystallization from glasses prepared by aerodynamic levitation and laser-heating method. Structural refinements from synchrotron and neutron powder diffraction data show that the ceramics adopt a 1 * 1 * 2 superstructure compared to the SrAl2O4 hexagonal polymorph. While the observed superstructure reflections indicate a long-range ordering of the Sr vacancies in the structure, 29Si and 27Al solid-state NMR measurements associated with DFT computations reveal a significant degree of disorder in the fully polymerized tetrahedral network. This is evidenced through the presence of Si-O Si bonds, as well as Si(OAl)4 units at remote distances of the Sr vacancies and Al(OAl)4 units in the close vicinity of Sr vacancies departing from local charge compensation in the network. The transparent ceramics can be doped by europium to induce light emission arising from the volume under UV excitation. Luminescence measurements then reveal the coexistence of Eu2+ and Eu3+ in the samples, thereby allowing tuning the emission color depending on the excitation wavelength and suggesting possible applications such as solid state lighting. PMID- 29152978 TI - Marginal Emissions Factors for Electricity Generation in the Midcontinent ISO. AB - Environmental consequences of electricity generation are often determined using average emission factors. However, as different interventions are incrementally pursued in electricity systems, the resulting marginal change in emissions may differ from what one would predict based on system-average conditions. Here, we estimate average emission factors and marginal emission factors for CO2, SO2, and NOx from fossil and nonfossil generators in the Midcontinent Independent System Operator (MISO) region during years 2007-2016. We analyze multiple spatial scales (all MISO; each of the 11 MISO states; each utility; each generator) and use MISO data to characterize differences between the two emission factors (average; marginal). We also explore temporal trends in emissions factors by hour, day, month, and year, as well as the differences that arise from including only fossil generators versus total generation. We find, for example, that marginal emission factors are generally higher during late-night and early morning compared to afternoons. Overall, in MISO, average emission factors are generally higher than marginal estimates (typical difference: ~20%). This means that the true environmental benefit of an energy efficiency program may be ~20% smaller than anticipated if one were to use average emissions factors. Our analysis can usefully be extended to other regions to support effective near-term technical, policy and investment decisions based on marginal rather than only average emission factors. PMID- 29152979 TI - Enantioselective Synthesis of alpha-Acetal-beta'-Amino Ketone Derivatives by Rhodium-Catalyzed Asymmetric Hydrogenation. AB - A range of beta-keto-gamma-acetal enamides has been synthesized and transformed into the corresponding enantioenriched alpha-acetal-beta'-amino ketones with enantioinductions of up to 99% by using rhodium/QuinoxP*-catalyzed enantioselective hydrogenation under mild conditions. This method also proved to be highly chemoselective toward the reduction of the C-C double bond. PMID- 29152980 TI - Palladium-Catalyzed [5 + 2] Cycloaddition of Vinyloxiranes with Sulfamate-Derived Cyclic Imines To Construct 1,3-Oxazepine Heterocycles. AB - Palladium-catalyzed [5 + 2] cycloaddition of 2-aryl-2-vinyloxiranes with sulfamate-derived cyclic imines is described. The zwitterionic allylpalladium intermediates act as five-membered synthon to react with sulfamate-derived cyclic imines to furnish [5 + 2] cycloaddition, giving 1,3-oxazepine derivatives in moderate to excellent yields with excellent regioselectivities. PMID- 29152981 TI - Asymmetric FeII-Catalyzed Thia-Michael Addition Reaction to alpha,beta Unsaturated Oxazolidin-2-one Derivatives. AB - A highly enantioselective FeII-catalyzed thia-Michael addition to alpha,beta unsaturated carbonyl derivatives was developed. The scope of the reaction was demonstrated with a selection of aromatic, heterocyclic and aliphatic thiols, and various Michael acceptors. The corresponding beta-thioethers were obtained in good to excellent yields (up to 98%) and moderate to excellent enantioselectivities (up to 96:4 er). Unusual hepta-coordination of the metal and chelation to alpha,beta-unsaturated oxazolidin-2-one derivatives allowed the construction of a coherent model rationalizing the enantioselective event. DFT calculations support the proposed model for observed stereoselectivities. PMID- 29152982 TI - Phosphine-Catalyzed Asymmetric (3+2) Annulations of delta-Acetoxy Allenoates with 2-Naphthols. AB - Phosphine-catalyzed (3+2) annulations of delta-acetoxy allenoates with 2 naphthols are reported, wherein the deltaC of allentoate reacts with the alphaC of 2-naphthol to form the C-C bond while a C-O bond is formed between the gammaC of allenoate and the hydroxyl group of 2-naphthol. When (R)-SITCP is used as the catalyst, 1,2-dihydronaphtho[2,1-b]furans are obtained in moderate to good yields and with high enantioselectivity. This method is useful for the construction of enantiomerically enriched atropoisomeric furans via a central to axial chirality conversion strategy. PMID- 29152983 TI - Copper-Catalyzed Enantioselective Henry Reaction of beta,gamma-Unsaturated alpha Ketoesters with Nitromethane in Water. AB - A highly enantioselective Henry reaction of beta,gamma-unsaturated alpha ketoesters with nitromethane in water by virtue of chiral copper complexes has been developed. A series of unsaturated beta-nitro-alpha-hydroxy esters bearing tetrasubstituted carbon stereocenters were obtained exclusively with high yields and excellent enantioselectivities. This method could avoid tedious anaerobic anhydrous manipulation and reduce the environmental pollution caused by organic solvents. PMID- 29152984 TI - Preparation of Polyfunctional Naphthyridines by Cobalt-Catalyzed Cross-Couplings of Halogenated Naphthyridines with Magnesium and Zinc Organometallics. AB - CoCl2 (5%) catalyzes cross-couplings of various halogenated naphthyridines with alkyl- and arylmagnesium halides. Also, arylzinc halides undergo smooth cross couplings with various naphthyridines in the presence of CoCl2.2LiCl (5%) and sodium formate (50%), leading to polyfunctional arylated naphthyridines. Two of these arylated naphthyridines are highly fluorescent, with quantum efficiencies reaching 95% and long excited-state lifetimes of up to 12 ns. PMID- 29152985 TI - Visible-Light-Driven alpha-Allenylic C-O Bond Cleavage and Alkenyl C-S Formation: Metal-Free and Oxidant-Free Thiolation of Allenyl Phosphine Oxides. AB - A visible-light photoredox cleavage of alpha-allenylic C-O bond and alkenyl C-S formation is disclosed for the first time. The thiolation of allenyl phosphine oxides with diaryl disulfides occurs smoothly in metal-free and mild conditions, affording novel S,P-bifunctionalized butadienes with moderate to excellent yields. Mechanistic studies explain the cleavage of a C(sp3)-O(Ar) bond in initiating a key alkenyl radical intermediate. PMID- 29152986 TI - A rare cause of upper gastrointestinal bleeding in a patient with end stage renal disease: gastric amyloidosis. AB - This letter has two purpose: First, evaluate the correlation between our endoscopic findings of gastric amyloidosis with previous report of Vargas et al. Second, draw attention to the fact that amyloidosis may occur upper gastrointestinal bleeding (UGIB) in patients with end-stage renal disease (ESRD). PMID- 29152987 TI - High short-term rebleeding rate in patients undergoing a second endoscopic therapy for small-bowel angioectasias after recurrent bleeding. AB - BACKGROUND: Angioectasias represents the most frequently found lesion in the small bowel by device-assisted enteroscopy for obscure gastrointestinal bleeding in Western countries. Recurrence of gastrointestinal bleeding after angioectasias therapy remains unclear and data regarding the efficacy of additional endoscopic therapeutic sessions to reduce the rebleeding rate is limited. AIM: To evaluate the rebleeding rate in small bowel angioectasias after a second endoscopic treatment with balloon-assisted enteroscopy after an initial bleed during the first endoscopic treatment. METHODS: A retrospective double-center study of patients with small-bowel angioectasias undergoing a second enteroscopy treatment due to a first rebleeding episode. The endpoint was rebleeding, defined as the need for a blood transfusion, the presence of overt bleeding or a decrease in hemoglobin >= 2 g/dL. RESULTS: Fifteen of 37 (40.5%) patients with small-bowel angioectasias that underwent a second endoscopic therapy after a first rebleeding episode (n = 15) experienced a second rebleeding episode. Kaplan-Meier curve analysis showed that most rebleeding episodes occurred within the first 12 months of follow-up, resulting in a rebleeding rate of 33.1% at 6 months, 39.1% at 12 months and 52.6% at 24 months. CONCLUSIONS: Despite the high absolute short-term rebleeding rate, further endoscopic treatments may be beneficial due to the effective reduction of rebleeding in a subset of patients. PMID- 29152988 TI - Value and innovation of direct-acting antivirals: long-term health outcomes of the strategic plan for the management of hepatitis C in Spain. AB - OBJECTIVE: To assess the long-term healthcare costs and health outcomes in association with the access to new direct-acting antivirals (DAAs), during the first year of the National Strategic Plan for Chronic Hepatitis C (SPCHC) in patients with chronic hepatitis C (CHC) in Spain. METHODS: A decision tree and a lifetime Markov model were developed to simulate the natural history, morbidity, and mortality of a cohort of 51,900 patients with CHC before (pre-DAA strategy) and after (post-DAA strategy) access to DAAs, following SPCHC approval. The percentage of patients treated, transition probabilities, disease management costs, health state utility values, sustained virologic response rates and treatment costs were obtained from the literature and published data from Spain. The results were expressed in terms of costs (?, 2016), quality-adjusted life years (QALYs) and prevention of clinical events, with an annual discount rate of 3%. RESULTS: The post-DAA strategy would prevent 8,667 cases of decompensated cirrhosis, 5,471 cases of hepatocellular carcinoma, 1,137 liver transplants and 9,608 liver-related deaths. The cohort of 51,900 patients would require investments of 1,606 and 1,230 million euros with the post-DAA and pre-DAA strategies, respectively. This would produce 819,674 and 665,703 QALYs. CONCLUSIONS: The use of new DAA-based treatments in CHC patients during the first year after the implementation of the SPCHC significantly reduced long-term morbidity and mortality and increased quality of life; demonstrating that this plan is an efficient use of public health resources. PMID- 29152989 TI - Real time visualization may be advisable to exclude aspiration in patients undergoing capsule endoscopy examination. AB - Capsule endoscopy (CE) is currently considered as a first line diagnostic tool for small bowel examination. Some patients find swallowing the capsule difficult. However, capsule aspiration is relatively uncommon and is only reported in isolated cases. The majority of these cases are male (39/41; 95.1%) with an age ranging from 56-93 years and only 4 (9.8%) patients had a recorded history of dysphagia. Twenty-four out of 41 (58.5%) patients experienced symptoms of capsule aspiration. The aspiration self-resolved in 11/41 patients and the CE was retrieved during bronchoscopy in the other cases. We present the case of a 75 year old man with a history of chronic anemia who was referred for CE. PMID- 29152990 TI - Gastroduodenal lesions detected during small bowel capsule endoscopy: incidence, diagnostic and therapeutic impact. AB - BACKGROUND: Capsule endoscopy was primarily designed for the investigation of the small bowel. However, it may also identify lesions in other segments of the gastrointestinal tract. The aim of the current study was to evaluate the incidence of gastroduodenal abnormalities during small bowel capsule endoscopy and its impact on patient diagnosis and management. PATIENTS AND METHODS: This study is a retrospective analysis of data from 2,217 consecutive capsule endoscopy procedures performed at a single tertiary-care center between January 2008 and February 2016. Patient baseline characteristics, gastroduodenal lesions, diagnosis and management before and after capsule endoscopy were recorded and a descriptive analysis was performed. RESULTS: Two thousands and two hundred seventeen patients were finally included in the analysis. One thousand and seventy patients were male (48.2%) and the mean age was 56.1 +/- 19.5 years (range: 12-93). Obscure gastrointestinal bleeding (52.3%) and inflammatory bowel disease (18.3%) were the main procedure indications. Gastroduodenal abnormalities were detected by capsule endoscopy in 696 (31.4%) of 2,217 patients. The most common types of missed gastric and duodenal lesions found were gastric erosions (35.4%), findings suggestive of chronic gastritis (22.9%), duodenal erosions (28.1%) and duodenal erythema (23.5%). This information had a clinical or diagnostic impact of 26.2% and a therapeutic impact of 15.5%. CONCLUSION: Capsule endoscopy detects not only small bowel lesions but also some gastroduodenal lesions that may be overlooked during an initial gastroscopy. Therefore, all gastroduodenal images should be read during small bowel capsule endoscopy as it may provide relevant information that result in changes in patient management. PMID- 29152992 TI - The levels of physical activity and motor skills in young children with and without autism spectrum disorder, aged 2-5 years. AB - Autism spectrum disorder is the fastest growing developmental disability in the United States. As such, there is an unprecedented need for research examining factors contributing to the health disparities in this population. This research suggests a relationship between the levels of physical activity and health outcomes. In fact, excessive sedentary behavior during early childhood is associated with a number of negative health outcomes. A total of 53 children participated in this study, including typically developing children (mean age = 42.5 +/- 10.78 months, n = 19) and children with autism spectrum disorder (mean age = 47.42 +/- 12.81 months, n = 34). The t-test results reveal that children with autism spectrum disorder spent significantly less time per day in sedentary behavior when compared to the typically developing group ( t(52) = 4.57, p < 0.001). Furthermore, the results from the general linear model reveal that there is no relationship between motor skills and the levels of physical activity. The ongoing need for objective measurement of physical activity in young children with autism spectrum disorder is of critical importance as it may shed light on an often overlooked need for early community-based interventions to increase physical activity early on in development. PMID- 29152991 TI - Four synchronous primary cancers of the aerodigestive tract and thyroid. AB - We report the case of a 60-year-old man with 4 concurrent primary cancers: thyroid papillary carcinoma, esophageal squamous cell carcinoma, lung adenocarcinoma, gastric stromal tumor, and nodular goiter. A minimally invasive McKeown esophagectomy with 3-field lymph node resection played a major role in the diagnosis and resection of all primary tumors in the same sitting. Multiorgan primary cancers are not uncommon but pose challenges in diagnosis and treatment. The mechanism of development is unknown but exposure to the same carcinogens in multiple organs has been implicated. PMID- 29152993 TI - Program experiences of adults with autism, their families, and providers: Findings from a focus group study. AB - A growing number of individuals with autism spectrum disorder are aging into adulthood. In the United States, Medicaid is the primary payer for services for adults with autism spectrum disorder, yet there are few funded programs that provide dedicated supports to this population. This study examined the experiences of adults with autism spectrum disorder in two Medicaid-funded programs in Pennsylvania through focus groups. Researchers conducted 20 focus groups with a total of 36 adults with autism spectrum disorder, 32 family members, 32 direct care staff, and 20 program administrators. Using thematic analysis, we identified three themes: training needs, community engagement and socialization, and employment. There was a need for additional training to meet the varying needs of program participants including co-occurring diagnoses, sexuality, and long-term planning. Adults with autism spectrum disorder prioritized more individualized community activities based on their interests. Finally, barriers to and strategies for successful employment were discussed. It will be crucial for policy makers to utilize the findings to inform program improvement and development based on the experiences of individuals impacted by these services and systems directly. Additionally, researchers should use the findings from this study to design interventions for adults with autism spectrum disorder as it includes their voices. PMID- 29152994 TI - Decreased Connectivity and Increased Blood Oxygenation Level Dependent Complexity in the Default Mode Network in Individuals with Chronic Fatigue Syndrome. AB - The chronic fatigue syndrome (CFS)/myalgic encephalomyelitis is a debilitating disease with unknown pathophysiology and no diagnostic test. This study investigated the default mode network (DMN) to understand the pathophysiology of CFS and to identify potential biomarkers. Using functional MRI (fMRI) collected from 72 subjects (45 CFS and 27 controls) with a temporal resolution of 0.798 sec, we evaluated the DMN using static functional connectivity (FC), dynamic functional connectivity (DFC) and DFC complexity, blood oxygenation level dependent (BOLD) activation maps, and complexity of activity. General linear model univariate analysis was used for intergroup comparison to account for age and gender differences. Hierarchical regression analysis was used to test whether fMRI measures could be used to explain variances of health scores. BOLD signals in the posterior cingulate cortex (PCC), the driving hub in the DMN, were more complex in CFS in both resting state and task (p < 0.05). The FCs between medial prefrontal cortex (mPFC) and both inferior parietal lobules (IPLs) were weaker (p < 0.05) during resting state, whereas during task mPFC-left IPL and mPFC-PCC were weaker (p < 0.05). The DFCs between the DMN hubs were more complex in CFS (p < 0.05) during task. Each of these differences accounted for 7-11% variability of health scores. This study showed that DMN activity is more complex and less coordinated in CFS, suggesting brain network analysis could be potentially used as a diagnostic biomarker for CFS. PMID- 29152995 TI - Endorsement of Social and Personal Values Predicts the Desirability of Men and Women as Long-Term Partners. AB - A prospective romantic partner's desirability as a long-term partner may be affected by the values that he or she endorses. However, few studies have examined the effects of "values" on a person's desirability as a long-term partner. We hypothesized that individuals who endorse social values (vs. personal values) will be perceived as more desirable long-term partners (Hypothesis 1) and that the endorsement of social values will be especially desirable in a male (vs. female) long-term partner (Hypothesis 2). The current study employed a 2 (sex of prospective partner: male vs. female) * 2 (values of prospective partner: personal vs. social) * 2 (physical attractiveness of prospective partner: unattractive vs. highly attractive) mixed-model design. Participants were 339 undergraduates (174 men, 165 women), with ages varying between 18 and 33 years ( M = 19.9, SD = 3.6), and mostly in a romantic relationship (53.7%). Participants reported interest in a long-term relationship with prospective partners depicted in four scenarios (within subjects), each varying along the dimensions of values (personal vs. social) and physical attractiveness (unattractive vs. highly attractive). Individuals endorsing personal values (vs. social values) and men (vs. women) endorsing personal values were rated as less desirable as long-term partners. The current research adds to the partner preferences literature by demonstrating that an individual's ascribed values influence others' perceptions of desirability as a long-term partner and that these effects are consistently sex differentiated, as predicted by an evolutionary perspective on romantic partner preferences. PMID- 29152996 TI - Birth Defects Associated With Congenital Zika Virus Infection in Mexico. AB - Part of the work agenda of international health authorities is to define the clinical spectrum of the congenital Zika syndrome (CZS) in different territories. We describe the clinical variability that gave rise to the suspicion of CZS in 3 newborn patients in the south of Mexico with active transmission of Zika. All of them presented Zika RNA by reverse transcription-polymerase chain reaction and positive antibodies for IgM by enzyme-linked immunosorbent assay. None of the mothers tested positive for active viremia, only one mother had Zika-symptoms and titers of Zika-positive IgM. Intrauterine growth restriction, brain disruption sequence, and intracranial calcifications are the clinical characteristics common in all. One patient had neural tube defect and other, arthrogryposis. Because the majority of pregnant women will be asymptomatic to Zika, we must be alert to the clinical variability of the birth defects associated to pregnancy Zika infection. Reports of clinical cases encourage the medical community to make diagnostic decisions. PMID- 29152997 TI - Prevalence of Jones Fracture Repair and Impact on Short-Term NFL Participation. AB - BACKGROUND: Elite American football athletes are at high risk for Jones fractures. Fixation is recommended to minimize nonunion and allow early return to play. The purpose of this investigation was to evaluate the prevalence of Jones fracture repair in athletes invited to the National Football League (NFL) Combine and the impact of fracture repair on short-term NFL participation compared to athletes with no history of repair. METHODS: A total of 1311 athletes participating in the Combine from 2012 to 2015 were evaluated. Athletes with history of Jones fracture repair were identified. Athlete demographic information was collected while physical examination findings were recorded. Radiographs were evaluated to determine fixation type and the presence of nonunion. Future participation in the NFL was evaluated based on draft status, games played, and games started in the athlete's first season following the Combine. RESULTS: Fixation was performed for 41 Jones fractures in 40 athletes (3.1%). The highest prevalence was in defensive linemen (n = 10 athletes), with the greatest rate in tight ends (5.1%, n = 4 of 79 athletes). Intramedullary screw fixation was used for all fractures. Incomplete bony union was present in 3 (8%) fractures. Athletes with a history of repair were not at significant risk for going undrafted ( P = .61), playing ( P = .23), or starting ( P = .76) fewer NFL games compared to athletes with no history of repair during athletes' first NFL season. CONCLUSION: Athletes with a history of Jones fracture repair were not at significant risk of going undrafted or for diminished participation during their first season in the NFL. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29152998 TI - Relationship between lung function and inhalation devices for LAMA/LABA therapy for chronic obstructive pulmonary disease. PMID- 29152999 TI - What kind of information and communication technologies do patients with COPD prefer to use? A cross-sectional study in Latin America. AB - The aim of the present study was to assess the frequency of uses and preferences of information and communication technologies (ICTs) among Latin American chronic obstructive pulmonary disease (COPD) patients. We conducted an anonymous cross sectional survey study on Latin American COPD patients. The adapted version of the Michigan questionnaire was employed in eligible outpatients in different cities of Latin America. We categorized age and educational levels into three groups. The time passed since COPD diagnosis was categorized as <=5 years and >5 years. chi2 and crude and adjusted logistic regressions were performed. A total of 256 patients were enrolled with a mean age of 68.7 years old. The most recurrently used ICTs were short message service (SMS; 47.1%) and WhatsApp (30.7%) for receiving COPD information. Moreover, SMS (85.8%) and Facebook (36.1%) were rated as useful for asking physicians information about COPD. Regression analysis showed that the best predictor for patients using ICTs, for any purpose, was higher education (undergraduate or graduate school). Understanding the preferences of ICTs among COPD patients could help improve patient's outcomes through developing applications in response to specific requirements of each patient. PMID- 29153001 TI - Understanding parents' concerns about their children with autism taking public school transportation in Los Angeles County. AB - There are a number of recent US news media reports of children and youth with autism becoming lost, injured, or even dying while taking public school transportation, yet research on this problem is scarce. This ethnographic study examines the experiences of 14 parents whose children with autism take public school transportation in Los Angeles County. We present two case studies of children with autism being "lost" while in transit from school to home on the bus to (1) describe how the situation was experienced, responded to, and managed by the parents; (2) consider three interrelated themes that emerged from interviews with 14 parents, related to children's safety, independence, and participation, across multiple contexts and analytic levels; and (3) discuss the findings in relation to US news media reports of incidents involving children with autism on school buses to identify specific weaknesses in school transportation infrastructure, particularly in the context of privatization, that create conditions in which children with autism can "fall through the cracks" in potentially life-threatening ways. We argue that there is a critical need to address transportation accessibility for individuals on the autism spectrum to ensure their safety and support their independence and community participation. PMID- 29153000 TI - Coronary bypass in left ventricular dysfunction and differential cardiac recovery. AB - Background We aimed to examine the efficacy of surgical revascularization with respect to improvement in ventricular function and survival in patients with ischemic cardiomyopathy and poor left ventricular function. Methods We retrospectively analyzed the data of 429 patients (median age 64.6 years, 81.1% male) with ejection fractions <40% undergoing isolated primary coronary artery bypass grafting from 2000 to 2016. Techniques included on-pump cardioplegic arrest ( n = 312), off-pump ( n = 75), and on-pump beating heart ( n = 42). Propensity matching was performed to compare the cardioplegic arrest group ( n = 114) with the combined off-pump and beating heart groups ( n = 114). Results Postoperatively, ejection fraction increased by 10.1% +/- 13.1% (from 31.4% +/- 7.1% to 41.6% +/- 13.6%; p < 0.001) and mitral regurgitation grade improved ( p < 0.001) but right ventricular function on echocardiographic assessment worsened over time ( p = 0.04). No difference in ejection fraction improvement was seen in the time periods <1 (9.8% +/- 11.2%), 1-5 (11.6% +/- 14.5%), and >5 (8.8% +/- 14.2%) years ( p = 0.442). Following propensity matching, there was no significant difference between the combined off-pump/beating heart and cardioplegic arrest groups with respect to survival or postoperative complications. Conclusions Patients with moderate to severe left ventricular dysfunction experience long-term improvement in left ventricular ejection fraction after coronary artery bypass. However, right ventricular function often continues to decline, contributing to persistent or worsening heart failure symptoms and late mortality. No difference in survival was seen between the 2 techniques. PMID- 29153002 TI - The use of behavior modeling training in a mobile app parent training program to improve functional communication of young children with autism spectrum disorder. AB - Communication intervention in early life can significantly impact long-term outcomes for young children with autism. Parents can be vital resources in the midst of the current manpower shortage. Map4speech is a new mobile application developed for parents of children with autism spectrum disorder. It is specially designed to provide high-quality, interactive learning, coupled with frequent feedback and live coaching to train parents in a naturalistic language intervention. A multiple-baseline single-case experimental design was conducted across three parent-child dyads. Results indicate that procedural integrity of parents' intervention techniques was above 85% during post-training intervention, and their respective children showed increases in spontaneous word/gesture use. The results show that mobile applications with feedback can be a promising means for improving efficiency and effectiveness in disseminating evidence-based practices for autism intervention. PMID- 29153003 TI - 'Suddenly the first fifty years of my life made sense': Experiences of older people with autism. AB - Research on the experience of growing older with autism is very limited. In this study, 13 people with autism aged over 50 years participated in semi-structured interviews about their experiences of diagnosis, social support and getting older. Interviews were analysed using thematic analysis. Three overarching themes were generated: difference, life review and longing for connection. Prior to diagnosis, individuals had awareness of their difficulties, attributed these to intrinsic difference and engaged in a deliberate process of reducing the visibility of this difference. Diagnosis prompted a process of life review and externalisation, whereby past negative experiences were reattributed to autism as opposed to the self. Loneliness, isolation and yearning for interpersonal connection were ubiquitous and longstanding. Autism support and social groups were highly valued, offering opportunities for belonging, acceptance and social comparison. Results highlight the similarity to younger age groups in terms of lived experience and need for greater support, particularly with respect to reducing isolation and improving access to diagnosis. PMID- 29153004 TI - Assisted reproductive technology has no association with autism spectrum disorders: The Taiwan Birth Cohort Study. AB - The use of assisted reproduction technology has increased over the last two decades. Autism spectrum disorders and assisted reproduction technology share many risk factors. However, previous studies on the association between autism spectrum disorders and assisted reproduction technology have shown inconsistent results. The purpose of this study was to investigate the association between assisted reproduction technology and autism spectrum disorder diagnosis in a national birth cohort database. Furthermore, the results from the assisted reproduction technology and autism spectrum disorder propensity score matching exact matched datasets were compared. For this study, the 6- and 66-month Taiwan Birth Cohort Study datasets were used (N = 20,095). In all, 744 families were propensity score matching exact matched and selected as the assisted reproduction technology sample (ratio of assisted reproduction technology to controls: 1:2) and 415 families as the autism spectrum disorder sample (ratio of autism spectrum disorder to controls: 1:4). Using a national birth cohort dataset, controlling for the confounding factors of assisted reproduction technology conception and autism spectrum disorder diagnosis, both assisted reproduction technology and autism spectrum disorder propensity score matching matched datasets showed the same results of no association between assisted reproduction technology and autism spectrum disorder. Further study on the detailed information regarding the processes and methods of assisted reproduction technology may provide us with more information on the association between assisted reproduction technology and autism spectrum disorder. PMID- 29153005 TI - Screening for Delirium: Development and Validation of the Buffalo Delirium Scale for Use in a Home-Based Hospice Setting. AB - BACKGROUND: Delirium is a challenging occurrence among people at end of life. It can be difficult to detect and treat because of its episodic nature. The Buffalo Delirium Scale (BDS) was designed to identify risk factors for hospice patients in the prodromal stage of delirium. OBJECTIVE: This study evaluated the psychometric properties of items assessing delirium risk factors related to cognitive problems, psychological distress, and sleep problems. METHODS: Hospice nursing staff assessed patients with the 11-item BDS over a 6-month period as part of standard weekly visits to monitor for emerging signs of delirium, for example, sleep patterns, cognition, and behavior. SETTING/PARTICIPANTS: The rating period produced 4992 assessments from 817 hospice home care patients. RESULTS: Factor analysis of nurses' ratings identified 3 factors: (1) cognitive problems, (2) distress, and (3) sleep problems. Coefficient alphas for these factors and total score were moderate to high (range = .66-.82). Nurses' ratings of presence of delirium highly correlated with scores on distress ( r = .40, P < .01), while dementia highly correlated with cognitive problems ( r = .50, P < .01). Analysis of at-risk cases with high BDS total scores where no delirium was assessed indicated that quality sleep may mitigate delirium onset. CONCLUSION: Preliminary psychometric testing suggests BDS to be a valid and appropriate measure for hospice patients. Use of BDS may help differentiate individuals in prodromal stage of delirium versus dementia. Examination of BDS scores may help identify patients for whom sleep interventions may delay onset of or reduce the frequency of delirium. PMID- 29153006 TI - Effect of bariatric surgery on diabetic nephropathy in obese type 2 diabetes patients in a retrospective 2-year study: A local pilot. AB - PURPOSE: To determine the effects of bariatric surgery on albuminuria in obese patients with type 2 diabetes mellitus. METHODS: Retrospective analyses of clinical records of obese patients with type 2 diabetes mellitus who had either micro- or macroalbuminuria and had undergone various bariatric surgery were retrieved from a local hospital database. Their clinical data from follow-up appointments including albuminuria were analysed. RESULTS: Of the 46 subjects with type 2 diabetes mellitus, 15 subjects had diabetic nephropathy and had pre- and post-bariatric surgery urine albumin-to-creatinine ratio or urine protein-to creatinine ratio data available for analysis; 13 out of the 15 subjects (86.7%) showed improvement of urine albumin-to-creatinine ratio or urine protein-to creatinine ratio after surgery; 2 showed equivocal results; 9 of 13 subjects (69.2%) showed remission of diabetic nephropathy; 7 of these 9 patients had microalbuminuria before surgery, 2 had macroalbuminuria before surgery. There were significant improvements to glycosylated haemoglobin, fasting plasma glucose, blood pressure and body weight post surgery. The usage of insulin and oral medications dropped significantly post surgery for all subjects. CONCLUSION: This study shows that bariatric surgery significantly improves diabetic nephropathy in obese type 2 diabetes mellitus subjects. The results suggest that in our local type 2 diabetes mellitus patients, it is possible not only to improve metabolic parameters, but also to reverse what may be considered established microvascular complications by means of bariatric surgery. PMID- 29153007 TI - Ultrasound-Guided Hyaluronic Acid Injection for the Management of Morton's Neuroma. AB - BACKGROUND: Morton's neuroma is one of the common causes of forefoot pain. In the present study, hyaluronic acid injection was performed on patients to determine the efficacy and adverse effects of hyaluronic acid in management of Morton's neuroma. METHODS: Eighty-three patients with Morton's neuroma in their third intermetatarsal space with definite Mulder's click were included in the study. Those with severe forefoot deformities such as forefoot cavus or hallux valgus on plain X-rays were excluded. Ultrasound-guided hyaluronic acid injections were performed on all patients weekly for 3 weeks. Pain during walking using visual analogue scale (VAS) and AOFAS Forefoot Scale were prospectively evaluated preinjection, and at 2, 4, 6, 12 months postinjection. RESULTS: Significant improvement in VAS and AOFAS Forefoot Scale were seen overall at 2 months after hyaluronic acid injections ( P < .05). Then, there were almost no changes after 4 months, continuing until 12 months. The mean VAS was decreased from 73.1 initially to 23.0 at 12 months and AOFAS Forefoot Scale was increased from 32.2 to 86.5. There were no complications which occurred. CONCLUSION: In the present study, ultrasound-guided hyaluronic injection was clinically effective for pain relief and functional improvement for at least 12 months in patients with Morton's neuroma. However, numbness associated with Morton's neuroma should be addressed more cautiously since it may persist without much improvement. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29153008 TI - Teaching Health versus Treating Illness: The Efficacy of Three Principles Correctional Counseling with People in an English Prison. AB - Three principles correctional counseling (3PCC) posits that people in prison have inner mental health they have obscured to varying degrees with their own thinking. 3PCC further posits that people in prison can rekindle and sustain this inner health via understanding how three psychospiritual principles-Universal Mind, consciousness, and thought-coalesce to form people's psychological experience. We review the three principles and explain how exposure to these principles can lead to improved mental health and improved behavior. Then, we describe 3PCC and distinguish it from prevailing correctional counseling methods. Finally, we present a preliminary study that examines the efficacy of 3PCC for improving the mental health and behavior of people in an English prison. Our findings show that participants exposed to 3PCC showed a significant improvement in mental well-being and purpose in life, significant reductions in anxiety and anger, and improved behavior in the prison community. PMID- 29153010 TI - Family Experiences and Sexual Victimization Histories: A Comparative Analysis Between Youth Sexual and Nonsexual Offenders. AB - Youth who commit sexual offenses often have sexual victimization histories that occur in the family context. These victimization experiences can be exacerbated by other risks present in the family environment. This research study uses MANOVAs to explore how family environments including substance use, mental health, physical and emotional victimization experiences, attachment, and parenting styles differentiate subgroups of youth offenders including youth sexual offenders with ( n = 179) and without ( n = 176) sexual victimization histories, and nonsexual offenders without sexual victimization histories ( n = 150). Results reveal that youth sexual offenders with sexual victimization histories had greater risks in family environments relative to youth sexual and nonsexual offenders without sexual victimization histories. Treatment and research implications are discussed. PMID- 29153009 TI - Mothers' perspectives on the lived experience of children with intellectual disability and challenging behaviour. AB - Children with intellectual disability and behavioural needs (challenging behaviour) are vulnerable to exclusion from services and communities. The situation is exacerbated by difficulties in accessing appropriate support and services to effectively meet the needs of children and carers. Family perspectives on the 'lived experience' of children can provide insight into how behavioural needs can affect their ability to access everyday experiences. Semi structured interviews were conducted with mothers of children with intellectual disabilities and challenging behaviours. Phenomenological thematic analysis provided four key themes: finding our way; square services, round needs; behaviour touches everything and belonging. Experience of inclusion and exclusion was a central tenet of the lived experience. Recommendations call for timely proactive and bespoke interventions to identify and support children at risk of exclusion from communities. Early intervention and effective local provision will avoid increased burdens placed on families and services, in supporting children whose needs are currently unmet within child-centred provision. PMID- 29153011 TI - All that glitters is not lupus. PMID- 29153012 TI - Conflict between nursing student's personal beliefs and professional nursing values. AB - BACKGROUND: Studies have established that negative perceptions of people living with HIV/AIDS exist among nursing students throughout the world, perceptions which can be detrimental to the delivery of high-quality nursing care. OBJECTIVES: The purpose of this research was to explore socio-cultural influences on the perceptions of nursing students towards caring for people living with HIV/AIDS. RESEARCH DESIGN: The study was guided by stigma theory, a qualitative descriptive research approach was adopted. Data collected via semi-structured interviews were thematically analysed. Participants and research context: Participants were 21 international and Australian undergraduate nursing students enrolled in a Bachelor of Nursing programme at an Australian university. Ethical considerations: Ethical approval was granted by the Social and Behavioural Research Ethics Committee at the study university. Participation was entirely voluntary; informed consent was obtained before the study commenced; confidentiality and anonymity were assured. FINDINGS: Three major themes were found: blame, othering and values. Complex and interrelated factors constructed participant perceptions of people living with HIV/AIDS, perceptions underscored by the prevailing culturally construed blame and othering associated with HIV/AIDS. The study found discordance between the negative personal beliefs and perceptions some nursing students have towards people living with HIV/AIDS, and the professional values expected of them as Registered Nurses. DISCUSSION: There was considerable commonality between this and previous studies on how homosexuality and illicit drug use were perceived and stigmatised, correlating with the blame directed towards people living with HIV/AIDS. These perceptions indicated some nursing students potentially risked not fulfilling the ethical and professional obligations the Registered Nurse. CONCLUSION: Nursing curriculum should be strengthened in relation to comprehending the meaning of being stigmatised by society. Educational institutions need to work towards enhancing strategies that assist nursing students to reconcile any incongruity between their personal beliefs and requisite professional nursing values. PMID- 29153013 TI - Estimation of overdiagnosis in breast cancer screening using a non-homogeneous multi-state model: A simulation study. AB - OBJECTIVES: Overdiagnosis is regarded as a harm of screening. We aimed to develop a non-homogeneous multi-state model to consider the age-specific transition rates for estimation of overdiagnosis, to validate the model by a simulation study where the true frequency of overdiagnosis can be calculated, and to compare our estimate with the cumulative incidence method. METHODS: We constructed a four state model to describe the natural history of breast cancer. The latent disease progression and the observed states for each individual were simulated in a trial with biennial screening of women aged 51-69 and a control group of the same size without screening. We performed 100 repetitions of the simulation with one million women to evaluate the performance of estimates. A sensitivity analysis with reduced number of controls was performed to imitate the data from the service screening programme. RESULTS: Based on the 100 repetitions, the mean value of the true frequency of overdiagnosis was 12.5% and the average estimates by the cumulative incidence method and the multi-state model were 12.9% (interquartile range: 2.46%) and 13.4% (interquartile range: 2.16%), respectively. The multi-state model had a greater bias of overdiagnosis than the cumulative incidence method, but the variation in the estimates was smaller. When the number of unscreened group was reduced, the variation of multi-state model estimates increased. CONCLUSIONS: The multi-state model produces a proper estimate of overdiagnosis and the results are comparable with the cumulative incidence method. The multi-state model can be used in the estimation of overdiagnosis, and might be useful for the ongoing service screening programmes. PMID- 29153014 TI - Evolution of the National Breast Screening Programme in Ireland: Two-year interval analysis (2004-2013) of BreastCheck. AB - OBJECTIVE: Monitoring breast screening programmes is essential to ensure quality. BreastCheck, the national breast screening programme in the Republic of Ireland, commenced screening in 2000, with full national expansion in 2007, and digital mammography introduced in 2008. We aimed to review the performance of BreastCheck from 1 January 2004 to 31 December 2013. METHODS: Using the customised clinical and administrative database, performance indicator data were collected from BreastCheck and compared with programme and European guideline standards. RESULTS: Over the decade, 972,236 screening examinations were performed. Uptake initially rose following national expansion, but fell in the subsequent years to <70% in 2012-2013. Following the introduction of digital mammography, initial recall rates increased from 5.2% in 2004-2005 to 8.1% in 2012-2013. Subsequent recall rates remained within the target of <3%. On average, invasive cancer detection rates were 6.6/1000 for initial and 4.5/1000 for subsequent women. Small cancer detection rates were for <15 mm 43.4% (initial women) and 51.7% (subsequent) and for <=10 mm 24.0% (initial) and 29.5% (subsequent). Ductal carcinoma in situ detection as a percentage of all cancers averaged 21.2% for initial and 20.0% for subsequent women. The majority were intermediate or high grade ductal carcinoma in situ. The positive predictive value was 11.9% for initial and 21.8% for subsequent women. Standardized detection ratios remained above the programme target. CONCLUSION: Revised indicators to reflect the digital mammography era are anticipated in revised European Guidelines on breast cancer screening. PMID- 29153015 TI - Prevention and treatment of radiation-induced acute dermatitis in head and neck cancer patients: a systematic review. AB - Acute dermatitis is the most common radio-induced side effect during treatment for head and neck cancer. The use of a wide variety of agents is reported to handle skin toxicity. Our aim was to review the literature and synthesize current available evidence. A comprehensive search was performed on multiple electronic databases until February 2017 and a systematic approach was carried out according to PRISMA guidelines. A total of 17 papers (950 patients on the whole) met the inclusion/exclusion criteria, with 12 randomized controlled trials and five nonrandomized observational and prospective studies. Generally speaking, there was no strong evidence to support the superiority of any specific intervention neither in prevention nor in therapeutic settings. Well-designed randomized studies including quality of life measurements are needed. PMID- 29153016 TI - Whole Root Transcriptomic Analysis Suggests a Role for Auxin Pathways in Resistance to Ralstonia solanacearum in Tomato. AB - The soilborne pathogen Ralstonia solanacearum is the causal agent of bacterial wilt and causes significant crop loss in the Solanaceae family. The pathogen first infects roots, which are a critical source of resistance in tomato (Solanum lycopersicum L.). Roots of both resistant and susceptible plants are colonized by the pathogen, yet rootstocks can provide significant levels of resistance. Currently, mechanisms of this 'root-mediated resistance' remain largely unknown. To identify the molecular basis of this resistance, we analyzed the genome-wide transcriptional response of roots of resistant 'Hawaii 7996' and susceptible 'West Virginia 700' (WV) tomatoes at multiple timepoints after inoculation with R. solanacearum. We found that defense pathways in roots of the resistant Hawaii 7996 are activated earlier and more strongly than roots of susceptible WV. Further, auxin signaling and transport pathways are suppressed in roots of the resistant variety. Functional analysis of an auxin transport mutant in tomato revealed a role for auxin pathways in bacterial wilt. Together, our results suggest that roots mediate resistance to R. solanacearum through genome-wide transcriptomic changes that result in strong activation of defense genes and alteration of auxin pathways. PMID- 29153017 TI - Mentoring the Next Generation of Peer Reviewers: A Triple Win. PMID- 29153018 TI - [Editor's commentary]. PMID- 29153019 TI - [The actual questions of the care of rare diseases]. AB - The aim was to present the actual situation of rare diseases, especially to characterize the circumstances in Hungary. The most important developments were summarized which could help the care of rare disease patients in the everyday practice. There are around 800 000 patients with rare diseases in Hungary. The lack of information leads to "invisibility" for the health and social care system (most of them without ICD code). Therefore, these patients still have a huge disadvantage even when compared to the patients of common diseases. Important national and international measures took place in the last years to decrease these disadvantages. The Hungarian Centres of Expertise were officially approved, thus several health care providers were able to get membership in the forming European Reference Networks. The rare disease specific "Lifebelt" Information Centre and Help Line was established by HUFERDIS. These steps assist the implementation of the National Rare Disease Plan, although its formal approval process has temporarily stopped because of the reorganization of the health care system. The summarized developments can contribute to define better patient directions, and thus decrease the family knocks about the maze of health, social and educational systems. The realization of Rare Disease National Strategy is needed to improve the current fragmentation of services and enable patients and health, social and educational professionals to provide and use best practice care. This will ensure that all patients with rare disease cannot only be diagnosed quickly, but also have timely access to the care and support that they need, resulting in a decreasing burden of families and society. Orv Hetil. 2017; 158(47): 1851-1856. PMID- 29153020 TI - [Williams-Beuren syndrome (Williams syndrome). Case report]. AB - Williams syndrome is a rare genetic disorder, that occurs equally in all ethnic groups and both sexes. The diagnosis might be missed during childhood in mild cases. However, establishing the diagnosis is important, not only to find the cause of intellectual disability but to look for cardiovascular, endocrine, psychiatry, urology and other conditions, which can occur at any age in the patients' lifetime. This case report presents the story of 47-year-old woman, who was admitted with haematemesis. During her stay on the ward, in the light of the distinctive facial features, mental retardation, and social behaviour patterns, the possibility of Williams syndrome emerged. Later, the diagnosis was confirmed by genetic analysis. This female is the oldest living patient with Williams syndrome in Hungary. Orv Hetil. 2017; 158(47): 1883-1888. PMID- 29153021 TI - [Adult phenylketonuria]. AB - Starting from 1975 phenylketonuria is part of the newborn screening program in Hungary. Since then a generation, treated with special diet and medical foods right after neonatal diagnosis has reached adulthood. Thanks to early treatment initiation, children with phenylketonuria are able to lead life to the full. Consequently, phenylketonuria is no longer considered a pediatric disease. Follow up of adult patients with phenylketonuria is performed in internal medicine centers specialized in metabolic diseases. The outcome of the lifelong special treatment, and the particularities of phenylketonuria in adulthood are yet to be determined. The aim of our review is to present recent findings in phenylketonuria focusing mainly on the adult care. After long time the first international guidelines appeared, new therapies were put in use, and these current developments are expected to be implemented in daily practice in the near future. New challenges must be met such as maternal phenylketonuria, long term effects of dietotherapy and the sequelae of untreated phenylketonuria in adulthood. Orv Hetil. 2017; 158(46): 1857-1863. PMID- 29153022 TI - [Rhabdomyolysis - may it be a metabolic myopathy? Case report and diagnostic algorithm]. AB - We report the case of a 46-year-old female patient with recurrent rhabdomyolysis. In the background of her metabolic myopathy an inherited metabolic disorder of the fatty acid oxidation, very long-chain acyl-coenzyme A-dehydrogenase deficiency was diagnosed. The diagnosis was based on abnormal acyl-carnitine- and urine organic-acid profile in addition to low residual enzyme activity, and was confirmed by genetic testing. After introduction of dietotherapy metabolic crisis necessitating hospital admission has not occurred neither have fixed myopathic changes developed. We present here the differential diagnosis of rhabdomyolysis and exertional muscle complaints, with the metabolic myopathies in focus. The main features of fatty acid oxidation disorders are highlighted, acute and chronic managements of very long-chain acyl-coenzyme A-dehydrogenase deficiency are discussed. Metabolic myopathies respond well to treatment, so good quality of life can be achieved. However, especially in fatty acid oxidation disorders, a metabolic crisis may develop quickly and can be fatal, albeit rarely. Some of these disorders can be identified by newborn screening, but occasionally the symptoms may manifest only in adulthood. With the presentation of this case we would like to point out that in the differential diagnosis of recurrent rhabdomyolysis inherited metabolic disorders should be considered regardless of the patient's age. Orv Hetil. 2017; 158(46): 1873-1882. PMID- 29153023 TI - [Bone metabolism in adults with phenylketonuria - Hungarian data]. AB - INTRODUCTION: Patients with phenylketonuria have lower bone mineral density compared to healthy people, however, the ethiology of these alterations is not clear. Hungarian data were missing in this topic. AIM: The main aim of our study was to survey the correlation between metabolic control and change of bone mineral density in early treated Hungarian adult patients with phenylketonuria. METHOD: In this monocentric study bone mineral density of 59 adult PKU patients have been repeatedly measured in a 4-year interval using dual-energy X-ray absorptiometry. Two subgroups have been established based on average blood phenylalanine levels. The correlation between the change in bone mineral density and average phenylalanine, tyrosine concentrations have been determined while initial bone mineral density and change have also been examined in the subgroups. RESULTS: Mean phenylalanine concentration was 614 (182-1222) micromol/L, whereas mean tyrosine concentration was 49 (24-99) micromol/L and the calculated ratio was 16 (4,5-35). Three patients have had severely decreased bone mineral density in either localisation while 22 have had mild decrease. Low bone mineral density compared to cronological age has been found by 9 patient. The mean change was +0.0380 (-0.1550-0.7800) g/cm2 in femur, and +0.0120 (-0.57300-0.3130) g/cm2 in the lumbar spine. There was a correlation in the change in Z-score neither with mean phenylalanine nor with tyrosine concentration. CONCLUSIONS: Bone mineral density was not changed and hardly influenced by the metabolic control in early treated young adult phenylketonuria patients in a few years interval. Orv Hetil. 2017; 158(47): 1868-1872. PMID- 29153024 TI - [Diet treatment of classical galactosemia]. AB - Classical galactosemia is an inherited disorder of the carbohydrate metabolism, most often caused by the deficient activity of the enzyme galactose-1-phosphate uridyltransferase. Classical galactosemia presents in the neonatal period with life threatening illness after galactose is introduced in the diet. Symptoms and signs include poor feeding, vomiting, and diarrhea, weight loss, jaundice, hypotension, cataracts, hepatosplenomegaly, hepatocellular insufficiency, and encephalopathy. Since 1975 the testing for galactosemia is part of the neonatal screening program in Hungary. Affected newborns are recognized in the first days of their life, and special diet is introduced immediately. The therapy of galactosemia is the lactose-free and galactose-poor diet for life. As a result of the nationwide newborn screening and the lifelong medical therapy, early treatment with galactosemia can achieve a normal life without serious complications. Orv Hetil. 2017; 158(47): 1864-1867. PMID- 29153025 TI - Gestational age-specific reference intervals for 15 biochemical measurands during normal pregnancy in China. AB - Aims Physiological changes that occur during pregnancy can influence biochemical parameters. Therefore, using reference intervals based on specimens from non pregnant women to interpret laboratory results during pregnancy may be inappropriate. This study aimed to establish the essential reference intervals for a range of analytes during pregnancy. Methods A cross-sectional study was performed in 13,656 healthy pregnant and 2634 non-pregnant women. Fifteen biochemical measurands relating to renal and hepatic function were analysed using an Olympus AU5400 analyzer (Olympus, Tokyo, Japan). All the laboratory results were checked for outliers using Dixon's test. Reference intervals were established using a non-parametric method. Results Alanine aminotransferase, aspartate aminotransferase, albumin, cholinesterase, creatinine, direct bilirubin, gamma-glutamyl transpeptidase, total bilirubin, total bile acid and total protein showed a decrease during the whole gestational period, while alkaline phosphatase and uric acid increased. Urea nitrogen, beta2-microglobulin and cystatin-C fell significantly during the first trimester and then remained relatively stable until third trimester. Reference intervals of all the measurands during normal pregnancy have been established. Conclusions The reference intervals established here can be adopted in other clinical laboratories after appropriate validation. We verified the importance, for some measurands, of partitioning by gestational age when establishing reference intervals during pregnancy. PMID- 29153026 TI - An inductively coupled plasma mass spectrometry method for relative free copper determination and generation of a paediatric reference interval. AB - Background Diagnosis of Wilson's disease is currently performed using caeruloplasmin as a first-line screening test; however, this test has well described limitations. Monitoring of known Wilson's disease patients often uses 24-h urine collection; however, this is inaccurate in children. Methods for directly measuring plasma free copper have been described, but no reference interval data exist for a paediatric population. Methods An inductively coupled plasma mass spectrometry method for measuring free copper was developed and validated, using ultracentrifugation. A paediatric reference interval was generated using 85 plasma samples from children attending outpatient clinics at University Hospital Southampton. Results Results showed no significant contamination of copper using the ultracentrifugation technique, and validation showed the method was accurate and precise with an analytical coefficient of variation between 5 and 7% depending on the concentration of free copper. Conclusions We describe the use and validation of an ultrafiltration inductively coupled plasma mass spectrometry method for plasma free copper with the first published paediatric reference interval. Free copper could provide much needed assistance for the monitoring of Wilson's disease in children and also for adults. PMID- 29153027 TI - Large abnormal peak on capillary zone electrophoresis due to contrast agent. AB - Background Some iodinated radio-contrast media absorb ultraviolet light and can therefore be detected by capillary zone electrophoresis. If seen, these peaks are typically small with 'quantifications' of below 5 g/L. Here, we describe the detection of a large peak on capillary zone electrophoresis that was due to the radio-contrast agent, OmnipaqueTM. Methods Serum from a patient was analysed by capillary zone electrophoresis, and the IgG, IgA, IgM and total protein concentrations were measured. The serum sample was further analysed by gel electrophoresis and immunofixation. Results Capillary zone electrophoresis results for the serum sample showed a large peak with a concentration high enough to warrant urgent investigation. However, careful interpretation alongside the serum immunoglobulin concentrations and total protein concentration showed that the abnormal peak was a pseudoparaprotein rather than a monoclonal immunoglobulin. This was confirmed by analysis with gel electrophoresis and also serum immunofixation. The patient had had a CT angiogram with the radio-contrast agent OmnipaqueTM; addition of OmnipaqueTM to a normal serum sample gave a peak with comparable mobility to the pseudoparaprotein in the patient's serum. Conclusions Pseudoparaproteins can appear as a large band on capillary zone electrophoresis. This case highlights the importance of a laboratory process that detects significant electrophoretic abnormalities promptly and interprets them in the context of the immunoglobulin concentrations. This should avoid incorrect reporting of pseudoparaproteins which could result in the patient having unnecessary investigations. PMID- 29153028 TI - Development of a simple indocyanine green measurement method using an automated biochemical analyser. AB - Background The indocyanine green retention rate is important for assessing the severity of liver disorders. In the conventional method, blood needs to be collected twice. In the present study, we developed an automated indocyanine green method that does not require blood sampling before intravenous indocyanine green injections and is applicable to an automated biochemical analyser. Methods The serum samples of 471 patients collected before and after intravenous indocyanine green injections and submitted to the clinical laboratory of our hospital were used as samples. The standard procedure established by the Japan Society of Hepatology was used as the standard method. In the automated indocyanine green method, serum collected after an intravenous indocyanine green injection was mixed with the saline reagent containing a surfactant, and the indocyanine green concentration was measured at a dominant wavelength of 805 nm and a complementary wavelength of 884 nm. Results The coefficient of variations of the within- and between-run reproducibilities of this method were 2% or lower, and dilution linearity passing the origin was noted up to 10 mg/L indocyanine green. The reagent was stable for four weeks or longer. Haemoglobin, bilirubin and chyle had no impact on the results obtained. The correlation coefficient between the standard method (x) and this method (y) was r=0.995; however, slight divergence was noted in turbid samples. Conclusion Divergence in turbid samples may have corresponded to false negativity with the standard procedure. Our method may be highly practical because blood sampling before indocyanine green loading is unnecessary and measurements are simple. PMID- 29153029 TI - A sense of belonging: The importance of fostering student nurses' affective bonds. PMID- 29153030 TI - Cytotoxicity Study of Textile Fabrics Impregnated With CuO Nanoparticles in Mammalian Cells. AB - Copper and copper compounds have multifunctional properties (antibacterial, antiviral, and antifungal) with promising applications. Copper in its nanoparticle (Cu NPs) forms has been widely used in various industrial and commercial applications. In the current research, the cytotoxic effects of textile fabrics impregnated with copper oxide nanoparticles (CuO NPs) were studied in mammalian cell lines. CuO NPs were impregnated onto textile substrates using 2 different techniques: the sonochemical generation and impregnation of NPs from metal complexes ( insitu) and a "throwing the stones" technology using commercially prepared CuO NPs. The cytotoxicity of these 2 textile fabric types was assayed on human dermal fibroblast (HDF) cells and human hepatocellular carcinoma cells (HepG2) and was evaluated by indirect contact using an MTT assay. The impregnated fabrics were not exposed to the cells, rather their leachates were used to test cytotoxicity. The fabrics were soaked into the growth media for up to 7 days, and the leachates from day 1 and day 7 were incubated with the cell lines for 24 hours prior to the testing. The discharge or leaching from antimicrobial nanomaterials into the surroundings and surface waters is posing a serious environmental threat, which needs to be addressed. Hence, with regard to product safety, it is a good approach to study the fabric leachates rather than the intact material. The results showed that CuO NPs are not toxic to HDF cells. However, cytotoxicity was seen in HepG2 cells with cell viability decreasing by 20% to 25% for all the fabrics after 24 hours. PMID- 29153031 TI - Human Co-culture Model of Neurons and Astrocytes to Test Acute Cytotoxicity of Neurotoxic Compounds. AB - Alternative methods and their use in planning and conducting toxicology experiments have become essential for modern toxicologists, thus reducing or replacing living animals. Although in vitro human co-culture models allow the establishment of biologically relevant cell-cell interactions that recapitulate the tissue microenvironment and better mimic its physiology, the number of publications is limited specifically addressing this scientific area and utilizing this test method which could provide an additional valuable model in toxicological studies. In the present study, an in vitro model based on central nervous system (CNS) cell co-cultures was implemented using a transwell system combining human neuronal cells (SH-SY5Y cell line) and glial cells, namely astrocytes (D384 cell line), to investigate neuroprotection of D384 on SH-SY5Y and vice versa. The model was applied to test acute (24-48 hours) cytotoxicity of 3 different neurotoxicants: (1) methyl mercury (1-2.5 MUM), (2) Fe3O4 nanoparticles (1-100 MUg/mL), and (3) methylglyoxal (0.5-1 mM). Data were compared to mono-cultures evaluating the mitochondrial function and cell morphology. The results clearly showed that all compounds tested affected the mitochondrial activity and cell morphology in both mono-culture and co-culture conditions. However, astrocytes, when cultured together with neurons, diminish the neurotoxicant-induced cytotoxic effects that occurred in neurons cultured alone, and astrocytes become more resistant in the presence of neurons. This human CNS co-culture system seems a suitable cell model to feed high-throughput acute screening platforms and to evaluate both human neuronal and astrocytic toxicity and neuroprotective effects of new and emerging materials (eg, nanomaterials) and new products with improved sensitivity due to the functional neuron-astrocyte metabolic interactions. PMID- 29153032 TI - Evaluation of the Carcinogenic Potential of Roxadustat (FG-4592), a Small Molecule Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase in CD-1 Mice and Sprague Dawley Rats. AB - The carcinogenic potential of roxadustat (FG-4592), a novel orally active, heterocyclic small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes in clinical development for treatment of anemia, was evaluated in CD-1 mice and Sprague Dawley rats. Inhibition of HIF-PH by roxadustat leads to a rapid increase in cytoplasmic HIF-alpha concentrations, followed by translocation of HIF-alpha to the nucleus and upregulation of HIF responsive genes, including erythropoietin. Roxadustat was dosed by oral gavage 3 times weekly (TIW) for up to 104 weeks in mice at 0, 15, 30, and 60 mg/kg and in rats at 0, 2.5, 5, and 10 mg/kg. Treatment-associated changes in hematology parameters were consistent with the pharmacologic activity of roxadustat and included elevations in hematocrit in mice at 30 and 60 mg/kg TIW and elevations in erythrocyte count, hemoglobin, hematocrit, and red cell distribution width in rats at 10 mg/kg TIW. No increase in mortality or neoplastic effects compared with vehicle controls was observed after roxadustat treatment in either species. No treatment-related nonneoplastic findings were observed in mice, whereas nonneoplastic microscopic findings in rats were limited to atrial/aortic thromboses at 10 mg/kg TIW males and bone marrow hypercellularity in all treated male and female groups, consistent with the pharmacology of roxadustat. In conclusion, roxadustat administered by oral gavage to mice and rats TIW for up to 104 weeks resulted in dose-dependent exposure and hematologic effects with no effect on survival or development of neoplastic lesions at up to 60 mg/kg in mice and up to 10 mg/kg in rats. PMID- 29153034 TI - Advances in MALDI Mass Spectrometry within Drug Discovery. PMID- 29153035 TI - An unusual presentation of pseudocowpox associated with an outbreak of pustular ulcerative vulvovaginitis in a Swedish dairy herd. AB - Species Pseudocowpox virus (PCPV; family Poxviridae) is known to cause pustular cutaneous disease in cattle. We describe an outbreak of pseudocowpox with an unusual clinical picture in a free-stall dairy herd of ~80 cows. Approximately 90% of the cows had vesicles, erosions, papules, and scabs on the vulva and vaginal mucosa. Histologic analysis of biopsy tissues indicated a primary, although not specified, viral infection. Transmission electron microscopy revealed parapoxvirus particles in both tissue and vesicular materials. Deep sequencing analysis of extracted DNA from swabbed vesicle areas gave a contig of nearly 120,000 nucleotides, matching the PCPV strain VR 634 with 100% identity. Analyses confirmed the absence of other potential causes of pustular vulvovaginitis such as bovine herpesvirus 1 and Ureaplasma diversum. A rolling cow brush was suspected to be the fomite. PMID- 29153036 TI - Waste management barriers in developing country hospitals: Case study and AHP analysis. AB - Healthcare waste management is an essential field for both researchers and practitioners. Although there have been few studies using statistical methods for its evaluation, it has been the subject of several studies in different contexts. Furthermore, the known precarious practices for waste management in developing countries raise questions about its potential barriers. This study aims to investigate the barriers in healthcare waste management and their relevance. For this purpose, this paper analyses waste management practices in two Brazilian hospitals by using case study and the Analytic Hierarchy Process method. The barriers were organized into three categories - human factors, management, and infrastructure, and the main findings suggest that cost and employee awareness were the most significant barriers. These results highlight the main barriers to more sustainable waste management, and provide an empirical basis for multi criteria evaluation of the literature. PMID- 29153037 TI - "Contract to Volunteer": South African Community Health Worker Mobilization for Better Labor Protection. AB - In this paper, we explore the increasing activity around labor rights for South African community health workers (CHWs). Contextualizing this activity within broader policy and legal developments, we track the emergence of sporadic mobilizations for decent work (supported by local health activist organizations) and subsequently, the formation of a CHW union. The National Union of Care Workers of South Africa (NUCWOSA) was inaugurated in 2016, hoping to secure formal and secure employment through government and the consequent labor and occupational health protections. Various tensions were observed during fieldwork in the run up to NUCWOSA's formation and raise important questions about representation, legitimacy, and hierarchies of power. We close by offering suggestions for future research in this developing space. PMID- 29153038 TI - A divergent pseudoglandular configuration of cutaneous plasmacytoma in dogs. AB - Cutaneous and mucocutaneous plasmacytoma (PCT) is a common neoplasm of dogs. Tumors can be single or multiple and occur predominantly in the oral cavity, lip, ears, digits, and trunk. Although these tumors typically offer no diagnostic challenge for the pathologist, subsets of PCTs with atypical morphologic configurations may make differentiation from other neoplasms difficult. We describe 6 cases of canine cutaneous and mucocutaneous PCT with pseudoglandular arrangement of neoplastic cells. The mean age of affected dogs was 11.3 y, and multiple breeds and sites were affected. Histologically, neoplastic cells were arranged in sheets, packets, and pseudoglandular structures containing central accumulations of blood or eosinophilic material admixed with neoplastic cells and hemosiderin-laden macrophages. Given the presence of pseudoglandular structures resembling neoplastic acini, epithelial neoplasia was occasionally included in the differential diagnosis. Neoplastic cells were strongly immunopositive for multiple myeloma oncogene 1 ( MUM-1) and immunonegative for pancytokeratin AE1/AE3. Canine cutaneous and mucocutaneous PCTs with pseudoglandular morphology may resemble epithelial neoplasia and raise questions about tumor histogenesis. PMID- 29153039 TI - Higher Anxiety Symptoms Predict Progressive Hippocampal Atrophy in the Chronic Stages of Moderate to Severe Traumatic Brain Injury. AB - BACKGROUND: In the chronic stages of moderate-severe traumatic brain injury (TBI), progressive hippocampal volume loss-continuing well after acute neurological insults have resolved-has now been well documented. Previous research in other populations suggests that elevated anxiety symptoms are associated with compromise to the medial temporal lobes. OBJECTIVE: To examine whether higher anxiety symptoms predict greater hippocampal volume loss in moderate-severe TBI. METHODS: We conducted an analysis of prospectively collected, longitudinal behavioral and magnetic resonance imaging (MRI) data from 5 to 12 to 30 months post-injury. Eighty participants were included in the study, with anxiety symptom and MRI data collected at a minimum of 2 time points. Correlational and bivariate latent difference score (with imputation) analyses were used to examine the relationship of Beck Anxiety Inventory scores with hippocampal volume loss, while controlling for depressive symptoms and total brain volume. RESULTS: Analyses revealed that higher anxiety symptoms at 5 and at 12 months following moderate-severe TBI predicted significant later volume loss in the right hippocampal complex and the right hippocampal head. Right hippocampal volume and volume change did not predict subsequent anxiety scores or anxiety change scores. CONCLUSIONS: These novel findings implicate anxiety symptoms as a possible predictor of progressive hippocampal volume loss in the chronic stages of moderate-severe TBI. PMID- 29153040 TI - Inpatient thrombophilia testing: Impact of healthcare system technology and targeted clinician education on changing practice patterns. PMID- 29153041 TI - Association of procalcitonin values and bacterial infections in pediatric patients receiving extracorporeal membrane oxygenation. AB - OBJECTIVE: There is increasing data in pediatrics demonstrating procalcitonin (PCT) is more sensitive and specific than other biomarkers in the setting of bacterial infections. However, the use of PCT in neonatal and pediatric extracorporeal membrane oxygenation (ECMO) is not well described. Therefore, the purpose of this study was to describe the clinical utility of PCT in determining the absence or presence of bacterial infections in neonatal and pediatric patients on ECMO. METHODS: This was a retrospective electronic medical record (EMR) review of data between January 1, 2010 to June 30, 2016 at a single, free standing, children 's hospital. All patients on ECMO with >=1 PCT level obtained while receiving ECMO support were eligible for inclusion. The EMR was searched for chest radiographs (CXR) and bacterial culture results (urine, blood, cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL) and respiratory cultures). All bacterial and viral cultures obtained within 5 days of PCT levels being obtained were analyzed. PCT levels of 0.5, 0.9, 1.0, 1.4 and 2.0 were used as the initial cut-off values for the analysis. The sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV) and likelihood ratios were calculated for each of the PCT levels. RESULTS: Twenty-seven patients met the inclusion criteria and contributed 193 PCT values for the analysis. The median age was 8 months (range 0 days to 18 years). Linear regression analysis demonstrated that a PCT cut-off of 0.5, 0.9 and 1.4 predicted the presence of a bacterial infection. The PCT value with the most utility was 0.5, with a sensitivity of 92%, a specificity of 43%, a positive predictive value of 60% and a negative predictive value (NPV) of 86%. CONCLUSION: This is the largest data set evaluating PCT in neonatal and pediatric patients on ECMO. A PCT value of 0.5 ng/mL had the most utility for determining the absence or presence of a bacterial infection in the setting of ECMO with a high sensitivity and NPV. PMID- 29153042 TI - The relationship of saturated fats and coronary heart disease: fa(c)t or fiction? A commentary. PMID- 29153043 TI - Effectiveness of mirror therapy, motor imagery, and virtual feedback on phantom limb pain following amputation: A systematic review. AB - BACKGROUND: Phantom limb pain is reported in 50%-85% of people with amputation. Clinical interventions in treating central pain, such as mirror therapy, motor imagery, or virtual visual feedback, could redound in benefits to amputee patients with phantom limb pain. OBJECTIVES: To provide an overview of the effectiveness of different techniques for treating phantom limb pain in amputee patients. STUDY DESIGN: Systematic review. METHODS: A computerized literature search up to April 2017 was performed using the following databases: PubMed, Scopus, CINAHL, MEDLINE, ProQuest, PEDro, EBSCOhost, and Cochrane Plus. Methodological quality and internal validity score of each study were assessed using PEDro scale. For data synthesis, qualitative methods from the Cochrane Back Review Group were applied. RESULTS: In all, 12 studies met our inclusion criteria, where 9 were rated as low methodological quality and 3 rated moderate quality. All studies showed a significant reduction in pain, but there was heterogeneity among subjects and methodologies and any high-quality clinical trial (PEDro score <=8; internal validity score <=5) was not found. CONCLUSION: Mirror therapy, motor imaginary, and virtual visual feedback reduce phantom limb pain; however, there is limited scientific evidence supporting their effectiveness. Future studies should include designs with more solid research methods, exploring short- and long-term benefits of these therapies. Clinical relevance This systematic review investigates the effectiveness of mirror therapy, motor imagery, and virtual visual feedback on phantom limb pain, summarizing the currently published trials and evaluating the research quality. Although these interventions have positive benefits in phantom limb pain, there is still a lack of evidence for supporting their effectiveness. PMID- 29153044 TI - The modular socket system in a rural setting in Indonesia. AB - BACKGROUND: Prosthetic services are inaccessible to people living in rural areas. Systems like the modular socket system have the potential to be fabricated outside of the prosthetic workshop. OBJECTIVES: This study aimed to evaluate the patient's performance and satisfaction with the use of the modular socket system, and the technical feasibility of its implementation in a rural setting. STUDY DESIGN: A quantitative longitudinal descriptive study design was followed. METHODS: A total of 15 persons with a lower limb amputation were fitted with the modular socket system and followed over 4-6 months. Performance was measured using a 2-min walk test, 10-m walk test and mobility and function questionnaire. Satisfaction was measured by the Socket Fit Comfort Score, Prosthesis Evaluation Questionnaire and EuroQoL 5 Dimensions 5 Levels. Notes on technical feasibility were taken at the moment of fitting ( t0), at 1-3 months post fitting ( t1) and at the end evaluation at 4-6 months post fitting ( t2). RESULTS: Performance did not change between t0 and t2. The comfort of the socket fit reduced between t0 and t2. Satisfaction with prosthesis and general health status stayed constant over time. The average fitting-time for the modular socket system was 6.4 h. CONCLUSION: The modular socket system can be considered a useful alternative for use in rural settings. Clinical relevance The use of the modular socket system is feasible and can improve accessibility to prosthetic technology in rural areas. Experienced prosthetic users were satisfied with the performance and the device. The shorter manufacturing time and use of only hand-held tools makes it an ideal alternative for use in remote and rural settings. PMID- 29153049 TI - UK Stroke Forum Abstracts, 2017. PMID- 29153045 TI - Treatment of clubfoot with the modified Copenhagen method: A 10-year follow-up. AB - BACKGROUND: Clubfoot is one of the most frequent congenital malformations in the world. Non-operative methods follows limiting surgery to a minimum. The modified Copenhagen method has not been studied enough. STUDY DESIGN: longitudinal retrospective study. OBJECTIVES: To evaluate prognostic factors for clinical rehabilitation with the modified Copenhagen method in a 10-year follow-up period. METHODS: A retrospective study was carried out on a 10-year follow-up of 82 children diagnosed with clubfoot at birth and treated with the modified Copenhagen method. Their sex, side, severity, bilaterality, forefoot orientation, and age when the nonoperative treatment was started were registered, and a cluster analysis was performed to determine which variables were most significant for predicting whether surgical treatment was needed. RESULTS: Of the clubfeet, 13.4% were grade I, 65.9% were grade II, and 20.7% were grade III according to the Harrold and Walker classification. In total, 58 patients needed surgery at some point during the follow-up period. The severity and talo-first metatarsal angle made it possible to determine whether the patients required surgery in 68% (56/82) of the cases. CONCLUSION: The results of the study suggest the possibility of providing physicians with an algorithm which might facilitate assessing whether the children will require surgery or not, depending on the data obtained from the cluster analysis. Clinical relevance This study provides health professionals with an algorithm that might facilitate assessing whether the children will require surgery or not. PMID- 29153050 TI - Factors influencing irradiance of locally fabricated phototherapy devices in Jos, north-central Nigeria. AB - Locally fabricated phototherapy devices (LFPDs) are widely used in Nigeria for the treatment of neonatal jaundice. Ours was a cross-sectional observational study of all LFPDs in major hospitals in Jos between January and March 2015. We evaluated a total of 24 LFPDs. The irradiance at the level of the baby was in the range of 2-23.9 uW/cm2/nm. Fourteen devices had the recommended irradiance of >=10 uW/cm2/nm and none had irradiance in the intensive range. Decreasing distance from the baby, presence of reflectors and increasing number of flourecent tubes significantly contributed to higher irradiance. A combination of six tubes, presence of reflectors and a distance of 10 cm from the baby produced a mean irradiance of 23.40 uW/cm2/nm. The irradiance of LFPDs varies widely and can be improved by simple modifications. PMID- 29153051 TI - Confirmation that the Novel Cercozoa Phytocercomonas venanatans Is the Cause of the Disease Chlorotic Streak in Sugarcane. AB - A cercomonad, named Phytocercomonas venanatans, is confirmed as the cause of the sugarcane disease chlorotic streak. This was achieved by establishing aseptic liquid cultures of the pathogen isolated from internal pieces of sugarcane stalk tissue. Actively motile cultures of the pathogen were inoculated into sugarcane roots, stalks, and leaf whorls. Infected plants subsequently developed the characteristic symptoms of chlorotic streak. Infection was confirmed by PCR screening of plant tissues and by reisolation of the pathogen into aseptic culture followed by PCR and microscopic confirmation. P. venanatans is the first reported pathogenic cercomonad able to systemically infect higher plants and the first plant pathogenic cercozoan able to be successfully grown in axenic culture on common microbiological media. PMID- 29153052 TI - Palliative Care Issues and Challenges in Saudi Arabia: Knowledge Assessment Among Nursing Students. AB - BACKGROUND: Nurses are the heart of the palliative care team who provide high standards of care since they spend the longest time with patients. However, lack of adequate knowledge of palliative care is considered as one of the main obstacles to palliative care improvement. AIM: A survey was conducted to assess Saudi nursing students' knowledge about palliative care. METHODS: Using a descriptive design, 154 students who enrolled in first year and who will graduate within 1 year were surveyed in a nursing college located in Riyadh, the capital of Saudi Arabia. The Palliative Care Quiz for Nursing (PCQN) was used to assess students' knowledge. RESULTS: The sample mean age was 22.1 (standard deviation (SD): 2.2), and most of the students were predominately female (93; 60.4%) and the majority were senior students who will be graduated within the current academic year (105; 68.2%). The total mean score of palliative care knowledge was low at 7.30 (SD: 0.56; range: 0-13), and the number of correctly answered statements ranged from 16 (10.4%, statement no. 7) to 91 (59.1%, statement no. 18). Eleven misconceptions about palliative care among participants are conceptually categorized into 3categories: principle and philosophy of palliative care, pain and symptom management, and psychological and spiritual care. CONCLUSION: Integrating palliative care education within the nursing programs is the backbone to improve nursing students' knowledge, namely, in principles of palliative care and symptom management. PMID- 29153054 TI - Care Workers in Argentina. AB - The working conditions, relative wages, and social standing of care occupations are the result of diverse causes that can worsen, improve, or neutralize the labor disadvantages usually found in care occupations. This article seeks to provide a perspective on the factors underlying care workers' working conditions in Argentina. It presents a comparative analysis of three highly feminized occupations-early education teachers, nurses, and domestic workers. After highlighting the different working conditions among these occupations, the paper focuses on the critically important role that unionization and state policies have played in defining each labor context in Argentina. The analysis shows how workers' evaluation of their occupation and working conditions are fundamentally shaped by these two variables. PMID- 29153053 TI - Experimental investigation of temperature rise in bone drilling with cooling: A comparison between modes of without cooling, internal gas cooling, and external liquid cooling. AB - Bone fracture occurs due to accident, aging, and disease. For the treatment of bone fractures, it is essential that the bones are kept fixed in the right place. In complex fractures, internal fixation or external methods are used to fix the fracture position. In order to immobilize the fracture position and connect the holder equipment to it, bone drilling is required. During the drilling of the bone, the required forces to chip formation could cause an increase in the temperature. If the resulting temperature increases to 47 degrees C, it causes thermal necrosis of the bone. Thermal necrosis decreases bone strength in the hole and, subsequently, due to incomplete immobilization of bone, fracture repair is not performed correctly. In this study, attempts have been made to compare local temperature increases in different processes of bone drilling. This comparison has been done between drilling without cooling, drilling with gas cooling, and liquid cooling on bovine femur. Drilling tests with gas coolant using direct injection of CO2 and N2 gases were carried out by internal coolant drill bit. The results showed that with the use of gas coolant, the elevation of temperature has limited to 6 degrees C and the thermal necrosis is prevented. Maximum temperature rise reached in drilling without cooling was 56 degrees C, using gas and liquid coolant, a maximum temperature elevation of 43 degrees C and 42 degrees C have been obtained, respectively. This resulted in decreased possibility of thermal necrosis of bone in drilling with gas and liquid cooling. However, the results showed that the values obtained with the drilling method with direct gas cooling are independent of the rotational speed of drill. PMID- 29153055 TI - Routine colonoscopy, diabetic eye care, mammogram and pap smear screening in vascular surgery patients. AB - Objective An increasing emphasis on preventive medicine has been supported by the recent reforms in United States health care system. Majority of the patients seen in vascular surgery clinics are elderly with more extensive medical comorbidities compared to the general population. Thus, these patients would be expected at higher risk for common malignant pathologies such as colon, breast and cervical cancer, and nonmalignant diseases such as diabetic retinopathy. This study looked at the screening compliance of vascular patients compared to data provided by Centers for Disease Control on the national and state levels. Methods The office records of 851 consecutive patients seen in Brooklyn and Staten Island vascular clinics were examined. We queried patients regarding their last colonoscopy, diabetic eye exams, recent mammograms, and Pap smears. Our patient screening compliance was compared between the two clinics as well as to the national and New York state data provided by Centers for Disease Control. Compliance with regard to patient's age was also examined. Results Patients referred to the Staten Island office have a better colonoscopy compliance compared to the Brooklyn office ( P = .0001) and the national Centers for Disease Control average ( P = .026). Compliance for mammography and cervical cancer screening was higher in Staten Island office compared to the Brooklyn office ( P = .0001, P < .0001), respectively. Compliance was lower for Pap smear ( P = .0273) in Brooklyn when compared to the national average. Compliance for colonoscopy increased with age for both clinics ( P = .001, P < .001), while Pap smear decreased ( P < .001, P = .004). Conclusion Patients in vascular clinics in an urban setting had better adherence to screening protocol than the national and state average, with the exception of female patients for colonoscopy in our Brooklyn vascular office. There exists variability in both patient populations based on sub-specific locality and demographics including socioeconomic status. Overall, however patients in Staten Island had better compliance and adherence to the screening protocol than Brooklyn vascular clinic. PMID- 29153056 TI - Association of Retroplacental Blood With Basal Plate Myofibers. AB - Objectives Diagnosed clinical abruption showing blood clot should be signed out in the pathology report as retroplacental hemorrhage with or without parenchymal indentation, and submitted clot separate from the placenta should be weighed. In our experience, some cases sent as clinical abruptions have been cases of morbid adherence. This study was undertaken to evaluate the association of retroplacental blood with basal plate myofibers (BPMF). Methods One hundred fifty six placentas reviewed by a board-certified pediatric pathologist at a community hospital were evaluated for significant retroplacental blood. Basal plates were reviewed for deviations from normal. Results Of the 156 placentas, 33 (21%) had significant retroplacental blood; 21/156 (13%) had a separate clot, of which 11/21 (52%) had BPMF. Eleven BPMF-associated separate clots ranged from 10.5 to 60 g (average 23), while the clots of 10 cases with no demonstrated BPMF ranged from 19 to 440 g (average 82), tending to be larger ( p < .03). Basal plate damage prior to delivery was noted in both sets of placentas. BPMF placentas could have myometrial damage prior to delivery. Conclusions Since BPMF may confer a risk for accreta in a subsequent pregnancy, submission of a separate clot with the placenta should lead the pathologist to evaluate for basal plate myofibers on H&E and consider if there is an evidence-based indication to do an actin stain, before presuming a diagnosis of abruption. PMID- 29153057 TI - Sex-Dependent Influence of Developmental Toxicant Exposure on Group B Streptococcus-Mediated Preterm Birth in a Murine Model. AB - Infectious agents are a significant risk factor for preterm birth (PTB); however, the simple presence of bacteria is not sufficient to induce PTB in most women. Human and animal data suggest that environmental toxicant exposures may act in concert with other risk factors to promote PTB. Supporting this "second hit" hypothesis, we previously demonstrated exposure of fetal mice (F1 animals) to the environmental endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to an increased risk of spontaneous and infection-mediated PTB in adult animals. Surprisingly, adult F1males also confer an enhanced risk of PTB to their control partners. Herein, we used a recently established model of ascending group B Streptococcus (GBS) infection to explore the impact of a maternal versus paternal developmental TCDD exposure on infection-mediated PTB in adulthood. Group B Streptococcus is an important contributor to PTB in women and can have serious adverse effects on their infants. Our studies revealed that although gestation length was reduced in control mating pairs exposed to low-dose GBS, dams were able to clear the infection and bacterial transmission to pups was minimal. In contrast, exposure of pregnant F1females to the same GBS inoculum resulted in 100% maternal and fetal mortality. Maternal health and gestation length were not impacted in control females mated to F1males and exposed to GBS; however, neonatal survival was reduced compared to controls. Our data revealed a sex-dependent impact of parental TCDD exposure on placental expression of Toll like receptor 2 and glycogen production, which may be responsible for the differential impact on fetal and maternal outcomes in response to GBS infection. PMID- 29153058 TI - Induction of the LH Surge in Premenarchal Girls Confirms Early Maturation of the Hypothalamic-Pituitary-Ovarian Axis. AB - PURPOSE: To determine whether premenarchal girls exhibit positive estradiol feedback similar to regularly cycling adult women when given exogenous estradiol. METHODS: This was a prospective clinical cohort study at 2 institutions. Nine girls and 6 women received a 7-day course of transdermal estradiol designed to produce physiologic, mid-cycle circulating estradiol levels. Participants collected daily morning urine for luteinizing hormone (LH), estradiol metabolites (E1c), and progesterone metabolites (Pdg), corrected for creatinine. Main outcomes were percentage increase in LH from nadir to peak and the absolute value of peak LH between the 2 groups, using t testing and linear mixed-effects modeling. RESULTS: All participants exhibited a positive feedback response to estradiol. Adult women had a 532.8% (95% confidence interval [CI]: 253.7-1119) increase in LH after estradiol exposure; premenarchal girls had a 497.9% increase (95% CI: 274.5-903.2; P = .86). The absolute value of the LH surge in women was 9.50 mLU/mgCr (95% CI: 2.59- 43 34.90) and in premenarchal girls was 2.57 mLU/mgCr (95% CI: 0.53-12.49; P = .15). CONCLUSIONS: Premenarchal girls can mount an LH surge proportionally similar to regularly cycling adults. This occurs earlier in puberty than previously believed, in contrast to current dogma that maturation of the hypothalamic-pituitary-ovarian axis occurs after menarche and is the rate-limiting step for the establishment of regular, ovulatory cycles. Failure to achieve regular cycles may instead be due to nutritional or ovarian factors. Young girls who fail to ovulate shortly after menarche may warrant further evaluation for endocrinopathies. PMID- 29153059 TI - Mid-to-Late Gestational Changes in Inflammatory Gene Expression in the Rat Placenta. AB - BACKGROUND: The placenta plays an important role during pregnancy providing maternal blood supply from the uterus to the developing fetus. The structure and function of the placenta changes with gestation, as the fetus develops and its demands change. This study aims to elucidate changes in cytokine and chemokine gene expression throughout mid-to-late gestation in rat placenta. METHODS: Sprague Dawley rats were time-mated, and placentae were obtained from 6 pregnant dams at 4 different gestational periods: E14.25, E15.25, E17.25, and E20. Changes in placental gene expression were measured by microarray analysis. Differentially expressed inflammatory genes were functionally categorized by pathway analysis. To validate the microarray results, a subset of genes was analyzed by quantitative real-time polymerase chain reaction (qPCR) in a validation cohort of 22 rats. RESULTS: Changes in messenger RNA (mRNA) expression of various cytokines, chemokines, and genes of the tumor growth factor beta and tumor necrosis factor family were analyzed in rat placentae at E14.25, E15.25, E17.25, and E20. Forty-six genes were differentially expressed, and of these 21 genes had increased expression in late gestation (E20). The gestational age pattern of gene expression was confirmed by qPCR in the validation cohort. CONCLUSION: The observed acute, prelabor changes in the expression of these genes during gestation warrant further investigation to elucidate their role in pregnancy and parturition. PMID- 29153060 TI - Using Pyruvate Kinase as a Predictor for Patient With Endometrial Cancer Having Complex Hyperplasia With Atypia to Prevent Hysterectomy and Preserve Fertility: Retrospective Immunohistochemical Study. AB - OBJECTIVES: To explore whether the metabolic switches proceed or succeed the histological changes in precancerous lesions. To validate pyruvate kinase isoform 1 (PKM1) and pyruvate kinase isoform 2 (PKM2) as a histological biomarker to predict the progression of endometrial hyperplasia into invasive cancer status. METHODS: The records of 56 patients with a primary diagnosis of complex hyperplasia with atypia after endometrial biopsy were selected and analyzed retrospectively. A set of 3 consecutive sections at 4-MUm thickness were cut and studied with immunohistochemical stains. From each case, 2 to 3 fields with a diagnosis of complex hyperplasia with atypia were selected and compared. A single pathologist blinded to the final diagnosis assigned the scoring. RESULTS: Positive immunostaining for PKM1 was observed in 31.25% (10 out of 32) of initial endometrial biopsy with the diagnosis of complex hyperplasia with atypia and final diagnosis of endometrial cancer, while 91.67% (out of 24) of patients with final diagnosis of negative endometrial cancer had endometrial biopsy with positive PKM1 staining ( P < .001). Positive immunostaining for PKM2 was observed in 100% of patient with endometrial biopsy result of endometrial hyperplasia with atypia (56 of 56). CONCLUSIONS: Lack of staining with PKM1 expression may help to predict the fate of endometrial hyperplasia. The disappearance of this marker is associated with the progression of hyperplasia toward cancer phenotype. Further studies are needed to understand the causes and potential mechanisms for suppressing Pyruvate Kinase Isoform 1 expression in endometrial hyperplasia. PMID- 29153061 TI - [Defining of gene mutations and minimal inhibitory concentrations in isoniazid resistant Mycobacterium tuberculosis isolates]. AB - Tuberculosis is a very important disease all over the world despite the advanced diagnostic and treatment regimens. Resistant tuberculosis, which has increased in recent years in particular, is a global problem and prevents the fight against tuberculosis. For this reason, it is important to determine the etiologic agent early and its sensitivity against antituberculosis drugs. Resistance profiles of the isolates and the gene mutations causing resistance are determined for epidemiological purposes and mutation regions of the isolates are being investigated on the basis of countries. The aim of our study was to determine the minimal inhibitor concentration (MIC) of isoniazid (INH) and to investigate the relationship between mutations in resistance genes and MIC values. For this purpose, 25 isoniazid (INH) monoresistant and 25 multidrug resistant (MDR), in total 50 clinical isolates were used and gene mutations causing INH resistance and the relationship of these mutations with minimal inhibitor concentrations (MICs) were searched by GenoType MTBDRplus (Hain Lifescience GMBH, Nehren, Germany) and antibiotic gradient test (E-test, AB BIODISK, Solna, Sweden) methods. The concordance of GenoType MTBDRplus and antibiotic gradient test methods for INH sensitivity, was 88% in INH monoresistant isolates, 80% in MDR isolates and 84% in all isolates. The most frequent mutation zone in INH monoresistant isolates was inhA C15T promotor zone (12 isolates, 54.5%) however, MIC of INH was > 256 ug/ml in two isolates and mutation in katG S315T was observed in both of these isolates. The most frequent mutation zone in MDR isolates was katG S315T (14 isolates, 56%) codon. MIC of INH was > 256 ug/ml in 10 isolates and mutation was observed in katG S315T codon in 5 (50%) isolates, in katG S315T codon and inhA C15T promotor zone in 3 (30%) isolates and in inhA promotor zone in 2 (20%) isolates, respectively. When all the isolates were analyzed, the most frequent mutation was found in katG S315T codon (24 isolates, 48%), MIC of INH was > 256 ug/ml among 12 isolates and the most frequent mutation zone in these isolates which have high MIC for INH was katG S315T codon. In conclusion, the results of this study have shown that the value of MICs for INH is high in isolates with katG S315T mutation, nevertheless, further investigations are needed to support this result. PMID- 29153062 TI - [Diagnostic accuracy of the LightCycler(r) SeptiFast assay in the childhood febrile neutropenia]. AB - Infection is the main problem among the patients receiving cancer therapy. The mortality rate can be reduced by the appropriate treatment in the right time. Although blood culture is the gold standard for the diagnoses of sepsis, many factors influence the results of blood culture in children. For this reason, real time polymerase chain reaction (Rt-PCR) has gained importance for the diagnoses of microbiological agents as it is faster than the conventional methods. In this study, we aimed to compare the efficacy of SeptiFast (SF) test with blood culture among children with neutropenic fever. Between January 2013 and December 2014, 62 children (34 boys, 38 girls) mean age 7.56 +/- 4.8 (0-18) years with cancer were included in this study during their 94 febrile attacks of neutropenia (NA). Blood samples for blood culture and Septifast test were taken before the initiation of antibiotic therapy. Blood cultures were routinely collected in aerobic and anaerobic media and incubated using the BACTEC 9120 system (Becton-Dickinson Diagnostic Systems, USA). Identification and antimicrobial susceptibility testing of the isolates were performed using the Vitek2(r) system (bioMerieux, France) according to the recommendations of the Clinical and Laboratory Standards Institute. The LightCycler SF test was used according to the manufacturer instructions. Of 94 attacks 34 (36.1%) were positive for blood culture and 33 (35.1%) for SF test. The positivity ratio is found as 29.7% (28/94) by blood culture when the analysis of five coagulase negative staphylococci were excluded due to contamination. Positivity was detected in 25 (26.6%) of the 94 NA both with blood culture and SF test.The difference between these two tests was statistically significant (p< 0.05). There was discordance with a rate of 28.7% between these two methods. Polymicrobial infections were detected only with SF test. The detection of fungal infection rate was higher with SF test than blood culture. When SF test was compared with blood culture the results were as follows; sensitivity 91%, specificity 98.3%, positive predictive value 97%, negative predictive value 96.7%, diagnostic performance was 96.2%, respectively. As a result, PCR based tests can be used in children with NA attacks even though blood culture is still needed to perform the antibiotic sensitivity tests. SF test seems to be a sensitive test for the early diagnosis of the pathogens and the initiation of the appropriate therapy according to the etiological agent. PMID- 29153063 TI - [Investigation of various virulence factors of Klebsiella pneumoniae strains isolated from nosocomial infections]. AB - Klebsiella pneumoniae is an opportunistic pathogen that commonly affects immunosuppressed patients and causes nosocomial infections. K.pneumoniae has a variety of virulence factors, especially capsule polysaccharide, hypermucoviscosity (HV), fimbriae, toxins and determinants for iron acquisition. The aim of this study was to detect the virulence factors in K.pneumoniae strains isolated from nosocomial infections in two years. Fifty three K.pneumoniae strains isolated from the samples of patients with nosocomial infections in the Medical Microbiology Laboratory of Selcuk University Faculty of Medicine Hospital between 2011 and 2013 were included in the study. Identification and antimicrobial susceptibilities of the isolates were performed by VITEK 2 automatic system. Biofilm formation,alpha-hemolysin, capsule and HV were investigated by phenotypic methods. Polymerase chain reaction (PCR) was used to detect virulence genes encoding adhesins (fimH-1, mrkD, kpn, ycfM), siderophores (entB: enterobactin, iutA: aerobactin, irp-1, irp-2, ybtS, fyuA: yersiniabactin, iroN: catechols receptor), protectines or invasins (rmpA, magA, traT) and toxins (hlyA, cnf-1). Of the 53 K.pneumoniae isolates,12 (22.6%) were isolated from in patients of reanimation intensive care unit, 8 (15.1%) medical oncology, 7 (13.2%) newborn intensive care unit and 26 (49%) other clinics. The distribution of the isolates according to the samples was as follows: urine (n= 14), blood (n= 13), wound (n= 8), drainage fluid (n= 10), broncho-alveolar lavage (n= 7), and cerebrospinal fluid (n= 1). Isolates which were resistant to meropenem were 5.7% and production of extended spectrum beta-lactamase (ESBL) was 71.7%. The capsule, biofilm formation, and HV were observed in 100%, 79.2%, and 1.9% of the isolates, respectively. Production of alpha-hemolysin was not detected in any of the isolates. The genes; entB (96.2%), ycfM (86.8%), and mrkD (83.0%) showed high prevalence. The other genes were detected in different ratios: fimH-1 (64.2%), fyuA (54.7%), kpn (49.1%), ybtS (41.5%), irp-1(41.5%), irp-2 (37.7%), traT (11.3%) and iutA (5.7%). Virulence genes; iroN, rmpA, magA, hlyA and cnf-1 were not detected in any of the isolates. Enterobactin had the highest rate among siderophores, and ycfM and mrkD in adhesins. The capsule and biofilm formation were commonly found in the isolates. Hypermucoviscosity was only found in one isolate but associated genes were not detected. Alfa hemolysin production and hlyA gene were not determined. As a result, it seems that the basis of the pathogenicity of K.pneumoniae strains isolated from nosocomial infections are capsule, adhesins, enterobactin and ability of biofilm formation. There is a need for new studies for the continuous monitoring of toxin and invasion ability as well as antibiotic resistance in the control of hospital infection caused by K.pneumoniae. PMID- 29153064 TI - [Comparison of polymerase chain reaction using kinetoplast DNA specific primers and other parasitological methods in the diagnosis of clinical samples of suspected patients with cutaneous leishmaniasis in Sanliurfa]. AB - Visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL) are seen endemically in Turkey and CL caused by Leishmania tropica is an important public health problem in southeastern as well as other regions of Turkey. The diagnosis has been usually made by clinical view of lesion and/or parasitologically using lesion aspiration smears. Histological examination does not, always reveal the parasite in the skin biopsy, particularly in chronic lesions. Besides this, due to CL infections caused by different species in endemic areas, diagnostic methods enabling species identification are in great need. Species identification, in the time of diagnosis, is an important procedure for helping the clinicians in the planning of treatment as well as control measures. Polymerase chain reaction (PCR) is a specific and sensitive diagnostic tool that can also identify the parasite at species level. Kinetoplast DNA (kDNA) is one of the genetic regions that can be used for the detection of Leishmania parasites in clinical specimens, kDNA PCR is reported as one of the most sensitive methods related to species specific variable regions in mini-circle long time ago. It has been considered as one of the most ideal targets for the diagnosis of leishmaniasis. The aim of the study was to perform PCR targeting kDNA by using the primers of Uni21/Lmj4 in clinical samples and compare the results with other parasitological methods like smear and culture, for the diagnosis of CL. The kDNA PCR, parasite culture and microscopical evaluation of stained smears of 62 specimens from suspected CL cases who have referred to Cutaneous Leishmaniasis Diagnosis and Treatment Center in Sanliurfa, Turkey were included in the study. The kDNA PCR showed the highest sensitivity 100% of the samples (35/35) among all diagnostic assays, followed by the microscopy (25/35 positive, 71.4% sensitivity) and culture (19/35 positive, 54.3% sensitivity). The sensitivity of combination of culture and microscopy was 88.6% (31/35 positive). These results suggested that performing kDNA PCR in addition to conventional techniques is important for improving the true diagnosis of CL to the species level and also important for establishing treatment regimens and designing appropriate precautions in highly endemic area like the southeastern region of Turkey. PMID- 29153065 TI - [Genotypes of rhinoviruses in children and adults patients with acute respiratory tract infections]. AB - Rhinovirus (RV) is one of the most frequent causative agent of acute respiratory tract infections in the world. The virus may cause a mild cold, as well as more serious clinical symptoms in patients with immune system deficiency or comorbidities. Rhinoviruses have been identified by molecular methods under three types: RV-A, RV-B and RV-C. In most of the cases, it was reported that RV-A and RV-C were related with lower respiratory tract infections and asthma exacerbations, while RV-B was rarely reported in lower respiratory tract infections. The main objective of this study was to investigate RV species by sequence analysis in nasopharyngeal samples in pediatric and adult patients who were admitted to hospital with acute respiratory tract infections and to establish the relationship between species and age, gender and clinical diagnosis of the patients. Secondly, it was planned to emphasize the efficiency of the sequence analysis method in the determination of RV species. One hundred twenty seven patients (children and adults) who were followed up with acute respiratory tract infections in our university hospital were evaluated between January 2014 and January 2016. Viral loads were determined by quantitative real-time PCR in RV positive patients detected by a commercial kit in nasopharyngeal swab specimens. Thirty-one samples whose viral loads could not be determined were excluded from the study. The remaining 96 samples (50 children and 46 adults) were retested by conventional PCR using the target of VP4/VP2 gene region. A total of 65 samples (32 adults and 33 children) with the bands (549 bp) corresponding to the VP4/VP2 gene regions after the conventional PCR were analyzed by DNA sequencing. A phylogenetic tree was constructed using the neighbour-joining method. After sequence analysis it was determined that 28 (43.07%) were RV-A, 7 (10.76%) were RV-B and 28 (43.07%) were RV-C; and moreover one of each enterovirus (EV) species EV-D68 (1.53%) and EV-C (1.53%) were detected. The distribution of the species in adults was: 15 (48.3%) RV-A, 5 (16.1%) RV-B and 11 (35.4%) RV-C. The distribution of the species in children was 13 (40.6%) RV-A, 2 (6.3%) RV-B and 17 (53.1%) RV C. RV-A is more frequent in adults, while RV-C is more frequent among children. It has been observed that RV-C infection is detected in children with bronchiolitis, while RV-A infection is detected in adults with pneumonia. There was no statistically significant difference between RV species and clinical diagnosis, age and gender in both of the age groups (p> 0.05). In conclusion, this is the first study that reports the frequency of RV species in children and adult patients with acute respiratory tract infections; the frequency of RV-A and RV-C species were found to be similar but higher than RV-B species in all age groups. RV-C and RV-A was the highest species seen in children and adult patients, respectively. There is a need for further research to identify the types of RV circulating in the community and the prevalence of infections caused by the species. PMID- 29153066 TI - [Age-related prevalence of toxoplasmosis among pregnant women in Hatay: Estimation depending on model]. AB - Toxoplasmosis, caused by the obligate intracellular protozoan Toxoplasma gondii, is a common parasitic infection affecting approximately one-third of the world population. T.gondii infections are usually acquired by ingesting raw or insufficiently cooked meat and from unwashed fruits and vegetables contaminated with soil or water with cat feces. Primary infection acquired during pregnancy can cause severe congenital abnormalities in the fetus such as neurologic and ocular malformations, abortion, or stillbirth according to the degree of infection. The aim of this study was to estimate the prevalence and rate of seroconversion of T.gondii IgG antibodies in a selected population of pregnant women in Hatay by using a mathematical model. T.gondii-specific serological screening test results of 11.564 pregnant women who have attended the Private Antakya Mosaic Obstetrics and Gynecology Hospital between 01.04.2009 and 31.04.2016 were analysed in the study. The prevalence of T.gondii-specific IgG antibodies in the studied population were found as 48.70% (95% CI, 0.48-0.50). The prevalence of T.gondii-specific IgG antibodies were increased linearly with age in our study population. The relationship between age and prevalence was statistically significant (p< 0.001). The age-specific rate of seroconversion was estimated as 0.8% for T.gondii infection in pregnant women. It was observed that the rate of T.gondii-specific IgG antibodies decreased from 55.12% (95% Cl, 0.52 0.57) detected in 2009 to 42.22% (95% Cl, 0.37-0.46) in 2016. The estimated number of cases carrying the risk of primer T.gondii infection was calculated as 69 in the study population. Our results have suggested that the prevalence of T.gondii-specific antibodies is high among pregnant women in Hatay. Early maternal diagnosis and treatment methods may reduce the risk of transplacental transmission during pregnancy. The on time diagnosis can only be achieved with prenatal serological screening. The knowledge of the incidence and prevalence of toxoplasma infection in pregnant women plays a crucial role in estimating the burden of the disease and evaluating the effectiveness of the public health protection policies including screening programmes. Expanding of training activities, drawing attention to hygiene, taking nutritional precautions and increasing awareness of toxoplasmosis in pregnant women are important to prevent congenital toxoplasmosis or minimize the disease. PMID- 29153067 TI - [Detection of influenza virus infections by molecular and immunofluorescence methods]. AB - Influenza virus infections are extremely important for human health due to the occurence of seasonal epidemics and pandemics worldwide. Influenza is associated with high morbidity and may result in serious complications such as life threatening viral or bacterial pneumonia. Especially, young children, older adults, patients with chronic diseases such as heart, lung, kidney, and diabetes and immunosuppressed people are at higher risk for complications and death from influenza virus infections. The aim of this study was to determine the incidence of influenza type A and B virus infections and influenza A virus subtypes in hospitalized patients with respiratory tract infections by real-time reverse transcriptase-polymerase chain reaction (RT-PCR, Sacace, Italy), conventional RT PCR and direct immunofluorescence antibody (DFA, Argene SA, France) tests. Nasopharyngeal swab specimens were collected from a total of 476 patients with respiratory tract symptoms by using flocked swabs (Copan Diagnostics, Italy) between 1 April 2012 and 31 December 2013. Influenza A virus was detected in 20.5% (98/476) and influenza B virus in 3.3% (16/476) of the cases by real-time RT-PCR test. During the study period, 63.3% of 98 influenza virus isolates were found as influenza A(H1N1)pdm09 and 36.7% were influenza A(H3N2) subtypes. Influenza A (H1N1) pdm09 subtype was observed in 12 cases in January 2013 and influenza A(H3N2) subtype was observed in 11 cases in December 2013 as the highest values. When the real-time RT-PCR test was regarded as the reference test, the sensitivities of DFA test for influenza A and B and conventional RT-PCR test with WHO primers (M30F2/08 and M264R3/08) for influenza A were detected as 72.4%, 75%, 96% and the specificities were detected as 99.2%, 99.5% and 100%, respectively. In conclusion, influenza A virus infection was detected rather high with a rate of 20.5% in the study group. The monitoring of influenza virus types and subtypes is required for the evaluation of influenza vaccine strains and circulating influenza viruses and for the identification of subtypes with pandemic potential. Planning for appropriate antiviral therapy using real-time RT PCR in the early diagnosis of influenza virus infections will significantly contribute to the management of the patient's treatment. Thus, unnecessary drug use will be prevented and controlled with effective treatment of the disease at the time of infection. PMID- 29153068 TI - [Atypical profile problem in serological diagnosis of EBV]. AB - Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis. Burkitt's lymphoma, nasopharyngeal carcinoma and post-transplant lymphoproliferative diseases are also associated with EBV. Diagnosis is frequently based on detection of specific antibodies. Using three parameters (anti VCA-IgM, anti VCA-IgG and anti EBNA-1 IgG), it is possible to define infection status and diagnose acute or past infection. However, sometimes the detection of atypical serological profiles makes it difficult to interpret these results. This study aims to evaluate the serological profiles of patient sera suspected of EBV infection and to determine atypical profiles. Sera of 2749 patients were analyzed between January 2014 and August 2016, in the Dokuz Eylul University Hospital Central Laboratory and evaluated retrospectively. Serum samples were tested for EBV VCA IgM and EBV VCA IgG antibodies with immunofluorescence test (Euroimmun, Germany), EBNA-1 IgG antibodies with enzyme immunoassay (Euroimmun, Germany). Medical files of the patients with two or more samples and have an atypical profile were reviewed. Patients were grouped as no EBV infection, acute infection, past infection and atypical serologic profile according to three routine laboratory assays (VCA IgG, VCA IgM and EBNA-1 IgG). Out of 2794 subjects 1334 (48.5%) were female and 1415 (51.5%) were male, with mean age 30 (< 1-89 years, median value: 27). The distribution of the results was; 72.5% past infection, 10.9% absence of EBV infection and 5.2% acute infection and 11.4% showed atypical serologic profile. Among the atypical profiles, isolated VCA-IgG positivity was the most frequent pattern detected in 7.9% which is followed by 2.7% of the cases with all three markers positive and 0.8% with isolated EBNA-1 IgG positivity. Off the patients, 72.5% were seropositive for EBV and this result is consistent with the seroprevalence studies previously conducted in Turkey. The rate of atypical profiles was 11.4% which is close to the result (15%) of another study performed in Izmir. Nearly one third of the patients with atypical serological profile had an immune disorder and it was possible to reach a conclusion only among half of the patients during serological follow-up. This study points out that clinical diagnosis and serologic follow-up is important for the interpretation of the atypical profiles. PMID- 29153069 TI - [Emerging pathogen: Candida kefyr (Kluvyeromyces marxianus)]. AB - In the central microbiology laboratory of Gazi University Hospital Candida kefyr was isolated from different clinical samples as 5.3% in 2016 and in 2017 this rate increased to 9.3% which was nearly two-fold and this has drawn our attention. The aim of this study was to evaluate the special characteristics, antifungal susceptibility and virulence properties of C.keyfr species. Germ tube, corn meal-tween 80 agar morphology and carbohydrate assimilation profiles on ID32C yeast identification system were used for the diagnosis of Candida species. In this study, DNA sequencing was performed using ITS1 and ITS4 primers amplifying fungal gene between 5.8S and 18S regions of rRNA. Antifungal susceptibility was performed using M27A microdilution method recommended by Clinical and Laboratory Standards Institute (CLSI). Minimum inhibitory concentration (MIC) values for amphotericin B, fluconazole, voriconazole and itraconazole were determined. MIC distribution, MIC50 and MIC90 values and geometric mean (GM) were detected. The existence of virulence factors caseinase, secreted aspartyl proteinase, esterase and phospholipase were investigated in vitro. A total of 865 Candida species were isolated from different clinical samples in the central microbiology laboratory of Gazi University Hospital in 2016. Among them, 46 (5.3%) were C.kefyr. In the first four months of 2017, 30 (9.3%) C.kefyr were identified among 320 Candida isolates. Ten isolates which have shown atypical morphology on corn meal agar were selected. Among these 10 isolates, nine of them were identified as C.kefyr by using ID32C system and DNA sequencing method. Amphotericin B MIC value was 2 ug/ml for one isolate, and fluconazole MIC value was 8 ug/ml for another isolate among 46 isolates. Among the 30 isolates of the year 2017, one of them presented MIC value for fluconazole as 8 ug/ml. No marked antifungal resistance was detected in our isolate group. Caseinase was positive in one C.kefyr isolate, and phospholipase were positive in eight of nine isolates. As a result, the reason of increase in the incidence of this Candida species, which does not show significant resistance and presents mostly phospholipase activity as a virulence factor, should be investigated in more detail. PMID- 29153070 TI - [The importance of the contribution of rapid test, serological and molecular methods in the diagnosis of two imported malaria cases with atypical microscopy]. AB - Malaria is a widespread and life-threatening disease in tropical and subtropical regions. In patients with typical clinical symptoms, malaria is considered as a preliminary diagnosis if there is a travel history to malaria-endemic areas. The basis of the laboratory diagnosis of malaria is the microscopic examination of Giemsa stained smears. On the other hand, the diagnosis and differentiation of Plasmodium species with microscopic examination may have some difficulties. In the first case, adifferent appearance from the classical Plasmodium vivax erythrocytic forms in infected erythrocytes were detected in 1% of all erythrocytes in thin smear blood preparations of a 26-year-old male with complaints of fever and chills and a story of travel to Nigeria. It was observed that parasitic nuclei were not prominent, and were located in the cytoplasm irregularly as chromatin or dye particles, nucleus fragments similar to Schuffner's granules in the form of scattered and granular spots were present in some erythrocytes, the cytoplasm of some Plasmodium erythrocytic forms were irregular and nuclei were not seen. There were no Schuffner's granules in any of the infected erythrocytes. P.vivax was detected by the rapid diagnostic test (OptiMAL, DiaMed GmbH, Switzerland), which searches for the antigens of Plasmodium species, in the peripheral blood sample of the patients. The P.vivax 18S rRNA gene was also detected by the multiplex real-time polymerase chain reaction. Antibodies against Plasmodium species were searched by using the Pan Malaria Antibody CELISA (CeLLabs Pty Ltd, Brookvale, Australia) kit in the patient's serum sample and the optical density (OD) value of the patient sample was measured five times the OD value of the positive control. In the second case, adifferent appearance from the classical P.falciparum erythrocytic forms in infected erythrocytes were detected in 12% of all erythrocytes in thin smear blood preparations of a 31-year-old male who has been suffering from persistent fever, severe headache, pain in the eyes and was known to be working in Nigeria. It was observed that some Plasmodium trophozoites have 1/3 of the size of erythrocytes such as P.vivax and have non-granular cytoplasm, some erythrocytic forms were round and the nucleus and cytoplasm were hardly distinguished, some of them were seen as crescent and close to the nucleus of the cytoplasm and some erythrocytic forms had characteristically a single nucleus and a scattered cytoplasm, similar to mature trophozoites of P.vivax. Although the Plasmodium young trophozoites were similar to P.vivax in means of magnitude, the forms in which the nuclei adhered to the erythrocyte wall were common. There were no P.falciparum gametocyte forms. P.falciparum like young trophozoite was observedonly in one of the four smears. P.falciparum was detected by the commercial rapid diagnostic test and P.falciparum 18S rRNA gene was also detected by the multiplex real-time polymerase chain reaction. Antibody formation against Plasmodium species was not detected in the ELISA test. In these case reports, the importance of the support of rapid diagnostic tests, serological and molecular methods to microscopic diagnosis and species determination of two imported malaria cases were demonstrated. PMID- 29153071 TI - [Mycoviruses and importance in mycology]. AB - Opportunistic fungal infections like invasive candidiasis and aspergillozis have high mortality rate particularly in immunosupressive patients. The rate of therapy success with antifungal agents is usually low. Although immunotherapy methods have been developed to increase the host response against antifungals, there has been a need for new antifungal therapeutic agents in the treatment of invasive aspergillozis and other opportunistic fungal infections. Mycoviruses are the viruses that specifically infect fungi. The use of mycoviruses in the treatment of invasive fungal infections has not been suggested yet. However, as mentioned in this review, the researches about the use of mycoviruses as a therapeutic agent have been still carried on. Mycoviruses have no infectivity as free particules. Many of them have RNA genome. They are classified as: Fungi containing "double stranded (ds) RNA, ds DNA or single stranded RNA". Although most of them are found in plant pathogenic fungi, they are also found in human pathogenic fungi. In most of the mycoviruses identified up to now, dsRNA genome are present. Mycoviruses that can be pathogenic for human and carrying dsRNA genome have been classified as Partitiviridae, Totiviridae, Chrysoviridae, Reoviridae and Hypoviridae. A part of mycoviruses may not cause any sign of infection in fungal host. The other part of mycoviruses causes hypovirulence or lethal effect. When hypovirulence occured in fungi, the observed effects are the decrease in pigmentation, mycelium formation, asexual sporulation, growing rate and the loss of fertility. The transfer of mycovirus to fungi may occur by intracellular or extracellular way. The transfer of genetic content to fungi occurs in two way: transformation and transfection. In both ways, there is a need for a spheroblast that has no cell wall. There are various scenarios about mycoviruses for the their use in the treatment. In the first scenario, the transfer of selective mycovirus is ensured by extracellular way, and then the binding of mycovirus to target fungus by genetic modifications is aimed. The second scenario is about the use of mycovirus as a vector for genetic transformation. In fact, this method is applied by using toxins in fungal diseases of plants. In addition, the production of lethal antibodies or peptides derived from antibodies obtained from toxin-coding cytoplasmic dsRNA mycovirus toxins may be a new therapeutic approach. It has been claimed that these derivatives may be used as parentheral therapeutic agents against human pathogenic fungi including Candida albicans. In this review article, the importance of mycoviruses in mycology has been discussed. PMID- 29153072 TI - Smoking Abstinence Twelve Months after an Acute Coronary Syndrome. AB - Studies on the cognitive working mechanism of smoking cessation in high-risk populations are few and much needed, and identifying long-term psychosocial factors to smoking cessation are relevant to improve intervention for cardiac patient groups. This longitudinal study followed patients who smoked and suffered an acute coronary syndrome from hospitalization to 12 months after clinical discharge. Questionnaires were administered to assess nicotine dependence, behavioral dependence, autonomous self-regulation, perceived competence, social support, anxiety, depressive symptoms and meaning in life at baseline, six months and twelve months after clinical discharge. The results showed that anxiety (F(2, 62) = 28.10, p < .001, eta p 2 = .48) and depressive symptoms (F(2, 62) = 10.42, p < .001, eta p 2 = .25) decreased over time, whereas meaning in life (F(2, 61) = 44.77, p < .001, eta p 2 = .59) and social support increased (t(63) = -4.54, p < .001, 95% IC[-11.05, 4.29], eta2 =.25). Smoking dependence was negatively predicted by change in perceived competence (B = -2.25, p = .011, 95% IC[.02, .60]) and positively by change in depressive symptoms (B =.37, p = .042, 95% IC[1.01, 2.05]) 12 months after clinical discharge. Nicotine dependence (t(17) = 2.76, p = .014, 95% IC[.39, 2.94], eta2 =.31) and the number of cigarettes smoked per day (t(17) = 4.48, p < .001, 95% IC[5.49, 15.29], eta2 =.54) decreased over time, whereas behavioral dependence increased among smokers (t(17) = -2.37, p = .030, 95% IC[-4.30, 2.54], eta2 =.25). This study suggests that long term abstinence in cardiac patients may be enhanced by psychological interventions addressing perceived competence, depressive symptoms and behavioral dependence. PMID- 29153073 TI - Social Support from Developmental Contexts and Adolescent Substance Use and Well Being: A Comparative Study of Spain and Portugal. AB - The aim of this study was to analyse the contribution of social support from family, friend and school (teacher and classmate) contexts in substance use (tobacco and alcohol use) and well-being (life satisfaction and health-related quality of life). Participants were 5,784 Portuguese and 22,610 Spanish adolescents aged 11 to 16 years, from the 2014 edition of the Health Behavior in School-aged Children (HBSC) study in Portugal and Spain. Results showed that for a higher life satisfaction, family (p < .001, partial eta2 = .032), teacher (p < .001, partial eta2 = .018) and classmate (p < .001, partial eta2 = .031) support were important in Portugal, and family (p < .001, partial eta2 = .056) and friend (p < .001, partial eta2 = .015) support in Spain. Similarly, for a better health related quality of life, all the social support variables were relevant in Portugal (family: p < .001, partial eta2 = .063; teacher: p < .001, partial eta2 = .032; classmate: p < .001, partial eta2 = .054; friend: p < .001, partial eta2 = .034) and in Spain (family: p < .001, partial eta2 = .054; teacher: p < .001, partial eta2 = .014; classmate: p < .001, partial eta2 = .018; friend: p < .001, partial eta2 = .040). In contrast, only family support (p < .001, partial eta2 = .014) was relevant in Portugal for tobacco use. Therefore, social support was more relevant for adolescent well-being than for adolescent substance use, and the most relevant source of support was family support, in both Spain and Portugal. PMID- 29153074 TI - Is being Punished at School an Indicator of Psychosocial Risk? AB - Research carried out in different cultural contexts shows that the use of exclusively coercive disciplinary measures does not improve the behavior of those punished, and may even increase the risks underpinning those behaviors. The aim of this research was to study whether there is a link between repeatedly suffering punishment at school and psychosocial risks in adolescence. A non experimental design was implemented with selected groups. The participants were 507 adolescents from four groups with different risk levels: in social protection (n = 189); subject to court measures (n = 104); in treatment for drug abuse (n = 25); and comparison group (n = 189). A questionnaire was applied collectively. The variables measured were school punishments, violence, drug consumption and commission of crimes. The mild punishments variable predicted and increased the probability of consuming alcohol, tobacco and cannabis by 34% (95% CI [1.1, 1.5]), and increased the probability of using illegal drugs by 11% (95% CI [1.11, 1.30]). Te severe punishments variable increased the probability of using illegal drugs by 86% (95% CI [1.41, 2.49]) and increased the probability of committing crimes by 40% (95% CI [1.13, 1.73]). School punishments, particularly if severe, stand as a visible indicator of psychosocial risk. Behaviors subjected to punishment should alert us to the need to intervene with individuals who manifest them for which the use of exclusively coercive measures is ineffective. A wider educational intervention is required to help them find their place in school instead of excluding them from it. PMID- 29153076 TI - Editorial overview: Emerging importance of social media for real-time communication in the modern medical era. PMID- 29153075 TI - Is whole-colon investigation by colonoscopy, computerised tomography colonography or barium enema necessary for all patients with colorectal cancer symptoms, and for which patients would flexible sigmoidoscopy suffice? A retrospective cohort study. AB - BACKGROUND: For patients referred to hospital with suspected colorectal cancer (CRC), it is current standard clinical practice to conduct an examination of the whole colon and rectum. However, studies have shown that an examination of the distal colorectum using flexible sigmoidoscopy (FS) can be a safe and clinically effective investigation for some patients. These findings require validation in a multicentre study. OBJECTIVES: To investigate the links between patient symptoms at presentation and CRC risk by subsite, and to provide evidence of whether or not FS is an effective alternative to whole-colon investigation (WCI) in patients whose symptoms do not suggest proximal or obstructive disease. DESIGN: A multicentre retrospective study using data collected prospectively from two randomised controlled trials. Additional data were collected from trial diagnostic procedure reports and hospital records. CRC diagnoses within 3 years of referral were sourced from hospital records and national cancer registries via the Health and Social Care Information Centre. SETTING: Participants were recruited to the two randomised controlled trials from 21 NHS hospitals in England between 2004 and 2007. PARTICIPANTS: Men and women aged >= 55 years referred to secondary care for the investigation of symptoms suggestive of CRC. MAIN OUTCOME MEASURE: Diagnostic yield of CRC at distal (to the splenic flexure) and proximal subsites by symptoms/clinical signs at presentation. RESULTS: The data set for analysis comprised 7380 patients, of whom 59% were women (median age 69 years, interquartile range 62-76 years). Change in bowel habit (CIBH) was the most frequently presenting symptom (73%), followed by rectal bleeding (38%) and abdominal pain (29%); 26% of patients had anaemia. CRC was diagnosed in 551 patients (7.5%): 424 (77%) patients with distal CRC, 122 (22%) patients with cancer proximal to the descending colon and five patients with both proximal and distal CRC. Proximal cancer was diagnosed in 96 out of 2021 (4.8%) patients with anaemia and/or an abdominal mass. The yield of proximal cancer in patients without anaemia or an abdominal mass who presented with rectal bleeding with or without a CIBH or with a CIBH to looser and/or more frequent stools as a single symptom was low (0.5%). These low-risk groups for proximal cancer accounted for 41% (3032/7380) of the cohort; only three proximal cancers were diagnosed in 814 low-risk patients examined by FS (diagnostic yield 0.4%). LIMITATIONS: A limitation to this study is that changes to practice since the trial ended, such as new referral guidelines and improvements in endoscopy quality, potentially weaken the generalisability of our findings. CONCLUSIONS: Symptom profiles can be used to determine whether or not WCI is necessary. Most proximal cancers were diagnosed in patients who presented with anaemia and/or an abdominal mass. In patients without anaemia or an abdominal mass, proximal cancer diagnoses were rare in those with rectal bleeding with or without a CIBH or with a CIBH to looser and/or more frequent stools as a single symptom. FS alone should be a safe and clinically effective investigation in these patients. A cost-effectiveness analysis of symptom-based tailoring of diagnostic investigations for CRC is recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN95152621. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 66. See the NIHR Journals Library website for further project information. PMID- 29153077 TI - Twitter 101 and beyond: introduction to social media platforms available to practicing hematologist/oncologists. AB - Social media utilizes specific media platforms to allow increased interactivity between participants. These platforms serve diverse groups and purposes including participation from patients, family caregivers, research scientists, physicians, and pharmaceutical companies. Utilization of these information outlets has increased with integration at conferences and between conferences with the use of hashtags and "chats". In the realm of the "e-Patient" it is key to not underestimate your audience. Highly technical information is just as useful as a basic post. With growing use, social media analytics help track the volume and impact of content. Additionally, platforms are leveraging each other for uses, including Twitter, blogs, web radio, and recorded video and images. We explore information on social media resources and applications from varying perspectives. While these platforms will evolve over time, or disappear with new platforms taking their place, it is apparent they are now a part of the everyday experience of oncology communication. PMID- 29153078 TI - The use and impact of Twitter at medical conferences: Best practices and Twitter etiquette. AB - The use of social media, and in particular, Twitter, for professional use among healthcare providers is rapidly increasing across the world. One medical subspecialty that is leading the integration of this new platform for communication into daily practice and for information dissemination to the general public is the field of hematology/oncology. A growing amount of research in this area demonstrates that there is increasing interest among physicians to learn not only how to use social media for consumption of educational material, but also how to generate and contribute original content in one's interest/expert areas. One aspect in which this phenomenon has been highlighted is at the time of maximum new information presentation: at a major medical conference. Hematologists/oncologists are engaging regularly in one of the most common forms of social media, Twitter, during major medical conferences, for purposes of debate, discussion, and real-time evaluation of the data being presented. As interest has grown in this area, this article aims to review the new norms, practices, and impact of using Twitter at the time of medical conferences, and also explores some of the barriers and pitfalls that users are encountering in this emerging field. PMID- 29153079 TI - Disease-specific hashtags and the creation of Twitter medical communities in hematology and oncology. AB - Twitter is being increasingly used for information gathering and dissemination of ideas in both medical practice and scientific research. A major limitation to its use has been the surplus of available information and difficulty in categorizing that information into topics of individual interest. However, a Twitter feature known as the hashtag (#), which denotes a specific category or topic, helps in streamlining this wealth of information. The creation and adoption of disease specific hashtags by healthcare stakeholders has led to a greater uniformity of medical discussions that can be retrieved and referenced at later time-points. As new disease-specific hashtags are created for hematologic and oncologic diseases, more users can connect across the world, even for the rarest of cancer subtypes. A major challenge for this emerging application will be the development of specific and easily identifiable hashtags over time to add more clarity, while still trying to grow Twitter users and expand its reach. PMID- 29153080 TI - Impact of social media for the hematologist/oncologist. AB - In the era of modern communication, the physician and patient relationship has evolved to include an entirely new dimension-social media. This new dimension offers several opportunities for patient education, research and its dissemination, and professional development for health care providers; it can also serve as a platform for addressing important public health issues. However, these advantages come with challenges such as threats to patient and professional privacy. In this article, we dissect the benefits and drawbacks of this social evolution on the practicing hematologist-oncologist. We also perform a review of the current literature on the integration of social media in the practice of hematology/oncology; examine available guidelines for information exchange between health care professionals, industry, pharmaceutical companies, advocacy groups, and patients; and offer ways to create its seamless integration into clinical hematology-oncology practice. PMID- 29153081 TI - Risks and benefits of Twitter use by hematologists/oncologists in the era of digital medicine. AB - Twitter use by physicians, including those in the hematology-oncology field, is increasing. This microblogging platform provides a means to communicate and collaborate on a global scale. For the oncology professional, an active Twitter presence provides opportunities for continuing medical education, patient engagement and education, personal branding, and reputation management. However, because Twitter is an open, public forum, potential risks such as patient privacy violations, personal information disclosures, professionalism lapses, and time management need to be considered and managed. The authors have summarized the benefits and risks of Twitter use by the hematology-oncology physician. In addition, strategies to maximize benefit and minimize risk are discussed, and resources for additional learning are provided. PMID- 29153082 TI - Advances in sensing and biosensing of bisphenols: A review. AB - Bisphenols (BPs) are well known endocrine disrupting chemicals (EDCs) that cause adverse effects on the environment, biotic life and human health. BPs have been studied extensively because of an increasing concern for the safety of the environment and for human health. They are major raw materials for manufacturing polycarbonates, thermal papers and epoxy resins and are considered hazardous environmental contaminants. A vast array of sensors and biosensors have been developed for the sensitive screening of BPs based on carbon nanomaterials (carbon nanotubes, fullerenes, graphene and graphene oxide), quantum dots, metal and metal oxide nanocomposites, polymer nanocomposites, metal organic frameworks, ionic liquids and molecularly imprinted polymers. This review is devoted mainly to a variety of sensitive, selective and reliable sensing and biosensing methods for the detection of BPs using electrochemistry, fluorescence, colorimetry, surface plasmon resonance, luminescence, ELISAs, circular dichroism, resonance Rayleigh scattering and adsorption techniques in plastic products, food samples, food packaging, industrial wastes, pharmaceutical products, human body fluids and many other matrices. It summarizes the advances in sensing and biosensing methods for the detection of BPs since 2010. Furthermore, the article discusses challenges and future perspectives in the development of novel sensing methods for the detection of BP analogs. PMID- 29153083 TI - Behavior and kinetic of hydrolysis of amine boranes in acid media employed in chemical vapor generation. AB - The behavior of NaBH4 (THB) and the amine boranes, NH3BH3 (AB), tertbutylNH2BH3 (TBAB), Me2NHBH3 (DMAB) was investigated in continuous flow chemical vapor generation of H2Se from aqueous SeIV coupled with atomic absorption spectrometry. Unexpected higher efficiency of H2Se generation was obtained with amine boranes compared to THB (TBAB > AB > THB) using millimolar concentration of reductant (0.001-0.1 mol L-1) under strongly acidic conditions (HCl, HClO4, H2SO4, HNO3, 0.5-5 mol L-1 H+). Analytical applicability of the CVG system was tested by the determination of SeIV in natural water samples certified reference materials, using 0.01 mol L-1 TBAB in 0.5 M H2SO4. In order to explain this unexpected higher efficiency of amine boranes with respect of THB, the kinetic of hydrolysis of AB, TBAB and DMAB was investigated in acid media typically employed in chemical vapor generation for trace element determination. The kinetic was investigated by monitoring the rate the hydrogen gas evolved during hydrolysis, using a laboratory made thermostated reaction cell. Kinetics were measured for AB, TBAB and DMAB in 0.1, 0.5, 5 mol L-1 HCl or HClO4 reaction media and in 0.1 mol L-1 cysteine +0.1 mol L-1 HCl or HClO4 buffer, for reaction times from 0 to 30 min. Under strongly acidic conditions, the rates of hydrogen evolution produced by amine boranes hydrolysis appear to be much slower than those predicted by a pseudo-first order reaction and using the rate constants reported in the literature. This suggests that, at elevated acidities (5 mol L-1 HCl or HClO4), the hydrolysis of amine boranes takes place in two steps, generating a first amount of H2 (0.67-1.15 mol) much faster than the remaining about 2 mol. This evidence indicates a different mechanism of hydrolysis to the one accepted in the literature for amine boranes. The relatively high efficiencies of H2Se observed with amine borane reduction of inorganic SeIV at elevated acidities can be addressed to the action of borane intermediates, most probably amine borane cations, formed during amine borane hydrolysis in the same reaction conditions. PMID- 29153084 TI - Combined Differential scanning calorimetry, Raman and Brillouin spectroscopies: A multiscale approach for materials investigation. AB - A new experimental setup combining DSC, Raman and Brillouin spectroscopies was developed. In order to estimate its accuracy and stability a study of silicon and the alpha-beta quartz phase transition were performed. The data obtained demonstrated good agreement with previous studies using these three different techniques. For quartz, the temperature behavior of its 147 cm-1 Raman mode was studied in detail. Using a two-phonon coupling treatment of the Raman band, we show for the first time that its behavior can be well described by Landau theory of first-order phase transitions. The combined DSC-Raman-Brillouin technique is a powerful tool for material science capable of studying thermal, structural and elastic properties simultaneously. PMID- 29153085 TI - An ultra-sensitive fluorescent "Turn On" biosensor for glutathione and its application in living cells. AB - In this work, an effective controlled-release biosensor based on Au nanocages (AuNCs) capped with disulfide-containing DNA molecular gates was developed for ultra-sensitive and highly selective detection of glutathione (GSH). Oligonucleotides containing the S-S bonds were assembled on the surface of the AuNCs by means of electrostatic interactions in order to inhibit the release of fluorescent molecules such as Rhodamine B (RhB) loaded by AuNCs. In the presence of GSH, due to the specific cleavage of S-S bonds in disulfide-containing single stranded DNAs (ssDNAs) as well as their subsequent departure from the surface of AuNCs, the pores could be opened, and then the dye molecules would be released from AuNCs. The concentration of GSH ranged from 1.0 * 10-12 to 6.0 * 10-10 M could be detected. The developed amplification strategy based on the controlled release of fluorescent molecules reached an extraordinary sensitivity of GSH. A detection limit of as low as 4.8 * 10-13 M with an excellent selectivity toward GSH could be achieved. The results of fluorescence microscopy imaging of GSH in living cells indicate that the fabricated system is an efficient controlled release biosensor in response to intracellular target molecules and predict its potential use for in situ molecular imaging in living systems. PMID- 29153086 TI - Novel immunochromatographic assay based on Eu (III)-doped polystyrene nanoparticle-linker-monoclonal antibody for sensitive detection of Escherichia coli O157:H7. AB - Colloidal gold immunochromatographic assay (ICA) has poor sensitivity when used for Escherichia coli O157:H7 (E. coli O157:H7) detection. Eu (III)-doped polystyrene nanoparticle (EuNP) has a large range of stokes shift, long decay time, and wide excitation spectrum and narrow emission spectra. EuNP has been used as novel probe in ICA to improve sensitivity. In this study, carboxyl modified EuNPs were prepared with different linkers. ICA based on EuNP, EuNP-6 carbon chain (CC) complex, EuNP-200CC complex, EuNP-1000CC complex, and EuNP streptavidin (EuNP-SA) complex were systematically compared for the detection of E. coli O157:H7. Under optimized working conditions, the limits of detection (LOD) of EuNP-ICA, EuNP-6CC-ICA, EuNP-200CC-ICA, EuNP-1000CC-ICA, and EuNP-SA-ICA were 9.54 * 102, 1.59 * 102, 3.18 * 102, 2.98 * 102, and 1.08 * 102 colony forming units (CFU) mL-1, respectively. The linear ranges of EuNP-ICA, EuNP-6CC ICA, EuNP-200CC-ICA, EuNP-1000CC-ICA, and EuNP-SA-ICA were 6.36 * 102-1.59 * 105, 3.18 * 102-1.59 * 105, 6.36 * 102-1.59 * 105, 6.36 * 102-1.59 * 105, and 8.0 * 101-1.59 * 105 CFU mL-1, respectively. EuNP-SA-ICA exhibited the highest sensitivity and the widest linear range with good specificity, accuracy, and precision. It could be a promising analytical method for detecting E. coli O157:H7 in food samples. EuNP-SA-ICA may be a good model for detecting low concentrations of other food-borne pathogens. PMID- 29153087 TI - A fluorescence aptasensor based on two-dimensional sheet metal-organic frameworks for monitoring adenosine triphosphate. AB - In the present study, a facile fluorescence aptasensor based on two-dimensional sheet metal-organic frameworks of N,N-bis(2-hydroxyethyl)dithiooxamidato copper(II) (H2dtoaCu) was developed for the sensitive detection of adenosine triphosphate (ATP). The sensing mechanism was based on the noncovalent interaction between FAM-labeled (fluorescein amidite) ATP aptamers and H2dtoaCu. In the absence of ATP, the FAM-labeled aptamer readily adsorbs onto H2dtoaCu, mainly via pi-pi stacking and hydrogen bond interactions between the nucleotide bases and the H2dtoaCu surface, leading to the reduction of fluorescence intensity of the FAM by photoinduced electron transfer (PET). In the presence of ATP, the FAM-labeled aptamer specifically forms ATP-binding aptamer complexes which exhibit only weak adsorption on the H2dtoaCu surface. Thus, the fluorescence of the FAM-labeled ATP aptamer remained largely unchanged. The fluorescence aptasensor exhibited a good linear relationship between the fluorescence intensity and the logarithm concentration of ATP over a range of 25 400 nM, with a detection limit of 8.19 nM (3S/N). ATP analogs such as guanosine triphosphate, uridine triphosphate, and cytidine triphosphate have negligible effect on the aptasensor performance due to the high selectivity of the ATP aptamer to its target, showing promising potential in real sample analysis. PMID- 29153088 TI - Methodology of analysis of very weak acids by isotachophoresis with electrospray ionization mass-spectrometric detection: Anionic electrolyte systems for the medium-alkaline pH range. AB - This work describes for the first time a functional electrolyte system setup for anionic isotachophoresis (ITP) with electrospray-ionization mass-spectrometric (ESI-MS) detection in the neutral to medium-alkaline pH range. So far no application was published on the analysis of very weak acids by anionic ITP-MS although there is a broad spectrum of potential analytes with pKa values in the range 5-10, where application of this technique promises interesting gains in both sensitivity and specificity. The problem so far was the lack of anionic ESI compatible ITP systems in the mentioned pH range as all typical volatile anionic system components are fully ionized at neutral and alkaline pH and thus too fast to suit as terminators. We propose an original solution of the problem based on the combination of two ITP methods: (i) use of the hydroxyl ion as a natural and ESI-compatible terminator, and (ii) use of configurations based on moving boundary ITP. The former method ensures effective stacking of analytes by an alkaline terminator of sufficiently low mobility and the latter offers increased flexibility for tuning of the separation window and selectivity according to actual needs. A theoretical description of the proposed model is presented and applied to the design of very simple functional electrolyte configurations. The properties of example systems are demonstrated by both computer simulation and experiments with a group of model analytes. Potential effects of carbon dioxide present in the solutions are demonstrated for particular systems. Experimental results confirm that the proposed methodology is well capable of performing sensitive and selective ITP-MS analyses of very weak acidic analytes (e.g. sulfonamides or chlorophenols). PMID- 29153089 TI - Chromatographic separation of the theranostic radionuclide 111Ag from a proton irradiated thorium matrix. AB - Column chromatographic methods have been developed to separate no-carrier-added 111Ag from proton irradiated thorium targets and associated fission products as an ancillary process to an existing 225Ac separation design. Herein we report the separation of 111Ag both prior and subsequent to 225Ac recovery using CL resin, a solvent impregnated resin (SIR) that carries an organic solution of alkyl phosphine sulfides (R3P = S) and alkyl phosphine oxides (R3P = O). The recovery yield of 111Ag was 93 +/- 9% with a radiochemical purity of 99.9% (prior) and 87 +/- 9% with a radiochemical purity of 99.9% (subsequent to) 225Ac recovery. Both processes were successfully performed with insignificant impacts on 225Ac yields or quality. Measured equilibrium distribution coefficients for silver and ruthenium (a residual contaminant) on CL resin in hydrochloric and nitric acid media are reported, to the best of our knowledge, for the first time. Additionally, measured cross sections for the production of 111Ag and 110mAg for the 232Th(p,f)110m,111Ag reactions are reported within. PMID- 29153090 TI - Chiral analysis of 3-sulfanylhexan-1-ol and 3-sulfanylhexyl acetate in wine by high-performance liquid chromatography-tandem mass spectrometry. AB - A number of polyfunctional thiols are well-recognised as some of the most potent aroma compounds in nature and have been identified in various foods, and beverages such as wine. These potent character impact compounds are present at nanogram-per-litre levels and are particularly challenging to measure. Where present, enantiomeric forms having different odour qualities further complicate the analysis. In this work, a chiral high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method using stable isotope dilution analysis (SIDA) has been developed and validated for the individual enantiomers of 3-sulfanylhexan-1-ol (3-SH, 1) and its O-acetate, 3-sulfanylhexyl acetate (3 SHA, 2), in wine after extraction as their 4-thiopyridine derivatives. Authentic derivatised thiols were first synthesised and used for chiral column screening and method development with polysaccharide-based HPLC phases. Validation of the method using a Lux Amylose-1 column for quantification of the enantiomers of 1 and 2 gave linear calibrations, and excellent figures for accuracy (recovery: 90% 111%, Z-score: -1.8-1.9), precision (RSDr<8%), and limits of detection (0.7 ng L 1 or less) in model media and different wine matrices. The newly developed method was applied to determine the enantiomer profiles of 1 and 2 in range of commercial wines. PMID- 29153091 TI - Detection of complex genomic signatures associated with risk in plasma cell disorders. AB - Plasma cell disorders (PCD) range from benign to highly malignant disease. The ability to detect risk-stratifying aberrations based on cytogenetic and molecular genetic assays plays an increasing role in therapeutic decision making. In this study, 58 patients were chosen for screening by comparative genomic hybridisation microarray (aCGH) to identify the new high-risk prognostic markers of chromothripsis and chromoanasynthesis. All patients had an unequivocal clinical diagnosis of a plasma cell disorder (plasma cell myeloma (PCM)(n = 51) or monoclonal gammopathy of undetermined significance (MGUS)(n = 7)) and an abnormal FISH result. There were a total of 17 complex genomic events identified across 9 patient samples, which were selected for further investigation by high definition single nucleotide polymorphism (HD-SNP) microarray. Each event was analysed and characterised for chromothripsis, chromoanasynthesis or a complex step-wise chromosomal event. We describe an effective method to identify the new high-risk prognostic markers of chromothripsis and chromoanasynthesis in plasma cell disorders. PMID- 29153092 TI - Is intrachromosomal amplification of chromosome 21 (iAMP21) always intrachromosomal? AB - Recurrent chromosomal abnormalities in childhood B-cell acute lymphoblastic leukemia (B-ALL) provide prognostic information that is useful in determining treatment stratification. iAMP21 is a more recently recognized cytogenetic entity of B-ALL that was originally described as multiple copies of the RUNX1 gene on a structurally abnormal chromosome 21. Subsequent studies elucidated a common region of highest-level amplification that includes RUNX1. Fluorescence in situ hybridization (FISH) is the most common method used to identify iAMP21, which is defined as the presence of five or more total copies of RUNX1, with three or more extra RUNX1 signals on a single abnormal chromosome 21. More recently, chromosomal microarray (CMA) and next generation sequencing have uncovered a characteristic chromosome 21 copy number profile in cases of iAMP21. We present a case of iAMP21 that does not fit the formal FISH definition. However, CMA uncovered the characteristic chromosome 21 copy number profile that is seen in iAMP21, demonstrating that CMA is helpful for the detection of this entity when FISH results are ambiguous. Furthermore, CMA showed that the highest level of amplification in this case did not include the RUNX1 gene, consistent with current evidence that RUNX1 is not the primary target of amplification. PMID- 29153093 TI - Next-generation sequencing and molecular cytogenetic characterization of ETV6-LYN fusion due to chromosomes 1, 8 and 12 rearrangement in acute myeloid leukemia. AB - In a newly diagnosed patient with acute myeloid leukemia (AML) and complex cytogenetics and negative for gene mutations associated with myeloid neoplasms, RNA sequencing by next-generation sequencing (NGS) through a large cancer-related gene panel showed ETV6-LYN leukemic fusion transcript. Breakpoint analysis of the NGS reads showed fusion of exon 5 of the ETV6 gene to exon 8 of the LYN gene. Metaphase fluorescence in situ hybridization (FISH) inferred a four-break rearrangement of three chromosomes, namely 1, 8 and 12. First, there was a balanced translocation t(1;12)(p13;p13.2) in which the ETV6 was split between der(1) and der(12). Second, an inverted insertion of 8q12.1~q24.21 into 1p13 occurred, thus bringing ETV6 and LYN into juxtaposition in the correct 5' to 3' orientation to produce an in-frame chimeric fusion gene on der(1). Notwithstanding two previous reports of ETV6-LYN fusion in myeloproliferative neoplasms (MPN), we report the first case of this fusion in AML and hence broaden its disease association. We also illustrate the clinical utility of NGS based detection of gene fusion in the setting of complex karyotype or cryptic aberration, since this method does not require a priori knowledge of the translocation partner and exact breakpoints to guide the application of appropriate primers or probes. PMID- 29153094 TI - Differences between chronic lymphocytic leukaemia and small lymphocytic lymphoma cells by proteomic profiling and SNP microarray analysis. AB - The majority of malignant cells in chronic lymphocytic leukaemia (CLL) circulate in the peripheral blood whereas small lymphocytic lymphoma (SLL) cells reside in tissues. The aim of this study was to detect differences in chemokine receptor expression, DNA single nucleotide polymorphism (SNP) microarray analysis and proteomic profiling to help elucidate why the cells remain in their respective environments. We identified by flow cytometric studies of chemokine receptors and DNA SNP microarray analysis significant differences between cells from CLL and SLL patients. Proteomic analysis revealed two potential markers (m/z 3091 and 8707) to distinguish the two disorders. There was a significantly greater expression of leucocyte trafficking receptor CXCR3 (CD183) and migration and homing receptor CXCR4 (CD184), and significantly lower expression of cell adhesion molecule integrin alpha4 chain (CD49d), on CLL cells, compared with SLL cells. Conversely, SNP microarrays revealed greater numbers of copy-neutral loss of heterozygosity chromosomal aberrations, as well as gross chromosomal aberrations, in the SLL group, compared with the CLL group. These findings revealed that there was a significantly greater expression of trafficking, migration and homing receptors and significantly lower expression of adhesion molecules on CLL cells than on SLL cells, and that SLL may be a more progressive disease than CLL, with a more complex genotype. PMID- 29153095 TI - Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer. AB - Cancer is a heterogeneous disease harboring diverse subclonal populations that can be discriminated by their DNA mutations. Environmental pressure selects subclones that ultimately drive disease progression and tumor relapse. Circulating cell-free DNA (ccfDNA) can be used to approximate the mutational makeup of cancer lesions and can serve as a marker for monitoring disease progression at the molecular level without the need for invasively acquired samples from primary or metastatic lesions. This potential for molecular analysis makes ccfDNA attractive for the study of clonal evolution and for uncovering emerging therapeutic resistance or sensitivity. We assessed ccfDNA from colon and pancreatic adenocarcinoma patients using next generation sequencing of 56 cancer associated genes at the time of primary resectable disease and metastatic progression and compared this to the mutational patterns of the primary tumor. 28%-47% of non-synonymous mutations in the primary tumors were also detected in the ccfDNA while 71%-78% mutations found in ccfDNA were not detected in the primary tumors. ccfDNA collected at the time of progression harbored 3-5 new mutations not detected in ccfDNA at the earlier collection time points. We conclude that incorporation of ccfDNA analysis provides crucial insights into the changing molecular makeup of progressive colon and pancreatic cancer. PMID- 29153096 TI - Correlations between microsatellite instability, ERCC1/XRCC1 polymorphism and clinical characteristics, and FOLFOX adjuvant chemotherapy effect of colorectal cancer patients. AB - Patients with MSI colorectal tumor have good prognosis and cannot benefit from 5 fluorouracil (5-Fu)-based chemotherapy reported by previous studies. While, single nucleotide polymorphisms (SNP) of ERCC1 and XRCC1 have be proved to influence clinical outcome of colorectal cancer patients treated with oxaliplatin based chemotherapy. We aim to study the correlation between molecular status and clinical- pathological features, and their effect on CRC patients' clinical outcome treated with mFOLFOX6 adjuvant chemotherapy. In this study, MSI status was determined in tumors and paired normal tissues from 101 colorectal cancer (CRC) patients. We also examined SNP of ERCC1 (c. C354T) and XRCC1 (c.G1196A) in 83 and 85 patients' blood. MSI was found to be significantly correlated with well/moderate histopathological differentiation (p = 0.038) and CRC family history (p = 0.003). CEA and CA19-9 levels was positive correlated significantly by Spearman correlation analysis (Pearson's r = 0.823, p < 0.0001). No significant correlation was found between MSI status and ERCC1/XRCC1 polymorphisms. We found greater drop of CEA level in mFOLFOX6 sensitive group than low sensitive group after mFOLFOX6 adjuvant chemotherapy according to MSI status, ERCC1 and XRCC1 SNP. MSI was significantly correlated with well/moderate histopathological differentiation (p = 0.038) and CRC family history (p = 0.003). The MSI status, ERCC1 and XRCC1 polymorphisms may influence the clinical outcome of colorectal cancer patients treated with mFOLFOX6 adjuvant chemotherapy. PMID- 29153097 TI - Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories. AB - Genetic testing for inherited cancer risk is now widely used to target individuals for screening and prevention. However, there is limited evidence available to evaluate the clinical utility of various testing strategies, such as single-syndrome, single-cancer, or pan-cancer gene panels. Here we report on the outcomes of testing with a 25-gene pan-cancer panel in a consecutive series of 252,223 individuals between September 2013 and July 2016. The majority of individuals (92.8%) met testing criteria for Hereditary Breast and Ovarian Cancer (HBOC) and/or Lynch syndrome (LS). Overall, 17,340 PVs were identified in 17,000 (6.7%) of the tested individuals. The PV positive rate was 9.8% among individuals with a personal cancer history, compared to 4.7% in unaffected individuals. PVs were most common in BRCA1/2 (42.2%), other breast cancer (BR) genes (32.9%), and the LS genes (13.2%). Half the PVs identified among individuals who met only HBOC testing criteria were in genes other than BRCA1/2. Similarly, half of PVs identified in individuals who met only LS testing criteria were in non-LS genes. These findings suggest that genetic testing with a pan-cancer panel in this cohort provides improved clinical utility over traditional single-gene or single syndrome testing. PMID- 29153099 TI - B-cell acute lymphoblastic leukemia with +der(1)t(1;19) (p13;p13.1) arising in the setting of CALR exon 9 mutated essential thrombocythemia. PMID- 29153098 TI - High amplification levels of MDM2 and CDK4 correlate with poor outcome in patients with dedifferentiated liposarcoma: A cytogenomic microarray analysis of 47 cases. AB - Dedifferentiated liposarcoma (DDLS) is characterized at the molecular level by amplification of genes within 12q13-15 including MDM2 and CDK4. However, other than FNCLCC grade, prognostic markers are limited. We aim to identify molecular prognostic markers for DDLS to help risk stratify patients. To this end, we studied 49 cases of DDLS in our institutional archives and performed cytogenomic microarray analysis on 47 cases. Gene copy numbers for 12 loci were evaluated and correlated with outcome data retrieved from our institutional electronic medical records. Using cut point analysis and comparison of Kaplan-Meier survival curves by log rank tests, high amplification levels of MDM2 (>38 copies) and CDK4 (>30 copies) correlated with decreased disease free survival (DFS) (P = .0168 and 0.0169 respectively) and disease specific survival (DSS) (P = .0082 and 0.0140 respectively). Additionally, MDM2 and CDK4 showed evidence of a synergistic effect so that each additional copy of one enhances the effect on prognosis of each additional copy of the other for decreased DFS (P = .0227, 0.1% hazard). High amplification of JUN (>16 copies) also correlated with decreased DFS (P = .0217), but not DSS. The presence of copy number alteration at 3q29 correlated with decreased DSS (P = .0192). The presence of >10 mitoses per 10 high power fields and FNCLCC grade 3 also correlated with decreased DFS (P = .0310 and 0.0254 respectively). MDM2 and CDK4 gene amplification levels, along with JUN amplification and copy alterations at 3q29, can be utilized for predicting outcome in patients with DDLS. PMID- 29153100 TI - Predictors and impacts of colostrum consumption by 4h after birth in newborn beef calves. AB - Newborn beef calf vigor is a vital survival characteristic that promotes timely colostrum consumption. Modified APGAR scores intended to identify compromised calves are not widely adopted due to impracticality, inconsistent associations with blood gas disturbances, and unclear recommendations for intervention. The objectives were to: (1) determine differences in at-birth blood parameters between calves that were successful in colostrum consumption by 4h (CC4) compared to those that failed; (2) develop a Beef Calf Vigor Assessment by determining calving characteristics and clinical examination parameters associated with CC4; and (3) evaluate impacts of failed CC4 on transfer of passive immunity and treatment risk. As a predictor for CC4, suckle reflex had the highest specificity (98%), whereas calving ease had the highest sensitivity (89%). Calves with a weak suckle reflex had 41.6 (95% CI: 7.4-787.5) times greater odds of failed CC4 compared to calves with a strong suckle reflex (P<0.0001). Calves with failed CC4 had lower serum IgG (P=0.01), had lower odds of acquiring optimal passive immunity (>24g/L serum IgG; OR=6.4, 95% CI: 1.2-34.4; P=0.02), and higher odds of being treated (OR=2.8, 95% CI: 1.1-7.4; P=0.03) than those that succeeded. Measuring suckle reflex in combination with calving ease was a quick and easy method to assess newborn beef calf vigor. The value of this Beef Calf Vigor Assessment was further emphasized by the negative impacts of failed CC4 on transfer of passive immunity and pre-weaning health. PMID- 29153101 TI - Local anaesthetics: More than meets the eye. PMID- 29153102 TI - Stability of compounded trilostane suspension in cod liver oil. AB - Trilostane is a synthetic steroid analog used to treat canine hyperadrenocorticism. For small dogs, the dose found in commercially available dosage forms of trilostane is sometimes too high. Compounding trilostane in a liquid diluent provides an option for more precise dosing and adjustments, and can be easier to administer, versus a tablet or capsule. Trilostane suspends well in cod liver oil, which is generally palatable to dogs. The stability of a compounded trilostane suspension in cod liver oil stored at room temperature was investigated for 90 days. Compounded trilostane retained stability, defined as maintaining 90-105% labeled value, for 60 days when stored in amber glass bottles. However, drug potency fell >10% below the labeled value when stored in amber plastic bottles after 7 days. PMID- 29153103 TI - Comprehensive analysis of gene expression profiles reveals novel candidates of chemotherapy resistant factors in canine lymphoma. AB - The molecular mechanisms of acquisition of chemotherapy resistance in canine lymphoma have not been elucidated. The aim of the present study was to identify novel molecular mechanisms of chemotherapy resistance by a comprehensive analysis of changes in gene expression profiles (GEPs). Tumor samples were obtained from 10 dogs with lymphoma at chemotherapy sensitive and chemotherapy resistant phases. During chemotherapy resistance, the expression of genes associated with immune responses and inflammatory reactions was decreased compared to chemotherapy sensitive phases. In addition, 11 genes, with significant changes in expression (P<0.05), were extracted from seven dogs with chemotherapy resistant lymphoma. Further studies are needed to investigate the associations of these changes in GEPs with the acquisition of chemotherapy resistance in canine lymphoma. PMID- 29153105 TI - Proposed method for estimating clinical cut-off (COCL) values: An attempt to address challenges encountered when setting clinical breakpoints for veterinary antimicrobial agents. PMID- 29153104 TI - Development and preliminary psychometric evaluation of an owner-completed measure of feline quality of life. AB - Due to improved healthcare and pet longevity, measurement of health-related quality of life (HRQoL) is increasingly important in companion animal medicine. The aim of this study was to develop and evaluate the content and psychometric properties of an owner-completed assessment of health and quality of life (QoL) in cats for use in general veterinary clinical practice. A 23-item feline QoL measure, drafted based on findings from an online survey completed by 45 pet owners, was revised following qualitative interviews with 10 pet owners of healthy cats to assess content validity. The resulting 22-item measure was completed twice by 199 owners of healthy cats to assess the reliability and validity of the measure via psychometric evaluation, including assessment of missing data, item response distributions, item correlations, factor analysis, internal consistency, test-retest reliability, multi-trait analysis, known groups analyses and estimation of minimally important differences. There were no missing data. Responses for all items were heavily skewed due to the sample being healthy. Analysis of items and factor analysis supported deletion of six items and calculation of two domain scores and a total score. Internal consistency and test-retest reliability were strong for all domains (0.70-0.80), indicating good reliability. All but three items demonstrated strong item convergent validity (item-scale correlation>0.40) and correlated highest with their respective domain (item discriminant validity). Significant between-group differences in scores differing according to a global impression of feline health item provided evidence of discriminative validity. Findings provide evidence that the final 16 item feline QoL measure has strong cross-sectional psychometric properties. PMID- 29153106 TI - Risk factors associated with case fatality in 225 diarrhoeic calves: A retrospective study. AB - The aim of this retrospective study was to identify the major risk factors associated with case fatality in diarrhoeic calves undergoing a standard therapeutic protocol. Clinical and laboratory findings were reviewed in 225 Holstein Friesian diarrhoeic calves over a 2 year period. Calves were treated according to a fluid therapy protocol using an oral electrolyte solution or an IV infusion. After therapy, 159 calves were discharged in a healthy state, whereas 66 calves died. Logistic regression analysis showed that serum total protein (STP) concentration (odds ratio, OR, 0.51; 95% confidence interval, CI 0.31-0.84; P<0.01) and the strength of suckle reflex (OR 4.83; CI 1.17-19.88; P<0.05) were the major risk factors associated with case fatality in diarrhoeic calves. These results could help to distinguish between diarrhoeic calves with a good prognosis and those with a major risk of treatment failure. PMID- 29153107 TI - Interictal cardiac autonomic nervous system disturbances in dogs with idiopathic epilepsy. AB - Autonomic nervous system (ANS) activity in the interictal period (InIp) in dogs with presumed idiopathic epilepsy (pIE) was assessed using heart rate variability (HRV) analysis. The HRVs obtained from 28 pIE dogs with interictal epileptic discharges (InIEd; 11 with treatment and 17 without treatment) detected on electroencephalography (EEG) were compared with those obtained from 13 healthy dogs. On electrocardiographic (ECG) study, the P wave dispersion (PWD; P<0.001), P max (P=0.004) and corrected QT interval (QTc; P=0.025) were significantly increased in the pIE group. On the basis of HRV analysis, the pIE dogs had an increased activity of the parasympathetic component of the ANS, including the percentage of R-R interval (pNN50%) that differs more than 50ms (P=0.011) and high frequency band (HF; P=0.041). Administration of phenobarbitone had no influence on the ANS pattern when pIE subgroups were compared (P>0.05). In InIp, dogs elicited specific conductibility delays of the electrical impulses (increased PWD and QTc interval); these delays are considered to be risk factors for developing severe arrhythmias, such as atrial fibrillation and ventricular tachycardia. When compared with human beings, a different ANS pattern characterised by increased parasympathetic activity was observed, which may influence the therapeutic approach of IE in dogs. PMID- 29153108 TI - Evaluation of a semi-automated computer algorithm for measuring total fat and visceral fat content in lambs undergoing in vivo whole body computed tomography. AB - Computed tomography (CT) is a suitable tool for measuring body fat, since it is non-destructive and can be used to differentiate metabolically active visceral fat from total body fat. Whole body analysis of body fat is likely to be more accurate than single CT slice estimates of body fat. The aim of this study was to assess the agreement between semi-automated computer analysis of whole body volumetric CT data and conventional proximate (chemical) analysis of body fat in lambs. Data were collected prospectively from 12 lambs that underwent duplicate whole body CT, followed by slaughter and carcass analysis by dissection and chemical analysis. Agreement between methods for quantification of total and visceral fat was assessed by Bland-Altman plot analysis. The repeatability of CT was assessed for these measures using the mean difference of duplicated measures. When compared to chemical analysis, CT systematically underestimated total and visceral fat contents by more than 10% of the mean fat weight. Therefore, carcass analysis and semi-automated CT computer measurements were not interchangeable for quantifying body fat content without the use of a correction factor. CT acquisition was repeatable, with a mean difference of repeated measures being close to zero. Therefore, uncorrected whole body CT might have an application for assessment of relative changes in fat content, especially in growing lambs. PMID- 29153109 TI - Non-invasive blood pressure measurement in ferrets (Mustela putorius furo) using high definition oscillometry. AB - This study was conducted to validate the use of high definition oscillometry (HDO) for non-invasive blood pressure (NIBP) measurements in ferrets and to establish reference ranges for NIBP in minimally sedated, healthy, young adult ferrets (<4years of age). The bias, limits of agreement and correlation for HDO compared to direct arterial blood pressure (DABP) measurement were established in 14 anaesthetised ferrets. Measurements were performed at the forelimb, hind limb and tail under hypo- (<110mmHg), normo- (110-170mmHg) and hypertensive (>170mmHg) conditions. Although HDO correlated well with DABP (r>0.90), it showed significant proportional bias, whereby HDO generally underestimated DABP with hyper- and normotensive conditions, and overestimated DABP with hypotensive conditions. Measurements obtained from the hind limb showed higher bias than those obtained from the tail or forelimb (P<0.001). Based on the above, and for practical reasons, the tail was selected as the preferred site of cuff placement in ferrets. Subsequently, a cross-over study was performed in 10 ferrets to establish the minimum dose of butorphanol and midazolam needed to successfully obtain NIBP in 100% of cases. Using this dose (0.2mg/kg IM, each), reference intervals for NIBP from 63 healthy, young adult ferrets were established at 95 155mmHg (systolic), 69-109mmHg (mean) and 51-87mmHg (diastolic) arterial pressures. PMID- 29153110 TI - Increased adrenocortical response to adrenocorticotropic hormone (ACTH) in sport horses with equine glandular gastric disease (EGGD). AB - This study tested the hypothesis that adrenocortical function would be altered in horses with equine gastric ulcer syndrome (EGUS). Twenty-six sport horses competing at national or international levels in eventing (n=15) or endurance (n=11) were subjected to a gastroscopic examination and an adrenocorticotropic hormone (ACTH) stimulation test. Salivary cortisol concentrations were measured before (baseline) and after (30, 60, 90, 120 and 150min) IV ACTH injection (1MUg/kg bodyweight). Within EGUS, two distinct diseases, equine squamous gastric disease (ESGD) and equine glandular gastric disease (EGGD), can be distinguished. ESGD was diagnosed in 8/11 (73%; 95% confidence intervals [95%CI], 43-92%) endurance horses and 5/15 (33%; 95% CI, 14-58%) eventing horses. EGGD was observed in 9/11 (82%; 95% CI, 53-96%) endurance horses and 9/15 (60%; 95% CI, 35 81%) eventing horses. The presence or severity of ESGD was unrelated to the presence or severity of EGGD. ACTH stimulation induced a larger increase in cortisol concentration in horses with moderate EGGD than in horses with mild EGGD. Cortisol concentration during the entire sampling period (total increase in cortisol concentration during the entire sampling period [dAUC], 31.1+/-6.4ng/mL) and the highest measured concentration at a single time point (maximal increase in cortisol concentration [dMAX], 10.3+/-2.3ng/mL) were increased (P=0.005 and P=0.038, respectively), indicating that horses with glandular gastric disease exhibited increased adrenocortical responses to ACTH stimulation. These results suggest that EGGD might be associated with an enhanced adrenocortical sensitivity. Further investigations are warranted to confirm the association between adrenocortical sensitivity and EGGD and to elucidate the pathophysiological mechanisms involved. PMID- 29153111 TI - Conducting Research on the Economics of Hypertension to Improve Cardiovascular Health. PMID- 29153112 TI - How Economic Findings Can Inform Prevention Research in Cardiovascular Disease. PMID- 29153113 TI - A Systematic Review of Economic Evidence on Community Hypertension Interventions. AB - CONTEXT: Effective community-based interventions are available to control hypertension. It is important to determine the economics of these interventions. EVIDENCE ACQUISITION: Peer-reviewed studies from January 1995 through December 2015 were screened. Interventions were categorized into educational interventions, self-monitoring interventions, and screening interventions. Incremental cost-effectiveness ratios were summarized by types of interventions. The review was conducted in 2016. EVIDENCE SYNTHESIS: Thirty-four articles were included in the review (16 from the U.S., 18 from other countries), including 25 on educational interventions, three on self-monitoring interventions, and six on screening interventions. In the U.S., five (31.3%) studies on educational interventions were cost saving. Among the studies that found the interventions cost effective, the median incremental costs were $62 (range, $40-$114) for 1 mmHg reduction in systolic blood pressure (SBP) and $13,986 (range, $6,683 $58,610) for 1 life-year gained. Outside the U.S., educational interventions cost from $0.62 (China) to $29 (Pakistan) for 1-mmHg reduction in SBP. Self-monitoring interventions, evaluated in the U.S. only, cost $727 for 1-mmHg reduction in SBP and $41,927 for 1 life-year gained. For 1 quality-adjusted life-year, screening interventions cost from $21,734 to $56,750 in the U.S., $613 to $5,637 in Australia, and $7,000 to $18,000 in China. Intervention costs to reduce 1 mmHg blood pressure or 1 quality-adjusted life-year were higher in the U.S. than in other countries. CONCLUSIONS: Most studies found that the three types of interventions were either cost effective or cost saving. Quality of economic studies should be improved to confirm the findings. PMID- 29153114 TI - Cost-effectiveness Analyses of Antihypertensive Medicines: A Systematic Review. AB - CONTEXT: Hypertension affects one third of the U.S. adult population. Although cost-effectiveness analyses of antihypertensive medicines have been published, a comprehensive systematic review across medicine classes is not available. EVIDENCE ACQUISITION: PubMed, Embase, Cochrane Library, and Health Technology Assessment were searched to identify original cost-effectiveness analyses published from 1990 through August 2016. Results were summarized by medicine class: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), thiazide-type diuretics, beta blockers, and others. Incremental cost-effectiveness ratios (ICERs) were adjusted to 2015 U.S. dollars. EVIDENCE SYNTHESIS: Among 76 studies reviewed, 14 compared medicines with no treatment, 16 compared medicines with conventional therapy, 29 compared between medicine classes, 13 compared within medicine class, and 11 compared combination therapies. All antihypertensives were cost effective compared with no treatment (ICER/quality-adjusted life year [QALY]=dominant $19,945). ARBs were more cost effective than CCBs (ICER/QALY=dominant-$13,016) in nine comparisons, whereas CCBs were more cost effective than ARBs (ICER/QALY=dominant) in two comparisons. ARBs were more cost effective than ACEIs (ICER/QALY=dominant-$34,244) and beta-blockers (ICER/QALY=$1,498-$18,137) in all eight comparisons. CONCLUSIONS: All antihypertensives were cost effective compared with no treatment. ARBs appeared to be more cost effective than CCBs, ACEIs, and beta-blockers. However, these latter findings should be interpreted with caution because these findings are not robust due to the substantial variability across the studies, including study settings and analytic models, changes in the cost of generic medicines, and publication bias. PMID- 29153115 TI - Prevalence and Medical Costs of Chronic Diseases Among Adult Medicaid Beneficiaries. AB - INTRODUCTION: This review summarizes the current literature for the prevalence and medical costs of noncommunicable chronic diseases among adult Medicaid beneficiaries to inform future program design. METHODS: The databases MEDLINE and CINAHL were searched in August 2016 using keywords, including Medicaid, health status, and healthcare cost, to identify original studies that were published during 2000-2016, examined Medicaid as an independent population group, examined prevalence or medical costs of chronic conditions, and included adults within the age group 18-64 years. The review and data extraction was conducted in Fall 2016 Spring 2017. Disease-related costs (costs specifically to treat the disease) and total costs (all-cause medical costs for a patient with the disease) are presented separately. RESULTS: Among the 29 studies selected, prevalence estimates for enrollees aged 18-64 years were 8.8%-11.8% for heart disease, 17.2% 27.4% for hypertension, 16.8%-23.2% for hyperlipidemia, 7.5%-12.7% for diabetes, 9.5% for cancer, 7.8%-19.3% for asthma, 5.0%-22.3% for depression, and 55.7% 62.1% for one or more chronic conditions. Estimated annual per patient disease related costs (2015 U.S. dollars) were $3,219-$4,674 for diabetes, $3,968-$6,491 for chronic obstructive pulmonary disease, and $989-$3,069 for asthma. Estimated hypertension-related costs were $687, but total costs per hypertensive beneficiary ranged much higher. Estimated total annual healthcare costs were $29,271-$51,937 per beneficiary with heart failure and $11,446-$20,585 per beneficiary with schizophrenia. Costs among beneficiaries with cancer were $29,384-$46,194 for the 6 months following diagnosis. CONCLUSIONS: These findings could help inform the evaluation of interventions to prevent and manage noncommunicable chronic diseases and their potential to control costs among the vulnerable Medicaid population. PMID- 29153116 TI - Community Guide Cardiovascular Disease Economic Reviews: Tailoring Methods to Ensure Utility of Findings. AB - The Community Preventive Services Task Force recommended five interventions for cardiovascular disease prevention between 2012 and 2015. Systematic economic reviews of these interventions faced challenges that made it difficult to generate meaningful policy and programmatic conclusions. This paper describes the methods used to assess, synthesize, and evaluate the economic evidence to generate reliable and useful economic conclusions and address the comparability of economic findings across interventions. Specifically, steps were taken to assess completeness of data and identify the components and drivers of cost and benefit. Except for the intervention cost of self-measured blood pressure monitoring intervention, either alone or with patient support, all cost and benefit estimates were standardized as per patient per year. When possible, intermediate outcomes were converted to quality-adjusted life year. Differences within and between interventions were considered to generate economic conclusions and inform their comparability. The literature search period varied among interventions. This analysis was completed in 2016. Although team-based care, self-measured blood pressure monitoring with patient support, and self-measured blood pressure monitoring within team-based care were found to be cost effective, their cost-effectiveness estimates were not comparable because of differences in the intervention characteristics. Lack of enough data or incomplete information made it difficult to reach an overall economic finding for the other interventions. The Community Guide methods discussed here may help others conducting systematic economic reviews of public health interventions to respond to challenges with the synthesis of evidence and provide useful findings for public health decision makers. PMID- 29153117 TI - Medical Expenditures Associated With Hypertension in the U.S., 2000-2013. AB - INTRODUCTION: Trends of prevalence, treatment, and control of hypertension have been documented in the U.S., but changes in medical expenditures associated with hypertension over time have not been evaluated. This study analyzed these expenditures during 2000-2013 among U.S. adults. METHODS: Data from the Medical Expenditure Panel Survey were analyzed in 2016. The study population was non institutionalized men and non-pregnant women aged >=18 years. Hypertension was defined as ever been diagnosed with hypertension or currently taking antihypertensive medications. Medical expenditures included all payments to medical care providers. Expenditures associated with hypertension were estimated by two-part regression models and adjusted into 2015 U.S. dollars. Controlling variables included sociodemographic characteristics, marital status, insurance, region, smoking status, weight status, health status, and comorbidities. Trends were analyzed using joinpoint method. RESULTS: Total per-person annual expenditures associated with hypertension in 2000-2001 ($1,399) were not significantly different from those in 2012-2013 ($1,494) (average annual percent change [AAPC]= -0.6%, p=0.794), but annual national spending increased significantly from $58.7 billion to $109.1 billion (AAPC=8.3%, p=0.015), mainly because of the increase in the number of people treated for hypertension. Per person outpatient payments were 22.7% higher in 2012-2013 than in 2000-2001 ($416 vs $322, p<0.05; AAPC=0.8%, p-trend=0.826). Payments for prescription medications took up a larger proportion of the medical expenditures associated with hypertension, compared to payments for outpatient or other services (33%-46%). CONCLUSIONS: During 2000-2013, annual national medical expenditures associated with hypertension increased significantly. Preventing hypertension could alleviate hypertension-associated economic burden. PMID- 29153118 TI - Comorbidity Status and Annual Total Medical Expenditures in U.S. Hypertensive Adults. AB - INTRODUCTION: The purpose of this study is to investigate comorbidity status and its impact on total medical expenditures in non-institutionalized hypertensive adults in the U.S. METHODS: Data from the 2011-2014 Medical Expenditure Panel Survey were used. Patients were included if they had a diagnosis code for hypertension, were aged >=18 years, and were not pregnant during the study period (N=26,049). The Elixhauser Comorbidity Index was modified to add hypertension related comorbidities. The outcome variable was annual total medical expenditures, and a generalized linear model regression (gamma distribution with a log link function) was used. All costs were adjusted to 2014 U.S. dollars. RESULTS: Based on the modified Elixhauser Comorbidity Index, 14.0% of patients did not have any comorbidities, 23.0% had one, 24.4% had two, and 38.7% had three or more. The five most frequent comorbidities were hyperlipidemia, diabetes, rheumatoid arthritis, depression, and chronic pulmonary disease. Estimated mean annual total medical expenditures were $3,914 (95% CI=$3,456, $4,372) for those without any comorbidity; $5,798 (95% CI=$5,384, $6,213) for those with one comorbidity; $8,333 (95% CI=$7,821, $8,844) for those with two comorbidities; and $13,920 (95% CI=$13,166, $14,674) for those with three or more comorbidities. Of the 15 most frequent comorbidities, the condition with the largest impact on expenditures for an individual person was congestive heart failure ($7,380). Hypertensive adults with stroke, coronary heart disease, diabetes, renal diseases, and hyperlipidemia had expenditures that were $6,069, $6,046, $5,039, $4,974, and $4,851 higher, respectively, than those without these conditions. CONCLUSIONS: Comorbidities are highly prevalent among hypertensive adults, and this study shows that each comorbidity significantly increases annual total medical expenditures. PMID- 29153119 TI - Annual Total Medical Expenditures Associated with Hypertension by Diabetes Status in U.S. Adults. AB - INTRODUCTION: Hypertension and diabetes, both independent risk factors for cardiovascular disease, often coexist. The hypertension-increased medical expenditures by diabetes status is unclear, however. This study estimated annual total medical expenditures in U.S. adults by hypertension and diabetes status. METHODS: The study population consisted of 40,746 civilian, non-institutionalized adults aged >=18 years who participated in the 2013 or 2014 Medical Expenditure Panel Survey. The authors separately estimated hypertension-increased medical expenditures using two-part econometric and generalized linear models for the total; diabetes (n=4,396); and non-diabetes (n=36,250) populations and adjusted the results into 2014 U.S. dollars. Data were analyzed in 2017 and estimated the hypertension-increased medical expenditures by type of medical service and payment source. RESULTS: The prevalence of hypertension was 34.9%, 78.3%, and 30.1% for the total, diabetes, and non-diabetes populations, respectively. The respective mean unadjusted annual per capita medical expenditures were $5,225, $12,715, and $4,390. After controlling for potential confounders, hypertension increased expenditures were $2,565, $4,434, and $2,276 for total, diabetes, and non-diabetes populations, respectively (all p<0.001). The hypertension-increased expenditure was highest for inpatient stays among the diabetes population ($1,730, p<0.001), and highest for medication among the non-diabetes population ($687, p<0.001). By payment source, Medicare ranked first in hypertension increased expenditures for the diabetes ($2,753) and second for the non-diabetes ($669) populations (both p<0.001). CONCLUSIONS: Hypertension-increased medical expenditures were substantial and varied by medical service type and payment sources. These findings may be useful as inputs for cost- effectiveness evaluations of hypertension interventions by diabetes status. PMID- 29153120 TI - Medical Expenditures Associated With Diabetes in Myocardial Infarction and Ischemic Stroke Patients. AB - INTRODUCTION: The coexistence of diabetes among people with acute myocardial infarction (AMI) or acute ischemic stroke (AIS) is common. However, little is known about the extent of excess medical expenditures associated with having diabetes among AMI and AIS patients. METHODS: Data on 3,307 AMI patients and 2,460 AIS patients aged >=18 years from the 2008 to 2014 Medical Expenditure Panel Survey were analyzed. Per capita annual medical expenditures associated with diabetes were separately estimated by healthcare components with generalized linear models and two-part models. Excess expenditure associated with diabetes is the difference between estimated expenditure conditional on having both diabetes and AMI (or AIS) and the estimated expenditure conditional on having AMI (or AIS) but not diabetes. All expenditures were adjusted to 2014 U.S. dollars. The analysis was conducted in 2017. RESULTS: Per capita annual total excess expenditures associated with diabetes were $5,117 (95% CI=$4,989, $5,243) for AMI patients and $5,734 (95% CI=$5,579, $5,887) for AIS patients. Of the total excess expenditures, prescription drugs accounted for 40% among AMI patients and 42% among AIS patients. Higher expenditures associated with diabetes were explained more by higher volume of utilization than higher per unit expenditures. CONCLUSIONS: Excess expenditures associated with diabetes were substantial among both AMI and AIS patients. These results highlight the needs for both prevention and better management of diabetes among AMI and AIS patients, which in turn may lower the financial burden of treating these conditions. PMID- 29153121 TI - Economic Burden of Informal Caregiving Associated With History of Stroke and Falls Among Older Adults in the U.S. AB - INTRODUCTION: Older adults are at high risk for stroke and falls, both of which require a large amount of informal caregiving. However, the economic burden of informal caregiving associated with stroke and fall history is not well known. METHODS: Using the 2010 Health and Retirement Study, data on non institutionalized adults aged >=65 years (N=10,129) in 2015-2017 were analyzed. Two-part models were used to estimate informal caregiving hours. Based on estimates from the models using a replacement cost approach, the authors derived informal caregiving hours and costs associated with falls in the past 2 years for stroke and non-stroke persons. RESULTS: Both the prevalence of falls overall and of falls with injuries were higher among people with stroke than those without (49.5% vs 35.1% for falls and 16.0% vs 10.3% for injurious falls, p<0.01). Stroke survivors needed more informal caregiving hours than their non-stroke counterparts, and the number of informal caregiving hours was positively associated with non-injurious falls and even more so with injurious falls. The national burden of informal caregiving (2015 U.S. dollars) associated with injurious falls amounted to $2.9 billion (95% CI=$1.1 billion, $4.7 billion) for stroke survivors (about 0.5 million people), and $6.5 billion (95% CI=$4.3 billion, $8.7 billion) for those who never had a stroke (about 3.6 million people). CONCLUSIONS: In U.S. older adults, informal caregiving hours and costs associated with falls are substantial, especially for stroke survivors. Preventing falls and fall-related injuries, especially among stroke survivors, therefore has potential for reducing the burden of informal caregiving. PMID- 29153123 TI - Healthcare Access Among Young Adults: Impact of the Affordable Care Act on Young Adults With Hypertension. AB - INTRODUCTION: The Patient Protection and Affordable Care Act provision implemented policies to improve coverage for young adults. It is not known if it affected access to care among young adults with hypertension. METHODS: National Health Interview Survey data from 2006 to 2009 and 2011 to 2014 were used. Young adults aged 19-25 years were assessed for potential barriers to access to health care. The authors compared the percentage of each indicator of barriers to access to health care among young adults in general, as well as those with hypertension in the two time periods and estimated the AOR. All data were self-reported. The analyses were conducted in 2016. RESULTS: Among young adults, the frequencies of barrier indicators were significantly lower in 2011-2014 than 2006-2009, except "did not see doctor in the past 12 months." Among those with hypertension, the percentage reporting "no health insurance" (31.3% vs 23.3%, p=0.037); "no place to see a doctor when needed" (30.5% vs 21.6%, p=0.031); or "cannot afford prescribed medicine" (23.0% vs 15.3%, p=0.023) were significantly lower in 2011 2014 compared with that of 2006-2009. The differences maintained statistical significance after adjusting for sex, race/ethnicity, and level of education. CONCLUSIONS: Significant differences in select access to care measures were found among young adults with hypertension between 2006-2009 and 2011-2014, as was found among young adults generally. Changes in extension of dependent insurance coverage in 2010 may have led to improvements in access to care among this group. PMID- 29153122 TI - Age-specific Cost Effectiveness of Using Intravenous Recombinant Tissue Plasminogen Activator for Treating Acute Ischemic Stroke. AB - INTRODUCTION: Studies have demonstrated that intravenous recombinant tissue plasminogen activator (IV rtPA) is a cost-effective treatment for acute ischemic stroke. Age-specific cost effectiveness has not been well examined. This study estimated age-specific incremental cost-effectiveness ratios (ICERs) of IV rtPA treatment versus no IV rtPA. METHODS: A Markov model was developed to examine the economic impact of IV rtPA over a 20-year time horizon on four age groups (18-44, 45-64, 65-80, and >=81 years) from the U.S. healthcare sector perspective. The model used health outcomes from a national stroke registry adjusted by parameters from previous literature and current hospitalization costs in 2013 U.S. dollars. Long-term annual costs and quality-adjusted life years (QALYs) in the years after a stroke were discounted at 3% per year. Incremental costs, incremental QALYs, and ICERs were estimated and sensitivity analyses were conducted between 2015 and 2017. RESULTS: Use of IV rtPA gained 0.55 QALYs and cost $3,941 more than no IV rtPA for stroke patients aged >=18 years over a 20-year time horizon. IV rtPA was a dominant strategy compared to no IV rtPA for patients aged 18-44 and 45-64 years. For patients aged 65-80 years, IV rtPA gained 0.44 QALYs and cost $4,872 more than no IV rtPA (ICER=$11,132/QALY). For patients aged >=81 years, ICER was estimated at $48,676/QALY. CONCLUSIONS: IV rtPA saved costs and improved health outcomes for patients aged 18-64 years and was cost effective for those aged >=65 years. These findings support the use of IV rtPA. PMID- 29153125 TI - Importance of the early identification of the palliative patient: Butterfly effect theory. PMID- 29153124 TI - Nutrition Label Use and Sodium Intake in the U.S. AB - INTRODUCTION: High sodium intake is a major risk factor for hypertension, but evidence is limited on which interventions are effective in reducing sodium consumption. This study examined the associations between frequent use of nutrition labels and daily sodium intake and the consumption of high-sodium foods in the U.S. METHODS: Using the 2007-2008 and 2009-2010 Flexible Consumer Behavior Survey, this study compared sodium intake measured from the 24-hour dietary recalls, availability of salty snacks at home, and frequencies of eating frozen meals/pizzas between frequent (i.e., always or most of the time) and infrequent nutrition label users. Also, the study examined the association between nutrition label use and sodium-related dietary behaviors across different demographic and socioeconomic groups. Data were analyzed in 2016. RESULTS: Frequent users of nutrition labels consumed 92.79 mg less sodium per day (95% CI= -160.21, -25.37), were less likely to always or most of the time have salty snacks available at home (OR=0.86, 95% CI=0.76, 0.97), but were just as likely to eat frozen meals or pizzas (incidence rate ratio=0.96, 95% CI=0.84, 1.08) compared with infrequent label users. The associations between nutrition label use and sodium intake differed considerably across age, gender, and socioeconomic groups. CONCLUSIONS: Frequent use of nutrition labels appears to be associated with lower consumption of sodium and high-sodium foods in the U.S. Given this small reduction, interventions such as enhancing nutrition label use could be less effective if implemented without other strategies. PMID- 29153126 TI - Cost Effectiveness of a Shingles Vaccine Booster for Currently Vaccinated Adults in the U.S. AB - INTRODUCTION: The Advisory Committee on Immunization Practices recommends a single dose of the live attenuated herpes zoster vaccine in people aged >=60 years. Because vaccine-induced protection decreases to zero after 10 years, many vaccinated people will soon be subject to an increased risk of the disease. The study objective was to determine the cost effectiveness of a herpes zoster vaccine booster and its optimal timing among immunocompetent adults first vaccinated at aged >=60 years. METHODS: A Markov model was built to follow vaccinated individuals for a lifetime. From the societal perspective, costs and quality-adjusted life years were compared between no booster versus booster options. A booster was given any time between 1 and 20 years after the first dose, and for those who had the first dose at different ages: 60, 70, and 80 years. Because people entered the model already vaccinated, costs and side effects of the first dose were not included. The booster was assumed to have the same efficacy and waning rate as the initial vaccination. Model inputs were based on published literature. A cost effectiveness threshold of $100,000/quality adjusted life year was used. The analysis was conducted in 2016. RESULTS: Cost effectiveness of a booster varied by age and time since vaccination. The booster cost <$100,000/quality-adjusted life year if given >5 years after the initial dose, but was most cost effective at around 10 years. The finding was robust to wide variations in model inputs. CONCLUSIONS: Under current assumptions, a booster dose of herpes zoster vaccine would be cost effective for all vaccinated people 10 years after initial vaccination. PMID- 29153127 TI - Enforcement Associated With Higher School-Reported Immunization Rates. AB - INTRODUCTION: North Dakota's school-reported kindergarten immunization rates were among the lowest in the U.S. during the 2015-2016 school year. Ninety percent of kindergartners were fully immunized in accordance with state requirements, 3% had an exemption, and as many as 7% were noncompliant. School enforcement of immunization requirements has been noted as variable. This study sought to better understand the relationship between school-reported immunization rates and the enforcement of immunization requirements. METHODS: Kindergarten immunization rates were compared between schools annually enforcing immunization requirements to the point of excluding noncompliant children and schools not enforcing. In addition, immunization rates were assessed after an educational intervention that led some school districts to change their enforcement policies during the 2015 2016 school year. Analyses were completed in 2016 and 2017. RESULTS: Kindergarten immunization rates were significantly higher in schools that annually enforced compared with schools that did not enforce (p<=0.001, all vaccines; difference between means: diphtheria-tetanus-attenuated pertussis=7.5% [95% CI=3.9%, 11.1%]; polio=6.2% [95% CI=3.3%, 9.1%]; measles, mumps, and rubella=7% [95% CI=3.5%, 10.5%]; hepatitis B=3.7% [95% CI=1.5%, 5.9%]; and varicella=6.9% [95% CI=3.4%, 10.4%]). School districts that began enforcing saw a significant increase in vaccination rates (diphtheria-tetanus-attenuated pertussis=6% [95% CI=2%, 11%] and measles, mumps, and rubella=7% [95% CI=3%, 11%]). Enforcement in newly enforcing districts led to a large decrease in the number of noncompliant students and did not lead to significant increases in exemption rates. CONCLUSIONS: In North Dakota, lack of school enforcement is strongly associated with lower immunization rates and a large noncompliant population. Addressing noncompliance through school enforcement could significantly increase school reported immunization rates. PMID- 29153129 TI - The changing of the guard: the past, the present, and the future of Kidney International. PMID- 29153130 TI - The key role of health professionals in preventing and combating transplant related crimes. PMID- 29153131 TI - Donor SIRP-alpha polymorphisms: widening the innate-to-adaptive continuum in allograft rejection. AB - In the usual paradigm, self:nonself recognition is attributed to calls of the adaptive immune system, owing to variations in specialized genes encoded within the major histocompatibility complex loci. However, an increasing body of data has shown that cells of the innate immune system also have self:nonself recognition functions relevant to organ transplantation, and this trait may derive from genes located outside the major histocompatibility complex loci. A recent publication identifies the donor SIRP-alpha gene as a non-major histocompatibility complex locus responsible for nonself recognition by monocytes, with variability resulting in changes in the surface interaction of SIRP-alpha with its ligand CD47. PMID- 29153132 TI - A novel role for renal epithelial cells and the medullary sodium gradient in the local immune response. AB - The extreme hypertonicity of the renal medulla plays a central role in regulating volume status. A recent publication in Cell has identified a novel role for the high sodium environment and the local epithelial cells in the recruitment of mononuclear phagocytes, potentially contributing to the defense against ascending urinary tract infection. PMID- 29153133 TI - Adaptor protein is a new therapeutic target in chronic kidney disease. AB - Ergothinoneine, derived from food, has powerful antioxidant effects. In this issue, Shinozaki et al. showed a novel kidney-intestine interaction, mediated by the postsynaptic density 95/disk-large/ZO-1 domain-containing protein (PDZK1) organic cation transporter 1 (OCTN1)-ergothinoneine axis. In chronic kidney disease, decreased PDZK1 disturbed the localization of OCTN1 on the intestine, resulting in decreased serum ergothinoneine, which canceled the compensatory expression of OCTN1 in the kidney. Because PDZK1 regulates the function of several transporters, targeting PDZK1 may be a new therapeutic target in chronic kidney disease. PMID- 29153134 TI - PHD in the FOXD1 lineage cells links hypoxia to inappropriate nephrogenesis. AB - Insufficient oxygenation during pregnancy negatively influences kidney development, which likely serves as a predisposing factor in chronic kidney disease at later stages in life. In this issue of Kidney International, Kobayashi et al. demonstrate that deletion of prolyl hydroxylase 2 and 3, 2 of the major oxygen sensors, in the FoxD1 lineage cells reduces kidney size and inhibits nephrogenesis in mice. Temporospatial expression pattern and studies on additional knockouts suggest the involvement of hypoxia-inducible factor 2. PMID- 29153135 TI - Understanding the pathogenesis of vascular calcification: timing is everything. AB - A number of histologic changes are associated with the medial arterial calcification that occurs in chronic kidney disease, leading to several different hypotheses concerning the underlying mechanism. Careful timing of these changes in relation to the onset of the calcification, as reported in this issue of the journal, can shed light on which changes are pathogenic as opposed to secondary in reaction to the calcification. PMID- 29153136 TI - Randomized controlled trials: significant results-fragile, though. AB - In their systematic review, Shochet et al. question the robustness of the statistical significance of the results of randomized controlled trials (RCTs) in nephrology reported in high-impact journals (2005-2014). They hypothesized that a high proportion of RCTs in nephrology would be fragile. They calculated a Fragility Index that is a tool for testing robustness of RCTs, based on 107 RCT reports. The observation of an alarming median Fragility Index equal to 3 suggests that in half of the trials, the sole additional occurrence of 3 events would compromise the significance of nominally significant results. PMID- 29153137 TI - CKD stage V in AL amyloidosis: is it too late to treat? Maybe not. AB - Ig light chain amyloidosis is a protein misfolding disease capable of causing multiorgan failure. Organ failure can be stopped by reducing the production of Ig light chain. The current study by Rezk et al. found that even patients with advanced chronic kidney disease can benefit if the serum free light chain can be substantially reduced within the first 3 months. This, if confirmed, can have a huge impact in the management of these patients. PMID- 29153138 TI - p-cresol sulfate and indoxyl sulfate: some clouds are gathering in the uremic toxin sky. AB - An increasing body of experimental and clinical evidence suggests that p-cresol sulfate and indoxyl sulfate contribute to the high cardiovascular burden in patients with chronic kidney disease. In a post hoc analysis on the HEMO trial, Shafi et al. failed to confirm an association between total p-cresol sulfate and indoxyl sulfate and cardiovascular outcomes in dialysis patients. Analytical issues and case-mix may explain the discrepant findings. PMID- 29153139 TI - Importance of reliable variant calling and clear phenotyping when reporting on gene panel testing in renal disease. AB - Genetic testing in kidney disease has been gaining more attention in recent years as an important diagnostic tool. Especially in selected cases, genetic testing can be a first mode of diagnostics in various renal diseases. Mallett et al. are the first to report on the overall diagnostic yield of targeted gene panel testing in familial kidney disease, both in pediatric and adult cases. In this commentary we discuss the importance of a clear gene panel design, with an up-to date enrichment offering sufficient coverage for each gene, and a validated pipeline for variant calling. We also emphasize the necessity of detailed phenotyping, including a pedigree, as a critical factor for gene panel selection and variant interpretation. PMID- 29153140 TI - The complex high-density lipoprotein proteome: a matter of purification? PMID- 29153141 TI - Both platelets and fibrin deposition are increased in the glomeruli of mice after treatment with Shiga toxin-2. PMID- 29153143 TI - Moradi H, Said HM. Functional thiamine deficiency in end-stage renal disease: malnutrition despite ample nutrients. Kidney Int. 2016;90:252-254. PMID- 29153142 TI - The Authors Reply. PMID- 29153144 TI - Ayme S, Bockenhauer D, Day S, et al. Common Elements in Rare Kidney Diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2017;92:796-808. PMID- 29153145 TI - Ketteler M, Block GA, Evenepoel P, et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters. Kidney Int. 2017;92:26-36. PMID- 29153146 TI - Li L, Lai EY, Luo Z, et al. Superoxide and hydrogen peroxide counterregulate myogenic contractions in renal afferent arterioles from a mouse model of chronic kidney disease. Kidney Int. 2017;92:625-633. PMID- 29153147 TI - Trifecta of light chain cast nephropathy, monoclonal plasma cell infiltrates, and light chain proximal tubulopathy. PMID- 29153148 TI - The Case | Weeding out the cause of acute kidney injury. PMID- 29153149 TI - Corrigendum to "Candidatus Accumulibacter phosphatis clades enriched under cyclic anaerobic and microaerobic conditions simultaneously use different electron acceptors" [Water Res. 102 (2016) 125-137]. PMID- 29153150 TI - Enhancing the role of vaccines in combatting antimicrobial resistance. AB - Interest in addressing antimicrobial resistance (AMR) has grown recently but little effort has been made to consider how existing and new vaccines could impact on AMR. A 2017 Chatham House meeting considered the role of vaccines and how to demonstrate their value through their impact on AMR. Ways existing vaccines have reduced antibiotic prescribing and the prevalence of some resistant organisms were reviewed. Other new vaccines could have a similar impact. In gonorrhoea, where complete resistance has developed, vaccine may be the best option. Valuing the impact of vaccines on AMR was challenging: there were difficult methodological issues and a lack of data for modelling. A participant poll suggested priorities for accelerated vaccine development were tuberculosis, typhoid, influenza, RSV and gonorrhoea. More evidence is needed to convince policymakers but that vaccine development projects should be considered by funders on the same basis as those for new antibiotics or diagnostics. PMID- 29153151 TI - What is the best ST-segment recovery parameter to predict clinical outcome and myocardial infarct size? Amplitude, speed, and completeness of ST-segment recovery after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. AB - AIMS: ST-segment recovery (STR) is a strong mechanistic correlate of infarct size (IS) and outcome in ST-segment elevation myocardial infarction (STEMI). Characterizing measures of speed, amplitude, and completeness of STR may extend the use of this noninvasive biomarker. METHODS AND RESULTS: Core laboratory continuous 24-h 12-lead Holter ECG monitoring, IS by single-photon emission computed tomography (SPECT), and 30-day mortality of 2 clinical trials of primary percutaneous coronary intervention in STEMI were combined. Multiple ST measures (STR at last contrast injection (LC) measured from peak value; 30, 60, 90, 120, and 240min, residual deviation; time to steady ST recovery; and the 3-h area under the time trend curve [ST-AUC] from LC) were univariably correlated with IS and predictive of mortality. After multivariable adjustment for ST-parameters and GRACE risk factors, STR at 240min remained an additive predictor of mortality. Early STR, residual deviation, and ST-AUC remained associated with IS. CONCLUSIONS: Multiple parameters that quantify the speed, amplitude, and completeness of STR predict mortality and correlate with IS. PMID- 29153152 TI - A 100-Year Review: Milestones in the development of frozen desserts. AB - Ice cream has come a long way since the first snow cone was made. Innovations in a variety of areas over the past century have led to the development of highly sophisticated, automated manufacturing plants that churn out pint after pint of ice cream. Significant advances in fields such as mechanical refrigeration, chilling and freezing technologies, cleaning and sanitation, packaging, and ingredient functionality have shaped the industry. Advances in our understanding of the science of ice cream, particularly related to understanding the complex structures that need to be controlled to create a desirable product, have also enhanced product quality and shelf stability. Although significant advances have been made, there remain numerous opportunities for further advancement both scientifically and technologically. PMID- 29153153 TI - A 100-Year Review: Advances in goat milk research. AB - In the century of research chronicled between 1917 and 2017, dairy goats have gone from simply serving as surrogates to cows to serving as transgenic carriers of human enzymes. Goat milk has been an important part of human nutrition for millennia, in part because of the greater similarity of goat milk to human milk, softer curd formation, higher proportion of small milk fat globules, and different allergenic properties compared with cow milk; however, key nutritional deficiencies limit its suitability for infants. Great attention has been given not only to protein differences between goat and cow milk, but also to fat and enzyme differences, and their effect on the physical and sensory properties of goat milk and milk products. Physiological differences between the species necessitate different techniques for analysis of somatic cell counts, which are naturally higher in goat milk. The high value of goat milk throughout the world has generated a need for a variety of techniques to detect adulteration of goat milk products with cow milk. Advances in all of these areas have been largely documented in the Journal of Dairy Science (JDS), and this review summarizes such advances. PMID- 29153154 TI - A 100-Year Review: From ascorbic acid to zinc-Mineral and vitamin nutrition of dairy cows. AB - Mineral and vitamin nutrition of dairy cows was studied before the first volume of the Journal of Dairy Science was published and is still actively researched today. The initial studies on mineral nutrition of dairy cows were simple balance experiments (although the methods available at the time for measuring minerals were anything but simple). Output of Ca and P in feces, urine, and milk was subtracted from intake of Ca and P, and if values were negative it was often assumed that cows were lacking in the particular mineral. As analytical methods improved, more minerals were found to be required by dairy cows, and blood and tissue concentrations became primary response variables. Those measures often were poorly related to cow health, leading to the use of disease prevalence and immune function as a measure of mineral adequacy. As data were generated, mineral requirements became more accurate and included more sources of variation. In addition to milk yield and body weight inputs, bioavailability coefficients of minerals from different sources are used to formulate diets that can meet the needs of the cow without excessive excretion of minerals in manure, which negatively affects the environment. Milk, or more accurately the lack of milk in human diets, was central to the discovery of vitamins, but research into vitamin nutrition of cows developed slowly. For many decades bioassays were the only available method for measuring vitamin concentrations, which greatly limited research. The history of vitamin nutrition mirrors that of mineral nutrition. Among the first experiments conducted on vitamin nutrition of cows were those examining the factors affecting vitamin concentrations of milk. This was followed by determining the amount of vitamins needed to prevent deficiency diseases, which evolved into research to determine the amount of vitamins required to promote overall good health. The majority of research was conducted on vitamins A, D, and E because these vitamins have a dietary requirement, and clinical and marginal deficiencies became common as diets for cows changed from pasture and full exposure to the sun to stored forage and limited sun exposure. As researchers learned new functions of fat-soluble vitamins, requirements generally increased over time. Diets generally contain substantial amounts of B vitamins, and rumen bacteria can synthesize large quantities of many B vitamins; hence, research on water-soluble vitamins lagged behind. We now know that supplementation of specific water-soluble vitamins can enhance cow health and increase milk production in certain situations. Additional research is needed to define specific requirements for many water-soluble vitamins. Both mineral and vitamin research is hampered by the lack of sensitive biomarkers of status, but advanced molecular techniques may provide measures that respond to altered supply of minerals and vitamins and that are related to health or productive responses of the cow. The overall importance of proper mineral and vitamin nutrition is known, but as we discover new and more diverse functions, better supplementation strategies should lead to even better cow health and higher production. PMID- 29153155 TI - A 100-Year Review: Fat feeding of dairy cows. AB - Over 100 years, the Journal of Dairy Science has recorded incredible changes in the utilization of fat for dairy cattle. Fat has progressed from nothing more than a contaminant in some protein supplements to a valuable high-energy substitute for cereal grains, a valuable energy source in its own right, and a modifier of cellular metabolism that is under active investigation in the 21st century. Milestones in the use of fats for dairy cattle from 1917 to 2017 result from the combined efforts of noted scientists and industry personnel worldwide, with much of the research published in Journal of Dairy Science. We are humbled to have been asked to contribute to this historical collection of significant developments in fat research over the past 100 years. Our goal is not to detail all the work published as each development moved forward; rather, it is to point out when publication marked a significant change in thinking regarding use of fat supplements. This approach forced omission of critically important names and publications in many journals as ideas moved forward. However, we hope that a description of the major changes in fat feeding during the past 100 years will stimulate reflection on progress in fat research and encourage further perusal of details of significant events. PMID- 29153156 TI - A 100-Year Review: Carbohydrates-Characterization, digestion, and utilization. AB - Our knowledge of the role of carbohydrates in dairy cattle nutrition has advanced substantially in the 100 years of the publication of the Journal of Dairy Science. In this review, we trace the history of scientific investigation and discovery from crude fiber, nitrogen-free extract, and "unidentified factors" to our present analytical schemes and understanding of ruminal and whole-animal utilization and effects of dietary carbohydrates. Historically, advances in research and new feeding standards occurred in parallel with and fostered by new methods of analysis. The 100 years of research reviewed here has bequeathed to us an impressive legacy of information, which we will continue to grow. PMID- 29153157 TI - A 100-Year Review: Protein and amino acid nutrition in dairy cows. AB - Considerable progress has been made in understanding the protein and amino acid (AA) nutrition of dairy cows. The chemistry of feed crude protein (CP) appears to be well understood, as is the mechanism of ruminal protein degradation by rumen bacteria and protozoa. It has been shown that ammonia released from AA degradation in the rumen is used for bacterial protein formation and that urea can be a useful N supplement when lower protein diets are fed. It is now well documented that adequate rumen ammonia levels must be maintained for maximal synthesis of microbial protein and that a deficiency of rumen-degradable protein can decrease microbial protein synthesis, fiber digestibility, and feed intake. Rumen-synthesized microbial protein accounts for most of the CP flowing to the small intestine and is considered a high-quality protein for dairy cows because of apparent high digestibility and good AA composition. Much attention has been given to evaluating different methods to quantify ruminal protein degradation and escape and for measuring ruminal outflows of microbial protein and rumen undegraded feed protein. The methods and accompanying results are used to determine the nutritional value of protein supplements and to develop nutritional models and evaluate their predictive ability. Lysine, methionine, and histidine have been identified most often as the most-limiting amino acids, with rumen protected forms of lysine and methionine available for ration supplementation. Guidelines for protein feeding have evolved from simple feeding standards for dietary CP to more complex nutrition models that are designed to predict supplies and requirements for rumen ammonia and peptides and intestinally absorbable AA. The industry awaits more robust and mechanistic models for predicting supplies and requirements of rumen-available N and absorbed AA. Such models will be useful in allowing for feeding lower protein diets and increased efficiency of microbial protein synthesis. PMID- 29153158 TI - A 100-Year Review: Metabolic modifiers in dairy cattle nutrition. AB - The first issue of the Journal of Dairy Science in 1917 opened with the text of the speech by Raymond A. Pearson, president of the Iowa State College of Agriculture, at the dedication of the new dairy building at the University of Nebraska (J. Dairy Sci. 1:4-18, 1917). Fittingly, this was the birth of a new research facility and more importantly, the beginning of a new journal devoted to the sciences of milk production and manufacture of products from milk. Metabolic modifiers of dairy cow metabolism enhance, change, or interfere with normal metabolic processes in the ruminant digestive tract or alter postabsorption partitioning of nutrients among body tissues. Papers on metabolic modifiers became more frequent in the journal around 1950. Dairy farming changed radically between 1955 and 1965. Changes in housing and feeding moved more cows outside, and cows and heifers in all stages of lactation, including the dry period, were fed as a single group. Rations became wetter with the shift to corn silage as the major forage in many rations. Liberal grain feeding met the requirements of high producing cows and increased production per cow but introduced new challenges; for example, managing and feeding cows as a group. These changes led to the introduction of new strategies that identified and expanded the use of metabolic modifiers. Research was directed at characterizing the new problems for the dairy cow created by group feeding. Metabolic modifiers went beyond feeding the cow and included environmental and housing factors and additives to reduce the incidence and severity of many new conditions and pathologies. New collaborations began among dairy cattle specialties that broadened our understanding of the workings of the cow. The Journal of Dairy Science then and now plays an enormously important role in dissemination of the findings of dairy scientists worldwide that address existing and new technologies. PMID- 29153159 TI - A 100-Year Review: Total mixed ration feeding of dairy cows. AB - Total mixed rations (TMR) as we know them today did not exist in 1917. In fact, TMR are an invention of primarily the last half of the past 100 yr. Prior to that time many dairy herds were fed only forages, but dairy producers started moving toward TMR feeding as milk production per cow increased, herds became larger, freestall and large-group handling of cows became more common, and milking parlors became more prevalent. The earliest known reports in the Journal of Dairy Science of feeding "complete rations" or TMR may have appeared in the 1950s, but those studies were often reported only as abstracts at annual meetings of the American Dairy Science Association or in extension-type publications. The earliest full-length article on TMR in the journal was published in 1966. An advantage of feeding TMR as opposed to feeding forages supplemented with concentrates is the opportunity to make every bite of feed essentially a complete, nutritionally balanced diet for all cows. Nutritionally related off feed (e.g., ingredient separation due to poor mixing, feed sorting by the animal, and so on), milk fat depression, and other digestive upsets were less likely to occur with TMR feeding. Feed mixer wagons, feed particle sizes, moisture content of diets, and other factors were not concerns before TMR feeding but are concerns today. Today, most dairy herds, especially larger herds in the United States and elsewhere, feed TMR. PMID- 29153160 TI - A 100-Year Review: Calf nutrition and management. AB - The first calf paper, published in the May 1919 issue of the Journal of Dairy Science (JDS), described factors affecting birth body weight of different breeds of calves. Other studies were done on nonmilk ingredients, growth charts were developed, and early weaning was followed to conserve milk fed to calves. Calf papers did not report use of statistics to control or record variation or to determine whether treatment means were different. Many experiments were more observational than comparative. Typically fewer than 5 calves, and sometimes 1 or 2 calves, were used per treatment. During the next 20 yr, calf studies increased and included colostrum feeding, milk and milk replacer feeding, minerals and vitamins, and fats and oils. Many concepts fundamental to current knowledge and understanding of digestion, rumen development, and milk replacer formulation were developed during this period. In addition, the concept of using antibiotic growth promoters in dairy calf diets was first evaluated and developed during the 1950s. During the 20-yr period of January 1957 through December 1976, a large number of universities in the United States and 1 in Canada contributed almost 150 papers on a variety of calf-related topics. These topics included genetics, physiology of the calf, review of calf immunity, antibiotic feeding, and milk replacer ingredients. This became the golden era of calf rumen development studies, which also engendered studies of calf starter rations and ingredients. A classic review of management, feeding, and housing studies summarized research related to calf feeding and management systems up to that point with an emphasis on maintaining calf growth and health while reducing labor and feed costs. It was also during this period that metric measurements replaced English units. In the 20-yr period from 1977 to 1996, more than 400 articles on calf nutrition and management were published in JDS. With the growing research interest in calves, a paper outlining standardized procedures for conducting and reporting data from calf experiments was first published. A very active area of calf nutrition research from the late 1970s to the mid 1980s was colostrum quality, feeding, and preservation; more than 60 such research articles were published in the journal during this time. Various nonmilk protein sources were evaluated. Extensive studies were done evaluating trace and major mineral requirements in calves along with some vitamin studies. Throughout the 1970s, 1980s, and 1990s, the primary objective of most calf research was how to wean healthy, adequately grown calves at an early age generally less than 30 d of age. This program was reviewed in a 1979 publication. Research on calf starter ingredients, nutrient composition, and additives was minimal in the 1980s and 1990s given the importance of starter intake to the success of early weaning, but the role of water intake in starter intake and growth was established. Research on issues with calves continued to increase during the last 20-yr period as evidenced by publication of more than 580 articles in JDS as well as many more in other refereed journals. In addition to papers contributed by several universities in the United States and Canada, the number of papers authored by scientists at universities and institutes in other countries increased dramatically during this period. Factors influencing colostral antibody absorption, heat treatment of colostrum, and efficacy of colostrum supplements and replacers were reported. Most studies in this period related to nutrition. Studies were published supporting greater neonatal growth rates from feeding more milk replacer but with a higher crude protein content than traditional. Protein energy effects on growth and body composition were evaluated in concert with greater growth rates. Milk and nonmilk protein sources in milk replacers along with AA supplementation were evaluated. Limited studies were done with fat sources and fatty acid supplementation along with trace minerals and fat-soluble vitamins. Waste milk feeding and heat treatment became more prevalent. Studies established starter ingredient palatability and use of forage when fed with pelleted starters. With the advent of automatic milk and milk replacer feeders, factors influencing how and when to wean were established. Research programs established factors affecting calf behavior and welfare. Several databases were evaluated along with various published studies, and established calf growth during the first 2 mo was subsequently reflected in first and later-lactation milk production of those calves. A new area of calf research that emerged from 1997 on was the effects of maternal environment and nutrition on calf health, growth, and future productivity. From a mechanistic standpoint, the field of epigenetics seems likely to explain many of these phenomena. Some possibilities for future calf nutrition and management were elaborated. PMID- 29153161 TI - A 100-Year Review: A century of dairy heifer research. AB - The years 1917 to 2017 saw many advances in research related to the dairy heifer, and the Journal of Dairy Science currently publishes more than 20 articles per year focused on heifers. In general, nutrition and management changes made in rearing the dairy heifer have been tremendous in the past century. The earliest literature on the growing heifer identified costs of feeding and implications of growth on future productivity as major concepts requiring further study to improve the overall sustainability of the dairy herd. Research into growth rates and standards for body size and stature have been instrumental in developing rearing programs that provide heifers with adequate nutrients to support growth and improve milk production in first lactation. Nutrient requirements, most notably for protein but also for energy, minerals, and vitamins, have been researched extensively. Scientific evaluation of heifer programs also encouraged a dramatic shift toward a lower average age at first calving over the past 30 yr. Calving at 22 to 24 mo best balances the cost of growing heifers with their production and lifetime income potential. Increasingly, farms have become more progressive in adopting management practices based on the physiology and nutrient needs of the heifer while refining key economic strategies to be successful. Research published in the Journal of Dairy Science has an integral role in the progress of dairy heifer programs around the world. PMID- 29153162 TI - A 100-Year Review: A century of change in temperate grazing dairy systems. AB - From 1917 to 2017, dairy grazing systems have evolved from uncontrolled grazing of unimproved pastures by dual-purpose dairy-beef breeds to an intensive system with a high output per unit of land from a fit-for-purpose cow. The end of World War I signaled significant government investments in agricultural research institutes around the world, which coincided with technological breakthroughs in milk harvesting and a recognition that important traits in both plants and animals could be improved upon relatively rapidly through genetic selection. Uptake of milk recording and herd testing increased rapidly through the 1920s, as did the recognition that pastures that were rested in between grazing events yielded more in a year than those continuously grazed. This, and the invention and refinement of the electric fence, led to the development of "controlled" rotational grazing. This, in itself, facilitated greater stocking rates and a 5 to 10% increase in milk output per hectare but, perhaps more importantly, it allowed a more efficient use of nitrogen fertilizer, further increasing milk output/land area by 20%. Farmer inventions led to the development of the herringbone and rotary milking parlors, which, along with the "unshortable" electric fence and technological breakthroughs in sperm dilution rates, allowed further dairy farm expansion. Simple but effective technological breakthroughs in reproduction ensured that cows were identified in estrus early (a key factor in maintaining the seasonality of milk production) and enabled researchers to quantify the anestrus problem in grazing herds. Genetic improvement of pasture species has lagged its bovine counterpart, but recent developments in multi-trait indices as well as investment in genetic technologies should significantly increase potential milk production per hectare. Decades of research on the use of feeds other than pasture (i.e., supplementary feeds) have provided consistent milk production responses when the reduction in pasture intake associated with the provision of supplementary feed (i.e., substitution rate) is accounted for. A unique feature of grazing systems research over the last 70 yr has been the use of multi-year farm systems experimentation. These studies have allowed the evaluation of strategic changes to a component of the system on all the interacting features of the system. This technique has allowed excellent component research to be "systemized" and is an essential part of the development of the intensive grazing production system that exists today. Future challenges include the provision of skilled labor or specifically designed automation to optimize farm management and both environmental sustainability and animal welfare concerns, particularly relating to the concentration of nitrogen in each urine patch and the associated risk of nitrate leaching, as well as concerns regarding exposure of animals to harsh climatic conditions. These combined challenges could affect farmers' "social license" to farm in the future. PMID- 29153163 TI - A 100-Year Review: Methods and impact of genetic selection in dairy cattle-From daughter-dam comparisons to deep learning algorithms. AB - In the early 1900s, breed society herdbooks had been established and milk recording programs were in their infancy. Farmers wanted to improve the productivity of their cattle, but the foundations of population genetics, quantitative genetics, and animal breeding had not been laid. Early animal breeders struggled to identify genetically superior families using performance records that were influenced by local environmental conditions and herd-specific management practices. Daughter-dam comparisons were used for more than 30 yr and, although genetic progress was minimal, the attention given to performance recording, genetic theory, and statistical methods paid off in future years. Contemporary (herdmate) comparison methods allowed more accurate accounting for environmental factors and genetic progress began to accelerate when these methods were coupled with artificial insemination and progeny testing. Advances in computing facilitated the implementation of mixed linear models that used pedigree and performance data optimally and enabled accurate selection decisions. Sequencing of the bovine genome led to a revolution in dairy cattle breeding, and the pace of scientific discovery and genetic progress accelerated rapidly. Pedigree-based models have given way to whole-genome prediction, and Bayesian regression models and machine learning algorithms have joined mixed linear models in the toolbox of modern animal breeders. Future developments will likely include elucidation of the mechanisms of genetic inheritance and epigenetic modification in key biological pathways, and genomic data will be used with data from on-farm sensors to facilitate precision management on modern dairy farms. PMID- 29153164 TI - A 100-Year Review: Identification and genetic selection of economically important traits in dairy cattle. AB - Over the past 100 yr, the range of traits considered for genetic selection in dairy cattle populations has progressed to meet the demands of both industry and society. At the turn of the 20th century, dairy farmers were interested in increasing milk production; however, a systematic strategy for selection was not available. Organized milk performance recording took shape, followed quickly by conformation scoring. Methodological advances in both genetic theory and statistics around the middle of the century, together with technological innovations in computing, paved the way for powerful multitrait analyses. As more sophisticated analytical techniques for traits were developed and incorporated into selection programs, production began to increase rapidly, and the wheels of genetic progress began to turn. By the end of the century, the focus of selection had moved away from being purely production oriented toward a more balanced breeding goal. This shift occurred partly due to increasing health and fertility issues and partly due to societal pressure and welfare concerns. Traits encompassing longevity, fertility, calving, health, and workability have now been integrated into selection indices. Current research focuses on fitness, health, welfare, milk quality, and environmental sustainability, underlying the concentrated emphasis on a more comprehensive breeding goal. In the future, on farm sensors, data loggers, precision measurement techniques, and other technological aids will provide even more data for use in selection, and the difficulty will lie not in measuring phenotypes but rather in choosing which traits to select for. PMID- 29153165 TI - A 100-Year Review: Historical development of female reproductive physiology in dairy cattle. AB - The objective of this historical review in female reproductive physiology is to encapsulate major advancements since the founding of the American Dairy Science Association in 1906. The emphasis is on landmark publications in the Journal of Dairy Science since its first volume in 1917. A historical perspective and inferences are made in forecasting evolution of female reproduction and links between physiology of reproduction and the mammary gland. Subsequent sections are focused into main physiological categories and the temporal advancements within these physiological windows. Time points of understanding vary considerably within categories due to various advancements in technology, biological techniques, experimental design, data collection, statistical analyses, and computational forecasting. The physiological windows examined are hypothalamic and pituitary control of the ovary related to estrous behavior and cycle; differential control of the corpus luteum and uterus as influenced by cycling and pregnancy statuses; peripartum and postpartum programing of reproduction; and scientific foundation for the next century. The importance of interdisciplinary programs and integration of reproduction, nutrition/metabolism, genetics, health, and management are emphasized. The modern dairy cow of 2017 exemplifies excellence in both reproductive and lactational performance and is the foundation biological model for the next century. PMID- 29153166 TI - A 100-Year Review: Practical female reproductive management. AB - Basic knowledge of mechanisms controlling reproductive processes in mammals was limited in the early 20th century. Discoveries of physiologic processes and mechanisms made early in the last century laid the foundation to develop technologies and programs used today to manage and control reproduction in dairy cattle. Beyond advances made in understanding of gonadotropic support and control of ovarian and uterine functions in basic reproductive biology, advancements made in artificial insemination (AI) and genetics facilitated rapid genetic progress of economically important traits in dairy cattle. Technologies associated with management have each contributed to the evolution of reproductive management, including (1) hormones to induce estrus and ovulation to facilitate AI programs; (2) pregnancy diagnosis via ultrasonography or by measuring conceptus-derived pregnancy-associated glycoproteins; (3) estrus-detection aids first devised for monitoring only physical activity but that now also quantitate feeding, resting, and rumination times, and ear temperature; (4) sex-sorted semen; (5) computers and computerized record software packages; (6) handheld devices for tracking cow location and retrieving cow records; and (7) genomics for increasing genetic progress of reproductive and other economically important traits. Because of genetic progress in milk yield and component traits, the dairy population in the United States has been stable since the mid 1990s, with approximately 9 to 9.5 million cows. Therefore, many of these technologies and changes in management have been developed in the face of increasing herd size (4-fold since 1990), and changes from pastoral or dry-lot dairies to increased housing of cows in confinement buildings with freestalls and feed-line lockups. Management of groups of "like" cows has become equally important as management of the one. Management teams, including owner-managers, herdsmen, AI representatives, milkers, and numerous consultants dealing with health, feeding, and facilities, became essential to develop working protocols, monitor training and day-to-day chores, and evaluate current trends and revenues. Good management teams inspect and follow through with what is routinely expected of workers. As herd size will undoubtedly increase in the future, practical reproductive management must evolve to adapt to the new technologies that may find more herds being milked robotically and applying technologies not yet conceived or introduced. PMID- 29153167 TI - A 100-Year Review: Reproductive technologies in dairy science. AB - Reproductive technology revolutionized dairy production during the past century. Artificial insemination was first successfully applied to cattle in the early 1900s. The next major developments involved semen extenders, invention of the electroejaculator, progeny testing, addition of antibiotics to semen during the 1930s and 1940s, and the major discovery of sperm cryopreservation with glycerol in 1949. The 1950s and 1960s were particularly productive with the development of protocols for the superovulation of cattle with both pregnant mare serum gonadotrophin/equine chorionic gonadotrophin and FSH, the first successful bovine embryo transfer, the discovery of sperm capacitation, the birth of rabbits after in vitro fertilization, and the development of insulated liquid nitrogen tanks. Improved semen extenders and the replacement of glass ampules with plastic semen straws followed. Some of the most noteworthy developments in the 1970s included the initial successes with in vitro culture of embryos, calves born after chromosomal sexing as embryos, embryo splitting resulting in the birth of twins, and development of computer-assisted semen analysis. The 1980s brought flow cytometric separation of X- and Y-bearing sperm, in vitro fertilization leading to the birth of live calves, clones produced by nuclear transfer from embryonic cells, and ovum pick-up via ultrasound-guided follicular aspiration. The 20th century ended with the birth of calves produced from AI with sexed semen, sheep and cattle clones produced by nuclear transfer from adult somatic cell nuclei, and the birth of transgenic cloned calves. The 21st century has seen the introduction of perhaps the most powerful biotechnology since the development of artificial insemination and cryopreservation. Quick, inexpensive genomic analysis via the use of single nucleotide polymorphism genotyping chips is revolutionizing the cattle breeding industry. Now, with the introduction of genome editing technology, the changes are becoming almost too rapid to fully digest. PMID- 29153168 TI - A 100-Year Review: Mammary development and lactation. AB - What is old is new again-and with respect to the study of the mammary development and function in dairy animals, the expression resonates. Many of the mammary and milk production questions raised in the early years of the Journal of Dairy Science apply today. To be sure, scientists have filled in many details regarding, for example, identification of hormones and growth factors important in the control of mammary growth, the onset of copious milk production at calving, and maintenance of lactation. Early years focused on identification and subsequent availability of classic mammogenic, lactogenic, and galactopoietic hormones (e.g., steroids, prolactin, and growth hormone). The advent of sensitive assays to measure concentrations of these hormones and, subsequently, myriad growth factors in blood, milk, and tissues, allowed creation of multiple hypotheses to explain mammary cell proliferation and regulation of function. It is also apparent that we understand many of the fundamentals of milk removal, milking frequency, milking management, and milk ejection for successful lactation. However, some questions remain. Are the principles that were identified when cows produced markedly less milk still valid for the high producing cows of today and the future? What mechanism(s) explain the positive effects of early increased milking frequency on subsequent milk production? Can the persistency of lactation be improved (secretory cell number vs. secretory cell function) or does early management "program" future mammary development or productivity (epigenetics, immune responsiveness, other)? The explosion of tools and techniques (Southern and Northern blots, PCR, and the "-omics" revolution) has driven an almost overwhelming evaluation of cellular and molecular functions in the mammary gland and other tissues. One key may be the discovery of a "Rosetta stone" that will allow understanding of this mass of detailed information on gene expression, cell signaling, and so on. Many scientists can now better appreciate the difficulty of the dairy farmer seeking to process DHIA or Dairy Comp 305 data, milking data, weights, feeding reports, pedometer readings, or genomic evaluations to manage their operations. PMID- 29153169 TI - A 100-Year Review: Regulation of nutrient partitioning to support lactation. AB - We have seen remarkable advances in animal productivity in the last 75 years, with annual milk yield per cow increasing over 4-fold and no evidence of nearing a plateau. Because of these gains in productive efficiency, there have been dramatic reductions in resource inputs and the carbon footprint per unit of milk produced. The primary source for the historic gains relates to animal variation in nutrient partitioning. The regulation of nutrient use for productive functions has the overall goal of maintaining the cow's well-being regardless of the physiological or environmental challenges. From a conceptual standpoint, it involves both acute homeostatic controls operating on a minute-by-minute basis and chronic homeorhetic controls operating on a long-term basis to provide orchestrated adaptations that coordinate tissues and body processes. This endocrine regulation is mediated by changes in circulating anabolic and catabolic hormones, hormone membrane receptors and intracellular signaling pathways. The coordination of tissues and physiological systems includes a plethora of hormones, but insulin and somatotropin are 2 key regulators of nutrient trafficking. Herein, we review the advances in our understanding of both conceptual and actual regulation of nutrient partitioning in support of milk synthesis and identify examples of the challenges and future opportunities in dairy science. PMID- 29153171 TI - A 100-Year Review: Mastitis detection, management, and prevention. AB - Mastitis is the most frequent disease of dairy cows and has well-recognized detrimental effects on animal wellbeing and dairy farm profitability. Since the beginning of modern dairy farming, producers have sought effective methods to minimize the occurrence of mastitis in their herds. The objective of this paper is to review and highlight important advances in detection, management, and prevention of mastitis that have occurred since the first volume of the Journal of Dairy Science was published in 1917. Initial research efforts were directed at understanding the nature of pathogenic bacteria that were responsible for most intramammary infections. For decades, researchers worked to identify effective strategies to control mastitis caused by Streptococcus agalactiae and Staphylococcus aureus. To develop successful control programs, mastitis workers first had to identify mechanisms of infection, define the clinical and subclinical states of the disease, discover appropriate screening tests, determine likely points of exposure, identify pathogen-specific characteristics, and develop effective procedures for machine milking. Pioneering researchers eventually recognized that mastitis control was based on preventing new infections from occurring in healthy cows and reducing the duration that cows remained infected. Development of a control program that incorporated post milking teat dipping, hygienic milking procedures, and strategic use of antibiotic therapy at dry-off resulted in widespread control of contagious pathogens. As herd management changed, researchers were tasked with defining control of mastitis caused by opportunistic pathogens originating from environmental sources. As mastitis pathogens have evolved, researchers have sought to define antimicrobial usage that will maintain animal wellbeing while minimizing unnecessary usage. During the last century, tremendous significant advances in mastitis control have been made but changing herd structure and more rigorous processor standards ensure that mastitis will remain an important subject focus of future research. PMID- 29153170 TI - A 100-Year Review: Stress physiology including heat stress. AB - Stress is an external event or condition that places a strain on a biological system. The animal response to a stress involves the expenditure of energy to remove or reduce the impact of the stress. This increases maintenance requirements of the animal and results in loss of production. The biological response to stress is divided into acute and chronic phases, with the acute phase lasting hours to a few days and the chronic phase lasting several days to weeks. The acute response is driven by homeostatic regulators of the nervous and endocrine systems and the chronic phase by homeorhetic regulators of the endocrine system. Both responses involve alterations in energy balance and metabolism. Thermal environment affects all animals and therefore represents the largest single stressor in animal production. Other types of stressors include housing conditions, overcrowding, social rank, disease, and toxic compounds. "Acclimation" to a stress is a phenotypic response developed by the animal to an individual stressor within the environment. However, under natural conditions, it is rare for only one environmental variable to change over time. "Acclimatization" is the process by which an animal adapts to several stressors within its natural environment. Acclimation is a homeorhetic process that takes several weeks to occur and occurs via homeorhetic, not homeostatic, mechanisms. It is a phenotypic change that disappears when the stress is removed. When the stress is severe and not relieved by acclimatization or management changes, the animal is considered chronically stressed and is susceptible to increased incidence of disease and poor health. Milk yield and reproduction are extremely sensitive to stress because of the high energy and protein demands of lactation and the complexity of the reproductive process and multiple organs that are involved. Improvements in protection of animals against stress require improved education of producers to recognize stress and methods for estimating degree of stress on animals. PMID- 29153172 TI - A 100-Year Review: Metabolic health indicators and management of dairy cattle. AB - Our aim in this Journal of Dairy Science centennial review is to describe the evolution of focus on metabolic indicators, from discovery and description to evaluation at the individual cow and subsequently herd levels, over the past 100 yr. Furthermore, we discuss current and future technologies that will be used in the dairy industry to utilize these indicators widely going forward. Knowledge of chemical changes in various fluids (e.g., blood, urine, and milk) accompanying numerous metabolic disease states in the dairy cow has existed since almost the beginning of the Journal of Dairy Science 100 yr ago. However, only during the last 25 yr have these metabolic indicators been developed into useful tools for cow- and herd-level monitoring for disease and management. From the 1920s through the 1940s, our understanding of the changes in blood chemistry accompanying milk fever and ketosis increased, as did our understanding of the underlying biology. In the 1950s and 1960s, workers studying ketosis and energy metabolism began to evaluate changes in lipid metabolism reflected by concentrations of circulating nonesterified fatty acids; furthermore, initial development occurred for on-farm tests of milk ketones. During the 1970s, blood metabolic profiling was applied to dairy farms but found to be of varied and limited usefulness. The turning point occurred when large epidemiologic studies of periparturient cow disease were pioneered in the United States, Canada, and Europe in the 1980s; these studies further solidified our understanding of risk factors and epidemiological interrelationships among disease, production, and reproduction. In the early 1990s, scientists first incorporated indicators of metabolic health into large observational studies and determined important epidemiological relationships between these indicators and outcomes of interest. This field of study blossomed during the 2000s as several research groups conducted multiple investigations into metabolic indicators related to energy metabolism and began to develop cow level thresholds and herd-level alarms for use in monitoring and management. This work was accompanied by additional studies to validate point-of-care instruments that could be used to implement these strategies at the cow and herd levels. Work in the 2000s continued to identify and evaluate other physiological indicators of inflammation and oxidative stress; however, these have yet to be incorporated into large-scale cohort studies. Finally, use of technology (e.g., activity monitoring, cow-monitoring collars and tags, milk-based analysis using Fourier transform infrared spectroscopy) continues to receive significant attention going forward to eventually allow for real-time and automatic monitoring of metabolic indicators and improved health and herd management on dairy farms. PMID- 29153173 TI - A 100-Year Review: Lactating dairy cattle housing management. AB - Since the mid-1800s, farmers have been housing livestock. What began as a part time solution for cold winters, stormy days, or injured animals has evolved into the main or only area in which cows spend their adult lives. With this change, farmers, academic researchers, and industry innovators have shaped the farm landscape, literally. Over the last 100 years, changes have been made for productivity, health, milk quality, reproduction, animal well-being, and farm profitability. We review a snapshot of those changes and look ahead to the future of lactating dairy cattle housing. All housing systems are moving toward improved cow comfort. Stalls in tiestall and freestall systems are now designed to accommodate cows based on body size and, in some cases, stage of lactation. Farmers may choose to build a compost bedded or traditional bedded-pack barn to maximize cattle rest or accommodate various breeds or sizes of cows. Looking to the future, external pressure and public perception may push farmers to consider other alternatives to total confinement. Future housing plans may include access to pasture or exercise lots, allowing cows to express their preferences for being outside or inside. Housing that allows natural expression of behavior while maintaining cow cleanliness and health may improve the lives of cows and farmers. PMID- 29153174 TI - A 100-Year Review: Animal welfare in the Journal of Dairy Science-The first 100 years. AB - This paper outlines the history and development of research in the area of animal welfare as reflected in the 100 yr that the Journal of Dairy Science has been published. The first paper using the term "animal welfare" was published in 1983; since then (to May 2017), 244 papers that reflect growing interest regarding how farm animals are cared for have been published. Much of the scientific work to date has focused on issues related to cow health, such as lameness, and methodologically many papers use behavioral measures. In addition to this science based research, the journal has taken on the role of publishing work of social scientists that addresses the role of the human factors relating to animal welfare, including research on citizen, consumer, and farmer attitudes toward welfare issues. We call for further research focused on societal perspectives and for new biological research focused on developing issues, such as cow-calf separation and pasture access. PMID- 29153175 TI - Journal of Dairy Science Volume 100 Special Issue: Summary. PMID- 29153176 TI - ADSA(r) Presidential Report. PMID- 29153177 TI - Journal of Dairy Science Volume 100 Special Issue: Introduction. PMID- 29153178 TI - A 100-Year Review: The production of fluid (market) milk. AB - During the first 100 years of the Journal of Dairy Science, dairy foods and dairy production dairy scientists have partnered to publish new data and research results that have fostered the development of new knowledge. This knowledge has been the underpinning of both the commercial development of the fluid milk processing industry and regulations and marketing policies for the benefit of dairy farmers, processors, and consumers. During the first 50 years, most of the focus was on producing and delivering high-quality raw milk to factories and improving the shelf life of pasteurized fluid milk. During the second 50 years, raw milk quality was further improved through the use of milk quality payment incentives. Due to changing demographics and lifestyle, whole fluid milk consumption declined and processing technologies were developed to increase the range of fluid milk products (skim and low-fat milks, flavored milks, lactose reduced milk, long-shelf-life milks, and milks with higher protein and calcium contents) offered to the consumer. In addition, technology to produce specialty high-protein sports beverages was developed, which expanded the milk-based beverage offerings to the consumer. PMID- 29153179 TI - A 100-Year Review: A century of dairy processing advancements-Pasteurization, cleaning and sanitation, and sanitary equipment design. AB - Over the past century, advancements within the mainstream dairy foods processing industry have acted in complement with other dairy-affiliated industries to produce a human food that has few rivals with regard to safety, nutrition, and sustainability. These advancements, such as milk pasteurization, may appear commonplace in the context of a modern dairy processing plant, but some consideration of how these advancements came into being serve as a basis for considering what advancements will come to bear on the next century of processing advancements. In the year 1917, depending on where one resided, most milk was presented to the consumer through privately owned dairy animals, small local or regional dairy farms, or small urban commercial dairies with minimal, or at best nascent, processing capabilities. In 1917, much of the retail milk in the United States was packaged and sold in returnable quart-sized clear glass bottles fitted with caps of various design and composition. Some reports suggest that the cost of that quart of milk was approximately 9 cents-an estimated $2.00 in 2017 US dollars. Comparing that 1917 quart of milk to a quart of milk in 2017 suggests several differences in microbiological, compositional, and nutritional value as well as flavor characteristics. Although a more comprehensive timeline of significant processing advancements is noted in the AppendixTable A1 to this paper, we have selected 3 advancements to highlight; namely, the development of milk pasteurization, cleaning and sanitizing technologies, and sanitary specifications for processing equipment. Finally, we provide some insights into the future of milk processing and suggest areas where technological advancements may need continued or strengthened attention and development as a means of securing milk as a food of high safety and value for the next century to come. PMID- 29153180 TI - A 100-Year Review: Progress on the chemistry of milk and its components. AB - Understanding the chemistry of milk and its components is critical to the production of consistent, high-quality dairy products as well as the development of new dairy ingredients. Over the past 100 yr we have gone from believing that milk has only 3 protein fractions to identifying all the major and minor types of milk proteins as well as discovering that they have genetic variants. The structure and physical properties of most of the milk proteins have been extensively studied. The structure of the casein micelle has been the subject of many studies, and the initial views on submicelles have given way to the current model of the micelle as being assembled as a result of the concerted action of several types of interactions (including hydrophobic and the formation of calcium phosphate nanoclusters). The benefits of this improved knowledge of the type and nature of casein interactions include better control of the cheesemaking process, more functional milk powders, development of new products such as cream liqueurs, and expanded food applications. Increasing knowledge of proteins and minerals was paralleled by developments in the analysis of milk fat and its synthesis together with greater knowledge of its packaging in the milk fat globule membrane. Advances in analytical techniques have been essential to the isolation and characterization of milk components. Milk testing has progressed from gross compositional analyses of the fat and total solids content to the rapid analysis of milk for a wide range of components for various purposes, such as diagnostic issues related to animal health. Up to the 1950s, research on dairy chemistry was mostly focused on topics such as protein fractionation, heat stability, acid-base buffering, freezing point, and the nature of the calcium phosphate present in milk. Between the 1950s and 1970s, there was a major focus on identifying all the main protein types, their sequences, variants, association behavior, and other physical properties. During the 1970s and 1980s, one of the major emphases in dairy research was on protein functionality and fractionation processes. The negative cloud over dairy fat has lifted recently due to multiple reviews and meta-analyses showing no association with chronic issues such as cardiovascular disease, but changing consumer misconceptions will take time. More recently, there has been a great deal of interest in the biological and nutritional components in milk and how these materials were uniquely designed by the cow to achieve this type of purpose. PMID- 29153181 TI - A 100-Year Review: Microbiology and safety of milk handling. AB - Microbes that may be present in milk can include pathogens, spoilage organisms, organisms that may be conditionally beneficial (e.g., lactic acid bacteria), and those that have not been linked to either beneficial or detrimental effects on product quality or human health. Although milk can contain a full range of organisms classified as microbes (i.e., bacteria, viruses, fungi, and protozoans), with few exceptions (e.g., phages that affect fermentations, fungal spoilage organisms, and, to a lesser extent, the protozoan pathogens Cryptosporidium and Giardia) dairy microbiology to date has focused predominantly on bacteria. Between 1917 and 2017, our understanding of the microbes present in milk and the tools available for studying those microbes have changed dramatically. Improved microbiological tools have enabled enhanced detection of known microbes in milk and dairy products and have facilitated better identification of pathogens and spoilage organisms that were not known or well recognized in the early 20th century. Starting before 1917, gradual introduction and refinement of pasteurization methods throughout the United States and many other parts of the world have improved the safety and quality of milk and dairy products. In parallel to pasteurization, others strategies for reducing microbial contamination throughout the dairy chain (e.g., improved dairy herd health, raw milk tests, clean-in-place technologies) also played an important role in improving microbial milk quality and safety. Despite tremendous advances in reducing microbial food safety hazards and spoilage issues, the dairy industry still faces important challenges, including but not limited to the need for improved science-based strategies for safety of raw milk cheeses, control of postprocessing contamination, and control of sporeforming pathogens and spoilage organisms. PMID- 29153182 TI - A 100-Year Review: Cheese production and quality. AB - In the beginning, cheese making in the United States was all art, but embracing science and technology was necessary to make progress in producing a higher quality cheese. Traditional cheese making could not keep up with the demand for cheese, and the development of the factory system was necessary. Cheese quality suffered because of poor-quality milk, but 3 major innovations changed that: refrigeration, commercial starters, and the use of pasteurized milk for cheese making. Although by all accounts cold storage improved cheese quality, it was the improvement of milk quality, pasteurization of milk, and the use of reliable cultures for fermentation that had the biggest effect. Together with use of purified commercial cultures, pasteurization enabled cheese production to be conducted on a fixed time schedule. Fundamental research on the genetics of starter bacteria greatly increased the reliability of fermentation, which in turn made automation feasible. Demand for functionality, machinability, application in baking, and more emphasis on nutritional aspects (low fat and low sodium) of cheese took us back to the fundamental principles of cheese making and resulted in renewed vigor for scientific investigations into the chemical, microbiological, and enzymatic changes that occur during cheese making and ripening. As milk production increased, cheese factories needed to become more efficient. Membrane concentration and separation of milk offered a solution and greatly enhanced plant capacity. Full implementation of membrane processing and use of its full potential have yet to be achieved. Implementation of new technologies, the science of cheese making, and the development of further advances will require highly trained personnel at both the academic and industrial levels. This will be a great challenge to address and overcome. PMID- 29153183 TI - A 100-Year Review: Sensory analysis of milk. AB - Evaluation of the sensory characteristics of food products has been, and will continue to be, the ultimate method for evaluating product quality. Sensory quality is a parameter that can be evaluated only by humans and consists of a series of tests or tools that can be applied objectively or subjectively within the constructs of carefully selected testing procedures and parameters. Depending on the chosen test, evaluators are able to probe areas of interest that are intrinsic product attributes (e.g., flavor profiles and off-flavors) as well as extrinsic measures (e.g., market penetration and consumer perception). This review outlines the literature pertaining to relevant testing procedures and studies of the history of sensory analysis of fluid milk. In addition, evaluation methods outside of traditional sensory techniques and future outlooks on the subject of sensory analysis of fluid milk are explored and presented. PMID- 29153184 TI - A 100-Year Review: Yogurt and other cultured dairy products. AB - The history of the last 100 years of the science and technology of yogurt, sour cream, cultured butter, cultured buttermilk, kefir, and acidophilus milk has been one of continuous development and improvement. Yogurt leads the cultured dairy product category in terms of volume of production in the United States and recent research activity. Legal definitions of yogurt, sour cream and acidified sour cream, and cultured milk, including cultured buttermilk, are presented in the United States Code of Federal Regulations and summarized here. A tremendous amount of research has been done on traditional and novel ingredients, starter cultures and probiotics, mix processing, packaging, chemical aspects, physical and sensory properties, microstructure, specialized products, composition, quality and safety of yogurt and various manufacturing methods, addition of flavorings, viscosity measurements, and probiotic use for sour cream. Over time, there have arisen alternative manufacturing methods, flavor problems, addition of flavorings, and use of probiotics for cultured buttermilk. Many health benefits are provided by yogurt and other cultured dairy products. One hundred years of testing and development have led to wider uses of cultured dairy products and new processing methods for enhanced shelf life and safety. Future research directions will likely include investigating the effects of probiotic dairy products on gut microbiota and overall health. PMID- 29153185 TI - Nonsurgical Management of Congenital Auricular Anomalies. AB - Congenital auricular deformities often can be corrected by neonatal ear molding techniques, which have evolved significantly over a 25-year period with commercially available molding systems now available. Indications for molding and methodology for best optimizing results have been well described in the literature, although recent studies have explored methodology for reduction in the cost of technique and also called for increased awareness among pediatric practitioners of the importance of early institution of therapy. PMID- 29153186 TI - Cosmetic Otoplasty. AB - Otoplasty for prominent ears is a rewarding yet exacting surgery that demands the precise application of anatomic knowledge, anthropometric norms, and surgical creativity. The practitioner must be able to use a variety of different techniques to provide durable and acceptable cosmetic results to patients. This article provides an in-depth description of normal and abnormal auricular anatomy, the historical context for modern otoplasty, and describes in detail the common otoplastic procedures currently performed. PMID- 29153187 TI - Otoplasty for Congenital Auricular Malformations. AB - Among the less common congenital auricular anomalies are cryptotia, Stahl ear, constricted ear, and macrotia. The vast majority of these occur spontaneously without accompanying syndromes or other deformities. This article provides a comprehensive overview of these anomalies, as well as common techniques to correct these anomalies. PMID- 29153188 TI - Autologous Rib Microtia Construction: Nagata Technique. AB - Nagata technique becomes most popular method of autologous rib microtia construction. To achieve successful outcome, 3 keys must be perfect: skin envelope, 3D cartilage framework, and proper location of the construct. The first step of the surgery is to identify "auricular rectangle." Relationship between the auricular rectangle and the vestige will determine if the vestige is usable for surgery. Rib cartilage must be harvested without perichondrium to prevent chest deformity. Lobule split technique is the hallmark of the Nagata technique, which allows skin envelope expansion, and allows deeper conchal cavity. Surgeons must master 3D framework construct before clinical cases. PMID- 29153189 TI - Pediatric Microtia Reconstruction with Autologous Rib: Personal Experience and Technique with 1000 Pediatric Patients with Microtia. AB - Reconstruction of the microtic ear is one of the most challenging, yet gratifying surgical experiences. Careful planning, attention to detail, and conservative tissue management are necessary for excellent results. Technologies continue to evolve; with the advancement of cartilage tissue engineering, the future of ear reconstruction is very promising. PMID- 29153190 TI - Auricular Reconstruction Using Porous Polyethylene Implant Technique. AB - Alloplast-based ear reconstruction has become more popular over the years because it offers many advantages compared with the traditional staged autologous costal cartilage approach. Advantages include earlier reconstruction in the setting of microtia, fewer procedures, less donor site morbidity, shorter surgeon learning curve, and improved consistency in the final aesthetic result. Although other implantable materials have been used in auricular reconstruction with variable success, porous high-density polyethylene frameworks combined with recent advances in the creation of the soft tissue coverage have significantly improved outcomes with minimal complications and long-term viability. This article describes the authors' technique. PMID- 29153191 TI - Atresiaplasty in Congenital Aural Atresia: What the Facial Plastic Surgeon Needs to Know. AB - Patients with microtia and congenital aural atresia should have a comprehensive hearing assessment early in life. Options for hearing habilitation should be presented, and children with bilateral aural atresia should be fitted with a bone conducting hearing device to support normal speech and language development. If atresia surgery is pursued, the microtia surgeon must be aware of certain principles. This article presents recommendations on options for potentially improving hearing in children with congenital aural atresia: assessing surgical candidacy; chronology and timing of surgeries; functional importance of certain ear structures; and understanding the possible locations of an aberrant facial nerve to avoid injury in these patients. PMID- 29153192 TI - Surgical Otoplasty: An Evidence-Based Approach to Prominent Ears Correction. AB - Otoplasty is one of the first procedures learned during residency. A myriad of surgical techniques and nuances exist. Many have merit, some are ineffective, some destructive, and some frankly fanciful. Adopting an effective and safe technique should be based on proven efficacy and effectiveness to avoid early disappointments. We present a review of traditional otoplasty techniques and more recent innovations. Their pros and cons are discussed in view of the relative risks/benefits balance. Recurrence rates are low for most techniques. Some techniques carry a higher risk of significant complications. A ladder approach preferring techniques that minimize cartilage damage appears advisable. PMID- 29153193 TI - Auricular Prostheses in Microtia. AB - The progress made in the development of the silicones and percutaneous titanium implants allow for rehabilitation of patients with microtia with an inconspicuous auricular prosthesis. The art of making the prosthesis by the dedicated anaplastologist is the key for the success of this approach. Most patients with microtia desire camouflage. The greatest advantage of the auricular prosthesis is that it can be manufactured as a mirrored replica of the opposite side. The outcome is predictable. Computer science with virtual planning and rapid prototyping is about to revolutionize the process of prosthetic auricular rehabilitation. PMID- 29153194 TI - Cosmetic and Reconstructive Surgery of Congenital Ear Deformities. PMID- 29153195 TI - Proenkephalin in Heart Failure. AB - The opioid system is activated in heart failure, which may be cardioprotective but may also be counter-regulatory. Recently, systemic proenkephalin activation has been investigated in various conditions predicting mortality and kidney injury. In acute heart failure, proenkephalin independently predicts mortality and heart failure rehospitalization in addition to traditional risk markers. It also predicts worsening renal function, increasingly recognized as an important risk predictor for poor outcome in heart failure. This article explores the role of enkephalins and delta-opioid receptors in the heart, then reviews studies measuring proenkephalin levels in the circulation and their associations with prognosis. PMID- 29153197 TI - Natriuretic Peptides in Heart Failure: Atrial and B-type Natriuretic Peptides. AB - The natriuretic peptides play a vital role in normal physiology and as counter regulatory hormones in heart failure (HF). Clinical assessment of their levels (for B-type natriuretic peptide [BNP], N-terminal proBNP, and the midregion of N terminal pro-atrial natriuretic peptide) have become valuable tools in diagnosing patients with HF as well as risk stratifying and guiding therapy. Their roles have further expanded beyond HF to other cardiovascular conditions and for risk stratification in asymptomatic individuals. Understanding the clinical use of these hormones is vital to achieving their full potential. PMID- 29153196 TI - Metabolic Biomarkers in Heart Failure. AB - Metabolomics is the study of small, organic molecules within biochemical pathways. With advancement of technology, nuclear magnetic resonance, gas chromatography, and mass spectrometry have allowed for the discovery and analysis of large databases of metabolites implicated in heart failure. Metabolomics also explores the patient and environment interactions and unlocks the link between environmental exposures and the development of cardiovascular disease. Although a relatively new field, metabolomics is poised to become a clinically impactful field that develops novel biomarkers and explores new therapeutic interventions in heart failure. PMID- 29153198 TI - N-Terminal B-type Natriuretic Peptide in Heart Failure. AB - Plasma amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a guideline mandated biomarker in heart failure (HF). Used as an inclusion criterion for therapeutic trials, NT-proBNP enriches trial populations and is a valid surrogate endpoint. Its diagnostic performance is best validated in acute decompensated HF (ADHF). NT-proBNP offers prognostic information independent of standard clinical predictors and refines risk stratification. With the advent of combined angiotensin 2 type 1 receptor blockade and neprilysin inhibition (ARNI) NT-proBNP retains its relationship to cardiac status and is the marker of choice in assessment of possible ADHF and in serial monitoring of HF patients receiving ARNI treatment. PMID- 29153199 TI - Soluble ST2 in Heart Failure. AB - Suppression of tumorigenicity 2 (ST2) is a member of the interleukin (IL)-1 receptor family, whose role was originally established in the context of inflammatory and autoimmune diseases. More recently, testing for ST2 has been used in the setting of cardiovascular disease. The soluble form of ST2 is a decoy receptor that inhibits beneficial cardioprotective effects of IL-33; such inhibition results in cardiac hypertrophy, myocardial fibrosis, and ventricular dysfunction. Measurement of soluble ST2 has utility for assessing heart failure severity and prognosis. In this review, we examine the role of soluble ST2 in both acute and chronic heart failure. PMID- 29153200 TI - Adrenomedullin as a Biomarker of Heart Failure. AB - Adrenomedullin (AM) is a vasodilatory peptide originally discovered in human pheochromocytoma tissue. Although AM is highly expressed in the adrenal glands, heart, lungs, and kidneys, vascular endothelium and smooth muscle are thought to be the main source of plasma AM. The AM precursor is processed to AM-glycine, which is then converted to AM-mature through C-terminal amidation. In this process, mid-regional pro-adrenomedullin (MR-proAM) is also produced. Plasma AM, AM-mature, AM-glycine, and MR-proAM levels are all higher in patients with heart failure than healthy subjects in proportional to the disease severity. All molecular forms of AM are prognostic markers for heart failure. PMID- 29153201 TI - Troponin in Heart Failure. AB - Cardiac troponin is an integral biomarker in the evaluation and management of patients with acute coronary syndrome. Troponin is also established as a valuable prognostic marker in patients with acute or chronic heart failure (HF). As the sensitivity of troponin assays transition to high sensitive troponin, more patients with HF will have detectable troponin. In this review, the authors discuss the current literature on the value of troponin in the management of patients with HF. Furthermore, the authors highlight the potential for future strategies to use troponin as a potential target for therapy in patients with HF. PMID- 29153202 TI - Growth Hormone as Biomarker in Heart Failure. AB - The impairment of growth hormone (GH)/insulin growth factor-1(IGF-1) plays a crucial role in chronic heart failure (CHF). Several studies have shown that patients affected by this condition display a more aggressive disease, with impaired functional capacity and poor outcomes. Interestingly, GH replacement therapy represents a possible future therapeutic option in CHF. In this review, the authors focus on the assessment of the main abnormalities in GH/IGF-1 axis in CHF, the underlying molecular background, and their impact on disease progression and outcomes. PMID- 29153203 TI - Galectin-3 in Heart Failure: An Update of the Last 3 Years. AB - Galectin-3 plays a role in tissue inflammation, repair, and fibrosis. This article specifically focuses on heart failure (HF), in which galectin-3 has been shown to be a useful biomarker in prognosis and risk stratification, especially in HF with preserved ejection fraction. Experimental research has shown that galectin-3 directly induces pathologic remodeling of the heart, and is therefore considered a culprit protein in the development of cardiac fibrosis in HF, with potentially relevant clinical implications. In summary, galectin-3 is a biomarker and biotarget in cardiac remodeling and fibrosis and future research will target galectin-3-centered diseases. PMID- 29153204 TI - Proteomic Biomarkers of Heart Failure. AB - Heart failure (HF) is associated with significant morbidity and mortality. Biomarkers are used to assist clinicians with timely diagnosis, prognosis, and risk prediction of patients for personalized treatment. Using modern proteomic methods such as mass spectrometry, an increasing number of novel biomarkers have been identified that further aid clinicians in the early diagnosis and outcome prediction of HF. This article focuses on the array of common and novel protein based biomarkers that provide diagnostic and prognostic information in HF. PMID- 29153206 TI - Erratum. PMID- 29153207 TI - Preface. PMID- 29153205 TI - Biomarkers of Heart Failure: Past, Present, and Future. PMID- 29153208 TI - ? PMID- 29153209 TI - [Using negative pressure therapy to prevent and treat wounds]. AB - The offer of Negative Pressure Wound Therapy (NPWT) has considerably increased these last years. Nowadays, one can choose between different tools such as motorised systems - or not - like pumps; devices which are particularly portables; automated therapies allowing regular instillations; or finally systems adapted to specific indications like "open abdominal wounds". This diversity of devices implies more than ever that prescriptions from the medical doctor be detailed and a good trackability of the nursing follow-up. PMID- 29153210 TI - ? PMID- 29153211 TI - [Heart failure, progress and challenges]. AB - Heart failure is a pathology which is constantly growing due to the ageing population. It is defined as the heart's inability to pump enough blood to meet the body's metabolic and nutritional needs. Treatment varies depending on the acute or chronic phases. The care pathway is sometimes complex. Monitoring and patient education are essential. PMID- 29153212 TI - [New treatments for heart failure]. AB - New direct oral anticoagulants are recommended as first-line therapy in case of atrial fibrillation within a heart failure. In the absence of atrial fibrillation, the role for new direct oral anticoagulants would have to be confirmed in the next years. Sacubitril/valsartan, angiotansin II receptor neprilysin inhibitor, presents with an efficacy superior to that of angiotensin converting enzyme inhibitors. It is now recommended in the treatment of heart failure as a third-line therapy. Modalities of prescription are strict, and safety is good. PMID- 29153213 TI - [Circulatory assistance, an alternative to heart transplantation]. AB - Circulatory assistance is developing as a treatment for patients with end-stage heart failure. There are two alternative devices: a univentricular circulatory assist pump, or a total artificial heart. It is used to bridge the time to transplantation and, increasingly, as a definitive alternative to a heart transplant. PMID- 29153214 TI - [Psychological support for patients with a ventricular assist device]. AB - In the case of end-stage heart failure, the medical-surgical team can suggest the use of an external circulatory assist device as a definitive therapy. Living with this assistance requires a certain amount of adaptation on the part of the patients and their family, but can significantly improve quality of life. Support groups give them the opportunity to talk about their new life and receive psychological support. PMID- 29153215 TI - [Cardiac resynchronisation]. AB - A fifth of patients with heart failure suffer from conduction disorders. A prolonged QRS duration on the electrocardiogram is an indicator of cardiac dyssynchrony. Several studies have shown the efficacy of cardiac resynchronisation therapy (CRT) in patients with a wide QRS duration: CRT is associated with reduced morbidity and mortality. An overview of the methods of implantation of CRT devices, the results of this electrical treatment and its limits. PMID- 29153216 TI - [Therapeutic education for patients with heart failure, a performance factor]. AB - Heart failure is a little-known disease which is both frequent and serious. It is particularly concerned by therapeutic education as it is linked to a high level of avoidable hospitalisations and requires daily monitoring of simple clinical parameters. It also imposes a change of lifestyle on the patient. PMID- 29153217 TI - [Private practice nurses and support for patients' return home in cardiology]. AB - The Prado Cardio programme is designed to support patients' return home and helps to identify the early warning signs of heart decompensation, thereby avoiding unscheduled hospitalisation. It also gives private practice nurses the chance to develop new expertise. The follow-up is personalised and established jointly with the patient and the multi-professional team. PMID- 29153218 TI - [A health passport for patients with heart failure]. AB - The health passport gives concrete form to the patient's care project. It constitutes a tool for sharing information between the community and hospital centred on and kept by the patient. It favours coordination between the different professionals involved in the care of patients with heart failure. Given to all patients from the beginning of their treatment, this personalised care programme enables the proposed treatment to be formalised. PMID- 29153219 TI - [Deployment of telemedicine, context and challenges]. AB - The last decade has contributed to the emergence of telemedicine. Legislation and regulations, new tools, efficient networks and regional deployments have all played their part in its growth. There are several regional solutions, often experimental. The implementation of telemedicine services nevertheless comes up against obstacles which concern all specialities, including cardiology. PMID- 29153220 TI - [Telemonitoring by the nurse of patients equipped with an implantable heart device]. AB - The nurse is at the heart of the caregiving relationship in the remote monitoring of patients with heart failure equipped with an implantable device. Her direct contact with the patient erases the distance imposed by telemonitoring and her close connection with the cardiologist-arrhythmia specialist ensures the patient follow-up is optimal. After her training in telemedicine, the nurse plays a key role in the telerhythmology activity. PMID- 29153221 TI - [Pressure sensors to prevent cardiac decompensation]. AB - Most cases of hospitalisation for heart failure are preceded by episodes of cardiac decompensation. Preventing these episodes would improve quality of life and reduce mortality and treatment costs. The monitoring of intracardiac pressures, using innovative sensors, coupled with telemedicine, offers interesting perspectives. PMID- 29153222 TI - [Simulation in health to improve the delivery of care]. AB - Simulation in health care is a very effective training tool. Using mannequins, 'standardised patients' or virtual care environments, it encourages participants to reflect on nursing practices while practising in a safe and controlled space. PMID- 29153223 TI - ? PMID- 29153224 TI - From the Editor's perspective.... PMID- 29153225 TI - Are there clinical signs and symptoms of infection to indicate the presence of multidrug-resistant bacteria in venous ulcers? AB - The selection of topical and systemic therapies for the treatment of venous ulcers with signs of infection is challenging and should be accompanied by specific precautionary measures to protect against cross-contamination in the presence of multidrug-resistant microorganisms. However, there are still no clinical indicators for this situation, and confirmation of resistant strains occurs through culture and sensitivity, which can take up to 14 days. During this period, protective measures may no longer be taken, contributing to the spread of these pathogens. This study aimed to analyze the relationship between clinical signs and symptoms of infection in venous ulcers and the presence of antimicrobial-resistant Staphylococcus aureus and/or Pseudomonas spp. A cross sectional study was developed including 69 patients with 98 venous ulcers. Clinical observation protocol was applied to detect infection indicators established by the European Wound Management Association and microbiological analysis of samples of the lesions. Fisher's exact test and chi2 were used for analyses (P < 0.05). Two indicators of infection predominated (f >70%): discoloration of the opaque type and/or dark brick red and increased exudate volume; 31 (31.6%) ulcer samples showed positive culture for the bacteria studied. There was no relationship between signs and symptoms of infection and the presence of multidrug-resistant microorganisms. Taking into account the percentage of lesions with resistant strains, for safe care, contact precautionary measures should be implemented in the treatment rooms, in addition to standard precautions. PMID- 29153226 TI - Relationship between person's health beliefs and diabetes self-care management regimen. AB - PURPOSE: To examine the relationship between the health beliefs of Saudi adults with type 2 diabetes mellitus (T2DM) and their adherence to daily diabetes self care management regimen. A secondary aim was to examine the health beliefs of adults with a diabetic foot ulcer (DFU) and participants without a DFU. METHOD: Descriptive correlational design with a convenience sample of 30 participants. Participants were recruited for this pilot study from an outpatient clinic at King Abdulaziz Medical City in Riyadh. The participants completed self-reported questionnaires about their health beliefs, daily diabetes self-care management regimen, and demographic characteristics. Hierarchical multiple regression analysis was used to test the interaction effects. FINDINGS: Participants who reported having a high internal health locus of control (IHLoC) and a high level of self-efficacy (SE) adhered well to their foot care regimen (P = .038). The more the participants believed that God controls their health, and the higher their SE, the greater the participant's adherence to their medication regimen (P = .035). The stronger the participant's belief that following their diabetes treatment regimen will lead to good outcomes, the greater the participant's adherence to their dietary regimen for those with a low IHLoC (P = .015). Participants with a high SE and reported that their doctor is able to help them control their diabetes were more likely to follow their dietary regimen (P = .048). Participants with a DFU reported having additional health conditions besides T2DM (P = .018) and had less than a college education (P = .015). Although participants with a DFU reported that they were responsible for their diabetes (P = .21), they stated that God manages their diabetes (P = .29), and the disease can be controlled based on luck (P = .10). CONCLUSIONS: Participants' beliefs were found to influence their daily self-care management regimen. Further studies are needed using a larger sample. PMID- 29153227 TI - Effect of changing the duration of keeping sandbag over catheter insertion site on the coronary angiography acute complications: A controlled clinical trial. AB - Transfemoral coronary angiography may cause acute and chronic complications. The aim of the present study was to assess the effects of changing the duration of keeping sandbag over the catheter insertion site on the acute complications of coronary angiography. This quasiexperimental study was conducted on 60 patients undergoing transfemoral coronary angiography. Participants were selected using convenience sampling and were randomly assigned to intervention (n = 30) or control group (n = 30). In the intervention group, the sandbag over the insertion site of catheter was taken off at the third hour, whereas in the control group, based on the routine care, sandbag was taken off at the sixth hour after the angiography. At the entrance hours, 3, 6, 8, and 24 hours after the angiography, the patients in both groups were evaluated in terms of groin pain, low back pain, urinary retention, discomfort, and vascular complications. Data were analyzed by repeated measures, Mann-Whitney, Friedman, independent t-test, chi-square, and Kolmogorov-Smirnov tests. The two groups showed no significant difference in terms of demographic, clinical, and preinterventional catheterization characteristics (P > .05). Patients in both groups were examined at five time points in terms of groin pain (P = .000), back pain (P = .000), urinary retention (P = .02), and comfort (P = .001) which were significantly different but with regard to vascular complications including hematoma (P = .113), bleeding (P = .32), and bruise (P = .134) were not significantly different. The results of this study showed that removing the patients' sandbag, who are under postangiography cares at the third hour, did not increase the incidence of vascular complications, whereas it decreased patients' back pain, groin pain, and urinary retention and promotes their comfort. PMID- 29153228 TI - Tools for evidence-based vascular nursing practice: Achieving information literacy for lifelong learning. AB - Information literacy is essential in facilitating evidence-based practice (EBP) activities. In vascular nursing, the implementation of EBP is of utmost importance. Best practice grounded in research evidence can contribute to improved patient care outcomes for individuals with vascular disease. The following paper discusses information literacy competencies for nurses to develop in the context of EBP, with an emphasis on formulating a clinical question and searching for evidence. Relevant health science information resources are described, including their value and purpose in the 6S model of evidence. Also discussed are practical and supportive solutions with proven effectiveness in ensuring nurses' success with EBP. PMID- 29153229 TI - Psychosocial consequences in men taking part in a national screening program for abdominal aortic aneurysm. AB - Screening for abdominal aortic aneurysm (AAA) has proven to reduce AAA-related mortality, but how the knowledge of having an untreated AAA affects health and daily life requires further clarification. The aim was to investigate the psychosocial consequences and sense of coherence (SOC) in 65-year-old men diagnosed with AAA and participating in a national screening program during a 6 month follow-up compared with men with no AAA. The single-center cohort study included 52 men with AAA and 118 men without AAA. A questionnaire including the Short Form 36 Health Survey, Hospital Anxiety and Depression Scale, SOC, questions concerning stress, and questions related to AAA were answered at baseline and after 6 months. Men with AAA reported more problems with physical functioning, pain, and general health than men with a normal aorta at baseline. After 6 months, men with AAA still reported more problems with physical functioning and stress in relation to disease than men with normal aortic diameter. No differences were observed between groups in SOC, anxiety, and depression. A significantly higher satisfaction with information from the physician and desire to learn about the AAA diagnosis was reported at baseline compared with that at follow-up. Having knowledge about the AAA diagnosis may moderately impact physical health and perceived stress, and in combination with the increased prevalence of other cardiovascular diseases, may lead to impaired perceived health for men diagnosed with AAA. PMID- 29153230 TI - Review of article: Rivaroxaban with or without aspirin in stable cardiovascular disease. Eikelboom JW, Connolly SJ, Bosch J, et al. for the COMPASS investigators. PMID- 29153231 TI - Calciphylaxis: Overview for the vascular nurse. PMID- 29153232 TI - Development of the Pediatric Temporomandibular Joint. AB - This article focuses on the embryologic development and growth of the temporomandibular joint (TMJ) and touches on the development and growth of surrounding structures. Aberrations in structures surrounding the TMJ can affect its development as well. The normal adult anatomy of the TMJ is described as well as common malformations. The clinical ramifications of a malformed TMJ are also discussed in order to understand future necessary consultants involved in the care of these patients. PMID- 29153233 TI - Temporomandibular Joint Reconstruction in the Growing Child. AB - Indications and considerations for reconstruction of the temporomandibular joint (TMJ) differ between growing and skeletally mature patients. Osteoarthritis, which is the most common cause of TMJ destruction in adults, is comparatively rare in children. The most common indications in young patients are congenital deformities, pathology, ankylosis and progressive resorptive processes. Options for reconstruction include distraction osteogenesis, autologous reconstruction (ie, costochondral graft, free fibula flap), and total alloplastic joint replacement. The choice of the ideal reconstruction is based on multiple factors, which include extent and laterality of the deformity, patient age, jaw growth pattern, and potential for progressive destruction. PMID- 29153234 TI - Evaluation of Pain Syndromes, Headache, and Temporomandibular Joint Disorders in Children. AB - After a thorough review of the history and presentation of a child's facial pain, a targeted head and neck examination is critical to the appropriate diagnosis of facial pain and temporomandibular joint disorders. It is critical to distinguish between the structural (trauma, degenerative disease, and tumor) and nonstructural (neurogenic, myogenic, and psychological) causes of pain, which will allow for incorporation of appropriate strategies of medical, psychological, dental, and surgical therapies. PMID- 29153235 TI - Imaging of the Pediatric Temporomandibular Joint. AB - Imaging of the temporomandibular joint in pediatric patients is a critical component in the evaluation and treatment of children with temporomandibular joint symptoms. MRI can provide detailed joint anatomy and identify inflammation, sometimes before symptom onset. Ultrasound scan is a convenient emerging modality to evaluate the joint and guide therapeutic injections. Radiography and computed tomography offer osseous detail to recognize early morphologic changes of the mandibular condyle and provide operative planning. Imaging promises to direct treatment to prevent future joint destruction and maintain function. PMID- 29153236 TI - Nonsurgical Management of Pediatric Temporomandibular Joint Dysfunction. AB - Temporomandibular disorders (TMD) are a subgroup of craniofacial pain problems involving the temporomandibular joint (TMJ), masticatory muscles, and associated head and neck musculoskeletal structures. These disorders are subclassified into TMJ articular disorders and masticatory muscle disorders. Patients with TMD most commonly present with pain, restricted or asymmetric mandibular motion, and TMJ sounds during mandibular movements. The prevalence tends to increase with age. Management of TMJ articular disorders consists of a combination of patient education, home-care plan, biobehavioral therapy, physical therapy, orthotic jaw appliance therapy, pharmacotherapy, and/or surgery. The goal is to increase function, reduce pain, and improve quality of life. PMID- 29153237 TI - Trauma to the Pediatric Temporomandibular Joint. AB - Management of pediatric condylar fractures presents a unique challenge because the developing mandible provides limited available bone for fixation and primary teeth preclude the use of typical closed reduction techniques. The available literature is reviewed with regard to closed and open treatment approaches. PMID- 29153238 TI - Pediatric Tumors of the Temporomandibular Joint. AB - The incidence of tumors and pseudotumors of the temporomandibular joint (TMJ) in the pediatric population is low. They are often challenging to recognize unless associated with signs and symptoms that may erroneously be interpreted as TMJ dysfunction. Tumors of the TMJ can be divided into 3 categories based on the nature and type of precursor cell involved in the tumor: benign tumors, malignant tumors, and pseudotumors. This article discusses the most common entities in these categories. PMID- 29153239 TI - Congenital Abnormalities of the Temporomandibular Joint. AB - Congenital deformities of the temporomandibular joint (TMJ) complex can present as a heterogeneous continuum of growth disturbances of the mandibular condyle, articular eminence, and temporal bone. This article describes several syndromes with congenital condylar deformity, including mandibulofacial dysostosis (Treacher Collins syndrome), hemifacial microsomia, oculoauriculovertebral syndrome, oculomandibulodyscephaly (Hallermann-Streiff syndrome), and Nager syndrome. Variations in the extent of TMJ deficiency seen in each individual case influence the timing and techniques of TMJ reconstruction. PMID- 29153240 TI - Acquired Abnormalities of the Temporomandibular Joint. AB - Mandibular growth is a complex process that involves the "functional matrix," an interaction of the muscles of mastication, occlusion, and jaw function. Although not a typical growth center, the mandibular condyle has a significant effect on the ultimate size, shape and function of the mandible and secondarily on overall facial form. Acquired temporomandibular joint (TMJ)/condylar abnormalities, such as juvenile idiopathic arthritis, idiopathic condylar resorption, TMJ ankylosis, and condylar hyperplasia, often result in facial deformity and functional deficits. Accurate diagnosis is critical for the clinician to assess potential progression of deformity, predict prognosis, and plan treatment. PMID- 29153242 TI - Erratum. PMID- 29153241 TI - Treatment of the Temporomandibular Joint in a Child with Juvenile Idiopathic Arthritis. AB - The oral and maxillofacial surgeon is instrumental in the management and care of pediatric patients with juvenile idiopathic arthritis (JIA) and should include JIA in the differential when evaluating pediatric patients with temporomandibular joint (TMJ) dysfunction. Medical management has largely decreased the need for surgical intervention, but these patients may require intraarticular steroid injections of the TMJ, close follow-up to monitor their facial growth, and management of the subsequent postinflammatory degenerative TMJ changes. This article reviews the oral and maxillofacial surgeon's role in the care of patients with JIA involvement in the TMJ. PMID- 29153243 TI - The pH dependent surface charging and points of zero charge. VII. Update. AB - The pristine points of zero charge (PZC) and isoelectric points (IEP) of metal oxides and IEP of other materials from the recent literature, and a few older results (overlooked in previous searches) are summarized. This study is an update of the previous compilations by the same author [Surface Charging and Points of Zero Charge, CRC, Boca Raton, 2009; J. Colloid Interface Sci. 337 (2009) 439; 353 (2011) 1; 426 (2014) 209]. The field has been very active, but most PZC and IEP are reported for materials, which are very well-documented already (silica, alumina, titania, iron oxides). IEP of (nominally) Gd2O3, NaTaO3, and SrTiO3 have been reported in the recent literature. Their IEP were not reported in older studies. PMID- 29153244 TI - Outcomes of Transcatheter Tricuspid Valve-in-Valve Implantation in Patients With Ebstein Anomaly. AB - We sought to describe the acute results and short- to medium-term durability of transcatheter tricuspid valve-in-valve (TVIV) implantation within surgical bioprostheses among patients with Ebstein anomaly (EA). Cases were identified from a voluntary, multicenter, international registry of 29 institutions that perform TVIV. Demographic, clinical, procedural, and follow-up data were analyzed. Eighty-one patients with EA underwent TVIV from 2008 to 2016. Thirty four patients (42%) were New York Heart Association (NYHA) class 3/4 at time of TVIV. The most common indication for TVIV was the presence of moderate or severe tricuspid regurgitation (40%). Most patients received a Melody valve (64%). TVIV was ultimately successful in all patients, and there was no procedural mortality. Four patients (5%) developed acute valve thrombosis, 4 patients (5%) developed endocarditis, and 9 patients (11%) developed valve dysfunction not related to thrombosis or endocarditis. Eight patients (10%) underwent reintervention (2 transcatheter, 6 surgical) due to thrombosis (3), endocarditis (2), other valve dysfunction (2), and patient-prosthesis mismatch without valve dysfunction (1). Among 69 patients who were alive without reintervention at latest follow-up, 96% of those with NYHA status reported were class 1/2, a significant improvement from baseline (62% NYHA class 1/2, p <0.001). In conclusion, transcatheter TVIV offers a low-risk, minimally invasive alternative to surgical tricuspid valve re replacement in patients with EA and a failing tricuspid valve bioprosthesis. PMID- 29153245 TI - Frequency of and Prognostic Significance of Cardiac Involvement at Presentation in Hereditary Transthyretin-Derived Amyloidosis and the Value of N-Terminal Pro-B Type Natriuretic Peptide. AB - The aim of this study is to assess the prevalence of cardiac involvement in hereditary transthyretin-derived (ATTRm) amyloidosis at the time of diagnosis and to determine the diagnostic and clinical value of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The University Medical Center Groningen is the national center of expertise for amyloidosis. All consecutive patients between 1994 and 2016 with ATTRm amyloidosis were followed prospectively. Baseline was set at the time of the first positive biopsy. All patients underwent a standard cardiac and neurologic work-up. Cardiac involvement was defined by otherwise unexplained left and/or right ventricular wall hypertrophy on cardiac ultrasound and/or advanced conduction disturbances. Seventy-seven patients had ATTRm amyloidosis and were included in the study. The TTR V30M mutation was present in 30 patients (39%). In both the V30M and the non-V30M groups, the neurologic presentation dominated (77% vs 51%), whereas cardiac presentation was infrequent (7% vs 15%). Clinical work-up showed that cardiac involvement was present at baseline in 51% of all patients irrespective of genotype and was associated with increased overall mortality (hazard ratio 5.95, 95% confidence interval 2.12 to 16.7), independent from clinical confounders. At a cutoff level of 125 ng/L, NT proBNP had a sensitivity of 92% for establishing cardiac involvement. In conclusion, irrespective of the frequent noncardiac presentation of ATTRm amyloidosis, cardiac involvement is already present at diagnosis in half of the patients and is associated with increased mortality. NT-proBNP is a useful marker to determine cardiac involvement in this disease. PMID- 29153246 TI - Usefulness of the American Heart Association's Life Simple 7 to Predict the Risk of Atrial Fibrillation (from the REasons for Geographic And Racial Differences in Stroke [REGARDS] Study). AB - The American Heart Association has identified metrics of ideal cardiovascular (CV) health known as Life's Simple 7 (LS7). We determined the prospective relationship between the LS7 and the incident atrial fibrillation (AF) in a biracial cohort. The REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled non-Hispanic black and white adults 45 years or older. This analysis included 9,576 REGARDS participants (mean age 63 +/- 8.4 years; 57% women; 30% black) who were free of AF at baseline and completed a follow-up examination 9.4 years later. An overall LS7 score was calculated at baseline as the sum of the LS7 component scores and classified as inadequate (0 to 4), average (5 to 9), or optimal (10 to 14) CV health. The primary outcome was incident AF, identified at follow-up by either electrocardiogram or a self reported medical history of a physician diagnosis. A total of 725 incident AF cases were detected. Compared with the inadequate category (n = 534), participants in the optimal category (n = 1,953) had a 32% lower odds of developing AF (odds ratio 0.68; 95% confidence interval 0.47, 0.99) in a logistic regression model adjusted for demographic characteristics, alcohol use, left ventricular hypertrophy, coronary heart disease, and stroke. A 1-point higher LS7 score was associated with a 5% lower odds of incident AF (odds ratio = 0.95; 95% confidence interval 0.91, 0.99). In conclusion, better CV health, as defined by the LS7 score, is associated with a reduction in development of AF. PMID- 29153247 TI - Early versus delayed appendectomy: A comparison of outcomes. AB - BACKGROUND: The optimal timing for performing appendectomy in adults remains controversial. METHOD: A one-year retrospective review of adult patients with acute appendicitis who underwent appendectomy. The cohort was divided by time-to intervention into two groups: patients who underwent appendectomy within 8 h (group 1), and those who had surgery after 8 h (group 2). Outcome measures including perioperative morbidity and mortality, post-operative length of stay, and the 30-day readmission rate were compared between the two groups. RESULTS: A total of 116 patients who underwent appendectomy met the inclusion criteria: 75 patients (65%) in group 1, and 41 (35%) in group 2. There were no differences between group 1 & 2 in perioperative complications (6.7% vs. 9.8%, P = 0.483), postoperative length of stay (median [IQR]; 19.5 [11.5-40.5] vs. 20.0 [11.25 58.5] hours, P = 0.632), or 30-day readmission rate (2.7% vs. 4.9%, P = 0.543). There were no deaths in either group. CONCLUSION: Delayed appendectomy performed more than 8 h was not associated with increased perioperative complications, postoperative length of stay, 30-day readmission rate, or mortality. PMID- 29153248 TI - Efficacy of proximal colectomy for surgical management of right-sided first colorectal cancer in Lynch Syndrome mutation carriers. AB - BACKGROUND: This study analyzes the occurrence of colorectal cancer (CRC) in Lynch syndrome (LS) mutation carriers, interval until diagnosis of metachronous CRC, and survival after proximal colectomy (PC) compared with total (TC) and subtotal colectomy (STC) for right-sided first CRC in LS mutation carriers. METHODS: Sixty-four LS mutation carriers with right-sided first CRC treated with PC or TC + STC were confirmed by clinical records. Bivariate analyses were examined for significance and life tables were generated for risk of metachronous CRC and survival estimates following surgery. RESULTS: One of 16 (6.3%) mutation carriers treated with TC + STC developed subsequent CRC compared with 13/48 (27%) treated by PC. There was no significant difference in survival estimates between PC compared with TC + STC through 25 years after surgery. CONCLUSION: Risk of subsequent CRC and survival estimates following PC and TC + STC should be considered in surgical management of right-sided first CRC in LS mutation carriers. PMID- 29153249 TI - Accurate surgical skills evaluation: Does it mandate raters have a medical background? AB - BACKGROUND: Surgeons rarely have time to assess/rate trainee performance. From a 10 year-experience of implementing OSCE style assessments, we hypothesize that the accurate scoring of interns in selected tests is not affected by the rater's medical background. METHODS: A prospective collection of quantitative scoring data by both medical school graduates and college students was compared. Each rater underwent training and then watched three videos of actors performing in each of two OSCE stations and individually scored them. RESULTS: Twelve college students and 16 medical graduates participated. There was no difference in the mean scores between rating groups for chest tube insertion (Video 1: 1.7 vs. 2.0; Video 2: 2.9 vs 3.1; Video 3: 6.1 vs 6.1; p = 0.8) and cricothyrotomy (Video 1: 4.0 vs 4.5; Video 2: 4.8 vs 5.1; Video 3: 9.2 vs 9.1; p = 0.7). CONCLUSION: Accurate scoring of surgical performance does not mandate a medical background. Given the limited availability of attending surgeons for assessments, use of validated, simple checklists can help raters with minimal medical experience perform assessments proficiently. PMID- 29153250 TI - Mental skills training effectively minimizes operative performance deterioration under stressful conditions: Results of a randomized controlled study. AB - BACKGROUND: Stress can negatively impact surgical performance, but mental skills may help. We hypothesized that a comprehensive mental skills curriculum (MSC) would minimize resident performance deterioration under stress. METHODS: Twenty four residents were stratified then randomized to receive mental skills and FLS training (MSC group), or only FLS training (control group). Laparoscopic suturing skill was assessed on a live porcine model with and without external stressors. Outcomes were compared with t-tests. RESULTS: Twenty-three residents completed the study. The groups were similar at baseline. There were no differences in suturing at posttest or transfer test under normal conditions. Both groups experienced significantly decreased performance when stress was applied, but the MSC group significantly outperformed controls under stress. CONCLUSIONS: This MSC enabled residents to perform significantly better than controls in the simulated OR under unexpected stressful conditions. These findings support the use of psychological skills as an integral part of a surgical resident training. PMID- 29153251 TI - Re: Letter to the Editor of Public Health in response to 'After 50 years and 200 papers, what can the Midspan cohort studies tell us about our mortality?' PMID- 29153252 TI - Antimicrobial stewardship in pediatric post-acute care facilities. AB - Providers in pediatric post-acute care facilities were surveyed about knowledge of and resources for antimicrobial stewardship. All agreed that antibiotics were overused in such pediatric facilities, but 60% had not implemented stewardship strategies. Lack of treatment guidelines (47%) was identified as the most common barrier to antimicrobial stewardship. PMID- 29153253 TI - Is the limit of 60mg of oral morphine equivalent daily dose still actual for the access to rapid onset opioids therapy? PMID- 29153254 TI - Facial reanimation surgery in Mobius syndrome: Experience from 76 cases from a tertiary referral hospital in Latin America. AB - INTRODUCTION: Mobius syndrome is defined as a combined congenital bilateral facial and abducens nerve palsies. The main goal of treatment is to provide facial reanimation by means of a dynamic surgical procedure. The microneurovascular transfer of a free muscle transplant is the procedure of choice for facial animation in a child with facial paralysis. OBSERVATION: Between January 2008 and January 2017, 124 patients with the syndrome have been approached at our institution. Distribution according to Mobius Syndrome classification presents as follows: Complete Mobius syndrome (n=88), Incomplete Mobius syndrome (n=28), Mobius-Like syndrome (n=8). Seventy-nine female and 45 male patients. Sixty-one percent have undergone a microsurgical procedure (n=76), in all of them, a free gracilis flap transfer was performed. DISCUSSION: Our proposed treatment protocol for complete Mobius syndrome is determined by the available donor nerves. We prefer to use the masseteric nerve as first choice, however, if this nerve is not available, then our second choice is the spinal accesory nerve. For this purpose, all patients have an electromyography performed preoperatively. Overall, dynamic facial reanimation obtained through the microvascular transfer of the gracilis muscle have proved to improve notoriously oral comissure excursion and speech intelligibility. CONCLUSION: The free gracilis flap transfer is a reproducible procedure for patients with Mobius syndrome. It is of utmost importance to select the best motor nerve possible, based on an individualized preoperative clinical and electromyographic evaluation. To our best knowledge, this is the largest series of patients with Mobius syndrome globally, treated at a single-institution. PMID- 29153255 TI - [Management of hypopigmented scars following burn injuries]. AB - OBJECTIVE: Permanent hypopigmentation of burn scars is a common consequence after partial and full thickness burns that heal by secondary intent, and they can cause severe aesthetic issues. The surgical goals for effective treatment of postburn hypopigmentation are to remove scar tissues, and to produce healthy melanocytes, with minimal donor site morbidity. This article reviews the current literature about the different ways to treat hypopigmentation following burn injuries and discusses the indications. METHODS: The PubMed database was searched for articles published from 1985 and up to 2016. Papers with regards to the management of hypopigmented lesions were included only if scars were following burn injuries. The treatments were assessed according to body region treated, surface involved, skin color, effectiveness on restoring skin pigmentation. RESULTS: Sixteen studies were included in this review. Non-surgical treatments like makeup and tattooing, and surgical treatments including thin skin grafting, chip skin grafting, punch grafting, non-cultured keratinocyte-melanocyte cell suspension, and cultured epidermal cells were all compared. CONCLUSION: Thin skin grafting is a reliable treatment especially for patient who suffer from small hypopigmented lesions as this method requires a donor skin of the same size. The cell suspension procedure may be beneficial for larger scars. Moreover demarcation between skin graft and normal skin may exist and when a precise color match is required, particularly in the head, tattooing and chip skin grafting produce a good pigmentation outcome. PMID- 29153256 TI - Intraoperative force and electrocochleography measurements in an animal model of cochlear implantation. AB - To preserve residual hearing, techniques for monitoring and reducing the effects of trauma during cochlear implant surgery are being developed. This study examines the relationships between intraoperative recordings (electrode insertion force and electrocochleography), trauma, and hearing loss after cochlear implantation. The study also evaluated the efficacy of intravenous steroids for reducing hearing loss after implantation. Thirty-two normal-hearing guinea pigs were randomly implanted with electrode arrays of differing stiffness ('hard' or 'soft'). These arrays used an intracochlear electrode to record electrode insertion force and electrocochleography responses to a multi-frequency acoustic stimulus during implantation. Additionally, sub-cohorts of animals were administered intravenous saline ('control') or dexamethasone ('steroid') prior to surgery. Subsequent hearing loss was assessed using electrocochleography recordings from the round window membrane prior to surgery and 4 weeks after implantation. After 4 weeks, cochleae were harvested and imaged with thin sheet laser imaging microscopy. After 4 weeks, compound action potential (CAP) thresholds did not differ between steroid and control groups. The CAP amplitude at low-mid frequencies decreased after implantation with a hard electrode, an effect which was partly negated by administering steroids. A decrease in the 'intraoperative' CAP amplitude preceded the reporting of insertion resistance by the surgeon by 5.94 s (+/-4.03 s SEM). Intraoperative CAP declines were also correlated with higher grades of trauma (r = 0.56, p < 0.01) and greater hearing loss (r = 0.56, p < 0.01). This relationship was not repeated with intraoperative cochlear microphonics. A rise in intraoperative force, which preceded the reporting of resistance by 0.71 s (+/-0.15 s SEM), was correlated with trauma (r = 0.400, p = 0.04) but not hearing loss (r = 0.297, p = 0.27). Preserving intraoperative CAP amplitudes during implantation was predictive of an atraumatic insertion and reduced post-implantation hearing loss. A rise in force usually preceded the reporting of resistance, although by less than 1 s. These results suggest that intraoperative CAPs may offer a more robust feedback mechanism for improving hearing preservation rates than cochlear microphonic and electrode insertion force recordings, especially considering the rapid changes in insertion force and relatively slow human reaction times. Pre-operative steroids were effective in reversing loss of CAP amplitude with hard electrodes and evoked by lower frequency tones, which suggests a possible role in reducing synaptopathy. PMID- 29153257 TI - Pseudomonas silesiensis sp. nov. strain A3T isolated from a biological pesticide sewage treatment plant and analysis of the complete genome sequence. AB - Microorganisms classified in to the Pseudomonas genus are a ubiquitous bacteria inhabiting variety of environmental niches and have been isolated from soil, sediment, water and different parts of higher organisms (plants and animals). Members of this genus are known for their metabolic versatility and are able to utilize different chemical compounds as a source of carbon, nitrogen or phosphorus, which makes them an interesting microorganism for bioremediation or bio-transformation. Moreover, Pseudomonas sp. has been described as a microorganism that can easily adapt to new environmental conditions due to its resistance to the presence of high concentrations of heavy metals or chemical pollution. Here we present the isolation and analysis of Pseudomonas silesiensis sp. nov. strain A3T isolated from peaty soil used in a biological wastewater treatment plant exploited by a pesticide packaging company. Phylogenetic MLSA analysis of 4 housekeeping genes (16S rRNA, gyrB, rpoD and rpoB), complete genome sequence comparison (ANIb, Tetranucleotide identity, digital DDH), FAME analysis, and other biochemical tests indicate the A3T strain (type strain PCM 2856T=DSM 103370T) differs significantly from the closest relative species and therefore represents a new species within the Pseudomonas genus. Moreover, bioinformatic analysis of the complete sequenced genome showed that it consists of 6,823,539bp with a 59.58mol% G+C content and does not contain any additional plasmids. Genome annotation predicted the presence of 6066 genes, of which 5875 are coding proteins and 96 are RNA genes. PMID- 29153258 TI - Novel Equations for Estimating Lean Body Mass in Patients With Chronic Kidney Disease. AB - OBJECTIVE: Simplified methods to estimate lean body mass (LBM), an important nutritional measure representing muscle mass and somatic protein, are lacking in nondialyzed patients with chronic kidney disease (CKD). We developed and tested 2 reliable equations for estimation of LBM in daily clinical practice. DESIGN AND METHODS: The development and validation groups both included 150 nondialyzed patients with CKD Stages 3 to 5. Two equations for estimating LBM based on mid arm muscle circumference (MAMC) or handgrip strength (HGS) were developed and validated in CKD patients with dual-energy x-ray absorptiometry as referenced gold method. RESULTS: We developed and validated 2 equations for estimating LBM based on HGS and MAMC. These equations, which also incorporated sex, height, and weight, were developed and validated in CKD patients. The new equations were found to exhibit only small biases when compared with dual-energy x-ray absorptiometry, with median differences of 0.94 and 0.46 kg observed in the HGS and MAMC equations, respectively. Good precision and accuracy were achieved for both equations, as reflected by small interquartile ranges in the differences and in the percentages of estimates that were 20% of measured LBM. The bias, precision, and accuracy of each equation were found to be similar when it was applied to groups of patients divided by the median measured LBM, the median ratio of extracellular to total body water, and the stages of CKD. CONCLUSIONS: LBM estimated from MAMC or HGS were found to provide accurate estimates of LBM in nondialyzed patients with CKD. PMID- 29153259 TI - Reduction of olfactory sensitivity during normobaric hypoxia. AB - OBJECTIVE: Acute mountain sickness (AMS) is caused by a low partial pressure of oxygen and may occur above 2500m. The aim of this research was to evaluate olfactory and gustatory abilities of healthy subjects during baseline conditions and after seven hours of normobaric hypoxia. METHODS: Sixteen healthy subjects were assessed using the Sniffin' Sticks, as well as intensity and pleasantness ratings. Gustatory function was evaluated utilizing the Taste Strips. Experiments were carried out under baseline conditions (518m altitude) followed by a second testing session after seven hours of normobaric hypoxia exposure (comparable to 4000m altitude). RESULTS: During normobaric hypoxia olfactory sensitivity and intensity estimates were significantly reduced. CONCLUSIONS: We conclude that normobaric hypoxia leads to a significant decrease of olfactory sensitivity and intensity ratings. PMID- 29153260 TI - Diagnostic criteria for Patulous Eustachian Tube: A proposal by the Japan Otological Society. AB - Patulous Eustachian Tube (PET) is of increasing importance in otology. However, despite the abundance of diseases requiring a differential diagnosis from PET, such as superior semicircular canal dehiscence syndrome, perilymphatic fistula, acute low-tone sensorineural hearing loss, etc., there are currently no established diagnostic criteria for PET. In view of these circumstances, the Japan Otological Society (JOS) Eustachian Tube Committee proposed the diagnostic criteria for Patulous Eustachian Tube in 2012, in order to promote clinical research on PET. A revision was made in 2016, maintaining the original concept that the criteria should be very simple, avoid any contamination of "Definite PET" with uncertain cases. Moreover, it was also intended to minimize the number of cases that could be accidentally excluded even in the presence of some suspected findings ("Possible PET"). The criteria can be used by all otolaryngologists even without using the Eustachian tube function test apparatus. However, the use of such an apparatus may increase the chances of detecting "Definite PET". The algorithm for the diagnosis of PET using the criteria has also been described. The JOS diagnostic criteria for Patulous Eustachian Tube will further promote international scientific communication on PET. PMID- 29153261 TI - Improving surgical results in complex nerve anatomy during implantation of selective upper airway stimulation. AB - The following report presents a case of two late embedded hypoglossus branches during implantation of an upper airway stimulation device that caused a mixed activation of the tongue when included in the stimulation cuff. In the end, correct cuff placement could be achieved by careful examination of the hypoglossal nerve anatomy, precise nerve dissection, tongue motion analysis and intraoperative nerve monitoring. PMID- 29153262 TI - A Call to Introduce Structured Zika Surveillance in India. AB - India has the climatic conditions conducive to year-round transmission of Zika virus, and a structured disease surveillance program should be implemented to prevent an outbreak. Such a program should (i) start screening before an outbreak arises; (ii) collect baseline data to assess future disease risk and monitor potential birth defects; and (iii) provide new insights into the ecology of the disease and inform public health policy following the one health concept. PMID- 29153263 TI - Simona Stager: Sabotaging a Master Manipulator. PMID- 29153264 TI - Relationship of peripheral blood neutrophil to lymphocyte ratio and irritable bowel syndrome AB - Background/aim: This study aimed to determine the relationship between the peripheral blood neutrophil to lymphocyte ratio (NLR) and irritable bowel syndrome (IBS). Materials and methods: A total of 107 patients suffering from constipation-predominant IBS, diagnosed in accordance with the ROMA III criteria and having complete blood count tests, were enrolled in this study. All patients underwent total colonoscopy in order to rule out any probable underlying organic colonic pathology. Results: The control group consisted of 106 healthy people with no medical complaints. The peripheral blood NLR was 2.80 +/- 2.52 on average in the IBS group. The NLR average was 2.37 +/- 1.65 in the control group, and the average NLR ratio in the patient group was statistically significant (P < 0.03) and higher than that of the control group when the patient and the control groups were compared. Conclusion: Peripheral blood NLR as a reliable, precise indicator of inflammation in constipation-predominant IBS patients, detected with a simple complete blood count, was slightly elevated but statistically significant compared to the control group. PMID- 29153265 TI - Hepatitis C virus treatment as prevention in an extended network of people who inject drugs in the USA: a modelling study. AB - BACKGROUND: Chronic infections with hepatitis C virus (HCV) and HIV are highly prevalent in the USA and concentrated in people who inject drugs. Treatment as prevention with highly effective new direct-acting antivirals is a prospective HCV elimination strategy. We used network-based modelling to analyse the effect of this strategy in HCV-infected people who inject drugs in a US city. METHODS: Five graph models were fit using data from 1574 people who inject drugs in Hartford, CT, USA. We used a degree-corrected stochastic block model, based on goodness-of-fit, to model networks of injection drug users. We simulated transmission of HCV and HIV through this network with varying levels of HCV treatment coverage (0%, 3%, 6%, 12%, or 24%) and varying baseline HCV prevalence in people who inject drugs (30%, 60%, 75%, or 85%). We compared the effectiveness of seven treatment-as-prevention strategies on reducing HCV prevalence over 10 years and 20 years versus no treatment. The strategies consisted of treatment assigned to either a randomly chosen individual who injects drugs or to an individual with the highest number of injection partners. Additional strategies explored the effects of treating either none, half, or all of the injection partners of the selected individual, as well as a strategy based on respondent driven recruitment into treatment. FINDINGS: Our model estimates show that at the highest baseline HCV prevalence in people who inject drugs (85%), expansion of treatment coverage does not substantially reduce HCV prevalence for any treatment as-prevention strategy. However, when baseline HCV prevalence is 60% or lower, treating more than 120 (12%) individuals per 1000 people who inject drugs per year would probably eliminate HCV within 10 years. On average, assigning treatment randomly to individuals who inject drugs is better than targeting individuals with the most injection partners. Treatment-as-prevention strategies that treat additional network members are among the best performing strategies and can enhance less effective strategies that target the degree (ie, the highest number of injection partners) within the network. INTERPRETATION: Successful HCV treatment as prevention should incorporate the baseline HCV prevalence and will achieve the greatest benefit when coverage is sufficiently expanded. FUNDING: National Institute on Drug Abuse. PMID- 29153266 TI - Ebola virus disease: an update on post-exposure prophylaxis. AB - The massive outbreak of Ebola virus disease in west Africa between 2013 and 2016 resulted in intense efforts to evaluate the efficacy of several specific countermeasures developed through years of preclinical work, including the first clinical trials for therapeutics and vaccines. In this Review, we discuss how the experience and data generated from that outbreak have helped to advance the understanding of the use of these countermeasures for post-exposure prophylaxis against Ebola virus infection. In future outbreaks, post-exposure prophylaxis could play an important part in reducing community transmission of Ebola virus by providing more immediate protection than does immunisation as well as providing additional protection for health-care workers who are inadvertently exposed over the course of their work. We propose provisional guidance for use of post exposure prophylaxis in Ebola virus disease and identify the priorities for future preparedness and further research. PMID- 29153267 TI - How to eliminate HCV in people who inject drugs in the USA. PMID- 29153268 TI - Advancing political will to end the tuberculosis epidemic. PMID- 29153269 TI - Vitamin D pathway gene polymorphisms influenced vitamin D level among pregnant women. AB - AIMS: To explore the relationship between vitamin D pathway genes, gene environment interactions and vitamin D level among southeast Chinese pregnant women. METHODS: 759 participants from Zhoushan Pregnant Women Cohort (ZPWC) study, were enrolled from August 2011 to April 2014 in China. Plasma 25(OH)D levels and genetic variants in vitamin D pathway (NADSYN1/DHCR7, GC, CYP3A4, CYP2R1, CYP27A1, CYP27B1, VDR, CYP24A1, and LRP2) were measured using the blood sample collected at the first trimester. Information on demographics, lifestyle, and health behavior were collected using a questionnaire. Multilinear regression and logistic regression models were performed to estimate the associations between SNPs and 25(OH)D level. RESULTS: Mean plasma 25(OH)D concentrations were 15.6 ng/mL among the pregnant women. Variants of GC rs16846876, rs17467825, rs2282679, rs3755967, rs2298850, rs4588, rs7041 and rs1155563, CYP3A4 rs2242480 and CYP24A1 rs2209314 were significantly associated with both 25(OH)D concentrations and vitamin D deficiency (25(OH)D < 15 ng/mL). Variants of NADSYN1/DHCR7 were significantly associated with 25(OH)D concentrations among pregnant women without vitamin D supplements. Pregnant women with vitamin D binding protein (Gc) Gc-1f (P = 0.02) and Gc-1s (P = 0.005) had higher plasma 25(OH)D levels compared to women with Gc-2. Genotype risk score (GRS) calculated from rs7041, rs2242480 and rs2209314 shown a significantly negative association with 25(OH)D levels. Participants with GRS > 3 had a higher risk for vitamin D deficiency than individuals with GRS <= 3 (OR = 1.71, 95% CI = 1.25-2.35). Interactions between seasons and CYP27A1 rs933994, CYP3A4 rs2246709 on plasma 25(OH)D concentrations were also observed. Haplotypes of GC and LRP2 genes shown significant associations with 25(OH)D levels among pregnant women, respectively. CONCLUSIONS: Genetic mutants in vitamin D pathway (GC, CYP3A4, CYP24A1, and NADSYN1/DHCR7) had significant associations with 25(OH)D levels among pregnant women in southeast China. Furthermore, their associations were modified by vitamin D supplementation and season. PMID- 29153270 TI - Science as momentary truth. PMID- 29153272 TI - Multilevel paravertebral nerve blockade for abdominal wall resection in a dog. PMID- 29153271 TI - Subacute corticobasal syndrome following internal carotid endarterectomy. AB - The present report is of two patients who, immediately after internal carotid endarterectomy, presented with unexplained hemiplegia, despite normal findings on repeated MRI scans, which secondarily evolved into homolateral subacute corticobasal syndrome (CBS), with asymmetrical hemispheric hypometabolism and evidence of dopaminergic denervation. This prompted us to propose an hypothesis of transient cerebral hypoxia arising during the surgical clamping period that might have provoked a prolonged or permanent functional lesion of the left hemisphere and basal ganglia, with no visible infarction on MRI but only synaptic rearrangement of the neural networks, thereby revealing or exacerbating a potentially preexisting silent impairment. PMID- 29153273 TI - Women's experiences of having depression during pregnancy and receiving acupuncture treatment-A qualitative study. AB - BACKGROUND: Research indicates some women experiencing depression during pregnancy are dissatisfied with conventional depression treatments due to incomplete effectiveness, dislike of side effects, unsatisfactory experiences with providers and concerns regarding in-utero and breastfeeding safety. Consequently, many explore alternative options including acupuncture. To further understand women's views, preferences and motivations in this regard, as well as their experiences of receiving acupuncture as part of a three-armed pragmatic randomised controlled trial evaluating acupuncture for antenatal depression in Sydney, Australia, in-depth interviews were conducted with a group of acupuncture recipients. METHODS: Eight participants who had completed the eight-treatment intervention were interviewed. Data was analysed using thematic analysis. RESULTS: The overarching theme to emerge was that women 'felt trapped between a rock and a hard place', in not wanting to feel the way they did, but also not knowing what else to do, as conventional treatments had been inadequate or unsatisfactory, or were now unacceptable during pregnancy. With a mixture of curiosity and open-mindedness, or scepticism and desperation, the women in this study decided to try acupuncture, to 'give it a go', in the hope of receiving benefits. After treatment, these women reported being surprised by 'gaining relief' from symptoms, that they also felt were cumulative and ongoing. CONCLUSIONS: The women in this study described gaining benefits from acupuncture that they felt enabled them to better manage their lives and the changes that pregnancy brings. These findings provide new understanding regarding the possible role acupuncture could provide as a supportive treatment for antenatal depression. PMID- 29153274 TI - [Classical and molecular methods for identification and quantification of domestic moulds]. AB - INTRODUCTION: To study the impact of the constant and inevitable inhalation of moulds, it is necessary to sample, identify and count the spores. BACKGROUND: Environmental sampling methods can be separated into three categories: surface sampling is easy to perform but non quantitative, air sampling is easy to calibrate but provides time limited information, and dust sampling which is more representative of long term exposure to moulds. The sampling strategy depends on the objectives (evaluation of the risk of exposure for individuals; quantification of the household contamination; evaluation of the efficacy of remediation). The mould colonies obtained in culture are identified using microscopy, Maldi-TOF, and/or DNA sequencing. VIEWPOINTS: Electrostatic dust collectors are an alternative to older methods for identifying and quantifying household mould spores. They are easy to use and relatively cheap. Colony counting should be progressively replaced by quantitative real-time PCR, which is already validated, while waiting for more standardised high throughput sequencing methods for assessment of mould contamination without technical bias. CONCLUSION: Despite some technical recommendations for obtaining reliable and comparable results, the huge diversity of environmental moulds, the variable quantity of spores inhaled and the association with other allergens (mites, plants) make the evaluation of their impact on human health difficult. Hence there is a need for reliable and generally applicable quantitative methods. PMID- 29153275 TI - Clinician, dental student, and orthognathic patient perception of black-and-white silhouette lateral profile dimensions of ideal chin position in a Chinese population. AB - OBJECTIVES: This study aimed to investigate differences in the influence of chin prominence and length on perception of facial aesthetics by Chinese dental clinicians, orthognathic patients, and dental students. STUDY DESIGN: Male and female silhouette lateral profiles were modified to obtain 28 facial profiles by altering chin prominence and length by 3 mm in the sagittal and vertical planes. Images were rated by 70 clinicians, 30 orthognathic patients, and 100 dental students on a 7-point Likert scale. RESULTS: Perceived attractiveness was highest when the male chin prominence (MCP) was -3 mm to 3 mm and the female chin prominence (FCP) was 3 mm. In contrast, male chin length (MCL) of 0 to 3 mm and female chin length (FCL) of 0 mm were considered the most attractive. In the sagittal and vertical profiles, MCP (-9 mm), FCP (-9 mm), FCL (-9 mm), and MCL ( 9 mm) were ranked least attractive. CONCLUSIONS: The overall aesthetic opinions of orthognathic patients, clinicians, and dental students are similar. The greater the retrusion or protrusion of the chin and the shorter or longer the chin length, the lower were the rates of facial aesthetics and the greater were the desire for surgery. PMID- 29153276 TI - "Is it Sjogren's syndrome or burning mouth syndrome? Distinct pathoses with similar oral symptoms"-Response. PMID- 29153277 TI - A novel ROGDI gene mutation is associated with Kohlschutter-Tonz syndrome. AB - OBJECTIVE: Kohlschutter-tonz syndrome (KTS) is a rare neurodegenerative disorder that presents with seizures, developmental regression, characteristic hypoplastic dental enamel indicative of amelogenesis imperfecta and dysmorphologies. Genetic analysis has identified loss-of-function mutations within the coding region of the ROGDI gene in KTS patients of European or Jewish decent. In the present study, we have investigated the genetic status of ROGDI in a fourteen year old South Indian patient of Dravidian race born to consanguineous parents, who was clinically diagnosed with KTS STUDY DESIGN: To confirm the clinical diagnosis of KTS in the patient, primers were designed flanking each of the 11 exons of the ROGDI gene. We then used 50 nanograms of chromosomal DNA extracted from peripheral blood of the patient and his parents to amplify with above primers. The PCR amplicons were then subjected to direct sequencing with same set of primers. RESULTS: Genetic analysis identified a novel homozygous nonsense mutation in exon 6 of the ROGDI gene; the mutation caused premature termination of ROGDI translation, resulting in truncation and loss of function of the ROGDI protein. CONCLUSIONS: Taken together, the clinical presentation and loss-of function mutation in the ROGDI gene confirms the clinical diagnosis of KTS. PMID- 29153278 TI - Corrigendum to "Molecular modeling of the lipase-catalyzed hydrolysis of acetoxymethyl(i-propoxy)phenylphosphine oxide and its P-borane analogue" [J. Mol. Graph. Model. 38 (2012) 290-297]. PMID- 29153279 TI - Corrigendum to "Neuroprotective role of Ginkgo biloba against cognitive deficits associated with bisphenol A exposure: An animal model study" [Neurochem. Int. 108 (2017) 199-212]. PMID- 29153280 TI - ? PMID- 29153281 TI - European College of Orthodontics: Commission of affiliation and titularisation. AB - : Date of birth: 05/01/1993; sex: female. A. PRETREATMENT RECORDS: 3/2005 (12 years 1 month). DIAGNOSIS: Angle class I. Teeth missing before treatment: 0. TREATMENT PLAN: Appliances and devices: bimaxillary multibracket appliances, technique Edgewise (.022*.028"); extractions of 14-24-34-44; intermaxillary traction. B. PRETREATMENT RECORDS: 4/2005 (12 years 3 months). C. POSTTREATMENT RECORDS: 12/2007 (14 years 11 months). DURATION OF ACTIVE TREATMENT: 32 months. RETENTION: Bonded wires (12-22 and 33-43); maxillary slip-cover retainer worn at night until 12/2007. D. POSTRETENTION RECORDS: (1 year minimum): 06/2010 (17 years 4 months); duration of retention: 30 months. PMID- 29153282 TI - Efficacy of elastic memory chains versus nickel-titanium coil springs in canine retraction: A two-center split-mouth randomized clinical trial. AB - OBJECTIVE: The use of newly-introduced elastic memory chains (EMCs) in space closure is increasingly gaining popularity. However, no clinical studies have evaluated their efficacy. Therefore, this study was conducted. METHODS: In this two-center split-mouth single-blind randomized controlled trial, 21 jaws were divided into 42 quadrants. The two treatments [canine retraction using EMCs versus nickel-titanium (NiTi) coil springs (as control)] were randomly assigned to two quadrants of each jaw. The premolar space was measured at the baseline, and in the 1st, 2nd, and 3rd months of canine retraction, by a blinded orthodontist. Space closure rates were compared using a paired t-test. RESULTS: The rates of space closure using NiTi springs were 1.93+/-0.62, 1.71+/-0.75, and 1.36+/-0.51mm/month, during the 1st, 2nd, and 3rd months of treatment, respectively. The 3-month average rates of space closure were 1.67+/-0.39 and 1.89+/-0.36mm/month in the NiTi and elastic groups, respectively (faster in the elastic group, P=0.022). CONCLUSIONS: The application of elastic memory chains is as effective as NiTi springs. PMID- 29153283 TI - ? PMID- 29153284 TI - Ross reversal: One to one, one to two, or two to two? PMID- 29153285 TI - Conduit conundrum: If not two, why three? PMID- 29153286 TI - Combined transaortic and transapical approach to septal myectomy in patients with complex hypertrophic cardiomyopathy. AB - OBJECTIVES: Residual midventricular obstruction after transaortic myectomy may lead to recurrent symptoms and reoperation in patients with hypertrophic cardiomyopathy and long-segment septal hypertrophy. A combined transaortic and transapical approach to septal myectomy during initial operation allows for the complete relief of subaortic and midventricular gradients and may reduce the risk of poor late functional results. METHODS: We analyzed the early outcomes of 86 patients aged 18 years or more who underwent combined transaortic and transapical septal myectomy for left ventricular outflow tract obstruction due to systolic anterior motion and midventricular obstruction or cavitary obliteration due to apical hypertrophic cardiomyopathy. RESULTS: Midventricular obstruction was present in 59 patients (68.6%); 12 patients (14.0%) had cavitary obliteration, and 15 patients (17.4%) had a combination of both. Overall, median (25th, 75th percentile) prebypass and postbypass directly measured intracavitary gradients were 85 mm Hg (48, 125) and 4 mm Hg (0, 10.8), respectively; median predischarge transthoracic left ventricular outflow tract and midventricular gradients were 0 mm Hg (0, 0) and 0 mm Hg (0, 8.5). Median crossclamp and perfusion times were 35 minutes (27, 44) and 48.5 minutes (40, 64). The 30-day and 1-year survivals were both 95%, with 2 early deaths. Functional status beyond 30 days postoperatively was available in 42 patients, and 41 patients reported improvement in symptoms and were in New York Heart Association class I/II. CONCLUSIONS: Combined transaortic and transapical septal myectomy is an effective and reasonably safe approach for patients with hypertrophic cardiomyopathy with complex septal hypertrophy. This method may prevent residual midventricular obstruction and permits myectomy to augment diastolic filling and improve left ventricular stroke volume in patients with apical hypertrophic cardiomyopathy. PMID- 29153287 TI - Avulsion Fracture of the Calcaneal Tuberosity: Case Report and Literature Review. AB - Avulsion fractures of the calcaneal tuberosity are predominantly seen in patients with poor bone quality, the commonly used lag screw fixation might not be strong enough even with bony fragments of sufficient size. We present a case of a closed displaced avulsion fracture of the calcaneal tuberosity due to blunt trauma to the calf in a 74-year-old female. Open reduction and internal fixation with two 3.5-mm cannulated cortical screws with washers was performed, and anatomic reduction was achieved. Without further trauma, secondary displacement of the fracture occurred on day 3. Revision was performed with a single 3.5-mm cortical screw and transosseous fixation with 2 suture anchors, followed by partial weightbearing for 6 weeks. At 12 weeks postoperative, the fracture had completely healed, and she was doing well at 16 months after the revision surgery. Transosseous suture anchor fixation of an osteoporotic avulsion fracture of the calcaneal tuberosity seems to provide better and stronger fixation than that using lag screws. PMID- 29153288 TI - Miltefosine-based regimen as salvage therapy in Lomentospora prolificans bone and joint infection. PMID- 29153289 TI - Lymphocele infection due to Peptoniphilus harei after radical prostatectomy. PMID- 29153290 TI - Locally advanced pancreatic cancer: An emerging entity. AB - Pancreatic adenocarcinoma (PDAC) remains a highly fatal disease that is increasing in incidence. PDAC can be classified according to resectability status with 3 nonmetastatic groups defined: resectable, borderline resectable, and locally advanced PDAC (LAPC). Delineating these subtypes is important with the optimal treatment approach dictated by high-quality CT imaging and multidisciplinary team discussion. Patients with LAPC are thought unresectable and are therefore rarely cured. In these patients, chemotherapy remains the mainstay of treatment. Aggressive approaches in this cohort are increasingly employed. Local therapies after induction chemotherapy including standard fractionation radiation, stereotactic body radiotherapy (SBRT), and irreversible electroporation (IRE) are being investigated in an attempt to improve long-term control. In some cases, responses to neoadjuvant therapy may facilitate surgical resection. Biomarkers that can select patients most likely to benefit from these options are urgently needed. This review aims to highlight the emerging treatment of patients with LAPC and to discuss current trials. PMID- 29153291 TI - Structural perturbation by arsenic triggers the aggregation of hen egg white lysozyme by promoting oligomers formation. AB - Arsenic trioxide is one of the most common metallic pollutants entering the food chain both by human activities and nature. Its entry inside the living organism through food, air and water results into the accumulation of heavy metal in several tissues which manifest several metabolic or hormonal disorders. Till now the effect of arsenic trioxide on protein misfolding and aggregation culminating into several neurodegenerative disorders is poorly understood. In the present study, we reveal the aggregation process of Hen Egg White Lysozyme (HEWL) in presence of arsenic trioxide (As2O3) at physiological conditions. We show that As2O3 promote the in vitro aggregation of HEWL in concentration dependent manner. Early phase of aggregation is observed to be induced by exposure of hydrophobic surfaces which later reorganized to promote further self-association leading to beta sheet structure. Presence of lower ordered oligomers after two days and higher ordered oligomers along with amorphous aggregates after week long incubation indicate that As2O3 drives the self-assembly of lysozyme towards oligomeric form. PMID- 29153292 TI - Editorial. PMID- 29153293 TI - Innovative Designs, Methods and Application for Disease Risk Prediction and Drug Development: Frequentist, Bayesian, and Beyond. PMID- 29153294 TI - Impact of Family History of Substance Abuse on Admission Opioid Dose, Depressive Symptoms, and Pain Catastrophizing in Patients with Chronic Pain. AB - The objectives of this study were to examine association between a family history of substance abuse and admission morphine equivalent dose, depression and pain catastrophizing screening scores, as well as reported personal history of substance use. The retrospective research was completed in an interdisciplinary three-week pain rehabilitation center. The subject cohort included admissions from January through December 2014 with 351 datasets for family history of substance abuse and oral morphine equivalency and 341 for depression, pain catastrophizing and use of substances. Outcome measures included admission self reported data on family history of substance abuse and past and current substance use, admission morphine equivalency dose, and scores on the Center for Epidemiologic Studies-Depression Scale and the Pain Catastrophizing Scale. One hundred forty-seven patients were using opioid medications on admission and those with a positive family history of substance abuse had an oral morphine equivalency (M = 92.12, SD = 95.32) compared to a negative history (M = 80.34, SD = 64.86); the difference was not statistically significant, t (120.01) =.87, p = .39. Patients with a positive family history reported higher levels of both depression, t (327.40) = 3.15, p = .002 and pain catastrophizing, t (338) = 2.76, p = .01. Those with a positive family history endorsed greater frequency of past alcohol use chi2 (1, N = 326) = 6.67, p = 0.1 and marijuana use chi2 (1, N = 341) = 4.23, p = .04 and past chi2 (1, N = 329) = 9.90, p = .002 and current tobacco use chi2 (1, N = 327) = 8.81, p = .003. Use of family history of substance abuse information may help provide data for multimodal treatments of chronic non-cancer pain. The findings from this study can be used to guide future research. PMID- 29153295 TI - Effect of Single Intra-cutaneous Injection for Acute Thoracic Herpes Zoster and Incidence of Postherpetic Neuralgia. AB - The therapeutic effect of postherpetic neuralgia (PHN) is often disappointing and challenging. The role of intra-cutaneous injection of local anesthetic and steroids in preventing PHN remains unknown. The purpose of this study was to investigate the effect of a single intra-cutaneous injection of ropivacaine plus methylprednisolone on acute thoracic herpes zoster (HZ) pain intensity and duration, eruptive duration, and PHN incidence. A total of 97 patients with acute thoracic HZ diagnosed 1-7 days after the onset of the rash were randomly assigned to receive either 15 mL of 37.5 mg ropivacaine plus 40 mg methylprednisolone (active group, n = 49) or 15 mL of saline (placebo group, n = 48). Over 7 days, all patients received 800 mg of acyclovir 5 times daily and 150 mg pregabalin twice daily. Acetaminophen was used as a rescue analgesia when visual analog scale >=4. Pain intensity was measured with visual analog scale and the amount of analgesic taken was evaluated at the initial visit and at weeks 1, 4, 12, and 24 after the intra-cutaneous injection. The time of complete resolution of pain, time of healing of skin eruption, and incidence of PHN were reported. The active group displayed a significantly shorter duration of pain (28.4 +/- 46.7 vs. 59.2 +/- 65.0, respectively; p = .009) and herpetic eruption (22.5 +/- 6.8 vs. 32.6 +/ 7.6, respectively; p < .001) than the placebo group. A significantly lower incidence of PHN was encountered in the active group after 4 weeks (16.3% vs. 47.9%, respectively; p = .001) and 12 weeks (10.2% vs. 29.2%, respectively; p = .019). Lower incidence of PHN was noticed in the active group after 24 weeks; however, this was not statistically significant (6.1% vs. 18.8%, respectively; p = .059). There was a significant reduction in the average and total doses of pregabalin and acetaminophen in the active group after the injection. No serious side effects were noticed during the study period. Early single intra-cutaneous injection, in combination with antiviral agents and optimal analgesics, in the course of acute thoracic HZ seems to be a simple, well-tolerated, and effective adjuvant treatment modality. It dramatically decreased pain intensity, shortened pain duration, reduced skin eruption, and reduced and may even prevent the development of PHN. PMID- 29153296 TI - Use of Self-management Interventions for Chronic Pain Management: A Comparison between Rural and Nonrural Residents. AB - Individuals with chronic pain who live in rural communities often lack access to pain specialists and rely on primary care providers who may be less prepared. Research has indicated that rural residents with chronic pain are more likely to receive an opioid prescription than nonrural residents. Although self-management approaches are available for chronic pain management, it is unclear to what extent rural residents use these interventions. This study compares usage of self management interventions and opioid-based analgesics for chronic pain management between rural and nonrural residents. This study is a secondary analysis of baseline data from a randomized controlled trial evaluating a telehealth intervention for chronic pain management. Participants, recruited from primary care clinics, were 65 rural residents and 144 nonrural residents with similar demographic characteristics. Differences in the use of self-management interventions, pain intensity, and opioid dose were evaluated between rural and nonrural residents. Rural residents (n = 50, 77%) were less likely to use self management interventions compared with nonrural residents (n = 133, 92%) (p = .019). Opioids were taken for pain relief by 76% of the rural residents compared with 52% of the nonrural residents. A disparity exists in the use of self management interventions for chronic pain management by rural residents compared with nonrural residents. Further study is needed to determine if this is related to the lack of access to specialists and/or pain management training of primary care providers. Nurses can play an essential role in addressing this disparity by educating patients about self-management interventions. PMID- 29153297 TI - Pain Management Practice and Guidelines in Jordanian Pediatric Intensive Care Units. AB - Limited knowledge exists of current pain management practices and supporting guidelines in Jordanian pediatric intensive care units. To determine the current pain management practices and the availability and content of practice guidelines in Jordanian pediatric intensive care units, we conducted a cross-sectional and multisite survey of four pediatric intensive care units in Jordan. A questionnaire was developed and orally administered over the phone or in person to head nurses or their nominees to capture pain management practices and the existence and content of guidelines. All units had written pain management guidelines that included pain assessment, documentation, and management. All four units used one or more pain assessment tools. In three units, pain management was considered multidisciplinary and routinely discussed on unit rounds. In two units, continuous infusion of intravenous opioids was used as well as sedatives and neuromuscular blockers for most ventilated patients. In the two other units, continuous intravenous infusion of opioids was not used and only sedatives were administered for patients on mechanical ventilation. In two units, there were no specific guidelines on the use of nonopioid analgesics, patient-controlled anesthesia, or the management of postoperative pain. No unit used an opioid or sedative withdrawal assessment tool or had pain management guidelines on the use of topical anesthetic agents or sucrose. Pain management practices and guidelines varied across the four units, suggesting that there is an opportunity for improvement in pain management in pediatric intensive care units in Jordan. PMID- 29153298 TI - Barriers to Optimal Pain Management in Aged Care Facilities: An Australian Qualitative Study. AB - Up to 80% of residents in aged care facilities (ACFs) experience pain, which is often suboptimally managed. The purpose of this study was to characterize pain management in ACFs and identify the barriers to optimal pain management. This exploratory descriptive qualitative study used semistructured interviews in five Southern Tasmania, Australian ACFs. Interviewees included 23 staff members (18 nurses and 5 facility managers) and were conducted from September to November 2015. Interviews included questions about how pain was measured or assessed, what happened if pain was identified, barriers to pain management, and potential ways to overcome these barriers. Interviewees noted that there were no formal requirements regarding pain assessment at the ACFs reviewed; however, pain was often informally assessed. Staff noted the importance of adequate pain management for the residents' quality of life and employed both nonpharmacologic and pharmacologic techniques to reduce pain when identified. The barriers to optimal pain management included difficulty identifying and assessing pain, residents' resistance to reporting pain and/or taking medications, and communication barriers between the nursing staff and GPs. Staff interviewed were dedicated to managing residents' pain effectively; however, actions in a number of areas could improve resident outcomes. These include a more consistent approach to documenting pain in residents' progress notes and improving nurse-GP communications to ensure that new or escalating pain is identified and expedient changes can be made to the resident's management. Additionally, resident, family, nurse, and carer education, conducted within the facilities on a regular basis, could help improve the pain management of residents. PMID- 29153299 TI - Effects of Educational Intervention on State Anxiety and Pain in People Undergoing Spinal Surgery: A Randomized Controlled Trial. AB - Preoperative educational intervention for anxiety and pain affects patients undergoing spinal surgery. The effects, however, have never been examined using randomized controlled designs. To investigate the effects of education on anxiety and pain for patients undergoing spinal surgery, a randomized trial with block design was used. Patients were recruited from a medical center in central Taiwan. We invited 90 patients to participate in this study. Inclusion criteria were (a) age >=20 years, (b) voluntary participation, (c) able to understand Taiwanese Mandarin Chinese or Taiwanese, and (4) no hearing or vision impairments after using aids. Patients (n = 86) undergoing lumbar spinal surgery were randomized into either an Intervention group (using educational intervention; n = 43) or a Control group (n = 43); four patients voluntarily dropped out after surgery (one in Intervention group; three in Control group). Patients had their anxiety (using the State-Trait Anxiety Inventory; STAI) and pain (using a visual analog scale) measured the day before surgery, 30 minutes before surgery, and the day after surgery. After controlling for demographics, the adjusted anxiety and pain levels were significantly lower for the Intervention group: mean STAI scores were 52.67 at baseline and 47.54 at 30 minutes before surgery (p < .001); mean pain scores were 6.07 at baseline and 5.28 on day after surgery (p < .001). Preoperative educational intervention is effective in informing patients undergoing spinal surgery that can lead to a reduction in pain, anxiety, and fear postoperatively. PMID- 29153300 TI - Cognitive Dissonance and Pediatric Procedural Pain Management: A Concept Clarification. AB - BACKGROUND: Pediatric nurses have often reported that pain management is a vital part of patient care. Evidence, however, suggests pediatric procedural pain treatments are often underused. Cognitive dissonance, the mental conflict leading to unpleasant thoughts and or feelings, may be related to this evidence-based gap found between what pediatric nurses claim about procedural pain management (that it is important) and what they actually do (underutilize pain treatments). OBJECTIVE: The purpose of this manuscript is to clarify and further develop the concept of cognitive dissonance in terms of its relationship to nurses' mental struggles with underutilization of pediatric procedural pain treatments. A more relevant and extended definition of cognitive dissonance is presented. DESIGN: The concept of cognitive dissonance was examined using Rodgers' evolutionary concept analysis approach/framework. Analysis Methods: Through a six-step process of concept identification, setting and sample identification, data collection, data analysis, and future implication discussion, a more accurate and representative definition of cognitive dissonance is described. Databases used included CINAHL, Google Scholar, PsycINFO, ERIC, and PubMed. Seminal, recent, and relevant works were included in the review to adequately develop and clarify the concept. CONCLUSIONS: Procedural pain management breech among pediatric nurses is proposed to occur before the mental conflict produced. The unpleasant mental conflict created after the breech is followed by the nurse's determination to reduce mental conflict through attitude change followed by cognition change, which more closely reflects his or her behavior. PMID- 29153301 TI - Does Neurofunction Monitoring Enhance Nursing Confidence and Comfort? AB - Despite advances in the science of sedation and pain assessment, few studies have examined the impact of various assessment tools on nursing confidence. This study examines how bispectral index monitoring impacts nursing confidence in the assessment and comfort in medication administration based on that assessment. In this prospective observational Quality Improvement project, nurses using bispectral index (BIS) and the Richmond Agitation Sedation Scale (RASS) were randomly selected to complete a self-assessment survey intended to measure their personal confidence and comfort regarding care they were providing for a specific patient on the day the survey was completed. From 110 nurse surveys, nurses had higher confidence assessing pain and sedation when BIS monitor was used in concert with RASS assessments for patients with neuromuscular blockade agents. There was no different in confidence in- nor comfort with- sedation and pain assessments for patients not receiving neuromuscular blockade agents. PMID- 29153302 TI - Accuracy of Carotid Duplex Criteria in Diagnosis of Significant Carotid Stenosis in Asian Patients. AB - BACKGROUND: Extracranial carotid stenosis can be diagnosed by velocity criteria of carotid duplex. Whether they are accurately applied to define severity of internal carotid artery (ICA) stenosis in Asian patients needs to be proved. The purpose of this study was to evaluate the accuracy of 2 carotid duplex velocity criteria in defining significant carotid stenosis. METHODS: Carotid duplex studies and magnetic resonance angiography were reviewed. Criteria 1 was recommended by the Society of Radiologists in Ultrasound; moderate stenosis (50% 69%): peak systolic velocity (PSV) 125-230 cm/s, diastolic velocity (DV) 40-100 cm/s; severe stenosis (>70%): PSV greater than 230 cm/s, DV greater than 100 cm/s. Criteria 2 used PSV greater than 140 cm/s, DV less than 110 cm/s to define moderate stenosis (50%-75%) and PSV greater than 140 cm/s, DV greater than 110 cm/s for severe stenosis (76%-95%). RESULTS: A total of 854 ICA segments were reviewed. There was moderate stenosis in 72 ICAs, severe stenosis in 50 ICAs, and occlusion in 78 ICAs. Criteria 2 had slightly lower sensitivity, whereas higher specificity and accuracy than criteria 1 were observed in detecting moderate stenosis (criteria 1: sensitivity 95%, specificity 83%, accuracy 84%; criteria 2: sensitivity 92%, specificity 92%, and accuracy 92%). However, in detection of severe ICA stenosis, no significant difference in sensitivity, specificity, and accuracy was found (criteria 1: sensitivity 82%, specificity 99.57%, accuracy 98%; criteria 2: sensitivity 86%, specificity 99.68%, and accuracy 99%). CONCLUSIONS: In the subgroup of moderate stenosis, the criteria using ICA PSV greater than 140 cm/s had higher specificity and accuracy than the criteria using ICA PSV 125-230 cm/s. However, there was no significant difference in detection of severe stenosis or occlusion of ICA. PMID- 29153303 TI - Goreisan Prevents Brain Edema after Cerebral Ischemic Stroke by Inhibiting Aquaporin 4 Upregulation in Mice. AB - BACKGROUND: Aquaporin 4 (AQP4) is a water-selective transport protein expressed in astrocytes throughout the central nervous system. AQP4 level increases after cerebral ischemia and results in ischemic brain edema. Brain edema markedly influences mortality and motor function by elevating intracranial pressure that leads to secondary brain damage. Therefore, AQP4 is an important target to improve brain edema after cerebral ischemia. The Japanese herbal Kampo medicine, goreisan, is known to inhibit AQP4 activity. Here, we investigated whether goreisan prevents induction of brain edema by cerebral ischemia via AQP4 using 4 hour middle cerebral artery occlusion (4h MCAO) mice. METHODS: Goreisan was orally administered at a dose of 500 mg/kg twice a day for 5 days before MCAO. AQP4 expression and motor coordination were measured by Western blotting and rotarod test, respectively. RESULTS: Brain water content of 4h MCAO mice was significantly increased at 24 hours after MCAO. Treatment with goreisan significantly decreased both brain water content and AQP4 expression in the ischemic brain at 24 hours after MCAO. In addition, treatment with goreisan alleviated motor coordination deficits at 24 hours after MCAO. CONCLUSIONS: The results of this study suggested that goreisan may be a useful new therapeutic option for ischemic brain edema. PMID- 29153304 TI - Thrombectomy Using "Clamping Embolus with Semi-Retrieval" Technique in Acute Ischemic Stroke. AB - BACKGROUND: Embolization of thrombus fragments in new or downstream vascular territories is a potential adverse event in neurothrombectomy, requiring additional repeated thrombectomy attempts. This study aims to describe technical results of the thrombectomy with clamping embolus technique (TCET) method in acute ischemic stroke. This study also aims to evaluate the efficiency of mechanical thrombectomy by TCET, and to compare it with conventional stent retriever thrombectomy (CSRT). MATERIALS AND METHODS: A retrospective analysis was performed in 52 consecutive patients treated between January 2015 and October 2016 for intracranial large vessel occlusion by stent retriever thrombectomy. Recanalization rates, procedure durations, and thrombectomy attempts were compared between the TCET and the CSRT groups. RESULTS: Successful recanalization (thrombolysis in cerebral infarction [TICI] 2b or 3) with TCET was achieved in 91.7% (22 of 24) versus 92.9% (26 of 28) in the CSRT group (P = .921). To preserve the restored patency of severely affected atherosclerotic intracranial vessels, 7 and 8 patients received angioplasty or stenting in the TCET and CSRT groups, respectively. In embolic cases, the number of thrombectomy attempts with TCET was significantly lower than that obtained with CSRT (1.7 +/- .2 versus 2.6 +/- .5, respectively; P = .001); the one-pass thrombectomy rate was significantly higher in the TCET group than in the CSRT-treated patients (58.8% versus 25.0%, respectively; P = .014). Procedure duration was significantly shorter by TCET than by CSRT (35.8 +/- 5.8 minutes versus 55.5 +/- 7.2 minutes, respectively; P = .001). CONCLUSIONS: The efficiency of mechanical thrombectomy by TCET in acute ischemic stroke might be improved compared with CSRT. PMID- 29153305 TI - Current practice of autologous hematopoietic progenitor cell mobilization in adult patients with multiple myeloma and lymphoma: The results of a survey from Turkish hematology research and education group (ThREG). AB - Autologous hematopoietic cell transplantation (AHCT) is an established treatment option for adult patients presenting with multiple myeloma (MM), Hodgkin lymphoma (HL) and various subtypes of non-Hodgkin lymphoma (NHL) in upfront and/or relapsed/refractory disease settings. Although there are recently published consensus guidelines addressing critical issues regarding autologous hematopoietic progenitor cell mobilization (HPCM), mobilization strategies of transplant centers show high variability in terms of routine practice. In order to understand the current institutional policies regarding HPCM in Turkey and to obtain the required basic data for preparation of a national positional statement on this issue, Turkish Hematology Research and Education Group (ThREG) conducted a web-based HPCM survey. The survey was designed to include multiple-choice questions regarding institutional practice of HPCM in adults presenting MM, HL, and NHL. The representatives of 27 adult HCT centers participated to the study. Here we report the results of this survey shedding light on the real-world experience in Turkey in terms of autologous HPCM mobilization strategies in patients presenting with MM and lymphoma. PMID- 29153307 TI - New insights into clinical aspects of automated RBC depletion in pediatric settings; sepsis-induced RBC defects and exploring new facets of Factor V-Lieden & sampling methods to the SPC of blood component production. PMID- 29153306 TI - Autologous hematopoietic progenitor cell mobilization and collection in adult patients presenting with multiple myeloma and lymphoma: A position-statement from the Turkish Society of Apheresis (TSA). AB - Autologous hematopoietic cell transplantation (AHCT) is a routinely used procedure in the treatment of adult patients presenting with multiple myeloma (MM), Hodgkin lymphoma (HL) and various subtypes of non-Hodgkin lymphoma (NHL) in upfront and relapsed/refractory settings. Successful hematopoietic progenitor cell mobilization (HPCM) and collection are the rate limiting first steps for application of AHCT. In 2015, almost 1700 AHCT procedures have been performed for MM, HL and NHL in Turkey. Although there are recently published consensus guidelines addressing critical issues regarding autologous HPCM, there is a tremendous heterogeneity in terms of mobilization strategies of transplant centers across the world. In order to pave the way to a more standardized HPCM approach in Turkey, Turkish Society of Apheresis (TSA) assembled a working group consisting of experts in the field. Here we report the position statement of TSA regarding autologous HPCM mobilization strategies in adult patients presenting with MM and lymphoma. PMID- 29153308 TI - Leukapheresis do not improve early death rates in acute myeloid leukemia patients with hyperleukocytosis. AB - Hyperleukocytosis (HL) is defined as the clinical condition when the white blood cell (WBC) count is above 100,000/mm3 in peripheral blood. It has been already shown in the literature that leukapheresis, a conventional technique to decrease the serum WBC level, is ineffective for long-term survival in cases of hyperleukocytotic acute myeloid leukemia (AML) with leukostasis. However, the effect of leukapheresis on early mortality is still unclear. In this study, we aimed to evaluate the effect of leukapheresis on early mortality of patients with AML who have HL. Twenty-eight de novo patients with AML, diagnosed with HL between 2002 and 2015 at the Hacettepe Hematology Department, were analyzed retrospectively. Leukapheresis was performed in 10 patients, and the mean WBC decrease with leukapheresis was 57.4*103/MUl which accounts for 31% of the initial WBC count. The indications for leukapheresis were hyperviscosity and prophylaxis in four and six patients, respectively. In the group of patients who received leukapheresis, three of four patients who had hyperviscosity symptoms died, and three of six patients died who did not have symptoms. In our study, we observed that the leukapheresis procedure is highly effective in reducing plasma WBC levels. However, although it is statistically insignificant, our findings also revealed that there is a much higher rate of death in patients who were treated with leukapheresis. Therefore we conclude that leukapheresis does not lower rates of early death; nevertheless, this finding should be confirmed by prospective studies with larger cohorts. PMID- 29153309 TI - Are all therapeutic plasma preparations the same: Is it worth assessing them in clinical trials? AB - Contrary to what is generally considered, plasma for direct therapeutic use is all but "standard" and can be made using a multitude of variable processes differing from one preparation to another; in sum, those changes make the final component inhomogeneous especially within inter-blood bank comparisons. The variability is further multiplied by the donors' genetic polymorphisms. This is rarely addressed in the clinical trials and meta analyses, though this may have impact on clinical outcome in patients. This short review encompasses the variability parameters in the processing of therapeutic plasma and advocates for novel, prospective, trials to assess which type of plasma is the most beneficial to patients in need, as this type may differ depending on the patients' pathological condition. PMID- 29153310 TI - Age does not matter: Mobilization and harvesting are safe and effective for elderly allogeneic peripheral hematopoietic stem cell donors. AB - It took several years to succeed safe hematopoietic stem cell transplantations. HLA-matched unrelated donors have become the most common donor source for allogeneic hematopoietic stem cell transplants worldwide. The sibling donor may have more comorbidity and decreased regenerative potential of stem and immune cells. The purpose of this retrospective study was to examine whether aging had any negative effect on aging donor or patient. 27 patients who received a hematopoietic stem cell transplantation (HSCT) from February 2013 to May 2016 and their donors were analyzed. We showed that transplantation from older relative donor was feasible. Adverse event rate was low. Donors tolerated the procedure very well. Good CD34+ cell harvest was possible. PMID- 29153311 TI - Two versus three day upfront use of granulocyte-colony stimulating factor in healthy bone marrow donors for pediatric bone marrow transplantation. AB - In order to decrease donors' exposure to granulocyte-colony stimulating factor (G CSF), we compared the effect of two versus three days of G-CSF priming on CD34+ yield in bone marrow (BM) harvest. Although the number of BM-CD34+ cells was higher in 3day G-CSF priming, we achieved the same number of CD34+ cells per recipient's weight in 2day G-CSF priming group, too. In addition, the number of total nucleated cells (TNC) harvested from BM were similar with two or three day regimen. But mononuclear cells (MNC) of the BM graft was higher in the 3day G-CSF priming group. Similar to CD34+ cell numbers, BM harvest yielded similar TNC, and MNC numbers per kilogram of the recipient. We also found that, young donors (<=10year) had more peripheral blood MNC, bone marrow MNC and CD34+ cell numbers. Another interesting finding of this study was obtaining adequate number of peripheral blood stem cells for leukapheresis with three day G-CSF administration. Since engrafment times were also similar in two groups, we concluded that 2-days G-CSF priming was resulted in sufficient mobilization of BM stem cells. PMID- 29153312 TI - Discordant intrauterine transfusion in dichorionic twin pregnancy with Rh isoimmunization. AB - Discordant intrauterine transfusion (IUT) in twin pregnancy with Rh isoimmunization is uncommon and complicated. We report a gravida 3, para 2 woman with a dichorionic diamniotic (DCDA) twin pregnancy and two fetuses received discordant transfusions. Middle cerebral artery peak systolic velocity (MCA-PSV) was used to evaluate the anemic degree in each foetus. IUT was performed 3 times in twin A and 4 times in twin B to reverse foetal anaemia. Transfusions were distinct due to the different tolerance to IUT, and the procedure could be continued in one foetus even if the other one underwent complications. Two male babies were born at 36 weeks of gestation and were given different treatments after birth. Twins were subsequently healthy after 2 years of follow up. The discordant IUT was due to the different tolerance to transfusion in the DCDA twins. Zygosity is important for the management and treatment of haemolytic anaemia in twin pregnancies. PMID- 29153313 TI - What is the role of biosimilar G-CSF agents in hematopoietic stem cell mobilization at present? AB - Mobilization of hematopoietic stem cells, which has largely replaced bone marrow harvesting as a source of hematopoietic stem cells, using recombinant agents such as filgrastim or lenograstim has become a standard procedure in both patients and healthy donors prior to peripheral blood stem cell collection for autologous and allogeneic stem cell transplantation. Published literature data suggest that mobilization with recombinant granulocyte-colony stimulating factor (G-CSF) is safe and mobilization outcomes are satisfactory. In recent years, besides G-CSF originators, biosimilar G-CSF agents have been approved by the regulatory agencies for the same indications. Current data showed that by using the biosimilar G-CSF, similar results regarding safety and efficacy of hematopoietic stem cell mobilization may be achieved compared to the originator G-CSF. Although the issues such as the similarity to a licenced biological medicine, differences in manufacturing processes, the potential to cause immunogenicity, extrapolation and interchangeability of these biosimilar products are still being discussed by the scientific area, however, more experience with these agents now exists in approved endications and there seems to be no reason to expect significant differences between biosimilar G-CSF and originator G-CSF regarding their efficacy and safety in both patients and healthy donors. Also, the significant cost savings of biosimilars in real life setting may enhance the use of these agents in the future. Nonetheless, the collection of long-term follow-up data is mandatory for both patients and healthy donors, and multicentre randomized clinical trials that directly compare biosimilar G-CSF with the originator G-CSF are needed in order to allow the transplant community to make informed decisions regarding the choice of G-CSF. PMID- 29153314 TI - Unilateral optic nerve hypoplasia: Optical coherence tomography and magnetic resonance imaging study. PMID- 29153315 TI - What are the keys to a longer, happier life? Answers from five decades of health psychology research. AB - RATIONALE: It has long been known that factors of the mind and of interpersonal relationships influence health, but it is only in the last 50 years that an independent scientific field of health psychology appeared, dedicated to understanding psychological and behavioral processes in health, illness, and healthcare. OBJECTIVE AND METHOD: This article (a) reviews important research that answers the question of how human beings can have longer, happier lives; and (b) highlights trends in health psychology featuring articles in Social Science & Medicine as well as other related literature. RESULTS: Since the 1970s, health psychology has embraced a biopsychosocial model such that biological factors interact and are affected by psychological and social elements. This model has illuminated all subjects of health, ranging from interventions to lower stress and/or to improve people's ability to cope with stressors, to mental and physical health. Importantly, a health psychology perspective is behavioral: The majority of chronic diseases of today can be avoided or reduced through healthy lifestyles (e.g., sufficient exercise, proper diet, sufficient sleep). Thus, behavior change is the key target to help reduce the immense public health burden of chronic lifestyle illnesses. Health psychology also focuses on how social patterns influence health behavior and outcomes, in the form of patient-provider interactions or as social forces in communities where people live, work, and play. Health psychology is congenial to other health sciences, especially when allied with ecological perspectives that incorporate factors upstream from individual behavior, such as networks linked to individuals (e.g., peer groups, communities). Over its history, health psychology research has been responsive to societal and medical needs and has routinely focused on understanding health disparities. CONCLUSION: By relying on a strong interdisciplinary approach, research in health psychology provides a remarkably comprehensive perspective on how people can live healthier lives. PMID- 29153317 TI - Retraction and republication-Misoprostol drug to be withdrawn from French market. PMID- 29153316 TI - Investment in child and adolescent health and development: key messages from Disease Control Priorities, 3rd Edition. AB - The realisation of human potential for development requires age-specific investment throughout the 8000 days of childhood and adolescence. Focus on the first 1000 days is an essential but insufficient investment. Intervention is also required in three later phases: the middle childhood growth and consolidation phase (5-9 years), when infection and malnutrition constrain growth, and mortality is higher than previously recognised; the adolescent growth spurt (10 14 years), when substantial changes place commensurate demands on good diet and health; and the adolescent phase of growth and consolidation (15-19 years), when new responses are needed to support brain maturation, intense social engagement, and emotional control. Two cost-efficient packages, one delivered through schools and one focusing on later adolescence, would provide phase-specific support across the life cycle, securing the gains of investment in the first 1000 days, enabling substantial catch-up from early growth failure, and leveraging improved learning from concomitant education investments. PMID- 29153318 TI - Misoprostol drug to be withdrawn from French market. PMID- 29153319 TI - Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter. AB - Allostery plays a crucial role in the mechanism of neurotransmitter-sodium symporters, such as the human dopamine transporter. To investigate the molecular mechanism that couples the transport-associated inward release of the Na+ ion from the Na2 site to intracellular gating, we applied a combination of the thermodynamic coupling function (TCF) formalism and Markov state model analysis to a 50-MUs data set of molecular dynamics trajectories of the human dopamine transporter, in which multiple spontaneous Na+ release events were observed. Our TCF approach reveals a complex landscape of thermodynamic coupling between Na+ release and inward-opening, and identifies diverse, yet well-defined roles for different Na+-coordinating residues. In particular, we identify a prominent role in the allosteric coupling for the Na+-coordinating residue D421, where mutation has previously been associated with neurological disorders. Our results highlight the power of the TCF analysis to elucidate the molecular mechanism of complex allosteric processes in large biomolecular systems. PMID- 29153320 TI - Novel Microbial Diversity and Functional Potential in the Marine Mammal Oral Microbiome. AB - The vast majority of bacterial diversity lies within phylum-level lineages called "candidate phyla," which lack isolated representatives and are poorly understood. These bacteria are surprisingly abundant in the oral cavity of marine mammals. We employed a genome-resolved metagenomic approach to recover and characterize genomes and functional potential from microbes in the oral gingival sulcus of two bottlenose dolphins (Tursiops truncatus). We detected organisms from 24 known bacterial phyla and one archaeal phylum. We also recovered genomes from two deep branching, previously uncharacterized phylum-level lineages (here named "Candidatus Delphibacteria" and "Candidatus Fertabacteria"). The Delphibacteria lineage is found in both managed and wild dolphins; its metabolic profile suggests a capacity for denitrification and a possible role in dolphin health. We uncovered a rich diversity of predicted Cas9 proteins, including the two longest predicted Cas9 proteins to date. Notably, we identified the first type II CRISPR Cas systems encoded by members of the Candidate Phyla Radiation. Using their spacer sequences, we subsequently identified and assembled a complete Saccharibacteria phage genome. These findings underscore the immense microbial diversity and functional potential that await discovery in previously unexplored environments. PMID- 29153321 TI - Consistency of Spatial Representations in Rat Entorhinal Cortex Predicts Performance in a Reorientation Task. AB - Goal-directed behavior can be affected by environmental geometry. A classic example is the rectangular arena reorientation task, where subjects commonly confuse opposite but geometrically identical corners [1]. Until recently, little was known about how environmental geometry shapes spatial representations in a neurobehavioral context [2] (although see [3]). In the present study, we asked: Under what circumstances does the internal cognitive map predict behavior? And when does it fail to do so? To this end, we developed a variant of the classical reorientation task that allows for investigation of temporal dynamics of reorientation. We recorded head-direction (HD) cells and grid cells in the medial entorhinal cortex (MEC) of rats before, during, and after performing the task. MEC cells showed a bimodal response of being either aligned or rotated, relative to the free-foraging open-field sessions. Alignment was remarkably stable between disorientations and indicative of corner choice as a function of current and past alignment of spatial representations. Accordingly, when the cells showed consistent and properly aligned readout across multiple trials, behavioral choices were better predicted by HD and grid cell readout, with a probability of more than 70%. This was not the case when the cells did not show a stable consistent readout. Our findings indicate that entorhinal spatial representations predict corner choice, contingent on the stability and reliability of their readout. This work sets the stage for further studies on the link between the reliability of the neuronal signal and behavior, with implications for many brain systems in many organisms. PMID- 29153322 TI - Bats Use Path Integration Rather Than Acoustic Flow to Assess Flight Distance along Flyways. AB - Navigation can be achieved using different strategies from simple beaconing to complex map-based movement [1-4]. Bats display remarkable navigation capabilities, ranging from nightly commutes of several kilometers and up to seasonal migrations over thousands of kilometers [5]. Many bats have been suggested to fly along fixed routes termed "flyways," when flying from their roost to their foraging sites [6]. Flyways commonly stretch along linear landscape elements such as tree lines, hedges, or rivers [7]. When flying along a flyway, bats must estimate the distance they have traveled in order to determine when to turn. This can be especially challenging when moving along a repetitive landscape. Some bats, like Kuhl's pipistrelles, which we studied here, have limited vision [8] and were suggested to rely on bio-sonar for navigation. These bats could therefore estimate distance using three main sensory-navigation strategies, all of which we have examined: acoustic flow, acoustic landmarks, or path integration. We trained bats to fly along a linear flyway and land on a platform. We then tested their behavior when the platform was removed under different manipulations, including changing the acoustic flow, moving the start point, and adding wind. We found that bats do not require acoustic flow, which was hypothesized to be important for their navigation [9-15], and that they can perform the task without landmarks. Our results suggest that Kuhl's pipistrelles use internal self-motion cues-also known as path integration-rather than external information to estimate flight distance for at least dozens of meters when navigating along linear flyways. PMID- 29153324 TI - The Paradox of Environmental Symbiont Acquisition in Obligate Mutualisms. AB - Mutually beneficial interactions between species (mutualisms) shaped the evolution of eukaryotes and remain critical to the survival of species globally [1, 2]. Theory predicts that hosts should pass mutualist symbionts to their offspring (vertical transmission) [3-8]. However, offspring acquire symbionts from the environment in a surprising number of species (horizontal acquisition) [9-12]. A classic example of this paradox is the reef-building corals, in which 71% of species horizontally acquire algal endosymbionts [9]. An untested hypothesis explaining this paradox suggests that horizontal acquisition allows offspring to avoid symbiont-induced harm early in life. We reconstructed the evolution of symbiont transmission across 252 coral species and detected evolutionary transitions consistent with costs of vertical transmission among broadcast spawners, whose eggs tend to be positively buoyant and aggregate at the sea surface. Broadcasters with vertical transmission produce eggs with traits that favor reduced buoyancy (less wax ester lipid) and rapid development to the swimming stage (small egg size), both of which decrease the amount of time offspring spend at the sea surface. Wax ester provisioning decreased after vertically transmitting species evolved brooding from broadcasting, indicating that reduced buoyancy evolves only when offspring bear symbionts. We conclude that horizontal acquisition protects offspring from damage caused by high light and temperatures near the sea surface while providing benefits from enhanced fertilization and outcrossing. These findings help explain why modes of symbiont transmission and reproduction are strongly associated in corals and highlight benefits of delaying mutualist partnerships, offering an additional hypothesis for the pervasiveness of this theoretically paradoxical strategy. PMID- 29153323 TI - Microtubule Tip Tracking by the Spindle and Kinetochore Protein Ska1 Requires Diverse Tubulin-Interacting Surfaces. AB - The macromolecular kinetochore functions to generate interactions between chromosomal DNA and spindle microtubules [1]. To facilitate chromosome movement and segregation, kinetochores must maintain associations with both growing and shrinking microtubule ends. It is critical to define the proteins and their properties that allow kinetochores to associate with dynamic microtubules. The kinetochore-localized human Ska1 complex binds to microtubules and tracks with depolymerizing microtubule ends [2]. We now demonstrate that the Ska1 complex also autonomously tracks with growing microtubule ends in vitro, a key property that would allow this complex to act at kinetochores to mediate persistent associations with dynamic microtubules. To define the basis for Ska1 complex interactions with dynamic microtubules, we investigated the tubulin-binding properties of the Ska1 microtubule binding domain. In addition to binding to the microtubule lattice and dolastatin-induced protofilament-like structures, we demonstrate that the Ska1 microtubule binding domain can associate with soluble tubulin heterodimers and promote assembly of oligomeric ring-like tubulin structures. We generated mutations on distinct surfaces of the Ska1 microtubule binding domain that disrupt binding to soluble tubulin but do not prevent microtubule binding. These mutants display compromised microtubule tracking activity in vitro and result in defective chromosome alignment and mitotic progression in cells using a CRISPR/Cas9-based replacement assay. Our work supports a model in which multiple surfaces of Ska1 interact with diverse tubulin substrates to associate with dynamic microtubule polymers and facilitate optimal chromosome segregation. PMID- 29153326 TI - Altered Structural Connectivity of the Left Visual Thalamus in Developmental Dyslexia. AB - Developmental dyslexia is a highly prevalent reading disorder affecting about 5% 10% of children [1]. It is characterized by slow and/or inaccurate word recognition skills as well as by poor spelling and decoding abilities [2]. Partly due to technical challenges with investigating subcortical sensory structures, current research on dyslexia in humans by and large focuses on the cerebral cortex [3-7]. These studies found that dyslexia is typically associated with functional and structural alterations of a distributed left-hemispheric cerebral cortex network (e.g., [8, 9]). However, findings from animal models and post mortem studies in humans suggest that dyslexia might also be associated with structural alterations in subcortical sensory pathways [10-14] (reviewed in [7]). Whether these alterations also exist in dyslexia in vivo and how they relate to dyslexia symptoms is currently unknown. Here, we used ultra-high-resolution structural magnetic resonance imaging (MRI), diffusion MRI, and probabilistic tractography to investigate the structural connections of the visual sensory pathway in dyslexia in vivo. We discovered that individuals with dyslexia have reduced structural connections in the direct pathway between the left visual thalamus (lateral geniculate nucleus [LGN]) and left middle temporal area V5/MT, but not between the left LGN and left primary visual cortex. In addition, left V5/MT-LGN connectivity strength correlated with rapid naming abilities-a key deficit in dyslexia [15]. These findings provide the first evidence of specific structural alterations in the connections between the sensory thalamus and cortex in developmental dyslexia. The results challenge current standard models and provide novel evidence for the importance of cortico-thalamic interactions in explaining dyslexia. PMID- 29153325 TI - Genetic and Epigenetic Strategies Potentiate Gal4 Activation to Enhance Fitness in Recently Diverged Yeast Species. AB - Certain genes show more rapid reactivation for several generations following repression, a conserved phenomenon called epigenetic transcriptional memory. Following previous growth in galactose, GAL gene transcriptional memory confers a strong fitness benefit in Saccharomyces cerevisiae adapting to growth in galactose for up to 8 generations. A genetic screen for mutants defective for GAL gene memory revealed new insights into the molecular mechanism, adaptive consequences, and evolutionary history of memory. A point mutation in the Gal1 co activator that disrupts the interaction with the Gal80 inhibitor specifically and completely disrupted memory. This mutation confirms that cytoplasmically inherited Gal1 produced during previous growth in galactose directly interferes with Gal80 repression to promote faster induction of GAL genes. This mitotically heritable mode of regulation is recently evolved; in a diverged Saccharomyces species, GAL genes show constitutively faster activation due to genetically encoded basal expression of Gal1. Thus, recently diverged species utilize either epigenetic or genetic strategies to regulate the same molecular mechanism. The screen also revealed that the central domain of the Gal4 transcription factor both regulates the stochasticity of GAL gene expression and potentiates stronger GAL gene activation in the presence of Gal1. The central domain is critical for GAL gene transcriptional memory; Gal4 lacking the central domain fails to potentiate GAL gene expression and is unresponsive to previous Gal1 expression. PMID- 29153327 TI - Auditory Sensitivity and Decision Criteria Oscillate at Different Frequencies Separately for the Two Ears. AB - Many behavioral measures of visual perception fluctuate continually in a rhythmic manner, reflecting the influence of endogenous brain oscillations, particularly theta (~4-7 Hz) and alpha (~8-12 Hz) rhythms [1-3]. However, it is unclear whether these oscillations are unique to vision or whether auditory performance also oscillates [4, 5]. Several studies report no oscillatory modulation in audition [6, 7], while those with positive findings suffer from confounds relating to neural entrainment [8-10]. Here, we used a bilateral pitch identification task to investigate rhythmic fluctuations in auditory performance separately for the two ears and applied signal detection theory (SDT) to test for oscillations of both sensitivity and criterion (changes in decision boundary) [11, 12]. Using uncorrelated dichotic white noise to induce a phase reset of oscillations, we demonstrate that, as with vision, both auditory sensitivity and criterion showed strong oscillations over time, at different frequencies: ~6 Hz (theta range) for sensitivity and ~8 Hz (low alpha range) for criterion, implying distinct underlying sampling mechanisms [13]. The modulation in sensitivity in left and right ears was in antiphase, suggestive of attention-like mechanisms sampling alternatively from the two ears. PMID- 29153329 TI - Efficient removal of EDTA-complexed Cu(II) by a combined Fe(III)/UV/alkaline precipitation process: Performance and role of Fe(II). AB - Efficient removal of heavy metal-EDTA complexes from water remains a challenge because of their good solubility and chemical stability. Herein, we employed a proprietary process, i.e., the Fe(III) displacement/UV irradiation/alkaline precipitation (denoted as Fe(III)/UV/OH), to enable an efficient removal of Cu(II)-EDTA complex from 19.2 mg Cu(II)/L to <1 mg Cu(II)/L. The combined process includes Fe(III) replacement with the complexed Cu(II) to form Fe(III)-EDTA and release the free Cu(II), UV-mediated catalytic decarboxylation of EDTA to form amine ligands and reduction of Fe(III) to Fe(II), and the final removal of Cu(II) through precipitation. The in situ formed Fe(II) is crucial to the final Cu(II) removal because it tends to form stable complexes with amine ligands (EDTA and its decarboxylation products), thereby inhibiting their re-complexation with the released Cu(II) and facilitating the formation of copper precipitates. Consequently, the methods capable of prolonging the life of Fe(II), e.g., increasing the Fe(III) addition or direct addition of Fe(II) into the Cu(II)-EDTA solution and deoxygenating the solution, could dramatically enhance the final Cu(II) removal. We also optimized the operational conditions of the process at the initial Cu(II)-EDTA of 19.2 mg Cu(II)/L. PMID- 29153330 TI - Corrigendum to "Interactions between three typical endocrine-disrupting chemicals (EDCs) in binary mixtures exposure on myocardial differentiation of mouse embryonic stem cell" [Chemosphere 178 (2017) 378-383]. PMID- 29153328 TI - TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. AB - Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD). PMID- 29153331 TI - Reduced Mortality Risk in the Recent Era in Early-Stage Hodgkin Lymphoma Patients Treated With Radiation Therapy With or Without Chemotherapy. AB - PURPOSE: To determine the effect of treatment changes over time on all-cause mortality risk in patients with early-stage Hodgkin lymphoma (HL) after radiation therapy. The long-term survivorship of those with HL necessitates quantification of the late risk of mortality from HL and other causes. METHODS AND MATERIALS: An institutional review board-approved retrospective study was conducted using a multi-institutional database of 1541 stage I and II HL patients treated from 1968 to 2007 with radiation therapy alone or combined-modality treatment. The analytic methods included cumulative incidence function, Kaplan-Meier estimates and log rank tests for overall survival (OS) differences, and Cox proportional hazards modeling. RESULTS: The median age at diagnosis was 27 years. At a median follow up of 15.2 years (35% of patients with >20 years of follow-up), 395 patients had died of all causes, including 85 HL, 168 second malignancy (25 hematologic and 143 nonhematologic), 70 cardiovascular, and 21 pulmonary deaths. The cumulative incidence of non-HL mortality had surpassed HL mortality at 8.3 years. For patients treated from 1968 to 1982, 1983 to 1992, and 1993 to 2007, the 15-year OS rates were 78%, 85%, and 88%, respectively (P=.0016). On Cox proportional hazards analysis, age, B symptoms, and number of disease sites were significantly associated with all-cause mortality in the first decade of follow-up, with a trend toward significance for radiation field extent. CONCLUSIONS: The all-cause mortality risk was significantly lower for patients treated in the most recent era during the first decade of follow-up, likely due to improved HL therapy resulting in a higher cure rate and lower treatment-related toxicity from smaller radiation fields. Current efforts toward radiation treatment reduction might further reduce the long-term mortality risk for these patients. PMID- 29153332 TI - Sensorimotor performance and function in people with osteoarthritis of the hand: A case-control comparison. AB - OBJECTIVES: To determine whether hand left/right judgements, tactile acuity, and body perception are impaired in people with hand OA. To examine the relationships between left right judgements, tactile acuity and hand pain. To explore the relationships between sensorimotor measures (left/right judgements and tactile acuity) and measures of hand function in people with hand OA. METHODS: Twenty patients with symptomatic hand OA and 19 healthy pain-free controls undertook a hand left/right judgment task, a control left/right judgement task, two-point discrimination (TPD) threshold testing (assessing tactile acuity), a neglect-like symptoms questionnaire (assessing body perception) and several established measures of hand function. RESULTS: Neglect-like symptoms were experienced more frequently in the hand OA group (P < 0.05). People with hand OA were slower (P < 0.05) and less accurate (P < 0.05) in the hand left/right judgement task when compared to healthy controls, with no significant difference in the control task. Significant associations were found between hand left/right judgement reaction time and pain intensity (P < 0.05) and accuracy and pain intensity (P < 0.05). TPD was not different between groups, and no correlation was found between TPD and left/right judgement performance. No association was found between left/right judgement performance and measures of hand function (all P > 0.05). However, TPD (tactile acuity) was related to several measures of hand function (all P < 0.05). CONCLUSION: People with hand OA had more frequent neglect-like symptoms and were slower and less accurate compared to healthy controls at hand left/right judgments, which was indicative of disrupted working body schema. Future studies may wish to examine whether interventions targeting sensorimotor dysfunction are effective at reducing pain and improving hand function and dexterity in people with hand OA. PMID- 29153333 TI - New excavations at the HWK EE site: Archaeology, paleoenvironment and site formation processes during late Oldowan times at Olduvai Gorge, Tanzania. AB - This paper reports the results of renewed fieldwork at the HWK EE site (Olduvai Gorge, Tanzania). HWK EE is positioned across the boundary between Lower and Middle Bed II, a crucial interval for studying the emergence of the Acheulean at Olduvai Gorge. Our excavations at HWK EE have produced one of the largest collections of fossils and artefacts from any Oldowan site, distributed across several archaeological units and a large excavation surface in four separate trenches that can be stratigraphically correlated. Here we present the main stratigraphic and archaeological units and discuss site formation processes. Results show a great density of fossils and stone tools vertically through two stratigraphic intervals (Lemuta and Lower Augitic Sandstone) and laterally across an area of around 300 m2, and highlight the confluence of biotic and abiotic agents in the formation of the assemblage. The large size and diversity of the assemblage, as well as its good preservation, qualify HWK EE as a reference site for the study of the late Oldowan at Olduvai Gorge and elsewhere in Africa. In addition, the description of the stratigraphic and archaeological sequence of HWK EE presented in this paper constitutes the foundation for further studies on hominin behavior and paleoecology in Lower and Middle Bed II. PMID- 29153334 TI - [Identification and prioritisation of low value clinical practices: The Primary Care professionals decide]. PMID- 29153335 TI - The Acoustic Voice Quality Index Version 03.01 for the Japanese-speaking Population. AB - OBJECTIVES: We aimed to determine the most appropriate syllable number for analyzing the Acoustic Voice Quality Index for the Japanese-speaking population (AVQIv3-JP) and to validate AVQIv3-JP using the determined syllable number. METHODS: First, we counted how many syllables should be included in each continuous speech (CS) sample to achieve time-balanced analysis between CS and sustained vowel samples using our previous dataset including 336 CS samples with 58 syllables. From the descriptive statistics of the counted syllable numbers, the most appropriate syllable number was identified. Subsequently, we performed validation procedures of AVQIv3-JP using our latest dataset including 455 recordings. RESULTS: Thirty Japanese syllables were judged to be the most appropriate syllable number. The concurrent validity of the AVQIv3-JP using 30 syllables was confirmed by Spearman's rho of 0.873. Subsequently, the receiver operating characteristic analysis demonstrated the excellent discriminative capability of AVQIv3-JP, showing the area under the curve of 0.915. The AVQIv3's original threshold of 2.43 in the Dutch language corresponded to sensitivity and specificity of 64.6% and 97.3%, respectively. In the present study, a threshold of 1.41 achieved the best accuracy with balanced sensitivity and specificity of 84.4% and 85.6%, respectively. Furthermore, the 95th percentile of the control participants exhibited a threshold of 2.06, showing sensitivity and specificity of 72.1% and 93.8%, respectively, as well as reasonable positive and negative likelihood ratios of 11.7 and 0.298, respectively. CONCLUSION: The AVQIv3 using 30 Japanese syllables is a reliable measurement tool for estimating the severity of voice quality and detecting abnormal voices. PMID- 29153336 TI - [Genetics and family medicine]. AB - There have been spectacular advances in genetics in the last decades. Their implications in medicine have been so relevant that the family doctor cannot ignore them. However, interestingly, our specialty training program has hardly any contents related to this discipline. For this reason, several publications have warned of the need to correct this deficit and to determine the knowledge, skills and abilities in genetics that should be acquired by family physicians. It is considered that, in addition to some general concepts, we must have training related to genetic testing, genetic counselling, aspects related to hereditary cancers, and to be aware of the ethical and legal limits of genetic information. It is also necessary to establish guidelines for collaboration with the genetic services. PMID- 29153338 TI - Prevalence and prognosis of intracranial stenosis in acute ischemic stroke; a single center registry from Turkey AB - Background/aim: Intracranial stenosis (ICS) is identified in 2.2%?70.4% of patients with ischemic stroke and transient ischemic attack. This study aimed to determine the prevalence of ICS in a single center registry from Turkey. Materials and methods: We reviewed the charts of 619 patients with acute ischemic stroke. ICS was defined as any ICS > 50% on cerebrovascular imaging. The demographic data, risk factors, NIHSS scores and C reactive protein level at admission, mortality in hospital, recurrent stroke, and mRS in the follow-up period were recorded. Results: A total of 72 (11.6%) patients with ICS (45 males (62.5%); mean age 68.3 +/- 12.6 years) were included. Sixty-seven patients (10.8%) had symptomatic ICS and 44 patients (7.1%) had ICS without extracranial stenosis. Diabetes mellitus (DM) was significantly higher in the ICS group compared to the others (P = 0.017). Disability was significantly better in patients with ICS compared to the others (P < 0.001). On logistic regression analysis, DM and follow up mRS were significantly associated with ICS (P < 0.05). Conclusion: ICS was seen in 11.6% of acute ischemic stroke cases in our registry. DM appears to be the major risk factor for ICS. Disability was better in patients with ICS. Ethnicity could be a factor causing better disability. PMID- 29153337 TI - [Optimal cholesterol levels in patients in real-life. A systematic review]. AB - Dyslipidaemia is one of the main risk factors for the development of atherosclerosis. Different studies have demonstrated that the lower the LDL cholesterol, the better. Current evidence shows that the LDL cholesterol targets recommended by the clinical practice guidelines are beneficial and safe. However, consistent data show that higher reductions might provide additional cardiovascular beneficial effects, without an increase in side effects. Unfortunately, the current control of dyslipidaemia is very poor. Although statins are the treatment of choice in the majority of patients with dyslipidaemia, the current therapeutic armamentarium has different alternatives that effectively reduce LDL cholesterol levels, and that alone, or in combination, help to achieve LDL cholesterol targets in the majority of patients. PMID- 29153339 TI - Polycyclic aromatic hydrocarbon formation during the gasification of sewage sludge in sub- and supercritical water: Effect of reaction parameters and reaction pathways. AB - The formation of polycyclic aromatic hydrocarbon is a widespread issue during the supercritical water gasification of sewage sludge, which directly reduces the gasification efficiency and restricts the technology practical application. The changes of the concentrations and forms as well as the synthesis rate of polycyclic aromatic hydrocarbons in the residues from supercritical water gasification of dewatered sewage sludge were investigated to understand influence factors and the reaction pathways. Results showed that the increase of reaction temperature during the heating period favours directly concentration of polycyclic aromatic hydrocarbon (especially higher-molecular-weight), especially when it raise above 300 degrees C. Lower heating and cooling rate essentially extend the total reaction time. Higher polycyclic aromatic hydrocarbon concentration and higher number of rings were generally promoted by lower heating and cooling rate, longer reaction time and higher reaction temperature. The lower molecular-weight polycyclic aromatic hydrocarbons can be directly generated through the decomposition of aromatic-containing compounds in sewage sludge, as well as 3-ring and 4-ring polycyclic aromatic hydrocarbons can be formed by aromatization of steroids. Possible mechanisms of reaction pathways of supercritical water gasification of sewage sludge were also proposed. PMID- 29153340 TI - Impacts of delayed addition of N-rich and acidic substrates on nitrogen loss and compost quality during pig manure composting. AB - Delayed addition of Nitrogen (N)-rich and acidic substrates was investigated to evaluate its effects on N loss and compost quality during the composting process. Three different delayed adding methods of N-rich (pig manure) and acidic substrates (phosphate fertilizer and rotten apples) were tested during the pig manure and wheat straw is composting. The results showed that delayed addition of pig manure and acidic materials led two temperature peaks, and the durations of two separate thermophilic phase were closely related to the amount of pig manure. Delayed addition reduced total N loss by up to 14% when using superphosphate as acidic substrates, and by up to 12% when using rotten apples as acidic substrates, which is mainly due to the decreased NH3 emissions. At the end of composting, delayed the addition of pig manure caused a significant increase in the HS (humus substance) content, and the highest HS content was observed when 70% of the pig manure was applied at day 0 and the remaining 30% was applied on day 27. In the final compost, the GI in all treatments almost reached the maturity requirement by exceeding 80%. The results suggest that delayed addition of animal manure and acidic substrates could prevent the N loss during composting and improve the compost quality. PMID- 29153341 TI - Spatial and temporal characteristics of elevated temperatures in municipal solid waste landfills. PMID- 29153342 TI - Periods of unexplained higher deaths and medical admissions have occurred previously - But have apparently been ignored, misinterpreted or not investigated. PMID- 29153343 TI - Prevalence of anemia in hospitalized internal medicine patients: Correlations with comorbidities and length of hospital stay. AB - BACKGROUND: Several studies have documented a linear growth of the prevalence of anemia with aging. Especially in hospitalized elderly patients, anemia can aggravate the course of chronic disorders, and ultimately get worse the clinical outcomes. METHODS: To evaluate the distribution, the main causes, and the possible correlations of anemia with comorbidities and length of hospitalization in a population of internal medicine inpatients, we carried out an observational study on a cohort of 923 consecutive admissions relative to 856 subjects. RESULTS: Anemia was observed in 58.4% of patients, with an increase of the prevalence with increasing age regardless gender difference. In more than one half of anemic patients, anemia was mild. Chronic inflammation and chronic renal failure were the most frequent causes of anemia in our population, and in >35% of patients a multifactorial anemia was diagnosed. Age, chronic renal failure, chronic liver disease, hematological malignancies, solid tumors, and antiplatelet therapy showed a significantly independent association with the presence of anemia. Hemoglobin levels were influenced by the presence of chronic lung disease, chronic renal failure, hematological malignancies, solid tumors, and antiplatelet therapy. The presence and the degree of anemia also correlated with a significantly longer hospital stay. CONCLUSIONS: Our data confirm the high prevalence of anemia in patients hospitalized in an Internal Medicine Department, with a remarkable burden of mild forms, and of chronic inflammation's pathogenic mechanism. Correlations with comorbidities and duration of hospital stay highlight the crucial part played by anemia in determining the clinical complexity of such patients. PMID- 29153344 TI - Sex differences in humor processing: An event-related potential study. AB - Numerous behavioral studies and a handful of functional neuroimaging studies have reported sex differences in humor. However, no study to date has examined differences in the time-course of brain activity during multistage humor processing between the sexes. The purpose of this study was to compare real-time dynamics related to humor processing between women and men, with reference to a proposed three-stage model (involving incongruity detection, incongruity resolution, and elaboration stages). Forty undergraduate students (20 women) underwent event-related potential recording while subjectively rating 30 question answer-type jokes and 30 question-answer-type statements in a random order. Sex differences were revealed by analyses of the mean amplitudes of difference waves during a specific time window between 1000 and 1300 ms poststimulus onset (P1000 1300). This indicates that women recruited more mental resources to integrate cognitive and emotional components at this late stage. In contrast, men recruited more automated processes during the transition from the cognitive operations of the incongruity resolution stage to the emotional response of the humor elaboration stage. Our results suggest that sex differences in humor processing lie in differences in the integration of cognitive and emotional components, which are closely linked and interact reciprocally, particularly in women. PMID- 29153345 TI - [Heart failure of unusual cause]. PMID- 29153346 TI - Gravity, Tissue Engineering, and the Missing Link. AB - The influence of microgravity and hypergravity on living systems has attracted significant attention, but the use of these tools in tissue engineering (TE) remains relatively unexplored. This Forum article highlights an emerging field of research to uncover new potential applications at the interface between altered gravity and TE. PMID- 29153347 TI - Autologous stem cell transplantation and stem cell mobilization kinetics in elderly patients with B cell non-Hodgkin lymphoma. AB - As known, the world population is aging and as the life span increases the number of advanced-age lymphomas also shows an upward trend. Autologous hematopoietic stem cell transplantation (HSCT) is the standard treatment modality in chemotherapy-sensitive relapsed or refractory aggressive lymphomas. Increased morbidity and mortality related to both the transplant itself and comorbid diseases can be observed in elderly lymphoma patients. Patients who are 65 years or older and underwent autologous HSCT with B-cell non-Hodgkin lymphoma were retrospectively included in our study. In terms of survival analysis, median follow-up was 34.5 months (8-159) while the overall survival (OS) was 58%. In the univariate analysis of prognostic data in OS, patients who were referred to transplantation with complete response had a statistically significant survival advantage (p=0.043). In terms of the effect of pre-transplant conditioning regimens on survival, BEAM regimen yielded better results, though not statistically significant. Age, number of chemotherapy cycles received before mobilization and radiation therapy had no significant effect on the CD34 (+) cell count in the final product (p=0.492, 0.746 and 0.078 respectively). In conclusion, autologous HSCT is a practicable treatment modality that provides survival advantage in suitable advanced-age patients with a diagnosis of B-cell non-Hodgkin lymphoma. PMID- 29153349 TI - World Apheresis Association: Member-Society Updates. PMID- 29153348 TI - Sampling methods to the statistical control of the production of blood components. AB - The control of blood components specifications is a requirement generalized in Europe by the European Commission Directives and in the US by the AABB standards. The use of a statistical process control methodology is recommended in the related literature, including the EDQM guideline. The control reliability is dependent of the sampling. However, a correct sampling methodology seems not to be systematically applied. Commonly, the sampling is intended to comply uniquely with the 1% specification to the produced blood components. Nevertheless, on a purely statistical viewpoint, this model could be argued not to be related to a consistent sampling technique. This could be a severe limitation to detect abnormal patterns and to assure that the production has a non-significant probability of producing nonconforming components. This article discusses what is happening in blood establishments. Three statistical methodologies are proposed: simple random sampling, sampling based on the proportion of a finite population, and sampling based on the inspection level. The empirical results demonstrate that these models are practicable in blood establishments contributing to the robustness of sampling and related statistical process control decisions for the purpose they are suggested for. PMID- 29153350 TI - Management of mobilization failure in 2017. AB - In contemporary clinical practice, almost all allogeneic transplantations and autologous transplantations now capitalize on peripheral blood stem cells (PBSCs) as opposed to bone marrow (BM) for the source of stem cells. In this context, granulocyte colony-stimulating factor (G-CSF) plays a pivotal role as the most frequently applied frontline agent for stem cell mobilization. For patients classified as high-risk, chemotherapy based mobilization regimens can be preferred as a first choice and it is notable that this also used for remobilization. Mobilization failure occurs at a rate of 10%-40% with traditional strategies and it typically leads to low-efficiency practices, resource wastage, and delayed in treatment intervention. Notably, however, several factors can impact the effectiveness of CD34+ progenitor cell mobilization, including patient age and medical history (prior chemotherapy or radiotherapy, disease and marrow infiltration at the time of mobilization). In recent years, main (yet largely ineffective) approach was to increase G-CSF dose and add SCF, but novel and promising pathways have been opened up by the synergistic impact of a reversible inhibitor of CXCR4, plerixafor, with G-CSF. The literature shows to its favorable results in upfront and failed mobilizers, and it is necessary to use plerixafor (or equivalent agents) to optimize HSC harvest in poor mobilizers. Different CXCR4 inhibitors, growth hormone, VLA4 inhibitors, and parathormone, have been cited as new agents for mobilization failure in recent years. In view of the above considerations, the purpose of this paper is to examine the mobilization of PBSC while focusing specifically on poor mobilizers. PMID- 29153351 TI - Choosing Wisely - An international and multimorbid perspective. AB - Some medical diagnostic and therapeutic interventions are non-beneficial or even harmful. The Choosing Wisely campaign has encouraged the generation of "top five" lists of unnecessary low-value services in different specialist areas. In the USA alone, where the campaign was launched, these lists include a total of 450 evidence-based recommendations. Medical scientific societies in further countries such as Canada, Australia, New Zealand, England, Switzerland and Germany have since initiated Choosing Wisely campaigns. Besides implementing top five lists, these aim to change attitudes, expectations and practices in the culture of medicine. The field of internal medicine has initiated change in Switzerland (Swiss Society of General Internal Medicine: Smarter Medicine) and Germany (German Society of Internal Medicine: Klug entscheiden). Formulating Choosing Wisely principles in managing complex patients with multiple concurrent acute or chronic diseases, i. e., multimorbidity (MM), will present a particular challenge. Research is needed to determine the primary sources of overuse in specific combinations of diseases (i. e., MM clusters) and spearhead corresponding recommendations. National Choosing Widely campaigns may serve as a forerunner to a more global initiative. PMID- 29153352 TI - [Choosing Wisely in medical education]. AB - Choosing Wisely recommendations address situations where physicians will have to make decisions about further diagnostic and therapeutic steps. Undergraduate medical education needs to equip students with the foundations on which clinical reasoning skills can be acquired and fostered throughout their clinical career. Teaching these skills usually involves patients (e.g., bedside teaching, electives, clinical attachments) but it can also be delivered in the format of formalised small-group, case-based learning. Case-based key feature tests have been developed to facilitate the assessment of learning outcomes related to clinical reasoning. Repeated testing with key feature cases yields better medium term retention than repeatedly studying the same material (without questions). The project 'Choosing Wisely in medical education', which was funded by the German Association for Internal Medicine, involves the creation of key feature cases with reference to the German set of Choosing Wisely recommendations. This article presents the results of the first pilot study using these new cases. PMID- 29153353 TI - ["Something humane has been lost". Re-evaluation of the attitudes of senior physicians towards the G-DRG System - a qualitative normative analysis]. AB - Only a few years after the implementation of the G-DRG (German Diagnosis Related Group) system physicians already began to complain of its negative effects on the quality of inpatient healthcare. The present study examines the recent experiences senior physicians have made with regard to the impact of the G-DRG system on the quality of healthcare and medical professionalism. Nine qualitative guided expert interviews were conducted focusing on the experiences of physicians in leading positions dealing with the G-DRG system in their everyday work. The interviewees report an intensification of work attributable to an increasing number of inpatient cases, a more lenient definition of medical indications and a reduction in patient retention time. The physicians interviewed have felt increasingly constrained by economic conditions. Additionally, they stated that the G-DRG system's incentive structure encourages the discrimination of older, care-dependent and multimorbid patients. Possible countermeasures include a political revision of incentive regulation as well as a strengthening of up-to date professional ethical education and teaching. PMID- 29153354 TI - The Choosing Wisely Initiative: A critical analysis with a special focus on primary care. AB - The Choosing Wisely initiative (CWI), a campaign led by the American Board of Internal Medicine (ABIM) Foundation, promotes doctor-patient communication and reducing waste in healthcare. At present, many of the top 5 lists from the Choosing Wisely Initiative appear to be primarily eminence-based and influenced by self-interest. The implementation of recommendations from these lists may mean taking a step backwards to the time before evidence-based medicine. On the other hand, despite all the challenges that the Choosing Wisely initiatives are currently facing, it is difficult to deny that they also hold great potential in terms of making healthcare systems more efficient and beneficial to patients. The aim of the ongoing work in Germany and Austria is to create conditions that are necessary if CW initiatives are to evolve into a model tool that will help introduce the principles of evidence-based medicine into daily practice. PMID- 29153355 TI - [The Choosing Wisely Initiative (CWI): Background, aims and problems of a professional campaign against oversupply]. AB - The Choosing Wisely Initiative (CWI) started in 2012 follows a proposal by Howard Brody (2010). Using CWI, the US ABIM Foundation continued its work to strengthen medical professionalism. The text describes CWI's development, aims, mission, and dissemination. It discusses some of its limits and problems. An appendix tabulates similarities and differences between CWI and a (2016) subsequent initiative from the German Society of Internal Medicine (DGIM: Klug Entscheiden Empfehlungen/decide wisely recommendations). PMID- 29153356 TI - [How to develop Choosing Wisely recommendations for internal medicine]. AB - "Choosing Wisely" is an initiative of the German Society of Internal Medicine with the aim to provide recommendations for diagnostic and therapeutic procedures that are of clear medical and scientifically proven benefit, but are rather underused in daily practice. As such, these positive recommendations are indicative of an undersupply. On the other hand, the German Society of Internal Medicine also developed "negative recommendations", pointing out diagnostic and therapeutic procedures that are frequently used but for which there is little or no scientific evidence. They indicate oversupply. So far, the various internal medicine societies have each developed five positive and five negative recommendations, and there are more to come. PMID- 29153357 TI - [Choosing Wisely - Klug Entscheiden: conceptual and ethical considerations]. AB - Choosing Wisely and Klug Entscheiden (KE) are recent physician-triggered campaigns that aim at identifying and reducing blatant over-treatment as well as a specialty of KE - occurring under-treatment. This paper provides some conceptual and normative analyses of these campaigns' goals and justifications. PMID- 29153358 TI - Impact of noise-optimized virtual monoenergetic dual-energy computed tomography on image quality in patients with renal cell carcinoma. AB - OBJECTIVE: The aim of this study was to evaluate the impact of a noise-optimized virtual monoenergetic imaging (VMI+) reconstruction technique on image quality and lesion delineation in patients with renal cell carcinoma (RCC) undergoing abdominal dual-energy computed tomography (DECT). MATERIALS AND METHODS: Fifty two patients (33 men; 61.5+/-13.6years) with RCC underwent contrast-enhanced DECT during the corticomedullary and nephrogenic phase of renal enhancement. DECT datasets were reconstructed with standard linearly-blended (M_0.6), as well as traditional virtual monoenergetic (VMI) and VMI+ algorithms in 10-keV increments from 40 to 100 keV. Contrast-to-noise (CNR) and tumor-to-cortex ratios for corticomedullary- and nephrogenic-phase images were objectively measured by a radiologist with 3 years of experience. Subjective image quality and RCC delineation were evaluated by three independent radiologists. RESULTS: Greatest CNR values were found for 40-keV VMI+ series in both corticomedullary- (8.9+/ 4.9) and nephrogenic-phase (7.1+/-4.6) images and were significantly higher compared to all other reconstructions (P<0.001). Furthermore, tumor-to-cortex ratios were highest for 40-keV nephrogenic-phase VMI+ (2.1+/-3.5; P<=0.016), followed by 50-keV and 60-keV VMI+ (2.0+/-3.2 and 1.8+/-2.8, respectively). Qualitative image quality scored highest for 50-keV VMI+ series in corticomedullary-phase reconstructions and 60-keV in nephrogenic-phase reconstructions (P<=0.031). Highest scores for lesion delineation were assigned for 40-keV VMI+ reconstructions (P<=0.074). CONCLUSION: Low-keV VMI+ reconstructions lead to improved image quality and lesion delineation of corticomedullary- and nephrogenic-phase DECT datasets in patients with RCC. PMID- 29153359 TI - Multi-detector CT: Liver protocol and recent developments. AB - Multi-detector computed tomography is today the workhorse in the evaluation of the vast majority of patients with known or suspected liver disease. Reasons for that include widespread availability, robustness and repeatability of the technique, time-efficient image acquisitions of large body volumes, high temporal and spatial resolution as well as multiple post-processing capabilities. However, as the technique employs ionizing radiation and intravenous iodine-based contrast media, the associated potential risks have to be taken into account. In this review article, liver protocols in clinical practice are discussed with emphasis on optimisation strategies. Furthermore, recent developments such as perfusion CT and dual-energy CT and their applications are presented. PMID- 29153360 TI - Magnetic resonance imaging of intracranial atherosclerosis: Comparison of ex vivo 3T MRI and histologic findings. AB - PURPOSE: Imaging the lipid-rich necrotic core (LRNC) is very important when evaluating the response of lipid-lowering therapy. The purpose of this study was to assess ex vivo LRNC of intracranial atherosclerosis using 3T MRI. MATERIALS AND METHODS: Thirty-one atherosclerotic lesions from 17 specimens were analyzed (basilar artery=15, middle cerebral artery=16) using 3T MRI. Specimens were not chemically processed for imaging studies. Reconstructed MRI was matched with histologic sections at corresponding locations. RESULTS: The median plaque thickness of intracranial atherosclerosis was 0.6mm (0.4-2.0mm). All specimens had a LRNC on histologic findings. Three specimens had plaque calcification on histologic findings. LRNC of 30 specimens (96.8%) appeared as homogeneous isointensity/hypointensity on T1-weighted imaging and hypointensity on T2 weighted imaging compared with T1-weighted imaging. CONCLUSIONS: All specimens with ex vivo intracranial atherosclerosis had LRNC. Intracranial atherosclerosis could be an indication for lipid-lowering therapy, similar to previous carotid MR studies. PMID- 29153361 TI - Noise reduction angiographic imaging technology reduces radiation dose during bronchial artery embolization. AB - PURPOSE: Comparison of radiation doses in patients undergoing angiographic bronchial artery embolization (BAE) before and after a noise reduction imaging technology upgrade. METHODS: We performed a retrospective study of 70 patients undergoing BAE. Procedures were performed before (n=32) and after (n=38) the technology upgrade containing additional filters and improved image-processing. Cumulative air kerma (AK), cumulative dose area product (DAP), number of exposure frames, total fluoroscopy time and amount of contrast agent were recorded. Mean values were calculated and compared using two-tailed t-tests. DSA image quality was assessed independently by two blinded readers and compared using the Wilcoxon signed-rank test. RESULTS: Using the new technology resulted in a significant reduction of 59% in DAP (149.2 (103.1-279.1) vs. 54.8 (38.2-100.7) Gy*cm2, p<0.001) and a significant reduction of 60% for AK (1.3 (0.6-1.9) vs. 0.5 (0.3 0.9) Gy, p<0.001) in comparison to procedures before the upgrade. There was no significant difference between the number of exposure frames in both groups (251+/-181 vs. 254+/-133 frames, p=0.07), time of fluoroscopy (28.8 (18.5-50.4) vs. 28.1 (23.3-38.7) min, p=0.73), or the amount of contrast agent used (139.5+/ 70.8 vs. 163.1+/-63.1ml, p=0.11). No significant difference regarding image quality could be detected (3 (2,3) vs. 3 (2-4), p=0.64). CONCLUSIONS: The new angiographic noise reduction technology significantly decreases the radiation dose during bronchial artery embolization without compromising image quality or increasing time of fluoroscopy or contrast volume. PMID- 29153362 TI - In vivo assessment of placental elasticity in intrauterine growth restriction by shear-wave elastography. AB - PURPOSE: In this study, we evaluated the placental elasticity in vivo by shear wave elastography in pregnant women under follow-up for intrauterine growth restriction (IUGR) and compared the elasticity values to normal pregnancies. MATERIAL AND METHODS: This prospective study included 42 pregnant women with a possible diagnosis of intrauterine growth restriction based on obstetrical grayscale and Doppler ultrasonography and 42 women with a normal pregnancy during the 2nd and 3rd trimester. During follow-up examinations, seven fetuses showed an increased growth and were delivered with a birth-weight above the 10 percentile. However, for statistical purposes we included these seven patients in the IUGR group due to prospective nature of the study. All patients initially underwent obstetrical grayscale and Doppler ultrasonography with measurement of resistivity and pulsatility indices from uterine arteries. Subsequently, elasticity values of the peripheral and central part of the placentas from fetal and maternal surfaces were measured by shear-wave elastography. Following delivery, Apgar scores at 1st and 5th minute, birth weight were collected. For statistical analysis, Mann Whitney U test was used. ROC curves were plotted and cut-off values for elasticity values were analyzed. RESULTS: Median elasticity values of the central part of the placentas from maternal (28kPa vs 6kPa) and fetal sides (21.5kPa vs 5kPa) were significantly higher in IUGR pregnancies compared to the control group (p<0.001). Similarly, median elasticity values of peripheral part of placentas from maternal (22kPa vs 5.35kPa) and fetal sides (22.5kPa vs 5.3kPa) were significantly higher in IUGR pregnancies compared to the control group (p<0.001). CONCLUSION: Placental stiffness values are significantly higher in patients with IUGR. Shear-wave elastography can be used as a non-invasive, complementary method to gray-scale and Doppler ultrasound for diagnosing IUGR. PMID- 29153363 TI - Uterine fibroids: Influence of "T2-Rim sign" on immediate therapeutic responses to magnetic resonance imaging-guided high-intensity focused ultrasound ablation. AB - OBJECTIVES: To investigate the influence of a high-signal-intensity peripheral rim on T2-weighted MR images (i.e., T2-rim sign) on the immediate therapeutic responses of MR-guided high intensity focused ultrasound (MR-HIFU) ablation of uterine fibroids. METHODS: This retrospective study was approved by the institutional review board, and patient informed consent was obtained for MR-HIFU ablation. In total, 196 fibroids (diameter 6.2+/-2.6cm) in 123 women (age 43.4+/ 5.0 years) who underwent MR-HIFU ablation from January 2013 to April 2016 were included. The effects of a T2-rim sign on the immediate therapeutic responses (non-perfused volume [NPV] ratio, ablation efficiency [NPV/treatment cell volume], ablation quality [grade 1-5, poor to excellent]) were investigated with univariable and multivariable analyses using generalized estimating equation (GEE) analysis. In multivariable analysis, T2 signal intensity ratio of fibroids to-skeletal muscle, relative peak enhancement of fibroids, and subcutaneous fat thickness were also considered. RESULTS: The presence of a T2-rim sign significantly lowered the NPV ratio (54.0+/-28.0% vs. 83.7+/-17.7%), ablation efficiency (0.6+/-0.5 vs. 1.3+/-0.6), ablation quality (3.1+/-1.2 vs. 4.2+/-0.8), (P<0.0001). GEE analysis showed that the presence of a T2-rim sign was independently significant for ablation efficiency and ablation quality (P<0.05). CONCLUSION: Uterine fibroids with a T2-rim sign showed significantly poorer immediate therapeutic responses to MR-HIFU ablation. PMID- 29153364 TI - Application of arterial spin labeling perfusion MRI to differentiate benign from malignant intracranial meningiomas. AB - PURPOSE: Differentiating WHO grade I-III of meningioma by non-invasive imaging is challenging. This study investigated the potential of MR arterial spin labeling (ASL) to establish tumor grade in meningioma patients. MATERIAL AND METHODS: Pseudo-continuous ASL with 3D background suppressed gradient and spin echo (GRASE) was acquired on 54 patients with newly diagnosed or recurrent intracranial meningioma. Perfusion patterns characterized in CBF color maps were independently evaluated by three neuroradiologists blinded to patient history, and correlated with tumor grade from histo-pathological review. RESULTS: Three perfusion patterns could be discerned by visual evaluation of CBF maps. Pattern 1 consisted of homogeneous hyper-perfusion of the entire tumor; pattern 2 demonstrated heterogeneous hyper-perfusion; pattern 3 showed no substantial hyper perfusion. Evaluation of the perfusion patterns was highly concordant among the three readers (Kendall W=0.9458, P<0.0001). Pattern 1 was associated with WHO Grade I meningioma of (P<0.0001). Patterns 2 and 3 were predictive of WHO Grade II and III meningioma (P<0.0001), with an odds ratio (OR, versus pattern 1) of 49.6 (P<0.01) in a univariate analysis, and an OR of 186.4 (P<0.01) in a multivariate analysis. CONCLUSION: Qualitative evaluation of ASL CBF maps can help differentiate benign (WHO Grade I) from higher grade (WHO Grade II and III) intracranial meningiomas, potentially impacting therapeutic strategy. PMID- 29153366 TI - Papillary glioneuronal tumors: A radiopathologic correlation. AB - OBJECTIVE: Papillary glioneuronal tumors (PGNT) are a rare and recently recognized tumor entity. The neuroimaging findings were reviewed to determine if any specific findings emerge to assist a preoperative diagnosis of PGNT. MATERIALS AND METHODS: Seven histologically confirmed cases of PGNT were evaluated from 2004 to 2014. Clinical, neuroimaging and histological findings were reviewed and tabulated. RESULTS: Headache and seizures were observed in 4 patients (57.1%) each. The majority (n=5, 71.4%) of lesions were periventricular and located in temporal lobe with 57.1% cases being solid cystic (n=4), and 42.9% being purely solid (n=3). Calcification and hemorrhage were noted in 3 cases (42.9%) and 5 cases (71.4%) respectively. The most frequent imaging feature was the presence of septations in the cystic component that enhanced on contrast which correlated with long pseudopapillary projections into the cyst cavity on histopathology. The solid inner component demonstrated heterogeneous enhancement. One case with tumor recurrence demonstrated hemorrhage with superficial siderosis, patchy diffusion restriction, raised choline and focal areas of raised perfusion which correlated on histopathology with increased cellularity and anaplasia. CONCLUSION: Presence of cystic mass in periventricular location with septations and a solid inner component should raise a suspicion of PGNT on neuroimaging. PMID- 29153365 TI - Comparison of screening CEDM and MRI for women at increased risk for breast cancer: A pilot study. AB - OBJECTIVES: Contrast enhanced digital mammography (CEDM) is a new breast imaging technology increasingly used in the diagnostic setting but its utility in the pure screening setting has not been reported. The goal of this pilot study is to prospectively compare screening CEDM to breast MRI in women with an increased risk for breast cancer. METHODS: In this IRB-approved HIPAA-compliant study, 318 women at increased breast cancer risk were consented (December 2012-May 2015) to undergo CEDM in addition to their scheduled MRI. CEDM was performed within 30days of screening MRI. CEDM was interpreted blinded to MRI. The reference standard was defined as a combination of pathology and 2-year imaging follow-up. RESULTS: Data from 307/318 patients were evaluable. Three cancers (two invasive cancers, one ductal carcinoma in situ) were detected at first round screening: MRI detected all three and CEDM detected the two invasive cancers. None of the three cancers was seen on the low energy mammograms which are comparable to conventional mammography. At 2year imaging follow up, there were 5 additional screen detected cancers and no palpable cancers. The positive predictive value 3 (PPV3) for CEDM was 15% (2/13, 95% CI: 2-45%) and 14% for MRI (3/21, 95% CI: 3-36%). The specificity of CEDM and MRI were 94.7% and 94.1% respectively. CONCLUSIONS: Both CEDM and MRI detected additional cancers not seen on conventional mammography, primarily invasive cancers. Our pilot data suggest that CEDM could be valuable as a supplemental imaging exam for women at increased risk for breast cancer who do not meet the criteria for MRI or for whom access to MRI is limited. Validation in larger multi institutional trials is warranted. PMID- 29153367 TI - Real-time two-dimensional Shear-wave elastography for liver stiffness in children: Interobserver variation and effect of breathing technique. AB - OBJECTIVES: To evaluate interobserver variation and to assess the effect of the breathing technique on liver stiffness (LS) measurement using real-time two dimensional shear-wave elastography (2D-SWE) in children. METHODS: Patients who underwent real-time 2D-SWE by two operators (group 1) and patients who underwent real-time 2D-SWE by one operator using the free-breathing and breath-holding techniques (group 2) were included. In group 1, interobserver agreement was assessed using the intraclass correlation coefficient (ICC) and the 95% limits-of agreement was analyzed to evaluate the maximum change in the LS values based on Bland-Altman analysis. In group 2, the Bland-Altman plot and the paired t-test were used to determine the effect of breathing technique on LS measurement. RESULTS: The interobserver agreement of the LS measurement in group 1 (n=63) was excellent (ICC, 0.953), and the 95% limits-of-agreement was 31.8% of the mean LS values. In group 2 (n=45), the free-breathing technique revealed systematically lower LS with a mean difference of -11.1% of the mean LS values, compared to the breath-holding technique (P=0.016). CONCLUSION: LS measurement assessed by real time 2D-SWE in children showed excellent interobserver agreement. Changes in LS values less than 31.8% of the mean LS values may represent the measurement error. The free-breathing technique showed lower LS values, compared to the breath holding technique. PMID- 29153368 TI - Diagnostic value of cone beam computed tomography (CBCT) in occult scaphoid and wrist fractures. AB - OBJECTIVE: Evaluate the diagnostic value of cone beam computed tomography (CBCT) for scaphoid and wrist fractures that are missed on standard radiographs. MATERIALS AND METHODS: Between September 2014 and October 2015, we prospectively enrolled 49 patients with a clinically suspected scaphoid fracture following an acute injury but had normal radiographs. Each patients underwent radiographs, CBCT and (magnetic resonance imaging) MRI within 7days of the initial injury event. Both exam were evaluated independently by two radiologists. RESULTS: For scaphoid cortical fractures CBCT sensitivity is 100% (95% CI: 75%-100%), specificity 97% (95% CI: 83%-100%). CBCT diagnosed all 24 corticals wrist fractures, corresponding to a sensitivity of 100% (95% CI: 83%-100%), specificity of 95% (95% CI: 75%-100%). Kappa agreement rate between the two radiologists was K=0.95 (95% CI: 0.85-1) for scaphoid fractures and K=0.87 (95% CI: 0.73-1) for wrist fractures. CONCLUSIONS: CBCT is superior to radiographs for diagnosing occult cortical fractures. Because of its low radiation dose, we believe that CBCT can be used in current practice as a replacement or supplement to radiographs to detect these fractures and optimize the cost-effectiveness ratio by limiting the number of needless immobilizations. PMID- 29153369 TI - Retrospective comparison of three-dimensional imaging sequences in the visualization of posterior fossa cranial nerves. AB - PURPOSE: To compare efficancy of three-dimentional SPACE (sampling perfection with application-optimized contrasts using different flip-angle evolutions) and CISS (constructive interference in steady state) sequences in the imaging of the cisternal segments of cranial nerves V-XII. METHODS: Temporal MRI scans from 50 patients (F:M ratio, 27:23; mean age, 44.5+/-15.9 years) admitted to our hospital with vertigo, tinnitus, and hearing loss were retrospectively analyzed. All patients had both CISS and SPACE sequences. Quantitative analysis of SPACE and CISS sequences was performed by measuring the ventricle-to-parenchyma contrast-to noise ratio (CNR). Qualitative analysis of differences in visualization capability, image quality, and severity of artifacts was also conducted. A score ranging 'no artefact' to 'severe artefacts and unreadable' was used for the assessment of artifacts and from 'not visualized' to 'completely visualized' for the assesment of image quality, respectively. The distribution of variables was controlled by the Kolmogorov-Smirnov test. Samples t-test and McNemar's test were used to determine statistical significance. RESULTS: Rates of visualization of posterior fossa cranial nerves in cases of complete visualization were as follows: nerve V (100% for both sequences), nerve VI (94% in SPACE, 86% in CISS sequences), nerves VII-VIII (100% for both sequences), IX-XI nerve complex (96%, 88%); nerve XII (58%, 46%) (p<0.05). SPACE sequences showed fewer artifacts than CISS sequences (p<0.002). PMID- 29153370 TI - Loco-regional staging accuracy in oesophageal cancer-How good are we in the modern era? AB - INTRODUCTION: Accuracy of locoregional staging in patients with oesophageal cancer is critical in determining operability and the need for neoadjuvant treatment. Imaging technology has advanced significantly in recent years but it is not known whether this translates to improved staging accuracy. This study investigates staging accuracy in relation to CT, EUS, PET-CT and final pre operative stage. It specifically addresses the accuracy of staging with respect to the threshold for administering neoadjuvant therapies. MATERIALS AND METHODS: Pre-operative staging according to CT, EUS, PET-CT and final pre-operative stage were compared to the postoperative histological staging in 133 patients undergoing potentially curative surgery (without neoadjuvant therapy) for oesophageal cancer between January 2010 and January 2015. T and N stage accuracies were reported separately for each imaging modality. Patients were also divided into two groups depending on whether the final pre-operative stage was below (<=T2, N0, early tumours) or above (>=T3 and/or >=N1, locally advanced tumours) the threshold for offering neoadjuvant therapy. Accuracy of pre operative staging was then analysed with respect to identification of patients below/above this threshold. The additional benefit offered by EUS for this purpose was investigated. RESULTS: T stage accuracies were 72.6%, 76.7% and 79.3% for CT, EUS and final pre-operative stage respectively. N stage accuracies were 75.6%, 77.2%, 74.5% and 78.6% for CT, EUS, PET-CT and final pre-operative stage respectively. Staging accuracy with respect to threshold for neoadjuvant treatment showed 62.0% early tumours were correctly staged and 80.5% advanced tumours were correctly staged. Whether or not patients underwent EUS did not affect the staging accuracy with respect to neoadjuvant treatment threshold. CONCLUSIONS: Staging accuracy with respect to the threshold for treatment with neoadjuvant therapy is poor, leading to potential over/under treatment. Predicting individual response to neoadjuvant therapy would provide a better way to determine which patients should receive this additional treatment. PMID- 29153371 TI - Liver metastases: Detection and staging. AB - The liver is more often involved with metastatic disease than primary liver tumors. The accurate detection and characterization of liver metastases are crucial since patient management depends on it. The imaging options, mainly consisting of contrast-enhanced ultrasound (CEUS), multidetector computed tomography (CT), magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI), extra-cellular contrast media and liver-specific contrast media as well as positron emission tomography/computed tomography (PET/CT), are constantly evolving. PET/MRI is a more recent hybrid method and a topic of major interest concerning liver metastases detection and characterization. This review gives a brief overview about the spectrum of imaging findings and focus on an update about the performance, advantages and potential limitations of each modality as well as current developments and innovations. PMID- 29153373 TI - Improving digital breast tomosynthesis reading time: A pilot multi-reader, multi case study using concurrent Computer-Aided Detection (CAD). AB - PURPOSE: Evaluate concurrent Computer-Aided Detection (CAD) with Digital Breast Tomosynthesis (DBT) to determine impact on radiologist performance and reading time. MATERIALS AND METHODS: The CAD system detects and extracts suspicious masses, architectural distortions and asymmetries from DBT planes that are blended into corresponding synthetic images to form CAD-enhanced synthetic images. Review of CAD-enhanced images and navigation to corresponding planes to confirm or dismiss potential lesions allows radiologists to more quickly review DBT planes. A retrospective, crossover study with and without CAD was conducted with six radiologists who read an enriched sample of 80 DBT cases including 23 malignant lesions in 21 women. Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) compared the readings with and without CAD to determine the effect of CAD on overall interpretation performance. Sensitivity, specificity, recall rate and reading time were also assessed. Multi-reader, multi-case (MRMC) methods accounting for correlation and requiring correct lesion localization were used to analyze all endpoints. AUCs were based on a 0-100% probability of malignancy (POM) score. Sensitivity and specificity were based on BI-RADS scores, where 3 or higher was positive. RESULTS: Average AUC across readers without CAD was 0.854 (range: 0.785-0.891, 95% confidence interval (CI): 0.769,0.939) and 0.850 (range: 0.746-0.905, 95% CI: 0.751,0.949) with CAD (95% CI for difference: 0.046,0.039), demonstrating non-inferiority of AUC. Average reduction in reading time with CAD was 23.5% (95% CI: 7.0-37.0% improvement), from an average 48.2 (95% CI: 39.1,59.6) seconds without CAD to 39.1 (95% CI: 26.2,54.5) seconds with CAD. Per-patient sensitivity was the same with and without CAD (0.865; 95% CI for difference: -0.070,0.070), and there was a small 0.022 improvement (95% CI for difference: -0.046,0.089) in per-lesion sensitivity from 0.790 without CAD to 0.812 with CAD. A slight reduction in specificity with a -0.014 difference (95% CI for difference: -0.079,0.050) and a small 0.025 increase (95% CI for difference: -0.036,0.087) in recall rate in non-cancer cases were observed with CAD. CONCLUSIONS: Concurrent CAD resulted in faster reading time with non inferiority of radiologist interpretation performance. Radiologist sensitivity, specificity and recall rate were similar with and without CAD. PMID- 29153372 TI - Impact of experimental design on PET radiomics in predicting somatic mutation status. AB - PURPOSE: PET-based radiomic features have demonstrated great promises in predicting genetic data. However, various experimental parameters can influence the feature extraction pipeline, and hence, Here, we investigated how experimental settings affect the performance of radiomic features in predicting somatic mutation status in non-small cell lung cancer (NSCLC) patients. METHODS: 348 NSCLC patients with somatic mutation testing and diagnostic PET images were included in our analysis. Radiomic feature extractions were analyzed for varying voxel sizes, filters and bin widths. 66 radiomic features were evaluated. The performance of features in predicting mutations status was assessed using the area under the receiver-operating-characteristic curve (AUC). The influence of experimental parameters on feature predictability was quantified as the relative difference between the minimum and maximum AUC (delta). RESULTS: The large majority of features (n=56, 85%) were significantly predictive for EGFR mutation status (AUC>=0.61). 29 radiomic features significantly predicted EGFR mutations and were robust to experimental settings with deltaOverall<5%. The overall influence (deltaOverall) of the voxel size, filter and bin width for all features ranged from 5% to 15%, respectively. For all features, none of the experimental designs was predictive of KRAS+ from KRAS- (AUC<=0.56). CONCLUSION: The predictability of 29 radiomic features was robust to the choice of experimental settings; however, these settings need to be carefully chosen for all other features. The combined effect of the investigated processing methods could be substantial and must be considered. Optimized settings that will maximize the predictive performance of individual radiomic features should be investigated in the future. PMID- 29153374 TI - Histopathologic diversity of gastric cancers: Relationship between enhancement pattern on dynamic contrast-enhanced CT and histological type. AB - PURPOSE: To evaluate the diagnostic value of contrast-enhanced computed tomography gastrography (CE-CTG) to predict the histological type of gastric cancer. MATERIALS AND METHODS: We analyzed 47 consecutive patients with resectable advanced gastric cancer preoperatively evaluated by multiphasic dynamic contrast-enhanced CT. Two radiologists independently reviewed the CT images and they determined the peak enhancement phase, and then measured the CT attenuation value of the gastric lesion for each phase. The histological types of gastric cancers were assigned to three groups as differentiated-type, undifferentiated-type, and mixed-type. We compared the peak enhancement phase of the three types and compared the CT attenuation values in each phase. RESULTS: The peak enhancement was significantly different between the three types of gastric cancers for both readers (reader 1, p=0.001; reader 2, p=0.009); most of the undifferentiated types had peak enhancement in the delayed phase. The CT attenuation values of undifferentiated type were significantly higher than those of differentiated or mixed type in the delayed phase according to both readers (reader 1, p=0.002; reader 2, p=0.004). CONCLUSION: CE-CTG could provide helpful information in diagnosing the histological type of gastric cancers preoperatively. PMID- 29153375 TI - Patterns of CT use in Japan, 2014: A nationwide cross-sectional study. AB - OBJECTIVES: To describe CT usage in Japan by age, gender, and region and to clarify the relationship between aging and CT examination rate. MATERIALS AND METHODS: We conducted a cross-sectional study using openly accessible data from the National Database, which includes all Japanese health insurance claim data from 2014. These data are anonymized and publicly available as spreadsheets. Therefore, this study did not require institutional review board approval. We calculated the rate of CT examinations per 1000 population by age, sex, and region with 99% confidence intervals. Pearson correlation coefficients were calculated between CT rate and aging in each region. RESULTS: We analyzed 28.1 million CT scans, and the rate per 1000 population was 221.5 (99% CI, 221.4 221.6). By age, the corresponding rate for age 0-9 years was 28.9, that for age 10-9 years was 48.6, that for 20-29 years was 52.2, that for 30-39 years was 69.0, that for 40-49 years was 105.9, that for 50-59 years was 177.6, that for 60 69 years was 303.3, that for 70-79 years was 532.5 and that for >=80 years was 801.5. The rate for male individuals was 233.6 and that for females was 210.0. The CT examination rate was 171.7 and 296.0 in the lowest- and highest-frequency regions, respectively. The average correlation coefficient between the aging rate in each region and the CT examination rate was 0.58 (0.35-0.74, p=0.00002). CONCLUSION: In Japan, the CT examination rate per 1000 population was high (third highest in the world). Age may be a factor that increases CT use. Furthermore, because variation in CT examination rates by age, gender, and region were observed, it is necessary to standardize CT utilization. PMID- 29153376 TI - [Imaging in the initial and preoperative assessment of endometriosis]. AB - The diagnosis of pelvic endometriosis is based on the combination of clinical examination, endovaginal ultrasonography and pelvic MRI. Ultrasonography displays a moderate sensitivity and a high specificity. Pelvien MRI displays a better sensitivity and lower specificity. PMID- 29153377 TI - Iatrogenic iron overload and its potential consequences in patients on hemodialysis. AB - Iron overload was considered rare in hemodialysis patients until recently, but its clinical frequency is now increasingly recognized. The liver is the main site of iron storage and the liver iron concentration (LIC) is closely correlated with total iron stores in patients with secondary hemosiderosis and genetic hemochromatosis. Magnetic resonance imaging (MRI) is now the gold standard method for estimating and monitoring LIC. Studies of LIC in hemodialysis patients by magnetic susceptometry thirteen years ago and recently by quantitative MRI have demonstrated a relation between the risk of iron overload and the use of intravenous (IV) iron products prescribed at doses determined by the iron biomarker cutoffs contained in current anemia management guidelines. These findings have challenged the validity of both iron biomarker cutoffs and current clinical guidelines, especially with respect to recommended IV iron doses. Moreover, three recent long-term observational studies suggested that excessive IV iron doses might be associated with an increased risk of cardiovascular events and death in hemodialysis patients. It has been hypothesized that iatrogenic iron overload in the era of erythropoiesis-stimulating agents might silently increase complications in dialysis patients without creating obvious, clinical signs and symptoms. High hepcidin-25 levels were recently linked to fatal and nonfatal cardiovascular events in dialysis patients. It has been postulated that the main pathophysiological pathway leading to these events might involve the pleiotropic master hormone hepcidin, which regulates iron metabolism, leading to activation of macrophages in atherosclerotic plaques and then to clinical cardiovascular events. Thus, the potential iron overload toxicity linked to chronic administration of IV iron therapy is now becoming one of the most controversial topics in the management of anemia in hemodialysis patients. PMID- 29153378 TI - Corrigendum to "Dexmedetomidine relieves formaldehyde-induced pain in rats through both alpha2 adrenoceptor and imidazoline receptor" [Biomed. Pharmacother. 90 (2017) 914-920]. PMID- 29153379 TI - Bariatric patients' reported motivations for surgery and their relationship to weight status and health. AB - BACKGROUND: Literature on patient motivation for bariatric surgery remains limited. A few studies have examined relation to outcomes and found no established connection between motivation and weight loss. SETTING: A retrospective convenience sample of 345 participants was recruited from an obesity support website to complete an online survey. METHODS: Content analysis was used to describe motivations for surgery, and analysis of variance and covariance were completed to compare groups of participants created from the qualitative analysis on pre- and postsurgical factors like body mass index, number of co-morbidities, and percentage of excess weight loss. RESULTS: A primary perceived affective response category for motivation was created that included 3 levels: desperate, tired, and pragmatic. Within these levels participants reported motivations related to quality of life, prevent death, last option, and trigger. Participants in the desperate level exhibited higher presurgical body mass index, greater number of presurgical co-morbidities, more attempted methods for weight loss, and more negative perceptions of health before surgery. Participants in the tired group experienced the greatest percentage of excess weight loss and participants in desperate and tired showed greater weight loss, percentage of weight lost, and percentage of excess weight lost compared with the pragmatic group when controlling for presurgical weight. CONCLUSIONS: Most participants reported a physical health-related motivation, but participants with greater perceived affective motivational responses cited prevention of death and viewing surgery as their last option to a higher extent. Participants with greater perceived affective response exhibited significantly better weight loss outcomes, indicating that some emotional component to motivation may improve long term success. Presurgical consultation might incorporate principles from the Transtheoretical Model and Motivational Interviewing to connect the emotional impacts of obesity on patients' health and well being to health behaviors promoting weight maintenance. PMID- 29153380 TI - [Cancer stem cells in colon cancer]. PMID- 29153381 TI - Prenatal TVOCs exposure negatively influences postnatal neurobehavioral development. AB - Prenatal exposure to volatile organic compounds may restrict fetal development and adversely influence infants' life. Therefore, we investigated the relationship between prenatal exposure to total volatile organic compounds (TVOC) and postnatal neurobehavioral development. A subsample of 383 pregnant participants was chosen from the prospective birth cohort study of Mother and Children's Environmental Health Study; MOCEH (N=1,751) from three regions of the Republic of Korea (Seoul, Cheon-an, and Ulsan). Participants were enrolled during their first trimester with informed consent. We investigated maternal characteristics including socio-economic and obstetrical history using questionnaires. An environmental hygienist measured participating mothers' personal TVOC exposure using passive samplers during pregnancy. Participants visited the research center at 6, 12, 24 and 36 months. At each visit, questionnaires about infantile environment and health conditions were answered and a neurobehavioral test (BSID-II) was conducted by certified investigators. We conducted multiple general linear and mixed model analyses to investigate the relationship between TVOC and infantile neurobehavioral development (SAS 9.3). Mean prenatal TVOC exposure was 284.2MUg/m3. In longitudinal analyses on infantile neurobehavioral development, adjusted mean psychomotor development index and mental developmental index scores in high TVOC exposure group (cut off at Q3: 374.0 ug/m3) were 3 points lower than the low exposure group. Results suggested exposure to higher TVOC during the fetal period may adversely influence neurobehavioral development in the early life stage. PMID- 29153382 TI - A pilot study: Alternative biomaterials in critical sized bone defect treatment. AB - BACKGROUND: Critical-sized bone defects are a significant challenge with limited effective reconstructive options. The Masquelet Technique (MT) offers a solution to help restore form and function. Although this technique has produced promising results; a clear mechanism has not been determined. Theories include that the induced membrane has osteogenic potential or the membrane acts as a physical barrier to prevent fibrous tissue ingrowth. We hypothesize the induced membrane acts primarily as a physical barrier and that a synthetic non-biological membrane will allow a comparable amount of bone volume in the defect site. METHODS: Ten New Zealand rabbit forelimbs (n=10) were divided into three study groups. A critical sized defect of 3.5cm in the ulna was created. In the control group, a traditional MT was performed (n=4). The experimental arm varied by replacement of the PMMA with a non-porous (n=3) or porous (150um) (n=3) polytetrafluoroethylene (PTFE) membrane filled with allograft. Micro-CT analysis was done to compare bone volume to tissue volume ratios (BV/TV). Defect sections were examined histologically with alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) and von kossa (VK) staining. RESULTS: MicroCT analysis comparing BV/TV between the control and experimental arms showed no difference. BV/TV of the MT was 7.77%+/-2.34 compared to porous 9.12%+/-3.66 and nonporous 9.76%+/-1.57 PTFE membranes (p1=0.761, p2=0.572, respectively). Histological sections from both samples stained for ALP and TRAP displayed osteoblastic and osteoclastic activity. There was a higher amount of ALP and TRAP positively stained cells near the native bone ends in comparison to the center of the defect, in both sample types. CONCLUSION AND SIGNIFICANCE: Replacing the induced membrane from the MT with a synthetic PTFE membrane illustrated that the membrane acts primarily as a functional barrier. Compared to the induced membrane, the PTFE membrane was able to display similar osteointegrative properties. These results allow for future optimization of the technique with the potential to further streamline towards a single stage procedure. PMID- 29153383 TI - Understanding hypertension in the light of Ayurveda. AB - Different theories have been proposed to explain hypertension from an Ayurvedic perspective, but there is no consensus amongst the experts. A better understanding of the applied physiology and etio-pathogenesis of hypertension in the light of Ayurvedic principles is being attempted to fill this gap. A detailed review of available Ayurvedic literature was carried out to understand the physiology of blood pressure and etio-pathogenesis of hypertension from the perspective of Ayurveda. Many parallels were drawn from the concepts such as Shad Kriyakala (six stages of Dosha imbalance) and Avarana of Doshas (occlusion in the normal functioning of the Doshas) to the modern pathogenesis of hypertension to gain a deeper understanding of it. Hypertension without specific symptoms in its mild and moderate stages cannot be considered as a disease in Ayurveda. It appears to be an early stage of pathogenesis and a risk factor for development of diseases affecting the heart, brain, kidneys and eyes etc. Improper food habits and modern sedentary lifestyle with or without genetic predisposition provokes and vitiates all the Tridoshas to trigger the pathogenesis of hypertension. It is proposed that hypertension is to be understood as the Prasara-Avastha which means spread of vitiated Doshas from their specific sites, specifically of Vyana Vata, Prana Vata, Sadhaka Pitta and Avalambaka Kapha along with Rakta in their disturbed states. The Avarana (occlusion of normal functioning) of Vata Dosha by Pitta and Kapha can be seen in the Rasa-Rakta Dhathus, which in turn hampers the functioning of the respective Srotas (micro-channels) of circulation. PMID- 29153384 TI - Dual-energy X-ray Absorptiometry Quality Matters. PMID- 29153385 TI - Foreword. PMID- 29153386 TI - New normative data from the Spanish-language version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), form A. AB - INTRODUCTION: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is frequently used in clinical practice to evaluate cognitive function. It is quick to administer (20-30minutes) and is not influenced by a learning effect. The RBANS includes 4 parallel versions and has a high discriminative ability. Our study provides normative data from the RBANS-E (Spanish-language version of RBANS form A) for a Spanish population aged 20 to 89 years. METHODS: The study included 609 subjects aged 20 to 89 years. Participants were evaluated at baseline with a short interview, a cognitive screening test (Mini-Mental State Examination), and a functional scale (Rapid Disability Rating Scale). The RBANS-E was then administered to all 609 participants. RESULTS: Our results show the influence of education on all subtest scores. Sex was observed to have no impact on any subtest. CONCLUSION: Our study provides highly useful normative data for the cognitive evaluation of young and adult populations. PMID- 29153387 TI - [A paratesticular nodule]. PMID- 29153388 TI - [Endometrial osseous metaplasia: A case report]. AB - Endometrial osseous metaplasia (EOM) is a rare condition characterised by the presence of bone in the uterine cavity. Some patients with this condition present with secondary infertility due to the presence of a foreign body in the endometrium. We report a case of a 39-year-old woman who presented with secondary infertility due to EOM. EOM is a rare cause of infertility that can be easily managed by hysteroscopic removal of the bony fragments. PMID- 29153389 TI - [An unexplained fever]. PMID- 29153390 TI - Current Trends and Future Perspectives in the Treatment of Pulmonary Hypertension: WHO Group II-V. AB - Pulmonary hypertension continues to be a life-threatening illness with debilitating physical and emotional consequences affecting around 1% of global population. The progression of this devastating disease is characterized by increase in pulmonary vascular resistance resulting in elevated pulmonary pressure, eventually leading to right heart failure and death. Better understanding of pathophysiology has led to substantial improvements in terms of availability of treatment options. The purpose of this review is to summarize the currently available treatment options along with pertinent trials and possible future therapies of pulmonary hypertension group II-V. PMID- 29153391 TI - Structure of a Thermostable Group II Intron Reverse Transcriptase with Template Primer and Its Functional and Evolutionary Implications. AB - Bacterial group II intron reverse transcriptases (RTs) function in both intron mobility and RNA splicing and are evolutionary predecessors of retrotransposon, telomerase, and retroviral RTs as well as the spliceosomal protein Prp8 in eukaryotes. Here we determined a crystal structure of a full-length thermostable group II intron RT in complex with an RNA template-DNA primer duplex and incoming deoxynucleotide triphosphate (dNTP) at 3.0-A resolution. We find that the binding of template-primer and key aspects of the RT active site are surprisingly different from retroviral RTs but remarkably similar to viral RNA-dependent RNA polymerases. The structure reveals a host of features not seen previously in RTs that may contribute to distinctive biochemical properties of group II intron RTs, and it provides a prototype for many related bacterial and eukaryotic non-LTR retroelement RTs. It also reveals how protein structural features used for reverse transcription evolved to promote the splicing of both group II and spliceosomal introns. PMID- 29153392 TI - Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription. AB - Polycomb repressive complex 2 (PRC2-EZH2) methylates histone H3 at lysine 27 (H3K27) and is required to maintain gene repression during development. Misregulation of PRC2 is linked to a range of neoplastic malignancies, which is believed to involve methylation of H3K27. However, the full spectrum of non histone substrates of PRC2 that might also contribute to PRC2 function is not known. We characterized the target recognition specificity of the PRC2 active site and used the resultant data to screen for uncharacterized potential targets. The RNA polymerase II (Pol II) transcription elongation factor, Elongin A (EloA), is methylated by PRC2 in vivo. Mutation of the methylated EloA residue decreased repression of a subset of PRC2 target genes as measured by both steady-state and nascent RNA levels and perturbed embryonic stem cell differentiation. We propose that PRC2 modulates transcription of a subset of low expression target genes in part via methylation of EloA. PMID- 29153394 TI - VCP/p97-Mediated Unfolding as a Principle in Protein Homeostasis and Signaling. AB - The AAA+-type ATPase p97 governs an ever-expanding number of cellular processes reaching from degradation of damaged proteins and organelles to key signaling events and chromatin regulation with thousands of client proteins. With its relevance for cellular homeostasis and genome stability, it is linked to muscular and neuronal degeneration and, conversely, constitutes an attractive anti-cancer drug target. Its molecular function is ATP-driven protein unfolding, which is directed by ubiquitin and assisted by a host of cofactor proteins. This activity underlies p97's diverse ability to pull proteins out of membranes, unfold proteins for proteasomal degradation, or segregate proteins from partners for downstream activity. Recent advances in structural analysis and biochemical reconstitution have underscored this notion, resolved detailed molecular motions within the p97 hexamer, and suggested substrate threading through the central channel of the p97 hexamer as the driving mechanism. We will discuss the mechanisms and open questions in the context of the diverse cellular activities. PMID- 29153393 TI - Protein-Based Inheritance: Epigenetics beyond the Chromosome. AB - Epigenetics refers to changes in phenotype that are not rooted in DNA sequence. This phenomenon has largely been studied in the context of chromatin modification. Yet many epigenetic traits are instead linked to self-perpetuating changes in the individual or collective activity of proteins. Most such proteins are prions (e.g., [PSI+], [URE3], [SWI+], [MOT3+], [MPH1+], [LSB+], and [GAR+]), which have the capacity to adopt at least one conformation that self-templates over long biological timescales. This allows them to serve as protein-based epigenetic elements that are readily broadcast through mitosis and meiosis. In some circumstances, self-templating can fuel disease, but it also permits access to multiple activity states from the same polypeptide and transmission of that information across generations. Ensuing phenotypic changes allow genetically identical cells to express diverse and frequently adaptive phenotypes. Although long thought to be rare, protein-based epigenetic inheritance has now been uncovered in all domains of life. PMID- 29153395 TI - Ultrasound-Mediated Kallidinogenase-Loaded Microbubble Targeted Therapy for Acute Cerebral Infarction. AB - BACKGROUND: The neuroprotective effects of kallidinogenase against acute cerebral infarction have been demonstrated, and the use of microbubbles has been suggested as a therapeutic mechanism for drug delivery. This study was designed to investigate the optimal parameters for preparing kallidinogenase-loaded microbubbles (KLMs) and to evaluate the effects of KLM-targeted therapy on neurogenesis and angiogenesis following experimental acute cerebral infarction in rats. MATERIALS AND METHODS: KLMs were prepared by mechanical shaking. Male Wistar rats were randomly divided into an ultrasound-mediated KLM-treated group and 4 control groups. Treatments were administered via daily tail vein injection on 6 consecutive days, starting at 24 hours after middle cerebral artery occlusion (MCAO). The ultrasound-treated groups were subjected to a 2-MHz pulse of ultrasonic irradiation on the lateral skull of the ischemic side for 10 minutes during injection. Cell proliferation was examined using a 5-bromo-2 deoxyuridine assay. Infarct volume and neurological function were evaluated on days 3 and 7 after MCAO. RESULTS: The ultrasound-mediated KLM and kallidinogenase treatments significantly increased the numbers of doublecortin-immunoreactive cells in the subventricular zone (SVZ) and laminin+ cells in the peri-infarction region on day 7 after MCAO, compared with the other 3 groups (all P <.05). The neurological function scores of the ultrasound-mediated KLM-treated group were significantly better than those of rats treated with kallidinogenase alone or with the other treatments (all P <.05). CONCLUSIONS: Treatment with the ultrasound-mediated KLMs promoted the proliferation of SVZ neuroblasts and vascular regeneration, which contributed to functional improvement after stroke. These findings provide a novel therapy for ischemic stroke. PMID- 29153396 TI - The Prognostic Value of Serum Uric Acid in the Acute Phase of Ischemic Stroke in Black Africans. AB - BACKGROUND: The association between hyperuricemia and stroke outcome still remains controversial worldwide. This study aims to determine the prevalence of hyperuricemia and its association with the outcome of patients with acute ischemic stroke in a tertiary care hospital. METHODS: This was a hospital-based prospective cohort study that included patients with ischemic stroke with baseline uric acid levels and 3-month post-stroke follow-up data. Associations between hyperuricemia and stroke outcomes were analyzed using multiple logistic regression, Kaplan-Meier, and Cox proportional hazards regression analysis. RESULTS: A total of 480 patients were reviewed with a mean age of 62.8 +/- 13.3 years. The prevalence of hyperuricemia was 52.3% with mean uricemia of 71.1 +/- 25.3 mg/dL. There was a significant association between hyperuricemia and mortality with unadjusted odds ratio (OR) = 4.120 [95% (confidence interval [CI]: 2.466-7.153); P = .001)], but on multivariate analysis, hyperuricemia was not an independent predictor of stroke mortality [OR = 1.270 (CI: .547-2.946); P = .578)]. An independent association between increasing uric acid levels and mortality was noted on Cox proportional hazards regression; adjusted hazard ratio (95% CI) of 3.395 (2.114-5.452), P value greater than .001. Stroke mortality significantly increased across higher uric acid quintiles in patients with acute stroke (P < .001). Hyperuricemia was an independent predictor of poor functional outcome within 3 months after stroke with adjusted OR (95% CI) of 2.820 (1.359 5.851); P = .005. CONCLUSIONS: Half of black African patients with ischemic stroke present with hyperuricemia, and hyperuricemia is a predictor of mortality and adverse functional outcomes. Further studies are therefore warranted to determine whether reducing hyperuricemia after stroke would be beneficial within our setting. PMID- 29153397 TI - Embolic Stroke due to Carotidynia Potentially Associated with Moving Carotid Artery Caused by Swallowing. AB - A 63-year-old woman with end-stage renal disease on maintenance hemodialysis discontinued her medication for rheumatoid arthritis with prednisolone and azathioprine. One month later, she was admitted because of consciousness disturbance and right hemiparesis. Diffusion-weighted brain magnetic resonance imaging (MRI) revealed multiple hyperintensities in her left frontal and parietal lobes. She also developed high fever and left neck pain. Carotid ultrasonography showed calcified plaque with vessel wall swelling at the bifurcation of the left common carotid artery (LCCA) and surrounding hypoechoic soft tissue. The tissue was identified as an isodense lesion on noncontrast computed tomography (CT) and as a high-intensity lesion on fat-saturated T2-weighted MRI. From her symptoms and radiological findings, she was diagnosed with carotidynia. Cervical MRI also showed that the LCCA was transposed to a retropharyngeal location, suggesting a moving carotid artery. Carotid ultrasonography revealed that the LCCA moved to and from the retropharyngeal position with swallowing and was thus being compressed by the hyoid bone. After corticosteroid therapy was initiated with 30 mg of prednisolone, her symptoms and radiological findings improved. To our knowledge, this is the first report of a case of cerebral embolism due to carotidynia. The repetitive compressions by the hyoid bone during swallowing were presumed to have provoked shear stress and inflammation of the carotid vessel wall, which was aggravated by discontinuation of steroid therapy in our case. These mechanical and inflammatory stresses might cause dysfunction of endothelial cells, hypercoagulation, platelet hyperaggregation, and vulnerability and rupture of carotid plaques, and may subsequently result in embolic strokes. PMID- 29153398 TI - Maximizing Power in Phylogenetics and Phylogenomics: A Perspective Illuminated by Fungal Big Data. AB - Since its original inception over 150 years ago by Darwin, we have made tremendous progress toward the reconstruction of the Tree of Life. In particular, the transition from analyzing datasets comprised of small numbers of loci to those comprised of hundreds of loci, if not entire genomes, has aided in resolving some of the most vexing of evolutionary problems while giving us a new perspective on biodiversity. Correspondingly, phylogenetic trees have taken a central role in fields that span ecology, conservation, and medicine. However, the rise of big data has also presented phylogenomicists with a new set of challenges to experimental design, quantitative analyses, and computation. The sequencing of a number of very first genomes presented significant challenges to phylogenetic inference, leading fungal phylogenomicists to begin addressing pitfalls and postulating solutions to the issues that arise from genome-scale analyses relevant to any lineage across the Tree of Life. Here we highlight insights from fungal phylogenomics for topics including systematics and species delimitation, ecological and phenotypic diversification, and biogeography while providing an overview of progress made on the reconstruction of the fungal Tree of Life. Finally, we provide a review of considerations to phylogenomic experimental design for robust tree inference. We hope that this special issue of Advances in Genetics not only excites the continued progress of fungal evolutionary biology but also motivates the interdisciplinary development of new theory and methods designed to maximize the power of genomic scale data in phylogenetic analyses. PMID- 29153399 TI - Fungal Gene Cluster Diversity and Evolution. AB - Metabolic gene clusters (MGCs) have provided some of the earliest glimpses at the biochemical machinery of yeast and filamentous fungi. MGCs encode diverse genetic mechanisms for nutrient acquisition and the synthesis/degradation of essential and adaptive metabolites. Beyond encoding the enzymes performing these discrete anabolic or catabolic processes, MGCs may encode a range of mechanisms that enable their persistence as genetic consortia; these include enzymatic mechanisms to protect their host fungi from their inherent toxicities, and integrated regulatory machinery. This modular, self-contained nature of MGCs contributes to the metabolic and ecological adaptability of fungi. The phylogenetic and ecological patterns of MGC distribution reflect the broad diversity of fungal life cycles and nutritional modes. While the origins of most gene clusters are enigmatic, MGCs are thought to be born into a genome through gene duplication, relocation, or horizontal transfer, and analyzing the death and decay of gene clusters provides clues about the mechanisms selecting for their assembly. Gene clustering may provide inherent fitness advantages through metabolic efficiency and specialization, but experimental evidence for this is currently limited. The identification and characterization of gene clusters will continue to be powerful tools for elucidating fungal metabolism as well as understanding the physiology and ecology of fungi. PMID- 29153400 TI - Deciphering Pathogenicity of Fusarium oxysporum From a Phylogenomics Perspective. AB - Fusarium oxysporum is a large species complex of both plant and human pathogens that attack a diverse array of species in a host-specific manner. Comparative genomic studies have revealed that the host-specific pathogenicity of the F. oxysporum species complex (FOSC) was determined by distinct sets of supernumerary (SP) chromosomes. In contrast to common vertical transfer, where genetic materials are transmitted via cell division, SP chromosomes can be transmitted horizontally between phylogenetic lineages, explaining the polyphyletic nature of the host-specific pathogenicity of the FOSC. The existence of a diverse array of SP chromosomes determines the broad host range of this species complex, while the conserved core genome maintains essential house-keeping functions. Recognition of these SP chromosomes enables the functional and structural compartmentalization of F. oxysporum genomes. In this review, we examine the impact of this group of cross-kingdom pathogens on agricultural productivity and human health. Focusing on the pathogenicity of F. oxysporum in the phylogenomic framework of the genus Fusarium, we elucidate the evolution of pathogenicity within the FOSC. We conclude that a population genomics approach within a clearly defined phylogenomic framework is essential not only for understanding the evolution of the pathogenicity mechanism but also for identifying informative candidates associated with pathogenicity that can be developed as targets in disease management programs. PMID- 29153401 TI - Multiple Approaches to Phylogenomic Reconstruction of the Fungal Kingdom. AB - Fungi are possibly the most diverse eukaryotic kingdom, with over a million member species and an evolutionary history dating back a billion years. Fungi have been at the forefront of eukaryotic genomics, and owing to initiatives like the 1000 Fungal Genomes Project the amount of fungal genomic data has increased considerably over the last 5 years, enabling large-scale comparative genomics of species across the kingdom. In this chapter, we first review fungal evolution and the history of fungal genomics. We then review in detail seven phylogenomic methods and reconstruct the phylogeny of 84 fungal species from 8 phyla using each method. Six methods have seen extensive use in previous fungal studies, while a Bayesian supertree method is novel to fungal phylogenomics. We find that both established and novel phylogenomic methods can accurately reconstruct the fungal kingdom. Finally, we discuss the accuracy and suitability of each phylogenomic method utilized. PMID- 29153402 TI - Phylogenetics and Phylogenomics of Rust Fungi. AB - Rust fungi (Pucciniales) are the most speciose and the most complex group of plant pathogens. Historically, rust taxonomy was largely influenced by host and phenotypic characters, which are potentially plastic. Molecular systematic studies suggest that the extant diversity of this group was largely shaped by host jumps and subsequent shifts. However, it has been challenging to reconstruct the evolutionary history for the order, especially at deeper (family-level) nodes. Phylogenomics offer a potentially powerful tool to reconstruct the Pucciniales tree of life, although researchers working at this vanguard still face unprecedented challenges working with nonculturable organisms that possess some of the largest and most repetitive genomes now known in kingdom fungi. In this chapter, we provide an overview of the current status and special challenges of rust genomics, and we highlight how phylogenomics may provide new perspectives and answer long-standing questions regarding the biology of rust fungi. PMID- 29153403 TI - Advances in Fungal Phylogenomics and Their Impact on Fungal Systematics. AB - In the past decade, advances in next-generation sequencing technologies and bioinformatic pipelines for phylogenomic analysis have led to remarkable progress in fungal systematics and taxonomy. A number of long-standing questions have been addressed using comparative analysis of genome sequence data, resulting in robust multigene phylogenies. These have added to, and often surpassed traditional morphology or single-gene phylogenetic methods. In this chapter, we provide a brief history of fungal systematics and highlight some examples to demonstrate the impact of phylogenomics on this field. We conclude by discussing some of the challenges and promises in fungal biology posed by the ongoing genomics revolution. PMID- 29153404 TI - Fungal Phylogeny in the Age of Genomics: Insights Into Phylogenetic Inference From Genome-Scale Datasets. AB - The genomic era has been transformative for many fields, including our understanding of the phylogenetic relationships between organisms. The wide availability of whole-genome sequences practically eliminated data availability as a limiting factor for inferring phylogenetic trees, providing hundreds to thousands of loci for analyses, leading to molecular phylogenetics gradually being replaced by phylogenomics. The new era has also brought new challenges: systematic errors (resulting from, e.g., model violation) can be more pronounced in phylogenomic datasets and can lead to strongly supported incorrect relationships, creating significant incongruence among studies. Here, we review common practices, technical and biological challenges of phylogenomic analyses, with examples illustrated from fungi. We compare major approaches of phylogenetic inference, and illustrate the advantages conferred and challenges presented in phylogenomic case studies across the fungal tree of life, including cases where genome-scale data could conclusively resolve contentious relationships, and others that remain challenging despite the flood of genomic data. PMID- 29153406 TI - Preface. PMID- 29153405 TI - Describing Genomic and Epigenomic Traits Underpinning Emerging Fungal Pathogens. AB - An unprecedented number of pathogenic fungi are emerging and causing disease in animals and plants, putting the resilience of wild and managed ecosystems in jeopardy. While the past decades have seen an increase in the number of pathogenic fungi, they have also seen the birth of new big data technologies and analytical approaches to tackle these emerging pathogens. We review how the linked fields of genomics and epigenomics are transforming our ability to address the challenge of emerging fungal pathogens. We explore the methodologies and bioinformatic toolkits that currently exist to rapidly analyze the genomes of unknown fungi, then discuss how these data can be used to address key questions that shed light on their epidemiology. We show how genomic approaches are leading a revolution into our understanding of emerging fungal diseases and speculate on future approaches that will transform our ability to tackle this increasingly important class of emerging pathogens. PMID- 29153408 TI - AMPK: Sensing Glucose as well as Cellular Energy Status. AB - Mammalian AMPK is known to be activated by falling cellular energy status, signaled by rising AMP/ATP and ADP/ATP ratios. We review recent information about how this occurs but also discuss new studies suggesting that AMPK is able to sense glucose availability independently of changes in adenine nucleotides. The glycolytic intermediate fructose-1,6-bisphosphate (FBP) is sensed by aldolase, which binds to the v-ATPase on the lysosomal surface. In the absence of FBP, interactions between aldolase and the v-ATPase are altered, allowing formation of an AXIN-based AMPK-activation complex containing the v-ATPase, Ragulator, AXIN, LKB1, and AMPK, causing increased Thr172 phosphorylation and AMPK activation. This nutrient-sensing mechanism activates AMPK but also primes it for further activation if cellular energy status subsequently falls. Glucose sensing at the lysosome, in which AMPK and other components of the activation complex act antagonistically with another key nutrient sensor, mTORC1, may have been one of the ancestral roles of AMPK. PMID- 29153409 TI - Editorial - Current advances in cancer research: Therapeutics, Targets, and Chemical Biology. PMID- 29153407 TI - Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis. AB - Brown adipose tissue (BAT) is a therapeutic target for metabolic diseases; thus, understanding its metabolic circuitry is clinically important. Many studies of BAT compare rodents mildly cold to those severely cold. Here, we compared BAT remodeling between thermoneutral and mild-cold-adapted mice, conditions more relevant to humans. Although BAT is renowned for catabolic beta-oxidative capacity, we find paradoxically that the anabolic de novo lipogenesis (DNL) genes encoding ACLY, ACSS2, ACC, and FASN were among the most upregulated by mild cold and that, in humans, DNL correlates with Ucp1 expression. The regulation and function of adipocyte DNL and its association with thermogenesis are not understood. We provide evidence suggesting that AKT2 drives DNL in adipocytes by stimulating ChREBPbeta transcriptional activity and that cold induces the AKT2 ChREBP pathway in BAT to optimize fuel storage and thermogenesis. These data provide insight into adipocyte DNL regulation and function and illustrate the metabolic flexibility of thermogenesis. PMID- 29153410 TI - Balancing ethics and care in disorders of consciousness. PMID- 29153411 TI - How do we critically use long-acting muscarinic receptor antagonists and beta adrenergic receptor agonists monotherapy, or these combination therapies depending on the situation in Japanese patients with COPD? PMID- 29153412 TI - Role of lung volume and airway inflammation in obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a prevalent disorder that affects not only the upper airways but also the intrathoracic airways. In this review, we summarize the results of studies on lung function and airway inflammation. We provide evidence that the alterations in intrathoracic airways observed in OSA are not purely consequences of mechanical trauma and oxidative stress during apneic events but have a causal role in the structural changes associated with OSA and increasing severity of this disorder. PMID- 29153413 TI - An objective evaluation of nocturnal cough count and cough pattern in children with psychogenic cough. AB - Two patients with a chronic, barking cough were diagnosed with psychogenic cough. Using an original cough counter we studied the nocturnal cough count and pattern. While the number of coughs when awake was extremely high for both patients, the number of coughs was remarkably reduced during sleep, similar to an exacerbation of asthma. Moreover, the properties of the coughs when awake were clearly different from those of coughs during sleep. In conclusion, an objective examination using a cough counter was useful for the diagnosis, treatment and management of psychogenic cough. PMID- 29153414 TI - Association of interleukin 1 receptor-like 1 gene polymorphisms with eosinophilic phenotype in Japanese adults with asthma. AB - BACKGROUND: IL1RL1 (ST2) is involved in Th2 inflammation including eosinophil activation. Single nucleotide polymorphisms (SNPs) of the IL1RL1 gene are associated with asthma development and increased peripheral blood eosinophil counts. However, the association between IL1RL1 SNPs and eosinophilic phenotype among adults with asthma remains unexplored. METHODS: In a primary cohort of 110 adult Japanese patients with stable asthma, we examined the associations between IL1RL1 SNPs and clinical measurements including forced expiratory volume (FEV1), airway reversibility of FEV1, exhaled nitric oxide (FeNO), serum soluble-ST2 (sST2) levels, peripheral blood eosinophil differentials and serum total IgE level. The findings in the primary cohort were confirmed in a validation cohort of 126 adult Japanese patients with stable asthma. RESULTS: Patients with minor alleles in 3 SNPs (rs17026974, rs1420101, and rs1921622) had high FeNO, blood eosinophil differentials, and reversibility of FEV1, but low levels of serum sST2 and FEV1. Minor alleles of rs1041973 were associated with low serum sST2 levels alone. In the validation cohort, minor alleles of rs1420101 were associated with high FeNO and blood eosinophil differentials, whereas minor alleles of rs17026974 and rs1921622 were associated with high blood eosinophil differentials and FeNO, respectively. Multivariate analyses revealed that the minor allele of rs1420101 additively contributed to the FeNO, blood eosinophil differentials, and reversibility of FEV1. CONCLUSIONS: The minor alleles of IL1RL1 SNPs were associated with high FeNO and peripheral blood eosinophilia among adult Japanese patients with stable asthma. IL1RL1 SNPs may characterize the eosinophilic phenotype with greater eosinophilic inflammation in the Japanese asthma cohort. PMID- 29153415 TI - Comparison of the rapid effects of single inhalations of formoterol and tiotropium bromide on respiratory function and COPD symptoms in a randomized crossover study. AB - BACKGROUND: This study aimed to compare rapid improvements in respiratory function and symptoms following single inhalation of formoterol (FOM) dry power inhaler (DPI) or tiotropium bromide (TIO) DPI in patients with chronic obstructive pulmonary disease (COPD). METHODS: Fifty-two outpatients with COPD (GOLD stage 2 or 3) received either a single inhalation of FOM DPI (9 MUg via a Turbuhaler(r)) or TIO DPI (18MUg via a HandiHaler(r)) in a randomized crossover manner. Respiratory function testing was performed before, and 15, 60, and 120min after drug administration. Indices of respiratory resistance (assessed with a Mostgraph(r)) were measured before, and 3, 7, 10, 15, 30, 60, and 120min after treatment.Visual analogue scale (VAS) (range 0-10cm) and modified Borg scale scores (CR10) were compared before and after treatment. RESULTS: Forced expiratory volume in 1 second (FEV1) significantly improved 15min after both FOM (p=0.002) and TIO (p=0.026). Respiratory resistance at 5Hz (R5) and resonant frequency indices significantly decreased 10min (p=0.007) and 3min (p=0.034) after inhaling FOM and remained reduced at 120min. Low frequency reactant indices at 5Hz (X5) significantly increased at 30min (p=0.012) VAS significantly correlated with FEV1 (r=-0.371, p=0.007), X5 (r=-0.304, p=0.029), and low frequency reactance area (AX; r=0.305, p=0.028) in FOM, but not in TIO. Borg scale scores significantly correlated with FEV1% (r=-0.398, p=0.004), R5 (r= 0.379, p=0.006), respiratory resistance at 20Hz (R20; r=0.321, p=0.020), and R5 R20 (r=0.377, p=0.006) in FOM, but not in TIO. CONCLUSIONS: FOM is more effective than TIO at rapidly improving pulmonary function and symptoms in patients with COPD. PMID- 29153416 TI - Frequency of detection of Chlamydophila pneumoniae using bronchoalveolar lavage fluid in patients with community-onset pneumonia. AB - BACKGROUND: Chlamydophila pneumoniae is a causative pathogen of lower respiratory tract infection, which generally infects healthy, young people. However, it is often difficult to evaluate acute C. pneumoniae infection using upper respiratory tract specimens and/or sputum samples due to its persistent infection or colonization. The interpretation of frequency of detection of C. pneumoniae seems to be insufficient in community-onset pneumonia. The aim of this study was to evaluate the presence of C. pneumoniae using bronchoalveolar lavage fluid (BALF) samples. METHODS: BALF samples from 147 patients with pneumonia were retrospectively evaluated using C. pneumoniae-specific polymerase chain reaction (PCR) primers. RESULTS: None of the samples had positive PCR results for C. pneumoniae using two different sets of specific primers. Single and paired serological analyses were performed in 54 (36.7%) and 37 (25.2%) patients, respectively. These analyses revealed that 1 of 37 (2.7%) patients had a presumptive acute infection with C. pneumoniae, 8 of the 54 (14.8%) patients were suspected of having a C. pneumoniae infection, and 7 of the 37 (18.9%) patients were suspected of having past C. pneumoniae infection. In addition, cultivation and/or 16S rRNA gene sequencing detected Haemophilus influenzae in the presumptive case using the serological method. CONCLUSIONS: The results of the present study revealed that C. pneumoniae might be a minor causative agent of community-onset pneumonia according to an evaluation of specimens obtained from the lower respiratory tract. PMID- 29153417 TI - The efficacy of transbronchial needle aspiration with endobronchial ultrasonography using a guide sheath for peripheral pulmonary lesions suspected to be lung cancer. AB - BACKGROUND: The efficacy of transbronchial needle aspiration (TBNA) with endobronchial ultrasonography using a guide sheath (EBUS-GS) for cases of peripheral pulmonary lesions (PPLs) has not been well established. The purpose of this study was to evaluate the efficacy of TBNA with EBUS-GS for PPLs. METHODS: We evaluated 130 patients suspected to have lung cancer who underwent transbronchial brushing (brushing), transbronchial biopsy (TBB), and TBNA with EBUS-GS. The pathological diagnostic yields of TBNA were compared to that of TBB and brushing. The histological diagnosis of TBNA was compared to that of surgical specimens. The results of epidermal growth factor receptor (EGFR) gene mutation in TBNA samples were compared to that in TBB or surgical specimens. RESULTS: The diagnostic yields of this study were 62.9% for brushing, 80.0% for TBB, and 77.1% for TBNA. Histological diagnosis was 84.8% for TBB and/or TBNA and pathological diagnosis was 86.7% for all the procedures. TBB and TBNA had significance higher than brushing (p < 0.05). TBB and TBNA had a tendency of higher diagnostic yields than brushing if EBUS probe was adjacent to PPLs (p = 0.058). Histological evaluations were obtained from TBNA specimens from 50 of 105 patients (47.6%) and these were identical to those of surgical specimens from 29 of 32 patients (90.6%). The results of EGFR gene mutation in TBNA specimens were identical to the same tissue obtained by surgery or TBB. CONCLUSIONS: TBNA with EBUS-GS for PPLs was a useful tool for accurate diagnosis and EGFR gene mutation analysis. This method may improve diagnostic accuracy and be useful for molecular testing. This study was approved by the institutional review board (Date of approval: May 27, 2013, approval number: 2816) of Tokyo Women's Medical University Hospital. PMID- 29153418 TI - Long-term complete response to carboplatin plus paclitaxel combined with bevacizumab in a patient with metastatic spindle cell carcinoma. AB - We report the case of a 62-year-old Japanese male with metastatic spindle cell carcinoma (SpCC) who showed a long-term complete response (CR) to bevacizumab combination chemotherapy. We performed chemotherapy with carboplatin (AUC 6, day 1) plus paclitaxel (200mg/m2, day 1) plus bevacizumab (15mg/kg, day 1) for four cycles. After the chemotherapy, CT imaging demonstrated a CR. We subsequently administered bevacizumab (15mg/kg) repeated every 3 weeks as maintenance therapy for 12 cycles. The patient discontinued maintenance chemotherapy because of grade 3 proteinuria, but the anti-tumor effect of CR was maintained at 35 months after the discontinuation of chemotherapy. PMID- 29153419 TI - Health checkup system and pulmonary nontuberculous mycobacterial disease. PMID- 29153421 TI - Corrigendum to 'Image Guidance to Aid Pedicle Screw Fixation of a Lumbar Fracture Dislocation Injury in a Toddler' [World Neurosurgery 105 (2017) 1041.e15 1041.e17]. PMID- 29153420 TI - The additive effect of clarithromycin on influenza A infection in the elderly patients and patients with comorbid diseases. PMID- 29153422 TI - A flap based on the plantar digital artery arch branch to improve appearance of reconstructed fingers: Anatomical and clinical application. AB - AIM: To investigate blood supply features of the flap based on the plantar digital artery arch and arch branch artery, and the treatment of outcomes of reconstructed fingers by the plantar digital artery arch branch island flap. METHODS: Eight fresh foot specimens were employed with red emulsion infusion and microdissection. The vascular organization was observed in the second toe, such as initiation site, the course, and the number of the plantar digital artery arch branch. There were 15 fingers of 13 patients (8 males and 5 females) with finger defects accompanied by toe transfer, using the plantar digital artery arch branch flap inserted in the neck of the second toe to correct the appearance defect caused by a narrow "neck" and a bulbous tip. RESULTS: The intact plantar digital arches were identified in all specimens. The plantar digital artery arch had 5 branches. The range of external diameter of the arch branch was 0.4-0.6 mm. All the plantar digital artery arch branch island flaps and the reconstructed fingers survived. These cases were conducted with a follow-up period for 3-18 months (average, 9 months). All the plantar digital artery arch branch island flaps and reconstructed fingers demonstrated a satisfactory appearance and favorable sense function. The reconstructed finger-tip characteristic was good, with no obvious scar hyperplasia. The range of flexion and extension of reconstructed fingers was favorable as well. CONCLUSIONS: The plantar digital artery arch and arch branch artery possess regular vasa vasorum and abundant vascularity. A flap based on the plantar digital artery arch branch is an ideal selection for plastic surgery of reconstructed fingers. PMID- 29153423 TI - Uracil-amino acid as a scaffold for beta-sheet peptidomimetics: Study of photophysics and interaction with BSA protein. AB - We report herein the uracil-di-aza-amino acid (UrAA) as a new family of molecular scaffold to induce beta-hairpin structure with H-bonded beta-sheet conformation in a short peptide. This has been demonstrated in two conceptual fluorescent pentapeptides wherein triazolylpyrenyl alanine and/or triazolylmethoxynapthyl alanine (TPyAlaDo and/or TMNapAlaDo) are embedded into two arms of the uracil amino acid via an intervening leucine. Conformational analysis by CD, IR, variable temperature and 2D NMR spectroscopy reveals the beta-hairpin structures for both the peptides. Study of photophysical property reveals that the pentapeptide containing fluorescent triazolyl unnatural amino acids TMNapAlaDo and TPyAlaDo at the two termini exhibits dual path entry to exciplex emission either via FRET from TMNapAlaDo to TPyAlaDo or via direct excitation of a FRET acceptor, TPyAlaDo. The other pentapeptide with TPyAlaDo/TPyAlaDo pair shows excimer emission. Furthermore, both the peptides maintaining their fundamental photophysics are found to interact with BSA as only a test biomolecule. PMID- 29153424 TI - Identification of a diverse synthetic abietane diterpenoid library and insight into the structure-activity relationships for antibacterial activity. AB - A diverse natural product-like (NPL) synthetic abietane diterpenoid library containing 86 compounds were obtained and the SARs were studied based on their antibacterial potential. Further in vitro cytotoxic and in silico drug-like properties evaluation showed that the potent antibacterial compound 84 had good drug-like properties and displayed low cytotoxicity toward noncancerous mammalian cells, indicating the study of AA and DHAA might be a good starting point for the search of novel antimicrobial molecules. Future work should be focused on the optimization of their potency and selectivity. PMID- 29153426 TI - Laparoscopic exploration for peritoneal carcinomatosis: Surgical technique. PMID- 29153425 TI - Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2. AB - A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4 diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [3H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [3H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [3H]dofetilide binding at the human ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [3H]DA uptake at VMAT2, Ki changes in the nanomolar range (Ki = 0.014-0.073 uM). Compound 15d exhibited the highest affinity (Ki = 0.014 uM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (Ki = 0.073 uM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2. PMID- 29153428 TI - Tricuspid Valve Clipping, Long-Term Solution or Transient Technology? PMID- 29153427 TI - Does a Mobile ECLS Program Reduce Mortality for Patients Transported for ECLS Therapy for Severe Acute Respiratory Failure? AB - OBJECTIVE: To understand if mobile extracorporeal membrane oxygenation reduces patient mortality during and after transport of patients requiring extracorporeal membrane oxygenation for acute respiratory distress syndrome. DESIGN: Retrospective chart review. SETTING: University affiliated tertiary care hospitals. PARTICIPANTS: Seventy-seven patients. INTERVENTIONS: Introduction of a mobile extracorporeal membrane oxygenation (ECMO) program designed to facilitate the implementation of ECMO at outside hospitals in patients too unstable for transport for ECMO. MEASUREMENTS AND MAIN RESULTS: The 28-day in-hospital mortality was significantly lower in the post-mobile group (12/51 [23.5%] v 12/24 [50%], adjusted risk difference: 28.6%, [95% CI 4.7-52.5, p = 0.011]). CONCLUSIONS: These findings suggest that patients with severe acute respiratory failure who require transport to a referral center for extracorporeal life support may benefit from the availability of a mobile extracorporeal life support team. PMID- 29153429 TI - Optimal Interval to Surgery After Neoadjuvant Chemoradiotherapy in Rectal Cancer: A Systematic Review and Meta-analysis. AB - This study aimed to evaluate the influence of a waiting interval of >= 8 weeks between the end of preoperative neoadjuvant chemoradiotherapy (nCRT) and surgery on the outcomes of patients with locally advanced rectal cancer. We conducted a comprehensive literature review of retrospective and prospective studies from PubMed, Embase, and Cochrane Library databases to investigate the length of the preoperative nCRT-surgery waiting interval and outcomes in patients with locally advanced rectal cancer. The primary outcome measure was pathologic complete response (pCR) rate. Secondary outcome measures included overall survival, disease-free survival, operative time, and the incidence of local recurrence, postoperative complications, anastomotic leakage, and sphincter-preserving surgery. Standardized mean differences and risk ratios were calculated. Thirteen studies involving 19,652 patients were included. The meta-analysis demonstrated that pCR was significantly increased in patients with locally advanced rectal cancer and a waiting interval of >= 8 weeks between preoperative nCRT and surgery compared to a waiting interval of < 8 weeks, or a waiting interval of > 8 weeks compared to <= 8 weeks (risk ratio = 1.25; 95% confidence interval, 1.16-1.35; P < .0001). There were no significant differences in overall survival, disease-free survival, operative time, or incidence of local recurrence, postoperative complications, or sphincter-preserving surgery. This study revealed that performing surgery after a waiting interval of >= 8 weeks after the end of preoperative nCRT is safe and efficacious for patients with locally advanced rectal cancer, significantly improving pCR without increasing operative time or incidence of postoperative complications, compared to a waiting interval of <= 8 weeks. PMID- 29153430 TI - Real-World Effect of Maintenance and Intermittent Chemotherapy on Survival in Metastatic Colorectal Cancer. AB - BACKGROUND: With improved survival and longer duration of treatment, clinicians managing metastatic colorectal cancer (mCRC) increasingly consider intermittent (IC) or maintenance chemotherapy (MC), but the effect of these treatment modifications on real-world outcomes is unclear. PATIENTS AND METHODS: Using a population-based cohort of mCRC patients who received combination chemotherapy, we aimed to describe the use of IC/MC and their effect on overall survival (OS). RESULTS: Among 617 patients, 120 (19%) had periods of IC, 67 (11%) had periods of MC, and 53 (9%) had periods of both. Most (85.5%) modifications occurred in the first-line setting. The receipt of IC (median OS [mOS], 37 vs. 21 months; P < .0001) or MC (mOS, 36 vs. 24 months; P = .0015) was associated with improved mOS compared with continuous combination therapy. In multivariate analysis adjusting for age, sex, and regimen used at the time of treatment modification, IC (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.42-0.65; P < .0001), MC (HR, 0.71; 95% CI, 0.58-0.88; P = .002), and the combination (HR, 0.45; 95% CI, 0.33 0.63; P < .0001) were all associated with improved mOS. Among patients receiving MC, individuals with (HR, 0.69; 95% CI, 0.53-0.90; P = .005) and without (HR, 0.74; 95% CI, 0.55-1.00; P = .048) re-escalation to their original cytotoxic regimen had improved mOS compared with continuous therapy. The use of IC was associated with an improved OS compared with MC (HR, 0.65; 95% CI, 0.47-0.90; P = .009). CONCLUSION: In patients with mCRC, IC and MC are reasonable options to maintain quality of life and do not appear to negatively affect OS in carefully selected patients. PMID- 29153432 TI - Shining light on sentinel node assessment for lung cancer: Quality is superior to quantity. PMID- 29153431 TI - Monoclonal Antibodies Targeting the IL-17/IL-17RA Axis: An Opportunity to Improve the Efficiency of Anti-VEGF Therapy in Fighting Metastatic Colorectal Cancer? AB - Colorectal cancer is a major problem for public health worldwide because of its frequency and its severity. Many efforts have been carried to target the vascular endothelial growth factor (VEGF) pathway, one of the main promoters of pathological angiogenesis. Therapeutic monoclonal antibodies against VEGF have emerged as essential biopharmaceuticals for the advanced stages of the disease, in association with appropriate backbone chemotherapy. Unfortunately, after an initial benefit for the patients, resistance invariably develops. These mechanisms of resistance are largely studied and recent publications indicate that the interleukin (IL)-17/IL-17 receptor (IL-17R)A axis could be a key player in the pathological progression. In this mini review, we present evidence for IL 17A/IL-17RA axis targeting in colorectal cancer to improve efficiency of anti VEGF therapy and to implement a new therapeutic strategy. PMID- 29153433 TI - Waiting on a friend: Now is the time for better devices! PMID- 29153434 TI - Surgical embolectomy for pulmonary embolism: About time for a randomized clinical trial? PMID- 29153435 TI - Decompressing extrinsic pulmonary vein obstruction. PMID- 29153436 TI - Expanding options to manage traumatic thoracic vascular injuries. PMID- 29153437 TI - The Institutional Review Board. PMID- 29153439 TI - Number of pulses or number of sessions? An open-label study of trajectories of improvement for once-vs. twice-daily dorsomedial prefrontal rTMS in major depression. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) shows efficacy in the treatment of major depressive episodes (MDEs), but can require >=4-6 weeks for maximal effect. Recent studies suggest that multiple daily sessions of rTMS can accelerate response without reducing therapeutic efficacy. However, it is unresolved whether therapeutic effects track cumulative number of pulses, or cumulative number of sessions. OBJECTIVE: This open-label study reviewed clinical outcomes over a 20-30 session course of high-frequency bilateral dorsomedial prefrontal cortex (DMPFC)-rTMS among patients receiving 6000 pulses/day delivered either in twice-daily sessions 80 min apart (at 20 Hz) or single, longer, once daily sessions (at 10 Hz). METHODS: A retrospective chart review identified 130 MDD patients who underwent 20-30 daily sessions of bilateral DMPFC-rTMS (Once daily, n = 65; Twice-daily, n = 65) at a single Canadian clinic. RESULTS: Mixed effects modeling revealed significantly faster improvement (group-by-time interaction) for twice-daily versus once-daily DMPFC-rTMS. Across both groups, the pace of improvement showed a consistent relationship with number of cumulative sessions, but not with cumulative number of pulses. Although the twice daily group completed treatment in half as many days, final clinical outcomes did not differ significantly between groups on dichotomous measures (response/remission rates: once-daily, 35.4%/33.8%; twice-daily, 41.5%/35.4%), or continuous measures, or on overall response distribution. CONCLUSIONS: Twice daily rTMS appears feasible, tolerable, and capable of achieving comparable results to once-daily rTMS, while also reducing course length approximately twofold. Therapeutic gains tracked the cumulative number of sessions, not pulses. Future randomized studies comparing once-daily to multiple-daily rTMS sessions, while controlling for number of pulses, may be warranted. PMID- 29153438 TI - Effect of the programme Plan de egreso on chronically ill patients and their family caregivers. AB - OBJECTIVE: To determine the effect of the programme Hospitalisation discharge plan for patients with chronic diseases and family caregivers to strengthen their home care competence -CUIDAR- and reduce the caregiver burden. METHOD: Quasi experimental study approach with intervention group. Participants were 62 patients and their caregivers who consulted with a health care institution in the city of Girardot (Colombia). The intervention was carried out for one month, during which, measurements were performed before and after the programme. RESULTS: Most patients were elderly, diagnosed with diabetes, hypertension or COPD, 35% of them with some degree of dependency. The caregivers were mostly women, between the ages of 35 and 59 years old, domestic caregivers, and responsible for caring for their patients for between 13-24hours a day. At the start of the programme the competency for care was low in both patients and caregivers, after the intervention there was a general increase in care and a statistically significant change. Also, at the beginning, 48% of caregivers had some level of burden, and after the study only 27% reported burden with care. CONCLUSIONS: The Hospitalisation discharge plan is a strategy that increases the home care competency of the patient and the caregiver, and decreases the caregiver burden. PMID- 29153440 TI - Relationship between ADAMTS4 and carotid atherosclerotic plaque vulnerability in humans. AB - BACKGROUND: Rupture of atherosclerotic plaques and the resulting thrombosis are vital causes of clinical ischemic events. Recent studies have shown that ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) is a pathogenic factor of plaque vulnerability in mice. However, the relationship between ADAMTS4 and carotid atherosclerotic vulnerable plaques in humans remains unclear. METHODS: Forty-eight carotid atherosclerotic plaque specimens were obtained from 48 carotid artery stenosis inpatients undergoing carotid endarterectomy. We performed hematoxylin and eosin and Movat pentachrome staining for histologic characteristics; immunohistochemical staining for ADAMTS4, versican, and macrophages; and serologic tests for ADAMTS4. Patients were divided into stable and vulnerable groups on the basis of histologic characterization according to the classification criteria of the American Heart Association. Comparison between the groups was carried out using SPSS 17.0 (SPSS Inc, Chicago, Ill). RESULTS: Expression of ADAMTS4 in the plaque and its serum concentration were significantly higher in the vulnerable group compared with the stable one (P = .004 and P = .021, respectively), whereas the expression of versican was lower in the vulnerable group than in the stable group (P = .015). Univariate analysis revealed that the incidence of symptomatic cerebral ischemic events and ADAMTS4 serum levels were statistically higher in the vulnerable group compared with the stable group (P = .021 and P = .029, respectively). Multivariate analysis showed that ADAMTS4 was an independent risk factor (odds ratio, 1.14; P = .038). CONCLUSIONS: Our study revealed that ADAMTS4 expression was upregulated during carotid atherosclerotic plaque development. Serum levels of ADAMTS4 were associated with increased plaque vulnerability in both symptomatic and asymptomatic patients with carotid artery stenosis. ADAMTS4 may be a potential biomarker for plaque vulnerability. PMID- 29153441 TI - Complex endovascular repair of postdissection arch and thoracoabdominal aneurysms. AB - OBJECTIVE: We report our experience of the treatment of postdissection arch aneurysms and thoracoabdominal aortic aneurysms (TAAAs) by endovascular repair using fenestrated and branched endografts. METHODS: This study includes all patients presenting with chronic postdissection aneurysms >55 mm in diameter deemed unfit for open surgery and treated by complex endografting between October 2011 and April 2017. Where appropriate, staged management strategies including left subclavian artery revascularization, thoracic endografting, dissection flap fenestration, and tear enlargement were performed before the complex endovascular repair. Outcome data were collected prospectively, specifically including technical success, endoleaks, target vessel patency, aneurysm diameter, adverse events, reinterventions, and mortality. RESULTS: We treated 40 patients with a median age of 63 years (55-71 years). In total, 43 procedures were performed: 19 arch repairs using inner branch endografts (one to three branches) and 24 TAAA repairs using fenestrated or branched endografts. Three patients were treated using both arch and TAAA repair. The median time between initial presentation with acute dissection and the first complex aortic repair was 5 years (3.0-10.0 years). Staged procedures were performed in 33 of 40 patients (82.5%). The technical success rate was 93%, the median procedure length was 240 minutes (170 285 minutes), and the median dose-area product was 80 Gy . cm2 (54.3-138.4 Gy . cm2). The 30-day and in-hospital mortality rates were 2.3% (1/43) and 4.7% (2/43), respectively. The spinal cord ischemia rate was 7% and occurred only after TAAA repair. One stroke with partial recovery and one transient ischemic attack were observed (4.7%) after arch repair. Six early reinterventions (14%) were performed: three for access complications, two to treat acute hemorrhage, and one to treat a type II endoleak. Median follow-up was 25.5 months (11-42.25 months). The 1- and 5-year survival rates were 90% and 76.4%, respectively. Late reinterventions were required in eight patients, two in the arch group (to treat endoleaks at 3 and 33 months) and six in the TAAA group (2 iliac and 1 bifurcated endograft extensions, 2 additional renal stents, 1 inferior mesenteric artery embolization). Aneurysm diameter was stable (72%) or shrank (23%) during follow up. Enlargement was shown in two patients with endoleaks. CONCLUSIONS: Complex endovascular repair of postdissection aneurysms is a safe procedure in patients deemed unfit for open surgery. Our experience suggests that close follow-up is mandatory as secondary procedures are frequently required to completely exclude the false lumen. PMID- 29153442 TI - Functional MRI Study to Examine Possible Emotional Connectedness in Identical Twins: A Case Study. AB - In the present case study, we investigated possible emotional connectedness between monozygotic twins by means of functional magnetic resonance imaging (fMRI). During the experimental condition, Twin 2 was randomly selected to participate in the neuroimaging protocol while Twin 1 participated in the experimental condition outside the MRI scanner (none of them was aware of the experimental procedure). The experimental condition included two sessions with visual and acoustic stimuli, respectively. Between the two experimental conditions, there was a 2-min break with Twin 1 (i.e., the subject outside the scanner) relaxing with eyes closed. Data analysis revealed significant brain activation in three regions, namely left orbitofrontal gyrus (during visual condition) and left cingulum and precentral gyrus (during the acoustic condition). Our findings denote emotional connectedness between a pair of monozygotic twins using fMRI. Further studies in larger sample sizes are needed to investigate if this is a generalized and systematic phenomenon or an incidental finding. PMID- 29153443 TI - Subjective sleep disturbances are associated with intrinsic motivation toward sleep-related thinking. AB - Biased information processing has been highlighted as a possible vulnerability factor for sleep problems. A theory states that perceived sleeplessness triggers a strong approach motivation (or craving) for sleep, and then activates persistent preoccupation with sleep. However, there is no clear evidence that perceived sleeplessness is associated with such a motivation toward sleep-related information. Thus, we examined the untested idea that people with subjective sleep disturbances would prefer sleep-related topics, using a modified version of the pay-per-view task. In this task, 58 participants were offered two question type options: the "sleep" option, where participants were asked to answer a question about their sleep, and the "eat" option, where participants needed to answer a question about their eating habits and beliefs. Each option is associated with a variable amount of economic reward and therefore participants sometimes face a conflict between the economic reward and their intrinsic preference for a specific question type. Results showed that people with higher levels of subjective sleep disturbances forgo greater amounts of reward to have an opportunity to answer sleep-related (as opposed to than eating-related) questions. These findings suggest that people who perceive themselves as lacking sleep are highly motivated to engage in sleep-related information processing. PMID- 29153444 TI - Retrospective evaluation of piperacillin-tazobactam, imipenem-cilastatin and meropenem used on surgical floors at a tertiary care hospital in Saudi Arabia. AB - BACKGROUND: The appropriate use of broad-spectrum antibiotics, including appropriate de-escalation, is essential to reduce the emergence of antibiotic resistance. In surgical floors antibiotics are prescribed for prophylaxis (mostly, single dose), empirical treatment (started if infection is suspected till bacteria are identified with its sensitivity to antibiotics), or treatment of well-defined infection of previously isolated bacteria with its sensitivity to antibiotics. In this study, we aimed to evaluate the use of broad-spectrum antibiotics based on requests for cultures and de-escalation based on sensitivity results of culture tests at tertiary care hospital. METHOD: A retrospective cohort study was conducted to evaluate the utilization of broad-spectrum antibiotics on surgical floors at a tertiary care center in Jeddah, Saudi Arabia. Patients who are admitted to surgical floors were included if they received any of three broad-spectrum antibiotics (piperacillin-tazobactam, imipenem-cilastatin or meropenem) from 1 June 2014 to 31 August 2014. Data were collected on whether culture and sensitivity test requests were made within 24h of starting antibiotics, the duration of antibiotic therapy and the number of days to de escalation after receiving culture and sensitivity results. RESULTS: Of the 163 patients who received broad-spectrum antibiotics, culture tests were requested in 112. Before receiving culture results, one patient was discharged and one died. The results of culture tests justified continuation of broad-spectrum antibiotics in only 22 patients, whereas 24 showed no microbial growth in any culture. De escalation was delayed >24h after culture results became available in 33 out of 64 eligible patients. On the other hand, 51 patients continued receiving broad spectrum antibiotics without any culture test during the whole treatment course. CONCLUSION: The use of broad-spectrum antibiotics in surgical floors at a tertiary care hospital in Saudi Arabia was largely unjustified by culture-test result. Interventions are needed to enforce culture and sensitivity test requests within 24h of starting the broad spectrum antibiotics therapy with further follow up to ensure appropriate de-escalation and discontinuation whenever indicated. PMID- 29153445 TI - Prevalence and Correlates of Youth Homelessness in the United States. AB - PURPOSE: Unaccompanied youth homelessness is a serious concern. Response, however, has been constrained by the absence of credible data on the size and characteristics of the population and reliable means to track youth homelessness over time. We sought to address these gaps. METHODS: Using a nationally representative phone-based survey (N = 26,161), we solicited household and individual reports on different types of youth homelessness. We collected household reports on adolescents aged 13-17 and young adults aged 18-25, as well as self-reports from young adults aged 18-25. Follow-up interviews with a subsample (n = 150) provided additional information on youth experiences and enabled adjustment for inclusion errors. RESULTS: Over a 12-month period, approximately 3.0% of households with 13- to 17-year-olds reported explicit youth homelessness (including running away or being asked to leave) and 1.3% reported experiences that solely involved couch surfing, resulting in an overall 4.3% household prevalence of any homelessness, broadly defined. For 18- to 25-year olds, household prevalence estimates were 5.9% for explicitly reported homelessness, 6.6% for couch surfing only, and 12.5% overall. The 12-month population prevalence estimates, available only for 18- to 25-year-olds, were 5.2%, 4.5%, and 9.7%, respectively. Incidence rates were about half as high as prevalence rates. Prevalence rates were similar across rural and nonrural counties. Higher risk of homelessness was observed among young parents; black, Hispanic, and lesbian, gay, bisexual, or transgender (LGBT) youth; and those who did not complete high school. CONCLUSIONS: The prevalence and incidence of youth homelessness reveal a significant need for prevention and youth-centric systems and services, as well as strategies to address disproportionate risks of certain subpopulations. PMID- 29153446 TI - The instability of functional connectivity in patients with schizophrenia and their siblings: A dynamic connectivity study. AB - BACKGROUND: The distributed connectivity among brain regions is in a constant state of flux, even when a subject is at rest. This instability (temporal variability), when optimal, may contribute to efficient cross-network communications. We investigate the role of this variability in the genetic diathesis and symptom expression of schizophrenia. METHODS: Resting state functional MRI data acquired from 116 subjects (28 patients with schizophrenia, 28 siblings and 60 matched healthy controls). Using a sliding-window dynamic connectivity approach, we quantified the variability of whole-brain connectivity (dynamic functional connectivity or dFC) of each of the 90 brain regions obtained using a parcellation scheme that covered all contiguous brain regions of the cerebral cortex. RESULTS: We noted a high degree of instability anchored on the precuneus in patients with schizophrenia compared to both healthy controls (t=3.60, p=0.0005) and unaffected siblings (t=3.61, p=0.001) indicating a role for dFC of precuneus in the clinical expression of schizophrenia. Compared to patients, siblings also showed an increase in medial orbitofrontal but reduced putaminal instability; these latter changes were not seen in patients when compared to controls, indicating a lack of specificity for diathesis or expression related effects. CONCLUSIONS: Instability in the intrinsic connectivity of precuneus, a functional core hub with a major role in task-free self-processing, is likely to be a core substrate of the clinical expression of schizophrenia. PMID- 29153447 TI - Abnormal brain activation during threatening face processing in schizophrenia: A meta-analysis of functional neuroimaging studies. AB - Impairment of face perception in schizophrenia is a core aspect of social cognitive dysfunction. This impairment is particularly marked in threatening face processing. Identifying reliable neural correlates of the impairment of threatening face processing is crucial for targeting more effective treatments. However, neuroimaging studies have not yet obtained robust conclusions. Through comprehensive literature search, twenty-one whole brain datasets were included in this meta-analysis. Using seed-based d-Mapping, in this voxel-based meta analysis, we aimed to: 1) establish the most consistent brain dysfunctions related to threating face processing in schizophrenia; 2) address task-type heterogeneity in this impairment; 3) explore the effect of potential demographic or clinical moderator variables on this impairment. Main meta-analysis indicated that patients with chronic schizophrenia demonstrated attenuated activations in limbic emotional system along with compensatory over-activation in medial prefrontal cortex (MPFC) during threatening faces processing. Sub-task analyses revealed under-activations in right amygdala and left fusiform gyrus in both implicit and explicit tasks. The remaining clusters were found to be differently involved in different types of tasks. Moreover, meta-regression analyses showed brain abnormalities in schizophrenia were partly modulated by age, gender, medication and severity of symptoms. Our results highlighted breakdowns in limbic MPFC circuit in schizophrenia, suggesting general inability to coordinate and contextualize salient threat stimuli. These findings provide potential targets for neurotherapeutic and pharmacological interventions for schizophrenia. PMID- 29153448 TI - Evidence of disturbances of deep levels of semantic cohesion within personal narratives in schizophrenia. AB - Since initial conceptualizations, schizophrenia has been thought to involve core disturbances in the ability to form complex, integrated ideas. Although this has been studied in terms of formal thought disorder, the level of involvement of altered latent semantic structure is less clear. To explore this question, we compared the personal narratives of adults with schizophrenia (n=200) to those produced by an HIV+ sample (n=55) using selected indices from Coh-Metrix. Coh Metrix is a software system designed to compute various language usage statistics from transcribed written and spoken language documents. It differs from many other frequency-based systems in that Coh-Metrix measures a wide range of language processes, ranging from basic descriptors (e.g., total words) to indices assessing more sophisticated processes within sentences, between sentences, and across paragraphs (e.g., deep cohesion). Consistent with predictions, the narratives in schizophrenia exhibited less cohesion even after controlling for age and education. Specifically, the schizophrenia group spoke fewer words, demonstrated less connection between ideas and clauses, provided fewer causal/intentional markers, and displayed lower levels of deep cohesion. A classification model using only Coh-Metrix indices found language markers correctly classified participants in nearly three-fourths of cases. These findings suggest a particular pattern of difficulties cohesively connecting thoughts about oneself and the world results in a perceived lack of coherence in schizophrenia. These results are consistent with Bleuler's model of schizophrenia and offer a novel way to understand and measure alterations in thought and speech over time. PMID- 29153449 TI - The changing epidemiology of open fractures in vehicle occupants, pedestrians, motorcyclists and cyclists. AB - AIMS: To investigate the changing epidemiology of open fractures in vehicle occupants, pedestrians, motorcyclists and cyclists. MATERIALS AND METHODS: Data on all non-spinal open fractures admitted to the Royal Infirmary of Edinburgh after a road traffic accident between 1988 and 2010 were collected and analysed to provide information about the changing epidemiology in different patient groups. Demographic information was collected on all patients with the severity of injury being analysed with the Injury Severity Score (ISS), Musculoskeletal Index (MSI) and the number of open fractures. The severity of the open fractures was analysed using the Gustilo classification. The 23-year study period was divided into four shorter periods and the results were compared. RESULTS: There were 696 patients treated in 23 years. Analysis showed that the incidence of RTA open fractures initially fell in both males and females and continued to fall in females during the 23 years. In males it levelled off about 2000. The age of the female patients also fell during the study period but it did not change in males. The only patient group to show an increased incidence of open fractures were cyclists. In vehicle occupants the incidence fell throughout the study period but it levelled off in pedestrians and motorcyclists. There was no difference in the severity of injury in any group during the study period. The most severe open fractures were those of the distal femur and femoral diaphysis although open tibial diaphyseal fractures were the most common fracture in all patient groups. CONCLUSIONS: Improved car design and road safety legislation has resulted in a reduction in the incidence of open fractures in vehicle occupants, pedestrians and motorcyclists. The most obvious group to have benefitted from this are older female pedestrians. The only group to show an increase in age during the study period were male motorcyclists. PMID- 29153450 TI - Is external fixation needed for the treatment of tibial fractures with acute compartment syndrome? AB - Acute compartment syndrome (ACS) after tibial fracture carries a risk of various complications, including infection, delayed union, nonunion, nerve damage, and poor prognosis. For the treatment of fractures with ACS, fasciotomy is conducted, and the method to stabilise the fracture has to be considered. Thirty-five patients who underwent surgery for ACS with tibial shaft fractures were evaluated, and the results of initial internal fixation (Group I, 20 patients) and initial external fixation (Group II, 15 patients) were analysed. The mean age was 41 years. Five patients needed additional surgery for bone union. Complications occurred in 4 cases, but no deep infection was reported. The time to bone union, the need for additional surgery, and the incidence of complications in Group I and Group II were not statistically different. For the treatment of ACS with tibial fracture, immediate internal fixation and changing from external fixation to internal fixation did not affect the clinical course. PMID- 29153451 TI - A novel minimally invasive surgery combined with early exercise therapy promoting tendon regeneration in the treatment of spontaneous Achilles tendon rupture. AB - OBJECTIVE: Acute closed spontaneous Achilles tendon rupture often occurs in elderly individuals and is usually accompanied with many complications. Conventional surgical approaches to remove the tendon lesions and enthesophytes are highly traumatic and cause complications. In this study, a previously established minimally invasive surgical approach was modified and combined with a Kazakh exercise therapy to reduce trauma, improve wound healing, and promote tendon regeneration in the management of acute closed spontaneous Achilles tendon rupture. METHODS: Fifty-two patients with acute closed spontaneous Achilles tendon rupture were randomly classified into 2 groups. Group A included 23 patients that were treated with the novel approach. Group B included 29 patients that were treated with a continuous medial oblique surgical approach. Follow-up examinations were performed at post-operative weeks 12 and 24, and year 2. Outcomes were assessed by Achilles tendon rupture score (ATRS), a heel-rise endurance test, and ultrasonographic and multislice spiral computerized tomography. RESULTS: Mean ATRS in Group A was 68.6 and 86.0 at post-operative week 12 and 24, respectively, significantly higher than that in Group B (55.9 and 72.0, respectively). Recovery of patients in Group A was significantly better compared to Group B (p < 0.01), allowing them to participate in early rehabilitating kinesiotherapy. Patients in Group A rarely experienced complications after surgery, such as infection and Achilles tendon exposure, while in Group B, the wound healing was slower, the inside flaps were prone to necrosis and infection, and Achilles tendon exposure occurred in 10% of patients. CONCLUSIONS: The novel minimally invasive surgery is more advantageous in the treatment of acute closed spontaneous Achilles tendon rupture over previous approaches by promoting wound healing and tendon regeneration. PMID- 29153452 TI - Diagnostics of tuberculosis and differentiation of nonspecific tuberculin reactions in animals. AB - Tuberculosis is a serious disease of humans and animals, caused by bacteria of the Mycobacterium genus. This leads to complications in the life of the sick person, and subsequently to death. The cattle, who have been diagnosed with this bacterium, are usually sent to the slaughter, with the result that their livestock is reduced. Mycobacteriosis is also a disease, after determining which cattle are most often sent to slaughter. Such a reduction in livestock numbers has a negative effect on the economy. Of the 300 samples from the animals, 25 cultures of atypical bacteria responding to tuberculin were isolated. A series of tests - intravenous tuberculin test, ophthalmic test, palpebral test, "ZhAT" test, showed that most of the tuberculosis changes in cattle were found in regional lymph nodes more often than in internal organs. In healthy for tuberculosis cows, at the age of 4-9 years, seasonal nonspecific sensitivity to tuberculin is observed. Implementation of the developed express method of glutaraldehyde test on farms in healthy tuberculosis will speed up the diagnosis of tuberculosis and mycobacteriosis in animals that reacted to tuberculin and will exclude short-term nonspecific sensitization of their organism to tuberculin. The introduction of this methodology can be used to diagnose and clearly differentiate the diagnoses of "tuberculosis" and "mycobacteriosis" in cattle. This will cure part of the livestock and reduce the amount of slaughter. PMID- 29153453 TI - Face-to-face instruction combined with online resources improves retention of clinical skills among undergraduate nursing students. AB - BACKGROUND: There is growing evidence that online resources used to develop clinical skills among students in the healthcare professions can produce equivalent learning outcomes to traditional face-to-face training methods. Whether clinical competence is retained equally well for online and face-to-face training methods is not yet established. OBJECTIVES: The objective of the study was to compare retention of competence in using an IV infusion pump among nursing students trained in its use using three different protocols. DESIGN: A quasi experimental design was used. SETTING: The study was conducted in the School of Nursing and Midwifery at a regional university in Queensland, Australia. PARTICIPANTS: Participants were 102 first year nursing students (female=89, male=13) enrolled in a medications course, ranging in age from 18 to 44years. METHODS: Three groups of participants were trained in the use of an IV infusion pump and competence was assessed following a 26-week period of no access to the pump. Group 1 participants (ONL; n=34) were trained online using an Intravenous Pump Emulator (IVPE); Group 2 participants (ONC; n=38) were trained on campus using an actual IV pump in a traditional face-to-face setting; Group 3 participants (ONL+ONC; n=30) were trained both on campus using the actual IV pump and online using the IVPE. RESULTS: As hypothesised, no significant differences in learning outcomes, measured by assessment scores out of 80 points, were found between the ONL (M=68.7+/-5.9) and ONC (M=65.5+/-11.5; p>0.05) groups. The ONL+ONC group recorded the highest mean assessment score (M=70.0+/-5.0) and completed the assessment task significantly faster (p<0.001) than the other two groups. CONCLUSIONS: This study suggests that nursing students retained clinical competence in preparing and administrating IV infusions better when face-to-face and online learning were combined. PMID- 29153454 TI - Beliefs and perceptions of mentorship among nursing faculty and traditional and accelerated undergraduate nursing students. AB - BACKGROUND: In order to meet the demands of a dynamic and complex health care landscape, nursing education must develop and implement programming to produce a highly educated nursing workforce. Interprofessional honors education in nursing with targeted mentorship is one such model. PURPOSE: To describe undergraduate nursing student and faculty perceptions and beliefs of mentorship in the context of interprofessional honors education, and compare and contrast the perceptions and beliefs about mentorship in interprofessional honors education between undergraduate nursing students and faculty. METHODS: The study used a cross sectional, descriptive design. Data were collected at an urban university in the northeast US, using a researcher-developed electronic survey. The sample included 24 full-time nursing faculty, and 142 undergraduate nursing students. RESULTS: Perceptions and beliefs regarding mentorship in the context of interprofessional honors education were similar for faculty and students, with both ranking mentorship among the most important components of a successful honors program. CONCLUSIONS: Honors education with a dedicated mentorship component may be implemented to improve the undergraduate education experience, facilitate advanced degree attainment, and develop future nursing leaders. PMID- 29153455 TI - Could we remedy the 'crisis of care' by incorporating mandatory group psychotherapy in nurse education? AB - This paper suggests a tentative proposal for nurse education that may go some way to remedying the 'crisis of care' described by Judge Francis and others. Any viable strategy to improve caring attitudes in nursing students must involve activities across the curriculum that foster self-awareness and empathy. It is suggested that the best way to do this is for all undergraduate nursing students to participate in regular, supervised group psychotherapy sessions as a mandated requirement for registration. This strategy would be helpful in at least two main ways. First, it would be enormously beneficial in terms of promoting emotional intelligence - a necessary requirement for providing ethical, person-centred care. Second, it would also serve as an excellent form of student support, which would likely improve student retention rates. This is because individuals with strong group support systems are less likely to become mentally or physically ill and are, therefore, more resilient. Finally, some possible objections to this proposal are considered. PMID- 29153456 TI - Association of Mortality with Ocular Diseases and Visual Impairment in the Age Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 13. AB - PURPOSE: To evaluate the association of mortality with visual acuity (VA) impairment, age-related macular degeneration (AMD), and cataract surgery. DESIGN: Cohort study. PARTICIPANTS: Participants with at least intermediate AMD enrolled in a randomized controlled clinical trial of lutein/zeaxanthin and/or omega-3 fatty acids, the Age-Related Eye Disease Study 2 (AREDS2), for treatment of AMD and cataract. METHODS: Baseline and annual eye examinations included best corrected visual acuity (BCVA) assessments, slit-lamp examinations, and stereoscopic fundus photographs that were centrally graded for development of late AMD (central geographic atrophy or neovascular AMD) or pseudophakia. Cause specific mortality was determined on the basis of the International Classification of Diseases 9th or 10th Revision codes. Risk of all-cause and cause-specific mortality was assessed with Cox proportional hazards models adjusted for age, sex, AMD severity, VA, history of cataract surgery, and assigned AREDS2 study treatment. Analyses included baseline covariates: race, education, smoking status, diabetes, and cardiovascular disease. RESULTS: During follow-up (median 5 years), 368 (9%) of the 4203 AREDS2 participants died. Participants with neovascular AMD in 1 eye at baseline had a statistically significant increased risk for mortality compared with participants with no or few drusen (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.21-2.01; P < 0.001). Poorer survival was associated with bilateral cataract surgery before enrollment compared with baseline bilateral phakia (HR, 1.63; 95% CI, 1.29-2.07; P < 0.001) and with BCVA of less than 20/40 compared with participants with 20/40 or better (HR, 1.56; 95% CI, 1.06-2.30; P = 0.024), adjusted for age, sex, and statistically significant covariates. Participants who received antivascular endothelial growth factor therapies for neovascular AMD had decreased mortality compared with those who did not (HR, 0.71; 95% CI, 0.57-0.88; P = 0.002). The association between all-cause mortality and AREDS2 treatment whether assessing the main or individual treatment effect was not significantly different (omega-3 fatty acids main effect HR, 1.18; 95% CI, 0.96-1.45; P = 0.12; lutein/zeaxanthin main effect HR, 1.04; 95% CI, 0.85-1.28; P = 0.71). CONCLUSIONS: In AREDS2, the presence of late AMD, bilateral cataract surgery, and VA less than 20/40 was associated with decreased survival. However, oral supplementation with omega-3 fatty acids, lutein plus zeaxanthin, zinc, or beta-carotene had no statistically significant impact on mortality. PMID- 29153457 TI - Pars Plana Vitrectomy and Endoresection of Refractory Intraocular Retinoblastoma. PMID- 29153458 TI - Thigh Cuffs as a Countermeasure for Ocular Changes in Simulated Weightlessness. PMID- 29153459 TI - [Intrafamilial disruptive behaviour disorders in children and adolescents: Present data and treatment prospects]. AB - Child-to-parent violence is a form of family violence that is still a well-kept secret. Abused parents can be victims of different types of abuse. Children can use both physical and psychological violence such as financial threats to take control of the home. In this situation, parents often no longer dare to contradict their children by fear of triggering uncontrollable violence. Although the phenomenon recently drew the attention of the media, there is still little knowledge about its prevalence and clinical characteristics. Most families remain isolated for a long time and, even in case of consulting in a mental health setting, disclosure of the nature of the difficulties is often delayed. This article presents the specificities of these children and their clinical characteristics. It also studies the victimized parents, the entire family, and their relation to the external environment. When observing these young offenders oppositional defiant disorder, conduct disorder and attention deficit hyperactivity disorder are frequently found. The diagnosis of "conduct disorder confined to family context" defined in the ICD 10 is the most appropriate to describe them. But it is regrettable that there has currently been no study to validate it and to determine its specificity. Compared with other young children who have "classic" disruptive disorders, children involved in violence against their parents have more difficulties with affect regulation, impulse control, and interpersonal skills. These children also frequently have low self-esteem and difficulties interacting with their peers. They may be isolated and bullied. They feel more sadness than these other young people and use violence as a way to express their emotions. Within the family both girls and boys commit violence against their parents. Girls will mostly use psychological violence but can also be involved in physical aggression. The first victim of child-to-parent violence is the mother. As mothers are often more present at home and seen by their children as weaker than the father, they are seen as an "easy target". If the "classic" conduct disorder is most frequently encountered in low social status families, intra familial disruptive behavior can be observed in families from all socio economic status. With respect to the parent-child relationship in those families, there are some relevant specificities. First, the quality of communication is bad, parents and children are not intimate and the tension is permanent. Furthermore, children do not respect their parents' authority. They perceive parenting style as permissive and negligent without enough support and control, and they may want to restore a coherent authority in the family. It is important to mention that potential vulnerability factors such as older age, a history of mental illness and social isolation have been described in parents of these children. Thereby, victimized parents have all the more difficulty to stand up against their children or to cleverly adapt their authority to their behavior. Other types of inappropriate education can be the origin of the child-to-parent violence. There is a direct correlation between the high frequency of punishments and violent attitude of the children towards their parents. So, the family dynamic is characterized by an inversion of the family hierarchy, the parents' fear of violent behavior from their child, and shame expressed by the parents with regards to the nature of familial relationships. Their fear and their shame will contribute to ensuring that their child's behavior is kept secret. Finally, several factors can therefore be at the source of the development of child-to- parent violence ; this study aims to raise awareness of clinicians of this impairing and frequently hidden condition. Due to the absence of specific studies, management of intra-familial disruptive disorder is likely to be less than optimal and heterogeneous. The development of a group of targeted parental psychoeducation is a promising management technique. We will describe the basic principles of " active parental control", a programme using techniques of " non violent resistance" to help parents cope with violence and control children's behavior. The results of this programme are still being evaluated, but preliminary results seem promising since the parents included in the pilot group have described a significant improvement in the feeling of parental competence and, notably, self-control. PMID- 29153460 TI - Real-world procedural and 30-day outcome using the Portico transcatheter aortic valve prosthesis: A large single center cohort. AB - BACKGROUND: Published procedural and short-term outcome of the Portico valve for Transcatheter Aortic Valve Implantation (TAVI) is limited. We report a single center patient series assessing procedural and 30-day outcome of this device. METHODS AND RESULTS: Procedural and 30-day follow-up data were prospectively collected from a consecutive series of 73 patients (80.7+/-6.9years, 45% male, mean STS score: 4.8+/-3.9) with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI). Transfemoral access was used in 69 patients (94.5%), whereas in the remainder subclavian access was used. Concomitant interventions were performed in 30% of the patients. At 30days, all-cause mortality and the rate of neurological events were both 2.7%. The rates of non minor bleeding and major vascular complications were 8.2% and 4.1%, respectively. Clinically significant aortic regurgitation was limited to a single case (1.4%) of moderate regurgitation at discharge, which was reduced to mild at 30days. Overall pacemaker rate after TAVI was 12% and the transprosthetic gradient was 6.9+/-3.2mmHg. CONCLUSIONS: TAVI using the Portico system was associated with low mortality and a low rate of neurological events at 30days and excellent hemodynamic outcome with no more than mild residual aortic regurgitation. PMID- 29153461 TI - Population-based Borrelia burgdorferi sensu lato seroprevalence and associated risk factors in Finland. AB - Lyme borreliosis (LB) is caused by Borrelia burgdorferi sensu lato (Bb-sl) and is the most common vector-borne disease in Europe. The objectives of this study were to determine the Bb-sl seroprevalence among the general Finnish adult population and to identify risk factors associated with Bb-sl-seropositive status. Two thousand sera from a nationwide health survey from 2011 were tested by whole-cell sonicate IgG ELISA, C6 peptide ELISA, and recomBead IgG 2.0 and test results were linked to a general health questionnaire. A multivariable logistic regression model was used to identify risk factors. The median age of the study population was 56 years (range 29-97) and the Bb-sl weighted seroprevalence was 3.9% (95% confidence interval (CI) 3.03-5.08). The weighted seroprevalence was significantly higher among males than females (adjusted odds ratio 1.91, 95%CI 1.21-3.04). The seroprevalence was highest in Southern, Central, and Eastern regions. The first Bb-sl seroprevalence study in Finland showed a seroprevalence of 3.9% (regional range 0.87%-6.12%). The results of this study can be used, together with previous data on LB incidence and spatial tick distribution, to target public health communication about preventive measures. PMID- 29153462 TI - Health-related-quality-of-life and toxicity after single fraction 19 Gy high-dose rate prostate brachytherapy: Phase II trial. AB - PURPOSE: To evaluate the safety, tolerance and impact on health-related-quality of-life (HRQoL) of the high-dose-rate brachytherapy of 19 Gy (BRT-HDR-19 Gy) single fraction in prostate cancer. METHODS: From January 2014 to July 2016, 43 patients with low/intermediate risk were treated with BRT-HDR-19 Gy. The patients were monitored prospectively for toxicity and HRQoL. RESULTS: The median age, initial PSA and the International Prostate Symptom Score (IPSS) were 71 years (55 78), 7.0 ng/mL (4.2-17.8) and 5 (0-14) respectively. 44% were low-risk and 56% intermediate-risk. Median CTV-V100 (where Vn is the fractional volume of the organ that receives n% of the prescribed dose) was 96.5%, Urethral-Dmax 106% and rectum-2 cc (the dose to 2 cc of rectal wall) 53%. After a median follow-up of 20 months (4-26), acute grade-2 genitourinary (GU) toxicity occurred in 4 patients (9%) and none presented acute gastrointestinal (GI) toxicity. Similarly, four patients (9%) presented late GU grade-2 toxicity. No grade-3 toxicity occurred. In terms of HRQoL, there was a statistically significant decline in Expanded Prostate Cancer Index Composite (EPIC) urinary urgency/obstructive domain at month 3 (p = 0.047), and returned to baseline by month 6. Mean EPIC urinary incontinence, bowel, sexual and hormonal domains did not present significant post BRT-HDR-19 Gy changes. Patients rated their satisfaction at 6 months as "very satisfied" (23%) or "extremely-satisfied" (77%). CONCLUSIONS: BRT-HDR-19 Gy demonstrates excellent results in terms of toxicity, tolerance, safety, patient satisfaction and HRQoL. PMID- 29153463 TI - Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials. AB - BACKGROUND AND PURPOSE: Adjuvant lymphatic radiotherapy (LNRT) is recommended for selected axillary node positive women with early breast cancer. We investigated whether hypofractionated LNRT is safe combined with similarly-hypofractionated breast/chest wall radiotherapy (RT). MATERIAL AND METHODS: The Standardisation of Breast Radiotherapy (START) pilot, A and B trials randomised women with early breast cancer to schedules of 2.67-3.3 Gy versus 2.0 Gy fractions (control). RT adverse effects were assessed by patients using the EORTC QLQ-BR23 and protocol specific questions, and by physicians. Rates of arm/shoulder effects were compared between schedules for patients given LNRT. RESULTS: 864/5861 (14.7%) patients received LNRT (385 START-pilot, 318 START-A, 161 START-B). Prevalences of moderate/marked arm/shoulder effects were low up to 10 years. There were no significant differences between the hypofractionated and control groups for patient- and physician-assessed symptoms in START-A or START-B. In START-pilot, adverse effect rates were higher after 13 fractions of 3.3 Gy, consistent with effects reported in the breast/chest wall (significant for shoulder stiffness, HR 3.07, 95%CI 1.62-5.83, p = 0.001). CONCLUSIONS: The START trial results suggest that appropriately-dosed hypofractionated LNRT is safe in the long-term, according to patient and physician-assessed arm and shoulder symptoms. These findings are consistent with those reported after the same schedules delivered to the breast/chest wall. PMID- 29153464 TI - International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma. AB - PURPOSE: Target delineation in nasopharyngeal carcinoma (NPC) often proves challenging because of the notoriously narrow therapeutic margin. High doses are needed to achieve optimal levels of tumour control, and dosimetric inadequacy remains one of the most important independent factors affecting treatment outcome. METHOD: A review of the available literature addressing the natural behaviour of NPC and correlation between clinical and pathological aspects of the disease was conducted. Existing international guidelines as well as published protocols specified by clinical trials on contouring of clinical target volumes (CTV) were compared. This information was then summarized into a preliminary draft guideline which was then circulated to international experts in the field for exchange of opinions and subsequent voting on areas with the greatest controversies. RESULTS: Common areas of uncertainty and variation in practices among experts experienced in radiation therapy for NPC were elucidated. Iterative revisions were made based on extensive discussion and final voting on controversial areas by the expert panel, to formulate the recommendations on contouring of CTV based on optimal geometric expansion and anatomical editing for those structures with substantial risk of microscopic infiltration. CONCLUSION: Through this comprehensive review of available evidence and best practices at major institutions, as well as interactive exchange of vast experience by international experts, this set of consensus guidelines has been developed to provide a practical reference for appropriate contouring to ensure optimal target coverage. However, the final decision on the treatment volumes should be based on full consideration of individual patients' factors and facilities of an individual centre (including the quality of imaging methods and the precision of treatment delivery). PMID- 29153465 TI - Impact of hybrid PET/MR technology on multiparametric imaging and treatment response assessment of cervix cancer. AB - BACKGROUND AND PURPOSE: Multimodal tissue characterization by combined MRI and PET has high clinical potential in the context of sub-target definition for dose painting and response assessment but its clinical exploration is yet limited. The aim of this study was to prove the potential and feasibility of hybrid PET/MRI to non-invasively measure tumor hypoxia, perfusion and microstructure at one stop in tumors of the uterine cervix during chemoradiotherapy. MATERIAL AND METHODS: Ten cervix cancer patients were subjected to simultaneous multiparametric PET/MRI with [18F]fluoromisonidazole ([18F]FMISO). Imaging was scheduled before, twice during and after chemoradiotherapy. Intra- and inter-time point analyses of the extracted parameters (i.e. ADC, Ktrans, ABrix, [18F]FMISO-tumor to background ratio (TBR)) were performed. The [18F]FMISO uptake- and ADC-spatio-temporal changes were assessed. RESULTS: Patient averaged ADC values increased from baseline to follow up (1.03 +/- 0.11/1.30 +/- 0.13 * 10-3 mm2/s), while the TBR decreased (1.73 +/- 0.24/1.36 +/- 0.19), Ktrans dropped over time (0.17 +/- 0.05/0.05 +/- 0.05 min-1); for all above p < 0.05. None of these parameters correlated significantly on a voxel-by-voxel basis. Low-ADC regions spatially varied over time. There was pronounced reduction of the [18F]FMISO-avid volumes during treatment. CONCLUSIONS: The suggested hybrid PET/MRI protocol to non invasively investigate tumor hypoxia, perfusion and microstructure at one stop was feasible, revealing spatio-temporal response patterns that could be utilized for comprehensive sub-target definition for dose painting and response assessment. PMID- 29153466 TI - Focal boost to residual gross tumor volume in brachytherapy for cervical cancer-A feasibility study. AB - PURPOSE: Image-guided plan optimization with MRI and CT for interstitial and intracavitary brachytherapy is an established technique in treating cervical cancer. The purpose of this study was to assess the feasibility of boosting the dose to the residual gross tumor volume (GTV-Tres) to 140% of the high-risk clinical target volume (HR-CTV) prescription. METHODS AND MATERIALS: Brachytherapy plans from 50 consecutive patients were analyzed in this study. All received external beam radiotherapy followed by brachytherapy (6 Gy * 4 fraction or 7 Gy * 4 fraction to HR-CTV). The original treatment plans were reoptimized escalating the GTV-Tres dose 140% of the original HR-CTV prescription dose to 8.4 Gy and 9.8 Gy/ per fraction, respectively, with the aim of achieving GTV-TresV140 >= 90% and D98 >= 100 Gy. The HR-CTV coverage and organ at risk (OAR) dose-volume histogram values were kept within the tolerance, which had been accepted for the original clinical plans. RESULTS: A total of 24 patients (48%) achieved the planning goal after reoptimization. There was no significant difference between the D2cc of the OARs of the clinical plan and the study boost plan. The factors having greatest impact on the delivered dose to the GTV-Tres are proximity of the OAR, intrauterine positioned outside the GTV-Tres, and suboptimal interstitial placement for boosting GTV-Tres. CONCLUSIONS: It is possible to boost the prescription dose to the GTV-Tres achieving 140% increase, which equates to an EQD2alpha/beta=10 > 100 Gy. Plans without both interstitial catheters and/or intrauterine within the GTV-Tres are most likely to be suboptimal. This planning study demonstrates that dose escalation to the GTV-Tres is feasible and further work into clinical application should be considered. PMID- 29153468 TI - Child sexual abuse and rectoanal endosonography: Ethical issues. PMID- 29153467 TI - Ovarian torsion in pediatric and adolescent patients: A systematic review. AB - OBJECTIVE: Ovarian torsion in pediatric patients is a rare event and is primarily managed by pediatric general surgeons. Torsion can be treated with detorsion of the ovary or oopherectomy. Oopherectomy is the most common procedure performed by pediatric general surgeons for ovarian torsion. The purpose of this systematic review by the American Pediatric Surgical Association Outcomes and Evidence Based Practice Committee was to examine evidence from the medical literature and provide recommendations regarding the optimal treatment of ovarian torsion. METHODS: Using PRISMA guidelines, six questions were addressed by searching Medline, Cochrane, Embase Central and National clearing house databases using relevant search terms. Risks of ovarian detorsion including thromboembolism and malignancy, indications for oophoropexy, benefits of detorsion including recovery of function and subsequent fertility, and recommended surveillance after detorsion were evaluated. Consensus recommendations were derived for each question based on the best available evidence. RESULTS: Ninety-six studies were included. Risks of ovarian detorsion such as thromboembolism and malignancy were reviewed, demonstrating minimal evidence for unknowingly leaving a malignancy behind in the salvaged ovary and no evidence in the literature of thromboembolic events after detorsion of a torsed ovary. There is no clear evidence supporting the benefit of oophoropexy after a single episode of ovarian torsion. The gross appearance of the ovary does not correlate with long-term ovarian viability or function. Pregnancies have occurred in patients after detorsion of an ovary both spontaneously and with harvested oocytes from previously torsed ovaries. The consensus recommendation for imaging surveillance following ovarian detorsion is an ultrasound at 3months postprocedure but sooner if there is a concern for malignancy. CONCLUSION: There appears to be overwhelming evidence supporting ovarian detorsion rather than oopherectomy for the management of ovarian torsion in pediatric patients. Ovarian salvage is safe and is the preferred treatment for ovarian torsion. Most salvaged ovaries will maintain viability after detorsion. TYPE OF STUDY: Systematic review of level 3-4 studies. LEVEL OF EVIDENCE: 3-4. PMID- 29153469 TI - Postoperative urinary retention or difficulties to empty the bladder in young patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis. AB - BACKGROUND: Postoperative urinary retention has been reported to affect up to 27% of adults undergoing degenerative lumbar spine surgery and approximately one third of children undergoing lower-extremity orthopedic surgery. No data exist on the incidence and risk factors of postoperative urinary tract retention/difficulties to empty the bladder in young patients undergoing instrumented posterior spinal fusion. We aimed to characterize incidence, risk factors and treatment of postoperative urinary retention (POUR) and difficulties to empty the bladder in young patients undergoing posterior spinal fusion (PSF) for idiopathic scoliosis. METHODS: One hundred and eleven consecutive patients (mean age 16years [range, 11-21years], 81 females and 30 males) undergoing PSF for adolescent idiopathic scoliosis were screened after removal of urinary catheter postoperatively for inability to void and residual volume of urinary bladder. The latter was measured using ultrasound on two separate occasions. POUR and the need for intermittent catheterization were defined as an inability to void after catheter removal and documented full bladder with ultrasound (a residual of 300mL or more) or a significant residual volume after voiding (>2mL/kg or >100mL). RESULTS: Fifty-one (46%) of the patients were either unable to void or had a clinically significant amount of residual volume after voiding. These fifty-one patients required intermittent catheterization for a mean of two days. Thirty patients (27%) had POUR, a residual volume of 300mL or more. Two (1.8%) patients experienced urinary tract infection postoperatively. Patients with urinary retention had a significantly higher mean intraoperative blood loss (mean 626mL vs. 464mL; p=0.020) and longer operation time (mean 3.3h vs. 2.8h; p=0.009) as compared with those not having urinary retention. In multivariate analyses the main risk factor for urinary retention was male gender (odds ratio 3.2 [95% confidence interval 1.1-9.2], p=0.028). CONCLUSIONS: Postoperative voiding difficulties affect almost half of the patients with age under 21years undergoing PSF for idiopathic scoliosis. The main risk factors were increased intraoperative blood loss, longer length of surgery and male gender. POUR should be actively screened and treated in this patient population. LEVEL OF EVIDENCE: Prospective Cohort Study II. PMID- 29153470 TI - Impact of a pharmacist-driven care package on Staphylococcus aureus bacteremia management in a large community healthcare network: A propensity score-matched, quasi-experimental study. AB - OBJECTIVES: Staphylococcus aureus bacteremia (SAB) is an important cause of morbidity and mortality. Suboptimal treatment has been associated with poor patient outcomes. Our antimicrobial stewardship program (ASP) evaluated SAB management based on predefined performance measures both prior to and after instituting a "care package" intervention led by clinical pharmacists and infectious diseases physicians. The primary outcome included a 4-point "optimal care score" (OCS) consisting of targeted antibiotic therapy within 24hours, repeating blood cultures, antibiotic duration assessment, and appropriate duration of therapy. The presence of an ID consult, SAB readmission and mortality were also assessed. METHODS: This was a quasi-experimental, propensity score matched study of SAB management. Adult patients were retrospectively evaluated from October 2011 - October 2012, and intervention took place from November 2013 December 2015. Intervention consisted of a clinical pharmacist contacting the primary team after identification of SAB to recommend (1) appropriate antibiotics within 24hours, (2) repeat blood cultures to document clearance, (3) assessment for metastatic infection, (4) and appropriate duration of therapy. These constituted the 4-point OCS. ID consult was also recommended. Patients were propensity score matched 1:2 based on age, diabetes, presence of hardware, methicillin-resistant S. aureus (MRSA) isolate, and stratified infectious source. Patients >=18 with SAB were included. RESULTS: Intervention was associated with improved adherence to each metric within the OCS, and more patients in the intervention cohort achieved a perfect OCS of 4. Intervention was associated with a lower rate of readmission and mortality. CONCLUSION: A pharmacist-driven, ASP intervention on SAB therapy was associated with increased adherence to core SAB care metrics and reduced relapse and mortality. PMID- 29153471 TI - Comparison of built environment adaptations to heat exposure and mortality during hot weather, West Midlands region, UK. AB - There is growing recognition of the need to improve protection against the adverse health effects of hot weather in the context of climate change. We quantify the impact of the Urban Heat Island (UHI) and selected adaptation measures made to dwellings on temperature exposure and mortality in the West Midlands region of the UK. We used 1) building physics models to assess indoor temperatures, initially in the existing housing stock and then following adaptation measures (energy efficiency building fabric upgrades and/or window shutters), of representative dwelling archetypes using data from the English Housing Survey (EHS), and 2) modelled UHI effect on outdoor temperatures. The ages of residents were combined with evidence on the heat-mortality relationship to estimate mortality risk and to quantify population-level changes in risk following adaptations to reduce summertime heat exposure. Results indicate that the UHI effect accounts for an estimated 21% of mortality. External shutters may reduce heat-related mortality by 30-60% depending on weather conditions, while shutters in conjunction with energy-efficient retrofitting may reduce risk by up to 52%. The use of shutters appears to be one of the most effective measures providing protection against heat-related mortality during periods of high summer temperatures, although their effectiveness may be limited under extreme temperatures. Energy efficiency adaptations to the dwellings and measures to increase green space in the urban environment to combat the UHI effect appear to be less beneficial for reducing heat-related mortality. PMID- 29153473 TI - Sensitivity of the early life stages of a mayfly to fine sediment and orthophosphate levels. AB - The ecological effects of interacting stressors within lotic ecosystems have been widely acknowledged. In particular, the ecological effects of elevated fine sediment inputs and phosphate have been identified as key factors influencing faunal community structure and composition. However, while knowledge regarding adult and larval life stage responses to environmental stressors has grown, there has been very limited research on their eggs. In this study, the eggs of the mayfly Serratella ignita (Ephemerellidae: Ephemeroptera) were collected and incubated in laboratory aquaria to hatching under differing concentrations of inert suspended sediment (SS) and orthophosphate (OP), individually and in combination. Results indicate that SS and OP have greater effects on egg hatching in combination than when either were considered in isolation. SS displayed a greater effect on egg survival than OP in isolation or when OP was added to elevated SS treatments. Egg mortality in control treatments was around 6% compared to 45% in treatments with 25 mg l-1 SS and 52% in 0.3 mg l-1 OP treatments. Even relatively modest levels of each stressor (10 mg l-1 SS; 0.1 mg l-1 OP), below national legal thresholds, had significant effects on egg survival to hatching. The results support calls for legal levels of SS to be reassessed and suggest that more research is required to assess the impacts of pollution on invertebrate egg development given their different sensitivity and exposure pathways compared to other life stages. PMID- 29153472 TI - Inorganic sulfur and mercury speciation in the water level fluctuation zone of the Three Gorges Reservoir, China: The role of inorganic reduced sulfur on mercury methylation. AB - The water level fluctuation zone (WLFZ) of the Three Gorges Reservoir (TGR) in China is a unique geomorphological unit that undergoes annual flooding and drying alternation cycle. The alternating redox conditions within the WLFZ are expected to result in dynamic cycling of reduced sulfur species, which could affect mercury (Hg) methylation due to the high affinity of reduced sulfur species to both inorganic divalent mercury (Hg(II)i) and methylmercury (MeHg). Variations of inorganic sulfur species (measured as acid volatile sulfide, chromium reductive sulfur, elemental sulfur, and water-soluble sulfate), total mercury (THg) and MeHg were studied at two typical WLFZ sites in the TGR from July 2015 to June 2016. Whereas the water-soluble sulfate contents stayed essentially constant, the reduced inorganic sulfur contents varied greatly as the water level changed. Compared with the control soils, the MeHg contents in the WLFZ soils increased, suggesting that water level fluctuations accelerated the methylation process of Hg(II)i. In situ Hg(II)i-methylation also appeared to occur in the sub-layer of the drained sediment during the draw-down season. The significant correlation between MeHg and elemental sulfur (S(0)) further suggests that polysulfides may have played a role in Hg(II)i-methylation by increasing the bioavailable Hg(II)i content in the WLFZ of the TGR. PMID- 29153474 TI - Impacts of environmental factors on the whole microbial communities in the rhizosphere of a metal-tolerant plant: Elsholtzia haichowensis Sun. AB - Rhizospheric microbes play important roles in plant growth and heavy metals (HMs) transformation, possessing great potential for the successful phytoremediation of environmental pollutants. In the present study, the rhizosphere of Elsholtzia haichowensis Sun was comprehensively studied to uncover the influence of environmental factors (EFs) on the whole microbial communities including bacteria, fungi and archaea, via quantitative polymerase chain reaction (qPCR) and high-throughput sequencing. By analyzing molecular ecological network and multivariate regression trees (MRT), we evaluated the distinct impacts of 37 EFs on soil microbial community. Of them, soil pH, HMs, soil texture and nitrogen were identified as the most influencing factors, and their roles varied across different domains. Soil pH was the main environmental variable on archaeal and bacterial community but not fungi, explaining 25.7%, 46.5% and 40.7% variation of bacterial taxonomic composition, archaeal taxonomic composition and a-diversity, respectively. HMs showed important roles in driving the whole microbial community and explained the major variation in different domains. Nitrogen (NH4-N, NO3-N, NO2-N and TN) explained 47.3% variation of microbial population composition and 15.9% of archaeal taxonomic composition, demonstrating its influence in structuring the rhizospheric microbiome, particularly archaeal and bacterial community. Soil texture accounted for 10.2% variation of population composition, 28.9% of fungal taxonomic composition, 19.2% of fungal a-diversity and 7.8% of archaeal a-diversity. Rhizosphere only showed strong impacts on fungi and bacteria, accounting for 14.7% and 4.9% variation of fungal taxonomic composition and bacterial a-diversity. Spatial distance had stronger influence on bacteria and archaea than fungi, but not as significant as other EFs. For the first time, our study provides a complete insight into key influential EFs on rhizospheric microbes and how their roles vary across microbial domains, giving a hand for understanding the construction of microbial communities in rhizosphere. PMID- 29153475 TI - Toxicity-associated changes in the invasive cyanobacterium Cylindrospermopsis raciborskii in response to nitrogen fluctuations. AB - The cyanobacterium Cylindrospermopsis raciborskii is of particular concern due to its ability to fix nitrogen (N), sporadic bloom, potential toxicity and apparent invasiveness. However, the toxicity associated behavior and response of toxic C. raciborskii under N fluctuations in water have been poorly investigated. The present study initiated based on the field survey in which Cylindrospermopsis species was found to have a high fitness under nitrate concentrations fluctuating from 0.02 mg L-1 to 2.90 mg L-1 in Chinese freshwater lakes. Examination on the role of short-term N fluctuations was conducted in two C. raciborskii strains which were exposed to a range of N concentrations supplied in two patterns, namely one-time pattern and ten-time pattern in which the equal amount of N was divided into ten-time accretions. The results showed the growth of both strains were not vulnerable to the transient nutrient fluctuations. The toxic strain showed considerable toxicological flexibility with the highest yield of cylindrospermopsin (CYN) obtained in the absence of N and the lowest in full medium. Generally, larger amounts of total CYN were observed at lower N levels, indicating that N deficiency promoted the intracellular accumulation and simultaneously restrained the extracellular release of CYN. Furthermore, CYN production was significantly different in two N supply patterns. The maximum quotas of intracellular and extracellular CYN in one-time pattern were respectively 2.79-3.53 and 3.94-7.20 times higher compared to the ten-time pattern. To our knowledge, our results are the first evidence of toxicity variations of C. raciborskii to the impermanent N fluctuations, shedding new light on its toxicological plasticity. PMID- 29153476 TI - Attitudes Toward Smoke-Free Public Housing Among U.S. Adults, 2016. AB - INTRODUCTION: Effective February 2017, the U.S. Department of Housing and Urban Development published a rule requiring each public housing agency to implement a smoke-free policy within 18 months. This study assessed the prevalence and determinants of favorability toward smoke-free public housing among U.S. adults. METHODS: Data from 2016 Summer Styles, a nationally representative web-based survey conducted among adults (N=4,203) were analyzed in 2017. Participants were asked: Do you favor or oppose prohibiting smoking in public housing, including all indoor areas of living units, common areas, and office buildings, as well as in all outdoor areas within 25 feet of buildings? Multivariate Poisson regression was used to calculate adjusted prevalence ratios of favorability (strongly or somewhat). RESULTS: Overall, 73.7% of respondents favored smoke-free public housing. Favorability was 44.3% among current cigarette smokers, 73.2% among former smokers, and 80.4% among never smokers. The adjusted likelihood of favorability was greater among non-Hispanic, non-black racial/ethnic minorities than whites, and among those in the West than the Northeast (p<0.05). Favorability was lower among adults with a high school education or less compared with those with a college degree, adults with annual household income <$15,000 than those with income >=$60,000, multiunit housing residents than non-multiunit housing residents, current cigarette smokers than never smokers, and current non cigarette tobacco product users than never users (p<0.05). CONCLUSIONS: Most U.S. adults favor prohibiting smoking in public housing. These data can inform the implementation and sustainment of smoke-free policies to reduce the public health burden of tobacco smoking in public housing. PMID- 29153477 TI - Biomechanical adaptations during running differ based on type of exercise and fitness level. AB - Lower extremity injuries are most common in more active and fit individuals, suggesting that adaptations from neuromuscular fatigue may differ depending on type of exercise and fitness level. The purpose of this study was to compare changes in gait in highly fit and recreationally active individuals before and after two exercise protocols. Lower extremity kinematics and kinetics were measured on the dominant leg during running before and after two exercise protocols (walking/sport) from 0 to 100% of gait in 24 healthy individuals divided into higher (n=13) and lower fitness (n=11) groups. Change scores were calculated for each point of the gait cycle with 95% confidence intervals. There were no differences between groups in knee or hip kinematics and kinetics in response to the walking exercise protocol, however the higher fit group increased trunk extension and the lower fit group increased trunk lateral flexion after walking exercise. After the sport exercise, the higher fit group increased knee extension, knee valgus, trunk extension, knee flexion moment, knee varus moment, knee abduction moment, knee internal rotation moment, and hip flexion moment compared to the lower fit group. The lower fit group increased hip extension, hip abduction, hip internal rotation, trunk lateral flexion, trunk rotation, and knee external rotation moment compared the higher fit group after sport exercise. Greater between group differences were found with sport exercise compared to walking exercise. It is important to consider type of exercise and fitness level when assessing altered movement patterns in response to fatiguing exercise. PMID- 29153478 TI - Reliability of upper limb and trunk joint angles in healthy adults during activities of daily living. AB - Assessments of upper limb performance should require participants to perform tasks that challenge the limits of their ability. In order to select appropriate tasks, it is important to know which joints are used to perform the movement and how reliably those movements can be measured. The purpose of this work was to quantify the reliability of upper limb and trunk joint angles in healthy adults during common activities of daily living (ADLs). Nineteen participants performed six ADLs with the right arm (applying deodorant, turning a doorknob, answering a desk telephone, placing a pushpin in a bulletin board, wiping a plate with a towel, and pouring water from a pitcher) during two separate sessions. Within- and between-session reliability was quantified using intraclass correlation coefficients (ICCs) and minimum detectable change values (MDCs). Reliability was generally better within-session than between-session. The ICCs exceeded 0.75 for 88% of the joint angles and exceeded 0.90 for 32% of the angles. All MDCs were less than 25 degrees and 61% were also less than 10 degrees . The MDCs represented a larger percent of the average angles for the trunk (61%) and wrist (62%) compared to the shoulder (18%) and elbow (26%). Although these results show that most angles can be measured reliably for these six ADLs, reliability varied considerably between joints. It is therefore important to select tasks for assessing of upper limb performance based on which specific joints need to be evaluated. PMID- 29153479 TI - Author response to the letter "The association of bradykinesia and balance control in patients with Alzheimer's disease?" PMID- 29153480 TI - Spatial orientation and postural control in patients with Parkinson's disease. AB - Postural instability is one of the most disabling and risky symptoms of advanced Parkinson's disease (PD). The purpose of this study was to investigate whether and how this is mediated by a centrally impaired spatial orientation. Therefore, we performed a spatial orientation study in 21 PD patients (mean age 68years, SD 8.5 years, 9 women) in a medically on condition and 21 healthy controls (mean age 68.9years, SD 5.5years, 14 women). We compared their spatial responses to the horizontal axis (Sakashita's visual target cancellation task), the vertical axis (bucket-test), the sagittal axis (tilt table test) and postural stability using the Fullerton Advanced Balance Scale (FAB). We found larger deviations on the vertical axis in PD patients, although the direct comparisons of performance in PD patients and healthy controls did not reveal significant differences. While the total scores of the FAB Scale were significantly worse in PD (25.9 points, SD 7.2 points) compared to controls (35.1 points, SD 2.3 points, p<0.01), the results from the spatialorientation task did not correlate with the FAB Scale. In summary, our results argue against a relation between perceptional deficits of spatial information and postural control in PD. These results are in favor of a deficit in higher order integration of spatial stimuli in PD that might influence balance control. PMID- 29153481 TI - What is the error margin of your signature analysis? AB - In our experience, it seems to become more and more common for mandating authorities or parties to ask forensic signature examiners to quantify the degree of certainty of their conclusion regarding a signature analysis. This paper reports the likelihood ratio approach followed by examiners to answer such a question, in a case where the Court asked whether a questioned signature was written, or not, by Mr Jones. The Court also required an assessment of the error margin of the signature analysis. This question was answered using Bayes' theorem (i.e., a full Bayesian approach) and this paper seeks to show that such an approach can be used despite the popular belief that Bayes' theorem is beyond what courts may accept. Using a practical example, we present advantages of the approach we have chosen to assess our results and show that a logical approach for evidence evaluation can be followed even in a forensic discipline where no tabulated data are available. This example also illustrates a practical way of addressing the error margin question, which helps the Court understand what can be the risk of being wrong in this particular case (and not in cases in general). We further present the way these results were communicated to the fact finders in the case at hand and provide guidance as how forensic observations can logically be combined with the other elements of the case. PMID- 29153482 TI - Level of magnesium in psychiatry - What is the cause of ambiguous results? PMID- 29153483 TI - Crosstalks between translation and metabolism in cancer. AB - Albeit cancer patients' heterogeneity, all tumor cells have alterations of both metabolism and translation. The simplest explanation for this common feature is that several oncogenes coordinate a translational and metabolic reprogramming that is necessary for tumor cells to thrive. Overall, at least three oncogenic pathways, namely c-Myc, RAS and PI3K-mTOR, are known to affect both translation and metabolism by stimulating glycolysis and protein synthesis. The crosstalk between metabolite production and the translational machinery is, instead, less understood. What is known is that, on one side, translation initiation factors, such as eIF4E and eIF6, drive tumor growth and regulate metabolism through selective translation of nucleotide biosynthesis, glycolysis and fatty acid synthesis rate-limiting mRNAs, and on the other, that nutrient levels regulate the translational machinery by inducing full activity of translation factors. Therefore, translation and metabolism offer several therapeutic targets to be fully exploited in future studies. PMID- 29153484 TI - Translation initiation factors and their relevance in cancer. AB - Deregulation of several translation initiation factors occurs in numerous types of cancers. Translation initiation factors are not merely ancillary players in cancer development and progression, but rather, they are key participants in cellular transformation and tumor development. In fact, the altered expression of translation initiation factors is involved in cancer cell survival, metastasis and tumor angiogenesis. Although the exact mechanisms remain to be fully characterized, translation initiation factors comprise novel targets for pharmacologic intervention. Here we review the most recently established roles of initiation factors in cancer development and progression, as well as unique methods used to study translational regulation. PMID- 29153486 TI - Glucose variability: Do we have to revisit the profusion of definitions to avoid confusion? PMID- 29153485 TI - Morning administration of 0.4U/kg/day insulin glargine 300U/mL provides less fluctuating 24-hour pharmacodynamics and more even pharmacokinetic profiles compared with insulin degludec 100U/mL in type 1 diabetes. AB - AIM: To compare steady state pharmacodynamic and pharmacokinetic profiles of insulin glargine 300U/mL (Gla-300) with insulin degludec 100U/mL (Deg-100) in people with type 1 diabetes. METHODS: This single-centre, randomized, double blind crossover euglycaemic clamp study included two parallel cohorts with fixed once-daily morning dose regimens. For both insulins participants received 0.4 (n=24) or 0.6U/kg/day (n=24), before breakfast, for 8 days prior to the clamp. The main endpoint was within-day variability (fluctuation) of the smoothed glucose infusion rate (GIR) over 24 hours (GIR-smFL0-24). RESULTS: Gla-300 provided 20% less fluctuation of steady state glucose infusion rate profiles than Deg-100 over 24 hours at 0.4U/kg/day (GIR-smFL0-24 treatment ratio 0.80 [90% confidence interval: 0.66 to 0.96], P=0.047), while at the dose of 0.6U/kg/day the difference between insulins was not statistically significant (treatment ratio 0.96 [0.83 to 1.11], P=0.603). Serum insulin concentrations appeared more evenly distributed with both dose levels of Gla-300 versus the same doses of Deg 100, as assessed by relative 6-hour fractions of the area under the curve within 24 hours. Both insulins provided exposure and activity until 30 hours (end of clamp). CONCLUSION: Gla-300 provides less fluctuating steady state pharmacodynamic profiles (i.e. lower within-day variability) and more evenly distributed pharmacokinetic profiles, compared with Deg-100 in a once-daily morning dosing regimen of 0.4U/kg/day. PMID- 29153487 TI - Endothelial Cell Metabolism in Health and Disease. AB - The metabolism of endothelial cells (ECs) has only recently been recognized as a driving force of angiogenesis. Metabolic pathways, such as glycolysis, fatty acid oxidation, and glutamine metabolism, have distinct, essential roles during vessel formation. Moreover, EC metabolism is markedly perturbed in pathologies such as cancer and diabetes. For instance, because tumor ECs increase glycolysis, lowering hyperglycolysis in tumor ECs induces therapeutic benefits in preclinical tumor models. Expanding our knowledge of how ECs alter their metabolism in disease could pave the way for novel therapeutic opportunities. In this review, we discuss the most recent insights into EC metabolism in health and disease, with emphasis on the changes in metabolism in the tumor endothelium. PMID- 29153488 TI - Authors' answers on comment of Abellona et al. on Metabolomic analysis for noninvasive diagnosis of hepatic fibrosis degree in patients with chronic hepatitis C. PMID- 29153489 TI - Endoscopic resection of an esophageal schwannoma. PMID- 29153490 TI - Comments on Gabbani, et al. Metabolomic analysis with 1H NMR for non-invasive diagnosis of hepatic fibrosis degree in patients with chronic hepatitis C. PMID- 29153492 TI - Immigrants commit crime and violence at lower rates than the US-born Americans. PMID- 29153491 TI - Measures of human immunodeficiency virus (HIV) community viral load and HIV incidence among people who inject drugs. AB - PURPOSE: To evaluate the measures of community human immunodeficiency virus (HIV) viral load (VL) and the association with HIV incidence among people who inject drugs (PWID). METHODS: Data were from 1986 to 1999 Urban Health Study conducted among PWID in the San Francisco Bay Area. Extant measures of community VL use mean VL among HIV + study participants, not accounting for the proportion of HIV- individuals. We compared the strength of the associations between HIV incidence and the traditionally measured mean community VL and a new prevalence-adjusted community VL, calculated by dividing the sum of VL among HIV + participants by the total participants irrespective of HIV status. RESULTS: Mean community VL was not correlated with HIV incidence in this sample of PWID (rs = 0.32, P = .28). However, prevalence-adjusted community VL was strongly correlated with HIV incidence (rs = 0.69, P = .009). Nested complimentary log-log linear models indicated that increases in community VL and prevalence-adjusted community VL were both associated with HIV incidence, but prevalence-adjusted community VL was a more sensitive measure (hazard ratio = 1.28, P = .038 and hazard ratio = 3.29, P < .001, respectively). CONCLUSIONS: The effect of community VL on HIV incidence may be stronger than previously reported. Future studies of community VL surveillance should consider accounting for the prevalence of HIV using a prevalence-adjusted community VL measure. PMID- 29153493 TI - The university hospital: Criteria for its accreditation. PMID- 29153494 TI - Increase in hand hygiene practices secondary to training through an online course to health personnel at a second level care hospital. PMID- 29153495 TI - Percutaneous Interventional Repair of an Intraoperative Right Coronary Artery Tear. PMID- 29153496 TI - Hemodynamic Threshold for Wound Healing in Critical Limb Ischemia. PMID- 29153497 TI - Is the Intracoronary Electrocardiogram Lesion Specific? PMID- 29153499 TI - Assessment of Serial Coronary Stenoses With Noninvasive Computed Tomography Derived Fractional Flow Reserve and Treatment Planning Using a Novel Virtual Stenting Application. PMID- 29153498 TI - Hemodynamic Assessment Before and After Endovascular Therapy for Critical Limb Ischemia and Association With Clinical Outcomes. AB - OBJECTIVES: This study sought to determine the relationship between change in ankle-brachial index (ABI) and toe-brachial index (TBI) and outcomes following revascularization of critical limb ischemia (CLI). BACKGROUND: An increase in ABI of 0.15 after revascularization for peripheral artery disease with claudication is considered significant. However, the utility of using change in ABI or TBI to predict outcomes in patients with CLI is unproven. METHODS: This was an observational study of 218 patients with Rutherford class V or VI CLI that underwent endovascular therapy. Receiver-operating characteristic curve analysis determined cutpoints in post-procedure ABI and TBI, as well as change in these values for endpoints of wound healing, major adverse limb events (MALE), and repeat revascularization. RESULTS: After multivariable Cox proportional hazards analysis adjusting for age, diabetes, glomerular filtration rate, smoking, Rutherford class, and baseline ABI or TBI, neither static post-procedure ABI nor post-procedure TBI were associated with wound healing (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.77 to 1.89; p = 0.40; HR: 1.49; 95% CI: 0.98 to 2.27; p = 0.065, respectively). However, change in ABI >=0.23 was independently associated with wound healing (HR: 1.87; 95% CI: 1.12 to 3.15; p = 0.018) and less repeat revascularization (HR: 0.40; 95% CI: 0.19 to 0.84; p = 0.015), but not MALE. Increase in TBI >=0.21 was independently associated with wound healing (HR: 1.63; 95% CI: 1.02 to 2.59; p = 0.039), and reduced MALE (HR: 0.27; 95% CI: 0.09 to 0.77; p = 0.014), but not repeat revascularization. CONCLUSIONS: A change in ABI and TBI from pre-procedural values provides prognostic value in determining which patients may have wound healing and reduced MALE. PMID- 29153500 TI - Intravascular Imaging, Stent Implantation, and the Elephant in the Room. PMID- 29153501 TI - Percutaneous Closure of a Left Ventricular Pseudoaneurysm Causing Recurrent Embolization, With Cerebral Protection and Extracorporeal Membrane Oxygenation Support. PMID- 29153502 TI - Clinical Outcomes Following Intravascular Imaging-Guided Versus Coronary Angiography-Guided Percutaneous Coronary Intervention With Stent Implantation: A Systematic Review and Bayesian Network Meta-Analysis of 31 Studies and 17,882 Patients. AB - OBJECTIVES: The authors sought to explore the comparative clinical efficacy of different imaging modalities for guiding percutaneous coronary interventions (PCI). BACKGROUND: Coronary angiography (CA) is the standard imaging modality for intraprocedural guidance of PCI. Intracoronary imaging techniques, including intravascular ultrasound (IVUS) and optical coherence tomography (OCT), can overcome some limitations of CA. METHODS: Comprehensive hierarchical Bayesian network meta-analysis of randomized clinical trials and adjusted observational studies comparing clinical outcomes of PCI with stent implantation guided by CA, IVUS, or OCT. RESULTS: A total of 31 studies encompassing 17,882 patients were included. Compared with CA guidance, the risks of all-cause death (odds ratio [OR]: 0.74; 95% credible interval [CrI]: 0.58 to 0.98), myocardial infarction (OR: 0.72; 95% CrI: 0.52 to 0.93), target lesion revascularization (OR: 0.74, 95% CrI: 0.58 to 0.90) and stent thrombosis (OR: 0.42; 95% CrI: 0.20 to 0.72) were significantly reduced by IVUS guidance. PCI guidance using either IVUS or OCT was associated with a significant reduction of major adverse cardiovascular events (OR: 0.79; 95% CrI: 0.67 to 0.91 and OR: 0.68; 95% CrI: 0.49 to 0.97, respectively) and cardiovascular death (OR: 0.47; 95% CrI: 0.32 to 0.66 and OR: 0.31; 95% CrI: 0.13 to 0.66, respectively). No differences in terms of comparative clinical efficacy were found between IVUS and OCT for all the investigated outcomes. Pooled estimates were consistent across several sensitivity analyses. However, the treatment effect of IVUS on all-cause death was neutralized in the analysis restricted to randomized clinical trials (OR: 1.03; 95% CrI: 0.41 to 2.14). CONCLUSIONS: Compared with CA, the use of intravascular imaging techniques for PCI guidance reduces the risk of cardiovascular death and adverse events. PMID- 29153503 TI - Successful Removal of an Entrapped Rotational Atherectomy Burr Using a Soft Guide Extension Catheter. PMID- 29153504 TI - Pressure-Dependent Chemical Shifts in the R3 Domain of Talin Show that It Is Thermodynamically Poised for Binding to Either Vinculin or RIAM. AB - Talin mediates attachment of the cell to the extracellular matrix. It is targeted by the Rap1 effector RIAM to focal adhesion sites and subsequently undergoes force-induced conformational opening to recruit the actin-interacting protein vinculin. The conformational switch involves the talin R3 domain, which binds RIAM when closed and vinculin when open. Here, we apply pressure to R3 and measure 1H, 15N, and 13C chemical shift changes, which are fitted using a simple model, and indicate that R3 is only 50% closed: the closed form is a four-helix bundle, while in the open state helix 1 is twisted out. Strikingly, a mutant of R3 that binds RIAM with an affinity similar to wild-type but more weakly to vinculin is shown to be 0.84 kJ mol-1 more stable when closed. These results demonstrate that R3 is thermodynamically poised to bind either RIAM or vinculin, and thus constitutes a good mechanosensitive switch. PMID- 29153505 TI - Structural Basis for the Inhibitory Effects of Ubistatins in the Ubiquitin Proteasome Pathway. AB - The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed direct interactions with ubiquitin's hydrophobic surface patch and the basic/polar residues surrounding it. Ubistatin B binds ubiquitin and diubiquitin tighter than a high-affinity ubiquitin receptor and shows strong preference for K48 linkages over K11 and K63. Furthermore, ubistatin B shields ubiquitin conjugates from disassembly by a range of deubiquitinases and by the 26S proteasome. Finally, ubistatin B penetrates cancer cells and alters the cellular ubiquitin landscape. These findings highlight versatile properties of ubistatins and have implications for their future development and use in targeting ubiquitin signaling pathways. PMID- 29153506 TI - Role of Non-local Interactions between CDR Loops in Binding Affinity of MR78 Antibody to Marburg Virus Glycoprotein. AB - An atomic-detail model of the Marburg virus glycoprotein in complex with a neutralizing human monoclonal antibody designated MR78 was constructed using Phenix.Rosetta starting from a 3.6A crystallographic density map. The Asp at T6 in the HCDR3's bulged torso cannot form the canonical salt bridge as position T2 lacks an Arg or Lys residue. It instead engages in a hydrogen bond interaction with a Tyr contributed by the HCDR1 loop. This inter-CDR loop interaction stabilizes the bulged conformation needed for binding to the viral glycoprotein: a Tyr to Phe mutant displays a binding affinity reduced by a factor of at least 10. We found that 5% of a database of 465 million human antibody sequences has the same residues at T2 and T6 positions in HCDR3 and Tyr in HCDR1 that could potentially form this Asp-Tyr interaction, and that this interaction might contribute to a non-canonical bulged torso conformation. PMID- 29153507 TI - Structural Evidence for a Role of the Multi-functional Human Glycoprotein Afamin in Wnt Transport. AB - Afamin, a human plasma glycoprotein and putative transporter of hydrophobic molecules, has been shown to act as extracellular chaperone for poorly soluble, acylated Wnt proteins, forming a stable, soluble complex with functioning Wnt proteins. The 2.1-A crystal structure of glycosylated human afamin reveals an almost exclusively hydrophobic binding cleft capable of harboring large hydrophobic moieties. Lipid analysis confirms the presence of lipids, and density in the primary binding pocket of afamin was modeled as palmitoleic acid, presenting the native O-acylation on serine 209 in human Wnt3a. The modeled complex between the experimental afamin structure and a Wnt3a homology model based on the XWnt8-Fz8-CRD fragment complex crystal structure is compelling, with favorable interactions comparable with the crystal structure complex. Afamin readily accommodates the conserved palmitoylated serine 209 of Wnt3a, providing a structural basis how afamin solubilizes hydrophobic and poorly soluble Wnt proteins. PMID- 29153508 TI - Patient characteristics in variable left ventricular recovery from Takotsubo syndrome. AB - BACKGROUND: Takotsubo syndrome (TTS) is a heart failure syndrome which is usually reversible. Factors associated with degree of recovery of left ventricular systolic function in TTS are poorly understood. MATERIALS AND METHODS: We conducted a retrospective analysis of 90 TTS patients treated at our institution from 2006 to 2014. Patients were grouped based on recovery of left ventricular ejection fraction (LVEF) on follow-up transthoracic echocardiogram as left ventricular ejection fraction <50% (partial group) or preserved ejection fraction >=50% (full group). Patient baseline characteristics, comorbidities, biomarkers, electrocardiography, and echocardiogram were collected. We also compared adverse events that occurred during hospitalization. RESULTS: In comparison to full recovery group patients (n=63), partial recovery patients (n=27) were older (76.9+/-13 vs. 70.6+/-13years; P=0.02) and had a higher prevalence of comorbid hypothyroidism (26% vs. 8%; P=0.02). A greater number of patients from the partial group were also taking levothyroxine replacement (22% vs. 3%; P=0.003). We found no significant between-group differences in type of triggering event or cardiac biomarker levels. QT interval was longer in the partial group (540.6+/ 71msec vs. 460.7+/-35msec; P=0.01). Follow-up LVEF was 37.9+/-8% in the partial group and 58.0+/-4% in the full group (P<0.001). There were no statistically significant differences in length of stay or adverse events. CONCLUSION: Takotsubo patients with partial myocardial recovery were older, presented with longer QT intervals, and were more likely to have comorbid hypothyroidism. PMID- 29153509 TI - Transcatheter embolization of a giant coronary artery pseudoaneurysm. AB - A 53-year-old diabetic male with sternal dehiscence presented with recurrent staphylococcus bacteremia 2years after coronary artery bypass grafting (CABG). He was found to have a giant right coronary artery (RCA) pseudoaneurysm and a coronary cameral fistula on imaging. Due to excessive surgical risk, the patient underwent percutaneous treatment with a 5mm Amplatzer vascular plug 4 (St. Jude Medical, St.Paul, MN). Post-procedure imaging showed successful cessation of flow into the pseudoaneurysm and follow-up CT scan demonstrated significant improvement in the size of the pseudoaneurysm. PMID- 29153510 TI - Resumption of antiplatelet therapy in patients with primary intracranial hemorrhage-benefits and risks: A meta-analysis of cohort studies. AB - BACKGROUND: Clinical disagreement over antiplatelet (AP) resumption in patients with primary intracranial hemorrhage (ICH) has long existed. This meta-analysis aimed to evaluate the benefits of AP resumption on preventing ischemic or thromboembolic events against its risks of promoting ICH recurrence or hematoma expansion. METHODS: All relevant articles published in Pubmed, EMBASE, the Cochrane Library, and Science Direct from January 1950 to March 2017 were sourced, and the combined relative risk (RR) was calculated. RESULTS: A total of 3648 articles were found, and after screening, 6 cohort studies including 1916 patients were included in this meta-analysis. AP resumption was associated with a decreased risk of ischemic or thromboembolic events (RR, 0.61; 95% confidence interval (CI), 0.48-0.79; P<0.01). There was no significant difference in the risk of ICH recurrence or hematoma expansion between patients with or without AP resumption (RR, 0.84; 95% CI, 0.47-1.51; P=0.56). CONCLUSION: AP resumption in patients with primary ICH reduced the risk of ischemic or thromboembolic events, without significant increase of risk of ICH recurrence or hematoma expansion. PMID- 29153512 TI - Dose- and type-dependent effects of long-chain fatty acids on adipogenesis and lipogenesis of bovine adipocytes. AB - Differentiation and lipid metabolism of adipocytes have a great influence on milk performance, health, and feed efficiency of dairy cows. The effects of dietary long-chain fatty acids (FA) on adipogenesis and lipogenesis of dairy cows are often confounded by other nutritional and physiological factors in vivo. Therefore, this study used an in vitro approach to study the effect of dose and type of long-chain FA on adipogenesis and lipogenesis of bovine adipocytes. Stromal vascular cells were isolated from adipose tissue of dairy cows and induced into mature adipocytes in the presence of various long-chain FA including myristic, palmitic, stearic, oleic, or linoleic acid. When concentrations of myristic, palmitic, and oleic acids in adipogenic mediums were 150 and 200 MUM, the induced mature adipocytes had greater lipid content compared with other concentrations of FA. In addition, mature adipocytes induced at 100 MUM stearic acid and 300 MUM linoleic acid had the greatest content of lipid than at other concentrations. High concentrations of saturated FA were more toxic for cells than the same concentration of unsaturated FA during the induction. When commitment stage was solely treated with FA, the number of differentiated mature adipocytes was greater for oleic and linoleic acids than other FA. When the maturation stage was treated with FA, the number of mature adipocytes was not affected, but the lipid content in adipocytes was affected and ranked oleic > linoleic > myristic > stearic > palmitic. In summary, this study showed that adipogenesis and lipogenesis of bovine adipocytes were differentially affected by long-chain FA, with unsaturated FA more effective than saturated FA. PMID- 29153513 TI - Biofilm formation of Staphylococcus aureus dairy isolates representing different genotypes. AB - The objective of this study was to compare the biofilm-forming capabilities of different genotypes of Staphylococcus aureus dairy isolates from Switzerland and northern Italy, including Staph. aureus genotype B (GTB) and methicillin resistant Staph.aureus (MRSA). We hypothesized that biofilm formation might be more pronounced in the contagious GTB isolates compared with other genotypes affecting individual animals. Twenty-four dairy isolates, including 9 MRSA, were further characterized by genotyping by using ribosomal spacer PCR, spa typing, biofilm formation under static and dynamic conditions, and scanning electron microscopy. The GTB isolates (n = 6) were more able to form biofilms than other genotypes at 37 degrees C and at 20 degrees C after 48 and 72 h of incubation in the static assay using polystyrene microtiter plates. This result was supported by scanning electron micrographs showing a GTB isolate producing strong biofilm with extracellular matrix in contrast to a genotype C isolate. Furthermore, none of the MRSA isolates formed strong biofilms in the static assay. However, some MRSA produced low or moderate amounts of biofilm depending on the applied conditions. Under dynamic conditions, a much more diverse situation was observed. The ability of GTB isolates to be strong biofilm formers was not observed in all cases, emphasizing the importance of growth conditions for the expression of biofilm-related genes. No specific genotype, spa type, or MRSA isolate could be categorized significantly into one level of biofilm formation. Nineteen percent of isolates behaved similarly under static and dynamic conditions. The results of this study expand our knowledge of different dairy-related Staph. aureus subtypes and indicate the benefit of genotyping when biofilms are studied. PMID- 29153511 TI - How Are Proteins Reduced in the Endoplasmic Reticulum? AB - The reversal of thiol oxidation in proteins within the endoplasmic reticulum (ER) is crucial for protein folding, degradation, chaperone function, and the ER stress response. Our understanding of this process is generally poor but progress has been made. Enzymes performing the initial reduction of client proteins, as well as the ultimate electron donor in the pathway, have been identified. Most recently, a role for the cytosol in ER protein reduction has been revealed. Nevertheless, how reducing equivalents are transferred from the cytosol to the ER lumen remains an open question. We review here why proteins are reduced in the ER, discuss recent data on catalysis of steps in the pathway, and consider the implications for redox homeostasis within the early secretory pathway. PMID- 29153514 TI - Determination of fat, protein, moisture, and salt content of Cheddar cheese using mid-infrared transmittance spectroscopy. AB - The objective of our work was to develop and evaluate the performance of a rapid method for measuring fat, protein, moisture, and salt content of Cheddar cheese using a combination mid-infrared (MIR) transmittance analysis and an in-line conductivity sensor in an MIR milk analyzer. Cheddar cheese was blended with a dissolving solution containing pentasodium triphosphate and disodium metasilicate to achieve a uniform, particle-free dispersion of cheese, which had a fat and protein content similar to milk and could be analyzed using a MIR transmittance milk analyzer. Annatto-colored Cheddar cheese samples (34) from one cheese factory were analyzed using reference chemistry methods for fat (Mojonnier ether extraction), crude protein (Kjeldahl), moisture (oven-drying total solids), and salt (Volhard silver nitrate titration). The same 34 cheese samples were also dissolved using the cheese dissolver solution, and then run through the MIR and used for calibration. The reference testing for fat and crude protein was done on the cheese after dispersion in the dissolver solution. Validation was done using a total of 36 annatto-colored Cheddar cheese samples from 4 cheese factories. The 36 validation cheese samples were also analyzed using near-infrared spectroscopy for fat, moisture, and the coulometric method for salt in each factory where they were produced. The validation cheeses were also tested using the same chemical reference methods that were used for analysis of the calibration samples. Standard error of prediction (SEP) values for moisture and fat on the near infrared spectroscopy were 0.30 and 0.45, respectively, whereas the MIR produced SEP values of 0.28 and 0.23 for moisture (mean 36.82%) and fat (mean 34.0%), respectively. The MIR also out-performed the coulometric method for salt determination with SEP values of 0.036 and 0.139 at a mean level of salt of 1.8%, respectively. The MIR had an SEP value of 0.19 for estimation at a mean level of 24.0% crude protein, which suggests that MIR could be an easy and effective way for cheese producers to measure protein to determine protein recovery in cheese making. PMID- 29153515 TI - Daily and seasonal trends of electricity and water use on pasture-based automatic milking dairy farms. AB - The objective of this study was to identify the major electricity and water consuming components of a pasture-based automatic milking (AM) system and to establish the daily and seasonal consumption trends. Electricity and water meters were installed on 7 seasonal calving pasture-based AM farms across Ireland. Electricity-consuming processes and equipment that were metered for consumption included milk cooling components, air compressors, AM unit(s), auxiliary water heaters, water pumps, lights, sockets, automatic manure scrapers, and so on. On farm direct water-consuming processes and equipment were metered and included AM unit(s), auxiliary water heaters, tubular coolers, wash-down water pumps, livestock drinking water supply, and miscellaneous water taps. Data were collected and analyzed for the 12-mo period of 2015. The average AM farm examined had 114 cows, milking with 1.85 robots, performing a total of 105 milkings/AM unit per day. Total electricity consumption and costs were 62.6 Wh/L of milk produced and 0.91 cents/L, respectively. Milking (vacuum and milk pumping, within AM unit water heating) had the largest electrical consumption at 33%, followed by air compressing (26%), milk cooling (18%), auxiliary water heating (8%), water pumping (4%), and other electricity-consuming processes (11%). Electricity costs followed a similar trend to that of consumption, with the milking process and water pumping accounting for the highest and lowest cost, respectively. The pattern of daily electricity consumption was similar across the lactation periods, with peak consumption occurring at 0100, 0800, and between 1300 and 1600 h. The trends in seasonal electricity consumption followed the seasonal milk production curve. Total water consumption was 3.7 L of water/L of milk produced. Water consumption associated with the dairy herd at the milking shed represented 42% of total water consumed on the farm. Daily water consumption trends indicated consumption to be lowest in the early morning period (0300-0600 h), followed by spikes in consumption between 1100 and 1400 h. Seasonal water trends followed the seasonal milk production curve, except for the month of May, when water consumption was reduced due to above-average rainfall. This study provides a useful insight into the consumption of electricity and water on a pasture-based AM farms, while also facilitating the development of future strategies and technologies likely to increase the sustainability of AM systems. PMID- 29153516 TI - Determination of lactadherin concentration in dairy by-products by ELISA: Effect of heat treatment and hydrolysis. AB - Lactadherin is a peripheral glycoprotein of the milk fat globule membrane with several attributed biological activities. In this study, we developed an indirect competitive ELISA to determine lactadherin concentration by using a rabbit polyclonal antiserum. The ELISA was applied to quantify lactadherin in several dairy by-products. Of the products tested, raw and commercial buttermilk had the highest concentrations of lactadherin (6.79 and 5.27 mg/g of product, respectively), followed by commercial butter serum (4.86 mg/g), commercial skim milk (4.84 mg/g), and raw whey (1.20 mg/g). The concentration of immunoreactive lactadherin was also determined in dairy by-products after they were subjected to different technological treatments. Thus, raw products were heat treated at combinations of temperature and time typically used in the dairy industry, and commercial products were hydrolyzed using 3 proteolytic enzyme preparations. Heat treatments of whey and buttermilk resulted in a smaller decrease in lactadherin concentration than did hydrolysis as determined by ELISA and electrophoresis. At high temperatures for long durations, the loss of lactadherin was higher in whey than in buttermilk, with the maximal reduction of around 48% found after treating whey at 72 degrees C for 60 min. Hydrolysis of commercial products with proteolytic enzymes resulted in a marked decrease of immunoreactivity within the first 5 min of treatment, which thereafter was constant throughout 4 h of hydrolysis. These results demonstrate that dairy by-products from milk fat processing are good natural sources of lactadherin, although technological processes have to be considered, because they have different effects on lactadherin content. PMID- 29153517 TI - Rapid species- and subspecies-specific level classification and identification of Lactobacillus casei group members using MALDI Biotyper combined with ClinProTools. AB - Using common taxonomic methods such as 16S rDNA sequencing and physiological and biochemical analysis to identify members of the Lactobacillus casei group (LCG) is time-consuming, expensive and inaccurate. In this study, we applied matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to rapid discriminate LCG strains by creating an analytical in-house database (IHDB) and to develop a classification model for subspecies-level differentiation based on MS biomarkers using ClinProTools bioinformatics software (Bruker Daltonics, Billerica, MA). Genotypic methods (housekeeping gene sequencing and species-specific PCR) were also established to validate the MALDI-TOF MS platform. A total of 48 LCG reference strains were correctly identified at the species level (mean score: 2.45 +/- 0.1) by using MALDI-TOF MS with an IHDB and had high score values, which was in accordance with results from mutL gene sequencing and specific PCR-based methods. However, one strain that was identified as L. casei had a relatively low score value (2.02 +/- 0.02), lower sequence similarities (mutL: 90.4%), and failed to amplify a species-specific amplicon; it may therefore represent an undescribed novel species. In addition, after implementation of the classification model (based on 2 biomarker peaks: m/z 4,930 and 5,303), L. paracasei strains could be clearly and easily differentiated to the subspecies level. Afterward, 7 LCG-related isolates from different probiotic samples were analyzed and accurately identified. Our data demonstrate the high-resolution performance of MALDI-TOF MS for fast and accurate demarcation of LCG strains when used with an IHDB coupled to ClinProTools; this methodology can serve as an alternative for quality control of probiotic products. PMID- 29153518 TI - Subacute ruminal acidosis affects fermentation and endotoxin concentration in the rumen and relative expression of the CD14/TLR4/MD2 genes involved in lipopolysaccharide systemic immune response in dairy cows. AB - The first objective of this study was to investigate the effects of subacute ruminal acidosis (SARA) on fermentation, ruminal free lipopolysaccharides (LPS), and expression of the cluster of differentiation 14 (CD14), toll-like receptor 4 (TLR4), and myeloid differentiation protein 2 (MD2) complex in white blood cells involved in the systemic immune response in dairy cows. The second objective was a study of whether increased expression of the LPS receptor complex led to increases in the concentrations of plasma high-density lipoprotein (HDL) and serum Ca. Three hundred five dairy cows located in 13 Polish high-yielding dairy commercial farms were selected according to their days in milk (40-150 d; average = 75), 305-d milk yield (10,070-12,041 kg; average = 10,940), and number of lactations (primiparous, n = 139 and multiparous, n = 166). Next, the herds were segregated into 3 groups based on the percentages of cows with an assigned value of ruminal fluid pH: SARA-positive, SARA-risk, and SARA-negative herds. Moreover, 305 selected dairy cows were divided according to the classification based on ruminal fluid pH into 3 groups as healthy (pH >5.81), risk (pH 5.8-5.6) and acidotic cows (pH <5.6). Rumen fluid samples were collected via rumenocentesis. In the AC group, we recorded higher concentrations of ruminal free LPS [4.57 Log10 endotoxin units (EU)/mL; 42,206 EU/mL] compared with the healthy group (4.48 Log10 EU/mL; 34,179 EU/mL). Similarly, the concentration of ruminal free LPS was higher in SARA-positive herds (4.60 Log10 EU/mL; 43,000 EU/mL) compared with SARA-negative herds (4.47 Log10 EU/mL; 32,225 EU/mL). The relative mRNA abundance of genes associated with the function of LPS receptors, such as CD14, TLR4, and MD2, in white blood cells differed between all experimental groups on both cow and herd levels. In the acidotic group, we recorded higher concentrations of HDL (78.16 vs. 68.32 mg/dL) and serum amyloid A (10.80 vs. 9.16 ug/mL) and lower concentrations of Ca (8.26 vs. 10.16 mg/dL) and haptoglobin (470.19 vs. 516.85 ng/mL) compared with the healthy group. Similar results were obtained in the SARA herd status analysis, but the concentration of lipopolysaccharide-binding protein differed statistically. Moreover, the pH of ruminal fluid was negatively correlated with relative mRNA abundance of genes such as CD14, TLR4, MD2, and concentrations of serum HDL and serum amyloid A, although positively correlated with serum Ca. The results indicated that decreases in ruminal fluid pH increased the release of free LPS into the rumen and stimulated the expression of the LPS receptor complex and immune response. Moreover, an increase in the expression of the LPS receptor led to higher concentrations of plasma HDL and lower serum Ca, which may be a protective mechanism against endotoxemia. However, the biological significance of these results needs to be investigated further in larger field trials. PMID- 29153519 TI - Invited review: Practical feeding management recommendations to mitigate the risk of subacute ruminal acidosis in dairy cattle. AB - Rumen health is of vital importance in ensuring healthy and efficient dairy cattle production. Current feeding programs for cattle recommend concentrate-rich diets to meet the high nutritional needs of cows during lactation and enhance cost-efficiency. These diets, however, can impair rumen health. The term "subacute ruminal acidosis" (SARA) is often used as a synonym for poor rumen health. In this review, we first describe the physiological demands of cattle for dietary physically effective fiber. We also provide background information on the importance of enhancing salivary secretions and short-chain fatty acid absorption across the stratified squamous epithelium of the rumen; thus, preventing the disruption of the ruminal acid-base balance, a process that paves the way for acidification of the rumen. On-farm evaluation of dietary fiber adequacy is challenging for both nutritionists and veterinarians; therefore, this review provides practical recommendations on how to evaluate the physical effectiveness of the diet based on differences in particle size distribution, fiber content, and the type of concentrate fed, both when the latter is part of total mixed ration and when it is supplemented in partial mixed rations. Besides considering the absolute amount of physically effective fiber and starch types in the diet, we highlight the role of several feeding management factors that affect rumen health and should be considered to control and mitigate SARA. Most importantly, transitional feeding to ensure gradual adaptation of the ruminal epithelium and microbiota; monitoring and careful management of particle size distribution; controlling feed sorting, meal size, and meal frequency; and paying special attention to primiparous cows are some of the feeding management tools that can help in sustaining rumen health in high-producing dairy herds. Supplementation of feed additives including yeast products, phytogenic compounds, and buffers may help attenuate SARA, especially during stress periods when the risk of a deficiency of physically effective fiber in the diet is high, such as during early lactation. However, the usage of feed additives cannot fully compensate for suboptimal feeding management. PMID- 29153520 TI - Retrospective analysis of Austrian health recording data of antibiotic or nonantibiotic dry-off treatment on milk yield, somatic cell count, and frequency of mastitis in subsequent lactation. AB - Typically, dairy cows are dried off at the end of lactation. During the dry period, intramammary infections may be cured or persist, and new infections may occur. Traditionally, antibiotics (AB) have been used at dry-off. However, blanket antibiotic dry-off treatment may no longer be justifiable and, recently, selective use of antibiotics at dry off has been proposed and different decision criteria suggested. The objective of the study was to evaluate cows receiving antibiotic treatment at dry off (AB group) compared with cows dried off without antibiotics (non-AB group) using a large data set. Primary outcome parameters were milk yield, somatic cell count (SCC), and frequency of mastitis in the subsequent lactation. Additionally, we aimed to calculate cut-off values to determine, at the cow level, whether antibiotic dry-off treatment is indicated. A data set of 88,534 lactations was used; 27,723 cows were dried off using antibiotics (AB group; 31.3%) and 60,811cows were dried off without antibiotics (non-AB group; 68.7%). Milk yield in previous and subsequent lactations was higher in the AB group. Cows in the AB group produced, on average, 91 kg more milk in the subsequent lactation. The average SCC during the final 90 d of the previous lactation and at dry-off did not differ between the 2 groups. The probability of drying off using antibiotics increased almost linearly with higher milk yield and with higher SCC. The use of antibiotics resulted in an average decrease in SCC of 1,500 cells/mL in the subsequent lactation. The frequency of clinical mastitis during the previous lactation was higher in the AB group than in the non-AB group. Independently of the dry-off treatment, this difference remained in the subsequent lactation within 90 d in milk. The use of antibiotics at dry-off had no significant effect on the frequency of mastitis within 90 d in milk of the subsequent lactation. The study indicates that Austrian farmers and veterinarians are applying selective dry-cow treatment using milk yield and, to a lesser extent, SCC and mastitis frequency, for decision-making. However, even though a large data set was used, cut-off values with sufficient diagnostic value for selective dry-cow treatment could not be identified. It is likely that cut off values must be identified at the herd level or in combination with additional parameters (e.g., results of bacterial culture). PMID- 29153521 TI - Efficacy of colostrum replacer versus maternal colostrum on immunological status, health, and growth of preweaned dairy calves. AB - Commercially available colostrum replacers (CR) are commonly used when maternal colostrum (MC) is unavailable, for managerial convenience, to ensure quality consistency at first feeding, or in disease control and eradication programs. The objective of this study was to determine the efficacy of feeding First Day Formula (Accelerated Genetics, Baraboo, WI) CR versus pooled MC on immunological status, growth, and health of preweaned dairy calves. A total of 1,220 Jersey and Jersey * Holstein calves born on a California Central Valley dairy farm were assigned after birth to receive either CR or MC following a systematic allocation procedure. Calves assigned to MC were tube fed 2.8 L of MC, and calves assigned to CR were tube fed a total of 500 g of CR (150 g of immunoglobulin G; IgG) mixed into 1.9 L of water at 1 h +/- 5 min after the calf was born. A subset of calves was selected for passive transfer (n = 592) and growth (n = 268) analyses. Although both coliform count and total bacteria count were low for MC and CR fed to calves during the study, the predicted probability of calves receiving contaminated liquid feed (coliform count >10,000 cfu/mL) at first feeding was reduced for calves fed CR (1.5%) compared with calves fed MC (6.1%). The mean blood concentration of IgG was lower for calves fed CR than for calves fed MC (19.6 vs. 23.4 mg/mL). However, the apparent efficiency of absorption of IgG did not differ between treatments (34.4 and 35.9% for CR and MC, respectively). Total proteins were lower in calves fed CR compared with MC at 24 h (5.16 vs. 5.84 g/dL, respectively). Calves fed CR were 1.5 kg lighter at weaning and gained 0.03 kg less per day (0.30 vs. 0.33 kg/d, respectively) than calves fed MC before weaning. Height at weaning did not differ between the 2 treatment groups. Calves fed CR tended to have a higher predicted probability of not being treated for diarrhea than calves fed MC (0.142 vs. 0.110, respectively). However, when the disease was present, CR had a higher number of treatment days compared with MC (11.6 vs. 10.8 d, respectively). The hazard ratio of dying did not differ between MC and CR; however, CR calves had a numerically higher risk (hazard ratio = 1.347) of dying compared with calves that received MC. In conclusion, IgG absorption and serum concentration of calves were adequate when calves were fed either CR or MC. The CR-fed calves had a lower probability of receiving contaminated liquid feed and performed similar in terms of health compared with calves receiving high-quality MC, although they were slightly lighter at weaning. Therefore, the CR evaluated in this study is a valid alternative to high-quality (>50 mg of IgG/mL) MC. PMID- 29153522 TI - Short communication: Growth of dairy isolates of Geobacillus thermoglucosidans in skim milk depends on lactose degradation products supplied by Anoxybacillus flavithermus as secondary species. AB - Thermophilic bacilli such as Anoxybacillus and Geobacillus are important contaminants in dairy powder products. Remarkably, one of the common contaminants, Geobacillus thermoglucosidans, showed poor growth in skim milk, whereas significant growth of G. thermoglucosidans was observed in the presence of an Anoxybacillus flavithermus dairy isolate. In the present study, we investigated the underlying reason for this growth dependence of G. thermoglucosidans. Whole-genome sequences of 4 A. flavithermus strains and 4 G. thermoglucosidans strains were acquired, with special attention given to carbohydrate utilization clusters and proteolytic enzymes. Focusing on traits relevant for dairy environments, comparative genomic analysis revealed that all G. thermoglucosidans strains lacked the genes necessary for lactose transport and metabolism, showed poor growth in skim milk, and produced white colonies on X-gal plates, indicating the lack of beta-galactosidase activity. The A. flavithermus isolates scored positive in these tests, consistent with the presence of a putative lactose utilization gene cluster. All tested isolates from both species showed proteolytic activity on milk plate count agar plates. Adding glucose or galactose to liquid skim milk supported growth of G. thermoglucosidans isolates, in line with the presence of the respective monosaccharide utilization gene clusters in the genomes. Analysis by HPLC of A. flavithermus TNO-09.006 culture filtrate indicated that the previously described growth dependence of G. thermoglucosidans in skim milk was based on the supply of glucose and galactose by A. flavithermus TNO-09.006. PMID- 29153523 TI - Uncertainty assessment of the breath methane concentration method to determine methane production of dairy cows. AB - The breath methane concentration method uses the methane concentrations in the cow's breath during feed bin visits as a proxy for the methane production rate. The objective of this study was to assess the uncertainty of a breath methane concentration method in a feeder and its capability to measure and rank cows' methane production. A range of controlled methane fluxes from a so-called artificial reference cow were dosed in a feed bin, and its exhaled air was sampled by a tube inside the feeder and analyzed. The artificial reference cow simulates the lungs, respiratory tract, and rumen of a cow and releases a variable methane flux to generate a concentration pattern in the exhaled breath that closely resembles a real cow's pattern. The strength of the relation between the controlled methane release rates of the artificial reference cow and the measured methane concentrations was analyzed by linear regression, using the coefficient of determination (R2) and the residual standard error as performance indicators. The effect of error sources (source-sampling distance, air turbulence, and cow's head movement) on this relation was experimentally investigated, both under laboratory and barn conditions. From the laboratory to the dairy barn at the 30-cm sampling distance, the R2-value decreased from 0.97 to 0.37 and the residual standard error increased from 75 to 86 ppm as a result of barn air turbulence, the latter increasing to a theoretical 94 ppm if modeled variability due to cow's head movement was accounted for as well. In practice, the effect of these random errors can be compensated by sampling strategies including repeated measurements on each cow over time, thus increasing the distinctive power between cows. However, systematic errors that may disturb the relation between concentration and production rate, such as cow variation in air exhalation rate and air flow patterns around sampling locations that differ between barns, cannot be compensated by repeated measurements. As a result, the methane concentrations of breath air will vary between cows with the same methane production. We conclude that the capability of the breath concentration measurement method to adequately measure and rank methane production rates among cows is highly uncertain and requires further investigation into variation sources with a systematic nature. PMID- 29153524 TI - Minimum inhibitory concentrations of frequently used antibiotics against Escherichia coli and Trueperella pyogenes isolated from uteri of postpartum dairy cows. AB - The objective of this study was to determine minimum inhibitory concentrations (MIC) of frequently used antimicrobials for Escherichia coli and Trueperella pyogenes isolated from postpartum bovine uteri of cows with acute puerperal metritis (APM, n = 67), cows suspected to have APM (n = 37), and healthy cows (n = 37) and to evaluate possible differences in MIC according to clinical signs. Cows with APM had reddish-brown, fetid vaginal discharge and rectal temperature (RT) >=39.5 degrees C within 21 d in milk; cows suspected to have APM had either reddish-brown, fetid vaginal discharge or RT >=39.5 degrees C within 21 d in milk; and healthy cows had neither fetid discharge nor RT >=39.5 degrees C. Samples were collected from cows on commercial dairy herds (n = 7) using the cytobrush technique. A total of 37 T. pyogenes isolates and 85 E. coli isolates were tested. Ceftiofur, a third-generation cephalosporin that is often used to treat APM, was the focus of analysis. Trueperella pyogenes and E. coli were isolated more often from samples of cows with APM (46 and 90%, respectively) compared with samples from healthy cows (19 and 54%, respectively). Regarding cows suspected to have APM, T. pyogenes and E. coli were numerically more often isolated (30 and 70%, respectively) than in healthy cows (19 and 54%, respectively). Minimum inhibitory concentrations of ceftiofur were low. For T. pyogenes and E. coli, MIC50 (concentration that inhibited growth of 50% of isolates) were 0.25 and 0.5 ug/mL and MIC90 (concentration that inhibited growth of 90% of isolates) were 0.5 and 1 ug/mL, respectively. Although ceftiofur inhibited all T. pyogenes at the highest concentration tested (64 ug/mL), the growth of 5.9% of E. coli was not impaired. Recently, ampicillin has been suggested as an alternative treatment for APM. Although the T. pyogenes isolates exhibited low MIC in general (MIC50 <=0.015 ug/mL and MIC90 = 0.06 ug/mL) and 81.1% of all T. pyogenes could be inhibited at the lowest ampicillin concentration tested, 11.8% of the E. coli isolates were not impaired at the highest concentration (64 ug/mL) tested in this study. The MIC50 and MIC90 of E. coli were 4 and >=128 ug/mL, respectively. We detected no difference in the MIC distributions of ceftiofur or ampicillin among isolates from the 3 APM groups. In summary, E. coli with high MIC against ceftiofur as well as against ampicillin were found in this study. PMID- 29153525 TI - Association of milking interval and milk production rate in an automatic milking system. AB - The primary aim of this research was to describe the association between milking interval (MI) and milk production rate (MPR) at the quarter level in a large commercial farm using an automatic milking system. A secondary aim was to determine whether a 2-h decrease in MI would increase MPR at the cow level in midlactation multiparous cows. Six months of data from 1,280 cows were used to assess the association between MI (h) and quarter MPR (kg/h). Increasing MI was associated with decreased MPR for early, mid, and late lactation, both primiparous and multiparous cows, and all 4 quarter positions and across time. The decrease in MPR is approximately 2%/h of increasing MI for multiparous cows and 1.5%/h for primiparous cows. Regardless of quarter, multiparous cows had a greater MPR than primiparous cows, and rear quarters had greater MPR than front quarters. An experiment to test the causal relationship between changing MI and cow-level MPR was conducted using 26 animal pairs matched on MI, days in milk, and milk yield. During the 21-d treatment period, the average MI of treatment cows was decreased by 2.4 h compared with control cows. In both the 21-d treatment and 42-d posttreatment periods, no significant difference was found in cow-level MPR between the treatment and control groups. Despite the negative association between increasing MI and MPR being consistent across all assessed days in milk windows and all quarters, results from this experiment suggest that intervention to decrease MI might require an MI change greater than 2 h or be applied in early lactation to significantly increase MPR. PMID- 29153526 TI - Economic and genetic performance of various combinations of in vitro-produced embryo transfers and artificial insemination in a dairy herd. AB - The objective of this study was to find the optimal proportions of pregnancies from an in vitro-produced embryo transfer (IVP-ET) system and artificial insemination (AI) so that profitability is maximized over a range of prices for embryos and surplus dairy heifer calves. An existing stochastic, dynamic dairy model with genetic merits of 12 traits was adapted for scenarios where 0 to 100% of the eligible females in the herd were impregnated, in increments of 10%, using IVP-ET (ET0 to ET100, 11 scenarios). Oocytes were collected from the top donors selected for the trait lifetime net merit (NM$) and fertilized with sexed semen to produce IVP embryos. Due to their greater conception rates, first ranked were eligible heifer recipients based on lowest number of unsuccessful inseminations or embryo transfers, and then on age. Next, eligible cow recipients were ranked based on the greatest average estimated breeding values (EBV) of the traits cow conception rate and daughter pregnancy rate. Animals that were not recipients of IVP embryos received conventional semen through AI, except that the top 50% of heifers ranked for EBV of NM$ were inseminated with sexed semen for the first 2 AI. The economically optimal proportions of IVP-ET were determined using sensitivity analysis performed for 24 price sets involving 6 different selling prices of surplus dairy heifer calves at approximately 105 d of age and 4 different prices of IVP embryos. The model was run for 15 yr after the start of the IVP-ET program for each scenario. The mean +/- standard error of true breeding values of NM$ of all cows in the herd in yr 15 was greater by $603 +/- 2 per cow per year for ET100 when compared with ET0. The optimal proportion of IVP ET ranged from ET100 (for surplus dairy heifer calves sold for >=$300 along with an additional premium based on their EBV of NM$ and a <=$100 embryo price) to as low as ET0 (surplus dairy heifer calves sold at $300 with a $200 embryo price). For the default assumptions, the profit/cow in yr 15 was greater by $337, $215, $116, and $69 compared with ET0 when embryo prices were $50, $100, $150, and $200. The optimal use of IVP-ET was 100, 100, 62, and 36% of all breedings for these embryo prices, respectively. At the input price of $165 for an IVP embryo, the difference in the net present value of yr 15 profit between ET40 (optimal scenario) and ET0 was $33 per cow. In conclusion, some use of IVP-ET was profitable for a wide range of IVP-ET prices and values of surplus dairy heifer calves. PMID- 29153527 TI - Short communication: Genomic prediction using imputed whole-genome sequence variants in Brown Swiss Cattle. AB - The accuracy of genomic prediction determines response to selection. It has been hypothesized that accuracy of genomic breeding values can be increased by a higher density of variants. We used imputed whole-genome sequence data and various single nucleotide polymorphism (SNP) selection criteria to estimate genomic breeding values in Brown Swiss cattle. The extreme scenarios were 50K SNP chip data and whole-genome sequence data with intermediate scenarios using linkage disequilibrium-pruned whole-genome sequence variants, only variants predicted to be missense, or the top 50K variants from genome-wide association studies. We estimated genomic breeding values for 3 traits (somatic cell score, nonreturn rate in heifers, and stature) and found differences in accuracy levels between traits. However, among different SNP sets, accuracy was very similar. In our analyses, sequence data led to a marginal increase in accuracy for 1 trait and was lower than 50K for the other traits. We concluded that the inclusion of imputed whole-genome sequence data does not lead to increased accuracy of genomic prediction with the methods. PMID- 29153528 TI - Modeling greenhouse gas emissions from dairy farms. AB - Dairy farms have been identified as an important source of greenhouse gas emissions. Within the farm, important emissions include enteric CH4 from the animals, CH4 and N2O from manure in housing facilities during long-term storage and during field application, and N2O from nitrification and denitrification processes in the soil used to produce feed crops and pasture. Models using a wide range in level of detail have been developed to represent or predict these emissions. They include constant emission factors, variable process-related emission factors, empirical or statistical models, mechanistic process simulations, and life cycle assessment. To fully represent farm emissions, models representing the various emission sources must be integrated to capture the combined effects and interactions of all important components. Farm models have been developed using relationships across the full scale of detail, from constant emission factors to detailed mechanistic simulations. Simpler models, based upon emission factors and empirical relationships, tend to provide better tools for decision support, whereas more complex farm simulations provide better tools for research and education. To look beyond the farm boundaries, life cycle assessment provides an environmental accounting tool for quantifying and evaluating emissions over the full cycle, from producing the resources used on the farm through processing, distribution, consumption, and waste handling of the milk and dairy products produced. Models are useful for improving our understanding of farm processes and their interacting effects on greenhouse gas emissions. Through better understanding, they assist in the development and evaluation of mitigation strategies for reducing emissions and improving overall sustainability of dairy farms. PMID- 29153529 TI - Evaluation of carinata meal as a feedstuff for growing dairy heifers: Effects on growth performance, rumen fermentation, and total-tract digestibility of nutrients. AB - Our objective was to determine the effects of feeding carinata meal (CRM) compared with distillers dried grains with solubles (DDGS) on growth performance, rumen fermentation, and nutrient utilization in peripubertal dairy heifers. A 16 wk randomized block design experiment with 24 Holstein heifers [6.6 +/- 0.7 mo and 218 +/- 27 kg of body weight (BW)] was conducted. Treatments diets were (1) 10% cold-pressed CRM and (2) 10% DDGS on a dry matter (DM) basis. The remainder of the diets consisted of grass hay, ground corn, soybean meal, and mineral mix. Diets were formulated to be isonitrogenous and isocaloric. Heifers were individually fed using a Calan gate feeding system, and the rations were limit fed at 2.65% of BW on a DM basis to target a 0.8 kg/d of average daily gain. Heifers were weighed every 2 wk and the ration amount offered was adjusted accordingly. Frame sizes, BW, and body condition scores were measured 2 d every 2 wk throughout the study. During wk 12 and 16, rumen fluid samples were collected via esophageal tubing for pH, ammonia N, and volatile fatty acid analyses. In wk 16, fecal grab samples were collected for apparent total-tract digestibility estimation. Heifer DM intake, BW, average daily gain, and gain:feed were similar between treatments. No differences were observed between treatments in frame measurements or body condition scores. Rumen pH tended to be greater in CRM compared with DDGS. Rumen ammonia N and total volatile fatty acid concentration were not different between treatments. Apparent total-tract digestibility of DM, neutral detergent fiber, and acid detergent fiber were decreased in CRM compared with DDGS. A tendency was detected for reduced organic matter digestibility in CRM. No difference was observed between treatments for crude protein total-tract digestibility. However, these differences in total-tract nutrient digestibility were not large enough to influence growth performance. Overall, results demonstrated that growing heifers can be limit-fed diets with 10% CRM and maintain growth performance compared with a control diet containing 10% DDGS. PMID- 29153530 TI - Physicochemical and sensory properties of yogurts containing sacha inchi (Plukenetia volubilis L.) seeds and beta-glucans from Ganoderma lucidum. AB - Dairy products have been widely used for adding various biomolecules with the aim of improving their functional properties and health benefits. In this study, the physicochemical properties and sensory acceptance of yogurts enriched with sacha inchi (Plukenetia volubilis) seeds (SIS) and beta-glucans from Ganoderma lucidum (BGGL) were investigated. The angiotensin-converting enzyme-inhibitory activity of some yogurt samples was also evaluated. Yogurts were produced from reconstituted skim milk powder, and SIS (4% wt/wt) and BGGL were added at different concentrations (0-1.5% wt/wt). The fermentation kinetics were not affected by the enrichment process. The addition of SIS and BGGL significantly increased the contents of protein, fat, carbohydrates, ash, total solids, aspartic acid, serine, arginine, glycine, threonine, tyrosine, and alanine. alpha Linolenic (49.3%) and linoleic (32.2%) acids were the main fatty acids found in the enriched samples, whose values were about 50- and 25-fold higher than those of the control yogurt. The textural parameters (firmness, consistency, cohesiveness, and index of viscosity) of the enriched yogurts were significantly lower than those of the control samples during the whole storage period. All enriched yogurts showed a sensorial acceptance higher than 70% by untrained panelists. The angiotensin-converting enzyme-inhibitory activity of some selected yogurt samples ranged between 36 and 59%. These results indicate that SIS and BGGL could be used as natural ingredients for improving the nutritional value of yogurt and fermented milks. PMID- 29153531 TI - Short communication: Detection of lameness in dairy cows using a grooming device. AB - Lameness in dairy cattle is a common welfare problem with significant economic implications. All too often, appropriate treatment is delayed or neglected due to insufficient detection of lame cows. Brush usage is considered a low-resilience activity; that is, one that typically decreases when energy resources are limited or when the cost involved in the activity increases, such as during sickness and stress. The aim of this study was to determine the association between brush usage and different degrees of lameness. Locomotion scores of 209 lactating Holstein dairy cows were collected individually once a week for 14 consecutive weeks, using a 5-point visual assessment scoring system (1 = nonlame, 2 = uneven gait, 3 = mild lameness, 4 = lameness, 5 = severe lameness). Daily brush usage was collected automatically from 3 cowsheds of similar size and structure located on a commercial dairy farm. In each of the 3 cowsheds, 2 brushes were installed, one next to the feed bunk, and the other away from the feed bunk (on the opposite side of the cowshed). Linear and generalized linear mixed-effects models were used to evaluate the association between locomotion scores and daily measures of brush usage. We found a significant interaction between locomotion score and brush location (near to/distant from feed bunk) on the daily proportion of cows using the brush at least once and on daily duration of brush usage. Specifically, we showed that lame and severely lame cows did not use brushes that were installed away from the feed bunk but continued to use brushes that were installed next to the feed bunk. Brush usage by cows with uneven gait (locomotion score 2) or with mild lameness (locomotion score 3) did not differ from that of nonlame cows (locomotion score 1). The results of this study suggest that monitoring of daily usage of brushes located away from the feed bunk could be a useful method for detecting lameness and severe lameness in dairy cows. However, the use of this method to detect mild lameness or cases of abnormal gait is, at this stage, less promising. PMID- 29153532 TI - The blind pushing technique for peripherally inserted central catheter placement through brachial vein puncture. AB - OBJECTIVE: The objective of this study was to conduct a prospective clinical trial evaluating the technical feasibility and short-term clinical outcome of the blind pushing technique for placement of pretrimmed peripherally inserted central catheters (PICCs) through brachial vein access. METHODS: Patients requiring PICC placement at any of the three participating institutions were prospectively enrolled between January and December 2016. The review boards of all participating institutions approved this study, and informed consent was obtained from all patients. PICC placement was performed using the blind pushing technique and primary brachial vein access. The following data were collected from unified case report forms: access vein, obstacles during PICC advancement, procedure time, and postprocedural complications. RESULTS: During the 12-month study period, 1380 PICCs were placed in 1043 patients. Of these, 1092 PICCs placed in 837 patients were enrolled, with 834 PICCs (76%) and 258 PICCs (34%) placed through brachial vein and nonbrachial vein access, respectively. In both arms, obstacles were most commonly noted in the subclavian veins (n = 220) and axillary veins (n = 94). Successful puncture of the access vein was achieved at first try in 1028 PICCs (94%). The technical success rate was 99%, with 1055 PICCs (97%) placed within 120 seconds of procedure time and 1088 PICCs (99%) having the tip located at the ideal position. Follow-up Doppler ultrasound detected catheter associated upper extremity deep venous thrombosis (UEDVT) for 18 PICCs in 16 patients and late symptomatic UEDVT for 16 PICCs in 16 patients (3.1%). Catheter associated UEDVT was noted for 28 PICCs (82%) and 6 PICCs (18%) placed through brachial vein and nonbrachial vein access, respectively. The incidence of obstacles and the procedure time (<120 seconds) differed significantly between brachial vein and nonbrachial vein access (P = .001). There was no statistically significant difference between brachial vein and nonbrachial vein access in the incidence of UEDVT (odds ratio, 0.68; 95% confidence interval, 0.59-3.52; P = .22). CONCLUSIONS: The placement of pretrimmed PICCs by the blind pushing technique and primary brachial vein access is technically feasible and may represent an alternative to the conventional PICC placement technique, having low incidences of UEDVT and other complications, with no significant difference in outcomes between brachial vein and nonbrachial vein access. PMID- 29153533 TI - Outcomes at a single center after subintimal arterial flossing with antegrade retrograde intervention for critical limb ischemia. AB - OBJECTIVE: The subintimal arterial flossing with antegrade-retrograde intervention technique has been used to overcome antegrade recanalization failures for peripheral lower limb arterial occlusive disease. There are few outcomes published for this technique and we sought to evaluate outcomes at our institution over a 7-year period. METHODS: A retrospective review was performed of all subintimal arterial flossing with antegrade-retrograde intervention procedures of infrainguinal occlusive disease from 2009 to 2016. Retrograde and antegrade accesses were combined when occlusions could not be crossed from the antegrade direction. Baseline patient characteristics, procedures, procedure time, fluoroscopy time, contrast used, and radiation dose were collected. Posterior tibial waveforms, ankle-brachial index, limb salvage, vessel patency, and the presence of symptoms were assessed at follow-up. RESULTS: Treatment was performed in 52 limbs in 52 patients (35 men and 17 women; mean age, 77.62 +/- 11.61 years) with critical limb ischemia and no appropriate venous conduit for surgical bypass. Among the cohort, 63.5% were diabetics, 98% had hypertension, 53.8% had a prior myocardial infarction, and 36.5% end-stage renal disease. The average Rutherford Category before the intervention was 5.08 +/- 1.01. Retrograde pedal access was most commonly obtained in the anterior tibial artery/dorsalis pedis (55.7%), followed by the posterior tibial artery (40.3%). The technical success rate was 63.5% (33/52); adjunctive stenting was needed in 19 (36.5%) to optimize results. Preprocedural ankle-brachial index score was 0.54 +/- 0.25, which improved after the procedure to an ankle-brachial index score of 0.77 +/- 0.25. The primary patency rates at 3 and 6 months were 65% and 60%, respectively. The limb salvage rate at a mean follow-up of 5.4 months was 78.8%. There were 5 complications; 4 were hematomas managed conservatively and 1 was a major retroperitoneal bleed resulting in patient death. CONCLUSIONS: Retrograde pedal access is a viable revascularization technique for achieving limb salvage in patients with critical limb ischemia with acceptable patency for limb-threatening ischemia. This technique expands revascularization options after failed conventional endovascular antegrade approaches. PMID- 29153534 TI - Configuration affects parallel stent grafting results. AB - OBJECTIVE: A number of adjunctive "off-the-shelf" procedures have been described to treat complex aortic diseases. Our goal was to evaluate parallel stent graft configurations and to determine an optimal formula for these procedures. METHODS: This is a retrospective review of all patients at a single medical center treated with parallel stent grafts from January 2010 to September 2015. Outcomes were evaluated on the basis of parallel graft orientation, type, and main body device. Primary end points included parallel stent graft compromise and overall endovascular aneurysm repair (EVAR) compromise. RESULTS: There were 78 patients treated with a total of 144 parallel stents for a variety of pathologic processes. There was a significant correlation between main body oversizing and snorkel compromise (P = .0195) and overall procedural complication (P = .0019) but not with endoleak rates. Patients were organized into the following oversizing groups for further analysis: 0% to 10%, 10% to 20%, and >20%. Those oversized into the 0% to 10% group had the highest rate of overall EVAR complication (73%; P = .0003). There were no significant correlations between any one particular configuration and overall procedural complication. There was also no significant correlation between total number of parallel stents employed and overall complication. Composite EVAR configuration had no significant correlation with individual snorkel compromise, endoleak, or overall EVAR or procedural complication. The configuration most prone to individual snorkel compromise and overall EVAR complication was a four-stent configuration with two stents in an antegrade position and two stents in a retrograde position (60% complication rate). The configuration most prone to endoleak was one or two stents in retrograde position (33% endoleak rate), followed by three stents in an all antegrade position (25%). There was a significant correlation between individual stent configuration and stent compromise (P = .0385), with 31.25% of retrograde stents having any complication. CONCLUSIONS: Parallel stent grafting offers an off-the-shelf option to treat a variety of aortic diseases. There is an increased risk of parallel stent and overall EVAR compromise with <10% main body oversizing. Thirty-day mortality is increased when more than one parallel stent is placed. Antegrade configurations are preferred to any retrograde configuration, with optimal oversizing >20%. PMID- 29153535 TI - Prevalence of psychiatric disorders in patients with inherited or idiopathic dystonia. PMID- 29153536 TI - Frailty in Hospitalized Older Adults: Comparing Different Frailty Measures in Predicting Short- and Long-term Patient Outcomes. AB - OBJECTIVES: Data for the assessment of frailty in acutely ill hospitalized older adults remains limited. Using the Frailty Index (FI) as "gold standard," we compared (1) the diagnostic performance of 3 frailty measures (FRAIL, Clinical Frailty Scale [CFS], and Tilburg Frailty Indicator [TFI]) in identifying frailty, and (2) their ability to predict negative outcomes at 12 months after enrollment. DESIGN: Prospective cohort study. PARTICIPANTS: We recruited 210 patients (mean age 89.4 +/- 4.6 years, 69.5% female), admitted to the Department of Geriatric Medicine in a 1300-bed tertiary hospital. MEASUREMENTS: Premorbid frailty status was determined. Data on comorbidities, severity of illness, functional status, and cognitive status were gathered. We compared area under receiver operator characteristic curves (AUC) for each frailty measure against the reference FI. Multiple logistic regression was used to examine the independent association between frailty and the outcomes of interest. RESULTS: Frailty prevalence estimates were 87.1% (FI), 81.0% (CFS), 80.0% (TFI), and 50.0% (FRAIL). AUC against FI ranged from 0.81 (95% confidence interval [CI] 0.72-0.90: FRAIL) to 0.91 (95% CI 0.87-0.95: CFS). Only FRAIL was associated with higher in-hospital mortality (6.7% vs 1.0%, P = .031). FRAIL and CFS were significantly associated with increased length of hospitalization (10 [6.0-17.5] vs 8 [5.0-14.0] days, P = .043 and 9 [5.0-17.0] vs 7 [4.25-11.75] days, P = .036, respectively). CFS and FI were highly associated with mortality at 12-month (CFS, frail vs nonfrail: 32.9% vs 2.5%, P < .001, and FI, frail vs nonfrail: 30.6% vs 3.7%, P < .001). CFS also conferred the greatest risk of 12-month mortality (odds ratio [OR] 5.78, 95% CI 3.19-10.48, P < .001) and composite outcomes of institutionalization and/or mortality (OR 3.69, 95% CI 2.31-5.88, P < .001), adjusted for age, sex, and severity of illness. CONCLUSION: Our study affirms the utility of frailty assessment tools among older persons in acute care. FRAIL conferred highest risk of in-hospital mortality. However, CFS had greatest risk of mortality and institutionalization within 12 months. PMID- 29153537 TI - Could delirium and anti-dementia drugs effect the treatment of agitated nursing home residents with Alzheimer dementia? PMID- 29153539 TI - Deviations in frequency and mode of vibration in whole-body vibration training devices with long-term and regular use. AB - Research regarding whole body vibration training (WBVT) and its practical use may be hindered by the fact that WBVT devices generate frequencies and/or modes of vibration different from their preset adjustments. This research aimed to clarify whether prolonged regular use can generate such deviations in frequency and mode of vibration. Three WBVT devices, each used for approximately 13 months in two research projects, were tested with an accelerometer before start of the 1st study, after four months, and after 13 months (the completion of the 2nd study). Divergences between the preset and measured frequencies were calculated for all measurements. Furthermore, the total harmonic distortion (THD), an index for signal deviations from a perfect sine wave, and the sum signal-to-modulation noise-ratio (SMNR), an indicator of fidelity, were recorded. One device had a significantly larger machine run time than the other two, and it displayed the most pronounced signs of impaired function concerning frequency, mode of vibration, and random variability (SMNR) after prolonged use. These results indicate that prolonged use will result in divergences between the preset and actual applied frequencies as well as in the mode of vibration and other accuracy measurements. PMID- 29153538 TI - Oral paracoccidioidomycosis in a single-center retrospective analysis from a Brazilian southeastern population. AB - BACKGROUND: Paracoccidioidomycosis (PCM) is the most prevalent endemic systemic fungal infection in Latin America. In Brazil, it stands out as the eighth-highest cause of mortality among chronic or recurrent infections and has the highest mortality rate among systemic mycoses. Oral mucosal lesions may be the first visible physical manifestation of the disease. This study traced the epidemiological and clinical profiles of patients with oral lesions treated at the University Hospital Cassiano Antonio Moraes, Federal University of Espirito Santo. METHODS: A retrospective cross-sectional analysis of patient medical records was performed. RESULTS: Among the 161 patients identified with a confirmed diagnosis of PCM, 97 (60.24%) presented with oral lesions. The male:female ratio was 15:1, the mean age was 50.5 years, and the chronic form of paracoccidioidomycosis was predominant. Most of the patients had smoking habits and were rural workers. The most common oral lesions present in various anatomical sites were mulberry-like ulcers, more frequently observed in the gingiva, with regression within one to three months. Patients completed the treatment in one to two years (32.99%), and 47.42% of cases discontinued treatment. CONCLUSIONS: In addition to the characteristics of the oral lesions, information from the clinical profiles of patients with oral PCM is a central tool for dentists for early diagnosis. Earlier diagnosis may result in fewer consequences, especially respiratory ones that may cause an inability to work and poor quality of life. PMID- 29153540 TI - Prognostic value of pre-treatment human papilloma virus DNA status in cervical cancer. AB - OBJECTIVE: Although the relationship between human papilloma virus (HPV) and cervical cancer is well established, the prognostic value of HPV status has not been determined, largely because previous studies have yielded conflicting results. This study aimed to investigate the prognostic value of pre-treatment HPV DNA for predicting tumor recurrence in cervical cancer. METHODS: The study included 248 eligible patients who provided cervical cell specimens for HPV genotyping before surgery or concurrent chemoradiotherapy (CCRT). Of these 248 patients, 108 were treated with radical hysterectomy for International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IIA cervical cancer, and 140 were treated with CCRT for FIGO stage IB2-IV cervical cancer. RESULTS: HPV 16 and 18 were the two most common HPV types detected, with prevalence rates of 52.4% and 12.5%, respectively. The pre-treatment HPV DNA test showed that 18.5% of cervical cancers were HPV negative. Multivariate analysis showed that HPV negativity was associated with poorer disease-free survival (DFS) than HPV-positive status (hazard ratio [HR], 3.97; 95% confidence interval [CI], 1.84-8.58; p=0.0005), and patients with HPV 16-positive cancers had better DFS (HR, 0.41; 95% CI, 0.23 0.72; p=0.0019). In the surgery group, only HPV 16 positivity was significantly correlated with DFS (HR, 0.34; 95% CI, 0.12-0.96; p=0.0416). In the CCRT group, only HPV negativity was significantly correlated with DFS (HR, 3.75; 95% CI, 1.78 7.90; p=0.0005). CONCLUSIONS: Pre-treatment HPV DNA status may be a useful prognostic biomarker in cervical cancer. The presence of HPV 16 DNA was associated with better DFS, and HPV negativity was associated with worse DFS. However, larger sample sizes and more comprehensive studies are required to verify our findings. PMID- 29153541 TI - Screening for cervical cancer among HIV-positive and HIV-negative women in Cameroon using simultaneous co-testing with careHPV DNA testing and visual inspection enhanced by digital cervicography: Findings of initial screening and one-year follow-up. AB - OBJECTIVE: The World Health Organization (WHO)'s cervical cancer screening guidelines for limited-resource settings recommend sequential screening followed by same-day treatment under a "screen-and-treat" approach. We aimed to (1) assess feasibility and clinical outcomes of screening HIV-positive and HIV-negative Cameroonian women by pairing visual inspection with acetic acid and Lugol's iodine enhanced by digital cervicography (VIA/VILI-DC) with careHPV, a high-risk human papillomavirus (HR-HPV) nucleic acid test designed for low-resource settings; and (2) determine persistence of HR-HPV infection after one-year follow up to inform optimal screening, treatment, and follow-up algorithms. METHODS: We co-tested 913 previously unscreened women aged >=30years and applied WHO recommended treatment for all VIA/VILI-DC-positive women. Baseline prevalence of HR-HPV and HIV were 24% and 42%, respectively. RESULTS: On initial screen, 44 (5%) women were VIA/VILI-DC-positive, of whom 22 had HR-HPV infection, indicating 50% of women screened false-positive and would have been triaged for unnecessary same-day treatment. VIA/VILI-DC-positive women with HIV infection were three times more likely to be HR-HPV-positive than HIV-negative women (65% vs. 20%). All women positive for either VIA/VILI-DC or HR-HPV (n=245) were invited for repeat co-testing after one year, of which 136 (56%) returned for follow-up. Of 122 women who were HR-HPV-positive on initial screen, 60 (49%) re-tested negative, of whom 6 had received treatment after initial screen, indicating that 44% of initially HR-HPV-positive women spontaneously cleared infection after one year without treatment. Women with HIV were more likely to remain HR-HPV-positive on follow-up than HIV-negative women (61% vs. 22%, p<0.001). Treatment was offered to all VIA/VILI-DC positive women on initial screen, and to all women screening VIA/VILI-DC or HR-HPV positive on follow-up. CONCLUSIONS: We found careHPV co-testing with VIA/VILI-DC to be feasible and valuable in identifying false-positives, but careHPV screening-to-result time was too long to inform same day treatment. PMID- 29153543 TI - [Aspirin and colorectal cancer]. AB - Colorectal cancer is a worldwide public health problem. Aspirin has been identified as a protective factor against the apparition of colorectal cancer. There are several mechanisms about the actions by aspirin on colorectal tumorogenesis. These are not perfectly known nowadays. On one hand, there are direct mechanisms on colorectal mucosa, on the other hand there are indirect mechanisms through platelet functions. Aspirin also plays a role by its anti inflammatory action and the stimulation of antitumor immunity. Several studies show that long-term treatment with low-doses of aspirin decreases the incidence of adenomas and colorectal cancers. In the United States, aspirin is currently recommended for primary prevention of the risk of colorectal cancer in all patients aged 50 to 59, with a 10-year risk of cardiovascular event greater than 10 %. However, primary prevention with aspirin should not be a substitute for screening in colorectal cancer. Furthermore, aspirin seems to be beneficial when used in post-diagnosis of colorectal cancer. It could actually decrease the risk of metastasis in case of a localized colorectal cancer, and increase the survival in particular, concerning PIK3CA mutated tumors. The association of aspirin with neoadjuvant treatment of colorectal cancer by radiochimiotherapy seems to have beneficial effects. French prospective randomized study is currently being conducted to investigate postoperative aspirin in colorectal cancers with a PIK3CA mutation. PMID- 29153542 TI - Adherence to treatment recommendations and outcomes for women with ovarian cancer at first recurrence. AB - OBJECTIVE: Treatment selection for recurrent ovarian cancer is typically based on the duration of time between the completion of adjuvant, platinum-based therapy and the time of recurrence, the platinum free interval (PFI). We examined the use of, and outcomes associated with platinum-based chemotherapy based on the PFI in women with recurrent ovarian cancer. METHODS: The Surveillance, Epidemiology, and End Results-Medicare database was used to identify women aged >65years with epithelial ovarian cancer who underwent surgery and platinum-based chemotherapy and who developed a recurrence >3months after the completion of adjuvant therapy. Patients were stratified by PFI into 3 groups: PFI <6months, PFI 7-12months, and PFI >12months. Multivariable models were used to examine predictors of use of platinum-based therapy and survival for each group. RESULTS: A total of 2369 patients were identified. In women with a PFI of <=6months, treatment consisted of platinum-based combination therapy in 28.2%, single agent platinum in 5.2% and non-platinum therapy in 66.6%. Corresponding rates of these treatments among women with a PFI of 7-12months were 39.7%, 12.4% and 47.9%, respectively; the rates were 57.6%, 13.2% and 29.3% in those with a PFI of >12months, respectively. Median survival was 13, 18, and 27months for patients with a PFI of <=6months, 7 12months, and >12months, respectively (P<0.0001). For all three groups, platinum combination therapy was associated with decreased risk of death compared to non platinum based therapy. CONCLUSION: Platinum free interval is a strong predictor of survival in elderly women with recurrent ovarian cancer. There is widespread variation in treatment selection for women with recurrent ovarian cancer with many women receiving non-guideline based regimens. PMID- 29153544 TI - [Cancer stem cells and metastatic dissemination]. PMID- 29153545 TI - [Cancer stem cells in glioblastoma]. PMID- 29153546 TI - Vitamin D3 supplementation and the IL-2/IL-2R pathway in multiple sclerosis: Attenuation of progressive disturbances? AB - Vitamin D3 upregulates IL-2 receptor alpha (IL2RA, CD25)-expression on CD4+ T cells in vitro. We investigated effects of 48-weeks vitamin D3 supplements on CD25-expression by CD4+ T cells of patients with multiple sclerosis (MS). There was no significant difference between the vitamin D3 (n=30) and placebo group (n=23) in IL2RA mRNA-expression by PBMC. Likewise, CD25 cell surface-expression by conventional or regulatory T cells (Treg) did not differ between groups, although Treg CD25-expression and circulating soluble-CD25 levels decreased significantly in the placebo but not vitamin D3-group. We speculate that vitamin D3 may promote the maintenance of CD25-related immune homeostasis in MS. PMID- 29153547 TI - Optimization of peptide-based polyagonists for treatment of diabetes and obesity. PMID- 29153548 TI - N-Me-trichodermamide B isolated from Penicillium janthinellum, with antioxidant properties through Nrf2-mediated signaling pathway. AB - A new trichodermamide-like alkaloid, N-Me-trichodermamide B (compound 1), was isolated from a marine fungus Penicillium janthinellum HDN13-309. The structure and absolute configuration of compound 1 were determined by extensive NMR analysis and the modified Mosher's method. This new alkaloid exhibited cellular protection from the H2O2-induced oxidative damage, and the mechanism study revealed that this antioxidant activity was regulated through Nrf2-mediated signaling pathway in HaCaT human keratinocytes. In addition, the inhibitor of p38 abrogated compound 1-induced phosphorylation of p38, up-expression of HO-1, and the nuclear localization of Nrf2. As a result, it suggested that this new alkaloid-induced antioxidant signaling pathway might be initiated through activation of p38. PMID- 29153550 TI - Why a disaster is not just normal business ramped up: Disaster response among ED nurses. AB - BACKGROUND: The emergency department (ED) is a familiar place for the emergency nurse who spends their working days inside it. A disaster threatens that familiarity and creates changes that make working in the ED during a disaster response different from the everyday experience of working in the ED. METHODS: This research reports on an aspect of the findings from a larger study about the experience of working as a nurse in the ED during a disaster response. Thirteen nurses from 8 different countries were interviewed about their experience. RESULTS: The findings from this research demonstrate that a disaster event leads to a chain reaction of changes in process, space and practice. Nurses' respond to the news of a disaster event with shock and disbelief. The ED may change as a result of the event requiring nurses to work in an altered environment or a completely different setting. These changes provoke nurses to alter their behaviour and practice and reflect on the experience after the response. CONCLUSIONS: Emergency nurses have a high likelihood of participating in disaster response and as such should be adequately prepared. This highlights how disaster response is different and leads to recommendations to enhance training for emergency nurses which will better prepare them Disasterresponse is not normal business ramped up. There are a number of challenges and changes that should be considered when preparing emergency nurses for the realities of disaster response. PMID- 29153549 TI - Anticancer activities of emetine prodrugs that are proteolytically activated by the prostate specific antigen (PSA) and evaluation of in vivo toxicity of emetine derivatives. AB - Emetine is a small molecule protein synthesis inhibitor that is toxic to all cell types and therefore suitable for complete killing of all types of heterogeneous cancer cells within a tumor. It becomes significantly inactive (non-toxic) when derivatized at its N-2' secondary amine. This provides a strategy for targeting emetine to cancerous tumor without killing normal cells. In this report, PSA activatable peptide prodrugs of emetine were synthesized. To overcome steric hindrances and enhance protease specific cleavage, a 2-stage prodrug activation process was needed to release emetine in cancer cells. In this 2-stage process, emetine prodrug intermediates are coupled to PSA peptide substrate (Ac-His-Ser Ser-Lys-Leu-Gln) to obtain the full prodrug. Both prodrug intermediates 10 (Ala Pro-PABC-Emetine) and 14 (Ser-Leu-PABC-Emetine) were evaluated for kinetics of hydrolysis to emetine and potency [Where PABC = p-aminobenzyloxycarbonyl]. While both intermediates quantitatively liberate emetine when incubated under appropriate conditions, upon coupling of PSA substrate to give the full prodrugs, only prodrug 16, the prodrug obtained from 14 was hydrolyzable by PSA. Cytotoxicity studies in PSA producing LNCaP and CWR22Rv1 confirm the activation of the prodrug by PSA with an IC50 of 75 nM and 59 nM respectively. The cytotoxicity of 16 is significantly reduced in cell lines that do not produce PSA. Further, in vivo toxicity studies are done on these prodrugs and other derivatives of emetine. The results show the significance of conformational modulation in obtaining safe emetine prodrugs. PMID- 29153551 TI - Remote sensing based deforestation analysis in Mahanadi and Brahmaputra river basin in India since 1985. AB - Land use and land cover (LULC) change has been recognized as a key driver of global climate change by influencing land surface processes. Being in constant change, river basins are always subjected to LULC changes, especially decline in forest cover to give way for agricultural expansion, urbanization, industrialization etc. We used on-screen digital interpretation technique to derive LULC maps from Landsat images at three decadal intervals i.e., 1985, 1995 and 2005 of two major river basins of India. Rain-fed, Mahanadi river basin (MRB) attributed to 55% agricultural area wherein glacier-fed, Brahmaputra river basin (BRB) had only 16% area under agricultural land. Though conversion of forest land for agricultural activities was the major LULC changes in both the basins, the rate was higher for BRB than MRB. While water body increased in MRB could be primarily attributed to creation of reservoirs and aquaculture farms; snow and ice melting attributed to creation of more water bodies in BRB. Scrub land acted as an intermediate class for forest conversion to barren land in BRB, while direct conversion of scrub land to waste land and crop land was seen in MRB. While habitation contributed primarily to LULC changes in BRB, the proximity zones around habitat and other socio-economic drivers contributed to LULC change in MRB. Comparing the predicted result with actual LULC of 2005, we obtained >97% modelling accuracy; therefore it is expected that the Dyna-CLUE model has very well predicted the LULC for the year 2025. The predicted LULC of 2025 and corresponding LULC changes in these two basins acting as early warning, and with the past 2-decadal change analysis this study is believed to help the land use planners for improved regional planning to create balanced ecosystem, especially in a changing climate. PMID- 29153552 TI - Cervical margin relocation in indirect adhesive restorations: A literature review. AB - PURPOSE: The aim of this review was to summarize the existing scientific literature investigating on cervical margin relocation technique (CMR) performed prior to the adhesive cementation of the indirect restorations. STUDY SELECTION: An electronic search with no date restriction was conducted in the MEDLINE database, accessed through PubMed. The following main keywords were used: "cervical margin relocation", "coronal margin relocation", "deep margin elevation" and "proximal box elevation". RESULTS: Seven in vitro studies and 5 clinical reports investigating on CMR are taken into consideration for the present review. The most frequently investigated parameter in almost all of the in vitro studies was the marginal adaptation of the indirect restorations. One study additionally assessed the influence of CMR on the fracture behavior of the restored teeth and one study assessed the bond strength of the indirect composite restoration to the proximal box floor. Clinical reports provided documentation with a detailed description of the treatment protocol. In the current literature no randomized controlled clinical trials or prospective or retrospective clinical studies on CMR technique could be found. CONCLUSIONS: On the basis of the reviewed literature, it can be concluded that currently there is no strong scientific evidence that could either support or discourage the use of CMR technique prior to restoration of deep subgingival defects with indirect adhesive restorations. Randomized controlled clinical trials are necessary to provide the reliable evidence on the influence of CMR technique on the clinical performance, especially on the longevity of the restorations and the periodontal health. PMID- 29153553 TI - Effectiveness of an early switch from intravenous to oral antimicrobial therapy for lower respiratory tract infection in patients with severe motor intellectual disabilities. AB - An early switch from intravenous to oral antimicrobial therapy is useful for reducing the duration of the hospitalization in adult patients with community acquired-pneumonia, whereas the efficacy of switch therapy for pediatric patients with community acquired (CA)-lower respiratory tract infection (LRTI) is uncertain. The aim of this study is to investigate the efficacy of switch therapy for LRTI in patients with severe motor intellectual disabilities (SMID). This retrospective study was performed on 92 patients with SMID who were admitted to the Department of Pediatrics at the Hospital of University of Occupational and Environmental Health, Japan from April 1, 2010 to March 31, 2017 for the suspicion of bacterial LRTI and were initially treated with an intravenous antimicrobial agent. Clinical outcomes were compared between patients with switch therapy (Switch therapy group) and conventional intravenous antimicrobial therapy (No switch therapy group). Thirteen and 79 in patients with SMID belonged to Switch thrapy group and No switch therapy group, respectively. Length of hospital stay in Switch therapy group was significantly shorter than that in No switch therapy group (P = 0.002). In the patients undergoing switch therapy, there was no patient who required re-treatment and/or re-hospitalization. Switch therapy for LRTI was useful for the reduction of length of hospital stay without increasing risk of re-treatment and re-hospitalization in patients with SMID. PMID- 29153554 TI - Organic synthesis in flow for medicinal chemistry. PMID- 29153555 TI - A prospective follow-up of quality of life, depression, and anxiety in children with lymphoma and solid tumors AB - Background/aim: The aim of this study was the determination and prospective follow-up of quality of life, depression, and anxiety in pediatric patients with cancer under chemotherapy, as well as the evaluation of related factors. Materials and methods: Fifty newly diagnosed pediatric cancer patients and their parents were prospectively monitored before, during, and after therapy, and tests were used. Results: Significantly lower quality of life scores were recorded during treatment, in the group with CNS tumors, in the group receiving chemotherapy plus radiotherapy plus surgery, in the inpatient-only treatment group, in the group receiving treatment for longer than 6 months, and in the group of patients whose diagnosis was delayed for more than 3 months. Total quality of life scores for children and their parents were 82.95 +/- 14.59 vs. 83.61 +/- 14.60 before, 54.69 +/- 16.51 vs. 55.78 +/- 16.05 during, and 83.88 +/- 12.44 vs. 84.19 +/- 13.22 at the end of treatment (P < 0.05). Anxiety and depression scores were significantly higher during treatment, in patients whose diagnoses were delayed for more than 3 months, and among inpatients. Conclusion: The quality of life of a majority of our patients was severely affected, and depression and anxiety were more frequently seen especially during treatment. PMID- 29153556 TI - Fatty Acids in Nephrotic Syndrome and Chronic Kidney Disease. AB - The role of fatty acids (FAs) in inflammation and in the related chronic diseases has been demonstrated. However, there is a lack of consistent and agreed knowledge about the role of FA profile and renal physiology and pathology, most articles focusing on the effect of polyunsaturated FAs supplementation, without considering the impact of basal FA metabolism on the efficacy of the supplementation. Here, we have summarized the specific literature concerning the assessment of circulating FA in 2 renal diseases, namely nephrotic syndrome and chronic kidney disease, also under hemodialytic treatment, and have received the most significant contributions in the last years. The effects of changes of FA profile and metabolism and the possible involvement of polyunsaturated FA metabolites in raising and modulating inflammation are discussed. PMID- 29153557 TI - Cardiovascular risk and obesity in sleep apnea syndrome assessed with the Stop Bang questionnaire. AB - INTRODUCTION: Sleep disorders include a number of different processes, of which the most prevalent is the sleep apnea-hypopnea syndrome (SAHS). Prevalence of SAHS has increased worldwide, and has a significant social and health impact because of the increased cardiometabolic risk attributed to obesity and the associated metabolic syndrome. MATERIAL AND METHODS: A cross-sectional epidemiological study of 1110 workers from public service companies in the Spanish Mediterranean area (Balearic Islands and Valencian Community) was conducted between January and December 2015. Cardiovascular risk was calculated using the Castelli, Kannel and TG/HDL indices, and prevalence of obesity using body mass index, waist circumference, waist-height ratio, and visceral fat. SAHS risk was assessed using the Stop-Bang questionnaire. RESULTS: Risk of SAHS was low in 77% of patients and intermediate-high in 23% of patients. All obesity parameters showed a statistically significant association (p value <.001) with intermediate/high risk of SAHS. Obesity prevalence is higher the worse the quality of sleep. There was a statistically significant relationship between risk of SAHS and cardiovascular risk with the atherogenic indexes found. CONCLUSIONS: Twenty-three percent of workers had intermediate/high SAHS risk. The results of this study support the relationship of SAHS with an increased CVR and with obesity parameters. Further prospective studies in different productive sectors may be useful to confirm the results of this research. PMID- 29153559 TI - Multiparametric assessment of "fluid status" in heart failure. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.ejim.2017.09.016. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 29153558 TI - Novel indole and triazole based hybrid molecules exhibit potent anti-adipogenic and antidyslipidemic activity by activating Wnt3a/beta-catenin pathway. AB - Obesity and dyslipidemia is the two facet of metabolic syndrome, which needs further attention. Recent studies indicate triazole and indole derivatives have remarkable anti-obesity/antidyslipidemic activity. To harness the above-mentioned potential, a series of novel triazole clubbed indole derivatives were prepared using click chemistry and evaluated for anti-adipogenic activity. Based on the structure-activity relationship, essential functional groups which potentiate anti-adipogenic activity were identified. The lead compound 13m exhibited potent anti-adipogenic activity compared to its parent compounds with the IC-50 value of 1.67 MUM. Further evaluation of anti-adipogenic activity was conducted in different cell lines such as C3H10T1/2 and hMSC with positive result. The anti adipogenic effect of compound 13m was most prominent in the early phase of adipogenesis, which is driven by the G1 to S phase cell cycle arrest during mitotic clonal expansion. The mechanistic study suggests that compound 13m exhibit anti-adipogenic property by activating Wnt3a/beta-catenin pathway, a known suppressor of key adipogenic genes PPARgamma and C/EBPalpha. It is noteworthy that the compound 13m also reduced serum triglyceride, LDL and total cholesterol in Syrian Golden hamster model of dyslipidemia. The anti-adipogenic activity of compound 13m can also be correlated with decreased expression of PPARgamma and increased expression of beta-catenin in epididymal white adipose tissue (eWAT) in vivo. The compound 13m also increased the expression of genes involved in reverse cholesterol transport (RCT) such as PPARalpha and LXR1alpha indicating another mechanism by which compound 13m ameliorates dyslipidemia in Syrian Golden hamster model. Overall this study provides a unique perspective into the anti-adipogenic/antidyslipidemic property of triazole and indole hybrids molecules with further scope to increase the anti-adipogenic potency for therapeutic intervention of obesity and metabolic syndrome. PMID- 29153560 TI - Distribution and determinants of QRS rotation of black and white persons in the general population. AB - BACKGROUND: The prevalence and determinants of QRS transition zones are not well established. METHODS: We examined the distributions of Normal, clockwise (CW) and counterclockwise (CCW)) QRS transition zones and their relations to disease, body size and demographics in 4624 black and white men and women free of cardiovascular disease and major ECG abnormalities enrolled in the NHANES-III survey. RESULTS: CW transition zones were least observed (6.2%) and CCW were most prevalent (60.1%) with Normal in an intermediate position (33.7%). In multivariable logistic regression analysis, the adjusted, significant predictors for CCW compared to Normal were a greater proportion of blacks and women, fewer thin people (BMI<20, thin), a greater ratio of chest depth to chest width, and an LVMass index <80g. By contrast, CW persons were older, had larger QRS/T angles, smaller ratio of chest depth to chest width, had a greater proportion of subjects with low voltage QRS, more pulmonary disease, a greater proportion with high heart rates, shorter QRS duration and were more obese (BMI>=30). CONCLUSIONS: Normal rather than being the most prevalent transition zone was intermediate in frequency between the most frequently encountered CCW and the least frequently encountered transition zone CW. Differences in the predictors of CW and CCW exist. This requires further investigation to examine how far these differences explain the differences in the published prognostic differences between CW and CCW. PMID- 29153561 TI - Use of Atrial Strain to Predict Atrial Fibrillation After Cerebral Ischemia. AB - OBJECTIVES: This study sought to identify whether atrial strain could be used as an imaging biomarker to predict atrial fibrillation (AF). BACKGROUND: AF is found in up to 30% of cryptogenic cerebrovascular accidents (CVAs), which themselves account for 30% to 40% of ischemic CVA. METHODS: This observational study evaluated all patients who had an echocardiogram (transthoracic echocardiogram [TTE]) following presentation with cryptogenic CVA from 2010 to 2014. The TTEs were evaluated for reservoir strain (ER), contractile strain (ECt), and conduit atrial strain (ECd) using speckle tracking. Baseline clinical and TTE characteristics of patients who developed AF over 5 years of follow-up and those who did not were compared. The independent and incremental predictive value of atrial strain over established clinical models was assessed. Discriminatory cutpoints were defined using a Classification and Regression Tree (CART) analysis to identify patients at risk of developing AF. RESULTS: Of 538 patients, 61 (11%) developed AF, and this occurred within 2 years in 85% of patients. Patients who developed AF were older, had higher clinical risk scores, had higher LA volume, and had lower atrial strain than did those who did not develop AF. The area under the receiver-operating characteristic curve was 0.85 for ER, 0.83 for ECt, and 0.76 for ECd (all p < 0.001). The nested Cox regression model showed that ER (p = 0.03) and ECt (p < 0.001) demonstrated independent and incremental predictive value over the clinical risk. CART analysis identified ER <=21.4%, ECd >10.4%, and CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation) score >7.8% as discriminatory for AF, with a 13-fold greater hazard of AF (p < 0.001) in patients with increased clinical risk and reduced ER. However, validation is needed for these strain cutoffs for detection of AF. CONCLUSIONS: Left atrial strain adds independent and incremental predictive value to current risk-prediction models for AF following cryptogenic CVA. Further studies should examine the implications of these findings for AF monitoring or empiric anticoagulation. PMID- 29153562 TI - Noncontrast Myocardial T1 Mapping by Cardiac Magnetic Resonance Predicts Outcome in Patients With Aortic Stenosis. AB - OBJECTIVES: The aim of this study was to evaluate whether native T1 value of the myocardium on cardiac magnetic resonance (CMR) could predict clinical events in patients with significant aortic stenosis (AS). BACKGROUND: Although previous studies have demonstrated the prognostic value of focal fibrosis using late gadolinium enhancement (LGE) by CMR in AS patients, the prognostic implication of diffuse myocardial fibrosis by noninvasive imaging remains unknown. METHODS: A prospective observational longitudinal study was performed in 127 consecutive patients with moderate or severe AS (68.8 +/- 9.2 years of age, 49.6% male) and 33 age- and sex-matched controls who underwent 3-T CMR. The degree of diffuse myocardial fibrosis was assessed by noncontrast mapping of T1 relaxation time using modified Look-Locker inversion-recovery sequence, and the presence and extent of LGE were also evaluated. The AS patients were divided into 3 groups by the native T1 value. Primary endpoint was a composite of all-cause death and hospitalization for heart failure. RESULTS: Native T1 value was higher in AS patients, compared with control subjects (1,232 +/- 53 ms vs. 1,185 +/- 37 ms; p = 0.008). During follow-up (median 27.9 months), there were 24 clinical events including 9 deaths (6 pre-operative and 3 post-operative), the majority of which occurred in the patients in the highest T1 tertile group (2.4% vs. 11.6% vs. 42.9% for lowest, mid-, and highest tertile groups; p < 0.001 by log-rank test). The total number of events for both pre- and post-operative events also occurred more frequently in patients in the highest T1 tertile group. EuroSCORE II, the presence and/or extent of LGE, and the native T1 value were predictors of poor prognosis (adjusted hazard ratio for every 20-ms increase of native T1: 1.28; p = 0.003). In particular, the highest native T1 value provided further risk stratification regardless of the presence of LGE. CONCLUSIONS: High native T1 value on noncontrast T1 mapping CMR is a novel, independent predictor of adverse outcome in patients with significant AS. PMID- 29153563 TI - Surrogate Survival: Battle Between Left Ventricular Ejection Fraction and Global Longitudinal Strain. PMID- 29153564 TI - Sex Dimorphism in the Myocardial Response to Aortic Stenosis. AB - OBJECTIVES: The goal of this study was to explore sex differences in myocardial remodeling in aortic stenosis (AS) by using echocardiography, cardiac magnetic resonance (CMR), and biomarkers. BACKGROUND: AS is a disease of both valve and left ventricle (LV). Sex differences in LV remodeling are reported in AS and may play a role in disease phenotyping. METHODS: This study was a prospective assessment of patients awaiting surgical valve replacement for severe AS using echocardiography, the 6-min walking test, biomarkers (high-sensitivity troponin T and N-terminal pro-brain natriuretic peptide), and CMR with late gadolinium enhancement and extracellular volume fraction, which dichotomizes the myocardium into matrix and cell volumes. LV remodeling was categorized into normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy. RESULTS: In 168 patients (age 70 +/- 10 years, 55% male, indexed aortic valve area 0.40 +/- 0.13 cm2/m2, mean gradient 47 +/- 4 mm Hg), no sex or age differences in AS severity or functional capacity (6-min walking test) were found. CMR captured sex dimorphism in LV remodeling not apparent by using 2 dimensional echocardiography. Normal geometry (82% female) and concentric remodeling (60% female) dominated in women; concentric hypertrophy (71% male) and eccentric hypertrophy (76% male) dominated in men. Men also had more evidence of LV decompensation (pleural effusions), lower left ventricular ejection fraction (67 +/- 16% vs. 74 +/- 13%; p < 0.001), and higher levels of N-terminal pro-brain natriuretic peptide (p = 0.04) and high-sensitivity troponin T (p = 0.01). Myocardial fibrosis was higher in men, with higher focal fibrosis (late gadolinium enhancement 16.5 +/- 11.2 g vs. 10.5 +/- 8.9 g; p < 0.001) and extracellular expansion (matrix volume 28.5 +/- 8.8 ml/m2 vs. 21.4 +/- 6.3 ml/m2; p < 0.001). CONCLUSIONS: CMR revealed sex differences in associations between AS and myocardial remodeling not evident from echocardiography. Given equal valve severity, the myocardial response to AS seems more maladaptive in men than previously reported. (Regression of Myocardial Fibrosis After Aortic Valve Replacement [RELIEF-AS]; NCT02174471). PMID- 29153565 TI - Left Atrial Strain to Address the Cryptogenic Puzzle. PMID- 29153566 TI - Incremental Diagnostic Value of Left Atrial Strain Over Left Atrial Volume: An Analogy of Glucose Level and Glycosylated Hemoglobin? PMID- 29153567 TI - Potential Usefulness and Clinical Relevance of Adding Left Atrial Strain to Left Atrial Volume Index in the Detection of Left Ventricular Diastolic Dysfunction. AB - OBJECTIVES: The purpose of this study was to analyze the potential usefulness and clinical relevance of adding left atrial (LA) strain to left atrial volume index (LAVI) in the detection of left ventricular diastolic dysfunction (LVDD) in patients with preserved left ventricular ejection fraction (LVEF). BACKGROUND: Recent studies have suggested that LA strain could be of use in the evaluation of LVDD. However, the potential utility and clinical significance of adding LA strain to LAVI in the detection of LVDD remains uncertain. METHODS: Using 2 dimensional speckle-tracking echocardiography, we analyzed a population of 517 patients in sinus rhythm at risk for LVDD such as those with arterial hypertension, diabetes mellitus, or history of coronary artery disease and preserved LVEF. RESULTS: In patients with LV diastolic alterations and estimated elevated LV filling pressures, the rate of abnormal LA strain was significantly higher than an abnormal LAVI (62.4% vs. 33.6%, p < 0.01). In line with this, in patients with normal LAVI, high rates of LV diastolic alterations and abnormal LA strain were present (rates 80% and 29.4%, respectively). In agreement with these findings, adding LA strain to LAVI in the current evaluation of LVDD increased significantly the rate of detection of LVDD (relative and absolute increase 73.3% and 9.9%; rate of detection of LVDD: from 13.5% to 23.4%; p < 0.01). Regarding the clinical relevance of these findings, an abnormal LA strain (i.e., <23%) was significantly associated with worse New York Heart Association functional class, even when LAVI was normal. Moreover, in a retrospective post hoc analysis an abnormal LA strain had a significant association with the risk of heart failure hospitalization at 2 years (odds ratio: 6.6 [95% confidence interval: 2.6 to 16.6]) even adjusting this analysis for age and sex and in patients with normal LAVI. CONCLUSIONS: The findings from this study provide important insights regarding the potential usefulness and clinical relevance of adding LA strain to LAVI in the detection of LVDD in patients with preserved LVEF. PMID- 29153569 TI - On Books, Covers, and Judgments in Heart Failure. PMID- 29153568 TI - Maternal Obesity and Cardiac Development in the Offspring: Study in Human Neonates and Minipigs. AB - OBJECTIVES: The aim of this study was to investigate the consequences of maternal overweight on cardiac development in offspring in infants (short term) and minipigs (short and longer term). BACKGROUND: The epidemic of overweight involves pregnant women. The uterine environment affects organ development, modulating disease susceptibility. Offspring of obese mothers have higher rates of cardiovascular events and mortality. METHODS: Echocardiography was performed in infants born to lean and overweight mothers at birth and at 3, 6, and 12 months of age. In minipigs born to mothers fed a high-fat diet or a normal diet, cardiac development (echocardiography, histology), glucose metabolism and perfusion (positron emission tomography), triglyceride and glycogen content, and myocardial enzymes regulating metabolism (mass spectrometry) were determined from birth to adulthood. RESULTS: In neonates, maternal overweight, especially in the last trimester, predicted a thicker left ventricular posterior wall at birth (4.1 +/- 0.3 vs. 3.3 +/- 0.2 mm; p < 0.05) and larger end-diastolic and stroke volumes at 1 year. Minipigs born to mothers fed a high-fat diet showed greater left ventricular mass (p = 0.0001), chambers (+100%; p < 0.001), stroke volume (+75%; p = 0.001), cardiomyocyte nuclei (+28%; p = 0.02), glucose uptake, and glycogen accumulation at birth (+100%; p < 0.005), with lower levels of oxidative enzymes, compared with those born to mothers fed a normal diet. Subsequently, they developed myocardial insulin resistance and glycogen depletion. Late adulthood showed elevated heart rate (111 +/- 5 vs. 84 +/- 8 beats/min; p < 0.05) and ejection fraction and deficient fatty acid oxidative enzymes. CONCLUSIONS: Neonatal changes in cardiac morphology were explained by late-trimester maternal body mass index; myocardial glucose overexposure seen in minipigs can justify early human findings. Longer term effects in minipigs consisted of myocardial insulin resistance, enzymatic alterations, and hyperdynamic systolic function. PMID- 29153570 TI - Transthoracic Echocardiographic Findings of Mitral Regurgitation Caused by Commissural Prolapse. PMID- 29153571 TI - Association of Abnormal Left Ventricular Functional Reserve With Outcome in Heart Failure With Preserved Ejection Fraction. AB - OBJECTIVES: This study sought to determine the prognostic value of abnormal diastolic and systolic responses to exercise (on the basis of exertional E/e' and global longitudinal strain rate [GSR]) in a well-characterized population of patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Impaired cardiovascular functional reserve is believed to contribute to adverse outcomes in HFpEF. However, the exact characteristics of pathophysiological profiles associated with increased clinical risk are still poorly defined. METHODS: A complete echocardiogram (including assessment of myocardial deformation) was performed at rest in 205 patients (64 +/- 8 years of age) with symptomatic HFpEF. Echocardiography following maximal exercise was undertaken to assess abnormal diastolic reserve (AbnDR) (exertional E/e' >14) and exercise GSR. Patients were followed over 26 +/- 5 months for death and cardiovascular or heart failure (HF) hospitalization. RESULTS: Cardiovascular hospitalization or death occurred in 64 patients (31%), including 51 (25%) with HF hospitalization. The composite endpoint was associated with AbnDR (hazard ratio: 2.69; 95% confidence interval: 1.44 to 5.04; p = 0.002) and reduced exercise GSR (hazard ratio: 0.14; 95% confidence interval: 0.04 to 0.49; p = 0.002). Both exercise parameters showed prognostic value, independent from and incremental to clinical data and B type natriuretic peptide. The ability of E/e' and GSR measurements to predict outcomes on exertion exceeded their prognostic value at rest, and the presence of reduced exertional GSR in patients with AbnDR was associated with worse prognosis (p = 0.03 for the composite endpoint and p = 0.01 for HF hospitalization). CONCLUSIONS: Both left ventricular systolic and diastolic reserves contribute to risk prediction in HFpEF. The inclusion of the exertional assessment of left ventricular function to diagnostic algorithms may improve the prognostication process in this disease condition. PMID- 29153573 TI - 3-Dimensional Echocardiographic Analysis of the Tricuspid Annulus Provides New Insights Into Tricuspid Valve Geometry and Dynamics. AB - OBJECTIVES: The authors used transthoracic 3-dimensional transthoracic echocardiography (3DE) to characterize tricuspid annulus (TA) geometry and dynamics in healthy volunteers. BACKGROUND: Accurate sizing of the TA is essential for planning tricuspid annuloplasty and for implantation of new percutaneous tricuspid devices. METHODS: 3DE of the TA from 209 healthy volunteers was analyzed using custom software to measure TA area, perimeter, circularity, and dimensions at end diastole (equals tricuspid valve closure), mid systole, end systole, and late diastole. TA intercommissural distances were measured at mid-systole. For comparison, TA diameters were measured at the same time points on multiplanar reconstruction of the 3DE datasets and on 2 dimensional transthoracic echocardiography (2DE) apical 4-chamber and right ventricular focused views. In 13 subjects with both 3DE and computed tomography, TA parameters were compared. RESULTS: 3DE TA area, perimeter, and dimensions were largest in late diastole and smallest at mid-systole/end systole. Normal tricuspid valve parameters in end diastole were 8.6 +/- 2.0 cm2 for area; 10.5 +/ 1.2 cm for perimeter; 36 +/- 4 mm and 30 +/- 4 mm for longest and shortest dimensions, respectively; and 0.83 +/- 0.10 for circularity. There were no age related changes in TA parameters. Women had larger indexed TA perimeter and longer long-axis dimensions compared with men. The longest 3DE TA dimension was significantly longer than diameters measured from both 2DE and 3D multiplanar reconstruction. 3DE TA area, perimeter, and dimensions correlated with both right atrial and right ventricular volumes, suggesting that both chambers may be determinants of TA size. TA fractional area change was 35 +/- 10%. Fractional changes in both perimeter and dimensions were >=20%. When compared with computed tomography, 3DE systematically underestimated TA parameters. CONCLUSIONS: Gender and body size should be taken into account to identify the reference values of TA dimensions. 2DE underestimates TA dimensions. PMID- 29153572 TI - Prognostic Value of Quantitative Stress Perfusion Cardiac Magnetic Resonance. AB - OBJECTIVES: This study sought to evaluate the prognostic usefulness of visual and quantitative perfusion cardiac magnetic resonance (CMR) ischemic burden in an unselected group of patients and to assess the validity of consensus-based ischemic burden thresholds extrapolated from nuclear studies. BACKGROUND: There are limited data on the prognostic value of assessing myocardial ischemic burden by CMR, and there are none using quantitative perfusion analysis. METHODS: Patients with suspected coronary artery disease referred for adenosine-stress perfusion CMR were included (n = 395; 70% male; age 58 +/- 13 years). The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, aborted sudden death, and revascularization after 90 days. Perfusion scans were assessed visually and with quantitative analysis. Cross-validated Cox regression analysis and net reclassification improvement were used to assess the incremental prognostic value of visual or quantitative perfusion analysis over a baseline clinical model, initially as continuous covariates, then using accepted thresholds of >=2 segments or >=10% myocardium. RESULTS: After a median 460 days (interquartile range: 190 to 869 days) follow-up, 52 patients reached the primary endpoint. At 2 years, the addition of ischemic burden was found to increase prognostic value over a baseline model of age, sex, and late gadolinium enhancement (baseline model area under the curve [AUC]: 0.75; visual AUC: 0.84; quantitative AUC: 0.85). Dichotomized quantitative ischemic burden performed better than visual assessment (net reclassification improvement 0.043 vs. 0.003 against baseline model). CONCLUSIONS: This study was the first to address the prognostic benefit of quantitative analysis of perfusion CMR and to support the use of consensus-based ischemic burden thresholds by perfusion CMR for prognostic evaluation of patients with suspected coronary artery disease. Quantitative analysis provided incremental prognostic value to visual assessment and established risk factors, potentially representing an important step forward in the translation of quantitative CMR perfusion analysis to the clinical setting. PMID- 29153574 TI - Myocardial Stiffness Assessment Using Shear Wave Imaging in Pediatric Hypertrophic Cardiomyopathy. PMID- 29153576 TI - Coronary Artery Calcium and Long-Term Risk of Death, Myocardial Infarction, and Stroke: The Walter Reed Cohort Study. AB - OBJECTIVES: This study aimed to assess the long-term risk of death and atherosclerotic cardiovascular disease (ASCVD) outcomes, including stroke, in a real-world cohort that underwent coronary artery calcium (CAC) scoring. BACKGROUND: Large-scale, long-term studies assessing the independent relationship of CAC for prediction of ASCVD events, to include stroke, in young, low-risk patients are uncommon outside of the clinical trial setting. METHODS: A total of 23,637 consecutive subjects without ASCVD who underwent CAC scoring from 1997 to 2009 were studied. Subjects were assessed for myocardial infarction (MI), stroke, major adverse cardiovascular events (MACE) (e.g., MI, stroke, or cardiovascular death), and all-cause mortality. Outcomes were extracted from the Military Data Repository and the National Death Index and assessed using Cox proportional hazards models, controlling for baseline risk factors, atrial fibrillation, and competing mortality. RESULTS: Patients (mean age 50.0 +/- 8.5 years) were followed over a median of 11.4 years. The relative adjusted subhazard ratio (aSHR) for CAC 1 to 100, 101 to 400, and >400 was 2.2, 3.8, and 5.9 for MI; 1.2, 1.4, and 1.9 for stroke; 1.4, 2.0, and 2.8 for MACE; and 1.2, 1.5 and 2.1 for death (p < 0.0001). The addition of CAC score to risk factors significantly improved the prognostic accuracy for all outcomes by the likelihood ratio test. Area under the curve increased from 0.658 to 0.738 for MI, 0.703 to 0.704 for stroke, 0.685 to 0.705 for MACE, and 0.759 to 0.767 for mortality. Among subjects without traditional risk factors (n = 6,208; mean age 43.8 +/- 4.4 years), the presence of any CAC (>0; n = 848) was associated with an increased risk of MACE (aSHR: 1.67; 95% confidence interval: 1.16 to 2.39). CONCLUSIONS: CAC scoring significantly improved long-term prognostic accuracy for MACE events and mortality, irrespective of age and risk factors. These results support CAC screening for improving individual ASCVD risk assessment and prevention in low risk, young adults. PMID- 29153575 TI - Persistent Iron Within the Infarct Core After ST-Segment Elevation Myocardial Infarction: Implications for Left Ventricular Remodeling and Health Outcomes. AB - OBJECTIVES: This study sought to determine the incidence and prognostic significance of persistent iron in patients post-ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The clinical significance of persistent iron within the infarct core after STEMI complicated by acute myocardial hemorrhage is poorly understood. METHODS: Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction]). Cardiac magnetic resonance imaging including T2* (observed time constant for the decay of transverse magnetization seen with gradient-echo sequences) mapping was performed at 2 days and 6 months post-STEMI. Myocardial hemorrhage or iron was defined as a hypointense infarct core with T2* signal <20 ms. RESULTS: A total of 203 patients (age 57 +/- 11 years, n = 158 [78%] male) had evaluable T2* maps at 2 days and 6 months post-STEMI; 74 (36%) patients had myocardial hemorrhage at baseline, and 44 (59%) of these patients had persistent iron at 6 months. Clinical associates of persistent iron included heart rate (p = 0.009), the absence of a history of hypertension (p = 0.017), and infarct size (p = 0.028). The presence of persistent iron was associated with worsening left ventricular (LV) end-diastolic volume (regression coefficient: 21.10; 95% confidence interval [CI]: 10.92 to 31.27; p < 0.001) and worsening LV ejection fraction (regression coefficient: -6.47; 95% CI: -9.22 to -3.72; p < 0.001). Persistent iron was associated with the subsequent occurrence of all cause death or heart failure (hazard ratio: 3.91; 95% CI: 1.37 to 11.14; p = 0.011) and major adverse cardiac events (hazard ratio: 3.24; 95% CI: 1.09 to 9.64; p = 0.035) (median follow-up duration 1,457 days [range 233 to 1,734 days]). CONCLUSIONS: Persistent iron at 6 months post-STEMI is associated with worse LV and longer-term health outcomes. (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI]; NCT02072850). PMID- 29153577 TI - 2D and 3D Echocardiography-Derived Indices of Left Ventricular Function and Shape: Relationship With Mortality. AB - OBJECTIVES: This study hypothesized that left ventricular (LV) ejection fraction (EF) and global longitudinal strain (GLS) derived from 3-dimensional echocardiographic (3DE) images would better predict mortality than those obtained by 2-dimensional echocardiographic (2DE) measurements, and that 3DE-based LV shape analysis may have added prognostic value. BACKGROUND: Previous studies have shown that both LVEF and GLS derived from 2DE images predict mortality. Recently, 3DE measurements of these parameters were found to be more accurate and reproducible because of independence of imaging plane and geometric assumptions. Also, 3DE analysis offers an opportunity to accurately quantify LV shape. METHODS: We retrospectively studied 416 inpatients (60 +/- 18 years of age) referred for transthoracic echocardiography between 2006 and 2010, who had good quality 2DE and 3DE images were available. Mortality data through 2016 were collected. Both 2DE and 3DE images were analyzed to measure LVEF and GLS. Additionally, 3DE-derived LV endocardial surface information was analyzed to obtain global shape indices (sphericity and conicity) and regional curvature (anterior, septal, inferior, lateral walls). Cardiovascular (CV) mortality risks related to these indices were determined using Cox regression. RESULTS: Of the 416 patients, 208 (50%) died, including 114 (27%) CV-related deaths over a mean follow-up period of 5 +/- 3 years. Cox regression revealed that age and body surface area, all 4 LV function indices (2D EF, 3D EF, 2D GLS, 3D GLS), and regional shape indices (septal and inferior wall curvatures) were independently associated with increased risk of CV mortality. GLS was the strongest prognosticator of CV mortality, superior to EF for both 2DE and 3DE analyses, and 2D EF was the weakest among the 4 functional indices. A 1% decrease in GLS magnitude was associated with an 11.3% increase in CV mortality risk. CONCLUSIONS: GLS predicts mortality better than EF by both 3DE and 2DE analysis, whereas 3D EF is a better predictor than 2D EF. Also, LV shape indices provide additional risk assessment. PMID- 29153578 TI - Long-Term Structural Integrity and Durability of the Medtronic CoreValve System After Transcatheter Aortic Valve Replacement. PMID- 29153579 TI - Liquid chromatography coupled to quadrupole-Orbitrap high resolution mass spectrometry based method for target analysis and suspect screening of non-ionic surfactants in textiles. AB - In this study, we describe a high-throughput and sensitive method for textiles analysis, using liquid chromatography coupled to quadrupole-Orbitrap high resolution mass spectrometry (LC-Q-Orbitrap HRMS), for the simultaneously quantitative analysis of 40 target alkylphenol polyethoxylates (APEO) oligomers with reference standards and screening of 160 alcohol polyethoxylates (AEO) oligomers without standards in textiles. The APEOs contain nonylphenol ethoxylates (NPEOs) and octylphenol ethoxylates (OPEOs) with an EO number of ethylene oxide of 1-20, while AEOs focus on C11EOs-C18EOs with an EO number of 1 20. After ultrasonic extraction in methanol, the extract was directly separated using a core-shell CORTECS C18+ column and analyzed by Full MS/dd-MS2 (data dependent acquisition) scan in ESI positive mode. Two best sensitivity experimental conditions for APEOs with short EO chains (AP(EO)1-2) and long EO chains (AP(EO)3-20) were investigated, respectively. Most APEO oligomers had wide concentration ranges and the correlation coefficients (R2) were higher than 0.999. The limit of quantitation (LOQ) values for NP(EO)3-20 oligomers ranges from 16.00 to 52.80MUg/kg and for OP(EO)3-20 oligomers is from 2.40 to 8.00MUg/kg. LOQ for NP(EO)1 and NP(EO)2, OP(EO)1 and OP(EO)2 was 2.40mg/kg and 0.24mg/kg, 1.20mg/kg and 0.16mg/kg, respectively. The average recovery for each APEO oligomer in cotton and polyester matrix was between 78% and 110% at three spiked levels and the relative standard deviation (RSD%) was below 10%. As to AEOs suspects, a HRMS compound database containing 160 AEO oligomers was built and several parameters such as exact m/z, isotopic patterns, predicted product ions and predicted retention time were used for screening and confirmation. The established method was successfully applied for analysis of 40 commercial textile samples. Compared with OPEOs, NPEOs, especially NP(EO)3-15 oligomers, were widely detected in samples and the total concentration ranged from 1.56 to 1376.31mg/kg. AEOs were also found in most samples, among which C12-14, C16 and C18 compounds appeared more frequently and the EO chains mainly ranged from 3 to 15. PMID- 29153580 TI - Effectiveness and Safety of Oro-Dispersible Sildenafil in a New Film Formulation for the Treatment of Erectile Dysfunction: Comparison Between Sildenafil 100-mg Film-Coated Tablet and 75-mg Oro-Dispersible Film. AB - BACKGROUND: A new oro-dispersible film (ODF) formulation of sildenafil has been developed for the treatment of erectile dysfunction (ED) to overcome the drawbacks that some patients experience when taking the conventional film-coated tablet (FCT). AIM: To assess the effectiveness and safety of sildenafil ODF formulation in patients with ED who were using the conventional FCT. METHODS: From May 2017 through July 2017, 139 patients with ED were enrolled. Data from penile color-duplex ultrasound, medical history, hormonal evaluation, and patient self-administered questionnaires were collected. All patients were administered sildenafil 100-mg FCT for 4 weeks. Thereafter, they underwent a 2-week washout period and subsequently took sildenafil 75-mg ODF for 4 weeks. OUTCOMES: The International Index of Erectile Function (IIEF-15), Hospital Anxiety and Depression Scale (HADS), Patient Global Impressions of Improvement (PGI-I), and Clinician Global Impressions of Improvement (CGI-I) questionnaires were administered and severity of ED was classified as severe (IIEF-15 score <= 10), moderate (IIEF-15 score 11-16), or mild (IIEF-15 score = 17-25). RESULTS: All patients completed the final protocol. Differences in mean IIEF scores for erectile function, orgasmic function, sexual desire, and intercourse satisfaction were significantly in favor of sildenafil 100-mg FCT, whereas the mean score for overall satisfaction was in favor of sildenafil 75-mg ODF. A significant difference in changes in HADS score was found from washout to final follow-up (mean difference = -0.19; P < .01). For the ODF formulation, the median CGI-I score was 3.5 (interquartile range [IQR] = 2.5-4.5) and the median PGI-I score was 3.0 (IQR = 2.0-4.0). The median action time was 20.0 minutes (IQR = 15.0 30.0) and the median mouth time was 60.0 seconds (IQR = 30.0-120.0). CLINICAL IMPLICATIONS: The ODF formulation of a widely known drug, with the same safety and effectiveness of the FCT, was better appreciated by patients in overall satisfaction. STRENGTHS AND LIMITATIONS: This is the first clinical trial to assess the efficacy of a new formulation of sildenafil in patients with ED. The limitations of the study are related to the methodology used: it was not a case control study and the patients were not drug-naive for ED treatment. Therefore, only the "additional" side effects of the ODF formulation compared with FCT are reported. CONCLUSION: The new ODF formulation is as efficient and safe as the FCT formulation and offers a new choice of treatment to specialists for more precisely tailored therapy. Cocci A, Capece M, Cito G, et al. Effectiveness and Safety of Oro-Dispersible Sildenafil in a New Film Formulation for the Treatment of Erectile Dysfunction: Comparison Between Sildenafil 100-mg Film-Coated Tablet and 75-mg Oro-Dispersible Film. J Sex Med 2017;14:1606-1611. PMID- 29153581 TI - Novel Application of Micro-Computerized Tomography for Morphologic Characterization of the Murine Penis. AB - BACKGROUND: The murine penis model has enriched our understanding of anomalous penile development. The morphologic characterization of the murine penis using conventional serial sectioning methods is labor intensive and prone to errors. AIM: To develop a novel application of micro-computerized tomography (micro-CT) with iodine staining for rapid, non-destructive morphologic study of murine penis structure. METHODS: Penises were dissected from 10 adult wild-type mice and imaged using micro-CT with iodine staining. Images were acquired at 5-MUm spatial resolution on a Bruker SkyScan 1272 micro-CT system. After images were acquired, the specimens were washed of any remaining iodine and embedded in paraffin for conventional histologic examination. Histologic and micro-CT measurements for all specimens were made by 2 independent observers. OUTCOMES: Measurements of penile structures were made on virtual micro-CT sections and histologic slides. RESULTS: The Lin concordance correlation coefficient demonstrated almost perfect strength of agreement for interobserver variability for histologic section (0.9995, 95% CI = 0.9990-0.9997) and micro-CT section (0.9982, 95% CI = 0.9963-0.9991) measurements. Bland-Altman analysis for agreement between the 2 modalities of measurement demonstrated mean differences of -0.029, 0.022, and -0.068 mm for male urogenital mating protuberance, baculum, and penile glans length, respectively. There did not appear to be a bias for overestimation or underestimation of measured lengths and limits of agreement were narrow. CLINICAL TRANSLATION: The enhanced ability offered by micro-CT to phenotype the murine penis has the potential to improve translational studies examining the molecular pathways contributing to anomalous penile development. STRENGTHS AND LIMITATIONS: The present study describes the first reported use of micro-CT with iodine staining for imaging the murine penis. Producing repeated histologic sections of identical orientation was limited by inherent imperfections in mounting and tissue sectioning, but this was compensated for by using micro-CT reconstructions to identify matching virtual sections. CONCLUSION: This study demonstrates the successful use of micro-CT with iodine staining, which has the potential for submicron spatial resolution, as a non-destructive method of characterizing murine penile morphology. O'Neill M, Huang GO, Lamb DJ. Novel Application of Micro-Computerized Tomography for Morphologic Characterization of the Murine Penis. J Sex Med 2017;14:1533-1539. PMID- 29153582 TI - Advancing collaborative vaccine benefits and safety research in Europe via the ADVANCE code of conduct. PMID- 29153583 TI - Canine vaccination: Bridging the rabies knowledge gap. PMID- 29153584 TI - The effect of selected molecules influencing the detrimental host immune response on a course of rabies virus infection in a murine model. AB - Rabies is invariably fatal, when post-exposure prophylaxis is administered after the onset of clinical symptoms. In many countries, rabies awareness is very low and the availability of post-exposure prophylaxis, as recommended by WHO guidelines, is very limited or non-existent, probably as a consequence of high cost. Therefore, new concepts for rabies therapy are needed. Innate immune mechanisms involving the production of pro-inflammatory cytokines and chemokines, activated after rabies infection, are thought to be involved in the neuropathogenesis of rabies. These mechanisms can contribute to a detrimental host response to the rabies virus (RABV) infection. The use of inhibitors of cytokines/chemokines are supposed to extend the survival of a sick individual. Inhibitors of TNF-alpha, IL-6 and MAPKs were used in RABV inoculated mice to define their influence on the survival time of rabid mice. The study demonstrated that all inhibitors extended mice survival, but at different rates. A log-rank test confirmed the statistically significant survival of mice treated with TNF alpha (p = .0087) and MAPKs inhibitors (p = .0024). A delay in the time of onset of rabies was also recorded, in mice given TNF-alpha and MAPKs inhibitors. The highest virus load was found in the spinal cord and the lowest in the cortex, regardless of the experimental group. Significant TNF-alpha (p <= .0001) and IL-6 (p <= .0001) gene upregulation was observed in mice, as a consequence of RABV infection. Regarding MAPKs pathways, there was significant upregulation of the caspase 3 (p = .012, p = .0026) and Mcl-1 (p = .0348, p = .0153) genes, whereas significant downregulation of the cytochrome C (p <= .0001), Bcl2 (p = .0002, p = .0007) and JNK3 (p = .042) genes. Rabies pathogenesis is multifactorial, involving both virus and host influences on the course of the infection. PMID- 29153585 TI - Identify the susceptibility profile to measles in the general population: Serological survey of measles antibodies in Shaanxi province, China, in 2016. AB - The reported coverage with two doses of the measles vaccine (MCV) in Shaanxi Province, China, is greater than 95%, but the measles incidence over the whole province remains high. Cross-sectional serological surveys of measles antibodies in Shaanxi Province were conducted in 2016 to assess the population's immunity. The measles IgG levels were measured in serum samples using ELISA. The geometric means concentration (GMC) levels and seroprevalence rates with 95% CIs were calculated by region, gender, and age. A total of 3574 serum samples were collected from participants aged from 2 months to 49 years. The GMC of measles antibodies was 471.3 mIU/ml (95% CI: 445.9-498.2 mIU/ml), and the seroprevalence was only 85.9% (95% CI: 84.8-87.1%). A significant difference in the GMC (P < .05) but not the seroprevalence (P > .05) was observed among the 3 regions. The report measles incidences were high in individuals aged 0-7 months (33.2/100 000) and 8-17 months (26.8/100 000). Although both measles immunity (90.7%) and MCV coverage (89.7%) were low in children aged 8-17 months, the measles seroprevalence in adults was high at greater than 90%. These results revealed that further actions may be taken to increase vaccination coverage in children aged 8 months to 5 years over the whole province and teenagers in the south region. In particular, timely administration of the first MCV dose should be emphasized to prevent measles epidemics in children aged 8-17 months. Vaccination strategies may be varied by age and region. PMID- 29153586 TI - Non-specific effects of childhood vaccinations - A case control study nested into a Health and Demographic Surveillance System in rural Burkina Faso. AB - INTRODUCTION: Previous studies in African countries have been suggestive of non specific effects (NSE) of vaccination on child survival. Live vaccines (e.g. measles, MV) have been found to reduce child mortality while inactivated vaccines (e.g. diphtheria-tetanus-pertussis, DTP) have been associated with increased mortality; NSE were often found to be sex-specific. METHODS: A case-control study nested into the Health and Demographic Surveillance System (HDSS) cohort of the Centre de Recherche en Sante de Nouna (CRSN) was conducted in northwestern Burkina Faso. A total of 3,010 children born in 2009-11, were included in the study, 375 cases and 2635 age and village matched controls. The main outcome measures were the mortality odds ratios for vaccinated versus unvaccinated children by antigen. The main outcome measures were the mortality odds ratios for vaccinated versus unvaccinated children by antigen. RESULTS: Most deaths occurred in late infancy, and there were significantly more deaths in males as compared to females (OR 1.29, CI 1.04-1.60). Overall, there was no statistically significant association between vaccine status and mortality. However, among children in the age group 2-8 months, there was a consistent sex-differential pattern for all doses of oral polio vaccine combined with pentavalent vaccine (OPV + Penta), with the vaccines being associated with lower mortality in boys, but not in girls. Routine MV + yellow fever vaccine was associated with reduced mortality, but only before mass vaccination campaigns with meningitis and measles vaccines took place. CONCLUSIONS: The findings of this study provide further support on the existence of NSE of childhood vaccinations in a large population of rural Burkina Faso. More randomized controlled trials are needed to confirm these observations. PMID- 29153587 TI - Advancing Research Models and Technologies to Overcome Biological Barriers to Plasmodium vivax Control. AB - Malaria prevalence has declined in the past 10 years, especially outside of sub Saharan Africa. However, the proportion of cases due to Plasmodium vivax is increasing, accounting for up to 90-100% of the malaria burden in endemic regions. Nonetheless, investments in malaria research and control still prioritize Plasmodium falciparum while largely neglecting P. vivax. Specific biological features of P. vivax, particularly invasion of reticulocytes, occurrence of dormant liver forms of the parasite, and the potential for transmission of sexual-stage parasites prior to onset of clinical illness, promote its persistence and hinder development of research tools and interventions. This review discusses recent advances in P. vivax research, current knowledge of its unique biology, and proposes priorities for P. vivax research and control efforts. PMID- 29153588 TI - Azole-hydrazone derivatives: Design, synthesis, in vitro biological evaluation, dual EGFR/HER2 inhibitory activity, cell cycle analysis and molecular docking study as anticancer agents. AB - In this research, three series of azole-hydrazone derivatives namely, benzimidazole, benzoxazole and benzothiazole were designed and synthesized. Their structures were confirmed by elemental analysis and spectroscopic techniques. Stereochemical configuration of the synthesized compounds (Z/E) was determined. The new derivatives were tested in vitro against both human breast adenocarcinoma (MCF-7) and human hepatic adenocarcinoma (HepG2) cell lines. The most active compounds 3h (IC50 = 0.067 MUM against MCF-7) and 3l (IC50 = 0.027 MUM against HepG2) were further tested for Epidermal Growth Factor Receptor (EGFR) inhibitory activity. The most active 3h on EGFR was then screened for HER2 and VEGFR enzymes. Caspase-3/9 protein level expression were measured for the two compounds 3h and 3l. Cell cycle analysis showed pre G1 apoptosis and cell cycle arrest at G2/M phase. Up-regulation of Bax and down-regulation of Bcl-2 protein expression level confirmed apoptosis. Molecular docking analysis was performed for all the synthesized compounds inside the active site of EGFR. PMID- 29153589 TI - Biocatalytic hydrolysis of chlorinated nicotinamides by a superior AS family amidase and its application in enzymatic production of 2-chloronicotinic acid. AB - 2-Chloronicotinic acid (2-CA) is an important building block for a series of agrochemicals and pharmaceuticals. Amidase-catalyzed hydrolysis of 2 chloronicotinamide is one of the most attractive approaches for 2-CA production. However, development of the bioprocess was plagued by low activity of amidase for 2-chloronicotinamide. In this work, an amidase signature (AS) family amidase from Pantoea sp. (Pa-Ami), with superior activity for nicotinamide and its chlorinated derivatives, was exploited and characterized. Kinetic analysis and molecular docking clearly indicated that chlorine substitution in the pyridine ring of nicotinamide, especially the substitution at 2-position led to a dramatic decrease of Pa-Ami activity. The productivity of the bioprocess was significantly improved using fed-batch mode at low reaction temperature and 2-CA was produced as high as 370 mM with a substrate conversion of 94.2%. These results imply that Pa-Ami is potentially promising biocatalyst for industrial production of 2-CA. PMID- 29153590 TI - Heterocyclic periphery in the design of carbonic anhydrase inhibitors: 1,2,4 Oxadiazol-5-yl benzenesulfonamides as potent and selective inhibitors of cytosolic hCA II and membrane-bound hCA IX isoforms. AB - A series of novel aromatic primary sulfonamides decorated with diversely substituted 1,2,4-oxadiazole periphery groups has been prepared using a parallel chemistry approach. The compounds displayed a potent inhibition of cytosolic hCA II and membrane-bound hCA IX isoforms. Due to a different cellular localization of the two target enzymes, the compounds can be viewed as selective inhibition tools for either isoform, depending on the cellular permeability profile. The SAR findings revealed in this study has been well rationalized by docking simulation of the key compounds against the crystal structures of the relevant hCA isoforms. PMID- 29153591 TI - Informing physician strategies to overcome language barriers in encounters with pediatric patients. AB - OBJECTIVES: To describe physician perceptions of differences in limited English proficient (LEP) pediatric encounters and the behavioral adaptations they make to provide quality care to LEP pediatric patients. METHODS: We conducted 30min, semi structured interviews with 6 family physicians and 5 pediatricians in one health system. Audiotapes from each interview were transcribed verbatim then coded using content analysis. RESULTS: Multiple aspects of the LEP pediatric encounter were perceived by physicians as different from other encounters: trust and relationship between physician and LEP child/child's family, continuity of care, encounter's structure and flow, patient assessment, and communication barriers. Within each of these themes, physicians identified how they adapt their behavior to improve the quality of care provided to LEP children and families. CONCLUSIONS: Physicians' made both positive and negative adaptations in LEP pediatric encounters that may impact the quality of care provided to these patients. PRACTICE IMPLICATIONS: By identification of specific positive and negative behavioral adaptations, this study emphasizes intervention targets, such as demonstrating interest in an LEP pediatric patient's family story and individuality and using common niceties in conversations with LEP children. PMID- 29153592 TI - Missing the mark for patient engagement: mHealth literacy strategies and behavior change processes in smoking cessation apps. AB - OBJECTIVE: To examine how Transtheoretical Model (TTM)'s processes of change and mHealth literacy strategies are employed in mobile smoking cessation apps. METHODS: A purposive sample of 100 iTunes apps were coded to assess descriptive (price, type, developer, user-rating) and engagement metrics, including processes of change and mHealth literacy strategies (plain language, usability, interactivity). One-way ANOVAs and independent samples t-tests examined associations between descriptive and engagement metrics. RESULTS: Over half of the apps included 7 (78%) processes of change. Fewer included self-liberation (36%) and reinforcement management (34%). Most apps incorporated plain language, but few integrated usability and interactivity strategies. Hypnotherapy and informational apps included more behavioral processes of change than apps incorporating a combination of features, including gaming, cigarette trackers, and motivational coaching (p<0.01). CONCLUSION: Apps included behavior change processes but rarely incorporated usability and interactivity features to promote patient engagement. Engagement metrics did not vary by app user-ratings, price-to download, or developer, including for-profit organizations or government and educational institutions. PRACTICE IMPLICATIONS: Providers should acknowledge the popularity of smoking cessation apps as potential cessation aids and communicate their benefits and drawbacks to patients. Future efforts to improve smoking cessation apps should focus on enhancing the quality of tailored and interactive content. PMID- 29153593 TI - The molecular phenotypes of ureteral telocytes are layer-specific. AB - Telocytes (TC) are the delicate interstitial (stromal) cells defined by their long, thin and moniliform processes termed telopodes. Numerous studies determined that different subsets of telocytes populate almost all tissues and attempted to relate these subsets to various functions, from cell signaling to tissue repair and regeneration. Extremely few studies addressed the urinary tract though few data on the molecular pattern of the urinary TCs actually exist. We therefore hypothesized that subsets of urinary TCs co-localize within the human ureter and we aimed at performing an immunohistochemical study to evaluate the tissue specific molecular pattern of TCs. On sample tissues of proximal ureter drawn from ten human adult patients during surgery were applied primary antibodies against CD34, CD105, von Willebrand Factor, the heavy chain of smooth muscle myosin (SMM) and c-erbB-2. The molecular pattern indicated three different subsets of ureteral TCs which are neither endothelial nor epithelial in nature: (a) type I: the CD34-/CD105+ TCs of the superficial layer of lamina propria; (b) type II: the CD34+/CD105+/- myoid TCs of the deep layer of lamina propria and (c) type III: the CD34+/CD105+ perivascular TCs. Although apparently different, all these subsets of TCs could belong to the stem/progenitor niche of the ureter. PMID- 29153594 TI - The effectiveness of extracorporeal shockwave treatment in subacromial impingement syndrome and its relation with acromion morphology. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of the extracorporeal shock wave therapy in the subacromial impingement syndrome and its relationship with the acromion morphology. METHODS: Thirty patients (24 women, 6 men) with subacromial impingement were evaluated. The average age of patients was 53.6 +/- 9.8 years (range 39-80). Patients were divided into 3 groups according to the acromion morphology. ESWT 1500 at 0.12 am mL/mm2 violence was applied once a week for 3 weeks. Shoulder pain and disability index (SPADI) was used to assess function and pain scores of the patients. The evaluations were made prior to and 12 weeks after the ESWT. RESULTS: Thirteen shoulders had type 1 acromion, 11 shoulders type 2 acromion and 6 shoulders type 3 acromion. After ESWT, the SPADI pain score decreased from 16.1 +/- 5.1 (7-25) to 10.4 +/- 4.9 (1-20); SPADI functional score decreased from 37.3 +/- 19.8 (5-70) to 26.7 +/- 17.5 (1-60); SPADI total score decreased from 53.4 +/- 24.5 (14-95) to 37.1 +/- 21.6 (2-74) (p < 0.05; paired t test). In each group better functional outcomes were achieved after ESWT (p < 0.05; paired t test). There were no differences between the groups according to functional outcome both before and after the ESWT treatment (p > 0.05, one way ANOVA test). CONCLUSION: ESWT was found to be effective in the treatment of impingement syndrome both for pain and functional outcome in the early period regardless of acromion morphology. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 29153595 TI - Animal models of HCC - When injury meets mutation. PMID- 29153596 TI - The Aging Neurosurgeon: When Is Enough, Enough? Attitudes Toward Ceasing Practice and Testing in Late Career. AB - OBJECTIVE: To present the first wide-scale survey to assess perceptions of testing the aging neurosurgeon. PATIENTS AND METHODS: This study included 4899 neurosurgeons, 2435 American Board of Neurological Surgery Diplomates participating in Maintenance of Certification (MOC), 1440 Diplomates certified before 1999 (grandfathered), and 1024 retired Diplomates. We developed an online confidential survey conducted from March 1, 2016, to May 31, 2016. We received 1449 responses overall (30% response rate). RESULTS: Most respondents (938; 65%) were aged 50 years and older. Overall, most respondents (718; 50%) believe that the aging neurosurgeon (65 years and older) should undergo additional testing, including cognitive assessment or a review of cases, in addition to a standard (MOC) examination. Nine hundred fifty-six (67%) respondents believed that there should be no absolute age cutoff at which neurosurgical practice is forced to end. Six hundred six (42%) respondents believed that MOC should be tailored to accommodate the aging neurosurgeon. Most respondents (766; 59%) believed that MOC should consist of a review individual case logs and patient outcomes for the aging neurosurgeon. CONCLUSION: Appropriately assessing the aging neurosurgeon is important to protect patient safety and also maximize the capacity of an aging neurosurgical workforce. This first of its kind survey of neurosurgeon diplomates of the American Board of Neurological Surgery provides important information as to what mechanisms can be created to fairly evaluate aging neurosurgeons. Although this is a study of neurosurgeons, the implications of these findings are widely applicable across specialties, and additional research on testing for aging and competency is needed across specialties. PMID- 29153597 TI - Challenges Facing the Aging Surgeon. PMID- 29153598 TI - NMDA antagonists in the treatment of catatonia: A review of case studies from the last 10years. PMID- 29153600 TI - Subclinical retinal atrophy in the unaffected fellow eyes of multiple sclerosis and neuromyelitis optica. AB - We compared the retinal thickness in the unaffected eyes among the following subtypes of unilateral optic neuritis (ON): multiple sclerosis (MS-ON), neuromyelitis optica spectrum disorder with anti-AQP4 autoantibody (AQP4-ON), patients with serum anti-MOG antibody (MOG-ON), and idiopathic ON. In the chronic phase, macular GCC and circum-papillary RNFL in the unaffected eyes were both atrophied in MS-ON and AQP4-ON, but were not atrophied in the others. Titers of anti-AQP4-Ab was suggested to be associated with such latent neurodegenerative process in AQP4-ON. Long-term follow up of OCT is recommended even in the unaffected side in MS-ON and AQP4-ON. PMID- 29153601 TI - Neurodegenerative diseases: The immunological perspective. AB - Increasing evidence supports the notion that the neurodegenerative process occurring in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) does not only imply the neuronal compartment but also involves a strong interaction with the immunological cells of the Central Nervous System (CNS), primarily microglia. Starting from the observation that the neurodegenerative disorders are frequent in elderly individuals, who have an immunological background that possibly favors this process, it is evident that a dysregulation of innate immune response triggered by misfolded and aggregated proteins, or by endogenous molecules released by injured neurons, directly contributes to disease pathogenesis and progression. There are important differences in the immunological processes occurring in AD, PD, ALS involving microglial function. Furthermore, although the contribution of adaptive immune cells in AD seems to be modest, in PD and especially in ALS models, T cells can influence microglial phenotype, inducing neuroprotection. A better understanding of the immunological mechanisms involved in the different phases of the neurodegenerative processes observed in AD, PD, ALS could effectively contribute to the development of new preventive and therapeutic strategies for such diseases. PMID- 29153599 TI - LPS-induced cortical kynurenic acid and neurogranin-NFAT signaling is associated with deficits in stimulus processing during Pavlovian conditioning. AB - The N-Methyl-d-Aspartate receptor (NMDAR) antagonist kynurenic acid (KYNA) and the post-synaptic calmodulin binding protein neurogranin (Nrgn) have been implicated in neurological and neuropsychiatric conditions including Alzheimer's disease and schizophrenia. This study indicates that systemic dual lipopolysaccharide (LPS) injections increases KYNA in the medial prefrontal cortex (mPFC), which is accompanied with increased phosphorylation of nuclear factor kappa chain of activated B cells (NFkappaB) and activation of the nuclear factor of activated T- cells (NFAT). Our results also indicate that dual-LPS increases Nrgn phosphorylation and concomitantly reduces phosphorylation of calmodulin kinase-II (CaMKII). We confirmed that systemic blockade of kynurenine 3 monooxygenase in conjunction with kynurenine administration results in significant increases in Nrgn phosphorylation and a significant reduction of CaMKII phosphorylation in the mPFC. Consequently, dual-LPS administration induced significant impairments in stimulus processing during Pavlovian conditioning. Taken together, our study indicates that elevations in KYNA in the mPFC can directly regulate NMDA-Nrgn-CaMKII signaling, suggesting that neuroinflammatory conditions affecting this pathway may be associated with cognitive dysfunction. PMID- 29153602 TI - Corrigendum to Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS) - Sensitivity and specificity of the Cunningham Panel [J. Neuroimmunol. 312. (2017) 31-37]. PMID- 29153603 TI - Impact of immunotherapy among patients with melanoma brain metastases managed with radiotherapy. AB - BACKGROUND: Patients with melanoma brain metastases (MBM) have been excluded from trials evaluating immunotherapy in melanoma. As such, immunotherapy's role in MBM is poorly understood, particularly in combination with radiotherapy. METHODS: The National Cancer Database was queried for patients with MBM receiving brain radiotherapy. They were classified according to immunotherapy receipt. Multivariate Cox regression was performed to identify factors associated with survival. RESULTS: Among 1287 patients, 185 received immunotherapy. Factors associated with improved survival included younger age, academic facility, lower extracranial disease burden, stereotactic radiotherapy, chemotherapy, and immunotherapy. CONCLUSIONS: Adding immunotherapy to radiotherapy for MBM is associated with improved survival. PMID- 29153604 TI - Characterization of isolated tau-reactive antibodies from the IVIG product, plasma of patients with Alzheimer's disease and cognitively normal individuals. AB - The presence of natural tau-reactive antibodies was reported in human blood. In this study, we isolated and characterized natural tau-reactive antibodies occurring in IVIG product Flebogamma, plasma of patients with Alzheimer's disease (AD) and older cognitively normal persons (controls). Using blotting immunoassays and ELISA, we showed reactivity of antibodies obtained from IVIG and controls against a recombinant fragment of tau (155-421aa) and aggregates present in brains of AD patients. In contrast, antibodies isolated from plasma of AD patients reacted mainly with the recombinant full-length tau form and tau monomeric forms in brain tissue. PMID- 29153605 TI - Associations between tumor necrosis factor-alpha gene polymorphisms and the risk of Guillain-Barre syndrome and its subtypes: A systematic review and meta analysis. AB - This meta-analysis aimed to assess the relationship between tumor necrosis factor alpha (TNF-alpha) polymorphisms and Guillain-Barre syndrome (GBS) or its subtypes of acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and acute motor-sensory axonal neuropathy (AMSAN). A total of six studies with 1013 cases and 1029 controls were included. Our pooled data indicated that TNF-alpha 308G/A polymorphism was significantly associated with GBS, AMAN, and AMSAN but not with AIDP; TNF-alpha 857C/T polymorphism was significantly associated with AMAN but not with GBS or AIDP. Besides, no association was found between TNF-alpha 238G/A and 863C/A polymorphisms and GBS or its subtypes. PMID- 29153606 TI - Pegylated interferon beta in the treatment of the Theiler's murine encephalomyelitis virus mouse model of multiple sclerosis. AB - We evaluated the effects of pegylated-interferonbeta-1a (pegIFNbeta) therapy on intrathecal antibody responses, disability progression, and viral load in the CNS in mice infected with the Theiler's virus (TMEV), an animal model of progressive disability in Multiple Sclerosis (MS). The lack of a direct antiviral activity in the CNS, the absence of any effect upon the intrathecal immune response, and the failure to treat disease progression, indicate that the immunomodulatory effects of pegIFNbeta-1a likely occur in the systemic circulation rather than within the CNS. These results may be relevant to the relative lack of effect of IFNbeta in progressive MS relative to relapsing MS. PMID- 29153607 TI - Serum levels of 25-hydroxyvitamin D predicts infarct volume and mortality in ischemic stroke patients. AB - BACKGROUND: The aim of this study is to determine 25-hydroxyvitamin D [25(OH) D] levels in serum, and investigate their associations with cardiovascular disease (CVD) or all-cause mortality in a 1-year follow-up study in patients with first ever ischemic stroke. METHODS: From November 2013 to October 2015, 387 consecutive patients with ischemic stroke admitted to our hospital were identified. Serum 25(OH) D levels were measured at admission. Infarct volume was measured using diffusion-weighted imaging (DWI). The primary end point was CVD mortality among 1year. The secondary end point was all-cause mortality. RESULTS: In this study, 387 patients were included. A statistically significant negative correlation between serum 25(OH) D level and infarct volume was found (r=-0.442; P<0.001). There were 74 patients (19.1%, 95%CI: 15.2%-23.0%) died, including 36 CVD mortality (9.3%, 95CI%: 6.4%-12.2%). The mortality distribution across the 25(OH) D quartiles ranged between 39.2% (first quartile) to 5.2% (fourth quartile) for all-cause mortality and between 18.6% (first quartile) to 2.1% (fourth quartile) for CVD mortality. In a multivariate model using the first quartiles of 25(OH) D vs. quartiles 2 through 4 together with the clinical variables, the marker displayed prognostic information CVD mortality: OR for first quartile, 3.06 [95% CI, 2.16-4.95]; all-cause mortality: OR for first quartile, 2.76 [95% CI, 2.01-4.32]. CONCLUSIONS: The data show serum levels of 25(OH) D at admission is useful prognostic marker of CVD and all-cause mortality in Chinese patients with ischemic stroke. PMID- 29153608 TI - Cofilin signaling in hemin-induced microglial activation and inflammation. AB - Intracerebral hemorrhage (ICH) is the most severe form of stroke and is further exacerbated by the secondary injury involving inflammatory response due to the activation of microglia. This secondary injury is partly due to the toxic effects of hemin, an endogenous breakdown product of hemoglobin. Cofilin, an actin depolymerizing factor, controls actin dynamics and has been previously shown to be involved in mediating neuronal cell death in ischemic conditions and during bacterial lipopolysaccharide induced microglial activation. There are limited studies regarding the deleterious effects of extremely high concentrations of hemin released during ICH and its effects on microglia and subsequent cofilin response. Therefore, investigations were conducted to study the effects of hemin on microglial activation induced inflammation and the critical role of cofilin in mediating the response. We observed that hemin treated microglia had a concentration dependent increase in cofilin expression and NO production. There were increased levels of iNOS, TNF-alpha, HO1, Nrf2, Wfs-1, XBP-1 and spliced XBP 1 observed in response to hemin treatment and the signaling was found to be partly mediated by cofilin. Acute hemin treatment did not evoke Ca2+ signaling and long-term treatment of hemin also resulted in the failure of microglial response to acetylcholine-evoked Ca2+ signaling. Knockdown of cofilin by siRNA also reduced acetylcholine-evoked Ca2+ signaling. These studies demonstrate that cofilin signaling is important in hemin-induced inflammation, oxidative stress, ER stress, microglial migration, and the ability to evoke Ca2+ signaling. Therefore, cofilin inhibition could be a potential therapy in brain injuries triggered by hemin toxicity in conditions like ICH. PMID- 29153609 TI - Serum CCL20 and its association with SIRT1 activity in multiple sclerosis patients. AB - CCL20 is a potentially important component in the pathogenesis of multiple sclerosis (MS). SIRT1 exhibits a negative regulatory effect on a variety of inflammatory cytokines and can relieve experimental autoimmune encephalomyelitis. The association between the level of CCL20 and SIRT1 activity in MS patients has not been investigated. In the present study, blood samples were collected from 38 RRMS patients and 40 healthy controls. The serum CCL20 levels were measured by ELISA. SIRT1 activity was evaluated by fluorometric assay. We revealed elevated serum CCL20 concentrations in MS, and discovered an inverse correlation between CCL20 and SIRT1 activity in MS patients. PMID- 29153610 TI - TDP-43 proteolysis is associated with astrocyte reactivity after traumatic brain injury in rodents. AB - The aggregation and deposition of transactivation response DNA-binding protein 43 (TDP-43) in neurons and astrocytes is characteristic in a number of neurodegenerative diseases including Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Nevertheless, the exact role of TDP-43 in astrocytes is unknown. Recently, TDP-43 was identified in neurons but not astrocytes after traumatic brain injury (TBI) in humans. In the present study, we evaluated TDP-43 expression and proteolysis in astrocytes in a rat model of TBI. We assessed TDP-43 fragment expression, astrocyte morphology, neuronal population numbers, and motor function after TBI with or without intracerebroventricular administration of a caspase-3 inhibitor. Motor dysfunction was observed after TBI in potential association astrocytic TDP-43 short fragment mislocalization and accumulation, astrogliosis, and neuronal loss. Notably, caspase-3 inhibition prevented these changes after TBI. Our findings suggest that TDP-43 proteolysis in astrocytes is related to astrogliosis and subsequent neuronal loss in TBI, and that TDP-43 may be an important therapeutic target for preventing motor dysfunction after TBI. PMID- 29153611 TI - Tissue resident macrophages are sufficient for demyelination during peripheral nerve myelin induced experimental autoimmune neuritis? AB - The contribution of resident endoneurial tissue macrophages versus recruited monocyte derived macrophages to demyelination and disease during Experimental Autoimmune Neuritis (EAN) was investigated using passive transfer of peripheral nerve myelin (PNM) specific serum antibodies or adoptive co-transfer of PNM specific T and B cells from EAN donors to leukopenic and normal hosts. Passive transfer of PNM specific serum antibodies or adoptive co-transfer of myelin specific T and B cells into leukopenic recipients resulted in a moderate reduction in nerve conduction block or in the disease severity compared to the normal recipients. This was despite at least a 95% decrease in the number of circulating mononuclear cells during the development of nerve conduction block and disease and a 50% reduction in the number of infiltrating endoneurial macrophages in the nerve lesions of the leukopenic recipients. These observations suggest that during EAN in Lewis rats actively induced by immunization with peripheral nerve myelin, phagocytic macrophages originating from the resident endoneurial population may be sufficient to engage in demyelination initiated by anti-myelin antibodies in this model. PMID- 29153612 TI - Amelioration of ongoing experimental autoimmune encephalomyelitis with fluoxetine. AB - In patients with multiple sclerosis, the selective serotonin reuptake inhibitor, fluoxetine, resulted in less acute disease activity. We tested the immune modulating effects of fluoxetine in a mouse model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis (EAE). We show that fluoxetine delayed the onset of disease and reduced clinical paralysis in mice with established disease. Fluoxetine had abrogating effects on proliferation of immune cells and inflammatory cytokine production by both antigen-presenting cells and T cells. Specifically, in CD4 T cells, fluoxetine increased Fas-induced apoptosis. We conclude that fluoxetine possesses immune-modulating effects resulting in the amelioration of symptoms in EAE. PMID- 29153613 TI - Brain expression of inflammatory mediators in Mesial Temporal Lobe Epilepsy patients. AB - Neuroinflammation may be central in epileptogenesis. In this study we analysed inflammatory reaction markers in brain tissue of Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS) patients. TLR4, IL-1beta and IL-10 gene expression as well as the presence of activated HLA-DR+ microglia was evaluated in 23 patients and 10 cadaveric controls. Inflammation characterized by the presence of HLA-DR+ microglia and TLR4, IL-1beta overexpression was evident in hippocampus and anterior temporal cortex of MTLE-HS patients. Anti-inflammatory IL-10 was also overexpressed in MTLE-HS patients. Our results show that hippocampal neuroinflammation extends beyond lesional limits, as far as the anterior temporal cortex. PMID- 29153614 TI - Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses. AB - Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab. PMID- 29153615 TI - Inflammation-induced depression: Its pathophysiology and therapeutic implications. AB - Inflammation is not the only cause of depression and cannot explain its entire pathophysiology, but it is an important pathogenic factor that explains one possible mechanism of depression, with the kynurenine (KYN) pathway of tryptophan at its center. In particular, greater impairment seems to exist in the KYN pathway in inflammation-induced depression related to immunotherapy, autoimmune disease, and infection. In patients with these conditions, immunopharmacology is likely to be an important therapy. To develop this therapy, clear evidence of the immune-KYN pathway must be established via multiple types of experiments. This paper reviews the body of evidence, not only for the action of tryptophan (TRY) and consequent serotonin depletion, but also for the detrimental effects of TRY catabolites and the key enzymes in the KYN pathway that play important roles in the pathophysiology of inflammation-induced depression. In addition, this paper explores a potential treatment strategy for inflammation-induced depression using KYN metabolism. PMID- 29153617 TI - Management of a cornual ectopic pregnancy. AB - Cornual pregnancy is rare. Treatment involves expulsion of the pregnancy and hemostasis of the cornus if required by hemorrhagic rupture. Two techniques are proposed to achieve hemostasis of the uterine cornus, cornuotomy with suture, or corneal resection with salpingectomy, generally laparoscopically. PMID- 29153616 TI - A role for B cells in facilitating defense against an NK cell-sensitive lung metastatic tumor is revealed by stress. AB - Stressors impair immune defenses and pose risks among cancer patients. Natural Killer cells are not the sole immune defense against tumor development. Utilizing an NK-sensitive tumor model, this study evaluated immune effects to stress and determined whether lung metastasis resulted from B cells' inability to augment tumorlytic function. Lung metastasis directly correlated with delayed lung B cell accumulation compared to NK, and T cells. Decreased interleukin-12 cytokine and CD80+ molecule expression by B cells correlated with decreased tumor lysis and increased tumor development. Thus, tumor defenses in the lung given stress exposure can depend on the B cell function. PMID- 29153618 TI - Advantages of a prospective multidisciplinary approach in transcatheter aortic valve implantation: Eight years of experience. AB - INTRODUCTION: Aortic stenosis is the most prevalent type of valvular disease in Europe. Surgical aortic valve replacement (SAVR) is the standard therapy, while transcatheter aortic valve implantation (TAVI) is an alternative in patients at unacceptably high surgical risk. Assessment by a heart team is recommended by the guidelines but there is little published evidence on this subject. The purpose of this paper is to describe the experience of a multidisciplinary TAVI program that began in 2008. METHODS: The heart team prospectively assessed 473 patients using a standardized approach. A total of 214 patients were selected for TAVI and 80 for SAVR. Demographic, clinical and procedural characteristics and long-term success rates were compared between the groups. RESULTS: TAVI patients were older than the SAVR group (median 83 vs. 81 years), and had higher surgical risk scores (median EuroSCORE II 5.3 vs. 3.6% and Society of Thoracic Surgeons score 5.1 vs. 3.1%), as did the patients under medical treatment only. These scores were unable to assess multiple comorbidities. Patients' outcomes were different between the three groups (mortality with SAVR 25% vs. TAVI 37.6% vs. conservative therapy 57.6%, p=0.001). CONCLUSIONS: The heart team program was able to select candidates appropriately for TAVI, SAVR and conservative treatment, taking into account the risk of both invasive treatments. The use of a prospective standardized heart team approach is recommended, but requires continuous monitoring to ensure effectiveness in a timely manner. PMID- 29153620 TI - Targeted DNA enrichment and whole genome sequencing of Neisseria meningitidis directly from clinical specimens. AB - In England and Wales, approximately one half of all laboratory-confirmed meningococcal disease cases fail to yield a viable invasive isolate, primarily due to the use of antibiotics. Characterisation of non-culture meningococci has been restricted to the detection or sequencing of specific gene targets within clinical specimens. In this study we investigated the ability of the Agilent SureSelectXT kit to facilitate DNA enrichment and genome sequencing of meningococcal DNA within a small panel of blood and CSF specimens. A target specific RNA oligonucleotide bait library was used to capture and enrich the bacterial DNA prior to next generation sequencing. A positive correlation between meningococcal DNA amount and genome coverage was observed with eight of the ten specimens producing genomes of acceptable quality. All commonly-used typing information derived from each acceptable non-culture genome matched those of an isolate from the same patient and the paired genomes showed a high level of congruence across indexed loci. We estimate that this technique could be used to perform whole genome sequencing on up to ~45% of the positive specimens received by the Public Health England's Meningococcal Reference Unit. Further optimisation of the extraction and/or enrichment processes may, however, increase the proportion of non-culture cases from which quality genomes can be obtained. PMID- 29153619 TI - The use of stool specimens reveals Helicobacter pylori strain diversity in a cohort of adolescents and their family members in a developed country. AB - Helicobacter pylori infection occurs within families but the transmission route is unknown. The use of stool specimens to genotype strains facilitates inclusion of complete families in transmission studies. Therefore, we aimed to use DNA from stools to analyze strain diversity in H. pylori infected families. We genotyped H. pylori strains using specific biprobe qPCR analysis of glmM, recA and hspA. Concentration of H. pylori organisms before DNA isolation enhanced subsequent DNA amplification. We isolated H. pylori DNA from 50 individuals in 13 families. Tm data for at least 2 of the 3 genes and sequencing of the glmM amplicon were analyzed. Similar strains were commonly found in both mothers and children and in siblings. However, 20/50 (40%) individuals had multiple strains and several individuals harbored strains not found in other family members, suggesting that even in developed countries sources of infection outside of the immediate family may exist. Whether infection occurs multiple times or one transmission event with several strains occurs is not known but future studies should aim to analyze strains from children much closer to infection onset. The presence of multiple stains in infected persons has implications for antibiotic sensitivity testing and treatment strategies. PMID- 29153621 TI - Medication management by informal caregivers - Under-recognized and under supported. PMID- 29153622 TI - En face-OCT reconstruction in Stargadt disease. PMID- 29153623 TI - Abiraterone acetate + prednisolone treatment beyond prostate specific antigen and radiographic progression in metastatic castration-resistant prostate cancer patients. AB - OBJECTIVES: To investigate the overall survival (OS) of chemotherapy refractory patients with metastatic castration-resistant prostate cancer who were treated with abiraterone acetate + prednisolone (AA + P) beyond prostate specific antigen (PSA) and radiographic progression (PRP) until clinical progression in comparison to patients treated until PRP. METHODS: At our institute the AA + P treatment started in 2011 in an early-access protocol trial. In October 2012 AA became generally available. From April 2011 to November 2014, 116 patients received AA + P. The clinical trial patients (T; n = 56) were treated beyond PRP until clinical progression. In the nonclinical trial group (NT; n = 57) the treatment was covered until PRP. Three patients are still under treatment. The 2 groups were statistically homogeneous, except AA + P treatment duration. The primary objective was the OS and the secondary the PSA progression-free and radiographic progression-free survivals. RESULTS: The median OS was significantly longer (P<0.0001) in the T group compared to the NT group: 21.9 (95% CI: 16.9-25) vs. 12.5 (9.3-14.1) months, respectively. In univariate analysis there were 11 parameters, which significantly affected OS, but in multivariate Cox analysis only alkaline phosphatase (AP) level at the start of treatment, systemic therapy after AA + P and cohort type (T or NT) proved to independently influence the OS. The progression-free survival curves of T and NT groups did not differ significantly. CONCLUSIONS: In our retrospective analysis low levels of AP at the start of treatment, systemic therapy applied after AA + P and treatment beyond PRP proved to be independent factors of longer OS in metastatic castration resistant prostate cancer. PMID- 29153625 TI - The Role of PD-1 Positivity in the Tumour Nest on Clinical Outcome in Upper Tract Urothelial Carcinoma Patients Treated with Radical Nephroureterectomy. AB - AIMS: The role of PD-1 (programmed cell death 1) expression on the clinical outcome of upper tract urothelial carcinoma has not yet been elucidated in detail. MATERIALS AND METHODS: PD-1 expression was immunohistochemically examined in 181 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy. A part of PD-1 protein expression in the tumour periphery and tumour nest was evaluated separately. The PD-1-positive cells were counted in the area showing the highest density of PD-1 expression at a magnification of 400*. RESULTS: PD-1 staining in the tumour nest was low in 137 (75.7%) and high in 44 (24.3%) patients. PD-1 staining in the tumour periphery was low in 78 (43.1%) and high in 103 (56.9%) patients. The 5 year progression-free survival rates in patients with the high PD-1 expression in the tumour nest and in the tumour periphery were 54.6% and 67.7%, respectively, which were significantly lower than those in their counterparts (79.4%, P < 0.001; 80.0%, P = 0.04). The 5 year cancer-specific survival rates in patients with the high PD-1 expression in the tumour nest and the tumour periphery were 69.1% and 75.7%, respectively, which were significantly lower than those in their counterparts (84.7%, P = 0.007; 87.8%, P = 0.01). A multivariate Cox regression analysis identified the high PD-1 expression in the tumour nest (hazard ratio 3.07, P < 0.001; hazard ratio 2.44, P = 0.011) and positive lymphovascular invasion (hazard ratio 4.86, P < 0.001; hazard ratio 4.03, P < 0.001) as independent predictors of disease progression and of cancer death, respectively. CONCLUSIONS: PD-1 positivity in the tumour nest could be a strong predictor for a worse clinical outcome and may be a useful indicator for selecting appropriate candidates for adjuvant therapy such as chemotherapy in upper tract urothelial carcinoma patients treated with radical nephroureterectomy. PMID- 29153624 TI - The effect of socioeconomic status, race, and insurance type on newly diagnosed metastatic prostate cancer in the United States (2004-2013). AB - BACKGROUND: Understanding the characteristics of men who initially present with metastatic prostate cancer (mPCa) can better enable directed improvement initiatives. The objective of this study was to assess the relationship between socioeconomic status (SES) and newly diagnosed mPCa. MATERIALS METHODS: All men diagnosed with PCa in the National Cancer Data Base from 2004 to 2013 were identified. Characteristics of men presenting with and without metastatic disease were compared. A 4-level composite metric of SES was created using Census-based income and education data. Multivariable logistic regression was used to evaluate the association between SES, race/ethnicity, and insurance and the risk of presenting with mPCa at the time of diagnosis. RESULTS: Of 1,034,754 patients diagnosed with PCa, 4% had mPCa at initial presentation. Lower SES (first vs. fourth quartile; odds ratio [OR] = 1.39, 95% CI: 1.35-1.44), black and Hispanic race/ethnicity (vs. white; OR = 1.47, 95% CI: 1.43-1.51 and OR = 1.22, 95% CI: 1.17-1.28, respectively), and having Medicaid or no insurance (vs. Medicare or private; OR = 3.91, 95% CI: 3.78-4.05) were each independently associated with higher odds of presenting with mPCa after adjusting for all other covariates. CONCLUSIONS: Lower SES, race/ethnicity, and having Medicaid or no insurance were each independently associated with higher odds of presenting with metastases at the time of PCa diagnosis. Our findings may partially explain current PCa outcomes disparities and inform future efforts to reduce disparities. PMID- 29153626 TI - The association between paternal and adolescent depressive symptoms: evidence from two population-based cohorts. AB - BACKGROUND: Incidence of depression increases markedly around age 13 years, and nearly three-quarters of adults report that their mental health problems started in adolescence. Although maternal depression is a risk factor for adolescent depression, evidence about the association between paternal and adolescent depression is inconclusive, and many studies have methodological limitations. We aimed to assess the association between paternal and adolescent depressive symptoms in two large population-based cohort studies. METHODS: We used data for two-parent families from two representative prospective cohorts in Ireland (Growing up in Ireland [GUI]) and the UK (Millennium Cohort Study [MCS]). Parental depressive symptoms were measured with the Centre for Epidemiological Studies Depression Scale in the GUI cohort when children were 9 years old, and the Kessler six-item psychological distress scale in the MCS cohort when children were 7 years old. Adolescent depressive symptoms were measured with the Short Mood and Feelings Questionnaire (SMFQ) at age 13 years in the GUI cohort and age 14 years in the MCS cohort. We analysed data using linear regression models, before and after adjustment for confounders, in both multiply imputed and complete case samples. FINDINGS: There were 6070 families in GUI and 7768 in MCS. After all adjustments, a 1 SD (three-point) increase in paternal depressive symptoms was associated with an increase of 0.24 SMFQ points (95% CI 0.03-0.45; p=0.023) in the GUI cohort and 0.18 SMFQ points (0.01-0.36; p=0.041) in the MCS cohort. This association was independent of, and not different in magnitude to, the association between maternal and adolescent depressive symptoms (Wald test p=0.435 in the GUI cohort and 0.470 in the MCS cohort). INTERPRETATION: Our results show an association between depressive symptoms in fathers and depressive symptoms in their adolescent offspring. These findings support the involvement of fathers as well as mothers in early interventions to reduce the prevalence of adolescent depression, and highlight the importance of treating depression in both parents. FUNDING: Department of Children and Youth Affairs and Economic and Social Research Council. PMID- 29153627 TI - The effect of paternal depression on depressive symptoms in adolescent offspring. PMID- 29153628 TI - Discovery and in vivo effects of novel human natriuretic peptide receptor A (NPR A) agonists with improved activity for rat NPR-A. AB - Natriuretic peptide receptor A (NPR-A) agonists were evaluated in vivo by optimizing the structure of quinazoline derivatives to improve agonistic activity for rat NPR-A. A 1,4-Cis-aminocyclohexylurea moiety at 4-position and hydroxy group of d-alaninol at 2-position on the quinazoline ring were found to be important factors in improving rat NPR-A activity. We identified potent quinazoline and pyrido[2,3-d]pyrimidine derivatives against rat NPR-A, with double-digit nanomolar EC50 values. The in vivo results showed that compound 56b administered at 1.0 mg/kg/min significantly increased plasma cGMP concentration and urine volume in rats. We discovered novel potent NPR-A agonists that showed agonistic effects similar to those of atrial natriuretic peptide. PMID- 29153629 TI - Elevated fingernail cortisol levels in major depressive episodes. AB - BACKGROUND: The extent to which cortisol levels are elevated in major depressive episodes (MDE), and hence could act as a biomarker of illness, remains unclear. Although patient characteristics may explain some of this variation - for example elevated cortisol being more often found in patients with severe, psychotic or melancholic depression - problems with the methods used to measure cortisol may also have contributed to the inconsistent findings. Fingernails are a novel sample that can be used to assess aggregate cortisol concentrations over a 15-day period, and may provide a more accurate reflection of longer term cortisol level changes in MDE and help clarify this issue. This methodology has not yet been utilised in MDE. METHODS: Cortisol levels reflecting a period of 15days were measured using fingernails in a group of 26 subjects experiencing a major depressive episode (MDE) and in an age and gender matched group of 45 healthy controls. RESULTS: Depressed subjects showed significantly higher mean cortisol levels measured in fingernails when compared with control subjects. Higher levels of cortisol were associated with higher depression severity scores, a diagnosis of non-reactive depression, and more prominent melancholic symptoms. Conversely, fatigue was negatively correlated with cortisol levels. CONCLUSION: There is elevated cortisol in MDE when assessed using an aggregate measure over two weeks.Alterations in fingernail cortisol correlate with key clinical symptoms and subtypes of depression. PMID- 29153631 TI - Human abuse potential of brivaracetam in healthy recreational central nervous system depressant users. AB - BACKGROUND: Brivaracetam is a new antiepileptic drug indicated for adjunctive treatment of focal seizures in adults at a dose of 50-200mg/day taken in two equal doses. The objective of this study was to evaluate the abuse potential of brivaracetam compared with alprazolam (positive control), placebo, and levetiracetam. METHODS: This was a randomized, double-blind, triple-dummy, crossover study in healthy male and female recreational central nervous system (CNS) depressant users aged 18-55years, who could distinguish between the subjective effects of alprazolam 2mg and placebo. All participants received single doses of brivaracetam (50 [therapeutic dose], 200, 1000mg [supratherapeutic doses]), alprazolam (1.5, 3mg), placebo, and levetiracetam (4000mg) in random order each separated by 7-10days. Subjective Visual Analogue Scales (VAS) and Addiction Research Center Inventory (ARCI) scales were completed at intervals up to 24h postdose. Primary endpoints were Drug Liking (at this moment) VAS, Overall Drug Liking VAS, Feeling High VAS, and ARCI Pentobarbital Chlorpromazine Alcohol Group (PCAG, sedation) maximum effect (Emax). Maximum effect values on each scale were analyzed using a mixed-effect model (per protocol population, N=44). RESULTS: The maximum effect for both alprazolam doses was significantly greater versus placebo for six designated endpoints, confirming study validity. Drug Liking (at this moment) VAS Emax was significantly lower for brivaracetam 50mg than alprazolam (both doses); there were no significant differences between brivaracetam 200mg and alprazolam (both doses), and brivaracetam 1000mg and alprazolam 1.5mg. Brivaracetam 1000mg (supratherapeutic single dose) had significantly higher Drug Liking (at this moment) VAS Emax than alprazolam 3mg. Overall, Drug Liking VAS Emax for brivaracetam 50 and 200mg was not significantly different from alprazolam (both doses). Brivaracetam 1000mg had significantly higher Overall Drug Liking VAS Emax than alprazolam 1.5mg, but was not significantly different from alprazolam 3mg. Feeling High VAS Emax was lower versus alprazolam with brivaracetam 50 and 200mg, while brivaracetam 1000mg was comparable with alprazolam (both doses). Addiction Research Center Inventory PCAG Emax for brivaracetam (all doses) was significantly lower than alprazolam (both doses). On the secondary/supportive endpoints, compared with alprazolam, brivaracetam had fewer positive effects (ARCI Morphine Benzedrine Group [euphoria]; Good Drug Effects VAS [50mg]) and fewer negative effects (Bad Drug Effects VAS; ARCI Lysergic Acid Diethylamide [dysphoria]). Brivaracetam was not significantly different from alprazolam for Take Drug Again VAS (50, 200mg). For most endpoints, brivaracetam (50-200mg) was not significantly different from levetiracetam (4000mg). CONCLUSION: This study in healthy recreational CNS depressant users showed that single doses of brivaracetam 50mg (therapeutic single dose) had lower sedative, positive, and negative drug effects than alprazolam, while brivaracetam 200 and 1000mg (supratherapeutic single doses) were more similar to alprazolam. The subjective profile of brivaracetam appeared to be similar to that of levetiracetam, but further evaluation using a range of levetiracetam doses would be needed to confirm similar abuse potential. PMID- 29153630 TI - Increasing HIV Testing in Inpatient Psychiatry. AB - BACKGROUND: People with serious mental illness (SMI) are at elevated risk of HIV infection, but do not receive HIV tests regularly. Inpatient psychiatric admissions provide opportunities for HIV testing. OBJECTIVE: This study retrospectively examined the impact of three sequential interventions designed to increase HIV testing on an acute inpatient psychiatry service: (1) advocacy by an administrative champion, (2) an on-site HIV counselor, and (3) a clinician championing HIV testing. METHOD: Demographic and HIV testing data were extracted from hospital data systems for 11,360 admissions of HIV-negative patients to an inpatient psychiatry service between 2006 and 2012. Relationships among interventions, length of stay, patient demographics, and receipt of an HIV test were examined using general estimating equation methods. RESULTS: In the year prior to the intervention, 7.2% of psychiatric inpatients received HIV tests. After 1 year of administrative advocacy, 11.2% received tests. Following the HIV counseling intervention, 25.1% of patients were tested. After the counseling intervention ended, continued administrative and clinical advocacy was associated with further increases in testing. In the final year studied, 30.3% of patients received HIV tests. Patients with shorter inpatient stays and those of Black or Asian race/ethnicity were less likely to be tested. Further, 1.6% of HIV tests were positive. CONCLUSION: Three interventions of varying intensity were associated with a 5-fold increase in HIV testing on an acute inpatient psychiatry service. Nonetheless, 70% of inpatients were not tested. Continued efforts are needed to increase HIV testing in inpatient psychiatric settings. PMID- 29153632 TI - A 2- to 16-Year Clinical Follow-Up of Revision Total Hip Arthroplasty Using a New Acetabular Implant Combined With Impacted Bone Allografts and a Cemented Cup. AB - BACKGROUND: Treatment of acetabular bone loss with impaction bone grafting (IBG) at revision total hip arthroplasty is highly dependent on mechanical stability and graft compression for clinical success. Here, we describe a new technique to further compress and stabilize the acetabular graft bed with a thin, perforated titanium shell. METHODS: We retrospectively analyzed 170 cases of acetabular revision arthroplasty 7 years (standard deviation 2.8) after IBG combined with a graft-compressing titanium shell implant. The patients were reviewed by clinical score and radiography. Three patients were lost to follow-up. The medical journals of the 33 deceased cases were reviewed for any reoperation. Of the 170 cases, 74 had a cavitary acetabular bone defect, 93 had combined segmental and cavitary bone defects, and 3 had a pelvic dissociation. Bone graft incorporation was assessed and correction of the hip center of rotation was calculated. RESULTS: Five cases (3%) were reoperated for mechanical loosening. One more was assessed as loose but asymptomatic and was not planned for revision. There were 3 reoperations for recurrent dislocation, 2 for deep infection and 1 for technical error. Reoperation for any reason, as the end point of survivorship, showed a survival rate of 92% after 10 years. Hip score according to Merle, d'Aubigne, and Postel increased from 10.8 (preoperatively) to 16.4 at follow-up. The clinical and radiological results were excellent. CONCLUSION: IBG combined with the compressing shell results in excellent results for this challenging condition. PMID- 29153633 TI - Opioids Consumed in the Immediate Post-Operative Period Do Not Influence How Patients Rate Their Experience of Care After Total Hip Arthroplasty. AB - BACKGROUND: Patient perception of care, commonly measured with Press Ganey (PG) surveys, is an important metric used to determine hospital and provider reimbursement. However, post-operative pain following total hip arthroplasty (THA) may negatively affect patient satisfaction. As a result, over administration of opioids may occur, even without marked evidence of pain. Therefore, this study evaluated whether opioid consumption in the immediate postoperative period bears any influence on satisfaction scores after THA. Specifically, this study assessed the correlation between post-operative opioid consumption and 7 PG domains: (1) Overall hospital rating; (2) Communication with nurses; (3) Responsiveness of hospital staff; (4) Communication with doctors; (5) Hospital environment; (6) Pain Management; and (7) Communication about medicines. METHODS: Our institutional PG database was reviewed for patients who received THA from 2011 to 2014. A total of 322 patients (mean age = 65 years; 61% female) were analyzed. Patient's opioid consumption was measured using a morphine milli equivalent conversion algorithm. Bivariate correlation analysis assessed the association between opioid consumption and Press-Ganey survey elements. Pearson's r assessed the strength of the association. RESULTS: No correlation was found between total opioid consumption and Overall hospital rating (r = 0.004; P = .710), Communication with nurses (r = 0.093; P = .425), Responsiveness of hospital staff (r = 0.104; P = .381), Communication with doctors (r = 0.009; P = .940), Hospital environment (r = 0.081; P = .485), and Pain management (r = 0.075; P = .536). However, there was a positive correlation between total opioid consumption and "Communication about medicines" (r = 0.262; P = .043). CONCLUSIONS: Our report demonstrates that PG patient satisfaction scores are not influenced by post-operative opioid use, with the exception of PG domain, "Communication about medications." These results suggest that opioid medications should be administered based solely on patient requirements without concern about patient satisfaction survey results. PMID- 29153634 TI - Mid-Term Survivals After Cementless Bipolar Hemiarthroplasty for Unstable Intertrochanteric Fractures in Elderly Patients. AB - BACKGROUND: Treatment of unstable intertrochanteric fracture in elderly patients remains challenging. The purpose of this prospective study is to determine clinical and radiological results of cementless bipolar hemiarthroplasty using a fully porous-coated stem in osteoporotic elderly patients with unstable intertrochanteric fractures with follow-up over 5 years. METHODS: From January 2010 to December 2011, we performed 123 cementless bipolar hemiarthroplasties using fully porous-coated stem to treat unstable intertrochanteric fractures in elderly patients with osteoporosis. Clinical and radiographic evaluations were performed. RESULTS: Fifty-three patients died and 14 patients were lost during the follow-up period. Mean follow-up period was 61.8 months postoperatively. Their mean Harris hip score was 77 points (range 36-100). None of these hips had loosening of the stem or osteolysis. Postoperative complications included nonunion of greater trochanter in 2 hips and dislocation in 2 hips. Two patients were reoperated due to periprosthetic fracture. One patient underwent implant revision due to periprosthetic infection. Thirty-one patients maintained walking activities similar to those before fracture. With follow-up period of 83 months, cumulative survival rates were 97.3% and 99.1% with reoperation for any reason and femoral stem revision as endpoint, respectively. CONCLUSION: Cementless bipolar hemiarthroplasty using a fully porous-coated stem is a useful surgical treatment option for unstable intertrochanteric fracture in elderly patients with osteoporosis. PMID- 29153635 TI - Expanded donor selection criteria can increase organ utilization. PMID- 29153636 TI - Early intervention for lactate dehydrogenase elevation improves clinical outcomes in patients with the HeartMate II left ventricular assist device: Insights from the PREVENT study. AB - BACKGROUND: Hemolysis, assessed by elevated serum lactate dehydrogenase (LDH), is strongly associated with HeartMate II pump thrombosis (PT). However, it is unknown whether early intervention for elevated LDH circumvents the risk of serious PT requiring pump exchange. We sought to evaluate the relationship between elevated LDH and clinical outcomes, the effectiveness of early medical intervention, and risk factors for elevated LDH. METHODS: We studied 268 patients in the prospective, multicenter PREVENT study who had 2 or more LDH measurements at >=30 days post-implant. Elevated LDH was defined as LDH >=2.5* upper limit of normal (ULN) for 2 consecutive measurements. RESULTS: Fourteen percent of patients had elevated LDH. Stroke-free survival at 6 months was lower in patients with elevated LDH vs patients with normal LDH (83 +/- 6% vs 93 +/- 2%, p = 0.035). Elevated LDH resolved without intervention in 19% of patients, with intensified medical therapy in 43% and required surgical intervention in 38%. For patients receiving only medical therapy, survival was 94 +/- 6% at 6 months post treatment. In this subgroup, resolution of symptoms with intensified medical therapy was sustained in 15 of 16 patients, with PT occurring in 1 patient at 171 days after initial treatment for elevated LDH (202 days post-implant). Early medical intervention at moderately elevated LDH (2.5* to 3.2* ULN), as compared with higher levels (>3.2* ULN), led to more sustained resolution of symptoms without subsequent PT or need for surgical intervention (91% vs 26% at 6 months post-treatment, p = 0.002). CONCLUSIONS: Early medical intervention can successfully resolve moderate LDH elevations (2.5* to 3.2* ULN) with a low incidence of death or PT at 6 months post-treatment. PMID- 29153637 TI - Quality of life and functional capacity outcomes in the MOMENTUM 3 trial at 6 months: A call for new metrics for left ventricular assist device patients. AB - BACKGROUND: The Multicenter Study of MAGLEV Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) clinical trial demonstrated improved 6-month event-free survival, but a detailed analysis of health-related quality of life (HR-QOL) and functional capacity (FC) was not presented. Further, the effect of early serious adverse events (SAEs) on these metrics and on the general ability to live well while supported with a left ventricular assist system (LVAS) warrants evaluation. METHODS: FC (New York Heart Association [NYHA] and 6-minute walk test [6MWT]) and HR-QOL (European Quality of Life [EQ-5D-5L] and the Kansas City Cardiomyopathy [KCCQ]) assessments were obtained at baseline and 6 months after HeartMate 3 (HM3, n = 151; Abbott, Abbott Park, IL) or HeartMate II (HMII, n = 138; Abbott) implant as part of the MOMENTUM 3 clinical trial. Metrics were compared between devices and in those with and without events. The proportion of patients "living well on an LVAS" at 6 months, defined as alive with satisfactory FC (NYHA I/II or 6MWT > 300 meters) and HR-QOL (overall KCCQ > 50), was evaluated. RESULTS: Although the median (25th-75th percentile) patient KCCQ (change for HM3: +28 [10-46]; HMII: +29 [9-48]) and EQ 5D-5L (change for HM3: -1 [-5 to 0]; HMII: -2 [-6 to 0]) scores improved from baseline to 6 months (p < 0.05), there were no differences between devices (p > 0.05). Likewise, there was an equivalent improvement in 6MWT distance at 6 months in HM3 (+94 [1-274] meters] and HMII (+188[43-340 meters]) from baseline. In patients with SAEs (n = 188), 6MWTs increased from baseline (p < 0.001), but gains for both devices were less than those without SAE (HM3: +74 [-9 to 183] meters with SAE vs +140 [35-329] meters without SAE; HMII: +177 [47-356] meters with SAE vs +192 [23-337] meters without SAE, both p < 0.003). SAEs did not affect the 6-month HR-QOL scores. The "living well" end point was achieved in 145 HM3 (63%) and 120 HMII (68%) patients (p = 0.44). CONCLUSIONS: Gains in HR-QOL and FC were similar early after HM3 and HMII implant. 6MWT improvements were attenuated in patients experiencing SAEs, but HR-QOL metrics did not change. The development of left ventricular assist device-specific HR-QOL tools is needed to better characterize the effect of SAEs on a patient's well-being. CLINICAL TRIAL NO: MOMENTUM 3 clinical trial #NCT02224755. PMID- 29153638 TI - alpha1-Anti-trypsin improves function of porcine donor lungs during ex-vivo lung perfusion. AB - BACKGROUND: Ex-vivo lung perfusion (EVLP), a technique for donor lung assessment, also represents a platform for donor lung repair and immunomodulation. alpha1 Anti-trypsin (A1AT), a medication used to treat emphysema in A1AT-deficient patients, has anti-inflammatory properties and has been shown to attenuate ischemia-reperfusion injury in rat and pig lung transplants. The objective of this study was to determine whether administration of A1AT during EVLP can improve donor lung quality after prolonged hypothermic preservation. METHODS: Pig donor lungs were retrieved, preserved at 4 degrees C for 24 hours, and then subjected to normothermic EVLP for 12 hours using the Toronto protocol. The treatment group (n = 6) received 3 mg/ml A1AT (Zemaira) in the EVLP perfusate, acellular Steen solution. The control group (n = 6) was perfused with Steen solution only. Physiologic functions and gas exchange were measured hourly. Pulmonary edema, lung injury, apoptosis and inflammatory mediators were evaluated in lung tissues and perfusate. RESULTS: A1AT treatment significantly reduced pulmonary arterial pressure, pulmonary vascular resistance and airway pressure changes from the baseline when compared with controls. A1AT treatment significantly improved both dynamic and static pulmonary compliance, and change in partial pressure of oxygen (DeltaPO2) between the left atrium and the pulmonary artery. Furthermore, A1AT treatment also significantly reduced pulmonary edema (wet-to-dry ratio), pulmonary cell apoptosis and pro-inflammatory cytokine levels (interleukin-1alpha and -8) in the perfusate. CONCLUSION: Treatment of 24-hour-preserved pig donor lungs with A1AT during EVLP resulted in improved physiologic function, reduced pulmonary edema and inflammation and decreased cell death. Our findings suggest that treatment of donor lungs during EVLP with A1AT is a promising strategy to attenuate early lung injury and improve donor lung function before lung transplantation. PMID- 29153639 TI - Heart transplantation in Danon disease: A single family displaying diverse phenotypes. PMID- 29153640 TI - [Analysis of the use of proton pump inhibitors in primary health care]. AB - OBJECTIVE: The increase in the consumption of anti-ulcer drugs is accompanied by a high rate of incorrect use. The objectives of this study were to analyse the adequacy of repeat prescriptions of proton pump inhibitors (PPIs) in a Medical Centre, and to evaluate the efficacy of an improvement intervention. MATERIAL AND METHOD: A cross-sectional, descriptive and observational study of prevalence was conducted on patients in a medical centre under treatment with PPIs for at least 3consecutive months (November 2016-January 2017). An analysis was performed that included the indication, dosage and time of treatment with PPIs, drug interactions, and possible risks that could be related with their use. An intervention was carried out to optimise rational and efficient prescribing of these medicines. RESULTS: A total of 703 patients were included in the study, which is 5.4% of the total adult patients that are assigned to the centre. Adequacy criteria were not met by 436 (62.0%). Of these, 52.5% were women, 70.0% were over 65 years old, and had been on treatment for a mean of 2.7 +/- 1.9 years. Interactions were observed in 48.1%, and 29.0% had some risk factors. After the intervention, the inadequate prescribing was corrected in 112 (25.7%) patients, which was a reduction of 46.1% (P<.001). CONCLUSIONS: There is a high prevalence of prescription and inadequacy of PPIs in the long term. This suggests that it is necessary to improve training of professionals to strengthen rational use and to reduce risks. The launch of an intervention programme has led to the revision and optimisation of treatments. PMID- 29153641 TI - A Middle East respiratory syndrome screening clinic for health care personnel during the 2015 Middle East respiratory syndrome outbreak in South Korea: A single-center experience. AB - BACKGROUND: Transmission of Middle East respiratory syndrome (MERS) to health care personnel (HCP) is a major concern. This study aimed to review cases of MERS related events, such as development of MERS-like symptoms or exposure to patients. METHODS: A MERS screening clinic (MSC) for HCP was setup in the National Medical Center during the MERS outbreak in 2015. Clinical and laboratory data from HCP who visited the MSC were retrospectively reviewed. Additionally, these data were compared with the results of postoutbreak questionnaire surveys and interviews about MERS-related symptoms and risk-related events. RESULTS: Of the 333 HCP who participated in MERS patient care, 35 HCP (10.5%) visited the MSC for MERS-like symptoms. No one was infected with MERS, and the most common symptom was fever (68.6%) followed by cough (34.3%). However, 106 of 285 postoutbreak survey participants experienced at least 1 MERS-related symptom and 26 reported exposure to patients without appropriate personal protective equipment, whereas only 4 HCP visited the MSC to report exposure events. CONCLUSIONS: Although a considerable number of HCP experienced MERS-related symptoms or unprotected exposure during MERS patient care, some did not take appropriate action. These findings imply that for infection control strategy to be properly performed, education should be strengthened so that HCP can accurately recognize the risk situation and properly notify the infection control officer. PMID- 29153642 TI - The association between hand hygiene compliance and glove use: Still unknown? PMID- 29153643 TI - Prevalence and predictive factors of urinary tract infection among patients with stroke: A meta-analysis. AB - BACKGROUND: Urinary tract infection (UTI) is thought to be a common complication of stroke and is regarded as a potential risk factor for poor stroke outcomes. However, there is a controversy among predictive factors of stroke-associated UTIs. We aim to estimate the prevalence and predisposing factors of UTIs among patients with stroke. METHODS: PubMed, EMBASE, and Elsevier Science Direct were searched by 2 independent researchers. Sixteen studies with a total of 13,513 patients were included to evaluate the prevalence and predictive factors of stroke-associated UTIs published from the earliest records to March 10, 2017. Pooled effect sizes were calculated using the fixed effect model or random effect model according to I2 and P values. RESULTS: The pooled prevalence of UTI was 19.0% (95% confidence interval [CI], 15%-22%; P <.01). The predisposing factors for UTIs include female sex (odds ratio [OR], 1.93; 95% CI, 1.55-2.41), older age (OR, 1.28; 95% CI, 1.09-1.50), higher modified Rankin Scale score (OR, 1.90; 95% CI, 1.43-2.53), and postvoid residual volume >100 mL (OR, 3.69; 95% CI, 2.09 6.52). CONCLUSIONS: Approximately one-fifth of patients with stroke contracted at least 1 UTI after cerebral apoplexy. Female sex, older age, higher modified Rankin Scale score, and postvoid residual volume >100 mL were associated with higher risk of UTI. PMID- 29153644 TI - Propionic acid production from soy molasses by Propionibacterium acidipropionici: Fermentation kinetics and economic analysis. AB - Propionic acid (PA) is a specialty chemical; its calcium salt is widely used as food preservative. Soy molasses (SM), a low-value byproduct from soybean refinery, contains sucrose and raffinose-family oligosaccharides (RFO), which are difficult to digest for most animals and industrial microorganisms. The feasibility of using SM for PA production by P. acidipropionici, which has genes encoding enzymes necessary for RFO hydrolysis, was studied. With corn steep liquor as the nitrogen source, stable long-term PA production from SM was demonstrated in sequential batch fermentations, achieving PA productivity of >0.8 g/L h and yield of 0.42 g/g sugar at pH 6.5. Economic analysis showed that calcium propionate as the main component (63.5%) in the product could be produced at US $1.55/kg for a 3000-MT plant with a capital investment of US $10.82 million. At $3.0/kg for the product, the process offers attractive 40% return of investment and is promising for commercial application. PMID- 29153645 TI - Protein corona between nanoparticles and bacterial proteins in activated sludge: Characterization and effect on nanoparticle aggregation. AB - In this work, the protein coronas of activated sludge proteins on TiO2 nanoparticles (TNPs) and ZnO nanoparticles (ZNPs) were characterized. The proteins with high affinity to TNPs and ZNPs were identified by shotgun proteomics, and their effects of on the distributions of TNPs and ZNPs in activated sludge were concluded. In addition, the effects of protein coronas on the aggregations of TNPs and ZNPs were evaluated. Thirty and nine proteins with high affinities to TNPs and ZNPs were identified, respectively. The proteomics and adsorption isotherms demonstrated that activated sludge had a higher affinity to TNPs than to ZNPs. The aggregation percentages of ZNPs at 35, 53, and 106 mg/L of proteins were 13%, 14%, and 18%, respectively, whereas those of TNPs were 21%, 30%, 41%, respectively. The proteins contributed to ZNPs aggregation by dissolved Zn ion-bridging, whereas the increasing protein concentrations enhanced the TNPs aggregation through macromolecule bridging flocculation. PMID- 29153646 TI - Waste to biodiesel: A preliminary assessment for Saudi Arabia. AB - This study presents a preliminary assessment of biodiesel production from waste sources available in the Kingdom of Saudi Arabia (KSA) for energy generation and solution for waste disposal issues. A case study was developed under three different scenarios: (S1) KSA population only in 2017, (S2) KSA population and pilgrims in 2017, and (S3) KSA population and pilgrims by 2030 using the fat fraction of the municipal solid waste. It was estimated that S1, S2, and S3 scenarios could produce around 1.08, 1.10 and 1.41 million tons of biodiesel with the energy potential of 43423, 43949 and 56493 TJ respectively. Furthermore, annual savings of US $55.89, 56.56 and 72.71 million can be generated from landfill diversion of food waste and added to the country's economy. However, there are challenges in commercialization of waste to biodiesel facilities in KSA, including waste collection and separation, impurities, reactor design and biodiesel quality. PMID- 29153647 TI - Hydrothermal liquefaction of Gracilaria gracilis and Cladophora glomerata macro algae for biocrude production. AB - The potential of Gracilaria gracilis (G. gracilis) and Cladophora glomerata (C. glomerata) macro-algae species harvested from Caspian Sea for biocrude oil production under Hydrothermal Liquefaction (HTL) reaction at 350 degrees C and 15 min has been investigated. Furthermore, the effect of using recycled aqueous phase as the HTL reaction solvent was studied. The biocrude yield for G. gracilis and C. glomerata was 15.7 and 16.9 wt%, respectively with higher heating value (HHV) of 36.01 and 33.06 MJ/kg. The sources of each existing component in bio-oil were identified by GC-MS based on their suggested reaction pathways. Moreover, after two series of aqueous solution recycling, experiments showed that the bio oil yield significantly increased compared with the initial condition. This increasing directly relates with recovery of carbon content from the aqueous solution residue. PMID- 29153648 TI - Efficient production of succinic acid from duckweed (Landoltia punctata) hydrolysate by Actinobacillus succinogenes GXAS137. AB - A novel process of enzyme pretreatment and semi-simultaneous saccharification and fermentation (SSSF) was developed in this work to improve succinic acid (SA) productivity from duckweed (Landoltia punctata) and achieve low viscosity. Viscosity (83.86%) was reduced by the pretreatment with combined enzymes at 50 degrees C for 2 h to a greater extent than that by single enzyme (26.19-71.75%). SSSF was an optimal combination with 65.31 g/L of SA content, which was remarkably higher than those obtained through conventional separate hydrolysis and fermentation (62.12 g/L) and simultaneous saccharification and fermentation (52.41 g/L). The combined approach was effective for SA production. Approximately 75.46 g/L of SA content with a yield of 82.87% and a productivity of 1.35 g/L/h was obtained after 56 h in a 2 L bioreactor. Further studies will focus on increasing the working scale of the proposed method. PMID- 29153649 TI - Demonstration and optimization of sequential microaerobic dark- and photo fermentation biohydrogen production by immobilized Rhodobacter capsulatus JP91. AB - Hydrogen generation from complex substrates composed of simple sugars has the potential to mitigate future worldwide energy demand. The biohydrogen potential of a sequential microaerobic dark- and photo-fermentative system was investigated using immobilized Rhodobacter capsulatus JP91. Biological hydrogen production from glucose was carried out using a batch process and a bench-scale bioreactor. Response surface methodology with a Box-Behnken design was employed to optimize key parameters such as inoculum concentration, oxygen concentration, and glucose concentration. The maximum hydrogen production (21 +/- 0.25 mmol H2/L) and yield (7.8 +/- 0.1 mol H2/mol glucose) were obtained at 6 mM glucose, 4.5% oxygen and 62.5 v/v% inoculum concentration, demonstrating the feasibility of enhanced hydrogen production by immobilized R. capsulatus JP91 in a sequential system. This is the first time that a sequential process using an immobilized system has been described. This system also achieved the highest hydrogen yield obtained by an immobilized system so far. PMID- 29153650 TI - Performance of phosphogypsum and calcium magnesium phosphate fertilizer for nitrogen conservation in pig manure composting. AB - This study investigated the performance of phosphogypsum and calcium magnesium phosphate fertilizer for nitrogen conservation during pig manure composting with cornstalk as the bulking agent. Results show that phosphogypsum increased nitrous oxide (N2O) emission, but significantly reduced ammonia (NH3) emission and thus enhanced the mineral and total nitrogen (TN) contents in compost. Although N2O emission could be reduced by adding calcium magnesium phosphate fertilizer, NH3 emission was considerably increased, resulting in an increase in TN loss during composting. By blending these two additives, both NH3 and N2O emissions could be mitigated, achieving effective nitrogen conservation in composting. More importantly, with the addition of 20% TN of the mixed composting materials, these two additives could synergistically improve the compost maturity and quality. PMID- 29153651 TI - Enhanced l-ornithine production by systematic manipulation of l-ornithine metabolism in engineered Corynebacterium glutamicum S9114. AB - l-Ornithine is a non-protein amino acid with extensive applications in medicine and the food industry. Currently, l-ornithine is produced by microbial fermentation; however, this process needs to be further improved in terms of l ornithine productivity and cost reduction. In this study, overexpression of LysE was observed to increase l-ornithine production in engineered Corynebacterium glutamicum S9114. To overcome the drawbacks of using a plasmid to express LysE, Ptac, a strong promoter, was inserted in the upstream region of lysE on the chromosome. This strain was further engineered by attenuating the expression of ncgl2228 and proB, and enhancing the expression of gdh and argCJBD. Combination of those targets resulted in l-ornithine production at a titer of 25 g/L, which was 63.4% higher than that produced by the original strain (15.3 g/L). These results demonstrated the positive effects of overexpressing LysE on l-ornithine production and provided novel targets for developing l-ornithine-producing C. glutamicum strains. PMID- 29153652 TI - Enzymes catalyzing pre-hydrolysis facilitated the anaerobic fermentation of waste activated sludge with acidogenic and microbiological perspectives. AB - This study investigated acidogenic and microbiological perspectives in the anaerobic fermentation (AF) of waste activated sludge (WAS) pre-hydrolyzed by enzymes catalysis. The enzymes catalysis boosted WAS biodegradability dramatically with nearly 8500 mg/L soluble chemical oxygen demand (SCOD) increase just within 4 h. The volatile fatty acids (VFAs) in the acidogenesis were accumulated effectively with over 3200 mg COD/L in 12 d, which reached 0.687 kWh/kg VSS electricity conversion efficiency (2.5 times higher than the control test). The fermentation process favored the compression of fermentative sludge with the distribution spread index (DSI) rising. The core populations of bacteria and archaea shifting enlarged the dissimilarity of communities at different fermentation stages. Increase of community diversity contributed to VFAs accumulation stability. Moreover, the intermediate bacterial community evenness favored VFAs accumulation potentially. The enzymes catalysis might be a promising solution for strengthening VFAs accumulation in the WAS fermentation with boosting the electricity conversion potential. PMID- 29153653 TI - Ferroferric oxide triggered possible direct interspecies electron transfer between Syntrophomonas and Methanosaeta to enhance waste activated sludge anaerobic digestion. AB - ZVI was reported to enrich H2-utilizing methanogens that enhanced interspecies H2 transfer, while Fe(III) oxide served as a conductive material to promote direct interspecies electron transfer (DIET). However, the interaction of these two modes in anaerobic digestion has not been clarified yet. In this study, when adding Fe3O4 and ZVI simultaneously into an anaerobic digester, the abundance of hydrogenotrophic methanogens decreased drastically compared to ZVI-added digester and Fe-free digester. However, the methane production of ZVI + Fe3O4 added digester were 68.9% higher than Fe-free digester and 20.0% higher than ZVI-added digester, respectively. Sludge reduction rate of these three digesters also showed similar results. These indicated that hydrogenotrophic methanogenesis was not the main reason for methanogenesis in Fe3O4-added digester. Instead, Syntrophomonas and Methanosaeta were specially enriched in Fe3O4-added digesters, which implied that the potential DIET between Syntrophomonas and Methanosaeta was likely a crucial reason for accelerating anaerobic digestion of waste sludge. PMID- 29153654 TI - 68(Ge+Ga) activity standardization by 4pibeta(LS)-gamma(NaI(Tl)) anticoincidence counting measurements. AB - In this work, a 68(Ge+Ga) solution has been standardized at the National Institute of Ionizing Radiation Metrology (LNMRI), in Brazil, in the frame of an international key comparison CCRI(II)-K2.Ge-68 piloted by National Institute of Standards and Technology (NIST/USA). The 4pibeta(LS)-gamma(NaI(Tl)) anticoincidence method with live-time and extended dead-time was used and its result was validated by 4pibeta(LS)-gamma(NaI(Tl)) coincidence counting and liquid scintillation counting using the Triple to Double Coincidence Ratio (TDCR) method. The deviations of the activity concentration values of coincidence and TDCR measurements from the anticoincidence result were 1.7% and 0.63%, respectively, which were within experimental evaluated uncertainties at ~95% level of confidence (coverage factor k = 2). The combined relative standard uncertainties were 0.65%, 0.70% and 0.53% for anticoincidence, coincidence and TDCR methods, respectively. These values are consistent with the results reported by Cessna at the ICRM2017 conference. PMID- 29153656 TI - Tune to touch: Affective touch enhances learning of face identity in 4-month-old infants. AB - Touch provides more than sensory input for discrimination of what is on the skin. From early in development it has a rewarding and motivational value, which may reflect an evolutionary mechanism that promotes learning and affiliative bonding. In the present study we investigated whether affective touch helps infants tune to social signals, such as faces. Four-month-old infants were habituated to an individual face with averted gaze, which typically does not engage infants to the same extent as direct gaze does. As in a previous study, in the absence of touch, infants did not learn the identity of this face. Critically, 4-month-old infants did learn to discriminate this face when parents provided gentle stroking, but they did not when they experienced a non-social tactile stimulation. A preliminary follow-up eye-tracking study (Supplementary material) revealed no significant difference in the visual scanning of faces between touch and no-touch conditions, suggesting that affective touch may not affect the distribution of visual attention, but that it may promote more efficient learning of facial information. PMID- 29153655 TI - Clinical Evidence Supports a Protective Role for CXCL5 in Coronary Artery Disease. AB - Our goal was to measure the association of CXCL5 and molecular phenotypes associated with coronary atherosclerosis severity in patients at least 65 years old. CXCL5 is classically defined as a proinflammatory chemokine, but its role in chronic inflammatory diseases, such as coronary atherosclerosis, is not well defined. We enrolled individuals who were at least 65 years old and undergoing diagnostic cardiac catheterization. Coronary artery disease (CAD) severity was quantified in each subject via coronary angiography by calculating a CAD score. Circulating CXCL5 levels were measured from plasma, and both DNA genotyping and mRNA expression levels in peripheral blood mononuclear cells were quantified via microarray gene chips. We observed a negative association of CXCL5 levels with CAD at an odds ratio (OR) of 0.46 (95% CI, 0.27-0.75). Controlling for covariates, including sex, statin use, hypertension, hyperlipidemia, obesity, self-reported race, smoking, and diabetes, the OR was not significantly affected [OR, 0.54 (95% CI, 0.31-0.96)], consistent with a protective role for CXCL5 in coronary atherosclerosis. We also identified 18 genomic regions with expression quantitative trait loci of genes correlated with both CAD severity and circulating CXCL5 levels. Our clinical findings are consistent with the emerging link between chemokines and atherosclerosis and suggest new therapeutic targets for CAD. PMID- 29153657 TI - Cardiac magnetic resonance imaging in myocardial inflammation in autoimmune rheumatic diseases: An appraisal of the diagnostic strengths and limitations of the Lake Louise criteria. AB - Myocardial inflammation in autoimmune rheumatic diseases (ARDs) is the endpoint of various pathophysiologic processes. The Lake Louise-criteria is the most popular approach for the diagnosis of myocarditis. However, due to the diversity of myocardial inflammation in ARDs, some issues should be acknowledged. Of the three Lake Louise indices, early and late gadolinium enhancement (EGE and LGE respectively) measurements may be affected by co-existing disease processes or be present due to a fibrotic ARD like systemic sclerosis, leaving T2-ratio as the only uniformly robust measurement across ARDs. It thus becomes apparent that the Lake Louise criteria suffer from a number of limitations when ARD patients are assessed based on them. The introduction of T1/T2 mapping allowed the quantification of intramyocardial fibrosis missed by LGE and the detection of myocardial oedema respectively, both commonly found in ARDs. The Lake Louise criteria play an important role in the evaluation of AIMI in ARDs. However, the pathophysiologic background of cardiac involvement in ARDs should always be acknowledged in their evaluation. Even though the inclusion of T1/T2 mapping and ECV may better describe diffuse oedema and fibrosis, further investigation pertaining to their implementation in ARD assessment algorithms through multicenter studies is needed. PMID- 29153658 TI - Neurological function in children born to preeclamptic and hypertensive mothers - A systematic review. AB - BACKGROUND: Offspring whose mothers developed preeclampsia (PE-F1s) show developmental effects that are now being identified, such as cognitive, behavioural, and mood differences compared to offspring from non-complicated pregnancies. We hypothesize that the progressive angiokine dysregulation associated with development of preeclampsia (PE) reflects gene dysregulation in pre-implantation conceptuses, and manifests in all developing fetal tissues rather than exclusively to the placenta. This hypothesis predicts that fetal cerebrovascular and brain development are deviated by fetal-intrinsic, brain based mechanisms during what is currently considered a placentally-induced maternal disease. Due to our initial results from brain-imaging and cognitive screening in a child pilot PE-F1 cohort, we developed this systematic review to answer the question of whether any consistent neurological measurements have been found to discriminate between brain functions in offspring of mothers who experienced a hypertensive pregnancy vs. offspring of mothers that did not. METHODS: Relevant studies were searched systematically up to June 2017 in MEDLINE, PsycINFO, EMBASE and the grey literature. RESULTS: Following predetermined inclusion and exclusion criteria, our search identified 27 out of 464 studies reporting on neurological function in offspring born to preeclamptic and hypertensive mothers. CONCLUSION: The current literature strongly supports the conclusion of the behavioural and cognitive deviations in PE-F1s. However, only three studies associated their findings with brain measurements via magnetic resonance imaging (MRI) in both healthy and at-risk pediatric populations. PE-F1s should be identified as an at-risk pediatric population during brain development and studied further as a defined group, perhaps stratified by maternal plasma angiokine levels. PMID- 29153659 TI - A simple clinical method to identify women at higher risk of preeclampsia. AB - An outstanding issue is how to efficiently identify women at high risk of preeclampsia. This retrospective cohort study included 8672 pregnancies at a single centre in Toronto. We tested our simple method - presence vs. absence of>=1 major (pre-pregnancy BMI>30kg/m2, chronic hypertension, pre-pregnancy diabetes mellitus and assisted reproductive therapy) or>=2 minor (prior stillbirth, age>40years, nulliparity, multifetal pregnancy, chronic kidney disease, and SLE) risk factors for PE. The RR of PE was 8.4 (95% CI 5.3-13.2) and the model C-statistic 0.74 (95% CI 0.69-0.79). Further testing of this method elsewhere is warranted. PMID- 29153660 TI - Fetal size and growth velocity in chronic hypertension. AB - OBJECTIVE: To investigate longitudinal fetal growth and growth velocity for commonly measured biometric parameters in women with chronic hypertension. METHODS: Two centre retrospective European study of women with chronic hypertension ascertained at pregnancy booking. Ultrasound measurements of head circumference (HC), abdominal circumference (AC) and femur length (FL) were used to derive longitudinal fetal growth charts derived using functional linear discriminant analysis (FLDA). These were compared to existing cross sectional and longitudinal charts, as was birthweight. RESULTS: 282 women with a median of 3 third trimester ultrasound examinations were included. Gestation at delivery was 37.5weeks (SD 2.68), birthweight 3049g (SD 785). Birthweight <10th percentile found in 15.6% deliveries, >90th percentile 20.2%. Fetal size curves derived from women with chronic hypertension were no different to cross sectional and longitudinal charts for a normal population. Compared to a standard longitudinal biometry chart, growth velocity (mm/day) in chronic hypertension was higher for AC and FL at 30-32weeks (AC 1.447vs 1.357 p<0.05; FL 0.296vs 0.269 p<0.01) and 34 36weeks (AC 1.325vs 1.140 p<0.01; FL 0.248vs 0.198 p<0.01). CONCLUSIONS: In women with chronic hypertension there is an excess of both SGA and LGA babies compared to population standards. Growth velocity of the AC and FL was greater after 30weeks compared to a normal population. PMID- 29153661 TI - PKB/Akt and MAPK/ERK phosphorylation is highly induced by inositols: Novel potential insights in endothelial dysfunction in preeclampsia. AB - PKB/Akt and MAP/ERK are intracellular kinases regulating cell survival, proliferation and metabolism and as such hold a strategical role in preeclampsia. In fact intracellular pathways related to immunological alterations, endothelial dysfunction and insulin resistance in preeclampsia converge on these molecules. Inositol second messengers are involved in metabolic and cell signaling pathways and are highly expressed during preeclampsia. To evaluate the pathophysiological significance of this response, the effect of myo-inositol and d-chiro inositol on the activation of PKB/Akt and MAPK/ERK was assessed in human endothelial cells in vitro. Time-course and dose-response analyses of phosphorylation following incubation with inositols showed an approximately 6-fold and 15-fold increase for myo-inositol and d-chiro inositol (p<0.05), respectively. Both inositols promoted a significantly higher PKB/Akt and MAPK/ERK phosphorylation than insulin. Thus, exogenously administered inositols can activate PKB/Akt and MAPK/ERK in human endothelial cells in vitro. The increased production of d-chiro inositol phosphoglycans (IPG-P) during preeclampsia may thus represent a compensatory response, potentially promoting cell survival and metabolism. PMID- 29153662 TI - Comparison of three algorithms for prediction preeclampsia in the first trimester of pregnancy. AB - OBJECTIVE: To compare a new simple algorithm for preeclampsia (PE) prediction among Brazilian women with two international guidelines - National Institute for Clinical Excellence (NICE) and American College of Obstetricians and Gynecologists (ACOG). METHODS: We performed a secondary analysis of two prospective cohort studies to predict PE between 11 and 13+6weeks of gestation, developed between August 2009 and January 2014. Outcomes measured were total PE, early PE (<34weeks), preterm PE (<37weeks), and term PE (>=37weeks). The predictive accuracy of the models was assessed using the area under the receiver operator characteristic curve (AUC-ROC) and via calculation of sensitivity and specificity for each outcome. RESULTS: Of a total of 733 patients, 55 patients developed PE, 12 at early, 21 at preterm and 34 at term. The AUC-ROC values were low, which compromised the accuracy of NICE (AUC-ROC: 0.657) and ACOG (AUC-ROC: 0.562) algorithms for preterm PE prediction in the Brazilian population. The best predictive model for preterm PE included maternal factors (MF) and mean arterial pressure (MAP) (AUC-ROC: 0.842), with a statistically significant difference compared with ACOG (p<0.0001) and NICE (p=0.0002) guidelines. CONCLUSION: The predictive accuracies of NICE and ACOG guidelines to predict preterm PE were low and a simple algorithm involving maternal factors and MAP performed better for the Brazilian population. PMID- 29153663 TI - Prognostic model for chronic hypertension in women with a history of hypertensive pregnancy disorders at term. AB - INTRODUCTION: The association between hypertensive pregnancy disorders and cardiovascular disease later in life is well described. In this study we aim to develop a prognostic model from patients characteristics known before, early in, during and after pregnancy to identify women at increased risk of cardiovascular disease e.g. chronic hypertension years after pregnancy complicated by hypertension at term. METHODS: We included women with a history of singleton pregnancy complicated by hypertension at term. Women using antihypertensive medication before pregnancy were excluded. We measured hypertension in these women more than 2years postpartum. Different patients characteristics before, early in, during and after pregnancy were considered to develop a prognostic model of chronic hypertension at 2-years. These included amongst others maternal age, blood pressure at pregnancy intake and blood pressure six weeks post-partum. Univariable analyses followed by a multivariable logistic regression analysis was performed to determine which combination of predictors best predicted chronic hypertension. Model performance was assessed by calibration (graphical plot) and discrimination (area under the receiver operating characteristic (AUC)). RESULTS: Of the 305 women in who blood pressure 2.5years after pregnancy was assessed, 105 women (34%) had chronic hypertension. The following patient characteristics were significant associated with chronic hypertension: higher maternal age, lower education, negative family history on hypertensive pregnancy disorders, higher BMI at booking, higher diastolic blood pressure at pregnancy intake, higher systolic blood pressure during pregnancy and higher diastolic blood pressure at six weeks post-partum. These characteristics were included in the prognostic model for chronic hypertension. Model performance was good as indicated by good calibration and good discrimination (AUC; 0.83 (95% CI 0.75 - 0.92). CONCLUSION: Chronic hypertension can be expected from patient characteristics before, early in, during and after pregnancy. These data underline the importance and awareness of detectable risk factors both for increased risk of complicated pregnancy as well as increased risk of cardiovascular disease later in life. PMID- 29153664 TI - Microcirculatory blood flow derangements during severe preeclampsia and HELLP syndrome. AB - OBJECTIVE: To evaluate the microcirculatory blood flow in severe preeclampsia and compare it with healthy pregnant and non-pregnant women controls, using a portable intravital-microscopy technique. METHODS: Using a side-stream dark field (SDF) device, we prospectively evaluated the sublingual microcirculatory blood flow before placental delivery in 40 women with severe preeclampsia (PE-group) complicated (n=8) or not (n=32) with HELLP syndrome, 40 healthy pregnant women (HP-group) matched by gestational and chronological age, and 20 healthy non pregnant women (NP-group). Microvessels were classified as large or small using a cutoff value of 20MUm and those with continuous flow were considered as normal while sluggish, intermittent and stopped flows were considered as abnormal. We computed the proportion of well-perfused small vessels (PPV), and total and functional capillary densities (TCD and FCD) were calculated according to the total number and quantity of well-perfused small vessels per area unit, respectively. RESULTS: Total capillary densities were significantly higher in all pregnant women when compared to non-pregnant controls. The PE-group exhibited, however, significantly lower TCD compared with the HP-group. Meanwhile, significant decreases in PPV and FCD were observed in the PE-group, with deeper alterations in those with coexisting HELLP syndrome. These altered PPVs were significant although incompletely reversed after placental delivery in pregnancies complicated by HELLP syndrome, while capillary densities remained unaltered at least during very early post-delivery period. CONCLUSIONS: Substantial distributive microcirculatory blood flow alterations and restricted capillary densities are observed in preeclampsia, suggesting a key role for microvascular dysfunction in the pathophysiology of this condition. PMID- 29153665 TI - Correlation between maternal body composition and haemodynamic changes in pregnancy: different profiles for different hypertensive disorders. AB - OBJECTIVES: To assess and correlate changes in body composition and haemodynamic function during pregnancy. To identify different haemodynamic profiles based on the onset of hypertensive diseases such as gestational hypertension and preeclampsia. METHODS: We enrolled 265 healthy, normotensive pregnant women throughout pregnancy (from 6+0 to 36+0weeks). They were subjected to assessment of body composition and haemodynamic function using non-invasive methods. We divided our population in three groups: group A with physiological pregnancy, group B with gestational hypertension and group C with preeclamptic patients. RESULTS: In patients who developed gestational hypertension we found lower total body water (TBW) percentage, higher Fat Mass (FM), associated with lower Cardiac Output (CO) and higher Total Vascular Resistance (TVR) during the second trimester. In the third trimester we didn't find haemodynamic differences, but a significative increase in extracellular water (ECW) percentage. In patients who developed preeclampsia we found since the first trimester significative higher TVR and hypodynamic circulation, associated with lower FM percentage. CONCLUSIONS: Assessment of body composition and maternal cardiac function may help to identify earlier in pregnancy, patients with different (mal) adaptations to pregnancy. Women with high TVR, hypodynamic circulation and low fat mass during the first trimester, might be at higher risk to develop preeclampsia. Patients with higher BMI and FM percentage, and increased TVR in the second trimester, might be at risk of gestational hypertension and excessive fluid retention at the end of pregnancy. PMID- 29153666 TI - Prevalence, risk factors and associated complications of postpartum hypertension in rural Haiti. AB - BACKGROUND: The prevalence of hypertensive disorders during pregnancy is high in developing countries such as Haiti, however little is known about postpartum hypertension (PPHTN). METHODS: This is a prospective study done at Hospital Albert Schweitzer in rural Haiti among pregnant women age 18 or older who were admitted for labor. Blood pressures were collected before and after delivery and medical charts were reviewed to gather delivery characteristics and fetal/neonatal outcomes. Differences between groups are presented based on postpartum blood pressures (BP) as mild PPHTN (systolic BP>=140 or diastolic BP>=90) and severe PPHTN (systolic BP>=160 or diastolic BP>=110). RESULTS: Of 175 women, the prevalence of PPHTN during the two-month study period was 57.1% (97/172) and included 56 parturients with mild and 41 with severe PPHTN. Severe PPHTN was associated with a higher proportion of complications including abruption (14.6%), fetal (14.6%) and neonatal death (7.3%). Thirty-nine (69.6%) patients with mild PPHTN and 9 (21.9%) patients with severe PPHTN did not receive any antihypertensive medications postpartum. Patients with severe PPHTN had prolonged hospitalization compared to the normal group (3.5 vs. 2.0days, p=0.0003). There was a strong correlation between antepartum and postpartum systolic and diastolic BP's (r=0.62 and 0.54, p<0.0001, respectively). CONCLUSION: In this study, we identified a high prevalence of PPHTN in rural Haiti. Severe PPHTN was associated with adverse outcomes and treatment is not universal. This data is a starting point to develop region-specific protocols to treat and control PPHTN. PMID- 29153667 TI - Preeclampsia and later cardiovascular disease - What do national guidelines recommend? AB - Preeclamptic women have an increased risk of hypertension and cardiovascular disease (CVD) later in life. The aim was to compare the latest clinical recommendations on post-preeclamptic prevention of hypertension and CVD published by eight National Associations of Gynecologists and Obstetricians. Definitions of preeclampsia differ internationally. Recommendations on when, how and who to screen to reduce post-preeclamptic CVD risk also show substantial variation. The diverging preeclampsia definitions make CVD prevention strategies difficult to compare. The variations in clinical recommendations are in line with the lacking evidence of cost-efficient follow-up strategies and stress the need for further research to optimize prevention strategies. PMID- 29153668 TI - Outcomes and mortality in parturient and non-parturient patients with peripartum cardiomyopathy: A national readmission database study. AB - BACKGROUND: Peripartum cardiomyopathy (PPCM) affects young females and mortality occurs after the peripartum period. Hospital readmissions for patients discharged with PPCM are poorly understood. The aim of this study was to evaluate differences in readmission rates, risk factors, and mortality in women with PPCM. METHODS: We conducted a retrospective cohort analysis using the Healthcare Cost and Utilization Project 2013 National Readmissions Database. From the database, we selected patients with PPCM to include patients discharged between January and November 2013. Readmission rate, mortality rate and risk factors were analyzed. In our cohort of 3800 patients, we found a readmission rate of 15.1% and a mortality rate of 1.6%. Comorbidities associated with readmission were pulmonary hypertension, obesity, renal failure, and drug abuse. Mortality on initial admission was associated with coagulation disorders and respiratory failure. Women who delivered on initial admission had a statistically lower rate of readmission than women who did not deliver on initial admission. CONCLUSIONS: In a large retrospective nationwide analysis of PPCM patients, we found associated conditions that may help predict which patients will have a higher risk for readmission and mortality. PMID- 29153669 TI - Maternal serum IGF-1, IGFBP-1 and 3, and placental growth hormone at 20weeks' gestation in pregnancies complicated by preeclampsia. AB - OBJECTIVE: To investigate whether maternal serum concentrations of placental growth hormone (GH-V), insulin-like growth factor (IGF) 1 and 2, and IGF binding proteins (IGFBP) 1 and 3 were altered in pregnancies complicated by later preeclampsia (PE). STUDY DESIGN: In a nested case-control study, PE cases (n=71) and matched controls (n=71) were selected from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Maternal serum hormone concentrations at 20weeks of gestation were determined by ELISA. RESULTS: We found that maternal serum GH-V concentration at 20weeks of gestation was unaltered in the PE group, compared to the control group (median, 1.78ng/ml vs. 1.65ng/ml, p=0.884). Maternal IGF-1 and IGFBP-3 concentrations and the IGF 1/IGFBP-3 ratio in PE pregnancies were significantly higher than in controls (median, 253.1ng/ml vs. 204.3ng/ml, p<0.0001; 8535ng/ml vs. 7711ng/ml, p=0.0023; 0.032vs. 0.026, p<0.0001, respectively), whereas maternal IGFBP-1 concentration was significantly lower in PE pregnancies than in controls (median, 34.85ng/ml vs. 48.92ng/ml, p=0.0006). CONCLUSION: Our findings suggest a potential role of IGFs and IGFBPs in the prediction of pregnancies complicated by PE. However, the maternal serum concentration of GH-V at 20weeks' gestation is unlikely to be useful in the early prediction of PE. PMID- 29153670 TI - Protocol for measurement of mean arterial pressure at 10-40weeks' gestation. AB - The study aimed to identify the simplest protocol for the measurement of mean arterial pressure (MAP) across 10-40weeks' gestation. 2726 women with uncomplicated singleton pregnancy attending for their routine hospital visit between 10 and 40weeks' gestation were recruited prospectively. The blood pressure (BP) was measured according to the National Heart Foundation of Australia (NHFA) protocol using automated devices. Linearizing regression models were determined for MAP derived from single, repeat and average measurements taken in the left and right arms using the same polynomial power of the best fit model determined using the NHFA protocol. Z-scores were used to compare the differences between the smoothed 50th percentiles. The first measurements taken in the left and right arms were on average 0.15SD and 0.12SD, respectively, higher than those obtained from the NHFA protocol. The second measurements taken in the left and right arms were both 0.26SD lower than the first measurement taken in the same arm and these values were lower than those from the NHFA protocol. The median MAP determined by the protocol of the average of two measurements taken in both arms was similar to the median MAP determined using the NHFA protocol (Z-score 0.0194SD). MAP derived by the average of two measurements in both arms had a quadratic relationship with gestation, with the measurement being the lowest in the mid-trimester. In conclusion, our study has demonstrated that at 10-40weeks' gestation, BP recordings can be obtained by a simpler protocol using the average of two measurements in both arms. PMID- 29153671 TI - Longitudinal evaluation of uterine perfusion, endothelial function and central blood flow in early onset pre-eclampsia. AB - OBJECTIVES: Physiopathological mechanisms that trigger clinical manifestations in pre-eclampsia (PE) remain unclear, and management is still a challenge. The identification of tools to predict the onset of the disease and prevent its complications is of great interest in medical practice. The present study aims to evaluate uterine perfusion, endothelial function and central nervous system blood flow in pregnant women with high-risk factors for PE, for comparison of the results between the group of patients who developed early onset PE and those who remained normotensive throughout pregnancy. STUDY DESIGN: Sixty-two patients were recruited from our high-risk prenatal service, and followed throughout gestation. Patients were submitted to flow-mediated dilation, Dopplervelocimetry of uterine arteries and Dopplervelocimetry of ophthalmic arteries at three distinct moments of pregnancy: between 16+0 and 19+6weeks, between 24+0 and 27+6weeks and at hospital admission to delivery. MAIN OUTCOME MEASURES: Pulsatility index of uterine arteries, flow-mediated dilation and ophthalmic arteries resistance index were evaluated and compared between the two groups of patients. RESULTS: Ten pregnancies were complicated by early onset PE, and these patients presented a significantly higher pulsatility index of uterine arteries between 16+0 and 19+6weeks of gestation, compared with the normotensive group (p=0,016). Both flow mediated dilation and ophthalmic arteries resistance index values were lower in affected patients at 24+0 to 27+6weeks (p=0,001), and by the time of delivery (p<0,002). CONCLUSIONS: Those findings suggest that impaired placental perfusion, endothelial dysfunction and central hyperperfusion temporarily precede the clinical manifestations of early onset pre-eclampsia. PMID- 29153672 TI - An intermediate sFlt-1/PlGF ratio indicates an increased risk for adverse pregnancy outcome. AB - OBJECTIVE: The sFlt-1/PlGF ratio is a valid marker in diagnosing or excluding preeclampsia. The currently used cut offs frame an intermediate zone of 33-85 (<340 weeks) or 33-110 (>=340 weeks), respectively. In this study we sought to evaluate the relevance of an intermediate sFlt-1/PlGF ratio for the clinical pregnancy course and outcome. MATERIAL AND METHODS: We retrospectively analysed 533 consecutive patients with sFlt-1/PlGF ratio measurements for suspected preeclampsia. In patients with an intermediate sFlt-1/PlGF ratio, fetal and maternal characteristics and also pregnancy outcome were documented. Furthermore, we compared the patient groups with <340/340-366/>=370 gestational weeks at first visit. RESULTS: 83/533 (15.6%) patients had an intermediate sFlt-1/PlGF ratio. Maternal or fetal diseases or twin pregnancies occurred in 87.9%. Preeclampsia/HELLP syndrome developed in 31.3% but were mostly mild or moderate (65.4%). However, severe adverse outcome was observed in 36.1% with severe preeclampsia in 10.8%. Even if further pregnancy duration and gestational week correlated negatively (r=-0.424; p<0.001), 92% of patients, tested with <340 weeks delivered prematurely. The overall preterm birth rate was 27.7%. CONCLUSIONS: Patients with an intermediate sFlt-1/PlGF ratio are at risk for severe adverse outcome. An intermediate sFlt-1/PlGF ratio indicates a risk for preterm birth, independent from the occurrence of preeclampsia. PMID- 29153673 TI - Pregnancy complications and later vascular ultrasound measures: A cohort study. AB - OBJECTIVES: Pregnancy complications predict or even predispose to later cardiovascular disease in the mother. We examined whether pregnancy complications are associated with post-pregnancy measures of endothelial dysfunction and arterial stiffness. STUDY DESIGN: Prospective cohort; Data for 847 women female participants in the Cardiovascular Risk in Young Finns study were linked with the national birth registry. Preterm birth (<37weeks), low birthweight (<2500g), small-for-gestational-age (weight <10th percentile for gestational age), and hypertensive disorders of pregnancy were examined as predictors of later vascular measures. MAIN OUTCOME MEASURES: Flow-mediated dilatation (FMD), carotid intima media thickness (IMT), Young's elastic modulus (YEM), and carotid artery distensibility. RESULTS: In some analyses, gestational hypertension and pre eclampsia were associated with increased YEM. Low birthweight was also associated with an increase in IMT, and this increased risk was present prior to the pregnancy. CONCLUSIONS: The increased cardiovascular risk in the mother observed after low birthweight and hypertensive disorders may be due to vascular changes, and some of this increased risk may be present before pregnancy. PMID- 29153674 TI - Labor therapeutics and BMI as risk factors for postpartum preeclampsia: A case control study. AB - OBJECTIVES: This study aims at identifying associations between therapeutics used during labor and the occurrence of postpartum preeclampsia (PPPE), a poorly understood entity. STUDY DESIGN AND MAIN OUTCOME MEASURES: This is a case-control study of women who received an ICD-9 code for PPPE (cases) during the years 2009 2011, compared to women with a normotensive term pregnancy, delivery and postpartum period until discharge (controls), matched on age (+/-1year) and delivery date (+/-3months). Cases were defined as women having a normotensive term pregnancy, delivery and initial postpartum period (48h post-delivery) but developing hypertension between 48h and 6weeks postpartum. Single variable and multiple variable models were used to determine significant risk factors. RESULTS: Forty-three women with PPPE were compared to 86 controls. Use of vasopressors and oxytocin did not differ between cases and controls, but rate of fluids administered during labor (OR=1.68 per 100cc/h; 95% CI: 1.09-2.59, p=0.02) and an elevated pre-pregnancy/first trimester BMI (OR=1.18 per kg/m2, 95% CI: 1.07-1.3, p=0.001) were identified as significant risk factors in multivariate analysis. CONCLUSIONS: We identified two potentially modifiable risk factors for PPPE; further studies are needed to better define the role of these two variables in the development of PPPE. PMID- 29153675 TI - sFlt-1 and soluble endoglin concentrations in serum vs plasma in preterm preeclampsia: Are they interchangeable for biomarker studies? AB - Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) are increased in the circulation of women with preeclampsia. We examined whether they differ in concentration between plasma and serum samples. Maternal blood was collected and processed for serum and plasma, from 28 women with preterm preeclampsia and 18 gestation matched controls (<34weeks). Significantly higher sFlt-1 was detected in preeclamptic serum compared to plasma. Significantly higher levels of sENG were identified in serum compared to plasma from control pregnancies. Thus these data show the sample type (serum or plasma) needs to be consistent within comparisons for both sFlt-1 and sENG. PMID- 29153676 TI - A pilot study of the relationship between preeclampsia and anti-tetanus toxoid antibody levels. PMID- 29153677 TI - The efficacy of peripartum transthoracic echocardiography in women with preeclampsia. AB - OBJECTIVE: To examine the features and efficacy of transthoracic echocardiography (TTE) in preeclampsia. METHODS: We retrospectively reviewed the medical records of 145 pregnant women with preeclampsia, who underwent TTE at Seoul St. Mary's Hospital between July 2006 and June 2016. We analyzed echocardiographic features in preeclampsia and the relationship between the severity of preeclampsia and TTE findings. Additionally, we examined the predictive echocardiographic factors of persistent hypertension and calculated the adjusted odds ratio (OR) and 95% confidence interval (CI) for multiple regression models by considering systolic and diastolic blood pressure and pre-pregnancy body mass index (BMI). RESULTS: Hemodynamic findings assessed by TTE in women with preeclampsia included systolic and diastolic dysfunction, increased left ventricular mass, and enlarged left atrium. Diastolic dysfunction and left ventricular hypertrophy (LVH) were more common in preeclampsia with severe features (39.84% vs. 32.05%, p=0.010, and 21.79% vs. 8.96%, p=0.041, respectively). In the patients with systolic dysfunction, the adjusted OR for persistent hypertension was 17.41 (95% CI=2.83 107.20). The ORs for grade 1 and grade 2 diastolic dysfunction were 12.58 and 32.84, respectively (95% CI, 2.99-52.92 and 3.61-298.58, respectively). When LVH assessed by TTE was considered with diastolic dysfunction, the risk for persistent hypertension increased (OR 19.28; 95% CI-4.36-85.20). CONCLUSION: TTE not only can reveal the severity of preeclampsia, but also can be a useful tool for the follow-up of persistent hypertension. PMID- 29153678 TI - Polymorphism of ERCC1 rs3212986 in Chinese Han women with preeclampsia. AB - OBJECTIVE: To investigate the association between polymorphism of rs3212986 in ERCC1 and susceptibility to preeclampsia in the Chinese Han population. STUDY DESIGN: Samples of 642 preeclampsia patients and 877 controls were genotyped for rs3212986 using TaqMan allele discrimination assays. The genetic and allelic distributions between the groups were compared by Pearson's chi2 test. RESULT: There was no difference in the genotypic and allelic distributions between cases and controls (P>0.05). Statistical difference in genotypic frequencies of rs3212986 was observed between early-onset and late-onset preeclampsia (chi2=6.985, P=0.030). When subdivided into TT/GG+GT groups, a significant difference was found between early-onset and late-onset preeclampsia (chi2=6.528, P=0.011, OR=2.011, 95%CI 1.167-3.465). CONCLUSION: The polymorphisms of rs3212986 showed no association with the risk of preeclampsia in the Chinese Han population. However, the difference in the genotypic distribution between early onset and late-onset preeclampsia suggest the need for future studies. PMID- 29153679 TI - Hypertensive disorders of pregnancy in women with gestational diabetes mellitus from Rio de Janeiro, Brazil. AB - Pregnant women with Gestational Diabetes Mellitus (GDM) have a greater chance of developing Hypertensive Disorders of Pregnancy (HDP) by the effect of insulin resistance in nitric oxide action.This study aims to describe factors associated with the development of HDP in pregnant women with GDM, assisted in a public maternity hospital in Rio de Janeiro, Brazil. This is a cross-sectional study including 292 pregnant adult women with GDM assisted at Maternidade Escola of the Universidade Federal do Rio de Janeiro. The women were examined during pregnancy and postpartum. Data were collected between 2011 and 2014 from medical records and through in-person interviews. The Student t-test and the chi-square test were applied; additionally, the magnitude of the association between independents variables and HDP was estimated by logistic regression models. The occurrence of HDP was observed in 19.5% (n=57) of the evaluated women: 9.2% had pregnancy hypertension and 10.3% had preeclampsia. The chance of HDP was higher among women with GDM in a previous pregnancy (Odds Ratio-OR=3.8; Confidence Interval of 95% 95% CI: 1.1; 12.8) and among those who were 35 years old or older (OR 3.3; 95% CI: 1.2; 8.7) after controlling the effects of pre-gestational weight and dietary ingestion of calcium, riboflavin, thiamine, vitamin A and protein. Women that had any alteration in blood pressure in a previous pregnancy and those over 35 years old were under higher risk of HDP. The findings may help in the design of interventions aiming to prevent HDP in adult women. PMID- 29153680 TI - Associations between bacterial infections and blood pressure in pregnancy. AB - OBJECTIVES: To test the hypothesis that bacterial infections in pregnancy are related to maternal blood pressure. STUDY DESIGN: Bacterial infection was assessed using antibiotic usage as a surrogate and its association with blood pressure in pregnancy tested in the Cambridge Baby Growth Study. MAIN OUTCOME MEASURES: Antibiotic usage in pregnancy was self-reported in questionnaires. Blood pressure measurements at four time points in pregnancy were collected from the hospital notes of 622 women. RESULTS: Using all the available blood pressure readings (adjusted for weeks gestation) antibiotic usage was associated with a higher mean arterial blood pressure across pregnancy: antibiotics used 85(84, 87)mmHg vs. no antibiotics used 83 (83, 84) mmHg (beta=2.3 (0.6, 4.0) mmHg, p=9.6*10-3, from 621 individuals). Further analysis revealed that antibiotic usage was associated with diastolic (beta=2.3 (0.6, 4.0) mmHg; p=7.0*10-3) more than systolic blood pressure (beta=1.4(-0.9, 3.7)mmHg; p=0.2). The effect size associated with antibiotic usage appeared to rise slightly after the first trimester. CONCLUSIONS: Bacterial infection in pregnancy, as assessed by self reported antibiotic usage, is associated with small rises in blood pressure. PMID- 29153681 TI - Various levels of circulating exosomal total-miRNA and miR-210 hypoxamiR in different forms of pregnancy hypertension. AB - INTRODUCTION: Hypertension is a common complication during pregnancy, affecting 10% of pregnant women worldwide. Several microRNA (miRNA) were shown to be involved in hypertensive disorders of pregnancy. In preeclampsia (PE), placental dysfunction causes the enhanced release of extracellular vesicle-derived miRNAs. The hypoxia-sensitive hsa-mir-210 is the most common PE-associated miRNA, but its exosomal profile has not been investigated. OBJECTIVES: Our aims were to measure exosomal total-miRNA concentration and to perform expression analysis of circulating exosomal hsa-miR-210 in women affected by chronic hypertension (CHT) gestational hypertension (GHT) or PE. MATERIALS AND METHODS: We collected plasma samples from women with CHT, GHT, PE (moderate: mPE and severe: sPE) and from normotensive pregnancies. Exosomal miRNAs were extracted and miRNA concentration was measured. RT-PCR was carried out with hsa-miR-210-3p-specific primers and relative expression was calculated using the comparative Ct method. RESULTS: The total-miRNA concentration was different in the disease subgroups, and was significantly higher in mPE and sPE compared to the other groups. We found a significant difference in the relative exosomal hsa-miR-210-3p expression between all hypertensive groups compared to the normotensive samples, but significant upregulation was only observed in case of mPE and sPE patients. Both the level of total-miRNA and hsa-miR-210 expression was higher in case of severe PE. CONCLUSIONS: The level of circulating exosomal total-miRNA and hsa-miR-210 was elevated in women with PE, and it was higher in the severe form. We showed that hsa-miR-210 is secreted via exosomes, which may have a role in the pathomechanism of the disease. PMID- 29153682 TI - Home blood pressure measurement in women with pregnancy-related hypertensive disorders. AB - OBJECTIVES: To determine if home blood pressure measurement (HBPM) provides comparable results to clinic blood pressure (BP) measurement. STUDY DESIGN: A prospective, single-centre study of 37 pregnant and early post-partum women with a hypertensive pregnancy or at high-risk of developing a hypertensive pregnancy were asked to perform HBPM for a minimum period of one week. This was subsequently compared to clinic BP measurement both before and after the period of home measurement. MAIN OUTCOME MEASURES: The accuracy of HBPM compared to clinic measurement, and the acceptability by patients for HBPM. RESULTS: The HBPM was comparable to clinic measurements [for the systolic blood pressure (SBP), the mean home reading was 123.4mmHg (122.0-124.9mmHg) versus 123.9mmHg (121.3 126.5mmHg) for the clinic reading (p=0.69); for the diastolic blood pressure (DBP) the mean home reading was 81.6mmHg (80.4-82.8mmHg) versus 84.4mmHg (82.6 86.2mmHg) for the clinic (p<0.01)]. There were no reported issues associated with the use of HBPM, but it did lead to 5 women contacting health care professionals for management of their BP between clinic visits. CONCLUSIONS: HBPM provides comparable results to the clinic BP measurement. It is also an acceptable technique for pregnant and early post-partum women. However, it should be used as an adjunct to clinic measurement, and cannot at this present stage replace clinic visits or clinic BP measurement. PMID- 29153683 TI - Preeclampsia is associated with ACE I/D polymorphism, obesity and oxidative damage in Mexican women. AB - OBJECTIVE: This study sought to determine whether the angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism, obesity and oxidative damage are risk factors for the development of preeclampsia in Mexican women. STUDY DESIGN: A total of 66 women with preeclampsia (PE) and 37 women with normal pregnancies (NP) were included in the study. DNA was extracted from whole blood, and the ACE I/D polymorphism was evaluated by polymerase chain reaction. ACE activity and oxidative damage were assessed in plasma. The intergroup comparisons were analyzed by an analysis of variance (ANOVA) with post hoc tests. Hardy Weinberg equilibrium (HWE) was tested by x2 analysis, odds ratios (OR) were calculated as a measure of the degree of relative risk of preeclampsia, and for correlations, we used Spearman's correlation coefficient. RESULTS: The frequency of the DD genotype was higher in PE (34.84%) than NP (10.82%). The OR of the DD genotype and D allele were associated with a 4.4-fold (CI=95% 2.24-14) and 3-fold (CI=95% 1.69-5.62) increased risk of developing PE, respectively. Major ACE activity in the DD genotype and obesity were features of the PE group; oxidative damage to proteins and a reduction in the activity of the antioxidant system showed a correlation with BMI (p<0.01). CONCLUSION: Our results suggest that ACE I/D polymorphism, high ACE activity, body mass index and oxidative damage may play key roles in the pathogenesis of PE in the Mexican population. Furthermore, these findings could be used as predictive factors of PE. PMID- 29153684 TI - Impact of maternal serum uric acid on perinatal outcome in women with hypertensive disorders of pregnancy: A prospective study. AB - INTRODUCTION: Worldwide hypertensive disorder of pregnancy is major cause of maternal and perinatal morbidity, mortality. AIM: To study impact of maternal serum uric acid on perinatal outcome in women with hypertensive disorder of pregnancy. METHODOLOGY: Present study was conducted in Obstetrics and Gynecology Department of rural tertiary care centre of Northern India over seven months (October 2016-May 2017). Total 110 pregnant women >-34weeks with hypertensive disorder of pregnancy were divided into three groups; Gestational hypertension (n = 35), Pre-eclampsia (n = 49), Eclampsia (n = 26). Maternal serum uric acid and its co-relation with perinatal outcome were assessed in each group. RESULTS: Of total 111 babies delivered to women with hypertensive disorder of pregnancy, 52 (46.85%) were preterm and 59 (53.15%) term. Of these; 43 (38.74%) were born healthy (APGAR > 7), 31 (27.93%) suffered minimal respiratory distress, 14 (12.61%) severe birth asphyxia and required ventilator support, of which two died, 19 (17.12%) babies died in utero and 4 (3.60%) were still births. Mean neonatal birth weight in all three groups was 2.956 +/- 0.273 kg, 2.475 +/- 0.324 kg and 2.177 +/- 0.282 kg respectively. Mean serum uric acid in gestational hypertension women with healthy foetuses was 5.16 +/- 1.74 mg/dl and with distressed foetuses was 6.52 +/- 2.31 mg/dl, in pre-eclampsia it was 5.3 +/- 1.44 mg/dl and 7.29 +/- 2.63 mg/dl and in eclamptic women 5.7 +/- 0 mg/dl and 8.83 +/- 2.96 mg/dl respectively. CONCLUSION: Adverse perinatal outcome was maximum in eclampsia group, followed by pre-eclampsia and lastly in gestational hypertension. Hence, higher maternal serum uric acid was associated with poor perinatal outcome (p < .05). PMID- 29153685 TI - Effects of delivery on maternal & neonatal irisin levels in normal and preeclamptic pregnant women. AB - STUDY OBJECTIVE: The aim of this work was to measure the irisin levels in maternal and umbilical cord serums at cesarean section and vaginal delivery. STUDY DESIGN: This is a case-control study conducted at the Obstetric Department of the Mansoura University Hospital, Mansoura University, Egypt. MATERIAL AND METHODS: The 150 nulliparous cases were divided into three groups. MAIN OUTCOME MEASURE: Serum irisin concentrations were assayed by enzyme-linked immunosorbent assay (ELISA) method. STATISTICAL ANALYSIS: Unpaired t-test and correlation were done by using the Statistical Package for Social Scientists (SPSS). RESULTS: The maternal irisin levels in cases with mild preeclampsia were found to be significantly lower than that of the normal cases. In cases with mild preeclampsia, the maternal irisin levels early in labor for vaginal deliveries were significantly higher than that during cesarean section. The maternal irisin levels after vaginal deliveries were significantly higher than the levels early in labor. The maternal serum irisin was a significantly correlated with the duration of the first stage. The umbilical cord serum irisin levels were significantly correlated with the neonatal weight and with the duration of the first stage of labor. MAJOR CONCLUSION: Labor is a strong stimulus to the release of irisin into the maternal and fetal circulations. Neonatal serum irisin levels are positively correlated with the birth weight and with the duration of the first stage. The neonatal birth weight and the duration of the first stage of labor are positively correlated with the umbilical cord serum irisin levels. PMID- 29153686 TI - Progression of gestational hypertension to pre-eclampsia: A cohort study of 20,103 pregnancies. AB - OBJECTIVE: To investigate previously un-identified risk factors for the progression of gestational hypertension (GH) to pre-eclampsia (PE) by considering Grade III preterm placental calcification (PPC) and excessive weight gain (?10kgw) at 28weeks gestation. METHODS: At a tertiary teaching hospital, obstetric ultrasonography was performed at 28weeks gestation to establish a diagnosis of grade III PPC. Weight gain during pregnancy was recorded at the same time. Pregnancies complicated with chronic hypertension, major fetal congenital anomalies, termination before 24weeks gestation, and abortion before 20 weeks gestation were excluded. RESULTS: In the current cohort study, 20,103 pregnancies were enrolled and categorized as normal blood pressure (NBP; n=18,223) and GH-PE (n=1880) groups. According to severity of the diseases, the GH-PE group was further divided into GH (n=1088), PE (n=792), and severe PE (n=209) groups. There were significant differences between the NBP and GH-PE groups in known factors, including maternal age, BMI, parity, multi-fetal pregnancy, and co-morbidities (all p<0.001), all of which increased the risk for GH-PE. Regarding the progression of GH to PE and severe PE, there was a much greater frequency of excessive weight gain (51.2% and 49.0% vs. 9.3%) or PPC (63.2% and 61.6% vs. 12.1%) in the severe PE and PE groups than the GH group. Logistic regression analysis revealed that PPC was a significant and independent risk factor for progression of GH to PE (OR, 13.71; 95% CI, 10.25-18.33) and severe PE (OR, 12.42; 95% CI, 8.89-17.35), as well as excessive weight gain during pregnancy (OR, 8.92; 95% CI, 6.67-11.92 and OR, 10.25; 95% CI, 7.30-12.40). CONCLUSION: Being a pathologic implication, the presence of PPC or excessive weight gain during pregnancy may precede progression of GH, and can serve as a warning or marker that requires closer surveillance for maternal and fetal well-being. Based on the findings of PPC and excessive weight gain, at-risk pregnant woman should be counseled to facilitate early intervention or referral. In addition, avoiding excessive weight gain during pregnancy may reduce the risk of GH progression to PE. PMID- 29153687 TI - Influence of non-dipping pattern of blood pressure in gestational hypertension on maternal cardiac function, hemodynamics and intrauterine growth restriction. AB - BACKGROUND: An association between gestational hypertension (GH) and changes of maternal cardiac function was previously reported. AIM: The study assessed the effect of non-dipping pattern of blood pressure (BP) in GH on haemodynamic function and intrauterine growth restriction (IUGR). METHODS: This study included 126 women (91 with GH and 35 normotensive controls). Based on the BP values measured by ambulatory blood pressure monitoring (ABPM), all hypertensive women were classified in dipper (46 women) or in non-dipper group (45 women). All participants underwent echocardiography and ABPM during the third trimester. RESULTS: Participants with GH and non-dipping pattern had significantly lower velocity of longitudinal systolic function (s') (p<0.0005), and cardiac output index (COi) compared to dippers (p<0.0005) and controls (p=0.002). Diastolic velocities at the mitral valve annulus were also lower in non-dippers e's (non dippers vs dippers p=0.023; non-dippers vs controls p<0.0005) and e'l (non dippers vs dippers p=0.048; non-dippers vs controls p<0.0005). There were significant differences in the index of the left ventricle filling pressure E/e' and myocardial mass index between women with GH and controls, but with no significant difference among dippers and non-dippers. Total vascular resistance was increased in non-dipping group compared to normotensives and dippers (p<0.0005). Multivariate regression analysis revealed that the peak night-time diastolic BP, left ventricular mass index and CO index were identified as independent predictors of IUGR. CONCLUSION: Changes in maternal hemodynamics, as well as IUGR, are strongly related to the non-dipping pattern of BP. PMID- 29153688 TI - Genetic association of the NQO1 rs1800566 (609C>T) variant with risk of preeclampsia in the Chinese Han population. AB - AIMS: The NQO1 gene, located on chromosome 16q22, encodes NAD(P)H dehydrogenase 1, an enzyme that can reduce the production of reactive oxygen species and thereby protect cells from oxidative damage. A functional variant of NQO1, rs1800566 (c.C609T/p.Pro187Ser), has significantly less enzymatic activity. Oxidative imbalance plays an important role in the pathogenesis of preeclampsia (PE). The purpose of our study is to investigate whether the NQO1 variant is associated with susceptibility to PE in Chinese women. METHOD: DNA was extracted from 1028 PE patients and 1400 normal pregnant women. We analyzed the genotypic and allelic distribution of the NQO1 rs1800566 variant using TaqMan allelic discrimination real-time PCR. Data were analyzed by SPSS v. 22.0 software. RESULTS: Although the rs1800566 variant affected NQO1 enzymatic activity, our results showed no statistically significant differences in the genotypic and allelic distribution of rs1800566 in PE patients compared with controls (allele: X2=2.736, p=0.098, OR=0.908, 95% CI=0.810-1.018; genotype: X2=3.694, p=0.158). In addition, we observed no statistically significant differences in these distributions between the control group and case sub-groups with mild versus severe PE or early-onset versus late-onset PE. CONCLUSION: Although our study indicated that the NQO1 rs1800566 variant may not have an effect on risk of PE in Chinese Han women, further studies of other loci are necessary to clarify the exact role of NQO1 in the pathogenesis of PE. PMID- 29153689 TI - Changes in echocardiographic parameters and hypertensive disorders in pregnancies of women with aortic coarctation. AB - OBJECTIVES: Pregnancy can be well tolerated after the repair of aortic coarctation. However, a higher incidence of hypertensive disorders during these pregnancies was reported. We analyzed the perinatal changes in echocardiographic parameters in women with aortic coarctation and investigated the risk factors of gestational hypertension (GH). METHODS: We retrospectively identified 15 pregnancies in nine Japanese women with aortic coarctation between 1982 and 2015. We categorized the patients according to the presence/absence of GH as the group with GH(n=3) and that without GH(n=12). The echocardiographic parameters were compared between groups. RESULTS: Our analysis revealed that a pre-pregnancy Doppler-measured pressure gradient>=20mmHg and a left ventricular mass index>=95g/m2 were significant risk factors for GH. The left ventricular end diastolic diameters at the first and the third trimesters, the left ventricular end-systolic diameters at the first trimester, and the left ventricular ejection fraction at the third trimester were also significantly higher in the pregnancies with GH. All of these findings had been obtained before the patients' GH occurred. CONCLUSIONS: Hypertrophy of the left ventricle with a lower ejection fraction and a high pressure gradient across the coarctation were risk factors for GH in the patients with aortic coarctation. Thus, serial measurements using echocardiography are important for predicting GH in women with aortic coarctation. However, further research investigating this finding with a larger sample size is needed. PMID- 29153690 TI - Time course of angiotensin II dependent vascular and metabolic effects of preeclampsia. AB - Pregnancy is characterized by a blunted pressor response to angiotensin II that is progressively lost during preeclampsia complicated pregnancies. Renin angiotensin system (RAS) plays a pivotal role in cardiovascular and renal function but its role in normal and pathological pregnancy is far from being clarified. It is not as clear if hypertension and particularly pregnancy-induced hypertension as the initial event, can trigger some of the metabolic syndrome components, and if these changes are angiotensin II mediated. The aim of this study was to determine the time course of angiotensin II contribution to the vascular and eventual metabolic changes of preeclampsia. An experimental model was developed by reducing feto-placental circulation through a subrenal aorta coarctation before pregnancy in rats. Control and pregnant (preeclamptic) animals were treated with captopril (5mg/kgpo) or saline solution for 21, 14 or 7days before delivery, and their body weight, plasma glucose andblood pressure were registered. Phenylephrine (Phe) induced contraction was evaluated using isolated aorta rings. Preeclampsia increased blood pressure (2nd and 3rd wk) but also weight (3rd wk) and glucose values (2nd and 3rd week). Captopril (for 21 or 14days) treatment prevented increases in blood pressure and plasma glucose but not in body weight. Also, captopril treatment significantly increased aorta contractility. These results provide evidence that cardiovascular and metabolic disturbances of preeclampsia appear simultaneously and are angiotensin II dependent. PMID- 29153691 TI - Hypertension and patterns of induced labor at term. AB - OBJECTIVE: To study patterns of induced labor at term in hypertensive women. STUDY DESIGN: We performed a retrospective cohort study using the Consortium on Safe Labor database; a multicenter study of labor and delivery practices from electronic medical records in 19 hospitals. 55,572 women were studied: 28,254 nulliparas and 27,318 multiparas, undergoing induction of labor at term without a prior cesarean with a singleton vertex live born fetus. Four hypertensive groups were defined: chronic hypertension (n=1164), gestational hypertension (n=1861), preeclampsia (n=1513) and superimposed preeclampsia (n=655), compared to controls (no hypertension, n=50,379). Labor characteristics and patterns were compared among the groups, stratified by parity. MAIN OUTCOME MEASURES: Interval-censored regression analysis estimated median and 95th% duration of labor, stratified by centimeter-by-centimeter dilation. Repeated-measures analysis established mean labor curves. RESULTS: Time to progress from 4 to 10 cm was 7.5, 6.4, 4.9 and 4.6h in nulliparous women with superimposed preeclampsia, chronic hypertension, preeclampsia and gestational hypertension respectively, which differed from controls (4.9h; p<0.05 for chronic hypertension and superimposed preeclampsia). Multiparous women required 3.8, 3.9, 3.2 and 3.3h, respectively, compared to controls (3.2h, p<0.05 except preeclampsia p=0.1) to progress from 4 to 10cm. Second stage of labor without epidural was longer for all nulliparous groups compared to controls except for women with chronic hypertension, but second stage did not differ in multiparas. CONCLUSION: Regardless of parity, women with chronic disease, chronic hypertension and superimposed preeclampsia, labor longer whereas those with relatively acute disease, gestational hypertension and preeclampsia, progress more rapidly. PMID- 29153692 TI - Effects of postpartum uterine curettage in the recovery from Preeclampsia/Eclampsia. A randomized, controlled trial. AB - OBJECTIVE: To evaluate if postpartum uterine curettage improved the clinical and laboratory parameters in patients with preeclampsia or eclampsia. METHODS: A total of 442 patients with preeclampsia/eclampsia were randomized to postpartum curettage (223) or no procedure (219). Systolic and diastolic blood pressure were recorded and analyzed at hours 6, 12, 24 and 48. Also, several laboratory values and diuresis were evaluated. RESULTS: No statistical differences were found between groups (curettage vs. no procedure) in regards to systolic [155.74(15.43) vs. 156.81(15.58)] and/or diastolic blood pressure [101.51(11.44) vs. 101.70(11.20)] before and after the allocated procedure, starting at hour 6 [SBP: 134.19(13.11) vs. 136.65(15.36); DBP: 87.20(9.42) vs. 88.57(10.98)] and up to 48 h after delivery [SBP: 126.59(15.54) vs. 128.21(13.85); DBP: 81.86(9.92) vs. 81.67(11.33)]. No statistical differences between groups were found in the rate of recovery of laboratory values, as well as in the need for additional antihypertensive medications in the postpartum period. These results applied to patients with severe preeclampsia (210 patients in both arms) and eclampsia (13 vs. 9). There were no cases of postpartum eclampsia or acute renal failure after delivery in any of the groups. CONCLUSION: To perform a postpartum uterine curettage does not present an advantage in the patient with preeclampsia/eclampsia. The procedure dos not improve clinical or laboratory values. PMID- 29153693 TI - Up-regulation of microRNA-202-3p in first trimester placenta of pregnancies destined to develop severe preeclampsia, a pilot study. AB - MicroRNA (miRNA) expression has not been studied during placentation in pregnancies that develop preeclampsia, when it likely manifests. In this pilot study, miRNA expression in late first trimester placenta from four pregnancies that developed severe preeclampsia matched to controls using the Affymetrix GeneChip(r) miRNA 3.0 Array identified 9 miRNAs differentially expressed, with miR-202-3p the most significantly overexpressed in severe preeclampsia. Real-time reverse transcription polymerase chain reaction (qRT-PCR) confirmed overexpression of miR-202-3p in a validation cohort, with a 7-fold increase in pregnancies that developed severe preeclampsia (p<=0.05). Differential miRNA expression, specifically miR-202-3p, is seen in first trimester placenta in severe preeclampsia. PMID- 29153694 TI - Evaluation of bone marrow function with immature platelet fraction in normal pregnancy. AB - BACKGROUND: Bone marrow function in pregnancy is influencing blood cell concentration of platelets. The steady state of consumption, recovery and production of platelets is essential for coagulation and bleeding prevention. Reticulated platelets are an intermediate form of thrombocytes during thrombopoiesis representing platelet production. The immature platelet fraction (IPF) represents these platelets as percentage of all thrombocytes. Until now, there is little knowledge on IPF during pregnancy. MATERIAL AND METHODS: 69 healthy pregnant women were included in this monocentric study. Serial blood samples of 27 women (study group 1) and single blood samples of 42 women (study group 2) were taken between 20 and 40weeks of gestation. IPF levels and thrombocytes were quantified by a routine clinical hematology analyzer. Both two study groups were analyzed separately. RESULTS: IPF levels increased between 20 and 40weeks of gestation in both study groups. Median absolute values of IPF increased from 8.1/nl to 13.6/nl in study group 1 and remained constant in study group 2. Values in percent rose from 3.63% to 6.06% in study group 1 and from 4.9% to 6.01% in study group 2. Most values stayed below 20/nl or 7-7.5%. Highest IPF levels were measured near term. In contrast, thrombocyte counts decrease slightly during this period. CONCLUSION: Bone marrow function is mirrored by IPF levels, which increase with gestational age in healthy pregnant women. Most IPF values remain below 20/nl or 7%. More studies are needed to improve understanding of thrombocyte turnover in pregnancy. PMID- 29153695 TI - Posterior encephalopathy syndrome in women with eclampsia: Predictors and outcome. AB - BACKGROUND: This study aims to study predictors of posterior encephalopathy syndrome in eclampsia and the impact of posterior encephalopathy syndrome on outcome. MATERIAL AND METHODS: This prospective study enrolled consecutive women with eclampsia. These women were subjected to magnetic resonance imaging of the brain. Predictors of posterior encephalopathy syndrome were determined using univariate, followed by multivariate, analysis. Women were followed for 30days. Maternal outcome was assessed using modified Rankin scale (mRS). RESULTS: One hundred and four consecutive women with eclampsia were included. Seventy-four women with eclampsia had posterior encephalopathy syndrome. Predictors of posterior encephalopathy syndrome were primigravida status, altered sensorium, impairment of vision, vomiting, status epilepticus, unregistered status in a regular ante-natal check-up programme, lactate dehydrogenase, uric acid, low platelet count and deranged kidney and liver functions on univariate analysis. On multivariate analysis, vision impairment, primigravida status, and unbooked pregnancy were independent factors. Posterior encephalopathy syndrome was associated with a poor maternal and fetal outcome. CONCLUSION: Vision impairment, primigravida status, and unbooked pregnancy are independent predictors of posterior encephalopathy syndrome, that in turn is associated with a poor maternal and fetal outcome. PMID- 29153696 TI - Dysregulation of circulating autoantibodies against VEGF-A, VEGFR-1 and PlGF in preeclampsia - A role in placental and vascular health? AB - OBJECTIVES: Preeclampsia is a state of antiangiogenesis, with high levels of maternal circulating sVEGFR-1 (soluble vascular endothelial growth factor receptor 1, also named sFlt1) and low levels of PlGF (placenta growth factor). Various autoantibodies have been detected in preeclamptic patients. We hypothesize that circulating autoantibodies against VEGF-A (AA-VEGF-A), VEGFR-1 (AA-VEGFR-1) and PlGF (AA-PlGF) are present in preeclamptic women, with different levels from pregnant women with normotensive pregnancies. Secondly, we wanted to analyze if autoantibody levels are associated to sFlt1 or PLGF levels. STUDY DESIGN: Retrospective cross sectional study of 88 women with singleton pregnancies who delivered at Oslo University Hospital of whom 46 had preeclampsia and 42 had uncomplicated normotensive pregnancies. Novel immunoassays for IgG autoantibodies against VEGFA, VEGFR-1 and PlGF were developed and serum samples were assayed. MAIN OUTCOME MEASURES AND RESULTS: AA-VEGF-A, AA-VEGF-R1 and AA PlGF were significantly lower in preeclamptic pregnancies (n=42) compared to normotensive pregnancies (n=46) (p<0.05). On unadjusted analysis, only AA-VEGFA and AA-VEGFR-1 were predictors of PE, but none were independent predictors after adjusting for BMI (body mass index) and parity. In the subgroup of normotensive and PE women with overlapping sVEGFR-1/PlGF-ratios, AA-VEGF was a significant predictor of PE with AUC: 0.735. CONCLUSION: IgG autoantibodies against VEGF-A VEGFR-1 and PlGF can be found in pregnant women. They are dysregulated in preeclampsia. The roles of these autoantibodies are unknown, but this study suggests they play a protective role in pregnancy. The levels of AA against VEGF A, VEGFR-1 and PlGF might be important factors contributing to anti-angiogenesis regulation. PMID- 29153697 TI - Increased tissue factor expression and promoter hypomethylation in preeclampsia placentas in a Chinese population. AB - OBJECTIVES: To explore the relationship between expression of tissue factor and its methylation levels in the placentas of preeclampsia among Chinese Han population. METHODS: In this study, we explored gene manifestation or expression of tissue factor, and evaluated methylation levels of tissue factor promoter areas in 16 clinical preeclampsia placentas as well as 16 paired normal pregnancy placentas from the Chinese Han population. Real-time PCR, immunohistochemistry, Western blotting, and methylation-specific PCR were conducted. RESULTS: Expression of tissue factor protein in the preeclampsia group was 0.857+/-0.043, which was considerably elevated over that in the control group (0.248+/-0.035) (P<0.05). Expression of tissue factor was elevated in mRNA as well as in protein quantities in preeclampsia placentas, compared with the control group (1.45+/ 0.42vs. 0.25+/-0.28, P<0.05). Immunohistochemical staining for tissue factor showed positive within syncytio-cytotrophoblast layers, and there was additional scattered staining in the preeclampsia group. Methylation-specific PCR showed that methylation levels of tissue factor promoter were considerably reduced in preeclamptic placentas (0.928+/-0.148), in comparison with control group (0.187+/ 0.112, P<0.05). CONCLUSIONS: Tissue factor is expected to participate in preeclampsia etiology through methylation regulation. PMID- 29153698 TI - Adolescent pregnancy: Maternal and fetal outcomes in patients with and without preeclampsia. AB - OBJECTIVE: To determine the prevalence of preeclampsia (PE) in adolescents and to evaluate its association with risk factors for, and the occurrence of, adverse maternal and fetal outcomes. RESULTS: Of 3006 deliveries, 533 (17.7%) were from teenage mothers, with twenty-eight (5.3%) presenting PE; 17.8% of these cases were classed as severe. Vitamin and mineral supplementation was associated with the occurrence of PE (p=0.034). Puerperal complications and prematurity were more frequent in the PE group. CONCLUSIONS: Prevalence of PE among adolescents was similar to the literature data and was associated with high rates of preterm birth and puerperal complications. PMID- 29153699 TI - Characterization of d-succinylase from Cupriavidus sp. P4-10-C and its application in d-amino acid synthesis. AB - d-Amino acids are important building blocks for various compounds, such as pharmaceuticals and agrochemicals. A more cost-effective enzymatic method for d amino acid production is needed in the industry. We improved a one-pot enzymatic method for d-amino acid production by the dynamic kinetic resolution of N succinyl amino acids using two enzymes: d-succinylase (DSA) from Cupriavidus sp. P4-10-C, which hydrolyzes N-succinyl-d-amino acids enantioselectively to their corresponding d-amino acid, and N-succinyl amino acid racemase (NSAR, EC.4.2.1.113) from Geobacillus stearothermophilus NCA1503. In this study, DSA and NSAR were purified and their properties were investigated. The optimum temperature of DSA was 50 degrees C and it was stable up to 55 degrees C. The optimum pH of DSA and NSAR was around 7.5. In d-phenylalanine production, the optical purity of product was improved to 91.6% ee from the examination about enzyme concentration. Moreover, 100 mM N-succinyl-dl-tryptophan was converted to d-tryptophan at 81.8% yield with 94.7% ee. This enzymatic method could be useful for the industrial production of various d-amino acids. PMID- 29153700 TI - Heparanase expression in blood is sensitive to monitor response to anticancer treatment in pancreatic cancer, a pilot study. AB - BACKGROUND: /Objectives: High heparanase level was shown in maliganant tumor; however, whether or not heparanase may serve as a sensitive marker to monitor response to anticancer treatment is still unknown. METHODS: In the pilot study, heparanase mRNA expression in peripheral blood mononuclear cell fraction (PBMC) and activity in plasma and urine were detected by quantitative real time RT-PCR and heparan-degrading enzyme assay in 31 pancreatic cancer patients. RESULTS: Heparanase mRNA and activity in samples from cancer patients were significantly higher than that in healthy donors. Both heparanase mRNA and activity in plasma and urine decreased significantly in 17 patients who underwent R0 resection, but increased remarkably in 6 patients when recurrence or metastasis occurred (P < 0.05). However, those who underwent R1 or R2 resection in 6 patients kept stable. For 8 patients who received chemotherapy, heparanase mRNA and activity in plasma and urine decreased in each of the samples (P < 0.05). Patients with high heparanase mRNA (>=a cutoff value of 1.84) in PBMC and activity in plasma (>=1.30U/ml) were associated with a poor postoperative survival (P = 0.02 and P = 0.04). CONCLUSIONS: Heparanase mRNA in PBMC and activity in plasma are closely correlated with therapeutic responsiveness and survival time, indicating that heparanase level in blood might be a sensitive but non-specific marker to monitor patients' response to anticancer treatment and to predict survival. PMID- 29153702 TI - Mechanical cell competition. AB - Maintenance of tissue organization is crucial to ensure normal organ function and organism viability. Tissues are loaded with the ability to sense the available space, measuring cell density and adapting their behaviour accordingly. To keep homeostasis, compression pressure generated by local cell density increment triggers cell elimination. During mechanical cell competition, winner cells compress the neighbouring cells, promoting tissue crowding, which leads to cell elimination. Thus, the hypersensitivity to crowding may confer a loser status, whereas resistance to mechanical-induced elimination may favour a winner status. Here we analyse the emerging field of mechanical cell competition, describing the mechanotransducers implicated in cell elimination. Furthermore, we highlight the dual role of mechanical cell competition (MCC) as tumour suppression or expansion mechanisms. PMID- 29153701 TI - Is distal pancreatectomy with en-bloc celiac axis resection effective for patients with locally advanced pancreatic ductal adenocarcinoma? -Multicenter surgical group study. AB - OBJECTIVES: We retrospectively investigated the operative outcomes of patients who underwent distal pancreatectomy (DP) for invasive pancreatic ductal adenocarcinoma (PDAC) located at the body and tail. METHODS: Data from 395 patients with PDAC who underwent DP with margin-negative resection (R0 or R1) were collected from seven high-volume centers in Japan from 2001 to 2012. Among them, 72 patients underwent DP with en-bloc celiac axis resection (DP-CAR). The remaining 323 patients underwent conventional DP with splenectomy (DP-S). To determine the efficacy of DP-CAR, clinicopathological data were compared between the DP-CAR and the DP-S groups. RESULTS: The DP-S group consisted mainly of patients with resectable disease (93%), and conversely, all patients in the DP CAR group had borderline resectable or unresectable disease. The overall morbidity was significantly higher in the DP-CAR group than in the DP-S group (63% vs 47%, respectively; P = 0.017). The median survival time (MST) of the DP CAR group was significantly shorter than that of the DP-S group (17.5 vs 28.6 months, respectively; P = 0.004). However, the MST of patients in the DP-CAR group (n = 61, 85%) who received adjuvant therapy was significantly longer than that of patients in the DP-S group (n = 65, 20%) who underwent R1 resection (21.9 vs 16.7 months, respectively; P = 0.024). CONCLUSION: DP-CAR followed by adjuvant chemotherapy provided an acceptable overall survival rate in patients with highly advanced PDAC, but should be performed with great caution because of high morbidity. Patients with a high risk of positive surgical margins with DP-S may be candidates for DP-CAR. PMID- 29153703 TI - Establishing and transducing cell polarity: common themes and variations. AB - All cells in vivo have a primary axis of polarity that controls many aspects of their behaviour, such as the direction of protein secretion and signalling, the orientation of cell division and directed cell movement and morphogenesis. Cell polarise in response to extracellular cues or intracellular landmarks that initiate a signal transduction process that establishes complementary cortical domains of conserved polarity factors. These cortical domains then transmit this polarity to the rest of the cell by regulating the organisation of the cytoskeleton and membrane trafficking systems. Here I review work over the past couple of years that has elucidated many key features of how polarity is established and transduced in different systems, but has also revealed unexpected variations in polarity mechanisms depending on context. PMID- 29153704 TI - Multiprotein complexes governing Wnt signal transduction. AB - Three multiprotein complexes have key roles in transducing Wnt signals from the plasma membrane to the cell nucleus - the beta-catenin destruction complex, or Axin degradasome, which targets the Wnt effector beta-catenin for proteasomal degradation in the absence of Wnt; the Wnt signalosome, assembled by polymerization of Dishevelled upon Wnt engaging its receptors, to inactivate the Axin degradasome, which allows beta-catenin to accumulate; and the Wnt enhanceosome which enables beta-catenin to gain access to target genes, to relieve their transcriptional repression by Groucho/TLE. This review focuses on recent advances that have highlighted mechanistic principles governing the assembly and function of these complexes. PMID- 29153705 TI - Spatial and temporal control of NODAL signaling. AB - Embryonic development is orchestrated by the activity of signal transduction pathways, amongst which are those downstream of the transforming growth factor beta (TGF-beta) family. Here I focus on signalling by one of these ligands, NODAL, which is essential for early embryonic axis patterning. I review recent advances in our understanding of how NODAL signalling is transduced from the plasma membrane to the nucleus to regulate the transcription of target genes, and how domains of NODAL activity are established and refined during embryonic development. The duration of signalling is emerging as a key determinant of the specificity of downstream responses in terms of cell fate decisions and I will discuss what is currently known about the underlying mechanisms. PMID- 29153706 TI - Load-sharing in the lumbosacral spine in neutral standing & flexed postures - A combined finite element and inverse static study. AB - Understanding load-sharing in the spine during in-vivo conditions is critical for better spinal implant design and testing. Previous studies of load-sharing that considered actual spinal geometry applied compressive follower load, with or without moment, to simulate muscle forces. Other studies used musculoskeletal models, which include muscle forces, but model the discs by simple beams or spherical joints and ignore the articular facet joints. This study investigated load-sharing in neutral standing and flexed postures using a detailed Finite Element (FE) model of the ligamentous lumbosacral spine, where muscle forces, gravity loads and intra-abdominal pressure, as predicted by a musculoskeletal model of the upper body, are input into the FE model. Flexion was simulated by applying vertebral rotations following spine rhythm measured in a previous in vivo study, to the musculoskeletal model. The FE model predicted intradiscal pressure (IDP), strains in the annular fibers, contact forces in the facet joints, and forces in the ligaments. The disc forces and moments were determined using equilibrium equations, which considered the applied loads, including muscle forces and IDP, as well as forces in the ligaments and facet joints predicted by the FE model. Load-sharing was calculated as the portion of the total spinal load carried along the spine by each individual spinal structure. The results revealed that spinal loads which increased substantially from the upright to the flexed posture were mainly supported by the discs in the upright posture, whereas the ligaments' contribution in resisting shear, compression, and moment was more significant in the flexed posture. PMID- 29153707 TI - The influence of muscle activation on impact dynamics during lateral falls on the hip. AB - Muscle activation has been demonstrated to influence impact dynamics during scenarios including running, automotive impacts, and head impacts. This study investigated the effects of targeted muscle activation magnitude on impact dynamics during low energy falls on the hip with human volunteers. Fifteen university-aged participants (eight females, seven males) underwent 12 lateral pelvis release trials. Half of the trials were muscle-'relaxed'; in the remaining 'contracted' trials participants isometrically contracted their gluteus medius to 20-30% of maximal voluntary contraction before the drop was initiated onto a force plate. Peak force applied to the femur-pelvis complex averaged 9.3% higher in contracted compared to relaxed trials (F = 6.798, p = .022). Muscle activation effects were greater for females, resulting in (on average) an 18.5% increase in effective pelvic stiffness (F = 5.838, p = .046) and a 23.4% decrease in time-to peak-force (F = 5.109, p = .042). In the relaxed trials, muscle activation naturally increased during the impact event, reaching levels of 12.8, 7.5, 11.1, and 19.1% MVC at the time of peak force for the gluteus medias, vastus lateralis, erector spinae, and external oblique, respectively. These findings demonstrated that contraction of trunk and hip musculature increased peak impact force across sexes. In females, increases in the magnitude and rate of loading were accompanied (and likely driven) by increases in system stiffness. Accordingly, incorporating muscle activation contributions into biomechanical models that investigate loading dynamics in the femur and/or pelvis during lateral impacts may improve estimate accuracy. PMID- 29153708 TI - Pathophysiology of IL-33 and IL-17 in allergic disorders. AB - Allergic diseases are among common clinical conditions, affecting millions of children and adults throughout the world. Food allergies, skin allergies (atopic dermatitis), and respiratory allergies (allergic rhinitis and asthma) are the common types of allergies. Recently discovered cytokines IL-17 and IL-33 have been found to play an important role in the pathogenicity of various hypersensitive disorders. After exposure to allergens or infection with parasites or viruses, IL-17 and IL-33 producing cells, such as Th17 and specialized epithelial cells respectively, become activated and trigger the pathogenic immune responses in different susceptible conditions. Potent inhibitors of these cytokines have been identified recently that may represent potential therapeutic agents to overcome the clinical complications of allergies. In the present review, we have discussed the cellular sources, modes of action and regulation of IL-17 and IL-33 in the context of hypersensitive diseases. We have also assessed the therapeutic potential of inhibitory molecules that may alter production of both these cytokines, and thus modulate susceptible conditions. PMID- 29153709 TI - Cytokines in the pathogenesis of hemophilic arthropathy. AB - Hemophilic arthropathy (HA) is one of the most common and typical manifestation in the course of recurrent bleeding episodes in patients with hemophilia. Clinical and subclinical joint bleeding episodes gradually lead to irreversible changes manifesting themselves as pain, progressing ankylosis, marked limitation of the range of motion, muscle atrophy and osteoporosis commonly concomitant with joint deformity resulting from chronic proliferative synovitis and both cartilage and bone degeneration leading to the final functional impairment of the joint. In spite of numerous studies, the pathophysiology of HA has not been fully elucidated, especially as regards immunopathological mechanisms which are associated with the subclinical and early stage of the disease and to be more precise, with chronic joint inflammation. It needs to be emphasized that the pathophysiological processes occurring in a joint with HA are most probably highly mediated by interactions within the cytokine network and other inflammatory mediators present in the tissues of affected joint. Among numerous compounds participating in the induction of an inflammatory process in the pathogenesis of HA, cytokines seem to play a leading role. The most important group controlling the disease seems to be well known inflammatory cytokines, including IL-1beta, TNFalpha and IL-6. The second group with antagonistic effect is formed by anti-inflammatory cytokines such as IL-4 and IL-10. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of HA with respect to cellular and intracellular signaling pathways is still under investigation. This review, summarizes and discusses the current knowledge about cytokine network in the pathogenesis of HA, indicating possible molecular and cellular mechanisms that may provide potential new therapeutic directions. PMID- 29153710 TI - Silver nanoparticle/fibrinogen bilayers - Mechanism of formation and stability determined by in situ electrokinetic measurements. AB - The kinetics of negatively charged silver nanoparticle (AgNP) deposition on the supporting fibrinogen monolayers of well-characterized coverage was determined by the atomic force microscopy (AFM). The kinetics was quantitatively interpreted in terms of the hybrid random sequential adsorption model. The electrokinetic properties of the fibrinogen monolayers and fibrinogen/AgNP bilayers were thoroughly characterized in situ by the streaming potential measurements. These results were interpreted in terms of the general electrokinetic model expressing the particle coverage in terms of the zeta potential of the bilayers. This allowed one to determine the adsorption constants and the binding energy of AgNPs, which was equal to -20.8 and -21.3 kT for pH 3.5 and 7.4, respectively. These results confirmed the end-on mechanism of fibrinogen adsorption and the presence of positively charged spots at its molecule at pH 7.4 where it exhibits an average negative charge. Besides significance to basic science, the obtained results can be exploited for developing a procedure for producing AgNP monolayers of well-defined coverage and controlled particle release profile. PMID- 29153711 TI - Characterisation of heterogeneity and spatial autocorrelation in phase separating mixtures using Moran's I. AB - In complex colloidal systems, particle-poor regions can develop within particle rich phases during sedimentation or creaming. These particle-poor regions are overlooked by 1D profiles, which are typically used to assess particle distributions in a sample. Alternative methods to visualise and quantify these regions are required to better understand phase separation, which is the focus of this paper. Magnetic resonance imaging has been used to monitor the development of compositional heterogeneity in a vesicle-polymer mixture undergoing creaming. T2 relaxation time maps were used to identify the distribution of vesicles, with vesicle-poor regions exhibiting higher T2 relaxation times than regions richer in vesicles. Phase separated structures displayed a range of different morphologies and a variety of image analysis methods, including first-order statistics, Fourier transformation, grey level co-occurrence matrices and Moran's I spatial autocorrelation, were used to characterise these structures, and quantify their heterogeneity. Of the image analysis techniques used, Moran's I was found to be the most effective at quantifying the degree and morphology of phase separation, providing a robust, quantitative measure by which comparisons can be made between a diverse range of systems undergoing phase separation. The sensitivity of Moran's I can be enhanced by the choice of weight matrices used. PMID- 29153712 TI - Facile preparation of hexagonal tin sulfide nanoplates anchored on graphene nanosheets for highly efficient sodium storage. AB - Tin sulfide/graphene nanocomposite with hexagonal tin sulfide (SnS2) nanoplates anchored on reduced graphene oxide (RGO) nanosheets was easily synthesized by one step controllable hydrothermal growth followed by mild reduction. The SnS2 hexagonal-plates distributed tightly and uniformly on the RGO support in a more favorable face-to-face (FTF) manner. The formation of SnS2 nanoplates with hexagonal morphology may result from the accelerating growth of six energetically equivalent high-index (1 1 0) crystal planes and prohibiting growth of the (0 0 1) crystal plane on graphene. The FTF architecture is beneficial for the optimal electric contact efficiency of SnS2 nanoplates with RGO matrix, thus leading to the greatly enhanced electrochemical performance of SnS2/RGO composite than bare SnS2. The graphene-constructed two-dimensional integrated conductive networks minimize the transport paths of electrons and Na ions between electrode and electrolyte as well as accommodate the mechanical strain during long term cyclic. The SnS2/RGO composite exhibits great application potential as an anode for sodium ion batteries with the advantages of unique structure and superior sodium storage performance. PMID- 29153714 TI - Polyphosphonate ligands: From synthesis to design of hybrid PEGylated nanoparticles toward phototherapy studies. AB - The use of phosphonate ligands to modify the nanoparticle (NPs) surface has attracted a strong interest in the last years for the design of highly functional hybrid materials. Here, we applied a methodology to synthesize bisphosphonates having functionalized PEG side chains with a specific length in order to design a novel class of hybrid nanomaterials composed by tetraphosphonate-complex-gold COOH-terminated PEG-coated NPs (Bis-PO-PEG-AuNPs). The synthetic approach consist in three steps: (1) Complexation between new phosphonate ligands (Bis PO) and tetrachloroauric acid (HAuCl4) to form gold clusters; (2) adsorption of COOH terminated PEG molecules (PEG) onto Bis PO-Au complex; (3) reduction of metal ions in that vicinity, growth of gold particles and colloidal stabilization. The obtained snow-shape-like hybrid nanoparticles, have been characterized by ultra violet/visible, Raman spectroscopies, and electron microscopy imaging, involving their optical properties and photothermal activity in pancreatic adenocarcinoma cancer cells (PDAC). PMID- 29153713 TI - Facile modification of nanodiamonds with hyperbranched polymers based on supramolecular chemistry and their potential for drug delivery. AB - Due to their excellent chemical stability and remarkable biocompatibility, nanodiamonds (NDs) have received widespread research attention by the biomedical field. The excellent water dispersibility of NDs has significant importance for biomedical applications. Therefore, surface modification of NDs with hydrophilic polymers has been extensively investigated over the past few decades. In this study, we synthesize beta-CD containing hyperbranched polymer functionalized ND (ND-beta-CD-HPG) composites with high water dispersibility via supramolecular chemistry based on the host-guest interactions between beta-Cyclodextrin (beta CD) and adamantine (Ad). The hydroxyl groups of NDs first reacted with 1, 1 adamantanecarbonyl chloride to obtain ND-Ad, which was further functionalized with beta-CD containing hyperbranched polymers to form the final ND-beta-CD-HPG composites. The successful preparation of ND-beta-CD-HPG composites was confirmed by several characterization techniques. Furthermore, the loading and release of the anticancer agent doxorubicin hydrochloride (DOX) on ND-beta-CD-HPG composites was also examined to explore its potential in drug delivery. When compared with traditional methods of surface modification of NDs, this method was convenient, fast and efficient. We demonstrated that ND-beta-CD-HPG composites have great water dispersibility, low toxicity, high drug-loading capacity and controlled drug-release behavior. Based on these characteristics, ND-beta-CD-HPG composites are expected to have high potential for biomedical applications. PMID- 29153715 TI - Cisplatin and doxorubicin high-loaded nanodrug based on biocompatible thioether- and ethane-bridged hollow mesoporous organosilica nanoparticles. AB - Herein, a mesoporous organosilica nanoparticle (MON) based nanodrug highly loaded with cisplatin (CDDP) and doxorubicin (DOX) (denoted as MONs/CDDP/DOX) has been successfully prepared for the first time. The MONs are characterized with core contained double hollow shells, thioether and ethane groups separately incorporated frameworks, uniform diameter (420 nm), large surface area (592 m2/g), and ordered pore size (2.5 nm). The safety evaluation of the MONs based on cell viability, haemolytic activity, histological change, and serum biochemical index demonstrates that they have excellent biological compatibility. The efficient uptake of the MONs by human breast cancer MCF-7 cells is further confirmed via confocal laser scanning imaging and flow cytometry. Importantly, the contents of CDDP and DOX in the MONs/CDDP/DOX nanodrug are as high as 120 mg/g and 85 mg/g, respectively. Therefore, the MONs/CDDP/DOX shows a significant improved killing effect against human breast cancer MCF-7 cells compared with sole DOX or CDDP loaded MONs, demonstating the promise of the nanodrug for cancer treatment. PMID- 29153716 TI - Facet and morphology dependent photocatalytic hydrogen evolution with CdS nanoflowers using a novel mixed solvothermal strategy. AB - As the highest energy facet of wurtzite CdS, (0 0 2) facet is well worth investigating toward the contribution in photocatalytic hydrogen (H2) evolution. In this study, flower-like CdS with highly preferred (0 0 2) facet was fabricated through a low temperature mixed-solvothermal strategy. The mixted-solvent of diethylenetriamine (DETA) and ethyl alcohol (EtOH) was used to inhibit the growth of (1 0 0) and (1 0 1) facets. For comparison, porous flower-like, belt-like and net-like CdS samples with different preferred degrees of (0 0 2) facet were controllably synthesized by the addition of H2O in different proportions. The preferred orientation degrees of (0 0 2) facet were qualitative proved by the mathematical fitting of XRD patterns. As expected, the flower-like CdS exhibited the highest photocatalytic activity on H2 evolution under visible light without any co-catalyst. Meanwhile, the photocatalytic H2 production increased with the increasement of exposed (0 0 2) facet, which suggested that (0 0 2) facet of CdS played a critical role in improving the photocatalytic activity. Moreover, the growth mechanisms of CdS with various morphologies were investigated and proposed in detail. PMID- 29153717 TI - Biomass-derived porous carbon modified glass fiber separator as polysulfide reservoir for Li-S batteries. AB - Biomass-derived porous carbon has been considered as a promising sulfur host material for lithium-sulfur batteries because of its high conductive nature and large porosity. The present study explored biomass-derived porous carbon as polysulfide reservoir to modify the surface of glass fiber (GF) separator. Two different carbons were prepared from Oak Tree fruit shells by carbonization with and without KOH activation. The KOH activated porous carbon (AC) provides a much higher surface area (796 m2 g-1) than pyrolized carbon (PC) (334 m2 g-1). The R factor value, calculated from the X-ray diffraction pattern, revealed that the activated porous carbon contains more single-layer sheets with a lower degree of graphitization. Raman spectra also confirmed the presence of sp3-hybridized carbon in the activated carbon structure. The COH functional group was identified through X-ray photoelectron spectroscopy for the polysulfide capture. Simple and straightforward coating of biomass-derived porous carbon onto the GF separator led to an improved electrochemical performance in Li-S cells. The Li-S cell assembled with porous carbon modified GF separator (ACGF) demonstrated an initial capacity of 1324 mAh g-1 at 0.2 C, which was 875 mAh g-1 for uncoated GF separator (calculated based on the 2nd cycle). Charge transfer resistance (Rct) values further confirmed the high ionic conductivity nature of porous carbon modified separators. Overall, the biomass-derived activated porous carbon can be considered as a promising alternative material for the polysulfide inhibition in Li-S batteries. PMID- 29153718 TI - Magnetic based nanocomposite sorbent combination with ultrasound assisted for solid-phase microextraction of Azure II in water samples prior to its determination spectrophotometric. AB - Present report designed for monitoring and recovery of Azure-II (Az-II) using ultrasound assisted- dispersive-magnetic nanocomposites-solid-phase microextraction (UA-DMNSPME) based on Zn@Cu-Fe2O4-NCs-CNT sorbent. The full contribution of conventional factors like pH, sorbent amount, eluent volume and sonication time on response were studied and optimized using response surface methodology (RSM) combined with central composite design (CCD). According best figures of merits were achieved at following conditions: pH of 8.0; 5.0 mg sorbent and 5 min sonication which all accumulation Az-II was efficiently eluted by 180 MUL of dimethylformamide which consequently permit achievement recovery of 99.8 +/- 1.1%. Under specified best conditions using 10.0 mL of sample at various conditions lead to detection limit (based on 3Sb/m), limit of quantification (10Sb/m) and the enrichment factor of 3.8, 12.6 ng mL-1 and 75.2, respectively. The while method has linear response over 30-4500 ng mL-1 of Az-II with acceptable correlation coefficient of R2 = 0.9996. Inter- and Intra-day precision expressed as relative standard deviation (n = 3) and the preconcentration factor were 1.1-4.0%, 1.4-5.0% and 55.6, respectively. Good recoveries (95.2-103.3%) with low relative standard deviations (1.1-5.0%) strongly support successful applicability of present method for Az-II preconcentration and determination. PMID- 29153719 TI - Platinum-silver alloyed octahedral nanocrystals as electrocatalyst for methanol oxidation reaction. AB - Previous reports show that the {1 1 1} crystal facets of Pt-based nanocrystal catalysts are highly active for the electrooxidation of methanol. In this work, platinum-silver (Pt-Ag) alloy octahedral nanocrystals with exposed {1 1 1} facets are successfully synthesized through a one-pot, wet-chemical route. The growth mechanism of octahedral nanocrystals can be attributed to the stabilization of {1 1 1} facets by PVP. The electrocatalytic performances of the Pt-Ag octahedral nanocrystals with different Pt/Ag ratio and commercial Pt/C are studied. The results show that the electrocatalytic performances of the Pt-Ag octahedral nanocrystals are much better than that of the commercial Pt/C catalyst, and the Pt-Ag octahedral nanocrystals with a Pt/Ag ratio of 2:1 show the best electrocatalytic performances among the Pt-Ag octahedral nanocrystals. The Pt-Ag octahedral nanocrystals might be a promising candidate as anode catalyst for DMFCs. PMID- 29153720 TI - Hierarchical nanoporous platinum-copper alloy nanoflowers as highly active catalysts for the hydrolytic dehydrogenation of ammonia borane. AB - Hierarchical nanoporous platinum-copper (hnp-PtCu) alloy nanoflowers with bimodal pore/ligament size are easily fabricated by selectively dissolving Al atoms and part of Cu atoms from PtCuAl ternary alloy. The dealloyed samples consist of cross-linking porous nanoflowers with interconnected network skeleton and hollow channels penetrated. Hnp-PtCu alloy nanoflowers with different compositions exhibit dramatically enhanced catalytic activities toward the hydrolysis of ammonia borane (AB) compared with their monometallic components. The hnp-Pt35Cu65 alloy shows superior catalytic performance than the other hnp-PtCu catalysts with an initial much higher turnover frequency of 108 mol H2 min-1 (mol Pt)-1. Moreover, the hnp-Pt35Cu65 displays excellent structure stability even after the five runs for the AB hydrolysis. The as-made hnp-PtCu catalysts hold promising application potential toward the AB hydrolysis with the advantages of facile preparation, high yielding, superior catalytic activity, and high structure durability. PMID- 29153722 TI - Tuberculosis makes it onto the international political agenda for health...finally. PMID- 29153721 TI - Preparation of ruthenium (III) ion-imprinted beads based on 2-pyridylthiourea modified chitosan. AB - Ru(III) ion-imprinted bio-adsorbent based on 2-pyridylthiourea modified chitosan (Ru-PTCS) had been manufactured, investigated and employed for selective extraction of Ru(III) ions from aqueous medium containing interfering metal ions that maybe coexist and compete with Ru(III) ions. Elemental analysis, FTIR and NMR techniques were performed to characterize the chemical structure of the synthesized polymeric materials. The optimum extraction conditions, selectivity and regeneration efficiency were evaluated via batch experiments. The maximum adsorption was obtained at pH 4, and the extraction kinetics followed the pseudo second order model. Also, the equilibrium isotherms were in accordance with Langmuir model and the maximum adsorption capacity was 249 +/- 1 mg/g. The prepared Ru-PTCS exhibited a high affinity toward the targeted Ru(III) ions even in multi-ionic media containing other similar competitive metal ions. In addition, the polymeric selective bio-adsorbent maintained about 96% of its efficiency after 8 adsorption/desorption cycles. PMID- 29153723 TI - Correction to Lancet Glob Health 2017; 5: e1192-207. PMID- 29153724 TI - Body Image: A joyous journey. PMID- 29153726 TI - Bioindicators for monitoring marine litter ingestion and its impacts on Mediterranean biodiversity. AB - The Mediterranean Sea has been described as one of the most affected areas by marine litter in the world. Although effects on organisms from marine plastic litter ingestion have been investigated in several oceanic areas, there is still a lack of information from the Mediterranean Sea. The main objectives of this paper are to review current knowledge on the impact of marine litter on Mediterranean biodiversity, to define selection criteria for choosing marine organisms suitable for use as bioindicator species, and to propose a methodological approach to assessing the harm related to marine litter ingestion in several Mediterranean habitats and sub-regions. A new integrated monitoring tool that would provide the information necessary to design and implement future mitigation actions in the Mediterranean basin is proposed. According to bibliographic research and statistical analysis on current knowledge of marine litter ingestion, the area of the Mediterranean most studied, in terms of number of species and papers in the Mediterranean Sea is the western sub-area as well as demersal (32.9%) and pelagic (27.7%) amongst habitats. Applying ecological and biological criteria to the most threatened species obtained by statistical analysis, bioindicator species for different habitats and monitoring scale were selected. A threefold approach, simultaneously measuring the presence and effects of plastic, can provide the actual harm and sub-lethal effects to organisms caused by marine litter ingestion. The research revealed gaps in knowledge, and this paper suggests measures to close the gap. This and the selection of appropriate bioindicator species would represent a step forward for marine litter risk assessment, and the implementation of future actions and mitigation measures for specific Mediterranean areas, habitats and species affected by marine litter ingestion. PMID- 29153725 TI - Differentiating among Attempted, Completed, and Multiple Nonfatal Strangulation in Women Experiencing Intimate Partner Violence. AB - PURPOSE: Because identification of intimate partner violence (IPV) in health care settings is low and strangulation increases lethality risk among women experiencing IPV, we examined the prevalence and correlates of nonfatal strangulation among 1,008 women survivors of IPV. METHODS: Trained researchers conducted semistructured interviews with women survivors of IPV referred by police. Multinomial logistic regression examined differential correlates of attempted, completed, and multiple strangulation. RESULTS: Interviews were conducted with 71.14% of eligible women contacted by researchers. A high proportion (79.66%) of the women interviewed experienced attempted (11.70%), completed (30.16%), or multiple (37.80%) strangulation. Each form of strangulation was independently significantly associated with sexual violence when compared with no strangulation. African American women were at increased risk of attempted (adjusted relative risk ratio [ARR], 2.02; p < .05), completed (ARR, 1.79; p < .05), and multiple strangulation (ARR, 2.62; p < .001). Compared with no strangulation, multiple strangulation was associated with more IPV injury and risk factors for homicide, including loss of consciousness (ARR, 2.95; p < .05) and miscarriage (ARR, 5.08; p < .05). Women who had lost consciousness owing to strangulation were more likely to seek medical care than those who had been strangled but had not lost consciousness (p < .01). CONCLUSIONS: Strangulation is a prevalent form of IPV that presents significant health risks to women. Women's health practitioners are optimally positioned to identify subtle signs and symptoms of strangulation, help women to understand the delayed sequelae and potential future fatality associated with strangulation, and connect them with appropriate resources to reduce the risk of morbidity and mortality. PMID- 29153727 TI - Lifetime exposure to particulate air pollutants is negatively associated with lung function in non-asthmatic children. AB - BACKGROUND: Pulmonary function is known to be affected by acute and subacute exposure to ambient air pollution. However, the impacts of lifetime exposure to air pollution on the pulmonary function of children have been inconsistent. The present study investigated the impact of lifetime residential exposure to intermediate levels of air pollution on the pulmonary function of schoolchildren. METHODS: In 2011, a survey of children aged 6-15 years was conducted in 44 schools in Taiwan. Atopic history, residential history, and environmental factors were recorded. Spirograms were obtained from a random sample of children without asthma. A total of 535 girls and 481 boys without a history of asthma were enrolled. Lifetime residential exposure to air pollutants, including particulate matter with an aerodynamic diameter less than 10 MUm (PM10), ozone (O3), sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO), was estimated using the kriging method, based on monitored data from the Taiwan Environmental Protection Administration. Multiple linear regression was used to analyze the association between lifetime air pollution exposure and pulmonary function, after adjustment for potential confounders and recent exposure. RESULTS: After adjustment for 7-day average air pollutant levels, a 10 MUg/m3 increase in PM10 was related to reductions in the forced expiratory volume in 1 s (-2.00%; 95% confidence interval [CI] -3.09% to -0.90%), forced vital capacity (-1.86%; CI: 2.96% to -0.75%), and maximal midexpiratory flow (-2.28%; CI: -4.04% to -0.51%). These associations were independent of the other pollutants. CONCLUSION: Lifetime exposure to 25-85 MUg/m3 of PM10 has negative impacts on the pulmonary function of children. PMID- 29153728 TI - Role of black carbon in soil distribution of organochlorines in Lesser Himalayan Region of Pakistan. AB - Black carbon and total organic carbon (TOC) along with organochlorines (OCs) were analyzed in soils from four sampling zones of Lesser Himalayan Region based on source proximity/anthropogenic influences along the altitude. CTO-375 method was used for BC analysis while OCs were analyzed by GC-MS/MS system. BC and TOC ranged between 0.16-1.77 and 6.8-41.3 mg g-1 while those of OCPs and PCBs ranged between 0.69 and 5.77 and 0.12-2.55 ng g-1, respectively. ?DDTs were the dominant (87.9%) among OCPs while tri- and tetra- (65.5%) homologue groups among PCBs. Hexa-PCBs, however also showed higher contribution (20.4%) in the region. Source diagnostic ratios of DDE + DDD/DDT (0.1-1.53) indicated both fresh and old input while alpha-HCH/gamma-HCH (0.19-2.49) showed presence of lindane in the region. Higher concentration of OCs were observed in Zone C at altitudinal range of 737 975 masl that are close to the human influences and potential sources of POPs. The results of linear regression analysis revealed potential input of BC in soil distribution of OC concentrations in the region. PMID- 29153729 TI - Ambient air pollution and the risk of pregnancy loss: a prospective cohort study. AB - OBJECTIVE: To estimate the association of pregnancy loss with common air pollutant exposure. Ambient air pollution exposure has been linked to adverse pregnancy outcomes, but few studies have investigated its relationship with pregnancy loss. DESIGN: Prospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 343 singleton pregnancies in a multisite prospective cohort study with detailed protocols for ovulation and pregnancy testing. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Timing of incident pregnancy loss (from ovulation). RESULT(S): The incidence of pregnancy loss was 28% (n = 98). Pollutant levels at women's residences were estimated using modified Community Multiscale Air Quality models and averaged during the past 2 weeks (acute) and the whole pregnancy (chronic). Adjusted Cox proportional hazards models showed that an interquartile range increase in average whole pregnancy ozone (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.07-1.17) and particulate matter <2.5 MUm (HR 1.13, 95% CI 1.03-1.24) concentrations were associated with faster time to pregnancy loss. Sulfate compounds also appeared to increase risk (HR 1.58, 95% CI 1.07-2.34). Last 2 weeks of exposures were not associated with loss. CONCLUSION(S): In a prospective cohort of couples trying to conceive, we found evidence that exposure to air pollution throughout pregnancy was associated with loss, but delineating specific periods of heightened vulnerability await larger preconception cohort studies with daily measured air quality. PMID- 29153730 TI - Effect of a Combination of Intranasal Ketorolac and Nitrous Oxide on the Success of the Inferior Alveolar Nerve Block in Patients with Symptomatic Irreversible Pulpitis: A Prospective, Randomized, Double-blind Study. AB - INTRODUCTION: Previous studies in patients with irreversible pulpitis have reported increased success of the inferior alveolar nerve block (IANB) using premedication with ketorolac. Preemptive nitrous oxide administration has also shown an increase in the success of the IANB. Recently, ketorolac has been made available for intranasal delivery. Perhaps combining ketorolac and nitrous oxide would increase success. Therefore, the purpose of this prospective, randomized, double-blind study was to determine the effect of a combination of intranasal ketorolac and nitrous oxide/oxygen on the anesthetic success of the IANB in patients presenting with symptomatic irreversible pulpitis. METHODS: One hundred two patients experiencing spontaneous moderate to severe pain with symptomatic irreversible pulpitis in a mandibular posterior tooth participated. Patients were randomly divided into 2 groups and received either 31.5 mg intranasal ketorolac or intranasal saline placebo 20 minutes before the administration of nitrous oxide/oxygen. Ten minutes after the administration of nitrous oxide/oxygen, the IANB was given. After profound lip numbness, endodontic treatment was performed. Success was defined as the ability to perform endodontic access and instrumentation with no pain or mild pain. RESULTS: The odds of success for the IANB was 1.631 in the intranasal saline/nitrous oxide group versus the intranasal ketorolac/nitrous oxide group with no significant difference between the groups (P = .2523). CONCLUSIONS: Premedication with intranasal ketorolac did not significantly increase the odds of success for the IANB over the use of nitrous oxide/oxygen alone. Supplemental anesthesia will still be needed to achieve adequate anesthesia. PMID- 29153731 TI - Bioactivity of Photoactivated Functionalized Nanoparticles Assessed in Lipopolysaccharide-contaminated Root Canals In Vivo. AB - INTRODUCTION: The persistence of dentin-bound lipopolysaccharides (LPS) in disinfected root canals impedes treatment outcomes of endodontic procedures. This study assessed the effects of photoactivated rose bengal-functionalized chitosan nanoparticles (CSRBnps) on LPS-contaminated root dentin in vivo using an intraosseous implantation model and neotissue formation as a marker. METHODS: Fifty human, 3-mm-long root segments with a 1.2-mm canal lumen were divided into 5 groups (n = 10): group 1, canals not contaminated; group 2, canals contaminated with Pseudomonas aeruginosa LPS; group 3, canals contaminated and disinfected with sodium hypochlorite (NaOCl); group 4, canals contaminated and disinfected with NaOCl and calcium hydroxide; and group 5, canals contaminated and disinfected with NaOCl and CSRBnps (300 MUg/mL) with photoactivation (lambda = 540 nm, 40 J/cm2). Specimens were implanted into mandibles of guinea pigs, block dissected after 4 weeks, and the canal content evaluated histologically and immunohistochemically. The ingrown neotissue interface (50 MUm) with dentin was characterized for fibroblasts, osteoclasts, inflammatory markers, dentin resorption, mineralization, and angiogenesis and dichotomized as type 1 (no inflammation and resorption, indicative of LPS inactivation) or type 2 (inflammation and resorption). The frequency of the observed parameters was analyzed using the Fisher exact test. RESULTS: The outcome was categorized as type 1 in groups 1 and 5, type 2 in group 2, and mixed type 1 and 2 in groups 3 and 4. The outcomes in groups 1 and 5 (P > .05) differed significantly (P < .05) from those in groups 2, 3, and 4. CONCLUSIONS: Disinfection of LPS-contaminated root canals with photoactivated CSRBnps in vivo supported ingrowth of neotissue without signs of inflammation or resorption, suggestive of effective inactivation of dentin-bound LPS. PMID- 29153732 TI - Reinforcement of Simulated Immature Permanent Teeth after Mineral Trioxide Aggregate Apexification. AB - OBJECTIVES: The objectives of this study were to compare the fracture resistance of simulated human immature teeth that have undergone mineral trioxide aggregate (MTA) apexification and have been root-filled with fiber post, composite resin, MTA, or gutta-percha. METHODS: Fifty-six human permanent maxillary incisors were selected. Ten teeth received no treatment (intact teeth group). The root canals of 46 teeth were prepared to an internal diameter of 1.75 mm. Six teeth were used as simulated immature teeth group. The remaining teeth received MTA apexification and were divided into 4 groups: MTA, fiber post, composite resin, and gutta percha groups. The root canals of each group were filled with each test material. All teeth were thermocycled and received cyclic loading before compression testing by an Instron universal testing machine. The load to fracture was recorded. Data were subjected to statistical analysis by using one-way analysis of variance and Tukey multiple comparison test. RESULTS: All teeth fractured at the cervical area of the root. The mean load to fracture of the intact tooth, MTA, fiber post, composite resin, gutta-percha, and the simulated immature tooth groups was 1988 N, 1921 N, 1691 N, 1623 N, 1476 N, and 962 N, respectively. Statistically, load to fracture of the simulated immature tooth group was significantly lower than in the intact tooth, MTA, fiber post, and composite resin groups but was not significantly different from the gutta-percha group. CONCLUSIONS: Within the limit of this study, after MTA apexification, intraradicular reinforcement with MTA, fiber post, or composite resin increased the fracture resistance of simulated immature teeth. PMID- 29153733 TI - Antibacterial Activity of Endodontic Sealers against Planktonic Bacteria and Bacteria in Biofilms. AB - INTRODUCTION: The aim of this study was to investigate the antibacterial activity of 4 endodontic sealers against bacteria planktonic grown or in biofilms commonly detected from persistent and secondary endodontic infections. METHODS: The antibacterial activity of the sealers AH Plus, TotalFill BC sealer, RoekoSeal, and Guttaflow 2 was investigated for planktonic grown and 24-hour-old biofilms of Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus aureus, and Streptococcus mutans. RESULTS: AH Plus had high antibacterial activity toward all species investigated, both planktonic and in biofilms. However, the antibacterial activity was lost after 24 hours. TotalFill BC sealer showed marked antibacterial effect on planktonic bacteria up to 7 days after setting. TotalFill BC sealer had lower antibacterial activity against biofilms of S. aureus and E. faecalis compared with AH Plus when direct contact between the sealer and biofilm was investigated and for all species investigated when a membrane was used to separate the biofilm and sealer. Guttaflow 2 and RoekoSeal had no antibacterial activity against planktonic bacteria or bacteria in biofilms. CONCLUSIONS: Bacteria in biofilms showed higher susceptibility for AH Plus compared with TotalFill BC sealer during the first 24 hours after setting. Investigating the antibacterial activity of endodontic sealers and materials against bacteria in biofilms is highly important to evaluate the materials' ability to eradicate bacteria from the infected root canal. PMID- 29153734 TI - The Incidence of Second Mesiobuccal Canals Located in Maxillary Molars with the Aid of Cone-beam Computed Tomography. AB - INTRODUCTION: Many endodontic treatment failures in maxillary molars result from missed second mesiobuccal (MB2) canals. An MB2 canal orifice is present in as many as 95% of maxillary molars, but these canals are not always located during endodontic procedures. Additional tools, such as cone-beam computed tomographic (CBCT) imaging, may be needed to locate these canals in maxillary molars. Hence, the aims of this study were to investigate the frequency of use of CBCT imaging during the treatment of maxillary molars and to evaluate the influence of its use on the detection of MB2 canals. METHODS: Endodontic treatment records, digital intraoral radiographs (when present), and CBCT images from all maxillary first and second molars treated at the University of Washington, Seattle, WA, between 2010 and 2014 (N = 886) were reviewed. Statistical analysis was performed to assess differences between the groups. RESULTS: Overall, an MB2 canal was found in 55.8% of the maxillary molars studied, and CBCT imaging assisted in detecting 11.7% of these canals. CBCT imaging was used in 16.5% of the cases treated and was used significantly more for retreatment cases. CBCT imaging was used preoperatively in 5.6% of cases, and the data show that significantly more MB2 canals were located when a preoperative CBCT image was available. More MB2 canals were located in first molars without full-coverage crowns. CONCLUSIONS: The data show that CBCT imaging is a valuable tool in locating MB2 canals. Based on the results of his study, the use of CBCT imaging could be warranted when treating maxillary molars. PMID- 29153735 TI - Clinical and laboratory characteristics of antithrombin deficiencies: A large cohort study from a single diagnostic center. AB - INTRODUCTION: Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype phenotype associations. The aim was to describe the clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays. PATIENTS AND METHODS: Non-related AT deficient patients (n=156) and their family members (total n=246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored. RESULTS: Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98%) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6%) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86%, 9% and 4% of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation. Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in ATBp3 homozygotes. The functional assay with high heparin concentration and pH7.4 as assay conditions had low (44%) sensitivity for ATBp3 and it was insensitive for AT Basel and Padua I. CONCLUSION: Type IIHBS deficiencies behave differently in clinical and laboratory phenotypes from each other and from other AT deficiencies. Heparin concentration and pH seem to be the key factors influencing the sensitivity of AT functional assays to IIHBS. PMID- 29153736 TI - Defining precision medicine. PMID- 29153738 TI - Pregnancy Outcomes Following Cardiac Transplantation. AB - OBJECTIVE: This study sought to report pregnancy outcomes in women following cardiac transplantation. METHODS: This was a descriptive retrospective cohort study of women with pregnancies following cardiac transplantation managed at two large tertiary centres in Canada and Belgium between 2001 and 2017. RESULTS: Sixteen women had 17 singleton pregnancies following cardiac transplantation. The mean maternal age was 28 +/- 5.8, and the transplant-to-pregnancy interval was 7.3 +/- 4.0 years. There were two first trimester terminations, one for teratogenicity concerns and the other because of a maternal cardiac condition. There was one spontaneous miscarriage. All women had normal left ventricular function at the start of pregnancy. Graft rejection occurred in two women. Other maternal complications included anemia requiring blood transfusion (n = 5), renal failure or deterioration (n = 4), preeclampsia (n = 2), and urine infections (n = 2). The mean GA at delivery was 35 +/- 3.5 weeks. Six infants were born preterm, and two were small-for-gestational-age. Fetal anomalies were identified in two pregnancies. Women were followed after pregnancy for a median of 5.6 years (range, 10 months to 15 years). Although there were no deaths during pregnancy, two women died at 10 and 18 months after delivery. CONCLUSION: With appropriate multidisciplinary care, women with cardiac transplants can have successful pregnancies. Although rates of fetal loss are low, these women continue to be at risk for graft rejection, preterm birth, other pregnancy-related complications, and cardiovascular death. PMID- 29153737 TI - Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1. AB - In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 MUM; 21, IC50 = 3.05 MUM; and 27, IC50 = 3.34 MUM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 MUM), while 7 showed the most potent CD value of 1.12 MUM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 MUM) as well as QR1 induction (CD = 5.76 MUM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2 arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3'-nitrogen coordinating with the heme group. PMID- 29153739 TI - Cultural diversification of communicative gestures through early childhood: A comparison of children in English-, German-, and Chinese- speaking families. AB - Previous literature has demonstrated cultural differences in young children's use of communicative gestures, but the results were mixed depending on which gestures were measured and what age of children were involved. This study included variety of different types of gestures and examined whether children's use of communicative gestures varies by their cultural backgrounds and ages. 714 parents of children (6-36 months old) from U.S.A. English-, German-, and Taiwan Chinese- speaking countries completed the questionnaire on their children's use of each gesture described in the survey. We used logistic regressions to examine the effect of children's culture and age, and the interaction effect (culture*age). Children were more likely to use all gestures except reaching, showing, and smacking lips for "yum, yum" as their age increases. In addition, there were gestures that showed significantly different probabilities across children's cultural backgrounds. A significant interaction effect was shown for five gestures: reaching, showing, pointing, arms up to be picked up, and "quiet" gesture. Results suggest that the influence of culture on young children's communication emerges from infancy. PMID- 29153740 TI - Cost effectiveness of transcatheter aortic valve implantation in patients with aortic stenosis in Japan. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a less invasive treatment for elderly patients with aortic stenosis. However, the cost of TAVI is a major issue. This study analyzed the cost effectiveness of TAVI in Japan. METHODS: We developed an economic model to evaluate the quality-adjusted life years (QALYs) and costs of TAVI, surgical aortic valve replacement (SAVR), and medical therapy over a 10-year time horizon from the perspective of Japanese public healthcare payers. The first model compared transapical or transfemoral TAVI with Sapien valve implantation and medical therapy in inoperable patients. The second model compared transfemoral TAVI with Sapien XT valve implantation and SAVR in operable patients with intermediate surgical risk. We assumed a cost effectiveness threshold of 5,000,000yen per QALY, and assessed the cost effectiveness probability with 100,000 simulations. We performed a broad sensitivity analysis to assess the effect of uncertainty on our results. RESULTS: Among inoperable patients, the incremental cost-effectiveness ratio for TAVI compared with medical therapy was 3,918,808yen per QALY. In operable patients, the incremental cost-effectiveness ratio for TAVI compared with SAVR was 7,523,821yen per QALY. The cost-effectiveness probability of TAVI was 60% for inoperable patients and 46% for operable patients. Among inoperable patients, the cost-effective threshold of TAVI was <7,759,085yen. Among operable patients, the cost-effective threshold of TAVI was <5,427,439yen. CONCLUSIONS: This study suggests that TAVI has good cost effectiveness for inoperable patients, but not for operable patients. PMID- 29153741 TI - Left atrial function in patients with light chain amyloidosis: A transthoracic 3D speckle tracking imaging study. AB - BACKGROUND: Systemic light chain amyloidosis (AL) is characterized by the extracellular deposition of amyloid fibrils. Transthoracic echocardiography is the modality of choice to assess cardiac function in patients with AL. Whereas left ventricular (LV) function has been well studied in this patient population, data regarding the value of left atrial (LA) function in AL patients are lacking. In this study, we aim to examine the impact of LA volumes and function on survival in AL patients as assessed by real-time 3D echocardiography. METHODS: A total of 77 patients (67+/-10 years, 60% men) with confirmed AL and 39 healthy controls were included. All standard 2D echocardiographic and 3D-LA parameters were obtained. RESULTS: Fourteen patients (18%) were in Mayo Clinic (MC) stage I, 30 (39%) in stage II, and 33 (43%) in stage III at initial evaluation. There was no significant difference among the MC stages groups in terms of age, gender, or cardiovascular risk factors. As compared to patients in MC II and MC I, those in MC III had significantly larger indexed 3D-LA volumes (MCIII: 46+/-15mL/m2, MC II: 38+/-12mL/m2, and MC I: 23+/-9mL/m2, p<0.0001), lower 3D-LA total emptying fraction (3D-tLAEF) (21+/-13% vs. 31+/-15% vs. 43+/-7%, respectively, p<0.0001), and worse 3D peak atrial longitudinal strain (3D-PALS) (11+/-9% vs. 18+/-13% vs. 20+/-7%, respectively, p=0.007). Two-year survival was significantly lower in patients with 3D-tLAEF <+34% (p=0.003) and in those with 3D-PALS <+14% (p=0.034). Both parameters provided incremental prognostic value over maximal LA volume in multivariate analysis. CONCLUSION: Functional LA parameters are progressively altered in AL patients according to the MC stage. A decrease in 3D-PALS is associated with worse outcome, independently of LA volume. PMID- 29153742 TI - Direct oral anticoagulants for Japanese atrial fibrillation in the elderly. PMID- 29153743 TI - What do help-seeking measures assess? Building a conceptualization framework for help-seeking intentions through a systematic review of measure content. AB - Mental health services are underutilised by people who could benefit from treatment. Research into help-seeking intentions (HSI) is required to support interventions to increase service use. Existing HSI measures are not psychometrically robust and problems with content validity undermine research in this field. Our purpose was to create a clear conceptualization of HSI and systematically review the content of existing measures. Previous researchers had defined help-seeking and intentions separately, so the first step was to create a more comprehensive definition. Seven theoretical perspectives identified in the HSI literature were mapped onto the new definition and aggregated to form a conceptual framework that reflects expert opinion. This framework guided an analysis of item relevance and a comparison of completeness across measures. Most individual items (99.1%) were relevant, lending credibility to the proposed framework. However, no measure provided a complete assessment of the HSI construct. This study used a novel methodology to develop a definition and conceptual framework, both of which reflect sound theoretical perspectives and represent the consensus-view of experts. The current results will guide the development of stronger measures with improved construct validity and will support interventions aimed at improving help-seeking. PMID- 29153744 TI - Molecular and functional characterization of familial chylomicronemia syndrome. AB - BACKGROUND AND AIMS: Familial chylomicronemia syndrome is a rare autosomal recessive disorder leading to severe hypertriglyceridemia (HTG) due to mutations in lipoprotein lipase (LPL)-associated genes. Few data exist on the clinical features of the disorder or on comprehensive genetic approaches to uncover the causative genes and mutations. METHODS: Eight patients diagnosed with familial hyperchylomicronemia with recessive inheritance were included in this study (two males and six females; median age of onset 23.0 years; mean triglyceride level 3446 mg/dl). We evaluated their clinical features, including coronary artery disease using coronary computed tomography, and performed targeted next generation sequencing on a panel comprising 4813 genes associated with known clinical phenotypes. After standard filtering for allele frequency <1% and in silico annotation prediction, we used three types of variant filtering to identify causative mutations: homozygous mutations in known familial hyperchylomicronemia-associated genes, homozygous mutations with high damaging scores in novel genes, and deleterious mutations within 37 genes known to be associated with HTG. RESULTS: A total of 1810 variants out of the 73,389 identified with 94.3% mean coverage (*20) were rare and nonsynonymous. Among these, our schema detected four pathogenic or likely pathogenic mutations in the LPL gene (p.Ala248LeufsTer4, p.Arg270Cys, p.Ala361Thr, and p.Val227Gly), including one novel mutation and a variant of uncertain significance. Patients harboring LPL gene mutations showed no severe atherosclerotic changes in the coronary arteries, but recurrent pancreatitis with long-term exposure to HTG was observed. CONCLUSIONS: These results demonstrate that LPL gene plays a major role in extreme HTG associated with hyperchylomicronemia, although the condition may not cause severe atherosclerosis. PMID- 29153745 TI - Analysis of the golden proportion and width/height ratios of maxillary anterior teeth in Arab and Kurdish populations. AB - STATEMENT OF PROBLEM: Dentists providing anterior restorations are guided by the principles of anatomic tooth dimension. Dental biometrics should consider ethnicity to produce a more comprehensive evaluation. PURPOSE: The purpose of this clinical study was to analyze the anatomic crowns of maxillary central incisors (CI), lateral incisors (LI), and canines (C) with respect to the golden proportion (GP) and width/height (W/H) ratio in Kurdish and Arab populations. MATERIAL AND METHODS: Maxillary gypsum casts were obtained from 100 participants (50 from a Kurdish and 50 from an Arab population). Standardized digital photographs of each cast were recorded. The apparent and actual anterior tooth dimensions were determined by ImageJ software for the calculation of the GP and W/H ratio. Data were statistically analyzed using ANOVA to investigate ethnic, sex, and arch side differences. The chi-square test was used to explore the GP, and the 1-sample t test was used to test the ideal W/H ratio (alpha=.05). RESULTS: The GP was found in both the Kurdish and Arab groups in the LI/CI mean (0.62, 0.63), but not in the C/LI mean (0.69, 0.73). No difference due to sex was detected in the LI/CI in either ethnic group, but Kurdish men had significantly larger C/LI than women (0.73, 0.66, P=.006) and larger right-side LI/CI than left (0.63, 0.60, P=.049). The W/H ratio was higher than the predicted ideal ratio of 80% (range, 88% to 90%). The LI W/H ratio in Arabs was significantly larger than in Kurds (90.3% versus 82.7%, respectively; P<.001). CONCLUSIONS: The GP was found to exist between the apparent widths of maxillary anterior teeth LI/CI for the both populations in both men and women but not for C/LI. No ideal ratio was detected for the W/H ratios. Specific population characteristics must be taken into consideration, especially when applying the proportions to Kurdish individuals. PMID- 29153746 TI - Degree of conversion of resin cement with varying methacrylate compositions used to cement fiber dowels: A Raman spectroscopy study. AB - STATEMENT OF PROBLEM: Studies on the degree of conversion of dental cement in relation to the number of methacrylate components are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the degree of conversion of single and multicomponent methacrylate-containing dental cements around opaque and translucent fiber dowels at varying depths. MATERIAL AND METHODS: Teeth were prepared for standard endodontic therapy, and a dowel space was created. Opaque and translucent fiber dowels consisting of Aestheti-Plus (AP) and FiberKleer were cemented with 4 methacrylate (MA)-containing cements, including RelyX U100 (R), which contains TEGDMA; Duolink (D), which contains TEGDMA and BisGMA; and Variolink N LC (V) and Breeze (B), which contain TEGDMA, BisGMA, and UDMA. Light emitting diode polymerization was performed for 60 seconds. The specimens were immediately cut into halves and measured within the first hour at depths of 1, 3, and 5 mm using Raman spectroscopy, and the degree of conversion (DC) of resin cement was calculated. Data were analyzed using 3-way ANOVA and the Tukey multiple comparison test (alpha=.05). RESULTS: The measured dowel regions were not significantly different at various depths (P=.10). The dowel and cement types significantly influenced the degree of conversion of the cement (P<.05). The V and B cements exhibited a higher DC than D and R cements. With AP dowels, the DC of cement D was lower than that of the V, B, and R cements. CONCLUSIONS: Within the limitations of this in vitro study, the degrees of conversion of the tested resin cements were not affected by the tested dowel depths. Higher DC was found in cement with more than 2 types of flexible MA. Opaque dowels produced a lower DC than translucent dowels. PMID- 29153747 TI - Modification of Makzoume vertical dimension recorder for individuals with a beard. PMID- 29153748 TI - Marginal discrepancy of noble metal-ceramic fixed dental prosthesis frameworks fabricated by conventional and digital technologies. AB - STATEMENT OF PROBLEM: Studies evaluating the marginal adaptation of available computer-aided design and computer-aided manufacturing (CAD-CAM) noble alloys for metal-ceramic prostheses are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the vertical marginal adaptation of cast, milled, and direct metal laser sintered (DMLS) noble metal-ceramic 3-unit fixed partial denture (FDP) frameworks before and after fit adjustments. MATERIAL AND METHODS: Two typodont teeth were prepared for metal-ceramic FDP abutments. An acrylic resin pattern of the prepared teeth was fabricated and cast in nickel-chromium (Ni-Cr) alloy. Each specimen group (cast, milled, DMLS) was composed of 12 casts made from 12 impressions (n=12). A single design for the FDP substructure was created on a laboratory scanner and used for designing the specimens in the 3 groups. Each specimen was fitted to its corresponding cast by using up to 5 adjustment cycles, and marginal discrepancies were measured on the master Ni-Cr model before and after laboratory fit adjustments. RESULTS: The milled and DMLS groups had smaller marginal discrepancy measurements than those of the cast group (P<.001). Significant differences were found in the number of adjustments among the groups, with the milled group requiring the minimum number of adjustments, followed by the DMLS and cast groups (F=30.643, P<.001). CONCLUSIONS: Metal-ceramic noble alloy frameworks fabricated by using a CAD-CAM workflow had significantly smaller marginal discrepancies compared with those with a traditional cast workflow, with the milled group demonstrating the best marginal fit among the 3 test groups. Manual refining significantly enhanced the marginal fit of all groups. All 3 groups demonstrated marginal discrepancies within the range of clinical acceptability. PMID- 29153749 TI - Esthetic abutment design for angulated screw channels: A technical report. AB - Angulated screw channel system abutments (ASCs) have recently been introduced to address the problem with visible screw access that may compromise esthetics. ASCs allow the screw access to be modified up to 25 degrees relative to the implant axis. However, a widened channel, which may cause thinning of the facial ceramic, is needed at the implant screw head to allow for proper engagement of the screwdriver. This technical report introduces a custom titanium insert design, the Satoshi Sakamoto (SS) abutment. The SS abutment consists of a custom titanium metal insert and zirconia coping in which the access hole is located in an esthetic position with an ASC system. The SS abutment results in a crown with more normal crown dimensions that also provides more space for the soft tissues. This SS abutment design allows clinicians to obtain screw-retained restorations with optimal esthetics and mechanical strength. PMID- 29153751 TI - Efficacy and Safety of Citalopram Compared With Atypical Antipsychotics on Agitation in Nursing Home Residents With Alzheimer Dementia. PMID- 29153750 TI - Family history of diabetes is associated with enhanced adipose lipolysis: Evidence for the implication of epigenetic factors. AB - AIMS: Type 2 diabetes is associated with insulin resistance, adipose hypertrophy and increased lipolysis. The heritability of these traits has been determined by associating them with a family history of diabetes. METHODS: Abdominal subcutaneous fat biopsies were obtained from 581 subjects in a cross-sectional study. Fat cells were isolated, and the difference between measured and expected fat-cell volume was used to determine adipose morphology (degree of hypertrophy or hyperplasia). Spontaneous lipolytic activity was determined in explants of adipose tissue by measuring glycerol release. Insulin-stimulated lipogenesis was assessed by measuring the incorporation of radiolabelled glucose into fat-cell lipids. Information on parental history of diabetes was gathered by a questionnaire. RESULTS: Adipose morphology correlated positively with lipolysis (P<0.0001) and inversely with insulin-stimulated lipogenesis (P<0.008). Also, 24% of probands had a family history of diabetes, which was associated with higher body mass index (BMI) scores, and more insulin resistance (HOMAIR) and adipose hypertrophy. Lipolytic activity was increased, and insulin-stimulated lipogenesis decreased, in probands with a parental history of diabetes. The results for HOMAIR, lipolysis and adipose morphology remained significant after adjusting for proband BMI. A maternal history of diabetes was associated with increased adipose lipolytic activity in probands. CONCLUSION: A family history of diabetes is independent of proband BMI, but associated with adipocyte hypertrophy and enhanced lipolysis, which suggests that these factors are genetically linked to diabetes. Moreover, the influence on lipolysis was only observed in probands with a maternal history of diabetes, thereby supporting an epigenetic impact. PMID- 29153752 TI - Hospice Care for Patients With Dementia in the United States: A Longitudinal Cohort Study. AB - BACKGROUND: Patients with dementia form an increasing proportion of those entering hospice care. Little is known about the types of hospices serving patients with dementia and the patterns of hospice use, including timing of hospice disenrollment between patients with and without dementia. OBJECTIVES: To characterize the hospices that serve patients with dementia, to compare patterns of hospice disenrollment for patients with dementia and without dementia, and to evaluate patient-level and hospice-level characteristics associated with hospice disenrollment. METHODS: We used data from a longitudinal cohort study (2008-2011) of Medicare beneficiaries (n = 149,814) newly enrolled in a national random sample of hospices (n = 577) from the National Hospice Survey and followed until death (84% response rate). RESULTS: A total of 7328 patients (4.9%) had a primary diagnosis of dementia. Hospices caring for patients with dementia were more likely to be for-profit, larger sized, provide care for more than 5 years, and serve a large (>30%) percentage of nursing home patients. Patients with dementia were less likely to disenroll from hospice in conjunction with an acute hospitalization or emergency department visit and more likely to disenroll from hospice after long enrollment periods (more than 165 days) as compared with patients without dementia. No significant difference was found between patients with and without dementia for disenrollment after shorter enrollment periods (less than 165 days). In the multivariable analyses, patients were more likely to be disenrolled after 165 days if they were served by smaller hospices and hospices that served a small percentage of nursing home patients. CONCLUSION: Patients with dementia are significantly more likely to be disenrolled from hospice following a long enrollment period compared with patients without dementia. As the number of individuals with dementia choosing hospice care continues to grow, it is critical to address potential barriers to the provision of quality palliative care for this population near the end of life. PMID- 29153754 TI - Effects of Combined Physical and Cognitive Exercises on Cognition and Mobility in Patients With Mild Cognitive Impairment: A Randomized Clinical Trial. AB - IMPORTANCE: Although participation in physical and cognitive activities is encouraged to reduce the risk of dementia, the preventive efficacy of these activities for patients with mild cognitive impairment is unestablished. OBJECTIVE: To compare the cognitive and mobility effects of a 40-week program of combined cognitive and physical activity with those of a health education program. DESIGN: A randomized, parallel, single-blind controlled trial. SETTING: A population-based study of participants recruited from Obu, a residential suburb of Nagoya, Japan. PARTICIPANTS: Between August 2011 and February 2012, we evaluated 945 adults 65 years or older with mild cognitive impairment, enrolled 308, and randomly assigned them to the combined activity group (n = 154) or the health education control group (n = 154). INTERVENTIONS: The combined activity program involved weekly 90-minute sessions for 40 weeks focused on physical and cognitive activities. The control group attended 90-minute health promotion classes thrice during the 40-week trial period. MEASUREMENT: The outcome measures were assessed at the study's beginning and end by personnel blinded to mild cognitive impairment subtype and group. The primary endpoints were postintervention changes in scores on (1) the Mini-Mental State Examination as a measure of general cognitive status and memory, (2) the Wechsler Memory Scale Revised-Logical Memory II, and (3) the Rey Auditory Verbal Learning Test. We applied mobility assessments and assessed brain atrophy with magnetic resonance imaging. RESULTS: Compared with the control group, the combined activity group showed significantly greater scores on the Mini-Mental State Examination (difference = 0.8 points, P = .012) and Wechsler Memory Scale-Revised-Logical Memory II (difference = 1.0, P = .004), significant improvements in mobility and the nonmemory domains and reduced left medial temporal lobe atrophy in amnestic mild cognitive impairment (Z-score difference = -31.3, P < .05). CONCLUSION: Combined physical and cognitive activity improves or maintains cognitive and physical performance in older adults with mild cognitive impairment, especially the amnestic type. PMID- 29153753 TI - An Easy Assessment of Frailty at Baseline Independently Predicts Prognosis in Very Elderly Patients With Acute Coronary Syndromes. AB - BACKGROUND: Information about the impact of frailty in patients with acute coronary syndromes (ACS) is scarce. No study has assessed the prognostic impact of frailty as measured by the FRAIL scale in very elderly patients with ACS. METHODS: The prospective multicenter LONGEVO-SCA registry included unselected patients with ACS aged 80 years or older. A comprehensive geriatric assessment was performed during hospitalization, including frailty assessment by the FRAIL scale. The primary endpoint was mortality at 6 months. RESULTS: A total of 532 patients were included. Mean age was 84.3 years, 61.7% male. Most patients had positive troponin levels (84%) and high GRACE risk score values (mean 165). A total of 205 patients were classified as prefrail (38.5%) and 145 as frail (27.3%). Frail and prefrail patients had a higher prevalence of comorbidities, lower left ventricle ejection fraction, and higher mean GRACE score value. A total of 63 patients (11.8%) were dead at 6 months. Both prefrailty and frailty were associated with higher 6-month mortality rates (P < .001). After adjusting for potential confounders, this association remained significant (hazard ratio [HR] 2.71; 95% confidence interval [CI] 1.09-6.73 for prefrailty and HR 2.99; 95% CI 1.20-7.44 for frailty, P = .024). The other independent predictors of mortality were age, Charlson Index, and GRACE risk score. CONCLUSIONS: The FRAIL scale is a simple tool that independently predicts mortality in unselected very elderly patients with ACS. The presence of prefrailty criteria also should be taken into account when performing risk stratification of these patients. PMID- 29153755 TI - A longitudinal study on patients with diabetes and symptoms of gastroparesis - associations with impaired quality of life and increased depressive and anxiety symptoms. AB - AIMS: To examine patient reported outcomes (PRO) in patients previously assessed for diabetic gastroparesis, and to investigate how symptoms of gastroparesis evolve over time. In addition, to further evaluate outcomes in those with versus without diabetic gastroparesis at baseline. METHODS: Thirty-four patients with diabetes and gastrointestinal (GI) symptoms, diagnosed with or without diabetic gastroparesis in 2011-2013, were included in this follow-up study. PRO were measured with the Patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM), 36-Item Short Form Survey (SF-36), Patient assessment of upper gastrointestinal disorders-quality of life (PAGI-QOL) and Hospital Anxiety and Depression Scale (HADS). Demographic factors and clinical variables were also recorded. RESULTS: Participants diagnosed with gastroparesis had improved glycemic control (p=0.04) and less GI symptoms (p=0.001), after a follow-up time of 3.2years (mean). Both groups reported severely impaired quality of life (QoL). In total 47% reported symptoms of anxiety, 38% symptoms of depression (scores>=8). GI symptom severity or other PRO could not differentiate between the two groups. CONCLUSIONS: Patients diagnosed with diabetic gastroparesis, as well as those with gastroparesis symptoms - but normal gastric emptying, suffer from severely impaired QoL and a high burden of anxiety and depressive symptoms. PMID- 29153756 TI - [Editorial: Indoor molds series]. PMID- 29153757 TI - [Pulmonary tumor thrombotic microangiopathy]. AB - Pulmonary tumor thrombotic microangiopathy syndrome is a rare clinicopathological entity in which tumor cell micro-emboli in the pulmonary microcirculation induced thrombotic microangiopathy. This can cause respiratory failure, and acute or sub acute right heart failure. Histological features include micro tumor emboli in the small arteries and arterioles of the lung associated with thrombus formation and fibro-cellular and fibro-muscular intimal proliferation. The diagnosis is however extremely difficult to make before death. Thus, most of the observations reported are based on autopsy data. Very rare diagnostic observations made before death suggest the potential effectiveness of chemotherapy. Many details remain to be elucidated, interdisciplinary research is a priority with close collaboration between pathologists and clinicians to better understand this, often fatal, syndrome. It may be that the use of targeted therapies will improve the very poor prognosis allowing survival of several weeks or months after diagnosis. PMID- 29153758 TI - Will use of patient portals help to educate and communicate with patients with diabetes? AB - OBJECTIVE: Chronic disease management can require daily attention, and increased levels of patient activation and engagement. We examined whether patients with diabetes perceive a greater benefit to having electronic access to their doctors' clinic notes compared to patients without diabetes. We hypothesized that easy electronic access to these notes may help patients with self-care by improving education and communication. METHODS: Survey of patients with and without diabetes in Massachusetts and Pennsylvania about perceptions of potential benefits and risks of reading their visit notes via an electronic patient information portal. Administrative data were used to identify patients with diabetes; we compared their perceptions to those of patients without diabetes. RESULTS: The majority of patients (both with and without diabetes) perceived a positive impact of using the portal. Patients with diabetes were significantly more likely to believe that having access to and reading their notes would help them take their medication better and take better care of themselves. CONCLUSIONS: Patients with chronic diseases such as diabetes might receive an even greater benefit from access to their doctors' notes than the general patient population. PRACTICE IMPLICATIONS: Doctors should encourage their patients with diabetes (or other chronic diseases) to use patient portals. PMID- 29153760 TI - Team based care. PMID- 29153759 TI - Shared heart failure knowledge and self-care outcomes in patient-caregiver dyads. AB - BACKGROUND: Patient's knowledge about heart failure (HF) contributes to successful HF self-care, but less is known about shared patient-caregiver knowledge. OBJECTIVES: The purpose of this analysis was to: 1) identify configurations of shared HF knowledge in patient-caregiver dyads; 2) characterize dyads within each configuration by comparing sociodemographic factors, HF characteristics, and psychosocial factors; and 3) quantify the relationship between configurations and patient self-care adherence to managing dietary sodium and HF medications. METHODS: This was a secondary analysis of cross-sectional data (N = 114 dyads, 53% spousal). Patient and caregiver HF knowledge was measured with the Atlanta Heart Failure Knowledge Test. Patient dietary sodium intake was measured by 3-day food record and 24 h urine sodium. Medication adherence was measured by Medication Events Monitoring System caps. Patient HF related quality of life was measured by the Minnesota Heart Failure Questionnaire; caregiver health-related quality of life was measured by the Short Form-12 Physical Component Summary. Patient and caregiver depression were measured with the Beck Depression Inventory-II. Patient and caregiver perceptions of caregiver-provided autonomy support to succeed in heart failure self-care were measured by the Family Care Climate Questionnaire. Multilevel and latent class modeling were used to identify dyadic knowledge configurations. T-tests and chi square tests were used to characterize differences in sociodemographic, clinical, and psychosocial characteristics by configuration. Logistic/linear regression were used to quantify relationships between configurations and patient dietary sodium and medication adherence. RESULTS: Two dyadic knowledge configurations were identified: "Knowledgeable Together" (higher dyad knowledge, less incongruence; N = 85, 75%) and "Knowledge Gap" (lower dyad knowledge, greater incongruence; N = 29, 25%). Dyads were more likely to be in the "Knowledgeable Together" group if they were White and more highly educated, if the patient had a higher ejection fraction, fewer depressive symptoms, and better autonomy support, and if the caregiver had better quality of life. In unadjusted comparisons, patients in the "Knowledge Gap" group were less likely to adhere to HF medication and diet. In adjusted models, significance was retained for dietary sodium only. CONCLUSIONS: Dyads with higher shared HF knowledge are likely more successful with select self-care adherence behaviors. PMID- 29153761 TI - Microfluidics for Combating Antimicrobial Resistance. AB - The ever-growing threat of antimicrobial resistance (AMR) demands immediate countermeasures. With its novelty and enabling features including downscaled analysis, precisely controlled local environment, and enhanced speed, accuracy, and cost-efficiency, microfluidics has demonstrated potential in several key areas, including furthering our understanding of bacteria, developing better susceptibility testing tools, and overcoming obstacles in discovery and research of new antibiotics. While ample research results in the field of microfluidics are available, their transformation into practical application is still lagging far behind. We believe that the challenge of AMR will give microfluidics a much needed opportunity to leap from research papers to true productivity, and gain wider acceptance as a mature technology. PMID- 29153762 TI - Basic and Clinical Approaches for Fertility Preservation and Restoration in Cancer Patients. AB - As gonadotoxic adverse effects of antineoplastic treatments can result in infertility, gamete cryopreservation is routinely offered to patients as the strategy to preserve their fertility. However, there are many cases where gold standards cannot be applied, as is the case for prepubertal cancer patients and others unable to produce gametes or their precursors at the moment of diagnosis. With an increasing number of cancer survivors in our society, strategies using either cryopreserved gonadal tissue or stem cells have been developed to allow cancer survivors to achieve fatherhood, and recent advances in the field have increased public interest. In this review, we discuss the latest updates in fertility preservation from a basic and a clinical point of view. PMID- 29153763 TI - Prevalence of adenoid hypertrophy: A systematic review and meta-analysis. AB - The purpose of our review was to synthesize the existing literature about the prevalence of adenoid hypertrophy (AH) in children and adolescents confirmed by the reference standard - the nasoendoscopy (NE). Six electronic databases and partial grey literature were searched. Studies were included if they reported the prevalence of AH confirmed via NE. Studies involving participants with associated comorbidities and/or fully diagnosed sleep apnea in their sample were excluded. The MAStARI tool assessed the potential risk of bias (RoB) among the studies, while the GRADE approach determined the level of evidence. A total of 5248 patients were included. Seventeen studies were included in the meta-analysis showing an AH prevalence of 49.70% (confidence interval (CI): 39.92 to 59.50). The studies were then divided into 3 groups based on the RoB assessment and patient selection method. The AH prevalence for group 1 (studies having low RoB) was 42.18% (CI: 34.93 to 49.60; n = 2794), for group 2 (studies having moderate RoB) was 70.02% (CI: 40.102 to 92.690; n = 538), and finally for group 3 (studies with randomly collected samples) was 34.46% (CI: 10.507 to 63.742; n = 1446). High heterogeneity between the studies was found. The GRADE approach classified the quality of evidence as moderate. In summary, in a randomized representative sample the prevalence of AH was 34.46%; however, in convenience samples the prevalence ranged from 42 to 70%. PMID- 29153764 TI - Corrigendum to "Monascus purpureus for statin and ezetimibe intolerant heterozygous familial hypercholesterolaemia patients: A clinical study" [Atherosclerosis (Supplements) 30C (2017) 86-91]. PMID- 29153765 TI - Correction to Lancet Glob Health 2017; 5: e1258-76. PMID- 29153766 TI - Ethnicity and maternal and child health outcomes and service coverage in western China: a systematic review and meta-analysis. AB - BACKGROUND: There is a dearth of accurate information about health outcomes and health service coverage among ethnic minorities in China. We assessed maternal and child health (MCH) outcomes and service coverage among ethnic minorities compared with Han populations in western China. METHODS: We did a systematic review searching English (Embase, MEDLINE, Web of Science) and Chinese (China National Knowledge Infrastructure [CNKI], VIP, Wanfang) databases for population based studies comparing MCH indicators between ethnic minorities between Jan 1, 1990, and Nov 9, 2016, in any language. For studies making individual comparisons we used the odds ratio (OR) and corresponding 95% CIs as the primary measure to assess the association between MCH indicators and ethnicity. We used a random effects model to pool odds ratios. FINDINGS: We included 29 Chinese and 16 English language studies, providing 31 individual comparisons and 15 ecological comparisons. Ethnic minority women had lower odds of antenatal care use (pooled crude OR 0.60 [95% CI 0.48-0.75]) and birth in health facilities (0.50 [0.39 0.64]) than did Han women; and their children had higher odds of mortality (2.02 [1.23-3.32]) and lower immunisation (0.34 [0.24-0.47]) than did Han children. After taking account of the potential confounding effects of socioeconomic factors, ethnic minority women were less likely to use antenatal care (pooled adjusted OR 0.54 [0.42-0.71]) or to immunise their children (0.57 [0.44-0.74]) compared with Han women. INTERPRETATION: China has a wealth of primary data that could further our understanding of why ethnic minority populations are lagging behind. As MCH outcomes continue to improve nationally, ethnic minorities will take a greater share of the overall burden of adverse outcomes, requiring strategic investments to address the specific challenges faced by people living in remote areas. FUNDING: China Medical Board. PMID- 29153767 TI - Ethnicity and MCH outcomes: widening gaps across time and space. PMID- 29153768 TI - Workplace Lactation Programs in Small WIC Service Sites: A Potential Model. AB - The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) has an opportunity to protect, promote, and support breastfeeding by implementing and modeling workplace lactation programs in small WIC agencies that may have barriers regarding the lack of both human and financial resources. The goal of this article was to describe effective strategies for agency administrators in small WIC service sites so that they can reduce barriers, successfully implement workplace lactation policies and programs, and model successful strategies for other small employers. PMID- 29153769 TI - Serum sodium response to hypertonic saline infusion therapy in traumatic brain injury. PMID- 29153770 TI - Rats exposed to 2.45GHz of non-ionizing radiation exhibit behavioral changes with increased brain expression of apoptotic caspase 3. AB - In recent years there has been a tremendous increase in use of Wi-Fi devices along with mobile phones, globally. Wi-Fi devices make use of 2.4GHz frequency. The present study evaluated the impact of 2.45GHz radiation exposure for 4h/day for 45days on behavioral and oxidative stress parameters in female Sprague Dawley rats. Behavioral tests of anxiety, learning and memory were started from day 38. Oxidative stress parameters were estimated in brain homogenates after sacrificing the rats on day 45. In morris water maze, elevated plus maze and light dark box test, the 2.45GHz radiation exposed rats elicited memory decline and anxiety behavior. Exposure decreased activities of super oxide dismutase, catalase and reduced glutathione levels whereas increased levels of brain lipid peroxidation was encountered in the radiation exposed rats, showing compromised anti-oxidant defense. Expression of caspase 3 gene in brain samples were quantified which unraveled notable increase in the apoptotic marker caspase 3 in 2.45GHz radiation exposed group as compared to sham exposed group. No significant changes were observed in histopathological examinations and brain levels of TNF-alpha. Analysis of dendritic arborization of neurons showcased reduction in number of dendritic branching and intersections which corresponds to alteration in dendritic structure of neurons, affecting neuronal signaling. The study clearly indicates that exposure of rats to microwave radiation of 2.45GHz leads to detrimental changes in brain leading to lowering of learning and memory and expression of anxiety behavior in rats along with fall in brain antioxidant enzyme systems. PMID- 29153771 TI - Outcome of Patients With In-Hospital Ventricular Tachycardia and Ventricular Fibrillation Arrest While Using a Wearable Cardioverter Defibrillator. AB - In-hospital sudden cardiac arrests occurring during nighttime and weekend hours or within unmonitored hospital areas have been reported to have a poorer outcomes than monitored cardiac arrest. This study sought to assess the outcome of in hospital ventricular tachycardia (VT) and ventricular fibrillation (VF) arrest by time of day, day of week, and within-hospital location when using a wearable cardioverter defibrillator (WCD). We retrospectively identified and reviewed consecutive in-hospital VT/VF arrests from January 2011 to May 2015 experienced by patients wearing a WCD using the manufacturer's postmarket registry. An index shockable sudden cardiac arrest event was defined as the first arrest caused by VT/VF. Event location and clinical outcome were extracted from patient call logs. Survival analysis was performed using the Kaplan-Meier method. A total of 234 in hospital VT/VF arrests were included (mean age = 65 +/- 12 years, male = 74%); 50% had a history of congestive heart failure. The median follow-up time was 6 days (interquartile range 1-4). In the 128 (55%) daytime events (7:00 a.m. to 7:00 p.m.), 24-hour survival was 91%. The 106 (45%) nighttime events (7:01 p.m. to 6:59 a.m.) had 89% 24-hour survival (p = 0.54). Survival outcome by monitored or unmonitored hospital locations were similar. Kaplan-Meir analyses showed no difference in 30-day survival either between weekend and weekday events (72% vs 65%, p = 0.79), or between daytime and nighttime events (64% vs 69%, p = 0.37). In conclusion, WCD use during in-hospital VT/VF arrest correlated with high survival rates regardless of event time or location inside a hospital. Use of a WCD appears to mitigate some of the risks associated with in-hospital VT/VF arrest. PMID- 29153772 TI - Effectiveness and Safety of Transcatheter Aortic Valve Implantation for Aortic Stenosis in Patients With "Porcelain" Aorta. AB - Surgical aortic valve replacement (SAVR) in patients with porcelain aorta is considered a high-risk procedure. Hence, transcatheter aortic valve implantation (TAVI) is emerging as the intervention of choice. However, there is a paucity of data directly comparing TAVI with SAVR in patients with porcelain aorta. We compared outcomes of TAVI versus SAVR in high-risk patients with porcelain between March 2012 and June 2015. The TAVI group included 54 patients, whereas 130 SAVR patients with porcelain aorta were identified (operated on between 2004 and 2015). Both groups were matched 1:1 based on the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score with a 0.5% a priori caliper, resulting in 52 matched pairs. The mean STS-PROM was 7.3 +/- 3.9 for both groups (p = 0.98), whereas mean age was 77.5 years for TAVI and 78.8 years for SAVR (p = 0.46). Compared with SAVR, TAVI patients had lower operative mortality (3.8% vs 17.3%; p = 0.052), significantly shorter median intensive care unit (40 vs 107 hours; p < 0.001) and hospital (5 vs. 7 days; p < 0.001) length of stay (LOS), but similar postoperative stroke rates (7.7% vs 11.5%; p = 0.74). One-year unadjusted survival was 81.7% (95% confidence interval [CI]: 69.8% to 93.5%) in the TAVI group versus 71.2% (95% CI: 61.0% to 85.1%) in the SAVR group, p = 0.093. Cox proportional hazard modeling identified preoperative chronic kidney disease (hazard ratio: 2.63 [95% CI: 1.03 to 6.70]; p = 0.043) and SAVR (hazard ratio: 2.641 [95% CI: 1.07 to 6.51]; p = 0.035) as significant predictors for decreased survival. Overall, TAVI was associated with reduced operative mortality, increased survival, and shorter intensive care unit and hospital length of stay compared with SAVR in patients with porcelain aorta. This study demonstrates that TAVI is a safe intervention in this high-risk population. PMID- 29153773 TI - Spectrum and Outcome of Patients Who Have Undergone Implantation of an Implantable Cardioverter Defibrillator After Aborted-Sudden Cardiac Arrest. AB - Most of implantable cardioverter defibrillator (ICD) secondary prevention studies have been published 2 decades ago. We aimed to describe a contemporary cohort of patients who have undergone implantation of an ICD after an aborted-sudden cardiac arrest (SCA). We retrospectively evaluated consecutive patients referred to our centers between 2005 and 2013. Predictors of overall mortality or heart transplant were analyzed using Cox proportional hazards models. A total of 250 patients (76.4% male, 48.7 +/- 16.7 years) were included (mean follow-up = 49.6 +/- 35 months). The presence of a structural heart disease (SHD) was considered as the primary cause of the aborted-SCA in 160 patients (64%). In 90 patients (36%), no SHD was observed, with patients much younger (40.9 +/- 16.2 years vs 53.0 +/- 15.5 years in the SHD group, p < 0.0001). The 5-year estimated rates of death or heart transplant were 14.3% and 5.2% in the group with and without SHD, respectively (hazard ratio = 4.65, 95% confidence interval 1.40 to 15.6, p = 0.014). The 5-year estimated rates of appropriate ICD therapy in the ventricular fibrillation zone were 16.7% and 25.1% in patients without and with SHD (p = 0.24), respectively. Only left ventricular ejection fraction remained independently associated with mortality or heart transplant (hazard ratio = 0.94, 95% confidence interval 0.90 to 0.97, p = 0.0004). Overall, 69 patients (27.6%) experienced at least 1 ICD-related complication. In conclusion, compared with secondary prevention pivotal studies, the current patients who have undergone implantation of an ICD after aborted-SCA are younger, with a high proportion of structurally normal hearts. Compared with patients without SHD, who depicted a relatively favorable outcome, patients with SHD present a fourfold higher risk of death during follow-up. Reduced left ventricular ejection fraction remains the major influencing factor. PMID- 29153774 TI - Palbociclib-Induced Thrombotic Microangiopathy in Metastatic Breast Cancer Patient Surviving for 18 Years: Case Report and Review of the Literature. PMID- 29153775 TI - Weekly Paclitaxel and Carboplatin Plus Bevacizumab as First-Line Treatment of Metastatic Triple-Negative Breast Cancer. A Multicenter Phase II Trial by the Hellenic Oncology Research Group. AB - BACKGROUND: Triple-negative breast cancer (TNBC) lacks a standard targeted therapeutic strategy and is treated with conventional cytotoxic agents. Because of the sensitivity of TNBC to platinum compounds and the synergistic effect of bevacizumab with paclitaxel we investigated the efficacy and toxicity of weekly paclitaxel and carboplatin in combination with bevacizumab as first-line treatment in metastatic TNBC. PATIENTS AND METHODS: This phase II study followed the Simon's 2-stage optimal design. Paclitaxel (90 mg/m2) and carboplatin (2 area under the curve) were administered on days 1, 8, and 15 every 4 weeks, preceded by bevacizumab 10 mg/kg on days 1 and 15. The primary end point was the objective response rate (ORR). The null hypothesis that the ORR is <= 40% could be rejected if the number of objective responses was >= 23 among 46 evaluable patients. RESULTS: A total of 46 patients were enrolled. Seven (15.2%) complete and 23 (50%) partial responses were observed for an ORR of 65.2% (95% confidence interval, 52.9%-80.4%). The median progression-free survival was 10.3 months, the median overall survival 25.7 months, and the median duration of response 18.2 months. Neutropenia Grade III and IV was experienced by 13 (28.3%) and 6 (13.04%) patients, respectively. One patient developed an uneventful Grade IV thrombocytopenia. There was 1 toxic death due to febrile neutropenia. Other Grade III toxicities included anemia (n = 2), neurotoxicity (n = 2), thrombocytopenia (n = 1), and diarrhea (n = 1). No serious bevacizumab-related toxicities were observed. CONCLUSION: The study achieved its primary end point by showing clinical activity for weekly paclitaxel with carboplatin and bevacizumab combination. This regimen merits further evaluation in this setting. PMID- 29153776 TI - Francisella noatunensis subspecies noatunensis clpB deletion mutant impairs development of francisellosis in a zebrafish model. AB - BACKGROUND: Francisella noatunensis ssp. noatunensis (F.n.n.) is the causative agent of francisellosis in Atlantic cod and constitutes one of the main challenges for future aquaculture on this species. A facultative intracellular bacterium like F.n.n. exert an immunologic challenge against which live attenuated vaccines in general are most effective. Thus, we constructed a deletion in the F.n.n. clpB gene as DeltaclpB mutants are among the most promising vaccine candidates in human pathogenic Francisella. PURPOSE: Characterization of F.n.n. DeltaclpB using primary Atlantic cod head kidney leukocytes, the zebrafish embryo and adult zebrafish model with focus on potential attenuation, relevant immune responses and immunogenic potential. MAIN RESULTS: Interleukin 1 beta transcription in Atlantic cod leukocytes was significantly elevated from 24 to 96 h post infection with F.n.n. DeltaclpB compared to F.n.n. wild-type (wt). Growth attenuation of the deletion mutant in zebrafish embryos was observed by fluorescence microscopy and confirmed by genome quantification by qPCR. In the immunization experiment, adult zebrafish were immunized with 7 * 106 CFU of F.n.n. DeltaclpB before challenge four weeks later with 6 * 108 CFU of F.n.n. wt. One day after challenge, immunized zebrafish responded with significantly lower interleukin 8 levels compared to the non immunized control. Immunized fish were protected against the acute mortality observed in non-immunized zebrafish after challenge and bacterial genomes quantified by qPCR were reduced to a minimum 28 days post challenge, indicating protective immunity stimulated by F.n.n. DeltaclpB. CONCLUSION: Deletion mutation of clpB in F.n.n. causes in vitro and in vivo attenuation and elicits a protective immune response in adult zebrafish against a lethal dose of F.n.n. wt. Taken together, the results presented increases the knowledge on protective immune responses against F.n.n. PMID- 29153777 TI - Vaccination with a human parainfluenza virus type 3 chimeric FHN glycoprotein formulated with a combination adjuvant induces protective immunity. AB - Human parainfluenza virus type 3 (PIV3) is a major cause of lower respiratory disease i.e. bronchitis, bronchiolitis or pneumonia, in infants and young children. Presently there is no licensed vaccine against PIV3. To produce an effective subunit vaccine, a chimeric FHN glycoprotein consisting of the N terminal ectodomain of the fusion (F) protein linked to the haemagglutinin neuraminidase (HN) protein without transmembrane domain, and secreted forms of the individual F and HN glycoproteins, were expressed in mammalian cells and purified. Mice and cotton rats were immunized intramuscularly (IM) with FHN or both F and HN proteins (F + HN), formulated with poly(I:C) and an innate defense regulator peptide in polyphosphazene (TriAdj). Significantly higher levels of systemic virus-neutralizing antibodies were observed in mice and cotton rats immunized with FHN/TriAdj when compared to animals immunized with the combination of F and HN proteins (F + HN/TriAdj). As PIV3 is a pneumotropic virus, another goal is to produce an effective mucosal subunit vaccine. Intranasal (IN) administration with FHN/TriAdj resulted in mucosal IgA production in the lung and virus neutralizing antibodies in the sera. After PIV3 challenge no virus was detected in cotton rats immunized with FHN/TriAdj regardless of the route of delivery. Protective immunity against PIV3 was also induced by FHN/TriAdj in hamsters. In conclusion, the FHN protein formulated with TriAdj has potential for development of a safe and effective vaccine against PIV3. PMID- 29153778 TI - The frontline of controlled human malaria infections: A report from the controlled human infection models Workshop in Leiden University Medical Centre 5 May 2016. AB - Controlled Human Malaria Infection (CHMI) is the most practiced controlled human infection model nowadays and there is an exponential increase in implementation of the model worldwide. During the Controlled Human Infection Models Workshop in Leiden, one day was dedicated to the discussion of the advances made and gaps in Controlled Human Malaria Infection (CHMI) trials. Factors contributing to this impressive expansion in the number of CHMI trials have been related to the ability to perform CHMI using injectable cryopreserved sporozoites (a product from Sanaria Inc. - PfSPZ Challenge), the development of a transmission blocking CHMI model and the need to test more vaccine candidates particularly in the field of whole-sporozoite vaccine development. However, with an increasing number of CHMI trials being undertaken, in an ever-growing number of trial sites, heterogeneity in trial design may compromise universal interpretation of results and require an ongoing dialogue on the need and feasibility of standardization. At the workshop, CHMI investigators convened to share their experiences in CHMI trials and discuss the possibilities for future trials. PMID- 29153779 TI - Lambda display phage as a mucosal vaccine delivery vehicle for peptide antigens. AB - Bacteriophage are structurally stable in the gastro-intestinal tract and have favorable traits of safety, stability, ease of production, and immunogenicity. These attributes make them potential candidates as oral vaccine delivery vehicles but little is known about their capacity to induce mucosal immune responses in the small intestine. Whole body imaging of mice confirmed lambda bacteriophage (LP) were distributed throughout the gastro-intestinal tract 24 h after oral delivery. In newborn calves, targeted delivery of LP within the small intestine confirmed LP were immunogenic in a dose-dependent manner and were taken up by Peyer's patches. LP-specific IgA responses were induced within both Peyer's patches and draining mesenteric lymph nodes. A lambda display phage (LDP) was constructed to present three immunogenic disease specific epitopes (DSE) from cervid prion protein (amino acids 130-140 [YML]; 163-170 [YRR]; and 171-178[YRR]) fused to phage capsid head protein D (LDP-DSE). Targeted delivery of purified LDP DSE to intestinal segments induced IgA responses to all three peptide epitopes. Further, delivery of bacteria expressing soluble D-DSE also induced epitope specific IgA responses in the targeted Peyer's patches. These are the first studies to report use of LDP to induce epitope-specific IgA responses in the small intestine andconfirm Peyer's patchesfunction as a site for LP uptake. Furthermore, IgA responses to peptide epitopes on LDP were observed in the absence of a mucosal adjuvant. These observations confirm LDP have the capacity to function as a mucosal delivery vehicle with protein D as an effective carrier for peptide epitopes. PMID- 29153780 TI - Barrier dysfunction in the skin allergy. AB - The skin is continuously exposed to external pathogens, and its barrier function is critical for skin homeostasis. Previous studies have shown that the barrier dysfunction is one of the most predisposing factors for the development of skin allergic diseases such as atopic dermatitis. In this article, we summarize how the physical barrier of the skin is organized and review its link to the pathomechanism of skin allergic diseases. We describe the formation of the SC barrier in terms of the following five categories: 1) filaggrin metabolism; 2) cornified envelope; 3) intercellular lipids; 4) corneodesmosome; and 5) corneocyte desquamation. New approaches to restoring the skin barrier function are also discussed. PMID- 29153781 TI - Genetic epidemiology of autosomal recessive hypercholesterolemia in Sicily: Identification by next-generation sequencing of a new kindred. AB - BACKGROUND: Autosomal recessive hypercholesterolemia (ARH) is a rare inherited lipid disorder. In Sardinia, differently from other world regions, the mutated allele frequency is high. It is caused by mutations in the low-density lipoprotein receptor adaptor protein 1 gene. Fourteen different mutations have been reported so far; in Sardinia, 2 alleles (ARH1 and ARH2) explain most of the cases. Four ARH patients, all carriers of the ARH1 mutation, have been identified in mainland Italy and 2 in Sicily. OBJECTIVE: The objectives of the study were to improve the molecular diagnosis of familial hypercholesterolemia (FH) and to estimate the frequency of the ARH1 allele in 2 free-living Sicilian populations. METHODS: We sequenced by targeted next-generation sequencing 20 genes related to low-density lipoprotein metabolism in 50 hypercholesterolemic subjects. Subjects from 2 free-living populations from Northern (Ventimiglia Heart Study, 848 individuals) and Southern Sicily (Zabut Zabut Aging Project, 1717 individuals) were genotyped for ARH1 allele. RESULTS: We identified 1 homozygous carrier of the ARH1 mutation among the 50 hypercholesterolemic outpatients. Population-based genotyping of ARH1 in 2565 subjects allowed the identification of 1 heterozygous carrier. The overall estimated allele frequency of ARH1 in Sicily was 0.0002 (0.02%). CONCLUSIONS: The identification of a new case of ARH in Sicily among 50 clinically diagnosed FH highlights the importance of next-generation sequencing analysis as tool to improve the FH diagnosis. Our results also indicate that ARH1 carrier status is present in ~1:2500 of Sicilian inhabitants, confirming that ARH is extremely rare outside Sardinia. PMID- 29153782 TI - Outcomes of cervical laminoplasty-Population-level analysis of a national longitudinal database. AB - OBJECTIVE: Cervical laminoplasty is an important alternative to laminectomy in decompressing of the cervical spine. Further evidence to assess the utility of laminoplasty is required. We examine outcomes of cervical laminoplasty via a population level analysis in the United States. METHODS: We performed a population-level analysis using the national MarketScan longitudinal database to analyze outcomes and costs of cervical laminoplasty between 2007 and 2014. Outcomes included postoperative complications, revision rates, and functional outcomes. RESULTS: Using a national administrative database, we identified 2613 patients (65.6% male, mean 58.5 years) who underwent cervical laminoplasty. Mean length of stay was 3.1 +/- 2.8 days and mean follow-up was 795.5 +/- 670.6 days. The overall complication rate was 22.5% (N = 587), 30-day readmission rate was 7.5% (N = 195), and mortality rate was 0.08% (N = 2, elderly patients only). The complication rate was significantly increased in elderly patients (age >65 years) compared to non-elderly patients (OR 0.751, p < .01). The use of intraoperative neuromonitoring (IONM) during the cervical laminoplasty procedure did not significantly impact outcomes. The overall re-operation rate after the initial procedure was 10.9%. Total costs of cervical laminoplasty were mainly driven by hospital charges with physician-related payments comprising a small amount. CONCLUSIONS: Our national analysis of cervical laminoplasty found the procedure to be clinically effective with low complication rates and postoperative symptomatic improvement. PMID- 29153784 TI - An empirical comparison of isolate-based and sample-based definitions of antimicrobial resistance and their effect on estimates of prevalence. AB - Antimicrobial resistance is primarily a problem in human medicine but there are unquantified links of transmission in both directions between animal and human populations. Quantitative assessment of the costs and benefits of reduced antimicrobial usage in livestock requires robust quantification of transmission of resistance between animals, the environment and the human population. This in turn requires appropriate measurement of resistance. To tackle this we selected two different methods for determining whether a sample is resistant - one based on screening a sample, the other on testing individual isolates. Our overall objective was to explore the differences arising from choice of measurement. A literature search demonstrated the widespread use of testing of individual isolates. The first aim of this study was to compare, quantitatively, sample level and isolate level screening. Cattle or sheep faecal samples (n=41) submitted for routine parasitology were tested for antimicrobial resistance in two ways: (1) "streak" direct culture onto plates containing the antimicrobial of interest; (2) determination of minimum inhibitory concentration (MIC) of 8-10 isolates per sample compared to published MIC thresholds. Two antibiotics (ampicillin and nalidixic acid) were tested. With ampicillin, direct culture resulted in more than double the number of resistant samples than the MIC method based on eight individual isolates. The second aim of this study was to demonstrate the utility of the observed relationship between these two measures of antimicrobial resistance to re-estimate the prevalence of antimicrobial resistance from a previous study, in which we had used "streak" cultures. Boot strap methods were used to estimate the proportion of samples that would have tested resistant in the historic study, had we used the isolate-based MIC method instead. Our boot-strap results indicate that our estimates of prevalence of antimicrobial resistance would have been considerably lower in the historic study had the MIC method been used. Finally we conclude that there is no single way of defining a sample as resistant to an antimicrobial agent. The method used greatly affects the estimated prevalence of antimicrobial resistance in a sampled population of animals, thus potentially resulting in misleading results. Comparing methods on the same samples allows us to re-estimate the prevalence from other studies, had other methods for determining resistance been used. The results of this study highlight the importance of establishing what the most appropriate measure of antimicrobial resistance is, for the proposed purpose of the results. PMID- 29153783 TI - Patterns and correlates of medical cannabis use for pain among patients prescribed long-term opioid therapy. AB - OBJECTIVE: Little is known about co-occurring long-term opioid therapy (LTOT) and medical cannabis use. We compared characteristics of patients prescribed LTOT who endorsed using medical cannabis for pain to patients who did not report cannabis use. METHOD: Participants (n=371) prescribed LTOT completed self-report measures about pain, substance use, and mental health. RESULTS: Eighteen percent of participants endorsed using medical cannabis for pain. No significant differences were detected on pain-related variables, depression, or anxiety between those who endorsed medical cannabis use and those who did not. Medical cannabis users had higher scores of risk for prescription opioid misuse (median=17.0 vs. 11.5, p<0.001), rates of hazardous alcohol use (25% vs. 16%, p<0.05), and rates of nicotine use (42% vs. 26%, p=0.01). Multivariable analyses indicated that medical cannabis use was significantly associated with risk of prescription opioid misuse (beta=0.17, p=0.001), but not hazardous alcohol use (aOR=1.96, 95% CI=0.96-4.00, p=0.06) or nicotine use (aOR=1.61, 95% CI=0.90-2.88, p=0.11). CONCLUSION: There are potential risks associated with co-occurring LTOT and medical cannabis for pain. Study findings highlight the need for further clinical evaluation in this population. Future research is needed to examine the longitudinal impact of medical cannabis use on pain-related and substance use outcomes. PMID- 29153785 TI - Big Brother Is Watching. PMID- 29153786 TI - Tracheal Reconstruction in the Pediatric Population: How I Teach It. PMID- 29153787 TI - The Society of Thoracic Surgeons National Database 2017 Annual Report. AB - The Society of Thoracic Surgeons (STS) National Database has three major component databases: the STS Adult Cardiac Surgery Database (ACSD), the STS Congenital Heart Surgery Database (CHSD), and the STS General Thoracic Surgery Database (GTSD). Beginning in January 2016, The Annals of Thoracic Surgery began publishing a monthly series of scholarly articles on outcomes analysis, quality improvement, and patient safety. This article summarizes the status of the STS National Database as of October 2017 and summarizes the articles about the STS National Database that appeared in The Annals of Thoracic Surgery 2017 series "Outcomes Analysis, Quality Improvement, and Patient Safety." PMID- 29153788 TI - Invited Commentary. PMID- 29153789 TI - Invited Commentary. PMID- 29153790 TI - Invited Commentary. PMID- 29153791 TI - Experience From the Thoracic Surgery Residents Association Traveling Fellowship: Adult and Pediatric Lung Transplantation in Toronto. PMID- 29153792 TI - Alternatives to Titanium Implants for Pectus Excavatum Repair. PMID- 29153793 TI - Reply. PMID- 29153794 TI - Risk Factors in the Management of Repeated Lung Resection for Colon Adenocarcinoma Metastasectomy. PMID- 29153795 TI - Reply. PMID- 29153796 TI - Cross-Clamp Time and Complications: Which Comes First, the Chicken or the Egg? PMID- 29153797 TI - Reply. PMID- 29153798 TI - Does Total Arterial Revascularization Truly Provide Additional Benefit? PMID- 29153799 TI - Reply. PMID- 29153800 TI - Reply. PMID- 29153801 TI - Repeated Coronary Revascularization in the Era of the Heart Team. PMID- 29153802 TI - When It Comes to the Aorta It May Be Unwise to Compromise. PMID- 29153803 TI - Cerebral Capillary Resistance Could Not Stand Against Carotid Perfusion. PMID- 29153804 TI - Right-Sided Interrupted Aortic Arch Repair. PMID- 29153805 TI - Reply. PMID- 29153806 TI - Corrigendum. PMID- 29153807 TI - Thoracic Endovascular Aortic Repair Using Vascular Plug for Chronic Type IIIb Aortic Dissection. AB - A 72-year-old man previously treated for an abdominal aortic aneurysm (AAA) was diagnosed with the 70-mm-sized type IIIb aortic dissection. Endovascular repair was considered, but there was no stent graft passing through the 8-mm iliac graft that was used for open repair of the AAA. We sealed the 5-mm-sized intimal tear site, using an Amplatzer Vascular Plug, which successfully repaired. The patient was discharged and had no complications. Serial follow-up computerized tomography scans showed that the vascular plug was positioned without migration, and the size of the aorta decreased. PMID- 29153808 TI - Redo Robotic Endoscopic Beating Heart Coronary Bypass (TECAB) After Previous TECAB. AB - Redo-totally endoscopic coronary artery bypass (TECAB) after previous TECAB to our knowledge has never been reported in the literature. We present a case report of a 65-year-old gentleman who underwent a second beating-heart TECAB with the right internal mammary artery (IMA) to the obtuse marginal branch, following previous TECAB (left IMA-diagonal/left anterior descending). An extensive experience in robotic coronary operation and anastomotic devices contributed to the successful outcome in this patient. We conclude that prior TECAB is not a contraindication to redo-TECAB as long as an IMA conduit is available and left lung adhesions are not prohibitive. PMID- 29153809 TI - HeartMate III Left Ventricular Assist Device Thrombosis Triggered by an Automatic Implantable Cardioverter-Defibrillator Shock. AB - We report the case of an HeartMate III left ventricular assist device (LVAD) thrombosis triggered by a shock from an automatic implantable cardioverter defibrillator, releasing a left ventricular thrombus sucked in the LVAD inflow cannula. With LVAD low flow only the increase in motor temperature gave a hint of the thrombosis and a computer tomography scan confirmed the diagnosis. Pump exchange was performed with an uneventful outcome. PMID- 29153810 TI - Edwards Sapien 3 Valve for Mitral Replacement in a Child After Melody Valve Endocarditis. AB - We present the surgical implantation in mitral position of the Edwards Sapien 3 valve for prosthetic valve endocarditis in a severely ill child after multiple valve replacements. The procedure was safely performed and provided adequate hemodynamic results in the short term. This report highlights the excellent potential of Sapien 3 valve for the treatment of mitral valve disease in children with a mitral valve annulus of appropriate size. Of note, the use of the Sapien 3 valve should be considered when a bioprosthesis is required at the time of valve re-replacement. PMID- 29153811 TI - Calcific Degeneration of CorMatrix 4 Years After Bicuspidization of Unicuspid Aortic Valve. AB - We report the long-term outcomes of a 12-year-old boy who underwent bicuspidization of a severely stenotic unicuspid aortic valve with CorMatrix small intestinal submucosal extracellular matrix (CorMatrix Cardiovascular, Roswell, GA). CorMatrix supported favorable immediate surgical and echocardiographic outcomes and maintained stable growing functional dynamics for 2 years. At 52.5 months in situ, however, the valve failed with severe calcification, fibrosis, and retraction necessitating a redo operation. Reconstructive operations with CorMatrix are feasible, but this result questions its capacity for constructive remodeling in left-sided valve repair. PMID- 29153812 TI - Surgical Management of Extensive Perinatal Myocardial Infarction. AB - Extensive perinatal myocardial infarction caused by coronary artery thrombosis is extremely rare and has a dismal prognosis. We report a 3.5-kg neonate who presented at birth with an extensive myocardial infarction caused by aortic root and left main coronary artery thrombus after an emergency cesarean section. We performed emergency surgical thrombectomy and insertion of extracorporeal membrane oxygenation support. After subsequent conversion to long-term left ventricular assist device with an EXCOR device (Berlin Heart, Berlin, Germany), the patient had no ventricular recovery after 163 days of support. He was successfully bridged to transplantation. PMID- 29153813 TI - Surgical Stabilization of Rib Fractures in a 6-Year-Old Child After Blunt Trauma. AB - When identified, rib fractures in children are associated with high-energy trauma, nonaccidental trauma, or both. Traditionally, the optimal management of rib fractures in children is supportive care. In this case report, we present a 6 year-old boy who underwent surgical rib fixation for multiple displaced and comminuted rib fractures after being stepped on by a horse. PMID- 29153814 TI - Surgical Management of Medically Refractory Tietze Syndrome. AB - Tietze syndrome is a rare and benign cause of chest pain that may be confused with life-threatening conditions. Characteristic findings are painful, localized inflammation of the costosternal, sternoclavicular, or costochondral joints typically of the second and third ribs. We present a patient with severe, medically refractory symptoms consistent with Tietze syndrome. Although surgical management is not the typical treatment course, symptomatic control was eventually achieved with complete resection of the involved cartilage and adjacent rib. We propose surgical management in patients with debilitating cases of Tietze syndrome that are resistant to conservative therapies. PMID- 29153815 TI - En Bloc Upper and Lower Lobe Trisegmentectomy Facilitated by Displaced Segmental Airway. AB - A 66-year-old woman was referred to our hospital. Computed tomography revealed a partly solid ground-glass nodule located in the left S1+2 and spread over the left S6. Pathologic diagnosis was primary adenocarcinoma (c-T2a N0 M0 c-stage IB). The left B1+2 arose from the left main bronchus and was displaced superiorly behind the left main pulmonary artery. Severely incomplete lobulation was also recognized. We performed trisegmentectomy, and negative margins were confirmed. The patient is now asymptomatic without recurrence. It is very important to grasp the anatomical structure and consider the surgical procedure preoperatively by making full use of computed tomography and bronchoscopy. PMID- 29153816 TI - A Decreased Preload Due to a Loaded Stomach: A Rare Presentation of a Paraesophageal Hernia. AB - A hiatal hernia is a condition in which intraabdominal content herniates into the intrathoracic cavity. On rare occasions, a hiatal hernia can lead to cardiorespiratory compromise. We report a case of chest pain followed by cardiac arrest in a patient not known to have hiatal hernia, and without preliminary symptoms. The patient was suspected of having cardiac ischemia; however, angiography did not reveal any abnormalities. Chest tomography revealed a large paraesophageal hernia with compression of the right ventricle causing decreased preload and cardiac output. Gastric decompression was performed, and definitive surgical treatment took place the subsequent day. The postoperative course was uncomplicated. PMID- 29153817 TI - Acute Type A Aortic Dissection After Sternal Bone Marrow Puncture. PMID- 29153818 TI - Expect the Unexpected: A Bizarre Lookalike of Left Atrial Tumor. PMID- 29153819 TI - Direct True Lumen Cannulation ("Samurai" Cannulation) for Acute Stanford Type A Aortic Dissection. AB - In operations for acute Stanford type A aortic dissection, several cannulation options are available for cardiopulmonary bypass arterial perfusion. These are femoral, axillary, Seldinger ascending aortic, transapical, and transatrial, each of which has advantages and drawbacks. We describe our surgical technique of direct true lumen cannulation ("Samurai" cannulation), which represents an easy, safe, and practical option in operations for acute type A aortic dissection. PMID- 29153820 TI - Aortic Arch Hybrid Repair: Stent-Bridging of the Supra-Aortic Vessel Anastomoses (SAVSTEB). AB - The reattachment of the supra-aortic vessels during hybrid arch repair using a branched prosthesis is time consuming and sometimes technically challenging. Here, we describe the surgical technique of bridging the end-to-end anastomoses between the graft branches and the supra-aortic vessels by self-expanding covered stents to reduce suturing time, avoid anastomotic bleeding, enhance true lumen remodeling, and improve vessel alignment to the hybrid graft. PMID- 29153821 TI - Custom-Made E-Vita Graft for Frozen Elephant Trunk With Arch-First Technique. AB - A novel custom-made E-Vita Open prosthesis (JOTEC GmbH, Hechingen, Germany) has been designed with 2 additional side branches. The first one, the reperfusion branch, allows distal aortic perfusion after the collar anastomosis of a frozen elephant trunk repair has been performed. The second one, the debranching branch, permits reimplantation of any configuration of supraaortic debranching to the dacron graft. This modified graft provides two main advantages: first, combined with prior carotid-subclavian bypass and bilateral axillary perfusion, it allows continuous bihemispheric antegrade perfusion and arch-first technique under mild hypothermia (32 degrees C); second, it grants distal aortic reperfusion after distal anastomosis completion performed under moderate hypothermia (28 degrees C). PMID- 29153822 TI - Clamp Ablation of Pulmonary Veins During Minimally Invasive Aortic Valve Replacement. AB - Here, we demonstrate bilateral pulmonary vein isolation using a bipolar clamp but without atriotomy during minimally invasive aortic valve replacement. The operation was performed through a right anterolateral minithoracotomy. The right pulmonary veins were ablated by using a radiofrequency clamp on the beating heart. After cardiac arrest, the ascending aorta was pulled up using umbilical tape passed through the transverse sinus. Appendage resection offered fine exposure around the lower pulmonary vein. The bipolar clamp was introduced into the oblique sinus under the aorta, and the left pulmonary veins were ablated. Finally, aortic valve replacement was performed in a standard manner. PMID- 29153823 TI - A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). AB - BACKGROUND: Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, has been shown to provide significant reductions in low-density lipoprotein cholesterol (LDL-C). Data about its efficacy and safety in patients from South Korea and Taiwan are limited. OBJECTIVE: ODYSSEY KT assessed the efficacy and safety of alirocumab in patients from South Korea and Taiwan. METHODS: Patients with hypercholesterolemia at high cardiovascular risk who were on maximally tolerated statin were randomized (1:1) to alirocumab (75 mg every 2 weeks, with dose increase to 150 mg every 2 weeks at week 12 if LDL-C >=70 mg/dL at week 8) or placebo for 24 weeks. The primary efficacy endpoint was percentage change in LDL-C from baseline to week 24. Safety was assessed throughout. RESULTS: At week 24, alirocumab changed LDL-C levels by 57.1% (placebo: +6.3%). In the alirocumab group, 9 patients (9.5%) received dose increase at week 12. At week 24, 85.8% of patients in the alirocumab group reached LDL-C <70 mg/dL (placebo: 14.2%; P <= .0001 vs placebo). Alirocumab significantly improved non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total cholesterol, lipoprotein (a), and HDL-C vs placebo (P <= .05). Two consecutive calculated LDL-C values <25 mg/dL were recorded in 27.8% of alirocumab-treated patients. Overall, 58.8% (alirocumab) and 61.8% (placebo) of patients experienced treatment-emergent adverse events; 2.1% and 1.0% discontinued treatment due to treatment-emergent adverse events, respectively. CONCLUSION: Alirocumab significantly improved LDL-C, apolipoprotein B, non-HDL-C, lipoprotein (a), HDL-C, and total cholesterol in Asian patients. Alirocumab was generally well tolerated. These findings are consistent with ODYSSEY findings to date. PMID- 29153824 TI - Cancer-related hypercalcemia in oral cancer. AB - Cancer-related hypercalcemia (CRH) is a critical paraneoplastic disorder in advanced cancer patients. In clinical practice, patients with CRH have a poor prognosis. The medical records of 3198 oral cancer patients with CRH diagnosed at Taichung Veterans General Hospital from 1 January 2003 to 31 December 2015 were reviewed. The criteria for patient enrolment were a diagnosis of hypercalcemia or the use of antihypercalcemia medication. Patients who met any of the following criteria were excluded: use of total parenteral nutrition, incomplete serum calcium data, and unknown date of death. The total incidence of CRH was 6.950/00 per year. A total of 91 patients were enrolled; their median survival time was 28 days. The patients were divided into two groups by survival time, with a cut-off point of 30 days. Reduced serum albumin, leucocytosis, and clodronate use had a statistically significant effect on survival in the univariate analysis (all P<0.05). Forty-five patients (49.5%) had recurrence of CRH, of whom nine died within 30days. These nine patients had a shorter interval to the first episode of CRH recurrence (median 13 days) than those who survived >=30days (median 28 days) (P<0.001). It was observed that a short interval to the first episode of CRH recurrence is a poor prognostic factor. PMID- 29153825 TI - Clinician and manager perceptions of factors leading to ward patient clinical deterioration. AB - BACKGROUND: Improving the timely recognition and response to clinical deterioration is a critical challenge for clinicians, educators, administrators and researchers. Clinical deterioration leading to Rapid Response Team review is associated with poor patient outcomes. A range of factors associated with clinical deterioration and its outcomes have been identified, and may help with early identification of deteriorating patients. However, the relative importance of each factor on the development of clinical deterioration is unknown. OBJECTIVE: To identify the relative importance of factors contributing to the development of clinical deterioration in ward patients, as perceived by health professionals who have experience in recognising or responding to clinical deterioration, or in the management, administration or governance of RRSs. METHODS: A written questionnaire containing 12 pre-determined factors was provided to participants. Participants were asked to rank the items from most to least important contributors to ward patient deterioration. The study took place during a session of the Australia and New Zealand Intensive Care Society Rapid Response Team conference. RESULTS: A final sample of 233 (83% response rate), returned the questionnaire. The sample comprised specialist ICU registered nurses with direct patient contact (64%), ICU consultant doctors (17%), ICU nurse managers (7%), hospital administrators (2%), ICU registrars (2%), quality coordinators (2%) and non-hospital staff (4%). The patient's presenting illness/main diagnosis was the highest ranked factor, followed by pre-existing co morbidities, seniority of nursing ward staff, medical documentation, senior medical staff, and interdisciplinary communication. Almost two-thirds of participants ranked patient characteristics as the most important contributor to clinical deterioration. CONCLUSION: Health professionals who have experience in recognising or responding to clinical deterioration, or in the management, administration or governance of RRSs perceive that patient characteristics such as the patient's primary diagnosis and comorbidities to be the most important contributors to clinical deterioration. PMID- 29153826 TI - Performance evaluation of phase angle and handgrip strength in patients undergoing cardiac surgery: Prospective cohort study. AB - BACKGROUND AND AIMS: The phase angle (PA), derived from bioelectrical impedance analysis (BIA), has been interpreted as a cell membrane integrity indicator, while handgrip strength (HGS) has been used as a prognostic indicator in certain clinical situations, such as in cardiac, oncologic patients with renal disease, hemodialysis patients, HIV-positive patients, and liver disease patients. In addition to prognostic scores, body changes due to surgical procedures indicate the importance of measuring muscle function and cell integrity. This study aimed to evaluate the behaviour of PA and HGS in patients undergoing cardiac surgery and associate these factors with clinical outcomes and prognosis. METHODS: This was a prospective cohort study of 50 consecutively recruited patients (aged >=18 years) undergoing cardiac surgery. Measures PA and HGS were at three set points: preoperative, at hospital discharge and three months postoperative. The following data were collected: time of cardiopulmonary bypass (CPB), ischemia, mechanical ventilation (MV), Intensive Care Unit (ICU) length of stay (LOS) and hospital LOS after surgery; the EuroSCORE was also calculated. RESULTS: A decrease in PA was observed between the preoperative and the two postoperative stages (p<0.001). There was a reduction in HGS between the preoperative and hospital discharge assessments (p<0.001) and a recovery three months postoperative (p<0.001). The MV and EuroSCORE were inversely associated with PA and HGS in all three assessments. The PA was correlated with EuroSCORE in the first assessment (p=0.007) and in the second and third assessments (p<0.001), as well as with MV in all three assessments (p<0.001). The HGS was correlated with EuroSCORE and MV in the first and second assessments (p<0.001) and in the third assessment (p=0.010 and p=0.018, respectively). CONCLUSION: PA and HGS appear to be related to MV time, ICU LOS and hospital LOS after surgery in patients undergoing cardiac surgery. PMID- 29153827 TI - Compassion satisfaction and fatigue: A cross-sectional survey of Australian intensive care nurses. AB - BACKGROUND: Compassion satisfaction and compassion fatigue influence nurses' intention to stay or leave nursing. Identification of compassion satisfaction or fatigue in critical care nurses is important in this high turnover workforce. OBJECTIVES: The aim of this study was to examine factors predicting and contributing to compassion satisfaction and compassion fatigue experienced by critical care nurses in Australian intensive care units. METHODS: A self-reported cross-sectional survey using an established tool collected data from critical care nurses of two adult Australian intensive care units. RESULTS: Overall, these critical care nurses reported what Professional Quality of Life Scale guidelines designated as 'average' levels of compassion satisfaction and burnout, and 'low' levels of Secondary Traumatic Stress (STS). Compared to Site B, nurses at Site A had significantly higher compassion satisfaction (p=0.008) and lower STS scores (p=0.025), with site significantly predictive for compassion satisfaction (p<0.024) and STS (p<0.002). Nurses with postgraduate qualifications had significantly higher compassion satisfaction scores (p=0.027), and compassion satisfaction significantly increased with increasing duration of practice (p=0.042) as a nurse and in their current ICU (p=0.038). Burnout scores significantly reduced with increasing age, years of tenure and practice; burnout was predicted by lower years of tenure (p<0.016). CONCLUSION: These critical care nurses revealed profiles that, whilst not in crisis, fell short of the ideal high compassion satisfaction and moderate/low fatigue. More recent tenure flags those potentially at higher risk of compassion fatigue, whilst the better scores associated with postgraduate education and from one site need further exploration. Further research should develop understanding and interventions to enhance compassion satisfaction and support retention of this crucial nursing workforce. PMID- 29153828 TI - Incentivizing Savings Among Poor Teenagers Can Reap Health and Other Benefits. PMID- 29153829 TI - The Power of Financial Inclusion: Reporting on the Efficacy of Economic Strengthening Interventions in Sub-Saharan Africa. PMID- 29153830 TI - 'Disc-o-Fever': Getting Down with Giardia's Groovy Microtubule Organelle. AB - Protists have evolved a myriad of highly specialized cytoskeletal organelles that expand known functional capacities of microtubule (MT) polymers. One such innovation - the ventral disc - is a cup-shaped MT organelle that the parasite Giardia uses to attach to the small intestine of its host. The molecular mechanisms underlying the generation of suction-based forces by overall conformational changes of the disc remain unclear. The elaborate disc architecture is defined by novel proteins and complexes that decorate almost all disc MT protofilaments, and vary in composition and conformation along the length of the MTs. Future genetic, biochemical, and functional analyses of disc associated proteins will be central toward understanding not only disc architecture and assembly, but also the overall disc conformational dynamics that promote attachment. PMID- 29153831 TI - Considering context and variability when observing other minds: Comment on "Seeing mental states: An experimental strategy for measuring the observability of other minds" by Cristina Becchio et al. PMID- 29153833 TI - Structure of the Post-catalytic Spliceosome from Saccharomyces cerevisiae. AB - Removal of an intron from a pre-mRNA by the spliceosome results in the ligation of two exons in the post-catalytic spliceosome (known as the P complex). Here, we present a cryo-EM structure of the P complex from Saccharomyces cerevisiae at an average resolution of 3.6 A. The ligated exon is held in the active site through RNA-RNA contacts. Three bases at the 3' end of the 5' exon remain anchored to loop I of U5 small nuclear RNA, and the conserved AG nucleotides of the 3'-splice site (3'SS) are specifically recognized by the invariant adenine of the branch point sequence, the guanine base at the 5' end of the 5'SS, and an adenine base of U6 snRNA. The 3'SS is stabilized through an interaction with the 1585-loop of Prp8. The P complex structure provides a view on splice junction formation critical for understanding the complete splicing cycle. PMID- 29153832 TI - Drastic Genome Reduction in an Herbivore's Pectinolytic Symbiont. AB - Pectin, an integral component of the plant cell wall, is a recalcitrant substrate against enzymatic challenges by most animals. In characterizing the source of a leaf beetle's (Cassida rubiginosa) pectin-degrading phenotype, we demonstrate its dependency on an extracellular bacterium housed in specialized organs connected to the foregut. Despite possessing the smallest genome (0.27 Mb) of any organism not subsisting within a host cell, the symbiont nonetheless retained a functional pectinolytic metabolism targeting the polysaccharide's two most abundant classes: homogalacturonan and rhamnogalacturonan I. Comparative transcriptomics revealed pectinase expression to be enriched in the symbiotic organs, consistent with enzymatic buildup in these structures following immunostaining with pectinase targeting antibodies. Symbiont elimination results in a drastically reduced host survivorship and a diminished capacity to degrade pectin. Collectively, our findings highlight symbiosis as a strategy for an herbivore to metabolize one of nature's most complex polysaccharides and a universal component of plant tissues. PMID- 29153834 TI - Precise Editing at DNA Replication Forks Enables Multiplex Genome Engineering in Eukaryotes. AB - We describe a multiplex genome engineering technology in Saccharomyces cerevisiae based on annealing synthetic oligonucleotides at the lagging strand of DNA replication. The mechanism is independent of Rad51-directed homologous recombination and avoids the creation of double-strand DNA breaks, enabling precise chromosome modifications at single base-pair resolution with an efficiency of >40%, without unintended mutagenic changes at the targeted genetic loci. We observed the simultaneous incorporation of up to 12 oligonucleotides with as many as 60 targeted mutations in one transformation. Iterative transformations of a complex pool of oligonucleotides rapidly produced large combinatorial genomic diversity >105. This method was used to diversify a heterologous beta-carotene biosynthetic pathway that produced genetic variants with precise mutations in promoters, genes, and terminators, leading to altered carotenoid levels. Our approach of engineering the conserved processes of DNA replication, repair, and recombination could be automated and establishes a general strategy for multiplex combinatorial genome engineering in eukaryotes. PMID- 29153835 TI - Efficient Generation of Transcriptomic Profiles by Random Composite Measurements. AB - RNA profiles are an informative phenotype of cellular and tissue states but can be costly to generate at massive scale. Here, we describe how gene expression levels can be efficiently acquired with random composite measurements-in which abundances are combined in a random weighted sum. We show (1) that the similarity between pairs of expression profiles can be approximated with very few composite measurements; (2) that by leveraging sparse, modular representations of gene expression, we can use random composite measurements to recover high-dimensional gene expression levels (with 100 times fewer measurements than genes); and (3) that it is possible to blindly recover gene expression from composite measurements, even without access to training data. Our results suggest new compressive modalities as a foundation for massive scaling in high-throughput measurements and new insights into the interpretation of high-dimensional data. PMID- 29153837 TI - A Method for the Acute and Rapid Degradation of Endogenous Proteins. AB - Methods for the targeted disruption of protein function have revolutionized science and greatly expedited the systematic characterization of genes. Two main approaches are currently used to disrupt protein function: DNA knockout and RNA interference, which act at the genome and mRNA level, respectively. A method that directly alters endogenous protein levels is currently not available. Here, we present Trim-Away, a technique to degrade endogenous proteins acutely in mammalian cells without prior modification of the genome or mRNA. Trim-Away harnesses the cellular protein degradation machinery to remove unmodified native proteins within minutes of application. This rapidity minimizes the risk that phenotypes are compensated and that secondary, non-specific defects accumulate over time. Because Trim-Away utilizes antibodies, it can be applied to a wide range of target proteins using off-the-shelf reagents. Trim-Away allows the study of protein function in diverse cell types, including non-dividing primary cells where genome- and RNA-targeting methods are limited. PMID- 29153836 TI - Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling. AB - mTORC1 is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1 activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. Genome-wide transcriptome analysis reveals that lipid biosynthetic enzymes are among the downstream targets of mTORC1-SRPK2 signaling. Mechanistically, SRPK2 promotes SR protein binding to U1-70K to induce splicing of lipogenic pre-mRNAs. Inhibition of this signaling pathway leads to intron retention of lipogenic genes, which triggers nonsense mediated mRNA decay. Genetic or pharmacological inhibition of SRPK2 blunts de novo lipid synthesis, thereby suppressing cell growth. These results thus reveal a novel role of mTORC1-SRPK2 signaling in post-transcriptional regulation of lipid metabolism and demonstrate that SRPK2 is a potential therapeutic target for mTORC1-driven metabolic disorders. PMID- 29153838 TI - Unsupervised Trajectory Analysis of Single-Cell RNA-Seq and Imaging Data Reveals Alternative Tuft Cell Origins in the Gut. AB - Modern single-cell technologies allow multiplexed sampling of cellular states within a tissue. However, computational tools that can infer developmental cell state transitions reproducibly from such single-cell data are lacking. Here, we introduce p-Creode, an unsupervised algorithm that produces multi-branching graphs from single-cell data, compares graphs with differing topologies, and infers a statistically robust hierarchy of cell-state transitions that define developmental trajectories. We have applied p-Creode to mass cytometry, multiplex immunofluorescence, and single-cell RNA-seq data. As a test case, we validate cell-state-transition trajectories predicted by p-Creode for intestinal tuft cells, a rare, chemosensory cell type. We clarify that tuft cells are specified outside of the Atoh1-dependent secretory lineage in the small intestine. However, p-Creode also predicts, and we confirm, that tuft cells arise from an alternative, Atoh1-driven developmental program in the colon. These studies introduce p-Creode as a reliable method for analyzing large datasets that depict branching transition trajectories. PMID- 29153839 TI - Asymmetry between Activation and Deactivation during a Transcriptional Pulse. AB - Transcription in eukaryotic cells occurs in gene-specific bursts or pulses of activity. Recent studies identified a spectrum of transcriptionally active "on states," interspersed with periods of inactivity, but these "off-states" and the process of transcriptional deactivation are poorly understood. To examine what occurs during deactivation, we investigate the dynamics of switching between variable rates. We measured live single-cell expression of luciferase reporters from human growth hormone or human prolactin promoters in a pituitary cell line. Subsequently, we applied a statistical variable-rate model of transcription, validated by single-molecule FISH, to estimate switching between transcriptional rates. Under the assumption that transcription can switch to any rate at any time, we found that transcriptional activation occurs predominantly as a single switch, whereas deactivation occurs with graded, stepwise decreases in transcription rate. Experimentally altering cAMP signalling with forskolin or chromatin remodelling with histone deacetylase inhibitor modifies the duration of defined transcriptional states. Our findings reveal transcriptional activation and deactivation as mechanistically independent, asymmetrical processes. PMID- 29153840 TI - Association of Omics Features with Histopathology Patterns in Lung Adenocarcinoma. AB - Adenocarcinoma accounts for more than 40% of lung malignancy, and microscopic pathology evaluation is indispensable for its diagnosis. However, how histopathology findings relate to molecular abnormalities remains largely unknown. Here, we obtained H&E-stained whole-slide histopathology images, pathology reports, RNA sequencing, and proteomics data of 538 lung adenocarcinoma patients from The Cancer Genome Atlas and used these to identify molecular pathways associated with histopathology patterns. We report cell-cycle regulation and nucleotide binding pathways underpinning tumor cell dedifferentiation, and we predicted histology grade using transcriptomics and proteomics signatures (area under curve >0.80). We built an integrative histopathology-transcriptomics model to generate better prognostic predictions for stage I patients (p = 0.0182 +/- 0.0021) compared with gene expression or histopathology studies alone, and the results were replicated in an independent cohort (p = 0.0220 +/- 0.0070). These results motivate the integration of histopathology and omics data to investigate molecular mechanisms of pathology findings and enhance clinical prognostic prediction. PMID- 29153841 TI - Fluorenone based fluorescent probe for selective "turn-on" detection of pyrophosphate and alanine. AB - To sense biologically important entities with different size and dimensions, a fluorenone based fluorescent receptor was designed and synthesized. Probe 1 displayed a distinct fluorescence enhancement emission at 565nm for pyrophosphate and 530nm for alanine in polar solvent. The fluorescence titration experiments confirm 1:1 stoichiometric ratio with high-binding constant and very low limit of detection (LoD) values. Receptor 1 showed a highly selective and sensitive recognition to HP2O73- and to alanine over other competitive anions and amino acids. In addition, the fluorescence lifetime measurement and reversible binding study results support the practical importance of 1. PMID- 29153844 TI - Treatment of brain disease in the mucopolysaccharidoses. AB - The mucopolysaccharidosis (MPS) disorders are a group of lysosomal storage diseases caused by lysosomal enzyme deficits that lead to glycosaminoglycan accumulation, affecting various tissues throughout the body based on the specific enzyme deficiency. These disorders are characterized by their progressive nature and a variety of somatic manifestations and neurological symptoms. There are established treatments for some MPS disorders, but these mostly alleviate somatic and non-neurological symptoms and do not cure the disease. Patients with MPS I, II, III, and VII can present with neurological manifestations such as neurocognitive decline and behavioral problems. Treatment of these neurological manifestations remains challenging due to the blood-brain barrier (BBB) that limits delivery of therapeutic agents to the central nervous system (CNS). New therapies that circumvent this barrier and target brain disease in MPS are currently under development. They primarily focus on facilitating penetration of drugs through the BBB, delivery of recombinant enzyme to the brain by gene therapy, or direct CNS administration. This review summarizes existing and potential future treatment approaches that target brain disease in MPS. The information in this review is based on current literature and presentations and discussions during a closed meeting by an international group of experts with extensive experience in managing and treating MPS. PMID- 29153842 TI - Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas. AB - Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals. PMID- 29153843 TI - Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance. AB - Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ~5% of primary prostate cancer that is characterized by abbreviated response to androgen deprivation therapy and in ~30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal-lineage genes, independent of androgen-receptor signaling. In HNF4G/HNF1A-double-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the gastrointestinal transcriptome, chromatin landscape, and leads to relative castration resistance. PMID- 29153845 TI - Identification of ABC transporters acting in vitamin B12 metabolism in Caenorhabditis elegans. AB - Vitamin B12 (cobalamin, Cbl) is a micronutrient essential to human health. Cbl is not utilized as is but must go through complex subcellular and metabolic processing to generate two cofactor forms: methyl-Cbl for methionine synthase, a cytosolic enzyme; and adenosyl-Cbl for methylmalonyl-CoA mutase, a mitochondrial enzyme. Some 10-12 human genes have been identified responsible for the intracellular conversion of Cbl to cofactor forms, including genes that code for ATP-binding cassette (ABC) transporters acting at the lysosomal and plasma membranes. However, the gene for mitochondrial uptake is not known. We hypothesized that ABC transporters should be candidates for other uptake and efflux functions, including mitochondrial transport, and set out to screen ABC transporter mutants for blocks in Cbl utilization using the nematode roundworm Caenorhabditis elegans. Thirty-seven mutant ABC transporters were screened for the excretion of methylmalonic acid (MMA), which should result from loss of Cbl transport into the mitochondria. One mutant, wht-6, showed elevated MMA excretion and reduced [14C]-propionate incorporation, pointing to a functional block in methylmalonyl-CoA mutase. In contrast, the wht-6 mutant appeared to have a normal cytosolic pathway based on analysis of cystathionine excretion, suggesting that cytosolic methionine synthase was functioning properly. Further, the MMA excretion in wht-6 could be partially reversed by including vitamin B12 in the assay medium. The human ortholog of wht-6 is a member of the G family of ABC transporters. We propose wht-6 as a candidate for the transport of Cbl into mitochondria and suggest that a member of the corresponding ABCG family of ABC transporters has this role in humans. Our ABC transporter screen also revealed that mrp-1 and mrp-2 mutants excreted lower MMA than wild type, suggesting they were concentrating intracellular Cbl, consistent with the cellular efflux defect proposed for the mammalian MRP1 ABC transporter. PMID- 29153846 TI - Surgical management of neurological manifestations of mucopolysaccharidosis disorders. AB - The mucopolysaccharidosis (MPS) disorders are ultra-rare lysosomal storage disorders associated with progressive accumulation of glycosaminoglycans (GAGs) in cells and tissues throughout the body. Clinical manifestations and progression rates vary widely across and within the different types of MPS. Neurological symptoms occur frequently, and may result directly from brain damage caused by infiltration of GAGs, or develop secondary to somatic manifestations such as spinal cord compression, hydrocephalus, and peripheral nerve entrapment. Management of secondary neurological manifestations often requires surgical correction of the underlying somatic cause. The present review discusses the surgical management of neurological disease in patients with MPS, including diagnostic imaging. Background information is derived from presentations and discussions during a meeting on the brain in MPS, attended by an international group of experts (April 28-30, 2016, Stockholm, Sweden), and additional literature searches. PMID- 29153847 TI - Effect of incentive payments on chronic disease management and health services use in British Columbia, Canada: Interrupted time series analysis. AB - We studied the effects of incentive payments to primary care physicians for the care of patients with diabetes, hypertension, and Chronic Obstructive Pulmonary Disease (COPD) in British Columbia, Canada. We used linked administrative health data to examine monthly primary care visits, continuity of care, laboratory testing, pharmaceutical dispensing, hospitalizations, and total h ealth care spending. We examined periods two years before and two years after each incentive was introduced, and used segmented regression to assess whether there were changes in level or trend of outcome measures across all eligible patients following incentive introduction, relative to pre-intervention periods. We observed no increases in primary care visits or continuity of care after incentives were introduced. Rates of ACR testing and antihypertensive dispensing increased among patients with hypertension, but none of the other modest increases in laboratory testing or prescriptions dispensed reached statistical significance. Rates of hospitalizations for stroke and heart failure among patients with hypertension fell relative to pre-intervention patterns, while hospitalizations for COPD increased. Total hospitalizations and hospitalizations via the emergency department did not change. Health care spending increased for patients with hypertension. This large-scale incentive scheme for primary care physicians showed some positive effects for patients with hypertension, but we observe no similar changes in patient management, reductions in hospitalizations, or changes in spending for patients with diabetes and COPD. PMID- 29153848 TI - [Maternal death by stroke. Results from the French enquiry into maternal deaths, 2010-2012]. AB - Stroke is a rare event during pregnancy (10/100,000) and can be ischemic (24%), hemorrhagic (74%) or both (2%). Pregnancy probably increases the risk even if it is discussed for arteriovenous malformation (AVM), aneurismal subarachnoid hemorrhage (SAH) and cavernomas. Between 2010 and 2012, 31 maternal deaths were associated with stroke. In 22 cases, stroke was the direct cause of death giving a maternal mortality ratio of 0,9/100,000 witch is not different from the former report (2007-2009). There were 2 cerebral thrombophlebitis, 2 ischemic strokes and 18 hemorrhagic strokes (4 SAH, 2 AVM). These deaths occurred during ongoing pregnancy in 5 cases (25%), after miscarriage in 1 case (5%) and in the post partum period in 14 cases (70%). In this last situation, stroke occurred before delivery in 4 cases and during the post-partum period in 9 cases (1 to 9 days) (1 unknown). There were 7 vaginal deliveries (50%) and 6 emergency cesarean sections (43%) (1 unknown). Most of those deaths were considered to be unavoidable (13/17, 76%). Four deaths were considered by the experts as being possibly avoidable (delay diagnosis, diagnostic error, inadequate treatment, lake of interruption of the pregnancy). Analyzing those deaths remind that any sudden, severe and unusual headache must be explored and that pregnancy does not contraindicate any of the diagnostic examinations (TDM, angio-TDM, MRI) or invasive treatments (surgery, arterio-embolization, fibrinolysis) necessary for its management. Furthermore, the diagnosis of postdural puncture headache should not be establishedwithout imaging when the symptomatology is not absolutely typical. PMID- 29153849 TI - Cutting balloon and high-pressure balloon dilation for palliative treatment of congenital double-chambered right ventricle and primary infundibular stenosis in a Golden retriever dog. AB - Combined cutting balloon and high-pressure balloon dilation was performed in a dog with a double-chambered right ventricle and severe infundibular stenosis of the right ventricular outflow tract. The peak systolic pressure gradient across the stenosis decreased by 65% after dilation (from 187 mmHg before to 66 mmHg after) affirming the intervention as successful. However, early re-stenosis occurred within 3 months leading to exercise intolerance, exercise-induced syncope, and right-sided congestive heart failure. Cutting balloon followed by high-pressure balloon dilation provided temporary but not long-term relief of right ventricular obstruction in this dog. PMID- 29153850 TI - Promises and Pitfalls of Metal Imaging in Biology. AB - A picture may speak a thousand words, but if those words fail to form a coherent sentence there is little to be learned. As cutting-edge imaging technology now provides us the tools to decipher the multitude of roles played by metals and metalloids in molecular, cellular, and developmental biology, as well as health and disease, it is time to reflect on the advances made in imaging, the limitations discovered, and the future of a burgeoning field. In this Perspective, the current state of the art is discussed from a self-imposed contrarian position, as we not only highlight the major advances made over the years but use them as teachable moments to zoom in on challenges that remain to be overcome. We also describe the steps being taken toward being able to paint a completely undisturbed picture of cellular metal metabolism, which is, metaphorically speaking, the Holy Grail of the discipline. PMID- 29153852 TI - The Therapeutic Potential of PTEN Modulation: Targeting Strategies from Gene to Protein. AB - Two decades have passed since the discovery of the tumor suppressor, PTEN. A multitude of biological functions have since been revealed, suggesting potential therapeutic applications for both PTEN activation (e.g., cancer) and inhibition (e.g., neuroregeneration). Nevertheless, PTEN's therapeutic suitability has been called into question due to its "risky" profile as a tumor suppressor. To evaluate PTEN function and its various roles in disease a number of molecules have so far been developed. However, intrinsic problems associated with phosphatase inhibition and PTEN's complex regulation via post-translational modifications hinder straightforward access to selective modulators. For this reason, central questions associated with PTEN targeting remain unanswered. In this perspective, we summarize current PTEN-targeting strategies and discuss potential approaches to modulate its functional dose, considering all stages of PTEN biogenesis from direct protein modulation to the targeting of relevant miRNAs as well as the PTEN gene and mRNA. PMID- 29153853 TI - Community pharmacist collaboration with a patient-centered medical home: Establishment of a patient-centered medical neighborhood and payment model. AB - OBJECTIVES: To determine the feasibility of a partnership between a community pharmacy and a patient-centered medical home (PCMH) by measuring the impact on office- and patient-level clinical outcomes. SETTING: Kroger Pharmacy and a PCMH practice in Cincinnati, OH. PRACTICE DESCRIPTION: The Kroger Co. is a large grocery store chain that operates 102 pharmacies in the Cincinnati-Dayton marketing area. The PCMH practice is an accredited PCMH office serving more than 9000 patients in the Cincinnati area. PRACTICE INNOVATION: In a medical neighborhood, a PCMH coordinates care with other local specialty practices or partners. A partnership between the community pharmacy chain and the PCMH was established to create a medical neighborhood. The pharmacist spent 2 half-days per week at the PCMH. The pharmacist provided initial medication therapy management appointments in the PCMH and offered follow-up services in the office, the pharmacy, or both, depending on patient preference. The pharmacy received a capitated payment per patient per month for a predetermined number of 1000 high risk patients. MAIN OUTCOME MEASURES: Office-level changes in clinical outcomes such as A1C, blood pressure, and lipid measures were collected and compared with those of a similar control office. In addition, patient-level outcomes such as change in A1C, blood pressure, lipids, and weight were measured. RESULTS: One hundred five patients were seen by the pharmacist during the study period, with 1.5% of the total managed at the office. There was a statistically significant increase in influenza vaccinations received. On a patient level, A1C and systolic blood pressure significantly improved. CONCLUSION: This project represents an exciting opportunity for community pharmacists to expand their scope of services through direct partnership with PCMHs and maintain a sustainable reimbursement structure. PMID- 29153851 TI - APOBEC Enzymes as Targets for Virus and Cancer Therapy. AB - Human DNA cytosine-to-uracil deaminases catalyze mutations in both pathogen and cellular genomes. APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H restrict human immunodeficiency virus 1 (HIV-1) infection in cells deficient in the viral infectivity factor (Vif), and have the potential to catalyze sublethal levels of mutation in viral genomes in Vif-proficient cells. At least two APOBEC3 enzymes, and in particular APOBEC3B, are sources of somatic mutagenesis in cancer cells that drive tumor evolution and may manifest clinically as recurrence, metastasis, and/or therapy resistance. Consequently, APOBEC3 enzymes are tantalizing targets for developing chemical probes and therapeutic molecules to harness mutational processes in human disease. This review highlights recent efforts to chemically manipulate APOBEC3 activities. PMID- 29153854 TI - What are pharmacists recommending for infant teething treatment? AB - OBJECTIVES: In 2011, the Food and Drug Administration issued a warning to avoid the use of any benzocaine-containing products for infant teething treatment owing to a risk of methemoglobinemia. Several benzocaine-containing products targeted for infant teething are currently available over the counter. Pharmacists are commonly asked for medical advice in the community, and there is no current literature evaluating what pharmacists are recommending for infant teething. The objectives of this study were to evaluate what pharmacists are currently recommending for infant teething treatment and assess what percentage would inappropriately recommend a benzocaine-containing product. METHODS: From March to June 2016, a 16-item in-person paper-and-pen questionnaire was administered to 200 pharmacists in the San Francisco Bay area at 115 outpatient over-the-counter pharmacies. Questions included demographic information, work and educational background, infant teething recommendations, and preferred educational resources. RESULTS: The overall response rate was 94.3%. One-half (50.5%) of the pharmacists' approaches to infant teething treatment was to recommend a nondrug option first and then, if needed, an over-the-counter medication. A majority (63.0%) of the pharmacists surveyed would inappropriately select a benzocaine containing product. CONCLUSION: Despite warnings, the majority of pharmacists would still inappropriately recommend a benzocaine-containing product for treatment of infant teething. Further education is warranted to ensure that all pharmacists, health care providers, and consumers are aware of the potential harm of benzocaine use in infants. PMID- 29153855 TI - Changes in element availability induced by sterilization in heavy metal contaminated substrates: A comprehensive study. AB - Microbiome analyses of soils and microcosm experiments depend on conditions that include sterilization in order to perform experimental manipulation of microbial communities. Still, they should represent conditions close to nature. When using metal contaminated soils, sterilization methods might alter metal availability. Here, four typical metal contaminated substrates were analyzed, representing different contamination histories and soil types. They included two very poor substrates, as they are often found at metal contaminated sites. The low contents in organic carbon and nitrogen as well as two substrates with slightly higher nutrient availability were used to perform a comprehesive study for element availability changes induced by sterilization. Autoclaving, dry heat or gamma ragamma sterilization were applied and compared to a non-treated control. The sterile substrates were analyzed using sequential extraction to account for different associations of the elements. Metals forming specific (hydro)oxide layers were specifically analyzed since they in turn may also impact other metals or ions. In addition, (heavy) metals and (micro)nutrients were analyzed for changes in speciation. The effects of autoclaving (wet heat) was found acceptable, while gamma-ray irradiation did show unexpected changes in metal associations, especially for one substrate. Dry heat changed metal availability to the highest degree. PMID- 29153856 TI - The effect of viscous soluble fiber on blood pressure: A systematic review and meta-analysis of randomized controlled trials. AB - AIMS: Dietary fiber intake, especially viscous soluble fiber, has been established as a means to reduce cardiometabolic risk factors. Whether this is true for blood pressure remains controversial. A systematic review and meta analysis of randomized controlled trials (RCTs) was conducted to investigate the effects of viscous soluble fiber supplementation on blood pressure and quantify the effect of individual fibers. DATA SYNTHESIS: MEDLINE, Embase, and Cochrane databases were searched. We included RCTs of >=4-weeks in duration assessing viscous fiber supplementation from five types: beta-glucan from oats and barley, guar gum, konjac, pectin and psyllium, on systolic blood pressure (SBP) and diastolic blood pressure (DBP). Study data were pooled using the generic inverse variance method with random effects models and expressed as mean differences (MD) with 95% confidence intervals (CIs). Twenty-two (N = 1430) and twenty-one RCTs (N = 1343) were included in the final analysis for SBP and DBP, respectively. Viscous fiber reduced SBP (MD = -1.59 mmHg [95% CI: -2.72,-0.46]) and DBP (MD = 0.39 mmHg [95% CI: -0.76,-0.01]) at a median dose of 8.7 g/day (1.45-30 g/day) over a median follow-up of 7-weeks. Substantial heterogeneity in SBP (I2 = 72%, P < 0.01) and DBP (I2 = 67%, P < 0.01) analysis occurred. Within the five fiber types, SBP reductions were observed only for supplementation using psyllium fiber (MD = -2.39 mmHg [95% CI: -4.62,-0.17]). CONCLUSION: Viscous soluble fiber has an overall lowering effect on SBP and DBP. Inclusion of viscous fiber to habitual diets may have additional value in reducing CVD risk via improvement in blood pressure. PROTOCOL REGISTRATION: ClinicalTrials.gov identifier-NCT02670967. PMID- 29153858 TI - An evaluation of the feedback loops in the poverty focus of world bank operations. AB - The World Bank Group in 2013 made the elimination of extreme poverty by 2030 a central institutional focus and purpose. This paper, based on an evaluation conducted by the Independent Evaluation Group of the World Bank Group, examines how, and how well, the Bank uses feedback loops to enhance the poverty focus of its operations. Feedback loops are important for every element of the results chain running from data, to diagnostics, to strategy formulation and finally to strategy implementation. The evaluation uses a range of instruments, including surveys of stakeholders and World Bank staff, focus group meetings, country case studies and systematic reviews of Bank lending and non-lending operations. We find that while the Bank generates useful information on poverty reduction from its projects and programs, the feedback loops - from outcomes to data analysis to diagnostics to strategy formulation and implementation - have generally been weak, with sizable variation across countries. PMID- 29153859 TI - Oligoprogressive Oncogene-addicted Lung Tumours: Does Stereotactic Body Radiotherapy Have a Role? Introducing the HALT Trial. PMID- 29153857 TI - Predicting the atopic march: Results from the Canadian Healthy Infant Longitudinal Development Study. AB - BACKGROUND: The atopic march describes the progression from atopic dermatitis during infancy to asthma and allergic rhinitis in later childhood. In a Canadian birth cohort we investigated whether concomitant allergic sensitization enhances subsequent development of these allergic diseases at age 3 years. METHODS: Children completed skin prick testing at age 1 year. Children were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control to any of 10 inhalant or food allergens. Children were also assessed for atopic dermatitis by using the diagnostic criteria of the UK Working Party. At age 3 years, children were assessed for asthma, allergic rhinitis, food allergy, and atopic dermatitis. Data from 2311 children were available. RESULTS: Atopic dermatitis without allergic sensitization was not associated with an increased risk of asthma at age 3 years after adjusting for common confounders (relative risk [RR], 0.46; 95% CI, 0.11-1.93). Conversely, atopic dermatitis with allergic sensitization increased the risk of asthma more than 7-fold (RR, 7.04; 95% CI, 4.13-11.99). Atopic dermatitis and allergic sensitization had significant interactions on both the additive (relative excess risk due to interaction, 5.06; 95% CI, 1.33-11.04) and multiplicative (ratio of RRs, 5.80; 95% CI, 1.20-27.83) scales in association with asthma risk. There was also a positive additive interaction between atopic dermatitis and allergic sensitization in their effects on food allergy risk (relative excess risk due to interaction, 15.11; 95% CI, 4.19-35.36). CONCLUSIONS: Atopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma. In combination, atopic dermatitis and allergic sensitization had strong interactive effects on both asthma and food allergy risk at age 3 years. PMID- 29153860 TI - The antimicrobial peptide HS-1 inhibits dengue virus infection. AB - Dengue virus (DENV) is an arbovirus that belongs to the Flaviviridae family. Studies reveal that peptides secreted by amphibians have many functions, such as antiviral and antimicrobial activities. As there is no antiviral drug effective against the DENV, the antiviral activity of a synthetic peptide called HS-1, derived from the secretion of the anuran Hypsiboas semilineatus, has been evaluated. The assays of neutralization in the Vero cells show a complete inhibition of infection of the serotypes 2 and 3. Furthermore, the direct action of peptides on the viral particle can be observed through atomic force microscopy. In vivo tests display 80% protection against the dengue-2 virus due to the presence of HS-1, which reveals its potential as an antiviral against the DENV. PMID- 29153861 TI - Extensive diversity and evolution of hepadnaviruses in bats in China. AB - To better understand the evolution of hepadnaviruses, we sampled bats from Guizhou, Henan and Zhejiang provinces, China, and rodents from Zhejiang province. Genetically diverse hepadnaviruses were identified in a broad range of bat species, with an overall prevalence of 13.3%. In contrast, no rodent hepadnaviruses were identified. The newly discovered bat hepadnaviruses fell into two distinct phylogenetic groups. The viruses within the first group exhibited high diversity, with some closely related to viruses previously identified in Yunnan province. Strikingly, the newly discovered viruses sampled from Jiyuan city in the second phylogenetic group were most closely related to those found in bats from West Africa, suggestive of a long-term association between bats and hepadnaviruses. A co-phylogenetic analysis revealed frequent cross-species transmission among bats from different species, genera, and families. Overall, these data suggest that there are likely few barriers to the cross-species transmission of bat hepadnaviruses. PMID- 29153863 TI - Assessment of uranium release to the environment from a disabled uranium mine in Brazil. AB - The Ore Treatment Unit (in Portuguese Unidade de Tratamento de Minerios - UTM) located in Caldas, MG, Brazil is a disabled uranium mine. Environmental conditions generate acid drainage leaching metals and radionuclides from the waste rock pile. This drainage is treated to remove the heavy metals and radionuclides, before allowing the release of the effluent to the environment. To validate the treatment, samples of the released effluents were collected at the interface of the installation with the environment. Sampling was carried out from 2010 to 2015, and the activity concentration (AC, in Bq.l-1) of uranium in the liquid effluent was analyzed by arzenazo UV-Vis spectrophotometry of the soluble and particulate fractions, and of the sum of both fractions. Descriptive statistics, Z test and Pearson R2 correlation among the fractions were performed. Then, the data were organized by year and both ANOVA and Tukey test were carried out to group the means by magnitude of AC. The annual mean ranged from 0.02 Bq.l 1 in 2015 to 0.11 Bq.l-1 in 2010. The soluble fraction showed a higher AC mean when compared to the mean of the particulate fraction and no correlation of the data could be observed. Concerning the magnitude of the release, the ANOVA associated with the Tukey test, identified three groups of annual means (AC2010> AC2011 = AC2012 = AC2013 = AC2014 > AC2015). The mean values of uranium release at the interface installation-environment checking point (point 014) were within the Authorized Annual Limit (AAL) set by the regulator (0.2 Bq.l-1) indicating compliance of treatment with the licensing established for the unit. Finally, the data showed a decreasing tendency of U release. PMID- 29153864 TI - Changes in Markers of Thrombin Generation and Interleukin-6 During Unicondylar Knee and Total Knee Arthroplasty. AB - BACKGROUND: Total knee arthroplasty (TKA) is associated with a risk of thromboembolism requiring routine thromboprophylaxis, but there is debate about the risk with unicondylar knee arthroplasty (UKA) as it is a more minor procedure. We sought to investigate the relative risk of thromboembolism with UKA compared to TKA and one-staged bilateral TKA (BTKA) by measuring the increase in circulating biochemical markers of thrombin generation during the procedures. Degree of surgical trauma was also assessed by measuring interleukin-6, a marker of metabolic injury. METHODS: We prospectively studied a total of 75 patients: 25 patients undergoing UKA, unilateral TKA, and BTKA, respectively. All patients had surgery performed with tourniquet and received no tranexamic acid. Blood samples were taken during surgery and assayed for circulating markers of thrombin generation: prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes plus interleukin-6. RESULTS: Thrombin-antithrombin complexes, increased during all time points (P < .001) but was not significantly different between surgical treatment groups. F1+2 also rose significantly during surgery, with no significant difference between UKA and TKA. There was, however, a significant difference in F1+2 between BTKA and UKA or TKA (P < .02). Interleukin-6 rose minimally with UKA but rose significantly with TKA and BTKA (P < .001). CONCLUSION: Based on these data of circulating biochemical markers, patients undergoing UKA are at similar risk of thromboembolism with respect to TKA despite a lower index of metabolic injury. We believe that UKA patients should receive thromboprophylaxis comparable to TKA patients. PMID- 29153865 TI - Treatments of Missing Values in Large National Data Affect Conclusions: The Impact of Multiple Imputation on Arthroplasty Research. AB - BACKGROUND: Despite the advantages of large, national datasets, one continuing concern is missing data values. Complete case analysis, where only cases with complete data are analyzed, is commonly used rather than more statistically rigorous approaches such as multiple imputation. This study characterizes the potential selection bias introduced using complete case analysis and compares the results of common regressions using both techniques following unicompartmental knee arthroplasty. METHODS: Patients undergoing unicompartmental knee arthroplasty were extracted from the 2005 to 2015 National Surgical Quality Improvement Program. As examples, the demographics of patients with and without missing preoperative albumin and hematocrit values were compared. Missing data were then treated with both complete case analysis and multiple imputation (an approach that reproduces the variation and associations that would have been present in a full dataset) and the conclusions of common regressions for adverse outcomes were compared. RESULTS: A total of 6117 patients were included, of which 56.7% were missing at least one value. Younger, female, and healthier patients were more likely to have missing preoperative albumin and hematocrit values. The use of complete case analysis removed 3467 patients from the study in comparison with multiple imputation which included all 6117 patients. The 2 methods of handling missing values led to differing associations of low preoperative laboratory values with commonly studied adverse outcomes. CONCLUSION: The use of complete case analysis can introduce selection bias and may lead to different conclusions in comparison with the statistically rigorous multiple imputation approach. Joint surgeons should consider the methods of handling missing values when interpreting arthroplasty research. PMID- 29153862 TI - Tumor necrosis factor alpha in sleep regulation. AB - This review details tumor necrosis factor alpha (TNF) biology and its role in sleep, and describes how TNF medications influence sleep/wake activity. Substantial evidence from healthy young animals indicates acute enhancement or inhibition of endogenous brain TNF respectively promotes and inhibits sleep. In contrast, the role of TNF in sleep in most human studies involves pathological conditions associated with chronic elevations of systemic TNF and disrupted sleep. Normalization of TNF levels in such patients improves sleep. A few studies involving normal healthy humans and their TNF levels and sleep are consistent with the animal studies but are necessarily more limited in scope. TNF can act on established sleep regulatory circuits to promote sleep and on the cortex within small networks, such as cortical columns, to induce sleep-like states. TNF affects multiple synaptic functions, e.g., its role in synaptic scaling is firmly established. The TNF-plasticity actions, like its role in sleep, can be local network events suggesting that sleep and plasticity share biochemical regulatory mechanisms and thus may be inseparable from each other. We conclude that TNF is involved in sleep regulation acting within an extensive tightly orchestrated biochemical network to niche-adapt sleep in health and disease. PMID- 29153866 TI - A Phase I Trial of the PI3K Inhibitor Buparlisib Combined With Capecitabine in Patients With Metastatic Breast Cancer. AB - BACKGROUND: Buparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients received buparlisib once daily (range, 50 to 100 mg) for 3 weeks with capecitabine twice daily (range, 1000 to 1250 mg/m2) for 2 weeks with a 1-week break. Dose escalation used a traditional "3 + 3" design with standard definitions of dose-limiting toxicity (DLT) and maximum tolerated dose. RESULTS: Of the 25 patients enrolled, 23 were evaluable for DLT and 17 were evaluable for response. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m2 twice daily. DLTs included grade 3 hyperglycemia and grade 3 confusion. The most common grade 3 toxicities were diarrhea and elevation of aspartate aminotransferase and alanine transaminase. One patient exhibited a complete response to treatment and four had a confirmed partial response. In cohorts 3 and 4, in which the buparlisib dose remained constant but the capecitabine dose was increased, significant increases in the buparlisib plasma concentration were noted. CONCLUSION: The combination of buparlisib with capecitabine in patients with metastatic breast cancer was generally well-tolerated, with several patients demonstrating prolonged responses. Unexpectedly low rates of PIK3CA mutations (3 of 17) were seen, and only 2 of 7 tumors with subtyping were luminal, making exploration of these putative predictive markers impossible. Further study of the combination is not unreasonable, with expanded pharmacokinetics and sequencing analysis to better elucidate potential drug-drug interactions and more accurate predictive biomarkers of response. PMID- 29153867 TI - Impact of upper body precooling during warm-up on subsequent time trial paced cycling in the heat. AB - OBJECTIVES: The purpose of this study was to test the hypothesis that cooling the upper body during a warm-up enhances performance during a subsequent 16.1-km simulated cycling time trial in a hot environment. DESIGN: Counterbalanced, repeated measures design. METHODS: Eight trained, male cyclists (peak oxygen uptake=57.8+/-5.0mLkg-1min-1) completed two simulated 16.1-km time trials in a hot environment (35.0+/-0.5 degrees C, 43.8+/-2.0% relative humidity) each separated by 72h. Treatments were counterbalanced; participants warmed up for 20min while either wearing head and neck ice wraps and an ice vest (COOLING) or no cooling apparatus (CONTROL). RESULTS: Following the warm-up mean skin temperature (T-sk), mean body temperature (T-b) and rating of thermal comfort were significantly lower than baseline following the COOLING trial (all P<0.05); however, rectal temperature was unaffected (P=0.35). Because the effects of precooling on T-sk and T-b were not sustained during exercise, values for COOLING and CONTROL were not different throughout the time trial (P=0.38). Nonetheless, time to completion was significantly faster following the COOLING intervention when compared to the CONTROL (29.3+/-3.6min, vs. 30.3+/-3.1min; P=0.04). CONCLUSIONS: These data suggest that in short distance time trials in hot conditions cyclists may benefit from utilizing a cooling modality during the warm up. PMID- 29153868 TI - [Transposition of the cephalic vein in free flap breast reconstruction: Technical note]. AB - Free flaps have become a reliable practice for breast reconstruction. However, the venous congestion is still the most frequent reason of flap failure. It is due to bad quality of the internal mammary veins, a preferential superficial venous outflow of the flap or due to venous thrombosis. The transposition of the cephalic vein could useful in some cases. We describe the surgical technique and suggest an intraoperative algorithm. Seventeen patients (15 DIEP and 2 PAP) were included. Twenty nine point four percent had an unusable internal mammary vein, 23.5% a preferential superficial venous outflow and 47.1% a venous thrombosis. The length of the cephalic vein dissected varied from 15 to 25cm. The mean time of dissection was 39min. There was no flap failure after cephalic vein transposition. The sequelae were one or two scars on the arm without any functional morbidity. The transposition of the cephalic vein is a reliable, less morbid alternative in case of bad quality internal mammary vein with a good quality internal mammary artery, in case of an additional venous outflow necessity or in case of venous thrombosis. PMID- 29153869 TI - [Benign tumors of the soft tissue of the hand, about 70 cases]. AB - Through a retrospective study of 70 cases of benign soft tissue tumors in the orthopedic traumatology department of the military hospital of Tunis over a 12 year period from January 2005 to December 2016, we have compared our findings to those of the literature in an attempt to identify epidemiological notions relevant to daily medical practice as epidemiological data on benign tumors of the soft parts of the hand remain few and sometimes discordant. The authors report a series of 70 active, young adults, mostly female, with a swelling at the level of the hand as the most common reason for consultation. The middle finger and index finger were the most affected fingers at equal frequencies. The key supplementary examination was the ultrasound of the soft parts. All patients were treated with a complete surgical biopsy of their tumor followed by a histological study of the surgical specimen. Three cases of recidivism were noted. Through this study, the frequency of tumors of the soft parts of the hand in a particular population (Tunisian military agents) is emphasized. Moreover, this study allowed us to confirm the data of the literature concerning the dominance of the digital localization. On the other hand, this study reports that the giant cell tumor is the most common histological type in the study population. PMID- 29153870 TI - Factors associated with use of disease modifying agents for rheumatoid arthritis in the National Hospital and Ambulatory Medical Care Survey. AB - OBJECTIVE: We examined the treatment patterns among adults with rheumatoid arthritis (RA) and identified factors influencing access to traditional and biological disease modifying antirheumatic drugs (DMARDs). METHODS: We analyzed visits recorded in the National Ambulatory Medical Care Survey from 2005 to 2014 with a RA diagnosis. The primary outcome was DMARD use (traditional and/or biological). We included prescriptions of all RA-related treatments such as traditional and biological DMARDs, glucocorticoids, gold preparations, immunosuppressants, and non-steroidal anti-inflammatory drugs. Covariates in the logistic regression models included age, gender, race/ethnicity, type of health care coverage, provider type, geographic region, and number of comorbidities. RESULTS: Among 1405 visits with a RA diagnosis, 60.4% (n = 807) were prescribed DMARDs and 23.8% (n = 334) biological DMARDs. In fully adjusted models, females have 1.57 times higher odds of any DMARD use (95% confidence interval (CI): 1.02 2.46). Also, Medicare beneficiaries as compared to privately insured have 2.31 times higher odds of receiving any DMARDs (95% CI: 1.40-3.82), while visits with specialist vs. general physician are 2.38 times more associated with any DMARD use (95% CI: 1.37-4.14). For biological DMARDs, Medicare beneficiaries were at 2.58 times higher odds (95% CI: 1.42-4.70) than privately insured, while visits with specialist are at 3.37 times higher odds than general physician (95% CI: 1.40-8.23). CONCLUSION: Visits with a specialist and Medicare beneficiaries were significantly associated with any DMARD or biological DMARD use. Additionally, contrary to prior evidence, race/ethnicity was not associated with any DMARD or biological DMARD use, which may indicate reduction in disparity of treatment access. PMID- 29153871 TI - Revisiting the impact of macroeconomic conditions on health behaviours. AB - This paper estimates the average population effect of macroeconomic conditions on health behaviours accounting for the heterogeneous impact of the business cycle on individuals. While previous studies use models relying on area-specific unemployment rates to estimate this average effect, this paper employs a model based on area-specific unemployment rates by gender and age group. The rationale for breaking down unemployment rates is that the severity of cyclical upturns and downturns does not only significantly vary across geographical areas, but also across gender and age. The empirical analysis uses microdata from the Italian Multipurpose Household Survey on Everyday Life Issues. The estimates suggest that models employing aggregated and disaggregated unemployment rate measures as a proxy for the business cycle produce similar findings for some health behaviours (such as smoking), whereas different results are obtained for others. While using unemployment rates by gender and age group, fruits and/or vegetables consumption turns out to be procyclical (a 1pp increase in this unemployment rate decreases the probability of consuming at least five daily fruit and/or vegetable servings by 0.0016pp), the opposite effect, though statistically insignificant, is observed once general unemployment rates are used. While both models conclude that physical activity declines during economic downturns, the size of the procyclical effect is much smaller when employing disaggregated rather than aggregated unemployment rates (a 1pp increase in the unemployment rate by gender and age group decreases the probability of doing any physical activity by 0.0017pp). PMID- 29153872 TI - Malignant lymphoma arising in cardiac myxoma, presenting with peripheral arterial emboli. AB - Composite tumors of cardiac myxoma and malignant lymphoma are extremely rare, with 11 of such cases reported in the literature. A 44-year-old man presented to us with abrupt right lower leg pain. A computed tomography angiogram revealed segmental obstruction of the right common femoral artery, and embolectomy was performed. The embolectomy specimen contained several clusters of degenerated round/oval atypical cells in the fibrinous or myxoid background. Immunohistochemical examination revealed that these atypical cells were negative for cytokeratin and non-specifically expressed CD45. After one year of follow-up, the patient presented with dyspnea on exertion. Transthoracic echocardiography revealed a 5.7*1.9 cm, lobulated, echogenic, intracardiac mass, and excision was performed. Microscopically, most of the mass was composed of stellate or curved cells with eosinophilic cytoplasm in the myxoid background. However, several clusters or scattered round/oval atypical cells, similar to those observed in the embolectomy specimen, were observed. These atypical cells were positive for CD45 and CD20, with a Ki-67 labeling index of 90%. Calretinin was expressed in stellate cells but not in atypical cells. Therefore, we made a diagnosis of diffuse large B cell lymphoma (DLBCL) arising in the cardiac myxoma. Our case is an extremely rare example of a composite tumor of cardiac myxoma and DLBCL presenting with peripheral arterial emboli. Thorough histological evaluation of embolectomy and cardiac myxoma specimen is crucial for the diagnosis of composite tumor. PMID- 29153874 TI - Psychological treatments for depression in adults with mild to moderate intellectual disabilities: are we there yet? PMID- 29153873 TI - Comparison of behavioural activation with guided self-help for treatment of depression in adults with intellectual disabilities: a randomised controlled trial. AB - BACKGROUND: Psychological therapies are first-line interventions for depression, but existing provision is not accessible for many adults with intellectual disabilities. We investigated the clinical and cost-effectiveness of a behavioural activation intervention (BeatIt) for people with intellectual disabilities and depression. BeatIt was compared with a guided self-help intervention (StepUp). METHODS: We did a multicentre, single-blind, randomised, controlled trial with follow-up at 4 months and 12 months after randomisation. Participants aged 18 years or older, with mild to moderate intellectual disabilities and clinically significant depression were recruited from health and social care services in the UK. The primary outcome was the Glasgow Depression Scale for people with a Learning Disability (GDS-LD) score at 12 months. Analyses were done on an intention-to-treat basis. This trial is registered with ISCRTN, number ISRCTN09753005. FINDINGS: Between Aug 8, 2013, and Sept 1, 2015, 161 participants were randomly assigned (84 to BeatIt; 77 to StepUp); 141 (88%) participants completed the trial. No group differences were found in the effects of BeatIt and StepUp based on GDS-LD scores at 12 months (12.03 [SD 7.99] GDS-LD points for BeatIt vs 12.43 [SD 7.64] GDS-LD points for StepUp; mean difference 0.26 GDS-LD points [95% CI -2.18 to 2.70]; p=0.833). Within-group improvements in GDS-LD scores occurred in both groups at 12 months (BeatIt, mean change -4.2 GDS LD points [95% CI -6.0 to -2.4], p<0.0001; StepUp, mean change -4.5 GDS-LD points [-6.2 to -2.7], p<0.0001), with large effect sizes (BeatIt, 0.590 [95% CI 0.337 0.844]; StepUp, 0.627 [0.380-0.873]). BeatIt was not cost-effective when compared with StepUp, although the economic analyses indicated substantial uncertainty. Treatment costs were only approximately 3.6-6.8% of participants' total support costs. No treatment-related or trial-related adverse events were reported. INTERPRETATION: This study is, to our knowledge, the first large randomised controlled trial assessing individual psychological interventions for people with intellectual disabilities and mental health problems. These findings show that there is no evidence that BeatIt is more effective than StepUp; both are active and potentially effective interventions. FUNDING: National Institute for Health Research. PMID- 29153875 TI - The role of operating parameters and oxidative damage mechanisms of advanced chemical oxidation processes in the combat against antibiotic-resistant bacteria and resistance genes present in urban wastewater. AB - An upsurge in the study of antibiotic resistance in the environment has been observed in the last decade. Nowadays, it is becoming increasingly clear that urban wastewater is a key source of antibiotic resistance determinants, i.e. antibiotic-resistant bacteria and antibiotic resistance genes (ARB&ARGs). Urban wastewater reuse has arisen as an important component of water resources management in the European Union and worldwide to address prolonged water scarcity issues. Especially, biological wastewater treatment processes (i.e. conventional activated sludge), which are widely applied in urban wastewater treatment plants, have been shown to provide an ideal environment for the evolution and spread of antibiotic resistance. The ability of advanced chemical oxidation processes (AOPs), e.g. light-driven oxidation in the presence of H2O2, ozonation, homogeneous and heterogeneous photocatalysis, to inactivate ARB and remove ARGs in wastewater effluents has not been yet evaluated through a systematic and integrated approach. Consequently, this review seeks to provide an extensive and critical appraisal on the assessment of the efficiency of these processes in inactivating ARB and removing ARGs in wastewater effluents, based on recent available scientific literature. It tries to elucidate how the key operating conditions may affect the process efficiency, while pinpointing potential areas for further research and major knowledge gaps which need to be addressed. Also, this review aims at shedding light on the main oxidative damage pathways involved in the inactivation of ARB and removal of ARGs by these processes. In general, the lack and/or heterogeneity of the available scientific data, as well as the different methodological approaches applied in the various studies, make difficult the accurate evaluation of the efficiency of the processes applied. Besides the operating conditions, the variable behavior observed by the various examined genetic constituents of the microbial community, may be directed by the process distinct oxidative damage mechanisms in place during the application of each treatment technology. For example, it was shown in various studies that the majority of cellular damage by advanced chemical oxidation may be on cell wall and membrane structures of the targeted bacteria, leaving the internal components of the cells relatively intact/able to repair damage. As a result, further in-depth mechanistic studies are required, to establish the optimum operating conditions under which oxidative mechanisms target internal cell components such as genetic material and ribosomal structures more intensively, thus conferring permanent damage and/or death and preventing potential post-treatment re-growth. PMID- 29153876 TI - Real-time evaluation of natural organic matter deposition processes onto model environmental surfaces. AB - Natural organic matter (NOM) is ubiquitous in aqueous systems and dynamically partitions onto/from environmental surfaces. However, such interfacial processes have not been uniformly quantified in situ and in real time. In this work, adsorption and deposition processes of Suwannee River humic acid (SRHA) and Suwannee River fulvic acid (SRFA), as model NOM, were evaluated for a series of environmentally relevant interfaces. Real-time, interfacial phenomenon, including deposition, release, and adlayer viscoelastic properties, were quantified over a variety of water chemistries via quartz crystal microbalance with dissipation monitoring (QCM-D). Specifically, adlayer mass and deposition rates of SRHA and SRFA were evaluated as a function of NOM concentration/molecular weight (fraction), pH, electrolyte composition (type and concentration), and collector surface type. For these, the adsorption of SRHA onto aluminum oxide (Al2O3) and polystyrene (PS) surfaces follows the Langmuir isotherm model. Rapid, near monolayer formation of SRHA/SRFA adlayers were observed on Al2O3, hydroxyapatite (HAP), and poly (l-lysine) (PLL) surfaces, but not on PS or iron oxide (Fe3O4) surfaces. The presence of divalent cations (Ca2+/Mg2+) at relatively low concentrations (0.5-5.0 mM) significantly enhances the mass of SRHA/SRFA deposited onto the surfaces of silica (SiO2), Al2O3, and PS. Viscoelastic properties of the adsorbed layer based on the ratio of dissipation to frequency revealed a relatively unique adlayer structure for SRHA in the presence of 5.0 mM Ca2+. PMID- 29153877 TI - Slowly biodegradable organic compounds impact the biostability of non-chlorinated drinking water produced from surface water. AB - It is possible to distribute drinking water without a disinfectant residual when the treated water is biologically stable. The objective of this study was to determine the impact of easily and slowly biodegradable compounds on the biostability of the drinking water at three full-scale production plants which use the same surface water, and on the regrowth conditions in the related distribution systems. Easily biodegradable compounds in the drinking water were determined with AOC-P17/Nox during 2012-2015. Slowly biodegradable organic compounds measured as particulate and/or high-molecular organic carbon (PHMOC), were monitored at the inlet and after the different treatment stages of the three treatments during the same period. The results show that PHMOC (300-470 MUg C L 1) was approximately 10% of the TOC in the surface water and was removed to 50 100 MUg C L-1. The PHMOC in the water consisted of 40-60% of carbohydrates and 10% of proteins. A significant and strong positive correlation was observed for PHMOC concentrations and two recently introduced bioassay methods for slowly biodegradable compounds (AOC-A3 and biomass production potential, BPC14). Moreover, these three parameters in the biological active carbon effluent (BACF) of the three plants showed a positive correlation with regrowth in the drinking water distribution system, which was assessed with Aeromonas, heterotrophic plate counts, coliforms and large invertebrates. In contrast, the AOC-P17/Nox concentrations did not correlate with these regrowth parameters. We therefore conclude that slowly biodegradable compounds in the treated water from these treatment plants seem to have a greater impact on regrowth in the distribution system than easily biodegradable compounds. PMID- 29153879 TI - Remodeling the Tumor Microenvironment with Emerging Nanotherapeutics. AB - The tumor microenvironment (TME) has profound impacts on cancer progression and remodeling of the TME has emerged as a strategy to facilitate cancer therapy. Recently, great progress in TME modulation has been made, especially with the rapid developments in nanomedicine. In this review we outline the latest advances in remodeling of the TME based on nanotherapeutics. First, novel strategies developed to modulate the tumor extracellular matrix (ECM) are discussed, including disruption, mimicking, and intervening in tumor ECM fabrication. Then, emerging tumor-associated fibroblast (TAF)-based nanotherapeutics are reviewed, including disruption and targeting of TAFs. Furthermore, recent developments in tumor vessel disruption and normalization are discussed. Finally, emerging approaches in response to tumor hypoxia are presented, with special emphasis on delivering oxygen, generating oxygen, and targeting tumor hypoxia. PMID- 29153878 TI - Extensive processing of sediment pore water dissolved organic matter during anoxic incubation as observed by high-field mass spectrometry (FTICR-MS). AB - Dissolved organic matter (DOM) contained in lake sediments is a carbon source for many microbial degradation processes, including aerobic and anaerobic mineralization. During anaerobic degradation, DOM is partially consumed and transformed into new molecules while the greenhouse gases methane (CH4) and carbon dioxide (CO2) are produced. In this study, we used ultrahigh resolution mass spectrometry to trace differences in the composition of solid-phase extractable (PPL resin) pore water DOM (SPE-DOM) isolated from surface sediments of three boreal lakes before and after 40 days of anoxic incubation, with concomitant determination of CH4 and CO2 evolution. CH4 and CO2 production detected by gas chromatography varied considerably among replicates and accounted for fractions of ~2-4 * 10-4 of sedimentary organic carbon for CO2 and ~0.8-2.4 * 10-5 for CH4. In contrast, the relative changes of key bulk parameters during incubation, such as relative proportions of molecular series, elemental ratios, average mass and unsaturation, were regularly in the percent range (1-3% for compounds decreasing and 4-10% for compounds increasing), i.e. several orders of magnitude higher than mineralization alone. Computation of the average carbon oxidation state in CHO molecules of lake pore water DOM revealed rather non selective large scale transformations of organic matter during incubation, with depletion of highly oxidized and highly reduced CHO molecules, and formation of rather non-labile fulvic acid type molecules. In general, proportions of CHO compounds slightly decreased. Nearly saturated CHO and CHOS lipid-like substances declined during incubation: these rather commonplace molecules were less specific indicators of lake sediment alteration than the particular compounds, such as certain oxygenated aromatics and carboxyl-rich alicyclic acids (CRAM) found more abundant after incubation. There was a remarkable general increase in many CHNO compounds during incubation across all lakes. Differences in DOM transformation between lakes corresponded with lake size and water residence time. While in the small lake Svarttjarn, CRAM increased during incubation, lignin-and tannin-like compounds were enriched in the large lake Bisen, suggesting selective preservation of these rather non-labile aromatic compounds rather than recent synthesis. SPE-DOM after incubation may represent freshly synthesized compounds, leftover bulk DOM which is primarily composed of intrinsically refractory molecules and/or microbial metabolites which were not consumed in our experiments. In spite of a low fraction of the total DOM being mineralized to CO2 and CH4, the more pronounced change in molecular DOM composition during the incubation indicates that diagenetic modification of organic matter can be substantial compared to complete mineralization. PMID- 29153880 TI - Food Allergy Is an Important Risk Factor for Childhood Asthma, Irrespective of Whether It Resolves. AB - BACKGROUND: The risk of developing asthma in those with early food allergy is unknown, particularly when early life food allergy has resolved. OBJECTIVE: To understand whether challenge-proven food allergy in infancy increases the risk of asthma at age 4 years, using data from a population-based cohort. METHODS: A total of 5,276 12-month-old infants were recruited using a population-based sampling frame. Infants underwent skin prick test to egg, peanut, and sesame and those with a detectable skin prick test result had oral food challenges. At age 4 years, food challenges were repeated to determine persistence or resolution of food allergy. The association between food allergy and doctor-diagnosed asthma was examined using binomial regression in 2,789 participants. RESULTS: Children with food allergy at age 1 year had an increased risk of asthma (1 food allergy: relative risk [RR], 1.69; 95% CI, 1.29-2.21; 2 or more food allergies: RR, 2.76; 95% CI, 1.94-3.92). The risk of asthma was highest in children with food allergy and coexistent eczema in infancy (RR, 2.87; 95% CI, 2.22-3.70). Transient food allergy and persistent food allergy were both associated with an increased risk of asthma (transient egg allergy: RR, 1.92; 95% CI, 1.46-2.51; persistent egg allergy: RR, 2.60; 95% CI, 1.76-3.85). CONCLUSIONS: Asthma at age 4 years is twice as common in those with challenge-proven food allergy at age 1 year, irrespective of whether the food allergy subsequently resolves. Children with 2 or more food allergies and those with coexistent eczema were almost 3 times as likely to develop asthma compared with those with no food allergies. PMID- 29153881 TI - Relationship of Blood Eosinophil Count to Exacerbations in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Eosinophilic airway inflammation characterizes a chronic obstructive pulmonary disease (COPD) phenotype that requires more study. OBJECTIVE: To investigate the relationship of blood eosinophil count to exacerbations in COPD. METHODS: Using administrative pharmacy and health care utilization data from 2009 to 2012, we retrospectively identified patients 40 years or older with a COPD diagnosis, postbronchodilator FEV1/forced vital capacity ratio of less than 0.7, and a blood eosinophil count (N = 7,245). COPD exacerbations were defined as hospitalizations or emergency department visits with a primary diagnosis of COPD, or outpatient visits with systemic corticosteroid dispensing within +/-14 days associated with an encounter code consistent with a COPD exacerbation. The relationship between the index blood eosinophil count and the rate of COPD exacerbations in the follow-up year was determined by multivariable analyses. RESULTS: Patients with COPD were predominantly male (57.1%), white (71.8%), often current or past smokers (75.4%), and had frequent comorbidities; 19.0% had eosinophil counts of greater than or equal to 300 cells/mm3, 76.1% were classified as moderate to very severe by lung function, and the COPD exacerbation rate was 0.38 per year (95% CI, 0.37-0.40). After adjustment for potential confounders, COPD exacerbations during 1-year follow-up were significantly greater for patients with blood eosinophil counts of greater than or equal to 300 cells/mm3 (rate ratio [RR], 1.25; 95% CI, 1.10-1.43), greater than or equal to 400 cells/mm3 (RR, 1.48; 95% CI, 1.26-1.75), and greater than or equal to 500 cells/mm3 (RR, 1.76; 95% CI, 1.45-2.14), respectively, compared with patients with eosinophils lower than the cutoffs. CONCLUSIONS: In this study, high blood eosinophil counts were an independent risk factor for future exacerbations in patients with COPD, a phenotype that might benefit from therapy directed at eosinophilic-driven disease and inflammation. PMID- 29153882 TI - Identification of probiotic effector molecules: present state and future perspectives. AB - Comprehension of underlying mechanisms of probiotic action will support rationale selection of probiotic strains and targeted clinical study design with a higher likelihood of success. This will consequently contribute to better substantiation of health claims. Here, we aim to provide a perspective from a microbiology point of view that such comprehensive understanding is not straightforward. We show examples of well-documented probiotic effector molecules in Lactobacillus and Bifidobacterium strains, including surface-located molecules such as specific pili, S-layer proteins, exopolysaccharides, muropeptides, as well as more widely produced metabolites such as tryptophan-related and histamine-related metabolites, CpG-rich DNA, and various enzymes such as lactase and bile salt hydrolases. We also present recent advances in genetic tool development, microbiome analyses and model systems, as well as perspectives on how the field could further progress. This opinion is based on a discussion group organized at the annual meeting of the International Scientific Association on Probiotics and Prebiotics (ISAPP) in June 2017. PMID- 29153883 TI - Conformational dynamics and free energy of BHRF1 binding to Bim BH3. AB - The interaction between the Bim BH3 peptide and the viral protein BHRF1 is pivotal to understanding the fundamental molecular details of the mechanism used by the Epstein-Barr virus to trick the mammalian immune system. Here, we study the mechanism of binding/unbinding and compute the free energy for the association of the Bim peptide to the BHRF1 protein. Key elements of the binding mechanism are the conformational rearrangement together with a main free energy barrier of 11.5kcal/mol. The simulations show complete unbinding and rebinding of the Bim peptide to BHRF1. The peptide slowly dissociates, disrupting the hydrophobic contacts, then tilting to one side. The peptide then completely disrupts all the remaining interactions and moves into the bulk solvent. The rebinding of the peptide from the solvent to the receptor binding site occurs slowly. This is because the helix partially unfolds in the unbound state. Rebinding involves an intermediate state, in which the peptide interacts with the hydrophobic binding pocket, which mainly involves Leu 62, Arg 63, Ile 65, and Phe 69. This novel intermediate structure forms 65 contacts with the receptor before the peptide again reaches the bound state. The standard binding free energy value is close to the experimental Kd in the nanomolar range. Finally, we observe how the breathing motions of alpha3-alpha4 are coupled with the binding/unbinding of the Bim BH3 peptide. The structure of the intermediate can be used for designing novel peptide inhibitors of the BHRF1 protein. PMID- 29153884 TI - Reactivation of varicella-zoster virus in two immunosuppressed patients. PMID- 29153885 TI - Are the Results of the Prostate Testing for Cancer and Treatment Trial Applicable to Contemporary Prostate Cancer Patients Treated with Radical Prostatectomy? Results from Two High-volume European Institutions. AB - : The Prostate Testing for Cancer and Treatment (ProtecT) trial reported excellent outcomes for patients with localized prostate cancer (PCa) managed with radical prostatectomy (RP), radiotherapy, or active monitoring. We aimed at assessing the generalizability of the ProtecT trial to contemporary patients undergoing RP at two high-volume institutions. Overall, 29147 PCa patients treated with RP between 1999 and 2016 were included. We evaluated changes in disease characteristics over time. Competing-risk analyses estimated the 10-yr cancer-specific mortality (CSM) and other-cause mortality (OCM) rates. Overall, 20598 (71%) patients were eligible for the ProtecT trial, ranging from 76% in 1999-2005 to 67% in 2014-2016. The proportion of prostate-specific antigen (PSA) >=20ng/ml, biopsy grade group 4-5, and high-risk disease increased over time (all p<0.001). Among men potentially eligible for the ProtecT trial included in our study, median PSA and grade group 4-5 were higher as compared with the ProtecT trial (6.5 vs 4.7ng/ml and 9% vs 2%), especially in individuals treated in more recent years (7.1ng/ml and 16% for 2014-2016). Median follow-up was 50 mo. When considering patients eligible for the ProtecT trial, the 10-yr OCM rate exceeded the CSM rate (7% vs 2%). Conversely, when focusing on patients not eligible due to disease aggressiveness, the risk of CSM exceeded that of OCM (10% vs 7%). Clinicians should carefully consider the inverse stage migration toward more aggressive disease among surgical candidates in more recent years. Individuals not eligible for the ProtecT trial are more likely to die from PCa than from OCM, thus being the optimal candidates for testing the role of primary treatments. PATIENT SUMMARY: Contemporary prostate cancer surgery candidates harbor more aggressive disease features at presentation as compared with men included in the Prostate Testing for Cancer and Treatment (ProtecT) trial and are, in turn, at an increased risk of progression and mortality. Clinicians should take this into consideration when generalizing the results of the ProtecT trial with a particular emphasis on the oncologic safety of active monitoring in contemporary patients not included in structured prostate-specific antigen-based screening programs. PMID- 29153886 TI - [Incidental finding of an adrenal lesion]. PMID- 29153887 TI - [Gallbladder metastasis of melanoma: Immunohistochemical and molecular data of a case and review of the literature]. AB - We report the case of a 57-year-old man, who is hospitalized for the surgery of a gallbladder mass associated by an increase in fluorodeoxyglucose-activity on positron emission tomography/computed tomography scan. This is an incidental finding occurring during monitoring of a skin melanoma. A cholecystectomy is performed. Microscopic examination identified an infiltration of the gallbladder wall by a proliferation of atypical pigmented spindled melanocytes with numerous mitoses. The immunohistochemical analysis confirmed the melanocytic nature of this proliferation with the staining of HMB-45, S100 protein and Melan-A. A complementary immunohistochemical (p16, desmin and BRAFV600E) and molecular (BRAF sequencing) study is performed. The results are consistent with the hypothesis of a gallbladder metastasis of a cutaneous melanoma is proposed. Gallbladder metastases of melanoma are exceptional. The aim of our work is to describe a new case with immunohistochemical and molecular characterization, to review the literature on this topic and to consider the main differential diagnosis (primary malignant melanoma of the gallbladder). PMID- 29153888 TI - [The 2015 classification of lung adenocarcinomas: Reproducibility in a Tunisian department specialised in thoracic pathology]. AB - INTRODUCTION: The new classification of lung cancer contains modifications of terminology and a new subdivision of the tumors with the most relevant modifications concerning the group of adenocarcinomas. The latter has been increasing and represents nowadays the most frequent type. Our aim was to assess the reproducibility of the new classification through the experience of a Department of Pathology specialized in thoracic pathology. METHODS: Our study included initially 106 cases diagnosed as adenocarcinomas and reviewed by 2 pathologists and 1 referee. Five cases were ruled out because they corresponded to squamous carcinoma according to the immunohistochemical findings. The same number of slides was reviewed without a limit of time. Statistical analysis was performed using the SPSS software. The Kappa index was estimated and a second coefficient: rho was analyzed. RESULTS: A total concordance was noticed in 82 cases (81.2%) and a discordance was noticed in 19 cases (18.8%). The agreement degree was good with an index Kappa estimated to 0.743 and a rho index reaching 0.763. CONCLUSION: Our study highlights the good reproducibility of the 2015 WHO classification of lung cancer among a trained team. Whereas, in order to improve the reproducibility of such a classification, even in non specialised departments, a training of the pathologists is necessary in order to highlight the prognostic impact of this classification. PMID- 29153889 TI - 3D-QSAR studies on indole and 7-azoindole derivatives as ROCK-2 inhibitors: An integrative computational approach. AB - Rho Kinases (ROCK) has been found to regulate a wide range of fundamental cell functions such as contraction, motility, proliferation, and apoptosis. Recent experiments have defined new functions of ROCKs in cells, including centrosome positioning and cell-size regulation, which might contribute to various physiological and pathological states. In this study, we have performed pharmacophore modeling and 3D QSAR studies on a series of 36 indoles and 7 azoindoles derivatives as ROCK2 inhibitors to elucidate the structural variations with their inhibitory activities. Ligand based CoMFA and CoMSIA models were generated based on three different alignment methods such as systematic search, simulated annealing and pharmacophore. A total of 15 CoMFA models and 27 CoMSIA were generated using different alignments. One model from each alignment is selected based on the statistical values. Contour maps of the selected models were compared, analysed and reported. The 3D QSAR study revealed that electro positive group linked to the methoxy-benzene ring position of the structure will enhance the biological activity and bulkier substitutions are preferred in the methyl dihydroindole region. Also, it is found that the hydrogen bond donor substituted at the R1 position enhances the inhibitory activity. In future, this study would give proper guidelines to further enhance the activity of novel inhibitors for ROCK2. PMID- 29153890 TI - Molecular dynamics-assisted pharmacophore modeling of caspase-3-isatin sulfonamide complex: Recognizing essential intermolecular contacts and features of sulfonamide inhibitor class for caspase-3 binding. AB - The identification of isatin sulfonamide as a potent small molecule inhibitor of caspase-3 had fuelled the synthesis and characterization of the numerous sulfonamide class of inhibitors to optimize for potency. Recent works that relied on the ligand-based approaches have successfully shown the regions of optimizations for sulfonamide scaffold. We present here molecular dynamics-based pharmacophore modeling of caspase-3-isatin sulfonamide crystal structure, to elucidate the essential non-covalent contacts and its associated pharmacophore features necessary to ensure caspase-3 optimal binding. We performed 20ns long dynamics of this crystal structure to extract global conformation states and converted into structure-based pharmacophore hypotheses which were rigorously validated using an exclusive focussed library of experimental actives and inactives of sulfonamide class by Receiver Operating Characteristic (ROC) statistic. Eighteen structure-based pharmacophore hypotheses with better sensitivity and specificity measures (>0.6) were chosen which collectively showed the role of pocket residues viz. Cys163 (S1 sub-site; required for covalent and H bonding with Michael acceptor of inhibitors), His121 (S1; pi stack with bicyclic isatin moiety), Gly122 (S1; H bond with carbonyl oxygen) and Tyr204 (S2; pi stack with phenyl group of the isatin sulfonamide molecule) as stringent binding entities for enabling caspase-3 optimal binding. The introduction of spatial pharmacophore site points obtained from dynamics-based pharmacophore models in a virtual screening strategy will be helpful to screen and optimize molecules belonging to sulfonamide class of caspase-3 inhibitors. PMID- 29153891 TI - Molecular modeling of cationic porphyrin-anthraquinone hybrids as DNA topoisomerase IIbeta inhibitors. AB - Human DNA Topoisomerase II has been regarded as a promising target in anticancer drug discovery. In the present study, we designed six porphyrin-anthraquinone hybrids bearing pyrazole or pyridine group as meso substituents and evaluated their potentials as DNA Topoisomerase IIbeta inhibitor. First, we investigated the binding orientation of porphyrin hybrids into DNA topoisomerase IIbeta employing AutoDock 4.2 and then performed 20-ns molecular dynamics simulations to see the dynamic stability of each porphyrin-Topo IIbeta complex using Amber 14. We found that the binding of porphyrin hybrids occured through intercalation and groove binding mode in addition interaction with the amino acid residues constituting the active cavity of Topo IIbeta. Each porphyrin-Topo IIbeta complex was stabilized during 20-ns dynamics simulations. The MM-PBSA free energy calculation shows that the binding affinities of porphyrin hybrids were modified with the number of meso substituent. Interestingly, the affinity of all porphyrin hybrids to Topo IIbeta was stronger than that of native ligand (EVP), indicating the potential of the designed porphyrin to be considered in experimental research. PMID- 29153892 TI - Penalized estimation of sparse concentration matrices based on prior knowledge with applications to placenta elemental data. AB - Identifying patterns of association or dependency among high-dimensional biological datasets with sparse precision matrices remains a challenge. In this paper, we introduce a weighted sparse Gaussian graphical model that can incorporate prior knowledge to infer the structure of the network of trace element concentrations, including essential elements as well as toxic metals and metaloids measured in the human placentas. We present the weighted L1 penalized regularization procedure for estimating the sparse precision matrix in the setting of Gaussian graphical models. First, we use simulation models to demonstrate that the proposed method yields a better estimate of the precision matrix than the procedures that fail to account for the prior knowledge of the network structure. Then, we apply this method to estimate sparse element concentration matrices of placental biopsies from the New Hampshire Birth Cohort Study. The chemical architecture for elements is complex; thus, the method proposed herein was applied to infer the dependency structures of the elements using prior knowledge of their biological roles. PMID- 29153894 TI - Design and construction of a tennis elbow brace with light-emitting diode in subjects with lateral epicondylitis. PMID- 29153893 TI - Selective ATP competitive leads of CDK4: Discovery by 3D-QSAR pharmacophore mapping and molecular docking approach. AB - The discovery of ATP competitive CDK4 inhibitors is an on-going challenging task in cancer therapy. Here, an attempt has been made to develop new leads targeting ATP binding site of CDK4 by applying 3D-QSAR pharmacophore mapping and molecular docking methods The outcome of 6 leads offers a significant contribution for selective CDK4 inhibition, since they show potential binding interactions with Val96, Arg101, and Glu144 residues of CDK4, that are unique and from other kinases. It is worth noting that there is a striking similarity in binding interactions of the leads and known CDK4 inhibitors, namely Abemaciclib, Palbociclib and Ribociclib. Further key features, including high dock score value, good predicted activity, scaffold diversity, and the acceptable ADME profile of leads, provide a great opportunity for the development of highly potent and selective ATP competitive inhibitors of CDK4. PMID- 29153895 TI - Design and construction of the static progressive flexion orthosis. PMID- 29153896 TI - Sequential CT Findings in Patients With Non-small-cell Lung Cancer Receiving Nivolumab. AB - BACKGROUND: Nivolumab is a novel immunotherapy that was recently approved for treatment of advanced non-small-cell lung cancer (NSCLC). Patients treated with checkpoint inhibitors may show variable computed tomography (CT) features on follow-up imaging, and it is unclear how reliable conventional response criteria are to determine patient management and outcomes. We report the spectrum of sequential CT findings in patients with advanced stage lung cancer who received nivolumab in an effort to better inform appropriate imaging strategies. MATERIALS AND METHODS: We identified all patients at our institution with advanced NSCLC who received nivolumab. Pre- and posttreatment CT scans were reviewed and categorized based on radiographic response to therapy. Demographic data as well as survival data were recorded. RESULTS: There were 34 patients with advanced NSCLC who received nivolumab with sufficient follow-up data. Nineteen patients were classified as responders to treatment; 6 (32%) of 19 showed improvement on their initial follow-up CT and had an average survival of 11.2 months, whereas 13 (68%) of 19 responders initially had stable or progressive disease on CT with an average survival of 11.6 months. Fifteen patients were classified as nonresponders to treatment with an average survival of 3.4 months. CONCLUSION: Novel immunotherapies such as nivolumab mechanistically differ from conventional chemotherapy. Some patients have improved survival despite initial radiographic progression of disease. Our findings underscore the heterogeneous radiographic appearance at follow-up CT in patients with lung cancer who ultimately respond to nivolumab. PMID- 29153897 TI - Comparison of Single- and Three-fraction Schedules of Stereotactic Body Radiation Therapy for Peripheral Early-stage Non-Small-cell Lung Cancer. AB - BACKGROUND: To compare the clinical outcomes of patients with early-stage non small-cell lung cancer (NSCLC) who had undergone either single-fraction (SF) or three-fraction (TF) stereotactic body radiation therapy (SBRT) at a single institution during over 8-year period. PATIENTS AND METHODS: Patients with peripherally located early-stage NSCLC who had undergone SBRT from February 2007 to November 2015 were included in the present study. SBRT was delivered without heterogeneity correction. Data were retrospectively reviewed and collected in an institutional review board-approved database. R software (version 3.3.2) was used for statistical analysis. RESULTS: Of 159 total lung tumors, 65 lesions received 30 Gy (median, 30 Gy) in 1 fraction, and 94 lesions received 48 to 60 Gy (median, 60 Gy) in 3 fractions. Patients with a Karnofsky performance status < 80 were more common in the SF-SBRT cohort (P = .050). After a median follow-up of 22.2 and 26.2 months for the SF-SBRT and TF-SBRT cohorts, respectively (P = .29), no statistically significant difference was found in overall survival (P = .86), progression-free survival (P = .95), local failure (P = .95), nodal failure (P = .91), and distant failure (P = .49) at 24 months. At 1 and 2 years, the overall survival rates were 86.1% and 63.2% for the SF-SBRT cohort and 80.8% and 61.6% for the TF-SBRT cohort, respectively. At 1 and 2 years, the local control rates were 95.1% and 87.8% for the SF-SBRT cohort and 92.7% and 86.2% for the TF-SBRT cohort, respectively. Both regimens were well tolerated. CONCLUSION: Despite more patients with poor performance status in the SF-SBRT cohort, the SF- and TF-SBRT regimens showed no differences in clinical outcomes. SF-SBRT is now our standard approach. PMID- 29153898 TI - The Significance of the PD-L1 Expression in Non-Small-Cell Lung Cancer: Trenchant Double Swords as Predictive and Prognostic Markers. AB - Lung cancer is the leading cause of death due to cancer worldwide. Surgery, chemotherapy, and radiotherapy have been the standard treatment for lung cancer, and targeted molecular therapy has greatly improved the clinical course of patients with non-small-cell lung cancer (NSCLC) harboring driver mutations, such as in epidermal growth factor receptor and anaplastic lymphoma kinase genes. Despite advances in such therapies, the prognosis of patients with NSCLC without driver oncogene mutations remains poor. Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC. The PD-L1 expression on the surface of tumor cells has emerged as a potential biomarker for predicting responses to immunotherapy and prognosis after surgery in NSCLC. However, the utility of PD-L1 expression as a predictive and prognostic biomarker remains controversial because of the existence of various PD-L1 antibodies, scoring systems, and positivity cutoffs. In this review, we summarize the data from representative clinical trials of PD-1/PD-L1 immune checkpoint inhibitors in NSCLC and previous reports on the association between PD-L1 expression and clinical outcomes in patients with NSCLC. Furthermore, we discuss the future perspectives of immunotherapy and immune checkpoint factors. PMID- 29153899 TI - Permeation of acetate across sheep ruminal epithelium is partly mediated by an anion channel. AB - The present study pursued the question if an anion channel could be partly responsible for the transport of acetate in the isolated ovine ruminal epithelium. Using the Ussing chamber technique, changes of short-circuit current (Isc) induced by mucosal or serosal addition of acetate was investigated. To further evaluate the Isc changes induced by acetate the epithelia were preincubated with ouabain or 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS). In addition, unidirectional flux rates of 14C-acetate were measured at different transepithelial potential difference (Vt). At Vt=0mV, acetate addition to the mucosal side of epithelia incubated in ouabain/DIDS free solution resulted in an Isc decrease, whereas application to the serosal side induced an Isc increase. Absolute Isc changes were significantly larger after serosal than after mucosal acetate addition. Ouabain pre-incubation abolished these side-specific differences. Pre-incubation with DIDS on the mucosal side inhibited the current induced by subsequent mucosal acetate addition in a voltage dependent manner, whereas serosal DIDS pre-incubation had no effect on acetate-induced changes of Isc. Mucosal-to-serosal acetate flux was partly voltage-dependent. The serosal-to mucosal flux of acetate was not influenced by Vt. The asymmetric changes of Isc after acetate application and the Vt dependence of the DIDS inhibition on the mucosal side indicate a partly electrogenic transcellular permeation of acetate which includes an apically located acetate conductance. It is suggested that this conductance may be important for epithelial cell homeostasis. PMID- 29153900 TI - Clinicopathological findings in sick dogs naturally infected with Leishmania infantum: Comparison of five different clinical classification systems. AB - A wide spectrum of clinical and clinicopathological findings in dogs with canine leishmaniosis (CanL) due to Leishmania infantum exists. However, the majority of clinical descriptions have been published a long time ago and recent studies in Europe are almost lacking. In addition, clinical classification of sick dogs is not well-standardized, with different classification systems used by clinical and epidemiological studies, making comparison of studies a difficult task. The aims of the study were to describe the clinicopathological findings of dogs naturally infected with L. infantum at the time of diagnosis and to review and compare the various clinical classification systems for CanL available in the literature. Eighty-one healthy dogs and fifty-one dogs with CanL were studied and clinical and clinicopathological data were recorded. The most common clinical findings at diagnosis were skin lesions (78.4%), lymphadenomegaly (64.7%) and weight loss (47.1%). The most frequent clinicopathological abnormalities included mild to moderate non-regenerative anemia (62.7%), lymphopenia (25.5%), hyperproteinemia (52.9%) dysproteinemia (78.4%). and proteinuria (47.8%). Renal azotemia was rare (5.9%). Only 5.9% of the patients studied were classified in similar categories (mild, moderate and severe disease) when five clinical classifications systems were compared, while 11.8% of cases were classified in similar categories when only two clinical classification systems were considered based on the fact that they included therapeutic and prognosis recommendations. In conclusion, anemia and protein-related alterations are common in dogs with CanL. In contrast, renal azotemia is infrequent despite the high percentage of diseased dogs with proteinuria, indicating kidney involvement. Adequate clinical staging system is desirable in order to establish proper management, treatment and prognosis in dogs with CanL and to facilitate the comparison of clinical and epidemiological studies. PMID- 29153901 TI - Use of 5-alpha-reductase inhibitors as alternatives to luteinizing-hormone releasing hormone (LHRH) analogs or anti-androgens for prostate downsizing before brachytherapy. AB - INTRODUCTION: Prostate hypertrophy, median lobe hypertrophy, and pubic arch interference (PAI) are relative contraindications to brachytherapy because of potential morbidity and technical considerations. GnRH analogs or non-steroidal anti-androgens are currently utilized to achieve prostatic downsizing prior to brachytherapy. However, such agents have been associated with effects on body habitus, metabolism, and quality of life. In contrast, 5-alpha reductase inhibitors (5-ARI) are far less frequently associated with these morbidities. METHODS AND MATERIALS: Patients with large gland size, median lobe hypertrophy, or PAI were offered 5-ARI therapy. Repeat transrectal ultrasound was performed at 3 or 4 months, followed by brachytherapy if resolution was achieved. If downsizing was inadequate, patients were offered continuation of 5-ARI for additional 3 months, gonadotropin-releasing hormone analog (GnRH) agonist or antiandrogen therapy, or other curative treatment. RESULTS: Of 59 patients with follow-up available, 42 (71%) were deemed to have adequate downsizing; 37 (63%) after 3 to 4 months of 5-ARI and 5 (8%) after 7 to 8 months. Seventeen patients (29%) received other treatments because of inadequate effect. Median volume reduction was 20%. Of 41 patients undergoing brachytherapy, 4 (9.7%) required temporary catheterization because of obstruction. Median follow-up after implantation was 25 months (range, 1-64). Median time for return to International Prostate Symptom Score <=5 of baseline score was 7 months (interquartile ratio, 6 13). All but 1 patient who received brachytherapy remain biochemically controlled. CONCLUSION: 5-ARI monotherapy is an alternative for downsizing in patients with hypertrophy or PAI, with more than 70% achieving adequate downsizing without use of GnRH analogs or antiandrogens. Patients who received brachytherapy experienced typical rates of postimplant urinary morbidity. PMID- 29153902 TI - Robotic Buccal Mucosal Graft Ureteroplasty for Complex Ureteral Stricture. AB - OBJECTIVE: To demonstrate robot-assisted ureterolysis and buccal mucosal graft (BMG) ureteroplasty for the management of a complex, long recurrent ureteral stricture developing after ureterolysis, and also to demonstrate the use of near infrared fluorescence (NIRF) imaging and intraoperative ureteroscopy during this procedure. METHODS: A 58-year-old man with a history of cabergoline treatment and a cardiac catheterization through the left groin presented with left flank pain and hydronephrosis. A computed tomography scan showed extensive fibrosis around the ureter and a ureteral stricture close to a tortuous left external iliac artery. A computed tomography-guided biopsy showed a benign fibrous tissue around the stricture with no increase in IgG4-expressing plasma cells. A robot-assisted ureterolysis with an omental wrap was performed. One year after the ureterolysis, the patient developed a recurrent ureteral stricture. Retrograde ureterogram showed a long, 6-cm stricture in the upper ureter. For the robotic ureteroplasty, the patient was placed in modified lateral position with port placement similar to the left pyeloplasty. Intraoperative flexible ureteroscopy and NIRF were used to define the distal extent of the stricture. For this, the ureteroscope was advanced until the stricture, and transilluminance of light from the ureteroscope was seen from the robotic camera using Firefly. Ureteral stricture was incised along its length over the ureteroscope. Two BMGs were harvested and sown together to obtain a longer graft. The graft was minimally defatted and brought in the abdomen through one of the ports. The composite graft was then sutured with 4-0 PDS as an onlay graft with the mucosal side facing toward the lumen of the ureter. Ureteroscopy was used to confirm patency, followed by stent placement. NIRF was used to confirm the viability of the ureter and the surrounding tissue. The omental flap was then harvested using a vessel sealer, fixed to the psoas fascia beneath the ureter, and then wrapped over the reconstructed ureter. The omental flap was also tacked to the side of the BMG with a suture to promote blood supply. RESULTS: The procedure was uncomplicated with an operative time of 280 minutes, an estimated blood loss of 75 mL, and an uneventful hospital stay. MAG3 Renal scan after 3 and 6 months of surgery showed no recurrence or obstruction. CONCLUSION: Despite the limitation of being a single case with only a 6-month follow-up, our report shows that robot-assisted BMG is a safe option for the reconstruction of long upper ureteral strictures. This procedure may be a less morbid alternative to an autotransplant and ileal ureter in these patients. However, outcomes need to be studied in a larger series with a longer follow-up. PMID- 29153903 TI - Nitrification within composting: A review. AB - Composting could be regarded as a process of processes because it entails a number of complex chemical and microbiological reactions and transformations. Nitrification is one of such processes that normally takes place during the curing phase. This process has been studied in detail for wastewater treatment, and it is becoming an extensively studied topic within composting. In the past, nitrate presence in compost has been clearly perceived as a maturation indicator; however, nowadays, nitrate formation is also conceived as a way of conserving nitrogen in compost. Nitrification is a process closely linked to other processes such as ammonification and the possible loss of ammonia (NH3). Nitrification is defined as conversion of the most reduced form of nitrogen (NH3) to its most oxidized form (i.e. nitrate) and it is performed in two steps which are carried out by two different groups of microorganisms: the ammonia-oxidizing bacteria or archaea (AOB/AOA) and the nitrite-oxidizing bacteria (NOB). The objectives of this review are: a) to gather relevant information on nitrification, which can specifically occur during composting, b) to outline ultimate findings described by the literature in order to increase the understanding and the application of nitrification within composting, and c) to outline future research direction. PMID- 29153904 TI - Comparison of cellulose vs. plastic cigarette filter decomposition under distinct disposal environments. AB - It is estimated that 4.5 trillion cigarette butts are discarded annually, making them numerically the most common type of litter on Earth. To accelerate their disappearance after disposal, a new type of cigarette filters made of cellulose, a readily biodegradable compound, has been introduced in the market. Yet, the advantage of these cellulose filters over the conventional plastic ones (cellulose acetate) for decomposition, remains unknown. Here, we compared the decomposition of cellulose and plastic cigarettes filters, either intact or smoked, on the soil surface or within a composting bin over a six-month field decomposition experiment. Within the compost, cellulose filters decomposed faster than plastic filters, but this advantage was strongly reduced when filters had been used for smoking. This indicates that the accumulation of tars and other chemicals during filter use can strongly affect its subsequent decomposition. Strikingly, on the soil surface, we observed no difference in mass loss between cellulose and plastic filters throughout the incubation. Using a first order kinetic model for mass loss of for used filters over the short period of our experiment, we estimated that conventional plastic filters take 7.5-14 years to disappear, in the compost and on the soil surface, respectively. In contrast, we estimated that cellulose filters take 2.3-13 years to disappear, in the compost and on the soil surface, respectively. Our data clearly showed that disposal environments and the use of cellulose filters must be considered when assessing their advantage over plastic filters. In light of our results, we advocate that the shift to cellulose filters should not exempt users from disposing their waste in appropriate collection systems. PMID- 29153905 TI - Combustion characteristics of biodried sewage sludge. AB - In this study, effects of biodrying on the characteristics of sewage sludge and the subsequent combustion behavior were investigated. 7-Day of biodrying removed 49.78% of water and 23.17% of VS initially contained in the sewage sludge and increased lower heating value (LHV) by 37.87%. Meanwhile, mass contents of C and N decreased from 36.25% and 6.12% to 32.06% and 4.82%, respectively. Surface of the biodried sewage sludge (BDSS) appeared granulated and multi-porous, which was thought to facilitate air transfer during combustion. According to thermogravimetric (TG) analysis coupled with mass spectrometer (MS) with a heating rate of 10 degrees C/min from 35 degrees C to 1000 degrees C, thermally-dried sewage sludge (TDSS) and BDSS lost 74.39% and 67.04% of the initial mass, respectively. In addition, combustibility index (S) of BDSS (8.67 * 10-8 min-2 K-3) was higher than TDSS. TG-MS analyses also showed that less nitrogenous gases were generated from BDSS than TDSS. It was again showed that the average CO and NO concentrations in exit gas from isothermal combustion of BDSS were lower than those from TDSS, especially at low temperatures (<=800 degrees C). Based on these results, it was concluded that biodrying of sewage sludge was an energy-efficient water-removal method with less emission of air pollutants when BDSS was combusted. PMID- 29153906 TI - Classical osseous lesions leading to an unsuspected diagnosis. PMID- 29153907 TI - [Violent outburst from teenagers in the pediatric emergency room: Complex cases]. AB - INTRODUCTION: Teenagers admitted to the emergency room for a violent attacks episode are increasingly numerous. The source of agitation is multifactorial for these teenagers, often with a complex course. They jeopardize hospital wards, which are often ill-suited for and overwhelmed during these outbursts. This study aims to identify and describe all the teenagers admitted to the hospital over 1 year for a violent outburst and discuss their management. METHODS AND EQUIPMENT: Retrospective and descriptive study of teenagers admitted to the pediatric emergency department of the Nantes University Hospital for a violent outburst in 2015. RESULTS: During this 1-year study, 99 teenagers out of a total of 182 consultations were admitted for a violent outburst. We noted that 85% of them had a previous history of a violent outburst, 70% of them were seeing a psychologist, and 56% were followed by the child welfare services. Most of the outbursts took place at home and were hetero-aggressive. Upon arrival at the pediatric emergency ward, 90% of the teenagers had calmed down. The mean time spent in the emergency ward was 3h42min. Finally, 31% of the teenagers were hospitalized in the general pediatric unit, 14% in the children's psychiatric department, and 8% in the adult psychiatry ward. CONCLUSION: We observed a high proportion of complex cases in the teenagers admitted to our emergency department for a violent outburst. These teenagers in distress, with a complex previous history, illustrated the relation between violence against themselves and their own violent behavior toward others. Developing short-stay units for a temporary isolation could be an advantageous multidisciplinary approach to allow somatic, psychological, and social evaluation of these vulnerable patients. PMID- 29153908 TI - [Analysis of obstetric-pediatric care in the perinatal period. Are births before 31 weeks' gestation in level 2B maternity units avoidable?] AB - INTRODUCTION: Regionalization of perinatal care has been developed to improve the survival of preterm babies. The mortality rate is higher among very premature infants born outside level-3 maternity units. The objective of this study was to evaluate the preventability of these very premature births occurring outside recommendations within level-2B maternity units. The secondary objective was to describe the care of premature infants between 23 and 24 weeks. METHODS: This is a single-center retrospective qualitative study of the care delivery pathways. Thirty-one deliveries in which the fetus was alive between 23 and 30 weeks+6 days occurred in a level-2B maternity unit in Thionville, France, between 1 January 2013 and 31 December 2015. After oral presentation of the cases, a level 2-3 multidisciplinary committee of experts in Lorraine evaluated the preventability criteria and reasons, and divided the deliveries into three groups: (i) birth in level-2B institutions avoidable, (ii) inevitable with factors related to the mother or the organization of care, (iii) with no inevitable factors. RESULTS: Out of the 31 deliveries included, the committee classified six deliveries as preventable, 14 as inevitable with factors, and 11 as inevitable with no factors. The criteria for preventability of birth in a level-2B unit were underestimation of maternal and fetal risk, an erroneous initial estimate of term or preterm labor, and two births in the upper limits of the French recommendations for in utero transfer. Nineteen of the 35 premature infants before 31 weeks' gestation died, 16 children were transferred to a level-3 maternity ward, and 16 children were allowed to go home. CONCLUSION: Analysis of the obstetrical-pediatric care course by an expert committee determined the preventability of the average birth and prematurity in level-2B maternity units in Lorraine for a small but significant number of cases. The local regionalization of neonatal care could be improved by the application of this method of analysis to other maternity wards in the Lorraine network. PMID- 29153909 TI - [A case of Orf disease complicated by erythema multiforme]. AB - Ecthyma contagiosum, or Orf, is a specific infection of small ruminants accidentally reaching humans. Few cases have been reported in the literature to date. We report here a case of ecthyma contagiosum occurred in a 9-year-old girl after contact with a flock of ecthyma sheep. This Orf was then complicated by superinfection and then by erythema multiforme. Orf is often underdiagnosed, probably because of small ruminant breeders' knowledge of this disease and its benignity in humans. It is caused by a very resistant Parapoxvirus in the environment. The diagnosis is clinical and anamnestic. Orf is therefore a benign pathology, the course of which is spontaneously favorable outside any specific treatment. However, it is important to prevent certain complications such as superinfections with appropriate local care. Other complications cannot be prevented and require appropriate care. PMID- 29153910 TI - [Multiple cardiac rhabdomyomas revealing tuberous sclerosis in a neonate]. PMID- 29153911 TI - Unusual osseous presentation of Wilson disease in a child. PMID- 29153912 TI - [Acute epiglottitis due to Haemophilus influenzae b: A severe consequence of increased skepticism about vaccination]. AB - Acute epiglottis is a life-threatening disease in relation with the occurrence of an acute upper airway obstruction. Its incidence has fallen dramatically since the widespread introduction of Haemophilus influenzae type b (Hib) conjugate vaccine. We report the case of a 26-month-old child who was not fully immunized and presented acute upper airway respiratory distress with fever. The symptoms quickly evolved to a respiratory arrest condition with bradycardia, revealing epiglottitis due to Hib. Despite high immunization coverage with great efficacy and occurrence of herd immunity, this entity still exists because of the French population's skepticism of the routine vaccination schedule. PMID- 29153913 TI - [Heart and brain in a newborn]. PMID- 29153914 TI - Determination of orientin in Trollius chinensis using ultrasound-assisted extraction and high performance liquid chromatography: Several often-overlooked sample preparation parameters in an ultrasonic bath. AB - The erratic pressure intensities and cavitation exhibited in an ultrasonic bath pose various during practical application. To achieve the most efficient experimental design, this manuscript aims to discover violently sites that are subject to the effect of slight changes in position on cavitation and ultrasound intensity distributed in the ultrasonic bath. In addition, optimization several often over-looked ultrasound parameters and experimental conditions, are intended to place the reaction vessel properly and operate under suitable experimental conditions to obtain the maximum yield of target analyte. In this study, an investigation of the various ultrasound intensities and cavitation in ultrasonic bath space were conducted with the help of the orientin yield using ultrasound assisted extraction. Conventional parameters such as the volume fraction of ethanol, liquid-solid ratio, ultrasound irradiation power, time and frequency, and reaction temperature were investigated, all of which affect the extractive yield factors. Also several often over-looked parameters such as the extraction vessel position in the ultrasonic bath base, the distance between the bottom of the extraction vessel and the ultrasonic bath base, the diameter, the shape and the texture of the extraction vessel, height of the liquid medium and the ultrasound propagating medium salt concentration in the ultrasonic bath were tested exhaustively in this study. These results can therefore serve as a guide to optimize the usage of the ultrasonic bath for future applications. PMID- 29153915 TI - In situ immobilization of layered double hydroxides as stationary phase for capillary electrochromatography. AB - Layered double hydroxides (LDHs) have gained much attention in absorption and extraction fields due to their special structure and properties like high porosity, large surface area and excellent anion exchange capacity. However, LDHs are rarely used in capillary electrochromatography (CEC) by date due to the lack of appropriate immobilization method. In this work, by utilizing the unique coordination bonding between metal ions on LDHs and catechol groups on polydopamine layer, a polydopamine modification method was developed for in situ immobilization of LDHs on the inner surface of fused silica capillary. The formation of CoAl-LDHs on polydopamine-immobilized capillary has been characterized by scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction. The CoAl-LDHs-modified open-tubular capillary exhibited good separation performance towards neutral compounds by cation-pi interaction and hydrophobic interaction. More interestingly, by virtue of the coordination interaction between metal ions on LDHs layer and phenolic hydroxyl groups, the LDHs-modified capillary has shown good separation efficiency towards various phenolic compounds. Repeatability of the column was studied, with the relative standard deviations for intra-day, inter-day and column-to-column lower than 4.3%. PMID- 29153916 TI - A case with CMTX1 disease showing transient ischemic-attack-like episodes. AB - Charcot-Marie-Tooth (CMT) disease is a hereditary neurologic disease which affects the sensorial and motor fibers of the peripheral nerves. CMTX1 is an X linked dominantly inherited subtype of CMT and is caused by mutations in gap junction beta 1 gene (GJB1). A small proportion of GJB1 mutations are associated with recurrent central nervous system findings. We describe a 15-year-old male patient with CMTX1 who had stroke-like findings along with foot deformities and peripheral neuropathy. Strokes and stroke-like attacks are rarely seen in children and adolescents. Herein, neurological signs, MRI findings and genetic results of a CMTX1 case are presented and discussed. PMID- 29153917 TI - O6-methylguanine-DNA-methyltransferase immunostaining intensity in glioblastoma. AB - Immunohistochemistry (IHC) for O6-methylguanine-DNA-methyltransferase (MGMT) has shown heterogeneous results. Cell staining intensity has not been included as a quantifiable variable in IHC analyses. We performed MGMT IHC in 29 patients diagnosed as glioblastoma classifying cells into three categories based on nuclear staining intensity compared with adjacent endothelium. The median proportions of strong-moderate, weak and no staining cells were 10%, 16% and 71%, respectively. The proportion of positive cases for MGMT expression varies from 38% to 52% depending on the classification of weakly stained cells. This letter challenges previous studies that have not included intensity as a variable for IHC analysis. PMID- 29153918 TI - Nursing Music Protocol and Postoperative Pain. AB - Pain has always been a major concern for patients and nurses during the postoperative period. Therapies, medicines, and protocols have been developed to improve pain and anxiety but have undesirable risks to the patient. Complementary and alternative medicine therapies have been studied but have not been applied as regular protocols in the hospital setting. Music is one type of complementary and alternative medicine therapy that has been reported to have favorable results on reducing postoperative pain, anxiety, and opioid usage. However, music lacks a protocol that nurses can implement during the perioperative process. This paper is an in-depth literature review assessing a best practice recommendation and protocol that establishes a consensus in the use of music therapy. The results suggest that music therapy may consist of calming, soft tones of 60-80 beats per minute for at least 15-30 minutes at least twice daily during the pre- and postoperative periods. It is suggested that music only be used in conjunction with standards of care and not as the primary intervention of pain or anxiety. This evidence suggests that proper use of music therapy can significantly reduce surgical pain. Implementing these protocols and allowing the freedom of nursing staff to use them may lead to greater reductions in surgical pain and anxiety and a reduction in opioid use. PMID- 29153919 TI - Patient and Health Care Provider Responses from a Prospective, Double-Blind, Randomized Controlled Trial Comparing Vapocoolant Spray versus Placebo Spray in Adults Undergoing Venipuncture in the Emergency Department. AB - BACKGROUND: Painful medical procedures are common. Topical anesthetics are easily applied, rapid onset, inexpensive, and avoid injection pain and needlestick injury. The aims of this study, using patient and health care provider questionnaires, were to answer the following questions: (1) Does vapocoolant spray decrease venipuncture pain? (2) Would patients be satisfied with and use a vapocoolant spray in the future? (3) Would providers be satisfied with and use a vapocoolant spray in the future? DESIGN: Adults (18-80 years) in a hospital emergency department (ED) were randomly assigned to sterile water placebo spray (S) (N = 50) or vapocoolant spray (V) (N = 50) before venipuncture. Questionnaires were completed by patients undergoing venipuncture (N = 100) and the health care providers (N = 100) who performed the venipuncture (total questionnaires = 200) as part of a prospective, double-blind, randomized controlled trial comparing the efficacy and safety of vapocoolant spray compared with placebo spray in patients undergoing venipuncture in the ED. RESULTS: Patient and venipuncture variables were not significantly different for the two groups (S vs. V). Responses to the questionnaires were significantly different for the S versus V groups for both the patients and the health care providers. Patient questionnaires: Did you have less pain with spray? S 14%, V 76% (p < .001). Compared with previous blood draws, the spray was much more painful/more painful: S 10%, V 6%; same: S 76%, V 16%; less painful/much less painful: S 14%, V 78% (p < .001). How satisfied were you with the spray? Satisfied/very satisfied: S 20%, V 74% (p < .001). Would you use this spray in future? Yes S 20%, V 80% (p < .001). Provider results: The patient had less pain with the use of the spray: S 14%, V 78% (p < .001). How satisfied were you with the use of the spray? Satisfied/very satisfied: S 12%, V 82% (p < .001). Would you use this spray in the future? Yes S 24%, V 84% (p < .001). CONCLUSIONS: The use of a vapocoolant spray in adult ED patients undergoing venipuncture significantly decreased venipuncture pain, was associated with high patient and provider satisfaction, and both patients and providers would use a vapocoolant spray in the future for venipuncture and other painful procedures. PMID- 29153920 TI - Pain Assessment and Management for Older Patients with Dementia in Hospitals: An Integrative Literature Review. AB - Previous studies have suggested that pain in older people with dementia is often underestimated and undertreated in acute hospitals. Undermanaged pain negatively affects a person's recovery and prolongs hospital stays. However, the issues related to pain assessment and management by nurses for this group have not been fully understood. (1) To synthesize evidence about pain assessment and management for older people with dementia in hospital settings, and (2) to discuss implications for nurses and their practice. Integrative literature review. A systematic search of evidence-based research from six electronic databases (CINAHL, MEDLINE, ProQuest, Cochrane, JBI, and Scopus) was conducted for the period of 2006-2016. Following Cooper's integrative review framework and a systematic screening process, the articles included were analyzed and synthesized to identify the common issues and relationships. Fourteen empirical research articles were examined and synthesized. Two main categories were identified and include: the nursing practice of pain assessment in older patients with dementia is less than optimal, and the nursing practice of pain management for this group varies. The lack of initiation of pain assessment and use of pain assessment tools may contribute to the inadequate pain management by nurses. Whereas this review uncovered the extent and challenges related to pain assessment and management, previous studies were explorative and descriptive. The findings from the review provide nurses with an opportunity to establish empirical evidence that may improve nursing practice of pain assessment and management for older people with dementia in hospital settings. PMID- 29153921 TI - Zika virus epidemic in Puerto Rico: Health justice too long delayed. AB - Over the course of 16 months, more than 35400 cases of Zika virus infection have been confirmed in Puerto Rico. This represents 85% of all cases reported in the USA and its territories. The Zika epidemic is exposing the profound failure of socioeconomic policies, as well as the failure to protect sexual and reproductive health rights in Puerto Rico. Considering the high poverty rates, high levels of sexuality-related stigma, poor quality sex education, limited access to contraception, and limited participation in the allocation of resources for prevention, it is unreasonable to focus public health efforts to prevent Zika virus infection on vector control. The allocation and equitable management of resources for research and intervention are required in order to understand and address the barriers to and facilitators of prevention at the individual, social, and structural levels. Further, the impact of efforts to tackle the social determinants of the Zika virus epidemic on the island should be assessed. PMID- 29153922 TI - E-health in Switzerland: The laborious adoption of the federal law on electronic health records (EHR) and health information exchange (HIE) networks. AB - Within the framework of a broader e-health strategy launched a decade ago, in 2015 Switzerland passed a new federal law on patients' electronic health records (EHR). The reform requires hospitals to adopt interoperable EHRs to facilitate data sharing and cooperation among healthcare providers, ultimately contributing to improvements in quality of care and efficiency in the health system. Adoption is voluntary for ambulatories and private practices, that may however be pushed towards EHRs by patients. The latter have complete discretion in the choice of the health information to share. Moreover, careful attention is given to data security issues. Despite good intentions, the high institutional and organisational fragmentation of the Swiss healthcare system, as well as the lack of full agreement with stakeholders on some critical points of the reform, slowed the process of adoption of the law. In particular, pilot projects made clear that the participation of ambulatories is doomed to be low unless appropriate incentives are put in place. Moreover, most stakeholders point at the strategy proposed to finance technical implementation and management of EHRs as a major drawback. After two years of intense preparatory work, the law entered into force in April 2017. PMID- 29153924 TI - Considerations to improve the safety of cervical spine manual therapy. AB - Manipulation and mobilisation of the cervical spine are well established interventions in the management of patients with headache and/or neck pain. However, their benefits are accompanied by potential, yet rare risks in terms of serious adverse events, including neurovascular insult to the brain. A recent international framework for risk assessment and management offers directions in the mitigation of this risk by facilitating sound clinical reasoning. The aim of this article is to critically reflect on and summarize the current knowledge about cervical spine manual therapy and to provide guidance for clinical reasoning for cervical spine manual therapy. PMID- 29153923 TI - Macrophages sensing oxidized DAMPs reprogram their metabolism to support redox homeostasis and inflammation through a TLR2-Syk-ceramide dependent mechanism. AB - OBJECTIVE: Macrophages control tissue homeostasis and inflammation by sensing and responding to environmental cues. However, the metabolic adaptation of macrophages to oxidative tissue damage and its translation into inflammatory mechanisms remains enigmatic. METHODS: Here we identify the critical regulatory pathways that are induced by endogenous oxidation-derived DAMPs (oxidized phospholipids, OxPL) in vitro, leading to formation of a unique redox-regulatory metabolic phenotype (Mox), which is strikingly different from conventional classical or alternative macrophage activation. RESULTS: Unexpectedly, metabolomic analyses demonstrated that Mox heavily rely on glucose metabolism and the pentose phosphate pathway (PPP) to support GSH production and Nrf2-dependent antioxidant gene expression. While the metabolic adaptation of macrophages to OxPL involved transient suppression of aerobic glycolysis, it also led to upregulation of inflammatory gene expression. In contrast to classically activated (M1) macrophages, Hif1alpha mediated expression of OxPL-induced Glut1 and VEGF but was dispensable for Il1beta expression. Mechanistically, we show that OxPL suppress mitochondrial respiration via TLR2-dependent ceramide production, redirecting TCA metabolites to GSH synthesis. Finally, we identify spleen tyrosine kinase (Syk) as a critical downstream signaling mediator that translates OxPL-induced effects into ceramide production and inflammatory gene regulation. CONCLUSIONS: Together, these data demonstrate the metabolic and bioenergetic requirements that enable macrophages to translate tissue oxidation status into either antioxidant or inflammatory responses via sensing OxPL. Targeting dysregulated redox homeostasis in macrophages could therefore lead to novel therapies to treat chronic inflammation. PMID- 29153925 TI - Lateral atlantoaxial joint meniscoid volume in individuals with whiplash associated disorder: A case-control study. AB - BACKGROUND: Lateral atlantoaxial (LAA) joints are established sources of nociceptive input in chronic whiplash associated disorder (WAD). These joints contain intra-articular meniscoids that may be damaged in whiplash trauma. LAA joint meniscoid morphology has not been investigated comprehensively in a chronic WAD population, and it is unclear whether morphological differences exist compared to a pain-free population. OBJECTIVES: This study examined LAA joint meniscoid volume in individuals with chronic WAD who report pain in a distribution consistent with LAA joint pain. DESIGN: Case-control study. METHOD: Fourteen individuals with chronic WAD with pain in an LAA joint distribution (mean [SD] age 38.1 [10.8] years; six female) and 14 age- and sex-matched pain free controls (38.0 [10.5] years) underwent cervical spine magnetic resonance imaging. LAA joint images were inspected for meniscoids; meniscoid volume was calculated in mm3 and as a percentage of articular cavity volume. Symptom duration, location and intensity were recorded. Data were analysed using paired t tests, Wilcoxon signed-rank testing, Spearman's rank testing, linear and logistic regression (alpha < 0.05). RESULTS: Ventral and dorsal meniscoids (n = 112) were found in each LAA joint. Greater dorsal meniscoid volume as a percentage of articular cavity volume was associated with higher pain intensity (odds ratio 1.48, p = 0.03; likelihood ratio test chi-square2 = 6.64, p = 0.04), however no significant differences existed between meniscoid volumes of WAD and control participants. CONCLUSIONS: Findings indicate a potential link between dorsal LAA joint meniscoid volume and pain, suggesting larger meniscoid size may have pathoanatomical significance in WAD. PMID- 29153926 TI - Pharmacokinetics of risperidone in different application forms - Comparing long acting injectable and oral formulations. AB - We aimed to explore the differences in the pharmacokinetics of risperidone between oral and long-acting injectable (LAI) formulations using a large database of therapeutic drug monitoring (TDM). Plasma concentrations of risperidone (RIS), its active metabolite (9-OH-RIS) and the active moiety (AM) (RIS+9-OH-RIS), their concentration-to-dose (C/D) ratios and ratio of RIS/9-OH-RIS (an index of CYP2D6 metabolic activity) were used to compare patients receiving risperidone orally (n = 851) and those treated with LAI RIS (n = 63). Patients taking CYP inducers or inhibitors or with liver/renal impairment were eliminated. Our study demonstrated that patients on LAI RIS, despite slightly higher RIS doses in the oral group, showed no significant differences in total AM or 9-OH-RIS. Conversely, RIS concentration, RIS C/D ratio and total C/D ratio were slightly higher in the LAI RIS group, reaching significance due to the large sample size. More importantly, the median ratio of RIS/9-OH-RIS was 0.52 in LAI RIS vs. 0.25 in the oral group, providing a significant difference (p < 0.001). After controlling for confounding factors, we replicated the RIS/9-OH-RIS ratio increases in patients with LAI RIS, probably reflecting a decrease in first-pass metabolism. More studies are required to establish the clinical use of TDM for patients on LAI RIS. PMID- 29153927 TI - 1Hz rTMS of the right orbitofrontal cortex for major depression: Safety, tolerability and clinical outcomes. AB - Conventional rTMS in major depressive disorder (MDD) targets the dorsolateral prefrontal cortex (DLPFC). However, many patients do not respond to DLPFC-rTMS. Recent evidence suggests that the right lateral orbitofrontal cortex (OFC) plays a key role in 'non-reward' functions and shows hyperconnectivity in MDD. OFC-rTMS has been used successfully in obsessive-compulsive disorder, and achieved remission in an MDD case nonresponsive to DLPFC- and DMPFC-rTMS. Here, we assess the safety and tolerability of right OFC-rTMS, and examine the effectiveness of inhibitory right OFC-rTMS in MDD, particularly among patients with previous nonresponse to DMPFC-rTMS. We performed a chart review to retrieve data on clinical characteristics, stimulation parameters, adverse events, and clinical symptom outcomes for a series of 42 patients with medication-resistant and/or DMPFC-rTMS-nonresponsive MDD, who underwent 20-30 sessions of 1Hz right OFC-rTMS at a single Canadian clinic from 2015 to 2017. Over 882 sessions of treatment, there were no seizures, visual/ocular complications, or other serious or treatment-limiting adverse events. Pain ratings averaged 6-7/10 (10=maximum tolerable); no patient discontinued treatment prematurely due to pain. 15/42 patients (35.7%) achieved response (>=50% symptom reduction) and 10/42 (23.8%) achieved remission. Among the 30/42 patients who were previous nonresponders to DMPFC-rTMS, 9/30 (30.0%) achieved response and 7/30 (23.8%) achieved remission. Response distribution was sharply bimodal. 1Hz right OFC-rTMS appears safe and tolerable, and may achieve remission in MDD patients even when conventional rTMS has failed. Sham-controlled follow-up studies may be warranted. PMID- 29153928 TI - Enhancing excitability of dopamine neurons promotes motivational behaviour through increased action initiation. AB - Motivational deficits are a key symptom in multiple psychiatric disorders, including major depressive disorder, schizophrenia and addiction. A likely neural substrate for these motivational deficits is the brain dopamine (DA) system. In particular, DA signalling in the nucleus accumbens, which originates from DA neurons in the ventral tegmental area (VTA), has been identified as a crucial substrate for effort-related and activational aspects of motivation. Unravelling how VTA DA neuronal activity relates to motivational behaviours is required to understand how motivational deficits in psychiatry can be specifically targeted. In this study, we therefore used designer receptors exclusively activated by designer drugs (DREADD) in TH:Cre rats, in order to determine the effects of chemogenetic DA neuron activation on different aspects of motivational behaviour. We found that chemogenetic activation of DA neurons in the VTA, but not substantia nigra, significantly increased responding for sucrose under a progressive ratio schedule of reinforcement. More specifically, high effort exertion was characterized by increased initiations of reward-seeking actions. This effect was dependent on effort requirements and instrumental contingencies, but was not affected by sucrose pre-feeding. Together, these findings indicate that VTA DA neuronal activation drives motivational behaviour by facilitating action initiation. With this study, we show that enhancing excitability of VTA DA neurons is a viable strategy to improve motivational behaviour. PMID- 29153929 TI - Accuracy of a Simulation Algorithm for Modelling LV Contractility, Diastolic Capacitance, and Energetics Using Data Available From Common Hemodynamic Monitors and Echocardiography. AB - OBJECTIVE: To test the hypothesis that a simulation algorithm populated with data readily available from hemodynamic monitors and echocardiography can accurately model cardiac contractility, diastolic capacitance, and energetics. DESIGN: Bland Altman analysis of paired data sets. SETTING: University laboratory. PARTICIPANTS: Archived data previously recorded from 7 anesthetized swine. MEASUREMENTS AND MAIN RESULTS: Left ventricular pressure and volume (LVV) data that had been continuously recorded over a range of inotropic conditions were used as reference data. One investigator performed conventional analysis of measured pressure/volume loops during preload reduction to derive reference values for end-systolic elastance (Ees-a measure of contractility), the predicted LVV at an end-diastolic pressure of 30 mmHg (V30-an index of diastolic capacitance and chamber dilation), and pressure-volume area (PVA-a correlate of myocardial oxygen consumption). Other investigators blinded to these results entered pressure, cardiac output, and ejection fraction measurements into a simulator that predicts Ees, V30, and PVA. Analysis of simulated data was performed before and after correction of the estimated LVV at which pressure would be 0 mmHg (V0), which was initially fixed in the model. Before V0 correction, accuracy and precision of Ees, V30, and PVA tended to fall outside predefined limits for method interchangeability, but utility for qualitative assessment of acute changes was evident. After V0 correction, the accuracy and precision of simulated data were within the defined limits for method interchangeability. CONCLUSIONS: These data support the potential for clinical utility of simulation models populated with data readily available at the bedside to characterize left ventricular mechanical performance and energetics. PMID- 29153930 TI - Anesthetic Technique for TAVR: More Than Just "Tube" or "No Tube". PMID- 29153931 TI - Disturbances in Oxygen Balance During Cardiopulmonary Bypass: A Risk Factor for Postoperative Delirium. AB - OBJECTIVE: The aim of this study was to determine risk factors for postoperative delirium after cardiac surgery, specifically associated with the conduct of cardiopulmonary bypass (CPB). DESIGN: Prospective observational study. SETTING: Heart Centre, University Hospital. PARTICIPANTS: The study included 142 patients aged 70 years and older scheduled for elective cardiac surgery with CPB. INTERVENTIONS: Risk factor analysis comprised information collected from the hospital clinical and CPB dedicated databases in addition to the medical chart. Delirium was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision criterion using the Mini Mental State Examination and the Organic Brain Syndrome scale. MEASUREMENTS AND MAIN RESULTS: Assessments of delirium diagnosis were executed preoperatively and on the following first and fourth postoperative days. Delirium occurred in 55% (78/142) of the patients. Patients with delirium were identified with significantly higher body weight and body surface area preoperatively, accompanied with longer CPB time, higher positive fluid balance per CPB, and lower systemic pump flow related to body surface area. Furthermore, the duration of the mixed venous oxygen saturation (SvO2) below 75% was significantly longer during CPB. The result from the multivariable logistic regression analysis included the duration of SvO2 below 75%, fluid balance per CPB and patient age as independent risk factors for postoperative delirium. CONCLUSIONS: The influence of the SvO2 level during CPB, fluid balance, and patient age should be recognized as risk factors for postoperative delirium after cardiac surgery in patients 70 years and older. PMID- 29153932 TI - Takotsubo Cardiomyopathy and Intraoperative Cardiac Arrest: Is Desvenlafaxine a Contributing Factor? PMID- 29153933 TI - Computed Tomographic Window Setting for Bronchial Measurement to Guide Double Lumen Tube Size. AB - OBJECTIVES: The bronchial diameter measured on computed tomography (CT) can be used to guide double-lumen tube (DLT) sizes objectively. The bronchus is known to be measured most accurately in the so-called bronchial CT window. The authors investigated whether using the bronchial window results in the selection of more appropriately sized DLTs than using the other windows. DESIGN: CT image analysis and prospective randomized study. SETTING: Tertiary hospital. PARTICIPANTS: Adults receiving left-sided DLTs. INTERVENTIONS: The authors simulated selection of DLT sizes based on the left bronchial diameters measured in the lung (width 1,500 Hounsfield unit [HU] and level -700 HU), bronchial (1,000 HU and -450 HU), and mediastinal (400 HU and 25 HU) CT windows. Furthermore, patients were randomly assigned to undergo imaging with either the bronchial or mediastinal window to guide DLT sizes. Using the underwater seal technique, the authors assessed whether the DLT was appropriately sized, undersized, or oversized for the patient. MAIN MEASUREMENTS AND RESULTS: On 130 CT images, the bronchial diameter (9.9 +/- 1.2 mm v 10.5 +/- 1.3 mm v 11.7 +/- 1.3 mm) and the selected DLT size were different in the lung, bronchial, and mediastinal windows, respectively (p < 0.001). In 13 patients (17%), the bronchial diameter measured in the lung window suggested too small DLTs (28 Fr) for adults. In the prospective study, oversized tubes were chosen less frequently in the bronchial window than in the mediastinal window (6/110 v 23/111; risk ratio 0.38; 95% CI 0.19-0.79; p = 0.003). No tubes were undersized after measurements in these two windows. CONCLUSIONS: The bronchial measurement in the bronchial window guided more appropriately sized DLTs compared with the lung or mediastinal windows. PMID- 29153934 TI - Family-Centered Care From the Perspective of Parents of Children Cared for in a Pediatric Intensive Care Unit: An Integrative Review. AB - PROBLEM: The Institute for Patient- and Family-Centered Care's (IPFCC) definition of family-centered care (FCC) includes the following four core concepts: respect and dignity, information sharing, participation, and collaboration. To date, research has focused on the provider experience of FCC in the PICU; little is known about how parents of children hospitalized in the pediatric intensive care unit (PICU) experience FCC. ELIGIBILITY CRITERIA: Articles were included if they were published between 2006 and 2016, included qualitative, quantitative, or mixed methods results, related to care received in a PICU, and included results that were from a parent perspective. SAMPLE: 49 articles from 44 studies were included in this review; 32 used qualitative/mixed methods and 17 used quantitative designs. RESULTS: The concepts of respect and dignity, information sharing, and participation were well represented in the literature, as parents reported having both met and unmet needs in relation to FCC. While not explicitly defined in the IPFCC core concepts, parents frequently reported on the environment of care and its impact on their FCC experience. CONCLUSIONS: As evidenced by this synthesis, parents of critically ill children report both positive and negative FCC experiences relating to the core concepts outlined by the IPFCC. IMPLICATIONS: There is a need for better understanding of how parents perceive their involvement in the care of their critically ill child, additionally; the IPFCC core concepts should be refined to explicitly include the importance of the environment of care. PMID- 29153935 TI - A Qualitative Assessment of Adolescent Girls' Perception of Living with Congenital Heart Disease: Focusing on Future Pregnancies and Childbirth. AB - PURPOSE: Congenital heart disease (CHD) is the most common birth anomaly in Japan, occurring in approximately 10.6 of every 1,000 live births. Advancements in medical and surgical care have increased births by women diagnosed with CHD. The study's purpose was to examine the perceptions of pregnancy and childbirth among adolescent girls with CHD. DESIGN AND METHODS: Twelve semi-structured interviews were conducted, and the data were analyzed using a modified grounded theory approach. RESULTS: Three categories and 16 subcategories were extracted. Adolescent girls with CHD reported feelings of distress and anxiety while struggling with their disease, and feared how their disease might negatively influence their future pregnancy. These concerns were related to a desire to become familiar with CHD. The girls also explored how their disease would be managed during pregnancy and childbirth. Overall, these perceptions were influenced by the girls' acceptance of their disease, and support from family, friends, and healthcare professionals. CONCLUSIONS: Healthcare professionals might assess adolescent girls' awareness of their disease before discussing pregnancy and childbirth risks. To encourage them to understand and cope with their disease, healthcare professionals might provide interventions tailored to the timing, stage, and degree of pregnancy and childbirth awareness. This could allow safer life planning, especially concerning pregnancy and childbirth decisions. PRACTICE IMPLICATIONS: To address adolescent girls' needs, healthcare professionals should continuously assess their awareness of pregnancy and childbirth as well as their psychological status, alongside CHD issues. PMID- 29153937 TI - Tribendimidine: an alternative to praziquantel to treat human liver fluke infection? PMID- 29153936 TI - Metal complexes promoting catalytic cleavage of nucleic acids-biochemical tools and therapeutics. AB - The development of metal complexes that promote degradation of nucleic acids has garnered significant interest as a result of their broad range of potential application. This review focuses on recent progress in the design and synthesis of metal complexes as artificial nucleases that promote either hydrolytic or oxidative cleavage of nucleic acids. Illustrative examples demonstrate the versatility of artificial nucleases for in vitro applications as molecular tools to address biochemical problems, as well as their potential use as therapeutic agents. We also address future challenges for improvement and avenues for further investigation. PMID- 29153938 TI - Efficacy and safety of tribendimidine versus praziquantel against Opisthorchis viverrini in Laos: an open-label, randomised, non-inferiority, phase 2 trial. AB - BACKGROUND: Praziquantel is the only option for treatment of the liver fluke infection Opisthorchis viverrini. Tribendimidine could be an alternative drug. We aimed to assess the efficacy and safety of a single, oral dose of tribendimidine, compared with praziquantel administered in two doses, in participants with O viverrini infection. METHOD: We did an open-label, randomised, non-inferiority, phase 2 trial in children (8-14 years) and adolescents and adults (>=15 years) in Champasack province, southern Laos. Participants infected with O viverrini were randomly assigned (1:1), via a computer-generated block-randomisation procedure (block sizes of two, four, and six), to receive a single, oral dose of tribendimidine (200 mg for children, 400 mg for adolescents and adults) or two oral doses of praziquantel (50 mg/kg bodyweight and 25 mg/kg bodyweight, 6 h apart). Physicians assessing adverse events and laboratory personnel were masked to treatment allocation, but the investigators administering treatment and the participants could have recognised the treatment group based on differences in the number, appearance, and odour of the tablets. The primary outcomes were cure rate, defined as no parasite eggs in stool at 3 weeks' follow-up, and egg reduction rate. We did available-case analysis of all participants with primary endpoint data. The non-inferiority margin for the difference in cure rates between the groups was pre-specified as -3 percentage points. Adverse events were monitored at 3 h and 24 h after treatment. This trial is registered, number ISRCTN96948551. FINDINGS: Between Feb 1, and April 30, 2014, we assigned 607 participants with confirmed O viverrini infection to receive tribendimidine (n=300) or praziquantel (n=307). 11 participants (five in the tribendimidine group and six in the praziquantel group) did not provide stool samples at 3 weeks' follow-up and were excluded from the available-case analysis. 276 (93.6%) of 295 participants in the tribendimidine group were cured compared with 293 (97.3%) of 301 participants in the praziquantel group. The difference in cure rates between the two groups was -3.8 percentage points (95% CI -7.1 to -0.4), thus the lower limit of the confidence interval exceeded the non-inferiority margin. In both treatment groups, egg reduction rates were 99.9%. Adverse events were of mild and moderate intensity and were more frequent in the praziquantel group than in the tribendimidine group (odds ratio 4.5, 95% CI 3.2-6.3; p<0.0001). The most frequent adverse events were headache, vertigo, nausea, and fatigue. INTERPRETATION: Tribendimidine has a slightly lower cure rate than praziquantel and non-inferiority was not shown. However, tribendimidine has a similar egg reduction rate to praziquantel and leads to fewer adverse events and thus might complement praziquantel in O viverrini control programmes, particularly in settings co-endemic for hookworm. FUNDING: Joint Global Health Trials scheme from the Wellcome Trust, Department for International Development, and Medical Research Council. PMID- 29153939 TI - Serum concentrations of fetuin B in lipodystrophic patients. AB - OBJECTIVE: Fetuin B is an adipokine/hepatokine which is significantly elevated in insulin resistance/type 2 diabetes mellitus and hepatic steatosis. Regulation of fetuin B in patients with lipodystrophy (LD) - a disease group which is characterized by subcutaneous adipose tissue loss, hypertriglyceridemia, hepatic steatosis, insulin resistance, and dysregulation of several adipokines - has not been elucidated so far. MATERIAL AND METHODS: Serum fetuin B levels were determined in 37 patients with LD, as well as in a control cohort consisting of 37 non-LD participants matched for age, gender, and body mass index. Furthermore, fetuin B was correlated with parameters of lipid metabolism, glucose control, renal function, and inflammation. RESULTS: Median fetuin B serum levels were not significantly different between patients with LD (2980.7 ug/l; interquartile range: 841.7 ug/l) and non-LD controls (2647.3 ug/l; interquartile range: 923.6 ug/l; p = .105). Fetuin B was associated with age, body mass index, markers of renal function, and C reactive protein (CRP) in univariate correlation analyses. The associations with age and creatinine remained significant in multiple linear regression analysis. CONCLUSIONS: Fetuin B serum concentrations are not significantly different between patients with LD and non-LD controls. Fetuin B does not seem to be a major pathogenetic factor in LD. PMID- 29153940 TI - Tumor-derived cytokines impair myogenesis and alter the skeletal muscle immune microenvironment. AB - Muscle wasting is a decline in skeletal muscle mass and function that is associated with aging, obesity, and a spectrum of pathologies including cancer. Cancer-associated wasting not only reduces quality of life, but also directly impacts cancer mortality, chemotherapeutic efficacy, and surgical outcomes. There is an incomplete understanding of the role of tumor-derived factors in muscle wasting and sparse knowledge of how these factors impact in vivo muscle regeneration. Here, we identify several cytokines/chemokines that negatively impact in vitro myogenic differentiation. We show that one of these cytokines, CXCL1, potently antagonizes in vivo muscle regeneration and interferes with in vivo muscle satellite cell homeostasis. Strikingly, CXCL1 triggers a robust and specific neutrophil/M2 macrophage response that likely underlies or exacerbates muscle repair/regeneration defects. Taken together, these data highlight the pleiotropic nature of a novel tumor-derived cytokine and underscore the importance of cytokines in muscle progenitor cell regulation. PMID- 29153941 TI - The impact of readmission hospital on failure-to-rescue rates following major urologic cancer surgery. AB - PURPOSE: Patients readmitted to secondary hospitals rather than the primary hospital where their surgery took place may be at risk for poorer outcomes. We sought to evaluate the effect of site of readmission on failure-to-rescue complication rates following urologic cancer surgery. MATERIALS AND METHODS: Retrospective review of major urologic cancer surgeries in the Washington State Comprehensive Hospital Abstract Reporting System between 1998 and 2013. Failure to-rescue (FTR) rates, defined as inpatient death after a complication requiring hospital readmission, were compared between patients readmitted to their primary hospital with those readmitted to a secondary hospital. Multivariable logistic regression (MVA) models evaluated the association between readmission site and FTR. RESULTS: Of 31,498 eligible patients, 3,113 patients were readmitted to hospital within 90 days of surgery, of whom 29.2% were readmitted to a secondary hospital. The highest FTR rates were following cardiac (11.6%), respiratory (11.2%), and sepsis-related complications (10.0%). When limiting to patients who underwent surgery in a high-volume center, the odds of FTR were 4-fold higher when complications were managed in a secondary hospital (OR = 4.06, 95% CI: 1.67 9.89). CONCLUSIONS: The institution where patients present for postoperative complications is associated with differential mortality outcomes. Upon validation in a large cohort, these findings may inform quality improvement initiatives that target postoperative readmissions, algorithm-based approaches to post-surgical management of complications, and guide clinical decision-making around hospital transfers. PMID- 29153942 TI - Metabolic syndrome and low high-density lipoprotein cholesterol are associated with adverse pathological features in patients with prostate cancer treated by radical prostatectomy. AB - BACKGROUND: Previous studies have suggested a link between metabolic syndrome (MetS) and prostate cancer (PCa). In the present study, we aimed to assess the association between MetS and markers of PCa aggressiveness on radical prostatectomy (RP). METHODS: All patients consecutively treated for PCa by RP in 6 academic institutions between August 2013 and July 2016 were included. MetS was defined as at least 3 of 5 components (obesity, elevated blood pressure, diabetes, low high-density lipoprotein (HDL)-cholesterol, and hypertriglyceridemia). Demographic, biological, and clinical parameters were prospectively collected, including: age, biopsy results, preoperative serum prostate-specific antigen, surgical procedure, and pathological data of RP specimen. Locally advanced disease was defined as a pT-stage >=3. International Society of Urological Pathology (ISUP) groups were used for pathological grading. Qualitative and quantitative variables were compared using chi-square and Wilcoxon tests; logistic regression analyses assessed the association of MetS and its components with pathological data. Statistical significance was defined as a P<0.05. RESULTS: Among 567 men, 249 (44%) had MetS. In a multivariate model including preoperative prostate-specific antigen, biopsy ISUP-score, clinical T stage, age, and ethnicity: we found that MetS was an independent risk factor for positive margins, and ISUP group >=4 on the RP specimen (odds ratio [OR] = 1.5; 95% CI: 1.1-2.3; P = 0.035; OR = 2.0; 95% CI: 1.1-4.0; P = 0.044, respectively). In addition, low HDL-cholesterol level was associated with locally advanced PCa (OR = 1.6; 95% CI: 1.1-2.4; P = 0.024). Risks of adverse pathological features increased with the number of MetS components: having >= 4 MetS components was significantly associated with higher risk of ISUP group >= 4 and higher risk of positive margins (OR = 1.9; 95% CI: 1.1-3.3; P = 0.017; OR = 1.8; 95% CI: 1.1 2.8; P = 0.007, respectively). CONCLUSION: MetS was an independent predictive factor for higher ISUP group and positive margins at RP. Low HDL-cholesterol alone, and having 4 and more MetS components were also associated with higher risk of adverse pathological features. PMID- 29153943 TI - Survival outcomes of organ sparing surgery, partial penectomy, and total penectomy in pathological T1/T2 penile cancer: Report from the National Cancer Data Base. AB - PURPOSE: To describe the survival outcomes of organ sparing surgery (OSS), partial penectomy (PP), and total penectomy (TP) in pathological stage pT1/pT2 penile cancer (PC) as reported in the United States National Cancer Data Base. METHODS: Patients with pT1/pT2 PC, treated with surgery as their primary treatment modality were classified into 3 groups according to the type of surgery into OSS, PP, and TP. Patient and tumor characteristics of the groups were compared using bivariate analysis, and Cox- proportional hazard model was used for survival analysis. RESULTS: A total of 4,238 patients were examined. There were 1,211, 2,360, and 584 patients in the OSS, PP, and TP groups, respectively. In 83 patients, the type of surgery was missing. The 5- and 10-year overall survival rates for OSS, PP, and TP were 88% and 74% vs. 85% and 72% vs. 79% and 63%, respectively (P <= 0.001). In addition, in a multivariable model for predictors of patient survival, OSS did not predict poor patient survival (hazard ratio = 0.88, CI: 0.64-1.21). CONCLUSIONS: Our results demonstrate, at national level, OSS in early stage PC provided comparable outcomes in selected patients compared to PP and TP. Also, organ preservation was not associated with any significant reduction in patient survival in early stage PC. Our results help with early stage PC patient informed treatment decisions and anticipated outcomes. PMID- 29153944 TI - Determination of degree of RBC agglutination for blood typing using a small quantity of blood sample in a microfluidic system. AB - Blood typing assay is a critical test to ensure the serological compatibility of a donor and an intended recipient prior to a blood transfusion. This paper presents a microfluidic blood typing system using a small quantity of blood sample to determine the degree of agglutination of red blood cell (RBC). Two measuring methods were proposed: impedimetric measurement and electroanalytical measurement. The charge transfer resistance in the impedimetric measurement and the power parameter in the electroanalytical measurement were used for the analysis of agglutination level. From the experimental results, both measuring methods provide quantitative results, and the parameters are linearly and monotonically related to the degree of RBC agglutination. However, the electroanalytical measurement is more reliable than the impedimetric technique because the impedimetric measurement may suffer from many influencing factors, such as chip conditions. Five levels from non-agglutination (level 0) to strong agglutination (level 4+) can be discriminated in this study, conforming to the clinical requirement to prevent any risks in transfusion. PMID- 29153945 TI - Cu@Pd core-shell nanostructures for highly sensitive and selective amperometric analysis of histamine. AB - We demonstrate a facile and rapid methodology for preparation of Cu@Pd core-shell nanostructures on a cost-effective pencil graphite substrate. Galvanic replacement reaction was carried out for palladium modification on template electrodeposited copper nanostructures on pencil graphite substrate. The nanostructures are shown to be very stable with excellent electrocatalytic activities. Under optimised conditions, they could be used for histamine sensing at a very low oxidation potential of +0.55V vs. Ag/AgCl. The low oxidation potential enabled sensitive and selective analysis of histamine using chronoamperometry without any interference from oxygen evolution reactions. We have demonstrated that the sensor shows excellent selectivity towards histamine even in the presence of many of the common interfering biogenic amines. The sensor exhibited a sensitivity of 0.082 MU A/MU M/cm 2 with a limit of detection as low as 3.2 +/- 0.1nM. The oxidation potential and limit of detection obtained using this sensor are much superior to the results reported so far in the literature. Practical feasibility of the developed sensor was manifested by histamine analysis in canned tuna fish samples, where the chronoamperometric estimation was also validated by conventional HPLC analysis. PMID- 29153946 TI - Effect of Brownian motion on reduced agglomeration of nanostructured metal oxide towards development of efficient cancer biosensor. AB - We report results of the studies relating to fabrication of nanostructured metal oxide (NMO) based cancer biosensor. With the help of 2D electroactive reduced graphene oxide (RGO), we successfully inhibited the Brownian motion of NMO that led to reduced agglomeration of NMO. The nanostructured hafnium oxide (nHfO2) was used as a model NMO. The reduced agglomeration of nHfO2 was achieved through controlled hydrothermal synthesis and investigated via nanoparticles tracking analysis (NTA). X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscope (TEM) techniques were used for phase identification as well as morphological analysis of the synthesized nanohybrid (nHfO2@RGO) material. The 3-aminopropyl triethoxysilane (APTES) was used for the functionalization of nHfO2@RGO and electrophoretic deposition (EPD) technique was used for its deposition onto ITO coated glass electrode. Further, antibodies of cancer biomarker (anti-CYFRA-21-1) were immobilized via EDC-NHS chemistry and Bovine serum albumin (BSA) was used for blocking of the non-specific binding sites. The electrochemical response studies of fabricated immunoelectrode (BSA/anti-CYFRA-21-1/APTES/nHfO2@RGO/ITO) revealed higher sensitivity (18.24uAmLng-1), wide linear detection range (0 to 30ngmL-1), with remarkable lower detection limit (0.16ngmL-1). The obtained results showed good agreement with the concentration of CYFRA-21-1 obtained through enzyme linked immunosorbent assay (ELISA) in saliva samples of oral cancer patients. PMID- 29153947 TI - Paper-based fluorogenic devices for in vitro diagnostics. AB - In vitro diagnostics (IVD) are essential in healthcare systems for detection of diseases, conditions, or infections. Affordable and sensitive methods remain a challenge in the development of IVD. In this article, we give an overview of paper-based fluorogenic devices, an emerging cost-effective analytical method for IVD applications. The paper-based devices are inexpensive, sensitive, selective, user-friendly and equipment-free. Furthermore, the fluorescent detection on paper based devices has recently attracted enormous attentions due to its high sensitivity and selectivity. We summarize and compare various fluorescent materials that are used in the paper-based fluorogenic devices, including fluorescent dyes, quantum dots, metal nanoclusters, upconversion nanoparticles, and carbon dots. We review a wide range of IVD applications of the paper-based fluorogenic devices, e.g., detection of nucleic acids, proteins, cells, and so on. It may open an avenue to improve the global healthcare systems in the developing countries at point of care settings and in emergency situations. PMID- 29153948 TI - Rh blood phenotyping (D, E, e, C, c) microarrays using multichannel surface plasmon resonance imaging. AB - The application of Surface Plasmon Resonance Imaging (SPRi) for the detection of transmembrane antigen of the Rhesus (Rh) blood group system is demonstrated. Clinically significant Rh blood group system antigens, including D, C, E, c, and e, can be simultaneously identified via solid phase immobilization assay, which offers significant time savings and assay simplification. Red blood cells (RBCs) flowed through the micro-channel, where a suitable condition for Rh blood group detection was an RBC dilution of 1:10 with a stop-flow condition. Stop flow showed an improvement in specific binding compared to continuous flow. Rh antigens required a longer incubation time to react with the immobilized antibody than A and B antigens due to the difference in antigen type and their location on the RBC. The interaction between the immobilized antibodies and their specific antigenic counterpart on the RBC showed a significant difference in RBC removal behavior using shear flow, measured from the decay of the SPR signal. The strength of the interaction between the immobilized antibody and RBC antigen was determined from the minimum wall shear stress required to start the decay process in the SPR signal. For a given range of immobilized antibody surface densities, the Rh antigen possesses a stronger interaction than A, B, and AB antigens. Identification of 82 samples of ABO and Rh blood groups using SPRi showed good agreement with the standard micro-column agglutination technique. A wider coverage of antigenic recognition for RBC when using the solid phase immobilization assay was demonstrated for the RBC with the antigenic site located on the transmembrane protein of the clinically significant Rh antigen. Given the level of accuracy and precision, the technique showed potential for the detection of the Rh minor blood group system. PMID- 29153949 TI - A novel label-free electrochemical immunosensor for ultra-sensitively detecting prostate specific antigen based on the enhanced catalytic currents of oxygen reduction catalyzed by core-shell Au@Pt nanocrystals. AB - Herein, bimetallic core-shell Au@Pt nanocrystals (Au@Pt NCs) were prepared by a simple one-pot aqueous method using 2-pyrrolidone-5-carboxylic acid sodium salt (PCA-Na) as a new and green growth-directing agent. The obtained architectures displayed excellent catalytic activity towards oxygen reduction reaction (ORR) compared with commercial Pt/C catalyst. A novel immunosensor was constructed via assembly prostate specific antibody on the surface of Au@Pt NCs. It was found that the ORR currents were significantly suppressed due to the specific antigen antibody reaction. The ultra-sensitive determination of prostate specific antigen (PSA) was realized on account of the immunocomplex impeding the redox probe accessible to the electrode. The immunosensor exhibited good analytical performance for the assay of PSA with the wide linear range of 0.1 ~ 50ngmL-1 and low detection limit of 0.018ngmL-1 (S/N = 3), coupled with the improved stability, reproducibility and selectivity. PMID- 29153951 TI - High-performance hybrid electrode decorated by well-aligned nanograss arrays for glucose sensing. AB - The worldwide boost in glucose related diseases such as diabetics over the last decade leads to an overwhelming demand for development of advanced electrochemical glucose sensors with high sensitivity, fast response and excellent selectivity. Herein we report a novel freestanding microelectrode comprising well-aligned Cu(OH)2 nanograss arrays and uniform nanoporous copper (NPC) substrate. Such a cost-effective hierarchical hybrid structure entails a unique combination of good conductivity of NPC and high electrocatalytic activity of Cu(OH)2. As a result, the glucose sensor based on the hybrid nanostructure exhibits extraordinary performance towards the oxidation of glucose with a high sensitivity of ~2.09mAcm-2mM-1, wide linear range of 0.2-9mM, low detection limit of 197nM, fast response time of less than 1s and excellent selectivity. The current work not only provides novel hybrid materials with great potential to be commercialized in blood glucose sensing, but also has important implications for designing enhanced nanostructured electrocatalysts for engineering applications in general. PMID- 29153950 TI - Highly sensitive electrochemical nuclear factor kappa B aptasensor based on target-induced dual-signal ratiometric and polymerase-assisted protein recycling amplification strategy. AB - In this work, an amplified electrochemical ratiometric aptasensor for nuclear factor kappa B (NF-kappaB) assay based on target binding-triggered ratiometric signal readout and polymerase-assisted protein recycling amplification strategy is described. To demonstrate the effect of "signal-off" and "signal-on" change for the dual-signal electrochemical ratiometric readout, the thiol-hairpin DNA (SH-HD) hybridizes with methylene blue (MB)-modified protection DNA (MB-PD) to form capture probes, which is rationally introduced for the construction of the assay platform. On the interface, the probes can specifically bind to target NF kappaB and expose a toehold region which subsequently hybridizes with the ferrocene (Fc)-modified DNA strand to take the Fc group to the electrode surface, accompanied by displacing MB-PD to release the MB group from the electrode surface, leading to the both "signal-on" of Fc (IFc) and "signal-off" of MB (IMB). In order to improve the sensitivity of the electrochemical aptasensor, phi29-assisted target protein recycling amplification strategy was designed to achieve an amplified ratiometric signal. With the above advantages, the prepared aptasensor exhibits a wide linear range of 0.1pgmL-1 to 15ngmL-1 with a low detection limit of 0.03pgmL-1. This strategy provides a simple and ingenious approach to construct ratiometric electrochemical aptasensor and shows promising potential applications in multiple disease marker detection by changing the recognition probe. PMID- 29153952 TI - Surveillance of the safety and efficacy of recombinant human soluble thrombomodulin in patients with obstetrical disseminated intravascular coagulation. AB - BACKGROUND: Recombinant human soluble thrombomodulin (TM-alpha) has been shown to be useful in the treatment of disseminated intravascular coagulation (DIC) in a heparin-controlled study, and has been available for clinical use in Japan since 2008. However, use of TM-alpha for obstetrical DIC has not yet been established, so efficacy and safety were analyzed in 117 obstetrical DIC patients identified from post-marketing surveillance. MATERIALS AND METHODS: From June 2010 to March 2012, the cases of 117 patients with obstetrical DIC treated with TM-alpha were registered. RESULTS: In the majority of cases, the underlying disease was DIC type postpartum hemorrhage (n=43) or placental abruption (n=37). Mean (+/ standard deviation) obstetrical DIC score was 10.6+/-4.9. Mean duration of TM alpha administration was 2.2+/-1.7days. The most commonly used concomitant anticoagulants were antithrombin (n=60) and gabexate mesilate (n=37). Concomitantly used blood components products included red blood cell concentrate (n=72), fresh frozen plasma (n=70), and platelet concentrate (n=31). Hemostatic test result profiles revealed significant improvement of fibrinogen/fibrin degradation products, D-dimer, fibrinogen, prothrombin time and activated partial thromboplastin time. Efficacies of TM-alpha as evaluated by "The efficacy evaluation criteria for DIC in obstetrics" at 24h, 48h and the day after last administration of TM-alpha were 72.3%, 82.4% and 90.2%, respectively. Total bleeding adverse drug reactions occurred in 6 patients (5.1%). CONCLUSIONS: This surveillance confirmed the safety and efficacy of TM-alpha in clinical practice. These findings thus indicated that the efficacy of TM-alpha is comparable to that of previously investigated obstetrical DIC pharmacotherapies. PMID- 29153953 TI - Inhibition of curcumin on influenza A virus infection and influenzal pneumonia via oxidative stress, TLR2/4, p38/JNK MAPK and NF-kappaB pathways. AB - Oxidative stress, Nrf2-HO-1 and TLR-MAPK/NF-kappaB signaling pathways have been proved to be involved in influenza A virus (IAV) replication and influenzal pneumonia. In the previous studies, we have performed several high-throughput drug screenings based on the TLR pathways. In the present study, through plaque inhibition test, luciferase reporter assay, TCID50, qRT-PCR, western blotting, ELISA and siRNA assays, we investigated the effect and mechanism of action of curcumin against IAV infection in vitro and in vivo. The results showed that curcumin could directly inactivate IAV, blocked IAV adsorption and inhibited IAV proliferation. As for the underlying mechanisms, we found that curcumin could significantly inhibit IAV-induced oxidative stress, increased Nrf2, HO-1, NQO1, GSTA3 and IFN-beta production, and suppressed IAV-induced activation of TLR2/4/7, Akt, p38/JNK MAPK and NF-kappaB pathways. Suppression of Nrf2 via siRNA significantly abolished the stimulatory effect of curcumin on HO-1, NQO1, GSTA3 and IFN-beta production and meanwhile blocked the inhibitory effect of curcumin on IAV M2 production. Oxidant H2O2 and TLR2/4, p38/JNK and NF-kappaB agonists could significantly antagonize the anti-IAV activity of curcumin in vitro. Additionally, curcumin significantly increased the survival rate of mice, reduced lung index, inflammatory cytokines and lung IAV titer, and finally improved pulmonary histopathological changes after IAV infection. In conclusion, curcumin can directly inactivate IAV, inhibits IAV adsorption and replication; and its inhibition on IAV replication may be via activating Nrf2 signal and inhibiting IAV-induced activation of TLR2/4, p38/JNK MAPK and NF-kappaB pathways. PMID- 29153954 TI - MiR-150-5p regulates EGR2 to promote the development of chronic rhinosinusitis via the DC-Th axis. AB - BACKGROUND AND AIMS: Accumulating studies indicate that miR-150-5p might play a significant role in dendritic cells (DCs) of peripheral blood in chronic rhinosinusitis (CRS) patients. We sought to investigate the effects and mechanism of miR-150-5p, which regulates early growth response 2 (EGR2) to promote the development of CRS via the DC-Th axis. METHODS: The upregulated expression of miR 150-5p in DCs of CRS was assayed by real-time quantitative polymerase chain reaction (qRT-PCR), and IL-17 cytokines in the supernatants of DC-naive T cells co-cultures were analysed by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to evaluate T cell proliferations. EGR2 was also identified as a direct target of miR-150-5p by establishing a miRNA-mRNA network, and this target was validated with a Dual-Luciferase(r) Reporter Assay System and Western blot. RESULTS: MiR-150-5p was up-regulated in DCs in peripheral blood from CRS patients, and this expression was down-regulated by EGR2 expression via the DC-Th axis. Up-regulated miR-150-5p Regulates DCs, and DCs Promote Naive T Cells Proliferation. MiR-150-5p Further Regulates EGR2 and Inhibits DCs, Which Makes the DC-Th Axis Abnormal in the Peripheral Blood of Patients with CRS. CONCLUSION: MiR-150-5p and its identified target, EGR2, are involved in the development of CRS. DCs can promote T cell proliferations of peripheral blood in CRS. PMID- 29153955 TI - Characterization of pH-tolerant and thermostable GH 134 beta-1,4-mannanase SsGH134 possessing carbohydrate binding module 10 from Streptomyces sp. NRRL B 24484. AB - A GH 134 beta-1,4-mannanase SsGH134 from Streptomyces sp. NRRL B-24484 possesses a carbohydrate binding module (CBM) 10 and a glycoside hydrolase 134 domain at the N- and C-terminal regions, respectively. Recombinant SsGH134 expressed in Escherichia coli. SsGH134 was maximally active within a pH range of 4.0-6.5 and retained >80% of this maximum after 90 min at 30 degrees C within a pH range of 3.0-10.0. The beta-1,4-mannanase activity of SsGH134 towards glucomannan was 30% of the maximal activity after an incubation at 100 degrees C for 120 min, indicating that SsGH134 is pH-tolerant and thermostable beta-1,4-mannanase. SsGH134, SsGH134-DeltaCBM10 (CBM10-linker-truncated SsGH134) and SsGH134-G34W (substitution of Gly34 to Trp) bound to microcrystalline cellulose, beta-mannan and chitin, regardless of the presence or absence of CBM10. These indicate that GH 134 domain strongly bind to the polysaccharides. Although deleting CBM10 increased the catalytic efficiency of the beta-1,4-mannanase, its disruption decreased the pH, solvent and detergent stability of SsGH134. These findings indicate that CBM10 inhibits the beta-1,4-mannanase activity of SsGH134, but it is involved in stabilizing its enzymatic activity within a neutral-to-alkaline pH range, and in the presence of various organic solvents and detergents. We believe that SsGH134 could be useful to a diverse range of industries. PMID- 29153957 TI - Adaptive neuro-heuristic hybrid model for fruit peel defects detection. AB - Fusion of machine learning methods benefits in decision support systems. A composition of approaches gives a possibility to use the most efficient features composed into one solution. In this article we would like to present an approach to the development of adaptive method based on fusion of proposed novel neural architecture and heuristic search into one co-working solution. We propose a developed neural network architecture that adapts to processed input co-working with heuristic method used to precisely detect areas of interest. Input images are first decomposed into segments. This is to make processing easier, since in smaller images (decomposed segments) developed Adaptive Artificial Neural Network (AANN) processes less information what makes numerical calculations more precise. For each segment a descriptor vector is composed to be presented to the proposed AANN architecture. Evaluation is run adaptively, where the developed AANN adapts to inputs and their features by composed architecture. After evaluation, selected segments are forwarded to heuristic search, which detects areas of interest. As a result the system returns the image with pixels located over peel damages. Presented experimental research results on the developed solution are discussed and compared with other commonly used methods to validate the efficacy and the impact of the proposed fusion in the system structure and training process on classification results. PMID- 29153956 TI - Effect of laser activated bleaching on the chemical stability and morphology of intracoronal dentin. AB - OBJECTIVES: To evaluate the effect of the bleaching with 35% hydrogen peroxide either activated or not by a 970nm diode laser on the chemical stability and dentin surface morphology of intracoronary dentin. METHODS: Twenty-seven slabs of intracoronary dentin specimens (3*3mm) were distributed into three groups (n=9), according to surface treatment: HP - 35% hydrogen peroxide (1*4'), DL - 970nm diode laser (1*30"/0,8W/10Hz), HP+DL - 35% HP activated with 970nm diode laser (1*30"/0,8W/10Hz leaving the gel in contact to the surface for 4' after activation). Three Raman spectra from each fragment were obtained to calculate the mean intensity of peaks of inorganic component (a.u.), organic collagen content (a.u.), and the ratio of inorganic/organic content, before and after treatment. Analyses of the samples by confocal laser microscopy were performed to evaluate the surface roughness, percentage of tubules, perimeter and area percentage of tubules, before and after treatment. Data were analyzed by Kruskal Wallis, Dunn's, and Wilcoxon test (P<0.05). RESULTS: Data analysis showed that HP+DL did not change the inorganic content peaks 8.31 [29.78] or the inorganic/organic ratio 3.37 [14.67] (P>0.05). Similarly, DL did not affect the chemical stability of the dentin surface (P>0.05). However, HP significantly increased inorganic content peaks 10.87 [22.62], as well as the inorganic/organic ratio 6.25 [27.78] (P<0.05). Regarding the morphological alterations, all surface treatments increase tubules exposure; HP treatment significantly increases perimeter and area percentage; and HP+DL increases surface roughness. CONCLUSIONS: Bleaching HP combined with DL offers an improvement in terms of intracoronal dentin surface protection, yielding better maintenance of dentin chemical stability and morphology. PMID- 29153959 TI - After-hours respiratory physiotherapy for intubated and mechanically ventilated patients with community-acquired pneumonia: An Australian perspective. AB - INTRODUCTION: Community acquired pneumonia (CAP) is a common reason for admission to an intensive care unit for intubation and mechanical ventilation, and results in high morbidity and mortality. The primary aim of the study was to investigate availability and provision of respiratory physiotherapy, outside of normal business hours, for intubated and mechanically ventilated adults with CAP in Australian hospitals. MATERIALS AND METHODS: A cross-sectional, mixed methods online survey was conducted. Participants were senior intensive care unit physiotherapists from 88 public and private hospitals. Main outcome measures included presence and nature of an after-hours physiotherapy service and factors perceived to influence the need for after-hours respiratory physiotherapy intervention, when the service was available, for intubated adult patients with CAP. Data were also collected regarding respiratory intervention provided after hours by other ICU professionals. RESULTS: Response rate was 72% (n=75). An after hours physiotherapy service was provided by n=31 (46%) hospitals and onsite after hours physiotherapy presence was limited (22%), with a combination of onsite and on-call service reported by 19%. Treatment response (83%) was the most frequent factor for referring patients with CAP for after-hours physiotherapy intervention by the treating day-time physiotherapist. Nurses performing respiratory intervention (77%) was significantly associated with no available after-hours physiotherapy service (p=0.04). DISCUSSION: Physiotherapy after-hours service in Australia is limited, therefore it is common for intubated patients with CAP not to receive any respiratory physiotherapy intervention outside of normal business hours. In the absence of an after-hours physiotherapist, nurses were most likely to perform after-hours respiratory intervention to intubated patients with CAP. CONCLUSION: Further research is required to determine whether the frequency of respiratory physiotherapy intervention, including after-hours provision of treatment, influences outcomes for ICU patients intubated with pneumonia. PMID- 29153958 TI - Major and minor life events, personality and psychopathology in children with tourette syndrome. AB - Environmental, psychological, and biological interactions underlie many psychopathologies. Tourette's Syndrome (TS) has an obvious biological substrate but environmental factors and personality play substantial roles in its expression. We aimed to study the interrelationships between stressful life events, personality traits, tics, and comorbid disorders in children with TS. To this end, 132 children with TS and 49 healthy controls were recruited for the study. Major life events in the 12-months prior to testing and minor life events in the month prior to testing were retrospectively assessed using the Life Experiences Survey (LES) and the Brief Adolescent Life Events Scale (BALES), respectively. Personality was assessed with the Junior Temperament and Character Inventory (JTCI). Tics, obsessive compulsive symptoms, attention deficit and hyperactivity symptoms, anxiety, depression and aggression were assessed by self report questionnaires and semi-structured interviews. We found that major life events correlated with the severity of tics expression and complexity, and comorbid psychopathology. Minor life events correlated with more severe symptomatology. High levels of harm avoidance were related to more obsessions, anxiety, and depression whereas high levels of self-directedness were protective. To conclude, TS expression in childhood should be understood as the result of an interaction between biological, personality and environmental factors. PMID- 29153960 TI - Barriers and facilitators to the implementation of an evidence-based electronic minimum dataset for nursing team leader handover: A descriptive survey. AB - INTRODUCTION: There is widespread use of clinical information systems in intensive care units however, the evidence to support electronic handover is limited. OBJECTIVES: The study aim was to assess the barriers and facilitators to use of an electronic minimum dataset for nursing team leader shift-to-shift handover in the intensive care unit prior to its implementation. METHODS: The study was conducted in a 21-bed medical/surgical intensive care unit, specialising in cardiothoracic surgery at a tertiary referral hospital, in Queensland, Australia. An established tool was modified to the intensive care nursing handover context and a survey of all 63 nursing team leaders was undertaken. Survey statements were rated using a 6-point Likert scale with selections from 'strongly disagree' to 'strongly agree', and open-ended questions. Descriptive statistics were used to summarise results. RESULTS AND DISCUSSION: A total of 39 team leaders responded to the survey (62%). Team leaders used general intensive care work unit guidelines to inform practice however they were less familiar with the intensive care handover work unit guideline. Barriers to minimum dataset uptake included: a tool that was not user friendly, time consuming and contained too much information. Facilitators to minimum dataset adoption included: a tool that was user friendly, saved time and contained relevant information. Identifying the complexities of a healthcare setting prior to the implementation of an intervention assists researchers and clinicians to integrate new knowledge into healthcare settings. CONCLUSION: Barriers and facilitators to knowledge use focused on usability, content and efficiency of the electronic minimum dataset and can be used to inform tailored strategies to optimise team leaders' adoption of a minimum dataset for handover. PMID- 29153961 TI - Welcoming expertise: Bereaved parents' perceptions of the parent-healthcare provider relationship when a critically ill child is admitted to the paediatric intensive care unit. AB - BACKGROUND: Entering the paediatric intensive care unit with a critically ill child is a stressful experience for parents. In addition to fearing for their child's well-being, parents must navigate both a challenging environment and numerous new relationships with healthcare staff. How parents form relationships with staff and how they perceive both their own and the healthcare providers' roles in this early stage of their paediatric intensive care journey is currently unknown. PURPOSE: This paper explores bereaved parents' perceptions of their role and their relationships with healthcare providers when their child is admitted to the intensive care unit, as part of a larger study exploring their experiences when their child dies in intensive care. METHODS: A constructivist grounded theory approach was utilised to recruit 26 bereaved parents from 4 Australian intensive care units. Parents participated in audio-recorded, semi-structured interviews lasting 90-150min. All data were analysed using the constant comparative analysis processes, supported by theoretical memos. RESULTS: Upon admission, parents viewed healthcare providers as experts, both of their child's medical care and of the hospital system. This expertise was welcomed, with the parent-healthcare provider relationship developing around the child's need for medical care. Parents engaged in 2 key behaviours in their relationships with staff: prioritising survival, and learning 'the system'. Within each of these behaviours are several subcategories, including 'Stepping back', 'Accepting restrictions' and 'Deferring to medical advice'. CONCLUSIONS: The relationships between parents and staff shift and change across the child's admission and subsequent death in the paediatric intensive care unit. However, upon admission, this relationship centres around the child's potential survival and their need for medical care, and the parent's recognition of the healthcare staff as experts of both the child's care and the hospital system. PMID- 29153962 TI - Sonographic Criteria Predictive of Malignant Thyroid Nodules: Which Lesions Should be Biopsied? AB - RATIONALE AND OBJECTIVES: The objective of this study was to evaluate the ultrasound features of thyroid nodules and their association with malignancy, focusing on establishing feature-oriented ultrasound criteria to determine proper management of a thyroid nodule. MATERIALS AND METHODS: A sample of 379 thyroid nodules were biopsied (from a total of 357 patients aged 59.8 +/- 14.8 years) and 300 were included in the final study (271 benign nodules and 29 malignant ones). Ultrasound features were recorded for each nodule: size, echogenicity, homogeneity, contours, shape, texture, peripheral halo, calcifications, and the presence of adenopathy. Statistical analysis of the data was performed using the Mann-Whitney U test and chi-square test. The sensitivity and the specificity of variables seen to have a statistically significant association with the malignancy of nodules were assessed and a logistic regression was performed. RESULTS: A taller-than-wide shape, an ill-defined contour, the presence of a halo, microcalcifications, and adenopathy were found to have a statistically significant relationship (P < 0.05) with malignancy, although with a low sensitivity and a high specificity. The presence of at least one suspicious feature yields great sensitivity (89.7%) in detecting malignant disease. CONCLUSIONS: The ultrasound features of thyroid nodules alone do not allow the radiologist to make a confident diagnosis regarding the malignancy of a nodule without performing a biopsy. However, a nodule showing a taller-than-wide shape, microcalcifications, a peripheral halo, an ill-defined contour, or associated adenopathy should be considered for cytology. PMID- 29153963 TI - Shear Wave Elastography (SWE) for Monitoring of Treatment of Tendinopathies: A Double-blinded, Longitudinal Clinical Study. AB - RATIONALE AND OBJECTIVES: We aimed to investigate the diagnostic accuracy with which shear wave elastography (SWE) can be used to monitor response to treatment of tendinopathies, and to compare it to conventional ultrasound (US)-imaging methods (B-mode US (B-US) and power Doppler US (PD-US)). MATERIALS AND METHODS: A prospective Institutional Review Board-approved longitudinal study on 35 patients with 47 symptomatic tendons (17 Achilles-, 15 patellar-, and 15 humeral epicondylar) who underwent standardized multimodal US and standardized clinical assessment before and after 6 months of treatment (tailored stretching exercise, sport break, and local Polidocanol) was carried out. All US studies were performed by radiologists blinded to the clinical symptoms on both tendon sides to avoid biased interpretations, by B-US, PD-US, and SWE, conducted in the same order, using a high-resolution linear 15 MHz probe (Aixplorer). Orthopedic surgeons who were in turn blinded to US imaging results used established orthopedic scores (Victorian Institute of Sports Assessment questionnaire for Achilles, Victorian Institute of Sports Assessment questionnaire for patellar tendons, and Disability Arm Shoulder Hand scoring system) to rate presence, degree, and possible resolution of symptoms. We analyzed the diagnostic accuracy with which the different US imaging methods were able to detect symptomatic tendons at baseline as well as treatment effects, with orthopedic scores serving as reference standard. RESULTS: B-US, PD-US, and SWE detected symptomatic tendons with a sensitivity of 66% (31 of 47), 72% (34 of 47), and 87.5% (41 of 47), respectively. Positive predictive value was 0.67 for B-US, 0.87 for PD-US, and 1 for SWE. After treatment, clinical scores improved in 68% (32 of 47) of tendons. Treatment effects were observable by B-US, PD-US, and SWE with a sensitivity of 3.1% (1 of 32), 28.1% (9 of 32), and 81.3% (26 of 32), respectively. B-US was false-positive in 68.8% (20 of 32), PD-US in 46.9% (15 of 32), and SWE in 12.5% (4 of 32) (SWE). Clinical scores and B-US, PD-US, and SWE findings correlated poorly (r = 0.24), moderately (r = 0.59), and strongly (r = 0.80). CONCLUSION: Unlike B-US or PD-US, SWE is able to depict processes associated with tendon healing and may be a useful tool to monitor treatment effects. PMID- 29153964 TI - Evaluation of Different Minimally Invasive Techniques in Surgical Treatment for Ventricular Septal Defect. AB - BACKGROUND: Minimally invasive cardiac surgery is becoming a safe and cosmetic alternative to standard median sternotomy (SMS). This retrospective study reviews our results and experience with the lower mini-sternotomy (LMS) technique and the right lateral thoracotomy (RLT) technique for ventricular septal defect (VSD) closure compared with SMS. METHODS: Between January 2013 and Dec 2015, 198 patients underwent repair VSD through lower mini-sternotomy (LMS Group, n=66), right lateral thoracotomy (RLT Group, n=59), standard median sternotomy (SMS Group, n=73). Cardiopulmonary bypass was achieved directly in the three different approaches. RESULTS: Procedures were performed successfully in all patients among the three groups and no in-hospital mortality occurred. No patient was reverted to standard median sternotomy in the LMS Group and RLT Group. The CPB time was 37.73+/-11.46 mins in the LMS Group, 41.3+/-13.97 mins in the RLT Group and 36.99+/-10.84 mins in the SMS Group (p=0.078); the cross-clamp times were 23.85+/ 9.78 mins in the LMS Group, 22.54+/-9.08 mins in the RLT Group and 19.23+/-6.92 mins in the SMS Group (p=0.009). The total incision length of the procedure in the SMS Group (7.45+/-1.54cm) was longer than the other groups (LMS Group, 5.58+/ 0.8cm and RLT Group, 5.96+/-1.48cm) and the difference was significant (p<0.001). CONCLUSIONS: Both the LMS and RLT approach can be performed with favourable cosmetic and acceptable clinical results for closing VSD. They are the promising alternatives to standard median sternotomy and merit further study. PMID- 29153965 TI - Information about epilepsy on the internet: An exploratory study of Arabic websites. AB - The aim of this study was to explore information about epilepsy found on Arabic websites. The researchers collected information from the internet between November 2016 and January 2017. Information was obtained using Google and Yahoo search engines. Keywords used were the Arabic equivalent of the following two keywords: epilepsy (Al-saraa) and convulsion (Tashanoj). A total of 144 web pages addressing epilepsy in Arabic were reviewed. The majority of web pages were websites of medical institutions and general health websites, followed by informational and educational websites, others, blogs and websites of individuals, and news and media sites. Topics most commonly addressed were medical treatments for epilepsy (50% of all pages) followed by epilepsy definition (41%) and epilepsy etiology (34.7%). The results also revealed that the vast majority of web pages did not mention the source of information. Many web pages also did not provide author information. Only a small proportion of the web pages provided adequate information. Relatively few web pages provided inaccurate information or made sweeping generalizations. As a result, it is concluded that the findings of the present study suggest that development of more credible Arabic websites on epilepsy is needed. These websites need to go beyond basic information, offering more evidence-based and updated information about epilepsy. PMID- 29153966 TI - Nomogram to Predict Cause-Specific Mortality in Patients With Surgically Resected Stage I Non-Small-Cell Lung Cancer: A Competing Risk Analysis. AB - BACKGROUND: The objective of this study was to evaluate the probability of cause specific death and other causes of death in patients with stage I non-small-cell lung cancer (NSCLC) who underwent surgery. We also built competing risk nomograms to predict the prognosis of patients with NSCLC. PATIENTS AND METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We identified patients who underwent surgery with stage I NSCLC between 2004 and 2013. We estimated the cumulative incidence function (CIF) for cause-specific death and other causes of death, and tested the differences using Gray's test. The Fine and Gray proportional subdistribution hazard approach was applied to model CIF. We also built competing risk nomograms on the basis of Fine and Gray's model. RESULTS: We identified 20,850 stage I NSCLC patients from 2004 to 2013 in the SEER database. The 5-year cumulative incidence of cause-specific death for stage I NSCLC was 21.9% and 14.2% for other causes of death. Variables associated with cause-specific mortality included age, sex, marital status, histological grade, TNM stage, and surgery. The nomograms were well calibrated, and had good discriminative ability, with a c-index of 0.64 for the cancer-specific mortality model and 0.66 for the competing mortality model. CONCLUSION: We evaluated the CIF of cause-specific death and competing risk death in patients with surgically resected stage I NSCLC using the SEER database. We also built proportional subdistribution models and the first competing risk nomogram to predict prognosis. Our nomograms show a relatively good performance and can be a convenient individualized predictive tool for prognosis. PMID- 29153967 TI - The Role of Advanced Imaging in Assessing Response to Definitive Chemoradiation Before Prophylactic Cranial Irradiation in Limited-Stage Small-Cell Lung Cancer. AB - INTRODUCTION: Prophylactic cranial irradiation (PCI) improves survival for small cell lung cancer (SCLC). Evidence for PCI in limited-stage SCLC largely derives from studies requiring only chest x-ray (CXR) to determine remission status. We analyzed thoracic chemoradiation therapy (TCRT) outcomes according to imaging modality to determine which patients benefitted most from PCI. PATIENTS AND METHODS: All limited-stage SCLC patients who received TCRT as well as PCI at our institution were reviewed. Imaging between TCRT end and PCI start was characterized as complete (CR), partial (PR), or other response. RESULTS: Thirty eight consecutive patients were assessed for TCRT response before PCI with CXR (n = 21), chest computed tomography (CT; n = 27), and/or positron emission tomography (PET)/CT (n = 11). CR was identified on 71% of CXRs, 41% of CT scans, and 18% of PET/CT scans. Median survival was 28.3 months for the entire cohort and did not differ for patients who had CXR alone versus CT and/or PET/CT for restaging (P = .78) or those with PR using any modality versus CR using all modalities (22.6 months vs. 45.5 months; P = .22). CT CR patients had numerical but not statistically significant improved 2-year (P = .18) and 3-year (P = .13) survival compared with CT PR. CONCLUSION: CXR remains an appropriate modality to assess TCRT response before PCI in limited-stage SCLC. Advanced imaging did not inform the decision to offer PCI in this study. Because of similar excellent survival profiles independent of imaging modality and TCRT response, this analysis suggests limited-stage SCLC patients with PR using any modality should not be denied PCI, akin to standards for extensive-stage SCLC. PMID- 29153968 TI - Effect of Contract Research Organization Bureaucracy in Clinical Trial Management: A Model From Lung Cancer. AB - INTRODUCTION: Contract research organization (CRO) support is largely included in clinical trial management, although its effect in terms of time savings and benefit has not yet been quantified. We performed a retrospective multicenter analysis of lung cancer trials to explore differences in term of trial activation timelines and accrual for studies with and without CRO involvement. MATERIALS AND METHODS: Results regarding study timelines from feasibility data to first patient enrollment were collected from 7 Italian thoracic oncology departments. The final accruals (screened/enrolled patients) are reported. We considered CRO/sponsor administered and CRO-free trials according to who was responsible for the management of the crucial setup phases. RESULTS: Of 113 trials, 62 (54.9%) were CRO-administered, 34 (30.1%) were sponsor-administered, and 17 (15.0%) were CRO free. The median time from feasibility invitation to documentation obtainment was 151 days in the CRO-administered trials versus 128 in the sponsor-administered and 120 in the CRO-free trials. The time from document submission to contract signature was 142 days in the CRO-administered versus 128 in the sponsor administered and 132 in the CRO-free trials. The time from global accrual opening to first patient enrollment was 247 days for the CRO-administered versus 194 in the sponsor-administered and 151 in the CRO-free trials. No significant differences were observed in terms of the median overall timeline: 21 months in the CRO-administered, 15 in the sponsor-administered, and 18 months in the CRO free studies (P = .29). CONCLUSION: Although no statistically significant differences were identified, the results of our analysis support the idea that bureaucratic procedures might require more time in CRO-administered trials than in sponsor-administered and CRO-free studies. This bureaucratic delay could negatively affect Italian patients' screening and enrollment compared with other countries. PMID- 29153969 TI - Targeted muscle reinnervation for pain control in an elective transradial amputation. PMID- 29153970 TI - Evidence for the formal development of trauma subspecialty within plastic surgery in the United Kingdom. PMID- 29153971 TI - New insights into bisphenols removal by nitrogen-rich nanocarbons: Synergistic effect between adsorption and oxidative degradation. AB - In this work, nitrogen-rich graphene-like carbon sheets (N-GLCS) with high specific surface area (488.4m2/g), narrow pore distribution and high N-doping (18.4 at%) were prepared and applied as both adsorbent and catalyst for the removal of bisphenols. Adsorption experiments demonstrated the high adsorption capacities of the N-GLCS toward bisphenol F (BPF) (222.9mg/g), bisphenol A (BPA) (317.8mg/g), and bisphenol C (BPC) (540.4mg/g). Results showed that about 98.6% of BPA (70mg/L) was removed at pH 7.0 within 80min after the adsorption-catalytic degradation process. The N-GLCS also showed a superb reusability for the catalytic oxidative degradation of BPA (70mg/L) with the removal percentage maintains over 83% after 5 cycles. With the synergistic combination of the excellent adsorption and catalytic properties of the N-GLCS, trace amount of pollutants can be preconcentrated and immobilized at the surface of N-GLCs, at the same time, active radicals were also produced at the surface of the N-GLCS by the activation of peroxydisulfate (PS), and finally the pollutants can be degraded in-situ by the active radicals. These findings provide a new avenue towards the efficient removal of trace-level EDCs from water solution by using the coupled adsorption-advanced oxidation processes. PMID- 29153972 TI - Uses of oral history and digital storytelling in public health research and practice. AB - OBJECTIVES: Oral history (OH) and digital storytelling (DST) have been used in a range of ways in public health, including educating populations about health protecting practices, advocating for improved clinical care and reflecting on public health efforts to combat infectious disease. Yet, these methods are rarely recognized for their potential to contribute to public health research and practice. The aim of this article is to assess how OH and DST have been used in the health fields and to provide examples of ways that these methods have contributed to work in several domains of public health. STUDY DESIGN: Narrative review. METHODS: We conducted a narrative review of articles gathered from PubMed using the search terms 'oral history' and 'digital storytelling', which resulted in 102 articles relevant to public health. We then conducted a thematic analysis to create a typology of article topics and to examine cross-cutting themes. RESULTS: OH and DST have been used for both research and interventions in public health. Specifically, they have been used to 1) examine health risks and experiences; 2) engage and educate populations; 3) educate clinical professionals and organizations; and 4) inform public health practice. CONCLUSIONS: Despite the time, resources, and training required to do OH and DST well, we argue that these methods have substantial potential for supplementing public health activities, allowing the field to glean additional lessons from its experiences, to educate its practitioners further, and to better learn from the experiences of communities affected by public health problems. PMID- 29153973 TI - Airborn gamma-ray spectrometric data as guide for probable hydrocarbon accumulations at Al-Laqitah area, Central Eastern Desert of Egypt. AB - An exploration method has been developed to understand the relation between the radiometric measurements and the subsurface petroleum accumulations, where subtle anomalous patterns of radiation flux are detected over subsurface hydrocarbon basins. This technique is mainly based on utilizing the aerial gamma-ray spectral data in the prospecting for petroleum in stratigraphic and structural traps. Al Laqitah area, Central Eastern Desert, Egypt, was selected to apply this method on its recorded aerial gamma-ray spectrometric survey data. The method presented in this work may play a major role in making these measurements an effective contributor for finding oil and gas resources. Thorium normalization, as an exploration technique, was applied on the Foreland sedimentary cover of Al Laqitah area to prospect the possible subsurface hydrocarbon accumulations. The DRAD arithmetic means, plus the three times standard deviations(X+3S) for the data set were computed. Any single DRAD value, within the boundary of rock units, greater than this quantity that possesses a probability of 99.87% represents a valid anomaly that is not caused by random variations in the background values. The application of these criteria has led to the identification of nine zones over the investigated area that are statistically valid. These might indicate a prospective possibility for feasible subsurface hydrocarbon accumulations and oil bearing pay zones at Al-Laqitah area. PMID- 29153974 TI - The decays of 117Cd following neutron activation of enriched 116Cd. AB - A new set of spectrometric data on gamma ray energies and intensities in the decays of the 117g.mCd isomers (2.5h and 3.4h) has been accumulated. Uncertainties in the energies and intensities have been reduced by about an order of magnitude relative to previous studies. Through observation of their time dependence, several transitions are shown as incorrectly assigned in previous studies, and many new transitions were assigned to the respective decays. The placements of other transitions are shown to be doubtful based on poor energy fits. Energies and beta-decay intensities have been deduced for the excited states in the 117In daughter. Some additional gamma rays from the decay of daughter 117gIn to 117Sn have also been observed. PMID- 29153977 TI - A precision medicine approach to haematological malignancies. PMID- 29153975 TI - Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. AB - BACKGROUND: Continuation of empirical antimicrobial therapy (EAT) for febrile neutropenia in patients with haematological malignancies until neutrophil recovery could prolong the therapy unnecessarily. We aimed to establish whether EAT discontinuation driven by a clinical approach regardless of neutrophil recovery would optimise the duration of therapy. METHODS: We did an investigator driven, superiority, open-label, randomised, controlled phase 4 clinical trial in six academic hospitals in Spain. Eligible patients were adults with haematological malignancies or haemopoietic stem-cell transplantation recipients, with high-risk febrile neutropenia without aetiological diagnosis. An independent, computer-generated randomisation sequence was used to randomly enrol patients (1:1) to the experimental or control group. Investigators were masked to assignment only before randomisation. EAT based on an antipseudomonal beta-lactam drug as monotherapy (ceftazidime or cefepime, meropenem or imipenem, or piperacillin-tazobactam) or as combination therapy (with an aminoglycoside, fluoroquinolone, or glycopeptide) was started according to local protocols and following international guidelines and recommendations. For the experimental group, EAT was withdrawn after 72 h or more of apyrexia plus clinical recovery; for the control group, treatment was withdrawn when the neutrophil count was also 0.5 * 109 cells per L or higher. The primary efficacy endpoint was the number of EAT-free days. Primary analyses were done in the intention-to-treat population. Efficacy and safety analyses were done in the intention-to-treat population and the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01581333. FINDINGS: Between April 10, 2012, and May 31, 2016, 157 episodes among 709 patients assessed for eligibility were included in analyses. 78 patients were randomly assigned to the experimental group and 79 to the control group. The mean number of EAT-free days was significantly higher in the experimental group than in the control group (16.1 [SD 6.3] vs 13.6 [7.2], absolute difference -2.4 [95% CI -4.6 to -0.3]; p=0.026). 636 adverse events were reported (341 in the experimental group vs 295 in the control group; p=0.057) and most (580 [91%]; 323 in the experimental group vs 257 in the control group) were considered mild or moderate (grade 1-2). The most common adverse events in the experimental versus the control group were mucositis (28 [36%] of 78 patients vs 20 [25%] of 79 patients), diarrhoea (23 [29%] of 78 vs 24 [30%] of 79), and nausea and vomiting (20 [26%] of 78 vs 22 [28%] of 79). 56 severe adverse events were reported, 18 in the experimental group and 38 in the control group. One patient died in the experimental group (from hepatic veno-occlusive disease after an allogeneic haemopoietic stem-cell transplantation) and three died in the control group (one from multiorgan failure, one from invasive pulmonary aspergillosis, and one from a post-chemotherapy intestinal perforation). INTERPRETATION: In high-risk patients with haematological malignancies and febrile neutropenia, EAT can be discontinued after 72 h of apyrexia and clinical recovery irrespective of their neutrophil count. This clinical approach reduces unnecessary exposure to antimicrobials and it is safe. FUNDING: Instituto de Salud Carlos III, Spanish Ministry of Economy (PI11/02674). PMID- 29153978 TI - The endometria of women with endometriosis exhibit dysfunctional expression of complement regulatory proteins during the mid secretory phase. AB - The control of complement activation within embryo-endometrium environment is critical for embryo survival. Cell evasion from complement attack requires interaction of complement regulatory proteins (CRPs) with cell adhesion alphavbeta3 integrin. We aim to compare the expression of CRPs in endometria of women with and without endometriosis and to examine the molecular interaction of decay accelerating factor (DAF) with alphavbeta3 integrin. Endometrial expression of Membrane cofactor protein (CD46), Decay accelerating factor (DAF), Membrane attack complex inhibitory factor (CD59) and beta3 integrin subunit were determined through menstrual cycle by immunohistochemistry. DAF protein quantity was determined by Western blot and mRNA levels measured in epithelial cells isolated by laser capture microdissection (LCM). Using in vitro assay, we examined DAF and beta3 integrin expression through paracrine regulation between endometrial compartments. To determine whether beta3 integrin and DAF interacts in vivo, endometrial samples were subjected to immunoprecipitation and colocalization using dual immunofluorescence technique. DAF and beta3 integrin expression were significantly low in samples from women with endometriosis during mid secretory phase. This observation was supported by decreased DAF protein quantity; faint DAF and beta3 integrin interaction and reduced mRNA levels in cells dissected by LCM. Moreover epithelial DAF and beta3 integrin expression through paracrine regulation by progesterone from stromal compartment was disrupted in endometriosis. Endometria from women with endometriosis exhibits aberrant expression of complement proteins. The abnormal DAF expression potentially compromises embryo survival, contributing to understand the implantation failure in women with endometriosis. PMID- 29153976 TI - Image-based ex-vivo drug screening for patients with aggressive haematological malignancies: interim results from a single-arm, open-label, pilot study. AB - BACKGROUND: Patients with refractory or relapsed haematological malignancies have few treatment options and short survival times. Identification of effective therapies with genomic-based precision medicine is hampered by intratumour heterogeneity and incomplete understanding of the contribution of various mutations within specific cancer phenotypes. Ex-vivo drug-response profiling in patient biopsies might aid effective treatment identification; however, proof of its clinical utility is limited. METHODS: We investigated the feasibility and clinical impact of multiparametric, single-cell, drug-response profiling in patient biopsies by immunofluorescence, automated microscopy, and image analysis, an approach we call pharmacoscopy. First, the ability of pharmacoscopy to separate responders from non-responders was evaluated retrospectively for a cohort of 20 newly diagnosed and previously untreated patients with acute myeloid leukaemia. Next, 48 patients with aggressive haematological malignancies were prospectively evaluated for pharmacoscopy-guided treatment, of whom 17 could receive the treatment. The primary endpoint was progression-free survival in pharmacoscopy-treated patients, as compared with their own progression-free survival for the most recent regimen on which they had progressive disease. This trial is ongoing and registered with ClinicalTrials.gov, number NCT03096821. FINDINGS: Pharmacoscopy retrospectively predicted the clinical response of 20 acute myeloid leukaemia patients to initial therapy with 88.1% accuracy. In this interim analysis, 15 (88%) of 17 patients receiving pharmacoscopy-guided treatment had an overall response compared with four (24%) of 17 patients with their most recent regimen (odds ratio 24.38 [95% CI 3.99-125.4], p=0.0013). 12 (71%) of 17 patients had a progression-free survival ratio of 1.3 or higher, and median progression-free survival increased by four times, from 5.7 (95% CI 4.1 12.1) weeks to 22.6 (7.4-34.0) weeks (hazard ratio 3.14 [95% CI 1.37-7.22], p=0.0075). INTERPRETATION: Routine clinical integration of pharmacoscopy for treatment selection is technically feasible, and led to improved treatment of patients with aggressive refractory haematological malignancies in an initial patient cohort, warranting further investigation. FUNDING: Austrian Academy of Sciences; European Research Council; Austrian Science Fund; Austrian Federal Ministry of Science, Research and Economy; National Foundation for Research, Technology and Development; Anniversary Fund of the Austrian National Bank; MPN Research Foundation; European Molecular Biology Organization; and Swiss National Science Foundation. PMID- 29153979 TI - Individual surgeon practice is the most important factor influencing diverting loop ileostomy creation for patients undergoing sigmoid colectomy for diverticulitis. AB - BACKGROUND: To identify factors associated with diverting ileostomy creation (DLI) in patients undergoing sigmoid colectomy for diverticular disease in a high volume colorectal unit and to obtain information for better preoperative patient counseling. METHODS: Patients who underwent sigmoid colectomy with colorectal anastomosis with or without DLI for diverticulitis between 01/1994-12/2014 were identified. Preoperative characteristics, surgeon practice year, individual surgeon and postoperative outcomes were compared between patients with DLI or not. RESULTS: 1320 patients were identified and DLI was created in 204 (15.4%) patients. DLI creation was associated with older age (p < 0.001), female gender (p = 0.01), higher ASA-class (p < 0.001), hypertension (p = 0.01), DM(p < 0.001), renal comorbidities (p < 0.001), preoperative steroid use (p = 0.03), preoperative anemia (p = 0.004), and open surgery (p < 0.001). While ileostomy creation rates did not vary over the years during the study period or with increased surgeons' experience, surgeon identity had significant impact on ileostomy creation (Rate range 6.8-60.7%, p < 0.001). Multivariate logistic regression analysis revealed that individual surgeon, open approach, preoperative steroid use, and disease-related factors remained independently associated with DLI creation. CONCLUSION: Individual surgeon's practice affects the rate of diverting ileostomy creation in patients undergoing sigmoid colectomy for diverticular disease. PMID- 29153980 TI - Why saying what you mean matters: An analysis of trauma team communication. AB - BACKGROUND: We hypothesized that team communication with unmatched grammatical form and communicative intent (mixed mode communication) would correlate with worse trauma teamwork. METHODS: Interdisciplinary trauma simulations were conducted. Team performance was rated using the TEAM tool. Team communication was coded for grammatical form and communicative intent. The rate of mixed mode communication (MMC) was calculated. MMC rates were compared to overall TEAM scores. Statements with advisement intent (attempts to guide behavior) and edification intent (objective information) were specifically examined. The rates of MMC with advisement intent (aMMC) and edification intent (eMMC) were also compared to TEAM scores. RESULTS: TEAM scores did not correlate with MMC or eMMC. However, aMMC rates negatively correlated with total TEAM scores (r = -0.556, p = 0.025) and with the TEAM task management component scores (r = -0.513, p = 0.042). CONCLUSIONS: Trauma teams with lower rates of mixed mode communication with advisement intent had better non-technical skills as measured by TEAM. PMID- 29153981 TI - Movement disorders in a cohort of Algerian patients with multiple sclerosis. AB - Multiple sclerosis is an inflammatory demyelinating disease of central nervous system. Except for cerebellar tremor, occurence of other movement disorders remains rare. Our study aimed to evaluate their prevalence in our population of patients with multiple sclerosis, and to compare it with literature data. Our results showed higher prevalence compared to European studies, raising the question of mechanisms of the disorder. MRI correlation was also studied, in 3 cases over 8 and a possible correlation was found. PMID- 29153982 TI - Factors associated with women's perception of and satisfaction with quality of intrapartum care practices in Swaziland. AB - OBJECTIVE: giving birth is a lifetime event, where the quality of care a woman receives has the potential to affect her or her baby both physically and emotionally either on a short-term or long-term basis. This study aimed at identifying factors associated with women's perception of and satisfaction with the quality of intrapartum care as well as their future loyalty intentions in two regional hospitals in Swaziland. METHODS: this is a correlational study where data were collected from 383 women conveniently selected from two regional hospitals where they gave birth. The QPP-I, SHPC, AND WOM questionnaires were used for data collection which was done from July to September 2016. FINDINGS: the results reflected that women's satisfaction with quality of intrapartum care total mean score was (M+/-SD = 74.17+/-10.1), a perceived reality of intrapartum care practices total mean score of (M+/-SD = 96.94+/-16.0), a high subjective importance total mean score (M+/-SD = 117.78+/-10.5), and above average future loyalty intension total mean score (M+/-SD 1.67+/-0.69). Factors that significantly predicted women's satisfaction with quality of intrapartum care include, perceived quality (F = 54.13, p<0.001 with 28% R2 variance), demographic variables (educational level, employment status and gestational weeks) (F = 10.66, p =<0.001, with 8% R2 variance), future loyalty intensions (F = 48.57, p<0.001with 7% R2 variance), and subjective importance (F = 44.74, p<0.001 with 1% R2 variance). CONCLUSION: the study revealed that women's perceived reality of and satisfaction with the quality of intrapartum care practices was suboptimal. Improvement should be focused on evidence-based intrapartum care that is women centered, involving the clients in decision-making and also a comprehensive childbirth education for the pregnant mothers. PMID- 29153983 TI - Perceptions, intentions and behavioral norms that affect pre-license driving among Arab youth in Israel. AB - The present study examines reported pre-license driving among youth from the population of Arab citizens of Israel. The purpose of the present study is to examine which sociodemographic variables, attitudes and perceptions about safe driving and individual and societal behavioral norms are associated with pre license driving. The research distinguished between the factors that actually contribute to pre-license driving (reported behavior, peer norms, gender and parents' messages) and the factors that explain the intention (parental authority, social norms, parents' messages and fear of road crashes). Even though there was a significant partial overlap (84%) between those who intend to drive without a license and those who reported driving without a license, the main factors that distinguish pre-license driving groups are different from the factors that distinguish the intention to drive before receiving a license. What is unique about the findings is the identification of the context in which social norms are influential and that in which parental authority is influential. The study indicated that in the case of pre-license driving, the main motivating factor is subjective norms, whereas in the case of expecting to drive without a license, the main motivating factor is the interaction between parental authority and the messages that parents convey. While actual behavior pertains to the behavioral level, we argue that intended behavior pertains to the cognitive level. At this level, rational considerations arise, such as fear of parental punishment and fear of accidents. These considerations compete with the influence of friends and their norms, and may outweigh them. The findings suggest that it is important to safeguard youth against the influence of peer pressure as early as the stage of behavioral intentions. Follow-up studies can simulate situations of pre-license driving due to social pressure and identify the factors that might affect young people's decision-making. Moreover, providing parents with training before the accompaniment period is highly recommended. PMID- 29153984 TI - Influence of Mixed Additives on the Physicochemical Properties of a 5.25% Sodium Hypochlorite Solution: An Unsupervised Multivariate Statistical Approach. AB - INTRODUCTION: This article reports for the first time the effects of multiple additives (polyethylene glycol 400, Triton X-100, benzalkonium chloride, and ethyl formate) on the surface tension, pH, and viscosity of 5.25% sodium hypochlorite (NaOCl) irrigant solution. Advanced statistical approaches based on unsupervised multivariate analysis (cluster analysis and principal component analysis) were used to quantify the variability of the physicochemical properties of the modified NaOCl solution for the first time in dentistry. METHODS: Solutions of 5.25% NaOCl were modified with multiple additives in various concentrations, physicochemical parameters were measured at 22 degrees C and 37 degrees C, and the results were statistically analyzed to group the solutions and reveal the effects of additives. RESULTS: Cluster analysis and principal component analysis revealed that pH and surface tension were the significant parameters (P < .05) for grouping the modified solutions. Four principal components, accounting for 90.6% of the total variance, were associated with flow characteristics (37.3%) determined by polyethylene glycol; the wetting property (22.5% and 10.5%), which was dependent on cationic and nonionic surfactant; and the antimicrobial effect (20.3%) influenced by ethyl formate. Varimax rotation of the principal components showed that the cationic surfactant (benzalkonium chloride) had significantly decreased surface tension compared with the nonionic surfactant (Triton-X). Although ethyl formate was introduced as an odor modifier, it had a significant effect on pH decrease and the occurrence of effervescence with O2 and hypochlorous acid release. CONCLUSIONS: The statistical results revealed that the 5.25% NaOCl irrigant solution should be modified with a mixture of 0.1% benzalkonium chloride, 1% ethyl formate, and 7% polyethylene glycol for obtaining a low pH and low surface tension. PMID- 29153985 TI - Diagnosis of Mesiodistal Vertical Root Fractures in Teeth with Metal Posts: Influence of Applying Filters in Cone-beam Computed Tomography Images at Different Resolutions. AB - INTRODUCTION: The aim of this article was to evaluate the influence of applying filters in cone-beam computed tomography (CBCT) images at different resolutions. These CBCT images were obtained for diagnosing mesiodistal vertical root fractures (VRFs) in teeth with metal posts. METHODS: Forty teeth were treated endodontically, and 20 received metal posts. Ten teeth without posts and 10 teeth with posts were subjected to VRF in the mesiodistal direction. The sample was submitted to periapical radiographs and CBCT exams with a voxel of 0.25 and 0.30 mm. To reduce the influence of the metal artifact in the CT images, the teeth were evaluated with and without the application of filters ("Sharpen" and "Hard"). The images were evaluated by 2 radiologists who identified the presence of VRF. Accuracy values (receiver operating characteristic curves) for the different variables were compared by using analysis of variance and t test. RESULTS: No difference was observed between images with and without filter application (P > .05). Images obtained with a 0.25-mm voxel were more accurate (P < .05). The presence of the metal post reduced the accuracy of the diagnosis of VRF (P < .05), and the CBCT images showed superior results compared with periapical radiographs (P < .05). CONCLUSIONS: The presence of a metal post and the voxel size significantly interfere with the diagnosis of VRF. Despite the formation of metal artifacts associated with metallic cores, applying filters did not improve the diagnosis. For mesiodistal VRF, the CBCT images are superior to the periapical radiographs. PMID- 29153986 TI - Efficient Induction of Syncytiotrophoblast Layer II Cells from Trophoblast Stem Cells by Canonical Wnt Signaling Activation. AB - The syncytiotrophoblast layer is the most critical and prominent tissue in placenta. SynT cells are differentiated from trophoblast stem cells (TSCs) during early embryogenesis. Mouse TSCs can spontaneously differentiate into cells of mixed lineages in vitro upon withdrawal of stemness-maintaining factors. However, differentiation into defined placental cell lineages remains challenging. We report here that canonical Wnt signaling activation robustly induces expression of SynT-II lineage-specific genes Gcm1 and SynB and suppresses markers of other placental lineages. In contrast to mouse TSCs, the induced SynT-II cells are migratory. More importantly, the migration depends on hepatocyte growth factor (HGF) and the c-MET signaling axis. Furthermore, HGF-expressing cells lie adjacent to SynT-II cells in developing murine placenta, suggesting that HGF/c MET signaling plays a critical role in SynT-II cell morphogenesis during the labyrinth branching process. The availability of SynT-II cells in vitro will facilitate molecular understanding of labyrinth layer development. PMID- 29153987 TI - Development and Characterization of a Human and Mouse Intestinal Epithelial Cell Monolayer Platform. AB - We describe the development and characterization of a mouse and human epithelial cell monolayer platform of the small and large intestines, with a broad range of potential applications including the discovery and development of minimally systemic drug candidates. Culture conditions for each intestinal segment were optimized by correlating monolayer global gene expression with the corresponding tissue segment. The monolayers polarized, formed tight junctions, and contained a diversity of intestinal epithelial cell lineages. Ion transport phenotypes of monolayers from the proximal and distal colon and small intestine matched the known and unique physiology of these intestinal segments. The cultures secreted serotonin, GLP-1, and FGF19 and upregulated the epithelial sodium channel in response to known biologically active agents, suggesting intact secretory and absorptive functions. A screen of over 2,000 pharmacologically active compounds for inhibition of potassium ion transport in the mouse distal colon cultures led to the identification of a tool compound. PMID- 29153988 TI - Isolation and Comparative Transcriptome Analysis of Human Fetal and iPSC-Derived Cone Photoreceptor Cells. AB - Loss of cone photoreceptors, crucial for daylight vision, has the greatest impact on sight in retinal degeneration. Transplantation of stem cell-derived L/M-opsin cones, which form 90% of the human cone population, could provide a feasible therapy to restore vision. However, transcriptomic similarities between fetal and stem cell-derived cones remain to be defined, in addition to development of cone cell purification strategies. Here, we report an analysis of the human L/M-opsin cone photoreceptor transcriptome using an AAV2/9.pR2.1:GFP reporter. This led to the identification of a cone-enriched gene signature, which we used to demonstrate similar gene expression between fetal and stem cell-derived cones. We then defined a cluster of differentiation marker combination that, when used for cell sorting, significantly enriches for cone photoreceptors from the fetal retina and stem cell-derived retinal organoids, respectively. These data may facilitate more efficient isolation of human stem cell-derived cones for use in clinical transplantation studies. PMID- 29153989 TI - PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a common neurodegenerative disorder and the leading cause of cognitive impairment. Due to insufficient understanding of the disease mechanisms, there are no efficient therapies for AD. Most studies have focused on neuronal cells, but astrocytes have also been suggested to contribute to AD pathology. We describe here the generation of functional astrocytes from induced pluripotent stem cells (iPSCs) derived from AD patients with PSEN1 DeltaE9 mutation, as well as healthy and gene-corrected isogenic controls. AD astrocytes manifest hallmarks of disease pathology, including increased beta-amyloid production, altered cytokine release, and dysregulated Ca2+ homeostasis. Furthermore, due to altered metabolism, AD astrocytes show increased oxidative stress and reduced lactate secretion, as well as compromised neuronal supportive function, as evidenced by altering Ca2+ transients in healthy neurons. Our results reveal an important role for astrocytes in AD pathology and highlight the strength of iPSC-derived models for brain diseases. PMID- 29153990 TI - Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability. AB - Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Abeta, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Abeta plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable) and caudal fates (relatively spared) in AD. We find that both the generation of Abeta and the responsiveness of TAU to Abeta are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD. PMID- 29153991 TI - Serine 347 Phosphorylation by JNKs Negatively Regulates OCT4 Protein Stability in Mouse Embryonic Stem Cells. AB - The POU transcription factor OCT4 is critical for maintaining the undifferentiated state of embryonic stem cells (ESCs) and generating induced pluripotent stem cells (iPSCs), but its precise mechanisms of action remain poorly understood. Here, we investigated the role of OCT4 phosphorylation in the biological functions of ESCs. We observed that c-Jun N-terminal kinases (JNKs) directly interacted with and phosphorylated OCT4 at serine 347, which inhibited the transcriptional activity of OCT4. Moreover, phosphorylation of OCT4 induced binding of FBXW8, which reduced OCT4 protein stability and enhanced its proteasomal degradation. We also found that the mutant OCT4 (S347A) might delay the differentiation process of mouse ESCs and enhance the efficiency of generating iPSCs. These results demonstrated that OCT4 phosphorylation on serine 347 by JNKs plays an important role in its stability, transcriptional activities, and self-renewal of mouse ESCs. PMID- 29153992 TI - To drink or to drink less? Distinguishing between effects of implementation intentions on decisions to drink and how much to drink in treatment-seeking individuals with alcohol use disorder. AB - INTRODUCTION: For many people with alcohol use disorders, alcohol drinking is a highly ingrained and automatized behavior with negative long-term health consequences. Implementation intentions, a behavioral intervention that links high-risk drinking situations with alternative, healthier responses, provide a means to intervene on habitual drinking behaviors. Here, a pilot treatment using implementation intentions was assessed with remote assessments and treatment prompts. METHODS: Treatment-seeking individuals with alcohol use disorder between the ages of 18 and 65 were recruited from the community from October 2014 to November 2016. Participants (N=35) were quasi-randomly assigned to complete either active (n=18) or control (n=17) two-week implementation intention interventions. Active implementation intentions linked high-risk situations with alternative responses whereas the control condition selected situations and responses but did not link these together. Daily ecological momentary interventions of participant-tailored implementation intentions were delivered via text message. Alcohol consumption was assessed once daily with self-reported ecological momentary assessments (EMAs) of drinks consumed the previous day and thrice daily remotely submitted breathalyzer samples to assess reliability of self-reports. RESULTS: On drinking days (80% of days), the active implementation intentions group reduced alcohol consumption during the intervention period compared to the control condition; however the difference between consumption was not observed at one-month follow-up. DISCUSSION: The implementation intention intervention was associated with a 1.09 drink per day decrease in alcohol consumption on drinking days compared to a decrease of 0.29 drinks per day in the control condition. Future studies may combine implementation intentions with other treatments to help individuals to reduce alcohol consumption. PMID- 29153993 TI - The high frequency of superior labrum, biceps tendon, and superior rotator cuff pathologies in patients with subscapularis tears: A cohort study. AB - BACKGROUND: The purpose of this study was to assess the frequency of superior labrum anterior posterior (SLAP) lesions, long head of biceps tendon (LHBT) pathologies, and superior rotator cuff tears accompanying subscapularis tears. We hypothesised that LHBT lesions, superior rotator cuff tears, and especially SLAP lesions were very frequent with subscapularis tears. METHODS: The digital files of patients who underwent shoulder arthroscopy were reviewed retrospectively. One hundred and eleven patients with subscapularis tears evident on surgery videos were examined. Superior labrum, LHBT, and superior rotator cuff lesions were investigated by the authors of this study. The statistical analyses were made with SPSS statistics software, and significance was set at P < 0.05 value. RESULTS: There were 111 patients with both subscapularis tears and surgery videos. The mean age was 58.09 +/- 10.21, and 63.1% of the patients were female. 98.2% of the 111 patients had a SLAP lesion. 7.2% of those were SLAP I and 91% were SLAP II lesions while 1.8% were healthy. The 75.7% of the patients had a LHBT pathology, and 83.8% had superior cuff tear. CONCLUSIONS: Subscapularis tears were almost always accompanied by SLAP lesions. On the other hand, biceps tendon pathologies and superior rotator cuff tears were also very frequent with subscapularis tears. LEVEL OF EVIDENCE: Prognostic study, Level IV (retrospective cohort study). PMID- 29153994 TI - Incident Atrial Fibrillation and the Risk of Congestive Heart Failure, Myocardial Infarction, End-Stage Kidney Disease, and Mortality Among Patients With a Decreased Estimated GFR. AB - BACKGROUND: The association of atrial fibrillation (AF), estimated glomerular filtration rate (eGFR), and adverse events remains unknown. STUDY DESIGN: Population-based retrospective cohort study from Ontario, Canada. SETTING & PARTICIPANTS: 1,422,978 adult residents with eGFRs < 90mL/min/1.73m2 from April 1, 2006, through March 31, 2015. FACTOR: A diagnosis of AF at hospitalization. OUTCOMES: Congestive heart failure (CHF), myocardial infarction (MI), end-stage kidney disease, all-cause mortality. RESULTS: All adverse events were more frequent in individuals with AF (93,414 propensity score matched) compared to no AF, and this difference was more pronounced within the first 6 months of the index date (CHF: 3.04% [AF] vs 0.28% [no AF], subdistribution HR [sHR] of 11.57 [95% CI, 10.26-13.05]; MI: 0.97% [AF] vs 0.21% [no AF], sHR of 4.76 [95% CI, 4.17 5.43]; end-stage kidney disease: 0.16% [AF] vs 0.03% [no AF], sHR of 5.84 [95% CI, 3.82-8.93]; and all-cause mortality: 6.11% [AF] vs 2.50% [no AF], HR of 2.62 [95% CI, 2.50-2.76]) than in the period more than 6 months after the index date (CHF: 6.87% [AF] vs 2.87% [no AF], sHR of 2.64 [95% CI, 2.55-2.74]; MI: 2.21% [AF] vs 1.81% [no AF], sHR of 1.24 [95% CI, 1.18-1.30]; end-stage kidney disease: 0.52% [AF] vs 0.32% [no AF], sHR of 1.75 [95% CI, 1.57-1.95]; and all-cause mortality: 15.55% [AF] vs 15.10% [no AF], HR of 1.07 [95% CI, 1.04-1.10]). The results accounted for the competing risk for mortality. eGFR level modified the effect of AF on CHF (P for interaction < 0.05). LIMITATIONS: Observational study design does not permit determination of causality; only a single outpatient eGFR measure was used; medication data were not included. CONCLUSIONS: Incident AF is associated with a high risk for adverse outcomes in patients with eGFRs < 90mL/min/1.73m2. Because the risk is exceedingly high within the first 6 months after AF diagnosis, therapeutic interventions and monitoring may improve outcomes. PMID- 29153995 TI - Longitudinal Estimated GFR Trajectories in Patients With and Without Type 2 Diabetes and Nephropathy. AB - BACKGROUND: In clinical practice and clinical trials, changes in serum creatinine concentrations are used to evaluate changes in kidney function. It has been assumed that these changes follow a linear pattern when serum creatinine concentration is converted to estimated glomerular filtration rate (eGFR). However, the paradigm that kidney function declines linearly over time has been questioned by studies showing either linear or nonlinear patterns. To verify how this impacts on kidney end points in intervention trials, we analyzed eGFR trajectories in multiple clinical trials of patients with and without diabetes. STUDY DESIGN: Longitudinal observational study. SETTING & PARTICIPANTS: 6 clinical trials with repeated measurements of serum creatinine. PREDICTOR: Patient demographic and clinical parameters. OUTCOMES: Probability of nonlinear eGFR function trajectory calculated for each patient from a Bayesian model of individual eGFR trajectories. RESULTS: The median probability of a nonlinear eGFR decline in all trials was 0.26 (interquartile range, 0.13-0.48). The median probability was 0.28 in diabetes versus 0.09 in nondiabetes trials (P<0.01). The percentage of patients with a >50% probability of nonlinear eGFR decline was generally low, ranging from 19.3% to 31.7% in the diabetes trials and from 15.1% to 21.2% in the nondiabetes trials. In the pooled data set, multivariable linear regression showed that higher baseline eGFR, male sex, diabetes status, steeper eGFR slope, and non-renin-angiotensin-aldosterone-system antihypertensives were independently associated with a greater probability of a nonlinear eGFR trajectory. LIMITATIONS: Relatively short follow-up and no measured GFR. CONCLUSIONS: In both diabetes and nondiabetes trials, the majority of patients show a more or less linear eGFR decline. These data support the paradigm that in diabetic and nondiabetic kidney disease, eGFR decline progresses linearly over time during a clinical trial period. However, in diabetes, one should take the nonlinearity proportion into account in the design of a clinical trial. PMID- 29153996 TI - Clinical presentation of anti-N-methyl-d-aspartate receptor and anti-voltage gated potassium channel complex antibodies in children: A series of 24 cases. AB - OBJECTIVE: The symptomatology and paraclinical findings of antibody-mediated encephalitis, a relatively novel disorder, are still being characterized in adults and children. A high index of suspicion is needed in order to identify these cases among children presenting with various neurological symptoms. The aim of this study is to examine the clinical, demographic and laboratory findings and outcome of children with anti-NMDAR and anti-VGKC encephalitis for any typical or distinctive features. METHODS: Cases diagnosed with anti-N-Methyl d-aspartate receptor (NMDAR) and anti-voltage gated potassium channel (VGKC) antibody mediated encephalopathy in four major child neurology centers are described. RESULTS: In four years, 16 children with NMDAR and 8 children with VGKC antibody associated disease were identified in the participating centers. The most frequent initial manifestation consisted of generalized seizures and cognitive symptoms in both groups. Movement abnormalities were frequent in anti-NMDAR patients and autonomic symptoms, in anti-VGKC patients. Cerebrospinal fluid (CSF) protein, cell count and IgG index were normal in 9/15 anti-NMDAR and 5/8 anti VGKC patients tested. EEG and MRI findings were usually nonspecific and non contributory. The rate and time of recovery was not related to age, sex, acute or subacute onset, antibody type, MRI, EEG or CSF results. Treatment within 3 months of onset was associated with normal neurological outcome. CONCLUSIONS: Our results suggest anti-NMDAR and VGKC encephalopathies mostly present with non focal neurological symptoms longer than 3 weeks. In contrast with adult cases, routine CSF testing, MRI and EEG did not contribute to the diagnosis in this series. PMID- 29153997 TI - First investigations for the characterization of glucosamine-6-phosphate synthase by capillary electrophoresis. AB - The enzyme glucosamine-6-phosphate synthase (GlmS) is an important point of metabolic control in biosynthesis of amino sugar-containing macromolecules and is therefore a potential target in order to design antibacterial and antifungal drugs. It has two oligomerization states, which are the active dimer and the inactive hexamer. For the first time, the potential of CE to separate and quantify the two forms was studied. After incubating GlmS with the d-glucosamine 6-phosphate (GlcN6P) inhibitor, an electrolyte based on sodium phosphate at pH 7.2 and an ionic strength of 100mM plus GlcN6P (either 2 or 20mM) allowed the hexamer-dimer separation. However, the displacement of the dimer/hexamer equilibrium during the analysis time prevented any improvement of the resolution when varying the effective separation length or the temperature of the analysis. Therefore, the use of a short-end CE method allowed the decrease in the analysis time to about 1min. Some parameters such as the temperature and the time of incubation and the ratio of the inhibitor and enzyme concentrations were studied. Then, it was also possible to test, very rapidly and with a very small amount, some molecules having an inhibition potential for the GlmS enzyme (arabinose-5 phosphate oxime, 2-amino-2-deoxy-d-glucitol 6-phosphate, and glucose-6 phosphate). PMID- 29153998 TI - Determination of isoquercitrin in rat plasma by high performance liquid chromatography coupled with a novel synergistic cloud point extraction. AB - A novel improved preconcentration method known as synergistic cloud point extraction was established for isoquercitrin preconcentration and determination in rat plasma prior to its determination by high performance liquid chromatography. Synergistic cloud point extraction greatly simplified isoquercitrin extraction and detection. This method was accomplished at room temperature (about 22 degrees C) in 1min with the nonionic surfactant Tergitol TMN-6 as the extractant, n-octanol as cloud point revulsant and synergic reagent. Parameters that affect the synergistic cloud point extraction processes, such as the concentrations of Tergitol TMN-6, volume of n-octanol, sample pH, salt content and extraction time were investigated and optimized. Under the optimum conditions, the calibration curve for the analyte was linear in the range from 5 to 500ngmL-1 with the correlation coefficients greater than 0.9996. Meanwhile, limit of detection (S/N=3) was less than 1.6ngmL-1 and limit of quantification (S/N=10) was less than 5ngmL-1. It demonstrated that the method can be successfully applied to the pharmacokinetic investigation of isoquercitrin. PMID- 29154000 TI - Retrospective audit of people treated with long-acting antipsychotic injectable medications: Usage patterns and outcomes. PMID- 29153999 TI - Improving the selectivity and sensitivity for quantifying 8-alpha-hydroxy-mutilin in rabbit tissues by using basic mobile phases and negative ionization. AB - Previously reported LC-MS methods for quantifying 8-alpha-hydroxy-mutilin (a marker residue of tiamulin) in tissues all used a pseudo MRM transition (from protonated molecular ion to protonated molecular ion, m/z 337->337) due to difficulties in finding a product ion, leading to suboptimal selectivity and sensitivity for detection. By using electrospray negative ionization in a basic medium, we, for the first time, found a highly selective and sensitive true MRM transition for 8-alpha-hydroxy-mutilin, m/z 335->179. With this newly found MRM transition and the use of pleuromutilin as the internal standard, a very sensitive, selective, and robust LC-MS/MS method has been developed and validated for quantifying 8-alpha-hydroxy-mutilin in rabbit tissues (muscle, liver, kidney, and fat). In comparison with the previously published methods, the selectivity and sensitivity were significantly improved. For the concentration range validated (0.2-10ppm or 0.2-10MUg/g), the within-run and between-run accuracies (% bias) ranged from -5.0 to 3.1 and -4.9 to 3.0, respectively. The% CV ranged from 2.2 to 6.6 and 4.7 to 8.3 for within-run and between-run precisions, respectively. The validated method was successfully used to support two GLP tissue residue depletion studies in rabbits. PMID- 29154001 TI - Tri-allelic patterns of STRs and partially homologous non-sister chromatid crossover observed in a parentage test. AB - A maternity testing case is reported, in which the child showed tri-allelic patterns in two short tandem repeat (STR) loci. The genotypes of Penta D of the mother and the child were 9,13 and 9,10,13, respectively. Those of D21S11 were 32.2,35 and 29,35, respectively, but intensity ratio of alleles 29 and 35 of the child was 1:2. These results suggested the copy number variations (CNVs) or trisomy of chromosome 21. By further examination using STR-based chromosome aneuploidy detection kit, three alleles were detected in D21S1411, LFG21 and Penta D, and 2 alleles with intensity ratio of 1:2 were observed in D21S2502, D21S1435, D21S11 and D21S1246. Karyotype and whole-genome SNP array analyses showed that the child had a free trisomy 21. In addition, partially homologous non-sister chromatid crossover occurred at the region 19181770-39499178 on the long arm of chromosome 21. PMID- 29154002 TI - Forensic evaluation of STR typing reliability in lung cancer. AB - Short tandem repeats (STR) analysis is the gold standard method in the forensics field for personal identification and paternity testing. In cancerous tissues, STR markers are gaining attention, with some studies showing increased instability. Lung cancer, which is one of the most commonmalignancies, has become the most lethal among all cancers. In certain situations, lung cancer tissues may be the only resource available for forensic analysis. Therefore, evaluating the reliability of STR markers in lung cancer tissues is required to avoid false exclusions. In this study, 75 lung cancer tissue samples were examined to evaluate the reliability of various STR markers. Out of the 75 examined samples, 24 of the cancerous samples (32%) showed genetic alterations on at least one STR loci, totaling 55 times. The most common type of STR variation was a partial loss of heterozygosity, with the D5S818 loci having the highest variation frequency and no alterations detected on the D2S441 and Penta E loci. Moreover, STR variation frequencies were shown to increase with an increased patient age and increased clinical and pathological characteristics, thus an older patient with an advanced stage of progression exhibited a higher variation frequency. Overall, this study provides forensic scientists with further insight into STR analysis relating to lung cancer tissue. PMID- 29154003 TI - Tracing the role of endogenous carbon in denitrification using wine industry by product as an external electron donor: Coupling isotopic tools with mathematical modeling. AB - Nitrate removal through enhanced biological denitrification (EBD), consisting of the inoculation of an external electron donor, is a feasible solution for the recovery of groundwater quality. In this context, liquid waste from wine industries (wine industry by-products, WIB) may be feasible for use as a reactant to enhance heterotrophic denitrification. To address the feasibility of WIB as electron donor to promote denitrification, as well as to evaluate the role of biomass as a secondary organic C source, a flow-through experiment was carried out. Chemical and isotopic characterization was performed and coupled with mathematical modeling. Complete nitrate attenuation with no nitrite accumulation was successfully achieved after 10 days. Four different C/N molar ratios (7.0, 2.0, 1.0 and 0) were tested. Progressive decrease of the C/N ratio reduced the remaining C in the outflow and favored biomass migration, producing significant changes in dispersivity in the reactor, which favored efficient nitrate degradation. The applied mathematical model described the general trends for nitrate, ethanol, dissolved organic carbon (DOC) and dissolved inorganic carbon (DIC) concentrations. This model shows how the biomass present in the system is degraded to dissolved organic C (DOCen) and becomes the main source of DOC for a C/N ratio between 1.0 and 0. The isotopic model developed for organic and inorganic carbon also describes the general trends of delta13C of ethanol, DOC and DIC in the outflow water. The study of the evolution of the isotopic fractionation of organic C using a Rayleigh distillation model shows the shift in the organic carbon source from the WIB to the biomass and is in agreement with the isotopic fractionation values used to calibrate the model. Isotopic fractionations (epsilon) of C-ethanol and C-DOCen were -10/00 and -50/00 (model) and -3.30/00 and -4.80/00 (Rayleigh), respectively. In addition, an inverse isotopic fractionation of +100/00 was observed for biomass degradation to DOCen. Overall, WIB can efficiently promote nitrate reduction in EBD treatments. The conceptual model of the organic C cycle and the developed mathematical model accurately described the chemical and isotopic transformations that occur during this induced denitrification. PMID- 29154004 TI - Influence of glass wool as separator on bioelectricity generation in a constructed wetland-microbial fuel cell. AB - To figure out the impact of the separator on the electrical performance of the newly established constructed wetland-microbial fuel cell (CW-MFC), two parallel upflow CW-MFC systems, with and without glass wool (GW), were set up in this study. System performances in terms of bioelectricity production were monitored for more than 4 months. Results showed that the highest voltage was achieved in non-separator (NS) system (465.7 +/- 4.2 mV with electrode spacing of 5 cm), which is 48.9% higher than the highest value generated in GW system (312 +/- 7.0 mV with electrode spacing of 2 cm). The highest power density was produced in NS system (66.22 mW/m2), which is 3.9 times higher than the value in GW system (17.14 mW/m2). The diffusion of oxygen from the open air was greatly hindered by the biofilm formed under the cathode. This kind of biofilm can be severed as the "microbial separator", playing the same role in a real separator. PMID- 29154005 TI - Levers supporting tariff growth for water services: evidence from a contingent valuation analysis. AB - The backwardness of the water utilities sector necessitates urgent investment in infrastructure to improve water quality and efficiency in water supply networks. A policy of tariff growth represents the main source to sustain such investments. Therefore, customer engagement in the form of willingness to pay (WTP) is highly desirable by water utilities to obtain social legitimization and support. This study examines the determinants of consumers' WTP for improvement programs for three drinking water issues: quality of water sources, renewal of water mains, and building of new wastewater treatment plants. The study is based on a survey conducted among a sample of 587 customers of a water utility located in the province of Verona in the north of Italy. The contingence valuation method is used to measure WTP. Specifically, an ordinal logistic regression model yields the following significant determinants of WTP: quality of water and services provided, preference for privatization of the water utility, sustainable consumption of water, and some socio-demographic variables. The findings provide interesting insights into the drivers of WTP as well as managerial recommendations for water utilities. In particular, the findings show that water utilities need to improve service and water quality to increase customers' acceptance of tariff growth. In addition, utilities should invest in customer education and communication activities focusing on specific age groups (e.g., older customers) to enhance their WTP. Finally, communication strategies should reinforce the possible role of liberalization and privatization in supporting infrastructure investments. PMID- 29154006 TI - Hydrodynamic modelling of the influence of stormwater and combined sewer overflows on receiving water quality: Benzo(a)pyrene and copper risks to recreational water. AB - The risk from chemical substances in surface waters is often increased during wet weather, due to surface runoff, combined sewer overflows (CSOs) and erosion of contaminated land. There are strong incentives to improve the quality of surface waters affected by human activities, not only from ecotoxicity and ecosystem health perspectives, but also for drinking water and recreational purposes. The aim of this study is to investigate the influence of urban stormwater discharges and CSOs on receiving water in the context of chemical health risks and recreational water quality. Transport of copper (Cu) and benzo[a]pyrene (BaP) in the Gota River (Sweden) was simulated using a hydrodynamic model. Within the 16 km modelled section, 35 CSO and 16 urban stormwater point discharges, as well as the effluent from a major wastewater treatment plant, were included. Pollutant concentrations in the river were simulated for two rain events and investigated at 13 suggested bathing sites. The simulations indicate that water quality guideline values for Cu are exceeded at several sites, and that stormwater discharges generally give rise to higher Cu and BaP concentrations than CSOs. Due to the location of point discharges and the river current inhibiting lateral mixing, the north shore of the river is better suited for bathing. Peak concentrations have a short duration; increased concentrations of the pollutants may however be present for several days after a rain event. Monitoring of river water quality indicates that simulated Cu and BaP concentrations are in the same order of magnitude as measured concentrations. It is concluded that hydrodynamic modelling is a useful tool for identifying suitable bathing sites in urban surface waters and areas of concern where mitigation measures should be implemented to improve water quality. PMID- 29154007 TI - Public responses to water reuse - Understanding the evidence. AB - Over the years, much research has attempted to unpack what drives public responses to water reuse, using a variety of approaches. A large amount of this work was captured by an initial review that covered research undertaken up to the early 2000s (Hartley, 2006). This paper showcases post-millennium evidence and thinking around public responses to water reuse, and highlights the novel insights and shifts in emphasis that have occurred in the field. Our analysis is structured around four broad, and highly interrelated, strands of thinking: 1) work focused on identifying the range of factors that influence public reactions to the concept of water reuse, and broadly looking for associations between different factors; 2) more specific approaches rooted in the socio-psychological modelling techniques; 3) work with a particular focus on understanding the influences of trust, risk perceptions and affective (emotional) reactions; and 4) work utilising social constructivist perspectives and socio-technical systems theory to frame responses to water reuse. Some of the most significant advancements in thinking in this field stem from the increasingly sophisticated understanding of the 'yuck factor' and the role of such pre-cognitive affective reactions. These are deeply entrenched within individuals, but are also linked with wider societal processes and social representations. Work in this area suggests that responses to reuse are situated within an overall process of technological 'legitimation'. These emerging insights should help stimulate some novel thinking around approaches to public engagement for water reuse. PMID- 29154008 TI - A combined model to assess technical and economic consequences of changing conditions and management options for wastewater utilities. AB - The paper presents a simplified model that quantifies economic and technical consequences of changing conditions in wastewater systems on utility level. It has been developed based on data from stakeholders and ministries, collected by a survey that determined resulting effects and adapted measures. The model comprises all substantial cost relevant assets and activities of a typical German wastewater utility. It consists of three modules: i) Sewer for describing the state development of sewer systems, ii) WWTP for process parameter consideration of waste water treatment plants (WWTP) and iii) Cost Accounting for calculation of expenses in the cost categories and resulting charges. Validity and accuracy of this model was verified by using historical data from an exemplary wastewater utility. Calculated process as well as economic parameters shows a high accuracy compared to measured parameters and given expenses. Thus, the model is proposed to support strategic, process oriented decision making on utility level. PMID- 29154009 TI - Efficiency of blue-green stormwater retrofits for flood mitigation - Conclusions drawn from a case study in Malmo, Sweden. AB - Coupled one-dimensional (1D) sewer and two-dimensional (2D) overland flow hydrodynamic models were constructed to evaluate the flood mitigation efficiency of a renowned blue-green stormwater retrofit, i.e. Augustenborg, in Malmo, Sweden. Simulation results showed that the blue-green stormwater systems were effective in controlling local surface flooding in inner-city catchments, having reduced the total flooded surfaces by about 70%. However, basement flooding could still be a potential problem depending on the magnitude of the inflows through combined sewer from upstream areas. Moreover, interactions between blue-green retrofits and the surrounding pipe-system were studied. It was observed that the blue-green retrofits reduced the peak flows by approximately 80% and levelled out the runoff. This is a substantial advantage for downstream pipe-bound catchments, as they do not receive a cloudburst-equivalent runoff from the retrofitted catchment, but a reduced flow corresponding to a much milder rainfall. Blue-green retrofits are more effective if primarily implemented in the upstream areas of a pipe-bound catchment since the resulting reduced runoff and levelled out discharge would benefit the entire network lying downstream. Implementing blue green retrofits from upstream towards downstream can be considered as a sustainable approach. PMID- 29154010 TI - Combined strategy for removal of Reactive Black 5 by biomass sorption on Macrocystis pyrifera and zerovalent iron nanoparticles. AB - Reactive Black 5, RB5, has been used as a model azo dye to evaluate the removal efficiency of sorption on Macrocystis pyrifera biomass (Mpyr) and commercial zerovalent iron nanoparticles (nZVI) in individual and combined treatments. The best conditions for the treatment with the isolated materials were first determined, and then, in series and combined treatments were performed under these conditions, achieving removal efficiencies higher than 80% of the initial dye concentration. Strengths and weaknesses of all removal strategies (individual, in series and combined) are analyzed regarding the application on real effluents. Mpyr efficiently adsorbed RB5, but also increased the total organic content by partial dissolution of components of the algal biomass. Removal experiments with commercial nZVI were also efficient but liberated Fe to the solution, and sulfanilic acid was observed after the treatment as a product of RB5 degradation. In contrast, after the Mpyr treatment, no sulfanilic acid was detected, suggesting that sulfanilic acid is efficiently adsorbed by the biomass. The best condition was the integrated use of Mpyr and nZVI, with a remarkable removal efficiency (69-80%) obtained after only 1 h of treatment. Finally, nZVI were successfully immobilized in Mpyr, and the hybrid material was used to remove RB5 in continuous flow experiments at pH 3, obtaining a removal capacity of 39.9 mg RB5 g-1 after a total processed volume of 630 mL of [RB5]0 = 100 mg L-1. PMID- 29154011 TI - The impact of regulatory complexity upon self-regulation: Evidence from the adoption and certification of environmental management systems. AB - This article focuses on environmental management systems (EMS) and aims to enhance our understanding of the relationship between environmental state regulation and self-regulation. Unlike previous studies that treat state regulation as uni-dimensional and focus on externally certified forms of environmental self-regulation, this article takes a more nuanced approach. It looks at how direct and indirect state regulation and its stringency influence both non-certified in-house and externally certified adoption of EMS. Methodologically, the study differentiates from previous research by acknowledging the interconnected nature of in-house and external certification decisions, viewing these decisions as sequential. Based on a survey of 2076 UK firms, findings show that effective environmental protection entails collaboration between environmental state regulation and in-house adoption of EMS. Results also reveal that externally certified EMS substitute for state environmental regulation, filling the void that results from weakening state regulation in the context of neoliberalism. PMID- 29154012 TI - Quantification of flood risk mitigation benefits: A building-scale damage assessment through the RASOR platform. AB - Flood risk mitigation usually requires a significant investment of public resources and cost-effectiveness should be ensured. The assessment of the benefits of hydraulic works requires the quantification of (i) flood risk in absence of measures, (ii) risk in presence of mitigation works, (iii) investments to achieve acceptable residual risk. In this work a building-scale is adopted to estimate direct tangible flood losses to several building classes (e.g. residential, industrial, commercial, etc.) and respective contents, exploiting various sources of public open data in a GIS environment. The impact simulations for assigned flood hazard scenarios are computed through the RASOR platform which allows for an extensive characterization of the properties and their vulnerability through libraries of stage-damage curves. Recovery and replacement costs are estimated based on insurance data, market values and socio-economic proxies. The methodology is applied to the case study of Florence (Italy) where a system of retention basins upstream of the city is under construction to reduce flood risk. Current flood risk in the study area (70 km2) is about 170 Mio euros per year without accounting for people, infrastructures, cultural heritage and vehicles at risk. The monetary investment in the retention basins is paid off in about 5 years. However, the results show that although hydraulic works are cost effective, a significant residual risk has to be managed and the achievement of the desired level of acceptable risk would require about 1 billion euros of investments. PMID- 29154013 TI - The potential of the newly isolated thermotolerant yeast Pichia kudriavzevii RZ8 1 for high-temperature ethanol production. AB - High potential, thermotolerant, ethanol-producing yeasts were successfully isolated in this study. Based on molecular identification and phylogenetic analysis, the isolated thermotolerant yeasts were clustered in the genera of Pichia kudriavzevii, Candida tropicalis, Candida orthopsilosis, Candida glabrata and Kodamea ohmeri. A comparative study of ethanol production using 160g/L glucose as a substrate revealed several yeast strains that could produce high ethanol concentrations at high temperatures. When sugarcane bagasse (SCB) hydrolysate containing 85g/L glucose was used as a substrate, the yeast strain designated P. kudriavzevii RZ8-1 exhibited the highest ethanol concentrations of 35.51g/L and 33.84g/L at 37 degrees C and 40 degrees C, respectively. It also exhibited multi-stress tolerance, such as heat, ethanol and acetic acid tolerance. During ethanol fermentation at high temperature (42 degrees C), genes encoding heat shock proteins (ssq1 and hsp90), alcohol dehydrogenases (adh1, adh2, adh3 and adh4) and glyceraldehyde-3-phosphate dehydrogenase (tdh2) were up regulated, suggesting that these genes might play a crucial role in the thermotolerance ability of P. kudriavzevii RZ8-1 under heat stress. These findings suggest that the growth and ethanol fermentation activities of this organism under heat stress were restricted to the expression of genes involved not only in heat shock response but also in the ethanol production pathway. PMID- 29154014 TI - Evaluation of sample extracting methods of FCSM by Lactobacillus acidophilus based on a UPLC-Q-TOF-MS global metabolomics analysis. AB - The study of metabolomics requires extracting as many metabolites as possible from a biological sample. This study aimed to determine the optimal method for the extraction of metabolites from solid-state fermented cottonseed meal (FCSM). The UPLC-Q-TOF-MS global metabolomics technology was used to detect the metabolites in FCSM, and the extraction quantity and extraction efficiency of seven different extraction methods, specifically the WA, 50MeOH, 50MeOHB, 50MeCNB, 80MeOHB, 80MeOH and AMF methods were evaluated. The results showed that the number of VIP metabolites extracted by AMF method are 196 and 184 in ESI+ and ESI- mode respectively, it is the largest number of all exacted methods; and the AMF methods also provided a higher extraction efficiency compared with the other methods, especially in indoleacrylic acid, dl-tryptophan and epicatechin (p<0.01). As a result, AMF/-4 degrees C method was identified as the best method for the extraction of metabolites from FCSM by Lactobacillus acidophilus. Our study establishes a technical basis for future metabolomics research of fermented feed. PMID- 29154016 TI - Preface for special issue. PMID- 29154015 TI - Albumin-bilirubin grade versus MELD score for predicting survival after transjugular intrahepatic portosystemic shunt (TIPS) creation. AB - OBJECTIVES: The purpose of this study was to compare the albumin-bilirubin (ALBI) grade and model for end-stage liver disease (MELD) scores for predicting survival after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS: A retrospective study of pre-procedure ALBI and MELD scores was performed in 197 patients who underwent TIPS from 2005 to 2012. There were 140 men and 57 women, with a mean age of 56+/-11 (SD) (range: 19-90years). The prognostic capability of ALBI and MELD scores were evaluated using competing risks survival analysis. Discriminatory ability was compared between models using the C-index derived from cause specific Cox proportional hazards models. RESULTS: TIPS were created for ascites or hydrothorax (128 patients), variceal hemorrhage (61 patients), or both (8 patients). Prior to TIPS, 5 patients were ALBI grade 1, 76 were grade 2, and 116 were grade 3. The average pre-TIPS MELD score was 14. Pre-TIPS ALBI score, ALBI grade, and MELD were each significant predictors of 30 day mortality from hepatic failure and overall survival (all P<0.05). Based on the C-index, the MELD score was a better predictor of both 30-day and overall survival (C-index=0.74 and 0.63) than either ALBI score (0.70 and 0.59) or ALBI grade (0.64 and 0.56). In multivariate models, after accounting for MELD score ALBI score provided no additional short- or long-term survival information. CONCLUSION: Although ALBI score and grade were statistically significantly associated with risk of death after TIPS, MELD remains the superior predictor. PMID- 29154017 TI - Patient attitudes and experiences that predict medication discontinuation in the Veterans Health Administration. AB - OBJECTIVES: Polypharmacy is associated with adverse medication effects. One potential solution is deprescribing, which is the intentional, proactive, rational discontinuation of a medication that is no longer indicated or for which the potential harms outweigh the potential benefits. We identified patient characteristics, attitudes, and health care experiences associated with medication discontinuation. DESIGN, SETTING, AND PARTICIPANTS: We conducted a national mail survey, with the use of the Patient Perceptions of Discontinuation (PPoD) instrument, of 1600 veterans receiving primary care at Veterans Affairs (VA) medical centers and prescribed 5 or more concurrent medications. MAIN OUTCOME MEASURES: The primary outcome was the response to: "Have you ever stopped taking a medicine (with or without your doctor's knowledge)?" The primary predictors of interest were 8 validated attitudinal scales. Other predictors included demographics, health status, and health care experiences. RESULTS: Respondents (n = 803; adjusted response rate 52%) were predominantly male (85%); non-Hispanic white (68%), 65 years of age or older (60%), and with poor (16%) or fair (45%) health. Participant attitudes toward medications and their providers were generally favorable. One in 3 patients (34%) reported having stopped a medicine in the past. In a multivariable logistic regression model (P < 0.001; pseudo-R2 = 0.31; c-statistic = 0.82), factors associated with discontinuation included being told or asking to stop a medicine, greater interest in deprescribing and shared decision making, and higher education. Factors associated with decreased discontinuation were more prescriptions, higher trust in provider, and seeing a VA clinical pharmacist. CONCLUSION: More highly educated patients with interest in deprescribing and shared decision making may be more receptive to discontinuation discussions. Future research evaluating how to incorporate this survey and these findings into clinical workflow through the design of clinical interventions may help to promote safe and rational medication use. PMID- 29154018 TI - Improving patient access to hepatitis C virus treatment. AB - OBJECTIVES: To discuss the current barriers to hepatitis C virus (HCV) treatment; to provide information and resources to assist health care providers with the prior authorization process; to provide resources for potential access to medications if a patient's third-party payer may not be an option; and to discuss the pharmacist's vital role as a patient advocate and considerations once medications are approved. SUMMARY: Access to HCV medications is often restricted by third-party payers. Pharmacists are poised to fill an immediate need and assist with providing the necessary clinical evidence to gain access to HCV medications and advocate on the patient's behalf. Once approval for HCV treatment has been obtained, considerations must be given to procurement of therapy, refills, monitoring, and avoid interruptions in therapy. CONCLUSION: The assistance of a pharmacist should be sought to overcome barriers related to medication access. Once therapy has been obtained, the pharmacist can assist the entire patient care team to ensure timely refills, appropriate monitoring, tolerability of therapy, and continued medication access. PMID- 29154019 TI - Local specialty pharmacy and specialty clinic collaboration assists access to hepatitis C direct-acting antivirals. AB - OBJECTIVES: To measure prescribed time to therapy (TtT) and sustained virologic response (SVR). Secondary objectives were to assess insurance appeals and copay assistance amount facilitated by a local specialty pharmacy (LSP). METHODS: This descriptive, retrospective study used a joint clinical and pharmacy database of patients who were prescribed direct-acting antivirals (DAAs) at a single-center liver specialty clinic and received LSP services from December 2013 to December 2015. RESULTS: Among 388 patients prescribed DAAs, 364 (94%) patients, who were 18 years of age or older, initiated DAA therapy, and received LSP services, were included in the study. Of these, 211 (58.0%) had cirrhosis, 159 (43.7%) had previous treatment, and 57 (15.7%) had previous liver transplants. Most patients had commercial insurance (n = 249; 68.4%), and 295 (81.0%) required prior authorization. Insurance initially denied coverage to 70 patients (19.2%), for who the LSP drafted appeals for 60 (85.7%). Copay information was available for 154 LSP patients. Although 66 had initial copays of more than $20 per month, the LSP was able to assist most (98.1%; n = 151) with copay reductions to $20 or less. Full financial assistance was received for 20 patients without insurance or any DAA coverage. Among 171 patients with SVR and prescribed TtT information, mean TtT was 12 days (median 4 days), and most received medications within 10 days (n = 122; 71.3%). The overall intention-to-treat SVR rate was 86.8%; the per protocol (PP) SVR rate was 93.8%. CONCLUSION: Collaboration between providers and an LSP minimized delay in therapy, lowered rates of DAA denial, facilitated patient financial assistance, and helped to optimize clinical outcomes. The PP SVR rate for this study was similar to rates reported in the literature and higher than expected, considering the inclusion of earlier-generation DAAs and many patients with advanced liver disease. PMID- 29154020 TI - Skeletal surveys in young, injured children: A systematic review. AB - Skeletal surveys (SSs) have been identified as a key component of the evaluation for suspected abuse in young children, but variability in SS utilization has been reported. Thus, we aimed to describe the utilization patterns, yield, and risks of obtaining SS in young children through a systematic literature review. We searched PubMed/MEDLINE and CINAHL databases for articles published between 1990 and 2016 on SS. We calculated study-specific percentages of SS utilization and detection of occult fractures and examined the likelihoods that patient characteristics predict SS utilization and detection of occult fractures. Data from 32 articles represents 64,983 children <60months old. SS utilization was high (85%-100%) in studies of infants evaluated by a child protection team for suspected abuse and/or diagnosed with abuse except in one study of primarily non pediatric hospitals. Greater variability in SS utilization was observed across studies that included all infants with specific injuries, such as femur fractures (0%-77%), significant head injury (51%-82%), and skull fractures (41%-86%). Minority children and children without private insurance were evaluated with SS more often than white children and children with private insurance despite lack of evidence to support this practice. Among children undergoing SS, occult fractures were frequently detected among infants with significant head injury (23%-34%) and long bone fractures (30%) but were less common in infants with skull fractures (1%-6%). These findings underscore the need for interventions to decrease disparities in SS utilization and standardize SS utilization in infants at high risk of having occult fractures. PMID- 29154021 TI - Diagnosis of Fanconi Anaemia by ionising radiation- or mitomycin C-induced micronuclei. AB - Fanconi Anaemia (FA) is an autosomal recessive disorder characterised by defects in DNA repair, associated with chromosomal instability and cellular hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC). The FA repair pathway involves complex DNA repair mechanisms crucial for genomic stability. Deficiencies in DNA repair genes give rise to chromosomal radiosensitivity. FA patients have shown increased clinical radiosensitivity by exhibiting adverse normal tissue side-effects. The study aimed to investigate chromosomal radiosensitivity of homozygous and heterozygous carriers of FA mutations using three micronucleus (MN) assays. The G0 and S/G2MN assays are cytogenetic assays to evaluate DNA damage induced by ionising radiation in different phases of the cell cycle. The MMC MN assay detects DNA damage induced by a crosslinking agent in the G0 phase. Patients with a clinical diagnosis of FA and their parents were screened for the complete coding region of 20 FA genes. Blood samples of all FA patients and parents were exposed to ionising radiation of 2 and 4Gy. Chromosomal radiosensitivity was evaluated in the G0 and S/G2 phase. Most of our patients were homozygous for the founder mutation FANCG c.637_643delTACCGCC; p.(Tyr213Lysfs*6) while one patient was compound heterozygous for FANCG c.637_643delTACCGCC and FANCG c.1379G > A, p.(Gly460Asp), a novel missense mutation. Another patient was compound heterozygous for two deleterious FANCA mutations. In FA patients, the G0- and S/G2-MN assays show significantly increased chromosomal radiosensitivity and genomic instability. Moreover, chromosomal damage was significantly elevated in MMC treated FA cells. We also observed an increase in chromosomal radiosensitivity and genomic instability in the parents using 3 assays. The effect was significant using the MMC MN assay. The MMC MN assay is advantageous as it is less labour intense, time effective and has potential as a reliable alternative method for detecting FA patients from parents and controls. PMID- 29154022 TI - The anti-tumor effect of RANKL inhibition in malignant solid tumors - A systematic review. AB - At present, accumulating evidence suggests that inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) does not only induce an increase in bone mass and strength, but also has anti-tumor effects. Denosumab, an antibody targeting RANKL, is used to treat osteoporosis and to prevent skeletal related events (SREs) in patients with bone metastases originating from solid tumors. However, expression of RANKL and its receptor activator of nuclear factor kappa-B (RANK) is not solely restricted to cells involved in homeostasis of the bone and RANKL-RANK signalling appears to play a substantial role in many other processes in the body like mammary physiology, mammary tumorigenesis and the immune system. In pre-clinical models, RANKL inhibition has been shown to reduce skeletal tumor burden and distant metastases as well as to decrease mammary carcinogenesis. Clinically, RANKL inhibition improves bone-metastasis free survival in patients with prostate cancer and disease-free survival in patients with breast cancer. In addition, RANKL treatment may form a preventative strategy in patients at high risk for malignancies of the breast. Current clinical studies are evaluating the effect of denosumab on survival, the immune system and other biomarkers into a greater extent. To that purpose, a systematic review of the literature was performed and a narrative review synthesized, describing the present pre-clinical and clinical evidence of an anti-tumor effect of RANKL inhibition and the potential role of the immune system as one of the underlying mechanisms. PMID- 29154024 TI - Global antimicrobial resistance in Gram-negative pathogens and clinical need. AB - Resistance in Gram-negative bacteria has become a serious problem in many regions of the world as it may reduce the treatment options substantially. Carbapenem resistance is a good marker for such situations and is most prevalent in Acinetobacter, Pseudomonas but also increasingly in Enterobacteriaceae, especially Klebsiella. This review gives a rough global picture highlighting the epicentres of resistance. The medical need for novel treatment options globally is undeniable even if many countries with good stewardship and infection control conditions are not highly affected. Antibiotic pipelines are encouraging, as new drugs in development reduce the resistance rate to individual pathogens. Despite some progress, efforts to discover and develop novel drugs that are not prone to cross-resistance to existing antibiotic classes should be intensified. PMID- 29154023 TI - Triple negative breast cancer in Asia: An insider's view. AB - While tremendous improvement has been made for the treatment of breast cancers, the treatment of triple negative breast cancer (TNBC) still remains a challenge due to its aggressive characteristics and limited treatment options. Most of the studies on TNBC were conducted in Western population and TNBC is reported to be more frequent in the African women. This review encapsulates the studies conducted on TNBC patients in Asian population and elucidates the similarities and differences between these two regions. The current treatment of TNBC includes surgery, radiotherapy and chemotherapy. In addition to the current chemotherapies, which mainly include cytotoxic agents, such as taxanes and anthracyclines, many clinical trials are investigating the potential use of other chemotherapy drugs, targeted therapeutics and combinational therapies to treat TNBC. Moreover, this review also integrates the studies involving novel markers, which will help us to dissect the pathologic process of TNBC and in turn facilitate the development of better treatment strategies to combat TNBC. PMID- 29154025 TI - Alternative transcriptional regulation in genome-reduced bacteria. AB - Transcription is a core process of bacterial physiology, and as such it must be tightly controlled, so that bacterial cells maintain steady levels of each RNA molecule in homeostasis and modify them in response to perturbations. The major regulators of transcription in bacteria (and in eukaryotes) are transcription factors. However, in genome-reduced bacteria, the limited number of these proteins is insufficient to explain the variety of responses shown upon changes in their environment. Thus, alternative regulators may play a central role in orchestrating RNA levels in these microorganisms. These alternative mechanisms rely on intrinsic features within DNA and RNA molecules, suggesting they are ancestral mechanisms shared among bacteria that could have an increased relevance on transcriptional regulation in minimal cells. In this review, we summarize the alternative elements that can regulate transcript abundance in genome-reduced bacteria and how they contribute to the RNA homeostasis at different levels. PMID- 29154026 TI - Inhibitors of metallo-beta-lactamases. AB - The beta-lactams are the most successful class of antibiotic drugs but they are vulnerable to inactivation by a growing cadre of beta-lactamases that now number more than a thousand variants. beta-Lactamases operate by one of two general chemical mechanisms either catalyzing beta-lactam ring hydrolysis via a covalent enzyme intermediate through the aegis of an active site serine residue or through a noncovalent Zn-dependent mechanism. The Ser-beta-lactamases are currently dominant in the clinic and consequently, there has been great effort to identify inhibitors and to co-formulate these with beta-lactam antibiotics. Four such inhibitors are approved for human clinical use and several more are in clinical trials. Metallo-beta-lactamases (MBLs), on the other hand, are only now emerging as a global threat and consequently, inhibitor discovery has lagged behind their Ser counterparts. There are now several examples of MBL inhibitors that operate either in a Zn-dependent or Zn-independent mode. The Zn-dependent compounds are more prevalent and some show efficacy in animal models of infection. These compounds function by either acting as an alternate metal ligand, usually displacing a jointly held hydroxide ion shared by enzymes with two Zn2+ ions, or alternately by striping Zn from the active site. The increase in the number of candidate MBL inhibitors over recent years reflects the growing clinical challenge of pathogens expressing these enzymes that result in a carbapenem resistance phenotype. While none of these inhibitors are yet in human clinical trials, the increasing importance of these enzymes in drug failure is a strong incentive to continue identifying and characterizing such molecules. PMID- 29154027 TI - Adult criticism and vigilance diminish free riding by children in a social dilemma. AB - In cooperative situations, individual interests can be in conflict with those of the group, creating a social dilemma in which one must choose whether to cooperate or not. Sensitivity to social stimuli is an important factor influencing cooperative behavior in such dilemmas. The current study investigated the influence of verbal feedback and vigilance by adults on children's donating behavior in a public goods game. The participants were 739 public school children, between 5 and 12 years of age, who were divided into 34 groups. Each group was assigned to one of four experimental conditions: control, positive feedback (praise), negative feedback (criticism), or vigilance. Participants then played eight rounds of the game. The children's donations were greater in the feedback and vigilance conditions, but the effects were mediated by age and rounds. The results are most likely related to concerns about reputation, which tend to become stronger with age. Older children are better at self-presentation and understanding social norms. Thus, compared with younger children, they seemed more concerned with appearing to be generous, but only when they could get credit for it. Nevertheless, children's donations still decreased across the rounds. Although adult vigilance and feedback influence children's cooperation among peers, other mechanisms are necessary to stabilize their behavior over time. PMID- 29154028 TI - Listening while reading promotes word learning from stories. AB - Reading and listening to stories fosters vocabulary development. Studies of single word learning suggest that new words are more likely to be learned when both their oral and written forms are provided, compared with when only one form is given. This study explored children's learning of phonological, orthographic, and semantic information about words encountered in a story context. A total of 71 children (8- and 9-year-olds) were exposed to a story containing novel words in one of three conditions: (a) listening, (b) reading, or (c) simultaneous listening and reading ("combined" condition). Half of the novel words were presented with a definition, and half were presented without a definition. Both phonological and orthographic learning were assessed through recognition tasks. Semantic learning was measured using three tasks assessing recognition of each word's category, subcategory, and definition. Phonological learning was observed in all conditions, showing that phonological recoding supported the acquisition of phonological forms when children were not exposed to phonology (the reading condition). In contrast, children showed orthographic learning of the novel words only when they were exposed to orthographic forms, indicating that exposure to phonological forms alone did not prompt the establishment of orthographic representations. Semantic learning was greater in the combined condition than in the listening and reading conditions. The presence of the definition was associated with better performance on the semantic subcategory and definition posttests but not on the phonological, orthographic, or category posttests. Findings are discussed in relation to the lexical quality hypothesis and the availability of attentional resources. PMID- 29154029 TI - Basic numerical competences in large-scale assessment data: Structure and long term relevance. AB - Basic numerical competences are seen as building blocks for later numerical and mathematical achievement. The current study aimed at investigating the structure of early numeracy reflected by different basic numerical competences in kindergarten and its predictive value for mathematical achievement 6 years later using data from large-scale assessment. This allowed analyses based on considerably large sample sizes (N > 1700). A confirmatory factor analysis indicated that a model differentiating five basic numerical competences at the end of kindergarten fitted the data better than a one-factor model of early numeracy representing a comprehensive number sense. In addition, these basic numerical competences were observed to reliably predict performance in a curricular mathematics test in Grade 6 even after controlling for influences of general cognitive ability. Thus, our results indicated a differentiated view on early numeracy considering basic numerical competences in kindergarten reflected in large-scale assessment data. Consideration of different basic numerical competences allows for evaluating their specific predictive value for later mathematical achievement but also mathematical learning difficulties. PMID- 29154030 TI - Perceptual completion of partly occluded contours during childhood. AB - An early functional onset of perceptual completion has been extensively documented during the first several months after birth. However, there is no indication for the developmental time periods at which these skills become fully developed. We used a version of an object-based attention task in which children and adults performed a same-different size judgment of two features appearing at two of four possible ends of overlapping objects. Single-object over two-object superiority (i.e., faster judgments when the features appeared on the same object than when they appeared on different objects) was observed for a complete object as early as at 4 years of age. However, it is only at 5 years of age that such a single-object advantage was obtained also for an occluded object, and even then the advantage of the single-object and occluded-object conditions over the two object condition was observed only when the two features in the two-object condition were spatially distant, demonstrating the critical role of spatial proximity in perceptual organization during childhood. The results suggest that perceptual completion during infancy and early childhood demonstrates some rudimentary perceptual skills that become more firmly established with age. PMID- 29154031 TI - Preschool children adapt grasping movements to upcoming object manipulations: Evidence from a dial rotation task. AB - In adults, the motor plans for object-directed grasping movements reflects the anticipated requirements of intended future object manipulations. This prospective mode of planning has been termed second-order planning. Surprisingly, second-order planning is thought to be fully developed only by 10 years of age, when children master seemingly more complex motor skills. In this study, we tested the hypothesis that already 5- and 6-year-old children consistently use second-order planning but that this ability does not become apparent in tasks that are traditionally used to probe it. We asked 5- and 6-year-olds and adults to grasp and rotate a circular dial in a clockwise or counterclockwise direction. Although children's grasp selections were less consistent on an intra- and inter individual level than adults' grasp selections, all children adjusted their grasps to the upcoming dial rotations. By contrast, in an also administered bar rotation task, only a subset of children adjusted their grasps to different bar rotations, thereby replicating previous results. The results indicate that 5- and 6-year-olds consistently use second-order planning in a dial rotation task, although this ability does not become apparent in bar rotation tasks. PMID- 29154032 TI - The development of intention-based sociomoral judgment and distribution behavior from a third-party stance. AB - The current study investigated children's intention-based sociomoral judgments and distribution behavior from a third-party stance. An actor puppet showed either positive or negative intention toward a target puppet, which had previously performed a prosocial or antisocial action toward others (i.e., children witnessed various types of indirect reciprocity). Children (3- and 5 year-olds) were asked to make sociomoral judgments and to distribute resources to the actor puppet. Results showed that 5-year-olds were more likely than 3-year olds to be influenced by intention when they made their judgment and distributed resources. The target's previous actions affected only 5-year-olds' intent-based social preference. These results suggest that children's judgments about intent based indirect reciprocity develop from ages 3 to 5 years. PMID- 29154033 TI - Measuring preschool learning engagement in the laboratory. AB - Learning engagement is a critical factor for academic achievement and successful school transitioning. However, current methods of assessing learning engagement in young children are limited to teacher report or classroom observation, which may limit the types of research questions one could assess about this construct. The current study investigated the validity of a novel assessment designed to measure behavioral learning engagement among young children in a standardized laboratory setting and examined how learning engagement in the laboratory relates to future classroom adjustment. Preschool-aged children (N = 278) participated in a learning-based Tangrams task and Story sequencing task and were observed based on seven behavioral indicators of engagement. Confirmatory factor analysis supported the construct validity for a behavioral engagement factor composed of six of the original behavioral indicators: attention to instructions, on-task behavior, enthusiasm/energy, persistence, monitoring progress/strategy use, and negative affect. Concurrent validity for this behavioral engagement factor was established through its associations with parent-reported mastery motivation and pre-academic skills in math and literacy measured in the laboratory, and predictive validity was demonstrated through its associations with teacher reported classroom learning behaviors and performance in math and reading in kindergarten. These associations were found when behavioral engagement was observed during both the nonverbal task and the verbal story sequencing tasks and persisted even after controlling for child minority status, gender, and maternal education. Learning engagement in preschool appears to be successfully measurable in a laboratory setting. This finding has implications for future research on the mechanisms that support successful academic development. PMID- 29154034 TI - Effects of grasp compatibility on long-term memory for objects. AB - Previous studies have shown action potentiation during conceptual processing of manipulable objects. In four experiments, we investigated whether these motor actions also play a role in long-term memory. Participants categorized objects that afforded either a power grasp or a precision grasp as natural or artifact by grasping cylinders with either a power grasp or a precision grasp. In all experiments, responses were faster when the affordance of the object was compatible with the type of grasp response. However, subsequent free recall and recognition memory tasks revealed no better memory for object pictures and object names for which the grasp affordance was compatible with the grasp response. The present results therefore do not support the hypothesis that motor actions play a role in long-term memory. PMID- 29154035 TI - Mapping language to visual referents: Does the degree of image realism matter? AB - Studies of real-time spoken language comprehension have shown that listeners rapidly map unfolding speech to available referents in the immediate visual environment. This has been explored using various kinds of 2-dimensional (2D) stimuli, with convenience or availability typically motivating the choice of a particular image type. However, work in other areas has suggested that certain cognitive processes are sensitive to the level of realism in 2D representations. The present study examined the process of mapping language to depictions of objects that are more or less realistic, namely photographs versus clipart images. A custom stimulus set was first created by generating clipart images directly from photographs of real objects. Two visual world experiments were then conducted, varying whether referent identification was driven by noun or verb information. A modest benefit for clipart stimuli was observed during real-time processing, but only for noun-driving mappings. The results are discussed in terms of their implications for studies of visually situated language processing. PMID- 29154036 TI - Inhibition of cathepsin L alleviates the microglia-mediated neuroinflammatory responses through caspase-8 and NF-kappaB pathways. AB - Cathepsin L (CTSL) has been shown to participate in the microglia-mediated neuroinflammation. However, the role of CTSL in neuroinflammation remains to be elucidated. In this study, CTSL was found to be upregulated on lipopolysaccharide (LPS) stimulation. The neuroinflammatory responses on LPS stimulation were ameliorated by inhibition or deficiency of CTSL in vitro or vivo. Treatment with conditioned medium of activated BV2 cells in SH-SY5Y cells showed that CTSL inhibition reduced microglia-mediated neurotoxicity. Further analysis indicated that CTSL was involved in the activation of caspase-8 and NF-kappaB, and overexpression of CTSL-enhanced expression of inflammatory mediators in response to LPS via caspase-8 and NF-kappaB pathways. Moreover, mRNA level of CTSL in peripheral blood mononuclear cells from patients with Parkinson's disease was higher compared with controls. Level of CTSL was positively correlated with expression of inflammatory mediators and NF-kappaB in Parkinson's disease patients. Taken together, these findings suggested that inhibition of CTSL alleviated the neuroinflammatory responses through caspase-8 and NF-kappaB pathways, and blocking CTSL might provide some clues to control the excessive neuroinflammation. PMID- 29154037 TI - Sex- and age-specific modulation of brain GABA levels in a mouse model of Alzheimer's disease. AB - Age and sex are risk factors of Alzheimer's disease (AD). Among the neurotransmitter systems, gamma-aminobutyric acid (GABA) has been implicated in AD pathogenesis but the relevance of sex-specific GABAergic dysfunction during AD progression remains unknown. In the present study, we utilized state-of-the-art high-resolution magic angle spinning nuclear magnetic resonance to systematically monitor the brain region-, age-, and sex-specific modulation of GABA levels in wild-type and Tg2576 mice with amyloid pathology. In addition, we followed the possible role of reactive astrocytes in sex-specific GABA modulation. In female Tg2576 mice, hippocampal GABA levels were significantly elevated, along with higher number of reactive astrocytes and amyloid deposition. The elevated GABA was found to be produced via the monoamine oxidase-B route from putrescine in reactive astrocytes, more substantially in female than male mice, thus suggesting a role of astrocytes in memory impairment and sex-related differences in AD. Our results paint a coherent model of memory impairment in AD and signify that dynamic changes in regional GABA may be at the root of marked sex disparities observed in AD. PMID- 29154039 TI - Rethinking transfusion medicine with a more holistic approach. PMID- 29154038 TI - DNA damage and neurodegenerative phenotypes in aged Ciz1 null mice. AB - Cell-cycle dysfunction and faulty DNA repair are closely intertwined pathobiological processes that may contribute to several neurodegenerative disorders. CDKN1A interacting zinc finger protein 1 (CIZ1) plays a critical role in DNA replication and cell-cycle progression at the G1/S checkpoint. Germline or somatic variants in CIZ1 have been linked to several neural and extra-neural diseases. Recently, we showed that germline knockout of Ciz1 is associated with motor and hematological abnormalities in young adult mice. However, the effects of CIZ1 deficiency in much older mice may be more relevant to understanding age related declines in cognitive and motor functioning and age-related neurologic disorders such as isolated dystonia and Alzheimer disease. Mouse embryonic fibroblasts from Ciz1-/- mice showed abnormal sensitivity to the effects of gamma irradiation with persistent DNA breaks, aberrant cell-cycle progression, and apoptosis. Aged (18-month-old) Ciz1-/- mice exhibited marked deficits in motor and cognitive functioning, and, in brain tissues, overt DNA damage, NF-kappaB upregulation, oxidative stress, vascular dysfunction, inflammation, and cell death. These findings indicate that the deleterious effects of CIZ1 deficiency become more pronounced with aging and suggest that defects of cell-cycle control and associated DNA repair pathways in postmitotic neurons could contribute to global neurologic decline in elderly human populations. Accordingly, the G1/S cell-cycle checkpoint and associated DNA repair pathways may be targets for the prevention and treatment of age-related neurodegenerative processes. PMID- 29154040 TI - Multifunctional protein microparticles for medical applications. AB - Micro- and nano-scale intelligent devices can revolutionize the medical field. Although proteins are promising materials for creating biocompatible miniature medical devices with biological functions, construction of complicated solid state architectures, using inherently vulnerable proteins, remains challenging. Here, I present a sophisticated strategy for constructing a multifunctional microparticle for medical applications using multiple proteins; this strategy achieved the retention of function, increased stability, and orientation control of the proteins in the fabricated particle. As proof-of-concept, the particle, designed to cope with excess reactive oxygen species (ROS) involved in many diseases, was constructed by combining three proteins with different functions. The body of the particle was fabricated using albumin and superoxide dismutase (SOD), and the antibody was incorporated into the surface of the particle in an orientation-controlled manner. The constructed protein microparticle exhibited coordinated activities for coping with ROS, such as capture of the ROS-secreting cells by the incorporated antibody, followed by the elimination of 70% ROS, secreted from the captured cells, by the SOD in the particle. Additionally, diapocynin, loaded to the particle via the drug-binding ability of albumin, was released from the particle, preventing ROS production in the cells. This multifunctional microparticle, constructed from proteins, will profoundly impact the development of intelligent protein-based miniature devices used in medical fields. PMID- 29154041 TI - Patient Characteristics, Treatment Patterns and Prognostic Factors in Squamous Cell Bladder Cancer. AB - BACKGROUND: Squamous cell carcinoma (SCC) is an uncommon histologic subtype of bladder cancer with limited data on treatment patterns, outcomes, and prognostic factors. "Real world" information might inform decision-making, prognostic estimates, and clinical trial designs. PATIENTS AND METHODS: A retrospective review of patients with tissue-confirmed bladder SCC treated at Cleveland Clinic from 2007 to 2016 was performed. Data on patient characteristics, treatment patterns, and clinical follow-up were extracted. Univariate analysis was used to identify predictors of overall survival (OS), recurrence-free survival (RFS) and time to recurrence. RESULTS: Of 58 identified patients, 42 had complete data available. Median age at diagnosis was 67 years (range, 37-90). Hematuria was the most common (71%) presenting symptom; 32 patients had pure SCC and 10 predominant/extensive squamous differentiation without major differences noted in clinicopathologic variables or outcomes among those 2 groups. Overall, 35 patients underwent cystectomy with 5 receiving neoadjuvant and 1 adjuvant chemotherapy, whereas 3 had chemotherapy for recurrent disease. Of patients with cystectomy, most had locally advanced disease (75% pT3/4, 35% pN+). Overall, 10 patients progressed and 14 died; median OS was not reached. The 2-year estimated OS, RFS, and cumulative incidence of recurrence were 61% +/- 9%, 50% +/- 9%, and 32% +/- 9%, respectively. Hydronephrosis, older age (70 years or older), lymphovascular invasion, nodal metastases, and advanced T stage were associated with 1 or more poor outcomes. CONCLUSION: In patients with resectable bladder SCC, radical cystectomy remains the main treatment modality. The role of perioperative chemotherapy remains unclear. The identified prognostic factors might be helpful for prognostication, treatment discussion, and trial eligibility/stratification. PMID- 29154042 TI - Oncological Outcomes of Laparoscopic Nephroureterectomy Versus Open Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: An European Association of Urology Guidelines Systematic Review. AB - CONTEXT: Most series have suggested better perioperative outcomes of laparoscopic radical nephroureterectomy (RNU) over open RNU. However, the oncological safety of laparoscopic RNU remains controversial. OBJECTIVE: To systematically review all relevant literature comparing oncological outcomes of open versus laparoscopic RNU. EVIDENCE ACQUISITION: A systematic literature search using the Medline, Embase, and Cochrane databases and clinicaltrial.gov was performed in December 2014 and updated in August 2016. Randomised controlled trials (RCTs) and prospective or retrospective nonrandomised comparative studies comparing the oncological outcomes of any laparoscopic RNU with those of open RNU were included. The primary outcome was cancer-specific survival. The risk of bias (RoB) was assessed using Cochrane RoB tools. A narrative synthesis of the evidence is presented. EVIDENCE SYNTHESIS: Overall, 42 studies were included, which accounted for 7554 patients: 4925 in the open groups and 2629 in the laparoscopic groups. Most included studies were retrospective comparative series. Only one RCT was found. RoB and confounding were high in most studies. No study compared the oncological outcomes of robotic RNU with those of open RNU. Bladder cuff excision in laparoscopic groups was performed via an open approach in most studies, with only three studies reporting laparoscopic removal of the bladder cuff. Port-site metastasis rates ranged from 0% to 2.8%. No significant difference in oncological outcomes was reported in most series. However, three studies, including the only RCT, reported significantly poorer oncological outcomes in patients who underwent laparoscopic RNU, especially in the subgroups of patients with locally advanced (pT3/pT4) or high-grade upper tract urothelial carcinoma (UTUC), as well as in instances when the bladder cuff was excised laparoscopically. CONCLUSIONS: The current available evidence suggests that the oncological outcomes of laparoscopic RNU may be poorer than those of open RNU when bladder cuff is excised laparoscopically and in patients with locally advanced high-risk (pT3/pT4 and/or high-grade) UTUC. PATIENT SUMMARY: We reviewed the literature comparing the outcomes of two different surgical procedures for the treatment of upper tract urothelial carcinoma. Open radical nephroureterectomy is a surgical procedure in which the kidney is removed through a large incision in the abdomen, while in laparoscopic radical nephroureterectomy, the kidney is removed through a number of small incisions. Our findings suggest that the outcomes of laparoscopic radical nephroureterectomy may be poorer than those of open radical nephroureterectomy, particularly when the bladder cuff is also required to be removed. Laparoscopic radical nephroureterectomy may also be less effective in patients with locally advanced (pT3/pT4) or high-grade upper tract urothelial carcinomas. PMID- 29154043 TI - The cause and effect of Cryptococcus interactions with the host. AB - Upon Cryptococcus neoformans infection of the host lung, the fungus enters a nutrient poor environment and must adapt to a variety of host-specific stress conditions (temperature, nutrient limitation, pH, CO2). Fungal spores enter this milieu with limited nutritional reserves, germinate, and begin proliferating by budding as yeast. Although relatively little is known about the initial stages of infection, recent work has characterized changes that occur upon germination. This program and subsequent yeast-phase proliferation progress in a dynamic environment as host nutrient immunity responds to the infection via toxic accumulation or sequestration of essential micronutrients and innate immune cells are recruited to the site of infection. Adaptation to the host environment and evasion of the immune response through pathogenicity factor expression allows proliferation and dissemination to multiple sites throughout the body, including, most significantly for human disease, the central nervous system. Here we will discuss recent insights into mechanisms underlying C. neoformans interactions with the host during infection. PMID- 29154045 TI - Cut-off frequencies of circumferential horizontal shear waves in various functionally graded cylinder shells. AB - In this study, cut-off frequencies of the circumferential SH waves in functionally graded piezoelectric-piezomagnetic material (FGPPM) cylinder shells with traction free, electrical and magnetic open boundary conditions are investigated analytically. The Wentzel-Kramers-Brillouin (WKB) method is employed for solving differential equations with variable coefficients for general cases. For comparison, Bessel functions and Kummer functions are used for solving cut off frequency problems in homogenous and ideal FGPPM cylinder shells. It is shown that the WKB solution for the cut-off frequencies has good precise. The set of cut-off frequencies is a series of approximate arithmetic progressions, for which the difference is a function of the density and the effective elastic parameter. The relationship between the difference and the gradient coefficient is described. These results provide theoretical guidance for the non-destructive evaluation of curved shells based on the cut-off frequencies. PMID- 29154046 TI - Simulation of guided-wave ultrasound propagation in composite laminates: Benchmark comparisons of numerical codes and experiment. AB - Ultrasonic wave methods constitute the leading physical mechanism for nondestructive evaluation (NDE) and structural health monitoring (SHM) of solid composite materials, such as carbon fiber reinforced polymer (CFRP) laminates. Computational models of ultrasonic wave excitation, propagation, and scattering in CFRP composites can be extremely valuable in designing practicable NDE and SHM hardware, software, and methodologies that accomplish the desired accuracy, reliability, efficiency, and coverage. The development and application of ultrasonic simulation approaches for composite materials is an active area of research in the field of NDE. This paper presents comparisons of guided wave simulations for CFRP composites implemented using four different simulation codes: the commercial finite element modeling (FEM) packages ABAQUS, ANSYS, and COMSOL, and a custom code executing the Elastodynamic Finite Integration Technique (EFIT). Benchmark comparisons are made between the simulation tools and both experimental laser Doppler vibrometry data and theoretical dispersion curves. A pristine and a delamination type case (Teflon insert in the experimental specimen) is studied. A summary is given of the accuracy of simulation results and the respective computational performance of the four different simulation tools. PMID- 29154044 TI - Modulating host immune responses to fight invasive fungal infections. AB - Modulation of host immunity in invasive fungal infection is an appealing but as yet mostly elusive treatment strategy. Animal studies in invasive candidiasis and aspergillosis have demonstrated beneficial effects of colony stimulating factors, interferon-gamma and monoclonal antibodies. More recent studies transfusing leukocytes pre-loaded with lipophilic anti-fungal drugs, or modulated T-cells, along with novel vaccination strategies show great promise. The translation of immune therapies into clinical studies has been limited to date but this is changing and the results of new Candida vaccine trials are eagerly awaited. Immune modulation in HIV-associated mycoses remains complicated by the risk of immune reconstitution inflammatory syndrome and although exogenous interferon gamma therapy may be beneficial in cryptococcal meningitis, early initiation of anti-retroviral therapy leads to increased mortality. Further study is required to better target protective immune responses. PMID- 29154047 TI - Association of diurnal temperature range with daily mortality in England and Wales: A nationwide time-series study. AB - BACKGROUND: Diurnal temperature range (DTR) reflects within-day temperature variability and is closely associated with climate change. In comparison to temperature extremes, up-to-date DTR-health evidence at the regional and national scales has been still very limited worldwide, especially in Europe. OBJECTIVES: This study aimed to provide nationwide estimates for DTR-associated effects on mortality, and explore whether season and regional-level characteristics modify DTR-mortality relation in United Kingdom. METHODS: Fourteen-year time-series data on weather and mortality were collected from 10 regions in England and Wales during 1993-2006, including 7,573,716 total deaths. A quasi-Poisson regression incorporated with distributed lag non-linear model was first applied to estimate region-specific DTR-mortality relationships. Then, a multivariate meta-analysis was employed to derive the pooled DTR effects at the national level. Also, the modifying effects of some regional characteristics (e.g., geographical and climatological) were examined by conducting multivariate meta-regression. RESULTS: A non-linear DTR-mortality relationship was identified in UK. At the national level, increasing DTR raised the mortality risk observably when DTR exposure was below 25th percentile or above 90th percentile of DTR distribution, with an intermediate risk plateau indicating no associations. Extremely high DTR exhibited greater adverse effect estimates in hot season compared with in cold and transitional season, whereas entirely different association patterns were observed for the season-specific effects of extremely low DTR. In addition to season, regional latitudes, average temperature and humidity were also found to significantly modify DTR-mortality relationship. CONCLUSIONS: Our study added strong evidence that extremely high DTR increased short-term mortality, whereas the effects of extremely low DTR exhibited entirely different seasonal patterns. Also, mortality vulnerability to DTR extremes varied greatly by regional latitudes and climate conditions. PMID- 29154048 TI - Hydrochemical controls on reservoir nutrient and phytoplankton dynamics under storms. AB - Eutrophication and undesired algal blooms in surface water are common and have been linked to increasing nutrient loading. Effects of extreme events such as storms on reservoir nutrient and phytoplankton remain unclear. Here we carried out continuous high-frequency measurements in a long and narrow dam reservoir in southeast China during a storm period in June-July 2015. Our results show a strong nutrient-phytoplankton relationship as well as a very rapid response to storm runoff. We observed an increase in total suspended matter (TSM), ammonium (NH4-N), and dissolved reactive phosphate (DRP), with a sharp decline in chlorophyll-a (Chl-a) in the high flow periods. Afterward, Chl-a, total phytoplankton abundance and Cyanophyta fraction elevated gradually. Nitrate was diluted at first with increasing discharge before concentration increased, likely following a delayed input of groundwater. Physiochemical parameters and Chl-a were evenly distributed in the water column during the flooding period. However, 10% of NH4-N and 25% of DRP were removed in surface water (0-1m) when an algal bloom (Chl-a>30MUgL-1) occurred 10days after peak discharge. Conversely, total particulate P (TPP) of surface water was 58% higher than in the deeper water. Dynamic factor analysis (DFA) revealed that TSM, NH4-N, DRP, total P and discharge significantly explain Chl-a variations following storms (Ceff=0.89). These findings highlight that the reservoir ecosystem was vulnerable to pulse input from storm runoff and the Cyanophyta bloom was likely fueled by phosphate and ammonium rather than nitrate. PMID- 29154049 TI - Date palm biochar-polymer composites: An investigation of electrical, mechanical, thermal and rheological characteristics. AB - The application of biochar (BC) as a filler in polymers can be viewed as a sustainable approach that incorporates pyrolysed waste based value-added material and simultaneously mitigate bio-waste in a smart way. The overarching aim of this work was to investigate the electrical, mechanical, thermal and rheological properties of biocomposite developed by utilizing date palm waste-derived BC for the reinforcing of polypropylene (PP) matrix. Date palm waste derived BC prepared at (700 and 900 degrees C) were blended at different proportions with polypropylene and the resultant composites (BC/PP) were characterized using an array of techniques (scanning electron microscope, energy-dispersive X-ray spectroscopy and Fourier transform infra-red spectroscopy). Additionally the thermal, mechanical, electrical and rheological properties of the BC/PP composites were evaluated at different loading of BC content (from 0 to15% w/w). The mechanical properties of BC/PP composites showed an improvement in the tensile modulus while that of electrical characterization revealed an enhanced electrical conductivity with increased BC loading. Although the BC incorporation into the PP matrix has significantly reduced the total crystallinity of the resulted composites, however; a positive effect on the crystallization temperature (Tc) was observed. The rheological characterization of BC/PP composites revealed that the addition of BC had minimal effect on the storage modulus (G') compared to the neat (PP). PMID- 29154050 TI - Decreased use of pesticides for increased yields of rice and fish-options for sustainable food production in the Mekong Delta. AB - This study assesses the use of pesticides and the attitude to pest management strategies among rice and rice-fish farmers in the Can Tho and Tien Giang provinces in Vietnam. Interviews were made with 80 farmers. The farmers were divided in to farmers cultivating only rice with a high use (RHP) and low use (RLP) of pesticides, and farmers cultivating rice and fish with a high use (RFHP) and low use (RFLP) of pesticides. 80% of the HP farmers relied mainly on pesticides to control pests, while >80% of the LP farmers also applied IPM strategies. Insecticides were the most commonly used pesticides. 85% of all farmers experienced health effects from using pesticides. 80% of the farmers felt that the yield of fish had decreased over the last three years, and that this mainly was caused by pesticides. The RFHP farmers had lower fish survival and fish yields as compared to the RFLP farmers. The RFHP farmers also had significant lower rice yields than the RFLP farmers, and there were significant correlations between both decreased fish yields and rice yields with increased use of pesticides among rice-fish farmers. Increased rice yields were positively correlated with increased fish survival, indicating the synergistic effects between rice and fish production. Overall, the RFLP farmers had the highest income of the four farmers' groups, while RFHP farmers had the lowest income. This shows that rice-fish farming provides a competitive and sustainable alternative to intensive rice-farming, but only if the farmer restricts the use of pesticides. This would not only help to reduce the production costs, but also to decrease environmental and health effects, and it is proposed that rice-fish farming with a low use of pesticides provides an attractive alternative to rice monocropping for a sustainable and diversified food production in the Mekong Delta. PMID- 29154051 TI - Ecotoxicological effects of carbon based nanomaterials in aquatic organisms. AB - An increasing amount of carbon-based nanomaterials (CNM) (mostly fullerenes, carbon nanotubes and graphene) has been observed in aquatic systems over the last years. However, the potential toxicity of these CNM on aquatic ecosystems remains unclear. This paper reviews the existing literature on the toxic effects of CNM in aquatic organisms as well as the toxic effects of CNM through influencing the toxicity of other micro-pollutants, and outlines a series of research needs to reduce the uncertainty associated with CNMs toxic effects. The results show that environmental concentrations of CNM do not pose a threat on aquatic organisms on their own. The observed concentrations of CNM in aquatic environments are in the order of ngL-1 or even lower, much below than the lowest observed effect concentrations (LOEC) on different aquatic organisms (in the order of mgL-1). Toxic effects have been mainly observed in short-term experiments at high concentrations, and toxicity principally depends on the type of organisms, exposition time and CNM preparation methods. Moreover, we observed that CNM interact (establishing synergistic and/or antagonistic effects) with other micro pollutants. Apparently, the resulting interaction is highly dependent on the chemical properties of each micro-pollutant, CNM acting either as carriers or as sorbents, thereby modifying the original toxicity of the contaminants. Results stress the need of studying the interactive effects of CNM with other micro pollutants at environmental relevant concentrations, as well as their effects on biological communities in the long-term. PMID- 29154052 TI - Unmasking decoupling: Redefining the Resource Intensity of the Economy. AB - Interest in investigating the complex link between resources and developments has revived recently following studies which support striking "dematerialized" growth over the last hundred years or so. This so-called decoupling effect is defined as the declining quantity of resources required for producing one unit of GDP. Decoupling studies adopt aggregate GDP as the measure of the outcome of the economy. However, this outcome is contributed by the total population which differs over time and between countries. A valid comparison should use a comparable, standardized indicator that adjusts for population size. GDP per capita, the income index, defines in monetary terms the ultimate outcome of the economy and is adopted by international organizations as the standard index for comparing economies. The income index approximates, in monetary terms, the welfare produced by the economic system and enjoyed by individuals. Recently developed alternative indexes of welfare lack broad data coverage and have limited empirical application as yet. For this reason and for ensuring direct comparison with the standard decoupling estimates, our study remains within the monetary context. The present paper re-evaluates the resources-economy link from the perspective of "the resources required for the production of one unit of GDP per capita (Income)" and hence evaluates the efficiency of turning resources into the actual outcome of the economic system. Our estimates suggest that the dependence of global economic growth on natural resources has increased by over 60% in the last 110years (1900-2009), contrasting with the prevailing decoupling estimates which suggest a reduction by 63%. We find that the actual decoupling, which began in the mid-1970s in post-industrial economies, is counterbalanced by the intensified resource intensity of several developing economies. Accordingly, in the pursuit of sustainability, the dematerialization target needs to be more clearly incorporated into environmental policies and pervade contemporary economic thinking. PMID- 29154053 TI - Acupuncture and Kinesio Taping for the acute management of Bell's palsy: A case report. AB - BACKGROUND: Bell's palsy is an idiopathic, acute peripheral palsy of the facial nerve that supplies the muscles of facial expression. Despite an expected 70% full recovery rate, up to 30% of patients are left with potentially disfiguring facial weakness, involuntary movements, or persistent lacrimation. The most frequently used treatment options are corticosteroids and antiviral drugs. However, accompanying clinical conditions, such as uncontrolled diabetes, hypertension, gastrointestinal disturbances, polypharmacy of geriatric patients, and significant sequelae ratios, indicate the need for safe and effective complementary therapies that would enhance the success of the conventional interventions. CASE SUMMARY: A 26-year-old female presented with numbness and earache on the left side of the face; these symptoms had been ongoing for 8-10h. Physical examination revealed peripheral facial paralysis of House-Brackmann grade III and corticosteroid-valacyclovir treatment was initiated. On the same day, Kinesio Taping was applied to the affected nerve and muscle area with the aim of primarily neurofacilitation and edema-pain relief. On the fifth day, acupuncture treatment was started and was continued for 3 consecutive days. A physical therapy program was administered for the subsequent 10days. At the 3 week follow-up examination, Bell's palsy was determined as grade I, and the treatment was stopped. CONCLUSION: Acupuncture and Kinesio Taping, in conjunction with physical therapy modalities, are safe and promising complementary therapies for the acute management of Bell's palsy. However, further large scale and randomized controlled studies are necessary to assess whether these complementary interventions have significant additive or synergistic effect for complete recovery of patients with Bell's palsy. PMID- 29154054 TI - The effects of chamomile extract on sleep quality among elderly people: A clinical trial. AB - BACKGROUND: The prevalence of insomnia increases with age. Chamomile is among the medicinal plants which are used as tranquilizer. Yet, there is inadequate experimental and clinical evidence regarding its hypnotic effects. This study sought to evaluate the effects of chamomile extract on sleep quality among elderly people. DESIGN: A single-blind randomized controlled trial was performed. SETTING: A convenient sample of sixty elderly people who aged sixty or more and lived in Kahrizak day care nursing home, Karaj, Iran, were randomly allocated to a control and a treatment group. The treatment group received chamomile extract capsules (200mg) twice a day for 28 consecutive days while the control group received wheat flour capsules (200mg) in the same manner. Using the Pittsburgh Sleep Quality Index, sleep quality was assessed immediately before, two weeks after beginning, immediately after the completion, and two weeks after the completion of the intervention. The data were analyzed via the independent-sample t, Chi-square, and Fisher's exact tests as well as the repeated measures analysis of variance. RESULTS: The means of age in the control and the treatment groups were 70.73+/-6.44 and 69.36+/-4.99, respectively. Except for the habitual sleep efficiency component of the Sleep Quality Index, the study groups did not differ significantly from each other at baseline regarding the scores of the other components of the index. Moreover, at baseline, sleep quality in both groups was low, with no statistically significant between-group difference (P=0.639). However, after the intervention, sleep quality in the treatment group was significantly better than the control group (P<0.05). CONCLUSION: The use of chamomile extract can significantly improve sleep quality among elderly people. Thus, it can be used as a safe modality for promoting elderly people's sleep. PMID- 29154055 TI - Complementary and alternative medicine use among elderly patients living with chronic diseases in a teaching hospital in Ethiopia. AB - BACKGROUND: The use of complementary and alternative medicine (CAM) among patients with chronic diseases has grown rapidly worldwide. Yet, little has been known about CAM use by elderly patients with chronic diseases in Ethiopia. This study aimed at assessing the prevalence and reasons for CAM utilization among elderly patients living with chronic diseases in Ethiopia. METHODS: An institution-based quantitative cross-sectional survey was conducted among elderly patients with chronic disease attending outpatient ambulatory clinics of University of Gondar referral and teaching hospital (UoGRTH). An interviewer administered and semi-structured questionnaire were utilized to collect the data. RESULT: Of the total respondents, 240 (74%) reported the use of CAM, with herbal medicine and spiritual healing being the most commonly utilized CAM modalities (50.4% and 40.8% respectively). Dissatisfaction with conventional therapy (40.8%) and belief in the effectiveness of CAM (30.8%) are the most commonly cited reasons for the use of CAM therapies. Rural residency, higher educational status, higher average monthly income and presence of co-morbidity were positively associated with the use of CAM. CONCLUSION: This survey revealed a higher rate of CAM use among elderly patients with chronic diseases, along with a very low rate of disclosing their use to their health care providers. Special attention should be given for these patient population due to the potentially harmful interaction of different herbal remedies with the prescribed medications, thereby predisposing the patient to untoward adverse effects and compromised overall health outcome. PMID- 29154056 TI - A single session of hatha yoga improves stress reactivity and recovery after an acute psychological stress task-A counterbalanced, randomized-crossover trial in healthy individuals. AB - OBJECTIVES: Yoga is promoted as an anti-stress activity, however, little is known about the mechanisms through which it acts. The present study investigated the acute effects of a hatha yoga session, displayed on a video, on the response to and recovery from an acute psychological stressor. METHODS: Twenty-four healthy young adults took part in a counterbalanced, randomized-crossover trial, with a yoga and a control condition (watching TV). Participants attended the laboratory in the afternoon on two days and each session comprised a baseline, control or yoga task, stress task and recovery. Blood pressure (BP), heart rate (HR) and salivary cortisol responses were measured. State cognitive- and somatic-anxiety along with self-confidence were assessed before and after the stressor. RESULTS: Although no difference in the BP or HR responses to stress were found between conditions, systolic BP (p=0.047) and diastolic BP (p=0.018) recovery from stress were significantly accelerated and salivary cortisol reactivity was significantly lower (p=0.01) in the yoga condition. A yoga session also increased self confidence (p=0.006) in preparation for the task and after completion. Moreover, self-confidence reported after the stress task was considered debilitative towards performance in the control condition, but remained facilitative in the yoga condition. CONCLUSION: Our results show that a single video-instructed session of hatha yoga was able to improve stress reactivity and recovery from an acute stress task in healthy individuals. These positive preliminary findings encourage further investigation in at-risk populations in which the magnitude of effects may be greater, and support the use of yoga for stress reactivity and recovery. PMID- 29154057 TI - Far-infrared ray patches relieve pain and improve skin sensitivity in myofascial pain syndrome: A double-blind randomized controlled study. AB - OBJECTIVE: Myofascial pain syndrome (MPS) is a common disorder characterized by muscle pain if myofascial trigger points (MTrP) are stimulated. This study evaluated the effectiveness of far-infrared ray (FIR) patches in reducing the severity of pain in patients with MPS. METHODS: A double-blind, randomized controlled study involving 125 patients with MPS and 201 MTrPs located in the trapezius muscle. A FIR patch was applied to 98 MTrPs for 24h in the intervention group (61 patients) and a placebo patch was applied to 91 MTrPs in the control group (57 patients) at the end. Pain intensity was measured using the visual analogue scale (V) while pressure pain threshold (P) and maximal pain tolerance (T) were measured using an algometer before and after treatment. RESULTS: The mean age of the patients was 37.16 years old and 67% were female. There was a positive correlation between P and T (p<0.001). Older Age was associated with higher P and T due to poor skin sensitivity (p<0.001). V improved significantly in both groups to a similar extent, but only in the intervention group, P and T decreased significantly (which implied better skin sensitivity) (p<0.05). P and T decreased the most in the female group aged over 35, probably due to thinner skin in this subgroup. CONCLUSIONS: FIR and placebo patches were equally effective at relieving pain (with decreased V), but P and T dropped only in the intervention group with FIR patches. This probably resulted from FIR penetrated only to the skin layer and improved skin sensitivity with more blood circulation, but the muscle remained unaffected. Further studies should investigate the effect of longer exposure or higher energy applications. PMID- 29154058 TI - Herbal medicines for treating acute otitis media: A systematic review of randomised controlled trials. AB - INTRODUCTION: This systematic review aimed to assess the clinical evidence for the widespread use of herbal medicines in treating acute otitis media. METHODS: Eleven electronic databases, including MEDLINE, EMBASE, and the CENTRAL were searched, without language limitations. All randomised controlled trials involving the use of herbal medicines, alone or in combination with conventional therapies, for acute otitis media were included. RESULTS: We identified 4956 studies, of which seven randomised clinical trials met the inclusion criteria. The overall risk of bias of the included trials was relatively high or unclear. Treatment with Longdan-xiegan decoction or Shenling-baizhu powder, combined with antibiotics, appeared to be more effective than treatment with antibiotics alone in terms of the proportion of patients with total symptom recovery. Moreover, combination treatment of Sinupret(r) and antibiotics facilitated the recovery of middle ear conditions and hearing acuity. CONCLUSIONS: Despite some indications of potential symptom improvement, the evidence regarding the effectiveness and efficacy of herbal medicine for acute otitis media is inconclusive due to the poor quality of trials included. Moreover, we only analysed seven trials in this review. Therefore, to properly evaluate the effectiveness of herbal medicine for acute otitis media, systematic reviews based on more rigorously designed randomized trials are warranted in the future. PMID- 29154059 TI - Traditional herbal medicine use among people living with HIV/AIDS in Gondar, Ethiopia: Do their health care providers know? AB - BACKGROUND: People living with HIV/AIDS (PLWHA) are increasingly using herbal remedies due to the chronic nature of the disease, the complexities of treatment modalities and the difficulty in adhering to the therapeutic regimens. Yet, research on herbal medicine use in this patient population is scarce in Ethiopia. The present study aimed at investigating the prevalence and factors associated with the use of traditional herbal medicine among PLWHA in Gondar, Ethiopia. METHODS: A cross sectional survey was conducted on 360 PLWHA attending the outpatient clinic of University of Gondar referral and teaching hospital from September 1 to 30, 2016. A questionnaire about the socio-demographic, disease characteristics as well as traditional herbal medicine use was filled by the respondents. Descriptive statistics, univariate and multivariate logistic regression analyses were performed to determine prevalence and correlates of herbal medicine use. RESULTS: Out of 360 respondents, 255 (70.8%) used traditional herbal medicine. The most common herbal preparations used by PLWHA were Ginger (Zingiber officinale) (47%), Garlic (Allium sativum L.) (40.8%) and Moringa (Moringa stenopetala) (31.4%). Majority of herbal medicine users rarely disclose their use of herbal medicines to their health care providers (61.2%). Only lower educational status was found to be strong predictors of herbal medicine use in the multivariate logistic regression. CONCLUSIONS: The use of herbal medicine among PLWHA is a routine practice and associated with a lower educational status. Patients also rarely disclose their use of herbal medicines to their health care providers. From the stand point of high prevalence and low disclosure rate, health care providers should often consult patients regarding herbal medicine use. PMID- 29154060 TI - Efficacy and safety of a combination of red yeast rice and olive extract in hypercholesterolemic patients with and without statin-associated myalgia. AB - Cholesfytol(r), a lipid-lowering dietary supplement with antioxidant and anti atherosclerotic properties, combines red yeast rice (RYR) and olive extract (5mg hydroxytyrosol equivalent) and represents an alternative for patients who do not wish or are unable to use chemical statins, including individuals with previous statin-associated muscle symptoms (SAMS). A 2-months observational non-randomized study was performed to evaluate the efficacy, tolerance and safety of Cholesfytol(r) (1 tablet/day) in 642 hypercholesterolemic patients (mean age: 59 yrs; total cholesterol (TC) >=200; LDL-C >=140mg/dl). Patients were followed by 126 GPs, and included irrespective of SAMS history and/or diabetes. None of the patients were taking statins or other lipid-modifying therapy at inclusion. At baseline, 26% had fasting glucose >100 <=125mg/dL, and 5% >125mg/dL; 32% (n=194) had a SAMS history; and 21% had atherogenic dyslipidemia (AD). In the entire cohort, pre-treatment TC; non-HDL-C; LDL-C; and TG were 259; 200; 168; 158mg/dL, respectively, and decreased significantly on treatment (-17.5% (TC) and -23.3% (LDL-C)). Fasting glucose and HbA1c decreased between visits. The reduction in lipids was greater in patients with higher values at baseline. For comparable pre treatment values, patients with SAMS history had reductions in TC, LDL-C, non-HDL C, and apoB100 slightly less than patients without myalgia. AD patients had greater on-treatment decrease in TG. Overall, 13 patients reported minor side effects, and 4 patients reporting myalgia had antecedent SAMS. In conclusion, a substantial decrease in LDL-C was obtained with a combination of RYR and olive extract in high-risk hypercholesterolemic patients, without inducing new-onset SAMS. PMID- 29154061 TI - Corrigendum to "The correlation between pulse diagnosis and constitution identification in traditional Chinese medicine" [Complementary Ther. Med. 30 (2017) 107-112]. PMID- 29154062 TI - Survey of complementary and alternative medicine in pediatric inpatient settings. AB - OBJECTIVES: While use of complementary and alternative medicine (CAM) is common in children, we know little about its use for hospitalized children. This survey measured the rate of CAM use, specific modalities used, and policies related to CAM use for hospitalized children. DESIGN: Anonymous survey of hospitals in the Pediatric Research in Inpatient Settings (PRIS) network SETTING: Hospitals in the PRIS network. MAIN OUTCOME MEASURES: Rate of overall and specific CAM modality use, including whether these modalities are provided, permitted, or prohibited, and presence of a written policy on CAM use. RESULTS: Of 99 sites queried, 22 responded. Of these, 82% of sites reported some CAM presence, and 63% reported official provision of CAM therapies. Freestanding children's hospitals provided more modalities than other types of hospitals. There was no difference in number of modalities by geographic location. The most commonly provided CAM modalities were massage and biofield therapies. The most commonly prohibited modalities were inpatient placebos outside of research settings, medical marijuana, and inpatient homeopathic preparations. Only one site reported having a written policy on CAM use. CONCLUSIONS: Among responding institutions, the most reported some CAM presence with a wide variety of CAM modalities provided and permitted. Written institutional policies on CAM were rare. PMID- 29154063 TI - The impact of silymarin on antioxidant and oxidative status in patients with beta thalassemia major: A crossover, randomized controlled trial. AB - BACKGROUND & AIMS: Blood transfusion therapy is lifesaving for individuals with beta-thalassemia major (beta-TM). Iron burden following blood transfusion is the main cause of oxidative stress (OS) and organ dysfunction in these patients. The aim of this study was to evaluate the effects of silymarin on serum antioxidant and oxidative status in patients with beta-TM. METHODS: A crossover, randomized controlled trial was performed on 82 thalassemia patients. In two periods of 12 weeks, patients received 420mg silymarin (divided into three equal 140-mg daily doses) and placebo. The washout period between the two phases was two weeks. Serum malondialdehyde (MDA), protein carbonyl (CO), total antioxidant capacity (TAC), and reduced glutathione (GSH) were measured before and after both periods. RESULTS: Sixty-nine patients completed the study. Mean serum MDA and protein CO significantly decreased in all patients with beta-TM after three months of treatment with silymarin. At the end of the study, serum MDA decreased from 20.36+/-20.11 to 4.79+/-4.71MUmol/l (compared to 17.81+/-16.05MUmol/l after administration of placebo), and protein CO dropped from 0.31+/-0.28 to 0.11+/ 0.09mM/l (compared to 0.24+/-0.17mM/l with placebo). Additional laboratory parameters (such as serum TAC and plasma GSH) were also significantly elevated after therapy with silymarin. At the end of the study, serum TAC increased in all patients from 620.7+/-202.64 to 971.83+/-328.16MUmol FeSO4/l (compared to 672.22+/-206.88MUmol FeSO4/l with placebo), and GSH increased from 46.16+/-41.68 to 195.35+/-210.98nM/l (compared to 58.52+/-48.95nM/l with placebo). The treatment effect of silymarin was measured using a mixed-effects model of variance analysis for changes in MDA, protein CO, TAC, and GSH, with significant effects being demonstrated for each laboratory parameter (P<0.001, P=0.002, P<0.001, and P<0.001, respectively). CONCLUSIONS: Silymarin was effective in decreasing serum OS and enhancing serum antioxidant capability in patients with beta-thalassemia major. Silymarin given as an adjuvant therapy to standard iron chelators may provide an improvement in the OS measurements obtained in these patients, with accompanying benefit. PMID- 29154064 TI - Living with chronic pain: Evaluating patient experiences with a medical group visit focused on mindfulness and non-pharmacological strategies. AB - OBJECTIVES: Little is known about the acceptance of non-pharmacological group strategies delivered to low income racially diverse patients with chronic pain and depression. This paper examines how the Integrative Medical Group Visit (IMGV) addresses many of the deficits identified with usual care. DESIGN AND SETTING: Six IMGVs cohorts were held at a safety net hospital and two federally funded community health centres. Data was gathered through focus groups. Transcripts were analysed using both a priori codes and inductive coding. INTERVENTION: The intervention included ten sessions of Integrative Medical Group Visits with a primary care provider and a meditation instructor. The curriculum uses principles of Mindfulness Based Stress Reduction and evidence based integrative medicine. The visit is structured similarly to other group medical visits. MAIN OUTCOME MEASURES: Data was gathered through four focus groups held after the cohorts were completed. RESULTS: Participants (N=20) were largely low income minority adults with chronic pain and comorbid depression. Six themes emerged from the coding including: chronic pain is isolating; group treatment contributes to better coping with pain; loss of control and autonomy because of the unpredictability of pain as well as dependence on medication and frequent medical appointments; groups improve agency and control over one's health condition; navigating the healthcare system and unsatisfactory treatment options; and changes after the IMGV due to non-pharmacological health management. CONCLUSIONS: The IMGV is a promising format of delivering integrative care for chronic pain and depression which addresses many of the problems identified by patients in usual care. PMID- 29154065 TI - Does nurses' role, health or symptoms influence their personal use of ingestible complementary and alternative medicines? AB - OBJECTIVES: To investigate the influence of work-related characteristics, health, health behaviours and symptoms on ingestible biologically-based Complementary and Alternative Medicine (CAM) use within the Australian nursing and midwifery workforce. BACKGROUND: CAM use is widespread worldwide, but there is little research into nurses' and midwives' personal use of ingestible CAM in Australia. METHODS: An online survey in 2014-15 used validated instruments and items to examine use of ingestible biologically-based CAM (herbs, foods and vitamins, minerals, amino acids, enzymes and other supplements), and the health and work related characteristics of 5041 nurses and midwives recruited through the New South Wales Nurses and Midwives Association and professional networks. RESULTS: A small proportion of nurses (6.8%) identified as personal CAM users. Most were female, older, worked in foundational roles (frontline Registered and Enrolled Nurses/Midwives) and used one CAM, most commonly a multivitamin, although Vitamin D, Fish Oil, Calcium and Glucosamine+/-Chondroitin were also common. In comparison to non-users, CAM users were less likely to take sick days or indulge in risky drinking, but more likely to be symptomatic (with stiff joints, bodily/joint pain, severe tiredness, allergies, indigestion/heartburn), diagnosed with osteoarthritis and to adhere to healthy diet recommendations. CONCLUSIONS: Findings showed a credible pattern of front line workers with physically demanding workloads that impact their physical health and are linked to frequent symptoms, using CAM treatments and achieving some success in being able to continue working and avoid sickness absence. Further investigation is warranted to protect and maintain the health of the nursing and midwifery workforce. PMID- 29154066 TI - Parent disclosure of complementary health approaches used for children with autism spectrum disorder: Barriers and facilitators. AB - BACKGROUND AND OBJECTIVES: Complementary health approaches (CHA) are widely used among children with autism spectrum disorder (ASD). As part of shared treatment decision-making, healthcare providers are encouraged to discuss CHA with parents of children with ASD. Yet prior research suggests that parents often do not disclose CHA used for children, and their reasons for nondisclosure are poorly understood. We, therefore, aimed to identify barriers and facilitators to parent disclosure of CHA used for children with ASD. DESIGN AND SETTING: In-depth interviews were conducted with 31 parents who reported that they were currently using CHA for their child's ASD in Denver, Colorado or Portland, Oregon. RESULTS: We used content analysis to identify six main themes indicating that the following factors play a role in disclosure: parents' drive to optimize their child's health, parent self-efficacy discussing CHA with healthcare providers, parent beliefs about the effectiveness of CHA, parent-provider relationship quality, provider attitudes and knowledge regarding CHA and ASD, and visit characteristics. CONCLUSIONS: Study findings suggest that family and health system factors, together, influence parent disclosure of CHA used for children with ASD. Multifaceted intervention concurrently targeting the CHA-related knowledge, beliefs, and self-efficacy of parents whose children have been recently diagnosed with ASD, in addition to the CHA-related attitudes and knowledge of their healthcare providers may promote disclosure and shared treatment decision-making about the use of CHA. PMID- 29154067 TI - Laser acupuncture treatment of neuropathic pain in a boy with brain tumour. AB - Neuropathic pain occurrence is associated with some cytostatic and antibiotics use. Pharmacological therapy for the treatment of neuropathic pain is sometimes unsuccessful, and complementary methods like acupuncture are included. In this case report, a 14-year-old boy with cerebral tumour and neuropathic pain in his feet after chemotherapy and linezolid use is presented. A complete cessation of neuropathic pain symptoms like hyperalgesia and allodynia was accomplished after laser acupuncture application. PMID- 29154068 TI - Yoga's effect on falls in rural, older adults. AB - BACKGROUND: Unintentional falls affect 30% of people over age 65 years. Yoga has been shown to improve balance. We designed this study to examine if yoga reduces falls. METHODS: We conducted 16 sessions of Hatha yoga over 8 weeks. Participants were randomly assigned to practice 10min of yoga daily at home in addition to 5 min relaxation exercises or relaxation exercises only (control group). RESULTS: Of the 38 participants completing the intervention, 15 participants reported a total of 27 falls in the 6-months before the study, compared to 13 participants sustaining 14 falls in the 6 months from the start of the study (p<0.047), without difference between yoga home-exercise and home relaxation-only groups. Compared to baseline scores, all participants improved on the Berg Balance Scale (53-54 out of 56, p=0.002), the Functional Gait Assessment (22.9-25.8 out of 30 points, p<0.001), and the Dynamic Gait Index (20.6-22.4 out of 24 points, p<0.001). Right leg stand time improved from a mean of 13.3s to 17.1s (p=0.020) and standing forward reach distance from 26.0cm to 29.6cm (p<0.001). Without difference between groups. Confidence, with the Activities-specific Balance Confidence Scale, increased in the yoga home-exercise group (88%-93%, p=0.037) compared to 90% unchanged from pre-intervention in the home relaxation-only group. CONCLUSION: Yoga classes reduce self-reported falls and improve balance measures. The addition of home yoga exercises did not enhance benefit over relaxation exercise only. PMID- 29154069 TI - Nigella sativa improves glucose homeostasis and serum lipids in type 2 diabetes: A systematic review and meta-analysis. AB - BACKGROUND & OBJECTIVE(S): Global prevalence of type 2 diabetes (T2D) is very high and is currently growing alarmingly. With respect to recent researchers' attention to the potential role of herbal medicine in disease prevention and management, the present meta-analysis review investigates the effectiveness of Nigella sativa (N. sativa), a popular herb, in T2D. METHODS: Literature search was conducted covering PubMed/Medline, Scopus, and Cochrane Registry of Clinical Trials up to February 2017 to obtain the relevant published intervention studies. Study selection, quality rating and data extraction of studies were investigated by two independent reviewers. Heterogeneity was assessed using I-squared (I2) statistics test. Subgroup analysis was done to assess type of N. sativa supplement as source of heterogeneity. Effect sizes of eligible studies were pooled using STATA software version 12 (STATA corp, College Station, TX, USA). RESULTS: Seven trials were included in the meta-analysis of glycemic and serum lipid profile end points. Supplementation with N. sativa significantly improved fasting blood sugar (FBS) [-17.84mg/dl, 95% CI: -21.19 to -14.49, p<0.001], HbA1c [-0.71%, 95% CI: -1.04 to -0.39, p<0.001], total-cholesterol (TC) [WMD: 22.99mg/dl, 95% CI: -32.16 to -13.83, p<0.001] and LDL-cholesterol (LDL-c) [ 22.38mg/dl, 95% CI: -33.60 to -11.15, p<0.001]. The overall effects for triglyceride (TG) [-6.80mg/dl, 95% CI: -33.59 to 19.99, p=0.61] and HDL cholesterol (HDL-c) [0.37mg/dl, 95% CI: -1.59 to 2.33, p=0.71] were insignificant. Subgroup analysis revealed significant reduction on TG with N. sativa seed oil [-14.8mg/dl, 95% CI: -23.1 to -6.5, p<0.001], while TG was increased with seed powder [29.4mg/dl, 95% CI: 16.9-42.0, p<0.001]. All measures, but HbA1c, showed no evidence of publication bias. CONCLUSION: Although, the meta analysis conducted included a few number of studies, but has shown promising results on the effectiveness of N. sativa on glucose homeostasis and serum lipids. Current findings suggest N. sativa supplementation a suitable choice in managing the complications of T2D, although future researches are necessary. PMID- 29154070 TI - Complementary and alternative therapies in dentistry and characteristics of dentists who recommend them. AB - OBJECTIVES: The aims of this study were to analyse whether dentists offer or recommend complementary and alternative medicine (CAM) remedies in their clinical routine, and how effective these are rated by proponents and opponents. A second aim of this study was to give a profile of the dentists endorsing CAM. DESIGN: A prospective, explorative, anonymised cross-sectional survey was spread among practicing dentists in Germany via congresses, dental periodicals and online (n=250, 55% male, 45% female; mean age 49.1+/-11.4years). RESULTS: Of a set of 31 predefined CAM modalities, the dentists integrated plant extracts from Arnica montana (64%), chamomile (64%), clove (63%), Salvia officinalis (54%), but also relaxation therapies (62%), homeopathy (57%), osteopathic medicine (50%) and dietetics (50%). The effectiveness of specific treatments was rated significantly higher (p<0.0001) by CAM proponents than opponents. However also CAM opponents classified some CAM remedies as highly effective, namely ear acupuncture, osteopathic medicine and clove. For ear acupuncture these scores did not significantly differ between both groups. With respect to the characteristic of the proponents, the majority of CAM endorsing dentists were women. The mean age (50.4+/-0.9 vs 47.0+/-0.9years) and number of years of professional experience (24.2+/-1.0 vs 20.0+/-1.0years) were significantly higher for CAM proponents than the means for opponents (p<0.0001 respectively). CAM proponents worked significantly less (p<0.0001) and their perceived workload was significantly lower (p=0.008). Their self-efficacy expectation (SEE) and work engagement (Utrecht work engagement, UWE) were significantly higher (p<=0.01 and p<0.0001) compared to dentists who abandoned these treatment options. The logistic regression model showed (exploratively) an increased association from CAM proponents with the UWES subscale dedication, with years of experience, and that men are less likely to be CAM proponents than women. CONCLUSION: Various CAM treatments are recommended by German dentists and requested by their patients, but the scientific evidence for these treatments are often low or at least unclear. CAM proponents are often female, have higher SE and work engagement. PMID- 29154071 TI - Clinical effects of Zingiber cassumunar (Plai): A systematic review. AB - Zingiber cassumunar Roxb. known locally as "Plai" in Thai, has been used for treating bruise, sprain and musculoskeletal pain. Several pre-clinical studies demonstrated the anti-inflammatory effect of Plai. However, current evidence of clinical effects of Plai is still unclear. This study aimed to determine the clinical efficacy and safety of Plai among all identified indications. Of the 808 articles identified by a systematic review, six studies were included. Four studies were randomized controlled trials, while two studies were quasi experimental studies involving 178 patients in intervention group and 177 patients in control group. Duration of treatment ranged from 7days to 2 months. Our findings showed that 14% Plai cream had a strong trend of benefits in pain reduction for muscle pain and ankle sprain. However, evidence supporting the effects of Plai on acne vulgaris treatment and anti-histamine effect are still unclear. PMID- 29154072 TI - Physiological effects of viewing fresh red roses. AB - OBJECTIVES: The present study aimed to clarify the effects of viewing fresh roses on prefrontal cortex activity, autonomic nervous activity and subjective assessments of psychological relaxation. DESIGN: A crossover design, in which each experimental group crosses over from one treatment to another, was used. SETTING AND INTERVENTIONS: A total of 15 female university students (mean age 21.7+/-1.1years) viewed fresh roses for 3min; the control consisted of no experimental stimulus. MAIN OUTCOME MEASURES: Physiological effects on prefrontal cortex activity were determined by near-infrared time-resolved spectroscopy, which was assessed by measuring oxyhemoglobin (oxy-Hb) concentration in the left and right prefrontal cortex; effects on autonomic nervous activity were assessed by measuring heart rate variability (HRV) and heart rate. Modified semantic differential method and Profile of Mood States were used to determine subjective evaluations. RESULTS: Viewing roses induced: 1) a significant decrease in oxy-Hb concentrations in the right prefrontal cortex; 2) a marginally significant decrease in ln[LF/(LF+HF)] of HRV, which is associated with sympathetic nervous activity; 3) a significant increase in perceptions of feeling 'comfortable,' 'relaxed,' and 'natural;' and 4) a significant improvement in mood state. CONCLUSIONS: These findings indicate that visual stimulation with roses induces physiological and psychological relaxation. PMID- 29154073 TI - A new topical treatment of atopic dermatitis in pediatric patients based on Ficus carica L. (Fig): A randomized, placebo-controlled clinical trial. AB - BACKGROUND: Atopic dermatitis (AD) is a common, chronic, relapsing and inflammatory skin disease characterized by pruritus and xerosis (dry skin). Its prevalence is on the increase worldwide, particularly in children. As the pathogenesis of AD involves a complex interaction of genetic, environmental and immunological factors, its definitive treatment is difficult. OBJECTIVE: This clinical trial was designed as equivalence study to investigate the effect of aqueous extract of edible dried fig fruit on the severity of AD as measured with scoring atopic dermatitis (SCORAD), in comparison with Hydrocortisone 1.0% as the routine treatment of AD and base cream as a placebo. METHOD: Forty five children aged 4 months to 14 years with mild to moderate AD (SCORAD <50) were randomly assigned, in a double blind manner, to three treatment groups in order to perform a randomised, double blinded, placebo-controlled clinical trial. The patients were instructed to apply their allocated creams twice a day for two weeks. RESULTS: The randomised, placebo-controlled trial indicates that the new treatment had significantly increased efficacy in terms of reducing the SCORAD index, pruritus and intensity scores in comparison with Hydrocortisone 1.0% (p<0.05) and the placebo failed to ameliorate the symptoms. CONCLUSION: Safety, efficacy, tolerability, and symptom relief were considerable in fig fruit extract in comparison with hydrocortisone 1.0%. This clinical trial suggests that fig fruit extract can be used instead of low potent corticosteroid in mild to moderate cases of AD. PMID- 29154074 TI - Knowledge and characteristics of herbal supplement usage among community pharmacy customers in a Malaysian population. AB - OBJECTIVES: We investigated the knowledge and characteristics of herbal supplement usage of the customers of community pharmacies in a Malaysian population. DESIGN AND SETTING: Self-administered questionnaires (in English, Malay, or Chinese) were provided to customers at three community pharmacies in Malaysia (Ipoh, Perak). Questionnaire validation and translation validation were performed. A pilot study was conducted before actual questionnaire distribution. Informed consent was obtained from all participants. RESULTS: Total number of participants was 270 (99 males and 171 females) with majority from the 31-50 age group (41.5%). Among the participants, 45.6% were herbal users. The most commonly used herbal supplements were evening primrose oil (17.9%), ginkgo biloba (13.0%), and milk thistle (8.5%). The participants seemed to have sufficient knowledge regarding herbal supplements including safety, quality, and indication of use from medical literature. Participants obtained information about herbal supplements from pharmacists (26.9%), package inserts (25.2%), friends (20.5%), and the Internet (13.3%) more often than from their doctors (9.8%). Most herbal users did not inform their doctors about their usage of herbal supplements (68.3%) or the side effects (61.5%). Herbal supplement users also tended to be women, >50-year-old, and those with higher monthly household incomes. CONCLUSIONS: Community pharmacists have a vital role in educating their customers about the safe use of herbal supplements. The participants had sufficient knowledge about herbal supplement usage; therefore, customers of these community pharmacies may have benefitted from the advice of the pharmacists. Further studies could be carried out in future on the knowledge, skills and roles of community pharmacists in the safe use of herbal supplements. PMID- 29154075 TI - Chronic disease? Healthy habits in a healthy habitat - Research on dietary therapies. PMID- 29154077 TI - Metabolic-flux dependent regulation of microbial physiology. AB - According to the most prevalent notion, changes in cellular physiology primarily occur in response to altered environmental conditions. Yet, recent studies have shown that changes in metabolic fluxes can also trigger phenotypic changes even when environmental conditions are unchanged. This suggests that cells have mechanisms in place to assess the magnitude of metabolic fluxes, that is, the rate of metabolic reactions, and use this information to regulate their physiology. In this review, we describe recent evidence for metabolic flux sensing and flux-dependent regulation. Furthermore, we discuss how such sensing and regulation can be mechanistically achieved and present a set of new candidates for flux-signaling metabolites. Similar to metabolic-flux sensing, we argue that cells can also sense protein translation flux. Finally, we elaborate on the advantages that flux-based regulation can confer to cells. PMID- 29154076 TI - Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice. AB - Stem cell therapy is considered a promising approach in the treatment of amyotrophic lateral sclerosis (ALS) and mesenchymal stem cells (MSCs) seem to be the most effective in ALS animal models. The umbilical cord (UC) is a source of highly proliferating fetal MSCs, more easily collectable than other MSCs. Recently we demonstrated that human (h) UC-MSCs, double labeled with fluorescent nanoparticles and Hoechst-33258 and transplanted intracerebroventricularly (ICV) into SOD1G93A transgenic mice, partially migrated into the spinal cord after a single injection. This prompted us to assess the effect of repeated ICV injections of hUC-MSCs on disease progression in SOD1G93A mice. Although no transplanted cells migrated to the spinal cord, a partial but significant protection of motor neurons (MNs) was found in the lumbar spinal cord of hUC-MSCs treated SOD1G93A mice, accompanied by a shift from a pro-inflammatory (IL-6, IL 1beta) to anti-inflammatory (IL-4, IL-10) and neuroprotective (IGF-1) environment in the lumbar spinal cord, probably linked to the activation of p-Akt survival pathway in both motor neurons and reactive astrocytes. However, this treatment neither prevented the muscle denervation nor delayed the disease progression of mice, emphasizing the growing evidence that protecting the motor neuron perikarya is not sufficient to delay the ALS progression. PMID- 29154078 TI - Discussion. PMID- 29154079 TI - Clinical performance of a next-generation sequencing assay (ThyroSeq v2) in the evaluation of indeterminate thyroid nodules. AB - BACKGROUND: Molecular testing with the Thyroseq v2 next generation sequencing panel ("Thyroseq") is used to estimate the risk of cancer in indeterminate thyroid nodules. METHODS: We analyzed 156 indeterminate thyroid nodules evaluated with Thyroseq, across 3 institutions. Thyroseq data and surgical pathology were matched via pathologic re-review. A result was considered Thyroseq positive if molecular alterations were annotated on the report with malignancy probability >30%. Performance characteristics were estimated using Bayes theorem. RESULTS: The Thyroseq-negative call rate was 65% (102/156). On surgical pathology, 16% (10/63) of nodules were malignant. The positive predictive value of a Thyroseq positive result was 22% (8/37; if 2 noninvasive follicular thyroid neoplasm with papillary-like nuclear features are counted as malignant, 27%, 10/37). There was 1 false-negative result (negative predictive value 96%, 22/23). The most common mutation was NRAS (19/37) with a positive predictive value of 7% (1/15). The positive predictive value of all RAS mutations (HRAS, KRAS, NRAS) was 9% (2/22). The second most common mutation, BRAF V600E, had positive predictive value of 100% (3/3). CONCLUSION: We report an external analysis of Thyroseq performance in the evaluation of indeterminate thyroid nodules. These data indicate that Thyroseq is likely to offer high negative predictive value but low positive predictive value. Many genetic alterations appear to be nonspecific for malignancy, and positive results should be interpreted with caution. These findings have implications for the management of indeterminate thyroid nodules profiled with Thyroseq. PMID- 29154081 TI - Discussion. PMID- 29154080 TI - Changes in gene expression in small bowel neuroendocrine tumors associated with progression to metastases. AB - BACKGROUND: Small bowel neuroendocrine tumors (SBNETs) present frequently with metastases, yet little is known about the molecular basis of this progression. This study sought to identify the serial differential expression of genes between normal small bowel, primary small bowel neuroendocrine tumors, and liver metastases. METHODS: RNA isolated from matched normal small bowel tissue, primary small bowel neuroendocrine tumors, and liver metastases in 12 patients was analyzed with whole transcriptome expression microarrays and RNA-Seq. Changes in gene expression between primary small bowel neuroendocrine tumors and normal small bowels, and liver metastases versus primary small bowel neuroendocrine tumors were calculated. Common genes that were differentially expressed serially (increasing or decreasing from normal small bowel to primary small bowel neuroendocrine tumors to liver metastases) were identified, and 10 were validated using qPCR. RESULTS: Use of 2 transcriptome platforms allowed for a robust discrimination of genes important in small bowel neuroendocrine tumors progression. Serial differential expression was validated in 7/10 genes, all of which had been described previously in abdominal cancers, and with several interacting with members of the AKT, MYC, or MAPK3 pathways. Liver metastases had consistent underexpression of PMP22, while high expression of SERPINA10 and SYT13 was characteristic of both pSBTs and liver metastases. CONCLUSION: Identification of the serial differential expression of genes from normal tissues to primary tumors to metastases lends insight into important pathways for SBNETs progression. Differential expression of various genes, including PMP22, SYT13 and SERPINA10, are associated with the progression of SBNETs and warrant further investigation. PMID- 29154083 TI - Discussion. PMID- 29154082 TI - Are preoperative sestamibi scans useful for identifying ectopic parathyroid glands in patients with expected multigland parathyroid disease? AB - BACKGROUND: The role of preoperative localization studies in patients with hyperparathyroidism and expected multigland disease remains poorly defined. Our study investigates the usefulness of obtaining preoperative sestamibi scans and ultrasonography of the neck in identifying ectopic glands in this group of patients. METHODS: Under Institutional Review Board approval, we performed a retrospective review of patients who underwent operation for secondary hyperparathyroidism, tertiary hyperparathyroidism, lithium-induced hyperparathyroidism, and multiple endocrine neoplasia syndrome at a tertiary institution between 2004 and 2015. We reviewed patient demographics, laboratory, radiology, pathology, and operative reports. RESULTS: Of 2,975 parathyroidectomies performed during this period, 154 operations were performed in 149 patients who met the criteria. Of the 149 patients, 82 (55.0%) had secondary, 31 (20.8%) had tertiary, 23 (15.4%) had lithium-induced HPT, and 13 (10.1%) had multiple endocrine neoplasia syndrome; 86 ectopic glands were identified in 64 patients (43.0%). Sensitivity for identification of ectopic glands was 29% for sestamibi scan and 7% for ultrasonography, while 89% of mediastinal glands were localized by sestamibi scans and thoracotomy, thoracoscopy, or sternotomy occurred in 4.7% of patients. CONCLUSION: We found a greater rate of preoperative localization of ectopic glands than reported previously. Because the sensitivity of sestamibi for identification of ectopic glands is 23.0%, the implication of missing mediastinal glands warrants preoperative imaging. PMID- 29154084 TI - Penetration of gold nanoparticles across the stratum corneum layer of thick-Skin. AB - BACKGROUND: Transdermal particulate penetration across thick-skin, such as that of palms and sole, is particularly important for drug delivery for disorders such as small fiber neuropathies. Nanoparticle-based drug delivery across skin is believed to have much translational applications, but their penetration especially through thick-skin, is not clear. OBJECTIVE: This study specifically investigates the effectiveness of gold nanoparticles (AuNPs) for thick-skin penetration, especially across the stratum corneum (SC) as a function of particle size. METHODS: The thick-skinned hind-paw of rat was used to characterize depth and distribution of AuNPs of varying sizes, namely, 22+/-3, 105+/-11, and 186+/ 20nm. Epidermal penetration of AuNPs was characterized both, in harvested skin from the hind-paw using a diffusion chamber, as well as in vivo. RESULTS: Harvested skin segments exposed to 22nm AuNPs for only 3h demonstrated higher penetration (p<0.05) as compared to the 105 and 186nm particles. In animal studies, hind-paw skin of adult rats exposed to AuNPs solution for the same time, demonstrated nanoparticles in blood on the 4th day, and histological analysis revealed AuNPs in epidermal layers just below the SC, with no apparent tissue response. CONCLUSION: We conclude that the thick-skin allows nanoparticle penetration and acts as a depot for release of AuNPs into circulation long after the initial exposure has ceased. PMID- 29154085 TI - BTX-A has notable effects contradicting some treatment aims in the rat triceps surae compartment, which are not confined to the muscles injected. AB - Botulinum toxin type-A (BTX-A) is widely used in treating gastrocnemius medial (GM) and lateral (GL) muscles in cerebral palsy to improve joint motion. However, recent animal experiments indicate inferior BTX-A effects beyond the injected muscle. The goal was to test the following hypotheses in a rat model. (1) BTX-A injected into the GM and GL does not spread into the soleus (SOL), and muscles exposed show (2) a wider length range of force exertion (Lrange), (3) reduced passive forces and (4) no intermuscular interaction effects. Confirming them was considered to indicate BTX-A effects in agreement with the treatment aims and confined to the target muscles. Two groups of Wistar rats were tested: Control (no BTX-A injected) and BTX (0.1 units of BTX-A were injected to the GM and GL, each). GM-GL and SOL muscle distal isometric forces were measured after GM-GL lengthening (condition-1, in which SOL length was kept constant) and with added SOL lengthening (condition-2). Five-days post, BTX-A injection caused significant effects: (1) all muscles showed force drops (minimally by 45%) indicating spread into the SOL. (2) Lrange of GM-GL (conditions-1 and 2) and SOL (condition-2) decreased (up to 25%). (3) Passive forces showed no change (condition-1) or opposite-coupled changes for the GM-GL (decrease by 26.6%) and SOL (increase by 25.4%) (condition-2). Intramuscular connective tissues of all muscles increased. (4) Intermuscular interactions affected BTX-A effects (e.g., GM-GL force drop increased by 48.7% in condition-2 vs. 1). Rejected hypotheses indicate complex widespread BTX-A effects contradicting some treatment aims, hence clinical testing. PMID- 29154086 TI - Mechanical characterization of in vitro-formed short-term salivary pellicle. AB - Human saliva consists of approximately 98% water and a variety of electrolytes and proteins. Those proteins can be selectively adsorbed onto the enamel surface. The cuticular material formed on the enamel surface is termed acquired salivary pellicle (ASP), which is critical for the health of oral mucosa and teeth. The ASP is composed of a inner layer and a outer layer. The lubricating properties of ASP are closely associated with the inner layer. The aim of this research is to characterize the structural and mechanical properties of the inner layer of ASP. In this paper, enamel specimens were immersed for 1 min in human saliva. The ASP formed in vitro within 1 min was studied using a nanoindenter. The results show that the thickness of the inner layer of ASP is approximately 18 nm. Moreover, the inner layer is a heterogeneous pellicle with a gradient in density. From the surface of the inner layer to the enamel surface, the density and mechanical properties gradually increase. The research results may be helpful to extend the understanding of mechanical properties of salivary pellicle and to the oral hygiene industry for diagnose oral diseases. PMID- 29154087 TI - Response to the letter to the editor by Morin JB et al. regarding "Sprint mechanics return to competition follow-up after 2 hamstring injury on a professional soccer player: A case study with an inertial sensor 3 unit based methodological approach" (Setuain et al. 2017). PMID- 29154088 TI - A hill-type muscle model expansion accounting for effects of varying transverse muscle load. AB - Recent studies demonstrated that uniaxial transverse loading (FG) of a rat gastrocnemius medialis muscle resulted in a considerable reduction of maximum isometric muscle force (DeltaFim). A hill-type muscle model assuming an identical gearing G between both DeltaFim and FG as well as lifting height of the load (Deltah) and longitudinal muscle shortening (DeltalCC) reproduced experimental data for a single load. Here we tested if this model is able to reproduce experimental changes in DeltaFim and Deltah for increasing transverse loads (0.64 N, 1.13 N, 1.62 N, 2.11 N, 2.60 N). Three different gearing ratios were tested: (I) constant Gc representing the idea of a muscle specific gearing parameter (e.g. predefined by the muscle geometry), (II) Gexp determined in experiments with varying transverse load, and (III) Gf that reproduced experimental DeltaFim for each transverse load. Simulations using Gc overestimated DeltaFim (up to 59%) and Deltah (up to 136%) for increasing load. Although the model assumption (equal G for forces and length changes) held for the three lower loads using Gexp and Gf, simulations resulted in underestimation of DeltaFim by 38% and overestimation of Deltah by 58% for the largest load, respectively. To simultaneously reproduce experimental DeltaFim and Deltah for the two larger loads, it was necessary to reduce Fim by 1.9% and 4.6%, respectively. The model seems applicable to account for effects of muscle deformation within a range of transverse loading when using a linear load-dependent function for G. PMID- 29154089 TI - Triple Achilles Tendon Rupture: Case Report. AB - We present a case report with 1-year follow-up data of a 57-year-old male soccer referee who had sustained an acute triple Achilles tendon rupture injury during a game. His triple Achilles tendon rupture consisted of a rupture of the proximal watershed region, a rupture of the main body (mid-watershed area), and an avulsion-type rupture of insertional calcific tendinosis. The patient was treated surgically with primary repair of the tendon, including tenodesis with anchors. Postoperative treatment included non-weightbearing for 4 weeks and protected weightbearing until 10 weeks postoperative, followed by formal physical therapy, which incorporated an "antigravity" treadmill. The patient was able to return to full activity after 26 weeks, including running and refereeing, without limitations. PMID- 29154091 TI - Tuning role and mechanism of paint sludge for characteristics of sewage sludge carbon: Paint sludge as a new macro-pores forming agent. AB - For the first time, paint sludge waste (PS) was used as a pore forming agent in the preparation of sewage sludge derived carbon (SC). The tuning role and mechanism of PS for characteristics of SC were explored. It was found that a sludge carbon (SCPS-Zn) with rich macro-, meso- and micro- porous could be produced by one-step pyrolytic process of sludge in the presence of PS and ZnCl2. Its surface area could reach as high as 680.5m2g-1 as 88.4 times and 4.8 times of sludge carbon without addition of PS and ZnCl2 (SC) and only addition of ZnCl2 (SCZn), respectively. The macro- pores fabricated by PS provided much inner-space for ZnCl2 to generate meso- and micro- porous, leading to a hierarchical porous structure. SCPS-Zn showed a high adsorption capacity of 685.4mgg-1 for Chrysophenine, which is 1.3 and 1.7 times that of SCPS and SCZn respectively. The adsorption difference could be simply attributed to the fact that the great molecules were difficult to enter micro- pores of SCZn. It was also found that the difference was also dependent on orientation of Chrysophenine, which was related to pH value of solution. PMID- 29154090 TI - Proliferative and metastatic roles for Phospholipase D in mouse models of cancer. AB - Phospholipase D (PLD) activity has been proposed to facilitate multiple steps in cancer progression including growth, metabolism, angiogenesis, and mobility. The canonical enzymes PLD1 and PLD2 enact their diverse effects through hydrolyzing the membrane lipid phosphatidylcholine to generate the second messenger and signaling lipid phosphatidic acid (PA). However, the widespread expression of PLD1 and PLD2 in normal tissues and the additional distinct enzymatic mechanisms through which PA can be generated have produced uncertainty regarding the optimal settings in which PLD inhibition might ameliorate cancer. Recent studies in mouse model systems have demonstrated that inhibition or elimination of PLD activity reduces tumor growth and metastasis. One mechanism proposed for this outcome involves proliferative signaling mediated by receptor tyrosine kinases (RTK) and G protein-coupled receptors (GPCR), which is attenuated when downstream PLD signal propagation is suppressed. The reduced proliferative signaling has been reported to be compounded by dysfunctional energetic metabolism in the tumor cells under conditions of nutrient deprivation. Moreover, cancer cells lacking PLD activity display inefficiencies across multiple steps of the metastatic cascade, limiting the tumor's lethal spread. Using PLD isoform knockout mice, recent studies have reported on the net effects of inhibition and ablation in multiple cancer models through examining the role of PLD in the non-tumor cells comprising the stroma and microenvironment. The promising results of such in vivo studies, combined with the apparent low toxicity of highly-specific and potent inhibitors, highlights PLD as an attractive target for therapeutic inhibition in cancer. We discuss here the array of anti-tumor effects produced by PLD inhibition and ablation in cancer models with a focus on animal studies. PMID- 29154092 TI - Anoxic biodegradation of triclosan and the removal of its antimicrobial effect in microbial fuel cells. AB - Triclosan (TCS) is an emerging organic contaminant in the environment. Here, the anoxic bio-degradation of TCS in microbial fuel cells (MFCs) was explored. It was found that anoxic biodegradation of TCS could be achieved in MFC, and the removal rate of TCS was accelerated after reactor acclimation. After 7 months of operation, 10mg/L TCS could be removed within 8days in MFCs. Fluorescence microscopy results revealed that the microbe cells in the reactors were intact, and the microbes were in active state. Flow cytometry test showed that the proliferation of inoculated microbe was higher in MFC effluent than that in TCS solution. These data indicate that the biotoxicity of TCS has been largely eliminated after the treatment. The microbial community shift during the TCS degradation process was investigated as well. Species such as Geothrix, Corynebacterium, Sulfobacillus, GOUTA19, Geobacter, Acidithiobacillus and Acinetobacter, which were capable for the degradation of benzene-related and dechlorination of chlorine-containing chemicals, were flourished in the electrode biofilm. They may participate in the biodegradation of TCS. This work provides a new perspective for the anoxic biodegradation of recalcitrant organics, and can be useful for the in-situ bioremediation of environmental pollutants with the removal of their biotoxicity. PMID- 29154093 TI - Highly selective and efficient adsorption of Hg2+ by a recyclable aminophosphonic acid functionalized polyacrylonitrile fiber. AB - Mercury ions, even an ultra-trace amount in water, present a serious environmental concern. Hence, searching for cost-effective and high-performance Hg2+ adsorbents has acquired increasingly attention but still remained challenging. In this work, aminophosphonic acid was immobilized onto polyacrylonitrile fiber by chemical grafting approaches. The functionalized fiber (PANAPF) possessed high adsorption selectivity and efficiency for Hg2+ when compared with other coexisting ions viz. Pb2+, Cd2+, Ag+, Zn2+, Cu2+, Ni2+, Co2+, Ca2+ and Mg2+. The adsorption results revealed that PANAPF exhibited high removal capacities for Hg2+ over a wide pH range from 3 to 11. The adsorption process was better described by the pseudo second-order kinetic model, indicating the chemical interaction between Hg2+ and active groups on the PANAPF. Moreover, the maximum adsorption capacity as calculated from the Langmuir adsorption model of 358mgg-1 was higher than that of many other adsorbents. The PANAPF could be reused more than 10 times and it is able to decrease Hg2+ below 50MUgL-1 which is the maximum discharge standard for mercury containing wastewater in China. A continuous-flow process was also implemented to remove Hg2+. The results suggested the environmentally friendly PANAPF could be a promising candidate for Hg2+ removal in wastewater treatment. PMID- 29154094 TI - Ultrasonic-enhanced Fenton-like degradation of bisphenol A using a bio synthesized schwertmannite catalyst. AB - Schwertmannite (Sch) was synthesized by Acidithiobacillus ferrooxidans and used as Fenton-like catalyst for bisphenol A (BPA) degradation combining with ultrasonic technology (US). Physicochemical characterizations showed that the bio synthesized Sch particles had a pompon-like morphology with high BET surface area of 92.92m2/g. The degradation reaction showed a two-stage pseudo-first-order kinetic process consisting of an induction period and a followed rapid degradation period. A synergistic effect existed between US and Sch on activating H2O2 and the synergy factor was calculated to be 2.32. The catalytic efficiency of the system was mainly affected by pH, Sch dosage and temperature, but less relevant to H2O2 concentration. Free OH radicals in the bulk solution were identified to be the dominant oxidant, which were produced by both heterogeneous and homogeneous processes. The promotional effect of US on Fenton-like degradation of BPA can be ascribed to the reasons of (1) increasing the radical generation by ultrasonic cavitation; (2) reducing the apparent activation energies of degradation reaction; (3) accelerating the dissolution of iron and (4) keeping the high surface area of catalyst by continuous surface cleaning. Ecotoxicity tests indicated lower toxicities of intermediates than BPA. In addition, Sch exhibited high reusability in the recycle study. PMID- 29154095 TI - Simultaneous molybdate (Mo(VI)) recovery and hazardous ions immobilization via nanoscale zerovalent iron. AB - Nanoscale zerovalent iron (nZVI) shows great promise in valuable metal recovery from wastewater due to its high removal capacity. However, nZVI-based processes mainly focus on the sequestration step, ignoring the desorption step, which is crucial for recovery. In this study, a novel method for simultaneous Mo(VI) recovery and hazardous metal ions immobilization by nZVI was developed and the reaction mechanism was further investigated. Results shown that removal capacity of nZVI was significantly influenced by surface charge and the number of active adsorption sites. X-ray photoelectron spectroscopy analysis demonstrated that Mo(VI) reduction occurred in the inner Fe(0) core. K-edge X-ray Absorption Near Edge Structure analysis further confirmed that 5.4% and 18.0% of Mo(VI) are reduced to Mo(IV) at pH 6 and 9, respectively, suggesting that high pH favors for Mo(VI) reduction and H+ is responsible for the hollow-out structure at pH 6. Through adjusting the pH of wastewater from 3 to 12, over 80% of adsorbed Mo(VI) could be recovered while other metal ions remained immobilized and limited influence with common ions/anions. Overall, the proposed mechanism was significant to the research of metal reduction and competition for proton of nZVI, and the developed method had great prospects in valuable anions recovery. PMID- 29154096 TI - Sorption and desorption of 17alpha-ethinylestradiol onto sediments affected by rhamnolipidic biosurfactants. AB - Many studies have addressed the desorption and mobilization performances of sorbed contaminants affected by different rhamnolipidic biosurfactants. Study results have been mixed and complicated. Rhamnolipids are always microbial produced with variable homologues. In this study, two representative rhamnolipidic fractions (i.e., RL-F1 and RL-F2, which are mono- and di rhamnolipids, respectively) were investigated and compared to determine their influence on 17alpha-ethynylestradiol (EE2) distribution within sediment-water sorption and desorption systems. In general, the coexistence of RL-F1 and EE2 enhanced EE2 sorption in a wider monorhamnolipidic dosage range when freshly treated sorbate was used. The sorbed EE2 concentration decreased as the RL-F1 dosage increased in the aged sorbate desorption systems. However, RL-F2 facilitated EE2 mobilization in both sorption and desorption processes. Experimental data were estimated using a conceptual model that considered the sorbed rhamnolipids and aqueous micelles for organic partitioning. The model results indicated that the rhamnolipid type is an important factor influencing organic distribution, in addition to sorbate aging process and sediment characteristics. The use of a rhamnolipidic mixture containing both mono- and di rhamnosyl components may not achieve the desired effect when the biosurfactant enhanced mobilization or immobilization approach is selected. These results are significant for selecting and applying rhamnolipids to remediate contaminants. PMID- 29154097 TI - Diversity, abundance, and persistence of antibiotic resistance genes in various types of animal manure following industrial composting. AB - Aerobic composting is used widely for animal manure recycling, and it may reduce the amount of antibiotic resistance genes (ARGs) that enter the environment. We sampled three types of animal (bovine, chicken, and pig) manure and the corresponding composts from 12 large-scale farms, and tested multiple ARGs and mobile genetic elements (MGEs) by high-throughput qPCR. A total of 109 ARGs were detected in the manure and compost samples, thereby demonstrating that both are important ARG reservoirs. The diversity and abundance of ARGs were significantly higher in chicken and pig manure than bovine manure, but industrial composting was more efficient at reducing the ARGs in chicken manure than pig and bovine manure. Composting universally reduced some ARGs, but inconsistently influenced other ARGs from different types of animal manures. Network analysis detected the widespread co-occurrence of ARGs and MGEs. floR, ermF, catB3, aac(6') lb(akaaacA4), and aadA were identified as suitable indicator genes for estimating the total abundance of ARGs. Our results suggest that different animal species had significant effects on the diversity, abundance, and persistence of ARGs, where the abundance of transposons, heavy metal concentration, total nitrogen level, and the dosage and duration of exposure to antibiotics may explain these differences. PMID- 29154098 TI - Generation and application of a novel transgenic zebrafish line Tg(cyp1a:mCherry) as an in vivo assay to sensitively monitor PAHs and TCDD in the environment. AB - The polycyclic aromatic hydrocarbons (PAHs) and 2,3,7,8-Tetrachlorodibenzo-p dioxin (TCDD) are classified as human carcinogens, and can also cause serious health problems. To develop a convenient bio-monitoring tool for the detection of PAHs and TCDD in the environment, we generated a transgenic zebrafish line Tg(cyp1a:mCherry) with cyp1a promoter driving mCherry expression. Here, Tg(cyp1a:mCherry) embryos were treated with different concentrations of TCDD and five US EPA priority PAHs congeners. The results showed that the expressions of mCherry and endogenous cyp1a were consistent with the PAHs exposure concentrations and were largely induced by TCDD and >=4-ring PAHs. Moreover, the sensitivity of Tg(cyp1a:mCherry) embryos was also evaluated through monitoring of the PAHs contamination in the water and soil samples. The elevated red fluorescent signals and cyp1a expression levels were observed in Tg(cyp1a:mCherry) zebrafish after exposure to water samples and soil organic extracts with higher concentrations of >=4-ring PAHs. These results further strengthen our findings of concentration- and congener-dependent response of the newly established zebrafish. Taken together, the newly established zebrafish line will prove as a sensitive, efficient and convenient tool for monitoring PAHs and TCDD contamination in the environment. PMID- 29154099 TI - Comparison analysis on the thermal runaway of lithium-ion battery under two heating modes. AB - The thermal stability evaluation of materials in a soft-pack commercial cell is tested using C80 calorimeter, including anode, cathode, separator and full cell (mixing of the three materials including additional electrolyte). Thermal runaway characteristic of the commercial cell is tested on the accelerating rate calorimeter (ARC) with two heating modes, including internal heating mode and external heating mode. The results show that the thermal stability of internal material for tested cell follows the below order: anode1000 mg La/kg dry soil. Isopod (Porcellio scaber) growth was the most sensitive endpoint, followed by earthworm (Eisenia andrei), enchytraeid (Enchytraeus crypticus), springtail (Folsomia candida) and oribatid mite (Oppia nitens) reproduction, with EC50s of 312 (95% confidence interval: 5.6-619), 529 (295-762), 1010 ((>377 < 3133), 1220 (1180-1250) and 1500 (1250-1750) mg La/kg dry soil, respectively. EC50s related to CaCl2-extractable concentrations ranged between 1.3 (0.046-2.6) and 15.6 (5.6-25.7) mg La/kg dry soil, while porewater based EC50s were 3.5 (-) and 10.2 (-) mg/L for the springtails and mites, respectively. La uptake in the earthworms linearly increased with increasing exposure concentration with bioaccumulation factors ranging between 0.04 and 0.53 (average +/- SE: 0.24 +/- 0.032). EC50 for effects on earthworm reproduction related to internal concentrations was 184 (61-301) mg La/kg dry body weight. A risk assessment based on the available toxicity for soil invertebrates, bacteria and plants resulted in an HC5 of approx. 50 mg La/kg dry soil, suggesting that La may affect soil ecosystems at concentrations slightly above natural background levels (6.6-50 mg La/kg dry soil) in non-polluted soils. PMID- 29154115 TI - Ecological risk assessment of microcystin-LR in the upstream section of the Haihe River based on a species sensitivity distribution model. AB - The eutrophication of surface water has been the main problem of water quality management in recent decades, and the ecological risk of microcystin-LR (MC-LR), which is the by-product of eutrophication, has drawn more attention worldwide. The aims of our study were to determine the predicted no effect concentration (PNEC) of MC-LR and to assess the ecological risk of MC-LR in the upstream section of the Haihe River. HC5 (hazardous concentration for 5% of biological species) and PNEC were obtained from a species sensitivity distribution (SSD) model, which was constructed with the acute toxicity data of MC-LR on aquatic organisms. The concentrations of MC-LR in the upstream section of the Haihe River from April to August of 2015 were analysed, and the ecological risk characteristics of MC-LR were evaluated based on the SSD model. The results showed that the HC5 of MC-LR in freshwater was 17.18 MUg/L and PNEC was 5.73 MUg/L. The concentrations of MC-LR ranged from 0.68 MUg/L to 32.21 MUg/L and were obviously higher in summer than in spring. The values of the risk quotient (RQ) ranged from 0.12 to 5.62, suggesting that the risk of MC-LR for aquatic organisms in the river was at a medium or high level during the study period. Compared with other waterbodies in the world, the pollution level of MC-LR in the Haihe River was at a moderate level. This research could promote the study of the ecological risk of MC-LR at the ecosystem level. PMID- 29154117 TI - Mercury pollution by gold mining in a global biodiversity hotspot, the Choco biogeographic region, Colombia. AB - Mercury (Hg) is a harmful pollutant released into the environment from gold mining activities, representing a risk to human health and the ecosystems. The aim of this study was to assess the levels of total Hg (T-Hg) in human hair, fish, sediments and air; and to determine fish consumption-based risks for T-Hg ingestion in the Choco biogeographic region, a global biodiversity hotspot located at the Colombian Pacific. Mercury concentrations in hair were measured in two locations, Quibdo, the state capital, and Paimado, a riverine community. The median T-Hg value in human hair in Quibdo was 1.26 MUg/g (range: 0.02-116.40 MUg/g), whereas in Paimado it was 0.67 MUg/g (range: 0.07-6.47 MUg/g). Mercury levels in examined locations were weakly associated with height (rho = 0.145, P = 0.024). Air T-Hg levels in Quibdo were high inside gold shops being up to 200.9 fold greater than the background. Mercury concentrations in fish from Atrato River were above WHO limit (0.5 MUg/g), with highest levels in Pseudopimelodus schultzi, Ageneiosus pardalis, Sternopygus aequilabiatus, Rhamdia quelen and Hoplias malabaricus, whereas the lowest appeared in Cyphocharax magdalenae and Hemiancistrus wilsoni. Based on fish consumption, these last two species offer low risk to human health. Sediment samples from fifty different sites of Atrato River showed low T-Hg concentrations, with little variability between stations. However, contamination factors revealed a moderate pollution in 44% of sampling sites along the river. In conclusion, Hg pollution is widespread in the Biogeographic Choco and governmental actions must be taken to protect the population and preserve its biodiversity. PMID- 29154118 TI - Effect of pH and added slag on the extractability of Si in two Si-deficient sugarcane soils. AB - The effects of increasing pH on the adsorption and extractability of Si in two Si deficient Australian sugarcane soils was investigated and the effects of increasing rates of fertilizer Si (as blast furnace slag) on pH and extractable Si were also examined. Equilibrium studies showed that maximum adsorption of Si by the two soils occurred in the pH range 9-10. When soil pH was increased from 5.0 to 6.5, subsequent adsorption of Si by the two soils, as measured by adsorption isotherms, increased. After incubation with progressive lime additions there was a decline in CaCl2- extractable Si due to its increased adsorption and an increase in acid (H2SO4- and acetic acid)-extractable (mainly adsorbed) Si. The increase in acid extractable Si was greater than the decrease in CaCl2- extractable Si suggesting a supply from an additional source. Alkali (Na2CO3 and Tiron)-extractable Si decreased greatly with increasing pH suggesting dissolution of the amorphous (mainly biogenic) pool of silica was occurring with increasing pH. When increasing rates of slag were incubated with the soils, pH, CaCl2- and acid- extractable Si were all increased because upon dissolution slags release both silicic acid and OH- ions. There was, therefore, a positive relationship between extractable Si and soil pH. However, Na2CO3-and Tiron-extractable Si decreased with increasing slag rates (and increasing soil pH) suggesting dissolution of the biogenic pool of soil Si. It was concluded that future research needs to examine the desorption potential of adsorbed Si and the effects of liming on dissolution of the biogenic pool of soil silica under field conditions. PMID- 29154119 TI - A conceptual study on the formulation of a permeable reactive pavement with activated carbon additives for controlling the fate of non-point source environmental organic contaminants. AB - To take advantage of the road pavement network where non-point source (NPS) pollution such as benzene, toluene, ethyl-benzene, and xylene (BTEX) from vehicle traffic exhaust via wet and dry atmospheric deposition occurs, the asphalt pavement may be used as a media to control the NPS pollution. An experiment to prepare an adsorptive porous reactive pavement (PRP) was initiated to explore the potential to reduce environmental NPS vehicle pollution. The PRP was prepared and studied as follows: various activated carbons (AC) were initially screened to determine if they were suitable as an additive in the porous asphalt mixture; various mixtures of a selected AC were incorporated with the design of porous asphalt concrete (PAC) to produce PRP, and the PRP formulations were tested to ensure that they comply with the required specifications; qualified specimens were subsequently tested to determine their adsorption capacity for BTEX in aqueous solution, as compared to conventional PAC. The PRP08 and PRP16 samples, named for the design formulations of 0.8% and 1.6% of AC (by wt. in the formulation), exhibited low asphalt drain-down and low abrasion loss and also met all regulated specifications. The BTEX adsorption capacity measurements of PRP08 and PRP16 were 33-46%, 36-51%, 20-22%, and 6-8% respectively, higher than those obtained from PACs. Based on the test results, PRPs showed good physical performance and adsorption and may be considered as a potential method for controlling the transport of NPS vehicle pollutants. PMID- 29154120 TI - Optimization of multi-residue method for targeted screening and quantitation of 243 pesticide residues in cardamom (Elettaria cardamomum) by gas chromatography tandem mass spectrometry (GC-MS/MS) analysis. AB - Higher matrix interference makes the multi-residue pesticide analysis in spices more challenging. A simple, sensitive, and robust large-scale multi-residue method was developed for the rapid analysis of 243 pesticides in cardamom matrix by gas chromatography tandem mass spectrometry (GC-MS/MS). Prehydration of cardamom in 1:4 sample:water for 30 min improved the homogeneity and extractability. QuEChERS extraction followed by cleanup with 25 mg primary secondary amine, 100 mg C18, and 10 mg graphitized carbon black to 1 ml supernatant was used for sample preparation. Reconstitution of final extract in ethyl acetate reduced matrix co-extract up to 60%. The method was validated according to the SANTE/11,945/2015 guidelines. The limit of quantification was <=0.01 mg kg-1, and the recovery was within 70.0-120.0%, with <=20% RSD for the majority of pesticides. The method was used for screening market samples, and the detected residues were devoid of any risk of acute toxicity related to dietary exposure. PMID- 29154121 TI - Trace elements in the liver of captive and free-ranging European bison (Bison bonasus L.). AB - European bison is classified as a vulnerable species because of many threats. We analyzed the content of toxic and essential elements (Ag, Al, As, Ba, Be, Cd, Co, Cr, Cu, Hg, Mg, Mn, Na, Ni, Pb, Se, Th, Tl, U, V, and Zn) in the livers of 30 captive and free-ranging European bison from the Bison Breeding Center in Smardzewice and from Bialowieza Primeval Forest in Poland. The contents of toxic elements were lower than reported previously in European Bison and were similar to those of wild ungulates from non-polluted areas. Accumulation of Cd and Cr was related to the age of animals. We compared the mineral status between captive and free-ranging European bison to verify whether the maintenance type could affect concentrations of trace elements in the liver. The concentration of Mn and Zn differed between captive and free-ranging group. Our results were compared to the reference values of essential elements for cattle. All animals from this study were Se-deficient and more than 80% of them have Cu deficiency. Deficiency of Mn was present in 20% of captive and 37% of free-ranging animals whereas Zn in 37% and 3% respectively. Statistical analysis confirmed that Mn and Zn deficiencies were related o the maintenance of animals (p<0.05). We revealed that mineral deficiencies could be an additional threat to the Polish population of European bison. Thus, the monitoring of essential minerals is necessary and future work is required to optimize the supplementation and foddering for preventing the occurrence of mineral deficiencies. PMID- 29154122 TI - Broncho-Vaxom in pediatric recurrent respiratory tract infections: A systematic review and meta-analysis. AB - OBJECTIVES: Assess the efficacy and safety of Broncho-Vaxom in pediatric recurrent respiratory tract infections (RRTIs). METHODS: Published randomized controlled trials (RCTs) of Broncho-Vaxom for pediatric RRTI were searched using PubMed, Embase, Cochrane Library, CBM, CNKI, WanFang Data, and VIP databases up to January 2017. Risk of bias was evaluated in accordance to the guidelines of the Cochrane collaboration and the level of evidence was graded according to the GRADE. RESULTS: 53 RCTs involving 4851 pediatric patients were included in this meta-analysis. It showed that Broncho-Vaxom was positively correlated with a reduction in the frequency of respiratory infection [MD=-2.33, 95% CI (-2.75, 1.90), P<0.00001] compared to the control group. The Broncho-Vaxom group was more effective than control groups in relation to the duration of antibiotics course, infections, fever, cough, and wheezing, increasing serum immunoglobulin levels (IgG, IgA or IgM), and T-lymphocytes subtype (CD3+, CD4+, or CD8+). However, Broncho-Vaxom had higher adverse event rates [RR=1.39, 95% CI (1.02, 1.88), P=0.04]; these were not serious and did not influence the treatment course. CONCLUSION: Broncho-Vaxom shows a good efficacy for pediatric RRTIs on the basis of routine therapy (e.g. anti-infection and antiviral therapy). However, the level of evidence was low and more international multicenter clinical trials are needed to explore the efficacy and safety of Broncho-Vaxom. PMID- 29154123 TI - 3D skeletonization feature based computer-aided detection system for pulmonary nodules in CT datasets. AB - Pulmonary nodule detection has a significant impact on early diagnosis of lung cancer. To effectively detect pulmonary nodules from interferential vessels in chest CT datasets, this paper proposes a novel 3D skeletonization feature, named as voxels remove rate. Based on this feature, a computer-aided detection system is constructed to validate its performance. The system mainly consists of five stages. Firstly, the lung tissues are segmented by a global optimal active contour model, which can extract all structures (including juxta-pleural nodules) in the lung region. Secondly, thresholding, 3D binary morphological operations, and 3D connected components labeling are utilized to extract candidates of pulmonary nodules. Thirdly, combining the voxels remove rate with other nine existing 3D features (including gray features and shape features), the extracted candidates are characterized. Then, prior anatomical knowledge is utilized for preliminary screening of numerous invalid nodule candidates. Finally, false positives are reduced by support vector machine. Our system is evaluated on early stage lung cancer subjects obtained from the publicly available LIDC-IDRI database. The result shows the proposed 3D skeletonization feature is a useful indicator that efficiently differentiates lung nodules from the other suspicious structures. The computer-aided detection system based on this feature can detect various types of nodules, including solitary, juxta-pleural and juxta-vascular nodules. PMID- 29154124 TI - The effectiveness and clinical outcomes of the Minerva cervical thoracic jacket in patients with type II odontoid fractures AB - Background/aim: The objective of this study was to carry out a detailed analysis and assess the outcomes for the Minerva cervical thoracic jacket (CTJ) in patients with type II odontoid fractures who could not be surgically treated. Materials and methods: Twenty-six patients for whom the Minerva CTJ was used rather than surgery for different reasons were included in the study. All patients were fitted with the Minerva CTJ within the first 24 h following diagnosis. The patients were followed 4 weeks after hospital discharge and then at 2-week intervals. Results were considered significant at P < 0.05 and a 95% confidence interval was calculated. Results: Of the 26 patients, 17 were male and 9 were female. The mean age was 49.03 years old (range: 16?86 years old). Fusion occurred in 25 of the 26 patients (P = 0.004), and the mean time to fusion was 6.8 weeks (P = 0.002). The mean length of hospital stay was 4 days and the mean follow-up period was 7.3 weeks. None of the patients had any complications due to the Minerva CTJ and the mortality rate was 0%. Conclusions: The Minerva CTJ application was a safe and cheap technique in the management of type II odontoid fractures. It had a high fusion rate and no complications. PMID- 29154125 TI - Endogenous Galphaq-Coupled Neuromodulator Receptors Activate Protein Kinase A. AB - Protein kinase A (PKA) integrates inputs from G-protein-coupled neuromodulator receptors to modulate synaptic and cellular function. Galphas signaling stimulates PKA activity, whereas Galphai inhibits PKA activity. Galphaq, on the other hand, signals through phospholipase C, and it remains unclear whether Galphaq-coupled receptors signal to PKA in their native context. Here, using two independent optical reporters of PKA activity in acute mouse hippocampus slices, we show that endogenous Galphaq-coupled muscarinic acetylcholine receptors activate PKA. Mechanistically, this effect is mediated by parallel signaling via either calcium or protein kinase C. Furthermore, multiple Galphaq-coupled receptors modulate phosphorylation by PKA, a classical Galphas/Galphai effector. Thus, these results highlight PKA as a biochemical integrator of three major types of GPCRs and necessitate reconsideration of classic models used to predict neuronal signaling in response to the large family of Galphaq-coupled receptors. PMID- 29154126 TI - The Wnt Inhibitor Apcdd1 Coordinates Vascular Remodeling and Barrier Maturation of Retinal Blood Vessels. AB - Coordinating angiogenesis with acquisition of tissue-specific properties in endothelial cells is essential for vascular function. In the retina, endothelial cells form a blood-retina barrier by virtue of tight junctions and low transcytosis. While the canonical Norrin/Fz4/Lrp5/6 pathway is essential for angiogenesis, vascular remodeling, and barrier maturation, how these diverse processes are coordinated remains poorly understood. Here we demonstrate that Apcdd1, a negative regulator of Wnt/beta-catenin signaling, is expressed in retinal endothelial cells during angiogenesis and barrier formation. Apcdd1 deficient mice exhibit a transient increase in vessel density at ages P10-P12 due to delayed vessel pruning. Moreover, Apcdd1 mutant endothelial cells precociously form the paracellular component of the barrier. Conversely, mice that overexpress Apcdd1 in retina endothelial cells have reduced vessel density but increased paracellular barrier permeability. Apcdd1 thus serves to precisely modulate Wnt/Norrin signaling activity in the retinal endothelium and coordinate the timing of both vascular pruning and barrier maturation. PMID- 29154127 TI - Lateral Orbitofrontal Inactivation Dissociates Devaluation-Sensitive Behavior and Economic Choice. AB - How do we choose between goods that have different subjective values, like apples and oranges? Neuroeconomics proposes that this is done by reducing complex goods to a single unitary value to allow comparison. This value is computed "on the fly" from the underlying model of the goods space, allowing decisions to meet current needs. This is termed "model-based" behavior to distinguish it from pre determined, habitual, or "model-free" behavior. The lateral orbitofrontal cortex (OFC) supports model-based behavior in rats and primates, but whether the OFC is necessary for economic choice is less clear. Here we tested this question by optogenetically inactivating the lateral OFC in rats in a classic model-based task and during economic choice. Contrary to predictions, inactivation disrupted model-based behavior without affecting economic choice. PMID- 29154128 TI - Discrete Circuits Support Generalized versus Context-Specific Vocal Learning in the Songbird. AB - Motor skills depend on the reuse of individual gestures in multiple sequential contexts (e.g., a single phoneme in different words). Yet optimal performance requires that a given gesture be modified appropriately depending on the sequence in which it occurs. To investigate the neural architecture underlying such context-dependent modifications, we studied Bengalese finch song, which, like speech, consists of variable sequences of "syllables." We found that when birds are instructed to modify a syllable in one sequential context, learning generalizes across contexts; however, if unique instruction is provided in different contexts, learning is specific for each context. Using localized inactivation of a cortical-basal ganglia circuit specialized for song, we show that this balance between generalization and specificity reflects a hierarchical organization of neural substrates. Primary motor circuitry encodes a core syllable representation that contributes to generalization, while top-down input from cortical-basal ganglia circuitry biases this representation to enable context-specific learning. PMID- 29154129 TI - Collective Behavior of Place and Non-place Neurons in the Hippocampal Network. AB - Discussions of the hippocampus often focus on place cells, but many neurons are not place cells in any given environment. Here we describe the collective activity in such mixed populations, treating place and non-place cells on the same footing. We start with optical imaging experiments on CA1 in mice as they run along a virtual linear track and use maximum entropy methods to approximate the distribution of patterns of activity in the population, matching the correlations between pairs of cells but otherwise assuming as little structure as possible. We find that these simple models accurately predict the activity of each neuron from the state of all the other neurons in the network, regardless of how well that neuron codes for position. Our results suggest that understanding the neural activity may require not only knowledge of the external variables modulating it but also of the internal network state. PMID- 29154131 TI - Impact of age, sex, therapeutic intent, race and severity of advanced heart failure on short-term principal outcomes in the MOMENTUM 3 trial. AB - BACKGROUND: Primary outcomes analysis of the Multicenter Study of MagLev Technology in Patients Undergoing MCS Therapy With HeartMate 3 (MOMENTUM 3) trial short-term cohort demonstrated a higher survival rate free of debilitating stroke and reoperation to replace/remove the device (primary end-point) in patients receiving the HeartMate 3 (HM3) compared with the HeartMate (HMII). In this study we sought to evaluate the individual and interactive effects of pre-specified patient subgroups (age, sex, race, therapeutic intent [bridge to transplant/bridge to candidacy/destination therapy] and severity of illness) on primary end-point outcomes in MOMENTUM 3 patients implanted with HM3 and HMII devices. METHODS: Cox proportional hazard models were used to analyze patients enrolled in the "as-treated cohort" (n = 289) of the MOMENTUM 3 trial to: (1) determine interaction of various subgroups on primary end-point outcomes; and (2) identify independent variables associated with primary end-point success. RESULTS: Baseline characteristics were well balanced among HM3 (n = 151) and HMII (n = 138) cohorts. No significant interaction between the sub-groups on primary end-point outcomes was observed. Cox multivariable modeling identified age (<=65 years vs >65 years, hazard ratio 0.42 [95% confidence interval 0.22 to 0.78], p = 0.006]) and pump type (HM3 vs HMII, hazard ratio 0.53 [95% confidence interval 0.30 to 0.96], p = 0.034) to be independent predictors of primary outcomes success. After adjusting for age, no significant impact of sex, race, therapeutic intent and INTERMACS profiles on primary outcomes were observed. CONCLUSIONS: This analysis of MOMENTUM 3 suggests that younger age (<=65 years) at implant and pump choice are associated with a greater likelihood of primary end-point success. These findings further suggest that characterization of therapeutic intent into discrete bridge-to-transplant and destination therapy categories offers no clear clinical advantage, and should ideally be abandoned. PMID- 29154130 TI - Neuropilin-2/PlexinA3 Receptors Associate with GluA1 and Mediate Sema3F-Dependent Homeostatic Scaling in Cortical Neurons. AB - Regulation of AMPA-type glutamate receptor (AMPAR) number at synapses is a major mechanism for controlling synaptic strength during homeostatic scaling in response to global changes in neural activity. We show that the secreted guidance cue semaphorin 3F (Sema3F) and its neuropilin-2 (Npn-2)/plexinA3 (PlexA3) holoreceptor mediate homeostatic plasticity in cortical neurons. Sema3F-Npn 2/PlexA3 signaling is essential for cell surface AMPAR homeostatic downscaling in response to an increase in neuronal activity, Npn-2 associates with AMPARs, and Sema3F regulates this interaction. Therefore, Sema3F-Npn-2/PlexA3 signaling controls both synapse development and synaptic plasticity. PMID- 29154133 TI - Signaling molecule methylglyoxal ameliorates cadmium injury in wheat (Triticum aestivum L) by a coordinated induction of glutathione pool and glyoxalase system. AB - Methylglyoxal (MG) now is found to be an emerging signaling molecule. It can relieve the toxicity of cadmium (Cd), however its alleviating mechanism still remains unknown. In this study, compared with the Cd-stressed seedlings without MG treatment, MG treatment could stimulate the activities of glutathione reductase (GR) and gamma-glutamylcysteine synthetase (gamma-ECS) in Cd-stressed wheat seedlings, which in turn induced an increase of reduced glutathione (GSH). Adversely, the activated enzymes related to GSH biosynthesis and increased GSH were weakened by N-acetyl-L-cysteine (NAC, MG scavenger), 2,4-dihydroxy benzylamine (DHBA) and 1,3-bischloroethyl-nitrosourea (BCNU, both are specific inhibitors of GR), buthionine sulfoximine (BSO, a specific inhibitors of GSH biosynthesis), and N-ethylmaleimide (NEM, GSH scavenger), respectively. In addition, MG increased the activities of glyoxalase I (Gly I) and glyoxalase II (Gly II) in Cd-treated seedlings, followed by declining an increase in endogenous MG as comparision to Cd-stressed seedlings alone. On the contrary, the increased glyoxalase activity and decreased endogenous MG level were reversed by NAC and specific inhibitors of Gly I (isoascorbate, IAS; squaric acid, SA). Furthermore, MG alleviated an increase in hydrogen peroxide (H2O2) and malondialdehyde (MDA) in Cd-treated wheat seedlings. These results indicated that MG could alleviate Cd toxicity and improve the growth of Cd-stressed wheat seedlings by a coordinated induction of glutathione pool and glyoxalase system. PMID- 29154134 TI - Validation of a biotic ligand model on site-specific copper toxicity to Daphnia magna in the Yeongsan River, Korea. AB - The objective of this study was to determine whether the water effect ratio (WER) or biotic ligand model (BLM) could be applied to efficiently develop water quality criteria (WQC) in Korea. Samples were collected from 12 specific sites along the Yeongsan River (YSR), Korea, including two sewage treatment plants and one estuary lake. A copper toxicity test using Daphnia magna was performed to determine the WER and to compare to the BLM prediction. The results of the WER from YSR samples also indicated significantly different copper toxicities in all sites. The model-based predictions showed that effluent and estuary waters had significantly different properties in regard to their ability to be used to investigate water characteristics and copper toxicity. It was supposed that the slight water characteristics changes, such as pH, DOC, hardness, conductivity, among others, influence copper toxicity, and these variable effects on copper toxicity interacted with the water composition. The 38% prediction was outside of the validation range by a factor of two in all sites, showing a poor predictive ability, especially in STPs and streams adjacent to the estuary, while the measured toxicity was more stable. The samples that ranged from pH 7.3-7.7 generated stable predictions, while other samples, including those with lower and the higher pH values, led to more unstable predictions. The results also showed that the toxicity of Cu in sample waters to D. magna was closely proportional to the amounts of acidity, including the carboxylic and phenolic groups, as well as the DOC concentrations. Consequently, the acceptable prediction of metal toxicity in various water samples needs the site-specific results considering the water characteristics such as pH and DOC properties particularly in STPs and estuary regions. PMID- 29154132 TI - Dexmedetomidine promotes biomimetic non-rapid eye movement stage 3 sleep in humans: A pilot study. AB - OBJECTIVES: Sleep, which comprises of rapid eye movement (REM) and non-REM stages 1-3 (N1-N3), is a natural occurring state of decreased arousal that is crucial for normal cardiovascular, immune and cognitive function. The principal sedative drugs produce electroencephalogram beta oscillations, which have been associated with neurocognitive dysfunction. Pharmacological induction of altered arousal states that neurophysiologically approximate natural sleep, termed biomimetic sleep, may eliminate drug-induced neurocognitive dysfunction. METHODS: We performed a prospective, single-site, three-arm, randomized-controlled, crossover polysomnography pilot study (n = 10) comparing natural, intravenous dexmedetomidine- (1-MUg/kg over 10 min [n = 7] or 0.5-MUg/kg over 10 min [n = 3]), and zolpidem-induced sleep in healthy volunteers. Sleep quality and psychomotor performance were assessed with polysomnography and the psychomotor vigilance test, respectively. Sleep quality questionnaires were also administered. RESULTS: We found that dexmedetomidine promoted N3 sleep in a dose dependent manner, and did not impair performance on the psychomotor vigilance test. In contrast, zolpidem extended release was associated with decreased theta (~5-8 Hz; N2 and N3) and increased beta oscillations (~13-25 Hz; N2 and REM). Zolpidem extended release was also associated with increased lapses on the psychomotor vigilance test. No serious adverse events occurred. CONCLUSIONS: Pharmacological induction of biomimetic N3 sleep with psychomotor sparing benefits is feasible. SIGNIFICANCE: These results suggest that alpha2a adrenergic agonists may be developed as a new class of sleep enhancing medications with neurocognitive sparing benefits. PMID- 29154135 TI - Acute exposure to sunscreen containing titanium induces an adaptive response and oxidative stress in Mytillus galloprovincialis. AB - The use of sunscreens to protect against ultraviolet radiation exposure progressively increases as result of a greater awareness of the people and the greater arrival of tourists. The components of these creams can end up in the waters affecting coastal species. Mediterranean mussels (Mytillus galloprovincialis) were subjected to an acute exposure of a sunscreen with TiO2 in their composition during 24h. The low and medium concentrations used in the assays contained a concentration of TiO2 in the range of values found in coastal waters of the Balearic Islands. Titanium and metallothionein concentrations were progressively increasing in gills with the sunscreen concentration in a dose dependent manner. The activities of the antioxidant enzymes and the detoxification glutathione s-transferase evidenced a hormetic shape response with increased activities at lower sunscreen concentrations, a response that was abolished at the highest concentration. In accordance with these enzyme activities, the levels of malondialdehyde, as a marker of lipid peroxidation, were significantly elevated by the higher sunscreen concentrations. Acetylcholinesterase activity maintained control activities except for the highest sunscreen concentration, where a significant decrease was evidenced. In conclusion, the treatment of mussels with a sunscreen containing TiO2 in the range of Balearic coastal waters induces an adaptive response that is overcome by the highest concentration. Follow-up biomonitoring studies are necessary to control the concentration of sunscreen compound in coastal waters such as titanium since they can induce oxidative stress to affected organisms. PMID- 29154136 TI - Transcriptional activity of detoxification genes is altered by ultraviolet filters in Chironomus riparius. AB - Ultraviolet (UV) filters are compounds used to prevent the damage produced by UV radiation in personal care products, plastics, etc. They have been associated with endocrine disruption, showing anti-estrogen activity in vertebrates and altering the ecdysone pathway in invertebrates. Although they have attracted the attention of multiple research teams there is a lack of data about how animals activate detoxification systems, especially in invertebrates. Here, analysis of the effects of two UV filters, benzophenone-3 (BP3) and 4-methylbenzylidene camphor (4MBC), on the transcriptional activity of nine genes covering the three steps of the detoxification process has been performed. Four cytochrome P450 genes belonging to different members of this family, five GST genes, and the multidrug resistance protein 1 (MRP1) gene were studied by RT-PCR to analyze their transcriptional activity in fourth instar larvae exposed to the UV filters for 8 and 24h. The obtained results show a differential response with downregulation of the different Cyp450s tested by 4MBC while BP3 seems not to modify their expression. On the other hand, some of the GST genes were affected by one or other of the filters, showing a less homogenous response. Finally, MRP1 was activated by both filters but at different times. These results demonstrate for first time that UV filters alter the expression of genes involved in the different steps of the detoxification process and that they can be processed by phase I enzymes other than Cyp450s. They also suggest that UV filters affect biotransformation processes, compromising the ability of the individual to respond to chemical stress, so further research is needed to know the extent of the damage that they can produce in the resistance of the cell to chemicals. PMID- 29154137 TI - The ecotoxicity of binary mixtures of Imazamox and ionized ammonia on freshwater copepods: Implications for environmental risk assessment in groundwater bodies. AB - Groundwater bodies are impacted by substances such as pesticides and N fertilizers, which usually occur in the environment as complex mixtures rather than isolated pollutants. The threat that these mixtures pose to groundwater dwelling organisms is still poorly understood. The aims of the present study were to test the acute effect of a binary mixture of a herbicide (Imazamox) and NH4+ on epigean (Eucyclops serrulatus) and hypogean (Diacyclops belgicus) freshwater copepod species. In addition, to evaluate if the effect of the mixture can be explained by referencing non-interaction models or by more complex interaction models; and the implications for groundwater risk assessment. Compared with the action of the compounds evaluated separately, the effects of Imazamox and NH4+ in the binary mixture were more than additive or synergistic for both species. MixTox models evidenced a dose ratio and dose level deviations from concentration addition and independent action traditional models. The hypogean species was three times more sensitive to NH4+ that the epigean species when assayed as a single chemical. However, D. belgicus was only 1.13 times more sensitive than E. serrulatus when NH4+ was assayed in the mixture. The use of an integrated approach for substances that are known to interact in groundwater, should include copepods species as test organisms. PMID- 29154138 TI - Preparation of biochar from Enteromorpha prolifera and its use for the removal of polycyclic aromatic hydrocarbons (PAHs) from aqueous solution. AB - EP-biochar was produced from Enteromorpha prolifera (EP) at temperatures of 200 600 degrees C under limited-oxygen conditions and then activated using HCl and HF. To optimize the sorption of pyrene (PYR) and benzo[a]pyrene (BaP), the effect of the pyrolysis temperature was studied, and the results showed that EP-biochar produced at 500 degrees C gave the highest removal efficiency. The physiochemical properties of EP-biochar pyrolyzed at 500 degrees C were characterized. The examination indicated that the surface area of EP-biochar was 205.32m2/g. The effect of the EP-biochar dosage and initial solution pH on the adsorption were studied in batch adsorption experiments. Kinetic studies indicated that the adsorption processes of PYR and BaP agreed well with a pseudo second-order kinetic model. The sorption equilibrium data were well described by the Langmuir model. Desorption experiments were conducted to test the strength of binding interactions of EP-biochar. The results showed that PYR and BaP were difficult to dissolve in water after adsorption. Regeneration experiments demonstrated that the biochars regenerated at 200 degrees C retained approximately 48% and 40% of their initial PYR and BaP uptake. PMID- 29154139 TI - Perfluorinated compounds in surface waters of Shanghai, China: Source analysis and risk assessment. AB - 17 perfluorinated compounds (PFCs) were systematically investigated in the surface water from principal watersheds of Shanghai, China. 10 PFCs were above the detection limit (0.08-0.28ng/L) in 39 surface water samples. The perfluorooctanoic acid (PFOA) and perfluorobutanesulfonate (PFBS) were the two dominant compounds with a median concentration 50.67ng/L and 29.84ng/L, respectively. Concentrations of perfluorooctanesulfonate (PFOS) were generally less than PFBS, which might result from the global phase-out of PFOS production and the use of PFBS as a substitute for PFOS-based products. There were three major polluted areas of PFOA along the Huangpu River. The PFOA concentration in groundwater samples collected from one of the three areas indicated that chemical industry might be the possible source. The perfluoroalkane sulfonates (PFSAs) level had a spatial trend that indicated northwest had higher concentrations than the southeast. The distribution of PFCs was not much affected by atmospheric deposition. Mass loading analysis in the surface water revealed that the Huangpu River exhibited relatively large mass loading of total PFCs of 1742.43kg/year to Yangtze River Estuary. The predominant of the PFC species was PFOA with 652.65kg/year. The current concentrations of PFOA and PFOS were at middle level comparing to other studies in China and worldwide. Risk assessment of 6 PFCs showed that there is no risk to the aquatic organisms in Shanghai. PFOS and PFBS had low risk to the avian. Furthermore, the adults living in Shanghai were at low risk to exposure to PFCs through water consumption. PMID- 29154140 TI - Mouthpart deformities in Chironomidae (Diptera) as bioindicators of heavy metals pollution in Shiroro Lake, Niger State, Nigeria. AB - In this study, mouthpart deformities in Chironomid larvae (Diptera) were investigated in relation to sediment contamination in the Shiroro Lake in Nigeria. Metals and chironomids were sampled monthly at three stations (A-C) between August 2013 and January 2014. Across the stations, zinc ranged (3.9 75mg/g), manganese (1.29-1.65mg/g), lead (0.00-0.10mg/g), iron (101-168mg/g) and copper (0.13-0.17mg/g). The metal ions did not differ significantly (P > 0.05) between the sampling stations. However, zinc and iron ions were significantly different between the sampling seasons (P < 0.05). Thirteen chironomid species were recorded, with Chironomus sp., Polypedilum sp. and Ablabesmyia sp. dominating the assemblage structure. Mouthpart deformities were significantly higher at Station A compared with Station C, and seasonally significantly higher during dry season compared with wet season. Elevated incidences of deformity were recorded in Chironomus spp larvae as compared to other genera therefore for further studies in this region assessments should be based solely on Chironomus species and ignoring the rest. Strategies need to be developed to reduce the contaminations and the biological effects. PMID- 29154142 TI - Child trafficking and the European migration crisis: The role of forensic practitioners. AB - Trafficking in children is one of the worst forms of human rights violation and is categorised as a serious crime. Children at high risk of becoming victims of trafficking are runaways, children with a history of abuse, and migrant children. Internationally, cases of child trafficking are increasing the most in Europe, which is likely the result of the current migration crisis. In crises, preventing and combating human trafficking needs to be prioritized, considering that the aims of humanitarian action include saving lives, easing suffering and preserving human dignity. The involvement of forensic practitioners in investigations of cases of child trafficking mainly concerning the identification of victims may save lives and certainly alleviate suffering of the child victims and their families searching for them. Moreover, by aiding the prosecution process through thorough documentation and expert reporting forensic practitioners may contribute to the protection, rehabilitation and possibly compensation of the child victims, and thus to the restoration of their rights and dignity. So far, forensic practitioners were rarely specifically mentioned as actors in the counter trafficking efforts in the multitude of policies, regulations, guidelines and recommendations concerning different aspects of child trafficking. This seems surprising considering that the expertise and experience of practitioners from forensic sciences including cyber forensics, document analysis, forensic biology, anthropology, and medicine can be utilised for gathering intelligence in cases of suspected human trafficking, for identifying the victims as well as perpetrators, and for securing evidence for legal proceedings as this paper shows. While this article mainly discusses the role of forensic pathologists and anthropologists, with a specific focus on the identification of child victims of trafficking in the context of the European migration crisis, the notions regarding the contribution of forensic sciences to the counter-trafficking efforts can be adapted to other geographical and sociopolitical contexts. PMID- 29154141 TI - Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. AB - BACKGROUND: The disease course of amyotrophic lateral sclerosis (ALS) is rapid and, because its pathophysiology is unclear, few effective treatments are available. Genetic research aims to understand the underlying mechanisms of ALS and identify potential therapeutic targets. The first gene associated with ALS was SOD1, identified in 1993 and, by early 2014, more than 20 genes had been identified as causative of, or highly associated with, ALS. These genetic discoveries have identified key disease pathways that are therapeutically testable and could potentially lead to the development of better treatments for people with ALS. RECENT DEVELOPMENTS: Since 2014, seven additional genes have been associated with ALS (MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF), all of which were identified by genome-wide association studies, whole genome studies, or exome sequencing technologies. Each of the seven novel genes code for proteins associated with one or more molecular pathways known to be involved in ALS. These pathways include dysfunction in global protein homoeostasis resulting from abnormal protein aggregation or a defect in the protein clearance pathway, mitochondrial dysfunction, altered RNA metabolism, impaired cytoskeletal integrity, altered axonal transport dynamics, and DNA damage accumulation due to defective DNA repair. Because these novel genes share common disease pathways with other genes implicated in ALS, therapeutics targeting these pathways could be useful for a broad group of patients stratified by genotype. However, the effects of these novel genes have not yet been investigated in animal models, which will be a key step to translating these findings into clinical practice. WHERE NEXT?: The identification of these seven novel genes has been important in unravelling the molecular mechanisms underlying ALS. However, our understanding of what causes ALS is not complete, and further genetic research will provide additional detail about its causes. Increased genetic knowledge will also identify potential therapeutic targets and could lead to the development of individualised medicine for patients with ALS. These developments will have a direct effect on clinical practice when genome sequencing becomes a routine and integral part of disease diagnosis and management. PMID- 29154143 TI - Investigation of various factors influencing Raman spectra interpretation with the use of likelihood ratio approach. AB - The main aim of this study was to verify whether selected analytical parameters may affect solving the comparison problem of Raman spectra with the use of the likelihood ratio (LR) approach. Firstly the LR methodologies developed for Raman spectra of blue automotive paints obtained with the use of 785nm laser source (results published by the authors previously) were implemented for good quality spectra recorded for these paints with the use of 514.5nm laser source. For LR models construction two types of variables were used i.e. areas under selected pigments bands and coefficients derived from discrete wavelet transform procedure (DWT). Few experiments were designed for 785nm and 514.5nm Raman spectra databases after constructing well performing LR models (low rates of false positive and false negative answers and acceptable results of empirical cross entropy approach). In order to verify whether objective magnification described by its numerical aperture affects spectra interpretation, three objective magnifications -20*(N.A.=0.4.), 50*(N.A.=0.75) and 100*(N.A.=0.85) within each of the applied laser sources (514.5nm and 785nm) were tested for a group of blue solid and metallic automotive paints having the same sets of pigments depending on the applied laser source. The findings obtained by two types of LR models indicate the importance of this parameter for solving the comparison problem of both solid and metallic automotive paints regardless of the laser source used for measuring Raman signal. Hence, the same objective magnification, preferably 50* (established based on the analysis of within- and between-samples variability and F-factor value), should be used when focusing the laser on samples during Raman measurements. Then the influence of parameters (laser power and time of irradiation) of one of the recommended fluorescence suppression techniques, namely photobleaching, was under investigation. Analysis performed on a group of solid automotive paint samples showed that time of irradiation upon established laser power does not affect solving the comparison problem with the use of LR test. Likewise upon established time of irradiation 5% or 10% laser power could be used interchangeably without changing conclusions within this problem. However, upon the established time of irradiation changes in laser power between control and recovered sample from 5% or 10% to 50% may cause erroneous conclusions. Additionally it was also proved that prolonged irradiation of paint does not quantitatively affect pigments bands areas revealed after such a pre treatment. PMID- 29154145 TI - Evaluation of a novel GRPR antagonist for prostate cancer PET imaging: [64Cu] DOTHA2-PEG-RM26. AB - INTRODUCTION: Gastrin releasing peptide receptors (GRPRs) are significantly over expressed on a large proportion of prostate cancers making them prime candidates for receptor-mediated nuclear imaging by PET. Recently, we synthesized a novel bifunctional chelator (BFC) bearing hydroxamic acid arms (DOTHA2). Here we investigated the potential of a novel DOTHA2-conjugated, 64Cu-radiolabeled GRPR peptide antagonist, [D-Phe6-Sta13-Leu14-NH2]bombesin(6-14) (DOTHA2-PEG-RM26) to visualize prostate tumors by PET imaging. METHODS: DOTHA2-PEG-RM26 was conveniently and efficiently assembled on solid support. The compound was radiolabeled with 64Cu and its affinity, stability, cellular uptake on PC3 prostate cancer cells were evaluated. The in vitro and in vivo behavior of [64Cu]DOTHA2-PEG-RM26 was examined by PET imaging using human PC3 prostate cancer xenografts and its behavior was compared to that of the analogous [64Cu]NOTA-PEG RM26. RESULTS: The inhibition constant of natCu-DOTHA2-PEG-RM26 was in the low nanomolar range (0.68+/-0.19 nM). The [64Cu]DOTHA2-PEG-RM26 conjugate was prepared with a labeling yield >95% and molar activity of 56+/-3 GBq/MUmol after a 5-min room temperature labeling. [64Cu]-DOTHA2-PEG-RM26 demonstrated rapid blood and renal clearance as well as a high tumor uptake. Small animal PET images confirmed high and specific uptake in PC3 tumor. Both [64Cu]-DOTHA2-PEG-RM26 and [64Cu]-NOTA-PEG-RM26 displayed similar tumor and normal tissue uptakes at early time point post injection. CONCLUSIONS: [64Cu]-DOTHA2-PEG-RM26 allows visualization of prostate tumors by PET imaging. DOTHA2 enables fast 64Cu chelation under mild condition, and as such could be used advantageously for the development of other 64Cu-labeled peptide-derived PET tracers. PMID- 29154147 TI - Selecting the minimum data set and quantitative soil quality indexing of alkaline soils under different land uses in northeastern China. AB - Understanding the influences of land use conversions on soil quality (SQ) and function are essential to adopt proper agricultural management practices for a specific region. The primary objective of this study was to develop soil quality indices (SQIs) to assess the short-term influences of different land uses on SQ in semiarid alkaline grassland in northeastern China. Land use treatments were corn cropland (Corn), alfalfa perennial forage (Alfalfa), monoculture Lyemus chinensis grassland (MG) and successional regrowth grassland (SRG), which were applied for five years. Twenty-two soil indicators were determined at 0-20cm depth as the potential SQ indicators. Of these, thirteen indicators exhibited treatment differences and were identified as the total data set (TDS) for subsequent analysis. Principal component analysis was used with the TDS to select the minimum data set (MDS), and four SQIs were calculated using linear/non-linear scoring functions and additive/weighted additive methods. Invertase, N:P ratio, water-extractable organic carbon and labile carbon were identified as the MDS. The four SQIs performed well, with significant positive correlations (P<0.001, n=16) among them. However, the SQI calculated using the non-linear weighted additive integration (SQI-NLWA) had the best discrimination under different land use treatments due to the higher F values and larger coefficient of variance as compared to the other SQIs. The SQI value under the MG treatment was the highest, followed by that under the SRG and Alfalfa treatments, and all of these were significantly higher than that of Corn treatment. These results indicated that conversion of cropland to perennial forage or grassland can significantly improve the SQ in the Songnen grassland. In addition, SQI-NLWA can provide a better practical, quantitative tool for assessing SQ and is recommended for soil quality evaluation under different land uses in semiarid agroecosystems. PMID- 29154146 TI - Multiple Administrations of 64Cu-ATSM as a Novel Therapeutic Option for Glioblastoma: a Translational Study Using Mice with Xenografts. AB - Glioblastoma is the most aggressive malignant brain tumor in humans and is difficult to cure using current treatment options. Hypoxic regions are frequently found in glioblastoma, and increased levels of hypoxia are associated with poor clinical outcomes of glioblastoma patients. Hypoxia plays important roles in the progression and recurrence of glioblastoma because of drug delivery deficiencies and induction of hypoxia-inducible factor-1alpha in tumor cells, which lead to poor prognosis. We focused on a promising hypoxia-targeted internal radiotherapy agent, 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), to address the need for additional treatment for glioblastoma. This compound can target the overreduced state under hypoxic conditions within tumors. Clinical positron emission tomography studies using radiolabeled Cu-ATSM have shown that Cu-ATSM accumulates in glioblastoma and its uptake is associated with high hypoxia inducible factor-1alpha expression. To evaluate the therapeutic potential of this agent for glioblastoma, we examined the efficacy of 64Cu-ATSM in mice bearing U87MG glioblastoma tumors. Administration of single dosage (18.5, 37, 74, 111, and 148 MBq) and multiple dosages (37 MBq * 4) of 64Cu-ATSM was investigated. Single administration of 64Cu-ATSM in high-dose groups dose-dependently inhibited tumor growth and prolonged survival, with slight and reverse signs of adverse events. Multiple dosages of 64Cu-ATSM remarkably inhibited tumor growth and prolonged survival. By splitting the dose of 64Cu-ATSM, no adverse effects were observed. Our findings indicate that multiple administrations of 64Cu-ATSM have effective antitumor effects in glioblastoma without side effects, indicating its potential for treating this fatal disease. PMID- 29154144 TI - Multi-platform 'Omics Analysis of Human Ebola Virus Disease Pathogenesis. AB - The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform 'omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integrated biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity. PMID- 29154148 TI - The relationship between executive functions and emotion regulation in females attending therapeutic community treatment for substance use disorder. AB - BACKGROUND: Difficulties in emotion regulation influence the development of substance use disorder (SUD), its severity, course, treatment outcomes, and relapse. Impaired executive functions (EFs) are common in SUD populations and may relate to emotion dysregulation. The current study tested whether performance on three basic EF tasks ('working memory', 'inhibition', and 'task-switching') and/or inventory-based assessment of EF were related to difficulties in emotion regulation in females attending residential SUD therapeutic community treatment. METHODS: Cross-sectional design in which participants (N=50, all female) completed a questionnaire battery including the Difficulties in Emotion Regulation Scale (DERS) and Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) was used. Participants also completed neuropsychological assessment of EF including the Working Memory Index (WMI; Wechsler Adult Intelligence Scale), and measures of inhibition and task-switching (Color-Word Interference Test; Delis-Kaplan Executive Function System). RESULTS: Executive dysfunction, as assessed by the Global Executive Composite (GEC; BRIEF-A), and personality disorder indicators (Standardised Assessment of Personality - Abbreviated Scale; SAPAS) were positively correlated with DERS scores. Sequential hierarchical regression indicated that task-switching, GEC, and SAPAS scores statistically predicted DERS scores, while working memory and inhibition did not. Mediation analysis indicated that there was a significant indirect effect of GEC scores and task-switching performance on DERS scores, through SAPAS scores. CONCLUSIONS: Impairment of EF, particularly task-switching, is related to difficulties in emotion regulation in a female sample attending residential SUD treatment. Cognitive training interventions that improve task-switching performance may be beneficial in promoting effective emotion regulation and improved SUD treatment outcomes. PMID- 29154150 TI - Exposure to tobacco websites: Associations with cigarette and e-cigarette use and susceptibility among adolescents. AB - INTRODUCTION: Exposure to tobacco advertising is a risk factor for tobacco use and susceptibility among adolescents. Although tobacco company websites are ostensibly targeted to adults, some youth access these websites and are exposed to tobacco-related content. METHODS: This study analyzed data from the Population Assessment of Tobacco and Health (PATH) survey to estimate the prevalence of exposure to tobacco websites and the associations between website exposure and tobacco product use and susceptibility among adolescents in the United States. RESULTS: Although only 2.3% of youth had ever visited a tobacco company website, youth who visited tobacco company websites were 3.2 times more likely to have used cigarettes and 3.0 times more likely to have used e-cigarettes in the past month, relative to those who had not visited a tobacco website. Among never users, those who had visited tobacco company websites were 2.4 times more likely to be susceptible to cigarettes and 2.9 times more likely to be susceptible to e cigarettes. CONCLUSIONS: Results indicate that more effective regulations are needed to prevent youth from accessing tobacco websites. Stricter age verification procedures on websites could minimize exposure to tobacco websites by youth. PMID- 29154149 TI - RARbeta2-dependent signaling represses neuronal differentiation in mouse ES cells. AB - Embryonic Stem (ES) cells are pluripotent cells that can be induced to differentiate into cells of all three lineages: mesoderm, endoderm, and ectoderm. In culture, ES cells can be differentiated into mature neurons by treatment with Retinoic Acid (RA) and this effect is mediated mainly through the activation of the RA nuclear receptors (RAR alpha, beta, and gamma), and their isoforms. However, little is known about the role played by specific RAR types on ES cell differentiation. Here, we found that treatment of ES cells with AC55649, an RARbeta2 agonist, increased endodermal marker gene expression. On the other hand, we found that the inhibition of RARbeta with 5MUM LE135, together with RA treatment, increased the efficiency of mouse ES cell differentiation into neurons by more than 4-fold as compared to cells treated with RA only. Finally, we performed proteomic analyses on ES cells treated with RA vs RA plus AC55649 in order to identify the signaling pathways activated by the RARbeta agonist. Our proteomic analyses using antibody microarrays indicated that proteins such as p38 and AKT were upregulated in cells treated with RA plus the agonist, as compared to cells treated with RA alone. Our results indicate that RARbeta may function as a repressor of neuronal differentiation through the activation of major cell signaling pathways, and that the pharmacological inhibition of this nuclear receptor may constitute a novel method to increase the efficiency of ES to neuronal differentiation in culture. PMID- 29154151 TI - Social discomfort moderates the relationship between drinking in response to negative affect and solitary drinking in underage drinkers. AB - OBJECTIVE: Research shows that solitary drinking is associated with negative reinforcement motives (i.e., relieving negative affect). An untested hypothesis proposes that this association may be especially strong for individuals who experience social discomfort. This study aimed to 1) replicate findings linking solitary drinking to social discomfort (i.e., loneliness, social anxiety, and lack of perceived social support), alcohol problems, and drinking in response to negative affect (i.e., drinking to cope motives and inability to resist alcohol during negative affect), and 2) investigate whether greater social discomfort moderates the relationship between drinking in response to negative affect and solitary drinking in underage drinkers. METHOD: Current alcohol drinkers ages 18 to 20 (N=664) recruited from a TurkPrime panel reported the percentage of time they drank solitarily and completed measures assessing social discomfort, drinking in response to negative affect, and alcohol involvement. Structural equation modeling was used to test the moderation model. RESULTS: Results replicated prior literature supporting the first aim. For the second aim, analyses indicated a positive association between solitary drinking and drinking in response to negative affect across all individuals, but contrary to prediction, this relationship was stronger for individuals with lower, rather than higher, social discomfort. CONCLUSION: Underage drinkers with lower, rather than higher, social discomfort appear to be at greater risk for drinking alone. These findings may inform our understanding of individuals at greatest risk for drinking alone and promote new avenues for intervention. PMID- 29154152 TI - A mathematical model to plan for long-term effects of water conservation choices on dry weather wastewater flows and concentrations. AB - In many cities, sewer systems are experiencing conditions that are significantly different from those for which they were designed. Factors such as water conservation efforts, changes in population, and efforts to reduce infiltration are altering the quantity and quality of sewage. These changes may affect the ability of sewers to maintain self-cleansing velocities, which are crucial to avoiding solids settling and corrosion issues. Further, such changes may alter the timeline for expected wastewater plant expansion. The present work proposes a method for predicting average annual dry weather wastewater flow, as well as pollutant load and concentration over time. The method takes into account potential declines in per person wastewater production due to water conservation and reuse practices, as well as other potential changes such as shifts in population, transformations in industrial wastewater production, and variations in dry weather infiltration. Results show that the amount of dry weather infiltration will play a large role in whether or not conservation will affect self-cleansing velocities or plant expansions. Conservation is most beneficial to systems with high levels of dry weather infiltration since plant expansion could be avoided; and most detrimental to systems with low levels of infiltration since low flow conditions could lead to settling and corrosion in the sewer. Furthermore, the rate of implementation of conservation efforts influences when impacts to the system would occur. Utility planners will be able to use this method to predict treatment plant upgrade and expansion needs more accurately as well as to assess the relative value of utility-based maintenance activities and conservation practices. PMID- 29154153 TI - Effects of temperature and HRT on performance of a novel insulated anaerobic filter (IAF) system incorporated with the waste heat input for building wastewater treatment. AB - Effects of temperature and hydraulic retention time (HRT) on the performance of the novel insulated anaerobic filter system (IAF) incorporated with the waste heat input in treating building wastewater were investigated. In this study, an electric heater was used to simulate the waste heat input from air conditioner to the IAF system. The wastewater was collected from an office building in Phitsanulok province, Thailand. The HRTs of IAF system were varied to 9, 18 and 27 h, whereas the water temperatures were raised from 30 degrees C to 35 degrees C, 40 degrees C and 45 degrees C by electric heating to the IAF tank with the covered insulator. From the results, it was found that the IAF system with HRT 27 h and water temperature 35 degrees C had the highest removal efficiencies for SS, COD, TKN and TP at 67.71, 61.35, 51.20 and 20.08%, respectively per applied heat energy of 4.70 Wh. The predominant bacteria and Archaea species in the system were Uncultured Flavobacterium sp. and Uncultured Methanosaeta sp. The performance index of the IAF system was developed in this study as the highest treatment performance per lowest energy consumption. Therefore, the IAF system incorporated with waste heat input can be a challenging on-site wastewater treatment system for further usage of renewable energy from waste heat as well as environmental conservation. PMID- 29154154 TI - Transitioning from intravenous to subcutaneous insulin in the medical intensive care unit. AB - BACKGROUND: There is a paucity of studies on transitions from IV insulin infusion (IVII) to subcutaneous (SC) insulin in the medical ICU (MICU). METHODS: We conducted a retrospective study of patients admitted to the Cleveland Clinic MICU from June 2013 to January 2014 who received IVII. We compared blood glucose (BG) control between 3 cohorts based on timing of basal insulin dose: (1) NB (no basal), (2) IB (incorrect basal), (3) CB (correct basal) at 5 time points post IVII discontinuation (1, 4, 8, 12, and 24h). Insulin doses used for transitioning were compared with 80% of estimated 24h IVII total. Analysis was done using chi square, ANOVA and t-tests. RESULTS: There were 269 patients (NB 166, IB 45, CB 58), 55% male with a mean age 58+/-16years. 103 patients (38%) had a transition attempted (IB 21%, CB 17%). The NB cohort had better BG than the IB cohort at all time points (p<0.001) but also lower HbA1c, prior DM diagnosis and home insulin use (p<0.001). IB and CB did not have significantly different BG with mean BG>180mg/dL at 4/5 time intervals. However, the dose of basal insulin used was less than 80% of estimated 24h IVII total (IB 21.4 vs 49.6U, CB 25vs 57.1U). Despite this, 15% of patients in the IB cohort and 24% of patients in the CB had hypoglycemic events. CONCLUSION: The low rates of IV to SC insulin transitions raises the question of challenges to transitions. PMID- 29154155 TI - The dynamic characteristics of the anterior cingulate cortex in resting-state fMRI of patients with depression. AB - BACKGROUND: The anterior cingulate cortex (ACC) is part of the limbic system of the brain. It is a bridge between attentional and emotional processing, which is responsible for the integration of visceral, attentional, and affective information. Lesioning of the ACC, which produces striking changes, is used to treat major depression disorder (MDD). Moreover, the brain dynamically integrates and coordinates functions of its different subparts to realize its cognitive capability. Hence, the spatio-temporal community distribution of the ACC is necessary to completely understand MDD. METHODS: First, community structure detection was used to reveal the community distribution of brain regions. Thereafter, the flexibility, i.e., the frequency of community assignment changes of the ACC in such a community, and the module allegiance matrix (MAM) between the ACC and other brain regions, were analyzed. RESULTS: Our analysis demonstrated significant differences in the distribution of community assignment and flexibility of the ACC in MDD, compared to healthy controls (HC). The results also showed that the pairwise values of the MAMs between the ACC and the amygdala, insula, precuneus, and thalamus were significantly lower in patients with MDD compared to those in HC. LIMITATIONS: The data collected is subject to patient-specific noise because (1) the medication effect varies from patient to patient, and (2) with most fMRI studies, the thoughts of the participants during imaging are difficult to control. CONCLUSION: ACC exhibits abnormal flexibility in community structures in MDD. The pairwise abnormal entries in the MAM for the ACC with four other brain regions, i.e., amygdala, insula, precuneus, and thalamus, quantified the role played by the ACC in MDD. PMID- 29154156 TI - Delta-beta correlation as a candidate endophenotype of social anxiety: A two generation family study. AB - BACKGROUND: Social anxiety disorder (SAD) is characterized by an extreme and intense fear and avoidance of social situations. In this two-generation family study we examined delta-beta correlation during a social performance task as candidate endophenotype of SAD. METHODS: Nine families with a target participant (diagnosed with SAD), their spouse and children, as well as target's siblings with spouse and children performed a social performance task in which they gave a speech in front of a camera. EEG was measured during resting state, anticipation, and recovery. Our analyses focused on two criteria for endophenotypes: co segregation within families and heritability. RESULTS: Co-segregation analyses revealed increased negative delta-low beta correlation during anticipation in participants with (sub)clinical SAD compared to participants without (sub)clinical SAD. Heritability analyses revealed that delta-low beta and delta high beta correlation during anticipation were heritable. Delta-beta correlation did not differ between participants with and without (sub)clinical SAD during resting state or recovery, nor between participants with and without SAD during all phases of the task. LIMITATIONS: It should be noted that participants were seen only once, they all performed the EEG tasks in the same order, and some participants were too anxious to give a speech. CONCLUSIONS: Delta-low beta correlation during anticipation of giving a speech might be a candidate endophenotype of SAD, possibly reflecting increased crosstalk between cortical and subcortical regions. If validated as endophenotype, delta-beta correlation during anticipation could be useful in studying the genetic basis, as well as improving treatment and early detection of persons at risk for developing SAD. PMID- 29154157 TI - Efficacy of antidepressants on measures of workplace functioning in major depressive disorder: A systematic review. AB - INTRODUCTION: Work-related disability and productivity loss in Major Depressive Disorder (MDD) are critical determinants of patient quality of life and contribute significantly to the human and economic costs of MDD. Notwithstanding the return to work and pre-morbid levels of functioning as a critical therapeutic objective among individuals with MDD, it is unclear whether antidepressant treatment significantly and reliably improves measures of workplace functioning. Herein, we investigate to what extent antidepressant treatment improves workplace functioning among adults with MDD. METHODS: We conducted a systematic review of randomized, double-blind, placebo-controlled or active comparator clinical trials primarily or secondarily investigating the efficacy of antidepressant agents on subjective ratings of workplace functioning and/or measures of work absence. RESULTS: Thirteen placebo-controlled and four active comparator clinical trials reported on the efficacy of agomelatine, bupropion, desvenlafaxine, duloxetine, fluoxetine, levomilnacipran, paroxetine, sertraline, venlafaxine, or vortioxetine on subjective measures of workplace impairment. Overall, antidepressant treatment improved standardized measures of workplace functioning (e.g., Sheehan Disability Scale-work item). One placebo-controlled trial of agomelatine and one clinical trial comparing the efficacy of vortioxetine to that of venlafaxine had mixed results on measures of work absence. LIMITATIONS: Included interventional trials evaluated work-related disability as a secondary outcome using subjective rating scales. CONCLUSION: Extant data suggest that antidepressant treatment improves workplace outcomes in MDD. The capability of antidepressants in improving measures of workplace functioning should be considered in cost-benefit analyses to better inform cost-modelling studies pertaining to antidepressant therapy. PMID- 29154158 TI - The prevalence, reporting, and treatment of anxiety among older adults in nursing homes and other residential aged care facilities. AB - BACKGROUND: Little is known about anxiety in aged care populations, despite its increase in this frail population. This study investigated the prevalence, recording, and treatment rate of anxiety disorders among aged care residents. METHODS: A cross-sectional, observational design was used to assess 180 elderly residents from 12 aged care facilities in Melbourne, Australia. Participants were assessed for threshold and subthreshold anxiety disorders and comorbid depression using the MINI for DSM-5. Medical files were also reviewed to determine whether there was any indication that anxiety had previously been detected, and what treatment those with a threshold/subthreshold diagnosis were receiving. RESULTS: Overall prevalence of threshold and subthreshold anxiety disorders was 19.4% and 11.7%, respectively. Generalized anxiety disorder was the most common threshold disorder and agoraphobia was the most prevalent subthreshold anxiety disorder. While less than half of those with a threshold or subthreshold anxiety disorder had an indication of anxiety in their file, the majority received psychotropic medication. Cognitive impairment was not significantly associated with the prevalence or treatment of anxiety. CONCLUSIONS: The prevalence of threshold and subthreshold anxiety in aged care settings is high, but remains under-reported by staff and GPs. Facility staff and GPs should ensure they are aware of how anxiety presents in elderly residents and routinely screen for this common mental health issue. This cohort had poor access to psychological treatments for their condition. PMID- 29154159 TI - Turning wounds into wisdom: Posttraumatic growth over the course of two types of trauma-focused psychotherapy in patients with PTSD. AB - BACKGROUND: Treatment studies in PTSD patients have mostly focused on adverse psychopathological outcomes whereas positive outcomes have received less attention. Objectives of this study were to investigate posttraumatic growth in response to two different psychotherapies, to examine the relationship between symptom improvement and growth, and to determine if posttraumatic growth predicted treatment response. METHODS: Outpatients diagnosed with PTSD after various types of trauma (n = 116) participated in a randomized controlled trial that compared Brief Eclectic Psychotherapy for PTSD (BEP) and Eye Movement Desensitization and Reprocessing therapy (EMDR). Posttraumatic growth was assessed pre- and post-treatment. PTSD severity was measured weekly. RESULTS: Posttraumatic growth scores significantly increased after trauma-focused psychotherapy, as well as scores in the subdomains personal strength, new possibilities, relating to others, and appreciation of life. Greater self reported and clinician-rated PTSD decline was significantly related to greater increase in posttraumatic growth. No changes were found between treatment conditions, except for a stronger correlation between PTSD symptom decrease and increase in relating to others in BEP as compared to EMDR. No predictive effects were found. LIMITATIONS: We were unable to control for time effects because for ethical reasons, no control group not receiving treatment was included, and the stability of the changes could not be determined. CONCLUSIONS: Findings indicate that increases in posttraumatic growth accompany symptom decline in EMDR and BEP, and that these changes occur independent of whether the treatment specifically addresses posttraumatic growth as therapeutic process. Further research is encouraged to disentangle the contribution of therapeutic elements to growth. PMID- 29154160 TI - Gender identity better than sex explains individual differences in episodic and semantic components of autobiographical memory and future thinking. AB - A recently tested hypothesis suggests that inter-individual differences in episodic autobiographical memory (EAM) are better explained by individual identification of typical features of a gender identity than by sex. This study aimed to test this hypothesis by investigating sex and gender related differences not only in EAM but also during retrieval of more abstract self-knowledge (i.e., semantic autobiographical memory, SAM, and conceptual self, CS), and considering past and future perspectives. No sex-related differences were identified, but regardless of the sex, feminine gender identity was associated with clear differences in emotional aspects that were expressed in both episodic and more abstract forms of AM, and in the past and future perspectives, while masculine gender identity was associated with limited effects. In conclusion, our results support the hypothesis that inter-individual differences in AM are better explained by gender identity than by sex, extending this assumption to both episodic and semantic forms of AM and future thinking. PMID- 29154161 TI - Effect of bovine sperm chromatin integrity evaluated using three different methods on in vitro fertility. AB - In vitro fertility potential of individual bulls is still relatively uncharacterized. Classical sperm analysis does not include the evaluation of all sperm characteristics and thus, some cell compartments could be neglected. In humans, sperm DNA integrity has already proven to have major influence in embryo development and assisted reproduction techniques successfully. In bovine, some studies already correlated chromatin integrity with field fertility. However, none of those have attempted to relate DNA assessment approaches such as chromatin deficiency (CMA3), chromatin stability (SCSA; AO+) and DNA fragmentation (COMET assay) to predict in vitro bull fertility. To this purpose, we selected bulls with high and low in vitro fertility (n = 6/group), based on embryo development rate (blastocyst/cleavage rate). We then performed CMA3, SCSA test and COMET assay to verify if the difference of in vitro fertility may be related to DNA alterations evaluated by these assays. For the three tests performed, our results showed only differences in the percentage of cells with chromatin deficiency (CMA3+; high: 0.19 +/- 0.03 vs low: 0.04 +/- 0.04; p = 0.03). No difference for chromatin stability and any of COMET assay categories (grade I to grade IV) was observed between high and low in vitro fertility bulls. A positive correlation between AO + cells and grade IV cells was found. Despite the difference between groups in CMA3 analysis, our results suggest that protamine deficiency in bovine spermatozoa may not have a strong biological impact to explain the difference of in vitro fertility between the bulls used in this study. PMID- 29154163 TI - Upstairs, downstairs: spatial regulation of Hippo signalling. AB - Cellular signalling lies at the heart of every decision involved in the development and homeostasis of multicellular organisms. The Hippo pathway was discovered nearly two decades ago through seminal work in Drosophila and rapidly emerged as a crucial signalling network implicated in developmental and oncogenic growth, tissue regeneration and stem cell biology. Here, we review recent advances in the field relating to the upstream regulation of Hippo signalling and the intracellular tug-of-war that tightly controls its main target, the transcriptional co-activator Yorkie/YAP. PMID- 29154164 TI - Molecular insights into inclusion complexes of mansonone E and H enantiomers with various beta-cyclodextrins. AB - The structural dynamics and stability of inclusion complexes of mansonone E (ME) and H (MH) including their stereoisomers with various betaCDs (methylated- and hydroxypropylated-betaCDs) were investigated by classical molecular dynamics (MD) simulations and binding free energy calculations. The simulation results revealed that mansonones are able to form inclusion complexes with betaCDs. The guest molecules are not completely inserted into the host cavity, their preferably positions are nearby the secondary rim with the oxane ring dipping into the hydrophobic inner cavity. The encapsulation process leads to a higher rigidity of the betaCDs enhancing the intramolecular hydrogen bond formation ability and decreasing the chance of glucopyranose rotation. According to the MM-PBSA binding free energy calculation, all considered inclusion complexes are stable and the binding energies are mainly caused by van der Waals interactions. Moreover, the free energy calculations showed significant differences in the complexation energies for the stereoisomers, which could enable the separation of the isomers by analytical techniques for further pharmaceutical applications. PMID- 29154162 TI - Epigenetic reprogramming in metabolic disorders: nutritional factors and beyond. AB - Environmental factors (e.g., malnutrition and physical inactivity) contribute largely to metabolic disorders including obesity, type 2 diabetes, cardiometabolic disease and nonalcoholic fatty liver diseases. The abnormalities in metabolic activity and pathways have been increasingly associated with altered DNA methylation, histone modification and noncoding RNAs, whereas lifestyle interventions targeting diet and physical activity can reverse the epigenetic and metabolic changes. Here we review recent evidence primarily from human studies that links DNA methylation reprogramming to metabolic derangements or improvements, with a focus on cross-tissue (e.g., the liver, skeletal muscle, pancreas, adipose tissue and blood samples) epigenetic markers, mechanistic mediators of the epigenetic reprogramming, and the potential of using epigenetic traits to predict disease risk and intervention response. The challenges in epigenetic studies addressing the mechanisms of metabolic diseases and future directions are also discussed and prospected. PMID- 29154165 TI - Engagement in mobile phone app for self-monitoring of emotional wellbeing predicts changes in mental health: MoodPrism. AB - BACKGROUND: Mobile apps are being used increasingly for mental health purposes, but evidence of their efficacy remains limited. The mechanisms underlying any effects of such apps are also unclear. This study examined the effectiveness of a self-monitoring mobile phone app by investigating the relationships between app engagement and mental health outcomes. METHOD: Participants downloaded the MoodPrism app from the iOS and Android app stores, completing in-app assessments at start of use and again 30days later. The app prompted participants daily to complete a short mood questionnaire and formulated their responses into a mood diary. Data from 234 assessment completers (73% female; M age = 34.8 years) were analysed via hierarchical and mediation regressions. RESULTS: In this community sample, app engagement ratings predicted decreases in depression and anxiety, and increases in mental well-being. These effects were mediated by increases in emotional self-awareness, but only for participants who were clinically depressed or anxious at the time of the baseline assessment. Mental health literacy and coping self-efficacy did not play mediating roles. LIMITATIONS: Findings suggest that other influential mediators may have not been measured, and future studies could verify the findings by using alternative methodologies, such as comparison with a control group. CONCLUSIONS: Engaging with an emotional wellbeing self monitoring app may reduce depressive and anxious symptoms, and increase mental well-being. Increases in emotional self-awareness may mediate these changes in clinical populations, and further research is needed to reveal other mechanisms that mental health apps can utilize. PMID- 29154166 TI - Sickness absence indicating depressive symptoms of working population in South Korea. AB - BACKGROUND: Sickness absence has been regarded as an important indicator of workers' health and work productivity. This study is aimed to evaluate the association between depressive symptoms and sickness absence in workers of South Korea. METHODS: We used nationwide cross-sectional survey data from 2889 individuals in the working population aged over 19 years in South Korea. Depressive symptoms were measured using Patient Health Questionnaire-9 (PHQ-9). Those respondents who scored above 10 on PHQ-9 were regarded as having depressive symptoms. Sickness absence was considered a binary variable with an absence of at least 1 day in the past month. The survey instrument contained questions about sociodemographic factors, lifestyle, work-related factors, and chronic illnesses. Logistic regression models were used to find odds ratios and confidence intervals. RESULTS: The prevalence of sickness absence was found to be overall 4.6%. The adjusted odds ratio of sickness absence with depressive symptoms (PHQ-9 score >= 10) was 3.63 (Confidence Interval: 2.13-6.20) after controlling of possible confounders. Compared to minimal depressive symptoms (PHQ-9 < 5), the differences between other types of severity of depressive symptoms (mild, moderate, and moderately severe) in terms of mean of all sickness absences were more significant. LIMITATION: The sickness absence based on the memory of the respondent in this study may result in a recall bias. CONCLUSIONS: Incidence of at least 1 day of sickness absence per month increased the risk of depressive symptoms after controlling for the possible confounding factors in general working population. It may be necessary to consider strategies for assessing depression in the workers who take sick leaves. PMID- 29154167 TI - Genetic clustering of depressed patients and normal controls based on single nucleotide variant proportion. AB - BACKGROUND: Genetic components play important roles in the susceptibility to major depressive disorder (MDD). The rapid development of sequencing technologies is allowing scientists to contribute new ideas for personalized medicine; thus, it is essential to design non-invasive genetic tests on sequencing data, which can help physicians diagnose and differentiate depressed patients and healthy individuals. METHODS: We have recently proposed a genetic concept involving single-nucleotide variant proportion (SNVP) in genes to study MDD. Using this approach, we investigated combinations of distance metrics and hierarchical clustering criteria for genetic clustering of depressed patients and ethnically matched controls. RESULTS: We analysed clustering results of 25 human subjects based on their SNVPs in 46 newly discovered candidate genes. CONCLUSIONS: According to our findings, we recommend Canberra metric with Ward's method to be used in hierarchical clustering of depressed and normal individuals. Futures studies are needed to advance this line of research validating our approach in larger datasets, those may also be allow the investigation of MDD subtypes. LIMITATIONS: High quality sequencing costs limited our ability to obtain larger datasets. PMID- 29154168 TI - Evaluating an e-mental health program ("deprexis") as adjunctive treatment tool in psychotherapy for depression: Results of a pragmatic randomized controlled trial. AB - BACKGROUND: Depressive disorders place a significant disease burden on individuals as well as on societies. Several web-based interventions for depression have shown to be effective in reducing depressive symptoms. However, it is not known whether web-based interventions, when used as adjunctive treatment tools to regular psychotherapy, have an additional effect compared to regular psychotherapy for depression. METHODS: Adults (N = 98) with a unipolar affective disorder were recruited in routine outpatient psychotherapy practices in Germany from therapists over the course of their initial sessions and randomized within therapists to one of two active treatment conditions: regular psychotherapy or psychotherapy plus a web-based depression program ("deprexis"). Primary outcome was depressive symptoms measured with the Beck Depression Inventory (BDI-II) at 12 weeks. Secondary outcomes were anxiety symptoms, somatic symptoms and quality of life at 12 weeks and six months follow-up. The study also included an assessment of the working alliance after six and 12 weeks. RESULTS: The combination of psychotherapy with the web-based program was more effective than psychotherapy alone at 12 weeks, with medium between-group effect sizes on primary depressive symptoms (Cohen's d = .51) and small to medium between-group effect sizes on secondary outcomes (Cohen's d = .07-.55). Furthermore, we did not observe negative side effects in the blended format, e.g., a lower working alliance than in psychotherapy alone. LIMITATIONS: The study had a smaller than planned sample size and the dropout rate at follow-up was high. CONCLUSIONS: This study provides first evidence that the use of a web-based program as an adjunctive tool in regular psychotherapy could be a promising option to consider in future treatment for depression. PMID- 29154169 TI - Validity of routine clinical diagnoses in acute psychiatric inpatients. AB - AIM: To examine the validity of diagnoses obtained by clinicians during routine clinical examination on acute psychiatric inpatient wards. METHODS: N=100 inpatients with a broad spectrum of major mental disorders were randomly selected in a mental hospital's department of general psychiatry. Patients were diagnosed by independent assessors within Md = 5 (Range: 1-18) days of admission using the SCID I in order to examine the validity of the diagnoses given by the clinical staff based on routine assessments. RESULTS: The commonly used clinical examination technique had good overall agreement with the SCID I assessments regarding primary diagnoses at the level of ICD-10 main categories (F2, F30-31, F32-F33, F4; kappa = 0.65). However, agreement between routine clinical diagnoses and the SCID I diagnoses tended to be low for some specific mental disorders (e.g., depressive disorders) and for secondary diagnoses. CONCLUSIONS: The validity of routine clinical diagnoses established in acute inpatient settings is limited and should be improved. PMID- 29154170 TI - Adverse life events and the onset of anxiety disorders. AB - This study tested the hypothesis that adverse events are associated with increased risk of onset of anxiety disorders. Data from Waves 1 (N = 43,093; 2001 2002) and 2 (N = 34,653; 2004-2005) of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) were used to assess whether adverse events at baseline are associated with increased risk of anxiety disorder onset over three years of follow up. Sixty-six percent (SE: 1.0) of respondents with an anxiety disorder in the intervening period between Waves 1 and 2 had experienced an adverse life event in the year prior to the Wave 1 interview. In logistic regression models adjusted for sociodemographic and psychiatric characteristics, adverse life events at baseline were associated with anxiety disorder onset within the three-year follow up period. The pattern of association between adverse events and anxiety disorder onset was similar across sub-types, and injury, illness or death of family or close friends consistently had the strongest association with anxiety disorder onset. These findings suggest that adverse life events play a role in the onset of anxiety disorders. PMID- 29154171 TI - Early maladaptive schemas as mediators between childhood maltreatment and later psychological distress among Chinese college students. AB - The aim of the current study was to examine whether early maladaptive schemas (EMSs) mediate the association between different kinds of childhood maltreatment and later psychopathology and the effect of different kinds of childhood maltreatment on psychological distress in later life. A total of 1102 college students from two local universities participated in the study; their average age was 20.46 +/- 1.13 years. The participants completed the Childhood Trauma Questionnaire (CTQ), the Early Maladaptive Schemas Scale (EMSs), the Zung Self Rating Depression Scale (SDS), and the Zung Self-Rating Anxiety Scale (SAS). Later psychological distress had a significant positive correlation with childhood EMSs, and almost all of the variables measuring childhood maltreatment had a significant positive correlation with EMSs. Structural equation modeling and mediation analyses were conducted based on Bootstrap estimations; the mediation analyses demonstrated the utility of EMSs as the mechanism through which childhood maltreatment has an indirect effect on later psychological distress. Moreover, the study found that emotional abuse had the strongest overall effect of all five types of child maltreatment on later psychological distress, followed in order of magnitude by emotional neglect, physical neglect, sexual abuse, and physical abuse. PMID- 29154172 TI - Association between B vitamins and schizophrenia: A population-based case-control study. AB - To explore the association between schizophrenia and six types of B vitamins, including choline, biotin, riboflavin, pyridoxamine, pyridoxine and nicotinamide, based on the hydrophilic interaction liquid chromatography column (HILIC) Liquid Chromatography-Mass Spectrometry (LC-MS) platform. We conducted the case-control study between November 2015 and September 2016 in Weifang, Shandong Province, China. Blood samples from 128 cases of schizophrenia and 101 controls were collected, and B vitamin were measured by LC-MS coupled with HILIC. The HILIC UPLC-MS based analysis of serum B vitamins levels from 128 cases (30 cases with first-episode, 98 cases with relapse) and 101 controls were performed. The results indicated that lower pyridoxine level and schizophrenia was related. (total cases versus controls: beta= -0.215, 95% CI: -0.271, -0.125, p < 0.001; first-episode cases versus controls: beta = -0.190, 95% CI: -0.277, -0.103, p < 0.001). Higher nicotinamide level was also associated with schizophrenia after adjusting confounders (beta = 0.343, 95% CI: 0.022, 0.664, p = 0.036). Other four B vitamins, including biotin, riboflavin, pridoxamine and choline, were showed no statistically difference in cases versus controls, first episode cases versus relapse cases. Two types of B Vitamins, pyridoxine and nicotinamide, show significant association with the schizophrenia. PMID- 29154173 TI - Prognostic value of tumour-infiltrating lymphocytes in small HER2-positive breast cancer. AB - BACKGROUND: The standard treatment for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)-positive breast cancer (BC) is still controversial. Our aim was to assess the prognostic role of tumour infiltrating lymphocytes (TILs) in patients with stage pT1a-b HER2-positive BC. PATIENTS AND METHODS: Haematoxylin and eosin slides from node-negative, pT1a-b HER2-positive BC surgical specimens were retrieved from pathology archives to assess TILs and their association with outcome. RESULTS: TILs were evaluated in 205 patients with HER2-positive, pT1a-b tumours, who underwent breast surgery between 1997 and 2009 at the European Institute of Oncology. At a median follow up of 11 years, we did not observe any association between the presence of TILs, either assessed as a continuous or dichotomous variable (<50 versus >= 50%), and outcome. Within the subgroup of patients with pT1a tumours who did not receive any adjuvant therapy (36/97 patients), the rate of disease-free survival events was lower in lymphocyte-predominant BC (LPBC) as compared with non-LPBC patients (p = 0.066). CONCLUSIONS: TILs cannot be used as a prognostic biomarker in pT1a-b HER2-positive BC. Additional biomarkers are needed for selecting patients with stage I HER2-positive BC who candidate to adjuvant therapy de-escalation. PMID- 29154174 TI - Immunoresolvents signaling molecules at intersection between the brain and immune system. AB - Understanding mechanisms that control immunity is central in the quest to gain insights into the etiopathology of many of the diseases that afflict modern societies. New results implicate the nervous system as a central player in controlling many aspects of both the innate and adaptive arms of the immune response. Furthermore it is now well appreciated that a novel group of autacoids termed as specialized proresolving mediators, which are enzymatically produced from essential fatty acids, orchestrate the immune response promoting the termination of inflammation as well as tissue repair and regeneration. The present brief review discusses evidence for the crosstalk between the nervous system and leukocytes in regulating SPM production. We will also discuss the impact that this has on controlling tissue resolution tone and the resolution of both infectious and sterile inflammation. PMID- 29154175 TI - Improving human health outcomes with a low-cost intervention to reduce exposures from lead acid battery recycling: Dong Mai, Vietnam. AB - This study details the first comprehensive evaluation of the efficacy of a soil lead mitigation project in Dong Mai village, Vietnam. The village's population had been subject to severe lead poisoning for at least a decade as a result of informal Used Lead Acid Battery (ULAB) recycling. Between July 2013 to February 2015, Pure Earth and the Centre for Environment and Community Development (Hanoi, Vietnam) implemented a multi-faceted environmental and human health intervention. The intervention consisted of a series of institutional and low-cost engineering controls including the capping of lead contaminated surface soils, cleaning of home interiors, an education campaign and the construction of a work-clothes changing and bathing facility. The mitigation project resulted in substantial declines in human and environmental lead levels. Remediated home yard and garden areas decreased from an average surface soil concentration of 3940mg/kg to <100mg/kg. One year after the intervention, blood lead levels in children (<6 years old) were reduced by an average of 67%-from a median of 40.4MUg/dL to 13.3MUg/dL. The Dong Mai project resulted in significantly decreased environmental and biological lead levels demonstrating that low-cost, rapid and well-coordinated interventions could be readily applied elsewhere to significantly reduce preventable human health harm. PMID- 29154176 TI - Seasonal changes in the sperm fatty acid composition of Shetland pony stallions. AB - Spermatozoa contain polyunsaturated fatty acids (PUFA). Cryopreservation damages sperm membranes and they become less functional after thawing. We analysed the lipid composition of spermatozoa from Shetland stallions (n = 15) collected monthly from January to June and hypothesized that sperm lipid patterns change with season. In addition, one ejaculate per month was submitted to cryopreservation. Content of saturated palmytic and stearic acid decreased from January to March (p < 0.001) while content of the PUFA docosapentaenoic (p < 0.001) and arachidonic acid (p < 0.05) and total PUFA (p < 0.001) increased. Docosapentaenoic acid was the predominant PUFA in stallion spermatozoa. In conclusion, the sperm fatty acid composition of Shetland pony stallions undergoes seasonal changes, and PUFA content increases from the non-breeding to the breeding season. Seasonal differences in sperm fatty acids might in part explain seasonal differences in the resistance of equine spermatozoa to cryopreservation and cooled-storage. PMID- 29154177 TI - Fundamentals of ion mobility spectrometry. AB - Fundamental questions in ion mobility spectrometry have practical implications for analytical applications in general, and omics in particular, in three respects. (1) Understanding how ion mobility and collision cross section values depend on the collision gas, on the electric field and on temperature is crucial to ascertain their transferability across instrumental platforms. (2) Predicting collision cross section values for new analytes is necessary to exploit the full potential of ion mobility in discovery workflows. (3) Finally, understanding the fate of ion structures in the gas phase is essential to infer meaningful information on solution structures based on gas-phase ion mobility measurements. We review here the most recent advances in ion mobility fundamentals, relevant to these three aspects. PMID- 29154178 TI - The effect of wedge and tibial slope angles on knee contact pressure and kinematics following medial opening-wedge high tibial osteotomy. AB - BACKGROUND: High tibial osteotomy is a surgical procedure to treat medial compartment osteoarthritis in varus knees. The reported success rates of the procedure are inconsistent, which may be due to sagittal plane alignment of the osteotomy. The objective of this study was to determine the effect of changing tibial slope, for a range of tibial wedge angles in high tibial osteotomy, on knee joint contact pressure location and kinematics during continuous loaded flexion/extension. METHODS: Seven cadaveric knee specimens were cycled through flexion and extension in an Oxford knee-loading rig. The osteotomy on each specimen was adjusted to seven clinically relevant wedge and slope combinations. We used pressure sensors to determine the position of the centre of pressure in each compartment of the tibial plateau and infrared motion capture markers to determine tibiofemoral and patellofemoral kinematics. FINDINGS: In early knee flexion, a 5 degrees increase in tibial slope shifted the centre of pressure in the medial compartment anteriorly by 4.5mm (P<=0.001), (from the neutral slope/wedge position). Increasing the tibial slope also resulted in the tibia translating anteriorly (P<=0.001). INTERPRETATION: Changes to the tibial slope during high tibial osteotomy for all tested wedge angles shifted the centre of pressure in both the medial and lateral compartments substantially and altered knee kinematics. Tibial slope should be controlled during high tibial osteotomy to prevent unwanted changes in tibial plateau contact loads. PMID- 29154179 TI - The effect of follicullar fluid pesticides and polychlorinated biphenyls concentrations on intracytoplasmic sperm injection (ICSI) embryological and clinical outcome. AB - OBJECTIVES: The present study evaluated the correlation between the concentrations of polychlorinated biphenyls (PCBs) and pesticides in the follicular fluid (FF) obtained during intracytoplasmic sperm injection (ICSI) with the ovarian response, endometrial thickness, and embryological and clinical outcomes. DESIGN: Cross-sectional observational study. MATERIALS AND METHODS: Women aged 20 to 38 years (300 infertile couples) presenting to a university affiliated fertility center were approached to participate in the study. Only 150 couples that underwent ICSI for male factor infertility agreed to participate, and 94 of them had retrieved enough FF samples suitable for laboratory testing. The FF sample was obtained, centrifuged, and stored in liquid nitrogen. Two organochlorine pesticides (OCPs), Lindane and DDT;three organophosphates (OPs);chlorpyrifos;Diazinon; malathion; one Chloroacetanilide (Pretilachlor);two pyrethroids(Bioallethrin and beta-cyfluthrin); and the concentrations of four PCBs, 28, 52, 138, 180, were estimated in the obtained FF samples by using gas chromatography/mass spectrometry. SPSS statistical analysis program (version 17) was used for analysis. Multiple regression analysis was used to correlate the PCBs and pesticides with ICSI outcomes. RESULTS: There were significant negative correlations between FF concentrations of the eight examined pesticides and the four PCBs on the endometrial thickness. However, Pretilachlor, chlorpyrifos, beta cyfluthrin, and Diazinon were the only toxic agents that negatively correlated with the number of the oocytes retrieved. Fertilization and early embryo cleavage rates were negatively correlated with Pretilachlor and beta-cyfluthrin. Moreover, high concentrations of Lindane,DDT, Diazinon,and chlorpyrifos were significantly associated lower implantation rate. PCB 28 and 180 concentration in the FF was associated with a lower number of retrieved oocytes and fertilization rate, respectively. The number of implanted embryos was negatively correlated with PCB 52 FF concentration. However, the clinical pregnancy rate did not reach the level of significance. CONCLUSION: Higher concentrations of any studied PCBs and pesticides are associated with thinner endometrial thickness. The higher the level of Pretilachlor, beta-cyfluthrin, PCB 28 and 180, the lower the retrieval, fertilization, and embryo cleavage rates. High PCB and pesticide concentrations in the FF adversely affected embryological ICSI outcomes. However, more data are needed to evaluate their effect on the clinical outcome. PMID- 29154180 TI - A twelve-year retrospective analysis of prevalence and antimicrobial susceptibility patterns of Ureaplasma spp. and Mycoplasma hominis in the province of Lower Silesia in Poland. AB - OBJECTIVE: Genital mycoplasmas are opportunistic pathogens that have been associated with urogenital infections in humans. Only a few groups of antimicrobials are available for treatment of urogenital tract infections caused by genital mycoplasmas. However, emerging resistance of mycoplasmas to antimicrobial agents has been reported worldwide. The aim of the study was a retrospective analysis of the prevalence and antimicrobial susceptibility patterns of M. hominis and Ureaplasma spp. in patients with urogenital tract infections during a twelve-year period between 2003 and 2015. STUDY DESIGN: Mycoplasma IST2 test was used for the detection, enumeration, identification and antimicrobial susceptibility testing of genital mycoplasmas in 1182 samples from 778 women and 404 men with genitourinary tract infection. Indicative enumeration in the test determines whether the mycoplasma count in the sample is equal or higher than the threshold set at 104 colony forming units. RESULTS: A total of 152 (12.8%) samples were found to be positive for genital mycoplasmas. M. hominis was detected only in three samples and Ureaplasma spp. in 141 samples. Both, M. hominis and Ureaplasma spp. were detected in the remaining eight samples. In the analyzed period between 2003 and 2015, a gradually increasing resistance of ureaplasmas to ciprofloxacin and clarithromycin and decreasing resistance to ofloxacin, erythromycin and tetracycline were observed. Pristinamycin, josamycin and doxycycline were most active against Ureaplasma spp. In contrast, fluoroquinolones had the lowest efficacy against Ureaplasma spp. and as many as 116 (82.3%) and 77 (54.6%) of Ureaplasma spp. isolates were resistant to ciprofloxacin and ofloxacin, respectively. M. hominis isolates were uniformly resistant to azithromycin, clarithromycin and erythromycin but susceptible to josamycin, ofloxacin, doxycycline and pristinamycin. One-third of these isolates were resistant to ciprofloxacin and tetracycline. CONCLUSION: In the study Ureaplasma spp. and M. hominis were detected with relatively low frequency in comparison with other studies however, most of these isolates were resistant to ciprofloxacin indicating the need for better management of ciprofloxacin prescription. Important limitations of Mycoplasma IST2 assay concerning antimicrobial susceptibility testing and divergences between breakpoints in the test and EUCAST guidelines point the need to introduce new methodologies to improve evaluation of resistant strains at our region. PMID- 29154181 TI - Female labour force participation and suicide rates in the world. AB - The current study aims to illustrate male to female suicide rate ratios in the world and explore the correlations between female labour force participation rates (FLPR) and suicide rates of both genders. Further, whether the relationship of FLPR and suicide rates vary according to the human capabilities of a given country are examined. Using suicide data obtained from the World Health Organization Statistical Information System, suicide gender ratios of 70 countries are illustrated. Based on the level of Human Development Index (HDI) and FLPR, the Bayesian Information Criteria (BIC) was used to determine the optimal number of clusters of those countries. Graphic illustrations of FLPR and gender-specific suicide rates, stratified by each cluster were presented, and Pearson's correlation coefficients calculated. Three clusters are identified, there was no correlation between FLPR and suicide rates in the first cluster where both the HDI and FLPR were the highest (Male: r = 0.29, P = 0.45; Female: r = 0.01, P = 0.97); whereas in Cluster 2, higher level of FLPR corresponded to lower suicide rates in both genders, although the statistical significance was only found in females (Male: r = -0.32, P = 0.15; Female: r = -0.48, P = 0.03). In Cluster 3 countries where HDI/FLPR were relatively lower, increased FLPR was associated with higher suicide rates for both genders (Male: r = 0.32, P = 0.04; Female: r = 0.32, P = 0.05). The relationship between egalitarian gender norms and suicide rates varies according to national context. A greater egalitarian gender norms may benefit both genders, but more so for women in countries equipped with better human capabilities. Although the beneficial effect may reach a plateau in countries with the highest HDI/FLPR; whereas in countries with relatively lower HDI/FLPR, increased FLPR were associated with higher suicide rates. PMID- 29154182 TI - Impact of ill-health on household consumption in Sri Lanka: Evidence from household survey data. AB - With significant increases in chronic non-communicable diseases (NCDs) in recent years, Sri Lanka has witnessed a growing trend of increased out-of-pocket payments for healthcare, imposing a severe burden on household budgets. This is exacerbated by limited government health funding and inadequate financial security from formal social security. We examine the association of NCD prevalence and healthcare utilization with household consumption, using the most recent Sri Lanka Household Income and Expenditure Survey 2012/2013. The unit of analysis is the household. We use data for 20,535 households to apply two-part models. Findings suggest that financial constraints induced by NCD-prevalence and hospitalization compel households primarily to sacrifice food consumption. Analysis further shows that poorer households are more vulnerable to food insecurity arising from these. Households sacrifice the basic needs of housing and clothing, and the burden on poorer households is higher, whereas richer households have the option of sacrificing more from non-basic needs to cope with NCDs and hospitalization and thereby to secure basic needs to a certain extent. Moreover, the burden of out-of-pocket healthcare expenses is found to be positively associated with NCDs and hospitalization. In addition to the direct association, public hospitalization favorably moderates the associations between NCDs and the allocations for food and healthcare. Private hospitalization is adversely associated with a wider range of consumption, creating negative welfare consequences. These findings provide valuable information on what needs to be done to reform Sri Lanka's health sector. The study contributes to international discussions on frameworks and national-level policies for effectively allocating public and private funds to the health sector to mitigate hardships faced by the poorest households. PMID- 29154183 TI - Use of healthcare consumer voices to increase empathy in nursing students. AB - Nurses need to be well prepared to address the needs of a diverse population and facilitate positive experiences in an equitable and inclusive approach to care. The aim of the study was to determine whether the integration of consumer lived experience interviews into the content of a first-year course influenced empathy in nursing students. A one group pre-test, post-test design was used. A convenience sample of first-year undergraduate nursing students (N = 32) from a regional Australian university was recruited for the study. The pre and post tests were conducted using the Kiersma Chen Empathy Scale and t-tests performed to analyse the data. Results showed overall that nursing students demonstrated moderate levels of empathy; pre-test score of (M = 75.53; SD = 5.76). After the intervention the post-test results showed that there was a statistically significant increase in students' empathy towards vulnerable, disadvantaged and stigmatised population groups. The healthcare consumer voice has the potential to strengthen current teaching practices that promote caring behaviours in nursing students. PMID- 29154184 TI - Perceptions of nursing students after performing an individual activity designed to develop their critical thinking: The "critical card" tool. AB - Critical thinking in Health Sciences is among the transversal competences in the Nursing Degree. The critical card is a tool of individual learning, designed to develop critical thinking, and set in the process of environmental health learning. Every student must perform the activity to obtain the highest qualification in Community Health Nursing subject. The aim of this project was to evaluate this learning tool using the students' perceptions after its performance. The evaluation was based on the answers to a questionnaire obtained from the third course students of Nursing Degree at the University of Zaragoza. The questionnaire was made up of 14 Likert-type questions, grouped in four dimensions. The student participation rate was higher than 50%. The analysis of the questionnaire obtained 67,8% positive answers. The variability between dimensions ranged between 49% of positive answers for application in other subjects and 87% of positive answers for the improvements applicable to the instrument. The students coincided in indicating that the critical card is a useful learning tool and could be applicable in other subjects. However, the weight it is given in the global evaluation of the subject is considered to be too low, considering the time used to complete the activity. PMID- 29154185 TI - Experiential learning in practice: An ethnographic study among nursing students and preceptors. AB - This study aimed to explore the reflective dialogues and processes that take place between preceptors and their nursing students and to examine how preceptors make use of their expert knowledge in order to enhance students' experiential learning during clinical placements. Two 30-h courses on reflective teaching were conducted. The study sample included 15 preceptors and 27 undergraduate nursing students. Data were collected during the course and during clinical placements at two X hospitals. Data collection included non-participatory observation and informal conversations with preceptors, in-depth interviews and focus groups. Preceptors used a series of strategies to promote experiential learning; these included creating links with practice, the use of examples, allowing students to adopt professional roles and enhancing autonomy. The value of preceptors is their wealth of professional experience, which is key during the learning process of nursing students. Preceptors must learn to master the art of questioning and stimulating reflective dialogues, in order to stimulate students' critical thinking and encourage them to resolve common problems that arise during practice. Students demand a more active role in their own learning processes. PMID- 29154186 TI - Parental reactions to children's negative affect: The moderating role of parental GAD. AB - The impact of parental anxiety disorders has been explored in broad categories of parenting behaviors; however, less is known about the impact of parental anxiety on emotion socialization behaviors. The current study tested the conditional effect of parental Generalized Anxiety Disorder (GAD) on one aspect of emotion socialization, parents' reactions to their child's negative affect. Participants were 89 children between ages 3 and 12 and their parents, from a community sample. Parents completed the Anxiety Disorders Interview Schedule-IV (ADIS-IV), an interaction task with their child, and the Beck Anxiety Inventory-II (BAI-II). Overall, the data supported study hypotheses. Parental GAD moderated the relationship between child's negative affect and parental over control and emotional discouragement. Specifically, children's negative affect was positively related to parental emotional discouragement for parents with GAD, but not for parents without a diagnosis. Conversely, children's negative affect was not predictive of parental overcontrol for parents with GAD, but increases in children's negative affect did predict increases in parental overcontrol for parents without a diagnosis. The present findings suggest parents diagnosed with GAD are discouraging of their children's emotional experiences and fail to adjust their level of guidance throughout situations which induce negative affect, leaving children to cope with negative emotions on their own. PMID- 29154187 TI - Compositional inductive biases in function learning. AB - How do people recognize and learn about complex functional structure? Taking inspiration from other areas of cognitive science, we propose that this is achieved by harnessing compositionality: complex structure is decomposed into simpler building blocks. We formalize this idea within the framework of Bayesian regression using a grammar over Gaussian process kernels, and compare this approach with other structure learning approaches. Participants consistently chose compositional (over non-compositional) extrapolations and interpolations of functions. Experiments designed to elicit priors over functional patterns revealed an inductive bias for compositional structure. Compositional functions were perceived as subjectively more predictable than non-compositional functions, and exhibited other signatures of predictability, such as enhanced memorability and reduced numerosity. Taken together, these results support the view that the human intuitive theory of functions is inherently compositional. PMID- 29154188 TI - Layer-by-layer films containing emodin or emodin encapsulated in liposomes for transdermal applications. AB - Dermal drug release systems are an important area of research because they can be applied to the skin in a non-invasive procedure using a lower concentration of drugs. In this study, we have developed two types of Layer-by-Layer (LbL) films for releasing emodin (EM). In one system, EM was intercalated with poly(ethylenimine) PEI and poly(vinyl sufonate) (PVS) polyelectrolytes, forming (PEI/PVS)2(PEI/EM)7; in another, EM was incorporated in liposomes obtained by mixing dipalmitoyl phosphatidyl glycerol (DPPG) and palmitoyl oleoyl phosphatidyl glycerol (POPG) lipids, forming (PEI/PVS)2(PEI/DPPG-POPG-EM)7. UV-vis and FTIR spectroscopies were used to characterize the LbL films. These showed that the depositions of material by LbL were efficient, with increases in the absorbance of each bilayer evidencing the presence of EM in the film. The (PEI/PVS)2(PEI/EM)7 and (PEI/PVS)2(PEI/DPPG-POPG-EM)7 films released EM in three and five days, respectively. The cyclic voltammetry (CV) assay of the (PEI/PVS)2(PEI/EM)7 results are in agreement with UV-vis measurements, which suggest that EM was protonated in acid environments, while the CV of (PEI/PVS)2(PEI/DPPG-POPG-EM)7 demonstrated distinct protonation behaviour for EM within the inner liposome structure, even in acid solutions. Therefore, this study presents two systems based on LbL films and provides additional details about the release of EM from these films to create a viable alternative for transdermal applications. PMID- 29154189 TI - Novel theranostic zinc phthalocyanine-phospholipid complex self-assembled nanoparticles for imaging-guided targeted photodynamic treatment with controllable ROS production and shape-assisted enhanced cellular uptake. AB - The novel drug delivery system based on self-assembly of zinc phthalocyanine soybean phosphatidylcholine (ZnPc-SPC) complex was developed by a co-solvent method followed by a nanoprecipitaion technique. DSPE-PEG-methotrexate (DSPE-PEG MTX) was introduced on the surface of ZnPc-SPC self-assembled nanoparticles (ZS) to endow them with folate receptor-targeting property. NMR, XRD, FTIR, and UV-vis NIR analysis demonstrated the weak molecular interaction between ZnPc and SPC. The ZS functionalized with DSPE-PEG-MTX (ZSPM) was successfully constructed with an average particle size of ~170nm, a narrow size distribution, and could remain physiologically stable for at least 7days. In vitro cellular uptake and cytotoxicity studies demonstrated that ZSPM exhibited stronger cellular uptake efficacy and photodynamic cytotoxicity against HeLa and MCF-7 cells than ZS functionalized with DSPE-mPEG (ZSP) and free ZnPc. More importantly, ZSPM showed the enhanced accumulation effect at the tumor region compared with ZSP by the active-plus-passive targeting via enhanced permeability and retention (EPR) effect and folate receptor-mediated endocytosis. Furthermore, in vivo antitumor effect and histological analysis demonstrated the superior tumor growth inhibition effect of ZSPM. In addition, the needle-shape ZSP (ZSPN) exhibited better in vitro cellular uptake and in vivo tumor accumulation compared with ZSP due to the shape-assisted effect. Moreover, the interesting off-on switch effect of reactive oxygen species (ROS) production of ZnPc-SPC complex-based nanoparticles was discovered to achieve photodynamic treatment in a controllable way. These findings suggested that the ZnPc-SPC complex-based self-assembled nanoparticles could serve as a promising and effective formulation to achieve tumor-targeting fluorescence imaging and enhanced photodynamic treatment. PMID- 29154190 TI - (-)-Epicatechin protects the intestinal barrier from high fat diet-induced permeabilization: Implications for steatosis and insulin resistance. AB - Increased permeability of the intestinal barrier is proposed as an underlying factor for obesity-associated pathologies. Consumption of high fat diets (HFD) is associated with increased intestinal permeabilization and increased paracellular transport of endotoxins which can promote steatosis and insulin resistance. This study investigated whether dietary (-)-epicatechin (EC) supplementation can protect the intestinal barrier against HFD-induced permeabilization and endotoxemia, and mitigate liver damage and insulin resistance. Mechanisms leading to loss of integrity and function of the tight junction (TJ) were characterized. Consumption of a HFD for 15 weeks caused obesity, steatosis, and insulin resistance in male C57BL/6J mice. This was associated with increased intestinal permeability, decreased expression of ileal TJ proteins, and endotoxemia. Supplementation with EC (2-20mg/kg body weight) mitigated all these adverse effects. EC acted modulating cell signals and the gut hormone GLP-2, which are central to the regulation of intestinal permeability. Thus, EC prevented HFD induced ileum NOX1/NOX4 upregulation, protein oxidation, and the activation of the redox-sensitive NF-kappaB and ERK1/2 pathways. Supporting NADPH oxidase as a target of EC actions, in Caco-2 cells EC and apocynin inhibited tumor necrosis alpha (TNFalpha)-induced NOX1/NOX4 overexpression, protein oxidation and monolayer permeabilization. Together, our findings demonstrate protective effects of EC against HFD-induced increased intestinal permeability and endotoxemia. This can in part underlie EC capacity to prevent steatosis and insulin resistance occurring as a consequence of HFD consumption. PMID- 29154191 TI - Integrin CD11b mediates alpha-synuclein-induced activation of NADPH oxidase through a Rho-dependent pathway. AB - The activation of microglial NADPH oxidase (NOX2) induced by alpha-synuclein has been implicated in Parkinson's disease (PD) and other synucleinopathies. However, how alpha-synuclein activates NOX2 remains unclear. Previous study revealed that both toll-like receptor 2 (TLR2) and integrin play important roles in alpha synuclein-induced microglial activation. In this study, we found that blocking CD11b, the alpha chain of integrin alphaMbeta2, but not TLR2 attenuated alpha synuclein-induced NOX2 activation in microglia. The involvement of CD11b in alpha synuclein-induced activation of NOX2 was further confirmed in CD11b-/- microglia by showing reduced membrane translocation of NOX2 cytosolic subunit p47phox and superoxide production. Mechanistically, alpha-synuclein bound to CD11b and subsequently activated Rho signaling pathway. alpha-Synuclein induced activation of RhoA and downstream ROCK but not Rac1 in a CD11b-dependent manner. Moreover, siRNA-mediated knockdown of RhoA impeded NOX2 activation in response to alpha synuclein. Furthermore, we found that inhibition of NOX2 failed to interfere with the activation of RhoA signaling and interactions between alpha-synuclein and CD11b, further confirming that NOX2 was the downstream target of CD11b. Finally, we found that genetic deletion of CD11b abrogated alpha-synuclein-induced NOX2 activatoin in vivo. Taken together, our results indicated that integrin CD11b mediates alpha-synuclein-induced NOX2 activation through a RhoA-dependent pathway, providing not only a novel mechanistic insight but also a new potential therapeutic target for synucleinopathies. PMID- 29154192 TI - Resveratrol attenuates testicular apoptosis in type 1 diabetic mice: Role of Akt mediated Nrf2 activation and p62-dependent Keap1 degradation. AB - Infertility is a common complication in diabetic men, mainly due to the loss of germ cells by apoptotic cell death. However, effective and safe approaches to prevent diabetic induction of testicular apoptosis for diabetic patients have not been available. Resveratrol (RSV), a group of compounds called polyphenols from plants, has been indicated its promising used clinically for cancers and cardiovascular diseases. Therefore, the present study aimed determining whether RSV attenuates type 1 diabetes (T1D)-induced testicular apoptotic cell death in a mouse model. We found that testicular apoptosis and oxidative stress levels were significantly higher in T1D mice than control mice. In addition, the phosphorylation level of metabolism-related Akt and GSK-3beta was downregulated and Akt negative regulators PTEN, PTP1B and TRB3 were upregulated in the T1D group. These effects were partially prevented by RSV treatment. Nrf2 and its downstream genes, such as NQO-1, HO-1, SOD, catalase and metallothionein were significantly upregulated by RSV treatment. In addition, RSV-induced Nrf2 activation was found due to Keap1 degradation, mainly reliant on p62 that functions as an adaptor protein during autophagy. These results indicate that the attenuation of T1D-induced testicular oxidative stress and apoptosis by RSV treatment was mainly related to Akt-mediated Nrf2 activation via p62-dependent Keap1 degradation. PMID- 29154193 TI - Fundamentals on the biochemistry of peroxynitrite and protein tyrosine nitration. AB - In this review we provide an analysis of the biochemistry of peroxynitrite and tyrosine nitration. Peroxynitrite is the product of the diffusion-controlled reaction between superoxide (O2*-) and nitric oxide (*NO). This process is in competition with the enzymatic dismutation of O2*- and the diffusion of *NO across cells and tissues and its reaction with molecular targets (e.g. guanylate cyclase). Understanding the kinetics and compartmentalization of the O2*- / *NO interplay is critical to rationalize the shift of *NO from a physiological mediator to a cytotoxic intermediate. Once formed, peroxynitrite (ONOO- and ONOOH; pKa = 6,8) behaves as a strong one and two-electron oxidant towards a series of biomolecules including transition metal centers and thiols. In addition, peroxynitrite anion can secondarily evolve to secondary radicals either via its fast reaction with CO2 or through proton-catalyzed homolysis. Thus, peroxynitrite can participate in direct (bimolecular) and indirect (through secondary radical intermediates) oxidation reactions; through these processes peroxynitrite can participate as cytotoxic effector molecule against invading pathogens and/or as an endogenous pathogenic mediator. Peroxynitrite can cause protein tyrosine nitration in vitro and in vivo. Indeed, tyrosine nitration is a hallmark of the reactions of *NO-derived oxidants in cells and tissues and serves as a biomarker of oxidative damage. Protein tyrosine nitration can mediate changes in protein structure and function that affect cell homeostasis. Tyrosine nitration in biological systems is a free radical process that can be promoted either by peroxynitrite-derived radicals or by other related *NO-dependent oxidative processes. Recently, mechanisms responsible of tyrosine nitration in hydrophobic biostructures such as membranes and lipoproteins have been assessed and involve the parallel occurrence and connection with lipid peroxidation. Experimental strategies to reveal the proximal oxidizing mechanism during tyrosine nitration in given pathophysiologically-relevant conditions include mapping and identification of the tyrosine nitration sites in specific proteins. PMID- 29154194 TI - MicroRNAs in intestinal barrier function, inflammatory bowel disease and related cancers-their effects and therapeutic potentials. AB - The initiation and development or inflammatory bowel disease (IBD) and associated colorectal cancers, have been linked to inflammation. MicroRNAs are non-coding regulators of gene expression that have gained great attention due to their capability to regulate the expression of a number of target transcripts. It is now generally admitted that microRNAs are instrumental in gut pathologies, in particular through their targeting of transcripts encoding proteins of the intestinal barrier (IB) and their regulators. Intense research is conducted to identify microRNAs susceptible to be used as biomarkers and to design new therapeutic approaches based upon using synthetic microRNA mimics and inhibitors as well as finding new drugs capable to restore or modify microRNA expression in the context of gut pathologies. PMID- 29154195 TI - Drug-loaded nanoemulsion as positive control is an alternative to DMSO solutions for in vitro evaluation of curcumin delivery to MCF-7 cells. AB - BACKGROUND: In vitro evaluation of toxicity and/or efficacy of nanostructured drug delivery systems involves the uses of different controls, including positive and negative controls, as well as a solution or dispersion of the drug in water. One of the most frequently solvent used to dilute poorly water soluble drugs to in vitro tests are dimethylsulfoxide (DMSO). However, its different specific surface area and different diffusion coefficients could make the comparative effects difficult. We proposed that a solvent-free dispersions having similar specific surface area could be a better control than drug in solution against cell lines. METHODS: We evaluate the effect of curcumin-loaded lipid-core nanocapsules, curcumin-loaded nanoemulsion and curcumin DMSO-water solution on viability and colony forming efficiency of human breast cancer cell line, MCF7. RESULTS: The cytotoxic effect of nanocapsules at 24-72h was similar to nanoemulsion and lower than drug solution. However, the nanocapsules had a superior anticancer activity when long periods (10days) were evaluated, which highlight the sustained drug release by nanocapsules. CONCLUSIONS: Our results showed a superior anticancer activity of curcumin-loaded lipid-core nanocapsules compared to curcumin-loaded nanoemulsion and curcumin dissolved in DMSO in long exposition time assay, wihch is not observed in short exposition time assays like MTT. When a poorly water-soluble drug is under investigation, the nanoemulsion prepared with the same compounds of the nanocapsules, except the polymer, could be a better control than DMSO-solution of drug. PMID- 29154196 TI - Analysis of potential genotoxic impurities in rabeprazole active pharmaceutical ingredient via Liquid Chromatography-tandem Mass Spectrometry, following quality by-design principles for method development. AB - A novel Liquid Chromatography-tandem mass spectrometry (LC-MS/MS) method is presented for the quantitative determination of two potential genotoxic impurities (PGIs) in rabeprazole active pharmaceutical ingredient (API). In order to overcome the analytical challenges in the trace analysis of PGIs, a development procedure supported by Quality-by-Design (QbD) principles was evaluated. The efficient separation between rabeprazole and the two PGIs in the shortest analysis time was set as the defined analytical target profile (ATP) and to this purpose utilization of a switching valve allowed the flow to be sent to waste when rabeprazole was eluted. The selected critical quality attributes (CQAs) were the separation criterion s between the critical peak pair and the capacity factor k of the last eluted compound. The effect of the following critical process parameters (CPPs) on the CQAs was studied: %ACN content, the pH and the concentration of the buffer salt in the mobile phase, as well as the stationary phase of the analytical column. D-Optimal design was implemented to set the plan of experiments with UV detector. In order to define the design space, Monte Carlo simulations with 5000 iterations were performed. Acceptance criteria were met for C8 column (50*4mm, 5MUm), and the region having probability pi>=95% to achieve satisfactory values of all defined CQAs was computed. The working point was selected with the mobile phase consisting of ACN, ammonium formate 11mM at a ratio 31/69v/v with pH=6,8 for the water phase. The LC protocol was transferred to LC-MS/MS and validated according to ICH guidelines. PMID- 29154197 TI - Investigation of the effect of blood hematocrit and lipid content on the blood volume deposited by a disposable dried blood spot collection device. AB - When using dried blood spot (DBS) sampling for the quantitative bioanalysis of circulating concentrations of drugs, metabolites and endogenous analytes, it is important that a fixed volume of blood is deposited to overcome the issues associated with blood hematocrit (HCT) and homogeneity. The volumetric performance of the KTH DBS collection device was tested with radiolabelled [14C] diclofenac. It was demonstrated that the device deposits a fixed volume of blood (13.5MUL) regardless of the HCT (25-65%), or lipid content of the blood sample. Further, it was found that the precision and accuracy of the derived dried blood samples were at least as good as those of a positive displacement pipette. The device was found to be easy to use and gave acceptable dried samples for 92.9% of the tests performed (n=42). PMID- 29154198 TI - Evaluation of antioxidant, DNA targeting, antimicrobial and cytotoxic studies of imine capped copper and nickel nanoparticles. AB - In this work, we have synthesized pyrimidine derivatives of Schiff base ligand 2 (4,6-dimethoxypyrimidin-2-ylimino)methyl)-6-methoxyphenol (DPMM) stabilized copper nanoparticles (DPMM-CuNPs) and nickel nanoparticles (DPMM-NiNPs) by modified Brust-Schiffrin technique as two step phase transfer assisted method and confirmed by UV-Visible, SEM and TEM analysis. The free radical scavenging activity of DPMM, DPMM-CuNPs &DPMM-NiNPs with 2, 2'-diphenylpicryl hydrazyl (DPPH), hydrogen peroxide (H2O2) super oxide dismutase (SOD) and nitric oxide (NO) shows that the antioxidant activity of DPMM-CuNPs is higher than DPMM &DPMM NiNPs. Interaction study of DPMM-CuNPs &DPMM-NiNPs with CT-DNA has been investigated by absorption spectral titration, fluorescence studies, cyclic voltammetry and viscometric measurements. Dose dependent antibacterial and antifungal studies of DPMM-CuNPs & DPMM-NiNPs against five different bacteria Shigella sonnei, Staphylococcus aureus, Escherichia coli, Klepsiella pneumoniae, Pseudomonas fluoroscens and five different fungi Aspergillus niger, Candida albicans, Candida tropicalis, Mucor indicus and Rhizopus show that the compounds have significant antibacterial and antifungal activity. Cytotoxicity studies of DPMM-CuNPs &DPMM-NiNPs on human breast cancer cell line (MCF-7) were studied by 3 (4, 5-dimethylthiazol-2-yl-)-2, 5-diphenyltetrazolium bromide (MTT) assay. 50% cell viability was found at 25MUg/mL for DPMM-CuNPs and 300MUg/mL for DPMM-NiNPs. Collective biological results reveal that the synthesized DPMM-CuNPs is more biologically active than DPMM-NiNPs. PMID- 29154199 TI - Ultraviolet B radiation down-regulates ULK1 and ATG7 expression and impairs the autophagy response in human keratinocytes. AB - Autophagy is a self-digestive pathway that helps to maintain cellular homeostasis, and many autophagy-related gene (ATG)s involved the regulation of the autophagy process. Ultraviolet light is a common stressor of skin, but it is unclear how autophagy is regulated after ultraviolet exposure in epidermal keratinocytes. Here, we found that the mRNAs of some key ATG genes such as ULK1, ATG5 and ATG7 exhibited significantly lower levels in the skin tissues of the face and chest with solar ultraviolet exposure, compared with perineal skin. Interestingly, UVB radiation down-regulated the expression of ULK1, ATG3 and ATG7, and it inhibited the autophagy flux via a mechanistic target of rapamycin (MTOR)-independent pathway in human keratinocytes. The inhibition of autophagy in UVB-treated keratinocytes cannot be restored by treatment with the MTOR-dependent autophagy inducer rapamycin. Importantly, UVB treatment perturbs the conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II and LC3-II turnover in response to treatment with MTOR inhibitors (Torin 1 and pp242), as well as endoplasmic reticular stress (A23187 and tunicamycin), inositol pathway (L690,330) and autophagy inducers (resveratrol and STF62247). Our study demonstrates that UVB radiation down-regulates several key autophagy-related proteins and impairs the autophagy response in keratinocytes. This study demonstrates a linkage between autophagy and skin disorders associated with ultraviolet exposure. PMID- 29154200 TI - UVR and PAR absorbing compounds of marine brown macroalgae along a latitudinal gradient of the Brazilian coast. AB - Absorption spectra are indicative of biological sample chemical composition and can be used as a basis for the construction of descriptive and predictive models for biotechnological screening or assays. In marine algae, chemical composition can vary due to species-specific differences in biochemistry, as well as intra specific responses to unique environmental variables. Different indices (UVCi, UVB+Ai and PARi) were proposed and calculated to evaluate how photoprotective compounds vary in 18 species of Phaeophyceae. In addition, they were correlated to abiotic factors. Through this technique, seven main peaks were detected in the absorbing spectra of marine brown algal extracts. The highest photoprotective indices values were found in species collected in tropical areas, where higher solar radiation is observed compared to the southern Brazilian coast. Considering additional abiotic factors, water temperature and nitrate concentration were negatively correlated with UV indices. PARi's indices were positively affected by nitrate. All species collected on the Brazilian coast have absorption peaks in the region of phenolic compounds and carotenoids, suggesting that tropical marine brown macroalgae may have developed an effective antioxidant defense system, suggesting adaptation to environments characterized by high solar radiation. UVR/PAR indices congregated essential information to possible future biotechnological screening, facilitating selection of high priority species or sites, fostering actions to enhance alternative sustainable management strategies of coastal environments. PMID- 29154201 TI - Neuroendocrine disorder in chronic fatigue syndrome AB - Background/aim: Neuroendocrine disorders are considered a possible pathogenetic mechanism in chronic fatigue syndrome (CFS). The aim of our study was to determine the function of the hypothalamic-pituitary-adrenal axis (HPA) and thyroid function in women of reproductive age suffering from CFS. Materials and methods: The study included 40 women suffering from CFS and 40 healthy women (15 45 years old). Serum levels of cortisol (0800 and 1800 hours), ACTH, total T4, total T3, and TSH were measured in all subjects. The Fibro Fatigue Scale was used for determination of fatigue level. Results: Cortisol serum levels were normal in both groups. The distinctively positive moderate correlation of morning and afternoon cortisol levels that was observed in healthy women was absent in the CFS group. This may indicate a disturbed physiological rhythm of cortisol secretion. Although basal serum T4, T3, and TSH levels were normal in all subjects, concentrations of T3 were significantly lower in the CFS group. Conclusion: One-time hormone measurement is not sufficient to detect hormonal imbalance in women suffering from CFS. Absence of a correlation between afternoon and morning cortisol level could be a more representative factor for detecting HPA axis disturbance. PMID- 29154202 TI - Polymorphisms in inflammasome genes and risk of asthma in Brazilian children. AB - Considering its role in inflammation and recently described "alternative" roles in epithelial homeostasis and Th1/Th2 balance, we hypothesize that inflammasome genetics could contribute to the development of asthma. Selected functional polymorphisms in inflammasome genes are evaluated in a cohort of asthmatic children and their families. Gain-of-function NLRP1 variants rs11651270, rs12150220 and rs2670660 resulted significantly associated to asthma in trios (TDT) analysis; and rs11651270 and rs2670660 also with asthma severity and total IgE level in asthmatic children. NLRP1 activators in humans are still unknown, however we hypothesized that individuals with gain-of-function SNPs in NLRP1 could be more prone in activating inflammasome in the presence of asthma-related cell stressors (i.e. ER stress or ROS), and this activation contribute to exacerbate inflammatory response and asthma development. Gain-of-function IL1A rs17561 resulted significantly associated with a reduced pulmonary capacity in asthmatic children. IL18 rs5744256 which lead to lower serum level of IL-18 appeared to be associated to a worse response to bronchodilators. Concluding, this work provides evidences about the contribution of inflammasome genetics in the development of paediatric asthma, both considering its inflammatory role in alveolar macrophages (i.e.: NLRP1) or its homeostatic role in lung epithelial cells (i.e.: IL1A, IL18). PMID- 29154203 TI - Unbending mind: Individuals with hoarding disorder do not modify decision strategy in response to feedback under risk. AB - Cognitive-behavioral models of hoarding disorder emphasize impairments in information processing and decision making in the genesis of hoarding symptomology. We propose and test the novel hypothesis that individuals with hoarding are maladaptively biased towards a deliberative decision style. While deliberative strategies are often considered normative, they are not always adaptable to the limitations imposed by many real-world decision contexts. We examined decision-making patterns in 19 individuals with hoarding and 19 healthy controls, using a behavioral task that quantifies selection of decision strategies in a novel environment with known probabilities (risk) in response to feedback. Consistent with prior literature, we found that healthy individuals tend to explore different decision strategies in the beginning of the experiment, but later, in response to feedback, they shift towards a compound strategy that balances expected values and risks. In contrast, individuals with hoarding follow a simple, deliberative, risk-neutral, value-based strategy from the beginning to the end of the task, irrespective of the feedback. This seemingly rational approach was not ecologically rational: individuals with hoarding and healthy individuals earned about the same amount of money, but it took individuals with hoarding a lot longer to do it: additional cognitive costs did not lead to additional benefits. PMID- 29154204 TI - Facebook intrusion, fear of missing out, narcissism, and life satisfaction: A cross-sectional study. AB - Facebook is one of the most popular social networking sites. The present paper examines the relations between fear of missing out, narcissism, Facebook intrusion, and life satisfaction. We hypothesized that the fear of missing out and narcissism would play a significant role in Facebook intrusion. The participants in the study were 360 Polish users of Facebook. We administered the Facebook Intrusion Scale, the Fear of Missing Out Scale, the Narcissistic Personality Inventory, and the Satisfaction with Life Scale. The results showed that a high level of fear of missing out and high narcissism are predictors of Facebook intrusion, while a low level of fear of missing out and high narcissism are related to satisfaction with life. Our findings provide a more comprehensive picture of the predictors of Facebook intrusion and reveal interesting patterns. PMID- 29154205 TI - Identification and temporal decrease of 137Cs and 134Cs in groundwater in Minami Soma City following the accident at the Fukushima Dai-ichi nuclear power plant. AB - The Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident on March 11, 2011, caused severe radioactive contamination in Fukushima Prefecture. In order to clarify the safety of drinking water, we have conducted radiocesium monitoring of public tap water and groundwater in Minami-Soma City, which is 10-40 km north of the nuclear power plant. The source of tap water for Minami-Soma City is groundwater, which is treated by rapid filtration before distribution in two of the three treatment plants. The tap water was collected from six stations during 2012-2016 and groundwater was collected from 11 stations with wells between 5 and 100 m deep during 2014-2016. Radiocesium contamination of groundwater has been considered unlikely in Japan because of the small vertical migration velocity of radiocesium in Japanese soil. However, radiocesium was detected in public tap water after 2012, and the maximum 137Cs concentration of 292 mBq L-1 was observed in 2013. In all the well water, radiocesium was detected between 2014 and 2015, at concentrations similar to those observed in tap water in the same period. In tap water and groundwater, radiocesium was decreased to below the detection limit in 2016 except for four stations. Radiocesium concentration in shallow water reached a maximum between 2013 and 2015, 2-4 years after the FDNPP accident, and then decreased. The results are interpreted that dissolved 137Cs migrated in the soil and reached aquifers of various depth. PMID- 29154206 TI - A new approach in separating microplastics from environmental samples based on their electrostatic behavior. AB - Numerous studies on microplastics (MPs; O < 5 mm) in the aquatic environment have been published, but knowledge about the occurrence and ecological risks of MPs is limited. This is in part because current data on the distribution of MPs are comparable only to a limited extent, due to the many different methods of investigation. In addition, sample preparation is often difficult such that standard procedures are lacking. The aim of this work was to simplify the preparation of different kinds of MP samples. Our method makes use of the electrostatic behavior of plastic particles to facilitate their separation from sample matter, with up to 99% of the original sample mass removed without any loss of MPs. To determine the efficacy of this approach, four different materials (quartz sand, freshwater suspended particulate matter, freshwater sediment, and beach sand) were spiked with MPs (size: 0.063-5 mm from the seven most common types of plastics, one bioplastic type, polyethylene fibers, and tire wear. A modified electrostatic metal/plastic separator was used to reduce the sample mass and concentrate the plastics based on their physical separation. The recovery achieved with this method was as high as nearly 100% for each type of material. The method was then tested on plastic particles of different shapes and types isolated from the Rhine River. These were successfully electroseparated from the four materials, which demonstrated the utility of this method. Its advantages include the simplified handling and preparation of different field samples as well as a much shorter processing time, because after the last separation step there is hardly any biological material remaining in the sample fraction. PMID- 29154207 TI - Particle size distribution and respiratory deposition estimates of airborne perfluoroalkyl acids during the haze period in the megacity of Shanghai. AB - This study presents the particle size distribution and respiratory deposition estimates of airborne perfluoroalkyl acids (PFAAs) during the haze period. Size segregated haze aerosols were collected from an urban location in Shanghai using an eight-stage air sampler. The samples were analyzed for eight PFAAs using ultra high-performance liquid chromatography tandem triple quadrupole mass spectrometry. The quantification results showed that the concentrations of particle-bound Sigma 8PFAAs ranged from 0.26 to 1.90 ng m-3 (mean: 1.44 ng m-3). All of the measured PFAAs particle size distributions had a bimodal mode that peaked respectively in accumulation size range (0.4 < Dp < 2.1 MUm) and coarse size ranges (Dp > 2.1 MUm), but the width of each distribution somewhat varied by compound. The emission source, molecular weight, and volatility of the PFAAs were important factors influencing the size distribution of particle-bound PFAAs. Of these compounds, PFUnDA presented a strong accumulation in the fine size range (average 75% associated with particles <2.1 MUm), followed by PFOA (69%) and PFDA (64%). The human risk assessment of PFOS via inhalation was addressed and followed the same pattern as the size distribution, with a 2-fold higher risk for the fine particle fraction compared to the coarse particle fraction at urban sites. Approximately 30.3-82.0% of PFAA deposition (?PFAA: 72.5%) in the alveolar region was associated with particles <2.1 MUm, although the contribution of fine particles to the total PFAAs concentration in urban air was only 28-57% (?8PFAAs: 48%). These results suggested that fine particles are significant contributors to the deposition of PFAAs in the alveolar region of the lung. PMID- 29154208 TI - Characteristics of NK cells from leukemic microenvironment in MLL-AF9 induced acute myeloid leukemia. AB - NK cells are indispensable components of tissue microenvironment and play vital in both innate and adaptive immunity. The activation and function of NK cells are affected by tumor microenvironments. NK cells are also important players in leukemic microenvironment. However, their characteristics in leukemic microenvironment, including maturation status, phenotype, subpopulations and functional roles especially immunoregulatory potential, have not been well established. Here, we studied these characteristics of NK cells in MLL-AF9 induced mouse acute myeloid leukemia (AML) model. Increase of more mature NK cells were detected in the AML spleen. Splenic AML microenvironment promoted NK cell activation in early and middle stages of leukemia. Cytotoxicity molecules and cytokines were up-regulated in activated NK cells. Furthermore, NK cells from AML microenvironment regulated T cell function, not only by maintaining the activation of CD4+ and promoting the degranulation of cytotoxic CD8+ T cells but also by influencing the differentiation of CD4+ T cells. Moreover, two NK cell subpopulations marked by DNAM-1 (CD226) had distinct cytokine expression patterns but similar regulatory effects on T cells. Collectively, these findings highlight the significance of immunoregulatory role of NK cells, and suggest novel therapeutic potential for leukemia by manipulating NK cell immunoregulatory activity. PMID- 29154209 TI - External signals regulate germinal center fate-determining transcription factors in the A20 lymphoma cell line. AB - Due to the apoptosis-prone nature of primary germinal center B (GCB) cells, it remains a huge challenge to dissect signals that guide their differentiation towards memory B cells and plasma cells in vitro. Here we show that the murine lymphoma cell line A20 resembles primary GCB cells in expression of GC-specific surface markers and the master transcription factor BCL6 and may serve as a useful system to model certain GCB cell behaviors in vitro. Using these cells, we found that both CD40 and B cell receptor (BCR) signaling are able to drive BCL6 downregulation, which is a prerequisite of post-GC B-cell differentiation. Under the steady state, BCL6 is constantly and rapidly degraded in A20 cells by the proteasome in a strictly FBXO11-dependent manner. This process can be further enhanced by signals downstream of the BCR. Both CD40 and BCR stimulation can upregulate IRF4, a transcription factor that suppresses BCL6 expression. However, only BCR signaling downregulate PAX5 and BACH2, two transcription factors that help maintain the GCB identity. Together, these results validate the A20 cell line as an experimental system suitable for studying regulation of BCL6 and potentially other transcription factors relevant to post-GC fate determination, and they support that combined signaling from BCR and CD40 receptors would drive termination of the GC program. PMID- 29154210 TI - Clinical pharmacokinetic-pharmacodynamic analyses: a critical element for developing antibacterial agents. AB - In the current of era of developing antibacterial agents, including those for unmet medical need, Sponsors are required to submit a robust pre-clinical pharmacokinetic-pharmacodynamic (PK-PD) data package in exchange for limited clinical data. However, the clinical data package also needs to be as robust as possible. The clinical data package needs to include the Phase 1 pharmacokinetic (PK) studies conducted in the target patient populations and special populations. Additionally, PK data need to be collected from all patients enrolled in the pivotal trial(s). Such data are critical to confirm adequate drug exposures relative to non-clinical PK-PD targets for efficacy, explain unexpected clinical failures in individuals or groups of patients, and evaluate exposure-response relationships for safety. PMID- 29154211 TI - Quasi-static and dynamic motions of the columellar footplate in ostrich (Struthio camelus) measured ex vivo. AB - The nature of the movement of the columellar footplate (CFP) in birds is still a matter of ongoing debate. Some sources claim that rocking motion is dominant, while others propose a largely piston-like motion. In this study, motions of the CFP are experimentally investigated in the ostrich using a post-mortem approach. For quasi-static loads, micro-CT scans of ostrich heads were made under positive and negative middle-ear pressures of 1 kPa. For dynamic loads, laser Doppler vibrometry was used to measure the velocity on multiple locations of the CFP as a function of excitation frequency from 0.125 to 4 kHz, and digital stroboscopic holography was used to assess the 1D full-field out-of-plane displacement of the CFP at different excitation frequencies. To expose the CFP in the experiments, measurements were made from the medial side of the CFP after opening and draining the inner ear. To determine the influence of the inner-ear load on CFP motions, a finite element model was created of the intact ostrich middle ear with inner-ear load included. For quasi-static loads, the CFP performed largely piston-like motions under positive ME pressure, while under negative ME pressure the difference between piston and rocking motion was smaller. For dynamic loads, the CFP motion was almost completely piston-like for frequencies below 1 kHz. For higher frequencies, the motions became more complicated with an increase of the rocking components, although they never exceeded the piston component. When including the inner-ear load to the model, the rocking components started to increase relative to the piston component when compared to the result of the model with unloaded CFP, but only at high frequencies above 1 kHz. In this frequency range, the motion could no longer be identified as purely piston-like or rocking. As a conclusion, the current results suggest that CFP motion is predominantly piston-like below 1 kHz, while at higher frequencies the motion becomes too complicated to be described as purely piston-like or rocking. PMID- 29154212 TI - Consensus scoring model for the molecular docking study of mTOR kinase inhibitor. AB - The discovery of mammalian target of rapamycin (mTOR) kinase inhibitors has always been a research hotspot of antitumor drugs. Consensus scoring used in the docking study of mTOR kinase inhibitors usually improves hit rate of virtual screening. Herein, we attempt to build a series of consensus scoring models based on a set of the common scoring functions. In this paper, twenty-five kinds of mTOR inhibitors (16 clinical candidate compounds and 9 promising preclinical compounds) are carefully collected, and selected for the molecular docking study used by the Glide docking programs within the standard precise (SP) mode. The predicted poses of these ligands are saved, and revaluated by twenty-six available scoring functions, respectively. Subsequently, consensus scoring models are trained based on the obtained rescoring results by the partial least squares (PLS) method, and validated by Leave-one-out (LOO) method. In addition, three kinds of ligand efficiency indices (BEI, SEI, and LLE) instead of pIC50 as the activity could greatly improve the statistical quality of build models. Two best calculated models 10 and 22 using the same BEI indice have following statistical parameters, respectively: for model 10, training set R2=0.767, Q2=0.647, RMSE=0.024, and for test set R2=0.932, RMSE=0.026; for model 22, raining set R2=0.790, Q2=0.627, RMSE=0.023, and for test set R2=0.955, RMSE=0.020. These two consensus scoring model would be used for the docking virtual screening of novel mTOR inhibitors. PMID- 29154213 TI - Liposomally formulated phospholipid-conjugated novel near-infrared fluorescence probe for particle size effect on cellular uptake and biodistribution in vivo. AB - Lipid based nanoparticles (LBNs) with excellent biocompatibility and versatility have received much attention from the drug delivery community recently. A detailed understanding of in vitro and vivo fate of LBNs is important for developing different types of LBNs with improved selectivity and low cytotoxicity. We developed a novel near-infrared (NIR) probe with high fluorescence, designated as DSPE-ir623 (iDSPE). Then, we prepared iDSPE-embeded liposomes (iLPs) with two different hydrodynamic sizes (~100nm and ~400nm) to evaluate the effect of particle size on cellular uptake and biodistribution of nanoliposomes in vivo. These iLPs were proved to exhibit good monodispersity, excellent fluorescence and stability. In vitro cell uptake tests demonstrated that iLPs-1 (~100nm) were taken up more by HT-29 cells than iLPs-2 (~400nm). Notably, the fluorescence of iLPs can be employed for real-time monitoring of the subcellular locating and its metabolic distribution in vivo. Near-infrared imaging in vivo illustrated that iLPs-1 was mainly accumulated in the tumor tissues, while iLPs-2 was accumulated in liver and spleen. The results indicated that the size of iLPs play an important role in the regulation of intracellular trafficking and biodistribution of liposomes, which also provide a new insight into the development of more effective LBNs. Hence, iDSPE might be a promising tool for the reliable tracing of different types of LBNs. PMID- 29154214 TI - Ennoblement, corrosion, and biofouling in brackish seawater: Comparison between six stainless steel grades. AB - In this work, six common stainless steel grades were compared with respect to ennoblement characteristics, corrosion performance and tendency to biofouling in brackish sea water in a pilot-scale cooling water circuit. Two tests were performed, each employing three test materials, until differences between the materials were detected. Open circuit potential (OCP) was measured continuously in situ. Potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) measurements were conducted before and after the tests. Exposed specimens were further subjected to examinations by scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS), and the biofouling was studied using epifluorescence microscopy, quantitative polymerase chain reaction (qPCR) and high-throughput sequencing (HTP sequencing). The results revealed dissimilarities between the stainless steel grades in corrosion behaviour and biofouling tendency. The test material that differed from the most of the other studied alloys was grade EN 1.4162. It experienced fastest and most efficient ennoblement of OCP, its passive area shrank to the greatest extent and the cathodic reaction was accelerated to a significant degree by the development of biofilm. Furthermore, microbiological analyses revealed that bacterial community on EN 1.4162 was dominated by Actinobacteria, whereas on the other five test materials Proteobacteria was the main bacterial phylum. PMID- 29154215 TI - Error propagation of partial least squares for parameters optimization in NIR modeling. AB - A novel methodology is proposed to determine the error propagation of partial least-square (PLS) for parameters optimization in near-infrared (NIR) modeling. The parameters include spectral pretreatment, latent variables and variable selection. In this paper, an open source dataset (corn) and a complicated dataset (Gardenia) were used to establish PLS models under different modeling parameters. And error propagation of modeling parameters for water quantity in corn and geniposide quantity in Gardenia were presented by both type I and type II error. For example, when variable importance in the projection (VIP), interval partial least square (iPLS) and backward interval partial least square (BiPLS) variable selection algorithms were used for geniposide in Gardenia, compared with synergy interval partial least squares (SiPLS), the error weight varied from 5% to 65%, 55% and 15%. The results demonstrated how and what extent the different modeling parameters affect error propagation of PLS for parameters optimization in NIR modeling. The larger the error weight, the worse the model. Finally, our trials finished a powerful process in developing robust PLS models for corn and Gardenia under the optimal modeling parameters. Furthermore, it could provide a significant guidance for the selection of modeling parameters of other multivariate calibration models. PMID- 29154216 TI - Colorimetric sensing of oxalate based on its inhibitory effect on the reaction of Fe (III) with curcumin nanoparticles. AB - In this research, a new colorimetric method for the determination of oxalate using curcumin nanoparticles (CURNs) in the presence Fe (III) is introduced. The method is based on the inhibitory effect of oxalate ion on the reaction of (CURNs) with Fe (III) in acidic media. This reaction was monitored by measuring the increase in absorbance of CURNs-Fe3+ complex in the presence of oxalate ion at 427nm. The effect of different parameters such as the pH of the sample solution, concentration of Fe (III), concentration of CURNs and the reaction time was examined and optimized. Under optimum experimental conditions, the absorption intensity was linear with the concentration of oxalate in the range of 0.15 to 1.70MUgmL-1. The limit of detection (LOD) was 0.077MUgmL-1 and the relative standard deviations (RSD) for 8 replicate measurements of 0.40 and 1.05MUgmL-1 of oxalate were 4.20% and 2.74%, respectively. The developed method was successfully employed to the determination of oxalate in water, food and urine samples with satisfactory results. PMID- 29154218 TI - Proteomics of dark cutting longissimus thoracis muscle from heifer and steer carcasses. AB - Studies have suggested that the phenomenon of dark cutting (Canada B4) beef may also be related to muscle glycolytic proteins. The objective of this study, therefore, was to analyze longissimus thoracis (LT; n=23), from Canada AA (n=8), atypical (AB4; pH<5.9, n=8) and typical (TB4; pH>5.9, n=7) B4 heifer and steer carcasses, for sarcoplasmic and myofibrillar proteins using 2-D gel electrophoresis and LC-MS/MS mass spectrometry. Results indicated that AB4 LT had intramuscular pH and lactate concentration similar to Canada AA but lower (P<0.05) L* and b*. Moreover, AB4 LT were tougher than Canada AA even at 21days post-mortem, unlike TB4. Canada AB4 LT had reduced (P<0.05) levels of creatine kinase, glyceraldehyde-3-phosphate dehydrogenase, lactate dehydrogenase and glycerol-3-phosphate dehydrogenase [NAD(+)], indicating a compromised glycolytic capacity in AB4. Canada AB4 LT had increased (P<0.05) abundances of phosphatidylethanolamine-binding protein 1 and small heat shock proteins. PMID- 29154217 TI - A novel turn-on fluorescent probe for Al3+ and Fe3+ in aqueous solution and its imaging in living cells. AB - A quinoline-based fluorescence probe has been prepared and characterized. Probe 1 showed a selective sensing ability for Al3+ and Fe3+ ions through fluorescence enhancement response at 515nm when it was excited at 360nm. In the presence of Fe3+ ion, probe 1 exhibited a detection limit of 2.10*10-6M. As for Al3+, its detection limit of 3.58*10-7M was significantly lower than the highest limit of Al3+ in drinking water recommended by the WHO (7.41MUM), representing a rare example in reported fluorescent probe for Al3+ ion. The fluorescence microscopy experiments have demonstrated that probe 1 could be used in live cells for the detection of Al3+ and Fe3+ ions. PMID- 29154219 TI - Performance of fluorescence spectroscopy for beef meat authentication: Effect of excitation mode and discriminant algorithms. AB - This study evaluated the performance of classical front face (FFFS) and synchronous (SFS) fluorescence spectroscopy combined with Partial Least Square Discriminant Analysis (PLSDA), Support Vector Machine associated with PLS (PLS SVM) and Principal Components Analysis (PCA-SVM) to discriminate three beef muscles (Longissimus thoracis, Rectus abdominis and Semitendinosus). For the FFFS, 5 excitation wavelengths were investigated, while 6 offsets were studied for SFS. Globally, the results showed a good discrimination between muscles with Recall and Precision between 47.82 and 94.34% and Error ranging from 6.03 to 32.39%. For the FFFS, the PLS-SVM with the 382nm excitation wavelength gave the best discrimination results (Recall, Precision and Error of 94.34%, 89.53% and 6.03% respectively). For SFS, when performing discrimination of the three muscles, the 120nm offset gave the highest Recall and Precision (from 57.66% to 94.99%) and the lowest Error values (from 6.78 to 8.66%) whatever the algorithm (PLSDA, PLS-SVM and PCA-SVM). PMID- 29154220 TI - Association of Melanocortin (MC4R) and Myostatin (MSTN) genes with carcass quality in rabbit. AB - The aim of this study was to investigate the association of Melanocortin (MC4R) and Myostatin (MSTN) with the carcass quality of V-line and Alexandria line rabbits. MC4R and MSTN were screened by single-strand conformational polymorphism analysis (SSCP) then DNA was sequenced. The results identified four novel SNPs using the four studied primers of the MC4R and MSTN genes. The genotype (BB) has significant higher body weight (BW), carcass weight (CW) and dressing percentage (DP) than AA rabbits. There were no significant differences within the two lines in the carcass color (light pink) and carcass fat (CF). GLM analysis for the effect of genotypes on carcass traits demonstrated that the genotype (BB) was significantly associated with high carcass weight (CW) and dressing percentage (DP). The detected mutations and the analysis of carcass quality means revealed a significant association between MSTN and MC4R polymorphisms with some carcass traits that affect meat quality of rabbits. PMID- 29154221 TI - Effects of aging treatment and freezing/thawing methods on the quality attributes of beef from Limousin*Holstein-Friesian and Hereford*Holstein-Friesian crossbreeds. AB - The objective was to investigate combined effects of aging-, freezing-, thawing- treatments on the water-holding capacity, Warner-Bratzler shear force (WBSF) and sensory properties of beef. Semitendinosus muscles from two crossbreeds were analysed. Carcasses were conventionally aged (4days post mortem), muscles were separated and divided into samples. Part of the samples were frozen without wet aging and the others were wet-aged for 3 or 6days (and then also frozen). Two freezing methods (conventional and cryogenic) and two thawing methods (at 4 degrees C and 20 degrees C) were applied. Stepwise conventional/wet-aging just as thawing at 20 degrees C, decreased the WBSF (P<0.05) and increased the scores for tenderness (P<0.05). Moreover, wet-aging for 3days gave an equal effect on tenderness (P>0.05) as the 6-days period. Meat from Hereford-crosses scored significantly higher for juiciness, compared with Limousin-crosses. These tips may be applied in the meat industry to reduce time of aging process and ensure a consistent high quality of frozen beef. PMID- 29154222 TI - Exploring innovative possibilities of recovering the value of dark-cutting beef in the Canadian grading system. PMID- 29154223 TI - Mitochondrial F1-ATPase extends glycolysis and pH decline in an in vitro model. AB - The experiment was conducted to identify the mitochondrial protein responsible for enhancing glycolytic flux. We hypothesized that mitochondrial F1-ATPase promotes ATP hydrolysis and thereby the flux through glycolysis. Porcine longissimus muscle mitochondria were incorporated into an in vitro system designed to recapitulate postmortem glycolysis with or without Na-azide to specifically inhibit the beta-subunit of mitochondrial F1-ATPase that catalyzes ATP hydrolysis. Addition of mitochondria enhanced ATP hydrolysis, glycogen degradation, lactate accumulation, and pH decline in the in vitro system. However, the majority of mitochondria-mediated enhancement in glycolytic flux was abolished in the presence of Na-azide. To investigate further, myofibrillar and mitochondrial proteins were added to the in vitro system after 240min from the initiation of the reaction. Greater pH decline and lactate accumulation were observed in system containing mitochondrial protein compared to their myofibrillar counterpart. In conclusion, mitochondrial F1-ATPase is capable of increasing glycolytic flux through promoting greater ATP hydrolysis at lower pH. PMID- 29154224 TI - Evaluation of whole pork belly qualitative and quantitative properties using selective belly muscle parameters. AB - The objective of this study was to identify parameters for the evaluation of pork belly quality (composition) and quantity (volume) and to develop regression equations that predict properties of whole pork belly. Through an image analysis of 648 bellies, newly characterized pork belly parameters were developed for evaluating pork belly quality and quantity. Importantly, the estimated muscle volume showed high positive correlation with the whole belly volume and the whole belly muscle percentage (r=0.458, and 0.654, respectively). Section 7 was identified as the best section for the evaluation of pork belly based on the muscle area in every vertebra. A stepwise regression showed that cutaneous trunci muscle (CTM) had an r2 of 0.624 in the model, and supplementation with the other muscles yielded an r2 of 0.784. Therefore, we propose that a prediction equation could be developed for a certain area in the belly for the evaluation of pork belly quantity and quality. The results could be applied to select breeding stock using techniques such as ultrasound with the aim of producing hogs with large as well as lean bellies. PMID- 29154225 TI - Matrix completion by deep matrix factorization. AB - Conventional methods of matrix completion are linear methods that are not effective in handling data of nonlinear structures. Recently a few researchers attempted to incorporate nonlinear techniques into matrix completion but there still exists considerable limitations. In this paper, a novel method called deep matrix factorization (DMF) is proposed for nonlinear matrix completion. Different from conventional matrix completion methods that are based on linear latent variable models, DMF is on the basis of a nonlinear latent variable model. DMF is formulated as a deep-structure neural network, in which the inputs are the low dimensional unknown latent variables and the outputs are the partially observed variables. In DMF, the inputs and the parameters of the multilayer neural network are simultaneously optimized to minimize the reconstruction errors for the observed entries. Then the missing entries can be readily recovered by propagating the latent variables to the output layer. DMF is compared with state of-the-art methods of linear and nonlinear matrix completion in the tasks of toy matrix completion, image inpainting and collaborative filtering. The experimental results verify that DMF is able to provide higher matrix completion accuracy than existing methods do and DMF is applicable to large matrices. PMID- 29154226 TI - Short-term exposures to PM2.5 and cause-specific mortality of cardiovascular health in China. AB - BACKGROUND: Many multi-center epidemiological studies have robustly examined the acute health effects of exposure to low concentrations of fine particulate matter (PM2.5) on cardiovascular mortality in developed counties. However, data limitations have resulted in few related studies being conducted in developing counties with high levels of PM2.5 exposure. In recent years, people in China with a heavy cardiovascular disease burden have been exposed to particularly high levels of PM2.5. OBJECTIVE: We conducted a multi-county time series study investigating the acute effects of PM2.5 on the increased risk of cardiovascular death across China, and explored subpopulations susceptible to PM2.5 exposure. METHODS: Appling a county-specific Poisson regression in 30 Chinese counties, we estimated PM2.5 effects on all-cause mortality and cause-specific mortality of cardiovascular health for 2013-2015. We also considered PM2.5 effects on several subpopulations, including males, females, and three age groups (< 65, 65-74 and > 74 years old). We pooled the county-specific results across China using a random effects meta-analysis by cause and by subpopulation. RESULTS: We found a 0.13% (95% confidence interval (CI), 0.04-0.22) increase in all-cause mortality, a 0.12% increase (95% CI, 0.001-0.25) increase in cardiovascular disease (CVD), a 0.42% (95% CI, 0.03-0.81) increase in AMI, a 0.17% (95% CI, -0.04-0.40) increase in coronary heart disease, and a 0.13% (95% CI, -0.12-0.33) increase in stroke in association with a 10-MUg/m3 increase in PM2.5 concentrations on the same day. The magnitudes of the associations were less than those reported in developed counties with lower PM2.5 levels. A vulnerable effect on all-cause mortality was observed in the elderly population (older than 65 years) and on CVD in males. CONCLUSIONS: This study showed the positive magnitude of PM2.5 effects with high exposure on all natural, CVD, and cause-specific mortality and on the susceptible populations in China. The findings complemented evidence related to exposure mortality relationships at the higher end of short-term exposure to PM2.5 on a global scale. PMID- 29154227 TI - Generation of integration-free induced pluripotent stem cell line (NJMUi001-A) from a phenylketonuria patient. AB - PKU is a prevalent type of inherited metabolic disease, caused by the defective phenylalanine metabolism. In most PKU cases, mutations in the PAH gene could be found. Dysfunction of this hepatic enzyme will lead to diverse clinical symptoms due to a failure in converting phenylalanine into tyrosine. Here, we report an integration-free human induced pluripotent stem cell line (NJMUi001-A) generated from peripheral blood mononuclear cells of a PKU patient by using Sendai virus. This iPS cell line has characteristics of pluripotent stem cells and can be used as a useful tool for the investigation of this inherited metabolic disease. PMID- 29154228 TI - Practical prognostic score for predicting the extent of resection and neurological outcome of gliomas in the sensorimotor area. AB - OBJECTIVE: In this prospective study, we assessed the utility of a novel prognostic score (PS) in guiding the surgical strategy of patients with sensorimotor area gliomas. PATIENTS AND METHODS: Form December 2012 to April 2016, we collected data from patients diagnosed with brain gliomas in the sensorimotor area. All the patients had intraoperatively confirmed contiguity or continuity with sensorimotor cortical and subcortical structures. Several clinical and radiological factors were analyzed to generate a PS for each patient (range 1-8). The end-points included the extent of resection (EOR) and neurological outcome (modified Rankin Score; mRS). We assessed the predictive power of the PS using different analyses. Crosstabs analyses and Fisher's exact test (Fet) were used to evaluate the possible predictive parameters, and for the classification of positive or negative outcomes for the chosen proxies; the significance threshold was set at p<0.05. RESULTS: Using independent t-tests, we compared the mRS at different time points (pre, post, and at 6 months) for 2 subgroups from the total sample using a cut-off PS value of 4. For the EOR, a PS value of >=5 was predictive of successful outcome, a value of 4 indicated an uncertain outcome, and a value of <=3 predicted a worse outcome. CONCLUSIONS: This PS value can be easily used in clinical settings to help predict the functional outcome and EOR in sensorimotor area tumors. Integration with information from fMRI, DTI, and TMS, along with MRI spectroscopy could further enhance the value of this PS. PMID- 29154229 TI - Iliac Fascia Compartment Block and Analgesic Consumption in Patients Operated on for Hip Fracture. AB - BACKGROUND: Fractures of the proximal femur in elderly patients are a challenge for orthopedics, anesthe-sio-logy and geriatrics. Early mobilization reduces postoperative mortality among these patients. Effective anal-gesia is necessary to achieve this goal. MATERIAL AND METHODS: A retrospective analysis of perioperative medical records of 78. patients undergoing surgical treatment of proximal femur fractures was performed. Group 1 (n=35)consisted of patients who were treated with pharmacologic analgesia only (systemic analgesics) and Group 2 (n=43) involved patients who re-ceived a preoperative fascia iliaca compartment block (FICB) and pharmacologic analgesia. FICB was per-formed under ultrasound guidance, and systemic analgesics were administered according to a standardized pro-to-col. Demographics, anesthesia and operation data as well as the dosage of analgesics used on postoperative day 0 were collected for the study. RESULTS: Patients with antecedent iliac fascia blockade required fewer analgesic interventions (3 vs. 11, p <0.0001) and showed significantly less need for analgesics than non-block patients. No complications were observed after performing FICB. CONCLUSION: The iliac fascia compartment block produces effective postoperative analgesia and reduces postoperative opioid consumption. PMID- 29154230 TI - Use of Kinesiology Taping in Rehabilitation after Knee Arthroplasty: a Randomised Clinical Study. AB - BACKGROUND: Proprioception and body balance after knee arthroplasty have a considerable impact on restoration of joint function and a normal gait pattern. Kinesiology Taping (KT) is a method that may be able to influence these factors. The aim of this study was to assess the effects of KT application on sensorimotor efficiency, balance and gait in patients undergoing rehabili-ta--tion after knee replacement surgery. MATERIAL AND METHODS: The study involved 120 male and female patients (mean age was 69 years) after total knee repla-cement. The patients were randomly assigned to one of two groups: Experimental Group (n=51) and Control Group (n=60). Both groups underwent standard rehabilitation lasting 20 days. In addition, the Experimental Group received KT applications. Treat-ment outcomes were assessed based on tests evaluating balance, joint position sense and functional gait performance, conducted both before and after the therapy. RESULTS: Statistically significant improvements were noted across all the parameters assessed in the Experimental Group (p<0.005). Significant improvements were also seen in the Control Group (p<0.005), but, in percentage terms, the improvement was higher in the Experimental Group. The only exception was the right/left foot load distribution, whose symmetry improved proportionally in both groups. CONCLUSIONS: 1. Patients after knee replacement surgery have considerable proprioception deficits, impaired body balance and reduced functional performance, which may increase the risk of falls in this group of patients. 2. Both standard physiotherapy and combination therapy with Kinesiology Taping (modified by the present authors) used in patients after knee arthroplasty may considerably improve the level of proprioception, body balance and overall functional performance. 3. The technique of dynamic taping proposed in this paper may optimise standard physiotherapy used in patients after knee arthroplasty and increase its clinical efficacy. Further studies are required. PMID- 29154231 TI - Avascular Necrosis of Femoral Condyles in a Patient Treated Due to Lymphoma. A Case Study. AB - Periarticular avascular osteonecrosis is one of the most severe joint diseases and may result in complete joint destruction. It may affect patients after chemotherapy involving regimens including steroids. The paper describes the case of a female patient who was just under 18 years old when she underwent surgery due to bilateral osteonecrosis of the femoral condyles that developed in the course of treatment of a haematological malignancy. The aim of the paper is to present clinical and imaging-based assessment of the outcome of surgical treatment by reconstruction of osteochondral joint defects with a collagen membrane and bone grafts. In this patient, radiographic and clinical improvement of the joints treated was noted in a 24-month follow-up period. The available literature indicates that this is the first example of using this technique in the treatment of articular lesions associated with osteonecrosis caused by aggressive chemotherapy. The so-called "sandwich" technique is useful in these cases and may be recommended by the present authors. PMID- 29154232 TI - Radial Extracorporeal Shockwave Therapy and Ultrasound Therapy in the Treatment of Tennis Elbow Syndrome. AB - BACKGROUND: Both ultrasound and radial shockwave therapies are used to treat tennis elbow syndrome. The aim of this study was to compare the therapeutic efficacy of both therapies by assessing the reduction in pain intensity and frequency, restoration of mobility, and reduction in the need for pain medication. MATERIAL AND METHODS: The study enrolled 60 people, who were randomly divided into two groups of 30 patients: those treated by radial shockwave therapy and those treated by ultrasound therapy. Radial shockwave therapy consisted of 3 sessions at weekly intervals. Ultrasound therapy consisted of 10 treatments performed daily. The clinical status of the patients before treatment, just after treatment, and after 8 weeks was assessed with the Leitinen questionnaire and a visual analogue scale (VAS). RESULTS: Pain reduction, as assessed by VAS scores, was observed in both groups, who were not different at baseline (p=0.807). While both therapies were effective (p<0.005), mean pain intensity assessed by VAS scores in patients treated by radial shockwave therapy was significantly lower compared to those treated by ultrasound therapy; this relationship was present just after treatment completion (p=0.001) and at 8 weeks after treatment completion (p=0.002). CONCLUSIONS: 1. Both radial shockwave and ultrasound therapies cause a reduction in the intensity and frequency of pain that persists for at least 8 weeks, reducing the need for pain medication and improving the function of the treated upper limb. 2. Ultrasound therapy is less effective than radial shockwave therapy. PMID- 29154233 TI - Objective Assessment of Knee Proprioception and Sensorimotor Function in Patients with Primary Gonarthrosis before and after Knee Replacement. AB - The sensorimotor system is a complicated tool allowing for maintaining body balance and responding to changing environmental conditions to prevent injury. It is difficult to objectively assess the function of balance control mechanisms due to the multidimensional nature of the sensorimotor system and multitude of variables that may interfere with the measurement. The function of the sensorimotor system is considerably compromised in osteoarthritis, including gona rthro-sis. The knee is the second most common location of osteoarthritis, after the hip, and total or partial replacement surgery of the knee joint represents the therapy of choice in advanced stages of the condition. As average life expectancy increases and state-of-the art medical technology develops, the number of total knee replacement surgeries is increasing dramatically and the re education of the sensorimotor system is of fundamental impo-rtance for restoring function in the patients. This paper describes the current methods for objective assessment of proprioception, sensorimotor function and balance in the knee. The current literature is also reviewed to discuss the use of such examinations in pa tients with gonarthrosis before and after knee replacement surgery. PMID- 29154235 TI - The Use of Neurodynamic Techniques in the Conservative Treatment of Carpal Tunnel Syndrome - a Critical Appraisal of the Literature. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is the most common peripheral neuropathy, characterized by the presence of many sensory and motor abnormalities. In the physiotherapy of patients with CTS, neurodynamic tech niques are very common, while the scientific literature does not show clear evidence of beneficial effects obtained by using these techniques. Therefore, the aim of this work was to critically evaluate the use of neurodynamic techniques in the conservative treatment of CTS. MATERIAL AND METHODS: Three electronic databases (MEDLINE, SCOPUS and POL-index) and Google Scholar were queried to find articles. The search terms were combinations of words (in Polish, English and German) contain-ing abbreviated and full versions of the following expressions: carpal tunnel syndrome, CTS, neuromobilization, neurodynamic techniques and manual therapy. RESULTS: Sixteen research papers met the conditions for inclusion in this review. Most of them used different methodologies of therapeutic intervention, making it difficult to interpret the results of individual works. Fourteen studies were randomized trials, one a case-control retrospective study and one was a clinical study without a control group. The most common evaluation variables were pain, nerve conduction, subjective symptoms and function, grip strength, sensation and range of motion. The therapy used neurodynamic techniques carried out by the patient or passive mobilization by the physiotherapist. CONCLUSIONS: 1. A review of existing studies evaluating the effec-tiveness of neurodynamic techniques in the treat-ment of CTS shows that most of them produced beneficial therapeutic effects. 2. Due to a considerable heteroge-n-ei--ty of the parti-cipants, study design and metho-do-logy of thera-peutic interventions, it is difficult to for-mulate a general conclusion. 3. Hence the need arises for further research to assess the effectiveness of neu-ro-dynamic techniques in conservative therapy of CTS based on a similar therapeutic methodology. PMID- 29154234 TI - Activity and Quality of Life after Total Hip Arthroplasty. AB - BACKGROUND: Coxarthrosis is a chronic musculoskeletal condition that causes severe pain and considerable limi-tation of the patient's motor performance. Total hip arthroplasty is one of the most common and effective methods used in the treatment of advanced degenerative changes. The aim of the present study was to evaluate the activity and quality of life of patients after unilateral total hip arthroplasty. MATERIAL AND METHODS: The study was conducted in a group of 189 patients who had undergone unilateral total hip arthroplasty. Goniometry was used to determine the range of motion of both hip joints. Patients' physical ability and pain severity were assessed based on the Harris Hip Score (HHS) questionnaire. RESULTS: The examination of the range of motion in the lower extremities revealed statistically significant diffe-rences in flexion (p<0.01), abduction (p=<0.01), adduction (p<0.01) and external rotation (p<0.01) between the operated and the healthy extremity. The greatest limitation of motion was demonstrated for external rotation (<14 degrees ). Approximately 14% of the patients were not able to perform this motion in their healthy hip joint, while 17.5% of them could not do so in the affected hip joint. Analysis of HHS results (mean = 79 pts) revealed that more than 50% of the patients described their functional ability and quality of life as good and excellent. It was demonstrated that 54% of patients did not suffer from pain, whereas minor or mild pain was noted in 35%. CONCLUSIONS: 1. A subjective clinical assessment of patients after total hip arthroplasty showed that their quality of life had improved. 2. It is necessary to perform physiotherapy after total hip arthroplasty, on both the operated and healthy side. 3. Exacerbation of pain and impaired activity in patients after total hip arthroplasty were associated with the female sex to a considerable extent. PMID- 29154236 TI - Risk factors of pancreatitis after endoscopic sphincterotomy. Review of literature and practical remarks based on approximately 10,000 ERCPs. AB - Post-endoscopic pancreatitis (PEP) is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Depending on the presence of risk factors, PEP can occur in 4,1% to about 43% of patients. According to the European Society of Gastrointestinal Endoscopy (ESGE) guidelines, only three to patient-associated risk factors have been identified: suspected sphincter of Oddi dysfunction (SOD) (OR 4.09), female gender (OR 2.23), and previous pancreatitis (OR 2.46). Another three procedure-associated factors include cannulation attempt duration > 10 minutes (OR 1.76), more than one pancreatic guidewire passage (OR 2.77, CI: 1.79 - 4.30), and pancreatic injection (OR 2.2, CI: 1.60 - 3.01). Importantly, analyses of cumulative risk due to coexistence of several factors emphasize the importance of female sex, difficult cannulation, CBD diameter <5 mm, young age, and many other factors. Unfortunately, studies performed to date have included only small numbers of patients with several co-existing risk factors. Therefore, further analysis of other risk factors and the cumulative risk related to their co-occurrence is necessary. Based on current evidence, special care must be given to patients with several risk factors. Also, care should be given to proper qualification of patients, use of guidewires, early pre cut incision, protective Wirsung's duct stenting, and rectal NSAID administration. PMID- 29154237 TI - Results of home parenteral nutrition in patients with severe inflammatory bowel disease - an alternative for surgery of malnourished patients. AB - INTRODUCTION: In the world, the inflammatory bowel disease affects an increasing number of younger and younger patients, and in some of them parenteral nutrition is an alternative to high-risk surgical intervention due to advancement of the disease and malnutrition. AIM: The aim of the study was to assess the results of home parenteral nutrition in patients with severe bowel inflammatory disease, in whom surgical treatment is associated with high risk of complications. MATERIALS AND METHODS: A retrospective analysis was conducted on 46 patients, who received home parenteral nutrition instead of another surgical intervention. The inclusion criteria included home parenteral nutrition and diagnosis of Crohn's disease or ulcerative colitis. RESULTS: Mean number of complications requiring hospital admission per patient was 1.76, the BMI increased by 4.3 on average [kg/m2]. During parenteral nutrition, the percentage of patients, in whom anti inflammatory or immunosuppressant drugs were completely discontinued, was 17.4%. In the whole group, at least one immunosuppressive drug was discontinued in onefifth of patients. Mean albumin level increased by 2.4 g/L, lymphocyte count dropped by 474 lymphocytes/mm3, and leukocyte count increased by 747.6/mm3. The patients described their condition as good in 87%, and 7.4% of patients were able to work. CONCLUSIONS: Home parenteral nutrition positively affects patient's general condition by increasing BMI and normalizing biochemical test results. The results indicate the need to consider this method as an alternative to surgical intervention in severe bowel inflammatory disease with high perioperative risk, which could reduce the complication rate. PMID- 29154239 TI - Stoppa method - forgotten surgery. AB - Stoppa method - forgotten surgery. PMID- 29154238 TI - CTRC gene polymorphism may increase pancreatic cancer risk - preliminary study. AB - : Pancreatic cancer is often fatal due to delayed diagnosis and treatment difficulties. OBJECTIVE: To analyze selected SPINK1, CTRC, CFTR, and PRSS1 gene mutations in cancer tissue and blood samples of patients with pancreatic tumors. MATERIALS AND METHOD: We enrolled 16 consecutive patients diagnosed with pancreatic tumors. We collected cancer tissue, normal pancreatic tissue, and blood samples for genetic tests. The control group consisted of 419 healthy individuals. Peripheral blood samples were collected from all study participants in EDTA-coated tubes. RESULTS: Out of 16 patients with pancreatic tumors, 12 had pancreatic cancer on microscopic examination (mean age, 60.2 years). The CTRC polymorphism Hetero p.G60=(c.180C>T) was found in 5 patients with pancreatic cancer (41.7% vs. 18.6% in the control group). One patient with pancreatic cancer and a positive family history had the SPINK1 (p.N34S) mutation [8.3% vs. 2.9% (12/419) in the control group]. One patient with pancreatic cancer had the CTRC (p.R254W) mutation [8.3% vs. 1% (4/419) in the control group]. CONCLUSIONS: Our preliminary results show that the CTRC polymorphism p.G60= (c.180C>T) is frequent in patients with pancreatic cancer. However, further research is needed to verify our findings. PMID- 29154240 TI - Polish Consensus on Treatment of Gastric Cancer; update 2017. AB - The "Polish Research on Gastric Cancer" project has been continued since 1986. The main aim of this project, which is a multicenter and interdisciplinary research, is enhancing the treatment results of gastric cancer patients by developing and promoting the use of optimal methods for diagnosis and treatment, both surgical as well as combined. One of the more important achievements of the project is the development and publication of a document named "Polish Consensus on Treatment of Patients with Gastric Cancer", whose first version was published in 1998. Following versions were updated adequately to changing trends in the proceedings in patients with gastric cancer. A scientific symposium on "Polish Consensus on Treatment of Gastric Cancer - update 2016" was held in 3-4 June 2016 in Cracow. During the symposium a panel session was held during which all authors publicly presented the Consensus assumptions to be discussed further. Moreover, the already mentioned session was preceded by a correspondence as well as a working meeting in order to consolidate the position. It has to be underlined that the directions and guidelines included in the Consensus are not the arbitrarily assumed rules of conduct in a legal aspect and as such every doctor/team of doctors is entitled to make different decisions as long as they are beneficial to a patient with gastric cancer. The Consensus discusses as follows: a) recommended qualifications (stage of advancement, pathological, lymph node topography and the extent of lymphadenectomy, division of cancer of the gastroesophageal junction), b) rules for diagnostics including recommendations regarding endoscopic examination and clinical evaluation of the advancement stage, c) recommendations regarding surgical treatment (extent of resection, extent of lymphadenectomy, tactics of proceedings in cancer of the gastroesophageal junction), d) recommendations regarding combined treatment with chemotherapy or radiotherapy, e) place of endoscopic and less invasive surgery in the treatment of gastric cancer. This publication is a summary of the arrangements made in the panel session during the abovementioned scientific symposium in Cracow in 2016. PMID- 29154241 TI - Przerzuty do otrzewnej raka jelita grubego. AB - Czestosc przerzutow do otrzewnej w raku jelita grubego wynosi 5%-15% w przypadku przerzutow synchronicznych i az 40% w przypadku wystapienia wznowy miejscowej. Najlepsze wyniki leczenia uzyskuje sie poprzez skojarzone wykonanie zabiegu cytoredukcyjnego w polaczeniu z dootrzewnowa chemioterapia perfuzyjna w hipertermii (HIPEC). Wyniki takiego leczenia sa zdecydowanie lepsze i pozwalaja na osiagniecie przezyc 5-letnich na poziomie 30%-50%. Zabiegi te wymagaja duzego doswiadczenia w chirurgii jamy brzusznej, sa czasochlonne (sredni czas procedury chirurgicznej wynosi 6-8 godzin) i obarczone powiklaniami zwiazanymi nie tylko z zabiegiem operacyjnym, ale takze podaniem cytostatyku do jamy otrzewnej w podwyzszonej temperaturze (41,5 st. C). Chorzy po zabiegu wymagaja pobytu na oddziale intensywnej terapii, co jest zwiazane z wystapieniem potencjalnych powiklan spowodowanych rozlegloscia zabiegu, dlugoscia procedury chirurgicznej, zastosowaniu chemioterapii w polaczeniu z hipertermia. Prowadzenie pooperacyjne tych chorych wymaga doswiadczenia calego zespolu lekarskiego i pielegniarskiego. Zabiegi cytoredukcyjne w polaczeniu z HIPEC jako wysoce specjalistyczne procedury medyczne powinny byc merytorycznie ocenione pod katem korzysci dlugoterminowych dla chorych i odpowiednio skalkulowane pod wzgledem realnej wysokosci refundacji. Jako procedura zalecana w wytycznych Kionsultanta Krajowego d.s. Chirurgii Onkologicznej oraz wytycznych ESMO, niezbedna jest jej realna wycena i refundacja pokrywajaca jej calkowite srednie koszty. PMID- 29154242 TI - Successful hemihepatectomy following chemotherapy for primary liver lymphoma: case report and review of literature. AB - Non-Hodgkin lymphomas (NHL) comprise a heterogeneous group of B-cell and T-cell neoplasms. Diffuse large B-cell lymphoma (DLBCL), the most common type of NHL, accounts for around 30-40% of NHL cases. However, primary hepatic location of NHLs is rare and constitutes 0.01% of all NHL cases. Due to this rarity and a lack of large randomized trails, it is still unclear what treatment should be used for primary hepatic DLBCLs. In this study, we report of a female patient with primary hepatic DLBCL who was successfully treated with neoadjuvant chemotherapy and surgery. We also shortly review the literature regarding surgical treatments for primary GI tract NHLs. Taking into account our experience and the current literature, surgical treatment with postoperative chemotherapy seems to be a feasible option for patients with focal primary hepatic DLBCLs. PMID- 29154243 TI - Internal hernia following laparoscopic colorectal surgery: single center experience. AB - : Although internal hernias are rare complications of laparoscopic colorectal surgery, they can lead to serious outcomes and are associated with a high mortality of up 20 %. AIM OF THE STUDY: The aim of this study was to describe our experience regarding internal herniation following laparoscopic colorectal surgery. MATERIALS AND METHODS: From 2009 to 2015, more than 1,093 laparoscopic colorectal procedures were performed, and 6 patients developed internal herniation. Data were obtained from patients' charts and reviewed retrospectively. Perioperative course and outcomes were analyzed. RESULTS: All patients were previously operated due to colorectal cancer. Two patients presented with ischemia at laparotomy, and 2 had endoscopic examinations before surgery. One patient was diagnosed with cancer on screening colonoscopy. One patient died after laparotomy. CONCLUSION: Internal herniation that develops following laparoscopic colorectal surgery may be associated with a high mortality. More efforts should be made to identify risk factors of internal herniation, as this could indicate which patients would benefit from closure of mesenteric defects during laparoscopic colorectal surgery. PMID- 29154244 TI - Nutrition accesses among patients receiving enteral treatment in the home environment. AB - : Enteral feeding in the home environment is connected with creating access to digestive tract, and thanks to that, this kind of treatment is possible. The gold standard in enteral nutrition is PEG, other types of access are: nasogastric tube, gastronomy and jejunostomy. In the article 851 patients who were treated nutritionally in the home environment, in the nutrition clinic, Nutrimed Gorny Slask, were analyzed. It was described how, in practice, the schedule of nutrition access looks like in the nutrition clinic at a time of qualifying patients to the treatment (PEG 47,35%, gastronomy 18,91%, nasogastric tube 17,39%,jejunostomy 16,33%) and how it changes among patients treated in the nutrition clinic during specific period of time - to the treatment there were qualified patients with at least three-month period of therapy ( second evaluation: PEG 37,01%, gastrostomy 31,13%, nasogastric tube 16,98%, jejunostomy 15,86%). The structure of changes was described, also the routine and the place in what exchanging or changing nutrition access was analyzed. CONCLUSIONS: The biggest changes in quantity, among all groups of ill people concerned patients with PEG and gastronomy. In most cases the intervention connected with exchanging access to the digestive tract could be implemented at patient's home. PMID- 29154245 TI - An association of the MCP-1 and CCR2 single nucleotide polymorphisms with colorectal cancer prevalence. AB - THE AIM OF THE STUDY: We evaluated the connection between the presence of the 2518 A/G MCP-1 as well as 190 G/A CCR2 polymorphic variants and colorectal cancer (CRC) occurrence. MATERIAL AND METHODS: Study group consisted of subjects with different stages of CRC as well as healthy controls. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: W observed an association between the colorectal cancer and the GG genotype of the -2518 A/G MCP-1 single nucleotide polymorphism. No statistically significant correlation was found between CRC and the 190 G/A CCR2 polymorphism. CONCLUSION: The results of this study support the hypothesis that polymorphism in the MCP-1 gene may contribute to the etiology of colorectal cancer. PMID- 29154246 TI - Do we need changes in the organization of training in the hernia treatment in Poland? A survey on the acknowledgment of the recommendations of international hernia societies by surgeons. AB - In the therapy of an inguinal hernia, there is a huge variety in the way of treating and the choice of surgical technique. Practice shows that the intraoperative improvisation and surgeons' own modifications of the original techniques have become part of routine procedure. No mandatory hernia registration system causes the actual detailed herniology status in our country remains unknown. The aim of the study was to summarize the results of a survey on knowledge of a hernia according to the standards developed by international hernia societies compared with everyday clinical practice. During the International Conference Hernia in Poland, which took place on 10 December 2016 in Zakopane we conducted an interactive session among 106 surgeons dealing with hernias. Surgeons responded to 66 questions about daily surgical practice and decision making in their centers, and 27 questions for the assessment of the world's latest treatment recommendations regarding groin hernias. The most common method of using the implant technique Lichtenstein, used by 91% of doctors. 20% of surgeons in planned operations in adult men routinely uses no mesh technique. Almost 80% of respondents do not apply TEP or TAPP. Only 45.7% of surgeons customize surgical technique to the patient. Only 7 of the 27 analyzed recommendation has been accepted by more than 90% of respondents. 9 of the 27 recommendations were approved by less than half of the surgeons. In the case of 11 recommendations, surgeons simultaneously failed to comply with these recommendations in daily practice. Deficiencies in the system of training and the underfunding of medical procedures cause insufficient TAPP/ TEP availability in Poland in an inguinal hernia. Improvement of the surgeons' knowledge on how to perform surgery. PMID- 29154247 TI - Diagnostic evaluation of neck torsion test in objective examination in patients with vertigo and/or hearing impairment. AB - INTRODUCTION: The aim of the study was to evaluate the neck torsion test in objective examinations of patients with vertigo and/or hearing loss. MATERIAL AND METHODS: The study was conducted in 100 patients, including 54 women and 46 men aged 17-79 years, who were divided into two groups: I - 50 patients, including 30 women and 20 men aged 17-79 years (mean age 49.92 years) with dizziness and/or hearing impairments, and confirmed asymmetry of intracranial vessels, II - 50 patients - the control group, including 24 women and 26 men aged 20-71 years without dizziness and/or hearing disorders and without disturbance in the construction of intracranial vessels. For each patient, the following tests were carried out: subjective, objective otorhinolaryngological, Doppler ultrasound specifying the diameter of vertebral and carotid arteries and the velocity of blood flow in these vessels, audiological diagnostics, including the examination of latency of waves I, III, V of the auditory evoked potentials of the brain stem, otoneurological diagnostics with used the neck torsion test. RESULTS: It appears from the analysis of the material presented that the application of the neck torsion test in the Doppler ultrasound results in the fact that the difference in the mean systolic velocity of blood flow in vertebral artery is higher on the side opposite to the turning of the neck, and the increase in the average diastolic blood flow velocity in the vertebral artery on the side of the test being performed and its reduction on the opposite side in the study group, when compared to the control group. The value of the wave I, II, V latency in the ABR test during the neck torsion test is extended more in the study group than in the controls, on the side of the performed test. The performed neck torsion test in the VNG test increases the occurrence of both, square waves and nystagmus (much higher in the study group than in the controls). CONCLUSION: The application of the neck torsion test in the Doppler ultrasound, ABR and VNG test in patients with vertigo and/or hearing loss means that these tests become functional, thereby increasing their diagnostic value and may be used to monitor the rehabilitation of inner ear disorders. PMID- 29154248 TI - The late results of 4000 Hz frequency bone conduction after tympanoplasty. AB - INTRODUCTION: Surgical treatment of conductive hearing loss runs the risk of damage to the inner ear in the mechanism of acoustic trauma. AIM: The aim of this study was to evaluate the function of the organ of Corti, expressed as bone conduction threshold at the frequency of 4000 Hz for selected operations: mastoidectomy and canal-wall-down procedure. MATERIAL AND METHODS: The material was collected from patients with chronic otitis media in the Department of Otolaryngology and ENT Oncology, Collegium Medicum of Nicolaus Copernicus University in Bydgoszcz in 2004-2009. All patients were examined with pure tone audiometry threshold before surgery and at least three years after surgery. The analyzed group of patients was divided into subgroups depending on the type of operation according to To classification and procedures for resection: mastoidectomy and canal-wall-down procedure. The results were statistically analyzed. RESULTS: In the analyzed period of three years after surgery there was no statistically significant difference between groups, although there were higher values for tympanoplasty type 1 with mastoidectomy compared with tympanoplasty type 1 without mastoidectomy - respectively 25.67 dB and 18.53 dB. In the study, there was no statistically significant the difference in bone conduction threshold for frequency 4000 Hz within the type 2 tympanoplasty according to Tosa comparing canal wall-up and canal-wall-down procedure. CONCLUSIONS: Mastoidectomy or canal-wall-down procedure do not affect the bone conduction threshold for a frequency of 4000 Hz after tympanoplasty in long-term observation. PMID- 29154249 TI - Deep neck infections: review of 263 cases. AB - OBJECTIVES: In patients hospitalized due to deep neck infections (DNIs), to investigate the association between demographic parameters, etiology, and localization of abscesses and/or phlegmons, complications, comorbidities, treatment, and bacterial cultures. METHODS: We analyzed data of 263 patients that were hospitalized from January 1, 2012, to December 31, 2015, due to deep neck space phlegmons and/or abscesses. We performed statistical analysis with the SPSS 22.0 software; statistical significance was set p<0.05. RESULTS: Among the analyzed patients, dental infections were the most frequent, followed by acute phlegmonous pharyngitis. Submandibular space abscesses or phlegmons of the neck were the most frequent complications of these infections. Re-operation was performed in 19.8% of cases, and complications developed in 11% (mostly airway obstruction). DNI complications were less common in smokers than in non-smokers (OR=0.038, p=0.025). DISCUSSION: In our study, dental infections accounted for 70.6% of DNI cases. Thus, our study explains why odontogenic DNIs are the most common DNI type studied in the literature. Poor oral health and odontogenic infections should not be underestimated because they can lead to uncommon but lethal diseases such as descending necrotizing mediastinitis, which requires aggressive surgical treatment and is associated with a mortality rate of 10%-40% despite treatment. The complication developed in 11.4% of cases. In conclusion, oral health and hygiene contribute to DNI development. PMID- 29154250 TI - Functional endoscopic sinus surgery (FESS) in unilateral sinus disease. AB - BACKGROUND: Unilateral sinus disease (USD) occurs in 23 % of all cases. It is believed that it is mainly associated with cancer development. Retrospective data from large rhinological centers show that the most common USD is chronic rhinosinusitis (CRS), followed by mycosis, inverted papilloma and finally cancer, but only in a small percent of cases. THE AIM OF THE STUDY: The analysis of USD in the group of patients who underwent FESS at the secondary referral center. MATERIAL AND METHOD: The retrospective study of patients treated for USD in the Department of Otolaryngology in the Provincial Hospital in Poznan between June 2014 and June 2016. The analysis includes age, sex, the localization of lesions, histopathological and microbiological results, an extension of the surgery and treatment results. RESULTS: Over the analyzed period of time, 415 FESS for chronic sinusitis were performed. In this group, 83 patients underwent surgery for USD. There were 35 women and 48 men.CRS was found in 48 cases, mycosis in nine cases, 12 patients were operated for non-malignant tumors, such as inverted papilloma (9), osteoma (2) and fibrosis tumor(1); seven patients had a choanal polyp and two of them had a foreign body in maxillary sinus - a tooth root lying loose. Four patients were diagnosed with a hypoplastic maxillary sinus and one patient suffered from frontal sinus pyocele. One side endoscopic opening of all sinuses was performed in the group with CRS, endoscopic medial maxillectomy was conducted in patients with inverted papilloma, and an isolated opening of the affected sinus was performed in the cases with mycosis. CONCLUSIONS: USD must be always suspected of malignant degeneration until proven otherwise. Endoscopic sinus surgery with the use of angled scope allows for the removal of even very extensive lesions. In our opinion, the extent of operation is determined by the nature of pathology. While extensive surgery is recommended in patients with inverted papilloma, a limited procedure should be performed in those with isolated mycosis. PMID- 29154251 TI - Long-term effects of laryngeal augmentation with calcium hydroxyapatite under local anaesthesia. AB - Wstep: Cel badania stanowi ocena efektow dlugoterminowych augmentacji krtani w znieczuleniu miejscowym przy pomocy hydroksyapatytu wapnia. Material i metody: W badaniu wzielo udzial 17 pacjentow, ktorzy z powodu niewydolnosci szpary glosni (z powodu jednostronnego porazenia krtani oraz niewydolnosci miesni wewnetrznych krtani) zostali zakwalifikowani do przeprowadzenia augmentacji krtani (10 kobiet i 17 mezczyzn), w wieku: 57,6+/-17,7 lat, mediana 61 lat, z zakresem: 32-83 lata. U wszystkich pacjentow wykonano augmentacje krtani w znieczuleniu miejscowym, przez jame ustna, podajac bocznie od faldu glosowego/ faldow glosowych hydroksyapatyt wapnia (preparat Radiesse). W celu oceny efektow dlugoterminowych augmentacji krtani - przeprowadzano ocene jakosci glosu pacjenta przed augmentacja, a nastepnie 3 i 12 miesiecy po augmentacji krtani, przy pomocy oceny videolaryngostroboskopowej krtani, oceny odsluchowej, analizy akustycznej, oceny aerodynamicznej oraz samooceny glosu dokonanej przez pacjenta przy pomocy kwestionariusza VRQoL. Wyniki: Uzyskano istotna statystycznie poprawe w ocenie odsluchowej glosu dla parametrow G i A, po 3 miesiacach, dobre wyniki utrzymywaly sie w czasie 12-miesiecznej obserwacji. W ocenie akustycznej MDVP_Jitt, MDVP_Shim i MDVP_NHR poprawily sie odpowiednio do wartosci: 2,5; 5 oraz 0,1 (3 miesiace po augmentacji) i 1,9; 3,6 oraz 0,1 (12 miesiace po augmentacji). MPTa wydluzyl sie do 12,2 i 11,9 s., odpowiednio po 3 i 12 miesiacach od augmentacji. Natezenie glosu poprawilo sie z 67 do 68 oraz 71 dB(A), odpowiednio po 3 i 12 miesiacach. Wyniki: VRQoL poprawily sie do wartosci 19,5 i 20, odpowiednio 3 i 12 miesiecy po augmentacji. Dyskusja Augmentacja krtani w znieczuleniu miejscowym przy pomocy hydroksyapatytu wapnia daje dlugotrwale, dobre efekty leczenia. PMID- 29154252 TI - Usage of piezoelectric instruments in larynx surgery. AB - OBJECTIVE: The aim of the study was to estimate usability of the piezoelectric knife in larynx surgery. Prove that the piezoelectric staff can be used to do any different shape incision within the larynx cartilages. MATERIAL AND METHODS: 35 patients hospitalized in our Department in 2014-2016 were enrolled in our study. 24 patients went vertical partial laryngectomy and 1 patient went horizontal partial laryngectomy because of larynx cancer. 5 patients went partial laryngectomy because of low stage of piriformis recess cancer. Piezoelectric staff was used to do thyroidectomy and resection of thyroid cartilage suspected of carcinomatosis infiltration. The rest 4 patients had done widening of larynx lumen due to larynx stenosis or slenderness. The piezoelectric tool was used to do different incision or resection within the larynx cartilages in case of widening lumen of the larynx. RESULTS: The larynx cartilages, especially thyroid cartilage could be cut in different shapes using piezoelectric tools. The usage of this equipment causes the minimal loss and small destruction of local healthy tissues. CONCLUSIONS: The Piezoelectric instrument is useful instrument suit to operate within larynx cartilages. Exchangeable tip available in different shapes enables different resections of cartilages. Using the piezoelectric staff we can remove pathological tissue with minimal local destruction. Our observation shows that larynx operation with a usage of the piezoelectric knife is safe and effective. Current English literature does not describe usage piezoelectric tools in larynx surgery. It is essential to do more observation about that type of operations. PMID- 29154253 TI - 45? sign switching of effective exchange bias due to competing anisotropies in fully epitaxial Co3FeN/MnN bilayers. AB - We report an unusual angular-dependent exchange bias effect in ferromagnet/antiferromagnet bilayers, where both ferromagnet and antiferromagnet are epitaxially grown. Numerical model calculations predict an approximately 45$^?circ$ period for the sign switching of the exchange-bias field, depending on the ratio between magnetocrystalline anisotropy and exchange coupling constant. The switching of the sign is indicative of a competition between a fourfold magnetocrystalline anisotropy of the ferromagnet and a unidirectional anisotropy field of the exchange coupling. This predicted unusual angular-dependent exchange bias and its magnetization switching process are confirmed by measurements on fully epitaxial Co$_3$FeN/MnN bilayers by longitudinal and transverse magneto-optic Kerr effect magnetometry. These results provide a deeper understanding of the exchange coupling phenomena in fully epitaxial bilayers with tailored materials and open up a complex switching energy landscape engineering by anisotropies. PMID- 29154254 TI - Preparation and characterization of self-assembly hydrogels with exfoliated montmorillonite nanosheets and chitosan. AB - Novel montmorillonite-nanosheet/chitosan (MMTNS/CS) hydrogels fabricated via the self-assembly of exfoliated MMTNS and CS chains were investigated. The exfoliation of MMTNS, self-assembly mechanism and structure of MMTNS/CS hydrogels were characterized by an atomic force microscope, scanning electron microscope, transmission electron microscope, Fourier transform infrared spectroscope, energy dispersive x-ray spectroscope and Brunauer-Emmett-Teller analyzer, respectively. The results indicated that MMT could be easily exfoliated to nanosheets with a thickness of 1 ~ 5 nm in aqueous solution by an ultrasonic base upon interlayer hydration. The formation mechanism of the self-assembly hydrogels was due to the hydrogen bond (-OH ... +NH3-) and electrostatic interaction between the MMTNS and CS. The MMTNSs were connected consecutively by CS in-plane to form a huge slice. The porous structure of the hydrogels was controllable by adjusting the MMTNS/CS mass ratio. The hydrogels could be used as adsorbents for sewage treatments, carriers for drugs, microorganisms and catalyzers due to their controllable porous structure and tremendous specific surface area which were derived from the completely exfoliated MMTNS. PMID- 29154255 TI - Trial latencies estimation of event-related potentials in EEG by means of genetic algorithms. AB - OBJECTIVE: Event-related potentials (ERPs) are usually obtained by averaging thus neglecting the trial-to-trial latency variability in cognitive electroencephalography (EEG) responses. As a consequence the shape and the peak amplitude of the averaged ERP are smeared and reduced, respectively, when the single-trial latencies show a relevant variability. To date, the majority of the methodologies for single-trial latencies inference are iterative schemes providing suboptimal solutions, the most commonly used being the Woody's algorithm. APPROACH: In this study, a global approach is developed by introducing a fitness function whose global maximum corresponds to the set of latencies which renders the trial signals most aligned as possible. A suitable genetic algorithm has been implemented to solve the optimization problem, characterized by new genetic operators tailored to the present problem. MAIN RESULTS: The results, on simulated trials, showed that the proposed algorithm performs better than Woody's algorithm in all conditions, at the cost of an increased computational complexity (justified by the improved quality of the solution). Application of the proposed approach on real data trials, resulted in an increased correlation between latencies and reaction times w.r.t. the output from RIDE method. SIGNIFICANCE: The above mentioned results on simulated and real data indicate that the proposed method, providing a better estimate of single-trial latencies, will open the way to more accurate study of neural responses as well as to the issue of relating the variability of latencies to the proper cognitive and behavioural correlates. PMID- 29154256 TI - Patient doses from medical examinations in Russia: 2009-2015. AB - The aim of this study was to evaluate adult patient doses in Russia in the context of patient protection. Effective doses from x-ray and nuclear medicine examinations were assessed using two approaches. The first was based on data collection performed by the authors in hospitals in St. Petersburg and other 17 Russian regions. The second approach was to assess mean doses through the collective dose estimated annually within the federal data bank ESKID. In 2015, 203 million examinations were conducted in Russia, i.e. 1.4 examinations per capita. The number of examinations has increased by 35% over the last 10 years. Patient doses from x-ray examinations are strongly dependent on the imaging modality. Mean dose increases by an order of magnitude with each x-ray modality from dental examinations (0.01-0.1 mSv) to radiography (0.1-1 mSv), fluoroscopy and CT (1-10 mSv) and to interventional examinations (more than 10 mSv). Mean doses for x-ray examinations are comparable with that of foreign countries. Scintigraphy examinations with 99mTc are associated with mean doses of 1-5 mSv. Mean doses from PET/CT whole body examinations are 15-25 mSv with similar contributions from CT and radiopharmaceuticals. In nuclear medicine, patient doses are lower compared to other countries. According to ESKID data the collective dose from medical exposure in Russia has decreased from 140 000 man-Sv in 2000 to 77 000 man-Sv in 2015. Medical exposure contributes about 13% into a total collective dose. The maximum contribution was from CT examinations, i.e. 45% in 2015. A range of mean doses between different hospitals was up to two orders of magnitude for radiography and one order of magnitude for CT. In interventional studies, the scatter of individual doses was significant. Significant variations in doses between hospitals and some regions indicate the potential for optimization with the focus on interventional examinations, CT and nuclear medicine examinations combined with CT. PMID- 29154257 TI - Low-field induced large magnetocaloric effect in Tm2Ni0.93Si2.93: influence of short-range magnetic correlation. AB - In this work, we report the successful synthesis of a new intermetallic compound Tm2 [Formula: see text] [Formula: see text] that forms in single phase only in defect crystal structure. The compound does not show any long range magnetic ordering down to 2 K. The material exhibits a large magnetic entropy change ([Formula: see text] J [Formula: see text] K-1) and adiabatic temperature change ([Formula: see text] K) at 2.2 K for a field change of 20 kOe which can be realized by permanent magnets, thus being very beneficial for application purpose. In the absence of long-range magnetic ordering down to 2 K, the metastable nature of low-temperature spin dynamics and short-range magnetic correlations are considered to be responsible for such a large magnetocaloric effect over a wide temperature region. PMID- 29154258 TI - Prediction of dose to the relatives of patients treated with radioiodine-131 using neural networks. AB - In this study, the effective dose received by the family members and caregivers of 52 thyroid cancer patients, who had been treated with radioiodine I-131, was measured to investigate the ability of the neural network to predict the doses to the relatives. The effectiveness of this method to predict the relatives who will receive doses of more than 1 mSv was evaluated. The effective doses were measured by TLD. The inputs of the neural network include 13 different parameters that can potentially affect the dose, and the output was the dose to the family members. The neural networks in this study were feed-forward with a sigmoid activation function and one hidden layer. The mean and median of the measured doses were 0.45 and 0.28 mSv and its range was 0.1-3.64 mSv. The mean square error of the predicted doses by the neural network and the measured doses by TLD (mean squared error) for 99 individuals was 0.142. The optimum neural network was able to predict all the relatives who received doses of more than 1 mSv. The area under the receiver operating characteristic curve for the trained neural network was 0.957, showing its ability to distinguish these groups. Predicting the dose to a patient's relatives before release is a helpful strategy for future optimisation. Using neural networks is a promising method for predicting the dose to the family members and defining high-risk patients and relatives. Patient-specific criteria for release and patient-specific advice and consultation can be used to reduce the dose to each family member. PMID- 29154259 TI - Evaluation of coefficients to derive organ and effective doses from cone-beam CT (CBCT) scans: a Monte Carlo study. AB - Regular imaging is used throughout image guided radiation therapy to improve treatment delivery. In order for treatment procedures to be optimized, the doses delivered by imaging exposures should be taken into account. CT dosimetry methods based on the CT dose index (CTDI), measured with a 100 mm long pencil ionization chamber (CTDI100) in standard phantoms, are not designed for cone-beam CT (CBCT) imaging systems used in radiotherapy, therefore a modified version has been proposed for CBCT by the International Electrotechnical Commission (CTDIIEC). Monte Carlo simulations based on a Varian On-Board Imaging system were used to derive conversion coefficients that enable organ doses for ICRP reference phantoms to be determined from the CTDIIEC for different scan protocols and different beam widths (80-320) mm. A dose-width product calculated by multiplying the CTDIIEC by the width of the CBCT beam is proposed as a quantity that can be used for estimating effective dose. The variation in coefficients with CBCT beam width was studied. Coefficients to allow estimation of effective doses were derived, namely 0.0034 mSv (mGy cm)-1 for the head, 0.0252 mSv (mGy cm)-1 for the thorax, 0.0216 mSv (mGy cm)-1 for the abdomen and 0.0150 mSv (mGy cm)-1 for the pelvis, and these may be applicable more generally to other CBCT systems in radiotherapy. If data on effective doses are available, these can be used in making judgements on the contributions to patient dose from imaging, and thereby assist in optimization of the treatment regimes. The coefficients can also be employed in converting dosimetry data recorded in patient records into quantities relating directly to patient doses. PMID- 29154260 TI - Spectral windows analysis method for monitoring anthropogenic radionuclides in real-time environmental gamma-ray scintillation spectrometry. AB - This paper proposes an analysis methodology based on the spectral windows technique aimed for environmental real-time gamma-ray spectra obtained with scintillation detectors. The method permits us to monitor activity concentrations of selected isotopes, such as anthropogenic radionuclides like 137Cs and 131I, by removing the Compton scattering plus other external contributions and resolving peak overlapping within any window. Activity concentrations are presented for 137Cs, 131I, 214Bi, and 214Pb when applying the method to a monitor using a LaBr3(Ce) detector. The method avoids false-positive and false-negative results of anthropogenic radionuclides in the presence of radiation from natural origins by obtaining activity concentrations that correspond to those obtained by a Gaussian fitting commercial software. PMID- 29154261 TI - Electrical impedance of the torso is associated with the pressure pain threshold on myofascial trigger points in patients with chronic neck pain: A cross sectional study. AB - BACKGROUND: Myofascial trigger points are dysfunctional structures present in skeletal muscles and are related to sensory, motor, and autonomic changes. Despite scientific advances in recent decades in the measurement of musculoskeletal pain, evaluation of this clinical phenomenon is supported with instruments that, although valid and reliable, have a considerable degree of subjectivity. OBJECTIVE: To correlate electrical impedance of the upper limbs and torso with pain intensity, functional capacity, catastrophizing, pressure pain threshold, and skin temperature on myofascial trigger points in the upper trapezius muscle of patients with neck pain. METHODS: A single-blind cross sectional study. Twenty-eight volunteers of both genders were included in the study, were aged 18-45 years, and had chronic neck pain and myofascial trigger points in the upper trapezius. The volunteers were assessed using the Numeric Rating Scale, the Neck Disability Index, the Pain-Related Self-Statement Scale, algometry, infrared thermography, and electrical bioimpedance. RESULTS: The following significant results were observed: a negative association between the pressure pain threshold on myofascial trigger point in the right upper trapezius and electrical impedance of the torso at 5 kHz (rs=-0.392, p= 0.032), 50 kHz (rs= 0.406, p= 0.026), 250 kHz (rs=-0.388, p= 0.034), and to the frequency 500 kHz (rs=-0.444, p= 0.014). CONCLUSION: Electrical impedance of the torso is associated with the pressure pain threshold of myofascial trigger points on the upper trapezius of individuals with neck pain. Thus, individuals with a lower pressure pain threshold have higher electrical impedance values of the torso and vice versa. PMID- 29154262 TI - Review of scapular movement disorders among office workers having ergonomic risk. AB - BACKGROUND: Work-related musculoskeletal disorders are the most common health problems which affect millions of office workers. OBJECTIVE: The objective of this study is to determine scapular positioning at rest and different anatomical planes, the assessment of pain, postural changes and the functionality of upper extremity that is caused by the lack of ergonomic principles among office workers of civil servants in TRNC (Turkish Republic of Northern Cyprus). METHODS: 183 individuals participated in the study and 2 groups were created by grand scores of Rapid Upper Limb Assessment (RULA) tool. Scapular dyskinesis, pain of upper extremity and back, physical functions and symptoms of upper extremity, the self rated neck disability, cervical and upper thoracic posture of workers were assessed. RESULTS: The difference between pain situation and the results of upper extremity and neck disability scores of the participants among the groups was significant (p< 0.05). No significant difference has been found statistically among the postural angle values of individuals (p> 0.05). A significant statistical difference has been found among the groups when the results of Lateral Scapular Slide Test (LSST) is examined (p< 0.05). CONCLUSIONS: Working environment and conditions cause the wrong of working posture and thus, lead individuals to spend more energy together with physical difficulty, and consequently affect general health. PMID- 29154263 TI - The effectiveness of proprioceptive and neuromuscular training compared to bracing in reducing the recurrence rate of ankle sprains in athletes: A systematic review and meta-analysis. AB - BACKGROUND: Ankle sprains are common musculoskeletal injuries in which the ligaments of the ankle partially or completely tear due to sudden stretching. OBJECTIVES: To critically appraise, evaluate and establish the best available evidence to determine the effectiveness of proprioceptive and neuromuscular training (PNT) compared to bracing in reducing the recurrence rate of ankle sprains in athletes. METHODOLOGY: The following seven databases were searched in June 2017: PubMed, Cochrane Library, PEDro, ScienceDirect, Scopus, SPORTDiscus, EBSCO Host: CINAHL. The main search terms used were "ankle sprains", "proprioceptive training", "neuromuscular training" and "bracing". The quality of the trials were critically appraised according to the PEDro scale. The RevMan 5(c) software was used to pool results. RESULTS: Three studies met the inclusion criteria and the quality according to the PEDro scale ranged from 4/10-7/10. The pooled data showed no difference between PNT and bracing in reducing the recurrence rate of ankle sprains in athletes at 12 months after initiation of the study. CONCLUSION: This systematic review of the overall effect suggested that current evidence (Level II) does not favour the use of PNT over bracing in reducing the recurrence rate of ankle sprains. Physiotherapists are advised to use either PNT or bracing according to the patients preference and their own expertise. PMID- 29154264 TI - The effect of a single massage based on the tensegrity principle on postural stability in young women. AB - OBJECTIVE: The aim of this study was to investigate the effects of normalized muscle tension via tensegrity-based massage on postural stability in a sample of female young adults. METHODS: Nineteen females aged 21.8 +/- 1.9 years were recruited presenting abnormal tension at muscles adhering to any of the following structural sites: superior iliac spine, lateral sacropelvic surface, linea aspera at 1/2 of femur length, and superior nuchal line of the occiput. Balance and postural control were assessed during bipedal stance using a force platform in multiple conditions: hard surface or soft foam surface with the head in either a neutral posture or tilted backward. Baseline and 3-min and 15-min post-treatment measures were collected while barefoot and eyes closed. Main outcomes measures included center of pressure variability, range, radius, and velocity in the anteroposterior (AP) mediolateral (ML) dimensions. RESULTS: In the solid surface with neutral head posture condition only AP COP measures decreased significantly (p< 0.05). In the soft surface condition, significant differences were observed in the AP and ML dimensions among most measures (p< 0.05). CONCLUSIONS: A single application of tensegrity-based massage positively influenced postural control in young adult females, particularly in the AP direction. PMID- 29154265 TI - Analysis of correlation between degeneration of lower lumbar paraspinal muscles and spinopelvic alignment in patients with osteoporotic vertebral compression fracture. AB - BACKGROUND: A few studies have pointed that trunk extensors may affect the spinopelvic alignment; however, little is known about the exact association between degeneration of lower lumbar paraspinal muscles and spinopelvic parameters. OBJECTIVE: The study aimed to analyze the relationship between degeneration of lower lumbar paraspinal muscles and spinopelvic alignment in patients with osteoporotic vertebral compression fracture (OVCF). METHODS: Thirty nine OVCF patients were involved in this study. All patients underwent a standing lateral radiographs of the entire spine and pelvis 6 months after kyphoplasty. Pelvic incidence, pelvic tilt, lower lumbar lordosis (LLL) were measured. On the MRI images, the cross-sectional areas of the erector spinae (ES), multifidus (MF), vertebral body and the signal intensity of ES, MF, subcutaneous fat were measured. Pearson's correlation coefficients was applied to analyze the correlation between the muscular degeneration degree (muscular atrophy and fatty infiltration) and spinopelvic parameters. RESULTS: The fatty change degree of ES at L4 inferior endplate level was positively correlated with pelvis retroversion (r= 0.480, p< 0.05). The grade of fat infiltration of ES plus MF at L5 level was negatively related to LLL (r=-0.446, p< 0.05). The fatty change of ES at L5 level, atrophy of ES at L4 and L5 level did not correlate with pelvis back tilt. The fat infiltration of ES plus MF at L4 level, the atrophy degree of ES plus MF at L4 and L5 level had no correlation with LLL. CONCLUSIONS: With the increase of fatty infiltration of the erector spinae, the degree of pelvis retroversion increases; the lower lumbar lordosis decreases with the increase of intramuscular adipose tissue of the erector spinae plus multifidus. The atrophy degree of the erector spinae and multifidus is not correlated with pelvis back tilt and lower lumbar lordosis. PMID- 29154266 TI - Rehabilitation of neglected Monteggia fracture: Dislocations in children. AB - PURPOSE: There are limited studies related to the rehabilitation of neglected Monteggia fracture-dislocations. This study reports the results of the rehabilitation of neglected Monteggia fractures and dislocations and the best treatment options available. MATERIAL AND METHODS: Thirteen children were rehabilitated between 2009 and 2012. A retrospective chart review was conducted to record the following: age, gender, anatomic region of fractures, time delay from symptom onset to fracture, Bado classification, Mayo Elbow Performance Index (MEPI) which includes pain, range of motion and daily life comfort, surgeries, length of hospitalization, location and pattern of fracture, length of follow-up and complications. RESULTS: The study group included thirteen children and adolescents; eleven males and two females with a mean age of 8.5 (range 2-15) years. According to the Bado classification, 11 patients had type 1, one had type 3 and one had type 4 fracture-dislocations. For Mayo Elbow Performance Index (MEPI) scales, patients that were less than ten years old had greater mean scores. Two patients had superficial infection, one had subluxation, one had osteoarthritis, one had delayed bone union and two had rigidity at the elbow. CONCLUSION: The goals of elbow rehabilitation following Neglected Monteggia cases include restoring function by restoring motion and muscle performance; influencing scar remodeling and preventing joint contracture; and restoring or maintaining joint stability. Patients aged younger than 10 years and intervals of less than one-year, between trauma and diagnosis, as well as early and effective rehabilitation were found as important parameters regarding favorable outcomes. PMID- 29154267 TI - Test-retest reliability and validity of a motion capture (MOCAP) system for measuring thoracic and lumbar spinal curvatures and sacral inclination in the sagittal plane. AB - OBJECTIVE: To evaluate the test-retest reliability and validity of the MOCAP system for measuring spinal sagittal thoracic and lumbar curvatures and sacral inclination in a standing posture. METHODS: Twenty-five male adults were evaluated on lateral standing radiographs. The thoracic and lumbar curvatures were calculated by Harrison's posterior tangent method. The sacral inclination was defined as the angle between the tangent line of the sacral and vertical plane. In addition, MOCAP was used to calculate the spinal curvatures and sacral inclination. RESULTS: The thoracic and lumbar spine and sacral inclination demonstrated excellent reliability, with mean ICCs levels greater than 0.980 and low CVs (mean: 2.15%). Systematic biases were not significant and were very near 0, and the mean standard errors were 0.257?. ANOVA of the radiographic and MOCAP measures did not report any statistically significant differences in the comparisons. The systematic biases and mean random errors were lower than 1?, with CVs lower than 5% and mean ICCs higher than 0.90 between sessions. CONCLUSION: The MOCAP system delivered consistently reliable and valid results for standing curvatures compared with a radiographic technique. This system could be used with confidence in research and clinical environments for sagittal spinal curvature measurements. PMID- 29154268 TI - Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. AB - BACKGROUND: Effectiveness of Alzheimer's disease (AD) treatments may depend critically on the timeliness of intervention. OBJECTIVE: To compare characteristics and outcomes of patients diagnosed with probable AD (prAD) based on time elapsed from first onset of cognitive decline. METHODS: Patients with >=1 prAD diagnosis and >=1 follow-up visit were selected from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS; 9/2005-6/2015) and stratified based on the time between the perceived onset of cognitive decline at baseline and first prAD diagnosis (i.e., earlier versus later diagnosis). Characteristics at baseline and prAD diagnosis, clinically meaningful progression, and medication use following prAD diagnosis were compared. RESULTS: Median time from perceived onset of cognitive decline to prAD diagnosis was 4.5 years (earlier diagnosis: <=3.46; later diagnosis: >5.71). Earlier-diagnosed patients (n = 1,476) were younger at baseline (74.3 versus 76.3 years) and had better cognitive and functional scores than later-diagnosed patients (n = 1,474). At first prAD diagnosis, earlier-diagnosed patients had lower mean global Clinical Dementia Rating (CDR) score (0.8 versus 1.1), higher mean Mini-Mental State Examination (MMSE) (22.6 versus 20.0), and lower mean Functional Activities Questionnaire (11.6 versus 17.3). Earlier- and later-diagnosed patients experienced similar time to a decrease of >=3 points in MMSE (median 23.2 versus 23.1 months, p = 0.83), but earlier-diagnosed patients had longer time to a CDR score of >=2 points, and longer times to initiation of AD medication and antipsychotic agents (all p < 0.01). CONCLUSION: Earlier prAD diagnosis in NACC data is associated with higher cognitive function and lower functional impairment at diagnosis. PMID- 29154269 TI - Early and Persistent O-GlcNAc Protein Modification in the Streptozotocin Model of Alzheimer's Disease. AB - O-GlcNAc transferase (OGT), an enzyme highly expressed in brain tissue, catalyzes the addition of N-acetyl-glucosamine (GlcNAc) to hydroxyl residues of serine and threonine of proteins. Brain protein O-GlcNAcylation is diminished in Alzheimer's disease (AD), and OGT targets include proteins of the insulin signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1). We hypothesized that ICV streptozotocin (STZ) also affects O-GlcNAc protein modification. We investigated hippocampal metabolic changes in Wistar rats, particularly OGT levels and insulin resistance, as well as related astroglial activities, immediately after ICV STZ administration (first week) and later on (fourth week). We found an early (at one week) and persistent (at fourth week) decrease in OGT in the ICV STZ model of AD, characterized by a spatial cognitive deficit. Consistent with this observation, we observed a decrease in protein O-GlnNAc modification at both times. Increased phosphorylation at serine-307 of IRS-1, which is related to insulin resistance, was observed on the fourth week. The decrease in OGT and consequent protein O-GlnNAc modifications appear to precede the decrease in glucose uptake and increment of the glyoxalase system observed in the hippocampus. Changes in glial fibrillary acidic protein and S100B in the hippocampus, as well as the alterations in cerebrospinal fluid S100B, confirm the astrogliosis. Moreover, decreases in glutamine synthetase and glutathione content suggest astroglial dysfunction, which are likely implicated in the neurodegenerative cascade triggered in this model. Together, these data contribute to the understanding of neurochemical changes in the ICV STZ model of sporadic AD, and may explain the decreases in protein O-GlcNAc levels and insulin resistance observed in AD. PMID- 29154270 TI - Ubisol-Q10 (a Nanomicellar Water-Soluble Formulation of CoQ10) Treatment Inhibits Alzheimer-Type Behavioral and Pathological Symptoms in a Double Transgenic Mouse (TgAPEswe, PSEN1dE9) Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ~6 mg/kg/day) reduced circulating amyloid-beta (Abeta) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Abeta plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD. PMID- 29154271 TI - Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies? AB - Low tissue levels of the major marine omega3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these omega3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism. PMID- 29154272 TI - Differences in Synaptic Dysfunction Between rTg4510 and APP/PS1 Mouse Models of Alzheimer's Disease. AB - Genetically modified mice have provided insights into the progression and pathology of Alzheimer's disease (AD). Here, we have examined two mouse models of AD: the rTg4510 mouse, which overexpresses mutant human Tau gene, and the APP/PS1 mouse, which overexpresses mutant human genes for amyloid precursor protein and presenilin 1. Both models exhibit deficits in hippocampal function, but comparative analyses of these deficits are sparse. We used extracellular field potential recordings in hippocampal slices to study basal synaptic transmission (BST), paired-pulse facilitation (PPF), and long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapses in both models. We found that 6 7, but not 2-3-month-old rTg4510 mice exhibited reduced pre-synaptic activation (fiber volley (FV) amplitude, ~50%) and field excitatory post-synaptic potential (fEPSP) slope (~40%) compared to wild-type controls. In contrast to previous reports, BST, when controlled for FV amplitude, was not altered in rTg4510. APP/PS1 mice (2-3 mo and 8-10 mo) had unchanged FV amplitude compared to wild type controls, while fEPSP slope was reduced by ~34% in older mice, indicating a deficit in BST. PPF was unchanged in 8-10-month-old APP/PS1 mice, but was reduced in 6-7-month-old rTg4510 mice. LTP was reduced only in older rTg4510 and APP/PS1 mice. Our data suggest that BST deficits appear earlier in APP/PS1 than in rTg4510, which exhibited no BST deficits at the ages tested. However, FV and synaptic plasticity deficits developed earlier in rTg4510. These findings highlight fundamental differences in the progression of synaptic pathology in two genetically distinct models of AD. PMID- 29154273 TI - Association between alpha-Klotho and Deep White Matter Lesions in the Brain: A Pilot Case Control Study Using Brain MRI. AB - BACKGROUND: The anti-aging protein, alpha-Klotho, may be involved in cognitive decline and has potential as a surrogate marker that reflects dementia. However, the role of alpha-Klotho in the brain has not been sufficiently investigated. OBJECTIVE: Here, we investigated the association between alpha-Klotho and cognitive decline that is associated with cerebral deep white matter lesions (DWMLs). METHODS: Two hundred-eighty participants (187 males and 93 females, mean age: 70.8 years old) were evaluated for DWMLs, and the Fazekas scale (Grade) was assessed following brain magnetic resonance imaging. A questionnaire concerning lifestyle and neuropsychological tests was administered, and their associations with the blood alpha-Klotho level were retrospectively investigated. RESULTS: The alpha-Klotho level was 685.1 pg/mL in Grade 0 (68 subjects), 634.1 in G1 (134), 596.0 in G2 (62), and 571.6 in G3 (16), showing that the level significantly decreased with advanced grades. Significant correlations were noted between the alpha-Klotho level and higher brain function tests including the Mini-Mental State Examination and word fluency tests (p < 0.05). When a 90th percentile value of the level in the G0 group (400 pg/mL) or lower was defined as a low alpha Klotho level, the odds ratio of the high-grade G3 group was 2.9 (95% confidence interval: 1.4-7.8) (after correction for age, sex, hypertension, and chronic kidney disease), which was significant. CONCLUSION: A reduced blood alpha-Klotho level was correlated with grading of cerebral DWMLs and was accompanied by cognitive decline as an independent risk factor. The alpha-Klotho level may serve as a useful clinical index of vascular cognitive impairment. PMID- 29154274 TI - Cognitive Decline in Preclinical Alzheimer's Disease: Amyloid-Beta versus Tauopathy. AB - We perform a large-scale meta-analysis of 51 peer-reviewed 3xTg-AD mouse publications to compare Alzheimer's disease (AD) quantitative clinical outcome measures, including amyloid-beta (Abeta), total tau, and phosphorylated tau (pTau), with cognitive performance in Morris water maze (MWM) and Novel Object Recognition (NOR). "High" levels of Abeta (Abeta40, Abeta42) showed significant but weak trends with cognitive decline (MWM: slope = 0.336, R2 = 0.149, n = 259, p < 0.001; NOR: slope = 0.156, R2 = 0.064, n = 116, p < 0.05); only soluble Abeta or directly measured Abeta meaningfully contribute. Tau expression in 3xTg-AD mice was within 10-20% of wild type and not associated with cognitive decline. In contrast, increased pTau is directly and significantly correlated with cognitive decline in MWM (slope = 0.408, R2 = 0.275, n = 371, p < < 0.01) and NOR (slope = 0.319, R2 = 0.176, n = 113, p < 0.05). While a variety of pTau epitopes (AT8, AT270, AT180, PHF-1) were examined, AT8 correlated most strongly with cognition (slope = 0.586, R2 = 0.521, n = 185, p < < 0.001). Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Abeta. Despite pTau's lower physical concentration than Abeta, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline. pTau's contribution to neurofibrillary tangles well after Abeta levels plateau makes pTau a viable treatment target even in late-stage clinical AD. Principal component analysis, which included hyperphosphorylation induced by kinases (pGSK3beta, GSK3beta, CDK5), identified phosphorylated ser9 GSK3beta as the primary contributor to MWM variance. In summary, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Abeta. Nonetheless, complex AD interactions dictate successful therapeutics harness synergy between Abeta and pTau, possibly through the GSK3 pathway. PMID- 29154275 TI - Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease. AB - BACKGROUND: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD). OBJECTIVE: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid beta and Tau. Additionally, we explore whether any such association differs by sex or APOE E4 genotype. METHODS: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66+/-9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-beta1-42, total (t-)Tau, and phosphorylated (p-)Tau. RESULTS: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p>=0.131). Importantly, however, we observed effect modification by sex and APOE E4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE E4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029). CONCLUSION: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE E4 genotype when assessing the role of insulin. PMID- 29154276 TI - SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging. AB - We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging. PMID- 29154278 TI - Effects of Physical Exercise on Alzheimer's Disease Biomarkers: A Systematic Review of Intervention Studies. AB - Physical exercise may be an important adjunct to pharmacological treatment of Alzheimer's disease (AD). Animal studies indicate that exercise may be disease modifying through several mechanisms including reduction of AD pathology. We carried out a systematic review of intervention studies of physical exercise with hippocampal volume (on MRI), amyloid-beta, total tau, phosphorylated tau in cerebrospinal fluid (CSF), 18F-FDG-PET or amyloid PET as outcome measures in healthy subjects, patients with subjective memory complaints, mild cognitive impairment, or AD. We identified a total of 8 studies of which 6 investigated the effects of exercise on hippocampal volume in healthy subjects and 1 on CSF biomarkers and 1 on hippocampal volume in AD, and none investigating the remaining outcome measures or patient groups. Methodological quality of identified studies was generally low. One study found a detrimental effect on hippocampal volume and one found a positive effect, whereas the remaining studies did not find an effect of exercise on outcome measures. The present systematic study identified a relatively small number of studies, which did not support an effect of exercise on hippocampal volume. Methodological issues such small to moderate sample sizes and inadequate ramdomization procedures further limits conclusions. Our findings highlight the difficulties in conducting high quality studies of exercise and further studies are needed before definite conclusions may be reached. PMID- 29154277 TI - Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial. AB - BACKGROUND: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. OBJECTIVES: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. METHODS: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. RESULTS: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. CONCLUSIONS: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis. PMID- 29154279 TI - Biological Factors Contributing to the Response to Cognitive Training in Mild Cognitive Impairment. AB - In mild cognitive impairment (MCI), small benefits from cognitive training were observed for memory functions but there appears to be great variability in the response to treatment. Our study aimed to improve the characterization and selection of those participants who will benefit from cognitive intervention. We evaluated the predictive value of disease-specific biological factors for the outcome after cognitive training in MCI (n = 25) and also considered motivation of the participants. We compared the results of the cognitive intervention group with two independent control groups of MCI patients (local memory clinic, n = 20; ADNI cohort, n = 302). The primary outcome measure was episodic memory as measured by verbal delayed recall of a 10-word list. Episodic memory remained stable after treatment and slightly increased 6 months after the intervention. In contrast, in MCI patients who did not receive an intervention, episodic memory significantly decreased during the same time interval. A larger left entorhinal cortex predicted more improvement in episodic memory after treatment and so did higher levels of motivation. Adding disease-specific biological factors significantly improved the prediction of training-related change compared to a model based simply on age and baseline performance. Bootstrapping with resampling (n = 1000) verified the stability of our finding. Cognitive training might be particularly helpful in individuals with a bigger left entorhinal cortex as individuals who did not benefit from intervention showed 17% less volume in this area. When extended to alternative treatment options, stratification based on disease-specific biological factors is a useful step towards individualized medicine. PMID- 29154281 TI - Gradual Cerebral Hypoperfusion Impairs Fear Conditioning and Object Recognition Learning and Memory in Mice: Potential Roles of Neurodegeneration and Cholinergic Dysfunction. AB - In the present study, male C57BL/6J mice were subjected to gradual cerebral hypoperfusion by implanting an ameroid constrictor (AC) on the left common carotid artery (CCA) and a stenosis on the right CCA. In the sham group, all surgical procedures were kept the same except no AC was implanted and stenosis was not performed. One month following the surgical procedures, fear conditioning and object recognition tests were conducted to evaluate learning and memory functions and motor functions were assessed using a balance beam test. At the experimental endpoint, mice were perfused and brains were collected for immunostaining and histology. Learning and memory as well as motor functions were significantly impaired in the hypoperfusion group. The immunoreactivity to choline acetyltransferase was decreased in dorsal striatum and basal forebrain of the hypoperfusion group indicating that cholinergic tone in these brain regions was compromised. In addition, an increased number of Fluoro-Jade positive neurons was also found in cerebral cortex, dorsal striatum and hippocampus indicating neurodegeneration in these brain regions. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia. Additionally, this model could be employed to exploit the effect of microvascular occlusions on cognitive impairment in the absence and presence of Alzheimer's disease pathology. PMID- 29154282 TI - Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer's Disease and Brain Aging. AB - To examine the role of ASK1 in Alzheimer's disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24 month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Abeta, which were also associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade may contribute to brain aging of wild-type mice. Collectively, our present results provided the evidence suggesting the involvement of ASK1/p38 cascade in AD and brain aging. PMID- 29154280 TI - Sisyphus in Neverland. AB - The study of life and living organisms and the way in which these interact and organize to form social communities have been central to my career. I have been fascinated by biology, neurology, and neuropathology, but also by history, sociology, and art. Certain current historical, political, and social events, some occurring proximally but others affecting people in apparently distant places, have had an impact on me. Epicurus, Seneca, and Camus shared their philosophical positions which I learned from. Many scientists from various disciplines have been exciting sources of knowledge as well. I have created a world of hypothesis and experiments but I have also got carried away by serendipity following unexpected observations. It has not been an easy path; errors and wanderings are not uncommon, and opponents close to home much more abundant than one might imagine. Ambition, imagination, resilience, and endurance have been useful in moving ahead in response to setbacks. In the end, I have enjoyed my dedication to science and I am grateful to have glimpsed beauty in it. These are brief memories of a Spanish neuropathologist born and raised in Barcelona, EU. PMID- 29154284 TI - Palmitoylethanolamide Blunts Amyloid-beta42-Induced Astrocyte Activation and Improves Neuronal Survival in Primary Mouse Cortical Astrocyte-Neuron Co Cultures. AB - BACKGROUND: Based on the pivotal role of astrocytes in brain homeostasis and the strong metabolic cooperation existing between neurons and astrocytes, it has been suggested that astrocytic dysfunctions might cause and/or contribute to neuroinflammation and neurodegenerative processes. Therapeutic approaches aimed at both neuroprotection and neuroinflammation reduction may prove particularly effective in slowing the progression of these diseases. The endogenous lipid mediator palmitoylethanolamide (PEA) displayed neuroprotective and anti(neuro)inflammatory properties, and demonstrated interesting potential as a novel treatment for Alzheimer's disease. OBJECTIVE AND METHODS: We firstly evaluated whether astrocytes could participate in regulating the Abeta42-induced neuronal damage, by using primary mouse astrocytes cell cultures and mixed astrocytes-neurons cultures. Furthermore, the possible protective effects of PEA against Abeta42-induced neuronal toxicity have also been investigated by evaluating neuronal viability, apoptosis, and morphometric parameters. RESULTS: The presence of astrocytes pre-exposed to Abeta42 (0.5MUM; 24 h) induced a reduction of neuronal viability in primary mouse astrocytes-neurons co-cultures. Furthermore, under these experimental conditions, an increase in the number of neuronal apoptotic nuclei and a decrease in the number of MAP-2 positive neurons were observed. Finally, astrocytic Abeta42 pre-exposure induced an increase in the number of neurite aggregations/100MUm as compared to control (i.e., untreated) astrocytes-neurons co-cultures. These effects were not observed in neurons cultured in the presence of astrocytes pre-exposed to PEA (0.1MUM), applied 1 h before and maintained during Abeta42 treatment. CONCLUSION: Astrocytes contribute to Abeta42-induced neurotoxicity and PEA, by blunting Abeta42-induced astrocyte activation, improved neuronal survival in mouse astrocyte-neuron co-cultures. PMID- 29154283 TI - Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin. AB - BACKGROUND: Recently, modifications of Abeta1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. OBJECTIVE: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. METHODS: Patients received between 3 and 18 PE with albumin (Albutein(r) 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam(r)) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. RESULTS: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. CONCLUSIONS: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion. PMID- 29154285 TI - Prediction of Alzheimer's Dementia in Patients with Amnestic Mild Cognitive Impairment in Clinical Routine: Incremental Value of Biomarkers of Neurodegeneration and Brain Amyloidosis Added Stepwise to Cognitive Status. AB - The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer's disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-Abeta1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs were used to dichotomize patients as 'negative' or 'positive' for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-Abeta provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows stepwise refinement of risk estimates for MCI-to-ADD progression. Incremental benefit strongly depends on the patient's status according to the preceding diagnostic steps. The stepwise Kaplan-Meier curves might be useful to optimize diagnostic workflow in individual patients. PMID- 29154286 TI - Clinic-Based Validation of Cerebrospinal Fluid Biomarkers with Florbetapir PET for Diagnosis of Dementia. AB - BACKGROUND: Cerebrospinal fluid (CSF) biomarker studies have shown variable accuracy for diagnosis of Alzheimer's disease (AD); therefore, internal validation is recommended. OBJECTIVE: To investigate the correlation between CSF biomarkers and cerebral 18-Florbetapir positron emission tomography (Amyloid-PET) and calculate their sensitivity and specificity to obtain the optimal clinical cut-off points to diagnose the etiology of cognitive impairment. METHODS: We performed Amyloid-PET scans and CSF biomarker levels analyses in 68 subjects (50 with mild cognitive impairment, 11 with AD dementia, and 7 with non-AD dementia). Visual examination of Amyloid-PET scans was performed. CSF analyses were performed using standard sandwich ELISA. RESULTS: Amyloid-PET was positive in 36 subjects, negative in 26, and inconclusive in 6. Optimal clinical cut-off points for CSF markers were the following: amyloid-beta 1-42 (Abeta42) = 629 pg/ml, total tau (t-tau) = 532 pg/ml, phosphorylated tau (p-tau) = 88 pg/ml, and t tau/Abeta42 ratio = 0.58. T-tau/Abeta42 ratio showed the best sensitivity and specificity (92 and 84%, respectively). T-tau and p-tau CSF levels (r2 = 0.867) followed by the t-tau and t-tau/Abeta42 CSF ratio (r2 = 0.666) showed the strongest inter-marker correlation. Interestingly, subjects with inconclusive Amyloid-PET showed intermediate values for all CSF markers between negative and positive Amyloid-PET groups. CONCLUSIONS: CSF t-tau/Abeta42 ratio appears to be the most accurate AD CSF marker. The presence of intermediate values for CSF markers among the subjects with inconclusive Amyloid-PET suggests the presence of other dementias associated with AD pathology or intermediate phenotypes. PMID- 29154287 TI - Did you know that your animals have consciousness? AB - Consciousness is the greatest enigma in human history. For centuries scientists and researchers have tried to describe it without coming to conclusions. In the last years with the neurosciences development, consciousness has become the common goal of numerous studies. But consciousness has always been studied only in humans, but after "Cambridge Declaration on Consciousness" in 2012, even non human animalsthey feel possessed of the consciousness. According to "theory Orch OR" of Hameroff and Penrose we have conducted a study on Alaskan malamute and German shepherd to analysed a triplet of platelet fatty acids (linoleic acid; palmitic acid; arachidonic acid). Through these analysis and the relative mapping of subjects within a SOM it was possible to make an assessment of the possible onset of mood disorders in the dogs. A critical analysis of the results obtained shows that animals have molecular analogies with humans compared to mood disorders. The German shepherd and Alaskan malamute, indeed, have, in the case of major depression, a bio-chemical profile, the most similar to man. PMID- 29154288 TI - Patterns of calcium signaling: A link between chronic emotions and cancer. AB - Intra and inter-cellular calcium signaling is present in all types of cells and body tissues. In the human brain, calcium currents and waves are related to mental activities, including emotions. We present a theoretical interpretation of these phenomena suggesting their involvement in chronic emotional patterns and in the pathology of cancer. Recent developments on biophysics, translational biology and psychoneuroendocrinoimmunology (PNEI) can support explanatory hypotheses about the link between emotional stresses and the origin and development of different types of tumor cells. Chronic stresses may cause perturbations of rhythms of the PNEI system, excessive activation of HPA axis and abnormal activation of calcium signals in somatic tissues, with deleterious effects on different parts of the body. The increasing of calcium signaling inside cells may lead to a deregulation of different pathways and epigenetic systems that promote the production of genomic mutations in a second phase. In particular, the hyperactivation of the transcription nuclear factor kappaB (NF-kappaB), if is not counterbalanced by the following activation of the nuclear factor (erythroid derived 2)-like 2 (NFE2L2 or Nrf2), increases the production of oxidative catabolites, as the advanced glycation end products (AGE), which play a key role in the progression of different types of cancer and other degenerative diseases. Cortisol binding to glucocorticoid receptor (GR) reduces the activity of both NF kappaB and Nrf2 inside the cells but inhibits the cellular immunity and the anabolic processes of tissue regeneration. The tissue atrophy and the defective anti-ageing mechanisms promotes the tumoral cells growth and their escape from the immune-surveillance. PMID- 29154289 TI - Subjective reality and brain topology: Inversion transformations on non orientable atomic surfaces of membrane channels. AB - Subject-object relations reflect the relation of phenomenology and physics and are at the centre of interest in brain research and neuro-psychology. The unresolved dichotomy behind this relation is one of the most challenging questions of our time. Setting out from causal modelling I suggest a particular topology for subject-object relations and argue that we can find a physical realization in living organism that provides a continuous transform between both domains. In a geometrical metaphor this transform has the topological properties of a one-sided surface or non-orientable flat. I argue that such a surface can be found within the electronic organization of atomic linings in the filter region of ion-conducting membrane proteins. Electron transfer along these atomic surfaces makes chiral induced spin changes to a promising signature of subject object relations and has found experimental evidence in previous studies. I finally advocate the view that there is a basic dualism between subject and object which is physical on both sides and realized by an inversion relation along one-sided surfaces. The transition between these two aspects however is non physical and hosts the phenomenology that characterizes subjectivity. PMID- 29154290 TI - Positive facial expressions during retrieval of self-defining memories. AB - In this study, we investigated, for the first time, facial expressions during the retrieval of Self-defining memories (i.e., those vivid and emotionally intense memories of enduring concerns or unresolved conflicts). Participants self-rated the emotional valence of their Self-defining memories and autobiographical retrieval was analyzed with a facial analysis software. This software (Facereader) synthesizes the facial expression information (i.e., cheek, lips, muscles, eyebrow muscles) to describe and categorize facial expressions (i.e., neutral, happy, sad, surprised, angry, scared, and disgusted facial expressions). We found that participants showed more emotional than neutral facial expressions during the retrieval of Self-defining memories. We also found that participants showed more positive than negative facial expressions during the retrieval of Self-defining memories. Interestingly, participants attributed positive valence to the retrieved memories. These findings are the first to demonstrate the consistency between facial expressions and the emotional subjective experience of Self-defining memories. These findings provide valuable physiological information about the emotional experience of the past. PMID- 29154291 TI - Neurophysiological markers of high anxiety level in man during the process of preparing for a visual recognition. AB - By means of EEG analysis the functional state of subjects with high and low levels of anxiety was studied in different periods preceding a cognitive task - a visual expression recognition. Several conditions were investigated: background/eyes closed; background/eyes opened; listening the instruction for the cognitive task; operative rest (time lapse between listening the instruction and the beginning of the task), as well as short intervals immediately preceding the exposition of target stimuli (stage of preparation) - pairs of faces pictures with identical or different emotional expressions. At all these pre-task stages high-anxiety subjects exhibited much lower amplitude values in alpha and theta bands (as compared with low-anxiety subjects). The most prominent differences were revealed in the phases of instruction listening and operative rest. These data could provide more precise electrophysiological markers of anxiety level in conditions preceeding cognitive task performance. PMID- 29154292 TI - Increased Prevalence of Polyneuropathy in Parkinson's Disease Patients: An Observational Study. AB - BACKGROUND: The independent contribution of levodopa exposure and Parkinson's disease (PD) to the risk of polyneuropathy is not established. OBJECTIVE: This study investigated whether patients with newly diagnosed PD without previous exposure to antiparkinsonian drugs have higher prevalence of polyneuropathy than the general population. METHODS: Using the UK General Practice Research Database, presence of polyneuropathy in the previous 3 years was assessed. RESULTS: Of 5089 PD patients and 19,897 controls, polyneuropathy was confirmed in 15 PD patients (0.29% ) and 24 controls (0.12% ). Polyneuropathy prevalence was 2.4-fold higher in PD patients than controls. CONCLUSIONS: In this observational study, PD patients had a higher prevalence of preexisting polyneuropathy that cannot be explained by adverse effects of antiparkinsonian drugs. PMID- 29154295 TI - Professional Tribute: Jay Neufeld. PMID- 29154294 TI - Creation of a professional network to improve spina bifida care: Argentina case. AB - The purpose of this paper is to render an account of the experience of a group of healthcare providers and to propose innovative solutions for patients with Spina Bifida (SB) in Argentina. Based on our practice, patients reach specialists too late (40% already undergoing chronic kidney disease stage 1). However, several strategies were implemented in order to reverse this trend, among which were: the setting up of a professional network (via emails and Google groups), team training at different locations, videoconferences, and calling the Ministry of Health to action. Additionally, we developed a project through telemedicine to inform patients and empower caregivers throughout Argentina. PMID- 29154293 TI - The Changing Landscape of Parkinson Epidemiologic Research. AB - Despite recent successes in understanding the genetics of Parkinson's disease (PD), the causes of late-onset sporadic PD remain elusive. Many of the epidemiologic findings on PD etiology have been challenged by alternative explanations such as reverse causation. This is mainly because PD often takes decades to develop before it can be diagnosed late in life. Convincing evidence shows that this prodromal stage of PD is characterized by various prodromal symptoms such as olfactory impairment and rapid-eye-movement sleep behavior disorder (RBD). As they likely reflect PD pathogenesis years, if not decades, before nigrostriatal involvement, research on these symptoms may represent an unprecedented opportunity to dissect the etiology of PD. Using PD prodromal symptoms as intermediate phenotypes, we may be able to identify factors that contribute to the development of these symptoms and factors that modify their progression to clinical PD. Further, this line of research will also enable examinations of novel etiological hypotheses of PD development such as the microbiome and prion hypotheses. In this article, the author used olfactory impairment and RBD as examples to illustrate the promises and challenges of epidemiologic research on prodromal symptoms to understand PD etiology. PMID- 29154297 TI - Personal Tribute to Jacob Neufeld. PMID- 29154296 TI - Spina Bifida. PMID- 29154298 TI - Global health and chronic non-communicable conditions: Spina bifida care across a worldwide community. PMID- 29154299 TI - Introduction to the Special Issue. PMID- 29154300 TI - Fracture generation in human vertebrae under compression loading: The influence of pedicle preservation and bone mineral density on in vitro fracture behavior. AB - BACKGROUND: Fractured vertebral bodies are a common and wide spread health issue. OBJECTIVE: The purpose of this study was to develop a standardized method to experimentally generate compression fractures in vertebral bodies. The influence of the pedicles has been investigated with regards to the fracture behavior. The correlation between bone mineral density (BMD), the cause of fractures and the fracture behavior was investigated. METHODS: Twenty-one fresh frozen human lumbar spines were examined for bone mineral density (BMD) by means of quantitative computed tomography (qCT). All soft tissue was removed, vertebrae were carefully separated from each other and the exposed cranial and caudal endplates were covered with a thin layer of resin to generate a plane and homogeneous surface. A total of 80 vertebral bodies were tested until fracture. RESULTS: A good positive correlation was found between BMD, fracture compression force and stiffness of the vertebral body. No significant differences were found between the fractures generated in vertebral bodies with and without pedicles, respectively. CONCLUSIONS: Our model represents a consolidation of already existing testing devices. The comparative measurement of the BMD and the fracture behavior shows validity. In contrast to other authors, the force was applied to the whole vertebral body. Furthermore the upper and lower plates were not parallelized and therefore the natural anatomic shape was imitated. Fracture behavior was not altered by removing the pedicles. PMID- 29154301 TI - A closer look at subjective caloric sensations: Is there more to vertigo than spinning? AB - BACKGROUND: There is a prevailing opinion that spinning sensations signify a peripheral vestibular pathology while non-spinning sensations are not of vestibular origin. OBJECTIVES: 1) Characterize the subjective sensations reported by patients during caloric testing. 2) Assess if the sensation was correlated with the peak slow phase velocity (SPV). METHODS: Retrospective chart review at a Canadian adult tertiary-quaternary care balance centre for patients undergoing diagnostic caloric testing between December 2014 and September 2015. RESULTS: Of 163 patients included, 122 had normal calorics and 41 demonstrated unilateral weakness. Spinning/rotatory movements were the most commonly reported sensations (55-70%). No sensation was reported among 10-20% of patients. Other non-rotatory sensations were reported 20-25% of the time. Both lack of sensation and other sensations were more likely to be correlated with SPVs that were significantly lower than those associated with spinning/rotating sensations. However, 18% of patients with normal calorics and robust SPVs with warm irrigation still reported non-spinning sensations. CONCLUSIONS: During caloric irrigation, subjective sensations other than spinning and rotating are reported 20-25% of the time and these tend to be associated with lower peak SPV. Non-spinning vertigo is not uncommon as a subjective description of vestibular sensation even in normal patients with strong SPVs. PMID- 29154302 TI - Don't abandon hope all ye who enter here: The protective role of formal mentoring and learning processes on burnout in correctional officers. AB - BACKGROUND: Within a Job Demands-Resources Model framework, formal mentoring can be conceived as a job resource expressing the organization's support for new members, which may prevent their being at risk for burnout. OBJECTIVE: This research aims at understanding the protective role of formal mentoring on burnout, through the effect of increasing learning personal resources. Specifically, we hypothesized that formal mentoring enhances newcomers' learning about job and social domains related to the new work context, thus leading to lower burnout. METHODS: In order to test the hypotheses, a multiple regression analysis using the bootstrapping method was used. RESULTS: Based on a questionnaire administered to 117 correctional officer newcomers who had a formal mentor assigned, our results confirm that formal mentoring exerts a positive influence on newcomers' adjustment, and that this in turn exerts a protective influence against burnout onset by reducing cynicism and interpersonal stress and also enhancing the sense of personal accomplishment. CONCLUSIONS: Confirming previous literature's suggestions, supportive mentoring and effective socialization seem to represent job and personal resources that are protective against burnout. This study provides empirical support for this relation in the prison context. PMID- 29154303 TI - Factors associated with participation on the competitive labour market of people with visual impairments in The Netherlands. AB - BACKGROUND: Worldwide, the employment rate of people with visual impairments (PVIs) is lower than that of the general working-age population. To improve the employment rate of this group, there is a need for knowledge about differences in modifiable factors between working and non-working PVIs. OBJECTIVE: To identify modifiable factors associated with participation on the competitive labour market of PVIs. Based on the findings, we aim to develop an individual assessment instrument for determining the odds of labour market success of PVIs. METHODS: Data were collected among 299 PVIs by means of a cross-sectional telephone survey based on existing (validated) and self-developed scales and items. Logistic regression analysis was used to find the strongest predictors of the dichotomous outcome of 'having paid work on the competitive labour market' (yes/no). RESULTS: We found three personal non-modifiable factors (level of education, comorbidity, level of visual impairment) and three modifiable factors (mobility, acceptance and optimism) to be significantly (p < 0.05) associated with having paid work. CONCLUSIONS: The factors of optimism, acceptance and mobility should be included in an individual assessment instrument which can provide PVIs and their job coaches with good starting points for improving the labour market situation of the PVIs. PMID- 29154304 TI - Assessment of work engagement among dentists in Hyderabad. AB - BACKGROUND: Work engagement has been conceptualized as a relatively stable phenomenon, partly explained by the presence of specific job and organizational characteristics. Work engagement is important to the dental workforce worldwide, and the lack of it has been known to cause burnout. Positivity among dentists is essential as it is directly proportional to the patient's satisfaction towards the dental care. OBJECTIVE: To assess work engagement among dentists in the city of Hyderabad, India. METHOD: A cross-sectional questionnaire study was conducted to assess work engagement among dentists enrolled with the local branch of the Indian Dental Association in the city of Hyderabad, India. The shortened form of the Utrecht Work Engagement Scale (UWES-9) questionnaire was employed for the assessment. The mean scores of total work engagement and its domains based on gender and educational qualifications were estimated using Student t- test. RESULTS: A total of 371 subjects participated in the study. Females reported higher mean scores than males for total work (p = 0.40) and its dimensions (Vigor; p = 0.23, Dedication; p = 0.53, Absorption; p = 0.69). Dentists with Master's degree had higher mean scores not only in the total work, but also in its dimensions. (p = 0.01). CONCLUSION: The present study reported that females had higher mean scores of total work engagement and its individual domains. In comparison with a Bachelor's degree, having a Master's degree enhanced work engagement among dentists in Hyderabad, India. PMID- 29154305 TI - An active transition from offshore work to family life: Activities that may impact recovery. AB - BACKGROUND: Night shift workers, particularly those working offshore, take a long time to recover from their shifts. The activities that shift workers, such as offshore employees, pursue during their leisure time can influence the process of recovery from work-related fatigue, but little is known about these leisure time activities. OBJECTIVE: To explore what leisure time activities are pursued that may be relevant to recovery for offshore employees. METHODS: Sixty-one offshore working family men-20 night shift, 16 swing shift, and 25 day shift workers reported on six predefined activities for 14 days following their offshore tours. Generalized estimating equations analysis was used to explore trends in the data. RESULTS: From the start of the free period, almost all participants were involved in household chores and childcare; these activities declined over the 14 days. Throughout the study period, participants actively pursued social, volunteer, and leisure time physical activities. Work-related activities were pursued by half of the participants at some time during the 14 days. Night and swing shift workers were more physically active than day workers throughout the first 14 days of the free period. CONCLUSIONS: The transition from offshore work to family life can be characterised as active. The activities engaged in by this sample of employees are likely to promote their recovery. PMID- 29154306 TI - Primary problems associated with the health and welfare of employees observed when implementing lean manufacturing projects. AB - BACKGROUND: Lean philosophy is used by companies to increase productivity and reduce costs. Although uncontested benefits are created, it is necessary to highlight the problems related to employees' health and welfare caused by implementing lean manufacturing projects. OBJECTIVE: The primary objective of this paper is to review the literature and identify the most relevant problems created by lean philosophy for employees. METHODS: Research about the theme was performed on many international databases over three months, and an initial sample of 77 papers was found. Twenty-seven sources were utilized. RESULTS: We identified 22 categories of problems related to health and welfare of employees. CONCLUSIONS: The most cited problem was work intensification, mentioned by thirteen papers. Increased stress and increased responsibilities, demands and, consequently, pressure on the workers are among the primary problems observed in the research. PMID- 29154307 TI - ADA Title I allegations and the Mining, Quarrying, and Oil/Gas Extraction industry. AB - BACKGROUND: The majority of research about employment discrimination in the U.S. Mining, Quarrying, and Oil/Gas (MQOGE) industries has concentrated on gender and race, while little attention has focused on disability. OBJECTIVE: To explore allegations of Americans with Disabilities Act (ADA) Title I discrimination made to the Equal Employment Opportunity Commission (EEOC) by individuals with disabilities against MQOGE employers. METHODS: Key data available to this study included demographic characteristics of charging parties, size of employers, types of allegations, and case outcomes. Using descriptive analysis, allegation profiles were developed for MQOGE's three main sectors (i.e., Oil/Gas Extraction, Mining except Oil/Gas, and Support Activities). These three profiles where then comparatively analyzed. Lastly, regression analysis explored whether some of the available data could partially predict MQOGE case outcomes. RESULTS: The predominant characteristics of MQOGE allegations were found to be quite similar to the allegation profile of U.S. private-sector industry as a whole, and fairly representative of MQOGE's workforce demographics. Significant differences between MQOGE's three main sector profiles were noted on some important characteristics. Lastly, it was found that MQOGE case outcomes could be partially predicted via some of the available variables. CONCLUSIONS: The study's limitations were presented and recommendations were offered for further research. PMID- 29154308 TI - Functional limitations and associated psychological factors in military personnel with chronic nonspecific neck pain with higher levels of kinesiophobia. AB - BACKGROUND: Neck pain is one of the largest health problems in the military sector. OBJECTIVE: To assess differences in the strength and endurance of the cervical muscles between military personnel with chronic nonspecific neck pain (CNSNP) with higher level of kinesiophobia (CNSNP-K) and individuals with lower levels of kinesiophobia (CNSNP-NK). METHODS: We used kinesiophobia as a classification method: (1) CNSNP-K and (2) CNSNP-NK. The variables measured were endurance and strength of cervical muscles; range of motion (ROM), disability, pain intensity and psychological factors. RESULTS: Eighty-three military personnel (26 CNSNP-K; 20 CNSNP-NK and 37 asymptomatic). Statistically significant differences in endurance and ROM were only found between the CNSNP-K group and the control group. In strength and disability differences were revealed between both symptomatic groups and the control group [CNSNP-K vs. control (flex ext p < 0.001); CNSNP-NK vs. control (flex p = 0.003) and (ext p < 0.001)]. For psychological variables, the CNSNP-K group showed differences compared with the CNSNP-NK (pain catastrophizing, p = 0.007; anxiety and depression, p < 0.001) and with the asymptomatic group (pain catastrophizing, p = 0.008; anxiety and depression, p < 0.001). CONCLUSIONS: Military personnel with CNSNP-K have functional limitations and associated psychosocial factors compared with asymptomatic subjects, and showed greater associated psychological factors than CNSNP-NK group. Military personnel with CNSNP-NK only showed decreased strength with respect to those who were asymptomatic. PMID- 29154311 TI - Precise measurement of inner diameter of mono-capillary optic using X-ray imaging technique. AB - BACKGROUND: Mono-capillary optics have been applied to increase the performance of X-ray instruments. However, performance of a mono-capillary optic strongly depends on the shape accuracy, which is determined by the diameters of the inner hollow of the capillary along the axial direction. OBJECTIVE: To precisely determine the inner diameter of the capillary optic used in X-ray imaging technique, which aims to replace the conventional method using a visible microscope. METHODS: High spatial resolution X-ray images of the mono-capillary optic were obtained by a synchrotron radiation beamline. The inner diameter of the mono-capillary optic was measured and analyzed by the pixel values of the X ray image. RESULT: Edge enhancement effect was quite useful in determining the inner diameter, and the accuracy of the diameter determination was less than 1.32 MUm. Many images obtained by scanning the mono-capillary optic along the axial direction were combined, and the axial profile, consisting of diameters along the axial direction, was obtained from the combined image. The X-ray imaging method could provide an accurate measurement with slope error of+/-19 MUrad. CONCLUSIONS: Applying X-ray imaging technique to determine the inner diameter of a mono-capillary optic can contribute to increasing fabrication accuracy of the mono-capillary optic through a feedback process between the fabrication and measurement of its diameter. PMID- 29154310 TI - Tutorial on X-ray photon counting detector characterization. AB - BACKGROUND: Recent advances in photon counting detection technology have led to significant research interest in X-ray imaging. OBJECTIVE: As a tutorial level review, this paper covers a wide range of aspects related to X-ray photon counting detector characterization. METHODS: The tutorial begins with a detailed description of the working principle and operating modes of a pixelated X-ray photon counting detector with basic architecture and detection mechanism. Currently available methods and techniques for charactering major aspects including energy response, noise floor, energy resolution, count rate performance (detector efficiency), and charge sharing effect of photon counting detectors are comprehensively reviewed. Other characterization aspects such as point spread function (PSF), line spread function (LSF), contrast transfer function (CTF), modulation transfer function (MTF), noise power spectrum (NPS), detective quantum efficiency (DQE), bias voltage, radiation damage, and polarization effect are also remarked. RESULTS: A cadmium telluride (CdTe) pixelated photon counting detector is employed for part of the characterization demonstration and the results are presented. CONCLUSIONS: This review can serve as a tutorial for X-ray imaging researchers and investigators to understand, operate, characterize, and optimize photon counting detectors for a variety of applications. PMID- 29154312 TI - Significant MRI indicators of malignancy for breast non-mass enhancement. AB - OBJECTIVE: To explore and evaluate new malignant predictors of breast non-mass enhancement lesions using the new BI-RADS MRI lexicon. METHODS: A dataset involving 422 consecutive women underwent breast 3.0 T MRI between January 2014 and July 2016 was assembled for this study. Each case was retrospectively reviewed by 3 radiologists. Eighty-four lesions that present non-mass enhancement in 79 patients were identified in the study. Dynamic contrast-enhanced MRI features were analyzed using univariate and multivariate analyses to identify significant indicators of malignancy. RESULTS: Of 84 non-mass enhancement lesions, 52 (61.9%) were malignant and 32 (38.1%) were benign. Segmental distribution (P = 0.015 from univariate analysis; OR = 4.739, P = 0.008 from multivariate analysis), cluster ring enhancement (P = 0.017 from univariate analysis; OR = 3.601, P = 0.032 from multivariate analysis), time-intensity curve of plateau (P = 0.002 from univariate analysis; OR = 3.525, P = 0.027 from multivariate analysis) and phase to peak (P = 0.06 from univariate analysis; OR = 6.327, P = 0.015 from multivariate analysis) were significantly different between malignant and benign lesions. CONCLUSIONS: This study demonstrated that segmental distribution, clustered ring enhancement, and short time to peak could act as new malignant predictors for breast non-mass enhancement detected on 3.0 T MRI. PMID- 29154313 TI - Automatic segmentation of tumors in B-Mode breast ultrasound images using information gain based neutrosophic clustering. AB - BACKGROUND: Since breast ultrasound images are of low contrast, contain inherent noise and shadowing effect due to its imaging process, segmentation of breast tumors depicting ultrasound image is a challenging task. Thus, a robust breast ultrasound image segmentation technique is inevitable. OBJECTIVE: To develop an automatic lesion segmentation technique for breast ultrasound images. METHODS: First, the technique automatically detects the suspicious tumor region of interest and discards the unwanted complex background regions. Next, based on the concept of information gain, the technique applies an existing neutrosophic clustering method to the detected region to segment the desired tumor area. The proposed technique computes information gain values from the local neighbourhood of each pixel, which is further used to update the membership values and the cluster centers for the neutrosophic clustering process. Integrating the concept of entropy and neutrosophic logic features into the technique enabled to generate better segmentation results. RESULTS: Results of proposed method were compared both qualitatively and quantitatively with fuzzy c-means, neutrosophic c-means and neutrosophic l-means clustering methods. It was observed that the proposed method outperformed the other three methods and yielded the best Mean (TP: 94.72, FP: 5.85, SI: 93.75, HD: 8.2, AMED: 2.4) and Standard deviation (TP: 3.2, FP: 3.7, SI: 3.8, HD: 2.6, AMED: 1.3) values for different quality metrics on the current set of breast ultrasound images. CONCLUSION: Study demonstrated that the proposed technique is robust to the shadowing effect and produces more accurate segmentation of the tumor region, which is very similar to that visually segmented by Radiologist. PMID- 29154315 TI - In Vitro Drug Sensitivity of Neisseria Gonorrhoeae Strains and Blood Penicillin Levels After Various Penicillin Preparations. PMID- 29154314 TI - Feasibility and its characteristics of CO2 laser micromachining-based PMMA anti scattering grid estimated by MCNP code simulation. AB - BACKGROUND: Anti-scattering grid has been used to improve the image quality. However, applying a commonly used linear or parallel grid would cause image distortion, and focusing grid also requires a precise fabrication technology, which is expensive. OBJECTIVE: To investigate and analyze whether using CO2 laser micromachining-based PMMA anti-scattering grid can improve the performance of the grid at a lower cost. Thus, improvement of grid performance would result in improvement of image quality. METHODS: The cross-sectional shape of CO2 laser machined PMMA is similar to alphabet 'V'. The performance was characterized by contrast improvement factor (CIF) and Bucky. Four types of grid were tested, which include thin parallel, thick parallel, 'V'-type and 'inverse V'-type of grid. RESULTS: For a Bucky factor of 2.1, the CIF of the grid with both the "V" and inverse "V" had a value of 1.53, while the thick and thick parallel types had values of 1.43 and 1.65, respectively. CONCLUSION: The 'V' shape grid manufacture by CO2 laser micromachining showed higher CIF than parallel one, which had same shielding material channel width. It was thought that the 'V' shape grid would be replacement to the conventional parallel grid if it is hard to fabricate the high aspect-ratio grid. PMID- 29154316 TI - Basophil Degranulation in Drug Allergy. PMID- 29154317 TI - Perianal Form of Suppurative Hidradentitis. PMID- 29154318 TI - Apocrine Gland Carcinoma in Axilla. PMID- 29154319 TI - Reactions in Leprosy with Various Doses of Dapsone. PMID- 29154320 TI - Case to Cure Chronic Paronychia. PMID- 29154321 TI - Porphyria and Photosensitivity. PMID- 29154323 TI - Dermatofibrosarcoma Protuberans. PMID- 29154324 TI - Contribution To the Study of Kaposi's Sarcoma (A case Report). PMID- 29154322 TI - Nocardia Pelletieri Causing Mycetoma in India. PMID- 29154325 TI - Sturge-weber Syndrome. PMID- 29154326 TI - Late Osseous Syphilis (Report of 4 Cases). PMID- 29154327 TI - Erythema ab Igne. PMID- 29154328 TI - "A Case of Toxic Epidermal Necrolysis or Scalded skin Syndrome". PMID- 29154329 TI - Personaiity. PMID- 29154330 TI - Actinic Reticuloid. PMID- 29154331 TI - Papillon Lefevre Syndrome (case report with cytogenetic study ). PMID- 29154332 TI - Trichoepithelioma. PMID- 29154334 TI - Pyogenic Infections of Skin Treated with Mimocycline. PMID- 29154333 TI - "Problems of Dermato-Venereology in India". PMID- 29154335 TI - Radiation Therapy in Herpes Zoster and Post Herpetic Neuralgia. PMID- 29154336 TI - A Study of 70 Cases of Drug Eruptions. PMID- 29154338 TI - Systemic Diseases and the Skin. PMID- 29154337 TI - Serum Ionic Copper in Vitiligo. PMID- 29154340 TI - Review of Literature of Epidermodysplasia Verructformis. PMID- 29154339 TI - Agar Gel Cutter For Emmunoelectrophoresis. PMID- 29154341 TI - Oral Granuloma Venereum. PMID- 29154342 TI - Pseudoxanthoma Elasticum. PMID- 29154343 TI - Demethylchlortetracycline in the Treatment of Gonorrhoea. PMID- 29154345 TI - Presidential Address. PMID- 29154344 TI - Clinical Trial with Jadit and Jadit-H in Dermatomycoses. PMID- 29154346 TI - Condylomata Acuminata. PMID- 29154348 TI - Clinical Evaluation of a Sustained Release Antihistamine, Avil Retard. PMID- 29154347 TI - Value of re-interviewing in Identifying Contacts and Contact Tracing. PMID- 29154349 TI - Marking Nut Dermatitis (Semicarpas anacardium). PMID- 29154350 TI - Aquired Fibrokeratomas. PMID- 29154351 TI - Statistics & Ventreal Diseases. PMID- 29154352 TI - Mycetoma with Haematogenous Dissemination & Therapy. PMID- 29154353 TI - Nevus Lipomatosus Cutaneous Superficialis (Case Repcrt with Review of Literature). PMID- 29154354 TI - Local Infiltration of Triamcinolone Acetonide Suspension in Various Skin Conditions. PMID- 29154355 TI - Primary Macular Atrophy (a case report of anetoderma of Jadassohn-Pellizari). PMID- 29154356 TI - Climatic Influence on the Prevalence of Donovanosis in India. PMID- 29154357 TI - Perforation of the Palate. PMID- 29154359 TI - Analysis of 141 Cases of Dermatophytosis. PMID- 29154358 TI - Gonorrhoea - Treated with Intravenous Penicillin. PMID- 29154360 TI - Granuloma Pyogenicum (Report of a case on Corona Glandularis). PMID- 29154361 TI - Leprosy and Histamine. PMID- 29154362 TI - Role of Plastic Reconstructive Surgery in Leprosy. PMID- 29154363 TI - Association Activities. PMID- 29154364 TI - Non-Contingent Exposure to Amphetamine in Adolescence Recruits miR-218 to Regulate Dcc Expression in the VTA. AB - The development of the dopamine input to the medial prefrontal cortex occurs during adolescence and is a process that is vulnerable to disruption by stimulant drugs such as amphetamine. We have previously linked the amphetamine-induced disruption of dopamine connectivity and prefrontal cortex maturation during adolescence to the downregulation of the Netrin-1 receptor, DCC, in dopamine neurons. However, how DCC expression in dopamine neurons is itself regulated is completely unknown. MicroRNA (miRNA) regulation of mRNA translation and stability is a prominent mechanism linking environmental events to changes in protein expression. Here, using male mice, we show that miR-218 is expressed in dopamine neurons and is a repressor of DCC. Whereas Dcc mRNA levels increase from early adolescence to adulthood, miR-218 exhibits the exact opposite switch, most likely maintaining postnatal Dcc expression. This dynamic regulation appears to be selective to Dcc since the expression of Robo 1, the other guidance cue receptor target of miR-218, does not vary with age. Amphetamine in adolescence, but not in adulthood, increases miR-218 in the VTA and this event is required for drug induced downregulation of Dcc mRNA and protein expression. This effect seems to be specific to Dcc because amphetamine does not alter Robo1. Furthermore, the upregulation of miR-218 by amphetamine requires dopamine D2 receptor activation. These findings identify miR-218 as regulator of DCC in the VTA both in normal development and after drug exposure in adolescence. PMID- 29154365 TI - Is Neural Processing of Negative Stimuli Altered in Addiction Independent of Drug Effects? Findings From Drug-Naive Youth with Internet Gaming Disorder. AB - Difficulties in emotion regulation are commonly reported among individuals with alcohol and drug addictions and contribute to the acquisition and maintenance of addictive behaviors. Alterations in neural processing of negative affective stimuli have further been demonstrated among individuals with addictions. However, it is unclear whether these alterations are a general feature of addictions or are a result of prolonged exposure to drugs of abuse. To test the hypothesis of altered negative affect processing independent of drug effects, this study assessed neural function among drug-naive youth with a behavioral addiction-Internet gaming disorder (IGD). Fifty-six young adults (28 with IGD, 28 matched controls) participated in fMRI scanning during performance of a well validated emotion regulation task. Between-group differences in neural activity during task performance were assessed using a whole-brain, mixed-effects ANOVA with correction for multiple comparisons at currently recommended thresholds (voxel-level p<0.001, pFWE<0.05). Compared to controls, youth with IGD exhibited significantly blunted neural responses within distributed subcortical and cortical regions including the striatum, insula, lateral prefrontal cortex and anterior cingulate in response to negative affective cues, as well as during emotion regulation. Independent component analysis (ICA) further identified between-group differences in engagement of a fronto-cingulo-parietal network, involving decreased engagement in IGD youth relative to controls. Study findings are largely consistent with those from prior neuroimaging studies in substance use disorders, thus raising the possibility that neural processing of negative affect may be blunted across drug and behavioral addictions independent of acute or chronic drug effects. PMID- 29154366 TI - Generalization of Conditioned Auditory Fear is Regulated by Maternal Effects on Ventral Hippocampal Synaptic Plasticity. AB - Maternal care shapes individual differences in fear-associated neural circuitry. In rats, maternal licking and grooming (LG) in early life regulates ventral hippocampal (VH) function and plasticity in adulthood, but its consequent effect on the regulation of fear memories remains unknown. We report an effect of maternal care on generalization of learned fear, such that offspring of high LG mothers express generalized fear responses when confronted with neutral stimuli following auditory fear conditioning. These animals simultaneously display a reduction in the magnitude of VH long-term potentiation (LTP) expressed and reduced input-output transformation in Schaffer collateral synapses. Inhibition of VH-LTP during learning specifically increases fear generalization in offspring of low LG mothers during recall, suggesting a role for VH synaptic plasticity in the specification of fear memories. These findings suggest that rearing by low LG dams enhances the efficacy of fear-related neural systems to support accurate encoding of fear memories through effects on the VH. PMID- 29154367 TI - Effects of Amphetamine on Sensorimotor Gating and Neurocognition in Antipsychotic Medicated Schizophrenia Patients. AB - Prepulse inhibition (PPI) of startle is being explored both as an indicator of target engagement for, and a biomarker predicting the sensitivity to, procognitive effects of drugs. We now report the effects of the pro-attentional drug, d-amphetamine, on PPI and neurocognition in antipsychotic-medicated schizophrenia patients and healthy subjects (HS) who were also tested in a targeted cognitive training (TCT) module. 44 HS and 38 schizophrenia patients completed a double-blind, placebo-controlled crossover study of the effects of a single dose of amphetamine (10 mg po) on PPI and MATRICS Consensus Cognitive Battery (MCCB) performance; TCT results were previously reported from 60 of these subjects. Moderators predicting AMPH sensitivity were assessed, including the rs4680 single-nucleotide polymorphism for catechol-O-methyltransferase (COMT). After placebo, patients exhibited PPI deficits with 60 ms prepulse intervals; these deficits were 'rescued' by amphetamine. The magnitude of amphetamine enhanced PPI was greater in patients than in HS (p<0.032), and was associated with positive symptoms (p<0.007), antipsychotic load (p<0.015), hedonic effects of AMPH (p<0.003), and with the presence of at least one methionine allele in rs4680 (p<0.008). No significant effects of amphetamine on MCCB performance were detected in either group, though pro-attentional effects of amphetamine in patients were associated with greater amphetamine-enhanced TCT learning. Amphetamine acutely 'normalized' PPI in antipsychotic-medicated schizophrenia patients; no concurrent acute neurocognitive changes were detected by the MCCB. Findings suggest that in the context of appropriate antipsychotic medication, a low dose of amphetamine enhances brain processes associated with higher function in schizophrenia patients, without accompanying changes in MCCB performance. PMID- 29154368 TI - Precision Medicine in Alcohol Dependence: A Controlled Trial Testing Pharmacotherapy Response Among Reward and Relief Drinking Phenotypes. AB - Randomized trials of medications for alcohol dependence (AD) often report no differences between active medications. Few studies in AD have tested hypotheses regarding which medication will work best for which patients (ie, precision medicine). The PREDICT study tested acamprosate and naltrexone vs placebo in 426 randomly assigned AD patients in a 3-month treatment. PREDICT proposed individuals whose drinking was driven by positive reinforcement (ie, reward drinkers) would have a better treatment response to naltrexone, whereas individuals whose drinking was driven by negative reinforcement (ie, relief drinkers) would have a better treatment response to acamprosate. The goal of the current analysis was to test this precision medicine hypothesis of the PREDICT study via analyses of subgroups. Results indicated that four phenotypes could be derived using the Inventory of Drinking Situations, a 30-item self-report questionnaire. These were high reward/high relief, high reward/low relief, low reward/high relief, and low reward/low relief phenotypes. Construct validation analyses provided strong support for the validity of these phenotypes. The subgroup of individuals who were predominantly reward drinkers and received naltrexone vs placebo had an 83% reduction in the likelihood of any heavy drinking (large effect size). Cutoff analyses were done for clinical applicability: individuals are reward drinkers and respond to naltrexone if their reward score was higher than their relief score AND their reward score was between 12 and 31. Using naltrexone with individuals who are predominantly reward drinkers produces significantly higher effect sizes than prescribing the medication to a more heterogeneous sample. PMID- 29154369 TI - Hepatitis E virus infection. AB - Hepatitis E virus (HEV) infection can lead to acute and chronic hepatitis as well as to extrahepatic manifestations such as neurological and renal disease; it is the most common cause of acute viral hepatitis worldwide. Four genotypes are responsible for most infection in humans, of which HEV genotypes 1 and 2 are obligate human pathogens and HEV genotypes 3 and 4 are mostly zoonotic. Until quite recently, HEV was considered to be mainly responsible for epidemics of acute hepatitis in developing regions owing to contamination of drinking water supplies with human faeces. However, HEV is increasingly being recognized as endemic in some developed regions. In this setting, infections occur through zoonotic transmission or contaminated blood products and can cause chronic hepatitis in immunocompromised individuals. HEV infections can be diagnosed by measuring anti-HEV antibodies, HEV RNA or viral capsid antigen in blood or stool. Although an effective HEV vaccine exists, it is only licensed for use in China. Acute hepatitis E is usually self-limiting and does not require specific treatment. Management of immunocompromised individuals involves lowering the dose of immunosuppressive drugs and/or treatment with the antiviral agent ribavirin. PMID- 29154370 TI - PRR11 immunoreactivity is a weak prognostic factor in non-mucinous invasive adenocarcinoma of the lung. AB - INTRODUCTION: Proline-rich protein 11 (PRR11) functions in the progression of cell cycle, and silencing the PRR11 gene in lung cancer cells results in the inhibition of cellular proliferation, cell cycle progression, cell migration, invasion and colony formation. PRR11 may therefore be a therapeutic target in lung cancer. MATERIALS AND METHODS: Microarrays of surgical specimens of non mucinous invasive adenocarcinoma of the lung, from 346 subjects that were not given preoperative therapy, were autoimmunostained with PRR11 and, except for trace and pseudo-positivity, assessed as "positive" at any proportion and intensity. RESULTS: PRR11 immunoreactivity demonstrated a tendency to associate with an aggressive phenotype (tumor size, vascular invasion, and adjuvant therapy) and some effect on overall survival (Hazard ratio 1.51). CONCLUSIONS: PRR11 may be a weak prognostic indicator of overall survival of patients with non mucinous invasive adenocarcinoma of the lung. PMID- 29154371 TI - Disseminated nocardiosis complicated by multiple brain abscesses and pleural empyema in a young diabetic man: a case report. AB - Nocardiosis is a life-threatening infection usually affecting immunocompromised patients. Very rarely it presented with intracranial abscesses and pleuro parenchymal infections. We herein report a very challenging case of a 34-year-old obese and diabetic man affected by disseminated nocardiosis with multiple brain abscesses and pleural empyema. Despite rare, this entity should be taken into account by the pathologists and urgently communicated to clinicians in order to promptly start an effective treatment. PMID- 29154372 TI - Kaposiform hemangioendothelioma in an adult with rheumatoid arthritis. AB - This report describes a case of kaposiform hemangioendothelioma arising in an adult man during the course of rheumatoid arthritis treated with steroids and methotrexate. The vascular proliferation began in the terminal phase of the disease, which culminated in acute renal failure and death. We discuss the possible relationship between rheumatoid arthritis, its treatment, and the onset of vascular proliferation, as well as the role of kaposiform hemangioendothelioma in aggravating the autoimmune disease and leading to its fatal outcome. PMID- 29154373 TI - Caliber persistent artery in the palate of an Egyptian patient with type 2 diabetes mellitus: a rare case report. AB - This paper reports a very rare case of isolated ulcerative lesion of the palate in a patient with type 2 diabetes mellitus. The patient refused to run any radiological tests, other than the periapical radiograph. This rendered the diagnostic dilemma more challenging. Through histochemical and immunohsitochemical stains, the case could be non-invasively diagnosed as caliber persistent artery. All differential diagnoses were excluded based on concrete findings. PMID- 29154374 TI - Microcystic transitional cell carcinoma: a rare tumor of the urinary bladder. AB - Microcystic urothelial carcinoma is a rare variant of invasive transitional cell carcinoma recognized by the WHO classification. It is characterized by its deceptively benign appearance. The clinical course of this uncommon variety of carcinoma is not well known and their histological and immunohistological features are not well defined. We report a case of a 37-year-old man with a microcystic transitional cell carcinoma of the urinary bladder. He was diagnosed 4 years ago with cystitis glandularis lesions and nephrogenic adenoma. Through this observation we will try to define the clinical and pathological features of this uncommon tumor which must be differentiated from a number of proliferative lesions of the urothelium. The poor prognosis and aggressiveness of this tumor seems to be related to a higher stage and grade at diagnosis. PMID- 29154375 TI - Glial choristoma of the ventral part of the tongue: first report in an elderly patient. AB - INTRODUCTION: The aims of this report are to illustrate the first case of glial and adipose tissue choristoma at the ventral part of the tongue in an elderly patient, to discuss the possible differential diagnoses and to speculate about its pathogenesis. CASE REPORT: A 65-year-old female was admitted to our hospital with a swelling at the base of the tongue. MRI revealed an oval lesion with indistinct borders without contrast enhancement. The patient underwent surgical complete excision and grossly, the specimen consisted of a gray-white mass measuring 25 mm in its great diameter. Microscopically the lesion contained fibrocollagenous stroma, mature adipose tissue and mature astrocytes. In the absence of cellular atypia, mitoses and necrosis a diagnosis of adipose and glial choristoma was performed. The patient is healthy 18 months postoperatively. DISCUSSION: Choristomas are cohesive tumor-like masses histologically composed by normal tissue occurring in an unusual anatomical location and mainly affecting children during the first years of life. Glial choristomas are considered malformations of the central nervous system and their localization in the tongue is exceptional. However they carry a favourable prognosis so it is of paramount importance to histologically diagnose them correctly. PMID- 29154376 TI - Post-irradiation vaginal spindle cell sarcoma. AB - The genetic profile is one of the major possible causes of spindle cell sarcoma. Irradiation has also been linked to this type of cancer. This means that if tissues have already been irradiated for other types of cancer, they can afterwards develop this form of sarcoma. Also, previous radiotherapy can determine specific genetic alterations, which result to uncontrolled cell division, that is neoplasia. We report one such cause in a female patient 80 years old with a uterus adenocarcinoma (endometrioid type) FIGO Stage IC, who had been treated with surgical resection and pelvic irradiation. Ten years after radiotherapy a vaginal spindle cell sarcoma was diagnosed by cytology (Pap smear) and confirmed by histology and immunohistology. This case is presented to focus the ability of cytology in diagnosis of spindle cell sarcoma in Pap smear with confirmation by histo-immunohistology. PMID- 29154377 TI - Tall cell variant of papillary breast carcinoma: an additional case with review of the literature. AB - Papillary lesions of the breast can be one of the most challenging aspects of mammary pathology because of a wide morphologic spectrum that may be encountered in these lesions. An unusual breast tumor has been first classified as "breast tumor resembling the tall cell variant of papillary thyroid carcinoma" and subsequently renamed "tall cell variant of papillary breast carcinoma". To our knowledge, only 13 cases of this neoplasm have been reported so far. Metastasis to the breast is not an uncommon event and about 5% of all such cases are of the thyroid origin. We report the clinico-pathological and immunohistochemical features, together with a molecular screening for BRAF mutations, of an additional case of tall cell variant of papillary breast carcinoma occurring in a 65-year-old woman. The immunohistochemical and molecular clues leading to the correct diagnosis have been correlated with the data of the literature. Tall cell variant of papillary breast carcinoma represents a unique histologic subtype of mammary carcinoma of probably low malignant potential which has to be recognized to avoid misdiagnosis as metastatic carcinoma from the thyroid. PMID- 29154378 TI - Idiopathic renal replacement lipomatosis. AB - Renal replacement lipomatosis (RRL) is a rare disorder which exhibits extensive proliferation of fatty tissue within the renal sinus, hilum, and perirenal region. The pathogenesis of this entity is unknown, though association with aging, renal atrophy, longstanding chronic urinary infections has been noted. Although imaging modalities may suggest the diagnosis of this entity, it is histopathology that clinches the diagnosis most accurately. We report a case of a 52 year old male who presented with nonfunctioning kidney and was histopathologically confirmed to be a case of renal replacement lipomatosis. PMID- 29154379 TI - Proposed In-Training Electrocardiogram Interpretation Competencies for Undergraduate and Postgraduate Trainees. AB - Despite its importance in everyday clinical practice, the ability of physicians to interpret electrocardiograms (ECGs) is highly variable. ECG patterns are often misdiagnosed, and electrocardiographic emergencies are frequently missed, leading to adverse patient outcomes. Currently, many medical education programs lack an organized curriculum and competency assessment to ensure trainees master this essential skill. ECG patterns that were previously mentioned in literature were organized into groups from A to D based on their clinical importance and distributed among levels of training. Incremental versions of this organization were circulated among members of the International Society of Electrocardiology and the International Society of Holter and Noninvasive Electrocardiology until complete consensus was reached. We present reasonably attainable ECG interpretation competencies for undergraduate and postgraduate trainees. Previous literature suggests that methods of teaching ECG interpretation are less important and can be selected based on the available resources of each education program and student preference. The evidence clearly favors summative trainee evaluation methods, which would facilitate learning and ensure that appropriate competencies are acquired. Resources should be allocated to ensure that every trainee reaches their training milestones and should ensure that no electrocardiographic emergency (class A condition) is ever missed. We hope that these guidelines will inform medical education programs and encourage them to allocate sufficient resources and develop organized curricula. Assessments must be in place to ensure trainees acquire the level-appropriate ECG interpretation skills that are required for safe clinical practice. PMID- 29154381 TI - Interhospital Transfer and Receipt of Specialty Procedures. AB - The practice of transferring patients between acute care hospitals is variable and largely nonstandardized. Although often-cited reasons for transfer include providing patients access to specialty services only available at the receiving institution, little is known about whether and when patients receive such specialty care during the transfer continuum. We performed a retrospective analysis using 2013 100% Master Beneficiary Summary and Inpatient claims files from Centers for Medicare and Medicaid Services. Beneficiaries were included if they were aged =65 years, continuously enrolled in Medicare A and B, with an acute care hospitalization claim, and transferred to another acute care hospital with a primary diagnosis of acute myocardial infarction, gastrointestinal bleed, renal failure, or hip fracture/dislocation. Associated specialty procedure codes (International Classification of Diseases, Ninth Revision, Clinical Modification) were identified for each diagnosis. We performed descriptive analyses to compare receipt of specialty procedural services between transferring and receiving hospitals, stratified by diagnosis. Across the 19,613 included beneficiaries, receipt of associated specialty procedures was more common at the receiving than the transferring hospital, with the exception of patients with a diagnosis of gastrointestinal bleed. Depending on primary diagnosis, between 32.4% and 89.1% of patients did not receive any associated specialty procedure at the receiving hospital. Our results demonstrate variable receipt of specialty procedural care across the transfer continuum, implying the likelihood of alternate drivers of interhospital transfer other than solely receipt of specialty procedural care. PMID- 29154380 TI - Primary Care Provider Preferences for Communication with Inpatient Teams: One Size Does Not Fit All. PMID- 29154382 TI - Review of Strategies to Reduce Central Line-Associated Bloodstream Infection (CLABSI) and Catheter-Associated Urinary Tract Infection (CAUTI) in Adult ICUs. AB - Central line-associated bloodstream infection (CLABSI) and catheter-associated urinary tract infection (CAUTI) are costly and morbid. Despite evidence-based guidelines, Some intensive care units (ICUs) continue to have elevated infection rates. In October 2015, we performed a systematic search of the peer-reviewed literature within the PubMed and Cochrane databases for interventions to reduce CLABSI and/or CAUTI in adult ICUs and synthesized findings using a narrative review process. The interventions were categorized using a conceptual model, with stages applicable to both CAUTI and CLABSI prevention: (stage 0) avoid catheter if possible, (stage 1) ensure aseptic placement, (stage 2) maintain awareness and proper care of catheters in place, and (stage 3) promptly remove unnecessary catheters. We also looked for effective components that the 5 most successful (by reduction in infection rates) studies of each infection shared. Interventions that addressed multiple stages within the conceptual model were common in these successful studies. Assuring compliance with infection prevention efforts via auditing and timely feedback were also common. Hospitalists with patient safety interests may find this review informative for formulating quality improvement interventions to reduce these infections. PMID- 29154383 TI - Detection of N6-methyladenosine based on the methyl-sensitivity of MazF RNA endonuclease. AB - We found that Escherichia coli MazF toxin, an ACA-sequence-specific endoribonuclease, was sensitive to N6-methyladenosine (m6A), representing the first m6A-sensitive RNA cleavage enzyme. The methyl-sensitivity of MazF allowed simple analyses of both m6A demethylase and methyltransferase activity. Furthermore, the approach could be used for inhibitor screening. PMID- 29154384 TI - Ruthenium-catalyzed olefinic C-H alkenylation of enol-carbamates: highly stereo selective synthesis of (Z,Z) and (Z,E)-butadienes. AB - Cross-coupling reactions of enol carbamates with alkynes or alkenes are reported, using an inexpensive ruthenium catalyst. With the assistance of the directing group OCONMe2, the protocols provide mild, stereo-selective and efficient routes for the preparation of valuable (Z,Z) and (Z,E)-butadiene skeletons. PMID- 29154385 TI - Dendrimers in combination with natural products and analogues as anti-cancer agents. AB - For the first time, an overview of dendrimers in combination with natural products and analogues as anti-cancer agents is presented. This reflects the development of drug delivery systems, such as dendrimers, to tackle cancers. The most significant advantages of using dendrimers in nanomedicine are their high biocompatibility, good water solubility, and their entry - with or without encapsulated, complexed or conjugated drugs - through an endocytosis process. This strategy has accelerated over the years in order to develop nanosystems as nanocarriers, to decrease the intrinsic toxicity of anti-cancer agents, to decrease the drug side effects, to increase the efficacy of the treatment, and consequently to improve patient compliance. PMID- 29154386 TI - Unusual extraction of trivalent f-cations using diglycolamide dendrimers in a room temperature ionic liquid: extraction, spectroscopic and DFT studies. AB - The complexation of Am3+ and Eu3+ was studied with three generations of diglycolamide (DGA)-functionalized poly(propylene imine) diaminobutane dendrimers (DGA-Den) with two, four and eight DGA moieties by solvent extraction and luminescence spectroscopy in a room temperature ionic liquid, viz. 3-butyl-1 methyl imidazolium bis(trifluoromethanesulfonyl)imide ([C4mim][Tf2N]). The extraction of trivalent f-cations was found to increase with decreasing HNO3 concentrations conforming to a cation exchange mechanism with the extraction of Eu3+ being higher than that of Am3+ in the acid concentration range of 0.01-6.0 M HNO3. The nature of the extracted species showed unusual trends compared to those reported previously in molecular diluents. Fluorescence lifetime data suggested the absence of H2O in the extracted complexes meaning strong inner-sphere complexes. The nature of the extracted complexes predicted by solvent extraction was supported by DFT computations. PMID- 29154387 TI - Postmodernism and beyond in occupational therapy. PMID- 29154388 TI - Systematic review of the effect of denosumab on children with osteogenesis imperfecta showed inconsistent findings. PMID- 29154389 TI - Latent autoimmune diabetes and limbic encephalitis with antibodies against glutamic acid decarboxylase. PMID- 29154390 TI - Circadian profiling reveals higher histamine plasma levels and lower diamine oxidase serum activities in 24% of patients with suspected histamine intolerance compared to food allergy and controls. AB - BACKGROUND: Histamine intolerance is thought to trigger manifold clinical symptoms after ingesting histamine-rich food due to reduced activity of diamine oxidase (DAO). No study has hitherto systematically assessed daily fluctuations of histamine levels and DAO activities in symptomatic patients. The aim of the study was to investigate the presence of histamine intolerance, to therefore establish day profiles of histamine levels and DAO activities, and to compare the results between patients with suspected histamine intolerance, food allergy and healthy controls. METHODS: We determined day profiles of histamine plasma levels and DAO serum activities in 33 patients with suspected histamine intolerance, in 21 patients with proven food allergy and in 10 healthy control patients. Clinical symptoms, food intolerances and further clinical and laboratory chemical parameters were evaluated. RESULTS: Twenty-four percent (8 of 33) suspected histamine-intolerant patients showed elevated histamine levels during the day. That might be caused by constantly and significantly reduced DAO activities in these patients compared to food-allergic and control patients. The remaining 25 patients presented normal histamine levels and DAO activities, but an increased prevalence of multiple food intolerances compared to the other subgroup of suspected histamine-intolerants. There was no correlation between subjective complaints and serological histamine parameters in patients with suspected histamine intolerance. CONCLUSIONS: We determined by daily profiling that decreased DAO activities correlated with elevated histamine levels in a subgroup of suspected histamine-intolerants. This finding discriminates these patients from food intolerant individuals with similar clinical symptoms and strongly suggests the presence of histamine intolerance. PMID- 29154391 TI - The value of microscopic-observation drug susceptibility assay in the diagnosis of tuberculosis and detection of multidrug resistance. AB - Inexpensive, rapid, and reliable tests for detecting the presence and drug susceptibility of Mycobacterium tuberculosis complex (MTBC) are urgently needed to control the transmission of tuberculosis. In this study, we aimed to assess the accuracy and speed of the microscopic-observation drug susceptibility (MODS) assay in the identification of MTBC and detection of multidrug resistance. Sputum samples from patients suspected to have tuberculosis were simultaneously tested with MODS and conventional culture [Lowenstein-Jensen (LJ) culture, BACTEC MGITTM 960 (MGIT) system], and drug susceptibility testing (MGIT system) methods. A total of 331 sputum samples were analyzed. Sensitivity and specificity of MODS assay for detection of MTBC strains were 96% and 98.8%, respectively. MODS assay detected multidrug resistant MTBC isolates with 92.3% sensitivity and 96.6% specificity. Median time to culture positivity was similar for MGIT (8 days) and MODS culture (8 days), but was significantly longer with LJ culture (20 days) (p < 0.0001 for both comparisons). Median time to availability of the susceptibility results was significantly (p < 0.0001) shorter with MODS assay (8 days) than MGIT system (20 days). In conclusion, MODS is an inexpensive and rapid test with good performance characteristics for direct diagnosis of tuberculosis and detection of multidrug resistance. PMID- 29154392 TI - Rapid and simple detection of Ureaplasma species from vaginal swab samples using a loop-mediated isothermal amplification method. AB - PROBLEM: Ureaplasma species occasionally cause chorioamnionitis and premature labor. We developed a novel assay employing a loop-mediated isothermal amplification (LAMP) method to detect Ureaplasma parvum and Ureaplasma urealyticum. METHOD OF STUDY: Loop-mediated isothermal amplification primers were designed to amplify Ureaplasma-specific ureaseB genes. Four U. parvum strains, 5 U. urealyticum strains and 14 reference bacterial species were evaluated. Forty six vaginal swab samples were analyzed by LAMP, culture, and PCR. RESULTS: Our LAMP primers were specific to each species and had no cross-reaction. Of 46 clinical specimens, the sensitivity, specificity, and positive and negative predictive values of the LAMP method were 100% (12/12), 100% (34/34), 100% (12/12), and 100% (34/34), respectively, whereas those of PCR were 66.7% (8/12), 100% (34/34), 100% (8/8), and 89.5% (34/38), respectively, compared to culture based detection. CONCLUSION: The LAMP detection method outperformed the culture and PCR methods. Early detection enables appropriate antibiotic selection for improved prenatal outcomes. PMID- 29154393 TI - Using Participatory System Dynamics Modeling to Examine the Local HIV Test and Treatment Care Continuum in Order to Reduce Community Viral Load. AB - Achieving community-level goals to eliminate the HIV epidemic requires coordinated efforts through community consortia with a common purpose to examine and critique their own HIV testing and treatment (T&T) care system and build effective tools to guide their efforts to improve it. Participatory system dynamics (SD) modeling offers conceptual, methodological, and analytical tools to engage diverse stakeholders in systems conceptualization and visual mapping of dynamics that undermine community-level health outcomes and identify those that can be leveraged for systems improvement. We recruited and engaged a 25-member multi-stakeholder Task Force, whose members provide or utilize HIV-related services, to participate in SD modeling to examine and address problems of their local HIV T&T service system. Findings from the iterative model building sessions indicated Task Force members' increasingly complex understanding of the local HIV care system and demonstrated their improved capacity to visualize and critique multiple models of the HIV T&T service system and identify areas of potential leverage. Findings also showed members' enhanced communication and consensus in seeking deeper systems understanding and options for solutions. We discuss implications of using these visual SD models for subsequent simulation modeling of the T&T system and for other community applications to improve system effectiveness. PMID- 29154394 TI - Fibrin thrombi in deceased donor kidneys: Prevalence and influence on graft function and graft survival in transplanted patients. AB - Fibrin thrombi (FT) are occasionally found in the pre-implantation biopsy of kidneys from deceased donors. The aim of this study was to monitor the prevalence and answer the question whether FT has any impact on future graft function in a Danish patient cohort. We looked for FT in all donor kidney biopsies taken at the time of renal transplantation in a Danish transplantation unit during a 10-year period. Every recipient transplanted with a FT donor kidney (n = 15) were matched with up to five control recipients (n = 69), and graft function and graft survival were assessed. FT was present in 3% of the transplanted donor kidneys. Graft function was reduced in the FT group 6 months after transplantation (median estimated glomerular filtration rate (eGFR): 29 mL/min vs 46 mL/min; p = 0.017), but at 12 months, an apparent difference did not reach statistical significance. More patients were on dialysis in the FT group after 12 months compared with the control group (27% vs 6%; p = 0.049). In conclusion, FT in donor kidney biopsies at time of transplantation is a risk factor for the development of reduced renal function during the first year of transplantation. PMID- 29154395 TI - Incidence and risk factors for mortality after release from prison in Australia: a prospective cohort study. AB - AIMS: To estimate the incidence and identify risk factors for mortality in adults released from prisons in the state of Queensland, Australia. DESIGN: Prospective cohort study, linking baseline survey data with a national death register. SETTING: Selected prisons within Queensland, Australia. PARTICIPANTS: Adults (n = 1320) recruited in Queensland prisons within 6 weeks of expected release, between August 2008 and July 2010, followed for up to 4.7 years in the community. MEASUREMENTS: Participants completed a comprehensive baseline survey covering psychosocial circumstances, physical and mental health, substance use and health risk behaviours. Clinical data were abstracted from prison medical records and obtained through probabilistic linkage with state-based, community health records. Dates of prison release and reincarceration were obtained from correctional records. Deaths were identified through probabilistic linkage with the National Death Index. Adjusted hazard ratios (AHR) were calculated using proportional hazards regression models. Standardized mortality ratios (SMR) were calculated using the population of Queensland as the reference. General population data were obtained from the Australian Bureau of Statistics. FINDINGS: The rate of mortality in the cohort was higher than in the age- and sex-matched general population of Queensland for all causes [SMR = 4.0, 95% confidence interval (CI) = 2.9-5.4] and drug-related causes (SMR = 32, 95% CI = 19-55). In a multivariable model, adjusting for age, sex and Indigenous status, factors associated with increased mortality risk included expecting to have average or better funds available on release (AHR = 2.9, 99% CI = 1.2-7.1), poor mental health (AHR = 2.6, 99% CI = 1.1-6.1) and self-reported life-time history of overdose (AHR = 2.5, 99% CI = 1.04-6.2). CONCLUSIONS: People released from prison in Queensland, Australia are at increased risk of death, due particularly to drug related causes. Those at greatest risk of death are characterized by poor physical and mental health and a history of risky substance use. PMID- 29154396 TI - Nurses' experiences of unprofessional behaviors in the emergency department: A qualitative study. AB - The nursing profession is focused on serving others and has high expectations that each member behaves professionally and ethically, as articulated in nursing codes of practice and conduct. Where these are not upheld, inappropriate and unprofessional workplace behaviors follow. Regrettably, unprofessional behavior is neither new nor constrained to the nursing profession, but is known to negatively impact staff and workplace relationships, and importantly, patient safety and care. The aim of this qualitative study was to explore Iranian nurses' experiences of professional communication between colleagues in the emergency department. Fifteen individual interviews were conducted. The overarching theme to emerge from the data was workplace communication, supported by two subthemes: unprofessional behavior and stressors in the workplace. Individually and collectively, these subthemes demonstrated staff attitudes and behaviors that are inconsistent with expectations of professional behavior and practice. Management proactively addressing unprofessional workplace behaviors is fundamental to establishing and maintaining positive workplace environments and supporting safe, quality patient care. PMID- 29154397 TI - Effects of high ambient temperature on plasma metabolomic profiles in chicks. AB - Exposure to high ambient temperature is detrimental to the poultry industry. To understand the influence from a metabolic perspective, we investigated the effects of exposure to high ambient temperature on plasma low-molecular-weight metabolite levels in chicks using gas chromatography/mass spectrometry-based non targeted metabolomic analysis. Heat exposure for 4 days suppressed growth and food intake. Of the 92 metabolites identified, the levels of 29 decreased, whereas the levels of nine increased. We performed an enrichment analysis on the identified metabolites and found 35 candidates for metabolic processes affected by heat exposure. Among them, the sulfur amino acid metabolic pathway was clearly detected and the levels of the following related metabolites were decreased: cystathionine, cysteine, cystine, homocysteine and hypotaurine. Changes in the kynurenine pathway in tryptophan metabolism, which is linked to the immune system and oxidative stress, were also observed: kynurenine and quinolinic acid levels increased, whereas nicotinamide levels decreased. These results suggest the possible involvement of various metabolic processes in heat-exposed chicks. Some of these metabolites would be important to understand the mechanism of biological responses to high ambient temperature in chicks. PMID- 29154398 TI - Community Data Collection with Children of Mothers Living with HIV: Boundaries of the Researcher Role. AB - The TRACK-II program is a multi-site, community-based randomized controlled trial evaluating an intervention to assist mothers living with HIV (MLH) in disclosing their HIV status to their young children. Many participants-both mothers and children-reported significant depression and/or suicidal ideation, a phenomenon that presented ethical challenges. This article focuses on participants at one site (Atlanta). Through the vignette of "Jordan," we describe ethical challenges that may arise when faced with the responsibility of maximizing participants' safety while maintaining the boundaries of the researcher role. Guided by community psychology values, our team has taken measures within our role as researchers to empower and protect children and mothers endorsing suicidal ideation. For example, we have relied on relationships with community-based organizations and AIDS service organizations to connect HIV-affected families to mental health services. Furthermore, we have expanded our system of documentation to follow-up adequately with families at risk, and we track family resources to promote a strengths-based framework. We have solicited families' feedback about their supports and needs to understand how we may best serve them by connecting them to the resources they report needing most and empowering them to care for themselves. PMID- 29154399 TI - For the Good of the Group? Balancing Individual and Collective Risks and Benefits in Community Psychology Research. AB - Balancing risks and benefits is a necessary ethical task for social science researchers. Community psychologists must often consider risks and benefits not just for individual participants, but also for the group, system, or society that those individuals inhabit. Little ethical guidance currently exists for how to navigate this ethical challenge across these multiple levels. In this article, we use a case example of social network research incorporating multiple levels of analysis to identify common risks and benefits and understand their relationship to each other. We conclude by discussing distinctive ethical considerations revealed by this case example. PMID- 29154401 TI - Reiner Benecke and the ISMD. PMID- 29154400 TI - A chiral enantioseparation generic strategy for anti-Alzheimer and antifungal drugs by short end injection capillary electrophoresis using an experimental design approach. AB - The present study describes a generic strategy using capillary electrophoretic (CE) method for chiral enantioseparation of anti-Alzheimer drugs, namely, donepezil (DON), rivastigmine (RIV), and antifungal drugs, namely, ketoconazole (KET), Itraconazole (ITR), fluconazole (FLU), and sertaconazole (SRT) in which these drugs have different basic and acidic properties. Several modified cyclodextrins (CDs) were applied for enantioseparation of racemates such as highly sulfated alpha, gamma CDs, hydroxyl propyl-beta-CD, and Sulfobutyl ether beta-CD. The starting screening conditions consist of 50-mM phosphate triethanolamine buffer at pH 2.5, an applied voltage of 15 kV, and a temperature of 25 degrees C. The CE strategy implemented in the separation starts by screening prior to the optimization stage in which an experimental design is applied. The design of experiment (DOE) was based on a full factorial design of the crucial two factors (pH and %CD) at three levels, to make a total of nine (32 ) experiments with high, intermediate, and low values for both factors. Evaluation of the proposed strategy pointed out that best resolution was obtained at pH 2.5 for five racemates using low percentages of HS-gamma-CD, while SBE-beta CD was the most successful chiral selector offering acceptable resolution for all the six racemates, with the best separation at low pH values and at higher %CD within 10-min runtime. Regression study showed that the linear model shows a significant lack of fit for all chiral selectors, anticipating that higher orders of the factors are most likely to be present in the equation with possible interactions. PMID- 29154402 TI - Transvaginal ultrasound vs magnetic resonance imaging for diagnosing deep infiltrating endometriosis: systematic review and meta-analysis. AB - OBJECTIVE: To perform a systematic review of studies comparing the accuracy of transvaginal ultrasound (TVS) and magnetic resonance imaging (MRI) in diagnosing deep infiltrating endometriosis (DIE) including only studies in which patients underwent both techniques. METHODS: An extensive search was carried out in PubMed/MEDLINE and Web of Science for papers from January 1989 to October 2016 comparing TVS and MRI in DIE. Studies were considered eligible for inclusion if they reported on the use of TVS and MRI in the same set of patients for the preoperative detection of endometriosis in pelvic locations in women with clinical suspicion of DIE and using surgical data as a reference standard. Quality was assessed using the QUADAS-2 tool. A random-effects model was used to determine pooled sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-) and diagnostic odds ratio (DOR). RESULTS: Of 375 citations identified, six studies (n = 424) were considered eligible. For MRI in the detection of DIE in the rectosigmoid, pooled sensitivity was 0.85 (95% CI, 0.78 0.90), specificity was 0.95 (95% CI, 0.83-0.99), LR+ was 18.4 (95% CI, 4.7-72.4), LR- was 0.16 (95% CI, 0.11-0.24) and DOR was 116 (95% CI, 23-585). For TVS in the detection of DIE in the rectosigmoid, pooled sensitivity was 0.85 (95% CI, 0.68 0.94), specificity was 0.96 (95% CI, 0.85-0.99), LR+ was 20.4 (95% CI, 4.7-88.5), LR- was 0.16 (95% CI, 0.07-0.38) and DOR was 127 (95% CI, 14-1126). For MRI in the detection of DIE in the rectovaginal septum, pooled sensitivity was 0.66 (95% CI, 0.51-0.79), specificity was 0.97 (95% CI, 0.89-0.99), LR+ was 22.5 (95% CI, 6.7-76.2), LR- was 0.38 (95% CI, 0.23-0.52) and DOR was 65 (95% CI, 21-204). For TVS in the detection of DIE in the rectovaginal septum, pooled sensitivity was 0.59 (95% CI, 0.26-0.86), specificity was 0.97 (95% CI, 0.94-0.99), LR+ was 23.5 (95% CI, 9.1-60.5), LR- was 0.42 (95% CI, 0.18-0.97) and DOR was 56 (95% CI, 11 275). For MRI in the detection of DIE in the uterosacral ligaments, pooled sensitivity was 0.70 (95% CI, 0.55-0.82), specificity was 0.93 (95% CI, 0.87 0.97), LR+ was 10.4 (95% CI, 5.1-21.2), LR- was 0.32 (95% CI, 0.20-0.51) and DOR was 32 (95% CI, 12-85). For TVS in the detection of DIE in the uterosacral ligaments, pooled sensitivity was 0.67 (95% CI, 0.55-0.77), specificity was 0.86 (95% CI, 0.73-0.93), LR+ was 4.8 (95% CI, 2.6-9.0), LR- was 0.38 (95% CI, 0.29 0.50) and DOR was 12 (95% CI, 7-24). Confidence intervals of pooled sensitivities, specificities and DOR were wide for both techniques in all the locations considered. Heterogeneity was moderate or high for sensitivity and specificity for both TVS and MRI in most locations assessed. According to QUADAS 2, the quality of the included studies was considered good for most domains. CONCLUSION: The diagnostic performance of TVS and MRI is similar for detecting DIE involving rectosigmoid, uterosacral ligaments and rectovaginal septum. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29154403 TI - Paleo-inspired Systems: Durability, Sustainability, and Remarkable Properties. AB - The process of mimicking properties of specific interest (such as mechanical, optical, and structural) observed in ancient and historical systems is designated here as paleo-inspiration. For instance, recovery in archaeology or paleontology identifies materials that are a posteriori extremely resilient to alteration. All the more encouraging is that many ancient materials were synthesized in soft chemical ways, often using low-energy resources and sometimes rudimentary manufacturing equipment. In this Minireview, ancient systems are presented as a source of inspiration for innovative material design in the Anthropocene. PMID- 29154405 TI - Editorial. PMID- 29154404 TI - Diabetes Canada 2017. AB - Ann M. Carracher, Payal H. Marathe, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Carracher, Marathe, and Close review the latest developments relevant to researchers and clinicians. PMID- 29154406 TI - Promoting Resilience Among African American Girls: Racial Identity as a Protective Factor. AB - This study examines school climate, racial identity beliefs, and achievement motivation beliefs within a cultural-ecological and risk and resilience framework. Data were drawn from a longitudinal study of 733 (Mage = 14.49) African American adolescent girls. A linear mixed effects model was used to determine if racial identity dimensions moderated the relationship between school climate and achievement motivation beliefs across four waves. Results revealed that racial identity (private regard and racial centrality) and ideology (nationalist) beliefs were associated with higher achievement motivation beliefs over time, while racial centrality and private regard, and a sense of belonging served as protective factors. The findings contribute to the importance of racial identity beliefs and increase the visibility of African American girls. PMID- 29154407 TI - Exercises of dynamic stability under unstable conditions increase muscle strength and balance ability in the elderly. AB - The purpose of this study was to assess the effectiveness of a specific exercise intervention of mechanisms to control dynamic postural stability under unstable conditions in old adults. Forty-seven old adults (65-80 years) were assigned to 2 experimental groups (muscle strength group, n = 15; perturbation-based group, n = 16) and a control group (n = 16). The strength group performed resistance exercises for leg and trunk muscles, while the perturbation-based group exercised mechanisms of dynamic stability under unstable conditions. The training duration was 14 weeks, with training sessions twice a week for 1.5 hours. Muscle strength, balance ability, and balance recovery performance were investigated before and after the interventions using maximal isometric plantar flexion and knee extension contractions, the approach of the center of pressure to the anterior limits of stability and simulated forward falls. Both interventions increased balance recovery performance in simulated forward falls (81%, d = 1.50 and 80%, d = 1.08 in the muscle strength and perturbation-based group, respectively), while the control group did not show any changes. Plantar flexor strength increased 20% (d = 0.72) in the muscle strength and 23% (d = 1.03) in the perturbation-based group, while muscle strength of the knee extensors increased only in the muscle strength group (8%, d = 0.76). On the other hand, only the perturbation-based group showed a significant improvement of standing balance ability (38%, d = 1.61). We conclude that a perturbation-based training program focusing on exercising mechanisms of dynamic stability in unstable conditions has the potential to enhance muscle strength as well as sensory information processing within the motor system during sudden and static balance tasks and, as a consequence, reduce the risk of falls in old adults. PMID- 29154408 TI - Chemokine (C-C motif) ligand 25 expressed by trophoblast cells and leukocytes bearing its receptor Ccr9: An alliance during embryo implantation? AB - PROBLEM: We hypothesized that trophoblast expression of Ccl25 attracts a specific leukocyte cell population to the implantation site for local regulation. METHOD OF STUDY: Mice blastocysts, ectoplacental cones, and decidua at gestational days 3.5-7.5 were evaluated for Ccl25 and Ccr9 expressions. Peripheral availability and characterization of Ccr9+ leukocytes were determined by flow cytometry. Leukocyte chemotaxis was assessed in the presence of Ccl25 recombinant protein and embryos using antisense oligomers (ODNs) to Ccl25 and Ccr9 neutralizing antibody. RESULTS: Ccl25 was expressed by embryonic cells, whereas Ccr9 expression was strong at the maternal compartment and in PBMC. Immunolocalization confirmed this expression. In vitro, chemotaxis assays showed that the embryonic Ccl25 signals to Ccr9+ PBMCs. Maternal Ccr9+alpha4beta7+ monocytes switch from an anti-inflammatory phenotype (F4/80+11b+Ly6C-TGF-beta+ cells, pre-implantation) to an inflammatory profile (F4/80+11b+Ly6C+TNF-alpha+ cells, post-implantation). CONCLUSION: Our data support the establishment of a CCL25/CCR9-axis at the maternal-fetal interface in mice, which may be involved in immune regulatory mechanisms during embryo implantation. PMID- 29154409 TI - Sensitive Topics, Missing Data, and Refusal in Social Network Studies: An Ethical Examination. AB - We describe our ethics-driven process of addressing missing data within a social network study about accountability for racism, classism, sexism, heterosexism, cis-sexism, ableism, and other forms of oppression among social justice union organizers. During data collection, some would-be participants did not return emails and others explicitly refused to engage in the research. All refusals came from women of color. We faced an ethical dilemma: Should we continue to seek participation from those who had not yet responded, with the hopes of recruiting more women of color from within the network so their perspectives would not be tokenized? Or, should we stop asking those who had been contacted multiple times, which would compromise the social network data and analysis? We delineate ways in which current discussions of the ethics of social network studies fell short, given our framework and our community psychology (CP) values. We outline literature that was helpful in thinking through this challenge; we looked outside of CP to the decolonization literature on refusal. Lessons learned include listening for the possible meanings of refusals and considering the level of engagement and the labor required of participants when designing research studies. PMID- 29154410 TI - Predicting success of methotrexate treatment by pretreatment HCG level and 24 hour HCG increment. AB - OBJECTIVE: To evaluate beta-human chorionic gonadotropin (beta-HCG) level and its 24-hour increment as predictors of successful methotrexate treatment for ectopic pregnancy. METHODS: Data were retrospectively reviewed from women with ectopic pregnancy who were treated by single-dose methotrexate (50 mg/m2 ) at a university hospital in Jerusalem, Israel, between January 1, 2000, and June 30, 2015. Serum beta-HCG before treatment and its percentage increment in the 24 hours before treatment were compared between treatment success and failure groups. RESULTS: Sixty-nine women were included in the study. Single-dose methotrexate treatment was successful for 44 (63.8%) women. Both mean beta-HCG level and its 24-hour increment were lower for women with successful treatment than for those with failed treatment (respectively, 1224 IU?L vs 2362 IU?L, P=0.018; and 13.5% vs 29.6%, P=0.009). Receiver operator characteristic curve analysis yielded cutoff values of 1600 IU?L and 14% increment with a positive predictive value of 75% and 82%, respectively, for treatment success. beta-HCG level and its 24-hour increment were independent predictors of treatment outcome by logistic regression (both P<0.01). CONCLUSIONS: A beta-HCG increment of less than 14% in the 24 hours before single-dose methotrexate and serum beta-HCG of less than 1600 IU?L were found to be good predictors of treatment success. PMID- 29154411 TI - Effect of graft size matching on pediatric living-donor liver transplantation at a single center. AB - We retrospectively analyzed 252 patients with end-stage liver disease who had undergone LDLT from January 2009 to September 2015. Of these, 25 had a GRWR of <2.0% (Group A), 204 had a GRWR of >=2.0% or <4.0% (Group B), and 23 had a GRWR >=4.0% (Group C). The three GRWR groups demonstrated similar characteristics, except for recipient age and recipient BMI. The overall 1-, 2-, and 3-year graft survival rates were 95.1%, 93.5%, and 93.5%, respectively. However, among the three groups, graft survival rates at 1 year, 2 years, and 3 years were significantly different (P = .0009). Hepatic artery stenosis/thrombosis was more frequently observed in Group C than in Groups A and B (P = .001). Wound infection was also more frequently observed in Group C than in Group A and B (P = .002). However, intestinal fistula/bile leakage/biliary-enteric anastomotic fistula was more frequently observed in Group A than in Groups B and C (P = .001). In addition, reoperation more frequently occurred in Group A and C than in Group B (P = .001). Recipients with a GRWR between 2.0% and 4.0% had significantly better graft survival rates. PMID- 29154412 TI - The impact of mating systems and dispersal on fine-scale genetic structure at maternally, paternally and biparentally inherited markers. AB - For decades, studies have focused on how dispersal and mating systems influence genetic structure across populations or social groups. However, we still lack a thorough understanding of how these processes and their interaction shape spatial genetic patterns over a finer scale (tens-hundreds of metres). Using uniparentally inherited markers may help answer these questions, yet their potential has not been fully explored. Here, we use individual-level simulations to investigate the effects of dispersal and mating system on fine-scale genetic structure at autosomal, mitochondrial and Y chromosome markers. Using genetic spatial autocorrelation analysis, we found that dispersal was the major driver of fine-scale genetic structure across maternally, paternally and biparentally inherited markers. However, when dispersal was restricted (mean distance = 100 m), variation in mating behaviour created strong differences in the comparative level of structure detected at maternally and paternally inherited markers. Promiscuity reduced spatial genetic structure at Y chromosome loci (relative to monogamy), whereas structure increased under polygyny. In contrast, mitochondrial and autosomal markers were robust to differences in the specific mating system, although genetic structure increased across all markers when reproductive success was skewed towards fewer individuals. Comparing males and females at Y chromosome vs. mitochondrial markers, respectively, revealed that some mating systems can generate similar patterns to those expected under sex-biased dispersal. This demonstrates the need for caution when inferring ecological and behavioural processes from genetic results. Comparing patterns between the sexes, across a range of marker types, may help us tease apart the processes shaping fine-scale genetic structure. PMID- 29154414 TI - The Costs and Benefits of Investing in Universal Preschool: Evidence From a Spanish Reform. AB - This study provides a cost-benefit analysis of expanding access to universal preschool education, focusing on a Spanish reform that lowered the age of eligibility for publicly provided universal preschool from age 4 to age 3. Benefits in terms of child development and maternal employment are estimated using evidence on the causal effects of this reform. In the baseline estimation the benefit-cost ratio is over 4, indicating sizeable net societal benefits of the preschool investment. The results show that the child development effects are the major determinant of the cost-benefit ratio; the employment gains for parents appear to play a relatively minor role. Overall, the cost-benefit analysis provides support for investing in high-quality preschool education. PMID- 29154413 TI - Isoindigo-3,4-Difluorothiophene Polymer Acceptors Yield "All-Polymer" Bulk Heterojunction Solar Cells with over 7 % Efficiency. AB - Poly(isoindigo-alt-3,4-difluorothiophene) (PIID[2F]T) analogues used as "polymer acceptors" in bulk-heterojunction (BHJ) solar cells achieve >7 % efficiency when used in conjunction with the polymer donor PBFTAZ (model system; copolymer of benzo[1,2-b:4,5-b']dithiophene and 5,6-difluorobenzotriazole). Considering that most efficient polymer-acceptor alternatives to fullerenes (e.g. PC61 BM or its C71 derivative) are based on perylenediimide or naphthalenediimide motifs thus far, branched alkyl-substituted PIID[2F]T polymers are particularly promising non fullerene candidates for "all-polymer" BHJ solar cells. PMID- 29154415 TI - Persistent high blood urea nitrogen level is associated with increased risk of cardiovascular events in patients with acute heart failure. AB - AIMS: The association between kinetics of blood urea nitrogen (BUN) levels in hospital and cardiovascular outcomes in patients with acutely decompensated congestive heart failure (HF) is unclear. We aimed to estimate the impact of changes in BUN level during hospitalization on clinical prognosis in patients with acute HF. METHODS AND RESULTS: A total of 353 consecutive patients that were urgently hospitalized due to acutely decompensated HF and discharged alive were divided into four subgroups depending on their BUN level at admission and discharge, using a cut-off level of 21.0 mg/dL. Among 206 patients with high baseline BUN level, 46 (22%) and 160 (78%) had normal and persistent high BUN levels at discharge, respectively. In contrast, of the 147 patients with normal baseline BUN level, 55 (37%) and 92 (63%) had high and normal BUN levels at discharge, respectively. During the observational period after discharge, Kaplan Meier analysis showed the highest rate of combined outcome of cardiovascular death and HF readmission in patients with persistent high BUN (log-rank test: P < 0.001). After adjustment for comorbidities, the hazard ratio for a combined outcome was significantly lower in patients with normalized BUN level compared with those with persistent high BUN (hazard ratio 0.48, 95% confidence interval 0.23-0.99, P = 0.049). CONCLUSIONS: Persistent high BUN levels in hospital are associated with an increased risk of cardiovascular death and HF readmission. Normalization of BUN levels during hospitalization may be associated with long term clinical outcomes. PMID- 29154416 TI - Left ventricular global longitudinal strain in patients with heart failure with preserved ejection fraction: outcomes following an acute heart failure hospitalization. AB - AIMS: While abnormal resting LV GLS has been described in patients with chronic heart failure with preserved ejection fraction (HFpEF), its prognostic significance when measured during an acute heart failure hospitalization remains unclear. We assessed the association between left ventricular global longitudinal strain (LV GLS) and outcomes in patients hospitalized with acute HFpEF. METHODS AND RESULTS: We studied patients discharged alive for acute HFpEF from Duke University Medical Center between 2007 and 2010. Among patients with measurable LV GLS, we performed 2D, speckle-tracking analysis and Cox proportional hazards models assessed the association between continuous LV GLS and outcomes. Baseline characteristics were stratified by normal (<=-16%) or abnormal (>-16%) LV GLS for comparison. Among 463 patients, the median LV GLS was -12.8% (Interquartile range, -15.8 to -10.8%) and was abnormal in 352 (76%). Overall patients in the cohort were generally elderly, female and had hypertension. After multivariable adjustment, worse outcomes were noted between LV GLS and mortality (HR 1.19 per 1% increase; 95% CI 1.00-1.42; P = 0.046) and a composite endpoint of mortality or rehospitalization at 30 days (HR 1.08 per 1% increase; 95% CI 0.99-1.18; P = 0.08). There was no association between LV GLS and mortality or a composite of mortality or rehospitalization at 1 year. CONCLUSIONS: A high prevalence of patients hospitalized with acute HFpEF have abnormal LV GLS suggesting unrecognized myocardial systolic dysfunction. Furthermore, worse LV GLS is associated with worse clinical outcomes at 30 days but not by1 year. PMID- 29154417 TI - Impact of chronic kidney disease on the diuretic response of tolvaptan in acute decompensated heart failure. AB - AIM: This study investigated the relationship between the initial diuretic response to tolvaptan and clinical predictors for tolvaptan responders in patients with acute decompensated heart failure (ADHF). METHODS AND RESULTS: Patients (153) with ADHF (clinical scenario 2 or 3 with signs of fluid retention) who were administered tolvaptan were enrolled. Tolvaptan (15 or 7.5 mg) was administered for at least 7 days to those patients in whom fluid retention was observed even after standard treatment. The maximum urine volume immediately after tolvaptan administration showed good correlations with the ejection fraction and estimated glomerular filtration rate that were independent predictors of the urine volume (UV) responders (>=1500 mL increase in urine volume). The diuretic response (in terms of maximum diuresis) diminished with advancing chronic kidney disease (CKD) stage and concomitant deterioration of the renal function. Furthermore, advanced CKD was a significant negative predictor for the body weight (BW) responders (2.0% decrease in the body weight within 1 week after starting tolvaptan). As compared with non-CKD, the presence of advanced CKD predicts poor diuretic response for both UV and BW responders. CONCLUSIONS: The diuretic response following tolvaptan administration gradually diminished with progressive deterioration of the CKD stage. Worsening renal function was not observed. Tolvaptan is effective in treating CS2 or CS3 ADHF patients who present fluid retention and congestion, suggesting its potential efficacy for fluid management in the ADHF patients with CKD without worsening the renal function. PMID- 29154418 TI - Measuring non-polyaminated lipocalin-2 for cardiometabolic risk assessment. AB - AIMS: Lipocalin-2 is a pro-inflammatory molecule characterized by a highly diversified pattern of expression and structure-functional relationships. In vivo, this molecule exists as multiple variants due to post-translational modifications and/or protein-protein interactions. Lipocalin-2 is modified by polyamination, which enhances the clearance of this protein from the circulation and prevents its excessive accumulation in tissues. On the other hand, animal studies suggest that non-polyaminated lipocalin-2 (npLcn2) plays a causal role in the pathogenesis of obesity-associated medical complications. The present study examined the presence of npLcn2 in samples from healthy volunteers or patients with cardiac abnormalities and evaluated npLcn2 as a biomarker for cardiometabolic risk assessment. METHODS AND RESULTS: Immunoassays were developed to quantify npLcn2 in blood and urine samples collected from 100 volunteers (59 men and 41 women), or venous plasma and pericardial fluid samples obtained from 37 cardiothoracic surgery patients. In healthy volunteers, npLcn2 levels in serum are significantly higher in obese and overweight than in lean subjects. After adjustment for age, gender, smoking, and body mass index (BMI), serum npLcn2 levels are positively correlated with heart rate, circulating triglycerides, high sensitivity C-reactive protein (hsCRP), and creatinine in plasma. The npLcn2 levels in urine are significantly increased in subjects with metabolic syndrome and positively correlated with BMI, heart rate, circulating triglycerides, and urinary aldosterone. In cardiothoracic surgery patients, the circulating concentrations of npLcn2 are higher (more than two-fold) than those of healthy volunteers and positively correlated with the accumulation of this protein in the pericardial fluid. Heart failure patients exhibit excessive expression and distribution of npLcn2 in mesothelial cells and adipocytes of the parietal pericardium, which are significantly correlated with the elevated plasma levels of npLcn2, total cholesterol, and creatinine. CONCLUSIONS: Quantitative and qualitative evaluation of npLcn2 in human biofluid samples and tissue samples can be applied for risk assessment of healthy individuals and disease management of patients with obesity-related cardiometabolic and renal complications. PMID- 29154419 TI - Clinical profiles and prognosis of acute heart failure in adult patients with dystrophinopathies on home mechanical ventilation. AB - AIMS: Duchenne muscular dystrophy (DMD) is characterized by respiratory and heart involvements. In the context of permanently wheelchair bound and on mechanical ventilation (MV) patients, the clinical presentation of acute heart failure (AHF) syndrome may be atypical. We sought to describe clinical and genetic profiles and to determine prognosis of DMD and Becker muscular dystrophy (BMD) patients on home MV (HMV), hospitalized for AHF. METHODS AND RESULTS: We included genetically proven DMD and BMD patients on HMV admitted for AHF. A total of 13 patients (11 DMD and 2 BMD) fulfilled the inclusion criteria. Median age was 34.0 [interquartile range (IQR) 26.0; 40.0] years. Median pulmonary vital capacity was 9.0% (6.0; 15.0) of predicted value. Long-term invasive ventilation was performed in 69% of patients. All the 11 DMD patients carried out-of-frame DMD gene mutations. At admission, dyspnoea was present in 46%, lipothymia in 23%, and abdominal discomfort in 38.4% of patients. A total of 53.8% of patients showed anasarca. Cardiogenic shock presentation was found in six patients (46%). Ejection fraction was severely altered [median 25% (IQR 20; 30)]. Intra-hospital mortality rate was 30%, reaching 53.8 % after 1 year. Previous episodes of AHF >= 2 were associated with intra-hospital mortality (P = 0.025). In patients with cardiogenic shock, intra-hospital mortality rate was 66.6%, reaching 83.3% after 1 year. CONCLUSIONS: In adult DMD and BMD patients with severe ejection fraction alteration and on HMV, admitted for AHF, right cardiac signs are frequent. The intra-hospital and 1 year mortality rate was high and was associated with previous episodes of AHF >= 2. PMID- 29154420 TI - Relationship between skeletal muscle mass and cardiac function during exercise in community-dwelling older adults. AB - AIMS: This study aimed to investigate the relationship between skeletal muscle mass and cardiac functional parameters in older adults during cardiopulmonary exercise testing (CPET). METHODS AND RESULTS: Sixty-three Japanese community dwelling older adults were enrolled (20 men and 43 women; mean age 80 years, range 65-97 years). Cardiac functional parameters during exercise were assessed using CPET. Skeletal muscle mass index (SMI) was calculated by dividing the appendicular lean mass (measured using dual-energy X-ray absorptiometry) by height in metres squared. Subjects were divided into two groups: men with SMI >= 7.0 kg/m2 and women with SMI >= 5.4 kg/m2 (non-sarcopenic group); or men with SMI < 7.0 kg/m2 and women with SMI < 5.4 kg/m2 (sarcopenic group). There were significant positive correlations between SMI and peak oxygen uptake (VO2 ) (r = 0.631, P < 0.001), and between SMI and peak VO2 /heart rate (HR) (r = 0.683, P < 0.001). However, only peak VO2 /HR significantly differed between groups in both sexes. Multiple linear regression analyses with peak VO2 /HR as a dependent variable showed that SMI was the only independent determinant after adjusting for potential confounders. After 4 month follow-up of 47 participants, there was still a significant positive correlation between SMI and peak VO2 /HR (r = 0.567, P < 0.001), and between percent change of SMI and percent change of peak VO2 /HR (r = 0.305, P < 0.05). CONCLUSIONS: Peak VO2 /HR, an index of stroke volume at peak exercise, was associated with SMI. This indicates that skeletal muscle mass might affect cardiac function during exercise. PMID- 29154421 TI - Haemodynamic monitoring of cardiac status using heart sounds from an implanted cardiac device. AB - AIM: The aim of this study was to evaluate the haemodynamic correlates of heart sound (HS) parameters such as third HS (S3), first HS (S1), and HS-based systolic time intervals (HSTIs) from an implantable cardiac device. METHODS AND RESULTS: Two unique animal models (10 swine with myocardial ischaemia and 11 canines with pulmonary oedema) were used to evaluate haemodynamic correlates of S1, S3, and HSTIs, namely, HS-based pre-ejection period (HSPEP), HS-based ejection time (HSET), and the ratio HSPEP/HSET during acute haemodynamic perturbations. The HS was measured using implanted cardiac resynchronization therapy defibrillator devices simultaneously with haemodynamic references such as left atrial (LA) pressure and left ventricular (LV) pressure. In the ischaemia model, S1 amplitude (r = 0.76 +/- 0.038; P = 0.002), HSPEP (r = -0.56 +/- 0.07; P = 0.002), and HSPEP/HSET (r = -0.42 +/- 0.1; P = 0.002) were significantly correlated with LV dP/dtmax . In contrast, HSET was poorly correlated with LV dP/dtmax (r = 0.14 +/- 0.14; P = 0.23). In the oedema model, a physiological delayed response was observed in S3 amplitude after acute haemodynamic perturbations. After adjusting for the delay, S3 amplitude significantly correlated with LA pressure in individual animals (r = 0.71 +/- 0.07; max: 0.92; min: 0.17) as well as in aggregate (r = 0.62; P < 0.001). The S3 amplitude was able to detect elevated LA pressure, defined as >25 mmHg, with a sensitivity = 58% and specificity = 90%. CONCLUSIONS: The HS parameters such as S1, S3, and HSTIs measured using implantable devices significantly correlated with haemodynamic changes in acute animal models, suggesting potential utility for remote heart failure patient monitoring. PMID- 29154422 TI - Beta blocker dose and markers of sympathetic activation in heart failure patients: interrelationships and prognostic significance. AB - AIMS: Extent of cardiac sympathetic activation can be estimated from physiological parameters, blood biomarkers, and imaging findings. This study examined the prognostic value of three markers of sympathetic activity and their relationship to beta blocker dose in heart failure patients. METHODS AND RESULTS: A post hoc analysis of 858 heart failure subjects in the ADMIRE-HF trial was performed. Variables related to sympathetic activity were plasma norepinephrine, baseline heart rate, the heart to mediastinum (H/M) ratio of 123 I-mIBG uptake, and beta blocker dose. Univariate and multivariate analyses for occurrence of mortality (all-cause and cardiac) and arrhythmic events were performed. Beta blocker dose was significantly related to age, heart rate, b-type natriuretic peptide (negatively), body mass index, body weight and plasma norepinephrine. Univariate predictors of all-cause and cardiac mortality were baseline heart rate (chi2 = 4.5, P = 0.029 and chi2 = 5 .2, P = 0.022, respectively), plasma norepinephrine level (chi2 = 8.9, P = 0.0006 and chi2 = 8.6, P = 0.003, respectively), and H/M (chi = 22.4, P < 0.0001 and chi2 = 17.8, P < 0.0001, respectively). In multivariate analyses, carvedilol-equivalent dose (P = 0.017), plasma norepinephrine (P = 0.002), and H/M (P = 0.0001) were significant predictors of all-cause mortality. In separate analyses using multiple measurements of heart rate, mean heart rate >67 b.p.m. was associated with significantly higher cardiac mortality. CONCLUSIONS: Higher beta blocker dose was associated with lower mortality, but of the variables associated with sympathetic activity examined, cardiac 123 I-mIBG uptake was the most powerful prognostic marker in heart failure patients. Elevated heart rate was associated with greater risk for cardiac death. PMID- 29154423 TI - The contractile adaption to preload depends on the amount of afterload. AB - AIMS: The Frank-Starling mechanism (rapid response (RR)) and the secondary slow response (SR) are known to contribute to increases contractile performance. The contractility of the heart muscle is influenced by pre-load and after-load. Because of the effect of pre-load vs. after-load on these mechanisms in not completely understood, we studied the effect in isolated muscle strips. METHODS AND RESULTS: Progressive stretch lead to an increase in shortening/force development under isotonic (only pre-load) and isometric conditions (pre- and after-load). Muscle length with maximal function was reached earlier under isotonic (Lmax-isotonic ) compared with isometric conditions (Lmax-isometric ) in nonfailing rabbit, in human atrial and in failing ventricular muscles. Also, SR after stretch from slack to Lmax-isotonic was comparable under isotonic and isometric conditions (human: isotonic 10 +/- 4%, isometric 10 +/- 4%). Moreover, a switch from isotonic to isometric conditions at Lmax-isometric showed no SR proving independence of after-load. To further analyse the degree of SR on the total contractile performance at higher pre-load muscles were stretched from slack to 98% Lmax-isometric under isotonic conditions. Thereby, the SR was 60 +/- 9% in rabbit and 51 +/- 14% in human muscle strips. CONCLUSIONS: This work shows that the acute contractile response largely depends on the degree and type of mechanical load. Increased filling of the heart elevates pre-load and prolongs the isotonic part of contraction. The reduction in shortening at higher levels of pre-load is thereby partially compensated by the pre-load-induced SR. After-load shifts the contractile curve to a better 'myofilament function' by probably influencing thin fibers and calcium sensitivity, but has no effect on the SR. PMID- 29154424 TI - Acute fulminant necrotizing eosinophilic myocarditis: early diagnosis and treatment. AB - Necrotizing eosinophilic myocarditis is a rare but potentially fatal condition that requires prompt recognition and treatment. We describe a case of a young athlete presenting with chest pain and breathlessness, with evidence of rapidly deteriorating cardiac function. The condition was successfully treated with corticosteroids, with no evidence of residual myocardial damage. This is the first reported case to demonstrate the utility of cardiac magnetic resonance imaging for diagnosis and monitoring response to treatment. It also highlights the value of endomyocardial biopsy in establishing a tissue diagnosis in cases of fulminant myocarditis, in order to direct treatment appropriately. PMID- 29154425 TI - Influence of renal impairment on aldosterone status, calcium metabolism, and vasopressin activity in outpatients with systolic heart failure. AB - AIMS: Renal dysfunction (RD) is associated with increased morbidity and mortality in heart failure (HF). At present, no specific treatment for patients with RD, to prevent progression of HF, has been developed. How different hormone axes-and thereby potential treatment options-are affected by RD in HF warrants further investigations. METHODS AND RESULTS: Patients with left ventricular ejection fraction (LVEF) <0.45% were enrolled prospectively from an outpatient HF clinic. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR), and patients were grouped by eGFR: eGFR group I, >=90 mL/min/1.73 m2 ; eGFR group II, 60-89 mL/min/1.73 m2 ; and eGFR group III, <=59 mL/min/1.73 m2 . Multivariate linear regression models were developed to evaluate the associations between eGFR groups and hormones. A total of 149 patients participated in the study. Median age was 69 [interquartile range (IQR): 64-73] and 26% were female; LVEF was 33% (IQR: 27-39), 78% were in functional class II-III, median eGFR was 74 (54-89) mL/min/1.73 m2 , and median N terminal pro-brain natriuretic peptide was 1303 pg/mL (IQR: 441-2740). RD was associated with increased aldosterone, parathyroid hormone (PTH), and copeptin concentrations (P < 0.05 for all) after adjustment for traditional confounders and medical treatment. CONCLUSIONS: RD is associated with increased concentrations of aldosterone, PTH, and copeptin in systolic HF outpatients. Our results underscore the importance of treatment with mineralocorticoid receptor antagonist in systolic HF in particular in patients with RD and suggest that vasopressin and parathyroid receptor antagonism are potential treatment options in HF patients with known RD. PMID- 29154426 TI - Microvascular dysfunction and cardiac fibrosis in heart failure with preserved ejection fraction: a case report. AB - We report the case of a 55-year-old woman with heart failure with preserved ejection fraction (HFpEF), who presented with hypertensive urgency and pulmonary oedema. The patient was medically optimized and underwent cardiac catheterization revealing pulmonary hypertension, elevated pulmonary capillary wedge pressure, normal cardiac index, and non-obstructive coronary disease. Invasive evaluation of coronary flow revealed blunted coronary flow reserve and increased index of microvascular resistance. Cardiac magnetic resonance imaging demonstrated reduced global myocardial perfusion and diffuse interstitial fibrosis. This case exhibits a potential HFpEF phenotype associated with microvascular dysfunction, fibrosis, and elevated filling pressures. PMID- 29154427 TI - Design of a multicentre randomized controlled trial to assess the safety and efficacy of dose titration by specialized nurses in patients with heart failure. ETIFIC study protocol. AB - AIMS: Heart failure (HF) is associated with many hospital admissions and relatively high mortality, rates decreasing with administration of beta-blockers (BBs), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists. The effect is dose dependent, suboptimal doses being common in clinical practice. The 2012 European guidelines recommend close monitoring and dose titration by HF nurses. Our main aim is to compare BB doses achieved by patients after 4 months in intervention (HF nurse-managed) and control (cardiologist-managed) groups. Secondary aims include comparing doses of the other aforementioned drugs achieved after 4 months, adverse events, and outcomes at 6 months in the two groups. METHODS: We have designed a multicentre (20 hospitals) non-inferiority randomized controlled trial, including patients with new-onset HF, left ventricular ejection fraction <=40%, and New York Heart Association class II-III, with no contraindications to BBs. We will also conduct qualitative analysis to explore potential barriers to and facilitators of dose titration by HF nurses. In the intervention group, HF nurses will implement titration as prescribed by cardiologists, following a protocol. In controls, cardiologists will both prescribe and titrate doses. The study variables are doses of each of the drugs after 4 months relative to the target dose (%), New York Heart Association class, left ventricular ejection fraction, N-terminal pro B-type natriuretic peptide levels, 6 min walk distance, comorbidities, renal function, readmissions, mortality, quality of life, and psychosocial characteristics. CONCLUSIONS: The trial seeks to assess whether titration by HF nurses of drugs recommended in practice guidelines is safe and not inferior to direct management by cardiologists. The results could have an impact on clinical practice. PMID- 29154429 TI - Contrast-enhanced computed tomography with myocardial three-dimensional printing can guide treatment in symptomatic hypertrophic obstructive cardiomyopathy. AB - Both surgical myectomy and percutaneous transluminal septal myocardial ablation are effective treatments for drug-refractory symptomatic hypertrophic obstructive cardiomyopathy (HOCM). However, in some cases, it is not easy to elucidate the abnormal structure of left ventricular outflow obstruction to adopt these treatments. Here, we presented a young female patient with drug-refractory symptomatic HOCM. In this case, contrast-enhanced computed tomography enabled us to assess the suitability of percutaneous transluminal septal myocardial ablation. By creating three-dimensional printed models using computed tomography data, we could also visualize intracardiac structure and simulate the surgical procedure. A multimodality assessment strategy is useful for evaluating patients complicated with drug-refractory symptomatic HOCM. PMID- 29154428 TI - Muscle wasting and sarcopenia in heart failure and beyond: update 2017. AB - Sarcopenia (loss of muscle mass and muscle function) is a strong predictor of frailty, disability and mortality in older persons and may also occur in obese subjects. The prevalence of sarcopenia is increased in patients suffering from chronic heart failure. However, there are currently few therapy options. The main intervention is resistance exercise, either alone or in combination with nutritional support, which seems to enhance the beneficial effects of training. Also, testosterone has been shown to increased muscle power and function; however, a possible limitation is the side effects of testosterone. Other investigational drugs include selective androgen receptor modulators, growth hormone, IGF-1, compounds targeting myostatin signaling, which have their own set of side effects. There are abundant prospective targets for improving muscle function in the elderly with or without chronic heart failure, and the continuing development of new treatment strategies and compounds for sarcopenia and cardiac cachexia makes this field an exciting one. PMID- 29154430 TI - Lower than expected burden of premature ventricular contractions impairs myocardial function. AB - AIMS: We aimed to explore the burden of frequent premature ventricular contractions (PVCs) associated with myocardial dysfunction in patients with outflow tract arrhythmia (OTA). We hypothesized that this threshold is lower than the previously suggested threshold of 24 000 PVCs/24 h (24%PVC) when systolic function is assessed by strain echocardiography. Furthermore, we aimed to characterize OTA patients with malignant arrhythmic events. METHODS AND RESULTS: We included 52 patients referred for OTA ablation (46 +/- 12 years, 58% female). Left ventricular global longitudinal strain (GLS) and mechanical dispersion were assessed by speckle tracking echocardiography. A subset underwent cardiac magnetic resonance imaging. PVC burden (%PVC) was assessed by Holter recording. Sinus rhythm QRS duration and PVC QRS duration were recorded from electrocardiogram, and the ratio was calculated (PVC QRS duration / sinus rhythm QRS duration). Median %PVC was 7.2 (0.2-60.0%). %PVC correlated with GLS (R = 0.44, P = 0.002) and with mechanical dispersion (R = 0.48, P < 0.001), but not with ejection fraction (R = 0.22, P = 0.12). %PVC was higher in patients with impaired systolic function by GLS (worse than -18%) compared with patients with normal function (22% vs. 5%, P = 0.001). Greater than 8%PVC optimally identified patients with abnormal GLS (area under the curve 0.79). Serious arrhythmic events occurred in 11/52 (21%) patients characterized by high QRS ratios (1.56 vs. 1.91, P < 0.001). CONCLUSIONS: More than 8%PVC was associated with impaired systolic function by GLS, which is a lower threshold than previously reported. Patients with serious arrhythmic events had higher QRS ratios, which may represent a more malignant phenotype of OTA. PMID- 29154431 TI - Association between electrocardiographic and echocardiographic markers of stage B heart failure and cardiovascular outcome. AB - AIMS: The detection of non-ischaemic (mainly hypertension, diabetes, and obesity) stage B heart failure (SBHF) may facilitate the recognition of those at risk of progression to overt HF and HF prevention. We sought the relationship of specific electrocardiographic (ECG) markers of SBHF to echocardiographic features of SBHF and their prognostic value for development of HF. The ECG markers were Cornell product (Cornell-P), P-wave terminal force in lead V1 (PTFV1), ST depression in lead V5 V6 (minSTmV5V6), and increased heart rate. Echocardiographic assessment of SBHF included left ventricular hypertrophy (LVH), impaired global longitudinal strain (GLS), and diastolic dysfunction (DD). METHOD AND RESULTS: Asymptomatic subjects >=65 years without prior cardiac history, but with HF risks, were recruited from the local community. At baseline, they underwent clinical assessment, 12-lead ECG, and comprehensive echocardiography. New HF was assessed clinically at mean follow-up of 14 +/- 4 months, and echocardiography was repeated in subjects with HF. Of the 447 study subjects (age 71 +/- 5, 47% men) with SBHF, 13% had LVH, 32% impaired GLS, and 65% >=grade I DD (10% >=grade II DD). Forty were lost to follow-up. Clinical HF developed in 47 of 407, of whom 20% had echocardiographic LVH, 51% abnormal GLS, and 76% DD at baseline. Baseline LVH and abnormal GLS (not grade I DD) were independently associated with outcomes (clinical HF and cardiovascular death). Cornell-P and heart rate (not minSTmV5V6 nor PTFV1) were independently associated with LVH, impaired GLS, and DD. Cornell P and minSTV5V6 (not heart rate nor PTFV1) were independently associated with outcomes. More ECG abnormalities improved sensitivity, but ECG-markers were not independent of or incremental to echocardiographic markers to predict HF in SBHF. CONCLUSIONS: In this elderly study population, ECG markers showed low diagnostic sensitivity for non-ischaemic SBHF and low prognostic value for outcomes. Cornell P and minSTmV5V6 had predictive value for outcomes in non-ischaemic SBHF independent of age, gender, and common comorbidities but were not incremental to echocardiography. PMID- 29154432 TI - Proposal for heart failure progression based on the 'chloride theory': worsening heart failure with increased vs. non-increased serum chloride concentration. AB - AIMS: Chloride (Cl) is an established key electrolyte for the activation of the renin-angiotensin-aldosterone system. Recent studies have shown the serum Cl as a key electrolyte for the regulation of body fluid distribution in heart failure (HF) patients. The clinical differences of worsening HF status according to the changes in serum Cl concentration are unclear. METHODS AND RESULTS: Data from 47 chronic HF patients were analysed. Upon worsening HF, each patient exhibited at least two HF-related signs. Blood tests included haemoglobin (Hb), haematocrit (Ht), mean red blood cell volume (MCV), albumin, serum solutes, and b-type natriuretic peptide. The relative change in the plasma volume (%PV) from stable to worsening HF was estimated as follows: 100 * {Hb (stable) * [1 - Ht (worse)]}/{Hb (worse) * [1 - Ht (stable)]} - 100. When patients were divided into two groups based on changes in serum Cl concentration from stable to worsening HF, the pathophysiologic features of the patients with increased Cl (range 1-23 mEq/L; n = 31) included a greater increase in serum sodium (2.94 +/- 4.15 vs. 0.69 +/- 3.75 mEq/L, P = 0.005), higher vascular expansion (12 +/- 11.1 vs. 4.81 +/- 7.94%, P = 0.026), a tendency towards a greater MCV (1.23 +/- 2.36 vs. -0.06 +/- 1.88 fL, P = 0.065), and preserved renal function defined by the absence of an increase of serum creatinine (-0.24 +/- 0.39 vs. -0.05 +/- 0.12 mg/dL, P = 0.057) compared to patients with non-increased Cl (range -9 to 0 mEq/L; n = 16). Clinically, the increased Cl group had fewer HF signs (2.65 +/- 0.71 vs. 3.31 +/- 0.79, P = 0.005) although the change in symptoms did not differ between groups (48% vs. 63%, P = 0.54). CONCLUSIONS: The present study suggests a new clinical entity of worsening HF status, that is, HF with increased vs. non-increased serum Cl concentration from clinical stability to worsening HF. PMID- 29154433 TI - Cardiac muscle wasting in individuals with cancer cachexia. AB - AIMS: Cachexia is a severe complication of cancer that adversely affects the course of the disease and is associated with high rates of mortality. Patients with cancer manifest symptoms, such as fatigue, shortness of breath, and impaired exercise tolerance, which are clinical signs of chronic heart failure. The aim of this study was to evaluate cardiac muscle wasting in cancer individuals. METHODS AND RESULTS: We retrospectively analysed 177 individuals who died of cancer, including 58 lung, 60 pancreatic, and 59 gastrointestinal (GI) cancers, and 42 cancer-free controls who died of other, non-cardiovascular reasons. Cancer cachexia (CC) was defined based on clinical and/or pathological diagnosis, body mass index (BMI) <20.0 kg/m2 and/or oedema-free body weight loss of 5.0% during the previous year or less. The pathology reports were analysed for BMI, heart weight (HW), and left and right ventricular wall thicknesses (LVWT and RVWT, respectively). The analysis of clinical data included recording of biochemical parameters and medication data of study patients. CC was detected in 54 (30.5%) subjects. Individuals with CC had a significantly lower HW than non-cachectic subjects (363.1 +/- 86.2 vs. 447.0 +/- 128.9 g, P < 0.001) and control group (412.9 +/- 75.8 g, P < 0.05). BMI correlated with HW in cases with GI cancer (r = 0.44, P < 0.001), lung cancer (r = 0.53, P < 0.0001), and pancreatic cancer (r = 0.39, P < 0.01). CONCLUSIONS: Body weight loss in individuals with lung, pancreatic, and GI cancers is accompanied by a decrease in HW. In patients with CC who receive cancer treatment, screening for cardiac muscle wasting may have clinical importance. PMID- 29154435 TI - Braking of a Light-Driven Molecular Rotary Motor by Chemical Stimuli. AB - Artificial molecular motors hold great promise for application in responsive functional materials as well as to control the properties of biohybrid systems. Herein a strategy is reported to modulate the rotation of light-driven molecular motors. That is, the rotary speed of a molecular motor, functionalized with a biphenol moiety, could be decreased in situ by non-covalent substrate binding, as was established by 1 H NMR and UV/Vis spectroscopy. These findings constitute an important step in the development of multi-responsive molecular machinery. PMID- 29154434 TI - Right ventricular involvement in cardiac sarcoidosis demonstrated with cardiac magnetic resonance. AB - AIMS: Cardiac involvement in sarcoidosis is reported in up to 30% of patients. Left ventricular involvement demonstrated by contrast-enhanced cardiac magnetic resonance has been well validated. We sought to determine the prevalence and distribution of right ventricular late gadolinium enhancement in patients diagnosed with pulmonary sarcoidosis. METHODS AND RESULTS: We prospectively evaluated 87 patients diagnosed with pulmonary sarcoidosis with contrast-enhanced cardiac magnetic resonance for right ventricular involvement. Pulmonary artery pressures were non-invasively evaluated with Doppler echocardiography. Patient characteristics were compared between the groups with and without right ventricular involvement, and right ventricular enhancement was correlated with pulmonary hypertension, ventricular mass, volume, and systolic function. Left ventricular late gadolinium enhancement was demonstrated in 30 patients (34%). Fourteen patients (16%) had right ventricular late gadolinium enhancement, with sole right ventricular enhancement in only two patients. The pattern of right ventricular enhancement consisted of right ventricular outflow tract enhancement in 1 patient, free wall enhancement in 8 patients, ventricular insertion point enhancement in 10 patients, and enhancement of the right side of the interventricular septum in 11 patients. Pulmonary arterial hypertension correlated with the presence of right ventricular enhancement (P < 0.001). Right ventricular enhancement correlated with systolic ventricular dysfunction (P < 0.001), hypertrophy (P = 0.001), and dilation (P < 0.001). CONCLUSIONS: Right ventricular enhancement was present in 16% of patients diagnosed with pulmonary sarcoidosis and in 48% of patients with left ventricular enhancement. The presence of right ventricular enhancement correlated with pulmonary arterial hypertension, right ventricular systolic dysfunction, hypertrophy, and dilation. PMID- 29154436 TI - The Ecology of Teachers' Experiences with Violence and Lack of Administrative Support. AB - Teacher-directed violence is a common, yet understudied, phenomenon. Perpetrators of violence against teachers include not just students, but also administrators, parents, and colleagues. Administrators are key stakeholders when it comes to shaping school climate and safety that can reduce or increase the negative impact of violence against teachers. In this study, 237 teachers' qualitative responses from a larger sample of 2,431 anonymous, online survey responses were examined to better understand their experiences with incidents of violence and how administrators played a role in these experiences. Results reveal that lack of administrator support negatively impacts teachers at multiple levels, including teachers' feelings (individual); challenges associated with addressing issues related to students, parents, and other perpetrators (interpersonal); and school systems and policies (organizational). This study highlights the importance of administrative support and illustrates how administrators' actions and inactions can have ripple effects at each level of the school microcosm. Implications for research, practice, and policy are discussed. PMID- 29154437 TI - Effect of adding different levels of rumen protected choline to the diet on productive and reproductive performance of female goats and growth of their kids from birthing to weaning. AB - Forty female goats in the third parity were randomly divided into four similar groups. The experiment was started 20 days before mating and lasted until the end of the suckling period for 60 days and weaning their kids. The first group were fed diet without supplementation and kept as control while in the second, third and fourth groups, each doe was fed diets with rumen protected choline (RPC) at the rate of 10, 20 and 40 g/day, respectively. Results showed that number of doe kidding twins and triplets and litter weight of kids born per group increased with increasing the level of RPC in the diet of goats and viability rate of born kids during the suckling period improved due to RPC supplementation in the diets of their mothers. Duration of estrous, days from weaning to estrous, days from kidding to estrous and kidding interval decreased significantly, while conception rate increased due to adding RPC. Milk choline concentrations and total choline secretion though milk were progressively increased significantly with increasing the level of RPC supplementation. Live body weight and daily body gain of their suckling male and female kids at weaning increased significantly with increasing RPC levels in the diets of their mothers. PMID- 29154438 TI - Impact of heat shock protein 60KD in combination with outer membrane proteins on immune response against Brucella melitensis. AB - Brucellosis caused by the bacterium Brucella affects various domestic and wild species. The outer membrane proteins 25 and 31 play key roles on stimulation of cell-mediated immune response against Brucella. GroEL as one of the major Brucella antigens stimulates the immune system and increases intracellular survival of bacteria. In the present study, we assumed injection of GroEL in combination with OMP25 and OMP31 would offer higher immunity levels. So, the impact of GroEL with different concentrations of recombinant outer membrane proteins emulsified in Chitosan Nanoparticles on immune responses was evaluated in mice model. Results showed both univalent (except rGroEL) and divalent immunized groups induced higher IFN-gamma, TNF-alpha, and IL-4 titers in comparison to negative control groups. While GroEL showed negative effect on TNF alpha titer, there were positive increase trends in IFN-gamma in some treatments. Analysis of humoral antibody response revealed both univalent and divalent immunized groups induced higher IgG2a titer than IgG1 titer, indicating strong bent of Th1 immune response. Also, results showed GroEL can have positive impact on lymphocyte proliferation response. Overall, mice immunization using individual OMP25 or OMP31 demonstrated more effective cell-mediated immunity, although some combinations of rGroEL and rOMP31 vaccines were more efficient than other divalent ones. PMID- 29154439 TI - Verbal short-term memory shows a specific association with receptive but not productive vocabulary measures in Down syndrome. AB - BACKGROUND: Verbal short-term memory (STM) capacity has been considered to support vocabulary learning in typical children and adults, but evidence for this link is inconsistent for studies in individuals with Down syndrome (DS). The aim of this study was explore the role of processing demands on the association between verbal STM and vocabulary measures in DS, by comparing receptive vocabulary measures with high STM processing demands to productive vocabulary measures with low STM processing demands. METHOD: Forty-seven adults with Down syndrome were administered receptive vocabulary and productive vocabulary tasks, as well as measures of verbal STM abilities and intellectual efficiency. RESULTS: Bayesian regression analyses showed that verbal STM abilities were strongly and specifically associated with receptive vocabulary measures but not productive lexical abilities after controlling for intellectual efficiency, and this is despite the fact that vocabulary abilities as measured by receptive and productive vocabulary tasks were closely associated. CONCLUSIONS: In Down syndrome, verbal STM abilities may be predictive of specific task demands associated with receptive vocabulary tasks rather than of vocabulary development per se. PMID- 29154440 TI - Mapping of the Available Chemical Space versus the Chemical Universe of Lead-Like Compounds. AB - This is, to our knowledge, the most comprehensive analysis to date based on generative topographic mapping (GTM) of fragment-like chemical space (40 million molecules with no more than 17 heavy atoms, both from the theoretically enumerated GDB-17 and real-world PubChem/ChEMBL databases). The challenge was to prove that a robust map of fragment-like chemical space can actually be built, in spite of a limited (?105 ) maximal number of compounds ("frame set") usable for fitting the GTM manifold. An evolutionary map building strategy has been updated with a "coverage check" step, which discards manifolds failing to accommodate compounds outside the frame set. The evolved map has a good propensity to separate actives from inactives for more than 20 external structure-activity sets. It was proven to properly accommodate the entire collection of 40 m compounds. Next, it served as a library comparison tool to highlight biases of real-world molecules (PubChem and ChEMBL) versus the universe of all possible species represented by FDB-17, a fragment-like subset of GDB-17 containing 10 million molecules. Specific patterns, proper to some libraries and absent from others (diversity holes), were highlighted. PMID- 29154441 TI - Root type and soil phosphate determine the taxonomic landscape of colonizing fungi and the transcriptome of field-grown maize roots. AB - Different root types of plants are colonized by a myriad of soil microorganisms, including fungi, which influence plant health and performance. The distinct functional and metabolic characteristics of these root types may influence root type-inhabiting fungal communities. We performed internal transcribed spacer (ITS) DNA profiling to determine the composition of fungal communities in field grown axial and lateral roots of maize (Zea mays) and in response to two different soil phosphate (P) regimes. In parallel, these root types were subjected to transcriptome profiling by RNA sequencing (RNA-Seq). We demonstrated that fungal communities were influenced by soil P levels in a manner specific to root types. Moreover, maize transcriptome sequencing revealed root type-specific shifts in cell wall metabolism and defense gene expression in response to high P. Furthermore, lateral roots specifically accumulated defense-related transcripts at high P levels. This observation was correlated with a shift in fungal community composition, including a reduction in colonization by arbuscular mycorrhizal fungi, as observed in ITS sequence data and microscopic evaluation of root colonization. Our findings suggest soil nutrient-dependent changes in functional niches within root systems and provide new insights into the interaction of individual root types with soil microbiota. PMID- 29154442 TI - A biomimetic tumor tissue phantom for validating diffusion-weighted MRI measurements. AB - PURPOSE: To develop a biomimetic tumor tissue phantom which more closely reflects water diffusion in biological tissue than previously used phantoms, and to evaluate the stability of the phantom and its potential as a tool for validating diffusion-weighted (DW) MRI measurements. METHODS: Coaxial-electrospraying was used to generate micron-sized hollow polymer spheres, which mimic cells. The bulk structure was immersed in water, providing a DW-MRI phantom whose apparent diffusion coefficient (ADC) and microstructural properties were evaluated over a period of 10 months. Independent characterization of the phantom's microstructure was performed using scanning electron microscopy (SEM). The repeatability of the construction process was investigated by generating a second phantom, which underwent high resolution synchrotron-CT as well as SEM and MR scans. RESULTS: ADC values were stable (coefficients of variation (CoVs) < 5%), and varied with diffusion time, with average values of 1.44 +/- 0.03 um2 /ms (Delta = 12 ms) and 1.20 +/- 0.05 um2 /ms (Delta = 45 ms). Microstructural parameters showed greater variability (CoVs up to 13%), with evidence of bias in sphere size estimates. Similar trends were observed in the second phantom. CONCLUSION: A novel biomimetic phantom has been developed and shown to be stable over 10 months. It is envisaged that such phantoms will be used for further investigation of microstructural models relevant to characterizing tumor tissue, and may also find application in evaluating acquisition protocols and comparing DW-MRI-derived biomarkers obtained from different scanners at different sites. Magn Reson Med 80:147-158, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 29154443 TI - Long-term outcomes of patients with type 2 diabetes attending a multidisciplinary diabetes kidney disease clinic. AB - BACKGROUND: The best model of care to retard diabetic kidney disease (DKD) in the clinic is underexplored. In this study we investigated the long-term renal outcomes of a joint endocrinologist-nephrologist clinic. METHODS: The present study was a nested case-control study derived from a cohort of patients with type 2 diabetes mellitus (T2DM) seen prospectively at a secondary care diabetes center (DC). Cases ("DKD clinic group") were patients seen at the CKD clinic after being referred by physicians in DCs for management of DKD. Controls ("non-DKD clinic group") were patients from the same DC (i.e. same source population) with the same inclusion criteria of Stages 3-4 chronic kidney disease (CKD) at baseline but not seen at the DKD clinic. The outcome was Stage 5 CKD, defined as an estimated glomerular filtration rate <15 mL/min per 1.73 m2 . RESULTS: During the median follow-up period of 3.0 years (interquartile range 1.2-5.1 years), 240 patients (28.7%) reached Stage 5 CKD, with 45.8% and 54.2% of those reaching Stage 5 CKD in the DKD and non-DKD clinic groups, respectively. Multivariable Cox regression revealed that the DKD clinic group had a lower risk of progressing to Stage 5 CKD (hazard ratio 0.55; 95% confidence interval 0.36-0.83; P = 0.004) compared with the non-DKD clinic group. CONCLUSIONS: Multidisciplinary endocrinology and nephrology care in the DKD clinic is associated with a lower risk of end-stage renal disease. These findings may inform future management strategies targeted at patients with T2DM and CKD, especially with regard to joint specialist management involving endocrinologists and nephrologists. PMID- 29154444 TI - Promotion of Civic Engagement with the Family Leadership Training Institute. AB - In this efficacy study, both quantitative and qualitative data were used to gauge the effects of the Family Leadership Training Institute (FLTI) on civic knowledge and empowerment, civic engagement, and community health. The sample of 847 FLTI participants and 166 comparison adults completed pretest and posttest surveys. Medium to very large short-term effects were observed in civic literacy, empowerment, and engagement. Results mapping interviews were conducted with a stratified random sample of FLTI graduates (n = 52) to assess long-term (M = 2.73 years) program impact. Most FLTI graduates (86%) sustained meaningful, sometimes transformative, levels of civic engagement after program completion. This engagement involved multiple forms of leadership, most often advocacy, program implementation, and media campaigns; 63% of graduates directed at least some of their activities to marginalized populations. Content analyses of graduates' civic (capstone) projects and results mapping story maps indicated that 81-90% of community activities aligned with public health priorities. Thus, one promising means to promote community health is to empower families to develop leadership skills, become engaged in civic life, and forge connections with diverse constituents. PMID- 29154445 TI - Long-term cardiovascular morbidity and mortality in patients treated for differentiated thyroid cancer. AB - OBJECTIVES: Thyroid hormone suppression therapy has been widely used in the treatment of thyroid cancer, but concerns have been raised about the cardiovascular risks of this treatment. The objective of this study was to evaluate long-term cardiovascular morbidity and mortality in patients treated for differentiated thyroid cancer (DTC) and to assess the effect of TSH suppression and radioiodine (RAI) treatment on the cardiovascular outcome. DESIGN: Retrospective cohort study. PATIENTS AND MEASUREMENTS: Patients (n = 901) treated for DTC between 1981 and 2002 at 2 Finnish University hospitals were compared with a randomly chosen reference group (n = 4485) matched for age, gender and the place of residence. Kaplan-Meier and Cox regression analyses were used to estimate the risk of morbidity or death due to different cardiovascular diseases (CVD) after the diagnosis of DTC. RESULTS: Morbidity due to any CVD (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.05-1.28) and due to all arrhythmias (HR 1.25, CI 1.06-1.48) and atrial fibrillation (AF) (HR 1.29, CI 1.06-1.57) was more frequent in the DTC patients than in the controls. The increased cardiovascular morbidity was confined to patients with a mean TSH level below 0.1 mU/L (HR 1.27, CI 1.03-1.58) and to those treated with RAI (HR 1.18, CI 1.05-1.31). Cardiovascular mortality, however, was lower among the patients than the controls (HR 0.73, CI 0.58-0.92), due to a lower mortality from coronary artery disease. CONCLUSIONS: Differentiated thyroid cancer patients have an increased CVD morbidity, which is mostly accountable to AF and to TSH suppression below 0.1 mU/L. PMID- 29154446 TI - Transmission electron microscopy helpfulness in Whipple's disease masked by immunosuppressant therapy for arthritis. AB - A 61-year-old woman received a diagnosis of undifferentiated non-erosive arthritis in 2010 and assumed methotrexate and steroids in 2014. After 1 year, she experienced watery diarrhea, vomiting, fever, weight loss, and severe hypoalbuminemia, thus being admitted into our Unit. Esophagogastroduodenoscopy showed duodenal lymphangiectasia and duodenal biopsy samples several foamy PAS positive macrophages and villous subtotal atrophy. Transmission electron microscope demonstrated several extracellular and intracellular rod-shaped bacteria (Tropheryma whipplei). Therefore, we diagnosed Whipple's disease. Our patient assumed doxycycline/hydroxychloroquine with prompt remission of gastrointestinal symptoms. At 1 year of follow-up, she was symptom-free, histological reassessment showed almost complete mucosal healing and transmission electron microscope demonstrated bacteria breaking/disappearance. The present report demonstrates that: (i) rheumatological manifestations are common onset symptoms of Whipple's disease; (ii) immunosuppressive therapy may delay the diagnosis and worsen clinical presentation; (iii) transmission electron microscopy for specific bacteria detection/disappearance is an helpful diagnostic tool, when available. PMID- 29154447 TI - Roles and clinical implications of microRNAs in acute lymphoblastic leukemia. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate the expression of target genes by binding to messenger RNAs. miRNAs play a role in various biological processes, including proliferation, apoptosis, and tumorigenesis. Dysregulation of miRNAs is implicated in invasion and metastasis in several human cancer types, and leukemia is not an exception. Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the proliferation of early lymphoid precursors that replace normal hematopoietic cells of the bone marrow. The expression profiling of miRNAs in ALL could be used for the classification of the disease establishing specific diagnoses and offering prognostic values in the near future. The correlation of miRNAs dysregulation and biology of ALL demonstrates that specific miRNA may be a potential therapeutic target. In this review we have focused our attention on the correlations between ALL and miRNAs, their link with signaling pathways and transcription factors in the disease and miRNA targeting therapeutic strategies with their advantages and potential use in clinical applications. PMID- 29154448 TI - Significance of bizarre cells in cervical screening liquid-based cytology: A prospective study of 15 cases. AB - OBJECTIVE: The aim of this study was to assess the significance of bizarre cells (cells of squamous origin with a superficial squamous cell-type cytoplasm and characterised by multinucleation that produces bizarre nuclear shapes) in liquid based cytology (LBC) Papanicoaou (pap) smears with clinical and histological follow-up correlation. METHODS: Fifteen patients, all with LBC samples containing bizarre cells, were identified in routine ThinPrep(r) LBC workload. HPV testing was performed in each case using residual LBC material. Cytological-histological correlations were reviewed. RESULTS: All 15 LBC samples contained bizarre cells and tested positive for high-risk HPV types. Ten of the 15 cases were identified as atypical squamous cells - cannot exclude an HSIL (ASC-H) with secondary diagnosis of low-grade squamous intraepithelial lesion (LSIL), while five cases were identified as high-grade squamous intraepithelial lesion (HSIL), and a subsequent biopsy was recommended. Additionally, 13/15 cases underwent cone biopsy or hysterectomy within 1-11 months, of which 10 showed histologically confirmed HSIL end-points. LSIL was present in three cases. Bizarre cells were identified in the HSIL epithelium of five cone biopsies. CONCLUSIONS: Identification of bizarre cells in LBC is straightforward and may facilitate diagnosis. The cytology of bizarre cells is associated with HSIL in cone biopsies. We recommend assigning LBC samples containing bizarre cells as ASC-H with secondary diagnosis of LSIL. PMID- 29154449 TI - Relation between foot pain and plantar pressure in pregnancy AB - Background/aim: Hormonal and structural changes that occur during pregnancy cause alterations in body biomechanics. These alterations reach their peak in the last trimester. Adaptive changes that appear in the foot result in pain in the foot and ankle. Pedobarography is a noninvasive measurement method that can be used to understand the origin of such pain. Materials and methods: One hundred and thirty one pregnant women who did not have a foot or ankle problem prior to pregnancy volunteered to take part in the study. Pain was quantified by a visual analog scale (VAS). A cut-off value of 2.95 was taken to divide the subjects into two groups: Group 1 (n = 70) with VAS scores of <2.95 and Group 2 (n = 61) with VAS scores of ?2.95. Plantar pressure measurements were taken by Tekscan HR Mat using midgait protocol. Results: Forces experienced by the total right foot area, right forefoot, and the midfoot for both feet were significantly higher in Group 2 (P < 0.05). Contact area was significantly larger in Group 2 (P < 0.05). Conclusion: Results indicate that presence and severity of foot pain during pregnancy are related to the force distribution along the foot, especially at midfoot and the contact area. PMID- 29154450 TI - Introduction to Special Issue: Spelling and Morphology in Different Orthographies among Readers with and without Dyslexia. PMID- 29154451 TI - The Role of Morphological and Phonological Awareness in the Early Development of Word Spelling and Reading in Typically Developing and Disabled Arabic Readers. AB - The study is a cross-sectional developmental investigation of morphological and phonological awareness in word spelling and reading in Arabic in reading-accuracy disabled (RD) children and in age-matched typically developing (TR) controls in grades 1-4 (N = 160). Morphological awareness tasks targeted the root and word pattern derivational system of Arabic, in both the oral and the written modalities. Phonological awareness employed a variety of orally administered segmentation and deletion tasks. The results demonstrated early deficits in morphological awareness, besides deficits in phonological awareness, in RD children as compared with typically developing controls, as well as in word and pseudoword spelling and reading (voweled and unvoweled). While phonological awareness emerged as the strongest predictor of reading, morphological awareness was also found to predict unique variance in reading, and even more so in spelling, beyond phonological awareness and cognitive skills. The results demonstrate the early emergence of morphological awareness deficits, alongside phonological deficits in Arabic RD, as well as the role of morphological processing in early reading and spelling. These findings reflect the centrality of derivational morphology in the structure of the spoken and the written Arabic word. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29154452 TI - Recent Advances in Nonfullerene Acceptors for Organic Solar Cells. AB - Recently, research on nonfullerene acceptors in organic solar cells has gradually become a hot topic due to such superior characteristics of light absorption and energy-level-convenient manipulation, multiformity of the photoactive material structures, as well as the extensive area in production compared to the fullerene derivatives. However, the nonfullerene acceptors evolved slowly before 2012 and, as a matter of fact, the power conversion efficiency values could only bear 2.0%. Strikingly, nonfullerene acceptors have developed at a fast pace since 2013, with the best device performance of 13.1% now. In this review, recent research progress on nonfullerene acceptors, including small molecules and polymers, are sorted and summarized on the basis of the different characteristics. PMID- 29154453 TI - Protoplast preparation from enriched flagellates and resting cells of Haematococcus pluvialis. AB - AIMS: To establish a proper protoplast-preparation route from enriched motile flagellates and nonmotile resting cells of Haematococcus pluvialis. METHODS AND RESULTS: Through cultivations in two mixotrophic media, enriched Haematococcus flagellates and resting cells were respectively produced and applied in enzymatic protoplast preparations. Great differences of enzymatic sensitivity and osmotic lability were identified between them. Flagellates showed the same osmotic lability as protoplasts and the extracellular matrix-removing rate was applied for an evaluation of protoplast-releasing. During the treatment of flagellates, an addition of more than 0.2 mmol l-1 Ca2+ was found to be essential for maintenance of high cellular viability. More than 80% cellular viability and a 90% protoplast-releasing rate were obtained simultaneously after 2-3 h treatment of 0.06% proteinase K in 0.05 mol l-1 Tris-HCl (pH7.8) buffer with 0.2 mmol l-1 CaCl2 and 0.2 mol l-1 sorbitol/mannitol. For resting cells, a treatment of both 0.12% proteinase K and a combination of 2% cellulase + 1% snailase could function similarly in order to degrade the cellulosic cell wall, while the protoplast yield was limited to about 40%, due to the existence of an undegradable secondary wall in the mature resting cell. CONCLUSION: Proteinase K was efficient for protoplast-releasing from either flagellates or resting cells. Due to the great difference of enzymatic sensitivity and osmotic-lability between flagellates and resting cells, it was necessary to select a different enzymatic treating process based upon the main cell type in the culture. A better protoplast-preparing efficiency was obtained from Haematococcus cells when flagellates were in the majority. SIGNIFICANCE AND IMPACT OF THE STUDY: The protoplast preparation of H. pluvialis was firstly established based on two main cell types of H. pluvialis, motile flagellates and nonmotile resting cells. Increase of flagellate stability and viable protoplast-preparing efficiency through addition of Ca2+ in enzymatic solution was firstly reported. PMID- 29154454 TI - Identification of de novo germline mutations and causal genes for sporadic diseases using trio-based whole-exome/genome sequencing. AB - Whole-genome or whole-exome sequencing (WGS/WES) of the affected proband together with normal parents (trio) is commonly adopted to identify de novo germline mutations (DNMs) underlying sporadic cases of various genetic disorders. However, our current knowledge of the occurrence and functional effects of DNMs remains limited and accurately identifying the disease-causing DNM from a group of irrelevant DNMs is complicated. Herein, we provide a general-purpose discussion of important issues related to pathogenic gene identification based on trio-based WGS/WES data. Specifically, the relevance of DNMs to human sporadic diseases, current knowledge of DNM biogenesis mechanisms, and common strategies or software tools used for DNM detection are reviewed, followed by a discussion of pathogenic gene prioritization. In addition, several key factors that may affect DNM identification accuracy and causal gene prioritization are reviewed. Based on recent major advances, this review both sheds light on how trio-based WGS/WES technologies can play a significant role in the identification of DNMs and causal genes for sporadic diseases, and also discusses existing challenges. PMID- 29154455 TI - Translational evidence of prothrombotic and inflammatory endothelial damage in Cushing syndrome after remission. AB - OBJECTIVE: Sustained evidence from observational studies indicates that after remission of Cushing syndrome (CS) a cardiovascular risk phenotype persists. Here, we performed a translational study in active CS and CS in remission (RCS) to evaluate the subclinical cardiometabolic burden and to explore the direct pro inflammatory and prothrombotic potential of their sera on the endothelium in an in vitro translational atherothrombotic cell model. PATIENTS: Cross sectional study. The groups were (n = 9/group): I. RCS; II. Active CS (ACS) and III. Controls (CTR), all matched for age, body mass index, sex, without other hormonal deficits. DESIGN: We evaluated in vivo: cardiometabolic profile; endothelial markers (sVCAM-1, NO); endothelial dysfunction (FMD); intima-media thickness and body composition (DEXA). In vitro endothelial cells (EC) were exposed to sera taken from the different subjects to evaluate inflammatory EC response (tisVCAM) and thrombogenicity of the generated extracellular matrix (ECM): von Willebrand factor (VWF) and platelet reactivity. RESULTS: Three of the 9 RCS subjects were on glucocorticoid replacement therapy (GC-RT). Patients on GC-RT had a shorter period of time in stable remission. In vivo analysis ACS showed typically metabolic features, while cardiometabolic markers reached statistical significance for RCS only for Hs-CRP (P < .01). In vitro:EC exposed to ACS and RCS sera displayed increased tisVCAM-1 (P < .01 for ACS and P < .05 for RCS vs CTR), VWF (P < .01 for ACS and P < .05 for RCS vs CTR) and platelet adhesion on ECM (P < .01 for ACC and P < .05 for RCS vs CTR). No statistically significant differences were observed between GC-RT RSC and RCS without GC-RT. CONCLUSIONS: The sera of premenopausal women with CS in remission, without atherothrombotic disease, contain circulatory endothelial deleterious factors with a direct thrombogenic and pro-inflammatory endothelial effect that could increase cardiovascular risk. PMID- 29154457 TI - Complications from microfocused transcutaneous ultrasound: Case series and review of the literature. AB - BACKGROUND AND OBJECTIVE: Microfocused ultrasound (MFUS) technology has been utilized since 2009 for improvement in mild to moderate skin and soft tissue laxity of the face and neck. Few complications have been previously reported, the majority of which include mild and transient erythema, edema, ecchymosis, and nerve paralysis. Rare yet serious potential complications of MFUS for noninvasive skin tightening of the face and neck are, however, possible. METHODS & MATERIALS: Retrospective multicenter case series of five patients from the authors' practice who developed serious adverse events directly related to MFUS with a commercially available device (Ultherapy; Merz North America, Inc., Raleigh, NC). RESULTS: Five patients developed blistering, erosion/ulceration, cutaneous, or subcutaneous tissue edema with resulting atrophy, and/or cutaneous necrosis following single sessions of MFUS. CONCLUSION: Despite their rarity, serious adverse events secondary to MFUS are nevertheless possible and may be underreported. Early management of complications includes local wound care, patient reassurance, and topical corticosteroids and/or pulsed-dye laser to mitigate inflammatory sequelae. Other cosmetic and surgical therapies should be utilized when conservative measures have failed. Lasers Surg. Med. 50:13-19, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29154456 TI - Predicting the bending properties of long bones: Insights from an experimental mouse model. AB - OBJECTIVES: Analyses of bone cross-sectional geometry are frequently used by anthropologists and paleontologists to infer the loading histories of past populations. To address some underlying assumptions, we investigated the relative roles of genetics and exercise on bone cross-sectional geometry and bending mechanics in three mouse strains: high bone density (C3H/He), low bone density (C57BL/6), and a high-runner strain homozygous for the Myh4Minimsc allele (MM). METHODS AND MATERIALS: Weanlings of each strain were divided into exercise (wheel) or control (sedentary) treatment groups for a 7-week experimental period. Morphometrics of the femoral mid-diaphysis and mechanical testing were used to assess both theoretical and ex vivo bending mechanics. RESULTS: Across all measured morphological and bending traits, we found relatively small effects of exercise treatment compared to larger and more frequent interstrain differences. In the exercised group, total distance run over the experimental period was not a predictor of any morphological or bending traits. Cross-sectional geometry did not accurately predict bone response to loading. DISCUSSION: Results from this experimental model do not support hypothesized associations among extreme exercise, cross-sectional geometry, and bending mechanics. Our results suggest that analysis of cross-sectional geometry alone is insufficient to predict loading response, and questions the common assumption that cross-sectional geometry differences are indicative of differential loading history. PMID- 29154458 TI - Epigenetic mechanisms of major depression: Targeting neuronal plasticity. AB - Major depressive disorder is one of the most common mental illnesses as it affects more than 350 million people globally. Major depressive disorder is etiologically complex and disabling. Genetic factors play a role in the etiology of major depression. However, identical twin studies have shown high rates of discordance, indicating non-genetic mechanisms as well. For instance, stressful life events increase the risk of depression. Environmental stressors also induce stable changes in gene expression within the brain that may lead to maladaptive neuronal plasticity in regions implicated in disease pathogenesis. Epigenetic events alter the chromatin structure and thus modulate expression of genes that play a role in neuronal plasticity, behavioral response to stress, depressive behaviors, and response to antidepressants. Here, we review new information regarding current understanding of epigenetic events that may impact depression. In particular, we discuss the roles of histone acetylation, DNA methylation, and non-coding RNA. These novel mechanisms of action may lead to new therapeutic strategies for treating major depression. PMID- 29154460 TI - Elevated CO2 increases R gene-dependent resistance of Medicago truncatula against the pea aphid by up-regulating a heat shock gene. AB - Resistance against pathogens and herbivorous insects in many plant results from the expression of resistance (R) genes. Few reports, however, have considered the effects of elevated CO2 on R gene-based resistance in plants. The current study determined the responses of two near isogenic Medicago truncatula genotypes (Jester has an R gene and A17 does not) to the pea aphid and elevated CO2 in open top chambers in the field. Aphid abundance, mean relative growth rate and feeding efficiency were increased by elevated CO2 on A17 plants but were reduced on Jester plants. According to proteomic and gene expression data, elevated CO2 enhanced pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) but decreased the effector-triggered immunity (ETI) in aphid-infested A17 plants. For aphid-infested Jester plants, by contrast, elevated CO2 enhanced the ETI related heat shock protein (HSP) 90 and its co-chaperones, the jasmonic acid (JA) signaling pathway, and ubiquitin-mediated proteolysis. In a loss-of-function experiment, silencing of the HSP90 gene in Jester plants impaired the JA signaling pathway and ubiquitin-mediated proteolysis against the aphid under ambient CO2 , and negated the increased resistance against the aphid under elevated CO2 . Our results suggest that increases in expression of HSP90 are responsible for the enhanced resistance against the aphid under elevated CO2 . PMID- 29154461 TI - Patient understanding of disease and the use and outcome of implantable cardioverter defibrillators in hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in young individuals. Implantable cardioverter defibrillators (ICD) are the primary therapy for sudden death prevention; however, are associated with both physical and psychological complications. We sought to determine factors associated with ICD understanding and patient satisfaction. This was a cross sectional study, using patient/parent answered questionnaires distributed to patients enrolled in the Hypertrophic Cardiomyopathy Association. Patient characteristics and satisfaction data were obtained via questionnaire. Patients were compared based on age at diagnosis and presence of ICD. ICD patients with high satisfaction were compared to those with low satisfaction to determine factors associated with poor satisfaction. A total of 538 responses were obtained (53 +/- 16 years); 46% were females. Seventy patients (13%) were diagnosed with HCM < 18 years of age and 356 (66%) had an ICD. Compared to those without an ICD, patients with ICDs were younger at age of diagnosis (P = 0.001) and time of study (P = 0.008). Patients with ICDs were more likely to have presented with syncope and have family history of ICD, SCD, or HCM-related death. Nineteen patients (5%) felt that issues surrounding their ICD outweighed its benefit. Compared to patients with a favorable satisfaction, the only significant difference was the preimplant ICD discussion (P < 0.001) and history of lead replacement (P = 0.01). In conclusion, the majority of HCM patients with ICDs are satisfied with their ICD management and feel the benefits of ICDs outweigh issues associated with ICDs. Additionally, these data highlight the importance of the preimplant patient physician discussion around the need for ICD prior to implantation. PMID- 29154462 TI - The role of indoleamine-2,3-dioxygenase in normal and pathological pregnancies. AB - The survival of allogeneic fetus during pregnancy contradicts the laws of immune responses. Behind this paradoxical phenomenon, the mechanism is quite complex. Indoleamine-2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism. Emerging evidence shows that IDO is expressed at the maternal-fetal interface, including trophoblast cells, decidual stroma cells, decidual immune cells (eg, natural killer cells, T cells, and macrophages), and vascular endothelial cells of decidua and chorion. Moreover, the expression and activity of IDO are different among non-pregnant, normal pregnant, and pathological pregnant conditions. IDO plays important roles in normal pregnancy through immune suppression and regulation of fetal invasion and circulation. However, the abnormal expression and dysfunction of IDO are associated with some pathological pregnancies (including recurrent spontaneous abortion, preeclampsia, preterm labor, and fetal growth restriction). PMID- 29154459 TI - Additive genetic variation in the craniofacial skeleton of baboons (genus Papio) and its relationship to body and cranial size. AB - OBJECTIVES: Determining the genetic architecture of quantitative traits and genetic correlations among them is important for understanding morphological evolution patterns. We address two questions regarding papionin evolution: (1) what effect do body and cranial size, age, and sex have on phenotypic (VP ) and additive genetic (VA ) variation in baboon crania, and (2) how might additive genetic correlations between craniofacial traits and body mass affect morphological evolution? MATERIALS AND METHODS: We use a large captive pedigreed baboon sample to estimate quantitative genetic parameters for craniofacial dimensions (EIDs). Our models include nested combinations of the covariates listed above. We also simulate the correlated response of a given EID due to selection on body mass alone. RESULTS: Covariates account for 1.2-91% of craniofacial VP . EID VA decreases across models as more covariates are included. The median genetic correlation estimate between each EID and body mass is 0.33. Analysis of the multivariate response to selection reveals that observed patterns of craniofacial variation in extant baboons cannot be attributed solely to correlated response to selection on body mass, particularly in males. DISCUSSION: Because a relatively large proportion of EID VA is shared with body mass variation, different methods of correcting for allometry by statistically controlling for size can alter residual VP patterns. This may conflate direct selection effects on craniofacial variation with those resulting from a correlated response to body mass selection. This shared genetic variation may partially explain how selection for increased body mass in two different papionin lineages produced remarkably similar craniofacial phenotypes. PMID- 29154464 TI - Patient-Centered Medical Home Implementation and Improved Chronic Disease Quality: A Longitudinal Observational Study. AB - OBJECTIVE: To examine associations between clinics' extent of patient-centered medical home (PCMH) implementation and improvements in chronic illness care quality. DATA SOURCE: Data from 808 Veterans Health Administration (VHA) primary care clinics nationwide implementing the Patient Aligned Care Teams (PACT) PCMH initiative, begun in 2010. DESIGN: Clinic-level longitudinal observational study of clinics that received training and resources to implement PACT. Clinics varied in the extent they had PACT components in place by 2012. DATA COLLECTION: Clinical care quality measures reflecting intermediate outcomes and care processes related to coronary artery disease (CAD), diabetes, and hypertension care were collected by manual chart review at each VHA facility from 2009 to 2013. FINDINGS: In adjusted models containing 808 clinics, the 77 clinics with the most PACT components in place had significantly larger improvements in five of seven chronic disease intermediate outcome measures (e.g., BP < 160/100 in diabetes), ranging from 1.3 percent to 5.2 percent of the patient population meeting measures, and two of eight process measures (HbA1c measurement, LDL measurement in CAD) than the 69 clinics with the least PACT components. Clinics with moderate levels of PACT components showed few significantly larger improvements than the lowest PACT clinics. CONCLUSIONS: Veterans Health Administration primary care clinics with the most PCMH components in place in 2012 had greater improvements in several chronic disease quality measures in 2009 2013 than the lowest PCMH clinics. PMID- 29154463 TI - Establishing upper limits on neuronal activity-evoked pH changes with APT-CEST MRI at 7 T. AB - PURPOSE: To detect neuronal activity-evoked pH changes by amide proton transfer chemical exchange saturation transfer (APT-CEST) MRI at 7 T. METHODS: Three healthy subjects participated in the study. A low-power 3-dimensional APT-CEST sequence was optimized through the Bloch-McConnell equations. pH sensitivity of the sequence was estimated both in phantoms and in vivo. The feasibility of pH functional MRI was tested in Bloch-McConnell-simulated data using the optimized sequence. In healthy subjects, the visual stimuli were used to evoke transient pH changes in the visual cortex, and a 3-dimensional APT-CEST volume was acquired at the pH-sensitive frequency offset of 3.5 ppm every 12.6 s. RESULTS: In theory, a three-component general linear model was capable of separating the effects of blood oxygenation level-dependent contrast and pH. The Bloch-McConnell equations indicated that a change in pH of 0.03 should be measurable at the experimentally determined temporal signal-to-noise ratio of 108. However, only a blood oxygenation level-dependent effect in the visual cortex could be discerned during the visual stimuli experiments performed in the healthy subjects. CONCLUSIONS: The results of this study suggest that if indeed there are any transient brain pH changes in response to visual stimuli, those are under 0.03 units pH change, which is extremely difficult to detect using the existent techniques. Magn Reson Med 80:126-136, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 29154465 TI - The role of immunological testing and intervention in reproductive medicine: A fertile collaboration? AB - Advances in reproductive medicine have significantly increased the success of fertility treatments. Nevertheless, some women experience recurrent implantation failure (RIF) after in-vitro fertilization (IVF) or recurrent pregnancy loss (RPL). Imbalances in the immune system and failure to achieve immune tolerance to the foetus have been implicated as potentially modifiable causes of idiopathic RIF and RPL. As such, women are increasingly being treated with immunomodulatory agents in an attempt to achieve a successful pregnancy. This systematic review examines the published evidence on immune changes in these patients, the use of immunomodulation therapies and diagnostic testing modalities to guide their use or to identify patient subsets most likely to benefit. The PubMed database was searched for the terms "recurrent implantation failure" and "recurrent pregnancy loss" in conjunction with T-helper (Th) cells and their subsets in particular; Th1, Th2, Th17 and T-regulatory (Treg) cells, natural killer (NK) cells, cytokine imbalance as well as immune modulators and immune suppressants. The reference lists of articles were examined to identify additional articles. There remains limited data on the immunological changes in cytokine and cellular profiles during the hormonal cycle as well as prior to, during and after implantation in health as well as idiopathic RIF and RPL. There is a need to advance immunological diagnostics to match the clinical need in this emerging field and to guide clinicians to make optimal and safe therapeutic choices. It is also imperative that the well-being of the infants conceived after such intervention is monitored. PMID- 29154466 TI - DeltaFosB regulates rosiglitazone-induced milk fat synthesis and cell survival. AB - Rosiglitazone induces adipogenesis in adipocyte and regulates cell survival and differentiation in number of cell types. However, whether PPARgamma regulates the synthesis of milk fat and cell survival in goat mammary gland remains unknown. Rosiglitazone strongly enhanced cellular triacylglycerol content and accumulation of lipid droplet in goat mammary epithelial cells (GMEC). Furthermore, DeltaFosB decreased the expression of PPARgamma at both mRNA and protein levels, and rosiglitazone-induced milk fat synthesis was abolished by DeltaFosB overexpression. DeltaFosB reduced milk fat synthesis and enhanced saturated fatty acid concentration. Rosiglitazone increased the number of GMEC in G0/G1 phase and inhibited cell proliferation, and these effects were improved by overexpression of DeltaFosB. DeltaFosB was found to promote the expression of Bcl-2 and suppress the expression of Bax, and protected GMEC from apoptosis induced by rosiglitazone. Intracellular calcium trafficking assay revealed that rosiglitazone markedly increased intracellular calcium concentration. DeltaFosB protected GMEC from apoptosis induced by intracellular Ca2+ overload. DeltaFosB increased MMP-9 gelatinolytic activity. SB-3CT, an MMP-9 inhibitor, suppressed the expression of Bcl-2, and increased intracellular calcium levels, and this effect was abolished by DeltaFosB overexpression. SB-3CT induced GMEC apoptosis and this effect was inhibited by DeltaFosB overexpression. These findings suggest that DeltaFosB regulates rosiglitazone-induced milk fat synthesis and cell survival. Therefore, DeltaFosB may be an important checkpoint to control milk fat synthesis and cell apoptosis. PMID- 29154467 TI - Central and peripheral leptin and agouti-related protein during and after pregnancy in relation to weight change. AB - OBJECTIVE: To study changes of neuropeptides and adipokines in cerebrospinal fluid (CSF) and serum from pregnancy to postpregnancy in relation to weight changes, fat mass and glucose metabolism. CONTEXT: With high postpartum weight retention being a risk factor in future pregnancies and of lifelong obesity, we evaluated neuropeptide and adipokine changes in women who either gained weight or were weight stable. DESIGN: Women were followed for 5 +/- 1 years after pregnancy and divided into two groups, weight stable and weight gain, by weight change from start of pregnancy. PATIENTS: Twenty-five women (BMI 27 +/- 5 kg/m2 ) recruited at admission for elective caesarean section. MEASUREMENTS: CSF and serum levels of agouti-related protein (AgRP), leptin and insulin, and serum levels of adiponectin and soluble leptin receptor were measured during and after pregnancy. These measurements were further related to fat mass and insulin sensitivity (HOMA IR). RESULTS: S-AgRP levels during pregnancy were lower in the weight stable group and a 1 unit increase in s-AgRP was associated with 24% higher odds of pertaining to the weight gain group. After pregnancy, s-AgRP increased in the weight stable group but decreased in the weight gain group. Decreased transport of leptin into CSF during pregnancy was reversed by an increased CSF:serum leptin ratio after pregnancy. In women who returned to their prepregnancy weight, serum adiponectin increased after pregnancy and correlated negatively with HOMA-IR. CONCLUSION: S-AgRP concentration in late pregnancy may be one factor predicting weight change after pregnancy, and circulating AgRP may be physiologically important in the long-term regulation of body weight. PMID- 29154468 TI - Fight, Flight, or Remain Silent? Juggling Multiple Accountabilities throughout the Formative Stage of a Neighborhood Revitalization Initiative. AB - This paper describes the experiences of a research team as they navigated uncertain ethical and political terrain throughout the formative stage of a public housing redevelopment project. Specifically, we discuss the challenges related to balancing multiple accountabilities and the tensions among the various roles and responsibilities that emanated from different accountabilities. Due to contractual obligations to our funding source, established relations with community partners, and an ethical imperative to align with those holding the least power, we grappled with embodying multiple and often conflicting roles. Without oversight provided by our university institutional review board or a clear ethical framework for community psychology research and action, our team was left to negotiate the challenges that emerged through critical reflection and financial considerations. Throughout the case example presented in this paper, we highlight our difficulty in ethical decision-making with respect to the principles of obligation, disclosure, consent, commitment, and professionalism. Community psychologists often straddle the realms of academia, community partnerships, and conscious engagement with little guidance in navigating often conflicting roles and value systems. We present our narrative to highlight the complexity of scholar-activism in the context of community psychology and the necessity for developing ethical standards and guidelines tailored to meet the unique needs of community psychologists. PMID- 29154469 TI - Novel non-alcoholic steatohepatitis model with histopathological and insulin resistant features. AB - Although several non-alcoholic steatohepatitis (NASH) models have been reported to date, few of these models fully reflect the histopathology and pathophysiology of human NASH. The aim of this study was to establish a novel NASH model by feeding a high-fat (HF) diet and administering both carbon tetrachloride (CCl4 ) and the Liver X receptor agonist T0901317. Male C57BL/6J mice were divided into four groups (each n = 5): HF, HF + CCl4 , HF + T0901317, and the novel NASH model (HF + CCl4 + T0901317). CCl4 (0.1 mL/kg) and T0901317 (2.5 mg/kg) were intraperitoneally administered four times and five times, respectively. The livers of the novel NASH model group presented a whitish colour. The serum levels of TNF-alpha and IL-6 were significantly increased in the novel NASH model group, and mice in this group exhibited histopathological features and insulin resistance reflective of NASH, i.e., macrovesicular hepatic steatosis, ballooning hepatocytes, Mallory-Denk bodies, lobular inflammation and fibrosis. The novel NASH model group presented significantly upregulated expression levels of mRNAs related to lipogenesis, oxidative stress, fibrosis and steatosis and significantly downregulated expression levels of mRNAs related to triglyceride export. We successfully established a novel experimental NASH model that exhibits similar histopathology and pathophysiology to human NASH. PMID- 29154470 TI - Re: Economic comparison of early intervention services with standard care: Flawed model of the costs of homicide. PMID- 29154471 TI - Reducing Diastereomorphous Bis(phosphane oxide) Atropisomers to One Atropisomerically Pure Diphosphane: A New Ligand and a Novel Ligand-Preparation Design. AB - 1,1'-Biphenyl-2,2'-diphosphanes with an achiral bridge spanning C-5 and C-5' form atropisomers that are enantiomers. Accessing them in an atropisomerically pure form requires resolving a racemic mixture thereof or of a bis(phosphane oxide) precursor. 1,1'-Biphenyl-2,2'-diphosphanes with a homochiral bridge spanning C-5 and C-5' form atropisomers that are diastereomers. We synthesized the first compound of this kind 1) atropselectively and 2) under thermodynamic control seemingly a first-time exploit in diphosphane synthesis. The selectivity-inducing step was a high-temperature reduction of two non-interconverting bis(phosphane oxide) atropisomers (60:40 mixture). It furnished the desired diphosphane atropisomerically pure (and atropconvergently because the yield was 67 %). This diphosphane proved worthwhile in Tsuji-Trost allylations, the Hayashi addition of phenylboronic acid to cyclohexenone, and the asymmetric hydrogenation of methyl acetoacetate (up to 95 % yield and 95 % ee). PMID- 29154472 TI - Thermal bowel injury after ultrasound-guided high-intensity focused ultrasound treatment of uterine adenomyosis. PMID- 29154473 TI - Influences of quorum-quenching probiotic bacteria on the gut microbial community and immune function in weaning pigs. AB - The aim of this study is to investigate the dynamic gut microbial diversity in weaning swine after administering feed supplemented with probiotic bacteria that specifically inhibit the activity of quorum molecules. Initially, the universal quorum molecule autoinducer-2 (AI-2) bioassay results indicated that AI-2 activity was profoundly inhibited in enterohemorrhagic Escherichia coli (EHEC) O157:H7 in the presence of Lactobacillus acidophilus strain 30SC cell extract, although the growth of EHEC was not affected. Based on plate counting results, bacterial community analysis revealed a specific reduction in coliforms compared to the control, whereas the population of lactobacilli increased in weaning swine in in vivo trials. Supplementation with L. acidophilus strain 30SC did not affect the counts of other communities, such as total aerobes and yeast/mold. In addition, PCR-denaturing gradient gel electrophoresis analysis showed a significant difference in the 16S rRNA gene products after administering L. acidophilus strain 30SC. Selected bands were sequenced, and most of them were identified as uncultured bacterium clones or a Lactobacillus- and Bifidobacterium specific community. Therefore, our results indicate that quorum-quenching probiotic bacteria can significantly modulate the gut microbiota of swine and these beneficial effects can contribute to the improvement of performance and health in the gastrointestinal tract of weaning pigs. PMID- 29154474 TI - Intracrine prostaglandin E2 pro-tumoral actions in prostate epithelial cells originate from non-canonical pathways. AB - Prostaglandin E2 (PGE2 ) increases cell proliferation and stimulates migratory and angiogenic abilities in prostate cancer cells. However, the effects of PGE2 on non-transformed prostate epithelial cells are unknown, despite the fact that PGE2 overproduction has been found in benign hyperplastic prostates. In the present work we studied the effects of PGE2 in immortalized, non-malignant prostate epithelial RWPE-1 cells and found that PGE2 increased cell proliferation, cell migration, and production of vascular endothelial growth factor-A, and activated in vitro angiogenesis. These actions involved a non canonic intracrine mechanism in which the actual effector was intracellular PGE2 (iPGE2 ) instead of extracellular PGE2 : inhibition of the prostaglandin uptake transporter (PGT) or antagonism of EP receptors prevented the effects of PGE2 , which indicated that PGE2 activity depended on its carrier-mediated translocation from the outside to the inside of cells and that EP receptors located intracellularly (iEP) mediated the effects of PGE2 . iPGE2 acted through transactivation of epidermal growth factor-receptor (EGFR) by iEP, leading to increased expression and activity of hypoxia-inducible factor-1alpha (HIF 1alpha). Interestingly, iPGE2 also mediates the effects of PGE2 on prostate cancer PC3 cells through the axis iPGE2 -iEP receptors-EGFR-HIF-1alpha. Thus, this axis might be responsible for the growth-stimulating effects of PGE2 on prostate epithelial cells, thereby contributing to prostate proliferative diseases associated with chronic inflammation. Since this PGT-dependent non canonic intracrine mechanism of PGE2 action operates in both benign and malignant prostate epithelial cells, PGT inhibitors should be tested as a novel therapeutic modality to treat prostate proliferative disease. PMID- 29154475 TI - Identification and analysis of a key long non-coding RNAs (lncRNAs)-associated module reveal functional lncRNAs in cardiac hypertrophy. AB - Cardiac hypertrophy (CH) is a common disease that originates from long-term heart pressure overload and finally leads to heart failure. Recently, long non-coding RNAs (lncRNAs) have attracted attention because they have broad and crucial functions in regulating complex biological processes. Some studies had found that lncRNAs play vital roles in complex cardiovascular diseases. However, the function and mechanism of lncRNAs in CH have not been elucidated. In our study, to investigate the potential roles of lncRNAs in CH, the Cardiac Hypertrophy associated LncRNAs-Protein coding genes Network (CHLPN) was constructed by integrating gene microarray re-annotation and subpathway enrichment analyses. After performing random walking with restart in CHLPN, we predicted 21 significant risk lncRNAs, of which 7 (Kis2, 1700110K17Rik, Gm17501, E330017L17Rik, C630043F03Rik, Gm9866 and Ube4bos1) formed a close module with their co-expressed protein-coding genes (PCGs). We found that the module might play crucial roles in the development of CH. In particular, 44 PCGs that were co expressed with six lncRNAs were enriched in CH-related biological processes and pathways. We also found that some lncRNAs participated in the competitive endogenous RNA cross-talk that might be involved in CH. These results indicate that the functional lncRNAs are related to post-transcriptional regulation and could shed light on a new molecular diagnostic target of CH. PMID- 29154476 TI - Valuing Our Communities: Ethical Considerations for Economic Evaluation of Community-Based Prevention. AB - Restricted public budgets and increasing efforts to link the impact of community interventions to public savings have increased the use of economic evaluation. While this type of evaluation can be important for program planning, it also raises important ethical issues about how we value the time of local stakeholders who support community interventions. In particular, researchers navigate issues of scientific accuracy, institutional inequality, and research utility in their pursuit of even basic cost estimates. We provide an example of how we confronted these issues when estimating the costs of a large-scale community-based intervention. Principles for valuing community members' time and conducting economic evaluations of community programs are discussed. PMID- 29154477 TI - Mutagenesis of Sequence Determinants of Truncated Porcine ALOX15 Induces Changes in the Reaction Specificity by Altering the Catalytic Mechanism of Initial Hydrogen Abstraction. AB - The reaction specificity of lipoxygenases is of physiological relevance since the various oxygenation products exhibit different biological activities. Among mammalian ALOX15 orthologs there are arachidonic acid 12- and 15-lipoxygenating enzymes and recent studies suggested an evolutionary switch in that reaction specificity during late primate development. Previous reports showed that 12 lipoxygenating ALOX15 orthologs can be converted to 15-lipoxygenating enzymes by site-directed mutagenesis of some sequence determinants. Unfortunately, the molecular basis for those alterations are not well understood. Here, the arachidonic acid 12-lipoxygenating N-terminal truncation variant of pig ALOX15, for which a crystal structure is available, was used to explore the catalytic mechanism of the specificity switch induced by mutagenesis of Val418 and Val419 sequence determinants. We found that Val418Ile+Val419Met double mutant is dominantly 15-lipoxygenating. Docking and MD simulations, and quantum mechanics/molecular mechanics calculations indicated that the wildtype energy barrier for arachidonic acid 15-lipoxygenation is 3.4 kcal mol-1 higher than for 12-lipoxygenation. In contrast, for the Val418Ile+Val419Met double mutant the energy barrier for 12-lipoxygenation is 6.0 kcal mol-1 higher than for 15 lipoxygenation. Our data suggest that enzyme-substrate complex geometries determine the value of these energy barriers and, as a consequence, the reaction specificity of ALOX15 orthologs. PMID- 29154478 TI - On the Dual Reactivity of a Nucleophilic Dihydrido-Diborane: Reaction at the B-B Bond and/or the B-H Bond. AB - The electron-rich, double-base stabilized dihydrido-diborane(4) [HB(hpp)]2 (hpp=1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidinate) combines two different, easily accessible reactive sites: the B-B and B-H bond. Herein, we report two basically similar reactions of [HB(hpp)]2 with catecholborane and B chlorocatecholborane unsuspectedly resulting in two different reactivities. While reaction of the diborane with two equivalents of HB(cat) proceeded with formation of a cationic triborane with a (3c2e) bond, [{HB(MU-hpp)}2 (MU-BH2 )]+ , reaction with ClB(cat) led to hydride-chloride substitution yielding [ClB(hpp)]2 . The cationic triborane was also obtained by the addition of BH3 to the in situ generated [HB(hpp)2 B]+ . Proceeding from the new compound [ClB(hpp)]2 , we investigated its reactivity towards chloride abstraction with AlCl3 and GaCl3 . Irrespectively of the salt chosen, the reaction led to formation of a radical tricationic tetraborane [{B(hpp)}4 ].3+ with a (4c,5e) bond. Moreover, the dichloro-diborane proves as a versatile reagent for further substitution cleanly reacting with the strong nucleophile nBuLi to a new dibutyl-diborane [nBuB(hpp)]2 . PMID- 29154479 TI - Efficient production of tri-acetylated mono-acylated mannosylerythritol lipids by Sporisorium sp. aff. sorghi SAM20. AB - AIMS: The aim of this study was to isolate a novel yeast strain, evaluate biosurfactant production by the strain and characterize the major product. METHODS AND RESULTS: The strain SAM20, isolated from grass, identified as Sporisorium sp. aff. sorghi based on phylogenetic analyses. The strain produced approximately 32 g l-1 glycolipid biosurfactants from 40 g l-1 soybean oil after 7 days at 28 degrees C. The glycolipids showed a unique pattern of mannosylerythritol lipids (MELs) on thin layer chromatography plate compared to those hitherto reported. Structural characterization of the major product, called GL-A, revealed that it was mainly tri-acetylated mono-acylated MELs (MEL-A2) with C14:0, C16:0, C12:0 or C14:1 as the hydrophobic chain. The critical micelle concentration (CMC), the surface tension at CMC and hydrophilic-lipophilic balance value for GL-A were estimated to be 20 mg l-1 , 30.0 mN m-1 and 8.7, respectively. CONCLUSIONS: A MEL-A2 with novel composition and surface activities was efficiently produced from a novel MEL producer. This is the first report on production of MEL-A2 as the major product and from soybean oil. The biosurfactant has potential application as a wetting agent and oil-in-water emulsifier. SIGNIFICANCE AND IMPACT OF THE STUDY: Discovery of novel structures and novel strains is valuable for further commercial development and application of MELs. Sporisorium sp. aff. sorghi SAM20 can be considered as a potential candidate for commercial production of biosurfactants. PMID- 29154480 TI - In vitro activity and time-kill curve analysis of sitafloxacin against a global panel of antimicrobial-resistant and multidrug-resistant Neisseria gonorrhoeae isolates. AB - Treatment of gonorrhoea is a challenge worldwide because of emergence of resistance in N. gonorrhoeae to all therapeutic antimicrobials available and novel antimicrobials are imperative. The newer-generation fluoroquinolone sitafloxacin, mostly used for respiratory tract infections in Japan, can have a high in vitro activity against gonococci. However, only a limited number of recent antimicrobial-resistant isolates from Japan have been examined. We investigated the sitafloxacin activity against a global gonococcal panel (250 isolates cultured in 1991-2013), including multidrug-resistant geographically, temporally and genetically diverse isolates, and performed time-kill curve analysis for sitafloxacin. The susceptibility to sitafloxacin (agar dilution) and seven additional therapeutic antimicrobials (Etest) was determined. Sitafloxacin was rapidly bactericidal, and the MIC range, MIC50 and MIC90 was <=0.001-1, 0.125 and 0.25 mg/L, respectively. There was a high correlation between the MICs of sitafloxacin and ciprofloxacin; however, the MIC50 and MIC90 of sitafloxacin were 6-fold and >6-fold lower, respectively. Sitafloxacin might be an option for particularly dual antimicrobial therapy of gonorrhoea and for cases with ceftriaxone resistance or allergy. However, further in vitro and particularly in vivo evaluations of potential resistance, pharmacokinetics/pharmacodynamics and ideal dosing for gonorrhoea, as well as performance of randomized controlled clinical, trials are crucial. PMID- 29154481 TI - Bayesian Word Learning in Multiple Language Environments. AB - Infant language learners are faced with the difficult inductive problem of determining how new words map to novel or known objects in their environment. Bayesian inference models have been successful at using the sparse information available in natural child-directed speech to build candidate lexicons and infer speakers' referential intentions. We begin by asking how a Bayesian model optimized for monolingual input (the Intentional Model; Frank et al., 2009) generalizes to new monolingual or bilingual corpora and find that, especially in the case of the bilingual input, the model shows a significant decrease in performance. In the next experiment, we propose the ME Model, a modified Bayesian model, which approximates infants' mutual exclusivity bias to support the differential demands of monolingual and bilingual learning situations. The extended model is assessed using the same corpora of real child-directed speech, showing that its performance is more robust against varying input and less dependent than the Intentional Model on optimization of its parsimony parameter. We argue that both monolingual and bilingual demands on word learning are important considerations for a computational model, as they can yield significantly different results than when only one such context is considered. PMID- 29154482 TI - Development of furnished cages re-using conventional cages for laying hens: Behaviour, physical condition and productivity. AB - Furnished cages for laying hens have advantages in allowing normal behaviors and maintaining productivity. As the cost of introduction is a barrier for farms, we developed furnished cages that re-use conventional cages. To determine the minimum and functional cage design, we compared six designs, combinations of two floor designs (artificial turf or wire cage floor) and three screening designs in the integrated area (no screening, one entrance side or four sides). In total, 144 hens were used, and we measured behavior, physical condition and productivity. Comparing the floors, the percentages of hens performing dust bathing and laying eggs in the integrated area were higher in cages with turf than wire floor (P < 0.05 for both). Comparing the screening, dust-bathing, litter-exploring and active behavior tended to be more frequent in cages with the integrated area screened on one side than four sides. Feather damage was lower in cages with the integrated area screened on one side than with no screening (P < 0.05). These results suggest that the cage design with an integrated area with artificial turf floor, screened on one side, was effective for furnished cages that re-use conventional cages. PMID- 29154483 TI - Evaluating the effectiveness of mental health nursing interventions. PMID- 29154484 TI - Memantine-Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma. AB - Glaucoma is a multifactorial neurodegenerative disease associated with retinal ganglion cells (RGC) loss. Increasing reports of similarities in glaucoma and other neurodegenerative conditions have led to speculation that therapies for brain neurodegenerative disorders may also have potential as glaucoma therapies. Memantine is an N-methyl-d-aspartate (NMDA) antagonist approved for Alzheimer's disease treatment. Glutamate-induced excitotoxicity is implicated in glaucoma and NMDA receptor antagonism is advocated as a potential strategy for RGC preservation. This study describes the development of a topical formulation of memantine-loaded PLGA-PEG nanoparticles (MEM-NP) and investigates the efficacy of this formulation using a well-established glaucoma model. MEM-NPs <200 nm in diameter and incorporating 4 mg mL-1 of memantine were prepared with 0.35 mg mL-1 localized to the aqueous interior. In vitro assessment indicated sustained release from MEM-NPs and ex vivo ocular permeation studies demonstrated enhanced delivery. MEM-NPs were additionally found to be well tolerated in vitro (human retinoblastoma cells) and in vivo (Draize test). Finally, when applied topically in a rodent model of ocular hypertension for three weeks, MEM-NP eye drops were found to significantly (p < 0.0001) reduce RGC loss. These results suggest that topical MEM-NP is safe, well tolerated, and, most promisingly, neuroprotective in an experimental glaucoma model. PMID- 29154485 TI - Epistatic effects between pairs of the growth hormone secretagogue receptor 1a, growth hormone, growth hormone receptor, non-SMC condensin I complex, subunit G and stearoyl-CoA desaturase genes on carcass, price-related and fatty acid composition traits in Japanese Black cattle. AB - Growth hormone secretagogue receptor 1a (GHSR1a), growth hormone (GH), growth hormone receptor (GHR), non-SMC condensin I complex, subunit G (NCAPG) and stearoyl-CoA desaturase (SCD), are known to play important roles in growth and lipid metabolisms. Single and epistatic effects of the five genes on carcass, price-related and fatty acid (FA) composition traits were analyzed in a commercial Japanese Black cattle population of Ibaraki Prefecture. A total of 650 steers and 116 heifers for carcass and price-related traits, and 158 steers for FA composition traits were used in this study. Epistatic effects between pairs of the five genes were found in several traits. Alleles showing strain-specific differences in the five genes had significant single and epistatic effects in some traits. The data suggest that a TG-repeat polymorphism of the GHSR1a.5'UTR (TG)n locus plays a central role in gene-gene epistatic interaction of FA composition traits in the adipose tissue of Japanese Black cattle. PMID- 29154486 TI - Relationships between atypical sensory processing patterns, maladaptive behaviour and maternal stress in Spanish children with autism spectrum disorder. AB - BACKGROUND: This study investigated sensory processing in a sample of Spanish children with autism spectrum disorder (ASD). Specifically, the study aimed to explore (1) the prevalence and distribution of atypical sensory processing patterns, (2) the relationship between adaptive and maladaptive behaviour with atypical sensory processing and (3) the possible relationship between sensory subtype and maternal stress. METHODS: The short sensory profile 2 (Dunn 2014) and the vineland adaptive behavior scale (Sparrow et al. 1984) were administered to examine the sensory processing difficulties and maladaptive behaviours of 45 children with ASD aged 3 to 14; their mothers also completed the parenting stress index-short form (Abidin 1995). RESULTS: Atypical sensory features were found in 86.7% of the children; avoider and sensor being the two most common patterns. No significant relationship was found between atypical sensory processing and adaptive behaviour. However, the analysis showed a strong relationship between sensory processing and maladaptive behaviour. Both maladaptive behaviour and sensory processing difficulties correlated significantly with maternal stress although maternal stress was predicted only by the sensory variable, and in particular by the avoider pattern. CONCLUSIONS: The findings suggest that sensory features in ASD may be driving the high prevalence of parental stress in carers. They also suggest that the effect on parental stress that has been attributed traditionally to maladaptive behaviours may be driven by sensory difficulties. The implications of these findings are discussed in relation to the development of interventions and the need to explore contextual and cultural variables as possible sources of variability. PMID- 29154487 TI - The importance of knowing when to be precise. PMID- 29154488 TI - Can interpersonal contact help improve attitudes toward soldiers with intellectual disability? An Israeli study. AB - BACKGROUND: It has been argued that interpersonal contact is the best intervention for reducing negative attitudes and discrimination toward individuals with intellectual disabilities (ID). In Israel, the Equal in Uniform project makes it possible for individuals with ID to serve alongside soldiers without ID in ordinary military units in the Israeli Defense Forces. The project provided the opportunity to examine the effect of contact on the attitudes of soldiers without ID. METHODS: Data analyses are based on data collected from 220 soldiers without ID via a self-administered questionnaire based on the Multidimensional Attitudes Scale. Of these, 138 were in contact with soldiers with ID as part of the project. RESULTS: A mediation model showed that the impact of contact with a soldier with ID on withdrawal behaviour was mediated by cognitive attributions and negative affect. Contact was directly associated with prosocial behaviour. DISCUSSION: Results support the importance of contact between soldiers with and without ID to bring about improved attitudes toward the former. PMID- 29154489 TI - Characteristics of prisoners with intellectual disabilities. AB - BACKGROUND: Previous studies have found high rates of intellectual disabilities (ID) in prison. However, little is understood about prisoners with ID. This study aimed to identify prisoners with ID and compare their characteristics with prisoners without neurodevelopmental disorders with regard to demographic profile, mental health, suicide risk and offences. METHOD: This was a descriptive, cross-sectional study carried out using face-to-face interviews with 240 participants in a London Category C prison. Standardised tools were used to assess prisoners for ID and mental disorder. RESULTS: The study identified 18 prisoners as having ID. Participants with ID were less likely to be from a black or minority ethnic background, be over 35 years of age or have any qualifications. They were more likely to have been single, homeless or unemployed before coming into prison. Prisoners with ID were significantly more likely to have mental health problems and 25% had thought about suicide in the last month and 63% had attempted suicide in the past. Prisoners with ID were also more likely to be housed in the vulnerable prisoners' wing and significantly more likely to have committed robbery than other prisoners. CONCLUSIONS: The findings confirm the presence of significant numbers of people with ID with high levels of mental illness in a male prison. Services across the CJS are required for this group, specifically, there is a need for raised awareness among those working in prison about ID and improved skills to recognise offenders with ID and address major gaps in current healthcare provision in prison. PMID- 29154490 TI - Corrigendum. PMID- 29154492 TI - Exploring factors that impact activity participation of children and adolescents with severe developmental disabilities. AB - BACKGROUND: Despite the benefits of social participation, children and adolescents with developmental disabilities (DD) are often excluded from taking part in social activities. There is a gap in the literature about the factors that contribute to adequate participation of children with severe DD in particular and the barriers to their participation. Taking an ecological perspective, the purpose of this study was to examine child, family and community variables that may impact the activity participation of children and adolescents with severe DD. METHODS: A total of 197 parents of children with severe DD (4-19 years) completed a survey, addressing a wide range of child, family and community related variables, as well as a measure of activity participation. RESULTS: Overall, the final model significantly accounted for 30% of the variance in activity participation. Higher adaptive behaviour, greater parental socialisation and placement in an integrated school programme were significant predictors of greater activity participation. CONCLUSION: Child, family and community factors were all important in understanding the activity participation of children with severe DD, thus supporting the value of an ecological approach. Suggestions for future research and clinical implications are discussed. PMID- 29154491 TI - Does differential visual exploration contribute to visual memory impairments in 22q11.2 microdeletion syndrome? AB - BACKGROUND: Chromosome 22q11.2 microdeletion syndrome (22q11.2DS) is a genetic syndrome characterised by a unique cognitive profile. Individuals with the syndrome present several non-verbal deficits, including visual memory impairments and atypical exploration of visual information. In this study, we seek to understand how visual attention may contribute to memory difficulties in 22q11.2DS by tracking eye movements during the encoding phase of a visual short term memory task. METHOD: Eye movements were recorded during a computerised version of the multiple-choice Benton Visual Retention Test, which consisted of exploring and then recognising complex visual stimuli. Seventy-four participants affected by 22q11.2DS were compared with 70 typically developing participants. RESULTS: Participants with 22q11.2DS performed less well than healthy controls on the task and spent more time and fixations on the principal (larger central) figures and less time and fixations on the smaller peripheral figures within the stimuli. CONCLUSIONS: This study is the first to investigate visual attention in 22q11.2DS during a memory task. The results delineate impaired processes during encoding that affect visual memory performance. The findings may be especially useful for informing interventions intended to boost visual learning in patients with 22q11.2DS. PMID- 29154493 TI - Writing a successful fellowship or grant application. AB - Writing a competitive grant application is an essential skill for any scientist who wants to embark on an independent career. This instalment of the Words of Advice series provides a comprehensive guide to preparing a successful grant or personal fellowship application. PMID- 29154495 TI - Corrigendum. PMID- 29154494 TI - Interplay between environmentally modulated feedback loops - hypoxia and circadian rhythms - two sides of the same coin? AB - Sensing of environmental parameters is critically important for cells of metazoan organisms. Members of the superfamily of bHLH-PAS transcription factors, involved in oxygen sensing and circadian rhythm generation, are important players in such molecular pathways. The interplay between both networks includes a so far unknown factor, connecting PER2 (circadian clocks) to hypoxia sensing (HIF-1 alpha) to result in a more adapted state of homeostasis at the right time. PMID- 29154498 TI - Ruthenium(II)-Catalyzed Synthesis of Spirobenzofuranones by a Decarbonylative Annulation Reaction. AB - The first decarbonylative insertion of an alkyne through C-H/C-C activation of six-membered compounds is reported. The Ru-catalyzed reaction of 3-hydroxy-2 phenyl-chromones with alkynes works most efficiently in the presence of the ligand PPh3 to provide spiro-indenebenzofuranones. Unlike previously reported metal-catalyzed decarbonylative annulation reactions, in the present decarbonylative annulation reaction, the annulation occurs before extrusion of carbon monoxide. PMID- 29154499 TI - FuzzyID2: A software package for large data set species identification via barcoding and metabarcoding using hidden Markov models and fuzzy set methods. AB - Species identification through DNA barcoding or metabarcoding has become a key approach for biodiversity evaluation and ecological studies. However, the rapid accumulation of barcoding data has created some difficulties: for instance, global enquiries to a large reference library can take a very long time. We here devise a two-step searching strategy to speed identification procedures of such queries. This firstly uses a Hidden Markov Model (HMM) algorithm to narrow the searching scope to genus level and then determines the corresponding species using minimum genetic distance. Moreover, using a fuzzy membership function, our approach also estimates the credibility of assignment results for each query. To perform this task, we developed a new software pipeline, FuzzyID2, using Python and C++. Performance of the new method was assessed using eight empirical data sets ranging from 70 to 234,535 barcodes. Five data sets (four animal, one plant) deployed the conventional barcode approach, one used metabarcodes, and two were eDNA-based. The results showed mean accuracies of generic and species identification of 98.60% (with a minimum of 95.00% and a maximum of 100.00%) and 94.17% (with a range of 84.40%-100.00%), respectively. Tests with simulated NGS sequences based on realistic eDNA and metabarcode data demonstrated that FuzzyID2 achieved a significantly higher identification success rate than the commonly used Blast method, and the TIPP method tends to find many fewer species than either FuzztID2 or Blast. Furthermore, data sets with tens of thousands of barcodes need only a few seconds for each query assignment using FuzzyID2. Our approach provides an efficient and accurate species identification protocol for biodiversity-related projects with large DNA sequence data sets. PMID- 29154500 TI - Structure-activity studies of peptidomimetics based on kinase-inhibitory region of suppressors of cytokine signaling 1. AB - Suppressors of Cytokine Signaling (SOCS) proteins are negative regulators of JAK proteins that are receptor-associated tyrosine kinases, which play key roles in the phosphorylation and subsequent activation of several transcription factors named STATs. Unlike the other SOCS proteins, SOCS1 and 3 show, in the N-terminal portion, a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Drug discovery processes of compounds based on KIR sequence demonstrated promising in functional in vitro and in inflammatory animal models and we recently developed a peptidomimetic called PS5, as lead compound. Here, we investigated the cellular ability of PS5 to mimic SOCS1 biological functions in vascular smooth muscle cells and simultaneously we set up a new binding assay for the screening and identification of JAK2 binders based on a SPR experiment that revealed more robust with respect to previous ELISAs. On this basis, we designed several peptidomimetics bearing new structural constraints that were analyzed in both affinities toward JAK2 and conformational features through Circular Dichroism and NMR spectroscopies. Introduced chemical modifications provided an enhancement of serum stabilities of new sequences that could aid the design of future mimetic molecules of SOCS1 as novel anti-inflammatory compounds. PMID- 29154501 TI - Challenges to laser-assisted drug delivery: Applying theory to clinical practice. AB - BACKGROUND: The percutaneous penetration of topically applied compounds can be enhanced using external chemical or physical sources and thus laser-assisted drug delivery is a burgeoning area of interest within the field of dermatology. OBJECTIVES: This article briefly discusses the mechanism of laser-assisted drug delivery and expands upon the challenges and safety issues that may arise in the clinical implementation of this modality. RESULTS: The existing literature demonstrates that investigators and clinicians in dermatology have successfully delivered anti-inflammatory, anti-neoplastic, and anti-oxidative medications transdermally for the treatment of a variety of conditions including scarring, photoageing, and cutaneous neoplasia. Despite growth of the field, much remains to be learned about the applicability of laser-assisted drug delivery in humans, and practitioners are faced with new safety concerns that may be associated with this treatment modality. CONCLUSIONS: Challenges in laser assisted drug delivery include unpredictability of dosing and response to therapy, possibility of inducing local and systemic reactions, and variability in treatment regimens. Lasers Surg. Med. 50:20-27, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29154502 TI - If it is absurd, then why do you do it? The richer the obsessional experience, the more compelling the compulsion. AB - Mounting evidence suggests that obsessive intrusions are often accompanied and amplified by perceptual experiences of different modalities (e.g., feeling dirt on one's skin while experiencing intrusive thoughts about contamination). Pilot studies conducted online with individuals endorsing mild obsessive-compulsive symptoms have linked the co-occurrence of perceptual experiences and obsessions to the severity of subsequent compulsive behaviour as well as low insight. However, it is presently unclear whether sensory experiences accompany all types of obsessional thoughts or are restricted to certain preoccupations (e.g., contamination and aggression). The present study examined a clinical inpatient and outpatient sample with a formally diagnosed obsessive-compulsive disorder (N = 34). Perceptual properties of intrusive thoughts were assessed with the Sensory Properties of Obsessions Questionnaire. The prevalence of perception-laden obsessive thoughts was comparable with prior studies (73.5%), but the intensity was significantly greater. No association was observed between perceptual experiences and expert-rated insight. However, the severity of perception-laden obsessions predicted the frequency of and impairment associated with compulsive behaviour. This was particularly strong for obsessions about contamination. The present study confirms the high prevalence and clinical relevance of perceptual experiences that accompany obsessions and further challenges the traditional trichotomy splitting mental phenomena into thoughts, intrusions, and hallucinations. PMID- 29154503 TI - Preface to special issue on Microscopy of Semiconducting Materials 2017 (MSM-XX). PMID- 29154504 TI - Comparative study of image contrast in scanning electron microscope and helium ion microscope. AB - Images of Ga+ -implanted amorphous silicon layers in a 110 n-type silicon substrate have been collected by a range of detectors in a scanning electron microscope and a helium ion microscope. The effects of the implantation dose and imaging parameters (beam energy, dwell time, etc.) on the image contrast were investigated. We demonstrate a similar relationship for both the helium ion microscope Everhart-Thornley and scanning electron microscope Inlens detectors between the contrast of the images and the Ga+ density and imaging parameters. These results also show that dynamic charging effects have a significant impact on the quantification of the helium ion microscope and scanning electron microscope contrast. PMID- 29154505 TI - Ultra-high risk phase: A missed opportunity for physical health care. PMID- 29154506 TI - Evaluation of major and minor lower extremity amputation in diabetic foot patients AB - Background/aim: We evaluated the existing risk factors with clinical results in patients who underwent major and minor amputation of the lower extremity as a result of diabetic foot ulcers (DFUs). Materials and methods: We retrospectively studied 107 patients who had undergone lower extremity amputation. The patients were divided into minor (Group 1, n = 75) and major (Group 2, n = 32) amputation groups. On clinical evaluation, the type of surgery performed, smoking history, comorbidities, duration of diabetes mellitus (DM) diagnosis, duration of DFU presence, peripheral neuropathy, peripheral arterial disease, results of deep tissue culture, length of hospitalization, and blood parameters were investigated. Results: In Group 2, mean hospitalization time was significantly longer than in Group 1 (P < 0.05). The proportion of patients with Wagner Grade 4 was significantly higher in Group 2 than in Group 1 (P < 0.05). The duration of DM and DFU was significantly longer in Group 2 (P < 0.05). The number of polymicrobial agents was significantly higher in Group 1 (P < 0.05). Conclusion: In our study, the most important risk factors that led to major amputation in patients with DFU were age, Wagner classification, duration of DM, duration of DFU, and C-reactive protein level. PMID- 29154507 TI - Relationship between selected micronutrient deficiencies and oxidative stress biomarkers in diabetes mellitus patients with foot ulcers in Ibadan, Nigeria AB - Background/aim: Micronutrients are indispensable in the prevention of diseases and maintenance of good health. Their deficiencies have been implicated in several diseases associated with oxidative stress (OS). This study aimed at investigating the levels of some vitamins and minerals in association with OS markers in diabetic foot ulcer (DFU) patients in Ibadan, Oyo State, Nigeria. Materials and methods: Seventy DFU patients and 50 apparently healthy volunteers (controls) were recruited for the study. Blood samples of 10 mL were collected after a 10-h overnight fast from each participant after obtaining their consent. Levels of oxidative stress biomarkers such as lipid peroxide (LPO), 8-hydroxyl-2? deoxyguanosine (8-OHdG), total antioxidant status (TAS), superoxide dismutase (SOD), and glutathione peroxidase (GPx) and micronutrients such as vitamin C, vitamin E, copper, selenium, and zinc were determined. Results: Significant increases in the levels of LPO and 8-OHdG and GPx activity were found in DFU patients compared to controls (P < 0.001). Significant decreases in vitamin C (P = 0.003), selenium, vitamin E, and TAS concentrations were detected between DFU patients and controls (P < 0.001). However, nonsignificant decreases in SOD activity and copper and zinc levels were observed when DFU patients and controls were compared (P > 0.05). Vitamin C was significantly positively correlated with GPx and selenium was significantly negatively correlated with 8-OHdG in the DFU group. However, nonsignificant correlations were observed between other micronutrients and oxidative stress biomarkers of both the DFU and control groups. Conclusion: Diabetes mellitus patients with foot ulcers may require micronutrient supplementation for proper control and maintenance of oxidant/antioxidant homeostasis. PMID- 29154508 TI - Primary gliosarcoma: epidemiology, clinical presentation, management and survival. AB - Gliosarcomas are malignant tumours of the central nervous system. As glioblastomas (GBM), they are treated in a similar fashion. However there is growing evidence to suggest that they may be a separate entity. Due to the rarity of primary gliosarcomas (PGS)Here we publish single centre data over a 14-year period, comprising possibly one of the biggest case series in the literature to our knowledge. The mean age at presentation was 59 years with male preponderance (1.75:1). The most common presenting symptoms were balance and mobility issues (61%), followed by headaches (50%) and visual problems (39%). Tumours were most likely to involve the frontal and parietal lobes (27% and 21% respectively). Patients under 50 had a significant survival advantage (50% versus 32%). All patients had surgery, 79% had adjuvant radiotherapy, with a further 21% also receiving chemotherapy. Median survival from surgery of patients diagnosed with PGS was 6.6 months. Median and one-year survival were significantly better for patients who received radiotherapy (14 months; 46% one year survival) and improved further with combined radioand chemotherapy (30 months; 77%, one year survival). For patients of good status, adjuvant chemo-radiotherapy is warranted and should be offered as it confers a muchimproved overall survival. PMID- 29154509 TI - Technology-assisted rehabilitation interventions following pediatric brain injury. AB - INTRODUCTION: Following traumatic brain injury (TBI), children experience a variety of physical, motor, speech, and cognitive deficits that can have a long term detrimental impact. The emergence and popularity of new technologies has led to research into the development of various apps, gaming systems, websites, and robotics that might be applied to rehabilitation. The objective of this narrative review was to describe the current literature regarding technologically-assisted interventions for the rehabilitation of motor, neurocognitive, behavioral, and family impairments following pediatric TBI. EVIDENCE ACQUISITION: We conducted a series of searches for peer-reviewed manuscripts published between 2000 and 2017 that included a technology-assisted component in the domains of motor, language/communication, cognition, behavior, social competence/functioning, family, and academic/school-based functioning. EVIDENCE SYNTHESIS: Findings suggested several benefits of utilizing technology in TBI rehabilitation including facilitating engagement/adherence, increasing access to therapies, and improving generalizability across settings. There is fairly robust evidence regarding the efficacy of online family problem-solving therapy in improving behavior problems, executive functioning, and family functioning. There was less compelling, but still promising, evidence regarding the efficacy other technology for motor deficits, apps for social skills, and computerized programs for cognitive skills. Overall, many studies were limited in the rigor of their methodology due to small heterogeneous samples and lack of control groups. CONCLUSIONS: Technology-assisted interventions have the potential to enhance pediatric rehabilitation after TBI. Future research is needed to further support their efficacy with larger controlled trials and to identify characteristics of children who are most likely to benefit. PMID- 29154510 TI - Occupational Health Survey of Cosmetologists in Minnesota. AB - Cosmetologists face a variety of occupational health and safety challenges. To gather information on respiratory issues related to work as a cosmetologist, licensed cosmetologists were invited by e-mail to participate in a short online survey. The survey collected demographic data, work history, respiratory symptoms, product usage, and health and safety training. Results revealed that while 57% of cosmetologists reported having received training on customer or consumer safety, only 10.5% had received training on worker health such as work related asthma and/or breathing issues. Respiratory symptoms were reported by 46% of respondents. Length of employment and the use of glues or adhesives were associated with a diagnosis of asthma. PMID- 29154511 TI - Treatment of multi-segmental cervical spondylotic myelopathy by posterior spatium intermusculare approach for spinal canal expansion and laminoplasty. PMID- 29154512 TI - Laparoscopic vs. open approach for pT3/pT4 colorectal cancer in the elderly: ten year experience in a single center. AB - BACKGROUND: The role of laparoscopic surgery for pT3/pT4 colorectal cancer (CRC) is still under debate. The aim of this study was to compare the outcomes of laparoscopic and open procedures for pT3/pT4 CRC in elderly patients. METHODS: From January 2004 to December 2015, 225 patients aged >=70 years underwent elective colorectal surgery for pT3/pT4 CRC at the Department of General Surgery, University Hospital of Trieste. Patients' demographics, tumor's characteristics, intraoperative factors, short-term and long-term outcomes were retrospectively analyzed. RESULTS: The study included 113 patients undergone open surgery and 112 who underwent laparoscopic surgery. Age was found to be statistically different between the two group, with open surgery patients being older than laparoscopic ones (P=0.009). The tumor location differed between the two groups (P=0.004), determining a variation in the incidence of surgical procedures performed (P<0.001). No other statistically significant differences were found in terms of intraoperative, histopathologic and oncologic factors. CONCLUSIONS: Laparoscopy is as safe as open surgery for pT3/pT4 CRC and it is often feasible, though in old patients higher conversion rates should be anticipated than in younger ones. PMID- 29154514 TI - Simultaneous splenectomy and cholecystectomy with single docking robotic platform. PMID- 29154513 TI - Propensity score-matched comparison between complete mesocolic excision and classic right hemicolectomy for colon cancer. AB - BACKGROUND: The prognosis of right colon cancer remains disappointing. Complete mesocolic excision (CME) with central vascular ligation (CVL), based on the same oncological principles of total mesorectal excision, has been speculated to result in a better outcome. To evaluate the oncological adequacy of CME with CVL, we carried out a comparative study with propensity score-matched analysis between two different surgical procedures performed at Italian and Egyptian University cancer centers. METHODS: Forty-six Egyptian patients underwent conventional right hemicolectomy, while eighty-eight Italian patients underwent CME with sharp dissection between the embryological planes, exposure of the superior mesenteric vessels with extended lymphadenectomy, and CVL. RESULTS: All operations were successful with no increase in postoperative complications (10% in the patients undergoing CME vs. 19.5% in Egyptian patients). Number of harvested nodes (21 vs. 13) and lymph node ratio (0.08 vs. 0.22) were significantly different in patients undergoing CME (P=0.0001 and P=0.005, respectively). In these patients, the risk of cancer relapse was reduced to as much as one third (8% vs. 22%), even in node positive tumors, and locoregional recurrences were never experienced. The classic operation was significantly associated with poor outcome (5-year disease-free survival rates were 89.2% in the group undergoing CME and 49.1% in the classic group, P=0.02). Propensity score-matched analysis warranted optimal balance and confirmed overall results. CONCLUSIONS: Right colon cancer patients undergoing CME benefitted from more oncological adequacy, with no increased postoperative complication rate, a decreased locoregional recurrence rate, and a better long term outcome than patients operated on with the conventional procedure. PMID- 29154515 TI - Impact of the new World Health Organization classification concept of neuroendocrine tumors. PMID- 29154516 TI - Computed tomography-guided minimally invasive selective approach of an isolated retroperitoneal melanoma metastasis. PMID- 29154518 TI - Effects of lower lumbar single-segment fusion on sagittal parameters of lumbar vertebra with different Roussouly types and its clinical efficacy. PMID- 29154517 TI - A proposal for a tailored approach to diverting ostomy for colorectal anastomosis. AB - BACKGROUND: The use of a protective stoma represents an important issue in colorectal surgery. Although evidence suggests that loop ileostomy may be superior, the optimal method for temporary decompression of colorectal anastomosis still remains controversial. Aim of this study was to make an evidence-based proposal for a tailored approach to the use of diverting colostomy or ileostomy. METHODS: A retrospective analysis of all patients subjected to creation and closure of a diverting loop colostomy or loop ileostomy between May 2007 and November 2014 in our institution was performed. Early and late complications, mortality and morbidity, time between formation and closure of the stoma in respect to adjuvant chemotherapy and the length of hospital stay were assessed and compared between the two groups. RESULTS: Outcomes of 167 patients (m=95; f=72) undergoing a loop colostomy (N.=130) or ileostomy (N.=37) were analyzed. The most frequent diagnosis was malignancy (64.1%), followed by abdominal emergency operations (18.6%) and complicated diverticular disease (17.4%). There was no mortality. Adjuvant chemotherapy (26.3%) resulted in delayed stoma reversal (P<0.001). Complications following construction of the stoma such as electrolyte disorder (P<0.001), renal insufficiency (P=0.048), and skin irritation (P=0.003) occurred significantly more often within the ileostomy group. Within the colostomy group, the rate of stoma prolapse (P=0.074) tended to be higher. CONCLUSIONS: Both methods have advantages and disadvantages. Loop transverse colostomy could be the preferred technique for older patients to avoid electrolyte disorder and renal insufficiency. Further prospective trials with documentation of electrolyte metabolism and quality of life should follow. PMID- 29154520 TI - JEH Quiz #6: Occupational Health Survey of Cosmetologists in Minnesota. PMID- 29154519 TI - Current treatments for anal condylomata acuminata. AB - INTRODUCTION: Condylomata acuminata are the most common sexually transmitted disease worldwide. They are not usually a serious problem, but it causes emotional distress to patient and physician alike because of its marked tendency to recurrence. The presence of anogenital warts mandates treatment, also for potential degeneration of the lesions. EVIDENCE ACQUISITION: A review of the literature has been performed to analyze proposed treatments for anogenital warts. EVIDENCE SYNTHESIS: Many treatments have been employed. They include cytotoxic agents, immunomodulation and physical ablation. The choice of the appropriate treatment varies depending on the number, size, and location of warts. Complications of various treatments are rare but include permanent depigmentation, itching, pain, scarring, bleeding, anal stenosis or incontinence and sepsis. The therapy of these lesions can sometimes be very painful and expensive, and therapy should not be worse than the disease. CONCLUSIONS: No specific antiviral treatment is currently available, and no consensus has been reached on the appropriate treatment for anogenital warts. No data are available to indicate whether treatment eliminates infectivity, the primary aim of treatment being to remove the lesions. There is a paucity of published randomized trials. Despite the introduction of antiviral treatments such as interferon, immunomodulating agents or imiquimod, surgical destruction or removal remains the treatment of choice. PMID- 29154521 TI - Cryptosporidiosis Outbreak Associated With a Single Hotel. AB - We investigated a gastrointestinal illness cluster among persons who attended a baseball tournament (>200 teams) during July 2015. We interviewed representatives of 19 teams; illness was reported among only the 9 (47%) teams that stayed at Hotel A (p < .01). We identified 55 primary cases. A case-control study demonstrated that pool exposure at Hotel A was significantly associated with illness (odds ratio: 7.3; 95% confidence interval: 3.6, 15.2). Eight out of nine (89%) stool specimens tested were positive for Cryptosporidium, with C. hominis IfA12G1 subtype identified in two specimens. The environmental health assessment detected a low free available chlorine level, and pool water tested positive for E. coli and total coliforms. A possible diarrheal contamination event, substantial hotel pool use, and use of cyanuric acid might have contributed to this outbreak and magnitude. Aquatic facilities practicing proper operation and maintenance (e.g., following the Centers for Disease Control and Prevention's Model Aquatic Health Code) can protect the public's health. PMID- 29154523 TI - Elevated Arsenic in Private Wells of Cerro Gordo County, Iowa: Causes and Policy Changes. AB - Private wells are unregulated and often at risk for arsenic contamination. Research objectives included distribution of groundwater arsenic concentrations, identification of arsenic sources, and establishment of best practices for well construction to minimize risk for wells in Cerro Gordo County, Iowa. We sampled 68 wells over 3 years with 393 water samples and 79 rock samples. Geochemical modeling was used to better understand arsenic mobilization. Arsenic in groundwater ranged from 1.0 to less than 10.0 MUg/L for 75 water samples and 31 water samples had arsenic concentrations greater than or equal to 10 MUg/L. The arsenic source is naturally occurring sulfide minerals (typically pyrite) in the bedrock aquifers. The shallow (100-150 feet) Lime Creek Aquifer was most at risk for arsenic. Arsenic is likely mobilized from the rock into the water in the shallow aquifer under more oxidizing conditions, subject to water level changes. The study resulted in a policy change for arsenic testing and well completion in Cerro Gordo County to better protect domestic well users. PMID- 29154524 TI - Osteomyelitis (Refractory) with literature review supplement PMID- 29154522 TI - Distribution and Evaluation of a Carbon Monoxide Detector Intervention in Two Settings: Emergency Department and Urban Community. AB - The objective of this study was to describe changes in carbon monoxide (CO) safety knowledge and observed CO detector use following distribution of a CO detector use intervention in two environments, a pediatric emergency department (Ohio) and an urban community (Maryland). A total of 301 participants completed the 6-month follow up (Ohio: n = 125; Maryland: n = 176). The majority of participants was female, 25-34 years of age, and employed (full or part time). We found that CO safety knowledge did not differ between settings at enrollment, but significantly improved at the follow-up visits. The majority of CO detectors observed were functional and installed in the correct location. Of those with CO detectors at follow up, the majority had not replaced the battery. The success of the intervention varied between settings and distribution methods. The majority of participants showed improved knowledge and behaviors. Improved device technology may be needed to eliminate the need for battery replacement. PMID- 29154525 TI - Minimizing Risk of Illness and Injury at Public Aquatic Facilities by Maximizing the Power of Aquatic Facility Inspection Data. PMID- 29154526 TI - DirecTalk: Musings From the 10th Floor: Oh, Atlanta. PMID- 29154527 TI - Water Quality Survey of Splash Pads After A Waterborne Salmonellosis Outbreak- Tennessee, 2014. AB - Waterborne outbreaks of salmonellosis are uncommon. The Tennessee Department of Health investigated a salmonellosis outbreak of 10 cases with the only common risk factor being exposure to a single splash pad. Risks included water splashed in the face at the splash pad and no free residual chlorine in the water system. We surveyed water quality and patron behaviors at splash pads statewide. Of the 29 splash pads participating in the water quality survey, 24 (83%) used a recirculating water system. Of the 24, 5 (21%) water samples were tested by polymerase chain reaction and found to be positive for E. coli, Giardia, norovirus, or Salmonella. Among 95 patrons observed, we identified common high risk behaviors of sitting on the fountain or spray head and putting mouth to water. Water venue regulations and improved education of patrons are important to aid prevention efforts. PMID- 29154528 TI - Building the Future of Environmental Public Health Tracking: Proceedings and Recommendations of an Expert Panel Workshop. AB - Since 2002, the national Environmental Health Tracking Program of the Centers for Disease Control and Prevention (CDC) has provided vital support to state environmental public health efforts while simultaneously building a nationwide network of state, local, and academic partners to improve our nation's capacity to understand and respond to environmental threats to public health. As part of program review and strategic planning, national thought leaders in environmental public health were convened to assess progress, identify gaps and challenges, and provide recommendations for enhancing the utility and impact of the Tracking Program. Several opportunities were identified. Chief among these was the need for continued and expanded CDC leadership to develop a coordinated Tracking Program agenda identifying specific scientific goals, data needs, and initiatives. Recommendations for future growth included expanded data availability and program coverage: i.e., making data available at the community scale and establishing tracking programs in all 50 states. Finally, a set of recommendations emphasizing communication to decision makers and the public was made that will be integral to the future utility and success of the Tracking Program. PMID- 29154529 TI - Consumer Perception of the Food and Drug Administration's Newest Recommended Food Facility Inspection Format: Words Matter. AB - The Food and Drug Administration recommended restaurant inspection scores change to a format that incorporated three new categories of violations: priority, priority foundation, and core. It was uncertain whether interested consumers would value the more in-depth information or become more confused. The purpose of this study was to assess consumer perception of the recommended inspection system. Data were collected from an online survey. Results showed that consumers want convenient access to the information either online or on the wall of restaurants, and some consumers do want to read inspection reports and use them in making dining decisions. Choice of restaurant inspection format did appear to change consumer understanding and perceptions about some of the violations. Results also demonstrated the importance of the words used to categorize violations. PMID- 29154531 TI - Study of Graphene Oxide Structural Features for Catalytic, Antibacterial, Gas Sensing, and Metals Decontamination Environmental Applications. AB - This study represents a comprehensive review about the structural features of graphene oxide (GO) and its significance in environmental applications. Two dimensional (2D) GO is tremendously focused in advanced carbon-based nanomaterials for environmental applications due to its tunable physicochemical characteristics. Herein, we report foundational structural models of GO and explore the chemical bonding of oxygen moieties, with graphite basal plane using various characterization tools. Moreover, the impact of these oxygen moieties and the morphology of GO for environmental applications such as removal of metal ions and catalytic, antibacterial, and gas sensing abilities have here been critically reviewed for the first time. Environmental applications of GO are highly significant because, in the recent era, the fast progress of industries, even in the countryside, results in air and water pollution. GO has been widely investigated by researchers to eradicate such environmental issues and for potential industrial and clinical applications due to its 2D structural features, large surface area, presence of oxygen moieties, nonconductive nature, intense mechanical strength, excellent water dispersibility, and tunable optoelectronic properties. Thence, particular emphasis is directed toward the modification of GO by varying the number of its oxygen functional groups and by coupling it with other exotic nanomaterials to induce unique properties in GO for potential environmental remediation purposes. PMID- 29154530 TI - ATG101 Single-Stranded Antisense RNA-Loaded Triangular DNA Nanoparticles Control Human Pulmonary Endothelial Growth via Regulation of Cell Macroautophagy. AB - Autophagy plays a key role in pulmonary vascular remodeling via regulation of apoptosis and hyperproliferation of pulmonary arterial endothelial cells, which are the subject of increased attention. Autophagy-related 101 (ATG101) is an essential gene for the initiation of autophagy. Although the structure of ATG101 has been well-characterized, its exact biological function in autophagy is still unknown. In this study, an ATG101 single-stranded antisense RNA-loaded DNA triangular nanoparticle (ssATG101-TNP) is constructed to knock down the ATG101 gene expression. ssATG101-TNP can be effectively transfected into human pulmonary arterial endothelial cells (HPAECs) in time- and dose-dependent manners. Knockdown of ATG101 promotes cell apoptosis as well as inhibits cell autophagy and proliferation with hypoxic stimulation. Additionally, the hedgehog/Gli signal pathway is involved in ATG101-mediated macroautophagy and HPAEC proliferation. This study found that ATG101, an important member of the autophagy gene family, can regulate cell macroautophagy, apoptosis, and growth in HPAECs. ssATG101-TNP is demonstrated to be a nontoxic, highly efficient, gene-delivery vehicle for HPAECs. These findings also suggest that ATG101 might be a potential therapeutic target in diseases involving endothelial injury. PMID- 29154533 TI - Voltage-Assisted Magnetic Switching in MgO/CoFeB-Based Magnetic Tunnel Junctions by Way of Interface Reconstruction. AB - Engineering of interfacial structures has become important more than ever before to find new scientific observations and to create novel applications. Here, we show that the interface reconstructed by atomic layer-thick Mg insertion substantially improved the magneto-electrical properties of perpendicular magnetic tunnel junctions essential for modern spintronic applications. The 0.2 0.4 nm-thick Mg inserted between the MgO tunnel barrier and CoFeB ferromagnet restructured the interface in such ways as to protect the CoFeB from overoxidation, to strengthen the texture, to make the interfacial roughness smooth, and to relax the mechanical stress. Observed were great increases in the perpendicular magnetic moment and perpendicular magnetic anisotropy of the CoFeB by 2.1 and 1.8 times, respectively, which can be ascribed to the optimum interfacial condition because of the least possible chemical damage. The strong enhancement of (010) in-plane and (001) out-of-plane texture and of interfacial roughness led to a significant increase in the tunnel magnetoresistance by 4.4 times from 13.2 to 57.6% by the insertion. Most importantly, such optimum chemical and physical structures at the interface could modulate the perpendicular magnetic properties by an electric field. The electric field controlled magnetic anisotropy coefficients became symmetrically bipolar to the electric field and were increased over 100 fJ/V.m, which is 6 times larger than one found before the Mg insertion. As a result, we could successfully demonstrate the voltage-induced magnetization switching of the perpendicular magnetic tunnel junctions with the help of an external magnetic field. Our findings will ignite further study on the new way of electrical control over magnetic switching and provide an essential ingredient to realize electric field-driven energy-effective magneto-electronic devices. PMID- 29154532 TI - CuS-Based Theranostic Micelles for NIR-Controlled Combination Chemotherapy and Photothermal Therapy and Photoacoustic Imaging. AB - Cancer remains a major threat to human health due to low therapeutic efficacies of currently available cancer treatment options. Nanotheranostics, capable of simultaneous therapy and diagnosis/monitoring of diseases, has attracted increasing amounts of attention, particularly for cancer treatment. In this study, CuS-based theranostic micelles capable of simultaneous combination chemotherapy and photothermal therapy (PTT), as well as photoacoustic imaging, were developed for targeted cancer therapy. The micelle was formed by a CuS nanoparticle (NP) functionalized by thermosensitive amphiphilic poly(acrylamide acrylonitrile)-poly(ethylene glycol) block copolymers. CuS NPs under near infrared (NIR) irradiation induced a significant temperature elevation, thereby enabling NIR-triggered PTT. Moreover, the hydrophobic core formed by poly(acrylamide-acrylonitrile) segments used for drug encapsulation exhibited an upper critical solution temperature (UCST; ~38 degrees C), which underwent a hydrophobic-to-hydrophilic transition once the temperature rose above the UCST induced by NIR-irradiated CuS NPs, thereby triggering a rapid drug release and enabling NIR-controlled chemotherapy. The CuS-based micelles conjugated with GE11 peptides were tested in an epidermal growth factor receptor-overexpressing triple negative breast cancer model. In both two-dimensional monolayer cell and three dimensional multicellular tumor spheroid models, GE11-tagged CuS-based micelles under NIR irradiation, enabling the combination chemotherapy and PTT, exhibited the best therapeutic outcome due to a synergistic effect. These CuS-based micelles also displayed a good photoacoustic imaging ability under NIR illumination. Taken together, this multifunctional CuS-based micelle could be a promising nanoplatform for targeted cancer nanotheranostics. PMID- 29154534 TI - A Route toward Ultrasensitive Layered Carbon Based Piezoresistive Sensors through Hierarchical Contact Design. AB - Ultrahigh sensitive piezoresistive sensors at small deformation are highly desired in many applications. Here, we propose a hierarchical contact design concept and implement it through a direct laser writing technique for fabricating layered carbon piezoresistive sensors with ultrahigh sensitivity. Sensors with unprecedented gauge factors (~5000-10 000) at small deformation (epsilon < 0.1%) were successfully fabricated and demonstrated for their use in sensing both static and high-frequency (20-30 kHz) dynamic mechanical loads. A simple basic structure unit (BSU) contact network model was developed for understanding the importance of the BSU/BSU contact strength and network fractal dimension in dictating the piezoresistive sensitivity of the layered carbon piezoresistive sensors with designed hierarchical contact structures. The hierarchical contact design concept and the contact network model proposed in our work could open a general route for developing ultrasensitive piezoresistive sensors based on granular matter and composite materials. PMID- 29154535 TI - Novel Gd-Loaded Silicon Nanohybrid: A Potential Epidermal Growth Factor Receptor Expressing Cancer Cell Targeting Magnetic Resonance Imaging Contrast Agent. AB - Continuing our research efforts in developing mesoporous silicon nanoparticle based biomaterials for cancer therapy, we employed here porous silicon nanoparticles as a nanocarrier to deliver contrast agents to diseased cells. Nanoconfinement of small molecule Gd-chelates (L1-Gd) enhanced the T1 contrast dramatically compared to distinct Gd-chelate (L1-Gd) by virtue of its slow tumbling rate, increased number of bound water molecules, and their occupancy time. The newly synthesized Gd-chelate (L1-Gd) was covalently grafted on silicon nanostructures and conjugated to an antibody specific for epidermal growth factor receptor (EGFR) via a hydrazone linkage. The salient feature of this nanosized contrast agent is the capability of EGFR targeted delivery to cancer cells. Mesoporous silicon nanoparticles were chosen as the nanocarrier because of their high porosity, high surface area, and excellent biodegradability. This type of nanosized contrast agent also performs well in high magnetic fields. PMID- 29154536 TI - Caged Naloxone: Synthesis, Characterization, and Stability of 3- O-(4,5-Dimethoxy 2-nitrophenyl)carboxymethyl Naloxone (CNV-NLX). AB - The photolabile analogue of the broad-spectrum opioid antagonist naloxone, 3- O (4,5-dimethoxy-2-nitrophenyl)carboxymethyl naloxone (also referred to as "caged naloxone", 3- O-(alpha-carboxy-6-nitroveratryl)naloxone, CNV-NLX), has been found to be a valuable biochemical probe. While the synthesis of CNV-NLX is simple, its characterization is complicated by the fact that it is produced as a mixture of alpha R,5 R,9 R,13 S,14 S and alpha S,5 R,9 R,13 S,14 S diastereomers. Using long range and heteronuclear NMR correlations, the 1H NMR and 13C NMR resonances of both diastereomers have been fully assigned, confirming the structures. Monitoring of solutions of CNV-NLX in saline buffer, in methanol, and in DMSO has shown CNV-NLX to be stable for over a week under fluorescent laboratory lights at room temperature. Exposure of such solutions to lambda 365 nm from a hand-held UV lamp led to the formation of naloxone and CNV-related breakdown products. PMID- 29154537 TI - Tools for Pathogen Proteomics: Fishing with Biomimetic Nanosponges. AB - The identification of the major virulence factors that drive pathogenicity is critical for gaining insight into the underlying molecular mechanisms of diseases. Although genetic approaches combined with functional analyses have markedly increased the rate of virulence factor discovery, the divergence between genome and proteome can impair the identification of important markers, in particular, of those that act in concert or depend on specific environmental factors. Recently, membrane-coated nanomaterials mimicking source cells of interest have emerged as powerful tools that can be used for improved tumor targeting and as "nanotraps" to capture chemokines and bacterial toxins. In this issue of ACS Nano, Lapek et al. demonstrate that membrane-coated nanosponges in combination with quantitative proteomics can also be used as efficient "fishing devices" for the identification of cell-type-specific virulence factors. PMID- 29154539 TI - Electrokinetic Removal of Dodecyl Sulfate Micelles from Digested Protein Samples Prior to Electrospray-Ionization Mass Spectrometry. AB - In proteomics, dodecyl sulfate (DS-) as sodium salt is commonly used in protein solubilization prior to tryptic digestion, but the presence of the DS- hampers the electrospray ionization mass spectrometric (ESI-MS) analysis. The development of DS- depletion techniques is therefore important especially when dealing with small samples where there could be poor sensitivity due to sample loss or dilution during sample preparation. Here, we present a simple and fast electrokinetic removal method of DS- from small volumes of peptide and digested protein samples prior to ESI-MS. The selective removal was accomplished using an acidic extraction solution (ES) containing acetonitrile (ACN) inside a fused silica capillary that was dipped into the sample. The use of acidic ES suppressed the electroosmotic flow; allowing the electrokinetic movement of DS- monomers and micelles into the capillary. The high amount of ACN present at the tip of the capillary served to collapse the micelles migrating into the capillary, thereby releasing the peptides that were bound to these micelles, facilitating peptide retention in the sample and efficient DS- removal. Increased % MS signal intensity (SI) restoration of the peptide was observed, while DS- removal was unaffected when the amount of ACN in the ES was increased. This is because of the micelle to solvent stacking mechanism (effective electrophoretic mobility reversal) working at high concentration of ACN for the improved recovery of the peptides. % MS SI restoration for the Z-Gly-Gly-Val and bradykinin peptides were 75-83% while % MS SI reduction of DS- was up to 99% under optimal conditions, that is, 40% ACN in the ES. Higher % peptide recoveries from digested protein samples were obtained using the proposed method compared to the conventional cold acetone precipitation method. PMID- 29154538 TI - Enhanced Removal of Dissolved Hg(II), Cd(II), and Au(III) from Water by Bacillus subtilis Bacterial Biomass Containing an Elevated Concentration of Sulfhydryl Sites. AB - In this study, the sorption of Hg(II), Cd(II), and Au(III) onto Bacillus subtilis biomass with an elevated concentration of sulfhydryl sites, induced by adding excess glucose to the growth medium (termed 'High Sulfhydryl Bacillus subtilis' or HSBS) was compared to that onto B. subtilis biomass with a low concentration of sulfhydryl sites (termed 'Low Sulfhydryl Bacillus subtilis' or LSBS) and to sorption onto a commercially available cation exchange resin. Our results show that HSBS exhibits sorption capacities for the three studied metals that are two to five times greater than the sorption capacities of LSBS for these metals. After blocking the bacterial cell envelope sulfhydryl sites using a qBBr treatment, the sorption of the metals onto HSBS was significantly inhibited, indicating that the enhanced sorption onto HSBS was mainly due to the elevated concentration of sulfhydryl sites on the bacteria. A direct comparison of the removal capacity of the HSBS and that of the cation exchange resin for the three metals demonstrates that HSBS, compared to this commercially available resin, exhibits superior sorption capacity and selectivity for the removal of Hg(II), Cd(II), and Au(III), especially in systems with dilute metal concentrations. These results suggest that bacterial sulfhydryl sites control the sorption behavior of these three metals, and therefore biomass with induced high concentrations of sulfhydryl sites represents a promising and low cost biosorbent for the effective removal and recovery of chalcophile heavy metals from aqueous media. PMID- 29154540 TI - Which is the Stronger Nucleophile, Platinum or Nitrogen in Rollover Cycloplatinated(II) Complexes? AB - The rollover cyclometalated platinum(II) complexes [PtMe(2,X'-bpy-H)(PPh3)], (X = 2, 1a; X = 3, 1b; and X = 4, 1c) containing two potential nucleophilic centers have been investigated to elucidate which center is the stronger nucleophile toward methyl iodide. On the basis of DFT calculations, complexes 1b and 1c are predicted reacting with MeI through the free nitrogen donor to form N-methylated platinum(II) complexes, while complex 1a reacts through oxidative addition on platinum to give a platinum(IV) complex, which is in agreement with experimental findings. The reasons for this difference in selectivity for complexes 1a-1c are discussed based on the energy barrier needed for N-methylation versus oxidative addition reactions. PMID- 29154541 TI - Characteristic alpha-Acid Derivatives from Humulus lupulus with Antineuroinflammatory Activities. AB - Twenty compounds, including 14 new alpha-acid derivatives, a new chromone, and five known compounds, were identified from the pistillate inflorescence of Humulus lupulus (hops), and their structures were elucidated via physical data analysis. The absolute configurations of new alpha-acid derivatives 1-11b were determined by comparing their computed and experimental electronic circular dichroism spectra using TDDFT and NMR spectroscopic data. A putative biosynthetic pathway for the identified components was deduced. Their antineuroinflammatory effects were assayed systematically, and their structure-activity relationships are discussed briefly. Among the identified compounds, compound 14 displayed moderate inhibitory effects against nitric oxide production with an IC50 value of 7.92 MUM. PMID- 29154542 TI - Diterpenoid Alkaloids from Two Aconitum Species with Antifeedant Activity against Spodoptera exigua. AB - Twenty-five diterpenoid alkaloids were isolated from the roots of two Aconitum species. The structures of seven new C19-diterpenoid alkaloids, apetaldines A-G (1-7), and 10 known alkaloids (8-17) from Aconitum apetalum and eight known alkaloids (18-25) from Aconitum franchetii var. villosulum were elucidated via HRESIMS, IR, and NMR data. Alkaloids 1-10, 15, 16, and 18-25 were screened for their antifeedant activity. Among the compounds tested, chasmanthinine (19) showed highly potent antifeedant activity with an effective concentration for 50% feeding reduction (EC50) at 0.07 mg/cm2. The antifeedant structure-activity relationship of the diterpenoid alkaloids is also discussed. PMID- 29154544 TI - Insights into the Mechanism of Ground and Excited State Double Proton Transfer Reaction in Formic Acid Dimer. AB - The mechanism of ground and excited state double proton transfer reaction in formic acid dimer has been analyzed with the help of reaction force and the reaction electronic flux. The separation of reaction electronic flux in terms of electronic activity and reactivity, NBO, and dual descriptor lends additional support for the mechanism. Interestingly we found that the ground state double proton transfer mechanism is concerted synchronic, whereas the excited state double proton transfer is concerted asynchronic in nature. PMID- 29154543 TI - Fluorogenic Targeting of Voltage-Sensitive Dyes to Neurons. AB - We present a method to target voltage-sensitive fluorescent dyes to specified cells using an enzyme-catalyzed fluorogenic reaction on cell surfaces. The dye/enzyme hybrids are composed of a photoinduced electron transfer (PeT)-based fluorescent voltage indicator and a complementary enzyme expressed on the cell surface. Action of the exogenous enzyme on the dye results in fluorogenic activation of the dye, enabling fast voltage imaging in defined neurons with sensitivity surpassing those of purely genetically encoded approaches. We employ a bulky methylcyclopropylacetoxymethyl ether to diminish the fluorescence of a PeT-based voltage-sensitive dye, or VoltageFluor. The hydrolytically stable ether can be removed by the action of porcine liver esterase (PLE) to reveal the bright unmodified VoltageFluor. We established that the chemically modified VoltageFluor is a substrate for PLE in vitro and in live cells. When PLE is targeted to the external face of cell membranes, it controls the apparent staining of cells. The use of neuron-specific promoters can direct staining to mammalian neurons to provide clear detection of neuronal action potentials in single trials. All of the new VoltageFluors targeted by esterase expression (VF-EXs) report single spikes in cultured mammalian neurons. The best, VF-EX2, does so with a signal-to noise ratio nearly double that of comparable genetically encoded voltage reporters. By targeting PLE to neurons, VF-EX2 can interrogate the neuromodulatory effects of serotonin in cultured hippocampal neurons. Taken together, our results show that a combination of synthetic chemistry and biochemistry enables bright and fast voltage imaging from genetically defined neurons in culture. PMID- 29154545 TI - Highly Enantioselective Hydrosilylation of Ketones Catalyzed by a Chiral Oxazaborolidinium Ion. AB - A highly enantioselective hydrosilylation of ketones was developed for the synthesis of a variety of chiral secondary alcohols. In the presence of a chiral oxazaborolidinium ion (COBI) catalyst, the reaction proceeded with good yields (up to 99%) with excellent enantioselectivities (up to 99% ee). PMID- 29154546 TI - Systematic Coupled Cluster Study of Noncovalent Interactions Involving Halogens, Chalcogens, and Pnicogens. AB - The noncovalent interactions of 32 complexes involving pnicogens, chalcogens, and halogens atoms were investigated at the CCSD(T)/aug-cc-pVTZ level of theory. Two different types of complexes could be distinguished on the basis of geometric parameters, electron difference densities, and the charge transfer mechanisms associated with each type. In the type I conformation, the monomers adopt a skewed orientation allowing charge to be transfer between both monomers, whereas in the type II conformation the monomers adopt a linear arrangement, maximizing charge transfer in only one direction. Type I complexes involving the interaction between pnicogens and chalcogens cannot be unambiguously defined as chalcogen or pnicogen bonds, they are an admixture of both. The charge transfer dependence on the conformation adopted by the complexes described in this work can serve as a novel conformationally driven design concept for materials. PMID- 29154547 TI - Synthesis of 4H-1,3-Benzoxazines via Metal- and Oxidizing Reagent-Free Aromatic C H Oxygenation. AB - An unprecedented electrochemical aromatic C-H oxygenation reaction for the synthesis of 4H-1,3-benzoxazines from easily available N-benzylamides is reported. These oxidative cyclization reactions proceed in a transition metal- and oxidizing reagent-free fashion and produce H2 as only theoretical byproduct. Adapting the C-H oxygenation reaction in an electrochemical microreactor has been demonstrated. PMID- 29154548 TI - Synthesis of 4-Isoxazolines via Visible-Light Photoredox-Catalyzed [3 + 2] Cycloaddition of Oxaziridines with Alkynes. AB - A method for [3 + 2] cycloaddition of oxaziridines with alkynes to form 4 isoxazolines via visible-light photoredox catalysis is described. This method is a greener, atom-economical reaction that tolerates various functional groups and provides good to excellent yield. Moreover, the cyclization products can be conveniently converted into tetrasubstituted allylic alcohols and enamines. A mechanistic study suggests that the reaction involves photoredox-catalyzed in situ generation of a nitrone from the oxaziridine by SET. PMID- 29154549 TI - Correction to "Electroanalysis of Neutral Precursors in Protic Ionic Liquids and Synthesis of High-Ionicity Ionic Liquids". PMID- 29154550 TI - Biophysical and Sequence-Based Methods for Identifying Monovalent and Bivalent Antibodies with High Colloidal Stability. AB - In vitro antibody discovery and/or affinity maturation are often performed using antibody fragments (Fabs), but most monovalent Fabs are reformatted as bivalent IgGs (monoclonal antibodies, mAbs) for therapeutic applications. One problem related to reformatting antibodies is that the bivalency of mAbs can lead to increased antibody self-association and poor biophysical properties (e.g., reduced antibody solubility and increased viscosity). Therefore, it is important to identify monovalent Fabs early in the discovery and/or optimization process that will display favorable biophysical properties when reformatted as bivalent mAbs. Here we demonstrate a facile approach for evaluating Fab self-association in a multivalent assay format that is capable of identifying antibodies with low self-association and favorable colloidal properties when reformatted as bivalent mAbs. Our approach (self-interaction nanoparticle spectroscopy, SINS) involves immobilizing Fabs on gold nanoparticles in a multivalent format (multiple Fabs per nanoparticle) and evaluating their self-association behavior via shifts in the plasmon wavelength or changes in the absorbance values. Importantly, we find that SINS measurements of Fab self-association are correlated with self interaction measurements of bivalent mAbs and are useful for identifying antibodies with favorable biophysical properties. Moreover, the significant differences in the levels of self-association detected for Fabs and mAbs with similar frameworks can be largely explained by the physicochemical properties of the complementarity-determining regions (CDRs). Comparison of the properties of the CDRs in this study relative to those of approved therapeutic antibodies reveals several key factors (net charge, fraction of charged residues, and presence of self-interaction motifs) that strongly influence antibody self association behavior. Increased positive charge in the CDRs was observed to correlate with increased risk of high self-association for the mAbs in this study and clinical-stage antibodies. We expect that these findings will be useful for improving the development of therapeutic antibodies that are well suited for high concentration applications. PMID- 29154551 TI - Photocatalyzed Site-Selective C(sp3)-H Functionalization of Alkylpyridines at Non Benzylic Positions. AB - Tetrabutylammonium decatungstate (TBADT)-photocatalyzed C-H functionalization of alkylpyridines was investigated. Unlike alkylbenzene counterparts, alkylation of alpha-C-H bonds did not proceed for the reaction of 2- and 4-alkylpyridines and reluctantly proceeded for 3-alkylpyridines, which allow site-selective C(sp3)-H functionalization at nonbenzylic positions. The observed nonbenzylic site selectivities are rationalized by the polar inductive effects of pyridyl groups in the SH2 transition states. Consecutive gamma-functionalization and alpha bromofunctionalization were successfully carried out in selected cases. PMID- 29154552 TI - Does shyness interact with peer group affiliation in predicting substance use in adolescence? AB - Cigarette use and binge drinking are risky behaviors emerging during adolescence. Although many beneficial factors are well documented, studies linking shyness to substance use are somehow conflicting, which may be due to the contribution of moderators. Therefore, the present study has 2 objectives: (a) to prospectively analyze the association between shyness and substance use during adolescence, and (b) to test the moderating role of peer group affiliation on the relationship between shyness and substance use. Participants are 1447 adolescents from the Quebec Longitudinal Study of Child Development, a representative cohort of single birth children born between 1997 and 1998 in the province of Quebec, Canada. Shyness was assessed at age 12 years. Peer group affiliation, as well as past year cigarette use and binge drinking were assessed at age 15 years. Logistic regressions were used to analyze the data. All analyses were carried out using weighted data accounting for the complex multistage sample design. Results show that shyness negatively predicts the use of tobacco and the occurrence of binge drinking while controlling for confounding variables. However, shyness does not interact with peer group affiliation in predicting substance use. This is the first study that confirms the presence of a negative relationship between shyness and substance use during adolescence over a 3-year period. Results suggest that shyness could exert a beneficial effect against substance use notwithstanding the adolescent's social context. (PsycINFO Database Record PMID- 29154553 TI - A randomized trial of female-specific cognitive behavior therapy for alcohol dependent women. AB - This study compared Female-Specific Cognitive Behavioral Therapy (FS-CBT) to evidence-based, gender-neutral CBT (GN-CBT; Epstein & McCrady, 2009) for women with alcohol use disorder (AUD). Women (N = 99) with AUD, mean age 48, were randomly assigned to 12 outpatient manual-guided sessions of FS-CBT (n = 44) or GN-CBT (n = 55). Women were assessed at baseline and 3, 9 and 15 months after baseline for drinking and for specific issues common among women with AUD. A FS CBT protocol was developed that was discriminable on treatment integrity ratings from GN-CBT. No treatment condition differences were found in treatment engagement, changes in drinking, alcohol-related coping, abstinence self efficacy, motivation to change, or constructs directly targeted in FS-CBT (sociotropy, autonomy, depression, anxiety). Women in both conditions were highly engaged and satisfied with treatment, and reported significant reductions in drinking and changes in desired directions for all other variables except social support for abstinence. In the year following treatment, women in the FS-CBT but not in the CBT condition reported an increase in percentage of abstainers in their social networks (0.69% per month, SE = 0.21, p = .002). The value and appeal of female-specific programming in AUD treatment has been established in the wider literature (Epstein & Menges, 2013), and the current study provides support for the use of the Female-Specific Cognitive Behavioral Therapy (FS-CBT) manual as an option that may yield outcomes similar to standard gender-neutral CBT for women with AUD. Future research should examine whether FS-CBT enhances treatment utilization for women. (PsycINFO Database Record PMID- 29154554 TI - Associations between executive functioning, affect-regulation drinking motives, and alcohol use and problems. AB - Motivation to use alcohol to regulate positive and negative affect and deficits in cognitive control (i.e., executive functions [EFs]) have both been associated with increased alcohol involvement and alcohol-related consequences. Although dual-process models predict that affect-driven motivations and cognitive control should interact to determine alcohol involvement and alcohol-related consequences, this intersection has remained largely unexplored. The present study examined the extent to which effects of enhancement and coping drinking motives on alcohol use, heavy drinking, and alcohol-related consequences are moderated by individual differences in three theorized components of EF. We anticipated, in general, that drinking motives would more strongly predict alcohol use, heavy drinking, and alcohol-related consequences among individuals low versus high in cognitive control-EF. Participants (N = 801) completed a battery of nine EF tasks, as well as measures of drinking motives, alcohol use, heavy drinking, and alcohol-related negative consequences. A baseline structural model indicated that (a) both enhancement motives and coping motives predicted alcohol use and heavy drinking, (b) both enhancement and coping motives exerted their effects on alcohol-related consequences both directly and indirectly via alcohol use, and (c) shifting-specific abilities were modestly positively associated with heavy drinking. Most important for the aims of the study, latent variable interaction analyses failed to provide consistent evidence that better EF abilities attenuate the effects of drinking motives on alcohol use, heavy drinking, and alcohol-related consequences, as predicted. (PsycINFO Database Record PMID- 29154555 TI - Family engagement in schoolwide positive behavioral interventions and supports: Barriers and facilitators to implementation. AB - The purpose of this study was to identify barriers and facilitators to family engagement in schools implementing schoolwide positive behavioral interventions and supports (PBIS). Participants consisted of 1 representative member each from 204 school PBIS teams across 3 states. Qualitative analysis guided examination of responses to 1 question regarding barriers and 2 questions about facilitators to family engagement. Survey respondents identified key barriers to family engagement as a lack of resources, inconsistent communication, and reluctance of families and school staff to partner. Specified facilitators included communication, PBIS, shared decision-making, and strategies to build relationships with families. (PsycINFO Database Record PMID- 29154556 TI - Communal motivation and well-being in interpersonal relationships: An integrative review and meta-analysis. AB - The motivation to care for the welfare of others, or communal motivation, is a crucial component of satisfying interpersonal relationships and personal well being. The current meta-analysis synthesized 100 studies (Ntotal = 26,645) on communal motivation to establish its associations with subjective personal well being (e.g., life satisfaction, positive affect, and negative affect) and relationship well-being (e.g., relationship satisfaction, partner-oriented positive affect, and partner-oriented negative affect) for both the person providing communal care and their partner. Three types of communal motivation were examined, including general, partner-specific (for children, parents, romantic partners, and friends), and unmitigated (i.e., devoid of agency and self oriented concern). Results revealed positive associations between all three forms of communal motivation and relationship well-being for the self (.11 <= rs <= .44) and relationship partners (.11 <= rs <= .15). However, only general and partner-specific communal motivation, and not unmitigated communal motivation, were linked with greater personal well-being for both the self (.12 <= rs <= .16) and relationship partners (.04 <= rs <= .09). These associations were generally consistent across gender, relationship length, publication status, and lab. Finally, relationship partners were similar in partner-specific (r = .26) and unmitigated (r = .15) communal motivation only. Findings from the current meta analysis suggest that care for the welfare of others is linked to greater relationship well-being for both members of a relationship. However, communal care is only linked to personal well-being insofar as it is mitigated by a degree of self-oriented concern. We provide theoretical and power recommendations for future research. (PsycINFO Database Record PMID- 29154557 TI - In the shadow of coal: How large-scale industries contributed to present-day regional differences in personality and well-being. AB - Recent research has identified regional variation of personality traits within countries but we know little about the underlying drivers of this variation. We propose that the Industrial Revolution, as a key era in the history of industrialized nations, has led to a persistent clustering of well-being outcomes and personality traits associated with psychological adversity via processes of selective migration and socialization. Analyzing data from England and Wales, we examine relationships between the historical employment share in large-scale coal based industries (coal mining and steam-powered manufacturing industries that used this coal as fuel for their steam engines) and today's regional variation in personality and well-being. Even after controlling for possible historical confounds (historical energy supply, education, wealth, geology, climate, population density), we find that the historical local dominance of large-scale coal-based industries predicts today's markers of psychological adversity (lower Conscientiousness [and order facet scores], higher Neuroticism [and anxiety and depression facet scores], lower activity [an Extraversion facet], and lower life satisfaction and life expectancy). An instrumental variable analysis, using the historical location of coalfields, supports the causal assumption behind these effects (with the exception of life satisfaction). Further analyses focusing on mechanisms hint at the roles of selective migration and persisting economic hardship. Finally, a robustness check in the U.S. replicates the effect of the historical concentration of large-scale industries on today's levels of psychological adversity. Taken together, the results show how today's regional patterns of personality and well-being (which shape the future trajectories of these regions) may have their roots in major societal changes underway decades or centuries earlier. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29154558 TI - Pilot evaluation of a resilience training program for people with multiple sclerosis. AB - OBJECTIVE: To evaluate the feasibility and psychosocial outcomes of an Acceptance and Commitment Therapy (ACT)-based group resilience training program for people with multiple sclerosis (PwMS). Research Method/Design: The study used a pre-post group intervention design with 3-month follow-up. The intervention consisted of 8 group sessions of 2.5 hours each with 7 weekly sessions plus a booster Session 5 weeks later. Thirty-seven PwMS completed questionnaires. Primary psychosocial outcomes were resilience, quality of life (QoL), and distress. Secondary outcomes were the ACT processes: mindfulness, defusion, values and acceptance. RESULTS: Significant improvements were observed for resilience (p = .005; Hedge's g = .47), physical health QoL (p < .001; g = -.76), mental health QoL (p = .006; g = .46), depression (p = .009; g = .38), stress (p = .025; g = .33), and 3 ACT processes: defusion (p = .013; g = -.54), values (p = .010; g = -.38), and acceptance (p = .006; g = -.39). Values and defusion emerged as mediators of physical health QoL and stress (90% CI), respectively. Program feasibility was supported by positive participant feedback; high rates of recruitment, attendance, retention, and homework engagement; and good intervention fidelity. CONCLUSIONS: Findings provide preliminary support for the utility and feasibility of a community organization delivered ACT-based group resilience training program for improving resilience, QoL, depression, stress, and protective factors (defusion, values, acceptance) in PwMS. (PsycINFO Database Record PMID- 29154559 TI - Stress and cultural resilience among low-income Latino adolescents: Impact on daily mood. AB - OBJECTIVES: Given that Latino adolescents endorse more negative mood when compared to their counterparts of other backgrounds (Kann et al., 2016), it is important to evaluate the impact of risk and resilience factors on negative mood among this population. The current study uses daily diary methodology to examine the associations that daily economic stress, daily family stress, familism, and ethnic identity commitment and exploration have with average daily negative mood and variability in daily negative mood. METHODS: Participants included 58 (M = 13.31, 47% female) low-income Latino adolescents who completed study measures over a 1-week period along with a baseline assessment. RESULTS: Results show that daily family stress was strongly linked to daily negative mood, whereas familism emerged as a salient resilience factor. Contrary to predictions, ethnic identity commitment appeared to be detrimental for youth's daily negative mood; furthermore, ethnic identity exploration was found to exacerbate daily negative mood when youth were experiencing high economic stress. However, youth with stronger identities also had less variability in negative mood, specifically when experiencing high family stress. CONCLUSIONS: Although results of this study suggest familism is a key promotive factor, ethnic identity may increase vulnerability in stressful contexts. Thus, programs should build adaptive coping in order for youth with stronger ethnic identities to be prepared to deal with the harmful societal climate they reside in. (PsycINFO Database Record PMID- 29154560 TI - Racial discrimination experiences and African American youth adjustment: The role of parenting profiles based on racial socialization and involved-vigilant parenting. AB - OBJECTIVES: The purpose of this study was to test whether parenting profiles based on racial socialization and involved-vigilant parenting would compensate for or moderate associations between racial discrimination experiences and academic outcomes and psychological well-being among African American adolescents. METHOD: Participants were 1,363 African American adolescents (Mage = 14.19; 52.3% female) from 3 Midwestern suburban school districts. Latent profile analysis was used to examine whether there were distinct combinations of parenting. The relationships among racial discrimination experiences, parenting profiles, and adjustment were examined using structural equation modeling (SEM). RESULTS: Three distinct parenting profiles were found: moderate positive (n = 767; moderately high involved-vigilant parenting and racial barrier, racial pride, behavioral, and egalitarian messages, and low negative messages), unengaged (n = 351; low racial socialization messages and moderately low involved vigilant parenting), and high negative parenting (n = 242; high negative messages, moderate other racial socialization messages, and moderately low involved-vigilant parenting). Racial discrimination experiences were negatively associated with youth adjustment. Moderate positive parenting was related to the best academic outcomes and unengaged parenting was associated with more positive academic outcomes than high negative parenting. Moderate positive parenting was associated with better psychological well-being than unengaged or high negative parenting although the benefits were greater for adolescents with fewer racial discrimination experiences. CONCLUSIONS: Distinct patterns of racial socialization messages and involved-vigilant parenting contribute to differences in African American youth adjustment. (PsycINFO Database Record PMID- 29154561 TI - Acculturative stress, mental health symptoms, and the role of salivary inflammatory markers among a Latino sample. AB - OBJECTIVES: Exposure to psychosocial stressors is associated with increases in adverse mental health outcomes and inflammatory markers. Limited research has investigated if acculturative stress, related to cultural adaptation in Latinos, one of the fastest growing minority groups in the United States, follows a similar pattern. This study hypothesized that acculturative stress would be associated with increased mental health symptoms as well as increases in salivary inflammatory markers. In addition, it was hypothesized that higher levels of salivary inflammatory markers would mediate the pathways between acculturative stress and mental health symptoms. The ability of salivary inflammatory markers to moderate the relationship between acculturative stress and mental health symptoms was also tested. METHOD: One hundred and fifty-four Latino participants were recruited from a local university. Participants completed measures of acculturative stress, perceived stress, state/trait anxiety, and depressive symptoms. Saliva samples measured C-reactive protein (CRP) and interleukin (IL) 1beta. RESULTS: Acculturative stress was significantly associated with increases in perceived stress, state/trait anxiety and depressive symptoms. Salivary inflammatory markers did not mediate the relationship between acculturative stress and mental health symptoms. Alternatively, CRP, but not IL-1beta, moderated the relationship between acculturative stress and state anxiety, such that when salivary CRP levels were low, there was a positive association between acculturative stress and state anxiety symptoms. DISCUSSION: Results suggests that the interplay between acculturative stress and salivary inflammation might indicate risk for anxiety in vulnerable populations. (PsycINFO Database Record PMID- 29154562 TI - Psychophysics of associative learning: Quantitative properties of subjective contingency. AB - Allan and collaborators (Allan, Hannah, Crump, & Siegel, 2008; Allan, Siegel, & Tangen, 2005; Siegel, Allan, Hannah, & Crump, 2009) recently proposed to apply signal detection theory to the analysis of contingency judgment tasks. When exposed to a flow of stimuli, participants are asked to judge whether there is a contingent relation between a cue and an outcome, that is, whether the subjective cue-outcome contingency exceeds a decision threshold. In this context, we tested the following hypotheses regarding the relation between objective and subjective cue-outcome contingency: (a) The underlying distributions of subjective cue outcome contingency are Gaussian; (b) The mean distribution of subjective contingency is a linear function of objective cue-outcome contingency; and (c) The variance in the distribution of subjective contingency is constant. The hypotheses were tested by combining a streamed-trial contingency assessment task with a confidence rating procedure. Participants were exposed to rapid flows of stimuli at the end of which they had to judge whether an outcome was more (Experiment 1) or less (Experiment 2) likely to appear following a cue and how sure they were of their judgment. We found that although Hypothesis A seems reasonable, Hypotheses B and C were not. Regarding Hypothesis B, participants were more sensitive to positive than to negative contingencies. Regarding Hypothesis C, the perceived cue-outcome contingency became more variable when the contingency became more positive or negative, but only to a slight extent. (PsycINFO Database Record PMID- 29154565 TI - Exploring the idiographic dynamics of mood and anxiety via network analysis. AB - Individual variation is increasingly recognized as important to psychopathology research. Concurrently, new methods of analysis based on network models are bringing new perspectives on mental (dys)function. This current work analyzed idiographic multivariate time series data using a novel network methodology that incorporates contemporaneous and lagged associations in mood and anxiety symptomatology. Data were taken from 40 individuals with generalized anxiety disorder (GAD), major depressive disorder (MDD), or comorbid GAD and MDD, who answered questions about 21 descriptors of mood and anxiety symptomatology 4 times a day over a period of approximately 30 days. The model provided an excellent fit to the intraindividual symptom dynamics of all 40 individuals. The most central symptoms in contemporaneous systems were those related to positive and negative mood. The temporal networks highlighted the importance of anger to symptomatology, while also finding that depressed mood and worry-the principal diagnostic criteria for GAD and MDD-were the least influential nodes across the sample. The method's potential for analysis of individual symptom patterns is demonstrated by 3 exemplar participants. Idiographic network-based analysis may fundamentally alter the way psychopathology is assessed, classified, and treated, allowing researchers and clinicians to better understand individual symptom dynamics. (PsycINFO Database Record PMID- 29154564 TI - Self-criticism and dependency in female adolescents: Prediction of first onsets and disentangling the relationships between personality, stressful life events, and internalizing psychopathology. AB - There is substantial evidence that personality traits, such as self-criticism and dependency, predict the development of depression and anxiety symptoms, as well as depressive episodes. However, it is unknown whether self-criticism and dependency predict the first onset of depressive and anxiety disorders, and unclear how to characterize dynamic mechanisms by which these traits, stressful life events, and psychopathology influence one another over time. In this study, 550 female adolescents were assessed at baseline, 528 and 513 of whom were assessed again at Waves 2 and 3, respectively, over the course of 18 months. Self criticism and dependency were assessed with self-report inventories, depressive and anxiety disorders were assessed with diagnostic interviews, and stressful life events were assessed via semistructured interview. Logistic regression analyses showed that self-criticism and dependency significantly predicted the first onset of nearly all depressive and anxiety disorders (significant polychoric rs ranged from .15-.42). Subsequent path analyses focused on prediction of depression, and supported several conceptual models of personality stress-psychopathology relationships. In particular, Personality * Stress interactions were evident for both dependency and self-criticism. These interactions took the form of dual vulnerability, such that stressful life events predicted an increased probability of a later depressive disorder only at low levels of each trait. Results suggest the traits of self-criticism and dependency are important to consider in understanding who is at risk for depressive and anxiety disorders. (PsycINFO Database Record PMID- 29154566 TI - The temporal interplay of self-esteem instability and affective instability in borderline personality disorder patients' everyday lives. AB - Borderline personality disorder (BPD) is defined by a pervasive pattern of instability. Although there is ample empirical evidence that unstable self-esteem is associated with a myriad of BPD-like symptoms, self-esteem instability and its temporal dynamics have received little empirical attention in patients with BPD. Even worse, the temporal interplay of affective instability and self-esteem instability has been neglected completely, although it has been hypothesized recently that the lack of specificity of affective instability in association with BPD might be explained by the highly intertwined temporal relationship between affective and self-esteem instability. To investigate self-esteem instability, its temporal interplay with affective instability, and its association with psychopathology, 60 patients with BPD and 60 healthy controls (HCs) completed electronic diaries for 4 consecutive days during their everyday lives. Participants reported their current self-esteem, valence, and tense arousal levels 12 times a day in approximately one-hr intervals. We used multiple state-of-the-art statistical techniques and graphical approaches to reveal patterns of instability, clarify group differences, and examine the temporal interplay of self-esteem instability and affective instability. As hypothesized, instability in both self-esteem and affect was clearly elevated in the patients with BPD. In addition, self-esteem instability and affective instability were highly correlated. Both types of instability were related to general psychopathology. Because self-esteem instability could not fully explain affective instability and vice versa and neither affective instability nor self esteem instability was able to explain psychopathology completely, our findings suggest that these types of instability represent unique facets of BPD. (PsycINFO Database Record PMID- 29154563 TI - HPA axis multilocus genetic profile score moderates the impact of interpersonal stress on prospective increases in depressive symptoms for offspring of depressed mothers. AB - Although offspring of depressed mothers are at an increased risk for depression themselves, not all of these children develop depression, highlighting the need to identify specific environmental and genetic moderators of risk. The goal of this study was to examine the aggregate influence of genetic polymorphisms associated with the regulation of the hypothalamic-pituitary-adrenal (HPA) axis as a potential moderator of the relation between environmental stress and prospective changes in depressive symptoms for offspring of depressed mothers. Participants were 238 mother-offspring dyads recruited from the community based on the mother's lifetime history of major depression during the youth's lifetime (present vs. absent). Mothers and youth completed assessments every 6 months for 2 years (5 total). Results indicated that offspring of depressed mothers showing the greatest increases in depressive symptoms during the follow up were those who had higher HPA multilocus genetic profile scores and who experienced the highest levels of interpersonal stress. These relations were significant for interpersonal stress and were not observed for noninterpersonal stress. These findings suggest that HPA multilocus genetic profile scores may be important genetic markers of stress reactivity and depression risk for offspring of depressed mothers. They also highlight interpersonal stress as a potentially modifiable risk factor for these high-risk youth. (PsycINFO Database Record PMID- 29154567 TI - Faces and facets: The variability of emotion recognition in psychopathy reflects its affective and antisocial features. AB - Psychopathy consists of a constellation of affective-interpersonal features including lack of empathy, callousness, manipulativeness and interpersonal charm, impulsiveness and irresponsibility. Despite its theoretical and predictive value in forensic contexts, the relationships between the psychometric dimensions of psychopathy, including its antisocial features, and the construct's neuropsychological characteristics remain uncertain. In this study, 685 personality-disordered prisoners with histories of serious violent or sexual offenses were assessed for psychopathy before completing a computerized and well validated assessment of the ability to recognize emotional expressions in the face. Prisoners with more of the affective features of psychopathy, and prisoners with more of its antisocial manifestations, showed relatively poor recognition accuracy of fearfulness and disgust. These relationships were independent and modest but were still evident following correction for demographic features (e.g., ethnicity and socioeconomic status), mental illness (e.g., substance and alcohol misuse), personality disorders (other than antisocial personality disorder) and treatment status. By contrast, the associations between these dimensions of psychopathy and emotion recognition were diminished by controlling for cognitive ability. These findings demonstrate that variability in the ability of high-risk personality-disordered prisoners to recognize emotional expressions in the face-in particular, fear and disgust-reflects both the affective and antisocial aspects of psychopathy, and is moderated by cognitive ability. (PsycINFO Database Record PMID- 29154568 TI - Altered spatial profile of distraction in people with schizophrenia. AB - Attention is critical for effective processing of incoming information and has long been identified as a potential area of dysfunction in people with schizophrenia (PSZ). In the realm of visual processing, both spatial attention and feature-based attention are involved in biasing selection toward task relevant stimuli and avoiding distraction. Evidence from multiple paradigms has suggested that PSZ may hyperfocus and have a narrower "spotlight" of spatial attention. In contrast, feature-based attention seems largely preserved, with some suggestion of increased processing of stimuli sharing the target-defining feature. In the current study, we examined the spatial profile of feature-based distraction using a task in which participants searched for a particular color target and attempted to ignore distractors that varied in distance from the target location and either matched or mismatched the target color. PSZ differed from healthy controls in terms of interference from peripheral distractors that shared the target-color presented 200 ms before a central target. Specifically, PSZ showed an amplified gradient of spatial attention, with increased distraction to near distractors and less interference to far distractors. Moreover, consistent with hyperfocusing, individual differences in this spatial profile were correlated with positive symptoms, such that those with greater positive symptoms showed less distraction by target-colored distractors near the task relevant location. (PsycINFO Database Record PMID- 29154569 TI - The social transmission of risk: Maternal stress physiology, synchronous parenting, and well-being mediate the effects of war exposure on child psychopathology. AB - While chronic early stress increases child susceptibility to psychopathology, risk and resilience trajectories are shaped by maternal social influences whose role requires much further research in longitudinal studies. We examined the social transmission of risk by assessing paths leading from war-exposure to child symptoms as mediated by 3 sources of maternal social influence; stress physiology, synchronous parenting, and psychiatric disorder. Mothers and children living in a zone of continuous war were assessed in early childhood (1.5-5 years) and the current study revisited families in late (9-11years) childhood (N = 177; N = 101 war-exposed; N = 76 controls). At both time-points, maternal and child's salivary cortisol (SC), social behavior, and externalizing and internalizing symptoms were assessed. In late childhood, hair cortisol concentrations (HCC) were also measured and mother and child underwent psychiatric diagnosis. The social transmission model was tested against 2 alternative models; 1 proposing direct impact of war on children without maternal mediation, the other predicting late-childhood symptoms from early childhood variables, not change trajectories. Path analysis controlling for early childhood variables supported our conceptual model. Whereas maternal psychopathology was directly linked with child symptoms, defining direct mediation, the impact of maternal stress hormones was indirect and passed through stress contagion mechanisms involving coupling between maternal and child's HCC and SC. Similarly, maternal synchrony linked with child social engagement as the pathway to reduced symptomatology. Findings underscore the critical role of maternal stress physiology, attuned behavior, and well-being in shaping child psychopathology amid adversity and specify direct and indirect paths by which mothers stand between war and the child. (PsycINFO Database Record PMID- 29154570 TI - Interactive effects of ovarian steroid hormones on alcohol use and binge drinking across the menstrual cycle. AB - Patterns and features of substance use and abuse vary across the menstrual cycle in humans. Yet, little work has systematically examined the within-person relationships between ovarian hormone changes and alcohol use across the menstrual cycle. Our study was the first to examine the roles of within-person levels of estradiol (E2) and progesterone (P4) in relation to daily alcohol use and binge drinking in young women. Participants were 22 naturally cycling women, ages 18-22, recruited through a university subject pool who reported any alcohol use and who completed a screening visit assessing study eligibility, followed by 35 subsequent days of data collection. E2 and P4 were obtained via enzyme immunoassay of saliva samples collected by participants each morning, 30 min after waking. Presence and degree of daily substance use were obtained using an adaptation of the Timeline FollowBack Interview completed daily. Results indicated that elevated E2 in the context of decreased P4 levels were associated with higher risk of drinking and binge drinking. These effects were present only on weekend days. Results are suggestive of a dual risk model in which both ovulatory E2 increases and perimenstrual P4 decreases increase risk for drinking. Differential associations of steroids with drinking across the menstrual cycle may suggest the need for clinical assessment of substance use to take into account hormone dynamics and menstrual cycle phase. (PsycINFO Database Record PMID- 29154571 TI - Taxometric analyses of pedophilia utilizing self-report, behavioral, and sexual arousal indicators. AB - Pedophilia refers to the recurrent, intense sexual interest in prepubescent children who, by definition, have not developed any secondary sex characteristics. Researchers have begun to investigate whether persons with pedophilia are qualitatively different from those without pedophilia (pedophilia is a taxon) or if people vary in their level of sexual interest toward children (pedophilia is dimensional). Two relatively small studies have previously attempted to address this question, but produced conflicting results. The present study built on these studies with a substantially larger sample of 2,227 men who committed sexual offenses and were assessed at a sexual behavior clinic. The present study also examined a broader range of measures more closely approximating the diagnostic criteria for pedophilic disorder, including phallometric assessment of sexual arousal patterns. The results of 3 taxometric analyses did not find support for the assertion that pedophilia is a taxon. (PsycINFO Database Record PMID- 29154573 TI - Topics in the Journal of Counseling Psychology, 1963-2015. AB - Historical trends in a scientific field should be apparent in the changing content of journal articles over time. Using a topic modeling approach, a statistical method for quantifying the thematic content of text, 70 topics were extracted from the abstracts of 3,603 articles published in the Journal of Counseling Psychology from 1963 to 2015. After examining interpretability of 70 topics derived from the model, 64 meaningful topics and their trends were named. In addition, the authors also classified some of the related topics into 4 categories-counseling process and outcome, multiculturalism, research methodology, and vocational psychology. Counseling process and outcome related topics have decreased recently, while topics relating to multiculturalism and diversity have shown increasing trends. The authors also discussed trends that were observed and tried to account for the changing frequencies of some important research topics within these categories. (PsycINFO Database Record PMID- 29154572 TI - Introduction to special section on advanced methodology: Counseling the dog to wag its methodological tail. AB - In this article, we introduce a special section focused on the application of advanced methodologies to specific research questions in counseling psychology. The articles include applications of natural language processing, dynamic systems, mediation analyses in single studies and meta-analysis, and synthesis of qualitative research. We provide a brief overview of each article. (PsycINFO Database Record PMID- 29154574 TI - A multivariate dynamic systems model for psychotherapy with more than one client. AB - The dynamics of the give and take between therapist and client(s) is frequently of interest to therapy process researchers. Characterizing the ways that therapists respond to clients and clients respond to therapists can be challenging in therapeutic encounters involving a single therapist and a single client. The complexity of this challenge increases as the number of people involved in a therapeutic encounter increases not only because there are more people responding to one another but also because the patterns of responding can become more complex. This manuscript demonstrates how dyadic cross-lagged panel models can be extended to psychotherapeutic encounters involving 3 people and used to test processes that exist between dyadic subsets of the larger group as well as the group as one cohesive unit. Three hundred seventy-nine talk turns of fundamental frequency from a couple therapy session were modeled using 3 dyadic cross-lagged panel models, and each individual's respiratory sinus arrhythmia (RSA) was treated as a moderator. Although the regression coefficients for each dyadic subset (e.g., therapist-husband) were nonsignificant, an eigenvalue/eigenvector decomposition of the regression coefficients from the 3 dyadic cross-lagged panel models suggests that interdependence exists at the level of the whole group (i.e., therapist-husband-wife) rather than between pairs of individuals within the group (e.g., husband-wife). Further, an interaction involving husband's RSA suggested that interdependence involving the husband ceased when the husband displayed greater regulatory effort. This combination of statistical methods allows for clearly distinguishing between dyadic therapeutic processes and group-level therapeutic processes. (PsycINFO Database Record PMID- 29154575 TI - Metamethod study of qualitative psychotherapy research on clients' experiences: Review and recommendations. AB - A metamethod study is a qualitative meta-analysis focused upon the methods and procedures used in a given research domain. These studies are rare in psychological research. They permit both the documentation of the informal standards within a field of research and recommendations for future work in that area. This paper presents a metamethod analysis of a substantial body of qualitative research that focused on clients' experiences in psychotherapy (109 studies). This review examined the ways that methodological integrity has been established across qualitative research methods. It identified the numbers of participants recruited and the form of data collection used (e.g., semistructured interviews, diaries). As well, it examined the types of checks employed to increase methodological integrity, such as participant counts, saturation, reflexivity techniques, participant feedback, or consensus and auditing processes. Central findings indicated that the researchers quite flexibly integrated procedures associated with one method into studies using other methods in order to strengthen their rigor. It appeared normative to adjust procedures to advance methodological integrity. These findings encourage manuscript reviewers to assess the function of procedures within a study rather than to require researchers to adhere to the set of procedures associated with a method. In addition, when epistemological approaches were mentioned they were overwhelmingly constructivist in nature, despite the increasing use of procedures traditionally associated with objectivist perspectives. It is recommended that future researchers do more to explicitly describe the functions of their procedures so that they are coherently situated within the epistemological approaches in use. (PsycINFO Database Record PMID- 29154576 TI - Unique effects and moderators of effects of sources on self-efficacy: A model based meta-analysis. AB - Self-efficacy beliefs are strong predictors of academic pursuits, performance, and persistence, and in theory are developed and maintained by 4 classes of experiences Bandura (1986) referred to as sources: performance accomplishments (PA), vicarious learning (VL), social persuasion (SP), and affective arousal (AA). The effects of sources on self-efficacy vary by performance domain and individual difference factors. In this meta-analysis (k = 61 studies of academic self-efficacy; N = 8,965), we employed B. J. Becker's (2009) model-based approach to examine cumulative effects of the sources as a set and unique effects of each source, controlling for the others. Following Becker's recommendations, we used available data to create a correlation matrix for the 4 sources and self efficacy, then used these meta-analytically derived correlations to test our path model. We further examined moderation of these associations by subject area (STEM vs. non-STEM), grade, sex, and ethnicity. PA showed by far the strongest unique association with self-efficacy beliefs. Subject area was a significant moderator, with sources collectively predicting self-efficacy more strongly in non-STEM (k = 14) compared with STEM (k = 47) subjects (R2 = .37 and .22, respectively). Within studies of STEM subjects, grade level was a significant moderator of the coefficients in our path model, as were 2 continuous study characteristics (percent non-White and percent female). Practical implications of the findings and future research directions are discussed. (PsycINFO Database Record PMID- 29154577 TI - Confounding in statistical mediation analysis: What it is and how to address it. AB - Psychology researchers are often interested in mechanisms underlying how randomized interventions affect outcomes such as substance use and mental health. Mediation analysis is a common statistical method for investigating psychological mechanisms that has benefited from exciting new methodological improvements over the last 2 decades. One of the most important new developments is methodology for estimating causal mediated effects using the potential outcomes framework for causal inference. Potential outcomes-based methods developed in epidemiology and statistics have important implications for understanding psychological mechanisms. We aim to provide a concise introduction to and illustration of these new methods and emphasize the importance of confounder adjustment. First, we review the traditional regression approach for estimating mediated effects. Second, we describe the potential outcomes framework. Third, we define what a confounder is and how the presence of a confounder can provide misleading evidence regarding mechanisms of interventions. Fourth, we describe experimental designs that can help rule out confounder bias. Fifth, we describe new statistical approaches to adjust for measured confounders of the mediator-outcome relation and sensitivity analyses to probe effects of unmeasured confounders on the mediated effect. All approaches are illustrated with application to a real counseling intervention dataset. Counseling psychologists interested in understanding the causal mechanisms of their interventions can benefit from incorporating the most up-to-date techniques into their mediation analyses. (PsycINFO Database Record PMID- 29154578 TI - Sexual victimization, childhood emotional abuse, and distress: Daily coping and perceived control as mediators. AB - The primary aim of the present study was to assess 2 potential mediators (daily avoidant coping and perceived control) of the relations between past sexual victimization and childhood emotional abuse and current distress. Participants (N = 268) were undergraduate students in psychology courses at a large Midwestern university who completed measures of sexual victimization, childhood emotional abuse, neuroticism, and distress at baseline; daily measures of avoidant coping and perceived control over stressors for 14 days (Time 2); and measures of avoidant coping, perceived control, and distress at Time 3. Structural equation modeling (SEM) was used to test the mediation model. The indirect path between childhood emotional abuse and T3 distress through daily avoidant coping was significant and remained significant in an alternate model that controlled for baseline neuroticism. The indirect effect of childhood emotional abuse on T3 distress through perceived control was not significant. Sexual victimization was not associated with greater use of avoidant coping or perceived control in the SEM models. The present study added to the literature by assessing multiple traumas and multiple mediators using longitudinal, daily diary methods. (PsycINFO Database Record PMID- 29154579 TI - When daily planning improves employee performance: The importance of planning type, engagement, and interruptions. AB - Does planning for a particular workday help employees perform better than on other days they fail to plan? We investigate this question by identifying 2 distinct types of daily work planning to explain why and when planning improves employees' daily performance. The first type is time management planning (TMP) creating task lists, prioritizing tasks, and determining how and when to perform them. We propose that TMP enhances employees' performance by increasing their work engagement, but that these positive effects are weakened when employees face many interruptions in their day. The second type is contingent planning (CP) in which employees anticipate possible interruptions in their work and plan for them. We propose that CP helps employees stay engaged and perform well despite frequent interruptions. We investigate these hypotheses using a 2-week experience sampling study. Our findings indicate that TMP's positive effects are conditioned upon the amount of interruptions, but CP has positive effects that are not influenced by the level of interruptions. Through this study, we help inform workers of the different planning methods they can use to increase their daily motivation and performance in dynamic work environments. (PsycINFO Database Record PMID- 29154580 TI - What goes up must . . . Keep going up? Cultural differences in cognitive styles influence evaluations of dynamic performance. AB - Past research on dynamic workplace performance evaluation has taken as axiomatic that temporal performance trends produce naive extrapolation effects on performance ratings. That is, we naively assume that an individual whose performance has trended upward over time will continue to improve, and rate that individual more positively than an individual whose performance has trended downward over time-even if, on average, the 2 individuals have performed at an equivalent level. However, we argue that such naive extrapolation effects are more pronounced in Western countries than Eastern countries, owing to Eastern countries having a more holistic cognitive style. To test our hypotheses, we examined the effect of performance trend on expectations of future performance and ratings of past performance across 2 studies: Study 1 compares the magnitude of naive extrapolation effects among Singaporeans primed with either a more or less holistic cognitive style, and Study 2 examines holistic cognitive style as a mediating mechanism accounting for differences in the magnitude of naive extrapolation effects between American and Chinese raters. Across both studies, we found support for our predictions that dynamic performance trends have less impact on the ratings of more holistic thinkers. Implications for the dynamic performance and naive extrapolation literatures are discussed. (PsycINFO Database Record PMID- 29154581 TI - Supervisor-employee power distance incompatibility, gender similarity, and relationship conflict: A test of interpersonal interaction theory. AB - According to interpersonal interaction theory, relational harmony surfaces when two individuals have compatible interaction styles. Building from this theory, we propose that supervisor-employee power distance orientation incompatibility will be related to employees' experience of higher levels of relationship conflict with their supervisors. Additionally, we propose an asymmetrical incongruence effect such that relationship conflict will be highest when supervisors are high in power distance and employees are low in power distance. Furthermore, we address calls in interpersonal interaction research for more direct attention to the social context of the dyadic interaction and explore the moderating effects of supervisor-employee gender (dis)similarity on the relationship between this incompatibility and conflict. We propose that supervisor-employee gender dissimilarity (e.g., male-female or female-male pairs) acts as a conditional moderator, neutralizing the power distance incongruence effect and the asymmetrical incongruence effect. Using 259 supervisor-employee dyads in the physical therapy industry, the hypotheses were generally supported. Theoretical and practical implications regarding the unique benefits of power distance compatibility and gender diversity in supervisor-employee dyads are discussed. (PsycINFO Database Record PMID- 29154583 TI - When you see it coming: Stressor anticipation modulates stress effects on negative affect. AB - Research on the effect of exposure to minor stressors in people's daily lives consistently reports negative effects on indicators of well-being, often coined stress reactivity. Recent advances in the intensity of data collection have brought about an increasing interest in within-day associations of stress exposure and indicators of well-being, including dynamic aspects of the stress response such as stress recovery. In the present work, we investigated the other end of the stress response: the anticipation of a stressor. We hypothesized that anticipation of an upcoming stressor would be accompanied by higher negative affect. Based on the anticipatory coping account, lower negative affect after occurrence of anticipated (vs. not anticipated) stressors was predicted. We approached this question with a measurement burst study that allowed us to disentangle variation in stress processes across different time scales. One hundred and seventy-five participants (mean age = 50, range 20-79) completed up to 3 measurement bursts. Each burst consisted of an ecological momentary assessment with 5 assessments per day over 7 days. In line with our expectations, negative affect was significantly higher after stressor anticipation, especially on days with high levels of intrusive thoughts. However, negative affect was not lower after anticipated (vs. not anticipated) stressors. Findings point to the role of perseverative cognition in the effect of stressor anticipation. Directions for future research including the role of controllability and effects on stress recovery are outlined. (PsycINFO Database Record PMID- 29154582 TI - The dimensions and mechanisms of mindfulness in regulating aggressive behaviors. AB - On the basis of the notion that the ability to exert self-control is critical to the regulation of aggressive behaviors, we suggest that mindfulness, an aspect of the self-control process, plays a key role in curbing workplace aggression. In particular, we note the conceptual and empirical distinctions between dimensions of mindfulness (i.e., mindful awareness and mindful acceptance) and investigate their respective abilities to regulate workplace aggression. In an experimental study (Study 1), a multiwave field study (Study 2a), and a daily diary study (Study 2b), we established that the awareness dimension, rather than the acceptance dimension, of mindfulness plays a more critical role in attenuating the association between hostility and aggression. In a second multiwave field study (Study 3), we found that mindful awareness moderates the association between hostility and aggression by reducing the extent to which individuals use dysfunctional emotion regulation strategies (i.e., surface acting), rather than by reducing the extent to which individuals engage in dysfunctional thought processes (i.e., rumination). The findings are discussed in terms of the implications of differentiating the dimensions and mechanisms of mindfulness for regulating workplace aggression. (PsycINFO Database Record PMID- 29154584 TI - Digital altruists: Resolving key questions about the empathy-altruism hypothesis in an Internet sample. AB - Researchers have identified the capacity to take the perspective of others as a precursor to empathy-induced altruistic motivation. Consequently, investigators frequently use so-called perspective-taking instructions to manipulate empathic concern. However, most experiments using perspective-taking instructions have had modest sample sizes, undermining confidence in the replicability of results. In addition, it is unknown whether perspective-taking instructions work because they increase empathic concern or because comparison conditions reduce empathic concern (or both). Finally, some researchers have found that egoistic factors that do not involve empathic concern, including self-oriented emotions and self other overlap, mediate the relationship between perspective-taking instructions and helping. The present investigation was a high-powered, preregistered effort that addressed methodological shortcomings of previous experiments to clarify how and when perspective-taking manipulations affect emotional arousal and prosocial motivation in a prototypical experimental paradigm administered over the Internet. Perspective-taking instructions did not clearly increase empathic concern; this null finding was not due to ceiling effects. Instructions to remain objective, on the other hand, unequivocally reduced empathic concern relative to a no-instructions control condition. Empathic concern was the most strongly felt emotion in all conditions, suggesting that distressed targets primarily elicit other-oriented concern. Empathic concern uniquely predicted the quality of social support provided to the target, which supports the empathy-altruism hypothesis and contradicts the role of self-oriented emotions and self-other overlap in explaining helping behavior. Empathy-induced altruism may be responsible for many prosocial acts that occur in everyday settings, including the increasing number of prosocial acts that occur online. (PsycINFO Database Record PMID- 29154586 TI - Timing affect: Dimension-specific time-based expectancy for affect. AB - Affective information in our environment is often predictable by time; for example, positive answers are typically given faster than negative ones. Here we demonstrate, for the first time, that humans can implicitly adapt to time-based affect predictability. Participants were asked to categorize words, with the words' irrelevant valences being predictable by the timing of their occurrence. Adaptation to this pattern became evident by better performance for typical combinations of time and valence, relative to atypical combinations (Experiment 2). A comparable adaptation was observed for predictable activation (another affective dimension, Experiment 4), but not for predictable imageability (a nonaffective dimension, Experiment 3). In none of the experiments did participants become aware of the time-based predictability. These findings have significant implications for our theoretical understanding of human time-based expectancy, as well as important implications for the scheduling of system delays in artificial interaction and communication environments. (PsycINFO Database Record PMID- 29154585 TI - Cognitive reappraisal and acceptance: Effects on emotion, physiology, and perceived cognitive costs. AB - Two emotion regulation strategies-cognitive reappraisal and acceptance-are both associated with beneficial psychological health outcomes over time. However, it remains unclear whether these 2 strategies are associated with differential consequences for emotion, physiology, or perceived cognitive costs in the short term. The present study used a within-subjects design to examine the effects of reappraisal (reframing one's thoughts) and acceptance (accepting feelings without trying to control or judge them) on the subjective experience of negative emotions, positive emotions, and physiological responses during and following recovery from sad film clips shown in the laboratory. Participants also reported on perceived regulatory effort, difficulty, and success after deploying each emotion regulation strategy. In 2 samples of participants (N = 142), reappraisal (vs. acceptance) was associated with larger decreases in negative and larger increases in positive emotions, both during the film clips and recovery period. However, acceptance was perceived as less difficult to deploy than reappraisal, and was associated with a smaller dampening of skin conductance level (indicating more successful regulation) during the film clips in 1 sample. These results suggest that reappraisal and acceptance may exert differential short-term effects: Whereas reappraisal is more effective for changing subjective experiences in the short term, acceptance may be less difficult to deploy and be more effective at changing one's physiological response. Thus, these 2 strategies may both be considered "effective" for different reasons. (PsycINFO Database Record PMID- 29154587 TI - Attentional avoidance of emotional stimuli in postpartum women with childhood history of maltreatment and difficulties with emotion regulation. AB - Child abuse and neglect can lead to difficulties regulating responses to threatening and emotional situations. Exposure to childhood maltreatment has been linked to conflicting findings of both attention biases toward and away from threat-related information. The aim of the current study was to investigate whether emotion regulation moderated the association between history of childhood maltreatment and attention bias in a sample of postpartum women. One hundred forty women participated in the study at 7 months postpartum. Selective attention to both negative emotional and attachment-related negative emotional words was assessed using the Emotional Stroop task. The latent variable of difficulties with emotion regulation was found to significantly moderate the association between history of childhood maltreatment and attention bias to both negative emotional (beta = -0.15, t = -2.04, p < .05) and attachment-related negative emotional stimuli (beta = -0.16, t = -2.98, p < .05). In women with higher childhood trauma scores, those with greater emotion regulation difficulties displayed decreased attention to negative emotional and attachment-related emotional stimuli. In contrast, women reporting higher exposure to childhood maltreatment with greater emotion regulation capacity, displayed increased attention toward negative emotional and attachment-related emotional stimuli. This study provides evidence for attentional avoidance of emotional material in postpartum women with greater experiences of maltreatment and difficulties with emotion regulation. As the postpartum period has significant implications for maternal well-being and infant development, these findings are discussed in terms of maternal responsiveness, sensitivity to threat, and the intergenerational transmission of risk. (PsycINFO Database Record PMID- 29154588 TI - Automatic stimulus evaluation depends on goal relevance. AB - To examine whether automatic stimulus evaluation is dependent upon goal relevance, participants were presented with a mixture of (a) goal-induction trials to create a set of goal-relevant and goal-irrelevant stimuli, and (b) evaluative priming trials to capture the automatic evaluation of these stimuli as good or bad. In line with our predictions, a reliable evaluative priming effect was obtained only for stimuli that were relevant for the goal-induction task. Implications for the use of the evaluative priming paradigm as an assessment tool and the replicability of the evaluative priming effect in the absence of dimensional overlap between the prime set and the target set are discussed. (PsycINFO Database Record PMID- 29154589 TI - Down-regulation of amygdala response to infant crying: A role for distraction in maternal emotion regulation. AB - Infant crying elicits caregiving behaviors, which are indispensable for fulfilling the infant's needs. However, infant crying can also evoke negative and angry feelings in the caregiver. Therefore, parents need to regulate their own negative emotions to infant crying to sensitively respond to the distressed infant. Thus, the current study aims to examine the neural basis of emotional reactivity and emotional regulation in response to infant crying using functional MRI in primiparous mothers (N = 26). Amygdala activation in response to infant crying was negatively associated with maternal sensitivity and maternal nonhostility during mother-infant interaction. Furthermore, subjective emotional intensity and bilateral activations in the amygdala were decreased using distraction as emotion-regulation strategy. This finding adds neural evidence to the importance of maternal emotion-regulation in response to infant distress. This might be particularly important as some mothers may become overwhelmed by their infant's distress resulting in intense negative emotions that could potentially impair mother-child interaction and increase child abuse potential. (PsycINFO Database Record PMID- 29154590 TI - Labeling of deployment sexual harassment experiences among male and female veterans. AB - OBJECTIVE: Victims' conceptualizations of traumatic experiences can impact screening responses and decisions to utilize health care. Despite experiencing events constituting sexual harassment, many victims do not label their experiences as such. In the military, specific situational factors (e.g., occurred on-duty, higher ranking harasser) and victim appraisals of experiences (e.g., offensive, threatening) have been associated with increased labeling of sexual harassment. However, no research has examined sexual harassment labeling among those deployed in recent Afghanistan and Iraq conflicts, where the context of harassment may differ from peacetime settings. The purpose of the present study was to examine frequencies of labeling sexual harassment during deployment, factors associated with labeling, and associations between labeling and perceived need for and use of mental health services. METHOD: 2,348 veterans (51% women, 49% men) drawn from a random sample of veterans deployed in support of the wars in Afghanistan and Iraq completed a mail survey. RESULTS: Women were significantly more likely than men to label experiences as harassment. Whereas appraisals of events were associated with both women's and men's labeling, situational factors were only associated with women's labeling. Among women, labeling was associated with a greater perceived need for and use of mental health services among those who experienced nonassaultive harassment. CONCLUSIONS: These results confirm the importance of using behavioral language when screening for experiences of harassment among veterans returning from deployment. We discuss strategies for addressing labeling in the context of mental health treatment. (PsycINFO Database Record PMID- 29154591 TI - The impact of comorbid diagnoses on the course of posttraumatic stress disorder symptoms in residents of battered women's shelters. AB - OBJECTIVE: The current investigation sought to explore the impact of the comorbidities of substance use disorder (SUD), major depressive disorder (MDD), and borderline personality disorder (BPD) on the trajectory of intimate partner violence (IPV)-related posttraumatic stress disorder (PTSD) symptoms across a 6 month follow-up period in IPV survivors who seek shelter. Research has found significant comorbidity of SUD, MDD, and BPD with PTSD (see Green et al., 2006; Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995; Pagura et al., 2010); however, little to no research has explored these relationships in this unique population over time. METHOD: A sample of 147 residents of battered women's shelters completed study measures at baseline, 1 week, and 3 and 6 months following shelter stay. Participants completed measures assessing for demographics, abuse, and Diagnostic and Statistical Manual of Mental Disorders (4th edition, text revision) diagnoses. RESULTS: Results of latent growth modeling with the time invariant covariates of SUD, MDD, and BPD yielded a significant effect of SUD (beta = .002, p = .007) on the slope of IPV-related PTSD symptoms controlling for IPV victimization. Significant effects were not identified for BPD (beta = .001, p > .05) or MDD (beta = .002, p > .05). Results suggest IPV survivors with SUD demonstrated less improvement in PTSD symptoms over 6 months after they left shelter as compared to women without SUD. CONCLUSION: Findings emphasize the deleterious effects of SUD, above and beyond MDD and BPD, on IPV-related PTSD and highlight the need for assessment and treatment of SUD and PTSD simultaneously in residents of battered women's shelters. Clinical Impact Statement: Findings suggest the need to go beyond standard shelter services to more effectively address and treat co-occurring SUD-PTSD in IPV survivors. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29154592 TI - College females with maltreatment histories have atypical autonomic regulation and poor psychological wellbeing. AB - OBJECTIVES: This study uniquely examined the impact of maltreatment (without a diagnosis of posttraumatic stress disorder [PTSD]) on physiological responses to a physical and an emotional stressor. The study sample was composed exclusively of women, because men may differ in maltreatment experience and neural regulation of physiological reactivity. METHOD: Participants were 60 female college students. A significant proportion of the participants reported experiencing childhood maltreatment without a history of PTSD. Participants completed measures assessing psychological and PTSD symptomatology. Heart rate was monitored before, during, and after riding a stationary bike (physical stressor) and viewing a video of a child being maltreated (emotional stressor). Baseline and stressor related patterns of heart rate and respiratory sinus arrhythmia (RSA) were quantified from the beat-to-beat heart rate. RESULTS: Women with maltreatment histories reported more psychological distress and PTSD symptomatology, had lower levels of RSA and faster heart rate, and reacted to the stressors with atypical vagal regulation of RSA and heart rate. CONCLUSION: Accompanying psychological difficulties, women with maltreatment histories exhibit atypical physiological regulation to stressors consistent with clinical observations of lower thresholds to defensiveness and other manifestations of compromised resilience. The findings are consistent with polyvagal theory, which emphasizes the role of the "vagal brake" in social engagement and coregulation behaviors-features frequently compromised in survivors of emotional and physical abuse. Future research should investigate whether these features of atypical autonomic regulation are lead indicators of mental and physical health risks and whether these features can be reversed. (PsycINFO Database Record PMID- 29154593 TI - Shame and alienation related to child maltreatment: Links to symptoms across generations. AB - OBJECTIVE: The current study investigated associations between appraisals of shame and alienation related to mothers' own experiences of child maltreatment and symptoms across generations-in mothers themselves as well as their toddler/preschool-aged children. METHOD: Mothers who survived maltreatment (N = 113) with a child between the ages of 2 and 5 were recruited to participate in an online study on Maternal Coping, Attachment and Health. Mother participants completed a series of questionnaires, including those that asked about posttrauma appraisals of their own maltreatment experiences as well as their child's and their own mental health symptoms. RESULTS: When taking into account other posttrauma appraisals (e.g., fear, betrayal, anger, self-blame), maternal shame and alienation were both significantly associated with maternal trauma-related distress (a composite of anxiety, PTSD, dissociation, and depressive symptoms). Maternal shame was also significantly linked to child internalizing symptoms and externalizing symptoms. Lower levels of fear and higher levels of betrayal were associated with externalizing symptoms as well. Maternal trauma-related distress mediated the relationship between maternal shame and child externalizing symptoms, and partially mediated the relationship between shame and internalizing symptoms. CONCLUSION: This study is the first of its kind to examine the role of posttrauma appraisals among mother survivors of maltreatment as they relate to symptoms in their young children. Although additional research is necessary, findings suggest that mothers' posttrauma appraisals, such as shame, could be a relevant factor in the early social-emotional development of survivors' children. (PsycINFO Database Record PMID- 29154594 TI - Morally injurious events and psychological distress among veterans: Examining the mediating role of religious and spiritual struggles. AB - OBJECTIVE: Potentially morally injurious events (PMIEs)-violations (perpetrated or witnessed) of one's deeply held beliefs or values-have been associated with several forms of psychological distress. The values violated by PMIEs are often influenced by one's religion/spirituality (r/s). Struggles with one's r/s beliefs and/or practices may also contribute to elevated psychological distress. To further develop a framework for understanding and treating the sequelae of PMIE exposure, we examined the role of r/s struggles in the relation between PMIE exposure and psychological distress. METHOD: A diverse sample of 155 veterans at a large Veterans Affairs medical center completed questionnaires assessing PMIE exposure, r/s struggles, and psychological distress. RESULTS: Findings revealed greater PMIE exposure predicted elevated r/s struggles as well as elevated symptoms of anxiety and posttraumatic stress disorder (PTSD). Likewise, greater r/s struggles predicted elevated anxiety, PTSD, and depression symptoms. Regression analyses revealed r/s struggles fully mediated the relation between PMIE exposure and anxiety as well as PTSD, and a significant indirect effect of PMIE exposure on depression symptoms through r/s struggles was observed. Follow up analyses revealed that no specific domain of r/s struggles accounted for the relation between PMIE exposure and psychological distress; rather, the overarching construct of r/s struggles accounted for this relation. CONCLUSION: These findings advance the evolving theoretical framework of moral injury, elucidating the salience of r/s struggles in the development of distress. Implications for moral injury intervention call for attention to potential dissonance between actions (witnessed or perpetrated) and r/s underpinnings of the individual's moral framework. (PsycINFO Database Record PMID- 29154596 TI - The moderating role of trauma type on the relationship between event centrality of the traumatic experience and mental health outcomes. AB - OBJECTIVE: Event centrality, or the extent to which traumatic events are perceived to be integral to one's life, has been found to be predictive of trauma related symptoms, such as posttraumatic stress disorder (PTSD) and depression. Less research has been devoted to whether event centrality is related to adaptive outcomes, such as posttraumatic growth (PTG) and resiliency, and psychological well-being (PWB) has not been investigated. Given the unique circumstances of different types of traumas, the relationship between event centrality and posttrauma functioning may differ by the type of trauma experienced. METHOD: The present study investigated the direct relationships between event centrality and PTSD, depression, PTG, resiliency, and PWB, and then examined whether type of trauma (i.e., sexual victimization, death of a loved one, serious illness/injury, violence exposure) moderated the relationship between event centrality and mental health outcomes among 429 trauma-exposed college students (Mage = 19.66, SD = 1.65; 78.6% female; 49.9% White). RESULTS: Event centrality was positively related to PTSD, depression, and PTG, inversely linked with multiple indices of PWB, and unrelated to resiliency. Type of traumatic event moderated the relationship between event centrality and PTSD, as well as 4 subscales of PWB. When sexual trauma was the index event, event centrality was more strongly associated with PTSD and aspects of PWB compared to death of a loved one. CONCLUSIONS: Findings indicate the importance of trauma type when disentangling the relationships between event centrality and negative and positive outcomes and demonstrate the relevance of event centrality in understanding posttrauma functioning. (PsycINFO Database Record PMID- 29154595 TI - Predictors of somatic symptom severity: The role of cumulative history of trauma and adversity in a diverse community sample. AB - OBJECTIVE: Somatic symptoms are often reported among victims of trauma, and place a significant burden on primary care health providers. We examined the relationship between lifetime histories of trauma and adversity, including aspects not previously studied (i.e., perceived discrimination), and somatic symptoms, as well as the mediating role of posttraumatic stress symptoms (PTSS) and depressive symptoms. METHOD: A multiethnic community sample of 500 male and female participants (230 African American and 270 Latino) completed measures of demographic characteristics, the University of California, Los Angeles Lifetime Adversities Screener (LADS), depressive symptoms, PTSS, and somatic symptoms. RESULTS: An ordinary least-squares regression analysis controlling for age, gender, and race/ethnicity indicated that higher levels of lifetime adversity and trauma were significantly associated with more severe somatic symptoms (b = 6.95, p < .0001). Formal mediation tests indicated that there was a significant indirect effect of LADS on somatic symptoms via PTSS and depressive symptoms, indirect effect = 2.64 (95% confidence interval [CI] [1.2, 4.1]) and 2.19 (95% CI [1.3, 3.3]), respectively. Even after PTSS and depressive symptoms were taken into account, the LADS remained significantly associated with somatic symptoms (b = 2.13, p < .05), suggesting partial mediation. CONCLUSION: Exposure to traumatic and adverse events (the LADS) was associated with somatic symptom severity. Furthermore, although PTSS and depressive symptoms partially accounted for the association between the LADS and somatic symptoms, the LADS remained significant, suggesting that both exposure to trauma and adversity and the resultant development of PTSS and depressive symptoms influence the development of somatic symptoms. (PsycINFO Database Record PMID- 29154597 TI - Interactive effects of insomnia symptoms and trauma exposure on PTSD: Examination of symptom specificity. AB - OBJECTIVE: Although symptoms of posttraumatic stress disorder (PTSD) are common following exposure to a traumatic event, most people who experience trauma do not develop PTSD. Thus, the identification of risk factors that may interact with trauma exposure to confer vulnerability for the development of PTSD may highlight important targets for prevention and treatment. Recent research suggests that sleep disturbance amplifies the effect of maladaptive emotional processes on PTSD symptom severity. However, no study to date has examined the impact of sleep disturbance, such as insomnia symptoms, on the relationship between trauma exposure severity and specific PTSD symptom clusters. METHOD: The present study examined insomnia symptoms as a potential moderator of the relationship between trauma exposure severity and specific PTSD symptom clusters among combat exposed veterans (N = 72). RESULTS: Results revealed large associations between insomnia symptoms and PTSD symptom clusters, small to moderate associations between combat trauma severity and PTSD symptom clusters, and a significant interaction between insomnia symptoms and combat exposure to predict reexperiencing, but not avoidance or arousal, symptoms of PTSD. CONCLUSION: These findings suggest that poor sleep may be one risk context in which trauma exposure results in the development of reexperiencing symptoms of PTSD. The implications of these findings for the development and maintenance of reexperiencing symptoms of PTSD are discussed. (PsycINFO Database Record PMID- 29154598 TI - "I feel like I do not exist:" A study of dissociative experiences among war traumatized refugee youth. AB - OBJECTIVE: War-traumatized refugee children and adolescents have been overlooked in research on trauma-related dissociation, and whatever research has been conducted has relied almost exclusively on questionnaires. The present study was an exploration of dissociative experiences in multitraumatized war-refugee youth. METHOD: In this study, we used a mixed-method approach by grouping participants according to a Western-based dissociation measure (the Adolescent Dissociative Experiences Scale; Armstrong, Putnam, Carlson, Libero, & Smith, 1997), and conducting qualitative and quantitative analyses of their verbal descriptions of mental experiences related to dissociation in the aftermath of war and resettlement. The sample included 40 refugee youth, ages 13 to 21, 19 girls and 21 boys resettled in Sweden because of war and persecution. RESULTS: Severe trauma-related dissociation was a problem for a considerable subgroup of the sample. Some dissociative experiences were present in all the sample; others were restricted to the most dissociative group. The correlates of severe dissociation included high frequency and severity of emotional dysregulation and intensity, negative self- and body-perception, depressive mood, and experiences of detachment. CONCLUSION: Clinicians are urged to be aware of and assess trauma related dissociation in war-refugee youth, and consider not only dissociative phenomena, but also other important processes such as emotional dysregulation. (PsycINFO Database Record PMID- 29154599 TI - Negative outcomes after morally injurious experiences: A replication and extension. AB - OBJECTIVE: The current study replicates and extends a model of the relationship between morally injurious experiences, moral emotions, and posttraumatic stress disorder (PTSD; Jordan, Eisen, Bolton, Nash, & Litz, 2017). The current study builds on this earlier work by including broader measures of moral emotions and by including an assessment of symptoms of depression. METHOD: An online survey, distributed using crowdsourcing software, was completed by 161 military veterans. The survey included measures of transgressive acts, appraisals of these acts including self-transgressions and betrayal by leadership, and symptoms of PTSD and depression. The hypothesized model was tested using structural equation techniques. RESULTS: The results of the current study largely replicate the earlier work, suggesting the effects of morally injurious experiences are mediated by moral emotions while also indicating transgressive acts can have a direct effect on PTSD. The model accounted for a large percentage of the variance of both PTSD and depression and supported specific paths between forms of morally injurious experiences, moral emotions, and negative psychological outcomes. CONCLUSION: The current study replicates the model that suggested moral emotions mediate the role of morally injurious experiences on symptoms of PTSD. The results also demonstrate that future studies should account for the role of transgressive acts in addition to appraisals of these acts. Finally, the results suggest the model developed by Jordan and colleagues may be useful in predicting outcomes beyond PTSD. (PsycINFO Database Record PMID- 29154600 TI - A passionate call for dispassionate conclusion: Comment on Fossati et al. (2016). AB - In a recent article published by Fossati and colleagues (2016a, 2016b), the authors compared the empirical profiles derived from correlating measures of narcissism and narcissistic personality disorder (NPD) with a measure of the 25 personality disorder traits included in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013) to an expert-rated profile of NPD. The initial data, which included some mistakes, were interpreted as indicating comparable performance across all three self-report measures of narcissism and NPD, including two hotly debated measures, the Narcissistic Personality Inventory (NPI) and the Pathological Narcissism Inventory (PNI). However, upon correction, the NPI yielded a trait profile much more closely aligned with expert ratings of NPD than did the PNI Grandiose dimension (NPI: ralerting and rcontrast = .73 and .83, respectively; PNI Grandiose: ralerting and rcontrast = .42 and .39, respectively). Despite the large difference in construct validity coefficients, no change was made to the discussion that states that the PNI performs comparably to other self-report measures like the NPI. This is just one of several instances in the published literature where results that favor the NPI over the PNI are ignored or understated. We reviewed six head-to-head comparisons, including the revised results from Fossati et al., of the NPI and PNI in relation to expert predictions and demonstrate that the NPI strongly outperforms the PNI in all six. We believe that conclusions regarding these measures must be data-driven and dispassionate moving forward. (PsycINFO Database Record PMID- 29154601 TI - On studying narcissism in personality inventories rather than the Narcissistic Personality Inventory: Reply to Miller and Lynam (2017). AB - Miller and Lynam's (2017) commentary proved to be very helpful in clarifying that ralerting-CV and rcontrast-CV coefficient values reported in our study indicated that the Narcissistic Personality Inventory (NPI) yielded a trait profile much more closely aligned with expert ratings of Diagnostic and Statistical Manual of Mental Disorders (4th edition; DSM-IV) narcissistic personality disorder (NPD) than did other measures. The commentary gives us the opportunity to make it clear that our study was designed to demonstrate the clinical usefulness of Personality Inventory for DSM-5 (PID-5) domain and trait scales in profiling pathological narcissism. Thus, demonstrating the superiority/inferiority of the Pathological Narcissism Inventory (PNI) over the NPI was not among the aims of our study. The publication of the commentary also gives us the opportunity to clarify the reasons why we think that the interpretation of the ralerting-CV and rcontrast-CV coefficients deserves some cautions. As a final remark, we think that the time has come to move from personality disorder classifications based on "clinical wisdom" to a redefinition of personality pathology in terms of systems of traits. (PsycINFO Database Record PMID- 29154602 TI - How do tobacco power walls influence adolescents? A study of mediating mechanisms. AB - OBJECTIVES: Tobacco power walls display hundreds of tobacco products and are known to be a key part of the impact of point-of-sale tobacco advertising on risk for smoking in adolescents. The current study examined factors that are hypothesized to mediate the effect of tobacco power wall exposure on adolescents' susceptibility for smoking in the future. METHOD: Participants (N = 148) aged 11 17 years were invited to shop in the RAND StoreLab, a life-sized replica of a convenience store. They were randomized to 1 of 2 conditions: one in which the power wall was located in its typical position behind the cashier and the other in which it was hidden behind an opaque wall. Participants shopped in the RAND StoreLab and then completed measures of susceptibility for smoking in the future, perceived smoking norms, and perceived accessibility of cigarettes. Participants' movements in the store were electronically tracked. RESULTS: Having the tobacco power wall behind the cashier increased adolescents' susceptibility for smoking in the future by 14.3% (total effect) compared with when the power wall was hidden (p = .01), and 14% of this effect was mediated by participants' perceived smoking norms. Time spent in front of the cashier and perceived accessibility of cigarettes did not play a role in the association between study condition and susceptibility for smoking in the future. CONCLUSIONS: The tobacco power wall increases adolescents' smoking risk, and this effect is partly explained by the effect of the power wall on adolescents' perceptions of how normative smoking is. (PsycINFO Database Record PMID- 29154603 TI - Affective reactivity to daily stress and 20-year mortality risk in adults with chronic illness: Findings from the National Study of Daily Experiences. AB - OBJECTIVE: Daily stress processes have been previously linked to health-related outcomes, but implications for longevity remain unclear. The present study examined whether daily stress exposure and/or affective responses to daily stressors predicted mortality risk over a 20-year period. Based on the hypothesis that chronic illness confers vulnerability to deleterious effects of stress, we also examined whether its presence accentuated the association between daily stress processes and later mortality risk. METHOD: Participants were 1,346 middle aged adults from the survey of Midlife Development in the United States who also completed the National Study of Daily Experiences. Participants reported on their experiences of stress and affect for 8 consecutive evenings, and mortality data were collected over the next 20 years, using the National Death Index and other methods. RESULTS: There was a positive association between total number of stressors experienced across days and mortality risk. There was also a positive association between increases in negative affect on stressor days relative to nonstressor days and risk for mortality. The presence of a chronic illness moderated this association such that negative affective reactivity predicted mortality risk among individuals with at least one chronic illness but not among otherwise healthy individuals. This association was independent of sociodemographic characteristics, typical levels of negative affect on nonstressor days, and total number of endorsed stressors. CONCLUSION: These results suggest that greater increases in negative affect in response to stress in everyday life may have long-term consequences for longevity, particularly for individuals with chronic illness. (PsycINFO Database Record PMID- 29154604 TI - Traditional and cyber-victimization among adolescents with and without chronic pain. AB - OBJECTIVE: Prior research has revealed a link between peer victimization and somatic complaints in healthy youth; however, the peer victimization experiences of youth with clinically significant chronic pain have not been examined. This study aims to determine rates of peer victimization among youth seeking treatment for chronic pain and to compare these rates to a community control group. Relationships between peer victimization, depressive symptoms, and functional disability are also examined. METHOD: One hundred forty-three adolescents (70 with chronic pain) completed measures assessing their experience of traditional (physical, relational, reputational) and cyber-based peer victimization, as well as measures assessing their depressive symptoms and pain-related functional disability. RESULTS: Peer victimization experiences were common among youth with and without chronic pain. Within the chronic pain group, there were differences in rates of peer victimization as a function of the adolescent's school setting. Adolescents with chronic pain attending traditional schools reported more frequent peer victimization experiences than adolescents with pain not enrolled in school or attending online/home school. Within the chronic pain sample, peer victimization was moderately associated with depressive symptoms and functional disability. Tests of a simple mediation model revealed a significant indirect effect of peer victimization on functional disability, through depression. CONCLUSIONS: These results are the first to systematically document the peer victimization experiences of adolescents with chronic pain. Peer victimization is commonly experienced, particularly for those enrolled in traditional school settings. Associations with depressive symptoms and functional disability suggest that peer victimization may be a useful target for intervention. (PsycINFO Database Record PMID- 29154606 TI - Dyadic effects of depressive symptoms on medical morbidity in middle-aged and older couples. AB - OBJECTIVE: Depressive symptoms in middle and later life are associated with an increased risk of greater medical morbidity (i.e., number of chronic health conditions). Yet little is known about mutual influences that may occur within married couples. This study examined the effects of wives' and husbands' depressive symptoms on their own and their partner's number of chronic health conditions over an 8-year period. It was also determined whether these effects varied by gender. METHOD: The U.S. sample included 992 heterosexual couples (M = 63.58 years at baseline) drawn from 5 waves of the Health and Retirement Study (2006-2014). Dyadic growth curve models were estimated to evaluate the effects of own and partner baseline depressive symptoms on medical morbidity across time. Models controlled for baseline marital duration and negative marital quality along with age, education, minority status, health-related self-efficacy, body mass index, disability status, alcohol use, smoking, and moderate and vigorous physical activity. RESULTS: Husbands' higher baseline depressive symptoms were significantly linked to their own higher number of chronic conditions. When wives had higher depressive symptoms at baseline, husbands showed significantly greater increases in their number of chronic conditions over time. Own and partner depressive symptoms were not significantly associated with baseline levels or changes in wives' number of chronic conditions. CONCLUSIONS: This study demonstrates that depressive symptoms within middle-aged and older couples may have long-term associations with medical morbidity. Findings underscore the value of considering the implications of depressive symptoms for chronic health conditions among individuals and couples. (PsycINFO Database Record PMID- 29154605 TI - Psychological symptoms and subsequent healthy lifestyle after a colorectal cancer diagnosis. AB - OBJECTIVE: Although medical professionals recommend lifestyle changes following a colorectal cancer (CRC) diagnosis to improve outcomes, such changes are not consistently implemented. This study examines whether higher distress is associated with lower likelihood of engaging in favorable behaviors after CRC diagnosis. METHOD: Women from the Nurses' Health Study prospective cohort who completed anxiety (n = 145) and depression (n = 227) symptom scales within 4 years after receiving a CRC diagnosis were included. Measures of lifestyle (diet, physical activity, alcohol, smoking, body mass index [BMI]) were queried prediagnosis, when psychological symptoms were assessed (1988 and 1992, respectively), and then every 4 years thereafter until 2010. Women were categorized according to initial psychological symptoms levels and followed through 2010 or until last follow-up completed. RESULTS: Higher versus lower anxiety symptoms were significantly related to unhealthier lifestyle scores throughout follow-up (beta = -0.25, CI [-0.44, -0.05]); however, the rate of change over time was similar across groups (pinteraction effect = 0.41). Stratified analyses hinted that higher anxiety and depression symptoms were related to increased odds of reporting a future unhealthy lifestyle within 10 years postdiagnosis. Beyond 10 years, anxiety became statistically unrelated with future lifestyle, and higher depressive symptoms were associated with lower odds of subsequently having an unhealthy lifestyle, albeit nonstatistically significant (OR = 0.35, 95% CI [0.10, 1.24], p = 0.10). CONCLUSIONS: Among women with CRC, higher anxiety and depression symptoms were associated with subsequent unhealthier lifestyle in the 10 years following diagnosis. With replication, such findings may suggest that treating psychological symptoms early in the cancer trajectory may not solely reduce psychological distress but also promote healthier lifestyle. (PsycINFO Database Record PMID- 29154607 TI - Situation-specific social norms as mediators of social influence on snacking. AB - OBJECTIVE: Social factors are among the most powerful and pervasive influences on eating behavior, snacking in particular. Previous research has shown that being in the presence of people who are eating significantly increases the likelihood of eating and affects the types as well as the amount of food consumed. Much less is known about the processes underlying social influence, but previous research has suggested social norms as mediators. In this study, we extended this perspective to everyday settings and examined whether the presence of other people eating leads to a change in perceived momentary norms, and whether this change predicts snack consumption in real life. METHOD: We applied ecological momentary assessment to study 61 individuals in the normal-obese weight range (M BMI = 24.97 kg/m2; SD = 4.07) over a 14-day monitoring period. We used a combination of event-based snacking reports and randomly timed assessments. The presence of others eating and momentary perceptions of injunctive norms (facets of perceived appropriateness and encouragement) were measured for both assessment types. RESULTS: Mediated, multilevel logistic regression showed that social cues predict snacking (OR = 3.06), and that momentary perceptions of appropriateness (a*b = 0.14) and encouragement (a*b = 0.18) partially mediated these effects. CONCLUSION: Perceptions of momentary norms mediated the effects of social influence on everyday snacking, which highlights the importance of the social environment for understanding eating behavior. (PsycINFO Database Record PMID- 29154609 TI - Influence of sedentary, social, and physical alternatives on food reinforcement. AB - OBJECTIVE: This study examined the potential for nonfood alternative activities to compete with the reinforcing value of food. Participants rated the frequency and pleasantness of engaging in a variety of activities and made hypothetical choices between food and 4 types of alternatives; cognitive-enriching (reading, listening to music), social (attending a party or event), sedentary (watching TV), and physically active (running, biking). METHOD: Two-hundred seventy-six adults completed an online survey using a crowdsourcing platform. RESULTS: Adults with higher BMI reported engaging in fewer activities within the cognitive enriching, social, and physically active categories. When examining how well each alternative activity type was able to compete with food, sedentary alternatives were associated with the highest food reinforcement, or were least able to compete with food reinforcers, as compared with cognitive-enriching, social, and physical. Social activities were associated with the lowest food reinforcement, or the best able to compete with food reinforcers. CONCLUSION: These results suggest that increasing the frequency and range of nonfood alternative activities may be important to obesity. This study also suggests that the class of social activities may have the biggest impact on reducing food reinforcement, and the class of sedentary may have the smallest effect on food reinforcement. These tools have relevance to clinical interventions that capitalize on increasing access to behaviors that can reduce the motivation to eat in clinical interventions for obesity. (PsycINFO Database Record PMID- 29154610 TI - Identity concealment in transgender adults: A qualitative assessment of minority stress and gender affirmation. AB - Minority individuals might conceal their identity in social contexts in an effort to avoid stigma and victimization. Unfortunately, identity concealment is thought to impact psychological distress in transgender and gender nonconforming (TGNC) individuals. Thus, through 30 in-depth interviews, we sought to understand if and how identity concealment was experienced by TGNC individuals. Findings indicated that (a) TGNC identity concealment is a source of stress, (b) individuals might conceal their TGNC identity based on social context, (c) concealment of assigned sex and gender history can function to affirm one's true gender identity, and (d) concealment of gender history is a rejection of one's assigned sex. In addition, (a) passing/blending is an important interpersonal and intrapersonal process, (b) the importance of passing/blending can change over time, and (c) not passing/blending may result in worrying about personal safety. The authors discuss how concealment can both inhibit and promote psychological health for TGNC individuals, and they offer clinical applications for health providers. (PsycINFO Database Record PMID- 29154608 TI - A life-stress, emotional awareness, and expression interview for primary care patients with medically unexplained symptoms: A randomized controlled trial. AB - OBJECTIVE: Lifetime trauma, relationship adversities, and emotional conflicts are elevated in primary care patients with medically unexplained symptoms (MUS), and these risk factors likely trigger or exacerbate symptoms. Helping patients disclose stressors, increase awareness and expression of inhibited emotions, and link emotions to physical symptoms may improve health. We developed an emotional awareness and expression interview that targets stressful life experiences and conflicts and then tested its effects on primary care patients with MUS. METHOD: Patients (N = 75) with MUS were recruited at a family medicine clinic and randomized to an interview condition or treatment-as-usual (TAU) control condition. In a single 90-min interview in the clinic, the interviewer elicited disclosure of the patient's stressors, linked them to the patient's symptom history, and encouraged emotional awareness and expression about unresolved relationship trauma or conflict. At baseline and 6-week follow-up, patients completed self-report measures of their physical and psychological health. RESULTS: Analyses of covariance, controlling for baseline symptoms, compared patients in the interview condition with TAU at 6-week follow-up. Compared with TAU, the interview led to significantly lower pain severity, pain interference, sleep problems, and global psychological symptoms. CONCLUSIONS: This study provides preliminary evidence for the value of integrating a disclosure and emotional awareness and expression interview into the primary care setting for patients with MUS. (PsycINFO Database Record PMID- 29154611 TI - Individual and systemic barriers to health care: Perspectives of lesbian, gay, bisexual, and transgender adults. AB - Access to effective services is imperative to address the many health and mental health disparities that lesbian, gay, bisexual, and transgender (LGBT) people face. This population, however, remains underserved and often ill-served in health care environments. Furthermore, interactions between system- and individual-level dimensions of access create barriers to service engagement. Within much of the extant literature surrounding health care barriers among LGBT people, the rich narratives and varied experiences of LGBT community members from diverse backgrounds have often been excluded. The current interview-based study was conducted with a sample of 40 self-identified LGBT adults living in New York City. Participants were recruited through flyers distributed to LGBT-specific social and health service organizations. Twenty-nine participants who discussed health care access as a major health concern were included in the current study. Framework analysis revealed barriers stemming from characteristics of services and providers (system-level) and characteristics of care-seekers (individual level) as major health concerns. The root causes of system-level barriers were all attributed to social-structural factors that worked to exclude and erase LGBT people from the institutions that shape the health and mental health systems. Individual-level barriers were attributed to both individual and social structural factors, such as health literacy and stigma. Participants linked access barriers to forgone care and to other health and mental health concerns within their communities. We argue that addressing barriers at the individual and sociostructural levels will better serve LGBT communities. (PsycINFO Database Record PMID- 29154613 TI - The ego-moving metaphor of time relies on visual experience: No representation of time along the sagittal space in the blind. AB - In many cultures, humans conceptualize the past as behind the body and the future as in front. Whether this spatial mapping of time depends on visual experience is still not known. Here, we addressed this issue by testing early-blind participants in a space-time motor congruity task requiring them to classify a series of words as referring to the past or the future by moving their hand backward or forward. Sighted participants showed a preferential mapping between forward movements and future-words and backward movements and past-words. Critically, blind participants did not show any such preferential time-space mapping. Furthermore, in a questionnaire requiring participants to think about past and future events, blind participants did not appear to perceive the future as psychologically closer than the past, as it is the case of sighted individuals. These findings suggest that normal visual development is crucial for representing time along the sagittal space. (PsycINFO Database Record PMID- 29154612 TI - Alexithymia is associated with a multidomain, multidimensional failure of interoception: Evidence from novel tests. AB - Interoception, the perception of the body's internal state, contributes to numerous aspects of higher-order cognition. Several theories suggest a causal role for atypical interoception in specific psychiatric disorders, including a recent claim that atypical interoception represents a transdiagnostic impairment across disorders characterized by reduced perception of one's own emotion (alexithymia). Such theories are supported predominantly by evidence from only one interoceptive domain (cardiac); however, evidence of domain-specific interoceptive ability highlights the need to assess interoception in noncardiac domains. Using novel interoceptive tasks, we demonstrate that individuals high in alexithymic traits show a reduced propensity to utilize interoceptive cues to gauge respiratory output (Experiment 1), reduced accuracy on tasks of muscular effort (Experiment 2), and taste sensitivity (Experiment 3), unrelated to any co occurring autism, depression, or anxiety. Results suggest that alexithymia reflects a multidomain, multidimensional failure of interoception, which is consistent with theories suggesting that atypical interoception may underpin both symptom commonalities between psychiatric disorders and heterogeneity within disorders. (PsycINFO Database Record PMID- 29154614 TI - Unrealistic optimism in advice taking: A computational account. AB - Expert advisors often make surprisingly inaccurate predictions about the future, yet people heed their suggestions nonetheless. Here we provide a novel, computational account of this unrealistic optimism in advice taking. Across 3 studies, participants observed as advisors predicted the performance of a stock. Advisors varied in their accuracy, performing reliably above, at, or below chance. Despite repeated feedback, participants exhibited inflated perceptions of advisors' accuracy, and reliably "bet" on advisors' predictions more than their performance warranted. Participants' decisions tightly tracked a computational model that makes 2 assumptions: (a) people hold optimistic initial expectations about advisors, and (b) people preferentially incorporate information that adheres to their expectations when learning about advisors. Consistent with model predictions, explicitly manipulating participants' initial expectations altered their optimism bias and subsequent advice-taking. With well-calibrated initial expectations, participants no longer exhibited an optimism bias. We then explored crowdsourced ratings as a strategy to curb unrealistic optimism in advisors. Star ratings for each advisor were collected from an initial group of participants, which were then shown to a second group of participants. Instead of calibrating expectations, these ratings propagated and exaggerated the unrealistic optimism. Our results provide a computational account of the cognitive processes underlying inflated perceptions of expertise, and explore the boundary conditions under which they occur. We discuss the adaptive value of this optimism bias, and how our account can be extended to explain unrealistic optimism in other domains. (PsycINFO Database Record PMID- 29154615 TI - Differential discounting and present impact of past information. AB - How does information about a person's past, accessed now, affect individuals' impressions of that person? In 2 survey experiments and 2 experiments with actual incentives, we compare whether, when evaluating a person, information about that person's past greedy or immoral behaviors is discounted similarly to information about her past generous or moral behaviors. We find that, no matter how far in the past a person behaved greedily or immorally, information about her negative behaviors is hardly discounted at all. In contrast, information about her past positive behaviors is discounted heavily: recent behaviors are much more influential than behaviors that occurred a long time ago. The lesser discounting of information about immoral and greedy behaviors is not caused by these behaviors being more influential, memorable, extreme, or attention-grabbing; rather, they are perceived as more diagnostic of a person's character than past moral or generous behaviors. The phenomenon of differential discounting of past information has particular relevance in the digital age, where information about people's past is easily retrieved. Our findings have significant implications for theories of impression formation and social information processing. (PsycINFO Database Record PMID- 29154616 TI - Do we see it or not? Sensory attenuation in the visual domain. AB - Sensory consequences of an agent's actions are perceived less intensely than sensory stimuli that are not caused (and thus not predicted) by the observer. This effect of sensory attenuation has been discussed as a key principle of perception, potentially mediating various crucial functions such as agency and the discrimination of self-caused sensory stimulation from stimuli caused by external factors. Precise models describe the theoretical underpinnings of this phenomenon across a variety of modalities, especially the auditory, tactile, and visual domain. Despite these strong claims, empirical evidence for sensory attenuation in the visual domain is surprisingly sparse and ambiguous. In the present article, the authors therefore aim to clarify the role of sensory attenuation for learned visual action effects. To this end, the authors present a comprehensive replication effort including 3 separate, high-powered experiments on sensory attenuation in the visual domain with 1 direct and 2 preregistered, conceptual replication attempts of an influential study on this topic (Cardoso Leite et al., 2010). Signal detection analyses were targeted to distinguish between true visual sensitivity and response bias. Contrary to previous assumptions and despite high statistical power, however, the authors found no evidence for sensory attenuation of learned visual action effects. Bayesian analyses further supported the null hypothesis of no effect, thus constraining theories that promote sensory attenuation as an immediate and necessary consequence of voluntary actions. (PsycINFO Database Record PMID- 29154617 TI - Objectifying the subjective: Building blocks of metacognitive experiences in conflict tasks. AB - Metacognitive appraisals are essential for optimizing our information processing. In conflict tasks, metacognitive appraisals can result from different interrelated features (e.g., motor activity, visual awareness, response speed). Thanks to an original approach combining behavioral and electromyographic measures, the current study objectified the contribution of three features (reaction time [RT], motor hesitation with and without response competition, and visual congruency) to the subjective experience of urge-to-err in a priming conflict task. Both RT and motor hesitation with response competition were major determinants of metacognitive appraisals. Importantly, motor hesitation in absence of response competition and visual congruency had limited effect. Because science aims to rely on objectivity, subjective experiences are often discarded from scientific inquiry. The current study shows that subjectivity can be objectified. (PsycINFO Database Record PMID- 29154618 TI - Atheist horns and religious halos: Mental representations of atheists and theists. AB - Theists often receive the benefit of being stereotyped as trustworthy and moral, whereas atheists are viewed as untrustworthy and immoral. The extreme divergence between the stereotypes of theists and atheists suggests that mental images of the two groups may also diverge. We investigated whether people have biased mental images of theists and atheists. The results suggest that mental images of theists are associated with more positive attributes than images of atheists (Study 1), and these mental images influence who is believed to behave morally and immorally (Study 2). Together the findings suggest that mental images may represent a subtle mechanism reinforcing group-based prejudices. (PsycINFO Database Record PMID- 29154619 TI - Complementarity in false memory illusions. AB - For some years, the DRM illusion has been the most widely studied form of false memory. The consensus theoretical interpretation is that the illusion is a reality reversal, in which certain new words (critical distractors) are remembered as though they are old list words rather than as what they are-new words that are similar to old ones. This reality-reversal interpretation is supported by compelling lines of evidence, but prior experiments are limited by the fact that their memory tests only asked whether test items were old. We removed that limitation by also asking whether test items were new-similar. This more comprehensive methodology revealed that list words and critical distractors are remembered quite differently. Memory for list words is compensatory: They are remembered as old at high rates and remembered as new-similar at very low rates. In contrast, memory for critical distractors is complementary: They are remembered as both old and new-similar at high rates, which means that the DRM procedure induces a complementarity illusion rather than a reality reversal. The conjoint recognition model explains complementarity as a function of three retrieval processes (semantic familiarity, target recollection, and context recollection), and it predicts that complementarity can be driven up or down by varying the mix of those processes. Our experiments generated data on that prediction and introduced a convenient statistic, the complementarity ratio, which measures (a) the level of complementarity in memory performance and (b) whether its direction is reality-consistent or reality-reversed. (PsycINFO Database Record PMID- 29154620 TI - Seeing it both ways: Using a double-cuing task to investigate the role of spatial cuing in Level-1 visual perspective-taking. AB - Previous research using the dot-perspective task has produced evidence that humans may be equipped with a mechanism that spontaneously tracks others' gaze direction and thereby acquires information about what they can see. Other findings, however, support the alternative hypothesis that a spatial-cuing mechanism underpins the effect observed in the dot-perspective task. To adjudicate between these hypotheses, we developed a double-cuing version of Posner's (1980) spatial-cuing paradigm to be implemented in the dot-perspective task, and conducted 3 experiments in which we manipulated stimulus-onset asynchrony, as well as secondary task demands. Crucially, the 2 conflicting hypotheses generated divergent patterns of predictions across these experimental conditions. Our results support the hypothesis of an automatic perspective-taking mechanism. (PsycINFO Database Record PMID- 29154621 TI - Sensory constraints on perceptual simulation during sentence reading. AB - Resource-constrained models of language processing predict that perceptual simulation during language understanding would be compromised by sensory limitations (such as reading text in unfamiliar/difficult font), whereas strong versions of embodied theories of language would predict that simulating perceptual symbols in language would not be impaired even under sensory constrained situations. In 2 experiments, sensory decoding difficulty was manipulated by using easy and hard fonts to study perceptual simulation during sentence reading (Zwaan, Stanfield, & Yaxley, 2002). Results indicated that simulating perceptual symbols in language was not compromised by surface-form decoding challenges such as difficult font, suggesting relative resilience of embodied language processing in the face of certain sensory constraints. Further implications for learning from text and individual differences in language processing will be discussed. (PsycINFO Database Record PMID- 29154622 TI - How does "not left" become "right"? Electrophysiological evidence for a dynamic conflict-bound negation processing account. AB - Human thought and language is traditionally considered as abstract, amodal, and symbolic. However, recent theories propose that high-level human cognition is directly linked to basic, modal biological systems such as sensorimotor areas. Despite this influential representational debate very little is known regarding whether the mechanisms involved in sensorimotor control are also shared with higher-level cognitive processes, such as language comprehension. We investigated negation as a universal of human language, addressing two key questions: (a) Does negation result in a conflict-like representation? (b) Does negation trigger executive control adjustments in a similar manner as standard information processing conflicts do (e.g., Simon, Flanker)? Electrophysiological data indicated that phrases such as "not left/not right" result in initial activation of the to-be-negated information and subsequently the outcome of the negation process. More importantly, our findings also suggest that negation triggers conflict-related adjustments in information processing in line with traditional conflict tasks. Trial-by-trial conflict adaptation patterns in both behavioral and electrophysiological data indicated that negation processing dynamically changes depending on the current cognitive state. In summary, negation processing results in cognitive conflict, and dynamic influences of the cognitive state determine conflict resolution, that is, negation implementation. (PsycINFO Database Record PMID- 29154623 TI - Cognitive control over prospective task-set interference. AB - Recent studies have demonstrated that maintaining task-sets in working memory (WM) for prospective implementation can interfere with performance on an intervening task when the same stimulus requires incompatible responses in the ongoing versus the prospective task. This prospective task-set interference effect has previously been conceptualized as an obligatory process, resulting from instruction-based reflexivity (IBR). However, the extent to which strategic control can be exerted over interference in ongoing behavior from prospective task-sets held in WM has heretofore not been tested directly. To probe for strategic control over this effect, the authors conducted 3 experiments using a common inducer-diagnostic task design that manipulated the proportion compatibility of trials in the ongoing task. They hypothesized that if prospective task-set interference were malleable by control, participants would suppress the influence of the prospective set on ongoing processing when incompatible trials are frequent. Consistent with this prediction, the results show that prospective task-set interference is subject to modulation by strategic control such that the magnitude of interference is reduced, eliminated, or reversed in the presence of frequent incompatible trials. Thus, the influence on ongoing behavior of a prospective task-set held in WM is not obligatory, but subject to strategic control. (PsycINFO Database Record PMID- 29154624 TI - Task demands determine comparison strategy in whole probe change detection. AB - Detecting a change in our visual world requires a process that compares the external environment (test display) with the contents of memory (study display). We addressed the question of whether people strategically adapt the comparison process in response to different decision loads. Study displays of 3 colored items were presented, followed by 'whole-display' probes containing 3 colored shapes. Participants were asked to decide whether any probed items contained a new feature. In Experiments 1-4, irrelevant changes to the probed item's locations or feature bindings influenced memory performance, suggesting that participants employed a comparison process that relied on spatial locations. This finding occurred irrespective of whether participants were asked to decide about the whole display, or only a single cued item within the display. In Experiment 5, when the base-rate of changes in the nonprobed items increased (increasing the incentive to use the cue effectively), participants were not influenced by irrelevant changes in location or feature bindings. In addition, we observed individual differences in the use of spatial cues. These results suggest that participants can flexibly switch between spatial and nonspatial comparison strategies, depending on interactions between individual differences and task demand factors. These findings have implications for models of visual working memory that assume that the comparison between study and test obligatorily relies on accessing visual features via their binding to location. (PsycINFO Database Record PMID- 29154625 TI - Time-based expectancy in temporally structured task switching. AB - In many situations, people have to switch between different tasks. Previous research has shown that task switching leads to relatively slow responses and high error rates. In many real-life task-switching contexts, tasks are not randomly distributed over time, but the temporal distribution of tasks carries information. Often the delay before a task predicts to some degree which task it will be, like when a longer browser loading time for a website makes the search for an alternative more likely. The present study investigated whether and how humans adapt to such temporal regularities. In a series of five experiments, intertask delays predicted with different probabilities the task in the upcoming trial, or whether the task switches in the upcoming trial. Participants adapted their response behavior to the predictability of the task, for all tested degrees of predictability (70%, 80%, 90%), but only for the degree of 90% predictability when the task transition was temporally predictable. The adaptation was implicit and task repetitions as well as switches, both benefitted from this adaptation. Likewise, performance after 500 ms and 1,500 ms delays was facilitated by time based predictability. The results are discussed in the context of previous findings on nontemporal task predictability. (PsycINFO Database Record PMID- 29154626 TI - Attentional effect on contrast appearance: From enhancement to attenuation. AB - Does attention alter appearance? Recent studies have shown that an exogenous cue tends to increase the perceived contrast of a low-contrast stimulus. In the present study we systematically studied the attentional effect over a wide range of contrast levels (15% to 60%). Besides replicating the enhancement at lower contrast levels with higher comparative tasks (Experiment 1), the data revealed a cue-induced attenuation in apparent contrast at higher contrast levels with lower comparative tasks (Experiment 2) and same/different judgment task (Experiment 3). This attenuation effect was robust at the individual level, and it was not due to response bias or sensory interactions (Experiments 3 and 4). These results suggest that attention modulates contrast appearance and this effect depends on both the contrast level and the type of judgment task used. We propose that our findings can be understood through contrast gain mechanism on supersatuating neurons, whose response increases first as the stimulus intensity increases, but decrease the responses after the peak. This surprising phenomenon offers insights for the underlying neural mechanisms of visual processing. (PsycINFO Database Record PMID- 29154627 TI - Distinct kinematic markers of demonstration and joint action coordination? Evidence from virtual xylophone playing. AB - When performing joint actions, people modulate instrumental actions to provide additional information for a coactor (Pezzulo, Donnarumma, & Dindo, 2013). Similarly, demonstrators adjust instrumental actions to make them more informative for novice learners (Brand, Baldwin, & Ashburn, 2002). It is unknown whether the kinematic modulations performed to facilitate prediction in joint action coordination and the modulations performed to transmit information about the structure of novel actions are unique, or whether a general type of modulation can take on multiple functions. The present study therefore investigated whether there are unique kinematic markers for demonstration and for different types of joint action. In three experiments participants performed a virtual xylophone task, where they played simple xylophone melodies either alone, for a learner watching them, or together with another participant, while their movements were recorded. Participants increased movement amplitude during joint action and during demonstration. However, during joint action, participants modulated specific velocity parameters depending on whether their joint action partner knew or did not know the action sequence to be performed. The results demonstrate that there are specific kinematic cues to communicate the time and location of upcoming actions to a joint action partner but that there are no unique kinematic cues expressing the "pedagogical" intentions of a demonstrator. (PsycINFO Database Record PMID- 29154628 TI - The bandwidth of VWM consolidation varies with the stimulus feature: Evidence from event-related potentials. AB - Our previous work suggests that 2 colors can be consolidated into visual short term memory (VSTM) in parallel without a loss of memory precision, whereas consolidation of 2 orientations is performed in a strictly serial manner. Those experiments compared VSTM performance for simultaneously and sequentially presented stimuli. However, there is still controversy about whether the bandwidth for consolidation is determined by the type of information. To further investigate this issue, here we measured electroencephalography while participants attempted to consolidate 1, 2 or 4 simultaneously presented colors (Experiment 1) or orientations (Experiment 2) under limited presentation times. We used the contralateral delay activity (CDA) as an electrophysiological marker of the number of items that were consolidated. For colored stimuli, the CDA amplitude increased between set-size 1 and 2 but did not further increase for set size 4. By contrast, for orientation, the CDA amplitude remained at the set size 1 amplitude as set size increased to 2 or 4 items. Furthermore, in a long exposure duration (300 ms) condition that did not limit the consolidation process, the CDA amplitude pattern indicated that VSTM capacity is limited to about 3 colored items and about 2 orientation items in our paradigm. Thus, the CDA effects observed in the short presentation time was not limited by VSTM storage, but rather by consolidation. These results are consistent with our previous behavioral research and suggest that the bandwidth of VSTM consolidation is determined by the stimulus feature. (PsycINFO Database Record PMID- 29154629 TI - Emergent perception of gaze direction across time. AB - To determine where another person is looking, the visual system engages a process of emergent integration, pooling information across space from both the head and eyes. Gaze is dynamic, however, and in order to achieve a temporally stabilized metric of a person's direction of attention, this integrative process might also occur across time. Here, we tested and confirmed this prediction. Even when seen separately and in succession, the rotation of a head attracted the perceived gaze of a pair of eyes. This integration depended on temporal continuity-attraction decayed with longer delays between the face parts and prolonged viewing of the head reduced integration. Nevertheless, gaze integration persisted across delays of 2 s and even occurred against a backdrop of changing emotional expression. Gaze is a complex feature that orchestrates social interactions over time. Our results demonstrate that the representation and perception of emergent gaze is dynamic as well. (PsycINFO Database Record PMID- 29154630 TI - Automatic imitation of multiple agents: Simultaneous or random representation? AB - Research has shown that the observation of another's movement activates the corresponding motor representation in the observer. However, it is largely unknown how activation of these shared representations is influenced by the number of observed agents. In recent work, we have studied automatic imitation while participants saw 2 hands of which either one hand or both hands made a movement. These studies found that 2 hands produced a stronger imitative response than a single hand when the hands made an identical movement but not when they made different movements. It was argued that identical movements were mapped onto the same motor representation and therefore produced a stronger motor response. Nevertheless, an alternative explanation is that participants randomly represented 1 hand on each trial. The goal of the current study was to disentangle these 2 hypotheses. In Experiments 1 and 2, we replicate our results using a stimulus setup that made random sampling unlikely. In Experiment 3, we show that an additive effect was still present when attention was directed to 1 hand that always made a movement. Finally, in Experiment 4, we show that intentional imitation of 1 hand did not preclude automatic imitation of a second hand. Together, these findings support the hypothesis that the actions of multiple persons can be represented together in the motor system. (PsycINFO Database Record PMID- 29154631 TI - Alertness and cognitive control: Testing the early onset hypothesis. AB - Previous research has revealed a peculiar interaction between alertness and cognitive control in selective-attention tasks: Congruency effects are larger on alert trials (on which an alerting cue is presented briefly in advance of the imperative stimulus) than on no-alert trials, despite shorter response times (RTs) on alert trials. One explanation for this finding is the early onset hypothesis, which is based on the assumptions that increased alertness shortens stimulus-encoding time and that cognitive control involves gradually focusing attention during a trial. The author tested the hypothesis in 3 experiments by manipulating alertness and stimulus quality (which were intended to shorten and lengthen stimulus-encoding time, respectively) in an arrow-based flanker task involving congruent and incongruent stimuli. Replicating past findings, the alerting manipulation led to shorter RTs but larger congruency effects on alert trials than on no-alert trials. The stimulus-quality manipulation led to longer RTs and larger congruency effects for degraded stimuli than for intact stimuli. These results provide mixed support for the early onset hypothesis, but the author discusses how data and theory might be reconciled if stimulus quality affects stimulus-encoding time and the rate of evidence accumulation in the decision process. (PsycINFO Database Record PMID- 29154632 TI - Auditory over visual advantage of sensorimotor synchronization in 6- to 7-year old children but not in 12- to 15-year-old children and adults. AB - The superiority of the auditory over visual modality in sensorimotor synchronization-a fundamental ability to coordinate movements with external rhythms-has long been established, whereas recent metronome synchronization work showed that synchronization of a visual bouncing ball was not less stable than synchronization of auditory tones in adults. The present study examined synchronization to isochronous sequences composed of auditory tones, visual flashes, or a bouncing ball in 6- to 7-year-old children, 12- to 15-year-old children, and 19- to 29-year-old adults. Consistent with previous reporting, the results showed that synchronization stability increased with age and synchronization was less stable for flashes than for tones and bouncing balls. As for the focus of the present study, the results revealed that synchronization of the bouncing ball was less stable than synchronization of tones for younger children, but not for teenagers and adults. The finding suggests the predisposition of the auditory advantage of sensorimotor synchronization in early childhood. (PsycINFO Database Record PMID- 29154633 TI - Disentangling inhibition-based and retrieval-based aftereffects of distractors: Cognitive versus motor processes. AB - Selective attention refers to the ability to selectively act upon relevant information at the expense of irrelevant information. Yet, in many experimental tasks, what happens to the representation of the irrelevant information is still debated. Typically, 2 approaches to distractor processing have been suggested, namely distractor inhibition and distractor-based retrieval. However, it is also typical that both processes are hard to disentangle. For instance, in the negative priming literature (for a review Frings, Schneider, & Fox, 2015) this has been a continuous debate since the early 1980s. In the present study, we attempted to prove that both processes exist, but that they reflect distractor processing at different levels of representation. Distractor inhibition impacts stimulus representation, whereas distractor-based retrieval impacts mainly motor processes. We investigated both processes in a distractor-priming task, which enables an independent measurement of both processes. For our argument that both processes impact different levels of distractor representation, we estimated the exponential parameter (tau) and Gaussian components (MU, sigma) of the exponential Gaussian reaction-time (RT) distribution, which have previously been used to independently test the effects of cognitive and motor processes (e.g., Moutsopoulou & Waszak, 2012). The distractor-based retrieval effect was evident for the Gaussian component, which is typically discussed as reflecting motor processes, but not for the exponential parameter, whereas the inhibition component was evident for the exponential parameter, which is typically discussed as reflecting cognitive processes, but not for the Gaussian parameter. (PsycINFO Database Record PMID- 29154634 TI - The contribution of perceptual factors and training on varying audiovisual integration capacity. AB - The suggestion that the capacity of audiovisual integration has an upper limit of 1 was challenged in 4 experiments using perceptual factors and training to enhance the binding of auditory and visual information. Participants were required to note a number of specific visual dot locations that changed in polarity when a critical auditory stimulus was presented, under relatively fast (200-ms stimulus onset asynchrony [SOA]) and slow (700-ms SOA) rates of presentation. In Experiment 1, transient cross-modal congruency between the brightness of polarity change and pitch of the auditory tone was manipulated. In Experiment 2, sustained chunking was enabled on certain trials by connecting varying dot locations with vertices. In Experiment 3, training was employed to determine if capacity would increase through repeated experience with an intermediate presentation rate (450 ms). Estimates of audiovisual integration capacity (K) were larger than 1 during cross-modal congruency at slow presentation rates (Experiment 1), during perceptual chunking at slow and fast presentation rates (Experiment 2), and, during an intermediate presentation rate posttraining (Experiment 3). Finally, Experiment 4 showed a linear increase in K using SOAs ranging from 100 to 600 ms, suggestive of quantitative rather than qualitative changes in the mechanisms in audiovisual integration as a function of presentation rate. The data compromise the suggestion that the capacity of audiovisual integration is limited to 1 and suggest that the ability to bind sounds to sights is contingent on individual and environmental factors. (PsycINFO Database Record PMID- 29154635 TI - You 'have' to hear this: Using tone of voice to motivate others. AB - The present studies explored the role of prosody in motivating others, and applied self-determination theory (Ryan & Deci, 2000) to do so. Initial studies describe patterns of prosody that discriminate motivational speech. Autonomy support was expressed with lower intensity, slower speech rate and less voice energy in both motivationally laden and neutral (but motivationally primed) sentences. In a follow-up study, participants were able to recognize motivational prosody in semantically neutral sentences, suggesting prosody alone may carry motivational content. Findings from subsequent studies also showed that an autonomy-supportive as compared with a controlling tone facilitated positive personal (perceived choice and lower perceived pressure, well-being) and interpersonal (closeness to others and prosocial behaviors) outcomes commonly linked to this type of motivation. Results inform both the social psychology (in particular motivation) and psycho-linguistic (in particular prosody) literatures and offer a first description of how motivational tone alone can shape listeners' experiences. (PsycINFO Database Record PMID- 29154636 TI - Optimal task-sets override attentional capture by rare cues. AB - Many studies converge on the conclusion that spatially irrelevant precues do not capture attention when cue and target features do not match. However, a recent study reported that rare onset cues captured attention even though observers searched for a nonmatching color target. Hence, attentional capture by rare onsets cues might be cognitively impenetrable (Folk & Remington, 2015). Although we replicated these findings (Experiment 1), we hypothesized that capture by rare onset cues can be prevented when the target display promotes a stronger task-set for the target or suppression of the cue features (i.e., a white onset). Therefore, we presented the color target together with a single white nontarget, and indeed found that the rare onset cues failed to capture (Experiment 2). Moreover, we examined the previous suggestion that frequency effects are limited to onset cues by presenting rare color cues with nonmatching color targets (Experiment 3). We observed capture by rare color cues, but again, capture could be prevented when a nontarget in the cue color was added to the target display (Experiment 4). Overall, these findings suggest that capture by rare cues can be prevented when the suppressive bias against nontarget features is optimally directed against the cue properties. (PsycINFO Database Record PMID- 29154637 TI - Stability and change in mother-child planning over middle childhood. AB - This longitudinal research examines maternal and child behaviors during joint planning over a 3-year period of middle childhood. 118 mother-child dyads were observed once a year beginning when the children were 8 years of age. Coding focused on mother and child planning behaviors, maternal instructional support, and child task engagement. Multilevel modeling was used to compare 3 models of stability and change: stability, normative developmental change, and individual differences in change. Results indicate that normative developmental change was the best predictor of mother and child planning behaviors and maternal guidance. Individual differences in rate of change predicted mothers' instructional support in the use of physical demonstration and child engagement measured by attention, task responsibility, and cooperation. Task difficulty contributed to these patterns. This research advances understanding of social interaction on cognitive tasks for partners in an established relationship. Implications for theory and future research are discussed. (PsycINFO Database Record PMID- 29154639 TI - Developmental relations between alcohol expectancies and social norms in predicting alcohol onset. AB - Expectations about alcohol's effects and perceptions of peers' behaviors and beliefs related to alcohol use are each shown to strongly influence the timing of drinking onset during adolescence. The present study builds on prior work by examining the conjoint effects of within-person changes in these social-cognitive factors on age of adolescent drinking onset. We related youths' alcohol status (i.e., alcohol-naive, initiation during study, prior initiation) to increases in positive and negative alcohol outcome expectancies (AOEs), as well as increases in perceived peer/close friend alcohol use and acceptance, during adolescence. We also investigated whether changes in AOEs and perceived social norms prospectively predicted alcohol onset in alcohol-naive adolescents. Participants were 1,023 adolescents aged 12.2 years on average at enrollment (SD = 0.98), 52% female, participating in an ongoing longitudinal survey on substance use and health behaviors. Positive AOEs, close friends' norms, and same-age peer norms increased linearly, whereas negative AOEs decreased linearly. Changes were attenuated for participants who remained alcohol-naive and increased for participants who experienced initiation during the study. Furthermore, we found associations between individual changes in AOEs and perceived social norms. Finally, survival models revealed that onset of alcohol use was prospectively predicted by stronger initial positive AOEs, as well as increases in close friends' norms and decreases in negative AOEs over time. These findings emphasize codevelopment of AOEs and perceived social norms, coinciding with, and predictive of, onset of alcohol use, and point toward a unique role for within-individual changes in identifying youth at risk for early onset of alcohol use. (PsycINFO Database Record PMID- 29154640 TI - When saying "I'm best" is benign: Developmental shifts in perceptions of boasting. AB - Four studies explored developmental changes in attitudes toward boasting. Overall, 5- to 7-year-olds (N = 130) were more likely than 8- to 11-year-olds (N = 126) and adults (N = 263) to view characters who boasted about valued traits as likable. In Study 1, younger children, unlike the older participants, liked and morally valued boasters who were accurate about their boasts. Justifications suggested the 5- to 7-year-olds perceived the boaster as sharing knowledge and being potentially helpful. No age group liked boasters who misrepresented themselves. In Study 2, boasters about valued traits were less liked by all ages than those who untruthfully downplayed their own abilities to please others. Adults, however, preferred boasters when the traits were unimportant and easily verifiable. In Study 3, a boaster was contrasted with a humble character, who never spoke about possessing the positively valued trait. Younger children showed a significant preference for the boaster, while older children and adults strongly preferred the humble person. Finally, Study 4 supported the proposal that younger children like boasters because boasters provide information about a capacity to help. Indeed, younger children valued boasters as potential helpers as much as they valued those who explicitly offered to help. Older participants did not differ from chance in their expectations that boasters could help. These age-related shifts in attitudes toward boasting may arise from a convergence of developmental changes in 4 underlying related processes-social sharing, self presenting, discerning motives, and overoptimism. (PsycINFO Database Record PMID- 29154638 TI - Longitudinal associations between parenting and youth adjustment in twelve cultural groups: Cultural normativeness of parenting as a moderator. AB - To examine whether the cultural normativeness of parents' beliefs and behaviors moderates the links between those beliefs and behaviors and youths' adjustment, mothers, fathers, and children (N = 1,298 families) from 12 cultural groups in 9 countries (China, Colombia, Italy, Jordan, Kenya, Philippines, Sweden, Thailand, and the United States) were interviewed when children were, on average, 10 years old and again when children were 12 years old. Multilevel models examined 5 aspects of parenting (expectations regarding family obligations, monitoring, psychological control, behavioral control, warmth/affection) in relation to 5 aspects of youth adjustment (social competence, prosocial behavior, academic achievement, externalizing behavior, internalizing behavior). Interactions between family level and culture-level predictors were tested to examine whether cultural normativeness of parenting behaviors moderated the link between those behaviors and children's adjustment. More evidence was found for within- than between-culture differences in parenting predictors of youth adjustment. In 7 of the 8 instances in which cultural normativeness was found to moderate the link between parenting and youth adjustment, the link between a particular parenting behavior and youth adjustment was magnified in cultural contexts in which the parenting behavior was more normative. (PsycINFO Database Record PMID- 29154641 TI - Do the antecedents and consequences of loneliness change from middle adulthood into old age? AB - Loneliness is a stressful experience that appears to interfere with health and social integration (SI). Recently, researchers proposed that both antecedents and consequences of loneliness may change across the life span. To fully understand the processes related to loneliness it may thus be crucial to adopt an age differentiated perspective. This study contributes to the literature by investigating how the interrelationship between loneliness and SI and that between loneliness and physical health changes as people move from middle adulthood into old age. We also investigate the extent to which a person's level of negative affect (NA) may serve as age-differentiated mediator on the pathway that leads from loneliness to impaired physical health. The data for our study were gathered over up to 15 years of study from 11,010 participants in the German Ageing Survey (DEAS [Deutscher Alterssurvey]). We examined all interrelations of interest over a broad age range of 40 to 84 years by using an accelerated longitudinal data design. Autoregressive structural equation models were applied for statistical analyses. The results suggest a reciprocal relationship between loneliness and SI that appears to strengthen as people get older. The reciprocal relationship between loneliness and NA, in contrast, appears to grow weaker with increasing age. As a consequence, the NA-mediated effect that loneliness exerts on physical health may actually decrease as people grow older. We conclude that the processes related to loneliness are best understood using a developmental perspective that takes age-specific resources, roles, and living conditions into account. (PsycINFO Database Record PMID- 29154642 TI - Sensory processing sensitivity as a marker of differential susceptibility to parenting. AB - In this longitudinal multiinformant study negative emotionality and sensory processing sensitivity were compared as susceptibility markers among kindergartners. Participating children (N = 264, 52.9% boys) were Dutch kindergartners (Mage = 4.77, SD = 0.60), followed across three waves, spaced seven months apart. Results show that associations between parenting and child behavior did not depend on children's negative emotionality. Sensory processing sensitivity, however, interacted with both (changes in) negative and (changes in) positive parenting in predicting externalizing, but not prosocial, behavior. Depending on the interaction, vantage sensitivity and differential susceptibility models were supported. The findings suggest that sensory processing sensitivity may be a more proximal correlate of individual differences in susceptibility, compared with negative emotionality. (PsycINFO Database Record PMID- 29154643 TI - Gender nonconformity of identical twins with discordant sexual orientations: Evidence from childhood photographs. AB - Childhood gender nonconformity (femininity in males, masculinity in females) predicts a nonstraight (gay, lesbian, or bisexual) sexual orientation in adulthood. In previous work, nonstraight twins reported more childhood gender nonconformity than their genetically identical, but straight, cotwins. However, self-reports could be biased. We therefore assessed gender nonconformity via ratings of photographs from childhood and adulthood. These ratings came from independent observers naive to study hypotheses. Identical twins with discordant sexual orientations (24 male pairs, 32 female pairs) visibly differed in their gender nonconformity from mid-childhood, with higher levels of gender nonconformity observed in the nonstraight twins. This difference was smaller than the analogous difference between identical twins who were concordant straight (4 male pairs, 11 female pairs) and identical twins unrelated to them who were concordant nonstraight (19 male pairs, 8 female pairs). Further, twins in discordant pairs correlated in their observer-rated gender nonconformity. Nongenetic factors likely differentiated the discordant twins' gender-related characteristics in childhood, but shared influences made them similar in some respects. We further tested how recall of past rejection from others related to gender nonconformity. Rejection generally increased with gender nonconformity, but this effect varied by the twins' sexual orientation. (PsycINFO Database Record PMID- 29154645 TI - Center-based early care and education and children's school readiness: Do impacts vary by neighborhood poverty? AB - Neighborhoods provide resources that may affect children's achievement or moderate the influences of other developmental contexts, such as early care and education (ECE). Using a sample (N ~ 12,430) from the 2010-2011 Early Childhood Longitudinal Study-Kindergarten Cohort, merged with census tract-level poverty data from the 2008-2012 American Community Survey, this article examines associations between center-based ECE participation, neighborhood poverty, and children's academic skills and behavior at kindergarten entry. Findings suggest that children who attend center-based care in the year prior to kindergarten show higher math and reading scores across neighborhood contexts. Results provide limited evidence that neighborhood poverty moderates the associations between either Head Start or other types of center-based ECE participation and children's outcomes at kindergarten, with children in moderate-high poverty neighborhoods showing stronger positive associations between who participated in Head Start or center care participation and math and reading scores, respectively, compared to those participating in low-poverty neighborhoods. Research and policy implications are discussed. (PsycINFO Database Record PMID- 29154644 TI - A longitudinal analysis of adolescent decision-making with the Iowa Gambling Task. AB - Many researchers have used the standard Iowa Gambling Task (IGT) to assess decision-making in adolescence given increased risk-taking during this developmental period. Most studies are cross-sectional and do not observe behavioral trajectories over time, limiting interpretation. This longitudinal study investigated healthy adolescents' and young adults' IGT performance across a 10-year span. A total of 189 individuals (aged 9-23 at baseline) completed a baseline session and were followed at 2-year intervals yielding 5 time-points. IGT deck contingencies were shuffled over time to reduce practice effects. IGT performance (good minus bad decisions) was measured at each assessment point and separated into 3 metrics: overall performance (all blocks), decision-making under ambiguity (blocks 1 and 2), and decision-making under risk (blocks 3, 4, and 5). Covariates included estimated intelligence and affective dispositions as measured by the Behavioral Inhibition and Activation System (BIS/BAS) Scales. A linear effect of age yielded the best fit when comparing linear and quadratic effects of age on overall IGT performance. Age and intelligence positively predicted overall performance, whereas affective approach tendencies (BAS) negatively predicted overall performance. Practice effects were observed and controlled for. Models of ambiguity and risk metrics yielded different patterns of significant predictors. Age predicted better performance and affective approach tendencies predicted worse performance for both metrics. Intelligence was a significant predictor for risk, but not ambiguity. This longitudinal study extends prior work by showing age-related improvements in reward-based decision-making and associating those improvements with cognitive and affective variables. Implications of the results for adolescent development are discussed. (PsycINFO Database Record PMID- 29154646 TI - Developmental stability in gender-typed preferences between infancy and preschool age. AB - Infants exhibit visual preferences for gender-typed objects (e.g., dolls, toy vehicles) that parallel the gender-typed play preferences of preschool-aged children, but the developmental stability of individual differences in early emerging gender-typed preferences has not yet been characterized. In the present study, we examined the longitudinal association between infants' (N = 51) performance on an object-preference task, administered between 6 and 13 months of age, and their play preferences at 4 years of age. Greater visual interest in a toy truck relative to a doll in infancy predicted significantly greater male typical toy and activity preferences (e.g., play with vehicles, videogames) at age 4. These findings suggest that gender-typed object preferences present during the 1st year of life may represent the developmental precursors of gender-typed play preferences observed later in childhood. (PsycINFO Database Record PMID- 29154647 TI - Lability in the parent's hostility and warmth toward their adolescent: Linkages to youth delinquency and substance use. AB - According to family systems and life course theories, periods of intense change, such as early adolescence, can disrupt stable family systems, leading to changes in family relationships. In this longitudinal study, we investigate 2 types of change in parental hostility and warmth toward their children during early adolescence (Grades 6 to 8)-developmental trends (linear declines) and lability (within-person fluctuations around developmental trends)-and their linkages to youth substance use and delinquency in Grade 9 (N = 618). We also test if the linkages between lability and youth risky behavior are moderated by youth gender. After controlling for between-person differences in level and developmental trends, we find greater lability (more fluctuations) in youth-reported parents' warmth and hostility are associated with greater youth delinquency, tobacco use, and polysubstance use initiation. The associations between youth-reported lability in mother and father hostility and polysubstance use demonstrated an inverted U shape pattern: Moderate levels of lability were associated with higher substance use but very low and high lability was associated with relatively lower rates of substance use. Many of the linkages between lability and youth delinquency were significant for girls but not boys. Fewer effects of lability on youth outcomes were found using parent reports. Developmental trends in parents' warmth and hostility were also associated with youth delinquency. Lability has unique implications for youth adjustment, yet appears to differ by youth outcome, gender, and reporter. The discussion focuses on mechanisms that might link changes in parent-youth warmth and hostility to youth risky behavior. (PsycINFO Database Record PMID- 29154648 TI - Nimble negotiators: How theory of mind (ToM) interconnects with persuasion skills in children with and without ToM delay. AB - Persuasion is an essential social skill. Yet its development and underpinnings are poorly understood. In 2 studies, a total of 167 children aged 3 to 12 years took theory of mind (ToM) tests and participated in unscripted, seminaturalistic persuasive conversations. Children were typically developing (TD) or had deafness or autism spectrum disorder (ASD). High-level, informationally rich persuasive arguments increased with age in all groups in both studies, as did ToM. In both studies, ToM scores predicted persuasion skill over and above age, language ability, and deafness/ASD status. In Study 1, TD 8-year-olds outperformed age matched deaf and autistic children in ToM but only equaled them in persuasive skill. Study 2 employed more challenging persuasion tasks and revealed superior persuasion performance by school-aged TD children compared with same-aged children with deafness or ASD. Deaf and ASD groups did better on Study 1's straightforward persuasion tasks than on Study 2's more challenging ones, whereas TD children rose to the added challenge without their persuasion performance suffering. (PsycINFO Database Record PMID- 29154649 TI - The limits of visual working memory in children: Exploring prioritization and recency effects with sequential presentation. AB - Recent research has demonstrated that, when instructed to prioritize a serial position in visual working memory (WM), adults are able to boost performance for this selected item, at a cost to nonprioritized items (e.g., Hu, Hitch, Baddeley, Zhang, & Allen, 2014). While executive control appears to play an important role in this ability, the increased likelihood of recalling the most recently presented item (i.e., the recency effect) is relatively automatic, possibly driven by perceptual mechanisms. In 3 Experiments 7 to 10 year-old's ability to prioritize items in WM was investigated using a sequential visual task (total N = 208). The relationship between individual differences in WM and performance on the experimental task was also explored. Participants were unable to prioritize the first (Experiments 1 and 2) or final (Experiment 3) item in a 3-item sequence, while large recency effects for the final item were consistently observed across all experiments. The absence of a priority boost across 3 experiments indicates that children may not have the necessary executive resources to prioritize an item within a visual sequence, when directed to do so. In contrast, the consistent recency boosts for the final item indicate that children show automatic memory benefits for the most recently encountered stimulus. Finally, for the baseline condition in which children were instructed to remember all 3 items equally, additional WM measures predicted performance at the first and second but not the third serial position, further supporting the proposed automaticity of the recency effect in visual WM. (PsycINFO Database Record PMID- 29154651 TI - Reducing the language content in ToM tests: A developmental scale. AB - The goal of the current study was to statistically evaluate the reliable scalability of a set of tasks designed to assess Theory of Mind (ToM) without language as a confounding variable. This tool might be useful to study ToM in populations where language is impaired or to study links between language and ToM. Low verbal versions of the ToM tasks proposed by Wellman and Liu (2004) for their scale were tested in 234 children (2.5 years to 11.9 years). Results showed that 5 of the tasks formed a scale according to both Guttman and Rasch models whereas all 6 tasks could form a scale according to the Rasch model only. The main difference from the original scale was that the Explicit False Belief task could be included whereas the Knowledge Access (KA) task could not. The authors argue that the more verbal version of the KA task administered in previous studies could have measured language understanding rather than ToM. (PsycINFO Database Record PMID- 29154650 TI - Classifying trajectories of social-emotional difficulties through elementary school: Impacts of the Chicago school readiness project. AB - Although research has shown fade-out of the cognitive benefits of classroom-based preschool interventions, less is known regarding the durability of social emotional impacts. This study examines the extent to which the multicomponent Chicago School Readiness Project (CSRP) intervention lowered risk of internalizing, externalizing, attention, and social difficulties from Head Start through elementary school for 602 low-income children. Results suggest that most children in this sample showed few social-emotional difficulties over time. However, one quarter of the sample exhibited profiles of transitory or building difficulties over six years. Random assignment to the CSRP preschool intervention significantly reduced children's odds of transitory attention and social difficulties in middle childhood, with preliminary evidence suggesting stronger impacts for children attending elementary schools characterized by low academic rigor and high neighborhood crime. CSRP was not found to be effective in preventing more robust, increasing forms of difficulty in the externalizing and attention domains. Implications for early childhood intervention and policy are discussed. (PsycINFO Database Record PMID- 29154652 TI - Development of internalizing problems from adolescence to emerging adulthood: Accounting for heterotypic continuity with vertical scaling. AB - Manifestations of internalizing problems, such as specific symptoms of anxiety and depression, can change across development, even if individuals show strong continuity in rank-order levels of internalizing problems. This illustrates the concept of heterotypic continuity, and raises the question of whether common measures might be construct-valid for one age but not another. This study examines mean-level changes in internalizing problems across a long span of development at the same time as accounting for heterotypic continuity by using age-appropriate, changing measures. Internalizing problems from age 14-24 were studied longitudinally in a community sample (N = 585), using Achenbach's Youth Self-Report (YSR) and Young Adult Self-Report (YASR). Heterotypic continuity was evaluated with an item response theory (IRT) approach to vertical scaling, linking different measures over time to be on the same scale, as well as with a Thurstone scaling approach. With vertical scaling, internalizing problems peaked in mid-to-late adolescence and showed a group-level decrease from adolescence to early adulthood, a change that would not have been seen with the approach of using only age-common items. Individuals' trajectories were sometimes different than would have been seen with the common-items approach. Findings support the importance of considering heterotypic continuity when examining development and vertical scaling to account for heterotypic continuity with changing measures. (PsycINFO Database Record PMID- 29154653 TI - Symbolic number skills predict growth in nonsymbolic number skills in kindergarteners. AB - There is currently considerable discussion about the relative influences of evolutionary and cultural factors in the development of early numerical skills. In particular, there has been substantial debate and study of the relationship between approximate, nonverbal (approximate magnitude system [AMS]) and exact, symbolic (symbolic number system [SNS]) representations of number. Here we examined several hypotheses concerning whether, in the earliest stages of formal education, AMS abilities predict growth in SNS abilities, or the other way around. In addition to tasks involving symbolic (Arabic numerals) and nonsymbolic (dot arrays) number comparisons, we also tested children's ability to translate between the 2 systems (i.e., mixed-format comparison). Our data included a sample of 539 kindergarten children (M = 5.17 years, SD = .29), with AMS, SNS, and mixed comparison skills assessed at the beginning and end of the academic year. In this way, we provide, to the best of our knowledge, the most comprehensive test to date of the direction of influence between the AMS and SNS in early formal schooling. Results were more consistent with the view that SNS abilities at the beginning of kindergarten lay the foundation for improvement in both AMS abilities and the ability to translate between the 2 systems. It is important to note that we found no evidence to support the reverse. We conclude that, once one acquires a basic grasp of exact number symbols, it is this understanding of exact number (and perhaps repeated practice therewith) that facilitates growth in the AMS. Though the precise mechanism remains to be understood, these data challenge the widely held view that the AMS scaffolds the acquisition of the SNS. (PsycINFO Database Record PMID- 29154654 TI - Variety in parental use of "want" relates to subsequent growth in children's theory of mind. AB - In 2 cross-lagged, longitudinal studies we contrasted parental talk about want in a single context versus multiple contexts. Study 1 examined thirty-two 2 year olds, with mothers describing pictures to children. Mothers could use want in zero, one, or multiple contexts. Children whose mothers used want in multiple contexts experienced a significantly larger gain in mental state terms over a 6 month period. Study 2 examined 50 preschoolers, measuring theory of mind (ToM) with tasks and mental state terms, then had parents intervene by reading booklets in which want was used in 1 or multiple contexts. Over a 6-week period, the latter group made larger gains in ToM. We posit that maternal use of want in multiple contexts assists understanding that want refers to an underlying mental state rather than a single behavior. (PsycINFO Database Record PMID- 29154655 TI - Cognitive functioning in toddlerhood: The role of gestational age, attention capacities, and maternal stimulation. AB - Why do many preterm children show delays in development? An integrated model of biological risk, children's capacities, and maternal stimulation was investigated in relation to cognitive functioning at toddler age. Participants were 200 Dutch children (gestational age = 32-41 weeks); 51% boys, 96% Dutch nationality, 71.5% highly educated mothers. At 18 months, attention capacities were measured using eye-tracking, and maternal attention-directing behavior was observed. Cognitive functioning was measured at 24 months using the Bayley-III-NL. Cognitive functioning was directly predicted by children's attention capacities and maternal attention-maintaining behavior. Gestational age was indirectly related to cognitive functioning through children's attention capacities and through maternal attention-redirecting behavior. In this way, a combination of gestational age, children's attention capacities, and maternal stimulation was associated with early cognitive development. (PsycINFO Database Record PMID- 29154656 TI - Does lexical stress influence 17-month-olds' mapping of verbs and nouns? AB - English-learning infants attend to lexical stress when learning new words. Attention to lexical stress might be beneficial for word learning by providing an indication of the grammatical class of that word. English disyllabic nouns commonly have trochaic (strong-weak) stress, whereas English disyllabic verbs commonly have iambic (weak-strong) stress. We explored whether 17-month-old infants use word stress to resolve an ambiguous labeling event where objects and actions are equally plausible referents. Infants were habituated to 2 words paired with 2 objects, with each object performing a distinct path action. They were subsequently tested on (a) a change in object but not path action or (b) a change in path action but not the object. When infants were taught verb-friendly iambic labels, their looking times increased both when the action switched and when the object switched. Infants who were taught noun-friendly trochaic labels demonstrated an increase in looking time only when the object switched. These results demonstrate that in ambiguous labeling events infants map iambic labels to both actions and objects, and trochaic labels to the objects but not to the actions, suggesting a bias for words with trochaic stress to refer to objects. Seventeen-month-old infants can use trochaic lexical stress to guide their word learning in ambiguous situations, but iambic stress cues may not preferentially guide infants' mappings of actions or objects. (PsycINFO Database Record PMID- 29154657 TI - Trajectories of parental engagement in early childhood among dual-earner families: Effects on child self-control. AB - Parental engagement in positive activities with the child may show significant variation across time, assuming a crucial influence on child development. In dual earner families, work-family conflict can interfere with parental engagement, with negative consequences for children's behavior. The current study examined the change trajectories of mothers' and fathers' engagement in early childhood, analyzing whether these trajectories are influenced by parents' work-family conflict and whether they predict child behavioral self-control. Data from 156 four-year-old children (67 girls) from dual-earner families were collected annually for 3 consecutive years, through mothers', fathers', and teachers' reports. Results from latent growth curve analysis revealed mothers' engagement remained stable across time while fathers' engagement had a significant increase over time. The negative association between work-family conflict and parental engagement was constant over time both for mothers and fathers. For mothers, initial levels of engagement positively predicted child behavioral self-control. As for fathers, both the initial level and positive change in engagement positively predicted child self-control. These findings emphasize the role of parental engagement in fostering child behavioral adjustment, underlining the need for considering work-family dynamics to understand changes in parental engagement. (PsycINFO Database Record PMID- 29154658 TI - The development of individual physically aggressive behaviors from infancy to toddlerhood. AB - In the present investigation, we studied the development of 6 physically aggressive behaviors in infancy and toddlerhood, posing 3 questions (a) How do the prevalences of individual physically aggressive behaviors change from 8, 15, and 24 months? (b) Are there groups of children who show distinctive patterns in the way individual physically aggressive behaviors develop over time? (c) What are the behavioral pathways leading from 8- to 24-month acts of physical aggression? Mothers and fathers (N = 272) from a moderately at-risk population reported on their children's physical aggression at each time point. The results revealed the commonality of physical aggression at all ages studied and the diverging developmental patterns of individual behaviors. Some physically aggressive behaviors became less common (e.g., hair pulling), while others became more common (e.g., hitting), with age. Roughly 42% of the children exhibited an increased propensity, relative to their peers, to aggress at all ages. Kicking, biting, hair pulling, and pinching/scratching at 8 months were the first steps on behavioral pathways leading to physical aggression at 24 months. These pathways principally suggested heterotypic continuity in physical aggression. (PsycINFO Database Record PMID- 29154659 TI - [Background, objectives, and methods]. PMID- 29154660 TI - [Indications for parenteral nutrition]. PMID- 29154661 TI - [Venous access for pediatric parenteral nutrition]. PMID- 29154662 TI - [Requirements for pediatric parenteral nutrition]. PMID- 29154663 TI - [Parenteral nutrition in special clinical conditions]. PMID- 29154664 TI - [Available products for pediatric parenteral nutrition]. PMID- 29154665 TI - [Ordering and standardisation of pediatric parenteral nutrition]. PMID- 29154666 TI - [Preparation of pediatric parenteral nutrition solutions]. PMID- 29154667 TI - [Administration of pediatric parenteral nutrition]. PMID- 29154668 TI - [Monitoring pediatric parenteral nutrition]. PMID- 29154669 TI - [Complications of pediatric parenteral nutrition]. PMID- 29154670 TI - [Pediatric home parenteral nutrition]. PMID- 29154671 TI - Forensic Drug Identification, Confirmation, and Quantification Using Fully Integrated Gas Chromatography with Fourier Transform Infrared and Mass Spectrometric Detection (GC-FT-IR-MS). AB - This manuscript is a continuation of a recent study that described the use of fully integrated gas chromatography with direct deposition Fourier transform infrared detection and mass spectrometric detection (GC-FT-IR-MS) to identify and confirm the presence of sibutramine and AB-FUBINACA. The purpose of the current study was to employ the GC-FT-IR portion of the same instrument to quantify these compounds, thereby demonstrating the ability to identify, confirm, and quantify drug substances using a single GC-FT-IR-MS unit. The performance of the instrument was evaluated by comparing quantitative analytical figures of merit to those measured using an established, widely employed method for quantifying drug substances, high performance liquid chromatography with ultraviolet detection (HPLC-UV). The results demonstrated that GC-FT-IR was outperformed by HPLC-UV with regard to sensitivity, precision, and linear dynamic range (LDR). However, sibutramine and AB-FUBINACA concentrations measured using GC-FT-IR were not significantly different at the 95% confidence interval compared to those measured using HPLC-UV, which demonstrates promise for using GC-FT-IR as a semi quantitative tool at the very least. The most significant advantage of GC-FT-IR compared to HPLC-UV is selectivity; a higher level of confidence regarding the identity of the analyte being quantified is achieved using GC-FT-IR. Additional advantages of using a single GC-FT-IR-MS instrument for identification, confirmation, and quantification are efficiency, increased sample throughput, decreased consumption of laboratory resources (solvents, chemicals, consumables, etc.), and thus cost. PMID- 29154672 TI - CR-39 (PADC) Reflection and Transmission of Light in the Ultraviolet-Near Infrared (UV-NIR) Range. AB - The spectral reflection (specular and diffuse) and transmission of Columbia Resin 39 (CR-39) were measured for incoherent light with wavelengths in the range of 200-2500 nm. These results will be of use for the optical characterization of CR 39, as well as in investigations of the chemical modifications of the polymer caused by ultraviolet (UV) exposure. A Varian Cary 5000 was used to perform spectroscopy on several different thicknesses of CR-39. With proper analysis for the interdependence of reflectance and transmittance, results are consistent across all samples. The reflectivity from each CR-39-air boundary reveals an increase in the index of refraction in the near-UV. Absorption observations are consistent with the Beer-Lambert law. Strong absorption of UV light of wavelength shorter than 350 nm suggests an optical band gap of 3.5 eV, although the standard analysis is not conclusive. Absorption features observed in the near infrared are assigned to molecular vibrations, including some that are new to the literature. PMID- 29154673 TI - Spatially Resolved Temperature Measurements Above a Burning Wood Pellet Using Diode Laser-Based Two-Line Atomic Fluorescence. AB - Diode laser-based two-line atomic fluorescence (TLAF) thermometry applied to flames of combusting wood pellets is demonstrated. The temperature above burning wood pellets placed in the hot product gas of gallium seeded laminar flames is measured. The calibration-free technique provides spatially resolved temperatures in one dimension with sufficient temporal resolution to resolve all combustion stages of a pellet, even in highly sooting flames. The temperature above a burning pellet was found to decrease due to the release of volatile gases and the accuracy and precision of the technique is assessed at flame temperatures. PMID- 29154674 TI - Chemometric Methods for Estimating the Strain Hardening Modulus in Polyethylene Resins. AB - The feasibility of using multiway or N-way partial least square (NPLS) methods to estimate physical properties of 1-butene and 1-hexene polyethylene (PE) copolymers directly from multidimensional data obtained from size exclusion chromatography coupled to a Fourier transform infrared detector (SEC FT-IR) was explored. Digital sample sets of horizontal slices (slabs) of two-dimensional data simulating the molecular weight distribution and the corresponding orthogonal FT-IR spectra were correlated to a particular Y-block response using NPLS. The NPLS results were compared to those obtained through separate estimations using various algorithms and exploratory response surface methods. The estimated strain hardening modulus () for bimodal PE-like digital structures could adequately be modeled using both the linear response surface method (RSM) and NPLS. Although different input values were used, the predicted values for by NPLS was found to mirror both the analytical results and the expected structural effects obtained using linear RSM models. PMID- 29154675 TI - Preprocessing Tools Applied to Improve the Assessment of Aldrin Effects on Prostate Cancer Cells Using Raman Spectroscopy. AB - The study of pollutant effects on living organisms provides information about the possible biological and environmental response to a contaminant. Progression of prostate cancer may be related to exposure to pesticides or other chemical substances. In this work, the effect of the pesticide aldrin on human prostate cancer cells (DU145) is studied using Raman spectroscopy and chemometric techniques. Prostate cancer cell line DU145 has been exposed acutely the pesticide aldrin. Individual Raman spectra coming from control and treated cell populations have been acquired. Partial least squares discriminant analysis (PLSDA) has been used to assess differences among treated and control samples and to identify spectral biomarkers associated with pollutant stress. Some preprocessing methodologies have been tested in order to improve the capability of discrimination between fingerprints. Partial least squares discriminant analysis results suggest that the best normalization-scaling preprocessing combination is provided by Euclidean normalization (EN)-SIMPLISMA-based scaling (SBS). SIMPLISMA-based scaling has been proposed as a scaling method focused on the classification objective, which enhances variables with high relative variation among samples. The most relevant spectral variables related to aldrin effect on DU145 seem to be mainly related to lipids, proteins, and variations in nucleic acids. PMID- 29154676 TI - Effects of bone regeneration materials and tooth movement timing on canine experimental orthodontic treatment. AB - OBJECTIVES: To evaluate the effects of bone regeneration materials and orthodontic tooth movement (OTM) timing on tooth movement through alveolar bone defects treated with guided bone regeneration (GBR) utilizing xenografts (Bio Oss) and alloplast (beta-TCP). MATERIALS AND METHODS: Twenty-four standard alveolar bone defects in six male beagle dogs were treated by GBR using either Bio-Oss or beta-TCP (experimental), whereas the control defects were left empty. The defects were further grouped into early or late subgroups, depending on OTM timing after GBR (ie 1 month or 2 months, respectively). Rates of OTM were measured intraorally, while computed tomography scan images were used to assess bone density, alveolar bone height, second premolar displacement, and tipping tendency. RESULTS: Generally, the Bio-Oss early and Bio-Oss late subgroups recorded the lowest amount of tooth movement compared with other modes of GBRs assessed. Before OTM, the control group registered significantly lower bone height compared with the Bio-Oss and beta-TCP groups ( P < .01). The control group was inferior on bone density and bone height compared with Bio-Oss and beta TCP. CONCLUSIONS: The Bio-Oss group had favorable radiologic features (higher alveolar bone level and bone density with less premolar tipping) but showed slower OTM than the control group. The late OTM subgroup had favorable radiologic features and showed faster tooth movement than the early OTM in the beta -TCP group. PMID- 29154677 TI - An Innovative Approach to Exploit the Reflection Spectroscopy of Liquid Characteristics. AB - Reflection spectroscopy, in the visible-near-infrared-shortwave infrared region (Vis-NIR-SWIR, 350-2500 nm), is a useful technology to extract chemical and physical properties of materials, but might be useless in identifying the spectral features of transparent or dark opaque liquids. Low reflectance values of a liquid reduce the ability to identify characteristic absorption features at specific wavelengths in the reflectance spectrum. In this study, we present a rapid and easy-to-use method to increase the measured reflectance spectrum and expose characteristic absorption features of a liquid. This was done by mixing the liquid with a white enhanced substance (WES). For this purpose, we used aluminum oxide (Al2O3) powder-a very bright (high albedo) substance and featureless across the entire Vis-NIR-SWIR region. The reflectance spectrum of the mixture-liquid and WES-was measured using a spectroradiometer. This procedure enabled to identify characteristic spectral features of the liquids that would have not been observed in the reflectance spectrum measured from the liquid alone. PMID- 29154678 TI - Searching for the holy grail of cardiovascular prevention. PMID- 29154679 TI - The HeartQoL questionnaire is valid for use in implantable cardioverter defibrillator recipients.. What does this mean for clinical practice? PMID- 29154680 TI - Cardiovascular disease predictors and adipose tissue macrophage polarization: Is there a link? AB - Background The risk of cardiovascular disease is closely connected to adipose tissue inflammation. The links between cardiovascular risk predictors and pro and anti-inflammatory macrophages in human adipose tissue were analysed to gain an insight into the pathophysiology of cardiovascular disease. Design Subcutaneous and visceral adipose tissues were obtained from 79 subjects, 52 living kidney donors (during nephrectomy) and 27 patients with peripheral artery disease (during arterial tree reconstruction). Methods Macrophage subsets were isolated from adipose tissues and analysed by flow cytometry using CD14, CD16, CD36 and CD163 monoclonal antibodies. The mutually adjusted differences of phagocytic pro inflammatory (CD14 + CD16 + CD36high), anti-inflammatory (CD14 + CD16-CD163+) and transitional subsets of macrophages were analysed in relation to cardiovascular predictors (sex, age, body mass index, smoking, hypercholesterolaemia, hypertension and statin treatment). Results Age, male sex and hypercholesterolaemia were closely positively associated with the phagocytic pro inflammatory macrophage subset in visceral adipose tissues. Interestingly, the proportion of phagocytic pro-inflammatory macrophages was relevantly decreased by statin therapy. A strong positive association of body mass index to the phagocytic pro-inflammatory subset was found in subcutaneous adipose tissues only. A minor transitional subpopulation, CD14 + CD16 + CD36lowCD163+, increased with age in both adipose tissues. This transitional subpopulation was also negatively associated with obesity and hypercholesterolaemia in visceral adipose tissues. Conclusion An effect of cardiovascular risk predictors on adipose tissue macrophage subpopulations was revealed. Interestingly, while age, male sex and hypercholesterolaemia were connected with the pro-inflammatory macrophage subpopulation in visceral adipose tissues, body mass index had a prominent effect in subcutaneous adipose tissues only. A decreasing effect of statins on these pro inflammatory macrophages was documented. PMID- 29154681 TI - Accelerated renal function decline in obese post myocardial infarction patients - is weight reduction per se an adequate therapeutic consequence? PMID- 29154682 TI - Brick and mortar IMT core lab goes automated and online. PMID- 29154683 TI - Arterial stiffness in childhood: A predictor for later cardiovascular disease? PMID- 29154684 TI - Brain functional connectivity in headache disorders: A narrative review of MRI investigations. AB - Resting-state functional magnetic resonance imaging (rs-fMRI) is used to interrogate the functional connectivity and network organization amongst brain regions. Functional connectivity is determined by measuring the extent of synchronization in the spontaneous fluctuations of blood oxygenation level dependent (BOLD) signal. Here, we review current rs-fMRI studies in headache disorders including migraine, trigeminal autonomic cephalalgias, and medication overuse headache. We discuss (1) brain network alterations that are shared amongst the different headache disorders and (2) network abnormalities distinct to each headache disorder. In order to focus the section on migraine, the headache disorder that has been most extensively studied, we chose to include articles that interrogated functional connectivity: (i) during the attack phase; (ii) in migraine patients with aura compared to migraine patients without aura; and (iii) of regions within limbic, sensory, motor, executive and default mode networks and those which participate in multisensory integration. The results of this review show that headache disorders are associated with atypical functional connectivity of regions associated with pain processing as well as atypical functional connectivity of multiple core resting state networks such as the salience, sensorimotor, executive, attention, limbic, visual, and default mode networks. PMID- 29154685 TI - A Qualitative Analysis of Real-Time Continuous Glucose Monitoring Data Sharing with Care Partners: To Share or Not to Share? AB - BACKGROUND: Little research exists regarding how real-time continuous glucose monitoring (RT-CGM) data sharing plays a role in the relationship between patients and their care partners. OBJECTIVE: To (1) identify the benefits and challenges related to RT-CGM data sharing from the patient and care partner perspective and (2) to explore the number and type of individuals who share and follow RT-CGM data. METHODS: This qualitative content analysis was conducted by examining publicly available blogs focused on RT-CGM and data sharing. A thematic analysis of blogs and associated comments was conducted. RESULTS: A systematic appraisal of personal blogs examined 39 blogs with 206 corresponding comments. The results of the study provided insight about the benefits and challenges related to individuals with diabetes sharing their RT-CGM data with a care partner(s). The analysis resulted in three themes: (1) RT-CGM data sharing enhances feelings of safety, (2) the need to communicate boundaries to avoid judgment, and (3) choice about sharing and following RT-CGM data. RT-CGM data sharing occurred within dyads (n = 46), triads (n = 15), and tetrads (n = 2). CONCLUSIONS: Adults and children with type 1 diabetes and their care partners are empowered by the ability to share and follow RT-CGM data. Our findings suggest that RT-CGM data sharing between an individual with diabetes and their care partner can complicate relationships. Healthcare providers need to engage patients and care partners in discussions about best practices related to RT-CGM sharing and following to avoid frustrations within the relationship. PMID- 29154686 TI - A RETROSPECTIVE SUMMARY OF RAPTOR MORTALITY IN ONTARIO, CANADA (1991-2014), INCLUDING THE EFFECTS OF WEST NILE VIRUS. AB - The causes of mortality of free-ranging raptors range from anthropogenic (e.g., trauma) to dynamic environmental conditions that may affect habitat suitability and prey availability. The province of Ontario, Canada, is vulnerable to anthropogenic and environmental changes because of its northern latitudes and expanding human populations, both of which may impact wildlife. We retrospectively evaluated diagnostic data from raptors submitted to the Ontario/Nunavut node of the Canadian Wildlife Health Cooperative (CWHC) from 1991 to 2014 ( n=1,448). Submissions encompassed 29 species, most commonly the Red tailed Hawk ( Buteo jamaicensis; n=308) and Great Horned Owl ( Bubo virginianus; n=237). Trauma ( n=716) accounted for the majority of deaths among all species, followed by emaciation ( n=241). Traumatic deaths were most commonly attributed to collisions with stationary objects, and the odds of a diagnosis of trauma were significantly higher in adult versus immature raptors. The odds of being diagnosed with emaciation were significantly higher in males than in females but not in any age class or season. Mortality was less commonly attributed to infectious diseases ( n=214), for which West Nile virus (WNV) was the most common etiology, making up 53.1% of infectious diagnoses after its 2001 arrival in Ontario. The odds of a raptor being diagnosed with an infectious disease were significantly greater in summer and fall versus spring. Immature Red-tailed Hawks had significantly greater odds of being diagnosed with WNV compared to adults. These results reveal that human- and potentially environmentally-associated deaths (e.g., trauma and emaciation, respectively) are commonly diagnosed among Ontario raptors submitted to the CWHC. Infectious diseases are less commonly diagnosed, but WNV may have underlying, ongoing impacts on the health of some raptor species. PMID- 29154689 TI - Peripheral vagal nerve stimulation modulates the nociceptive withdrawal reflex in healthy subjects: A randomized, cross-over, sham-controlled study. AB - Introduction The mechanism of action of non-invasive vagal nerve stimulation in the treatment of migraine is elusive. We studied its effect in a human model of pain, the nociceptive withdrawal reflex. Methods We enrolled 10 healthy subjects who underwent active non-invasive vagal nerve stimulation and sham treatment in a randomized, cross-over, sham-controlled study. Non-invasive vagal nerve stimulation was delivered with gammaCore(r). The assessment of the nociceptive withdrawal reflex was performed at baseline (T0) and at 5 (T5) and 30 (T30) minutes after stimulation. Results Non-invasive vagal nerve stimulation significantly increased the reflex threshold to single stimulus at both T5 and T30 and the temporal summation threshold at T30. Sham treatment did not modify any parameters. Discussion These findings are consistent with a modulation of central descending pathways for pain control. An altered spinal and supraspinal control of pain has been described in primary headache, so this effect may partially explain the therapeutic effect of non-invasive vagal nerve stimulation. PMID- 29154688 TI - Substance Use and Cognitive Function as Drivers of Condomless Anal Sex Among HIV Positive Gay, Bisexual, and Other Men Who Have Sex with Men Aged 50 and Older: The Gold Studies. AB - PURPOSE: Substance use has been linked to the sexual transmission of HIV among gay, bisexual, and other men who have sex with men (MSM) across the lifespan. Among older, HIV-positive, MSM populations, cognitive dysfunction associated with age and HIV disease progression also may play a role in sexual risk-taking. People aged 50 years and older represent a growing proportion of the overall HIV positive population. This study aimed to explore relationships between substance use and cognitive function, and their impact on condomless anal sex (CAS) among HIV-positive gay, bisexual, and other MSM aged 50 years and older. METHODS: Data from a cross-sectional study of HIV-positive MSM, aged 50 and older (N = 169) were gathered using a computer-assisted survey, researcher-administered behavioral and neurocognitive measures. RESULTS: More than 50% of the men used substances and had one or more cognitive impairments. However, only 25% were at higher risk for dementia (i.e., two or more cognitive impairments). Multivariable modeling indicated that use of alcohol to intoxication and date of HIV diagnosis were the strongest predictors of CAS in both a model that included dementia risk and a model that included impaired executive function risk. Current illicit substance use was a significant predictor of CAS only in the model that included dementia risk. Those with better cognitive and executive function had higher odds of CAS. However, only executive function was a significant cognitive predictor of CAS. CONCLUSION: Further research is needed to clarify the impact of cognitive function and substance use on sexual risk behaviors as these HIV-positive men achieve normal life expectancies, while continuing to use substances and engage in CAS. Furthermore, addiction treatment remains a critical need for this group even as they transition into later adulthood. PMID- 29154690 TI - "What I Did for My Loved One Is More Important than Whether We Talked About Death": A Nationwide Survey of Bereaved Family Members. AB - BACKGROUND: Actions in preparation for death and talks about death between advanced cancer patients and their families are considered essential to achieve a good death. However, little is known about the prevalence of such actions compared with talks and their association with bereaved families' psychological morbidity. OBJECTIVE: To clarify the prevalence of bereaved families having acted in preparation for death and talked about death with their loved one, and to explore their associations with bereaved families' depression and complicated grief (CG). DESIGN: A nationwide survey. Setting/Subject: A total of 999 bereaved families of cancer patients admitted to 133 inpatient hospices in Japan. MEASUREMENTS: The prevalence of families' actions in preparation for and talks about death, Patient Health Questionnaire (PHQ)-9, and Brief Grief Questionnaire (BGQ). RESULTS: Among 678 bereaved families (response rate = 68%), 513 (76%) acted in preparation for death, and 315 (46%) talked about death with their loved one. Those who acted and talked were significantly less likely to suffer depression (PHQ-9 >= 10) than those who neither acted nor talked (odds ratio [OR], 0.405; 95% confidence interval [CI], 0.195-0.845; adjusted p = 0.016). Families who acted were significantly less likely to suffer complicated grief (CG; BGQ >=8), whether they talked (OR, 0.394; 95% CI, 0.185-0.84; adjusted p = 0.016) or not (OR, 0.421; 95% CI, 0.191-0.925; adjusted p = 0.031). CONCLUSIONS: Most families acted in preparation for death, and those who acted were less likely to suffer depression and CG. Clinicians may minimize families' later psychological morbidity by helping patients and families act in preparation for death. PMID- 29154687 TI - Pyruvate enhancement of cardiac performance: Cellular mechanisms and clinical application. AB - Cardiac contractile function is adenosine-5'-triphosphate (ATP)-intensive, and the myocardium's high demand for oxygen and energy substrates leaves it acutely vulnerable to interruptions in its blood supply. The myriad cardioprotective properties of the natural intermediary metabolite pyruvate make it a potentially powerful intervention against the complex injury cascade ignited by myocardial ischemia-reperfusion. A readily oxidized metabolic substrate, pyruvate augments myocardial free energy of ATP hydrolysis to a greater extent than the physiological fuels glucose, lactate and fatty acids, particularly when it is provided at supra-physiological plasma concentrations. Pyruvate also exerts antioxidant effects by detoxifying reactive oxygen and nitrogen intermediates, and by increasing nicotinamide adenine dinucleotide phosphate reduced form (NADPH) production to maintain glutathione redox state. These enhancements of free energy and antioxidant defenses combine to augment sarcoplasmic reticular Ca2+ release and re-uptake central to cardiac mechanical performance and to restore beta-adrenergic signaling of ischemically stunned myocardium. By minimizing Ca2+ mismanagement and oxidative stress, pyruvate suppresses inflammation in post-ischemic myocardium. Thus, pyruvate administration stabilized cardiac performance, augmented free energy of ATP hydrolysis and glutathione redox systems, and/or quelled inflammation in a porcine model of cardiopulmonary bypass, a canine model of cardiac arrest-resuscitation, and a caprine model of hypovolemia and hindlimb ischemia-reperfusion. Pyruvate's myriad benefits in preclinical models provide the mechanistic framework for its clinical application as metabolic support for myocardium at risk. Phase one trials have demonstrated pyruvate's safety and efficacy for intravenous resuscitation for septic shock, intracoronary infusion for heart failure and as a component of cardioplegia for cardiopulmonary bypass. The favorable outcomes of these trials, which argue for expanded, phase three investigations of pyruvate therapy, mirror findings in isolated, perfused hearts, underscoring the pivotal role of preclinical research in identifying clinical interventions for cardiovascular diseases. Impact statement This article reviews pyruvate's cardioprotective properties as an energy-yielding metabolic fuel, antioxidant and anti inflammatory agent in mammalian myocardium. Preclinical research has shown these properties make pyruvate a powerful intervention to curb the complex injury cascade ignited by ischemia and reperfusion. In ischemically stunned isolated hearts and in large mammal models of cardiopulmonary bypass, cardiac arrest resuscitation and hypovolemia, intracoronary pyruvate supports recovery of myocardial contractile function, intracellular Ca2+ homeostasis and free energy of ATP hydrolysis, and its antioxidant actions restore beta-adrenergic signaling and suppress inflammation. The first clinical trials of pyruvate for cardiopulmonary bypass, fluid resuscitation and intracoronary intervention for congestive heart failure have been reported. Receiver operating characteristic analyses show remarkable concordance between pyruvate's beneficial functional and metabolic effects in isolated, perfused hearts and in patients recovering from cardiopulmonary bypass in which they received pyruvate- vs. L-lactate-fortified cardioplegia. This research exemplifies the translation of mechanism-oriented preclinical studies to clinical application and outcomes. PMID- 29154691 TI - Optimal Screening Methods to Detect Cardiac Disorders in Athletes: An Evidence Based Review. AB - : Reference/Citation: Harmon KG, Zigman M, Drezner JA. The effectiveness of screening history, physical exam, and ECG to detect potentially lethal cardiac disorders in athletes: a systematic review/meta-analysis. J Electrocardiol. 2015;48(3):329-338. CLINICAL QUESTION: Which screening method should be considered best practice to detect potentially lethal cardiac disorders during the preparticipation physical examination (PE) of athletes? DATA SOURCES: The authors completed a comprehensive literature search of MEDLINE, CINAHL, Cochrane Library, Embase, Physiotherapy Evidence Database (PEDro), and SPORTDiscus from January 1996 to November 2014. The following key words were used individually and in combination: ECG, athlete, screening, pre-participation, history, and physical. A manual review of reference lists and key journals was performed to identify additional studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this review. STUDY SELECTION: Studies selected for this analysis involved (1) outcomes of cardiovascular screening in athletes using the history, PE, and electrocardiogram (ECG); (2) history questions and PE based on the American Heart Association recommendations and guidelines; and (3) ECGs interpreted following modern standards. The exclusion criteria were (1) articles not in English, (2) conference abstracts, and (3) clinical commentary articles. Study quality was assessed on a 7-point scale for risk of bias; a score of 7 indicated the highest quality. Articles with potential bias were excluded. DATA EXTRACTION: Data included number and sex of participants, number of true- and false-positives and negatives, type of ECG criteria used, number of cardiac abnormalities, and specific cardiac conditions. The sensitivity, specificity, false-positive rate, and positive predictive value of each screening tool were calculated and summarized using a bivariate random-effects meta-analysis model. MAIN RESULTS: Fifteen articles reporting on 47 137 athletes were fully reviewed. The overall quality of the 15 articles ranged from 5 to 7 on the 7-item assessment scale (ie, participant selection criteria, representative sample, prospective data with at least 1 positive finding, modern ECG criteria used for screening, cardiovascular screening history and PE per American Heart Association guidelines, individual test outcomes reported, and abnormal screening findings evaluated by appropriate diagnostic testing). The athletes (66% males and 34% females) were ethnically and racially diverse, were from several countries, and ranged in age from 5 to 39 years. The sensitivity and specificity of the screening methods were, respectively, ECG, 94% and 93%; history, 20% and 94%; and PE, 9% and 97%. The overall false-positive rate for ECG (6%) was less than that for history (8%) or PE (10%). The positive likelihood ratios of each screening method were 14.8 for ECG, 3.22 for history, and 2.93 for PE. The negative likelihood ratios were 0.055 for ECG, 0.85 for history, and 0.93 for PE. A total of 160 potentially lethal cardiovascular conditions were detected, for a rate of 0.3%, or 1 in 294 patients. The most common conditions were Wolff-Parkinson-White syndrome (n = 67, 42%), long QT syndrome (n = 18, 11%), hypertrophic cardiomyopathy (n = 18, 11%), dilated cardiomyopathy (n = 11, 7%), coronary artery disease or myocardial ischemia (n = 9, 6%), and arrhythmogenic right ventricular cardiomyopathy (n = 4, 3%). CONCLUSIONS: The most effective strategy to screen athletes for cardiovascular disease was ECG. This test was 5 times more sensitive than history and 10 times more sensitive than PE, and it had a higher positive likelihood ratio, lower negative likelihood ratio, and lower false-positive rate than history or PE. The 12-lead ECG interpreted using modern criteria should be considered the best practice in screening athletes for cardiovascular disease, and the use of history and PE alone as screening tools should be reevaluated. PMID- 29154692 TI - Landing Kinematics and Kinetics at the Knee During Different Landing Tasks. AB - CONTEXT: Several tasks have been used to examine landing biomechanics for evaluation and rehabilitation, especially as related to anterior cruciate ligament injuries. However, comparing results among studies in which different tasks were used can be difficult, and it is unclear which task may be most appropriate. OBJECTIVE: To compare lower extremity biomechanics across 5 commonly used landing tasks. DESIGN: Descriptive laboratory study. SETTING: University-operated US Air Force Special Operations Forces human performance research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 65 US Air Force Special Tactics Operators (age = 27.7 +/- 5.0 years, height = 176.5 +/- 5.7 cm, mass = 83.1 +/- 9.1 kg). INTERVENTION(S): Kinematic and kinetic analysis of double- and single-legged drop landing, double- and single-legged stop jump, and forward jump to single-legged landing. MAIN OUTCOME MEASURE(S): Hip-, knee-, and ankle-joint kinematics; knee-joint forces and moments; and ground reaction forces (GRFs) were the dependent measures. We used repeated-measures analyses of variance or Friedman tests, as appropriate, to assess within-subject differences across tasks. RESULTS: Peak vertical GRF and peak knee-flexion angle were different among all tasks ( P < .001). Single-legged landings generated higher vertical GRF (chi2 = 244.68, P < .001) and lower peak knee-flexion values ( F4,64 = 209.33, P < .001) except for forward jump to single-legged landing, which had the second highest peak vertical GRF and the lowest peak knee-flexion value. The single-legged drop landing generated the highest vertical (chi2 = 244.68, P < .001) and posterior (chi2 = 164.46, P < .001) GRFs. Peak knee-valgus moment was higher during the double-legged drop landing (chi2 = 239.63, P < .001) but similar for all others. CONCLUSIONS: Different landing tasks elicited different biomechanical responses; no single task was best for assessing a wide range of biomechanical variables related to anterior cruciate ligament injuries. Therefore, depending on the goals of the study, using multiple assessment tasks should be considered. PMID- 29154693 TI - Epidemiology of Injury Due to Race-Day Jockey Falls in Professional Flat and Jump Horse Racing in Ireland, 2011-2015. AB - CONTEXT: Professional horse racing is considered a high-risk sport, yet the last analysis of fall and injury incidence in this sport in Ireland was completed between 1999 and 2006. OBJECTIVE: To provide an updated analysis of the fall and injury incidence in professional flat and jump horse racing in Ireland from 2011 through 2015, compare it with the previous analysis, and detail the specific types and locations of injuries. DESIGN: Descriptive epidemiology study. SETTING: A medical doctor recorded all injuries that occurred at every official flat and jump race meeting for the 2011 through 2015 seasons using standardized injury-report forms. MAIN OUTCOME MEASURE(S): Injury and fall rates and their 95% confidence intervals (CIs) were reported for flat and jump racing. Incidence rate ratios and 95% CIs were calculated between flat and jump racing, between the 1999-2006 analysis and the current results, and between 2011 and 2015. The distribution of injuries for type and location of injury was reported. RESULTS: Compared with flat racing, jump racing had significantly more falls per 1000 rides (49.5 versus 3.8), injuries per 1000 rides (10.1 versus 1.4), and injuries per 1000 meetings (776.0 versus 94.1). However, the rate of injuries per 1000 falls was significantly higher in flat racing (352.8 versus 203.8). An increase in injuries per 1000 falls between 2011 and 2015 was found in flat racing ( P = .005). Since the previous analysis, a significant increase in injuries per 1000 rides and falls was noted in jump racing. Soft tissue injuries were predominant in flat and jump racing (61.54% and 68.80%, respectively), with fractures the second most common injury (15.38% and 18.06%, respectively). Concussions were more prevalent from flat-racing falls (incidence rate ratio = 0.30; 95% CI = 0.15, 0.61). The lower limb was the most frequent location of injury (32.89%) in flat racing; however, in jump racing, upper limb injuries (34.97%) were predominant. CONCLUSIONS: An update on professional flat- and jump-racing fall and injury epidemiology is provided. Further research to identify risk factors for injury, design and investigate the feasibility of injury-prevention strategies, and document their effects on fall and injury incidence is required. PMID- 29154694 TI - Gait and Quiet-Stance Performance Among Adolescents After Concussion-Symptom Resolution. AB - CONTEXT: Concussions affect a large number of US athletes each year. Returning an athlete to activity once self-reported symptoms have resolved can be problematic if unrecognized neurocognitive and balance deficits persist. Pairing cognitive and motor tasks or cognitive and quiet-stance tasks may allow clinicians to detect and monitor these changes postconcussion. OBJECTIVE: To prospectively examine adolescent athletes' gait and quiet-stance performance while concurrently completing a cognitive task acutely after concussion and after symptom resolution. DESIGN: Case-control study. SETTING: Sport concussion clinic. PATIENTS OR OTHER PARTICIPANTS: Thirty-seven athletes (age = 16.2 +/- 3.1 years; 54% female) were diagnosed with a concussion, and their performance was compared with that of a group of 44 uninjured control participants (age = 15.0 +/- 2.0 years; 57% female). INTERVENTION: Participants diagnosed with a concussion completed a symptom inventory and single- and dual-task gait and quiet stance evaluations within 21 days of injury and then again after symptom resolution. Gait and postural-control measurements were quantified using an inertial sensor system and analyzed using multivariate analyses of covariance. MAIN OUTCOME MEASURE(S): Post-Concussion Symptom Scale, single-task and dual task gait measures, quiet-stance measures, and cognitive task performance. RESULTS: At the initial postinjury examination, single-task gait stride length (1.16 +/- 0.14 versus 1.25 +/- 0.13 m, P = .003) and dual-task gait stride length (1.02 +/- 0.13 m versus 1.10 +/- 0.13 m, P = .011) for the concussion group compared with the control group, respectively, were shorter. After symptom resolution, no single-task gait differences were found, but the concussion group demonstrated slower gait velocity (0.78 +/- 0.15 m/s versus 0.92 +/- 0.14 m/s, P = .005), lower cadence (92.5 +/- 12.2 steps/min versus 99.3 +/- 7.8 steps/min, P < .001), and a shorter stride length (0.99 +/- 0.15 m versus 1.10 +/- 0.13 m, P = .003) during dual-task gait than the control group. No between-groups differences were detected during quiet stance at either time point. CONCLUSIONS: Acutely after concussion, single-task and dual-task stride-length alterations were present among youth athletes compared with a control group. Although single-task gait alterations were not detected after symptom resolution, dual-task gait differences persisted, suggesting that dual-task gait alterations may persist longer after concussion than single-task gait or objective quiet-stance alterations. Dual-task gait assessments may, therefore, be a useful component in monitoring concussion recovery after symptom resolution. PMID- 29154695 TI - An Evaluation of Portable Wet Bulb Globe Temperature Monitor Accuracy. AB - CONTEXT: Wet bulb globe temperature (WBGT) is the gold standard for assessing environmental heat stress during physical activity. Many manufacturers of commercially available instruments fail to report WBGT accuracy. OBJECTIVE: To determine the accuracy of several commercially available WBGT monitors compared with a standardized reference device. DESIGN: Observational study. SETTING: Field test. PATIENTS OR OTHER PARTICIPANTS: Six commercially available WBGT devices. MAIN OUTCOME MEASURE(S): Data were recorded for 3 sessions (1 in the morning and 2 in the afternoon) at 2-minute intervals for at least 2 hours. Mean absolute error (MAE), root mean square error (RMSE), mean bias error (MBE), and the Pearson correlation coefficient ( r) were calculated to determine instrument performance compared with the reference unit. RESULTS: The QUESTemp degrees 34 (MAE = 0.24 degrees C, RMSE = 0.44 degrees C, MBE = -0.64%) and Extech HT30 Heat Stress Wet Bulb Globe Temperature Meter (Extech; MAE = 0.61 degrees C, RMSE = 0.79 degrees C, MBE = 0.44%) demonstrated the least error in relation to the reference standard, whereas the General WBGT8778 Heat Index Checker (General; MAE = 1.18 degrees C, RMSE = 1.34 degrees C, MBE = 4.25%) performed the poorest. The QUESTemp degrees 34 and Kestrel 4400 Heat Stress Tracker units provided conservative measurements that slightly overestimated the WBGT provided by the reference unit. Finally, instruments using the psychrometric wet bulb temperature (General, REED Heat Index WBGT Meter, and WBGT-103 Heat Stroke Checker) tended to underestimate the WBGT, and the resulting values more frequently fell into WBGT based activity categories with fewer restrictions as defined by the American College of Sports Medicine. CONCLUSIONS: The QUESTemp degrees 34, followed by the Extech, had the smallest error compared with the reference unit. Moreover, the QUESTemp degrees 34, Extech, and Kestrel units appeared to offer conservative yet accurate assessments of the WBGT, potentially minimizing the risk of allowing physical activity to continue in stressful heat environments. Instruments using the psychrometric wet bulb temperature tended to underestimate WBGT under low wind-speed conditions. Accurate WBGT interpretations are important to enable clinicians to guide activities in hot and humid weather conditions. PMID- 29154696 TI - Applied Machine Learning Method to Predict Children With ADHD Using Prefrontal Cortex Activity: A Multicenter Study in Japan. AB - OBJECTIVE: To establish valid, objective biomarkers for ADHD using machine learning. METHOD: Machine learning was used to predict disorder severity from new brain function data, using a support vector machine (SVM). A multicenter approach was used to collect data for machine learning training, including behavioral and physiological indicators, age, and reverse Stroop task (RST) data from 108 children with ADHD and 108 typically developing (TD) children. Near-infrared spectroscopy (NIRS) was used to quantify change in prefrontal cortex oxygenated hemoglobin during RST. Verification data were from 62 children with ADHD and 37 TD children from six facilities in Japan. RESULTS: The SVM general performance results showed sensitivity of 88.71%, specificity of 83.78%, and an overall discrimination rate of 86.25%. CONCLUSION: A SVM using an objective index from RST may be useful as an auxiliary biomarker for diagnosis for children with ADHD. PMID- 29154697 TI - Rate of Subtalar Joint Arthrodesis After Retrograde Tibiotalocalcaneal Arthrodesis With Intramedullary Nail Fixation: Evaluation of the RAIN Database. AB - BACKGROUND: Hindfoot arthritis or significant deformity involving the ankle and subtalar joint (STJ) is a disabling condition with few salvage options. Many surgeons note a decreased STJ fusion rate compared with ankle union when a retrograde nail construct is used. The purpose of this study was to report the STJ fusion rate of tibiotalocalcaneal (TTC) arthrodesis with retrograde nail. METHODS: A chart and radiographic review was performed. TTC fusions performed in patients with osteoarthritis, posttraumatic arthritis, or deformity correction with retrograde nail fixation were included. Exclusion criteria included neuropathy, Charcot arthropathy, and failed total ankle replacement. RESULTS: Ultimately, 66 retrograde TTC fusions (in 63 patients) met inclusion criteria. The average age was 57.0 years. There were 29 female and 34 male patients. Radiographic fusion of the ankle and STJ was demonstrated in 68.2% of the patients. There were 11 cases (16.7%) of ankle arthrodesis with STJ nonunion, 6 cases (9.1%) of STJ fusion but ankle nonunion, and 4 cases (6.1%) of stable radiographic nonunion of both joints. The mean time to subtalar fusion was 112.1 days. One patient required revision surgery and conversion to below-knee amputation. One patient required a CROW walker for assistance with gait. CONCLUSION: A 22.8% radiographic nonunion rate of the STJ was noted in retrograde TTC fusion. Despite this, patients were stable and pain free. LEVELS OF EVIDENCE: Level IV: Retrospective Case series. PMID- 29154698 TI - Phacoemulsification of bilateral mature cataracts in a Texas rat snake (Elaphe obsoleta lindheimeri). AB - CASE DESCRIPTION A 10-year-old sexually intact male client-owned Texas rat snake (Elaphe obsoleta lindheimeri) was referred for evaluation because of a 5-month history of progressive bilateral ocular opacities and abnormal behavior. CLINICAL FINDINGS On ophthalmic examination, the snake had bilateral mature cataracts and uveal cysts. No additional ophthalmic or physical abnormalities were detected. Results of CBC, serum biochemical analysis, and ocular ultrasonography were unremarkable. TREATMENT AND OUTCOME Bilateral spectaculotomy was performed, followed by bilateral phacoemulsification and uveal cyst aspiration, without complication. Histologic evaluation of the phacoemulsified lens material revealed only nonspecific findings associated with cataractogenesis. Vision was restored and the abnormal behaviors resolved after cataract surgery. Long-term follow-up examination performed 60 weeks after surgery revealed no additional ocular or physical abnormalities. CLINICAL RELEVANCE The ocular anatomic and physiologic characteristics of snakes can pose intraoperative and postoperative challenges to phacoemulsification, but the outcome achieved for this surgical case suggested that successful cataract surgery is possible in these species. This case further demonstrated that cataracts may be associated with reversible behavioral abnormalities in captive snakes. PMID- 29154699 TI - Animal Behavior Case of the Month. PMID- 29154701 TI - Minimally invasive treatment of mesenteric arterioportal fistulas in two dogs. AB - CASE DESCRIPTION Two Pembroke Welsh Corgis with gastrointestinal signs including inappetence, diarrhea, lethargy, and hypersalivation were referred for evaluation. CLINICAL FINDINGS Diagnostic testing included abdominal ultrasonography and CT angiography. One patient had a cranial mesenteric artery to-mesenteric vein fistula with multiple acquired extrahepatic portosystemic shunts. The second patient had both cranial and caudal mesenteric artery-to mesenteric vein fistulas and multiple acquired extrahepatic portosystemic shunts. TREATMENT AND OUTCOME Both patients underwent minimally invasive coil embolization of the mesenteric arterioportal fistulas, with complete occlusion confirmed by means of angiography at procedure completion. Clinical outcome approximately 1 year after treatment was assessed as fair to good because of recurrence of clinical signs that required medical management in 1 dog and some persistent serum biochemical abnormalities. CLINICAL RELEVANCE Outcome for the 2 patients described suggested that coil embolization may be a feasible and effective minimally invasive technique for the treatment of mesenteric arterioportal fistulas in dogs. However, further investigation of the potential for chronic hepatic disease in patients with a history of acquired portosystemic shunts is warranted. PMID- 29154703 TI - Diagnostic Imaging in Veterinary Dental Practice. PMID- 29154704 TI - Enhancing our commitment to wellness, diversity, and inclusion in the veterinary profession. PMID- 29154705 TI - Compendium of Measures to Prevent Disease Associated with Animals in Public Settings, 2017. PMID- 29154706 TI - Pathology in Practice. PMID- 29154707 TI - Objective evaluation of the systemic effects of topical application of 1% atropine sulfate ophthalmic solution in healthy horses. AB - OBJECTIVE To determine the safety of topical administration of 1% atropine ophthalmic solution in healthy horses by objectively measuring gastrointestinal transit time. DESIGN Randomized, masked, controlled crossover study. ANIMALS 6 adult geldings. PROCEDURES Horses were randomly assigned (3/group) to first receive topical treatment of the left eye with 1% atropine or artificial tears solution; the right eye was left untreated. After 24 hours of treatment every 6 hours, 200 nontoxic beads were administered to each horse via nasogastric intubation and treatment frequency was decreased to every 12 hours for 4 more days. Pupillary light reflexes (PLRs), mydriasis, heart rate, fecal bead passage, abdominal girth measurements, auscultable gut sounds, fecal weight, and clinical signs of abdominal pain were monitored. Following a 4-week washout period, horses received the opposite treatment in the left eye and measurements were repeated. Serum atropine concentration (reflecting systemic absorption) was measured with an ELISA at various points after initial atropine administration. RESULTS No horse had subjective or objective evidence of colic or ileus at any monitoring point. Complete mydriasis of the left eye with absence of the PLR was identified in 5 horses within 6 hours and in all 6 horses within 12 hours after initial atropine administration. One horse had mydriasis with an absent PLR in the untreated eye by day 5 of atropine treatment. At no point was atropine detected in serum samples of any horse. CONCLUSIONS AND CLINICAL RELEVANCE Topical atropine application at clinically appropriate doses induced no evidence of ileus in healthy horses. PMID- 29154708 TI - Urethral diverticulum and urolithiasis in a female guinea pig (Cavia porcellus). AB - CASE DESCRIPTION A 5-year-old sexually intact female guinea pig was evaluated because of mild dysuria and a subcutaneous mass located cranioventral to the urogenital openings. CLINICAL FINDINGS Non-contrast-enhanced CT and surgical exploration of the distal aspect of the urethra revealed a urethral diverticulum with an intraluminal urolith. Analysis revealed that the urolith was composed of calcium carbonate and struvite. TREATMENT AND OUTCOME The urolith was surgically removed and ablation of the urethral diverticulum was attempted. Approximately 3 months later, the guinea pig was reevaluated for masses in the perineal region, and positive-contrast urethrocystography revealed 2 uroliths present in the same diverticulum. Uroliths were manually expressed with the patient under general anesthesia. Approximately 2 weeks later, urethroplasty was performed to create an enlarged stoma with the diverticulum, thereby preventing urine from pooling in the diverticulum and potentially reducing the risk of future urolith formation. The urethroplasty site healed well with no reported complications or evidence of urolith recurrence 6 months after surgery. CLINICAL RELEVANCE Urolithiasis is common in guinea pigs, and urethral diverticulum and intraluminal urolith formation should be considered as a potential differential diagnosis for a subcutaneous mass along the distal aspect of the urethra. Creation of a urethral stoma from a urethral diverticulum via urethroplasty achieved a successful outcome in this patient. PMID- 29154709 TI - What Is Your Diagnosis? PMID- 29154710 TI - Pathology in Practice. PMID- 29154711 TI - Recognizing, describing, and managing reduced food intake in dogs and cats. PMID- 29154712 TI - Prognosis for dogs with stage III osteosarcoma following treatment with amputation and chemotherapy with and without metastasectomy. AB - OBJECTIVE To determine survival times of selected dogs with metastatic (stage III) osteosarcoma, whether disease-free interval (DFI) was associated with survival time after diagnosis of stage III disease (ie, stage III survival time), and whether a survival benefit of metastasectomy existed. DESIGN Retrospective case series with nested cohort study. ANIMALS 194 client-owned dogs treated for histologically confirmed appendicular osteosarcoma from 1997 through 2009. PROCEDURES Dogs were included if they had stage I or II osteosarcoma at the time of initial evaluation, had amputation of the affected appendage and >= 1 dose of chemotherapy afterward, and developed metastasis within the follow-up period or prior to death. Data collected from the medical records included signalment, primary tumor location, clinical and laboratory findings, whether metastasectomy was performed, and outcome. Various factors were examined for associations with outcome. RESULTS Dogs that received no treatment for the metastasis had a median survival time between 49 and 57 days after diagnosis of stage III osteosarcoma. Duration of the preceding DFI had no association with this period. Metastasectomy alone was associated with a longer median stage III survival time (232 days) than no metastasectomy (49 days). Among all dogs identified as qualifying for pulmonary metastasectomy on the basis of < 3 pulmonary nodules visible on thoracic radiographs and a DFI > 275 days (n = 21), a survival advantage was also identified for those that actually received pulmonary metastasectomy (6). CONCLUSIONS AND CLINICAL RELEVANCE Preceding DFI had no influence on survival time of dogs with stage III osteosarcoma. Metastasectomy was associated with an increase in survival time for selected dogs. PMID- 29154713 TI - Sex Differences in the Psychometric Properties of the Pittsburgh Sleep Quality Index. AB - BACKGROUND: The Pittsburgh Sleep Quality Index (PSQI) is a well-known, validated, and reliable instrument used to measure the clinical construct of sleep quality. Little research has been done to measure its psychometric properties by sex. Previous researchers have established the validity of a three-factor structure, but it is unknown whether it applies to both men and women equally. MATERIALS AND METHODS: This study examined 198 participants; women (n = 104), men (n = 94) who were participants in the Diabetes Sleep Treatment Trial, an ongoing study examining the effect of continuous positive airway pressure on glycemic control in people with type 2 diabetes. A principal components analysis with varimax rotation, scree plots, parallel analysis, and Eigenvalues confidence intervals were all computed to determine factor structure using the seven components measured in the PSQI. RESULTS: Component one, a question about perceived sleep quality, loaded with "sleep efficiency" and "sleep duration" in men and with "daytime dysfunction" and "sleep disturbances" in women. CONCLUSION: This study confirms a three-factor structure as previously suggested; however, "perceived sleep quality" may load differently depending on the sex being examined. This result suggests that men and women may interpret what is meant by "overall sleep quality" differently. PMID- 29154715 TI - Virulence and Antibiotic Resistance of Vibrio parahaemolyticus Isolates from Seafood from Three Developing Countries and of Worldwide Environmental, Seafood, and Clinical Isolates from 2000 to 2017. AB - Vibrio parahaemolyticus is a leading cause of seafood-associated illness. This study investigated the prevalence, virulence, and antibiotic resistance of V. parahaemolyticus in three low- and middle-income countries. Freshly caught fish samples (n = 330) imported to Jordan from Yemen, India, and Egypt were tested. The overall prevalence of V. parahaemolyticus was 15% (95% confidence interval: 11 to 19%). Three isolates (6%) were positive for the thermostable direct hemolysin-related (trh) gene, and all isolates was negative for the thermostable direct hemolysin (tdh) gene. All isolates were resistant to colistin sulfate, neomycin, and kanamycin, and 51 and 43% of isolates were resistant to tetracycline and ampicillin, respectively. Only 4% of the isolates were resistant to cefotaxime and chloramphenicol, and no isolates were resistant to sulfamethoxazole-trimethoprim, streptomycin, gentamicin, ciprofloxacin, and nalidixic acid. All isolates were resistant to two classes of antibiotics, and 86% were multidrug resistant (resistant to at least one drug in three or more classes of antibiotics). A literature review of clinical, seafood, and environmental V. parahaemolyticus isolates worldwide revealed high rates of gentamicin and ampicillin resistance, emerging resistance to third-generation cephalosporins, and limited resistance to sulfamethoxazole-trimethoprim, ciprofloxacin, nalidixic acid, and chloramphenicol. Thus, last-resort antibiotics could be ineffective for treating V. parahaemolyticus infections. Several global reports also documented illness outbreaks in humans caused by trh- and tdh negative V. parahaemolyticus strains. More research is needed to determine whether the presence of these genes is sufficient to classify the strains as virulent. PMID- 29154714 TI - Improving Measures of Sexual and Gender Identity in English and Spanish to Identify LGBT Older Adults in Surveys. AB - PURPOSE: The goal of this research is to advance the study of health disparities faced by older sexual and gender minorities by assessing comprehension of and improving measures of sexual and gender identity in surveys. METHODS: Cognitive interviews were conducted by expert interviewers with 48 non-lesbian, gay, bisexual, and transgender (non-LGBT) and 9 LGBT older English and Spanish speakers. RESULTS: All respondents were able to answer questions about their sex assigned at birth and current gender identity successfully despite some cisgender respondents' lack of clear understanding of the transgender response option. On the contrary, while the vast majority of English speakers could answer the question about their sexual identity successfully, almost 60% of the non-LGBT Spanish speakers did not select the "heterosexual, that is, not gay (or lesbian)" response category. Qualitative probing of their response process pointed mainly to difficulties understanding the term "heterosexual," leading to their choosing "something else" or saying that they didn't know how to answer. A second round of testing of alternative response categories for the sexual identity question with Spanish speakers found a marked improvement when offered "not gay (or lesbian), that is, heterosexual" instead of beginning with the term "heterosexual." CONCLUSION: This research adds to our understanding of gender and sexual identity questions appropriate for population surveys with older adults. Inclusion of these measures in surveys is a crucial step in advancing insights into the needs of and disparities faced by LGBT older adults. PMID- 29154716 TI - Occurrence of Toxigenic Fungi and Mycotoxins during Smoked Paprika Production. AB - 'La Vera' smoked paprika is a traditional Spanish product regulated under a protected designation of origin. Mycotoxins are possible contaminants in paprika, yet there is little information about mycotoxin production during the processing of smoked paprika. In this study, samples of dried peppers collected from six traditional dryers from four producers were evaluated for physicochemical parameters, mycotoxins, and mycotoxin-producing fungi. The moisture content and water activity of the peppers ranged from 11.0 to 16.3% and 0.513 to 0.611, respectively, with significant differences among the dryers (P <= 0.05). Culture methods revealed fungal counts of 2.6 to 5.7 log CFU/g, with significant differences among the dryers (P <= 0.05), and real-time PCR revealed aflatoxin producing fungi (2.00 to 3.42 log CFU/g) in all dryers. However, mycotoxins were not detected in dried pepper samples. Sixty-seven mold species isolated from dried peppers were identified by sequencing of the ITS1-5.8S rRNA-ITS2 region and characterized by mycotoxigenic ability. Four isolates of Penicillium expansum, four isolates of Penicillium thomii, and one isolate of Aspergillus parasiticus were producers of patulin, penicillic acid, and aflatoxins, respectively. Toxigenic fungi were inoculated onto smoked dried peppers and stored at 84, 91, 94, and 97% relative humidity (RH) at 20 degrees C for 30 days. Patulin was not detected under any of these conditions. Penicillic acid was detected in dried samples stored at 91 to 97% RH, although the optimum condition was isolate dependent. Aflatoxins G2, B1, and B2 were detected at 91 to 97% RH, with the highest concentrations at 94% RH. According to our results, hazard analysis critical control point systems should be used to control the drying and storage conditions of dried peppers until the milling step to avoid rehydration, which encourages fungal growth and mycotoxin production. PMID- 29154717 TI - Characterization of Escherichia coli and Salmonella from Victoria, Australia, Dairy Farm Environments. AB - Safe dairy food production starts at the farm level, with the presence of pathogens on farms potentially impacting the downstream food supply. Studies often commence with looking for pathogens in fecal material of farm animals, predominantly cows; however, pathogens may arise from other on-farm sources. In Australia, few studies have looked at the broader farm environment, particularly in relation to Escherichia coli and Salmonella. The present study characterized the genetic similarity of these pathogens from bovine, ovine, and caprine dairy farm environments and related this to the stx1, stx2, eae, or ehx virulence markers in E. coli and antibiotic resistance in Salmonella. E. coli isolates with indistinguishable genetic profiles and at least one of the virulence factors were found in multiple samples on the farms, although profiles were unique to each farm. E. coli O26 with stx1 from one bovine farm had a different fingerprint type than all of the other E. coli O26 isolates, which lacked the Shiga toxin genes. They were from a separate bovine farm and were themselves closely related. No antibiotic resistance was detected among Salmonella isolates to the 17 antibiotics tested. Three Salmonella serotypes were identified: Orion, Infantis, and Zanzibar. The published PCR serotyping method used misidentified Salmonella Zanzibar as Salmonella Javiana, which was revealed after conventional antisera based serotyping; this illustrates the need for caution when using PCR techniques for Salmonella serotype identification. Of the three serotypes, Salmonella Orion was most prevalent and was potentially resident on the farm. This article describes the previously unreported genetic diversity of potentially pathogenic E. coli and Salmonella serotypes from the farm environments of three dairy animal species in Victoria, Australia. PMID- 29154718 TI - Pesticide Residues in Food: Attitudes, Beliefs, and Misconceptions among Conventional and Organic Consumers. AB - Pesticide use and pesticide residues in foods have been the subject of controversial public discussions and media coverage in Germany. Against this background, a better understanding of public risk perceptions is needed to promote efficient public health communication. To this end, this study captures the German public's perception of pesticide residues in foods. A representative sample of the population aged 14 years and older (n = 1,004) was surveyed via computer-assisted telephone interviewing on their attitudes and knowledge with regard to pesticide residues. Based on questions regarding their typical consumer behavior, respondents were classified into conventional and organic consumers to identify differences as well as similarities between these two consumer types. As assessed with an open-ended question, both organic and conventional consumers viewed pesticides, chemicals, and toxins as the greatest threats to food quality and safety. Evaluating the risks and benefits of pesticide use, more than two thirds of organic consumers (70%) rated the risks as greater than the benefits, compared with just over one-half of conventional consumers (53%). Concern about the detection of pesticide residues in the food chain and bodily fluids was significantly higher among organic compared with conventional consumers. Only a minority of respondents was aware that legal limits for pesticide residues (referred to as maximum residue levels) exist, with 69% of organic and 61% of conventional consumers believing that the presence of pesticide residues in foods is generally not permitted. A lack of awareness of maximum residue levels was associated with heightened levels of concern about pesticide residues. Finally, general exposure to media reporting on pesticide residues was associated with more frequent knowledge of legal limits for pesticide residues, whereas actively seeking information on pesticide residues was not. The possible mechanisms underlying these findings are discussed. PMID- 29154719 TI - Effect of Citrus reticulata Blanco Essential Oil on Cryptolestes ferrugineus (Stephens) Adults. AB - The rusty grain beetle, Cryptolestes ferrugineus (Stephens), is a major insect pest of stored products worldwide. In an effort to manage populations of C. ferrugineus in stored grains, the essential oil from Citrus reticulata Blanco peel was prepared by the Soxhlet method with anhydrous diethyl ether, and its contact activity, repellent activity, and fumigant activity were investigated against C. ferrugineus adults. C. reticulata peel essential oil had potent contact, repellent, and fumigant activity against C. ferrugineus adults, with activity significantly increasing with increasing exposure dosage during the same exposure time. Percent repellency values achieved >80.0% after 60 h of exposure. For contact toxicity, the corrected mortality of C. ferrugineus adults reached >99.0% after 48 h of exposure at the dosage of 2.0 MUL/cm2. For fumigant toxicity, the corrected mortality of C. ferrugineus adults reached 89.0 and 100.0% at the dosages of 40 and 80 MUL/L of air, respectively. These results suggest that the C. reticulata peel essential oil has strong potential for managing populations of C. ferrugineus in practice. PMID- 29154720 TI - A Crack in the Wall of Competition: Will Compassion Prevail? PMID- 29154721 TI - Validating the use of brain volume cutoffs to identify clinically relevant atrophy in RRMS. AB - BACKGROUND: Baseline brain volume (BV) is predictive at a group level but is difficult to interpret at the single patient level. OBJECTIVE: To validate BV cutoffs able to identify clinically relevant atrophy in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: The expected normalized brain volume (NBV) for each patient was calculated using RRMS patients from two phase III clinical trials, applying a linear formula developed on the baseline variable of an independent data set. The difference between these expected NBV values and those actually observed was calculated and used to categorize the patients in the low-NBV, medium-NBV, and high-NBV groups. RESULTS: The 2-year probability of 3 month confirmed disability worsening was significantly associated with the NBV categorization ( p = 0.006), after adjusting for treatment effect. Taking the high-NBV group as a reference, the hazard ratios for the medium-NBV and low-NBV groups were 1.22 (95% confidence interval (CI): 0.85-1.76, p = 0.27) and 1.69 (95% CI: 1.11-2.57, p = 0.01), respectively. CONCLUSION: This study validates the use of BV cutoffs to identify clinically relevant atrophy in RRMS study by showing that the three groups classified according to the baseline NBV adjusted for the other prognostic variables have a significant prognostic impact on the risk of disability progression. PMID- 29154723 TI - Evaluating rehabilitation: An ongoing challenge. PMID- 29154722 TI - Association of Kidney Function and Waist Circumference with Uric Acid Levels in South Africans. AB - BACKGROUND: Recent evidence that hyperuricemia is associated with incident chronic kidney disease (CKD) provides a potential therapeutic target for CKD that has not been explored in Africans. With hyperuricemia and gout increasing globally, we sought to determine their prevalence in South Africans with varying kidney function levels. METHODS: This was a cross-sectional study of ambulatory adult patients presenting at a General Internal Medicine Outpatients Clinic between September 2012 and March 2014. Demographic, clinical, and laboratory data collected were analyzed using STATA11. Odds ratios (ORs) and 95% confidence intervals were determined using multivariable logistic regression with bootstrapping. RESULTS: There were 225/261 (86.2%) black/Africans, 31/261 (11.9%) Indian South Africans, 3/261 (1.1%) Caucasians, and 2/261 (<1%) mixed ancestry South Africans. Mean age was 51.3 +/- 14.5 years. Median (interquartile range) estimated glomerular filtration rate (eGFR) was 71 (38) mL/min/1.73 m2 and 39.8% (104/261) of patients had CKD. Hyperuricemia prevalence was 43.7% (114/261) and increased from 16.7% in patients with eGFR >=90 mL/min/1.73 m2 to 74.2% with eGFR <30 mL/min/1.73 m2 (P < 0.001). Gout prevalence was 5.4% (14/261), with equal distribution across eGFR categories (0.814). Factors independently associated with hyperuricemia were eGFR <90 [ORs 3.24 (1.15-9.14), 7.28 (2.26-23.49), and 7.88 (1.95-31.82) for eGFR 60-89.9, 30-60, and <30, respectively], albuminuria [2.32 (1.11-4.85)], and waist circumference [1.04 (1.01-1.06) per 1 cm increase]. In univariate and multivariable analysis, gout was positively associated with male gender and cardiovascular disease, while it was negatively associated with African ancestry, but none of these factors remained significant after bootstrapping; ORs 6.65 (0.64-69.24), 4.14 (0.61-28.07), and 0.18 (0.01-2.21), respectively. CONCLUSION: Hyperuricemia prevalence was high, with CKD and waist circumference being the strongest predictors. Gout was uncommon in black Africans. With population data lacking, screening high-risk individuals may provide insight into the burden of hyperuricemia and gout in South Africa. PMID- 29154724 TI - Understanding how a palliative-specific patient-reported outcome intervention works to facilitate patient-centred care in advanced heart failure: A qualitative study. AB - BACKGROUND: Palliative care needs of patients with chronic heart failure are poorly recognised. Policy makers advise a patient-centred approach to holistically assess patients' needs and care goals. Patient-reported outcome measures are proposed to facilitate patient-centred care. AIM: To explore whether and how a palliative care-specific patient-reported outcome intervention involving the Integrated Palliative care Outcome Scale influences patients' experience of patient-centred care in nurse-led chronic heart failure disease management clinics. DESIGN: A feasibility study using a parallel mixed-methods embedded design was undertaken. The qualitative component which examined patients and nurses experience of the intervention is reported here. Semi-structured interviews were conducted and analysed using framework analysis. SETTING/PARTICIPANTS: Eligible patients attended nurse-led chronic heart failure disease management clinics in two tertiary referral centres in Ireland with New York Heart Association functional class II-IV. Nurses who led these clinics were eligible for inclusion. RESULTS: In all, 18 patients and all 4 nurses involved in the nurse-led clinics were interviewed. Three key themes were identified: identification of unmet needs, holistic assessment and patient empowerment. The intervention impacted on processes of care by enabling a shared understanding of patients' symptoms and concerns, facilitating patient-nurse communication by focusing on these unmet needs and empowering patients to become more involved in clinical discussions. CONCLUSION: This Integrated Palliative care Outcome Scale based intervention empowered patients to become more engaged in the clinical consultation and to highlight their unmet needs. This study adds to the evidence for the mechanism of action of patient-reported outcome measures to improve patient-centred care and will help inform outcome selection for future patient reported outcome measure research. PMID- 29154725 TI - Non-aneurysmal subarachnoid hemorrhage: When is a second angiography indicated? AB - Purpose Repeat imaging in patients with non-aneurysmal subarachnoid hemorrhage (NASAH) remains controversial. We aim to report our experience with NASAH with different hemorrhage patterns, and to investigate the need for further diagnostic workup to determine the underlying cause of hemorrhage. Method We conducted a retrospective analysis of all spontaneous SAH with an initial negative computed tomography (CT) with angiography (CTA) and/or digital subtraction angiography (DSA) from October 2011 through May 2017. According to the bleeding pattern on the admission CT scan, NASAH was divided into two subgroups: (1) perimesencephalic SAH (PMSAH) and (2) non-perimesencephalic SAH (nPMSAH). Radiological data included the admission CT, CTA, DSA, and magnetic resonance imaging (MRI) with angiography (MRA). Results Seventy-four patients met the inclusion criteria. Thirty-nine (52.7%) patients had PMSAH on the initial CT scan, and 35 (47.3%) had nPMSAH. All underwent CTA and/or DSA revealing no vascular abnormalities. Forty-seven (63.5%) patients underwent subsequent diagnostic workup. DSA was performed in all patients at least once. No abnormalities were found on the repeat DSA or other radiological follow-up studies except in one (1.4%) patient with nPMSAH, in whom a follow-up DSA revealed a small saccular anterior choroidal artery aneurysm, considered to be the source of hemorrhage. Conclusion A repeat DSA may not be needed in case of PMSAH, if the initial negative DSA is technically adequate with absence of hematoma and vasospasm. In contrast, a follow-up DSA should be mandatory for confirming or excluding vascular pathology in case of nPMSAH in order to prevent rebleeding. PMID- 29154726 TI - Comparison of Apolipoprotein (ApoB/ApoA-1) and Lipoprotein (Total Cholesterol/HDL) Ratios in Obese Adolescents. AB - BACKGROUND: Serum (ApoB/ApoA-1) ratio is considered a stronger predictor of systemic inflammation and atherosclerosis than serum total cholesterol/HDL (TC/HDL) ratio among adults. We evaluated the relationships between ApoB/ApoA-1 and TC/HDL ratios with surrogate markers of inflammation and insulin resistance (IR) among obese adolescents. METHODS: Body mass index z-score (BMI-z), body composition, fasting glucose, insulin, lipids, high-sensitive c-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), and homeostatic model assessment for insulin resistance (HOMA-IR) were evaluated in 143 obese adolescents. RESULTS: Male subjects had higher BMI-SDS, fat-free mass (FFM), and glucose than female subjects (P < 0.01). Furthermore, 54.5% met diagnostic criteria for metabolic syndrome (MS) and displayed higher SBP, BMI-SDS, fat mass (FM), HOMA-IR, hs-CRP, TG, TC/HDL, TG/HDL, ApoB/ApoA-1, and HbA1c, but lower HDL and ApoA-1 than the non MS group (P < 0.05) with similar gender distribution. In the entire cohort, TC/HDL and ApoB/ApoA-1 ratios were strongly correlated (r = 0.81, P < 0.0001). Receiver operating characteristic analysis indicated that the area under the curve in MS subjects for ApoB/ApoA-1 and TC/HDL-C ratios was not statistically different. ApoB/ApoA-1 and TC/HDL-C ratios were positively correlated with SBP (r = 0.29; P = 0.0004) and (r = 0.43; P < 0.0001), respectively. Finally, ApoB/ApoA 1 and TC/HDL-C ratios were correlated with hs-CRP (r = 0.21; P = 0.014) and (r = 0.26; P = 0.0016), respectively. However, the relationships between ApoB/ApoA-1 and TC/HDL ratios with HOMA-IR were not statistically significant. CONCLUSIONS: Unlike in the adult population, serum ApoA-1, ApoB, and ApoB/ApoA-1 ratio may not have significant advantage over conventional lipoproteins in evaluating the presence of systemic inflammation, MS, and risk of atherosclerosis in obese adolescents. PMID- 29154727 TI - Time is vision: The importance of the early discovery and diagnosis of optic neuritis. PMID- 29154728 TI - Neuromyelitis optica spectrum disorders and pregnancy: Interactions and management. AB - Neuromyelitis optica spectrum disorders (NMOSD) predominantly affect women who are of childbearing age. Understanding the interactions between pregnancy and NMOSD is important for clinical management. Aquaporin-4 (AQP4), the most common target antigen in NMOSD, is expressed on placenta in early pregnancy. A variety of immune and cytokine changes in pregnancy may impact pregnancy outcomes in NMOSD patients. Relapses continue during pregnancy and increase in frequency postpartum. Preeclampsia and fetal loss are more frequent in NMOSD than in controls. Transfer of AQP4-immunoglobulin G (IgG) from mother to baby occurs but appears not to cause disease. Several treatment options are relatively safe and mitigate the risk of relapse during pregnancy and postpartum. For patients with active NMOSD, it may be advisable to continue immunotherapy during pregnancy. PMID- 29154729 TI - Single-Bone Intramedullary Nailing of Pediatric Both-Bone Forearm Fractures A Systematic Review. AB - Traditional operative management of unstable, pediatric both-bone forearm fractures is fixation of both ulna and radius. Literature suggests single-bone fixation with intramedullary nailing obtains good results and is less technically demanding and invasive. This systematic review evaluates the efficacy of single bone intramedullary nailing of pediatric both-bone forearm fractures. Medline and Embase were searched for English-language primary studies published in peer reviewed journals. Two independent investigators extracted data. Eleven papers met the criteria for inclusion. Overall, studies found pronation and supination and radiographic angulation outcomes were comparable in single and both-bone fixation cohorts. Rates of pronation and supination loss and re-angulation were similar for radius-only compared to ulna-only fixation. PMID- 29154730 TI - Effect of increased milking frequency and residual milk removal on milk production and milk fatty acid composition in lactating cows. AB - It has been well established that milk yield is affected both by milking frequency and due to the removal of residual milk, but the influence of a combination of these factors is unclear. In this study, four mid-lactation cows were used in a 4 * 4 Latin square design to test the hypothesis that the effects of more frequent milking and residual milk removal on milk yield and composition are additive and alter milk fatty acid composition. Treatments comprised two or four times daily milking in combination with (or without) residual milk removal over a 96 h interval preceded by a 2 d pretreatment period and followed by a 8 d washout in each 14 d experimental period. Milk was sampled at each milking for the analysis of gross composition and SCC. Samples of available and residual milk collected on the last milking during each treatment period were collected and submitted for fatty acid composition analysis. Increases in milking frequency and residual milk removal alone or in combination had no effect on milk yield or on the secretion of lactose and protein in milk. However, residual milk removal during more frequent milking increased milk fat yield. Milking treatments had no major influence on the fatty acid composition of available milk, but resulted in rather small changes in the relative abundance of specific fatty acids, with no evidence that the additive effects of treatments were due to higher utilisation of preformed fatty acids relative to fatty acid synthesis de novo. For all treatments, fat composition of available and residual milk was rather similar indicating a highly uniform fatty acid composition of milk fat within the mammary gland. PMID- 29154731 TI - Using milk leukocyte differentials for diagnosis of subclinical bovine mastitis - CORRIGENDUM. PMID- 29154732 TI - CD49f+ mammary epithelial cells decrease in milk from dairy cows stressed by overstocking during the dry period. AB - The work reported in this Research Communication describes the modification in epithelial cell populations during the first and the last month of milking in Holstein Friesian cows that have undergone different management during the dry period, and we report the differential expression of CD49f+ and cytokeratin18+ cell subpopulations. Twenty six cows were randomly divided into 2 balanced groups that were housed at stocking density of either 11 m2 (CTR) or 5 m2 from 21 +/- 3 d before the expected calving until calving. Cells collected from milk samples taken in early lactation and late lactation were directly analysed for CD45, CD49f, cytokeratin 14, cytokeratin 18 and cell viability. We observed a differential expression with a significant reduction in CD49f+ (P < 0.01) and cytokeratin 18+ (P < 0.05) cells in early lactation. Differences were still evident in late lactation but were not significant. These observations suggest that mammary epithelial cell immunophenotypes could be associated with different animal management in the dry period and we hypothesise they may have a role as biomarkers for mammary gland function in dairy cows. PMID- 29154733 TI - Metabolomic analysis of alterations in lipid oxidation, carbohydrate and amino acid metabolism in dairy goats caused by exposure to Aflotoxin B1. AB - The purposes of this study were to investigate the systemic and characteristic metabolites in the serum of dairy goats induced by aflatoxin B1 (AFB1) exposure and to further understand the endogenous metabolic alterations induced by it. A nuclear magnetic resonance (NMR)-based metabonomic approach was used to analyse the metabolic alterations in dairy goats that were induced by low doses of AFB1 (50 ug/kg DM). We found that AFB1 exposure caused significant elevations of glucose, citrate, acetate, acetoacetate, betaine, and glycine yet caused reductions of lactate, ketone bodies (acetate, beta-hydroxybutyrate), amino acids (citrulline, leucine/isoleucine, valine, creatine) and cell membrane structures (choline, lipoprotein, N-acetyl glycoproteins) in the serum. These data indicated that AFB1 caused endogenous metabolic changes in various metabolic pathways, including cell membrane-associated metabolism, the tricarboxylic acid cycle, glycolysis, lipids, and amino acid metabolism. These findings provide both a comprehensive insight into the metabolic aspects of AFB1-induced adverse effects on dairy goats and a method for monitoring dairy animals exposed to low doses of AFB1. PMID- 29154734 TI - Effect of physical activity on cardiac autonomic function of dairy cows on commercial dairy farms. AB - Interbeat interval data were collected from 219 Holstein cows in 2 smaller-scale farms and 3 larger-scale farms to investigate the effects of posture (standing vs. lying), rumination (rumination vs. no rumination) and feeding on baseline values of heart rate (HR) and heart rate variability (HRV) parameters reflecting vagal and sympathetic activity. A General Linear Model was used for detecting factors (parity, milking technology, herd size) having possible effects on HRV calculated for undisturbed lying posture. Basal values of cardiac parameters were also compared between larger and smaller-scale farms. Neither parity nor milking technology affected HRV parameters. Sympathetic activity increased in the order of lying, ruminating when lying, standing, ruminating when standing and feeding on both sizes of farms. Vagal activity decreased in that order in both lower- and larger-scale farms. Rumination caused an increase in HR and a decrease in vagal tone in both lower- and larger-scale farms and an increase in sympathetic activity during lying in both farm sizes. Basal vagal activity was lower in larger-scale farms compared to smaller-scale farms, while greater sympathetic activity was found in cows housed on larger-scale farms. Our findings demonstrate that reference values of HRV parameters in lactating dairy cows cannot be generally defined for Holstein cattle as they are affected by physical activity and herd size. Higher HR and sympathetic activity at rest in larger-scale farms compared to farms with lower cow population might be associated with higher levels of social stress and therefore should be considered as a potential welfare concern. PMID- 29154735 TI - Rumination time as a potential predictor of common diseases in high-productive Holstein dairy cows. AB - We examined the hypothesis that rumination time (RT) could serve as a useful predictor of various common diseases of high producing dairy cows and hence improve herd management and animal wellbeing. We measured the changes in rumination time (RT) in the days before the recording of diseases (specifically: mastitis, reproductive system diseases, locomotor system issues, and gastroenteric diseases). We built predictive models to assess the association between RT and these diseases, using the former as the outcome variable, and to study the effects of the latter on the former. The average Pseudo-R 2 of the fitted models was moderate to low, and this could be due to the fact that RT is influenced by other additional factors which have a greater effect than the predictors used here. Although remaining in a moderate-to-low range, the average Pseudo-R 2 of the models regarding locomotion issues and gastroenteric diseases was higher than the others, suggesting the greater effect of these diseases on RT. The results are encouraging, but further work is needed if these models are to become useful predictors. PMID- 29154736 TI - Lactobacilli-fermented cow's milk attenuated lipopolysaccharide-induced neuroinflammation and memory impairment in vitro and in vivo. AB - Nutritional interventions are now recommended as strategies to delay Alzheimer's disease (AD) progression. The present study evaluated the neuroprotective effect (anti-inflammation) of lactic acid bacteria (either Lactobacillus fermentum LAB9 or L. casei LABPC) fermented cow's milk (CM) against lipopolysaccharide (LPS) activated microglial BV2 cells in vitro. The ability of CM-LAB in attenuating memory deficit in LPS-induced mice was also investigated. ICR mice were orally administered with CM-LAB for 28 d before induction of neuroinflammation by LPS. Learning and memory behaviour were assessed using the Morris Water Maze Test. Brain tissues were homogenised for measurement of acetylcholinesterase (AChE), antioxidative, lipid peroxidation (malondialdehyde (MDA)) and nitrosative stress (NO) parameters. Serum was collected for cytokine analysis. CM-LAB9 and CM-LABPC significantly (P < 0.05) decreased NO level but did not affect CD40 expression in vitro. CM-LAB attenuated LPS-induced memory deficit in mice. This was accompanied by significant (P < 0.05) increment of antioxidants (SOD, GSH, GPx) and reduction of MDA, AChE and also pro-inflammatory cytokines. Unfermented cow's milk (UCM) yielded greater cytokine lowering effect than CM-LAB. The present findings suggest that attenuation of LPS-induced neuroinflamation and memory deficit by CM LAB could be mediated via anti-inflammation through inhibition of AChE and antioxidative activities. PMID- 29154737 TI - Significant changes in ITIH4, AHSG, ORM1, and CD46 content in milk fat globule membrane proteins of ketotic dairy cows. AB - High concentrations of non-esterified fatty acid (NEFA) and beta-hydroxybutyrate (BHBA) in cows' blood caused by ketosis are associated with inflammatory states. We hypothesised that ketosis in postparturient dairy cows would result in altered levels on inflammation-related proteins not only in plasma but also in the milk fat globule membranes (MFGM). Thirty cows were selected from a dairy farm in Heilongjiang, China. Inflammatory milk fat globule membrane proteins were detected using ELISA kits, and a fully automatic biochemical analyser was used to measure the concentrations of BHBA, NEFA, glucose (GLU) and triglyceride (TG) in plasma. MFGM protein from milk of ketotic cows contained significantly different concentrations of acute-phase response proteins (complement C3 (C3), prothrombin (F2), alpha-1-acid glycoprotein (ORM1), inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), alpha-2-HS-glycoprotein (AHSG), complement C9 (C9), complement regulatory protein variant 4 (CD46)) in comparison with milk from non-ketotic cows. Blood concentrations of C3, complement C9 (C9), tumour necrosis factor alpha (TNFalpha), MFGM C3, monocyte differentiation antigen CD14 (CD14) and ORM1 levels were correlated with energy balance. ITIH4 and CD46 increased, and AHSG and ORM1 decreased before the onset of ketosis. These biomarkers offer potential as predictors and monitors of ketosis in at-risk cows. PMID- 29154738 TI - Validation of a pedometer algorithm as a tool for evaluation of locomotor behaviour in dairy Mediterranean buffalo. AB - This research communication validates an algorithm to monitor natural occurrence of locomotor behaviours in dairy Mediterranean buffalo based on the output of a 3 dimensional accelerometer (RumiWatch(r), pedometer). Several characteristics of the locomotor behaviour were detected with a very high (up-right, lying and standing time) or high degree of correlation (walking time and number of strides) and a low mean difference with the video recording. The proportion of correctly detected events exceeded 99 % for the following variables: stand up and lie down events, as well as number of lying, standing or walking bouts. The mean relative measurement error was less than 10 % for the variables: lying, standing, up-right times and number of strides as compared with gold standard. This new algorithm may represent the base for a future early and real-time disease warning system aiming to gain higher health standard in these ruminants. PMID- 29154739 TI - Oxidative stress-induced inflammatory responses and effects of N-acetylcysteine in bovine mammary alveolar cells. AB - Bovine mastitis, an inflammation of the udder, results in reduced milk production and poor milk quality. Mastitis is usually, but not always, a response to pathogen infection. High milk yield can produce oxidative stress in the mammary tissue. High milk yield is also known to be associated with bovine mastitis. Thus, in the current study, we hypothesised that oxidative stress increases inflammatory responses in bovine mammary cells. To examine the hypothesis, we produced cellular oxidative stress and investigated resulting inflammatory responses in bovine mammary alveolar cells (MAC-T). To produce oxidative stress, cells were treated with the reactive oxygen species (ROS; e.g., superoxide anion) producing agent, menadione (MD; 0-10 um; 6 h). To ensure the ROS-induced responses, cells were pretreated with an antioxidant NAC (0-10 mm; 1 h). Results showed that MD elevated intracellular ROS levels and protein expression of cyclooxygenase-2 (COX-2), a biomarker of inflammation. Pretreatment of cells with NAC attenuated MD-induced COX-2 expression by scavenging intracellular ROS and enhancing intracellular glutathione levels. MD-induced COX-2 expression was mediated by activation of extracellular signal receptor-activated kinase 1/2 (ERK1/2), Akt, and nuclear factor-kappa B (NF-kappaB). NAC attenuated activation of these intracellular signalling molecules. Treatment of cells with pharmacological inhibitors for ERK1/2, Akt, and NF-kappaB confirmed the association of these signalling pathways in MD-induced COX-2 expression. These results support our hypothesis that oxidative stress, which is found in high yielding dairy cows, can produce cellular inflammation in bovine mammary alveolar cells and prevention of oxidative stress can attenuate such pathological responses. This may be relevant for cases of clinical mastitis for which no pathogen can be isolated. PMID- 29154741 TI - Identification of factors affecting colostrum quality of dairy Lacaune ewes assessed with the Brix refractometer. AB - In this Research Communication we assessed factors affecting colostrum quality of dairy Lacaune ewes using the Brix-refractometer. Colostrum from 536 lambings from one commercial intensive dairy Lacaune farm were analysed for the following factors with potential influence in colostrum quality: (1) ewe parity (n = 84 132), (2) length of previous dry period (PDP) (n = 23-214), (3) age at first lambing (AFL) of primiparous ewes (n = 9-88), (4) lambing season (n = 192 or 344), and (5) year (2011-2013, n = 142-203). Parity significantly affected colostrum quality, with primiparous ewes showing the highest Brix refractometer values (22.6 +/- 5.6%, P < 0.0001), though values were similar among multiparous ewes. PDP length also significantly affected colostrum quality: ewes with the shortest PDP showed the worst quality (16.8 +/- 4.2%, P < 0.0001), with quality gradually rising with PDP length. Colostrum quality was significantly higher in 2011 (21.0 +/- 5.2%) than in 2012 or 2013 (P < 0.0001); this likely reflects the several-fold greater proportion of animals with long PDP in 2011. In contrast, neither AFL nor lambing season significantly affected colostrum quality. These results suggest that parity and PDP length can substantially affect ovine colostrum quality of dairy ewes under intensive management conditions and they further show the usefulness of the Brix refractometer for providing a rough estimation of colostrum quality on-farm. However, further studies are needed to determine a validated cut-off Brix value for identifying good-quality colostra in ovine species. PMID- 29154740 TI - An association analysis between PRL genotype and milk production traits in Italian Mediterranean river buffalo. AB - This Research Communication describes the association between genetic variation within the prolactin (PRL) gene and the milk production traits of Italian Mediterranean river buffalo (Bufala mediterranea Italiana). High resolution melting (HRM) techniques were developed for genotyping 465 buffaloes. The association of genetic polymorphism with milk production traits was performed and subsequently the effects of parity and calving season were evaluated. Single nucleotide polymorphisms (SNPs) were identified at exons 2 and 5 and at introns 1 and 2. All the SNPs were in Hardy-Weinberg equilibrium, and statistical analysis showed that the polymorphism of intron1 was significantly (P < 0.05) associated with milk yield, milk protein content and peak milk yield. The average contribution of the intron1 genotype (r 2 intron1) to total phenotypic variance in milk production traits was 0.09, and the TT genotype showed lower values than CC and CT genotypes. A nonsynonymous SNP was identified in exon 2, which resulted in an amino acid change from arginine to cysteine. Moreover, the polymorphism of exon 2 was associated significantly with milk fat content (P < 0.05), and the buffaloes with TT genotype showed higher total fat content than the buffaloes with CT genotype. These findings provide evidence that polymorphisms of the buffalo PRL gene are associated with milk production traits and PRL can be used as a candidate gene for marker-assisted selection in Italian Mediterranean river buffalo breeding. PMID- 29154742 TI - Variation in the Toll-like Receptor 4 (TLR4) gene affects milk traits in dairy cows. AB - The objective of this Research Communication was to use polymerase chain reaction single stranded conformational polymorphism (PCR-SSCP) analysis to investigate a region of the bovine TLR4 gene (TLR4) in pasture-fed New Zealand (NZ) Holstein Friesian * Jersey (HF * J) cross dairy cows and to determine whether gene variation was associated with milk production traits. Genetic variation was observed, with two variants (A and B) containing a single nucleotide polymorphism (SNP) (c.2021C/T) that was non-synonymous and putatively results in a p.Thr674Ile substitution in the transmembrane/cytoplasmic domain of TLR4. Variant A was associated with higher milk yields, but lower milk fat percentages, whereas B was associated with lower milk yields, but higher fat and protein percentages. Cows of genotype AA produced more milk than AB or BB cows, but the milk produced by AA cows contained less fat than AB or BB cows. PMID- 29154743 TI - Editorial: A year of contrasts. PMID- 29154744 TI - Generation and characterization of a novel candidate gene therapy and vaccination vector based on human species D adenovirus type 56. AB - The vectorization of rare human adenovirus (HAdV) types will widen our knowledge of this family and their interaction with cells, tissues and organs. In this study we focus on HAdV-56, a member of human Ad species D, and create ease-of-use cloning systems to generate recombinant HAdV-56 vectors carrying foreign genes. We present in vitro transduction profiles for HAdV-56 in direct comparison to the most commonly used HAdV-5-based vector. In vivo characterizations demonstrate that when it is delivered intravenously (i.v.) HAdV-56 mainly targets the spleen and, to a lesser extent, the lungs, whilst largely bypassing liver transduction in mice. HAdV-56 triggered robust inflammatory and cellular immune responses, with higher induction of IFNgamma, TNFalpha, IL5, IL6, IP10, MCP1 and MIG1 compared to HAdV-5 following i.v. administration. We also investigated its potential as a vaccine vector candidate by performing prime immunizations in mice with HAdV-56 encoding luciferase (HAdV-56-Luc). Direct comparisons were made to HAdV-26, a highly potent human vaccine vector currently in phase II clinical trials. HAdV-56-Luc induced luciferase 'antigen'-specific IFNgamma-producing cells and anti-HAdV-56 neutralizing antibodies in Balb/c mice, demonstrating a near identical profile to that of HAdV-26. Taken together, the data presented provides further insight into human Ad receptor/co-receptor usage, and the first report on HAdV-56 vectors and their potential for gene therapy and vaccine applications. PMID- 29154745 TI - Differential gene expression in chicken primary B cells infected ex vivo with attenuated and very virulent strains of infectious bursal disease virus (IBDV). AB - Infectious bursal disease virus (IBDV) belongs to the family Birnaviridae and is economically important to the poultry industry worldwide. IBDV infects B cells in the bursa of Fabricius (BF), causing immunosuppression and morbidity in young chickens. In addition to strains that cause classical Gumboro disease, the so called 'very virulent' (vv) strain, also in circulation, causes more severe disease and increased mortality. IBDV has traditionally been controlled through the use of live attenuated vaccines, with attenuation resulting from serial passage in non-lymphoid cells. However, the factors that contribute to the vv or attenuated phenotypes are poorly understood. In order to address this, we aimed to investigate host cell-IBDV interactions using a recently described chicken primary B-cell model, where chicken B cells are harvested from the BF and cultured ex vivo in the presence of chicken CD40L. We demonstrated that these cells could support the replication of IBDV when infected ex vivo in the laboratory. Furthermore, we evaluated the gene expression profiles of B cells infected with an attenuated strain (D78) and a very virulent strain (UK661) by microarray. We found that key genes involved in B-cell activation and signalling (TNFSF13B, CD72 and GRAP) were down-regulated following infection relative to mock, which we speculate could contribute to IBDV-mediated immunosuppression. Moreover, cells responded to infection by expressing antiviral type I IFNs and IFN-stimulated genes, but the induction was far less pronounced upon infection with UK661, which we speculate could contribute to its virulence. PMID- 29154746 TI - In vitro and in vivo activity of fosfomycin alone and in combination with rifampin and tigecycline against Gram-positive cocci isolated from surgical wound infections. AB - Complicated skin and soft tissue infections constitute a heterogeneous group of severe disorders, with surgical site infections being the most common hospital acquired ones. The aim of our study was to investigate the synergistic and bactericidal activities of antimicrobial combinations of fosfomycin with rifampicin and tigecycline against Enterococcus faecalis, Enterococcus faecium and methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates, and also to evaluate their in vivo effects in a mouse wound infection model. In in vitro studies, the combinations of fosfomycin with rifampicin and tigecycline were both synergistic. These synergies were confirmed in in vivo studies: the drug combinations showed the highest antimicrobial effects compared to monotherapy. In conclusion, the efficacy of fosfomycin combinations, also confirmed in our in vivo model, may suggest new directions in the treatment of infected skin and a possible alternative way to control bacterial skin infection. PMID- 29154747 TI - Disseminated methicillin-susceptible Staphylococcus aureus infection. AB - INTRODUCTION: When clinicians think about Staphylococcus aureus bacteria, what comes to the mind of most is the dreaded methicillin-resistant form. However, clinicians should not forget the methicillin-susceptible type, which is just as virulent. CASE PRESENTATION: The authors present the case of a 20-year-old woman who was admitted with septic shock and multi-organ failure and was found to have disseminated methicillin-susceptible Staphylococcus aureus (MSSA) infection. The patient had persistent blood cultures positive for MSSA. A transesophageal echocardiogram showed a 1.1 cm vegetation in the mitral valve, and the patient had bilateral pleural effusions that grew MSSA. An MRI of the brain showed multiple areas consistent with infarctions thought to be secondary to septic emboli. The patient underwent a mitral valve replacement and was treated with a prolonged course of parenteral nafcillin. DISCUSSION: This case illustrates a severe clinical presentation and management of MSSA infections. PMID- 29154748 TI - CDC Safety Training Course for Ebola Virus Disease Healthcare Workers. AB - Response to sudden epidemic infectious disease emergencies can demand intensive and specialized training, as demonstrated in 2014 when Ebola virus disease (EVD) rapidly spread throughout West Africa. The medical community quickly became overwhelmed because of limited staff, supplies, and Ebola treatment units (ETUs). Because a mechanism to rapidly increase trained healthcare workers was needed, the US Centers for Disease Control and Prevention developed and implemented an introductory EVD safety training course to prepare US healthcare workers to work in West Africa ETUs. The goal was to teach principles and practices of safely providing patient care and was delivered through lectures, small-group breakout sessions, and practical exercises. During September 2014-March 2015, a total of 570 participants were trained during 16 course sessions. This course quickly increased the number of clinicians who could provide care in West Africa ETUs, showing the feasibility of rapidly developing and implementing training in response to a public health emergency. PMID- 29154749 TI - Complications and monitoring of percutaneous renal biopsy - a retrospective study?. AB - BACKGROUND AND AIMS: Percutaneous renal biopsy is a necessary tool to diagnose renal diseases but complications may still occur. The aims of this study were to detect the rate of complications, possible risk factors and to identify the necessity of routine post-biopsy controls at 4 - 6, and 24 hours. MATERIALS AND METHODS: This single-center retrospective study included 500 consecutive biopsies of native and allograft kidneys performed at the Jena University Hospital. RESULTS: Major complications occurred in 2.4% of all cases: 9 patients received blood transfusions (1.8%), 2 arterial-venous fistulas (0.4%), 1 angiographic intervention (0.2%), no surgical intervention or death. Minor complications after 24 (4 - 6) hours appeared in 31.8 (41.2)%: 14.8 (11.0)% had hematomas detected by ultrasound (n = 74), 17.0 (30.2)% a reduction of hemoglobin concentration >= 1.0 g/dL (n = 85), 4.8 (2.6)% both (n = 24), 1 macrohematuria (0.2%). Systolic blood pressure (>= 155 mmHg vs. <= 126 mmHg, OR 2.007, 95% CI 1.003 - 4.018, p = 0.049) and younger age (per 1 year increase, OR 0.983, 95% CI 0.968 - 0.998, p = 0.027) were associated with the presence of hematoma. Baseline hemoglobin (per increase of 1.6 g/dL, OR 1.499, 95% CI 1.222 - 1.840, p < 0.001) and interstitial fibrosis (>= 50% vs. <= 16%, OR 2.694, 95% CI 1.212 - 5.987, p = 0.015) influenced the finding of a persistent hemoglobin reduction >= 1.0 g/dL after 24 hours. CONCLUSION: The complication rate after renal biopsy is low. Despite the lack of prospective data, our findings suggest that follow-up by a single blood count test combined with ultrasound examination at the day after renal biopsy would be sufficient, at least in the absence of explicit symptoms or risk factors for bleeding.?. PMID- 29154750 TI - Global perspectives on ensuring the safety of pharmaceutical products in the distribution process?. AB - OBJECTIVE: The distribution of counterfeit or falsified drugs is increasing worldwide. This can contribute to the high burden of disease and cost to society and is of global concern with the worldwide circulation of pharmaceuticals. The preparation and implementation of good distribution practice should be one of the most important aspects of ensuring safe drug circulation and administration. This research aimed to compare and analyze good distribution practice guidelines from advanced countries and international organizations, and to evaluate the status of the current good distribution practice guidelines in the world. MATERIALS AND METHODS: Advanced pharmaceutical countries and international organizations, such as the World Health Organization, European Union, Pharmaceutical Inspection Co operation Scheme, United States of America, Canada, and Australia, which have stable good distribution practice guidelines and public confidence, were included in the analysis. RESULTS: The World Health Organization and European Union guidelines are models for standardized good distribution practice for nations worldwide. The United States of America has a combination of four different series of distribution practices which have a unique structure and detailed content compared to those of other countries. The Canadian guidelines focus on temperature control during storage and transportation. The Australian guidelines apply to both classes of medicinal products and medical devices and need separate standardization. CONCLUSION: Transparent information about the Internet chain, international cooperation regarding counterfeiting, a high-standard qualification of sellers and customers, and technology to track and trace the whole life cycle of drugs should be the main focus of future good distribution practice guidelines worldwide.?. PMID- 29154751 TI - The etiology of spontaneous intracerebralhemorrhage: Insights from a neuropathological series. AB - The etiology of intracerebral hemorrhage (ICH) is frequently undetermined. We aimed to assess the impact of the neuropathological study on the etiologic diagnosis of ICH. Patients with ICH admitted to a tertiary hospital in the last 14 years were identified, and histological samples of surgically-drained ICH were retrieved. Blinded from neuropathological results, a clinical etiology was hypothesized. Pathological samples were reviewed, and immunohistochemistry study for beta-amyloid was performed in all the cases where structural abnormalities were not identified. From 2002 - 2016, 113 patients with ICH underwent surgical drainage and had specimens taken for histology. The mean age was 51.6 years (SD = 19.2). Clinical and imaging data defined a presumable etiology in 47 patients (44.2%), including 30 patients with suspected structural pathology, 11 patients under anticoagulation, and 8 patients with probable hypertensive hemorrhage, while most had an undetermined etiology. Using neuropathological analysis, a definitive diagnosis was possible in 88.5% of the patients. Arteriovenous malformations (38.1%) and cavernous hemangiomas (16.8%) represented the most common findings. In 9.7%, the blood vessels showed cerebral amyloid angiopathy (CAA). The neuropathological study established a definite etiology in an additional 44.3% of patients other than only using the clinical and imaging data.?. PMID- 29154752 TI - Idiopathic inflammatory myopathies overlapping with systemic diseases. AB - A muscle biopsy is currently requested to assess the diagnosis of an idiopathic inflammatory myopathy overlapping with a systemic disease. During the past few years, the classification of inflammatory myopathy subtypes has been revisited progressively on the basis of correlations between clinical phenotypes, autoantibodies and histological data. Several syndromic entities are now more clearly defined, and the aim of the present review is to clarify the contribution of muscle biopsy in a setting of idiopathic inflammatory myopathies overlapping with systemic diseases.?. PMID- 29154754 TI - Functional divergence of paralogous transcription factors supported the evolution of biomineralization in echinoderms. AB - Alx1 is a pivotal transcription factor in a gene regulatory network that controls skeletogenesis throughout the echinoderm phylum. We performed a structure function analysis of sea urchin Alx1 using a rescue assay and identified a novel, conserved motif (Domain 2) essential for skeletogenic function. The paralogue of Alx1, Alx4, was not functionally interchangeable with Alx1, but insertion of Domain 2 conferred robust skeletogenic function on Alx4. We used cross-species expression experiments to show that Alx1 proteins from distantly related echinoderms are not interchangeable, although the sequence and function of Domain 2 are highly conserved. We also found that Domain 2 is subject to alternative splicing and provide evidence that this domain was originally gained through exonization. Our findings show that a gene duplication event permitted the functional specialization of a transcription factor through changes in exon intron organization and thereby supported the evolution of a major morphological novelty. PMID- 29154753 TI - Cyclin A/Cdk1 modulates Plk1 activity in prometaphase to regulate kinetochore microtubule attachment stability. AB - The fidelity of chromosome segregation in mitosis is safeguarded by the precise regulation of kinetochore microtubule (k-MT) attachment stability. Previously, we demonstrated that Cyclin A/Cdk1 destabilizes k-MT attachments to promote faithful chromosome segregation. Here, we use quantitative phosphoproteomics to identify 156 Cyclin A/Cdk1 substrates in prometaphase. One Cyclin A/Cdk1 substrate is myosin phosphatase targeting subunit 1 (MYPT1), and we show that MYPT1 localization to kinetochores depends on Cyclin A/Cdk1 activity and that MYPT1 destabilizes k-MT attachments by negatively regulating Plk1 at kinetochores. Thus, Cyclin A/Cdk1 phosphorylation primes MYPT1 for Plk1 binding. Interestingly, priming of PBIP1 by Plk1 itself (self-priming) increased in MYPT1-depleted cells showing that MYPT1 provides a molecular link between the processes of Cdk1 dependent priming and self-priming of Plk1 substrates. These data demonstrate cross-regulation between Cyclin A/Cdk1-dependent and Plk1-dependent phosphorylation of substrates during mitosis to ensure efficient correction of k MT attachment errors necessary for high mitotic fidelity. PMID- 29154755 TI - Ribosome surface properties may impose limits on the nature of the cytoplasmic proteome. AB - Much of the molecular motion in the cytoplasm is diffusive, which possibly limits the tempo of processes. We studied the dependence of protein mobility on protein surface properties and ionic strength. We used surface-modified fluorescent proteins (FPs) and determined their translational diffusion coefficients (D) in the cytoplasm of Escherichia coli, Lactococcus lactis and Haloferax volcanii. We find that in E. coli D depends on the net charge and its distribution over the protein, with positive proteins diffusing up to 100-fold slower than negative ones. This effect is weaker in L. lactis and Hfx. volcanii due to electrostatic screening. The decrease in mobility is probably caused by interaction of positive FPs with ribosomes as shown in in vivo diffusion measurements and confirmed in vitro with purified ribosomes. Ribosome surface properties may thus limit the composition of the cytoplasmic proteome. This finding lays bare a paradox in the functioning of prokaryotic (endo)symbionts. PMID- 29154756 TI - Cocaine-induced adaptation of dopamine D2S, but not D2L autoreceptors. AB - The dopamine D2 receptor has two splice variants, D2S (Short) and D2L (Long). In dopamine neurons, both variants can act as autoreceptors to regulate neuronal excitability and dopamine release, but the roles of each variant are incompletely characterized. In a previous study we used viral receptor expression in D2 receptor knockout mice to show distinct effects of calcium signaling on D2S and D2L autoreceptor function (Gantz et al., 2015). However, the cocaine-induced plasticity of D2 receptor desensitization observed in wild type mice was not recapitulated with this method of receptor expression. Here we use mice with genetic knockouts of either the D2S or D2L variant to investigate cocaine-induced plasticity in D2 receptor signaling. Following a single in vivo cocaine exposure, the desensitization of D2 receptors from neurons expressing only the D2S variant was reduced. This did not occur in D2L-expressing neurons, indicating differential drug-induced plasticity between the variants. PMID- 29154759 TI - Radiation Exposure in Pediatric Urology Patients: How to Adhere to ALARA. PMID- 29154760 TI - Editorial Comment. PMID- 29154761 TI - Moving Beyond an Age-Old Intervention. PMID- 29154762 TI - Editorial Comment. PMID- 29154763 TI - Editorial Comment. PMID- 29154765 TI - Reply by Authors. PMID- 29154757 TI - Macrophage polarization and meta-inflammation. AB - Chronic overnutrition and obesity induces low-grade inflammation throughout the body. Termed "meta-inflammation," this chronic state of inflammation is mediated by macrophages located within the colon, liver, muscle, and adipose tissue. A sentinel orchestrator of immune activity and homeostasis, macrophages adopt variable states of activation as a function of time and environmental cues. Meta inflammation phenotypically skews these polarization states and has been linked to numerous metabolic disorders. The past decade has revealed several key regulators of macrophage polarization, including the signal transducer and activator of transcription family, the peroxisome proliferator-activated receptor gamma, the CCAAT-enhancer-binding proteins (C/EBP) family, and the interferon regulatory factors. Recent studies have also suggested that microRNAs and long noncoding RNA influence macrophage polarization. The pathogenic alteration of macrophage polarization in meta-inflammation is regulated by both extracellular and intracellular cues, resulting in distinct secretome profiles. Meta inflammation-altered macrophage polarization has been linked to insulin insensitivity, atherosclerosis, inflammatory bowel disease, cancer, and autoimmunity. Thus, further mechanistic exploration into the skewing of macrophage polarization promises to have profound impacts on improving global health. PMID- 29154764 TI - Editorial Comment. PMID- 29154766 TI - Editorial Comment. PMID- 29154767 TI - Reply by Authors. PMID- 29154758 TI - The role of fMRI in drug development. AB - Functional magnetic resonance imaging (fMRI) has been known for over a decade to have the potential to greatly enhance the process of developing novel therapeutic drugs for prevalent health conditions. However, the use of fMRI in drug development continues to be relatively limited because of a variety of technical, biological, and strategic barriers that continue to limit progress. Here, we briefly review the roles that fMRI can have in the drug development process and the requirements it must meet to be useful in this setting. We then provide an update on our current understanding of the strengths and limitations of fMRI as a tool for drug developers and recommend activities to enhance its utility. PMID- 29154768 TI - Editorial Comment. PMID- 29154770 TI - Density and Shape Factor Terms in Stokes' Equation for Aerodynamic Behavior of Aerosols. AB - Pharmaceutical aerosols are used to treat many pulmonary diseases. The use of low density powders has proven useful to support efficient drug delivery. Measurements must account for the low-density, spherical particle features contributing to aerodynamic behavior. Ideally, the aerodynamic particle size distribution (APSD) is measured experimentally. Without formal measurement of APSD, calculations may be performed using surrogate measures such as bulk or tapped density and dynamic shape factor in Stokes' equation. However, the particles' low density must be established independently for this approach to be valid. In addition, where particles deviate from sphericity, the dynamic shape factor must be estimated from aerodynamic measurement not from geometric imaging of morphology. Finally, geometric sizing from particle images results in number distributions that exhibit smaller median sizes than mass distributions for the same polydisperse system. Simply applying density and shape factor corrections to geometric particle sizes does not convert number distributions to mass distributions. For log-normally distributed particle size distributions, Hatch Choate equations, employing both median size and geometric standard deviation terms, may be used to convert number to mass distributions. Assigning small APSDs from calculations based on erroneous assumptions will result in serious interpretive flaws in subsequent in vitro and in vivo data. PMID- 29154769 TI - Extracellular Lipids Accumulate in Human Carotid Arteries as Distinct Three Dimensional Structures and Have Proinflammatory Properties. AB - Lipid accumulation is a key characteristic of advancing atherosclerotic lesions. Herein, we analyzed the ultrastructure of the accumulated lipids in endarterectomized human carotid atherosclerotic plaques using three-dimensional (3D) electron microscopy, a method never used in this context before. 3D electron microscopy revealed intracellular lipid droplets and extracellular lipoprotein particles. Most of the particles were aggregated, and some connected to needle shaped or sheet-like cholesterol crystals. Proteomic analysis of isolated extracellular lipoprotein particles revealed that apolipoprotein B is their main protein component, indicating their origin from low-density lipoprotein, intermediate-density lipoprotein, very-low-density lipoprotein, lipoprotein (a), or chylomicron remnants. The particles also contained small exchangeable apolipoproteins, complement components, and immunoglobulins. Lipidomic analysis revealed differences between plasma lipoproteins and the particles, thereby indicating involvement of lipolytic enzymes in their generation. Incubation of human monocyte-derived macrophages with the isolated extracellular lipoprotein particles or with plasma lipoproteins that had been lipolytically modified in vitro induced intracellular lipid accumulation and triggered inflammasome activation in them. Taken together, extracellular lipids accumulate in human carotid plaques as distinct 3D structures that include aggregated and fused lipoprotein particles and cholesterol crystals. The particles originate from plasma lipoproteins, show signs of lipolytic modifications, and associate with cholesterol crystals. By inducing intracellular cholesterol accumulation (ie, foam cell formation) and inflammasome activation, the extracellular lipoprotein particles may actively enhance atherogenesis. PMID- 29154771 TI - In-vitro blockade of the CD4 receptor co-signal in antigen-specific T-cell stimulation cultures induces the outgrowth of potent CD4 independent T-cell effectors. AB - T-cell receptor (TCR) redirected T cells are promising tools for adoptive cancer immunotherapy. Since not only CD8 but also CD4 T cells are key players for efficient antitumor responses, the targeted redirection of both subsets with the same antigen-specific TCR comes more and more into focus. Although rapidly evolving technologies enable the reliable genetic re-programming of T cells, the limited availability of TCRs that induce T-cell activation in both T-cell subsets without CD4/CD8 co-receptor contribution hampers the broad application of this approach. We developed a novel stimulation approach, which drives the activation and proliferation of CD4 T-cell populations capable of inducing effector functions in a CD4-independent manner. Naive-enriched CD4 T cells were stimulated against dendritic cells (DC) expressing allogeneic HLA-DP antigens upon RNA transfection and CD4/HLA interactions were blocked by the addition of CD4 binding antibody. Evolving CD4 T-cell populations were specifically activated independent of the CD4 co-signal and induced strong TCR-mediated IFN-gamma secretion as well as cytolysis upon recognition of leukemia cells expressing HLA-DP antigen. Our novel stimulation approach may facilitate the generation of CD4 T cells as source for co-receptor independent TCRs for future immunotherapies. PMID- 29154773 TI - Neuropharmacology of venom peptides. PMID- 29154772 TI - Endogenous peroxidases in sputum interfere with horse-radish peroxidase-based ELISAs. AB - Peroxidase-based immunoassays are commonly used for detecting inflammatory mediators in biological samples. We suggest caution while interpreting assays particularly in sputum samples that have endogenous peroxidases like eosinophil peroxidase (EPX), which may interact with a horseradish peroxidase (HRP)-based ELISA. Using IL-8 as an example, we demonstrate that values generated with an HRP ELISA (n=47) show significant positive correlation with the sputum EPX content (r=0.6, P=0.0004), which can be misconstrued to be affiliated with an eosinophilic event. The data-set generated with the same samples (n=47) using alkaline phosphatase (AP)-based ELISA and a non-enzymatic Milliplex system do not show any correlation with sputum EPX (Milliplex r=-0.24, P=0.13; AP r=0.26, P=0.09). Moreover, sub-group analysis shows significantly increased IL-8 levels detected by HRP-ELISA in eosinophilic patient sputa (n=28) compared to AP-ELISA (P=0.0001). We, therefore, recommend the use of AP-based ELISA or Multiplex system rather than peroxidase-based ELISA for detecting soluble mediators, and more importantly for non-Th2 related mediators in sputum samples with increased eosinophil activity. PMID- 29154774 TI - Recommendations for Care of Geriatric Maxillofacial Trauma Patients Following a Retrospective 10-Year Multicenter Review. AB - PURPOSE: The purpose of this study was to analyze maxillofacial trauma sustained by patients at least 75 years old. With the injury patterns identified, treatment recommendations for the contemporary oral and maxillofacial surgeon are made. PATIENTS AND METHODS: This study was a retrospective case series using data from 2 level 1 trauma centers. The variables of interest included age at traumatic event, gender, mechanism of trauma, concomitant injuries, radiographic studies performed, management of maxillofacial injuries, and disposition. Numerical analysis was completed with statistical software. RESULTS: One hundred seventy six patients at least 75 years old who sustained facial trauma were identified. Ground-level falls caused most cases of maxillofacial trauma in the geriatric population. The median age at the time of trauma was 83 and 85 years for men and women, respectively. The most common injuries were midface fractures. Intracranial hemorrhage was the most common concomitant injury, and all but 1 patient underwent computed tomography of at least the head after their traumatic event. Most maxillofacial injuries were treated without operative repair. CONCLUSIONS: The information gained from this study suggests that oral and maxillofacial surgeons should counsel geriatric patients on the risk of falls and encourage the prevention of potential hazards for falls in their homes. PMID- 29154775 TI - Alveolar Osteitis and Third Molar Pathologies. PMID- 29154776 TI - Zero-determinant strategies in finitely repeated games. AB - Direct reciprocity is a mechanism for sustaining mutual cooperation in repeated social dilemma games, where a player would keep cooperation to avoid being retaliated by a co-player in the future. So-called zero-determinant (ZD) strategies enable a player to unilaterally set a linear relationship between the player's own payoff and the co-player's payoff regardless of the strategy of the co-player. In the present study, we analytically study zero-determinant strategies in finitely repeated (two-person) prisoner's dilemma games with a general payoff matrix. Our results are as follows. First, we present the forms of solutions that extend the known results for infinitely repeated games (with a discount factor w of unity) to the case of finitely repeated games (0 < w < 1). Second, for the three most prominent ZD strategies, the equalizers, extortioners, and generous strategies, we derive the threshold value of w above which the ZD strategies exist. Third, we show that the only strategies that enforce a linear relationship between the two players' payoffs are either the ZD strategies or unconditional strategies, where the latter independently cooperates with a fixed probability in each round of the game, proving a conjecture previously made for infinitely repeated games. PMID- 29154777 TI - An attempt to understand glioma stem cell biology through centrality analysis of a protein interaction network. AB - Biological networks can be analyzed using "Centrality Analysis" to identify the more influential nodes and interactions in the network. This study was undertaken to create and visualize a biological network comprising of protein-protein interactions (PPIs) amongst proteins which are preferentially over-expressed in glioma cancer stem cell component (GCSC) of glioblastomas as compared to the glioma non-stem cancer cell (GNSC) component and then to analyze this network through centrality analyses (CA) in order to identify the essential proteins in this network and their interactions. In addition, this study proposes a new centrality analysis method pertaining exclusively to transcription factors (TFs) and interactions amongst them. Moreover the relevant molecular functions, biological processes and biochemical pathways amongst these proteins were sought through enrichment analysis. A protein interaction network was created using a list of proteins which have been shown to be preferentially expressed or over expressed in GCSCs isolated from glioblastomas as compared to the GNSCs. This list comprising of 38 proteins, created using manual literature mining, was submitted to the Reactome FIViz tool, a web based application integrated into Cytoscape, an open source software platform for visualizing and analyzing molecular interaction networks and biological pathways to produce the network. This network was subjected to centrality analyses utilizing ranked lists of six centrality measures using the FIViz application and (for the first time) a dedicated centrality analysis plug-in ; CytoNCA. The interactions exclusively amongst the transcription factors were nalyzed through a newly proposed centrality analysis method called "Gene Expression Associated Degree Centrality Analysis (GEADCA)". Enrichment analysis was performed using the "network function analysis" tool on Reactome. The CA was able to identify a small set of proteins with consistently high centrality ranks that is indicative of their strong influence in the protein protein interaction network. Similarly the newly proposed GEADCA helped identify the transcription factors with high centrality values indicative of their key roles in transcriptional regulation. The enrichment studies provided a list of molecular functions, biological processes and biochemical pathways associated with the constructed network. The study shows how pathway based databases may be used to create and analyze a relevant protein interaction network in glioma cancer stem cells and identify the essential elements within it to gather insights into the molecular interactions that regulate the properties of glioma stem cells. How these insights may be utilized to help the development of future research towards formulation of new management strategies have been discussed from a theoretical standpoint. PMID- 29154778 TI - Viral Hepatitis: Knowledge and Treatments for Hepatitis B and C Virus and Associated Transplantation and Neoplasia. PMID- 29154779 TI - Letrozole pretreatment prior to medical termination of pregnancy: a systematic review. AB - OBJECTIVE: The purpose of this systematic review was to evaluate the efficacy of pretreatment with letrozole prior to either a first- or second-trimester medical termination of pregnancy. STUDY DESIGN: We searched letrozole, femara, aromatase inhibitors, abortifacient agents, termination of pregnancy and labor induction in MEDLINE, EMBASE, Cochrane Database, Google Scholar and PubMed from inception of each database until September 2015 with no language limitation. A systematic review of all randomized controlled trials (RCTs) was performed where women received either letrozole and misoprostol or placebo and misoprostol for termination of pregnancy. The primary outcome was complete abortion rate, defined as complete evacuation of the products of conception from the uterus. Relative risk with 95% confidence intervals was used to report data. RESULTS: Our systematic review identified 7 studies; 4 RCTs were included in the review. Two RCTs evaluated terminations of pregnancy up to 9 weeks' gestation, while 2 evaluated terminations over 9 weeks' gestation. For each gestational age group, one trial supported an increase in complete abortion rate, while the other showed no difference, with letrozole and misoprostol compared with placebo and misoprostol. Time-to-abortion interval for terminations up to 9 weeks' gestation was not improved with the addition of letrozole to misoprostol. For terminations over 9 weeks' gestation, one trial supported and one trial refuted a decrease in time-to-abortion interval with letrozole and misoprostol. Similarly, for each gestational age group, one study supported a decrease and one study showed no difference in rate of dilation and curettage (D&C) with letrozole and misoprosol. Medication side effects were similar between both treatment groups. There was significant heterogeneity between the trials, and therefore, the results were not meta-analyzed. CONCLUSIONS: Some studies and trials report better outcomes (i.e., complete abortion rates, time-to-abortion and D&C rates) in women exposed to letrozole and misoprostol compared to placebo and misoprostol, while other trials demonstrate no difference. Further research exploring letrozole pretreatment prior to medical abortion is required. IMPLICATIONS: This systematic review demonstrated that a combination of letrozole and misoprostol increased the rate of complete abortion compared to misoprostol alone in some studies but not in others; additional well-designed RCT's are needed. PMID- 29154780 TI - The feedback loop of "EMMPRIN/NF-kappaB" worsens atherosclerotic plaque via suppressing autophagy in macrophage. AB - This study examined the significance of macrophage autophagy in extracellular matrix metalloproteinase inducer (EMMPRIN)-mediated atherosclerosis (AS). Apolipoprotein E-deficient (ApoE-/-) mice were fed a western diet to establish an AS model. EMMPRIN and p62/Sequestosome-1(SQSTM1) expression were evaluated in plaque macrophages from the AS mice using immunofluorescence. The EMMPRIN and p62/SQSTM1 protein expression levels in macrophages increased with the increasing vulnerability of the atherosclerotic plaques. RAW264.7 cells and ApoE-/- mice Bone Marrow-derived macrophages were transfected with different small interfering RNAs (siRNAs) or plasmids, or treated with different drugs in the presence or absence of oxidized low-density lipoprotein (oxLDL). The protein levels of the targets were evaluated using western blotting (WB), and the autophagosomes were observed under a transmission electron microscope (TEM). Over-expressed EMMPRIN dramatically inhibited oxLDL-mediated autophagy. EMMPRIN also negatively regulated autophagy primarily through the nuclear factor-kappa B (NF-kappaB) signalling pathway. In turn, activated NF-kappaB up-regulated EMMPRIN expression. Inhibition of EMMPRIN decreased cell apoptosis and the release of inflammatory cytokines via the promotion of macrophage autophagy. Infection with an adenovirus delivering the EMMPRIN-siRNA ameliorated AS, promoted macrophage autophagy in plaques and reduced the serum TNF-alpha, IL-6, MCP-1 and NF-kappaB expression levels in the AS mice. Chloroquine (CQ) reversed these effects. This study revealed for the first time that the feedback loop of the "EMMPRIN/NF-kappaB" pathway plays an important role in atherosclerotic plaques via modulation of autophagy in macrophages, which might provide a potential strategy for the clinical treatment of AS. PMID- 29154781 TI - Eucalyptus globulus extract protects against UVB-induced photoaging by enhancing collagen synthesis via regulation of TGF-beta/Smad signals and attenuation of AP 1. AB - UV irradiation triggers the overproduction of matrix metalloproteinases and collagen degradation, which in turn causes increased pigmentation, dryness, and deep wrinkling of the skin. These chronic symptoms are collectively referred to as photoaging. Eucalyptus globulus is an evergreen tree that is widely used in cosmetics because of its antimicrobial activity. In this study, we investigated the protective effect of 50% ethanol extracts of Eucalyptus globulus on UV induced photoaging in vitro and in vivo. Normal human dermal fibroblasts were treated with Eucalyptus globulus at concentrations ranging from 1 to 100 MUg/mL after UVB or non-UVB irradiation. We found that Eucalyptus globulus suppressed the expression of MMPs and IL-6, but increased the expression of TGF-beta1 and procollagen type 1. In addition, Eucalyptus globulus inhibited activation of the AP-1 transcription factor, an inducer of MMPs. Eucalyptus globulus was also found to regulate TGF-beta/Smad signaling by reversing the activity of negative Smad regulators. Lastly, in vivo studies showed that topical application of Eucalyptus globulus on UVB-irradiated hairless mice reduced wrinkle formation and dryness by down-regulating MMP-1 and up-regulating expression of elastin, TGF-beta1, and procollagen type 1. Taken together, these data suggest that Eucalyptus globulus may be a useful agent in cosmetic products. PMID- 29154782 TI - Neutrophil depletion protects against zomepirac-induced acute kidney injury in mice. AB - Acyl glucuronide (AG) metabolites of carboxylic acid-containing drugs have been implicated in drug toxicity. Zomepirac (ZP) is a non-steroidal anti-inflammatory drug that was withdrawn from the market because of anaphylactic reactions and renal injury. We recently established a novel mouse model of ZP-induced kidney injury by increasing zomepirac acyl-glucuronide (ZP-AG) concentration via pretreatment with tri-O-tolyl phosphate, a nonselective esterase inhibitor, and l buthionine-(S,R)-sulfoximine, a glutathione synthesis inhibitor. Although we have shown that ZP-AG is responsible for ZP-induced kidney injury in mice, the exact pathogenic mechanisms of ZP-induced kidney injury have not been investigated yet. In this study, we aimed to investigate the role of immune cells in the pathogenesis of ZP-induced kidney injury, as a representative of AG toxicity. We found that the counts of neutrophils and inflammatory monocytes increased in the blood of mice with ZP-induced kidney injury. However, clodronate liposome- or GdCl3-induced monocyte and/or macrophage depletion did not affect blood urea nitrogen and plasma creatinine levels in mice with ZP-induced kidney injury. Neutrophil infiltration into the kidneys was observed in mice with ZP-induced kidney injury, whereas anti-lymphocyte antigen 6 complex, locus G (Ly6G) antibody pretreatment prevented the renal neutrophil infiltration and partially protected against ZP-induced kidney injury. The mRNA expression of neutrophil-infiltrating cytokines and chemokines, interleukin-1alpha and macrophage inflammatory protein 2alpha, increased in mice with ZP-induced kidney injury, whereas pretreatment with anti-Ly6G antibody resulted in a marked reduction of their expression. These results suggest that ZP-AG might be involved in kidney injury, partly via induction of neutrophil infiltration. Therefore, this study may provide an important understanding on toxicological role of ZP-AG in vivo that helps to understand toxicity of AG metabolites. PMID- 29154783 TI - Involvement of monocarboxylate transporter 1 (SLC16A1) in the uptake of l-lactate in human astrocytes. AB - PURPOSE: Astrocytes, the most abundant glial cells in the central nervous system (CNS), help neurons survive. Monocarboxylate transporters (MCTs) are reported to transport l-lactate, which is important for CNS physiology and cognitive function. However, it remains unclear which MCT isoform is functionally expressed by human astrocytes. The aim of this study was to establish the contribution of each MCT isoform to l-lactate transport in human astrocytes. METHODS: The function of l-lactate transport was studied using NHA cells as a human astrocyte model and radiolabeled l-lactate. The expression of MCT in human astrocytes was detected by immunohistochemistry staining. RESULTS: The cellular uptake of l lactate was found to be pH- and concentration-dependent with a Km value for l lactate uptake of 0.64mM. This Km was similar to what has been previously established for MCT1-mediated l-lactate uptake. alpha-Cyano-4- hydroxycinnamate (CHC) and 5-oxoproline, which are both MCT1 inhibitors, were found to significantly inhibit the uptake of l-lactate, suggesting MCT1 is primarily responsible for l-lactate transport. Moreover, MCT1 protein was expressed in human astrocytes. CONCLUSION: pH-dependent l-lactate transport is mediated by MCT1 in human astrocytes. PMID- 29154784 TI - TGF-beta1 signaling regulates mouse hepatic stellate cell differentiation via the Jagged1/Notch pathway. AB - AIMS: We tested whether transforming growth factor beta1 (TGF-beta1) signaling plays an important role in hepatic stellate cell differentiation fate and investigated the role of Jagged1/Notch in this process. MATERIALS AND METHODS: TGF-beta1 was overexpressed and transforming growth factor receptor 1 (TGF-beta R1) was knocked down by a lentiviral vector in mouse hepatic stellate cells (mHSCs). Transfection efficiency was assessed with immunofluorescence, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and western blotting. The downstream genes alpha-smooth muscle actin (alpha-SMA), Jagged1 and the differentiation markers alpha-fetoprotein (AFP), albumin (ALB), cytokeratin19 (CK19), SRY (sex determining region Y)-box 9 (SOX9), and hairy and enhancer of split-1 (Hes1) were measured with qRT-PCR and western blotting. KEY FINDINGS: SpHBLV-CMVIE-TGF-beta1, pHBLV-CMVIE-GFP, pHBLV-U6-TGF-beta-R1 shRNA, and pHBLV-U6-RFP were successfully transfected. Over-expression of the TGF-beta1 gene caused mHSCs to transform into myofibroblasts (MFs) and expression of Jagged1 and cholangiocyte markers (CK19, SOX9, Hes1) were significantly upregulated (P<0.01). Importantly, after blocking TGF-beta1 signaling via gene silencing, expression of Jagged1 was much reduced, but the mature hepatocyte marker (ALB) was obviously increased. In addition, AFP, a hepatic stem cell marker, was expressed at the highest level in the control groups. SIGNIFICANCE: Our findings emphasize that the TGF-beta1 signaling pathway regulates expression of Jagged1 in mHSCs which is associated with transformation of mHSCs into MFs, thus demonstrating a novel mechanism via which TGF-beta1 signaling controls the differentiation fate of mHSCs through regulation of the Jagged1/Notch pathway. PMID- 29154785 TI - A rapid enhancement of locomotor sensitization to amphetamine by estradiol in female rats. AB - Estradiol moderates the effects of drugs of abuse in both humans and rodents. Estradiol's enhancement of behavioral effects resulting from high (>2.5mg/kg) doses of amphetamine is established in rats; there is less evidence for the role of estradiol in locomotor effects elicited by lower doses, which are less aversive, increase incentive motivation, involve different neural mechanisms than higher doses, and often more readily reveal group differences than do higher doses. Further, the extent to which estradiol is required for the induction versus the expression of sensitization is unknown. To establish a protocol, we replicated the effects of estradiol on locomotor sensitization to amphetamine reported in a previous study that involved a high locomotor-activating dose (1.5mg/kg) of amphetamine, but with a lower dose. Ovariectomized female rats received 5MUg of estradiol benzoate (EB) or OIL 30min before each of 5 treatments of 1.0mg/kg amphetamine or saline; all received a 0.5mg/kg challenge dose three days later. Compared with results for OIL, EB enhanced the locomotor-activating effects of repeated 1.0mg/kg amphetamine across treatment days. In contrast, on challenge day, there was no difference between EB-saline and EB-amphetamine to the lower dose (i.e., no sensitization). Experiments 2 and 3 involved a shorter induction (2days) and a lengthier withdrawal (9days) before the challenge test for the expression of sensitization to better differentiate the induction phase from the expression phase. In Expt2, EB-, and not OIL-, treated rats showed sensitization to 0.5mg/kg amphetamine; neither group showed sensitization to 1.5mg/kg amphetamine (ceiling effect?). In Expt3, rats were treated with EB either in both the induction and expression phases, in one of the phases only, or in neither phase. There was an effect of hormone treatment on challenge day and not on induction day; rats given EB on Challenge day showed sensitization to 0.5mg/kg amphetamine; OIL rats did not. The results suggest rapid effects of estradiol on amphetamine sensitization consistent with rapid effects of estradiol reported for other behaviours. PMID- 29154786 TI - Sex differences in high fat diet-induced impairments to striatal Akt signaling and enhanced sensitivity to the behavioral effects of dopamine D2/D3 receptor agonist quinpirole. AB - Eating a high fat laboratory chow enhances sensitivity of rats to the behavioral effects of drugs that act on dopamine systems (e.g., cocaine). Further, in male rats, eating high fat chow impairs expression of insulin signaling phosphorylated protein kinase B (pAkt), which is vital for maintaining dopamine homeostasis. Eating high fat chow enhances sensitivity of female rats to drugs that act indirectly on dopamine receptors (e.g., cocaine); however, less is known about sensitivity of females to drugs that act directly on dopamine receptors (e.g., quinpirole). Further, it is not known if pAkt expression is impaired in female rats eating high fat chow. Some quinpirole-induced behaviors (e.g., penile erections and yawning) are either absent or occur at very low frequency in adult female rats. It is not known if quinpirole sensitivity in adolescent rats is more comparable between sexes. The present report examined another unconditioned behavioral effect (i.e., rearing) induced by once-weekly cumulative doses of quinpirole (0.0032-0.32mg/kg) in male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat), for several weeks throughout development, (spanning adolescence and early adulthood). Following behavioral assessments, pAkt expression was examined using western blot protein analysis. Eating high fat chow increased sensitivity of male rats to the quinpirole-induced yawning, as compared to male rats eating standard chow. However, other unconditioned behavioral effects of quinpirole (yawning and hypothermia) remained unchanged. Female rats yawned significantly less than male rats, and eating a high fat chow had no effect on any quinpirole-induced unconditioned behavioral effect in female rats. Eating high fat chow also reduced pAkt levels in male, but not female rats. Taken together, these data suggest that alternative behavioral and biochemical assays should be considered to measure sensitivity of female rats to the behavioral effects of dopamine receptor agonists, and further demonstrate the importance of studying drug sensitivity in both male and female subjects. PMID- 29154787 TI - Functionalization of paramagnetic nanoparticles for protein immobilization and purification. AB - A paramagnetic nanocomposite coated with chitosan and N-(5-Amino-1-carboxy pentyl) iminodiacetic acid (NTA) that is suitable for protein immobilization applications has been prepared and characterized. The nanoparticle core was synthesized by controlled aggregation of Fe3O4 under alkaline conditions, and Transmission Electron Microscopy revealed a size distribution of 10-50 nm. The nanoparticle core was coated with chitosan and derivatized with glutaraldehyde and NTA, as confirmed by Fourier Transform Infrared Spectroscopy. The final nanoparticles were used as a metal affinity matrix to separate a recombinant polyhistidine-tagged beta-galactosidase from Bacillus subtilis directly from E. coli cell lysates with high purity (>95%). After loading with Ni2+, nanoparticles demonstrated a binding capacity of 250 MUg of a polyhistidine-tagged beta galactosidase per milligram of support. The immobilized enzyme retained 80% activity after 9 cycles of washing, and the immobilized recombinant protein could be eluted with high purity with imidazole. The applications for these nanomagnetic composites extend beyond protein purification, and can also be used for immobilizing enzymes, where the beta-galactosidase immobilized on the nanomagnetic support was used in multiple cycles of catalytic reactions with no significant loss of catalytic activity. PMID- 29154788 TI - A multianalytical approach to investigate the effect of nanofiltration on plasma derived factor IX clinical lots. AB - Plasma-derived proteins are a subset of relevant biotherapeutics also known as "well-characterized biologicals". They are enriched from plasma through several steps of physical and biochemical methodologies, reaching the regulatory accepted standards of safety, levels of impurities, activity and lot-to-lot consistency. Final products accepted for commercialization are submitted to tight analytical, functional and safety controls by a number of different approaches that fulfill the requirements of sensitivity and reliability. We report here the use of a multianalytical approach for the comparative evaluation of different lots of Factor IX isolated from plasma preparations and submitted or not to a step of nanofiltration. The approach include, among the other, proteomic techniques based on both MALDI-TOF and LC-MS Orbitrap mass spectrometry, circular dichroism for structural characterization, chromatographic and electrophoretic techniques, ELISA and functional assays based on clotting activity and binding to known anticoagulants. Comparative data obtained on two sets of nanofiltered and non nanofiltered lots with different final activity show that the products have substantially overlapping profiles in terms of activity, contaminants, structural properties and protein content, suggesting that the proposed multianalytical approach is robust enough to be used for the routine validation of clinical lots. PMID- 29154789 TI - Biosynthesis of microcystin hepatotoxins in the cyanobacterial genus Fischerella. AB - Microcystins (MCs) are serine/threonine phosphatase inhibitors synthesized by several members of the phylum Cyanobacteria. Mining the draft genome sequence of the nostocalean MC-producing Fischerella sp. strain CENA161 led to the identification of three contigs containing mcy genes. Subsequent PCR and Sanger sequencing allowed the assembling of its complete biosynthetic mcy gene cluster with 55,016 bases in length. The cluster encoding ten genes (mcyA-J) with a central bidirectional promoter was organized in a similar manner as found in other genera of nostocalean cyanobacteria. However, the nucleotide sequence of the mcy gene cluster of Fischerella sp. CENA161 showed significant differences from all the other MC-producing cyanobacterial genera, sharing only 85.2 to 74.1% identities. Potential MC variants produced by Fischerella sp. CENA161 were predicted by the analysis of the adenylation domain binding pockets and further investigated by LC-MS/MS analysis. To our knowledge, this study presents the first complete mcy cluster characterization from a strain of the genus Fischerella, providing new insight into the distribution and evolution of MCs in the phylum Cyanobacteria. PMID- 29154790 TI - Recognition of rare hemoglobin variants by hemoglobin A1c measurement procedures. AB - BACKGROUND: Unrecognized hemoglobinopathies can lead to measured hemoglobin A1c (Hb A1c) concentrations that are erroneous or misleading. We determined the effects of rare hemoglobin variants on capillary electrophoresis (CE) and HPLC methods for measurement of Hb A1c. METHODS: We prospectively investigated samples in which Hb A1c was measured by CE during a 14-month period. For samples in which the electropherograms suggested the presence of rare hemoglobinopathies, hemoglobin variants were identified by molecular analysis or by comparison with electropherograms of known variants. When sample volume permitted, Hb A1c was measured by 2 HPLC measurement procedures and by boronate affinity HPLC. RESULTS: Hb A1c was measured by CE in 33,859 samples from 26,850 patients. 15 patients (0.06%) were identified as having rare hemoglobinopathies: Hbs A2 prime, Agenogi, Fannin-Lubbock I, G Philadelphia, G San Jose, J Baltimore, La Desirade, N Baltimore, Nouakchott, and Roanne. Among 6 of these samples tested by 2 ion exchange HPLC methods, the rare Hb was detected by both HPLC methods in only one sample, and none were detected by boronate affinity HPLC. The mean of the Hb A1c results of 2 HPLC methods differed from the result of the CE method by 0.7-2.2% Hb A1c in samples with variant hemoglobins versus <0.2% Hb A1c in samples without variants. CONCLUSION: Measurement procedures differ in the ability to detect the presence of rare Hb variants and to quantify Hb A1c in patients who harbor such variants. PMID- 29154791 TI - Associations of early life urinary triclosan concentrations with maternal, neonatal, and child thyroid hormone levels. AB - BACKGROUND: Triclosan, an antimicrobial agent used in some consumer products, reduces endogenous thyroid hormone concentrations in rodents. Despite ubiquitous triclosan exposure and the importance of thyroid hormones for normal fetal development, few human studies have examined the impact of triclosan exposure on maternal, neonatal, or child thyroid hormones. METHODS: In the HOME Study, a prospective cohort from Cincinnati, OH, we measured urinary triclosan concentrations up to three times in pregnant women between 16weeks and delivery, and up to three times in children between age 1-3years. We quantified serum concentrations of thyroid stimulating hormone and total and free thyroxine and triiodothyronine in mothers at 16-weeks gestation (n=202), neonates at delivery (n=274), and children at age 3years (n=153). We estimated covariate-adjusted differences in thyroid hormones with a 10-fold increase in triclosan using linear regression and multiple informants models. RESULTS: Triclosan was not associated with thyroid hormones during pregnancy. We observed a few associations of triclosan concentrations with thyroid hormone concentrations in neonates at delivery and children at age 3years. Higher gestational triclosan, particularly around the time of delivery, was associated with lower cord serum total thyroxine (beta: 0.3MUg/dL; 95% CI: -0.6, -0.0). Childhood triclosan, particularly at age 1year, was positively associated with total thyroxine at age 3years (beta: 0.7MUg/dL; 95% CI: 0.3, 1.2). CONCLUSION: Our findings suggest that triclosan exposure may influence some features of neonatal and early child thyroid function. Given the large number of comparisons we made, these findings should be replicated in other cohorts. PMID- 29154792 TI - Robust real-time cell analysis method for determining viral infectious titers during development of a viral vaccine production process. AB - The classical cell-culture methods, such as cell culture infectious dose 50% (CCID50) assays, are time-consuming, end-point assays currently used during the development of a viral vaccine production process to measure viral infectious titers. However, they are not suitable for handling the large number of tests required for high-throughput and large-scale screening analyses. Impedance-based bio-sensing techniques used in real-time cell analysis (RTCA) to assess cell layer biological status in vitro, provide real-time data. In this proof-of concept study, we assessed the correlation between the results from CCID50 and RTCA assays and compared time and costs using monovalent and tetravalent chimeric yellow fever dengue (CYD) vaccine strains. For the RTCA assay, Vero cells were infected with the CYD sample and real-time impedance was recorded, using the dimensionless cell index (CI). The CI peaked just after infection and decreased as the viral cytopathic effect occurred in a dose-dependent manner. The time to the median CI (CITmed) was correlated with viral titers determined by CCID50 over a range of about 4-5log10 CCID50/ml. This in-house RTCA virus-titration assay was shown to be a robust method for determining real-time viral infectious titers, and could be an alternative to the classical CCID50 assay during the development of viral vaccine production process. PMID- 29154793 TI - Trends in Urologic Indications for Pediatric Renal Transplantation Over a 27-Year period United Network for Organ Sharing (UNOS) Database. AB - OBJECTIVE: To elucidate the trends in urologic causes for renal transplant in the pediatric population using a national database. Little is known about the specific pediatric urologic conditions and resultant trends that precede renal transplantation. MATERIAL AND METHODS: We reviewed the United Network for Organ Sharing (UNOS) database for pediatric patients (<18 years old) who underwent renal transplantation from January 1988 to September 2015. We included those patients who received a renal transplant because of a urologic condition. RESULTS: Over 27 years, 7291 of 20,213 children (36%) underwent renal transplant secondary to a urologic condition. The 2 most common indications were hypoplasia/dysplasia/dysgenesis/agenesis (HDDA, 35.1%) and congenital obstructive uropathy (COU, 25.7%). The incidence of COU has increased from 18% to 30%, and the incidence of Wilms tumor has remained relatively consistent at 1.8% per year. In addition, 68% of all urologic renal transplants were performed in men compared with women. However, a higher percentage of women required transplantation because of Wilms tumor (3.1% vs 1.2%) and chronic pyelonephritis (17.6% vs 7.9%). Overall, the majority of patients (61.5%) who underwent renal transplantation were white, 18.8% Hispanic, and 15.3% black. CONCLUSION: HDDA and COU consistently have been the most common urologic indications for renal transplantation. Both are the leading causes in men, whereas HDDA and chronic pyelonephritis are predominant in women. Higher rate of renal transplant during the ages of 11-17 years is suggestive of increased burden on poorly functioning kidneys during times of adolescent growth. PMID- 29154795 TI - Vision improvement in pilots with presbyopia following perceptual learning. AB - Israeli Air Force (IAF) pilots continue flying combat missions after the symptoms of natural near-vision deterioration, termed presbyopia, begin to be noticeable. Because modern pilots rely on the displays of the aircraft control and performance instruments, near visual acuity (VA) is essential in the cockpit. We aimed to apply a method previously shown to improve visual performance of presbyopes, and test whether presbyopic IAF pilots can overcome the limitation imposed by presbyopia. Participants were selected by the IAF aeromedical unit as having at least initial presbyopia and trained using a structured personalized perceptual learning method (GlassesOff application), based on detecting briefly presented low-contrast Gabor stimuli, under the conditions of spatial and temporal constraints, from a distance of 40 cm. Our results show that despite their initial visual advantage over age-matched peers, training resulted in robust improvements in various basic visual functions, including static and temporal VA, stereoacuity, spatial crowding, contrast sensitivity and contrast discrimination. Moreover, improvements generalized to higher-level tasks, such as sentence reading and aerial photography interpretation (specifically designed to reflect IAF pilots' expertise in analyzing noisy low-contrast input). In concert with earlier suggestions, gains in visual processing speed are plausible to account, at least partially, for the observed training-induced improvements. PMID- 29154794 TI - The relative persuasiveness of narrative versus non-narrative health messages in public health emergency communication: Evidence from a field experiment. AB - Previous studies indicated that narrative health messages are more effective than non-narrative messages in influencing health outcomes. However, this body of evidence does not account for differences in health domain, and little is known about the effectiveness of this message execution strategy during public health emergencies. In this study, we examined the relative effectiveness of the two formats in influencing knowledge and perceived response efficacy related to prevention of pandemic influenza, and determined whether effects of message format vary across population sub-groups. Data for the study come from an experiment fielded in 2013 that involved a nationally representative sample of 627 American adults. Participants were randomly assigned to view either a narrative (n=322) or a non-narrative (n=305) video clip containing closely matched information about knowledge and preventive actions related to pandemic influenza, and completed pre- and post-viewing questions assessing knowledge and perceived response efficacy related to the prevention of pandemic influenza. Results indicated that participants in the non-narrative condition reported greater knowledge and rated pandemic influenza prevention measures as more effective compared with those in the narrative condition. Message format effects did not vary across population sub-groups; post-viewing scores of knowledge and perceptions related to pandemic influenza were consistently higher in the non narrative condition compared with the narrative condition across five socio demographic groups: age, gender, education, race/ethnicity and income. We concluded that didactic, non-narrative messages may be more effective than narrative messages to influence knowledge and perceptions during public health emergencies. PMID- 29154796 TI - WITHDRAWN: Treatment of cancer by low intensity laser radiation therapy. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Editorial Board of Progress in Biophysics and Molecular Biology retracts this paper due to an accusation of plagiarism. After careful review, the Editorial Board believes sufficient evidence exists to support this accusation. The author does not dispute the fact that: (i) The paper "Treatment of cancer by low intensity laser radiation therapy" -- which was submitted to Progress in Biophysics and Molecular Biology (PBMB) in June 2017, and which was accepted for publication (http://doi.org/10.1016/j.pbiomolbio.2017.11.002)-- has been published previously in near-identical form. (ii) The previous publication appeared in the June 2017 issue of Cancer Biology (http://doi.org/10.7537/marscbj070217.11). (iii) The author explains that this is an administrative mix-up with another paper published in Cancer Biology in September 2017 (http://doi.org/10.7537/marscbj070317.03). The article duplicates significant paragraphs from the other published article. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. PMID- 29154797 TI - Caryophyllane sesquiterpenes inhibit DNA-damage by tobacco smoke in bacterial and mammalian cells. AB - In the present study, the ability of the natural sesquiterpene beta-caryophyllene (CRY) and its metabolite beta-caryophyllene oxide (CRYO) to inhibit the genotoxicity of a condensate of cigarette smoke (CSC) was evaluated both in bacterial and mammalian cells. Also, the inhibition of the CSC-mediated STAT3 phosphorylation and intracellular oxidative stress was evaluated as potential chemopreventive mechanism. Under our experimental conditions, both the sesquiterpenes exhibited antimutagenic properties, being CRY the most potent compound. The antimutagenicity was highlighted in all experimental protocols, being particularly strong in the co- and post-treatments. The test substances also reduced the micronuclei frequency induced by CSC, with a major effectiveness of CRY. CRY was also able to reduce the CSC-mediated increase of the Y705- pSTAT3 levels, in spite of a lacking effect of CRYO. Furthermore, the sesquiterpenes CRY and CRYO displayed a moderate antioxidant activity, with a 25 % and 40 % inhibition of the ROS-levels increased by CSC, respectively. On the basis of these results, CRY seems to be a multi-target chemopreventive agent, although the genoprotective and antioxidant effects of CRYO suggest that both compounds deserve to be deeply investigated for a possible application in the prevention and treatment of different smoke-related ailments. PMID- 29154798 TI - Non-pharmacological interventions for reducing mental distress in patients undergoing dental procedures: Systematic review and meta-analysis. AB - OBJECTIVES: This meta-analysis investigates the efficacy of non-pharmacological interventions in adults undergoing dental procedures under regional or general anesthesia compared to standard care alone or an attention control group on the reduction of mental distress, pain, and analgesic use. DATA SOURCES: To identify relevant papers a comprehensive literature search was carried out in MEDLINE, CENTRAL, Web of Science, and PsycINFO (last search August 2017). Additionally, lists of references of relevant articles and previous reviews were checked. ProQuest Dissertations and Theses Full Text Database was screened to identify any unpublished material. STUDY SELECTION: A total of 29 eligible randomized controlled trials were included, comprising a total of 2.886 patients. Included trials investigated the effects of hypnosis, enhanced information, relaxation, music, or cognitive-behavioral approaches including distraction. RESULTS: Random effects meta-analyses revealed significant positive treatment effects on the reduction of mental distress (g = 0.58, CI 95% [0.39; 0.76]). Effects on pain relief (g = 0.00, CI 95% [-0.28; 0.28]) and the reduction of analgesic use (g = 0.26, CI 95% [-0.22; 0.73]) were not significant. Because effects on mental distress were substantially heterogeneous, subgroup analyses were run yielding significantly larger effects for studies with low risk of bias compared to studies with high or unclear risk of selection and attrition bias. No significant differences appeared between various types of non-pharmacological interventions. CONCLUSIONS: In summary, benefits of non-pharmacological interventions on reducing mental distress were demonstrated with largest effects being shown for hypnosis. However, further high quality trials are needed to strengthen the promising evidence. CLINICAL SIGNIFICANCE: This systematic review and meta analysis indicated that non-pharmacological interventions may be beneficial for reducing mental distress in patients undergoing dental procedures and could thus be considered as valuable adjunct to standard care. PMID- 29154799 TI - Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. AB - Valproic acid (VPA) is a very potent anti-cancer and neuro-protective drug probably by its HDAC inhibiting properties, which may cause steatosis in the liver. The present study investigates the effect of repetitive VPA treatment of primary human hepatocytes (PHH) on whole genome gene expression-, DNA methylation , and miRNA changes, using microarrays and integrated data analyses. PHH were exposed to a non-cytotoxic dose of VPA for 5days daily which induced lipid accumulation. Part of the PHH was left untreated for 3days for studying the persistence of 'omics' changes. VPA treatment appeared to inhibit the expression of the transcription factors HNF1A and ONECUT1. HNF1A interacted with 41 differentially expressed genes of which 12 were also differentially methylated. None of the genes present in this network were regulated by a DE-miR. The subnetwork of ONECUT1 consisted of 44 differentially expressed genes of which 15 were differentially methylated, and 3 were regulated by a DE-miR. A number of genes in the networks are involved in fatty acid metabolism, and may contribute to the development of steatosis by increasing oxidative stress thereby causing mitochondrial dysfunction, and by shifting metabolism of VPA towards beta oxidation due to reduced glucuronidation. Part of the changes remained persistent after washing out of VPA, like PMAIP1 which is associated with cellular stress in liver of patients with NASH. The MMP2 gene showed the highest number of interactions with other persistently expressed genes, among which LCN2 which is a key modulator of lipid homeostasis. Furthermore, VPA modulated the expression and DNA methylation level of nuclear receptors and their target genes involved in the adverse outcome pathway of steatosis, thereby expanding our current knowledge of the pathway. In particular, VPA modulated PPARgamma, and PPARalpha, AHR and CD36 on both the gene expression and the DNA methylation level, thereby inhibiting beta-oxidation and increasing uptake of fatty acid into the hepatocytes, respectively. Overall, our integrative data analyses identified novel genes modulated by VPA, which provide more insight into the mechanisms of repeated dose toxicity of VPA, leading to steatosis. PMID- 29154800 TI - Using model fish to study the biological mechanisms of cooperative behaviour: A future for translational research concerning social anxiety disorders? AB - Human societies demand of its composing members the development of a wide array of social tools and strategies. A notable example is human outstanding ability to cooperate with others, in all its complex forms, depicting the reality of a highly demanding social framework in which humans need to be integrated as to attain physical and mental benefits. Considering the importance of social engagement, it's not entirely unexpected that most psychiatric disorders involve some disruption of normal social behaviour, ranging from an abnormal absence to a significant increase of social functioning. It is however surprising that knowledge on these social anxiety disorders still remains so limited. Here we review the literature focusing on the social and cooperative toolbox of 3 fish model species (cleaner fishes, guppies and zebrafish) which are amenable systems to test for social disorders. We build on current knowledge based on ethological information, arising from studies on cooperative behaviour in cleanerfishes and guppies, while profiting from the advantages of the intense use of zebrafish, to create novel paradigms aiming at the major socio-cognitive modules/dimensions in fish species. This focus may enable the discovery of putative conserved endpoints which are relevant for research into social disorders. We suggest that cross species, cross-domain, functional and genetic approaches could provide a wider array of information on the neurobiological bases of social and cooperative behaviour, crucial to understanding the neural bases of social disorders and key to finding novel avenues towards treatment. PMID- 29154801 TI - Human small bowel as a useful tool to investigate smooth muscle effects of potential therapeutics in organophosphate poisoning. AB - Isolated organs proofed to be a robust tool to study effects of (potential) therapeutics in organophosphate poisoning. Small bowel samples have been successfully used to reveal smooth muscle relaxing effects. In the present study, the effects of obidoxime, TMB-4, HI-6 and MB 327 were investigated on human small bowel tissue and compared with rat data. Hereby, the substances were tested in at least seven different concentrations in the jejunum or ileum both pre-contracted with carbamoylcholine. Additionally, the cholinesterase activity of native tissue was determined. Human small intestine specimens showed classical dose response curves, similar to rat tissue, with MB 327 exerting the most potent smooth muscle relaxant effect in both species (human EC50=0.7*10-5M and rat EC50=0.7*10-5M). The AChE activity for human and rat samples did not differ significantly (rat jejunum=1351+/-166 mU/mg wet weight; rat ileum=1078+/-123 mU/mg wet weight; human jejunum=1030+/-258 mU/mg wet weight; human ileum=1293+/-243 mU/mg wet weight). Summarizing, our isolated small bowel setup seems to be a solid tool to investigate the effects of (potential) therapeutics on pre-contracted smooth muscle, with data being transferable between rat and humans. PMID- 29154802 TI - MicroRNA profiling in MDA-MB-231 human breast cancer cell exposed to the Phaleria macrocarpa (Boerl.) fruit ethyl acetate fraction (PMEAF) through IIlumina Hi-Seq technologies and various in silico bioinformatics tools. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Phaleria macrocarpa (Scheff) Boerl, is a famous traditional medicinal plant which exhibited cytotoxicity against various cancerous cells. Traditionally, P. macrocarpa has been used to control cancer, impotency, hemorrhoids, diabetes mellitus, allergies, liver and heart disease, kidney disorders, blood diseases, acne, stroke, migraine, and various skin diseases. AIM OF THE STUDY: Recent studies have demonstrated a potent anticancer potential of P. macrocarpa, especially against HeLa cell. The objective of this study was to investigate the regulation of miRNAs on MDA-MB-231 treated with P. macrocarpa ethyl acetate fraction (PMEAF). MATERIALS AND METHODS: The regulation of miRNAs on MDA-MB-231 cells treated with PMEAF was studied through IIlumina, Hi Seq. 2000 platform of Next Generation Sequencing (NGS) and various in silico bioinformatics tools. RESULTS: The PMEAF treatment against MDA-MB-231 cells identified 10 upregulated and 10 downregulated miRNAs. A set of 606 target genes of 10 upregulated miRNAs and 517 target genes of 10 downregulated miRNAs were predicted based on computational and validated databases by using miRGate DB Query. Meanwhile, results from DAVID Bioinformatics Resources 6.8 specified the functional annotation of the upregulated miRNAs involvement in cancer pathway by suppressing the oncogenes and downregulating miRNAs by expressing the tumour suppressor genes in the regulation of apoptosis pathway. CONCLUSION: In conclusion, the results of this study proved that PMEAF is a promising anticancer agent with high cytotoxicity against MDA-MB-231 breast cancer cells and it induced apoptotic cell death mechanism through the regulation of miRNAs. PMEAF might be the best candidate for developing more potent anticancer drugs or chemo preventive supplements. PMID- 29154803 TI - New scale-down methodology from commercial to lab scale to optimize plant-derived soft gel capsule formulations on a commercial scale. AB - A new scale-down methodology from commercial rotary die scale to laboratory scale was developed to optimize a plant-derived soft gel capsule formulation and eventually manufacture superior soft gel capsules on a commercial scale, in order to reduce the time and cost for formulation development. Animal-derived and plant derived soft gel film sheets were prepared using an applicator on a laboratory scale and their physicochemical properties, such as tensile strength, Young's modulus, and adhesive strength, were evaluated. The tensile strength of the animal-derived and plant-derived soft gel film sheets was 11.7 MPa and 4.41 MPa, respectively. The Young's modulus of the animal-derived and plant-derived soft gel film sheets was 169 MPa and 17.8 MPa, respectively, and both sheets showed a similar adhesion strength of approximately 4.5-10 MPa. Using a D-optimal mixture design, plant-derived soft gel film sheets were prepared and optimized by varying their composition, including variations in the mass of kappa-carrageenan, iota carrageenan, oxidized starch and heat-treated starch. The physicochemical properties of the sheets were evaluated to determine the optimal formulation. Finally, plant-derived soft gel capsules were manufactured using the rotary die method and the prepared soft gel capsules showed equivalent or superior physical properties compared with pre-existing soft gel capsules. Therefore, we successfully developed a new scale-down methodology to optimize the formulation of plant-derived soft gel capsules on a commercial scale. PMID- 29154804 TI - Event-related brain potentials and the study of reward processing: Methodological considerations. AB - There is growing interest in using electroencephalography and specifically the event-related brain potential (ERP) methodology to study human reward processing. Since the discovery of the feedback related negativity (Miltner et al., 1997) and the development of theories associating the feedback related negativity and more recently the reward positivity with reinforcement learning, midbrain dopamine function, and the anterior cingulate cortex (i.e., Holroyd and Coles, 2002) researchers have used the ERP methodology to probe the neural basis of reward learning in humans. However, examination of the feedback related negativity and the reward positivity cannot be done without an understanding of some key methodological issues that must be taken into account when using ERPs and examining these ERP components. For example, even the component name - the feedback related negativity - is a source of debate within the research community as some now strongly feel that the component should be named the reward positivity (Proudfit, 2015). Here, ten key methodological issues are discussed - confusion in component naming, the reward positivity, component identification, peak quantification and the use of difference waveforms, frequency (the N200) and component contamination (the P300), the impact of feedback timing, action, and task learnability, and how learning results in changes in the amplitude of the feedback-related negativity/reward positivity. The hope here is to not provide a definitive approach for examining the feedback related negativity/reward positivity, but instead to outline the key issues that must be taken into account when examining this component to assist researchers in their study of human reward processing with the ERP methodology. PMID- 29154805 TI - The effects of imaginary voluntary muscle contraction and relaxation on cerebellar brain inhibition. AB - The purpose of this study was to investigate cerebellar brain inhibition (CBI) of the contralateral primary motor cortex (M1) during imaginary muscle contraction (Contract-I) and relaxation (Relax-I) using transcranial magnetic stimulation (TMS). Twenty-nine healthy adults completed two experiments. Motor evoked potentials (MEPs) in the right first dorsal interosseous (FDI) muscle were induced by TMS over the left M1 and measured with or without TMS over the right cerebellum during Contract-I (first experiment) and Relax-I (second experiment) of the right FDI, and these were compared to the findings in a no-imagery (No-I) condition. MEPs during Contract-I were significantly higher than those during No I, and MEPs during Relax-I were significantly lower than those during No-I. In contrast, CBI was significantly higher during Contract-I than during No-I, while there was no significant difference in CBI between Relax-I and No-I. These findings indicate that the cerebellum exerts facilitatory control over M1 excitability during imaginary muscle contraction but not during imaginary muscle relaxation. PMID- 29154806 TI - CRISPR Cas9 - Licensing the unlicensable. AB - A new gene engineering technology has recently made it through the media, not only because of its technical advantages, but also because it is in the focus of an epic patent battle between two academic institutions. The technology bears the cryptic name "CRISPR Cas9", and allows the manipulation of genes (so called "gene editing") with so far unseen simplicity and efficacy. Dana Carroll of the University of Utah said for this reason that CRISPR Cas9 has brought about the "democratization of gene targeting". However, due to legal battles and conflicting patent estates, third parties may find it difficult to decide where to acquire licenses. This article gives an overview. PMID- 29154807 TI - Rational design of antiviral drug combinations based on equipotency using HCV subgenomic replicon as an in vitro model. AB - Combination therapy of directly acting antivirals (DAA's) for the treatment of chronic HCV infections has proven to be a highly effective strategy to cure chronic infections with this virus. Here we studied, using HCV as an example, how to best design in vitro studies that explore the combined antiviral efficiency of combinations of three or more DAA's. To that end we used a HCV NS3 protease inhibitor, a NS5A targeting compound and two non-nucleoside NS5B polymerase inhibitors (each one targeting a different drug binding site). We demonstrate, employing HCV subgenomic replicon containing Huh 9-13 hepatoma cells, that quadruple therapy with these 4 different DAA's each at 1x their EC75, results in a highly efficient inhibition of viral replication. This is further reflected in the rapid clearance of the HCV replicon from the host cell. By contrast, neither equipotent combinations that consist of either molecules alone at 4x EC75 nor triple combinations at 1.33x the EC75 resulted in clearance. In contrast to the quadruple combo, drug-resistant variants emerged under mono-treatment and in most triple combo's. These data thus demonstrate that quadruple combinations at total suboptimal concentrations [i.e. concentrations at which neither mono- nor triple therapy is sufficiently potent] result rapidly in a pronounced antiviral efficacy. Altogether, this work provides an example as to how to design studies to explore the antiviral efficacy of combinations of more than two compounds. PMID- 29154808 TI - Genetic host factors in Helicobacter pylori-induced carcinogenesis: Emerging new paradigms. AB - Helicobacter Pylori is a gram negative rod shaped microaerophilic bacterium that colonizes the stomach of approximately half the world's population. Infection with c may cause chronic gastritis which via a quite well described process known as Correas cascade can progress through sequential development of atrophic gastritis, intestinal metaplasia and dysplasia to gastric cancer. H. pylori is currently the only bacterium that is classified as a class 1 carcinogen by the WHO, although the exact mechanisms by which this bacterium contributes to gastric carcinogenesis are still poorly understood. Only a minority of H. pylori-infected patients will eventually develop gastric cancer, suggesting that host factors may be important in determining the outcome of H. pylori infection. This is supported by a growing body of evidence suggesting that the host genetic background contributes to risk of H. pylori infection and gastric carcinogenesis. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors, H. pylori incidence and cancer. Many of these genes influence cellular pathways leading to inflammatory signaling, inflammasome formation and autophagy. In this review we summarize known carcinogenic effects of H. pylori, and discuss recent findings that implicate host genetic pattern recognition pathways in the development of gastric cancer and their relation with H. pylori. PMID- 29154809 TI - Facilitated acquisition of the classically conditioned eyeblink response in active duty military expressing posttraumatic stress disorder symptoms. AB - OBJECTIVE: Learning diathesis models underscore the role of hyper-conditioning in the development of PTSD following trauma exposure. Eyeblink classical conditioning is one method of examining associative learning biases independent of fear and threat produced by trauma. Facilitated learning is apparent in individuals self-expressing PTSD symptoms, as well as behaviorally inhibited (BI) temperament, a vulnerability factor for PTSD. Here, we examine eyeblink conditioning in active duty military personnel and relate learning with PTSD symptomology. METHOD: Volunteers were 83 active duty United States Coast Guard personnel (18 females) recruited from small boat stations. Personnel were administered the PTSD Checklist (PCL) to assess current PTSD symptoms using DSM IV criteria. BI temperament was assessed with the Adult Measure of Behavioural Inhibition (AMBI). Eyeblink conditioning was conducted using a partial reinforcement schedule, whereby paired trials (500-ms pure tone conditioned stimulus co-terminating with a 50-ms air-puff unconditional stimulus) were interpolated with 50% CS-alone trials. RESULTS: Consistent with previous work, there was a high degree of concordance between BI and incidence of PTSD. Further, PTSD was associated with faster learning during the acquisition period, with conditioned responding sustained through the extinction period. CONCLUSIONS: These results reinforce the relationship between BI and PTSD in an active duty military sample, supporting previous observations in veteran and civilian samples. The conditioning data are consistent with predictions derived from a learning diathesis model of stress and anxiety, suggesting facilitated associative learning may represent an additional vulnerability for the development and maintenance of stress-related pathology. PMID- 29154810 TI - Multiple performance measures are needed to evaluate triage systems in the emergency department. AB - OBJECTIVES: Emergency department triage systems can be considered prediction rules with an ordinal outcome, where different directions of misclassification have different clinical consequences. We evaluated strategies to compare the performance of triage systems and aimed to propose a set of performance measures that should be used in future studies. STUDY DESIGN AND SETTING: We identified performance measures based on literature review and expert knowledge. Their properties are illustrated in a case study evaluating two triage modifications in a cohort of 14,485 pediatric emergency department visits. Strengths and weaknesses of the performance measures were systematically appraised. RESULTS: Commonly reported performance measures are measures of statistical association (34/60 studies) and diagnostic accuracy (17/60 studies). The case study illustrates that none of the performance measures fulfills all criteria for triage evaluation. Decision curves are the performance measures with the most attractive features but require dichotomization. In addition, paired diagnostic accuracy measures can be recommended for dichotomized analysis, and the triage weighted kappa and Nagelkerke's R2 for ordinal analyses. Other performance measures provide limited additional information. CONCLUSION: When comparing modifications of triage systems, decision curves and diagnostic accuracy measures should be used in a dichotomized analysis, and the triage-weighted kappa and Nagelkerke's R2 in an ordinal approach. PMID- 29154811 TI - A systematic review highlights the need to investigate the content validity of patient-reported outcome measures for physical functioning in patients with low back pain. AB - OBJECTIVES: To summarize the evidence on content and structural validity of 17 patient-reported outcome measures (PROMs) to measure physical functioning in patients with low back pain (LBP). STUDY DESIGN AND SETTING: MEDLINE, EMBASE, CINAHL, PsycINFO, SportDiscus, and Google Scholar were searched (February 2017). Records on development and studies assessing content validity or unidimensionality in patients with LBP were included. Two reviewers defined eligible studies and assessed their methodological quality with updated Consensus based Standards for the Selection of Health Measurement Instruments standards. Evidence was synthesized for three separate aspects of content validity: relevance, comprehensiveness, and comprehensibility, and for unidimensionality, a modified GRADE approach was applied to evidence synthesis. RESULTS: High-quality evidence showed that 24-item Roland Morris Disability Questionnaire (RMDQ-24) is a comprehensible but not comprehensive PROM. Low to very low quality evidence underpinned the content validity of the other PROMs. Unidimensionality was: sufficient for Brief Pain Inventory pain interference subscale (moderate quality evidence); inconsistent for RMDQ-23, Oswestry Disability Index 2.1a (ODI 2.1a), and Quebec Back Pain Disability Scale (moderate quality); insufficient for RMDQ 24, ODI 1.0, and RMDQ-18 (high quality) and Short Form 36 physical functioning subscale (SF36-PF, moderate quality). CONCLUSION: The content validity of PROMs to measure physical functioning in patients with LBP is understudied. Structural validity of several widely used PROMs is problematic. PMID- 29154812 TI - Under stressful conditions activation of the ionotropic P2X7 receptor differentially regulates GABA and glutamate release from nerve terminals of the rat cerebral cortex. AB - gamma-Aminobutyric acid (GABA) and glutamate (Glu) are the main inhibitory and excitatory neurotransmitters in the central nervous system (CNS), respectively. Fine tuning regulation of extracellular levels of these amino acids is essential for normal brain activity. Recently, we showed that neocortical nerve terminals from patients with epilepsy express higher amounts of the non-desensitizing ionotropic P2X7 receptor. Once activated by ATP released from neuronal cells, the P2X7 receptor unbalances GABAergic vs. glutamatergic neurotransmission by differentially interfering with GABA and Glu uptake. Here, we investigated if activation of the P2X7 receptor also affects [3H]GABA and [14C]Glu release measured synchronously from isolated nerve terminals (synaptosomes) of the rat cerebral cortex. Data show that activation of the P2X7 receptor consistently increases [14C]Glu over [3H]GABA release from cortical nerve terminals, but the GABA/Glu ratio depends on extracellular Ca2+ concentrations. While the P2X7 induced [3H]GABA release is operated by a Ca2+-dependent pathway when external Ca2+ is available, this mechanism shifts towards the reversal of the GAT1 transporter in low Ca2+ conditions. A different scenario is verified regarding [14C]Glu outflow triggered by the P2X7 receptor, since the amino acid seems to be consistently released through the recruitment of connexin-containing hemichannels upon P2X7 activation, both in the absence and in the presence of external Ca2+. Data from this study add valuable information suggesting that ATP, via P2X7 activation, not only interferes with the high-affinity uptake of GABA and Glu but actually favors the release of these amino acids through distinct molecular mechanisms amenable to differential therapeutic control. PMID- 29154813 TI - 1-Year Outcomes of Patients Undergoing Primary Angioplasty for Myocardial Infarction Treated With Prasugrel Versus Ticagrelor. AB - BACKGROUND: Early outcomes of patients in the PRAGUE-18 (Comparison of Prasugrel and Ticagrelor in the Treatment of Acute Myocardial Infarction) study did not find any significant differences between 2 potent P2Y12 inhibitors. OBJECTIVES: The 1-year follow-up of the PRAGUE-18 study focused on: 1) a comparison of efficacy and safety between prasugrel and ticagrelor; and 2) the risk of major ischemic events related to an economically motivated post-discharge switch to clopidogrel. METHODS: A total of 1,230 patients with acute myocardial infarction (MI) treated with primary percutaneous coronary intervention were randomized to prasugrel or ticagrelor with an intended treatment duration of 12 months. The combined endpoint was cardiovascular death, MI, or stroke at 1 year. Because patients had to cover the costs of study medication after hospital discharge, some patients decided to switch to clopidogrel. RESULTS: The endpoint occurred in 6.6% of prasugrel patients and in 5.7% of ticagrelor patients (hazard ratio: 1.167; 95% confidence interval: 0.742 to 1.835; p = 0.503). No significant differences were found in: cardiovascular death (3.3% vs. 3.0%; p = 0.769), MI (3.0% vs. 2.5%; p = 0.611), stroke (1.1% vs. 0.7%; p = 0.423), all-cause death (4.7% vs. 4.2%; p = 0.654), definite stent thrombosis (1.1% vs. 1.5%; p = 0.535), all bleeding (10.9% vs. 11.1%; p = 0.999), and TIMI (Thrombolysis In Myocardial Infarction) major bleeding (0.9% vs. 0.7%; p = 0.754). The percentage of patients who switched to clopidogrel for economic reasons was 34.1% (n = 216) for prasugrel and 44.4% (n = 265) for ticagrelor (p = 0.003). Patients who were economically motivated to switch to clopidogrel had (compared with patients who continued the study medications) a lower risk of major cardiovascular events; however, they also had lower ischemic risk. CONCLUSIONS: Prasugrel and ticagrelor are similarly effective during the first year after MI. Economically motivated early post-discharge switches to clopidogrel were not associated with an increased risk of ischemic events. (Comparison of Prasugrel and Ticagrelor in the Treatment of Acute Myocardial Infarction [PRAGUE-18]; NCT02808767). PMID- 29154814 TI - Effects of aquarobic exercise and burdock intake on serum blood lipids and vascular elasticity in Korean elderly women. AB - BACKGROUND: The elderly's health issues are often complex and tend to lead to chronic diseases; such issues can be due to a fitness decline resulting from a lack of physical activities. The burdock root is a blood purifier, lymphatic system strengthener, and natural diuretic. The purpose of this study was to analyze the effects of aquarobic exercise and burdock intake on serum blood lipids and vascular elasticity in elderly women by implementing a 12-week program with these interventions. METHODS: Forty elderly female volunteer subjects aged 70 to 80years comprised the control group (n=8), aquarobic exercise group (n=11), aquarobic exercise and burdock intake combination group (n=11), and burdock intake group (n=10). The variables of serum blood lipids, and vascular elasticity were measured in all participants before and after the 12-week study. RESULTS: Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels significantly decreased in the aquarobic exercise group and aquarobic exercise and burdock intake combination group (p<0.05, p<0.01, p<0.001). No statistically significant changes in pulse wave velocity were also found within or between the groups before and after participation in the 12-week program. CONCLUSIONS: Our findings indicate that aquarobic exercise and burdock intake improved the serum blood lipid levels and vascular elasticity of Korean elderly women. Additionally, burdock extract intake may be useful in vascular health by playing a secondary role in disease prevention and health promotion. PMID- 29154815 TI - Vitamin D and new-onset atrial fibrillation: A meta-analysis of randomized controlled trials. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, which affects 1.5% to 2% of the general population. More than six million Europeans suffer from AF. To research vitamin D levels in the prevention of new-onset atrial fibrillation (AF), we conducted a systematic review of randomized controlled trials (RCTs). We focused on the vitamin D levels in the prevention of new-onset AF. The outcomes assessed were vitamin D levels, left ventricular ejection fraction (LVEF), and left atrium diameter. Six RCTs ultimately met the inclusion criteria in the meta-analysis. The outcomes of Vitamin D levels (MD = 4.27, 95% CI = -5.20 to-3.34, P = 0.30) in the new-onset AF showed no significant difference. The left atrium diameter (MD = 1.96, 95% CI = 1.48 to 2.60, P < 0.01) between new-onset AF and LVEF (MD = -0.92, 95% CI = -1.59 to -0.26, P < 0.01) showed significant difference. Our study shows that circulating vitamin D levels may not play a major role in the development of new-onset AF. PMID- 29154816 TI - Pacemaker malfunction risks within the electromagnetically rich hospital environment. PMID- 29154817 TI - Cancer stem cell-like population is preferentially suppressed by EGFR-TKIs in EGFR-mutated PC-9 tumor models. AB - AIMS: Although the epidermal growth factor receptor (EGFR) and Wnt/beta-catenin signaling systems synergistically regulate many essential developmental and regenerative processes in lung cancer, the mechanisms of their crosstalk remain poorly defined. Our study aimed to investigate an interaction between EGFR and the beta-catenin signal. RESULTS: In this study, we described a potent activation of beta-catenin by EGFR, which is dependent of the PtdIns3K/AKT pathway. We found EGF activated beta-catenin signaling via phosphorylation of EGFR and AKT in EGFR mutated PC-9 lung cancer cells. Meanwhile, EGFR tyrosine kinase inhibitors (EGFR TKIs) regulated cancer stem-like cells (CSCs) by inhibiting autophosphorylation of EGFR and downstream signaling proteins, as well as beta-catenin. Further, beta catenin depletion by RNA interference virtually eliminated cancer stem cell-like population in PC-9 cells in vitro. The nude mice transplantation model was also performed to confirm EGFR-TKIs strongly inhibited the beta-catenin signal and decreased CSCs. Importantly, the reduction of CSCs that sorted out by side population (SP) cells significantly reduced the migration capability. Thus, our results improved the understanding of this process to provide insights into mechanisms of responding to EGFR-TKIs. CONCLUSIONS: Our discoveries raise an intriguing question of the role of beta-catenin in EGFR-TKIs-treated cancer stem cell-like population(s) and its potential as a new therapeutic target for NSCLC in the future. PMID- 29154818 TI - MicroRNA-21 promotes wound healing via the Smad7-Smad2/3-Elastin pathway. AB - Wound healing is regulated by a complex network of cells, molecules, and cytokines, as well as microRNAs (miRNAs). miRNAs were confirmed to influence the wound healing process, and miR-21, an important member of the miRNA family, was also shown to regulate wound healing. The aim of the present study was to investigate the role of miR-21 in the wound healing process and the possible underlying cell signaling pathways. We isolated GMSCs from WT and miR-21-KO mouse gingiva. Flow cytometric analysis and immunocytofluorescense staining were used to identify the GMSCs acquired from WT and miR-21-KO mice. RT-PCR, western blot analysis and immunohistofluorescence staining were performed to examine the expression of extracellular matrix components and key proteins of cell signaling pathways. TargetScan and pmiR-RB-REPORT vectors were used to verify that Smad7 was a direct target of miR-21. Compared to WT mice, miR-21-KO mice showed slower wound healing. RT-PCR and western blot analysis indicated that Elastin expression was downregulated in miR-21-deficient samples. We confirmed that Smad7 was a direct target of miR-21. miR-21 knockout resulted in increased expression of Smad7 and impaired phosphorylation of the Smad2/3 complex. The expression of the Smad7-Smad2/3-Elastin axis in palate tissues sections acquired from WT and miR-21 KO mice showed the same trend. Based on all these results, we demonstrated that miR-21 promoted the wound healing process via the Smad7-Smad2/3-Elastin pathway. PMID- 29154819 TI - Abeta1-42 induces cell damage via RAGE-dependent endoplasmic reticulum stress in bEnd.3 cells. AB - Blood-brain barrier (BBB) breakdown has been determined to play a critical role in the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanisms of BBB disruption in AD remain unclear. Our previous study suggested that the receptor for advanced glycation end-products (RAGE) functioned as a signal transduction receptor in Abeta1-42-induced damage in endothelial cells. In our present study, we revealed that RAGE-mediated endoplasmic reticulum stress (ERS) is essential for Abeta-induced endothelial cell damage. Here, we found that Abeta1-42 activated ERS by upregulation of Grp78, xbp-1 and CHOP in endothelial cells and that Abeta1-42-resulted lesions, including the upregulations of caspase 12 and caspase-3, the augment of bax/bcl-2 ratio, and the downregulations of ZO-1 and Occludin in bEnd.3 cells, were ameliorated by the pretreatment of salubrinal, an ERS inhibitor. Furthermore, the expressions of Grp78, xbp-1 and CHOP induced by Abeta1-42 were blocked by transfection of RAGE small interfering RNA (siRNA), which indicated that Abeta1-42 activated ERS in a RAGE-dependent manner. Additionally, bEnd.3 cells transfected with RAGE siRNA showed lower expressions of caspase-12 and caspase-3, decreased bax/bcl-2 ratio, and higher expressions of ZO-1 and Occludin following Abeta1-42 treatment, comparing to control cells. In conclusion, our data demonstrated that Abeta1-42 induced endothelial cells damage via activation of ERS in a RAGE-dependent manner. PMID- 29154820 TI - Cytotoxic T cell responses to Streptococcus are associated with improved prognosis of oral squamous cell carcinoma. AB - Several species of Streptococcus, such as S. salivarius, S. mitis, and S. anginosus, are found to extensively colonize the oral cavity and the upper respiratory tract, and have been shown to increase in patients with oral squamous cell carcinoma (OSCC). Accumulating evidence have revealed that commensal bacteria are involved in antitumor immunity via T cell-mediated mechanisms, but the role of Streptococcus enrichment in OSCC is yet unclear. In this study, we stimulated peripheral blood mononuclear cells from non-cancer controls (NCs) and OSCC patients with S. salivarius, S. mitis, and S. anginosus. We observed that compared to NC subjects, OSCC patients at earlier stages had higher frequencies of granzyme B-expressing CD8 T cells for all Streptococcus species tested, while OSCC patients at more advanced stages had higher frequencies of granzyme B expressing CD8 T cells for S. anginosus but not other Streptococcus species. In OSCC patients, the Streptococcus-reactive CD8 T cells presented significantly lower levels of PD-1 and TIM-3 expression than Streptococcus-nonreactive CD8 T cells. The clinical outcomes of OSCC patients in our cohort were tracked for 24 months after the resection of the primary tumor. In patients that did not present tumor recurrence, the frequencies of S. salivarius-reactive and S. mitis-reactive CD8 T cells were significantly higher than that in patients that developed recurrent tumor. Furthermore, in patients with tumor recurrence, the duration between primary tumor resection and tumor recurrence was positively associated with the frequencies of S. salivarius-reactive and S. anginosus-reactive CD8 T cells. Together, we demonstrated that Streptococcus-reactive CD8 T cell responses might contribute to antitumor immunity in OSCC patients. PMID- 29154821 TI - Heterotaxy syndrome and associated arrhythmias in pediatric patients. AB - BACKGROUND: Heterotaxy syndrome (HS) is a rare disorder with complex anatomy involving misarrangements of the cardiac conduction system. Arrhythmias may be related to anatomic variations and contribute to morbidity. OBJECTIVE: The purpose of this study was to investigate the associations between arrhythmias, anatomy, and outcomes in a large HS cohort. METHODS: A single-center retrospective review of patients <=21 years of age diagnosed with HS was performed. RESULTS: A total of 337 patients were included in the study. During median follow-up of 7 years (interquartile range 2-16 years), 129 patients (38%) had >=1 clinically significant rhythm disturbance: tachyarrhythmias in 75 (22%), bradyarrhythmias in 29 (9%), and both in 25 (7%). Factors associated with tachyarrhythmia by multivariate analysis were at least moderate atrioventricular valve regurgitation (hazard ratio [HR] 1.66; 95% confidence interval [CI] 1.11 2.50), single ventricle anatomy (HR 2.30; 95% CI 1.09-4.85), and pulmonary venous obstruction (HR 2.33; 95% CI 1.45-3.76). Isomerism subtype was not associated with tachyarrhythmias. In adjusted and unadjusted analyses, bradyarrhythmias (symptomatic sinus/atrial bradycardia and high-grade or complete heart block) were associated with left atrial isomerism (LAI) compared to right atrial isomerism (HR 7.12; 95% CI 3.01-16.9). The overall transplant-free survival of the cohort was 66%. Tachyarrhythmias, but not bradyarrhythmias, were associated with mortality or need for transplant (HR 2.24; 95% CI 1.45-3.46). CONCLUSION: Clinically significant arrhythmias are common in HS. Although bradyarrhythmias are associated with LAI, tachyarrhythmia occurrence may depend more on hemodynamic and anatomic factors than isomerism subtype. Tachyarrhythmias, but not bradyarrhythmias, are associated with death or need for transplant. PMID- 29154822 TI - Mef2 and the skeletal muscle differentiation program. AB - Mef2 is a conserved and significant transcription factor in the control of muscle gene expression. In cell culture Mef2 synergises with MyoD-family members in the activation of gene expression and in the conversion of fibroblasts into myoblasts. Amongst its in vivo roles, Mef2 is required for both Drosophila muscle development and mammalian muscle regeneration. Mef2 has functions in other cell types too, but this review focuses on skeletal muscle and surveys key findings on Mef2 from its discovery, shortly after that of MyoD, up to the present day. In particular, in vivo functions, underpinning mechanisms and areas of uncertainty are highlighted. We describe how Mef2 sits at a nexus in the gene expression network that controls the muscle differentiation program, and how Mef2 activity must be regulated in time and space to orchestrate specific outputs within the different aspects of muscle development. A theme that emerges is that there is much to be learnt about the different Mef2 proteins (from different paralogous genes, spliced transcripts and species) and how the activity of these proteins is controlled. PMID- 29154823 TI - Regulation of cellular and PCP signalling by the Scribble polarity module. AB - Since the first identification of the Scribble polarity module proteins as a new class of tumour suppressors that regulate both cell polarity and proliferation, an increasing amount of evidence has uncovered a broader role for Scribble, Dlg and Lgl in the control of fundamental cellular functions and their signalling pathways. Here, we review these findings as well as discuss more specifically the role of the Scribble module in PCP signalling. PMID- 29154824 TI - Skeletal muscle development on the 30th Anniversary of MyoD. PMID- 29154825 TI - The SCF ubiquitin ligase Slimb controls Nerfin-1 turnover in Drosophila. AB - The C2H2 type zinc-finger transcription factor Nerfin-1 expresses dominantly in Drosophila nervous system and plays an important role in early axon guidance decisions and preventing neurons dedifferentiation. Recently, increasing reports indicated that INSM1 (homologue to nerfin-1 in mammals) is a useful marker for prognosis of neuroendocrine tumors. The dynamic expression of Nerfin-1 is regulated post-transcriptionally by multiple microRNAs; however, its post translational regulation is still unclear. Here we showed that the protein turnover of Nerfin-1 is regulated by Slimb, the substrate adaptor of SCFSlimb ubiquitin ligase complex. Mechanistically, Slimb associates with Nerfin-1 and promotes it ubiquitination and degradation in Drosophila S2R+ cells. Furthermore, we determined that the C-terminal half of Nerfin-1 (Nerfin-1CT) is required for its binding to Slimb. Genetic epistasis assays showed that Slimb misexpression antagonizes, while knock-down enhances the activity of Nerfin-1CT in Drosophila eyes. Our data revealed a new link to understand the underlying mechanism for Nerfin-1 turnover in post-translational level, and provided useful insights in animal development and disease treatment by manipulating the activity of Slimb and Nerfin-1. PMID- 29154826 TI - W9 peptide enhanced osteogenic differentiation of human adipose-derived stem cells. AB - W9 is a peptide that abrogates osteoclast differentiation via blockade of nuclear factor-kappaB ligand (RANKL)-RANK signaling, which activates bone formation. However, W9 stimulated osteogenesis in osteoblasts and mesenchymal stem cells. The present study demonstrated that the W9 peptide promoted osteogenic differentiation of human adipose-derived stem cells (hAdSCs) even under non osteogenic differentiation culture conditions. W9-treated hAdSCs exhibited several osteocalcin-expressing cells and great mineralization compared to the BMP2-treated hAdSCs, which suggests that the W9 peptide had potent osteogenic potential in hAdSCs. W9 treatment also markedly enhanced the phosphorylation of p38, JNK, Erk1/2, and Akt, and BMP2 treatment only enhanced the phosphorylation of p38 and Erk1/2 in hAdSCs. hAdSCs did not express the RANKL gene, but W9 treatment upregulated Runx2, Collagen type 1A1 and TGF receptor genes and increased Akt phosphorylation. These results suggest that the W9-induced potent osteogenic induction was attributed to activation of TGF and the PI3 kinase/Akt signaling pathway in hAdSCs. PMID- 29154827 TI - Secretogranin III promotes angiogenesis through MEK/ERK signaling pathway. AB - Secretogranin III (Scg3) was recently discovered as the first highly diabetic retinopathy-associated angiogenic factor, and its neutralizing antibody alleviated the disease with high efficacy in diabetic mice. Investigation of its molecular mechanisms will facilitate the translation of this novel therapy. Scg3 was reported to induce the phosphorylation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). Here we characterized the importance of MEK/ERK activation to Scg3 angiogenic activity. Our results showed that MEK inhibitor PD98059 blocked Scg3-induced proliferation of human umbilical vein endothelial cells (HUVECs). This finding was corroborated by PD98059 inhibition of HUVEC migration and tube formation. Furthermore, ERK inhibitor SCH772984 also suppressed Scg3-induced proliferation and migration of HUVECs. Taken together, these findings suggest that MEK-ERK pathway plays an important role in Scg3-induced angiogenesis. PMID- 29154828 TI - Interaction assessments of the first S-adenosylmethionine competitive inhibitor and the essential interacting partner methylosome protein 50 with protein arginine methyltransferase 5 by combined computational methods. AB - Protein arginine methyltransferase 5 (PRMT5) is the most promising anticancer target in PRMT family. In this study, based on the first S-adenosylmethionine (SAM) competitive small molecule inhibitor (17, compound number is from original paper) of PRMT5 reported in our recent paper, we determined the molecular mechanism of 17 interacting with PRMT5 by computational methods. Previously reported CMP5 was also thought of as a SAM competitive inhibitor of PRMT5, but the direct inhibition activity against PRMT5 at enzymatic level was not provided. Therefore, we tested the half-maximal inhibitory concentration (IC50) of CMP5 against PRMT5 at enzymatic level for the purpose of summarizing the interaction characteristics of SAM binding site inhibitors with PRMT5. Additionally, as the essential interacting partner of PRMT5, the binding attributes of the WD-repeat containing protein MEP50 (methylosome protein 50) was investigated, and nine key residues that contribute most to PRMT5:MEP50 interaction were identified. These results could be helpful in discovering new potent and specific inhibitors of PRMT5, as well as in designing mutant residue assay to modulate the catalytic activity of PRMT5. PMID- 29154829 TI - A role for Candida albicans superoxide dismutase enzymes in glucose signaling. AB - The Saccharomyces cerevisiae and Candida albicans yeasts have evolved to differentially use glucose for fermentation versus respiration. S. cerevisiae is Crabtree positive, where glucose represses respiration and promotes fermentation, while the opportunistic fungal pathogen C. albicans is Crabtree negative and does not repress respiration with glucose. We have previously shown that glucose control in S. cerevisiae involves the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1), where H2O2 generated by SOD1 stabilizes the casein kinase YCK1 for glucose sensing. We now demonstrate that C. albicans SODs also participate in glucose regulation. C. albicans expresses two cytosolic SODs, Cu/Zn SOD1 and Mn containing SOD3, and both complemented a S. cerevisiae sod1Delta mutant in stabilizing YCK1. Moreover, in C. albicans cells, both SODs functioned to repress glucose transporter genes in response to glucose. However, the action of SODs in glucose control has diverged in the two yeasts. In S. cerevisiae, SOD1 specifically functions in the glucose sensing pathway involving YCK1 and the RGT1 repressor, but the analogous YCK/RGT1 pathway in C. albicans shows no control by SOD enzymes. Instead C. albicans SODs work in the glucose repression pathway involving the MIG1 transcriptional repressor. In C. albicans, the SODs repress glucose uptake, while in S. cerevisiae, SOD1 activates glucose uptake, in accordance with the divergent modes for glucose utilization in these two distantly related yeasts. PMID- 29154830 TI - Understanding mechanisms to promote successful aging in persons living with HIV. AB - The mortality rate associated with HIV infection plummeted after the introduction of effective antiretroviral therapy pioneered two decades ago. As a result, HIV infected people now have life expectancies comparable to that of HIV-uninfected individuals. Despite this, increased rates of osteoporosis, chronic liver disease, and in particular cardiovascular disease have been reported among people living with HIV infection. With the aging HIV-infected population, the burden of these comorbid illnesses may continue to accrue over time. In this paper, we present an overview of the aging HIV-infected population, its epidemiology and the many challenges faced. How to define and measure successful aging will also be reviewed. Finally, opportunities that may help mitigate the challenges identified and ensure successful aging among people living with HIV infection will be examined. PMID- 29154831 TI - Detection of Mycobacterium tuberculosis-derived DNA in circulating cell-free DNA from a patient with disseminated infection using digital PCR. AB - Mycobacterium tuberculosis (MTB) can disseminate to extrapulmonary organs, particularly in severely immunosuppressed patients. Confirmation of active MTB infection is often difficult in subjects with a contraindication for invasive procedures. A case of disseminated MTB infection after hematopoietic stem cell transplantation is reported herein. Circulating cell-free DNA from the patient showed positive amplification of an MTB complex-specific sequence using a digital PCR technique. The MTB infection was confirmed by positive acid-fast staining and an approved quantitative PCR assay using liver tissue obtained at autopsy. The detection of MTB in circulating cell-free DNA using this technique may represent a less invasive diagnostic tool for pulmonary and extrapulmonary MTB infections. PMID- 29154832 TI - Carboxylesterase genes in pyrethroid resistant house flies, Musca domestica. AB - Carboxylesterases are one of the major enzyme families involved in the detoxification of pyrethroids. Up-regulation of carboxylesterase genes is thought to be a major component of insecticide resistant mechanisms in insects. Based on the house fly transcriptome and genome database, a total of 39 carboxylesterase genes of different functional clades have been identified in house flies. In this study, eleven of these genes were found to be significantly overexpressed in the resistant ALHF house fly strain compared with susceptible aabys and wild-type CS strains. Eight up-regulated carboxylesterase genes with their expression levels were further induced to a higher level in response to permethrin treatments, indicating that constitutive and inductive overexpression of carboxylesterases are co-responsible for the enhanced detoxification of insecticides. Spatial expression studies revealed these up-regulated genes to be abundantly distributed in fat bodies and genetically mapped on autosome 2 or 3 of house flies, and their expression could be regulated by factors on autosome 1, 2 and 5. Taken together, these results demonstrate that multiple carboxylesterase genes are co-upregulated in resistant house flies, providing further evidence for their involvement in the detoxification of insecticides and development of insecticide resistance. PMID- 29154833 TI - Photo-based PDT/PTT dual model killing and imaging of cancer cells using phycocyanin-polypyrrole nanoparticles. AB - Photodynamic therapy (PDT) and photothermal therapy (PTT) using nanoparticles have gained significant attention for its therapeutic effect for cancer treatment. In the present study, we fabricated polypyrrole nanoparticles by employing bovine serum albumin-phycocyanin complex and the formulated particles were stable in various physiological solutions like water, phosphate buffered saline and culture media. The formulated nanoparticles did not cause any noticeable toxicity to MDA-MB-231 and HEK-293 cells. The obtained nanoparticles effectively killed MDA-MB-231 cells in a dual way upon laser illumination, one is through phycocyanin propagated reactive oxygen species (PDT) upon laser illumination and in another way it eradicated the treated cells by converting optical energy into heat energy (PTT). Additionally, the nanoparticles generated good amplitude of ultrasound signals under photoacoustic imaging (PAT) system that facilitates imaging of treated cells. In conclusion, the fabricated particles could be used as a multimodal therapeutic agent for treatment of cancer in the biomedical field. PMID- 29154834 TI - Development and characterization of docetaxel-loaded lecithin-stabilized micellar drug delivery system (LsbMDDs) for improving the therapeutic efficacy and reducing systemic toxicity. AB - In the present study, we attempted to develop a lecithin-stabilized micellar drug delivery system (LsbMDDs) for loading docetaxel (DTX) to enhance its therapeutic efficacy and minimize systemic toxicity. A novel DTX-loaded LsbMDDs was optimally prepared by a thin-film hydration method and then hydrated with a lecithin nanosuspension while being subjected to ultrasonication. Physical characteristics of the optimized DTX-loaded LsbMDDs formulations were examined and found to have a mean size of <200 nm, an encapsulation efficiency of >90%, and drug loading of >6% with stability at room temperature and at 4 degrees C being longer than 2 and 7 days, respectively. The in vitro release of DTX from the DTX-loaded LsbMDDs was slower than that from the generic product of DTX (Tynen(r)). A cell viability assay demonstrated that the LsbMDDs showed better cytotoxicity than Tynen(r) against CT26 cancer cells. The in vivo antitumor efficacy of the DTX-loaded LsbMDDs was observed to be better than that of Tynen(r) in a CT26 tumor-bearing mice model. A high-dose regimen of the DTX-loaded LsbMDDs formulation showed greater inhibition of DU145 tumor growth than did Tynen(r), but with less to similar systemic toxicity. An in vivo study also showed that a greater amount of drug was able to accumulate in the tumor site with the DTX-loaded LsbMDDs, and its maximal tolerable doses for single and repeated injections were 2-2.5-fold higher than those of Tynen(r). In conclusion, the LsbMDDs could be a promising high drug-loaded nanocarrier for delivering hydrophobic chemotherapeutic agents that can enhance the efficacy of chemotherapy and reduce systemic toxicity. PMID- 29154835 TI - SIRT5 and post-translational protein modifications: A potential therapeutic target for myocardial ischemia-reperfusion injury with regard to mitochondrial dynamics and oxidative metabolism. AB - SIRT5 is a sirtuin family member that participates in dynamic and reversible protein chemical modification after translation. It has pivotal roles in the regulation of numerous aspects of myocardial energy metabolism and cardiac functions. Recent studies suggest that down-regulation of this regulator significantly increased the extent of myocardial infarction during ischemia reperfusion injury (IRI). Accordingly, SIRT5 is emerging as a major contributor to the pathogenesis of IRI and may possess therapeutic potential for reversing mitochondrial respiratory chain disturbances and cellular damage attributed to ischemia-reperfusion. To better understand this specific mechanism, we reviewed the structure of SIRT5, its gene distribution and the SIRT5 pathways that influence myocardial IRI associated with mitochondrial dynamics and oxidative phosphorylation. PMID- 29154836 TI - A new promising simultaneous approach for attenuating type II diabetes mellitus induced neuropathic pain in rats: iNOS inhibition and neuroregeneration. AB - In view of the pathologic basis for the treatment of diabetic neuropathy, it is important to enhance nerve regeneration as well as prevent nerve degeneration. So, in the present study, we have investigated the effect of S-Methylisothiourea Sulfate (selective iNOS inhibitor) and Citicoline, alone and in combination, on Type II diabetes mellitus induced neuropathic pain in wistar rats. Type II diabetes was induced by providing high fat diet and low dose of Streptozotocin for 35 days in rats. Type II diabetes mellitus was assessed in terms of increased glucose, triglycerides, cholesterol, LDL levels, glucose tolerance and decrease in HDL levels. Neuropathy as the complication of type II diabetes was assessed in terms of decreased nerve conduction velocity, mechanical and thermal hyperalgesia and cold allodynia. Oxidative stress was assessed in sciatic nerve and showed increase in LPO and nitrite levels whereas decrease was shown in GSH and catalase activity. Axonal degeneration marked by nerve fibre dearrangement and demyelination was observed in histopathological studies. SMT (iNOS inhibitor), Citicoline and low dose combination of both drugs significantly attenuates the diabetic neuropathic pain assessed in terms of parameters employed. Thus, it may be concluded that simultaneous administration of SMT and Citicoline may provide potential therapeutics for diabetic neuropathic pain. PMID- 29154837 TI - Neuroprotective effect of an Nrf2-ARE activator identified from a chemical library on dopaminergic neurons. AB - The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway, which induces the production of antioxidant enzymes, is a possible therapeutic target for treating diseases related to oxidative stress. Nrf2 activators often exhibit cytotoxicity due to nonspecific electrophilic reactions with thiol groups. We screened a chemical library to explore Nrf2 activators with a wide safety margin. In at least in vitro experiments, TPNA10168, identified from the library, showed a higher efficacy in Nrf2 activation and a lower cytotoxicity than sulforaphane, a well-known Nrf2 activator. The present study demonstrated the protective effect of TPNA10168 against 6-hydroxydopamine-induced cytotoxicity. In PC12 cells, NAD(P)H:quinone oxidoreductase 1 was upregulated by TPNA10168 and participated in the protective effect. In primary mesencephalic cultures, heme oxygenase-1, upregulated by TPNA10168 in astrocytes, provided protection of dopaminergic neurons via a guanylate cyclase/protein kinase G signaling pathway via carbon monoxide. These results suggest that the compound identified from the chemical library may be suitable as a neuroprotective agent with the ability to induce antioxidant enzymes. PMID- 29154838 TI - TP-0903 inhibits neuroblastoma cell growth and enhances the sensitivity to conventional chemotherapy. AB - Neuroblastoma (NB) is an embryonal tumor with low cure rate for patients classified as high-risk. This class of NB tumors shows a very complex genomic background and requires aggressive treatment strategies. In this work we evaluated the efficacy of the novel multi-kinase inhibitor TP-0903 in impairing NB cells' growth, proliferation and motility. In vitro studies were performed using cell lines with different molecular background, and in vivo studies were done using the zebrafish experimental model. Our results confirmed a strong cytotoxicity of TP-0903 already at the sub-micro molar concentrations. The observed cytotoxicity of TP-0903 was irreversible and the resulting apoptosis was caspase dependent. In addition, TP-0903 impaired colony formation and neurosphere creation. Depending on the molecular background of the selected NB cell lines, TP 0903 influenced either their capacity to migrate, to complete their cell cycle or both. Likewise, TP-0903 reduced NB cells intravasation in vitro and in vivo. Importantly, TP-0903 showed remarkable pharmacological efficacy not only as a mono-treatment, but also in combination with conventional chemotherapy drugs (ATRA, cisplatin, and VP16) in different types of NB cells. In conclusion, the multi-kinase activity of TP-0903 allowed the impairment of several biological processes required for expansion of NB cells, making them more vulnerable to the conventional chemotherapeutics. Altogether, our results support the eligibility of TP-0903 for further (pre)clinical assessments in NB. PMID- 29154840 TI - Thoughts on improving medication use. PMID- 29154839 TI - Participation of the anti-inflammatory and antioxidative activity of docosahexaenoic acid on indomethacin-induced gastric injury model. AB - Adverse gastrointestinal (GI) effects caused by nonsteroidal anti-inflammatory drugs (NSAIDs), including indomethacin, are recognized as the major limitation to their clinical use. NSAID-induced gastric damage is generated by cyclooxygenase inhibition, activation of inflammatory processes, and oxidative stress. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, has shown gastroprotective effects; however, the molecular mechanisms underlying these effects have not been fully explained. As a result, the aim of this study was to examine DHA's anti-inflammatory and antioxidative actions in a mouse model of indomethacin-induced gastric injury. Oral administration of DHA (3, 10, 30, and 100mg/kg) caused a reduction in indomethacin-induced gastric hemorrhagic lesions. We found that the gastroprotective effects of DHA treatment (100mg/kg) were accompanied by decreases in several parameters: in leukocyte recruitment; gastric levels of myeloperoxidase; leukotriene B4; intercellular adhesion molecule-1; tumor necrosis factor alpha; and nuclear translocation of nuclear factor-kB. Concurrently, we observed an improvement in antioxidant defenses produced by the increase in superoxide dismutase and glutathione activities but not catalase; in addition, a decrease in some oxidative damage markers such as malondialdehyde and carbonyl proteins in lipids and proteins was observed. Furthermore, resolvin D1 production and expression of free fatty acid receptor 4 were stimulated by DHA. Therefore, this study identified the antioxidant and anti-inflammatory actions of DHA as the main mechanisms involved in DHA's gastroprotective effects against indomethacin-induced gastric damage. PMID- 29154841 TI - Grateful and thankful. PMID- 29154843 TI - Clinical isolates of Escherichia coli solely resistant to mecillinam: prevalence and epidemiology. AB - In routine susceptibility testing of Gram-negative bacteria, a particular resistance phenotype was observed: an Escherichia coli isolate from a urine sample exhibited resistance solely to mecillinam (MEC) but was fully susceptible to other beta-lactam antibiotics (MEC-R-BL-S). The objectives as this study were to determine the prevalence of this phenotype and to describe the phenotype, molecular epidemiology and genetic background. Between 1 January 2014 and 31 January 2016, MEC-R-BL-S E. coli isolates from urine were collected and genes previously reported as mostly involved in MEC resistance were analysed. The genetic relatedness among isolates was investigated by repetitive element sequence-based PCR (rep-PCR) and multilocus sequence typing (MLST). Ten MEC-R-BL S isolates were collected, accounting for 0.4% (10/2547) of all E. coli obtained from urine samples, 0.9% (10/1135) of ampicillin-susceptible E. coli isolates and 9.6% (10/104) of MEC-R E. coli isolates. The isolates appeared as small colonies with round morphology and had impaired fitness. The isolates were not clonal and belonged to various extraintestinal or commensal E. coli phylogroups. Mutations in the cysB gene were evidenced in all clinical isolates. In conclusion, microbiologists should be aware of these isolates with a particular susceptibility phenotype, which is not due to error in disk diffusion but is a real non-enzymatic antibiotic resistance pattern. PMID- 29154842 TI - Delay in an Eating Disorder Diagnosis: The Reason Was a "Shox". AB - BACKGROUND: Patients' underlying medical conditions might affect the presentation and progression of an eating disorder. CASE: We describe a patient with an undiagnosed, rare, genetic skeletal dysplasia with effects on body mass index that likely led to body image distortion and delayed the diagnosis of an eating disorder. SUMMARY AND CONCLUSION: It is critical to fully assess disordered eating in the context of each patient's clinical status. PMID- 29154844 TI - Anticoccidial effects of areca nut (Areca catechu L.) extract on broiler chicks experimentally infected with Eimeria tenella. AB - To study the anticoccidial effects of areca nut extract (ANE) on coccidiosis, 270 one-day old Wenchang broiler chicks were divided into six equal groups, each with three replicate cages (n = 15 per cage). The six groups were the blank control group (BC), negative control group (NC), positive control group (PC), and three ANE-treated groups. The birds in the three control groups (BC, NC and PC) were fed a basal diet without ANE supplementation. The birds in the three ANE-treated groups were fed a basal diet supplied with ANE at 100 (T1), 200 (T2), or 300 (T3) mg/kg feed. At 15 days of age, the birds in the NC, PC and the three ANE groups were challenged orally with 1 * 105Eimeria tenella oocysts per chick. At 48 h after oocysts inoculation, the birds in group PC were supplied diclazuril with drinking water for 5 days. The results showed that ANE and diclazuril significantly improved feed intake and body weight gain (P < 0.05) relative to the NC group. Both ANE and diclazuril significantly (P < 0.05) reduced OPG on day 4-9 post-inoculation (p.i.) relative to the NC group. Coccidial infection damaged the integrity of the cecal mucosa and thickened cecal tunica muscularis. ANE and diclazuril mitigated the mucosal damage caused by coccidial infection. Diet ANE supplementation reduced the cecal lesion scores compared to the NC group (P < 0.05). ANE and diclazuril increased nitric oxide (NO) levels at 3 days p.i., but reduced NO levels at 6 days p.i. (P < 0.05) compared to the NC group. Diet ANE supplementation increased the concentration of interleukin 2 (IL-2) in infected chicken relative to the NC group. The current results showed the anticoccidial properties, and beneficial effect on intestinal mucosa damage of ANE in broiler chicks challenged with coccidiosis. PMID- 29154845 TI - Effects of trans-stilbene and terphenyl compounds on different strains of Leishmania and on cytokines production from infected macrophages. AB - Most of the antileishmanial modern therapies are not satisfactory due to high toxicity or emergence of resistance and high cost of treatment. Previously, we observed that two compounds of a small library of trans-stilbene and terphenyl derivatives, ST18 and TR4, presented the best activity and safety profiles against Leishmania infantum promastigotes and amastigotes. In the present study we evaluated the effects of ST18 and the TR4 in 6 different species of Leishmania and the modifications induced by these two compounds in the production of 8 different cytokines from infected macrophages. We observed that TR4 was potently active in all Leishmania species tested in the study showing a leishmanicidal activity higher than that of ST18 and meglumine antimoniate in the most of the species. Moreover, TR4 was able to decrease the levels of IL-10, a cytokine able to render the host macrophage inactive allowing the persistence of parasites inside its phagolysosome, and increase the levels of IL-1beta, a cytokine important for host resistance to Leishmania infection by inducible iNOS-mediated production of NO, and IL-18, a cytokine implicated in the development of Th1-type immune response. PMID- 29154847 TI - Behavioural informatics for improving water hygiene practice based on IoT environment. AB - The development of Internet of Things (IoT) and latest Information and Communication Technologies (ICT) have changed the nature of healthcare monitoring and health behaviour intervention in many applications. Water hygiene and water conservation behaviour intervention as important influence factors to human health are gaining much attentions for improving sustained sanitation practice. Based on face-to-face delivery, typical behaviour intervention method is costly and hardly to provide all day access to personalised intervention guidance and feedbacks. In this study, we presented a behavioural information system and water use behaviour model using IoT platform. Using Expanded Theory of Planned Behaviour (ETPB) and adopted structure equation model, this study offers a solution for understanding the behaviour intervention mechanism and methodology for developing empirical model. A case study of behaviour intervention model is presented by utilising residential water conservation behaviour data collected in China. Results suggested that cultural differences have significant influences on the understanding of intervention drivers, promoting projects and increasing awareness, which could improve the behaviour intervention efficiency and further facilitate the improvement of water hygiene practice. The performance evaluation of water saving dimension is discussed as well in the paper. PMID- 29154846 TI - Effect of Piper betle on Giardia intestinalis infection in vivo. AB - Piper betle has been used as a medicinal plant in traditional medical systems throughout South and South East Asia. Experimental studies have revealed its wide and diverse biological and pharmacological effects. In this study, antigiardial activity of Piper betle was tested using experimental infections of Giardia intestinalis, the most common cause of protozoal diarrhoea worldwide, in Mongolian gerbils. Plants were extracted in water, methanol and methanol:tetrahydrofuran. Gerbils were treated for ten days intragastrically twice a day, with the dose of 40 mg of the extract per 100 g of body weight. Drug metronidazole was used as a negative control. Gerbils' faeces were taken every day and examined by flotation method, the number of shed cysts were counted using a haemocytometer. After gerbils' sacrifice and dissection, their duodena were then processed for examination using histological sectioning and scanning electron microscopy. The antigiardial activity was evaluated by the course of cyst shedding throughout the entire experiment. A significant decline in cyst shedding, evaluated by linear regression was found in gerbils treated with the aqueous extract. Our results indicate that the aqueous extract of P. betle shows giardicidal effects. PMID- 29154848 TI - Role of Clinical and Surgical Factors for the Prediction of Immediate, Early and Late Functional Results, and its Relationship with Cardiovascular Outcome after Partial Nephrectomy: Results from the Prospective Multicenter RECORd 1 Project. AB - PURPOSE: We sought to determine the predictors of short-term and long-term renal function impairment after partial nephrectomy. MATERIALS AND METHODS: Clinical data on 769 consecutive patients who underwent partial nephrectomy were prospectively recorded at a total of 19 urological Italian centers from 2009 to 2012 in the RECORd 1 (Italian Registry of Conservative Renal Surgery) Project. We extracted clinical data on 708 of these patients who were alive, free of recurrent disease and with a minimum 2-year functional followup. RESULTS: Of the patients 47.3% underwent open, 36.6% underwent laparoscopic and 16.1% underwent robot-assisted partial nephrectomy. The median baseline estimated glomerular filtration rate was 84.5 ml/minute/1.73 m2 (IQR 69.9-99.1). Immediate (day 3 postoperatively), early (month 1) and late (month 24) renal function impairment greater than 25% from baseline was identified in 25.3%, 21.6% and 14.8% of cases, respectively. Female gender and the baseline estimated glomerular filtration rate were independent predictors of immediate, early and late renal function impairment. Age at diagnosis was an independent predictor of immediate and late impairment. Uncontrolled diabetes was an independent predictor of late impairment only. Open and laparoscopic approaches, and pedicle clamping were independent predictors of immediate and early renal function impairment. Overall 58 of 529 patients (11%) experienced postoperative cardiovascular events. Body mass index and late renal function impairment were independent predictors of those events. CONCLUSIONS: Surgically modifiable factors were significantly associated with worse immediate and early functional outcomes after partial nephrectomy while clinically unmodifiable factors affected renal function during the entire followup. Late renal function impairment is an independent predictor of postoperative cardiovascular events. PMID- 29154849 TI - Spinal Anesthesia is Associated with Lower Recurrence Rates after Resection of Nonmuscle Invasive Bladder Cancer. AB - PURPOSE: We sought to determine whether anesthetic type (general vs spinal) would influence cancer recurrence following transurethral resection of bladder tumors. MATERIALS AND METHODS: With institutional ethics board approval we examined the electronic medical records of all patients who underwent transurethral bladder tumor resection for nonmuscle invasive urothelial bladder cancer between 2011 and 2013 at a single tertiary care center. Followup information was gathered on all patients in December 2016. The time to first cancer recurrence and the incidence of cancer recurrence were the main outcome measures. RESULTS: A total of 231 patients underwent 1 or more transurethral bladder tumor resections between 2011 and 2013. Of the 231 patients 135 received spinal anesthesia and 96 received general anesthesia. On univariable analysis the 135 patients who received spinal anesthesia had a longer median time to recurrence than the 96 who received general anesthesia (42.1 vs 17.2 months, p = 0.014). As anticipated, adjuvant therapies and risk category were associated with recurrence rates (p = 0.003 and 0.042, respectively). On multivariable analyses incorporating a priori variables of nonmuscle invasive bladder cancer risk stratification and postoperative therapies the patients who received general anesthesia had a higher incidence of recurrence (OR 2.06, 95% CI 1.14-3.74, p = 0.017) and an earlier time to recurrence (HR 1.57, 95% CI 1.13-2.19, p = 0.008) than those who received spinal anesthesia. Anesthetic type was not associated with cancer progression or overall mortality. CONCLUSIONS: Patients who received spinal anesthesia had a lower incidence of recurrence and a delayed time to recurrence following transurethral bladder tumor resection for nonmuscle invasive bladder cancer. These findings should prompt large-scale prospective studies to confirm this association. PMID- 29154850 TI - Motor Response Matters: Optimizing Lead Placement Improves Sacral Neuromodulation Outcomes. AB - PURPOSE: We sought to determine the usefulness of motor responses during sacral neuromodulation lead placement by testing the hypothesis that a greater number of motor responses during intraoperative electrode testing would be associated with more durable therapy. MATERIALS AND METHODS: We retrospectively reviewed all sacral neuromodulation lead placements at a large academic center from 2010 to 2015. Included in study were all unilateral sacral lead placements for which the presence or absence of a motor response was documented discretely for each electrode. Motor responses were quantified into separate subscores, including bellows and toe response subscores (each range 0 to 4) for a possible maximum total score of 8 when combined. Revision surgery was the primary outcome. Univariate and multivariate analyses were performed for factors associated with lead revision. RESULTS: A total of 176 lead placements qualified for analysis. Mean +/- SD cohort age was 58.4 +/- 15.9 years, 86.4% of the patients were female and 93.2% had undergone implantation for overactive bladder. Median followup was 10.5 months (range 2 to 36). Overall 34 patients (19%) required lead revision. Revision was negatively associated with the total electrode response score (p = 0.027) and the toe subscore (p = 0.033) but not with the bellows subscore (p = 0.183). Predictors of revision on logistic regression included age less than 59 years at implantation (OR 5.5, 95% CI 2-14) and a total electrode response score less than 4 (OR 4.2, 95% CI 1.4-12.8). CONCLUSIONS: Fewer total electrode responses and specifically fewer toe responses were associated with sacral neuromodulation lead revision. These data suggest that placing a lead with more toe responses during testing may result in more durable sacral neuromodulation therapy. PMID- 29154851 TI - Effect of surgeon's experience on complications from laparoscopic hysterectomy. AB - OBJECTIVE: To analyze the effect of learning in two surgeons on complications and conversion to laparotomy during total and subtotal laparoscopic hysterectomy. MATERIAL AND METHODS: We analyzed retrospectively 236 total and subtotal laparoscopic hysterectomies done by two surgeons from the time they first performed the procedure. The interventions were classified in three groups based on the surgeon's experience: the first 75 hysterectomies ("novice period"), the subsequent 75 hysterectomies ("intermediate"), and the subsequent 86 hysterectomies ("routine period"). RESULTS: Patient's characteristics changed as surgeons gained experience, with more complex operations (greater obesity, previous surgery and malignant disease) becoming more frequent. During the second group of operations when surgeons had an intermediate level of experience, the risk of major complications decreased (adjusted odds ratio: 0.28, 95% confidence interval: 0.10-0.85), as did the risk of type III complications of Clavien-Dindo classification (adjusted odds ratio 0.15, 95% confidence interval: 0.03-0.93). However, the percent rate of conversion to laparotomy remained stable in the second (intermediate experience) group. In the third group, after the surgeons had performed 150 procedures and when the risk of any type of complication was lowest, the risk of conversion to laparotomy decreased compared to the routine group. CONCLUSIONS: The surgeon's experience in performing laparoscopic hysterectomy plays an essential role in the decrease in the risk of complications, and this finding supports the importance of providing appropriate training for residents and gynecologists to enable them to perform this procedure with an optimal degree of competence and safety. PMID- 29154852 TI - The mitochondrial uncoupling protein 2 gene is causal for the spontaneous polycystic liver diseases in mice. AB - Polycystic liver diseases (PCLDs) are autosomal dominant disorders. To date, 3 genes are known to be associated with the disease, SEC63 and PRKCSH and LRP5. Here, we report that mice deficient in the mitochondrial uncoupling protein 2 gene (Ucp2-/-) spontaneously developed PCLDs when they were over 12months old. Macroscopical observation, blood chemistry as well as histopathological analysis demonstrated the PCLDs found in Ucp2-/- mice were very similar to the findings in human PCLDs. This is the first report describing the gene encoding mitochondrial protein is causative for PCLDs. UCP2 may be a biomarker of the PCLDs in humans. PMID- 29154854 TI - Chicken IL-17A is expressed in alphabeta and gammadelta T cell subsets and binds to a receptor present on macrophages, and T cells. AB - IL-17A as important cytokine in host defense has been analysed intensively and various homologous have been identified. To further gain insight into the functional properties of chicken (gg) IL-17A its expression profile was analysed by intracellular cytokine staining. In splenocytes and peripheral blood mononuclear cells gg IL-17A was detected in subsets of CD4+ T cells and gammadelta T cells. In contrast the gg IL-17A producing populations in intestinal intraepithelial lymphocytes were characterized as either CD3+CD25+ cells or gammadelta T cells. Furthermore, using FLAG tagged gg IL-17A, binding to its receptor was demonstrated on the macrophage cell line HD11. In peripheral blood IL-17A binding activity was found on alphabeta and gammadelta T cell subsets, monocytes and a distinct population of CD25high cells. Treatment of HD11 cells with gg IL-17A induced IL-6 mRNA expression and nitric oxide production. These results demonstrate the presence of a alphabeta T helper17 cell subset and IL-17 producing gammadelta T cells in the chicken. PMID- 29154853 TI - Standards and Guidelines for Validating Next-Generation Sequencing Bioinformatics Pipelines: A Joint Recommendation of the Association for Molecular Pathology and the College of American Pathologists. AB - Bioinformatics pipelines are an integral component of next-generation sequencing (NGS). Processing raw sequence data to detect genomic alterations has significant impact on disease management and patient care. Because of the lack of published guidance, there is currently a high degree of variability in how members of the global molecular genetics and pathology community establish and validate bioinformatics pipelines. Improperly developed, validated, and/or monitored pipelines may generate inaccurate results that may have negative consequences for patient care. To address this unmet need, the Association of Molecular Pathology, with organizational representation from the College of American Pathologists and the American Medical Informatics Association, has developed a set of 17 best practice consensus recommendations for the validation of clinical NGS bioinformatics pipelines. Recommendations include practical guidance for laboratories regarding NGS bioinformatics pipeline design, development, and operation, with additional emphasis on the role of a properly trained and qualified molecular professional to achieve optimal NGS testing quality. PMID- 29154855 TI - Identification and characterization of a calcium-dependent lily-type lectin from black rockfish (Sebastes schlegelii): Molecular antennas are involved in host defense via pathogen recognition. AB - Lily-type lectins (LTLs) are soluble pathogen recognition receptors (PRRs) that contain one or more characteristic carbohydrate recognition domains (CRDs), through which LTLs bind reversibly and specifically to cognate sugar moieties present on the invading pathogen membrane and trigger the host innate immune responses. In this study, we identified a LTL homolog (SsLTL) from black rockfish (Sebastes schlegelii) transcriptome database and its functional roles in innate immunity was investigated in vitro and in vivo. Three mannose-binding sites were found in the protein sequence of SsLTL, among which two sites are conserved with those in mannose-binding lectins of monocotyledonous plants. SsLTL were highly expressed in both the external and internal mucosal tissues of healthy rockfish. During the immune challenge, early up-regulation of SsLTL mRNA expression showed in gill and blood upon both poly I:C and S. iniae challenges. In contrast, the challenge with lipopolysaccharide significantly down-regulated SsLTL expression in both examined tissues. Recombinant SsLTL showed a hemagglutination activity toward fish erythrocytes, which could be enhanced by the addition of calcium ions. Furthermore, strong agglutination activity of SsLTL was also observed with a broad range of fish pathogenic bacteria. Our results implied the crucial role of SsLTL as a PRR molecule in the black rockfish defense mechanism against invading microbial pathogens. PMID- 29154856 TI - Comparative study of two immunity-related GTPase genes in Chinese soft-shell turtle reveals their molecular characteristics and functional activity in immune defense. AB - The immunity-related GTPases (IRGs) are a family of proteins that play critical roles in innate resistance to intracellular pathogens. The number and diversity of IRG genes differ greatly in different species. Although IRG proteins have been well studies in mammals, they remain poorly characterized in lower vertebrates. In this study, we cloned two IRG genes, PsIRG5 and PsIRG8, from the Chinese soft shelled turtle and compared their characterization and functional activity with mammalian IRGs. The PsIRG5 is a gene of 1896 bp that encodes a protein of 413 amino acid and PsIRG8 is 1543 bp in length encoding another 413 aa protein. Sequence alignment between all turtle IRG-like genes and mammalian IRGs showed that both PsIRG5 and PsIRG8 were conserved with mammalian GKS IRGs, while PsIRG5 appeared a closer evolutionary relationship with mammalian GMS IRGs. The expression and subcellular characterization revealed that PsIRG5 was dramatically upregulated under Aeromonas hydrophila challenge and exhibited co-localization with lysosomes in cells; whereas PsIRG8 was downregulated and has no distinct localization. Functional activity assay demonstrated that PsIRG5 plays a role in autophagy induction and IFN-gamma contributes to enhance the induction, since it has IFN-inducible elements in its promoter region. These data above unravel the molecular characterization and functional activity of IRGs in lower vertebrate for the first time and will provide insights into the comparative immunity and evolutionary relationships of IRGs between mammals and reptiles. PMID- 29154857 TI - Astakines in arthropods-phylogeny and gene structure. AB - Astakine1 was isolated as a hematopoietic cytokine in the freshwater crayfish Pacifastacus leniusculus. In this study we detect and compare 79 sequences in GenBank, which we consider to be possible astakine orthologs, among which eleven are crustacean, sixteen are chelicerate and 52 are from insect species. Available arthropod genomes are searched for astakines, and in conclusion all astakine sequences in the current study have a similar exon containing CCXX(X), thus potentially indicating that they are homologous genes with the structure of this exon highly conserved. Two motifs, RYS and YP(N), are also conserved among the arthropod astakines. A phylogenetic analysis reveals that astakine1 and astakine2 from P. leniusculus and Procambarus clarkii are distantly related, and may have been derived from a gene duplication occurring early in crustacean evolution. Moreover, a structural comparison using the Mamba intestinal toxin (MIT1) from Dendroaspis polylepis as template indicates that the overall folds are similar in all crustacean astakines investigated. PMID- 29154859 TI - Expression of CGRP neurotransmitter and vascular genesis marker mRNA is age dependent in superior cervical ganglia of senescence-accelerated prone mice. AB - Calcitonin gene-related peptide (CGRP) is a neurotransmitter that is released from the superior cervical ganglion (SCG) and causes head and neck pain. The morphological properties of human SCG neurons, including neurotransmitter content, are altered during aging. However, morphological changes in CGRP in the SCG during aging are not known. Therefore, we investigated CGRP and other markers in the SCG during aging in an aging model of senescence-accelerated prone mouse (SAMP8) and senescence-accelerated resistant mice (SAMR1) using real-time RT-PCR mRNA analyses and in situ hybridization. The abundance of neurotransmitter (CGRP, NPY, TRPV1), vascular genesis marker (CD31, LYVE-1), and cytochrome C mRNA differed between 12-week-old and 24-week-old SAMP8 and SAMR1. Abundance of TRPV1, CD31 and cytochrome C mRNAs of SAMP8 decreased between 12- and 24-week-old. The ratio of CGRP mRNA positive cells and CGRP mRNA abundance levels of the SCG of aging mouse such as SAMP8 have already been also higher than that of SAMR1 at 12 week-old. The CGRP positive shrunken ganglion cells was increased from 12- to 24 weeks-old mouse in SAMR1 and SAMP8. The SCG primarily affected the internal and external carotid arteries, larynx thyroid gland, and pharyngeal muscle during aging. PMID- 29154858 TI - Visuospatial function predicts one-week motor skill retention in cognitively intact older adults. AB - Motor learning declines with aging, such that older adults retain less motor skill after practice compared to younger adults. However, it remains unclear if these motor learning declines are related to normal cognitive changes associated with aging. The purpose of this study was to examine which cognitive domains would best predict the amount of retention on a motor task one week after training in cognitively intact older adults. Twenty-one adults ages 65-84 years old were assessed with Repeatable Battery for the Assessment of Neuropsychological Status, which assesses five cognitive domains (immediate and delayed memory, visuospatial/constructional, language, and attention). Participants also completed one training session of a functional upper extremity task, and were re-tested one week later. Stepwise regression indicated that the visuospatial domain was the only significant predictor of how much skill participants retained over one week, with a visual perception subtest explaining the most variance. Results from this study support previous work reporting that older adults' capacity for motor learning can be probed with visuospatial tests. These tests may capture the structural or functional health of neural networks critical for skill learning within the aging brain, and provide valuable clinical insight about an individual's unique rehabilitation potential. PMID- 29154860 TI - The role of caveolin-1 in morphine-induced structural plasticity in primary cultured mouse cerebral cortical neurons. AB - Long-term repeated application of morphine induces plasticity changes in sensitive neurons, which represents the neurobiological basis of morphine addiction. Caveolin-1 (Cav-1) is an important scaffolding protein that plays a key role in the regulation of neurostructural plasticity. However, in-depth studies focused on the role of Cav-1 in morphine-induced changes in neurostructural plasticity are lacking. The present study explored the effects of Cav-1 on the expression levels of 2 markers of neurite outgrowth, growth association protein 43 (GAP-43) and microtubule-associated protein 2 (MAP-2), during the process of morphine-induced changes in the structural plasticity. A primary mouse cerebral cortical neuron culture was established, and Cav-1 knockdown was achieved. The results showed that morphine at a concentration of 10.0MUmol/L had no adverse effect on neuronal viability, but enhanced the Cav-1 and GAP-43 levels and induced the outgrowth of MAP-2-labeled neurites. The qRT PCR data showed that 10.0MUmol/L of morphine increased the Cav-1 mRNA level and promoted Cav-1 expression at the transcriptional level. Moreover, Cav-1 knockdown inhibited the morphine-induced upregulation of GAP-43 expression and the prolongation of MAP-2-labeled neurites. In conclusion, morphine was capable of inducing changes in the structural plasticity of primary cultured mouse cortical neurons, and Cav-1 played an important role in this process. Inhibition of Cav-1 expression reduced the morphine-induced increase in the neuronal growth markers GAP-43 and MAP-2. Thus, Cav-1 may be a potential molecular target for inhibiting morphine-induced neuroplasticity. PMID- 29154861 TI - Is saccade preparation required for inhibition of return (IOR)? AB - The effect of slower responses to validly than invalidly cued targets is known as inhibition of return (IOR). Opposing accounts of IOR have been proposed: one postulates a singular phenomenon explained by oculomotor mechanisms alone, while the other, more diverse account postulates both perceptual-cognitive and motor factors. In our research we considered the relation between motor programming and IOR. In an extended replication of an earlier study, using an eye abduction technique we restricted eye movement in the temporal half-space; this resulted in IOR attenuation in that area, compared to the unrestricted, nasal part of the visual field. Our results contradict the earlier result and demonstrate that IOR does depend on preparation of eye movement, as predicted by the oculomotor priming hypothesis. PMID- 29154862 TI - C21-steroidal glycosides and sesquiterpenes from the roots of Cynanchum bungei and their inhibitory activities against the proliferation of B and T lymphocytes. AB - Phytochemical investigation of the roots of Cynanchum bungei Decne (Asclepiadaceae) led to the elucidation of seven C21-steroidal glycosides (1-7) including three new compounds (1-3), named cynabungosides A-C, one new eudesmane type sesquiterpene (8), named cynabungone, and one new humulane-type sesquiterpene (9), named cynabungolide. Their structures were elucidated on the basis of extensive spectroscopic analysis. The absolute configurations of 8 and 9 were defined unequivocally by ECD analysis and X-ray crystallography, respectively. A putative biosynthetic pathway of humulane-type sesquiterpenes 9 and 10 is proposed. PMID- 29154863 TI - Development of a selective HPLC-DAD/ELSD method for the qualitative and quantitative assessment of commercially available Eurycoma longifolia products and plant extracts. AB - Aqueous extracts of the roots of Eurycoma longifolia are traditionally used to improve sexual performance, to treat infertility and other sexual dysfunctions but also to increase muscle strength. Nowadays, many different products are commercially available which are promoted as E. longifolia extracts and claim to possess beneficial aphrodisiac effects. Since such herbal aphrodisiac preparations have been recently the target of fraudulent product counterfeiting and because eurycomanone, one of the main quassinoids of E. longifolia, is suspected to possess toxic effects at higher concentrations, a highly selective HPLC-DAD/ELSD method has been established to analyze commercially available products and extracts of plant material. The presented method was established by the use of a mixture of 27 reference compounds for qualitative issues and fully validated according to the ICH guidelines for the quantification of three quassinoides: laurycolactone A, longilactone, and eurycomanone. The calibration curves of these showed a linearity over a range of 0.05 to 1.0mg/ml, with a regression coefficient not lower than R2=0.9969. The inter-day and intra-day precision (indicated as relative standard deviation) of the developed method was <2.9%. The recovery ranged from -3.3% to +6.0%. Eight randomly purchased products have been analyzed with this method, but only five of them contained E. longifolia compounds in detectable amounts. The concentration of eurycomanone in these products varied from 0.22+/-0.002mg eurycomanone per capsule to 1.84+/ 0.08mg corresponding to a maximal recommended daily intake of 0.76+/-0.02 to 31.90+/-0.21mg. PMID- 29154864 TI - Hydroxycinnamoylmalated flavone C-glycosides from Lemna japonica. AB - Three previously undescribed flavone C-glycosides (1-3), along with seven known ones (4-10), were isolated and characterized from the smallest flowering aquatic plant, Lemna japonica. On the basis of spectroscopic analysis and alkaline hydrolysis, compounds 1-3 were identified to be luteolin 6-C-(2"-O-trans-caffeoyl d-malate)-beta-glucoside (1), apigenin 6-C-(2"-O-trans-caffeoyl-d-malate)-beta glucoside (2), and luteolin 6-C-(2"-O-trans-coumaroyl-d-malate)-beta-glucoside (3). Compounds 1-3 are characteristic of a trans-coumaroyl-d-malate or trans caffeoyl-d-malate linked to C-2" of the glucose, which was reported for the first time. Compounds 1-3 exhibited weak cytotoxicity against HepG-2, SW-620, and A-549 cell lines, with IC50 values between 42.5 and 19.2MUg/ml, and moderate antioxidant activity. Meanwhile compound 3 displayed moderate nematocidal activity with an EC50 value of 1.56mg/ml. PMID- 29154865 TI - Serrulatic acid diastereomers identified from an antibacterial survey of Eremophila. AB - In an age of growing antimicrobial resistance, new antibacterial agents are desperately needed. A rapid antibacterial and phytochemical survey was designed to screen for antibacterial leads in plants. The survey was applied to over 90 Australian native plants from the genus Eremophila, revealing Eremophila complanata and E. nivea*E. drummondii as active against Gram positive bacteria. Thin layer chromatography with bioautography, flash chromatography and nuclear magnetic resonance led to the isolation and identification of two diastereomeric serrulatic acids. A single stereoisomer of 7,8,16-trihydroxyserrulat-19-oic acid has been previously described as its methyl ester. This paper describes the NMR of both serrulatic acids epimeric at C15 and their methyl esters, and demonstrates their Gram positive antibacterial activity. It is the first time that stereoisomers of this serrulatic acid have been found together in some Eremophila species. Further characterization of E. complanata additionally found an abundance of alpha-selinene and beta-selinene. The study validates a rapid survey approach to finding antibacterial phytochemicals. PMID- 29154866 TI - Activation of IGF-1/IGFBP-3 signaling by berberine improves intestinal mucosal barrier of rats with acute endotoxemia. AB - Insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) play a role in the maintenance of gut mucosal barrier function. Nevertheless, IGF-I/IGFBP-3 and tight junction protein (TJP) expression in small intestinal mucosa are often impaired during endotoxemia. In this model of acute endotoxemia, the regulatory effect of berberine on IGF-I/IGFBP-3 and TJP expression in ileal mucosa was evaluated. The findings revealed systemic injection of lipopolysaccharide (LPS) suppressed mRNA and protein expression of IGF-I and IGFBP-3, but berberine ameliorated their production. LPS injection inhibited occludin and claudin-1 protein generation, and this inhibitory effect of LPS was abolished by berberine. Inhibition of IGF-I/IGFBP-3 signaling by AG1024 or siRNAs reduced berberine induced occludin and claudin-1 production. Additionally, GW9662 was found to repress berberine-induced IGF-I/IGFBP-3 expression, indicating of a cross-link between PPARgamma and IGF-I/IGFBP-3 axis. PMID- 29154867 TI - Monoamine oxidases inhibitors from Colvillea racemosa: Isolation, biological evaluation, and computational study. AB - Bioassay-guided fractionation and chemical investigation of Colvillea racemosa stems led to identification of two new alpha, beta-dihydroxydihydrochalcones, colveol A (1) and colveol B (2) along with fifteen known compounds. The structures were elucidated via interpretation of spectroscopic data. The absolute configurations of the dihydrochalcones 1 and 2 were assigned by a combination of chemical modification and electronic circular dichroism data. The isolated compounds were evaluated for their inhibition activity toward recombinant human monoamine oxidases (rhMAO-A and -B). Compound 1 demonstrated preferential inhibition against hMAO-A isoenzyme (IC50 0.62MUM, SIA/B 0.02) while S-naringenin (13) and isoliquiritigein (15) demonstrated preferential hMAO-B inhibition (IC50 0.27 and 0.51MUM, SIA/B 31.77 and 44.69, respectively). Fisetin (11) showed inhibition against hMAO-A with IC50 value of 4.62MUM and no inhibitory activity toward hMAO-B up to 100MUM. Molecular docking studies for the most active compounds were conducted to demonstrate the putative binding modes. It suggested that 1 interacts with Gln215, Ala111, Phe352, and Phe208 amino acid residues which have a role in the orientation and stabilization of the inhibitor binding to hMAO-A, while S-naringenin (13) occupies both entrance and substrate cavities and interacts with Tyr326, a critical residue in inhibitor recognition in hMAO-B. PMID- 29154868 TI - Naphthoquinones from the leaves of Rhinacanthus nasutus having acetylcholinesterase inhibitory and cytotoxic activities. AB - Four new naphthoquinones (1-4), named rhinacanthins S (1), T (2), U (3) and V (4), together with 13 known naphthoquinones were isolated from the leaf extract of Rhinacanthus nasutus. The structures of isolated compounds were elucidated by spectroscopic methods, especially 1D and 2D NMR spectroscopy and mass spectrometry. Rhinacanthin S (1) exhibited acetylcholinesterase inhibition activity with a % inhibition value of 48.04+/-3.25. The known rhinacanthin A (5) showed cytotoxicity against a MCF-7 cell line with an IC50 value of 8.79MUM, while rhinacanthin N (15) was active against the NCI-H187 cell line with an IC50=2.24MUM and Vero cells (IC50=3.00MUM). PMID- 29154870 TI - The FTO variant is associated with chronic complications of diabetes mellitus in Czech population. AB - BACKGROUND: Genome-wide association studies have resulted in the identification of the FTO gene as an important genetic determinant of diabetes mellitus. The aim of this study was to confirm the role of this gene in the development of DM in the Czech-Slavonic population and to analyse whether this gene is associated with common DM complications. METHODS: Two groups of patients (814 with T1DM and 848 with T2DM) and a group of healthy controls (2339 individuals) - both of Czech origin - were genotyped for the FTO rs17817449 SNP. ANOVA and logistic regression were used for the statistical evaluations. RESULTS: The frequency of the GG genotype was significantly higher in T2DM (25.4% vs. 16.7%, P<0.0005) but not in T1DM patients (19.3% vs. 16.7%, P=0.20) than in controls. The increased risk of development of diabetic nephropathy was observed both for T1DM patients (GG vs. TT homozygotes, P<0.01) and T2DM patients (G carriers vs. TT homozygotes, P<0.05). FTO genotype predicted the development of diabetic neuropathy (GG vs. TT comparison; P<0.01) in the T2DM patients only. No association between FTO genotype and development of retinopathy was detected. All presented values are after adjustment for age, sex, BMI and duration of diabetes. CONCLUSIONS: We confirm the association between the FTO rs17817449 SNP and susceptibility to T2DM in the Czech-Slavonic population. The same variant is associated with a spectrum of chronic complications in both types of diabetes. PMID- 29154869 TI - Evaluating different DNA binding domains to modulate L1 ORF2p-driven site specific retrotransposition events in human cells. AB - DNA binding domains (DBDs) have been used with great success to impart targeting capabilities to a variety of proteins creating highly useful genomic tools. We evaluated the ability of five types of DBDs and strategies (AAV Rep proteins, Cre, TAL effectors, zinc finger proteins, and Cas9/gRNA system) to target the L1 ORF2 protein to drive retrotransposition of Alu inserts to specific sequences in the human genome. First, we find that the L1 ORF2 protein tolerates the addition of protein domains both at the amino- and carboxy-terminus. Although in some instances retrotransposition efficiencies slightly diminished, all fusion proteins containing an intact ORF2 were capable of driving retrotransposition. Second, the stability of individual ORF2 fusion proteins varies and difficult to predict. Third, DBDs that require the formation of multimers for target recognition are unlikely to modify targeting of ORF2p-driven insertions. Fourth, the more components needed to assemble into a complex to drive targeted retrotransposition, the less likely the strategy will increase targeted insertions. Fifth, abundance of target sequences present in the genome will likely dictate the effectiveness and efficiency of targeted insertions. Lastly, the cleavage capabilities of Cas9 (or a Cas9 nickase variant) are unable to substitute for the L1 ORF2 endonuclease domain functions, suggestive that the endonuclease domain has alternate functions needed for retrotransposition. From these studies, we conclude that the most critical component for the modification of the human L1 ORF2 protein to drive targeted insertions is the selection of the DBD due to the varying functional requirements and impacts on protein stability. PMID- 29154871 TI - Association between genetic polymorphisms in the promoters of let-7 and risk of cervical squamous cell carcinoma. AB - Numerous reports showed low levels of let-7 family in cervical cancer, acting as tumor suppressors by regulating multiple target genes. Genetic variants in the promoter of miRNA have been reported to influence individuals' susceptibility to human diseases. We aimed to investigate the association of rs10877887 and rs13293512 polymorphisms in the promoters of let-7 with risk of cervical squamous cell carcinoma (CSCC). A total of 331 patients with CSCC and 358 controls were included. Genotyping of rs10877887 was done using polymerase chain reaction restriction fragment length polymorphism analysis. Genotyping of rs13293512 was performed using Taqman allelic discrimination. Relative expression of let-7 family was determined using quantitative real-time polymerase chain reaction. The rs10877887CC genotype was significantly associated with an increased risk of CSCC compared with the rs10877887TT (adjusted OR=2.11, 95% CI, 1.31-3.40, p value=0.002) or rs10877887 TT/CT genotypes (adjusted OR=2.11, 95% CI, 1.34-3.31, p-value<0.001). Similarly increased risk of CSCC was observed when compared rs10877887T with rs10877887C allele (adjusted OR=1.35, 95% CI, 1.08-1.69, p value=0.008). Combined analysis showed that individuals carrying the genotypes of rs10877887CC+rs13293512CC had a 4.78-fold higher risk to develop CSCC compared with those carrying the genotypes of rs10877887CT/TT+rs13293512CT/TT (OR=4.78, 95% CI, 1.78-12.84, p-value=0.001). Additionally, patients harboring rs10877887CC genotype had a lower level of let-7i in CSCC tissues (p-value=0.02). This observation indicates that rs10877887 may be a useful biomarker for the etiology of CSCC. PMID- 29154872 TI - Starvation-, thermal- and heavy metal- associated expression of four small heat shock protein genes in Musca domestica. AB - In this study, starvation-, thermal- and heavy metal-associated expression of four small Musca domestica HSPs (abbreviated as MdomHSPs and they are MdomHSP10, MdomHSP27, MdomHSP27.1 and MdomHSP27.2) were determined. The following results were found: All MdomHSPs were significantly higher expressed during the active larval and adult stages than the egg and pupal stages; All MdomHSPs were expressed at relatively equal levels in the head, thorax and abdomen of adults; The expression of MdomHSP27 was significantly down-regulated in 4-day-old larvae that were starved for 6h, while the other 3 MdomHSPs were not significantly affected; Thermal treatment altered the expression of MdomHSPs in 4-day-old larvae: MdomHSP10 was significantly down-regulated in 4-day-old larvae that were maintained at 4 degrees C and 37 degrees C than in those that were maintained at 25 degrees C; Lead, cadmium and chromium exposure influenced larval expression of MdomHSPs to varying degrees. The expression dynamic profile of MdomHSPs would contribute to the understanding of their physiological role in M. domestica. PMID- 29154873 TI - Medaka igf1 identifies somatic cells and meiotic germ cells of both sexes. AB - Insulin-like growth factors (IGFs) play significant roles in regulating cell proliferation, differentiation and reproduction in diverse organisms. Here, we report the identification of medaka igf1 and the expression pattern of igf1 RNA in adult medaka gonads. Using RT-PCR, igf1 RNA was easily detected in several somatic organs and adult gonads of both sexes. Using chromogenic in situ hybridization, igf1 RNA in the ovary was found in stage I-IV oocytes and in the somatic cells throughout oogenesis. In the testis, igf1 RNA was present in meiotic products and the somatic cells surrounding male germ cells throughout spermatogenesis. We performed fluorescent in situ hybridization and immunostaining for the Vasa protein as a germ cell marker on gonadal cryosections. We showed that igf1 RNA in the ovary was most abundant in theca cells and meiotic oocytes at stage I-IV, which was detectable in granulosa cells and infrequently occurred in the mature oocytes at stage V but was absent in oogonia. The igf1 RNA in the testis was most prominent in Leydig cells and Sertoli cells and meiotic spermatids and sperm as well as detectable in spermaotgonia and spermatocytes. We conclude that differential igf1 RNA expression identifies medaka somatic cells and meiotic germ cells of both sexes. PMID- 29154874 TI - Preparation and characterization of three-dimensional scaffolds based on hydroxypropyl chitosan-graft-graphene oxide. AB - Hydroxypropyl chitosan (HPCH), a water soluble derivative of chitosan, is widely considered for tissue engineering and wound healing applications due to its biocompatibility and biodegradability. Graphene oxide (GO) is a carbon-based nanomaterial which is capable of imparting desired properties to the scaffolds. Hence, the integration of GO into HPCH could allow for the production of HPCH based scaffolds with improved swelling character, mechanical strength, and stability aimed at being used in tissue engineering. In this study, hydroxypropyl chitosan-graft-graphene oxide (HPCH-g-GO) with varying GO content (0.5, 1, 3 and 4wt.%) was prepared using HPCH and GO as a tissue engineering scaffold material. The formation of HPCH-g-GO was confirmed by FTIR and XRD analysis. Using the HPCH g-GO as a matrix material and glutaraldehyde as a crosslinking agent, the three dimensional (3D) porous scaffolds were fabricated by the freeze-drying method. The HPCH-g-GO scaffolds exhibited uniform porosity as observed in SEM analysis. The pore size and porosity reduced as the content of GO was increased. These scaffolds presented good swelling capacity, water retention ability, mechanical strength and in vitro degradation properties. The HPCH-g-GO scaffolds irrespective of their GO content demonstrated good cell viability when compared to control. Altogether, these results suggest that HPCH-g-GO scaffolds can be used as potential tissue engineering material. PMID- 29154875 TI - Optimization of PEGylation reaction time and molar ratio of rhG-CSF toward increasing bioactive potency of monoPEGylated protein. AB - PEGylation is one of the strategies used for enhancing in vivo residence time of recombinant human Granulocyte Colony-Stimulating Factor (rhG-CSF) and therefore reducing in dose frequency to better fit with patient comfort treatment. In this study, three methoxy polyethylene glycol propionaldehydes (mPEG- ALD) of 10, 20 and 30kDa MW were utilized to produce biologically active monoPEGylated rhG-CSF with enhanced molecular weight. PEGylation reactions were carried out at room temperature and pH 5.0 in the presence of cyanoborohydride and two mPEG-ALD: protein molar ratios (3:1 and 5:1). The reactions were monitored with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and size exclusion chromatography (SEC-HPLC). The results showed that a 2h reaction with 5:1 mPEG ALD: protein molar ratio was sufficient to direct the reaction toward optimal yields of monoPEGylated protein (86%). Subsequently, isolation of the monoPEGylated forms was successfully achieved. The purified products were compared with respect to their purity (>=95%), identity and isoelectric focusing parameter characteristics. Biological potencies were measured by cell proliferation assay and showed 20.80-42.73% retention of bioactivities. This study highlights the possible improvement of rhG-CSF efficiency by PEGylation. Further studies will investigate in vitro and in vivo immunogenicity and toxicity of monoPEGylated conjugates. PMID- 29154876 TI - Chondroitin sulfate from Scophthalmus maximus for treating osteoarthritis. AB - Osteoarthritis (OA) is a common joint disease characterized by cartilage degradation. Chondroitin sulfate from shark (CS-S) has a good effect on OA in clinical, but due to source limited of CS from shark. Therefore, it is important to find a novel CS source with similar efficacy to CS-S in the treatment of OA. Herein, we reported a therapeutic effect of CS from scophthalmus maximus (CS-SM) for treating OA in rats. The OA model was established. After intervention with CS SM by intragastric administration. Our results showed that CS-SM could protect articular cartilage in OA, inhibit the degradation of cartilage, decrease the apoptosis of chondrocytes, decline the content of interleukin-1, tumor necrosis factor-alpha and Prostaglandins E2 in synovial fluid, down-regulate the protein expression of matrix metalloproteinase-1 and up-regulate the protein expression of tissue inhibitor of metalloproteinase-1. Our results suggest that oral CS from SM is a new potential therapy for OA. PMID- 29154877 TI - Investigation the effect of graphene oxide and gelatin/starch weight ratio on the properties of starch/gelatin/GO nanocomposite films: The RSM study. AB - In this study, we reported the design and fabrication of starch/gelatin/graphene oxide biodegradable nanocomposite films with proper potential for food packaging applications. The experiments were designed using Design Expert software via RSM by defining gelatin/starch weight ratio (G/S wt. ratio) and graphene oxide (GO) wt.% as process parameters affecting on the properties of the prepared films. The optimization was done and various properties of the optimum film were investigated. The XRD and SEM images confirmed that GO layers could intercalate in the starch/gelatin matrix and proper dispersion of nanofillers in the matrix obtained via solution casting method. The mechanical strength, thermal stability, surface hydrophilicity, and water vapor permeability were improved in the present of GO which could be related to reinforcing effect and proper barrier property of GO. Degradation of the prepared films under the soil was investigated during 6 weeks and the results indicated at least 30% weight loss happened throughout the test duration. Overall, the obtained results corroborate that the starch/gelatin/GO compounding can be a good candidate for fabricating of biodegradable nanocomposite films for food packaging applications. PMID- 29154878 TI - Nanogel-based natural polymers as smart carriers for the controlled delivery of Timolol Maleate through the cornea for glaucoma. AB - Despite frequent scientific efforts, efficient ocular drug delivery is a major challenge for pharmaceutical scientists. Poor bioavailability of ophthalmic solutions can be overcome by using smart ophthalmic drug-delivery systems. In this research, loading and delivery of Timolol Maleate (TM) through the cornea by synthesized nanoparticles based on biopolymers (chitosan-alginate) were studied. The physico-chemical properties of these nanoparticles were characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS). Loading and release were evaluated by a UV-vis spectrometer and the ex vivo permeation study was carried out using the Franz Diffusion Cell and fluorescent microscopy studies. The results indicated that morphology and size of nanoparticles were spherical and in the range of 80-100nm. The loading capacity and encapsulation efficiency were about 42% and 94% respectively. They illustrated a burst release in the first hour followed by a slower and more sustained drug release during the next 24h. Also, the results indicated that the cornea penetration of TM loaded in nanoparticles was twice than that of TM. Hence, this nanocarrier can be considered as a suitable candidate for controlled TM delivery and release through the cornea. PMID- 29154879 TI - Perillyl alcohol alleviates amyloid-beta peptides-induced mitochondrial dysfunction and cytotoxicity in SH-SY5Y cells. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia in elderly ( >65years of age). Excessive extra cellular deposits of amyloid beta (Abeta) are a pathological feature of AD. Abeta can cause cell death through oxidative damage; recent studies have implicated opening of mPTP as a detrimental event in AD-related mitochondrial dysfunctions. Over the past few years, natural compounds with antioxidant properties have shown promise for intervention in AD. PMID- 29154880 TI - Consolidated bioprocessing for production of polyhydroxyalkanotes from red algae Gelidium amansii. AB - Noncompetitive carbon sources such as algae are unconventional and promising raw material for sustainable biofuel production. The capability of one marine bacterium, Saccharophagus degradans 2-40 to degrade red seaweed Gelidium amansii for production of polyhydroxyalkanoates (PHA) was evaluated in this study. S. degradans can readily attach to algae, degrade algal carbohydrates, and utilize that material as main carbon source. Minimal media containing 8g/L G. amansii were used for the growth of S. degradans. The PHA content obtained was 17-27% of dry cell weight by pure culture of S. degradans and co-culture of S. degradans and Bacillus cereus, a contaminant found with S. degradans cultures. The PHA type was found to be poly(3-hydroxybutyrate) by gas chromatography and Fourier transform-infrared spectroscopy. This work demonstrates PHA production through consolidated bioprocessing of insoluble, untreated red algae by bacterial pure culture and co-culture. PMID- 29154881 TI - Influence of polymer ratio and surfactants on controlled drug release from cellulosic microsponges. AB - Microsponge refers to a highly cross-linked particle system with a capacity to adsorb (like a dry sponge) pharmaceutical materials. There are various methods available to prepare microsponge formulations, in this study we used quasi emulsion-solvent diffusion method with a combination of hydrophobic (ethyl cellulose) and hydrophilic (hydroxypropyl methylcellulose) polymers mediated via Tween 80 and polyvinyl alcohol. Various ratios and amounts of the polymers and surfactants were used to prepare microsponge formulations using ketoprofen as a model drug and extensively characterised. Our results, for the first time, indicate successful and optimised formulation with desired pharmaceutical characteristics using a combination of hydrophobic and hydrophilic polymers. PMID- 29154882 TI - Interaction of a novel twin-tailed oxy-diester functionalized surfactant with lysozyme: Spectroscopic and computational perspective. AB - Herein, we have examined the interaction of oxy-diester novel twin tailed (gemini) surfactant, 2,2'-[(oxybis(ethane-1,2-diyl))bis(oxy)]bis(N-hexadecyl N,Ndimethyl-2-oxoethanaminium) dichloride (C16-E2O-C16) with hen egg white lysozyme (HEWL), utilizing a spectroscopic and molecular docking techniques. Steady-state fluorescence infers ground state C16-E2O-C16-HEWL complex formation. Other spectroscopic results validated the conformational, structural and micro environmental changes in HEWL upon interaction with C16-E2O-C16. Molecular modeling has shown that C16-E2O-C16 binds in the proximity of hydrophobic moieties (Trp-62/108). We believe the results of the current study will assist in designing the surfactant-enzyme systems for their end use as ingredients in pharmaceutical, cosmetic, drug delivery and industrial compilations. In terms of scientific literature standpoint, it will also enrich and widen the scope of biomacromolecule-surfactant interactions. PMID- 29154883 TI - Site specific labeling of two proteins in one system by atypical split inteins. AB - Atypical inteins have been used for protein site-specific labeling and modification. S1 or S11 intein contain a small N-intein or C-intein which can be chemically synthesized and added with desired labels or modifications. However, seldom reports have been found to develop multi-protein specific labeling in one system at the same time. Here, we established a specific labeling method for two proteins based on three pairs of atypical inteins, RBS1 (Rma DnaB S1)/SGS1 (Ssp GyrB S1) intein, TE3S11 (Ter DnaE-3 S11)/SGS11 (Ssp GyrB S11) intein, and RBS1/TE3S11 intein. Firstly, intein fragments were respectively fused with model proteins, expressed and purified as precursors. The non-cross reactivity between inteins was then determined by splicing reactions analysis through Western-blot. Finally, the model proteins were specifically labeled with fluorescent groups in one system mediating these intein pairs, and can be labeled even in the cell lysate. Our results for the first time report a method labeling the N/C-terminal of two proteins altogether in the same system based on above intein pairs with a marked splicing efficiency, which could potentially be used for protein structural and functional research or some specific applications. PMID- 29154884 TI - Double up! Examining the effects of adding inhibition training to food cue exposure in chocolate-loving female students. AB - In the present we study investigated whether addition of a Go/No Go training enhanced the effects of food cue exposure. We assessed desire to eat, salivation, CS-US expectancies, and eating in the absence of hunger (EAH) during and after cue exposure. Participants (N = 71) were chocolate-loving female students who tried to eat less chocolate in daily life. They received two sessions of either cue exposure with Go/No Go training (EXP + GNG), cue exposure with a sham training (EXP + shamGNG), or a control procedure with sham training (CON + shamGNG). Results showed that the exposure groups had higher desire to eat and higher levels of salivation during exposure compared to the control group during the control intervention, and that within session and between session habituation occurred in all conditions. In contrast to our hypotheses, lower levels of desire and salivation in the EXP + GNG compared to the EXP + shamGNG group at the end of exposure were not found. In addition, there was an overall decrease in CS-US expectancies with no group differences, and these beliefs were unrelated to EAH. Furthermore, groups did not differ on intake of either the exposed chocolate, non exposed chocolate or other snack food items. It is concluded that a short Go/No Go training does not have an effect on two sessions of cue exposure treatment. PMID- 29154885 TI - Consumers' health-related perceptions of bread - Implications for labeling and health communication. AB - There is a wide variety of commercial bread types and the present study identifies potential pitfalls in consumer evaluations of bread from a health perspective. The aim is to describe consumers' health-related perceptions of bread by exploring which health-related quality attributes consumers associate with bread and whether there are differences with regard to age, gender and education level. A postal and web-based sequential mixed-mode survey (n = 1134, 62% responded online and 38% by paper) with open-ended questions and an elicitation task with pictures of commercial breads were used. Responses were content analyzed and inductively categorized. Three fourths (n = 844) knew of breads they considered healthy; these were most commonly described using terms such as "coarse," "whole grain," "fiber rich," "sourdough," "crisp," "less sugar," "dark," "rye," "seeds," "a commercial brand," "homemade" and "kernels." The breads were perceived as healthy mainly because they "contain fiber," are "good for the stomach," have good "satiation" and beneficial "glycemic properties." The frequency of several elicited attributes and health effects differed as a function of age group (18-44 vs. 45-80 years), gender and education level group (up to secondary education vs. university). Difficulties identifying healthy bread were perceived as a barrier for consumption especially among consumers with a lower education level. Several of the health effects important to consumers cannot be communicated on food packages and consumers must therefore use their own cues to identify these properties. This may lead to consumers being misled especially if a bread is labeled e.g., as a sourdough bread or a rye bread, despite a low content. PMID- 29154886 TI - Personality and attitudinal correlates of meat consumption: Results of two representative German samples. AB - The vast amount of meat consumed in the Western world is critically discussed with regard to negative health consequences, environmental impact, and ethical concerns for animals, emphasizing the need to extend knowledge regarding the correlates of meat consumption in the general population. In the present article, we conducted two studies examining the associations between meat consumption and personality traits, political attitudes, and environmental attitudes in two large German representative samples (Ntotal = 8,879, aged 18-96 years). Cross-sectional data on frequency of meat consumption, socio-demographics, personality traits, and political and environmental attitudes were collected via self-reports. In both studies, male sex, younger age, and lower educational attainment were significantly positively related to meat consumption. In Study 1, results of the partial correlations and the hierarchical regression analysis controlling for socio-demographics showed that the personality traits of openness and agreeableness, as well as conservative political and social views, explained unique variance in meat consumption. In Study 2, partial correlations and hierarchical regression analyses showed that openness, agreeableness, and conscientiousness were all uniquely negatively related to meat consumption. Moreover, these analyses documented that people scoring high in right-wing attitudes and low in pro-environmental attitudes reported more overall meat consumption. Taken together, these two studies provided evidence that socio demographics, personality traits, and attitudes are indeed related to how much meat is consumed. Implications and future prospects for the study of individual differences in meat consumption are discussed. PMID- 29154887 TI - Food consumption when travelling abroad: Young Chinese sojourners' food consumption in the UK. AB - This qualitative study investigates the everyday food choices of 21 Chinese sojourners living in two different localities in the UK. Findings from a thematic analysis of semi-structured interviews reveal how participants adopt a food consumption pattern, negotiating between ordinary and extraordinary food choices, including home-made Chinese food, Chinese restaurant food, global brands, British food, to "foods of the world". Their zooming in and out of different food consumption choices reflects the transformative identity of the sojourners, between their student role during the week and becoming tourists at the weekends, meshing work and tourism during their sojourning in the UK. Theoretically this paper extends the limited understanding of sojourners, showing how their complex food choices reflect their swift transformative identity. Findings also illustrate how consumption patterns adopted by sojourners living in rural areas differ from the ones living in an urban setting. PMID- 29154889 TI - Developing a Path to Improve Cultural Competency in Islam Among Palliative Care Professionals. PMID- 29154888 TI - Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy. AB - Genetic manipulation of key components of the evolutionally conserved Hippo pathway has shown that the precise control of these signaling molecules is critical to cardiac development and response to stresses. However, how this pathway is involved in the progression of cardiac dysfunction in different heart diseases remains unclear. We investigated the expressional levels and subcellular localization of Yap1, Taz, and Tead1 and determined Hippo target gene expression in failing human hearts with ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (IDC) and mouse desmin-related cardiomyopathy (DES). Our results demonstrated that Yap1, Taz, and Tead1 were significantly increased in failing human and DES hearts compared with the non-failing controls (NFH) or wild type (WT) mouse hearts at both mRNA and protein levels. Interestingly, adult human and mouse hearts had more Taz than Yap1 by mRNA and protein expression and their increases in diseased hearts were proportional and did not change Yap1/Taz ratio. Yap1, Taz, and Tead1 were accumulated in the nuclear fraction and cardiomyocyte nuclei of diseased hearts. The ratio of Yap1 phosphorylated at serine 127 (human) or serine 112 (mouse) to the total Yap1 (pYap1/Yap1) was significantly lower in the nuclear fraction of diseased hearts than that in normal controls. More importantly, Hippo downstream targets Ankrd1, Ctgf, and Cyr61 were transcriptionally elevated in the diseased hearts. These results suggest that Yap1/Taz signaling is activated in human and mouse dysfunctional hearts. Further investigation with relevant animal models will determine whether this pathway is a potential target for preventing and reversing abnormal remodeling during the progression of different cardiac disorders. PMID- 29154890 TI - Relating to the Experience of Contingency in Patients With Advanced Cancer: An Interview Study in U.S. Patients. AB - CONTEXT: Being diagnosed with incurable cancer can be a life-changing experience, evoking different spiritual questions and needs. Confronting a serious life threatening event occurs not only often unexpected but also can disrupt a person's self-image and ideals of their personhood. This confrontation makes it difficult for people to integrate it into their personal life story-otherwise referred to as an experience of contingency. OBJECTIVES: Different modes of relating to the contingent life event of having cancer have been studied in a Dutch patient population. Here we present an interview study in an U.S. population with advanced cancer patients. METHODS: We included eight American patients with advanced cancer from the George Washington University Cancer Center. All patients were interviewed twice discussing their life events and life goals using a semistructured interview model. All interviews were transcribed and analyzed focusing on how patients described the way they related to the experience of having advanced cancer. The constant comparative method with a directed content analysis approach was used to code the themes in the interviews. RESULTS: The analyses show that the four modes of relating to contingency that we found in the Dutch study population can also be found in an American advanced cancer patient population. Differences were found in the extended way American patients described the fourth mode of "receiving." CONCLUSION: This study ensures a broader and deeper understanding of relating to the experience of contingency in having incurable cancer, which is crucial in developing accurate spiritual care in the palliative phase of patients. PMID- 29154891 TI - Acute Pain Perception During Different Sampling Methods for Respiratory Culture in Cystic Fibrosis Patients. AB - CONTEXT: Reliable identification of lower respiratory tract pathogens is crucial in the management of cystic fibrosis (CF). The multitude of treatments and clinical procedures are a considerable burden and are potentially provoking pain. OBJECTIVES: As part of another study (NCT02363764), investigating the bacterial yield of three sampling methods, nasal swabs (NSs), cough swabs (CSs), and (induced) sputum samples ([I]SSs), in both expectorating patients (EPs) and non expectorating patients (NEPs) with CF, the present study aimed to explore the prevalence of respiratory culture sampling-related pain as assessed by self report within a cohort of children and adults. METHODS: Literate patients with CF (aged six years or older) completed a questionnaire on pain perception related to the three aforementioned sampling methods (No/Yes; visual analogue scale for pain [VAS-Pain] [0-10 cm]). In addition, patients were asked to rank these methods by their own preference without taking into account the presumed bacterial yield. RESULTS: In total, 119 questionnaires were returned. In the EPs-group, CS was most frequently (n%; mean VAS-Pain if pain [range]) reported as painful method: overall (n = 101; 12.9%; 1.8 [0.2-4.8]), children (n = 41; 22.0%; 1.4 [0.2-2.7]), and adults (n = 60; 6.7%; 2.5 [0.5-4.8]). Highest pain intensity scores were observed with NS overall (3.0%; 2.4 [0.3-6.2]) and in children (4.9%; 3.3 [0.3 6.2]), but not in adults (1.7%; 0.6 [-]).NEPs-children (n = 17) reported ISS most frequently and as most painful sampling method (17.6%; 2.0 [1.0-4.0]). The only NEP-adult did not perceive pain. NEPs preferred NS > CS > ISS (61.1%, 33.3%, 5.6%, respectively [P = 0.001]) as primary sampling method, whereas EPs preferred SS > NS > CS (65.7%, 26.3%, 8.1%, respectively [P < 0.0001]). Patients' preference for a specific method inversely correlated to pain perception and intensity in EPs (phi = -0.155 [P = 0.007] and rho = -0.926 [P = 0.008], respectively), but not in NEPs (phi = -0.226 [P = 0.097] and rho = -0.135 [P = 0.798], respectively). CONCLUSION: A relatively large range of pain experiences was observed in patients with CF during respiratory culture sampling, which underlines the importance of individual pain assessment. Nevertheless, clinicians can confidently choose the sampling method based on validity over patients' preference. PMID- 29154892 TI - Reflection on the Role of the Spirit in Finding Meaning and Healing as Clinicians. AB - Reflections on the Role of the Spirit in Finding Meaning and Healing as Clinicians is based on a presentation for the George Washington Spirituality and Health Summer Institute on July 13, 2017. The presentation invited health care professionals to explore contemplative practices as ways to invite the Spirit to strengthening their resilience in caring for themselves and others. As clinicians, there is often a longing to be grounded in a regular contemplative practice centering one's inner life and to acknowledge the creative energy of the Spirit in relationships. This reflection draws on resilience research that finds that contemplative practices such as deep breathing, meditation, reflective writing, and peer or community support enhance ways of meaning making and healing. Contemplative practices are provided, which can connect clinicians to the Spirit with the purpose of leading to increased meaning and healing in self and relationships. PMID- 29154893 TI - An interleaved sequence for simultaneous magnetic resonance angiography (MRA), susceptibility weighted imaging (SWI) and quantitative susceptibility mapping (QSM). AB - PURPOSE: To image the entire vasculature of the brain with complete suppression of signal from background tissue using a single 3D excitation interleaved rephased/dephased multi-echo gradient echo sequence. This ensures no loss of signal from fast flow and provides co-registered susceptibility weighted images (SWI) and quantitative susceptibility maps (QSM) from the same scan. MATERIALS AND METHODS: The suppression of background tissue was accomplished by subtracting the flow-dephased images from the flow-rephased images with the same echo time of 12.5ms to generate a magnetic resonance angiogram and venogram (MRAV). Further, a 2.5ms flow-compensated echo was added in the rephased portion to provide sufficient signal for major arteries with fast flow. The QSM data from the rephased 12.5ms echo was used to suppress veins on the MRAV to generate an artery only MRA. The proposed approach was tested on five healthy volunteers at 3T. RESULTS: This three-echo interleaved GRE sequence provided complete background suppression of stationary tissues, while the short echo data gave high signal in the internal carotid and middle cerebral arteries (MCA). The contrast-to-noise ratio (CNR) of the arteries was significantly improved in the M3 territory of the MCA compared to the non-linear subtraction MRA and TOF-MRA. Veins were suppressed successfully utilizing the QSM data. CONCLUSION: The background tissue can be properly suppressed using the proposed interleaved MRAV sequence. One can obtain whole brain MRAV, MRA, SWI, true-SWI (or tSWI) and QSM data simultaneously from a single scan. PMID- 29154894 TI - Non-contrast quantitative pulmonary perfusion using flow alternating inversion recovery at 3T: A preliminary study. AB - PURPOSE: To demonstrate the initial feasibility of non-contrast quantitative pulmonary perfusion imaging at 3T using flow alternating inversion recovery (FAIR), and to evaluate the intra-session and inter-session reliability of FAIR measurements at 3T. MATERIALS AND METHODS: Nine healthy volunteers were imaged using our own implementation of FAIR pulse sequence at 3T. Quantitative FAIR perfusion, both with and without larger pulmonary vessels, was correlated with global phase contrast (PC) measured blood flow in the right pulmonary artery (RPA). The same volunteers were also imaged with SPECT perfusion using technetium 99m-macroaggregated albumin and relative dispersion (RD) was assessed between FAIR and SPECT perfusion. Four additional healthy volunteers were evaluated for FAIR repeatability, using intra-class correlation coefficient (ICC) and Bland Altman analysis. p<0.05 was considered statistically significant. RESULTS: FAIR perfusion across all subjects was 858+/-605mL/100g/min (with vessels) and 629+/ 294mL/100g/min (without vessels) and correlated significantly with the PC measured blood flow in the RPA (r=0.62, p<0.01 with vessels; r=0.73, p<0.001 without vessels). The median RD of FAIR perfusion across all subjects was 0.73 (with vessels) and 0.49 (without vessels), compared against 0.23 with SPECT perfusion. The intra/inter-session ICC of FAIR perfusion with vessels was 0.95/0.59 and improved to 0.96/0.72, when vessels were removed. CONCLUSIONS: Non contrast quantitative pulmonary perfusion imaging using FAIR is feasible at 3T. This may serve as a reliable method to assess regional lung perfusion at 3T to characterize and monitor treatment response in chronic lung disease without the concerns of repeated exposure to ionizing radiation or the accumulation of exogenous contrast agent. PMID- 29154895 TI - Nonrigid motion compensation in compressed sensing reconstruction of cardiac cine MRI. AB - In this work, a robust nonrigid motion compensation approach, is applied to the compressed sensing reconstruction of dynamic cardiac cine MRI sequences. Respiratory and cardiac motion separation coupled with a registration algorithm is used to provide accurate reconstruction of dynamic cardiac images. The proposed scheme employs a variable splitting based optimization strategy to enable joint motion estimation along with reconstruction. We define the recovery as an energy minimization scheme utilizing an objective function that combines data consistency, spatial smoothness, and motion penalties. The validation of the proposed algorithm using numerical phantom and in-vivo cine MRI data demonstrates reconstruction of cardiac MRI data with less spatio-temporal blurring and motion artifacts from extensively under-sampled data. The proposed method is observed to provide improved reconstructions over state-of-the-art motion compensation schemes. PMID- 29154896 TI - Diffusion tensor imaging of spinal cord parenchyma lesion in rat with chronic spinal cord injury. AB - PURPOSE: Adequate evaluation of spinal cord parenchyma and accurate identification of injury range are considered two premises for the research and treatment of chronic spinal cord injury (SCI). Diffusion tensor imaging (DTI) provides information about water diffusion in spinal cord, and thus makes it possible to realize these premises. METHOD: In this study, we conducted magnetic resonance imaging (MRI) for Wistar rats 84days after spinal cord contusion. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) from different positions of the injured cord were collected, analyzed, and compared with the histological results and locomotor outcomes. Moreover, we performed fiber tractography, and examined the difference in cavity percentage obtained respectively via conventional MRI, DTI and histology. RESULTS: Results showed that the chronic SCI rats had the largest changes of all DTI metrics at the epicenter; the farther away from the epicenter, the smaller the variation. FA, AD and RD were all influenced by SCI in a greater space range than MD. The good consistency of FA values and histological results in specific regions evidenced FA's capability of reflecting Wallerian degeneration after SCI. DTI metrics at the epicenter in ventral funiculus also showed a close correlation with the BBB scores. Additionally, supported by the histological results, DTI enables a more accurate measurement of cavity percentage compared to the conventional MRI. CONCLUSION: DTI parameters might comprehensively reflect the post-SCI pathological status of spinal cord parenchyma at the epicenter and distal parts during the chronic stage, while showing good consistency with locomotor performance. DTI combined with tractography could intuitively display the distribution of spared fibers after SCI and accurately provide information such as cavity area. This may shed light on the research and treatment of chronic SCI. PMID- 29154897 TI - Identification of ghost artifact using texture analysis in pediatric spinal cord diffusion tensor images. AB - PURPOSE: Ghost artifacts are a major contributor to degradation of spinal cord diffusion tensor images. A multi-stage post-processing pipeline was designed, implemented and validated to automatically remove ghost artifacts arising from reduced field of view diffusion tensor imaging (DTI) of the pediatric spinal cord. METHOD: A total of 12 pediatric subjects including 7 healthy subjects (mean age=11.34years) with no evidence of spinal cord injury or pathology and 5 patients (mean age=10.96years) with cervical spinal cord injury were studied. Ghost/true cords, labeled as region of interests (ROIs), in non-diffusion weighted b0 images were segmented automatically using mathematical morphological processing. Initially, 21 texture features were extracted from each segmented ROI including 5 first-order features based on the histogram of the image (mean, variance, skewness, kurtosis and entropy) and 16s-order feature vector elements, incorporating four statistical measures (contrast, correlation, homogeneity and energy) calculated from co-occurrence matrices in directions of 0 degrees , 45 degrees , 90 degrees and 135 degrees . Next, ten features with a high value of mutual information (MI) relative to the pre-defined target class and within the features were selected as final features which were input to a trained classifier (adaptive neuro-fuzzy interface system) to separate the true cord from the ghost cord. RESULTS: The implemented pipeline was successfully able to separate the ghost artifacts from true cord structures. The results obtained from the classifier showed a sensitivity of 91%, specificity of 79%, and accuracy of 84% in separating the true cord from ghost artifacts. CONCLUSION: The results show that the proposed method is promising for the automatic detection of ghost cords present in DTI images of the spinal cord. This step is crucial towards development of accurate, automatic DTI spinal cord post processing pipelines. PMID- 29154898 TI - Evaluation of dynamic contrast-enhanced MRI biomarkers for stratified cancer medicine: How do permeability and perfusion vary between human tumours? AB - BACKGROUND: Solid tumours exhibit enhanced vessel permeability and fenestrated endothelium to varying degree, but it is unknown how this varies in patients between and within tumour types. Dynamic contrast-enhanced (DCE) MRI provides a measure of perfusion and permeability, the transfer constant Ktrans, which could be employed for such comparisons in patients. AIM: To test the hypothesis that different tumour types exhibit systematically different Ktrans. MATERIALS AND METHODS: DCE-MRI data were retrieved from 342 solid tumours in 230 patients. These data were from 18 previous studies, each of which had had a different analysis protocol. All data were reanalysed using a standardised workflow using an extended Tofts model. A model of the posterior density of median Ktrans was built assuming a log-normal distribution and fitting a simple Bayesian hierarchical model. RESULTS: 12 histological tumour types were included. In glioma, median Ktrans was 0.016min-1 and for non-glioma tumours, median Ktrans ranged from 0.10 (cervical) to 0.21min-1 (prostate metastatic to bone). The geometric mean (95% CI) across all the non-glioma tumours was 0.15 (0.05, 0.45)min-1. There was insufficient separation between the posterior densities to be able to predict the Ktrans value of a tumour given the tumour type, except that the median Ktrans for gliomas was below 0.05min-1 with 80% probability, and median Ktrans measurements for the remaining tumour types were between 0.05 and 0.4min-1 with 80% probability. CONCLUSION: With the exception of glioma, our hypothesis that different tumour types exhibit different Ktrans was not supported. Studies in which tumour permeability is believed to affect outcome should not simply seek tumour types thought to exhibit high permeability. Instead, Ktrans is an idiopathic parameter, and, where permeability is important, Ktrans should be measured in each tumour to personalise that treatment. PMID- 29154899 TI - Combining diagnostic methods for antimicrobial susceptibility testing - A comparative approach. AB - BACKGROUND: The minimum inhibitory concentration (MIC) is a measure of antimicrobial susceptibility testing (AST) of a given antibiotic but provides insufficient information when bacterial killing is crucial, e.g., when treating immunocompromised patients. In these cases, the minimum bactericidal concentration (MBC) is a more reliable measure of antibiotic activity. Here, we aim to demonstrate and recommend combinations of methods for MIC and MBC measurements. We also aim to emphasize the importance of uniform protocols for these procedures including the time point for reading MIC results, which the authors suggest to be 20h. METHODS: To address the challenges with obtaining fast and reliable readouts on MIC as well as the kinetic and end-point effects of antibiotics, the broth micro dilution method, a calorimetric method and a microscopy-based screening system (MBSS) were evaluated in this study. For MBC determination, fluorophore staining with SYTO9 and propidium iodide was compared to the broth regrowth method. RESULTS: Three scenarios for combining the MIC and MBC methods depending on the investigators' primary concern (time, cost or sensitivity) are presented. Further, as the MBSS and the isothermal microcalorimetry method detected delayed bacterial growth up to 18h after initiation of experiments, the importance of reading MIC testing after a full 20h is emphasized. A one-fold change in MIC values can be observed when comparing data obtained at 16h and 20h of incubation. CONCLUSION: The authors suggest that combining MIC and MBC determinations will provide more detailed understanding of the bacteria susceptibility to antibiotic drugs and result in more clinically relevant data and optimized therapies. Furthermore, establishing 20h as a time point for reading MIC results will provide more uniform data across laboratories. PMID- 29154900 TI - Alternative Manufacturing Concepts for Solid Oral Dosage Forms From Drug Nanosuspensions Using Fluid Dispensing and Forced Drying Technology. AB - Flexible manufacturing technologies for solid oral dosage forms with a continuous adjustability of the manufactured dose strength are of interest for applications in personalized medicine. This study explored the feasibility of using microvalve technology for the manufacturing of different solid oral dosage form concepts. Hard gelatin capsules filled with excipients, placebo tablets, and polymer films, placed in hard gelatin capsules after drying, were considered as substrates. For each concept, a basic understanding of relevant formulation parameters and their impact on dissolution behavior has been established. Suitable matrix formers, present either on the substrate or directly in the drug nanosuspension, proved to be essential to prevent nanoparticle agglomeration of the drug nanoparticles and to ensure a fast dissolution behavior. Furthermore, convection and radiation drying methods were investigated for the fast drying of drug nanosuspensions dispensed onto polymer films, which were then placed in hard gelatin capsules. Changes in morphology and in drug and matrix former distribution were observed for increasing drying intensity. However, even fast drying times below 1 min could be realized, while maintaining the nanoparticulate drug structure and a good dissolution behavior. PMID- 29154901 TI - Translucence perception is not dependent on cortical areas critical for processing colour or texture. AB - Translucence is an important property of natural materials, and human observers are adept at perceiving changes in translucence. Perceptions of different material properties appear to arise from different cortical regions, and it is therefore plausible that the perception of translucence is dependent on specialised regions, separate from those important for colour and texture processing. To test for anatomical independence between areas necessary for colour, texture and translucence perception we assessed translucency perception in a cortically colour blind observer, who performs at chance on tasks of colour and texture discrimination. Firstly, in order to establish that MS has shown no significant recovery, we assessed his colour perception performance on the Farnsworth-Munsell 100 Hue Test. Secondly, we tested him with two translucence ranking tasks. In one task, stimuli were images of glasses of tea varying in tea strength. In the other, stimuli were glasses of tea varying only in milkiness. MS was able to systematically rank both strength and milkiness, although less consistently than controls, and for tea strength his rankings were in the opposite order. An additional group of controls tested with greyscale versions of the images succeeded at the tasks, albeit slightly less consistently on the milkiness task, showing that the performance of normal observers cannot be transformed into the performance of MS simply by removing colour information from the stimuli. The systematic performance of MS suggests that some aspects of translucence perception do not depend on regions critical for colour and texture processing. PMID- 29154902 TI - Dipeptidyl peptidase IV (DPP-IV) inhibition prevents fibrosis in adipose tissue of obese mice. AB - BACKGROUND: During the development of obesity the expansion of white adipose tissue (WAT) leads to a dysregulation and an excessive remodeling of extracellular matrix (ECM), leading to fibrosis formation. These ECM changes have high impact on WAT physiology and may change obesity progression. Blocking WAT fibrosis may have beneficial effects on the efficacy of diet regimen or therapeutical approaches in obesity. Since dipeptidyl peptidase IV (DPP-IV) inhibitors prevent fibrosis in tissues, such as heart, liver and kidney, the objective of this study was to assess whether vildagliptin, a DPP-IV inhibitor, prevents fibrosis in WAT in a mouse model of obesity, and to investigate the mechanisms underlying this effect. METHODS: We evaluated the inhibitory effect of vildagliptin on fibrosis markers on WAT of high-fat diet (HFD)-induced obese mice and on 3T3-L1 cell line of mouse adipocytes treated with a fibrosis inducer, transforming growth factor beta 1 (TGFbeta1). RESULTS: Vildagliptin prevents the increase of fibrosis markers in WAT of HFD-fed mice and reduces blood glucose, serum triglycerides, total cholesterol and leptin levels. In the in vitro study, the inhibition of DPP-IV with vildagliptin, neuropeptide Y (NPY) treatment and NPY Y1 receptor activation prevents ECM deposition and fibrosis markers increase induced by TGFbeta1 treatment. CONCLUSIONS: Vildagliptin prevents fibrosis formation in adipose tissue in obese mice, at least partially through NPY and NPY Y1 receptor activation. GENERAL SIGNIFICANCE: This study highlights the importance of vildagliptin in the treatment of fibrosis that occur in obesity. PMID- 29154904 TI - Risk of Upgrading from Prostate Biopsy to Radical Prostatectomy Pathology-Does Saturation Biopsy of Index Lesion during Multiparametric Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsy Help? AB - PURPOSE: We sought to determine whether saturation of the index lesion during magnetic resonance imaging-transrectal ultrasound fusion guided biopsy would decrease the rate of pathological upgrading from biopsy to radical prostatectomy. MATERIALS AND METHODS: We analyzed a prospectively maintained, single institution database for patients who underwent fusion and systematic biopsy followed by radical prostatectomy in 2010 to 2016. Index lesion was defined as the lesion with largest diameter on T2-weighted magnetic resonance imaging. In patients with a saturated index lesion transrectal fusion biopsy targets were obtained at 6 mm intervals along the long axis of the index lesion. In patients with a nonsaturated index lesion only 1 target was obtained from the lesion. Gleason 6, 7 and 8-10 were defined as low, intermediate and high risk, respectively. RESULTS: Included in the study were 208 consecutive patients, including 86 with a saturated and 122 with a nonsaturated lesion. Median patient age was 62.0 years (IQR 10.0) and median prostate specific antigen was 7.1 ng/ml (IQR 8.0). The median number of biopsy cores per index lesion was higher in the saturated lesion group (4 vs 2, p <0.001). The risk category upgrade rate from systematic only, fusion only, and combined fusion and systematic biopsy results to prostatectomy was 40.9%, 23.6% and 13.8%, respectively. The risk category upgrade from combined fusion and systematic biopsy results was lower in the saturated than in the nonsaturated lesion group (7% vs 18%, p = 0.021). There was no difference in the upgrade rate based on systematic biopsy between the 2 groups. However, fusion biopsy results were significantly less upgraded in the saturated lesion group (Gleason upgrade 20.9% vs 36.9%, p = 0.014 and risk category upgrade 14% vs 30.3%, p = 0.006). CONCLUSIONS: Our results demonstrate that saturation of the index lesion significantly decreases the risk of upgrading on radical prostatectomy by minimizing the impact of tumor heterogeneity. PMID- 29154903 TI - In vitro mesenchymal-epithelial transition in NIH3T3 fibroblasts results in onset of low-dose radiation hypersensitivity coupled with attenuated connexin-43 response. AB - BACKGROUND: Mesenchymal-to-epithelial transition (MET) is associated with altered cell adhesion patterns. Independent studies showed that cellular adhesion regulates low-dose hyper-radiosensitivity (HRS), a phenomenon reported widely in tumour cells. Therefore, present study aimed to investigate whether MET and associated cellular adhesion alterations affect cellular radiosensitivity. METHODS: We established multiple stages of MET by in vitro transformation of NIH3T3 mouse embryonic fibroblasts. Nutritional deprivation followed by repetitive treatment cycles of 3-methylcholanthrene and phorbol-12-myristate-13 acetate with frequent isolation of foci established three progressive strains (NIH3T3.1, NIH3T3x3, NIH3T3x8x3) depicting MET, and one strain (NIH3T3x12) with partial reversion. Alterations in morphology, cell adhesion properties, expression/intracellular localization of cell adhesion proteins, microRNA expression and cellular radiosensitivity were studied in these stably transformed cell strains. RESULTS: All four transformants had increased proliferation rate, saturation density, bipolarity, E-cadherin expression; coupled with reduced cell size/spreading, pseudopodia/migration, and fibroblast marker protein and vimentin. The most aggressive trans-differentiated (phenotypically epithelial) cell strain, NIH3T3x8x3 acquired ~30% higher growth potential associated with more than two-fold reduction in cell size and migration. These phenotypic changes accompanied ~40% reduction in endogenous or radiation-induced connexin-43 expression/mitochondrial translocation. Incidentally, all three progressive strains displayed prominent HRS (alphas/alphar: 7.95-37.29) whereas parental (NIH3T3) and reverting (NIH3T3x12) strains lacked HRS and had distinct radiation induced Cx43 translocation into mitochondria. CONCLUSION: Our study shows that trans-differentiating fibroblasts progressively acquiring epithelial features during MET process, display low-dose hyper-radiosensitivity associated with altered Cx43 behaviour. GENERAL SIGNIFICANCE: This study demonstrates that MET progression triggers low-dose hyper-radiosensitivity in trans-differentiating cells, which has significant therapeutic implications. PMID- 29154905 TI - Incidence of Extraprostatic Extension at Radical Prostatectomy with Pure Gleason Score 3 + 3 = 6 (Grade Group 1) Cancer: Implications for Whether Gleason Score 6 Prostate Cancer Should be Renamed "Not Cancer" and for Selection Criteria for Active Surveillance. AB - PURPOSE: We assessed the risk of locally aggressive behavior in pure Gleason score 6 (Grade Group 1) prostate cancer using contemporary grading criteria. To our knowledge this has been studied in only 1 prior cohort. MATERIALS AND METHODS: We evaluated consecutive radical prostatectomy specimens from an academic institution, including those from 3,291 men with Gleason score 6 and 4,202 with Gleason score 3 + 4 = 7 (Grade Group 2) disease between 2005 and 2016. For dichotomous variables the Pearson chi-square test was used. RESULTS: Of the 3,288 Gleason score 6 cancer cases 128 (3.9%) showed focal extraprostatic extension compared to 593 of the 4,202 (14.1%) with Gleason score 3 + 4 = 7 (p <0.0001). Of the 3,288 Gleason score 6 cancer cases 79 (2.4%) showed nonfocal extraprostatic extension compared to 639 of the 4,202 (15.2%) with Gleason score 3 + 4 = 7 (p <0.0001). The incidence of focal extraprostatic extension with Gleason score 3 + 4 = 7 with less than 5% Gleason pattern 4 was 129 of 1,147 cases (11.2%), which was between Gleason scores 6 and 3 + 4 = 7 with greater than 5% Gleason pattern 4. The incidence of nonfocal extraprostatic extension in Gleason score 3 + 4 = 7 with less than 5% Gleason pattern 4 was 96 of 1,147 cases (8.4%), which was between Gleason scores 6 and 3 + 4 = 7 with greater than 5% Gleason pattern 4. One of the 3,290 Gleason score 6 cases (0.03%) showed seminal vesicle invasion compared to 93 of the 4,202 (2.2%) of Gleason score 3 + 4 = 7 (p <0.0001). A limitation of our study was its retrospective design. CONCLUSIONS: It is not rare for pure Gleason score 6 prostate cancer to locally extend out of the prostate 3.9% focally and 2.4% nonfocally. In extremely rare cases Gleason score 6 can be associated with seminal vesicle invasion and yet not lymph node metastases. Our overall findings support the argument for continuing to use the term cancer for these tumors. PMID- 29154906 TI - Increase in taxonomic assignment efficiency of viral reads in metagenomic studies. AB - Metagenomics studies have revolutionized the field of biology by revealing the presence of many previously unisolated and uncultured micro-organisms. However, one of the main problems encountered in metagenomic studies is the high percentage of sequences that cannot be assigned taxonomically using commonly used similarity-based approaches (e.g. BLAST or HMM). These unassigned sequences are allegorically called " dark matter " in the metagenomic literature and are often referred to as being derived from new or unknown organisms. Here, based on published and original metagenomic datasets coming from virus-like particle enriched samples, we present and quantify the improvement of viral taxonomic assignment that is achievable with a new similarity-based approach. Indeed, prior to any use of similarity based taxonomic assignment methods, we propose assembling contigs from short reads as is currently routinely done in metagenomic studies, but then to further map unassembled reads to the assembled contigs. This additional mapping step increases significantly the proportions of taxonomically assignable sequence reads from a variety -plant, insect and environmental (estuary, lakes, soil, feces) - of virome studies. PMID- 29154908 TI - Auto-correlated directional swimming can enhance settlement success and connectivity in fish larvae. AB - Larvae of coastal-marine fishes have been shown repeatedly to swim directionally in the pelagic environment. Yet, biophysical models of larval dispersal typically impose a Simple Random Walk (SRW) algorithm to simulate non-directional movement in the open ocean. Here we investigate the use of a Correlated Random Walk (CRW) algorithm; imposing auto-correlated directional swimming onto simulated larvae within a high-resolution 3D biophysical model of the Gulf of Aqaba, the Red Sea. Our findings demonstrate that implementation of auto-correlated directional swimming can result in an increase of up to *2.7 in the estimated success rate of larval-settlement, as well as an increase in the extent of connectivity. With accumulating empirical support for the capacity for directional-swimming during the pelagic phase, we propose that CRW should be applied in biophysical models of dispersal by coastal marine fish-larvae. PMID- 29154907 TI - An integrated mathematical epithelial cell model for airway surface liquid regulation by mechanical forces. AB - A robust method based on reverse engineering was utilized to construct the ion channel conductance functions for airway epithelial sodium channels (ENaC), the cystic fibrosis transmembrane conductance regulator (CFTR), and calcium-activated chloride channels (CaCC). The ion-channel conductance models for both normal (NL) and cystic fibrosis (CF) airway epithelia were developed and then coupled to an adenosine triphosphate (ATP) metabolism model and a fluid transport model (collectively called the integrated cell model) to investigate airway surface liquid (ASL) volume regulation and hence mucus concentration, by mechanical forces in NL and CF human airways. The epithelial cell models for NL and CF required differences in Cl- secretion (decreased in CF) and Na+ absorption (raised in CF) to reproduce behaviors similar to in vitro epithelial cells exposed to mechanical forces (cyclic shear stress, cyclic compressive pressure and cilial strain) and selected modulators of ion channels and ATP release. The epithelial cell models were then used to investigate the effects of mechanical forces and evaporative flux on ASL and mucus homeostasis in both NL and CF airway epithelia. Because of reduced CF ASL volumes, CF mucus concentrations increased and produced a greater dependence of ASL volume regulation on cilia-mucus-ATP release interactions in CF than NL epithelial nodules. Similarly, the CF model was less tolerant to evaporation induced ASL volume reduction at all ATP release rates than the NL model. Consequently, this reverse engineered model appears to provide a robust tool for investigating CF pathophysiology and novel therapies. PMID- 29154909 TI - Effects of vitrification and transplantation on follicular development and expression of EphrinB1 and PDGFA in mouse ovaries. AB - The aim of this study was to assess the follicular development and the patterns of EphrinB1 and PDGFA immunostaining in vitrified mouse ovarian tissue (OT) with and without transplantation. Histological evaluation was performed on fresh and vitrified OTs, whether transplanted or not. RT-PCR was performed on fresh and vitrified ovarian samples (OSs) and vitrified OS graft. Vitrification alone did not significantly reduce the normal primordial, primary, and secondary follicles except antral ones (p > 0.05). However, transplantation decreased all the follicle types. The EphrinB1 immunoexpression showed high intensity in all follicular types in vitrified OT and the significant increased was detected in secondary and antral follicles (p < 0.05). PDGFA protein immunoexpression of primordial and primary follicles was decreased in vitrified OT (p < 0.05). However, the lowest immunoexpression of EphrinB1 and PDGFA was detected after transplantation (p < 0.05). The levels of ephrinb1 and pdgfa mRNA expressions in vitrified OS and vitrified OS grafts were found as comparable to the fresh OS. In conclusion, vitrification has no detrimental effect on the follicles at the different developmental stages, majority of ovarian follicular loss takes place after transplantation rather than vitrification. Overall, vitrification and grafting do not change the ephrinb1 and pdgfa gene expressions. In addition, EphrinB1 and PDGFA are expressed during different stages of folliculogenesis in a different manner in fresh, vitrified, or grafted OTs. Vitrification and/or grafting appear to affect the follicular expression of EphrinB1 and PDGFA. These findings suggest that these proteins could have several functions related to the development of follicles and angiogenesis after transplantation. PMID- 29154910 TI - Endoscopic string clip suturing method: a prospective pilot study (with video). AB - BACKGROUND AND AIMS: We developed a suturing method with string and clips for a single-channel endoscope. The feasibility of the string clip suturing method is evaluated in this prospective pilot study. METHODS: This study involved 10 consecutive patients who underwent endoscopic submucosal dissection (ESD) for a duodenal tumor. Polyester string was tied to the arm of a partially out thrust clip. The clip and string can be passed through the instrument channel (3.2 mm) of a single-channel endoscope. The clip with string was placed at the distal edge of the large mucosal defect. A second clip was hooked on the string and placed on the opposite side. Both clips were gathered by pulling the free end of the string, and additional clips were placed to achieve complete closure. This method was compared with that for the previous 10 patients without mucosal closure after duodenal ESD. RESULTS: Mean size of resected specimens was 39.1 +/- 12.4 mm. The success rate of the string clip suturing method was 100% (10/10). The mean procedure time was 23.4 +/- 13.8 minutes. Perforation during ESD occurred in 1 patient and was successfully closed by this method. None of the treated patients developed serious adverse events after the procedure. Compared with the no-suture group, the length of stay was significantly shorter (P = .038). CONCLUSION: The string clip suturing method appears to be a safe and effective method for closure of large mucosal defects. (Clinical trial registration number: UMIN000023698.). PMID- 29154911 TI - Diabetes is a cardiovascular disease, isn't it? PMID- 29154912 TI - Role of rs1501299 variant in the adiponectin gene on total adiponectin levels, insulin resistance and weight loss after a Mediterranean hypocaloric diet. AB - BACKGROUND/AIM: Several adiponectin gene (ADIPOQ) single nucleotide polymorphisms (SNPS) have been related with adiponectin levels and risk for obesity. Our aim was to analyze the effects of rs1501299 ADIPOQ gene polymorphism on total adiponectin levels, insulin resistance and weight loss after a Mediterranean hypocaloric diet in obese subjects. METHODS: A Caucasian population of 82 obese patients was analyzed, before and after 3 months on a Mediterranean hypocaloric diet. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. RESULTS: After dietary treatment and in wild type group, weight, BMI, fat mass, leptin levels, systolic blood pressure and waist circumference decreases were similar to the mutant type group. In wild type group, the decrease in total cholesterol was -28.1 +/- 15.3 mg/dl (mutant group: -12.6 +/- 16.7 mg/dl:p = 0.009), LDL- cholesterol was -31.8 +/- 20.5 mg/dl (-12.2 +/- 11.5 mg/dl:p = 0.006), fasting glucose plasma -4.8 +/- 2.5 mg/dL (-0.5 +/- 0.1 mg/dL:p = 0.02), insulin -3.6 +/- 1.5 mUI/L (+0.6 +/- 1.1 mUI/L:p = 0.02) and HOMA-IR 1.2 +/- 0.9 (-0.1 +/- 1.1:p = 0.03). CONCLUSION: The present study suggests that T allele of ADIPO (rs1501299) could be a predictor of a lack of response of HOMA IR, insulin, fasting glucose and LDL cholesterol secondary to a Mediterranean hypocaloric diet in obese subjects. PMID- 29154913 TI - The physiological and glycaemic changes in breastfeeding women with type 1 diabetes mellitus. AB - The World Health Organisation recommends exclusive breastfeeding for the first six months of life (Australian institute of health and welfare, 2011). Breastfeeding confers many short- and long-term benefits for infants and mothers, including reduced childhood obesity and lower maternal body weight (Infant feeding survey, 2010; CDC National immunization surveys, 2012 and 2013; Sorkio et al., 2010; Hummel et al., 2014; Finkelstein et al., 2013). Exclusive breastfeeding is also recommended in women with type 1 diabetes mellitus (T1DM), for at least four months (Nucci et al., 2017). However, the impact of breastfeeding on mothers with T1DM, and, conversely, the impact of maternal T1DM on breastfeeding, is not clear. This review summarizes current knowledge regarding the epidemiology and physiology of breastfeeding in women with T1DM. In particular, it highlights the relationship between breastfeeding and glycaemia. Potential areas for future research are also identified. PMID- 29154914 TI - How to make usage of the standardized EuroFlow 8-color protocols possible for instruments of different manufacturers. AB - A critical component of the EuroFlow standardization of leukemia/lymphoma immunophenotyping is instrument setup. Initially, the EuroFlow consortium developed a step-by-step standard operating protocol for instrument setup of >=8 color flow cytometers that were available in 2006, when the EuroFlow activities started. Currently, there are 14 instruments from 9 manufacturers capable of 3 laser excitation and >=8 color measurements. The specific adaptations required in the instrument set-up to enable them to acquire the standardized 8-color EuroFlow protocols are described here. Overall, all 14 instruments can be fitted with similar violet, blue and red lasers for simultaneous measurements of >=8 fluorescent dyes. Since individual instruments differ both on their dynamic range (scale) and emission filters, it is not accurate to simply recalculate the target values to different scale, but adjustment of PMT voltages to a given emission filter and fluorochrome, is essential. For this purpose, EuroFlow has developed an approach using Type IIB (spectrally matching) particles to set-up standardized and fully comparable fluorescence measurements, in instruments from different manufacturers, as demonstrated here for the FACSCanto II, and Navios and MACSQuant flow cytometers. Data acquired after such adjustment on any of the tested cytometry platforms could be fully superimposed and therefore analyzed together. The proposed approach can be used to derive target values for any combination of spectrally distinct fluorochromes and any distinct emission filter of any new flow cytometry platform, which enables the measurement of the 8-color EuroFlow panels in a standardized way, by creating superimposable datafiles. PMID- 29154915 TI - Cocaine- and amphetamine-regulated transcript peptide and calcium binding proteins immunoreactivity in the deep layers of the superior colliculus of the guinea pig: Implications for multisensory and visuomotor processing. AB - The superior colliculus (SC) of mammals is a midbrain center, that can be subdivided into the superficial (SCs) and deep layers (SCd). In contrast to the visual SCs, the SCd are involved in multisensory and motor processing. This study investigated the pattern of distribution and colocalization of cocaine- and amphetamine-regulated transcript peptide (CART) and three calcium-binding proteins (CaBPs) i.e. calbindin (CB), calretinin (CR) and parvalbumin (PV) in the SCd of the guinea pig. CART labeling was seen almost exclusively in the neuropil and fibers, which differed in regard to morphology and location. CART-positive neurons were very rare and restricted to a narrow area of the SCd. The most intense CART immunoreactivity was observed in the most dorsally located sublayer of the SCd, which is anatomically and functionally connected with the SCs. CART immunoreactivity in the remaining SCd was less intensive, but still relatively high. This characteristic pattern of immunoreactivity indicates that CART as a putative neurotransmitter or neuromodulator may play an important role in processing of visual information, while its involvement in the auditory and visuomotor processing is less significant, but still possible. CaBPs-positive neurons were morphologically diverse and widely distributed throughout all SCd. From studied CaBPs, CR showed a markedly different distribution compared to CB and PV. Overall, the patterns of distribution of CB and PV were similar in the entire SCd. Consequently, the complementarity of these patterns in the guinea pig was very weak. Double immunostaining revealed that CART did not colocalize with either CaBPs, which suggested that these neurochemical substances might not coexist in the multisensory and visuomotor parts of the SC. PMID- 29154917 TI - Maternal urinary cadmium levels during pregnancy associated with risk of sex dependent birth outcomes from an e-waste pollution site in China. AB - This study was to investigate whether exposure to cadmium (Cd) during pregnancy is associated with an increased risk of adverse birth outcomes in a sex-dependent manner. Cd concentrations in maternal urine (U-Cd) samples were measured in 237 subjects from Guiyu (e-waste area) and 212 subjects from Haojiang. A significance level of p <0.05 was used for all analyses. The maternal U-Cd levels in Guiyu residents were significantly higher than Haojiang. We found significant inverse associations between U-Cd concentrations and birth anthropometry (birth weight, birth length, Head Circumference and Apgar scores with 1min and 5 mins) in female neonates, but no significant associations were observed in male neonates except Apgar (1min) score after adjustment. The association was more pronounced among female neonates than male neonates, suggesting an association between Cd and adverse birth outcomes may be sex-specific. PMID- 29154918 TI - Attentional Modulation of Somatosensory Processing During the Anticipation of Movements Accompanying Pain: An Event-Related Potential Study. AB - : Attending to pain-relevant information is crucial to protect us from physical harm. Behavioral studies have already suggested that during anticipation of pain somatosensory input at the body location under threat is prioritized. However, research using daily life cues for pain, especially movements, is lacking. Furthermore, to our knowledge, no studies have investigated cortical processing associated with somatosensory processing during threatened movements. The current study aims to investigate whether movements accompanying pain automatically steer attention toward somatosensory input at the threatened location, affecting somatosensory evoked potentials (SEPs). Healthy volunteers were cued to perform movements with the left or the right hand, and one of these movements could be accompanied by pain on the moving hand. During movement anticipation, a task irrelevant tactile stimulus was presented to the threatened or pain-free hand to evoke SEPs. During anticipation of movements accompanying pain, the N120 component was increased for tactile stimuli at the threatened relative to the hand without pain. Moreover, the P200 SEP was enhanced during anticipation of movements accompanying pain relative to movements without pain, irrespective of which hand was stimulated. These findings show that the anticipation of pain accompanying movements may affect the processing of somatosensory input, and that this is likely to be driven by attentional processes. PERSPECTIVE: This study shows that the anticipation of pain-related movements automatically biases attention toward stimuli at a pain-related location, measured according to SEPs. The present study provides important new insights in the interplay between pain and attention, and its consequences at the cortical level. PMID- 29154916 TI - Acute intravenous exposure to silver nanoparticles during pregnancy induces particle size and vehicle dependent changes in vascular tissue contractility in Sprague Dawley rats. AB - The use of silver nanoparticles (AgNP) raises safety concerns during susceptible life stages such as pregnancy. We hypothesized that acute intravenous exposure to AgNP during late stages of pregnancy will increase vascular tissue contractility, potentially contributing to alterations in fetal growth. Sprague Dawley rats were exposed to a single dose of PVP or Citrate stabilized 20 or 110nm AgNP (700MUg/kg). Differential vascular responses and EC50 values were observed in myographic studies in uterine, mesenteric arteries and thoracic aortic segments, 24h post-exposure. Reciprocal responses were observed in aortic and uterine vessels following PVP stabilized AgNP with an increased force of contraction in uterine artery and increased relaxation responses in aorta. Citrate stabilized AgNP exposure increased contractile force in both uterine and aortic vessels. Intravenous AgNP exposure during pregnancy displayed particle size and vehicle dependent moderate changes in vascular tissue contractility, potentially influencing fetal blood supply. PMID- 29154920 TI - Switching from originator infliximab to biosimilar CT-P13 in real-life: The weight of patient acceptance. AB - OBJECTIVE: To explore acceptance and retention rate of biosimilar CT-P13 after switching from originator infliximab (OI) in patients with various rheumatic diseases. METHODS: Patients with stable rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriatic arthritis (PsA) under OI were proposed to switch to CT-P13 at the same regimen. A prospective cohort of infliximab-naive patients beginning CT-P13 and a retrospective cohort of patients treated with OI were used as controls. The primary outcome was to evaluate the retention rate of CT-P13. Secondary outcomes were the switch acceptance rate, reasons of failure and safety. RESULTS: Switch was proposed to 100 patients and accepted by 89 of them (63 AS, 12 PsA and 14 RA). After a median follow-up of 33 weeks, 72% of patients were still treated with CT-P13. This retention rate was significantly lower than the one found in our retrospective and prospective control cohorts: 88% and 90% respectively (P-value=0.0002). Within patients who asked to be reswitched to OI, 13/25 (52%) presented clinical disease activity, one developed serum sickness and 11 (44%) presented no objective activity. A subanalysis excluding these 11 patients abrogated difference in retention rates between the 3 cohorts (P value=0.453). After reswitching to OI, patients without objective disease activity claimed to recover original efficacy. CONCLUSIONS: Retention rate was lower after switching from OI to CT-P13 compared to our control cohorts. However, this difference faded after excluding patients without objective clinical activity, suggesting a reluctance of patients to the switch and a negative perception of the biosimilar. PMID- 29154919 TI - Patient-Reported Outcomes and Opioid Use by Outpatient Cancer Patients. AB - : The Memorial Sloan Kettering Pain Registry contains patient characteristics, treatments, and outcomes for a prospective cohort of 1,534 chronic pain cancer patients who were seen at outpatient pain service clinics. Average pain intensity (Brief Pain Inventory) was reported as mild by 24.6% of patients, moderate by 41.5%, and severe by 33.9%. The patient's report of average percent pain relief and health state (EuroQOL 5 dimensions) was inversely related to average pain intensity category, whereas measures of pain interference, number of worst pain locations, and physical and psychological distress were directly related to pain intensity category. Eighty-six percent of patients received an opioid at 1 or more clinic encounters. Regression analysis revealed that male sex or being younger (65 years of age or younger) was associated with a greater likelihood of an opioid ordered. Male sex nearly doubled the likelihood of a higher dose being ordered than female sex. Bivariate analysis found that patients receiving opioids reported significantly more pain relief than no-opioid patients. However, patients receiving opioids had higher pain interference scores, lower index of health state, and more physical distress than no-opioid patients Our results identify the need to consider opioid use and dosage when attempting to understand patient-reported outcomes (PROs) and factors affecting pain management. PERSPECTIVE: This report describes the results of the analyses of PROs and patient-related electronic health record data collected under standard of care from cancer patients at outpatient pain management clinics of Anesthesiology and Palliative Care at the Memorial Sloan Kettering Cancer Center. Consideration of sex and age as predictors of opioid use is critical in attempting to understand PROs and their relationship to pain management. PMID- 29154921 TI - Randomized Controlled Trials Evaluating Patient-Reported Outcomes after Cholecystectomy: A Systematic Review. PMID- 29154922 TI - Wound Care Center of Excellence: Guide to Operative Technique for Chronic Wounds. PMID- 29154923 TI - Dissociation of blood-brain barrier disruption and disease manifestation in an aquaporin-4-deficient mouse model of amyotrophic lateral sclerosis. AB - Aquaporin-4 (AQP4) is abundantly expressed in the central nervous system and is involved in the water balance in the cellular environment. Previous studies have reported that AQP4 expression is upregulated in rat models of amyotrophic lateral sclerosis (ALS), a fatal disease that affects motor neurons in the brain and spinal cord. In this study, we report that astrocytic AQP4 overexpression is evident during the course of disease in the spinal cord of an ALS mouse model, as well as in tissue from patients with ALS. AQP4 overexpression appears to be specifically associated with ALS because it was not induced by other experimental manipulations that produced acute or chronic gliosis. In order to examine the contribution of AQP4 to ALS disease development, we crossed AQP4 knockout mice with a mouse model of ALS. Significant improvement in blood-brain barrier (BBB) permeability was observed in the AQP4-deficient ALS mouse model. However, the time to disease onset and total lifespan were reduced in the AQP4-deficient ALS mouse model. The contradictory results suggest that changes in AQP4 may be context-dependent and further studies are required to understand the precise contribution of brain water balance in ALS. PMID- 29154924 TI - Characterization of three novel pathogenic SLC40A1 mutations and genotype/phenotype correlations in 7 Italian families with type 4 hereditary hemochromatosis. AB - Mutations of SLC40A1 encoding ferroportin (Fpn), the unique cellular iron exporter, severely affect iron homeostasis causing type 4 hereditary hemochromatosis, an autosomal dominant iron overload condition with variable phenotypic manifestations. This disease can be classified as type 4A, better known as "ferroportin disease", which is due to "loss of function" mutations that lead to decreased iron export from cells, or as type 4B hemochromatosis, which is caused by "gain of function" mutations, conferring partial or complete resistance to hepcidin-mediated Fpn degradation. In this work, we discuss clinical and molecular findings on a group of patients in whom a SLC40A1 single copy missense variant was identified. Three novel variants, p.D181N, p.G204R and p.R296Q were functionally characterized. Fpn D181N and R296Q mutants can be classified as full or partial loss of function, respectively. Replacement of G204 with arginine appears to cause a more complex defect with impact both on iron export function and hepcidin sensitivity. This finding confirms the difficulty of predicting the effect of a mutation on the molecular properties of Fpn in order to provide an exhaustive explanation to the wide variability of the phenotype in type 4 hereditary hemochromatosis. PMID- 29154925 TI - Membrane cholesterol depletion in cortical neurons highlights altered NMDA receptor functionality in a mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic Lateral Sclerosis (ALS) is a chronic neurodegenerative disease affecting upper and lower motor neurons, with unknown aetiology. Lipid rafts, cholesterol enriched microdomains of the plasma membrane, have been linked to neurodegenerative disorders like ALS. The NMDA-receptor subcellular localization in lipid rafts is known to play many roles, from modulating memory strength to neurotoxicity. In this study, performed on the widely used G93A mouse model of ALS, we have shown an equal content of total membrane cholesterol in Control and G93A cortical cultures. Moreover, by electrophysiological studies, we have recorded NMDA- and AMPA-evoked currents which were not significantly different between the two neuronal populations. To study the role of membrane cholesterol on glutamate receptor functionality, we have analysed NMDA and AMPA receptors following cholesterol membrane depletion by methyl-beta-cyclodextrin (MbetaCD). Interestingly, MbetaCD chronic treatment has provoked a significant reduction of NMDA-evoked currents in both cellular populations which was dose- and time dependent but significantly higher in ALS neurons compared to Control. The different MbetaCD effect on NMDA-evoked currents was not due to a different membrane receptor subunit composition but seemed to cause in both neuronal populations a NMDA receptor membrane redistribution. MbetaCD treatment effect was receptor-specific since no alterations in the two neuronal populations were detected on AMPA receptors. These results lead us to speculate for an altered proteomic composition of lipid rafts in cortical mutated neurons and suggest the need for further studies on the lipid rafts composition and on their interaction with membrane receptors in ALS cortices. PMID- 29154926 TI - Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation. AB - Apolipoprotein E (APOE) has been strongly implicated in the development of diet induced obesity. In the present study, we investigated the contribution of brain and peripherally expressed human apolipoprotein E3 (APOE3), the most common human isoform, to diet induced obesity. In our studies APOE3 knock-in (Apoe3knock-in), Apoe-deficient (apoe-/-) and brain-specific expressing APOE3 (Apoe3brain) mice were fed western-type diet for 12week and biochemical analyses were performed. Moreover, AAV-mediated gene transfer of APOE3 to apoe-/- mice was employed, as a means to achieve APOE3 expression selectively in periphery, since peripherally expressed APOE does not cross blood brain barrier (BBB) or blood-cerebrospinal fluid barrier (BCSFB). Our data suggest a bimodal role of APOE3 in visceral white adipose tissue (WAT) mitochondrial metabolic activation that is highly dependent on its site of expression and independent of postprandial dietary lipid deposition. Our findings indicate that brain APOE3 expression is associated with a potent inhibition of visceral WAT mitochondrial oxidative phosphorylation, leading to significantly reduced substrate oxidation, increased fat accumulation and obesity. In contrast, peripherally expressed APOE3 is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity. PMID- 29154927 TI - Integrative transcriptome and proteome analyses define marked differences between Neospora caninum isolates throughout the tachyzoite lytic cycle. AB - : Neospora caninum is one of the main causes of transmissible abortion in cattle. Intraspecific variations in virulence have been widely shown among N. caninum isolates. However, the molecular basis governing such variability have not been elucidated to date. In this study label free LC-MS/MS was used to investigate proteome differences between the high virulence isolate Nc-Spain7 and the low virulence isolate Nc-Spain1H throughout the tachyzoite lytic cycle. The results showed greater differences in the abundance of proteins at invasion and egress with 77 and 62 proteins, respectively. During parasite replication, only 19 proteins were differentially abundant between isolates. The microneme protein repertoire involved in parasite invasion and egress was more abundant in the Nc Spain1H isolate, which displays a lower invasion rate. Rhoptry and dense granule proteins, proteins related to metabolism and stress responses also showed differential abundances between isolates. Comparative RNA-Seq analyses during tachyzoite egress were also performed, revealing an expression profile of genes associated with the bradyzoite stage in the low virulence Nc-Spain1H isolate. The differences in proteome and RNA expression profiles between these two isolates reveal interesting insights into likely mechanisms involved in specific phenotypic traits and virulence in N. caninum. SIGNIFICANCE: The molecular basis that governs biological variability in N. caninum and the pathogenesis of neosporosis has not been well-established yet. This is the first study in which high throughput technology of LC-MS/MS and RNA-Seq is used to investigate differences in the proteome and transcriptome between two well-characterized isolates. Both isolates displayed different proteomes throughout the lytic cycle and the transcriptomes also showed marked variations but were inconsistent with the proteome results. However, both datasets identified a pre-bradyzoite status of the low virulence isolate Nc-Spain1H. This study reveals interesting insights into likely mechanisms involved in virulence in N. caninum and shed light on a subset of proteins that are potentially involved in the pathogenesis of this parasite. PMID- 29154928 TI - Sequence analysis of the thrombospondin-related adhesive protein gene and heat shock protein 70 gene of Babesia gibsoni isolated from dogs in Nanjing, China. AB - In this study, the thrombospondin-related adhesive protein (TRAP) gene and the heat shock protein 70 (Hsp70) gene of Babesia gibsoni isolated from the naturally infected dog in the Nanjing area were cloned and sequenced. Twenty blood samples were collected from the suspected cases of babesiosis at the animal hospital of Nanjing Agriculture University. Genomic DNA was extracted from the blood samples, and the 18S rDNAs were amplified by PCR to confirm Babesia infection. As a result, 10 cases of Babesia 18S rDNA gene amplification were positive in the 20 blood samples, confirming that the 10 cases were infected with canine Babesia. The TRAP and the Hsp70 gene fragments were amplified from all 10 positive cases. The four isolates, named NJN1, NJN2, NJN3 and NJN4, were sequenced and compared with other isolates in Asian. The similarity of TRAP and Hsp70 gene sequences among four isolates in Nanjing were above 99%. The Nanjing isolates were closely related to isolates from Taiwan and Japan. Indian isolates were different form Chinese and Japanese isolates, despite the very high similarity of the 18s rRNA genes sequence. These results suggest that the TRAP and Hsp70 genes have a reference value for the genetic diversity analysis of Babesia gibsoni. PMID- 29154929 TI - Identification of genetic variants of Brucella spp. through genome-wide association studies. AB - Brucellosis is an important zoonotic disease caused by Brucella spp. We present a phylogeny of 552 strains based on genome-wide single nucleotide polymorphisms (SNPs) determined by an alignment-free k-mer approach. A total of 138,029 SNPs were identified from 552 Brucella genomes. Of these, 31,152 and 106,877 were core and non-core SNPs, respectively. Based on pan-genome analysis 11,937 and 972 genes were identified as pan and core genome, respectively. The pan-genome-wide analysis studies (Pan-GWAS) could not identify the group-specific variants in Brucella spp. Therefore, we focused on SNP based genome-wide association studies (SNP-GWAS) to identify the species-specific genetic determinants in Brucella spp. Phylogenetic tree representing eleven recognized Brucella spp. showed 16 major lineages. We identified 143 species-specific SNPs in Brucella abortus that are conserved in 311 B. abortus genomes. Of these, 141 species-specific SNPs were confined in the positively significant SNPs of B. abortus using SNP-GWAS. Since conserved in all the B. abortus genomes studied, these SNPs might have originated very early during the evolution of B. abortus and might be responsible for the evolution of B. abortus with cattle as the preferred host. Similarly, we identified 383 species-specific SNPs conserved in 132 Brucella melitensis genomes. Of these 379 species-specific SNPs were identified as positively associated using GWAS. Interestingly, >98% of the SNPs that are significantly, positively associated with the traits showed 100% sensitivity and 100% specificity. These identified species-specific core-SNPs identified in Brucella genomes could be responsible for the speciation and their respective host adaptation. PMID- 29154930 TI - Suicide attempts in children and adolescents: The place of clock genes and early rhythm dysfunction. AB - Suicide remains one of the leading causes of death among young people, and suicidal ideation and behavior are relatively common in healthy and clinical populations. Suicide risk in childhood and adolescence is often approached from the perspective of nosographic categories to which predictive variables for suicidal acts are often linked. The cascading effects resulting from altered clock genes in a pediatric population could participate in biological rhythm abnormalities and the emergence of suicide attempts through impaired regulation of circadian rhythms and emotional states with neurodevelopmental effects. Also, early trauma and stressful life events can alter the expression of clock genes and contribute to the emergence of suicide attempts. Alteration of clock genes might lead to desynchronized and abnormal circadian rhythms impairing in turn the synchronization between external and internal rhythms and therefore the adaptation of the individual to his/her internal and external environment with the development of psychiatric disorders associated with increased risk for suicide attempts. PMID- 29154931 TI - Reducing the Rate of Abdominal Hysterectomies: Experience From a UK University Teaching Hospital. PMID- 29154932 TI - Correlation of Virtual Reality Simulation and Dry Lab Robotic Technical Skills. AB - STUDY OBJECTIVE: To examine whether a set of virtual reality (VR) surgical simulation drills have correlative validity when compared with the validated Robotic Objective Structured Assessment of Technical Skills (R-OSATS) dry lab drills. DESIGN: A prospective methods comparison study (Canadian Task Force classification II-2). SETTING: A teaching hospital. PARTICIPANTS: Thirty current residents, fellows, and faculty from the Departments of Obstetrics and Gynecology, Urology, and General Surgery. INTERVENTIONS: Participants completed 5 VR drills on the da Vinci Skills Simulator and 5 dry lab drills. Participants were randomized to the order of completion. MEASUREMENTS AND MAIN RESULTS: VR drills were scored automatically by the simulator. Dry lab drills were recorded, reviewed by 3 blinded experts, and scored using the R-OSATS assessment tool. Spearman correlation coefficients were calculated comparing simulator scores and R-OSATS scores for the same surgeon. The correlation for overall summary scores between VR and dry lab drills was strong (r = 0.83; p < .01). Each of the 5 VR drills was also found to have a statistically significant correlation to its corresponding dry lab drill, with correlation coefficients ranging from r = 0.49 to 0.73 (p < .01 for all). The performance on VR drills also confirmed construct validity. Faculty and fellows had consistently higher overall scores than residents (median VR scores: 458 for faculty, 425 for fellows, 339 for residents; p < .01). CONCLUSION: We selected a core set of VR drills that reliably correlate with validated dry lab R-OSATS drills. Because dry lab drills require significant time and effort on the part of the trainees and the evaluators, this set of VR drills could serve as an ancillary method of determining trainee competence. PMID- 29154933 TI - Opioid Prescription and Patient Use After Gynecologic Procedures: A Survey of Patients and Providers. AB - STUDY OBJECTIVE: To describe opioid distribution and patient use after gynecologic procedures. DESIGN: Survey study (Canadian Task Force classification III). SETTING: An urban academic tertiary care hospital. SUBJECTS: Ninety-six gynecologists in the Boston area, and 147 patients who underwent a benign hysterectomy between January 2015 and April 2016. INTERVENTIONS: Survey study of physicians and patients composed of 2 parts: (1) a physician survey on opioid prescribing practices after gynecologic procedures and (2) a patient survey on opioid consumption after hysterectomy. Physicians were contacted via e-mail to participate in an online survey. Eligible patients were contacted via telephone and asked to participate in a telephone survey. MEASUREMENTS AND MAIN RESULTS: Fifty-one physicians responded to an online survey and prescribed a mean of 27.1 tablets (range, 5-30) of oxycodone (5 mg) or hydromorphone (2 mg) after abdominal hysterectomy (AH), a mean of 22.6 tablets (range, 5-30) after laparoscopic hysterectomy (LH), and a mean of 16.8 tablets (range 5-30) after vaginal hysterectomy (VH). Physicians prescribed more opioids for AH compared with LH, with a mean difference of 4.5 tablets (standard deviation, 4.7; p < .01), and AH compared with VH, with a mean difference of 6.8 tablets (standard deviation, 5.8; p < .01), which were both statistically significant. In addition, 40.0% of physicians prescribe opioids after a hysteroscopy and 19.2% after a dilation and curettage. Fifty-six patients participated in the telephone survey: 64.6% of patients used less than half of the opioids prescribed and 16.1% used none. For AH, patients reported being prescribed a mean of 25.7 tablets and using a mean of 8.7 tablets (range, 0-60; 33.9% used). For LH or VH, patients reported being prescribed a mean of 24.2 tablets and using a mean of 10.0 tablets (range, 0-30; 41.4% used). Opioid consumption was not significantly different for AH compared with LH or VH (p = .613 for AH to LH, p = .279 for AH to VH). CONCLUSIONS: With respect to the physician survey, we conclude there is a wide range of opioid prescription practices and patient opioid consumption after gynecologic surgery. The patient survey revealed that physicians prescribe fewer opioid tablets after a minimally invasive approach to hysterectomy versus open hysterectomy. However, most patients use less than half of prescribed opioids, and a fraction did not use any opioids at all. PMID- 29154934 TI - Cephalostatin 1 analogues activate apoptosis via the endoplasmic reticulum stress signaling pathway. AB - The current study was conducted to compare the cytotoxicity of two stereospecific cephalostatin 1 analogues (CAs) against several human normal cell types and cancer cell lines and to determine their cytotoxic mechanism. Both CA analogues induced apoptosis and were cytotoxic with 50% growth inhibition (GI50) at ~1uM or less in six human cancer cell lines but neither analogue at 10uM killed more than 14% of any of three types of normal human cells suggesting their cytotoxicity is cancer-specific. CA treatment inhibited clonogenic tumor growth and activated caspase 3 and 9 but not caspase 8. CA-induced apoptosis was inhibited by the pan caspase inhibitor indicating the importance of caspase activation. CA treatment released smac/DIABLO but not cytochrome c from mitochondria and induced phosphorylation of eIF-2 and the activation of procaspase 4 in cancer cells, similar to cell treatment with thapsigargin, a known endoplasmic reticulum (ER) stress inducer. Finally, cells pretreated with a caspase 4 inhibitor were resistant to CA-induced apoptosis. In conclusion, both CAs induced apoptosis by triggering ER stress. Because of their ease of synthesis and low GI50, these cephalostatin analogues represent promising anticancer drugs. PMID- 29154935 TI - Ghrelin alleviates paclitaxel-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions in mice. AB - Paclitaxel is an effective chemotherapeutic agent, but has some treatment limiting adverse effects that markedly decrease patients' quality of life. Peripheral neuropathy is one of these, and no treatment for it has been established yet. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is secreted from the stomach and has widespread effects on multiple systems. We investigated the pharmacological potential of ghrelin in preventing paclitaxel-induced peripheral neuropathy using wild-type mice, ghrelin null mice, and growth hormone secretagogue receptor-null mice. In wild-type mice, ghrelin administration alleviated mechanical and thermal hypersensitivity, and partially prevented neuronal loss of small unmyelinated intraepidermal nerve fibers but not large myelinated nerve fibers. Moreover, ghrelin administration decreased plasma oxidative and nitrosative stress and increased the expression of uncoupling protein 2 (UCP2) and superoxide dismutase 2 (SOD2) in the dorsal root ganglia, which are mitochondrial antioxidant proteins, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), a regulator of mitochondrial number. Both ghrelin-null mice and growth hormone secretagogue receptor-null mice developed more severe nerve injuries than wild type mice. Our results suggest that ghrelin administration exerts a protective effect against paclitaxel-induced neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions, and that endogenous ghrelin has a neuroprotective effect that is mediated by ghrelin/growth hormone secretagogue receptor signaling. Ghrelin could be a promising therapeutic agent for the management of this intractable disease. PMID- 29154936 TI - Antidiabetic and antiobesity effects of SGLT2 inhibitor ipragliflozin in type 2 diabetic mice fed sugar solution. AB - Obesity due to excessive calorie intake is a known aggravating factor contributing to the development and progression of type 2 diabetes. Recently, excessive intake of sugar-sweetened beverages has presented challenges in stemming the tide of obesity. Here, we investigated the possible effects of sugar solution intake on the antidiabetic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin in type 2 diabetic mice that were fed ordinary drinking water, water + glucose solution, or water + sucrose solution. Under all feeding conditions, all mice exhibited type 2 diabetic symptoms, including hyperglycemia, hyperinsulinemia, and obesity; ipragliflozin subsequently improved these symptoms through increases in urinary glucose excretion. Effective dose of and response to ipragliflozin for diabetes improvement did not significantly differ by feeding condition. Further, under all feeding conditions, ipragliflozin administration resulted in significantly increased intake of both water and sugar solutions in association with increased urine volume resulting from increased urinary glucose excretion. In sugar solution-fed diabetic mice, ipragliflozin administration tended to slightly increase the proportion of sugar solution intake in total drinking volume, although not significantly so. In addition, ipragliflozin significantly decreased calorie balance, as calculated using calorie intake from food and sugar solution and calorie excretion via urinary glucose excretion. Our observation that the antidiabetic and antiobesity effects of the SGLT2 inhibitor ipragliflozin were not greatly affected by sugar solution intake in type 2 diabetic mice suggests that, in a clinical setting, ipragliflozin will remain an effective treatment for type 2 diabetic patients with excessive intake of carbohydrates. PMID- 29154937 TI - Effect of human recombinant prourokinase(rhpro-UK) on thromboembolic stroke in rats. AB - We evaluated the efficacy and safety of human recombinant prourokinase ( rhpro UK) on thromboembolic stroke in rats. 60 rats with thromboembolic stroke were divided into 6 groups (n = 10). The model group was given saline, the reagent groups were given rhpro-UK (5, 10, 20 * 104U/kg), and positive control groups were given urokinase (UK) 10 * 104U/kg and recombinant tissue plasminogen activator (rt-PA) 9mg/kg through intravenous infusion at 1.5h after embolism. And other 10 rats without occluded by autologous blood clots as the sham group were given saline. At 6h after treatment, neurological deficit score and Magnetic Resonance Imaging(MRI) including T1WI and T2WI sequence scanning were measured. At 24h after treatment, the brain was cut for 2,3,5-triphenyltetrazolium chloride (TTC) staining and aspectrophotometric assay to measure the infarct area and intracerebral hemorrhage after neurological deficit detection. rhpro-UK (5, 10, 20 * 104 U/kg) improved neurological disorder by 39.1 +/- 19.7% (n = 10, P > 0.05), 65.2 +/- 14.2% (n = 10, P < 0.01) and 65.2 +/- 14.2% (n = 10, P < 0.01) maximally; decreased brain lesion volume by 36.7 +/- 34.8% (n = 10, P < 0.05), 77.6 +/- 7.7% (n = 10, P < 0.01) and 80.5 +/- 6.9% (n = 10, P < 0.01); decreased infarction area by 38.2 +/- 24.0% (n = 10, P < 0.01), 73.9 +/- 5.2% (n = 10, P < 0.001) and 79.7 +/- 4.0% (n = 10, P < 0.001) respectively, and there were no statistics difference between rhpro-UK (5, 10, 20 * 104 U/kg) and each positive groups at intracerebral hemorrhage (P > 0.05). Rhpro-UK improved the damaged neural function, decreased the extent of the disease and did not raise bleeding, had protective effects for cerebral ischemia in rats. PMID- 29154938 TI - Assessments of cellular melatonin receptor signaling pathways: beta-arrestin recruitment, receptor internalization, and impedance variations. AB - Melatonin receptors belong to the family of G-protein coupled receptors. Agonist induced receptor activation is terminated with the recruitment of beta-arrestin, which leads to receptor internalization. Furthermore, agonist binding induces a shift in cellular shape that translates into a change in the electric impedance of the cell. In the present study, we employed engineered cells to study these internalization-related processes in the context of the two melatonin receptors, MT1 and MT2. To assess these three receptor internalization-related functions and validate the results, we employed four classical ligands of melatonin receptors: the natural agonist melatonin; the super-agonist 2-iodo-melatonin and the two antagonists luzindole and 4-phenyl-2-propionamidotetralin. The assessments confirmed the nature of the agonistic ligands but showed that 4-phenyl-2 propionamidotetralin, a described antagonist, is a biased partial agonist at MT2 with poorer affinity for MT1. The methods are now available to be applied to any receptor system for which multiple signaling pathways must be evaluated for new molecules. PMID- 29154939 TI - Hypothesis for cognitive effects of transcranial direct current stimulation: Externally- and internally-directed cognition. AB - A comprehensive explanation is lacking for the broad array of cognitive effects modulated by transcranial direct current stimulation (tDCS). We advanced the testable hypothesis that tDCS to the default mode network (DMN) increases processing of goals and stored information at the expense of external events. We further hypothesized that tDCS to the dorsal attention network (DAN) increases processing of external events at the expense of goals and stored information. A literature search (PsychINFO) identified 42 empirical studies and 3 meta-analyses examining effects of prefrontal and/or parietal tDCS on tasks that selectively required external and/or internal processing. Most, though not all, of the studies that met our search criteria supported our hypothesis. Three meta analyses supported our hypothesis. The hypothesis we advanced provides a framework for the design and interpretation of results in light of the role of large-scale intrinsic networks that govern attention. PMID- 29154940 TI - Ebulin-RP, a novel member of the Ebulin gene family with low cytotoxicity as a result of deficient sugar binding domains. AB - BACKGROUND: Sambucus ebulus is a rich source of ribosome-inactivating proteins (RIPs) and RIP-related lectins generated from multiple genes. These proteins differ in their structure, enzymatic activity and sugar binding specificity. METHODS: We have purified and characterized ebulin-RP from S. ebulus leaves and determined the amino acid sequence by cDNA cloning. Cytotoxicity was studied in a variety of cancer cells and a comparative study of the ability of ebulin-RP to bind sugars using "in vitro" and "in silico" approaches was performed. RESULTS: Ebulin-RP is a novel heterodimeric type 2 RIP present in S. ebulus leaves together with the type 2 RIP ebulin l, which displayed rRNA N-glycosidase activity but unlike ebulin l, lacked functional sugar binding domains. As a consequence of changes in its B-chain, ebulin-RP displayed lower cytotoxicity than ebulin l towards cancer cells and induced apoptosis as the predominant pattern of cell death. CONCLUSIONS: Ebulin-RP is a novel member of the ebulin gene family with low cytotoxicity as a result of deficient sugar binding domains. Type 2 RIP genes from Sambucus have evolved to render proteins with different sugar affinities that may be related to different biological activities and could result in an advantage for the plant. GENERAL SIGNIFICANCE: The ebulin family of RIPs and lectins can serve as a good model for studying the evolutionary process which may have occurred in RIPs. The lack of cytotoxicity of ebulin-RP makes it a good candidate as a toxic moiety in the construction of immunotoxins and conjugates directed against specific targets. PMID- 29154941 TI - In vitro percutaneous absorption and metabolism of Bisphenol A (BPA) through fresh human skin. AB - Bisphenol A (BPA) is a high production volume compound. It is mainly used as a monomer to make polymers for various applications including food-contact materials. The primary route of exposure to BPA in the general population is through oral intake (EFSA 2015) however, other potential sources of exposure have also been identified, such as dermal contact. In the present study, the percutaneous absorption through human skin has been investigated in an in vitro study according to OECD TG 428 (Skin Absorption: In Vitro Method). In order to investigate potential dermal BPA metabolism during absorption, radiolabelled BPA was applied to fresh, metabolically competent, human skin samples (ring labelled 14C BPA concentrations tested were 2.4, 12, 60 and 300mg/L). Measured as total radioactivity the mean absorbed dose (receptor compartment) ranged from 1.7-3.6% of the applied doses and the dermal delivery (epidermis+dermis+receptor compartment), sometimes also named bioavailable dose was 16-20% of the applied doses, with the majority of the radioactivity associated with epidermis compared to dermis and receptor fluid. No metabolism was observed in any of the epidermis samples; however some metabolism was observed in dermis and receptor fluid samples with formation of BPA-glucuronide and BPA-sulfate, and some polar metabolites. PMID- 29154942 TI - Levels of palmitic acid ester of hydroxystearic acid (PAHSA) are reduced in the breast milk of obese mothers. AB - To achieve optimal development of a newborn, breastfeeding is extensively recommended, but little is known about the role of non-nutritive bioactive milk components. We aimed to characterize the fatty acid esters of hydroxy fatty acids (FAHFAs), namely palmitic acid hydroxystearic acids (PAHSAs)-endogenous lipids with anti-inflammatory and anti-diabetic properties, in human breast milk. Breast milk samples from 30 lean (BMI=19-23) and 23 obese (BMI>30) women were collected 72h postpartum. Adipose tissue and milk samples were harvested from C57BL/6J mice. FAHFA lipid profiles were measured using reverse phase and chiral liquid chromatography-mass spectrometry method. PAHSA regioisomers as well as other FAHFAs were present in both human and murine milk. Unexpectedly, the levels of 5 PAHSA were higher relative to other regioisomers. The separation of both regioisomers and enantiomers of PAHSAs revealed that both R- and S-enantiomers were present in the biological samples, and that the majority of the 5-PAHSA signal is of R configuration. Total PAHSA levels were positively associated with weight gain during pregnancy, and 5-PAHSA as well as total PAHSA levels were significantly lower in the milk of the obese compared to the lean mothers. Our results document for the first time the presence of lipid mediators from the FAHFA family in breast milk, while giving an insight into the stereochemistry of PAHSAs. They also indicate the negative effect of obesity on 5-PAHSA levels. Future studies will be needed to explore the role and mechanism of action of FAHFAs in breast milk. PMID- 29154943 TI - Molecular characterization and expression analysis of a novel r-spondin member (rspo2l) in Chinese tongue sole (Cynoglossus semilaevis). AB - Numerous studies suggest R-spondins (Rspos) plays a role in mammalian sex development and differentiation by activating WNT signaling pathways. However, Rspos are frequently less reported in teleosts. In this study, a molecular characterization and expression analysis was conducted with a new rspondin member in the Chinese tongue sole, rspondin2-like (rspo2l). The length of rspo2l cDNA is 1251 bp with 732 bp of coding sequence. A qRT-PCR analysis revealed that the transcription of rspo2l was distributed in various tissues, with high transcription levels in the liver, skin, and gills which might indicate a possible role in immunity. We next examined a time-course of transcription levels in four immune tissues (gill, liver, spleen, and kidney) after Vibrio harveyi challenge. It was found that rspo2l was up-regulated in the gills, spleen, and kidney and down-regulated in the liver, and the greatest responses occurred at 24 and 48 h after bacterial challenge. An assessment of beta-catenin, the key regulator of the canonical WNT signaling pathway, at different time points in four immune organs revealed that its transcription profile was similar to that of rspo2l after bacterial challenge. The results suggest that tongue sole rspo2l might play a role in immune responses after bacterial challenge, while the potential link with the WNT signaling pathway still requires further investigation. This is the first report about the involvement of rspondins in fish immune responses. PMID- 29154945 TI - Veno-arterial ECMO in critically ill patients: The age of maturity? PMID- 29154944 TI - beta-Estradiol antagonizes the inhibitory effects of caffeine in BMMSCs via the ERbeta-mediated cAMP-dependent PKA pathway. AB - Caffeine negatively mediates bone homeostasis to cause bone loss and even osteoporosis. This phenomenon occurs in postmenopausal women with estrogen deficiency but not in healthy young women. In this study, we determined whether the effects of caffeine on bone homeostasis were antagonized by estrogen and the underlying mechanisms. In particular, because high levels of cAMP, an important second messenger, have been observed in postmenopausal women suffering from osteoporosis, we examined the role of cAMP in the effects of caffeine on bone homeostasis. In vivo study showed that caffeine accelerated bone loss in osteoporotic rats, whereas beta-estradiol blunted the negative effect of caffeine on bone. In vitro study, we harvested bone marrow-derived mesenchymal stromal cells (BMMSCs) from osteoporotic rats. We found that caffeine and beta-estradiol inversely affected BMMCSs proliferation, apoptosis, osteogenic lineage commitment, extracellular matrix synthesis and mineralization. These parameters were assessed according to the expression levels of osteogenic markers, alkaline phosphatase activity and Alizarin red staining. The deleterious effects of caffeine on BMMSCs were blunted by beta-estradiol. The cAMP-dependent PKA pathway was found to be involved in regulating caffeine/beta-estradiol-mediated cell growth, survival and osteogenesis. Additionally, after estrogen receptor (ER) beta knockdown, the antagonistic effects of beta-estradiol on caffeine were nearly abolished. These results indicated that by binding to ERbeta, beta estradiol antagonizes the negative impacts of caffeine on cell growth and osteogenic differentiation in BMMSCs through the cAMP-dependent PKA signaling pathway. PMID- 29154946 TI - Cloning and expression characterization in hypothalamic Dio2/3 under a natural photoperiod in the domesticated Brandt's vole (Lasiopodomys brandtii). AB - The Dio2/3 gene is related to the photoperiodic response in mammals and plays an important role in the development of gonadal organs and seasonal breeding. Our previous studies have reported synchronous variations in the gonadal mass and photoperiodical transition around the summer solstice in a wild Brandt's vole population, a species with striking seasonal breeding. To investigate the role of the Dio2/3 gene in the control of seasonal breeding in this species, we cloned and characterized its expression levels by high-throughput Real-Time PCR during the period around the summer solstice. We selected a domesticated strain to ensure similar development of samples. The synchronous variation pattern between the Dio2/3 expression levels and gonadal mass around the summer solstice supports the prediction that the Dio2/3 gene plays an important role in the seasonal transition in this species. We suggest that the observed photoperiod response may be triggered by differences in the day length rather than the absolute daylength in this species. However, the similar Dio2/3 gene expression patterns but inconsistent gonadal mass patterns between the domesticated strain and the wild strain in the samples collected on Sep 8th, an absolute nonbreeding stage in the wild, lead us to speculate that the core function of the Dio2/3 gene should be restricted in response to the photoperiod rather than factors directly regulating gonadal development, and this laboratory strain could be used as an animal model to test the mechanism of environmental adaptation. PMID- 29154947 TI - 16S rRNA gene amplicon sequencing reveals dominance of Actinobacteria in Rhodnius pallescens compared to Triatoma maculata midgut microbiota in natural populations of vector insects from Colombia. AB - Chagas disease affects more than 6 million people in Latin America, it is a parasitic disease caused by the protozoan Trypanosoma cruzi, which is transmitted mainly by bloodsucking insects of the Triatominae subfamily. Studies on microbial communities that inhabit the insect gut are important to understanding their role in the parasite transmission and development. The present work aims to evaluate the gut bacterial composition of natural populations of triatomine species from Vichada and Magdalena, administrative states called departments in Colombia, using high-throughput sequencing technologies. The insects were collected from housing peridomestic area and Attalea butyracea palms; they were identified by conventional taxonomy as Triatoma maculata and Rhodnius pallescens, and their guts were dissected under aseptic conditions in order to obtain total DNA. After DNA quality confirmation, the sequencing of the V4 region of 16S rRNA gene was carried out using the Illumina platform MiSeq. The results showed that 13 predominant bacterial genera were present in both species, being Burkholderia, Gordonia, and Ralstonia, the most prevailing bacterial genera. Furthermore, representative genera of each species were found. Williamsia and Kocuria were the most common in R. pallescens; and Dietzia, Aeromonas, and Pelomonas were only observed in T. maculata samples. This is the first study of microbiota associated with these triatomine species using massive sequencing methods The approach allowed inferring the presence of a dominant population of bacteria according to the triatomine species in Colombia, which may suggest a strong association between microbiota and their host. PMID- 29154948 TI - The mitochondrial TMEM177 associates with COX20 during COX2 biogenesis. AB - The three mitochondrial-encoded proteins, COX1, COX2, and COX3, form the core of the cytochrome c oxidase. Upon synthesis, COX2 engages with COX20 in the inner mitochondrial membrane, a scaffold protein that recruits metallochaperones for copper delivery to the CuA-Site of COX2. Here we identified the human protein, TMEM177 as a constituent of the COX20 interaction network. Loss or increase in the amount of TMEM177 affects COX20 abundance leading to reduced or increased COX20 levels respectively. TMEM177 associates with newly synthesized COX2 and SCO2 in a COX20-dependent manner. Our data shows that by unbalancing the amount of TMEM177, newly synthesized COX2 accumulates in a COX20-associated state. We conclude that TMEM177 promotes assembly of COX2 at the level of CuA-site formation. PMID- 29154949 TI - A novel microscopy-based assay identifies extended synaptotagmin-1 (ESYT1) as a positive regulator of anoctamin 1 traffic. AB - An attractive possibility to treat Cystic Fibrosis (CF), a severe condition caused by dysfunctional CFTR, an epithelial anion channel, is through the activation of alternative (non-CFTR) anion channels. Anoctamin 1 (ANO1) was demonstrated to be a Ca2+-activated chloride channel (CaCC) and thus of high potential to replace CFTR. Despite that ANO1 is expressed in human lung CF tissue, it is present at the cell surface at very low levels. In addition, little is known about regulation of ANO1 traffic, namely which factors promote its plasma membrane (PM) localization. Here, we generated a novel cellular model, expressing an inducible 3HA-ANO1-eGFP construct, and validated its usage as a microscopy tool to monitor for ANO1 traffic. We demonstrate the robustness and specificity of this cell-based assay, by the identification of siRNAs acting both as ANO1 traffic enhancer and inhibitor, targeting respectively COPB1 and ESYT1 (extended synaptotagmin-1), the latter involved in coupling of the endoplasmic reticulum to the PM at specific microdomains. We further show that knockdown of ESYT1 (and family members ESYT2 and ESYT3) significantly decreased ANO1 current density. This ANO1 cell-based assay constitutes an important tool to be further used in high-throughput screens and drug discovery of high relevance for CF and cancer. PMID- 29154951 TI - Regulation of neural ion channels by muscarinic receptors. AB - The excitable behaviour of neurons is determined by the activity of their endogenous membrane ion channels. Since muscarinic receptors are not themselves ion channels, the acute effects of muscarinic receptor stimulation on neuronal function are governed by the effects of the receptors on these endogenous neuronal ion channels. This review considers some principles and factors determining the interaction between subtypes and classes of muscarinic receptors with neuronal ion channels, and summarizes the effects of muscarinic receptor stimulation on a number of different channels, the mechanisms of receptor - channel transduction and their direct consequences for neuronal activity. Ion channels considered include potassium channels (voltage-gated, inward rectifier and calcium activated), voltage-gated calcium channels, cation channels and chloride channels. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'. PMID- 29154950 TI - Murine models of sleep apnea: functional implications of altered macrophage polarity and epigenetic modifications in adipose and vascular tissues. AB - Obstructive sleep apnea (OSA) is a highly prevalent disease across the lifespan, is characterized by chronic intermittent hypoxia and sleep fragmentation, and has been independently associated with substantial cardiometabolic morbidity. However, the reversibility of end-organ morbidity with treatment is not always apparent, suggesting that both tissue remodeling and epigenetic mechanisms may be operationally involved. Here, we review the cumulative evidence focused around murine models of OSA to illustrate the temporal dependencies of cardiometabolic dysfunction and its reversibility, and more particularly to discuss the critical contributions of tissue macrophages to adipose tissue insulin resistance and vascular atherogenesis. In addition, we describe initial findings potentially implicating epigenetic alterations in both the emergence of the cardiometabolic morbidity of OSA, and in its reversibility with treatment. We anticipate that improved understanding of macrophage biology and epigenetics in the context of intermittent hypoxia and sleep fragmentation will lead to discovery of novel therapeutic targets and improved cardiovascular and metabolic outcomes in OSA. PMID- 29154952 TI - In vitro mechanisms of Beauvericin toxicity: A review. AB - Beauvericin (BEA) is a mycotoxin produced by many species of fungus Fusarium and by Beauveria bassiana; BEA is a natural contaminant of cereals and cereals based products and possesses a wide variety of biological properties. The mechanism of action seems to be related to its ionophoric activity, that increases ion permeability in biological membranes. As a consequence, BEA causes cytotoxicity in several cell lines and is capable to produce oxidative stress at molecular level. Moreover, BEA is genotoxic (produces DNA fragmentation, chromosomal aberrations and micronucleus) and causes apoptosis with the involvement of mitochondrial pathway. However, several antioxidant mechanisms protect cells against oxidative stress produced by BEA. Despite its strong cytotoxicity, no risk assessment have been still carried out by authorities due to a lack of toxicity data, so research on BEA toxicological impact is still going on. This review reports information available regarding BEA mechanistic toxicology with the aim of updating information regarding last researches on this mycotoxin. PMID- 29154953 TI - Correlation between cefepime utilisation and Pseudomonas aeruginosa resistance rates to beta-lactams and carbapenems in patients with healthcare-associated infections. AB - OBJECTIVES: There is direct link between overutilisation or abuse of antibiotics and Pseudomonas aeruginosa resistance rates, but other factors may also influence the resistance rate. This study aimed to observe changes in P. aeruginosa resistance rates in patients with hospital-acquired infections (HAIs) following a period of cefepime unavailability in an ICU. METHODS: The study was designed as a retrospective observational analysis of trends in antibiotic utilisation and density of antibiotic resistance. It covered only P. aeruginosa isolates causing HAIs obtained from patients aged >18years. Isolates taken <48h after admission to the ICU and duplicate isolates were excluded. The effects of cefepime withdrawal from prescribing during the 2-year period on P. aeruginosa resistance density trends were also followed. RESULTS: During the study period (2009-2016), a total of 318 non-duplicate P. aeruginosa isolates causing HAIs in the ICU were collected. The predominant anatomical localisation of these infections (nearly 95%) was the lungs (pneumonia), surgical sites and urinary tract (69.18%, 18.24% and 6.92%, respectively). The isolates showed a lower resistance density (per/1000 PDs) in the last year (2016) compared with the first year of observation (2009) for all monitored antibiotics, with a peak in 2011. Although a decreasing trend of resistance density was recorded for all examined drugs, statistical significance was noted only for imipenem, meropenem and piperacillin/tazobactam (P<0.05) CONCLUSIONS: Temporary withdrawal of cefepime in a hospital resulted in a significant decrease in the density of P. aeruginosa isolates resistant to imipenem, meropenem, piperacillin/tazobactam, ceftazidime and cefepime. PMID- 29154954 TI - The impact of social exclusion on anticipatory attentional processing. AB - The importance of understanding how we anticipate and prepare for social rejection is underscored by the mental and physical toll of continual social vigilance. In this study, we investigate the impact of social rejection on anticipatory attentional processes using the well-known Cyberball task, a paradigm in which participants engage in a game of catch with virtual avatars who after an initial period of fair-play (inclusion condition) then exclude the participant from the game (exclusion condition). The degree of anticipatory attention allocated by subjects towards the avatars was assessed by measuring P3b responses towards the avatars' preparatory actions (i.e. the phase preceding their exclusionary actions) using high density EEG. The results of the study show that relative to the inclusion, participants exhibit elevated levels of anticipatory attentional allocation towards the avatars during the exclusion block. This shift was however significantly moderated by participants' self reported cognitive regulation tendencies. Participants with higher levels of self reported cognitive reappraisal tendencies showed larger anticipatory P3b increases from the inclusion to exclusion block relative to participants with reduced levels of reappraisal tendencies. These results highlight the impact of social exclusion on anticipatory neural processing and the moderating role of cognitive reappraisal on these effects. PMID- 29154955 TI - A global call to arms for clinical laboratories - Harmonised quantification and reporting of monoclonal proteins. PMID- 29154956 TI - Biomarkers in Mitral Regurgitation. AB - Mitral regurgitation (MR) is a common cause of heart failure but may also remain silent without either symptoms or altered cardiac function. In the latter case, management is still controversial and biomarkers could be an important means to solving remaining issues in MR management. As objective markers of myocardial stress and early left ventricular dysfunction, biomarkers may for example facilitate the identification of patients with benefit from early surgery of degenerative MR. The most studied biomarkers are the natriuretic peptides (NPs), especially brain NP, as well as its N terminal prohormone. In addition, other biologically relevant biomarkers have been recently proposed based on proteomic approaches. Finally, the large family of microRNA, that are the most abundant non coding RNA, may also be of future interest. In this review, we will summarize the current knowledge about NPs in degenerative and functional MR, and general "omic" discoveries and microRNAs. PMID- 29154957 TI - The yin/yang of inflammatory status: Blood-brain barrier regulation during sleep. AB - Sleep loss induces a low-grade inflammatory status characterized by a subtle but sustained increase of pro-inflammatory mediators, which are key regulators of blood-brain barrier function. To investigate the influence of inflammatory status on blood-brain barrier dysfunction induced by sleep restriction we performed an experiment using two strains of mice with different immunological backgrounds, C57BL/6 mice that have a predominant pro-inflammatory response and BALB/c mice that have a predominant anti-inflammatory response. Mice were sleep-restricted during 10 days using the flowerpot technique during 20 h per day with 4 h of daily sleep opportunity. The systemic inflammatory status, blood-brain barrier permeability, and the hippocampal expression of neuroinflammatory markers were characterized at the 10th day. Serum levels of TNF and IFN-gamma increased in sleep-restricted C57BL/6 but not in BALB/c mice; no changes in other cytokines were found. Sleep restriction increased blood-brain barrier permeability in C57BL/6 strain but not in BALB/c. The hippocampus of sleep-restricted C57BL/6 mice exhibited an increase in the expression of the neuroinflammatory markers Iba 1, A2A adenosine receptor, and MMP-9; meanwhile in sleep-restricted BALB/c mice the expression of this markers was lesser than the control group. These data suggest that cytokines may be playing a key role in modulating blood-brain barrier function during sleep restriction, and probably the effects are related to Iba-1, MMP-9 and A2A adenosine receptor overexpression. PMID- 29154959 TI - Early life innate immune signatures of persistent food allergy. AB - BACKGROUND: Food allergy naturally resolves in a proportion of food-allergic children without intervention; however the underlying mechanisms governing the persistence or resolution of food allergy in childhood are not understood. OBJECTIVES: This study aimed to define the innate immune profiles associated with egg allergy at age 1 year, determine the phenotypic changes that occur with the development of natural tolerance in childhood, and explore the relationship between early life innate immune function and serum vitamin D. METHODS: This study used longitudinally collected PBMC samples from a population-based cohort of challenge-confirmed egg-allergic infants with either persistent or transient egg allergy outcomes in childhood to phenotype and quantify the functional innate immune response associated with clinical phenotypes of egg allergy. RESULTS: We show that infants with persistent egg allergy exhibit a unique innate immune signature, characterized by increased numbers of circulating monocytes and dendritic cells that produce more inflammatory cytokines both at baseline and following endotoxin exposure when compared with infants with transient egg allergy. Follow-up analysis revealed that this unique innate immune signature continues into childhood in those with persistent egg allergy and that increased serum vitamin D levels correlate with changes in innate immune profiles observed in children who developed natural tolerance to egg. CONCLUSIONS: Early life innate immune dysfunction may represent a key immunological driver and predictor of persistent food allergy in childhood. Serum vitamin D may play an immune modulatory role in the development of natural tolerance. PMID- 29154958 TI - Pathogenic TH17 inflammation is sustained in the lungs by conventional dendritic cells and Toll-like receptor 4 signaling. AB - BACKGROUND: Mechanisms that elicit mucosal TH17 cell responses have been described, yet how these cells are sustained in chronically inflamed tissues remains unclear. OBJECTIVE: We sought to understand whether maintenance of lung TH17 inflammation requires environmental agents in addition to antigen and to identify the lung antigen-presenting cell (APC) types that sustain the self renewal of TH17 cells. METHODS: Animals were exposed repeatedly to aspiration of ovalbumin alone or together with environmental adjuvants, including common house dust extract (HDE), to test their role in maintaining lung inflammation. Alternatively, antigen-specific effector/memory TH17 cells, generated in culture with CD4+ T cells from Il17a fate-mapping mice, were adoptively transferred to assess their persistence in genetically modified animals lacking distinct lung APC subsets or cell-specific Toll-like receptor (TLR) 4 signaling. TH17 cells were also cocultured with lung APC subsets to determine which of these could revive their expansion and activation. RESULTS: TH17 cells and the consequent neutrophilic inflammation were poorly sustained by inhaled antigen alone but were augmented by inhalation of antigen together with HDE. This was associated with weight loss and changes in lung physiology consistent with interstitial lung disease. The effect of HDE required TLR4 signaling predominantly in lung hematopoietic cells, including CD11c+ cells. CD103+ and CD11b+ conventional dendritic cells interacted directly with TH17 cells in situ and revived the clonal expansion of TH17 cells both ex vivo and in vivo, whereas lung macrophages and B cells could not. CONCLUSION: TH17-dependent inflammation in the lungs can be sustained by persistent TLR4-mediated activation of lung conventional dendritic cells. PMID- 29154960 TI - Porphyromonas gingivalis Differentially Modulates Apoptosome Apoptotic Peptidase Activating Factor 1 in Epithelial Cells and Fibroblasts. AB - Porphyromonas gingivalis is able to invade and modulate host-immune response to promote its survival. This bacterium modulates the cell cycle and programed cell death, contributing to periodontal lesion worsening. Several molecular pathways have been identified as key triggers of apoptosis, including apoptosome apoptotic peptidase activating factor 1 (APAF-1). Apaf-1 and X-linked inhibitor of apoptosis protein (Xiap) mRNA were differentially expressed between gingival samples harvested from human healthy and chronic periodontitis tissues (Apaf-1, 19.2-fold; caspase-9, 14.5-fold; caspase-3, 6.8-fold; Xiap: 2.5-fold in chronic periodontitis) (P < 0.05), highlighting their potential role in periodontitis. An increased proteic expression of APAF-1 was also observed in a murine experimental periodontitis model induced by P. gingivalis-soaked ligatures. In vitro, it was observed that P. gingivalis targets APAF-1, XIAP, caspase-3, and caspase-9, to inhibit epithelial cell death at both mRNA and protein levels. Opposite effect was observed in fibroblasts in which P. gingivalis increased cell death and apoptosis. To assess if the observed effects were associated to APAF-1, epithelial cells and fibroblasts were transfected with siRNA targeting Apaf-1. Herein, we confirmed that APAF-1 is targeted by P. gingivalis in both cell types. This study identified APAF-1 apoptosome and XIAP as intracellular targets of P. gingivalis, contributing to the deterioration of periodontal lesion through an increased persistence of the bacteria within tissues and the subversion of host immune response. PMID- 29154961 TI - Inhibition of Cyclooxygenase-2 Suppresses the Recruitment of Endothelial Progenitor Cells in the Microvasculature of Endometriotic Lesions. AB - The incorporation of endothelial progenitor cells (EPCs) into newly developing blood vessels contributes to the vascularization of endometriotic lesions. We analyzed whether cyclooxygenase (COX)-2 signaling regulates this vasculogenic process. Endometriotic lesions were surgically induced in irradiated FVB/N mice, which were reconstituted with bone marrow from FVB/N-TgN [Tie2/green fluorescent protein (GFP)] 287 Sato mice. The animals received beta-estradiol 17-valerate once a week and were treated daily with the selective COX-2 inhibitor parecoxib (25 mg/kg) or vehicle (control) for 7 and 28 days. Analyses involved the determination of lesion growth, cyst formation, homing of GFP+/Tie2+ EPCs, numbers of circulating EPCs, vascularization, cell proliferation, apoptosis, and immune cell infiltration by means of high-resolution ultrasonography, caliper measurements, flow cytometry, histologic analysis, and immunohistochemical analysis. In parecoxib-treated mice, blood circulating EPCs were higher, but numbers of recruited EPCs in endometriotic lesions were significantly lower when compared with controls. This finding was associated with an impaired early vascularization and stromal tissue growth as well as reduced glandular secretory activity of the lesions. Parecoxib-treated lesions further contained less proliferating and more apoptotic cells and exhibited lower numbers of infiltrating macrophages and neutrophilic granulocytes. These findings demonstrate that the inhibition of COX-2 suppresses vasculogenesis in endometriotic lesions, which may contribute to an impaired lesion vascularization and growth. PMID- 29154962 TI - A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis. AB - Diabetic kidney disease and atherosclerotic disease are major causes of morbidity and mortality associated with type 2 diabetes (T2D), and diabetic kidney disease is a major cardiovascular risk factor. The black and tan, brachyury (BTBR) mouse strain with leptin deficiency (Lepob) has emerged as one of the best models of human diabetic kidney disease. However, no T2D mouse model of combined diabetic kidney disease and atherosclerosis exists. Our goal was to generate such a model. To this end, the low-density lipoprotein (LDL) receptor was targeted for degradation via inducible degrader of the LDL receptor (IDOL) overexpression, using liver-targeted adenoassociated virus serotype DJ/8 (AAV-DJ/8) in BTBR wild type and BTBR Lepob mice. Liver-targeted IDOL-AAV-DJ/8 increased plasma LDL cholesterol compared with the control enhanced green fluorescent protein AAV DJ/8. IDOL-induced dyslipidemia caused formation of atherosclerotic lesions of an intermediate stage, which contained both macrophages and smooth muscle cells. BTBR Lepob mice exhibited diabetic kidney disease. IDOL-induced dyslipidemia worsened albuminuria and glomerular macrophage accumulation but had no effect on mesangial expansion or podocyte numbers. Thus, by inducing hepatic degradation of the LDL receptor, we generated a T2D model of combined kidney disease and atherosclerosis. This model provides a new tool to study mechanisms, interactions, and treatment strategies of kidney disease and atherosclerosis in T2D. PMID- 29154964 TI - Lipotoxicity and the gut-liver axis in NASH pathogenesis. AB - The pathogenesis of non-alcoholic fatty liver disease, particularly the mechanisms whereby a minority of patients develop a more severe phenotype characterised by hepatocellular damage, inflammation, and fibrosis is still incompletely understood. Herein, we discuss two pivotal aspects of the pathogenesis of NASH. We first analyse the initial mechanisms responsible for hepatocellular damage and inflammation, which derive from the toxic effects of excess lipids. Accumulating data indicate that the total amount of triglycerides stored in hepatocytes is not the major determinant of lipotoxicity, and that specific lipid classes act as damaging agents on liver cells. In particular, the role of free fatty acids such as palmitic acid, cholesterol, lysophosphatidylcholine and ceramides has recently emerged. These lipotoxic agents affect the cell behaviour via multiple mechanisms, including activation of signalling cascades and death receptors, endoplasmic reticulum stress, modification of mitochondrial function, and oxidative stress. In the second part of this review, the cellular and molecular players involved in the cross-talk between the gut and the liver are considered. These include modifications to the microbiota, which provide signals through the intestine and bacterial products, as well as hormones produced in the bowel that affect metabolism at different levels including the liver. Finally, the activation of nuclear receptors by bile acids is analysed. PMID- 29154963 TI - Macrophage scavenger receptor 1 contributes to pathogenesis of fulminant hepatitis via neutrophil-mediated complement activation. AB - BACKGROUND & AIMS: The macrophage scavenger receptor 1 (Msr1, also called SRA) is a pattern recognition receptor primarily expressed on myeloid cells, which plays an important role in the maintenance of immune homeostasis. Since MSR1 expression was upregulated in the livers of patients with fulminant hepatitis (FH), we investigated the functional mechanism of Msr1 in FH pathogenesis. METHODS: Msr1 deficient (Msr1-/-) mice and their wild-type (WT) littermates were infected with mouse hepatitis virus strain-A59 (MHV-A59) to induce FH, and the levels of tissue damage, serum alanine aminotransferase, inflammatory cytokines and complement component 5a (C5a) were measured and compared. Liver injury was studied after MHV infection with or without neutrophil depletion. RESULTS: Our results showed that Msr1-/- mice were resistant to MHV-induced hepatitis. Treatment with the C5a receptor antagonist (C5aRa) diminished the differences in inflammatory responses and liver injury between MHV-infected wild-type and Msr1-/- mice, suggesting that C5a-induced pro-inflammatory response plays a critical role in the Msr1-mediated regulation of FH pathogenesis. We demonstrated that Msr1 efficiently enhanced transforming growth factor-activated kinase-1 phosphorylation in neutrophils upon MHV-A59 stimulation, thereby promoting the activation of the extracellular signal regulated kinase pathway and subsequent NETosis formation. Moreover, we provided evidence that blockage of Msr1 attenuated the liver damage caused by MHV-A59 infection. CONCLUSIONS: Msr1 promotes the pathogenesis of virus-induced FH by enhancing induction of neutrophil NETosis and subsequent complement activation. Targeting Msr1 may be employed as a new immunotherapeutic strategy for FH. LAY SUMMARY: Virus-induced fulminant hepatitis (FH) is a disease with a high mortality worldwide. Enhanced levels of macrophage scavenger receptor 1 (Msr1) in the liver of patients with FH and of murine experimental FH indicated Msr1 plays a role in the pathogenesis of FH. Herein, we demonstrate that mice deficient in Msr1 are resistant to FH induced by MHV-A59, and the Msr1 inhibitor fucoidan suppresses the progression of FH in mice. Our study suggests that use of drugs inhibiting MSR1 function could be beneficial to patients with FH. PMID- 29154965 TI - Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers. AB - The correct identification of patients at increased risk of non-alcoholic steatohepatitis (NASH) and advanced fibrosis is a critical step in the assessment of non-alcoholic fatty liver disease (NAFLD). Since liver biopsy is invasive, expensive and prone to sampling error, several clinical prediction rules and blood-based biomarkers have been developed as attractive and affordable alternatives for identification of patients at high risk of NASH and advanced fibrosis. Current biomarkers constitute predictive models (e.g. NAFLD fibrosis score, FIB-4 index and BARD score) or direct measures of inflammation (e.g. circulating keratin 18 fragments), or fibrosis (e.g. FibroTest(r), ELFTM or Pro C3 tests). In the clinical setting, biomarkers may discriminate between patients with NASH or advanced fibrosis, predict dynamic changes in NASH/fibrosis over time, and provide long-term prognostic information. Although clinically useful, current biomarker predictions may be influenced by hepatic and extrahepatic conditions (e.g. age, patient comorbidities, and fibrosis or NASH prevalence), which may lead to inaccurate estimates in small subsamples of patients. No highly sensitive and specific tests are available to differentiate NASH from simple steatosis. However, diagnostic accuracy can be improved by combining blood biomarkers. NAFLD fibrosis score and FIB-4 index are both cost-effective and highly sensitive tools to exclude patients with advanced fibrosis. Moreover, their higher scores may identify patients at higher risk of non-liver- and liver related morbidity and mortality. More expensive tests such as FibroTest or ELF are more specific for detection of patients with significant and advanced fibrosis. Recent efforts have concentrated on "omics" approaches for developing and validating novel biomarkers. Herein, we describe currently available clinical prediction rules and blood-based biomarkers for identifying NASH and advanced fibrosis in patients with NAFLD, discussing their advantages and disadvantages, as well as their potential clinical utility for predicting dynamic changes over time and identifying patients at increased risk of adverse outcomes. PMID- 29154966 TI - Determinants of fibrosis progression and regression in NASH. AB - Cirrhosis has become the major liver-related clinical endpoint in non-alcoholic steatohepatitis (NASH). However, progression to cirrhosis is less predictable in NASH than in other chronic liver diseases. This is due to the complex and multifactorial aetiology of NASH, which is determined by lifestyle and nutrition, multiple genetic and epigenetic factors, and a prominent role of hepatic and extrahepatic comorbidities. Thus, modest changes in these cofactors can also induce fibrosis regression, at least in patients with precirrhotic liver disease. Fibrogenesis in NASH correlates with, but is indirectly coupled to, classical inflammation, since fibrosis progression is driven by repetitive periods of repair. While hepatocyte lipoapoptosis is a key driving force of fibrosis progression, activated hepatic stellate cells, myofibroblasts, cholangiocytes, macrophages and components of the pathological extracellular matrix are major fibrogenic effectors and thus pharmacological targets for therapies aimed at inhibition of fibrosis progression or induction of fibrosis reversal. The advent of novel, highly sensitive and specific serum biomarkers and imaging methods to assess the dynamics of liver fibrosis in NASH will improve detection, stratification and follow-up of patients with progressive NASH . These non invasive tools will also promote the clinical development of antifibrotic drugs, by permitting the design of lean proof-of-concept studies, and enabling development of a personalised antifibrotic therapy for patients with rapid fibrosis progression or advanced disease. PMID- 29154967 TI - Bone marrow mechanotransduction in porcine explants alters kinase activation and enhances trabecular bone formation in the absence of osteocyte signaling. AB - Bone is a dynamic tissue that can adapt its architecture in response to mechanical signals under the control of osteocytes, which sense mechanical deformation of the mineralized bone. However, cells in the marrow are also mechanosensitive and may contribute to load-induced bone adaptation, as marrow is subjected to mechanical stress during bone deformation. We investigated the contribution of mechanotransduction in marrow cells to trabecular bone formation by applying low magnitude mechanical stimulation (LMMS) to porcine vertebral trabecular bone explants in an in situ bioreactor. The bone formation rate was higher in stimulated explants compared to unloaded controls which represent a disuse condition (CNT). However, sclerostin protein expression in osteocytes was not different between groups, nor was expression of osteocytic mechanoregulatory genes SOST, IGF-1, CTGF, and Cyr61, suggesting the mechanoregulatory program of osteocytes was unaffected by the loading regime. In contrast, c-Fos, a gene indicative of mechanical stimulation, was upregulated in the marrow cells of mechanically stimulated explants, while the level of activated c-Jun decreased by 25%. The activator protein 1 (AP-1) transcription factor is a heterodimer of c Fos and c-Jun, which led us to investigate the expression of the downstream target gene cyclin-D1, a gene associated with cell cycle progression and osteogenesis. Cyclin-D1 gene expression in the stimulated marrow was approximately double that of the controls. The level of phosphorylated PYK2, a purported inhibitor of osteoblast differentiation, also decreased in marrow cells from stimulated explants. Taken together, mechanotransduction in marrow cells induced trabecular bone formation independent of osteocyte signaling. Identifying the specific cells and signaling pathways involved, and verifying them with inhibition of specific signaling molecules, could lead to potential therapeutic targets for diseases characterized by bone loss. PMID- 29154968 TI - Non traumatic osteonecrosis of the femoral head is associated with low bone mass. AB - OBJECTIVE: Osteoporosis (OP) and osteonecrosis of the femoral head (ONFH) share common clinical and pathophysiological features we sought to determine whether ONFH was associated with an increased prevalence of OP and whether the increased prevalence of OP was related to the stage of ONFH at diagnosis. METHODS: We included 243 patients with ONFH and 399 age and sex-matched healthy controls. Data was gathered including demography, risk factors, ARCO staging of ONFH and bone mineral density (BMD). RESULTS: Overall, BMD (defined by the T-score) was significantly lower in the ONFH group at both the femoral head (-0.96+/-1.11) and the lumbar spine (-1.22+/-1.47) compared to the control group (-0.55+/-0.97 and 0.73+/-1.31) (p<0.01). The ONFH group depicted a significantly higher proportion of osteopenia (50.39% vs 40.87%, p=0.027) and of OP (18.78% vs 7.33%, p<0.001) relative to the control group. Stage 1 and 2 ONFH patients (53.86%, p=0.0203; OR=1.54 (95% CI: [1.04; 2.29])) were at a higher risk of osteopenia than the control group (40.88%), but not stages 3 or 4 (48.47%, p=0.2569; OR=1.27 (95% CI: [0.78; 2.06]). Patients with stage 3 or 4 ONFH (25.31%, p<0.001; OR=3.93 (95% CI: [1.63; 10.96])) were at a higher risk of osteoporosis than patients in the stage 1 and 2 ONFH (7.24%), and compared to the control group (7.33%, adj. p value<0.001; OR=4.89 (95% CI: [2.77; 8.76]). CONCLUSIONS: Non-traumatic osteonecrosis of the femoral heads is associated with low bone mineral density. This study showed that fractural stages ONFH were associated with a 5-fold risk of osteoporosis. PMID- 29154969 TI - Adults with cystic fibrosis have deficits in bone structure and strength at the distal tibia despite similar size and measuring standard and relative sites. AB - Individuals with cystic fibrosis (CF) have lower bone mineral density (BMD) by DXA and are at higher risk of fracture than healthy controls. However, the 2 dimensional measurement of areal BMD (aBMD) provided by DXA is influenced by bone size and the true extent of the bone deficit is unclear. Our objective was to use high-resolution peripheral quantitative computed tomography (HR-pQCT) and individual trabecula segmentation (ITS) analysis to compare volumetric BMD (vBMD), microarchitecture and estimated strength at the distal radius and tibia in 26 young adults with CF and 26 controls matched for age, gender, and race. To assess the effect of limb length and minimize the confounding effects of size on HR-pQCT outcomes, we scanned participants at both the standard fixed HR-pQCT measurement sites and at a subject-specific relative site that varied according to limb length. CF participants did not differ significantly in age, height, weight, or BMI from controls. Ulnar and tibial lengths were 9mm shorter in CF patients, though differences were not significant. CF patients had significantly lower BMI-adjusted aBMD by DXA at the lumbar spine (8.9%, p<0.01), total hip (11.5%, p<0.01) and femoral neck (14.5%, p<0.01), but not at the forearm. At the fixed radius site, thickness of trabecular plates and torsional stiffness were significantly lower in CF participants than controls. At the relative radius site, only torsional stiffness was significantly lower in CF participants. At the tibia, total, trabecular and cortical vBMD were significantly lower at both fixed and relative sites in CF participants, with fewer, more widely-spaced trabecular plates, lower trabecular connectivity, and lower axial and torsional stiffness. Our results confirm that aBMD is lower at the spine and hip in young adults with CF, independent of BMI and body size. We also conclude that vBMD and stiffness are lower at the weight-bearing tibia. The pathogenesis of these differences in bone density and strength at the tibia appear to be related to trabecular drop out and reduced trabecular connectivity and to be independent of differences in limb length, as assessed by scanning participants at both standard and relative sites. We concluded that significant deficits in bone structure and strength persist in young adults with CF, despite advances in care that permit them to attain relatively normal height and weight. PMID- 29154970 TI - Patient Engagement Using New Technology to Improve Adherence to Positive Airway Pressure Therapy: A Retrospective Analysis. AB - BACKGROUND: Sleep apnea has major neurocognitive and cardiovascular and metabolic risks. Treatment of sleep apnea is suboptimal because of variable adherence to existing therapies. METHODS: This trial compared positive airway pressure adherence among patients who were provided active patient engagement (APE) technology vs those who received usual care monitoring (UCM). The primary outcome was expressed by using the US Medicare definition of adherence. Adherence data from two cloud-based databases (AirView and myAir) were analyzed for patients with sleep apnea. Data were included if a patient's activation date in the APE tool was within 7 days of the therapy start date in the UCM database during a defined time window. Data were propensity matched in a 1:2 ratio (APE:UCM) based on baseline patient characteristics. RESULTS: A total of 128,037 patients were analyzed. Baseline characteristics were typical of a sleep clinic cohort. APE was associated with more patients achieving adherence criteria (87.3%) compared with UCM patients (70.4%; P < .0001 for the difference). Average therapy usage was 5.9 h per night in the APE group vs 4.9 h per night in the matched UCM patients (P < .0001). Patients with sleep apnea "struggling" with therapy adherence had a 17.6% absolute improvement in adherence using APE compared with UCM. CONCLUSIONS: Robust therapy adherence rates can be achieved by adding modern technology to usual care. Adopting advances in technology in care management may allow clinicians to more effectively and efficiently treat patients who have sleep apnea. Rigorous randomized controlled trials may be required before making strong clinical recommendations. PMID- 29154971 TI - Preemptive Anticoagulation in Patients With a High Pretest Probability of Pulmonary Embolism: Are Guidelines Followed? AB - BACKGROUND: Guidelines suggest anticoagulation of patients with high pretest probability of pulmonary embolism (PE) while awaiting diagnostic test results (preemptive anticoagulation). Data relevant to the practice of preemptive anticoagulation are not available. METHODS: We reviewed 3,500 consecutive patients who underwent CT pulmonary angiography (CTPA) at two EDs. We classified the pretest probability for PE using the revised Geneva Score (RGS) as low (RGS 0 3), intermediate (RGS 4-10), or high (RGS 11-18). We classified patients with a high pretest probability of PE as receiving preemptive anticoagulation if therapeutic anticoagulation was given before CTPA completion. Patients with a high bleeding risk and those receiving treatment for DVT before CTPA were excluded from the preemptive anticoagulation analysis. We compared the time elapsed between ED registration and CTPA completion for patients with a low, intermediate, and high pretest probability for PE. RESULTS: We excluded three of 3,500 patients because CTPA preceded ED registration. Of the remaining 3,497 patients, 167 (4.8%) had a high pretest probability for PE. After excluding 29 patients for high bleeding risk and 21 patients who were treated for DVT prior to CTPA, only two of 117 patients (1.7%) with a high pretest probability for PE received preemptive anticoagulation. Furthermore, 37 of the remaining 115 patients (32%) with a high pretest probability for PE had a preexisting indication for anticoagulation but did not receive preemptive anticoagulation. The time from ED registration to CTPA completion did not differ based on the pretest probability of PE. CONCLUSIONS: Physicians rarely use preemptive anticoagulation in patients with a high pretest probability for PE. Clinicians do not expedite CTPA examinations for patients with a high pretest probability for PE. PMID- 29154972 TI - Impact of Rapid On-Site Cytological Evaluation (ROSE) on the Diagnostic Yield of Transbronchial Needle Aspiration During Mediastinal Lymph Node Sampling: Systematic Review and Meta-Analysis. AB - BACKGROUND: Whether the use of rapid on-site cytologic evaluation (ROSE) increases the diagnostic yield of transbronchial needle aspiration (TBNA) remains unclear. This article is a systematic review of studies describing the utility of ROSE in subjects undergoing TBNA. METHODS: The study included a systematic review of the PubMed, Embase, and Scopus databases for randomized controlled trials investigating the diagnostic yield of conventional transbronchial needle aspiration (c-TBNA) or endobronchial ultrasound (EBUS)-TBNA, with or without ROSE, in subjects with mediastinal lymphadenopathy. RESULTS: Five studies (618 subjects; two EBUS-TBNA, two c-TBNA, and one both) were identified. Overall, the studies were of good quality. The pooled risk difference (95% CI) of the diagnostic yield of EBUS-TBNA and c-TBNA was 0.04 (-0.01 to 0.09) and 0.12 (-0.08 to 0.33), respectively, suggesting no added benefit with ROSE. The use of ROSE during EBUS-TBNA (but not c-TBNA) resulted in significantly fewer needle passes (mean difference [95% CI], -1.1 [-2.2 to -0.005]; P < .001). There was no difference in the procedure time during EBUS-TBNA. The complication rate was significantly lower (OR [95% CI], 0.26 [0.10 to 0.71]; P = .009) when ROSE was used during c-TBNA due to fewer additional procedures required to make a diagnosis. There was evidence of heterogeneity in the studies involving c-TBNA but not EBUS-TBNA. There was no publication bias. CONCLUSIONS: The use of ROSE neither improved the diagnostic yield nor reduced the procedure time during TBNA. However, the use of ROSE was associated with fewer number of needle passes during EBUS-TBNA and overall lower requirement for additional bronchoscopy procedures during TBNA to make a final diagnosis. TRIAL REGISTRY: PROSPERO; No.: CRD42017058937; URL: www.crd.york.ac.uk/prospero/. PMID- 29154973 TI - Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas. AB - Despite expressing high levels of the epidermal growth factor receptor (EGFR), a majority of oral squamous cell carcinoma (OSCC) patients show limited response to cetuximab and ultimately develop drug resistance. However, mechanism underlying cetuximab resistance in OSCC is not clearly understood. Here, using a mouse orthotopic xenograft model of OSCC, we show that bone morphogenic protein-7 phosphorylated Smad-1, -5, -8 (BMP7-p-Smad1/5/8) signaling contributes to cetuximab resistance. Tumor cells isolated from the recurrent cetuximab-resistant xenograft models exhibited low EGFR expression but extremely high levels of p Smad1/5/8. Treatment with the bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 significantly reduced cetuximab-resistant OSCC tumor growth, and combined treatment of DMH1 and cetuximab remarkably reduced relapsed tumor growth in vivo. Importantly, p-Smad1/5/8 level was elevated in cetuximab-resistant patients and this correlated with poor prognosis. Collectively, our results indicate that the BMP7-p-Smad1/5/8 signaling is a key pathway to acquired cetuximab resistance, and demonstrate that combination therapy of cetuximab and a BMP signaling inhibitor as potentially a new therapeutic strategy for overcoming acquired resistance to cetuximab in OSCC. PMID- 29154975 TI - The rule expectancy effect on the electrophysiological correlates underlying numerical rule acquisition. AB - The present study aimed to provide electrophysiological evidence about acquiring complex numerical rules when unexpected numbers were presented. Hence, we compared the neural correlates underlying the acquisition of unexpected complex rules (e.g., 12, 14, 18, 24) compared to expected simple rules (e.g., 12, 14, 16, 18). The event-related potential (ERP) results for the rule acquisition process for the third numbers showed that, in contrast to expected simple rules, unexpected complex rules elicited: an enhanced N200, reflecting the detection of a conflict between the expected numbers and the displayed numbers; a decreased P300, indicating a feeling of uncertainty accompanied by identifying numerical regularity; and an increased LPC, reflecting the working-memory updating caused by expectancy violation and rule acquisition. These results describe the precise time course of acquiring novel and complex rules when unexpected numbers were presented. PMID- 29154976 TI - Microneedle arrays coated with charge reversal pH-sensitive copolymers improve antigen presenting cells-homing DNA vaccine delivery and immune responses. AB - Successful delivery of a DNA vaccine to antigen-presenting cells and their subsequent stimulation of CD4+ and CD8+ T cell immunity remains an inefficient process. In general, the delivery of prophylactic vaccines is mainly mired by low transfection efficacy, poor immunogenicity, and safety issues from the materials employed. Currently, several strategies have been exploited to improve immunogenicity, but an effective strategy for safe and pain-free delivery of DNA vaccines is complicated. Herein, we report the rapid delivery of polyplex-based DNA vaccines using microneedle arrays coated with a polyelectrolyte multilayer assembly of charge reversal pH-responsive copolymer and heparin. The charge reversal pH-responsive copolymer, composed of oligo(sulfamethazine)-b poly(ethylene glycol)-b-poly(amino urethane) (OSM-b-PEG-b-PAEU), was used as a triggering layer in the polyelectrolyte multilayer assembly on microneedles. Charge reversal characteristics of this copolymer, that is, the OSM-b-PEG-b-PAEU copolymer exhibit, positive charge at low pH (pH4.03) and becoming negative charge when exposed to physiological pH conditions (pH7.4), allowing the facile assembly and disassembly of polyelectrolyte multilayers. The electrostatic repulsion between heparin and OSM-b-PEG-b-PAEU charge reversal copolymer triggered the release of DNA vaccines. DNA vaccines laden on microneedles are effectively transfected into RAW 264.7 macrophage cells in vitro. Vaccination of BALB/c mice by DNA vaccine-loaded microneedle arrays coated with a polyelectrolyte multilayer generated antigen-specific robust immune responses. These findings provide potential strategy of charge reversal pH-responsive copolymers coated microneedles for DNA vaccine delivery. PMID- 29154977 TI - Polymer nitric oxide donors potentiate the treatment of experimental solid tumours by increasing drug accumulation in the tumour tissue. AB - The delivery of nitric oxide (NO) specifically to solid tumours was explored in this study as a strategy to augment the passive accumulation of nanomedicines in tumours induced by the Enhanced Permeability and Retention (EPR) effect. An increase in accumulation was achieved by the binding of the chemical precursor of NO, based on an organic nitrate, to a water-soluble synthetic polymer drug carrier. Four structurally different N-(2-hydroxypropyl)methacrylamide (HPMA) based polymer NO donors were synthesized. Depending on their chemical structure, two of these donors were hydrolytically stable, while two rapidly released the parent nitrate under acidic conditions, mimicking the intracellular environment. The polymer NO donors were shown to overcome the drawbacks related to low molecular-weight NO releasing compounds, namely systemic toxicity, lack of site specificity, and fast blood clearance. The NO donors showed intracellular NO release upon incubation with tumour cells. In vivo, they potentiated the EPR effect, resulting in an increased accumulation of polymer-bound cytotoxic drug doxorubicin (Dox) in EL4 T-cell lymphoma inoculated in mice. This led to a better therapeutic outcome in the treatment of lymphoma with the high-molecular-weight polymer conjugates carrying Dox but not in the treatment with the free Dox. The localized augmentation of the EPR effect via the tumour-specific NO delivery system can be viewed as a promising strategy to potentiate polymer-based tumour therapy without increasing systemic toxicity. PMID- 29154978 TI - 7-Ketocholesterol induces ROS-mediated mRNA expression of 12-lipoxygenase, cyclooxygenase-2 and pro-inflammatory cytokines in human mesangial cells: Potential role in diabetic nephropathy. AB - 7-Ketocholesterol (7-KCHO) is a highly proinflammatory oxysterol and plays an important role in the pathophysiology of diabetic nephropathy (DN). Lipoxygenases (LOXs) and cyclooxygenases (COXs) are also involved in the development of DN. The aim of this study was to clarify the effects of 7-KCHO on mRNA expression of LOXs and COXs as well as pro-inflammatory cytokines in human mesangial cells (HMC). We evaluated cell viability by WST-8 assay and measured mRNA expression by reverse transcription-polymerase chain reaction. Intracellular reactive oxygen species (ROS) production was evaluated by flow cytometry. Although 7-KCHO did not affect cell viability of HMC, 7-KCHO stimulated significant increases in mRNA expression of 12-LOX, COX-2 and pro-inflammatory cytokines. 7-KCHO also induced an increase in ROS production, while N-acetylcysteine partially suppressed the increase. The 12-LOX and COX-2 inhibitors also suppressed mRNA expression of cytokines. These findings may contribute to the elucidation of the molecular mechanism of the pathophysiology of DN. PMID- 29154979 TI - Small fiber neuropathy: Diagnosis, causes, and treatment. AB - Small fiber neuropathy, which affects the sensory Adelta and C fibers, is now a major diagnostic and therapeutic challenge. Nearly 7% of the general population have chronic neuropathic pain responsible for severe quality-of-life impairments. Awareness must therefore be raised among clinicians of the somatosensory and autonomic symptoms that can reveal small fiber neuropathy, appropriate diagnostic investigations, most common causes, and best treatment options for each patient profile. To help achieve this goal, the present review article discusses the clinical presentation of neuropathic pain and paresthesia and/or autonomic dysfunction due to involvement of nerves supplying exocrine glands and smooth muscle; normal findings from standard electrophysiological investigations; most informative diagnostic tests (epidermal nerve fiber density in a skin biopsy, laser-evoked potentials, heat- and cold-detection thresholds, electrochemical skin conductance); main causes, which consist chiefly of metabolic diseases (diabetes mellitus, glucose intolerance), dysimmunity syndromes (Sjogren's syndrome, sarcoidosis, monoclonal gammopathy), and genetic abnormalities (familial amyloidosis due to a transthyretin mutation, Fabry disease, sodium channel diseases); and the available symptomatic and etiological treatments. PMID- 29154980 TI - Treatment of carpal tunnel syndrome : from ultrasonography to ultrasound guided carpal tunnel release. AB - Carpal tunnel syndrome is the most common nerve entrapment syndrome. The majority of cases are due to compression or irritation of the median nerve in the carpal canal. It is diagnosed clinically, often being confirmed by an electromyogram, while ultrasonography criteria have become increasingly useful for the diagnosis. Ultrasonography is better tolerated, less expensive, yet just as effective as other diagnostic methods. It provides a good indication of the severity of the condition and it allows anatomical variants to be discerned. In light of this, for a number of medical professionals it is the first-line examination. In terms of therapeutic use, ultrasound can be used to guide infiltrations. In case medical treatment is unsuccessful, release by transection of the flexor retinaculum is generally done surgically as an open procedure or by endoscopy. A new minimally invasive percutaneous treatment to release the nerve based on ultrasonography guided or ultrasound surgery appears to be a promising alternative, however, to conventional open surgery or endoscopic treatments. PMID- 29154974 TI - Prostate cancer health disparities: An immuno-biological perspective. AB - Prostate cancer (PCa) is the most commonly diagnosed malignancy in males, and, in the United States, is the second leading cause of cancer-related death for men older than 40 years. There is a higher incidence of PCa for African Americans (AAs) than for European-Americans (EAs). Investigations related to the incidence of PCa-related health disparities for AAs suggest that there are differences in the genetic makeup of these populations. Other differences are environmentally induced (e.g., diet and lifestyle), and the exposures are different. Men who immigrate from Eastern to Western countries have a higher risk of PCa than men in their native countries. However, the number of immigrants developing PCa is still lower than that of men in Western countries, suggesting that genetic factors are involved in the development of PCa. Altered genetic polymorphisms are associated with PCa progression. Androgens and the androgen receptor (AR) are involved in the development and progression of PCa. For populations with diverse racial/ethnic backgrounds, differences in lifestyle, diet, and biology, including genetic mutations/polymorphisms and levels of androgens and AR, are risk factors for PCa. Here, we provide an immuno-biological perspective on PCa in relation to racial/ethnic disparities and identify factors associated with the disproportionate incidence of PCa and its clinical outcomes. PMID- 29154981 TI - Epidermal Growth Factor Receptor Family Inhibition Identifies P38 Mitogen activated Protein Kinase as a Potential Therapeutic Target in Bladder Cancer. AB - OBJECTIVE: To investigate perturbations in downstream signaling pathway activation and potential resistance mechanisms to epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) inhibition in cell line models of bladder cancer. METHODS: We undertook a structured screening approach by phosphokinase array, followed by validation steps, to detect activated downstream signaling pathway nodes after therapeutic inhibition of EGFR or HER2 in bladder cancer cell lines. RESULTS: Erlotinib treatment of RT112 cells induced phosphorylation of 9 activated phosphoprotein targets (p38 mitogen activated protein kinase [MAPK] [Thr180/Tyr182], GSK-3alpha/beta [Ser21/9], MEK1/2 [Ser218/222, Ser222/226], Akt (protein kinase B) [Ser473], TOR [target of rapamycin] [Ser2448], Src [Tyr419], p27 [Thr198], p27 [Thr157], and PLCgamma-1 [Tyr783]), whereas STAT4 (signal transducer and activator of transcription 4) (Tyr693) phosphorylation was reduced. Of these, p38 MAPK phosphorylation was confirmed to occur in response to inhibition of either EGFR or HER2 signaling through multiple validation steps, including differing bladder cancer cell lines (RT112, UM-UC-3, and T24) and methods of receptor pathway inhibition (erlotinib, lapatinib, and siRNA depletion of EGFR or HER2). Chemical inhibition of p38 MAPK with SB203580 led to inhibition of proliferation in RT112, UM-UC-3, and T24 cell lines (IC50 20.85, 76.78, and 79.12 uM, respectively). Fractional effect analyses indicated a synergistic interaction for inhibition of cell proliferation when combining SB203580 with lapatinib. CONCLUSION: p38 MAPK is a potential therapeutic target in bladder cancer and this strategy warrants further development in this disease. It may also allow combination therapy strategies to be developed in conjunction with EGFR or HER2 inhibition. PMID- 29154982 TI - Evaluating Success Rates After Artificial Urinary Sphincter Placement: A Comparison of Clinical Definitions. AB - OBJECTIVE: To assess success rates of primary artificial urinary sphincter (AUS) implantation using various objective, subjective, or retreatment definitions. MATERIALS AND METHODS: We identified 309 male patients who underwent primary AUS placement at the Mayo Clinic from 2010 to 2016. Of those, 214 had not undergone repeat surgery, were sent a mailed survey, and 148 of 214 (69.2%) responded. Eleven definitions of success were evaluated among responders. Associations between the definitions and patient-reported success were assessed via logistic regression and c-statistic. RESULTS: Treatment success rates were highly variable depending on the definition used (14.8%-86.7%). Median follow-up was 24 months (interquartile range [IQR] 8, 40), during which 72% did not undergo reoperation. Among survey respondents, 87% felt at least "much better," and 47% reported surgery was "very successful." Roughly 15% reported zero pad use. Patient reported success was most strongly associated with the Patient Global Impression of Improvement (PGI-I) score (odds ratio [OR] 0.07, 95% confidence interval [CI] 0.02-0.19; P <.0001; c = 0.88). The largest difference in Michigan Incontinence Symptom Index (M-ISI) score between treatment successes and failures was noted when success was defined by PGI-I as well (success group M-ISI 11 vs failure group M-ISI 24.15; OR 0.48, 95% CI 0.37-0.63; P <.0001; c = 0.97). In terms of pad count, use of a security pad or less was most closely associated with patient reported success (OR 0.18, 95% CI 0.10-0.35; P <.0001; c = 0.75). CONCLUSION: The "success rate" after primary AUS implantation varies widely depending on the definition used. Although most patients report that surgery was beneficial, zero pad count was less common. Among definitions evaluated, the PGI-I had the strongest association with patients' evaluation of surgical success. PMID- 29154983 TI - Giant Renal Angiomyolipoma Following Ovarian Stimulation Therapy. AB - Renal angiomyolipomas (AMLs) are benign tumors with higher prevalence in women. Female hormones have been shown to induce AML enlargement. This case refers to a 40-year-old woman with 4 left kidney AMLs, the larger ones with 1.0 and 1.3 cm. Ten months after ovarian stimulation for egg harvesting, a computed tomography revealed an 18-cm AML with large-caliber vessels. Given her high risk of AML bleeding, the patient was submitted to selective arterial embolization, which turned out unsuccessful, supporting a plan of nephron-sparing surgery. Our case highlights the pro-growth effects of female hormones on AML, with particular emphasis to ovarian stimulation. PMID- 29154984 TI - Five Supernumerary Renal Arteries Originating From the Aorta Associated With Ureteropelvic Junction Extrinsic Compression. AB - A 65-year-old woman presented with recurrent urinary tract infections. A computed tomography of the abdomen and pelvis shows a dilated and malrotated right renal pelvis consistent with a ureteropelvic junction obstruction as well as multiple renal arteries arising from the aorta. A computed tomography angiography revealed 5 separate renal arteries originating from the aorta with a single renal artery crossing over and obstructing the right renal pelvis. On Lasix renogram, the affected kidney contributes 45% of total renal function. The patient remained asymptomatic (absent of hematuria, flank pain, infection) and opted for active surveillance. PMID- 29154985 TI - Adolescent Hydrocele Carrying a Surprise: A Case of Papillary Cystadenoma of the Epididymis. AB - Papillary cystadenoma of the epididymis (PCE) is a rare benign epithelial tumor remarkable for its association with von Hippel-Lindau disease. A 12-year-old boy consulted for a progressive enlargement of the left testicle. At time of surgery, the whole epididymis was enlarged. Pathologic diagnosis was PCE with a focus on borderline malignancy. Scrotal left epididymectomy was performed. von Hippel Lindau disease screening was negative. No relapse has been detected 2 years later. In case of atypical clinical examination of a hydrocele, unusual presentations such as PCE should be considered. The main differential diagnoses were adenomatoid tumor, nonpapillary cystadenoma, and metastatic clear cell renal carcinoma. PMID- 29154986 TI - GV1001 Induces Apoptosis by Reducing Angiogenesis in Renal Cell Carcinoma Cells Both In Vitro and In Vivo. AB - OBJECTIVE: To investigate the anticancer effects of GV1001 and its biological mechanism of action in renal cell carcinoma (RCC). METHODS: The effects of GV1001 on cell survival and apoptosis in RCC cells were examined in vitro using cell viability assay, fluorescence-activated cell sorting, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. To evaluate the effect of GV1001 on migration, invasion, and angiogenesis, we used wound healing, invasion, endothelial cell tube formation assay, and western blot analysis. Furthermore, we used an RCC xenograft model with either phosphate buffered saline or GV1001 to confirm the anticancer effect of GV1001 in vivo. Tumor volume was monitored during treatment, and tumor weight was measured after animals were killed. Apoptosis and angiogenesis of the tumor tissue were assessed using hematoxylin and eosin staining, immunohistochemistry, and western blot analysis. RESULTS: GV1001 reduced cell viability and induced apoptosis in RCC cells in vitro. Furthermore, GV1001 suppressed the migration and invasion of RCC cells through regulation of matrix metalloproteinases and tissue inhibitors of metalloproteinases. In addition, GV1001 reduced angiogenesis via regulation of hypoxia-inducible factor 1alpha. In xenograft mouse model experiment, GV1001 reduced tumor growth and induced apoptosis. As in the in vitro results, GV1001 significantly reduced angiogenesis through regulation of hypoxia-inducible factor 1alpha in vivo. CONCLUSION: Our data demonstrated that GV1001 induced apoptosis through suppression of angiogenesis in RCCs both in vitro and in vivo, which suggests that GV1001 may be a potential therapeutic target for RCC. PMID- 29154987 TI - Positioning the Instillation of Contrast Cystography: Does It Provide Any Clinical Benefit? AB - OBJECTIVE: To outline positioning the instillation of contrast cystography (PICC)'s benefits in clinical practice. MATERIALS AND METHODS: A total of 198 patients underwent PICC with the following indications: patients with positive preoperative conventional voiding cystourethrography (VCUG) for a single ureteric side, patients with urinary tract infection (UTI), and negative VCUG for both ureteric sides. Patients with positive VCUG served as the control group. Preoperative, intraoperative, and postoperative features of all patients were compared. RESULTS: The reflux rate for the contralateral vesicoureteric reflux (VUR) investigation group was 39.1%. Only the cystoscopic view of the anatomically deficient ureteric orifice was found to be a significant predictor of contralateral reflux (P = .002). For patients who presented with UTI, the reflux rate was 58.3%. Resolution of infection was assessed for patients who presented with UTI, and 54.1% of these patients had a complete response in the follow-up period. When the patients were classified as PICC positive and negative, infection-free rates were 58.3% and 48%, respectively (P = .296). CONCLUSION: PICC is an effective diagnostic method for revealing occult reflux. However, the clinical significance of this finding is vague. In patients with UTI, PICC was useful for diagnosing occult VUR and clearing the symptoms in more than half of the patients. Further, the symptom-free state in the follow up period was slightly higher but not more significant than it was in those with no VUR diagnosed. PMID- 29154988 TI - Role of p-MKK7 in myricetin-induced protection against intestinal ischemia/reperfusion injury. AB - Intestinal ischemia reperfusion (I/R) may cause inflammation-, oxidative stress-, and apoptosis-related tissue injuries and facilitate bacterial infection, leading to multiple organ failure. Myricetin, a flavonoid, is found to have diverse biological effects including anti-inflammatory, anti-oxidative, and anti bacterial effects. Based on our pre-experiment, we proposed that myricetin pretreatment (25, 50mg/kg) could ameliorate intestinal I/R injury and myricetin induced modulation on MKK7/JNK signal pathway might play a key role in the amelioration. The present study was designed to verify the proposal by using both rat intestinal I/R model in vivo and hypoxia/reoxygenation (H/R)-injured intestinal epithelial cell line (IEC-6 cells) model in vitro. The results confirmed our proposal. Myricetin selectively ameliorated I/R- and H/R-induced injuries in vivo and in vitro respectively without significantly affecting the corresponding normal controls. Myricetin significantly alleviated I/R-induced rat intestinal injury by reducing the generation of pro-inflammatory cytokines including TNF-alpha, IL-1beta, and IL-6 and by reducing MPO activity. Myricetin significantly reduced oxidative stress through decreasing MDA level and increasing the levels of SOD and GSH in the intestinal tissues compared with I/R control rats. Myricetin significantly decreased apoptosis by selectively down regulating the expression of p-MKK7 and p-JNK without affecting MKK7 and JNK, inhibiting Bax, caspase-3 protein expression, and up-regulating Bcl-2 protein expression in I/R-injured jejunum of rats. In vitro study indicated that MKK7 siRNA transfection significantly decreased both MKK7 and p-MKK7 and other apoptosis-related proteins, partially simulating myricetin-induced anti-apoptotic effects. MKK7 siRNA transfection+myricetin could not further decrease MKK7, p MKK7, and other apoptosis-related proteins, suggesting that inhibition of MKK7/JNK pathway plays a key role in myricetin-induced protection against intestinal I/R. MKK7 overexpression by cDNA transfection abrogated myricetin reduced apoptosis-related protein expression, confirming that the MKK7/JNK signal pathway is the key target for myricetin-induced amelioration. The present study indicated that pretreatment of myricetin induced selective protection against intestinal I/R injury without significantly affecting corresponding normal controls and p-MKK7 was the key target, suggesting that myricetin is worth further translational studies. PMID- 29154990 TI - Exosomes derived from human umbilical vein endothelial cells promote neural stem cell expansion while maintain their stemness in culture. AB - The neural stem cell (NSC) niche in subventricular zone (SVZ) of adult mammalian brain contains dense vascular plexus, where endothelial cells (ECs) regulate NSCs by releasing plenty of angiocrine factors. However, the role of ECs-derived exosomes, a novel type of mediators of intercellular communications, in the regulation of NSCs remains unclear. In the current study, primary NSCs isolated from embryonic mouse brains form more neurospheres when cultured in the presence of human umbilical vein endothelial cells (HUVECs). The supportive role of ECs in the coculture was significantly attenuated when GW4869, a blocker of exosome formation, was included, suggesting that HUVECs-derived exosomes played a significant role in supporting NSCs. In order to investigate the role of ECs derived exosomes on NSCs, we collected exosomes from HUVECs. We found that HUVECs derived exosomes could significantly promote the formation of neurospheres by primary murine NSCs. EdU incorporation and TUNEL assays indicated that the proliferation of NSCs increased while apoptosis decreased when cultured in the presence of HUVECs-derived exosomes. NSCs incubated with the HUVECs-derived exosomes maintained their potential of multi-lineage differentiation potentials. The expression of stemness-related genes was up-regulated. These data suggested that ECs-derived exosomes could play an importantly role in NSC niche, and they might be used as a reagent for ex vivo NSC amplification for medical application. PMID- 29154991 TI - The rice CONSTANS-like protein OsCOL15 suppresses flowering by promoting Ghd7 and repressing RID1. AB - The photoperiodic flowering pathway is one of the most important regulatory networks controlling flowering time in rice (Oryza sativa L.). Rice is a facultative short-day (SD) plant; flowering is promoted under inductive SD conditions and delayed under non-inductive long-day (LD) conditions. In rice, flowering inhibitor genes play an important role in maintaining the trade-off between reproduction and yield. In this study, we identified a novel floral inhibitor, OsCOL15, which encodes a CONSTANS-like transcription factor. Consistent with a function in transcriptional regulation, OsCOL15 localized to the nucleus. Moreover, OsCOL15 had transcriptional activation activity, and the central region of the protein between the B-box and CCT domains was required for this activity. We determined that OsCOL15 is most highly expressed in young organs and exhibits a diurnal expression pattern typical of other floral regulators. Overexpression of OsCOL15 resulted in a delayed flowering phenotype under both SD and LD conditions. Real-time quantitative RT-PCR analysis of flowering regulator gene expression suggested that OsCOL15 suppresses flowering by up-regulating the flowering repressor Grain number, plant height and heading date 7 (Ghd7) and down-regulating the flowering activator Rice Indeterminate 1 (RID1), thus leading to the down-regulation of the flowering activators Early heading date 1, Heading date 3a, and RICE FLOWERING LOCUS T1. These results demonstrate that OsCOL15 is an important floral regulator acting upstream of Ghd7 and RID1 in the rice photoperiodic flowering-time regulatory network. PMID- 29154992 TI - Structural and biophysical characterization of Rv3716c, a hypothetical protein from Mycobacterium tuberculosis. AB - Latent tuberculosis (TB) is the main hurdle in reaching the goal of "Stop TB 2050". Tuberculin skin and Interferon-gamma release assay tests used currently for the diagnosis of TB infection cannot distinguish between active disease and latent tuberculosis infection (LTBI) and hence new and sensitive protein markers need to be identified for the diagnosis. A protein Rv3716c from Mycobacterium tuberculosis (MtbRv3716c) has been identified as a potential surrogate marker for the diagnosis of LTBI. Here, we present characterization of MtbRv3716c (~13 kDa) using both biophysical and X-Ray crystallographic methods. EMSA study showed that MtbRv3716c binds to double stranded DNA. X-ray diffraction data collected on a crystal of MtbRv3716c at 1.9 A resolution was used for structure determination using the molecular replacement method. Significant electron density was not observed for the N-terminal 21 and C-terminal 41 residues in the final electron density map. The C- terminal disordered region is proline rich and displays characteristics of intrinsically disordered proteins. Although the crystal asymmetric unit contained a protomer, a tight dimer could be generated by the application of the crystal two-fold symmetry parallel to the b axis. Packing of dimers in the crystal is mediated by a cadmium ion (Cd2+) occurring at the interface of two dimers. Molecular packing analysis reveals large cavities that are probably occupied by the disordered segments of the N- and C-termini. Structural comparison with other homologous hypothetical DNA binding proteins (PDB codes: 1PUG, 1YBX) highlights structural features that might be significant for DNA binding. PMID- 29154993 TI - Serration pattern analysis for differentiating epidermolysis bullosa acquisita from other pemphigoid diseases. AB - BACKGROUND: Direct immunofluorescence (DIF) microscopy of a skin biopsy specimen is the reference standard for the diagnosis of pemphigoid diseases (PDs). Serration pattern analysis enables the differentiation of epidermolysis bullosa acquisita (EBA) from other PDs using DIF microscopy alone. However, practice gaps need to be addressed in order to implement this technique in the routine diagnostic procedure. OBJECTIVE: We sought to determine and optimize the technical requirements for serration pattern analysis of DIF microscopy and determine interrater conformity of serration pattern analysis. METHODS: We compared serration pattern analysis of routine DIF microscopy from laboratories in Groningen, The Netherlands and Lubeck, Germany with 4 blinded observers. Skin biopsy specimens from 20 patients with EBA and other PDs were exchanged and analyzed. Various factors were evaluated, including section thickness, transport medium, and biopsy specimen processing. RESULTS: The interrater conformity of our 4 observers was 95.7%. Recognition of serration patterns was comparable in samples transported in saline and in Michel's medium and with section thicknesses of 4, 6, and 8 MUm. LIMITATIONS: Limitations include our small sample size and the availability of 20 samples that were compared retrospectively. CONCLUSION: DIF serration pattern analysis is not restricted by variation in laboratory procedures, transport medium, or experience of observers. This learnable technique can be implemented as a routine diagnostic method as an extension of DIF microscopy for subtyping PD. PMID- 29154994 TI - Evolutionary epidemiology of schistosomiasis: linking parasite genetics with disease phenotype in humans. AB - Here we assess the role of parasite genetic variation in host disease phenotype in human schistosomiasis by implementing concepts and techniques from environmental association analysis in evolutionary epidemiology. Schistosomiasis is a tropical disease that affects more than 200 million people worldwide and is caused by parasitic flatworms belonging to the genus Schistosoma. While the role of host genetics has been extensively studied and demonstrated, nothing is yet known on the contribution of parasite genetic variation to host disease phenotype in human schistosomiasis. In this study microsatellite genotypes of 1561 Schistosoma mansoni larvae collected from 44 human hosts in Senegal were linked to host characteristics such as age, gender, infection intensity, liver and bladder morbidity by means of multivariate regression methods (on each parasite locus separately). This revealed a highly significant association between allelic variation at the parasite locus L46951 and host infection intensity and bladder morbidity. Locus L46951 is located in the 3' untranslated region of the cGMP dependent protein kinase gene that is expressed in reproductive organs of adult schistosome worms and appears to be linked to egg production. This putative link between parasite genetic variation and schistosomiasis disease phenotype sets the stage for further functional research. PMID- 29154989 TI - Targeting bromodomain and extraterminal proteins in breast cancer. AB - Breast cancer is a collection of distinct tumor subtypes that are driven by unique gene expression profiles. These transcriptomes are controlled by various epigenetic marks that dictate which genes are expressed and suppressed. During carcinogenesis, extensive restructuring of the epigenome occurs, including aberrant acetylation, alteration of methylation patterns, and accumulation of epigenetic readers at oncogenes. As epigenetic alterations are reversible, epigenome-modulating drugs could provide a mechanism to silence numerous oncogenes simultaneously. Here, we review the impact of inhibitors of the Bromodomain and Extraterminal (BET) family of epigenetic readers in breast cancer. These agents, including the prototypical BET inhibitor JQ1, have been shown to suppress a variety of oncogenic pathways while inducing minimal, if any, toxicity in models of several subtypes of breast cancer. BET inhibitors also synergize with multiple approved anti-cancer drugs, providing a greater response in breast cancer cell lines and mouse models than either single agent. The combined findings of the studies discussed here provide an excellent rationale for the continued investigation of the utility of BET inhibitors in breast cancer. PMID- 29154995 TI - A map of the subcellular distribution of phosphoinositides in the erythrocytic cycle of the malaria parasite Plasmodium falciparum. AB - Despite representing a small percentage of the cellular lipids of eukaryotic cells, phosphoinositides (PIPs) are critical in various processes such as intracellular trafficking and signal transduction. Central to their various functions is the differential distribution of PIP species to specific membrane compartments through the actions of kinases, phosphatases and lipases. Despite their importance in the malaria parasite lifecycle, the subcellular distribution of most PIP species in this organism is still unknown. We here localise several species of PIPs throughout the erythrocytic cycle of Plasmodium falciparum. We show that PI3P is mostly found at the apicoplast and the membrane of the food vacuole, that PI4P associates with the Golgi apparatus and the plasma membrane and that PI(4,5)P2, in addition to being detected at the plasma membrane, labels some cavity-like spherical structures. Finally, we show that the elusive PI5P localises to the plasma membrane, the nucleus and potentially to the transitional endoplasmic reticulum (ER). Our map of the subcellular distribution of PIP species in P. falciparum will be a useful tool to shed light on the dynamics of these lipids in this deadly parasite. PMID- 29154996 TI - Selective binding, magnetic separation and purification of histidine-tagged protein using biopolymer magnetic core-shell nanoparticles. AB - In previous studies, we synthesized the magnetic core-shell structured Fe3O4/PMG/IDA-Ni2+ nanoparticles. The Ni2+ on the surface of nanoparticles provides abundant docking sites for histidine, and the composite nanoparticles showed potential applications in the separation and purification of histidine tagged (His-tagged) proteins. Meanwhile, the presence of the superparamagnetic core (Fe3O4) in the nanoparticles allows them to be quickly separated and purified by an external magnetic field. Herein, the ability of magnetic nanoparticles to purify His-tagged human superoxide dismutase 1 (hSOD1) was verified. SDS-PAGE and activity data showed His-tagged hSOD1 specifically bound to Fe3O4/PMG/IDA-Ni2+, and there was no significant competition for binding between final and three intermediate products. The binding capacity of nanoparticles can reach to 62.0 mg/g (dry weight of hSOD1/nanoparticles). The nanoparticle-bound hSOD1 exhibited better thermal and storage stability compared to free hSOD1. Furthermore, the purification efficiency of the magnetic nanoparticles in the separation and purification of His-tagged proteins was comparable to the other two commercial materials (High Affinity Ni-NTA Resin, HisPur Ni-NTA Magnetic Beads). Finally, the magnetic nanoparticles can be reused in the binding of His-tagged protein for multiple times. In conclusion, the nanoparticles are ready to be applied in the separation and purification of His tagged protein. PMID- 29154997 TI - Kyphoplasty for osteoporotic vertebral fractures with posterior wall injury. AB - BACKGROUND CONTEXT: Cement augmentation techniques are standard treatments for osteoporotic vertebral fractures. Compared with vertebroplasty, kyphoplasty is associated with lower rates of cement leak and better deformity correction; however, posterior wall fractures are relative, but not absolute; contraindications for both techniques and hence treatment practices vary among spine centers. PURPOSE: The primary aim of this study was to assess our center's incidence of posterior cement leakage in osteoporotic vertebral fractures with posterior wall injury treated by balloon kyphoplasty (BKP). Secondarily, physiological results, pain relief, complication rates, and non-posterior cement leakage were also evaluated. STUDY DESIGN: This is a prospective cohort study done in a high-volume spine center in Germany. PATIENT SAMPLE: Eighty-two patients with 98 osteoporotic vertebral fractures with posterior wall cortical injury were studied from 2012 to 2016. OUTCOME MEASURES: The following were the outcome measures: (1) physiological measures: standing plain x-rays (anteroposterior and lateral views), with the following parameters evaluated: cement leak behind the posterior vertebral body border, Cobb angle for local sagittal deformity, vertebral wedge angle, and anterior vertebral height; (2) cement volume injected in each vertebra; and (3) self-report measures: visual analog scale (VAS). METHODS: All patients underwent BKP using a bipedicular approach. Preoperative clinical and neurologic evaluations were done. Radiological evaluations included plain X-ray images, computed tomography scans and magnetic resonance imaging. The average follow-up period was 18 months. RESULTS: No cement leakage into the spinal canal occurred in any of the patients. Asymptomatic leakage into other sites was seen in 22 vertebrae (22.45%). There was significant improvement in the Cobb angle, the vertebral wedge angle, and the anterior vertebral height in all cases. The mean preoperative VAS was 8.1, and this improved to 2.3 on the third postoperative day. CONCLUSION: Balloon kyphoplasty is a viable option for the treatment of osteoporotic vertebral fractures even with posterior wall involvement. PMID- 29154998 TI - Intraoperative vertebroplasty during surgical decompression and instrumentation for aggressive vertebral hemangiomas: a retrospective study of 39 patients and review of the literature. AB - BACKGROUND CONTEXT: Aggressive (Enneking stage 3, S3) vertebral hemangiomas (VHs) are rare, which might require surgery. However, the choice of surgery for S3 VHs remains controversial because of the rarity of these lesions. PURPOSE: We reported our experience of treating S3 VHs, and evaluated the effectiveness and safety of intraoperative vertebroplasty during decompression surgery for S3 VHs. STUDY DESIGN: This is a retrospective study. PATIENT SAMPLE: Thirty-nine patients with a definitive pathologic diagnosis of aggressive VHs who underwent primary decompression surgery in our department were included in this study. OUTCOME MEASURES: Basic data such as surgical procedure, surgical duration, estimated blood loss during surgery, and pathology were collected. The modified Frankel grade was used to evaluate neurologic function. Enneking staging was based on radiological findings. METHODS: We retrospectively examined aggressive VHs with neurologic deficits. Surgery was indicated if the neurologic deficit was severe or developed quickly or if radiotherapy was ineffective. Decompression surgery was performed. Intraoperative vertebroplasty during posterior decompression has been used since 2009. If contrast-enhanced computed tomography (CT) revealed a residual lesion, we recommended adjuvant radiotherapy with 40-50 Gy to prevent recurrence. Patients' basic and surgical information was collected. The minimum follow-up duration was 18 months. This study was partially funded by Peking University Third Hospital, Grant no. Y71508-01. RESULTS: Average age of the 39 patients with S3 VHs who underwent primary decompression surgery was 46.2 (range, 10-69) years. All patients had neurologic deficits caused by aggressive VHs. Aggressive VH lesions were located in the cervical, thoracic, and lumbar spine in 2, 32, and 5 patients, respectively. The decompression-alone group had 17 patients, and the decompression plus intraoperative vertebroplasty group had 22. There were no statistically significant intergroup differences in preoperative information (p>.05). The average estimated blood losses were 1,764.7 mL (range, 500-4,000 mL) and 1,068.2 mL (range, 300-3,000 mL) in the decompression-alone group and decompression plus vertebroplasty group, respectively (p=.017). One patient who underwent primary decompression alone without adjuvant radiotherapy experienced recurrence after the first decompression. The average follow-up was 50.2 (range, 18-134) months, and no cases of recurrence were observed at the last follow-up. CONCLUSIONS: Our results suggest that posterior decompression effectively provides symptom relief in patients with aggressive (S3) VHs with severe spinal cord compression. Intraoperative vertebroplasty is a safe and effective method for minimizing blood loss during surgery, whereas adjuvant radiotherapy or vertebroplasty helps in minimizing recurrence after decompression. PMID- 29154999 TI - Kinematic analysis of the space available for cord and disc bulging of the thoracic spine using kinematic magnetic resonance imaging (kMRI). AB - BACKGROUND CONTEXT: The thoracic spine was previously known as a relatively stable region in human spine. Several studies reported that the motion of the thoracic spine and changes in the cross-sectional area of the spinal cord changed with positions in the sagittal plane. The kinematic relationship between the thoracic disc and the space available for cord (SAC) with the positional change is still not well investigated. PURPOSE: The objective of this study was to evaluate the kinematic change of the intervertebral disc and space available for the spinal cord of the thoracic spine using kinematic magnetic resonance imaging (kMRI). STUDY DESIGN: This is a retrospective study. PATIENT SAMPLE: The patient sample included 105 patients who underwent thoracic spine kMRI. OUTCOME MEASUREMENT: Disc bulging and the SAC were evaluated from T4-T5 to T11-T12 in flexion, neutral, and extension positions. METHODS: MRAnalyzer3 (TrueMRI Corporation, Bellflower, CA, USA) was used to analyze disc bulging and SAC from T4-T5 to T11-T12. The Friedman test was used to analyze the differences in disc bulging and SAC between neutral, flexion, and extension positions at each segment. The Wilcoxon signed-rank test was used for post hoc analysis for the significant levels from the Friedman test. RESULTS: The mean value of the thoracic intervertebral disc area from T4-T5 to T11-T12 tended to be larger in flexion than in extension. Initial analysis with the Friedman test revealed a significant difference in disc bulging at T8-T9, T9-T10, and T11-T12 among the three positions (p<.05). Post hoc analysis showed that disc bulging was only significant at T8-T9 between flexion and extension (p<.001), at T9-T10 between neutral and flexion (0.003), and at T9-T10 between flexion and extension (p=.004). The SAC from T4-T5 to T11-T12 tended to be widest in extension and narrowest in flexion. Only T5-T6 exhibited a statistically significant difference in SAC between flexion and extension (p=.002). CONCLUSIONS: The thoracic discs and the SAC from T4-T5 to T11-T12 showed kinematic changes from flexion to extension. The thoracic spinal canal tended to be narrowest in flexion and widest in the extension. Thus, kyphotic deformities could be one of the etiologies for neurogenic deterioration in patients with thoracic myelopathy. PMID- 29155000 TI - Role of Cerebrolysin in cervical spondylotic myelopathy patients: a prospective randomized study. AB - BACKGROUND CONTEXT: Cerebrolysin is a mixture containing 85% free amino acids and 15% biologically active low-molecular weight peptides that is believed to mimic the effects of endogenous neurotrophic factors to interact with the pathologic process cascade of neurodegenerative diseases. No study has examined the effect of Cerebrolysin on cervical myelopathic patients. PURPOSE: The objective of this study was to evaluate the effect of Cerebrolysin as a conservative modality on cervical spondylotic myelopathic patients. STUDY DESIGN: This is a prospective randomized study. PATIENT SAMPLE: A total of 192 patients with cervical spondylotic myelopathy (CSM) were subdivided blindly into two equal groups. OUTCOME MEASURES: Followed-up was performed at 1, 3, and 6 months comparing the recovery rate Japanese Orthopaedic Association (JOA) score for cervical myelopathy between the two groups. METHODS: Group I received Cerebrolysin and Group II received placebo for 4 weeks; both groups received celecoxib 200 mg for 4 weeks. RESULTS: Myelopathy improved in 92% and 52% of patients at 1 month in Groups I and II, respectively; these changed at 6 months to 87% and 33%; the remaining 13% in Group I neither improved nor deteriorated, whereas 60% in Group II neither improved nor deteriorated and 7% deteriorated with statistically significant differences when comparing the mean JOA recovery rate between the 2 groups at 1, 3, and 6 months. CONCLUSIONS: Cerebrolysin over 4 weeks is safe and effective for the improvement of CSM as compared with placebo, with no reported cases of neurologic deterioration over 6 months of follow-up. PMID- 29155001 TI - Postoperative pain following posterior iliac crest bone graft harvesting in spine surgery: a prospective, randomized trial. AB - BACKGROUND CONTEXT: Postoperative pain at the site of bone graft harvest for posterior spine fusion is reported to occur in 6%-39% of cases. However, the area around the posterior, superior iliac spine is a frequent site of referred pain for many structures. Therefore, many postoperative spine patients may have pain in the vicinity of the posterior iliac crest that may not in fact be caused by bone graft harvesting. The literature may then overestimate the true incidence of postoperative iliac crest pain. PURPOSE: We performed a prospective study testing the hypothesis that patients will not report significantly higher visual analog scores over the graft harvest site when compared with the contralateral, non harvested side. STUDY DESIGN/SETTING: This is a prospective, randomized cohort study. PATIENT SAMPLE: Patients aged 18-75 years undergoing elective spinal fusion of one to two levels between L4 and S1 for spinal stenosis and spondylolisthesis were randomized to left-sided or right-sided iliac crest bone graft (ICBG) donor sites and blinded to the side of harvest. OUTCOME MEASURES: Primary outcome was a 10-point visual analog scale (VAS) for pain over the left and right posterior superior iliac spine. METHODS: Bone graft was harvested via spinal access incisions without making a separate skin incision over the crest. Each patient's non-harvested side served as an internal control. Data points were recorded by patients on their study visit sheets preoperatively and at 6 weeks, 3 months, 6 months, and 1 year postoperatively. RESULTS: Forty patients were enrolled in the study (23 females) with an average follow-up of 8.1 months (1.5 12 months). Mean age was 51.7 years (23-77 years). Left- and right-side ICBG harvesting was performed equally between the 40 patients. The average volume of graft harvested from the left was 35.3 mL (15-70 mL) and 36.1 mL (15-60 mL) from the right. There was no statistical difference between preoperative VAS score on the harvested side compared with the non-harvested side (p=.415). Postoperatively, there were consistently higher VAS scores on the operative side; however, these differences were not statistically significant at 6 weeks (p=.111), 3 months (p=.440), 6 months (p=.887), or 12 months (p=.240). Both groups did, however, show statistically significant improvements in VAS scores over time within the operative and nonoperative sides (p<.05). Graft volume had no effect on the VAS scores (p=.382). CONCLUSIONS: The current literature does not adequately illuminate the incidence of postoperative pain at the site of harvest and the relative magnitude of this pain in comparison with the patient's residual low back pain. This is the first study to blind the patient to the laterality of bone graft harvesting. Our randomized investigation showed that although pain on the surgical side was slightly higher, it was neither clinically nor statistically different from the nonsurgical side. Our conclusion supports surgeons' use of autologous bone graft, which offers a cost-effective, efficacious spinal fusion supplement. PMID- 29155002 TI - PDGF in organ fibrosis. AB - Fibrosis is part of a tissue repair response to injury, defined as increased deposition of extracellular matrix. In some instances, fibrosis is beneficial; however, in the majority of diseases fibrosis is detrimental. Virtually all chronic progressive diseases are associated with fibrosis, representing a huge number of patients worldwide. Fibrosis occurs in all organs and tissues, becomes irreversible with time and further drives loss of tissue function. Various cells types initiate and perpetuate pathological fibrosis by paracrine activation of the principal cellular executors of fibrosis, i.e. stromal mesenchymal cells like fibroblasts, pericytes and myofibroblasts. Multiple pathways are involved in fibrosis, platelet-derived growth factor (PDGF)-signaling being one of the central mediators. Stromal mesenchymal cells express both PDGF receptors (PDGFR) alpha and beta, activation of which drives proliferation, migration and production of extracellular matrix, i.e. the principal processes of fibrosis. Here, we review the role of PDGF signaling in organ fibrosis, with particular focus on the more recently described ligands PDGF-C and -D. We discuss the potential challenges, opportunities and open questions in using PDGF as a potential target for anti-fibrotic therapies. PMID- 29155003 TI - Application of amniotic fluid stem cells in repairing sciatic nerve injury in minipigs. AB - Many studies have demonstrated that combining nerve conduits with neural stem cells or growth factors can repair peripheral nerve injury in rodents. However, nerve damage does occur with longer gaps in human than in rodents, thus findings from rodent studies are difficult to translate to clinical practice. Minipigs have a longer gap that is more closely applicable to the challenge of human nerve grafting in extensive traumatic nerve damage. In this study, human amniotic fluid stem cells (AFSCs) and polylactate nerve conduits were used to repair sciatic nerve injury in minipigs. The AFSCs exhibited the properties of mesenchymal stem cells with a propensity toward neural stem cells. Measurements of compound muscle action potential implied that administration of conduits with AFSCs was beneficial in function recovery in the minipig model compared with conduits alone. The results of diffusion tensor magnetic resonance imaging (DTI) based fiber tractography assay in the minipig model suggest that combining AFSCs with conduits could expedite the repair of sciatic nerve injury. Further, MR-based DTI provides an effective and non-invasive method to visualize the sciatic nerve and to monitor the regeneration progress of injured nerve in a longitudinal study. PMID- 29155004 TI - Variability and temporal dynamics of novel object recognition in aging male C57BL/6 mice. AB - Despite its wide application in studies on memory and disease-related cognitive impairment, the use of the novel object recognition (NOR) test in research on aging has been limited and produced conflicting results. The purpose of this study was to characterize NOR across the lifespan of male C57BL/6 mice (3, 6, 9, 12, 15, and 24 months), the most popular rodent model of aging. NOR, measured after a delay of 24 hours, was analyzed with respect to variability, its dependence on locomotor and exploratory activity, and with an emphasis on its temporal dynamics. The latter has been recognized in rats, but never been investigated in mice. We find that although locomotor activity decreases monotonically above 3 months of age, exploratory activity in our setup remains constant and sufficient for NOR testing up to 12 months. As a major finding, we show that NOR depends on exploration time in the test phase in an age-dependent manner. Whereas NOR in our paradigm remains significant up to at least 20 seconds total exploration time in 3 and 6 months old mice, novel object preference at 9 and 12 months of age is detectable after 10 seconds exploration, but decreases rapidly and is missed when the first 20 seconds are analyzed. Analysis of the first 2 minutes of the test phase does not detect NOR except for 3 months old mice. We conclude that temporal aspects of NOR have been neglected and must be considered when making comparisons between or within mice at different ages. PMID- 29155006 TI - Retroperitoneoscopic Para-Aortic Lymphadenectomy with High-Level Vena Cava Bifurcation. PMID- 29155005 TI - Effects of genetic and environmental risk for schizophrenia on hippocampal activity and psychosis-like behavior in mice. AB - Schizophrenia is a serious mental illness most notably characterized by psychotic symptoms. In humans, psychotic disorders are associated with specific hippocampal pathology. However, animal model systems for psychosis often lack this pathology, and have been weak in providing a representation of psychosis. We utilized a double-risk model system combining genetic risk with environmental stress. We hypothesized these factors will induce hippocampal subfield pathology consistent with human findings, as well as behavioral phenotypes relevant to psychosis. To address this, we exposed wild-type and transgenic Disc1 dominant negative (Disc1 deficient) mice to maternal deprivation. In adulthood, hippocampal subfields were examined for signs of cellular and behavioral pathology associated with psychosis. Mice exposed to maternal deprivation showed a decrease in dentate gyrus activity, and an increase in CA3/CA1 activity. Furthermore, results demonstrated a differential behavioral effect between maternal deprivation and Disc1 deficiency, with maternal deprivation associated with a hyperactive phenotype and impaired prepulse inhibition, and Disc1 deficiency causing an impairment in fear conditioning. These results suggest distinct consequences of environmental and genetic risk factors contributing to psychosis, with maternal deprivation inducing a state more wholly consistent with schizophrenia psychosis. Further research is needed to determine if this pathology is causally related to a specific behavioral phenotype. The development of a strong inference animal model system for psychosis would satisfy a high medical need in schizophrenia research. PMID- 29155007 TI - Rare Obstructive Mullerian Anomaly with Endometriosis and Elevated CA-125. PMID- 29155008 TI - "Alternative" fuels contributing to mitochondrial electron transport: Importance of non-classical pathways in the diversity of animal metabolism. AB - The study of glycolysis, the TCA cycle, and oxidative phosphorylation in animals has yielded a wealth of information about bioenergetics. Less is known about how animals use fuels other than glucose and less characterized enzymes that are also used to provide electrons to the electron transport system. It has become clear that bioenergetic flexibility is employed by a wide variety of animals in order to successfully grow, maintain cells, and reproduce, and has contributed to the exploitation of new environments and ecological niches through evolution. In most cases, the discovery of these "alternative" fuels and non-classical pathways is relatively recent, but is starting to call into question long believed paradigms about the diversity of animal bioenergetics. We present several specific examples of these "alternatives" and the animals that use them and present some implications for animal mitochondrial physiology research. PMID- 29155009 TI - Thresholds for sine-wave corrugations defined by binocular disparity in random dot stereograms: Factor analysis of individual differences reveals two stereoscopic mechanisms tuned for spatial frequency. AB - Threshold functions for sinusoidal depth corrugations typically reach their minimum (highest sensitivity) at spatial frequencies of 0.2-0.4 cycles/degree (cpd), with lower thresholds for horizontal than vertical corrugations at low spatial frequencies. To elucidate spatial frequency and orientation tuning of stereoscopic mechanisms, we measured the disparity sensitivity functions, and used factor analytic techniques to estimate the existence of independent underlying stereo channels. The data set (N = 30 individuals) was for horizontal and vertical corrugations of spatial frequencies ranging from 0.1 to 1.6 cpd. A principal component analysis of disparity sensitivities (log-arcsec) revealed that two significant factors accounted for 70% of the variability. Following Varimax rotation to approximate "simple structure", one factor clearly loaded onto low spatial frequencies (<=0.4 cpd), and a second was tuned to higher spatial frequencies (>=0.8 cpd). Each factor had nearly identical tuning (loadings) for horizontal and vertical patterns. The finding of separate factors for low and high spatial frequencies is consistent with previous studies. The failure to find separate factors for horizontal and vertical corrugations is somewhat surprising because the neuronal mechanisms are believed to be different. Following an oblique rotation (Direct Oblimin), the two factors correlated significantly, suggesting some interdependence rather than full independence between the two factors. PMID- 29155010 TI - Intra-amoebal killing of Mycobacterium ulcerans by Acanthamoeba griffini: A co culture model. AB - Mycobacterium ulcerans, a decaying Mycobacterium marinum derivative is responsible for Buruli ulcer, a notifiable non-contagious disabling infection highly prevalent in some West African countries. Aquatic environments are suspected to host M. ulcerans, however, the exact reservoirs remain unknown. While M. marinum was found to resist amoebal microbicidal activities, this remains unknown for M. ulcerans. In this study M. ulcerans was co-cultured with the moderately halophile Acanthamoeba griffini at 30 degrees C to probe this tropical amoeba as a potential reservoir for M. ulcerans. In triplicate experiments, we observed engulfment of M. ulcerans by A. griffini trophozoites, followed by an unexpected significant difference of 98.4% (day 1), 99.5% (day 2), 99.5% (day 3) and 99.9% (day 7) between the number of intra-amoebal mycobacteria detected by PCR and the number of viable intra-amoebal mycobacteria measured by 10-week culture. Further encystment revealed only one Mycobacterium organism for 150 A. griffini cysts observed by electron microscopy and the culture of excysted amoebae remained sterile. In conclusion, these data install M. ulcerans as susceptible to A. griffini microbicidal activities rendering this amoeba species an unlikely host of M. ulcerans in natural environments. PMID- 29155011 TI - Evaluation the cytotoxic effect of cytotoxin-producing Klebsiella oxytoca isolates on the HEp-2 cell line by MTT assay. AB - BACKGROUND: The cytotoxic effects on epithelial cells of the human are not observed in other strains of Klebsiella spp and are only observed in K. oxytoca strains. MTT assay was used to evaluate cytotoxic activity. In this study, colorimetric method was used to evaluate the cytotoxic effect of cytotoxin producing isolates on Hep-2 cell line and determines the percentage of surviving cells. MATERIALS AND METHODS: In this study, we collected a total of 75 K. oxytoca strains isolate and we detected the production of toxins and their cytotoxic effects on HEp-2 cells. Colorimetric method such as MTT assay was used to evaluate the cytotoxic effect of cytotoxin-producing isolates on Hep-2 cell line and determines the percentage of surviving cells. RESULTS: Nine isolates had cytotoxic effects on HEp-2 cells. The results of MTT assay showed that the isolated strains were different from the control stain in terms of toxinogenicity and cytotoxic effects on HEp-2 cells at the studied dilutions (1:3, 1:6, 1:12, 1:24, 1:48, and 1:96). CONCLUSIONS: In the current study, Percentage of Hep-2 surviving cells exposed to 1:3, 1:6, 1:12, 1:24, 1:48, and 1:96 supernatant dilutions of cytotoxin-producing Klebsiella oxytoca isolates was different. PMID- 29155012 TI - Litopenaeus vannamei notch affects lipopolysaccharides induced reactive oxygen species. AB - Notch signaling pathway was originally discovered in the development stage of drosophila but has recently been found to play essential roles in innate immunity. Most previous studies on Notch have focused on mammals, whereas, in this study, we employed the shrimp Litopenaeus vannamei as a model to study the functions of Notch in invertebrate innate immune system. Our results showed that LvNotch was highly expressed in hemocytes and could be strongly induced by lipopolysaccharides (LPS) injection. Small interfering RNA (siRNA)-mediated knockdown of LvNotch could significantly increase LPS induced L. vannamei mortality, which might be due to the fact that LPS induced ROS was greatly enhanced in LvNotch knockdown shrimps. Further, quantitative polymerase chain reaction (qPCR) analysis revealed that LvNotch could affect the expression of multiple genes, including dorsal, relish, anti-lipopolysaccharide factor 1 (ALF1), ALF3 and NADH dehydrogenases which were upregulated, and Hypoxia inducible factor (HIF, alpha/beta) which were downregulated in LPS treated shrimps. In summary, LvNotch is important in the control of inflammation-induced ROS production in shrimp. PMID- 29155013 TI - 3,4-Dihydroxyphenylacetaldehyde synthase and cuticle formation in insects. AB - Cuticle is the most important structure that protects mosquitoes and other insect species from adverse environmental conditions and infections of microorganism. The physiology and biochemistry of insect cuticle formation have been studied for many years and our understanding of cuticle formation and hardening has increased considerably. This is especially true for flexible cuticle. The recent discovery of a novel enzyme that catalyzes the production of 3,4 dihydroxyphenylacetaldehyde (DOPAL) in insects provides intriguing insights concerning the flexible cuticle formation in insects. For convenience, the enzyme that catalyzes the production DOPAL from l-dopa is named DOPAL synthase. In this mini-review, we summarize the biochemical pathways of cuticle formation and hardening in general and discuss DOPAL synthase-mediated protein crosslinking in insect flexible cuticle in particular. PMID- 29155014 TI - Resveratrol dimer trans-epsilon-viniferin prevents rotaviral diarrhea in mice by inhibition of the intestinal calcium-activated chloride channel. AB - We previously identified, by a natural-product screen, resveratrol oligomers as inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Here, we report the resveratrol dimer trans-epsilon-viniferin (TV) and tetramer r-2-viniferin (RV) as inhibitors of the intestinal calcium activated chloride channel (CaCC) and demonstrate their antisecretory efficacy in a neonatal mouse model of rotaviral diarrhea. Short-circuit measurements show inhibition of CaCC current in the human colonic cell line HT-29 by TV and RV with IC50~1 and 20MUM, respectively. TV primarily inhibited the physiologically relevant, long-term CaCC current following agonist stimulation, without effect on cytoplasmic Ca2+ signaling. TV and RV inhibited short-circuit current in mouse colon as well. In a neonatal mouse model of rotaviral secretory diarrhea produced by oral inoculation with rotavirus, 2MUg TV or 11MUg RV inhibited secretory diarrhea by >50%, without effect on the rotaviral infection. Our results support the antisecretory efficacy of non-toxic, natural-product resveratrol oligomers for diarrheas produced by CaCC activation. Because these compounds also inhibit the CFTR chloride channel, they may be useful for antisecretory therapy of a wide range of diarrheas. PMID- 29155015 TI - Optimized lentiviral transduction of human amniotic mesenchymal stromal cells. AB - Mesenchymal stromal cells are excellent candidates for regenerative medicine since they are multipotent, easy to isolate, can be expanded to obtain clinically relevant numbers and are immunoprivileged. Stable genetic modification with viral vectors can improve mesenchymal stromal cell function and enhance their therapeutic potential. However, standard viral vectors achieve sub-optimal transduction efficiency with a single infection. On the other hand, multiple transduction cycles or antibiotic-based selection methods may alter the stem cell phenotype. We hypothesized that the use of lentiviral vectors containing specific regulatory sequences may result in improved transduction efficiency. Thus, we compared two types of third generation lentiviral vectors, one of which, the pLenti7.3 vector, contains the optimized sequences for Polypurine Tract and Woodchuck Post-transcriptional Regulatory Element. We demonstrated that with the pLenti7.3 it is possible to efficiently transduce human mesenchymal stromal cells with a single transduction cycle. Additionally, we successfully showed that by using the pLenti7.3 vector it is possible to efficiently over-express different growth factors, particularly relevant for cardiac protection and differentiation, in human mesenchymal stromal cells. PMID- 29155016 TI - Topical administration of reversible SAHH inhibitor ameliorates imiquimod-induced psoriasis-like skin lesions in mice via suppression of TNF-alpha/IFN-gamma induced inflammatory response in keratinocytes and T cell-derived IL-17. AB - DZ2002, a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor with immunosuppressive properties and potent therapeutic activity against various autoimmune diseases in mice. The present study was designed to characterize the potential therapeutic effects of DZ2002 on murine model of psoriasis and reveal the correlated mechanisms. In this report, we demonstrated that in vitro, DZ2002 significantly decreased the expression of pro-inflammatory cytokines and adhesion molecule including IL-1alpha, IL-1beta, IL-6, IL-8, TNF-alpha and ICAM-1 by inhibiting the phosphorylation of p38 MAPK, ERK and JNK in TNF-alpha/IFN-gamma stimulated HaCaT human keratinocytes. Topical administration of DZ2002 alleviated the imiquimod (IMQ)-induced psoriasis-like skin lesions and inflammation in mice, the therapeutic effect was comparable with the Calcipotriol. Moreover, the inflammatory skin disorder was restored by DZ2002 treatment characterized by reducing both of the CD3+ T cell accumulation and the psoriasis-specific cytokines expression. Further, we found that DZ2002 improved IMQ-induced splenomegaly and decreased the frequency of splenic IL-17-producing T cells. Our finding offered the convincing evidence that SAHH inhibitor DZ2002 might attenuate psoriasis by simultaneously interfering the abnormal activation and differentiation of keratinocytes and accumulation of IL-17-producing T cells in skin lesions. PMID- 29155017 TI - P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) affect brain accumulation and intestinal disposition of encorafenib in mice. AB - Encorafenib (LGX818) is a promising BRAFV600E inhibitor that has efficacy against metastatic melanoma. To better understand its pharmacokinetics, we studied its interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A. In polarized MDCK-II cells, encorafenib was efficiently transported by canine and human ABCB1 and ABCG2 and by mouse Abcg2. Upon oral administration to wild-type, Abcb1a/1b-/-, Abcg2-/-, and Abcb1a/1b;Abcg2-/- mice, encorafenib was absorbed very quickly and to very high plasma levels, but without clear changes in oral availability between the strains. Upon oral or intravenous administration, encorafenib brain accumulation was markedly increased in Abcb1a/1b;Abcg2-/- mice and to a lesser extent in Abcb1a/1b-/- mice. However, absolute brain concentrations and brain-to-plasma ratios remained very low in all strains, indicating intrinsically poor brain penetration of encorafenib. Upon intravenous administration, Abcb1a/1b;Abcg2-/- mice showed somewhat reduced plasma elimination of encorafenib compared to wild type mice, and lower accumulation of the drug in the intestinal tract, suggesting a limited role for these transporters in intestinal elimination of the drug. In Cyp3a-/- mice plasma levels of encorafenib were not markedly increased, suggesting a limited impact of Cyp3a on encorafenib oral availability. The low brain penetration of encorafenib might limit its efficacy against malignancies positioned behind a functional blood-brain barrier, but its oral bioavailability and distribution to other tested organs (liver, kidney, spleen, testis) was high. PMID- 29155018 TI - Emerging infections-an increasingly important topic: review by the Emerging Infections Task Force. AB - OBJECTIVES: This paper review trends in emerging infections and the need for increased clinical and laboratory surveillance. METHODS: Factors that contributed to the emergence of recent outbreaks have been reviewed. Known, major outbreaks over the past two decades were reviewed. RESULTS: We identified at least four major drivers of emergent infections: (i) increasing density of the human population; (ii) stress from farmland expansion on the environment; (iii) globalization of the food market and manufacturing; (iv) environmental contamination. The factors creating new opportunities for emerging infections include: (i) population growth; (ii) spread in health care facilities; (iii) an ageing population; (iv) international travel; (v) changing and expanding vector habitats. CONCLUSIONS: Emerging infections are unpredictable. In this review we argue that to discover new trends in infectious diseases, the clinicians have to look for the unusual and unexpected and ensure proper diagnostics and that syndromic surveillance must be supported by highly specialized laboratory services. Mathematical modeling has not been able to predict outbreaks More emphasis on the biology of evolution is needed. EID rarely stands out as unusual, and the continuous pressure on health care budgets forces clinicians and laboratories to prioritize their diagnostic work-up to common and treatable conditions. The European Society for Infectious Diseases and Clinical Microbiology, ESCMID, has established an Emerging Infections Task Force, EITaF, to strengthen the activities of the society on emerging infections and ensure that emerging infections is included in differential diagnostic considerations in everyday clinical practice. PMID- 29155019 TI - The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: role of the treatment regimen. AB - BACKGROUND & AIMS: Previous studies have reported a high frequency of hepatocellular carcinoma (HCC) occurrence in patients with advanced liver disease, after receipt of interferon (IFN)-free therapy for hepatitis C virus (HCV) infection. Our objective was to verify and account for this phenomenon using data from the Scottish HCV clinical database. METHODS: We identified HCC naive individuals with liver cirrhosis receiving a course of antiviral therapy in Scotland from 1997-2016 resulting in a sustained virologic response. Patients were followed-up from their treatment start date to the earliest of: date of death, date of HCC occurrence, or 31 January 2017. We used Cox regression to compare the risk of HCC occurrence according to treatment regimen after adjusting for relevant co-factors (including: demographic factors; baseline liver disease stage; comorbidities/health behaviours, virology, and previous treatment experience). HCC occurrence was ascertained through both the HCV clinical database and medical chart review. For our main analysis, treatment regimen was defined as IFN-free vs. IFN-containing. RESULTS: A total of 857 patients met the study criteria, of whom 31.7% received an IFN-free regimen. Individuals receiving IFN-free therapy were more likely to be: older; of white ethnicity, Child Turcotte-Pugh B/C vs. Child-Turcotte-Pugh A; thrombocytopenic; non-genotype 3; and treatment experienced. HCC occurrence was observed in 46 individuals during follow-up. In univariate analysis, IFN-free therapy was associated with a significantly increased risk of HCC (HR: 2.48; p = 0.021). However, after multivariate adjustment for baseline factors, no significant risk attributable to IFN-free therapy persisted (aHR: 1.15, p = 0.744). CONCLUSION: These findings suggest that the higher incidence of HCC following sustained virologic response with IFN-free therapy relates to baseline risk factors/patient selection, and not the use of IFN-free therapy per se. LAY SUMMARY: We examined the risk of liver cancer in 857 patients with cirrhosis in Scotland who received hepatitis C antiviral therapy and achieved a cure. We compared the risk of first-time liver cancer in patients treated with the newest interferon-free regimens, to patients treated with interferon. After accounting for the different characteristics of these two treatment groups, we found no evidence that interferon-free therapy is associated with a higher risk of liver cancer. PMID- 29155020 TI - The UK DCD Risk Score: A new proposal to define futility in donation-after circulatory-death liver transplantation. AB - BACKGROUND & AIMS: Primary non-function and ischaemic cholangiopathy are the most feared complications following donation-after-circulatory-death (DCD) liver transplantation. The aim of this study was to design a new score on risk assessment in liver-transplantation DCD based on donor-and-recipient parameters. METHODS: Using the UK national DCD database, a risk analysis was performed in adult recipients of DCD liver grafts in the UK between 2000 and 2015 (n = 1,153). A new risk score was calculated (UK DCD Risk Score) on the basis of a regression analysis. This is validated using the United Network for Organ Sharing database (n = 1,617) and our own DCD liver-transplant database (n = 315). Finally, the new score was compared with two other available prediction systems: the DCD risk scores from the University of California, Los Angeles and King's College Hospital, London. RESULTS: The following seven strongest predictors of DCD graft survival were identified: functional donor warm ischaemia, cold ischaemia, recipient model for end-stage liver disease, recipient age, donor age, previous orthotopic liver transplantation, and donor body mass index. A combination of these risk factors (UK DCD risk model) stratified the best recipients in terms of graft survival in the entire UK DCD database, as well as in the United Network for Organ Sharing and in our own DCD population. Importantly, the UK DCD Risk Score significantly predicted graft loss caused by primary non-function or ischaemic cholangiopathy in the futile group (>10 score points). The new prediction model demonstrated a better C statistic of 0.79 compared to the two other available systems (0.71 and 0.64, respectively). CONCLUSIONS: The UK DCD Risk Score is a reliable tool to detect high-risk and futile combinations of donor-and-recipient factors in DCD liver transplantation. It is simple to use and offers a great potential for making better decisions on which DCD graft should be rejected or may benefit from functional assessment and further optimization by machine perfusion. LAY SUMMARY: In this study, we provide a new prediction model for graft loss in donation-after-circulatory-death (DCD) liver transplantation. Based on UK national data, the new UK DCD Risk Score involves the following seven clinically relevant risk factors: donor age, donor body mass index, functional donor warm ischaemia, cold storage, recipient age, recipient laboratory model for end-stage liver disease, and retransplantation. Three risk classes were defined: low risk (0-5 points), high risk (6-10 points), and futile (>10 points). This new model stratified best in terms of graft survival compared to other available models. Futile combinations (>10 points) achieved an only very limited 1- and 5 year graft survival of 37% and less than 20%, respectively. In contrast, an excellent graft survival has been shown in low-risk combinations (<=5 points). The new model is easy to calculate at the time of liver acceptance. It may help to decide which risk combination will benefit from additional graft treatment, or which DCD liver should be declined for a certain recipient. PMID- 29155021 TI - Suitability of a chocolate agar-based medium for the transportation and long term storage of Neisseria gonorrhoeae isolates at room temperature. AB - Neisseria gonorrhoeae isolates were grown on chocolate agar slants comprising GC Agar Medium Base supplemented with 1% modified Kellogg's supplement and 1% beef blood hemoglobin. The bacterial growth was covered with sterilized paraffin oil. Cultures were used for transportation and storage of Neisseria gonorrhoeae for 3months at room temperature. PMID- 29155022 TI - VMG II transport medium stabilises oral microbiome samples for Next-Generation Sequencing. AB - Next-Generation Sequencing is providing insights into the critical role of the oral microbiome in dental diseases. Application of this method can require the collection of dental plaque from large cohorts in field-type conditions, which necessitates a transport medium to preserve the microbiome composition. We evaluated the use of two transport media, VMG II and RNAprotect(r) Bacteria Reagent (Qiagen), for room temperature storage of dental plaque. VMG II has not previously been assessed for suitability to store microbiome samples intended for deep sequencing. We compared the microbiome composition of dental plaque (total n=23) stored in either VMG II or RNAprotect Bacteria at room temperature with immediately-frozen plaque. 454 sequencing of 16S gene amplicons was used to assess the plaque microbial composition. While the bacterial diversity recovered was similar between storage conditions (p>0.1), the abundance of bacteria was influenced by storage environment. Dental plaque stored in VMG II was most similar to immediately-frozen material, with only one of the 324 bacterial species being differentially abundant (Neisseria, p<0.001). In comparison, dental plaque stored in RNAprotect Bacteria had 24 differentially abundant species compared with the immediately-frozen samples and a significantly different phylogenetic structure (p<0.01). We have identified VMG II as a new transport medium for room temperature storage of dental plaque samples being subject to Next-Generation Sequencing that stabilises oral microbial DNA makeup. PMID- 29155023 TI - Therapy-related myeloid neoplasm in an 18-year-old boy with B-lymphoblastic leukemia. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Acute myeloid leukemia or myelodysplastic syndrome during the course of ALL is a rare entity. Some of these cases are therapy-related while the others occur due to lineage switch. The correct diagnosis relies on comparing the immunophenotypes and cytogenetic/molecular alterations of the myeloid neoplasm and the ALL. We present the clinical, pathologic and cytogenetic features of a case of an 18-year-old male with prior treatment for B-lymphoblastic leukemia (B ALL) who developed therapy-related myeloid neoplasm (t-MN) 4-5years after his initial diagnosis of B-ALL. CASE PRESENTATION: A 13-year-old boy with no significant past medical history presented to Harbor-UCLA Medical Center (HUMC) in November 2012 with night sweats, fevers and chills, nausea, vomiting, diarrhea, fatigue, weakness, and weight loss. Peripheral blood flow cytometric analysis disclosed B-ALL. The blasts expressed CD10, CD19, CD22 (dim), CD34, CD38, HLA-DR, and TdT, and were negative for CD20, CD13, CD33, CD117, and cytoplasmic MPO. Chromosomal analysis and a supplemental fluorescence in situ hybridization (FISH) study performed on the bone marrow aspirate showed an abnormal karyotype (47,XY,+X,del(9)(p21p21)[4]/46,XY[16]). He achieved remission after induction chemotherapy and remained in remission until March 2016 when bilateral testicular masses were noted. Biopsy of the left testicular mass showed relapsed B-ALL. Cerebrospinal fluid (CSF) contained rare TdT-positive blasts, suggestive of minimal/early involvement by B-ALL. However, there was no evidence of acute leukemia in his bone marrow at this time. He was then treated with COG protocol AALL1331 randomized to blinatumomab arm and achieved second remission. In June 2017, the patient's peripheral blood smear showed 11% circulating monoblasts. By flow cytometry, the blasts expressed CD4, CD11b, CD13, CD15, CD33, CD38, CD56, and CD64. In addition, a few TdT-positive blasts were seen in his CSF cytospin smear. Bone marrow biopsy was subsequently performed which was consistent with evolving acute myeloid leukemia. A diagnosis of myeloid neoplasm, consistent with t-MN was made. Chromosomal analysis and FISH studies performed on his bone marrow aspirate showed normal karyotype (46,XY[20]), negative FISH result for deletion 9p21 locus, and positive KMT2A (MLL) rearrangement, respectively. Despite of chemotherapy, the patient died within one month after diagnosis. DISCUSSION AND CONCLUSION: Diagnosis of t-MN should be suspected in patients with a history of receiving cytotoxic agents and/or irradiation. In this case study, we diagnosed t-MN with KMT2A rearrangement in a patient with history of B-ALL with 9p deletion and gain of X chromosome. Unusual features associated with this case are discussed. PMID- 29155025 TI - Understanding the role of mammalian sterile 20-like kinase 1 (MST1) in cardiovascular disorders. AB - Hippo signaling is a conserved pathway and plays important roles in controlling cell proliferation and differentiation. As a critical component of the Hippo pathway in mammals, mammalian sterile 20-like kinase 1 (MST1) participates in cell apoptosis and cell proliferation. Yes-associated protein (YAP) acts as a downstream transcriptional co-activator of MST1. MST1 is present in heart tissue and helps determine the fate of cardiomyocytes by regulating the balance between autophagy and apoptosis. Recent studies showed MST1 signaling is an essential participant in many cardiovascular disorders, including aortic dissection, aortic aneurysm, atherosclerosis, myocardial ischemic injury, and cardiomyopathy. Previous studies have summarized the roles of MST1 in cardiovascular development. In this review, we focused on the roles of MST1 signaling in cardiovascular disorders. PMID- 29155024 TI - Linearization improves the repeatability of quantitative dynamic contrast enhanced MRI. AB - PURPOSE: The purpose of this study was to compare the repeatabilities of the linear and nonlinear Tofts and reference region models (RRM) for dynamic contrast enhanced MRI (DCE-MRI). MATERIALS AND METHODS: Simulated and experimental DCE-MRI data from 12 rats with a flank tumor of C6 glioma acquired over three consecutive days were analyzed using four quantitative and semi-quantitative DCE-MRI metrics. The quantitative methods used were: 1) linear Tofts model (LTM), 2) non-linear Tofts model (NTM), 3) linear RRM (LRRM), and 4) non-linear RRM (NRRM). The following semi-quantitative metrics were used: 1) maximum enhancement ratio (MER), 2) time to peak (TTP), 3) initial area under the curve (iauc64), and 4) slope. LTM and NTM were used to estimate Ktrans, while LRRM and NRRM were used to estimate Ktrans relative to muscle (RKtrans). Repeatability was assessed by calculating the within-subject coefficient of variation (wSCV) and the percent intra-subject variation (iSV) determined with the Gage R&R analysis. RESULTS: The iSV for RKtrans using LRRM was two-fold lower compared to NRRM at all simulated and experimental conditions. A similar trend was observed for the Tofts model, where LTM was at least 50% more repeatable than the NTM under all experimental and simulated conditions. The semi-quantitative metrics iauc64 and MER were as equally repeatable as Ktrans and RKtrans estimated by LTM and LRRM respectively. The iSV for iauc64 and MER were significantly lower than the iSV for slope and TTP. CONCLUSION: In simulations and experimental results, linearization improves the repeatability of quantitative DCE-MRI by at least 30%, making it as repeatable as semi-quantitative metrics. PMID- 29155026 TI - Personalized nanomedicine for CNS diseases. AB - Central nervous system (CNS) diseases are rapidly increasing globally. Currently used therapeutic agents to treat CNS diseases exhibit significant efficacy. However, the inability of these drugs to cross the blood-brain barrier (BBB) and invasiveness of the technologies to achieve localized drug delivery in disease specific parts of the brain have thwarted pain-free and complete treatment of CNS diseases. Therefore, the safe, non-invasive, and targeted delivery of drugs to the brain using nanoparticles (NPs) is currently receiving considerable research attention. Here, we highlight advances in state-of-the-art personalized nanomedicine for the treatment of CNS diseases (with a focus on dementia), the related challenges, possible solutions, and prospects for nano-enabled personalized medicine. PMID- 29155027 TI - Serum level of transforming growth factor beta 1 is associated with left atrial voltage in patients with chronic atrial fibrillation. AB - BACKGROUND: Atrial tissue fibrosis can cause electrical or structural remodeling in patients with atrial fibrillation. Transforming growth factor beta 1(TGF beta1) signaling acts as a central role in fibroblast activation. In this report, we aimed to investigate the relationship between serum level of TGF-beta1 and mean left atrial voltage in patients with chronic atrial fibrillation (CAF). METHODS: A total of 16 consecutive adult patients with CAF who underwent catheter ablation were enrolled. Blood samples for measurement of TGF-beta1 were collected from periphery veins and coronary sinus before pulmonary vein isolation. The measurement was performed with a commercially available ELISA kit. Cardiac indices were measured using echocardiography. The left atrial electroanatomic mapping was performed after pulmonary vein isolation. RESULTS: Serum level of TGF beta1 in peripheral blood was higher than that in coronary sinus (p < 0.001). TGF beta1 serum level in coronary sinus negatively correlated with mean left atrial voltage (r = -0.650, p = 0.012), While periphery TGF-beta1 level tended to be negatively correlated with mean left atrial voltage(r = -0.492, p = 0.053). Patients who treated with angiotensin II receptor antagonists had lower coronary sinus TGF-beta1 serum level than those who did not treated with angiotensin II receptor antagonists (p = 0.046). CONCLUSION: Level of TGF-beta1 in peripheral serum is higher than that in coronary sinus, and serum level of TGF-beta1 in coronary sinus is negatively associated with mean left atrial voltage in patients with CAF, angiotensin II receptor antagonists could affect TGF-beta1 serum level. PMID- 29155028 TI - Chitosan oligosaccharides with degree of polymerization 2-6 induces apoptosis in human colon carcinoma HCT116 cells. AB - Colon cancer is the third most common cancer, and yet there is a lack of effective therapeutic method with low side effects. Chitosan oligosaccharides (COS) is derived from chitosan after chitin deacetylation, and attracts more interests due to smaller molecular weight and soluble property. Previously, COS, mainly absorbed through intestinal epithelia, has been reported to exhibit many bioactivities, especially its anti-tumor effect. Recent references pay little attention to molecular weight distribution which is crucial for understanding its biological behavior. Here, we studied reducing sugar content and degree of polymerization (DP) of COS. 86.73% reducing sugar exists in COS sample and the content of chitosan fractions with 2-6 is 85.8%. COS suppressed the growth of HCT116 cells in vitro and in vivo, and the inhibition rate of tumor weight in vivo was high up to 58.6%. Moreover, the morphology observation, flow cytometry analysis and mRNA expression were applied to study the apoptosis related mechanism. COS treatment promoted mitosis, late stage apoptosis and S cell cycle arrest in HCT116 cells, and enhanced the mRNA expression of BAK and reduce BCL-2 and BCL-xL. These findings may provide an important clue for clinical applications of COS as anti-tumor drug or pharmaceutic adjuvant in the future. PMID- 29155030 TI - Transcriptome analysis and discovery of genes involved in immune pathways from coelomocytes of Onchidium struma after bacterial challenge. AB - Onchidium struma widely distributes in subtidal and low-tidal zones, which is considered to be an economical species with rich nutrition, a valuable biomonitor for heavy metal pollution and a representative species for evolution from ocean to land. However, there is limited genetic information available for O. struma development. This study compared transcriptomic profiles of coelomocytes from normal and bacteria infected O. struma by Illumina-based paired-end sequencing to explore the molecular immune mechanism of O. struma against bacterial infection. After assembly, a total of 92,450 unigenes with an average length of 1019 bp were obtained. Approximately 34,964 (37.82%) unigenes were annotated in the Nr NCBI database and 40.1% of unigenes were similar with that of Aplysia californica. Among them, 7609 unigenes were classified into three Gene Ontology (GO) categories: biological process (3250 unigenes, 42.7%), cellular component (2,281, 30.0%) and molecular function (2078 unigenes, 27.3%). A total of 22,776 unigenes were aligned to the Clusters of Orthologous Groups (COG) of proteins and classified into 25 functional categories. Following bacterial infection, 10,623 differently expressed unigenes (DEGs) were identified, including 7644 up regulated and 2979 down-regulated unigenes. Further KEGG analysis annotated 11,681 DEGs to 42 pathways, and 11 pathways were identified to be related with diseases and immune system. To our knowledge, it was first time to analyze transcriptome profiles of O. struma. Results of the present study will provide valuable theoretical resources for future genetic and genomic research on O. struma. The research results will be helpful for improving the efficiency and quality of artificial breeding, establishing genetic linkage map, and enhancing health management for this species. PMID- 29155029 TI - Molecular characterization and expression analysis of complement component 3 in dojo loach (Misgurnus anguillicaudatus). AB - The complement component 3 (C3) is a central component of complement system. All three pathways converge at formation of C3 convertases and share the terminal pathways of membrane attack complex (MAC) formation. In this study, three isoforms of C3 were discovered in Misgurnus anguillicaudatus, named "C3-1", "C3 2" and "C3-3", respectively. The full-length of C3-1 cDNA sequence was firstly identified and analyzed from dojo loach (Misgurnus anguillicaudatus). The Ma-C3-1 cDNA sequence comprised of 4509 bp encoding 1454 amino acids with a putative signal peptide of 20 amino acid residues. The deduced amino acid sequence showed that Ma-C3-1 has conserved residues and domain, which are known to be crucial for C3 function. Interestingly, an amino acid substitution of the highly conserved GCGEQ was discovered in Ma-C3-1. Phylogenetic analysis showed that Ma-C3-1 was closely related to Cyprinidae. The mRNA expression levels of three isoforms of C3 were detected in kidney, eye, spleen, gonad, heart, fin ray, gut, muscle, brain, gill, skin, blood and liver. The expression of Ma-C3-1 and Ma-C3-3 were mainly detected in liver, followed by spleen, gonad. However, the high expression of Ma C3-2 was found in kidney, followed by blood and gonad. The morphological changes of gill and skin, and the expression pattern of these three isoforms C3 molecular following the infection with Aeromonas hydrophila were investigated. The mRNA expression levels of three C3 isoforms were up-regulated in the gill, skin, liver and spleen after infection with A.hydrophila. Similarly, challenge experiments resulted in significant up-regulated expression of other complement-relevant genes in gill, liver and skin, such as C4, C5, C8b, especially at 24 h and 36 h. These results suggest that complement system might play an important role not only in liver, but also in the mucosal tissues as gill and skin of teleost fish. PMID- 29155031 TI - The involvement of suppressor of cytokine signaling 6 (SOCS6) in immune response of Chinese mitten crab Eriocheir sinensis. AB - Suppressor of cytokine signaling (SOCS) is a family of cytokine-inducible negative regulators of cytokine signaling and it plays a crucial role in various physiological processes. In the present study, the full-length cDNA of a SOCS (designated as EsSOCS6) was cloned from Chinese mitten crab Eriocheir sinensis. The open reading frame of EsSOCS6 cDNA was of 1266 bp, which encoded a polypeptide of 421 amino acid residues. There were two typically conserved SOCS family domains in EsSOCS6, including a central Src homology 2 (SH2) domain and a C-terminal SOCS box. The deduced amino acid sequence of EsSOCS6 shared 72-76% similarity with those of other SOCS6 family members. EsSOCS6 mRNA was constitutively expressed in all the examined tissues with higher expression levels in the immune-related tissues, such as hepatopancreas, hemocytes and gill. The mRNA expression levels of the EsSOCS6 in hemocytes were significantly up regulated after the stimulations with lipopolysaccharide (LPS), Aeromonas hydrophila and polyinosinic-polycytidylic acid (poly (I:C)). The mRNA expressions of threonine/serine protein kinase (EsAkt) and EsRelish were dramatically declined after EsSOCS6 was interfered by dsRNA. Collectively, these results demonstrated that EsSOCS6 might regulate the activation of the NF-kappaB signaling pathway and play an important role in the innate immune responses of E. sinensis. PMID- 29155032 TI - Pennington et al.: First demonstration of equid gammaherpesviruses within the gastric mucosal epithelium of horses. Virus Research volume 242, 15 October 2017, pages 30-36. PMID- 29155033 TI - The gut virome of the protochordate model organism, Ciona intestinalis subtype A. AB - The identification of host-specific bacterial and viral communities associated with diverse animals has led to the concept of the metaorganism, which defines the animal and all of its associated microbes as a single unit. Here we sequence the viruses found in the gut (i.e., the gut virome) of the marine invertebrate model system, Ciona intestinalis subtype A, in samples collected one year apart. We present evidence for a host-associated virome that is distinct from the surrounding seawater and contains some temporally-stable members. Comparison of gut tissues before and after starvation in virus-free water enabled the differentiation between the Ciona-specific virome and transient viral communities associated with dietary sources. The Ciona gut viromes were dominated by double stranded DNA tailed phages (Order Caudovirales) and sequence assembly yielded a number of complete circular phage genomes, most of which were highly divergent from known genomes. Unique viral communities were found in distinct gut niches (stomach, midgut and hindgut), paralleling the compartmentalization of bacterial communities. Additionally, integrase and excisionase genes, including many that are similar to prophage sequences within the genomes of bacterial genera belonging to the Ciona core microbiome, were prevalent in the viromes, indicating the active induction of prophages within the gut ecosystem. Knowledge of the gut virome of this model organism lays the foundation for studying the interactions between viruses, bacteria, and host immunity. PMID- 29155034 TI - Identification of a novel porcine OASL variant exhibiting antiviral activity. AB - 2', 5'-Oligoadenylate synthetase-lilke (OASL) protein is an atypical oligoadenylate synthetase (OAS) family member, which possesses antiviral activity but lacks 2', 5'-oligoadenylate synthetase activity. Here, a novel variant of porcine OASL (pOASL2) was identified through RT-PCR amplification. This gene is distinguishable from the previously described wild-type porcine OASL (pOASL1). The gene appears to be derived from a truncation of exon 4 plus 8 nucleotides of exon 5 with a premature termination, measuring only 633 bp in length, although its position corresponds to that of pOASL1. Given this novel gene appears to be a variant of pOASL, we assayed for antiviral activity of the protein. We demonstrated that pOASL2 could inhibit Japanese encephalitis virus (JEV) proliferation as well as pOASL1 in a transient overexpression assay of pOASL1 and pOASL2 in PK-15 and Vero cells. In addition to JEV, pOASL1 and pOASL2 also decreased the proliferations of Porcine reproductive and respiratory syndrome virus (PRRSV) and vesicular stomatitis virus (VSV), but did not exhibit antiviral activity against pseudorabies virus (PRV). Structural analysis showed that the pOASL2 gene retained only the first three exons at the 5'-. To investigate the role of the alphaN4 helix in pOASL in antiviral responses like that in hOASL, we mutated key residues in the anchor domain of the alphaN4 helix in pOASL2, based on the domain's location in hOASL. However, the antiviral activity of pOASL2 was not affected. Thus, the alphaN4 helix of pOASL likely does not play a significant role in its antiviral activity. In conclusion, pOASL2 acts as a new splice isoform of pOASL that plays a role in resistance to infection of several kinds of RNA viruses. PMID- 29155035 TI - Utility of anesthetic block for endometrial ablation pain: a randomized controlled trial. AB - BACKGROUND: Second-generation endometrial ablation has been demonstrated safe for abnormal uterine bleeding treatment, in premenopausal women who have completed childbearing, in short-stay surgical centers and in physicians' offices. However, no standard regarding anesthesia exists, and practice varies depending on physician or patient preference and hospital policy and setting. OBJECTIVE: The aim of this study was to evaluate whether local anesthetic, in combination with general anesthesia, affects postoperative pain and associated narcotic use following endometrial ablation. MATERIALS AND METHODS: This was a single-center single-blind randomized controlled trial conducted in an academic-affiliated community hospital. A total of 84 English-speaking premenopausal women, aged 30 to 55 years, who were undergoing outpatient endometrial ablation for benign disease were randomized to receive standardized paracervical injection of 20 mL 0.25% bupivacaine (treatment group) or 20 mL normal saline solution (control group) upon completion of ablation. The study was designed to test a 40% 1-hour mean visual analog scale (VAS) pain score difference with an average standard deviation of 75% of both groups' mean VAS scores, using a 2-tailed test, a type I error of 5%, and statistical power of 80%. A sample of 36 patients per study group was required. Assuming a 15% attrition rate, the study enrolled 42 patients per study arm randomized in blocks of 2 (84 total). Two-tailed cross-tabulations with Fisher exact significance values where appropriate and Student t tests were used to compare patient characteristics. Backward stepwise regressions were conducted to control for confounding. RESULTS: Between April 2016 and February 2017, a total of 108 women scheduled for endometrial ablation were screened (refusals, n = 21; ineligible, n = 3) to determine whether there were meaningful differences in postoperative VAS pain scores and postoperative narcotic use. Of the 84 randomized women, 2 age-ineligible women were excluded. Intent-to-treat analyses included 1 incorrect randomization (in which the provider consciously decided to provide analgesia regardless of the protocol, after which the provider was excluded from further study participation) and 3 women having no ablation because of operative difficulties. Three were lost to second-day follow-up. Treatment group patients (n = 41) experienced 1.3 points lower 1-hour postoperative VAS pain scores than the control group (n = 41, P = .02). The difference diminished by 4 hours (P = .31) and was negligible by 8 hours (P = .62). Treatment group patients used 3.6 less morphine equivalents of postoperative pain medication (P = .05). Regression analyses controlled for confounding reduced the 1-hour postoperative treatment group pain score difference to 0.8 (confidence interval [CI], -0.6 to 0.1) but slightly increased the average postoperative morphine equivalents to 3.7 (CI, -6.8 to -0.7). CONCLUSION: This randomized controlled trial found that local anesthetic with low risk for complications, used in conjunction with general anesthesia, decreased postoperative pain at 1 hour and significantly reduced postoperative narcotic use following endometrial ablation. Further research is needed to determine whether the study results are generalizable and whether post procedure is the best time to administer the paracervical block to decrease endometrial ablation pain. PMID- 29155037 TI - Long-term anal incontinence after obstetric anal sphincter injury-does grade of tear matter? AB - BACKGROUND: Anal incontinence is a major concern following delivery with obstetric anal sphincter injury (OASIS), and has been related to the degree of sphincter tear. OBJECTIVE: The aims of this study were (1) to evaluate whether women with a fourth-degree OASIS in the first delivery have an increased risk of long-term anal and fecal incontinence after a second delivery, and (2) to assess the impact of mode of second delivery on anal incontinence and related symptoms in these patients. MATERIALS AND METHODS: We performed secondary analyses of a national questionnaire study in all Danish women with an OASIS in their first delivery and 1 subsequent delivery, both deliveries in 1997 to 2005. The questionnaires were sent a minimum of 5 years since the second delivery. In Denmark, women with anal incontinence after a delivery with OASIS are recommended elective cesarean deliveries in subsequent pregnancies. We performed uni- and multivariable logistic regression analyses to evaluate the outcomes. RESULTS: In total, 2008 patients had an OASIS, of whom 12.2% (n = 245) had a fourth-degree tear in the first delivery. The median follow-up time since the first delivery with OASIS was 11.6 years (IQR, 10.2-13.2 years) and since the second delivery 8.5 years (IQR, 7.1-10.1 years). Women with a fourth-degree sphincter injury in the first delivery were at higher risk for anal incontinence (58.8%, n = 144) as well as fecal incontinence (30.6%, n = 75) than patients with a third-degree injury in the first delivery (41.0%, n = 723, and 14.6%, n = 258, respectively). The differences between groups persisted after adjustment for important maternal, fetal, and obstetric characteristics (adjusted odds ratio [aOR], 2.14; 95% confidence interval [CI], 1.52-3.02; P < 0.001 for anal incontinence; and aOR, 2.49; 95% CI, 1.73-3.56; P < 0.001 for fecal incontinence). In subgroup analyses of patients with fourth-degree anal sphincter injury in the first delivery, the mode of second delivery was not associated with the risk of anal incontinence (aOR, 0.97; 95% CI, 0.41-1.84; P = 0.71) or fecal incontinence (aOR, 1.28; 95% CI, 0.65-2.52; P = 0.48). The effect of the mode of the second delivery did not differ between women with a fourth-degree OASIS and those with a third-degree injury with regard to both anal (P = 0.09) and fecal (P = 0.96) incontinence. CONCLUSION: After a second delivery, women with a fourth-degree OASIS in the first delivery have a higher risk of long-term anal and fecal incontinence than women with a third-degree sphincter injury. Adjusted odds of long-term anal and fecal incontinence did not differ significantly by mode of second delivery. Women with a fourth-degree OASIS should be informed about the increased risk of long term anal incontinence and advised that subsequent elective cesarean delivery is not protective. PMID- 29155036 TI - Effectiveness of app-based self-acupressure for women with menstrual pain compared to usual care: a randomized pragmatic trial. AB - BACKGROUND: Primary dysmenorrhea is common among women of reproductive age. Nonsteroidal anti-inflammatory drugs and oral contraceptives are effective treatments, although the failure rate is around 20% to 25%. Therefore additional evidence-based treatments are needed. In recent years, the use of smartphone applications (apps) has increased rapidly and may support individuals in self management strategies. OBJECTIVE: We aimed to investigate the effectiveness of app-based self-acupressure in women with menstrual pain. MATERIALS AND METHODS: A 2-armed, randomized, pragmatic trial was conducted from December 2012 to April 2015 with recruitment until August 2014 in Berlin, Germany, among women aged 18 to 34 years with self-reported cramping pain of 6 or more on a numeric rating scale (NRS) for the worst pain intensity during the previous menstruation. After randomization, women performed either app-based self-acupressure (n = 111) or followed usual care only (n = 110) for 6 consecutive menstruation cycles. The primary outcome was the mean pain intensity (NRS 0-10) on the days with pain during the third menstruation. Secondary outcomes included worst pain intensity during menstruation, duration of pain, 50% responder rates (reduction of mean pain by at least 50%), medication intake, sick leave days, and body efficacy expectation assessed at the first, second, third, and sixth menstruation cycles. RESULTS: We included 221 women (mean age, 24.0 years; standard deviation [SD], 3.6 years). The mean pain intensity difference during the third menstruation was statistically significant in favor of acupressure (acupressure: 4.4; 95% confidence interval [CI], 4.0-4.7; usual care 5.0; 95% CI, 4.6-5.3; mean difference -0.6; 95% CI, - 1.2 to -0.1; P = .026). At the sixth cycle, the mean difference between the groups (-1.4; 95% CI, -2.0 to -0.8; P < .001) reached clinical relevance. At the third and sixth menstruation cycles, responder rates were 37% and 58%, respectively, in the acupressure group, in contrast to 23% and 24% in the usual care group. Moreover, the worst pain intensity (group difference -0.6; 95% CI, -1.2 to -0.02; and -1.4; 95% CI, -2.0 to -0.7), the number of days with pain (-0.4; 95% CI, -0.9 to -0.01; and -1.2; 95% CI, -1.6 to -0.7) and the proportion of women with pain medication at the third and sixth menstruation cycles (odds ratio [OR], 0.5; 95% CI, 0.3-0.9] and 0.3 (95% CI, 0.2-0.5) were lower in the acupressure group. At the third cycle, hormonal contraceptive use was more common in the usual care group than in the acupressure group (OR, 0.5; 95% CI, 0.3-0.97) but not statistically significantly different at the sixth cycle (OR, 0.6; 95% CI, 0.3-1.1]). The number of sick leave days and body efficacy expectation (self-efficacy scale) did not differ between groups. On a scale of 0 to 6, mean satisfaction with the intervention at the third cycle was 3.7 (SD 1.3), recommendation of the intervention to others 4.3 (1.5), appropriateness of acupressure for menstrual pain 3.9 (1.4), and application of acupressure for other pain 4.3 (1.5). The intervention was safe, and after the sixth cycle, two-thirds of the women (67.6%) still applied acupressure on all days with pain. CONCLUSION: Smartphone app-delivered self-acupressure resulted in a reduction of menstrual pain compared to usual care only. Effects were increasing over time, and adherence was good. Future trials should include comparisons with other active treatment options. PMID- 29155038 TI - A novel, modernized Golgi-Cox stain optimized for CLARITY cleared tissue. AB - BACKGROUND: High resolution neuronal information is extraordinarily useful in understanding the brain's functionality. The development of the Golgi-Cox stain allowed observation of the neuron in its entirety with unrivalled detail. Tissue clearing techniques, e.g., CLARITY and CUBIC, provide the potential to observe entire neuronal circuits intact within tissue and without previous restrictions with regard to section thickness. NEW METHOD: Here we describe an improved Golgi Cox stain method, optimised for use with CLARITY and CUBIC that can be used in both fresh and fixed tissue. RESULTS: Using this method, we were able to observe neurons in their entirety within a fraction of the time traditionally taken to clear tissue (48h). We were also able to show for the first-time that Golgi stained tissue is fluorescent when visualized using a multi-photon microscope, allowing us to image synaptic spines with a detail previously unachievable. COMPARISON WITH EXISTING METHODS: These novel methods provide cheap and easy to use techniques to investigate the morphology of cellular processes in the brain at a new-found depth, speed, utility and detail, without previous restrictions of time, tissue type and section thickness. CONCLUSIONS: This is the first application of a Golgi-Cox stain to cleared brain tissue, it is investigated and discussed in detail, describing different methodologies that may be used, a comparison between the different clearing techniques and lastly the novel interaction of these techniques with this ultra-rapid stain. PMID- 29155039 TI - Perinatal nicotine exposure increases obesity susceptibility by peripheral leptin resistance in adult female rat offspring. AB - Maternal nicotine (NIC) exposure causes overweight, hyperleptinemia and metabolic disorders in adult offspring. Our study aims to explore the underlying mechanism of perinatal NIC exposure increases obesity susceptibility in adult female rat offspring. In our model, we found that adult NIC-exposed females presented higher body weight and subcutaneous and visceral fat mass, as well as larger adipocytes, while no change was found in food intake. Serum profile showed a higher serum glucose, insulin and leptin levels in NIC-exposed females. In adipose tissue and liver, the leptin signaling pathway was blocked at 26 weeks, presented lower Janus tyrosine kinase 2 and signal transducer and activator of transcription 3 gene expression, higher suppressor of cytokine signaling 3 gene expression (in adipose tissue) and lower leptin receptors gene expression (in liver), indicating that peripheral leptin resistance occurred in NIC-exposed adult females. In female rats, the expression of lipolysis genes was affected dominantly in adipose tissue, but lipogenesis genes was affected in liver. Furthermore, the glucose and insulin tolerance tests showed a delayed glucose clearance and a higher area under the curve in NIC-exposed females. Therefore, perinatal NIC exposure programed female rats for adipocyte hypertrophy and obesity in adult life, through the leptin resistance in peripheral tissue. PMID- 29155040 TI - Radiolabelled soman binding to sera from Rats, Guinea Pigs and Monkeys. AB - Soman is a highly toxic organophosphorus chemical warfare compound that binds rapidly and irreversibility to a variety of serine active enzymes, i.e., butyryl- and acetyl-cholinesterases and carboxylesterase. The in vivo toxicity of soman has been reported to vary significantly in different animal species, such as rats and guinea pigs or non-human primates. This species variation makes it difficult to identify appropriate animal models for therapeutic drug development under the US Food and Drug Administration (FDA) Animal Rule. Since species variation in soman toxicity has been correlated with species variation in serum carboxylesterase, we undertook to determine if serum from guinea pigs, rats and non-human primates bound different levels of soman in vitro in the presence of equimolar concentrations of soman. Our results demonstrated that the amount of soman bound in the serum of rats was 4 uM, but essentially null in guinea pigs or non-human primates. The results strongly correlate with the presence or absence of carboxylesterase in the serum of animals and the difference in the toxic dose of soman in various species. Our results support prior suggestions that guinea pigs and non-human primates may be better animal models for the development of antidotes under the FDA Animal Rule. PMID- 29155041 TI - Epidemiologic and Clinical Characteristics of Coronavirus and Bocavirus Respiratory Infections after Allogeneic Stem Cell Transplantation: A Prospective Single-Center Study. AB - Epidemiologic data about coronaviruses (CoVs) and human bocavirus (HBoV) in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are scarce. We conducted a prospective longitudinal study on respiratory viral infections (RVIs) in allo-HSCT recipients with respiratory symptoms from December 2013 until June 2016. Respiratory virus in upper and/or lower respiratory tract (URT and LRT) specimens were tested using Luminex xTAG RVP Fast v1 assay. Seventy nine consecutive allo-HSCT recipients developed a total of 192 virologically documented RVI episodes over 30 months. The median follow-up after RVI was 388 days (range, 5 to 923). CoV or HBoV was detected in 27 of 192 episodes (14%); 18 of 79 recipients (23%) developed a total of 21 CoV RVI episodes, whereas 6 recipients (8%) had 1 HBoV RVI episode each. Fourteen CoV RVI episodes were limited to the URT, whereas 7 affected the LRT. Co-pathogens were detected in 8 (38%) CoV cases. Type OC43 CoV was the dominant type (48%) followed by NL63 (24%), KHU1 (19%), and 229E (9%); the CoV hospitalization rate was 19%, whereas mortality was 5% (1 patient without any other microbiologic documentation). Among the 6 recipients with HBoV (3%), only 1 had LRT involvement and no one died from respiratory failure. In 5 cases (83%) HBoV was detected along with other viral co pathogens. CoV RVIs are common after allo-HSCT, and in a significant proportion of cases CoV progressed to LRT and showed moderate to severe clinical features. In contrast, HBoV RVIs were rare and mostly presented in the context of co infections. PMID- 29155042 TI - Imaging flow cytometry to assess chromosomal abnormalities in chronic lymphocytic leukaemia. AB - Chronic Lymphocytic Leukaemia (CLL), the most common leukaemia in the Western world, has a characteristic phenotype and prognosis largely defined by the presence of cytogenetic aberrations. The gold standard for detecting these cytogenetic abnormalities is interphase fluorescence in situ hybridisation (FISH) performed on cell smears or tissue sections on glass slides. Fluorescently labelled DNA probes bind to specific chromosomal regions and the signal detected by fluorescent microscopy. Generally only 200 cells are assessed and the limit of sensitivity is 3% positive cells. Here we report the development and use of imaging flow cytometry to assess chromosomes by FISH in phenotyped CLL cells in suspension. Thousands of CLL cells, identified by their phenotype, are assessed for specific FISH probe signals using an automated, high throughput imaging flow cytometer. The "extended depth of field" capability of the imaging flow cytometer enables FISH probe signals ("spots") to be resolved and localised within the (stained) nucleus of the immunophenotyped cells. We report the development of the automated "immuno-flowFISH" on normal blood using the Amnis ImageStreamX mark II platform and illustrate the clinical application of the method for the assessment of chromosome 12 in CLL. It is a powerful new method which has potential to be applied at diagnosis for disease stratification, and following treatment to assess residual disease. These applications will assist clinicians in optimising therapeutic decision making and thereby improve patient outcome. PMID- 29155043 TI - Stk33 is required for spermatid differentiation and male fertility in mice. AB - Spermiogenesis is the final phase during sperm cell development in which round spermatids undergo dramatic morphological changes to generate spermatozoa. Here we report that the serine/threonine kinase Stk33 is essential for the differentiation of round spermatids into functional sperm cells and male fertility. Constitutive Stk33 deletion in mice results in severely malformed and immotile spermatozoa that are particularly characterized by disordered structural tail elements. Stk33 expression first appears in primary spermatocytes, and targeted deletion of Stk33 in these cells recapitulates the defects observed in constitutive knockout mice, confirming a germ cell-intrinsic function. Stk33 protein resides in the cytoplasm and partially co-localizes with the caudal end of the manchette, a transient structure that guides tail elongation, in elongating spermatids, and loss of Stk33 leads to the appearance of a tight, straight and elongated manchette. Together, these results identify Stk33 as an essential regulator of spermatid differentiation and male fertility. PMID- 29155046 TI - The effect of a default-based nudge on the choice of whole wheat bread. AB - Consumer choices are often influenced by the default option presented. This study examines the effect of whole wheat bread as a default option in a sandwich choice situation. Whole wheat bread consists of 100% whole grain and is healthier than other bread types that are commonly consumed, such as brown or white bread. A pilot survey (N = 291) examined the strength of combinations of toppings and bread type as carrier to select stimuli for the main study. In the main experimental study consisting of a two (bread type) by two (topping type) between subjects design, participants (N = 226) were given a free sandwich at a university stand with either a relatively unhealthy deep-fried snack (croquette) or a healthy topping. About half of the participants were offered a whole wheat bun unless they asked for white bun, and the other half were offered a white bun unless they asked for a whole wheat bun. Regardless of the topping, the results show that when the whole wheat bun was the default option, 108 out of 115 participants (94%) decided to stick with this default option. When the default of bread offered was white, 89 out of 111 participants (80%) similarly chose to stick with this default. Across conditions, participants felt equally free to make a choice. The attractiveness of and willingness to pay for the sandwich were not affected by default type of bread. This study demonstrated a strong default effect of bread type. This clearly shows the benefit of steering consumers towards a healthier bread choice, by offering healthier default bread at various locations such as restaurants, schools and work place canteens. PMID- 29155044 TI - The forkhead transcription factor UNC-130/FOXD integrates both BMP and Notch signaling to regulate dorsoventral patterning of the C. elegans postembryonic mesoderm. AB - The proper development of a multicellular organism requires precise spatial and temporal coordination of cell intrinsic and cell extrinsic regulatory mechanisms. Both Notch signaling and bone morphogenetic protein (BMP) signaling function to regulate the proper development of the C. elegans postembryonic mesoderm. We have identified the C. elegans FOXD transcription factor UNC-130 as a major target functioning downstream of both BMP signaling and Notch signaling to regulate dorsoventral patterning of the postembryonic mesoderm. We showed that unc-130 expression in the postembryonic M lineage is asymmetric: its absence of expression in the dorsal side of the M lineage requires the antagonism of BMP signaling by the zinc finger transcription factor SMA-9, while its expression in the ventral side of the M lineage is activated by LIN-12/Notch signaling. We further showed that the regulation of UNC-130 expression by BMP signaling and Notch signaling is specific to the M lineage, as the ventral expression of UNC 130 in the embryonically-derived bodywall muscles was not affected in either BMP pathway or Notch pathway mutants. Finally, we showed that the function of UNC-130 in the M lineage is independent of UNC-129, a gene previously shown to function downstream of and be repressed by UNC-130 for axon guidance. Our studies uncovered a new function of UNC-130/FOXD in the C. elegans postembryonic mesoderm, and identify UNC-130 as a critical factor that integrates two independent spatial cues for the proper patterning and fate specification of the C. elegans postembryonic mesoderm. PMID- 29155047 TI - Novel mosaic variants in two patients with Cornelia de Lange syndrome. AB - Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder caused by mutations in genes that encode for either structural (SMC1A, SMC3, RAD21) or regulatory (NIPBL, HDAC8) subunits of the cohesin complex. NIPBL represents the major gene of the syndrome and heterozygous mutations can be identified in more than 65% of patients. Interestingly, large portions of these variants were described as somatic mosaicism and often escape standard molecular diagnostics using lymphocyte DNA. Here we discuss the role of somatic mosaicism in CdLS and describe two additional patients with NIPBL mosaicism detected by targeted gene panel or exome sequencing. In order to verify the next generation sequencing data, Sanger sequencing or pyrosequencing on DNA extracted from different tissues were applied. None of the pathogenic variants was originally detected by Sanger sequencing on blood DNA. Patient 1 displays an unusual combination of clinical features: he is cognitively only mildly affected, but shows severe limb reduction defects. Patient 2 presents with a moderate phenotype. Interestingly, Sanger sequencing analysis on fibroblast DNA of this patient did not detect the disease-causing variant previously observed on the same DNA sample by exome sequencing. Subsequent analyses could confirm the variants by Sanger sequencing on buccal mucosa DNA. Notably, this is the first report of a higher mutational load in buccal mucosa than in fibroblast cells of a CdLS patient. Detection of low-level mosaicism is of utmost importance for an accurate molecular diagnosis and a proper genetic counseling of patients with a clinical diagnosis of CdLS. Next-generation sequencing technologies greatly facilitate the detection of low-level mosaicism, which might otherwise remain undetected by conventional sequencing approaches. PMID- 29155048 TI - Telomere Diagnostics for Pancreatic Neoplasms and Cysts. AB - This commentary highlights the article by Hata et al that examines markers for assessing pancreatic neoplastic progression. PMID- 29155045 TI - Independent and interactive associations of negative affect, restraint, and impulsivity in relation to binge eating among women. AB - There is growing recognition that impulsivity may serve as an underlying risk factor for binge eating. In addition, the association of impulsivity with binge eating may be moderated by other affective and cognitive risk factors. This study examined independent and interactive associations of negative affect, dietary restraint, and facets of impulsivity with binge eating. A diverse sample of 566 undergraduate women completed online questionnaires of study variables. Results revealed a three-way interaction of negative affect, dietary restraint, and attentional impulsivity in relation to binge eating. Women who were high on each of these three variables reported the greatest levels of binge eating. In addition, a two-way interaction was found for negative affect and nonplanning impulsivity in relation to binge eating, such that nonplanning impulsivity strengthened the association between negative affect and binge eating. Attentional and nonplanning facets of impulsivity may function as an underlying trait-level risk factor interacts with affective and/or cognitive risk (e.g., negative affect, dietary restraint) factors to predict elevated binge eating. PMID- 29155049 TI - Is Tubulocystic Renal Cell Carcinoma Real?: Genomic Analysis Confirms the World Health Organization Classification. AB - This commentary highlights the article by Lawrie et al that validates that tubulocystic renal cell carcinoma is a distinct type of renal neoplasm. PMID- 29155050 TI - Electrophysiological parameters as biomarkers for psychiatry: Intra-individual variability and influencing factors. PMID- 29155051 TI - Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and Neurodegeneration in a model of Parkinson disease. AB - Accumulation of alpha-synuclein (alpha-syn) in the central nervous system (CNS) is a core feature of Parkinson disease (PD) that leads to activation of the innate immune system, production of inflammatory cytokines and chemokines, and subsequent neurodegeneration. Here, we used heterozygous reporter knock-in mice in which the first exons of the fractalkine receptor (CX3CR1) and of the C-C chemokine receptor type 2 (CCR2) are replaced with fluorescent reporters to study the role of resident microglia (CX3CR1+) and infiltrating peripheral monocytes (CCR2+), respectively, in the CNS. We used an alpha-syn mouse model induced by viral over-expression of alpha-syn. We find that in vivo, expression of full length human alpha-syn induces robust infiltration of pro-inflammatory CCR2+ peripheral monocytes into the substantia nigra. Genetic deletion of CCR2 prevents alpha-syn induced monocyte entry, attenuates MHCII expression and blocks the subsequent degeneration of dopaminergic neurons. These results demonstrate that extravasation of pro-inflammatory peripheral monocytes into the CNS plays a key role in neurodegeneration in this model of PD synucleinopathy, and suggest that peripheral monocytes may be a target of neuroprotective therapies for human PD. PMID- 29155053 TI - Alpha tocopherol loaded chitosan oleate nanoemulsions for wound healing. Evaluation on cell lines and ex vivo human biopsies, and stabilization in spray dried Trojan microparticles. AB - An amphiphilic chitosan salt, chitosan oleate (CS-OA), was previously proposed for the physical stabilization of lemongrass antimicrobial nanoemulsions (NE) through a mild spontaneous emulsification process. As both chitosan and oleic acid are described in the literature for their positive effects in wound healing, in the present study CS-OA has been proposed to encapsulate alpha tocopherol (alphaTph) in NEs aimed to skin wounds. A NE formulation was developed showing about 220 nm dimensions, 36% drug loading, and alphaTph concentration up to 1 mg/ml. Both CS-OA and alphaTph NE stimulated cell proliferation on keratinocytes and fibroblast cell cultures, and in ex vivo skin biopsies, suggesting the suitability of CS-OA and of the antioxidant agent for topical application in wound healing. alphaTph stability was further improved with respect of encapsulation, by spray drying the NE into a powder (up to about 90% alphaTph residual after 3 months). The spray drying process was optimized, to improve powder yield and alphaTph recovery, by a design of experiments approach. The powder obtained was easily re-suspended to deliver the NE and resulted able to completely release alphaTph. PMID- 29155054 TI - Hospital-acquired pneumonia in ICU. AB - The French Society of Anesthesia and Intensive Care Medicine and the French Society of Intensive Care edited guidelines focused on hospital-acquired pneumonia (HAP) in intensive care unit (ICU). The goal of 16 French-speaking experts was to produce a framework enabling an easier decision-making process for intensivists. The guidelines were related to 3 specific areas related to HAP (prevention, diagnosis and treatment) in 4 identified patient populations (COPD, neutropenia, postoperative and pediatric). The literature analysis and the formulation of the guidelines were conducted according to the Grade of Recommendation Assessment, Development and Evaluation methodology. An extensive literature research over the last 10 years was conducted based on publications indexed in PubMedTM and CochraneTM databases. HAP should be prevented by a standardized multimodal approach and the use of selective digestive decontamination in units where multidrug-resistant bacteria prevalence was below 20%. Diagnosis relies on clinical assessment and microbiological findings. Monotherapy, in the absence of risk factors for multidrug-resistant bacteria, non fermenting Gram negative bacilli and/or increased mortality (septic shock, organ failure), is strongly recommended. After microbiological documentation, it is recommended to reduce the spectrum and to prefer monotherapy for the antibiotic therapy of HAP, including for non-fermenting Gram-negative bacilli. PMID- 29155052 TI - Characterization of covalent modifications of HDL apoproteins by endogenous oxidized phospholipids. AB - High density lipoprotein (HDL) is cardioprotective, unless it is pathologically modified under oxidative stress. Covalent modifications of lipid-free apoA-I, the most abundant apoprotein in HDL, compromise its atheroprotective functions. HDL is enriched in oxidized phospholipids (oxPL) in vivo in oxidative stress. Furthermore, oxidized phospholipids can covalently modify HDL apoproteins. We have now carried out a systematic analysis of modifications of HDL apoproteins by endogenous oxPL. Human HDL or plasma were oxidized using a physiologically relevant MPO-H2O2-NO2- system or AIPH, or were exposed to synthetic oxPL. Protein adduction by oxPL was assessed using LC-MS/MS and MALDI-TOF MS. The pattern of HDL apoprotein modification by oxPL was independent of the oxidation systems used. ApoA-I and apoA-II were the major modification targets. OxPL with a gamma hydroxy (or oxo)-alkenal were mostly responsible for modifications, and the Michael adduct was the most abundant adduct. Histidines and lysines in helices 5 8 of apoA-I were highly susceptible to oxPL modifications, while lysines in helices 1, 2, 4 and 10 were resistant to modification by oxPL. In plasma exposed to oxidation or synthetic oxPL, oxPL modification was highly selective, and four histidines (H155, H162, H193 and H199) in helices 6-8 of apoA-I were the main modification target. H710 and H3613 in apoB-100 of LDL and K190 of human serum albumin were also modified by oxPL but to a lesser extent. Comparison of oxPL with short chain aldehyde HNE using MALDI-TOF MS demonstrated high selectivity and efficiency of oxPL in the modification of HDL apoproteins. These findings provide a novel insight into a potential mechanism of the loss of atheroprotective function of HDL in conditions of oxidative stress. PMID- 29155056 TI - Age influences the skin reaction pattern to mechanical stress and its repair level through skin care products. AB - Skin aging is associated with alterations of surface texture, sebum composition and immune response. Mechanical stress induces repair mechanisms, which may be dependent on the age and quality of the skin. The response to mechanical stress in young and aged individuals, their subjective opinion and the objective effectiveness of skin care products were evaluated by biophysical skin quality parameters (stratum corneum hydration, transepidermal water loss, skin pH, pigmentation and erythema) at baseline, 1, 6, 24h and 7days at the forearms of 2 groups of healthy volunteers, younger than 35 years (n=11) and older than 60 years (n=13). In addition, casual surface lipid composition was studied under the same conditions at the baseline and day 7 after mechanical stress induction. Evaluations were also performed in stressed skin areas treated daily with skin care products and the subjective opinion of the volunteers was additionally documented. The tested groups exhibited age-associated baseline skin functions as well as casual surface lipid composition and different reaction patterns to mechanical stress. Skin care was more effective in normalizing skin reaction to stress in the young than in the aged group. The subjective volunteer opinion correlated with the objective measurements. PMID- 29155058 TI - FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models. AB - The XPO1/CRM1 inhibitor selinexor (KPT-330), is currently being evaluated in multiple clinical trials as an anticancer agent. XPO1 participates in the nuclear export of FoxO-1, which we previously found to be decreased in platinum-resistant ovarian carcinoma. The aim of this study was to determine whether enriching FoxO 1 nuclear localization using selinexor would increase ovarian cancer cell sensitivity to cisplatin. Selinexor, as a single agent, displayed a striking antiproliferative effect in different ovarian carcinoma cell lines. A schedule dependent synergistic effect of selinexor in combination with cisplatin was found in cisplatin-sensitive IGROV-1, the combination efficacy being more evident in sensitive than in the resistant cells. In IGROV-1 cells, the combination was more effective when selinexor followed cisplatin exposure. A modulation of proteins involved in apoptosis (p53, Bax) and in cell cycle progression (p21WAF1) was found by Western blotting. Selinexor-treated cells exhibited enriched FoxO-1 nuclear staining. Knock-down experiments with RNA interference indicated that FOXO1-silenced cells displayed a reduced sensitivity to selinexor. FOXO1 silencing also tended to reduce the efficacy of the drug combination at selected cisplatin concentrations. Selinexor significantly inhibited tumor growth, induced FoxO-1 nuclear localization and improved the efficacy of cisplatin in IGROV-1 xenografts. Taken together, our results support FoxO-1 as one of the key factors promoting sensitivity towards selinexor and the synergistic interaction between cisplatin and selinexor in ovarian carcinoma cells with selected molecular backgrounds, highlighting the need for treatment regimens tailored to the molecular tumor features. PMID- 29155055 TI - Cell culture models of fatty acid overload: Problems and solutions. AB - High plasma levels of fatty acids occur in a variety of metabolic diseases. Cellular effects of fatty acid overload resulting in negative cellular responses (lipotoxicity) are often studied in vitro, in an attempt to understand mechanisms involved in these diseases. Fatty acids are poorly soluble, and thus usually studied when complexed to albumins such as bovine serum albumin (BSA). The conjugation of fatty acids to albumin requires care pertaining to preparation of the solutions, effective free fatty acid concentrations, use of different fatty acid species, types of BSA, appropriate controls and ensuring cellular fatty acid uptake. This review discusses lipotoxicity models, the potential problems encountered when using these cellular models, as well as practical solutions for difficulties encountered. PMID- 29155057 TI - Effects of different hypoxia degrees on endothelial cell cultures-Time course study. AB - INTRODUCTION: Exposure of the endothelial cells to hypoxia, the decrease in oxygen supply can trigger an endothelial response. This response is involved in inflammatory diseases, tumorigenesis, and also with the micro vascular damage associated with aging. The aim of our study was to determine the hypoxia/re oxygenation induced response in vitro, using human umbilical vein endothelial cells (HUVEC) cultures, at different time points with focus on cell viability, apoptosis oxidative stress and angiogenesis stimulation. MATERIALS AND METHODS: Cells were exposed to 10%, 5% or 0% O2 for 6h, 12h, and 24h. Viability was measured through colorimetry, apoptosis - annexin V-FITC staining, DNA lesions (gammaH2AX), endothelial activation (sICAM1), angiogenesis (HIF1alpha), oxidative stress (malondialdehyde, superoxidismutase and NFkappaB activation) were determined by ELISA, Western Blot and spectrophotometry. RESULTS AND DISCUSSION: Hypoxia decreased viability, increased apoptosis, oxidative stress, endothelial activation and angiogenesis, depending on O2 concentration and time exposure. Short exposures to 5% and 10% O2, efficiently activated anti-apoptotic mechanisms through NFkappaB activation, HIF1alpha and gammaH2AX related DNA damage repair pathways. However, severe hypoxia and longer exposures to mild hypoxia induced high oxidative stress related damage and eventually led to apoptosis, through strong increases of HIF1alpha and accumulating DNA lesions. PMID- 29155059 TI - Microbial production of branched-chain dicarboxylate 2-methylsuccinic acid via enoate reductase-mediated bioreduction. AB - 2-Methylsuccinic acid (2-MSA) is a C5 branched-chain dicarboxylate that serves as an attractive synthon for the synthesis of polymers with extensive applications in coatings, cosmetic solvents and bioplastics. However, the lack of natural pathways for 2-MSA biosynthesis has limited its application as a promising bio replacement. Herein, we conceived a non-natural three-step biosynthetic route for 2-MSA, via employing the citramalate pathway in combination with enoate reductase mediated bioreduction of the pathway intermediate citraconate. First, over expression of codon-optimized citramalate synthase variant CimA* from Methanococcus jannaschii, endogenous isopropylmalate isomerase EcLeuCD and enoate reductase YqjM from Bacillus subtilis allowed the production of 2-MSA in Escherichia coli for the first time, with a titer of 0.35g/L in shake flask experiments. Subsequent screening of YqjM-like enoate reductases of different bacterial origins enabled identification and characterization of a new NAD(P)H dependent enoate reductase KpnER from Klebsiella pneumoniae, which exhibited higher activity towards citraconate than YqjM. Incorporation of KpnER into the 2 MSA biosynthetic pathway led to 2-MSA production improvement to a titer of 0.96g/L in aerobic condition. Subsequent optimizations including cofactor regeneration, microaerobic cultivation and host strain engineering, boosted 2-MSA titer to 3.61g/L with a molar yield of 0.36 in shake flask experiments. This work established a promising platform for 2-MSA bioproduction, which enabled the highest titer of 2-MSA production in microbial hosts so far. PMID- 29155060 TI - Controlling cell-free metabolism through physiochemical perturbations. AB - Building biosynthetic pathways and engineering metabolic reactions in cells can be time-consuming due to complexities in cellular metabolism. These complexities often convolute the combinatorial testing of biosynthetic pathway designs needed to define an optimal biosynthetic system. To simplify the optimization of biosynthetic systems, we recently reported a new cell-free framework for pathway construction and testing. In this framework, multiple crude-cell extracts are selectively enriched with individual pathway enzymes, which are then mixed to construct full biosynthetic pathways on the time scale of a day. This rapid approach to building pathways aids in the study of metabolic pathway performance by providing a unique freedom of design to modify and control biological systems for both fundamental and applied biotechnology. The goal of this work was to demonstrate the ability to probe biosynthetic pathway performance in our cell free framework by perturbing physiochemical conditions, using n-butanol synthesis as a model. We carried out three unique case studies. First, we demonstrated the power of our cell-free approach to maximize biosynthesis yields by mapping physiochemical landscapes using a robotic liquid-handler. This allowed us to determine that NAD and CoA are the most important factors that govern cell-free n butanol metabolism. Second, we compared metabolic profile differences between two different approaches for building pathways from enriched lysates, heterologous expression and cell-free protein synthesis. We discover that phosphate from PEP utilization, along with other physiochemical reagents, during cell-free protein synthesis-coupled, crude-lysate metabolic system operation inhibits optimal cell free n-butanol metabolism. Third, we show that non-phosphorylated secondary energy substrates can be used to fuel cell-free protein synthesis and n-butanol biosynthesis. Taken together, our work highlights the ease of using cell-free systems to explore physiochemical perturbations and suggests the need for a more controllable, multi-step, separated cell-free framework for future pathway prototyping and enzyme discovery efforts. PMID- 29155061 TI - Increasing oxygen availability for improving poly(3-hydroxybutyrate) production by Halomonas. AB - Technologies enabling high-cell-density growth are required for economical industrial production of most biotechnological products. However, the key factor limiting cell density in bioreactors is the availability of oxygen during the late phases of fermentation. Although the expression of bacterial Vitreoscilla hemoglobin (VHb) is useful for enhanced oxygen availability, bacterial cell membrane makes efficient hemoglobin-oxygen contact a challenge. On the other hand, periplasmic spaces of Gram-negative microorganisms offer an excellent compartment for the intermittent storage of hemoglobin-bound oxygen. In this study, the cell growth was increased by a remarkable 100% using the twin-arginine translocase (Tat) pathway to export active VHb into the periplasm of Escherichia coli, Halomonas bluephagenesis TD01 and H. campaniensis LS21. Furthermore, eight low-oxygen-inducible vgb promoters were constructed in tandem to become a strong promoter cassette termed P8vgb, which better induces expression of both gene vgb encoding VHb and the PHB synthesis operon microaerobically. Both the P8vgb and VHb performed excellently in E. coli and two Halomonas spp., demonstrating their universal applicability for various organisms. PMID- 29155062 TI - Fusion, Failure, Fatality: Long-term Outcomes After Surgical Versus Nonoperative Management of Type II Odontoid Fracture in Octogenarians. AB - BACKGROUND: Type II odontoid fracture is a highly morbid injury among octogenarians, with 41% 1-year mortality. Our objective was to assess long-term fusion, complication, and survival rates. METHODS: Retrospective review of prospective trauma registry and blinded review of follow-up radiographs. RESULTS: Follow-up cohort included 94 nonoperative and 17 operative patients (median, 52 and 79 months). The operative group had significantly higher rates of repeated surgery for primary treatment failure or complication (1% vs. 18%; P = 0.01) and dysphagia, aspiration events, or tracheostomy (29% vs. 78%, P = 0.002; 6% vs. 30%, P = 0.04; 1% vs. 18%, P = 0.01). Three-year all-cause mortalities were 71% and 76%, respectively (P = 0.78). No delayed myelopathy was observed. One-year postinjury radiographs were available for 13 and 6 patients in the nonoperative and operative groups (P = 0.9); bony union was observed in 3 and 5 patients (23% vs. 83%; P = 0.04). Retrolisthesis greater than 2 mm was observed in 2 and 1 patients (15% vs. 17%; P = 1.0). Two patients in the operative group underwent repeated surgery for primary treatment failure. Dysphagia was diagnosed in 3 and 5 operative patients (23% vs. 83%; P = 0.04), whereas aspiration events occurred in 0 and 3 patients (0% vs. 50%; P = 0.02). Three-year mortalities in this cohort were 38% and 67% (P = 0.35). CONCLUSIONS: Radiographic union is significantly associated with operative management, but the corresponding clinical benefit is unclear. Complications were significantly more common after surgery. Long-term survival in octogenarians following type II odontoid fracture is poor, independent of management. Frequent complications without a proven survival benefit suggest that most patients are better managed conservatively. PMID- 29155063 TI - Robotic-Guided Bihippocampal and Biparahippocampal Depth Placement for Responsive Neurostimulation in Bitemporal Lobe Epilepsy. AB - BACKGROUND: Patients with bitemporal lobe epilepsy are generally not considered for surgical resection. Fortunately, responsive neurostimulation provides another avenue for the management of this challenging disease process. In conjunction with our epileptologist, we consider responsive neurostimulation for patients who have clinical features of temporal lobe epilepsy without clear localization on imaging and stereoelectroencephalography. METHODS: Here we describe our technique for implanting a responsive neurostimulator (NeuroPace, NeuroPace Inc., Mountain View, California) with depth electrodes monitoring the hippocampus and parahippocampus using stereotactic robotic guidance (ROSA, Medtech SA, Montpeillier, France). RESULTS: We have used this technique with 5 patients without morbidity. Four of 5 patients have received clinical benefit (Engel classification I-III). Promisingly, long-term seizure monitoring with use of the NeuroPace system has suggested lateralizing information on 3 of these patients that was not apparent on previous invasive monitoring. CONCLUSIONS: Robotically implanted responsive neurostimulation is a safe and effective treatment for bitemporal epilepsy and can possibly lead to valuable diagnostic information to guide future surgical management in patients who previously were not considered candidates for resective or ablative surgery. PMID- 29155064 TI - Enterprise Deployment Through PulseRider To Treat Anterior Communicating Artery Aneurysm Recurrence. AB - BACKGROUND: PulseRider (Pulsar Vascular, Los Gatos, California, USA) is a new endovascular device designed to treat wide-neck bifurcation intracranial aneurysms. Deployment of a stent through a PulseRider to treat an aneurysm's recurrence has never been described before. CASE DESCRIPTION: We report the case of a 55-year-old man who underwent coiling of an 8-mm anterior communicating artery aneurysm with assistance of a PulseRider neck reconstruction device. The 6 month digital subtraction angiography control showed aneurysm recurrence, so we deployed an Enterprise 2 closed-cell stent (Codman, Miami Lakes, Florida, USA) in the A1-A2 segment passing across the previously implanted PulseRider. Enterprise correctly expanded and allowed for adequate coiling of the aneurysm. CONCLUSION: An Enterprise stent can be safely opened through a PulseRider in order to treat aneurysm recurrence. PMID- 29155065 TI - Intradural-Extramedullary Cervical Cord Lipoma: Case Report and Literature Review. AB - BACKGROUND: Spinal lipomas are generally thought to occur as a result of failed primary neurulation. Failed primary neurulation allows invasion of mesenchymal tissue of mesodermic origin into the neural structure, leading to the formation of a spinal lipoma. Despite most spinal lipomas being regarded as the result of failed primary neurulation, some confusion in terms of the embryogenesis of spinal lipomas remains. Recently, a novel classification of spinal lipomas based on embryonic changes seen during primary and secondary neurulation was has been proposed. CASE DESCRIPTION: We present a case of an intradural-extramedullary spinal cord lipoma, associated with a subjacent subcutaneous lipoma at the cervicothoracic region. The patient presented with worsening neurologic symptoms, indicating ongoing cervical myelopathy. A subtotal resection along with posterior cervical stabilization was achieved, with mild improvement of neurologic symptoms. Clinical, pathologic, and radiologic records are reviewed. CONCLUSIONS: To the best of our knowledge, this is the first described case of a spinal cord lipoma with at such a location, one that cannot be fully categorized within the newly proposed classification system. PMID- 29155067 TI - Contrasting roles of fungal siderophores in maintaining iron homeostasis in Epichloe festucae. AB - The symbiosis between Epichloe festucae and its host perennial ryegrass (Lolium perenne) is a model system for mutualistic interactions in which the fungal endophyte grows between plant shoot cells and acquires host nutrients to survive. E. festucae synthesises the siderophore epichloenin A (EA) via SidN, a non ribosomal peptide synthetase (NRPS). EA is involved in the acquisition of iron, an essential micronutrient, as part of the process of maintaining a stable symbiotic interaction. Here, we mutated a different NRPS gene sidC and showed that it is required for production of a second siderophore ferricrocin (FC). Furthermore mutations in sidA, encoding an l-ornithine N5-monooxygenase, abolished both EA and FC production. Axenic growth phenotypes of the siderophore mutants were altered relative to wild-type (WT) providing insights into the roles of E. festucae siderophores in iron trafficking and consequently in growth and morphogenesis. During iron-limitation, EA is the predominant siderophore and in addition to its role in iron acquisition it appears to play roles in intracellular iron sequestration and oxidative stress tolerance. FC in contrast is exclusively located intracellularly and is the dominant siderophore under conditions of iron sufficiency when it is likely to have roles in iron storage and iron transport. Intriguingly, EA acts to promote but may also moderate E. festucae growth (depending on the amount of available iron). We therefore hypothesise that coordinated cellular iron sequestration through FC and EA may be one of the mechanisms that E. festucae employs to manage and restrain its growth in response to iron fluxes and ultimately persist as a controlled symbiont. PMID- 29155068 TI - A noncanonical poly(A) RNA polymerase gene affects morphology in Phoma medicaginis. AB - Phoma medicaginis (syn. Ascochyta medicaginicola Qchen & L. Cai) causes spring black stem and leaf spot, an important disease of alfalfa and annual medics. P. medicaginis forms uninucleate conidia in melanized pycnidia and is genetically tractable using Agrobacterium mediated transformation (ATMT), resulting in random integration of T-DNA that occasionally generates pycnidial mutants. The T-DNA tagged mutant, P265 displayed smaller pycnidia and more aerial hyphae than the wild type. A single T-DNA disrupted a putative noncanonical poly(A) RNA polymerase gene, Pmncpap1, which in yeast interacts with ribonucleotide reductase (RNR). As in yeast mutants, P265 showed sensitivity to hydroxyurea (HU), a RNR inhibitor. To characterize the role of Pmncpap1, targeted DeltaPmncpap1 mutants were created using a hygromycin selectable marker flanked by 1 Kbp regions of Pmncpap1. DeltaPmncpap1 mutants possessed similar morphological features to those of P265. The plasmid for rescue of PmncPAP1, pCAM-Nat1 (nourseothricin selection) was constructed and used to introduce full-length PmncPAP1 into mutants. Rescued P265 showed partial recovery of wild type and the original T-DNA was lost due to homologous integration. To our knowledge, this is the first ncPAP to be examined in a filamentous fungus. PMID- 29155066 TI - Unruptured Versus Ruptured AVMs: Outcome Analysis from a Multicentric Consecutive Series of 545 Surgically Treated Cases. AB - BACKGROUND: Recent literature strongly challenged indications to perform preventive surgery in unruptured arteriovenous malformation (AVM) claiming that invasive AVM treatment is associated with a significant risk of complications and thus conservative management may be a preferable alternative in many patients. On the other hand, the recent improvement of surgical instrumentation and treatment strategies (both surgical and interventional) yielded better outcomes than those achieved only a decade ago. Therefore, even among specialists, a wide variety of opinions, concerning the treatment of unruptured AVM, can be found. METHODS: This multicenter retrospective study analyzes a consecutive series of 545 surgically treated AVMs in 10 different hospitals in Italy. RESULTS: Patients with AVMs treated after hemorrhage had an unfavorable (modified Rankin Scale score >1) outcome in more than one third (37.69%) of the cases. Conversely, with proper indications, unruptured AVMs treated preventively have a good outcome in 93.8% of cases, increasing to 95.7%, with no death, if only Spetzler-Martin grades 1-3 are considered (P < 0.05). Outcomes on discharge significantly (P < 0.05) improve at 6 months with the disappearance of many of the initial neurologic deficits that turn out to be transient. CONCLUSIONS: In unruptured low-risk AVMs (Spetzler Martin grades 1-3), over time, the risk of surgery-associated neurologic deficits becomes lower than that linked to spontaneous hemorrhage, with a crossover point at 6.5 years. Because the average bleeding age is less than 45 years, preventive surgery can be advocated to safeguard the patient and overcome the risks associated with the natural history of AVMs. PMID- 29155069 TI - Antiviral therapy improves survival in patients with HBV infection and intrahepatic cholangiocarcinoma undergoing liver resection. AB - BACKGROUND & AIMS: The impact of hepatitis B virus (HBV) infection on outcomes after resection of intrahepatic cholangiocarcinoma (ICC) has not been reported. The aim of this study was to examine the impact of antiviral therapy on survival outcomes after liver resection for patients with ICC and underlying HBV infection. METHODS: Data on 928 patients with ICC and HBV infection who underwent liver resection at two medical centers between 2006 and 2011 were analyzed. Data on viral reactivation, tumor recurrence, cancer-specific survival (CSS) and overall survival (OS) were obtained. Survival rates were analyzed using the time dependent Cox regression model adjusted for potential covariates. RESULTS: Postoperative viral reactivation occurred in 3.3%, 8.3% and 15.7% of patients who received preoperative antiviral therapy, who did not receive preoperative antiviral therapy with a low, or a high HBV-DNA level (< or >=2,000 IU/ml), respectively (p <0.001). A high viral level and viral reactivation were independent risk factors of recurrence (hazard ratio [HR] 1.22 and 1.34), CSS (HR 1.36 and 1.46) and OS (HR1.23 and 1.36). Five-year recurrence, CSS and OS were better in patients who received antiviral therapy (70.5%, 46.9% and 43.0%) compared with patients who did not receive antiviral therapy and had a high viral level (86.5%, 20.9% and 20.5%, all p <0.001), respectively. The differences in recurrence, CSS and OS were minimal compared with no-antiviral therapy patients with a low viral level (71.7%, 35.5% and 33.5%, p = 0.057, 0.051 and 0.060, respectively). Compared to patients with a high viral level who received no antiviral therapy, patients who initiated antiviral therapy either before or after surgery had better long-term outcomes (HR 0.44 and 0.54 for recurrence; 0.38 and 0.57 for CSS; 0.46 and 0.54 for OS, respectively). CONCLUSIONS: Viral reactivation was associated with worse prognoses after liver resection for HBV infected patients with ICC. Antiviral therapy decreased viral reactivation and prolonged long-term survival for patients with ICC and a high viral level. LAY SUMMARY: Postoperative hepatitis B virus reactivation was associated with an increased complication rate and a decreased survival rate after liver resection in patients with ICC and hepatitis B virus infection. Antiviral therapy before liver resection reduced the risk of postoperative viral reactivation. Both pre- and postoperative antiviral therapy was effective in prolonging patient survival. PMID- 29155070 TI - Cytosolic aminoacyl-tRNA synthetases: Unanticipated relocations for unexpected functions. AB - Prokaryotic and eukaryotic cytosolic aminoacyl-tRNA synthetases (aaRSs) are essentially known for their conventional function of generating the full set of aminoacyl-tRNA species that are needed to incorporate each organism's repertoire of genetically-encoded amino acids during ribosomal translation of messenger RNAs. However, bacterial and eukaryotic cytosolic aaRSs have been shown to exhibit other essential nonconventional functions. Here we review all the subcellular compartments that prokaryotic and eukaryotic cytosolic aaRSs can reach to exert either a conventional or nontranslational role. We describe the physiological and stress conditions, the mechanisms and the signaling pathways that trigger their relocation and the new functions associated with these relocating cytosolic aaRS. Finally, given that these relocating pools of cytosolic aaRSs participate to a wide range of cellular pathways beyond translation, but equally important for cellular homeostasis, we mention some of the pathologies and diseases associated with the dis-regulation or malfunctioning of these nontranslational functions. PMID- 29155071 TI - Structural rearrangements of the RNA polymerase III machinery during tRNA transcription initiation. AB - RNA polymerase III catalyses the synthesis of tRNAs in eukaryotic organisms. Through combined biochemical and structural characterisation, multiple auxiliary factors have been identified alongside RNA Polymerase III as critical in both facilitating and regulating transcription. Together, this machinery forms dynamic multi-protein complexes at tRNA genes which are required for polymerase recruitment, DNA opening and initiation and elongation of the tRNA transcripts. Central to the function of these complexes is their ability to undergo multiple conformational changes and rearrangements that regulate each step. Here, we discuss the available biochemical and structural data on the structural plasticity of multi-protein complexes involved in RNA Polymerase III transcriptional initiation and facilitated re-initiation during tRNA synthesis. Increasingly, structural information is becoming available for RNA polymerase III and its functional complexes, allowing for a deeper understanding of tRNA transcriptional initiation. This article is part of a Special Issue entitled: SI: Regulation of tRNA synthesis and modification in physiological conditions and disease edited by Dr. Boguta Magdalena. PMID- 29155072 TI - A protocol to study ex vivo mouse working heart at human-like heart rate. AB - Genetically modified mice are widely used as experimental models to study human heart function and diseases. However, the fast rate of normal mouse heart at 400 600bpm limits its capacity of assessing kinetic parameters that are important for the physiology and pathophysiology of human heart that beats at a much slower rate (75-180bpm). To extend the value of mouse models, we established a protocol to study ex vivo mouse working hearts at a human-like heart rate. In the presence of 300MUM lidocaine to lower pacemaker and conductive activities and prevent arrhythmia, a stable rate of 120-130bpm at 37 degrees C is achieved for ex vivo mouse working hearts. The negative effects of decreased heart rate on force frequency dependence and lidocaine as a myocardial depressant on intracellular calcium can be compensated by using a higher but still physiological level of calcium (2.75mM) in the perfusion media. Multiple parameters were studied to compare the function at the human-like heart rate with that of ex vivo mouse working hearts at the standard rate of 480bpm. The results showed that the conditions for slower heart rate in the presence of 300MUM lidocaine did not have depressing effect on left ventricular pressure development, systolic and diastolic velocities and stroke volume with maintained positive inotropic and lusitropic responses to beta-adrenergic stimulation. Compared with that at 480bpm, the human-like heart rate increased ventricular filling and end diastolic volume with enhanced Frank-Starling responses. Coronary perfusion was increased from longer relaxation time and interval between beats whereas cardiac efficiency was significantly improved. Although the intrinsic differences between mouse and human heart remain, this methodology for ex vivo mouse hearts to work at human like heart rate extends the value of using genetically modified mouse models to study cardiac function and human heart diseases. PMID- 29155073 TI - Dynamics of HPV viral loads reflect the treatment effect of photodynamic therapy in genital warts. AB - BACKGROUND: Photodynamic therapy (PDT) has demonstrated good clinical cure rates and low recurrence rates in the treatment of genital warts. Human papillomavirus (HPV) genotypes and viral load assays can reflect the status of persistent or latent infection and serve as a predictor of infection clearance. METHODS: Specimens from 41 patients with HPV infection were obtained, and the HPV genotypes and viral load were analyzed using real-time polymerase chain reaction (PCR) assays. Traditional treatment, such as radiofrequency, microwave, or surgical therapy, was used to remove the visible lesions, and then PDT treatment was performed every week. HPV DNA testing was performed at every patient visit and the frequency of PDT treatment was determined by changes in HPV viral loads. RESULTS: HPV viral loads decreased significantly after PDT treatment. There were significant differences in HPV viral loads between pretherapy and three or six rounds of PDT treatment. Significant differences were also observed between single and multiple type HPV infection after six rounds of PDT treatment. Patients with single type HPV infection had significantly higher rates of negative HPV DNA test results, as compared with patients with multiple infections after six rounds of PDT treatment; however, there was no difference in recurrence rates between the two groups. CONCLUSIONS: Dynamic monitoring of HPV genotypes and viral loads can be used to guide PDT treatment and indicate PDT treatment efficacy in eliminating HPV. PMID- 29155074 TI - Photodynamic diagnosis of parathyroid glands with nano-stealth aminolevulinic acid liposomes. AB - : Background The use of ALA to identify the parathyroid glands had been investigated both experimentally and clinically with promising results but the side effects from the systemic use of this photosensitizer reduce its widespread in clinical use. The aim of this study is to test the formulation of ALA in nano stealth liposomes for better photodiagnosis of parathyroid glands intraoperatively with less ALA dose. MATERIALS AND METHODS: Preparation of ALA nanovesicles and in vitro characterization for the drug encapsulation percentage, vesicle size and Zeta potential then the study of nanovesicles stability and in vitro drug release profile was done. The study compared nano-stealth liposomes and nano-liposomes with the free ALA solution, intraperitoneal administration of these different ALA formulations in rats and observing the ability to identify parathyroids intraoperatively and evaluation of fluorescence differences between these groups. RESULTS AND CONCLUSION: Stealth liposomes were insignificantly higher in drug encapsulation%, in vitro drug release and zeta potential compared to conventional liposomes. Additionally, they needed less time for the start of the photosensitization and recorded the highest signal after spectrometry compared to the other two preparations. These data provide a new evidence of the potentiality of ALA-stealth Liposomes for identification of PTGs intraoperatively and could lead to propose a non-invasive procedure with reduced postoperative side effects. PMID- 29155075 TI - Asymmetric distribution of CRUMBS polarity complex proteins from compacted 8-cell to blastocyst stage during mouse preimplantation development. AB - During mouse preimplantation development, blastomeres are equipotent until polarity establishment at compacted 8-cell stage. The intrinsic nature of polarity is the asymmetric distribution of polarity proteins between inside and outside blastomeres along the direction of apical-basal axis. This study investigated the early developmental temporal and spatial expression of the main CRUMBS polarity complex proteins in the mouse preimplantation embryo. We observed that Crb3, Pals1, Patj and Mpdz are transcribed in the mouse preimplantation embryo. However, the asymmetric distribution of these polarity proteins is not established until the compacted 8-cell stage. From compaction and thereafter, CRB3 and PALS1 are progressively enriched in the apical membrane, while PATJ and MPDZ are discretely localized at both tight junctions and the apical membrane adjacent to tight junctions. These temporal and spatial distribution patterns suggest that CRUMBS polarity complex might be involved in the cell polarity establishment in the early mouse embryo and reinforce the viewpoint that developmentally spatial asymmetries are first set up at the compaction stage. The present study provides a foundation for further investigation on the functions of CRUMBS polarity complex in trophectoderm specification and blastocyst morphogenesis. PMID- 29155076 TI - Genotoxicity and 28-day oral toxicity studies of a functional food mixture containing maltodextrin, white kidney bean extract, mulberry leaf extract, and niacin-bound chromium complex. AB - Steady-fiber granule (SFG) is a functional food mixture that is composed of four major ingredients, resistant maltodextrin, white kidney bean (Phaseolus vulgaris) extract, mulberry leaf (Morus alba L.) extract, and niacin-bound chromium complex. This study focused on determining the safety of SFG. Genotoxicity and 28 day oral toxicity were evaluated. SFG did not induce mutagenicity in the bacterial reverse mutation assay using five Salmonella typhimurium strains (TA98, TA100, TA102, TA1535, and TA1537) in the presence or absence of metabolic activation (S9 system). SFG also did not induce clastogenic effects in Chinese hamster ovary cells with or without S9 treatment. Similarly, SFG did not induce genotoxicity in a micronucleus test conducted with mice. A dose-dependent 28-day oral toxicity assessment of SFG for rats revealed no significant effects on mortality, body weight, selected organ weights, and behavior. Evaluations of hematology, clinical biochemistry, and histopathology showed no adverse effects in rats treated with SFG. These results suggest that SFG has no significant mutagenic or toxic properties, and the no observed adverse effect level of SFG was defined as at least 5000 mg/kg/day orally for 28 days for male and female rats. PMID- 29155077 TI - Subchronic oral toxicity study of Korean red ginseng extract in Sprague-Dawley rats with a 4-week recovery period. AB - Ginseng is a major herbal remedy used in Asian countries for thousands of years and known to restore and enhance vital energy. Korean red ginseng, which is processed by steaming and drying fresh Panax ginseng, is most popular and contains unique ginsenosides, which have anticancer and anti-inflammatory properties. The present study was carried out to evaluate the repeated oral dose toxicity of Korean red ginseng extract. The test article was administered orally once a day to male and female Sprague-Dawley rats at dose levels of 0, 500, 1000, or 2000 mg/kg/day for 13 consecutive weeks (15 animals/sex/group in the vehicle control and 2000 mg/kg/day groups, and 10 animals/sex/group in the 500 and 1000 mg/kg/day groups). Ten animals per group were sacrificed at the end of the 13 week treatment period, and the remaining rats were sacrificed after a 4-week recovery period. Administration of Korean red ginseng extract did not result in any toxicologically significant changes in mortality, body weight, food consumption, ophthalmoscopy, hematology, serum biochemistry, gross pathological findings, absolute/relative organ weights, or histopathology. It was established that the no observed adverse effect level (NOAEL) of the test article was 2000 mg/kg/day for both sexes in this study. PMID- 29155078 TI - Radial asymmetries in population receptive field size and cortical magnification factor in early visual cortex. AB - Human visual cortex does not represent the whole visual field with the same detail. Changes in receptive field size, population receptive field (pRF) size and cortical magnification factor (CMF) with eccentricity are well established, and associated with changes in visual acuity with eccentricity. Visual acuity also changes across polar angle. However, it remains unclear how RF size, pRF size and CMF change across polar angle. Here, we examine differences in pRF size and CMF across polar angle in V1, V2 and V3 using pRF modeling of human fMRI data. In these visual field maps, we find smaller pRFs and larger CMFs in horizontal (left and right) than vertical (upper and lower) visual field quadrants. Differences increase with eccentricity, approximately in proportion to average pRF size and CMF. Similarly, we find larger CMFs in the lower than upper quadrant, and again differences increase with eccentricity. However, pRF size differences between lower and upper quadrants change direction with eccentricity. Finally, we find slightly smaller pRFs in the left than right quadrants of V2 and V3, though this difference is very small, and we find no differences in V1 and no differences in CMF. Moreover, differences in pRF size and CMF vary gradually with polar angle and are not limited to the meridians or visual field map discontinuities. PRF size and CMF differences do not consistently follow patterns of cortical curvature, despite the link between cortical curvature and polar angle in V1. Thus, the early human visual cortex has a radially asymmetric representation of the visual field. These asymmetries may underlie consistent reports of asymmetries in perceptual abilities. PMID- 29155079 TI - Analyzing EEG and MEG signals recorded during tES, a reply. AB - Transcranial Electric Stimulation (tES) is a widely used non-invasive brain stimulation technique. However, strong stimulation artifacts complicate the investigation of neural activity with EEG or MEG during tES. Thus, studying brain signals during tES requires detailed knowledge about the properties of these artifacts. Recently, we characterized the phase- and amplitude-relationship between tES stimulation currents and tES artifacts in EEG and MEG and provided a mathematical model of these artifacts (Noury and Siegel, 2017, and Noury et al., 2016, respectively). Among several other features, we showed that, independent of the stimulation current, the amplitude of tES artifacts is modulated time locked to heartbeat and respiration. In response to our work, a recent paper (Neuling et al., 2017) raised several points concerning the employed stimulation device and methodology. Here, we discuss these points, explain potential misunderstandings, and show that none of the raised concerns are applicable to our results. Furthermore, we explain in detail the physics underlying tES artifacts, and discuss several approaches how to study brain function during tES in the presence of residual artifacts. PMID- 29155080 TI - A comprehensive analysis of resting state fMRI measures to classify individual patients with Alzheimer's disease. AB - Alzheimer's disease (AD) patients show altered patterns of functional connectivity (FC) on resting state functional magnetic resonance imaging (RSfMRI) scans. It is yet unclear which RSfMRI measures are most informative for the individual classification of AD patients. We investigated this using RSfMRI scans from 77 AD patients (MMSE = 20.4 +/- 4.5) and 173 controls (MMSE = 27.5 +/- 1.8). We calculated i) FC matrices between resting state components as obtained with independent component analysis (ICA), ii) the dynamics of these FC matrices using a sliding window approach, iii) the graph properties (e.g., connection degree, and clustering coefficient) of the FC matrices, and iv) we distinguished five FC states and administered how long each subject resided in each of these five states. Furthermore, for each voxel we calculated v) FC with 10 resting state networks using dual regression, vi) FC with the hippocampus, vii) eigenvector centrality, and viii) the amplitude of low frequency fluctuations (ALFF). These eight measures were used separately as predictors in an elastic net logistic regression, and combined in a group lasso logistic regression model. We calculated the area under the receiver operating characteristic curve plots (AUC) to determine classification performance. The AUC values ranged between 0.51 and 0.84 and the highest were found for the FC matrices (0.82), FC dynamics (0.84) and ALFF (0.82). The combination of all measures resulted in an AUC of 0.85. We show that it is possible to obtain moderate to good AD classification using RSfMRI scans. FC matrices, FC dynamics and ALFF are most discriminative and the combination of all the resting state measures improves classification accuracy slightly. PMID- 29155081 TI - Population receptive field (pRF) measurements of chromatic responses in human visual cortex using fMRI. AB - The spatial sensitivity of the human visual system depends on stimulus color: achromatic gratings can be resolved at relatively high spatial frequencies while sensitivity to isoluminant color contrast tends to be more low-pass. Models of early spatial vision often assume that the receptive field size of pattern sensitive neurons is correlated with their spatial frequency sensitivity - larger receptive fields are typically associated with lower optimal spatial frequency. A strong prediction of this model is that neurons coding isoluminant chromatic patterns should have, on average, a larger receptive field size than neurons sensitive to achromatic patterns. Here, we test this assumption using functional magnetic resonance imaging (fMRI). We show that while spatial frequency sensitivity depends on chromaticity in the manner predicted by behavioral measurements, population receptive field (pRF) size measurements show no such dependency. At any given eccentricity, the mean pRF size for neuronal populations driven by luminance, opponent red/green and S-cone isolating contrast, are identical. Changes in pRF size (for example, an increase with eccentricity and visual area hierarchy) are also identical across the three chromatic conditions. These results suggest that fMRI measurements of receptive field size and spatial resolution can be decoupled under some circumstances - potentially reflecting a fundamental dissociation between these parameters at the level of neuronal populations. PMID- 29155082 TI - Association of gastric intestinal metaplasia and East Asian ethnicity with the risk of gastric adenocarcinoma in a U.S. population. AB - BACKGROUND AND AIMS: Although the incidence of gastric cancer is higher than that of esophageal cancer in the United States, no screening or surveillance guidelines exist. The aim of this study is to evaluate the association between gastric intestinal metaplasia and the risk of gastric cancer in a U.S. tertiary care system with a large immigrant population. METHODS: This is a retrospective case-control study with cases of biopsy-proven gastric cancer matched (by age and gender) to controls without gastric cancer who had undergone EGD. The presence of gastric intestinal metaplasia was ascertained from pathology reports. Other potential risk factors for gastric cancer were abstracted from medical records as follows: country of origin, Helicobacter pylori infection, family history of gastric cancer, alcohol consumption, smoking, and history of partial gastrectomy (Billroth I or II). Conditional logistic regression was used to identify independent risk factors for gastric cancer. RESULTS: One hundred fifty-two cases of gastric cancer were compared with 456 age- and gender-matched controls. The mean age was 66 years, and 57% were male. Multivariable analysis identified 2 significant predictors of gastric cancer: the presence of gastric intestinal metaplasia (odds ratio [OR], 9.3; 95% confidence interval [CI], 4.5-18.9; P < .001) and East Asian ethnicity (OR, 15.9; 95% CI, 5.8-43.6; P < .001). CONCLUSION: The presence of gastric intestinal metaplasia on endoscopy and East Asian ethnicity were significant risk factors for gastric cancer. Screening East Asian immigrants and surveying patients with gastric intestinal metaplasia may improve the rates of early detection of gastric cancer in the United States. PMID- 29155083 TI - TbVps15 is required for vesicular transport and cytokinesis in Trypanosoma brucei. AB - The class III phosphatidylinositol 3-kinase (PI3K) Vps34 is an important regulator of key cellular functions, including cell growth, survival, intracellular trafficking, autophagy and nutrient sensing. In yeast, Vps34 is associated with the putative serine/threonine protein kinase Vps15, however, its role in signaling has not been deeply evaluated. Here, we have identified the Vps15 orthologue in Trypanosoma brucei, named TbVps15. Knockdown of TbVps15 expression by interference RNA resulted in inhibition of cell growth and blockage of cytokinesis. Scanning electron microcopy revealed a variety of morphological abnormalities, with enlarged parasites and dividing cells that often exhibited a detached flagellum. Transmission electron microscopy analysis of TbVps15 RNAi cells showed an increase in intracellular vacuoles of the endomembrane system and some cells displayed an enlargement of the flagellar pocket, a common feature of cells defective in endocytosis. Moreover, uptake of dextran, transferrin and Concanavalin A was impaired. Finally, TbVps15 downregulation affected the PI3K activity, supporting the hypothesis that TbVps15 and TbVps34 form a complex as occurs in other organisms. In summary, we propose that TbVps15 has a role in the maintenance of cytokinesis, endocytosis and intracellular trafficking in T. brucei. PMID- 29155084 TI - Anti-inflammatory, antinociceptive and antioxidant properties of Schinopsis brasiliensis bark. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Schinopsis brasiliensis is a native plant from Brazil, popularly used in folk medicine to relieve pain and treat inflammation. This study evaluated the antinociceptive and anti-inflammatory activities and antioxidant properties of the hydroethanol extract (HEE) and ethyl acetate fraction (EAF) obtained from S. brasiliensis bark. MATERIALS AND METHODS: The HEE and EAF of S. brasiliensis bark (10, 30 and 100mg/kg, p.o.) were evaluated using models of analgaesia (formalin-induced licking and hot-plate models) or inflammation (licking response by formalin-induced and carrageenan-induced cell migration into the subcutaneous air pouch). The antioxidant activities of HEE and EAF (50, 100 and 200ug/ml) were evaluated using the lipoperoxidation method induced in egg yolk by 2'-azobis(2-amidinopropane) dihydrochloride (AAPH) and FeSO4. RESULTS: HEE and EAF presented a central antinociceptive effect (at 100mg/kg dose), increasing the baseline and area under the curve in the hot plate model. EAF (100mg/kg) significantly reduced (p< 0.005) the pain response in the first (45%) and second (35%) phases of the formalin-induced licking model, while HEE (100mg/kg) reduced (38%) only the pain response in the second phase. Regarding anti-inflammatory activity, EAF (100mg/kg) also inhibited the inflammatory process induced by subcutaneous carrageenan injection in the SAP model, reducing the amount of the cytokine TNF-alpha produced. CONCLUSION: HEE and EAF from S. brasiliensis bark show pharmacological interest because they were able to inhibit the peripheral and central transmission of pain. Our data also suggest that the anti-inflammatory activity caused by EAF exposure occurs through the inhibition of the pro-inflammatory cytokine TNF-alpha, also reducing the spreading of the inflammatory processes by neutralizing reactive oxygen species, which are by-products in the biosynthesis of pain mediators. PMID- 29155085 TI - IR spectroscopy analysis of pancreatic lipase-related protein 2 interaction with phospholipids: 2. Discriminative recognition of various micellar systems and characterization of PLRP2-DPPC-bile salt complexes. AB - The interaction of pancreatic lipase-related protein 2 (PLRP2) with various micelles containing phospholipids was investigated using pHstat enzyme activity measurements, differential light scattering, size exclusion chromatography (SEC) and transmission IR spectroscopy. Various micelles of 1,2-dipalmitoyl-sn-glycero 3-phosphocholine (DPPC) and lysophosphatidylcholine were prepared with either bile salts (sodium taurodeoxycholate or glycodeoxycholate) or Triton X-100, which are substrate-dispersing agents commonly used for measuring phospholipase activities. PLRP2 displayed a high activity on all phospholipid-bile salt micelles, but was totally inactive on phospholipid-Triton X-100 micelles. These findings clearly differentiate PLRP2 from secreted pancreatic phospholipase A2 which is highly active on both types of micelles. Using an inactive variant of PLRP2, SEC experiments allowed identifying two populations of PLRP2-DPPC-bile salt complexes corresponding to a high molecular weight 1:1 PLRP2-micelle association and to a low molecular weight association of PLRP2 with few monomers of DPPC/bile salts. IR spectroscopy analysis showed how DPPC-bile salt micelles differ from DPPC-Triton X-100 micelles by a higher fluidity of acyl chains and higher hydration/H-bonding of the interfacial carbonyl region. The presence of bile salts allowed observing changes in the IR spectrum of DPPC upon addition of PLRP2 (higher rigidity of acyl chains, dehydration of the interfacial carbonyl region), while no change was observed with Triton X-100. The differences between these surfactants and their impact on substrate recognition by PLRP2 are discussed, as well as the mechanism by which high and low molecular weight PLRP2 DPPC-bile salt complexes may be involved in the overall process of DPPC hydrolysis. PMID- 29155086 TI - Systemic exposure of vinpocetine in pregnant Sprague Dawley rats following repeated oral exposure: An investigation of fetal transfer. AB - Vinpocetine is being used worldwide by people of all ages, including pregnant women, for its purported multiple health benefits. However, limited data is available addressing the safety/toxicity of vinpocetine. The National Toxicology Program conducted studies to examine potential effects of vinpocetine on the developing rat. Disposition data is helpful to put the fetal findings into context and provide information on the potential risk for humans. The current study reports the systemic exposure and toxicokinetic (TK) parameters of vinpocetine and metabolite, apovincaminic acid (AVA), in pregnant Harlan Sprague Dawley rats, fetuses and amniotic fluid following oral gavage exposure of dams to 5 and 20mg/kg vinpocetine from gestational day 6 to 18. Vinpocetine was absorbed rapidly in dams with a maximum plasma concentration (Cmax) reaching <=1.37h. Predicted Cmax and area under the concentration versus time curve (AUC) increased less than proportionally to the dose. Vinpocetine was rapidly distributed to the peripheral compartment. More importantly, significant transfer of vinpocetine from dam to fetuses was observed with fetal Cmax and AUC>=55% of dams. Vinpocetine was cleared rapidly from dam plasma with an elimination half-life of <=4.02h with no apparent dose-related effect. Vinpocetine was rapidly and highly metabolized to AVA with AVA plasma levels in dams >=2.7-fold higher than vinpocetine, although in the fetuses, AVA levels were much lower than vinpocetine. Comparison of current rat data with literature human data demonstrates that systemic exposure to vinpocetine in rats following repeated exposure to 5mg/kg is similar to that following a single human relevant dose of 10mg suggesting that the findings from the toxicology study may be relevant to humans. PMID- 29155087 TI - Capsaicin reduces genotoxicity, colonic cell proliferation and preneoplastic lesions induced by 1,2-dimethylhydrazine in rats. AB - Capsaicin (8-Methyl-N-vanillyl-(trans)-6-nonenamide) is the major pungent ingredient found in chili peppers consumed worldwide. Most reports on capsaicin potential carcinogenicity have yielded inconsistent findings. Some studies have shown that capsaicin exerts anti-proliferative and pro-apoptotic effects on different cancer cell lines, while others have reported an association between capsaicin at high doses with mutagenicity and carcinogenicity. Thus, this study aimed at assessing the effects of capsaicin administration on 1,2-dimethyl hydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. Our results show that capsaicin administration, before and during carcinogen exposure, modified DMH-induced cytotoxicity and genotoxicity, promoting anti-proliferative and pro-apoptotic responses through the expression of the genes involved in apoptosis, cell cycle suppression and cell/tissue differentiation. Furthermore, capsaicin reduced aberrant crypt foci (ACF) number and multiplicity, although there were no differences in tumor incidence and multiplicity among the groups. Taken together, the results suggest that capsaicin may have a preventive effect against DMH-induced colorectal carcinogenesis. PMID- 29155088 TI - Response to the review article "Imaging in extrapulmonary tuberculosis" from the International Atomic Energy Agency Extra-pulmonary TB Consortium; March 2017, volume 56, pages 237-247. PMID- 29155089 TI - Genotyping and macrolide resistance of Mycoplasma pneumoniae identified in children with community-acquired pneumonia in Medellin, Colombia. AB - OBJECTIVES: The aim of this study was to describe the genotypes and the main characteristics of community-acquired pneumonia (CAP) caused by Mycoplasma pneumoniae in hospitalized children in Medellin and neighboring municipalities during the period 2011-2012. METHODS: The M. pneumoniae genotype was determined by PCR and sequencing of the p1 and 23S rRNA genes from induced sputum samples and nasopharyngeal swabs (NPS). Samples were obtained from children with CAP who were hospitalized in 13 healthcare centers. In addition, a spatio-temporal analysis was performed to identify the potential risk areas and clustering of the cases over time. RESULTS: A variant of type 2 was the dominant genotype in the induced sputum (96.1%) and NPS (89.3%) samples; the type 1 variant was identified in 3.9% and 10.7% of these samples, respectively. No strains with mutations in the 23S rRNA gene associated with macrolide resistance were found. The cases in Medellin were mainly concentrated in the northeastern areas and western districts. However, no temporal relationship was found among these cases. CONCLUSIONS: A variant of type 2 of M. pneumoniae prevailed among children with CAP during the study period. No strains with mutations associated with macrolide resistance were found. PMID- 29155090 TI - Proteome and phosphoproteome analysis of commensally induced dendritic cell maturation states. AB - Dendritic cells (DCs) can shape the immune system towards an inflammatory or tolerant state depending on the bacterial antigens and the environment they encounter. In this study we provide a proteomic catalogue of differentially expressed proteins between distinct DC maturation states, brought about by bacteria that differ in their endotoxicity. To achieve this, we have performed proteomics and phosphoproteomics on murine DC cultures. Symbiont and pathobiont bacteria were used to direct dendritic cells into a semi-mature and fully-mature state, respectively. The comparison of semi-mature and fully-mature DCs revealed differential expression in 103 proteins and differential phosphorylation in 118 phosphosites, including major regulatory factors of central immune processes. Our analyses predict that these differences are mediated by upstream elements such as SOCS1, IRF3, ABCA1, TLR4, and PTGER4. Our analyses indicate that the symbiont bacterial strain affects DC proteome in a distinct way, by downregulating inflammatory proteins and activating anti-inflammatory upstream regulators. Biological significance In this study we have investigated the responses of immune cells to distinct bacterial stimuli. We have used the symbiont bacterial strain B. vulgatus and the pathobiont E. coli strain to stimulate cultured primary dendritic cells and performed a shotgun proteome analysis to investigate the protein expression and phosphorylation level differences on a genome level. We have observed expression and phosphorylation level differences in key immune regulators, transcription factors and signal transducers. Moreover, our subsequent bioinformatics analysis indicated regulation at several signaling pathways such as PPAR signaling, LXR/RXR activation and glucocorticoid signaling pathways, which are not studied in detail in an inflammation and DC maturation context. Our phosphoproteome analysis showed differential phosphorylation in 118 phosphosites including those belonging to epigenetic regulators, transcription factors and major cell cycle regulators. We anticipate that our study will facilitate further investigation of immune cell proteomes under different inflammatory and non-inflammatory conditions. PMID- 29155091 TI - Dynamic molecular events associated to Plasmodium berghei gametogenesis through proteomic approach. AB - : Plasmodium mature sexual cycle occurs in the vector mosquitoes and ensures the transmission to a new host. Gametogenesis takes place within minutes in the vector midgut. Gametocytes have to complete a deep nuclear reorganization, quick differentiation, and in the case of male gametocytes, intracytoplasmic flagellum assembly that results in free-swimming microgametes required for macrogamete fertilization. In efforts to improve our knowledge of molecular mechanisms involved in gamete morphogenesis, we carried out a nanoLC/MSMS based quantitative proteomic analysis throughout the xanthurenic acid-induced gametogenesis of the rodent parasite P. berghei. Time-course analyses were performed 7 and 15min after gametogenesis induction. From 2617 iTRAQ-labelled peptides, 49 proteins were found differentially abundant. Proteins related to RNA translation, DNA, and protein biosynthesis were most prominent and strongly regulated. The energetic metabolic pathway, glycolysis, environmental stress response, RNA/protein biosynthesis, mitosis and axoneme formation, both related to tubulin-associated cytoskeleton dynamic, were predominant regulated cell processes at protein level during the differentiation. Our results also include 26 phosphoproteins in gametocytes/gametes. This first iTRAQ-based proteomic time course analysis of Plasmodium gamete development sheds light on the biological protein orchestration within gametogenesis. SIGNIFICANCE: Malaria is one of the most serious and widespread parasitic diseases that affected humans in medicine history. The increasing emergence of resistance of parasites from Plasmodium genus to the available antimalarial drugs and the absence of efficient vaccines require an urgent need of development of new therapeutic strategies to fight against that disease. The sexual reproduction is a key step of Plasmodium life cycle and constitutes an attractive target for the development of new therapeutic approaches since it would control malaria based on an inhibition of the parasite transmission to Anopheles, and then to humans. Male and female gamete formation (gametogenesis) is thus a biological event that is determinant for the perpetuation of the parasite in which drastic morphological and metabolic changes occur in a short time interval, resulting in the production of 8 male gametes from a male gametocyte, and fertilization of the female gamete. Development of such transmission-blocking strategies required in deep understanding of the molecular and cellular events associated to gametogenesis. Despite several studies, our understanding on gametogenesis is still incomplete and requires further investigations. This work is the first large-scale quantitative proteomic insight into the P. berghei gamete morphogenesis providing valuable time course data. Plasmodium gametogenesis clearly requires regulation of expression and phosphorylation of proteins belonging to different metabolic pathways and functions, in order to produce mature male and female gametes. PMID- 29155092 TI - Effects of medial prefrontal cortex 5-HT7 receptor knockdown on cognitive control after acute heroin administration. AB - Heroin abuse is linked to a deleterious effect on cognitive functioning in the individual. Recent evidences suggest that the serotonin7 receptor (5-HT7R) is engaged in the regulation of cognitive control and the drug use-associated behaviors. However, the role of 5-HT7R in the cognitive control after acute heroin administration has not been studied. The present study aims to investigate whether the knockdown of the 5-HT7R by virus-mediated gene silencing in the medial prefrontal cortex (mPFC) could ameliorate the acute heroin-induced cognitive impairments. The attentional function, impulsivity and compulsivity were assessed by the 5-choice serial reaction time task (5-CSRTT) in mice. The memory ability and locomotor activity were examined by the novel objects recognition (NOR), Y-maze and open-field test (OFT). Acute heroin administration at 5 mg/kg produced robust disruptions in attention, impulsivity and motivation in mice. 5-HT7R knockdown in the mPFC did not affect the 5-CSRTT baseline performance, spatial working memory, visual episodic memory and locomotion. However, mPFC 5-HT7R knockdown selectively ameliorated acute heroin-induced increase in omissions and premature responses under conditions of increased perceptual load. In addition, mPFC 5-HT7R knockdown induced increases in perseverative responding observed across both saline and heroin-treated animals. Moreover, 5-HT7R knockdown prevented the heroin-induced decrease in NR1/CaMKII phosphorylation in mPFC, thus suggesting that 5-HT7R and N-methyl-d-aspartic acid (NMDA) receptor signaling may be involved in the cognitive outcomes of acute heroin administration. Altogether, these observations suggest modest and restricted effects of mPFC 5-HT7R knockdown on cognitive behaviors, both in the presence or absence of acute heroin treatment. PMID- 29155093 TI - Histone acetylation of oligodendrocytes protects against white matter injury induced by inflammation and hypoxia-ischemia through activation of BDNF-TrkB signaling pathway in neonatal rats. AB - The major pathological damage in encephalopathy of prematurity is white matter injury (WMI). Perinatal hypoxic-ischemia (HI) and inflammation are two major risk factors in the development of WMI. To study the cellular and molecular mechanisms of WMI, we set up a WMI model using lipopolysaccharide-sensitized HI injury in 2 day postnatal rats. Immunofluorescence staining was used to measure the expression of acetylated histone H3 (AH3) in oligodendrocytes, the target cells of WMI; the oligodendrocyte protein markers, NG2, O4, MBP, PLP, and MAG, were detected at different developmental stages. 5-bromo-2'-deoxyuridine (BrdU) was used to detect the proliferation of oligodendrocytes. We found that the expression of AH3 was markedly decreased in oligodendrocytes at 7 days after WMI. The differentiation and maturation of oligodendrocytes were inhibited in the WMI group. After inducing histone acetylation in oligodendrocytes by treatment with sodium butyrate, the inhibition of differentiation and maturation of oligodendrocytes was reversed. Furthermore, we found that these protective effects of histone acetylation were associated with the upregulation of brain derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase B (TrkB). In conclusion, histone acetylation protects oligodendrocytes from WMI through activation of the BDNF-TrkB signaling pathway in immature brains. PMID- 29155094 TI - Motivational state controls the prediction error in Pavlovian appetitive-aversive interactions. AB - Contemporary theories of learning emphasize the role of a prediction error signal in driving learning, but the nature of this signal remains hotly debated. Here, we used Pavlovian conditioning in rats to investigate whether primary motivational and emotional states interact to control prediction error. We initially generated cues that positively or negatively predicted an appetitive food outcome. We then assessed how these cues modulated aversive conditioning when a novel cue was paired with a foot shock. We found that a positive predictor of food enhances, whereas a negative predictor of that same food impairs, aversive conditioning. Critically, we also showed that the enhancement produced by the positive predictor is removed by reducing the value of its associated food. In contrast, the impairment triggered by the negative predictor remains insensitive to devaluation of its associated food. These findings provide compelling evidence that the motivational value attributed to a predicted food outcome can directly control appetitive-aversive interactions and, therefore, that motivational processes can modulate emotional processes to generate the final error term on which subsequent learning is based. PMID- 29155095 TI - Behavioral and neural mechanisms by which prior experience impacts subsequent learning. AB - Memory is often thought about in terms of its ability to recollect and store information about the past, but its function likely rests with the fact that it permits adaptation to ongoing and future experience. Thus, the brain circuitry that encodes memory must act as if stored information is likely to be modified by subsequent experience. Considerable progress has been made in identifying the behavioral and neural mechanisms supporting the acquisition and consolidation of memories, but this knowledge comes largely from studies in laboratory animals in which the training experience is presented in isolation from prior experimentally controlled events. Given that memories are unlikely to be formed upon a clean slate, there is a clear need to understand how learning occurs upon the background of prior experience. This article reviews recent studies from an emerging body of work on metaplasticity, memory allocation, and synaptic tagging and capture, all of which demonstrate that prior experience can have a profound effect on subsequent learning. Special attention will be given to discussion of the neural mechanisms that allow past experience to affect future learning and to the time course by which past learning events can alter subsequent learning. Finally, consideration will be given to the possible significance of a non synaptic component of the memory trace, which in some cases is likely responsible for the priming of subsequent learning and may be involved in the recovery from amnestic treatments in which the synaptic mechanisms of memory have been impaired. PMID- 29155096 TI - Patients with atopic dermatitis and history of eczema herpeticum elicit herpes simplex virus-specific type 2 immune responses. PMID- 29155097 TI - 14-3-3z sequesters cytosolic T-bet, upregulating IL-13 levels in TC2 and CD8+ lymphocytes from patients with scleroderma. AB - BACKGROUND: IL-13-producing CD8+ T cells have been implicated in the pathogenesis of type 2-driven inflammatory human conditions. We have shown that CD8+IL-13+ cells play a critical role in cutaneous fibrosis, the most characteristic feature of systemic sclerosis (SSc; scleroderma). However, the molecular mechanisms underlying production of IL-13 and other type 2 cytokines by CD8+ T cells remain unclear. OBJECTIVE: We sought to establish the molecular basis of IL-13 overproduction by CD8+ T cells from patients with SSc, focusing on T-bet modulation of GATA-3 activity, which we showed to underlie IL-13 overproduction in CD8+IL-13+ cells from patients with SSc. METHODS: Biochemical and biophysical methods were used to determine the expression and association of T-bet, GATA-3, and regulatory factors in CD8+ T cells isolated from the blood and lesional skin of patients with SSc with severe skin thickening. Chromatin immunoprecipitation analysis determined GATA-3 binding to the IL-13 promoter. ImageStream analysis and confocal microscopy visualized the subcellular localization of T-bet and GATA 3. Transcript levels were decreased by small interfering RNAs. RESULTS: Interaction of T-bet with the adaptor protein 14-3-3z in the cytosol of CD8+ T cells from patients with SSc reduces T-bet translocation into the nucleus and its ability to associate with GATA-3, allowing more GATA-3 to bind to the IL-13 promoter and inducing IL-13 upregulation. Strikingly, we show that this mechanism is also found during type 2 polarization of CD8+ T cells (TC2) from healthy donors. CONCLUSIONS: We identified a novel molecular mechanism underlying type 2 cytokine production by CD8+ T cells, revealing a more complete picture of the complex pathway leading to SSc disease pathogenesis. PMID- 29155099 TI - Novel therapies for alopecia areata: The era of rational drug development. AB - Treatments for alopecia areata (AA) have evolved over the decades from broad and nonspecific therapies to those that are now more targeted and rationally selected. This was achieved by means of close cooperation and communication between clinicians and basic scientists, which resulted in the elucidation and understanding of the unique pathophysiology of AA. In this review we discuss this evolution and how novel therapies for AA have changed over the decades, what we have in our current arsenal of drugs for this potentially devastating disease, and what the future holds. PMID- 29155100 TI - Defects in plasma cell differentiation are associated with primary immunodeficiency in human subjects. PMID- 29155098 TI - ORAI1 mutations abolishing store-operated Ca2+ entry cause anhidrotic ectodermal dysplasia with immunodeficiency. AB - BACKGROUND: Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ channels is an essential signaling pathway in many cell types. Ca2+ release activated Ca2+ channels are formed by ORAI1, ORAI2, and ORAI3 proteins and activated by stromal interaction molecule (STIM) 1 and STIM2. Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms. OBJECTIVE: We performed molecular and immunologic analysis of patients with CID, anhidrosis, and ectodermal dysplasia of unknown etiology. METHODS: We performed DNA sequencing of the ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, SOCE measurements, immunologic analysis of peripheral blood lymphocyte populations by using flow cytometry, and histologic and ultrastructural analysis of patient tissues. RESULTS: We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis, and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts. In addition to impaired T cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer T and regulatory T (Treg) cells and altered composition of gammadelta T-cell and natural killer cell subsets. CONCLUSION: ORAI1 null mutations are associated with reduced numbers of invariant natural killer T and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity. ORAI1-deficient patients have dental enamel defects and anhidrosis, representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency that is distinct from previously reported patients with anhidrotic ectodermal dysplasia with immunodeficiency caused by mutations in the nuclear factor kappaB signaling pathway (IKBKG and NFKBIA). PMID- 29155101 TI - Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency. AB - BACKGROUND: Pathological inflammatory syndromes of unknown etiology are commonly observed in ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in patients with STING-associated vasculopathy in infancy (SAVI). OBJECTIVE: We sought to test the hypothesis that the inflammation-associated manifestations observed in patients with AT and Artemis deficiency stem from increased type I IFN signature leading to neutrophil mediated pathological damage. METHODS: Cytokine/protein signatures were determined by ELISA, cytometric bead array, or quantitative PCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells were quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy, and flow cytometry. RESULTS: Type I and III IFN signatures were elevated in plasma and peripheral blood cells of patients with AT, Artemis deficiency, and SAVI. Chronic IFN production stemmed from the accumulation of DNA in the cytoplasm of AT and Artemis-deficient cells. Neutrophils isolated from patients spontaneously produced NETs and displayed indicators of oxidative and mitochondrial stress, supportive of their NETotic tendencies. A similar phenomenon was also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFN-alpha. CONCLUSIONS: Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in patients with AT, Artemis deficiency, and SAVI. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature. PMID- 29155102 TI - Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness. AB - BACKGROUND: The molecular mechanisms responsible for airway smooth muscle cells' (aSMCs) contraction and proliferation in airway hyperresponsiveness (AHR) associated with asthma are still largely unknown. The small GTPases of the Rho family (RhoA, Rac1, and Cdc42) play a central role in SMC functions including migration, proliferation, and contraction. OBJECTIVE: The objective of this study was to identify the role of Rac1 in aSMC contraction and to investigate its involvement in AHR associated with allergic asthma. METHODS: To define the role of Rac1 in aSMC, ex and in vitro analyses of bronchial reactivity were performed on bronchi from smooth muscle (SM)-specific Rac1 knockout mice and human individuals. In addition, this murine model was exposed to allergens (ovalbumin or house dust mite extract) to decipher in vivo the implication of Rac1 in AHR. RESULTS: The specific SMC deletion or pharmacological inhibition of Rac1 in mice prevented the bronchoconstrictor response to methacholine. In human bronchi, a similar role of Rac1 was observed during bronchoconstriction. We further demonstrated that Rac1 activation is responsible for bronchoconstrictor-induced increase in intracellular Ca2+ concentration and contraction both in murine and in human bronchial aSMCs, through its association with phospholipase C beta2 and the stimulation of inositol 1,4,5-trisphosphate production. In vivo, Rac1 deletion in SMCs or pharmacological Rac1 inhibition by nebulization of NSC23766 prevented AHR in murine models of allergic asthma. Moreover, nebulization of NSC23766 decreased eosinophil and neutrophil populations in bronchoalveolar lavages from mice with asthma. CONCLUSIONS: Our data reveal an unexpected and essential role of Rac1 in the regulation of intracellular Ca2+ and contraction of aSMCs, and the development of AHR. Rac1 thus appears as an attractive therapeutic target in asthma, with a combined beneficial action on both bronchoconstriction and pulmonary inflammation. PMID- 29155103 TI - RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease. AB - BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to impaired apoptosis. It was initially regarded as a very rare disease, but recent studies show that it may be more common than previously thought. Defects in a couple of genes have been identified in a proportion of patients with ALPS, but around one-third of such patients remain undefined genetically. OBJECTIVE: We describe 2 siblings presenting with ALPS like disease. This study aimed to identify the genetic cause responsible for this phenotype. METHODS: Whole-exome sequencing and molecular and functional analyses were used to identify and characterize the genetic defect. Clinical and immunological analysis was also performed and reported. RESULTS: The 2 patients presented with chronic lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, and the presence of antinuclear autoantibody and other autoantibodies, but normal double-negative T cells. They also suffered from recurrent infections. Novel compound heterozygous mutations of RASGRP1 encoding Ras guanyl nucleotide releasing protein 1 were identified in the 2 siblings. The mutations impaired T-cell receptor signaling, leading to defective T-cell activation and proliferation, as well as impaired activation-induced cell death of T cells. CONCLUSIONS: This study shows for the first time that RASGRP1 mutation should be considered in patients with ALPS-like disease. We also propose to investigate the intracellular proteins involved in the T-cell receptor signaling pathway in similar patients but with unknown genetic cause. PMID- 29155104 TI - Treatment strategies for psoriatic arthritis. AB - The therapeutic management of psoriatic arthritis has seen major changes over the last few years, as illustrated by the recent updates of the GRAPPA and EULAR recommendations. These changes were driven by new studies establishing important benefits from early management and tight control of disease activity. The concepts underlying the treatment of psoriatic arthritis must be reappraised in the light of these new data. The objectives of this review are to discuss new concepts, to describe and assess the new drug classes introduced for psoriatic arthritis and, whenever possible, to define the specific indications of each class based on the rheumatic disease phenotype and presence of extraarticular manifestations. PMID- 29155105 TI - Functional diversification of sea lamprey globins in evolution and development. AB - Agnathans have a globin repertoire that markedly differs from that of jawed (gnathostome) vertebrates. The sea lamprey (Petromyzon marinus) harbors at least 18 hemoglobin, two myoglobin, two globin X, and one cytoglobin genes. However, agnathan hemoglobins and myoglobins are not orthologous to their cognates in jawed vertebrates. Thus, blood-based O2 transport and muscle-based O2 storage proteins emerged twice in vertebrates from a tissue-globin ancestor. Notably, the sea lamprey displays three switches in hemoglobin expression in its life cycle, analogous to hemoglobin switching in vertebrates. To study the functional changes associated with the evolution and ontogenesis of distinct globin types, we determined O2 binding equilibria, type of quaternary assembly, and nitrite reductase enzymatic activities of one adult (aHb5a) and one embryonic/larval hemoglobin (aHb6), myoglobin (aMb1) and cytoglobin (Cygb) of the sea lamprey. We found clear functional differentiation among globin types expressed at different developmental stages and in different tissues. Cygb and aMb1 have high O2 affinity and nitrite reductase activity, while the two hemoglobins display low O2 affinity and nitrite reductase activity. Cygb and aHb6 but not aHb5a show cooperative O2 binding, correlating with increased stability of dimers, as shown by gel filtration and molecular modeling. The high O2-affinity and the lack of cooperativity confirm the identity of the sea lamprey aMb1 as O2 storage protein of the muscle. The dimeric structure and O2-binding properties of sea lamprey and mammalian Cygb were very similar, suggesting a conservation of function since their divergence around 500million years ago. PMID- 29155106 TI - Monomerization and aggregation of beta-lactoglobulin under adverse condition: A fluorescence correlation spectroscopic investigation. AB - beta-Lactoglobulin is one of the major components of bovine milk and it remains in a dimeric form under physiological conditions. The present contribution elucidates the structural change of beta-lactoglobulin at pH7.4 under the action of guanidine hydrochloride (GnHCl) and heat at the single molecular level. The only free cysteine (Cys-121) of beta-lactoglobulin has been tagged with 7 diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin (CPM) for this purpose. The dimeric structure of beta-lactoglobulin found to undergoes a monomerization prior to the unfolding process upon being subjected to GnHCl. The hydrodynamic diameter of the native dimer, native monomer and the unfolded monomer has been estimated as ~55A, ~29A and ~37A, respectively. The free energy change for the monomerization and denaturation are respectively 1.57kcalmol-1 and 8.93kcalmol-1. With change in temperature, development of two types of aggregates (small aggregates and large aggregates) was observed, which is triggered by the formation of the monomeric structure of beta-lactoglobulin. The hydrodynamic diameters of the smaller and larger aggregates have been estimated to be ~77A and ~117A, respectively. The formation of small aggregates turns out to be reversible whereas that of larger aggregates is irreversible. The free energy associated with these two steps are 0.69kcalmol-1 and 9.09kcalmol-1. Based on the size parameters, the smaller and larger aggregates have been proposed to contain ~twenty and ~sixty monomeric units. It has also been concluded that the monomeric subunits retain their native like secondary structure in these aggregates. PMID- 29155107 TI - Structural insights of RmXyn10A - A prebiotic-producing GH10 xylanase with a non conserved aglycone binding region. AB - Hydrolysis of arabinoxylan (AX) by glycoside hydrolase family 10 (GH10) xylanases produces xylo- and arabinoxylo-oligosaccharides ((A)XOS) which have shown prebiotic effects. The thermostable GH10 xylanase RmXyn10A has shown great potential to produce (A)XOS. In this study, the structure of RmXyn10A was investigated, the catalytic module by homology modelling and site-directed mutagenesis and the arrangement of its five domains by small-angle X-ray scattering (SAXS). Substrate specificity was explored in silico by manual docking and molecular dynamic simulations. It has been shown in the literature that the glycone subsites of GH10 xylanases are well conserved and our results suggest that RmXyn10A is no exception. The aglycone subsites are less investigated, and the modelled structure of RmXyn10A suggests that loop beta6alpha6 in the aglycone part of the active site contains a non-conserved alpha-helix, which blocks the otherwise conserved space of subsite +2. This structural feature has only been observed for one other GH10 xylanase. In RmXyn10A, docking revealed two alternative binding regions, one on either side of the alpha-helix. However, only one was able to accommodate arabinose-substitutions and the mutation study suggests that the same region is responsible for binding XOS. Several non conserved structural features are most likely to be responsible for providing affinity for arabinose-substitutions in subsites +1 and +2. The SAXS rigid model of the modular arrangement of RmXyn10A displays the catalytic module close to the cell-anchoring domain while the carbohydrate binding modules are further away, likely explaining the observed lack of contribution of the CBMs to activity. PMID- 29155108 TI - Targeting of NT5E by miR-30b and miR-340 attenuates proliferation, invasion and migration of gallbladder carcinoma. AB - MicroRNAs (miRNAs) have been closely associated with the proliferation, invasion and migration of various cancers, including gallbladder carcinoma (GBC). Previous studies have revealed dysregulation of miR-30b and miR-340 in many types of cancer. However, the role of miR-30b and miR-340 in the development and progression of GBC remains unclear. Moreover, epithelial-to-mesenchymal transition (EMT) has been gradually viewed as a significant contributor to tumor metastasis. In this study, the cell line GBC-SD was used and we explored that EMT promoted GBC cells invasion and migration and inhibited the expression level of miR-30b and miR-340 compared with the control. We showed that overexpression of miR-30b and miR-340 suppressed GBC cells proliferation, invasion and migration, as well as the expression of EMT-associated genes. In addition, we identified ecto-5'-nucleotidase (NT5E) as a common target of miR-30b and miR-340 using bioinformatics analysis and a luciferase assay. Further experiments found that exogenous expression of NT5E in GBC cells could partially reverse the inhibitory effect of miR-30b and miR-340 on cell proliferation, invasion and migration. Our findings suggest that NT5E-targeting miRNAs (miR-30b and miR-340) function as tumor suppressors and may represent promising therapeutic targets for GBC. PMID- 29155109 TI - Heat stress in the heart and muscle of the Antarctic fishes Notothenia rossii and Notothenia coriiceps: Carbohydrate metabolism and antioxidant defence. AB - Carbohydrate metabolism and the antioxidant defence system of heart and muscle of the Antarctic notothenioids Notothenia rossii and Notothenia coriiceps were evaluated in response to heat stress (8 degrees C) over 144 h. N. rossii heart exhibited decreased glycolysis and aerobic metabolism after up to 12 h of exposure to 8 degrees C, and anaerobiosis was inhibited within 24 h. However, these pathways were stimulated after 72 h at 8 degrees C. The consumption of glucose-6-phosphate, derived from hexokinase (HK), by glucose-6-phosphate dehydrogenase (G6PDH) decreased in N. rossii heart within 6 h at 8 degrees C, with a subsequent increase at 72 h. In N. rossii muscle at 8 degrees C, glycolysis was stimulated within 2 h by an increase in pyruvate kinase (PK), and aerobic metabolism was stimulated at 144 h, together with anaerobiosis. In N. coriiceps heart at 8 degrees C, glucose break down by HK decreased within 2 h and subsequently increased at 12 and 24 h. Increased glucose-6-phosphate consumption by G6PDH occurred within 6 h at 8 degrees C. In N. coriiceps muscle at 8 degrees C, glycolysis was stimulated at 2 and 6 h, with subsequent inhibition within 24 h, as indicated by HK activity. Aerobic metabolism was inhibited at 72 and 144 h at 8 degrees C through the inhibition of citrate synthase (CS). Heat stress caused responses were only occasional and transient in antioxidant defence system of both species in the heart and muscle, leading to increased glutathione (GSH) and decreased levels of lipoperoxidation in the heart of both species. The results obtained in this study in the heart and muscles indicate that under heat stress at 8 degrees C, N. rossii is more responsive than N. coriiceps with respect to carbohydrate metabolism. PMID- 29155110 TI - Delayed Traumatic Aortic Pseudoaneurysm Formation Causing Vertebral Body Erosion and Back Pain: Case Report and Literature Review. AB - BACKGROUND: Aortic pseudoaneurysms are a rare cause of chronic back pain, usually resulting from compression of the adjacent neurovasculature. It is uncommon for patients with pseudoaneurysms of the abdominal aorta to present in a delayed fashion after initial traumatic injury. CASE DESCRIPTION: We describe an unusual case of delayed pseudoaneurysm formation with subsequent erosion into the adjacent L1 vertebral body. This pseudoaneurysm was secondary to a gunshot wound with retained ballistic fragment that had occurred 27 years previously. Herein, we discuss the patient's presenting symptoms, imaging, and overall treatment. In this particular case, we used a combined surgical and endovascular (hybrid) approach after the patient experienced recurrent low back pain, weeks after a primary endovascular treatment was performed. We additionally review the current literature on the management of aortic pseudoaneurysms causing vertebral body erosion and back pain. CONCLUSIONS: In our patient, a combined surgical and endovascular (hybrid) approach led to the complete resolution of his back pain symptoms and to complete exclusion of the pseudoaneurysm on follow-up imaging. Endovascular management of aortic pseudoaneurysms may be a reasonable alternative to open surgery in high-risk patients; however, this approach may result in a higher recurrence of pseudoaneurysm and initial presenting symptoms. Further investigation is needed to elucidate the efficacy of endovascular treatment of these lesions. PMID- 29155111 TI - Surgical Treatment of Spinal Synovial Cysts in Elderly Patients: Symptoms, Treatment Course, and Outcome in Patients >75 Years of Age. AB - BACKGROUND: With the aging of our society comes a rising number of elderly patients with progressive degeneration of the spine associated with synovial cysts. Surgical treatment may be particularly challenging in elderly patients because of comorbidities. METHODS: Patients treated in our department between 1999 and 2014 for spinal synovial cysts were screened. The 28 patients >=75 years old were classified as elderly and were compared with 96 patients 50-74 years old. No patient underwent fusion as part of cyst resection. RESULTS: Despite a significantly higher frequency of muscle reflex changes in elderly patients at presentation, symptoms, cyst levels, rate of complications, and surgical method were not different between groups. Cyst adherence to the dura and subtotal resection were observed significantly more often in the elderly group (18% vs. 3%; P < 0.05). Outcome according to the Oswestry Disability Index was classified as no disability or minimal disability in 85% of the elderly group and in 82% of the control group. Recurrent cyst and delayed fusion rates were lower in the elderly group (4% and 4%) compared with the control group (7% and 8%). CONCLUSIONS: The clinical course of elderly patients with surgical treatment of spinal synovial cysts did not differ compared with younger patients. Good or excellent results could be achieved and persisted for a long time in most cases. Fusion should be performed only in cases of severe instability. Nonaggressive cyst removal in cases of dural attachment enables low cerebrospinal fluid fistula rates without increasing cyst recurrence rates. PMID- 29155112 TI - Posterior Lumbar Interbody Fusion with 3D-Navigation Guided Cortical Bone Trajectory Screws for L4/5 Degenerative Spondylolisthesis: 1-Year Clinical and Radiographic Outcomes. AB - OBJECTIVE: We describe our technique and evaluate clinical and radiographic outcomes for patients undergoing L4/5 posterior lumbar interbody fusion with 3D navigation guided cortical bone trajectory screws (PLIF-CBT) for grade 1 or 2 degenerative spondylolisthesis with a minimum follow-up time of 12 months. METHODS: A single-institution series of 18 patients was evaluated with data prospectively collected and retrospectively analyzed. Pain and disability scores were collected preoperatively and at a minimum of 12 months postoperatively, including back and bilateral leg pain visual analog scores (VAS) and Oswestry Disability Index (ODI) scores. Radiographic fusion was assessed as complete, partial, or none based on the presence of bridging bones across the disc space, posterior elements, or both. RESULTS: Patients demonstrated statistically significant reductions in back pain VAS (P = 0.0025), leg pain VAS (P < 0.0001), and ODI (P < 0.0001) at a minimum of 12 months postoperatively. Radiographic fusion at an average of 14.9 months postoperatively was available for 16/18 patients, with 6 patients demonstrating fusion (4/6 with complete fusion; 2/6 with partial fusion). There were no instances of intraoperative complications or delayed complications requiring subsequent interventions. CONCLUSIONS: PLIF-CBT can be performed in a safe and reproducible fashion with excellent clinical outcomes at 1 year postoperatively. The outcomes did not correlate with fusion status, which was unexpectedly low at 37.5% without significant hardware abnormalities necessitating reoperations. PLIF-CBT offers several perioperative advantages compared with traditional open PLIF and requires longer-term studies to demonstrate its durability with regard to improvement in clinical pain and radiographic endpoints, including anterior and/or posterior element fusion. PMID- 29155113 TI - Small Cell Glioblastoma of the Sella Turcica Region: Case Report and Review of the Literature. AB - BACKGROUND: Glioblastomas in the sellar region are very rare; in most cases, the tumor originates from the optic nerve or optic chiasm. Only 4 cases of sellar glioblastoma with a nonoptic origin have been reported. We present such a case with detailed clinical, imaging, and histopathologic information. We also review similar published cases. CASE DESCRIPTION: A 42-year-old woman presented with endocrinologic abnormalities, including amenorrhea and lactation, symptoms of diabetes insipidus, and signs of elevated intracranial pressure. Magnetic resonance imaging showed a giant, heterogeneously enhancing lesion involving the intrasellar, parasellar, and suprasellar regions, with hypercellularity and signs of infiltration of adjacent structures. Intraoperative examination revealed the tumor to be independent from the optic pathways, but it showed infiltration of the hypothalamic region. Histopathologic examination demonstrated uniformly packed small cells and negative staining for glial fibrillary acidic protein, which was consistent with a diagnosis of small cell glioblastoma. CONCLUSIONS: This is the first report of a small cell glioblastoma in the sella turcica region. Glioblastomas in the sellar region with no clear evidence of an optic origin should be viewed as an independent disease entity. The typical characteristics of this tumor indicate it should be considered a rare subtype of glioblastoma. Further accumulation of experience is needed to better differentiate these cases and to offer optimal treatment. PMID- 29155114 TI - Risks of Endoscopic Temporal Ventriculocisternostomy for Isolated Lateral Ventricle: Anatomic Surgical Nuances. AB - BACKGROUND: Entrapment of the temporal horn, known as isolated lateral ventricle (ILV), is a rare type of noncommunicating focal hydrocephalus, and standard treatment has not been established. We report 2 cases of endoscopic surgery for ILV and highlight the anatomic surgical nuances to avoid associated surgical risks. CASE DESCRIPTION: The first patient presented with recurrent ILV following initial shunt placement for ILV, owing to shunt malfunction. In the second patient, ILV recurred secondary to choroid plexus inflammation caused by cryptococcal infection. Endoscopic temporal ventriculocisternostomy was effective in both cases. However, in the second case, the choroidal fissure was fenestrated, which led to cerebral infarction in the territory of the choroidal artery zone, attributed to damage of the branches of the choroidal segment of the anterior choroidal artery. CONCLUSIONS: Although endoscopic temporal ventriculocisternostomy is considered a safe and less invasive procedure for treatment of symptomatic ILV, the technique is still associated with risks. To avoid complications, it is necessary to be familiar with the anatomy of the choroidal arteries and the pertinent endoscopic intraventricular orientation. Additionally, sufficient experience is required before it can be recommended as the treatment of choice. PMID- 29155115 TI - Transtentorial Distortion Syndrome: Consistent Complication Following Lateral and Fourth Ventricular Shunting in Adults. AB - BACKGROUND: Complex hydrocephalus affecting lateral and fourth ventricles separately is occasionally managed with cerebrospinal fluid diversion via supratentorial and infratentorial ventricular catheters. The optimal configuration to reduce complications is currently unknown in adults. We describe a consistently similar clinical presentation of patients with complex hydrocephalus and a fourth ventricle separately drained by infratentorial shunt insertion. METHODS: This was a retrospective single-center case series. Medical notes were reviewed for clinical presentation, brain imaging, and neurophysiologic tests results. All patients underwent intracranial pressure monitoring (ICPM). Outcomes were determined by ventricular appearance on brain imaging computed tomography and symptomatic improvements postoperatively. RESULTS: Five adult patients referred to the hydrocephalus service had separate infratentorial and supratentorial shunt systems. A common clinical presentation was observed, including lower motor neuron facial palsy (confirmed with electrophysiology), ophthalmoplegia, dysarthria, impaired gait headache, and nausea. We refer to this as transtentorial distortion syndrome. Twenty-four-hour ICPM demonstrated clear low pressures. All patients underwent shunt revision connecting the transtentorial shunts via a Y-connector and the addition of a distal valve. All subjects had improved ventricular appearance on computed tomography scans post revision, and normalization of ICPM was observed. In the follow-up period of 6 months, no patient required further shunt revision. CONCLUSION: To prevent transtentorial distortion syndrome, supratentorial and infratentorial shunt constructs in adults with encysted fourth ventricles should be similar to the shunt systems widely known in the pediatric population with Dandy-Walker syndrome (i.e., joint output to a single valve distal to the connection of the 2 proximal drainage catheters). PMID- 29155116 TI - The Effect of Steroids on Complications, Readmission, and Reoperation After Posterior Lumbar Fusion. AB - BACKGROUND: The effects of chronic corticosteroid therapy on complications, readmission, and reoperation after posterior lumbar fusion (PLF) remain underinvestigated, and were examined to determine differences in outcomes. METHODS: We analyzed patients undergoing PLF between 2006 and 2013 using the National Surgery Quality Improvement Program database (NSQIP). Patients taking steroids for a chronic condition were compared with those not taking steroids. Multivariable regression identified factors independently associated with complications, readmission, and reoperation. A risk score was calculated for predicting complications. RESULTS: A total of 8492 patients were identified, of whom 353 used steroids. The patients using steroids were older (mean age, 65.4 years vs. 61.0 years; P < 0.001), were more likely to be female (61.2% vs. 55.1%; P = 0.025), had a higher American Society of Anesthesiologists class (P < 0.001), were less likely to be functionally independent (90.3% vs. 96.5%; P < 0.001), and were more likely to have a history of hypertension (69.1% vs. 58.3%; P < 0.001), diabetes mellitus (21.8% vs. 17.4%; P = 0.033), cardiac disease (74.8% vs. 66.1%; P = 0.001), and/or severe chronic obstructive pulmonary disease (10.5% vs. 4.2%; P < 0.001). The rates of readmission (9.4% vs. 6.0%; P = 0.023), reoperation (6.5% vs. 3.6%; P = 0.004), overall complications (14.5% vs. 9.6%; P = 0.003), and infections (9.6% vs. 5.1%; P < 0.001) were higher in the steroid group. On multivariable regression, steroids were independently associated with overall complications (odds ratio [OR], 1.38; P = 0.044) and infectious complications (OR, 1.65; P < 0.001), but not with medical complications, readmission, or reoperation. Patients with higher risk scores had higher complication rates. CONCLUSIONS: The use of corticosteroid therapy is associated with a moderately increased risk of overall complications, but no association was found with readmission or reoperation. PMID- 29155117 TI - Pediatric Nonmissile Penetrating Head Injury: Case Series and Literature Review. AB - BACKGROUND: Pediatric nonmissile penetrating head injury (NMPHI) is usually accidental attributed mainly to the softer skulls of growing children. However, it is a rare entity, and therefore no consensus exists regarding treatment to effectively prevent immediate and long-term complications. Throughout the literature, these injuries are mostly discussed in case reviews and case series in the general population. No data originating from randomized studies are available because of ethical and practical limitations. METHODS: We retrospectively studied and present 5 cases of children with NMPHI treated in the last 6 years in the Neurosurgery Department of Children's Hospital "Aghia Sofia". We performed a review of the literature in PubMed, using the key words "non missile," "penetrating head injury," and "pediatric." We included case reports and case series involving pediatric cases since 2008 and selected older reports as well as certain literature reviews focusing on analysis of complications and treatment suggestions. We compared reported practice in various institutions with suggestions from the literature. RESULTS: In the last year, 4 literature reviews were published suggesting treatment algorithms of NMPHIs. Surgery timing and method as well as anticonvulsant and antibiotic therapy still remain debatable. The only review concentrating on pediatric populations dates back to 1994, based on patient outcome studies from the 1980s. In our review, treatment steps were similar among various institutions and resembled recently suggested algorithms, with better treatment outcomes than originally reported 30 years ago. PMID- 29155118 TI - Patterns of neuroendocrine coupling in 9-year-old children: Effects of sex, body mass index, and life stress. AB - Previous investigations have explored stress and pubertal hormones in parallel; it has been a recent development, however, to explore the relationships between different hormones during puberty, and how this hormonal cross-talk may be influenced by the environment. The current study investigated neuroendocrine coupling, or the extent to which hormones are correlated within the individual, and also investigated early life stressors that may influence coupling. Participants were 405 adrenarcheal children (mean Tanner stage=1.73 for girls and 1.38 for boys) from a longitudinal study who provided saliva samples for analysis of cortisol, dehydroepiandrosterone (DHEA), and testosterone. Saliva was collected when children were 9-years-old, while early life stressors were assessed at each longitudinal assessment (ages 3, 6, and 9). Results from multi level modeling (MLM) analyses provided evidence of positive cortisol dehydroepiandrosterone (DHEA) and cortisol-testosterone coupling in middle childhood, and identified body mass index as a predictor of the strength of hormone coordination. While exposure to stressful life events did not impact cortisol-DHEA coupling patterns, stress interacted with sex to predict looser cortisol-testosterone coupling in girls, but not boys. The current study adds to the existing literature on the development of neuroendocrine coupling, and provided further evidence of sex differences in the impact of stress. Furthermore, hormone coupling may be investigated in the future as a mechanism by which puberty is associated with negative behavioral outcomes. PMID- 29155119 TI - High serum bilirubin is associated with lower prevalence of peripheral arterial disease among cardiac patients. AB - Several studies have shown that subjects with higher serum bilirubin may have a lower risk of cardiovascular disorders. We herein investigated whether serum bilirubin concentration is associated with lower extremity ischemia among cardiology patients. In total, 935 patients without a history of angioplasty or bypass surgery of the lower limb arteries and who had bilateral ankle-brachial index measurements were included in the study. Peripheral arterial disease (PAD) was defined to be present when ABI of either or both sides was <0.9. Overall, the serum total bilirubin concentration ranged between 0.1 and 2.7mg/dL (normal range, 0.1-1.0mg/dL). Across the bilirubin tertiles, age did not differ significantly. On the other hand, male patients (median 0.6mg/dL, interquartile range (IQR) 0.4-0.7mg/dL) had significantly higher bilirubin levels than female patients (median 0.5mg/dL, IQR 0.4-0.7mg/dL, P=0.014). Logistic regression analysis showed that, as compared with the lowest bilirubin tertile (0.1 0.4mg/dL), the highest tertile (0.7-2.7mg/dL) was significantly negatively associated with prevalent PAD after adjusting for sex, age, eGFR, white blood cell count, inorganic phosphate, HbA1C, total and HDL cholesterol, triglycerides, current smoking, diabetic medication, and statin use. This association remained significant when only those with serum bilirubin in the normal range were included in the analysis. Among cardiology patients, serum bilirubin concentration was significantly negatively associated with prevalence of PAD. The underlying mechanism and therapeutic indications should be investigated in further investigations. PMID- 29155120 TI - Risk of type 2 diabetes mellitus associated with plasma lipid levels: The rural Chinese cohort study. AB - AIM: To investigate the association of type 2 diabetes mellitus (T2DM) risk and plasma lipid levels in rural Chinese. METHODS: Each lipid variable was divided into quartiles and dichotomized by clinical cutoff points. Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of T2DM risk and plasma lipid levels and explore the interaction between plasma lipid levels and other risk factors. RESULTS: 11,929 participants were included in the analysis. We documented 720 incident cases of T2DM over 70,720.84 person-years of follow-up, for an incidence of 10.18/1,000 person-years. In the multivariable-adjusted model, risk of T2DM was increased with the highest versus lowest quartiles of total cholesterol (TC) and triglycerides (TG) levels and TC/high-density lipoprotein-cholesterol (HDL-C) and TG/HDL-C ratios. The HRs (95% CIs) for the fourth quartiles, for example, were 1.34 (1.03-1.74), 2.32 (1.73-3.13), 1.66 (1.23-2.25), and 1.84 (1.38-2.45), respectively. In addition, risk of T2DM was increased with high TG level and TC/HDL-C and TG/HDL-C ratios by clinical cutoffs. The HRs (95% CIs) were 1.50 (1.25-1.80), 1.24 (1.03-1.48), and 1.44 (1.18-1.75), respectively. Risk of T2DM was associated with interactions between all lipid variables and age and BMI. TG level and TG/HDL-C ratio additionally interacted with gender (all Pinteraction < 0.0001). CONCLUSIONS: Risk of T2DM was increased with elevated serum levels of TC and TG and TC/HDL-C and TG/HDL-C ratios and also with interactions between high TC and TG levels and TC/HDL-C and TG/HDL-C ratios and age and BMI in a rural Chinese population. PMID- 29155121 TI - Evaluation of protein C and protein S levels in patients with diabetes mellitus receiving therapy with statins and ACE inhibitors or angiotensin II receptor blockers. AB - AIMS: To evaluate protein C, protein S level in patients with diabetes mellitus receiving statin and ACE inhibitor/ARB therapy. METHODS: 95 patients were included in the study and divided into four groups depending on the use of statin and ACE inhibitor/ARB therapy. Group 1 comprised of patients receiving statin therapy (n = 15), Group 2 comprised of patients receiving ACE inhibitor/ARB therapy (n = 31), Group 3 comprised of patients receiving statin and ACE inhibitor/ARB therapy (n = 23), and Group 4 comprised of patients who did not receive either statin or ACE inhibitor/ARB therapy (n = 26). These four groups were compared with respect to protein C, protein S, fibrinogen, D-dimer, INR, and aPTT levels. RESULTS: There were statistically significant differences with respect to protein C levels. Group 1 and group 2 had higher protein C levels compared with group 4. (p < .01). Similarly, Group 3 had higher protein C levels compared with group 4. (p < .01). There was no significant difference between the groups with respect to protein S, INR, aPTT, and D-dimer levels. CONCLUSIONS: Diabetic patients receiving statin or ACE inhibitor/ARB therapy had higher protein C levels. Use of statin and ACE inhibitor/ARB therapy in diabetic patients decrease hypercoagulability and therefore could reduce the occurrence of cardiovascular events. PMID- 29155122 TI - Screening for diabetes prevention with diabetes risk scores - A balancing act. AB - AIMS: To compare the diabetes prevention impact and cost of several screening scenarios for diabetes prevention programs with the scenario which included an oral glucose tolerance test (OGTT). METHODS: We included 4864 participants of the Australian Diabetes, Obesity and Lifestyle study who were aged >=40 years, did not have known diabetes at baseline, and attended the five year follow-up. The proportions of participants eligible or ineligible for diabetes prevention program were estimated for each scenario. The costs of screening and diabetes prevention programs were also estimated. RESULTS: Screening with OGTT alone identified 21% of participants as eligible for diabetes prevention. While 3.1% of the cohort were identified as high risk and developed diabetes after five years, 1.0% of the cohort were identified as low risk and developed diabetes. The population prevention potential (i.e. sensitivity) for OGTT alone was 76.5%. Screening all Australian adults aged >=40 years in 2015 by OGTT would have cost a total of AU$2025 million (AU$1031 million on screening and AU$994 million on prevention programs). The total costs of screening and prevention were substantially lower when AUSDRISK was used alone or in combination with a blood test. However, the population prevention potentials were also lower (ranged from 20.1% to 50.7%). CONCLUSIONS: A blood test post non-invasive risk assessment is a worthwhile step in the process of enrolling participants in a diabetes prevention program. Nevertheless, there will be ineligible individuals who proceed to diabetes. PMID- 29155123 TI - Baseline factors associated with better response to insulin lispro low mixture or insulin glargine: A post hoc analysis of the DURABLE study. AB - AIMS: To identify baseline characteristics associated with better efficacy and safety responses to twice-daily insulin lispro low mixture (LM) or once-daily insulin glargine (IG) in insulin-naive patients with type 2 diabetes (T2D). METHODS: This post hoc analysis of the DURABLE study used the gradient-boosting method to generate hypothetical outcomes with the alternative treatment to assigned study drug to evaluate the potential additional benefit of one insulin over the other in association with influential baseline covariates in the same patient. The magnitude of additional benefit was further quantified by the generalized linear model and recursive partitioning regression tree method. RESULTS: Baseline characteristics with the highest relative influence on 24-week outcomes in the overall population (LM, n = 1045; IG, n = 1046) were: for HbA1c change: fasting plasma glucose (FPG) (29.31%), age (28.57%); for reaching target HbA1c <7% (<53 mmol/mol): weight (22.41%); for weight change: weight (18.54%); for FPG: FPG (43.66%), age (20.8%); for 30-day hypoglycemia: FPG (57.09%), weight (10.1%). LM showed superiority over IG for HbA1c reduction and reaching HbA1c <7% overall, with clinically significant differences in HbA1c reduction (>0.4%) in some subpopulations. IG was superior over LM in most patients for less weight gain and hypoglycemia and lower FPG. CONCLUSIONS: Differences in magnitude of response to twice-daily LM and once-daily IG in association with baseline characteristics of insulin-naive patients with T2D were found. Future real-world studies using these statistical methods could help identify patients who respond better to certain insulin regimens to help guide clinicians in treatment decisions. PMID- 29155124 TI - Common mental disorders in adolescents with and without type 1 diabetes: Reported occurrence from a countrywide survey. AB - AIMS: The aim of this study was to evaluate the frequency of common mental disorders symptoms in adolescents with type 1 diabetes in comparison to a population-based sample of adolescents in Brazil. METHODS: We compared characteristics of 116 youth with type 1 diabetes and 73,508 youth without type 1 diabetes from the same population-based sample of adolescents aged 12-17years, taken from the Brazilian Study of Cardiovascular Risk in Adolescents (ERICA). We evaluated the 12-item General Health Questionnaire (GHQ) score, which is a self administered screening survey for detecting mental health symptoms. Scores >=3 were used to determine common mental disorder. RESULTS: Adolescents with and without type 1 diabetes were comparable with respect to age and race/ethnicity distributions. Youth with type 1 diabetes did not report higher scores on the weighted GHQ analyses in comparison to youth without type 1 diabetes (3.16, SE 0.76 vs. 2.10, SE 0.03, respectively; P = .167). No differences were found regarding the odds of having a GHQ score >=3 (OR 1.48, 95% CI 0.72-3.08). However, analyses of mental health symptoms separately consistently showed that youth with type 1 diabetes more frequently endorsed mental health barriers in comparison to youth without type 1 diabetes. CONCLUSIONS: Mental health symptoms seem to be more frequent than diagnosis of common mental disorders in adolescents with type 1 diabetes, which may also interfere in glycemic control. Our findings highlight the need for appropriate mental health assessment in diabetes care in order to prevent glycemic control deterioration. PMID- 29155125 TI - Virulence characteristics and molecular relatedness of methicillin resistant Staphylococcus aureus harboring different staphylococcal cassette chromosome mec. AB - INTRODUCTION: Methicillin resistant Staphylococcus aureus (MRSA) is a versatile pathogen capable of causing multitude of human diseases. It is one of the most important nosocomial pathogen that implicated in community and healthcare associated infections. Therefore, this study aims to characterize different SCCmec elements found in MRSA isolates. Moreover, molecular typing was performed to investigate the genetic relatedness among MRSA isolates. METHODS: Phenotypic identification of MRSA was done by disc diffusion method. The MRSA isolates were typed based on the SCCmec, coa and agr genes. Phenotypic characterization included the detection of biofilm, lipase, protease, lecithinase, staphylokinase and hemagglutination. Also, hla, hlb, hlg, hld, tsst-1, psm-mec and mecI genes were detected genotypically. The correlation between the molecular types identified and the profile of virulence factors, clinical and geographical sources was determined for all isolates. RESULTS: Eighty five isolates were identified as MRSA. Eight types of SCCmec elements were detected among these isolates. Type V was the most observed type (56.47%). Regarding the correlation between SCCmec types and virulence factors, type V SCCmec exhibited a significant association with biofilm (p < 0.0001), staphylokinase (p = 0.0495) and tsst-1 (p = 0.0498). Molecular typing of coa gave an insight to the presence of specific types in specific hospital wards. Based on agr typing, agr I was the highest prevalent type in MRSA isolates (54.11%). CONCLUSION: There is an increase of MRSA infections particularly the community acquired with high variability in the distribution of virulence factors among different SCCmec types. The association between type III and V SCCmec with certain hospitals may be an evidence of nosocomial infection among these hospitals. PMID- 29155126 TI - Treatment strategy by lactoperoxidase and lactoferrin combination: Immunomodulatory and antibacterial activity against multidrug-resistant Acinetobacter baumannii. AB - Lactoperoxidase (Lpo) and Lactoferrin (Lf) were extracted from camel colostrum milk and purified. The antibacterial activity of the two purified proteins was estimated against 14 isolates of multidrug resistance Acinetobacter baumannii. A combination of Lpo and Lf exhibited bactericidal action against A. baumannii in vitro. A mouse model of acute A. baumannii pneumonia was improved. The injection of combined Lpo and Lf after infection leads to significant clearance of A. baumannii rates in lung as well as blood culture P < 0.05 in comparing with control. Furthermore, the results showed a significant P < 0.05 reduction in the Bronchoalveolar lavage albumin concentration, lung injury and lactate dehydrogenase activity in comparing with control. In addition, the combination of Lpo and Lf treatment induced substantial elevation of IL-4 and IL10 concentrations p < 0.0 5 that helped to prevent damage caused by the inflammatory response. We concluded that combination of Lpo and Lf had a major inhibition effect against A. baumannii in comparing with imipenem as well as their immunomodulatory activity against resistant A. baumannii was increased by a synergistic effect of them as a crude combination. This study indicated two combined proteins consider as crucial strategy for practical treatment of pneumonia in the future. PMID- 29155127 TI - MDR1 gene C3435T polymorphism in chronic hepatitis C patients. AB - BACKGROUND: MDR1 is a highly polymorphic gene that encodes P-glycoprotein (P-gp). This protein anchor to the cell membrane and transports toxins, xenobiotic, chemicals, and drugs from the intracellular to extracellular and thus protect cells. Polymorphism of the MDR1 gene seems to be effective in gene expression and response to treatment. Since one of the main mechanisms of drug resistance is the removal of the drug from the cell by ATP-dependent efflux proteins, thus MDR1, single nucleotide polymorphism (SNP) C3435T can be used as a predictor for treatment outcomes. METHODS: The peripheral blood-EDTA samples were collected from 71 patients with chronic hepatitis C. The total genomic DNA extraction was carried out. The PCR was performed for detection of the MDR1 gene in HCV patients and MDR1 gene polymorphism was genotyped by the PCR-RFLP method. RESULTS: Out of 71 patients 52 (73.3%) were male, 19 (26.7%) female with mean age-min-max; 41.17 +/- 8.3-(26-59). The distribution of MDR1 genotype in 48(67.6%) responders were CC 13 (27%), CT 34 (71%) and TT 1(2%), while MDR1 genotypes in 8 (11.3%) non responders were CC 2(25%), CT 1(12.5%) TT 5(62.5%) and in 15(21.1%) recurrence were 5 (33%) CC, 6 (40%) CT and 4 (27%) TT genotype. The patients with heterozygous CT (C3435T) genotype 34/48(71%) were found better response than non responders with TT 5/8(62.5%) genotype (p < 0.05). CONCLUSION: Our result reveals that 71% of the responders were CT genotypes (C3435T) and 62.5% of non-responders were TT genotype (T3435T). With aforementioned results, determination of different forms of SNPs in MDR1 gene should be considered as a predictor in the treatment of all chronic HCV patients. The homozygous TT genotype and high prevalence of T allele may be related to low antiviral response during combined therapy in treatment of chronic HCV patients. PMID- 29155128 TI - Introduction to fluorescence correlation Spectroscopy-Brief and simple. PMID- 29155129 TI - Nervonoylceramide (C24:1Cer), a lipid biomarker for ocular irritants released from the 3D reconstructed human cornea-like epithelium, MCTT HCETM. AB - Due to invasive and painful procedures during in vivo rabbit eye irritation test, in vitro alternative methods have been widely investigated. Recently, 3D reconstructed human cornea-like epitheliums (RhCEs) garner a huge attention. RhCEs employ the tissue viability as a primary endpoint to determine ocular irritancy but additional biomarkers may improve its predictive capacity. Here, we explored lipid biomarkers for ocular irritants in MCTT HCETM RhCE model. Three irritants; sodium lauryl sulfate, benzalkonium chloride and triton X-100 were selected to represent anionic, cationic and non-ionic detergent respectively. After treating MCTT HCETM with irritants, the alteration of lipids in the treated tissues was examined with Nile Red staining, which revealed the depletion of corneal lipids. We further quantitated the release of ceramides and free fatty acids, major lipid components of cornea, into the medium during the post treatment incubation, employing a sensitive UPLC-MS/MS method. Among 44 lipid species, nervonoylceramide (C24:1Cer) was found to be released commonly by all three irritants in a concentration-dependent manner. Tests with 10 additional reference substances further supported that C24:1Cer release was significantly correlated with viability. Examination of the genes involved in the biosynthetic pathway for C24:1Cer revealed that stearoylCoA desaturase (SCD) and elongase1 (ELOVL1) were upregulated, suggesting that lipids and related genes may be employed as biomarkers for ocular irritants. PMID- 29155130 TI - Dibromoacetic acid induced Cl.Ly1+2/-9 T-cell apoptosis and activation of MAPKs signaling cascades. AB - Dibromoacetic acid (DBA), a haloacetic acid by-product of disinfection of drinking water, can cause many adverse effects in test animals, including immunotoxicity. However, the underlying molecular mechanism for the immunomodulatory effects remains unclear. The present study was undertaken to help in defining some potential mechanisms for this type of toxicity. Here, Cl.Ly1+2/-9 T-cells were exposed to varying levels of DBA and then several parameters, including cell survival, apoptosis, changes in mitochondrial potentials, and effects on select kinases (i.e., p38, ERK1/2, JNK1/2) were examined. The data showed that DBA significantly decreased Cl.Ly1+2/-9 cell viability in a dose-related manner. DBA also induced apoptosis, a decrease in mitochondrial trans-membrane potential, and up-regulated the protein expression of cleaved caspase-3. Moreover, DBA increased the phosphorylation of all three mitogen-activated protein kinases (MAPKs) evaluated. Pre-treatment with specific p38, ERK1/2, and JNK1/2 inhibitors (SB203580, U0126, SP600125, respectively) attenuated the inducible phosphorylation events. DBA also induced up-regulation of mRNA levels of the MAPKs downstream transcription factors ATF-2 and Elk-1. When taken together, the results suggest that DBA could induce murine Cl.Ly1+2/-9 T-cells apoptosis through mitochondria-dependent way, and activate the MAPKs pathways and downstream transcription factors ATF-2 and Elk-1. PMID- 29155132 TI - Stiffening of flexible SUMO1 protein upon peptide-binding: Analysis with anisotropic network model. AB - SUMO (small ubiquitin-like modifier) proteins interact with a large number of target proteins via a key regulatory event called sumoylation that encompasses activation, conjugation and ligation of SUMO proteins through specific E1, E2, and E3-type enzymes respectively. Single-molecule atomic force microscopic (AFM) experiments performed to unravel bound SUMO1 along its NC termini direction reveal that E3-ligases (in the form of small peptides) increase mechanical stability (along the axis) of the flexible protein upon binding. The experimental results are expected to correlate with the intrinsic flexibility of bound SUMO1 protein in the native state i.e., the bound conformation of SUMO1 without the binding peptide. The native protein flexibility/stiffness can be measured as a spring constant by normal mode analysis. In the present study, protein normal modes are computed from the protein structural data (as input from protein databank) via a simple anisotropic network model (ANM). ANM is computationally inexpensive and hence, can be explored to investigate and compare the native conformational dynamics of unbound and bound (without the binding partner) structures, if the corresponding structural data (NMR/X-ray) are available. The paper illustrates that SUMO1 stiffens (native flexibility decreases) along the NC termini (end-to-end) direction of the protein upon binding to small peptides; however, the degree of stiffening is peptide sequence-specific. The theoretical results are demonstrated for NMR structures of unbound SUMO1 and that bound to two peptides having short amino acid motifs and of similar size, one being an M IR2 peptide derived from RanBP2 protein and the other one derived from PIASX protein. The peptide derived from PIASX stiffens SUMO1 remarkably which is evident from an atomic-level normal mode analysis. PMID- 29155131 TI - Human lung epithelial cell cultures for analysis of inhaled toxicants: Lessons learned and future directions. AB - The epithelium that covers the conducting airways and alveoli is a primary target for inhaled toxic substances, and therefore a focus in inhalation toxicology. The increasing concern about the use of animal models has stimulated the development of in vitro cell culture models for analysis of the biological effects of inhaled toxicants. However, the validity of the current in vitro models and their acceptance by regulatory authorities as an alternative to animal models is a reason for concern, and requires a critical review. In this review, focused on human lung epithelial cell cultures as a model for inhalation toxicology, we discuss the choice of cells for these models, the cell culture system used, the method of exposure as well as the various read-outs to assess the cellular response. We argue that rapid developments in the 3D culture of primary epithelial cells, the use of induced pluripotent stem cells for generation of lung epithelial cells and the development of organ-on-a-chip technology are among the important developments that will allow significant advances in this field. Furthermore, we discuss the various routes of application of inhaled toxicants by air-liquid interface models as well as the vast array of read-outs that may provide essential information. We conclude that close collaboration between researchers from various disciplines is essential for development of valid methods that are suitable for replacement of animal studies for inhalation toxicology. PMID- 29155133 TI - SEIRS epidemics with disease fatalities in growing populations. AB - An SEIRS epidemic with disease fatalities is introduced in a growing population (modelled as a super-critical linear birth and death process). The study of the initial phase of the epidemic is stochastic, while the analysis of the major outbreaks is deterministic. Depending on the values of the parameters, the following scenarios are possible. i) The disease dies out quickly, only infecting few; ii) the epidemic takes off, the number of infected individuals grows exponentially, but the fraction of infected individuals remains negligible; iii) the epidemic takes off, the number of infected grows initially quicker than the population, the disease fatalities diminish the growth rate of the population, but it remains super critical, and the fraction of infected go to an endemic equilibrium; iv) the epidemic takes off, the number of infected individuals grows initially quicker than the population, the diseases fatalities turn the exponential growth of the population to an exponential decay. PMID- 29155134 TI - The expected value of the squared cophenetic metric under the Yule and the uniform models. AB - The cophenetic metrics dphi,p, for p ? {0} ? [1, infinity), are a recent addition to the kit of available distances for the comparison of phylogenetic trees. Based on a fifty years old idea of Sokal and Rohlf, these metrics compare phylogenetic trees on a same set of taxa by encoding them by means of their vectors of cophenetic values of pairs of taxa and depths of single taxa, and then computing the Lp norm of the difference of the corresponding vectors. In this paper we compute the expected value of the square of dphi,2 on the space of fully resolved rooted phylogenetic trees with n leaves, under the Yule and the uniform probability distributions. PMID- 29155136 TI - Adipose tissue and reproductive health. AB - The understanding of adipose tissue role has evolved from that of a depot energy storage organ to a dynamic endocrine organ. While genetics, sexual phenotype and sex steroids can impact the mass and distribution of adipose tissue, there is a counter-influence of white adipocytes on reproduction. This primarily occurs via the secretion of adipokines, the most studied of which- leptin and adiponectin- are highlighted in this article. Leptin, the "satiety hormone" primarily acts on the hypothalamus via pro-opiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related peptide (AgRP) neurons to translate acute changes in nutrition and energy expenditure, as well as chronic adipose accumulation into changes in appetite and potentially mediate insulin resistance via shared pathway and notably impacting reproductive health via influence on GnRH secreting neurons. Meanwhile, adiponectin is notable for its action in mediating insulin sensitivity, with receptors found at every level of the reproductive axis. Both have been examined in the context of physiologic and pathologic reproductive conditions. Leptin has been shown to influence puberty, pregnancy, hypothalamic amenorrhea, and lipodystrophy, and with a potential therapeutic role for both metabolic and reproductive health. Adiponectin mediates the relative state of insulin resistance in pregnancy, and has been implicated in conditions such as polycystic ovary syndrome and reproductive malignancies. There are numerous other adipokines, including resistin, visfatin, chemerin and retinol binding protein-4, which may also play roles in reproductive health and disease states. The continued examination of these and other adipokines in both normal reproduction and reproductive pathologies represents an important avenue for continued study. Here, we seek to provide a broad, yet comprehensive overview of many facets of these relationships and highlight areas of consideration for clinicians and future study. PMID- 29155135 TI - Exercise-induced 'browning' of adipose tissues. AB - Global rates of obesity continue to rise and are necessarily the consequence of a long-term imbalance between energy intake and energy expenditure. This is the result of an expansion of adipose tissue due to both the hypertrophy of existing adipocytes and hyperplasia of adipocyte pre-cursors. Exercise elicits numerous physiological benefits on adipose tissue, which are likely to contribute to the associated cardiometabolic benefits. More recently it has been demonstrated that exercise, through a range of mechanisms, induces a phenotypic switch in adipose tissue from energy storing white adipocytes to thermogenic beige adipocytes. This has generated the hypothesis that the process of adipocyte 'browning' may partially underlie the improved cardiometabolic health in physically active populations. Interestingly, 'browning' also occurs in response to various stressors and could represent an adaptive response. In the context of exercise, it is not clear whether the appearance of beige adipocytes is metabolically beneficial or whether they occur as a transient adaptive process to exercise induced stresses. The present review discusses the various mechanisms (e.g. fatty acid oxidation during exercise, decreased thermal insulation, stressors and angiogenesis) by which the exercise-induced 'browning' process may occur. PMID- 29155137 TI - Streaming data from a smartphone application: A new approach to mapping health during travel. AB - BACKGROUND: New research methods offer opportunities to investigate the influence of environment on health during travel. Our study uses data from a smartphone application to describe spatial and environmental patterns in health among travellers. METHODS: A prospective cohort of travellers to Thailand used a smartphone application during their trips to 1) answer a daily questionnaire about health behaviours and events, and 2) collect streaming data on environment, itinerary, and weather. Incidence of health events was described by region and trip type. The relationship between environmental factors and health events was modelled using a logistic mixed model. RESULTS: The 75/101 (74.3%) travellers that completed the study answered 940 questionnaires, 796 (84.7%) of which were geolocated to Southeast Asia. Accidents occurred to 20.0% of participants and were mainly in the Thai islands, while self-rated "severe" mental health events (21.3%) were centred in Bangkok. The odds of a health event were higher in Chiang Mai (2.34, 95% CI: 1.08, 5.08) and on rainy days (1.86, 95% CI: 1.03, 3.36). CONCLUSIONS: Distinct patterns in spatial and environmental risk factors emerged in travellers to Thailand. Location based tracking could identify "hotspots" for health problems and update travel advice to target specific risk groups and regions. PMID- 29155138 TI - HPV16 E5 is produced from an HPV16 early mRNA spliced from SD226 to SA3358. AB - The HPV16 E5 open reading frame (ORF) is present on the majority of all alternatively spliced HPV16 mRNAs, but it is currently unknown how well it is translated into E5 protein. To identify HPV16 mRNAs that are efficiently translated into E5, we have generated cDNA plasmids expressing individual, alternatively spliced HPV16 mRNAs with the potential to produce E5. By replacing the E5 ORF with sLuc, we could quantitate sLuc and determine how well each cDNA was translated. Our results showed that the upstream E1 and E7 AUGs inhibited translation of the E5 ORF and revealed that only one HPV16 mRNA produced high levels of E5. This was an HPV16 early mRNA spliced from SD226 to SA3358. These results were confirmed in the context of the entire HPV16 genome. Taken together, our results indicate that E5 is expressed early in the HPV16 replication cycle since it is translated efficiently only by one early mRNA. PMID- 29155139 TI - The generation and characterisation of neutralising antibodies against the Theiler's murine encephalomyelitis virus (TMEV) GDVII capsid reveals the potential binding site of the host cell co-receptor, heparan sulfate. AB - The early stages of picornavirus capsid assembly and the host factors involved are poorly understood. Since the localisation of viral proteins in infected cells can provide information on their function, antibodies against purified Theiler's murine encephalomyelitis virus (TMEV) GDVII capsids were generated by immunisation of rabbits. The resultant anti-TMEV capsid antibodies recognised a C terminal region of VP1 but not VP2 or VP3 by Western analysis. Examination of the sites of TMEV capsid assembly by indirect immunofluorescence and confocal microscopy showed that at 5h post infection, capsid signal was diffusely cytoplasmic with strong perinuclear staining and moved into large punctate structures from 6 to 8h post infection. A plaque reduction neutralisation assay showed that the anti-TMEV capsid antibodies but not anti-VP1 antibodies could neutralise viral infection in vitro. The VP1 C-terminal residues recognised by the anti-TMEV capsid antibodies were mapped to a loop on the capsid surface near to the putative receptor binding pocket. In silico docking experiments showed that the known TMEV co-receptor, heparan sulfate, interacts with residues of VP1 in the putative receptor binding pocket, residues of VP3 in the adjacent pit and residues of the adjoining VP1 C-terminal loop which is recognised by the anti TMEV capsid antibodies. These findings suggest that the anti-TMEV capsid antibodies neutralise virus infection by preventing heparan sulfate from binding to the capsid. The antibodies produced in this study are an important tool for further investigating virus-host cell interactions essential to picornavirus assembly. PMID- 29155140 TI - Pregnancy and parturition negatively impact vaginal angle and alter expression of vaginal MMP-9. AB - BACKGROUND: Parity is the greatest risk factor for the development of pelvic organ prolapse. The normally supported vagina is pulled up and back over the levator ani. Loss of vaginal angulation has been associated with prolapse and may represent injury to the vaginal supportive tissues. OBJECTIVE: We proposed and examined the following hypotheses: (1) pregnancy and delivery impact vaginal support, leading to loss of vaginal angle; (2) vaginal angulation is restored postpartum; and (3) uncomplicated vaginal delivery (VD) is associated with accelerated remodeling of the vaginal fibrillar matrix. MATERIALS AND METHODS: We prospectively enrolled a cohort of nulliparas in the first trimester of pregnancy, and abstracted demographic and delivery data. Metalloproteinase 9 (MMP 9) activity in the vagina was determined in the first and third trimesters and 1 year postpartum using a substrate activity assay. Uncomplicated VD was defined as none of the following: cesarean delivery, forceps or vacuum use, shoulder dystocia, obstetric anal sphincter laceration, or prolonged second-stage labor. Women were grouped dichotomously for comparison based on this definition. A subset of participants underwent transperineal ultrasound. RESULTS: We enrolled 173 women with mean age of 25 +/- 6 years and a body mass index of 20 +/- 7 kg/m2. Of the women, 67% identified as white/Caucasian, 27% black/African American, or 6% Hispanic/Latina. The mean delivery age was 39 +/- 3 weeks, with 59% of participants experiencing uncomplicated VD. The MMP-9 median activity (ng/mg protein) was 242.0 (IQR, 18.7, 896.8; n = 157) in the first trimester, 130.8 (IQR, 14.6, 883.8; n = 148) in the third trimester, and 463.5 (IQR, 92.2, 900.0; n = 94) postpartum. The MMP-9 activity increased between the third trimester and 1 year postpartum (P = .006), with no significant difference between MMP-9 values in the first and third trimesters (P = .674). The vaginal angle became less acute from the first to the third trimester, and this change persisted postpartum. The vaginal angulation over the levator plate became more acute between the third trimester and postpartum in women who experienced uncomplicated VD compared to those who did not (-6.4 +/- 22.1 degrees vs 17.5 +/- 14.8 degrees; P = .017). Higher MMP-9 activity postpartum was associated with uncomplicated VD, with 67% of women in the third tertile achieving uncomplicated VD versus 39% in the first tertile (P = .029). CONCLUSION: Loss of vaginal angulation occurs between trimesters, and women do not recover their baseline resting angle postpartum. MMP-9 activity increases postpartum. Women experiencing uncomplicated VD demonstrate higher postpartum MMP-9 activity and are more likely to have recovered their vaginal angle. PMID- 29155141 TI - Reply. PMID- 29155142 TI - MicroRNA-30a-3p is overexpressed in the placentas of patients with preeclampsia and affects trophoblast invasion and apoptosis by its effects on IGF-1. AB - OBJECTIVE: Preeclampsia (PE) affects many women globally and remains a primary cause of neonatal and maternal morbidity and mortality. Aberrant placental microRNA (miRNA) expression might be associated with PE. Previously, 33 PE related miRNAs, 11 up-regulated and 23 down-regulated, were detected in placentas of women with severe PE when compared with those of normal patients. One of the most up-regulated miRNAs in PE is miR-30a-3p. The predicted target of it is insulin-like growth factor 1 (IGF-1), which has been reported to have a relatively low expression level in PE patients. This study was conducted to determine the aberrant increased of miR-30a-3p in the placentas of women with preeclampsia and to elucidate the target and function of it in trophoblast cells. STUDY DESIGN: miR-30a-3p expression in placenta tissues was compared between women with preeclampsia (n = 25) and normal pregnant women (n = 20). The miRNA target was studied by in silico and functional assay. The effects of the miRNA were verified by apoptosis assay and invasion assay in the trophoblast cell line. RESULTS: miR-30a-3p was increased significantly in the placenta of women with preeclampsia when compared to those with normal pregnancies. Luciferase assay confirmed direct regulation of miR-30a-3p on the expression of IGF-1. Forced expression of miR-30a-3p suppressed IGF-1 protein expression in the HTR-8/SVneo cells. The functional assay suggests that the over-expression of miR-30a-3p alter the invasive capacity of JEG-3 cells and induce the apoptosis of HTR-8/SVneo cells (Figure). CONCLUSION: Expression of miR-30a-3p was significantly increased in the placentas of patients with preeclampsia. miR-30a-3p might be involved in the pathogenesis of preeclampsia by targeting IGF-1 and regulating the invasion and apoptosis of trophoblast cells. PMID- 29155143 TI - Obeticholic acid raises LDL-cholesterol and reduces HDL-cholesterol in the Diet Induced NASH (DIN) hamster model. AB - The use of rat and mouse models limits the translation to humans for developing novel drugs targeting nonalcoholic steatohepatitis (NASH). Obeticholic acid (OCA) illustrates this limitation since its dyslipidemic effect in humans cannot be observed in these rodents. Conversely, Golden Syrian hamsters have a lipoprotein metabolism mimicking human dyslipidemia since it does express the cholesteryl ester transfer protein (CETP). We therefore developed a Diet-Induced NASH (DIN) hamster model and evaluated the impact of OCA. Compared with chow fed controls, hamsters fed for 20 weeks with a free-choice (FC) diet, developed obesity, insulin resistance, dyslipidemia and NASH (microvesicular steatosis, inflammation, hepatocyte ballooning and perisinusoidal to bridging fibrosis). After 20 weeks of diet, FC fed hamsters were treated without or with obeticholic acid (15mg/kg/day) for 5 weeks. Although a non-significant trend towards higher dietary caloric intake was observed, OCA significantly lowered body weight after 5 weeks of treatment. OCA significantly increased CETP activity and LDL-C levels by 20% and 27%, and reduced HDL-C levels by 20%. OCA blunted hepatic gene expression of Cyp7a1 and Cyp8b1 and reduced fecal bile acids mass excretion by 64% (P < 0.05). Hamsters treated with OCA showed a trend towards higher scavenger receptor Class B type I (SR-BI) and lower LDL-receptor hepatic protein expression. OCA reduced NAS score for inflammation (P < 0.01) and total NAS score, although not significantly. Compared to mouse and rat models, the DIN hamster replicates benefits and side effects of OCA as observed in humans, and should be useful for evaluating novel drugs targeting NASH. PMID- 29155144 TI - BAY 60-2770 activates two isoforms of nitric oxide sensitive guanylyl cyclase: Evidence for stable insertion of activator drugs. AB - Nitric oxide sensitive guanylyl cyclase (NOsGC), a hemoprotein and the major physiological receptor for nitric oxide (NO), is a heterodimer with the alpha1/beta1 and alpha2/beta1 isoforms known to be important for NO-signaling and conversion of GTP to cGMP in humans. Two innovative classes of compounds modulating the NO/cGMP signaling pathway have been discovered: the heme-dependent sGC stimulators, that stimulate NOsGC directly and also increase the affinity towards NO, and the heme-independent sGC activators, that are thought to bind to oxidized and heme-free NOsGC in tissues exposed to oxidative stress. In the current study, we evaluate the effects of the sGC activators BAY 58-2667 (cinaciguat) and BAY 60-2770 on the isoforms alpha1/beta1 and alpha2/beta1 expressed in Sf9 cells. Western blot analysis of cytosolic fractions revealed a decrease in overexpressed NOsGC in the presence of sGC activators, which is dependent on an intact catalytic site of the enzyme. For both isoforms, we show a higher efficacy for BAY 60-2770 compared to cinaciguat after purification of NOsGC by affinity and size exclusion chromatography. Using a new experimental strategy of expression of NOsGC with activator and subsequent purification, we demonstrate a stable insertion of activator drugs into the enzyme during protein biosynthesis independent of the heme redox state. We postulate that the balance between stable insertion of activator during de novo synthesis and replacement of NOsGC ferric heme in tissues exposed to oxidative stress can be influenced by the dosage regimen. PMID- 29155145 TI - Differential effects of the Nrf2 activators tBHQ and CDDO-Im on the early events of T cell activation. AB - We previously demonstrated that activation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) promotes CD4+ Th2 differentiation. In the current study, we assessed the role of Nrf2 in early events following T cell activation. The Nrf2 activators, tBHQ (tert-butylhydroquinone) and CDDO-Im (the imidazolide derivative of the triterpenoid CDDO), were used in conjunction with splenocytes derived from wild-type and Nrf2-null mice to distinguish between Nrf2 specific and off-target effects. CDDO-Im inhibited early IFNgamma production in a largely Nrf2-dependent manner. In contrast, tBHQ and CDDO-Im had little effect on expression of CD25 or CD69. Furthermore, tBHQ inhibited GM-CSF and IL-2 production in both wild-type and Nrf2-null T cells, suggesting this effect is Nrf2-independent. Conversely, CDDO-Im caused a concentration-dependent increase in IL-2 secretion in wild-type, but not Nrf2-null, splenocytes, suggesting that Nrf2 promotes IL-2 production. Interestingly, both compounds inhibit NFkappaB DNA binding, where the suppression by tBHQ is Nrf2-independent and CDDO-Im is Nrf2 dependent. Surprisingly, as compared to wild-type splenocytes, Nrf2-null splenocytes showed lower nuclear accumulation of c-Jun, a member of the AP-1 family of transcription factors, which have been shown to drive multiple immune genes, including IL-2. Both Nrf2 activators caused a Nrf2-dependent trend toward increased nuclear accumulation of c-Jun. These data suggest that modulation of cytokine secretion by tBHQ likely involves multiple pathways, including AP-1, NFkappaB, and Nrf2. Overall, the data suggest that Nrf2 activation inhibits secretion of the Th1 cytokine IFNgamma, and increases early production of IL-2, which has been shown to promote Th2 differentiation, and may support the later occurrence of Th2 polarization. PMID- 29155146 TI - HDAC inhibitor suppresses proliferation and invasion of breast cancer cells through regulation of miR-200c targeting CRKL. AB - Although histone deacetylase (HDAC) inhibitors have been shown to effectively induce the inhibition of proliferation and migration in breast cancer, the anticancer mechanism remains poorly understood. Our studies show that miR-200c was significantly downregulated in breast cancer cell lines compared to normal cell lines and inversely correlated with the levels of class IIa HDACs and CRKL. HDAC inhibitors and the ectopic expression of miR-200c as tumor suppressors inhibited the proliferation, invasion, and migration of breast cancer cells by downregulating CRKL. These results indicate that the anticancer mechanism of HDAC inhibitor was realized partially by regulating miR-200c via CRKL targeting. Our findings suggest that the HDAC-miR200c-CRKL signaling axis could be a novel diagnostic marker and potential therapeutic target in breast cancer. PMID- 29155148 TI - Functional properties and mechanism of action of PPTQ, an allosteric agonist and low nanomolar positive allosteric modulator at GABAA receptors. AB - The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator (PAM) at GABAA receptors (GABAARs) (Hammer et al., 2015). In the present study, we have identified a novel methaqualone analog, 2-phenyl-3-(p-tolyl)quinazolin-4(3H)-one (PPTQ), in a screening of 67 analogs at five alphabeta2gamma2S GABAAR subtypes and delineated its functional properties and mechanism of action at wild-type and mutant GABAARs expressed in Xenopus laevis oocytes by two-electrode voltage clamp electrophysiology. PPTQ was found to be an allosteric agonist and a PAM (ago-PAM) at human alpha1beta2gamma2S and alpha4beta2delta GABAARs, exhibiting intrinsic activity at micromolar concentrations and potentiating the GABA-evoked signaling through the receptors at concentrations down to the low-nanomolar range. Whereas PPTQ exclusively increased the potency of GABA at the alpha1beta2gamma2S receptor, it increased both GABA potency and efficacy at alpha4beta2delta and displayed modest potency-based preference for alpha4beta2delta over alpha1beta2gamma2S. In elaborate mutagenesis and competition experiments PPTQ was found to act through the same or an overlapping site as etomidate in the transmembrane beta(+)/alpha(-) subunit interfaces, whereas it did not seem to target the other three transmembrane interfaces in the GABAAR. Finally, the PPTQ site was shown to be allosterically linked with sites targeted by neurosteroids and barbiturates but not with the high-affinity benzodiazepine site in the alpha1beta2gamma2S receptor. In conclusion, the development of a highly potent, bioavailable GABAAR ago-PAM by subtle modifications to the methaqualone scaffold demonstrates that derivatization of this infamous drug from the past can lead to modulators with distinct functional characteristics at the receptors. PMID- 29155147 TI - Selective and membrane-permeable small molecule inhibitors of nicotinamide N methyltransferase reverse high fat diet-induced obesity in mice. AB - There is a critical need for new mechanism-of-action drugs that reduce the burden of obesity and associated chronic metabolic comorbidities. A potentially novel target to treat obesity and type 2 diabetes is nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with newly identified roles in cellular metabolism and energy homeostasis. To validate NNMT as an anti-obesity drug target, we investigated the permeability, selectivity, mechanistic, and physiological properties of a series of small molecule NNMT inhibitors. Membrane permeability of NNMT inhibitors was characterized using parallel artificial membrane permeability and Caco-2 cell assays. Selectivity was tested against structurally related methyltransferases and nicotinamide adenine dinucleotide (NAD+) salvage pathway enzymes. Effects of NNMT inhibitors on lipogenesis and intracellular levels of metabolites, including NNMT reaction product 1-methylnicotianamide (1 MNA) were evaluated in cultured adipocytes. Effects of a potent NNMT inhibitor on obesity measures and plasma lipid were assessed in diet-induced obese mice fed a high-fat diet. Methylquinolinium scaffolds with primary amine substitutions displayed high permeability from passive and active transport across membranes. Importantly, methylquinolinium analogues displayed high selectivity, not inhibiting related SAM-dependent methyltransferases or enzymes in the NAD+ salvage pathway. NNMT inhibitors reduced intracellular 1-MNA, increased intracellular NAD+ and S-(5'-adenosyl)-l-methionine (SAM), and suppressed lipogenesis in adipocytes. Treatment of diet-induced obese mice systemically with a potent NNMT inhibitor significantly reduced body weight and white adipose mass, decreased adipocyte size, and lowered plasma total cholesterol levels. Notably, administration of NNMT inhibitors did not impact total food intake nor produce any observable adverse effects. These results support development of small molecule NNMT inhibitors as therapeutics to reverse diet-induced obesity and validate NNMT as a viable target to treat obesity and related metabolic conditions. Increased flux of key cellular energy regulators, including NAD+ and SAM, may potentially define the therapeutic mechanism-of-action of NNMT inhibitors. PMID- 29155149 TI - Drug hypersensitivity: We need to do more. PMID- 29155150 TI - Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation. AB - BACKGROUND: Immunity decreases with age, which leads to reactivation of varicella zoster virus (VZV). In human subjects age-associated immune changes are usually measured in blood leukocytes; however, this might not reflect alterations in tissue-specific immunity. OBJECTIVES: We used a VZV antigen challenge system in the skin to investigate changes in tissue-specific mechanisms involved in the decreased response to this virus during aging. METHODS: We assessed cutaneous immunity based on the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsy specimens taken from the challenge site in young (<40 years) and old (>65 years) subjects. RESULTS: Old human subjects exhibited decreased erythema and induration, CD4+ and CD8+ T-cell infiltration, and attenuated global gene activation at the site of cutaneous VZV antigen challenge compared with young subjects. This was associated with increased sterile inflammation in the skin in the same subjects related to p38 mitogen-activated protein kinase-related proinflammatory cytokine production (P < .0007). We inhibited systemic inflammation in old subjects by means of pretreatment with an oral small-molecule p38 mitogen-activated protein kinase inhibitor (Losmapimod; GlaxoSmithKline, Brentford, United Kingdom), which reduced both serum C-reactive protein levels and peripheral blood monocyte secretion of IL-6 and TNF-alpha. In contrast, cutaneous responses to VZV antigen challenge were increased significantly in the same subjects (P < .0003). CONCLUSION: Excessive inflammation in the skin early after antigen challenge retards antigen-specific immunity. However, this can be reversed by inhibition of inflammatory cytokine production that can be used to promote vaccine efficacy and the treatment of infections and malignancy during aging. PMID- 29155151 TI - HbA1c monitoring interval in patients on treatment for stable type 2 diabetes. A ten-year retrospective, open cohort study. AB - [Aims] This study aims to suggest an informative interval for HbA1c in DM patients with stable glycemic control, based on test characteristics of the HbA1C assay using the signal-to-noise ratio method. [Methods] This was a retrospective, open cohort study. Data were collected between January 2005 to December 2014 at a tertiary-level community hospital in Japan. All adult patients aged under 75 years, with stable glycemic control on a first pharmaceutical regimen for Type II diabetes, and at least two HbA1c measurements after they achieved glycemic stability, were included in the analysis. We defined stable glycemic control as HbA1c <7.0% (52 mmol/mol) and requiring no change in the medication regimen after three consecutive measurements. We adapted a signal-to-noise method for distinguishing true change from measurement error by constructing a linear random effects model to calculate signal and noise for HbA1c. The screening interval for HbA1c was defined as informative when the signal-to-noise ratio exceeded 1. [Results] Among 1066 adults with diabetes, 639 patients (18.5%) were identified as achieving stable glycemic control (511 male (67.3%)), with a mean HbA1c (SD) of 6.4 (0.4)% (46 mmol/mol). Patients with stable glycemic control increase their HbA1c 0.27% (3 mmol/mol) every year while HbA1c has 0.32% (3.5 mmol/mol) noise, as testing characteristics. Signal exceeds noise after 1.2 years (95%CI: 0.9 1.6). [Conclusion] Once patients achieve stable glycemic control at their HbA1c goal, an informative interval for HbA1c monitoring is once every year. Current guidelines, which suggest testing every six months, may contribute to substantial over-testing. PMID- 29155152 TI - Higher prevalence and earlier appearance of geriatric phenotypes in old adults with type 2 diabetes mellitus. AB - AIMS: To compare the prevalence of cognitive dysfunction, depression, lower mobility performance, disability and falls in older community-dwelling individuals with type 2 diabetes mellitus (T2DM) and in controls of similar age. METHODS: We conducted a cross-sectional study in primary health care settings in 3 semi-urban regions in Greece. Were assessed 403 community-dwelling older persons (age >=65 years, median: 73), 198 with and 205 without diabetes. Common geriatric syndromes were studied using structured individual interviews and widely-used screening scales. An ensuing secondary analysis per age group was performed. RESULTS: After adjusting for several confounding factors, the diabetes group presented a 2-fold greater odds of having abnormal scores in Mini Mental State Examination (95%CI: 1.2-3.4, p = 0.006), a 1.5-fold greater odds of abnormal performance in the Clock Drawing Test (95%CI: 1.0-2.4, p = 0.05) and a 2 fold greater odds of slower performance in Timed-Up-And-Go test (95%CI: 1.1-3.4, p = 0.022). In the analysis per age group, impaired cognitive and mobility performances were observed in individuals with diabetes of the younger subgroup (65-74 years), while in the older subgroup (>=75 years), those differences disappeared. CONCLUSIONS: In a community-dwelling population aged >=65 years, cognitive and physical fragilisation is more frequent and is observed at an earlier age in individuals with T2DM than in those without. PMID- 29155153 TI - The GLP-1 response to glucose does not mediate beta and alpha cell dysfunction in Hispanics with abnormal glucose metabolism. AB - AIMS: Glucagon-like peptide-1 (GLP-1) contributes to insulin secretion after meals. Though Hispanics have increased risk for type 2 diabetes mellitus, it is unknown if impaired GLP-1 secretion contributes to this risk. We therefore studied plasma GLP-1 secretion and action in Hispanic adults. METHODS: Hispanic (H; n = 31) and non-Hispanic (nH; n = 15) participants underwent an oral glucose tolerance test (OGTT). All participants were categorized by glucose tolerance into four groups: normal glucose tolerant non-Hispanic (NGT-nH; n = 15), normal glucose tolerant Hispanic (NGT-H; n = 12), impaired glucose tolerant Hispanic (IGT-H; n = 11), or newly diagnosed type 2 diabetes mellitus, Hispanic (T2D-H; n = 8). RESULTS: Glucose-induced increments in plasma GLP-1 (Delta-GLP-1) were not different in NGT-H and NGT-nH (p = .38), nor amongst Hispanic subgroups with varying degrees of glucose homeostasis (p = .6). In contrast, the insulinogenic index in T2D-H group was lower than the other groups (p = .016). Subjects with abnormal glucose homeostasis (AGH), i.e., T2D-H plus IGT-H, had a diminished glucagon suppression index compared to patients with normal glucose homeostasis (NGT-H plus NGT-nH) (p = .035). CONCLUSIONS: GLP-1 responses to glucose were similar in Hispanic and Non-Hispanic NGT. Despite similar glucose-induced Delta GLP-1, insulin and glucagon responses were abnormal in T2D-H and AGH, respectively. Thus, impaired GLP-1 secretion is unlikely to play a role in islet dysfunction in T2D. Although GLP-1 therapeutics enhance insulin secretion and glucagon suppression, it is likely due to pharmacological amplification of the GLP-1 pathways rather than treatment of hormonal deficiency. PMID- 29155154 TI - Poly(L-lactic acid) nanofibers containing Cissus quadrangularis induced osteogenic differentiation in vitro. AB - Cissus quadrangularis (CQ) is known as "bone setter" in Ayurvedic Medicine because of its ability to promote fracture healing. Polymers incorporated with CQ at lower concentration have shown to enhance osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro. However, for the healing of clinically relevant critical sized bone defects, large amount of CQ would be required. Based on this perception, a herbal fibrous sheet containing high weight percentage of CQ [20,40 and 60wt/wt% in poly (L-lactic acid) (PLLA)] was fabricated through electrospinning. The solution concentration, flow rate, voltage and tip-target distance was optimized to obtain nanofibers. The hydrophobicity of PLLA fibers was reduced through CQ incorporation. There was considerable increase in the adhesion, proliferation and osteogenic differentiation of MSCs on herbal fibers than normal fibers, mainly on P-Q20 and P-CQ40. MSCs were differentiated into osteoblasts without providing any osteogenic supplements in the medium, indicating its osteoinductive capability. The herbal sheet also could promote mineralization when immersed in simulated body fluid for 14days. These studies specify that PLLA nanofibers loaded with 20 and 40wt% of CQ could serve as a potential candidate for bone tissue engineering applications. PMID- 29155155 TI - Green carboxymethyl cellulose-silver complex versus cellulose origins in biological activity applications. AB - This article deals with evaluating the role of cellulose origin, from wood and non-wood, on preparing green CMC-Ag complex as biological active agent. Viscose pulp as well as bagasse and rice straw pulps were used in preparation of CMCs, followed by complexation with AgNO3. The complex structure (free-Ag, IR-spectra and TGA), morphology (TEM), antibiological and anti-tumor activities were studied. The data revealed that, the main interaction between CMC and silver is occurred via carboxylate groups and ether link of 1ry alcohol, with formation stable 5-membered ring structure. For the case of RS-based CMC-Ag complex the interaction between COO groups and silica included RS is also possible, via hydrogen bonds. These complexes have anti-biological especially towards gram positive bacteria (B.subtilis, NCID-3610), and uni- and multi cellular fungi. AgNPs from viscose (VCMC-Ag complex) has relatively higher anti-tumor activity for breast cancer MCF-7 in vitro than bagasse-based CMC-Ag complex (BCMC-Ag complex) with IC50 128MUg/ml (as Ag). It is interesting to note that; viscose based CMC-Ag complex (VCMC-Ag) has higher efficient behaviour as bioactive agent than literature reported agents, e.g., Pyridine derivative (~300MUg/ml). PMID- 29155157 TI - Synthesis, characterization, and the antifungal activity of chitosan derivatives containing urea groups. AB - As an abundant and renewable polysaccharide, chitosan has been drawing broad attention due to its natural properties. For the further utilization of chitosan, chemical modification can be applied in improving its water solubility and the bioactivities. In this study, four chitosan derivatives were synthesized by the reaction of chloracetyl chitosan derivative with quaternary ammonium salt (CTCS) and urea groups bearing 4-amino-pyridine, including BCTCS, 2CBCTCS, 3CBCTCS, and 4CBCTCS. The structure characteristics of synthesized products were established based on FT-IR spectroscopy, 1H NMR, and elemental analysis. Their antifungal activities against Fusarium oxysporum f. sp. niveum, Phomopsis asparagus, Fusarium oxysporum f. sp. cucumebrium Owen, and Botrytis cinerea were estimated by hyphal measurement in vitro. Generally, the inhibition ratio of most products was higher than 80% at 1.0mg/mL. Their inhibitory activity decreased roughly in the order: 4CBCTCS>3CBCTCS>2CBCTCS>BCTCS>CTCS>chitosan, resulted from the different degrees of substitution of the effectively active groups-urea groups. Meanwhile, the effects on beneficial soil microbes, including Bacillus cereus, Bacillus subtilis, and Sinorhizobium saheli LMG7837, of these synthesized chitosan derivatives were evaluated by disk diffusion method. The results showed that these substances do not inhibit the growth of beneficial bacteria and some of them could be employed as green antifungal biomaterials. PMID- 29155156 TI - Allicin functionalized locust bean gum nanoparticles for improved therapeutic efficacy: An in silico, in vitro and in vivo approach. AB - The field of nanotechnology has overgrown over the past few years and has even ventured into the field of medicine. The aim of the present study is to develop a novel allicin functionalized locust bean gum nanoparticle using the nanoprecipitation technique. The synthesized nanoparticles were characterized by dynamic light scattering, scanning electron microscopy and transmission electron microscopy. The characterization study revealed the nanoscale structure (~100nm) of the prepared particles. In silico toxicology analysis were carried out to assess the drug-like properties and virtual toxicity of allicin. Toxicity of the prepared nanoparticles were carried out in RAW 264.7 cell lines in vitro and in vivo studies were carried out in Sprague-Dawley rats. In in vitro study, LBGAN showed a maximum toxicity of 10.51% in MTT assay, no reactive oxygen species generation on DCFDA staining and LBGAN was effective to protect the cells from apoptosis. In in vivo toxicity studies LBGAN showed no significant change in the activities of the marker enzymes like LDH, CK-MB, ALP, ACP, AST and ALT. Thus, the functionalization of nanoparticles with allicin has the benefit of providing protection and stability to the allicin, in addition to increasing its pharmacological activity. PMID- 29155158 TI - Thermodynamic investigation of an alkaline protease from Aspergillus tamarii URM4634: A comparative approach between crude extract and purified enzyme. AB - The thermostable crude proteolytic extract and purified protease produced by Aspergillus tamarii URM4634 were investigated at different temperatures. The activity results were used to estimate the activation energy of the hydrolysis reaction catalyzed by crude extract and purified protease (E*=34.2 and 16.2kJ/mol) as well as the respective standard enthalpy variations of reversible enzyme unfolding (DeltaH degrees u=31.9 and 13.9kJ/mol). When temperature was raised from 50 to 80 degrees C in residual activity tests, the specific rate constant of crude proteolytic extract thermoinactivation increased from 0.0072 to 0.0378min-1, while that of purified protease from 0.0099 to 0.0235min-1. These values, corresponding to half-life decreases from 96.3 to 18.3min and from 70.0 to 29.5min, respectively, enabled us to estimate the activation energy (E*d=49.7 and 28.8kJ/mol), enthalpy (DeltaH*d=47.0 and 26.1kJ/mol), entropy (DeltaS*d= 141.3 and -203.1J/molK) and Gibbs free energy (92.6<=DeltaG*d<=96.6kJ/mol and 91.8<=DeltaG*d<=98.0kJ/mol) of thermoinactivation. Such values suggest that this protease, which proved to be highly thermostable in both forms, could be profitably exploited in industrial applications. To the best of our knowledge, this is the first comparative study on thermodynamic parameters of a serine protease produced by Aspergillus tamarii URM4634. PMID- 29155159 TI - Purification, characterization and anti-tumor activities of polysaccharides extracted from wild Russula griseocarnosa. AB - The anti-tumor activity of a novel polysaccharide, PRG1-1, obtained from Russula griseocarnosa sporocarp was investigated in this paper. PRG1-1 has a molecular weight of 630kDa and was extracted and purified using DEAE-cellulose and gel filtration chromatography from crude polysaccharide extract of R. griseocarnosa sporocarp. PRG1-1 was composed of glucose, galactose, mannose, xylose and fructose, in a molar ratio of 66.5:29.2:3.17: 0.663:0.447, respectively. Purified PRG1-1 significantly reduced cell viability, increased the production of lactate dehydrogenase (LDH) and reactive oxygen species (ROS), and enhanced the apoptotic rate in HeLa and SiHa cells. Furthermore, after 24h of PRG1-1 exposure the expression levels of cleaved PARP and caspase-3 were increased and mitochondrial cytochrome c was induced to release to the cytosol. Collectively, our results suggested that the cytotoxicity effects of PRG1-1 on human cervical carcinoma are associated with the apoptotic pathway. These data indicate the promising potential of bioactive PRG1-1 as natural agent to inhibit tumor cell proliferation in the treatment of cervical carcinoma. PMID- 29155160 TI - alphavbeta3 and alpha5beta1 integrin-specific ligands: From tumor angiogenesis inhibitors to vascularization promoters in regenerative medicine? AB - Integrins are cell adhesion receptors predominantly important during normal and tumor angiogenesis. A sequence present on several extracellular matrix proteins composed of Arg-Gly-Asp (RGD) has attracted attention due to its role in cell adhesion mediated by integrins. The development of ligands that can bind to integrins involved in tumor angiogenesis and brake disease progression has resulted in new investigational drug entities reaching the clinical trial phase in humans. The use of integrin-specific ligands can be useful for the vascularization of regenerative medicine constructs, which remains a major limitation for translation into clinical practice. In order to enhance vascularization, immobilization of integrin-specific RGD peptidomimetics within constructs is a recommended approach, due to their high specificity and selectivity towards certain desired integrins. This review endeavours to address the potential of peptidomimetic-coated biomaterials as vascular network promoters for regenerative medicine purposes. Clinical studies involving molecules tracking active integrins in cancer angiogenesis and reasons for their failure are also addressed. PMID- 29155161 TI - Extracellular vesicles compartment in liquid biopsies: Clinical application. AB - Liquid biopsy is becoming a new source of biomarkers that complement and resolve some of the most important limitations of surgical biopsy, which are the accessibility to the diseased tissue and its heterogeneity, especially relevant for tumors. The diseased tissues release their molecule content to the bloodstream in free form, inside a cell or within extracellular vesicles (EVs). While the identification of molecular alterations in total DNA isolated from peripheral blood is already in use for some tumors that secrete large amounts of DNA, it is challenging to assay those secreting lower amounts of molecules as well as for many other non-tumoral pathologies like immunological and cardiovascular diseases. In this scenery, the compartment of diseased tissue derived EVs will be one of the best alternatives for the detection and identification of current and new biomarkers and targets in the clinical management of these diseases. Here, we review the mechanisms of molecular internalization as well as the correlation of EV's cargo with clinical parameters in tumor and non-tumor diseases, with special emphasis in clinical application. PMID- 29155162 TI - Chorioamnionitis due to Leptotrichia trevisanii. AB - Very long fusiform gram-negative bacilli were observed after Gram staining of amniotic fluid from a 36-year-old multigravida woman. At 24 hours, pure, abundant growth of smooth, gray, only slightly convex catalase-positive and oxidase negative colonies measuring about 2 mm were observed. Growth was greater in anaerobic than in aerobic conditions. The bacterium was identified as Leptotrichia trevisanii by matrix-assisted laser desorption ionization time of flight mass spectrometry. Ampicillin and gentamicin were prescribed for chorioamnionitis, and vaginal prostaglandins were administered to terminate the pregnancy. The patient remained afebrile throughout 48 hours and was discharged. Microscopic examination of the placenta revealed severe acute chorioamnionitis with a maternal inflammatory response and abundant bacillary-shaped microorganisms. To our knowledge, this isolate constitutes the first reported case of chorioamnionitis caused by L. trevisanii. PMID- 29155163 TI - Antifungal azoles itraconazole and posaconazole exhibit potent in vitro antiviral activity against clinical isolates of parechovirus A3 (Picornaviridae). AB - Parechovirus A3 (Par-A3, formerly human parechovirus 3) is an emerging viral infection of the central nervous system in children. We used an automated, homogeneous, cell based assay to identify itraconazole and posaconazole as inhibitors of Par-A3, with antiviral activity below concentrations clinically attainable in pediatric patients. Currently, there is no approved antiviral treatment for Par-A3 infection, despite numerous reports of serious Par-A3 disease in neonates and infants. PMID- 29155164 TI - A new promising candidate to overcome drug resistant herpes simplex virus infections. AB - Infections with Herpes simplex viruses (HSV) belong to the most common human diseases worldwide, resulting in symptoms ranging from painful, but commonly self limiting lesions of the orofacial or genital tract to severe infections of the eye or life-threatening generalized infections. Frequent HSV-reactivations at the eye may lead to the development of herpetic stromal keratitis, which is one of the major causes of infectious blindness in developed countries. The vast majority of life-threatening generalized infections occur in immunocompromised individuals, such as transplant recipients or patients suffering from advanced human immunodeficiency virus (HIV) infection with concurrent HSV-reactivation. Over the past decades, Acyclovir (ACV) became the golden standard for the treatment of HSV infections. However, long-term antiviral treatment, as it is required mainly in immunocompromised patients, led to the emergence of resistances towards ACV and other antivirals. Therefore, there is a clear need for the development of new potent antivirals which combine good oral bioavailability and tolerability with low side effects. In the current study we present SC93305 as a novel potent antiviral substance that proved to be highly effective not only against different HSV-1 and HSV-2 strains but also towards ACV and multi-resistant HSV-1 and HSV-2 isolates. SC93305 shows comparable antiviral activity as reported for ACV and very importantly it does not interfere with the activation of specific immune cells. Here we report that SC93305 does not affect the biological function of dendritic cells (DC), the most potent antigen presenting cells of the immune system to induce antiviral immune responses, nor T cell stimulation or the release of inflammatory cytokines. Thus, SC93305 is a new and promising candidate for the treatment of HSV-1 and HSV-2 infections and in particular also for the inhibition of drug-resistant HSV-1/2 strains. PMID- 29155165 TI - Bovine babesiosis: Cattle protected in the field with a frozen vaccine containing Babesia bovis and Babesia bigemina cultured in vitro with a serum-free medium. AB - An attenuated live vaccine containing Babesia bovis and B. bigemina cultured in vitro with a serum-free medium was assessed for its clinical protection conferred of naive cattle, under natural tick-challenge in a high endemicity zone to Babesia spp. Three groups of six animals were treated as follows: group I (GI) received a vaccine derived from parasites cultured with a free-serum medium; group II (GII) were immunized with the standard vaccine, with parasites cultured in a medium supplemented with 40% (v/v) bovine serum; and a control group (GIII) inoculated with non-infected bovine erythrocytes. Inocula were administered by IM route. Experimental animals were kept during 23days after vaccination in a cattle farm free of ticks and Babesia spp. Thereafter, cattle were moved to a high endemicity farm for natural exposure to Babesia spp. transmitted by Rhipicephalus microplus ticks. Protection against clinical babesiosis was observed in bovines belonging to GI (100%) and GII (83.33%), while the control animals (GIII) were not protected, and showed severe clinical signs, closely related to babesiosis, were observed for at least three consecutive days during the challenge. These were fever, anemia, which were measured simultaneously, and circulating parasites were detected by optic light microscopy. All cattle showed B. bovis and B. bigemina in stained blood films during the challenge; B. bovis antibody titers were higher than those to B. bigemina in GI and GII, and lower titers were determined in GIII. The protective capacity of the vaccine derived from B. bovis and B. bigemina cultured in vitro in a serum-free medium was demonstrated. PMID- 29155166 TI - Do Correlates of Pain-Related Stoicism and Cautiousness Differ in Younger and Older People With Advanced Cancer? AB - : Age differences are not evident in pain-related stoicism and cautiousness in people with cancer pain. Little is known about the factors associated with these pain-related attitudes or age-related patterns in these associations. The present cross-sectional study investigated the biopsychosocial correlates of the attitudes in younger and older patients with advanced cancer. Pain-related stoicism (fortitude, concealment, superiority) and cautiousness (self-doubt, reluctance) were assessed using the Pain Attitudes Questionnaire-Revised (PAQ-R). Participants, 155 younger (younger than 60 years old) and 114 older (60 years old or older) patients with advanced cancer completed the PAQ-R and measures of sociodemographic and medical characteristics, pain intensity, cognitive-affective pain-related responses, physical functioning, psychological distress and well being, and psychosocial functioning. Backwards regression analyses identified correlates for each PAQ-R factor separately for younger and older patients. Activity engagement was a frequent correlate, but its relationship with concealment was the only association common to both age groups. Younger and older patients exhibited different avoidance-related constructs suggesting relational challenges in the former group (avoidant attachment) and intrapersonal fear in the latter (cognitive avoidance). Medical correlates also showed age differences: younger patients showed symptom-focused correlates, whereas older patients showed aging-related correlates. Findings support a biopsychosocial framework of cancer pain adaptation incorporating a lifespan-developmental perspective. PERSPECTIVE: To our knowledge, this article is the first to identify biopsychosocial correlates of stoic and cautious attitudes toward cancer pain in younger and older patients with advanced cancer. Findings highlight possible age-related motivations for greater pain-related stoicism or cautiousness and can potentially inform interventions addressing challenges in cancer-pain adaptation in advanced cancer. PMID- 29155167 TI - Bile Acids and Bowel Function: Do They Play a Role in Constipation-Associated Irritable Bowel Syndrome? PMID- 29155168 TI - Improved Assessment of Bolus Clearance in Patients With Achalasia Using High Resolution Impedance Manometry. AB - BACKGROUND & AIMS: Esophageal retention is typically evaluated by timed-barium esophagram in patients treated for achalasia. Esophageal bolus clearance can also be evaluated using high-resolution impedance manometry. We evaluated the associations of conventional and novel high-resolution impedance manometry metrics, esophagram, and patient-reported outcomes (PROs) in achalasia. METHODS: We performed a prospective study of 70 patients with achalasia (age, 20-81 y; 30 women) treated by pneumatic dilation or myotomy who underwent follow-up evaluations from April 2013 through December 2015 (median, 12 mo after treatment; range, 3-183 mo). Patients were assessed using timed-barium esophagrams, high resolution impedance manometry, and PROs, determined from Eckardt scores (the primary outcome) and the brief esophageal dysphagia questionnaire. Barium column height was measured from esophagrams taken 5 minutes after ingestion of barium (200 mL). Impedance-manometry was analyzed for bolus transit (dichotomized) and with a customized MATLAB program (The MathWorks, Inc, Natick, MA) to calculate the esophageal impedance integral (EII) ratio. RESULTS: Optimal cut points to identify a good PRO (defined as Eckardt score of <=3) were esophagram barium column height of 3 cm (identified patients with a good PRO with 63% sensitivity and 75% specificity) and an EII ratio of 0.41 (identified patients with a good PRO with 83% sensitivity and 75% specificity). Complete bolus transit identified patients with a good PRO with 28% sensitivity and 75% specificity. Of the 25 patients who met these cut points for both esophagram barium column height and EII ratio, 23 (92%) had a good PRO. Of the 17 patients who met neither cut point, 14 (82%) had a poor PRO (Eckardt score above 3). CONCLUSIONS: In a prospective study of 70 patients with achalasia, we found EII ratio identified patients with good PROs with higher levels of sensitivity (same specificity) than timed-barium esophagram or impedance-manometry bolus transit assessments. The EII ratio should be added to achalasia outcome evaluations that involve high-resolution impedance manometry as an independent measure and to complement timed-barium esophagram. PMID- 29155169 TI - Does Subclinical Inflammation Play a Role in the Pathogenesis of Diverticulosis? PMID- 29155170 TI - Bench-to-bedside translation of dendrimers: Reality or utopia? A concise analysis. AB - Nanomedicine, which is an application of nanotechnologies in healthcare is developed to improve the treatments and lives of patients suffering from a range of disorders and to increase the successes of drug candidates. Within the nanotechnology universe, the remarkable unique and tunable properties of dendrimers have made them promising tools for diverse biomedical applications such as drug delivery, gene therapy and diagnostic. Up-to-date, very few dendrimers has yet gained regulatory approval for systemic administration, why? In this critical review, we briefly focus on the list of desired basic dendrimer requirements for decision-making purpose by the scientists (go/no-go decision), in early development stages, to become clinical candidates, and to move towards Investigational New Drugs (IND) application submission. In addition, the successful translation between research and clinic should be performed by the implementation of a simple roadmap to jump the 'valley of death' successfully. PMID- 29155171 TI - Manganese chloride induces histone acetylation changes in neuronal cells: Its role in manganese-induced damage. AB - Manganese neurotoxicity presents with Parkinson-like symptoms, with degeneration of dopaminergic neurons in the basal ganglia as the principal pathological feature. Manganese neurotoxicity studies may contribute to a better understanding of the mechanism of Parkinson's disease. Here, we examined the effects of manganese on histone acetylation, a major epigenetic change in chromatin that can regulate gene expression, chromatin remodelling, cell cycle progression, DNA repair and apoptosis. In this study, we found that manganese chloride (MnCl2) may significantly suppress the acetylation of histone H3 and H4 in PC12 cells and SHSY5Y cells in a time-dependent manner. Then we tested the role of manganese chloride on histone acetyltransferase (HAT) and histone deacetylase (HDAC). The results showed that MnCl2 increased the activity of HDAC but decreased that of HAT in PC12 cells. Further experiments showed that MnCl2 selectively increased the expression levels of HDAC3 and HDAC4 rather than HDAC1 and HDAC2, but decreased that of HAT in PC12 cells and SHSY5Y cells. Pretreatment with the HAT inhibitor anacardic acid (AA) enhanced manganese-induced decrease in cell viability and apoptosis, but HDAC inhibition by TSA drug had an opposite effect in PC12 cells. Collectively, MnCl2 inhibited the acetylation of core histones in cell culture models of PD, and that inhibition of HDAC activity by TSA protects against manganese-induced cell death, indicating that histone acetylation may represent key epigenetic changes in manganese-induced dopaminergic neurotoxicity. PMID- 29155172 TI - Navigating motherhood and maternal transitional infant feeding: Learnings for health professionals. AB - Given the lifelong associations between infant diet and weight, understanding maternal transitional infant feeding decisions can assist efforts to establish healthy eating habits early in life. Feeding experiences were explored using semi structured interviews with 15 first-time mothers who were selected based on their concerns about their infants' weight in an infant feeding survey. Thematic synthesis of the interview transcripts identified three main themes: (1) Expectations of a "responsible mother", (2) Trusting oneself and trust in others, and (3) From stress to successful feeding. Dominant social ideals of motherhood and infant behaviour influenced feeding practices, some of which are associated with obesity. Judgments of mothers' infant feeding practices and infant size alongside feeding and weight gain 'checklists' undermines maternal transitional feeding knowledge. Family-centred, non-judgmental guidance from peers, family members and health professionals would better support mothers to navigate the day to-day reality of feeding and caring for an infant throughout the first year of life that is based on achievable personal goals rather than societal ideals. PMID- 29155173 TI - Domestic food practices: A study of food management behaviors and the role of food preparation planning in reducing waste. AB - Recent research has started to show the key role of daily food provision practices in affecting household food waste. Building on and extending these previous contributions, the objective of this paper is to investigate how individuals' everyday practices regarding food (e.g., shopping, cooking, eating, etc.) lead to food waste, and how policy makers and the food industry can implement effective strategies to influence such practices and ultimately help consumers reduce food waste. The research performs three Studies; a critical incident qualitative study (Study 1; N = 514) and a quantitative, survey-based study (Study 2; N = 456) to identify and examine relevant food management behaviors associated with domestic waste. Lastly, findings from a field experiment (Study 3; N = 210) suggest that a specific educational intervention, directed at increasing consumers' perceived skills related to food preparation planning behaviors, reduces domestic food waste. Implications of the research for policy makers and the food industry are discussed. PMID- 29155174 TI - Ethnopharmacology, phytochemistry, and pharmacology of Cornus officinalis Sieb. et Zucc. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis (Cornaceae), known in Chinese as "Shanzhuyu," is a frequently used traditional Chinese medicine. It tastes sour and is astringent and slightly warm in nature. Its fruits have long been used to treat kidney deficiency, high blood pressure, waist and knee pain, dizziness, tinnitus, impotence, spermatorrhea, menorrhagia, and other diseases in China. The main distribution areas are Shanxi and Gansu. AIM OF THE STUDY: This review focused on the ethnopharmacological uses of the herb. We also focus on the phytochemical, pharmacological, and toxicological studies on C. officinalis. The recent analytical methods developed for the quality control of the herb's constituents are also reviewed. Additionally, future trends and prospects in the study of this herb are proposed. MATERIALS AND METHODS: Information on C. officinalis was gathered by searching the internet (PubMed, ScienceDirect, Wiley, ACS, CNKI, Scifinder, Web of Science, Google Scholar, and Baidu Scholar) and libraries. RESULTS: This review compiled the ethnopharmacological uses, including the classic prescriptions and historical applications. Approximately 300 chemical compounds have been isolated and identified from C. officinalis. The major active components of the plant are organic acids and iridoids, among which morroniside and loganin have been extensively investigated. The fruit of the plant has been used in treating many diseases in traditional medicine. Scientific studies indicated the herb's wide range of pharmacological activities, such as hepatic and renal protection, antidiabetes activity, cardioprotection, antioxidation, neuroprotection, antitumor activity, anti-inflammation, analgesic effects, antiaging activity, antiamnesia, antiosteoporosis, and immunoregulation. The analytical methods developed for the quantitative and qualitative determination of various compounds in the herb were further reviewed. CONCLUSIONS: In this paper, we reviewed various studies conducted on C. officinalis, especially in areas of its ethnopharmacological use, as well as on its phytochemistry, pharmacology, and modern analytical methods used. Some of the herb's ethnomedical indications have been confirmed by the herb's pharmacological effects, such as its hepatic and renal protection and the antidiabetic effects. In particular, the crude extract and its chemical composition have exerted good therapeutic effect in diabetic treatment. C. officinalis entails additional attention on its pharmacological effects and drug development to expand its effective use clinically. Many advanced technologies are used for quality testing, but the detection component is exceedingly scarce for synthetically evaluating the quality of C. officinalis herbs. Thus, further research is necessary to investigate the quality control and toxicology of the plant, to further elucidate its clinical use, and to control herbal quality. PMID- 29155175 TI - FCGR2A single nucleotide polymorphism confers susceptibility to childhood-onset idiopathic nephrotic syndrome. AB - Childhood-onset idiopathic nephrotic syndrome affects 1.15-3.4 children/100,000 children/year in Western Countries. Immune-mediated mechanisms, particularly T cell-mediated, are thought to play a key pathogenic role. The genetic basis of the disease is still poorly understood. We tested the association between single nucleotide polymorphisms (SNPs) of four genes encoding Fc gamma receptors (FCGR2A, FCGR2B, FCGR3A, FCGR3B) and idiopathic nephrotic syndrome in a case control study of paediatric patients. Children with idiopathic nephrotic syndrome (aged 1-16 years) were included. FCGR2A rs1801274 and FCGR3A rs396991 SNPs were genotyped using real-time PCR with the TaqMan method, while FCGR2B rs1050501 and FCGR3B NA1/NA2 were genotyped using Sanger sequencing. Fisher's exact test was used to explore genetic association. We enrolled 103 idiopathic nephrotic syndrome patients and 181 healthy controls. A significant association was found between idiopathic nephrotic syndrome and FCGR2A rs1801274 SNP (both with the T allele and the TT genotype, p value=0.0009, OR 1.81, 95% CI 1.27-2.59 and p value=0.0007, OR 2.39, 95% CI 1.44-3.99, respectively). No associations were found for the remaining SNPs. Fc gamma receptors might modulate response to rituximab; since 60 of the enrolled patients were treated with rituximab, we also tested the association between the studied SNPs and rituximab efficacy in this patient subgroup, but found only a weak association with FCGR2A CC genotype (p value=0.03). The FCGR2A rs1801274 SNP in the gene encoding the activating receptor CD32A confers susceptibility to idiopathic nephrotic syndrome. PMID- 29155176 TI - Toward understanding barnacle cementing by characterization of one cement protein 100kDa in Amphibalanus amphitrite. AB - Barnacles, as major fouling organisms, have attracted more attentions. It is no doubt that the study on cement proteins is required to illustrate the mechanism of barnacle cementing. A cement protein defined as Aa-cp100k was characterized from Amphibalanus amphitrite in this study. The amino acid sequence of Aa-cp100k was shown a high similarity to other three barnacles including Megabalanus rosa (Mr-cp100k), Tetraclita japonica formosana (Tj-cp100k) and Pollicipes pollicipes (Pp-cp100k). Moreover, the localization of Aa-cp100k in the vacuoles of cyprid beta secretory cells and the adult cement gland cells by immunofluorescence microscopy, indicating that Aa-cp100k existed in both cyprid and adult barnacle. Aa-cp100k from basal plate could be dissolved in urea buffer without high concentration of dithiothreitol (DTT), different from that in Megabalanus rosa, implying diverse possible roles of cp100k in cementing. PMID- 29155178 TI - Induction of immune-related gene expression by seminal exosomes in the porcine endometrium. AB - Seminal plasma (SP) is considered as a vehicle to carry sperm into female reproductive tract, of which functions have not been completely understood. This study aimed to identify the function of seminal exosomes on porcine endometrium. Exosomes were isolated from the sperm-rich fraction of boar semen and were confirmed by the expression of exosome marker HSP70 and size distribution using nano-sight tracking analysis. Porcine endometrial epithelial cells (EECs) were then treated with seminal exosomes, and RNA extracted were subjected to global expression analysis. Transcripts related to "immune response", "inflammatory response" and their associated signaling pathways were up-regulated in EECs treated with seminal exosome, whereas those associated with "steroid biosynthesis", "metabolic pathways" and "T cell differentiation" were down regulated. The decrease in PMVK, SC5D, INSIG1, HSD17B7, NSDHL, HMGCR, SQLE and FDFT1, and increase in CCL20, TNFSF15, AMCFII, CXCL2 and CXCL8 were also found in the endometrium from the naturally mated pigs. Moreover, changes in exosome induced CYP24A1, EBP, CCL20, AMCFII and IL1A expression were not regulated by the exosome removed SP. These observations indicated that exosomes present in SP are involved in the immune-related gene regulation in the uterus, which could pave the passage for sperm and possibly fertilized eggs. PMID- 29155177 TI - Co-treatment with a C1B5 peptide of protein kinase Cgamma and a low dose of gemcitabine strongly attenuated pancreatic cancer growth in mice through T cell activation. AB - Although gemcitabine is an effective chemotherapeutic for pancreatic cancer, severe side effects often accompany its use. Since we have discovered that locally administered C1B domain peptides effectively control tumor growth without any side effects, the efficacy of co-treatment with this peptide and a low dose of gemcitabine on the growth of pancreatic cancer was examined. Two- and three dimensional cell culture studies clarified that a co-treatment with C1B5 peptide and gemcitabine significantly attenuated growth of PAN02 mouse and PANC-1 human pancreatic cancer cells in 2D and 3D cultures. Although treatment with the low dose of gemcitabine alone (76%) or the C1B5 peptide alone (39%) inhibited tumor growth moderately, a co-treatment with C1B5 peptide and a low dose of gemcitabine markedly inhibited the growth of PAN02 autografts in the mouse peritoneal cavity (94% inhibition) without any noticeable adverse effect. The number of peritoneal cavity-infiltrating neutrophils and granzyme B+ lymphocytes was significantly higher in the co-treatment group than in the control group. A significant increase of granzyme B mRNA expression was also detected in human T cells by the co-treatment. Taken together, the current study suggests that C1B5 peptide offers a remarkably effective combination treatment strategy to reduce side effects associated with gemcitabine, without losing its tumoricidal effect. PMID- 29155179 TI - MicroRNA let-7f-5p regulates neuronal differentiation of rat bone marrow mesenchymal stem cells by targeting Par6alpha. AB - Par6alpha (partitioning defective 6 homologue alpha), a component of the Par3/Par6/aPKC complex, was recently shown to be essential for axon specification during neuronal development. However, the biological functions and regulatory mechanisms of Par6alpha in the mesenchymal stem cell (MSC) differentiation process have not been investigated. In this study, we found that the expression of let-7f-5p was downregulated during differentiation of bone marrow-derived MSCs to neuron-like cells. Interestingly, Par6alpha was predicted to be a target gene of let-7f-5p by computerized analysis and the luciferase reporter assay. Using gain- and loss-of-function approaches, we found that expression of Par6alpha was inversely correlated with let-7f-5p levels during differentiation (p < 0.05). By silencing Par6alpha using siRNAs, we demonstrated that Par6alpha was necessary for MSC neuronal differentiation. Altogether, our studies proved that inhibition of let-7f-5p facilitates induction of MSCs into neuron-like cells by directly targeting Par6alpha. PMID- 29155180 TI - Cell membrane dynamics induction using optogenetic tools. AB - Structures arising from actin-based cell membrane movements, including ruffles, lamellipodia, and filopodia, play important roles in a broad spectrum of cellular functions, such as cell motility, axon guidance in neurons, wound healing, and micropinocytosis. Previous studies investigating these cell membrane dynamics often relied on pharmacological inhibition, RNA interference, and constitutive active/dominant negative protein expression systems. However, such studies did not allow the modulation of protein activity at specific regions of cells, tissues, and organs in animals with high spatial and temporal precision. Recently, optogenetic tools for inducing cell membrane dynamics have been developed which address several disadvantages of previous techniques. In a recent study, we developed a powerful optogenetic tool, called the Magnet system, to change cell membrane dynamics through Tiam1 and PIP3 signal transductions with high spatial and temporal resolution. In this review, we summarize recent advances in optogenetic tools that allow us to induce actin-regulated cell membrane dynamics and unique membrane ruffles that we discovered using our Magnet system. PMID- 29155181 TI - The role of N-terminal segment and membrane association in MyD88-mediated signaling. AB - MyD88 is a central signaling mediator of innate immunity, composed of the N terminal death (DD) and C-terminal Toll/interleukin-1 receptor (TIR) domain linked by an intermediary (INT) domain. We showed that the N-terminal domain (NTD), composed of apparently unstructured 21 amino-acid residues, is involved in localization and clustering of MyD88 and is required for the efficient signaling, since the deletion mutant is unable to reconstitute MyD88-dependent signaling. Furthermore, we found that the NTD peptide interacts with phosphatidic acid, which potentiates MyD88-mediated signaling through TLRs. Propranolol and expression of lysophosphatidyl acid acyltransferase 1, which increase the level of phosphatidic acid augment cell activation via MyD88. Moreover, anchoring of MyD88 to the cell membrane augments signaling supporting the importance of membrane localization in MyD88-mediated signaling. PMID- 29155182 TI - Inspector Perceptions of the Food and Drug Administration's Newest Recommended Food Facility Inspection Format: Training Matters. AB - The Food and Drug Administration publishes the Food Code to guide restaurant inspections. The most recent version proposes a three-tier system categorizing violations as priority, priority foundation, and core. This study used a scenario based questionnaire to examine inspector perceptions and preferences for inspection formats. Results suggest that inspectors would be able to maintain consistent evaluations when changing to the three-tier system, although the classifying terms under the three-tier system were confusing. Additionally, inspectors were not very positive about the new system; they were concerned that the new system would not be easy to understand and use, inspections would take a longer time, it would not accurately reflect the amount of risk associated with violations, and it would not be easy for consumers and managers to understand and use. The results suggest the need for additional training for inspectors before adoption, especially on the rationale and benefits of changing to a three-tier system. PMID- 29155183 TI - Insights into brain microstructure from in vivo DW-MRS. AB - Many developmental processes, such as plasticity and aging, or pathological processes such as neurological diseases are characterized by modulations of specific cellular types and their microstructures. Diffusion-weighted Magnetic Resonance Imaging (DW-MRI) is a powerful technique for probing microstructure, yet its information arises from the ubiquitous, non-specific water signal. By contrast, diffusion-weighted Magnetic Resonance Spectroscopy (DW-MRS) allows specific characterizations of tissues such as brain and muscle in vivo by quantifying the diffusion properties of MR-observable metabolites. Many brain metabolites are predominantly intracellular, and some of them are preferentially localized in specific brain cell populations, e.g., neurons and glia. Given the microstructural sensitivity of diffusion-encoding filters, investigation of metabolite diffusion properties using DW-MRS can thus provide exclusive cell and compartment-specific information. Furthermore, since many models and assumptions are used for quantification of water diffusion, metabolite diffusion may serve to generate a-priori information for model selection in DW-MRI. However, DW-MRS measurements are extremely challenging, from the acquisition to the accurate and correct analysis and quantification stages. In this review, we survey the state of-the-art methods that have been developed for the robust acquisition, quantification and analysis of DW-MRS data and discuss the potential relevance of DW-MRS for elucidating brain microstructure in vivo. The review highlights that when accurate data on the diffusion of multiple metabolites is combined with accurate computational and geometrical modeling, DW-MRS can provide unique cell specific information on the intracellular structure of brain tissue, in health and disease, which could serve as incentives for further application in vivo in human research and clinical MRI. PMID- 29155185 TI - Video Endoscopic Inguinal Lymphadenectomy vs Open Inguinal Lymphadenectomy for Carcinoma Penis: Expanding Role and Comparison of Outcomes. AB - OBJECTIVE: To compare differences of morbidity profile, oncological yield, and efficacy between video endoscopic inguinal lymphadenectomy and open inguinal lymphadenectomy cases. MATERIALS AND METHODS: A total of 29 patients with proven squamous cell carcinoma of the penis were selected for inguinal lymphadenectomy from August 2013 to January 2017. Video endoscopic lymphadenectomy was performed on 1 limb and open inguinal lymphadenectomy was performed on the contralateral side. Relevant outcome data such as operative time, complication rate, number of lymph nodes removed, number of positive nodes, and recurrence during the follow up period were collected, analyzed, and compared. RESULTS: The mean operative time was significantly longer for the video endoscopic inguinal lymphadenectomy group (mean = 162.83 minutes) as compared with the open group (mean = 92.35 minutes). However, the mean numbers of lymph nodes removed were 7.6 in the endoscopic group and 8.3 in the open group. Postoperative complications occurred in 10 limbs (34.48%) in the open group and in 3 limbs (10.34%) in the endoscopic group. In the follow-up period ranging from 7 to 28 (mean 14) months, 2 patients died because of either distant or visceral metastasis. CONCLUSION: The present study clearly outlines the fact that video endoscopic inguinal lymphadenectomy can deliver an equivalent lymph node yield similar to open inguinal lymphadenectomy with significantly less morbidity and is not affected by either the palpability or the number of palpable nodes. Thus, we believe that this minimally invasive technique can provide a prudent alternative for the management of the inguinal region in carcinoma of the penis. PMID- 29155184 TI - Harmonization of cortical thickness measurements across scanners and sites. AB - With the proliferation of multi-site neuroimaging studies, there is a greater need for handling non-biological variance introduced by differences in MRI scanners and acquisition protocols. Such unwanted sources of variation, which we refer to as "scanner effects", can hinder the detection of imaging features associated with clinical covariates of interest and cause spurious findings. In this paper, we investigate scanner effects in two large multi-site studies on cortical thickness measurements across a total of 11 scanners. We propose a set of tools for visualizing and identifying scanner effects that are generalizable to other modalities. We then propose to use ComBat, a technique adopted from the genomics literature and recently applied to diffusion tensor imaging data, to combine and harmonize cortical thickness values across scanners. We show that ComBat removes unwanted sources of scan variability while simultaneously increasing the power and reproducibility of subsequent statistical analyses. We also show that ComBat is useful for combining imaging data with the goal of studying life-span trajectories in the brain. PMID- 29155186 TI - Prediction of Prostate Cancer Risk Among Men Undergoing Combined MRI-targeted and Systematic Biopsy Using Novel Pre-biopsy Nomograms That Incorporate MRI Findings. AB - OBJECTIVE: To develop nomograms that predict the probability of overall prostate cancer (PCa) and clinically significant PCa (Gleason >=7) on magnetic resonance imaging (MRI)-targeted, and combined MRI-targeted and systematic, prostate biopsy. MATERIALS AND METHODS: From June 2012 to August 2014, magnetic resonance imaging to ultrasound fusion-targeted prostate biopsy was performed on 464 men with suspicious regions identified on pre-biopsy 3T MRI along with systematic 12 core biopsy. Logistic regression modeling was used to evaluate predictors of overall and clinically significant PCa, and corresponding nomograms were generated for men who were not previously biopsied or had 1 or more prior negative biopsies. Models were created with 70% of a randomly selected training sample and bias-corrected using bootstrap resampling. The models were then validated with the remaining 30% testing sample pool. RESULTS: A total of 459 patients were included for analysis (median age 66 years, prostate-specific antigen [PSA] 5.2 ng/mL, prostate volume 49 cc). Independent predictors of PCa on targeted and systematic prostate biopsy were PSA density, age, and MRI suspicion score. PCa probability nomograms were generated for each cohort using the predictors. Bias-corrected areas under the receiver-operating characteristic curves for overall and clinically significant PCa detection were 0.82 (0.78) and 0.91 (0.84) for men without prior biopsy and 0.76 (0.65) and 0.86 (0.87) for men with a prior negative biopsy in the training (testing) samples. CONCLUSION: PSA density, age, and MRI suspicion score predict PCa on combined MRI-targeted and systematic biopsy. Our generated nomograms demonstrate high diagnostic accuracy and may further aid in the decision to perform biopsy in men with clinical suspicion of PCa. PMID- 29155187 TI - When Chemotherapy Is Not Enough-Management of Prostatic Embryonal Rhabdomyosarcoma in an Infant. AB - A baby boy was diagnosed with embryonal rhabdomyosarcoma causing left hydroureteronephrosis. A loop ureterostomy was performed, and the infant was treated per the RMS13 protocol. After 3 months of chemotherapy, the infant's tumor burden increased, and he underwent radical cystoprostatectomy and right-to left transureteroureterostomy (end-to-end fashion utilizing the distal limb of his ureterostomy). This innovative method was utilized because the infant's tumor burden was too large to be treated effectively and safely with radiation. One year later, the infant has no evidence of disease. This demonstrates that optimal management of rhabdomyosarcoma is still unknown; therefore, each child warrants an individualized approach for optimal outcomes. PMID- 29155188 TI - A Case of Spontaneous Bilateral Renal Artery Dissection Following Robotic Surgery. PMID- 29155189 TI - Re: Freire et al.: Deep Infiltrating Endometriosis-Urinary Tract Involvement and Predictive Factors for Major Surgery (Urology 2017;108:65-70). PMID- 29155190 TI - Use of Routine Home Health Care and Deviations From an Uncomplicated Recovery Pathway After Radical Prostatectomy. AB - OBJECTIVE: To evaluate the statistical association between routine home health use after prostatectomy, short-term surgical outcomes, and payments. METHODS: We identified all men who underwent a robotic radical prostatectomy from April 1, 2014, to October 31, 2015, in the Michigan Urological Surgery Improvement Collaborative (MUSIC) with insurance from Medicare or a large commercial payer. We calculated rates of "routine" home care use after prostatectomy by urology practice. We defined "routine" home care as home care initiated within 4 days of discharge among patients discharged without a pelvic drain. We then compared emergency department (ED) visits, readmissions, prolonged catheter use, catheter reinsertion rates, and 90-day episode payments, in unadjusted and using a propensity-adjusted analysis, for those who did and did not receive home care. RESULTS: We identified 647 patients, of whom 13% received routine home health care. At the practice level, the use of routine home care after prostatectomy varied from 0% to 53% (P = .05) (mean: 3.6%, median: 0%). Unadjusted, patients with routine home care had increased ED visits within 16 days (15.5% vs 6.9%, P <.01), similar rates of catheter duration for >16 days (3.6% vs 3.0%, P = .79) and need for catheter replacement (1.2% vs 2.5%, P = .46), and a trend toward decreased readmissions (0% vs 4.1%, P = .06). Only the increased ED visits remained significant in adjusted analyses (P <.01). Home health had an average payment of $1000 per episode. CONCLUSION: Thirteen percent of patients received routine home health care after prostatectomy, without improved outcomes. These findings suggest that patients do not routinely require home health care to improve short-term outcomes following radical prostatectomy, however, the appropriate use of home health care should be evaluated further. PMID- 29155191 TI - Ultrasound-guided Pudendal Block Is a Viable Alternative to Caudal Block for Hypospadias Surgery: A Single-Surgeon Pilot Study. AB - OBJECTIVE: To evaluate pudendal nerve block as an alternative to caudal block for hypospadias surgery. METHODS: Data were obtained by chart review. Children who underwent hypospadias repair between 2012 and 2016 by a single surgeon at an academic institution were included. Patients received ultrasound-guided pudendal block (n = 21) or caudal block (n = 19) as a regional adjunct to general anesthesia. Primary outcomes included analgesic requirement and postoperative length of stay in the recovery unit. RESULTS: The pudendal block cohort was slightly older (27.6 vs 18.5 months, P = .017) and had more severe hypospadias than the caudal block cohort (53% vs 35% proximal hypospadias, respectively). We detected no statistically significant difference in intraoperative opioid, postoperative opioid, or nonopioid analgesic requirement (17.9 vs 12.9 mcg fentanyl, P = .267; 0.3 vs 0.3 doses, P = .92; 0.2 vs 0.1 doses, P = .46, respectively). Postoperative length of stay was significantly shorter in the pudendal block cohort (96 vs 128 minutes, P = .016). DISCUSSION: We are the first to report the use of ultrasound-guided pudendal block for hypospadias repair. This appears to be a safe and effective alternative to caudal block with no perioperative delays. Pudendal block has several advantages over caudal block. It avoids the risks of urinary retention and lower extremity weakness and can be administered to older patients and children with spinal anomalies. CONCLUSION: Compared with caudal block, ultrasound-guided pudendal nerve block is safe, provides equivalent pain control for hypospadias repair, and results in a shorter time to discharge. PMID- 29155192 TI - External Genital Development, Urethra Formation, and Hypospadias Induction in Guinea Pig: A Double Zipper Model for Human Urethral Development. AB - OBJECTIVE: To determine whether the guinea pig phallus would be an appropriate model of human penile development, we characterized the embryology and sexual differentiation of guinea pig external genitalia and attended to induce hypospadias in males and tubular urethra formation in females pharmacologically. MATERIALS AND METHODS: The external genitalia of guinea pig were collected from genital swelling initiation to newborn stages, and scanning electronic microscopy and histology were performed to visualize the morphology and structure. Immunohistochemistry was used to determine the androgen receptor localization. Bicalutamide and methyltestosterone were given to pregnant dams to reveal the role and timing of androgen in guinea pig penile masculinization. RESULTS: Canalization and dorsal-to-ventral movement of the urethral canal develops the urethral groove in both sexes, and then the males perform distal-opening-proximal closing to form tubular urethra. More nuclear-localized androgen receptor is found in proximal genital tubercles of males than in females at (E) 29. Antiandrogen treatment at E26-E30 can cause hypospadias, and methyltestosterone administration at E27-E31 can induce tubular urethra formation in females. CONCLUSION: Fetal development of the guinea pig phallus is homologous to that of humans. Although guinea pig has structures similar to mouse, the urethral groove and the tubular urethra formation are more similar to humans. Antiandrogen treatment causes hypospadias in males and additional androgen induces tubular urethra formation in females. Thus, guinea pig is an appropriate model for further study of cellular and molecular mechanisms involved in distal-opening proximal-closing in tubular urethra formation and the evaluation of the pathophysiological processes of hypospadias. PMID- 29155193 TI - Is Removal of the Pressure-regulating Balloon Necessary After Artificial Urinary Sphincter Cuff Erosion? AB - OBJECTIVE: To characterize the risk of delayed infectious complications from retained pressure-regulating balloons (PRBs) after artificial urinary sphincter (AUS) cuff erosion. METHODS: From our database of 530 AUS cases between 2007 and 2016, we identified 40 total AUS cuff erosions. Twenty-four (60%) presented without evidence of gross device infection and underwent explant of cuff and pump without removal of the PRB. Space of Retzius (SoR) and high submuscular (HSM) balloon locations were analyzed to assess for ease of removal. Presenting clinical features and retained balloon-related outcomes are reported. RESULTS: Of the 24 AUS cuff erosions with retained balloons, 6 (25%) men subsequently required PRB removal for infection during the median follow-up of 36 months (interquartile range 29-53). The median time to balloon infection after AUS erosion surgery was 4 months (interquartile range 4-16). Infection risk was reduced in those without concurrent inflatable penile prosthesis (20%) and in those who underwent "drain and retain" of the PRB (13%). The most common presenting clinical symptoms with retained PRB infection were pain and erythema near the site of the PRB (83%). No patient developed sepsis-related complications. The location of the PRB in this subcohort included 2 SoR and 4 HSM placements. The median operative time for balloon removal in the SoR was 3.5 times greater than that for HSM PRBs (133 minutes vs 38 minutes). CONCLUSION: With extended follow-up, three-quarters of the men with retained PRBs after AUS cuff erosion experienced no infectious complications. Removal of infected SoR PRBs was associated with greater operative times and surgical complexity relative to HSM PRBs. PMID- 29155194 TI - A Case of Prenatally Diagnosed Wilms Tumor Managed With Laparoscopic Nephrectomy. AB - We present a case of prenatally diagnosed Wilms tumor, with subsequent operative approach and management. The patient was referred to our institution with an abnormal prenatal renal ultrasound. Computed tomography scan after delivery showed a multifocal enhancing left renal mass. The patient underwent an uncomplicated left laparoscopic radical nephrectomy and retroperitoneal lymph node sampling using a novel hidden incision endoscopic surgery technique. Final pathology revealed favorable histology stage II Wilms tumor. The patient underwent adjuvant chemotherapy with vincristine and dactinomycin based on the EE4A regimen. We highlight the diagnostic pathway, perioperative management, surgical approach, and early postoperative follow-up in this case report. PMID- 29155195 TI - Unreliability of the Duplex Scan in Diagnosing Corporeal Venous Occlusive Disease in Young Healthy Men With Erectile Deficiency. AB - OBJECTIVE: To define the role of cavernosal venous occlusive dysfunction (CVOD) as the only cause of erectile dysfunction (ED). MATERIALS AND METHODS: Patients meeting the CVOD criteria without any risk factors for organic ED were randomized into 2 groups; the end-diastolic velocity (EDV), peak systolic velocity (PSV), and resistive index (RI) of their cavernosal arteries were assessed using color duplex Doppler ultrasound (CDDU) after intracavernous injection (ICI) of 10 ug alprostadil. Group 1 (153 patients) underwent repeated CDDU + ICI assessments (a maximum of 3 rounds). Group 2 (149 patients) underwent CDDU + ICI before and after sexological counseling. The percentage data were analyzed using the Cochran Mantel-Haenszel test; the numerical data were analyzed using the Wilcoxon test. RESULTS: For group 1, the PSVs (median values: first round 42 cm/s; second round 54 cm/s; third round 66 cm/s) and RIs (median values: first round 70%; second round 89%; third round 92%) increased significantly in each CDDU + ICI round, whereas the EDVs were significantly lower (median values: first round 11 cm/s; second round 5 cm/s; third round 1 cm/s). For group 2, the PSVs (median values: from 44 to 67 cm/s) and RIs (from 72% to 93%) increased significantly after sexological counseling, whereas the EDVs (median values: from 12 to 1 cm/s) were significantly lower. CONCLUSION: Repeated CDDU + ICI and counseling strongly diminished the percentage of patients meeting the CVOD criteria, leading to the suspicion that CVOD is linked to psychological issues in highly selected young healthy men with ED. PMID- 29155196 TI - Insights into the structural characteristics and substrate binding analysis of chondroitin AC lyase (PsPL8A) from Pedobacter saltans. AB - The structure of chondroitin AC lyase (PsPL8A) of family 8 polysaccharide lyase was characterized. Modeled PsPL8A structure showed, it contains N-terminal (alpha/alpha)6 incomplete toroidal fold and a layered beta sandwich structure at C-terminal. Ramchandran plot displayed 98.5% residues in favoured and 1.2% in generously allowed region. Secondary structure of PsPL8A by CD revealed 27.31% alpha helices 22.7% beta sheets and 49.9% random coils. Protein melting study showed, PsPL8A completely unfolds at 60 degrees C. SAXS analysis showed, PsPL8A is fully folded in solution form. The ab initio derived dummy model of PsPL8A superposed well with its modeled structure excluding some alpha-helices and loop region. Structural superposition and docking analysis showed, N153, W105, H203, Y208, Y212, R266 and E349 were involved in catalysis. Mutants N153A, H203A, Y212F, R266A and E349A created by SDM revealed no residual activity. Isothermal titration calorimetry analysis of Y212F and H203A with C4S polysaccharide, showed moderate binding by Y212F (Ka=9.56+/-3.81*105) and no binding with H203A, showing active contribution of Y212 in substrate binding. Residues Y212 and H203 or R266 might act as general base and general acid respectively. Residues N153 and E349 are likely contributing in charge neutralization and stabilizing enolate anion intermediate during beta-elimination. PMID- 29155197 TI - Dyrk2 mediated the release of proinflammatory cytokines in LPS-induced BV2 cells. AB - NF-kappaB pathway and p38MAPK (p38mitogen-activated protein kinase) pathway have been shown to play a key role in neuroinflammation, however, the phosphorylation modification is an important process that affects the activation of above pathways. Dual-specificity tyrosine-phosphorylation-regulated kinase 2(Dyrk2), as a phosphokinase that can phosphorylate signal molecules, has been demonstrated to regulate Type I Interferon(TIF) by promoting ser527 phosphorylation of TBK1. Therefore, to investigate the role of Dyrk2 in neuroinflammation, we analyzed the effect of Dyrk2 on LPS-induced the activation of microglia. Here, we found Dyrk2 expressed in BV2 cells, and LPS induced different expression trend of Dyrk2 in the cytoplasm and nucleus. In addition, we revealed that Dyrk2 interacted with Akt, p38MAPK and NF-kappaB subunit p65, however, in the nucleus of BV2 cells, Dyrk2 selectively interacted with p38MAPK instead of with p65. Although the overexpression of Dyrk2 increased the expression level of phospho-p65, phospho Akt and phospho-p38MAPK in LPS-stimulated BV2 cells, less TNF-alpha and IL-1beta were detected. Probably, the inhibitory effect of Dyrk2 on the release of TNF alpha and IL-1beta was associated with the induction of phospho-Akt. In conclusion, these data suggested Dyrk2 involved in regulating LPS-induced the release of proinflammatory cytokines through its phosphokinase function. PMID- 29155198 TI - Immunomodulating activity of the polysaccharide TLH-3 from Tricholomalobayense in RAW264.7 macrophages. AB - Polysaccharide TLH-3 extracted from Tricholoma lobayense possessed unique antioxidant and anti-aging activities, whereas its immunomodulatory properties remain unexplored. Herein in order to explore TLH-3 biological activities, the immunomodulatory effects on RAW264.7 macrophages and its molecular mechanisms were investigated. It was showed that TLH-3 could significantly enhance the phagocytic activity, releasing toxic molecules NO (nitricoxide), secretion of the cytokine TNF-?(tumor necrosis factor-?, IL-6 (interleukin-6). Further, TNF-?and IL-6 were blocked by the inhibitor of TLR4 (Toll-like receptor4), suggesting TLR4 was a receptor of TLH-3, and immunomodulatory activity of TLH-3 was mediated by TLR4. Moreover, immunofluorescence indicated that TLH-3 lead to the nuclear translocation of NF-?B (nuclear factor-?B) subunit p65. Western blotting demonstrated that NF-?B levels in nucleuses increased and cytoplasmic I?B ?(inhibitor of NF-?B) degraded after TLH-3 treatment, suggesting that TLH-3 probably stimulated macrophage by activating the IkappaB-alpha-NF-kappaB pathway via TLR-4. This study demonstrated that TLH-3 could be potentially used as immunomodulatory agent for healthcare and disease control. PMID- 29155199 TI - Physiochemical and functional properties of tiger puffer (Takifugu rubripes) skin gelatin as affected by extraction conditions. AB - The study investigated physiochemical and functional properties of gelatins from tiger puffer skin (GTPS) extracted with warm-water method at 45, 55 and 65 degrees C for 3, 6 and 12h. GTPS45 exhibited strong gamma-, beta-, alpha1- and alpha2-chains, but they faded with the presence of fragments (<80KDa) in other GTPS. As the increase of temperature and time, amide I and A were shifted to higher wavenumber and their amplitudes in GTPS65-12 decreased. Lightness declined while redness and yellowness were enhanced. Gel strength was in a range of 144.5 79.8g, where it of GTPS45-3 was the highest while it of GTPS65-12 was the lowest (p<0.05), coincided with the longer relaxation time of T22 for immobilized water. Decline in gelling and melting temperature was observed when temperature and time increased. EAI and ESI increased as time prolonged or temperature climbed (p<0.05), in agreement with the form of emulsion droplet by microscopy. Both category and level of volatile compounds increased GTPS65-12 and 55-12 compared with those in GTPS45-12. Results suggest that temperature and time greatly affect the properties of GTPS. To ensure good properties, GTPS should be extracted at a temperature of 45-55 degrees C for less than 12h. PMID- 29155200 TI - Recent advances on polysaccharides, lipids and protein based edible films and coatings: A review. AB - Food is a vital product for the survival of human beings and with passage of time quality concerns of consumers are rising. Edible films and coatings are thin layers applied on food products to protect them and improve their quality. Films/coatings are prepared from naturally occurring renewable sources (polysaccharides, proteins, lipids and composites) which we can eat without disposing them. These films are environment friendly and contain antioxidants, anti-browning agents and colorants. Various methods (spraying, brushing, electro spraying) are used to apply a coating on food material to protect them from microbial growth, prolonging their shelf life and improving other quality aspects like sensory attributes, appearance, originality and freshness of ingredients. In addition to edible films, some special additives like glycerol, sorbitol etc. is used to improve the efficiency of edible films and coatings. Chemistry and nature of these films and coatings vary in the vast range of hydrophilic and hydrophobic boundaries to cover the whole range of food products. In recent times, herbal coatings are widely used for the coating purposes e.g. Aloe Vera, citral and eugenol essential oils. However, some challenges presented are focusing the scientific attention for viable solution. PMID- 29155201 TI - Biochemical properties of the HtrA homolog from bacterium Stenotrophomonas maltophilia. AB - The HtrA proteins due to their proteolytic, and in many cases chaperone activity, efficiently counteract consequences of stressful conditions. In the environmental bacterium and nosocomial pathogen Stenotrophomonas maltophilia HtrA (HtrASm) is induced as a part of adaptive response to host temperature (37 degrees C). We examined the biochemical properties of HtrASm and compared them with those of model HtrAEc from Escherichia coli. We found that HtrASm is a protease and chaperone that operates over a wide range of pH and is highly active at temperatures between 35 and 37 degrees C. The temperature-sensitive activity corresponded well with the lower thermal stability of the protein and weaker stability of the oligomer. Interestingly, the enzyme shows slightly different substrate cleavage specificity when compared to other bacterial HtrAs. A computational model of the three-dimensional structure of HtrASm indicates differences in the S1 substrate specificity pocket and suggests weaker inter trimer interactions when compared to HtrAEc. The observed features of HtrASm suggest that this protein may play a protective role under stressful conditions acting both as a protease and a chaperone. The optimal temperatures for the protein activity may reflect the evolutionary adaptation of S. maltophilia to life in soil or aqueous environments, where the temperatures are usually much below 37 degrees C. PMID- 29155202 TI - Bioactive polysaccharides and oligosaccharides as possible feed additives to manipulate rumen fermentation in Rusitec fermenters. AB - Bioactive polysaccharides and oligosaccharides (POSs) have been used as safe non antibiotic alternatives in animal diets; however, only limited data are available on their effects in rumen manipulation. This study was undertaken to systematically evaluate and compare the efficacies of six different bioactive POSs (10g/kg diet) with respect to ruminal fermentation, feed digestibility, biohydrogenation and bacterial population using a rumen simulation technique. The experiment consisted of 4 independent 12-d incubation periods (each including 8 d for acclimation, followed with 4 d for sample collection). The results demonstrated that Lycium barbarum polysaccharide had no effect and Astragalus polysaccharide only increased the total VFA production. Chitooligosaccharide decreased the propionate proportion with a corresponding increase of acetate to propionate ratio. Fructooligosaccharide increased fatty acid biohydrogenation and the abundances of R. albus, B. fibrisolvens and S. ruminantium. Both Lentinan polysaccharide and xylooligosaccharide increased the total VFA production, fatty acid biohydrogenation and the abundance of B. fibrisolvens. In addition, Lentinan polysaccharide increased 48-h dietary protein degradation and the abundance of R. flavefaciens, while xylooligosaccharide increased 24-h dietary fiber degradation and the abundance of R. albus. In conclusion, bioactive POSs, especially Lentinan polysaccharide and xylooligosaccharide, can serve as potential feed additives to manipulate rumen fermentation. PMID- 29155203 TI - The hydrogen-bond network around Glu160 contributes to the structural stability of chitosanase CsnA from Renibacterium sp. QD1. AB - CsnA, a chitosanase from Renibacterium sp. QD1, has great potential for industrial applications due to its high yield and broad pH stability. In this study, a specific Glu160 in CsnA was identified by sequence alignment, and structural analysis and MD simulation predicted that Glu160 formed a hydrogen bond network with Lys163 and Thr114. To evaluate the effect of the network, we constructed four mutants, including E160A, E160Q, K163A, and T114A, which partially or completely destroy this network. Characterization of these mutants demonstrated that the disruption of the network significantly decreased the enzyme thermostability. The underlying mechanisms responsible for the change of thermostability analyzed by circular dichroism spectroscopy revealed that the hydrogen-bond network conferred the structural stability of CsnA. Moreover, the length of the side chain of residue at 160 impacted conformational stability of the enzyme. Taken together, the hydrogen-bond network around Glu160 plays important roles in stabilization of CsnA. PMID- 29155204 TI - Reciprocal contribution of clinical studies and the HP10 antigen ELISA for the diagnosis of extraparenchymal neurocysticercosis. AB - To evaluate diagnosis of active neurocysticercosis, paired cerebral spinal fluid (CSF) and serum samples from 24 neurocysticercosis (NCC) patients and 17 control neurological patients were assayed in the HP10 Taenia antigen (Ag) ELISA. The CSF samples were also tested with an HP10 Lateral Flow Assay (LFA). The HP10 Ag was detected by ELISA in the CSF of 5/5 patients with Definitive extraparenchymal NCC, and in 4/5 of the corresponding sera. In the Definitive parenchymal group, on the other hand, the HP10 Ag was absent in 2/3 CSF (with a very low value in the one positive sample) and all the corresponding serum samples. Samples of CSF from 4/7 patients in the Probable parenchymal group, were also significantly HP10 Ag positive, suggesting the presence of extraparenchymal cysts not identified by the imaging studies. With the possible exception of one patient, the corresponding serum samples of the Probable parenchymal NCC group, were all HP10 Ag negative. Samples of CSF from 9 NCC patients diagnosed with Mixed parenchymal and extraparenchymal NCC were all significantly HP10 Ag positive, confirming the presence of extraparenchymal cysts, with only 7/9 of the corresponding serum samples being HP10 positive. Thus detection of the HP10 Ag indicates extraparenchymal and not parenchymal cyst localization and is more sensitive with CSF than serum. Three neurological patients clinically diagnosed as subarachnoid cyst, hydrocephalus and tuberculoma, respectively, were clearly positive for HP10 Ag. Of these, two were confirmed as NCC by subsequent imaging; the third died prior to further examination. Thus, a total of 8 patients had their clinical diagnosis questioned. Finally, there was good agreement between the HP10 Ag ELISA and LFA with CSF samples giving an optical density >=0.4 in the ELISA assay. In conclusion, the HP10 Ag assay should provide a valuable and reciprocal tool in the clinical diagnosis and follow up of extraparenchymal NCC. PMID- 29155205 TI - Cystic echinococcosis in Turkana, Kenya: 30 years of imaging in an endemic region. AB - Cystic echinococcosis (CE), a widespread, complex zoonosis, causes chronic disease associated with high morbidity. The pastoral Turkana people of Kenya have one of the highest prevalence rates of CE in the world. Between 1983 and 2015, a CE control program in the Turkana region used ultrasound (US) screening surveys and surgical outreach visits to evaluate CE prevalence and treat those with the disease. As the gold standard modality for diagnosing CE, US reveals a great deal of information about the disease in affected populations. The aim of this study is to discuss the characteristics of untreated CE in the Turkana people as revealed by US data collected during the CE control program and evaluate disease presentation, factors influencing the risk of transmission, and the timeline of disease progression. Data were obtained from written patient notes from US screenings and images; cysts were classified using the World Health Organization (WHO) standardized US classification of CE. Findings include greater prevalence of cysts, later stages of cysts, and multiple cysts in older age groups, with no multiple cysts occurring in patients under six years of age, which are consistent with the assertion that rates of exposure, transmission, and infection increase with age in endemic regions. Findings also raise questions regarding the timeline of disease progression, and factors potentially influencing disease transmission within this and other endemic populations. A comprehensive survey focusing on cultural and community observations (e.g., changing behaviors, hygienic practices, etc.) may provide more detailed information regarding factors that facilitate transmission. PMID- 29155206 TI - Inhibition of Connexin 43 translocation on mitochondria accelerates CoCl2-induced apoptotic response in a chemical model of hypoxia. AB - Hypoxia is the basis of many myocardial conditions, and it can initiate cell death programs, among which apoptosis is well-known. Connexin 43 (Cx43), the major component of cardiomyocyte Gap Junctions, is important in cardioprotection. Cx43is involved in ischemia/reperfusion injury and ischemic preconditioning's protection in vitro; however, its role on cardiomyocyte under hypoxia is still unclear. Reports have shown that Cx43 is also located at the inner membrane of mitochondria where it has been implicated in enhanced ischemic preconditioning response. In this study, to evaluate the role of mitochondrial Cx43 in hypoxia, we used an in vitro model of chemical hypoxia induced by Cobalt chloride (CoCl2) in H9c2 cell line. CoCl2 (50-100-150MUM) was administered for 3 or 6h, alone or combined with Radicicol, that inhibits Cx43 translocation on mitochondria, to demonstrate the crucial role of mitochondrial Cx43 in the cardioprotection. In fact, reduction of Cx43 translocation on mitochondria increases mitochondrial ROS production, cytosolic and mitochondrial calcium overload and mitochondrial membrane depolarization, thus resulting in an increase of the triggering apoptotic pathway. In conclusion, our study demonstrates the involvement of mitochondrial Cx43 in the apoptotic process in a chemical hypoxia model and suggests that mitochondrial Cx43 plays a crucial role in cytoprotection. PMID- 29155207 TI - Cytotoxic effect of the serotonergic drug 1-(1-Naphthyl)piperazine against melanoma cells. AB - 1-(1-Naphthyl)piperazine (1-NPZ) is a serotonergic derivative of quipazine acting both as antagonist and agonist of different serotonin receptors, with promising results for the management of skin cancer. In this work, we studied the effect of 1-NPZ on human MNT-1 melanoma cells by evaluating its effects on cell viability, ability to form colonies, cell cycle dynamics, reactive oxygen species (ROS) production and apoptosis. Treatment of MNT-1 cells with 1-NPZ for 24h decreased cell viability and induced apoptosis in a dose-dependent manner. Activity against melanoma was confirmed with a different melanoma cell line, SK-MEL-28. Simultaneously, 1-NPZ affected cell cycle progression by mediating a S-phase delay. Higher levels of ROS were also detected in MNT-1 cells after treatment with 1-NPZ. Furthermore, 1-NPZ significantly increased the expression of cyclooxygenase-2 in MNT-1 cells. These findings suggest that 1-NPZ pretreatment is able to induce oxidative stress, and consequently apoptotic cell death in melanoma cells. In conclusion, this study demonstrates the cytotoxic and genotoxic potential of 1-NPZ against melanoma cells. PMID- 29155209 TI - Altered Primary Motor Cortex Structure, Organization, and Function in Chronic Pain: A Systematic Review and Meta-Analysis. AB - : Chronic pain can be associated with movement abnormalities. The primary motor cortex (M1) has an essential role in the formulation and execution of movement. A number of changes in M1 function have been reported in studies of people with chronic pain. This review systematically evaluated the evidence for altered M1 structure, organization, and function in people with chronic pain of neuropathic and non-neuropathic origin. Database searches were conducted and a modified STrengthening the Reporting of OBservational studies in Epidemiology checklist was used to assess the methodological quality of included studies. Meta-analyses, including preplanned subgroup analyses on the basis of condition were performed where possible. Sixty-seven studies (2,290 participants) using various neurophysiological measures were included. There is conflicting evidence of altered M1 structure, organization, and function for neuropathic and non neuropathic pain conditions. Meta-analyses provided evidence of increased M1 long interval intracortical inhibition in chronic pain populations. For most measures, the evidence of M1 changes in chronic pain populations is inconclusive. PERSPECTIVE: This review synthesizes the evidence of altered M1 structure, organization, and function in chronic pain populations. For most measures, M1 changes are inconsistent between studies and more research with larger samples and rigorous methodology is required to elucidate M1 changes in chronic pain populations. PMID- 29155208 TI - Inflammatory Renin-Angiotensin System Disruption Attenuates Sensory Hyperinnervation and Mechanical Hypersensitivity in a Rat Model of Provoked Vestibulodynia. AB - : Vestibulodynia is characterized by perivaginal mechanical hypersensitivity, hyperinnervation, and abundant inflammatory cells expressing renin-angiotensin system proteins. We developed a tractable rat model of vestibulodynia to further assess the contributions of the renin-angiotensin system. Complete Freund's adjuvant injected into the posterior vestibule induced marked vestibular hypersensitivity throughout a 7-day test period. Numbers of axons immunoreactive for PGP9.5, calcitonin gene-related peptide, and GFRalpha2 were increased. Numbers of macrophages and T cells were also increased whereas B cells were not. Renin-angiotensin-associated proteins were abundant, with T cells as well as macrophages contributing to increased renin and angiotensinogen. Media conditioned with inflamed vestibular tissue promoted neurite sprouting by rat dorsal root ganglion neurons in vitro, and this was blocked by the angiotensin II receptor type 2 receptor antagonist PD123319 or by an angiotensin II function blocking antibody. Sensory axon sprouting induced by inflamed tissue was dependent on activity of angiotensin-converting enzyme or chymase, but not cathepsin G. Thus, vestibular Complete Freund's adjuvant injection substantially recapitulates changes seen in patients with provoked vestibulodynia, and shows that manipulation of the local inflammatory renin-angiotensin system may be a useful therapeutic strategy. PERSPECTIVE: This study provides evidence that inflammation of the rat vestibule induces a phenotype recapitulating behavioral and cytological features of human vestibulodynia. The model confirms a crucial role of the local inflammatory renin-angiotensin system in hypersensitivity and hyperinnervation. Targeting this system holds promise for developing new nonopioid analgesic treatment strategies. PMID- 29155210 TI - Transition from androgenic to neurosteroidal action of 5alpha-androstane-3alpha, 17beta-diol through the type A gamma-aminobutyric acid receptor in prostate cancer progression. AB - Androgen ablation is the standard of care prescribed to patients with advanced or metastatic prostate cancer (PCa) to slow down disease progression. Unfortunately, a majority of PCa patients under androgen ablation progress to castration resistant prostate cancer (CRPC). Several mechanisms including alternative intra prostatic androgen production and androgen-independent androgen receptor (AR) activation have been proposed for CRPC progression. Aldo-keto reductase family 1 member C3 (AKR1C3), a multi-functional steroid metabolizing enzyme, is specifically expressed in the cytoplasm of PCa cells; and positive immunoreactivity of the type A gamma-aminobutyric acid receptor (GABAAR), an ionotropic receptor and ligand-gated ion channel, is detected on the membrane of PCa cells. We studied a total of 72 radical prostatectomy cases by immunohistochemistry, and identified that 21 cases exhibited positive immunoreactivities for both AKR1C3 and GABAAR. In the dual positive cancer cases, AKR1C3 and GABAAR subunit alpha1 were either expressed in the same cells or in neighboring cells. Among several possible substrates, AKR1C3 reduces 5alpha dihydrotesterone (DHT) to form 5alpha-androstane-3alpha, 17beta-diol (3alpha diol). 3alpha-diol is a neurosteroid that acts as a positive allosteric modulator of the GABAAR in the central nervous system (CNS). We examined the hypothesis that 3alpha-diol-regulated pathological effects in the prostate are GABAAR dependent, but are independent of the AR. In GABAAR-positive, AR-negative human PCa PC-3 cells, 3alpha-diol significantly stimulated cell growth in culture and the in ovo chorioallantoic membrane (CAM) xenograft model. 3alpha-diol also up regulated expression of the epidermal growth factor (EGF) family of growth factors and activation of EGF receptor (EGFR) and Src as measured by quantitative polymerase chain reaction and immunoblotting, respectively. Inclusion of GABAAR antagonists reversed 3alpha-diol-stimulated tumor cell growth, expression of EGF family members, and activation of EGFR and Src to the level observed in untreated cells. Results from the present study suggest that 3alpha-diol may act as an alternative intra-prostatic neurosteroid that activates AR-independent PCa progression. The involvement of AKR1C3-mediated steroid metabolisms in modulating GABAAR activation and promoting PCa progression requires continued studies. PMID- 29155211 TI - Modeling squid axon K+ channel by a nucleation and growth kinetic mechanism. AB - A kinetic model accounting for all salient features of the K+ channel of the squid giant axon, including the rising phase of the ON gating charge and the Cole Moore effect, is provided. Upon accounting for a significant feature distinguishing K+, Na+ and Ca2+ channels from channel-forming peptides modeled in our previous 2016 BBA paper, the nucleation-and-growth kinetic model developed therein is extended to simulate ON ionic and gating currents of the K+ channel of the squid giant axon at different depolarization potentials by the use of only two free parameters. K+ channel opening is considered to proceed by progressive aggregation of single subunits, while they are moving their gating charge outward under depolarizing conditions within their tetrameric structure; K+ channel closing proceeds in the opposite direction, by repolarization-induced disaggregation of subunits, accompanied by inward movement of their gating charge. PMID- 29155212 TI - Effect of isoquercitrin on membrane dynamics and apoptosis-like death in Escherichia coli. AB - Minimum inhibitory concentration (MIC) is defined as the lowest concentration of a compound that completely inhibits microbial growth. Antibacterial mechanisms of compounds have been investigated at their sub-MICs as well as at their MIC. In this study, the effects of sub-MIC and MIC of isoquercitrin on Escherichia coli were investigated. The antibacterial effect of isoquercitrin was tested using the microdilution method. Sub-MICs of isoquercitrin induced the production of reactive oxygen species and depletion of glutathione. The oxidative effects induced by sub-MICs of isoquercitrin could be prolonged, finally resulting in apoptosis-like death. DNA fragmentation and phosphatidylserine externalization, which are regarded as the hallmarks of apoptosis, were evaluated using the TUNEL assay and Annexin V staining, respectively. Furthermore, isoquercitrin induced the peroxidation of membrane lipids and inner membrane permeabilization at both its sub-MIC and MIC. This suggested membrane damage in response to lipid oxidation. The uptake of membrane impermeable dyes, propidium iodide and calcein, demonstrated that isoquercitrin damaged the cell membrane at concentrations higher than its MIC. Thus, isoquercitrin induced apoptosis-like death and dysregulation of cell membrane dynamics. PMID- 29155214 TI - Optimization of trypsins for influenza A/H1N1 virus replication in MDCK SI-6 cells, a novel MDCK cell line. AB - A cell-based vaccine production method for influenza virus may be an effective and more rapid alternative to egg-based systems. For high-yield virus production, the effect of bovine, porcine, fungal, and recombinant trypsins on influenza A/H1N1 virus replication in MDCK SI-6 cells (SI-6 cells), a novel MDCK cell line developed by our research group, was examined. SI-6 cells infected with influenza A/H1N1 virus were incubated in the presence of four trypsin types at various concentrations, and virus yields in the culture medium were evaluated by a hemagglutination (HA) assay. Virus growth was most efficient in the presence of bovine and porcine trypsins. An analysis of the optimized concentration and definitive HA titer of each trypsin by Gaussian distribution revealed that comparable high virus yields (166.1 and 164.2 HAU/50MUl) were obtained at the optimized concentrations of bovine (0.4MUg/ml) and porcine (2.1MUg/ml) trypsins, respectively, the yields of which were significantly higher than that of fungal and recombinant trypsins. We conclude that bovine and porcine trypsins are suitable for influenza A/H1N1 virus replication in SI-6 cells. This result complements our previous study and suggests the possible application of SI-6 cells to the development of cell-based influenza vaccines. PMID- 29155213 TI - Human umbilical vein endothelium-derived exosomes play a role in foetoplacental endothelial dysfunction in gestational diabetes mellitus. AB - Gestational diabetes mellitus (GDM) characterizes by foetoplacental endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) from women with GDM show increased L-arginine transport via the human cationic amino acid transporter 1 (hCAT-1). Moreover, expression of endothelial nitric oxide synthase (eNOS) and nitric oxide synthesis are increased. Exosomes are increased in maternal plasma from GDM. We evaluated the role of foetoplacental endothelial exosomes on endothelial dysfunction in GDM. Exosomes were isolated from HUVECs from normal (ExN) and GDM (ExGDM) pregnancies. HUVECs were exposed (8h) to ExN or ExGDM and used for wound recovery assay (up to 8h), L-arginine transport, hCAT-1 and eNOS expression and activity, reactive oxygen species (ROS) generation, and 44 and 42kDa mitogen activated protein kinases (p44/42mapk) and protein kinase B/Akt (Akt) activation. Wound recovery was slower in GDM compared with normal pregnancies and was recovered by ExN. However, ExGDM delayed wound recovery in cells from normal pregnancies. GDM-increased L-arginine transport, hCAT-1 and eNOS expression and activity, and p44/42mapk activation were blocked by ExN, but ExGDM increased these parameters and ROS generation, and reduced eNOS phosphorylation at threonine495 in cells from normal pregnancies. Inhibition of p44/42mapk, but not Akt reversed GDM-increased L-arginine uptake. In conclusion foetoplacental endothelial-released exosomes play a role in the maintenance of a GDM phenotype in HUVECs. It is suggested that ExN and ExGDM cargo are different with differential effects in cells from normal or GDM pregnancies. This phenomenon could contribute to the understanding of mechanisms behind foetoplacental endothelial dysfunction in GDM pregnancies. PMID- 29155215 TI - Membrane estrogen receptors signal to determine transcription factor function. AB - Estrogen receptors (ER) alpha and beta as well as many other steroid receptors are found both within the nucleus and outside the nucleus. This includes extra nuclear receptors in many organelles, including mitochondria, endoplasmic reticulum, cytosolic endosomes, and membrane lipid rafts, such as caveolae. The functions of these receptors in the various extra-nuclear cell organelles are not well described, but progress for understanding steroid receptor signaling from the membrane has advanced. In this Review I will discuss the enlarging role of membrane ER signaling to the expression, cell localization, and function of transcription factors that are essential to mediate cell physiology or pathophysiology in many organs. PMID- 29155216 TI - Communication between genomic and non-genomic signaling events coordinate steroid hormone actions. AB - Steroid hormones are lipophilic molecules produced in one cell that can travel great distances within the body to elicit biological effects in another cell. In the canonical pathway, steroid hormone binding to a nuclear receptor (NR), often in the cytoplasm, causes the receptor to undergo a conformational change and translocate to the nucleus, where it interacts with specific sequences of DNA to regulate transcription. In addition to the classical genomic mechanism of action, alternate mechanisms of steroid activity have emerged that involve rapid, non genomic signaling. The distinction between these two major mechanisms of action lies in the subcellular location of the initiating steroid hormone action. Importantly, the mechanisms of action are not exclusive, in that each can affect the activity of the other. Here, we describe the different types of genomic and non-genomic steroid hormone signaling mechanisms and how they can influence one another to ultimately regulate biology. Further, we discuss the approaches being used to study the non-genomic signaling events and address important caveats to be considered when designing new experiments. Thus, this minireview can serve as an introduction to the diverse signaling mechanisms of steroid hormones and offers initial, experimental guidance to those entering the field. PMID- 29155218 TI - The collective influence of 1, 25-dihydroxyvitamin D3 with physiological fluid shear stress on osteoblasts. AB - 1, 25-dihydroxyvitamin D3 (1, 25 (OH)2 D3) and mechanical stimuli in physiological environment contributes greatly to osteoporosis pathogenesis. Wide investigations have been conducted on how 1, 25-dihydroxyvitamin D3 and mechanical stimuli separately impact osteoblasts. This study reports the collective influences of 1, 25-dihydroxyvitamin D3 and flow shear stress (FSS) on biological functions of osteoblasts. 1, 25 (OH)2 D3 were prepared in various kinds of concentrations (0, 1, 10, 100 nmmol/L), while physiological fluid shear stress (12 dynes/cm2) was produced by using a parallel-plate fluid flow system. 1, 25 (OH)2 D3 affects the responses of ROBs to FSS, including the inhibition of NO release and cell proliferation as well as the promotion of PGE2 release and cell differentiation. These findings provide a possible mechanism by which 1, 25(OH)2 D3 influences osteoblasts' responses to FSS, thus most probably providing guidance for the selection of 1, 25(OH)2 D3 concentration and mechanical loading in order to produce functional bone tissues in vitro. PMID- 29155219 TI - Complement anaphylatoxins C3a and C5a: Emerging roles in cancer progression and treatment. AB - Recent insights into the role of complement anaphylatoxins C3a and C5a in cancer provide new opportunities for the development of innovative biomarkers and therapeutic strategies. These two complement activation products can maintain chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and increase the motility and metastatic potential of cancer cells. Still, the diverse heterogeneity of responses mediated by these peptides poses a challenge both to our understanding of the role played by these molecules in cancer progression and to the development of effective treatments. This review attempts to summarize the evidence surrounding the involvement of anaphylatoxins in the biological contexts associated with tumor progression. We also describe the recent developments that support the inhibition of anaphylatoxins, or their cognate receptors C3aR and C5aR1, as a treatment option for maximizing the clinical efficacy of current immunotherapies that target the PD-1/PD-L1 immune checkpoint. PMID- 29155217 TI - Neutrophil elastase in the tumor microenvironment. AB - Myeloid cell production within the bone marrow is accelerated in the setting of cancer, and the numbers of circulating and infiltrating neutrophils and granulocytic myeloid derived suppressor cells (MDSCs) correlate with tumor progression and patient survival. Cancer is therefore able to hijack the normally host-protective immune system and use it to further fuel growth and metastasis. Myeloid cells secrete neutrophil elastase and neutrophil extracellular traps (NETs) in response to cues within the tumor microenvironment, thereby leading to enhanced activity in a variety of cancer types. Neutrophil elastase may indeed be a driver of tumorigenesis, since genetic deletion and pharmacological inhibition markedly reduces tumor burden and metastatic potential in numerous preclinical studies. In this review, we examine the current evidence for neutrophil elastase as a stimulatory factor in cancer, focusing on precise mechanisms by which it facilitates primary tumor growth and secondary organ metastasis. We conclude with a brief overview of neutrophil elastase inhibitors and discuss their potential use in cancer therapy. PMID- 29155220 TI - Complement components as promoters of immunological tolerance in dendritic cells. AB - Complement and dendritic cells (DCs) share many functional features that drive the outcome of immune-inflammatory processes. Both have a sentinel function, acting as danger sensors specialized for a rapid, comprehensive and selective action against potential threats without damaging the healthy host cells. But while complement has been considered as a "master alarm" system poised for direct pathogen killing, DCs are regarded as "master regulators" or orchestrators of a vast range of effector immune cells for an effective immune response against threatening insults. The original definition of the complement system, coined to denote its auxiliary function to enhance or assist in the role of antibodies or phagocytes to clear microbes or damaged cells, envisaged an important crosstalk between the complement and the mononuclear phagocyte systems. More recent studies have shown that, depending on the microenvironmental conditions, several complement effectors are competent to influence the differentiation and/or function of different DC subsets toward immunogenicity or tolerance. In this review we will infer about the capability of complement activators and inhibitors to "condition" a tolerogenic and anti-inflammatory immune response by direct interaction with DC surface receptors, and about the implications of this knowledge to devise new complement-based therapeutic approaches for autoimmune pathologies. PMID- 29155221 TI - Motor axon guidance in Drosophila. AB - The Drosophila motor system starts to assemble during embryonic development. It is composed of 30 muscles per abdominal hemisegment and 36 motor neurons assembling into nerve branches to exit the CNS, navigate within the muscle field and finally establish specific connections with their target muscles. Several families of guidance molecules that play a role controlling this process as well as transcriptional regulators that program the behavior of specific motor neuron have been identified. In this review we summarize the role of both groups of molecules in the motor system as well as their relationship where known. It is apparent that partially redundant guidance protein families and membrane molecules with different functional output direct guidance decisions cooperatively. Some distinct transcriptional regulators seem to control guidance of specific nerve branches globally directing the expression of groups of pathfinding molecules in all motor neurons within the same motor branch. PMID- 29155222 TI - The decline in active school transportation (AST): A systematic review of the factors related to AST and changes in school transport over time in North America. AB - Active travel to school has declined during the last 50years in North America. During the last decade, the children's active school transportation (AST) literature has grown. This systematic review provides an updated examination of AST correlates, and discusses why school travel mode (STM) share may have changed over time. AST trends are described and a systematic literature review of AST correlates in North America for the period 1990-2016 was conducted. Strength of association between correlates and AST, and relationship direction are assessed and reported. Graphical presentation of correlates included in >=5 studies were included. Sixty-three studies were identified and reviewed. Distance to school was most strongly associated with AST. Individual, parental and societal correlates had moderate positive associations with AST including: child age, lower parental education, income and other income related factors, race and positive perceptions of AST. Longitudinal studies were few in number, as were studies about exceptional populations, policy, and interventions. AST intervention should focus on key AST correlates. Social and environmental diversity calls for local solutions to school travel challenges. Changes in AST correlates over time should be considered for evaluating existing policy approaches, and to support development of new policy, regulation, design, and program interventions. PMID- 29155223 TI - Multilevel model to estimate county-level untreated dental caries among US children aged 6-9years using the National Health and Nutrition Examination Survey. AB - Because conducting population-based oral health screening is resource intensive, oral health data at small-area levels (e.g., county-level) are not commonly available. We applied the multilevel logistic regression and poststratification method to estimate county-level prevalence of untreated dental caries among children aged 6-9years in the United States using data from the National Health and Nutrition Examination Survey (NHANES) 2005-2010 linked with various area level data at census tract, county and state levels. We validated model-based national estimates against direct estimates from NHANES. We also compared model based estimates with direct estimates from select State Oral Health Surveys (SOHS) at state and county levels. The model with individual-level covariates only and the model with individual-, census tract- and county-level covariates explained 7.2% and 96.3% respectively of overall county-level variation in untreated caries. Model-based county-level prevalence estimates ranged from 4.9% to 65.2% with median of 22.1%. The model-based national estimate (19.9%) matched the NHANES direct estimate (19.8%). We found significantly positive correlations between model-based estimates for 8-year-olds and direct estimates from the third grade State Oral Health Surveys (SOHS) at state level for 34 states (Pearson coefficient: 0.54, P=0.001) and SOHS estimates at county level for 53 New York counties (Pearson coefficient: 0.38, P=0.006). This methodology could be a useful tool to characterize county-level disparities in untreated dental caries among children aged 6-9years and complement oral health surveillance to inform public health programs especially when local-level data are not available although the lack of external validation due to data unavailability should be acknowledged. PMID- 29155224 TI - Medical-encounter mental health diagnoses, non-fatal injury and polypharmacy indicators of risk for accident death in the US Army enlisted soldiers, 2004 2009. AB - Accidents are a leading cause of deaths in U.S. active duty personnel. Understanding accident deaths during wartime could facilitate future operational planning and inform risk prevention efforts. This study expands prior research, identifying health risk factors associated with U.S. Army accident deaths during the Afghanistan and Iraq war. Military records for 2004-2009 enlisted, active duty, Regular Army soldiers were analyzed using logistic regression modeling to identify mental health, injury, and polypharmacy (multiple narcotic and/or psychotropic medications) predictors of accident deaths for current, previously, and never deployed groups. Deployed soldiers with anxiety diagnoses showed higher risk for accident deaths. Over half had anxiety diagnoses prior to being deployed, suggesting anticipatory anxiety or symptom recurrence may contribute to high risk. For previously deployed soldiers, traumatic brain injury (TBI) indicated higher risk. Two-thirds of these soldiers had first TBI medical encounter while non-deployed, but mild, combat-related TBIs may have been undetected during deployments. Post-Traumatic Stress Disorder (PTSD) predicted higher risk for never deployed soldiers, as did polypharmacy which may relate to reasons for deployment ineligibility. Health risk predictors for Army accident deaths are identified and potential practice and policy implications discussed. Further research could test for replicability and expand models to include unobserved factors or modifiable mechanisms related to high risk. PTSD predicted high risk among those never deployed, suggesting importance of identification, treatment, and prevention of non-combat traumatic events. Finally, risk predictors overlapped with those identified for suicides, suggesting effective intervention might reduce both types of deaths. PMID- 29155225 TI - A systematic review of the long-term effectiveness of work-based lifestyle interventions to tackle overweight and obesity. AB - Obesity is one of the five leading global risks for mortality, accounting for 5% of deaths worldwide. Workplace health promotion programs have the potential to deliver population-level interventions combining physical activity and exercise. However, there is no recent critical review of trials on long-term effectiveness of multicomponent lifestyle interventions in the workplace targeting obesity. Good quality evidence is needed to develop optimal strategies to tackle adult obesity. 1035 studies were retrieved by literature search in MEDLINE, Embase, PSYCH INFO and Cochrane library from 2005 to September 2016. 11 studies were identified, which were critiqued using 2010 CONSORT guideline. Most of the studies were not high quality. Five studies reported positive findings. Many studies included environmental interventions, but only two showed significant Body Mass Index (BMI) reduction. Studies showing significant BMI reduction were of high intensity or included a specific motivational component. Although there is some evidence demonstrating long-term effectiveness of multicomponent lifestyle interventions in the workplace targeting obesity, more research is needed into the best methods of conducting these interventions. This study provides evidence that could be used as the basis for implementing similar programs. PMID- 29155226 TI - Interaction between cardiovascular risk factors and body mass index and 10-year incidence of cardiovascular disease, cancer death, and overall mortality. AB - The effect of above-normal body mass index (BMI) on health outcomes is controversial because it is difficult to distinguish from the effect due to BMI associated cardiovascular risk factors. The objective was to analyze the impact on 10-year incidence of cardiovascular disease, cancer deaths and overall mortality of the interaction between cardiovascular risk factors and BMI. We conducted a pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35-79years old at basal examination. Body mass index was measured at baseline being the outcome measures ten-year cardiovascular disease, cancer and overall mortality. Multivariable analyses were adjusted for potential confounders, considering the significant interactions with cardiovascular risk factors. We included 54,446 individuals (46.5% with overweight and 27.8% with obesity). After considering the significant interactions, the 10-year risk of cardiovascular disease was significantly increased in women with overweight and obesity [Hazard Ratio=2.34 (95% confidence interval: 1.19-4.61) and 5.65 (1.54 20.73), respectively]. Overweight and obesity significantly increased the risk of cancer death in women [3.98 (1.53-10.37) and 11.61 (1.93-69.72)]. Finally, obese men had an increased risk of cancer death and overall mortality [1.62 (1.03-2.54) and 1.34 (1.01-1.76), respectively]. In conclusion, overweight and obesity significantly increased the risk of cancer death and of fatal and non-fatal cardiovascular disease in women; whereas obese men had a significantly higher risk of death for all causes and for cancer. Cardiovascular risk factors may act as effect modifiers in these associations. PMID- 29155227 TI - Linking physician attitudes to their breast cancer screening practices: A survey of US primary care providers and gynecologists. AB - Despite changes to breast cancer screening guidelines intended to decrease screening in younger and older women, mammography rates remain high. We investigated physician attitudes towards screening younger and older women. Surveys were mailed to US primary care providers and gynecologists between May and September 2016 (871/1665, 52.3% adjusted response rate). We assessed physician (1) attitudes towards screening younger (45-49years) and older (75+ years) women and (2) recommendations for routine mammography. We used exploratory factor analysis to identify underlying themes among physician attitudes and created measures standardized to a 5-point scale. Using multivariable logistic regression models, we examined associations between physician attitudes and screening recommendations. Attitudes identified with factor analysis included: potential regret, expectations, and discordant guidelines (referred to as potential regret), patient-related hazards due to screening, physician limitations and uncertainty, and concerns about rationing care. Gynecologists had higher levels of potential regret compared to internists. In adjusted analyses, physicians with increasing potential regret (1-point increment on 5-point scale) had higher odds of recommending mammography to younger (OR 8.68; 95% CI 5.25 14.36) and older women (OR 4.62; 95% CI 3.50-6.11). Increasing concern for patient-related hazards was associated with decreased odds of recommending screening to older women (OR 0.68; 95% CI 0.56-0.83). Physicians were more motivated by potential regret in recommending screening for younger and older women than by concerns for patient-related hazards in screening. Addressing physicians' most salient concerns, such as fear of missing cancer diagnoses and malpractice, may present an important opportunity to improving delivery of guideline-concordant cancer screening. PMID- 29155228 TI - Barriers and facilitators to the implementation of physical activity policies in schools: A systematic review. AB - : Research consistently indicates that schools fail to implement mandatory physical activity policies. This review aimed to describe factors (barriers and facilitators) that may influence the implementation of school physical activity policies which specify the time or intensity that physical activity should be implemented and to map these factors to a theoretical framework. A systematic search was undertaken in six databases for quantitative or qualitative studies published between 1995-March 2016 that examined teachers', principals' or school administrators' reported barriers and/or facilitators to implementing mandated school physical activity policies. Two independent reviewers screened texts, extracted and coded data from identified articles using the Theoretical Domains Framework (TDF). Of the 10,346 articles identified, 17 studies met the inclusion criteria (8 quantitative, 9 qualitative). Barriers and facilitators identified in qualitative studies covered 9 and 10 TDF domains respectively. Barriers and facilitators reported in quantitative studies covered 8 TDF domains each. The most common domains identified were: 'environmental context and resources' (e.g., availability of equipment, time or staff), 'goals' (e.g., the perceived priority of the policy in the school), 'social influences' (e.g., support from school boards), and 'skills' (e.g., teachers' ability to implement the policy). Implementation support strategies that target these factors may represent promising means to improve implementation of physical activity policies and increase physical activity among school-aged children. Future studies assessing factors that influence school implementation of physical activity policies would benefit from using a comprehensive framework to help identify if any domains have been overlooked in the current literature. REGISTRATION: This review was prospectively registered with PROSPERO (CRD42016051649) on the 8th December 2016. PMID- 29155229 TI - Particle agglomeration of chitosan-magnesium aluminum silicate nanocomposites for direct compression tablets. AB - Exfoliated nanocomposites of chitosan-magnesium aluminum silicate (CS-MAS) particles are characterized by good compressibility but poor flowability. Thus, the aims of this study were to investigate agglomerates of CS-MAS nanocomposites prepared using the agglomerating agents water, ethanol, or polyvinylpyrrolidone (PVP) for flowability enhancement and to evaluate the agglomerates obtained as direct compression fillers for tablets. The results showed that the addition of agglomerating agents did not affect crystallinity, but slightly influenced thermal behavior of the CS-MAS nanocomposites. The agglomerates prepared using water were larger than those prepared using 95% ethanol because high swelling of the layer of chitosonium acetate occurred, allowing formation of solid bridges and capillary force between particles, leading to higher flowability and particle strength. Incorporation of PVP resulted in larger agglomerates with good flowability and high strength due to the binder hardening mechanism. The tablets prepared from agglomerates using water showed lower hardness, shorter disintegration times and faster drug release than those using 95% ethanol. In contrast, greater hardness and more prolonged drug release were obtained from the tablets prepared from agglomerates using PVP. Additionally, the agglomerates of CS-MAS nanocomposites showed good carrying capacity and provided desirable characteristics of direct compression tablets. PMID- 29155230 TI - The association of monoamine-related gene polymorphisms with behavioural correlates of response inhibition: A meta-analytic review. AB - Response inhibition has been shown to be associated with monoamine-related gene polymorphisms, although evidence is inconclusive. To comprehensively examine these genotype effects on behavioural correlates of response inhibition in non clinical adult populations, we performed a two-step approach. A systematic review of studies using Go/No-Go and/or Stop-Signal paradigms was first carried out. Thirty-eight eligible research articles were identified, which examined over 15 candidate genes. Remarkably, no firm conclusions could be drawn from these studies. Thus, in a second step, we conducted meta-analyses using random effects models on those polymorphisms that had previously been investigated in at least three studies. Specifically, data from 11 studies was analysed in three meta analyses for the following polymorphisms: SLC6A3 3'UTR VNTR (k=6 samples; n=1463 participants), COMT Val158Met SNP (k=7 samples; n=784) and SLC6A4 5-HTTLPR (k=4 samples, n=204). None of these polymorphisms showed a reliable association with response inhibition performance. The methodological and theoretical implications of these findings are discussed, along with recommendations for future research. PMID- 29155231 TI - RTFAdb: A database of computationally predicted associations between retrotransposons and transcription factors in the human and mouse genomes. AB - In recent years, retrotransposons have gained increasing attention as a source of binding motifs for transcription factors (TFs). Despite the substantial roles of these mobile genetic elements in the regulation of gene expression, a comprehensive resource enabling the investigation of retrotransposon species that are bound by TFs is still lacking. Herein, I introduce for the first time a novel database called RTFAdb, which allows exploring computationally predicted associations between retrotransposons and TFs in diverse cell lines and tissues of human and mouse. My database, using over 3.000 TF ChIP-seq binding profiles collected from human and mouse samples, makes possible searching more than 1.500 retrotransposon species in the binding sites of a total of 596 TFs. RTFAdb is freely available at http://tools.ibg.deu.edu.tr/rtfa/ and has the potential to offer novel insights into mammalian transcriptional networks by providing an additional layer of information regarding the regulatory roles of retrotransposons. PMID- 29155232 TI - Refusal of cervical spine immobilization after blunt trauma: Implications for initial evaluation and management: A retrospective cohort study. AB - INTRODUCTION: Rigid cervical collars are routinely placed in the pre-hospital setting after significant blunt trauma. Patients who are deemed competent by field personnel (Glasgow Coma Scale (GCS) >=13, no major distracting injury and not grossly intoxicated) may refuse cervical collar placement. MATERIAL AND METHODS: A retrospective review was conducted of all adult trauma patients presenting to a Level 1 trauma center after blunt trauma with a GCS>=13 and no distracting injury or gross intoxication from January 2014 to December 2014. Pre hospital data was collected from emergency medical service reports and hospital data from patient charts. Cervical spine injury was identified by International Classification of Disease-9th Revision codes. Patients refusing cervical spine immobilization prior to arrival are compared to those who were compliant. RESULTS: A total of 629 patients met inclusion criteria. Cervical spine immobilization was refused by 28 patients, while 601 complied. There were 16 cervical spine injuries (2.5%), with 3 (10.7%) in noncompliant patients and 13 (2.2%) among those who were complaint (p = 0.03). CONCLUSION: The incidence of cervical spine injuries in patients refusing cervical collar immobilization is higher than in compliant patients. Patients arriving for initial evaluation having refused cervical collar immobilization should be treated with caution. PMID- 29155233 TI - Autologous hematopoietic stem cell transplantation in systemic sclerosis: A reset to tolerance? AB - Autologous hematopoietic stem cell transplantation (ASCT) is an effective therapy for refractory autoimmune disease, in particular diffuse cutaneous systemic sclerosis (dcSSc). ASCT is the only treatment that can induce long term remission in dcSSc. However, the mechanism of action of ASCT has not yet been fully elucidated. The current hypothesis is that ASCT induces a long term 'reset' of the immune system, but there is no clear definition yet of such an immunological 'reset to tolerance', nor has it been established how to distinguish a 'reset' from long term immunosuppression. Here, we review the literature on immunological changes after ASCT in dcSSc patients to gain more insight whether changes in immunological parameters can help elucidate the mechanism of action of ASCT. We identified 12 studies. While some immunological parameters could be correlated to clinical response, heterogeneity in the studies, short follow-up time and the small sample sizes preclude firm conclusions. Importantly, most patients displayed a sustained clinical response despite the presence of auto-antibodies or higher-than-normal concentrations of cytokines and proteins associated with disease activity. This suggests that the mechanism of ASCT may not be solely immunological. Future research should focus on larger cohorts of patients and also take functional evaluation of immune cells into account in order to determine whether ASCT induces long term immunosuppression or resets the immune system to tolerance. Answering this question is key to further optimizing ASCT for dcSSc patients. PMID- 29155234 TI - Survivin and autoimmunity; the ins and outs. AB - Autoimmunity is a status that immune mechanisms react against self-structure. The immune mechanisms, including cellular and molecular elements have been developed to immune body against foreign invades. Multiple factors such as genetic and epigenetic background, hormonal status, microbiome, and other factors can cause launching the autoreactive responses, in which the immune tolerance breaks and immune mechanisms are against self-antigens. Apoptosis is one of the important mechanisms in maintaining the tolerance and eliminating the autoreactive lymphocyte clones. Due to survivin roles in apoptosis and proliferation, numerous researches have been paying attention to survivin expression and function in autoreactive lymphocytes and tissue cells, playing important roles in the pathogenesis of autoimmune diseases. New line of evidence has been supporting the role of survivin dysfunction or aberrant expression in deriving autoreactive lymphocytes or some important immune tissues, which may underpin the autoimmune conditions such as Lichen planus (LP), Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Myasthenia gravis (MG), Multiple sclerosis (MS), Systemic sclerosis (SSc), Psoriasis, and Inflammatory bowel disease (IBD). Hence, the purpose of the current paper was to review the survivin role in the etiology and pathogenesis of abovementioned autoimmune diseases. PMID- 29155235 TI - Comparative Assessment of Miniaturized Screening Approaches for Selection of Polymers for Amorphous Drug Stabilization. AB - The present work highlights the use of miniaturized approaches to screen and prioritize development of solid dispersions that provide stabilization of the amorphous drug against crystallization and enhanced dissolution over the crystalline form. The approaches evaluated include solvent casting and solvent displacement-based techniques. Four compounds were evaluated with both these screening approaches. A dual-pH dilution method using fasted state simulated gastric fluid and fasted state simulated intestinal fluid as media was used to evaluate solubility enhancement ratio in each well of the screen. The concentration at 15 mins after dilution with fasted state simulated intestinal fluid and super-saturation ratio at the end of the dissolution study is used as 2 descriptors of solubility enhancement. The empirical screening approaches were supplemented with theoretical calculations of solubility enhancement to gauge the best-performing amorphous solid dispersion (ASD). Physical stability of the amorphous systems was also evaluated, where applicable. Lead ASD compositions from the screens were scaled up to verify the predictions. To our knowledge, this is the first report where the 2 most common screening approaches for the development of ASDs are compared head to head. These approaches are rapid, material sparing, and can be adapted to accommodate screening of multiple variables such as polymer type, drug load, and ternary systems simultaneously. The strengths, limitations, and most suitable applications for each of the 2 methods are also discussed. PMID- 29155236 TI - Evaluation of sampling and storage procedures on preserving the community structure of stool microbiota: A simple at-home toilet-paper collection method. AB - BACKGROUND: The increasing interest on the impact of the gut microbiota on health and disease has resulted in multiple human microbiome-related studies emerging. However, multiple sampling methods are being used, making cross-comparison of results difficult. To avoid additional clinic visits and increase patient recruitment to these studies, there is the potential to utilize at-home stool sampling. The aim of this pilot study was to compare simple self-sampling collection and storage methods. METHODS: To simulate storage conditions, stool samples from three volunteers were freshly collected, placed on toilet tissue, and stored at four temperatures (-80, 7, 22 and 37 degrees C), either dry or in the presence of a stabilization agent (RNAlater(r)) for 3 or 7days. Using 16S rRNA gene sequencing by Illumina, the effect of storage variations for each sample was compared to a reference community from fresh, unstored counterparts. Fastq files may be accessed in the NCBI Sequence Read Archive: Bioproject ID PRJNA418287. RESULTS: Microbial diversity and composition were not significantly altered by any storage method. Samples were always separable based on participant, regardless of storage method suggesting there was no need for sample preservation by a stabilization agent. DISCUSSION: In summary, if immediate sample processing is not feasible, short term storage of unpreserved stool samples on toilet paper offers a reliable way to assess the microbiota composition by 16S rRNA gene sequencing. PMID- 29155237 TI - A standardized toolkit for genetic engineering of CTG clade yeasts. AB - We have developed a series of synthetic constructs suitable to genetically manipulate a broad range of yeast species belonging to the fungal CTG clade. This molecular toolbox notably allows heterologous gene expression, single or dual fluorescence labeling and construction of luciferase-expressing strains for bioluminescence imaging. PMID- 29155238 TI - Evaluation of two real time PCR assays for the detection of bacterial DNA in amniotic fluid. AB - PURPOSE: The aim of this study was to evaluate two non-commercial Real-Time PCR assays for the detection of microorganisms in amniotic fluid followed by identification by pyrosequencing. METHODS: We collected 126 amniotic fluids from 2010 to 2015 for the evaluation of two Real-Time PCR assays for detection of bacterial DNA in amniotic fluid (16S Universal PCR and Ureaplasma spp. specific PCR). The method was developed in the Department of Microbiology of the University Hospital La Paz. RESULTS: Thirty-seven samples (29.3%) were positive by PCR/pyrosequencing and/or culture, 4 of them were mixed cultures with Ureaplasma urealyticum. The Universal 16S Real-Time PCR was compared with the standard culture (81.8% sensitivity, 97.4% specificity, 75% positive predictive value, 98% negative predictive value). The Ureaplasma spp. specific Real-Time PCR was compared with the Ureaplasma/Mycoplasma specific culture (92.3% sensitivity, 89.4% specificity, 50% positive predictive value, 99% negative predictive value) with statistically significant difference (p=0.005). CONCLUSIONS: Ureaplasma spp. PCR shows a rapid response time (5h from DNA extraction until pyrosequencing) when comparing with culture (48h). So, the response time of bacteriological diagnosis in suspected chorioamnionitis is reduced. PMID- 29155239 TI - Mechanisms controlling the anti-neoplastic functions of FoxO proteins. AB - The Forkhead box O (FoxO) proteins comprise a family of evolutionarily conserved transcription factors that predominantly function as tumor suppressors. These proteins assume diverse roles in the cellular anti-neoplastic response, including regulation of apoptosis and autophagy, cancer metabolism, cell-cycle arrest, oxidative stress and the DNA damage response. More recently, FoxO proteins have been implicated in cancer immunity and cancer stem-cell (CSC) homeostasis. Interestingly, in some sporadic sub-populations, FoxO protein function may also be manipulated by factors such as beta-catenin whereby they instead can facilitate cancer progression via maintenance of CSC properties or promoting drug resistance or metastasis and invasion. This review highlights the essential biological functions of FoxOs and explores the areas that may be exploited in FoxO protein signaling pathways in the development of novel cancer therapeutic agents. PMID- 29155240 TI - Matrix Metalloproteinases: A challenging paradigm of cancer management. AB - Matrix metalloproteinases (MMPs) are members of zinc-dependent endopeptidases implicated in a variety of physiological and pathological processes. Over the decades, MMPs have been studied for their role in cancer progression, migration, and metastasis. As a result, accumulated evidence of MMPs incriminating role has made them an attractive therapeutic target. Early generations of broad-spectrum MMP inhibitors exhibited potent inhibitory activities, which subsequently led to clinical trials. Unexpectedly, these trials failed to meet the desired goals, mainly due to the lack of efficacy, poor oral bioavailability, and toxicity. In this review, we discuss the regulatory role of MMPs in cancer progression, current strategies in targeting MMPs for cancer treatment including prodrug design and tumor imaging, and therapeutic value of MMPs as biomarkers in breast, lung, and prostate cancers. PMID- 29155241 TI - Multilocus sequence typing-based analysis of Moraxella catarrhalis population structure reveals clonal spreading of drug-resistant strains isolated from childhood pneumonia. AB - This work revealed the drug resistance and population structure of Moraxella catarrhalis strains isolated from children less than three years old with pneumonia. Forty-four independent M. catarrhalis strains were analyzed using broth dilution antimicrobial susceptibility testing and multilocus sequence typing (MLST). The highest non-susceptibility rate was observed for amoxicillin (AMX), which reached 95.5%, followed by clindamycin (CLI) (n=33; 75.0%), azithromycin (AZM) (61.4%), cefaclor (CEC) (25.0%), trimethoprim-sulfamethoxazole (SXT) (15.9%), cefuroxime (CXM) (4.5%), tetracycline (TE) (2.3%), and doxycycline (DOX) (2.3%). There was no strain showing non-susceptibility to other six antimicrobials. Using MLST, the 44 M. catarrhalis strains were divided into 33 sequence types (STs). Based on their allelic profiles, the 33 STs were divided into one CC (CC363) and 28 singletons. CC363 contained five STs and ST363 was the founder ST. CC363 contained 63.6%, 33.3%, and 40.7% of CEC non-susceptible, CLI non-susceptible and AZM non-susceptible strains, respectively. The proportions of CEC non-susceptible, CLI non-susceptible and AZM non-susceptible strains in CC363 were higher than that of singletons; these differences were significant for CEC (p=0.002) and AZM (p=0.011). Furthermore, CC363 contained more AMX-CLI-AZM co-non susceptible and AMX-CEC-CLI-AZM co-non-susceptible strains than the singletons (p=0.007 and p<0.001, respectively). CC363 is a drug-resistant clone of clinical M. catarrhalis strains in China. Expansion of this clone under selective pressure of antibiotics should be noted and long-term monitoring should be established. PMID- 29155242 TI - Age-related differences in rate of power development exceed differences in peak power. PMID- 29155243 TI - The 24,25 to 25-hydroxyvitamin D ratio and fracture risk in older adults: The cardiovascular health study. AB - 25-hydroxyvitamin D [25(OH)D] may not optimally indicate vitamin D receptor activity. Higher concentrations of its catabolic product 24,25-dihydroxyvitmin D [24,25(OH)2D] and a higher ratio of 24,25(OH)2D to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide additional information on receptor activity. We compared the strength of associations of these markers with serum PTH concentrations, hip bone mineral density (BMD), and risk of incident hip fracture in community-living older participants in the Cardiovascular Health Study. Among 890 participants, the mean age was 78years, 60% were women, and the mean 25(OH)D was 28+/-11ng/ml. In cross-sectional analysis, the strength of association of each vitamin D measure with PTH was similar; a 1% higher 25(OH)D, 24,25(OH)2D, and VMR were associated with 0.32%, 0.25%, and 0.26% lower PTH, respectively (p<0.05 for all). Among 358 participants with available BMD data, we found no associations of 25(OH)D or VMR with BMD, whereas higher 24,25(OH)2D was modestly associated with greater hip BMD (1% higher 24,25(OH)2D associated with 0.04% [95% CI 0.01-0.08%] higher BMD). Risk of incident hip fracture risk was evaluated using a case-cohort design. There were 289 hip fractures during a mean follow up time of 8.4years. Both higher 24,25(OH)2D and VMR were associated with lower risk of hip fracture (HR per SD higher, 0.73 [0.61, 0.87] and 0.74 [0.61, 0.88], respectively) whereas 25(OH)D was not associated with hip fracture (HR 0.93 [0.79, 1.10]). We conclude that evaluating vitamin D status by incorporating assessment of 24,25(OH)D and the VMR provides information on bone health above and beyond 25(OH)D alone. PMID- 29155244 TI - Letter to the editor: "Determinants of short term fracture risk in patients with a recent history of low-trauma non-vertebral fracture". PMID- 29155245 TI - Answer to the letter to the editor regarding the article: "Determinants of short term fracture risk in patients with a recent history of low-trauma non-vertebral fracture". PMID- 29155247 TI - Cells have sex chromosomes and circadian clocks: Implications for organismal level functions. AB - A great number of stakeholders have a keen interest in issues surrounding sex differences. These participants in the discourse often use the same evidence to draw opposite conclusions, with implications for individuals and society as a whole. One part of the maelstrom and associated emotionality derives from confounds between the concepts of "sex" vs. "gender", even among professionals. Here, the oft-repeated point is made that evidence for gender differences can't be derived from the animal research, once the generally accepted conception of gender as a process unique to humans, is acknowledged. Nevertheless, considered at a more general level, the developmental and epigenetic mechanisms that give rise to differences in behavior among individuals and groups is exquisitely explored in animal studies but relatively poorly in research on humans. The focus on animal research here, starts with the fact that virtually each cell of the body has sex chromosomes (XX and XY), along with the intracellular genetic and cytoplasmic mechanisms associated with circadian (circa-about, dies-day) timing. The consequences of these sex*circadian interactions for physiology and behavior at cellular and higher levels of organization are considered in systems where compelling evidence is available. These include sex differences in the circadian timing system, the hypothalamic-pituitary-adrenal (HPA) axis, and in metabolism. The evidence highlights sex differences in cells throughout the body and thus has implications for higher level processes and systems such as sleep/wake patterns. In a more general sense, they point to mechanisms that could give rise to gender differences. In summary, the viewpoint presented here is that the circadian timing system can be used very elegantly to explore the contributions of genetic and hormonal sex differences on biological systems at many levels. PMID- 29155246 TI - Relatively enriched housing conditions delay binge onset but do not attenuate binge size. AB - Housing and enrichment conditions are essential factors to consider when using animal models of behavior, as they can alter the behavior that is under investigation. The goal of this study was to determine the impact of the relatively enriched environment recommended by current animal care guidelines on development and maintenance of binge-type behavior in rats, using the limited access (LA) binge model. Non-food-deprived rats were divided into two groups, enriched and nonenriched, with all rats housed in shoebox cages. Bedding, nesting material, toys, and a solid floor were provided only to the enriched group to create a state of relative enrichment, or RE, compared to the nonenriched conditions historically used in the LA model. Enriched and nonenriched groups were further divided into control and experimental groups. Control rats received access to an optional source of fat (vegetable shortening) for 30min each day (daily access) while experimental rats received 30-min optional fat access on Monday, Wednesday, and Friday only (intermittent access). The four groups were designated C-E (Control-Enriched), C-NE (Control-Nonenriched), I-E (Intermittent Enriched), and I-NE (Intermittent-Nonenriched). Bingeing in the LA model is established when a group with intermittent access (i.e., the I-E or I-NE group) consumes significantly more vegetable shortening during the limited access period than a group with daily access (i.e., the C-E or C-NE group). Access sessions continued for 8weeks under these conditions, at which time the housing conditions of the I-E and I-NE groups were reversed for an additional 8weeks of access sessions. Intakes of the C-E and C-NE groups were similar and data from these two groups were combined. Relative to this Combined Control Group (CCG), the I-NE group began bingeing in week 3 while the I-E group binged during weeks 6 and 8. Following the reversal at the beginning of week 9, the newly enriched I-NE group ceased bingeing in week 9 but resumed bingeing in weeks 10-16. The newly nonenriched I-E group continued bingeing through the remainder of the study. Intakes of the I-E and I-NE groups were not significantly different at any time during the study. These results indicate that RE delays binge onset; that is, RE increases the time between the first fat access session and the first occurrence of bingeing. However, RE does not significantly alter the amount of fat consumed during binge sessions. Furthermore, addition of RE to a nonenriched group of animals (I-NE) does not reverse established binge behavior. Thus it appears that regardless of enrichment condition, intermittent access to vegetable shortening induces greater consumption of fat than does daily access. However, it is clear that a certain level of austerity in housing conditions is required for rapid development of lasting binge-type eating to occur. In addition, results suggest that it is unlikely that enrichment, to the degree provided in this study, can prevent or reverse binge-type eating in rats. PMID- 29155248 TI - A biphasic reduction in a measure of palatability following sucrose consumption in mice. AB - Consumption of foods results in a transient reduction in hedonic value that influences the extent and nature of feeding behavior. The time course of this effect, however, is poorly specified. In an initial experiment, using an analysis of the microstructure of licking in mice we found that consumption of sucrose led to a rapid reduction in lick cluster size, a measure of palatability, which recovered after 10 min, but reemerged 60min after initial consumption. We then replicated the finding that lick cluster size is reduced after 60min, but not 10min, under conditions in which a number of potential behavioural confounds were removed. In Experiment 2 the effect was replicated using a between-subjects design that ruled out the possibility that the effect was a specific consequence of the within-subjects procedures used in the first experiment, in which mice may have come to expect sucrose at different time points within the feeding session. While Experiments 1 and 2 confounded the time between periods of access to sucrose with time since the start of the feeding session, this confound was removed in Experiment 3, and, similar to the previous experiments, it was found that a second reduction in palatability occurred after 60min. Therefore, the effect was dependent only on the time since the previous exposure to sucrose, demonstrating that sucrose consumption initiates a biphasic reduction in palatability. The reduction in lick cluster size after 60min was not typically accompanied by a reduction in consumption suggesting that the more slowly developing reduction in the palatability measure was not simply a consequence of post-ingestive satiety. The cause of the biphasic change is not yet clear, and may reflect independent processes or the consequence of a single process that initiates multiple changes in palatability over time. PMID- 29155249 TI - Interoceptive accuracy and body awareness - Temporal and longitudinal associations in a non-clinical sample. AB - OBJECTIVE: Various aspects of interoception are regarded as temporally stable phenomena. This study investigates the temporal stability of and longitudinal associations between interoceptive accuracy (as measured with heartbeat tracking task) and a related concept, body awareness (assessed by self-report). METHODS: In a two-month longitudinal study 103 university students (31% male, 23.34+/ 4.34yrs.; 44 Hungarians; 36.4% male, 21.4+/-1.67yrs. and 59 Norwegians; 25.4% male, 24.8+/-5.09yrs) were investigated using Schandry's heartbeat tracking task and the Body Awareness Questionnaire. RESULTS: Both interoceptive accuracy and body awareness showed good test-retest reliability (r=0.60 and r=0.73, respectively; p<0.001 in both cases). The two concepts were independent of each other at baseline (r=0.06, p=0.587), and did not predict each other over an eight weeks period of time. CONCLUSION: Self-reported body awareness and objectively measured interoceptive accuracy are temporally stable and not related to each other. PMID- 29155250 TI - Surgical management of acute appendicitis in adults: A review of current techniques. AB - Acute appendicitis is one of the most frequent disorders in abdominal surgery. Therefore, appendectomy is a matter of significant interest in that field. Yet, four different techniques are available: open appendectomy, (conventional) laparoscopic appendectomy, single port laparoscopic appendectomy and NOTES appendectomy with its different variations. To evaluate the current state of the art in appendectomy a bibliographic search was conducted. All prospectively randomized trials and national register cohort studies published between 1/2010 and 5/2016 were included into the analysis. Overall, 25 respective studies were identified. All studies were screened for the following parameters: surgical site infection (SSI) (wound infection (WI) or intraabdominal abscess (IAA)), postoperative pain (PP), length of surgery (LoS), length of hospital stay (LHS), return to normal activities (RNA). Today the rate of laparoscopic appendectomy is reported to be up to 86% in the recent literature. Open appendectomy remains a safe and effective technique. Single port laparoscopic appendectomy presented almost equal in terms of safety and patient satisfaction. The method is still not as widespread as conventional three port laparoscopic appendectomy, presumably due to the necessity of special equipment and training. NOTES appendectomy is the newest development in appendectomy technique. First prospective cohort studies proved the safety and feasibility in experienced hands. However, the method is still experimental and further prospectively randomized trials are necessary. Concluding the current evidence, a laparoscopic approach, which is most commonly and increasingly frequently used, could be called "state of the art" in the treatment of appendicitis. PMID- 29155251 TI - The Rothman Index as a predictor of postdischarge adverse events after elective spine surgery. AB - BACKGROUND CONTEXT: The Rothman Index (RI) is a comprehensive rating of overall patient condition in the hospital setting. It is used at many medical centers and calculated based on vital signs, laboratory values, and nursing assessments in the electronic medical record. Previous research has demonstrated an association with adverse events, readmission, and mortality in other fields, but it has not been investigated in spine surgery. PURPOSE: The present study aims to determine the potential utility of the RI as a predictor of adverse events after discharge following elective spine surgery. STUDY DESIGN/SETTING: This retrospective cohort study was carried out at a large academic medical center. PATIENT SAMPLE: A total of 2,687 patients who underwent elective spine surgery between 2013 and 2016 were included in the present study. OUTCOME MEASURES: The occurrence of adverse events and readmission after discharge from the hospital, within postoperative day 30, was determined in the present study. METHODS: Patient characteristics and 30-day perioperative outcomes were characterized, with events being classified as "major adverse events" or "minor adverse events" using standardized criteria. Rothman Index scores from the hospitalization were analyzed and compared for those who did or did not experience adverse events after discharge. The association of lowest and latest scores on adverse events was determined with multivariate regression, controlling for demographics, comorbidities, surgical procedure, and length of stay. RESULTS: Postdischarge adverse events were experienced by 7.1% of patients. The latest and lowest RI values were significantly inversely correlated with any adverse events, major adverse events, minor adverse events and readmissions after controlling for age, gender, body mass index, American Society of Anesthesiologists (ASA) class, surgical site, and hospital length of stay. Rates of readmission and any adverse event consistently had an inverse correlation with lowest and latest RI scores, with patients at increased risk with lowest score below 65 or latest score below 85. CONCLUSIONS: The RI is a tool that can be used to predict postdischarge adverse events after elective spine surgery that adds value to commonly used indices such as patient demographics and ASA. It is found that this can help physicians identify high risk patients before discharge and should be able to better inform clinical decisions. PMID- 29155252 TI - Three-dimensional visualization and pathologic characteristics of cartilage and subchondral bone changes in the lumbar facet joint of an ovariectomized mouse model. AB - BACKGROUND CONTEXT: Low back pain (LBP) is more prevalent among postmenopausal women than men. Ovariectomy (OVX) is an established animal model that mimics the estrogen deficiency of postmenopausal women. Little is known about the three dimensional (3D) morphologic properties of cartilage and subchondral bone changes in the lumbar facet joint (LFJ) of an OVX mouse model. PURPOSE: The purpose of this study was to characterize the 3D morphologic change of cartilage and subchondral bone in the LFJ of an OVX mouse model. STUDY DESIGN: Three dimensional visualization and a histologic study on degenerative changes in cartilage and subchondral bone in the LFJ of an OVX mouse model were conducted. MATERIALS AND METHODS: Ovariectomy is performed to mimic postmenopausal changes in adult female mice. We present an imaging tool for 3D visualization of the pathologic characteristics of cartilage and subchondral bone changes LFJ degradation using propagation-based phase-contrast computed tomography (PPCT). The samples were further dissected, fixed, and stained for histologic examination. RESULTS: Propagation-based phase-contrast computed tomography imaging provides a 3D visualization of altered cartilage with a simultaneous high detail of the subchondral bone abnormalities in an OVX LFJ model. A quantitative analysis demonstrated that the cartilage volume, the surface area, and thickness were decreased in the OVX group compared with the control group (p<.05). Meanwhile, these decreases were accompanied by an obvious destruction of the subchondral bone surface and a loss of trabecular bone in the OVX group (p<.05). The delineation of the 3D pathologic changes in the PPCT imaging was confirmed by a histopathologic method with Safranin-O staining. Tartrate-resistant acid phosphatase staining revealed an increased number of osteoclasts in the subchondral bone of the OVX mice compared with that of the control group. CONCLUSIONS: These results demonstrated that a mouse model of OVX-induced LFJ osteoarthritis (OA)-like changes was successfully established and showed a good resemblance to the human OA pathology. Propagation-based phase-contrast computed tomography has great potential to becomea powerful 3D imaging method to comprehensively characterize LFJ OA and to effectively monitor therapeutics. Moreover, degenerative LFJ possesses a severe morphologic change in the subchondral bone, may be the source of postmenopausal LBP, and has the potential to be a novel therapeutic target for LBP treatment. PMID- 29155254 TI - Association of riluzole and dantrolene improves significant recovery after acute spinal cord injury in rats. AB - BACKGROUND CONTEXT: Damage to the spinal cord can result in irreversible impairment or complete loss of motor, sensory, and autonomic functions. Riluzole and dantrolene have been shown to provide neuroprotection by reducing neuronal apoptosis after brain and spinal cord injury (SCI) in several animal models of neurologic disorders. As these drugs protect the injured spinal cord through different mechanisms, we investigated the cumulative effects of riluzole and dantrolene. PURPOSE: This study aimed to investigate the neuroprotective efficacy of the combined administration of riluzole and dantrolene in experimental thoracic SCI. STUDY DESIGN: Twenty-nine Wistar rats were laminectomized at T12 and divided in five groups. Rats in GI (n=6) underwent laminectomy alone and were treated with placebo. Rats in GII (n=6) underwent laminectomy followed by SCI and were treated with placebo. Rats in GIII (n=5) underwent laminectomy followed by SCI and were treated with riluzole and placebo 15 minutes and 1 hour after laminectomy, respectively. Rats in GIV (n=6) underwent laminectomy followed by SCI and were treated with placebo and dantrolene 15 minutes and 1 hour after laminectomy, respectively. Rats in GV (n=6) underwent laminectomy followed by SCI and were treated with riluzole and dantrolene 15 minutes and 1 hour after laminectomy, respectively. A compressive trauma was performed to induce SCI. METHODS: Behavioral testing of hind limb function was performed using the Basso Beattie Bresnahan locomotor rating scale, which revealed significant recovery in the group treated with the association of riluzole and dantrolene compared with other groups. After euthanasia, the spinal cord was evaluated using light microscopy and immunochemistry with anti-NeuN and transferase dUTP nick-end labeling (TUNEL) staining. RESULTS: Animals treated with the association of riluzole and dantrolene showed a larger number of NeuN-positive neurons adjacent to the epicenter of injury (p<=.05). Furthermore, the TUNEL staining was similar between animals treated with riluzole and dantrolene and those that did not receive spinal cord trauma (p>.05). CONCLUSIONS: These results showed that riluzole and dantrolene have a synergistic effect in neuroprotection after traumatic SCI by decreasing apoptotic cell death. PMID- 29155253 TI - The association of inflammatory bowel disease and immediate postoperative outcomes following lumbar fusion. AB - BACKGROUND CONTEXT: The United States Centers for Disease Control and Prevention estimates the prevalence of inflammatory bowel disease (IBD) at more than 3.1 million people. As diagnostic techniques and treatment options for IBD improve, the prevalence of IBD is expected to increase. For spine surgeons, patients with IBD have a unique complication profile because patients with IBD may present with poor nutritional status and because the medications used to manage IBD have been associated with poor vertebral bone mineralization and immunosuppression. Presently, there are very limited data regarding perioperative outcomes among patients with IBD who undergo spinal surgery. The present study begins to address this knowledge gap by describing trends in patients with IBD undergoing lumbar fusion and by quantifying the association between IBD and immediate postoperative outcomes using a large, national database. PURPOSE: To advance our understanding of the potential pitfalls and risks associated with lumbar fusion surgery in patients with IBD. DESIGN/SETTING: Retrospective cross-sectional analysis. PATIENT SAMPLE: The Nationwide Inpatient Sample (NIS) database was queried from 1998 to 2011 to identify adult patients (18+) who underwent primary lumbar fusion operations using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) coding. OUTCOME MEASURES: Incidence of lumbar fusion procedures, prevalence of IBD, complication rates, length of stay, and total hospital charges. METHODS: The annual number of primary lumbar fusion operations performed between 1998 and 2011 was obtained from the NIS database. Patients younger than 18 years of age were excluded. The prevalence of IBD in this population (both Crohn disease and ulcerative colitis) was determined using ICD-9-CM codes. Logistic regression models were estimated to determine the association between IBD and the odds of postoperative medical and surgical complications, while controlling for patient demographics, comorbidity burden, and hospital characteristics. The complex survey design of the NIS was taken into account by clustering on hospitals and assuming an exchangeable working correlation using the discharge weights supplied by the NIS. We accounted for multiple comparisons using the Bonferroni correction and an alpha level for statistical significance of . 0028. RESULTS: The prevalence of IBD is increasing among patients undergoing lumbar fusion, from 0.21% of all patients undergoing lumbar fusion in 1998 to 0.48% of all patients undergoing lumbar fusion in 2011 (p<.001). The odds of experiencing a postoperative medical or surgical complication were not significantly different when comparing patients with IBD with control patients without IBD after controlling for patient demographics, comorbidity burden, and hospital characteristics (adjusted odds ratio=1.1, 95% confidence interval [CI] 0.99-1.3, p=.08). On multivariable analysis, the presence of IBD in patients undergoing lumbar fusion surgery was associated with longer length of stay and greater hospitalization charges. CONCLUSIONS: Among patients who underwent lumbar fusion, IBD is a rare comorbidity that is becoming increasingly more common. Importantly, patients with IBD were not at increased risk of postoperative complications. Spine surgeons should be prepared to treat more patients with IBD and should incorporate the present findings into preoperative risk counseling and patient selection. PMID- 29155255 TI - The role of epigenetics in cardiovascular health and ageing: A focus on physical activity and nutrition. AB - The cardiovascular system is responsible for transport of blood and nutrients to tissues, and is pivotal to the physiological health and longevity. Epigenetic modification is a natural, age-associated process resulting in highly contextualised gene expression with clear implications for cell differentiation and disease onset. Biological/epigenetic age is independent of chronological age, constituting a highly reflective snapshot of an individual's overall health. Accelerated vascular ageing is of major concern, effectively lowering disease threshold. Age-related chronic illness involves a complex interplay between many biological processes and is modulated by non-modifiable and modifiable risk factors. These alter the static genome by a number of epigenetic mechanisms, which change gene expression in an age and lifestyle dependent manner. This 'epigenetic drift' impacts health and contributes to the etiology of chronic illness. Lifestyle factors may cause acceleration of this epigenetic "clock", pre disposing individuals to cardiovascular disease. Nutrition and physical activity are modifiable lifestyle choices, synergistically contributing to cardiovascular health. They represent a powerful potential epigenetic intervention point for effective cardiovascular protective and management strategies. Thus, together with traditional risk factors, monitoring the epigenetic signature of ageing may prove beneficial for tailoring lifestyle to fit biology - supporting the increasingly popular concept of "ageing well". PMID- 29155256 TI - Role of toll-like receptors in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is the chronic inflammation of the gastrointestinal tract. Recently, studies of the interplay between the adaptive and innate immune responses have provided a better understanding of the immunopathogenesis of inflammatory disorders such as IBD, as well as identification of novel targets for more potent interventions. Toll-like receptors (TLRs) are a class of proteins that play a significant role in the innate immune system and are involved in inflammatory processes. Activation of TLR signal transduction pathways lead to the induction of numerous genes that function in host defense, including those for inflammatory cytokines, chemokines, and antigen presenting molecules. It was proposed that TLR mutations and dysregulation are major contributing factors to the predisposition and susceptibility to IBD. Thus, modulating TLRs represent an innovative immunotherapeutic approach in IBD therapy. This article outlines the role of TLRs in IBD, focusing on both animal and human studies; the role of TLR-targeted agonists or antagonists as potential therapeutic agents in the different stages of the disease is discussed. PMID- 29155257 TI - Contrasting the microbiomes from forest rhizosphere and deeper bulk soil from an Amazon rainforest reserve. AB - Pristine forest ecosystems provide a unique perspective for the study of plant associated microbiota since they host a great microbial diversity. Although the Amazon forest is one of the hotspots of biodiversity around the world, few metagenomic studies described its microbial community diversity thus far. Understanding the environmental factors that can cause shifts in microbial profiles is key to improving soil health and biogeochemical cycles. Here we report a taxonomic and functional characterization of the microbiome from the rhizosphere of Brosimum guianense (Snakewood), a native tree, and bulk soil samples from a pristine Brazilian Amazon forest reserve (Cunia), for the first time by the shotgun approach. We identified several fungi and bacteria taxon significantly enriched in forest rhizosphere compared to bulk soil samples. For archaea, the trend was the opposite, with many archaeal phylum and families being considerably more enriched in bulk soil compared to forest rhizosphere. Several fungal and bacterial decomposers like Postia placenta and Catenulispora acidiphila which help maintain healthy forest ecosystems were found enriched in our samples. Other bacterial species involved in nitrogen (Nitrobacter hamburgensis and Rhodopseudomonas palustris) and carbon cycling (Oligotropha carboxidovorans) were overrepresented in our samples indicating the importance of these metabolic pathways for the Amazon rainforest reserve soil health. Hierarchical clustering based on taxonomic similar microbial profiles grouped the forest rhizosphere samples in a distinct clade separated from bulk soil samples. Principal coordinate analysis of our samples with publicly available metagenomes from the Amazon region showed grouping into specific rhizosphere and bulk soil clusters, further indicating distinct microbial community profiles. In this work, we reported significant shifts in microbial community structure between forest rhizosphere and bulk soil samples from an Amazon forest reserve that are probably caused by more than one environmental factors such as rhizosphere and soil depth. PMID- 29155258 TI - Insights into the multifunctional role of natural killer enhancing factor-A (NKEF A/Prx1) in big-belly seahorse (Hippocampus abdominalis): DNA protection, insulin reduction, H2O2 scavenging, and immune modulation activity. AB - Natural killer enhancing factor A (NKEF-A), also known as peroxiredoxin 1 (Prx1), is a well-known antioxidant involved in innate immunity. Although NKEF-A/Prx1 has been studied in different fish species, the present study broadens the knowledge of NKEF-A gene in terms of molecular structure, function, and immune responses in fish species. Hippocampus abdominalis NKEF-A (HaNKEF-A) cDNA encoded a putative protein of 198 amino acids containing a thioredoxin_2 domain, VCP motifs, and three conserved cysteine residues including peroxidatic and resolving cysteines. Amino acid sequence comparison and phylogenetic breakdown showed the higher sequence identity and closer evolutionary position of HaNKEF-A to those of other fish counterparts. A recombinant protein of HaNKEF-A was shown to i) protect supercoiled DNA against mixed catalyzed oxidation, ii) reduce insulin disulfide bonds, and iii) scavenge extracellular H2O2. Results of in vitro assays demonstrated the concentration dependent antioxidant function of recombinant HaNKEF-A. In addition, qPCR assessments revealed that the HaNKEF-A transcripts were constitutively expressed in fourteen tissues with the highest expression in liver. As an innate immune response, HaNKEF-A transcripts were up-regulated in liver post injection of LPS, Edwardsiella tarda, Streptococcus iniae, and polyinosinic-polycytidylic acid. Thus, HaNKEF-A can safeguards big-belly seahorse from oxidative damage and pathogenic infections. This study provides insight into the functions of NKEF-A/Prx1 in fish species. PMID- 29155259 TI - Poly(I:C) model of schizophrenia in rats induces sex-dependent functional brain changes detected by MRI that are not reversed by aripiprazole treatment. AB - BACKGROUND AND PURPOSE: One of the hallmarks of schizophrenia is altered brain structure, potentially due to antipsychotic treatment, the disorder itself or both. It was proposed that functional changes may precede the structural ones. In order to understand and potentially prevent this unwanted process, brain function assessment should be validated as a diagnostic tool. METHODS: We used Arterial Spin Labelling MRI technique for the evaluation of brain perfusion in several brain regions in a neurodevelopmental poly(I:C) model of schizophrenia (8mg/kg on a gestational day 15) in rats taking into account sex-dependent effects and chronic treatment with aripiprazole (30days), an atypical antipsychotic acting as a partial agonist on dopaminergic receptors. RESULTS: We found the sex of the animal to have a highly significant effect in all regions of interest, with females showing lower blood perfusion than males. However, both males and females treated prenatally with poly(I:C) showed enlargement of the lateral ventricles. Furthermore, we detected increased perfusion in the circle of Willis, hippocampus, and sensorimotor cortex, which was not influenced by chronic atypical antipsychotic aripiprazole treatment in male poly(I:C) rats. CONCLUSION: We hypothesize that perfusion alterations may be caused by the hyperdopaminergic activity in the poly(I:C) model, and the absence of aripiprazole effect on perfusion in brain regions related to schizophrenia may be due to its partial agonistic mechanism. PMID- 29155260 TI - Selective autophagy: The new player in the fight against neurodegenerative diseases? AB - Autophagy is the lysosome-mediated bulk degradation of cellular components for material recycling to maintain cellular homeostasis. Autophagy was initially regarded as a nonselective process, however, recent evidence indicates that this process can in fact be highly selective, especially for targeting and degrading organelles, invading pathogens and protein aggregates. Recent studies have revealed an intrinsic connection between selective autophagy and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Given the vital roles of selective autophagy in these neurodegenerative diseases, modulation of this process is emerging as a new therapeutic strategy for neuroprotection. This review introduces the concept of selective autophagy, provides an overview of the pathological connection between selective autophagy and neurodegenerative diseases, and discusses approaches to modulate selective autophagy for therapeutic effects against neurodegenerative diseases. PMID- 29155261 TI - The phosphodiesterase-4 inhibitor, FCPR16, attenuates ischemia-reperfusion injury in rats subjected to middle cerebral artery occlusion and reperfusion. AB - Current phosphodiesterase-4 (PDE4) inhibitors exert beneficial effects in central nervous system diseases via anti-inflammatory and anti-apoptotic properties, but many of them are plagued by side effects like nausea and emesis. FCPR16, a novel PDE4 inhibitor synthesized in our lab, has potential anti-inflammatory property. In the present study, we aimed to investigate the effects of FCPR16 in a rat model of ischemic stroke and evaluate its emetogenic potential. Our results showed that FCPR16 treatment improved neurological function, reduced cerebral infarct volume, and attenuated brain histological changes in rats subjected to middle cerebral artery occlusion and reperfusion (MCAO/R). Furthermore, levels of proinflammatory cytokines tumor necrosis factor alpha, interleukin-6 and interleukin-1beta were decreased after FCPR16 treatment, as well as the ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein in MCAO/R rats. TUNEL staining and Western blot results showed that FCPR16 reduced apoptosis and regulated apoptotic-related proteins, with increased level of phosphorylated protein kinase B. Moreover, FCPR16 treatment increased cyclic adenosine monophosphate (cAMP) levels and cAMP-response element binding protein (CREB) phosphorylation in ischemic tissue. In addition, oral administration of 3mg/kg FCPR16 did not cause vomiting in beagle dogs. This study indicates that FCPR16 has protective effects against cerebral ischemia-reperfusion injury through inhibiting inflammation and apoptosis via the cAMP/CREB pathway, while it has low emetogenic potential. PMID- 29155262 TI - Glucocorticoids and CBG during pregnancy in mammals: diversity, pattern, and function. AB - Pregnancy is one of the defining characteristics of placental mammals. Key in the growth and development of the fetus during pregnancy are the dynamics of glucocorticoids (GCs) and their binding protein,corticosteroid-binding globulin (CBG), which determines how much of the GCs are free and biologically active. Out of more than 5000 species of placental mammals in 19 different orders, our understanding of the dynamics of maternal GCs and CBG during pregnancy is largely limited to the detailed study of 3 groups - sheep, laboratory rodents, and humans. The assumption is often made that what we see in these few species applies to the rest. To examine this generality, we compared patterns of maternal GCs over pregnancy from all placental mammals where data is available: in the blood of 13 species from 5 different orders and in metabolites in excreta in an additional 20 species from 9 orders. We found that maternal free GCs increase by late pregnancy in most taxa. This increase is achieved by either an increase in total GC secretion or a decrease in CBG. A major exception is found in the even toed ungulates (sheep, cows, etc.) where maternal GCs and CBG remain stable, but where the fetal adrenals mature in late pregnancy and produce the majority of their own GCs. We conclude that patterns of change in maternal GCs and CBG during pregnancy are species-specific but are alternative means to the same end: increased fetal exposure to GCs in late pregnancy, which is essential for development. PMID- 29155263 TI - Identification and characterisation of the epididymal proteins in the lizard, Eutropis carinata (Reptilia, Squamata) (Schneider, 1801). AB - Lizards are seasonal breeders. Cyclic reproductive nature makes lizard as a useful model for the study of the reproductively active protein secretions in the epididymis. During breeding season, the epididymides of the lizard secret proteins that mixes with the spermatozoa and create a favourable environment for sperm maturation. In this spectrum, the aim of this study is to identify and characterize proteins which are present in the lumen of the epididymis of the lizard, E. carinata during the active phase of reproduction. The identification and analysis of the proteins are done through the proteomic approaches. The epididymal luminal fluid sample was taken from the reproductively active and inactive phase and these are subjected to the size exclusion chromatography. Two major peaks (peak 1 and peak 2) were obtained in the epididymal luminal fluid sample taken during the reproductively active phase. On the other hand, the sample from the reproductively inactive phase showed one peak (peak 1) whereas, peak 2 is not present during this phase. The peak 2 belong to reproductively active phase was later subjected to the proteomic analysis. Appropriate gel electrophoresis separation and purification methods are combined with LC-MS/MS in order to identify and characterize the proteins that are presented during the reproductively active phase. Further, in this work, nine proteins are identified including three enzymes and three heat shock proteins. Among the identified proteins, bioinformatics analysis predicts that majority of them are localized in the cytoplasm. In addition to this, an observation is made in the endoplasmic reticulum where it is seen that a close protein-protein interaction network of three molecular chaperones are involved in protein processing. Overall, this paper opens up a new dimension search for epididymal markers for the first time in reptiles, particularly lizards. PMID- 29155264 TI - Modulation of adrenal steroidogenesis by testosterone in the lizard, Coleonyx elegans. AB - Our previous work with adrenocortical cells from several Sceloporus lizard species suggests that gonadal hormones influence the steroidogenic capacity and the sensitivity to ACTH. However, there are discrepancies in these cellular response parameters suggesting that the effects of gonadal hormones on adrenocortical function vary with species, sex, age, season, and environmental/experimental conditions. To gain further insight into these complex interactions, here we report studies on Coleonyx elegans, Eublepharidae (Yucatan Banded Gecko), which is only distantly related to Sceloporus lizards via a basal common ancestor and in captivity, reproduces throughout the year. We hypothesized that a more constant reproductive pattern would result in less variable effects of gonadal hormones on adrenocortical function. Reproductively mature male geckos were orchiectomized with and without replacement of testosterone (300 MUg) via an implanted Silastic(r) tube. Reproductively mature intact female geckos received implants with and without testosterone. After 11 weeks, adrenocortical cells were isolated from these lizards and incubated with corticotropin (ACTH) for 3 h at 28 degrees C. Three adrenocortical steroids, progesterone, corticosterone and aldosterone, were measured by highly specific radioimmunoassays. The production rate of each steroid was statistically analyzed using established software and net maximal rate (by subtracting the basal rate) in response to ACTH was determined. In general, corticosterone predominated and comprised ~83% of the total net maximal rate, followed by progesterone (~14%) and aldosterone (~3%). Compared to the functional responses of adrenocortical cells derived from other lizards thus far, adrenocortical cells from C. elegans exhibited a depressed steroid response to ACTH and this depressed response was more pronounced in male cells. In addition, other sex differences in cellular response were apparent. In female cells, the net maximal rates of progesterone, corticosterone and aldosterone were, respectively, 161, 122 and 900% greater than those in intact male cells. In contrast, cellular sensitivity to ACTH, as determined by the half maximally effective steroidogenic concentration (EC50) of ACTH, did not differ between intact-male and intact-female adrenocortical cells. Treatment effects were most striking for corticosterone, the putative, major glucocorticoid in lizards. Orchiectomy caused an increase in the net maximal corticosterone rate equivalent to that of intact-female cells. Testosterone maintenance in orchiectomized lizards completely suppressed the stimulatory effect of orchiectomy. However, orchiectomy with or without testosterone maintenance did not alter cellular sensitivity to ACTH. The effect of testosterone supplementation in intact females, although suppressive, was notably different from its effect in orchiectomized males. Its effect on the net maximal corticosterone rate was relatively modest and did not completely "masculinize" the greater rate seen in intact-female cells. However, testosterone supplementation dramatically suppressed the basal corticosterone rate (by 82%) and enhanced the overall cellular sensitivity to ACTH by 150%, two effects not seen in cells derived from testosterone-treated orchiectomized lizards. Collectively, these findings clearly indicating that the gonad directly or indirectly regulates lizard adrenocortical cell function. Whereas other gonadal or extra-gonadal factors may play a role, testosterone appears to be an essential determinant of the observed sex differences in adrenocortical function. PMID- 29155265 TI - Neuroanatomical distribution and function of the vasopressin V1B receptor in the rat brain deciphered using specific fluorescent ligands. AB - It is now accepted that vasopressin, through V1A/V1B receptors, centrally regulates cognitive functions such as memory, affiliation, stress, fear and depression. However, the respective roles of these receptor isoforms and their contribution to stress-related pathologies remain uncertain. The development of new therapeutic treatments requires a precise knowledge of the distribution of these receptors within the brain, which has been so far hampered by the lack of selective V1B markers. In the present study, we have determined the pharmacological properties of three new potent rat V1B fluorescent ligands and demonstrated that they constitute valuable tools for simultaneous visualization and activation of native V1B receptors in living rat brain tissue. Thus, d[Leu4,Lys-Alexa 647)8]VP (analogue 3), the compound with the best affinity selectivity/fluorescence ratio for the V1B receptor emerged as the most promising. The rat brain regions most concerned by stress such as hippocampus, olfactory bulbs, cortex and amygdala display the highest V1B fluorescent labelling with analogue 3. In the hippocampus CA2, V1B receptors are located on glutamatergic, not GABAergic neurones, and are absent from astrocytes. Using AVP EGFP rats, we demonstrate the presence of V1B autoreceptors on AVP-secreting neurones not only in the hypothalamus, but also sparsely in the hippocampus. Finally, using both electrophysiology and visualization of ERK phosphorylation, we show analogue 3-induced activation of the V1B receptor in situ. This will help to analyse expression and functionality of V1B receptors in the brain and contribute to further explore the AVPergic circuitry in normal and pathological conditions. PMID- 29155266 TI - Chronic dexamethasone exposure markedly decreased the hepatic triglyceride accumulation in growing goats. AB - Chronic stress seriously threatens welfare and health in animals and humans. Consecutive dexamethasone (Dex) injection was used to mimic chronic stress previously. In order to investigate the effect of chronic stress on hepatic lipids metabolism, in this study, 10 healthy male goats were randomly allocated into two groups, one received a consecutive injection of Dex via intramuscularly for 3 weeks (Dex group), the other received the same volume of saline as the control group (Con group). Hepatic health and triglyceride (TG) metabolism were analyzed and compared between two groups. The data showed that a significant decrease of TG in plasma and the liver was significantly decreased by Dex (P < .05), while the hepatic nonesterified fatty acid (NEFA) concentration was increased compared to the Con group (P < .05). Consistent with the decrease of TG level, the activity of hepatic lipoprotein lipase (LPL) and hepatic lipase (HL) enzymes activities were significantly enhanced by Dex. Real-time PCR results showed that the mRNA expression of sterol regulatory element binding transcription factor 1 (SREBP-1), acyl-CoA dehydrogenase long chain (ACADL) and acyl-CoA synthetase bubblegum family member 1 (ACSBG1) genes in liver was significantly up-regulated by chronic Dex injection (P < .05), whereas perilipin 2 (PLIN2) and adipose triglyceride lipase (ATGL) mRNA expression was significantly decreased by Dex (P < .05). In addition, no obvious damages were observed in the liver in both Con and Dex groups demonstrating by the sirius red staining, HE staining as well as several biochemical parameters related to the functional status of hepatocytes. Our data indicate that chronic Dex exposure decreases TG levels in the circulation and the liver through activating lipolysis and inhibiting lipogenesis without causing hepatic damages in the growing goats. PMID- 29155267 TI - Chronic subcutaneous infusion of neurosecretory protein GM increases body mass gain in chicks. AB - Recently we discovered a small hypothalamic protein in the chicken, named neurosecretory protein GL (NPGL), which is associated with body growth and energy metabolism in birds and rodents. Genome database analysis suggested that the NPGL gene has a paralogous gene in vertebrates, named neurosecretory protein GM (NPGM). However, the biological action of NPGM remains unclear. In this study, we investigated whether NPGM affects body growth in chicks. We found that subcutaneous infusion of NPGM for six days increased body mass gain in a dose dependent manner. Despite the observed increase in body mass, infusion of NPGM did not alter food and water intake. Of note, we observed tendency of mass increase of several peripheral tissues, specifically. When we compared several tissue types, NPGM seemed to induce the largest growth increase in white adipose tissue mass. These results suggest that NPGM may accelerate fat accumulation and body growth. In addition, we analyzed whether NPGM increases body growth through the action of pituitary hormones. However, we observed no significant changes in mRNA expression of pituitary hormones or plasma levels of growth hormone in NPGM treated chicks. This is the first report describing the biological action of NPGM in vertebrates. PMID- 29155268 TI - New 5-Factor Modified Frailty Index Using American College of Surgeons NSQIP Data. AB - BACKGROUND: The modified frailty index (mFI-11) is a NSQIP-based 11-factor index that has been proven to adequately reflect frailty and predict mortality and morbidity. These 11 factors, made of 16 variables, map to the original 70-item Canada Study of Health and Aging Frailty Index. In past years, certain NSQIP variables have been removed from the database; as of 2015, only 5 of the original 11 factors remained. The predictive power and usefulness of these 5 factors in an index (mFI-5) have not been proven in past literature. The goal of our study was to compare the mFI-5 to the mFI-11 in terms of value and predictive ability for mortality, postoperative infection, and unplanned 30-day readmission. STUDY DESIGN: The mFI was calculated by dividing the number of factors present for a patient by the number of available factors for which there were no missing data. Spearman's rho was used to assess correlation between the mFI-5 and mFI-11. Predictive models, using both unadjusted and adjusted logistic regressions, were created for each outcome for 9 surgical sub-specialties using 2012 NSQIP data, the last year all mFI-11 variables existed. RESULTS: Correlation between the mFI 5 and mFI-11 was above 0.9 across all surgical specialties except for cardiac and vascular surgery. Adjusted and unadjusted models showed similar c-statistics for mFI-5 and mFI-11, and strong predictive ability for mortality and postoperative complications. CONCLUSIONS: The mFI-5 and the mFI-11 are equally effective predictors in all sub-specialties and the mFI-5 is a strong predictor of mortality and postoperative complications. It has credibility for future use to study frailty within the NSQIP database. It also has potential in other databases and for clinical use. PMID- 29155269 TI - Influence of Time to Appendectomy and Operative Duration on Hospital Cost in Children with Uncomplicated Appendicitis. AB - BACKGROUND: The goal of this study was to examine the influence of time to appendectomy (TTA) and operative duration (OD) on hospital cost as surrogate measures of perioperative efficiency. STUDY DESIGN: We conducted a retrospective cohort analysis of 2,116 children undergoing appendectomy for uncomplicated appendicitis at 16 children's hospitals from January 2013 to December 2014. Time to appendectomy (emergency department presentation to incision) and OD were obtained from the NSQIP Pediatric Appendectomy Pilot Database and merged with cost data from the Pediatric Health Information System Database. Multivariate regression was used to examine the influence of TTA and OD (categorized by quartiles of hospital-level means) on hospital cost, adjusting for patient and hospital-level characteristics. RESULTS: Median TTA and OD across all patients was 7.3 hours (interquartile range 4.4 to 12.4 hours) and 36 minutes (interquartile range 26 to 49 minutes), respectively. The longest quartile of OD was associated with 38% higher total cost ($2,512/case; rate ratio [RR] 1.38; 95% CI 1.27 to 1.5; p < 0.001) and 27% higher operating room-associated cost ($960/case; RR 1.27; 95% CI 1.22 to 1.34; p < 0.001) compared with the shortest quartile. The longest quartile of TTA was associated with 23% higher total cost ($1,589/case; RR 1.23; 95% CI 1.14 to 1.32; p < 0.001) and 53% higher room associated cost ($906/case; RR 1.53; 95% CI 1.35 to 1.74; p < 0.001) compared with the shortest quartile. The influence of TTA and OD were independent but potentiating effects, with median cost for hospitals in both the longest quartiles of TTA and OD being 79% higher than those in the shortest quartiles. CONCLUSIONS: Longer TTA and OD were independently associated with increased hospital cost, with OD being the most significant driver of cost variation across hospitals. Identification of best practices from high-efficiency hospitals might provide a high-yield strategy for improving value in appendicitis care. PMID- 29155270 TI - Efficient Hemorrhage Control Skills Training for Healthcare Employees. AB - BACKGROUND: Several national initiatives are aimed at training citizens to assist bleeding victims. The purpose of this study was to evaluate an effort to quickly and efficiently teach basic bleeding control techniques to a clinical and nonclinical workforce. STUDY DESIGN: The research study was conducted at 4 hospitals in a mid-sized metropolitan area. In spring 2017, the trauma department at a Level I trauma center set an ambitious goal to provide hands-on training to 1,000 employees during the course of 6 weeks. Trainings occurred in small groups and lasted approximately 6 to 10 minutes, during which time participants were taught and practiced 2 skills: packing a wound and holding direct pressure, and applying a stretch-wrap-and-tuck tourniquet. Participants completed pre- and post surveys indicating their likelihood to use these skills. RESULTS: More than 1,000 individuals were trained, and there were survey data for 870 participants. More than 40% of participants worked in nonclinical roles and 29% had no first aid or medical training. After completing skills training, 98% of participants indicated that they would be likely to take action to assist a bleeding victim and that they could correctly apply direct pressure or a tourniquet to control severe bleeding. CONCLUSIONS: Results demonstrate that basic hemorrhage control skills can be taught to clinical and nonclinical people in brief, hands-on training. Efforts like this can be deployed across large workplace environments to prepare the maximum number of employees to take action to assist bleeding victims. PMID- 29155271 TI - T-cell-replete haploidentical transplantation in acute myeloid leukemia. AB - In the last decade, the number of haploidentical stem cell transplantation has increased because of the widespread use of T-cell-replete platforms developed worldwide. Acute myeloid leukemia (AML) is the main indication to perform allogeneic stem cell transplantation. Here, we reviewed the clinical results obtained using T-cell-replete platforms in different clinical situations such as first or further complete remission, refractory disease, and in the elderly population. Overall, the toxic profile of T-cell-replete haploidentical transplantation is similar to transplantation from other donors, with positive aspects such as a reduced incidence of chronic graft-versus-host disease. Leukemia-free survival and overall survival are also similar. In conclusion, T cell-replete haploidentical transplantation represents a new frontier in the treatment landscape of AML, lessening problems linked to donor search and ensuring that a donor can be found for all patients in a timely manner. PMID- 29155272 TI - Oral immunization with recombinant Lactobacillus casei expressing OmpAI confers protection against Aeromonas veronii challenge in common carp, Cyprinus carpio. AB - Aeromonas veronii is a gram-negative pathogen capable of infecting both fish and mammals, including humans, and natural infection in fish results in irreparable damage to the aquaculture industry. Lactic acid bacteria (LAB) have a number of properties that make them attractive candidates as delivery vehicles for presentation to the mucosa sites of compounds with pharmaceutical interest, in particular vaccines. In this study, we generated two recombinant Lactobacillus casei (surface-displayed or secretory) expressing the OmpAI of A.veronii and evaluated the effect on immune responses in fish model. A 1022 bp gene fragment of the 42 kDa OmpAI antigen of A.veronii was cloned into pPG-1 (surface displayed) and pPG-2 (secretory) and electrotransformed into Lactobacillus casei CC16. The recombinant plasmid in L.casei could be stably inherited over 50 generations, and production of OmpAI protein had slight limited effects on cells growth. Treatment of common carp with the recombinant vaccine candidate stimulated high serum or skin mucus specific antibody titers and induced a higher lysozyme, ACP, SOD activity, while fish fed with Lc-pPG or PBS had no detectable immobilizing immune responses. Expression of IL-10, IL-beta, IFN-gamma, TNF-alpha genes in the group immunized with recombinant L.casei were significantly (P < 0.05) up regulated as compared with control groups, indicating that inflammatory response and cell immune response were triggered. Further, viable recombinant L.casei strains were directly delivered and survive throughout the intestinal tract, the recombinant OmpAI was also detected in intestine mucosal. The results showed that common carp received Lc-pPG1-OmpAI (66.7%) and Lc-pPG2-OmpAI (50.0%) had higher survival rates compared with the controls after challenge with A.veronii, indicating that Lc-pPG1-OmpAI and Lc-pPG2-OmpAI had beneficial effects on immune response and enhanced disease resistance of common carp against A.veronii infection. Our study here demonstrates, for the first time, the ability of recombinant L.casei as oral vaccine against A.veronii infection in carps. The combination of OmpAI delivery and LAB approach may be a promising mucosal therapeutic agent for treating and controlling A.veronii. PMID- 29155273 TI - Mu-opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptor activation both contribute to the discriminative stimulus properties of cebranopadol in the rat. AB - The novel potent analgesic cebranopadol is an agonist at nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors, with the highest in-vitro activity at NOP and mu-opioid peptide (MOP) receptors, and somewhat lower activity at kappa-opioid peptide (KOP) and delta-opioid peptide (DOP) receptors. We addressed the question of which of these pharmacological activities contribute to the stimulus properties of cebranopadol using a rat drug discrimination procedure. First, cebranopadol was tested in generalization tests against a morphine cue, including receptor-specific antagonism. Second, cebranopadol was established as a cue, and MOP, NOP, KOP and DOP receptor-selective agonists were tested in generalization tests. Third, cebranopadol in combination with receptor-selective antagonists was tested against the cebranopadol cue. Cebranopadol generalized to the morphine cue. Full generalization was only seen at clearly supra-analgesic doses. The effect of cebranopadol was reduced by naloxone, but was enhanced by the NOP receptor antagonist J-113397. In cebranopadol-trained rats, cebranopadol as well as morphine produced generalization. A NOP receptor agonist did not, while a DOP receptor agonist and a KOP receptor agonist weakly generalized to the cebranopadol cue. Conversely, generalization of cebranopadol was reduced by naloxone and J-113397, but not by a DOP or a KOP receptor antagonist. These results suggest a contribution of MOP receptor activity and a relative lack of contribution of DOP and KOP receptor activity to cebranopadol's stimulus properties. The findings regarding the contribution of NOP receptor activity were equivocal, but interestingly, the morphine-like stimulus property of cebranopadol appears to be reduced by its intrinsic NOP receptor activity. PMID- 29155274 TI - Polysaccharides from the South African medicinal plant Artemisia afra: Structure and activity studies. AB - Artemisia afra (Jacq. Ex. Willd), is an indigenous plant in South Africa and other parts of the African continent, where it is used as traditional medicine mostly for respiratory conditions. The objective of this study was to investigate the structural features of the polysaccharides from the leaves of this plant, as well as the biological activities of the polysaccharide fractions against the complement assay. Leaves of Artemisia afra were extracted sequentially with organic solvents (dichloromethane and methanol), 50% aqueous ethanol, and water at 50 and 100 degrees C respectively. The polysaccharide extracts were fractionated by ion exchange chromatography and the resulting fractions were tested for biological activity against the complement fixation assay. Active fractions were further fractionated using gel filtration. Monosaccharide compositions and linkage analyses were determined for the relevant fractions. Polysaccharides were shown to be of the pectin type, and largely contain arabinogalactan, rhamnogalacturonan and homogalacturonan structural features. The presence of arabinogalactan type II features as suggested by methylation analysis was further confirmed by the ready precipitation of the relevant polysaccharides with the Yariv reagent. An unusual feature of some of these polysaccharides was the presence of relatively high levels of xylose as one of its monosaccharide constituents. Purified polysaccharide fractions were shown to possess higher biological activity than the selected standard in the complement assay. Digestion of these polysaccharides with an endo-polygalacturonase enzyme resulted in polymers with lower molecular weights as expected, but still with biological activity which exceeded that of the standard. Thus on the basis of these studies it may be suggested that immunomodulating properties probably contribute significantly to the health-promoting effects of this medicinal plant. PMID- 29155275 TI - Antibacterial compounds from the Australian native plant Eremophila glabra. AB - Recent reports of Eremophila glabra (R.Br.) Ostenf. (Scrophulariaceae) displaying antibacterial activity has led us to investigate the bioactive secondary metabolites responsible for this activity. Bioassay-directed fractionation of solvent extracts prepared from the leaves of E. glabra led to the isolation of seven serrulatane diterpenes, three flavonoids and the caffeoyl ester disaccharide verbascoside. Among these, four serrulatanes, namely 18-acetoxy-8, 20-dihydroxyserrulat-14-en-19-oic acid (14), 18,20-diacetoxy-8-hydroxyserrulat-14 en-19-oic acid (16), 8,18,20-triacetoxyserrulat-14-en-19-oic acid (17) and 18 acetoxy-8-hydroxyserrulat-14-en-19-oic acid (18) are described for the first time, while 8,20-diacetoxyserrulat-14-en-19-oic acid (3), 8,18,20 trihydroxyserrulat-14-en-19-oic acid (5) and 20-acetoxy-8-hydroxyserrulat-14-en 19-oic acid (19) were previously reported. All three flavonoids hispidulin (12), jaceosidin (13) and cirsimaritin (15) are known but reported for the first time in E. glabra. All compounds were tested in an agar diffusion antimicrobial assay against Staphylococcus aureus (NCTC 10442) and Staphylococcus epidermidis (ATCC 14990). Compounds 12, 13, 17, 18 and 19 exhibited moderate activity, with minimum inhibitory concentrations (MICs) ranging from 32 to 512MUg/mL. Compound 19 demonstrated the highest activity against S. epidermidis ATCC 14990 with MIC of 32MUg/mL, while 13 demonstrated the highest activity against S. aureus NCTC 10442 with MIC of 128MUg/mL. PMID- 29155276 TI - Cortical plasticity as a basis of phantom limb pain: Fact or fiction? AB - Cortical reorganization has been proposed as a major factor involved in phantom pain with prior nociceptive input to the deafferented region and input from the non-deafferented cortex creating neuronal activity that is perceived as phantom pain. There is substantial evidence that these processes play a role in neuropathic pain, although causal evidence is lacking. Recently it has been suggested that a maintenance of the cortical representation of the former hand area is related to phantom pain. Although interesting, evidence for this process is so far scarce. In addition, peripheral factors have been proposed as important for phantom limb pain. Although often introduced as contradictory, we suggest that cortical reorganization, preserved limb function and peripheral factors interact to create the various painful and nonpainful aspects of the phantom limb experience. In addition, the type of task (sensory versus motor), the interaction of injury- and use-dependent plasticity, the type of data analysis, contextual factors such as the body representation and psychological variables determine the outcome and need to be considered in models of phantom limb pain. Longitudinal studies are needed to determine the formation of the phantom pain experience. PMID- 29155277 TI - Neurotrophin and FGF Signaling Adapter Proteins, FRS2 and FRS3, Regulate Dentate Granule Cell Maturation and Excitatory Synaptogenesis. AB - Dentate granule cells (DGCs) play important roles in cognitive processes. Knowledge about how growth factors such as FGFs and neurotrophins contribute to the maturation and synaptogenesis of DGCs is limited. Here, using brain-specific and germline mouse mutants we show that a module of neurotrophin and FGF signaling, the FGF Receptor Substrate (FRS) family of intracellular adapters, FRS2 and FRS3, are together required for postnatal brain development. In the hippocampus, FRS promotes dentate gyrus morphogenesis and DGC maturation during developmental neurogenesis, similar to previously published functions for both neurotrophins and FGFs. Consistent with a role in DGC maturation, two-photon imaging revealed that Frs2,3-double mutants have reduced numbers of dendritic branches and spines in DGCs. Functional analysis further showed that double mutant mice exhibit fewer excitatory synaptic inputs onto DGCs. These observations reveal roles for FRS adapters in DGC maturation and synaptogenesis and suggest that FRS proteins may act as an important node for FGF and neurotrophin signaling in postnatal hippocampal development. PMID- 29155278 TI - MeCP2 Expression in a Rat Model of Risky Decision Making. AB - Many neuropsychiatric disorders are associated with abnormal decision making involving risk of punishment, but the underlying molecular basis remains poorly understood. Methyl CpG-binding protein 2 (MeCP2) is an epigenetic factor that regulates transcription by directly binding to methylated DNA. Here, we evaluated MeCP2 expression in the context of risk-taking behaviors using the Risky Decision making Task (RDT), in which rats make discrete choices between a small "safe" food reward and a large "risky" food reward accompanied by varying probabilities of punishment. In Experiment 1, expression of MeCP2 as assessed by immunoblotting in the medial prefrontal cortex (mPFC), but not the striatum, was inversely correlated with the degree of preference for the large, risky reward (risk taking) seven days after the last RDT test. In Experiment 2, MeCP2 expression 90 min after RDT testing, assessed using immunohistochemistry, was suppressed in both the dorsal mPFC (dmPFC) and nucleus accumbens compared to home cage controls, indicating that MeCP2 expression is modulated by RDT performance. Additional experiments revealed that RDT performance increased expression of MeCP2 phosphorylated at Ser421 (associated with neuronal activity and activation of gene expression) in dmPFC principal neurons. Finally, as in Experiment 1, lower expression of MeCP2 in the ventral mPFC was associated with greater risk taking under baseline conditions. Together, these findings indicate a complex regulatory role of MeCP2 in risky decision making, and suggest that epigenetic factors may be an important component of the molecular mechanisms underlying such decision-making processes. PMID- 29155279 TI - Scalar timing in memory: A temporal map in the hippocampus. AB - Many essential tasks, such as decision making, rate calculation and planning, require accurate timing in the second to minute range. This process, known as interval timing, involves many cortical areas such as the prefrontal cortex, the striatum, and the hippocampus. Although the neurobiological origin and the mechanisms of interval timing are largely unknown, we have developed increasingly accurate mathematical and computational models that can mimic some properties of time perception. The accepted paradigm of temporal durations storage is that the objective elapsed time from the short-term memory is transferred to the reference memory using a multiplicative "memory translation constant" K*. It is believed that K* has a Gaussian distribution due to trial-related variabilities. To understand K* genesis, we hypothesized that the storage of temporal memories follows a topological map in the hippocampus, with longer durations stored towards dorsal hippocampus and shorter durations stored toward ventral hippocampus. We found that selective removal of memory cells in this topological map model shifts the peak-response time in a manner consistent with the current experimental data on the effect of hippocampal lesions on time perception. This opens new avenues for experimental testing of our topological map hypothesis. We found numerically that the relative shift is determined both by the lesion size and its location and we suggested a theoretical estimate for the memory translation constant K*. PMID- 29155280 TI - Molecular analysis of tick-borne protozoan and rickettsial pathogens in small ruminants from two South African provinces. AB - Tick-borne protozoan and rickettsial diseases are a major threat to livestock in tropical and sub-tropical regions of Africa. In this study we investigated the presence and distribution of Theileria spp., Babesia ovis, Anaplasma ovis, Anaplasma phagocytophilum, Ehrlichia ruminantium and SFG Rickettsia in sheep and goats from Free State and KwaZulu-Natal provinces. A total of 91 blood samples were screened in this study, 61 from goats and 30 from sheep. PCR assay was conducted using primers based on Theileria spp. 18S rRNA, Babesia ovis (BoSSU rRNA), Anaplasma ovis (AoMSP4), Anaplasma phagocytophilum epank1, Ehrlichia ruminantium pCS20 and SFG Rickettsia OmpA. Overall infection rates of Theileria spp., Anaplasma ovis and Ehrlichia ruminantium were 18 (19.8%), 33 (36.3%) and 13 (14.3%), respectively. The co-infection of two pathogens were detected in 17/91 (18.7%) of all samples, goats having higher rates of co-infection compared to sheep. Phylogenetic tree analysis sequence of pCS20 gene of E. ruminantium of this study was found to be in the same clade with Kumm2 and Riverside strains both from South Africa. The phylogram of SSU rRNA of Theileria ovis had longer branch length compared to all other sequences most of which were from Asia and Middle East. This study provides important data for understanding the tick-borne diseases occurrence in the study area and it is expected to improve the approach for the diagnosis and control of these diseases. PMID- 29155281 TI - Effect of oregano essential oil and carvacrol on Cryptosporidium parvum infectivity in HCT-8 cells. AB - Cryptosporidium parvum is the second leading cause of persistent diarrhea among children in low-resource settings. This study examined the effect of oregano essential oil (OEO) and carvacrol (CV) on inhibition of C. parvum infectivity in vitro. HCT-8 cells were seeded (1*106) in 96-well microtiter plates until confluency. Cell viability and infectivity were assessed by seeding HCT-8 cell monolayers with C. parvum oocysts (1*104) in two modalities: 1) 4h co-culture with bioactive (0-250MUg/mL) followed by washing and incubation (48h, 37 degrees C, 5% CO2) in bioactive-free media; and 2) 4h co-culture of C. parvum oocysts followed by washing and treatment with bioactive (0-250MUg/mL) during 48-h incubation. Cell viability was tested using Live/DeadTM assay whereas infectivity was measured using C. parvum-specific antibody staining via immunofluorescence detection. Loss of cell viability was observed starting at 125MUg/mL and 60MUg/mL for OEO and CV, respectively. Neither OEO nor CV modulated the invasion of C. parvum sporozoites in HCT-8 cells. Treatment with bioactive after invasion reduced relative C. parvum infectivity in a dose-dependent manner to 55.6+/-10.4% and 45.8+/-4.1% at 60 and 30MUg/mL of OEO and CV, respectively. OEO and CV are potential bioactives to counteract C. parvum infection in children. PMID- 29155282 TI - Seizure liability assessments using the hippocampal tissue slice: Comparison of non-clinical species. AB - INTRODUCTION: Traditionally, rat hippocampal tissue slice models are used as an in vitro electrophysiology assay to assess seizurogenic potential in early drug development despite non-clinical species-specific differences noted during in vivo seizure studies. METHODS: Hippocampal tissue slices were acutely isolated from rats, minipigs, dogs and nonhuman primates (NHP). Population spikes (PS) were evoked through stimulation of the CA3 Schaffer collateral pathway and recorded using in vitro electrophysiological techniques via an extracellular electrode placed within the CA1 stratum pyramidale cell body layer. RESULTS: Hippocampal slices, across all species, displayed a concentration-dependent increase in PS area and number with the pro-convulsant pentylenetetrazol (PTZ; 0.1-10mM). Beagle dogs exhibited higher sensitivities to PTZ-induced changes in PS area and number compared to both rats and NHPs which presented nuanced differences in their responsiveness to PTZ modulation. Minipigs were comparatively resistant to PTZ-induced changes in both PS area and number. Rat and NHP hippocampal tissues were further characterized with the pro-convulsant agents 4-aminopyradine (4-AP; 1-100MUM) and cefazolin (0.001-10mM). Rats possessed higher sensitivities to 4-AP- and cefazolin-induced changes to both PS area and number whereas NHP displayed greater modulation in PS duration. The anti convulsant agents, diazepam (10-500MUM) and lidocaine (1-500MUM), were also tested on either rat and/or NHP tissue with both drugs repressing PS activation at high concentrations. DISCUSSION: Hippocampal tissue slices, across all species, possessed distinct sensitivities to pro- and anti-convulsant agents which may benefit the design of non-clinical seizure liability studies and their associated data interpretation. PMID- 29155283 TI - Comparative analysis of media effects on human induced pluripotent stem cell derived cardiomyocytes in proarrhythmia risk assessment. AB - INTRODUCTION: Cardiotoxicity assessment using human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) forms a key component of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). A potentially impactful factor on iPSC-CM testing is the presence of serum in the experimental media. Generally, serum-free media is used to most accurately reproduce "free" drug concentration. However, caution is needed; drug solubility and cardiomyocyte electrophysiology could be affected by media formulation, potentially impacting interpretation of drug induced effects. METHODS: Effects of 25 drugs on properties of spontaneous field potentials in iPSC-CMs were assayed using a high-throughput microelectrode array (MEA) in two media formulations: serum-containing and serum-free. Comparative analysis was conducted on rate-corrected field potential duration (FPDc) and prevalence of arrhythmic events. Further MEA experiments were conducted, varying percentages of serum as well as carbon substrate components. Comparative LC-MS/MS analysis was done on two compounds to evaluate drug concentrations. RESULTS: In serum-free media, 9 drugs prolonged FPDc. In serum-containing, 11 drugs prolonged FPDc. Eighteen drugs induced arrhythmias, 8 of these induced arrhythmias at lower concentrations in serum-containing media. At the highest non-arrhythmic concentrations, 13 of 25 drugs exhibited significant differences in FPDc prolongation/shortening between the media. Increasing fractions of serum in media yielded higher FPDc measurements. LC-MS/MS analysis of moxifloxacin and quinidine showed higher concentrations in serum-containing media. DISCUSSION: The present study highlights media formulation as an important consideration for cardiac safety testing with iPSC-CMs. Results described here suggest that media formulation influences both compound availability and baseline electrophysiological properties. Special attention should be paid to media for future iPSC-CM assays. PMID- 29155285 TI - Parasite infection of specific host genotypes relates to changes in prevalence in two natural populations of bumblebees. AB - The antagonistic relationship between parasites and their hosts is strongly influenced by genotype-by-genotype interactions. Defense against parasitism is commonly studied in the context of immune system-based mechanisms and, thus, the focus in the search for candidate genes in host-parasite interactions is often on immune genes. In this study, we investigated the association between prevalence of parasite infection and host mitochondrial DNA (mtDNA) haplotypes in two natural populations of bumblebees (Bombus terrestris). The two most common haplotypes of the host populations, termed A and B, differ by a single nonsynonymous nucleotide substitution within the coding region of cytochrome oxidase I, an important player in metabolic pathways. We screened infection by Nosema bombi, a common endoparasite of bumblebees, and the corresponding host mtDNA-haplotype frequencies in over 1400 bumblebees between 2000 and 2010. The island population of Gotland showed lower mtDNA diversity compared to the mainland population in Switzerland. Over time, we observed large fluctuations in infection prevalence, as well as variation in host haplotype frequencies in both populations. Our long-term observation revealed that N. bombi infection of specific host genotypes is transient: We found that with increasing infection prevalence, proportionally more individuals with haplotype B, but fewer individuals with haplotype A were infected. This suggests that the presence of N. bombi in specific host genotypes relates to infection prevalence. This may be a result of parasite competition, or differential resilience of host types to ward off infections. The findings highlight the important role of host mtDNA haplotypes in the interaction with parasites. PMID- 29155284 TI - The dynamic evolution of Drosophila innubila Nudivirus. AB - Viruses coevolve with their hosts to overcome host resistance and gain the upper hand in the evolutionary arms race. Drosophila innubila nudivirus (DiNV) is a double stranded DNA virus, closely related to Oryctes rhinoceros nudivirus (OrNV) and Kallithea virus. DiNV is the first DNA virus found to naturally infect Drosophila and therefore has the potential to be developed as a model for DNA virus immune defense and host/virus coevolution within its well-studied host system. Here we sequence and annotate the genome of DiNV and identify signatures of adaptation, revealing clues for genes involved in host-parasite coevolution. The circular genome is 155,555bp and contains 107 coding open reading frames (ORFs) and a wealth of AT-rich simple sequence repeats. While synteny is highly conserved between DiNV and Kallithea virus, it drops off rapidly as sequences become more divergent, consistent with rampant rearrangements across nudiviruses. Overall, we show that evolution of DiNV is likely due to adaptation of a very few genes coupled with high gene turnover. PMID- 29155286 TI - Sulfur mustard-induced epigenetic modifications over time - a pilot study. AB - The chemical warfare agent sulfur mustard (SM) can cause long-term health effects that may occur even years after a single exposure. The underlying pathophysiology is unknown, but epigenetic mechanisms are discussed as feasible explanation. "Epigenetics" depicts regulation of gene function without affecting the DNA sequence itself. DNA-methylation and covalent histone modifications (methylation or acetylation) are regarded as important processes. In the present in vitro study using early endothelial cells (EEC), we analyzed SM-induced DNA methylation over time and compared results to an in vivo skin sample that was obtained approx. one year after an accidental SM exposure. EEC were exposed to low SM concentrations (0.5 and 1.0MUM). DNA methylation and histone acetylation (H3-K9, H3-K27, H4-K8) or histone di-methylation (H3-K9, H3-K27, H3-K36) were investigated 24h after exposure, and after 2 or 4 additional cell passages. The human skin sample was assessed in parallel. SM had only some minor effects on histone modifications. However, a significant and pronounced increase of DNA methylation was detected in the late cell passages as well as in the skin sample. Our results indicate that SM does indeed cause epigenetic modifications that appear to persist over time. PMID- 29155287 TI - Challenges to Safe and Effective Pain Management in Patients With Super Obesity: Case Report and Literature Review. PMID- 29155289 TI - The Diagnostic Sensitivity of the Memorial Delirium Assessment Scale-Spanish Version. AB - BACKGROUND: Although Memorial Delirium Assessment Scale (MDAS) is a successful tool for delirium evaluation and monitoring, it is nevertheless important to determine whether cutoff scores vary according to the studied population. The main objective of this study was to evaluate the diagnostic sensitivity of the recently validated Spanish version of the MDAS. The secondary objective was to analyze possible diagnostic differences when used in a hospice or general hospital setting. METHODOLOGY: A prospective study was conducted with advanced cancer patients in two settings (hospice and general hospital). A diagnosis of delirium was established according to clinical criteria and the Confusion Assessment Method. Sensitivity (S), specificity (Sp), positive predictive value, and negative predictive value were determined according to the receiver operating characteristics curve. The MDAS values for different centers were studied using nonparametric tests (Mann-Whitney). RESULTS: A total of 67 patients were included, 28 of whom had been diagnosed with delirium (15/40 hospice and 13/27 general hospital). The mean MDAS scores were 13.6 and 5.5 for the delirium and nondelirium groups, respectively. A cutoff score of 7 gave the optimal screening diagnosis balance (S 92.6%, Sp 71.8%, positive predictive value 70.1%, and negative predictive value 93.3%). Diagnoses of anxiety and depression were not related with delirium (P <= 0.44). A diagnosis of dementia was related to delirium (P <= 0.052) but did not influence the diagnostic sensitivity of MDAS (P <= 0.26). No differences were found between hospice and general hospital settings as regards the diagnostic sensitivity of MDAS. CONCLUSION: A screening cutoff of 7 appears to be optimal for MDAS Spanish version. No differences were found between advanced cancer patients cared for in a hospice or general hospital. However, more research is required to define the MDAS cutoff for patients with advanced cancer and dementia. PMID- 29155288 TI - Investigation of the Practices, Legislation, Supply Chain, and Regulation of Opioids for Clinical Pain Management in Southern Africa: A Multi-sectoral, Cross National, Mixed Methods Study. AB - CONTEXT: Sub-Saharan Africa faces an increasing incidence and prevalence of life limiting and life-threatening conditions. These conditions are associated with a significant burden of pain linked to high morbidity and disability that is poorly assessed and undertreated. Barriers to effective pain management partly relate to lack of access to opioid analgesia and challenges in their administration. OBJECTIVES: To identify country-specific and broader regional barriers to access, as well as the administration of opioids, and generate recommendations for advancing pain management in Southern Africa. METHODS: A parallel mixed methods design was used across three countries: Mozambique, Swaziland, and Zimbabwe. Three activities were undertaken: 1) a review of regulatory and policy documentation, 2) group interviews, and 3) a self-administered key informant survey. RESULTS: Barriers to accessing opioid analgesics for medical use include overly restrictive controlled medicines' laws; use of stigmatizing language in key documents; inaccurate actual opioid consumption estimation practices; knowledge gaps in the distribution, storage, and prescription of opioids; critical shortage of prescribers; and high out-of-pocket financial expenditures for patients against a backdrop of high levels of poverty. CONCLUSION: Policies and relevant laws should be updated to ensure that the legislative environment supports opioid access for pain management. Action plans for improving pain treatment for patients suffering from HIV or non-communicable diseases should address barriers at the different levels of the supply chain that involve policymakers, administrators, and service providers. PMID- 29155290 TI - Factors Associated With Attrition in a Multicenter Longitudinal Observational Study of Patients With Advanced Cancer. AB - CONTEXT: Attrition is common in longitudinal observational studies in palliative care. Few studies have examined predictors of attrition. OBJECTIVES: To identify patient characteristics at enrollment associated with attrition in palliative oncology outpatient setting. METHODS: In this longitudinal observational study, advanced cancer patients enrolled in an outpatient multicenter study were assessed at baseline and two to five weeks later. We compared baseline characteristics between patients who returned for follow-up and those who dropped out. RESULTS: Seven hundred forty-four patients were enrolled from Jordan, Brazil, Chile, Korea, and India. Attrition rate was 33%, with variation among countries (22%-39%; P = 0.023). In univariate analysis, baseline predictors for attrition were cognitive failure (odds ratio [OR] 1.23 per point in Memorial Delirium Assessment Scale; P < 0.01), functional status (OR 1.55 per 10-point decrease in Karnofsky Performance Status; P < 0.01), Edmonton Symptom Assessment Scale [ESAS] physical score (OR 1.03 per point; P < 0.01), ESAS emotional score (OR 1.05 per point; P < 0.01), and shorter duration between cancer diagnosis and palliative care referral in months (OR 0.89 per log; P = 0.028). In multivariate analysis, cognitive failure (OR 1.12 per point; P = 0.007), ESAS physical score (OR 1.18 per point; P = 0.027), functional status (OR 1.35 per 10-point decrease; P < 0.001), and shorter duration from cancer diagnosis (OR 0.86 per log; P = 0.01) remained independent predictors of attrition. CONCLUSION: Advanced cancer patients with cognitive failure, increased physical symptoms, poorer performance status, and shorter duration from cancer diagnosis were more likely to dropout. These results have implications for research design, patient selection, and data interpretation in longitudinal observational studies. PMID- 29155291 TI - Measuring the Psychosocial Dimensions of Quality of Life in Patients With Advanced Cancer: Psychometrics of the German Quality of Life at the End of Life Cancer-Psychosocial Questionnaire. AB - CONTEXT: Quality of life (QoL) is a central focus of care in advanced cancer. Specialized instruments, such as the Quality of Life at the End of Life-Cancer (QUAL-EC), may be useful to assess psychosocial issues associated with QoL unique to this population. OBJECTIVES: To evaluate the measurement of the psychosocial dimensions of QoL using the German translation of the QUAL-EC-Psychosocial (QUAL EC-P) questionnaire, including factor structure and psychometrics. METHODS: About 183 patients with advanced cancer from the University Medical Center Hamburg Eppendorf and University Medical Center Leipzig completed the QUAL-EC-P questionnaire. We conducted exploratory factor analysis as well as item and reliability analysis. We examined convergent validity with correlations between the scale and relevant psychological constructs. RESULTS: The sample was 60% female with mean age of 57.7 (SD = 11.7). We extracted three factors accounting for 44% of the variance aligning with the structure of the instrument. The QUAL EC-P questionnaire showed good to acceptable internal consistency for the QoL psychosocial total score (alpha = 0.77), the Life completion subscale (alpha = 0.77), and the Relationship with health care provider subscale (alpha = 0.81). The Preparation for end of life subscale had adequate albeit low internal consistency (alpha = 0.64) because concerns about family were less associated with financial worry and fear of death than expected. The psychosocial dimensions of QoL correlated negatively with depression (r = -0.27, P <= 0.001), anxiety (r = -0.32, P <= 0.001), demoralization (r = -0.63, P <= 0.001), and attachment insecurity (r = -0.51, P <= 0.001) and positively with spiritual well-being (r = 0.63, P <= 0.001). CONCLUSION: The QUAL-EC-P questionnaire may be used to assess the psychosocial aspects of QoL and promote their clinical discussion in patients with advanced cancer. PMID- 29155292 TI - 24/7 in house attending staff coverage improves neonatal short-term outcomes: A retrospective study. AB - OBJECTIVES: to compare short-term outcomes of newborns over 36 weeks with Apgar scores<=3 at 1min, following the adoption of a 24/7 in house coverage schedule STUDY DESIGN: A retrospective chart review comparing two 12-month epochs. Epoch 1: coverage provided by residents with availability on call at home of attending staff. Epoch 2: On site coverage by attending staff. RESULTS: 71 and 60 charts were reviewed from Epoch 1 and 2 respectively. The number of infants receiving chest compressions was reduced during Epoch 2 (from 19% to 1.6%, p<0.0001). The proportion of infants admitted to the NICU (81% vs 61%, p<0.01), and the median length of stay in hospital (61 vs 48h, p=0.03) were significantly reduced in Epoch 2. CONCLUSION(S): Continuous coverage by attending staff decreased the number of admissions to intensive care as well as the duration of hospitalization stay for newborns with low Apgar scores. PMID- 29155293 TI - Telephone CPR: Adopting the standard of care, Just-in-time. PMID- 29155295 TI - Decoding Code Blue: A process to assess and improve code team function. PMID- 29155294 TI - Long-term survival in patients with acute myocardial infarction and out-of hospital cardiac arrest: A prospective cohort study. AB - AIM: To compare short- and long-term survival in patients admitted to hospital after acute myocardial infarction (AMI) with and without out-of-hospital cardiac arrest (OHCA). METHODS: Prospective cohort study of all AMI patients admitted to Oslo University Hospital Ulleval from September 1, 2005 to December 31, 2011. All cause mortality was obtained from the Norwegian Cause of Death Registry with censoring date December 31, 2013. Cumulative survival was assessed with the Kaplan-Meier and the Life-table method. Logistic- and Cox regression were used for risk comparisons. RESULTS: We identified 404 AMI patients with OHCA and 9425 AMI patients without. AMI patients without OHCA were categorized as ST-elevation myocardial infarction (STEMI, n=4522) or non-STEMI (NSTEMI, n=4903). Mean age was 63.6+/-standard deviation (SD) 12.5, 63.8+/-13.1 and 69.7+/-13.6 years in OHCA, STEMI and NSTEMI, respectively. Coronary angiography with subsequent percutaneous coronary intervention if indicated, was performed in 87% of OHCA, 97% of STEMI and 80% of NSTEMI patients. Thirty-day survival was 63%, 94% and 94%, and 8-year survival was 49%, 74%, and 57%, respectively. Among patients surviving the first 30days, no significant difference in risk during long-term follow-up was found (adjusted Hazard Ratio (aHR)OHCAvsSTEMI 1.15 [95% CI 0.82-1.60], aHROHCAvsNSTEMI 0.89 [95% CI 0.64-1.24]). CONCLUSIONS: Long-term survival after OHCA due to AMI was good, with 49% of admitted patients being alive after eight years. Although short-term mortality remained high, OHCA patients alive after 30days had similar long-term risk as AMI patients without OHCA. PMID- 29155296 TI - Optogenetic manipulation of ENS - The brain in the gut. AB - Optogenetics has emerged as an important tool in neuroscience, especially in central nervous system research. It allows for the study of the brain's highly complex network with high temporal and spatial resolution. The enteric nervous system (ENS), the brain in the gut, plays critical roles for life. Although advanced progress has been made, the neural circuits of the ENS remain only partly understood because the appropriate research tools are lacking. In this review, I highlight the potential application of optogenetics in ENS research. Firstly, I describe the development of optogenetics with focusing on its three main components. I discuss the applications in vitro and in vivo, and summarize current findings in the ENS research field obtained by optogenetics. Finally, the challenges for the application of optogenetics to the ENS research will be discussed. PMID- 29155297 TI - Divergent profile between hypothalamic and plasmatic aminopeptidase activities in WKY and SHR. Influence of beta-adrenergic blockade. AB - AIMS: Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) differ in their renin-angiotensin system function and sympathetic tone. The metabolism of angiotensins and vasopressin depends on the action of certain aminopeptidases whose activity may be influenced by the autonomic nervous system. Their regulation may differ between WKY and SHR in hypothalamus and plasma according to the sympathetic tone. We analyzed aminopeptidases responsible for the hydrolysis of certain angiotensins, vasopressin, cholecystokinin or enkephalins in hypothalamus and plasma of WKY and SHR in untreated controls rats and under beta adrenoceptor blockade. Systolic blood pressure, food intake, water intake and diuresis were measured as parameters modulated by the autonomic nervous system and the above mentioned peptides. MAIN METHODS: Glutamyl-, aspartyl-, cystinyl- and alanyl-aminopeptidase activities were analyzed fluorimetrically in plasma and hypothalamus of control and propranolol-treated (100mg/kg/day administered in drinking water for 1month) WKY and SHR, using arylamide derivatives as substrates. KEY FINDINGS: An opposite response of aminopeptidases to propranolol treatment between plasma and hypothalamus was observed in either WKY and SHR. Furthermore, the behavior of aminopeptidases was inversed between WKY and SHR either in hypothalamus and plasma: while the activity increased in hypothalamus and decreased in plasma of WKY, it decreased in hypothalamus and increased in plasma of SHR. SIGNIFICANCE: These results revealed an inverse response of aminopeptidases between hypothalamus and plasma and also an opposite behavior of these enzymes between WKY and SHR in hypothalamus and plasma. These observations support the involvement of the sympathetic system in the modulation of aminopeptidase activities. PMID- 29155298 TI - Mechanisms of l-alpha-lysophosphatidylinositol-induced relaxation in human pulmonary arteries. AB - AIMS: l-Alpha-lysophosphatidylinositol (LPI) is an endogenous agonist of G protein-coupled receptor 55 (GPR55) which relaxes mesenteric arteries on activation. The aim of the present study was to determine the influence and underlying mechanisms of LPI-induced relaxation in human pulmonary arteries (hPAs). MAIN METHODS: Functional studies were performed in isolated hPAs using organ bath technique. The expression of GPR55 in hPAs and bronchioles was determined by real-time qPCR, Western blot analysis, and immunohistochemistry. KEY FINDINGS: LPI induced a concentration-dependent vasorelaxation in endothelium intact hPAs. This effect was attenuated by the GPR55 antagonist CID16020046, the peroxisome proliferator-activated receptor-gamma (PPARgamma) antagonist GW9662, the putative endothelial cannabinoid receptor (CBe) antagonist O-1918 and the inhibitor of nitric oxide (NO) synthase (L-NAME). In addition, vasorelaxation was also attenuated by the presence of a high KCl concentration, selective blockers of small (KCa2.3; UCL1684), intermediate (KCa3.1; TRAM-34) and large conductance (KCa1.1; iberiotoxin) calcium-activated potassium channels and by endothelium denudation. However, vasorelaxation was not attenuated by the cannabinoid CB1 receptor antagonist AM251 or by the cyclooxygenase inhibitor indomethacin. SIGNIFICANCE: The study showed that the LPI-induced vasorelaxation was endothelium-dependent and mediated by GPR55, PPARgamma and CBe receptors, occurred in a NO- and calcium-activated potassium channel-dependent manner in isolated hPAs. LPI seems to possess positive, hypotensive properties in pulmonary vascular bed. PMID- 29155299 TI - Evaluation of inositol phosphates in urine after topical administration of myo inositol hexaphosphate to female Wistar rats. AB - AIMS: Previous studies demonstrated a remarkable increase of urinary InsP6 by topical administration. However, the methodology used for InsP6 analysis was not specific. The aim of this paper is to measure urinary inositol phosphates InsPs using more advanced methodologies and to compare the results with those obtained by the non-specific method. MATERIALS AND METHODS: We fed 12 female rats with a diet without InsP6 for 16days. Then, we administered a topical InsP6 gel at high doses for 7days (50mgInsP6/day) or at low doses for 28days (20mgInsP6/day). We measured urine levels InsPs using a nonspecific method (based on the ability of InsPs to complex Al3+) and levels of InsP6 by a specific method (using polyacrylamide gel electrophoresis). Identification of different InsPs was performed by MS. KEY FINDINGS: At baseline, after dietary deprivation of InsP6, rats only excreted InsP2 in their urine, and there was no detectable InsP6 or other InsPs. Rats given the high dose treatment for 7days had abundant urinary InsP6, but also had other InsPs in their urine; cessation of InsP6 administration led to decreased levels of urinary InsPs. Rats given the low dose treatment for 28days had increasing levels of urinary InsPs over time. The maximum urinary InsP6 was at 21days, after which InsPs excretion decreased. SIGNIFICANCE: We conclude that the skin can absorb InsP6 from a topical gel, and that InsP6 is excreted in the urine, along with other InsPs (InsP5, InsP4, InsP3, and InsP2). PMID- 29155300 TI - Mitochondrial dysfunction in obesity. AB - Obesity leads to various changes in the body. Among them, the existing inflammatory process may lead to an increase in the production of reactive oxygen species (ROS) and cause oxidative stress. Oxidative stress, in turn, can trigger mitochondrial changes, which is called mitochondrial dysfunction. Moreover, excess nutrients supply (as it commonly is the case with obesity) can overwhelm the Krebs cycle and the mitochondrial respiratory chain, causing a mitochondrial dysfunction, and lead to a higher ROS formation. This increase in ROS production by the respiratory chain may also cause oxidative stress, which may exacerbate the inflammatory process in obesity. All these intracellular changes can lead to cellular apoptosis. These processes have been described in obesity as occurring mainly in peripheral tissues. However, some studies have already shown that obesity is also associated with changes in the central nervous system (CNS), with alterations in the blood-brain barrier (BBB) and in cerebral structures such as hypothalamus and hippocampus. In this sense, this review presents a general view about mitochondrial dysfunction in obesity, including related alterations, such as inflammation, oxidative stress, and apoptosis, and focusing on the whole organism, covering alterations in peripheral tissues, BBB, and CNS. PMID- 29155301 TI - Matrine inhibiting pancreatic cells epithelial-mesenchymal transition and invasion through ROS/NF-kappaB/MMPs pathway. AB - AIMS: Matrine has demonstrated an exclusive anti-tumor effect, including inhibiting cancer cells proliferation and inducing cancer cells apoptosis and autophagy. Whether it can inhibit cancer cells invasion is remain obscure. MAIN METHODS: The Panc-1 cells were cultured with matrine, NAC and methanol, wound healing assay and transwell invasion assay were applied to detect the migration and invasion ability. The expression of MMP-2 and MMP-9 were assessed, as well as the Epithelial-Mesenchymal Transition marker. Further detect the expression of pP65, total P65, pIkappaBalpha, total IkappaBalpha, MMP-2, MMP-9 and Panc-1 cells migration and invasion ability to detect whether NF-kappaB signaling pathway is involved. KEY FINDINGS: In matrine treated group, the expression of E-cadherin was up-regulated while N-cadherin, Vimentin was down-regulated. In addition, wound healing assay and transwell invasion assay showed that the cells treated with matrine expressed weaker migration and invasion ability, and MMP-2 and MMP-9 was down-regulated in matrine treated group. Further research reveals that the effect of Matrine could decreased the level of intracellular ROS. Furthermore, pP65, pIkappaBalpha level was down-regulated in the matrine and NAC group when compared to control group. The panc-1 cells showed less migration and invasion ability, as well as lower MMP-2 and MMP-9 expression in the group treated with NF kappaBI along with H2O2 when compared with treated with H2O2 only. SIGNIFICANCE: Matrine inhibit pancreatic cancer cells migration and invasion through ROS/NF kappaB/MMPs pathway, further validate the anticancer effect of matrine. PMID- 29155302 TI - Repeated exposure to sevoflurane impairs the learning and memory of older male rats. AB - AIMS: Critically ill old patients sometimes require repeated surgical interventions, and thus it is important to determine the influence of repeated exposure to anesthetics on learning and memory. Sevoflurane, a widely used inhalation anesthetic, has few neurological adverse effects and offers a rapid return to consciousness. But the long-term influence of sevoflurane exposure and the effect of repeated sevoflurane exposure on cognition have rarely been reported, and available studies are contradictory. MATERIALS AND METHODS: In the present study, the Morris water maze test was employed to investigate the long term influence of single (4h) or repeated (2h daily for 5 consecutive days) exposure to 1.5% or 2.5% sevoflurane on the learning ability and memory of old (16-18months old) male rats. Testing was performed from 1day to 4weeks after the last exposure. In the hippocampus, brain derived neurotrophic factor (BDNF), NF kappaB mRNA, and apoptosis rate were also examined to determine whether cellular biochemical changes related to cognition and memory occurred after single or repeated exposure to sevoflurane. KEY FINDINGS: Repeated exposure to 2.5% sevoflurane decreased hippocampal levels of BDNF protein, enhanced hippocampal levels of NF-kappaB mRNA, and increased the apoptosis rate of pyramidal cells. Single exposure to 2.5% sevoflurane, and repeated exposure to either 1.5% or 2.5% sevoflurane significantly compromised learning and memory of old male rats. SIGNIFICANCE: Repeated exposure to sevoflurane impaired the learning and memory of old male rats, an impairment that was accompanied by cognition-related biochemical changes in the hippocampus. PMID- 29155303 TI - Therapeutic vaccine against IL-1beta improved glucose control in a mouse model of type 2 diabetes. AB - AIMS: Inflammation is strongly associated with the mechanism of beta-cell failure in type 2 diabetes mellitus (T2DM). Blockade of the key proinflammatory cytokine IL-1beta has been implicated as a promising therapeutic strategy for the prevention and treatment of type 2 diabetes. In this study, we developed an IL 1beta-targeted therapeutic vaccine consisting of an IL-1beta epitope peptide (A1beta) and assessed its efficacy on a diabetic KK-Ay mouse model. MAIN METHODS: KK-Ay mice were immunized with A1beta for three injections at a 2-week interval. The induced antibody titers, body weights and blood glucose levels were monitored every two weeks. Then the intraperitoneal glucose tolerance test and insulin tolerance test were performed. The beta-cell mass, beta-cell apoptosis and proliferation were evaluated by immunofluorescence. IL-1beta gene expression in islets was also measured by quantitative RT-PCR. KEY FINDINGS: A1beta immunization induced robust antibody responses, reduced body weight gain, improved glucose tolerance and insulin sensitivity in KK-Ay mice. Moreover, A1beta restored beta-cell mass, inhibited beta-cell apoptosis, enhanced beta-cell proliferation and downregulated IL-1beta expression. SIGNIFICANCE: The novel IL 1beta-targeted epitope vaccine has the therapeutic potential for T2DM. PMID- 29155304 TI - Metabolomics: Taking snapshots of cellular physiology in health and disease. PMID- 29155305 TI - Hey1 and Hey2 are differently expressed during mouse tooth development. AB - The Hey family (also known as Chf, Herp, Hesr, and Hrt) is a set of Hairy/Enhancer of Split-related basic helix-loop-helix type transcription factors. Hey1, Hey2, and HeyL have been identified in mammals. Although Hey proteins are known to regulate cardiovascular development, muscle homeostasis, osteogenesis, neurogenesis, and oncogenesis, their roles in tooth development have been largely obscure. Therefore, this study aimed to clarify detailed spatiotemporal expression patterns of Hey1 and Hey2 in developing molars and incisors of mice by section in situ hybridization. Hey1 and Hey2 were not significantly expressed in tooth germs at epithelial thickening, bud, and cap stages during molar development. In the dental epithelium in molars at the bell stage and incisors, Hey2 transcripts were restricted to the undifferentiated inner enamel epithelium and down-regulated in preameloblasts and ameloblasts. On the other hand, Hey1 was mainly expressed in preameloblasts and down-regulated in differentiated ameloblasts. Both genes were not significantly expressed in other dental epithelial tissues, including the outer enamel epithelium, stellate reticulum, and stratum intermedium cells. In the dental mesenchyme, Hey1 was intensely transcribed in the subodontoblastic layer of the dental pulp in both molars and incisors, whereas Hey2 was barely detectable in mesenchymal components. Our data implied that Hey2 function is restricted to transient amplifying cells of the ameloblast cell lineage and that Hey1 plays a role in the composition of the subodontoblastic layer, in addition to ameloblast differentiation. These findings provide novel clues for the better understanding of tooth development. PMID- 29155306 TI - Reverse T3 interacts with alphavbeta3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: Insight on signaling mechanisms. AB - In the present study we provide evidence that 3,3',5'-triiodothyronine (reverse T3, rT3) restores neurochemical parameters induced by congenital hypothyroidism in rat hippocampus. Congenital hypothyroidism was induced by adding 0.05% propylthiouracil in the drinking water from gestation day 8 and continually up to lactation day 15. In the in vivo rT3 exposure, hypothyroid 12-day old pups were daily injected with rT3 (50 ng/kg body weight) or saline until day 14. In the ex vivo rT3 treatment, hippocampal slices from 15-day-old hypothyroid pups were incubated for 30 min with or without rT3 (1 nM). We found that ex vivo and/or in vivo exposure to rT3 failed in restoring the decreased 14C-glutamate uptake; however, restored the phosphorylation of glial fibrillary acidic protein (GFAP), 45Ca2+ influx, aspartate transaminase (AST), glutamine synthetase (GS) and gamma glutamate transferase (GGT) activities, as well as glutathione (GSH) levels in hypothyroid hippocampus. In addition, rT3 improved 14C-2-deoxy-D-glucose uptake and lactate dehydrogenase (LDH) activity. Receptor agonists/antagonists (RGD peptide and AP-5), kinase inhibitors of p38MAPK, ERK1/2, CaMKII, PKA (SB239063, PD98059, KN93 and H89, respectively), L-type voltage-dependent calcium channel blocker (nifedipine) and intracellular calcium chelator (BAPTA-AM) were used to determine the mechanisms of the nongenomic rT3 action on GGT activity. Using molecular docking analysis, we found rT3 interaction with alphavbeta3 integrin receptors, nongenomically activating signaling pathways (PKA, CaMKII, p38MAPK) that restored GGT activity. We provide evidence that rT3 is an active TH metabolite and our results represent an important contribution to elucidate the nonclassical mechanism of action of this metabolite in hypothyroidism. PMID- 29155307 TI - Sex steroids and the kidney: role in renal calcium and phosphate handling. AB - Calcium and phosphate are vital for the organism and constitute essential components of the skeleton. Serum levels are tightly hormonally regulated and maintained by exchange with three major sources: the intestines, the kidney and the bone. The effects of sex steroids on the bone have been extensively studied and it is well known that sex steroid deficiency induces bone loss, indirectly influencing renal calcium and phosphate homeostasis. However, it is unknown whether sex steroids also directly regulate renal calcium and phosphate handling, hereby potentially indirectly impacting on bone. The presence of androgen receptors (AR) and estrogen receptors (ER) in both human and rodent kidney, although their exact localization within the kidney remains debated, supports direct effects. Estrogens stimulate renal calcium reabsorption as well as phosphate excretion, while the effects of androgens are less clear. Many of the studies performed with regard to renal calcium and/or phosphate homeostasis do not correct for the calcium and phosphate fluxes from the bone and intestines, which complicates the differentiation between the direct effects of sex steroids on renal calcium and phosphate handling and the indirect effects via the bone and intestines. The objective of this study is to review the literature and current insight of the role of sex steroids in calcium and phosphate handling in the kidney. PMID- 29155308 TI - Play and optimal welfare: Does play indicate the presence of positive affective states? AB - Play is commonly used to assess affective states in both humans and non-human animals. Play appears to be most common when animals are well-fed and not under any direct threats to fitness. Could play and playfulness therefore indicate pre existing positive emotions, and thence optimal animal welfare? We examine this question by surveying the internal and external conditions that promote or suppress play in a variety of species, starting with humans. We find that negative affective states and poor welfare usually do suppress play (although there are notable exceptions where the opposite occurs). Furthermore, research in children suggests that beyond the frequency or total duration of play, poor welfare may additionally be reflected in qualitative aspects of this heterogeneous behaviour (e.g. display of solitary over social play; and the 'fragmentation' of play bouts) that are often overlooked in animals. There are surprisingly few studies of play in subjects with pre-existing optimal welfare or in unambiguously highly positive affective states, making it currently impossible to determine whether play can distinguish optimal or good welfare from merely neutral welfare. This therefore represents an important and exciting area for future research. PMID- 29155310 TI - Legg-Calve-Perthes disease. AB - Current knowledge of the causes and risk factors of Legg-Calve-Perthesdisease (LCPD) does not allow effective preventive strategies. The outcome in adulthood is usually good. Hip osteoarthritis rarely develops before 50 years of age. The risk of osteoarthrosis depends chiefly on the final degree of joint incongruence. Age at onset and the lateral pillar classification are the two main outcome predictors and serve to guide the surgical indications based on the studies by Herring's group. Non-operative treatment is not effective. In contrast, femoral varus osteotomy and Salter's innominate osteotomy provide good outcomes. In severe forms, however, combining these two techniques or performing a triple pelvic osteotomy seem preferable. Surgery is now performed considerably less often than in the past, as it is effective only in patients with lateral pillar group B or B/C disease with onset after eight years of age. In other situations, therapeutic abstention is recommended. PMID- 29155311 TI - Glenoid exposure in total shoulder arthroplasty. AB - Glenoid exposure is agreed to be a difficult step, but is also a key step in total shoulder arthroplasty, both anatomic and reverse. It conditions unhindered use of the ancillary instrumentation and thus correct glenoid component positioning. The main stages comprise arthrotomy, by opening the rotator cuff, humeral head cut, and inferior glenohumeral release, enabling shifting of the humerus and good exposure of the glenoid cavity. The two main approaches are deltopectoral and anterosuperior transdeltoid. Using the deltopectoral approach, arthrotomy is performed through the subscapularis muscle, by various techniques. This approach enables extensive inferior glenohumeral release and thus an approach to the inferior apex of the glenoid cavity, which is a key area for glenoid implant positioning. The main drawbacks are postoperative shoulder instability and limited access to the posterior part of the glenoid in case of significant retroversion. Moreover, subscapularis healing is uncertain, which can impair the clinical outcomes, with risk of glenoid component loosening. Advantages, on the other hand, include the fact that it can be implemented in all cases, even the most difficult ones, and that the deltoid muscle is respected. The transdeltoid approach has the advantage of being simple, providing direct exposure of the glenoid cavity through a rotator cuff tear after passing through the deltoid. It is therefore especially indicated for reverse prosthesis in case of rotator cuff tear, and in traumatology. However, the approach to the inferior part of the glenoid cavity can be restricted, with insufficient exposure and a risk of glenoid component malpositioning (superior tilt). The preoperative assessment is essential, to detect at-risk situations such as severe stiffness and anticipate difficulties in glenoid exposure. PMID- 29155312 TI - Designing clinical studies in orthopedic traumatology. AB - The design of clinical studies in orthopedic traumatology is challenging in several respects. In this era of evidence-based medicine, the pressure is high to choose our treatments solely based on randomized controlled studies. This type of study, when well-constructed, makes it possible to discern the best treatment for a specific fracture in a given group of patients and in connection with a specific outcome. Randomized controlled trials require a lot of resources and are not designed to answer all research questions. Observational studies, such as case-control studies, prospective cohort studies, and cross-sectional studies, also have a role to play in improving scientific knowledge in orthopedic trauma. Regardless of the type of study chosen, the researcher must follow a strict methodology that conforms to practice guidelines in order to ensure the study's conclusions are valid. The guidelines for randomized studies can be found at http://www.consort-statement.org and at http://www.strobe-statement.org for cohort studies. It is also very important to register randomized studies before they begin on a website such as http://www.clinicaltrials.gov, since registration is an increasingly common requirement when submitting an article for publication. Although this preparation is relatively cumbersome, it is essential for producing articles that meet modern scientific criteria. PMID- 29155309 TI - Prognostic Utility of Total 68Ga-DOTATATE-Avid Tumor Volume in Patients With Neuroendocrine Tumors. AB - BACKGROUND & AIMS: Survival times vary among patients with neuroendocrine tumors (NETs) - even among those with the same site, stage, and grade of primary tumor. This makes it difficult to select treatment for patients with unresectable NETs because some patients can survive decades without treatment. 68Gallium-DOTATATE positron emission tomography with computed tomography (68Ga-DOTATATE PET/CT) is a sensitive imaging technique for detection of NETs. We investigated the prognostic accuracy of 68Ga-DOTATATE PET/CT-based analysis of tumor volume in patients with NETs. METHODS: We performed a prospective study of 184 patients with NETs (128 [69.6%] with metastases and 11 patients [6.0%] with locally advanced disease) at the National Institutes of Health Clinical Center (Bethesda, MD) from 2013 through 2017. All patients underwent 68Ga-DOTATATE PET/CT image analysis and total 68Ga-DOTATATE-Avid tumor volume (68Ga-DOTATATE TV) was determined. We also measured fasting serum chromogranin A, neuron-specific enolase, gastrin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, and 24-hour urinary 5-hydroxyindoleacetic acid levels in all patients. Disease progression was defined as a new lesion or a growth of a known lesion during the interval between baseline 68Ga-DOTATATE PET/CT scan and follow-up imaging (14.0 +/- 6.1 months; range, 1-35 months). The primary outcomes were progression-free survival (PFS) and disease-specific mortality during a median follow-up time of 18 months (range, 4-35 months). RESULTS: We found an inverse correlation between quartiles of 68Ga-DOTATATE TV and PFS (P = .001) and disease-specific survival (P = .002). A 68Ga-DOTATATE TV of 7.0 mL or more was associated with higher odds of disease progression (hazard ratio, 3.0; P = .04). A 68Ga-DOTATATE TV of 35.8 mL or more was associated with increased risk of disease-specific death (hazard ratio, 10.6) in multivariable analysis (P = .01), as well as in subgroup analysis of patients with pancreatic NETs. CONCLUSIONS: In a prospective study, we demonstrated the prognostic utility of 68Ga-DOTATATE TV in a large cohort of patients with NETs, in terms of PFS and disease-specific mortality. PMID- 29155313 TI - A Phase II, Multicenter, Single-Arm Study to Evaluate the Safety and Efficacy of Deferasirox after Hematopoietic Stem Cell Transplantation in Children with beta Thalassemia Major. AB - We conducted a prospective, phase II, multicenter, single-arm study to evaluate the efficacy and safety of deferasirox in patients age >2 to <18 years with beta thalassemia major (TM) who underwent hematopoietic stem cell transplantation (HSCT) and had evidence of iron overload (serum ferritin >1000 ug/L; cardiac MRI T2* <20 ms, or liver iron concentration [LIC; by MRI R2] >=5 mg/g). Patients received deferasirox at an initial dose of 10 mg/kg/day, with up-titration to a maximum of 20 mg/kg/day. The study continued for 52 weeks and included a total of 27 patients (mean age, 9.1 +/- 3.8 years; 70.4% male). One patient (3.7%) was lost to follow-up. The majority of patients (n = 20; 74.1%) were able to achieve the intended dose of 20 mg/kg/day. No deaths occurred. A total of 134 adverse events (AEs) were reported in 25 patients (92.6%) during the study. The majority of patients had grade 1 or 2 AEs, with only 8 patients (29.6%) experiencing grade 3 AEs. Only 10 AEs occurring in 4 patients (14.8%) were suspected to be related to deferasirox (ALT/AST increase, n = 4; urinary tract infection, n = 1). The deferasirox dose had to be adjusted or interrupted for 6 AEs occurring in 4 patients (14.8%). A total of 6 serious AEs occurred in 3 patients (11.1%), none of which were suspected to be related to deferasirox. From baseline to week 52, there were decreases in median concentrations of alanine aminotransferase (ALT), from 30.0 to 17.0 IU/L, and aspartate aminotransferase (AST), from 35.5 to 26.0 IU/L. Median serum creatinine and cystatin C concentrations were similar at baseline and week 52. There was a continuous and significant decrease in median serum ferritin level from 1718.0 ug/L at baseline to 845.3 ug/L following 52 weeks of therapy (P < .001); 9 patients (33.3%) achieved a level of <500 ug/L. There was also a significant decrease in median LIC (from 8.6 to 4.1 mg/g; P < .001) and an increase in median cardiac T2* (from 26.0 to 28.0 ms; P = .520) from baseline to week 52. Our findings indicate that deferasirox treatment at doses up to 20 mg/kg/day reduces the iron burden in children with TM post-HSCT, with a manageable safety profile. PMID- 29155314 TI - Mesenchymal Stromal Cell Irradiation Interferes with the Adipogenic/Osteogenic Differentiation Balance and Improves Their Hematopoietic-Supporting Ability. AB - Bone marrow mesenchymal stromal cells (MSCs) are precursors of adipocytes and osteoblasts and key regulators of hematopoiesis. Irradiation is widely used in conditioning regimens. Although MSCs are radio-resistant, the effects of low-dose irradiation on their behavior have not been extensively explored. Our aim was to evaluate the effect of 2.5 Gy on MSCs. Cells from 25 healthy donors were either irradiated or not (the latter were used as controls). Cells were characterized following International Society for Cellular Therapy criteria, including in vitro differentiation assays. Apoptosis was evaluated by annexin V/7-amino-actinomycin staining. Gene expression profiling and reverse transcriptase (RT)-PCR of relevant genes was also performed. Finally, long-term bone marrow cultures were performed to test the hematopoietic-supporting ability. Our results showed that immunophenotypic characterization and viability of irradiated cells was comparable with that of control cells. Gene expression profiling showed 50 genes differentially expressed. By RT-PCR, SDF-1 and ANGPT were overexpressed, whereas COL1A1 was downregulated in irradiated cells (P = .015, P = .007, and P = .031, respectively). Interestingly, differentiation of irradiated cells was skewed toward osteogenesis, whereas adipogenesis was impaired. Higher expression of genes involved in osteogenesis as SPP1 (P = .039) and lower of genes involved in adipogenesis, CEBPA and PPARG (P = .003 and P = .019), together with an increase in the mineralization capacity (Alizarin Red) was observed in irradiated cells. After differentiation, adipocyte counts were decreased in irradiated cells at days 7, 14, and 21 (P = .018 P = .046, and P = .018, respectively). Also, colony forming unit granulocyte macrophage number in long-term bone marrow cultures was significantly higher in irradiated cells after 4 and 5 weeks (P = .046 and P = .007). In summary, the irradiation of MSCs with 2.5 Gy improves their hematopoietic-supporting ability by increasing osteogenic differentiation and decreasing adipogenesis. PMID- 29155315 TI - Individualizing Optimal Dosing of Antithymocyte Globulin in Allogeneic Hematopoietic Cell Transplantation. PMID- 29155317 TI - Treosulfan and Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Children with Primary Immunodeficiency: UK Experience. AB - We previously published results for 70 children who received conditioning with treosulfan and cyclophosphamide (n = 30) or fludarabine (n = 40) before undergoing hematopoietic stem cell transplantation (HSCT) for primary immunodeficiency (PID). Toxicity was lower and T cell chimerism was better in the patients receiving fludarabine, but cohort numbers were relatively small and follow-up was short. Here we report outcomes of 160 children who received homogeneous conditioning with treosulfan, fludarabine, and, in most cases, alemtuzumab (n = 124). The median age at transplantation was 1.36 years (range, .09 to 18.25 years). Donors included 73 matched unrelated, 54 1 to 3 antigen mismatched unrelated, 12 matched sibling, 17 other matched family, and 4 haploidentical donors. Stem cell source was peripheral blood stem cells (PBSCs) in 70, bone marrow in 49, and cord blood in 41. Median duration of follow-up was 4.3 years (range, .8 to 9.4 years). Overall survival was 83%. No patients had veno-occlusive disease. Seventy-four patients (46%) had acute GVHD, but only 14 (9%) greater than grade II. Four patients underwent successful retransplantation for graft loss or poor immune reconstitution. Another patient experienced graft rejection and died. There was no association between T cell chimerism >95% and stem cell source, but a significant association was seen between myeloid chimerism >95% and use of PBSCs without an increased risk of significant GVHD compared with other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth were alive at up to 8.7 years of follow-up. Long-term studies are needed to determine late gonadotoxic effects, and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine, and alemtuzumab is associated with excellent results in HSCT for PID. PMID- 29155318 TI - Kidney Pathology after Hematologic Cell Transplantation-A Single-Center Observation Study of Indication Biopsies and Autopsies. AB - Hematopoietic cell transplantation (HCT) is an increasingly used treatment for hematologic malignancies as well as for nonmalignant diseases. Kidney impairment remains an important early and late post-transplantation complication. Although numerous histopathological changes have been reported, the pathophysiology remains incompletely understood. Furthermore, correlations between clinical findings and morphological changes have not been well studied. Between 2000 and 2016, 17 recipients of allogeneic (n = 12) or autologous (n = 5) HCT underwent kidney biopsy for either proteinuria or deterioration of kidney function at our center. The most common biopsy findings were therapy-related changes with thrombotic microangiopathy (n = 5), calcineurin inhibitor toxicity (n = 4), and membranous glomerulonephritis (n = 3), representing the majority of cases in this category. In addition, kidney findings from 137 autopsies performed between 1995 and March 2017 were analyzed. The most common changes were acute kidney injury (n = 55), most likely due to the patients' premortal deteriorated state, and thrombotic microangiopathy (n = 14). Several cases demonstrated involvement by either infectious agents (n = 6) or tumors (n = 9). Distinct kidney diseases, such as glomerulonephritis, were rare (3% of cases). Uncommon and yet rarely described diagnoses for this patient cohort were IgG4-related tubulointerstitial nephritis and fibrillary nephritis. This study provides a comprehensive overview of the histomorphological findings in kidney biopsy specimens from HCT recipients. Along with treatment-related complications, one putative correlate of chronic GVHD of the kidney could be documented: membranous glomerulonephritis. In contrast, no morphological correlate of acute GVHD of the kidney was identified. Findings at the time of autopsy varied greatly, spanning a wider range than those of indication biopsies. PMID- 29155316 TI - Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis. AB - Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR], .42; 95% confidence interval [CI], .26 to .70; P = .0008), grade II-IV aGVHD (HR, .24; 95% CI, .10 to .56; P = .001), and cGVHD (HR, .32; 95% CI, .19 to .54; P < .001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .36; 95% CI, .20 to .65; P = .0007) and in 2009-2013 (HR, .24; 95% CI. .11 to .53; P = .0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .23; 95% CI, .08 to .65; P = .0056) and 2009-2013 (HR, .16; 95% CI, .04 to .67; P = .0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis. PMID- 29155319 TI - Impact of HLA Alleles on Outcomes of Allogeneic Transplantation for B Cell Non Hodgkin Lymphomas: A Center for International Blood and Marrow Transplant Research Analysis. AB - Even in the modern era of targeted therapies, allogeneic hematopoietic stem cell transplantation (allo-HCT) can offer a chance of extended survival in B cell non Hodgkin lymphoma (B-NHL) patients who relapse after or are deemed ineligible for autologous transplantation. A better understanding of the factors influencing the graft-versus-lymphoma (GVL) response would be useful in identifying B-NHL patients who may benefit from allo-HCT. Based on prior single-center reports, we hypothesized that certain HLA alleles, or haplotypes, may be associated with superior GVL compared with others after allo-HCT. To test this possibility we retrospectively evaluated whether the presence of HLA-A2, HLA-C1C1, HLA DRB1*01:01, or HLA-DRB1*13 alleles or the presence of HLA-A1+, HLA-A2-, and HLA B44- haplotypes is associated with outcomes in a cohort of 1314 HLA-8/8 matched sibling or unrelated donor HCT for relapsed/refractory B-NHL. We observed no significant association between any HLA allele or haplotype and overall survival or any of the secondary endpoints. In conclusion, this study represents the largest reported series of allo-HCT outcomes of B-NHL patients based on HLA type. Identification of other variables will be required to delineate the immunologic impact of donor-host interactions on outcomes of allo-HCT for B-NHL. PMID- 29155320 TI - Risk Assessment in Adult T Cell Leukemia/Lymphoma Treated with Allogeneic Hematopoietic Stem Cell Transplantation. AB - Disease status at allogeneic hematopoietic cell transplantation (HCT) is an important pretransplant prognostic factor of HCT in adult T cell leukemia/lymphoma (ATL); however, other prognostic factors, including comorbidities, were not predictive in small cohort analyses. Several scoring systems (HCT-specific comorbidity index [HCT-CI]/modified European Group for Blood and Marrow Transplantation risk score [mEBMT]) have been adopted to predict HCT outcomes in other hematologic malignancies. We retrospectively evaluated HCT CI and mEBMT to predict nonrelapse mortality (NRM) in 824 ATL patients registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database, from 2008 until 2013. A higher HCT-CI was associated with greater NRM when comparing HCT-CI 0 versus HCT-CI 1 to 3 and HCT-CI 0 versus HCT-CI >= 4. A higher mEBMT score was not associated with higher NRM when comparing mEBMT 0 to 3 with 4 to 6. Because ATL patients are older and consequently at risk of additional complications, we developed an optimized prognostic index for ATL (ATL-HCT-PI) using known risk factors: age, HCT-CI, and donor-recipient sex combination. The ATL-HCT-PI scores effectively predicted the 2-year NRM (22.0%, 27.7%, and 44.4%, respectively). Therefore, the newly developed ATL-HCT-PI, in combination with other risk factors, is more useful for predicting NRM in HCT for ATL patients. PMID- 29155321 TI - Clp Protease and OR Directly Control the Proteostasis of Phytoene Synthase, the Crucial Enzyme for Carotenoid Biosynthesis in Arabidopsis. AB - Phytoene synthase (PSY) is the crucial plastidial enzyme in the carotenoid biosynthetic pathway. However, its post-translational regulation remains elusive. Likewise, Clp protease constitutes a central part of the plastid protease network, but its substrates for degradation are not well known. In this study, we report that PSY is a substrate of the Clp protease. PSY was uncovered to physically interact with various Clp protease subunits (i.e., ClpS1, ClpC1, and ClpD). High levels of PSY and several other carotenogenic enzyme proteins overaccumulate in the clpc1, clpp4, and clpr1-2 mutants. The overaccumulated PSY was found to be partially enzymatically active. Impairment of Clp activity in clpc1 results in a reduced rate of PSY protein turnover, further supporting the role of Clp protease in degrading PSY protein. On the other hand, the ORANGE (OR) protein, a major post-translational regulator of PSY with holdase chaperone activity, enhances PSY protein stability and increases the enzymatically active proportion of PSY in clpc1, counterbalancing Clp-mediated proteolysis in maintaining PSY protein homeostasis. Collectively, these findings provide novel insights into the quality control of plastid-localized proteins and establish a hitherto unidentified post-translational regulatory mechanism of carotenogenic enzymes in modulating carotenoid biosynthesis in plants. PMID- 29155322 TI - Digestive tract colonization by multidrug-resistant Enterobacteriaceae in travellers: An update. AB - BACKGROUND: Enterobacteriaceae have become increasingly resistant, especially due to the acquisition and spread of extended-spectrum beta-lactamases (ESBLs), which confer resistance to the majority of beta-lactams. Multi-resistant Enterobacteriaceae (MRE) were first isolated in hospitals, but now they are disseminating in the community setting, mostly in low and middle income countries. Consequently, the increasing number of international travels leads to the importation of MRE from high-prevalence to low-prevalence countries. METHODS: The Pubmed database was used to conduct research from 1980 to 2016 by combining the following key words: travel, antibiotic resistance, ESBL, Enterobacteriaceae, genomic, metagenomic, urinary tract infection, infection. RESULTS: The research found that the MRE acquisition rates in healthy travellers from low-prevalence countries ranged from 21% to 51% depending on the study design and the visited geographic regions. After a trip to Asia and especially to South Asia, the acquisition rate could reach 85%. A trip to Africa or to the Middle East was associated with lower rates but still worrisome (13-44%). Digestive disorder, diarrhoea and antibiotics used during travel are major risks factors associated with the acquisition of MRE. Travel to endemic areas has also been identified as a risk factor for MRE infection, including urinary tract infections. CONCLUSION: Travellers are at high risk of MRE acquisition and consequently of MRE infection. This risk should not be ignored by general practitioners. To reduce the risk of acquisition and subsequent transmission to relatives, travellers should be given recommendations prior to their travel. PMID- 29155323 TI - The role of P2X7R/ERK signaling in dorsal root ganglia satellite glial cells in the development of chronic postsurgical pain induced by skin/muscle incision and retraction (SMIR). AB - The mechanisms of chronic postsurgical pain remain to be elucidated. We reported here that skin/muscle incision and retraction (SMIR), a rat model of postsurgical pain, phosphorylated the extracellular regulated protein kinases (ERK) signaling components c-Raf, MEK (ERK kinase) and ERK1/2 in lumbar 3 dorsal root ganglion (L3 DRG) in rats. Intrathecal injection of ERK specific inhibitor SCH772984 suppressed the mechanical allodynia induced by SMIR. Furthermore, SMIR upregulated tumor necrosis factor alpha (TNFalpha) in L3 DRG, which could be inhibited by SCH772984. Intrathecal injection of TNF antagonist Etanercept could also inhibit the mechanical allodynia and the increased ERK phosphorylation in L3 DRG induced by SMIR. In addition, immunofluorescent data showed that P2X7R was located exclusively in GFAP labeled satellite glial cells and was highly colocalized with p-ERK1/2 following SMIR. Pretreatment with P2X7R antagonist Brilliant Blue G (BBG) could also block the mechanical allodynia, inhibited the phosphorylation of c-Raf, MEK, ERK1/2, and decrease the expression of TNF-alpha. Finally, intrathecal injection of BzATP produced mechanical allodynia and induced ERK phosphorylation in satellite glial cells in L3 DRG. Thus, P2X7R activation in satellite glial cells in L3 DRG, leading to a positive feedback between ERK pathway activation and TNF-alpha production, is suggested to be involved in the induction of chronic postsurgical pain following SMIR. PMID- 29155324 TI - Angiotensin receptor blocker irbesartan reduces stress-induced intestinal inflammation via AT1a signaling and ACE2-dependent mechanism in mice. AB - Stress is associated with pathophysiology of both irritable bowel syndrome (IBS) and hypertension. Angiotensin receptor blockers (ARB) have anti-inflammatory properties via inhibition of angiotensin II (Ang II)/Ang II type I receptor axis (AT1). Inhibition of the classical RAS pathway is also involved in upregulation of angiotensin converting enzyme-2 (ACE2), which activates the Ang-(1-7)/Mas pathway to counteract inflammatory signaling and acts as a partner of the amino acid transporter, B0AT-1, to absorb tryptophan for regulation of microbiota-gut brain axis. In this study, we determined the effects of ARB irbesartan on stress induced intestinal inflammation. C57BL/6J mice were subjected to 2-week intermittent restraint stress. They were orally treated during the stress with either vehicle, 3 or 10 mg/kg/day irbesartan. Restraint stress resulted in colon inflammation with higher histological damage scores, increased expression of Nox4, TLR-4 and IL1-beta, accumulation of reactive oxygen species (ROS), and activation of the ACE-angiotensin II-AT1 receptor axis. Stress also downregulated intestinal amino acid transporter, ACE2/B0AT-1, and activity of intestinal mammalian target of rapamycin (mTOR) and p70 S6 kinase (p70S6K), resulting in decrease in alpha-defensins, changes in intestinal microbial contents, and perturbation of tryptophan metabolism with activation of the kynurenine pathway. Administration of irbesartan inhibited activation of stress-induced AT1 pathway to reduce intestinal ROS accumulation and inflammation, restored expression of ACE2/B0AT-1, activity of mTOR and p70S6K, dysbiosis and tryptophan metabolism. Our results suggest that AT1 is a potentially suitable therapeutic target in stress-induced intestinal inflammation, and that irbesartan could be beneficially suitable for the treatment of stressed patients with IBS. PMID- 29155325 TI - Promoter activity and regulation of the Pou5f1 homolog from a teleost, Nile tilapia. AB - Mammalian POU5F1 (also known as OCT4) is an essential transcription factor that induces and controls stemness in the inner cell mass and embryonic stem (ES) cells. Its expression results from intricate regulatory networks involving its 5' upstream DNA elements and numerous transcription factors. Pou5f3, the ortholog of POU5F1, has been identified in non-mammalians including fish. However, little is known about the molecular mechanisms controlling its expression up to date. Here we report the promoter activity and regulation of Nile tilapia (Oreochromis niloticus) pou5f3 (Onpou5f3) in fish early-stage embryos and ES cells. A 3.1-kb Onpou5f3 promoter region was cloned, analyzed and constructed into pT2AL-GFP vector. Multiple potential regulatory elements including potential octamer sequence for Pou domain and retinoic acid-responsive elements were found in the 5' upstream region. In vivo and in vitro transfection assays reveal that the 3.1 kb DNA sequence was sufficient to drive strong GFP expression in blastula-stage embryos and ES cells, but low or undetectable expression in either late developmental stage embryos or differentiated cells, suggesting the feasibility as a tool to monitor the pluripotency state in fish stem cells. Deletion luciferase assays reveal that the region from -726 to -219 contains positive regulatory elements, whereas both the regions from -3056 to -1306 and -1306 to 729 contain negative regulatory elements. Notably, just like mammalian POU5F1, OnPou5f3 significantly enhanced its own expression in a dose-dependent manner, whereas RA treatment dramatically reduced its expression. Taken together, our study not only provides a tool for monitoring the pluripotency state of fish stem cells in vitro, but also experimentally demonstrates the molecular mechanisms underlying the Pou5f1 homolog expression might be conserved to some content between mammals and fish. PMID- 29155326 TI - Genome-wide identification of the SWEET gene family in wheat. AB - The SWEET (sugars will eventually be exported transporter) family is a newly characterized group of sugar transporters. In plants, the key roles of SWEETs in phloem transport, nectar secretion, pollen nutrition, stress tolerance, and plant pathogen interactions have been identified. SWEET family genes have been characterized in many plant species, but a comprehensive analysis of SWEET members has not yet been performed in wheat. Here, 59 wheat SWEETs (hereafter TaSWEETs) were identified through homology searches. Analyses of phylogenetic relationships, numbers of transmembrane helices (TMHs), gene structures, and motifs showed that TaSWEETs carrying 3-7 TMHs could be classified into four clades with 10 different types of motifs. Examination of the expression patterns of 18 SWEET genes revealed that a few are tissue-specific while most are ubiquitously expressed. In addition, the stem rust-mediated expression patterns of SWEET genes were monitored using a stem rust-susceptible cultivar, 'Little Club' (LC). The resulting data showed that the expression of five out of the 18 SWEETs tested was induced following inoculation. In conclusion, we provide the first comprehensive analysis of the wheat SWEET gene family. Information regarding the phylogenetic relationships, gene structures, and expression profiles of SWEET genes in different tissues and following stem rust disease inoculation will be useful in identifying the potential roles of SWEETs in specific developmental and pathogenic processes. PMID- 29155327 TI - Expression profiles of the p38 MAPK signaling pathway from Chinese shrimp Fenneropenaeus chinensis in response to viral and bacterial infections. AB - Mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in cellular response to inflammatory cytokines, environmental stress and pathogenic infection, However, compared with mammals and insects, the potential function of p38 MAPK from Chinese shrimp (Fenneropenaeus chinensis) in response to viruses and bacterial infection is limited. In the study, the immune responses of four genes MKK3, MKK4, p38 and ATF-2 from F. chinensis were investigated in defending against white spot syndrome virus (WSSV), Vibrio anguillarum (V. anguillarum) and Staphylococcus aureus (S. aureus) infection. Results demonstrated that the expression levels of these four genes were apparently modulated in hemocytes and gills when shrimp were stimulated by WSSV or bacteria, particularly at 3-24h after infection. MKK3, p38 and ATF-2 were most sensitive to V. anguillarum (Gram-negative bacteria), followed by WSSV and S. aureus (Gram positive bacteria), while MKK4 gene was most sensitive to S. aureus, followed by WSSV and V. anguillarum. Knockdown of Fcp38 by RNA interference (RNAi) resulted in a reduction in the expression of FcMKK3 and FcATF-2. The results indicate that p38MAPK signaling pathway plays a role in defending against viral and bacterial infections in F. chinensis. PMID- 29155328 TI - Mitochondrial tRNALeu(UUR) C3275T, tRNAGln T4363C and tRNALys A8343G mutations may be associated with PCOS and metabolic syndrome. AB - Polycystic ovary syndrome (PCOS) is a very prevalent endocrine disease affecting reproductive women. Clinically, patients with this disorder are more vulnerable to develop type 2 diabetes mellitus (T2DM), cardiovascular events, as well as metabolic syndrome (MetS). To date, the molecular mechanism underlying PCOS remains largely unknown. Previously, we showed that mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutation was an important cause for PCOS. In the current study, we described the clinical and biochemical features of a three generation pedigree with maternally transmitted MetS, combined with PCOS. A total of three matrilineal relatives exhibited MetS including obesity, high triglyceride (TG) and Hemoglobin A1c (HbA1c) levels, and hypertension. Whereas one patient from the third generation manifestated PCOS. Mutational analysis of the whole mitochondrial genes from the affected individuals identified a set of genetic variations belonging to East Asia haplogroup B4b1c. Among these variants, the homoplasmic C3275T mutation disrupted a highly evolutionary conserved base pairing (28A-46C) on the variable region of tRNALeu(UUR), whereas the T4363C mutation created a new base-pairing (31T-37A) in the anticodon stem of tRNAGln, furthermore, the A8343G mutation occurred at the very conserved position of tRNALys and may result the failure in mitochondrial tRNAs (mt-tRNAs) metabolism. Biochemical analysis revealed the deficiency in mitochondrial functions including lower levels of mitochondrial membrane potential (MMP), ATP production and mtDNA copy number, while a significantly increased reactive oxygen species (ROS) generation was observed in polymononuclear leukocytes (PMNs) from the individuals carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for the clinical phenotypes. Taken together, our data indicated that mt-tRNA mutations were associated with MetS and PCOS in this family, which shaded additional light into the pathophysiology of PCOS that were manifestated by mitochondrial dysfunction. PMID- 29155329 TI - Cloning and characterization of two novel beta-glucosidase genes encoding isoenzymes of the cellobiase complex from Cellulomonas biazotea. AB - Enzymatic degradation of cellulosic waste to generate renewable biofuels has offered an attractive solution to the energy problem. Synergistic hydrolysis of cellulose residues requires the participation of three different types of cellulases - endoglucanases, exoglucanases, and beta-glucosidases (Bgl). Our group has been interested in using Bgl of Cellulomonas biazotea in studies designed to investigate cooperative action among different cellulases. We previously have cloned bgl genes encoding Cba and Cba3, which are C. biazotea Bgl isozymes representing two different Bgl families, respectively; specifically, Glycoside Hydrolase Family 3 (GH3) and Glycoside Hydrolase Family 1 (GH1). To gain an understanding of the complexity of Bgl in C. biazotea, we analyzed E. coli clones containing plasmids into which C. biazotea DNA had been inserted; these clones could hydrolyze 4-methylumbelliferyl beta-d-glucopyranoside (MUG) supplemented in solid agar media, suggesting they might contain bgl genes. Through restriction analysis and DNA sequencing, two novel bgl genes, designated cba4 and cba5 and encoding Cba4 (484 amino acids) and Cba5 (758 amino acids) were identified. Cba4 and Cba5 appear to be members of GH1 and GH3, respectively. Both Cba4 and Cba5 were concluded to be genuine cellobiases as each was found to enable their E. coli hosts to survive on media in which cellobiose was the sole carbon source. Despite lacking a typical secretory signal sequence, Cba4 and Cba5 are secretory proteins. Although they are isoenzymes, Cba, Cba3, Cba4, and Cba5 were shown to possess distinct substrate specificities. These four Bgl members may play important roles in hydrolyzing a wide variety of beta-glucosides including cellobiose and non-cellulosic substrates. PMID- 29155330 TI - Expression pattern and functional analysis of R-spondin1 in tongue sole Cynoglossus semilaevis. AB - R-spondin 1 (Rspo1) is a potential female-determining gene in mammals that could regulate the Wnt/beta-catenin signaling pathway. The deletion of Rspo1 causes sex reversal in females. To investigate sexual determination and differentiation, we cloned and analyzed the Rspo1 gene in Cynoglossus semilaevis. Phylogenetic and gene structure analyses revealed that Rspo1 gene exhibited high sequence conservation and contained an N-terminal signal peptide, two furin-like cysteine rich domains (FU1 and FU2), a thrombospondin type 1 repeat, and a C-terminal region enriched with basic charged amino acids. qRT-PCR revealed that Rspo1 expressed sexual dimorphism in gonad, with higher expression levels in the ovary than in the testis, thus, suggesting the involvement of Rspo1 in gonad differentiation. In situ hybridization results demonstrated that Rspo1 was expressed in premature germ cells, including spermatogonia and spermatocytes in the testis and stage II and stage III oocytes in the ovary. The methylation levels in two CpG sites of Rspo1 promoter significantly differed among females, males, and pseudomales. After 30days of exposure to high temperature, the expression of Rspo1 significantly decreased in female individuals, some of which were prone to males. However, no difference of Rspo1 gene expression was observed between the control group and high-temperature group in males. These preliminary findings suggested that Rspo1 played a crucial role in sex determination and development. This study laid the groundwork for further sex control breeding techniques in C. semilaevis. PMID- 29155331 TI - Evolution of vomeronasal receptor 1 (V1R) genes in the common marmoset (Callithrix jacchus). AB - Pheromones are crucial for eliciting innate responses and inducing social and sexual behaviors in mammals. The vomeronasal receptor 1 genes, V1Rs, encode members of a pheromone receptor family that are mainly expressed in the vomeronasal organ (VNO). The V1R family shows extraordinary variety in gene number among vertebrates owing to successive gene gains and losses during evolution. Such diversity is believed to reflect a degree of dependence on the VNO. We investigated V1R evolution in primate lineages closely related to humans because these VNOs show a trend toward degeneration. We performed extensive phylogenetic analyses for V1Rs from a broad range of primate species. Although the decline of intact genes was evident in anthropoids (hominoids, Old World monkeys and New World monkeys), we found that a certain number of intact genes persist in New World monkeys. In one New World monkey species, the common marmoset (Callithrix jacchus), we examined seven putatively functional V1Rs using in situ hybridization and reverse transcription-PCR. Based on their mRNA expression patterns in the VNO and other organs, two types of V1Rs emerged: the canonical class with VNO-specific expression, and a second group having more ubiquitous expression in various organs as well as VNO. Furthermore, phylogenetic analysis revealed that the class with the more widespread expression had been retained longer in evolution than the VNO-specific type. We propose that the acquisition of a novel non-VNO-related function(s) may have led to the survival of a small but persistent number of V1Rs in anthropoid primates. PMID- 29155332 TI - Unusual features of the large linear plasmid pSA3239 from Streptomyces aureofaciens CCM 3239. AB - We previously identified the aur1 gene cluster, responsible for the production of the angucycline antibiotic auricin in Streptomyces aureofaciens CCM 3239. Pulse field gel electrophoresis showed a single, 241kb linear plasmid, pSA3239, in this strain, and several approaches confirmed the presence of the aur1 cluster in this plasmid. We report here the nucleotide sequence of this 241,076-bp plasmid. pSA3239 contains an unprecedentedly small (13bp) telomeric sequence CCCGCGGAGCGGG, which is identical to the conserved Palindrome I sequence involved in the priming of end-patching replication. A bioinformatics analysis revealed 234 open reading frames with high number (28) of regulatory genes from various families. In contrast to most other linear plasmids, pSA3239 contains a pair of replication initiation genes (sa76 and sa75) located at its extreme left end, adjacent to the telomere. Together with similar proteins from several other linear plasmids (pFRL2, pSLA2-M, pSV2, pSDA1, and SAP1), they constitute a new family of replication initiation proteins. This left end also contains two genes, tpgSa and tapSa, encoding the terminal protein and the telomere associated protein involved in telomere end-patching replication. pSA3239 also contains two genes homologous to the parAB partitioning system, and deletion of the parA homologue (sa43) affects structural stability of the plasmid. pSA3239 carries five potential secondary metabolite gene clusters. In addition to aur1 and a non ribosomal peptide synthase (NRPS) gene cluster for the blue pigment indigoidine, it also contains a partial type II polyketide synthase (PKS) gene cluster, a partial type I PKS gene cluster, and a NRPS/PKSI gene cluster for unknown secondary metabolites. The last gene cluster contains a subcluster of seven genes (sa91-sa97), highly similar to part of the valanimycin biosynthetic cluster vlm. A S. aureofaciens strain lacking pSA3239 was prepared. This deletion did not substantially affect growth and differentiation. A comparative analysis of secondary metabolites between both strains did not identify any product, except auricin and indigoidine, which is dependent upon pSA3239. Thus, the other three identified gene clusters are likely silent under these conditions. PMID- 29155333 TI - IMA: Identifying disease-related genes using MeSH terms and association rules. AB - Genes play an important role in several diseases. Hence, in biology, identifying relationships between diseases and genes is important for the analysis of diseases, because mutated or dysregulated genes play an important role in pathogenesis. Here, we propose a method to identify disease-related genes using MeSH terms and association rules. We identified genes by analyzing the MeSH terms and extracted information on gene-gene interactions based on association rules. By integrating the extracted interactions, we constructed gene-gene networks and identified disease-related genes. We applied the proposed method to study five cancers, including prostate, lung, breast, stomach, and colorectal cancer, and demonstrated that the proposed method is more useful for identifying disease related and candidate disease-related genes than previously published methods. In this study, we identified 20 genes for each disease. Among them, we presented 34 important candidate genes with evidence that supports the relationship of the candidate genes with diseases. PMID- 29155334 TI - Respiratory muscle strength is decreased after maximal incremental exercise in trained runners and cyclists. AB - The respiratory muscle fatigue seems to be able to limit exercise performance and may influence the determination of maximal oxygen uptake (VO2max) or maximum aerobic work rate during maximal incremental test. The aim of this study was therefore to investigate whether maximal incremental exercise decreases respiratory muscle strength. We hypothesized that respiratory muscle strength (maximal pressure) will decrease after maximal incremental exercise to exhaustion. 36 runners and 23 cyclists completed a maximal incremental test on a treadmill or a cycle ergometer with continuous monitoring of expired gases. Maximal inspiratory (MIP) and expiratory (MEP) pressure measurements were taken at rest and post- exercise. At rest, the MIP and MEP were 140+/-25 and 172+/-27 in runners vs. 115+/-26 and 146+/-33 in cyclists (p<0.05 between groups, respectively). The rest values of MIP and MEP were correlated to the VO2peak in all athletes, r=0.34, p<0.01 and r=0.36, p<0.01, respectively. At exhaustion, the MIP and MEP decreased significantly post- test by 13+/-7% and 13+/-5% in runners vs. 17+/-11% and 15+/-10% in cyclists (p>0.05), respectively. Our results suggest that respiratory muscle strength is decreased following maximal incremental exercise in trained runners and cyclists. PMID- 29155335 TI - Exercise testing in patients with diaphragm paresis. AB - PURPOSE: Diaphragm paresis (DP) is characterized by abnormalities of respiratory muscle function. However, the impact of DP on exercise capacity is not well known. This study was performed to assess exercise tolerance in patients with DP and to determine whether inspiratory muscle function was related to exercise capacity, ventilatory pattern and cardiovascular function during exercise. METHODS: This retrospective study included patients with DP who underwent both diaphragmatic force measurements, and cardiopulmonary exercise testing (CPET). RESULTS: Fourteen patients were included. Dyspnea was the main symptom limiting exertion (86%). Exercise capacity was slightly reduced (median VO2peak: 80% [74.5%-90.5%]), mostly due to ventilatory limitation. Diaphragm and overall inspiratory muscle function were correlated with exercise ventilation. Moreover, overall inspiratory muscle function was related with oxygen consumption (r=0.61) and maximal workload (r=0.68). CONCLUSIONS: DP decreases aerobic capacity due to ventilatory limitation. Diaphragm function is correlated with exercise ventilation whereas overall inspiratory muscle function is correlated with both exercise capacity and ventilation suggesting the importance of the accessory inspiratory muscles during exercise for patients with DP. Further larger prospective studies are needed to confirm these results. PMID- 29155336 TI - Evaluation of the combined effect of NIR laser and ionizing radiation on cellular damages induced by IUdR-loaded PLGA-coated Nano-graphene oxide. AB - Glioma is one of the most common malignant cancers of the central nervous system (CNS). Radiatherapy and chemotherapy may be used to slow the growth of tumors that cannot be removed with surgery. The current study developed a combination therapy tool using Nanographene oxide (NGO) functionalized with poly lactic-co glycolic acid (PLGA) as a carrier of 5-iodo-2-deoxyuridine (IUdR) for glioma cancer treatment. U87MG cells were treated in different groups with IUdR, PLGA coated Nanographene oxide (PLGA-NGO), IUdR-loaded PLGA-coated Nanographene oxide (IUdR-PLGA-NGO), 2Gy 6MV X-ray radiation, and near-infrared region (NIR) laser radiation. PLGA-NGO showed excellent biocompatibility, high storage capacity for IUdR and high photothermal conversion efficiency. It was effectively employed to create cell damage in the U87MG cell line in the presence of X-ray (6 MV) and NIR laser. Moreover, IUdR-PLGA-NGO+X-ray+NIR laser significantly reduced the plating efficiency of the cells in comparison with IUdR-PLGA-NGO+X-ray and IUdR-PLGA NGO+NIR laser. Furthermore, Prussian blue staining showed that IUdR-PLGA-NGO SPIONs were delivered into glioblastoma cells. The PLGA-NGO loaded with IUdR under NIR and X-ray radiation exhibited the highest cytotoxicity toward U87MG cells when compared with other treatment methods, indicating efficient radio photothermal targeted therapy. PMID- 29155337 TI - Photodynamic therapy in fibrosarcoma BALB/c animal model: Observation of the rebound effect. AB - In vivo spectrofluorometric analysis during photodynamic therapy (PDT) is a fundamental tool to obtain information about drug bleaching kinetics. Using a portable spectrofluorometer with an excitation source emitting at 400nm wavelength and a spectral analyzer ranging from 500nm to 800nm, the evolution of the meta-tetra(hydroxyphenyl) chlorin (m-THPC) photosensitizer fluorescence spectrum at the tumoral tissue of BALB/c murines with fibrosarcoma located at their flank was followed up. Ex vivo fluorescence measurements of the tumor and skin were also performed with the aim of better characterizing the in vivo signal at different parts of the tumor. PDT was performed employing a LED 637nm light source. Fluorescence at different parts of the tumor and at the tail and armpit of mice was measured immediately after injection and followed daily. The average fluorescence intensity in the tumor reached a maximum after 24-72h. Subsequently, illuminations 24, 48, 72 and 96h post-injection were performed, and the fluorescence was measured immediately before and after each illumination. Eventually, 24h post-illumination, the fluorescence at certain parts of the tumor increased in comparison with that measured immediately after illumination. This effect, named "rebound effect", was due to the new local accumulation of the drug, and was used to perform a second illumination on some mice to increase the amount of photodynamic reaction and significantly improve the PDT outcome. These results are encouraging to optimize PDT in the proposed animal model, thinking about the possible translation to humans. PMID- 29155338 TI - Financial Toxicity among Patients with Bladder Cancer: Reasons for Delay in Care and Effect on Quality of Life. AB - PURPOSE: Costly surveillance and treatment of bladder cancer can lead to financial toxicity, a treatment related financial burden. Our objective was to define the prevalence of financial toxicity among patients with bladder cancer and identify delays in care and its effect on health related quality of life. MATERIALS AND METHODS: We identified patients with bladder cancer in the University of North Carolina Health Registry/Cancer Survivorship Cohort. Financial toxicity was defined as agreement with having "to pay more for medical care than you can afford." Health related quality of life was measured using general and cancer specific validated questionnaires. Statistical analyses were performed using the Fisher exact test and the Student t-test. RESULTS: A total of 138 patients with bladder cancer were evaluated. Median age was 66.9 years, 75% of the patients were male and 89% were white. Of the participants 33 (24%) endorsed financial toxicity. Participants who were younger (p = 0.02), black (p = 0.01), reported less than a college degree (p = 0.01) and had noninvasive disease (p = 0.04) were more likely to report financial toxicity. On multivariable analysis only age was a significant predictor of financial toxicity. Patients who endorsed financial toxicity were more likely to report delaying care (39% vs 23%, p = 0.07) due to the inability to take time off work or afford general expenses. On general health related quality of life questionnaires patients with financial toxicity reported worse physical and mental health (p = 0.03 and <0.01, respectively), and lower cancer specific health related quality of life (p = 0.01), physical well-being (p = 0.01) and functional well-being (p = 0.05). CONCLUSIONS: Financial toxicity is a major concern among patients with bladder cancer. Younger patients were more likely to experience financial toxicity. Those who endorsed financial toxicity experienced delays in care and poorer health related quality of life, suggesting that treatment costs should have an important role in medical decision making. PMID- 29155339 TI - Body mass index predicts risk of complications in lumbar spine surgery based on surgical invasiveness. AB - BACKGROUND CONTEXT: Obesity as a comorbidity in spine pathology may increase the risk of complications following surgical treatment. The body mass index (BMI) threshold at which obesity becomes clinically relevant, and the exact nature of that effect, remains poorly understood. PURPOSE: Identify the BMI that independently predicts risk of postoperative complications following lumbar spine surgery. STUDY DESIGN/SETTING: Retrospective review of the National Surgery Quality Improvement Program (NSQIP) years 2011-2013. PATIENT SAMPLE: A total of 31,763 patients were undergoing arthrodesis, discectomy, laminectomy, laminoplasty, corpectomy, or osteotomy of the lumbar spine. OUTCOME MEASURES: Complication rates. METHODS: The patient sample was categorized preoperatively by BMI according to the World Health Organization stratification: underweight (BMI <18.5), normal overweight (BMI 20.0-29.9), obesity class 1 (BMI 30.0-34.9), 2 (BMI 35.0-39.9), and 3 (BMI>=40). Patients were dichotomized based on their position above or below the 75th surgical invasiveness index (SII) percentile cutoff into low-SII and high-SII. Differences in complication rates in BMI groups were analyzed by Bonferroni analysis of variance (ANOVA) method. Multivariate binary logistic regression evaluated relationship between BMI and complication categories in all patients and in high-SII and low-SII surgeries. RESULTS: Controlling for baseline difference in SII, Charlson Comorbidity Index (CCI) score, diabetes, hypertension, and smoking, complications significantly increased at a BMI of 35 kg/m2. The odds ratios for any complication (odds ratio [OR] [95% confidence interval {CI}]; obesity 2: 1.218 [1.020-1.455]; obesity 3: 1.742 [1.439-2.110]), infection (obesity 2: 1.335 [1.110-1.605]; obesity 3: 1.685 [1.372-2.069]), and surgical complication (obesity 2: 1.622 [1.250-2.104]; obesity 3: 2.798 [2.154-3.634]) were significantly higher in obesity classes 2 and 3 relative to the normal-overweight cohort (all p<.05). CONCLUSION: There is a significant increase in complications, specifically infection and surgical complications, in patients with BMI>=35 following lumbar spine surgery, with that rate further increasing with BMI>=40. PMID- 29155340 TI - Ambulatory anterior cervical discectomy and fusion is associated with a higher risk of revision surgery and perioperative complications: an analysis of a large nationwide database. AB - BACKGROUND CONTEXT: With the changing landscape of health care, outpatient spine surgery is being more commonly performed to reduce cost and to improve efficiency. Anterior cervical discectomy and fusion (ACDF) is one of the most common spine surgeries performed and demand is expected to increase with an aging population. PURPOSE: The objective of this study was to determine the nationwide trends and relative complication rates associated with outpatient ACDF. STUDY DESIGN/SETTING: This is a large-scale retrospective case control study. PATIENT SAMPLE: The patient sample included Humana-insured patients who underwent one- to two-level ACDF as either outpatients or inpatients from 2011 to 2016 OUTCOME MEASURES: The outcome measures included incidence and the adjusted odds ratio (OR) of postoperative medical and surgical complications within 1 year of the index surgery. MATERIALS AND METHODS: A retrospective review was performed of the PearlDiver Humana insurance records database to identify patients undergoing one- to two-level ACDF (Current Procedural Terminology [CPT]-22551 and International Classification of Diseases [ICD]-9-816.2) as either outpatients or inpatients from 2011 to 2016. The incidence of perioperative medical and surgical complications was determined by querying for relevant ICD and CPT codes. Multivariate logistic regression adjusting for age, gender, and Charlson Comorbidity Index was used to calculate ORs of complications among outpatients relative to inpatients undergoing ACDF. RESULTS: Cohorts of 1,215 patients who underwent outpatient ACDF and 10,964 patients who underwent inpatient ACDF were identified. The median age was in the 65-69 age group for both cohorts. The annual relative incidence of outpatient ACDF increased from 0.11 in 2011 to 0.22 in 2016 (R2=0.82, p=.04). Adjusting for age, gender, and comorbidities, patients undergoing outpatient ACDF were more likely to undergo revision surgery for posterior fusion at both 6 months (OR 1.58, confidence interval [CI] 1.27-1.96, p<.001) and 1 year (OR 1.79, CI 1.51-2.13, p<.001) postoperatively. Outpatient ACDF was also associated with a higher likelihood of revision anterior fusion at 1 year postoperatively (OR 1.46, CI 1.26-1.70, p<.001). Among medical complications, postoperative acute renal failure was more frequently associated with outpatient ACDF than inpatient ACDF (OR 1.25, CI 1.06-1.49, p=.010). Adjusted rates of all other queried surgical and medical complications were comparable. CONCLUSIONS: Outpatient ACDF is increasing in frequency nationwide over the past several years. Nationwide data demonstrate a greater risk of perioperative surgical complications, including revision anterior and posterior fusion, as well as a higher risk of postoperative acute renal failure. Candidates for outpatient ACDF should be counseled and carefully selected to reduce these risks. PMID- 29155341 TI - Outpatient elective posterior lumbar fusions appear to be safely considered for appropriately selected patients. AB - BACKGROUND CONTEXT: There has been growing interest in performing posterior lumbar fusions (PLFs) in the outpatient setting to optimize patient satisfaction and reduce cost. Although still done in only a small percentage of cases, this has been more possible because of advances in surgical techniques and anesthesia. However, data on the perioperative course of outpatient compared with inpatient PLF in a large sample size are scarce. PURPOSE: This study aimed to compare perioperative complications between outpatient and inpatient PLF in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. STUDY DESIGN/SETTING: A retrospective cohort comparison study was carried out. PATIENT SAMPLE: Patients undergoing PLF with or without interbody fusion from the 2005 to 2015 NSQIP database comprised the sample. OUTCOME MEASURES: Outcome measures were postoperative complications within 30 days and readmission within 30 days. METHODS: Patients who underwent PLF with or without interbody fusion were identified in the 2005-2015 NSQIP database. Outpatient procedures were defined as cases that had hospital length of stay (LOS)=0 days, whereas inpatient procedures were defined as LOS=1-30 days. Patient characteristics, comorbidities, and procedural variables (inclusion of interbody fusion, instrumentation, and number of levels fused) were compared between the two cohorts. Propensity score-matched comparisons were then performed for postoperative complications and 30-day readmissions between the two groups. RESULTS: The current study included 360 outpatient and 36,610 inpatient PLF cases. After propensity matching to control potential confounding factors, statistical analysis revealed no significant difference in postoperative adverse events other than significantly lower blood transfusions in the outpatient group (2.78% vs. 10.83%, p<.001). Notably, the rate of readmissions was not different between the groups. CONCLUSIONS: Based on the lack of differences in rates of most perioperative complications and 30-day readmissions between the outpatient and inpatient cohorts, it seems that outpatient PLF may be appropriately considered for select patients. However, extremely careful patient selection should be exercised. PMID- 29155342 TI - Predictors before and after multimodal rehabilitation for pain acceptance and engagement in activities at a 1-year follow-up for patients with whiplash associated disorders (WAD)-a study based on the Swedish Quality Registry for Pain Rehabilitation (SQRP). AB - BACKGROUND CONTEXT: Studies have shown that pain acceptance strategies related to psychological flexibility are important in the presence of chronic musculoskeletal pain. However, the predictors of these strategies have not been studied extensively in patients with whiplash-associated disorders (WAD). PURPOSE: The purpose of this study was to predict chronic pain acceptance and engagement in activities at 1-year follow-up with pain intensity, fear of movement, perceived responses from significant others, outcome expectancies, and demographic variables in patients with WAD before and after multimodal rehabilitation (MMR). STUDY DESIGN: The design of this investigation was a cohort study with 1-year postrehabilitation follow-up. STUDY SETTING: The subjects participated in MMR at a Swedish rehabilitation clinic during 2009-2015. PATIENT SAMPLE: The patients had experienced a whiplash trauma (WAD grade I-II) and were suffering from pain and reduced functionality. A total of 386 participants were included: 297 fulfilled the postrehabilitation measures, and 177 were followed up at 1 year after MMR. OUTCOME MEASURES: Demographic variables, pain intensity, fear of movement, perceived responses from significant others, and outcome expectations were measured at the start and after MMR. Chronic pain acceptance and engagement in activities were measured at follow-up. METHODS: The data were obtained from a Swedish Quality Registry for Pain Rehabilitation (SQRPR). RESULTS: Outcome expectancies of recovery, supporting and distracting responses of significant others, and fear of (re)injury and movement before MMR were significant predictors of engagement in activities at follow-up. Pain intensity and fear of (re)injury and movement after MMR significantly predicted engagement in activities at follow-up. Supporting responses of significant others and fear of (re)injury and movement before MMR were significant predictors of pain acceptance at the 1-year follow-up. Solicitous responses of significant others and fear of (re)injury and movement at postrehabilitation significantly predicted pain acceptance at follow-up. CONCLUSION: For engagement in activities and pain acceptance, the fear of movement appears to emerge as the strongest predictor, but patients' perceived reactions from their spouses need to be considered in planning the management of WAD. PMID- 29155343 TI - Health outcomes and costs of acute traumatic spinal injury in New South Wales, Australia. AB - BACKGROUND CONTEXT: Traumatic spinal injuries are often associated with both long term disability, higher frequency of hospital readmissions, and high medical costs for individuals of all ages. Age differences in terms of injury profile and health outcomes among those who sustain a spinal cord injury have been identified. However, factors that may influence health outcomes among those with a spinal injury have not been extensively examined at a population level. PURPOSE: The present study aims to describe the characteristics of traumatic spinal injury, identify factors predictive of mortality, and estimate the cost of hospital treatment for younger and older people. STUDY DESIGN/SETTING: This is a population-based retrospective epidemiological study using linked hospitalization and mortality records during January 1, 2010 to June 30, 2014 in New South Wales, Australia. PATIENT SAMPLE: The present study included 13,429 hospitalizations. OUTCOME MEASURES: Mortality within 30 and 90 days of hospitalization, hospital length of stay (LOS), and hospitalization costs were determined. METHODS: Hospitalizations with a principal diagnosis of spinal cord injury or spinal fractures were used to identify traumatic spinal injuries. Age-standardized incidence rates were calculated and negative binomial regression was used to examine statistical significant changes over time. Cox proportional hazard regression was used to examine the effect of risk factors on survival at 90 days. RESULTS: There were 13,429 hospitalizations, with 52.4% of individuals aged >=65 years. The hospitalization rates for individuals aged <=64 and >=65 years were both estimated to significantly increase per year by 3.3% (95% confidence interval [CI] 0.97-5.79, p<.006) and 3.3% (95% CI 1.02-5.71, p=.005), respectively. For individuals aged >=65 years, there were a higher proportion of women injured, comorbid conditions, injuries after a fall in the home or aged care facility, a longer hospital LOS, unplanned hospital admissions, and deaths than individual aged <=64 years. The average cost per index hospitalization was AUD$23,808 for individuals aged <=64 years and AUD$31,187 for individuals aged >=65 years with a total estimated cost of AUD$371 million. Mortality risk at 90 days was increased for individuals who had one or more comorbidities, a higher injury severity score, and if their injury occurred in the home or an aged care facility. CONCLUSIONS: Spinal injury represents a substantial cost and results in debilitating injuries, particularly for older individuals. Spinal injury prevention efforts for older people should focus on the implementation of fall injury prevention, whereas for younger individuals, prevention measures should target road safety. PMID- 29155344 TI - Freehand technique for C2 pedicle and pars screw placement: is it safe? AB - BACKGROUND CONTEXT: During placement of C2 pedicle and pars screws, intraoperative fluoroscopy is used so that neurovascular complications can be avoided, and screws can be placed in the proper position. However, this method is time consuming and increases radiation exposure. Furthermore, it does not guarantee a completely safe and accurate screw placement. PURPOSE: The objective of this study was to evaluate the safety of the C2 pedicle and pars screw placement without fluoroscopic or other guidance methods. STUDY DESIGN: This is a retrospective comparative study. PATIENT SAMPLE: One hundred ninety-eight patients who underwent placement of C2 pedicle or pars screws without any intraoperative radiographic guidance were included in the study. OUTCOME MEASURES: Medical records and postoperative computed tomography (CT) scans were evaluated. MATERIALS AND METHODS: Clinical data were reviewed for intraoperative and postoperative complications. The accuracy of screw placement was evaluated with postop CT scans using a previously published cortical-breach grading system (described by the location and the percentage of the screw diameter over the cortical edge [0=none, Grade I<=25% of the screw diameter, Grade II=26%-50%, Grade III=51%-75%, and Grade IV=76%-100%]). RESULTS: A total of 148 pedicle screws and 219 pars screws were inserted by two experienced surgeons. There were no cases of cerebral spinal fluid leakage and no neurovascular complications during screw placement. Postoperative CT scans were available for 76 patients, which included 52 pedicle screws and 87 pars screws. For cases with C2 pedicle screws, there were 12 breaches (23%); these included 10 screws with a Grade I breach (19%), 1 screw with a Grade II breach (2%), and 1 screw with a Grade IV breach (2%). Lateral breaches occurred in seven screws (13%), inferior breaches occurred in three screws (6%), and superior breaches occurred in two screws (4%). For cases with C2 pars screws, there were 10 breaches (11%); these included 6 screws with a Grade I breach (7%), 2 screws with a Grade II breach (2%), and 2 screws with a Grade IV breach (2%). Medial breaches were found in four (5%), lateral breaches in two (2%), inferior breaches in two (2%), and superior breaches in two (2%). Two of the cases with superior breaches (one for pedicle and one for pars) experienced occipital neuralgia months after surgery. There was no statistically significant difference in the incidence of overall and high grade breaches between the groups (p=.07 and 1.0, respectively). CONCLUSIONS: Although even in experienced hands up to 23% of C2 pedicle screws and 11% of C2 pars screws placed using a freehand technique without guidance may be malpositioned, a clear majority of malpositioned screws demonstrated a low-grade breach, and only 2 of 198 patients (1%) experienced complications related to screw placement. PMID- 29155345 TI - The Relationship Between Hematoma and Pachymeninges in an Interdural Hematoma: Diagnosis and Surgical Strategy. AB - BACKGROUND: The exact location of a hematoma in relation to the pachymeninges contributes to typical radiographic presentations. However, because of the complexity of hematoma evolution and neomembrane formation, an unexpected intraoperative finding can lead to a change of surgical strategy. In addition, the concentration of hemoglobin and its degradation products, the integrity of red blood cells, and the infiltration of fibroblasts, polymorphonuclear neutrophils, and macrophages are factors that affect the imaging characteristics on computed tomography and magnetic resonance imaging as the hematoma ages. CASE DESCRIPTION: An interdural hematoma (IDH)-a hemorrhage that splits the periosteal dura mater from the meningeal dura mater-is an extremely rare occurrence, and the diagnosis requires confirmation by surgical or pathologic findings. By presenting a case of an IDH that was misdiagnosed as a chronic subdural hematoma before surgery, and reviewing the literature, we propose the radiologic characteristics of presenting both dural border sign and dural beak sign on magnetic resonance imaging as a specific indicator for IDH preoperatively. CONCLUSIONS: A careful evaluation of cerebral expansion before membranectomy was mandatory intraoperatively. For IDH, wide inner membranectomy (i.e., excision of meningeal dura mater) should not be necessary. An IDH should be considered as a distinct disease category when evaluating an extra-axial hematoma despite its rarity, because the characters of radiologic, histopathologic findings are different. In addition, surgical strategy varies for epidural or subdural hematoma in different hematoma stages. PMID- 29155346 TI - Intraoperative Monitoring of the Integrity of the Anterior Visual Pathways: A Methodologic Review and Meta-Analysis. AB - BACKGROUND: Diverse methods have been developed for intraoperative monitoring of the integrity of the visual pathways. We performed a review of the literature to determine the methodology of each technique as well as their recent development. The predictive power of each eligible technique was determined based on a meta analysis. METHODS: A literature review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Techniques adopted for intraoperative monitoring of the integrity of the visual pathways were extracted and described. The power of each eligible technique to predict the visual outcome was tested. RESULTS: Visual evoked potentials showed marked methodologic improvement in recent studies. Predictive power for visual deterioration after surgery was approximately 60% and reached 100% when coupled with simultaneous monitoring of electroretinography. The sensitivity of visual evoked potentials for detection of deterioration was 47.2%. The decrease of fractional anisotropy of the optic chiasma showed significant correlation with improvement of vision after chiasma compression and showed 100% predictive power for improvement. CONCLUSION: Each technique had limitations. Visual evoked potentials had a high predictive power for detection of deterioration but with low sensitivity. Fractional anisotropy of the optic chiasma had high predictive power for improvement of vision with low predictive power for deterioration. PMID- 29155347 TI - Postoperative Gamma Knife Radiosurgery for Cavernous Sinus-Invading Growth Hormone-Secreting Pituitary Adenomas. AB - OBJECTIVE: We aimed to determine the long-term effects of Gamma knife radiosurgery (GKS) on remnants in the cavernous sinus (CS) after transsphenoidal surgery (TSS) for acromegaly and to identify its possible adverse effects. METHODS: Thirty patients who had remnant tumors only inside the CS after TSS and who consequently underwent GKS were included. They were followed for a median period of 47 months after GKS with regular hormonal and radiologic examinations. RESULTS: The mean tumor volume and margin dose irradiated by GKS was 3.7 cm3 and 26.2 Gy, respectively. Radiologic tumor control was identified in all patients, and no tumor regrowth or recurrent tumors were identified. For 14 patients who achieved endocrinologic remission, the median duration from GKS until remission was 35 months. The actuarial rates of remission at 2, 5, and 10 years were 7.1%, 43.6%, and 65.6%, respectively. The degree of decrease in the nadir GH level in the OGTT at 6 months after GKS was a statistically significant predictor of remission. Newly developed hypopituitarism frequently developed in a time dependent manner. Radiation necrosis developed in 4 patients with relatively large remnant volumes. CONCLUSIONS: GKS is an effective adjuvant treatment option for remnant tumors inside the CS after TSS. Maximal surgical resection, leaving minimal volume of remnants only inside the CS, allows the safe and sufficient delivery of a radiation dose to tumors, thereby increasing the possibility of remission. However, the risk of new hypopituitarism and radiation necrosis should be considered when tumors inside the CS are treated with GKS. PMID- 29155348 TI - Progress and challenges of predictive biomarkers of anti PD-1/PD-L1 immunotherapy: A systematic review. AB - Despite the marked success of applications of PD-1/PD-L1 checkpoint blockades in clinical, the efficacy and responsiveness of these agents varies greatly among different tumor types and across individual patients. Therefore, establishment of predictive biomarkers for checkpoint blockades is of the most importance to maximize the therapeutic benefits. In this review, we discuss the current progress and challenges of developing predictive biomarkers of immunotherapy responsiveness, aiming to provide some directions for future studies. PD-L1 expression is a logical biomarker for the prediction of response to anti-PD-(L)1 immunotherapies. However, the predictive values of PD-L1 expressions for immunotherapy are currently debating and challenging. Multiplex detecting methods and combined biomarkers may provide new strategies. For example, tumor mutation and neoantigens burden, some oncogene mutations, like EGFR, ALK, KRAS and STK11. In addition, with development of new probes and tracers, immuno-PET provide a new, non-invasive and quantitative strategy to monitor treatment response. As current evidence of those potential predictors, a consensus and standardization is needed to establish to widely applied in future studies. Multiplex detecting methods and combined biomarkers may provide new strategies. PMID- 29155349 TI - Endogenous sulfur dioxide regulates hippocampal neuron apoptosis in developing epileptic rats and is associated with the PERK signaling pathway. AB - Epilepsy is among the most common neurological diseases in children. Recurrent seizures can result in hippocampal damage and seriously impair learning and memory functions in children. However, the mechanisms underlying epilepsy-related brain injury are unclear. Neuronal apoptosis is among the most common neuropathological manifestations of brain injury. Endogenous sulfur dioxide (SO2) has been shown to be involved in seizures and related neuron apoptosis. However, the role of endogenous SO2 in epilepsy remains unclear. This study assessed whether endogenous SO2 is involved in epilepsy and its underlying mechanisms. Using a rat epilepsy model induced by an intraperitoneal injection of kainic acid (KA), we found that hippocampal neuron apoptosis was induced in epileptic rats, and the SO2 content and aspartate aminotransferase (AAT) activity in the plasma were increased compared to those in the control group. However, the inhibition of SO2 production by l-aspartate-beta-hydroxamate (HDX) can subvert this response 72h after an epileptic seizure. No difference in apoptosis was observed 7 d after the epileptic seizure in the KA and KA+HDX groups. The protein expression levels of AAT2, glucose-regulated protein 78 (GRP78), pancreatic eIF2 kinase-like ER kinase (PERK) and phospho-PERK (p-PERK) were remarkably elevated in the hippocampi of the epileptic rats, while the HDX treatment was capable of reversing this process 7 d after the epileptic seizure. These results indicate that the inhibition of endogenous SO2 production can alleviate neuronal apoptosis and is associated with the PERK signaling pathway during the initial stages after epileptic seizure, but inhibiting SO2 production only delayed the occurrence of apoptosis and did not prevent neuronal apoptosis in the epileptic rats. PMID- 29155350 TI - The PMCA pumps in genetically determined neuronal pathologies. AB - Ca2+ signals regulate most aspects of animal cell life. They are of particular importance to the nervous system, in which they regulate specific functions, from neuronal development to synaptic plasticity. The homeostasis of cell Ca2+ must thus be very precisely regulated: in all cells Ca2+ pumps transport it from the cytosol to the extracellular medium (the Plasma Membrane Ca2+ ATPases, hereafter referred to as PMCA pumps) or to the lumen of intracellular organelles (the Sarco/Endoplasmatic Reticulum Ca2+ ATPase and the Secretory Pathway Ca2+ ATPase, hereafter referred to as SERCA and SPCA pumps, respectively). In neurons and other excitable cells a powerful plasma membrane Na+/Ca2+ exchanger (NCX) also exports Ca2+ from cells. Quantitatively, the PMCA pumps are of minor importance to the bulk regulation of neuronal Ca2+. However, they are important in the regulation of Ca2+ in specific sub-plasma membrane microdomains which contain a number of enzymes that are relevant to neuronal function. The PMCA pumps (of which 4 basic isoforms are expressed in animal cells) are P-type ATPases that are characterized by a long C-terminal cytosolic tail which is the site of interaction with most of the regulatory factors of the pump, the most important being calmodulin. In resting neurons, at low intracellular Ca2+the C-terminal tail of the PMCA interacts with the main body of the protein keeping it in an autoinhibited state. Local Ca2+ increase activates calmodulin that removes the C terminal tail from the inhibitory sites. Dysregulation of the Ca2+ signals are incompatible with healthy neuronal life. A number of genetic mutations of PMCA pumps are associated with pathological phenotypes, those of the neuron-specific PMCA 2 and PMCA 3 being the best characterized. PMCA 2 mutations are associated with deafness and PMCA 3 mutations are linked to cerebellar ataxias. Biochemical analysis of the mutated pumps overexpressed in model cells have revealed their decreased ability to export Ca2+. The defect in the bulk cytosolic Ca2+ homeostasis is minor, in keeping with the role of the PMCA pumps in the local control of Ca2+ in specialized plasma membrane microdomains. PMID- 29155351 TI - ERP responses greater for faces in the temporal compared to the nasal visual field. AB - The distribution of retino-tectal projections is dissimilar depending on whether the receptors are situated in the nasal and temporal visual hemiretinas. Indeed, it has been claimed that the superior colliculus receives a greater proportion of its input from the temporal visual hemifield (nasal hemi-retina) relative to the nasal hemifield (temporal hemi-retina). In order to investigate whether these subcortical projections influence face processing, we investigated the early cortical ERP responses to faces and houses presented in the temporal and nasal retinas using monocular viewing. Neutral or fearful faces were presented concurrently with houses on either side of a central fixation cross, while participants were asked to discriminate changes in luminance at the center. Results showed that the lateralized N170, computed as the contralateral ipsilateral electrode difference, was greater for faces appearing in the nasal relative to the temporal visual hemifield. This was due to a greater ipsilateral N170 for temporal relative to nasal presentations. By contrast, no difference was found across emotional expressions. The enhanced ERP response to faces appearing in the temporal visual field, suggests that the retinotectal pathway modulates cortical processing, most likely through activation of a colliculo-pulvino amygdalar pathway, with subsequent back-projections from the amygdala to visual cortical regions. However, unattended facial expressions do not seem to modulate the response, at least at these angles of eccentricity. PMID- 29155352 TI - Patient-Reported Outcomes Following Treatment of Chronic Hepatitis C Virus Infection With Sofosbuvir and Velpatasvir, With or Without Voxilaprevir. AB - BACKGROUND & AIMS: Chronic infection with hepatitis C virus (HCV) has many hepatic and extrahepatic manifestations, measured by patient-reported outcomes (PROs). We measured changes in PROs during HCV treatment with recently developed pangenotypic regimens and from a sustained virologic response 12 weeks after treatment ended (SVR12). METHODS: We collected PRO data from 2 multi-center, blinded, international phase 3 trials of sofosbuvir, velpatasvir, and voxilaprevir, from 748 patients previously treated with direct-acting antivirals for chronic infection with HCV of any genotype (59% HCV genotype 1, 43% with compensated cirrhosis) (POLARIS-1 and POLARIS-4). The combination of sofosbuvir, velpatasvir, and voxilaprevir was given to 445 patients, the combination of sofosbuvir and velpatasvir to 151 patients, and placebo to 152 patients. Patients completed the SF-36, FACIT-F, CLDQ-HCV, and WPAI:SHP questionnaires at baseline, during treatment, and during the follow-up period. RESULTS: There was no difference in baseline clinical or demographic features or PRO scores among the groups (all P > .05). The group that received the combination of sofosbuvir, velpatasvir, and voxilaprevir had more gastrointestinal symptoms than the groups that received sofosbuvir and velpatasvir or placebo (P = .0001). An SVR12 was achieved by 90.1% of patients who received sofosbuvir and velpatasvir vs 96.9% of patients who received sofosbuvir, velpatasvir, and voxilaprevir (P = .0008). After 12 weeks of treatment, some PRO scores improved in both treatment groups (by 2.5 or by 9.1 points, on a 0-100 scale; P < .05) but not in the placebo group. All increases in PRO scores were sustained or increased after treatment ended (an increase of up to 11.1 points at 12 weeks after treatment and an increase of up to 16.6 points at 24 weeks after treatment ended) (P < .05 for all but 2 PROs). There were no differences in PROs between the sofosbuvir and velpatasvir group vs the sofosbuvir, velpatasvir, and voxilaprevir group (all P > .05). In multivariate analysis, after adjustment for clinical and demographic factors and baseline PRO scores, receiving treatment was associated with higher PROs scores than receiving placebo (beta as high as 5.1) (P < .05). CONCLUSIONS: In an analysis of data from 2 phase 3 clinical trials of patients with chronic HCV infection of any genotype, we found the combination of sofosbuvir, velpatasvir, with or without voxilaprevir, to increase PRO scores compared with placebo. These findings indicate the comprehensive benefit of these regimens during treatment and after SVR. PMID- 29155353 TI - Advantages and Limitations of the Federal Adverse Events Reporting System in Assessing Adverse Event Reporting for Eluxadoline. PMID- 29155354 TI - Incidence of Gastric-to-Pulmonary Aspiration in Patients Undergoing Elective Upper Gastrointestinal Endoscopy. PMID- 29155355 TI - Molecular Ellipticity of Circulating Albumin-Bilirubin Complex Associates With Mortality in Patients With Severe Alcoholic Hepatitis. AB - BACKGROUND & AIMS: Hyperbilirubinemia and hypoalbuminemia are features of hepatic dysfunction that associate with disease severity. This is because hepatic insufficiency causes hypoalbuminemia, which indirectly increases the circulating levels of free bilirubin. Circular dichroism (CD) spectroscopy can be used to quantify the molecular ellipticity (ME) of the albumin-bilirubin complex, and might associate with the severity or outcome of severe alcoholic hepatitis (SAH). METHODS: We performed a cross-sectional study of 265 patients with SAH admitted in the Department of Hepatology, Institute of Liver and Biliary Sciences in New Delhi, India from January 2014 through January 2016. Blood samples were collected and patients were followed for 12 months or death. The molar ratios of bilirubin: albumin and albumin-bilirubin complexes were determined for a discovery cohort (30 patients who survived the study period and 60 patients who did not survive) and compared with those of 60 patients with alcoholic cirrhosis and 30 healthy individuals (controls). Optical activities of albumin-bilirubin complexes in blood samples were determined by CD spectroscopy and compared among groups. Findings were validated in a separate cohort of 150 patients with SAH from the same institute. We studied the correlation between ME and albumin binding capacity (ABiC). RESULTS: The molar ratio of bilirubin: albumin was higher in patients with SAH than with alcoholic cirrhosis or controls (P < .05). Patients with SAH had different CD spectra and higher ME than the other groups (P < .01); ME correlated with model for end-stage liver disease score (with and without Na) and discriminant function (r2 > .3; P < .01). ME values above a cut off of 1.84 mdeg predicted 3-month mortality in patients with SAH with an area under receiver operating characteristic curve of 0.87 (95% CI, 0.79-0.95), a 77% positive predictive value, and a 90% negative predictive value. The hazard ratio and concordance index of ME values for 3-month mortality in patients with SAH was 10% higher than the hazard ratio and concordance index of model for end-stage liver disease score. In patients with SAH, there was an inverse correlation between ME and ABiC (r2 > 0.7; P < .01). We observed a significant reduction in ABiC with increasing levels of bilirubin in vitro prepared albumin-bilirubin complex. CONCLUSION: In a cross-sectional study of patients with SAH, we associated ME of the albumin-bilirubin complex, measured by CD spectroscopy, with outcomes of patients with SAH. Increased loading of bilirubin on albumin could explain reduced albumin function. Bilirubin removal by albumin dialysis might benefit patients with SAH. PMID- 29155356 TI - Refined assessment and perspectives on the cumulative risk resulting from the dietary exposure to pesticide residues in the Danish population. AB - : Relatively few studies are available on realistic cumulative risk assessments for dietary pesticide exposure. Despite available studies showing low risk, public concern remains. A method to estimate realistic residue levels based on information from spraying journals and supervised residue trials was described in a previous publication. The present article proposes a new method to estimate average residue levels in imported foods based on residue monitoring data and knowledge about agronomic practices. The two methods were used in combination to estimate average pesticide residue levels in 47 commodities on the Danish market. The chronic consumer exposure was estimated in six Danish diets. The Hazard Index (HI) method was used to assess consumer risk. Despite the conservative (cautious) risk assessment approach, low HI values where obtained. The HI was 16% for adults and 44% for children, combining the risk of all pesticides in the diet. CONCLUSION: the present study adds support to the evidence showing that adverse health effects of chronic pesticide residue exposure in the Danish population are very unlikely. The HI for pesticides for a Danish adult was on level with that of alcohol for a person consuming the equivalent of 1 glass of wine every seventh year. PMID- 29155358 TI - Criticism of EFSA's scientific opinion on combinatorial effects of 'stacked' GM plants. AB - Recent genetically modified plants tend to include both insect resistance and herbicide tolerance traits. Some of these 'stacked' GM plants have multiple Cry toxins expressed as well as tolerance to several herbicides. This means that non target organisms in the environment (biodiversity) will be co-exposed to multiple stressors simultaneously. A similar co-exposure may happen to consumers through chemical residues in the food chain. EFSA, the responsible unit for minimizing risk of harm in European food chains, has expressed its scientific interest in combinatorial effects. However, when new data showed how two Cry-toxins acted in combination (added toxicity), and that the same Cry-toxins showed combinatorial effects when co-exposed with Roundup (Bohn et al., 2016), EFSA dismissed these new peer-reviewed results. In effect, EFSA claimed that combinatorial effects are not relevant for itself. EFSA was justifying this by referring to a policy question, and by making invalid assumptions, which could have been checked directly with the lead-author. With such approach, EFSA may miss the opportunity to improve its environmental and health risk assessment of toxins and pesticides in the food chain. Failure to follow its own published requests for combinatorial effects research, may also risk jeopardizing EFSA's scientific and public reputation. PMID- 29155357 TI - RIFM fragrance ingredient safety assessment, cyclohexanecarboxylic acid, 1,4 dimethyl-, methyl ester, trans- CAS Registry Number 23250-42-2. PMID- 29155360 TI - My syncopated heart: A patient's perspective. PMID- 29155359 TI - 4-Methylthio-3-butenyl isothiocyanate mediates nuclear factor (erythroid-derived 2)-like 2 activation by regulating reactive oxygen species production in human esophageal epithelial cells. AB - 4-Methylthio-3-butenyl isothiocyanate (MTBITC) extracted from daikon (Raphanus sativus), which shows antimutagenicity, may have applications as an effective chemopreventive agent in several cancers; however, few reports have described the associated mechanisms. We investigated whether MTBITC induced cytoprotective genes, including phase II enzymes, in Het-1A human esophageal epithelial cells. HMOX1, NQO1, and GCLC mRNA levels and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein levels were increased in Het-1A cells treated with 10 MUM MTBITC. Reactive oxygen species (ROS) tended to increase when Het-1A cells were treated with MTBITC, and the increases in ROS and Nrf2 expression in the cells treated with MTBITC were completely abolished by treatment with N-acetyl-l-cysteine. We also examined the relationships between Nrf2 activation and mitogen-activated protein kinase (MAPK) signaling by western blot analysis. MTBITC induced extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 phosphorylation in Het-1A cells; however, MTBITC did not affect the relationship between Nrf2 activation and MAPK responses. In the present study, we found that MTBITC induced Nrf2 activation and cytoprotective genes via ROS production in Het 1A cells. These results suggest that MTBITC may have the potential for preventing esophageal carcinogenesis through modification of carcinogen metabolism by phase II enzyme induction via ROS production. PMID- 29155361 TI - Silver-nanoparticles increase bactericidal activity and radical oxygen responses against bacterial pathogens in human osteoclasts. AB - Bone infections are difficult to treat and can lead to severe tissue destruction. Acute bone infections are usually caused by Staphylococcus aureus. Osteoclasts, which belong to the monocyte/macrophage lineage, are the key cells in bone infections. They are not well equipped for killing bacteria and may serve as a reservoir for bacterial pathogens. Silver has been known for centuries for its bactericidal activity. Here, we investigated the bactericidal effects of nano silver particles in bacteria infected human osteoclasts. We found that nano silver in per se non-toxic concentration enhanced the bactericidal activity in osteoclasts against intracellular Methicillin-resistant, virulent Staphylococcus aureus. The reduced bacterial survival in nano-silver pretreated cells correlated with increased reactive oxygen responses towards the invading pathogens. Overall, these results indicate that nano-silver compounds should be considered as an effective treatment and prevention option for bacterial bone and orthopedic implant infections. PMID- 29155362 TI - Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment. AB - Co-administration of functionally distinct anti-cancer agents has emerged as an efficient strategy in lung cancer treatment. However, a specially designed drug delivery system is required to co-encapsulate functionally different agents, such as a combination of siRNA and chemotherapy, for targeted delivery. We developed a folic acid (FA)-conjugated polyamidoamine dendrimer (Den)-based nanoparticle (NP) system for co-delivery of siRNA against HuR mRNA (HuR siRNA) and cis-diamine platinum (CDDP) to folate receptor-alpha (FRA) -overexpressing H1299 lung cancer cells. The co-delivery of HuR siRNA and CDDP using the FRA-targeted NP had a significantly greater therapeutic effect than did individual therapeutics. Further, the FRA-targeted NP exhibited improved cytotoxicity compared to non targeted NP against lung cancer cells. Finally, the NP showed negligible toxicity towards normal MRC9 lung fibroblast cells. Thus, the present study demonstrates FRA-targeted Den nanoparticle system as a suitable carrier for targeted co delivery of siRNA and chemotherapy agents in lung cancer cells. PMID- 29155363 TI - Homocysteine inhibits endothelial progenitor cells proliferation via DNMT1 mediated hypomethylation of Cyclin A. AB - Endothelial progenitor cells (EPCs) contribute to neovasculogenesis and reendothelialization of damaged blood vessels to maintain the endothelium. Dysfunction of EPCs is implicated in the pathogenesis of vascular injury induced by homocysteine (Hcy). We aimed to investigate the role of Cyclin A in Hcy induced EPCs dysfunction and explore its molecular mechanism. In this study, by treatment of EPCs with Hcy, we found that the expression of Cyclin A mRNA and protein were significantly downregulated in a dose-dependent manner. Knockdown of Cyclin A prominently reduced proliferation of EPCs, while over-expression of Cyclin A significantly promoted the cell proliferation, suggesting that Hcy inhibits EPCs proliferation through downregulation of Cyclin A expression. In addition, epigenetic study also demonstrated that Hcy induces DNA hypomethylation of the Cyclin A promoter in EPCs through downregulated expression of DNMT1. Moreover, we found that Hcy treatment of EPCs leads to increased SAM, SAH and MeCP2, while the ratio of SAM/SAH and MBD expression decrease. In summary, our results indicate that Hcy inhibits Cyclin A expression through hypomethylation of Cyclin A and thereby suppress EPCs proliferation. These findings demonstrate a novel mechanism of DNA methylation mediated by DNMT1 in prevention of Hcy associated cardiovascular disease. PMID- 29155364 TI - Knockdown of pyruvate kinase type M2 suppresses tumor survival and invasion in osteosarcoma cells both in vitro and in vivo. AB - Osteosarcoma (OS) is the mostly diagnosed primary bone malignancy. Emerging evidence indicates that the activity of pyruvate kinase M2 (PKM2) isoform is crucial for the survival of tumor cells. In the present study, the effect of PKM2 knockdown on the proliferation and migration of OS cells were assessed both in vitro and in vivo. Small hairpin RNA (shRNA) technology were employed to suppress the expression of PKM2 in MG-63 and Saos-2 cell lines. In vitro, shRNA-mediated knockdown of PKM2 efficiently inhibited cell proliferation, and induced G1 cell cycle arrest and apoptosis in both cell lines, which was associated with decreased expressions of cyclin D1 and Bcl-2 as well as increased expressions of Bax, cleaved-caspase-3, and cleaved-PARP. The invasion and migration potential of OS cell lines were also inhibited by PKM2 knockdown through the regulating effect of PKM2 on MMP-2 and VEGF signaling. In vivo, knockdown of PKM2 decelerated tumor growth rate and induced structure deterioration in tumor tissues. The current study for the first time showed that the activity of PKM2 was indispensable for the development and metastasis of OS, thereby providing the basic information for the future development of PKM2-based anti-OS therapies. PMID- 29155365 TI - Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors. AB - Disulfiram (DSF) in combination with copper (Cu) has been reported to override drug resistance in cancer cells, and DSF combined with chemotherapy based on the microtubule inhibitor vinorelbine appears to prolong survival in non-small cell lung cancer patients. Here, we investigated the mechanisms underlying these findings. DSF/Cu reversed the microtubule inhibitor resistance in A549/Taxol and KB/VCR cells in vitro, and had anti-tumor effects in A549/Taxol and KB/VCR xenograft mice. DSF/Cu and DSF reduced the cancer stem cell (CSC) characteristics of drug-resistant A549/Taxol and KB/VCR cells, including sphere formation, colony generation and migration, and DSF/Cu was more effective than DSF alone. DSF/Cu also decreased the aldehyde dehydrogenase (ALDH) activity and the expression of P gp and stem cell transcription factors in A549/Taxol and KB/VCR cells. Knockdown of ALDH2 attenuated the CSC characteristics of resistant cancer cells and enhanced their sensitivity to Taxol or VCR. Importantly, DSF/Cu treatment inhibited the expression of ALDH2 in vitro and in vivo. Our findings suggest that DSF/Cu reverses microtubule inhibitor resistance in cancer cells by suppressing ALDH2 expression, and Cu improves the activity of DSF. PMID- 29155366 TI - Applications of stimuli-responsive nanoscale drug delivery systems in translational research. AB - Nanoscale drug delivery systems or nanocarriers have shown tremendous promise in the target-specific delivery of therapeutics as well as diagnostic agents. Additional properties can be introduced into nanocarriers to enhance the bioavailability and targeting efficiency of the transported drugs at diseased sites. Such nanocarriers are usually incorporated with stimuli-responsive components that can be triggered by specific stimuli (e.g., temperature, pH, or enzymes) and further induced by certain biological responses, such as enzyme hydrolysis and molecular conformational changes, leading to the controlled release of the transported molecules at targeted sites. In this review, we discuss various stimuli-responsive nanoscale delivery systems and summarize the current perspectives as well as challenges facing the successful translation of these innovative stimuli-responsive nanocarriers from the bench to the bedside. PMID- 29155367 TI - Predicted indirectly recognizable HLA epitopes are not associated with clinical outcomes after haploidentical hematopoietic stem cell transplantation. AB - Haploidentical stem cell transplantation (haplo-SCT) provides an alternative method to cure patients with malignant and nonmalignant hematologic diseases who lack a human leukocyte antigen (HLA) matched related or unrelated donor. HLA disparity between donor and patient was the main reason causing lots of clinical immune response. The aim of this study was to investigate whether indirect recognition of mismatched HLA could predict the clinical outcomes in haplo-SCT. The probability of indirect recognition was predicted by the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) model. 577 patients with acute leukemia or myelodysplastic syndrome receiving haplo-SCT were enrolled in the study. Patients were divided into 4 quartiles according to PIRCHE-I or PIRCHE-II. Although the cumulative incidences of chronic graft-versus-host disease (GVHD) were significantly different among the 4 PIRCHE-Igroups, with 20.4% for group 0-6, 40.5% for group >6-11, 26.1% for group >11-19 and 23.9% for group >19 (P = .007), PIRCHE-I was not significantly associated with chronic GVHD in multivariate models (RR, 0.993; 95% CI, 0.858-1.149; P = .926). And no significant associations were observed between PIRCHE-I or PIRCHE-II and other clinical outcomes. In summary, PIRCHE did not correlate with clinical outcomes and could not predict haplo-SCT outcomes. PMID- 29155369 TI - Virtual Rehabilitation with Children: Challenges for Clinical Adoption [From the Field]. AB - Virtual, augmented, and mixed reality environments are increasingly being developed and used to address functional rehabilitation goals related to physical, cognitive, social, and psychological impairments. For example, a child with an acquired brain injury may participate in virtual rehabilitation to address impairments in balance, attention, turn taking, and engagement in therapy. The trend toward virtual rehabilitation first gained momentum with the adoption of commercial off-the-shelf active video gaming consoles (e.g., Nintendo Wii and XBox). Now, we are seeing the rapid emergence of customized rehabilitation-specific systems that integrate technological advances in virtual reality, visual effects, motion tracking, physiological monitoring, and robotics. PMID- 29155368 TI - Urinary 11-dehydro-thromboxane B2 levels are associated with vascular inflammation and prognosis in atherosclerotic cardiovascular disease. AB - Cyclooxygenase-derived thromboxane (TxA2) and prostacyclin (PGI2) regulate atherogenesis in preclinical models. However, the relationship between TxA2 and PGI2 biosynthesis, vascular inflammation, and atherosclerotic cardiovascular disease (ASCVD) progression in humans remains unclear. The association between stable urine metabolites of thromboxane (TxA2-M) and prostacyclin (PGI2-M), circulating levels of cellular adhesion molecules (CAMs: E-selectin, P-selectin), chemokines and C-reactive protein, and the incidence of major adverse cardiovascular events (MACE) were evaluated in 120 patients with stable ASCVD on aspirin therapy. Urinary TxA2-M levels were significantly correlated with circulating P-selectin (r=0.319, p<0.001) and E-selectin (r=0.245, p=0.007) levels, and associated with higher risk of MACE (p=0.043). In contrast, PGI2-M levels were not significantly associated with CAM levels or MACE. These results provide insight into the contribution of TxA2 biosynthesis to ASCVD progression in humans, and suggest that patients with elevated TxA2-M levels may be predisposed to advanced platelet and endothelial activation and higher risk of adverse cardiovascular outcomes. PMID- 29155370 TI - Sharing Data to Solve the Autism Riddle: An Interview with Adriana Di Martino and Michael Milham of ABIDE. AB - Worldwide, at least one in 100 people has autism spectrum disorder (ASD). In the United States, the Centers for Disease Control and Prevention put the number at one in 68 [1]. Despite this high rate of prevalence and the increased public awareness of autism in recent years, the underlying mechanisms of ASD still remain unclarified. PMID- 29155371 TI - What?s Happening to Your DNA Data?: Genetic Testing Services Abound, but Consumers Opting to Use Them Should Be Aware of the Pitfalls. AB - Over the last decade, technology advances in the field of genetics have led to cheaper and more accurate testing. Public interest in personal genetics has grown thanks to media coverage and high-profile stories, such as actress Angelina Jolie's decision to undergo a double mastectomy as a preventative measure against breast cancer when she learned she carries the BRCA1 mutation (relating to breast cancer type 1 susceptibility). PMID- 29155372 TI - Gut Feeling: Researchers Are Discovering a Link Between Depression and Gut Bacteria. AB - The human gut is home to an abundant and diverse community of microbes–each of us carries roughly 100 trillion, representing more than 1,000 different species. The composition of one?s gut microbiota is individually specific, dynamic, and influenced by genetics, diet, age, metabolism, medication use, stress, and geography. These bacteria perform a range of necessary and beneficial functions, including breaking down our food and supporting our immune systems. PMID- 29155373 TI - Imaging Depression: New Biological Markers May Mean More Targeted Treatments are Just over the Horizon. AB - On a balmy evening in mid-May 2017, Chris Cornell, the legendary head of the internationally renowned rock band Soundgarden, strummed his last chord at the Fox Theater in Detroit and headed to the MGM Grand Hotel. According to the police report, he swallowed a few tablets of the antidepression drug Ativan in his room and called his wife. "I'm just tired," he said and hung up the phone. Later that night, at the request of his concerned wife, his bodyguard forced open Cornell's door to discover him on the bathroom floor, an exercise band tied around his neck. His death was ruled a suicide by hanging, the conclusion of a life riddled with drug abuse and a depression he'd never managed to shake. PMID- 29155374 TI - Testing the Waters: From Moringa Seeds to Fruit Peels, Researchers Are Seeking Out New Ways to Clean Up the World?s Drinking Water. AB - Water on Earth-in our oceans, rivers, lakes, and wetlands-might seem plentiful, but water that is clean and safe enough to drink actually isn't so abundant. Nearly one in ten people still lacks access to safe water worldwide, according to the World Health Organization. In some of the world's most remote and impoverished communities, people live with no taps, showers, flushing toilets, or nearby springs, making it difficult to keep water supplies safe from bacteria, chemicals, and particulates. Moreover, access to clean drinking water isn't just a problem in the developing world; groundwater in developed countries is typically used far more quickly than it is being replenished. As the world population rises, growing numbers of thirsty people could exacerbate already scant resources. PMID- 29155375 TI - ARMI Tackles Regenerative Medicine: A New Initiative is Bringing Industrial-Scale Engineering Approaches to the Biomedical World. AB - Pulmonary arterial hypertension is a rare and potentially life-threatening disorder. But when prominent entrepreneur Martine Rothblatt (Figure 1), founder of Sirius radio, learned in the 1990s that her daughter had been diagnosed with this little-known condition and given only three months to live, she refused to accept that grim prognosis. Instead, Rothblatt transformed her life. PMID- 29155376 TI - Smartphone Apps Meet Evidence-Based Medicine: The Future of Medicine May (Or May Not) Be in Your Smartphone. AB - "The future of medicine is in your smartphone," proclaimed an eminent medical researcher in a 2015 Wall Street Journal essay. In a sense, that future has already arrived, judging from the proliferation of apps and medical devices now connected to smartphones. One 2015 industry study identified more than 165,000 health-related smartphone apps available from the Google Play Store and Apple iTunes. But to what extent does this technology lead to improved patient outcomes? That question is one for evidence-based medicine, to be answered by clinical trials and systematic reviews by medical experts. PMID- 29155377 TI - New Forensics Methods Looking More Like CSI: Rapid DNA Analysis, Proteomics, and New Technology Increasingly Impact Forensics Investigations. AB - If CSI and those other police procedural TV shows are to be believed, criminals don't have a chance. A finger smudge on a light switch, a flake of skin, or a sweat-stained fiber is all the information an investigator needs to positively identify the perpetrator and put him or her behind bars. PMID- 29155378 TI - 50 Years to Gender Parity: Can STEM Afford to Wait?: A Cardiologist and NIH Chief Officer of Scientific Workforce Diversity Reflects on What It Will Take to Keep Women in Biomedicine. AB - The first spark of my desire to become a cardiologist came, believe it or not, in a third-grade art class where I was asked to draw and color the circulation of blood as depicted by 16th-century English physician William Harvey. This task enraptured me-seeing that something so beautiful could work so flawlessly. So, many years later, I remain intrigued by cardiac transplantation, the subspecialty in which I ultimately chose to anchor my career as a physician scientist. Each day I live in awe of the fact that you can remove someone's organ, place it in another, and still have that organ work beautifully, most of the time. But why does it sometimes fail? PMID- 29155379 TI - Women Break an Engineering Barrier: While Other Engineering Disciplines Stumble, BME Represents a Success Story in Attracting American Women to a Male-Dominated Field. AB - While the field of engineering as a whole is largely male-dominated, biomedical engineering (BME) is one area poised to overturn this trend. Women in the United States were awarded only 20% of all engineering B.S. degrees in 2015; in BME, however, 40.9% of the degree recipients were women. This stands in stark contrast to the more traditional fields of mechanical and electrical engineering, where women were awarded just 13.2% and 12.5% of B.S. degrees, respectively. This trend toward more female participation in BME continues at both the M.S. and Ph.D. degree levels. In fact, in 2015, BME had the highest percentage of female engineering M.S. degree recipients in the United States of all engineering disciplines, according to the American Society for Engineering Education (Figure 1). PMID- 29155380 TI - Making Clothing Smarter: Rita Paradiso of Smartex is Engineering Clothes That Can Monitor a Wearer?s Condition. AB - As bedtime approaches, take note! Your pajamas may have something important to tell you. PMID- 29155381 TI - Sinoatrial and Atrioventricular Blocks: Who First Described Them and How? [Retrospectroscope]. AB - The relationship among cardiac pacemakers is characterized by the fact that one pacemaker is usually dominant and all the others are subsidiary. The sinoatrial node acts as the dominant pacemaker, and all other potential pacemaker tissues are discharged by a conducted impulse before their respective diastolic depolarizations attain threshold. These pacemakers are called subsidiary to emphasize the fact that, under normal circumstances, they are engaged in conducting impulses, but, under abnormal circumstances, they may become actual pacemakers. PMID- 29155382 TI - Very late scaffold thrombosis: insights from optical coherence tomography and histopathology. PMID- 29155383 TI - Efficacy of Optical Coherence Tomography-derived Morphometric Assessment in Predicting the Physiological Significance of Coronary Stenosis: Head-to-Head Comparison with Intravascular Ultrasound. AB - AIMS: This study aimed to investigate the diagnostic efficacy of optical coherence tomography (OCT) in identifying functional significance via fractional flow reserve (FFR) compared with that of intravascular ultrasound (IVUS). METHODS AND RESULTS: We investigated 203 de novo intermediate coronary lesions of 186 patients who underwent frequency-domain OCT, IVUS and FFR measurements. Diagnostic efficacy of the minimal lumen area (MLA) obtained by OCT (OCT-MLA) and IVUS (IVUS-MLA) in predicting an FFR <0.75 was evaluated. Receiver operating characteristic curve analysis showed that OCT-MLA had significantly better diagnostic efficacy than IVUS-MLA in identifying functional ischaemia. OCT analysis revealed that the incidence of false positives (OCT-MLA <=1.39 mm2 and FFR >=0.75) was 46% (41/90), whereas the incidence of false negatives (OCT-MLA >1.39 mm2 and FFR <0.75) was 19% (22/113). Multivariate analysis showed that older age, non-left anterior descending artery and smaller angiographic reference diameter were independent predictors of false-positive results using the OCT-MLA criteria, whereas younger age and low left ventricular ejection fraction were independent predictors of false-negative results. CONCLUSIONS: Intravascular imaging is not interchangeable with FFR in clinical decision making. However, OCT may have superior efficacy to IVUS in detecting functional ischaemia. Discrepancies between OCT-MLA and FFR should be taken into account for OCT-guided decision making. PMID- 29155384 TI - First serial optical coherence tomography assessment at baseline, 12 and 24 months in STEMI patients treated with the second-generation Absorb bioresorbable vascular scaffold. AB - AIMS: The aim of the study was to assess the vascular healing response after Absorb bioresorbable vascular scaffold (BVS) implantation in patients with ST segment elevation myocardial infarction (STEMI) utilising truly serial optical coherence tomography (OCT) examination at baseline, 12 and 24 months. METHODS AND RESULTS: This was a single-centre, prospective, longitudinal study with baseline, 12- and 24-month OCT evaluation of 18 STEMI patients treated with 22 Absorb BVS. The healing pattern was evaluated based upon lumen area, neointimal hyperplasia, strut coverage and apposition. The lumen area decreased at 12 months compared to baseline (8.52+/-1.69 mm2 vs. 7.0+/-1.70 mm2, p<0.01), but it did not change from that point onwards up to 24 months (7.0+/-1.70 mm2 vs. 6.94+/-1.65 mm2, p=0.92). At 12 months after the index procedure, the mean neointimal thickness was 217+/ 69 MUm and further neointimal hyperplasia was observed between 12 and 24 months though less pronounced (Delta62+/-44 MUm, p<0.0001). Full circumferential coverage of the vessel wall by neointima was observed in 92% of frames at 24 months. The low number of malapposed struts at the index procedure (<5%) further decreased over the observation period and was found in only one patient at 12 and 24 months. The ratio of uncovered struts was low at both 12 and 24 months. CONCLUSIONS: This serial OCT analysis of the second-generation everolimus-eluting BVS in a STEMI population confirmed a favourable healing pattern as expressed by moderate neointimal growth, preserved lumen area and no late acquired malapposition. PMID- 29155385 TI - Local low-dose urokinase thrombolysis for the management of haemodynamically stable pulmonary embolism with right ventricular dysfunction. AB - AIMS: The aim of this study was to evaluate the effectiveness of local low-dose urokinase thrombolysis (LLDUT) in haemodynamically stable pulmonary embolism with right ventricular dysfunction (RVD). METHODS AND RESULTS: This was a prospective study. LLDUT with a 200,000 IU bolus followed by a 100,000 IU/hr infusion was given. Treatment duration was determined through radiological control performed 48-72 hrs into treatment. A follow-up echocardiogram was performed within seven days after LLDUT completion. Evolution of thrombus burden, pulmonary artery pressures (PAP) and RVD were studied, and haemorrhagic complications and mortality were recorded. Eighty-seven patients were included (62.5+/-16.5 years). In 67 patients (77%), the baseline echocardiogram showed mild-to-severe RVD, a dilated right ventricle (diameter: 44.4+/-6.2 mm) and a decreased tricuspid annular plane systolic excursion (14 mm [12-17]). Seventy-six patients (87.4%) experienced radiological improvement. Initially high PAP (mmHg) decreased after LLDUT: systolic 52.4 vs. 35.2 (17.2 [95% CI: 14.5-19.9]; p<0.0001), mean 34.2 vs. 23.5 (10.7 [95% CI: 9.0-12.5]; p<0.0001) and diastolic 23.9 vs. 16.0 (7.9 [95% CI: 6.1-9.7]; p<0.0001). Follow-up echocardiography showed overall improvement of RVD. No life-threatening haemorrhagic complications were reported. Six-month survival was 96.5%. CONCLUSIONS: LLDUT rapidly decreased thrombus burden and PAP, improving right ventricular function, and was not associated with any life threatening complications or pulmonary embolism (PE)- or treatment-related mortality. PMID- 29155386 TI - One-year clinical outcome of early administration of intravenous beta-blockers in patients with ST-segment elevation myocardial infarction before primary percutaneous coronary reperfusion. PMID- 29155387 TI - The impact of chronic kidney disease on outcomes following percutaneous coronary intervention versus coronary artery bypass grafting in patients with complex coronary artery disease: five-year follow-up of the SYNTAX trial. AB - AIMS: The aim of this study was to investigate short-term and five-year follow-up results from patients randomised to coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) with paclitaxel-eluting stents in the SYNTAX trial, focusing on patients with chronic kidney disease (CKD). METHODS AND RESULTS: Baseline glomerular filtration rate estimates (eGFR) were available in 1,638 patients (PCI=852 and CABG=786). The Kidney Disease: Improving Global Outcomes (KDIGO) threshold was used to define staging of CKD. At five years, death was significantly higher in patients with CKD compared to patients with normal kidney function after PCI (26.7% vs. 10.8%, p<0.001) and CABG (21.2% vs. 10.6%, p=0.005). Comparing PCI with CABG, there was a significant interaction according to kidney function for death (pint=0.017) but not the composite endpoint of death/stroke/MI (pint=0.070) or MACCE (pint=0.15). In patients with CKD, the rate of MACCE was significantly higher after PCI compared with CABG (42.1% vs. 31.5%, p=0.019), driven by repeat revascularisation (21.9% vs. 8.9%, p=0.004) and all-cause death (26.7% vs. 21.2%, p=0.14). In patients with CKD who also had diabetes, PCI versus CABG was significantly worse in terms of death/stroke/MI (47.9% vs. 24.4%, p=0.005) and all-cause death (40.9% vs. 17.7%, p=0.004). CONCLUSIONS: During a five-year follow-up, adverse event rates were comparable between PCI and CABG patients with moderate CKD but significantly higher compared to the patients with impaired or normal kidney function. The negative impact of CKD on long-term outcome following PCI appears to be stronger when compared to CABG, especially in the CKD patients with diabetes and extensive coronary disease. PMID- 29155388 TI - Polyelectrolyte multilayers for bio-applications: recent advancements. AB - The synergistic relationship between structure and the bulk properties of polyelectrolyte multilayer (PEM) films has generated tremendous interest in their application for loading and release of bioactive species. Layer-by-layer assembly is the simplest, cost effective process for fabrication of such PEMs films, leading to one of the most widely accepted platforms for incorporating biological molecules with nanometre precision. The bulk reservoir properties of PEM films render them a potential candidate for applications such as biosensing, drug delivery and tissue engineering. Various biomolecules such as proteins, DNA, RNA or other desired molecules can be incorporated into the PEM stack via electrostatic interactions and various other secondary interactions such as hydrophobic interactions. The location and availability of the biological molecules within the PEM stack mediates its applicability in various fields of biomedical engineering such as programmed drug delivery. The development of advanced technologies for biomedical applications using PEM films has seen rapid progress recently. This review briefly summarises the recent successes of PEM being utilised for diverse bio-applications. PMID- 29155389 TI - Effect of the polyelectrolyte coating on the photothermal efficiency of gold nanorods and the photothermal induced cancer cell damage. AB - Coating gold nanorods (GNRs) with polyelectrolytes is an effective approach to make them biocompatible for potential use in photothermal treatment (PTT) of cancer. The authors report the effect of coating of the GNRs with polystyrene sulphonate (PSS-GNRs) and PSS plus poly di-allyl di-methyl ammonium chloride (PDDAC-GNRs) on its photothermal conversion efficiency (PTE), cellular uptake and subsequently the photothermal induced cytotoxicity in human oral cancer cells (NT8e). Coating of GNRs with PSS led to decrease in PTE by ~30% and further coating it with PDDAC led to its increase to similar level, with respect to as- prepared GNRs. The cellular uptake of PDDAC-GNRs in cancer cells was double than that for PSS-GNRs. PTT of cancer cells after treatment with 60 pM of either PDDAC GNRs or PSS-GNRs resulted in cytotoxicty of ~90%. At higher concentration of 120 pM, while PSS-GNRs showed no further change, for PDDAC-GNR the photothermal induced cytotoxicity decreased to ~50%. The broadening of longitudinal surface plasmon peak of PDDAC-GNRs and appearance of dark clusters in cells under bright field microscope suggested intracellular clustering of PDDAC-GNRs. In conclusion, despite high PTE and cellular uptake of PDDAC-GNRs, its intracellular clustering (due to acidic pH ) adversely affect the PTT of cancer cells. PMID- 29155390 TI - Biosynthesised silver and copper nanoformulation as foliar spray to control bird's eye spot disease in tea plantations. AB - Tea leaves have economic importance in preparation of the popular beverage of the world "tea". Bird's eye spot disease of tea leaves creates significant revenue loss in tea trade of many tea plant cultivating countries. Management of this disease by silver (AgNps) and copper (CuNps) nanoparticles that are biosynthesised by efficient antagonists was studied. The biocontrol agents like Pseudomonas fluorescens, Trichoderma atroviride and Streptomyces sannanensis were evaluated for nanoparticle synthesis against Cercospora theae isolates namely KC10, MC24 and VC38. Initially, the freshly prepared extracellular AgNps showed high disease control (59.42 - 79.76%), but the stability of antagonistic property in stored nanoparticles were significantly high in CuNps (58.71 - 73.81%). Greenhouse studies on various treatments imposed also showed reduced disease incidence percentage of 13.4, 7.57 and 10.11% when treated with CuNps synthesized by P. fluorescens, T. atroviride and S. sannanensis respectively. Various treatment schedule in fields suggested the use of Bionanocopper@1.5 ppm for highest yield (3743 kg/ha) with 66.1% disease prevention. The results suggest the use of biosynthesised CuNps using Streptomyces sannanensis for controlling the tea plant pathogens causing foliar disease with higher stability in releasing the antagonistic activity during sporadic disease incidence of bird's eye spot disease in tea plants. PMID- 29155391 TI - Facile synthesis of reduced graphene oxide/trimethyl chlorosilane-coated cellulose nanofibres aerogel for oil absorption. AB - A hydrophobic and oleophilic trimethyl chlorosilane/reduced graphene oxide-coated cellulose nanofibres (TMCS/rGO/CNFs) aerogel with a three-dimensional structure was fabricated through a facile dip-coating process. The prepared aerogel exhibited several advantageous properties for absorption and expulsion of oils from water surfaces, such as a high specific surface area, low density (6.78 mg/cm3) and good porosity (99.12%). In addition, the TMCS/rGO/CNFs aerogel demonstrated good absorption capacities up to 39 times its own weight over a short time (1.5 min) for a broad range of oils. This research suggests that practical application of TMCS/rGO/CNFs aerogel in the cleanup of an oil spill is feasible. PMID- 29155392 TI - Green synthesised zinc oxide nanostructures through Periploca aphylla extract shows tremendous antibacterial potential against multidrug resistant pathogens. AB - To grapple with multidrug resistant bacterial infections, implementations of antibacterial nanomedicines have gained prime attention of the researchers across the globe. Nowadays, zinc oxide (ZnO) at nano-scale has emerged as a promising antibacterial therapeutic agent. Keeping this in view, ZnO nanostructures (ZnO NS) have been synthesised through reduction by P. aphylla aqueous extract without the utilisation of any acid or base. Structural examinations via scanning electron microscopy (SEM) and X-ray diffraction have revealed pure phase morphology with highly homogenised average particle size of 18 nm. SEM findings were further supplemented by transmission electron microscopy examinations. The characteristic Zn-O peak has been observed around 363 nm using ultra-violet visible spectroscopy. Fourier-transform infrared spectroscopy examination has also confirmed the formation of ZnO-NS through detection of Zn-O bond vibration frequencies. To check the superior antibacterial activity of ZnO-NS, the authors' team has performed disc diffusion assay and colony forming unit testing against multidrug resistant E. coli, S. marcescens and E. cloacae. Furthermore, protein kinase inhibition assay and cytotoxicity examinations have revealed that green fabricated ZnO-NS are non-hazardous, economical, environmental friendly and possess tremendous potential to treat lethal infections caused by multidrug resistant pathogens. PMID- 29155393 TI - Enhanced antibacterial effect of azlocillin in conjugation with silver nanoparticles against Pseudomonas aeruginosa. AB - In recent years, the problems associated with bacterial resistance to antibiotics caused nanodrugs to be considered as a new way for infectious diseases treatment. The main purpose of this study was to develop a new agent against Pseudomonas aeruginosa, a very difficult bacterium to treat, based on azlocillin antibiotic and silver nanoparticles (AgNPs). Azlocillin was conjugated with AgNPs by chemical methods and its antimicrobial activity was studied against P. aeruginosa using well diffusion agar method. Then, minimum inhibitory concentration and minimum bactericidal concentration of the new conjugate was specified with macro dilution method. The animal study showed the considerable enhanced antibacterial effect of azlocillin in conjugation with AgNPs against P. aeruginosa in comparison with azlocillin alone, AgNPs alone and azlocillin in combination with AgNPs. PMID- 29155394 TI - Label-free and dynamic monitoring of cytotoxicity to the blood-brain barrier cells treated with nanometre copper oxide. AB - A cytotoxicity study was conducted with a primary culture of the nervous system cells, including brain microvascular endothelial cells (BMECs) and astrocytes, which are important components of the blood-brain barrier. The real-time cell analysis (RTCA) was used to determine the cytotoxicity of copper-oxide nanoparticles (CuO NPs). The IC50 values of CuO NPs in astrocytes and BMECs were determined by the RTCA at different exposure times and were used as base values for further research. DNA damage after exposure to CuO NPs for 3 and 24 h was assessed using comet assay at the IC50 obtained from RTCA. The onset time of cytotoxicity induced by CuO NPs was 2 and 2-4 h post-exposure in BMECs and astrocytes, respectively. Furthermore, the degree of cytotoxicity induced by exposure to CuO NPs for 24-48 h in the BMECs and astrocytes was similar. Treatment with CuO NPs at 1/2*IC50 and 1/5*IC50 for 3 h induced genotoxicity in both cells as assessed by a measurement of DNA damage, although no cytotoxicity was observed. However, significant DNA damage was observed at all concentrations of CuO NPs used in this study, when the treatment time was 24 h. PMID- 29155395 TI - Porcine skin gelatin-silver nanocomposites: synthesis, characterisation, cell cytotoxicity, and antibacterial properties. AB - Silver nanoparticles (AgNPs) were synthesised with hydrothermal autoclaving technique by using AgNO3 salt (silver precursor) at different concentrations (0.01, 0.1, 0.55, 1.1, 5.5, and 11 mM) and porcine skin (1% (w/v) ) gelatin polymeric matrix (reducing and stabiliser agent). The reaction was performed in an autoclave at 103 kPa and 121 degrees C and the hydrothermal autoclaving exposure time and AgNO3 molar concentration were varied at a constant porcine skin gelatin concentration. The as-prepared AgNPs were characterised by UV visible spectroscopy, transmission electron microscopy, and Fourier transform infrared spectroscopy. The antibacterial properties of AgNPs were tested against gram-positive and gram-negative bacteria. Furthermore, 3-(4,5-dimethylthiazol-2 yl) 2,5-diphenyltetrazolium bromide and 2,2-diphenyl-1-picrylhydrazyl assays were used to test whether the synthesised AgNPs can be potentially applied in cancer therapy or used as an antioxidant. This approach is a promising simple route for synthesising AgNPs with a smaller average particle 10 nm diameter. Furthermore, AgNPs exhibited a good cytotoxicity activity, reducing the viability of the liver cancer cell line HepG2 with a moderate IC50; they also showed a low-to-fair antioxidant activity. In addition, AgNPs had a remarkable preferential antibacterial activity against gram-positive bacteria than gram-negative bacteria. Therefore, these fabricated AgNPs can be used as an antibacterial agent in curative and preventive health care. PMID- 29155397 TI - Facile phyto-mediated synthesis of silver nanoparticles using Chinese winter jujube (Ziziphus jujuba Mill. cv. Dongzao) extract and their antibacterial/catalytic properties. AB - The aqueous extract of Chinese winter jujube (Ziziphus jujuba Mill. cv. Dongzao) was used as reducing and capping agents for the synthesis of silver nanoparticles (AgNPs) for the first time. The resulting AgNPs were characterised by UV/Visible (UV-Vis) spectroscopy, atomic force microscope, transmission electron microscopy, selected area electron diffraction, X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray and Fourier transform infrared spectroscopy (FTIR). The colloidal solution of AgNPs gave a maximum UV-Vis absorbance at 446 nm. The synthesised nanoparticles were almost in the spherical shapes with an average size of 11.5 +/- 4. 8 nm. FTIR spectra were applied to identify the functional groups which were possibly responsible for the conversion of metal ions into nanoparticles. The results showed that the prepared AgNPs were coated with the biomolecules in the extract. The biosynthesised AgNPs showed a remarkable catalytic activity at room temperature, and they also showed good antibacterial properties against Escherichia coli and Staphylococcus aureus. PMID- 29155396 TI - Biomimetic synthesis of silver nanoparticles from Streptomyces atrovirens and their potential anticancer activity against human breast cancer cells. AB - Silver nanoparticles (AgNPs) have been undeniable for its antimicrobial activity while its antitumour potential is still limited. Therefore, the present study focused on determining cytotoxic effects of AgNPs on Michigan cancer foundation-7 (MCF-7) breast cancer cells and its corresponding mechanism of cell death. Herein, the authors developed a bio-reduction method for AgNPs synthesis using actinomycetes isolated from marine soil sample. The isolated strain was identified by 16s ribotyping method and it was found to be Streptomyces atrovirens. Furthermore, the synthesised AgNPs were characterised by various bio analytical techniques such as ultraviolet-visible spectrophotometer, atomic force microscopy, transmission electron microscopy, Fourier transform infra-red spectroscopy, and X-ray diffraction. Moreover, the results of 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay reveals 44.51 ug of AgNPs to have profound inhibition of cancer cell growth; furthermore, the inhibition of MCF-7 breast cancer cell line was found to be dose dependent on treatment with AgNPs. Acridine orange and ethidium bromide double staining methods were performed for cell morphological analysis. The present results showed that biosynthesised AgNPs might be emerging alternative biomaterials for human breast cancer therapy. PMID- 29155398 TI - Investigation of graphene-on-metal substrates for SPR-based sensor using finite difference time domain. AB - In this study, the authors investigated the effects of a single layer graphene as a coating layer on top of metal thin films such as silver, gold, aluminum and copper using finite-difference time domain method. To enhance the resolution of surface plasmon resonance (SPR) sensor, it is necessary to increase the SPR reflectivity and decrease the full-width-half maximum (FWHM) of the SPR curve so that there is minimum uncertainty in the determination of the resonance dip. Numerical data was verified with analytical and experimental data where all the data were in good agreement with resonance angle differing in <10% due to noise present in components such as humidity and temperature. In further analysis, reflectivity and FWHM were compared among four types of metal with various thin film thicknesses where graphene was applied on top of the metal layers, and data was compared against pure conventional metal thin films. A 60 nm-thick Au thin film results in higher performance with reflectivity of 92.4% and FWHM of 0.88 degrees whereas single layer graphene-on-60 nm-thick Au gave reflectivity of 91.7% and FWHM of 1.32 degrees . However, a graphene-on-40 nm-thick Ag also gave good performance with narrower FWHM of 0.88 degrees and reflection spectra of 89.2%. PMID- 29155399 TI - Green synthesis of anisotropic gold nanoparticles using hordenine and their antibiofilm efficacy against Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a notorious pathogen that causes biofilm aided infections in patients with cystic fibrosis and burn wounds, resulting in significant mortality in immunocompromised individuals. This study reports a novel one-step biosynthesis of gold nanoparticles using phytocompound, hordenine (HD), as a reducing and capping agent. The synthesis of the anisotropic hordenine fabricated gold nanoparticles (HD-AuNPs) with an average particle size of 136.87 nm was achieved within 12 h of incubation at room temperature. Both HD and HD AuNPs exhibited significant antibiofilm activity against P. aeruginosa PAO1, although greater biofilm inhibition was observed for the nanoparticles as compared to hordenine alone. In the microtitre plate assay and tube method, the nanoparticles significantly inhibited the biofilm formation by 73.69 and 78.41%, respectively. The exopolysaccharide production by the test pathogen was arrested by 68.46% on treatment with the nanoparticles. Further, the effect of HD and HD AuNPs on the biofilm architecture of P. aeruginosa was revealed by light and confocal laser-scanning microscopy micrographs. The overall results of this study suggested the synergistic antibiofilm effect of AuNPs and HD for the treatment of chronic bacterial infections caused by biofilms forming pathogens. PMID- 29155400 TI - Co-condensation synthesis of well-defined mesoporous silica nanoparticles: effect of surface chemical modification on plasmid DNA condensation and transfection. AB - Chemically modified mesoporous silica nanoparticles (MSNs) are of interest due to their chemical and thermal stability with adjustable morphology and porosity; therefore, it was aimed to develop and compare the MCM-41 MSNs functionalised with imidazole groups (MCM-41-Im) to unmodified (MCM-41-OH) and primary amine functionalised (MCM-41-NH2) MSNs for experimental gene delivery. The results show efficient transfection of the complexes of the plasmid and either MCM-41-NH2 or MCM-41-Im. Furthermore, following transfection of HeLa cells using MCM-41-Im, an enhanced GFP expression was achieved consistent with the noticeable DNase1 protection and endosomal escape properties of MCM-41-Im using carboxyfluorescein tracer. PMID- 29155401 TI - Reconstructing phylogenetic tree using a protein-protein interaction technique. AB - In this study, a novel substitution method for finding potential protein-protein interactions (PPIs) has been discussed. This newly designed method for analyzing PPI also aids in the comparison of evolutionary distances. The method deals with various data sets, and additionally performs measurable assessment to determine PPIs is introduced. PPIs are biologically relevant and aid in better conceptual framework of phylogenetic profiling. The newly designed framework gives vision to relate the topological properties of the system with evolutionary behavior of datasets. Firstly, this study found that the most conserved protein motifs exist at the roots of the system, whereas newer motifs with mutations have a tendency to dwell on the branches. In-depth functional analysis revealed that the most conserved motifs have high specificity for improved structural procedures and pathway engagements, which may help identify their formative parts in cells. In conclusion, this study demonstrates several important aspects for future studies focusing to enhance phylogenetic profiling systems. This study can also be used effectively to utilize such strategies to develop new biological insights which will further lead to understanding of disease mechanisms. PMID- 29155402 TI - Synthesis of silver nanoparticles from a Desmodium adscendens extract and its antibacterial evaluation on wound dressing material. AB - The one-pot synthesis of silver nanoparticles (AgNPs) using the medium-polar extract of Desmodium adscendens (Sw.) DC. is presented here as an alternative synthesis of metal NPs. Characterisation of the formed NPs showed polydispersed AgNPs ranging from 15 to 100 nm where the concentration of metal ions was found to play a role in the size and shape of the prepared NPs. It could be established that the flavonoids, saponins, and alkaloids present in the extract acted as both reducing and stabilising agents during the formation of the capped metal NPs. This means of NP synthesis was also employed during the in situ immobilisation of AgNPs on gauze and plaster. An evaluation of the antibacterial activity of the medium-polar D. adscendens extract, AgNPs suspended in solution, and the immobilised AgNPs against Staphylococcus aureus (ATCC 25923), Bacillus cereus (ATCC 11778), and Escherichia coli (ATCC 25922) showed high efficacy against the latter in particular. This suggests that gauze, dilute silver nitrate solutions, and D. adscendens extract could be used successfully in the simple in situ preparation of effective antibacterial wound dressings. PMID- 29155403 TI - Phyto-assisted synthesis of bio-functionalised silver nanoparticles and their potential anti-oxidant, anti-microbial and wound healing activities. AB - Bio- synthesis of silver nanoparticles (AgNPs) was made by using the aqueous leaf extract of Ardisia solanacea. Rapid formation of AgNPs was observed from silver nitrate upon treatment with the aqueous extract of A. solanacea leaf. The formation and stability of the AgNPs in the colloidal solution were monitored by UV-visible spectrophotometer. The mean particle diameter of AgNPs was calculated from the DLS with an average size ~4 nm and ~65 nm. ATR-FTIR spectroscopy confirmed the presence of alcohols, aldehydes, flavonoids, phenols and nitro compounds in the leaf which act as the stabilizing agent. Antimicrobial activity of the synthesized AgNPs was performed using agar well diffusion and broth dilution method against the Gram-positive and Gram-negative bacteria. Further, robust anti-oxidative potential was evaluated by DPPH assay. The highest antimicrobial activity of synthesized AgNPs was found against Pseudomonas aeruginosa (28.2 +/- 0.52 mm) whereas moderate activity was found against Bacillus subtilis (16.1 +/- 0.76), Candida kruseii (13.0 +/- 1.0), and Trichophyton mentagrophytes (12.6 +/- 1.52). Moreover, the potential wound healing activity was observed against the BJ-5Ta normal fibroblast cell line. Current research revealed that A. solanacea was found to be a suitable source for the green synthesis of silver nanoparticles. PMID- 29155404 TI - Carbohydrate source affects the synthesis of silver nanoparticles by Lactobacillus plantarum 1449 and Lactobacillus ruminis 1313. AB - Strains of Lactobacillus have been used for the synthesis of metallic nanoparticles. Since the carbohydrate source could influence the yield and size of the synthesised nanoparticles, the authors evaluated the potential of Lactobacillus plantarum 1449 and Lactobacillus ruminis 1313 to produce silver nanoparticles (AgNPs) using three carbohydrate sources and AgNO3. The presence of AgNO3 in the medium extended the duration of the acceleration and logarithmic phases of the two strains independently of the carbohydrate source used but did not inhibit their growth. The synthesis of AgNPs started at the second day of culture. In general, the size of the AgNPsranged from 10 to 150 nm; they were smaller and more homogeneous in lactose. In the medium supplemented with glucose, there was a lower production of nanoparticles for both strains. The AgNPs synthesised by L. ruminis 1313 remained enclosed in an extracellular polymeric substance, which probably played an important role in the synthesis of the nanoparticles. The carbohydrate source influenced the yield and size of the AgNPssynthesised by L. plantarum 1449 and L. ruminis 1313; the pH was also important for obtaining nanoparticles of uniform size. PMID- 29155405 TI - Kinnow peel extract as a reducing and capping agent for the fabrication of silver NPs and their biological applications. AB - An effective approach used for the synthesis of silver nanoparticles (AgNPs) through green chemistry by using Kinnow peel extract as a reducing and capping agent is presented. Two different approaches, diluted and concentrated peel extracts, were used for the synthesis of AgNPs. Ultraviolet-visible spectroscopy exhibits characteristic absorption peaks at 425 and 400 nm for nanoparticles (NPs) synthesised by diluted and concentrated extracts, respectively. The X-ray diffraction analysis of nanofabricated silver exhibited a pure face centred cubic structure of 27.4 and 18.1 nm sizes calculated by using Scherrer equation. Scanning electron microscopy analysis showed a uniform morphology of synthesised NPs. Significant antioxidant, phytochemical and antibacterial assays show that both AgNPs can be effectively used in biomedical applications. Furthermore, the use of citrus peel for the synthesis of NPs can be an effective tool in waste management. PMID- 29155406 TI - Biocompatible antimicrobial cotton fibres for healthcare industries: a biogenic approach for synthesis of bio-organic-coated silver nanoparticles. AB - Cotton fibres coated with biogenically fabricated silver nanoparticles (SNPs) are most sought material because of their enhanced activity and biocompatibility. After successful synthesis of SNPs on cotton fibres using leaf extract of Vitex negundo Linn, the fibres were studied using diffuse reflectance spectroscopy, scanning electron microscopy, nanoparticle tracking analysis, energy dispersive X ray, and inductively coupled plasma atomic emission spectrometry. The characterisation revealed uniformly distributed spherical agglomerates of SNPs having individual particle size around 50 nm with the deposition load of 423 MUg of silver per gram of cotton. Antimicrobial assay of cotton-SNPs fibres showed effective performance against pathogenic bacteria and fungi. The method is biogenic, environmentally benign, rapid, and cost-effective, producing highly biocompatible antimicrobial coating required for the healthcare industry. PMID- 29155407 TI - Synthesis of porous GdF3:Er3+,Yb3+-COOH core-shell structured bi-functional nanoparticles for drug delivery. AB - The authors synthesised porous GdF3:Er3+,Yb3+-COOH core-shell structured bi functional nanoparticles through a one-step hydrothermal route during which ethylene diamine tetraacetic acid) was bound to the surface of the nanoparticles. It has high up-conversion emission intensity for monitoring the drug release process and magnetisation saturation value (10.2 emu/g) for drug targeting under foreign magnetic fields. Moreover, porous GdF3:Er3+,Yb3+ as drug carriers with a high drug-loading efficiency. cis-Dichlorodiammineplatinum(II) (cisplatin, CDDP) loaded GdF3:Er3+,Yb3+ nanoparticles (GdF3:Er3+,Yb3+-CDDP) were characterised by the Fourier transform infrared spectra, and CDDP was loaded in the form of electrostatic interaction and hydrogen bonds. Compared with CDDP alone, GdF3:Er3+,Yb3+-CDDP nanoparticles increase concentration of CDDP in the target site and enhance its anticancer efficiency. Therefore, the as-prepared GdF3:Er3+,Yb3+-COOH nanoparticles allow simultaneous targeted drug delivery and monitoring as promising anti-cancer theranostic agents. PMID- 29155408 TI - Dark field differential dynamic microscopy enables accurate characterization of the roto-translational dynamics of bacteria and colloidal clusters. AB - Micro- and nanoscale objects with anisotropic shape are key components of a variety of biological systems and inert complex materials, and represent fundamental building blocks of novel self-assembly strategies. The time scale of their thermal motion is set by their translational and rotational diffusion coefficients, whose measurement may become difficult for relatively large particles with small optical contrast. Here we show that dark field differential dynamic microscopy is the ideal tool for probing the roto-translational Brownian motion of anisotropic shaped particles. We demonstrate our approach by successful application to aqueous dispersions of non-motile bacteria and of colloidal aggregates of spherical particles. PMID- 29155410 TI - Gate-tunable strong-weak localization transition in few-layer black phosphorus. AB - Atomically-thin black phosphorus (BP) field-effect transistors show strong-weak localization transition, which is tunable through gate voltages. Hopping transports through charge impurity-induced localized states are observed at low carrier density regime. Variable-range hopping model is applied to simulate scattering behaviors of charge carriers. In the high carrier concentration regime, a negative magnetoresistance indicates weak localization effects. The extracted phase coherence length is power-law temperature-dependent [Formula: see text] and demonstrates inelastic electron-electron interactions and the 2D transport features in few-layer BP field-effect devices. The competition between localization and phase coherence lengths is investigated and analyzed based on observed gate-tunable strong-weak localization transition in few-layer BP. PMID- 29155411 TI - Porosity effect of 3D-printed polycaprolactone membranes on calvarial defect model for guided bone regeneration. AB - The appropriate porosity and pore size of barrier membranes were associated with the transportation of biomolecules required for new bone formation and angiogenesis. In this study, we fabricated three-dimensional (3D)-printed resorbable polycaprolactone (PCL) membranes with different porosities (30%, 50%, and 70%) to evaluate the effective pore size for guided bone regeneration (GBR) membranes. To analyze mechanical properties and cytocompatibility, PCL membranes prepared using extrusion-based 3D printing technology were compared in dry and wet conditions and tested in vitro. The proliferation rates and pattern of fibroblasts and preosteoblasts on PCL membranes with different porosities were determined using a cell counting kit-8 assay and scanning electron microscopy. PCL membrane porosity did not affect cell proliferation, but osteogenic differentiation and mechanical properties were increased with lower porosity (30%) on day 14 (p < 0.001). Similar results were found in an in vivo calvarial defect model; new bone formation was significantly higher in PCL membranes with lower porosity (p < 0.001). These results indicate that 3D-printed PCL with 30% porosity (130 MUm pore size) is an excellent pore size for GBR membranes. PMID- 29155409 TI - Biomaterial strategies for limiting the impact of secondary events following spinal cord injury. AB - The nature of traumatic spinal cord injury (SCI) often involves limited recovery and long-term quality of life complications. The initial injury sets off a variety of secondary cascades, which result in an expanded lesion area. Ultimately, the native tissue fails to regenerate. As treatments are developed in the laboratory, the management of this secondary cascade is an important first step in achieving recovery of normal function. Current literature identifies four broad targets for intervention: inflammation, oxidative stress, disruption of the blood-spinal cord barrier, and formation of an inhibitory glial scar. Because of the complex and interconnected nature of these events, strategies that combine multiple therapies together show much promise. Specifically, approaches that rely on biomaterials to perform a variety of functions are generating intense research interest. In this review, we examine each target and discuss how biomaterials are currently used to address them. Overall, we show that there are an impressive amount of biomaterials and combinatorial treatments which show good promise for slowing secondary events and improving outcomes. If more emphasis is placed on growing our understanding of how materials can manage secondary events, treatments for SCI can be designed in an increasingly rational manner, ultimately improving their potential for translation to the clinic. PMID- 29155412 TI - Tunable nanostructured columnar growth of SnO2 for efficient detection of CO gas. AB - The present work is focused on the growth and modification of the columnar nanostructures of SnO2 using a glancing angle deposition (GLAD) assisted rf sputtering technique for low temperature detection of carbon monoxide (CO) gas. The GLAD angle and deposition pressure are optimized to tailor the grow of columnar nanostructures of SnO2, which exhibit an enhanced gas sensing response of 1.50 * 102 towards 500 ppm of CO gas at a comparatively lower operating temperature of 110 degrees C. The enhanced sensing response at low operating temperature is related to the growth of nanoporous columnar structures of SnO2 thin film under the GLAD configuration, which results in an enhanced interaction of target CO gas molecules with the large surface area of sensing SnO2 thin film. The origin of the sensing mechanism supporting the observed response characteristics towards CO gas is identified and discussed in detail. PMID- 29155413 TI - Gas-exfoliated porous monolayer boron nitride for enhanced aerobic oxidative desulfurization performance. AB - Hexagonal boron nitride has been regarded to be an efficient catalyst in aerobic oxidation fields, but limited by the less-exposed active sites. In this contribution, we proposed a simple green liquid nitrogen gas exfoliation strategy for preparation of porous monolayer nanosheets (BN-1). Owing to the reduced layer numbers, decreased lateral sizes and artificially-constructed pores, increased exposure of active sites was expected, further contributed to an enhanced aerobic oxidative desulfurization (ODS) performance up to ~98% of sulfur removal, achieving ultra-deep desulfurization. This work not only introduced an excellent catalyst for aerobic ODS, but also provided a strategy for construction of some other highly-efficient monolayer two-dimensional materials for enhanced catalytic performance. PMID- 29155414 TI - Quasiparticles in condensed matter systems. AB - Quasiparticles are a powerful concept of condensed matter quantum theory. In this review, the appearence and the properties of quasiparticles are presented in a unifying perspective. The principles behind the existence of quasiparticle excitations in both quantum disordered and ordered phases of fermionic and bosonic systems are discussed. The lifetime of quasiparticles is considered in particular near a continuous classical or quantum phase transition, when the nature of quasiparticles on both sides of a transition into an ordered state changes. A new concept of critical quasiparticles near a quantum critical point is introduced, and applied to quantum phase transitions in heavy fermion metals. Fractional quasiparticles in systems of restricted dimensionality are reviewed. Dirac quasiparticles emerging in so-called Dirac materials are discussed. The more recent discoveries of topologically protected chiral quasiparticles in topological matter and Majorana quasiparticles in topological superconductors are briefly reviewed. PMID- 29155415 TI - Phase diagrams of ferroelectric nanocrystals strained by an elastic matrix. AB - Ferroelectric crystallites embedded into a dielectric matrix experience temperature-dependent elastic strains caused by differences in the thermal expansion of the crystallites and the matrix. Owing to the electrostriction, these lattice strains may affect polarization states of ferroelectric inclusions significantly, making them different from those of a stress-free bulk crystal. Here, using a nonlinear thermodynamic theory, we study the mechanical effect of elastic matrix on the phase states of embedded single-domain ferroelectric nanocrystals. Their equilibrium polarization states are determined by minimizing a special thermodynamic potential that describes the energetics of an ellipsoidal ferroelectric inclusion surrounded by a linear elastic medium. To demonstrate the stability ranges of such states for a given material combination, we construct a phase diagram, where the inclusion's shape anisotropy and temperature are used as two parameters. The 'shape-temperature' phase diagrams are calculated numerically for PbTiO3 and BaTiO3 nanocrystals embedded into representative dielectric matrices generating tensile (silica glass) or compressive (potassium silicate glass) thermal stresses inside ferroelectric inclusions. The developed phase maps demonstrate that the joint effect of thermal stresses and matrix-induced elastic clamping of ferroelectric inclusions gives rise to several important features in the polarization behavior of PbTiO3 and BaTiO3 nanocrystals. In particular, the Curie temperature displays a nonmonotonic variation with the ellipsoid's aspect ratio, being minimal for spherical inclusions. Furthermore, the diagrams show that the polarization orientation with respect to the ellipsoid's symmetry axis is controlled by the shape anisotropy and the sign of thermal stresses. Under certain conditions, the mechanical inclusion-matrix interaction qualitatively alters the evolution of ferroelectric states on cooling, inducing a structural transition in PbTiO3 nanocrystals and suppressing in BaTiO3 inclusions some transformations occurring in their bulk counterpart. The constructed phase maps open the possibility to calculate dielectric properties of strained PbTiO3 and BaTiO3 nanocrystals and ferroelectric nanocomposites comprising such crystallites. PMID- 29155416 TI - Eye lens dose monitoring in the UK nuclear industry using active personal dosemeters. AB - The reduction of the dose limit for eye lens from 150 to 20 mSv yr-1 must be implemented by EU member states by February 2018. Consequently, there is a requirement for all employers engaged with work with ionising radiation to have appropriate monitoring arrangements in place by this date to demonstrate that they can meet this new limit for all workers. Eye lens dose is conventionally monitored by specific dosemeters worn near the eye. However, it is usually impractical for these dosemeters to be worn at all times in the workplace which can lead to problems accounting for any periods of work when an eye lens dosemeter has not been worn. The Berkeley Approved Dosimetry Service provides a monitoring service for 22 nuclear sites in the UK using active personal dosemeters (APDs) for measuring H p(10) and H p(0.07). TLDs for extremity and eye are also issued as appropriate for the working conditions. An analysis of the data from 2007 to 2016 concludes that the values for H p(0.07) as monitored indirectly by APDs worn on the trunk are comparable to the values assessed by specific H p(3) eye TLDs. This paper sets out evidence that compliance with the 20 mSv dose limit for the eye lens can be demonstrated using routine issue APDs although specific eye TLDs may still be required to meet international guidance for non-uniform workplace fields. This evidence supports the recent statement from International Radiation Protection Association that 'for the nuclear industry and other non-medical sectors the use of a whole body dosimeter is considered likely to be sufficient for the majority of workers'. PMID- 29155417 TI - Growth of rutile TiO2 nanorods in Ti and Cu ion sequentially implanted SiO2 and the involved mechanisms. AB - TiO2 in nanoscale exhibits unique physicochemical and optoelectronic properties and has attracted much more interest of the researchers. In this work, TiO2 nanostructures are synthesized in amorphous SiO2 slices by implanting Ti ions, or sequentially implanting Ti and Cu ions combined with annealing at high temperature. The morphology, structure, spatial distribution and optical properties of the formed nanostructures have been investigated in detail. Our results clearly show that the thermal growth of TiO2 nanostructures in SiO2 substrate is significantly enhanced by presence of post Cu ion implantation, which depends strongly on the applied Cu ion fluence, as well as the annealing atmosphere. Due to the formation of Cu2O in the substrate, rutile TiO2 nanorods of large size have been well fabricated in the Ti and Cu sequentially implanted SiO2 after annealing in N2 atmosphere, in which Cu2O plays a role as a catalyst. Moreover, the sample with well-fabricated TiO2 nanorods exhibits a narrowed band gap, an enhanced optical absorption in visible region, and catalase-/peroxidase like catalytic characteristics. Our findings provide an effective route to fabricate functional TiO2 nanorods in SiO2 via ion implantation. PMID- 29155418 TI - ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells. AB - This corrects the article DOI: 10.1038/oncsis.2017.87. PMID- 29155420 TI - Medication adherence among allogeneic hematopoietic stem cell transplant recipients: a pilot single-center study. PMID- 29155419 TI - Catching hidden variation: systematic correction of reference minor allele annotation in clinical variant calling. AB - PurposeWe comprehensively assessed the influence of reference minor alleles (RMAs), one of the inherent problems of the human reference genome sequence.MethodsThe variant call format (VCF) files provided by the 1000 Genomes and Exome Aggregation Consortium (ExAC) consortia were used to identify RMA sites. All coding RMA sites were checked for concordance with UniProt and the presence of same codon variants. RMA-corrected predictions of functional effect were obtained with SIFT, PolyPhen-2, and PROVEAN standalone tools and compared with dbNSFP v2.9 for consistency.ResultsWe systematically characterized the problem of RMAs and identified several possible ways in which RMA could interfere with accurate variant discovery and annotation. We have discovered a systematic bias in the automated variant effect prediction at the RMA loci, as well as widespread switching of functional consequences for variants located in the same codon as the RMA. As a convenient way to address the problem of RMAs we have developed a simple bioinformatic tool that identifies variation at RMA sites and provides correct annotations for all such substitutions. The tool is available free of charge at http://rmahunter.bioinf.me.ConclusionCorrection of RMA annotation enhances the accuracy of next-generation sequencing-based methods in clinical practice. PMID- 29155423 TI - Experimental models of pancreatic cancer desmoplasia. AB - Desmoplasia is a fibro-inflammatory process and a well-established feature of pancreatic cancer. A key contributor to pancreatic cancer desmoplasia is the pancreatic stellate cell. Various in vitro and in vivo methods have emerged for the isolation, characterization, and use of pancreatic stellate cells in models of cancer-associated fibrosis. In addition to cell culture models, genetically engineered animal models have been established that spontaneously develop pancreatic cancer with desmoplasia. These animal models are currently being used for the study of pancreatic cancer pathogenesis and for evaluating therapeutics against pancreatic cancer. Here, we review various in vitro and in vivo models that are being used or have the potential to be used to study desmoplasia in pancreatic cancer. PMID- 29155421 TI - Characterization of neural stem cells modified with hypoxia/neuron-specific VEGF expression system for spinal cord injury. AB - Spinal cord injury (SCI) is an incurable disease causing an ischemic environment and functional defect, thus a new therapeutic approach is needed for SCI treatment. Vascular endothelial growth factor (VEGF) is a potent therapeutic gene to treat SCI via angiogenesis and neuroprotection, and both tissue-specific gene expression and high gene delivery efficiency are important for successful gene therapy. Here we design the hypoxia/neuron dual-specific gene expression system (pEpo-NSE) and efficient gene delivery platform can be achieved by the combination ex vivo gene therapy with erythropoietin (Epo) enhancer, neuron specific enolase (NSE) promoter and neural stem cells (NSCs). An in vitro model, NSCs transfected with pEpo-NSE were consistently and selectively overexpressing therapeutic genes in response to neural differentiation and hypoxic conditions. Also, in SCI model, ex vivo gene therapy using pEpo-NSE system with NSCs significantly enhanced gene delivery efficiency compared with pEpo-NSE system gene therapy alone. However, microarray analysis reveals that introducing exogenous pEpo-NSE and VEGF triggers biological pathways in NSCs such as glycolysis and signaling pathways such as Ras and mitogen-activated protein kinase, leading to cell proliferation, differentiation and apoptosis. Collectively, it indicates that the pEpo-NSE gene expression system works stably in NSCs and ex vivo gene therapy using pEpo-NSE system with NSCs improves gene expression efficiency. However, exogenously introduced pEpo-NSE system has an influence on gene expression profiles in NSCs. Therefore, when we consider ex vivo gene therapy for SCI, the effects of changes in gene expression profiles in NSCs on safety should be investigated. PMID- 29155422 TI - Secretion-mediated STAT3 activation promotes self-renewal of glioma stem-like cells during hypoxia. AB - High-grade gliomas (HGGs) include the most common and the most aggressive primary brain tumor of adults and children. Despite multimodality treatment, most high grade gliomas eventually recur and are ultimately incurable. Several studies suggest that the initiation, progression, and recurrence of gliomas are driven, at least partly, by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew. We have identified a hypoxia-induced pathway that utilizes the Hypoxia Inducible Factor 1alpha (HIF 1alpha) transcription factor and the JAK1/2-STAT3 (Janus Kinase 1/2 - Signal Transducer and Activator of Transcription 3) axis to enhance the self-renewal of glioma stem-like cells. Hypoxia is a commonly found pathologic feature of HGGs. Under hypoxic conditions, HIF-1alpha levels are greatly increased in glioma stem like cells. Increased HIF-1alpha activates the JAK1/2-STAT3 axis and enhances tumor stem-like cell self-renewal. Our data further demonstrate the importance of Vascular Endothelial Growth Factor (VEGF) secretion for this pathway of hypoxia mediated self-renewal. Brefeldin A and EHT-1864, agents that significantly inhibit VEGF secretion, decreased stem cell self-renewal, inhibited tumor growth, and increased the survival of mice allografted with S100beta-v-erbB/p53-/- glioma stem-like cells. These agents also inhibit the expression of a hypoxia gene expression signature that is associated with decreased survival of HGG patients. These findings suggest that targeting the secretion of extracellular, autocrine/paracrine mediators of glioma stem-like cell self-renewal could potentially contribute to the treatment of HGGs. PMID- 29155424 TI - Immune checkpoint inhibitors in sarcomas: in quest of predictive biomarkers. AB - Sarcomas are a rare group of tumors of mesenchymal origin. Metastatic sarcomas are often difficult to treat and unresponsive to standard radio- and chemotherapy, resulting in a poor survival rate for patients. Novel treatments with immune checkpoint inhibitors have been proven to prolong survival of patients with a variety of cancers, including metastatic melanoma, lung, and renal cell carcinoma. Since immune checkpoint inhibitors could provide a novel treatment option for patients with sarcomas, clinical trials investigating their efficacy in these group of tumors are ongoing. However, the discrimination of patients that are the most likely to respond to these treatments is still an obstacle in the design of clinical trials. In this review, we provide a brief overview of the mechanisms of action of immune checkpoint inhibitors and discuss the proposed biomarkers of therapy response, such as lymphocytic infiltration, intratumoral PD-L1 expression, and mutational load in sarcomas. PMID- 29155425 TI - Granulocyte-derived TNFalpha promotes vascular and hematopoietic regeneration in the bone marrow. AB - Endothelial cells are a critical component of the bone marrow (BM) stromal network, which maintains and regulates hematopoietic cells. Vascular regeneration precedes, and is necessary for, successful hematopoietic stem cell (HSC) transplantation, the only cure for most hematopoietic diseases. Recent data suggest that mature hematopoietic cells regulate BM stromal-cell function. Whether a similar cross-talk regulates the BM vasculature is not known. Here we found that donor hematopoietic cells act on sinusoidal endothelial cells and induce host blood vessel and hematopoietic regeneration after BM transplantation in mice. Adoptive transfer of BM, but not peripheral, granulocytes prevented the death of mice transplanted with limited numbers of HSCs and accelerated recovery of host vessels and hematopoietic cells. Moreover, selective granulocyte ablation in vivo impaired vascular and hematopoietic regeneration after BM transplantation. Gene expression analyses indicated that granulocytes are the main source of the cytokine TNFalpha, whereas its receptor TNFR1 is selectively upregulated in regenerating blood vessels. In adoptive transfer experiments, wild type, but not Tnfa-/-, granulocytes induced vascular recovery, and wild-type granulocyte transfer did not prevent death or promote vascular regeneration in Tnfr1-/-; Tnfr2-/- mice. Thus, by delivering TNFalpha to endothelial cells, granulocytes promote blood vessel growth and hematopoietic regeneration. Manipulation of the cross-talk between granulocytes and endothelial cells may lead to new therapeutic approaches to improve blood vessel regeneration and increase survival and hematopoietic recovery after HSC transplantation. PMID- 29155426 TI - CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. AB - Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre-B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy. Dose-dependent antileukemic activity was observed, with complete remission obtained in 73% (11/15) of patients receiving >=1 * 106 CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19dim or CD19- B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted CD22+ cell escape from killing by CD22-CAR T cells. These results are the first to establish the clinical activity of a CD22-CAR in B-ALL, including leukemia resistant to anti-CD19 immunotherapy, demonstrating potency against B-ALL comparable to that of CD19-CAR at biologically active doses. Our results also highlight the critical role played by antigen density in regulating CAR function. PMID- 29155427 TI - PDB-wide identification of biological assemblies from conserved quaternary structure geometry. AB - Protein structures are key to understanding biomolecular mechanisms and diseases, yet their interpretation is hampered by limited knowledge of their biologically relevant quaternary structure (QS). A critical challenge in inferring QS information from crystallographic data is distinguishing biological interfaces from fortuitous crystal-packing contacts. Here, we tackled this problem by developing strategies for aligning and comparing QS states across both homologs and data repositories. QS conservation across homologs proved remarkably strong at predicting biological relevance and is implemented in two methods, QSalign and anti-QSalign, for annotating homo-oligomers and monomers, respectively. QS conservation across repositories is implemented in QSbio (http://www.QSbio.org), which approaches the accuracy of manual curation and allowed us to predict >100,000 QS states across the Protein Data Bank. Based on this high-quality data set, we analyzed pairs of structurally conserved interfaces, and this analysis revealed a striking plasticity whereby evolutionary distant interfaces maintain similar interaction geometries through widely divergent chemical properties. PMID- 29155428 TI - Small-molecule inhibition of TLR8 through stabilization of its resting state. AB - Endosomal Toll-like receptors (TLR3, TLR7, TLR8, and TLR9) are highly analogous sensors for various viral or bacterial RNA and DNA molecular patterns. Nonetheless, few small molecules can selectively modulate these TLRs. In this manuscript, we identified the first human TLR8-specific small-molecule antagonists via a novel inhibition mechanism. Crystal structures of two distinct TLR8-ligand complexes validated a unique binding site on the protein-protein interface of the TLR8 homodimer. Upon binding to this new site, the small molecule ligands stabilize the preformed TLR8 dimer in its resting state, preventing activation. As a proof of concept of their therapeutic potential, we have demonstrated that these drug-like inhibitors are able to suppress TLR8 mediated proinflammatory signaling in various cell lines, human primary cells, and patient specimens. These results not only suggest a novel strategy for TLR inhibitor design, but also shed critical mechanistic insight into these clinically important immune receptors. PMID- 29155429 TI - Monobactam formation in sulfazecin by a nonribosomal peptide synthetase thioesterase. AB - The N-sulfonated monocyclic beta-lactam ring characteristic of the monobactams confers resistance to zinc metallo-beta-lactamases and affords the most effective class to combat carbapenem-resistant enterobacteria (CRE). Here we report unprecedented nonribosomal peptide synthetase activities, wherein an assembled tripeptide is N-sulfonated in trans before direct synthesis of the beta-lactam ring in a noncanonical, cysteine-containing thioesterase domain. This means of azetidinone synthesis is distinct from the three others known in nature. PMID- 29155431 TI - Chemical synthesis and NMR spectroscopy of long stable isotope labelled RNA. AB - We showcase the high potential of the 2'-cyanoethoxymethyl (CEM) methodology to synthesize RNAs with naturally occurring modified residues carrying stable isotope (SI) labels for NMR spectroscopic applications. The method was applied to synthesize RNAs with sizes ranging between 60 to 80 nucleotides. The presented approach gives the possibility to selectively modify larger RNAs (>60 nucleotides) with atom-specifically 13C/15N-labelled building blocks. The method harbors the unique potential to address structural as well as dynamic features of these RNAs with NMR spectroscopy but also using other biophysical methods, such as mass spectrometry (MS), or small angle neutron/X-ray scattering (SANS, SAXS). PMID- 29155430 TI - Engineering peptide ligase specificity by proteomic identification of ligation sites. AB - Enzyme-catalyzed peptide ligation is a powerful tool for site-specific protein bioconjugation, but stringent enzyme-substrate specificity limits its utility. We developed an approach for comprehensively characterizing peptide ligase specificity for N termini using proteome-derived peptide libraries. We used this strategy to characterize the ligation efficiency for >25,000 enzyme-substrate pairs in the context of the engineered peptide ligase subtiligase and identified a family of 72 mutant subtiligases with activity toward N-terminal sequences that were previously recalcitrant to modification. We applied these mutants individually for site-specific bioconjugation of purified proteins, including antibodies, and in algorithmically selected combinations for sequencing of the cellular N terminome with reduced sequence bias. We also developed a web application to enable algorithmic selection of the most efficient subtiligase variant(s) for bioconjugation to user-defined sequences. Our methods provide a new toolbox of enzymes for site-specific protein modification and a general approach for rapidly defining and engineering peptide ligase specificity. PMID- 29155432 TI - In situ formed Fe-N doped metal organic framework@carbon nanotubes/graphene hybrids for a rechargeable Zn-air battery. AB - This study presents an in situ route to produce 3D Fe-N doped metal organic framework@carbon nanotubes/graphene (Fe-MOF@CNTs-G) hybrids as efficient oxygen reduction reaction (ORR) catalysts in both basic and acidic solutions. A rechargeable zinc-air battery assembled with Fe-MOF@CNTs-G exhibits a lower charge/discharge overpotential than the commercial IrO2 + 20% Pt/C catalyst. PMID- 29155433 TI - [Neuroanatomy of the Visual Pathway]. AB - Precise knowledge of the neuroanatomy of the visual system including the perception of visual stimuli in the retina, the transmission of visual information to other areas of the central nervous system and the processing of visual information, are most important for diagnostics of diseases, which are affecting this system. Such knowledge allows, even after just a clinical examination, already a quite precise localisation of potential lesions. The aim of this article is to illustrate the neuroanatomy of the visual system with the focus on the visual pathway and the processing of visual information. Next to the main visual pathway, also other retinofugal projections are discussed. Domains, which are important for the oculomotor system, are discussed in another article in this edition of the journal. PMID- 29155434 TI - [Neuro-Ophthalmological History Taking]. AB - Neuro-ophthalmological history may be very complex and difficult. This article provides 14 hints about how to construct history taking efficiently and how to avoid collecting unnecessary information. PMID- 29155435 TI - Periventricular White Matter Hyperintensities and Functional Decline. AB - BACKGROUND/OBJECTIVES: We previously showed that global brain white matter hyperintensity volume (WMHV) was associated with accelerated long-term functional decline. The objective of the current study was to determine whether WMHV in particular brain regions is more predictive of functional decline. DESIGN: Prospective population-based study. SETTING: Northern Manhattan magnetic resonance imaging (MRI) study. PARTICIPANTS: Individuals free of stroke at baseline (N = 1,195; mean age 71 +/- 9; n = 460 (39%) male). MEASUREMENTS: Participants had brain MRI with axial T1, T2, and fluid attenuated inversion recovery sequences. Volumetric WMHV distribution across 14 brain regions (brainstem; cerebellum; bilateral frontal, occipital, temporal, and parietal lobes; and bilateral anterior and posterior periventricular white matter (PVWM)) was determined using a combination of bimodal image intensity distribution and atlas-based methods. Participants had annual functional assessments using the Barthel Index (BI) (range 0-100) over a mean of 7.3 years and were followed for stroke, myocardial infarction (MI), and mortality. Because there were multiple collinear variables, least absolute shrinkage and selection operator (LASSO) regression-selected regional WMHV variables most associated with outcomes and adjusted generalized estimating equations models were used to estimate associations with baseline BI and change over time. RESULTS: Using LASSO regularization, only right anterior PVWM was found to meet criteria for selection, and each standard deviation greater WMHV was associated with accelerated functional decline of 0.95 additional BI points per year (95% confidence interval (CI) = -1.20 to -0.70) in an unadjusted model, -0.92 points per year (95% CI = -1.18 to -0.67) with baseline covariate adjustment, and -0.87 points per year (95% CI = -1.12 to -0.62) after adjusting for incident stroke and MI. CONCLUSION: In this large population-based study with long-term repeated measures of function, periventricular WMHV was particularly associated with accelerated functional decline. PMID- 29155436 TI - Enzyme replacement therapy for infantile-onset Pompe disease. AB - BACKGROUND: Infantile-onset Pompe disease is a rare and progressive autosomal recessive disorder caused by a deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Current treatment involves enzyme replacement therapy (with recombinant human alglucosidase alfa) and symptomatic therapies (e.g. to control secretions). Children who are cross-reactive immunological material (CRIM) negative require immunomodulation prior to commencing enzyme replacement therapy.Enzyme replacement therapy was developed as the most promising therapeutic approach for Pompe disease; however, the evidence is lacking, especially regarding the optimal dose and dose frequency. OBJECTIVES: To assess the effectiveness, safety and appropriate dose regimen of enzyme replacement therapy for treating infantile-onset Pompe disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, which is compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the Cochrane Central Register of Controlled Trials (CENTRAL), Embase (Ovid), PubMed and LILACS, and CBM, CNKI, VIP, and WANFANG for literature published in Chinese. In addition, we searched three online registers: WHO International Clinical Trials Registry Platform ClinicalTrials.gov, and www.genzymeclinicalresearch.com. We also searched the reference lists of relevant articles and reviews.Date of last search of the Group's Inborn Errors of Metabolism Trials Register: 24 November 2016. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials of enzyme replacement therapy in children with infantile-onset Pompe disease. DATA COLLECTION AND ANALYSIS: Two authors independently selected relevant trials, assessed the risk of bias and extracted data. We contacted investigators to obtain important missing information. MAIN RESULTS: We found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo.We found one trial (18 participants) that fulfilled the selection criteria, comparing different doses of alglucosidase alfa. The trial provided low-quality evidence (this was a small trial, there were no numerical results available by dose group, random sequence generation and allocation concealment were unclear, and there was a lack of blinding). The duration of alglucosidase alfa treatment ranged from 52 weeks (the length of the original study) to up to three years (including the extended phase of the trial), with a median duration of treatment being 2.3 years.The trial only reported that clinical responses including cardiac function and motor development, as well as the proportion of children that were free of invasive ventilation, were similar in the 20 mg/kg every two weeks and the 40 mg/kg every two weeks groups (low-quality evidence). Long-term alglucosidase alfa treatment markedly extended survival as well as ventilation-free survival and improved cardiomyopathy (low-quality evidence). In relation to the number of children experiencing one or more infusion-related events, there was no significant difference between dose groups, risk ratio 0.83 (95% confidence interval 0.40 to 1.76) (low-quality of evidence). However, of note, at 52 weeks, five children in the 20 mg/kg every two weeks dose group experienced a total of 41 mild or moderate (none severe) infusion-related events and the six children in the 40 mg/kg every two weeks dose group experienced a total of 123 infusion-related events. By the end of the extended phase of the trial, five children in the 20 mg/kg every two weeks dose group experienced a total of 47 infusion-related events and the six children in the 40 mg/kg every two weeks dose group experienced a total of 177 infusion-related events. The trial was supported by the Genzyme Corporation. AUTHORS' CONCLUSIONS: The search found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo. One small randomized controlled trial provided no robust evidence for which dosing schedule of alglucosidase alfa was more effective to treat infantile-onset Pompe disease. It is not deemed ethical to proceed with new placebo-controlled trials, therefore a randomized controlled trial with a large sample size comparing different dosing schedules of enzyme replacement therapy is needed. The main clinical outcomes (i.e. cardiac function, invasive ventilation, survival, motor development, adverse events (e.g. the development of antibodies)) should be standardized when evaluated and reported. PMID- 29155437 TI - Reply To: Interprofessional Teamwork in Acute Geriatric Care: Where Are the Pharmacists? PMID- 29155438 TI - Circular RNAs mediated by transposons are associated with transcriptomic and phenotypic variation in maize. AB - Circular RNAs (circRNAs) are covalently closed RNA molecules. Recent studies have shown that circRNAs can arise from the transcripts of transposons. Given the prevalence of transposons in the maize genome and dramatic genomic variation driven by transposons, we hypothesize that transposons in maize may be involved in the formation of circRNAs and further modulate phenotypic variation. We performed circRNA-Seq on B73 seedling leaves and uncovered 2804 high-confidence maize circRNAs, which show distinct genomic features. Comprehensive analyses demonstrated that sequences related to LINE1-like elements (LLEs) and their Reverse Complementary Pairs (LLERCPs) are significantly enriched in the flanking regions of circRNAs. Interestingly, as the number of LLERCPs increase, the accumulation of circRNAs varies, whereas that of linear transcripts decreases. Furthermore, genes with LLERCP-mediated circRNAs are enriched among loci that are associated with phenotypic variation. These results suggest that circRNAs are likely to be involved in the modulation of phenotypic variation by LLERCPs. Further, we showed that the presence/absence variation of LLERCPs was associated with expression variation of circRNA-circ1690 and was related to ear height, potentially through the interplay between circRNAs and functional linear transcripts. Our first study of maize circRNAs uncovers a potential new way for transposons to modulate transcriptomic and phenotypic variations. PMID- 29155439 TI - Applications and Challenges for the Use of Phosphatidylethanol Testing in Liver Disease Patients (Mini Review). AB - Phosphatidylethanol (PEth) is a direct nonoxidative metabolite of ethanol that may be measured in clinical samples as a marker for monitoring alcohol consumption. It has been used in a wide variety of clinical and nonclinical settings; however, its investigation in relation to liver disease has been limited. This study aims at providing a short review on the applications and challenges for the incorporation of PEth testing in identifying alcohol intake in this patient population. PMID- 29155440 TI - Severe Hypoglycemia Caused by Lenalidomide. AB - Lenalidomide is commonly used for multiple myeloma as either induction or maintenance therapy. The agent is associated with a host of adverse effects, but hypoglycemia has only been reported in one phase I trial in patients with solid tumors. We describe a 74-year-old woman who experienced grade 3 hypoglycemia (blood glucose level 35 mg/dl) likely related to lenalidomide. Her medical history was significant for refractory myeloma and type 2 diabetes mellitus. Lenalidomide was started as maintenance therapy following autologous bone marrow transplantation. Approximately 3 years later, she developed refractory hypoglycemia necessitating hospital admission despite stopping antihyperglycemic agents 4 weeks prior to admission. Lenalidomide was withheld during her admission and restarted 2 days prior to discharge. Work-up for causes of persistent hypoglycemia was negative, and her glucose levels improved over her 26-day hospitalization. She was readmitted approximately one month later for hypoglycemia, and lenalidomide was permanently discontinued. Again, work-up for causes of hypoglycemia was negative, and her glucose levels stabilized over her hospitalization. After discontinuation of lenalidomide, hypoglycemia did not recur, and within 1 year the patient required reinitiation of antihyperglycemic medications to control her glucose levels. Given the resolution of hypoglycemia with lenalidomide discontinuation and return of hyperglycemia after restarting the agent, it is likely that lenalidomide was the cause of the patient's hypoglycemia. Use of the Naranjo adverse drug reaction probability scale indicated a definite relationship (score of 9) between the patient's development of grade 3 hypoglycemia and lenalidomide therapy. Although this adverse drug reaction had been previously reported with lenalidomide during phase I trials in patients with solid tumors, only grade 1 or 2 hypoglycemia was reported in three patients. To our knowledge, this is the first reported case of grade 3 hypoglycemia caused by lenalidomide. PMID- 29155441 TI - Interprofessional Teamwork in Acute Geriatric Care: Where Are the Pharmacists? PMID- 29155443 TI - The Philosophy of Practice for Comprehensive Medication Management: Evaluating Its Meaning and Application by Practitioners. AB - OBJECTIVE: Philosophy of practice is the foundation of any patient care practice because it provides a set of professional values and beliefs that guide actions and decisions in practice. Study objectives were to understand how pharmacists providing comprehensive medication management (CMM) describe their philosophy of practice and compare how participants' philosophies align with predefined tenets of a CMM philosophy of practice. METHODS: An instrument with closed and open ended items was developed and administered online to the lead pharmacist at 36 clinics participating in a large CMM study. Participants were asked to describe their philosophy of practice, rate how well their current practice activities align with five predefined CMM philosophy of practice tenets, and provide examples of how they carry out each tenet and how they could improve. Responses were coded, and descriptive analysis was used to calculate participants' practice alignment with the five philosophy of practice tenets. RESULTS: Thirty pharmacists completed the instrument. Twelve codes emerged that participants used to describe their philosophy of practice. These codes were mapped to five predefined tenets of a philosophy of practice. Only 3 (10%) participants included all five tenets in their philosophy of practice, 8 (26.7%) included four, 8 (26.7%) included three, 6 (20%) included two, and 5 (16.7%) included one tenet. Overall, participants rated their alignment with the five tenets highly. "Embracing a patient-centered approach" received the highest mean score of 9.17/10; "Meeting a societal need" had the lowest mean score of 8.37/10. CONCLUSION: Participants described their philosophy of practice with significant variability. CMM requires a single and consistently applied philosophy of practice to guide practice and the role of the practitioner. We propose five core tenets that resulted from this assessment to be embraced by pharmacists providing CMM and included in their philosophy of practice. PMID- 29155444 TI - Neutrophil to Lymphocyte Ratio As a Risk Stratification Tool for Older Adults with Pneumonia. PMID- 29155442 TI - Safety of folic acid. AB - There is a large body of literature demonstrating the efficacy of maternal folic acid intake in preventing birth defects, as well as investigations into potential adverse consequences of consuming folic acid above the upper intake level (UL). Recently, two authoritative bodies convened expert panels to assess risks from high intakes of folic acid: the U.S. National Toxicology Program and the UK Scientific Advisory Committee on Nutrition. Overall, the totality of the evidence examined by these panels, as well as studies published since the release of their reports, have not established risks for adverse consequences resulting from existing mandatory folic acid fortification programs that have been implemented in many countries. Current folic acid fortification programs have been shown to support public health in populations, and the exposure levels are informed by and adherent to the precautionary principle. Additional research is needed to assess the health effects of folic acid supplement use when the current upper limit for folic acid is exceeded. PMID- 29155445 TI - Individualizing Prevention for Older Adults. AB - Prevention can help older adults avoid illness by identifying and addressing conditions before they cause symptoms, but prevention can also harm older adults if conditions that are unlikely to cause symptoms in the individual's lifetime are identified and treated. To identify older adults who preventive interventions are most likely to benefit (and most likely to harm), we propose a framework that compares an individual's life expectancy (LE) with the time to benefit (TTB) for an intervention. If LE is less than the TTB, the individual is unlikely to benefit but is exposed to the risks of the intervention, and the intervention should generally NOT be recommended. If LE is longer than the TTB, the individual could benefit, and the intervention should generally be recommended. If LE is similar to the TTB, the individual's values and preferences should be the major determinant of the decision. To facilitate the use of this framework in routine clinical care, we explored ways to estimate LE, identified the TTB for common preventive interventions, and developed strategies for communicating with individuals. We have synthesized these strategies and demonstrate how they can be used to individualize prevention for a hypothetical beneficiary in the setting of a Medicare annual wellness visit. Finally, we place prevention in the context of curative and symptom-oriented care and outline how prevention should be focused on healthier older adults, whereas symptom-oriented care should predominate in sicker older adults. PMID- 29155446 TI - The China Plant Trait Database: toward a comprehensive regional compilation of functional traits for land plants. AB - Plant functional traits provide information about adaptations to climate and environmental conditions, and can be used to explore the existence of alternative plant strategies within ecosystems. Trait data are also increasingly being used to provide parameter estimates for vegetation models. Here we present a new database of plant functional traits from China. Most global climate and vegetation types can be found in China, and thus the database is relevant for global modeling. The China Plant Trait Database contains information on morphometric, physical, chemical, and photosynthetic traits from 122 sites spanning the range from boreal to tropical, and from deserts and steppes through woodlands and forests, including montane vegetation. Data collection at each site was based either on sampling the dominant species or on a stratified sampling of each ecosystem layer. The database contains information on 1,215 unique species, though many species have been sampled at multiple sites. The original field identifications have been taxonomically standardized to the Flora of China. Similarly, derived photosynthetic traits, such as electron-transport and carboxylation capacities, were calculated using a standardized method. To facilitate trait-environment analyses, the database also contains detailed climate and vegetation information for each site. The data set is released under a Creative Commons BY license. When using the data set, we kindly request that you cite this article, recognizing the hard work that went into collecting the data and the authors' willingness to make it publicly available. PMID- 29155447 TI - Older adults may not consider life expectancy an important factor in cancer screening. PMID- 29155448 TI - Influence of national centralization of oesophagogastric cancer on management and clinical outcome from emergency upper gastrointestinal conditions. AB - BACKGROUND: In England in 2001 oesophagogastric cancer surgery was centralized. The aim of this study was to evaluate whether centralization of oesophagogastric cancer to high-volume centres has had an effect on mortality from different emergency upper gastrointestinal conditions. METHODS: The Hospital Episode Statistics database was used to identify patients admitted to hospitals in England (1997-2012). The influence of oesophagogastric high-volume cancer centre status (20 or more resections per year) on 30- and 90-day mortality from oesophageal perforation, paraoesophageal hernia and perforated peptic ulcer was analysed. RESULTS: Over the study interval, 3707, 12 441 and 56 822 patients with oesophageal perforation, paraoesophageal hernia and perforated peptic ulcer respectively were included. There was a passive centralization to high-volume cancer centres for oesophageal perforation (26.9 per cent increase), paraoesophageal hernia (19.5 per cent increase) and perforated peptic ulcer (23.0 per cent increase). Management of oesophageal perforation in high-volume centres was associated with a reduction in 30-day (HR 0.58, 95 per cent c.i. 0.45 to 0.74) and 90-day (HR 0.62, 0.49 to 0.77) mortality. High-volume cancer centre status did not affect mortality from paraoesophageal hernia or perforated peptic ulcer. Annual emergency admission volume thresholds at which mortality improved were observed for oesophageal perforation (5 patients) and paraoesophageal hernia (11). Following centralization, the proportion of patients managed in high-volume cancer centres that reached this volume threshold was 88.0 per cent for oesophageal perforation, but only 30.3 per cent for paraoesophageal hernia. CONCLUSION: Centralization of low incidence conditions such as oesophageal perforation to high-volume cancer centres provides a greater level of expertise and ultimately reduces mortality. PMID- 29155449 TI - Baicalein inhibits acinar-to-ductal metaplasia of pancreatic acinal cell AR42J via improving the inflammatory microenvironment. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers. Recent research has demonstrated that chronic pancreatitis (CP) is associated with an increased risk of PDAC, partly due to acinar-to-ductal metaplasia (ADM). Baicalein has been shown to exert anti-inflammatory and anti-tumor effects for CP or PDAC, respectively. The aim of our study was to investigate the effect of baicalein, and the putative underlying mechanism, on inflammatory cytokines induced ADM of rat pancreatic acinar cell line AR42J. To investigate ADM and baicalein effects in vitro, AR42J were treated with recombinant rat Tumor Necrosis Factor alpha (rTNFalpha) with or without baicalein for 5 days. Results showed that rTNFalpha-induced AR42J cells switched their phenotype from dominantly amylase-positive acinar cells to dominantly cytokeratin 19-positive ductal cells. Moreover, expression of the transcripts for TNFalpha or Hes-1, a Notch target, was up-regulated in these cells. Interestingly, baicalein reduced the population of ADM as well as cytokines gene expression but not Hes-1. Baicalein inhibited NF-kappaB activation induced by rTNFalpha in AR42J, but no effect on Notch 1activation. Moreover, baicalein suppressed the secretion of TNFalpha and Nitric Oxide (NO) in macrophages stimulated with LPS and further inhibited ADM of conditional medium-treated AR42J cells. Baicalein also suppressed the inflammatory response of LPS-activated macrophages, thereby inhibited ADM of AR42J by altering their microenvironment. Taken together, our study indicates that baicalein reduces rTNFalpha-induced ADM of AR42J cells by inhibiting NF-kappaB activation. It also sheds new light on Chinese material medica therapy of pancreatitis and thereby prevention of PDAC. PMID- 29155450 TI - Risk of ovarian function recovery should be considered when switching from treatment with adjuvant tamoxifen to aromatase inhibitor therapy in women with chemotherapy-induced amenorrhea. PMID- 29155451 TI - Reply To: Neutrophil to Lymphocyte Ratio As a Risk Stratification Tool for Older Adults with Pneumonia. PMID- 29155452 TI - Nursing Home Regulations Redefined: Implications for Providers. AB - The Centers for Medicare and Medicaid Services (CMS) finalized a comprehensive update to nursing home requirements of participation in October 2016. Nearly 10,000 public comments were received regarding the proposed rule, and CMS made multiple modifications based on comments from providers, advocacy organizations, and others before issuing the final rule. The final rule describing nursing home requirements of participation modernizes nursing home regulation. It is being implemented in three phases-beginning in November 2016, November 2017, and November 2019. There are multiple provisions that have implications for clinicians caring for nursing home residents, particularly in terms of management of infections, medication prescribing and monitoring, and delegation of medical orders. PMID- 29155453 TI - Large-scale bleaching of corals on the Great Barrier Reef. AB - In 2015-2016, record temperatures triggered a pan-tropical episode of coral bleaching. In the southern hemisphere summer of March-April 2016, we used aerial surveys to measure the level of bleaching on 1,156 individual reefs throughout the 2,300 km length of the Great Barrier Reef, the world's largest coral reef system. The accuracy of the aerial scores was ground-truthed with detailed underwater surveys of bleaching at 260 sites (104 reefs), allowing us to compare aerial and underwater bleaching data with satellite-derived temperatures and with associated model predictions of bleaching. The severity of bleaching on individual reefs in 2016 was tightly correlated with the level of local heat exposure: the southernmost region of the Great Barrier Reef escaped with only minor bleaching because summer temperatures there were close to average. Gradients in nutrients and turbidity from inshore to offshore across the Great Barrier Reef had minimal effect on the severity of bleaching. Similarly, bleaching was equally severe on reefs that are open or closed to fishing, once the level of satellite-derived heat exposure was accounted for. The level of post bleaching mortality, measured underwater after 7-8 months, was tightly correlated with the aerial scores measured at the peak of bleaching. Similarly, reefs with a high aerial bleaching score also experienced major shifts in species composition due to extensive mortality of heat-sensitive species. Reefs with low bleaching scores did not change in composition, and some showed minor increases in coral cover. Two earlier mass bleaching events occurred on the Great Barrier Reef in 1998 and 2002, that were less severe than 2016. In 2016, <9% of scored reefs had no bleaching, compared to 42% in 2002 and 44% in 1998. Conversely, the proportion of reefs that were severely bleached (>60% of corals affected) was four times higher in 2016. The geographic footprint of each of the three events is distinctive, and matches satellite-derived sea surface temperature patterns. Our aerial surveys indicate that past exposure to bleaching in 1998 and 2002 did not lessen the severity of bleaching in 2016. This data set of aerial bleaching scores provides a historical baseline for comparison with future bleaching events. No copyright restrictions apply to the use of this data set other than citing this publication. PMID- 29155455 TI - Living with a Spouse or Others: Beneficial or Harmful in the Presence of Depressive Symptoms? PMID- 29155456 TI - Identifying Sarcopenia in Female Long-Term Care Residents: A Comparison of Current Guidelines. AB - OBJECTIVES: To establish the prevalence of sarcopenia in a long-term care population, assess agreement among different consensus sarcopenia diagnostic criteria, and examine agreement of a self-reported questionnaire with consensus guidelines. DESIGN: Cross-sectional secondary analysis. SETTING: Long-term care communities in the greater Pittsburgh, Pennsylvania, area. PARTICIPANTS: Women aged 65 and older (mean 83.6) undergoing eligibility screening for a fracture reduction trial (N = 141). MEASUREMENTS: We measured appendicular lean muscle mass using dual-energy X-ray absorptiometry. Hand grip strength and usual gait speed were also evaluated. Sarcopenia status was determined according to European Working Group on Sarcopenia in Older People (EWGSOP) and the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project criteria and the SARC-F questionnaire. RESULTS: Eleven participants were sarcopenic (7.8%) according to the EWGSOP criteria, six (4.3%) according to FNIH conservative cut-point guidelines, and 32.6% (n = 46) according to FNIH intermediate cut-points. Only 2 of 141 participants met criteria for sarcopenia according to all three guidelines. Sarcopenia was identified in 30 (21.3%) participants according to the SARC-F questionnaire. Sensitivity of the SARC-F with consensus panel definitions ranged from 18.2% to 33.3%. Specificity ranged from 78.7% to 81.1%. CONCLUSION: Current consensus criteria from the EWGSOP and FNIH Sarcopenia Project do not agree and have little overlap in older female long-term care residents. The SARC F questionnaire is a simple tool that could be implemented in long-term care, but it has low sensitivity compared with current consensus guidelines in the identification of sarcopenic individuals. PMID- 29155457 TI - Impact of Substituent Variation on the Presence of Thermal Spin Crossover in a Series of Mononuclear Iron(III) Schiff Base Complexes with Terminal Pseudohalido Co-ligands. AB - A series of novel iron(III) complexes of the general formula [Fe(L)X] (where L is a dianion of pentadentate Schiff base ligand N,N'-bis({2-hydroxy-3,5 dimethylphenyl}phenyl)methylidene-1,6-diamino-3-azapentane=H2 L1 for 1 and 2; N,N'-bis({2-hydroxy-3-ethoxyphenyl}methylidene)-1,6-diamino-3-azapentane=H2 L2 for 3 and 3?C3 H6 O) and X is terminal pseudohalido ligand (X=N3 for 1, X=NCS for 2, and X=NCSe for 3 and 3?C3 H6 O) were synthesized and thoroughly characterized. Magnetic measurements revealed the above room temperature spin crossover for isomorphic complexes 1 and 2 (T1/2 =441 K and T1/2 =435 K, respectively), whereas the solvent-free complex 3 showed a half complete spin crossover (T1/2 =250 K), which was detected by variable temperature crystallography as well. On the other hand, solvated complex 3?C3 H6 O exhibited permanent high spin state behaviour and either recrystallization or in situ thermal desolvation converts 3?C3 H6 O to solvent-free and spin-crossover-active form 3. Magnetic properties of all the reported complexes were also supported by EPR spectroscopy experiments and in addition, DFT and ab initio calculations were employed for the evaluation of the g-factor and zero field splitting parameters. PMID- 29155454 TI - Harnessing the power of regulatory T-cells to control autoimmune diabetes: overview and perspective. AB - Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease resulting in islet beta-cell destruction, hypoinsulinaemia and severely altered glucose homeostasis. Although the mechanisms that initiate T1D still remain elusive, a breakdown of immune tolerance between effector T-cells (Teff ) and regulatory T-cells (Treg ) is considered to be the crucial component leading to autoimmunity. As such, strategies have been developed to boost the number and/or function of Treg in the hope of specifically hampering the pathogenic Teff activity. In this review, we will summarize the current understanding of biomarkers and functions of both forkhead box protein 3 (FoxP3)+ Treg and type 1 regulatory T (Tr1) cells in health and in T1D, examine the outcome of experimental therapies in both animal models and humans via manipulation of Treg responses and also provide an outlook on the potential of Treg -based immunotherapies in the prevention and treatment of this disease. Discussed immunotherapies include adoptive transfer of ex-vivo expanded FoxP3+ Treg , manipulation of Treg cells via the interleukin (IL)-2/IL 2R pathway and induction of Treg by tolerogenic peptides, tolerogenic dendritic cells or altered gut microbiota. PMID- 29155458 TI - Localization of surfactant protein-D in the rheumatoid synovial membrane. AB - Surfactant protein-D (SP-D) is a collectin, which plays an important role in airway protection and inflammation. The molecule has both pro- and anti inflammatory capacities depending on its molecular size. Its involvement in joint diseases is largely unknown and the aim of this investigation was to study SP-D occurrence and distribution in the synovial membrane of patients with long standing rheumatoid arthritis (RA) and osteoarthritis (OA). Six RA patients and six OA patients, who underwent total hip arthroplasty, were included in the study. Synovial tissue biopsies were obtained during surgery and subsequently prepared for immunohistochemistry. In this first, small-scale comparative study on the occurrence of SP-D in the synovial membrane of RA and OA, we report that SP-D was only present in the microvascular endothelium in subsynovial and pannus tissue and that the immunostaining was much stronger than in OA. This distribution pattern suggests that SP-D modulates RA inflammatory activities. PMID- 29155459 TI - Erysipelothrix rhusiopathiae serotype 5-associated metritis in a Norwegian Red heifer. AB - This report summarized the findings of a case of Erysipelothrix rhusiopathiae infection in a farmed Norwegian Red heifer located in the south-east of Norway. The 2.5-year-old pregnant heifer was found dead after a short episode of inappetence. On gross exam, the heifer was severely dehydrated with uterine torsion. Microscopically, necrosis of the endometrium was present throughout the uterus along with presence of intralesional Gram-positive bacteria, interstitial nephritis, and pyelonephritis. E. rhusiopathiae was isolated from the uterus and placenta and was also demonstrated by immunohistochemistry (IHC) in the uterus, placenta, and kidney. The E. rhusiopathiae isolate was further characterized as serotype 5. To the authors' knowledge, this is the first report of bacterial metritis associated with E. rhusiopathiae serotype 5 infection. The etiology of the infection is unknown but the E. rhusiopathiae could have been a primary or opportunistic pathogen. Serotype 5 of E. rhusiopathiae has been identified in several mammalian species in recent years and could be emerging. PMID- 29155461 TI - Nanoscale Trimetallic Metal-Organic Frameworks Enable Efficient Oxygen Evolution Electrocatalysis. AB - Metal-organic frameworks (MOFs) are a class of promising materials for diverse heterogeneous catalysis, but they are usually not directly employed for oxygen evolution electrocatalysis. Most reports focus on using MOFs as templates to in situ create efficient electrocatalysts through annealing. Herein, we prepared a series of Fe/Ni-based trimetallic MOFs (Fe/Ni/Co(Mn)-MIL-53 accordingly to the Material of Institute Lavoisier) by solvothermal synthesis, which can be directly adopted as highly efficient electrocatalysts. The Fe/Ni/Co(Mn)-MIL-53 shows a volcano-type oxygen evolution reaction (OER) activity as a function of compositions. The optimized Fe/Ni2.4 /Co0.4 -MIL-53 can reach a current density of 20 mA cm-2 at low overpotential of 236 mV with a small Tafel slope of 52.2 mV dec-1 . In addition, the OER performance of these MOFs can be further enhanced by directly being grown on nickel foam (NF). PMID- 29155460 TI - Antarctic emerald rockcod have the capacity to compensate for warming when uncoupled from CO2 -acidification. AB - Increases in atmospheric CO2 levels and associated ocean changes are expected to have dramatic impacts on marine ecosystems. Although the Southern Ocean is experiencing some of the fastest rates of change, few studies have explored how Antarctic fishes may be affected by co-occurring ocean changes, and even fewer have examined early life stages. To date, no studies have characterized potential trade-offs in physiology and behavior in response to projected multiple climate change stressors (ocean acidification and warming) on Antarctic fishes. We exposed juvenile emerald rockcod Trematomus bernacchii to three PCO2 treatments (~450, ~850, and ~1,200 MUatm PCO2 ) at two temperatures (-1 or 2 degrees C). After 2, 7, 14, and 28 days, metrics of physiological performance including cardiorespiratory function (heart rate [fH ] and ventilation rate [fV ]), metabolic rate (MO2), and cellular enzyme activity were measured. Behavioral responses, including scototaxis, activity, exploration, and escape response were assessed after 7 and 14 days. Elevated PCO2 independently had little impact on either physiology or behavior in juvenile rockcod, whereas warming resulted in significant changes across acclimation time. After 14 days, fH , fV and MO2 significantly increased with warming, but not with elevated PCO2 . Increased physiological costs were accompanied by behavioral alterations including increased dark zone preference up to 14%, reduced activity by 12%, as well as reduced escape time suggesting potential trade-offs in energetics. After 28 days, juvenile rockcod demonstrated a degree of temperature compensation as fV , MO2, and cellular metabolism significantly decreased following the peak at 14 days; however, temperature compensation was only evident in the absence of elevated PCO2 . Sustained increases in fV and MO2 after 28 days exposure to elevated PCO2 indicate additive (fV ) and synergistic (MO2) interactions occurred in combination with warming. Stressor-induced energetic trade-offs in physiology and behavior may be an important mechanism leading to vulnerability of Antarctic fishes to future ocean change. PMID- 29155462 TI - Iron(II)-Catalyzed Direct Synthesis of NH Sulfoximines from Sulfoxides. AB - Free NH-sulfoximines were directly prepared from sulfoxides through iron catalysis by applying a readily available, shelf-stable hydroxylamine triflic acid salt. No additional oxidant is needed, and the substrate scope is broad, including a range of heterocyclic compounds. PMID- 29155463 TI - Free gracilis muscle transfer for smile reanimation after treatment for advanced parotid malignancy. AB - BACKGROUND: The purpose of this study was to characterize the outcomes of free gracilis muscle transfer for delayed smile reanimation after radical parotidectomy. METHODS: A retrospective chart review of patients who underwent free gracilis muscle transfer for smile reanimation after radical parotidectomy between 2003 and 2016 was performed. Patient-reported quality of life (Facial Clinimetric Evaluation Scale [FaCE]), physician-reported facial function ("eFACE" facial grading scale), and oral commissure excursion were compared preoperatively and postoperatively. RESULTS: Twelve patients were identified with prior surgery and adjuvant therapy (radiotherapy in 6 cases and chemoradiotherapy in 6 cases). Significant postoperative improvements were demonstrated for ipsilateral commissure excursion with smile (preoperatively: -2.2 mm [SD 2.3 mm] vs postoperatively: 7.9 mm [SD 2.5 mm]; P = .002), with meaningful smile achieved in 11 of 12 cases (91.7%). The average duration of facial paralysis before intervention was 72 months (range 12-204 months). CONCLUSION: Free gracilis muscle transfer is an option for dynamic smile reanimation in select patients who have undergone treatment for advanced parotid malignancy. PMID- 29155464 TI - Both life-history plasticity and local adaptation will shape range-wide responses to climate warming in the tundra plant Silene acaulis. AB - Many predictions of how climate change will impact biodiversity have focused on range shifts using species-wide climate tolerances, an approach that ignores the demographic mechanisms that enable species to attain broad geographic distributions. But these mechanisms matter, as responses to climate change could fundamentally differ depending on the contributions of life-history plasticity vs. local adaptation to species-wide climate tolerances. In particular, if local adaptation to climate is strong, populations across a species' range-not only those at the trailing range edge-could decline sharply with global climate change. Indeed, faster rates of climate change in many high latitude regions could combine with local adaptation to generate sharper declines well away from trailing edges. Combining 15 years of demographic data from field populations across North America with growth chamber warming experiments, we show that growth and survival in a widespread tundra plant show compensatory responses to warming throughout the species' latitudinal range, buffering overall performance across a range of temperatures. However, populations also differ in their temperature responses, consistent with adaptation to local climate, especially growing season temperature. In particular, warming begins to negatively impact plant growth at cooler temperatures for plants from colder, northern populations than for those from warmer, southern populations, both in the field and in growth chambers. Furthermore, the individuals and maternal families with the fastest growth also have the lowest water use efficiency at all temperatures, suggesting that a trade off between growth and water use efficiency could further constrain responses to forecasted warming and drying. Taken together, these results suggest that populations throughout species' ranges could be at risk of decline with continued climate change, and that the focus on trailing edge populations risks overlooking the largest potential impacts of climate change on species' abundance and distribution. PMID- 29155465 TI - Catalytic Dibenzocyclooctene Synthesis via Cobalt(III)-Carbene Radical and ortho Quinodimethane Intermediates. AB - The metalloradical activation of ortho-benzallylaryl N-tosyl hydrazones with [Co(TPP)] (TPP=tetraphenylporphyrin) as the catalyst enabled the controlled exploitation of the single-electron reactivity of the redox non-innocent carbene intermediate. This method offers a novel route to prepare eight-membered rings, using base metal catalysis to construct a series of unique dibenzocyclooctenes through selective Ccarbene -Caryl cyclization. The desired eight-membered-ring products were obtained in good to excellent yields. A large variety of aromatic substituents are tolerated. The proposed reaction mechanism involves intramolecular hydrogen atom transfer (HAT) to CoIII -carbene radical intermediates followed by dissociation of an ortho-quinodimethane that undergoes 8pi cyclization. The mechanism is supported by DFT calculations, and the presence of radical-type intermediates was confirmed by trapping experiments. PMID- 29155466 TI - Letter to the Editor-2 regarding "Extracapsular dissection versus superficial parotidectomy in benign parotid gland tumors: The Vienna Medical School experience". PMID- 29155467 TI - Synthesis, Characterisation and Reactions of Truly Cationic NiI -Phosphine Complexes. AB - The recently published purely metallo-organic NiI salt [Ni(cod)2 ][Al(ORF )4 ] (1, cod=1,5-cyclooctadiene, RF =C(CF3 )3 ) provides a starting point for a new synthesis strategy leading to NiI phosphine complexes, replacing cod ligands by phosphines. Clearly visible colour changes indicate reactions within minutes, while quantum chemical calculations (PBE0-D3(BJ)/def2-TZVPP) approve exergonic reaction enthalpies in all performed ligand exchange reactions. Hence, [Ni(dppp)2 ][Al(ORF )4 ] (2, dppp=1,3-bis(diphenylphosphino)propane), [Ni(dppe)2 ][Al(ORF )4 ] (3, dppe=1,3-bis(diphenyl-phosphino)ethane), three-coordinate [Ni(PPh3 )3 ][Al(ORF )4 ] (4) and a remarkable two-coordinate NiI phosphine complex [Ni(PtBu3 )2 ][Al(ORF )4 ] (5) were characterised by single crystal X-ray structure analysis. EPR studies were performed, confirming a nickel d9 -configuration in complexes 2, 4 and 5. This result is supported by additional magnetization measurements of 4 and 5. Further investigations by cyclic voltammetry indicate relatively high oxidation potentials for these NiI compounds between 0.7 and 1.7 V versus Fc/Fc+ . Screening reactions with O2 and CO gave first insights on the reaction behaviour of the NiI phosphine complexes towards small molecules with formation of mixed phosphine-CO-NiI complexes and oxidation processes yielding new NiI and/or NiII derivatives. Moreover, 4 reacted with CH2 Cl2 at RT to give a dimeric NiII ylide complex (4 c). As CH2 Cl2 is a rather stable alkyl halide with relatively high C-Cl bond energies, 4 appears to be a suitable reagent for more general C-Cl bond activation reactions. PMID- 29155468 TI - Gram-Scale Synthesis of the (-)-Sparteine Surrogate and (-)-Sparteine. AB - An 8-step, gram-scale synthesis of the (-)-sparteine surrogate (22 % yield, with just 3 chromatographic purifications) and a 10-step, gram-scale synthesis of (-) sparteine (31 % yield) are reported. Both syntheses proceed with complete diastereocontrol and allow access to either antipode. Since the syntheses do not rely on natural product extraction, our work addresses long-term supply issues relating to these widely used chiral ligands. PMID- 29155469 TI - Voltage-Controlled Switching of Strong Light-Matter Interactions using Liquid Crystals. AB - We experimentally demonstrate a fine control over the coupling strength of vibrational light-matter hybrid states by controlling the orientation of a nematic liquid crystal. Through an external voltage, the liquid crystal is seamlessly switched between two orthogonal directions. Using these features, for the first time, we demonstrate electrical switching and increased Rabi splitting through transition dipole moment alignment. The C-Nstr vibration on the liquid crystal molecule is coupled to a cavity mode, and FT-IR is used to probe the formed vibropolaritonic states. A switching ratio of the Rabi splitting of 1.78 is demonstrated between the parallel and the perpendicular orientation. Furthermore, the orientational order increases the Rabi splitting by 41 % as compared to an isotropic liquid. Finally, by examining the influence of molecular alignment on the Rabi splitting, the scalar product used in theoretical modeling between light and matter in the strong coupling regime is verified. PMID- 29155470 TI - Safety and effectiveness of endovascular embolization or stent-graft reconstruction for treatment of acute carotid blowout syndrome in patients with head and neck cancer: Case series and systematic review of observational studies. AB - BACKGROUND: Indications for treatment and outcomes after endovascular management of carotid blowout syndrome for patients with head and neck cancer are not well defined. We investigated the safety and effectiveness of endovascular embolization and stent-graft reconstruction. METHODS: A literature review was performed for studies published between 2001 and 2015 with relevance to treatment outcomes. Our institutional database was examined to identify patients treated with endovascular techniques. RESULTS: A total of 266 patients were included. Rates of procedural stroke were higher after embolization of internal carotid artery (ICA)/common carotid artery (CCA) compared to stent graft (embolization 10.3%; stent graft 2.5%; P < .02). Stent graft of ICA/CCA was associated with higher rates of recurrent bleeding (embolization 9.1%; stent graft 31.9%; P < .01). CONCLUSION: Both embolization and stent grafts are safe therapeutic options for acute carotid blowout syndrome. Embolization for ICA/CCA carotid blowout syndrome was associated with higher risks of procedural stroke and lower recurrent bleeding compared to stent grafts. PMID- 29155471 TI - Alcohol-related harm in emergency departments: a prospective, multi-centre study. AB - BACKGROUND AND AIMS: Emergency department (ED) alcohol-related presentation data are not routinely collected in Australia and New Zealand. It is likely that previous research has underestimated the numbers of patients presenting with alcohol-related conditions. This study aimed to quantify the level of alcohol harm presenting to EDs in Australia and New Zealand [Correction added on 23 Jan 2018, after first online publication: The 'aims' section was missing and is updated in this version]. DESIGN: Multi-centre, prospective study. Patients were screened prospectively for alcohol-related presentations during a 7-day period in December 2014. Part 1 involved screening to determine alcohol-positive ED presentations and data collection of patient demographic and clinical information. Part 2 involved a consent-based survey conducted with patients aged >= 14 years to perform Alcohol Use Disorders Identification Test (AUDIT) scores. SETTING: Eight EDs in Australia and New Zealand, representing differing hospital role delineations. PARTICIPANTS: A total of 8652 patients aged >= 14 years attended and 8435 (97.5%) were screened. MEASUREMENTS: The main outcome measure was the proportion of patients who had an alcohol-related presentation termed 'alcohol-positive', using pre-defined criteria. It included injuries, intoxication, medical conditions and injuries caused by an alcohol-affected third party. Secondary outcomes included demographic and clinical information, the type of alcohol-related presentations and AUDIT scores. FINDINGS: A total of 801 [9.5%; 95% confidence interval (CI) = 8.9-10.1%] presentations were identified as alcohol-positive, ranging between 4.9 and 15.2% throughout sites. Compared with alcohol-negative patients, alcohol-positive patients were more likely to be male [odds ratio (OR) = 1.90, 95% CI = 1.63-2.21], younger (median age 37 versus 46 years, P < 0.0001), arrive by ambulance (OR = 1.94, 95% CI = 1.68-2.25) or police/correctional vehicle (OR = 4.56, 95% CI = 3.05-6.81) and require immediate treatment (OR = 3.20, 95% CI = 2.03-05.06). The median AUDIT score was 16 (interquartile range = 10-24). CONCLUSIONS: Almost one in 10 presentations to emergency departments in Australia and New Zealand are alcohol related. PMID- 29155472 TI - Experimental reconstruction of double-stranded break repair-mediated plastid DNA insertion into the tobacco nucleus. AB - The mitochondria and plastids of eukaryotic cells evolved from endosymbiotic prokaryotes. DNA from the endosymbionts has bombarded nuclei since the ancestral prokaryotes were engulfed by a precursor of the nucleated eukaryotic host. An experimental confirmation regarding the molecular mechanisms responsible for organelle DNA incorporation into nuclei has not been performed until the present analysis. Here we introduced double-stranded DNA breaks into the nuclear genome of tobacco through inducible expression of I-SceI, and showed experimentally that tobacco chloroplast DNAs insert into nuclear genomes through double-stranded DNA break repair. Microhomology-mediated linking of disparate segments of chloroplast DNA occurs frequently during healing of induced nuclear double-stranded breaks (DSB) but the resulting nuclear integrants are often immediately unstable. Non Mendelian inheritance of a selectable marker (neo), used to identify plastid DNA transfer, was observed in the progeny of about 50% of lines emerging from the screen. The instability of these de novo nuclear insertions of plastid DNA (nupts) was shown to be associated with deletion not only of the nupt itself but also of flanking nuclear DNA within one generation of transfer. This deletion of pre-existing nuclear DNA suggests that the genetic impact of organellar DNA transfer to the nucleus is potentially far greater than previously thought. PMID- 29155473 TI - Relationship between hepatic progenitor cells and stellate cells in chronic hepatitis C genotype 4. AB - Hepatitis C virus (HCV) infection represents a major health problem in many areas of the world, especially Egypt. Hepatic progenitor cells (HPCs) and hepatic stellate cells (HSCs) have been implicated in fibrosis progression in chronic HCV. The aim of this study was to investigate the role of HPCs and HSCs in chronic HCV infection and the relationship between both cell types. This retrospective study was conducted on 100 chronic HCV patients. Immunohistochemistry was performed on liver tissue sections for cytokeratin 19 (progenitor cell markers), smooth muscle actin (stellate cell markers), matrix metalloproteinase-9 (MMP-9), and transforming growth factor beta (TGF-beta). The necroinflammatory activity was significantly related to the number of isolated HPCs and TGF-beta expression (p = 0.003 and p = 0.001 respectively). Advanced stages of fibrosis showed significantly increase number of HPCs (p = 0.001), higher ratio of HSCs (p = 0.004), more expression of TGF-beta (p = 0.001) and MMP 9 (p = 0.001). There was a significant direct correlation between immunoexpression of HPCs and HSCs for isolated cells (r = 0.569, p = 0.001) and ductular reaction (r = 0.519, p = 0.001). Hepatic progenitor cells and stellate cells play a significant role in the development and progression of fibrosis in chronic HCV. More interestingly, the significant direct correlation between HPCs and HSCs suggests a synergistic interrelation. PMID- 29155474 TI - Visual biofeedback using transperineal ultrasound in second stage of labor. AB - OBJECTIVE: To assess the obstetric and psychological effects of visual biofeedback by transperineal ultrasound (TPU) during the second stage of labor. METHODS: This was a prospective, single-center observational study of low-risk nulliparous women with epidural analgesia undergoing vaginal delivery. Visual biofeedback using TPU was provided to 26 women during the second stage of labor. Pushing efficacy was assessed by the change in the angle of progression (AoP) at rest and during pushing efforts, before and after biofeedback. Obstetric outcomes included incidence of perineal tearing, mode of delivery and length of second stage of labor. Psychological outcomes were assessed by self-reported measures obtained during the postnatal hospital stay and included measures of perceived control and maternal satisfaction with childbirth, as well as level of maternal feelings of connectedness with the newborn. Obstetric and psychological results were compared with those of a control group of 69 women who received standard obstetric coaching from midwives. RESULTS: Pushing efficacy increased significantly following visual biofeedback by TPU (P = 0.01), as indicated by a significantly lower delta AoP before (mean, 22.2 degrees (95% CI, 13.9-31.7 degrees )) compared with after (mean, 35.2 degrees (95% CI, 25.9-45.3 degrees )) biofeedback. A significant association was found between visual biofeedback and an intact perineum following delivery (P = 0.03). No significant differences were found between the two groups with regard to mode of delivery or length of the second stage. Feelings of maternal connectedness with the newborn were significantly stronger (P = 0.003) in women who received visual biofeedback than in those who did not. However, perceived control during childbirth and maternal satisfaction with childbirth did not differ significantly between the biofeedback and control groups. CONCLUSIONS: This pilot study suggests that biofeedback using TPU may serve as a complementary tool to coached maternal pushing during the second stage of labor, with obstetric as well as psychological benefits. Further studies are required to confirm our findings and define the optimal duration of the intervention. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29155475 TI - Weight discordance and perinatal mortality in twin pregnancy: systematic review and meta-analysis. AB - OBJECTIVES: The primary aim of this systematic review was to explore the strength of association between birth-weight (BW) discordance and perinatal mortality in twin pregnancy. The secondary aim was to ascertain the contribution of gestational age and growth restriction in predicting mortality in growth discordant twins. METHODS: MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched. Only studies reporting on the risk of mortality in twin pregnancies affected compared with those not affected by BW discordance were included. The primary outcomes explored were incidence of intrauterine death (IUD), neonatal death (NND) and perinatal death. Outcome was assessed separately for monochorionic (MC) and dichorionic (DC) twin pregnancies. Analyses were stratified according to BW discordance cut-off (>= 15%, >= 20%, >= 25% and >= 30%) and selected gestational characteristics, including incidence of IUD or NND before and after 34 weeks' gestation, presence of at least one small-for gestational age (SGA) fetus in the twin pair and both twins being appropriate-for gestational age. Risk of mortality in the larger vs smaller twin was also assessed. Meta-analyses using individual data random-effects logistic regression and meta-analyses of proportion were used to analyze the data. RESULTS: Twenty two studies (10 877 twin pregnancies) were included in the analysis. In DC pregnancies, a higher risk of IUD, but not of NND, was observed in twins with BW discordance >= 15% (odds ratio (OR) 9.8, 95% CI, 3.9-29.4), >= 20% (OR 7.0, 95% CI, 4.15-11.8), >= 25% (OR 17.4, 95% CI, 8.3-36.7) and >= 30% (OR 22.9, 95% CI, 10.2-51.6) compared with those without weight discordance. For each cut-off of BW discordance explored in DC pregnancies, the smaller twin was at higher risk of mortality compared with the larger one. In MC twin pregnancies, excluding cases affected by twin-twin transfusion syndrome, twins with BW discordance >= 20% (OR 2.8, 95% CI, 1.3-5.8) or >= 25% (OR 3.2, 95% CI, 1.5-6.7) were at higher risk of IUD, compared with controls. MC pregnancies with >= 25% weight discordance were also at increased risk of NND (OR 4.66, 95% CI, 1.8-12.4) compared with those with concordant weight. The risk of IUD was higher when considering discordant pregnancies involving at least one SGA fetus. The overall risk of mortality in MC pregnancies was similar between the smaller and larger twin, except in those with BW discordance >= 20%. CONCLUSION: DC and MC twin pregnancies discordant for fetal growth are at higher risk of IUD but not of NND compared with pregnancies with concordant BW. The risk of IUD in BW-discordant DC and MC twins is higher when at least one fetus is SGA. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29155476 TI - Reply to the Letter to the Editor-2 regarding "Extracapsular dissection versus superficial parotidectomy in benign parotid gland tumors: The Vienna Medical School experience". PMID- 29155477 TI - Oxidized low-density lipoprotein suppresses mouse granulosa cell differentiation through disruption of the hypoxia-inducible factor 1 pathway. AB - Obesity predisposes women to reproductive disorders. One symptom of obesity in women is higher levels of oxidized Low-density lipoprotein (oxLDL) in serum and preovulatory follicles. The present study was designed to test the hypothesis that oxLDL might impair follicle differentiation and luteinization. Given that Hypoxia-inducible factor 1 (HIF1) plays crucial roles in supporting follicle differentiation and luteinization in mammals, we focused on oxLDL-mediated events that may affect the HIF1 pathway. We report that exposure to oxLDL diminished the expression of HIF1alpha and its target genes and suppressed the differentiation of mouse luteinized granulosa cells following induction by human Chorionic gonadotophin (hCG) under hypoxic conditions (1% oxygen). Significantly, the proteasome inhibitor MG-132 prevented this oxLDL-attenuation differentiation phenotype by blocking HIF1alpha degradation. Together, these findings suggest that suppression of granulosa cell differentiation by oxLDL, via HIF1alpha down regulation, may contribute the negative effects of obesity on female fertility. PMID- 29155478 TI - Alternative polyadenylation is involved in auxin-based plant growth and development. AB - Auxin is widely involved in plant growth and development. However, the molecular mechanism on how auxin carries out this work is unclear. In particular, the effect of auxin on pre-mRNA post-transcriptional regulation is mostly unknown. By using a poly(A) tag (PAT) sequencing approach, mRNA alternative polyadenylation (APA) profiles after auxin treatment were revealed. We showed that hundreds of poly(A) site clusters (PACs) are affected by auxin at the transcriptome level, where auxin reduces PAC distribution in 5'-untranslated region (UTR), but increases in the 3'UTR. APA site usage frequencies of 42 genes were switched by auxin, suggesting that auxin affects the choice of poly(A) sites. Furthermore, poly(A) signal selection was altered after auxin treatment. For example, a mutant of poly(A) signal binding protein CPSF30 showed altered sensitivity to auxin treatment, indicating interactions between auxin and the poly(A) signal recognition machinery. We also found that auxin activity on lateral root development is likely mediated by altered expression of ARF7, ARF19 and IAA14 through poly(A) site switches. Our results shed light on the molecular mechanisms of auxin responses relative to its interactions with mRNA polyadenylation. PMID- 29155479 TI - Managing uterine artery pseudoaneurysm after myomectomy. PMID- 29155480 TI - Intensity-modulated radiotherapy for elderly patients with nasopharyngeal carcinoma. AB - BACKGROUND: The purpose of this study was to evaluate the clinical outcomes and patterns of failure after intensity-modulated radiotherapy (IMRT) for elderly patients with nasopharyngeal carcinoma (NPC). METHODS: Fifty-two patients treated with IMRT were eligible for study inclusion. Comorbidity was rated using the Adult Comorbidity Evaluation-27 (ACE-27) system. RESULTS: Twenty-six patients (50.0%) had an ACE-27 score of 1; and 6 (11.5%) had an ACE-27 score of 2. Eleven patients had died and 5 (45.5%) of them died of NPC. Two patients had developed local recurrence only, 1 had developed regional recurrence only, and 7 had developed distant metastasis only. The locoregional failure-free survival, distant failure-free survival, cancer-specific survival (CSS), and overall survival (OS) rates at 5 years were 92.6%, 83.7%, 84.9%, and 69.4%, respectively. CONCLUSION: The results of treating elderly patients with NPC by IMRT were excellent. Distant metastasis remains the most difficult treatment challenge for elderly patients with NPC. PMID- 29155481 TI - Peroxisome proliferator activated receptor-gamma stimulation for prevention of 5 fluorouracil-induced oral mucositis in mice. AB - BACKGROUND: Oral mucositis is a side effect of treatment regimens containing 5 fluorouracil (5-FU). The purpose of this study was to present our evaluation to see if rosiglitazone (RGZ) protected normal tissues from chemotherapy-induced oral mucositis. METHODS: C57BL/6J mice were treated with 5-FU for 5 days, with or without RGZ. Mice were euthanized after 5, 8, 11, or 15 days, and mucosal segments were collected. RESULTS: The RGZ did not affect the 5-FU-induced decrease in mouse body weight. The 5-FU caused loss of epithelial architecture, collagen fiber impairment, and inflammatory infiltration. The RGZ reduced leukocyte infiltration, preserved tissue structure, and dampened the 5-FU-induced expression of p53 and matrix metalloproteinase (Mmp)-2 after 5 days, and of Mmp-2 and interleukin (Il-1beta after 15 days. The RGZ inhibited the 5-FU-induced increase of transforming growth factor-beta (TGF-beta) and nuclear factor-kappa B (NF-kappaB) proteins and restored collagen protein levels. CONCLUSION: The RGZ had a protective effect on oral mucosa damaged by chemotherapy. These data encourage the further study of RGZ for the prevention of 5-FU-induced mucositis in patients with cancer. PMID- 29155482 TI - Prenatal sonographic diagnosis of acardiac twin embedded within placenta. PMID- 29155484 TI - Elevated difenacoum metabolism is involved in the difenacoum-resistant phenotype observed in Berkshire rats homozygous for the L120Q mutation in the vitamin K epoxide reductase complex subunit 1 (Vkorc1) gene. AB - BACKGROUND: Soon after difenacoum began to be used, resistance to this rodenticide was detected in rats in northeast Hampshire and northwest Berkshire in England. Resistance to difenacoum has been reported to be stronger in rats from Berkshire than in rats from Hampshire. Surprisingly, after the discovery of the vitamin K epoxide reductase complex subunit 1 (Vkorc1) gene, rats from Berkshire and Hampshire were all shown to be homozygous for the L120Q mutation in Vkorc1. RESULTS: This study aimed to evaluate the resistance of Berkshire rats to confirm their extreme resistance and determine mechanisms supporting this resistance. For this purpose, we created a quasicongenic rat F7 strain by using a Berkshire rat as a donor to introduce the L120Q mutation in Vkorc1 into the genetic background of an anticoagulant-susceptible recipient strain. The use of F7 rats enabled demonstration of (i) the level of resistance to difenacoum conferred by the L120Q mutation, (ii) co-dominance of the L120 and Q120 alleles, (iii) the extreme resistance of Berkshire rats compared with Q120/Q120 rats as a consequence of additional resistance mechanisms, and (iv) the involvement of cytochrome P 450 (CYP450) enzymes in this extreme resistance. CONCLUSION: This study demonstrated that elevated CYP450 oxidative metabolism leading to accelerated difenacoum detoxification is involved in the Berkshire phenotype. (c) 2017 Society of Chemical Industry. PMID- 29155483 TI - Modelling persistent Mycoplasma pneumoniae infection of human airway epithelium. AB - Mycoplasma pneumoniae is a human respiratory tract pathogen causing acute and chronic airway disease states that can include long-term carriage and extrapulmonary spread. The mechanisms of persistence and migration beyond the conducting airways, however, remain poorly understood. We previously described an acute exposure model using normal human bronchial epithelium (NHBE) in air-liquid interface culture, showing that M. pneumoniae gliding motility is essential for initial colonisation and subsequent spread, including localisation to epithelial cell junctions. We extended those observations here, characterizing M. pneumoniae infection of NHBE for up to 4 weeks. Colonisation of the apical surface was followed by pericellular invasion of the basolateral compartment and migration across the underlying transwell membrane. Despite fluctuations in transepithelial electrical resistance and increased NHBE cell desquamation, barrier function remained largely intact. Desquamation was accompanied by epithelial remodelling that included cytoskeletal reorganisation and development of deep furrows in the epithelium. Finally, M. pneumoniae strains S1 and M129 differed with respect to invasion and histopathology, consistent with contrasting virulence in experimentally infected mice. In summary, this study reports pericellular invasion, NHBE cytoskeletal reorganisation, and tissue remodelling with persistent infection in a human airway epithelium model, providing clear insight into the likely route for extrapulmonary spread. PMID- 29155485 TI - Advantages of diapause in Trichogramma dendrolimi mass production on eggs of the Chinese silkworm, Antheraea pernyi. AB - BACKGROUND: Trichogramma dendrolimi Matsumura is widely used as a biological control agent for control of lepidopteran agricultural pests in China and can be successfully reared using the large eggs of the Chinese silkworm, Antheraea pernyi. In this study, biological parameters of diapaused, non-diapaused, and cold-stored T. dendrolimi were investigated for two generations on host eggs of A. pernyi under laboratory conditions. RESULTS: The cold-stored T. dendrolimi performed more poorly than diapaused and non-diapaused T. dendrolimi based on biological parameters. In the F1 generation, the non-diapaused T. dendrolimi had a higher emergence rate, longer longevity, and a lower proportion of deformed individuals than diapaused T. dendrolimi. In the F2 generation, the diapaused T. dendrolimi had a lower proportion of unemerged parasitoids than non-diapaused T. dendrolimi. However, the diapaused T. dendrolimi had a higher number of parasitized hosts than non-diapaused T. dendrolimi in both generations. In the F1 generation, the index of population trend (I) was found to be similar for diapaused (140.792) and non-diapaused (141.542) T. dendrolimi and was approximately 3.4 times that of cold-stored T. dendrolimi (41.698). In the F2 generation, the diapaused T. dendrolimi showed the largest I (146.791), followed by non-diapaused (136.859) and cold-stored T. dendrolimi (59.607). CONCLUSION: In a 3-year augmentative field release from 2014 to 2016, diapaused T. dendrolimi showed effective parasitism on eggs of the Asian corn borer, Ostrinia furnacalis. These results indicated that diapaused T. dendrolimi can be an efficient alternative method for mass rearing of T. dendrolimi for long-term cold storage. (c) 2017 Society of Chemical Industry. PMID- 29155486 TI - Toxic stress and child refugees. AB - : The purpose of this article was to describe the phenomenon of toxic stress and its impact on the physical and mental health of child refugees. Almost two decades ago, researchers found that recurring adverse childhood events (ACEs; e.g., physical, psychological, and sexual abuse, neglect, and household dysfunction such as substance abuse, mental illness, and criminal behavior) were associated with a significant increase in serious illnesses during adulthood. Illnesses include heart, lung, and liver disease, cancer, and bone fractures. The scientists reported that experiencing four or more ACEs during childhood significantly increases the risk for toxic stress. Toxic stress is defined as the exposure to extreme, frequent, and persistent adverse events without the presence of a supportive caretaker. There is a paucity of literature related to toxic stress and child refugees. However, it has been clearly established that the prolonged brutal and traumatizing war in Syria is having a profound impact on the physical and mental health of child refugees at a distressing rate. Prevention of toxic stress should be a primary goal of all pediatric healthcare professionals working with child refugees. While this seems daunting given the population, and the seemingly insurmountable stressors they experience, some basic interventions should be considered. Providing basic anticipatory guidance to parents and caregivers of child refugees, to encourage positive parenting and strengthening support networks, will be highly effective in developing the requisite buffers that mitigate the effects of stress and avoid toxic stress. Efforts should also be focused on addressing caregiver stress and improving their ability to provide safe, reliable, and nurturing care that will help to mitigate any stress response experienced by a child. PRACTICE IMPLICATIONS: It is critical that greater awareness be placed on the effects of toxic stress on child refugees who are exposed to significant adverse events early in life. PMID- 29155487 TI - Novel cytochrome P450 (CYP6D1) and voltage sensitive sodium channel (Vssc) alleles of the house fly (Musca domestica) and their roles in pyrethroid resistance. AB - BACKGROUND: The house fly Musca domestica is an important disease vector. Point mutation-mediated target-site insensitivity of the voltage sensitive sodium channel (VSSC) and increased detoxification mediated by cytochrome P450 (CYP6D1) overexpression have been characterized as two major mechanisms of pyrethroid resistance. In this study, genetic mutations in the Vssc and CYP6D1 genes and their contribution to pyrethroid resistance were investigated. RESULTS: Twelve lines of house flies homozygous for four genotypes were established. House flies carrying the VSSC 1014F mutation and overexpressing CYP6D1 had higher resistance to pyrethroids than those carrying 1014F alone. The presence of the 15-bp insert in the promoter region of the CYP6D1 gene did not necessarily result in a significant increase in CYP6D1 mRNA and pyrethroid resistance levels. A novel Vssc allele carrying two mutations (G1924D and G2004S) in combination with the classic 1014F and a novel CYP6D1 allele that is very similar to CYP6D1v1 were identified in Chinese house flies. CONCLUSION: This work demonstrates the effect of genetic mutations in CYP6D1 and Vssc on the susceptibility of house flies to pyrethroids, and verifies that 15-bp insert-containing CYP6D1 alleles have a single origin. These findings offer insights into the evolution of insecticide resistance and have implications for house fly control. (c) 2017 Society of Chemical Industry. PMID- 29155488 TI - Effectiveness of a virtual reality intervention to minimize pediatric stress and pain intensity during venipuncture. AB - PURPOSE: Virtual reality (VR) technology is an effective tool in treatment of acute pain. Numerous studies show the effectiveness of this method both in a clinical context and in the laboratory. However, research results on the effectiveness of VR in pediatric venipuncture pain is not conclusive-not all studies report the analgesic effect of VR. In addition to testing effectiveness of VR, we also assess the usability of a novel hands-free interface. DESIGN AND METHODS: Patients of paediatric nephrology clinic (N = 38; mean age 11 years, range 7-17) participated in a posttest only between group quasi-experimental study. Participants in the treatment group received the venipuncture procedure with VR distraction. They were wearing a head-mounted Oculus DK2 HMD, and playing a game designed by the authors of the study. The game was based on Multiple Object Tracking (MOT) task, where players have to remember and simultaneously track several moving targets. MOT has been used in many studies on attention and working memory. Participants rated their pain and stress intensity on visual analogue scales (VAS) on a scale of 0 to 100 and answered a short questionnaire. RESULTS: The VR group reported significantly lower pain intensity than the controls (mean = 15.16 +/- 20.51 vs. 37.05 +/- 30.66; t = 2.59, df = 36, p < .02, d = 0.863). Similar results were obtained for stress level (11.16 +/-18.58 vs 41.89 +/- 40.89; t = 2.98, df = 36, p < .01, d = 0.993). There were no correlations with age. PRACTICE IMPLICATIONS: VR can be as an effective tool to minimize pediatric pain and stress due to venipuncture. The MOT-based VR game was suitable for children at the studied age range. This solution can be easily applied by nurses in their clinical practice. PMID- 29155489 TI - Priming of cowpea volatile emissions with defense inducers enhances the plant's attractiveness to parasitoids when attacked by caterpillars. AB - BACKGROUND: The manipulation of herbivore-induced volatile organic compounds (HI VOCs) via the application of the inducers benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester (BTH) and laminarin (beta-1,3-glucan) is known to enhance the attractiveness of caterpillar-damaged cotton and maize plants to parasitoids. To test if this is also the case for legumes, we treated cowpea (Vigna unguiculata var. unguiculata) with these inducers and studied the effects on HI-VOC emissions and the attraction of three generalist endoparasitoids. RESULTS: After the inducers had been applied and the plants subjected to either real or mimicked herbivory by Spodoptera littoralis caterpillars, females of the parasitoids Campoletis sonorensis and Microplitis rufiventris showed a strong preference for BTH-treated plants, whereas Cotesia females were strongly attracted to both BTH- and laminarin-treated plants with real or mimicked herbivory. Treated plants emitted more of certain HI-VOCs, but considerably less indole and linalool and less of several sesquiterpenes. Multivariate data analysis revealed that enhanced wasp attraction after treatment was correlated with high relative concentrations of nonanal, alpha-pinene, (E)-beta-ocimene and (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT), and with low relative concentrations of indole, (S)-linalool and (E)-beta farnesene. Inducer treatments had no significant effect on leaf consumption by the caterpillars. CONCLUSION: Our findings confirm that treating cowpea plants with inducers can enhance their attractiveness to biological control agents. (c) 2017 Society of Chemical Industry. PMID- 29155490 TI - Elimination profile of triamcinolone in urine following oral administration. AB - Triamcinolone (T) is a glucocorticoid commonly used to relieve inflammation and treat arthritis, severe allergies, and asthma; however, it is banned by the World Anti-Doping Agency in competition for athletes when administered orally, intravenously, intramuscularly, or rectally. The minimum required performance limit (MRPL) for urinary T is 30 ng/mL. However, the data about the urinary excretion of T after oral administration is limited. We investigate the elimination profile and determine whether single-dose administration of T would cause a positive doping result. Twelve healthy volunteers received a single-dose of 4-mg T rally, and urine samples were collected for 24 hours. A validated liquid chromatography-tandem mass spectrometry method was used to determine urinary T levels. Non-compartmental modeling was used to estimate the pharmacokinetic parameters. All the urinary T concentrations were much higher than the MRPL. The peak urinary T concentration was 3211.4 +/- 860.3 ng/mL (mean +/- SD), time to peak concentration was 1.7 +/- 0.9 hours, and the estimated elimination half-life was 4.4 +/- 2.8 hours. About 27.76% of the consumed dose was eliminated via urine within 24 hours of intake. After a single-dose oral administration, urinary T concentrations still exceeded the MRPL after 24 hours. This information could be useful for limiting the misuse of T. Athletes should be aware when using T in competition and acquire approval for a therapeutic use exemption prior to use. Moreover, the elimination profile of orally administered T may be crucial information for distinguishing different dosage routes. PMID- 29155491 TI - Variation in the Response of Clozapine Biotransformation Pathways in Human Hepatic Microsomes to CYP1A2- and CYP3A4-selective Inhibitors. AB - The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to conventional antipsychotic drugs. Cytochromes P450 (CYPs) 1A2 and 3A4 oxidize CLZ to norCLZ and CLZ N-oxide in human liver. Concurrent treatment with inducers and inhibitors of CYP1A2 modulates CLZ elimination that disrupts therapy. Drug-drug interactions involving CYP3A4 are also significant but less predictable. To further characterize the factors underlying these interactions, we used samples from a cohort of human livers to assess variation in CLZ oxidation pathways in relation to intrinsic CYP3A4 and CYP1A2 activities and the effects of the corresponding selective inhibitors ketoconazole (0.2 and 2 MUM) and fluvoxamine (1 and 10 MUM). The CYP3A4-selective inhibitor ketoconazole (2 MUM) impaired CLZ N-oxide formation in all 14 of the livers used in inhibition studies (>=50% inhibition) while the CYP1A2-selective inhibitor fluvoxamine (10 MUM) decreased norCLZ formation in nine. Ketoconazole effectively inhibited CLZ metabolism in five of seven livers that catalysed CYP3A4-dependent testosterone 6beta-hydroxylation at or above the median rate and in four other livers with lower intrinsic CYP3A4 activity. Similarly, fluvoxamine (10 MUM) readily inhibited CLZ oxidation in seven livers with high CYP1A2-mediated 7 ethoxyresorufin O-deethylation activity (at or above the median) and three livers with lower intrinsic CYP1A2 activity. In three livers, CLZ biotransformation was impaired by both ketoconazole and fluvoxamine, consistent with a major role for both CYPs. These findings suggest that the intrinsic activities of CYPs 1A2 and 3A4 are unrelated to the response to CYP-selective inhibitors and that assessment of the activities in vivo may not assist the prediction of drug-drug interactions. PMID- 29155493 TI - The crystal structure and catalytic mechanism of hydroxynitrile lyase from passion fruit, Passiflora edulis. AB - : Hydroxynitrile lyases (HNLs) are enzymes used in the synthesis of chiral cyanohydrins. The HNL from Passiflora edulis (PeHNL) is R-selective and is the smallest HNL known to date. The crystal structures of PeHNL and its C-terminal peptide depleted derivative were determined by molecular replacement method using the template structure of a heat stable protein, SP1, from Populus tremula at 2.8 and 1.8 A resolution, respectively. PeHNL belongs to dimeric alpha+beta barrel superfamily consisting of a central beta-barrel in the middle of a dimer. The structure of PeHNL complexed with (R)-mandelonitrile ((R)-MAN) was also determined. The hydroxyl group of (R)-MAN forms hydrogen bonds with His8 and Tyr30 in the active site, whereas the nitrile group is oriented toward the carboxyl group of Glu54, unlike other HNLs, where it interacts with basic residues typically. The results of mutational analysis indicate that the catalytic dyad of His8-Asn101 is critical for the enzymatic reaction. The length of the hydrogen bond between His-Ndelta1 and Asn101-Odelta1 is short in the PeHNL (R)-MAN complex (~ 2.6 A), which would increase the basicity of His8 to abstract a proton from the hydroxyl group of (R)-MAN. The cyanide ion released from the nitrile group abstracts a proton from the protonated His8 to generate a hydrogen cyanide. Thus, the His8 in the active site of PeHNL acts both as a general acid and a general base in the reaction. ENZYMES: EC 4.1.2.10 DATABASE: Structural data are available in PDB database under the accession numbers 5XZQ, 5XZT, and 5Y02. PMID- 29155492 TI - The prevalence of gluten free diet use among preschool children with autism spectrum disorder. AB - : Our objective was to estimate prevalence of current or ever use of a gluten free diet (GFD) in children aged 30-68 months with autism spectrum disorder (ASD) and population controls (POP); and to identify characteristics associated with ever having used GFD among children with ASD. We used data from the Study to Explore Early Development (SEED), a multi-site, case-control study of children with ASD. Caregivers reported GFD use by their children through structured questionnaires about diet patterns, gastrointestinal (GI) issues, and ASD specific treatments. Prevalence was estimated and compared using log-Poisson regression, adjusting for confounders. In children with ASD, we examined whether child or mother's GI conditions or child's phenotypic traits were associated with ever trying a GFD. In SEED, 71 children with ASD (11.1% prevalence after adjustment) were on a GFD at time of the study and 130 (20.4%) had ever used a GFD, a greater percentage than in POP children (N = 11, 0.9% current use). Of current users with ASD, 50.7% had a dietary intervention that was prescribed by a medical professional. Among children with ASD, child GI conditions and developmental regression were positively and independently associated with having ever used a GFD. Current use and ever use of a GFD were prevalent in children with ASD identified in SEED. GFD usage was associated with GI issues and child phenotype. Clinicians may consider advising parents on how best to use these diets in the context of the child's GI presentation and current scientific knowledge about effectiveness in relation to ASD symptoms. Autism Res 2018, 11: 185-193. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Gluten free diets (GFDs) are commonly used as an alternative therapy for autism spectrum disorder (ASD); however, the effectiveness is still uncertain which makes it important to know who tries this type of diet. We found that one in five preschool aged children with ASD had ever used a GFD. Children with gastrointestinal conditions and developmental regression were more likely to have tried a GFD. PMID- 29155494 TI - Modulating attentional biases of adults with autistic traits using transcranial direct current stimulation: A pilot study. AB - : While neurotypical individuals over-attend to the left-side of centrally presented visual stimuli, this bias is reduced in individuals with autism/high levels of autistic traits. Because this difference is hypothesized to reflect relative reductions in right-hemisphere activation, it follows that increasing right-hemisphere activation should increase leftward bias. We administered transcranial direct current stimulation (tDCS) over the right posterior parietal cortex to individuals with low levels (n = 19) and high levels (n = 19) of autistic traits whilst they completed a greyscales task. Anodal tDCS increased leftward bias for high-trait, but not low-trait, individuals, while cathodal tDCS had no effect. This outcome suggests that typical attentional patterns driven by hemispheric lateralization could potentially be restored following right hemisphere stimulation in high-trait individuals. Autism Res 2018, 11: 385-390. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Attentional differences between individuals with and without autism may reflect differences in underlying activation of the left and right hemispheres. In this study, we combine an attentional task that reflects relative hemispheric activation with non-invasive cortical stimulation, and show that attentional differences between healthy individuals with low and high levels of autistic-like traits can be reduced. This outcome is encouraging, and suggests that other aspects of attention in autism (e.g., face processing) may stand to benefit from similar stimulation techniques. PMID- 29155495 TI - Addressing the burden of dialysis around the world: A summary of the roundtable discussion on dialysis economics at the First International Congress of Chinese Nephrologists 2015. AB - To address the issue of heavy dialysis burden due to the rising prevalence of end stage renal disease around the world, a roundtable discussion on the sustainability of managing dialysis burden around the world was held in Hong Kong during the First International Congress of Chinese Nephrologists in December 2015. The roundtable discussion was attended by experts from Hong Kong, China, Canada, England, Malaysia, Singapore, Taiwan and United States. Potential solutions to cope with the heavy burden on dialysis include the prevention and retardation of the progression of CKD; wider use of home-based dialysis therapy, particularly PD; promotion of kidney transplantation; and the use of renal palliative care service. PMID- 29155496 TI - Insulin resistance in chronic kidney disease. AB - This review provides an overview of insulin resistance (IR) in patients with chronic kidney disease (CKD). IR is a pathological state in which target tissues fail to respond normally to insulin. IR is understood as a consequence of CKD and its prevalence rises particularly in advanced CKD stages. Mechanisms leading to IR are complex and multifactorial, involving post-receptor signaling defects, unhealthy lifestyles, metabolic acidosis, inflammation, oxidative stress, vitamin D deficiency, anemia, and uremic toxicity, as shown by human and experimental studies over the last 30 years. Whereas hyperinsulinemic euglycemic clamp is the gold standard, it is unpractical at the bedside, and either estimated IR indices by fasting glucose or insulin and oral glucose tolerance tests (OGTT) provide satisfactory estimates of IR also in patients with CKD. IR is likely to play a key role in the development of cardiometabolic complications, but not all studies associate IR with the risk of cardiovascular events and death. Various interventions at the level of lifestyle modifications, adaptations in dialysis therapy (such as use of icodextrin based solutions) and pharmacological strategies such as thiazolidinediones or vitamin D therapy may improve IR in patient with CKD. PMID- 29155497 TI - Clinical and pathological factors associated with progression of diabetic nephropathy. AB - As an important complication of diabetic mellitus, diabetic kidney disease (DKD) is becoming a major cause of morbidity and mortality worldwide. Given the diminished quality of life and the economic cost, identification of the risk factors for DKD and initiation of in-time therapies are of great importance. The initiators of DKD include hyperglycemia and predisposing genes, while the promotors of DKD include hyperglycemia, albuminuria, hypertension, dyslipdemia, insulin resistance, anemia, long duration of diabetes, smoking, ethnicity, westernization, sex, age, and so on. This article summarizes the values and limitations of some factors in the development and progression of DKD. Further study is needed to establish whether modulating these factors can improve the outcomes of DKD. PMID- 29155498 TI - Global impact of nephropathies. AB - The global burden of chronic kidney disease (CKD) has increased substantially in recent years, partly attributed to the global epidemic of diabetes mellitus. In many countries including China, glomerulonephritis was the most common cause of end stage renal disease (ESRD). The mortality rate of dialysis patients can be as high as patients with colon, breast and prostate cancers. CKD has important socio economic impact on the healthcare system and society. Increasing awareness and early detection of CKD cannot be overemphasized. In places where healthcare resources are limited, peritoneal dialysis first policy has allowed local governments and health authorities to maximize healthcare resources to provide renal replacement therapy for more ESRD patients. In conclusion, management of CKD remains a global health challenge and continued medical research is most important. PMID- 29155499 TI - Endoplasmic reticulum stress-induced cell death in podocytes. AB - Endoplasmic reticulum (ER) stress occurs in a variety of pathophysiological mechanisms, and there has been great interest in managing this pathway for the treatment of clinical diseases. Increased ER stress can block integrin-beta1 glycosylation, decrease integrin-beta1 protein expression and enhance cell death in podocytes. Autophagy is closely interconnected with ER stress to counteract the possible injurious effects related to the impairment of protein folding and is one of the intracellular protein degradation systems. Studies have shown that podocytes exhibit a high rate of autophagy to maintain as terminally differentiated cells. We have attempted to induce autophagy in podocytes with ER stress to increase the longevity of proteins and the degradation of damaged organelles. However, regardless of ER stress or autophagy that protects the cells at early stages, cells cannot adapt to this situation when the stress is already well established, and podocytes will undergo severe injury finally. In summary, ER stress may induce cell death in podocyte, and autophagy mediate to salvage the injuries caused by ER stress in the short term. It seems that adequate, but not excessive, autophagy is crucial to help maintain the cell viability of podocytes. PMID- 29155500 TI - Chinese medicine for diabetic kidney disease in China. AB - Diabetic kidney disease (DKD) is a major global public health concern due to its high prevalence and mortality, and high healthcare cost. Conventional Western therapies for DKD fail to provide favourable efficacy. Chinese medicine (CM) has been widely used to combat DKD in China and other Asian countries. The clinical effects and mechanism of CM in treating DKD have not been fully elucidated. This review summarizes current knowledge of CM therapeutic modalities for DKD, especially Chinese herbal medicine (CHM), and potential mechanisms. PMID- 29155501 TI - Urinary mRNA and lupus disease flare. AB - In the past 20 years, extraction and quantification of mRNA from urinary sediment has emerged as a novel laboratory technique. The potential application of urinary mRNA quantification to the clinical care of patients with SLE has become an active field of research. However, published studies in this area are limited to small-scale ones. mRNA levels of several of cytokine and transcript factor genes have been found to have the potential for the diagnosis or monitoring of disease activity in patients with lupus nephritis. Our previous studies showed that a high urinary mRNA level of T-bet, the key transcription factor of type 1 T helper cells (Th1), was an independent predictor of lupus flare and probably reflects an intrinsic characteristic of patients with predisposition to Th1 activation. Other studies suggest that monitoring of monocyte chemoattractant protein-1(MCP-1), interleukin (IL)-17, GATA-3 (the key transcription factor of type 2 T helper cells) and forkhead box P3 (FOXP3, the key transcription factor of regulatory T cells) mRNA level in urinary sediment may provide an early clue for detecting disease flare in lupus patients. As a simple and non-invasive method, urinary mRNA level deserves further studies to validate its role in risk stratification and monitoring of patients with lupus nephritis. PMID- 29155502 TI - Elderly patients with glomerular diseases and IgA nephropathy. AB - As the population ages, greater numbers of elderly patients will present with kidney diseases. Many kidney diseases, such as IgA nephropathy, will require kidney biopsy for diagnostic confirmation, treatment guidance and prognostication. In this paper, we review the current and expected future healthcare landscape with a focus on the ageing population, pros and cons of kidney biopsy in elderly patients, as well as treatment strategies and precautions. We also review the available data on IgA nephropathy in the elderly, including its occurrence rate based on the kidney biopsy, clinicohistopathological features, differentiation with IgA-dominant postinfectious glomerulonephritis, treatment options and outcome prediction. Overall, information on kidney diseases in patients with advanced age, including IgA nephropathy, is limited. Clinical evaluation and management strategies are extrapolated largely from studies in younger adults. Age-specific clinical and translational investigations of kidney diseases are eminently needed. PMID- 29155503 TI - Relatives in silent kidney disease screening (RISKS) study: A Chinese cohort study. AB - AIM: Family members of patients with end-stage renal disease (ESRD) have higher risk for chronic kidney disease (CKD). Limited study has examined the risk of developing CKD in relatives of patients in earlier stages of CKD. METHODS: From January 2008 to June 2009, the Hong Kong Society of Nephrology studied first degree relatives of stage 1-5 CKD patients from 11 local hospitals. A total of 844 relatives of 466 index CKD patients (stages 1-2: 29.6%; stage 3: 16.7%; stage 4: 10.9%; stage 5: 42.7%) were reviewed for various risk factors of CKD. We also defined a composite marker of kidney damage by the presence of one or more following features: (i) positive urine protein, (ii) spot urine protein-to creatinine ratio >=0.15 mg/mg, (iii) hypertension and (iv) estimated glomerular filtration rate (eGFR) <=60 mL/min per 1.73 m2 and determine its association with participant and index patient factors. RESULTS: Among these 844 relatives, 23.1%, 25.9% and 4.4% of them had proteinuria (urine protein >=1+), haematuria (urine red blood cell >=1+) and glycosuria (urine glucose >=1+), respectively. Proteinuria (P = 0.10) or glycosuria (P = 0.43), however, was not associated with stages of CKD of index patients. Smoking participants had a significantly lower eGFR (102.7 vs. 107.1 mL/min per 1.73 m2 ) and a higher prevalence of proteinuria (33.6% vs. 21.4%). Multivariate analysis showed that older age, male gender, obesity, being parents of index patients and being the relatives of a female index patient were independently associated with a positive composite marker. CONCLUSION: First-degree relatives of all stages of CKD are at risk of developing CKD and deserve screening. Parents, the elderly, obese and male relatives were more likely to develop markers of kidney damage. PMID- 29155505 TI - PHISTc protein family members localize to different subcellular organelles and bind Plasmodium falciparum major virulence factor PfEMP-1. AB - Plasmodium falciparum encodes a novel repertoire of the Plasmodium helical interspersed subtelomeric (PHIST) family of exported proteins, which play diverse roles in infected red blood cells, contributing to malaria pathogenesis. PHIST proteins are central to parasite biology and modify human erythrocytes by interacting with parasite and host proteins. Here, we have attempted to understand the localization and function of two unexplored proteins of the PHISTc subfamily, PFD1140w and PF11_0503, and compared these with a well-characterized member, PFI1780w. We demonstrate that Phist domains assume different oligomeric states owing to a distinct array of subunit interface residues. Colocalization of a Maurer's cleft signature protein, P. falciparum skeleton-binding protein-1 (PfSBP-1), and P. falciparum erythrocyte membrane protein-1 (PfEMP-1) revealed different subcellular destinations for these PHIST members. We further show the binding of recombinant PHIST proteins to the cytoplasmic tail of PfEMP-1 and a novel interaction with PfSBP-1. Interestingly, PFD1140w interacts with PfEMP-1 and PfSBP-1 simultaneously in vitro leading to formation of a complex. These two distant PHISTc members also bind PfEMP-1 on distinct sites, despite sharing the Phist domain. Our data re-emphasize a supportive role for PHIST proteins in cytoadhesion, and identify a new binding partner, PfSBP-1, for members of this family. This information therefore adds another chapter to the understanding of P. falciparum biology and highlights the significance of the unexplored PHIST family. PMID- 29155506 TI - How desirable and undesirable features of naive or genetically reengineered mesenchymal stem cells are being considered in preclinical or clinical assays. AB - The implantation of adult mesenchymal stem cells (MSCs) has become a promising alternative in cancer treatments. Accordingly, in this article we revised the ultimate advances in the knowledge on the MSC-homing mechanism, the cancer cell and MSCs interactions and the microvesicles and exosomes used by malignant cells to transport and deliver pro-cancer cytokines or microRNA (miRNA), or by MSCs to favor or fight cancer progression. In addition, we analyzed the current knowledge generated by ongoing or terminated preclinical and clinical trials, using naive MSCs as natural anti-cancer living factors or gene-engineered MSCs as cytokine delivering vehicles, where anti-cancer cytokines were chosen and the pro-cancer factors were avoided. Finally, we present some concerns about the implantation of MSCs and anti-cancer therapies and hypothesize the MSC implantation combines with conventional or new therapies to treat cancer. PMID- 29155507 TI - The role of radiation therapy in the modern management of oligometastatic disease. AB - Multimodal treatment approaches are indispensable for patients with advanced stage cancer, while radiation therapy has been established as essential part of therapeutic approaches and has been introduced as a better option to face challenges, such as, local relapse or oligometastatic disease. The mere insight of the concept of oligometastases, proposed for the first time in the middle 1990s, led to the hypothesis that this condition may be cured using local ablative weapons. This hypothesis has already been demonstrated by surgical ablative techniques. Even though been considered a gold-standard approach for ablation of metastatic lesions, surgery limitations, technical obstacles, or patients refusal, or advanced age, or associated comorbidities, or advancements in radiation delivery and imaging technology, all have allowed the progressive implementation of radiation therapy as an alternative local ablative weapon. The advanced technique of stereotactic body radiation therapy has been shown to be safe and effective, and achieved high local control rates, and long-term survival. Despite its good results, stereotactic radiotherapy still faces significant clinical challenges, including selection of candidate patients most likely to being in oligometastatic state and most likely to being in the therapeutic technique. In this article, we will make an overview of the oligometastatic disease and review the growing clinical literature of patients suffering from this condition and treated with radiation therapy. PMID- 29155508 TI - Microarray bioinformatics in cancer- a review. AB - Bioinformatics is one of the newest fields of biological research, and should be viewed broadly as the use of mathematical, statistical, and computational methods for the processing and analysis of biological data. Over the last decade, the rapid growth of information and technology in both "genomics" and "omics" eras has been overwhelming for the laboratory scientists to process experimental results. Traditional gene-by-gene approaches in research are insufficient to meet the growth and demand of biological research in understanding the true biology. The massive amounts of data generated by new technologies as genomic sequencing and microarray chips make the management of data and the integration of multiple platforms of high importance; this is then followed by data analysis and interpretation to achieve biological understanding and therapeutic progress. Global views of analyzing the magnitude of information are necessary and traditional approaches to lab work have steadily been changing towards a bioinformatics era. Research is moving from being restricted to a laboratory environment to working with computers in a "virtual lab" environment. The present review article shall put light on this emerging field and its applicability towards cancer research. PMID- 29155504 TI - Cervical funneling or intra-amniotic debris and preterm birth in nulliparous women with midtrimester cervical length less than 30 mm. AB - OBJECTIVE: To evaluate whether the presence of cervical funneling or intra amniotic debris identified in the second trimester is associated with a higher rate of preterm birth (PTB) in asymptomatic nulliparous pregnant women with a midtrimester cervical length (CL) less than 30 mm (i.e. below the 10th percentile). METHODS: This was a secondary cohort analysis of data from a multicenter trial in nulliparous women between 16 and 22 weeks' gestation with a singleton gestation and CL less than 30 mm on transvaginal ultrasound, randomized to treatment with either 17-alpha-hydroxyprogesterone caproate or placebo. Sonographers were centrally certified in CL measurement, as well as in identification of intra-amniotic debris and cervical funneling. Univariable and multivariable analysis was performed to assess the associations of cervical funneling and intra-amniotic debris with PTB. RESULTS: Of the 657 women randomized, 112 (17%) had cervical funneling only, 33 (5%) had intra-amniotic debris only and 45 (7%) had both on second-trimester ultrasound. Women with either of these findings had a shorter median CL than those without (21.0 mm vs 26.4 mm; P < 0.001). PTB prior to 37 weeks was more likely in women with cervical funneling (37% vs 21%; odds ratio (OR), 2.2 (95% CI, 1.5-3.3)) or intra-amniotic debris (35% vs 23%; OR, 1.7 (95% CI, 1.1-2.9)). Results were similar for PTB before 34 and before 32 weeks' gestation. After multivariable adjustment that included CL, PTB < 34 and < 32 weeks continued to be associated with the presence of intra-amniotic debris (adjusted OR (aOR), 1.85 (95% CI, 1.00-3.44) and aOR, 2.78 (95% CI, 1.42-5.45), respectively), but not cervical funneling (aOR, 1.17 (95% CI, 0.63-2.17) and aOR, 1.45 (95% CI, 0.71-2.96), respectively). CONCLUSIONS: Among asymptomatic nulliparous women with midtrimester CL less than 30 mm, the presence of intra-amniotic debris, but not cervical funneling, is associated with an increased risk for PTB before 34 and 32 weeks' gestation, independently of CL. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29155509 TI - Current strategies and future perspectives in fertility preservation for cancer patients. AB - Nowadays, cancer is being detected at younger ages. Health care providers should consider cancer patients' desire towards fertility preservation before the initiation of possibly sterilizing treatments. The aim of the current review was to register the current state of fertility preservation procedures available for male and female cancer patients. PMID- 29155510 TI - In situ preservation of parathyroid glands:advanced surgical tips for prevention of permanent hypoparathyroidism in thyroid surgery. AB - Hypoparathyroidism (HPT) is one of the most frequentand severe complications of thyroid surgery. It is caused by intraoperative damage, devascularization or accidental removal of the parathyroid glands (PTGs). The incidence of postoperative HPT is directly proportional to surgery extent and surgeon's experience. After 40 years of experience in thyroid surgery, the first author summarizes the already known surgical steps in thyroid surgery and adds some useful practical tips for in situ preservation of PTGs. Our surgical technique focuses on meticulous capsular dissection and preservation of the middle thyroid, Kocher's vein trunk, as well as vein branches that accompany the posterior branch of the superior thyroid artery and inferior thyroid artery trunk. Ligation of all blood vessels should be as close as possible to the thyroid capsule. Identified PTGs should be de-attached from the thyroid capsule on the vascular pedicle without significant dislocation. PTGs preservation during central neck dissection (CND) can be facilitated by using methylene blue dye for sentinel lymph nodes biopsy. PTGs are not colored in blue, unlike central lymph nodes, which facilitates central neck dissection and reduces the possibility of accidental removal of PTGs. After several thousands of preserved PTGs using this original technique, a total prevalence of permanent HPT in the first author's series is less than 0.5%. Following given key points and recommendations to surgical in situ preservation of PTGs, a surgeon can provide good outcome for patients after total thyroidectomy (with or without central neck dissection), regarding HPT as one of the most severe complications of thyroid surgery. PMID- 29155511 TI - Laparoscopic hepatectomy for colorectal liver metastases located in all segments of the liver. AB - PURPOSE: Laparoscopic hepatectomy is not a well-established treatment modality for colorectal liver metastases. Moreover, most reports have been limited to tumors in the anterolateral segments (segments 2, 3, 4b, 5, and 6). In this study we evaluated the short- and long-term outcomes after laparoscopic hepatectomy for colorectal liver metastases located in all segments, including tumors located in the posterosuperior segments (segments 1, 4a, 7, and 8). METHODS: This retrospective study included 102 patients who underwent laparoscopic hepatectomy for colorectal liver metastases with radical intent between January 2009 and January 2016. The patients were divided into two groups (anterolateral and posterosuperior group) according to tumor location. The clinical and follow-up data of the two groups were reviewed. RESULTS: There was no 30-day postoperative mortality. Most of the postoperative 30-day complications were classified as minor complications (Clavien-Dindo classification). There was no difference in clinicopathologic characteristics between the two groups. Although posterosuperior group patients had significantly longer operative time (p=0.008) and postoperative hospital stay duration (p=0.041), as well as a greater blood loss (p=0.012), there was no significant difference in the rate and severity of postoperative complications (p=0.314 and 1.000 respectively). During a median follow-up of 41 months, the 5-year overall survival (OS) (p=0.449), and disease free survival (DFS) (p=0.370) showed no significant difference between the two groups. CONCLUSIONS: Laparoscopic hepatectomy for colorectal liver metastases located in all segments of the liver can be safely performed in selected patients, with acceptable postoperative morbidity and oncologic results. PMID- 29155512 TI - Efficacy and safety of cetuximab plus FOLFOX in second-line and third-line therapy in metastatic colorectal cancer. AB - PURPOSE: To evaluate the efficacy and adverse events with cetuximab plus FOLFOX administered as second- and third-line therapy in metastatic colorectal cancer (mCRC) patients. METHODS: IPatients were administered cetuximab plus FOLFOX as second- and third-line therapy from January 2010 through October 2015. mCRC patients with wild type KRAS were alsi given irinitecan and/ir ixaliplatin cimbined with fluoripyrimidine+/-bevacizumab. Tumor respinse and survival were evaluated using RECIST and Kaplan-Meier methid respectively. RESULTS: Sixty patients were included this study. Cetuximab plus FOLFOX was administered to 40 (66.7%) patients as second-line and to 20 (33.3%) as third-line therapy. The majority of the patients had a good ECOG performance status (PS) (0 or 1). Clinical benefit was partial plus stable disease and it was 75.0% for both of these two lines. The median progression free survival (PFS) was 7.1 months (95% CI=3.2-10.9) and 6.0 months (95% CI=2.4-9.6), in the second-and third-line (p=0.484). The median iverall survival (IS) was 14.3 and 9.2 minths in secind-and third-line therapy respectively (p=0.071). The common toxicities were haematologic and gastrointestinal, mostly grade 1 and 2. CONCLUSION: The addition of cetuximab to FOLFOX was well-tolerated and had antitumor activity both in second- and third-line therapy in patients with mCRC. PMID- 29155513 TI - Laparoscopic surgery after neoadjuvant therapy in elderly patients with rectal cancer. AB - PURPOSE: The standard treatment for mid or low locally advanced rectal cancer is neoadjuvant therapy followed by surgical resection. Laparoscopic surgery has recently been applied for the treatment of rectal cancer. However, few studies have reported the outcomes of laparoscopic surgery for elderly patients with rectal cancer after neoadjuvant therapy. This study aimed to investigate the short- and long-term outcomes of laparoscopic surgery for elderly patients with rectal cancer after neoadjuvant therapy. METHODS: Patients received a total dose of 50.4 Gy over 5.5 weeks (45 Gy in 25 fractions to the pelvid and 5.4 Gy boost in 3 fractions to the primary tumor). Laparoscopic surgery for rectal cancer after neoadjuvant therapy was performed at our hospital on 89 elderly patients aged 75 years or older (the elderly group) from January 2008 to January 2016. Outcomes of the 89 patients were compared to those of 269 patients younger than 75 years enrolled during the same time period (the nonelderly group). RESULTS: Compared with the nonelderly group, the Charlson comorbidity index (CCI) and American Society of Anesthesiologists (ASA) scores were higher in the elderly group. For short-term outcomes, there were no statistically significant differences. Differences between the two groups in the 5-year overall survival (OS) rate and 5-year disease-free survival (DFS) rate were not statistically significant. CONCLUSION: Although the CCI was higher in elderly patients than in the nonelderly patients, laparoscopic surgery after neoadjuvant therapy was safe and effective in elderly patients with rectal cancer. Therefore, in the absence of any contraindications, laparoscopic surgery after neoadjuvant therapy is an appropriate treatment approach for elderly patients with rectal cancer. PMID- 29155514 TI - The prognostic effect of neoadjuvant chemoradiotherapy on the change of PD-L1 expression in patients with locally advanced rectal adenocarcinoma. AB - PURPOSE: To evaluate the prognostic effect of neoadjuvant chemoradiotherapy on the change of programmed death ligand 1 (PD-L1) expression in patients with locally advanced rectal adenocarcinoma, by comparing PD-L1 expression in pretreatment biopsies and PD-L1 expression in pathological specimens after neoadjuvant chemoradiotherapy. METHODS: A total of 25 patients with rectal adenocarcinoma were evaluated. Patients were treated by neoadjuvant chemoradiotherapy (radiotherapy:44Gy normofraxionation; chemotherapy: capecitabine 825 mg/m2 in two daily doses). Surgery was performed 6-8 weeks after the chemoradiotherapy completion. PD-L1 expression was determined in endoscopic biopsies and in resected specimens with immunohistochemistry. RESULTS: All 25 patients received radiotherapy without interruption, while concomitant chemotherapy was discontinued prematurely in one patient because of hematological toxicity. In 13 patients sphincter-saving surgery were performed, and 12 patients underwent rectum resection. Downstaging was noticed in 17 patients. Stable disease was found in 5 patients, and progression in 3. The median disease free survival (DFS) was not reached. Three-year DFS was 54.3% (95% CI 34.3-74.2). The median overall survival (OS) was 60 months (95% CI 48-60). Three-year OS was 75 % (95% CI 57.7-92.3). No PD-L1 expression was noticed in pretreatment biopsy and in resected tissue after chemoradiotherapy. CONCLUSION: No prognostic effect of neoadjuvant chemoradiotherapy on the change of PD-L1 expression was demonstrated in patients with locally advanced rectal adenocarcinoma. PMID- 29155515 TI - Temporal characteristics of social support in colorectal cancer survivors during the first year post operation. AB - PURPOSE: To describe the level of perceived social support and to identify its predictors among Chinese colorectal cancer (CRC) survivors during the first year post operation. METHODS: Newly diagnosed cases of colorectal cancer aged 18 and above who were admitted for curative surgery in a tertiary care hospital between January 2012 and July 2014 were consecutively recruited. This cohort study included 5 assessment waves over the first year post surgery (at baseline, 4-6 week, 3-month, 6-month and 12-month follow-up) regarding social support level among 189 CRC survivors. ANOVA and linear mixed models were applied to determine the change in social support and its predictors using SPSS version 18.0. RESULTS: Social support level remained relatively stable and high in the first 3 months post surgery, but decreased significantly at 6 months and then remained low afterwards, displaying an overall decreasing trend over time. Females, lower family income, lack of health insurance and advanced clinical disease stage were negatively associated with social support. CONCLUSION: These findings suggest that the future intervention programs should commence soon after surgery, despite the fact that they were high before this time point. PMID- 29155516 TI - Association of IL-12Bpro polymorphism with tumor-infiltrating dendritic cells in colorectal cancer. AB - PURPOSE: Chronic inflammation is a key component in the development and progression of colorectal cancer (CRC). A notable hallmark of the inflammation process is the release of pro-inflammatory cytokines by infiltrating cells of the immune system. Defects in dendritic cells (DCs) recruitment, maturation and cytokine release are a hallmark of the CRC strategy to escape immune surveillance.The purpose of our study was to evaluate the possible role of IL-12B polymorphism in the promoter region of the IL-12B gene (rs17860508) as a genetic factor contributing to the risk for CRC development. Additionally, we aimed to evaluate the influence of this polymorphism on DCs infiltration in tumor microenvironment. METHODS: IL-12Bpro polymorphism was genotyped by Amplification Refractory Mutation System- Polymerase Chain Reaction (ARMS-PCR). Immunohistochemistry was performed for DCs infiltration. RESULTS: Statistically significant correlation between the expression of S100 and CD1a DCs and the 11- genotype of the studied polymorphism was found. No statistically significant difference in genotype distribution between cases and controls was observed (p=0.163). Analysis of the overall survival (OS) of genotyped patients revealed a tendency among the carriers of the 22-genotype to have shorter survival of 36 months versus the 11- and 12-cariers- 61 months (log rank, p=0.117). CONCLUSIONS: The IL-12Bpro polymorphism does not constitute a risk factor for CRC development. However, genotype-11 might have a complex role in the recruitment and maturation of DCs in tumor microenvironment. PMID- 29155517 TI - Expression of CD40/CD40L in colon cancer, and its effect on proliferation and apoptosis of SW48 colon cancer cells. AB - PURPOSE: To study was to study the expression of CD40/CD40L in colon cancer and investigate the effects of CD40/CD40L overexpression on the proliferation and apoptosis of SW48 colon cancer cell line. METHODS: Immunohistochemistry was used to detect the expression of CD40 protein in colon cancer tissue samples from 70 patients, and 10 adjacent normal tissue samples. A CD40L gene-containing plasmid was transfected into SW48 colon cancer cells using lipofectamine 2000. Cell proliferation was measured by MTT assay. The expression of CD40/CD40L was measured by real-time PCR (RT-PCR). Protein expression of Bcl-2 and Bax was detected by Western blot. RESULTS: Immunohistochemical analysis showed that CD40 was mainly expressed in the cell membrane and scarcely in the cytoplasm. The expression of CD40 in colorectal cancer tissue was significantly higher than in normal adjacent tissue. RT-PCR showed that CD40 was highly expressed in SW48 cells. The expression of CD40L mRNA was significantly increased in SW40 cells transfected with the CD40L gene-containing plasmid (p<0.01). MTT assay showed that the activity of CD40L transfected cells was significantly inhibited compared with control cells transfected with empty plasmid (p<0.01). Western blot analysis demonstrated significantly decreased Bcl-2 expression, and significantly increased Bax expression in cells transfected with the CD40L gene-containing plasmid compared with the control cells (p<0.01). CONCLUSION: In conclusion, CD40 protein expression was significantly higher in colon cancer tissue compared with normal tissue, and the apoptosis of SW48 colon cancer cells can be induced by CD40L gene transfection. PMID- 29155518 TI - A meta-analysis of clinical trials over regimens with or without cetuximab for advanced gastric cancer patients. AB - PURPOSE: To evaluate the efficiency and toxicity of treatment with or without cetuximab in patients with advanced gastric cancer (AGC). METHODS: Randomized phase III clinical trials (RCTs) on chemotherapy with or without cetuximab for AGC were searched in PUBMED and CNKI. A total of 874 patients were analyzed for their overall survival (OS), disease control rate (DCR), and toxicity. Reported hazard ratio (HR) with 95% CI from each study were used as the primary outcome measure. RESULTS: Three RCTs were detected on chemotherapy with or without cetuximab regimens for AGC. Chemotherapy plus cetuximab was not significantly advantageous over chemotherapy alone for OS rate and DCR odds ratio (OR) (OS: OR=0.89, 95% CI=0.50-1.56; DCR:OR=1.11, 95% CI=0.78-1.59). However, haematological toxicity and neutropenia were lower in the experimental group (chemotherapy plus cetuximab) than in the control group (chemotherapy alone) (OR=0.65, 95% CI=0.50-0.84). No evidence of publication bias was found in this study. CONCLUSION: Adding cetuximab to chemotherapy does not improve OS or DCR compared with chemotherapy alone. Cetuximab-containing combination chemotherapy can reduce the risk of neutropenia. PMID- 29155519 TI - Quantitative changes of gastric mucosa during carcinogenesis using stereological methods. AB - PURPOSE: To investigate the effects of helicobacter pylori (H. pylori) infection on the quantitative changes of gastric mucosa in cancerous and precancerous lesions using stereological methods. METHODS: One hundred and twenty-two gastric samples were studied. After determination of H. pylori infection, 42 gastric tissues of intestinal metaplasia (IM) patients, 38 specimens from dysplasia (DYS), and 42 specimens from gastric cancer (GC) types were selected from the pathology archive of Imam Ali Hospital, Zahedan, Iran. Gastric tissues were sectioned and stained with p53 and Ki-67 immunohistochemical (IHC) method and haematoxylin/eosin (H&E). Then, the numerical density (NV) of p53-positive, Ki-67 positive cells, eosinophil and polymorphonuclear (PMN) cells were estimated using dissector counting technique in IM, DYS and GC lesions. RESULTS: In IM, DYS and GC specimens, the NV of p53-positive cells in the presence of H. pylori infection (H. pylori+) was significantly higher than in H. pylori absence (H. pylori-). The NV of Ki-67- positive cells only in DYS specimens, showed significant difference between H. pylori+ and H. pylori- groups. The NV of eosinophil cells in DYS and GC specimens in H. pylori+ groups were significantly higher than in H. pylori- groups and the NV of polymorphonuclear cells in IM specimens showed significant difference between H. pylori+ and H. pylori- groups. CONCLUSION: The results showed that H. pylori infection could cause significant quantitative changes in the cellular structure of gastric mucosa that might be influential on gastric carcinogenesis. PMID- 29155520 TI - High expression level of long non-coding RNA HOTAIR is associated with poor overall survival in gastric cancer patients: evidence from meta-analysis. AB - PURPOSE: Although several studies have investigated the association between the development of gastric cancer (GC) and the expression level of long non-coding (lnc) RNA HOTAIR, no clear evidence about whether its expression is associated with the overall survival (OS) of GC patients exists. In this study we tried to explore the association between lncRNA HOTAIR expression levels with OS and other clinical features in GC patients. METHODS: Databases including PubMed, EMBASE and the Cochrane Library were used to search eligible studies. The quality of included studies was assessed according to reporting recommendations for tumor marker prognostic studies (REMARK). The association between the expression level of lncRNA HOTAIR and OS was evaluated by calculating the pooled hazard ratio (HR) and 95% confidence interval (95% CI) using the STATA software, version 12.0. RESULTS: A total of 9 studies involving 740 GC and 768 normal gastric tissues were included in this meta-analysis. The average score of quality assessment was 18.89+/-1.08, (range 16.5-20). The results indicated that high expression levels of lncRNA HOTAIR were associated with poor OS in GC patients (pooled HR: 1.43, 95% CI:1.17-1.76, p=0.000). Subgroup analyses showed that elevated expression of lncRNA HOTAIR was significantly associated with poor OS in Chinese GC patients (HR=1.414, 95%CI: 1.120-1.785, p=0.000), and not treated GC patients (HR=1.464, 95%CI: 1.179-1.817, p=0.001). Subgroup analyses also revealed that some GC patients features (e.g. T3-T4, III/IV stage, differentiation) were associated with an unfavorable outcome. CONCLUSIONS: High expression level of lncRNA HOTAIR is associated with a poor OS in GC patients. Thus, lncRNA HOTAIR might be a potentially useful independent prognostic biomarker for GC. PMID- 29155521 TI - Gastric adenocarcinoma with neuroendocrine differentiation: Clinicopathological features and efficacy of modified DCF chemotherapy. AB - PURPOSE: The aim of this study was to investigate the clinicopathological characteristics of patients with gastric carcinoma with neuroendocrine differentiation (NEDGC) and the efficacy of the modified DCF (mDCF) chemotherapy regimen. METHODS: Patients with NEDGC and non-NEDGC (pure adenocarcinoma) were evaluated comparatively in terms of pathological parameters, clinical parameters and treatment efficacy. Patients received treatment with mDCF (docetaxel, cisplatin and 5-fluorouracil). RESULTS: In total, 391 patients (35 with NEDGC and 356 with non-NEDGC) were included in this study. In particular, in the NEDGC group, the presence of lymphovascular invasion (LVI), presence of perineural invasion (PNI), median tumor size, and metastasis at the time of diagnosis were significantly higher than in the non-NEDGC group. mDCF was used as first-line chemotherapy regimen in 16 patients in the NEDGC group, and in 151 patients in the non-NEDGC group. In NEDGC and non-NEDGC groups overall disease control rate was 87.5% [partial response (PR) (50.0%), stable disease (SD) (37.5%)] and 80.8% [complete response (CR) (2.6%), PR (38.4%), SD (39.8%)], respectively. In the advanced-stage patients who had first-line mDCF, the median overall survival (OS) was 10.6 months (95% CI: 5.9-15.4) and 12.2 months (95% CI: 10.3-14.2) in NEDGC and non-NEDGC groups, respectively (p=0.88). The median progression-free survival (PFS) in the NEDGC and the non-NEDGC groups were 7.6 months (95% CI: 5.5-9.7) and 7.5 months (95% confidence interval/CI: 6.8-8.1), respectively (p=0.82). CONCLUSION: NEDGC patients usually have higher LVI and PNI rates, and they present with advanced disease. In this group of patients, mDCF regimen may be an effective treatment option. However this statement needs to be verified by further prospective and multi-centered studies including a larger patient cohort. PMID- 29155522 TI - Impact of conversion during laparoscopic gastrectomy on outcomes of patients with gastric cancer. AB - PURPOSE: This study reports the impact of conversion from laparoscopic gastrectomy to open gastrectomy on the short- and long-term outcomes of patients with gastric cancer. METHODS: Retrospective analysis of clinical and follow-up data of 236 patients with gastric cancer who underwent laparoscopic gastrectomy between January 2010 and October 2016 was performed. Patients were divided into the conversion and complete laparoscopy groups based on whether conversion to open gastrectomy occurred during surgery or not. Short- and long-term outcomes were compared between these two groups. RESULTS: The conversion rate was 10.1% (24/236). The reported reasons for conversion were adhesion, obesity, uncontrollable bleeding, and T4 stage tumor during surgery. Compared to the complete laparoscopy group, patients in the conversion group had longer operation time (p=0.028), greater intraoperative blood loss (p=0.011), and longer hospital stay (p=0.030). No statistically significant differences were found in the incidence and severity of complications within postoperative 30 days between the two groups. Obesity, tumor site in the upper gastric region, and surgery performed between 2010 and 2012 were independent predictors for conversion. Additionally, no statistical differences in the pathological findings and long term outcomes were found between the two groups. CONCLUSION: Except from increased operation time, intraoperative blood loss, and length of hospital stay, conversion from laparoscopic gastrectomy to open gastrectomy had no impact on postoperative complications and long-term outcomes of patients with gastric cancer. PMID- 29155523 TI - Building Environmental Health Capacity in the Cloud. PMID- 29155524 TI - Revisiting Trichloroethylene Contaminated Hazardous Waste Sites After New Science Indicates the Need for a Lower Health Guideline. PMID- 29155525 TI - Whither UK dentistry after Brexit? PMID- 29155526 TI - The Dental Update Readers' Panel. PMID- 29155527 TI - Provisional Restorations - A Permanent Problem? AB - Provisional restorations play an important role when providing indirect restorations. There are a number of materials and techniques available for their construction. Careful planning and construction can protect the prepared tooth surface, improve the periodontal condition and help plan for the definitive restoration. A good provisional restoration can save time, money and effort. Clinical relevance: Provisional restoration construction is an integral part of the indirect restorative process for inlays, onlays, crowns and bridges. PMID- 29155528 TI - Tools to Drive Quality Improvement of Vector Control Services. PMID- 29155529 TI - DirecTalk: Musings From the 10th Floor: Distribution>Content>Brand. PMID- 29155530 TI - Dental Trauma 2- Acute Management of Fracture Injuries. AB - Fortunately, traumatic dental injuries are a relatively uncommon occurrence in general dental practice. However, when they do present, timely diagnosis and treatment of such injuries is essential to maximize the chance of a successful outcome. This is the second part of a two-part series on traumatic dental injuries that are commonly encountered in the clinical setting. Part one covered the management of acute luxation/displacement injuries affecting the supporting structures of the tooth, while part two will cover the management of fracture injuries associated with teeth and the alveolar bone. Clinical relevance: Traumatic dental injuries are uncommon occurrences in everyday general dental practice. This article aims to provide a simple, step-by-step approach in the diagnosis and clinical management of acute fracture injuries. PMID- 29155531 TI - A Review of the Available Guidance Regarding Management of Medical Emergencies in Primary Dental Care. AB - This article provides an overview of the recent changes in guidance relating to the management of medical emergencies in primary dental care in the UK. The guidance relating to automated external defibrillators is also presented. The expectations of our regulatory bodies are discussed, as are the requirements for continued professional development. The potential shortcomings of the changes to the guidance are also discussed, as well as proposed solutions, such as the development of algorithms to use in a dental practice setting. Clinical relevance: All dental practitioners should be able to deal with medical emergencies in their practice. PMID- 29155532 TI - The Restorability Assessment and Endodontic Access Cavity Interface. AB - Successful root canal treatment requires management of the bacterial infection within the root canal space and protection of residual tooth structure with direct/indirect restorations. Long-term success depends upon prevention of re infection of the root canal space as well as ensuring favourable distribution of the occlusal forces throughout the residual tooth structure. Appropriate planning and design of the final restoration prior to initiating root canal treatment is paramount in achieving this objective. This article describes simultaneous restorability assessment and access cavity preparation to optimize outcome of both endodontic and prosthodontic treatment of the endodontically involved tooth. Clinical relevance: This paper proposes a method to improve visibility and reduce iatrogenic errors whilst simultaneously facilitating effective design of the definitive restoration based on the quantity and distribution of residual tooth structure. PMID- 29155533 TI - Conservative Prosthetic Rehabilitation of Medication-Related Osteonecrosis of the Jaw (MRONJ). AB - Osteonecrosis of the jaw associated with bisphosphonates and other medications is a growing problem facing dentists. It can have a significant and debilitating impact upon patients. Various treatment options ranging from surgical intervention to management with antibiotics and analgesics have been proposed. This article presents one method of conservative treatment and prosthetic rehabilitation in a patient with ongoing BRONJ of the maxilla unsuitable for surgical management. Clinical relevance: Dentists need to be able to identify patients who are at risk of developing BRONJ and have an awareness of the appropriate management as well as potential oral rehabilitation options for these patients. PMID- 29155534 TI - Evidence-Based Dentistry in Everyday Practice. AB - This article informs readers of a method of implementing evidence-based dentistry in practice. Following these steps, practitioners should be able to use this skill in an efficient manner. The importance of evidence-based dentistry and its relevance to situations encountered in everyday practice is also highlighted. Clinical relevance: This article highlights a series of steps to be followed by practitioners to ensure that treatment provided is supported by the most recent, good quality evidence. PMID- 29155535 TI - An Interesting Case of Oral Inverted Ductal Papilloma. AB - Ductal papillomas are rare benign papillary tumours of the minor salivary glands. Previously they have been classified into three subtypes: inverted ductal papilloma (IDP), sialadenoma papilliferum and intraductal papilloma. The oral inverted ductal papilloma is the least common of these lesions, with 48 cases reported to date in a search of the English-language literature. We describe an interesting case of oral IDP and highlight the pertinent clinical and histopathological features. Importantly, unlike the histologically similar inverted papilloma (IP) of the nose and paranasal sinuses, oral IDP is a completely benign lesion and is not associated with malignant change. Clinical relevance: This case report aims to raise awareness of the lesion, oral inverted ductal papilloma (IDP). We outline the clinical features and unique histopathology of oral IDP so that clinicians may correctly diagnose such a lesion and implement appropriate treatment. PMID- 29155536 TI - Antimicrobial Resistance and Antibiotic Prescribing in Dental Practice. AB - The purpose of this paper is to review the principles of antibiotic prescribing in light of the increasing worldwide problem of antimicrobial resistance and the evidence of inappropriate use of antibiotics in dentistry. Guidance on the management of dental infections and antibiotic prophylaxis based on a review of the scientific evidence will be given to ensure good patient care. Clinical relevance: To discuss the relevance of legislation around antimicrobial prescribing and antimicrobial stewardship for dentists. PMID- 29155537 TI - Case Study: Management of a Loose Upper Denture Opposed by a Shortened Dental Arch. AB - For many years, it has been considered necessary to restore posterior support with a bilateral free-end saddle when a full upper denture is opposed by a shortened dental arch. It was thought that this would provide occlusal stability and prevent anterior bite collapse and temporomandibular dysfunction. As free-end saddle partial dentures are often poorly tolerated by patients, this case study tests whether a retentive full-upper denture occluding with a shortened dental arch offers enough to fulfil a patient's needs. Clinical relevance: An increasingly elderly population will present dental practitioners with more partially dentate patients requiring treatment. PMID- 29155538 TI - Aetiological, Histopathological, Clinical, Diagnostic and Therapeutical Features of Idiopathic Cervical Resorption. AB - Root resorption is the loss of hard dental tissue as a result of odontoclastic action involving vital and pulpless teeth. Cervical root resorption (CRR) is a type of external resorption which usually occurs immediately below the epithelial attachment of the tooth in the cervical region. The idiopathic cervical resorption (ICR) refers to a clinical situation in which all other causes, whether local or systemic, have been ruled out as the origin of the disease. The early stage is asymptomatic and might be diagnosed by a routine radiograph or a clinical examination. In this study, the aetiological, histological, clinical and radiological analysis is undertaken; a review is made concerning the pathologies to which the differential diagnosis should be applied; and the different therapeutical options are discussed. This lesion sometimes demands the management of a broad field of multidisciplinary techniques such as restorative dentistry, endodontics, surgery, implants and prosthesis. Clinical relevance: Cone-beam computed tomography (CBCT) may be a useful tool to determine the true extent of external cervical resorption lesions. PMID- 29155539 TI - Sore or Swollen Lips Part 2: Systemic Causes. AB - This series of three papers reviews the causes, diagnosis and differential diagnosis, and outlines the management of sore and/or swollen lips. Clinical relevance: Sore and/or swollen lips are not uncommon, often have a local cause, but may reflect a systemic disease. The previous article reviewed important causes, from actinic to contact cheilitis, while this paper starts with drug induced cheilitis and completes that alphabetical list. PMID- 29155542 TI - Flossing, remoaning and remainia - dentistry in denial'. PMID- 29155541 TI - A Festive Case Series of Emergencies, Admissions and Friendship at a Busy Oral and Maxillofacial Unit. AB - The festive season presents oral and maxillofacial surgery (OMFS) dental core trainees (DCTs) with the challenges of managing an eclectic mix of emergencies. We present three such patients in this case series. First, Patient A, a 39-year old homeless male who presented with a maxillary extra-oral draining sinus. Secondly, Patient B, a 38-year-old intra-venous (IV) drug user who suffered pan facial fractures following an alcohol-fuelled assault. Finally, Patient C, a 38 year-old male who sustained a left zygomatic complex fracture a week previously, in attendance for corrective surgery. Despite the hardship, there was still festive cheer to be had by these individuals. Clinical relevance: Primary and secondary care practitioners should be aware of the advanced clinical presentation of dental and maxillofacial emergencies that occur over holiday periods. PMID- 29155543 TI - Dear editor. PMID- 29155544 TI - Wearing elastics in the 21st century. PMID- 29155545 TI - Diagnosis: the difficult part! PMID- 29155546 TI - A Novel Electrochemical Biosensor Based on a Double-Signal Technique for d(CAG)n Trinucleotide Repeats. AB - Electrochemical sensors now play an important role in analysis and detection of nucleic acids. In this work, we present a novel double-signal technique for electrochemically measuring the sequence and length of the d(CAG)n repeat. The double-signal technique used an electrochemical molecular beacon (a hairpin DNA labeled with ferrocene), which was directly modified on the surface of a gold electrode, while a reporter probe (a DNA sequence labeled with horseradish peroxidase) was hybridized to the target DNA. First a simple single-signal sensor was characterized in which d(CAG)n repeats were detected using a short reporter DNA strand labeled with horseradish peroxidase. To obtain a reliable signal that was dependent on repeat number, a double-signal biosensor was created in which the single strand capture DNA in single-signal sensor was replaced by an electrochemical molecular beacon labeled with ferrocene. When the hairpin DNA hybridized to the target-reporter DNA complex, it opened, resulting in a decreased ferrocene current. Both electrochemical biosensors exhibited high selectivity and sensitivity with low detection limits of 0.21 and 0.15 pM, respectively, for the detection of d(CAG)n repeats. The double-signal sensor was more accurate for the determination of repeat length, which was measured from the ratio of signals for HRP and ferrocene (H/F). A linear relationship was found between H/F and the number of repeats (n), H/F = 0.1398n + 9.89788, with a correlation coefficient of 0.974. Only 10 nM of target DNA was required for measurements based on the value of H/F in the double-signal technique. These results indicated that this new double-signal electrochemical sensor provided a reliable method for the analysis of CAG trinucleotide repeats. PMID- 29155547 TI - Aggregation-Induced Fluorescence Probe for Monitoring Membrane Potential Changes in Mitochondria. AB - Fluorescent probe 2 was designed for selectively determining mitochondria membrane potential changes. The probe selectively detects changes in the mitochondria membrane potential in a manner that is more sensitive than that of the commercially available indicator, Rodamine 123. As a result, the probe 2 is ideal for future studies designed to assess the functions of mitochondria in cells. PMID- 29155549 TI - Icephobic Behavior of UV-Cured Polymer Networks Incorporated into Slippery Lubricant-Infused Porous Surfaces: Improving SLIPS Durability. AB - Ice accretion causes damage on power generation infrastructure, leading to mechanical failure. Icephobic materials are being researched so that ice buildup on these surfaces will be shed before the weight of the ice causes catastrophic damage. Lubricated materials have imposed the lowest-recorded forces of ice adhesion, and therefore lubricated materials are considered the state-of-the-art in this area. Slippery lubricant-infused porous surfaces (SLIPS) are one type of such materials. SLIPS are initially very effective at repelling ice, but the trapped fluid layer that affords their icephobic properties is easily depleted by repeated icing/deicing cycles, even after one deicing event. UV-cured siloxane resins were infused into SLIPS to observe effects on icephobicity and durability. These UV-cured polymer networks enhanced both the icephobicity and longevity of the SLIPS; values of ice adhesion below 10 kPa were recorded, and appreciable icephobicity was maintained up to 10 icing/deicing cycles. PMID- 29155550 TI - Carbon Fiber Ionization Mass Spectrometry for the Analysis of Analytes in Vapor, Liquid, and Solid Phases. AB - Various ionization methods in mass spectrometry (MS) are available for the analysis of analytes with different properties. Nonetheless, the use of a single ionization method to analyze mixtures containing analytes with different polarities and volatilities in different phases at atmospheric pressure remains a challenge. Exploring an ionization method that can ionize small organics and large biomolecules with different properties for MS analysis is advantageous. Carbon fiber ionization mass spectrometry (CFI-MS), which uses a carbon fiber bundle as the ion source, is useful for the analysis of small organics with low polarities. Voltage needs to be applied on the carbon fiber bundle to initiate corona discharge for ionization of analytes. In this study, we explore the suitability of using CFI-MS in the analysis of analytes in vapor, liquid, and solid phases using a single carbon fiber (length : ~1 cm; diameter: ~10 MUm) as the ion source. Furthermore direct electric contact on the carbon fiber is not required. We demonstrate that CFI-MS is useful for analyzing not only small and low-polarity organics but also polar biomolecules, such as peptides and proteins. The limits of detection for analytes with high polarities such as dodecyl trimethylammonium bromide and bradykinin are estimated to be ~16 and ~53 pM, respectively. Ionization mechanisms, including corona discharge and electrospray, are involved in the ionization of analytes with the polarity from low to high. Furthermore, sesame oil containing aromatic volatiles and compounds with different polarities is used as a model sample to demonstrate the capability of the developed ionization method to provide comprehensive chemical information from a complex sample. In addition, the feasibility of using the developed method for quantitative analysis of nonpolar as well as medium and high polarity analytes is also demonstrated. The sensitivity of the developed method toward analytes with high polarity is higher than those with low polarity. The method precision was estimated to be ~7.8%. PMID- 29155548 TI - Site-Selective RNA Splicing Nanozyme: DNAzyme and RtcB Conjugates on a Gold Nanoparticle. AB - Modifying RNA through either splicing or editing is a fundamental biological process for creating protein diversity from the same genetic code. Developing novel chemical biology tools for RNA editing has potential to transiently edit genes and to provide a better understanding of RNA biochemistry. Current techniques used to modify RNA include the use of ribozymes, adenosine deaminase, and tRNA endonucleases. Herein, we report a nanozyme that is capable of splicing virtually any RNA stem-loop. This nanozyme is comprised of a gold nanoparticle functionalized with three enzymes: two catalytic DNA strands with ribonuclease function and an RNA ligase. The nanozyme cleaves and then ligates RNA targets, performing a splicing reaction that is akin to the function of the spliceosome. Our results show that the three-enzyme reaction can remove a 19 nt segment from a 67 nt RNA loop with up to 66% efficiency. The complete nanozyme can perform the same splice reaction at 10% efficiency. These splicing nanozymes represent a new promising approach for gene manipulation that has potential for applications in living cells. PMID- 29155551 TI - Template-Assisted Wet-Combustion Synthesis of Fibrous Nickel-Based Catalyst for Carbon Dioxide Methanation and Methane Steam Reforming. AB - Efficient capture and recycling of CO2 enable not only prevention of global warming but also the supply of useful low-carbon fuels. The catalytic conversion of CO2 into an organic compound is a promising recycling approach which opens new concepts and opportunities for catalytic and industrial development. Here we report about template-assisted wet-combustion synthesis of a one-dimensional nickel-based catalyst for carbon dioxide methanation and methane steam reforming. Because of a high temperature achieved in a short time during reaction and a large amount of evolved gases, the wet-combustion synthesis yields homogeneously precipitated nanoparticles of NiO with average particle size of 4 nm on alumina nanofibers covered with a NiAl2O4 nanolayer. The as-synthesized core-shell structured fibers exhibit outstanding activity in steam reforming of methane and sufficient activity in carbon dioxide methanation with 100% selectivity toward methane formation. The as-synthesized catalyst shows stable operation under the reaction conditions for at least 50 h. PMID- 29155552 TI - Reliably Modeling the Mechanical Stability of Rigid and Flexible Metal-Organic Frameworks. AB - Over the past two decades, metal-organic frameworks (MOFs) have matured from interesting academic peculiarities toward a continuously expanding class of hybrid, nanoporous materials tuned for targeted technological applications such as gas storage and heterogeneous catalysis. These oft-times crystalline materials, composed of inorganic moieties interconnected by organic ligands, can be endowed with desired structural and chemical features by judiciously functionalizing or substituting these building blocks. As a result of this reticular synthesis, MOF research is situated at the intriguing intersection between chemistry and physics, and the building block approach could pave the way toward the construction of an almost infinite number of possible crystalline structures, provided that they exhibit stability under the desired operational conditions. However, this enormous potential is largely untapped to date, as MOFs have not yet found a major breakthrough in technological applications. One of the remaining challenges for this scale-up is the densification of MOF powders, which is generally achieved by subjecting the material to a pressurization step. However, application of an external pressure may substantially alter the chemical and physical properties of the material. A reliable theoretical guidance that can presynthetically identify the most stable materials could help overcome this technological challenge. In this Account, we describe the recent research the progress on computational characterization of the mechanical stability of MOFs. So far, three complementary approaches have been proposed, focusing on different aspects of mechanical stability: (i) the Born stability criteria, (ii) the anisotropy in mechanical moduli such as the Young and shear moduli, and (iii) the pressure-versus-volume equations of state. As these three methods are grounded in distinct computational approaches, it is expected that their accuracy and efficiency will vary. To date, however, it is unclear which set of properties are suited and reliable for a given application, as a comprehensive comparison for a broad variety of MOFs is absent, impeding the widespread use of these theoretical frameworks. Herein, we fill this gap by critically assessing the performance of the three computational models on a broad set of MOFs that are representative for current applications. These materials encompass the mechanically rigid UiO-66(Zr) and MOF-5(Zn) as well as the flexible MIL-47(V) and MIL-53(Al), which undergo pressure-induced phase transitions. It is observed that the Born stability criteria and pressure-versus-volume equations of state give complementary insight into the macroscopic and microscopic origins of instability, respectively. However, interpretation of the Born stability criteria becomes increasingly difficult when less symmetric materials are considered. Moreover, pressure fluctuations during the simulations hamper their accuracy for flexible materials. In contrast, the pressure-versus-volume equations of state are determined in a thermodynamic ensemble specifically targeted to mitigate the effects of these instantaneous fluctuations, yielding more accurate results. The critical Account presented here paves the way toward a solid computational framework for an extensive presynthetic screening of MOFs to select those that are mechanically stable and can be postsynthetically densified before their use in targeted applications. PMID- 29155553 TI - Thiyl Radical-Based Charge Tagging Enables Sterol Quantitation via Mass Spectrometry. AB - Inspired by the high reactivity and specificity of thiyl radicals toward alkenes, we have developed a new charge derivatization method to enable fast and quantitative analysis of sterols via electrospray ionization-mass spectrometry (ESI-MS). Thioglycolic acid (TGA), a commercially available compound, has been established as a highly efficient tagging reagent. Initiated from photochemical reactions, the thiyl radical derived from TGA abstracts an allylic hydrogen in the B ring of sterols, forming a radical intermediate which rapidly recombines with a second thiyl radical to produce the final tagged product. Because of the incorporation of a carboxylic acid group, TGA tagging not only improves the limit of detection (sub-nM) for sterols but also facilitates their quantitation via characteristic 44 Da neutral loss scan. This radical based derivatization is fast (1 min) and efficient (>90% yield) when conducted in a flow microreactor. The analytical utility of thiyl radical charge tagging method has been demonstrated by quantifying sterols from human plasma and vegetable oil. PMID- 29155554 TI - Zn/V2O5 Aqueous Hybrid-Ion Battery with High Voltage Platform and Long Cycle Life. AB - Aqueous zinc-ion batteries attract increasing attention due to their low cost, high safety, and potential application in stationary energy storage. However, the simultaneous realization of high cycling stability and high energy density remains a major challenge. To tackle the above-mentioned challenge, we develop a novel Zn/V2O5 rechargeable aqueous hybrid-ion battery system by using porous V2O5 as the cathode and metallic zinc as the anode. The V2O5 cathode delivers a high discharge capacity of 238 mAh g-1 at 50 mA g-1. 80% of the initial discharge capacity can be retained after 2000 cycles at a high current density of 2000 mA g 1. Meanwhile, the application of a "water-in-salt" electrolyte results in the increase of discharge platform from 0.6 to 1.0 V. This work provides an effective strategy to simultaneously enhance the energy density and cycling stability of aqueous zinc ion-based batteries. PMID- 29155555 TI - Medication Exposure in Highly Adherent Psychiatry Patients. AB - Medication exposure is dependent upon many factors, the single most important being if the patient took the prescribed medication as indicated. To assess medication exposure for psychotropic and other medication classes, we enrolled 115 highly adherent psychiatry patients prescribed five or more medications. In these patients, we measured 21 psychotropic and 38 nonpsychotropic medications comprising a 59 medication multiplex assay panel. Strict enrollment criteria and reconciliation of the electronic health record medication list prior to study initiation produced a patient cohort that was adherent with 91% of their prescribed medications as determined by comparing medications detected empirically in blood to the electronic health record medication list. In addition, 13% of detected medications were not in the electronic health record medication list. We found that only 53% of detected medications were within the literature-derived reference range with 41% below and 6% above the reference range specific to each medication. When psychotropic medications were analyzed near trough-level, only sertraline was found to be within the literature-derived reference range for all patients tested. Concentrations of the remaining medications indicated extensive exposure below the reference range. This is the first study to empirically and comprehensively assess medication exposure obtained in comorbid polypharmacy patients, minimizing the important behavioral factor of adherence in the study of medication exposure. These data indicate that low medication exposure is extensive and must be considered when therapeutic issues arise, including the lack of response to medication therapy. PMID- 29155556 TI - Anthracite-Derived Dual-Phase Carbon-Coated Li3V2(PO4)3 as High-Performance Cathode Material for Lithium Ion Batteries. AB - In this study, low cost anthracite-derived dual-phase carbon-coated Li3V2(PO4)3 composites have been successfully prepared via a traditional solid-phase method. XRD results show that the as-prepared samples have high crystallinity and anthracite introduction has no influence on the LVP crystal structure. The LVP/C particles are uniformly covered with a dual-phase carbon layer composed of amorphous carbon and graphitic carbon. The effect of the amount of anthracite on the battery performance of LVP as a cathode material has also been studied. The LVP/C composite obtained with 10 wt % anthracite (LVP/C-10) delivers the highest initial charge/discharge capacities of 186.1/168.2 mAh g-1 at 1 C and still retains the highest discharge capacity of 134.0 mAh g-1 even after 100 cycles. LVP/C-10 also displays an outstanding average capacity of 140.8 mAh g-1 at 5 C. The superior rate capability and cycling stability of LVP/C-10 is ascribed to the reduced particle size, decreased charge-transfer resistance, and improved lithium ion diffusion coefficient. Our results demonstrate that using anthracite as a carbon source opens up a new strategy for larger-scale synthesis of LVP and other electrode materials with poor electronic conductivity for lithium ion batteries. PMID- 29155557 TI - Wearable Nanoplasmonic Patch Detecting Sun/UV Exposure. AB - Sun exposure is known to yield beneficial health outcomes, including synthesis of adequate levels of vitamin D and beneficial modulation of blood pressure, and it is a valuable factor in mental health care. However, the increasing incidence of sun/UV exposure-related illness, such as skin cancer, is seriously concerning public health authorities as well as the scientific community. Consequently, moderate sun/UV exposure is strongly recommended. A wearable nanoplasmonic patch whose original color changes upon sun exposure due to its UV-responsive capabilities that are visually detectable has been engineered. The main scaffold of this patch is made of nanopaper, which is a flexible, lightweight, optically transparent and biocompatible material. Moreover, its UV-responsive agent is based on silver nanoparticles (AgNP), whose nanoplasmonic properties and safe use in bioapplications are widely covered in the literature. As UV light can modulate the size of AgNP significantly, the nanoplasmonic properties of the AgNP decorated nanopaper are also modulated leading to a change in color, which is readily observable upon sun exposure. This facilitates that the users can be alerted to moderate sun exposure and may prevent skin damage. Given the transparent nanoplasmonic nature of the resulting device, after 15 min of artificial sunlight exposure, the change in color of the patch was proven more observable in skins with the highest and moderate risk of developing skin cancer (skin types I, II, III, and IV) than in skin types V and VI-which are reported to tolerate relatively high levels of sun exposure safely. This low-cost wearable device is amenable to facilitating healthcare in low-resource settings using biomaterials and nanoplasmonics. PMID- 29155558 TI - Correlated Absorption and Scattering Spectroscopy of Individual Platinum Decorated Gold Nanorods Reveals Strong Excitation Enhancement in the Nonplasmonic Metal. AB - Bimetallic nanocatalysts have the potential to surmount current limitations in industrial catalysis if their electronic and optical properties can be effectively controlled. However, improving the performance of bimetallic photocatalysts requires a functional understanding of how the intricacies of their morphology and composition dictate every element of their optical response. In this work, we examine Au and Pt-decorated Au nanorods on a single-particle level to ascertain how Pt influences the plasmon resonance of the bimetallic nanostructure. We correlated scattering, photoluminescence, and pure absorption of individual nanostructures separately to expose the impact of Pt on each component. We found that the scattering and absorption spectra of uncoated Au nanorods followed expected trends in peak intensity and shape and were accurately reproduced by finite difference time domain simulations. In contrast, the scattering and absorption spectra of single Pt-decorated Au nanorods exhibited red-shifted, broad features and large deviations in line shape from particle to particle. Simulations using an idealized geometry confirmed that Pt damps the plasmon resonance of individual Au nanorods and that spectral changes after Pt deposition were a consequence of coupling between Au and Pt in the hybrid nanostructure. Simulations also revealed that the Au nanorod acts as an antenna and enhances absorption in the Pt islands. Furthermore, comparing photoluminescence spectra from Au and Pt-decorated Au nanorods illustrated that emission was significantly reduced in the presence of Pt. The reduction in photoluminescence intensity indicates that Pt lowers the number of hot carriers in the Au nanorod available for radiative recombination through either direct production of hot carriers in Pt following enhanced absorption or charge transfer from Au to Pt. Overall, these results confirm that the Pt island morphology and distribution on the nanorod surface contribute to the optical response of individual hybrid nanostructures and that the damping observed in ensemble measurements originates not only from structural heterogeneity but also because of significant damping in single nanostructures. PMID- 29155559 TI - Crafting of Neuroprotective Octapeptide from Taxol-Binding Pocket of beta Tubulin. AB - Microtubules play a crucial role in maintaining the shape and function of neurons. During progression of Alzheimer's disease (AD), severe destabilization of microtubules occurs, which leads to the permanent disruption of signal transduction processes and memory loss. Thus, microtubule stabilization is one of the key requirements for the treatment of AD. Taxol, a microtubule stabilizing anticancer drug, has been considered as a potential anti-AD drug but was never tested in AD patients, likely because of its' toxic nature and poor brain exposure. However, other microtubule-targeting agents such as epothilone D (BMS 241027) and TPI-287 (abeotaxane) and NAP peptide (davunetide) have entered in AD clinical programs. Therefore, the taxol binding pocket of tubulin could be a potential site for designing of mild and noncytotoxic microtubule stabilizing molecules. Here, we adopted an innovative strategy for the development of a peptide based microtubule stabilizer, considering the taxol binding pocket of beta-tubulin, by using alanine scanning mutagenesis technique. This approach lead us to a potential octapeptide, which strongly binds to the taxol pocket of beta tubulin, serves as an excellent microtubule stabilizer, increases the expression of acetylated tubulin, and acts as an Abeta aggregation inhibitor and neuroprotective agent. Further, results revealed that this peptide is nontoxic against both PC12 derived neurons and primary cortical neurons. We believe that our strategy and discovery of peptide-based microtubule stabilizer will open the door for the development of potential anti-AD therapeutics in near future. PMID- 29155560 TI - Asymmetric Assembling of Iron Oxide Nanocubes for Improving Magnetic Hyperthermia Performance. AB - Magnetic hyperthermia (MH) based on magnetic nanoparticles (MNPs) is a promising adjuvant therapy for cancer treatment. Particle clustering leading to complex magnetic interactions affects the heat generated by MNPs during MH. The heat efficiencies, theoretically predicted, are still poorly understood because of a lack of control of the fabrication of such clusters with defined geometries and thus their functionality. This study aims to correlate the heating efficiency under MH of individually coated iron oxide nanocubes (IONCs) versus soft colloidal nanoclusters made of small groupings of nanocubes arranged in different geometries. The controlled clustering of alkyl-stabilized IONCs is achieved here during the water transfer procedure by tuning the fraction of the amphiphilic copolymer, poly(styrene-co-maleic anhydride) cumene-terminated, to the nanoparticle surface. It is found that increasing the polymer-to-nanoparticle surface ratio leads to the formation of increasingly large nanoclusters with defined geometries. When compared to the individual nanocubes, we show here that controlled grouping of nanoparticles-so-called "dimers" and "trimers" composed of two and three nanocubes, respectively-increases specific absorption rate (SAR) values, while conversely, forming centrosymmetric clusters having more than four nanocubes leads to lower SAR values. Magnetization measurements and Monte Carlo based simulations support the observed SAR trend and reveal the importance of the dipolar interaction effect and its dependence on the details of the particle arrangements within the different clusters. PMID- 29155561 TI - Fabrication of CsxFA1-xPbI3 Mixed-Cation Perovskites via Gas-Phase-Assisted Compositional Modulation for Efficient and Stable Photovoltaic Devices. AB - Over the past few years, significant attention has been focused on HC(NH2)2PbI3 (FAPbI3) perovskite due to its reduced band gap and enhanced thermal stability compared with the most studied CH3NH3PbI3 (MAPbI3). However, FAPbI3 is sensitive to moisture and also encounters a serious structural phase-transition from photoactive alpha-phase to photoinactive delta-phase. Herein, we first develop a novel FAI gas-phase-assisted mixed-cation compositional modulation method to fabricate CsxFA1-xPbI3 perovskite solar cells (PSCs), and realize the structural stabilization of alpha-phase FAPbI3 with the incorporation of smaller inorganic Cs+ ions. Through the setting of different Cs+ contents (x = 0, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.50) along with a moderate FAI vapor deposition process, a series of CsxFA1-xPbI3 films with consistent compositions are fabricated, which perfectly resolves the main blocking problems of the conventional solution approach, such as difficulty in compositional control and rough film morphology. Meanwhile, we find that the Cs+ amount is crucial for generating phase-pure CsxFA1-xPbI3 (0 < x < 0.30) while higher contents result in phase segregation. Consequently, the optimum amount of Cs+ (x = 0.15) is verified, and Cs0.15FA0.85PbI3 shows the smallest unit cell volume and good moisture-resistant feature. Correspondingly, the highest power conversion efficiency (PCE) of 14.45% based on Cs0.15FA0.85PbI3 PSCs is successfully achieved in this work. PMID- 29155562 TI - Quantification of Nanomaterial/Nanomedicine Trafficking in Vivo. PMID- 29155563 TI - Cellular Effects and Delivery Propensity of Penetratin Is Influenced by Conjugation to Parathyroid Hormone Fragment 1-34 in Synergy with pH. AB - The cell-penetrating peptide (CPP) penetratin has demonstrated potential as a carrier for transepithelial delivery of cargo peptides, such as the therapeutically relevant part of parathyroid hormone, i.e., PTH(1-34). The purpose of the present study was to elucidate the relevance of pH for PTH(1-34) penetratin conjugates and coadministered penetratin with PTH(1-34) regarding transepithelial permeation of PTH(1-34) and cellular effects. Transepithelial permeation was assessed using monolayers of the Caco-2 cell culture model, and effects on Caco-2 cellular viability kinetics were evaluated by using the Real Time-GLO assay as well as by microscopy following Tryphan blue staining. Morphological Caco-2 cell changes were studied exploiting the impedance-based xCELLigence system as well as optically using the oCelloscope setup. Finally, the effect of pH on the folding propensity of the PTH(1-34)-penetratin conjugate and its ability to disrupt lipid membranes were assessed by circular dichroism (CD) spectroscopy and the calcein release assay, respectively. The transepithelial PTH(1-34) permeation was not pH-dependent when applying the coadministration approach. However, by applying the conjugation approach, the PTH(1-34) permeation was significantly enhanced by lowering the pH from 7.4 to 5 but also associated with a compromised barrier and a lowering of the cellular viability. The negative effects on the cellular viability following cellular incubation with the PTH(1 34)-penetratin conjugate were moreover confirmed during real-time monitoring of the Caco-2 cell viability as well as by enhanced Tryphan blue uptake. In addition, morphological changes were primarily observed for cells incubated with the PTH(1-34)-penetratin conjugate at pH 5, which was moreover demonstrated to have an enhanced membrane permeating effect following lowering of the pH from 7.4 to 5. The latter observation was, however, not a result of better secondary folding propensity at pH 5 when compared to pH 7.4. PMID- 29155565 TI - An Integrated Hot-Stage Microscope-Direct Analysis in Real Time-Mass Spectrometry System for Studying the Thermal Behavior of Materials. AB - This paper describes a new analytical instrument that combines a precisely temperature-controlled hot-stage with digital microscopy and Direct Analysis in Real Time-mass spectrometry (DART-MS) detection. The novelty of the instrument lies in its ability to monitor processes as a function of temperature through the simultaneous recording of images, quantitative color changes, and mass spectra. The capability of the instrument was demonstrated through successful application to four very varied systems including profiling an organic reaction, decomposition of silicone polymers, and the desorption of rhodamine B from an alumina surface. The multidimensional, real-time analytical data provided by this instrument allow for a much greater insight into thermal processes than could be achieved previously. PMID- 29155566 TI - Structure-Based Insights into the Dynamics and Function of Two-Domain SlpA from Escherichia coli. AB - SlpA (SlyD-like protein A) comprises two domains, a FK506 binding domain (FKBP fold) of moderate prolyl cis/trans-isomerase activity and an inserted in flap (IF) domain that hosts its chaperone activity. Here we present the nuclear magnetic resonance (NMR) solution structure of apo Escherichia coli SlpA determined by NMR that mirrors the structural properties seen for various SlyD homologues. Crucial structural differences in side-chain orientation arise for F37, which points directly into the hydrophobic core of the active site. It forms a prominent aromatic stacking with F15, one of the key residues for PPIase activity, thus giving a possible explanation for the inherently low PPIase activity of SlpA. The IF domain reveals the highest stability within the FKBP-IF protein family, most likely arising from an aromatic cluster formed by four phenylalanine residues. Both the thermodynamic stability and the PPIase and chaperone activity let us speculate that SlpA is a backup system for homologous bacterial systems under unfavorable conditions. PMID- 29155567 TI - Ratiometric Fluorescent Detection of Pb2+ by FRET-Based Phthalocyanine-Porphyrin Dyads. AB - Sensitive and selective detection of Pb2+ is a very worthwhile endeavor in terms of both human health and environmental protection, as the heavy metal is fairly ubiquitous and highly toxic. In this study, we designed phthalocyanine-porphyrin (Pc-Por) heterodyads, namely, H2Pc-alpha-ZnPor (1) and H2Pc-beta-ZnPor (2), by connecting a zinc(II) porphyrin moiety to the nonperipheral (alpha) or peripheral (beta) position of a metal-free phthalocyanine moiety. Upon excitation at the porphyrin Soret region (420 nm), both of the dyads exhibited not only a porphyrin emission (605 nm) but also a phthalocyanine emission (ca. 700 nm), indicating the occurrence of intramolecular fluorescence resonance energy transfer (FRET) processes from the porphyrin donor to the phthalocyanine acceptor. The dyads can selectively bind Pb2+ in the phthalocyanine core leading to a red shift of the phthalocyanine absorption and thus a decrease of spectral overlap between the porphyrin emission and phthalocyanine absorption, which in turn suppresses the intramolecular FRET. In addition, the binding of Pb2+ can highly quench the emission of phthalocyanine by heavy-metal ion effects. The synergistic coupled functions endow the dyads with remarkable ratiometric fluorescent responses at two distinct wavelengths (F605/F703 for 1 and F605/F700 for 2). The emission intensity ratio increased as a linear function to the concentration of Pb2+ in the range of 0-4.0 MUM, whereas the detection limits were determined to be 3.4 * 10-9 and 2.2 * 10-8 M for 1 and 2, respectively. Furthermore, by comparative study of 1 and 2, the effects of distance and relative orientation between Pc and ZnPor fluorophores on the FRET efficiency and sensing performance were highlighted, which is helpful for further optimizing such FRET systems. PMID- 29155568 TI - Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach. AB - A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC50 values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker. PMID- 29155569 TI - Redox Behavior of a Dinuclear Ruthenium(II) Complex Bearing an Uncommon Bridging Ligand: Insights from High-Pressure Electrochemistry. AB - A dinuclear ruthenium complex bridged by 2,3,5,6-pyrazinetetracarboxylic acid (MU LH22-) was synthesized and characterized by X-ray crystallography, cyclic voltammetry under ambient and elevated pressures, electron paramagnetic resonance (EPR) and UV/vis-NIR (NIR = near-infrared) spectroelectrochemistry, pulse radiolysis, and computational methods. We probed for the first time in the field of mixed-valency the use of high-pressure electrochemical methods. The investigations were directed toward the influence of the protonation state of the bridging ligand on the electronic communication between the ruthenium ions, since such behavior is interesting in terms of modulating redox chemistry by pH. Starting from the [RuII(MU-LH22-)RuII]0 configuration, which shows an intense metal-to-ligand charge transfer absorption band at 600 nm, cyclic voltammetry revealed a pH-independent, reversible one-electron reduction and a protonation state-dependent (proton coupled electron transfer, PCET) reversible oxidation. Deeper insight into the electrode reactions was provided by pressure-dependent cyclic voltammetry up to 150 MPa, providing insight into the conformational changes, the protonation state, and the environment of the molecule during the redox processes. Spectroelectrochemical investigations (EPR, UV/vis-NIR) of the respective redox reactions suggest a ligand-centered radical anion [RuII(MU-LH2*3 )RuII]- upon reduction (EPR Deltag = 0.042) and an ambiguous, EPR-silent one electron oxidized state. In both cases, the absence of the otherwise typical broad intervalence charge transfer bands in the NIR region for mixed-valent complexes support the formulation as radical anionic bridged compound. However, on the basis of high-pressure electrochemical data and density functional theory calculations the one-electron oxidized form could be assigned as a charge delocalized [RuII.5(MU-LH22-)RuII.5]+ valence tautomer rather than [RuIII(MU LH2*3-)RuIII]+. Deprotonation of the bridging ligand causes a severe shift of the redox potential for the metal-based oxidation toward lower potentials, yielding the charge-localized [RuIII(MU-LH3-)RuII]0 complex. This PCET process is accompanied by large intrinsic volume changes. All findings are supported by computational methods (geometry optimization, spin population analysis). For all redox processes, valence alternatives are discussed. PMID- 29155564 TI - Mass Spectrometry Imaging: A Review of Emerging Advancements and Future Insights. PMID- 29155570 TI - Chemistry, Antimicrobial Mechanisms, and Antibiotic Activities of Cinnamaldehyde against Pathogenic Bacteria in Animal Feeds and Human Foods. AB - Cinnamaldehyde is a major constituent of cinnamon essential oils produced by aromatic cinnamon plants. This compound has been reported to exhibit antimicrobial properties in vitro in laboratory media and in animal feeds and human foods contaminated with disease-causing bacteria including Bacillus cereus, Campylobacter jejuni, Clostridium perfringens, Escherichia coli, Listeria monocytogenes, and Salmonella enterica. This integrated review surveys and interprets our current knowledge of the chemistry, analysis, safety, mechanism of action, and antibiotic activities of cinnamaldehyde in food animal (cattle, lambs, calves, pigs, poultry) diets and in widely consumed liquid (apple, carrot, tomato, and watermelon juices, milk) and solid foods. Solid foods include various fruits (bayberries, blueberries, raspberries, and strawberries), vegetables (carrots, celery, lettuce, spinach, cucumbers, and tomatoes), meats (beef, ham, pork, and frankfurters), poultry (chickens and turkeys), seafood (oysters and shrimp), bread, cheese, eggs, infant formula, and peanut paste. The described findings are not only of fundamental interest but also have practical implications for food safety, nutrition, and animal and human health. The collated information and suggested research needs will hopefully facilitate and guide further studies needed to optimize the use of cinnamaldehyde alone and in combination with other natural antimicrobials and medicinal antibiotics to help prevent and treat food animal and human diseases. PMID- 29155572 TI - Boosting Hot Electrons in Hetero-superstructures for Plasmon-Enhanced Catalysis. AB - Hetero-nanostructures featured with both strong plasmon absorption and high catalytic activity are believed to be ideal platforms to realize efficient light driven catalysis. However, in reality, it remains a great challenge to acquire high-performance catalysis in such hetero-nanostructures due to poor generation and transfer of plamson-induced hot electrons. In this report, we demonstrate that Au nanorod@Pd superstructures (Au@Pd SSs), where the ordered Pd nanoarrays are precisely grown on Au nanorod surfaces via solution-based seed-mediated approach, would be an excellent solution for this challenge. Both experiment and theory disclose that the ordered arrangement of Pd on Au nanorod surfaces largely promotes hot electron generation and transfer via amplified local electromagnetic field and decreased electron-phonon coupling, respectively. Each effect is separately highlighted in experiments by the significant plasmon-enhanced catalytic activity of Au@Pd SSs in two types of important reactions with a distinct time scale of bond-dissociation event: molecular oxygen activation and carbon-carbon coupling reaction. This work opens the door to design and application of new generation photocatalysts. PMID- 29155573 TI - Kinetics and Mechanism of the Palladium-Catalyzed Oxidative Arylating Carbocyclization of Allenynes. AB - Pd-catalyzed C-C bond-forming reactions under oxidative conditions constitute a class of important and widely used synthetic protocols. This Article describes a mechanistic investigation of the arylating carbocyclization of allenynes using boronic acids and focuses on the correlation between reaction conditions and product selectivity. Isotope effects confirm that either allenic or propargylic C H activation occurs directly after substrate binding. With an excess of H2O, a triene product is selectively formed via allenic C-H activation. The latter C-H activation was found to be turnover-limiting and the reaction zeroth order in reactants as well as the oxidant. A dominant feature is continuous catalyst activation, which was shown to occur even in the absence of substrate. Smaller amounts of H2O lead to mixtures of triene and vinylallene products, where the latter is formed via propargylic C-H activation. The formation of triene occurs only in the presence of ArB(OH)2. Vinylallene, on the other hand, was shown to be formed by consumption of (ArBO)3 as a first-order reactant. Conditions with sub stoichiometric BF3.OEt2 gave selectively the vinylallene product, and the reaction is first order in PhB(OH)2. Both C-H activation and transmetalation influence the reaction rate. However, with electron-deficient ArB(OH)2, C-H activation is turnover-limiting. It was difficult to establish the order of transmetalation vs C-H activation with certainty, but the results suggest that BF3.OEt2 promotes an early transmetalation. The catalytically active species were found to be dependent on the reaction conditions, and H2O is a crucial parameter in the control of selectivity. PMID- 29155574 TI - Mechanism of Formation of Chlorinated Pyrene during Combustion of Polyvinyl Chloride. AB - Chlorinated polycyclic aromatic hydrocarbons (ClPAHs) are an emerging class of environmental contaminants, but the sources of these chemicals in the environment are not well-known. In this study, we developed a kinetic model describing the chlorination of PAHs to elucidate the mechanism of formation of ClPAHs during the combustion of organic waste containing chlorinated compounds and/or chlorine in an incinerator. Pyrene (Pyr) and polyvinyl chloride (PVC) were selected as a model PAH and a model organic substrate, respectively. All combustion experiments were carried out using a model furnace operated under similar experimental conditions. Combustion of PVC in the model furnace produced 1-ClPyr, 1,3-Cl2Pyr, 1,6-Cl2Pyr, 1,8-Cl2Pyr, 1,3,6-Cl3Pyr, and 1,3,6,8-Cl4Pyr. The developed model supported the experimental data on the sequential chlorination of pyrene. The rate constants for the formation of mono- to trichlorinated pyrenes were over 30 times of those for the formation of tetra- and penta-chlorinated pyrenes. A qualitative analysis of the formation of highly chlorinated pyrenes based on the comparison of theoretical and empirical isotopic patterns of the mass spectrum revealed that penta- and hexa-chlorinated pyrenes, whose analytical standards were not available, were also produced by the combustion of PVC. PMID- 29155575 TI - Temporal Trends of C8-C36 Chlorinated Paraffins in Swedish Coastal Sediment Cores over the Past 80 Years. AB - Temporal trends of chlorinated paraffins (CPs) were analyzed in three sediment cores collected near different potential CP sources along the Swedish Baltic Sea coast. C8-C36 CPs were found in sediment dating back to the 1930s. The maximum CP concentrations found in proximity to a metropolitan sewage treatment plant, a wood-related industrial area, and a steel factory were 48, 160, and 1400 ng/g d.w., respectively, in sediment sections dated from the early 1990s or the 2000s. The temporal trends agree with statistics on CP importation in Sweden or local industrial activities. MCCPs (C14-C17 CPs) and LCCPs (C>=18 CPs) predominated in most sediments with average percentage compositions of 47 +/- 20% and 37 +/- 20%, respectively. Concentrations of SCCPs in the three cores showed a decreasing trend in recent years. The temporal trends of MCCPs indicated that these are currently the predominant CPs in use. This study showed for the first time that LCCPs from C18 to C36, as well as C8-C17 CPs, are persistent in sediments over the last 50-80 years, indicating that CPs are persistent chemicals regardless of alkane-chain lengths. PMID- 29155571 TI - Oxygen Activation by Cu LPMOs in Recalcitrant Carbohydrate Polysaccharide Conversion to Monomer Sugars. AB - Natural carbohydrate polymers such as starch, cellulose, and chitin provide renewable alternatives to fossil fuels as a source for fuels and materials. As such, there is considerable interest in their conversion for industrial purposes, which is evidenced by the established and emerging markets for products derived from these natural polymers. In many cases, this is achieved via industrial processes that use enzymes to break down carbohydrates to monomer sugars. One of the major challenges facing large-scale industrial applications utilizing natural carbohydrate polymers is rooted in the fact that naturally occurring forms of starch, cellulose, and chitin can have tightly packed organizations of polymer chains with low hydration levels, giving rise to crystalline structures that are highly recalcitrant to enzymatic degradation. The topic of this review is oxidative cleavage of carbohydrate polymers by lytic polysaccharide mono oxygenases (LPMOs). LPMOs are copper-dependent enzymes (EC 1.14.99.53-56) that, with glycoside hydrolases, participate in the degradation of recalcitrant carbohydrate polymers. Their activity and structural underpinnings provide insights into biological mechanisms of polysaccharide degradation. PMID- 29155576 TI - Chronic Arsenic Exposure Increases Abeta(1-42) Production and Receptor for Advanced Glycation End Products Expression in Rat Brain. AB - Chronic arsenic exposure during development is associated with alterations of chemical transmission and demyelination, which result in cognitive deficits and peripheral neuropathies. At the cellular level, arsenic toxicity involves increased generation of reactive species that induce severe cellular alterations such as DNA fragmentation, apoptosis, and lipid peroxidation. It has been proposed that arsenic-associated neurodegeneration could evolve to Alzheimer disease in later life.1,2 In this study, the effects of chronic exposure to inorganic arsenic (3 ppm by drinking water) in Wistar rats on the production and elimination of Amyloid-beta (Abeta) were evaluated. Male Wistar rats were exposed to 3 ppm of arsenic in drinking water from fetal development until 4 months of age. After behavioral deficits induced by arsenic exposure through contextual fear conditioning were verified, the brains were collected for the determination of total arsenic by inductively coupled plasma-mass spectrometry, the levels of amyloid precursor protein and receptor for advanced glycation end products (RAGE) by Western blot analysis as well as their transcript levels by RT-qPCR, Abeta(1 42) estimation by ELISA assay and the enzymatic activity of beta-secretase (BACE1). Our results demonstrate that chronic arsenic exposure induces behavioral deficits accompanied of higher levels of soluble and membranal RAGE and the increase of Abeta(1-42) cleaved. In addition, BACE1 enzymatic activity was increased, while immunoblot assays showed no differences in the low-density lipoprotein receptor-related protein 1 (LRP1) receptor among groups. These results provide evidence of the effects of arsenic exposure on the production of Abeta(1-42) and cerebral amyloid clearance through RAGE in an in vivo model that displays behavioral alterations. This work supports the hypothesis that early exposure to metals may contribute to neurodegeneration associated with amyloid accumulation. PMID- 29155577 TI - Identification of Conserved Water Sites in Protein Structures for Drug Design. AB - Identification of conserved waters in protein structures is a challenging task with applications in molecular docking and protein stability prediction. As an alternative to computationally demanding simulations of proteins in water, experimental cocrystallized waters in the Protein Data Bank (PDB) in combination with a local structure alignment algorithm can be used for reliable prediction of conserved water sites. We developed the ProBiS H2O approach based on the previously developed ProBiS algorithm, which enables identification of conserved water sites in proteins using experimental protein structures from the PDB or a set of custom protein structures available to the user. With a protein structure, a binding site, or an individual water molecule as a query, ProBiS H2O collects similar proteins from the PDB and performs local or binding site-specific superimpositions of the query structure with similar proteins using the ProBiS algorithm. It collects the experimental water molecules from the similar proteins and transposes them to the query protein. Transposed waters are clustered by their mutual proximity, which enables identification of discrete sites in the query protein with high water conservation. ProBiS H2O is a robust and fast new approach that uses existing experimental structural data to identify conserved water sites on the interfaces of protein complexes, for example protein-small molecule interfaces, and elsewhere on the protein structures. It has been successfully validated in several reported proteins in which conserved water molecules were found to play an important role in ligand binding with applications in drug design. PMID- 29155579 TI - Catalytic Conversion of Carbohydrates to Initial Platform Chemicals: Chemistry and Sustainability. AB - The replacement of fossil resources that currently provide more than 90% of our energy needs and feedstocks of the chemical industry in combination with reduced emission of carbon dioxide is one of the most pressing challenges of mankind. Biomass as a globally available resource has been proposed as an alternative feedstock for production of basic building blocks, which could partially or even fully replace the currently utilized fossil-based ones in well-established chemical processes. The destruction of lignocellulosic feed followed by oxygen removal from its cellulose and hemicellulose content by catalytic processes results in the formation of initial platform chemicals (IPCs). However, their sustainable production strongly depends on the availability of resources, their efficient or even industrially viable conversion processes, and replenishment time of feedstocks. Herein, we overview recent advances and developments in catalytic transformations of the carbohydrate content of lignocellulosic biomass to IPCs (i.e., ethanol, 3-hydroxypropionic acid, isoprene, succinic and levulinic acids, furfural, and 5-hydroxymethylfurfural). The mechanistic aspects, development of new catalysts, different efficiency indicators (yield and selectivity), and conversion conditions of their production are presented and compared. The potential biochemical production routes utilizing recently engineered microorganisms are reviewed, as well. The sustainability metrics that could be applied to the chemical industry (individual set of sustainability indicators, composite indices methods, material and energy flow analysis-based metrics, and ethanol equivalents) are also overviewed as well as an outlook is provided to highlight challenges and opportunities associated with this huge research area. PMID- 29155578 TI - Determination of Hydrophobic Lengths of Membrane Proteins with the HDGB Implicit Membrane Model. AB - A protocol for predicting the hydrophobic length of membrane proteins using the heterogeneous dielectric generalized Born (HDGB) implicit membrane model is presented. The method involves optimal positioning in the membrane and identification of lipid-facing and inward-facing residues, followed by energy optimization of the implicit membrane model to obtain the hydrophobic length from the optimal membrane width. The latest HDGB version 3 (HDGBv3) and HDGB van der Waals (HDGBvdW) models were applied to a test set containing 15 proteins (seven beta-barrel and eight alpha-helical proteins), for which matching membrane widths are available from experiment, and an additional set contains ten alpha-helical and ten beta-barrel proteins without any experimental data. The results with the HDGB model compare favorably with predictions from methods used in the Orientations of Proteins in Membranes (OPM) and Protein Data Bank of Transmembrane Proteins (PDB-TM) databases. PMID- 29155580 TI - A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors. AB - The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we disclosed the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region and then building into the LPF shelf. Herein, we report the "hybridization" of a variety of KAc-binding fragments with a tetrahydroquinoline scaffold that makes optimal interactions with the LPF shelf, imparting enhanced potency and selectivity to the hybridized ligand. To demonstrate the utility of our hybridization approach, two analogues containing unique Asn binders and the optimized tetrahydroquinoline moiety were rapidly optimized to yield single-digit nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1) and the broader bromodomain family. PMID- 29155581 TI - Phosphorescence Control Mediated by Molecular Rotation and Aurophilic Interactions in Amphidynamic Crystals of 1,4-Bis[tri-(p-fluorophenyl)phosphane gold(I)-ethynyl]benzene. AB - Here we present a structural design aimed at the control of phosphorescence emission as the result of changes in molecular rotation in a crystalline material. The proposed strategy includes the use of aurophilic interactions, both as a crystal engineering tool and as a sensitive emission probe, and the use of a dumbbell-shaped architecture intended to create a low packing density region that permits the rotation of a central phenylene. Molecular rotor 1, with a central 1,4-diethynylphenylene rotator linked to two gold(I) triphenylphosphane complexes, was prepared and its structure confirmed by single-crystal X-ray diffraction, which revealed chains mediated by dimeric aurophilic interactions. We showed that green-emitting crystals exhibit reversible luminescent color changes between 298 and 193 K, which correlate with changes in rotational motion determined by variable-temperature solid-state 2H NMR spin-echo experiments. Fast two-fold rotation with a frequency of ca. 4.00 MHz (tau = 0.25 MUs) at 298 K becomes essentially static below 193 K as emission steadily changes from green to yellow in this temperature interval. A correlation between phosphorescence lifetimes and rotational frequencies is interpreted in terms of conformational changes arising from rotation of the central phenylene, which causes a change in electronic communication between the gold-linked rotors, as suggested by DFT studies. These results and control experiments with analogue 2, possessing a hindered tetramethylphenylene that is unable to rotate in the crystal, suggest that the molecular rotation can be a useful tool for controlling luminescence in the crystalline state. PMID- 29155582 TI - Improved Chemical Stability and Antiproliferative Activities of Curcumin-Loaded Nanoparticles with a Chitosan Chlorogenic Acid Conjugate. AB - A chitosan (CS)-chlorogenic acid (CA) conjugate was successfully prepared through free-radical-induced protocols with a substitution of CA on CS of 103.5 mg/g. ATR FTIR and 1H NMR results validated the covalent conjugation of CA onto CS. XRD results indicated the decrease of crystallinity after CA conjugation. DPPH scavenging activity and reducing-power studies indicated that the CS-CA conjugate had stronger antioxidant activity than chitosan. The particle diameters of curcumin-loaded CS and CS-CA nanoparticles simultaneously formed by ionic gelling in the presence of tripolyphosphate (TPP) were less than 300 nm (243.6 and 256.5 nm, respectively), and zeta-potential values between 25 and 30 mV were obtained. TEM results showed that the nanoparticles were spherically shaped and homogeneously dispersed. Curcumin with the CS-CA conjugate showed better heat stability than with CA at both temperatures (25 and 95 degrees C) (p <0.05). Curcumin release was inhibited by the CS-CA conjugate. The total release amount of curcumin from CS and CS-CA-conjugate nanoparticles were 70.5 and 61.7%, respectively (p <0.05). A methyl thiazolyl tetrazolium (MTT) assay showed that the antiproliferative activity of curcumin in CS-CA nanoparticles was remarkably higher than that in CS nanoparticles because of the higher chemical stability. The results suggest that CS-CA-based nanoparticles are promising candidates for the encapsulation and controlled release of hydrophobic, bioactive compounds and can improve these compounds' chemical stabilities and anticancer activities. PMID- 29155583 TI - Formation of Long-Lived Color Centers for Broadband Visible Light Emission in Low Dimensional Layered Perovskites. AB - We investigate the origin of the broadband visible emission in layered hybrid lead-halide perovskites and its connection with structural and photophysical properties. We study ?001? oriented thin films of hexylammonium (HA) lead iodide, (C6H16N)2PbI4, and dodecylammonium (DA) lead iodide, (C12H28N)2PbI4, by combining first-principles simulations with time-resolved photoluminescence, steady-state absorption and X-ray diffraction measurements on cooling from 300 to 4 K. Ultrafast transient absorption and photoluminescence measurements are used to track the formation and recombination of emissive states. In addition to the excitonic photoluminescence near the absorption edge, we find a red-shifted, broadband (full-width at half-maximum of about 0.4 eV), emission band below 200 K, similar to emission from ?110? oriented bromide 2D perovskites at room temperature. The lifetime of this sub-band-gap emission exceeds that of the excitonic transition by orders of magnitude. We use X-ray diffraction measurements to study the changes in crystal lattice with temperature. We report changes in the octahedral tilt and lattice spacing in both materials, together with a phase change around 200 K in DA2PbI4. DFT simulations of the HA2PbI4 crystal structure indicate that the low-energy emission is due to interstitial iodide and related Frenkel defects. Our results demonstrate that white-light emission is not limited to ?110? oriented bromide 2D perovskites but a general property of this class of system, and highlight the importance of defect control for the formation of low-energy emissive sites, which can provide a pathway to design tailored white-light emitters. PMID- 29155584 TI - Correction to Real-Time Quantum Dynamics of Long-Range Electronic Excitation Transfer in Plasmonic Nanoantennas. PMID- 29155585 TI - Allosteric Inhibitors of SHP2 with Therapeutic Potential for Cancer Treatment. AB - SHP2, a cytoplasmic protein-tyrosine phosphatase encoded by the PTPN11 gene, is involved in multiple cell signaling processes including Ras/MAPK and Hippo/YAP pathways. SHP2 has been shown to contribute to the progression of a number of cancer types including leukemia, gastric, and breast cancers. It also regulates T cell activation by interacting with inhibitory immune checkpoint receptors such as the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA). Thus, SHP2 inhibitors have drawn great attention by both inhibiting tumor cell proliferation and activating T cell immune responses toward cancer cells. In this study, we report the identification of an allosteric SHP2 inhibitor 1-(4-(6 bromonaphthalen-2-yl)thiazol-2-yl)-4-methylpiperidin-4-amine (23) that locks SHP2 in a closed conformation by binding to the interface of the N-terminal SH2, C terminal SH2, and phosphatase domains. Compound 23 suppresses MAPK signaling pathway and YAP transcriptional activity and shows antitumor activity in vivo. The results indicate that allosteric inhibition of SHP2 could be a feasible approach for cancer therapy. PMID- 29155587 TI - Static and Dynamic Electron Correlation in the Ligand Noninnocent Oxidation of Nickel Dithiolates. AB - Metal dithiolates have a wide range of applications from catalysis to molecular conductors with the ligands being the source of electrons during electrochemical oxidation in an effect known as ligand noninnocence. Recent large-scale variational two-electron reduced-density matrix (2-RDM) calculations of the vanadium oxo complex and manganese superoxide dismutase show that quantum entanglement stabilizes the addition of an electron to the ligands, providing a quantum mechanical explanation for ligand noninnocence. In this paper, we confirm and explore the ligand noninnocence in the electron oxidation series of bis(ethylene-1,2-dithiolato)nickel or [Ni(edt2)](-2,-1,0) with variational 2-RDM calculations. While previous wave function calculations of this series have selected only the ligand pi orbitals as the critical (active) orbitals to be correlated, we find that both ligand pi and nickel d orbitals must be correlated to generate a realistic picture of the electron-transfer process. Using the computed 2-RDM to seed a solution of the anti-Hermitian contracted Schrodinger equation, we predict that the singlet state is lower in energy than the triplet state, which is consistent with experimental observations. PMID- 29155586 TI - Deconstructing Lipid Kinase Inhibitors by Chemical Proteomics. AB - Diacylglycerol kinases (DGKs) regulate lipid metabolism and cell signaling through ATP-dependent phosphorylation of diacylglycerol to biosynthesize phosphatidic acid. Selective chemical probes for studying DGKs are currently lacking and are needed to annotate isoform-specific functions of these elusive lipid kinases. Previously, we explored fragment-based approaches to discover a core fragment of DGK-alpha (DGKalpha) inhibitors responsible for selective binding to the DGKalpha active site. Here, we utilize quantitative chemical proteomics to deconstruct widely used DGKalpha inhibitors to identify structural regions mediating off-target activity. We tested the activity of a fragment (RLM001) derived from a nucleotide-like region found in the DGKalpha inhibitors R59022 and ritanserin and discovered that RLM001 mimics ATP in its ability to broadly compete at ATP-binding sites of DGKalpha as well as >60 native ATP binding proteins (kinases and ATPases) detected in cell proteomes. Equipotent inhibition of activity-based probe labeling by RLM001 supports a contiguous ligand-binding site composed of C1, DAGKc, and DAGKa domains in the DGKalpha active site. Given the lack of available crystal structures of DGKs, our studies highlight the utility of chemical proteomics in revealing active-site features of lipid kinases to enable development of inhibitors with enhanced selectivity against the human proteome. PMID- 29155588 TI - Determination of Equilibrium Constant and Relative Brightness in FRET-FCS by Including the Third-Order Correlations. AB - Fluorescence correlation spectroscopy (FCS) encodes the information on the equilibrium constant (K), the relative fluorescence brightness of fluorophore (Q), and the forward and backward reaction rate constants (k+ and k-) on a physical or chemical relaxation. However, it has been a long-standing problem to completely resolve the FCS data to get the thermodynamic and kinetic information. Recently, we have solved the problem for fluorescence autocorrelation spectroscopy (FACS). Here, we extend the method to fluorescence cross-correlation spectroscopy (FCCS), which appears when FCS is coupled with fluorescence resonance energy transfer (FRET). Among 12 total second-order and third-order pre exponential factors in a relaxation process probed by the FRET-FCS technique, 3 are independent. We presented and discussed 3 sets of explicit solutions to use these pre-exponential factors to calculate K and Q. Together with the relaxation time, the acquired K will allow people to obtain k+ and k-, so that the goal of deciphering the FRET-FCS data will be fully reached. The theory is verified by extensive computer simulations and tested experimentally on a system of oligonucleotide hybridization. PMID- 29155589 TI - Reaction Mechanism of Isopentenyl Phosphate Kinase: A QM/MM Study. AB - Isopentenyl phosphate kinase (IPK) catalyzes the Mg2+-ATP dependent phosphorylation reactions to produce isopentenyl diphosphate, an important precursor in the synthesis of isopentenols. However, the position of the divalent metal ion in the crystal structures of IPK in complex with ATP and its native substrate IP has not been definitively resolved, and as a result ambiguity surrounds the catalytic mechanism of IP, limiting its exploitation as a biofuel and in drug design. Here we report the catalytically competent structure in complex with the metal ion Mg2+ and elucidate the phosphorylation reaction mechanism using molecular dynamic simulations and density functional theory-based quantum mechanics/molecular mechanics calculations (B97d/AMBER99). Comparing the substrate-bound and substrate-free IPK complexes, we observed that substrate binding results in significant conformational change of three residues Lys204, Glu207, and Lys211 located on the alphaG helix to form a strong salt bridge network with Asp145, which in turn tethers the invariant Ser142 via H-bond interaction. The conformational change shuts the subtrate entrance channel formed between the alphaG and alphaE helices. Further, we demonstrate the phosphorylation reaction occurs with a reaction barrier of 17.58 kcal/mol, which is in agreement with the previous experimental kinetic data. We found that a highly conserved Gly8 on a glycine-rich loop, together with Lys14, stabilizes the transition state. PMID- 29155590 TI - Semisynthesis and Biological Evaluation of Xanthone Amphiphilics as Selective, Highly Potent Antifungal Agents to Combat Fungal Resistance. AB - New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural alpha-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of alpha-mangostin resulted in interesting antifungal agents with a novel mode of action. Two lead compounds (1 and 2) showed potent antifungal activity against a wide range of fungal pathogens, including drug-resistant Candida albicans, Aspergillus, and Fusarium strains and low cytotoxicity and hemolytic activity against mammalian cells. Both compounds can kill fungus rapidly by directly disrupting fungal cell membranes and avoid developing drug resistance. Additionally, compound 1 exhibited potent in vivo antifungal activity in the murine model of fungal keratitis. To our knowledge, membrane-targeting xanthone based antifungals have not been reported previously. These results demonstrated that compounds 1 and 2 may be promising candidates for treating drug-resistant fungal infections. PMID- 29155591 TI - Mechanics of Protein Adaptation to High Temperatures. AB - Inspired by Somero's corresponding state principle that relates protein enhanced thermal stability with mechanical rigidity, we deployed state of the art computational techniques (based on atomistic steered molecular dynamics and Hamiltonian-replica exchange simulations) to study the in silico realization of mechanical and thermal unfolding of two homologous Csp proteins that have evolved to thrive in different thermal environments. By complementing recent single molecule experiments, we unambiguously show that, for these homologues whose structures are very similar, the increased thermal resistance of the thermophilic variant is not associated with an increased mechanical stability. Our approach provides microscopic insights that are otherwise inaccessible to experimental techniques, and explains why the protein weak spots for thermal and mechanical denaturation are distinct. PMID- 29155592 TI - Spatial Control of Crystallographic Direction in 2D Microarrays of Anisotropic Nanoblocks on Trenched Substrates. AB - Elaborate two-dimensional (2D) microarrays of tetragonal Mn3O4 nanocuboids 10-20 nm in size were constructed with parallel trenches 500 nm wide and 500 nm deep on a silicon substrate. By adjusting the conditions, including the dispersion medium, particle concentration, and evaporation rate, the a-face and c-face 2D arrays were selectively deposited on the upper and lower stages of the trenches, respectively. The crystallographic direction of the tetragonal crystal was alternately switched in the 2D microarrays under these specific conditions at the optimal particle concentration and evaporation rate. Spatial switching of their crystallographic direction was achieved via interaction of the anisotropic nanoblocks and the specifically shaped surfaces. PMID- 29155593 TI - Dynamical Density Functional Theory for the Evaporation of Droplets of Nanoparticle Suspension. AB - We develop a lattice gas model for the drying of droplets of a nanoparticle suspension on a planar surface, using dynamical density functional theory (DDFT) to describe the time evolution of the solvent and nanoparticle density profiles. The DDFT assumes a diffusive dynamics but does not include the advective hydrodynamics of the solvent, so the model is relevant to highly viscous or near to equilibrium systems. Nonetheless, we see an equivalent of the coffee-ring stain effect, but in the present model it occurs for thermodynamic rather the fluid-mechanical reasons. The model incorporates the effect of phase separation and vertical density variations within the droplet and the consequence of these on the nanoparticle deposition pattern on the surface. We show how to include the effect of slip or no-slip at the surface and how this is related to the receding contact angle. We also determine how the equilibrium contact angle depends on the microscopic interaction parameters. PMID- 29155594 TI - Visible-Light-Induced Aza-Pinacol Rearrangement: Ring Expansion of Alkylidenecyclopropanes. AB - A novel visible-light-induced aza-pinacol rearrangement was developed for the first time. In this approach, the addition of the N-centered radical to the C?C bond of alkylidenecyclopropanes delivers a variety of cyclobutanimines and gamma butyrolactones, with all-carbon quaternary centers via the ring expansion of the cyclopropyl group, in moderate to good yields under mild reaction conditions. PMID- 29155595 TI - Water Wicking and Droplet Spreading on Randomly Structured Thin Nanoporous Layers. AB - Growing thin, nanostructured layers on metallic surfaces is an attractive, new approach to create superhydrophilic coatings on heat exchangers that enhance spray cooling heat transfer. This paper presents results of an experimental study of enhanced droplet spreading on zinc oxide, nanostructured surfaces of this type that were thermally grown on copper substrates. The spreading rate data obtained from experimental high speed videos was used to develop a model specifically for this type of ultrathin, nanoporous layer. This investigation differs from previous related studies of droplet spreading on porous surfaces, which have generally considered either ordered, thin, moderately permeable layers, or thicker, microporous layers. Our layers are both very thin and have nanoscale porosity, making them low-permeability layers that exhibit strong wicking. An added benefit is that the thermally grown, stochastic nature of our surfaces make manufacturing easily scalable and particularly attractive for spray-cooled heat exchanger applications. The model presented here can predict the spreading rate for the wetted footprint of a deposited water droplet over two spreading stages: an early synchronous spreading stage, followed by hemispreading. The comparison of experimental data and model predictions confirms the presence of these two specific spreading stages. The model defines the transition conditions between synchronous and hemispreading regimes based on the change in spreading mechanisms, and we demonstrate that the model predictions of spreading rate are in good agreement with the experimental determinations of droplet footprint variation with time. The results indicate that the early synchronous spreading regime is characterized by flow in the porous layer that is primarily localized near the upper droplet contact line. The potential use of these experimental findings and model for optimizing superhydrophilic, nanostructured surface coatings is also discussed, as it pertains to the surface's ability to enhance water vaporization processes. PMID- 29155596 TI - Photoinduced, Copper-Promoted Regio- and Stereoselective Decarboxylative Alkylation of alpha,beta-Unsaturated Acids with Alkyl Iodides. AB - The first example of UV light-induced, copper-catalyzed regio- and stereoselective decarboxylative coupling of alpha,beta-unsaturated acids with alkyl iodides was reported. Under standard conditions, the 1 degrees , 2 degrees , and 3 degrees alkyl iodides proceeded smoothly with the E-selective alkenes obtained in uniformly good yields and high stereoselectivities. PMID- 29155597 TI - Aggregation and Rheological Behavior of the Lavender Oil-Pluronic P123 Microemulsions in Water-Ethanol Mixed Solvents. AB - The effect of lavender oil on aggregation characteristics of P123 in aqueous ethanolic solutions is investigated systematically by DLS, SANS, and rheology. The solubilization capacity of the P123 based formulations toward Lavender oil increased by increasing P123 concentration. The study unveiled the importance of the short chain alcohol-ethanol, as solubilization enhancer. The apparent hydrodynamic radius (Rh) increased significantly with an increase in lavender oil concentration up to maximum oil solubilization capacity of the copolymer at a particular ethanol concentration. DLS measurements on 5, 10, and 15 wt% P123 in the presence of 25% ethanol revealed the presence of large-sized micellar clusters in addition to the oil swollen micelles. The core size (RC), radius of hard sphere (RHS), and aggregation number (N) obtained from SANS profiles showed considerable enhancement with the addition of lavender oil confirming penetration of oil inside the copolymer. Rheological studies showed that viscosity also increased significantly with the addition of lavender oil near the maximum loading limit of the P123 concentration. Quite interestingly, the sol-gel transition temperature displayed a strong dependence on both P123 as well as oil concentration and decreased almost linearly by increasing oil concentration. This study demonstrates the use of a biocompatible and temperature sensitive self assembled P123 based formulation for lavender oil solubilization that can be beneficial in the cosmetic industry wherein controlled release of fragrances and so forth is demanded. PMID- 29155598 TI - Total Synthesis of Neodysiherbaine A via 1,3-Dipolar Cycloaddition of a Chiral Nitrone Template. AB - The total synthesis of neodysiherbaine A was achieved via 1,3-dipolar cycloaddition of a chiral nitrone template with a sugar-derived allyl alcohol in the presence of MgBr2.OEt2. This cycloaddition constructed the C2 and C4 asymmetric centers in a single step. Then reductive cleavage, intramolecular SN2 reaction of the tertiary alcohol, and oxidation of the primary alcohol afforded neodysiherbaine A. PMID- 29155599 TI - Recombinant Fragment of Human Surfactant Protein D: A Hierarchical Regulator of Pulmonary Hypersensitivity. PMID- 29155600 TI - Pulmonology in Pregnancy. PMID- 29155601 TI - Supplement A, July 2009. PMID- 29155602 TI - Supplement A, July 2013. PMID- 29155603 TI - Supplement A, July 2012. PMID- 29155604 TI - Modelling Evolutionary Algorithms with Stochastic Differential Equations. AB - There has been renewed interest in modelling the behaviour of evolutionary algorithms (EAs) by more traditional mathematical objects, such as ordinary differential equations or Markov chains. The advantage is that the analysis becomes greatly facilitated due to the existence of well established methods. However, this typically comes at the cost of disregarding information about the process. Here, we introduce the use of stochastic differential equations (SDEs) for the study of EAs. SDEs can produce simple analytical results for the dynamics of stochastic processes, unlike Markov chains which can produce rigorous but unwieldy expressions about the dynamics. On the other hand, unlike ordinary differential equations (ODEs), they do not discard information about the stochasticity of the process. We show that these are especially suitable for the analysis of fixed budget scenarios and present analogues of the additive and multiplicative drift theorems from runtime analysis. In addition, we derive a new more general multiplicative drift theorem that also covers non-elitist EAs. This theorem simultaneously allows for positive and negative results, providing information on the algorithm's progress even when the problem cannot be optimised efficiently. Finally, we provide results for some well-known heuristics namely Random Walk (RW), Random Local Search (RLS), the (1+1) EA, the Metropolis Algorithm (MA), and the Strong Selection Weak Mutation (SSWM) algorithm. PMID- 29155605 TI - A Large-Scale Experimental Evaluation of High-Performing Multi- and Many Objective Evolutionary Algorithms. AB - Research on multi-objective evolutionary algorithms (MOEAs) has produced over the past decades a large number of algorithms and a rich literature on performance assessment tools to evaluate and compare them. Yet, newly proposed MOEAs are typically compared against very few, often a decade older MOEAs. One reason for this apparent contradiction is the lack of a common baseline for comparison, with each subsequent study often devising its own experimental scenario, slightly different from other studies. As a result, the state of the art in MOEAs is a disputed topic. This article reports a systematic, comprehensive evaluation of a large number of MOEAs that covers a wide range of experimental scenarios. A novelty of this study is the separation between the higher-level algorithmic components related to multi-objective optimization (MO), which characterize each particular MOEA, and the underlying parameters-such as evolutionary operators, population size, etc.-whose configuration may be tuned for each scenario. Instead of relying on a common or "default" parameter configuration that may be low performing for particular MOEAs or scenarios and unintentionally biased, we tune the parameters of each MOEA for each scenario using automatic algorithm configuration methods. Our results confirm some of the assumed knowledge in the field, while at the same time they provide new insights on the relative performance of MOEAs for many-objective problems. For example, under certain conditions, indicator-based MOEAs are more competitive for such problems than previously assumed. We also analyze problem-specific features affecting performance, the agreement between performance metrics, and the improvement of tuned configurations over the default configurations used in the literature. Finally, the data produced is made publicly available to motivate further analysis and a baseline for future comparisons. PMID- 29155607 TI - Supplement A, July 2016. PMID- 29155606 TI - A New Framework for Analysis of Coevolutionary Systems-Directed Graph Representation and Random Walks. AB - Studying coevolutionary systems in the context of simplified models (i.e., games with pairwise interactions between coevolving solutions modeled as self plays) remains an open challenge since the rich underlying structures associated with pairwise-comparison-based fitness measures are often not taken fully into account. Although cyclic dynamics have been demonstrated in several contexts (such as intransitivity in coevolutionary problems), there is no complete characterization of cycle structures and their effects on coevolutionary search. We develop a new framework to address this issue. At the core of our approach is the directed graph (digraph) representation of coevolutionary problems that fully captures structures in the relations between candidate solutions. Coevolutionary processes are modeled as a specific type of Markov chains-random walks on digraphs. Using this framework, we show that coevolutionary problems admit a qualitative characterization: a coevolutionary problem is either solvable (there is a subset of solutions that dominates the remaining candidate solutions) or not. This has an implication on coevolutionary search. We further develop our framework that provides the means to construct quantitative tools for analysis of coevolutionary processes and demonstrate their applications through case studies. We show that coevolution of solvable problems corresponds to an absorbing Markov chain for which we can compute the expected hitting time of the absorbing class. Otherwise, coevolution will cycle indefinitely and the quantity of interest will be the limiting invariant distribution of the Markov chain. We also provide an index for characterizing complexity in coevolutionary problems and show how they can be generated in a controlled manner. PMID- 29155608 TI - History of lobotomy in Poland. AB - In Poland, there were 176 cases of prefrontal leucotomy performed by Moniz's method between 1947 and 1951. There were also several cases in which alternative psychosurgical techniques were used: prefrontal topectomy by Bilikiewicz and colleagues, and prefrontal topischemia by Ziemnowicz. This article analyses the following: publications by Chorobski, who performed lobotomy in Poland, and by Korzeniowski, who assessed its short-term results; a report by Bornsztajn, who reviewed general results of the method; and clinical research by Broszkiewicz and by Konieczynska, who assessed Polish patients in terms of long-term results of lobotomy. Negative clinical evaluation of lobotomy led to its abandonment in Poland, a decision strengthened by a regulation that forbade lobotomy in the USSR and impacted Polish psychiatry. PMID- 29155609 TI - Using Neural Networks to predict HFACS unsafe acts from the pre-conditions of unsafe acts. AB - Human Factors Analysis and Classification System (HFACS) is based upon Reason's organizational model of human error which suggests that there is a 'one to many' mapping of condition tokens (HFACS level 2 psychological precursors) to unsafe act tokens (HFACS level 1 error and violations). Using accident data derived from 523 military aircraft accidents, the relationship between HFACS level 2 preconditions and level 1 unsafe acts was modelled using an artificial neural network (NN). This allowed an empirical model to be developed congruent with the underlying theory of HFACS. The NN solution produced an average overall classification rate of ca. 74% for all unsafe acts from information derived from their level 2 preconditions. However, the correct classification rate was superior for decision- and skill-based errors, than for perceptual errors and violations. Practitioner Summary: A model to predict unsafe acts (HFACS level 1) from their preconditions (HFACS level 2) was developed from the analysis of 523 military aircraft accidents using an artificial NN. The results could correctly predict approximately 74% of errors. PMID- 29155610 TI - Seasonal and Sexual Variation in Metabolism, Thermoregulation, and Hormones in the Big Brown Bat (Eptesicus fuscus). AB - In response to seasonal variation in energy availability and thermal environment, physiological and endocrine mechanisms have evolved in temperate zone animals. Seasonal changes in hormone activity affect metabolism, body temperature, and reproductive activity. We examined the seasonal regulatory role of hormones on basal metabolic rate (BMR) and regulatory nonshivering thermogenesis (RNST) in 98 female and 17 male adult Eptesicus fuscus (big brown bat). We measured BMR, RNST, and plasma levels of thyroid hormone (T3), leptin, and cortisol in bats captured in maternity colonies in eastern Massachusetts from May to August (from arousal from the hibernation phase to the prehibernation phase). We hypothesized that all three hormones are seasonally primarily metabolic hormones and secondarily thermogenic hormones. In males, only BMR significantly changed seasonally. In females, all five variables significantly changed seasonally. The seasonal pattern of plasma leptin and cortisol levels correlated with the seasonal pattern of BMR, with an initial increase followed by a decrease, suggesting that leptin and cortisol are primarily metabolic hormones. The seasonal pattern of plasma T3 levels generally paralleled the basic seasonal pattern of RNST, with both increasing at the second half of the season, suggesting that T3 is primarily a thermogenic hormone. The observed decrease in plasma leptin levels may be necessary to allow for the observed seasonal decrease in BMR, with the similar cortisol pattern important for leptin regulation. While T3 is needed to maintain BMR, it may play a more critical role in the seasonal regulation of RNST than of BMR. PMID- 29155611 TI - Can Chemotherapy-Related Acute Care Visits Be Accurately Identified in Administrative Data? AB - PURPOSE: There is increasing interest in using administrative data to examine treatment-related complications that lead to emergency department (ED) visits or hospitalizations (H). The purpose of this study was to evaluate the reliability of billing codes for identifying chemotherapy-related acute care visits (CRVs) among women with early-stage breast cancer. MATERIALS AND METHODS: The cohort was identified by using deterministically linked health databases and consisted of women who were diagnosed with early-stage breast cancer who started adjuvant chemotherapy between 2007 and 2009 in Ontario, Canada. A random sample of 496 patient cases was chosen as the validation cohort. Sensitivity (SN) and specificity (SP) were calculated for three scenarios: chemotherapy-related ED visit, chemotherapy-related H, and febrile neutropenia (FN)-related visit. For FN related visits, three definitions were considered: general, moderate, and strict. RESULTS: The administrative cohort consisted of 8,359 patients, 43.4% of whom had at least one ED or H, including 1,496 women who had multiple visits that resulted in 6,293 unique visits. Of these, 73.1% were considered CRVs. The algorithm performed well in identifying CRVs that included H either from ED (SN, 90%; SP, 100%) or directly from home (SN, 91%; SP, 93%), but less well for ED visits that did not result in H (SN, 65%; SP, 80%). Depending on which FN algorithm was used, 4.8% to 24% of visits were considered related. The moderate FN algorithm provided the best tradeoff between SN (69% to 97%) and SP (83% to 98%). CONCLUSION: Administrative data can be valuable in evaluating chemotherapy-related serious events. Algorithm validation in other cohorts is needed. PMID- 29155613 TI - Supplement A, July 2015. PMID- 29155612 TI - Health Reform and Utilization of High-Volume Hospitals for Complex Cancer Operations. AB - PURPOSE: Underinsured patients are less likely to receive complex cancer operations at hospitals with high surgical volumes (high-volume hospitals, or HVHs), which contributes to disparities in care. To date, the impact of insurance coverage expansion on site of complex cancer surgery remains unknown. METHODS: Using the 2006 Massachusetts coverage expansion as a natural experiment, we searched the Hospital Cost and Utilization Project state inpatient databases for Massachusetts and control states (New York, New Jersey, and Florida) between 2001 and 2011 to evaluate changes in the utilization of HVHs for resections of bladder, esophageal, stomach, pancreatic, rectal, or lung cancer after the expansion of insurance coverage. We studied nonelderly, adult patients with private insurance and those with government-subsidized or self-pay (GSSP) coverage with a difference-in-differences framework. RESULTS: We studied 11,687 patients in Massachusetts and 56,300 patients in control states. Compared with control states, the 2006 Massachusetts insurance expansion was associated with a 14% increased rate of surgical intervention for GSSP patients (incident rate ratio, 1.14; P = .015), but there was no significant change in the probability of GSSP patients undergoing surgery at an HVH (1.0 percentage-point increase; P = .710). The reform was associated with no change in the uninsured payer-mix at HVHs (0.6 percentage-point increase; P = .244) and with a 5.1 percentage-point decrease for the uninsured payer mix at low-volume hospitals ( P < .001). CONCLUSION: The 2006 Massachusetts insurance expansion, a model for the Affordable Care Act, was associated with increased rates of complex cancer operations and increased insurance coverage but with no change in utilization of HVH for complex cancer operations. PMID- 29155614 TI - Supplement A, July 2011. PMID- 29155615 TI - Supplement A, August 2014. PMID- 29155616 TI - Uncovering the Power of Personality to Shape Income. AB - The notion of person-environment fit implies that personal and contextual factors interact in influencing important life outcomes. Using data from 8,458 employed individuals, we examined the combined effects of individuals' actual personality traits and jobs' expert-rated personality demands on earnings. Results from a response surface analysis indicated that the fit between individuals' actual personality and the personality demands of their jobs is a predictor of income. Conclusions of this combined analysis were partly opposite to conclusions reached in previous studies using conventional regression methods. Individuals can earn additional income of more than their monthly salary per year if they hold a job that fits their personality. Thus, at least for some traits, economic success depends not only on having a "successful personality" but also, in part, on finding the best niche for one's personality. We discuss the findings with regard to labor-market policies and individuals' job-selection strategies. PMID- 29155617 TI - 2017 RSNA Outstanding Researcher. PMID- 29155618 TI - Classification of Muscle Injuries: A Misunderstanding? PMID- 29155619 TI - Gadolinium Retention and Deposition Revisited: How the Chemical Properties of Gadolinium-based Contrast Agents and the Use of Animal Models Inform Us about the Behavior of These Agents in the Human Brain. PMID- 29155620 TI - Role of Cerebrospinal Fluid in Spaceflight-induced Ocular Changes and Visual Impairment in Astronaut. PMID- 29155622 TI - Imaging of Muscle Injuries in Sports Medicine: Sports Imaging Series. PMID- 29155621 TI - Science to Practice: Enhancing Photothermal Ablation of Colorectal Liver Metastases with Targeted Hybrid Nanoparticles. AB - Image-guided percutaneous thermal ablation has been one of the principal tools in management of unresectable liver malignancies, including colorectal liver metastases (CRLM) ( 1 ). Currently, however, this technique is suitable mainly for tumors less than 4-5 cm in diameter and also results in incomplete ablation at tumor margins ( 2 ). To solve these problems, efforts have been made to combine thermal ablation with other treatment options, such as systemic and intra arterial administration of therapeutics ( 3 - 5 ). In this issue of Radiology, White et al ( 6 ) introduced their work on development of an alternative approach by using biofunctionalized hybrid magnetic gold nanoparticles (HNPs) as catalysts for photothermal ablation of CRLM. They found that (a) the targeted (anti-MG1) HNPs are noncytotoxic and have greater than 20% intratumoral accumulation and (b) systemic administration of anti-MG1 HNPs can enlarge a tumor's necrotic zone with photothermal ablation. The results of this study establish the proof of the concept that targeted HNPs can enhance the therapeutic effect of photothermal ablation, which presents an exciting strategy for complete removal of CRLM by integrating two rapidly advancing scientific fields-interventional radiology and nanotechnology. PMID- 29155623 TI - Case 252. PMID- 29155625 TI - Effect of Iodine-based Contrast Material on Radiation Dose at CT. PMID- 29155624 TI - Functional and Targeted Lymph Node Imaging in Prostate Cancer: Current Status and Future Challenges. AB - Patients with prostate cancer who have regional lymph node (LN) metastases face an increased risk of death from disease and are therefore treated aggressively. Surgical LN dissection is the established method of staging regional nodes; however, this invasive technique carries substantial morbidities and a noninvasive imaging method is needed to reduce or eliminate the need for extended pelvic LN dissections (ePLND). Conventional computed tomography and magnetic resonance (MR) imaging have proven insensitive and nonspecific because both use nodal size criteria, which is notoriously inaccurate. Novel imaging techniques such as functional MR imaging by using diffusion-weighted MR imaging, MR lymphography with iron oxide particles, and targeted positron emission tomography imaging are currently under development and appear to improve LN staging of prostate cancer. Although progress is being made in staging nodes with imaging, it has not reached the point of replacing ePLND. In this review, the strengths and limitations of these new functional and targeted LN imaging techniques for prostate cancer are discussed. (c) RSNA, 2017. PMID- 29155626 TI - Dimensional Reduction and Feature Selection: Principal Component Analysis for Data Mining. PMID- 29155627 TI - Breast Cancer Recurrence after Initial Detection with Screening US. PMID- 29155628 TI - MR Imaging-guided Strategies for Detection of Prostate Cancer in Biopsy-Naive Men. PMID- 29155630 TI - David E. Kuhl, MD. PMID- 29155631 TI - Atsuko Heshiki, MD. PMID- 29155632 TI - Regional Fractional Ventilation by Using Multibreath Wash-in 3He MR Imaging. PMID- 29155633 TI - Robert McLelland, MD. PMID- 29155634 TI - How Does Imaging of Congenital Zika Compare with Imaging of Other TORCH Infections? AB - The acronym TORCH is used to refer to congenital infections, such as toxoplasmosis, other infections (such as syphillis, varicella-zoster, and parvovirus B19), cytomegalovirus, and herpes simplex virus. The classic findings in patients with TORCH infections include rash in the mother during pregnancy and ocular findings in the newborn. Zika virus has emerged as an important worldwide congenital infection. It fits well with other congenital TORCH infections since there is a rash in the mother and there are commonly ocular abnormalities in the newborn. TORCH infections are recognized to have neurologic effects, such as ventriculomegaly, intraventricular adhesions, subependymal cysts, intracerebral calcifications, and microcephaly; however, the Zika virus is intensely neurotropic. Thus, it targets neural progenitor cells, leading to a more severe spectrum of central nervous system abnormalities than is typically seen in other TORCH infections, while relatively sparing the other organ systems. In this review, nonspecific findings of congenital infections initially will be described, then individual TORCH infections will be described and compared with the imaging findings associated with congenital Zika virus infection. For the radiologist, awareness of imaging features of common congenital infections may facilitate early diagnosis and may, at times, lead to prompt initiation of therapy. Online supplemental material is available for this article. PMID- 29155635 TI - Case 248: Cystic Duodenal Dystrophy with Groove Pancreatitis. AB - History A 59-year-old man presented to the gastroenterology outpatient department with acute abdominal pain centered in the epigastrium. He had experienced similar episodes of abdominal pain in the past that had been treated with surgery. He reported multiple failed attempts at upper gastrointestinal endoscopy. Laboratory tests were performed at the time of admission and revealed a serum glutamic oxaloacetic transaminase level of 9 U/L [0.15 MUkat/L] (normal range, 5-40 U/L [0.08-0.67 MUkat/L]), a serum glutamic-pyruvic transaminase level of 34 U/L [0.57 MUkat/L] (normal range, 5-45 U/L [0.08-0.75 MUkat/L]), a serum gamma glutamyltransferase level of 210 U/L (3.50 MUkat/L) (normal range, 10-50 U/L [0.17-0.83 MUkat/L]), a serum alkaline phosphatase level of 157 U/L (2.62 MUkat/L) (normal range, 30-120 U/L [0.50-2.0 MUkat/L]), a serum amylase level of 210 U/L (3.50 MUkat/L) (normal range, 30-100 U/L [0.50-1.66 MUkat/L]), a serum lipase level of 391 U/L (6.52 MUkat/L) (normal range, 13-60 U/L [0.21-1.0 MUkat/L]), an alpha-fetoprotein level of 3.81 ng/ mL (normal range, 0-9 ng/mL), a total protein level of 4.6 g/dL (normal range, 6.0-8.5 g/dL), and an albumin level of 2.6 g/dL (normal range, 3.5-5.2 g/dL). The rest of the laboratory data were unremarkable. The patient underwent erect abdominal radiography, contrast material-enhanced multidetector row computed tomography (CT) of the abdomen with 100 mL of iohexol (300 mg iodine per milliliter, Omnipaque; GE Healthcare, Shanghai, China) followed by combined positron emission tomography (PET) and CT (hereafter, PET/CT) with 6.9 mCi of fluorodeoxyglucose (FDG) and magnetic resonance (MR) imaging of the upper abdomen. PMID- 29155638 TI - 2017: A Look Back. PMID- 29155636 TI - Hepatic Imaging in Neonates and Young Infants: State of the Art. AB - Neonatal liver disease is an important source of morbidity in the pediatric population. The manifestation of liver disease in young infants may be different than in older patients, and there are a number of diagnoses that are unique to this age group. Familiarity with these entities is important as imaging plays a key role in the diagnostic workup, and prompt diagnosis is necessary to prevent complications. This article reviews the spectrum of liver pathologies that can manifest in the first 6 months of life and is intended to educate the general radiologist who may be faced with interpretation of neonatal liver imaging. Categories of disease that will be reviewed include cholestatic diseases, tumors, vascular anomalies, and acquired diseases. The authors will also review optimization of ultrasonography (US) and magnetic resonance imaging of the liver and present a systematic method for interpretation of neonatal liver US findings in the context of clinical and laboratory findings. (c) RSNA, 2017. PMID- 29155639 TI - When Machines Think: Radiology's Next Frontier. AB - Artificial intelligence (AI), machine learning, and deep learning are terms now seen frequently, all of which refer to computer algorithms that change as they are exposed to more data. Many of these algorithms are surprisingly good at recognizing objects in images. The combination of large amounts of machine consumable digital data, increased and cheaper computing power, and increasingly sophisticated statistical models combine to enable machines to find patterns in data in ways that are not only cost-effective but also potentially beyond humans' abilities. Building an AI algorithm can be surprisingly easy. Understanding the associated data structures and statistics, on the other hand, is often difficult and obscure. Converting the algorithm into a sophisticated product that works consistently in broad, general clinical use is complex and incompletely understood. To show how these AI products reduce costs and improve outcomes will require clinical translation and industrial-grade integration into routine workflow. Radiology has the chance to leverage AI to become a center of intelligently aggregated, quantitative, diagnostic information. Centaur radiologists, formed as a synergy of human plus computer, will provide interpretations using data extracted from images by humans and image-analysis computer algorithms, as well as the electronic health record, genomics, and other disparate sources. These interpretations will form the foundation of precision health care, or care customized to an individual patient. (c) RSNA, 2017. PMID- 29155640 TI - Recurrence of Renal Cell Cancers after Thermal Ablation. PMID- 29155641 TI - Pulsed Focused Ultrasound Stimulates the Release of Tumor Biomarkers into the Blood Circulation. PMID- 29155642 TI - Extracting Regional Oxygen Tension from Multibreath Wash-in 3He MR Imaging. PMID- 29155643 TI - Structural and Functional Network Dysfunction in Parkinson Disease. PMID- 29155644 TI - Radiogenomics Map: A Novel Approach for Noninvasive Identification of Molecular Properties? PMID- 29155645 TI - From Images to Actions: Opportunities for Artificial Intelligence in Radiology. PMID- 29155646 TI - Combination treatment of docosahexaenoic acid (DHA) and all-trans-retinoic acid (ATRA) inhibit IL-17 and RORgammat gene expression in PBMCs of patients with relapsing-remitting multiple sclerosis. AB - OBJECTIVES: Multiple sclerosis (MS) is a demyelinating disorder with a complex autoimmune pathophysiology. Its initiation and progression correlate with IL-17 and the related transcription factor, RORgammat. All-trans retinoic acid (ATRA) is a bioactive derivative of vitamin A, and docosahexaenoic acid (DHA) is an active metabolite of omega-3 fatty acid; both have immunomodulatory effects in many immune disorders. This study investigated the effects of DHA and ATRA individually and in combination on IL-17 and RORgammat gene expression in peripheral blood mononuclear cells (PBMCs) of relapsing-remitting MS (RRMS) patients who were receiving interferon beta (IFN-beta). METHODS: The PBMCs of 15 RRMS patients were treated in vitro with 1 MUM of ATRA and 15 MUM of DHA as single and combination treatments for assessing probable additive or synergistic effects. RESULTS: The results showed that single treatment of ATRA (p = 0.05) could significantly decrease the expression of IL-17 gene and single treatment of ATRA (p = 0.04) and single treatment of DHA (p = 0.05) induced significant inhibition on the expression of RORgammat gene. The suppressive effect of combined treatment with ATRA and DHA on IL-17 (p = 0.02) and RORgammat (p = 0.01) was also found significant showing that the combined treatments can have additive effects. DISCUSSION: These results indicate that both DHA and ATRA might help control disease progression in IFN-beta treated RRMS patients with the strongest effects produced by a combination of the two compounds. PMID- 29155647 TI - It does not occur by chance: a mediation model of the influence of workers' characteristics, work environment factors, and near misses on agricultural machinery-related accidents. AB - Agriculture is among the most hazardous productive sectors, and farm machinery is a major source of injury. In the present study, a mediated model was used to test the role played by workers' characteristics, work environment factors, and near misses in predicting agricultural machinery-related accidents in a sample of Italian users (n = 290). Hours worked per week (via the mediation of an adverse work environment) showed a positive association and years of work experience (via the mediation of risk perception) showed a negative association with the probability of being involved in a near miss, which in turn showed a positive association with the probability of being involved in a machinery-related accident. Implications for tailored preventive interventions are discussed. PMID- 29155649 TI - Sustainable Model for Public Health Emergency Operations Centers for Global Settings. AB - Capacity to receive, verify, analyze, assess, and investigate public health events is essential for epidemic intelligence. Public health Emergency Operations Centers (PHEOCs) can be epidemic intelligence hubs by 1) having the capacity to receive, analyze, and visualize multiple data streams, including surveillance and 2) maintaining a trained workforce that can analyze and interpret data from real time emerging events. Such PHEOCs could be physically located within a ministry of health epidemiology, surveillance, or equivalent department rather than exist as a stand-alone space and serve as operational hubs during nonoutbreak times but in emergencies can scale up according to the traditional Incident Command System structure. PMID- 29155650 TI - Assessment of National Public Health and Reference Laboratory, Accra, Ghana, within Framework of Global Health Security. AB - The Second Year of Life project of the Global Health Security Agenda aims to improve immunization systems and strengthen measles and rubella surveillance, including building laboratory capacity. A new laboratory assessment tool was developed by the Centers for Disease Control and Prevention to assess the national laboratory in Ghana to improve molecular surveillance for measles and rubella. Results for the tool showed that the laboratory is well organized, has a good capacity for handling specimens, has a good biosafety system, and is proficient for diagnosis of measles and rubella by serologic analysis. However, there was little knowledge about molecular biology and virology activities (i.e., virus isolation on tissue culture was not available). Recommendations included training of technical personnel for molecular techniques and advocacy for funding for laboratory equipment, reagents, and supplies. PMID- 29155651 TI - Enhancing Surveillance and Diagnostics in Anthrax-Endemic Countries. AB - Naturally occurring anthrax disproportionately affects the health and economic welfare of poor, rural communities in anthrax-endemic countries. However, many of these countries have limited anthrax prevention and control programs. Effective prevention of anthrax outbreaks among humans is accomplished through routine livestock vaccination programs and prompt response to animal outbreaks. The Centers for Disease Control and Prevention uses a 2-phase framework when providing technical assistance to partners in anthrax-endemic countries. The first phase assesses and identifies areas for improvement in existing human and animal surveillance, laboratory diagnostics, and outbreak response. The second phase provides steps to implement improvements to these areas. We describe examples of implementing this framework in anthrax-endemic countries. These activities are at varying stages of completion; however, the public health impact of these initiatives has been encouraging. The anthrax framework can be extended to other zoonotic diseases to build on these efforts, improve human and animal health, and enhance global health security. PMID- 29155652 TI - CDC Support for Global Public Health Emergency Management. AB - Recent pandemics and rapidly spreading outbreaks of infectious diseases have illustrated the interconnectedness of the world and the importance of improving the international community's ability to effectively respond. The Centers for Disease Control and Prevention (CDC), building on a strong foundation of lessons learned through previous emergencies, international recognition, and human and technical expertise, has aspired to support nations around the world to strengthen their public health emergency management (PHEM) capacity. PHEM principles streamline coordination and collaboration in responding to infectious disease outbreaks, which align with the core capacities outlined in the International Health Regulations 2005. CDC supports PHEM by providing in-country technical assistance, aiding the development of plans and procedures, and providing fellowship opportunities for public health emergency managers. To this end, CDC partners with US agencies, international partners, and multilateral organizations to support nations around the world to reduce illness and death from outbreaks of infectious diseases. PMID- 29155653 TI - Enhancing Laboratory Response Network Capacity in South Korea. AB - Laboratory Response Network (LRN) laboratories help protect populations from biological and chemical public health threats. We examined the role of LRN biological laboratories in enhancing capacity to detect and respond to public health infectious disease emergencies in South Korea. The model for responding to infectious disease emergencies leverages standardized laboratory testing procedures, a repository of standardized testing reagents, laboratory testing cooperation among hospital sentinel laboratories and reference laboratories, and maintenance of a trained workforce through traditional and on-demand training. Cooperation among all network stakeholders helps ensure that laboratory response is an integrated part of the national response. The added laboratory testing capacity provided by the US Centers for Disease Control and Prevention LRN assets helps protect persons who reside in South Korea, US military personnel and civilians in South Korea, and those who reside in the continental United States. PMID- 29155654 TI - Surveillance Training for Ebola Preparedness in Cote d'Ivoire, Guinea-Bissau, Senegal, and Mali. AB - The 2014-2015 epidemic of Ebola virus disease in West Africa primarily affected Guinea, Liberia, and Sierra Leone. Several countries, including Mali, Nigeria, and Senegal, experienced Ebola importations. Realizing the importance of a trained field epidemiology workforce in neighboring countries to respond to Ebola importations, the Centers for Disease Control and Prevention Field Epidemiology Training Program unit implemented the Surveillance Training for Ebola Preparedness (STEP) initiative. STEP was a mentored, competency-based initiative to rapidly build up surveillance capacity along the borders of the at-risk neighboring countries Cote d'Ivoire, Mali, Senegal, and Guinea-Bissau. The target audience was district surveillance officers. STEP was delivered to 185 participants from 72 health units (districts or regions). Timeliness of reporting and the quality of surveillance analyses improved 3 months after training. STEP demonstrated that mentored, competency-based training, where learners attain competencies while delivering essential public health services, can be successfully implemented in an emergency response setting. PMID- 29155655 TI - Synergies between Communicable and Noncommunicable Disease Programs to Enhance Global Health Security. AB - Noncommunicable diseases are the leading cause of death and disability worldwide. Initiatives that advance the prevention and control of noncommunicable diseases support the goals of global health security in several ways. First, in addressing health needs that typically require long-term care, these programs can strengthen health delivery and health monitoring systems, which can serve as necessary platforms for emergency preparedness in low-resource environments. Second, by improving population health, the programs might help to reduce susceptibility to infectious outbreaks. Finally, in aiming to reduce the economic burden associated with premature illness and death from noncommunicable diseases, these initiatives contribute to the objectives of international development, thereby helping to improve overall country capacity for emergency response. PMID- 29155656 TI - US Centers for Disease Control and Prevention and Its Partners' Contributions to Global Health Security. AB - To achieve compliance with the revised World Health Organization International Health Regulations (IHR 2005), countries must be able to rapidly prevent, detect, and respond to public health threats. Most nations, however, remain unprepared to manage and control complex health emergencies, whether due to natural disasters, emerging infectious disease outbreaks, or the inadvertent or intentional release of highly pathogenic organisms. The US Centers for Disease Control and Prevention (CDC) works with countries and partners to build and strengthen global health security preparedness so they can quickly respond to public health crises. This report highlights selected CDC global health protection platform accomplishments that help mitigate global health threats and build core, cross-cutting capacity to identify and contain disease outbreaks at their source. CDC contributions support country efforts to achieve IHR 2005 compliance, contribute to the international framework for countering infectious disease crises, and enhance health security for Americans and populations around the world. PMID- 29155657 TI - Frontline Field Epidemiology Training Programs as a Strategy to Improve Disease Surveillance and Response. AB - Since 1980, Field Epidemiology Training Programs (FETPs) have trained highly qualified field epidemiologists to work for ministries of health (MOH) around the world. However, the 2013-2015 Ebola epidemic in West Africa, which primarily affected Guinea, Liberia, and Sierra Leone, demonstrated a lack of field epidemiologists at the local levels. Trained epidemiologists at these levels could have detected the Ebola outbreak earlier. In 2015, the US Centers for Disease Control and Prevention (CDC) launched FETP-Frontline, a 3-month field training program targeting local MOH staff in 24 countries to augment local public health capacity. As of December 2016, FETP-Frontline has trained 1,354 graduates in 24 countries. FETP-Frontline enhances global health security by training local public health staff to improve surveillance quality in their jurisdictions, which can be a valuable strategy to strengthen the capacity of countries to more rapidly detect, respond to, and contain public health emergencies at the source. PMID- 29155658 TI - Building Global Epidemiology and Response Capacity with Field Epidemiology Training Programs. AB - More than ever, competent field epidemiologists are needed worldwide. As known, new, and resurgent communicable diseases increase their global impact, the International Health Regulations and the Global Health Security Agenda call for sufficient field epidemiologic capacity in every country to rapidly detect, respond to, and contain public health emergencies, thereby ensuring global health security. To build this capacity, for >35 years the US Centers for Disease Control and Prevention has worked with countries around the globe to develop Field Epidemiology Training Programs (FETPs). FETP trainees conduct surveillance activities and outbreak investigations in service to ministry of health programs to prevent and control infectious diseases of global health importance such as polio, cholera, tuberculosis, HIV/AIDS, malaria, and emerging zoonotic infectious diseases. FETP graduates often rise to positions of leadership to direct such programs. By training competent epidemiologists to manage public health events locally and support public health systems nationally, health security is enhanced globally. PMID- 29155659 TI - US Federal Travel Restrictions for Persons with Higher-Risk Exposures to Communicable Diseases of Public Health Concern. AB - Published guidance recommends controlled movement for persons with higher-risk exposures (HREs) to communicable diseases of public health concern; US federal public health travel restrictions (PHTRs) might be implemented to enforce these measures. We describe persons eligible for and placed on PHTRs because of HREs during 2014-2016. There were 160 persons placed on PHTRs: 142 (89%) involved exposure to Ebola virus, 16 (10%) to Lassa fever virus, and 2 (1%) to Middle East respiratory syndrome coronavirus. Most (90%) HREs were related to an epidemic. No persons attempted to travel; all persons had PHTRs lifted after completion of a maximum disease-specific incubation period or a revised exposure risk classification. PHTR enforced controlled movement and removed risk for disease transmission among travelers who had contacts who refused to comply with public health recommendations. PHTRs are mechanisms to mitigate spread of communicable diseases and might be critical in enhancing health security during epidemics. PMID- 29155660 TI - Real-Time Surveillance in Emergencies Using the Early Warning Alert and Response Network. AB - Humanitarian emergencies often result in population displacement and increase the risk for transmission of communicable diseases. To address the increased risk for outbreaks during humanitarian emergencies, the World Health Organization developed the Early Warning Alert and Response Network (EWARN) for early detection of epidemic-prone diseases. The US Centers for Disease Control and Prevention has worked with the World Health Organization, ministries of health, and other partners to support EWARN through the implementation and evaluation of these systems and the development of standardized guidance. Although protocols have been developed for the implementation and evaluation of EWARN, a need persists for standardized training and additional guidance on supporting these systems remotely when access to affected areas is restricted. Continued collaboration between partners and the Centers for Disease Control and Prevention for surveillance during emergencies is necessary to strengthen capacity and support global health security. PMID- 29155661 TI - Zoonotic Disease Programs for Enhancing Global Health Security. AB - Most infectious diseases that recently emerged in humans originated in animals. Besides close contact between animals and humans, other factors probably contribute to the cross-species transmission of infectious diseases. It is critical to establish effective mechanisms for coordination and collaboration between the animal, human, and environmental health sectors before new threats emerge by bringing the different sectors together to tackle endemic zoonotic diseases of greatest concern. Such multisectoral partnerships should begin by identifying priority zoonotic diseases for national engagement with equal input from the different sectors. Improvements in surveillance and data sharing for prioritized zoonotic diseases and enhancements of laboratory testing and joint outbreak response capacities in the human and animal health sectors will create and strengthen the mechanisms necessary to effectively detect and respond to emerging health threats, and thereby enhance global health security. PMID- 29155662 TI - Global Disease Detection-Achievements in Applied Public Health Research, Capacity Building, and Public Health Diplomacy, 2001-2016. AB - The Centers for Disease Control and Prevention has established 10 Global Disease Detection (GDD) Program regional centers around the world that serve as centers of excellence for public health research on emerging and reemerging infectious diseases. The core activities of the GDD Program focus on applied public health research, surveillance, laboratory, public health informatics, and technical capacity building. During 2015-2016, program staff conducted 205 discrete projects on a range of topics, including acute respiratory illnesses, health systems strengthening, infectious diseases at the human-animal interface, and emerging infectious diseases. Projects incorporated multiple core activities, with technical capacity building being most prevalent. Collaborating with host countries to implement such projects promotes public health diplomacy. The GDD Program continues to work with countries to strengthen core capacities so that emerging diseases can be detected and stopped faster and closer to the source, thereby enhancing global health security. PMID- 29155663 TI - Frameworks for Preventing, Detecting, and Controlling Zoonotic Diseases. AB - Preventing zoonotic diseases requires coordinated actions by government authorities responsible for human and animal health. Constructing the frameworks needed to foster intersectoral collaboration can be approached in many ways. We highlight 3 examples of approaches to implement zoonotic disease prevention and control programs. The first, rabies control in Ethiopia, was implemented using an umbrella approach: a comprehensive program designed for accelerated impact. The second, a monkeypox program in Democratic Republic of the Congo, was implemented in a stepwise manner, whereby incremental improvements and activities were incorporated into the program. The third approach, a pathogen discovery program, applied in the country of Georgia, was designed to characterize and understand the ecology, epidemiology, and pathogenesis of a new zoonotic pathogen. No one approach is superior, but various factors should be taken into account during design, planning, and implementation. PMID- 29155664 TI - Prioritizing Zoonoses for Global Health Capacity Building-Themes from One Health Zoonotic Disease Workshops in 7 Countries, 2014-2016. AB - Zoonotic diseases represent critical threats to global health security. Effective mitigation of the impact of endemic and emerging zoonotic diseases of public health importance requires multisectoral collaboration and interdisciplinary partnerships. The US Centers for Disease Control and Prevention created the One Health Zoonotic Disease Prioritization Tool to help countries identify zoonotic diseases of greatest national concern using input from representatives of human health, agriculture, environment, and wildlife sectors. We review 7 One Health Zoonotic Disease Prioritization Tool workshops conducted during 2014-2016, highlighting workshop outcomes, lessons learned, and shared themes from countries implementing this process. We also describe the tool's ability to help countries focus One Health capacity-building efforts to appropriately prevent, detect, and respond to zoonotic disease threats. PMID- 29155665 TI - Cholera Mortality during Urban Epidemic, Dar es Salaam, Tanzania, August 16, 2015 January 16, 20161. AB - In 2015, a cholera epidemic occurred in Tanzania; most cases and deaths occurred in Dar es Salaam early in the outbreak. We evaluated cholera mortality through passive surveillance, burial permits, and interviews conducted with decedents' caretakers. Active case finding identified 101 suspected cholera deaths. Routine surveillance had captured only 48 (48%) of all cholera deaths, and burial permit assessments captured the remainder. We interviewed caregivers of 56 decedents to assess cholera management behaviors. Of 51 decedents receiving home care, 5 (10%) used oral rehydration solution after becoming ill. Caregivers reported that 51 (93%) of 55 decedents with known time of death sought care before death; 16 (29%) of 55 delayed seeking care for >6 h. Of the 33 (59%) community decedents, 20 (61%) were said to have been discharged from a health facility before death. Appropriate and early management of cholera cases can reduce the number of cholera deaths. PMID- 29155666 TI - CDC Activities for Improving Implementation of Human Papillomavirus Vaccination, Cervical Cancer Screening, and Surveillance Worldwide. AB - Cervical cancer incidence and mortality rates are high, particularly in developing countries. Most cervical cancers can be prevented by human papillomavirus (HPV) vaccination, screening, and timely treatment. The US Centers for Disease Control and Prevention (CDC) provides global technical assistance for implementation and evaluation of HPV vaccination pilot projects and programs and laboratory-related HPV activities to assess HPV vaccines. CDC collaborates with global partners to develop global cervical cancer screening recommendations and manuals, implement screening, create standardized evaluation tools, and provide expertise to monitor outcomes. CDC also trains epidemiologists in cancer prevention through its Field Epidemiology Training Program and is working to improve cancer surveillance by supporting efforts of the World Health Organization in developing cancer registry hubs and assisting countries in estimating costs for developing population-based cancer registries. These activities contribute to the Global Health Security Agenda action packages to improve immunization, surveillance, and the public health workforce globally. PMID- 29155667 TI - Use of a Diagonal Approach to Health System Strengthening and Measles Elimination after a Large Nationwide Outbreak in Mongolia. AB - Measles is a highly transmissible infectious disease that causes serious illness and death worldwide. Efforts to eliminate measles through achieving high immunization coverage, well-performing surveillance systems, and rapid and effective outbreak response mechanisms while strategically engaging and strengthening health systems have been termed a diagonal approach. In March 2015, a large nationwide measles epidemic occurred in Mongolia, 1 year after verification of measles elimination in this country. A multidisciplinary team conducted an outbreak investigation that included a broad health system assessment, organized around the Global Health Security Agenda framework of Prevent-Detect-Respond, to provide recommendations for evidence-based interventions to interrupt the epidemic and strengthen the overall health system to prevent future outbreaks of measles and other epidemic-prone infectious threats. This investigation demonstrated the value of evaluating elements of the broader health system in investigating measles outbreaks and the need for using a diagonal approach to achieving sustainable measles elimination. PMID- 29155668 TI - Responding to Communicable Diseases in Internationally Mobile Populations at Points of Entry and along Porous Borders, Nigeria, Benin, and Togo. AB - Recent multinational disease outbreaks demonstrate the risk of disease spreading globally before public health systems can respond to an event. To ensure global health security, countries need robust multisectoral systems to rapidly detect and respond to domestic or imported communicable diseases. The US Centers for Disease Control and Prevention International Border Team works with the governments of Nigeria, Togo, and Benin, along with Pro-Health International and the Abidjan-Lagos Corridor Organization, to build sustainable International Health Regulations capacities at points of entry (POEs) and along border regions. Together, we strengthen comprehensive national and regional border health systems by developing public health emergency response plans for POEs, conducting qualitative assessments of public health preparedness and response capacities at ground crossings, integrating internationally mobile populations into national health surveillance systems, and formalizing cross-border public health coordination. Achieving comprehensive national and regional border health capacity, which advances overall global health security, necessitates multisectoral dedication to the aforementioned components. PMID- 29155669 TI - Centers for Disease Control and Prevention Public Health Response to Humanitarian Emergencies, 2007-2016. AB - Humanitarian emergencies, including complex emergencies associated with fragile states or areas of conflict, affect millions of persons worldwide. Such emergencies threaten global health security and have complicated but predictable effects on public health. The Centers for Disease Control and Prevention (CDC) Emergency Response and Recovery Branch (ERRB) (Division of Global Health Protection, Center for Global Health) contributes to public health emergency responses by providing epidemiologic support for humanitarian health interventions. To capture the extent of this emergency response work for the past decade, we conducted a retrospective review of ERRB's responses during 2007-2016. Responses were conducted across the world and in collaboration with national and international partners. Lessons from this work include the need to develop epidemiologic tools for use in resource-limited contexts, build local capacity for response and health systems recovery, and adapt responses to changing public health threats in fragile states. Through ERRB's multisector expertise and ability to respond quickly, CDC guides humanitarian response to protect emergency affected populations. PMID- 29155670 TI - Lessons Learned from Emergency Response Vaccination Efforts for Cholera, Typhoid, Yellow Fever, and Ebola. AB - Countries must be prepared to respond to public health threats associated with emergencies, such as natural disasters, sociopolitical conflicts, or uncontrolled disease outbreaks. Rapid vaccination of populations vulnerable to epidemic-prone vaccine-preventable diseases is a major component of emergency response. Emergency vaccination planning presents challenges, including how to predict resource needs, expand vaccine availability during global shortages, and address regulatory barriers to deliver new products. The US Centers for Disease Control and Prevention supports countries to plan, implement, and evaluate emergency vaccination response. We describe work of the Centers for Disease Control and Prevention in collaboration with global partners to support emergency vaccination against cholera, typhoid, yellow fever, and Ebola, diseases for which a new vaccine or vaccine formulation has played a major role in response. Lessons learned will help countries prepare for future emergencies. Integration of vaccination with emergency response augments global health security through reducing disease burden, saving lives, and preventing spread across international borders. PMID- 29155671 TI - Capacity Development through the US President's Malaria Initiative-Supported Antimalarial Resistance Monitoring in Africa Network. AB - Antimalarial drug resistance is an evolving global health security threat to malaria control. Early detection of Plasmodium falciparum resistance through therapeutic efficacy studies and associated genetic analyses may facilitate timely implementation of intervention strategies. The US President's Malaria Initiative-supported Antimalarial Resistance Monitoring in Africa Network has assisted numerous laboratories in partner countries in acquiring the knowledge and capability to independently monitor for molecular markers of antimalarial drug resistance. PMID- 29155672 TI - Establishment of CDC Global Rapid Response Team to Ensure Global Health Security. AB - The 2014-2016 Ebola virus disease epidemic in West Africa highlighted challenges faced by the global response to a large public health emergency. Consequently, the US Centers for Disease Control and Prevention established the Global Rapid Response Team (GRRT) to strengthen emergency response capacity to global health threats, thereby ensuring global health security. Dedicated GRRT staff can be rapidly mobilized for extended missions, improving partner coordination and the continuity of response operations. A large, agencywide roster of surge staff enables rapid mobilization of qualified responders with wide-ranging experience and expertise. Team members are offered emergency response training, technical training, foreign language training, and responder readiness support. Recent response missions illustrate the breadth of support the team provides. GRRT serves as a model for other countries and is committed to strengthening emergency response capacity to respond to outbreaks and emergencies worldwide, thereby enhancing global health security. PMID- 29155673 TI - Strengthening Global Surveillance for Antimicrobial Drug-Resistant Neisseria gonorrhoeae through the Enhanced Gonococcal Antimicrobial Surveillance Program. AB - Monitoring trends in antimicrobial drug-resistant Neisseria gonorrhoeae is a critical public health and global health security activity because the number of antimicrobial drugs available to treat gonorrhea effectively is rapidly diminishing. Current global surveillance methods for antimicrobial drug-resistant N. gonorrhoeae have many limitations, especially in countries with the greatest burden of disease. The Enhanced Gonococcal Antimicrobial Surveillance Program is a collaboration between the World Health Organization and the Centers for Disease Control and Prevention. The program aims to monitor trends in antimicrobial drug susceptibilities in N. gonorrhoeae by using standardized sampling and laboratory protocols; to improve the quality, comparability, and timeliness of gonococcal antimicrobial drug resistance data across multiple countries; and to assess resistance patterns in key populations at highest risk for antimicrobial drug resistant gonorrhea so country-specific treatment guidelines can be informed. PMID- 29155674 TI - Ebola Response Impact on Public Health Programs, West Africa, 2014-2017. AB - Events such as the 2014-2015 West Africa epidemic of Ebola virus disease highlight the importance of the capacity to detect and respond to public health threats. We describe capacity-building efforts during and after the Ebola epidemic in Liberia, Sierra Leone, and Guinea and public health progress that was made as a result of the Ebola response in 4 key areas: emergency response, laboratory capacity, surveillance, and workforce development. We further highlight ways in which capacity-building efforts such as those used in West Africa can be accelerated after a public health crisis to improve preparedness for future events. PMID- 29155675 TI - Enhancing Workforce Capacity to Improve Vaccination Data Quality, Uganda. AB - In Uganda, vaccine dose administration data are often not available or are of insufficient quality to optimally plan, monitor, and evaluate program performance. A collaboration of partners aimed to address these key issues by deploying data improvement teams (DITs) to improve data collection, management, analysis, and use in district health offices and health facilities. During November 2014-September 2016, DITs visited all districts and 89% of health facilities in Uganda. DITs identified gaps in awareness and processes, assessed accuracy of data, and provided on-the-job training to strengthen systems and improve healthcare workers' knowledge and skills in data quality. Inaccurate data were observed primarily at the health facility level. Improvements in data management and collection practices were observed, although routine follow-up and accountability will be needed to sustain change. The DIT strategy offers a useful approach to enhancing the quality of health data. PMID- 29155677 TI - Expanding Pertussis Epidemiology in 6 Latin America Countries through the Latin American Pertussis Project. AB - The Latin American Pertussis Project (LAPP), established in 2009, is a collaboration between the Centers for Disease Control and Prevention, Pan American Health Organization, Sabin Vaccine Institute, and the ministries of health of 6 countries in Latin America. The project goal is to expand understanding of pertussis epidemiology in Latin America to inform strategies for control and prevention. Here we describe LAPP structure and activities. After an initial surveillance evaluation, LAPP activities are tailored to individual country needs. LAPP activities align with Global Health Security Agenda priorities and have focused on expanding laboratory diagnostic capacity, implementing a laboratory quality control and quality assurance program, and providing epidemiologic support to strengthen reporting of pertussis surveillance data. Lessons learned include that ongoing mentoring is key to the successful adoption of new technologies and that sustainability of laboratory diagnostics requires a regional commitment to procure reagents and related supplies. PMID- 29155678 TI - Joint External Evaluation-Development and Scale-Up of Global Multisectoral Health Capacity Evaluation Process. AB - The Joint External Evaluation (JEE), a consolidation of the World Health Organization (WHO) International Health Regulations 2005 (IHR 2005) Monitoring and Evaluation Framework and the Global Health Security Agenda country assessment tool, is an objective, voluntary, independent peer-to-peer multisectoral assessment of a country's health security preparedness and response capacity across 19 IHR technical areas. WHO approved the standardized JEE tool in February 2016. The JEE process is wholly transparent; countries request a JEE and are encouraged to make its findings public. Donors (e.g., member states, public and private partners, and other public health institutions) can support countries in addressing identified JEE gaps, and implementing country-led national action plans for health security. Through July 2017, 52 JEEs were completed, and 25 more countries were scheduled across WHO's 6 regions. JEEs facilitate progress toward IHR 2005 implementation, thereby building trust and mutual accountability among countries to detect and respond to public health threats. PMID- 29155679 TI - Antidepressant Use Among Persons Aged 12 and Over:United States,2011-2014. AB - Antidepressants are one of the three most commonly used therapeutic drugclasses in the United States (1). While the majority of antidepressants aretaken to treat depression, antidepressants can also be taken to treat otherconditions, like anxiety disorders. This Data Brief provides the most recentestimates of antidepressant use in the U.S. noninstitutionalized population,including prevalence of use by age, sex, race and Hispanic origin, and lengthof use. This report also describes trends in the prevalence of antidepressant usefrom 1999 2002 to 2011-2014. PMID- 29155680 TI - Unmarried Men's Contraceptive Use at Recent Sexual Intercourse: United States, 2011-2015. AB - Contraception is used to help prevent unintended pregnancies and sexuallytransmitted infections (STI). Higher percentages of pregnancies to unmarriedpersons are unintended than for those who are married (1). Patterns ofcontraceptive use as reported by women, including differences by maritalstatus, are well documented using National Survey of Family Growth (NSFG)data (2-4); however, less research focuses on contraceptive use as reported bymen. Using 2011 2015 NSFG data from men, with selected time trends, thisdata brief describes contraceptive use at last recent vaginal sexual intercourse(within 3 months) among unmarried men, focusing primarily on male methodsof contraception (condom, withdrawal, and vasectomy). PMID- 29155676 TI - Contributions of the US Centers for Disease Control and Prevention in Implementing the Global Health Security Agenda in 17 Partner Countries. AB - The Global Health Security Agenda (GHSA), a partnership of nations, international organizations, and civil society, was launched in 2014 with a mission to build countries' capacities to respond to infectious disease threats and to foster global compliance with the International Health Regulations (IHR 2005). The US Centers for Disease Control and Prevention (CDC) assists partner nations to improve IHR 2005 capacities and achieve GHSA targets. To assess progress through these CDC-supported efforts, we analyzed country activity reports dating from April 2015 through March 2017. Our analysis shows that CDC helped 17 Phase I countries achieve 675 major GHSA accomplishments, particularly in the cross cutting areas of public health surveillance, laboratory systems, workforce development, and emergency response management. CDC's engagement has been critical to these accomplishments, but sustained support is needed until countries attain IHR 2005 capacities, thereby fostering national and regional health protection and ensuring a world safer and more secure from global health threats. PMID- 29155681 TI - Drug Overdose Deaths Among Adolescents Aged 15-19 in the United States: 1999 2015. AB - Drug overdose deaths in the United States are a pressing public healthchallenge (1-3). In particular, drug overdoses involving opioids have increasedsince 1999 (1). This report focuses specifically on drug overdose deaths forolder adolescents aged 15-19. In 2015, 772 drug overdose deaths occurredin this age group. Rates for 1999-2015 are presented and trends comparedfor both females and males. Percent distributions of drug overdose deaths for2015 by intent (e.g., unintentional, suicide, homicide) are presented. Trends indrug overdose death rates by type of drug involved are also presented. PMID- 29155682 TI - Hypertension Prevalence and Control Among Adults: United States, 2015-2016. AB - Hypertension remains an important public health challenge in theUnited States because it increases the risk for cardiovascular disease. Effectiveblood pressure management has been shown to decrease the incidence ofstroke, heart attack, and heart failure (1-3). This report presents updatedestimates for the prevalence and control of hypertension in the UnitedStates for 2015-2016. Trends in hypertension prevalence and control from1999-2000 through 2015-2016 are also presented. PMID- 29155684 TI - Births in the United States, 2016. AB - This report presents several key demographic and maternal and infant healthindicators using 2016 final birth data. Trends in the general fertility rate (thenumber of births per 1,000 women aged 15-44), age-specific birth rates,cesarean delivery, preterm, and triplet and higher-order multiple birth rates arepresented by age of mother. For each indicator, data for 2016 are comparedwith 2015, and also with a year representing a recent high or low rate. PMID- 29155683 TI - Condom Use During Sexual Intercourse Among Women and Men Aged 15-44 in the United States: 2011-2015 National Survey of Family Growth. AB - condom use during sexual intercourse in a nationally representative sample of women and men aged 15-44 in the United States using the 2011-2015 National Survey of Family Growth (NSFG). Where data were available, patterns of condom use during sexual intercourse from the 2011-2015 NSFG were compared with the 2002 and 2006 2010 NSFG. Methods-Data were collected through in-person interviews with nationally representative, independent samples of women and men aged 15-44 in the household population of the United States. Interviews were conducted between September 2011 and September 2015 with 11,300 women and 9,321 men. The response rates for the 2011-2015 NSFG were 72.3% for women and 69.6% for men aged 15-44. Results-During 2011-2015, 23.8% of women and 33.7% of men aged 15-44 used a condom at last sexual intercourse in the past 12 months, an increase for men since 2002 (29.5%). Among condom users, 59.9% of women and 56.4% of men aged 15 44 used only a condom and no other method during last intercourse in the past 12 months; another 25.0% of women and 33.2% of men used condoms plus hormonal methods; and 15.1% of women and 10.5% of men used condoms plus nonhormonal methods. During any intercourse in the past 4 weeks, 18.2% of women and 23.9% of men aged 15-44 used a condom "100%" of the time. The prevalence of condom use during any intercourse in the past 4 weeks varied by age, education, Hispanic origin and race, relationship at last sexual intercourse, and number of opposite sex sexual partners in the past 12 months. Almost 7% of women aged 15-44 who used a condom in the past 4 weeks said the condom broke or completely fell off during intercourse or withdrawal, and 25.8% said the condom was used for only part of the time during intercourse. PMID- 29155685 TI - Infant Mortality Rates in Rural and Urban Areas in the United States, 2014. AB - The infant mortality rate is often used as a measure of a country's healthbecause similar factors influence population health and infant mortality (1).Although infant mortality has declined in the United States, disparities stillexist across geographic areas and demographic groups (2-4). Urbanizationlevel, based on the number and concentration of people in a county, can impacthealth outcomes (3-9). Previous research indicates that infant mortality ratesvary by urbanization level and also by maternal and infant characteristics(3-9). This report describes differences in infant mortality among rural, smalland medium urban, and large urban counties in the United States by infant'sage at death, mother's age, and race and Hispanic origin in 2014. PMID- 29155686 TI - Total and High-density Lipoprotein Cholesterol in Adults: United States, 2015 2016. AB - High total cholesterol (>= 240 mg/dL) and low high-density lipoprotein (HDL)cholesterol (< 40 mg/dL) levels are risk factors for cardiovascular disease, theleading cause of U.S. deaths (1-3). From 2007-2008 to 2013-2014, decliningtrends were observed in high total and low HDL cholesterol prevalence(4). This report provides 2015-2016 estimates for high total and low HDLcholesterol and trends based on available comparable data through 2015 2016.Analysis is based on measured cholesterol. PMID- 29155687 TI - United States Life Tables, 2014. AB - Objectives-This report presents complete period life tables for the United States by race, Hispanic origin, and sex, based on age-specific death rates in 2014. Methods-Data used to prepare the 2014 life tables are 2014 final mortality statistics; July 1, 2014 population estimates based on the 2010 decennial census; and 2014 Medicare data for persons aged 66-99. The methodology used to estimate the life tables for the Hispanic population remains unchanged from the methodology developed for the publication of life tables by Hispanic origin for data year 2006. The methodology used to estimate the 2014 life tables for all other groups was first implemented with data year 2008. Results-In 2014, the overall expectation of life at birth was 78.9 years, a 0.1-year increase from 2013. Between 2013 and 2014, life expectancy at birth increased by 0.1 year for both males (76.4 to 76.5) and females (81.2 to 81.3) and for the black (75.5 to 75.6) and white (79.0 to 79.1) populations. Life expectancy at birth increased by 0.2 years for the Hispanic (81.9 to 82.1) and non-Hispanic black (75.1 to 75.3) populations. Life expectancy at birth remained unchanged for the non-Hispanic white population (78.8). PMID- 29155688 TI - Characteristics of Visits to Primary Care Physicians by Adults Diagnosed With Hypertension. AB - Objective-This report describes the demographic, state, and regional differences in hypertension control and pharmaceutical treatment among visits to primary care physicians made by hypertensive adults during 2013-2014. Methods-Data are from the 2013-2014 National Ambulatory Medical Care Survey (NAMCS), a nationally representative survey of visits to nonfederal, office-based physicians. The sample design for the 2013-2014 NAMCS included oversampling in selected states. Estimates are provided for the 18 states oversampled in both years. Estimates are also presented for the nine census divisions. The study population includes all primary care physician visits made by nonpregnant adults who have hypertension, as defined by documentation of hypertension in their medical record. Hypertensive visits indicating hypertension control as well as those with mention of a hypertensive medication were examined by selected demographic characteristics as well as by region and state. Sample weights were applied to each case to provide national estimates of health care utilization. Results-During 2013-2014, in the United States, hypertension control was indicated [a blood pressure (BP) measurement of less than 140/90 mm Hg] at an estimated 66.0% of hypertensive visits. There was mention of at least one hypertensive medication documented in the medical record at 72.0% of hypertensive visits. Hypertension control was indicated at a lower percentage of hypertensive visits made by non-Hispanic black persons (57.4%) than hypertensive visits made by all other racial or ethnic groups. Hypertension was under control or there was mention of a hypertensive medication at a lower percentage of hypertensive visits made by adults aged 18-44 than hypertensive visits by older adults. The percentage of visits with an indication of hypertension control varied widely by state (ranging from 53.7% in Tennessee to 73.2% in Florida) and region (ranging from 60.1% in the East South Central division to 71.1% in the New England division). Among the 18 states, the percentage of hypertensive visits that had mention of a hypertensive medication ranged from 57.1% in Georgia to 85.0% in Washington. Conclusion- The demographic and geographical differences identified in this report may help inform state and local policies aimed at controlling hypertension. PMID- 29155689 TI - Prevalence of Obesity Among Adults and Youth: United States, 2015-2016. AB - Obesity is associated with serious health risks. Monitoring obesityprevalence is relevant for public health programs that focus on reducingor preventing obesity. Between 2003-2004 and 2013-2014, there were nosignificant changes in childhood obesity prevalence, but adults showed anincreasing trend. This report provides the most recent national estimatesfrom 2015-2016 on obesity prevalence by sex, age, and race and Hispanicorigin, and overall estimates from 1999-2000 through 2015-2016. PMID- 29155691 TI - Magnetic fields are causing small, but significant changes of the radiochromic EBT3 film response to 6 MV photons. AB - The optical density (OD) of EBT3 radiochromic films (Ashland Specialty Ingredients, Bridgewater, NJ, USA) exposed to absorbed doses to water up to D = 20 Gy in magnetic fields of B = 0.35 and 1.42 T was measured in the three colour channels of an Epson Expression 10000XL flatbed scanner. A 7 cm wide water phantom with fixed film holder was placed between the pole shoes of a constant current electromagnet with variable field strength and was irradiated by a 6 MV photon beam whose axis was directed at right angles with the field lines. The doses at the film position at water depth 5 cm were measured with a calibrated ionization chamber when the magnet was switched off and were converted to the doses in presence of the magnetic field via the monitor units and by a Monte Carlo-calculated correction accounting for the slight change of the depth dose curves in magnetic fields. In the presence of the 0.35 and 1.42 T fields small negative changes of the OD values at given absorbed doses to water occurred and just significantly exceeded the uncertainty margin given by the stochastic and the uncorrected systematic deviations. This change can be described by a +2.1% change of the dose values needed to produce a given optical density in the presence of a 1.42 T field. The thereby modified OD versus D function remained unchanged irrespective of whether the original short film side-the preference direction of the monomer crystals of the film-was directed parallel or orthogonal to the magnetic field. The 'orientation effect', the difference between the optical densities measured in the 'portrait' or 'landscape' film positions on the scanner bed caused by the reflection of polarised light in the scanner's mirror system, remained unaltered after EBT3 film exposure in magnetic fields. An independent optical bench investigation of EBT3 films exposed to doses of 10 and 20 Gy at 0.35 and 1.42 T showed that the direction of the electric vector of polarised light experiencing the largest transmission through EBT3 films remained unaltered after film exposure in the magnetic fields. The observed small modification of the OD versus D curve of the radiochromic film EBT3 in the range up to 20 Gy and 1.42 T, hardly exceeding the experimental uncertainty margin, numerically confirms other recent studies on EBT3 film. A stronger magnetic field effect had been observed with the previous product EBT2 exposed to 60Co gamma radiation at 0.35 T. PMID- 29155690 TI - Cryo-EM structure of a late pre-40S ribosomal subunit from Saccharomyces cerevisiae. AB - Mechanistic understanding of eukaryotic ribosome formation requires a detailed structural knowledge of the numerous assembly intermediates, generated along a complex pathway. Here, we present the structure of a late pre-40S particle at 3.6 A resolution, revealing in molecular detail how assembly factors regulate the timely folding of pre-18S rRNA. The structure shows that, rather than sterically blocking 40S translational active sites, the associated assembly factors Tsr1, Enp1, Rio2 and Pno1 collectively preclude their final maturation, thereby preventing untimely tRNA and mRNA binding and error prone translation. Moreover, the structure explains how Pno1 coordinates the 3'end cleavage of the 18S rRNA by Nob1 and how the late factor's removal in the cytoplasm ensures the structural integrity of the maturing 40S subunit. PMID- 29155692 TI - Mass Transport Modeling for The Electroreduction of CO2 on Cu Nanowires. AB - Mass transport plays an important role in the CO2 reduction electrocatalysis. Albeit being more pronounced on nanostructured electrodes, the studies of mass transport for CO2 reduction have yet been limited to planar electrodes. We report here the development of a mass transport model for the electroreduction of CO2 on Cu nanowire electrodes. Fed with the experimental data from electrocatalytic studies, the local concentrations of CO2, HCO3-, CO32- and OH- on the nanostructured electrodes are calculated by solving the diffusion equations with spatially distributed electrochemical reaction terms incorporated. The mass transport effects on the catalytic activity and selectivity of the Cu nanowire electrocatalysts are thus discussed by using the local pH as the descriptor. The established correlations between the electrocatalytic performance and the local pH shows that, the latter does not only determine the acid-base reaction equilibrium, but also regulates the mass transport and reaction kinetics. Based on these findings, the optimal range of local pH for the CO2 reduction is discussed in terms of a fine balance of the suppression of hydrogen evolution, improvement of C2 product selectivity and limitation of CO2 supply. Our work highlights the importance of understanding the mass transport effects in interpretation of the CO2 reduction electrocatalysis on high-surface-area catalysts. PMID- 29155693 TI - CLOSTRIDIUM PERFRINGENS PANOPHTHALMITIS AFTER INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTION. AB - PURPOSE: This report describes a fulminant infection with Clostridium perfringens after an intravitreal anti-vascular endothelial growth factor injection. METHODS: This is a retrospective case review. RESULTS: Our patient's rapid infection eventually led to enucleation, despite broad-spectrum antibiotic therapy. CONCLUSION: Reporting rare causes and common clinical findings of C. perfringens ocular infection may lead to earlier detection and intervention. PMID- 29155694 TI - PARACENTRAL ACUTE MIDDLE MACULOPATHY IN PRIMARY CONGENITAL GLAUCOMA. AB - PURPOSE: To report a case of primary congenital glaucoma associated with paracentral acute middle maculopathy. METHODS: A case report. RESULTS: A 14-year old girl with undiagnosed primary congenital glaucoma was referred for the evaluation of sudden vision loss a week after the initial symptoms. Visual acuity was counting fingers at 2 m in the right eye. Examination of her right eye revealed corneal stromal scar like Haab striae, splinter hemorrhage at the temporal border of the optic disk, perivenular hemorrhage, and fern-like white area at the macula. On optical coherence tomography of the right eye, hyperreflective plaques at the level of the inner nuclear layer/outer plexiform layer were present, corresponding to the opaque areas in fundoscopy. On optical coherence tomography angiography of the right eye, ischemic areas in deep capillary plexuses were present. These findings in optical coherence tomography angiography and optical coherence tomography were consistent with paracentral acute middle maculopathy. CONCLUSION: This is the first case of primary congenital glaucoma associated with paracentral acute middle maculopathy in the literature, and primary congenital glaucoma might be a predisposing factor. PMID- 29155695 TI - CITROBACTER ENDOGENOUS ENDOPHTHALMITIS: A CASE REPORT AND REVIEW OF THE LITERATURE. AB - PURPOSE: We present a case of endogenous endophthalmitis because of an unusual bacterium, Citrobacter koseri. PATIENT: A 57-year-old woman without previous history of eye surgery or trauma presented with diabetic ketoacidosis and a painful right eye with the reduction of vision. C. koseri was identified in blood culture; thus, a diagnosis of right eye endogenous endophthalmitis was made. Intravenous and intravitreal antibiotics were both started, and vitreous culture further confirmed C. koseri as the causative organism. Computed tomography of the abdomen and pelvis revealed a right C-shaped perinephric abscess, which was drained under ultrasound guidance. RESULTS: Because of rapid progression to corneal melting, evisceration was performed. CONCLUSION: Cases of endogenous endophthalmitis caused by Citrobacter are very limited, and a review of all published cases in the English literature and the present case revealed that endogenous Citrobacter endophthalmitis arose almost entirely from Citrobacter renal infection. Early recognition and drainage of renal abscess may lower the chance of uncontrolled infection and endogenous spread to the eyes. Despite prompt and intensive treatment, the clinical outcome of Citrobacter endogenous endophthalmitis seems to be poor. PMID- 29155696 TI - SAFETY OF CONSECUTIVE SAME-DAY BILATERAL INTRAVITREAL DEXAMETHASONE IMPLANT (OZURDEX). AB - PURPOSE: The objective of this study was to evaluate patient safety and tolerance of consecutive bilateral intravitreal dexamethasone (Ozurdex) injections during a single visit for the treatment of cystoid macular edema secondary to retinal vein occlusion, diabetic macular edema, or noninfectious posterior uveitis. METHODS: This was a retrospective single-center institutional review board-approved study from March 1, 2013, through August 1, 2016. All patients had a complete ophthalmologic examination and optical coherence tomography imaging. Bilateral intravitreal dexamethasone (Ozurdex) injection was performed according to standard sterile procedure. Twelve patients (24 eyes) were included in the study. RESULTS: A total of 48 injections were administered to 24 eyes of 12 patients that qualified for the study. Patients received intravitreal dexamethasone (Ozurdex) injections for treatment of diabetic macular edema (10 patients), retinal vein occlusion (1 patient), or noninfectious posterior uveitis (1 patient). There were no complications. CONCLUSION: Consecutive same-day bilateral intravitreal dexamethasone (Ozurdex) is safe and well tolerated. There were no significant complications, and patients preferred continuing bilateral implantation after their initial trial. Same-day treatment may optimize efficiency and decrease patient visits and ultimate treatment burden without compromising patient safety or clinical efficacy. PMID- 29155697 TI - ACUTE INTRAOPERATIVE SUPRACHOROIDAL HEMORRHAGE DURING SMALL-GAUGE PARS PLANA VITRECTOMY. AB - PURPOSE: To report the intraoperative occurrence of acute intraoperative suprachoroidal hemorrhage during small-gauge pars plana vitrectomy. METHOD: A review of a surgical patient who developed acute intraoperative suprachoroidal hemorrhage during small-gauge pars plana vitrectomy because of bucking under general anesthesia. RESULTS: A 32-year-old obese woman with proliferative diabetic retinopathy and traction retinal detachment in the left eye who developed intraoperative suprachoroidal hemorrhage during small-gauge pars plana vitrectomy because of bucking under general anesthesia while doing endolaser under air infusion. The pressure was immediately elevated to stabilize the hemorrhage without sclerotomy creation, and then gas (14% C3F8) was injected, with subsequent face-down positioning. The patient subsequently developed proliferative vitreoretinopathy, requiring additional surgery. The final visual acuity at 14-month follow-up was hand motions with a reattached retina in the left eye. CONCLUSION: Valsalva-induced suprachoroidal hemorrhage during pars plana vitrectomy under general anesthesia may result in sight-threatening visual consequences. Current small-gauge vitrectomy techniques using valved cannulas may allow for better intraoperative management of this complication through control of the intraocular pressure in a closed system. PMID- 29155698 TI - BULL'S EYE MACULOPATHY WITH MUTATIONS IN RDS/PRPH2 AND ROM-1. AB - PURPOSE: To report a case of bull's eye maculopathy associated with mutations in RDS/PRPH2 and ROM-1 genes. METHODS: We present a case report of a patient with a characteristic maculopathy and describe the multimodal retinal imaging findings including spectral domain optical coherence tomography and fundus autofluorescence and full-field electrophysiology. The results of genetic testing are also reported. RESULTS: A 60-year-old woman presented with decreased vision and a remarkable bull's eye maculopathy with retinal examination. Fundus autofluorescence illustrated a striking pattern of speckled hyperautofluorescence and hypoautofluorescence that highlighted the bull's eye maculopathy in each eye and guided genetic testing, which confirmed a mutation of the RDS/PRPH2 gene and a novel mutation of the ROM-1 gene. CONCLUSION: Multimodal imaging including fundus autofluorescence may guide genetic testing in patients with a characteristic maculopathy. RDS/PRPH2 genetic mutation can be associated with a bull's eye maculopathy with a signature fundus autofluorescence presentation. PMID- 29155699 TI - Selective Angiographic Embolization of Blunt Hepatic Trauma Reduces Failure Rate of Nonoperative Therapy and Incidence of Post-Traumatic Complications. AB - BACKGROUND Conflict still remains as to the benefit of angioembolization (AE) for non-operative therapy (NOT) of blunt hepatic trauma (BHT). The aim of this study was to determine whether AE could result in lower failure rates in hemodynamically stable BHT patients with high failure risk factors for NOT, and to systematically evaluate the effectiveness of AE for NOT of BHT. MATERIAL AND METHODS Medical records of all BHT patients from January 1, 1998 to December 31, 2015 at a large trauma center were collected and analyzed. Failure of NOT (FNOT) occurred if hepatic surgery was performed after attempted NOT. Logistic regression analysis was used to identify factors associated with FNOT. Hepatobiliary complications related to hepatic trauma during follow-up were reviewed. RESULTS No significant difference in FNOT for the no angiographic embolization (NO-AE) group versus angiographic embolization (AE) group was found in hepatic trauma of grades I, II, and V. However, decrease in FNOT was significant with AE performed for hepatic trauma of grades III to IV. Risk factors for FNOT included grade III to IV injuries and contrast blush on CT. Follow-up data of six months also showed that the incidence of hepatobiliary complications in the NO-AE group was higher than the AE group. CONCLUSIONS Hemodynamically stable BHT patients with grade III to IV injuries, contrast blush on initial CT, and/or decreasing hemoglobin levels can be candidates for selective AE during NOT course. PMID- 29155700 TI - Phase Behavior of Charged Vesicles Under Symmetric and Asymmetric Solution Conditions Monitored with Fluorescence Microscopy. AB - Phase-separated giant unilamellar vesicles (GUVs) exhibiting coexisting liquid ordered and liquid-disordered domains are a common biophysical tool to investigate the lipid raft hypothesis. Numerous studies, however, neglect the impact of physiological solution conditions. On that account, the current work presents the effect of high-salinity buffer and trans-membrane solution asymmetry on liquid-liquid phase separation in charged GUVs grown from dioleylphosphatidylglycerol, egg sphingomyelin, and cholesterol. The effects were studied under isothermal and varying temperature conditions. We describe equipment and experimental strategies applicable for monitoring the stability of coexisting liquid domains in charged vesicles under symmetric and asymmetric high salinity solution conditions. This includes an approach to prepare charged multicomponent GUVs in high-salinity buffer at high temperatures. The protocol entails the option to perform a partial exchange of the external solution by a simple dilution step while minimizing the vesicle dilution. An alternative approach is presented utilizing a microfluidic device that allows for a complete external solution exchange. The solution effects on phase separation were also studied under varying temperatures. To this end, we present the basic design and utility of an in-house built temperature control chamber. Furthermore, we reflect on the assessment of the GUV phase state, pitfalls associated with it and how to circumvent them. PMID- 29155701 TI - An Ultrasonic Tool for Nerve Conduction Block in Diabetic Rat Models. AB - Nerve conduction block with a high intensity-focused ultrasound (HIFU) transducer has been performed in normal and diabetic animal models recently. HIFU can reversibly block the conduction of peripheral nerves without damaging the nerves while using an appropriate ultrasonic parameter. Temporary and partial block of the action potentials of nerves shows that HIFU has the potential to be a useful clinical treatment for pain relief. This work demonstrates the procedures for suppressing the action potentials of neuropathic nerves in diabetic rats in vivo using an HIFU transducer. The first step is to generate adult male diabetic neuropathic rats by streptozotocin (STZ) injection. The second step is to evaluate the peripheral diabetic neuropathy in STZ-induced diabetic rats by an electronic von Frey probe and a hot plate. The final step is to record in vivo extracellular action potentials of the nerve exposed to HIFU sonication. The method showed here may benefit the study of ultrasound analgesic applications. PMID- 29155702 TI - Using the Sleeve Technique in a Mouse Model of Aortic Transplantation - An Instructional Video. AB - Orthotopic aortic transplantation using the sleeve technique reduces injury to the aorta with failure rate of only 10-20%. The time to anastomose the aorta in mice using the sleeve method was short and easy averaging 20 min, permitting studies of iso/allo grafts. The following article describes the aortic transplantation procedure used in our laboratory. The mice were anesthetized with a mixture of 1.5% volume isoflurane and 100% oxygen through a face mask. At this point, the segment of the aorta between the renal arteries and its bifurcation was separated from the vena cava, freely prepared and clampedat the proximal and distal segments with a single silk suture. Prior to the removal of the aorta, a saline solution containing heparin was injected into the inferior vena cava. Then the aorta was cut between the clamps and a saline heparin solution was used to flush the lumen. The sleeve technique with monofilament sutures was used in order to transplant the abdominal aorta in the orthotopic position. PMID- 29155704 TI - Experimental System of Solar Adsorption Refrigeration with Concentrated Collector. AB - To improve the performance of solar adsorption refrigeration, an experimental system with a solar concentration collector was set up and investigated. The main components of the system were the adsorbent bed, the condenser, the evaporator, the cooling sub-system, and the solar collector. In the first step of the experiment, the vapor-saturated bed was heated by the solar radiation under closed conditions, which caused the bed temperature and pressure to increase. When the bed pressure became high enough, the bed was switched to connect to the condenser, thus water vapor flowed continually from the bed to the condenser to be liquefied. Next, the bed needed to cool down after the desorption. In the solar-shielded condition, achieved by aluminum foil, the circulating water loop was opened to the bed. With the water continually circulating in the bed, the stored heat in the bed was took out and the bed pressure decreased accordingly. When the bed pressure dropped below the saturation pressure at the evaporation temperature, the valve to the evaporator was opened. A mass of water vapor rushed into the bed and was adsorbed by the zeolite material. With the massive vaporization of the water in the evaporator, the refrigeration effect was generated finally. The experimental result has revealed that both the COP (coefficient of the performance of the system) and the SCP (specific cooling power of the system) of the SAPO-34 zeolite was greater than that of the ZSM-5 zeolite, no matter whether the adsorption time was longer or shorter. The system of the SAPO-34 zeolite generated a maximum COP of 0.169. PMID- 29155703 TI - Modeling Amyloid-beta42 Toxicity and Neurodegeneration in Adult Zebrafish Brain. AB - Alzheimer's disease (AD) is a debilitating neurodegenerative disease in which accumulation of toxic amyloid-beta42 (Abeta42) peptides leads to synaptic degeneration, inflammation, neuronal death, and learning deficits. Humans cannot regenerate lost neurons in the case of AD in part due to impaired proliferative capacity of the neural stem/progenitor cells (NSPCs) and reduced neurogenesis. Therefore, efficient regenerative therapies should also enhance the proliferation and neurogenic capacity of NSPCs. Zebrafish (Danio rerio) is a regenerative organism, and we can learn the basic molecular programs with which we could design therapeutic approaches to tackle AD. For this reason, the generation of an AD-like model in zebrafish was necessary. Using our methodology, we can introduce synthetic derivatives of Abeta42 peptide with tissue penetrating capability into the adult zebrafish brain, and analyze the disease pathology and the regenerative response. The advantage over the existing methods or animal models is that zebrafish can teach us how a vertebrate brain can naturally regenerate, and thus help us to treat human neurodegenerative diseases better by targeting endogenous NSPCs. Therefore, the amyloid-toxicity model established in the adult zebrafish brain may open new avenues for research in the field of neuroscience and clinical medicine. Additionally, the simple execution of this method allows for cost effective and efficient experimental assessment. This manuscript describes the synthesis and injection of Abeta42 peptides into zebrafish brain. PMID- 29155705 TI - Identification and Characterization of Metastatic Factors by Gene Transfer into the Novel RIP-Tag; RIP-tva Murine Model. AB - Metastatic cancer accounts for 90% of deaths in patients with solid tumors. There is an urgent need to better understand the drivers of cancer metastasis and to identify novel therapeutic targets. To investigate molecular events that drive the progression from primary cancer to metastasis, we have developed a bitransgenic mouse model, RIP-Tag; RIP-tva. In this mouse model, the rat insulin promoter (RIP) drives the expression of the SV40 T antigen (Tag) and the receptor for subgroup A avian leukosis virus (tva) in pancreatic beta cells. The mice develop pancreatic neuroendocrine tumors with 100% penetrance through well defined stages that are similar to human tumorigenesis, with stages including hyperplasia, angiogenesis, adenoma, and invasive carcinoma. Because RIP-Tag; RIP tva mice do not develop metastatic disease, genetic alterations that promote metastasis can be identified easily. Somatic gene transfer into tva-expressing, proliferating pancreatic beta premalignant lesions is achieved through intracardiac injection of avian retroviruses harboring the desired genetic alteration. A titer of >1 x 108 infectious units per ml is considered appropriate for in vivo infection. In addition, avian retroviruses can infect cell lines derived from tumors in RIP-Tag; RIP-tva mice with high efficiency. The cell lines can also be used to characterize the metastatic factors. Here we demonstrate how to utilize this mouse model and cell lines to assess the functions of candidate genes in tumor metastasis. PMID- 29155706 TI - Comprehensive Endovascular and Open Surgical Management of Cerebral Arteriovenous Malformations. AB - Arteriovenious malformations (AVMs) are associated with significant morbidity and mortality, and have a rupture risk of ~3% per year. Treatment of AVMs must be tailored specifically to the lesion, with surgical resection being the gold standard for small, accessible lesions. Pre-operative embolization of AVMs can reduce nidal blood flow and remove high-risk AVM features such as intranidal or venous aneurysms, thereby simplifying a challenging neurosurgical procedure. Herein, we describe our approach for the staged endovascular embolization and open resection of AVMs, and highlight the advantages of having a comprehensively trained neurovascular surgeon leading a multi-disciplinary clinical team. This includes planning the craniotomy and resection to immediately follow the final embolization stage, thereby using a single session of anesthesia for aggressive embolization, and rapid resection. Finally, we provide a representative case of a 22-year-old female with an unruptured right frontal AVM diagnosed during a seizure workup, who was successfully treated via staged embolizations followed by open surgical resection. PMID- 29155707 TI - Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients. AB - Defects in the cystic fibrosis trans-membrane conductance regulator (CFTR) are the cause of cystic fibrosis (CF), a disease with life-threatening pulmonary manifestations. Ivacaftor (IVA) and ivacaftor-lumacaftor (LUMA) combination are two new breakthrough CF drugs that directly modulate the activity and trafficking of the defective CFTR-protein. However, there is still a dearth of understanding on pharmacokinetic/pharmacodynamic parameters and the pharmacology of ivacaftor and lumacaftor. The HPLC-MS technique for the simultaneous analysis of the concentrations of ivacaftor, hydroxymethyl-ivacaftor, ivacaftor-carboxylate, and lumacaftor in biological fluids in patients receiving standard ivacaftor or ivacaftor-lumacaftor combination therapy has previously been developed by our group and partially validated to FDA standards. However, to allow the high throughput analysis of a larger number of patient samples, our group has optimized the reported method through the use of a smaller pore size reverse phase chromatography column (2.6 um, C8 100 A; 50 x 2.1 mm) and a gradient solvent system (0-1 min: 40% B; 1-2 min: 40-70% B; 2-2.7 min: held at 70% B; 2.7 2.8 min: 70-90% B; 2.8-4.0 min: 90% B washing; 4.0-4.1 min: 90-40% B; 4.1-6.0 min: held at 40% B) instead of an isocratic elution. The goal of this study was to reduce the HPLC-MS analysis time per sample dramatically from ~15 min to only 6 min per sample, which is essential for the analysis of a large amount of patient samples. This expedient method will be of considerable utility for studies into the exposure-response relationships of these breakthrough CF drugs. PMID- 29155708 TI - Enrichment of Detergent-insoluble Protein Aggregates from Human Postmortem Brain. AB - In this study, we describe an abbreviated single-step fractionation protocol for the enrichment of detergent-insoluble protein aggregates from human postmortem brain. The ionic detergent N-lauryl-sarcosine (sarkosyl) effectively solubilizes natively folded proteins in brain tissue allowing the enrichment of detergent insoluble protein aggregates from a wide range of neurodegenerative proteinopathies, such as Alzheimer's disease (AD), Parkinson's disease and amyotrophic lateral sclerosis, and prion diseases. Human control and AD postmortem brain tissues were homogenized and sedimented by ultracentrifugation in the presence of sarkosyl to enrich detergent-insoluble protein aggregates including pathologic phosphorylated tau, the core component of neurofibrillary tangles in AD. Western blotting demonstrated the differential solubility of aggregated phosphorylated-tau and the detergent-soluble protein, Early Endosome Antigen 1 (EEA1) in control and AD brain. Proteomic analysis also revealed enrichment of beta-amyloid (Abeta), tau, snRNP70 (U1-70K), and apolipoprotein E (APOE) in the sarkosyl-insoluble fractions of AD brain compared to those of control, consistent with previous tissue fractionation strategies. Thus, this simple enrichment protocol is ideal for a wide range of experimental applications ranging from Western blotting and functional protein co-aggregation assays to mass spectrometry-based proteomics. PMID- 29155709 TI - A Computational Method to Quantify Fly Circadian Activity. AB - In most animals and plants, circadian clocks orchestrate behavioral and molecular processes and synchronize them to the daily light-dark cycle. Fundamental mechanisms that underlie this temporal control are widely studied using the fruit fly Drosophila melanogaster as a model organism. In flies, the clock is typically studied by analyzing multiday locomotor recording. Such a recording shows a complex bimodal pattern with two peaks of activity: a morning peak that happens around dawn, and an evening peak that happens around dusk. These two peaks together form a waveform that is very different from sinusoidal oscillations observed in clock genes, suggesting that mechanisms in addition to the clock have profound effects in producing the observed patterns in behavioral data. Here we provide instructions on using a recently developed computational method that mathematically describes temporal patterns in fly activity. The method fits activity data with a model waveform that consists of four exponential terms and nine independent parameters that fully describe the shape and size of the morning and evening peaks of activity. The extracted parameters can help elucidate the kinetic mechanisms of substrates that underlie the commonly observed bimodal activity patterns in fly locomotor rhythms. PMID- 29155710 TI - DNA Nanotubes as a Versatile Tool to Study Semiflexible Polymers. AB - Mechanical properties of complex, polymer-based soft matter, such as cells or biopolymer networks, can be understood in neither the classical frame of flexible polymers nor of rigid rods. Underlying filaments remain outstretched due to their non-vanishing backbone stiffness, which is quantified via the persistence length (lp), but they are also subject to strong thermal fluctuations. Their finite bending stiffness leads to unique, non-trivial collective mechanics of bulk networks, enabling the formation of stable scaffolds at low volume fractions while providing large mesh sizes. This underlying principle is prevalent in nature (e.g., in cells or tissues), minimizing the high molecular content and thereby facilitating diffusive or active transport. Due to their biological implications and potential technological applications in biocompatible hydrogels, semiflexible polymers have been subject to considerable study. However, comprehensible investigations remained challenging since they relied on natural polymers, such as actin filaments, which are not freely tunable. Despite these limitations and due to the lack of synthetic, mechanically tunable, and semiflexible polymers, actin filaments were established as the common model system. A major limitation is that the central quantity lp cannot be freely tuned to study its impact on macroscopic bulk structures. This limitation was resolved by employing structurally programmable DNA nanotubes, enabling controlled alteration of the filament stiffness. They are formed through tile-based designs, where a discrete set of partially complementary strands hybridize in a ring structure with a discrete circumference. These rings feature sticky ends, enabling the effective polymerization into filaments several microns in length, and display similar polymerization kinetics as natural biopolymers. Due to their programmable mechanics, these tubes are versatile, novel tools to study the impact of lp on the single-molecule as well as the bulk scale. In contrast to actin filaments, they remain stable over weeks, without notable degeneration, and their handling is comparably straightforward. PMID- 29155711 TI - Monitoring Astrocyte Reactivity and Proliferation in Vitro Under Ischemic-Like Conditions. AB - Ischemic stroke is a complex brain injury caused by a thrombus or embolus obstructing blood flow to parts of the brain. This leads to deprivation of oxygen and glucose, which causes energy failure and neuronal death. After an ischemic stroke insult, astrocytes become reactive and proliferate around the injury site as it develops. Under this scenario, it is difficult to study the specific contribution of astrocytes to the brain region exposed to ischemia. Therefore, this article introduces a methodology to study primary astrocyte reactivity and proliferation under an in vitro model of an ischemia-like environment, called oxygen glucose deprivation (OGD). Astrocytes were isolated from 1-4 day-old neonatal rats and the number of non-specific astrocytic cells was assessed using astrocyte selective marker Glial Fibrillary Acidic Protein (GFAP) and nuclear staining. The period in which astrocytes are subjected to the OGD condition can be customized, as well as the percentage of oxygen they are exposed to. This flexibility allows scientists to characterize the duration of the ischemic-like condition in different groups of cells in vitro. This article discusses the timeframes of OGD that induce astrocyte reactivity, hypertrophic morphology, and proliferation as measured by immunofluorescence using Proliferating Cell Nuclear Antigen (PCNA). Besides proliferation, astrocytes undergo energy and oxidative stress, and respond to OGD by releasing soluble factors into the cell medium. This medium can be collected and used to analyze the effects of molecules released by astrocytes in primary neuronal cultures without cell-to-cell interaction. In summary, this primary cell culture model can be efficiently used to understand the role of isolated astrocytes upon injury. PMID- 29155712 TI - Minimum Burning Pressures of Water-based Emulsion Explosives. AB - This manuscript describes a protocol to measure the minimum pressure required for sustained burning of water-based emulsion explosives. Pumping water-based emulsion explosives for blasting applications can be very hazardous, as demonstrated by a number of pump accidents around the globe in the last decades, including some that resulted in fatalities. In Canada, the recognition of this hazard has led to the development of pumping guidelines that were endorsed by both the explosives industry and the Explosive Regulatory Division of the Canadian government. In these guidelines, it was noted that the minimum burning pressures (MBP) measured in a laboratory would provide a good guide to characterize the behaviour of these products in pumping systems. The same guidelines also call for the design of pump systems that prevent, whenever possible, pressures from exceeding the MBP of the product being pumped. At the time of publication of these guidelines, a methodology existed for measuring such MBP values but it had never been validated to measure the MBP of ammonium nitrate water-based emulsions (AWEs). AWEs are now used much more widely than any other water-based explosives and precursors in on-site bulk loading operations. The Canadian Explosives Research Laboratory (CanmetCERL) has been conducting research over the last ten years to develop a validated testing protocol to measure and interpret representative MBP values for AWEs. The test, as it is performed today, will be described and the critical components will be justified by reference to recent published data. Results of MBP measurements, for a range of AWE products, will be presented. Inclusion of the MBP test in the test standards for the authorization of high explosives in Canada will also be discussed. PMID- 29155713 TI - Quantifying Human Monocyte Chemotaxis In Vitro and Murine Lymphocyte Trafficking In Vivo. AB - Chemotaxis is migration along a specific chemical gradient1. Chemokines are chemotactic cytokines that promote cellular trafficking with anatomic and temporal specificity2. Chemotaxis is a critical function of lymphocytes and other immune cells that can be quantitatively assessed in vitro. This manuscript describes methods that permit the evaluation of chemotaxis, both in vitro and in vivo, for diverse cell types including cell lines and native cells. The in vitro, plate-based format permits the comparison of several conditions simultaneously in real-time, and can be completed within 1-4 h. In vitro assay conditions can be manipulated to introduce agonists and antagonists, as well as differentiate chemotaxis from chemokinesis, which is random movement. For in vivo trafficking assessments, immune cells can be labeled with multiple fluorescent dyes and used for adoptive transfer. The differential labeling of cells allows for mixed cell populations to be introduced into the same animal, thereby decreasing variance and reducing the number of animals required for an adequately powered experiment. Migration into lymphoid tissue occurs in as little as 1 h, and multiple tissue compartments can be sampled. Flow cytometry following tissue harvest allows for a rapid and quantitative analysis of the migratory patterns of multiple cell types. PMID- 29155714 TI - Application of MultiColor FlpOut Technique to Study High Resolution Single Cell Morphologies and Cell Interactions of Glia in Drosophila. AB - Cells display different morphologies and complex anatomical relationships. How do cells interact with their neighbors? Do the interactions differ between cell types or even within a given type? What kinds of spatial rules do they follow? The answers to such fundamental questions in vivo have been hampered so far by a lack of tools for high resolution single cell labeling. Here, a detailed protocol to target single cells with a MultiColor FlpOut (MCFO) technique is provided. This method relies on three differently tagged reporters (HA, FLAG and V5) under UAS control that are kept silent by a transcriptional terminator flanked by two FRT sites (FRT-stop-FRT). A heat shock pulse induces the expression of a heat shock-induced Flp recombinase, which randomly removes the FRT-stop-FRT cassettes in individual cells: expression occurs only in cells that also express a GAL4 driver. This leads to an array of differently colored cells of a given cell type that allows the visualization of individual cell morphologies at high resolution. As an example, the MCFO technique can be combined with specific glial GAL4 drivers to visualize the morphologies of the different glial subtypes in the adult Drosophila brain. PMID- 29155715 TI - Indoor Experimental Assessment of the Efficiency and Irradiance Spot of the Achromatic Doublet on Glass (ADG) Fresnel Lens for Concentrating Photovoltaics. AB - We present a method to characterize achromatic Fresnel lenses for photovoltaic applications. The achromatic doublet on glass (ADG) Fresnel lens is composed of two materials, a plastic and an elastomer, whose dispersion characteristics (refractive index variation with wavelength) are different. We first designed the lens geometry and then used ray-tracing simulation, based on the Monte Carlo method, to analyze its performance from the point of view of both optical efficiency and the maximum attainable concentration. Afterwards, ADG Fresnel lens prototypes were manufactured using a simple and reliable method. It consists of a prior injection of plastic parts and a consecutive lamination, together with the elastomer and a glass substrate to fabricate the parquet of ADG Fresnel lenses. The accuracy of the manufactured lens profile is examined using an optical microscope while its optical performance is evaluated using a solar simulator for concentrator photovoltaic systems. The simulator is composed of a xenon flash lamp whose emitted light is reflected by a parabolic mirror. The collimated light has a spectral distribution and an angular aperture similar to the real Sun. We were able to assess the optical performance of the ADG Fresnel lenses by taking photographs of the irradiance spot cast by the lens using a charge-coupled device (CCD) camera and measuring the photocurrent generated by several types of multi junction (MJ) solar cells, which have been previously characterized at a solar simulator for concentrator solar cells. These measurements have demonstrated the achromatic behavior of ADG Fresnel lenses and, as a consequence, the suitability of the modelling and manufacturing methods. PMID- 29155716 TI - Evaluation of Injury-induced Senescence and In Vivo Reprogramming in the Skeletal Muscle. AB - Cellular senescence is a stress response that is characterized by a stable cellular growth arrest, which is important for many physiological and pathological processes, such as cancer and ageing. Recently, senescence has also been implicated in tissue repair and regeneration. Therefore, it has become increasingly critical to identify senescent cells in vivo. Senescence-associated beta-galactosidase (SA-beta-Gal) assay is the most widely used assay to detect senescent cells both in culture and in vivo. This assay is based on the increased lysosomal contents in the senescent cells, which allows the histochemical detection of lysosomal beta-galactosidase activity at suboptimum pH (6 or 5.5). In comparison with other assays, such as flow cytometry, this allows the identification of senescent cells in their resident environment, which offers valuable information such as the location relating to the tissue architecture, the morphology, and the possibility of coupling with other markers via immunohistochemistry (IHC). The major limitation of the SA-beta-Gal assay is the requirement of fresh or frozen samples. Here, we present a detailed protocol to understand how cellular senescence promotes cellular plasticity and tissue regeneration in vivo. We use SA-beta-Gal to detect senescent cells in the skeletal muscle upon injury, which is a well-established system to study tissue regeneration. Moreover, we use IHC to detect Nanog, a marker of pluripotent stem cells, in a transgenic mouse model. This protocol enables us to examine and quantify cellular senescence in the context of induced cellular plasticity and in vivo reprogramming. PMID- 29155717 TI - Synthesis of High Purity Nonsymmetric Dialkylphosphinic Acid Extractants. AB - We present the synthesis of (2,3-dimethylbutyl)(2,4,4'-trimethylpentyl)phosphinic acid as an example to demonstrate a method for the synthesis of high purity nonsymmetric dialkylphosphinic acid extractants. Low toxic sodium hypophosphite was chosen as the phosphorus source to react with olefin A (2,3-dimethyl-1 butene) to generate a monoalkylphosphinic acid intermediate. Amantadine was adopted to remove the dialkylphosphinic acid byproduct, as only the monoalkylphosphinic acid can react with amantadine to form an amantadine?mono alkylphosphinic acid salt, while the dialkylphosphinic acid cannot react with amantadine due to its large steric hindrance. The purified monoalkylphosphinic acid was then reacted with olefin B (diisobutylene) to yield nonsymmetric dialkylphosphinic acid (NSDAPA). The unreacted monoalkylphosphinic acid can be easily removed by a simple base-acid post-treatment and other organic impurities can be separated out through the precipitation of the cobalt salt. The structure of the (2,3-dimethylbutyl)(2,4,4'-trimethylpentyl)phosphinic acid was confirmed by 31P NMR, 1H NMR, ESI-MS, and FT-IR. The purity was determined by a potentiometric titration method, and the results indicate that the purity can exceed 96%. PMID- 29155718 TI - The Murine Choline-Deficient, Ethionine-Supplemented (CDE) Diet Model of Chronic Liver Injury. AB - Chronic liver diseases, such as viral hepatitis, alcoholic liver disease, or non alcoholic fatty liver disease, are characterized by continual inflammation, progressive destruction and regeneration of the hepatic parenchyma, liver progenitor cell proliferation, and fibrosis. The end-stage of every chronic liver disease is cirrhosis, a major risk factor for the development of hepatocellular carcinoma. To study processes regulating disease initiation, establishment, and progression, several animal models are used in laboratories. Here we describe a six-week time course of the choline-deficient and ethionine-supplemented (CDE) mouse model, which involves feeding six-week old male C57BL/6J mice with choline deficient chow and 0.15% DL-ethionine-supplemented drinking water. Monitoring of animal health and a typical body weight loss curve are explained. The protocol demonstrates the gross examination of a CDE-treated liver and blood collection by cardiac puncture for subsequent serum analyses. Next, the liver perfusion technique and collection of different hepatic lobes for standard evaluations are shown, including liver histology assessments by hematoxylin and eosin or Sirius Red stainings, immunofluorescent detection of hepatic cell populations as well as transcriptome profiling of the liver microenvironment. This mouse model is suitable for studying inflammatory, fibrogenic, and liver progenitor cell dynamics induced through chronic liver disease and can be used to test potential therapeutic agents that may modulate these processes. PMID- 29155719 TI - Exploring Deep Space - Uncovering the Anatomy of Periventricular Structures to Reveal the Lateral Ventricles of the Human Brain. AB - Anatomy students are typically provided with two-dimensional (2D) sections and images when studying cerebral ventricular anatomy and students find this challenging. Because the ventricles are negative spaces located deep within the brain, the only way to understand their anatomy is by appreciating their boundaries formed by related structures. Looking at a 2D representation of these spaces, in any of the cardinal planes, will not enable visualisation of all of the structures that form the boundaries of the ventricles. Thus, using 2D sections alone requires students to compute their own mental image of the 3D ventricular spaces. The aim of this study was to develop a reproducible method for dissecting the human brain to create an educational resource to enhance student understanding of the intricate relationships between the ventricles and periventricular structures. To achieve this, we created a video resource that features a step-by-step guide using a fiber dissection method to reveal the lateral and third ventricles together with the closely related limbic system and basal ganglia structures. One of the advantages of this method is that it enables delineation of the white matter tracts that are difficult to distinguish using other dissection techniques. This video is accompanied by a written protocol that provides a systematic description of the process to aid in the reproduction of the brain dissection. This package offers a valuable anatomy teaching resource for educators and students alike. By following these instructions educators can create teaching resources and students can be guided to produce their own brain dissection as a hands-on practical activity. We recommend that this video guide be incorporated into neuroanatomy teaching to enhance student understanding of the morphology and clinical relevance of the ventricles. PMID- 29155720 TI - Muller Glia Cell Activation in a Laser-induced Retinal Degeneration and Regeneration Model in Zebrafish. AB - A fascinating difference between teleost and mammals is the lifelong potential of the teleost retina for retinal neurogenesis and regeneration after severe damage. Investigating the regeneration pathways in zebrafish might bring new insights to develop innovative strategies for the treatment of retinal degenerative diseases in mammals. Herein, we focused on the induction of a focal lesion to the outer retina in adult zebrafish by means of a 532 nm diode laser. A localized injury allows investigating biological processes that take place during retinal degeneration and regeneration directly at the area of damage. Using non-invasive optical coherence tomography (OCT), we were able to define the location of the damaged area and monitor subsequent regeneration in vivo. Indeed, OCT imaging produces high-resolution, cross-sectional images of the zebrafish retina, providing information which was previously only available with histological analyses. In order to confirm the data from real-time OCT, histological sections were performed and regenerative response after the induction of the retinal injury was investigated by immunohistochemistry. PMID- 29155721 TI - Visualizing Macrophage Extracellular Traps Using Confocal Microscopy. AB - A primary method used to define the presence of neutrophil extracellular traps (NETs) is confocal microscopy. We have modified established confocal microscopy methods to visualize macrophage extracellular traps (METs). These extracellular traps are defined by the presence of extracellular chromatin with co-expression of other components such as granule proteases, citrullinated histones, and peptidyl arginase deiminase (PAD). The expression of METs is generally measured after exposure to a stimulus and compared to un-stimulated samples. Samples are also included for background and isotype control. Cells are analyzed using well defined image analysis software. Confocal microscopy may be used to define the presence of METs both in vitro and in vivo in lung tissue. PMID- 29155722 TI - Automated Gait Analysis in Mice with Chronic Constriction Injury. AB - The von Frey test is a classical method that has been widely used to examine the sensory function of neuropathic pain animals. However, it has some disadvantages such as subjective data and the requirement of a skilled, experienced experimenter. To date, a variety of modifications have improved the von Frey method, but it still has a few limitations. Recent reports have suggested that gait analysis produces more accurate and objective data from the neuropathic animals. This protocol demonstrates how to perform the automated gait analysis to determine the degree of neuropathic pain in mice. After several days of acclimation, the mice were allowed to walk freely on the glass floor to illuminate footprints. Then, quantification of the footprints and gait were performed through video clips with automatic analysis of various walking parameters, such as area of paw print, swing time, angle of paw, etc. The main purpose of this study is to describe the methodology of automated gait analysis and briefly compare it with data from the classical sensory test using von Frey filament. PMID- 29155723 TI - One-step Protocol for Evaluation of the Mode of Radiation-induced Clonogenic Cell Death by Fluorescence Microscopy. AB - Research on ionizing radiation (IR)-induced clonogenic cell death is important for understanding the effect of IR on malignant tumors and normal tissues. Here, we describe a quick and cost-effective one-step assay for simultaneously assessing the major modes of clonogenic cell death induced by IR, i.e., apoptosis, mitotic catastrophe, and cellular senescence. In this method, cells grown on a cover slip are irradiated with X-rays and stained with 4',6-diamidino 2-phenylindole dihydrochloride (DAPI). Using fluorescence microscopy, apoptosis, mitotic catastrophe, and cellular senescence are identified based on the characteristic morphologies of the DAPI-stained nuclei. Apoptosis is determined by the presence of apoptotic bodies (i.e., condensed and fragmented nuclei). Mitotic catastrophe is determined by the presence of nuclei that exhibit two or more distinct lobes and micronuclei. Cellular senescence is determined by the presence of senescence-associated heterochromatic foci (i.e., nuclear DNA containing 30-50 bright, dense foci). This approach allows the experimenter to easily screen for clonogenic cell death modes using various cell lines, treatment settings, and/or time points, with the goal of elucidating the mechanisms of cell death in the target cells and conditions of interest. PMID- 29155724 TI - Generation of a Gene-disrupted Streptococcus mutans Strain Without Gene Cloning. AB - Typical methods for the elucidation of the function of a particular gene involve comparative phenotypic analyses of the wild-type strain and a strain in which the gene of interest has been disrupted. A gene-disruption DNA construct containing a suitable antibiotic resistance marker gene is useful for the generation of gene disrupted strains in bacteria. However, conventional construction methods, which require gene cloning steps, involve complex and time-consuming protocols. Here, a relatively facile, rapid, and cost-effective method for targeted gene disruption in Streptococcus mutans is described. The method utilizes a 2-step fusion polymerase chain reaction (PCR) to generate the disruption construct and electroporation for genetic transformation. This method does not require an enzymatic reaction, other than PCR, and additionally offers greater flexibility in terms of the design of the disruption construct. Employment of electroporation facilitates the preparation of competent cells and improves the transformation efficiency. The present method may be adapted for the generation of gene disrupted strains of various species. PMID- 29155725 TI - An Efficient and Reproducible Protocol for Distraction Osteogenesis in a Rat Model Leading to a Functional Regenerated Femur. AB - This protocol describes the use of a newly developed external fixator for distraction osteogenesis in a rat femoral model. Distraction osteogenesis (DO) is a surgical technique leading to bone regeneration after an osteotomy. The osteotomized extremities are moved away from each other by gradual distraction to reach the desired elongation. This procedure is widely used in humans for lower and upper limb lengthening, treatment after a bone nonunion, or the regeneration of a bone defect following surgery for bone tumor excision, as well as in maxillofacial reconstruction. Only a few studies clearly demonstrate the efficiency of their protocol in obtaining a functional regenerated bone, i.e., bone that will support physiological weight-bearing without fracture after removal of the external fixator. Moreover, protocols for DO vary and reproducibility is limited by lack of information, making comparison between studies difficult. The aim of this study was to develop a reproducible protocol comprising an appropriate external fixator design for rat limb lengthening, with a detailed surgical technique that permits physiological weight-bearing by the animal after removal of the external fixator. PMID- 29155726 TI - Visualization and Live Imaging of Oligodendrocyte Organelles in Organotypic Brain Slices Using Adeno-associated Virus and Confocal Microscopy. AB - Neurons rely on the electric insulation and trophic support of myelinating oligodendrocytes. Despite the importance of oligodendrocytes, the advanced tools currently used to study neurons, have only partly been taken on by oligodendrocyte researchers. Cell type-specific staining by viral transduction is a useful approach to study live organelle dynamics. This paper describes a protocol for visualizing oligodendrocyte mitochondria in organotypic brain slices by transduction with adeno-associated virus (AAV) carrying genes for mitochondrial targeted fluorescent proteins under the transcriptional control of the myelin basic protein promoter. It includes the protocol for making organotypic coronal mouse brain slices. A procedure for time-lapse imaging of mitochondria then follows. These methods can be transferred to other organelles and may be particularly useful for studying organelles in the myelin sheath. Finally, we describe a readily available technique for visualization of unstained myelin in living slices by Confocal Reflectance microscopy (CoRe). CoRe requires no extra equipment and can be useful to identify the myelin sheath during live imaging. PMID- 29155729 TI - Sample Preparation and Analysis of RNASeq-based Gene Expression Data from Zebrafish. AB - The analysis of global gene expression changes is a valuable tool for identifying novel pathways underlying observed phenotypes. The zebrafish is an excellent model for rapid assessment of whole transcriptome from whole animal or individual cell populations due to the ease of isolation of RNA from large numbers of animals. Here a protocol for global gene expression analysis in zebrafish embryos using RNA sequencing (RNASeq) is presented. We describe preparation of RNA from whole embryos or from cell populations obtained using cell sorting in transgenic animals. We also describe an approach for analysis of RNASeq data to identify enriched pathways and Gene Ontology (GO) terms in global gene expression data sets. Finally, we provide a protocol for validation of gene expression changes using quantitative reverse transcriptase PCR (qRT-PCR). These protocols can be used for comparative analysis of control and experimental sets of zebrafish to identify novel gene expression changes, and provide molecular insight into phenotypes of interest. PMID- 29155727 TI - MicroRNA Based Liquid Biopsy: The Experience of the Plasma miRNA Signature Classifier (MSC) for Lung Cancer Screening. AB - The development of a minimally invasive test, such as liquid biopsy, for early lung cancer detection in its preclinical phase is crucial to improve the outcome of this deadly disease. MicroRNAs (miRNAs) are tissue specific, small, non-coding RNAs regulating gene expression, which may act as extracellular messengers of biological signals derived from the cross-talk between the tumor and its surrounding microenvironment. They could thus represent ideal candidates for early detection of lung cancer. In this work, a methodological workflow for the prospective validation of a circulating miRNA test using custom made microfluidic cards and quantitative Real-Time PCR in plasma samples of volunteers enrolled in a lung cancer screening trial is proposed. In addition, since the release of hemolysis-related miRNAs and more general technical issues may affect the analysis, the quality control steps included in the standard operating procedures are also presented. The protocol is reproducible and gives reliable quantitative results; however, when using large clinical series, both pre-analytical and analytical features should be cautiously evaluated. PMID- 29155728 TI - Liquid-cell Transmission Electron Microscopy for Tracking Self-assembly of Nanoparticles. AB - Drying a nanoparticle dispersion is a versatile way to create self-assembled structures of nanoparticles, but the mechanism of this process is not fully understood. We have traced the trajectories of individual nanoparticles using liquid-cell transmission electron microscopy (TEM) to investigate the mechanism of the assembly process. Herein, we present the protocols used for liquid-cell TEM studies of the self-assembly mechanism. First, we introduce the detailed synthetic protocols used to produce uniformly sized platinum and lead selenide nanoparticles. Next, we present the microfabrication processes used to produce liquid cells with silicon nitride or silicon windows and then describe the loading and imaging procedures of the liquid-cell TEM technique. Several notes are included to provide helpful tips for the entire process, including how to manage the fragile cell windows. The individual motions of nanoparticles tracked by liquid-cell TEM revealed that changes in the solvent boundaries caused by evaporation affected the self-assembly process of nanoparticles. The solvent boundaries drove nanoparticles to primarily form amorphous aggregates, followed by flattening of the aggregates to produce a 2-dimensional (2D) self-assembled structure. These behaviors are also observed for different nanoparticle types and different liquid-cell compositions. PMID- 29155730 TI - Long-term Live Imaging Device for Improved Experimental Manipulation of Zebrafish Larvae. AB - The zebrafish larva is an important model organism for both developmental biology and wound healing. Further, the zebrafish larva is a valuable system for live high-resolution microscopic imaging of dynamic biological phenomena in space and time with cellular resolution. However, the traditional method of agarose encapsulation for live imaging can impede larval development and tissue regrowth. Therefore, this manuscript describes the zWEDGI (zebrafish Wounding and Entrapment Device for Growth and Imaging), which was designed and fabricated as a functionally compartmentalized device to orient larvae for high-resolution microscopy while permitting caudal fin transection within the device and subsequent unrestrained tail development and re-growth. This device allows for wounding and long-term imaging while maintaining viability. Given that the zWEDGI mold is 3D printed, the customizability of its geometries make it easily modified for diverse zebrafish imaging applications. Furthermore, the zWEDGI offers numerous benefits, such as access to the larva during experimentation for wounding or for the application of reagents, paralleled orientation of multiple larvae for streamlined imaging, and reusability of the device. PMID- 29155731 TI - The Nematode Caenorhabditis Elegans - A Versatile In Vivo Model to Study Host microbe Interactions. AB - We demonstrate a method using Caenorhabditis elegans as a model host to study microbial interaction. Microbes are introduced via the diet making the intestine the primary location for disease. The nematode intestine structurally and functionally mimics mammalian intestines and is transparent making it amenable to microscopic study of colonization. Here we show that pathogens can cause disease and death. We are able to identify microbial mutants that show altered virulence. Its conserved innate response to biotic stresses makes C. elegans an excellent system to probe facets of host innate immune interactions. We show that hosts with mutations in the dual oxidase gene cannot produce reactive oxygen species and are unable to resist microbial insult. We further demonstrate the versatility of the presented survival assay by showing that it can be used to study the effects of inhibitors of microbial growth. This assay may also be used to discover fungal virulence factors as targets for the development of novel antifungal agents, as well as provide an opportunity to further uncover host microbe interactions. The design of this assay lends itself well to high throughput whole-genome screens, while the ability to cryo-preserve worms for future use makes it a cost-effective and attractive whole animal model to study. PMID- 29155733 TI - The Modular Design and Production of an Intelligent Robot Based on a Closed-Loop Control Strategy. AB - Intelligent robots are part of a new generation of robots that are able to sense the surrounding environment, plan their own actions and eventually reach their targets. In recent years, reliance upon robots in both daily life and industry has increased. The protocol proposed in this paper describes the design and production of a handling robot with an intelligent search algorithm and an autonomous identification function. First, the various working modules are mechanically assembled to complete the construction of the work platform and the installation of the robotic manipulator. Then, we design a closed-loop control system and a four-quadrant motor control strategy, with the aid of debugging software, as well as set steering gear identity (ID), baud rate and other working parameters to ensure that the robot achieves the desired dynamic performance and low energy consumption. Next, we debug the sensor to achieve multi-sensor fusion to accurately acquire environmental information. Finally, we implement the relevant algorithm, which can recognize the success of the robot's function for a given application. The advantage of this approach is its reliability and flexibility, as the users can develop a variety of hardware construction programs and utilize the comprehensive debugger to implement an intelligent control strategy. This allows users to set personalized requirements based on their needs with high efficiency and robustness. PMID- 29155732 TI - Fabrication and Characterization of Griffithsin-modified Fiber Scaffolds for Prevention of Sexually Transmitted Infections. AB - Electrospun fibers (EFs) have been widely used in a variety of therapeutic applications; however, they have only recently been applied as a technology to prevent and treat sexually transmitted infections (STIs). Moreover, many EF technologies focus on encapsulating the active agent, relative to utilizing the surface to impart biofunctionality. Here we describe a method to fabricate and surface-modify poly(lactic-co-glycolic) acid (PLGA) electrospun fibers, with the potent antiviral lectin Griffithsin (GRFT). PLGA is an FDA-approved polymer that has been widely used in drug delivery due to its outstanding chemical and biocompatible properties. GRFT is a natural, potent, and safe lectin that possesses broad activity against numerous viruses including human immunodeficiency virus type 1 (HIV-1). When combined, GRFT-modified fibers have demonstrated potent inactivation of HIV-1 in vitro. This manuscript describes the methods to fabricate and characterize GRFT-modified EFs. First, PLGA is electrospun to create a fiber scaffold. Fibers are subsequently surface-modified with GRFT using 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N hydroxysuccinimide (NHS)chemistry. Scanning electron microscopy (SEM) was used to assess the size and morphology of surface-modified formulations. Additionally, a gp120 or hemagglutinin (HA)-based ELISA may be used to quantify the amount of GRFT conjugated to, as well as GRFT desorption from the fiber surface. This protocol can be more widely applied to fabricate fibers that are surface-modified with a variety of different proteins. PMID- 29155734 TI - Structural Characterization of Mannan Cell Wall Polysaccharides in Plants Using PACE. AB - Plant cell wall polysaccharides are notoriously difficult to analyze, and most methods require expensive equipment, skilled operators, and large amounts of purified material. Here, we describe a simple method for gaining detailed polysaccharide structural information, including resolution of structural isomers. For polysaccharide analysis by gel electrophoresis (PACE), plant cell wall material is hydrolyzed with glycosyl hydrolases specific to the polysaccharide of interest (e.g., mannanases for mannan). Large format polyacrylamide gels are then used to separate the released oligosaccharides, which have been fluorescently labeled. Gels can be visualized with a modified gel imaging system (see Table of Materials). The resulting oligosaccharide fingerprint can either be compared qualitatively or, with replication, quantitatively. Linkage and branching information can be established using additional glycosyl hydrolases (e.g., mannosidases and galactosidases). Whilst this protocol describes a method for analyzing glucomannan structure, it can be applied to any polysaccharide for which characterized glycosyl hydrolases exist. Alternatively, it can be used to characterize novel glycosyl hydrolases using defined polysaccharide substrates. PMID- 29155735 TI - Quantification of Monocyte Transmigration and Foam Cell Formation from Individuals with Chronic Inflammatory Conditions. AB - Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Atherosclerosis, a leading cause of CAD, is initiated by the transmigration of innate immune monocytes to inflammatory sites of deposited lipid called fatty streaks, which are present in arterial walls of medium to large arteries. The key pathogenic feature of lesions at this early stage of atherosclerosis is the maturation of monocytes which migrate into arteries to form foam cells or lipid-laden macrophages. Considerable evidence supports the hypothesis that risk of atherosclerosis is increased by chronic inflammatory conditions accompanying diseases such as rheumatoid arthritis and HIV, as well as general ageing, and that this risk is predicted by monocyte activation. While mouse models provide a good platform to investigate the role of monocytes in atherogenesis in vivo, they require genetic alteration of natural cholesterol metabolism and drastic alteration of normal mouse diets, and have limited suitability for the study of atherogenic influences of human comorbid diseases. This motivated us to develop a human in vitro model to measure the atherogenic potential of monocytes isolated from individuals with defined disease states. Currently, human in vitro models are limiting in that they evaluate monocyte transmigration and foam cell formation in isolation. Here we describe a protocol in which monocytes isolated from patient blood transmigrate across human endothelial cells into a type 1 collagen matrix, and their propensity to mature into foam cells in the presence or absence of exogenous lipid is measured. The protocol has been validated for the use of human monocytes purified from individuals with HIV infection and elderly HIV uninfected individuals. This model is versatile and allows monocyte transmigration and foam cell formation to be evaluated using either microscopy or flow cytometry as well as allowing the assessment of atherogenic factors present in serum or plasma. PMID- 29155736 TI - High Resolution Fluorescent In Situ Hybridization in Drosophila Embryos and Tissues Using Tyramide Signal Amplification. AB - In our efforts to determine the patterns of expression and subcellular localization of Drosophila RNAs on a genome-wide basis, and in a variety of tissues, we have developed numerous modifications and improvements to our original fluorescent in situ hybridization (FISH) protocol. To facilitate throughput and cost effectiveness, all steps, from probe generation to signal detection, are performed using exon 96-well microtiter plates. Digoxygenin (DIG) labelled antisense RNA probes are produced using either cDNA clones or genomic DNA as templates. After tissue fixation and permeabilization, probes are hybridized to transcripts of interest and then detected using a succession of anti-DIG antibody conjugated to biotin, streptavidin conjugated to horseradish peroxidase (HRP) and fluorescently conjugated tyramide, which in the presence of HRP, produces a highly reactive intermediate that binds to electron dense regions of immediately adjacent proteins. These amplification and localization steps produce a robust and highly localized signal that facilitates both cellular and subcellular transcript localization. The protocols provided have been optimized to produce highly specific signals in a variety of tissues and developmental stages. References are also provided for additional variations that allow the simultaneous detection of multiple transcripts, or transcripts and proteins, at the same time. PMID- 29155737 TI - Synthesis and Evaluation of a Ruthenium-based Mitochondrial Calcium Uptake Inhibitor. AB - We detail the synthesis and purification of a mitochondrial calcium uptake inhibitor, [(OH2)(NH3)4Ru(u-O)Ru(NH3)4(OH2)]5+. The optimized synthesis of this compound commences from [Ru(NH3)5Cl]Cl2 in 1 M NH4OH in a closed container, yielding a green solution. Purification is accomplished with cation-exchange chromatography. This compound is characterized and verified to be pure by UV-vis and IR spectroscopy. The mitochondrial calcium uptake inhibitory properties are assessed in permeabilized HeLa cells by fluorescence spectroscopy. PMID- 29155738 TI - Imaging Amyloid Tissues Stained with Luminescent Conjugated Oligothiophenes by Hyperspectral Confocal Microscopy and Fluorescence Lifetime Imaging. AB - Proteins that deposit as amyloid in tissues throughout the body can be the cause or consequence of a large number of diseases. Among these we find neurodegenerative diseases such as Alzheimer's and Parkinson's disease afflicting primarily the central nervous system, and systemic amyloidosis where serum amyloid A, transthyretin and IgG light chains deposit as amyloid in liver, carpal tunnel, spleen, kidney, heart, and other peripheral tissues. Amyloid has been known and studied for more than a century, often using amyloid specific dyes such as Congo red and Thioflavin T (ThT) or Thioflavin (ThS). In this paper, we present heptamer-formyl thiophene acetic acid (hFTAA) as an example of recently developed complements to these dyes called luminescent conjugated oligothiophenes (LCOs). hFTAA is easy to use and is compatible with co-staining in immunofluorescence or with other cellular markers. Extensive research has proven that hFTAA detects a wider range of disease associated protein aggregates than conventional amyloid dyes. In addition, hFTAA can also be applied for optical assignment of distinct aggregated morphotypes to allow studies of amyloid fibril polymorphism. While the imaging methodology applied is optional, we here demonstrate hyperspectral imaging (HIS), laser scanning confocal microscopy and fluorescence lifetime imaging (FLIM). These examples show some of the imaging techniques where LCOs can be used as tools to gain more detailed knowledge of the formation and structural properties of amyloids. An important limitation to the technique is, as for all conventional optical microscopy techniques, the requirement for microscopic size of aggregates to allow detection. Furthermore, the aggregate should comprise a repetitive beta-sheet structure to allow for hFTAA binding. Excessive fixation and/or epitope exposure that modify the aggregate structure or conformation can render poor hFTAA binding and hence pose limitations to accurate imaging. PMID- 29155740 TI - Creation of a Rodent Model of Abdominal Aortic Aneurysm by Blocking Adventitial Vasa Vasorum Perfusion. AB - The adventitial vasa vasorum (VV) provides oxygen and nourishment to the aortic wall. Hypoxia in the aortic wall can cause enlarged abdominal aortic aneurysms (AAAs). This article introduces and describes a standard protocol used to induce AAAs through adventitial VV hypoperfusion created with a combination of polyurethane catheter insertion into the aortic lumen and suture ligation of the infrarenal abdominal aorta. The protocol involves the use of male rats weighing 300-400 g, which are provided food and water ad libitum. After laparotomy with a ventral midline abdominal incision, exfoliation of the aorta is performed, which blocks blood flow from the perivascular tissue. Aortotomy involving a small incision adjacent to the renal artery branches is performed, and a polyurethane catheter is inserted using an 18-gauge indwelling needle. After repairing the incision, tight ligation of the aorta over the catheter blocks VV blood flow from the proximal direction through the aortic wall without disturbing the aortic blood flow. This technique can induce an AAA with progressive aortic dilatation. The greatest benefit of this model is that VV hypoperfusion causes tissue hypoxia and the development of an infrarenal AAA, which has morphological and pathological characteristics similar to those of a human AAA. PMID- 29155739 TI - Standardized Method for High-throughput Sterilization of Arabidopsis Seeds. AB - Arabidopsis thaliana (Arabidopsis) seedlings often need to be grown on sterile media. This requires prior seed sterilization to prevent the growth of microbial contaminants present on the seed surface. Currently, Arabidopsis seeds are sterilized using two distinct sterilization techniques in conditions that differ slightly between labs and have not been standardized, often resulting in only partially effective sterilization or in excessive seed mortality. Most of these methods are also not easily scalable to a large number of seed lines of diverse genotypes. As technologies for high-throughput analysis of Arabidopsis continue to proliferate, standardized techniques for sterilizing large numbers of seeds of different genotypes are becoming essential for conducting these types of experiments. The response of a number of Arabidopsis lines to two different sterilization techniques was evaluated based on seed germination rate and the level of seed contamination with microbes and other pathogens. The treatments included different concentrations of sterilizing agents and times of exposure, combined to determine optimal conditions for Arabidopsis seed sterilization. Optimized protocols have been developed for two different sterilization methods: bleach (liquid-phase) and chlorine (Cl2) gas (vapor-phase), both resulting in high seed germination rates and minimal microbial contamination. The utility of these protocols was illustrated through the testing of both wild type and mutant seeds with a range of germination potentials. Our results show that seeds can be effectively sterilized using either method without excessive seed mortality, although detrimental effects of sterilization were observed for seeds with lower than optimal germination potential. In addition, an equation was developed to enable researchers to apply the standardized chlorine gas sterilization conditions to airtight containers of different sizes. The protocols described here allow easy, efficient, and inexpensive seed sterilization for a large number of Arabidopsis lines. PMID- 29155741 TI - Directed Differentiation of Primitive and Definitive Hematopoietic Progenitors from Human Pluripotent Stem Cells. AB - One of the major goals for regenerative medicine is the generation and maintenance of hematopoietic stem cells (HSCs) derived from human pluripotent stem cells (hPSCs). Until recently, efforts to differentiate hPSCs into HSCs have predominantly generated hematopoietic progenitors that lack HSC potential, and instead resemble yolk sac hematopoiesis. These resulting hematopoietic progenitors may have limited utility for in vitro disease modeling of various adult hematopoietic disorders, particularly those of the lymphoid lineages. However, we have recently described methods to generate erythro-myelo-lymphoid multilineage definitive hematopoietic progenitors from hPSCs using a stage specific directed differentiation protocol, which we outline here. Through enzymatic dissociation of hPSCs on basement membrane matrix-coated plasticware, embryoid bodies (EBs) are formed. EBs are differentiated to mesoderm by recombinant BMP4, which is subsequently specified to the definitive hematopoietic program by the GSK3beta inhibitor, CHIR99021. Alternatively, primitive hematopoiesis is specified by the PORCN inhibitor, IWP2. Hematopoiesis is further driven through the addition of recombinant VEGF and supportive hematopoietic cytokines. The resulting hematopoietic progenitors generated using this method have the potential to be used for disease and developmental modeling, in vitro. PMID- 29155742 TI - Isolation of Intact, Whole Mouse Mammary Glands for Analysis of Extracellular Matrix Expression and Gland Morphology. AB - The goal of this procedure was to harvest the #4 abdominal mammary glands from female nulliparous mice in order to assess ECM expression and ductal architecture. Here, a small pocket below the skin was created using Mayo scissors, allowing separation of the glands within the subcutaneous tissue from the underlying peritoneum. Visualization of the glands was aided by the use of 3.5x-R surgical micro loupes. The pelt was inverted and pinned back allowing identification of the intact mammary fat pads. Each of the #4 abdominal glands was bluntly dissected by sliding the scalpel blade laterally between the subcutaneous layer and the glands. Immediately post-harvest, glands were placed in 10% neutral buffered formalin for subsequent tissue processing. Excision of the entire gland is advantageous because it primarily eliminates the risk of excluding important tissue-wide interactions between ductal epithelial cells and other microenvironmental cellular populations that could be missed in a partial biopsy. One drawback of the methodology is the use of serial sections from fixed tissues which limits analyses of ductal morphogenesis and protein expression to discrete locations within the gland. As such, changes in ductal architecture and protein expression in 3 dimensions (3D) is not readily obtainable. Overall, the technique is applicable to studies requiring whole intact murine mammary glands for downstream investigations such as developmental ductal morphogenesis or breast cancer. PMID- 29155743 TI - Snap Chip for Cross-reactivity-free and Spotter-free Multiplexed Sandwich Immunoassays. AB - Multiplexed protein analysis has shown superior diagnostic sensitivity and accuracy compared to single proteins. Antibody microarrays allow for thousands of micro-scale immunoassays performed simultaneously on a single chip. Sandwich assay format improves assay specificity by detecting each target with two antibodies, but suffers from cross-reactivity between reagents thus limiting their multiplexing capabilities. Antibody colocalization microarray (ACM) has been developed for cross-reactivity-free multiplexed protein detection, but requires an expensive spotter on-site for microarray fabrication during assays. In this work, we demonstrate a snap chip technology that transfers reagent from microarray-to-microarray by simply snapping two chips together, thus no spotter is needed during the sample incubation and subsequent application of detection antibodies (dAbs) upon storage of pre-spotted slides, dissociating the slide preparation from assay execution. Both single and double transfer methods are presented to achieve accurate alignment between the two microarrays and the slide fabrication for both methods are described. Results show that <40 MUm alignment has been achieved with double transfer, reaching an array density of 625 spots/cm2. A 50-plexed immunoassay has been conducted to demonstrate the usability of the snap chip in multiplexed protein analysis. Limits of detection of 35 proteins are in the range of pg/mL. PMID- 29155744 TI - Capturing Flow-weighted Water and Suspended Particulates from Agricultural Canals During Drainage Events. AB - The purpose of this study is to describe the methods used to capture flow weighted water and suspended particulates from farm canals during drainage discharge events. Farm canals can be enriched by nutrients such as phosphorus (P) that are susceptible to transport. Phosphorus in the form of suspended particulates can significantly contribute to the overall P loads in drainage water. A settling tank experiment was conducted to capture suspended particulates during discrete drainage events. Farm canal discharge water was collected in a series of two 200 L settling tanks over the entire duration of the drainage event, so as to represent a composite subsample of the water being discharged. Imhoff settling cones are ultimately used to settle out the suspended particulates. This is achieved by siphoning water from the settling tanks via the cones. The particulates are then collected for physico-chemical analyses. PMID- 29155745 TI - Hand-held Clinical Photoacoustic Imaging System for Real-time Non-invasive Small Animal Imaging. AB - Translation of photoacoustic imaging into the clinic is a major challenge. Handheld real-time clinical photoacoustic imaging systems are very rare. Here, we report a combined photoacoustic and clinical ultrasound imaging system by integrating an ultrasound probe with light delivery for small animal imaging. We demonstrate this by showing sentinel lymph node imaging in small animals along with minimally invasive real-time needle guidance. A clinical ultrasound platform with access to raw channel data allows the integration of photoacoustic imaging leading to a handheld real-time clinical photoacoustic imaging system. Methylene blue was used for sentinel lymph node imaging at 675 nm wavelength. Additionally, needle guidance with dual modal ultrasound and photoacoustic imaging was shown using the imaging system. Depth imaging of up to 1.5 cm was demonstrated with a 10 Hz laser at a photoacoustic imaging frame rate of 5 frames per second. PMID- 29155746 TI - Saturated Fatty Acids Induce Ceramide-associated Macrophage Cell Death. AB - Macrophages highly express epidermal fatty acid-binding protein and adipose fatty acid-binding protein. They actively uptake saturated and unsaturated fatty acids, which might play a critical role in regulating their immune functions. Numerous studies have shown that various fatty acids, saturated or unsaturated, may possess different impacts on cell growth and function. However, the approaches used for fatty acid preparation vary, which may lead to non-physiological results. Serum albumin, a natural carrier for fatty acids in mammalian peripheral blood, is recommended for forming a conjugate complex with the sodium salt of fatty acids to study fatty acid function in mammalian cells, thus minimizing the toxicity of fatty acid soap. Thus, a simple, relatively quick heating and sonicating method is developed and presented here for BSA-fatty acid conjugate formation. We describe a protocol using saturated fatty acids, especially stearic acids to induce severe cell death in mouse bone-marrow derived macrophages. We further demonstrate that saturated fatty acid-induced cell death is positively associated with accumulated cellular ceramide levels. This method can be extended for studies of the impact of fatty acid on other mammalian cells. PMID- 29155747 TI - Isolation of Salmonella typhimurium-containing Phagosomes from Macrophages. AB - Salmonella typhimurium is a facultative intracellular bacterium that causes gastroenteritis in humans. After invasion of the lamina propria, S. typhimurium bacteria are quickly detected and phagocytized by macrophages, and contained in vesicles known as phagosomes in order to be degraded. Isolation of S. typhimurium containing phagosomes have been widely used to study how S. typhimurium infection alters the process of phagosome maturation to prevent bacterial degradation. Classically, the isolation of bacteria-containing phagosomes has been performed by sucrose gradient centrifugation. However, this process is time-consuming, and requires specialized equipment and a certain degree of dexterity. Described here is a simple and quick method for the isolation of S. typhimurium-containing phagosomes from macrophages by coating the bacteria with biotin-streptavidin conjugated magnetic beads. Phagosomes obtained by this method can be suspended in any buffer of choice, allowing the utilization of isolated phagosomes for a broad range of assays, such as protein, metabolite, and lipid analysis. In summary, this method for the isolation of S. typhimurium-containing phagosomes is specific, efficient, rapid, requires minimum equipment, and is more versatile than the classical method of isolation by sucrose gradient-ultracentrifugation. PMID- 29155748 TI - Using In Vitro Live-cell Imaging to Explore Chemotherapeutics Delivered by Lipid based Nanoparticles. AB - Conventional imaging techniques can provide detailed information about cellular processes. However, this information is based on static images in an otherwise dynamic system, and successive phases are easily overlooked or misinterpreted. Live-cell imaging and time-lapse microscopy, in which living cells can be followed for hours or even days in a more or less continuous fashion, are therefore very informative. The protocol described here allows for the investigation of the fate of chemotherapeutic nanoparticles after the delivery of doxorubicin (dox) in living cells. Dox is an intercalating agent that must be released from its nanocarrier to become biologically active. In spite of its clinical registration for more than two decades, its uptake, breakdown, and drug release are still not fully understood. This article explores the hypothesis that lipid-based nanoparticles are taken up by the tumor cells and are slowly degraded. Released dox is then translocated to the nucleus. To prevent fixation artifacts, live-cell imaging and time-lapse microscopy, described in this experimental procedure, can be applied. PMID- 29155749 TI - Immobilization of Caenorhabditis elegans to Analyze Intracellular Transport in Neurons. AB - Axonal transport and intraflagellar transport (IFT) are essential for axon and cilia morphogenesis and function. Kinesin superfamily proteins and dynein are molecular motors that regulate anterograde and retrograde transport, respectively. These motors use microtubule networks as rails. Caenorhabditis elegans (C. elegans) is a powerful model organism to study axonal transport and IFT in vivo. Here, I describe a protocol to observe axonal transport and IFT in living C. elegans. Transported cargo can be visualized by tagging cargo proteins using fluorescent proteins such as green fluorescent protein (GFP). C. elegans is transparent and GFP-tagged cargo proteins can be expressed in specific cells under cell-specific promoters. Living worms can be fixed by microbeads on 10% agarose gel without killing or anesthetizing the worms. Under these conditions, cargo movement can be directly observed in the axons and cilia of living C. elegans without dissection. This method can be applied to the observation of any cargo molecule in any cells by modifying the target proteins and/or the cells they are expressed in. Most basic proteins such as molecular motors and adaptor proteins that are involved in axonal transport and IFT are conserved in C. elegans. Compared to other model organisms, mutants can be obtained and maintained more easily in C. elegans. Combining this method with various C. elegans mutants can clarify the molecular mechanisms of axonal transport and IFT. PMID- 29155750 TI - Ground State Depletion Super-resolution Imaging in Mammalian Cells. AB - Advances in fluorescent microscopy and cell biology are intimately correlated, with the enhanced ability to visualize cellular events often leading to dramatic leaps in our understanding of how cells function. The development and availability of super-resolution microscopy has considerably extended the limits of optical resolution from ~250-20 nm. Biologists are no longer limited to describing molecular interactions in terms of colocalization within a diffraction limited area, rather it is now possible to visualize the dynamic interactions of individual molecules. Here, we outline a protocol for the visualization and quantification of cellular proteins by ground-state depletion microscopy for fixed cell imaging. We provide examples from two different membrane proteins, an element of the endoplasmic reticulum translocon, sec61beta, and a plasma membrane localized voltage-gated L-type Ca2+ channel (CaV1.2). Discussed are the specific microscope parameters, fixation methods, photo-switching buffer formulation, and pitfalls and challenges of image processing. PMID- 29155751 TI - Dissection and Immunofluorescent Staining of Mushroom Body and Photoreceptor Neurons in Adult Drosophila melanogaster Brains. AB - Nervous system development involves a sequential series of events that are coordinated by several signaling pathways and regulatory networks. Many of the proteins involved in these pathways are evolutionarily conserved between mammals and other eukaryotes, such as the fruit fly Drosophila melanogaster, suggesting that similar organizing principles exist during the development of these organisms. Importantly, Drosophila has been used extensively to identify cellular and molecular mechanisms regulating processes that are required in mammals including neurogenesis, differentiation, axonal guidance, and synaptogenesis. Flies have also been used successfully to model a variety of human neurodevelopmental diseases. Here we describe a protocol for the step-by-step microdissection, fixation, and immunofluorescent localization of proteins within the adult Drosophila brain. This protocol focuses on two example neuronal populations, mushroom body neurons and retinal photoreceptors, and includes optional steps to trace individual mushroom body neurons using Mosaic Analysis with a Repressible Cell Marker (MARCM) technique. Example data from both wild type and mutant brains are shown along with a brief description of a scoring criteria for axonal guidance defects. While this protocol highlights two well established antibodies for investigating the morphology of mushroom body and photoreceptor neurons, other Drosophila brain regions and the localization of proteins within other brain regions can also be investigated using this protocol. PMID- 29155752 TI - Sagittal Plane Kinematic Gait Analysis in C57BL/6 Mice Subjected to MOG35-55 Induced Experimental Autoimmune Encephalomyelitis. AB - Kinematic gait analysis in the sagittal plane has frequently been used to characterize motor deficits in multiple sclerosis (MS). We describe the application of these techniques to identify gait deficits in a mouse model of MS, known as experimental autoimmune encephalomyelitis (EAE). Paralysis and motor deficits in mice subjected to EAE are typically assessed using a clinical scoring scale. However, this scale yields only ordinal data that provides little information about the precise nature of the motor deficits. EAE disease severity has also been assessed by rotarod performance, which provides a measure of general motor coordination. By contrast, kinematic gait analysis of the hind limb in the sagittal plane generates highly precise information about how movement is impaired. To perform this procedure, reflective markers are placed on a hind limb to detect joint movement while a mouse is walking on a treadmill. Motion analysis software is used to measure movement of the markers during walking. Kinematic gait parameters are then derived from the resultant data. We show how these gait parameters can be used to quantify impaired movements of the hip, knee, and ankle joints in EAE. These techniques may be used to better understand disease mechanisms and identify potential treatments for MS and other neurodegenerative disorders that impair mobility. PMID- 29155754 TI - A Method for Growing Bio-memristors from Slime Mold. AB - Our research is aimed at gaining a better understanding of the electronic properties of organisms in order to engineer novel bioelectronic systems and computing architectures based on biology. This specific paper focuses on harnessing the unicellular slime mold Physarum polycephalum to develop bio memristors (or biological memristors) and bio-computing devices. The memristor is a resistor that possesses memory. It is the 4th fundamental passive circuit element (the other three are the resistor, the capacitor, and the inductor), which is paving the way for the design of new kinds of computing systems; e.g., computers that might relinquish the distinction between storage and a central processing unit. When applied with an AC voltage, the current vs. voltage characteristic of a memristor is a pinched hysteresis loop. It has been shown that P. polycephalum produces pinched hysteresis loops under AC voltages and displays adaptive behavior that is comparable with the functioning of a memristor. This paper presents the method that we developed for implementing bio memristors with P. polycephalum and introduces the development of a receptacle to culture the organism, which facilitates its deployment as an electronic circuit component. Our method has proven to decrease growth time, increase component lifespan, and standardize electrical observations. PMID- 29155753 TI - Using Retinal Imaging to Study Dementia. AB - The retina offers a unique "window" to study pathophysiological processes of dementia in the brain, as it is an extension of the central nervous system (CNS) and shares prominent similarities with the brain in terms of embryological origin, anatomical features and physiological properties. The vascular and neuronal structure in the retina can now be visualized easily and non-invasively using retinal imaging techniques, including fundus photography and optical coherence tomography (OCT), and quantified semi-automatically using computer assisted analysis programs. Studying the associations between vascular and neuronal changes in the retina and dementia could improve our understanding of dementia and, potentially, aid in diagnosis and risk assessment. This protocol aims to describe a method of quantifying and analyzing retinal vasculature and neuronal structure, which are potentially associated with dementia. This protocol also provides examples of retinal changes in subjects with dementia, and discusses technical issues and current limitations of retinal imaging. PMID- 29155755 TI - In Vivo Detection and Analysis of Rb Protein SUMOylation in Human Cells. AB - The post-translational modifications of proteins are critical for the proper regulation of intracellular signal transduction. Among these modifications, small ubiquitin-related modifier (SUMO) is a ubiquitin-like protein that is covalently attached to the lysine residues of a variety of target proteins to regulate cellular processes, such as gene transcription, DNA repair, protein interaction and degradation, subcellular transport, and signal transduction. The most common approach to detecting protein SUMOylation is based on the expression and purification of recombinant tagged proteins in bacteria, allowing for an in vitro biochemical reaction which is simple and suitable for addressing mechanistic questions. However, due to the complexity of the process of SUMOylation in vivo, it is more challenging to detect and analyze protein SUMOylation in cells, especially when under endogenous conditions. A recent study by the authors of this paper revealed that endogenous retinoblastoma (Rb) protein, a tumor suppressor that is vital to the negative regulation of the cell cycle progression, is specifically SUMOylated at the early G1 phase. This paper describes a protocol for the detection and analysis of Rb SUMOylation under both endogenous and exogenous conditions in human cells. This protocol is appropriate for the phenotypical and functional investigation of the SUMO-modification of Rb, as well as many other SUMO-targeted proteins, in human cells. PMID- 29155756 TI - Transcranial Electrical Brain Stimulation in Alert Rodents. AB - Transcranial electrical brain stimulation can modulate cortical excitability and plasticity in humans and rodents. The most common form of stimulation in humans is transcranial direct current stimulation (tDCS). Less frequently, transcranial alternating current stimulation (tACS) or transcranial random noise stimulation (tRNS), a specific form of tACS using an electrical current applied randomly within a pre-defined frequency range, is used. The increase of noninvasive electrical brain stimulation research in humans, both for experimental and clinical purposes, has yielded an increased need for basic, mechanistic, safety studies in animals. This article describes a model for transcranial electrical brain stimulation (tES) through the intact skull targeting the motor system in alert rodents. The protocol provides step-by-step instructions for the surgical set-up of a permanent epicranial electrode socket combined with an implanted counter electrode on the chest. By placing a stimulation electrode into the epicranial socket, different electrical stimulation types, comparable to tDCS, tACS, and tRNS in humans, can be delivered. Moreover, the practical steps for tES in alert rodents are introduced. The applied current density, stimulation duration, and stimulation type may be chosen depending on the experimental needs. The caveats, advantages, and disadvantages of this set-up are discussed, as well as safety and tolerability aspects. PMID- 29155757 TI - Dissection of Human Retina and RPE-Choroid for Proteomic Analysis. AB - The human retina is composed of the sensory neuroretina and the underlying retinal pigmented epithelium (RPE), which is firmly complexed to the vascular choroid layer. Different regions of the retina are anatomically and molecularly distinct, facilitating unique functions and demonstrating differential susceptibility to disease. Proteomic analysis of each of these regions and layers can provide vital insights into the molecular process of many diseases, including Age-Related Macular Degeneration (AMD), diabetes mellitus, and glaucoma. However, separation of retinal regions and layers is essential before quantitative proteomic analysis can be accomplished. Here, we describe a method for dissection and collection of the foveal, macular, and peripheral retinal regions and underlying RPE-choroid complex, involving regional punch biopsies and manual removal of tissue layers from a human eye.One-dimensional SDS-PAGE as well as downstream proteomic analysis, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS), can be used to identify proteins in each dissected retinal layer, revealing molecular biomarkers for retinal disease. PMID- 29155758 TI - Methodology for Developing Life Tables for Sessile Insects in the Field Using the Whitefly, Bemisia tabaci, in Cotton As a Model System. AB - Life tables provide a means of measuring the schedules of birth and death from populations over time. They also can be used to quantify the sources and rates of mortality in populations, which has a variety of applications in ecology, including agricultural ecosystems. Horizontal, or cohort-based, life tables provide for the most direct and accurate method of quantifying vital population rates because they follow a group of individuals in a population from birth to death. Here, protocols are presented for conducting and analyzing cohort-based life tables in the field that takes advantage of the sessile nature of the immature life stages of a global insect pest, Bemisia tabaci. Individual insects are located on the underside of cotton leaves and are marked by drawing a small circle around the insect with a non-toxic pen. This insect can then be observed repeatedly over time with the aid of hand lenses to measure development from one stage to the next and to identify stage-specific causes of death associated with natural and introduced mortality forces. Analyses explain how to correctly measure multiple mortality forces that act contemporaneously within each stage and how to use such data to provide meaningful population dynamic metrics. The method does not directly account for adult survival and reproduction, which limits inference to dynamics of immature stages. An example is presented that focused on measuring the impact of bottom-up (plant quality) and top-down (natural enemies) effects on the mortality dynamics of B. tabaci in the cotton system. PMID- 29155759 TI - Transplantation of Schwann Cells Inside PVDF-TrFE Conduits to Bridge Transected Rat Spinal Cord Stumps to Promote Axon Regeneration Across the Gap. AB - Among various models for spinal cord injury in rats, the contusion model is the most often used because it is the most common type of human spinal cord injury. The complete transection model, although not as clinically relevant as the contusion model, is the most rigorous method to evaluate axon regeneration. In the contusion model, it is difficult to distinguish regenerated from sprouted or spared axons due to the presence of remaining tissue post injury. In the complete transection model, a bridging method is necessary to fill the gap and create continuity from the rostral to the caudal stumps in order to evaluate the effectiveness of the treatments. A reliable bridging surgery is essential to test outcome measures by reducing the variability due to the surgical method. The protocols described here are used to prepare Schwann cells (SCs) and conduits prior to transplantation, complete transection of the spinal cord at thoracic level 8 (T8), insert the conduit, and transplant SCs into the conduit. This approach also uses in situ gelling of an injectable basement membrane matrix with SC transplantation that allows improved axon growth across the rostral and caudal interfaces with the host tissue. PMID- 29155760 TI - Echocardiographic and Histological Examination of Cardiac Morphology in the Mouse. AB - An increasing number of genetically modified mouse models has become available in recent years. Moreover, the number of pharmacological studies performed in mice is high. Phenotypic characterization of these mouse models also requires the examination of cardiac function and morphology. Echocardiography and magnetic resonance imaging (MRI) are commonly used approaches to characterize cardiac function and morphology in mice. Echocardiographic and MRI equipment specialized for use in small rodents is expensive and requires a dedicated space. This protocol describes cardiac measurements in mice using a clinical echocardiographic system with a 15 MHz human vascular probe. Measurements are performed on anesthetized adult mice. At least three image sequences are recorded and analyzed for each animal in M-mode in the parasternal short-axis view. Afterwards, cardiac histological examination is performed, and cardiomyocyte diameters are determined on hematoxylin-eosin- or wheat germ agglutinin (WGA) stained paraffin sections. Vessel density is determined morphometrically after Pecam-1 immunostaining. The protocol has been applied successfully to pharmacological studies and different genetic animal models under baseline conditions, as well as after experimental myocardial infarction by the permanent ligation of the left anterior descending coronary artery (LAD). In our experience, echocardiographic investigation is limited to anesthetized animals and is feasible in adult mice weighing at least 25 g. PMID- 29155762 TI - High-throughput Analysis of Locomotor Behavior in the Drosophila Island Assay. AB - Advances in next-generation sequencing technologies contribute to the identification of (candidate) disease genes for movement disorders and other neurological diseases at an increasing speed. However, little is known about the molecular mechanisms that underlie these disorders. The genetic, molecular, and behavioral toolbox of Drosophila melanogaster makes this model organism particularly useful to characterize new disease genes and mechanisms in a high throughput manner. Nevertheless, high-throughput screens require efficient and reliable assays that, ideally, are cost-effective and allow for the automatized quantification of traits relevant to these disorders. The island assay is a cost effective and easily set-up method to evaluate Drosophila locomotor behavior. In this assay, flies are thrown onto a platform from a fixed height. This induces an innate motor response that enables the flies to escape from the platform within seconds. At present, quantitative analyses of filmed island assays are done manually, which is a laborious undertaking, particularly when performing large screens. This manuscript describes the "Drosophila Island Assay" and "Island Assay Analysis" algorithms for high-throughput, automated data processing and quantification of island assay data. In the setup, a simple webcam connected to a laptop collects an image series of the platform while the assay is performed. The "Drosophila Island Assay" algorithm developed for the open-source software Fiji processes these image series and quantifies, for each experimental condition, the number of flies on the platform over time. The "Island Assay Analysis" script, compatible with the free software R, was developed to automatically process the obtained data and to calculate whether treatments/genotypes are statistically different. This greatly improves the efficiency of the island assay and makes it a powerful readout for basic locomotion and flight behavior. It can thus be applied to large screens investigating fly locomotor ability, Drosophila models of movement disorders, and drug efficacy. PMID- 29155761 TI - Advanced Confocal Microscopy Techniques to Study Protein-protein Interactions and Kinetics at DNA Lesions. AB - Local microirradiation with lasers represents a useful tool for studies of DNA repair-related processes in live cells. Here, we describe a methodological approach to analyzing protein kinetics at DNA lesions over time or protein protein interactions on locally microirradiated chromatin. We also show how to recognize individual phases of the cell cycle using the Fucci cellular system to study cell-cycle-dependent protein kinetics at DNA lesions. A methodological description of the use of two UV lasers (355 nm and 405 nm) to induce different types of DNA damage is also presented. Only the cells microirradiated by the 405 nm diode laser proceeded through mitosis normally and were devoid of cyclobutane pyrimidine dimers (CPDs). We also show how microirradiated cells can be fixed at a given time point to perform immunodetection of the endogenous proteins of interest. For the DNA repair studies, we additionally describe the use of biophysical methods including FRAP (Fluorescence Recovery After Photobleaching) and FLIM (Fluorescence Lifetime Imaging Microscopy) in cells with spontaneously occurring DNA damage foci. We also show an application of FLIM-FRET (Fluorescence Resonance Energy Transfer) in experimental studies of protein-protein interactions. PMID- 29155763 TI - Quantifying Microorganisms at Low Concentrations Using Digital Holographic Microscopy (DHM). AB - Accurately detecting and counting sparse bacterial samples has many applications in the food, beverage, and pharmaceutical processing industries, in medical diagnostics, and for life detection by robotic missions to other planets and moons of the solar system. Currently, sparse bacterial samples are counted by culture plating or epifluorescence microscopy. Culture plates require long incubation times (days to weeks), and epifluorescence microscopy requires extensive staining and concentration of the sample. Here, we demonstrate how to use off-axis digital holographic microscopy (DHM) to enumerate bacteria in very dilute cultures (100-104 cells/mL). First, the construction of the custom DHM is discussed, along with detailed instructions on building a low-cost instrument. The principles of holography are discussed, and a statistical model is used to estimate how long videos should be to detect cells, based on the optical performance characteristics of the instrument and the concentration of the bacterial solution (Table 2). Video detection of cells at 105, 104, 103, and 100 cells/mL is demonstrated in real time using un-reconstructed holograms. Reconstruction of amplitude and phase images is demonstrated using an open-source software package. PMID- 29155764 TI - Multiplex Cytokine Profiling of Stimulated Mouse Splenocytes Using a Cytometric Bead-based Immunoassay Platform. AB - Bead-based immunoassays employ the same basic principle as sandwich immunoassays. Capture beads, which can be differentiated by size and internal allophycocyanin (APC) fluorescence intensity, are conjugated to antibodies specific to a particular analyte. Next, a selected panel of defined capture bead sets is incubated with a biological sample containing target analytes specific to the capture antibodies. A biotinylated detection antibody cocktail is added, which leads to the formation of capture bead-analyte-detection antibody sandwiches. Finally, streptavidin-phycoerythrin (SA-PE) is added, which binds to biotinylated detection antibodies, providing fluorescent signal intensities in proportion to the amount of bound analyte. The PE fluorescent signal of analyte-specific beads regions is quantified using flow cytometry, and the concentrations of particular analytes are determined using data analysis software and the standard curve generated in the assay. In this experiment, we use a mouse T helper cytokine panel to simultaneously quantify the concentration of 13 separate cytokine targets in tissue culture supernatants collected from mouse splenocytes cultured under various stimulatory conditions. PMID- 29155765 TI - Continuous Hydrologic and Water Quality Monitoring of Vernal Ponds. AB - Vernal ponds, also referred to as vernal pools, provide critical ecosystem services and habitat for a variety of threatened and endangered species. However, they are vulnerable parts of the landscapes that are often poorly understood and understudied. Land use and management practices, as well as climate change are thought to be a contribution to the global amphibian decline. However, more research is needed to understand the extent of these impacts. Here, we present methodology for characterizing a vernal pond's morphology and detail a monitoring station that can be used to collect water quantity and quality data over the duration of a vernal pond's hydroperiod. We provide methodology for how to conduct field surveys to characterize the morphology and develop stage-storage curves for a vernal pond. Additionally, we provide methodology for monitoring the water level, temperature, pH, oxidation-reduction potential, dissolved oxygen, and electrical conductivity of water in a vernal pond, as well as monitoring rainfall data. This information can be used to better quantify the ecosystem services that vernal ponds provide and the impacts of anthropogenic activities on their ability to provide these services. PMID- 29155766 TI - Assessment of Blood-brain Barrier Permeability by Intravenous Infusion of FITC labeled Albumin in a Mouse Model of Neurodegenerative Disease. AB - Disruption of blood-brain barrier (BBB) integrity is a common feature for different neurological and neurodegenerative diseases. Although the interplay between perturbed BBB homeostasis and the pathogenesis of brain disorders needs further investigation, the development and validation of a reliable procedure to accurately detect BBB alterations may be crucial and represent a useful tool for potentially predicting disease progression and developing targeted therapeutic strategies. Here, we present an easy and efficient procedure for evaluating BBB leakage in a neurodegenerative condition like that occurring in a preclinical mouse model of Huntington disease, in which defects in the permeability of BBB are clearly detectable precociously in the disease. Specifically, the high molecular weight fluorescein isothiocyanate labelled (FITC)-albumin, which is able to cross the BBB only when the latter is impaired, is acutely infused into a mouse jugular vein and its distribution in the vascular or parenchymal districts is then determined by fluorescence microscopy. Accumulation of green fluorescent albumin in the brain parenchyma functions as an index of aberrant BBB permeability and, when quantitated by using Image J processing software, is reported as Green Fluorescence Intensity. PMID- 29155767 TI - A Wireless, Bidirectional Interface for In Vivo Recording and Stimulation of Neural Activity in Freely Behaving Rats. AB - In vivo electrophysiology is a powerful technique to investigate the relationship between brain activity and behavior at a millisecond and micrometer scale. However, current methods mostly rely on tethered cable recordings or only use unidirectional systems, allowing either recording or stimulation of neural activity, but not at the same time or same target. Here, a new wireless, bidirectional device for simultaneous multichannel recording and stimulation of neural activity in freely behaving rats is described. The system operates through a single portable head stage that both transmits recorded activity and can be targeted in real-time for brain stimulation using a telemetry-based multichannel software. The head stage is equipped with a preamplifier and a rechargeable battery, allowing stable long-term recordings or stimulation for up to 1 h. Importantly, the head stage is compact, weighs 12 g (including battery) and thus has minimal impact on the animal's behavioral repertoire, making the method applicable to a broad set of behavioral tasks. Moreover, the method has the major advantage that the effect of brain stimulation on neural activity and behavior can be measured simultaneously, providing a tool to assess the causal relationships between specific brain activation patterns and behavior. This feature makes the method particularly valuable for the field of deep brain stimulation, allowing precise assessment, monitoring, and adjustment of stimulation parameters during long-term behavioral experiments. The applicability of the system has been validated using the inferior colliculus as a model structure. PMID- 29155768 TI - Slice Patch Clamp Technique for Analyzing Learning-Induced Plasticity. AB - The slice patch clamp technique is a powerful tool for investigating learning induced neural plasticity in specific brain regions. To analyze motor-learning induced plasticity, we trained rats using an accelerated rotor rod task. Rats performed the task 10 times at 30-s intervals for 1 or 2 days. Performance was significantly improved on the training days compared to the first trial. We then prepared acute brain slices of the primary motor cortex (M1) in untrained and trained rats. Current-clamp analysis showed dynamic changes in resting membrane potential, spike threshold, afterhyperpolarization, and membrane resistance in layer II/III pyramidal neurons. Current injection induced many more spikes in 2 day trained rats than in untrained controls. To analyze contextual-learning induced plasticity, we trained rats using an inhibitory avoidance (IA) task. After experiencing foot-shock in the dark side of a box, the rats learned to avoid it, staying in the lighted side. We prepared acute hippocampal slices from untrained, IA-trained, unpaired, and walk-through rats. Voltage-clamp analysis was used to sequentially record miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) from the same CA1 neuron. We found different mean mEPSC and mIPSC amplitudes in each CA1 neuron, suggesting that each neuron had different postsynaptic strengths at its excitatory and inhibitory synapses. Moreover, compared with untrained controls, IA-trained rats had higher mEPSC and mIPSC amplitudes, with broad diversity. These results suggested that contextual learning creates postsynaptic diversity in both excitatory and inhibitory synapses at each CA1 neuron. AMPA or GABAA receptors seemed to mediate the postsynaptic currents, since bath treatment with CNQX or bicuculline blocked the mEPSC or mIPSC events, respectively. This technique can be used to study different types of learning in other regions, such as the sensory cortex and amygdala. PMID- 29155769 TI - A Simple Approach to Induce Experimental Autoimmune Neuritis in C57BL/6 Mice for Functional and Neuropathological Assessments. AB - Experimental autoimmune neuritis (EAN) is a well-appreciated experimental model of autoimmune peripheral demyelinating diseases. EAN disease is induced by immunizing mice with neurogenic peptides to direct an inflammatory attack toward components of the peripheral nervous system (PNS). Recent advances have enabled the induction of EAN in the relatively resistant C57BL/6 mouse line using myelin protein zero (P0)106-125 or P0180-199 peptides delivered in adjuvant combined with the injection of pertussis toxin. The ability to induce EAN in the C57BL/6 strain allows for the use of the numerous genetic tools that exist on this mouse background, and thus allows the sophisticated study of disease pathogenesis and interrogation of the mechanistic action of novel therapeutics in combination with transgenic approaches. In this study, we demonstrate a simple approach to successfully induce EAN using the P0180-199 peptide in C57BL/6 mice. We also outline a protocol for the assessment of functional deficits that occur in this model, accompanied by an array of neuropathological features. Thus, this model is a powerful experimental model to study the pathogenesis of human peripheral demyelinating neuropathies, and to determine the efficacy of potential therapies that aim to promote myelin repair and protect against nerve damage in autoimmune neuritis. PMID- 29155770 TI - Determination of Thermodynamic Properties of Alkaline Earth-liquid Metal Alloys Using the Electromotive Force Technique. AB - A novel electrochemical cell based on a CaF2 solid-state electrolyte has been developed to measure the electromotive force (emf) of binary alkaline earth liquid metal alloys as functions of both composition and temperature in order to acquire thermodynamic data. The cell consists of a chemically stable solid-state CaF2-AF2 electrolyte (where A is the alkaline-earth element such as Ca, Sr, or Ba), with binary A-B alloy (where B is the liquid metal such as Bi or Sb) working electrodes, and a pure A metal reference electrode. Emf data are collected over a temperature range of 723 K to 1,123 K in 25 K increments for multiple alloy compositions per experiment and the results are analyzed to yield activity values, phase transition temperatures, and partial molar entropies/enthalpies for each composition. PMID- 29155771 TI - Endotracheal Intubation of Rabbits Using a Polypropylene Guide Catheter. AB - Endotracheal intubation in rabbits can be challenging due to their unusual anatomy. Achieving a patent airway during anesthesia is critical for the avoidance of airway obstruction, prevention of gastric tympany, and to allow ventilatory support. Due to the difficulty of intubation, alternative methods such as the use of laryngeal mask airways or laryngeal tubes have been explored. However, these methods do not result in direct access to the trachea and thus may present a risk for development of complications. In addition, lack of direct intubation of the trachea can result in personnel exposure to waste anesthetic gases. Numerous methods for endotracheal intubation have been described, including blind placement, use of a fiberoptic laryngoscope or endoscope, and cricoid placement. Despite these numerous publications, many still struggle to achieve success. Here we provide a detailed description of an intubation technique that can be taught with minimal training with a short time to proficiency. Briefly, after administration of injectable anesthesia and proper positioning of the rabbit, a polypropylene catheter is placed into the trachea by direct visualization using a laryngoscope. The catheter is then used as a guide to direct the endotracheal tube into the trachea. This method allows for intubation without the need for expensive equipment and can be performed by a single individual without the need for an assistant. In conclusion, this technique can be easily taught and performed at very little cost in any clinical or research setting. PMID- 29155772 TI - Preparation of Primary Acute Lymphoblastic Leukemia Cells in Different Cell Cycle Phases by Centrifugal Elutriation. AB - The ability to synchronize cells has been central to advancing our understanding of cell cycle regulation. Common techniques employed include serum deprivation; chemicals which arrest cells at different cell cycle phases; or the use of mitotic shake-off which exploits their reduced adherence. However, all of these have disadvantages. For example, serum starvation works well for normal cells but less well for tumor cells with compromised cell cycle checkpoints due to oncogene activation or tumor suppressor loss. Similarly, chemically-treated cell populations can harbor drug-induced damage and show stress-related alterations. A technique which circumvents these problems is counterflow centrifugal elutriation (CCE), where cells are subjected to two opposing forces, centrifugal force and fluid velocity, which results in the separation of cells on the basis of size and density. Since cells advancing through the cycle typically enlarge, CCE can be used to separate cells into different cell cycle phases. Here we apply this technique to primary acute lymphoblastic leukemia cells. Under optimal conditions, an essentially pure population of cells in G1 phase and a highly enriched population of cells in G2/M phases can be obtained in excellent yield. These cell populations are ideally suited for studying cell cycle-dependent mechanisms of action of anticancer drugs and for other applications. We also show how modifications to the standard procedure can result in suboptimal performance and discuss the limitations of the technique. The detailed methodology presented should facilitate application and exploration of the technique to other types of cells. PMID- 29155773 TI - DNA-magnetic Particle Binding Analysis by Dynamic and Electrophoretic Light Scattering. AB - Isolation of DNA using magnetic particles is a field of high importance in biotechnology and molecular biology research. This protocol describes the evaluation of DNA-magnetic particles binding via dynamic light scattering (DLS) and electrophoretic light scattering (ELS). Analysis by DLS provides valuable information on the physicochemical properties of particles including particle size, polydispersity, and zeta potential. The latter describes the surface charge of the particle which plays major role in electrostatic binding of materials such as DNA. Here, a comparative analysis exploits three chemical modifications of nanoparticles and microparticles and their effects on DNA binding and elution. Chemical modifications by branched polyethylenimine, tetraethyl orthosilicate and (3-aminopropyl)triethoxysilane are investigated. Since DNA exhibits a negative charge, it is expected that zeta potential of particle surface will decrease upon binding of DNA. Forming of clusters should also affect particle size. In order to investigate the efficiency of these particles in isolation and elution of DNA, the particles are mixed with DNA in low pH (~6), high ionic strength and dehydration environment. Particles are washed on magnet and then DNA is eluted by Tris-HCl buffer (pH = 8). DNA copy number is estimated using quantitative polymerase chain reaction (PCR). Zeta potential, particle size, polydispersity and quantitative PCR data are evaluated and compared. DLS is an insightful and supporting method of analysis that adds a new perspective to the process of screening of particles for DNA isolation. PMID- 29155774 TI - Operation of a 25 KWth Calcium Looping Pilot-plant with High Oxygen Concentrations in the Calciner. AB - Calcium looping (CaL) is a post-combustion CO2 capture technology that is suitable for retrofitting existing power plants. The CaL process uses limestone as a cheap and readily available CO2 sorbent. While the technology has been widely studied, there are a few available options that could be applied to make it more economically viable. One of these is to increase the oxygen concentration in the calciner to reduce or eliminate the amount of recycled gas (CO2, H2O and impurities); therefore, decreasing or removing the energy necessary to heat the recycled gas stream. Moreover, there is a resulting increase in the energy input due to the change in the combustion intensity; this energy is used to enable the endothermic calcination reaction to occur in the absence of recycled flue gases. This paper presents the operation and first results of a CaL pilot plant with 100% oxygen combustion of natural gas in the calciner. The gas coming into the carbonator was a simulated flue gas from a coal-fired power plant or cement industry. Several limestone particle size distributions are also tested to further explore the effect of this parameter on the overall performance of this operating mode. The configuration of the reactor system, the operating procedures, and the results are described in detail in this paper. The reactor showed good hydrodynamic stability and stable CO2 capture, with capture efficiencies of up to 70% with a gas mixture simulating the flue gas of a coal fired power plant. PMID- 29155775 TI - Mapping Genome-wide Accessible Chromatin in Primary Human T Lymphocytes by ATAC Seq. AB - Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC seq) is a method used for the identification of open (accessible) regions of chromatin. These regions represent regulatory DNA elements (e.g., promoters, enhancers, locus control regions, insulators) to which transcription factors bind. Mapping the accessible chromatin landscape is a powerful approach for uncovering active regulatory elements across the genome. This information serves as an unbiased approach for discovering the network of relevant transcription factors and mechanisms of chromatin structure that govern gene expression programs. ATAC-seq is a robust and sensitive alternative to DNase I hypersensitivity analysis coupled with next-generation sequencing (DNase-seq) and formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) for genome wide analysis of chromatin accessibility and to the sequencing of micrococcal nuclease-sensitive sites (MNase-seq) to determine nucleosome positioning. We present a detailed ATAC-seq protocol optimized for human primary immune cells i.e. CD4+ lymphocytes (T helper 1 (Th1) and Th2 cells). This comprehensive protocol begins with cell harvest, then describes the molecular procedure of chromatin tagmentation, sample preparation for next-generation sequencing, and also includes methods and considerations for the computational analyses used to interpret the results. Moreover, to save time and money, we introduced quality control measures to assess the ATAC-seq library prior to sequencing. Importantly, the principles presented in this protocol allow its adaptation to other human immune and non-immune primary cells and cell lines. These guidelines will also be useful for laboratories which are not proficient with next-generation sequencing methods. PMID- 29155776 TI - Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles. AB - Treatment of dyslipidemia patients with lipid-lowering drugs leads to a significant reduction in low-density lipoproteins (LDL) level and a low to moderate level of increase in high-density lipoprotein (HDL) cholesterol in plasma. However, a possible role of these drugs in altering morphology and distribution of cholesterol particles is poorly understood. Here, we describe the in vitro evaluation of lipid-lowering drug effects in modulating morphological features of cholesterol particles using the plaque array method in combination with imaging flow cytometry. Image analyses of the cholesterol particles indicated that lovastatin, simvastatin, ezetimibe, and atorvastatin induce the formation of both globular and linear strand-shaped particles, whereas niacin, fibrates, fluvastatin, and rosuvastatin induce the formation of only globular shaped particles. Next, purified very low-density lipoprotein (VLDL) and LDL particles incubated with these drugs showed changes in the morphology and image texture of cholesterol particles subpopulations. Furthermore, screening of 50 serum samples revealed the presence of a higher level of linear shaped HDL cholesterol particles in subjects with dyslipidemia (mean of 18.3%) compared to the age-matched normal (mean of 11.1%) samples. We also observed considerable variations in lipid-lowering drug effects on reducing linear shaped LDL and HDL cholesterol particles formation in serum samples. These findings indicate that lipid-lowering drugs, in addition to their cell-mediated hypolipidemic effects, may directly modulate morphology of cholesterol particles by a non-enzymatic mechanism of action. The outcomes of these results have potential to inform diagnosis of atherosclerosis and predict optimal lipid-lowering therapy. PMID- 29155777 TI - Transurethral Instillation Procedure in Adult Male Mouse. AB - Transurethral instillation can be used to deliver different solutions with active ingredients (e.g., drugs, chemicals, bacteria, and viruses) locally into the urinary bladder to either induce animal models of bladder pathologies or evaluate the effectiveness of intravesical treatments. Most rodent models of lower urinary tract (LUT) pathologies are induced in female mice due to ease of intravesical instillation of the substances via the female urethra. However, due to anatomical differences between the female and male LUT, transurethral instillation in a male mouse has been deemed a very challenging procedure, and it has not been previously described. In this manuscript, we provide a detailed description of how to prepare polyethylene (PE) tubing for subsequent insertion into the urethra of a male mouse. In addition, we discuss the ideal types of PE tubing to be used depending on the desired site of inoculation. Furthermore, we describe point by point how to prepare an animal for a successful transurethral instillation to avoid injury to the urethra and ensure the delivery of the solution to the desired location. The procedure is started by retracting the prepuce and the glans to expose the opening of the urethral meatus. Next, the glans are grasped by blunt non-crushing forceps to stabilize the penis and the PE tubing. The PE tubing is first inserted into the urethral meatus parallel to the animal body, then its angle is adjusted by tilting the catheter to maneuver it to follow the natural curvature of the urethra. This technique can be used to induced murine models of bladder pathologies and/or evaluate the effectiveness of intravesical treatments in male mice. PMID- 29155778 TI - A Detailed Protocol for Physiological Parameters Acquisition and Analysis in Neurosurgical Critical Patients. AB - Intracranial pressure (ICP) monitoring is now widely used in neurosurgical critical patients. Besides mean ICP value, the ICP derived parameters such as ICP waveform, amplitude of pulse (AMP), the correlation of ICP amplitude and ICP mean (RAP), pressure reactivity index (PRx), ICP and arterial blood pressure (ABP) wave amplitude correlation (IAAC), and so on, can reflect intracranial status, predict prognosis, and can also be used as guidance of proper treatment. However, most of the clinicians focus only on the mean ICP value while ignoring these parameters because of the limitations of the current devices. We have recently developed a multimodality monitoring system to address these drawbacks. This portable, user-friendly system will use a data collecting and storing device to continuously acquire patients' physiological parameters first, i.e., ABP, ICP, and oxygen saturation, and then analyze these physiological parameters. We hope that the multimodality monitoring system will be accepted as a key measure to monitor physiological parameters, to analyze the current clinical status, and to predict the prognosis of the neurosurgical critical patients. PMID- 29155779 TI - A Novel Use of Three-dimensional High-frequency Ultrasonography for Early Pregnancy Characterization in the Mouse. AB - High-frequency ultrasonography (HFUS) is a common method to non-invasively monitor the real-time development of the human fetus in utero. The mouse is routinely used as an in vivo model to study embryo implantation and pregnancy progression. Unfortunately, such murine studies require pregnancy interruption to enable follow-up phenotypic analysis. To address this issue, we used three dimensional (3-D) reconstruction of HFUS imaging data for early detection and characterization of murine embryo implantation sites and their individual developmental progression in utero. Combining HFUS imaging with 3-D reconstruction and modeling, we were able to accurately quantify embryo implantation site number as well as monitor developmental progression in pregnant C57BL6J/129S mice from 5.5 days post coitus (d.p.c.) through to 9.5 d.p.c. with the use of a transducer. Measurements included: number, location, and volume of implantation sites as well as inter-implantation site spacing; embryo viability was assessed by cardiac activity monitoring. In the immediate post-implantation period (5.5 to 8.5 d.p.c.), 3-D reconstruction of the gravid uterus in both mesh and solid overlay format enabled visual representation of the developing pregnancies within each uterine horn. As genetically engineered mice continue to be used to characterize female reproductive phenotypes derived from uterine dysfunction, this method offers a new approach to detect, quantify, and characterize early implantation events in vivo. This novel use of 3-D HFUS imaging demonstrates the ability to successfully detect, visualize, and characterize embryo-implantation sites during early murine pregnancy in a non invasive manner. The technology offers a significant improvement over current methods, which rely on the interruption of pregnancies for gross tissue and histopathologic characterization. Here we use a video and text format to describe how to successfully perform ultrasounds of early murine pregnancy to generate reliable and reproducible data with reconstruction of the uterine form in mesh and solid 3-D images. PMID- 29155781 TI - Application of Aorta-gonad-mesonephros Explant Culture System in Developmental Hematopoiesis. AB - The limitation of using mouse embryos for hematopoiesis studies is the added inconvenience in operations, which is largely due to the intrauterine development of the embryo. Although genetic data from knockout (KO) mice are convincing, it is not realistic to generate KO mice for all genes as needed. In addition, performing in vivo rescue experiments to consolidate the data obtained from KO mice is not convenient. To overcome these limitations, the Aorta-Gonad Mesonephros (AGM) explant culture was developed as an appropriate system to study hematopoietic stem cell (HSC) development. Especially for rescue experiments, it can be used to recover the impaired hematopoiesis in KO mice. By adding the appropriate chemicals into the medium, the impaired signaling can be reactivated or up-regulated pathways can be inhibited. With the use of this method, many experiments can be performed to identify the critical regulators of HSC development, including HSC related gene expression at mRNA and protein levels, colony formation ability, and reconstitution capacity. This series of experiments would be helpful in defining the underlying mechanisms essential for HSC development in mammals. PMID- 29155780 TI - Rapid, Directed Differentiation of Retinal Pigment Epithelial Cells from Human Embryonic or Induced Pluripotent Stem Cells. AB - We describe a robust method to direct the differentiation of pluripotent stem cells into retinal pigment epithelial cells (RPE). The purpose of providing a detailed and thorough protocol is to clearly demonstrate each step and to make this readily available to researchers in the field. This protocol results in a homogenous layer of RPE with minimal or no manual dissection needed. The method presented here has been shown to be effective for induced pluripotent stem cells (iPSC) and human embryonic stem cells. Additionally, we describe methods for cryopreservation of intermediate cell banks that allow long-term storage. RPE generated using this protocol might be useful for iPSC disease-in-a-dish modeling or clinical application. PMID- 29155782 TI - Partial Optic Nerve Transection in Rats: A Model Established with a New Operative Approach to Assess Secondary Degeneration of Retinal Ganglion Cells. AB - Previous studies have shown that the secondary degeneration of retinal ganglion cells (RGCs) occurs commonly in glaucoma. Partial optic nerve transection is considered a useful and reproducible model. Compared with other optic nerve injury models used commonly for assessing secondary degeneration, e.g. complete optic nerve transection and optic nerve crush models, the partial optic nerve transection model is superior as it distinguishes primary from secondary degeneration in situ. Therefore, it serves as an excellent tool for evaluating secondary degeneration. This study describes a novel operative approach of partial optic nerve transection by directly accessing the area of the retrobulbar optic nerve through the orbital lateral wall of the eyeball. Moreover, we present a newly designed, low cost surgical instrument to assist with transection. As demonstrated by the representative results in distinguishing the boundary of primary and secondary injury areas, the new approach and instrument ensures high efficiency and stability of the model by providing adequate space for surgical operation. This in turn makes it easy to separate the meningeal sheath and ophthalmic vessels from the optic nerve before transection. An additional benefit is that this space-saving operative approach improves the investigators' ability to administer drugs, carriers, or selective RGC tracers to the stump of the partially transected optic nerve, allowing the exploration of mechanisms behind secondary injury in RGCs, in a new way. PMID- 29155783 TI - Scale-up Chemical Synthesis of Thermally-activated Delayed Fluorescence Emitters Based on the Dibenzothiophene-S,S-Dioxide Core. AB - We report a procedure to linearly scale-up the synthesis of 2,8-bis(3,6-di-tert butyl-9H-carbazol-9-yl)dibenzothiophene-S,S-dioxide (compound 4) and 2,8-bis(10H phenothiazin-10-yl)dibenzothiophene-S,S-dioxide (compound 5) using Buchwald Hartwig cross-coupling reaction conditions. In addition, we demonstrate a scaled up synthesis of all non-commercially available starting materials that are required for the amination cross-coupling reaction. In the present article, we provide the detailed synthetic procedures for all of the described compounds, alongside their spectral characterization. This work shows the possibility to produce organic molecules for optoelectronic applications on a large scale, which facilitates their implementation into real world devices. PMID- 29155784 TI - Correlative Super-resolution and Electron Microscopy to Resolve Protein Localization in Zebrafish Retina. AB - We present a method to investigate the subcellular protein localization in the larval zebrafish retina by combining super-resolution light microscopy and scanning electron microscopy. The sub-diffraction limit resolution capabilities of super-resolution light microscopes allow improving the accuracy of the correlated data. Briefly, 110 nanometer thick cryo-sections are transferred to a silicon wafer and, after immunofluorescence staining, are imaged by super resolution light microscopy. Subsequently, the sections are preserved in methylcellulose and platinum shadowed prior to imaging in a scanning electron microscope (SEM). The images from these two microscopy modalities are easily merged using tissue landmarks with open source software. Here we describe the adapted method for the larval zebrafish retina. However, this method is also applicable to other types of tissues and organisms. We demonstrate that the complementary information obtained by this correlation is able to resolve the expression of mitochondrial proteins in relation with the membranes and cristae of mitochondria as well as to other compartments of the cell. PMID- 29155785 TI - Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons. AB - Cerebellar granule neurons (CGNs) are a commonly used neuronal model, forming an abundant homogeneous population in the cerebellum. In light of their post-natal development, abundance, and accessibility, CGNs are an ideal model to study neuronal processes, including neuronal development, neuronal migration, and physiological neuronal activity stimulation. In addition, CGN cultures provide an excellent model for studying different modes of cell death including excitotoxicity and apoptosis. Within a week in culture, CGNs express N-methyl-D aspartate (NMDA) receptors, a specific ionotropic glutamate receptor with many critical functions in neuronal health and disease. The addition of low concentrations of NMDA in conjunction with membrane depolarization to rodent primary CGN cultures has been used to model physiological neuronal activity stimulation while the addition of high concentrations of NMDA can be employed to model excitotoxic neuronal injury. Here, a method of isolation and culturing of CGNs from 6 day old pups as well as genetic manipulation of CGNs by adenoviruses and lentiviruses are described. We also present optimized protocols on how to stimulate NMDA-induced excitotoxicity, low-potassium-induced apoptosis, oxidative stress and DNA damage following transduction of these neurons. PMID- 29155786 TI - Isolation and Cultivation of Adult Rat Cardiomyocytes. AB - In an intact heart, adjacent cells influence adult cardiomyocytes. With the method of isolation and cultivation of adult cardiomyocytes, a precise investigation of the behavior of these cells under specific treatments and environments is possible. This manuscript presents a protocol for successful isolation and cultivation of adult rat ventricular cardiomyocytes (ARVC). The rat is sacrificed by cervical dislocation under deep anesthesia. Then, the heart is extracted and the aorta is uncovered. Subsequently, perfusion on the Langendorff perfusion system with calcium depletion and collagenase treatment is performed. Afterwards, ventricular tissue gets minced, re-circulated, and filtered, followed by three centrifugation steps with gradual addition of CaCl2 until physiological calcium concentration is reached. ARVC are plated on cell culture dishes. After refreshing the cell culture medium, ARVC can be cultivated for up to six days without changing the serum-containing culture medium. Isolation of ARVC is a calcium sensitive process. Small changes in the intracellular calcium concentration cause a decrease in the quality and viability of the isolated cells. Freshly isolated ARVC are rod shaped. Within the first days of cultivation they lose the rod-shaped morphology and form pseudopodia-like structures (spreading). During this morphological formation ARVC initially degrade their contractile elements followed by a reformation through actin stress fibers and de novo sarcomerogenesis. After one week of cultivation, most ARVC show a widespread appearance with a clearly detectable cross striation. This process is sensitive to intracellular calcium concentration, as treatment with ionomycin attenuates spreading. Key markers in this process of de- and re-differentiation are beta myosin heavy chain (beta-MHC), oncostatin M (OSM), and swiprosin-1 (EFHD2). Recent studies have suggested that cardiac re- and de-differentiation occurring under culture conditions mimics features seen in vivo during cardiac remodeling. Therefore, isolation and cultivation of ARVC play a key role in understanding the biology of cardiomyocytes. PMID- 29155787 TI - Synthesis of Core-shell Lanthanide-doped Upconversion Nanocrystals for Cellular Applications. AB - Lanthanide-doped upconversion nanocrystals (UCNs) have attracted much attention in recent years based on their promising and controllable optical properties, which allow for the absorption of near-infrared (NIR) light and can subsequently convert it into multiplexed emissions that span over a broad range of regions from the UV to the visible to the NIR. This article presents detailed experimental procedures for high-temperature co-precipitation synthesis of core shell UCNs that incorporate different lanthanide ions into nanocrystals for efficiently converting deep-tissue penetrable NIR excitation (808 nm) into a strong blue emission at 480 nm. By controlling the surface modification with biocompatible polymer (polyacrylic acid, PAA), the as-prepared UCNs acquires great solubility in buffer solutions. The hydrophilic nanocrystals are further functionalized with specific ligands (dibenzyl cyclooctyne, DBCO) for localization on the cell membrane. Upon NIR light (808 nm) irradiation, the upconverted blue emission can effectively activate the light-gated channel protein on the cell membrane and specifically regulate the cation (e.g., Ca2+) influx in the cytoplasm. This protocol provides a feasible methodology for the synthesis of core-shell lanthanide-doped UCNs and subsequent biocompatible surface modification for further cellular applications. PMID- 29155788 TI - Use of Synaptic Zinc Histochemistry to Reveal Different Regions and Laminae in the Developing and Adult Brain. AB - Characterization of anatomical and functional brain organization and development requires accurate identification of distinct neural circuits and regions in the immature and adult brain. Here we describe a zinc histochemical staining procedure that reveals differences in staining patterns among different layers and brain regions. Others have utilized this procedure not only to reveal the distribution of zinc-containing neurons and circuits in the brain, but also to successfully delineate areal and laminar boundaries in the developing and adult brain in several species. Here we illustrate this staining procedure with images from developing and adult ferret brains. We reveal a zinc-staining pattern that serves as an anatomical marker of areas and layers, and can be reliably used to distinguish visual cortical areas in the developing and adult visual cortex. The main goal of this protocol is to present a histochemical method that allows the accurate identification of layers and regions in the developing and adult brain where other methods fail to do so. Secondarily, in conjunction with densitometric image analysis, this method allows one to assess the distribution of synaptic zinc to reveal potential changes throughout development. This protocol describes in detail the reagents, tools, and steps necessary to successively stain frozen brain sections. Although this protocol is described using ferret brain tissue, it can easily be adapted for use in rodents, cats, or monkeys as well as in other brain regions. PMID- 29155789 TI - Efficient Generation and Editing of Feeder-free IPSCs from Human Pancreatic Cells Using the CRISPR-Cas9 System. AB - Embryonic and induced pluripotent stem cells can self-renew and differentiate into multiple cell types of the body. The pluripotent cells are thus coveted for research in regenerative medicine and are currently in clinical trials for eye diseases, diabetes, heart diseases, and other disorders. The potential to differentiate into specialized cell types coupled with the recent advances in genome editing technologies including the CRISPR/Cas system have provided additional opportunities for tailoring the genome of iPSC for varied applications including disease modeling, gene therapy, and biasing pathways of differentiation, to name a few. Among the available editing technologies, the CRISPR/Cas9 from Streptococcus pyogenes has emerged as a tool of choice for site specific editing of the eukaryotic genome. The CRISPRs are easily accessible, inexpensive, and highly efficient in engineering targeted edits. The system requires a Cas9 nuclease and a guide sequence (20-mer) specific to the genomic target abutting a 3-nucleotide "NGG" protospacer-adjacent-motif (PAM) for targeting Cas9 to the desired genomic locus, alongside a universal Cas9 binding tracer RNA (together called single guide RNA or sgRNA). Here we present a step-by step protocol for efficient generation of feeder-independent and footprint-free iPSC and describe methodologies for genome editing of iPSC using the Cas9 ribonucleoprotein (RNP) complexes. The genome editing protocol is effective and can be easily multiplexed by pre-complexing sgRNAs for more than one target with the Cas9 protein and simultaneously delivering into the cells. Finally, we describe a simplified approach for identification and characterization of iPSCs with desired edits. Taken together, the outlined strategies are expected to streamline generation and editing of iPSC for manifold applications. PMID- 29155790 TI - A Mouse 5/6th Nephrectomy Model That Induces Experimental Uremic Cardiomyopathy. AB - Chronic kidney disease (CKD) is a great risk factor for cardiovascular disease events and mortality, and progressively develops to the clinical phenotype called "uremic cardiomyopathy". We describe here an experimental CKD mouse model, named 5/6th partial nephrectomy (PNx) with pole ligation, which developed uremic cardiomyopathy at four weeks post-surgery. This PNx model was performed by a two step surgery. In step-one surgery, both poles of the left kidney were ligated. In step-two surgery, which was performed 7 days after the step-one surgery, the right kidney was removed. For the sham surgery, the same surgery procedures were performed but without pole ligation of the left kidney or removal of the right kidney. The surgical procedures are easier and less time-consuming, compared to other methods. However, the remnant functional renal mass is not as easily controlled as the renal artery ligation. Four weeks after surgery, in comparison with the sham-operated mice, the PNx mice developed impaired renal function, anemia, cardiac hypertrophy, cardiac fibrosis, and decreased heart systolic and diastolic function. PMID- 29155791 TI - Improved Protocol for Chromatin Immunoprecipitation from Mouse Skeletal Muscle. AB - We describe an efficient and reproducible protocol for the preparation of chromatin from adult mouse skeletal muscle, a physically resistant tissue with a high content of structural proteins. Dissected limb muscles from adult mice are physically disrupted by mechanical homogenisation, or a combination of mincing and douncing, in a hypotonic buffer before formaldehyde fixation of the cell lysate. The fixed nuclei are purified by further cycles of mechanical homogenisation or douncing and sequential filtrations to remove cell debris. The purified nuclei can be sonicated immediately or at a later stage after freezing. The chromatin can be efficiently sonicated and is suitable for chromatin immunoprecipitation experiments, as illustrated by the profiles obtained for transcription factors, RNA polymerase II, and covalent histone modifications. The binding events detected using chromatin prepared by this protocol are predominantly those taking place in the muscle fiber nuclei despite the presence of chromatin from other fiber-associated satellite and endothelial cells. This protocol is therefore adapted to study gene regulation in the adult mouse skeletal muscle. PMID- 29155792 TI - Assessment of Dictyostelium discoideum Response to Acute Mechanical Stimulation. AB - Chemotaxis, or migration up a gradient of a chemoattractant, is the best understood mode of directed migration. Studies using social amoeba Dictyostelium discoideum revealed that a complex signal transduction network of parallel pathways amplifies the response to chemoattractants, and leads to biased actin polymerization and protrusion of a pseudopod in the direction of a gradient. In contrast, molecular mechanisms driving other types of directed migration, for example, due to exposure to shear flow or electric fields, are not known. Many regulators of chemotaxis exhibit localization at the leading or lagging edge of a migrating cell, as well as show transient changes in localization or activation following global stimulation with a chemoattractant. To understand the molecular mechanisms of other types of directed migration we developed a method that allows examination of cellular response to acute mechanical stimulation based on brief (2 - 5 s) exposure to shear flow. This stimulation can be delivered in a channel while imaging cells expressing fluorescently-labeled biosensors to examine individual cell behavior. Additionally, cell population can be stimulated in a plate, lysed, and immunoblotted using antibodies that recognize active versions of proteins of interest. By combining both assays, one can examine a wide array of molecules activated by changes in subcellular localization and/or phosphorylation. Using this method we determined that acute mechanical stimulation triggers activation of the chemotactic signal transduction and actin cytoskeleton networks. The ability to examine cellular responses to acute mechanical stimulation is important for understanding the initiating events necessary for shear flow-induced motility. This approach also provides a tool for studying the chemotactic signal transduction network without the confounding influence of the chemoattractant receptor. PMID- 29155793 TI - Metabolic Support of Excised, Living Brain Tissues During Magnetic Resonance Microscopy Acquisition. AB - This protocol describes the procedures necessary to support normal metabolic functions of acute brain slice preparations during the collection of magnetic resonance (MR) microscopy data. While it is possible to perform MR collections on living, excised mammalian tissue, such experiments have traditionally been constrained by resolution limits and are thus incapable of visualizing tissue microstructure. Conversely, MR protocols that did achieve microscopic image resolution required the use of fixed samples to accommodate the need for static, unchanging conditions over lengthy scan times. The current protocol describes the first available MR technique that enables imaging of living, mammalian tissue samples at microscopic resolutions. Such data is of great importance to the understanding of how pathology-based contrast changes occurring at the microscopic level influence the content of macroscopic MR scans such as those used in the clinic. Once such an understanding is realized, diagnostic methods with greater sensitivity and accuracy can be developed, which will translate directly to earlier disease treatment, more accurate therapy monitoring and improved patient outcomes. While the described methodology focuses on brain slice preparations, the protocol is adaptable to any excised tissue slice given that changes are made to the gas and perfusate preparations to accommodate the tissue's specific metabolic needs. Successful execution of the protocol should result in living, acute slice preparations that exhibit MR diffusion signal stability for periods up to 15.5 h. The primary advantages of the current system over other MR compatible perfusion apparatuses are its compatibility with the MR microscopy hardware required to attain higher resolution images and ability to provide constant, uninterrupted flow with carefully regulated perfusate conditions. Reduced sample throughput is a consideration with this design as only one tissue slice may be imaged at a time. PMID- 29155794 TI - An Array-based Comparative Genomic Hybridization Platform for Efficient Detection of Copy Number Variations in Fast Neutron-induced Medicago truncatula Mutants. AB - Mutants are invaluable genetic resources for gene function studies. To generate mutant collections, three types of mutagens can be utilized, including biological such as T-DNA or transposon, chemical such as ethyl methanesulfonate (EMS), or physical such as ionization radiation. The type of mutation observed varies depending on the mutagen used. For ionization radiation induced mutants, mutations include deletion, duplication, or rearrangement. While T-DNA or transposon-based mutagenesis is limited to species that are susceptible to transformation, chemical or physical mutagenesis can be applied to a broad range of species. However, the characterization of mutations derived from chemical or physical mutagenesis traditionally relies on a map-based cloning approach, which is labor intensive and time consuming. Here, we show that a high-density genome array-based comparative genomic hybridization (aCGH) platform can be applied to efficiently detect and characterize copy number variations (CNVs) in mutants derived from fast neutron bombardment (FNB) mutagenesis in Medicago truncatula, a legume species. Whole genome sequence analysis shows that there are more than 50,000 genes or gene models in M. truncatula. At present, FNB-induced mutants in M. truncatula are derived from more than 150,000 M1 lines, representing invaluable genetic resources for functional studies of genes in the genome. The aCGH platform described here is an efficient tool for characterizing FNB-induced mutants in M. truncatula. PMID- 29155795 TI - In Vivo Imaging of Cx3cr1gfp/gfp Reporter Mice with Spectral-domain Optical Coherence Tomography and Scanning Laser Ophthalmoscopy. AB - Spectral domain optical coherence tomography (SD-OCT) and scanning laser ophthalmoscopy (SLO) are extensively used in experimental ophthalmology. In the present protocol, mice expressing green fluorescent protein (gfp) under the promoter of Cx3cr1 (BALB/c-Cx3cr1gfp/gfp) were used to image microglia cells in vivo in the retina. Microglia are resident macrophages of the retina and have been implicated in several retinal diseases1,2,3,4,5,6. This protocol provides a detailed approach for generation of retinal B-scans, with SD-OCT, and imaging of microglia cell distribution in Cx3cr1gfp/gfp mice with SLO in vivo, using an ophthalmic imaging platform system. The protocol can be used in several reporter mouse lines. However, there are some limitations to the protocol presented here. First, both SLO and SD-OCT, when used in the high-resolution mode, collect data with high axial resolution but the lateral resolution is lower (3.5 um and 6 um, respectively). Moreover, the focus and saturation level in SLO is highly dependent on parameter selection and correct alignment of the eye. Additionally, using devices designed for human patients in mice is challenging due to the higher total optical power of the mouse eye compared to the human eye; this can lead to lateral magnification inaccuracies7, which are also dependent on the magnification by the mouse lens among others. However, despite that the axial scan position is dependent upon lateral magnification, the axial SD-OCT measurements are accurate8. PMID- 29155796 TI - Optimized Setup and Protocol for Magnetic Domain Imaging with In Situ Hysteresis Measurement. AB - This paper elaborates the sample preparation protocols required to obtain optimal domain patterns using the Bitter method, focusing on the extra steps compared to standard metallographic sample preparation procedures. The paper proposes a novel bespoke rig for dynamic domain imaging with in situ BH (magnetic hysteresis) measurements and elaborates the protocols for the sensor preparation and the use of the rig to ensure accurate BH measurement. The protocols for static and ordinary dynamic domain imaging (without in situ BH measurements) are also presented. The reported method takes advantage of the convenience and high sensitivity of the traditional Bitter method and enables in situ BH measurement without interrupting or interfering with the domain wall movement processes. This facilitates establishing a direct and quantitative link between the domain wall movement processes-microstructural feature interactions in ferritic steels with their BH loops. This method is anticipated to become a useful tool for the fundamental study of microstructure-magnetic property relationships in steels and to help interpret the electromagnetic sensor signals for non-destructive evaluation of steel microstructures. PMID- 29155797 TI - Immunofluorescence Microscopy of gammaH2AX and 53BP1 for Analyzing the Formation and Repair of DNA Double-strand Breaks. AB - DNA double-strand breaks (DSB) are serious DNA lesions. Analysis of the formation and repair of DSB is relevant in a broad spectrum of research areas including genome integrity, genotoxicity, radiation biology, aging, cancer, and drug development. In response to DSB, the histone H2AX is phosphorylated at Serine 139 in a region of several megabase pairs forming discrete nuclear foci detectable by immunofluorescence microscopy. In addition, 53BP1 (p53 binding protein 1) is another important DSB-responsive protein promoting repair of DSB by nonhomologous end-joining while preventing homologous recombination. According to the specific functions of gammaH2AX and 53BP1, the combined analysis of gammaH2AX and 53BP1 by immunofluorescence microscopy may be a reasonable approach for a detailed analysis of DSB. This manuscript provides a step-by-step protocol supplemented with methodical notes for performing the technique. Specifically, the influence of the cell cycle on gammaH2AX foci patterns is demonstrated in normal fibroblasts of the cell line NHDF. Further, the value of the gammaH2AX foci as a biomarker is depicted in x-ray irradiated lymphocytes of a healthy individual. Finally, genetic instability is investigated in CD34+ cells of a patient with acute myeloid leukemia by immunofluorescence microscopy of gammaH2AX and 53BP1. PMID- 29155798 TI - Paternal experience impacts cognitive function in offspring: a pre-existing concept. PMID- 29155799 TI - Risk of prevalent and incident dementia associated with insulin-like growth factor and insulin-like growth factor-binding protein 3. AB - Insulin-like growth factor 1 (IGF-1) influences cell proliferation and survival. In the extracellular environment, IGF-1 circulates bound to proteins (IGF-binding proteins; IGFBP), some of which have physiological effects that seem independent of IGF-1, including the brain (for example, IGFBP-3). We completed a systematic review of the association between dementia and IGF-1 and IGFBP-3, and a cross sectional and longitudinal study designed to investigate if lower plasma concentration of these proteins increased the risk of prevalent and incident dementia. A total of 3967 men aged 71-89 years joined the study, of whom 535 (13.5%) showed evidence of prevalent cognitive impairment. The plasma concentrations of IGF-1 and IGFBP-3 were similar for men with and without cognitive impairment. The 3432 men free of cognitive impairment were then followed for up to 13 years. During this time 571 (16.6%) developed dementia. The plasma concentration of IGF-1 had no association with incident dementia. The doubling of the plasma concentration of IGFBP-3 decreased the hazard ratio of dementia by 23% (95% confidence interval=5-37%). The results were not affected by age, body mass index and history of smoking, diabetes, hypertension, coronary heart disease or stroke. If these findings are confirmed by others, the plasma concentration of IGFBP-3 could be used to improve the accuracy of predictive models of dementia and as a potential new factor to assist in the development of prevention and treatment strategies. PMID- 29155800 TI - Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells' activity. AB - Epidemiological studies report strong association between mood disorders and tobacco addiction. This high comorbidity requires adequate treatment but the underlying mechanisms are unknown. We demonstrate that nicotine exposure, independent of drug withdrawal effects, increases stress sensitivity, a major risk factor in mood disorders. Nicotine and stress concur to induce long-lasting cellular adaptations within the dopamine (DA) system. This interplay is underpinned by marked remodeling of nicotinic systems, causing increased ventral tegmental area (VTA) DA neurons' activity and stress-related behaviors, such as social aversion. Blocking beta2 or alpha7 nicotinic acetylcholine receptors (nAChRs) prevents, respectively, the development and the expression of social stress-induced neuroadaptations; conversely, facilitating alpha7 nAChRs activation specifically in the VTA promotes stress-induced cellular and behavioral maladaptations. Our work unravels a complex nicotine-stress bidirectional interplay and identifies alpha7 nAChRs as a promising therapeutic target for stress-related psychiatric disorders. PMID- 29155801 TI - A comparative expression analysis of isocitrate dehydrogenase-3 gene and protein levels in postmortem brain tissues from subjects with bipolar disorder. PMID- 29155803 TI - PET imaging of dopamine-D2 receptor internalization in schizophrenia. AB - This corrects the article DOI: 10.1038/mp.2017.107. PMID- 29155804 TI - Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. AB - It has been suggested that the superiority of antidepressants over placebo in controlled trials is merely a consequence of side effects enhancing the expectation of improvement by making the patient realize that he/she is not on placebo. We explored this hypothesis in a patient-level post hoc-analysis including all industry-sponsored, Food and Drug Administration-registered placebo controlled trials of citalopram or paroxetine in adult major depression that used the Hamilton Depression Rating Scale (HDRS) and included a week 6 symptom assessment (n=15). The primary analyses, which compared completers on active treatment without early adverse events to completers on placebo (with or without adverse events) with respect to reduction in the HDRS depressed mood item showed larger symptom reduction in patients given active treatment, the effect sizes being 0.48 for citalopram and 0.33 for paroxetine. In actively treated subjects reporting early adverse events, who also outperformed those given placebo, the severity of the adverse events did not predict response. Several sensitivity analyses, for example, including (i) those using change of the sum of all HDRS-17 items as effect parameter, (ii) those excluding all subjects with adverse events (that is, also those on placebo) and (iii) those based on the intention-to-treat population, were all in line with the primary analyses. The finding that both paroxetine and citalopram are clearly superior to placebo also when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects. PMID- 29155805 TI - Epidemiology and outcomes of community-acquired and hospital-acquired acute kidney injury in children and adolescents. AB - BackgroundHospital-acquired acute kidney injury (HA-AKI) is associated with an increased risk of childhood mortality; however, only a few studies have addressed community-acquired AKI (CA-AKI).MethodsAKI network classification was used to assess CA- and HA-AKI, 2010-2014. Patients with CA-AKI who were admitted to an inpatient setting were categorized as CAA-AKI. CANA-AKI was for CA-AKI not admitted to inpatient care. Epidemiology, factors associated with AKI, and in hospital outcomes were assessed for variation.ResultsPrevalence of CANA-AKI was 4/1,000 outpatient visits, 17/1,000 hospital admissions for CAA-AKI, and 9.69/1,000 hospital admissions for HA-AKI. Mortality was higher among AKI patients (HA-AKI, 13.64%; CAA-AKI, 3.7%) than in no-AKI patients (0.57%). Patients with AKI and those with severe stages of AKI resulted in an increase in health-care service utilization (both P<0.001). Prior renal disease and recent hospitalization were associated with pediatric AKI in both outpatient and inpatient settings. Hematological malignancies, congenital anomalies, circulatory disease, and nephrotoxic medication use were associated with AKI, although the extent of associations varied slightly by setting.ConclusionIncreasing incidence of AKI in the community emphasizes the need for an increased awareness of AKI among health professionals to identify at-risk children and monitor SCr, so that modifiable risk factors can be managed. PMID- 29155806 TI - Anogenital distance as a phenotypic signature through infancy. AB - BackgroundAnogenital distance (AGD) has been suggested to represent a phenotypic signature reflecting in utero androgen action. However, it is not known whether an individual's AGD at birth correlates to the AGD later in life. We investigate correlations of AGD between 3 and 18 months of age and assess reproducibility of measurements.MethodsWe measured AGD from anus to scrotum (AGDas) and to penis (AGDap) in 407 boys, and to posterior fourchette (AGDaf) and clitoris (AGDac) in 282 girls. Each measure was repeated three times at 3 and 18 months of age, and some children were, furthermore, examined by two different examiners. We assessed age-related changes and reproducibility of measurements.ResultsAGD increased between the two examinations and correlated within the child. A large proportion of the observed variation in AGD was due to true differences between the children (AGDas: 62%, AGDap: 40%, AGDaf: 30%, AGDac: 21%), and measurement error due to between- and within-examiner variation was low.ConclusionsOur study showed that measures of AGD within a child correlated during infancy, especially in boys and particularly for AGD measured as the distance between anus and scrotum. A planned cohort follow-up through childhood and puberty will reveal whether AGD represents a phenotypic signature throughout life. PMID- 29155807 TI - A synbiotic-containing amino-acid-based formula improves gut microbiota in non IgE-mediated allergic infants. AB - BackgroundPrebiotics and probiotics (synbiotics) can modify gut microbiota and have potential in allergy management when combined with amino-acid-based formula (AAF) for infants with cow's milk allergy (CMA).MethodsThis multicenter, double blind, randomized controlled trial investigated the effects of an AAF-including synbiotic blend on percentages of bifidobacteria and Eubacterium rectale/Clostridium coccoides group (ER/CC) in feces from infants with suspected non-IgE-mediated CMA. Feces from age-matched healthy breastfed infants were used as reference (healthy breastfed reference (HBR)) for primary outcomes. The CMA subjects were randomized and received test or control formula for 8 weeks. Test formula was a hypoallergenic, nutritionally complete AAF including a prebiotic blend of fructo-oligosaccharides and the probiotic strain Bifidobacterium breve M 16V. Control formula was AAF without synbiotics.ResultsA total of 35 (test) and 36 (control) subjects were randomized; HBR included 51 infants. At week 8, the median percentage of bifidobacteria was higher in the test group than in the control group (35.4% vs. 9.7%, respectively; P<0.001), whereas ER/CC was lower (9.5% vs. 24.2%, respectively; P<0.001). HBR levels of bifidobacteria and ER/CC were 55% and 6.5%, respectively.ConclusionAAF including specific synbiotics, which results in levels of bifidobacteria and ER/CC approximating levels in the HBR group, improves the fecal microbiota of infants with suspected non-IgE mediated CMA. PMID- 29155808 TI - A hierarchical stochastic model for bistable perception. AB - Viewing of ambiguous stimuli can lead to bistable perception alternating between the possible percepts. During continuous presentation of ambiguous stimuli, percept changes occur as single events, whereas during intermittent presentation of ambiguous stimuli, percept changes occur at more or less regular intervals either as single events or bursts. Response patterns can be highly variable and have been reported to show systematic differences between patients with schizophrenia and healthy controls. Existing models of bistable perception often use detailed assumptions and large parameter sets which make parameter estimation challenging. Here we propose a parsimonious stochastic model that provides a link between empirical data analysis of the observed response patterns and detailed models of underlying neuronal processes. Firstly, we use a Hidden Markov Model (HMM) for the times between percept changes, which assumes one single state in continuous presentation and a stable and an unstable state in intermittent presentation. The HMM captures the observed differences between patients with schizophrenia and healthy controls, but remains descriptive. Therefore, we secondly propose a hierarchical Brownian model (HBM), which produces similar response patterns but also provides a relation to potential underlying mechanisms. The main idea is that neuronal activity is described as an activity difference between two competing neuronal populations reflected in Brownian motions with drift. This differential activity generates switching between the two conflicting percepts and between stable and unstable states with similar mechanisms on different neuronal levels. With only a small number of parameters, the HBM can be fitted closely to a high variety of response patterns and captures group differences between healthy controls and patients with schizophrenia. At the same time, it provides a link to mechanistic models of bistable perception, linking the group differences to potential underlying mechanisms. PMID- 29155809 TI - Multivariate pattern dependence. AB - When we perform a cognitive task, multiple brain regions are engaged. Understanding how these regions interact is a fundamental step to uncover the neural bases of behavior. Most research on the interactions between brain regions has focused on the univariate responses in the regions. However, fine grained patterns of response encode important information, as shown by multivariate pattern analysis. In the present article, we introduce and apply multivariate pattern dependence (MVPD): a technique to study the statistical dependence between brain regions in humans in terms of the multivariate relations between their patterns of responses. MVPD characterizes the responses in each brain region as trajectories in region-specific multidimensional spaces, and models the multivariate relationship between these trajectories. We applied MVPD to the posterior superior temporal sulcus (pSTS) and to the fusiform face area (FFA), using a searchlight approach to reveal interactions between these seed regions and the rest of the brain. Across two different experiments, MVPD identified significant statistical dependence not detected by standard functional connectivity. Additionally, MVPD outperformed univariate connectivity in its ability to explain independent variance in the responses of individual voxels. In the end, MVPD uncovered different connectivity profiles associated with different representational subspaces of FFA: the first principal component of FFA shows differential connectivity with occipital and parietal regions implicated in the processing of low-level properties of faces, while the second and third components show differential connectivity with anterior temporal regions implicated in the processing of invariant representations of face identity. PMID- 29155802 TI - Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa. AB - Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 * 10-6), and rs7700147, an intergenic variant (P=2.93 * 10-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes. PMID- 29155810 TI - Regulation of transcription elongation in response to osmostress. AB - Cells trigger massive changes in gene expression upon environmental fluctuations. The Hog1 stress-activated protein kinase (SAPK) is an important regulator of the transcriptional activation program that maximizes cell fitness when yeast cells are exposed to osmostress. Besides being associated with transcription factors bound at target promoters to stimulate transcriptional initiation, activated Hog1 behaves as a transcriptional elongation factor that is selective for stress responsive genes. Here, we provide insights into how this signaling kinase functions in transcription elongation. Hog1 phosphorylates the Spt4 elongation factor at Thr42 and Ser43 and such phosphorylations are essential for the overall transcriptional response upon osmostress. The phosphorylation of Spt4 by Hog1 regulates RNA polymerase II processivity at stress-responsive genes, which is critical for cell survival under high osmostress conditions. Thus, the direct regulation of Spt4 upon environmental insults serves to stimulate RNA Pol II elongation efficiency. PMID- 29155811 TI - An efficient moments-based inference method for within-host bacterial infection dynamics. AB - Over the last ten years, isogenic tagging (IT) has revolutionised the study of bacterial infection dynamics in laboratory animal models. However, quantitative analysis of IT data has been hindered by the piecemeal development of relevant statistical models. The most promising approach relies on stochastic Markovian models of bacterial population dynamics within and among organs. Here we present an efficient numerical method to fit such stochastic dynamic models to in vivo experimental IT data. A common approach to statistical inference with stochastic dynamic models relies on producing large numbers of simulations, but this remains a slow and inefficient method for all but simple problems, especially when tracking bacteria in multiple locations simultaneously. Instead, we derive and solve the systems of ordinary differential equations for the two lower-order moments of the stochastic variables (mean, variance and covariance). For any given model structure, and assuming linear dynamic rates, we demonstrate how the model parameters can be efficiently and accurately estimated by divergence minimisation. We then apply our method to an experimental dataset and compare the estimates and goodness-of-fit to those obtained by maximum likelihood estimation. While both sets of parameter estimates had overlapping confidence regions, the new method produced lower values for the division and death rates of bacteria: these improved the goodness-of-fit at the second time point at the expense of that of the first time point. This flexible framework can easily be applied to a range of experimental systems. Its computational efficiency paves the way for model comparison and optimal experimental design. PMID- 29155812 TI - fluEvidenceSynthesis: An R package for evidence synthesis based analysis of epidemiological outbreaks. AB - Public health related decisions often have to balance the cost of intervention strategies with the benefit of the reduction in disease burden. While the cost can often be inferred, forward modelling of the effect of different intervention options is complicated and disease specific. Here we introduce a package that is aimed to simplify this process. The package allows one to infer parameters using a Bayesian approach, perform forward modelling of the likely results of the proposed intervention and finally perform cost effectiveness analysis of the results. The package is based on a method previously used in the United Kingdom to inform vaccination strategies for influenza, with extensions to make it easily adaptable to other diseases and data sources. PMID- 29155813 TI - Post-guidance signaling by extracellular matrix-associated Slit/Slit-N maintains fasciculation and position of axon tracts in the nerve cord. AB - Axon-guidance by Slit-Roundabout (Robo) signaling at the midline initially guides growth cones to synaptic targets and positions longitudinal axon tracts in discrete bundles on either side of the midline. Following the formation of commissural tracts, Slit is found also in tracts of the commissures and longitudinal connectives, the purpose of which is not clear. The Slit protein is processed into a larger N-terminal peptide and a smaller C-terminal peptide. Here, I show that Slit and Slit-N in tracts interact with Robo to maintain the fasciculation, the inter-tract spacing between tracts and their position relative to the midline. Thus, in the absence of Slit in post-guidance tracts, tracts de fasciculate, merge with one another and shift their position towards the midline. The Slit protein is proposed to function as a gradient. However, I show that Slit and Slit-N are not freely present in the extracellular milieu but associated with the extracellular matrix (ECM) and both interact with Robo1. Slit-C is tightly associated with the ECM requiring collagenase treatment to release it, and it does not interact with Robo1. These results define a role for Slit and Slit-N in tracts for the maintenance and fasciculation of tracts, thus the maintenance of the hardwiring of the CNS. PMID- 29155814 TI - Optimal synaptic signaling connectome for locomotory behavior in Caenorhabditis elegans: Design minimizing energy cost. AB - The detailed knowledge of C. elegans connectome for 3 decades has not contributed dramatically to our understanding of worm's behavior. One of main reasons for this situation has been the lack of data on the type of synaptic signaling between particular neurons in the worm's connectome. The aim of this study was to determine synaptic polarities for each connection in a small pre-motor circuit controlling locomotion. Even in this compact network of just 7 neurons the space of all possible patterns of connection types (excitation vs. inhibition) is huge. To deal effectively with this combinatorial problem we devised a novel and relatively fast technique based on genetic algorithms and large-scale parallel computations, which we combined with detailed neurophysiological modeling of interneuron dynamics and compared the theory to the available behavioral data. As a result of these massive computations, we found that the optimal connectivity pattern that matches the best locomotory data is the one in which all interneuron connections are inhibitory, even those terminating on motor neurons. This finding is consistent with recent experimental data on cholinergic signaling in C. elegans, and it suggests that the system controlling locomotion is designed to save metabolic energy. Moreover, this result provides a solid basis for a more realistic modeling of neural control in these worms, and our novel powerful computational technique can in principle be applied (possibly with some modifications) to other small-scale functional circuits in C. elegans. PMID- 29155815 TI - Allopurinol attenuates acute kidney injury following Bothrops jararaca envenomation. AB - Snakebites have been recognized as a neglected public health problem in several tropical and subtropical countries. Bothrops snakebites frequently complicate with acute kidney injury (AKI) with relevant morbidity and mortality. To date, the only treatment available for Bothrops envenomation is the intravenous administration of antivenom despite its several limitations. Therefore, the study of novel therapies in Bothrops envenomation is compelling. The aim of this study was to evaluate the protective effect of Allopurinol (Allo) in an experimental model of Bothrops jararaca venom (BJ)-associated AKI. Five groups of Wistar rats were studied: Sham, Allo, BJ, BJ+Allo, BJ+ipAllo. BJ (0.25 mg/kg) was intravenously injected during 40'. Saline at same dose and infusion rate was administered to Sham and Allo groups. Allo and BJ+Allo groups received Allo (300 mg/L) in the drinking water 7 days prior to Saline or BJ infusion respectively. BJ+ipAllo rats received intraperitoneal Allo (25 mg/Kg) 40' after BJ infusion. BJ rats showed markedly reduced glomerular filtration rate (GFR, inulin clearance) associated with intense renal vasoconstriction, hemolysis, hemoglobinuria, reduced glutathione and increased systemic and renal markers of nitro-oxidative stress (Nitrotyrosine). Allo ameliorated GFR, renal blood flow (RBF), renal vascular resistance and arterial lactate levels. In addition, Allo was associated with increased serum glutathione as well as reduced levels of plasma and renal Nitrotyrosine. Our data show that Allo attenuated BJ-associated AKI, reduced oxidative stress, improved renal hemodynamics and organ perfusion. It might represent a novel adjuvant approach for Bothrops envenomation, a new use for an old and widely available drug. PMID- 29155816 TI - Liposomal amphotericin B in travelers with cutaneous and muco-cutaneous leishmaniasis: Not a panacea. AB - BACKGROUND: Complex cutaneous and muco-cutaneous leishmaniasis (CL and MCL) often requires systemic therapy. Liposomal amphotericin B (L-AmB) has a strong potential for a solid clinical benefit in this indication. METHODS: We conducted a retrospective analysis of data from a French centralized referral treatment program and from the "LeishMan" European consortium database. All patients with parasitologically proven CL or MCL who received at least one dose of L-AmB were included. Positive outcome was based on ulcer closure as per recent WHO workshop guidelines. RESULTS: From 2008 through 2016, 43 travelers returning from 18 countries (Old World n = 28; New World n = 15) were analyzed with a median follow up duration of 79 days [range 28-803]. Main clinical forms were: localized CL with one or multiple lesions (n = 32; 74%) and MCL (n = 8; 19%). As per published criteria 19 of 41 patients (46%) were cured 90 days after one course of L-AmB. When the following items -improvement before day 90 but no subsequent follow-up, delayed healing (>3 months) and healing after a second course of L-AmB- were included in the definition of cure, 27 of 43 patients (63%) had a positive outcome. Five patients (MCL = 1; CL = 4) experienced a relapse after a median duration of 6 months [range 3-27] post treatment and 53% of patients (23/43) experienced at least one adverse event including severe hypokalaemia and acute cardiac failure (one patient each). In multivariate analysis, tegumentary infection with L. infantum was associated with complete healing after L-AmB therapy (OR 5.8 IC 95% [1.03-32]) while infection with other species had no impact on outcome. CONCLUSION: In conditions close to current medical practice, the therapeutic window of L-AmB was narrow in travellers with CL or MCL, with the possible exception of those infected with L. infantum. Strict follow-up is warranted when using L-AmB in patients with mild disease. PMID- 29155817 TI - Analysis of the interactome of Schistosoma mansoni histone deacetylase 8. AB - BACKGROUND: Histone deacetylase 8 from Schistosoma mansoni (SmHDAC8) is essential to parasite growth and development within the mammalian host and is under investigation as a target for the development of selective inhibitors as novel schistosomicidal drugs. Although some protein substrates and protein partners of human HDAC8 have been characterized, notably indicating a role in the function of the cohesin complex, nothing is known of the partners and biological function of SmHDAC8. METHODOLOGY/PRINCIPAL FINDINGS: We therefore employed two strategies to characterize the SmHDAC8 interactome. We first used SmHDAC8 as a bait protein in yeast two-hybrid (Y2H) screening of an S. mansoni cDNA library. This allowed the identification of 49 different sequences encoding proteins. We next performed co immunoprecipitation (Co-IP) experiments on parasite extracts with an anti-SmHDAC8 antibody. Mass spectrometry (MS) analysis allowed the identification of 160 different proteins. CONCLUSIONS/SIGNIFICANCE: SmHDAC8 partners are involved in about 40 different processes, included expected functions such as the cohesin complex, cytoskeleton organization, transcriptional and translational regulation, metabolism, DNA repair, the cell cycle, protein dephosphorylation, proteolysis, protein transport, but also some proteasome and ribosome components were detected. Our results show that SmHDAC8 is a versatile deacetylase, potentially involved in both cytosolic and nuclear processes. PMID- 29155818 TI - SNAIL1-mediated downregulation of FOXA proteins facilitates the inactivation of transcriptional enhancer elements at key epithelial genes in colorectal cancer cells. AB - Phenotypic conversion of tumor cells through epithelial-mesenchymal transition (EMT) requires massive gene expression changes. How these are brought about is not clear. Here we examined the impact of the EMT master regulator SNAIL1 on the FOXA family of transcription factors which are distinguished by their particular competence to induce chromatin reorganization for the activation of transcriptional enhancer elements. We show that the expression of SNAIL1 and FOXA genes is anticorrelated in transcriptomes of colorectal tumors and cell lines. In cellular EMT models, ectopically expressed Snail1 directly represses FOXA1 and triggers downregulation of all FOXA family members, suggesting that loss of FOXA expression promotes EMT. Indeed, cells with CRISPR/Cas9-induced FOXA-deficiency acquire mesenchymal characteristics. Furthermore, ChIP-seq data analysis of FOXA chromosomal distribution in relation to chromatin structural features which characterize distinct states of transcriptional activity, revealed preferential localization of FOXA factors to transcriptional enhancers at signature genes that distinguish epithelial from mesenchymal colon tumors. To validate the significance of this association, we investigated the impact of FOXA factors on structure and function of enhancers at the CDH1, CDX2 and EPHB3 genes. FOXA deficiency and expression of dominant negative FOXA2 led to chromatin condensation at these enhancer elements. Site-directed mutagenesis of FOXA binding sites in reporter gene constructs and by genome-editing in situ impaired enhancer activity and completely abolished the active chromatin state of the EPHB3 enhancer. Conversely, expression of FOXA factors in cells with inactive CDX2 and EPHB3 enhancers led to chromatin opening and de novo deposition of the H3K4me1 and H3K27ac marks. These findings establish the pioneer function of FOXA factors at enhancer regions of epithelial genes and demonstrate their essential role in maintaining enhancer structure and function. Thus, by repressing FOXA family members, SNAIL1 targets transcription factors at strategically important positions in gene-regulatory hierarchies, which may facilitate transcriptional reprogramming during EMT. PMID- 29155819 TI - Determinants of site of tuberculosis disease: An analysis of European surveillance data from 2003 to 2014. AB - BACKGROUND: We explored host-related factors associated with the site of tuberculosis (TB) disease using variables routinely collected by the 31 EU/EEA countries for national surveillance. METHODS: Logistic regression models were fitted to case-based surveillance data reported to the European Centre for Disease Prevention and Control for TB cases notified from 2003 to 2014. Missing data on HIV infection and on susceptibility to isoniazid and rifampicin for many patients precluded the inclusion of these variables in the analysis. Records from Finland, Lithuania, Spain and the United Kingdom were excluded for lack of exact details of disease localisation; other records without one or more variable (e.g. previous treatment history, geographical origin) or who had mixed pulmonary and extrapulmonary disease or more than one form of extrapulmonary disease were also removed (total exclusion = 38% of 913,637 notifications). RESULTS: 564,916 TB cases reported by 27 EU/EEA countries had exclusive pulmonary (PTB; 83%) or extrapulmonary (EPTB; 17%) disease. EPTB was associated with age <15 years (aOR: 5.50), female sex (aOR: 1.60), no previous TB treatment (aOR: 3.10), and geographic origin (aOR range: 0.52-3.74). Origin from the Indian subcontinent or Africa was most strongly associated with lymphatic, osteo-articular and peritoneal/digestive localization (aOR>3.7), and age <15 years with lymphatic (aOR: 17.96) and central nervous system disease (aOR: 11.41). CONCLUSIONS: Awareness of host-related determinants of site of TB is useful for diagnosis. The predilection for EPTB among patients originating from countries outside Europe may reflect strain preferences for disease localization, geographic/ethnic differences in disease manifestation and other factors, like HIV. PMID- 29155820 TI - Mass spectrometry-based quantification of the cellular response to ultraviolet radiation in HeLa cells. AB - Ultraviolet (UV) irradiation is a common form of DNA damage that can cause pyrimidine dimers between DNA, which can cause gene mutations, even double-strand breaks and threaten genome stability. If DNA repair systems default their roles at this stage, the organism can be damaged and result in disease, especially cancer. To better understand the cellular response to this form of damage, we applied highly sensitive mass spectrometry to perform comparative proteomics of phosphorylation in HeLa cells. A total of 4367 phosphorylation sites in 2100 proteins were identified, many of which had not been reported previously. Comprehensive bioinformatics analysis revealed that these proteins were involved in many important biological processes, including signaling, localization and cell cycle regulation. The nuclear pore complex, which is very important for RNA transport, was changed significantly at phosphorylation level, indicating its important role in response to UV-induced cellular stress. Protein-protein interaction network analysis and DNA repair pathways crosstalk were also examined in this study. Proteins involved in base excision repair, nucleotide repair and mismatch repair changed their phosphorylation pattern in response to UV treatment, indicating the complexity of cellular events and the coordination of these pathways. These systematic analyses provided new clues of protein phosphorylation in response to specific DNA damage, which is very important for further investigation. And give macroscopic view on an overall phosphorylation situation under UV radiation. PMID- 29155821 TI - Progress towards a leprosy-free country: The experience of Oman. AB - INTRODUCTION: The World Health Organization (WHO) released the Global Leprosy Strategy 2016-2020 towards a leprosy-free world. The author described the progress made towards the elimination of leprosy and suggested recommendations for the acceleration towards a Leprosy-free country according to WHO laid out criterion. METHODOLOGY: Case record review of Leprosy patients managed between the years 1992 to 2015 were registered and analyzed. Data were collected from annual reports of the Ministry of Health including demographics, classification of leprosy new cases, relapse, childhood, grades of disability (GD) and multidrug therapy (MDT) completion rates. RESULTS: Leprosy prevalence rate declined from 1.64 to 0.09 per 10,000 population during the period 1992 and 2015 (p<0.0001). Between 2005 and 2015, 77 patients were diagnosed with Leprosy as per definition and 75/77 (98%) had smear or biopsy positive. Of these, 53 (69%) cases were among foreign-born (non-national) (p<0.003) and 19 (25%) were among women. Most of the leprosy cases were notified in Muscat governorate 29 (38%) and among patients between 25-44 years of age 41 (53%), followed by >=45 years 29 (38%) and 6 (8%) were children age <= 14 years. Multi-bacillary (MB) cases reported 60 versus 17 for Pauci-bacillary (PB) (p< 0.01), while MB was highest among both nationals (83%) and foreign-born (75%). MDT completion rate was 100% and no relapse cases were notified among nationals. The rate of new patients diagnosed with leprosy related disability was 2.3 per million population, and grade 2 disability (G2D) rate among nationals was 0.9 per million population. No disability was recorded among women or children less than 14 years within the nationals group from 2013. Almost all the foreign-born patients didn't complete their treatment in Oman as they left the country shortly after diagnosis of leprosy due to a very short term contract, discretionary employment practices by the employers and prefer to go home to complete their treatment. CONCLUSION: Oman has met the elimination goals and made great strides towards becoming a leprosy-free country. However, challenges such as improving surveillance system efficiency and sensitivity for detecting timely leprosy cases, as well as foreign-born workers are still a major concerns. PMID- 29155822 TI - Heavy-atom effect on optically excited triplet state kinetics. AB - In several fields of research, like e.g. photosensitization, photovoltaics, organic electroluminescent devices, dynamic nuclear polarization, or pulsed dipolar electron paramagnetic resonance spectroscopy, triplet state kinetics play an important role. It is therefore desirable to tailor the kinetics of photoexcited triplet states, e.g. by exploiting the intramolecular heavy-atom effect, and to determine the respective kinetic parameters. In this work, we set out to systematically investigate the photoexcited triplet state kinetics of a series of haloanthracenes by time-resolved electron paramagnetic resonance spectroscopy in combination with synchronized laser excitation. For this purpose, a procedure to simulate time traces by solving the differential equation system governing the triplet kinetics numerically is developed. This way, spin lattice relaxation rates and zero-field triplet life times are obtained concurrently by a global fit to experimental data measured at three different cryogenic temperatures. PMID- 29155823 TI - Development and preliminary evaluation of a multiplexed amplification and next generation sequencing method for viral hemorrhagic fever diagnostics. AB - BACKGROUND: We describe the development and evaluation of a novel method for targeted amplification and Next Generation Sequencing (NGS)-based identification of viral hemorrhagic fever (VHF) agents and assess the feasibility of this approach in diagnostics. METHODOLOGY: An ultrahigh-multiplex panel was designed with primers to amplify all known variants of VHF-associated viruses and relevant controls. The performance of the panel was evaluated via serially quantified nucleic acids from Yellow fever virus, Rift Valley fever virus, Crimean-Congo hemorrhagic fever (CCHF) virus, Ebola virus, Junin virus and Chikungunya virus in a semiconductor-based sequencing platform. A comparison of direct NGS and targeted amplification-NGS was performed. The panel was further tested via a real time nanopore sequencing-based platform, using clinical specimens from CCHF patients. PRINCIPAL FINDINGS: The multiplex primer panel comprises two pools of 285 and 256 primer pairs for the identification of 46 virus species causing hemorrhagic fevers, encompassing 6,130 genetic variants of the strains involved. In silico validation revealed that the panel detected over 97% of all known genetic variants of the targeted virus species. High levels of specificity and sensitivity were observed for the tested virus strains. Targeted amplification ensured viral read detection in specimens with the lowest virus concentration (1 10 genome equivalents) and enabled significant increases in specific reads over background for all viruses investigated. In clinical specimens, the panel enabled detection of the causative agent and its characterization within 10 minutes of sequencing, with sample-to-result time of less than 3.5 hours. CONCLUSIONS: Virus enrichment via targeted amplification followed by NGS is an applicable strategy for the diagnosis of VHFs which can be adapted for high-throughput or nanopore sequencing platforms and employed for surveillance or outbreak monitoring. PMID- 29155824 TI - Reducing the rate of cesarean delivery on maternal request through institutional and policy interventions in Wenzhou, China. AB - The objective of this study was to evaluate the effect of institutional and policy interventions on reducing the rate of cesarean delivery on maternal request (CDMR) in Wenzhou, China. Institutional interventions included health education, painless delivery introduction, and doula care. Additionally, a series of health policies were developed by the Chinese central and local governments to control cesarean section rates, mostly through controlling CDMR rates. We conducted a pre-/post-intervention study using 131,312 deliveries between 2006 and 2014 in three tertiary-level public hospitals in Wenzhou, China. Chi-square tests and predictive models were used to examine changes in the CDMR rate before and after institutional and policy interventions. After institutional interventions were introduced, the overall CDMR rate increased from 15.76% to 16.34% (p = 0.053), but the average annual growth rate (AAGR) of the overall CDMR rate quickly declined from 20.11% to -4.30%. After policy interventions were introduced, the overall CDMR rate, the AAGR of the overall CDMR rate, and the probability of performing CDMR declined. Further, the overall probability of a woman undergoing CDMR decreased in all three age groups (group one: <24; group two: 24-34; group three: >34) after institutional and policy interventions. These results show that institutional and policy interventions can reduce the CDMR rate. Additionally, the CDMR rate should be included in hospitals' performance assessment matrix to reduce the CDMR rate further. PMID- 29155825 TI - Poverty and health among CDC plantation labourers in Cameroon: Perceptions, challenges and coping strategies. AB - Creating better access to good quality healthcare for the poor is a major challenge to development. In this study, we examined inter-linkages between poverty and disease, referred to as poverty-related diseases (PRDs), by investigating how Cameroon Development Corporation (CDC) camp dwellers respond to diseases that adversely affect their health and wellbeing. Living in plantation camps is associated with poverty, overcrowding, poor sanitation and the rapid spread of diseases. In a survey of 237 CDC camp dwellers in Cameroon, we used the health belief model to understand the drivers (perceived threats, benefits and cues for treatment seeking) of reported responses. Using logistic regression analysis, we looked for trends in people's response to malaria. We calculated the odds ratio of factors shown to have an influence on people's health, such as food, water, sanitation challenges and seeking formal healthcare for malaria. Malaria (40.3%), cholera (20.8%) and diarrhoea (17.7%) were the major PRDs perceived by camp dwellers. We found a strong link between what respondents perceived as PRDS and hygiene conditions. Poverty for our respondents was more about living in poor hygiene conditions than lack of money. Respondents perceived health challenges as stemming from their immediate living environment. Moreover, people employed self-medication and other informal health practices to seek healthcare. Interestingly, even though respondents reported using formal healthcare services as a general response to illness (84%), almost 90% stated that, in the case of malaria, they would use informal healthcare services. Our study recommends that efforts to curb the devastating effects of PRDs should have a strong focus on perceptions (i.e. include diseases that people living in conditions of poverty perceive as PRDs) and on hygiene practices, emphasising how they can be improved. By providing insights into the inter-linkages between poverty and disease, our study offers relevant guidance for potentially successful health promotion interventions. PMID- 29155827 TI - The Asian house shrew Suncus murinus as a reservoir and source of human outbreaks of plague in Madagascar. AB - Identifying key reservoirs for zoonoses is crucial for understanding variation in incidence. Plague re-emerged in Mahajanga, Madagascar in the 1990s but there has been no confirmed case since 1999. Here we combine ecological and genetic data, from during and after the epidemics, with experimental infections to examine the role of the shrew Suncus murinus in the plague epidemiological cycle. The predominance of S. murinus captures during the epidemics, their carriage of the flea vector and their infection with Yersinia pestis suggest they played an important role in the maintenance and transmission of plague. S. murinus exhibit a high but variable resistance to experimental Y. pestis infections, providing evidence of its ability to act as a maintenance host. Genetic analyses of the strains isolated from various hosts were consistent with two partially-linked transmission cycles, with plague persisting within the S. murinus population, occasionally spilling over into the rat and human populations. The recent isolation from a rat in Mahajanga of a Y. pestis strain genetically close to shrew strains obtained during the epidemics reinforces this hypothesis and suggests circulation of plague continues. The observed decline in S. murinus and Xenopsylla cheopis since the epidemics appears to have decreased the frequency of spillover events to the more susceptible rats, which act as a source of infection for humans. Although this may explain the lack of confirmed human cases in recent years, the current circulation of plague within the city highlights the continuing health threat. PMID- 29155826 TI - Programmatic factors associated with the limited impact of Community-Directed Treatment with Ivermectin to control Onchocerciasis in three drainage basins of South West Cameroon. AB - INTRODUCTION: The CDTI model is known to have enhanced community participation in planning and resource mobilization toward the control of onchocerciasis. These effects were expected to translate into better individual acceptance of the intervention and hence high Treatment Coverage, leading to a sustainable community-led strategy and reduction in the disease burden. A survey revealed that after 10-12 rounds of treatment, prevalence of onchocerciasis was still high in three drainage basins of South West Cameroon and transmission was going on. METHODS: We designed a three (3)-year retrospective (2012, 2013 and 2014), descriptive cross-sectional study to explore the roles of operational challenges in the failure of CDTI to control the disease as expected. We administered 83 semi-structured questionnaires and conducted 12 in-depth interviews with Chiefs of Bureau Health, Chiefs of Centers, CDDs and Community Heads. Descriptive statistics was used to explore indicators of performance which were supported with views from in-depth interviews. RESULTS: We found that community participation was weak; communities were not deciding time and mode of distributions. Only 6 (15.0%) of 40 Community Drug Distributors reported they were selected at general community meetings as required. The health service was not able to meet and discuss Community-Directed Treatment with Ivermectin activities with individual communities partly due to transportation challenges; this was mostly done through letters. Funding was reported to be inadequate and not timely. Funds were not available to conduct Community-Self Monitoring after the 2014 Mass Drug Administration. There was inadequate health staff at the frontline health facility levels, and some Chiefs of Center reported that Community-Directed Treatment with Ivermectin work was too much for them. The mean operational Community Drug Distributor-population ratio was 1 Community Drug Distributor per 317 populations (range: 194-464, expected is 1:250). Community Drug Distributor attrition rate was 14% (2012), 11% (2013) and 12% (2014) of total Community Drug Distributors trained in the region. Lack of incentive for Community Drug Distributor was primary reason for Community Drug Distributor attrition. Number of Community Drug Distributors trained together by health area ranged from 14 to 127 (mean +/- SD = 51 +/-32) with duration of training ranging from 4-7 hours (mean +/- SD = 5.05 +/- 1.09). The trainings were conducted at the health centers. Community Drug Distributors always conducted census during the past three distributions (Mean +/- SD = 2.85 +/- 0.58). Community-Self Monitoring was facing challenge. Several of the community heads, Chiefs of Bureau Health and Chiefs of Center agreed that Community-Self Monitoring was not being carried out effectively due to lack of incentives for monitors in the communities. CONCLUSION: Inadequate human resource, funding issues and transportation challenges during distribution periods reduced the ability of the health service to thoroughly sensitize communities and supervise CDTI activities. This resulted in weak community understanding, acceptance and participation in the process. CDTI in our study area did not achieve sustainable community-led campaign and this may have led to the reduced impact on Onchocerciasis. PMID- 29155828 TI - Role of co-repressor genomic landscapes in shaping the Notch response. AB - Repressors are frequently deployed to limit the transcriptional response to signalling pathways. For example, several co-repressors interact directly with the DNA-binding protein CSL and are proposed to keep target genes silenced in the absence of Notch activity. However, the scope of their contributions remains unclear. To investigate co-repressor activity in the context of this well defined signalling pathway, we have analysed the genome-wide binding profile of the best characterized CSL co-repressor in Drosophila, Hairless, and of a second CSL interacting repressor, SMRTER. As predicted there was significant overlap between Hairless and its CSL DNA-binding partner, both in Kc cells and in wing discs, where they were predominantly found in chromatin with active enhancer marks. However, while the Hairless complex was widely present at some Notch regulated enhancers in the wing disc, no binding was detected at others, indicating that it is not essential for silencing per se. Further analysis of target enhancers confirmed differential requirements for Hairless. SMRTER binding significantly overlapped with Hairless, rather than complementing it, and many enhancers were apparently co-bound by both factors. Our analysis indicates that the actions of Hairless and SMRTER gate enhancers to Notch activity and to Ecdysone signalling respectively, to ensure that the appropriate levels and timing of target gene expression are achieved. PMID- 29155829 TI - Environmental and socio-demographic individual, family and neighborhood factors associated with children intestinal parasitoses at Iguazu, in the subtropical northern border of Argentina. AB - BACKGROUND: Intestinal parasitoses are a major concern for public health, especially in children from middle and low-income populations of tropical and subtropical areas. We examined the presence and co-infection of parasites in humans as well as parasitic environmental contamination in Puerto Iguazu, Argentina. We explored the environmental and socio-demographic characteristics of the persistence of parasites in children and their environment. METHODOLOGY/PRINCIPAL FINDINGS: This cross-section survey was conducted among children population comprised into the area of the public health care centers of Iguazu during June 2013 to May 2016. Copro-parasitological status of 483 asymptomatic children was assessed. Simultaneously, a design-based sampling of 744 soil samples and 530 dog feces was used for characterize the environmental contamination. The 71.5% of these sites were contaminated. Sixteen genera were detected in the environment being hookworms (62.0%) the main pathogens group detected followed by Toxocara spp (16.3%), Trichuris spp (15.2%) and Giardia (6.5%). Total children prevalence raised 58.8%, detecting twelve genera of parasite with Giardia intestinalis as the most prevalent pathogen (29.0%) followed by Enterobius vermicularis (23.0%), Hymenolepis nana (12.4%) and hookworms (4.4%). Through questionnaires and census data, we characterized the socio-demographics conditions at an individual, family and neighborhood levels. A multi-level analysis including environmental contamination data showed that the 'presence of parasites' was mostly determined by individual (e.g. age, playing habits, previous treatment) and household level (e.g. UBN, WASH, mother's literacy) determinants. Remarkably, to define the level of 'parasite co infection', besides individual and household characteristics, environmental factors at a neighborhood level were important. CONCLUSION/SIGNIFICANCE: Our work represents the major survey of intestinal parasites in human and environmental samples developed in the region. High prevalence was detected in the children population as well as in their environment. This work shows the importance of considering and promoting multi-level actions over the identified determinants to face this public health problem from integrative approaches. PMID- 29155831 TI - Prevalence and risk factors associated with Leishmania infection in Trang Province, southern Thailand. AB - BACKGROUND: Autochthonous cutaneous and visceral leishmaniasis (VL) caused by Leishmania martiniquensis and Leishmania siamensis have been considered emerging infectious diseases in Thailand. The disease burden is significantly underestimated, especially the prevalence of Leishmania infection among HIV positive patients. METHODS: A cross-sectional study was conducted to determine the prevalence and risk factors associated with Leishmania infection among patients with HIV/AIDS living in Trang province, southern Thailand, between 2015 and 2016. Antibodies against Leishmania infection were assayed using the direct agglutination test (DAT). DNA of Leishmania was detected by ITS1-PCR using the buffy coat. Species of Leishmania were also identified. RESULTS: Of 724 participants, the prevalence of Leishmania infection was 25.1% (182/724) using either DAT or PCR assays. Seroprevalence of Leishmania infection was 18.5% (134/724), while Leishmania DNA detected by the PCR method was 8.4% (61/724). Of these, 24.9% (180/724) were asymptomatic, whereas 0.3% (2/724) were symptomatic VL and VL/CL (cutaneous leishmaniasis). At least five species were identified: L. siamensis, L. martiniquensis, L. donovani complex, L. lainsoni, and L. major. Multivariate analysis showed that CD4+ levels <500 cells/MUL and living in stilt houses were independently associated with Leishmania infection. Those who were PCR positive for Leishmania DNA were significantly associated with a detectable viral load, whereas non-injection drug use (NIDU) and CD4+ levels <500 cells/MUL were potential risk factors of Leishmania seropositivity. CONCLUSIONS: A magnitude of the prevalence of underreporting Leishmania infection among Thai patients with HIV was revealed in this study. Effective public health policy to prevent and control disease transmission is urgently needed. PMID- 29155830 TI - Molecular characterization of tsetse's proboscis and its response to Trypanosoma congolense infection. AB - Tsetse flies (Glossina spp.) transmit parasitic African trypanosomes (Trypanosoma spp.), including Trypanosoma congolense, which causes animal African trypanosomiasis (AAT). AAT detrimentally affects agricultural activities in sub Saharan Africa and has negative impacts on the livelihood and nutrient availability for the affected communities. After tsetse ingests an infectious blood meal, T. congolense sequentially colonizes the fly's gut and proboscis (PB) organs before being transmitted to new mammalian hosts during subsequent feedings. Despite the importance of PB in blood feeding and disease transmission, little is known about its molecular composition, function and response to trypanosome infection. To bridge this gap, we used RNA-seq analysis to determine its molecular characteristics and responses to trypanosome infection. By comparing the PB transcriptome to whole head and midgut transcriptomes, we identified 668 PB-enriched transcripts that encoded proteins associated with muscle tissue, organ development, chemosensation and chitin-cuticle structure development. Moreover, transcripts encoding putative mechanoreceptors that monitor blood flow during tsetse feeding and interact with trypanosomes were also expressed in the PB. Microscopic analysis of the PB revealed cellular structures associated with muscles and cells. Infection with T. congolense resulted in increased and decreased expression of 38 and 88 transcripts, respectively. Twelve of these differentially expressed transcripts were PB-enriched. Among the transcripts induced upon infection were those encoding putative proteins associated with cell division function(s), suggesting enhanced tissue renewal, while those suppressed were associated with metabolic processes, extracellular matrix and ATP-binding as well as immunity. These results suggest that PB is a muscular organ with chemosensory and mechanosensory capabilities. The mechanoreceptors may be point of PB-trypanosomes interactions. T. congolense infection resulted in reduced metabolic and immune capacity of the PB. The molecular knowledge on the composition and putative functions of PB forms the foundation to identify new targets to disrupt tsetse's ability to feed and parasite transmission. PMID- 29155832 TI - Implementing universal HIV treatment in a high HIV prevalence and rural South African setting - Field experiences and recommendations of health care providers. AB - BACKGROUND: We aimed to describe the field experiences and recommendations of clinic-based health care providers (HCP) regarding the implementation of universal antiretroviral therapy (ART) in rural KwaZulu-Natal, South Africa. METHODS: In Hlabisa sub-district, the local HIV programme of the Department of Health (DoH) is decentralized in 18 clinics, where ART was offered at a CD4 count <=500 cells/MUL from January 2015 to September 2016. Within the ANRS 12249 TasP trial, implemented in part of the sub-district, universal ART (no eligibility criteria) was offered in 11 mobile clinics between March 2012 and June 2016. A cross-sectional qualitative survey was conducted in April-July 2016 among clinic based nurses and counsellors providing HIV care in the DoH and TasP trial clinics. In total, 13 individual interviews and two focus groups discussions (including 6 and 7 participants) were conducted, audio-recorded, transcribed, and thematically analyzed. RESULTS: All HCPs reported an overall good experience of delivering ART early in the course of HIV infection, with most patients willing to initiate ART before being symptomatic. Yet, HCPs underlined that not feeling sick could challenge early ART initiation and adherence, and thus highlighted the need to take time for counselling as an important component to achieve universal ART. HCPs also foresaw logistical challenges of universal ART, and were especially concerned about increasing workload and ART shortage. HCPs finally recommended the need to strengthen the existing model of care to facilitate access to ART, e.g., community-based and integrated HIV services. CONCLUSIONS: The provision of universal ART is feasible and acceptable according to HCPs in this rural South-African area. However their experiences suggest that universal ART, and more generally the 90-90-90 UNAIDS targets, will be difficult to achieve without the implementation of new models of health service delivery. PMID- 29155833 TI - Do intra-articular hyaluronic acid injections delay total knee replacement in patients with osteoarthritis - A Cox model analysis. AB - OBJECTIVES: This study aimed to describe patients treated for knee osteoarthritis between 2006 and 2013 in France and to compare the delay from diagnosis to total knee replacement between patients who received intra-articular hyaluronic acid injections and those who did not receive the injections. A second objective was to compare direct medical costs for ambulatory care between treatment groups. MATERIALS AND METHODS: Patients were selected from a representative sample of the real world administrative claims database using an algorithm developed by experts from the scientific committee of the study. Data were matched with the medico administrative database for hospital care. A Cox proportional hazards model was stratified for the treatment group and adjusted for available socio-demographic and medical covariates to compare restricted mean survival times at different time points (1, 3, 5 and 7.5 years) between groups. Costs were expressed in 2013 euros. RESULTS: A total of 14,782 patients were treated for knee osteoarthritis (67% women; mean age = 68 years). Among this population, 1,662 patients had total knee replacement (11.2%). At each time point, restricted mean survival time without total knee replacement was significantly higher (p-values<0.001) for hyaluronic acid group, from +51 to +217 days at 1 and 7.5 years, respectively. For the year preceding total knee replacement, the means for total direct medical costs were similar between groups, ?744 vs ?805 for treatment and control groups, respectively, (p-value = 0.104). Intra-articular injections accounted for less than 10% of the total costs. CONCLUSION: This is the first retrospective longitudinal study involving knee osteoarthritis patients using medico administrative databases in France. The results support the effectiveness of hyaluronic acid injections in delaying total knee replacement and show that patients treated with hyaluronic acid have similar direct medical costs for ambulatory care compared to patients treated with corticosteroids only. PMID- 29155834 TI - Measuring the microbiome of chronic wounds with use of a topical antimicrobial dressing - A feasibility study. AB - BACKGROUND: Polymicrobial communities colonize all wounds, and biofilms are hypothesized to be a key link to the chronic state and stalled healing. Molecular methods offer greater insight when studying microbial ecology in chronic wounds, as only a small fraction of wound bacteria are cultured by currently available methods and studies have shown little agreement between culture and molecular based approaches. Some interventions, like dressings with oxidized silver, are reported to help the stalled wounds move to a normal healing trajectory but the underlying mechanisms are difficult to measure. One hypothesis is that the use of topical antimicrobial dressings targets the wound microbiome and reduces bioburden. OBJECTIVES: Our objective was to determine if culture-independent molecular methods could be used to identify the microbial composition in chronic wounds, and measure the microbiome over time when a topical antimicrobial dressing is used to reduce bioburden. METHODS: Patients with chronic wounds defined as >6 weeks in duration and not taking systemic antibiotics were recruited to participate. A wound contact layer containing silver oxynitrate was applied immediately after routine sharp debridement material was collected and swabs of the wound bed taken. Next-generation sequencing of the bacterial 16S rRNA gene in each specimen was used to measure the microbiome. RESULTS: Distinct bacterial communities were observed between swab and debridement samples, highlighting spatial differences and the importance of sampling consistency. The microbial communities appeared to be similar between different diabetes statuses, but different among the three wound categories included. CONCLUSIONS: Culture independent methods can be applied to measure the microbiome of chronic wounds even when a topical antimicrobial dressing is applied to the wound. PMID- 29155835 TI - Assessment of transposition of the great arteries associated with multiple malformations using dual-source computed tomography. AB - PURPOSE: To determine the value of dual-source computed tomography (DSCT) in depicting the morphological characteristics and diagnosing the associated malformations for patients with transposition of the great arteries (TGA) before surgery. MATERIALS AND METHODS: Twenty-five patients with TGA who underwent DSCT and transthoracic echocardiography (TTE) examination were retrospectively reviewed. The morphological types of TGA, the spatial relationship between the pulmonary artery and the aorta, as well as coronary artery-associated abnormalities were assessed by DSCT. In contrast to TTE, the diagnostic accuracy of associated malformations on DSCT were analyzed and calculated with reference to surgical or digital subtraction angiography (DSA) findings. Effective doses (EDs) were also calculated. RESULTS: Among the 25 patients, 12 (48%) had ventricular septal defects and left ventricular outflow tract stenosis. Sixteen patients (16/25, 64%) had great arteries with an oblique spatial relationship on DSCT. In addition, we found seven patients (7/25, 28%) with coronary artery malformation, including five with an abnormal coronary origin and two with signs of a myocardial bridge. According to DSA or surgical findings, DSCT was superior to TTE in demonstrating extracardiac anomalies (sensitivity, anomalies of great vessels: 100% vs. 93.33%, other anomalies: 100% vs. 46.15%). The mean estimated ED for those aged <10 years was <2 mSv (1.59 +/- 0.95 mSv). CONCLUSIONS: DSCT can achieve an overall assessment of patients with TGA, including any associated malformations as well as the identification of the spatial relationship of the great arteries. DSCT can therefore be considered as an alternative imaging modality for surgical decision making. PMID- 29155836 TI - Genetic variation in Dip5, an amino acid permease, and Pdr5, a multiple drug transporter, regulates glyphosate resistance in S. cerevisiae. AB - S. cerevisiae from different environments are subject to a wide range of selective pressures, whether intentional or by happenstance. Chemicals classified by their application, such as herbicides, fungicides and antibiotics, can affect non-target organisms. First marketed as RoundUpTM, glyphosate is the most widely used herbicide. In plants, glyphosate inhibits EPSPS, of the shikimate pathway, which is present in many organisms but lacking in mammals. The shikimate pathway produces chorismate which is the precursor to all the aromatic amino acids, para aminobenzoic acid, and Coenzyme Q10. Crops engineered to be resistant to glyphosate contain a homolog of EPSPS that is not bound by glyphosate. Here, we show that S. cerevisiae has a wide-range of glyphosate resistance. Sequence comparison between the target proteins, i.e., the plant EPSPS and the yeast orthologous protein Aro1, predicted that yeast would be resistant to glyphosate. However, the growth variation seen in the subset of yeast tested was not due to polymorphisms within Aro1, instead, it was caused by genetic variation in an ABC multiple drug transporter, Pdr5, and an amino acid permease, Dip5. Using genetic variation as a probe into glyphosate response, we uncovered mechanisms that contribute to the transportation of glyphosate in and out of the cell. Taking advantage of the natural genetic variation within yeast and measuring growth under different conditions that would change the use of the shikimate pathway, we uncovered a general transport mechanism of glyphosate into eukaryotic cells. PMID- 29155837 TI - Reduced order modeling and analysis of the human complement system. AB - Complement is an important pathway in innate immunity, inflammation, and many disease processes. However, despite its importance, there are few validated mathematical models of complement activation. In this study, we developed an ensemble of experimentally validated reduced order complement models. We combined ordinary differential equations with logical rules to produce a compact yet predictive model of complement activation. The model, which described the lectin and alternative pathways, was an order of magnitude smaller than comparable models in the literature. We estimated an ensemble of model parameters from in vitro dynamic measurements of the C3a and C5a complement proteins. Subsequently, we validated the model on unseen C3a and C5a measurements not used for model training. Despite its small size, the model was surprisingly predictive. Global sensitivity and robustness analysis suggested complement was robust to any single therapeutic intervention. Only the simultaneous knockdown of both C3 and C5 consistently reduced C3a and C5a formation from all pathways. Taken together, we developed a validated mathematical model of complement activation that was computationally inexpensive, and could easily be incorporated into pre-existing or new pharmacokinetic models of immune system function. The model described experimental data, and predicted the need for multiple points of therapeutic intervention to fully disrupt complement activation. PMID- 29155838 TI - The tick biocontrol agent Metarhizium brunneum (= M. anisopliae) (strain F52) does not reduce non-target arthropods. AB - Previous studies have found that Met52(r), which contains the entomopathogenic fungus Metarhizium brunneum, is effective in reducing the abundance of Ixodes scapularis, the tick vector for the bacterium causing Lyme disease and for other tick-borne pathogens. Given widespread interest in effective, safe methods for controlling ticks, Met52 has the potential to be used at increasing scales. The non-target impacts of Met52, as applied for tick control, have not yet been assessed. A Before-After-Control-Impact experiment was conducted to assess the effects of Met52 on non-target arthropods in lawn and forest habitats typical of residential yards. Ground-dwelling arthropods were collected using bulk sampling of soil and litter, and pitfall sampling. Arthropods were sampled once before and twice after treatment of plots with either Met52 or water (control). Multivariate general linear models were used to jointly model the abundance of arthropod orders. For each sampling method and post-spray sampling occasion, Akaike Information Criterion values were used to compare the fits of two alternative models: one that included effects of period (before vs. after spray), habitat (lawn vs. forest), and treatment (Met52 vs. control), versus a nested null model that included effects of period, and habitat, but no treatment effect. The null model was consistently better supported by the data. Significant effects were found of period and habitat but not treatment. Retrospective power analysis indicated the study had 80% power to detect a 50% reduction in arthropod abundance, as measured by bulk samples taken before versus one week after treatment. The deployment of Met52 in suburban settings is unlikely to cause meaningful reductions in the abundance of non-target arthropods. PMID- 29155839 TI - Performance of thigh-mounted triaxial accelerometer algorithms in objective quantification of sedentary behaviour and physical activity in older adults. AB - Accurate monitoring of sedentary behaviour and physical activity is key to investigate their exact role in healthy ageing. To date, accelerometers using cut off point models are most preferred for this, however, machine learning seems a highly promising future alternative. Hence, the current study compared between cut-off point and machine learning algorithms, for optimal quantification of sedentary behaviour and physical activity intensities in the elderly. Thus, in a heterogeneous sample of forty participants (aged >=60 years, 50% female) energy expenditure during laboratory-based activities (ranging from sedentary behaviour through to moderate-to-vigorous physical activity) was estimated by indirect calorimetry, whilst wearing triaxial thigh-mounted accelerometers. Three cut-off point algorithms and a Random Forest machine learning model were developed and cross-validated using the collected data. Detailed analyses were performed to check algorithm robustness, and examine and benchmark both overall and participant-specific balanced accuracies. This revealed that the four models can at least be used to confidently monitor sedentary behaviour and moderate-to vigorous physical activity. Nevertheless, the machine learning algorithm outperformed the cut-off point models by being robust for all individual's physiological and non-physiological characteristics and showing more performance of an acceptable level over the whole range of physical activity intensities. Therefore, we propose that Random Forest machine learning may be optimal for objective assessment of sedentary behaviour and physical activity in older adults using thigh-mounted triaxial accelerometry. PMID- 29155840 TI - Indications and determinants of caesarean section delivery: Evidence from a population-based study in Matlab, Bangladesh. AB - BACKGROUND AND METHODS: Caesarean section (C-section) is a major obstetric intervention for saving lives of women and their newborns from pregnancy and childbirth related complications. Un-necessary C-sections may have adverse impact upon maternal and neonatal outcomes. In Bangladesh there is paucity of data on clinical indication of C-section at population level. We conducted a retrospective study in icddr,b Health and Demographic Surveillance System (HDSS) area of Matlab to look into the indications and determinants of C-sections. All resident women in HDSS service area who gave birth in 2013 with a known birth outcome, were included in the study. Women who underwent C-section were identified from birth and pregnancy files of HDSS and their indication for C section were collected reviewing health facility records where the procedure took place, supplemented by face-to-face interview of mothers where data were missing. Indications of C-section were presented as frequency distribution and further divided into different groups following 3 distinct classification systems. Socio demographic predictors were explored following statistical method of binary logistic regression. FINDINGS: During 2013, facility delivery rate was 84% and population based C-section rate was 35% of all deliveries in icddr,b service area. Of all C-sections, only 1.4% was conducted for Absolute Maternal Indications (AMIs). Major indications of C-sections included: repeat C-section (24%), foetal distress (21%), prolonged labour (16%), oligohydramnios (14%) and post-maturity (13%). More than 80% C-sections were performed in for-profit private facilities. Probability of C-section delivery increased with improved socio-economic status, higher education, lower birth order, higher age, and with more number of Antenatal Care use and presence of bad obstetric history. Eight maternal deaths occurred, of which five were delivered by C-section. CONCLUSIONS: C-section rate in this area was much higher than national average as well as global recommendations. Very few of C-sections were undertaken for AMIs. Routine monitoring of clinical indication of C-section in public and private facilities is needed to ensure rational use of the procedure. PMID- 29155841 TI - Habitat- and soil-related drivers of the root-associated fungal community of Quercus suber in the Northern Moroccan forest. AB - Soil fungi associated with plant roots, notably ectomycorrhizal (EcM) fungi, are central in above- and below-ground interactions in Mediterranean forests. They are a key component in soil nutrient cycling and plant productivity. Yet, major disturbances of Mediterranean forests, particularly in the Southern Mediterranean basin, are observed due to the greater human pressures and climate changes. These disturbances highly impact forest cover, soil properties and consequently the root-associated fungal communities. The implementation of efficient conservation strategies of Mediterranean forests is thus closely tied to our understanding of root-associated fungal biodiversity and environmental rules driving its diversity and structure. In our study, the root-associated fungal community of Q. suber was analyzed using high-throughput sequencing across three major Moroccan cork oak habitats. Significant differences in root-associated fungal community structures of Q. suber were observed among Moroccan cork oak habitats (Maamora, Benslimane, Chefchaoun) subjected to different human disturbance levels (high to low disturbances, respectively). The fungal community structure changes correlated with a wide range of soil properties, notably with pH, C:N ratio (P = 0.0002), and available phosphorus levels (P = 0.0001). More than 90 below-ground fungal indicators (P < 0.01)-either of a type of habitat and/or a soil property-were revealed. The results shed light on the ecological significance of ubiquitous ectomycorrhiza (Tomentella, Russula, Cenococcum), and putative sclerotia associated/ericoid mycorrhizal fungal taxa (Cladophialophora, Oidiodendron) in the Moroccan cork oak forest, and their intraspecific variability regarding their response to land use and soil characteristics. PMID- 29155842 TI - Posterior column acetabular fracture fixation using a W-shaped angular plate: A biomechanical analysis. AB - OBJECTIVE: The purpose of this study was to compare the stability and feasibility of four fixation constructs in a posterior column acetabular fracture: one reconstruction plate, one reconstruction plate and lag screw, two reconstruction plates, and a W-shaped acetabular angular plate. METHODS: Twenty embalmed cadaveric pelvises with a posterior column acetabular fractures were allocated to one of four groups: 1) a reconstruction plate, 2) a reconstruction plate with a posterior column lag screw, 3) double reconstruction plates, and 4) a W-shaped acetabular angular plate. These constructs were mechanically loaded on a testing machine, and construct stiffness values were measured. Strain gauges were utilized to measure the mechanical behavior in the condition of compressive force. RESULTS: Final stiffness was not different between the two reconstruction plates (445.81+/-98.30 N/mm) and the W-shaped acetabular angular plate (447.43+/ 98.45 N/mm, p = 0.524), both of which were superior to a single reconstruction plate (248.90+/-61.95 N/mm) and a combined plate and lag screw (326.41+/-94.34 N/mm). Following the fixation of the W-shaped acetabular angular plate, the strain distribution was similar to the intact condition around the acetabulum. The parameters of the W-shaped acetabular angular plate that were observed at the superior region of the acetabulum were less than those of a single reconstruction plate (p<0.05), a single reconstruction plate with lag screw (p<0.05), and two reconstruction plates (p<0.05). CONCLUSIONS: The novel W-shaped acetabular angular plate fixation technique was able to provide the biomechanically stiffest construct for stabilization of a posterior column acetabular fracture; it also resulted in a partial restoration of joint loading parameters toward the intact state. PMID- 29155844 TI - Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells. AB - Human cancers are known to downregulate Major Histocompatibility Complex (MHC) class I expression thereby escaping recognition and rejection by anti-tumor T cells. Here we report that oxygen tension in the tumor microenvironment (TME) serves as an extrinsic cue that regulates antigen presentation by MHC class I molecules. In support of this view, hypoxia is shown to negatively regulate MHC expression in a HIF-dependent manner as evidenced by (i) lower MHC expression in the hypoxic TME in vivo and in hypoxic 3-dimensional (3D) but not 2-dimensional (2D) tumor cell cultures in vitro; (ii) decreased MHC in human renal cell carcinomas with constitutive expression of HIF due to genetic loss of von Hippel Lindau (VHL) function as compared with isogenically paired cells with restored VHL function, and iii) increased MHC in tumor cells with siRNA-mediated knockdown of HIF. In addition, hypoxia downregulated antigen presenting proteins like TAP 1/2 and LMP7 that are known to have a dominant role in surface display of peptide MHC complexes. Corroborating oxygen-dependent regulation of MHC antigen presentation, hyperoxia (60% oxygen) transcriptionally upregulated MHC expression and increased levels of TAP2, LMP2 and 7. In conclusion, this study reveals a novel mechanism by which intra-tumoral hypoxia and HIF can potentiate immune escape. It also suggests the use of hyperoxia to improve tumor cell-based cancer vaccines and for mining novel immune epitopes. Furthermore, this study highlights the advantage of 3D cell cultures in reproducing hypoxia-dependent changes observed in the TME. PMID- 29155843 TI - The relation between statistical power and inference in fMRI. AB - Statistically underpowered studies can result in experimental failure even when all other experimental considerations have been addressed impeccably. In fMRI the combination of a large number of dependent variables, a relatively small number of observations (subjects), and a need to correct for multiple comparisons can decrease statistical power dramatically. This problem has been clearly addressed yet remains controversial-especially in regards to the expected effect sizes in fMRI, and especially for between-subjects effects such as group comparisons and brain-behavior correlations. We aimed to clarify the power problem by considering and contrasting two simulated scenarios of such possible brain-behavior correlations: weak diffuse effects and strong localized effects. Sampling from these scenarios shows that, particularly in the weak diffuse scenario, common sample sizes (n = 20-30) display extremely low statistical power, poorly represent the actual effects in the full sample, and show large variation on subsequent replications. Empirical data from the Human Connectome Project resembles the weak diffuse scenario much more than the localized strong scenario, which underscores the extent of the power problem for many studies. Possible solutions to the power problem include increasing the sample size, using less stringent thresholds, or focusing on a region-of-interest. However, these approaches are not always feasible and some have major drawbacks. The most prominent solutions that may help address the power problem include model-based (multivariate) prediction methods and meta-analyses with related synthesis oriented approaches. PMID- 29155845 TI - Effect of ActiGraph's low frequency extension for estimating steps and physical activity intensity. AB - This study examined the effects of the ActiGraph's (AG) low-frequency extension (LFE) filter on steps and physical activity classification in the free-living environment. Thirty-four African-American women (age, 24.5+/-5.2 years; BMI, 24.9+/-4.5 kg/m2) had daily activity measured simultaneously with an AG-GT3X+ accelerometer and a New Lifestyles NL-800 pedometer for seven days. Steps per day (steps/day) and time (minutes/day) spent in sedentary, light, and moderate-to vigorous physical activity (MVPA) were examined with and without the LFE filter (AG-LFE and AG-N, respectively). The AG-LFE recorded more total steps (13,723+/ 4,983 steps/day) compared to AG-N and NL-800 (6,172+/-2,838 and 5,817+/-3,037 steps/day, respectively; p<0.001). Compared to the AG-N, the AG-LFE estimated less time in sedentary behaviors (518.7+/-92.1 vs. 504.2+/-105.4 min/day, respectively; p<0.001), and more time in light (247.7+/-70.4 vs. 279.1+/-74.7 min/day, respectively; p<0.001) and MVPA (18.9+/-16.9 vs. 21.5+/-18.2 min/day, respectively; p<0.001), respectively. These data suggest that steps and physical activity classifications will be affected when using the ActiGraph with and without the LFE filter. Future research should investigate the accuracy of these measures using the LFE filter. PMID- 29155846 TI - Soluble CD40 ligand directly alters glomerular permeability and may act as a circulating permeability factor in FSGS. AB - CD40/CD40 ligand (CD40L) dyad, a co-stimulatory bi-molecular complex involved in the adaptive immune response, has also potent pro-inflammatory actions in haematopoietic and non-haematopoietic cells. We describe here a novel role for soluble CD40L (sCD40L) as modifier of glomerular permselectivity directly acting on glomerular epithelial cells (GECs). We found that stimulation of CD40, constitutively expressed on GEC cell membrane, by the sCD40L rapidly induced redistribution and loss of nephrin in GECs, and increased albumin permeability in isolated rat glomeruli. Pre-treatment with inhibitors of CD40-CD40L interaction completely prevented these effects. Furthermore, in vivo injection of sCD40L induced a significant reduction of nephrin and podocin expression in mouse glomeruli, although no significant increase of urine protein/creatinine ratio was observed after in vivo injection. The same effects were induced by plasma factors partially purified from post-transplant plasma exchange eluates of patients with focal segmental glomerulosclerosis (FSGS), and were blocked by CD40-CD40L inhibitors. Moreover, 17 and 34 kDa sCD40L isoforms were detected in the same plasmapheresis eluates by Western blotting. Finally, the levels of sCD40Lwere significantly increased in serum of children both with steroid-sensitive and steroid-resistant nephrotic syndrome (NS), and in adult patients with biopsy proven FSGS, compared to healthy subjects, but neither in children with congenital NS nor in patients with membranous nephropathy. Our results demonstrate that sCD40L directly modifies nephrin and podocin distribution in GECs. Moreover, they suggest that sCD40L contained in plasmapheresis eluates from FSGS patients with post-transplant recurrence may contribute, presumably cooperating with other mediators, to FSGS pathogenesis by modulating glomerular permeability. PMID- 29155847 TI - Context and culture associated with alcohol use amongst youth in major urban cities: A cross-country population based survey. AB - BACKGROUND: Alcohol consumption patterns are dependent upon culture and context. The aim of this study was to interview people aged 18-34 year old living in four cities in different regions of the world to explore differences in a range of alcohol measures to assist in determining culturally appropriate alcohol initiatives for this age group. METHOD: Multistage random sampling was consistent across the four cities (Ilorin (Nigeria), Wuhan (China), Montevideo (Uruguay) and Moscow (Russia)). The questionnaire was forward and back translated into relevant languages and face-to-face interviewing undertaken. The data were weighted to the population of each city. Uni-variable analysis (ever consumed, first time consumed, age when drunk for first time, number of days consumed, type consumed) and logistic regression modeling were undertaken. The final model for each city was adjusted for age, sex, marital status, highest education and employment status. In total 6235 interviews were undertaken (1391 in Ilorin, 1600 in Montevideo, 1604 in Moscow and 1640 in Wuhan). RESULTS: Alcohol was consumed by 96.4% in Montevideo, 86.1% in Moscow, 53.4% in Wuhan and 33.3% in Ilorin. There was very little difference by gender except Ilorin males were more likely to consume alcohol than females. Alcohol was consumed on more days for Ilorin males; Wuhan females consumed alcohol on the least number of days; Ilorin had the most abstainers; Montevideo and Moscow the highest proportion of light drinkers; Ilorin and Montevideo the highest proportion of heavy drinkers. Differences by type of alcohol were also apparent. The final logistic regression model provided different models including higher alcohol consumption rates for males, 25-34 years of age, divorced/separated marital status and employed part time for Ilorin respondents; males and higher educated for Montevideo; males, 25 to 29 years of age and higher educated for Moscow; and 25-29 years of age, non-married and vocationally trained for those in Wuhan. CONCLUSION: Alcohol consumption in these four cities does not increase with age as found in most high income countries. The alcohol consumption patterns during this stage of the life cycle are important to assess so that high level, as well as country-specific, planning and interventions can be implemented. PMID- 29155848 TI - An electronic health record based model predicts statin adherence, LDL cholesterol, and cardiovascular disease in the United States Military Health System. AB - HMG-CoA reductase inhibitors (or "statins") are important and commonly used medications to lower cholesterol and prevent cardiovascular disease. Nearly half of patients stop taking statin medications one year after they are prescribed leading to higher cholesterol, increased cardiovascular risk, and costs due to excess hospitalizations. Identifying which patients are at highest risk for not adhering to long-term statin therapy is an important step towards individualizing interventions to improve adherence. Electronic health records (EHR) are an increasingly common source of data that are challenging to analyze but have potential for generating more accurate predictions of disease risk. The aim of this study was to build an EHR based model for statin adherence and link this model to biologic and clinical outcomes in patients receiving statin therapy. We gathered EHR data from the Military Health System which maintains administrative data for active duty, retirees, and dependents of the United States armed forces military that receive health care benefits. Data were gathered from patients prescribed their first statin prescription in 2005 and 2006. Baseline billing, laboratory, and pharmacy claims data were collected from the two years leading up to the first statin prescription and summarized using non-negative matrix factorization. Follow up statin prescription refill data was used to define the adherence outcome (> 80 percent days covered). The subsequent factors to emerge from this model were then used to build cross-validated, predictive models of 1) overall disease risk using coalescent regression and 2) statin adherence (using random forest regression). The predicted statin adherence for each patient was subsequently used to correlate with cholesterol lowering and hospitalizations for cardiovascular disease during the 5 year follow up period using Cox regression. The analytical dataset included 138 731 individuals and 1840 potential baseline predictors that were reduced to 30 independent EHR "factors". A random forest predictive model taking patient, statin prescription, predicted disease risk, and the EHR factors as potential inputs produced a cross-validated c-statistic of 0.736 for classifying statin non-adherence. The addition of the first refill to the model increased the c-statistic to 0.81. The predicted statin adherence was independently associated with greater cholesterol lowering (correlation = 0.14, p < 1e-20) and lower hospitalization for myocardial infarction, coronary artery disease, and stroke (hazard ratio = 0.84, p = 1.87E-06). Electronic health records data can be used to build a predictive model of statin adherence that also correlates with statins' cardiovascular benefits. PMID- 29155849 TI - Unusual occurrence of a DAG motif in the Ipomovirus Cassava brown streak virus and implications for its vector transmission. AB - Cassava is the main staple food for over 800 million people globally. Its production in eastern Africa is being constrained by two devastating Ipomoviruses that cause cassava brown streak disease (CBSD); Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV), with up to 100% yield loss for smallholder farmers in the region. To date, vector studies have not resulted in reproducible and highly efficient transmission of CBSV and UCBSV. Most virus transmission studies have used Bemisia tabaci (whitefly), but a maximum of 41% U/CBSV transmission efficiency has been documented for this vector. With the advent of next generation sequencing, researchers are generating whole genome sequences for both CBSV and UCBSV from throughout eastern Africa. Our initial goal for this study was to characterize U/CBSV whole genomes from CBSD symptomatic cassava plants sampled in Kenya. We have generated 8 new whole genomes (3 CBSV and 5 UCBSV) from Kenya, and in the process of analyzing these genomes together with 26 previously published sequences, we uncovered the aphid transmission associated DAG motif within coat protein genes of all CBSV whole genomes at amino acid positions 52-54, but not in UCBSV. Upon further investigation, the DAG motif was also found at the same positions in two other Ipomoviruses: Squash vein yellowing virus (SqVYV), Coccinia mottle virus (CocMoV). Until this study, the highly-conserved DAG motif, which is associated with aphid transmission was only noticed once, in SqVYV but discounted as being of minimal importance. This study represents the first comprehensive look at Ipomovirus genomes to determine the extent of DAG motif presence and significance for vector relations. The presence of this motif suggests that aphids could potentially be a vector of CBSV, SqVYV and CocMov. Further transmission and ipomoviral protein evolutionary studies are needed to confirm this hypothesis. PMID- 29155850 TI - Pre-pubertal exposure with phthalates and bisphenol A and pubertal development. AB - OBJECTIVE: Epidemiological studies indicate associations between childhood exposure with phthalates and bisphenol A (BPA) and the pubertal development. We examined associations between the pre-pubertal phthalate and BPA body burden and the longitudinally assessed sexual maturation of eight- to thirteen-year-old children. METHODS: We started with eight- to ten-year-old children in the baseline study and quantified phthalate metabolites and BPA in 472 urine samples (250 boys; 222 girls; mean age: 8.8 years). Associations between the pubertal development, assessed in three annual follow-up studies by Puberty Development scale questionnaires (PD scales), and the chemical exposure from the baseline visit were longitudinally analyzed with generalized estimation equations. RESULTS: The number of children with both chemical measures and PD scores (calculated from the PD scales) was 408. In the third follow-up, 49% of the girls and 18% of the boys had reached mid-puberty. For girls, we observed a delayed pubertal development with the di-hexyl-ethyl phthalate (DEHP) metabolites (beta: 0.16 to -0.23; p <= 0.05 or p <= 0.1), mono-n-butyl phthalate (beta: -0.15; 95% CI: -0.31; 0.01), mono-benzyl phthalate (beta: -0.11; 95% CI: -0,24; -0,01), and mono-ethyl phthalate (MEP) (beta: -0.15; 95% CI: -0.28; -0.01). In addition, significant non-linear associations of the DEHP metabolites and BPA with the PD scores were found, when their quadratic effects were included in the GEE models. In boys, no consistent relationships between the PD scores and the chemicals were detected except of an accelerated development with the ?DEHP metabolites (beta: 0.16; 95% CI: -0.02; -0.34). CONCLUSION: We found indications that pre-pubertal exposures with phthalates and BPA were associated with pubertal timing in children, particularly in girls. For boys, associations were inconsistent, and not necessarily in line with the known anti-androgenicity of some phthalates during prenatal exposure. PMID- 29155851 TI - PAC1- and VPAC2 receptors in light regulated behavior and physiology: Studies in single and double mutant mice. AB - The two sister peptides, pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) and their receptors, the PAC1 -and the VPAC2 receptors, are involved in regulation of the circadian timing system. PACAP as a neurotransmitter in the retinohypothalamic tract (RHT) and VIP as a neurotransmitter, involved in synchronization of SCN neurons. Behavior and physiology in VPAC2 deficient mice are strongly regulated by light most likely as a result of masking. Consequently, we used VPAC2 and PAC1/VPAC2 double mutant mice in comparison with PAC1 receptor deficient mice to further elucidate the role of PACAP in the light mediated regulation of behavior and physiology of the circadian system. We compared circadian rhythms in mice equipped with running wheels or implanted radio-transmitter measuring core body temperature kept in a full photoperiod ((FPP)(12:12 h light dark-cycles (LD)) and skeleton photo periods (SPP) at high and low light intensity. Furthermore, we examined the expression of PAC1- and VPAC2 receptors in the SCN of the different genotypes in combination with visualization of PACAP and VIP and determined whether compensatory changes in peptide and/or receptor expression in the reciprocal knockouts (KO) (PAC1 and VPAC2) had occurred. Our data demonstrate that in although being closely related at both ligand and receptor structure/sequence, PACAP/PAC1 receptor signaling are independent of VIP/VPAC2 receptor signaling and vice versa. Furthermore, lack of either of the receptors does not result in compensatory changes at neither the physiological or anatomical level. PACAP/PAC1 signaling is important for light regulated behavior, VIP/VPAC2signaling for stable clock function and both signaling pathways may play a role in shaping diurnality versus nocturnality. PMID- 29155852 TI - The role of adenosine diphosphate mediated platelet responsiveness for the stability of platelet integrity in citrated whole blood under ex vivo conditions. AB - BACKGROUND: Platelets are important for effective hemostasis and considered to be involved in pathophysiological processes, e.g. in cardiovascular diseases. Platelets provided for research or for therapeutic use are frequently separated from citrated whole blood (WB) stored for different periods of time. Although functionally intact platelets are required, the stability of platelet integrity, e.g. adenosine diphosphate (ADP) mediated responsiveness, has never been thoroughly investigated in citrated WB under ex vivo conditions. OBJECTIVES: Platelet integrity was evaluated at different time points in citrated WB units, collected from healthy donors and stored for 5 days at ambient temperature. The analysis included the measurement of activation markers, of induced light transmission aggregometry and of purinergic receptor expression or function. Inhibitory pathways were explored by determination of basal vasodilator stimulated phosphoprotein (VASP)-phosphorylation, intracellular cyclic nucleotide levels and the content of phosphodiesterase 5A. Fresh peripheral blood (PB) samples served as controls. RESULTS: On day 5 of storage, thrombin receptor activating peptide-6 (TRAP-6) stimulated CD62P expression and fibrinogen binding were comparable to PB samples. ADP induced aggregation continuously decreased during storage. Purinergic receptor expression remained unchanged, whereas the P2Y1 activity progressively declined in contrast to preserved P2Y12 and P2X1 function. Inhibitory pathways were unaffected except for a slight elevation of VASP phosphorylation at Ser239 on day 5. CONCLUSION: After 5 days of storage in citrated WB, platelet responsiveness to TRAP-6 is sufficiently maintained. However, ADP-mediated platelet integrity is more sensitive to deterioration, especially after storage for more than 2 days. Decreasing ADP-induced aggregation is particularly caused by the impairment of the purinergic receptor P2Y1 activity. These characteristics should be considered in the use of platelets from stored citrated WB for experimental or therapeutic issues. PMID- 29155853 TI - Novel chloroacetamido compound CWR-J02 is an anti-inflammatory glutaredoxin-1 inhibitor. AB - Glutaredoxin (Grx1) is a ubiquitously expressed thiol-disulfide oxidoreductase that specifically catalyzes reduction of S-glutathionylated substrates. Grx1 is known to be a key regulator of pro-inflammatory signaling, and Grx1 silencing inhibits inflammation in inflammatory disease models. Therefore, we anticipate that inhibition of Grx1 could be an anti-inflammatory therapeutic strategy. We used a rapid screening approach to test 504 novel electrophilic compounds for inhibition of Grx1, which has a highly reactive active-site cysteine residue (pKa 3.5). From this chemical library a chloroacetamido compound, CWR-J02, was identified as a potential lead compound to be characterized. CWR-J02 inhibited isolated Grx1 with an IC50 value of 32 MUM in the presence of 1 mM glutathione. Mass spectrometric analysis documented preferential adduction of CWR-J02 to the active site Cys-22 of Grx1, and molecular dynamics simulation identified a potential non-covalent binding site. Treatment of the BV2 microglial cell line with CWR-J02 led to inhibition of intracellular Grx1 activity with an IC50 value (37 MUM). CWR-J02 treatment decreased lipopolysaccharide-induced inflammatory gene transcription in the microglial cells in a parallel concentration-dependent manner, documenting the anti-inflammatory potential of CWR-J02. Exploiting the alkyne moiety of CWR-J02, we used click chemistry to link biotin azide to CWR-J02 adducted proteins, isolating them with streptavidin beads. Tandem mass spectrometric analysis identified many CWR-J02-reactive proteins, including Grx1 and several mediators of inflammatory activation. Taken together, these data identify CWR-J02 as an intracellularly effective Grx1 inhibitor that may elicit its anti-inflammatory action in a synergistic manner by also disabling other pro inflammatory mediators. The CWR-J02 molecule provides a starting point for developing more selective Grx1 inhibitors and anti-inflammatory agents for therapeutic development. PMID- 29155854 TI - Profiling of proteins secreted in the bovine oviduct reveals diverse functions of this luminal microenvironment. AB - The oviductal microenvironment is a site for key events that involve gamete maturation, fertilization and early embryo development. Secretions into the oviductal lumen by either the lining epithelium or by transudation of plasma constituents are known to contain elements conducive for reproductive success. Although previous studies have identified some of these factors involved in reproduction, knowledge of secreted proteins in the oviductal fluid remains rudimentary with limited definition of function even in extensively studied species like cattle. In this study, we used a shotgun proteomics approach followed by bioinformatics sequence prediction to identify secreted proteins present in the bovine oviductal fluid (ex vivo) and secretions from the bovine oviductal epithelial cells (in vitro). From a total of 2087 proteins identified, 266 proteins could be classified as secreted, 109 (41%) of which were common for both in vivo and in vitro conditions. Pathway analysis indicated different classes of proteins that included growth factors, metabolic regulators, immune modulators, enzymes, and extracellular matrix components. Functional analysis revealed mechanisms in the oviductal lumen linked to immune homeostasis, gamete maturation, fertilization and early embryo development. These results point to several novel components that work together with known elements mediating functional homeostasis, and highlight the diversity of machinery associated with oviductal physiology and early events in cattle fertility. PMID- 29155855 TI - Iron status and anaemia in Sri Lankan secondary school children: A cross sectional survey. AB - BACKGROUND: Iron deficiency, the most common micronutrient disorder and cause of anaemia globally, impairs growth, cognition, behaviour and resistance to infection. METHODS/RESULTS: As part of a national survey of inherited haemoglobin variants in 7526 students from 72 secondary schools purposefully selected from the 25 districts of Sri Lanka, we studied 5912 students with a normal haemoglobin genotype. Median age was 16.0 (IQR 15.0-17.0) years and 3189 (53.9%) students were males. Most students were Sinhalese (65.7%), with fewer Tamils (23.1%) and Muslims (11.2%). Anaemia occurred in 470 students and was more common in females (11.1%) than males (5.6%). Haemoglobin, serum ferritin, transferrin receptor and iron were determined in 1196 students with low red cell indices and a structured sample of those with normal red cell indices (n = 513). The findings were weighted to estimate the frequencies of iron deficiency and iron deficiency anaemia classified according to WHO criteria. Iron depletion (serum ferritin <15ug/ml) occurred in 19.2% and cellular iron deficiency (low serum ferritin and transferrin receptor >28.1 nmol/l) in 11.6% students. Iron deficiency anaemia (cellular iron deficiency with low haemoglobin) occurred in only 130/2794 (4.6%) females and 28/2789 (1.0%) males. Iron biomarkers were normal in 83/470 (14.6%) students with anaemia. In multiple regression analysis, the odds for iron depletion and cellular iron deficiency were about one-third in males compared with females, and the odds for iron deficiency anaemia were about one fifth in males compared to females. Tamil ethnicity and age <16 years increased the risk of all three stages of iron deficiency and living at high altitude significantly reduced the risk of iron depletion. CONCLUSIONS: Low iron status and anaemia remain common problems in Sri Lankan secondary school students especially females, younger students and the socioeconomically disadvantaged Tamil population. More research is needed to identify factors other than low iron status that contribute to anaemia in adolescents. PMID- 29155856 TI - Treatment with solubilized Silk-Derived Protein (SDP) enhances rabbit corneal epithelial wound healing. AB - There is a significant clinical need to improve current therapeutic approaches to treat ocular surface injuries and disease, which affect hundreds of millions of people annually worldwide. The work presented here demonstrates that the presence of Silk-Derived Protein (SDP) on the healing rabbit corneal surface, administered in an eye drop formulation, corresponds with an enhanced epithelial wound healing profile. Rabbit corneas were denuded of their epithelial surface, and then treated for 72-hours with either PBS or PBS containing 5 or 20 mg/mL SDP in solution four times per day. Post-injury treatment with SDP formulations was found to accelerate the acute healing phase of the injured rabbit corneal epithelium. In addition, the use of SDP corresponded with an enhanced tissue healing profile through the formation of a multi-layered epithelial surface with increased tight junction formation. Additional biological effects were also revealed that included increased epithelial proliferation, and increased focal adhesion formation with a corresponding reduction in the presence of MMP-9 enzyme. These in vivo findings demonstrate for the first time that the presence of SDP on the injured ocular surface may aid to improve various steps of rabbit corneal wound healing, and provides evidence that SDP may have applicability as an ingredient in therapeutic ophthalmic formulations. PMID- 29155858 TI - Time trends of comparative self-rated health in adults aged 25-34 in the Northern Sweden MONICA study, 1990-2014. AB - Self-rated health (SRH) accounts comprehensively for many health domains. The aim of this paper was to investigate time trends and associations between age comparative self-rated health and some known determinants in a general population aged 24-34 years. Population-based cross-sectional surveys were performed in 1990, 1994, 1999, 2004, 2009 and 2014 in Northern Sweden. Out of 3500 invited persons, 1811 responded. Comparative SRH was measured on a three-grade ordinal scale by the question: "How would you assess your general health condition compared to persons of your own age?" with the alternatives "better/worse/similar". Over the period 1990 to 2014, the percentage of women rating comparative SRH as "worse" increased steadily, from 8.5% in 1990 reaching 20% in 2014 (p for trend 0.007). Among men, this pattern was almost the opposite, with increasing proportions rating "better" (p for trend <0.000). Time trends for physical activity in leisure time; length of education; Body Mass Index; anxiety; depressive emotions and satisfaction with economy showed a similar pattern for men and women. Factors that might contribute to the development of time trends for comparative SRH are discussed. PMID- 29155857 TI - Impaired AQP2 trafficking in Fxyd1 knockout mice: A role for FXYD1 in regulated vesicular transport. AB - The final adjustment of urine volume occurs in the inner medullary collecting duct (IMCD), chiefly mediated by the water channel aquaporin 2 (AQP2). With vasopressin stimulation, AQP2 accumulation in the apical plasma membrane of principal cells allows water reabsorption from the lumen. We report that FXYD1 (phospholemman), better known as a regulator of Na,K-ATPase, has a role in AQP2 trafficking. Daytime urine of Fxyd1 knockout mice was more dilute than WT despite similar serum vasopressin, but both genotypes could concentrate urine during water deprivation. FXYD1 was found in IMCD. In WT mice, phosphorylated FXYD1 was detected intracellularly, and vasopressin induced its dephosphorylation. We tested the hypothesis that the dilute urine in knockouts was caused by alteration of AQP2 trafficking. In WT mice at baseline, FXYD1 and AQP2 were not strongly co localized, but elevation of vasopressin produced translocation of both FXYD1 and AQP2 to the apical plasma membrane. In kidney slices, baseline AQP2 distribution was more scattered in the Fxyd1 knockout than in WT. Apical recruitment of AQP2 occurred in vasopressin-treated Fxyd1 knockout slices, but upon vasopressin washout, there was more rapid reversal of apical AQP2 localization and more heterogeneous cytoplasmic distribution of AQP2. Notably, in sucrose gradients, AQP2 was present in a detergent-resistant membrane domain that had lower sedimentation density in the knockout than in WT, and vasopressin treatment normalized its density. We propose that FXYD1 plays a role in regulating AQP2 retention in apical membrane, and that this involves transfers between raft-like membrane domains in endosomes and plasma membranes. PMID- 29155859 TI - Reduced starch granule number per chloroplast in the dpe2/phs1 mutant is dependent on initiation of starch degradation. AB - An Arabidopsis double knock-out mutant lacking cytosolic disproportionating enzyme 2 (DPE2) and the plastidial phosphorylase (PHS1) revealed a dwarf-growth phenotype, reduced starch content, an uneven distribution of starch within the plant rosette, and a reduced number of starch granules per chloroplast under standard growth conditions. In contrast, the wild type contained 5-7 starch granules per chloroplast. Mature and old leaves of the double mutant were essentially starch free and showed plastidial disintegration. Several analyses revealed that the number of starch granules per chloroplast was affected by the dark phase. So far, it was unclear if it was the dark phase per se or starch degradation in the dark that was connected to the observed decrease in the number of starch granules per chloroplast. Therefore, in the background of the double mutant dpe2/phs1, a triple mutant was generated lacking the initial starch degrading enzyme glucan, water dikinase (GWD). The triple mutant showed improved plant growth, a starch-excess phenotype, and a homogeneous starch distribution. Furthermore, the number of starch granules per chloroplast was increased and was similar to wild type. However, starch granule morphology was only slightly affected by the lack of GWD as in the triple mutant and, like in dpe2/phs1, more spherical starch granules were observed. The characterized triple mutant was discussed in the context of the generation of starch granules and the formation of starch granule morphology. PMID- 29155860 TI - ChIP-Seq analysis identifies p27(Kip1)-target genes involved in cell adhesion and cell signalling in mouse embryonic fibroblasts. AB - The protein p27Kip1 (p27), a member of the Cip-Kip family of cyclin-dependent kinase inhibitors, is involved in tumorigenesis and a correlation between reduced levels of this protein in human tumours and a worse prognosis has been established. Recent reports revealed that p27 also behaves as a transcriptional regulator. Thus, it has been postulated that the development of tumours with low amounts of p27 could be propitiated by deregulation of transcriptional programs under the control of p27. However, these programs still remain mostly unknown. The aim of this study has been to define the transcriptional programs regulated by p27 by first identifying the p27-binding sites (p27-BSs) on the whole chromatin of quiescent mouse embryonic fibroblasts. The chromatin regions associated to p27 have been annotated to the most proximal genes and it has been considered that the expression of these genes could by regulated by p27. The identification of the chromatin p27-BSs has been performed by Chromatin Immunoprecipitation Sequencing (ChIP-seq). Results revealed that p27 associated with 1839 sites that were annotated to 1417 different genes being 852 of them protein coding genes. Interestingly, most of the p27-BSs were in distal intergenic regions and introns whereas, in contrast, its association with promoter regions was very low. Gene ontology analysis of the protein coding genes revealed a number of relevant transcriptional programs regulated by p27 as cell adhesion, intracellular signalling and neuron differentiation among others. We validated the interaction of p27 with different chromatin regions by ChIP followed by qPCR and demonstrated that the expressions of several genes belonging to these programs are actually regulated by p27. Finally, cell adhesion assays revealed that the adhesion of p27-/- cells to the plates was much higher that controls, revealing a role of p27 in the regulation of a transcriptional program involved in cell adhesion. PMID- 29155862 TI - A multi-paradigm framework to assess the impacts of climate change on end-use energy demand. AB - Projecting the long-term trends in energy demand is an increasingly complex endeavor due to the uncertain emerging changes in factors such as climate and policy. The existing energy-economy paradigms used to characterize the long-term trends in the energy sector do not adequately account for climate variability and change. In this paper, we propose a multi-paradigm framework for estimating the climate sensitivity of end-use energy demand that can easily be integrated with the existing energy-economy models. To illustrate the applicability of our proposed framework, we used the energy demand and climate data in the state of Indiana to train a Bayesian predictive model. We then leveraged the end-use demand trends as well as downscaled future climate scenarios to generate probabilistic estimates of the future end-use demand for space cooling, space heating and water heating, at the individual household and building level, in the residential and commercial sectors. Our results indicated that the residential load is much more sensitive to climate variability and change than the commercial load. Moreover, since the largest fraction of the residential energy demand in Indiana is attributed to heating, future warming scenarios could lead to reduced end-use demand due to lower space heating and water heating needs. In the commercial sector, the overall energy demand is expected to increase under the future warming scenarios. This is because the increased cooling load during hotter summer months will likely outpace the reduced heating load during the more temperate winter months. PMID- 29155861 TI - Pancreatic exocrine insufficiency in patients with chronic heart failure and its possible association with appetite loss. AB - BACKGROUND: Appetite loss is one complication of chronic heart failure (CHF), and its association with pancreatic exocrine insufficiency (PEI) is not well investigated in CHF. AIM: We attempted to detect the association between PEI and CHF-induced appetite. METHODS: Patients with CHF were enrolled, and body mass index (BMI), left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) cardiac function grading, B-type natriuretic peptide (BNP), serum albumin, pro-albumin and hemoglobin were evaluated. The pancreatic exocrine function was measured by fecal elastase-1 (FE-1) levels in the enrolled patients. Appetite assessment was tested by completing the simplified nutritional appetite questionnaire (SNAQ). The improvement of appetite loss by supplemented pancreatic enzymes was also researched in this study. RESULTS: The decrease of FE-1 levels was found in patients with CHF, as well as SNAQ scores. A positive correlation was observed between SNAQ scores and FE-1 levels (r = 0.694, p < 0.001). Pancreatic enzymes supplement could attenuate the decrease of SNAQ scores in CHF patients with FE-1 levels <200 MUg/g stool and SNAQ < 14. CONCLUSIONS: Appetite loss is commonly seen in CHF, and is partially associated with pancreatic exocrine insufficiency. Oral pancreatic enzyme replacement therapy attenuates the chronic heart failure-induced appetite loss. These results suggest a possible pancreatic-cardiac relationship in chronic heart failure, and further experiment is needed for clarifying the possible mechanisms. PMID- 29155863 TI - Molecular detection of tick-borne pathogens in cattle from Southwestern Ethiopia. AB - Tick-borne diseases (TBDs) cause significant losses among livestock and impact the livelihoods of resource-poor farming communities worldwide. In Ethiopia, detailed studies on the epidemiology of tick-borne pathogens (TBPs) in cattle using sensitive molecular detection methods are scarce. The objective of this study was to determine the prevalence and species composition of bovine TBPs of veterinary significance in local cattle populations. A comprehensive cross sectional epidemiological study was conducted in cattle populations of Illubabor zone in Southwestern Ethiopia from June to August 2013. For this purpose, blood samples were collected from 392 cattle. A combination of polymerase chain reaction (PCR) and a Reverse Line Blot (RLB) hybridization assay was employed for the detection of TBPs in these samples. The PCR/RLB results of the 392 blood samples indicated a high overall prevalence of 96.9% for TBPs, including Theileria mutans (66.1%), Theileria orientalis (51.8%), Anaplasma sp. Omatjenne (25.5%), Anaplasma marginale (14.5%), Babesia bigemina (14.0%) and Theileria velifera (13.0%) and minor occurrences of Ehrlichia ruminantium (0.5%) and Ehrlichia minasensis (0.26%). Moreover, three novel Anaplasma genotypes were detected in bovine blood samples. A phylogenetic analysis revealed that they most likely represent three, but at least two, new species. The prevalence of the three novel Anaplasma species, preliminary designated as Anaplasma sp. Hadesa, Anaplasma sp. Saso and Anaplasma sp. Dedessa, was 12.5%, 14.3% and 5.6%, respectively. Overall, a total of 227 cattle (57.9%) were found to be co-infected with two or more TBPs simultaneously and 86 different species combinations were observed. The findings show a very high burden of infection of cattle with TBPs in Ethiopia. The high frequency of co-infections suggests that clinical manifestations might be complex. Further research is required to determine the pathogenicity, host cell types and vector of the three novel Anaplasma species identified in this study. PMID- 29155864 TI - Supraglottic squamous cell carcinomas have distinctive clinical features and prognosis based on subregion. AB - OBJECTIVE: To analyze the clinicopathologic characteristics and prognosis of patients with squamous cell carcinoma localized to different supraglottic subregions. METHODS: Clinicopathologic data were reviewed retrospectively for 111 patients with supraglottic squamous cell carcinoma who were diagnosed between January 1, 1995 and December 31, 2005 and were initially treated with surgery. DNA from human papillomavirus (HPV) 16 and (or /and) HPV 18 were detected in all the 111 supraglottic carcinoma specimens using in situ hybridization. Survival analysis was performed by Kaplan-Meier analysis, factors were compared using log rank test, and prognostic factors were determined using Cox proportional hazards model. The relationship between subregions and clinicopathologic factors was analyzed using Chi-square tests. RESULTS: HPV prevalence differed between patients with aryepiglottic fold carcinoma and ventricle carcinoma (P < .05). The local-regional control rates, overall survival rates or cancer specific survival rates were significantly different between different subregions. Univariate analysis indicated that pTNM classification, pN spread, and subregion were associated with prognosis (P < .05). Multivariate analysis indicated that pTNM classification and subregion were associated with supraglottic carcinoma prognosis. The survival rate was better for patients with carcinoma of the epiglottis or ventricular bands compared to those with carcinoma in the aryepiglottic fold or ventricle (P = .012). CONCLUSIONS: Subregion may be a new prognostic factor for supraglottic squamous cell carcinoma. Different supraglottic carcinoma subregions have distinct clinical features such as HPV expression, lymph node metastasis rate, local-regional control and prognosis. Therefore, it is necessary to subdivide supraglottic squamous cell carcinomas into several subregion groups to individualize therapy. PMID- 29155865 TI - Drivers of metacommunity structure diverge for common and rare Amazonian tree species. AB - We analysed the flora of 46 forest inventory plots (25 m x 100 m) in old growth forests from the Amazonian region to identify the role of environmental (topographic) and spatial variables (obtained using PCNM, Principal Coordinates of Neighbourhood Matrix analysis) for common and rare species. For the analyses, we used multiple partial regression to partition the specific effects of the topographic and spatial variables on the univariate data (standardised richness, total abundance and total biomass) and partial RDA (Redundancy Analysis) to partition these effects on composition (multivariate data) based on incidence, abundance and biomass. The different attributes (richness, abundance, biomass and composition based on incidence, abundance and biomass) used to study this metacommunity responded differently to environmental and spatial processes. Considering standardised richness, total abundance (univariate) and composition based on biomass, the results for common species differed from those obtained for all species. On the other hand, for total biomass (univariate) and for compositions based on incidence and abundance, there was a correspondence between the data obtained for the total community and for common species. Our data also show that in general, environmental and/or spatial components are important to explain the variability in tree communities for total and common species. However, with the exception of the total abundance, the environmental and spatial variables measured were insufficient to explain the attributes of the communities of rare species. These results indicate that predicting the attributes of rare tree species communities based on environmental and spatial variables is a substantial challenge. As the spatial component was relevant for several community attributes, our results demonstrate the importance of using a metacommunities approach when attempting to understand the main ecological processes underlying the diversity of tropical forest communities. PMID- 29155866 TI - Correction: Multiscale adaptive analysis of circadian rhythms and intradaily variability: Application to actigraphy time series in acute insomnia subjects. AB - [This corrects the article DOI: 10.1371/journal.pone.0181762.]. PMID- 29155867 TI - Spectrum of pathogen- and model-specific histopathologies in mouse models of acute pneumonia. AB - Pneumonia may be caused by a wide range of pathogens and is considered the most common infectious cause of death in humans. Murine acute lung infection models mirror human pathologies in many aspects and contribute to our understanding of the disease and the development of novel treatment strategies. Despite progress in other fields of tissue imaging, histopathology remains the most conclusive and practical read out tool for the descriptive and semiquantitative evaluation of mouse pneumonia and therapeutic interventions. Here, we systematically describe and compare the distinctive histopathological features of established models of acute pneumonia in mice induced by Streptococcus (S.) pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Legionella pneumophila, Escherichia coli, Middle East respiratory syndrome (MERS) coronavirus, influenza A virus (IAV) and superinfection of IAV-incuced pneumonia with S. pneumoniae. Systematic comparisons of the models revealed striking differences in the distribution of lesions, the characteristics of pneumonia induced, principal inflammatory cell types, lesions in adjacent tissues, and the detectability of the pathogens in histological sections. We therefore identified core criteria for each model suitable for practical semiquantitative scoring systems that take into account the pathogen- and model-specific patterns of pneumonia. Other critical factors that affect experimental pathologies are discussed, including infectious dose, time kinetics, and the genetic background of the mouse strain. The substantial differences between the model-specific pathologies underscore the necessity of pathogen- and model-adapted criteria for the comparative quantification of experimental outcomes. These criteria also allow for the standardized validation and comparison of treatment strategies in preclinical models. PMID- 29155868 TI - Tocilizumab potentially prevents bone loss in patients with anticitrullinated protein antibody-positive rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is associated with a high risk of osteoporosis and fracture. Interleukin (IL)-6 inhibitors may suppress osteoclast activation. Anticitrullinated protein antibody (ACPA) titers are inversely associated with bone mineral density (BMD). However, the differential effect of ACPA on bone turnover marker (BTM) and BMD changes after IL-6 inhibition remains unclear. This prospective study recruited patients with active RA with inadequate response to methotrexate or biologics. BMD was measured before and after 2-year tocilizumab (TCZ) treatment. Serum osteocalcin, N-terminal propeptide of type I collagen (P1NP), and C-terminal cross-linking telopeptide of type I collagen (CTX) levels were assessed at the baseline and after treatment. We enrolled 76 patients with RA (89.5% women, age: 57.2 +/- 13.3 years) receiving TCZ. The 28-joint disease activity score was negatively correlated with BMD and T-scores of the lumbar spine and bilateral femoral neck. ACPA-positive patients had lower lumbar spine and femoral neck T-scores. After 2-year TCZ treatment, CTX levels significantly decreased (0.32 +/- 0.21 vs. 0.26 +/- 0.17, p = 0.038). Femoral neck BMD increased significantly (0.71 +/- 0.22 vs. 0.69 +/- 0.55, p = 0.008). Decreased CTX levels and improved BMD were observed only in ACPA-positive patients. After treatment, femoral neck BMD significantly increased only in patients receiving a glucocorticoid dose of >=5 mg/day. Two-year TCZ treatment reduced bone resorption and increased femoral BMD in ACPA-positive patients. The net effects of glucocorticoids and IL-6 inhibition on BMD imply that strict inflammation control might affect bone metabolism. PMID- 29155869 TI - NF-kappaB pathways are involved in M1 polarization of RAW 264.7 macrophage by polyporus polysaccharide in the tumor microenvironment. AB - Bladder cancer is one of the most malignant tumors closely associated with macrophages. Polyporus polysaccharide (PPS) has shown excellent efficacy in treating bladder cancer with minimal side effects. However, the molecular mechanisms underlying the effects of PPS in inhibiting bladder cancer remain unclear. In this study, we used macrophages cultured alone or with T24 human bladder cancer cell culture supernatant as study models. We found that PPS enhanced the activities of IFN-gamma-stimulated RAW 264.7 macrophages, as shown by the release of inducible nitric oxide synthase (INOS), secretion of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, phagocytosis activity, as well as expression of M1 phenotype indicators, such as CD40, CD284 and CD86. PPS acted upstream in activation cascade of nuclear factor (NF)-kappaB signaling pathways by interfering with IkappaB phosphorylation. In addition, PPS regulated NF-kappaB (P65) signaling by interfering with Toll-like receptor (TLR)-4, INOS and cyclooxygenase (COX)-2. Our results indicate that PPS activates macrophages through TLR4/NF-kappaB signaling pathways. PMID- 29155871 TI - Correction: Sequence Homology at the Breakpoint and Clinical Phenotype of Mitochondrial DNA Deletion Syndromes. AB - [This corrects the article DOI: 10.1371/journal.pone.0015687.]. PMID- 29155870 TI - A modified Delphi study to determine the level of consensus across the European Union on the structures, processes and desired outcomes of the management of polypharmacy in older people. AB - BACKGROUND: Inappropriate use of multiple medicines (inappropriate polypharmacy) is a major challenge in older people with consequences of increased prevalence and severity of adverse drug reactions and interactions, and reduced medicines adherence. The aim of this study was to determine the levels of consensus amongst key stakeholders in the European Union (EU) in relation to aspects of the management of polypharmacy in older people. METHODS: Forty-six statements were developed on aspects of healthcare structures, processes and desired outcomes, with consensus defined at >= 80% agreement. Panel members were strategists (e.g. directors, leading clinicians and commissioners) from each of the 28 EU member states, with a target recruitment of five per member state. Three Delphi rounds were conducted via email, with panel members being provided with summative results and collated, anonymised comments at the commencement of Rounds 2 and 3. RESULTS: Ninety panel members were recruited (64.3% of target), with high participation levels throughout the three Delphi rounds (91.1%, 83.3%, 72.2%). During Round 1, consensus was obtained for 27/46 statements (58.7%), with an additional two statements in Round 2 and none in Round 3. Consensus was obtained for statements relating to: potential gain arising from polypharmacy management (3/4 statements); strategic development (7/7); change management (5/7) indicator measures (4/6); legislation (0/3); awareness raising (5/5); polypharmacy reviews (5/7); and EU vision (0/7). Analysis of free text comments indicated that the vision statements were too ambitious and not achievable by the specified timeframe of 2025. CONCLUSION: Consensus was obtained amongst key EU strategists around many aspects of polypharmacy management in older people. Notably, no consensus was achieved in relation to statements relating to the need to alter legislation in areas of healthcare delivery, remuneration and practitioner scope of practice. While the vision for the EU by 2025 was considered rather ambitious, there is great potential and clear opportunity to advance polypharmacy management throughout the EU and beyond. PMID- 29155872 TI - Sulfur dioxide alleviates programmed cell death in barley aleurone by acting as an antioxidant. AB - Sulfur dioxide (SO2), a gaseous signaling molecule in animal cells, has recently been found to play a physiological role in plants. Here we studied the role of SO2 in gibberellic acid (GA3)-induced programmed cell death (PCD) in barley (Hordeum vulgare L.) aleurone layers. The application of the SO2 donor (NaHSO3/Na2SO3, 1:3 M/M) effectively alleviated PCD in barley aleurone layers in a dose-dependent manner with an optimal concentration of 50 MUM. Further investigations showed that SO2 reduced the accumulation of hydrogen peroxide (H2O2), superoxide anion (?O2-) and malondialdehyde (MDA) in aleurone layers. Moreover, the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), glutathione reductase (GR) and guaiacol peroxidase (POD) were enhanced by SO2 donor treatment. Meanwhile, lipoxygenase (LOX) activity was attenuated by SO2 donor treatment. Furthermore, an induction of endogenous H2S and NO were also observed in SO2-treated aleurone layers, suggesting interactions of SO2 with other well-known signaling molecules. Taken together, we show that SO2 negatively regulated PCD by acting as an antioxidant to scavenge excessive reactive oxygen species (ROS) generated during PCD. PMID- 29155873 TI - Short-term anti-proteinuric effect of tacrolimus is not related to preservation of the glomerular filtration rate in IgA nephropathy: A 5-year follow-up study. AB - BACKGROUND: The immunosuppressive drug tacrolimus has the short-term effect of reducing proteinuria in patients with immunoglobulin A nephropathy (IgAN). Our study investigated the effects on proteinuria and kidney function after discontinuation of tacrolimus. METHODS: Patients with biopsy-proven IgAN were included in the study and randomly divided into two treatment groups. There was a corresponding control group for each treatment group. The first group included patients treated with tacrolimus (Tac vs non-Tac group) and the second group included patients with a renin angiotensin system blocker (RASi vs non-RASi group). The Tac group received treatment for up to 16 weeks, with the administration of tacrolimus being ceased at the final visit (trial phase). We tracked the patients at 12, 24, 52, and 240 weeks (observational phase). The primary outcomes examined were the percentage change (from the trial phase to the observational phase) of time-averaged proteinuria (TA-proteinuria; g/g creatinine [cr]) and the estimated glomerular filtration rate (eGFR). Time-averaged proteinuria was defined as the average of urine protein to creatinine ratio (UPCR), measured every 3 months during both the trial and observational phases of the study. RESULTS: A significant reduction in UPCR was observed in the Tac group compared to non-Tac group at the 4 and 8 week visits during the trial phase (p = 0.023 and p = 0.003, respectively). However, the difference between the Tac group and non-Tac group was not evident in the other review periods, estimated by linear mixed effect model. The percentage change in TA-proteinuria was greater in the Tac group than that in the corresponding control group (116 +/- 96% vs. 63 +/ 239%, p = 0.004). Therefore, during the observational phase, TA-proteinuria was not significantly different between the Tac group and the non-Tac group (1.150 +/ 0.733 g/g cr vs. 1.455 +/- 2.017 g/g cr, p = 0.775). The levels of eGFR throughout the observational phase were not significantly different between the two groups. Furthermore, the mean rate of eGFR change throughout both phases of the study was -6.4 +/- 5.9 mL/min/1.73 m2/year in the non-Tac group and -5.4 +/- 7.9 mL/min/1.73 m2/year in the Tac group (p = 0.988). CONCLUSION: The anti proteinuric effect of tacrolimus was promptly reversed 3 months after discontinuing the drug. The use of tacrolimus for a short period of time for patients with IgAN temporarily reduces proteinuria, but the data showed no long term efficacy regarding proteinuria reduction and improvement of renal function. PMID- 29155874 TI - Morphological characteristics of diffuse idiopathic skeletal hyperostosis in the cervical spine. AB - OBJECTIVES: Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by anterior ossification of the spine and can lead to dysphagia and airway obstruction. The morphology of the newly formed bone in the cervical spine is different compared to the thoracic spine, possibly due to dissimilarities in local vascular anatomy. In this study the spatial relationship of the new bone with the arterial system, trachea and esophagus was analyzed and compared between subjects with and without DISH. METHODS: Cervical computed tomography (CT) scans were obtained from five patients with dysphagia and DISH and ten control subjects. The location of the vertebral and carotid arteries, surface area of the hyperostosis and distance between the vertebral body and the trachea and esophagus was assessed in the axial view. RESULTS: The surface area of the newly formed bone was located symmetrically anterior to the vertebral body. The ossifications were non-flowing in the sagittal view and no segmental vessels were observed. Substantial displacement of the trachea/esophagus was present in the group with DISH compared to the controls. CONCLUSIONS: The hyperostosis at the cervical level was symmetrically distributed anterior to the vertebral bodies without a flowing pattern, in contrast to the asymmetrical flowing pattern typically found in the thoracic spine. The hypothesis that the vascular system acts as a natural barrier against new bone formation in DISH could be further supported with these findings. The significant ventral displacement of the trachea and esophagus may explain the mechanism of dysphagia and airway obstruction in DISH. PMID- 29155875 TI - Effect of long-term irrigation patterns on phosphorus forms and distribution in the brown soil zone. AB - Continuous application of P fertilizers under different irrigation patterns can change soil phosphorus (P) chemical behavior and increase soil P levels that are of environmental concern. To assess the effect of long-term different irrigation patterns on soil P fractions and availability, this study examined sequential changes in soil organic P and inorganic P from furrow irrigation (FI), surface drip irrigation (SUR), and subsurface drip irrigation (SDI) in the brown soil zone (0-60 cm) during 1998 to 2011. Analyses of soil P behavior showed that the levels of total P are frequently high on top soil layers. The total P (TP) contents of the entire soil profiles under three irrigation treatments were 830.2 3180.1 mg/kg. The contents of available P (AP) were 72.6-319.3 mg P/kg soil through soil profiles. The greatest TP and AP contents were obtained within the upper soil layers in FI. Results of Hedley's P fractionation indicate that HCl-P is a dominant form and the proportion to TP ranges from 29% to 43% in all three methods. The contents of various fractions of P were positively correlated with the levels of total carbon (TC), total inorganic carbon (TIC), and calcium (Ca), whereas the P fractions had negative correlation with pH in all soil samples. Regression models proved that NaHCO3-Po was an important factor in determining the amount of AP in FI. H2O-Po, NaHCO3-Po, and NaOH-Pi were related to available P values in SUR. NaHCO3-Po and NaOH-Po played important roles in SDI. The tomato yield under SUR was higher than SDI and FI. The difference of P availability was also controlled by the physicochemical soil properties under different irrigation schedule. SUR was a reasonable irrigation pattern to improve the utilization efficiency of water and fertilizer. PMID- 29155876 TI - Docking analysis and the possibility of prediction efficacy for an anti-IL-13 biopharmaceutical treatment with tralokinumab and lebrikizumab for bronchial asthma. AB - Interleukin-13 (IL-13) is associated with allergic airway inflammation and airway remodeling. Our group found a variant with a single nucleotide polymorphism in the IL13 gene at position +2044G>A (rs20541) that was expected to result in the non-conservative replacement of a positively charged arginine (R) with a neutral glutamine (Q) at position 144. IL-13Q144 was associated with augmented allergic airway inflammation and bronchial asthma remodeling. There is some indication that anti-IL-13 monoclonal antibodies can demonstrate a positive effect on the clinical course of refractory asthmatic patients. To date, the binding stability of these agents for IL-13Q144 is unknown. The objective of this study was to investigate the prediction efficacy of the anti-IL-13 monoclonal antibodies tralokinumab and lebrikizumab in asthmatic patients with IL-13R144 and IL-13Q144. The three-dimensional (3-D) structure of tralokinumab was obtained from the Protein Data Bank (PDB ID: 5L6Y), and the complete 3-D structure of lebrikizumab was built through homology modeling. For the binding stability analysis, we performed and analyzed docking simulations of IL-13 with tralokinumab or lebrikizumab. The tralokinumab and lebrikizumab structures changed after binding to IL-13 to facilitate binding with IL-13Q144. The stability analysis with tralokinumab and lebrikizumab demonstrated that IL-13Q144 was more stable than IL 13R144 for both the Rosetta energy score and for the free energy of binding. IL 13Q144 might be a promising predictor of responsiveness to tralokinumab and lebrikizumab treatment for bronchial asthma. PMID- 29155877 TI - Immune response profiles of calves following vaccination with live BCG and inactivated Mycobacterium bovis vaccine candidates. AB - Conventional control and eradication strategies for bovine tuberculosis (BTB) face tremendous difficulties in developing countries; countries with wildlife reservoirs, a complex wildlife-livestock-human interface or a lack of veterinary and veterinary public health surveillance. Vaccination of cattle and other species might in some cases provide the only suitable control strategy for BTB, while in others it may supplement existing test-and-slaughter schemes. However, the use of live BCG has several limitations and the global rise of HIV/AIDS infections has furthermore warranted the exploration of inactivated vaccine preparations. The aim of this study was to compare the immune response profiles in response to parenteral vaccination with live BCG and two inactivated vaccine candidates in cattle. Twenty-four mixed breed calves (Bos taurus) aged 4-6 months, were allocated to one of four groups and vaccinated sub-cutaneously with live M. bovis BCG (Danish 1331), formalin-inactivated M. bovis BCG, heat-killed M. bovis or PBS/MontanideTM (control). Interferon-gamma responsiveness and antibody production were measured prior to vaccination and at weekly intervals thereafter for twelve weeks. At nine weeks post-priming, animals were skin tested using tuberculins and MTBC specific protein cocktails and subsequently challenged through intranodular injection of live M. bovis BCG. The animals in the heat killed M. bovis group demonstrated strong and sustained cell-mediated and humoral immune responses, significantly higher than the control group in response to vaccination, which may indicate a protective immune profile. Animals in this group showed reactivity to the skin test reagents, confirming good vaccine take. Lastly, although not statistically significant, recovery of BCG after challenge was lowest in the heat-killed M. bovis group. In conclusion, the parenteral heat killed M. bovis vaccine proved to be clearly immunogenic in cattle in the present study, urging further evaluation of the vaccine in challenge studies using virulent M. bovis and assessment of vaccine efficacy in field conditions. PMID- 29155878 TI - iRhom2 is essential for innate immunity to RNA virus by antagonizing ER- and mitochondria-associated degradation of VISA. AB - VISA (also known as MAVS, IPS-1 and Cardif) is an essential adaptor protein in innate immune response to RNA virus. The protein level of VISA is delicately regulated before and after viral infection to ensure the optimal activation and timely termination of innate antiviral response. It has been reported that several E3 ubiquitin ligases can mediate the degradation of VISA, but how the stability of VISA is maintained before and after viral infection remains enigmatic. In this study, we found that the ER-associated inactive rhomboid protein 2 (iRhom2) plays an essential role in mounting an efficient innate immune response to RNA virus by maintaining the stability of VISA through distinct mechanisms. In un-infected and early infected cells, iRhom2 mediates auto ubiquitination and degradation of the E3 ubiquitin ligase RNF5 and impairs the assembly of VISA-RNF5-GP78 complexes, thereby antagonizes ER-associated degradation (ERAD) of VISA. In the late phase of viral infection, iRhom2 mediates proteasome-dependent degradation of the E3 ubiquitin ligase MARCH5 and impairs mitochondria-associated degradation (MAD) of VISA. Maintenance of VISA stability by iRhom2 ensures efficient innate antiviral response at the early phase of viral infection and ready for next round of response. Our findings suggest that iRhom2 acts as a checkpoint for the ERAD/MAD of VISA, which ensures proper innate immune response to RNA virus. PMID- 29155879 TI - Subtypes of breast cancer show different spatial distributions of brain metastases. AB - The aim of our study was to test the hypothesis that the spatial distribution of breast cancer brain metastases (BM) differ according to their biological subtypes. MR images of 100 patients with BM from primary breast cancer were retrospectively reviewed. Patients were divided according to the biological subtype of the primary tumor, (triple-negative: 24, HER2 positive: 48, luminal: 28). All images marked with BMs were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. Distribution pattern of BM was evaluated with intra-group and intergroup analysis. In intra group analysis, hot spots of metastases from triple-negative are evenly distributed in the brain, meanwhile BMs from HER2 positive and luminal type occur dominantly in occipital lobe and cerebellum. In intergroup analysis, BMs from triple-negative type occurred more often in frontal lobe, limbic region, and parietal lobe, compared with other types (P < .05). Breast cancer subtypes tend to demonstrate different spatial distributions of their BMs. These findings may have direct implications for dose modulation in prophylactic irradiation as well as for differential diagnoses. Thus, this result should be validated in future study with a larger population. PMID- 29155880 TI - Molecular characterization of novel mosquito-borne Rickettsia spp. from mosquitoes collected at the Demilitarized Zone of the Republic of Korea. AB - Rickettsiae are associated with a diverse range of invertebrate hosts. Of these, mosquitoes could emerge as one of the most important vectors because of their ability to transmit significant numbers of pathogens and parasites throughout the world. Recent studies have implicated Anopheles gambiae as a potential vector of Rickettsia felis. Herein we report that a metagenome sequencing study identified rickettsial sequence reads in culicine mosquitoes from the Republic of Korea. The detected rickettsiae were characterized by a genus-specific quantitative real time PCR assay and sequencing of rrs, gltA, 17kDa, ompB, and sca4 genes. Three novel rickettsial genotypes were detected (Rickettsia sp. A12.2646, Rickettsia sp. A12.2638 and Rickettsia sp. A12.3271), from Mansonia uniformis, Culex pipiens, and Aedes esoensis, respectively. The results underscore the need to determine the Rickettsia species diversity associated with mosquitoes, their evolution, distribution and pathogenic potential. PMID- 29155881 TI - Correction: Relationship between response to aripiprazole once-monthly and paliperidone palmitate on work readiness and functioning in schizophrenia: A post hoc analysis of the QUALIFY study. AB - [This corrects the article DOI: 10.1371/journal.pone.0183475.]. PMID- 29155882 TI - Pharmacological inhibition of RORgammat suppresses the Th17 pathway and alleviates arthritis in vivo. AB - Retinoic acid receptor-related-orphan-receptor-C (RORgammat) is the key transcription factor that is driving the differentiation of IL-17 producing T helper 17 (Th17) cells that are implicated in the pathology of various autoimmune and inflammatory diseases. Based on the importance of RORgammat in promoting Th17 driven pathology, there is considerable interest to develop low-molecular-weight compounds with the aim of inhibiting the transcriptional activity of this nuclear hormone receptor. In this article, we describe the in vitro and in vivo pharmacology of a potent and selective small-molecular-weight RORgammat inverse agonist. The compound binds to the ligand binding domain (LBD) of RORgammat leading to displacement of a co-activator peptide. We show for the first time that a RORgammat inverse agonist down-regulates permissive histone H3 acetylation and methylation at the IL17A and IL23R promoter regions, thereby providing insight into the transcriptional inhibition of RORgammat-dependent genes. Consistent with this, the compound effectively reduced IL-17A production by polarized human T-cells and gammadeltaT-cells and attenuated transcription of RORgammat target genes. The inhibitor showed good in vivo efficacy in an antigen induced arthritis model in rats and reduced the frequencies of IL-17A producing cells in ex vivo recall assays. In summary, we demonstrate that inhibiting RORgammat by a low-molecular-weight inhibitor results in efficient and selective blockade of the pro-inflammatory Th17/IL-17A pathway making it an attractive target for Th17-mediated disorders. PMID- 29155883 TI - Admixture mapping in the Hispanic Community Health Study/Study of Latinos reveals regions of genetic associations with blood pressure traits. AB - Admixture mapping can be used to detect genetic association regions in admixed populations, such as Hispanics/Latinos, by estimating associations between local ancestry allele counts and the trait of interest. We performed admixture mapping of the blood pressure traits systolic and diastolic blood pressure (SBP, DBP), mean arterial pressure (MAP), and pulse pressure (PP), in a dataset of 12,116 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Hispanics/Latinos have three predominant ancestral populations (European, African, and Amerindian), for each of which we separately tested local ancestry intervals across the genome. We identified four regions that were significantly associated with a blood pressure trait at the genome-wide admixture mapping level. A 6p21.31 Amerindian ancestry association region has multiple known associations, but none explained the admixture mapping signal. We identified variants that completely explained this signal. One of these variants had p-values of 0.02 (MAP) and 0.04 (SBP) in replication testing in Pima Indians. A 11q13.4 Amerindian ancestry association region spans a variant that was previously reported (p-value = 0.001) in a targeted association study of Blood Pressure (BP) traits and variants in the vitamin D pathway. There was no replication evidence supporting an association in the identified 17q25.3 Amerindian ancestry association region. For a region on 6p12.3, associated with African ancestry, we did not identify any candidate variants driving the association. It may be driven by rare variants. Whole genome sequence data may be necessary to fine map these association signals, which may contribute to disparities in BP traits between diverse populations. PMID- 29155884 TI - The importance of mean time in therapeutic range for complication rates in warfarin therapy of patients with atrial fibrillation: A systematic review and meta-regression analysis. AB - BACKGROUND: ?Anticoagulation is used for stroke prophylaxis in non-valvular atrial fibrillation, amongst other by use of the vitamin K antagonist, warfarin. Quality in warfarin therapy is often summarized by the time patients spend within the therapeutic range (percent time in therapeutic range, TTR). The correlation between TTR and the occurrence of complications during warfarin therapy has been established, but the influence of patient characteristics in that respect remains undetermined. The objective of the present papers was to examine the association between mean TTR and complication rates with adjustment for differences in relevant patient cohort characteristics. METHODS: A systematic literature search was conducted in MEDLINE and Embase (2005-2015) to identify eligible studies reporting on use of warfarin therapy by patients with non-valvular atrial fibrillation and the occurrence of hemorrhage and thromboembolism. Both randomized controlled trials and observational cohort studies were included. The association between the reported mean TTR and major bleeding and stroke/systemic embolism was analyzed by random-effects meta-regression with and without adjustment for relevant clinical cohort characteristics. In the adjusted meta regressions, the impact of mean TTR on the occurrence of hemorrhage was adjusted for the mean age and the proportion of populations with prior stroke or transient ischemic attack. In the adjusted analyses on thromboembolism, the proportion of females was, furthermore, included. RESULTS: Of 2169 papers, 35 papers met pre specified inclusion criteria, holding relevant information on 31 patient cohorts. In univariable meta-regression, increasing mean TTR was significantly associated with a decreased rate of both major bleeding and stroke/systemic embolism. However, after adjustment mean TTR was no longer significantly associated with stroke/systemic embolism. The proportion of residual variance composed by between study heterogeneity was substantial for all analyses. CONCLUSIONS: Although higher mean TTR in warfarin therapy was associated with lower complication rates in atrial fibrillation, the strength of the association was decreased when adjusting for differences in relevant clinical characteristics of the patient cohorts. This study suggests that mainly the safety of warfarin therapy increases with higher mean TTR, whereas effectiveness appears not to be substantially improved. Due to the limitations immanent in the meta-regression methods, the results of the present study should be interpreted with caution. Further research on the association between the quality of warfarin therapy and risk of complications is warranted with adjustment for clinically relevant characteristics. PMID- 29155885 TI - Alcohol intoxication at Swedish football matches: A study using biological sampling to assess blood alcohol concentration levels among spectators. AB - Alcohol use and alcohol-related problems, including accidents, vandalism and violence, at sporting events are of increased concern in Sweden and other countries. The relationship between alcohol use and violence has been established and can be explained by the level of intoxication. Given the occurrence of alcohol use and alcohol-related problems at sporting events, research has assessed intoxication levels measured through biological sampling among spectators. This cross-sectional study aimed to assess the level of alcohol intoxication among spectators at football matches in the Swedish Premier Football League. Spectators were randomly selected and invited to participate in the study. Alcohol intoxication was measured with a breath analyser for Blood Alcohol Concentration levels, and data on gender, age, and recent alcohol use were gathered through a face-to-face interview. Blood Alcohol Concentration samples from 4420 spectators were collected. Almost half (46.8%) had a positive Blood Alcohol Concentration level, with a mean value of 0.063%, while 8.9% had a Blood Alcohol Concentration level >= 0.1%, with a mean value of 0.135%. Factors that predicted a higher Blood Alcohol Concentration level included male gender (p = 0.005), lower age (p < 0.001), attending a local derby (p < 0.001), alcohol use prior to having entered the arena (p < 0.001), attending a weekend match (p < 0.001), and being a spectator at supporter sections (p < 0.001). About half of all spectators at football matches in the Swedish Premier Football League drink alcohol in conjunction with the match. Approximately one tenth have a high level of alcohol intoxication. PMID- 29155886 TI - Insights into the mechanism of isoenzyme-specific signal peptide peptidase mediated translocation of heme oxygenase. AB - It has recently been shown that signal peptide peptidase (SPP) can catalyze the intramembrane cleavage of heme oxygenase-1 (HO-1) that leads to translocation of HO-1 into the cytosol and nucleus. While there is consensus that translocated HO 1 promotes tumor progression and drug resistance, the physiological signals leading to SPP-mediated intramembrane cleavage of HO-1 and the specificity of the process remain unclear. In this study, we used co-immunoprecipitation and confocal laser scanning microscopy to investigate the translocation mechanism of HO-1 and its regulation by SPP. We show that HO-1 and the closely related HO-2 isoenzyme bind to SPP under normoxic conditions. Under hypoxic conditions SPP mediates intramembrane cleavage of HO-1, but not HO-2. In experiments with an inactive HO-1 mutant (H25A) we show that translocation is independent of the catalytic activity of HO-1. Studies with HO-1 / HO-2 chimeras indicate that the membrane anchor, the PEST-domain and the nuclear shuttle sequence of HO-1 are necessary for full cleavage and subsequent translocation under hypoxic conditions. In the presence of co-expressed exogenous SPP, the anchor and the PEST-domain are sufficient for translocation. Taken together, we identified the domains involved in HO-1 translocation and showed that SPP-mediated cleavage is isoform-specific and independent of HO-activity. A closer understanding of the translocation mechanism of HO-1 is of particular importance because nuclear HO-1 seems to lead to tumor progression and drug resistance. PMID- 29155888 TI - Correction: Potentiated virucidal activity of pomegranate rind extract (PRE) and punicalagin against Herpes simplex virus (HSV) when co-administered with zinc (II) ions, and antiviral activity of PRE against HSV and aciclovir-resistant HSV. AB - [This corrects the article DOI: 10.1371/journal.pone.0179291.]. PMID- 29155889 TI - Correction: Prevalence of abortion and adverse pregnancy outcomes among working women in Korea: A cross-sectional study. AB - [This corrects the article DOI: 10.1371/journal.pone.0182341.]. PMID- 29155887 TI - Effects of an Abeta-antibody fragment on Abeta aggregation and astrocytic uptake are modulated by apolipoprotein E and J mimetic peptides. AB - Abeta-Immunotherapy has long been studied in the treatment of Alzheimer's disease (AD), but not how other molecules involved in the disease can affect antibody performance. We previously designed an antibody fragment, scFv-h3D6, and showed that it precludes Abeta-induced cytotoxicity by withdrawing Abeta oligomers from the amyloid pathway towards a non-toxic, worm-like pathway. ScFv-h3D6 was effective at the behavioral, cellular, and molecular levels in the 3xTg-AD mouse model. Because scFv-h3D6 treatment restored apolipoprotein E (apoE) and J (apoJ) concentrations to non-pathological values, and Abeta internalization by glial cells was found to be decreased in the presence of these apolipoproteins, we now aimed to test the influence of scFv-h3D6 on Abeta aggregation and cellular uptake by primary human astrocytes in the presence of therapeutic apoE and apoJ mimetic peptides (MPs). Firstly, we demonstrated by CD and FTIR that the molecules used in this work were well folded. Next, interactions between apoE or apoJ-MP, scFv h3D6 and Abeta were studied by CD. The conformational change induced by the interaction of Abeta with apoE-MP was much bigger than the induced with apoJ-MP, in line with the observed formation of protective worm-like fibrils by the scFv h3D6/Abeta complex in the presence of apoJ-MP, but not of apoE-MP. ScFv-h3D6, apoJ-MP, and apoE-MP to a different extent reduced Abeta uptake by astrocytes, and apoE-MP partially interfered with the dramatic reduction by scFv-h3D6 while apoJ-MP had no effect on scFv-h3D6 action. As sustained Abeta uptake by astrocytes may impair their normal functions, and ultimately neuronal viability, this work shows another beneficence of scFv-h3D6 treatment, which is not further improved by the use of apoE or apoJ mimetic peptides. PMID- 29155890 TI - Longitudinal fasting blood glucose patterns and arterial stiffness risk in a population without diabetes. AB - OBJECTIVE: To identify long-term fasting blood glucose trajectories and to assess the association between the trajectories and the risk of arterial stiffness in individuals without diabetes. METHODS: We enrolled 16,454 non-diabetic participants from Kailuan cohort. Fasting blood glucose concentrations were measured in 2006, 2008, and 2010 survey. Brachial-ankle pulse wave velocities were measured during 2011 to 2016. Multivariate regression model was used to estimate the difference of brachial-ankle pulse wave velocity levels and logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95%CIs) of arterial stiffness risk, according to the fasting blood glucose trajectories. RESULTS: We identified five distinct fasting blood glucose trajectories and each of the trajectories was labeled according to its range and change over 2006-2010 survey: elevated-stable pattern (5.0% of participants), elevated-decreasing pattern (6.6%), moderate-increasing pattern (10.9%), moderate stable pattern (59.3%), and low-stable pattern (18.2%). After adjustment for potential confounders, individuals with elevated-stable pattern had a 42.6 cm/s (95%CI: 24.7 to 60.6 cm/s) higher brachial-ankle pulse wave velocity level and a 37% (OR 1.37, 95%CI: 1.14 to 1.66) higher arterial stiffness risk, and individuals with moderate-increasing pattern had a 19.6 cm/s (95%CI: 6.9 to 32.3 cm/s) higher brachial-ankle pulse wave velocity level and a 17% (OR 1.17, 95%CI: 1.03 to 1.33) higher arterial stiffness risk, related to individuals with moderate-stable pattern. We did not find significant associations of the elevated decreasing or low-stable patterns with arterial stiffness. Consistently, the cumulative average, variability, and increased rate of fasting blood glucose during 2006-2010 survey were significantly associated with the arterial stiffness risk. CONCLUSION: Discrete fasting blood glucose trajectories were associated with the arterial stiffness risk in non-diabetic individuals. PMID- 29155891 TI - The burden of gynecomastia among men on antiretroviral therapy in Zomba, Malawi. AB - BACKGROUND: Many Africans who are on life-saving ART face challenges from a variety of toxicities. After the introduction of a standardized first-line efavirenz-containing ART regimen, reports of gynecomastia appeared in Malawian popular media, however data on the prevalence and risk factors of gynecomastia from Africa are lacking. METHODS: We conducted a cross-sectional study in males >=18 years registered on ART at the HIV clinic in Zomba Central Hospital. Men who reported to have ever experienced breast or nipple enlargement received a standard questionnaire and underwent physical examination. Questions included perceptions and concerns about gynecomastia. Clinicians confirmed the presence and severity of gynecomastia. Routinely collected data on current and previous ART regimens, CD4 count, WHO clinical stage, anthropometric measurements and history of tuberculosis were extracted from the electronic database. RESULTS: We enrolled 1,027 men with median age 44 years (IQR: 38-52). The median ART duration was 57 months (IQR: 27-85); 46.7% were in WHO stage III/IV at ART initiation, 88.2% had exposure to efavirenz and 9% were overweight or obese. The prevalence of self-reported gynecomastia was 6.0% (62/1027) (95%-CI: 4.7-7.7%). Of men with gynecomastia 83.6% reported nipple enlargement and 98.4% enlarged breasts (85.5% bilateral). One-third said they had not reported gynecomastia to a health care worker. Over three-quarters mentioned that gynecomastia was an important or very important problem for them, while more than half were embarrassed by it. On examination gynecomastia was present in 90% (confirmed gynecomastia prevalence 5.5%; 95%-CI: 4.2-7.0%) and 51.8% had severity grade III or IV. History of tuberculosis treatment was independently associated with self-reported gynecomastia, adjusted OR 2.10 (95%-CI: 1.04-4.25). CONCLUSIONS: The burden of gynecomastia among men on ART in Malawi was higher than previously reported, and was associated with adverse psychological consequences, calling for increased awareness, a proactive diagnostic approach and diligent clinical management. PMID- 29155892 TI - Derivation and application of an analytical rock displacement solution on rectangular cavern wall using the inverse mapping method. AB - Rectangular caverns are increasingly used in underground engineering projects, the failure mechanism of rectangular cavern wall rock is significantly different as a result of the cross-sectional shape and variations in wall stress distributions. However, the conventional computational method always results in a long-winded computational process and multiple displacement solutions of internal rectangular wall rock. This paper uses a Laurent series complex method to obtain a mapping function expression based on complex variable function theory and conformal transformation. This method is combined with the Schwarz-Christoffel method to calculate the mapping function coefficient and to determine the rectangular cavern wall rock deformation. With regard to the inverse mapping concept, the mapping relation between the polar coordinate system within plane sigma and a corresponding unique plane coordinate point inside the cavern wall rock is discussed. The disadvantage of multiple solutions when mapping from the plane to the polar coordinate system is addressed. This theoretical formula is used to calculate wall rock boundary deformation and displacement field nephograms inside the wall rock for a given cavern height and width. A comparison with ANSYS numerical software results suggests that the theoretical solution and numerical solution exhibit identical trends, thereby demonstrating the method's validity. This method greatly improves the computing accuracy and reduces the difficulty in solving for cavern boundary and internal wall rock displacements. The proposed method provides a theoretical guide for controlling cavern wall rock deformation failure. PMID- 29155893 TI - Inhibitory control and decimal number comparison in school-aged children. AB - School-aged children erroneously think that 1.45 is larger 1.5 because 45 is larger than 5. Using a negative priming paradigm, we investigated whether the ability to compare the magnitude of decimal numbers in the context in which the smallest number has the greatest number of digits after the decimal point (1.45 vs. 1.5) is rooted in part on the ability to inhibit the "greater the number of digits the greater its magnitude" misconception derived from a property of whole numbers. In Experiment 1, we found a typical negative priming effect with 7th graders requiring more time to compare decimal numbers in which the largest number has the greatest number of digits after the decimal point (1.65 vs. 1.5) after comparing decimal numbers in which the smallest number has the greatest number of digits after the decimal point (1.45 vs. 1.5) than after comparing decimal numbers with the same number of digits after the decimal point (1.5 vs. 1.6). In Experiment 2, we found a negative priming effect when decimal numbers preceded items in which 7th graders had to compare the length of two lines. Taken together our results suggest that the ability to compare decimal numbers in which the smallest number has the greatest number of digits is rooted in part on the ability to inhibit the "greater the number of digits the greater its magnitude" misconception and in part on the ability to inhibit the length of the decimal number per se. PMID- 29155894 TI - Estimating virus effective population size and selection without neutral markers. AB - By combining high-throughput sequencing (HTS) with experimental evolution, we can observe the within-host dynamics of pathogen variants of biomedical or ecological interest. We studied the evolutionary dynamics of five variants of Potato virus Y (PVY) in 15 doubled-haploid lines of pepper. All plants were inoculated with the same mixture of virus variants and variant frequencies were determined by HTS in eight plants of each pepper line at each of six sampling dates. We developed a method for estimating the intensities of selection and genetic drift in a multi allelic Wright-Fisher model, applicable whether these forces are strong or weak, and in the absence of neutral markers. This method requires variant frequency determination at several time points, in independent hosts. The parameters are the selection coefficients for each PVY variant and four effective population sizes Ne at different time-points of the experiment. Numerical simulations of asexual haploid Wright-Fisher populations subjected to contrasting genetic drift (Ne ? [10, 2000]) and selection (|s| ? [0, 0.15]) regimes were used to validate the method proposed. The experiment in closely related pepper host genotypes revealed that viruses experienced a considerable diversity of selection and genetic drift regimes. The resulting variant dynamics were accurately described by Wright-Fisher models. The fitness ranks of the variants were almost identical between host genotypes. By contrast, the dynamics of Ne were highly variable, although a bottleneck was often identified during the systemic movement of the virus. We demonstrated that, for a fixed initial PVY population, virus effective population size is a heritable trait in plants. These findings pave the way for the breeding of plant varieties exposing viruses to stronger genetic drift, thereby slowing virus adaptation. PMID- 29155895 TI - Correction: Enhancing antibacterial effect of sodium hypochlorite by low electric current-assisted sonic agitation. AB - [This corrects the article DOI: 10.1371/journal.pone.0183895.]. PMID- 29155896 TI - Progesterone impairs antigen-non-specific immune protection by CD8 T memory cells via interferon-gamma gene hypermethylation. AB - Pregnant women and animals have increased susceptibility to a variety of intracellular pathogens including Listeria monocytogenes (LM), which has been associated with significantly increased level of sex hormones such as progesterone. CD8 T memory(Tm) cell-mediated antigen-non-specific IFN-gamma responses are critically required in the host defense against LM. However, whether and how increased progesterone during pregnancy modulates CD8 Tm cell mediated antigen-non-specific IFN-gamma production and immune protection against LM remain poorly understood. Here we show in pregnant women that increased serum progesterone levels are associated with DNA hypermethylation of IFN-gamma gene promoter region and decreased IFN-gamma production in CD8 Tm cells upon antigen non-specific stimulation ex vivo. Moreover, IFN-gamma gene hypermethylation and significantly reduced IFN-gamma production post LM infection in antigen-non specific CD8 Tm cells are also observed in pregnant mice or progesterone treated non-pregnant female mice, which is a reversible phenotype following demethylation treatment. Importantly, antigen-non-specific CD8 Tm cells from progesterone treated mice have impaired anti-LM protection when adoptive transferred in either pregnant wild type mice or IFN-gamma-deficient mice, and demethylation treatment rescues the adoptive protection of such CD8 Tm cells. These data demonstrate that increased progesterone impairs immune protective functions of antigen-non specific CD8 Tm cells via inducing IFN-gamma gene hypermethylation. Our findings thus provide insights into a new mechanism through which increased female sex hormone regulate CD8 Tm cell functions during pregnancy. PMID- 29155897 TI - Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine. AB - INTRODUCTION: The relationship between pituitary TSH and thyroid hormones is central to our understanding of thyroid physiology and thyroid function testing. Here, we generated distribution patterns by using validated tools of thyroid modelling. METHODS: We simulated patterns of individual set points under various conditions, based on a homeostatic model of thyroid feedback control. These were compared with observed data points derived from clinical trials. RESULTS: A random mix of individual set points was reconstructed by simulative modelling with defined structural parameters. The pattern displayed by the cluster of hypothetical points resembled that observed in a natural control group. Moderate variation of the TSH-FT4 gradient over the functional range introduced further flexibility, implementing a scenario of adaptive set points. Such a scenario may be a realistic possibility for instance in treatment where relationships and equilibria between thyroid parameters are altered by various influences such as LT4 dose and conversion efficiency. CONCLUSIONS: We validated a physiologically based homeostatic model that permits simulative reconstruction of individual set points. This produced a pattern resembling the observed data under various conditions. Applied modelling, although still experimental at this stage, shows a potential to aid our physiological understanding of the interplay between TSH and thyroid hormones. It should eventually benefit personalised clinical decision making. PMID- 29155898 TI - Protective effect of Malva sylvestris L. extract in ischemia-reperfusion induced acute kidney and remote liver injury. AB - Mallow (Malva sylvestris L.) has had medicinal and therapeutic uses in addition to its oral consumption. The present study was conducted to examine the protective effect of Malva sylvestris L. extract on ischemia-reperfusion-induced kidney injury and remote organ injuries in the liver. Before ischemia reperfusion, rats in the different groups received intraperitoneal normal saline or mallow extract at the doses of 200, 400 or 600 mg/kg of body weight. After 30 minutes of bilateral renal ischemia followed by 24-hours of reperfusion, tissue damage in the kidney and liver samples were determined through studying H&E stained slides under a light microscope. The degree of leukocyte infiltration and tissue mRNA expressions of TNF- and ICAM-1 were then measured to examine the degree of renal inflammation. The renal tissue MDA and FRAP levels were measured for determining the amount of oxidative stress. Plasma concentrations of creatinine, urea, ALT and ALP were also measured. Ischemia-reperfusion led to a significant increase in plasma concentrations of creatinine, urea, ALT and ALP, and renal tissue MDA, and a significant decrease in renal tissue FRAP. The expression of pro-inflammatory factors in the kidney tissue, the level of leukocyte infiltration and the amount of tissue damage in the kidney and liver also increased. Pretreatment by mallow extract led to a significant improvement in all the variables measured. The 200- and 400-mg doses yielded better results in most parameters compared to the 600-mg dose. The findings showed that mallow extract protects the kidney against ischemia-reperfusion and reduces remote organ injury in the liver. PMID- 29155899 TI - Subtle variation within conserved effector operon gene products contributes to T6SS-mediated killing and immunity. AB - Type VI secretion systems (T6SS) function to deliver lethal payloads into target cells. Many studies have shown that protection against a single, lethal T6SS effector protein requires a cognate antidote immunity protein, both of which are often encoded together in a two-gene operon. The T6SS and an effector-immunity pair is sufficient for both killing and immunity. HereIn this paper we describe a T6SS effector operon that differs from conventional effector-immunity pairs in that eight genes are necessary for lethal effector function, yet can be countered by a single immunity protein. In this study, we investigated the role that the PefE T6SS immunity protein plays in recognition between two strains harboring nearly identical effector operons. Interestingly, despite containing seven of eight identical effector proteins, the less conserved immunity proteins only provided protection against their native effectors, suggesting that specificity and recognition could be dependent on variation within an immunity protein and one effector gene product. The variable effector gene product, PefD, is encoded upstream from pefE, and displays toxic activity that can be countered by PefE independent of T6SS-activity. Interestingly, while the entire pef operon was necessary to exert toxic activity via the T6SS in P. mirabilis, production of PefD and PefE alone was unable to exert this effector activity. Chimeric PefE proteins constructed from two P. mirabilis strains were used to localize immunity function to three amino acids. A promiscuous immunity protein was created using site-directed mutagenesis to change these residues from one variant to another. These findings support the notion that subtle differences between conserved effectors are sufficient for T6SS-mediated kin discrimination and that PefD requires additional factors to function as a T6SS-dependent effector. PMID- 29155901 TI - Corrigenda. AB - [This corrects the article DOI: 10.2471/BLT.16.189894.]. PMID- 29155900 TI - Correction: A massive update of non-indigenous species records in Mediterranean marinas. AB - [This corrects the article DOI: 10.7717/peerj.3954.]. PMID- 29155902 TI - Correction to: Mental health training for primary health care workers and implication for success of integration of mental health into primary care: evaluation of effect on knowledge, attitude and practices (KAP). AB - [This corrects the article DOI: 10.1186/s13033-017-0169-8.]. PMID- 29155903 TI - A surprising substituent effect in corroles on the electrochemical activation of oxygen reduction. AB - Four beta-pyrrole-substituted cobalt(iii) corroles were studied as electrocatalysts for the oxygen reduction reaction. The results disclose high dependence of the corrole's performance on its substituents, but once adsorbed on a high surface area carbon, this effect vanishes, resulting in a better catalytic performance than most well-defined molecular electrocatalysts for this reaction. PMID- 29155904 TI - A route to small clusters: a twisted half-hexagram-shaped M4(OH)4 cluster and its capacity for hosting closed-shell metals. AB - By combining different oxidation states, coordination indices and bridging systems, it has been possible to obtain the structurally novel M4(OH)4 cluster core (M = transition metal) found in the organometallic compound (NBu4)2[PtIVPt(C6Cl5)8(MU2-OH)2(MU3-OH)2] (1). The cluster is formed by two (MU3 OH) and two (MU2-OH) units that bond platinum atoms in different oxidation states. The cluster core geometry can best be described as a half-hexagram. Compound 1 is an excellent precursor for preparing heterometallic clusters since it can host d10 or s2 Lewis-acid metal centers through Pt->M dative bonds, as demonstrated by its reaction with Ag(i) to produce the heterometallic [Ag2PtIVPt(C6Cl5)8(MU2-OH)2(MU3-OH)2] (2), which has four unbridged Pt-Ag bonds. PMID- 29155905 TI - Adsorption of three-domain antifreeze proteins on ice: a study using LGMMAS theory and Monte Carlo simulations. AB - In the present work, the adsorption of three-domain antifreeze proteins on ice is studied by combining a statistical thermodynamics based theory and Monte Carlo simulations. The three-domain protein is modeled by a trimer, and the ice surface is represented by a lattice of adsorption sites. The statistical theory, obtained from the exact partition function of non-interacting trimers adsorbed in one dimension and its extension to two dimensions, includes the configuration of the molecule in the adsorbed state, and allows the existence of multiple adsorption states for the protein. We called this theory "lattice-gas model of molecules with multiple adsorption states" (LGMMAS). The main thermodynamics functions (partial and total adsorption isotherms, Helmholtz free energy and configurational entropy) are obtained by solving a non-linear system of j equations, where j is the total number of possible adsorption states of the protein. The theoretical results are contrasted with Monte Carlo simulations, and a modified Langmuir model (MLM) where the arrangement of the adsorption sites in space is immaterial. The formalism introduced here provides exact results in one dimensional lattices, and offers a very accurate description in two dimensions (2D). In addition, the scheme is capable of predicting the proportion between coverage degrees corresponding to different conformations in the same energetic state. In contrast, the MLM does not distinguish between different adsorption states, and shows severe discrepancies with the 2D simulation results. These findings indicate that the adsorbate structure and the lattice geometry play fundamental roles in determining the statistics of multistate adsorbed molecules, and consequently, must be included in the theory. PMID- 29155906 TI - A combined continuous wave electron paramagnetic resonance and DFT calculations of copper-doped [Cd0.98Cu0.02(prz-trz-ia)] metal-organic framework. AB - Continuous wave X-band electron paramagnetic resonance (EPR) and density functional theory (DFT) were successfully applied to explore the incorporation and coordination state of the Cu2+ ions in the [Cd0.98Cu0.02(prz-trz-ia)] porous metal-organic frameworks. EPR measurements on powder samples and single crystals provided the full electron Zeeman g and copper hyperfine ACu interaction tensors including the orientation of their principal axes frames. DFT computations allowed for a detailed interpretation of the experimental results in terms of coordination symmetry and binding properties of the paramagnetic Cu2+ ions. Cupric ions were found to substitute Cd2+ ions in the dinuclear Cd-Cd units where they experience a noticeably distorted elongated pyramidal coordination environment formed by three nitrogen and two oxygen atoms from three linker molecules. PMID- 29155907 TI - Surface Fe vacancy defects on haematite and their role in light-induced water splitting in artificial photosynthesis. AB - Haematite (alpha-Fe2O3) is a potential candidate for photo-electrochemical water splitting. It is abundant and its electronic properties fit those needed for this kind of device. However, very little is known about the intermediate steps of this photon-induced water splitting process. We propose here that surface iron vacancies can be the main defects responsible for the activity of haematite in the photoelectrochemical reaction. We perform DFT+U calculations and explicitly add holes to show that these defects are common in iron-terminated (0001) surfaces. As holes tend to be localized at these centers, they should be available for the dissociation of water under sunlight. Our calculations also reveal that the water adsorption energy close to the vacancy is 1 eV stronger than far from it, and when the formation of multi-holes is considered, a thermodynamically stable water dissociation mechanism can be developed. We determined that both Fe[double bond, length as m-dash]O and Fe-OOH intermediate steps are stable, although Fe-OOH quickly leads to the formation of O2, having therefore a very short lifetime. Phonon calculations on these structures reveal the appearance of peaks in the 800-900 cm-1 frequency range only for the intermediate steps, connected to Fe[double bond, length as m-dash]O vibrations, in agreement with recent measurements. PMID- 29155908 TI - Iminium and enamine catalysis in enantioselective photochemical reactions. AB - Although enantioselective catalysis under thermal conditions has been well established over the last few decades, the enantioselective catalysis of photochemical reactions is still a challenging task resulting from the complex enantiotopic face differentiation in the photoexcited state. Recently, remarkable achievements have been reported by a synergistic combination of organocatalysis and photocatalysis, which have led to the expedient construction of a diverse range of enantioenriched molecules which are generally not easily accessible under thermal conditions. In this tutorial review, we summarize and highlight the most significant advances in iminium and enamine catalysis of enantioselective photochemical reactions, with an emphasis on catalytic modes and reaction types. PMID- 29155909 TI - Dissociative ionisation of adamantane: a combined theoretical and experimental study. AB - Diamond nanoparticles, or nanodiamonds, are intriguing carbon-based materials which, maybe surprisingly, are the most abundant constituent of presolar grains. While the spectroscopic properties of even quite large diamondoids have already been explored, little is known about their unimolecular fragmentation processes. In this paper we characterise the dissociative ionisation of adamantane (C10H16) the smallest member of the diamondoid family - utilising imaging Photoelectron Photoion Coincidence (iPEPICO) spectroscopy and Density Functional Theory (DFT) calculations. We have found adamantane to dissociatively photoionise via several parallel channels of which H, C3H7 and C4H8 losses are the most important ones. Calculations confirm the existence of a rate-limiting transition state for the multiple C-loss channels, which is located at 10.55 eV with respect to neutral adamantane. In addition, we found dissociation channels leading to small cationic hydrocarbons, which may be relevant in the interstellar medium. PMID- 29155910 TI - Probing plasma fluorinated graphene via spectromicroscopy. AB - Plasma fluorination of graphene is studied using a combination of spectroscopy and microscopy techniques, giving insight into the yield and fluorination mechanism for functionalization of supported graphene with both CF4 and SF6 gas precursors. Ion acceleration during fluorination is used to probe the effect on grafting functionalities. Adatom clustering, which occurs with CF4 plasma treatment, is suppressed when higher kinetic energy is supplied to the ions. During SF6 plasma functionalization, the sulfur atoms tend to bond to bare copper areas instead of affecting the graphene chemistry, except when the kinetic energy of the ions is restricted. Using scanning photoelectron microscopy, with a 100 nm spatial resolution, the chemical bonding environment is evaluated in the fluorinated carbon network at selected regions and the functionalization homogeneity is controlled in individual graphene flakes. PMID- 29155911 TI - Direct alkylheteroarylation of alkenes via photoredox mediated C-H functionalization. AB - The direct alkylheteroarylation of alkenes with cyclic and acyclic ethers via distal heteroaryl ipso-migration has been accomplished through the design of a photoredox-mediated C-H functionalization pathway. The use of inexpensive ethers as radical precursors combined with a straightforward method makes this a practical approach. PMID- 29155912 TI - A novel sulfonamide non-classical carbenoid: a mechanistic study for the synthesis of enediynes. AB - Alkynyl sulfonamides undergo sequential 1,4- then 1,2-addition/rearrangement with lithium acetylides to yield enediynes in the absence of any promoters or catalysts. Mechanistic investigations suggest that the reaction proceeds via 1,4 conjugate addition of the nucleophile to the unsaturated system to give a key alkenyl lithium species which is stabilised by an intramolecular coordination effect by a sulfonamide oxygen atom. This species can be considered a vinylidene carbenoid given the carbon atom bears both an anion (as a vinyllithium) and a leaving group (the sulfonamide). The intramolecular coordination effect serves to stabilise the vinyllithium but activates the sulfonamide motif towards nucleophilic attack by a second mole of acetylide. The resulting species can then undergo rearrangement to yield the enediyne framework in a single operation with concomitant loss of aminosulfinate. PMID- 29155913 TI - Probing electrochemically induced resistive switching of TiO2 using SPM techniques. AB - Resistive switching on the nanoscale is an emerging research field and Scanning Probe Microscopy (SPM) is a powerful tool for studies in this area. Under the SPM tip, the electrical field is very high due to the small tip radius on the order of tens of nanometers, and this can enable a range of ionic/electrochemical phenomena during the resistive switching of the materials under the SPM tip. Although the ionic/electrochemical phenomena have long been considered vital for the resistive switching of materials, a few pieces of experimental evidence, as well as the decoupling of the effects of the electrochemical processes at different stages, are still needed. In this work, we applied SPM based techniques to study resistive switching as well as the electrochemical phenomena during the resistive switching of the TiO2 thin films prepared using Pulse Laser Deposition (PLD). It was found that the reversible or irreversible electrochemical processes initiated at different voltages can promote or degrade the resistive switching behavior of TiO2. Combined with an electrical cell with environmental control, these electrochemical processes have been shown to require the involvement of moisture; the accumulation of oxygen vacancies, protons, and hydroxyls at the tip/TiO2 junction may contribute to the promoting effect of the reversible electrochemical process on resistive switching, while the oxygen vacancy ordering and the injection of protons and hydroxyls into the lattice may lead to the irreversible electrochemical process. This work provides a detailed insight into the characteristics, origins, and the effects of the electrochemical phenomena on resistive switching performance, and will provide a further understanding of the electrochemical phenomena in various functional materials. PMID- 29155914 TI - The surface plasmon resonance, thermal, support and size effect induced photocatalytic activity enhancement of Au/reduced graphene oxide for selective oxidation of benzylic alcohols. AB - Reduced graphene oxide (RGO) as an electron-conductive medium and photosensitizer have been widely used to construct efficient RGO/semiconductor photocatalysts for solar energy conversion; however, the role of RGO has been largely underestimated. Herein, the surface plasmon resonance (SPR) effect, thermal effect, support effect, and size effect of Au/RGO are demonstrated to play important roles in enhancing the photocatalytic activity, which has not been considered previously. Au/RGO nanocomposites, synthesized via a facile wet chemistry route, exhibit an excellent visible light photocatalytic performance for selective oxidation of benzylic alcohols. A collection of joint techniques and control experiments have been employed to explain the SPR effect, thermal effect, support effect, and size effect over the Au/RGO photocatalyst. The possible reaction mechanism for the photocatalytic and thermocatalytic selective oxidation of alcohols over Au/RGO has also been discussed. PMID- 29155915 TI - Optimizing soil-coring strategies to quantify root-length-density distribution in field-grown maize: virtual coring trials using 3-D root architecture models. AB - Background and Aims: Root distribution has a major influence on soil exploration and nutrient and water acquisition by plants. Soil coring is a well-known way to estimate root distribution. However, identifying an optimal core-sampling strategy is important if one is to strike the right balance between the high cost of making field estimates of root length density (RLD) vs. the need for accurate estimates. Virtual assessment of competing soil-coring strategies, based on three dimensional (3-D) models of root system architecture (RSA), is a highly effective way to find that balance. Methods: The trajectories of the axile roots of two maize cultivars having contrasting axile root angles were measured in the field using in situ 3-D digitization. Lateral roots were also measured by recording topological and geometrical parameters. Based on the measurement dataset obtained, contrasting 3-D RSA models of individual maize plants were constructed in which the different lateral rooting angles were represented. Using these RSA models the accuracies of various core-sampling strategies for estimating RLD were assessed in a series of virtual experiments. Key Results: Substantial biases occur if a one-core sampling strategy is used to estimate RLD. The biases largely remain for two-core sampling, although a weighting method can reduce these. However, given that identification of an optimal weighting method is difficult in practice, a new sampling strategy is proposed based on an area-weighting algorithm. In this way low deviations in RLD estimation can be achieved by sampling between rows and also by using larger-diameter (7.5 or 10 cm) cores. Conclusions: A 3-D root architecture model based on a detailed measurement dataset provides an ideal platform for assessing a range of soil-coring strategies. The improved two-core sampling strategy, based on an area-weighting algorithm, shows considerable promise as a cost-efficient way of obtaining good quality RLD estimates for maize. PMID- 29155916 TI - Invited Commentary: A Novel Strategy for Addressing Unmeasured Confounding When Comparing Opioid Agonist Therapies in Pregnancy. AB - Opioid addiction in pregnancy is a growing concern that has recently received a great deal of attention. When comparing recommended opioid agonist therapies, many currently published studies guiding practice may have been affected by unmeasured confounding by indication. Populations of women who receive methadone are generally different from those treated with buprenorphine. Women treated with methadone frequently have more severe and uncontrolled addiction than buprenorphine-treated patients; however, these factors are typically unmeasured or unavailable in large observational data sets. Consequently, findings of superior perinatal outcomes with buprenorphine may in truth be a result of an overall healthier profile of women taking this medication. In this issue of the Journal, Brogly et al. (Am J Epidemiol. 2018;187(6):1153-1161) describe an approach utilizing detailed data from an external cohort (n = 113) to account for confounding by indication in a larger Medicaid population (n = 1,020) in order to more accurately compare opioid agonist therapies in pregnancy. They found that the decreases in risk of preterm birth and length of infant hospitalization associated with buprenorphine as compared with methadone were attenuated after accounting for the additional confounding. Brogly et al. should be commended for providing a novel method with which to address this bias in future studies. PMID- 29155918 TI - Annals of Oncology: factors for making a real impact. PMID- 29155917 TI - Associations Between Divorce and Onset of Drug Abuse in a Swedish National Sample. AB - Rates of drug abuse are higher among divorced individuals than among those who are married, but it is not clear whether divorce itself is a risk factor for drug abuse or whether the observed association is confounded by other factors. We examined the association between divorce and onset of drug abuse in a population based Swedish cohort born during 1965-1975 (n = 651,092) using Cox proportional hazards methods, with marital status as a time-varying covariate. Potential confounders (e.g., demographics, adolescent deviance, and family history of drug abuse) were included as covariates. Parallel analyses were conducted for widowhood and drug-abuse onset. In models with adjustments, divorce was associated with a substantial increase in risk of drug-abuse onset in both sexes (hazard ratios > 5). Co-relative analyses (among biological relatives) were consistent with a partially causal role of divorce on drug-abuse onset. Widowhood also increased risk of drug-abuse onset, although to a lesser extent. Divorce is a potent risk factor for onset of drug abuse, even after adjusting for deviant behavior in adolescence and family history of drug abuse. The somewhat less pronounced association with widowhood, particularly among men, suggests that the magnitude of association between divorce and drug abuse may not be generalizable to the end of a relationship. PMID- 29155919 TI - Neonatal Outcomes in a Medicaid Population With Opioid Dependence. AB - Confounding may account for the apparently improved infant outcomes after prenatal exposure to buprenorphine versus methadone. We used Massachusetts Medicaid Analytic eXtract (MAX) data to identify a cohort of opioid-dependent mother-infant pairs (2006-2011), supplemented with confounder data from an external Boston, Massachusetts, cohort (2015-2016). Associations between prenatal buprenorphine exposure versus methadone exposure and infant outcomes in the MAX cohort were adjusted for measured MAX confounders and were additionally adjusted for unmeasured confounders with bias analysis using external cohort data. A total of 477 women in MAX were treated with methadone and 543 with buprenorphine. More buprenorphine users than methadone users were white and used psychotropic medications. After adjustment for MAX confounders, risk ratios among infants exposed to buprenorphine versus those exposed to methadone were 0.45 (95% confidence interval (CI): 0.34, 0.61) for preterm birth (birth at <37 weeks) and 0.75 (95% CI: 0.51, 1.11) for low birth weight for gestational age. The mean difference in infant hospitalization was -7.35 days (95% CI: -9.16, -5.55). After further adjustment with bias analysis, the risk ratios were 0.53 (95% CI: 0.39, 0.71) for preterm birth and 1.14 (95% CI: 0.77, 1.69) for low birth weight for gestational age, and the mean difference in infant hospitalization was -3.66 days (95% CI: -5.46, -1.87). External confounder data can be used to adjust for unmeasured confounding in studies of prenatal outcomes among women on opioid agonist therapy based on administrative databases. PMID- 29155920 TI - Early-Pregnancy Plasma Concentrations of Perfluoroalkyl Substances and Birth Outcomes in Project Viva: Confounded by Pregnancy Hemodynamics? AB - Associations of prenatal exposure to perfluoroalkyl substances (PFAS), ubiquitous chemicals used in stain- and water-resistant products, with adverse birth outcomes may be confounded by pregnancy hemodynamics. We measured plasma concentrations of 4 PFAS in early pregnancy (median length of gestation, 9 weeks) among 1,645 women in Project Viva, a study of a birth cohort recruited during 1999-2002 in eastern Massachusetts. We fitted multivariable models to estimate associations of PFAS with birth weight-for-gestational age z score and length of gestation, adjusting for sociodemographic confounders and 2 hemodynamic markers: 1) plasma albumin concentration, a measure of plasma volume expansion, and 2) plasma creatinine concentration, used to estimate glomerular filtration rate. Perfluorooctane sulfonate (PFOS) and perfluorononanoate (PFNA) were weakly inversely associated with birth weight-for-gestational age z scores (adjusted beta = -0.04 (95% confidence interval (CI): -0.08, 0.01) and adjusted beta = 0.06 (95% CI: -0.11, -0.01) per interquartile-range increase, respectively). PFOS and PFNA were also associated with higher odds of preterm birth (e.g., for highest PFOS quartile vs. lowest, adjusted odds ratio = 2.4, 95% CI: 1.3, 4.4). Adjusting for markers of pregnancy hemodynamics (glomerular filtration rate and plasma albumin), to the extent that they accurately reflect underlying pregnancy physiology, did not materially affect associations. These results suggest that pregnancy hemodynamics may not confound associations with birth outcomes when PFAS are measured early in pregnancy. PMID- 29155921 TI - Aridification as a driver of biodiversity: a case study for the cycad genus Dioon (Zamiaceae). AB - Background and Aims: Aridification is considered a selective pressure that might have influenced plant diversification. It is suggested that plants adapted to aridity diversified during the Miocene, an epoch of global aridification (~15 million years ago). However, evidence supporting diversification being a direct response to aridity is scarce, and multidisciplinary evidence, besides just phylogenetic estimations, is necessary to support the idea that aridification has driven diversification. The cycad genus Dioon (Zamiaceae), a tropical group including species occurring from humid forests to arid zones, was investigated as a promising study system to understand the associations among habitat shifts, diversification times, the evolution of leaf epidermal adaptations, and aridification of Mexico. Methods: A phylogenetic tree was constructed from seven chloroplast DNA sequences and the ITS2 spacer to reveal the relationships among 14 Dioon species from habitats ranging from humid forests to deserts. Divergence times were estimated and the habitat shifts throughout Dioon phylogeny were detected. The epidermal anatomy among Dioon species was compared and correlation tests were performed to associate the epidermal variations with habitat parameters. Key Results: Events of habitat shifts towards arid zones happened exclusively in one of the two main clades of Dioon. Such habitat shifts happened during the species diversification of Dioon, mainly during the Miocene. Comparative anatomy showed epidermal differences between species from arid and mesic habitats. The variation of epidermal structures was found to be correlated with habitat parameters. Also, most of the analysed epidermal traits showed significant phylogenetic signals. Conclusions: The diversification of Dioon has been driven by the aridification of Mexico. The Miocene timing corresponds to the expansion of arid zones that embedded the ancestral Dioon populations. As response, species in arid zones evolved epidermal traits to counteract aridity stress. This case study provides a robust body of evidence supporting the idea that aridification is an important driver of biodiversity. PMID- 29155923 TI - Atrial fibrillation ablation long-term outcomes: is there light at the end of the tunnel? PMID- 29155922 TI - Population Level Effects of a Mass Media Alcohol and Breast Cancer Campaign: A Cross-Sectional Pre-Intervention and Post-Intervention Evaluation. AB - Aims: To examine the relationship between a TV-led breast cancer mass-media campaign in the North East of England (conducted in two waves: Jul/2015 and Nov/2015), awareness of the link between alcohol and cancer, intention to reduce alcohol consumption and support for alcohol related policies. Methods: Three cross-sectional surveys were conducted; one over the 2 weeks pre-campaign (n = 572); one immediately following campaign wave 1 (n = 576); and another immediately following campaign wave 2 (n = 552). Survey questions assessed; campaign exposure; awareness of the links between alcohol and related cancers; intention to change alcohol consumption; and support for alcohol related policies. Results: The proportion of respondents indicating awareness of alcohol as a cancer risk factor was larger post-campaign compared to pre-campaign. The largest increase was seen for breast cancer with 45% aware of the links post campaign wave 2 compared to 33% pre-campaign. The proportion of respondents indicating 'strong support' of the seven alcohol related policies significantly increased between surveys. The proportion of respondents both aware of alcohol as a cancer risk factor and supportive of the seven alcohol related policies significantly increased between surveys. There was no significant change in self reported intention to reduce alcohol consumption amongst increasing/higher risk drinkers. Conclusion: These findings indicate that a mass-media campaign raising awareness of the links between alcohol and breast cancer is associated with increased awareness and alcohol related policy support at a population level. However, there was no association found with a change in short-term drinking intentions. Short summary: A mass-media campaign raising awareness of the links between alcohol and breast cancer is associated with increased awareness and alcohol policy support at a population level but does not appear to be associated with a change in short term drinking intentions. PMID- 29155924 TI - Accounting for Time-Varying Confounding in the Relationship Between Obesity and Coronary Heart Disease: Analysis With G-Estimation: The ARIC Study. AB - In longitudinal studies, standard analysis may yield biased estimates of exposure effect in the presence of time-varying confounders that are also intermediate variables. We aimed to quantify the relationship between obesity and coronary heart disease (CHD) by appropriately adjusting for time-varying confounders. This study was performed in a subset of participants from the Atherosclerosis Risk in Communities (ARIC) Study (1987-2010), a US study designed to investigate risk factors for atherosclerosis. General obesity was defined as body mass index (weight (kg)/height (m)2) >=30, and abdominal obesity (AOB) was defined according to either waist circumference (>=102 cm in men and >=88 cm in women) or waist:hip ratio (>=0.9 in men and >=0.85 in women). The association of obesity with CHD was estimated by G-estimation and compared with results from accelerated failure-time models using 3 specifications. The first model, which adjusted for baseline covariates, excluding metabolic mediators of obesity, showed increased risk of CHD for all obesity measures. Further adjustment for metabolic mediators in the second model and time-varying variables in the third model produced negligible changes in the hazard ratios. The hazard ratios estimated by G-estimation were 1.15 (95% confidence interval (CI): 0.83, 1.47) for general obesity, 1.65 (95% CI: 1.35, 1.92) for AOB based on waist circumference, and 1.38 (95% CI: 1.13, 1.99) for AOB based on waist:hip ratio, suggesting that AOB increased the risk of CHD. The G-estimated hazard ratios for both measures were further from the null than those derived from standard models. PMID- 29155925 TI - Invited Commentary: Exposure Biomarkers Indicate More Than Just Exposure. AB - Biomarkers of environmental exposures have notable strengths in integrating information across diverse sources and routes of exposure and providing a marker reflecting biological dose. However, the physiological determinants of biomarker toxicokinetics and measured levels may also affect or be affected by disease determinants and thus introduce confounding. In a study published in this issue of the Journal, Sagiv et al. (Am J Epidemiol. 2018;187(4):793-802) sought empirical evidence on the role of renal clearance in biasing the association between perfluoroalkyl compounds measured in plasma during pregnancy and infant birth weight. They found little empirical support for such bias. The risk of such bias is greater when the exposure and health outcome are assessed closely in time, when physiological differences are large relative to variability in environmental levels, and when the physiological determinant has diverse functions and implications. While empirical examination has value, the potential bias is difficult to measure and control when the underlying associations among exposure biomarker, health outcome, and physiological determinant are weak. PMID- 29155927 TI - Specialized fungal parasites reduce fitness of their lichen hosts. AB - Background and aims: Understanding to what extent parasites affect host fitness is a focus of research on ecological interactions. Fungal parasites usually affect the functions of vascular plants. However, parasitic interactions comprising effects of fungal parasites on the fitness of lichen hosts are less well known. This study assesses the effects of the abundance of two highly specialized gall-forming fungi on growth of their two respective lichen hosts and tests whether these fungal parasites reduce lichen fitness. Methods: The relative biomass and thallus area growth rates, and change in specific thallus mass of Lobaria pulmonaria and L. scrobiculata were compared between lichens with and without galls of the lichenicolous fungi Plectocarpon lichenum and P. scrobiculatae, cultivated in a growth chamber for 14 d. By estimating the thallus area occupied by the galls, it was also assessed whether growth rates varied with effective photosynthetic lichen surface area. Key results: Plectocarpon galls significantly reduced relative growth rates of the lichen hosts. Growth rates decreased with increasing cover of parasitic galls. The presence of Plectocarpon galls per se, not the reduced photosynthetic thallus surface due to gall induction, reduced relative growth rates in infected hosts. Specific thallus mass in the hosts changed in species-specific ways. Conclusions: This study shows that specialized fungal parasites can reduce lichen fitness by reducing their growth rates. Higher parasite fitness correlated with lower host fitness, supporting the view that these associations are antagonistic. By reducing hosts' growth rates, these parasites in their symptomatic life stage may affect important lichen functions. This fungal parasite-lichen study widens the knowledge on the ecological effects of parasitism on autotrophic hosts and expands our understanding of parasitic interactions across overlooked taxonomic groups. PMID- 29155926 TI - Codon usage and codon pair patterns in non-grass monocot genomes. AB - Background and Aims: Studies on codon usage in monocots have focused on grasses, and observed patterns of this taxon were generalized to all monocot species. Here, non-grass monocot species were analysed to investigate the differences between grass and non-grass monocots. Methods: First, studies of codon usage in monocots were reviewed. The current information was then extended regarding codon usage, as well as codon-pair context bias, using four completely sequenced non grass monocot genomes (Musa acuminata, Musa balbisiana, Phoenix dactylifera and Spirodela polyrhiza) for which comparable transcriptome datasets are available. Measurements were taken regarding relative synonymous codon usage, effective number of codons, derived optimal codon and GC content and then the relationships investigated to infer the underlying evolutionary forces. Key Results: The research identified optimal codons, rare codons and preferred codon-pair context in the non-grass monocot species studied. In contrast to the bimodal distribution of GC3 (GC content in third codon position) in grasses, non-grass monocots showed a unimodal distribution. Disproportionate use of G and C (and of A and T) in two- and four-codon amino acids detected in the analysis rules out the mutational bias hypothesis as an explanation of genomic variation in GC content. There was found to be a positive relationship between CAI (codon adaptation index; predicts the level of expression of a gene) and GC3. In addition, a strong correlation was observed between coding and genomic GC content and negative correlation of GC3 with gene length, indicating a strong impact of GC-biased gene conversion (gBGC) in shaping codon usage and nucleotide composition in non-grass monocots. Conclusion: Optimal codons in these non-grass monocots show a preference for G/C in the third codon position. These results support the concept that codon usage and nucleotide composition in non-grass monocots are mainly driven by gBGC. PMID- 29155928 TI - Modeling positional effects of regulatory sequences with spline transformations increases prediction accuracy of deep neural networks. AB - Motivation: Regulatory sequences are not solely defined by their nucleic acid sequence but also by their relative distances to genomic landmarks such as transcription start site, exon boundaries or polyadenylation site. Deep learning has become the approach of choice for modeling regulatory sequences because of its strength to learn complex sequence features. However, modeling relative distances to genomic landmarks in deep neural networks has not been addressed. Results: Here we developed spline transformation, a neural network module based on splines to flexibly and robustly model distances. Modeling distances to various genomic landmarks with spline transformations significantly increased state-of-the-art prediction accuracy of in vivo RNA-binding protein binding sites for 120 out of 123 proteins. We also developed a deep neural network for human splice branchpoint based on spline transformations that outperformed the current best, already distance-based, machine learning model. Compared to piecewise linear transformation, as obtained by composition of rectified linear units, spline transformation yields higher prediction accuracy as well as faster and more robust training. As spline transformation can be applied to further quantities beyond distances, such as methylation or conservation, we foresee it as a versatile component in the genomics deep learning toolbox. Availability and implementation: Spline transformation is implemented as a Keras layer in the CONCISE python package: https://github.com/gagneurlab/concise. Analysis code is available at https://github.com/gagneurlab/Manuscript_Avsec_Bioinformatics_2017. Contact: avsec@in.tum.de or gagneur@in.tum.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29155929 TI - Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. AB - The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries. PMID- 29155930 TI - Corrigendum to: "Who Take Naps? Self-Reported and Objectively Measured Napping in Very Old Women". PMID- 29155931 TI - Long-Term Risk of Cardiovascular Death With Use of Clarithromycin and Roxithromycin: A Nationwide Cohort Study. AB - Recent studies have raised concern that macrolide antibiotics may be associated with an increased long-term risk of cardiovascular death. We examined the 1-year risk associated with treatment with clarithromycin (n = 187,887) or roxithromycin (n = 698,899) compared with penicillin V (n = 3,473,081), matched 1:4 on propensity score, in a nationwide, registry-based cohort study in Danish outpatients, 1997-2011. Among clarithromycin courses, the rate ratio for cardiovascular death was 1.24 (95% confidence interval (CI): 0.96, 1.59). Among roxithromycin courses, the rate ratio was 0.99 (95% CI: 0.86, 1.16). In analyses by time after treatment start, the rate ratio associated with clarithromycin was 1.66 (95% CI: 0.98, 2.79) during days 0-7. This was attenuated in later time periods (days 8-89, rate ratio = 1.30, 95% CI: 0.88, 1.94; and days 90-364, rate ratio = 0.96, 95% CI: 0.63, 1.47). For roxithromycin, the rate ratios were 0.88 (95% CI: 0.59, 1.32) during days 0-7, 1.17 (95% CI: 0.92, 1.48) during days 8-89, and 0.88 (95% CI: 0.70, 1.10) during days 90-364. We found no increased risk of cardiovascular death in a general outpatient population. With clarithromycin, we observed a transient increased risk during days 0-7 after treatment start, which corresponds to the period of active treatment. This association was absent in later time periods, which is consistent with no long-term toxicity resulting in cardiovascular death. PMID- 29155932 TI - Commentary: PLAAF score as a novel predictor of long-term outcome after second generation cryoballoon pulmonary vein isolation. PMID- 29155933 TI - PD-L1 Antibodies for EBV-Positive Gastric Cancer, Going Beyond PD-L1 Expression and Microsatellite Instability. PMID- 29155934 TI - Controlled flow diversion in hybrid venoarterial-venous extracorporeal membrane oxygenation. AB - OBJECTIVES: Patients on venoarterial or venovenous extracorporeal membrane oxygenation (ECMO) support may require venoarterial-venous (VAV-ECMO) configuration during follow-up. We report 12 cases of VAV-ECMO with significant outflow steal. METHODS: Between October 2014 and November 2016, a total of 97 patients (56.6 +/- 12.0 years; 59 men/38 women; body surface area 1.84 +/- 0.36 m2) were supported with venoarterial ECMO (n = 85) or venovenous ECMO (n = 12). Among the 97 patients, 12 patients (age 61.5 +/- 3.5 years; 8 men/4 women; body surface area 1.8 +/- 0.8 m2) required hybrid use of VAV-ECMO. Control and monitoring of flow ratios in supplying cannulae using flow sensors were performed, and occluder devices were used according to patient requirements to achieve optimum haemodynamics and oxygenation. RESULTS: Among the 85 venoarterial ECMO-supported patients, Harlequin syndrome was detected in 9 cases (10.6%) who required switching to VAV-ECMO. Among the 12 patients, 3 (25%) patients required VAV-ECMO while on venovenous ECMO support as a result of initial respiratory failure subsequently developed cardiac decompensation. Mean duration of VAV-ECMO support was 6.4 +/- 1.8 days. Overall, on VAV-ECMO support, 70.0 +/- 4.6% of blood flow was detected within the supplying right internal jugular vein cannula as a result of lower afterload in venous system. We partially occluded the internal jugular vein cannula and directed flow to the common femoral artery. After adjustment, 34.3 +/- 7.4% flow was directed to internal jugular vein and 65.6 +/- 7.4% to common femoral artery. CONCLUSIONS: Non-invasive monitoring of flow rates within the supplying cannulae of VAV-ECMO and the use of partial occlusion for venous-supplying cannula enable individualized patient management and effective weaning from VAV-ECMO. PMID- 29155935 TI - Early and late outcomes of open repair for dissecting aneurysms of the descending or thoraco-abdominal aorta. AB - OBJECTIVES: Although open repair is the standard surgical option for dissecting descending thoracic aneurysms (DTAs) and thoraco-abdominal aorta aneurysms (TAAAs), it remains a significant challenge with considerable perioperative morbidity and mortality. We retrospectively analysed early and late outcomes of open repair for these aortic aneurysms. METHODS: Early and late outcomes were investigated for 223 consecutive patients who underwent open repair for dissecting DTA or TAAA between January 2003 and December 2014 (mean age 55 +/- 16 years). The basic strategy for open surgery comprised liberal use of deep hypothermia and aggressive preservation or reattachment of intercostal arteries, i.e. donor arteries for the artery of Adamkiewicz. RESULTS: Deep hypothermia was used in 150 (67.3%) patients. The overall in-hospital mortality rate was 3.6% and 1.5% for elective cases. The rates of spinal cord ischaemic injury and stroke were 3.1% and 4.5%, respectively. During follow-up (mean 63 +/- 40 months), overall 5-year survival rates was 89.2 +/- 2.4% and 91.3 +/- 2.8% and 86.3 +/- 4.1% for DTA and TAAA, respectively. Five- and 10-year rates of freedom from aortic events, defined as surgery for initial operation-related events or for downstream aortic dilation, were 89.1 +/- 3.5% and 68.2 +/- 7.8% for DTA and 100% and 96.6 +/- 3.4% for TAAA, respectively (P < 0.01). CONCLUSIONS: Our approach in treating this aortic pathology showed favourable early and long-term outcomes with acceptable neurological complication rates. More careful follow-up is necessary in patients with DTA repair, because downstream aortic enlargement occurs in some patients. PMID- 29155936 TI - Age, sex and the quantity of atrial fibrosis before AF ablation: what about systematic bias and confounding factors? PMID- 29155937 TI - Nanoparticle-based lateral flow biosensor combined with multiple cross displacement amplification for rapid, visual and sensitive detection of Vibrio cholerae. AB - Vibrio cholerae is an important human pathogen that is responsible for cholera, a severe acute watery diarrhea. In the current study, a multiple cross displacement amplification (MCDA) coupled with amplicon detection by chromatographic lateral flow biosensor (LFB) method (MCDA-LFB) was successfully established and evaluated for the identification of V. cholerae. A set of 10 primers was designed specifically to recognize 10 different regions of the V. cholerae-specific gene ompW. The optimized time and temperature conditions for the MCDA were 30 min and 63 degrees C, respectively. The MCDA-LFB assay correctly identified 31 strains of V. cholerae but did not detect 13 non-cholerae Vibrio strains and 30 non-Vibrio strains. The sensitivity of MCDA-LFB for target pathogen detection in pure culture was 10 fg per reaction. In the case of spiked shrimp samples without enrichment, the limit of detection was 4.1 CFUs per reaction or equivalent to 4.1 * 102 CFU g-1. The whole process, including shrimp homogenates processing (30 min), MCDA reaction (30 min) and results reporting (2 min), could be finished within 65 min. These results show that this assay is suitable for the rapid, sensitive and specific detection of V. cholerae in food, environmental and clinical samples. PMID- 29155938 TI - Cerebral autoregulation in cardiopulmonary bypass surgery: a systematic review. AB - Cardiopulmonary bypass surgery is associated with a high incidence of neurological complications, including stroke, delirium and cognitive impairment. The development of strategies to reduce the incidence of such neurological events has been hampered by the lack of a clear understanding of their pathophysiology. Cerebral autoregulation (CA), which describes the ability of the brain to maintain a stable cerebral blood flow over a wide range of cerebral perfusion pressures despite changes in blood pressure, is known to be impaired in various neurological disorders. Therefore, we aimed to systematically review studies reporting indices of CA in cardiopulmonary bypass surgery. Databases such as MEDLINE, Web of Science, Cochrane Database of Systematic Reviews and EMBASE were searched for relevant articles. Titles, abstracts and full texts of articles were scrutinized according to predefined selection criteria. Two independent reviewers undertook the methodological quality screening and data extraction of the included studies. Twenty of 2566 identified studies were relevant. Studies showed marked heterogeneity and weaknesses in key methodological criteria (e.g. population size and discussion of limitations). All but 3 of the 20 studies described impairments of CA with cardiac surgery. Eleven studies investigated clinical outcomes, and 9 of these found a significant relationship between these and impaired CA. There is a general agreement that cardiac surgery is associated with changes in CA and that clinical outcomes appear to be significantly related to impaired CA. Further studies are now needed to determine prognostic significance and to inform future therapeutic strategies. PMID- 29155940 TI - Stented balloon fenestration before entry repair using the frozen elephant trunk technique for chronic aortic dissection. AB - Endovascular fenestration on the abdominal aorta is effective for preventing visceral malperfusion in aortic dissection. We report a case of stented balloon fenestration before residual entry repair using the frozen elephant trunk technique for chronic aneurysmal dissection after ascending aortic replacement for DeBakey I aortic dissection. We recognized poor communication between the true lumen and false lumen in the abdominal aorta, and visceral perfusion depended almost entirely on the proximal large entry. Therefore, we scheduled catheter angioplasty on the small re-entry before upstream entry closure. After balloon angioplasty using a PTA catheter, a 10-mm * 4-cm self-expandable stent was deployed at the re-entry. We performed open surgery 5 days after angioplasty. Computed tomography after entry repair showed complete thrombosis of the false lumen on the descending aorta, and the celiac and superior mesenteric arteries were supplied via the abdominal re-entry stent. Stented balloon fenestration before entry repair using frozen elephant trunk with chronic aortic dissection was effective for preventing visceral malperfusion. PMID- 29155939 TI - Group B streptococcus activates transcriptomic pathways related to premature birth in human extraplacental membranes in vitro. AB - Streptococcus agalactiae (group B streptococcus [GBS]) infection in pregnant women is the leading cause of infectious neonatal morbidity and mortality in the United States. Although inflammation during infection has been associated with preterm birth, the contribution of GBS to preterm birth is less certain. Moreover, the early mechanisms by which GBS interacts with the gestational tissue to affect adverse pregnancy outcomes are poorly understood. We hypothesized that short-term GBS inoculation activates pathways related to inflammation and premature birth in human extraplacental membranes. We tested this hypothesis using GBS-inoculated human extraplacental membranes in vitro. In agreement with our hypothesis, a microarray-based transcriptomics analysis of gene expression changes in GBS-inoculated membranes revealed that GBS activated pathways related to inflammation and preterm birth with significant gene expression changes occurring as early as 4 h postinoculation. In addition, pathways related to DNA replication and repair were downregulated with GBS treatment. Conclusions based on our transcriptomics data were further supported by responses of prostaglandin E2 (PGE2), and matrix metalloproteinases 1 (MMP1) and 3 (MMP3), all of which are known to be involved in parturition and premature rupture of membranes. These results support our initial hypothesis and provide new information on molecular targets of GBS infection in human extraplacental membranes. PMID- 29155941 TI - New graft sizing rings for aortic valve reimplantation procedures. AB - OBJECTIVES: The objective was to design sizing rings that would enable proper sizing of the graft in reimplantation procedures and to perform leaflet repair before graft implantation. METHODS: The rings were designed in Autodesk Fusion 360 (San Rafael, CA, USA) and 3D printed using a commercial online 3D printing service. We designed incomplete rings with a low profile and complete rings with a high profile. The complete rings are best suited for reimplantation procedures, whereas low profile C rings are intended for isolated aortic valve repair, where the ascending aorta is not transected. The rings come in sizes corresponding to Vascutek Gelweave graft sizes (Vascutek Terumo, Renfrewshire, Scotland). The ring internal diameters are 5% larger than the designated ring sizes and account for the 5% stretch of the grafts when pressurized. Blades of the rings are placed at 20 degrees intervals. The slits between the blades are designed in such a way that the commissural U-sutures, when put in place and under tension, will lock the ring in position. RESULTS: The rings were successfully used in 10 of our latest reimplantation procedures. After dissection of the aortic root, the commissures were suspended with U-stitches and then the ring was seated onto them. Complete leaflet repair with plication to achieve adequate effective height was then performed, followed by graft implantation. No additional leaflet repair was needed. CONCLUSIONS: The newly designed sizing rings enable proper sizing of the graft in reimplantation procedures and enable complete leaflet repair before graft implantation. PMID- 29155942 TI - Detergent-based decellularization strategy preserves macro- and microstructure of heart valves. AB - OBJECTIVES: Biological tissue has great potential to function as bioprostheses in patients for heart valve replacement. As these matrices are mainly xenogenic, the immunogenicity needs to be reduced by decellularization steps. Reseeding of bioscaffolds has tremendous potential to prevent calcification upon implantation, so intact microstructure of the material is mandatory. An optimal decellularization protocol of heart valves resulting in adequate preservation of the extracellular architecture has still not been developed. Biological scaffolds must be decellularized to remove the antigenic potential while preserving the complex mixture of structural and functional proteins that constitute the extracellular matrix. METHODS: Here, we compared 3 different decellularization strategies for their efficiency to remove cells completely while preserving the porcine heart valve ultrastructure. Porcine pulmonary heart valves were treated either with trypsin-ethylenediaminetetraacetic acid (TRP), a protocol using detergents in combination with nucleases (DET + ENZ), or with Accutase(r) solution followed by nuclease treatment (ACC + ENZ). The treated heart valves then were subjected to histological, DNA and scanning electron microscopic analyses. RESULTS: All DNA fragments were removed after ACC + ENZ treatment, whereas cellular removal was incomplete in the TRP group. TRP and ACC + ENZ treated valves were enlarged and showed a disrupted architecture and degraded ultrastructure. In contrast, fully acellular heart valves with intact architecture, layer composition and surface topography were achieved with DET + ENZ treatment. DET + ENZ treatment yielded excellent results in terms of preservation of material architecture and removal of DNA content. CONCLUSIONS: Compared to TRP and ACC + ENZ procedures, DET + ENZ-treated porcine pulmonary heart valves demonstrated well-preserved macroscopic structures and microscopic matrix components and represent an excellent scaffold for further application in tissue engineering. PMID- 29155945 TI - Glyphosate Use and Cancer Incidence in the Agricultural Health Study: An Epidemiologic Perspective. PMID- 29155944 TI - Molecular Interaction Search Tool (MIST): an integrated resource for mining gene and protein interaction data. AB - Model organism and human databases are rich with information about genetic and physical interactions. These data can be used to interpret and guide the analysis of results from new studies and develop new hypotheses. Here, we report the development of the Molecular Interaction Search Tool (MIST; http://fgrtools.hms.harvard.edu/MIST/). The MIST database integrates biological interaction data from yeast, nematode, fly, zebrafish, frog, rat and mouse model systems, as well as human. For individual or short gene lists, the MIST user interface can be used to identify interacting partners based on protein-protein and genetic interaction (GI) data from the species of interest as well as inferred interactions, known as interologs, and to view a corresponding network. The data, interologs and search tools at MIST are also useful for analyzing 'omics datasets. In addition to describing the integrated database, we also demonstrate how MIST can be used to identify an appropriate cut-off value that balances false positive and negative discovery, and present use-cases for additional types of analysis. Altogether, the MIST database and search tools support visualization and navigation of existing protein and GI data, as well as comparison of new and existing data. PMID- 29155943 TI - Logical engineering of D-arm and T-stem of tRNA that enhances d-amino acid incorporation. AB - A bacterial translation factor EF-P alleviates ribosomal stalling caused by polyproline sequence by accelerating Pro-Pro formation. EF-P recognizes a specific D-arm motif found in tRNAPro isoacceptors, 9-nt D-loop closed by a stable D-stem sequence, for Pro-selective peptidyl-transfer acceleration. It is also known that the T-stem sequence on aminoacyl-tRNAs modulates strength of the interaction with EF-Tu, giving enhanced incorporation of non-proteinogenic amino acids such as some N-methyl amino acids. Based on the above knowledge, we logically engineered tRNA's D-arm and T-stem sequences to investigate a series of tRNAs for the improvement of consecutive incorporation of d-amino acids and an alpha, alpha-disubstituted amino acid. We have devised a chimera of tRNAPro1 and tRNAGluE2, referred to as tRNAPro1E2, in which T-stem of tRNAGluE2 was engineered into tRNAPro1. The combination of EF-P with tRNAPro1E2NNN pre-charged with d-Phe, d-Ser, d-Ala, and/or d-Cys has drastically enhanced expression level of not only linear peptides but also a thioether-macrocyclic peptide consisting of the four consecutive d-amino acids over the previous method using orthogonal tRNAs. PMID- 29155946 TI - GPCRdb in 2018: adding GPCR structure models and ligands. AB - G protein-coupled receptors are the most abundant mediators of both human signalling processes and therapeutic effects. Herein, we report GPCRome-wide homology models of unprecedented quality, and roughly 150 000 GPCR ligands with data on biological activities and commercial availability. Based on the strategy of 'Less model - more Xtal', each model exploits both a main template and alternative local templates. This achieved higher similarity to new structures than any of the existing resources, and refined crystal structures with missing or distorted regions. Models are provided for inactive, intermediate and active states-except for classes C and F that so far only have inactive templates. The ligand database has separate browsers for: (i) target selection by receptor, family or class, (ii) ligand filtering based on cross-experiment activities (min, max and mean) or chemical properties, (iii) ligand source data and (iv) commercial availability. SMILES structures and activity spreadsheets can be downloaded for further processing. Furthermore, three recent landmark publications on GPCR drugs, G protein selectivity and genetic variants have been accompanied with resources that now let readers view and analyse the findings themselves in GPCRdb. Altogether, this update will enable scientific investigation for the wider GPCR community. GPCRdb is available at http://www.gpcrdb.org. PMID- 29155948 TI - Predictors of fatigue and work ability in cancer survivors. AB - Background: Workers diagnosed with cancer are at risk for job loss or work disability. Aims: To determine predictors of fatigue and work ability at 36 months after diagnosis in a population of cancer survivors. Methods: Individuals diagnosed with cancer and who applied for work disability benefit at 24 months of sick leave were surveyed at the time of application and again 12 months later. Fatigue was measured using the Functional Assessment of Chronic Illness-Fatigue scale questionnaire and work ability was measured using the work ability index. Linear regression analyses were applied to identify predictors. Results: There were 336 participants. Participants who were divorced or widowed had more physical limitations, more depressive symptoms and were more fatigued at baseline, and who worked in health care demonstrated higher levels of fatigue. Lower fatigue was predicted by having received chemotherapy. A higher level of work ability was predicted by having received chemotherapy, better global health and better work ability at baseline. Lower work ability was predicted by being principal wage earner, insecurity about being free of disease, having more physical limitations and having greater wage loss. Conclusions: Socio demographic, health- and work-related factors were associated with fatigue and work ability in cancer survivors on long-term sick leave. As fatigue and poor work ability are important risk factors for work disability, addressing the identified predictive factors may assist in mitigation of work disability in cancer survivors. PMID- 29155947 TI - Dementia After Moderate-Severe Traumatic Brain Injury: Coexistence of Multiple Proteinopathies. AB - We report the clinical, neuroimaging, and neuropathologic characteristics of 2 patients who developed early onset dementia after a moderate-severe traumatic brain injury (TBI). Neuropathological evaluation revealed abundant beta-amyloid neuritic and cored plaques, diffuse beta-amyloid plaques, and frequent hyperphosphorylated-tau neurofibrillary tangles (NFT) involving much of the cortex, including insula and mammillary bodies in both cases. Case 1 additionally showed NFTs in both the superficial and deep cortical layers, occasional perivascular and depth-of-sulci NFTs, and parietal white matter rarefaction, which corresponded with decreased parietal fiber tracts observed on ex vivo MRI. Case 2 additionally showed NFT predominance in the superficial layers of the cortex, hypothalamus and brainstem, diffuse Lewy bodies in the cortex, amygdala and brainstem, and intraneuronal TDP-43 inclusions. The neuropathologic diagnoses were atypical Alzheimer disease (AD) with features of chronic traumatic encephalopathy and white matter loss (Case 1), and atypical AD, dementia with Lewy bodies and coexistent TDP-43 pathology (Case 2). These findings support an epidemiological association between TBI and dementia and further characterize the variety of misfolded proteins that may accumulate after TBI. Analyses with comprehensive clinical, imaging, genetic, and neuropathological data are required to characterize the full clinicopathological spectrum associated with dementias occurring after moderate-severe TBI. PMID- 29155949 TI - Pseudoaneurysm rupture after acute Type A dissection repair: possible reaction to BioGlue. AB - A 45-year-old man with acute Type A aortic dissection underwent the ascending aorta replacement with BioGlue (CryoLife Europa, Guildford, Surrey, UK) for anastomotic reinforcement. Postoperatively, he developed descending aortic dilation, a giant mediastinal cyst, Henoch-Schonlein purpura and an anastomotic site pseudoaneurysm rupture. A BioGlue-induced inflammatory reaction was likely, according to a positive patch test (delayed allergic reaction). PMID- 29155951 TI - Public awareness and healthcare professional advice for obesity as a risk factor for cancer in the UK: a cross-sectional survey. AB - Background: Overweight and obesity is the second biggest preventable cause of cancer after smoking, causing ~3.4 million deaths worldwide. This study provides current UK data on awareness of the link between obesity and cancer by socio demographic factors, including BMI, and explores to what degree healthcare professionals provide weight management advice to patients. Methods: Cross sectional survey of 3293 adults completed an online survey in February/March 2016, weighted to be representative of the UK population aged 18+. Results: Public awareness of the link between obesity and cancer is low (25.4% unprompted and 57.5% prompted). Higher levels of awareness existed for least deprived groups (P < 0.001), compared to more deprived groups. Most respondents had seen a healthcare practitioner in the past 12 months (91.6%) and 17.4% had received advice about their weight, although 48.4% of the sample were overweight/obese. Conclusion: Cancer is not at the forefront of people's minds when considering health conditions associated with overweight or obesity. Socio-economic disparities exist in health knowledge across the UK population, with adults from more affluent groups being most aware. Healthcare professionals are uniquely positioned to provide advice about weight, but opportunities for intervention are currently under-utilized in healthcare settings. PMID- 29155952 TI - A Report by the Editor-in-Chief for MBE, Volume 33. PMID- 29155950 TI - Ensembl 2018. AB - The Ensembl project has been aggregating, processing, integrating and redistributing genomic datasets since the initial releases of the draft human genome, with the aim of accelerating genomics research through rapid open distribution of public data. Large amounts of raw data are thus transformed into knowledge, which is made available via a multitude of channels, in particular our browser (http://www.ensembl.org). Over time, we have expanded in multiple directions. First, our resources describe multiple fields of genomics, in particular gene annotation, comparative genomics, genetics and epigenomics. Second, we cover a growing number of genome assemblies; Ensembl Release 90 contains exactly 100. Third, our databases feed simultaneously into an array of services designed around different use cases, ranging from quick browsing to genome-wide bioinformatic analysis. We present here the latest developments of the Ensembl project, with a focus on managing an increasing number of assemblies, supporting efforts in genome interpretation and improving our browser. PMID- 29155953 TI - MAX Mutations in Endometrial Cancer: Clinicopathologic Associations and Recurrent MAX p.His28Arg Functional Characterization. AB - Background: Genomic studies have revealed that multiple genes are mutated at varying frequency in endometrial cancer (EC); however, the relevance of many of these mutations is poorly understood. An EC-specific recurrent mutation in the MAX transcription factor p.His28Arg was recently discovered. We sought to assess the functional consequences of this hotspot mutation and determine its association with cancer-relevant phenotypes. Methods: MAX was sequenced in 509 endometrioid ECs, and associations between mutation status and clinicopathologic features were assessed. EC cell lines stably expressing MAXH28R were established and used for functional experiments. DNA binding was examined using electrophoretic mobility shift assays and chromatin immunoprecipitation. Transcriptional profiling was performed with microarrays. Murine flank (six to 11 mice per group) and intraperitoneal tumor models were used for in vivo studies. Vascularity of xenografts was assessed by MECA-32 immunohistochemistry. The paracrine pro-angiogenic nature of MAXH28R-expressing EC cells was tested using microfluidic HUVEC sprouting assays and VEGFA enzyme-linked immunosorbent assays. All statistical tests were two-sided. Results: Twenty-two of 509 tumors harbored mutations in MAX, including 12 tumors with the p.His28Arg mutation. Patients with a MAX mutation had statistically significantly reduced recurrence-free survival (hazard ratio = 4.00, 95% confidence interval = 1.15 to 13.91, P = .03). MAXH28R increased affinity for canonical E-box sequences, and MAXH28R-expressing EC cells dramatically altered transcriptional profiles. MAXH28R-derived xenografts statistically significantly increased vascular area compared with MAXWT and empty vector tumors (P = .003 and P = .008, respectively). MAXH28R-expressing EC cells secreted nearly double the levels of VEGFA compared with MAXWT cells (P = .03, .005, and .005 at 24, 48, and 72 hours, respectively), and conditioned media from MAXH28R cells increased sprouting when applied to HUVECs. Conclusion: These data highlight the importance of MAX mutations in EC and point to increased vascularity as one mechanism contributing to clinical aggressiveness of EC. PMID- 29155955 TI - Changes in Sleep Difficulties During the Transition to Statutory Retirement. AB - Study Objectives: This study examined changes in sleep during the transition from full-time work to statutory retirement. Both the prevalence of any sleep difficulty and the prevalence of specific sleep difficulties, such as difficulties falling asleep, difficulties maintaining sleep, waking up too early in the morning, and nonrestorative sleep, were examined. Methods: Data from the Finnish Public Sector study were used. The study population consisted of 5,807 Finnish public sector employees who retired on statutory basis between 2000 and 2011. The participants responded on the Jenkins Sleep Problem Scale Questionnaire before and after retirement in surveys conducted every 4 years. Results: At the last study wave before retirement, 30% of the participants had sleep difficulties. Prevalence of any sleep difficulty decreased during the retirement transition: the risk ratio (RR) for having sleep difficulties in the first study wave following retirement compared with the last study wave preceding retirement was 0.89 (95% confidence interval [CI] 0.85-0.94). During the retirement transition, both waking up too early in the morning (RR = 0.76, 95% CI 0.69-0.82) and nonrestorative sleep (RR = 0.47, 95% CI 0.42-0.53) decreased, whereas there was no change in difficulties falling asleep or difficulties maintaining sleep. The decreases in sleep difficulties occurred primarily among those with psychological distress, suboptimal self-rated health, short sleep duration, and job strain before retirement. Conclusions: These longitudinal data suggest that transition to statutory retirement is associated with a decrease in sleep difficulties, especially waking up too early in the morning and nonrestorative sleep. PMID- 29155954 TI - The human papillomavirus DNA helicase E1 binds, stimulates, and confers processivity to cellular DNA polymerase epsilon. AB - The papillomavirus (PV) helicase protein E1 recruits components of the cellular DNA replication machinery to the PV replication fork, such as Replication Protein A (RPA), DNA polymerase alpha-primase (pol alpha) and topoisomerase I (topo I). Here we show that E1 binds to DNA polymerase epsilon (pol epsilon) and dramatically stimulates the DNA synthesis activity of pol epsilon. This stimulation of pol epsilon by E1 is highly specific and occurs even in the absence of the known pol epsilon cofactors Replication Factor C (RFC), Proliferating Cell Nuclear Antigen (PCNA) and RPA. This stimulation is due to an increase in the processivity of pol epsilon and occurs independently of pol epsilon's replication cofactors. This increase in processivity is dependent on the ability of the E1 helicase to hydrolyze ATP, suggesting it is dependent on E1's helicase action. In addition, RPA, thought to be vital for processive DNA synthesis by both pol epsilon and pol delta, was found to be dispensable for processive synthesis by pol epsilon in the presence of E1. Overall, E1 appears to be conferring processivity to pol epsilon by directly tethering pol epsilon to the DNA parental strand and towing epsilon behind the E1 helicase as the replication fork progresses; and thereby apparently obviating the need for RPA for leading strand synthesis. Thus far only pol alpha and pol delta have been implicated in the DNA replication of mammalian viruses; this is the first reported example of a virus recruiting pol epsilon. Furthermore, this demonstrates a unique capacity of a viral helicase having evolved to stimulate a cellular replicative DNA polymerase. PMID- 29155956 TI - Associations Between Parental SES and Children's Health-Related Quality of Life: The Role of Objective and Subjective Social Status. AB - Objective: We examined (1) the relationship that parental objective social status (OSS) and subjective social status (SSS) have with children's health-related quality of life (HRQOL), (2) whether SSS mediates the association between OSS and HRQOL, and (3) whether these associations differ among Black, Latino, and White children. Method: Data came from 4,824 Black, Latino, and White 5th graders in the Healthy PassagesTM study. OSS was measured as parent educational attainment and net equivalent household income. SSS was measured by parent rating of community and national standing on the MacArthur Scale of Subjective Social Status. Child HRQOL was measured with child report on the Pediatric Quality of Life Inventory (PedsQL) physical and psychosocial scales. Structural equation modeling path analysis was conducted using Mplus version 7.4. Results: The data supported the hypothesized measurement and structural models. Whereas parental OSS was positively related to psychosocial HRQOL for all three racial/ethnic groups and to physical HRQOL for Latino children, parental SSS was not related to either for any of the racial/ethnic groups. Therefore, mediation by SSS was not supported for any group. Conclusion: OSS was confirmed to have stronger association with children's HRQOL than parental SSS. This is in contrast to some research on adults, raising the questions of how best to assess SSS relevant to children and at what point in development SSS may influence children's health and well-being. The persistent relationship found between parental OSS and child health suggests that efforts to improve low socioeconomic resources in families may contribute to improve children's health. PMID- 29155957 TI - Identification of cells expressing OLFM4 and LGR5 mRNA by in situ hybridization in the yolk sac and small intestine of embryonic and early post-hatch chicks. AB - The chicken yolk sac (YS) and small intestine are essential for nutrient absorption during the pre-hatch and post-hatch periods, respectively. Absorptive enterocytes and secretory cells line the intestinal villi and originate from stem cells located in the intestinal crypts. Similarly, in the YS, there are absorptive and secretory cells that presumably originate from a stem cell population. Leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5) and olfactomedin 4 (Olfm4) are 2 widely used markers for intestinal stem cells. The objective of this study was to map the distribution of putative stem cells expressing LGR5 and OLFM4 mRNA in the chicken small intestine from the late embryonic period to early post hatch and the YS during embryogenesis. At embryonic d 11, 13, 15, 17, and 19, the YS was collected (n = 3), and small intestine was collected at embryonic d 19, d of hatch (doh), and d 1, 4, and 7 post hatch (n = 3). Cells expressing OLFM4 and LGR5 mRNA were identified by in situ hybridization. In the YS, cells expressing only LGR5 and not OLFM4 mRNA were localized to the vascular endothelial cells lining the blood vessels. In the small intestine, cells in the intestinal crypt expressed both LGR5 and OLFM4 mRNA. Staining for OLFM4 mRNA was more intense than LGR5 mRNA, demonstrating that Olfm4 is a more robust marker for stem cells than Lgr5. At embryonic d 19 and doh, cells staining for OLFM4 mRNA were already present in the rudimentary crypts, with the greatest staining in the duodenal crypts. The intensity of OLFM4 mRNA staining increased from doh to d 7 post hatch. Dual label staining at doh for the peptide transporter PepT1 and Olfm4 revealed a population of cells above the crypts that did not express Olfm4 or PepT1 mRNA. These cells are likely progenitor transit amplifying cells. Thus, avians and mammals share similarity in the ontogeny of stem cells in the intestinal crypts. PMID- 29155958 TI - Effect of Preoperative Opioid Dosage on Postoperative Period After Thoracic Spinal Cord Stimulator Surgery. AB - Objective: We aim to study the impact of preoperative opioid dosage on postoperative length of stay (LOS) in patients undergoing thoracic spinal cord stimulator (SCS) placement surgery as a primary objective. Secondary objectives of this study include investigating patient-controlled analgesia (PCA) usage and postoperative complications like fever in relation to patients' preoperative opioid dosage and postoperative LOS. Methods: A total of 47 patients who underwent thoracic SCS for first time were retrospectively studied through chart review. These patients were categorized into two groups, with Group I patients taking a morphine equivalent dose (MED) of less than 100 mg and Group II patients taking an MED of more than 100 mg preoperatively. Results: Group I had 22 patients, and Group II had 25 patients. The average age in Group I was 53.45 years, and the average age in Group II was 50.16 years. There were seven males (38%) and 15 females (62%) in Group I, and in Group II there were 11 males (44%) and 14 females (56%). The average LOS in both groups was two days. In Group I, there were 16 patients (73%) who had an LOS of one day and six patients (27%) who had an LOS of more than one day, and in Group II there were 11 patients (44%) who had an LOS of less than one day and 14 patients (56%) who had an LOS of more than one day, with a P value of 0.047. On univariate analysis, postoperative fever and PCA usage correlated with longer hospital stay, with a P value of < 0.001. Conclusion: Patients on high-dose chronic opioid therapy, defined as an MED greater than 100 mg, who undergo thoracic spinal cord stimulator surgery tend to have longer postoperative hospital stays compared with patients on lower-dose opioid therapy. PMID- 29155960 TI - Occupational medicine specialist referral triggers: Mixed-methods analysis of teleconsult cases. AB - Background: Qualitative analyses can yield critical lessons for learning organizations in healthcare. Few studies have applied these techniques in the field of occupational and environmental medicine (OEM). Aims: To describe the characteristics of complex cases referred for OEM subspecialty evaluation and variation by referring provider's training. Methods: Using a mixed methods approach, we conducted a content analysis of clinical cases submitted to a national OEM teleconsult service. Consecutive cases entered between April 2014 and July 2015 were screened, coded and analysed. Results: 108 cases were available for analysis. Local Veterans Health Administration (VHA) non-specialist providers entered a primary medical diagnosis in 96% of cases at the time of intake. OEM speciality physicians coded significant medical conditions based on free text comments. Coder inter-rater reliability was 84%. The most frequent medical diagnosis types associated with tertiary OEM referral by non-specialists were endocrine (19%), cardiovascular (18%) and mental health (16%). Concern for usage of controlled and/or sedating medications was cited in 1% of cases. Compared to referring non-specialists, OEM physicians were more likely to attribute case complexity to musculoskeletal (OR: 2.3, 1.68-3.14) or neurological (OR: 1.69, 1.28-2.24) conditions. Medication usage (OR: 2.2, 1.49-2.26) was more likely to be a source of clinical concern among referring providers. Conclusions: The findings highlight the range of triggers for OEM physician subspecialty referral in clinical practice with employee patients. The results of this study can be used to inform development of provider education, standardized clinical practice pathways, and quality review activities for occupational medicine practitioners. PMID- 29155959 TI - The discovery potential of RNA processing profiles. AB - Small non-coding RNAs (sncRNAs) are highly abundant molecules that regulate essential cellular processes and are classified according to sequence and structure. Here we argue that read profiles from size-selected RNA sequencing capture the post-transcriptional processing specific to each RNA family, thereby providing functional information independently of sequence and structure. We developed SeRPeNT, a new computational method that exploits reproducibility across replicates and uses dynamic time-warping and density-based clustering algorithms to identify, characterize and compare sncRNAs by harnessing the power of read profiles. We applied SeRPeNT to: (i) generate an extended human annotation with 671 new sncRNAs from known classes and 131 from new potential classes, (ii) show pervasive differential processing of sncRNAs between cell compartments and (iii) predict new molecules with miRNA-like behaviour from snoRNA, tRNA and long non-coding RNA precursors, potentially dependent on the miRNA biogenesis pathway. Furthermore, we validated experimentally four predicted novel non-coding RNAs: a miRNA, a snoRNA-derived miRNA, a processed tRNA and a new uncharacterized sncRNA. SeRPeNT facilitates fast and accurate discovery and characterization of sncRNAs at an unprecedented scale. SeRPeNT code is available under the MIT license at https://github.com/comprna/SeRPeNT. PMID- 29155961 TI - Disease activity decrease is associated with improvement in work productivity over 1 year in early axial spondyloarthritis (SPondyloArthritis Caught Early cohort). AB - Objectives: To assess if a change in disease activity is associated with a change in work productivity loss (WPL) over 1 year in early axial SpA (axSpA) patients. Methods: Baseline and 1 year data of axSpA patients in the SPondyloArthritis Caught Early cohort were analysed. Linear regression models were built explaining the change in the Ankylosing Spondylitis Disease Activity Score (ASDAS) over time by the change in absenteeism, presenteeism, WPL and activity impairment over time. Effect modification and confounding were tested for age, gender, arm of Assessment of SpondyloArthritis international Society classification criteria, HLA-B27, duration of chronic back pain, profession and medication. Results: At baseline, in 105 axSpA patients (48% female, mean age 30.8 years, mean symptom duration 13.6 months, 92% HLA-B27 positive, 24% radiographic sacroiliitis), the mean ASDAS was 2.4 (s.d. 1.0), absenteeism 9% (s.d. 23), presenteeism 33% (s.d. 28), WPL 36% (s.d. 30) and activity impairment 37% (s.d. 25). After 1 year, the mean ASDAS decreased to 2.0 (s.d. 0.8) and absenteeism, presenteeism, WPL and activity impairment improved to 6% (s.d. 22), 26% (s.d. 26), 27% (s.d. 29) and 27% (s.d. 26), respectively. Models showed that if ASDAS decreased 1 unit, absenteeism, presenteeism, WPL and activity impairment improved by 5, 17, 16 and 18%, respectively. The impact of disease activity on work productivity was higher in patients with shorter symptom duration and the impact on absenteeism was higher in patients starting pharmacological treatment. Conclusions: In early axSpA patients, work productivity and daily activities are seriously impacted at baseline and 1 year. However, decreasing disease activity is associated with marked improvements in work productivity and daily activities. PMID- 29155962 TI - IgG4-related disease presenting with raised serum IgG2-real timeline of IgG4-RD? PMID- 29155963 TI - Generating Modeling Data From Repeat-Dose Toxicity Reports. AB - Over the past decades, pharmaceutical companies have conducted a large number of high-quality in vivo repeat-dose toxicity (RDT) studies for regulatory purposes. As part of the eTOX project, a high number of these studies have been compiled and integrated into a database. This valuable resource can be queried directly, but it can be further exploited to build predictive models. As the studies were originally conducted to investigate the properties of individual compounds, the experimental conditions across the studies are highly heterogeneous. Consequently, the original data required normalization/standardization, filtering, categorization and integration to make possible any data analysis (such as building predictive models). Additionally, the primary objectives of the RDT studies were to identify toxicological findings, most of which do not directly translate to in vivo endpoints. This article describes a method to extract datasets containing comparable toxicological properties for a series of compounds amenable for building predictive models. The proposed strategy starts with the normalization of the terms used within the original reports. Then, comparable datasets are extracted from the database by applying filters based on the experimental conditions. Finally, carefully selected profiles of toxicological findings are mapped to endpoints of interest, generating QSAR-like tables. In this work, we describe in detail the strategy and tools used for carrying out these transformations and illustrate its application in a data sample extracted from the eTOX database. The suitability of the resulting tables for developing hazard-predicting models was investigated by building proof-of concept models for in vivo liver endpoints. PMID- 29155964 TI - Effects of replacing soybean meal with chickpea seeds in the diet on mechanical and thermal properties of tendon tissue in broiler chicken. AB - The efficiency of the musculoskeletal system of broiler chickens, in particular during locomotion and in ensuring its supportive function, depends directly on the adequate function and mechanical endurance of soft tissues, including tendons. However, little is known whether the properties of musculoskeletal soft tissues can be influenced by changes of dietary protein. We substituted soybean meal with raw chickpea seeds as the primary protein source in the diet and studied the effects it had on the mechanical and thermal properties of drumstick tendons in broiler Ross 308 chickens. In the experiment, 160 chicks were divided into 2 groups, receiving in their diet either soybean meal (n = 80) or chickpea seeds (n = 80). The experiment lasted 42 days. The physical condition of the drumstick tendons was analyzed on the basis of a tensile test and the results of thermal denaturation as measured by a differential scanning calorimetry. The mechanical evaluation of tendon tensile strength of the broilers fed with chickpea seeds demonstrated an increase in the ultimate strain (for over 22%, P < 0.04) and total energy absorbed by the tendon until rupture (for over 57%, P < 0.05) as when compared to the group fed with soybean meal. Thermal analysis demonstrated alterations in tendon collagen cross-linking as transition onset temperature decreased (from 63.8 to 61.8 degrees C, P < 0.001), whereas the calorimetric enthalpy increased (from 16.2 to 22.1 J?g-1, P < 0.05) in the group fed with chickpea seeds. In summary, this study demonstrated that dietary protein source can impact the physical properties of tendons and showed that thermal analysis can be a useful tool for studying the effect of nutrition on the development and structural changes in tendons of broiler chickens. PMID- 29155965 TI - Is frozen embryo transfer better for mothers and babies? Can cumulative meta analysis provide a definitive answer? AB - BACKGROUND: Initial observational studies and a systematic review published 5 years ago have suggested that obstetric and perinatal outcomes are better in offspring conceived following frozen rather than fresh embryo transfers, with reduced risks of preterm birth, small for gestational age, low birth weight and pre-eclampsia. More recent primary studies are beginning to challenge some of these findings. We therefore conducted an updated systematic review and cumulative meta-analysis to examine if these results have remained consistent over time. OBJECTIVE AND RATIONALE: The aim of this study was to perform a systematic review and cumulative meta-analysis (trend with time) of obstetric and perinatal complications in singleton pregnancies following the transfer of frozen thawed and fresh embryos generated through in-vitro fertilisation. SEARCH METHODS: Data Sources from Medline, EMBASE, Cochrane Central Register of Clinical Trials DARE and CINAHL (1984-2016) were searched using appropriate key words. Observational and randomised studies comparing obstetric and perinatal outcomes in singleton pregnancies conceived through IVF using either fresh or frozen thawed embryos. Two independent reviewers extracted data in 2 * 2 tables and assessed the methodological quality of the relevant studies using CASP scoring. Both aggregated as well as cumulative meta-analysis was done using STATA. OUTCOMES: Twenty-six studies met the inclusion criteria. Singleton babies conceived from frozen thawed embryos were at lower relative risk (RR) of preterm delivery (0.90; 95% CI 0.84-0.97) low birth weight (0.72; 95% CI 0.67-0.77) and small for gestational age (0.61; 95% CI 0.56-0.67) compared to those conceived from fresh embryo transfers, but faced an increased risk (RR) of hypertensive disorders of pregnancy (1.29; 95% CI 1.07-1.56) large for gestational age (1.54; 95% CI 1.48-1.61) and high birth weight (1.85; 95% CI 1.46-2.33). There was no difference in the risk of congenital anomalies and perinatal mortality between the two groups. The direction and magnitude of effect for these outcomes have remained virtually unchanged over time while the degree of precision has improved with the addition of data from newer studies. WIDER IMPLICATIONS: The results of this cumulative meta-analysis confirm that the decreased risks of small for gestational age, low birth weight and preterm delivery and increased risks of large for gestational age and high birth weight associated with pregnancies conceived from frozen embryos have been consistent in terms of direction and magnitude of effect over several years, with increasing precision around the point estimates. Replication in a number of different populations has provided external validity for the results, for outcomes of birth weight and preterm delivery. Meanwhile, caution should be exercised about embarking on a policy of electively freezing all embryos in IVF as there are increased risks for large for gestational age babies and hypertensive disorders of pregnancy. Therefore, elective freezing should ideally be undertaken in specific cases such as ovarian hyperstimulation syndrome, fertility preservation or in the context of randomised trials. PMID- 29155966 TI - Crustacean Larvae-Vision in the Plankton. AB - We review the visual systems of crustacean larvae, concentrating on the compound eyes of decapod and stomatopod larvae as well as the functional and behavioral aspects of their vision. Larval compound eyes of these macrurans are all built on fundamentally the same optical plan, the transparent apposition eye, which is eminently suitable for modification into the abundantly diverse optical systems of the adults. Many of these eyes contain a layer of reflective structures overlying the retina that produces a counterilluminating eyeshine, so they are unique in being camouflaged both by their transparency and by their reflection of light spectrally similar to background light to conceal the opaque retina. Besides the pair of compound eyes, at least some crustacean larvae have a non imaging photoreceptor system based on a naupliar eye and possibly other frontal eyes. Larval compound-eye photoreceptors send axons to a large and well-developed optic lobe consisting of a series of neuropils that are similar to those of adult crustaceans and insects, implying sophisticated analysis of visual stimuli. The visual system fosters a number of advanced and flexible behaviors that permit crustacean larvae to survive extended periods in the plankton and allows them to reach acceptable adult habitats, within which to metamorphose. PMID- 29155967 TI - Subcellular metabolomics: the choice of method depends on the aim of the study. PMID- 29155968 TI - Novel Spiroplasma Spp. Cultured From Brains and Lymph Nodes From Ruminants Affected With Transmissible Spongiform Encephalopathy. AB - Spiroplasma spp., tiny filterable wall-less bacteria, are consistently associated with the transmissible spongiform encephalopathies (TSE). Spiral forms have been transiently isolated from TSE-affected brain tissues in SP4 growth media designed for isolation of Spiroplasma spp., but the isolate could not be propagated in SP4 media. A bacterium must grow in vitro in cell-free cultures to allow full characterization of a suspect pathogen. Here, a novel Spiroplasma sp. was isolated from scrapie- and chronic wasting disease (CWD)-affected brains and lymph nodes. Filtrates of tissue homogenates inoculated into Brucella media incubated for 14 days at 35 degrees C resulted in high titers of spiroplasma as shown by dark-field microscopy. A drop assay of infected media on Bacto Schaedler agar showed spiroplasma isolates forming unique subsurface colonies after 21 days incubation. Spiroplasma coils, coccoid forms and clumps of entwined spiroplasma filaments were seen on the agar by scanning electron microscopy. Since Brucella media has a sodium bisulfite additive that lowers oxygen tension, TSE spiroplasma growth requires media with low oxygen tension. Brucella media allows for isolation and propagation of spiroplasma from TSE-affected tissues, which will lead to complete characterization of this TSE pathogen and determine its role as a candidate causative agent of TSE. PMID- 29155969 TI - Reducing barriers to consulting a General Practitioner in patients at increased risk of lung cancer: a qualitative evaluation of the CHEST Australia intervention. AB - Background: Lung cancer has one of the lowest survival outcomes of any cancer because over two-thirds of patients are diagnosed when curative treatment is no longer possible, partly due to later presentation with symptoms to a healthcare provider. Objective: To explore the theoretical underpinning of the Scottish CHEST intervention in participants randomized to the intervention group within the CHEST Australia trial. Methods: A purposive maximum variation sample of participants who received the intervention in the CHEST trial in Perth, Western Australia (N = 13) and Melbourne, Victoria, (N = 7) were interviewed. Patients were asked about their experience of the CHEST consultation, their recall of the main messages, their symptom appraisal and issues relating to help seeking when they develop symptoms. Thematic analysis was conducted to draw common themes between the participants. Results: We identified themes consistent with the theoretical basis of the CHEST intervention. Barriers to consultation identified in the CHEST Australia trial participants were smoker stigmatization, guilt, fatalism and symptom normalization. We identified a general perceived mistrust of GPs based on previous negative experiences of visiting their GP in relation to their smoking. The intervention tackled barriers around lecturing and feelings of guilt and stigma related to smoking. We identified expected effects on salience and personal relevance of symptoms. Participants reported a clearer understanding of what to look out for and when to take action after the CHEST intervention. Conclusions: These findings suggest that the CHEST Australia intervention is achieving the desired objectives at the qualitative level through the proposed theoretical mechanisms. PMID- 29155970 TI - Cognitive Function, Coping, and Depressive Symptoms in Children and Adolescents with Sickle Cell Disease. AB - Objective: The objective of this study was to investigate the association between cognitive functioning, coping, and depressive symptoms in children and adolescents with sickle cell disease (SCD). Method: Forty-four children (M age = 9.30, SD = 3.08; 56.8% male) with SCD completed cognitive assessments measuring working memory (Wechsler Intelligence Scale for Children-Fourth Edition) and verbal comprehension (Wechsler Abbreviated Scale of Intelligence-Second Edition). Participants' primary caregivers completed questionnaires assessing their child's coping and depressive symptoms. Results: Verbal comprehension was significantly positively associated with secondary control coping (cognitive reappraisal, acceptance, distraction), and both working memory and secondary control coping were negatively associated with depressive symptoms. In partial support of the primary study hypothesis, verbal comprehension had an indirect association with depressive symptoms through secondary control coping, whereas working memory had a direct association with depressive symptoms. Conclusions: The results provide new evidence for the associations between cognitive function and coping, and the association of both of these processes with depressive symptoms in children with SCD. Findings provide potential implications for clinical practice, including interventions to improve children's cognitive functioning to attenuate depressive symptoms. PMID- 29155972 TI - Screening Guideline for Cervical Cancer Recommends Against Human Papillomavirus Pap Cotesting. PMID- 29155971 TI - In ovo injection of ascorbic acid modulates antioxidant defense system and immune gene expression in newly hatched local Chinese yellow broiler chicks. AB - The present study was conducted to investigate the effects of in ovo injection of ascorbic acid on antioxidant capacity and immune-related gene expression in the newly hatched local Chinese yellow broiler chicks. Fertile Chinese yellow broiler eggs (n = 90) were assigned to three equal groups. The first group was a non injected control group. The second group was another control group where the eggs were injected with saline in the air sac after 18 days of incubation. The third group was injected with 3 mg/egg AA in the air sac after 18 days of incubation. In ovo injection of 3 mg/egg AA significantly (P < 0.0001) increased plasma glutathione peroxidase (GSH-PX), total antioxidant capacity (T-AOC), and significantly reduced plasma malondialdehyde (MDA) at 1 d old. Moreover, in ovo injection of 3 mg/egg AA significantly increased mRNA expression of glutathione peroxidase (GSH-PX) and superoxide Dismutase (SOD) in the chick's spleen.Additionally, the mRNA level of interleukin 1 beta (IL-1beta), interleukin 6 (IL-6), and tumour necrosis factor alpha (TNF-alpha) in the spleen were significantly decreased (P < 0.0001), which indicates an improvement in chick's immunity. In conclusion, our data suggest that in ovo injection of AA at 3 mg/egg enhance antioxidant defense system and immune system for newly hatched chicks. PMID- 29155973 TI - Tapering versus steady-state methotrexate in combination with tocilizumab for rheumatoid arthritis: a randomized, double-blind trial. AB - Objective: To explore whether tocilizumab + tapering MTX has comparable efficacy and safety vs tocilizumab + stable MTX in adult RA patients with inadequate response to MTX. Methods: This randomized, placebo-controlled non-inferiority study involved patients with severe active RA [28-joint DAS (DAS28) >5.1] who had initiated tocilizumab + MTX at the study start. Patients received open-label tocilizumab (8 mg/kg i.v. every 4 weeks) and open-label MTX. At week 24, patients achieving good/moderate EULAR response were randomized to group A (double-blind MTX taper) or group B (double-blind MTX maintenance); both arms continued open label tocilizumab. Primary analysis was the proportion of patients maintaining good/moderate EULAR response from week 24 to 60. Results: The study stopped early due to low recruitment, although the predetermined non-inferiority criteria were still met; 427 patients were enrolled to the open-label phase at week 0. At week 24, EULAR good/moderate response was achieved in 272 individuals (64.4%) who were randomized, 136 in each arm (36% withdrew/were not eligible). Additionally, 45.0% achieved DAS28 ?3.2, 33.5% achieved remission (DAS28 <2.6) and 64.2% had a DAS28 change ?1.2. After week 24 randomization, the proportion of patients maintaining good/moderate EULAR response to week 60 was significantly greater for MTX taper vs stable MTX (76.5 vs 65.4%; P = 0.036), and since the lower limit of the 95% CI was >0.9, the pre-determined criteria for non-inferiority was fulfilled despite reduced recruitment. Safety analysis revealed no unexpected tocilizumab safety signals. Conclusions: Tapering MTX in patients with RA receiving tocilizumab was non-inferior to continuing stable MTX in maintaining a good/moderate EULAR response. There were no unexpected safety signals; tocilizumab and MTX therapy was generally well tolerated in both groups. Trial registration number: EudraCT 2011-005260-20. PMID- 29155974 TI - Transcript profiling of a bitter variety of narrow-leafed lupin to discover alkaloid biosynthetic genes. AB - Lupins (Lupinus spp.) are nitrogen-fixing legumes that accumulate toxic alkaloids in their protein-rich beans. These anti-nutritional compounds belong to the family of quinolizidine alkaloids (QAs), which are of interest to the pharmaceutical and chemical industries. To unleash the potential of lupins as protein crops and as sources of QAs, a thorough understanding of the QA pathway is needed. However, only the first enzyme in the pathway, lysine decarboxylase (LDC), is known. Here, we report the transcriptome of a high-QA variety of narrow leafed lupin (L. angustifolius), obtained using eight different tissues and two different sequencing technologies. In addition, we present a list of 33 genes that are closely co-expressed with LDC and that represent strong candidates for involvement in lupin alkaloid biosynthesis. One of these genes encodes a copper amine oxidase able to convert the product of LDC, cadaverine, into 1-piperideine, as shown by heterologous expression and enzyme assays. Kinetic analysis revealed a low KM value for cadaverine, supporting a role as the second enzyme in the QA pathway. Our transcriptomic data set represents a crucial step towards the discovery of enzymes, transporters, and regulators involved in lupin alkaloid biosynthesis. PMID- 29155976 TI - Description of a Mass Poisoning in a Rural District in Mozambique: The First Documented Bongkrekic Acid Poisoning in Africa. AB - Background: On 9 January 2015, in a rural town in Mozambique, >230 persons became sick and 75 died of an illness linked to drinking pombe, a traditional alcoholic beverage. Methods: An investigation was conducted to identify case patients and determine the cause of the outbreak. A case patient was defined as any resident of Chitima who developed any new or unexplained neurologic, gastrointestinal, or cardiovascular symptom from 9 January at 6:00 am through 12 January at 11:59 pm. We conducted medical record reviews, healthcare worker and community surveys, anthropologic and toxicologic investigations of local medicinal plants and commercial pesticides, and laboratory testing of the suspect and control pombe. Results: We identified 234 case patients; 75 (32%) died and 159 recovered. Overall, 61% of case patients were female (n = 142), and ages ranged from 1 to 87 years (median, 30 years). Signs and symptoms included abdominal pain, diarrhea, vomiting, and generalized malaise. Death was preceded by psychomotor agitation and abnormal posturing. The median interval from pombe consumption to symptom onset was 16 hours. Toxic levels of bongkrekic acid (BA) were detected in the suspect pombe but not the control pombe. Burkholderia gladioli pathovar cocovenenans, the bacteria that produces BA, was detected in the flour used to make the pombe. Conclusions: We report for the first time an outbreak of a highly lethal illness linked to BA, a deadly food-borne toxin in Africa. Given that no previous outbreaks have been recognized outside Asia, our investigation suggests that BA might be an unrecognized cause of toxic outbreaks globally. PMID- 29155977 TI - An unusual cause of dysphagia. PMID- 29155975 TI - Induced cortical responses require developmental sensory experience. AB - Sensory areas of the cerebral cortex integrate the sensory inputs with the ongoing activity. We studied how complete absence of auditory experience affects this process in a higher mammal model of complete sensory deprivation, the congenitally deaf cat. Cortical responses were elicited by intracochlear electric stimulation using cochlear implants in adult hearing controls and deaf cats. Additionally, in hearing controls, acoustic stimuli were used to assess the effect of stimulus mode (electric versus acoustic) on the cortical responses. We evaluated time-frequency representations of local field potential recorded simultaneously in the primary auditory cortex and a higher-order area, the posterior auditory field, known to be differentially involved in cross-modal (visual) reorganization in deaf cats. The results showed the appearance of evoked (phase-locked) responses at early latencies (<100 ms post-stimulus) and more abundant induced (non-phase-locked) responses at later latencies (>150 ms post stimulus). In deaf cats, substantially reduced induced responses were observed in overall power as well as duration in both investigated fields. Additionally, a reduction of ongoing alpha band activity was found in the posterior auditory field (but not in primary auditory cortex) of deaf cats. The present study demonstrates that induced activity requires developmental experience and suggests that higher-order areas involved in the cross-modal reorganization show more auditory deficits than primary areas. PMID- 29155978 TI - Results of repeated video-assisted thoracic surgery for recurrent pneumothorax after primary spontaneous pneumothorax. AB - OBJECTIVES: This study aimed to identify the causes of recurrent pneumothorax and to evaluate the results of repeated video-assisted thoracic surgery (VATS) for recurrent pneumothorax after VATS wedge resection for primary spontaneous pneumothorax (PSP). METHODS: A retrospective review was conducted on 188 patients with recurrent PSP, of a population of 1414 patients who underwent VATS wedge resection for PSP. Reoperations were performed when an air leak persisted longer than 3 days after closed thoracostomy, when a visible bulla of greater than 1 cm on high-resolution computed tomography (HRCT) was observed and when rerecurrence took place after other treatments. The HRCT findings before and after recurrence were compared to evaluate the type of the new bulla. Patients were divided into 2 groups according to the additional procedure performed during the first operation; in Group I, a coverage procedure was performed, and in Group II, mechanical pleurodesis was performed after VATS wedge resection. RESULTS: During a median follow-up period of 27.7 months, 76 patients underwent repeated VATS for ipsilateral recurrent PSP after VATS. The indications for repeated VATS were the presence of a bulla on HRCT in 41 patients and a persistent air leak in 35 patients. Group I comprised 36 patients and Group II comprised 40 patients. The HRCT findings showed no bulla in 3 (4%) patients, were suspicious for a bulla in 11 (15%) patients, showed a bulla at the staple line in 26 (34%) patients and showed a new bulla in a location other than on the staple line in 36 (47%) patients. The frequency of new bullae was not different between the 2 groups, but Group I showed a lesser tendency for bullae to occur at the staple line than Group II. Dense fibrosis around the staple line was also found intraoperatively. CONCLUSIONS: Repeated VATS was a feasible method to treat recurrent PSP after VATS for PSP. PMID- 29155980 TI - An evaluation of the patient-administered Rheumatoid Arthritis Disease Activity Index for assessing disease activity during pregnancy. PMID- 29155979 TI - Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice. AB - The Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer's disease and Huntington's disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigenetic landscape in hippocampal tissue and designed a Dlg4/PSD95 gene-targeting strategy: a Dlg4/PSD95 zinc finger DNA binding domain was engineered and fused to effector domains to either repress (G9a, Suvdel76, SKD) or activate (VP64) transcription, generating artificial transcription factors or epigenetic editors (methylating H3K9). These epi-editors altered critical histone marks and subsequently Dlg4/PSD95 expression, which, importantly, impacted several hippocampal neuron plasticity processes. Intriguingly, transduction of the artificial transcription factor PSD95-VP64 rescued memory deficits in aged and Alzheimer's disease mice. Conclusively, this work validates PSD95 as a key player in memory and establishes epigenetic editing as a potential therapy to treat human neurological disorders. PMID- 29155982 TI - Economic and survival burden of dysphagia among inpatients in the United States. AB - The inpatient burden of dysphagia has primarily been evaluated in patients with stroke. It is unclear whether dysphagia, irrespective of cause, is associated with worse clinical outcomes and higher costs compared to inpatients with similar demographic, hospital, and clinical characteristics without dysphagia. The aim of this study is to assess how a dysphagia diagnosis affects length of hospital stay (LOS), costs, discharge disposition, and in-hospital mortality among adult US inpatients. Annual and overall dysphagia prevalence, LOS, hospital charges, inpatient care costs, discharge disposition, and in-hospital mortality were measured using the AHRQ Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (2009-2013). Patients aged 45 years or older with <=180 days of stay in hospital with and without dysphagia were included. Multivariable survey regression methods with propensity weighting were used to assess associations between dysphagia and different outcomes. Overall, 2.7 of 88 million (3.0%) adult US inpatients had a dysphagia diagnosis (50.2% male, 72.4% white, 74.6% age 65-90 years) and prevalence increased from 408,035 (2.5% of admissions) in 2009 to 656,655 (3.3%) in 2013. After inverse probability of treatment weighting adjustment, mean hospital LOS in patients with dysphagia was 8.8 days (95% CI 8.66-8.90) compared to 5.0 days (95% CI 4.97-5.05) in the non-dysphagia group (P < 0.001). Total inpatient costs were a mean $6,243 higher among those with dysphagia diagnoses ($19,244 vs. 13,001, P < 0.001). Patients with dysphagia were 33.2% more likely to be transferred to post-acute care facility (71.9% vs. 38.7%, P < 0.001) with an adjusted OR of 2.8 (95% CI 2.73-2.81, P < 0.001). Compared to non-cases, adult patients with dysphagia were 1.7 times more likely to die in the hospital (95% CI 1.67-1.74). Dysphagia affects 3.0% of all adult US inpatients (aged 45-90 years) and is associated with a significantly longer hospital length of stay, higher inpatient costs, a higher likelihood of discharge to post-acute care facility, and inpatient mortality when compared to those with similar patient, hospital size, and clinical characteristics without dysphagia. Dysphagia has a substantial health and cost burden on the US healthcare system. PMID- 29155983 TI - Meox1 accelerates myocardial hypertrophic decompensation through Gata4. AB - Aims: Pathological hypertrophy is the result of gene network regulation, which ultimately leads to adverse cardiac remodelling and heart failure (HF) and is accompanied by the reactivation of a 'foetal gene programme'. The Mesenchyme homeobox 1 (Meox1) gene is one of the foetal programme genes. Meox1 may play a role in embryonic development, but its regulation of pathological hypertrophy is not known. Therefore, this study investigated the effect of Meox1 on pathological hypertrophy, including familial and pressure overload-induced hypertrophy, and its potential mechanism of action. Methods and results: Meox1 expression was markedly down-regulated in the wild-type adult mouse heart with age, and expression was up-regulated in heart tissues from familial dilated cardiomyopathy (FDCM) mice of the cTnTR141W strain, familial hypertrophic cardiomyopathy (FHCM) mice of the cTnTR92Q strain, pressure overload-induced HF mice, and hypertrophic cardiomyopathy (HCM) patients. Echocardiography, histopathology, and hypertrophic molecular markers consistently demonstrated that Meox1 overexpression exacerbated the phenotypes in FHCM and in mice with thoracic aorta constriction (TAC), and that Meox1 knockdown improved the pathological changes. Gata4 was identified as a potential downstream target of Meox1 using digital gene expression (DGE) profiling, real-time PCR, and bioinformatics analysis. Promoter activity data and chromatin immunoprecipitation (ChIP) and Gata4 knockdown analyses indicated that Meox1 acted via activation of Gata4 transcription. Conclusion: Meox1 accelerated decompensation via the downstream target Gata4, at least in part directly. Meox1 and other foetal programme genes form a highly interconnected network, which offers multiple therapeutic entry points to dampen the aberrant expression of foetal genes and pathological hypertrophy. PMID- 29155981 TI - Desacyl Ghrelin Decreases Anxiety-like Behavior in Male Mice. AB - Ghrelin is a 28-amino acid polypeptide that regulates feeding, glucose metabolism, and emotionality (stress, anxiety, and depression). Plasma ghrelin circulates as desacyl ghrelin (DAG) or, in an acylated form, acyl ghrelin (AG), through the actions of ghrelin O-acyltransferase (GOAT), exhibiting low or high affinity, respectively, for the growth hormone secretagogue receptor (GHSR) 1a. We investigated the role of endogenous AG, DAG, and GHSR1a signaling on anxiety and stress responses using ghrelin knockout (Ghr KO), GOAT KO, and Ghsr stop floxed (Ghsr null) mice. Behavioral and hormonal responses were tested in the elevated plus maze and light/dark (LD) box. Mice lacking both AG and DAG (Ghr KO) increased anxiety-like behaviors across tests, whereas anxiety reactions were attenuated in DAG-treated Ghr KO mice and in mice lacking AG (GOAT KO). Notably, loss of GHSR1a (Ghsr null) did not affect anxiety-like behavior in any test. Administration of AG and DAG to Ghr KO mice with lifelong ghrelin deficiency reduced anxiety-like behavior and decreased phospho-extracellular signal regulated kinase phosphorylation in the Edinger-Westphal nucleus in wild-type mice, a site normally expressing GHSR1a and involved in stress- and anxiety related behavior. Collectively, our data demonstrate distinct roles for endogenous AG and DAG in regulation of anxiety responses and suggest that the behavioral impact of ghrelin may be context dependent. PMID- 29155984 TI - Cysteine-rich angiogenic inducer 61 (Cyr61): a novel soluble biomarker of acute myocardial injury improves risk stratification after acute coronary syndromes. AB - Aims: We aimed to identify a novel biomarker involved in the early events leading to an acute coronary syndrome (ACS) and evaluate its role in diagnosis and risk stratification. Methods and results: Biomarker identification was based on gene expression profiling. In coronary thrombi of ACS patients, cysteine-rich angiogenic inducer 61 (Cyr61, CCN1) gene transcripts were highly up-regulated compared with peripheral mononuclear cells. In a murine ischaemia-reperfusion model (I/R), myocardial Cyr61 expression was markedly increased compared with the controls. Cyr61 levels were determined in human serum using an enzyme-linked immunosorbent assay. Cohorts of ACS (n = 2168) referred for coronary angiography, stable coronary artery disease (CAD) (n = 53), and hypertrophic obstructive cardiomyopathy (HOCM) patients (n = 15) served to identify and evaluate the diagnostic and prognostic performance of the biomarker. Cyr61 was markedly elevated in ST-elevation myocardial infarction patients compared with non-ST elevation myocardial infarction/unstable angina or stable CAD patients, irrespective of whether coronary thrombi were present. Cyr61 was rapidly released after occlusion of a septal branch in HOCM patients undergoing transcoronary ablation of septal hypertrophy. Cyr61 improved risk stratification for all-cause mortality when added to the reference GRACE risk score at 30 days (C-statistic 0.88 to 0.89, P = 0.001) and 1 year (C-statistic 0.77 to 0.80, P < 0.001) comparable to high-sensitivity troponin T (30 days: 0.88 to 0.89, P < 0.001; 1 year: 0.77 to 0.79, P < 0.001). Similar results were obtained for the composite endpoint of all-cause mortality or myocardial infarction. Conversely, in a population-based case-control cohort (n = 362), Cyr61 was not associated with adverse outcome. Conclusion: Cyr61 is a novel early biomarker reflecting myocardial injury that improves risk stratification in ACS patients. PMID- 29155985 TI - A Systematic Review: The Management and Outcomes of Ileal Pouch Strictures. AB - Background: Restorative proctocolectomy with ileal pouch-anal anastomosis removes the diseased tissue in ulcerative colitis but also allows gastrointestinal continuity and stoma-free living. Pouch strictures are a complication with a reported incidence of 5-38%. The three areas where pouch strictures occur are in the pouch inlet, mid-pouch and pouch-anal anastomosis. Aim: To undertake a systematic review of the literature and to identify management strategies available for pouch-anal, mid-pouch and pre-pouch ileal strictures and their outcomes. Methods: A computer-assisted search of the online bibliographic databases MEDLINE and EMBASE limited to 1966 to February 2016 was performed. Randomized controlled trials, cohort studies, observational studies and case reports were considered. Those where data could not be extracted were excluded. Results: Twenty-two articles were considered eligible. Pouch-anal strictures have been initially managed using predominately dilators which include bougie and Hegar dilators with various surgical procedures advocated when initial dilatation fails. Mid-pouch strictures are relatively unstudied with both medical, endoscopic and surgical management reported as successful. Pouch inlet strictures can be safely managed using a combined medical and endoscopic approach. Conclusion: The limited evidence available suggests that pouch-anal strictures are best treated in a stepwise fashion with initial treatment to include digital or instrumental dilatation followed by surgical revision or resection. Management of mid-pouch strictures requires a combination of medical, endoscopic and surgical management. Pouch inlet strictures are best managed using a combined medical and endoscopic approach. Future studies should compare different treatment modalities on separate stricture locations to enable an evidenced-based treatment algorithm. PMID- 29155986 TI - Prenatal High Estradiol Exposure Induces Sex-Specific and Dietarily Reversible Insulin Resistance Through Decreased Hypothalamic INSR. AB - An adverse intrauterine environment may induce adult disease in offspring, but the mechanisms are not well understood. It is reported that fresh embryo transfer (ET) in assisted reproductive technology leads to high maternal estradiol (E2), and prenatal high E2 exposure increases the risk of organ disorders in later life. We found that male newborns and children of fresh ET showed elevated fasting insulin and homeostasis model of assessment for insulin resistance index (HOMA-IR) scores. Male mice with high prenatal estradiol exposure (HE) grew heavier than control mice and developed insulin resistance; they also showed increased food intake, with increased orexigenic hypothalamic neuropeptide Y (NPY) expression. The hypothalamic insulin receptor (INSR) was decreased in male HE mice, associated with elevated promoter methylation. Chronic food restriction (FR) in HE mice reversed insulin resistance and rescued hypothalamic INSR expression by correcting the elevated Insr promoter methylation. Our findings suggest that prenatal exposure to high E2 may induce sex-specific metabolic disorders in later life through epigenetic programming of hypothalamic Insr promoter, and dietary intervention may reverse insulin resistance by remodeling its methylation pattern. PMID- 29155988 TI - Opioid Prescribing Patterns and Patient Outcomes by Prescriber Type in the Oregon Prescription Drug Monitoring Program. AB - Objective: Prescription drug monitoring programs (PDMPs) were created to facilitate responsible use of controlled substances. In Oregon, physicians, physician's assistants (MDs/DOs/PAs), dentists, nurse practitioners (NPs), and naturopathic physicians (NDs) may prescribe opioids, but differences in prescribing practices, patient mix, and patient outcomes among prescriber types have not been characterized. Methods: De-identified Oregon PDMP data from October 2011 through October 2014 were linked with vital records and a statewide hospital discharge registry. The disciplines of registered prescribers were identified by board affiliations. Prescription profiles associated with opioid overdose risk were tabulated for patients with at least one registered prescriber. Opioid related hospitalizations and deaths were identified using ICD-9 and ICD-10 codes. Results: There were 5,935 prescribers registered during the study period. Patients of NPs or NDs received more high-risk opioid prescriptions than patients of MDs/DOs/PAs. For example, they received greater proportions of high-dose prescriptions (NP 12.9%, ND 15%, MD/DO/PA 11.1%), and had greater opioid-related hospitalization (NP 1.7%, ND 3.1%, MD/DO/PA 1.2%; P < 0.005 for all). However, patients of NPs or NDs were also more likely to have four or more prescribers (NP 45.3%, ND 58.5%, MD/DO/PA 27.1%), and most of their patients' high-risk opioid prescriptions came from prescribers in other disciplines. Conclusions: Our analysis suggests significant differences in opioid prescription profiles and opioid-related hospitalization and mortality among patients receiving opioid prescriptions from nurse practitioners, naturopathic physicians, or medical clinicians in Oregon. However, these differences appear largely due to differences in patient mix between provider types rather than discipline-specific prescribing practices. PMID- 29155987 TI - Sleep Duration Trajectories and Systemic Inflammation in Young Adults: Results From the National Longitudinal Study of Adolescent to Adult Health (Add Health). AB - Study Objectives: This study examines the effects of short and long sleep duration patterns in young adults on the levels of C-reactive protein (CRP), as well as the potential effect modification by sex. Methods: Using data from waves III (age 18-26) and IV (age 24-32) of the National Longitudinal study of adolescent to adult health, we examined the association between sleep trajectories in young adults, and the risk of elevated high sensitivity-CRP (hs CRP), a marker of systemic inflammation. Results: Short sleep trajectories were associated with significantly elevated log-transformed hs-CRP (coefficient = 0.11, p-value .03) and with significantly higher odds of having hs-CRP levels > 3 mg/L (OR = 1.86, 95% CI 1.29, 2.67). The association was modified by sex, with the association between short sleep duration and hs-CRP limited to males. Both the continuous (coefficient 0.117, p-value = .0362) and the categorized hs-CRP (OR = 2.21, 95% CI 1.48, 3.30) were significantly elevated with short sleep durations in males, whereas no significant associations were seen in females with short sleep durations. By contrast, log hs-CRP was significantly elevated in females with long sleep durations (coefficient = 0.232, p-value = .0296), with a nonsignificant increase in the odds of having hs-CRP levels greater than 3 mg/L (OR = 1.48, 95% CI 0.75, 2.93), whereas there were no associations with long sleep duration in males. Conclusions: Systemic inflammation, measured by an elevated level of hs-CRP, is seen with persistent short sleep duration in young adult men and persistent long sleep duration in young adult women. PMID- 29155989 TI - 5-Hydroxytryptamine-Independent Antidepressant Actions of (R)-Ketamine in a Chronic Social Defeat Stress Model. AB - Background: Previous reports suggest that 5-hydroxytryptamine might play a role in the antidepressant actions of (R,S)-ketamine. However, its role in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, is unknown. This study was conducted to examine whether 5-hydroxytryptamine depletion affects the antidepressant actions of (R)-ketamine in a chronic social defeat stress model. Methods: An inhibitor of 5-hydroxytryptamine synthesis, para chlorophenylalanine methyl ester hydrochloride (300 mg/kg, twice daily for 3 consecutive days), or vehicle was administered to control and chronic social defeat stress-susceptible mice. Levels of 5-hydroxytryptamine and its metabolite, 5-hydroxyindoleacetic acid, in mouse brain regions were measured using high performance liquid chromatography. Furthermore, antidepressant effects of (R) ketamine (10 mg/kg) in the vehicle- and para-chlorophenylalanine methyl ester hydrochloride-treated susceptible mice were assessed using tail suspension test and 1% sucrose preference test. Results: para-Chlorophenylalanine methyl ester hydrochloride treatment caused marked reductions of 5-hydroxytryptamine and 5 hydroxyindoleacetic acid in the brain regions of control and chronic social defeat stress susceptible mice. In the tail suspension test, (R)-ketamine significantly attenuated the increased immobility time in the chronic social defeat stress-susceptible mice with or without 5-hydroxytryptamine depletion. In the sucrose preference test (2 and 5 days after a single dose), (R)-ketamine significantly enhanced reduced sucrose consumption in the chronic social defeat stress-susceptible mice with or without 5-hydroxytryptamine depletion. Conclusions: These findings show that 5-hydroxytryptamine depletion did not affect the antidepressant effects of (R)-ketamine in a chronic social defeat stress model. Therefore, it is unlikely that 5-hydroxytryptamine plays a major role in the antidepressant actions of (R)-ketamine. PMID- 29155990 TI - A systematic review of interventions and performance measures for antifungal stewardship programmes. AB - Objectives: Antifungal resistance is a significant and emerging threat. Stewardship programmes (SPs) have been proposed as an opportunity to optimize antifungal use. While examples of antifungal SP implementation have been recently described, there is yet to be an overview of interventions and their impacts on performance measures. Methods: We systematically reviewed published articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses check-list 2009. MEDLINE was searched using the term 'antifungal stewardship' on 15 February 2017. Eligible studies were those that described an antifungal SP and included an intervention and an evaluation of performance measures. Results: A total of 97 studies were identified and 14 were included. Only five studies reported an antifungal stewardship team composed of all the recommended members. The main intervention was the formulation of recommendations to change treatment (12 of 14). The main performance measure collected was antifungal consumption (10 of 14), followed by antifungal expenditure (7 of 14), adherence to therapeutic advice (4 of 14) and impact on mortality (4 of 14). Antifungal consumption was reduced by 11.8% to 71% and antifungal expenditure by as much as 50%. Adherence to therapeutic advice ranged from 40% to 88%, whereas antifungal SPs had no impact on mortality. Conclusions: All antifungal SPs had an impact, in particular on antifungal consumption and antifungal expenditure. Active intervention including a review of prescriptions seems to have more impact than implementation of treatment guidelines only. According to available published studies, antifungal consumption appears to be the most achievable performance measure to evaluate the impact of an antifungal SP. PMID- 29155991 TI - Efficacy and Safety of Switching to Pasireotide in Patients With Acromegaly Controlled With Pegvisomant and First-Generation Somatostatin Analogues (PAPE Study). AB - Aim: To assess the efficacy and safety of pasireotide long-acting release (PAS LAR) alone or in combination with pegvisomant by switching patients with acromegaly who were well controlled with long-acting somatostatin analogues (LA SSAs) and pegvisomant to PAS-LAR with or without pegvisomant. Methods: Sixty-one patients with acromegaly were enrolled in a prospective open-label study. We included patients with an insulin-like growth factor I (IGF-I) <=1.2 * upper limit of normal (ULN) during treatment with LA-SSAs and pegvisomant. At baseline, the pegvisomant dose was reduced by 50% up to 12 weeks. When IGF-I remained <=1.2 * ULN after 12 weeks, patients were switched to PAS-LAR 60 mg monotherapy. When IGF-I was >1.2 * ULN, patients were switched to PAS-LAR 60 mg, and they continued with the 50% reduced pegvisomant dose. Results: At baseline, mean IGF-I was 0.97 * ULN, and the median pegvisomant dose was 80 mg/wk. At 12 weeks, mean IGF-I increased to 1.59 * ULN, and IGF-I levels <=1.2 ULN were observed in 24.6% of participants. At 24 weeks, IGF-I levels were reduced into the reference range in 73.8% of patients. Between baseline and 24 weeks, the pegvisomant dose was reduced by 66.1%. PAS-LAR was well tolerated, but hyperglycemia was the most frequent adverse event. The frequency of diabetes increased from 32.8% at baseline to 68.9% at 24 weeks. Conclusions: Switching to PAS-LAR, either as monotherapy or combination with pegvisomant, can control IGF-I levels in most patients. PAS-LAR demonstrated a pegvisomant-sparing effect of 66% compared with the combination with LA-SSAs. Hyperglycemia was the most important safety issue. PMID- 29155992 TI - IHH Gene Mutations Causing Short Stature With Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy. AB - Context: Genetic evaluation has been recognized as an important tool to elucidate the causes of growth disorders. Objective: To investigate the cause of short stature and to determine the phenotype of patients with IHH mutations, including the response to recombinant human growth hormone (rhGH) therapy. Patients and Methods: We studied 17 families with autosomal-dominant short stature by using whole exome sequencing and screened IHH defects in 290 patients with growth disorders. Molecular analyses were performed to evaluate the potential impact of N-terminal IHH variants. Results: We identified 10 pathogenic or possibly pathogenic variants in IHH, an important regulator of endochondral ossification. Molecular analyses revealed a smaller potential energy of mutated IHH molecules. The allele frequency of rare, predicted to be deleterious IHH variants found in short-stature samples (1.6%) was higher than that observed in two control cohorts (0.017% and 0.08%; P < 0.001). Identified IHH variants segregate with short stature in a dominant inheritance pattern. Affected individuals typically manifest mild disproportional short stature with a frequent finding of shortening of the middle phalanx of the fifth finger. None of them have classic features of brachydactyly type A1, which was previously associated with IHH mutations. Five patients heterozygous for IHH variants had a good response to rhGH therapy. The mean change in height standard deviation score in 1 year was 0.6. Conclusion: Our study demonstrated the association of pathogenic variants in IHH with short stature with nonspecific skeletal abnormalities and established a frequent cause of growth disorder, with a preliminary good response to rhGH. PMID- 29155993 TI - Lack of Antidepressant Effects of (2R,6R)-Hydroxynorketamine in a Rat Learned Helplessness Model: Comparison with (R)-Ketamine. AB - Background: (R)-Ketamine exhibits rapid and sustained antidepressant effects in animal models of depression. It is stereoselectively metabolized to (R) norketamine and subsequently to (2R,6R)-hydroxynorketamine in the liver. The metabolism of ketamine to hydroxynorketamine was recently demonstrated to be essential for ketamine's antidepressant actions. However, no study has compared the antidepressant effects of these 3 compounds in animal models of depression. Methods: The effects of a single i.p. injection of (R)-ketamine, (R)-norketamine, and (2R,6R)-hydroxynorketamine in a rat learned helplessness model were examined. Results: A single dose of (R)-ketamine (20 mg/kg) showed an antidepressant effect in the rat learned helplessness model. In contrast, neither (R)-norketamine (20 mg/kg) nor (2R,6R)-hydroxynorketamine (20 and 40 mg/kg) did so. Conclusions: Unlike (R)-ketamine, its metabolite (2R,6R)-hydroxynorketamine did not show antidepressant actions in the rat learned helplessness model. Therefore, it is unlikely that the metabolism of ketamine to hydroxynorketamine is essential for ketamine's antidepressant actions. PMID- 29155994 TI - Work productivity in systemic sclerosis, its economic burden and association with health-related quality of life. AB - Objective: To evaluate work productivity and its economic burden in SSc patients. Methods: Consecutive SSc patients enrolled in the Australian Scleroderma Cohort Study were mailed questionnaires assessing employment (Workers' Productivity and Activity Impairment Questionnaire and a custom-made questionnaire) and health related quality of life (HRQoL) (36-item Short Form Health Survey and Patient Reported Outcomes Measurement Information System 29). Linear regression methods were used to determine factors associated with work productivity. Results: Among 476 patients submitting responses, 55.2% <65 years of age were employed. Unemployed patients were older at the time of survey completion (57.1 vs 53.7 years; P < 0.001) and had longer disease duration from first SSc clinical manifestation (16.2 vs 14.9 years; P = 0.01) than employed patients. The mean age at unemployment onset was 13.2 years below the average Australian retirement age. Of those working in the week prior to completing the survey, 16.0% reported missing work (absenteeism) due to their SSc, accounting for 32.9% of their working week. Reduced productivity while at work (presenteeism) accounted for 22% of their working week. Annual costs per patient as a consequence of unemployment and reduced productivity equated to a total of AUD$67 595.40. Factors independently associated with reduced work productivity were presence of synovitis and sicca symptoms, while tertiary education protected against work impairment. Patients with low HRQoL scores also had low work productivity. Conclusion: SSc is associated with considerable unemployment and reduced productivity, which in turn is associated with a substantial economic burden and poor HRQoL. Raising awareness and identifying modifiable factors are possible ways of reducing this burden. PMID- 29155996 TI - Hierarchical attention networks for information extraction from cancer pathology reports. AB - Objective: We explored how a deep learning (DL) approach based on hierarchical attention networks (HANs) can improve model performance for multiple information extraction tasks from unstructured cancer pathology reports compared to conventional methods that do not sufficiently capture syntactic and semantic contexts from free-text documents. Materials and Methods: Data for our analyses were obtained from 942 deidentified pathology reports collected by the National Cancer Institute Surveillance, Epidemiology, and End Results program. The HAN was implemented for 2 information extraction tasks: (1) primary site, matched to 12 International Classification of Diseases for Oncology topography codes (7 breast, 5 lung primary sites), and (2) histological grade classification, matched to G1 G4. Model performance metrics were compared to conventional machine learning (ML) approaches including naive Bayes, logistic regression, support vector machine, random forest, and extreme gradient boosting, and other DL models, including a recurrent neural network (RNN), a recurrent neural network with attention (RNN w/A), and a convolutional neural network. Results: Our results demonstrate that for both information tasks, HAN performed significantly better compared to the conventional ML and DL techniques. In particular, across the 2 tasks, the mean micro and macro F-scores for the HAN with pretraining were (0.852,0.708), compared to naive Bayes (0.518, 0.213), logistic regression (0.682, 0.453), support vector machine (0.634, 0.434), random forest (0.698, 0.508), extreme gradient boosting (0.696, 0.522), RNN (0.505, 0.301), RNN w/A (0.637, 0.471), and convolutional neural network (0.714, 0.460). Conclusions: HAN-based DL models show promise in information abstraction tasks within unstructured clinical pathology reports. PMID- 29155995 TI - Lysosome biogenesis regulated by the amino-acid transporter SLC15A4 is critical for functional integrity of mast cells. AB - Mast cells possess specialized lysosomes, so-called secretory granules, which play a key role not only in allergic responses but also in various immune disorders. The molecular mechanisms that control secretory-granule formation are not fully understood. Solute carrier family member 15A4 (SLC15A4) is a lysosome resident amino-acid/oligopeptide transporter that is preferentially expressed in hematopoietic lineage cells. Here, we demonstrated that SLC15A4 is required for mast-cell secretory-granule homeostasis, and limits mast-cell functions and inflammatory responses by controlling the mTORC1-TFEB signaling axis. In mouse Slc15a4-/- mast cells, diminished mTORC1 activity increased the expression and nuclear translocation of TFEB, a transcription factor, which caused secretory granules to degranulate more potently. This alteration of TFEB function in mast cells strongly affected the FcepsilonRI-mediated responses and IL-33-triggered inflammatory responses both in vitro and in vivo. Our results reveal a close relationship between SLC15A4 and secretory-granule biogenesis that is critical for the functional integrity of mast cells. PMID- 29155997 TI - Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer. AB - Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV positive tumors had low mutation burden (median = 2.07 vs 3.13 in log10 scale, P < 10-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P < 10-4; log2 fold-change of CD8A = 1.85, P < 10-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log2 fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P < 10 4 each), and higher lymphocytic infiltration by histology (median tumor infiltrating lymphocyte score = 3 vs 2, P < .001) compared with MSS tumors. These data suggest that EBV-positive low-mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy. PMID- 29155998 TI - Limited Impact of Adolescent Meningococcal ACWY Vaccination on Neisseria meningitidis Serogroup W Carriage in University Students. AB - Background: In the United Kingdom, rising levels of disease due to Neisseria meningitidis serogroup W clonal complex (cc) sequence type (ST) 11 (MenW:cc11) strains led to introduction of meningococcal conjugate vaccine (MenACWY) for teenagers. We investigated the impact of immunization on carriage of meningococci targeted by the vaccine, using whole-genome sequencing of isolates recovered from a cohort of vaccinated university students. Methods: Strain designation data were extracted from whole-genome sequencing data. Genomes from carried and invasive MenW:cc11 strains were compared using a gene-by-gene approach. Serogrouping identified isolates expressing capsule antigens targeted by the vaccine. Results: Isolates with a W: P1.5,2: F1-1: ST-11 (cc11) designation and belonging to the emerging 2013-strain of the South American-United Kingdom MenW:cc11 sublineage were responsible for an increase in carried group W strains. A multifocal expansion was evident, with close transmission networks extending beyond individual dormitories. Carried group Y isolates were predominantly from cc23 but showed significant heterogeneity, and individual strain designations were only sporadically recovered. No shifts toward acapsulate phenotypes were detected in targeted meningococcal populations. Conclusions: In a setting with high levels of MenACWY use, expansion of capsule-expressing isolates from the 2013-strain of MenW:cc11 but not MenY:cc23 isolates is indicative of differential susceptibilities to vaccine-induced immunity. PMID- 29155999 TI - High Incomplete Skeletal Muscle Fatty Acid Oxidation Explains Low Muscle Insulin Sensitivity in Poorly Controlled T2D. AB - Context: Almost 50% of type 2 diabetic (T2D) patients are poorly controlled [glycated hemoglobin (HbA1c) >= 7%]; however, the mechanisms responsible for progressively worsening glycemic control are poorly understood. Lower skeletal muscle mitochondrial respiratory capacity is associated with low insulin sensitivity and the development of T2D. Objective: We investigated if skeletal muscle insulin sensitivity (SI) was different between well-controlled T2D (WCD) and poorly controlled T2D (PCD) and if the difference was associated with differences resulting from mitochondrial respiratory function. Design: Vastus lateralis muscle mitochondrial respiration, mitochondrial content, mitochondrial enzyme activity, and fatty acid oxidation (FAO) were measured. SI and the acute response to glucose (AIRg) were calculated by MINMOD analysis from glucose and insulin obtained during a modified, frequently sampled, intravenous glucose tolerance test. Results: SI and AIRg were lower in PCD than WCD. Muscle incomplete FAO was greater in PCD than WCD and greater incomplete FAO was associated with lower SI and higher HbA1c. Hydroxyacyl-coenzyme A dehydrogenase expression and activity were greater in PCD than WCD. There was no difference in maximal mitochondrial respiration or content between WCD and PCD. Conclusion: The current results suggest that greater skeletal muscle incomplete FAO in poorly controlled T2D is due to elevated beta oxidation and is associated with worsening muscle SI. PMID- 29156000 TI - Structural rearrangements in mRNA upon its binding to human 80S ribosomes revealed by EPR spectroscopy. AB - The model mRNA (MR), 11-mer RNA containing two nitroxide spin labels at the 5'- and 3'-terminal nucleotides and prone to form a stable homodimer (MR)2, was used for Electron Paramagnetic Resonance study of structural rearrangements in mRNA occurring upon its binding to human 80S ribosomes. The formation of two different types of ribosomal complexes with MR was observed. First, there were stable complexes where MR was fixed in the ribosomal mRNA-binding channel by the codon anticodon interaction(s) with cognate tRNA(s). Second, we for the first time detected complexes assembled without tRNA due to the binding of MR most likely to an exposed peptide of ribosomal protein uS3 away from the mRNA channel. The analysis of interspin distances allowed the conclusion that 80S ribosomes facilitate dissociation of the duplex (MR)2: the equilibrium between the duplex and the single-stranded MR shifts to MR due to its efficient binding with ribosomes. Furthermore, we observed a significant influence of tRNA bound at the ribosomal exit (E) and/or aminoacyl (A) sites on the stability of ribosomal complexes. Our findings showed that a part of mRNA bound in the ribosome channel, which is not involved in codon-anticodon interactions, has more degrees of freedom than that interacting with tRNAs. PMID- 29156001 TI - DGIdb 3.0: a redesign and expansion of the drug-gene interaction database. AB - The drug-gene interaction database (DGIdb, www.dgidb.org) consolidates, organizes and presents drug-gene interactions and gene druggability information from papers, databases and web resources. DGIdb normalizes content from 30 disparate sources and allows for user-friendly advanced browsing, searching and filtering for ease of access through an intuitive web user interface, application programming interface (API) and public cloud-based server image. DGIdb v3.0 represents a major update of the database. Nine of the previously included 24 sources were updated. Six new resources were added, bringing the total number of sources to 30. These updates and additions of sources have cumulatively resulted in 56 309 interaction claims. This has also substantially expanded the comprehensive catalogue of druggable genes and anti-neoplastic drug-gene interactions included in the DGIdb. Along with these content updates, v3.0 has received a major overhaul of its codebase, including an updated user interface, preset interaction search filters, consolidation of interaction information into interaction groups, greatly improved search response times and upgrading the underlying web application framework. In addition, the expanded API features new endpoints which allow users to extract more detailed information about queried drugs, genes and drug-gene interactions, including listings of PubMed IDs, interaction type and other interaction metadata. PMID- 29156002 TI - Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X. AB - Sequences with the potential to form RNA G-quadruplexes (G4s) are common in mammalian introns, especially in the proximity of the 5' splice site (5'SS). However, the difficulty of demonstrating that G4s form in pre-mRNA in functional conditions has meant that little is known about their effects or mechanisms of action. We have shown previously that two G4s form in Bcl-X pre-mRNA, one close to each of the two alternative 5'SS. If these G4s affect splicing but are in competition with other RNA structures or RNA binding proteins, then ligands that stabilize them would increase the proportion of Bcl-X pre-mRNA molecules in which either or both G4s had formed, shifting Bcl-X splicing. We show here that a restricted set of G4 ligands do affect splicing, that their activity and specificity are strongly dependent on their structures and that they act independently at the two splice sites. One of the ligands, the ellipticine GQC 05, antagonizes the major 5'SS that expresses the anti-apoptotic isoform of Bcl-X and activates the alternative 5'SS that expresses a pro-apoptotic isoform. We propose mechanisms that would account for these see-saw effects and suggest that these effects contribute to the ability of GQC-05 to induce apoptosis. PMID- 29156003 TI - Chronic respiratory disease: an unrecognized risk factor in dialysis. AB - Background: Few studies have analysed the impact of chronic respiratory disease (CRD) on outcomes in dialysis. We therefore sought to describe patients with CRD and end-stage renal disease and their outcomes after dialysis start, compared with patients without CRD, focusing especially on causes of death, access to renal transplantation and causes of hospital admissions. Methods: The study included 52 797 adults aged 18 years and older who began dialysis from 2008 to 2013 and are recorded in the French national REIN registry. Survival, specific mortality and access to the waiting list and to renal transplantation were analysed, with adjustment for various comorbidities and consideration of competitive risks. The numbers of hospitalizations and hospital days, together with their causes, were analysed through an indirect link between the REIN database and the national French hospital discharge database. Results: The frequency of CRD at dialysis start was 12% and was associated with various other comorbidities, including obesity and tobacco use. After adjustment for those comorbidities, CRD remained associated with a higher risk of death [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.16-1.25]. Patients with CRD were 30% less likely to undergo transplantation (HR 0.67, 95% CI 0.6-0.7) than patients without CRD. Their risk of dying from a respiratory disease was 8.8 times higher; their risk of dying from infection was also higher. Patients with CRD had a higher rate of admissions and more hospital days, for all causes and for every cause, except cancer. Conclusions: CRD was associated with higher risks of death and hospital admissions and with lower likelihoods of being wait-listed for and undergoing renal transplantation. Increasing clinical awareness by patients and doctors and encouragement of spirometry use should promote more accurate clinical diagnosis and better preventive care for CRD. PMID- 29156004 TI - Obesity modulates the association between systolic blood pressure and albuminuria. AB - Background: Obesity is associated with albuminuria and incident kidney disease. Increased vulnerability of the glomerular microcirculation to elevated systemic blood pressure is postulated to contribute to adverse effects of obesity on the kidney. We therefore hypothesized that obesity would modulate the association between systolic blood pressure (sBP) and albuminuria. Methods: The relationship between obesity and albuminuria [fractional albumin excretion (FE alb ) or albumin:creatinine ratio (ACR)] was modelled using linear/logistic regression in the US National Health and Nutrition Examination Survey 1999-2010 cohorts ( N = 23 710). Associations between sBP and albuminuria were examined across strata of waist circumference and body mass index (BMI) using interaction terms. Results: Obesity was associated with albuminuria through an interaction with sBP. Among participants in the 4th/5th quintiles of waist circumference each 10 mmHg increase in sBP was accompanied by approximately double the increment in FE alb observed among those in quintile 2 (14% versus 7%, P < 0.001). There was also evidence of a lower sBP threshold for the relationship between sBP and albuminuria in obesity. While FE alb increased with sBP >110 mmHg in quintile 5 of waist circumference, in quintile 2 FE alb did not increase until sBP was >130 mmHg. Findings were consistent when defining obesity by BMI or waist circumference and when quantifying albuminuria by ACR or FE alb . Assessing albuminuria as the odds ratio of ACR >30 mg/g also gave similar results. Conclusion: The interaction between sBP and obesity supports the premise that obesity sensitizes the kidney to increased systemic blood pressure. PMID- 29156005 TI - aBiofilm: a resource of anti-biofilm agents and their potential implications in targeting antibiotic drug resistance. AB - Biofilms play an important role in the antibiotic drug resistance, which is threatening public health globally. Almost, all microbes mimic multicellular lifestyle to form biofilm by undergoing phenotypic changes to adapt adverse environmental conditions. Many anti-biofilm agents have been experimentally validated to disrupt the biofilms during last three decades. To organize this data, we developed the 'aBiofilm' resource (http://bioinfo.imtech.res.in/manojk/abiofilm/) that harbors a database, a predictor, and the data visualization modules. The database contains biological, chemical, and structural details of 5027 anti-biofilm agents (1720 unique) reported from 1988-2017. These agents target over 140 organisms including Gram negative, Gram-positive bacteria, and fungus. They are mainly chemicals, peptides, phages, secondary metabolites, antibodies, nanoparticles and extracts. They show the diverse mode of actions by attacking mainly signaling molecules, biofilm matrix, genes, extracellular polymeric substances, and many more. The QSAR based predictor identifies the anti-biofilm potential of an unknown chemical with an accuracy of ~80.00%. The data visualization section summarized the biofilm stages targeted (Circos plot); interaction maps (Cytoscape) and chemicals diversification (CheS-Mapper) of the agents. This comprehensive platform would help the researchers to understand the multilevel communication in the microbial consortium. It may aid in developing anti-biofilm therapeutics to deal with antibiotic drug resistance menace. PMID- 29156006 TI - DIANA-TarBase v8: a decade-long collection of experimentally supported miRNA-gene interactions. AB - DIANA-TarBase v8 (http://www.microrna.gr/tarbase) is a reference database devoted to the indexing of experimentally supported microRNA (miRNA) targets. Its eighth version is the first database indexing >1 million entries, corresponding to ~670 000 unique miRNA-target pairs. The interactions are supported by >33 experimental methodologies, applied to ~600 cell types/tissues under ~451 experimental conditions. It integrates information on cell-type specific miRNA-gene regulation, while hundreds of thousands of miRNA-binding locations are reported. TarBase is coming of age, with more than a decade of continuous support in the non-coding RNA field. A new module has been implemented that enables the browsing of interactions through different filtering combinations. It permits easy retrieval of positive and negative miRNA targets per species, methodology, cell type and tissue. An incorporated ranking system is utilized for the display of interactions based on the robustness of their supporting methodologies. Statistics, pie-charts and interactive bar-plots depicting the database content are available through a dedicated result page. An intuitive interface is introduced, providing a user-friendly application with flexible options to different queries. PMID- 29156007 TI - Desmoplastic nodular medulloblastoma in young children: a management dilemma. AB - Background: Children with desmoplastic nodular medulloblastoma (DNMB) have excellent survival, leading multiple groups globally to attempt reduction of treatment-related morbidity. In 2013, the Children's Oncology Group began a clinical trial (ACNS1221) eliminating both radiation therapy (RT) and intraventricular methotrexate for children under 3 years of age with localized DNMB, aiming to build upon the excellent outcomes of the German HIT trials. ACNS1221 has recently closed due to increased incidence of recurrences noted at the 2-year interim analysis, raising important questions regarding optimal therapy for DNMB. Methods: A review of major clinical trials that included children with DNMB was performed through July 2017. Results: One hundred and eighty-eight DNMB patients enrolled on 11 prospective clinical trials were identified. The use of marrow-ablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) or treatment with intraventricular methotrexate has been associated with excellent outcomes. RT was usually required for patients with evidence of disease at the end of therapy. Conclusions: The minimal intensity and duration of chemotherapy required to maximally cure children with DNMB without need of RT remains unknown. Further trials are required to better identify a subset of DNMB patients who can be cured without marrow-ablative chemotherapy or intraventricular methotrexate. PMID- 29156008 TI - Urinalysis for the diagnosis of glomerulonephritis: role of dysmorphic red blood cells. AB - Background: Dysmorphic red blood cells (dRBCs) on urine microscopy have been associated with glomerulonephritis (GN). We assessed the prevalence and ability of dRBCs to differentiate GN from other kidney diseases. Methods: Adult patients with kidney biopsy performed between 2012 and 2015 at a single center who had a concurrent urinalysis were retrospectively studied. The association of >=25% dRBCs with the presence of glomerular pathology was assessed. Univariate and multivariate logistic regression were performed on significantly associated variables. Results: The mean age of the 482 eligible subjects was 55 years and 47.7% were female. Overall, 173 (35.9%) had <25% and 76 (15.8%) had >=25% urine dRBCs. Kidney biopsies revealed glomerular disease in 372 (77.2%) (GN 46% and non GN 54%). At the dRBC threshold of >=25% used at our center, a sensitivity of 20.4%, specificity of 96.3% and positive predictive value of 94.6% for glomerular disease were observed. In a logistic regression model, urine RBCs [>10 versus <=10 (P < 0.001)] but not dRBCs >=25% (P = 0.3) independently predicted the presence of GN. A scoring system (0-3) based on hematuria and proteinuria levels revealed the risk for biopsy-proven GN was 15% when the score was 0 compared with 83% when it was 3. Conclusions: The presence of >=25% urine dRBCs is specific but not sensitive for GN. In this cohort, the combined hematuria (>10 RBCs/high-power field) and proteinuria performed just as well as dRBCs plus proteinuria to predict underlying GN. A model based on the degree of hematuria and proteinuria found on urinalysis was able to predict the presence of GN. PMID- 29156009 TI - Discovering cancer vulnerabilities using high-throughput micro-RNA screening. AB - Micro-RNAs (miRNAs) are potent regulators of gene expression and cellular phenotype. Each miRNA has the potential to target hundreds of transcripts within the cell thus controlling fundamental cellular processes such as survival and proliferation. Here, we exploit this important feature of miRNA networks to discover vulnerabilities in cancer phenotype, and map miRNA-target relationships across different cancer types. More specifically, we report the results of a functional genomics screen of 1280 miRNA mimics and inhibitors in eight cancer cell lines, and its presentation in a sophisticated interactive data portal. This resource represents the most comprehensive survey of miRNA function in oncology, incorporating breast cancer, prostate cancer and neuroblastoma. A user-friendly web portal couples this experimental data with multiple tools for miRNA target prediction, pathway enrichment analysis and visualization. In addition, the database integrates publicly available gene expression and perturbation data enabling tailored and context-specific analysis of miRNA function in a particular disease. As a proof-of-principle, we use the database and its innovative features to uncover novel determinants of the neuroblastoma malignant phenotype. PMID- 29156010 TI - MitraClip removal: surgical techniques to preserve native mitral valve leaflets. AB - Transcatheter valve procedures are wide-spreading techniques for the treatment of heart valves pathologies. In case of implantation failure, the transcatheter device often needs to be removed. This procedure, which can alter the biological structure integrity, can limit the option available for the subsequent traditional surgery. One of the most popular devices for transcatheter mitral valve repair is the MitraClip system. In this work, we describe 2 different techniques for the surgical removal of MitraClip. These techniques aim to preserve the valve leaflets integrity, to allow for subsequent mitral valve surgical repair. PMID- 29156011 TI - Pulmonary resection for patients with multidrug-resistant tuberculosis based on survival outcomes: a systematic review and meta-analysis. AB - We investigated the survival benefit of pulmonary resection for patients with multidrug-resistant tuberculosis. To weigh the survival benefit of pulmonary resection for patients with multidrug-resistant tuberculosis who have undergone surgical treatment combined with medical chemotherapy compared with medical chemotherapy alone, we did a meta-analysis of available studies containing a hazard ratio for pulmonary resection. Among 1726 articles, 6 clinical reports, with a mean sample size of 47 patients per report, met the inclusion criteria. The pooled hazard ratio of 0.68 with a 95% confidence interval of approximately 0.44-1.07 suggested that the survival benefit of surgical pulmonary resection combined with chemotherapy, in a comparison of the groups 'with surgery' and 'without surgery', is not significantly greater than that of chemotherapy alone. Selection bias, due to the absence of rigid predetermined indications for pulmonary resection, limited the validity of this analysis. Due to the heterogeneity of the patient groups, greater attention is required to compute additional hazard ratios in future studies with stratification of factors such as cardiopulmonary functions, disease extent and the presence of a cavity. These additional computations in future studies are necessary to determine the survival benefit and to support the rigid surgical indications. PMID- 29156012 TI - Mitral valve repair using a prosthetic ring with chordal sizing system: a modified technique in the presence of myxomatous leaflets. AB - A semi-rigid complete ring including a chordal sizing system has been introduced with the aim of standardizing neochordae implantation. Instructions for use of this ring suggest to pass the neochordae through the free margin of mitral leaflets. We introduce a modification of this technique in the presence of myxomatous leaflets. PMID- 29156013 TI - A novel strategy to initiate a peroral endoscopic myotomy program. AB - OBJECTIVES: The standard of care for achalasia remains laparoscopic Heller myotomy with partial fundoplication. Peroral endoscopic myotomy (POEM) has been introduced as an alternative, but safety and long-term comparative efficacy are not yet established. We report our experience in developing a POEM program using a novel hybrid approach. METHODS: We developed a hybrid approach to POEM with a POEM followed by laparoscopic evaluation, extension of the myotomy, if necessary, and partial fundoplication. We reviewed the results of the programme from April 2012 until May 2015. Starting in 2014, we began offering patients stand-alone POEM. Patient data were collected. Preoperative and postoperative Eckardt scores were compared. RESULTS: A total of 28 patients underwent POEM or POEM plus laparoscopic evaluation with partial fundoplication. Patient characteristics and perioperative and postoperative data were recorded. The median preoperative Eckardt score was 6 (range 4-11). The mean follow-up period was 136 days (range 41-330) and the median postoperative Eckardt score was 0 (range 0-6) at 6 weeks. Of our initial 10 patients, 6 required laparoscopic extension of the myotomy; 7 subsequent patients did not require an additional myotomy. Three patients who underwent POEM without laparoscopy continued to have dysphagia postoperatively. One patient had an attempted POEM that was aborted secondary to bleeding, and a standard laparoscopic modified Heller myotomy with partial fundoplication was performed. CONCLUSIONS: The excellent results of laparoscopic myotomy with partial fundoplication are challenging to duplicate during the initial adoption of a POEM approach. We present a program developed to steepen the learning curve and enhance patient safety while implementing this new procedure. PMID- 29156014 TI - Exhaustive preoperative staging increases survival in resected adrenal oligometastatic non-small-cell lung cancer: a multicentre study. AB - OBJECTIVES: Adrenal oligometastatic non-small-cell lung cancer is rare, and surgical management remains controversial. METHODS: We performed a multicentre, retrospective study from January 2004 to December 2014. The main objective was to evaluate survival in patients who had undergone adrenalectomy after resection of primary lung cancer. Secondary objectives were to determine prognostic, survival and recurrence factors. RESULTS: Fifty-nine patients were included. Forty-six patients (78%) were men. The median age was 58 years [39-75 years]. Twenty-six cases (44%) showed synchronous presentation, and 33 cases (56%) had a metachronous presentation. The median time to onset of metastasis was 18.3 months [6-105 months]. The 5-year overall survival rate was 59%; the median survival time was 77 months [0.6-123 months]. A recurrence was observed in 70% of the population. Mediastinal lymph node invasion (P = 0.035) is a detrimental prognostic factor of survival. CONCLUSIONS: After exhaustive staging, patients with adrenal oligometastatic non-small-cell lung cancer benefit from bifocal surgery. PMID- 29156015 TI - European prospective multicentre study of hybrid thoracoscopic and transcatheter ablation of persistent atrial fibrillation: the HISTORIC-AF trial. AB - OBJECTIVES: The HISTORIC-AF trial is a prospective, multicentre, single-arm study designed to evaluate the outcomes of a staged endoscopic and transcatheter ablation in patients with stand-alone, persistent or long-standing persistent atrial fibrillation (AF). METHODS: From 2012 to 2015, 100 consecutive patients were enrolled and underwent thoracoscopic left atrial epicardial isolation ('box lesion') followed by transcatheter ablation in case of AF recurrency. The safety end point was the composite outcome of freedom from major adverse events at 30 days, while efficacy end points were: (i) primary: freedom from AF and stable sinus rhythm following isolated thoracospic ablation >60% and (ii) secondary: freedom from AF and stable sinus rhythm >80% following hybrid ablation (as per HRS criteria). RESULTS: No death occurred and surgical thoracoscopic procedure was successfully completed in all patients. Survival free from major adverse events at 30 days was 94%: there were 3 permanent pacemaker implants, 2 episodes of stroke and 1 revision for bleeding. At discharge, 87% of patients were in sinus rhythm. A staged transcatheter ablation was carried out in all patients with AF recurrences at the end of 3 months blanking period (17% of patients). At 12-months follow-up, a stable restoration of sinus rhythm was achieved in 75% and 88% of patients following isolated thoracoscopic ablation and hybrid ablation, respectively. CONCLUSIONS: The HISTORIC-AF trial showed that thoracoscopic isolated surgical ablation reached both the safety and the efficacy end points. Hybrid ablation steadily improved rhythm outcomes and may be considered in the future as the treatment of choice for patients with persistent and long-standing persistent AF. ClinicalTrials.gov Identifier: NCT01622907. PMID- 29156016 TI - Pectus excavatum repair after sternotomy: the Chest Wall International Group experience with substernal Nuss bars. AB - OBJECTIVES: Patients with pectus excavatum (PE) after prior sternotomy for cardiac surgery present unique challenges for repair of PE. Open repairs have been recommended because of concerns about sternal adhesions and cardiac injury. We report a multi-institutional experience with repair utilizing substernal Nuss bars in this patient population. METHODS: Surgeons from the Chest Wall International Group were queried for experience and retrospective data on PE repair using sub-sternal Nuss bars in patients with a history of median sternotomy for cardiac surgery (November 2000 to August 2015). A descriptive analysis was performed. RESULTS: Data for 75 patients were available from 14 centres. The median age at PE repair was 9.5 years (interquartile range 10.9), and the median Haller index was 3.9 (interquartile range 1.43); 56% of the patients were men. The median time to PE repair was 6.4 years (interquartile range 7.886) after prior cardiac surgery. Twelve patients (16%) required resternotomy before support bar placement: 7 pre-emptively and 5 emergently. Sternal elevation before bar placement was used in 34 patients (45%) and thoracoscopy in 67 patients (89%). Standby with cardiopulmonary bypass was available at 9 centres (64%). Inadvertent cardiac injury occurred in 5 cases (7%) without mortality. CONCLUSIONS: Over a broad range of institutions, substernal Nuss bars were used in PE repair for patients with a history of sternotomy for cardiac surgery. Several technique modifications were reported and may have facilitated repair. Cardiac injury occurred in 7% of cases, and appropriate resources should be available in the event of complications. Prophylactic resternotomy was reported at a minority of centres. PMID- 29156017 TI - Early and late outcomes after surgical repair of congenital supravalvular aortic stenosis: a European Congenital Heart Surgeons Association multicentric study. AB - OBJECTIVES: Our goal was to evaluate the early and late results of the surgical management of congenital supravalvular aortic stenosis (SVAS). METHODS: We performed a retrospective, multicentre study using data from the European Congenital Heart Surgeons Association. Exclusion criteria were age >18 years, operation before 1990 and redo supravalvular aortic stenosis operations. Multivariate Cox regression analysis was performed to detect independent predictors of adverse events. RESULTS: Of a total of 301 patients (male/female = 194/107; median age 3.9 years, range 13 days-17.9 years), 17.6% had a prior surgical or interventional procedure. Pulmonary artery stenosis was present in 41.5% and coronary anomalies in 13.6%. The operation consisted of a single patch repair in 36.7%, a pantaloon-shaped patch in 36.7%, a 3-patch technique in 14.3% and other techniques in 11.7%. Postoperative complications occurred in 14.9%, and the early mortality rate was 5%. At a median follow-up of 13 years (interquartile range 3.5-7.8; follow-up completed 79.1%), there were 10 late deaths (4.2%). A surgical reoperation or an interventional cardiology procedure occurred in 12.6% and 7.2%, respectively. No significant differences in outcomes between the techniques were found. Age at repair <12 months and pulmonary artery stenosis were associated with an increased risk of early (P = 0.0001) and overall mortality (P = 0.025), respectively. Having an operation after 2005 and co existing pulmonary artery stenosis were significant predictors of late reintervention (P = 0.0110 and P = 0.001, respectively). CONCLUSIONS: Surgical repair of congenital stenosis is an effective procedure with acceptable surgical risk and good late survival, but late morbidity is not negligible, especially in infants and when associated pulmonary artery stenosis is present. PMID- 29156018 TI - Risk factors of myasthenic crisis after thymectomy for thymoma patients with myasthenia gravis. AB - OBJECTIVES: Total thymectomy should be performed on thymoma patients with myasthenia gravis. The aim of the present study was to investigate the risk factors of postoperative myasthenic crisis (POMC) occurrence in these patients. METHODS: The clinical records of 127 thymoma patients with myasthenia gravis (68 men, 59 women; median age, 50 years) who underwent total thymectomy at our institution from 2005 to 2014 were retrospectively reviewed. The following factors were analysed in relation to POMC: gender, age, duration of symptoms, bulbar symptoms, smoking history, history of myasthenic crisis, comorbidities, perioperative pyridostigmine and prednisolone therapy, spirometric and blood gas parameters, Osserman stage, operation approach, major complications, World Health Organization (WHO) histologic classification, Masaoka stage and use of immunoglobulins or plasmapheresis. RESULTS: Thirteen patients (10%) experienced POMC and required intubation. All patients were weaned after 2-28 days (median 9 days) and were discharged. Univariate analysis revealed a correlation between POMC and Osserman-stage IIA-IV [odds ratio (OR) = 4.928, 95% confidence interval (CI) = 1.286-18.882, P = 0.01], bulbar symptoms (OR = 3.828, 95% CI = 1.112 13.176, P = 0.04), and forced expiratory volume in one second <70% pred forced expiratory volume in one second (OR = 4.856, 95% CI = 1.380-17.081, P = 0.02). In addition, more frequent POMC occurred in WHO type B2-B3 than in type A-B1 thymomas (OR = 8.118, 95% CI = 1.020-64.590, P = 0.03). Multivariate logistic regression analysis showed that WHO histologic classification B2-B3 (OR = 10.041, 95% CI = 1.228-82.090, P = 0.03) and Osserman-stage IIA-IV (OR = 5.953, 95% CI = 1.506-23.538, P = 0.01) independently predicted POMC. CONCLUSIONS: Osserman stage (IIA-IV) and WHO type B2-B3 thymomas are independent predictors of POMC in thymoma patients with myasthenia gravis who have undergone total thymectomy. Thus, adequate perioperative care should be provided to these patients. PMID- 29156019 TI - The aspartate transaminase/alanine transaminase (DeRitis) ratio predicts mid-term mortality and renal and respiratory dysfunction after left ventricular assist device implantation. AB - OBJECTIVES: Preoperative liver dysfunction is a well-known risk factor for adverse events after major surgery. However, there is only little data regarding the precise role of the Model of End-Stage Liver Disease (MELD) score and the De Ritis ratio (DRR, alanine transaminase/aspartate aminotransferase) as a predictor for outcome after left ventricular assist device (LVAD) implantation. METHODS: A retrospective analysis of all patients undergoing LVAD implantation at our institution between January 2012 and August 2014 was performed. The primary outcome was survival at 180 days after surgery. RESULTS: During the observation period, 63 patients underwent LVAD implantation (mean age 59.9 +/- 8.3 years, 50% male). Mean preoperative ejection fraction was 16.3 +/- 7.7, 13 patients required preoperative renal replacement therapy and 9 patients were on extracorporeal life support. Mean Interagency Registry for Mechanically Assisted Circulatory Support level was 2.8 +/- 1.3, mean preoperative MELD was 12.7 +/- 7.2, mean preoperative DRR was 2.01 +/- 4.4. Aspartate aminotransferase (102 +/- 220.8 vs 57.8 +/- 123.4 U/l, P = 0.041), MELD score (16.1 +/- 8.8 vs 11.4 +/- 6.1, P = 0.017) and DRR (4.2 +/- 7.8 vs 1.1 +/- 1.1, P = 0.001) were significantly higher in non survivors than in survivors after 180 days. Using logistic regression analyses, a DRR >1.37 was an independent predictor for 30-day mortality [odds ratio (OR) 4.5] and 180-day mortality (OR 4.1). In addition, the DRR was associated with postoperative acute kidney injury with need for renal replacement therapy (OR 4.2) and prolonged postoperative ventilation time >72 h (OR 3.8). Using receiver operator characteristics analyses, DRR showed a sensitivity of 0.80 and a specificity of 0.81 (area under the curve 0.834, cut-off 1.37) for 180-day mortality. CONCLUSIONS: The DRR is predictive of early and mid-term mortality as well as relevant morbidities in patients undergoing LVAD implantation. Therefore, the DRR should be considered within the preoperative risk stratification and patient selection for LVAD implantation. PMID- 29156020 TI - Doubly committed ventricular septal defect closure using eccentric occluder via ultraminimal incision. AB - OBJECTIVES: This study aimed to investigate the safety, feasibility and availability of doubly committed ventricular septal defect (DCVSD) closure via an ultraminimal intercostal incision under the guidance of transoesophageal echocardiography in children. METHODS: From August 2014 to August 2016, 35 children with DCVSDs (<=5 mm in diameter) were enrolled in this study. A left parasternal ultraminimal intercostal incision (<=1 cm) and a pericardium hanging technique were employed without sternal incision. DCVSDs were closed through a short delivery sheath assembled with an eccentric occluder device. Transoesophageal echocardiography was used to guide and monitor the entire procedure. All patients were followed up. RESULTS: All 35 children had complete closures with an operation success rate of 100%. The average size of DCVSDs was 3.50 +/- 0.79 (range 2.2-5.0) mm, and the average device size was 5 +/- 2 (range 4-9) mm. The average operation duration was 45.42 +/- 11.77 (range 25-70) min, and the average hospital stay was 8 +/- 2 (range 7-16) days. The median follow-up period was 17 months (range 6 months-2.5 years). Pre-existing aortic regurgitation disappeared after surgery in 1 patient and remained the same in 4 patients. No other complications were found during the operation or during follow up. CONCLUSIONS: Under transoesophageal echocardiography guidance, DCVSD closure using an eccentric occluder via an ultraminimal intercostal incision is feasible, safe and effective in children. The use of this approach is recommended. PMID- 29156021 TI - Type 1a endoleak following Zone 1 and Zone 2 thoracic endovascular aortic repair: effect of bird-beak configuration. AB - OBJECTIVES: Type 1a endoleak is one of the most severe complications after thoracic endovascular aortic repair (TEVAR), because it carries the risk of aortic rupture. The association between bird-beak configuration and Type 1a endoleak remains unclear. The purpose of this study was to analyse the predictors of Type 1a endoleak following Zone 1 and Zone 2 TEVAR, with a particular focus on the effect of bird-beak configuration. METHODS: From April 2008 to July 2015, 105 patients (mean age 68.6 years) who underwent Zone 1 and 2 landing TEVAR were enrolled, with a mean follow-up period of 4.3 years. The patients were categorized into 2 groups, according to the presence (Group B, n = 32) or the absence (Group N, n = 73) of bird-beak configuration on the first postoperative multidetector computed tomography. RESULTS: The Kaplan-Meier event-free rate curve showed that Type 1a endoleak and bird-beak progression occurred less frequently in Group N than in Group B. Five-year freedom from Type 1a endoleak rates were 79.7% and 100% for Groups B and N, respectively (P = 0.007). Multivariable logistic regression analysis showed that dissecting aortic aneurysm (odds ratio 3.72, 95% confidence interval 1.30-11.0; P = 0.014) and shorter radius of inner curvature (odds ratio 1.09, 95% confidence interval 0.85-0.99; P = 0.025) were significant risk factors for bird-beak configuration. Multivariable Cox proportional hazard regression showed that Z-type stent graft (hazard ratio 2.69, 95% confidence interval 1.11-6.51; P = 0.030) was a significant risk factor for bird-beak progression. CONCLUSIONS: Appropriate stent grafts need to be chosen carefully to prevent Type 1a endoleak and bird-beak configuration after landing Zone 1 and 2 TEVAR. Patients with bird-beak configuration on early postoperative multidetector computed tomography require closer follow-up to screen for Type 1a endoleak. PMID- 29156025 TI - Cerebral blood flow and its autoregulation - when will there be some light in the black box? PMID- 29156022 TI - Anaortic off-pump versus clampless off-pump using the PAS-Port device versus conventional coronary artery bypass grafting: mid-term results from a matched propensity score analysis of 5422 unselected patients. AB - OBJECTIVES: Meta-analyses from observational and randomized studies have demonstrated benefits of off-pump surgery for hard and surrogate endpoints. In some of them, increased re-revascularization was noted in the off-pump groups, which could impact their long-term survival. Therefore, we analyzed the course of all patients undergoing isolated coronary surgery regarding the major cardiac and cerebrovascular event (MACCE) criteria. METHODS: A prospective register was taken from a high-volume off-pump center recording all anaortic off-pump (ANA), clampless off-pump (PAS-Port) and conventional (CONV) coronary artery bypass operations between July 2009 and June 2015. Propensity Score Matching was performed based on 28 preoperative risk variables. RESULTS: We identified 935 triplets (N = 2805). Compared with CONV, in-hospital mortality of both the ANA group (OR for ANA [95% CI] 0.25 [0.06; 0.83], P = 0.021), and the PAS-Port group was lower (OR for PAS-Port [95% CI] 0.50 [0.17; 1.32], P = 0.17). In the mid-term follow-up there were no significant differences between the groups regarding mortality (HR for ANA [95%-CI] 0.83 [0.55-1.26], P = 0.38; HR for PAS-Port [95% CI] 1.06 [0.70-1.59], P = 0.79), incidence of stroke (HR for ANA 0.81 [0.43 1.53], P = 0.52; HR for PAS-Port 0.78 [0.41-1.50], P = 0.46), myocardial infarction (HR for ANA 0.53 [0.22-1.31], P = 0.17; HR for PAS-Port 0.78 [0.37 1.66], P = 0.52) or re-revascularization rate (HR for ANA 0.99 [0.67-1.44], P = 0.94; HR for PAS-Port 0.95 [0.65-1.38], P = 0.77). CONCLUSIONS: Both off-pump clampless techniques were associated with lower in-hospital mortality compared with conventional CABG. The mid-term course showed no difference with regard to the MACCE criteria between anaortic off-pump, clampless off-pump using PAS-Port and conventional CABG. PMID- 29156023 TI - 2017 ESC/EACTS Guidelines for the management of valvular heart disease. PMID- 29156024 TI - Transatlantic Editorial: thoracic surgeons need recognition of competence in thoracic oncology. PMID- 29156026 TI - The role of propofol for remote ischaemic preconditioning in the setting of cardiac surgery - a Cochrane systematic review. PMID- 29156027 TI - Why has NHS England introduced an innovation and technology tariff to improve safer arterial systems in England? PMID- 29156028 TI - Landmarks in UK anaesthesia. PMID- 29156029 TI - Intraoperative permissive oliguria - how much is too much? PMID- 29156030 TI - Correlational studies of unconsciousness under anaesthesia: how far can preclinical studies take us? PMID- 29156031 TI - Formulation of a National Surgical Plan in Rwanda: a model for integration of physician and non-physician anaesthetists. PMID- 29156032 TI - Reply to: Pulse oximeter perfusion index for assessment of brachial plexus block: a holy grail or a design fail? PMID- 29156033 TI - Sensitivity is not enough. Response to: Postoperative delirium portends descent to dementia. PMID- 29156034 TI - Don't crush the sensitive snout. Reply to: Sensitivity is not enough. PMID- 29156035 TI - Perioperative cognitive disorders. Response to: Postoperative delirium portends descent to dementia. PMID- 29156036 TI - New nomenclature: Clarion call or siren song. Reply to: perioperative cognitive disorders. PMID- 29156037 TI - Does intraoperative magnesium lessen pain after knee replacement surgery? PMID- 29156038 TI - Reply to: Does intraoperative magnesium lessen pain after knee replacement surgery? PMID- 29156039 TI - Pulse oximeter perfusion index for assessment of brachial plexus block: a holy grail or a design fail? PMID- 29156040 TI - Response to: 'Failed supraglottic airway': an algorithm for suboptimally placed supraglottic airway devices based on videolaryngoscopy. PMID- 29156041 TI - Author's reply to Thomas et al. PMID- 29156042 TI - Limitations of clinical studies evaluating tertiary hyperalgesia. PMID- 29156043 TI - Tenofovir Alafenamide Fumarate: A New Tenofovir Prodrug for the Treatment of Chronic Hepatitis B Infection. AB - Tenofovir alafenamide fumarate (TAF), a new prodrug of tenofovir and a potential successor of tenofovir disoproxil fumarate (TDF), has been approved in the United States and Europe for treating adolescents and adults with chronic hepatitis B infection. TAF is formulated to deliver the active metabolite to target cells more efficiently than TDF at lower doses, thereby reducing systemic exposure to tenofovir. In patients with chronic hepatitis B, TAF appears to be as effective as TDF, with lower bone and renal toxicity. TAF has the potential advantages that dose adjustment is not required in patients with renal impairment, and monitoring can be less intense because of the better safety profile. Results from 2 large, randomized, phase 3 studies after 48 weeks of therapy have shown that TAF may be a good alternative to TDF for treating chronic hepatitis B. Whether the short term benefits observed in these 48-week trials will translate into improvements in bone and renal health in patients receiving long-term treatment remains to be seen. PMID- 29156044 TI - Characteristics, Prevention, and Management of Hepatitis B Virus (HBV) Reactivation in HBV-Infected Patients Who Require Immunosuppressive Therapy. AB - Hepatitis B virus (HBV) reactivation becomes a challenging issue with increasing use of immunosuppressive agents and cytotoxic chemotherapy for varied medical conditions, including cancer. The spectrum of HBV reactivation in the setting of immunosuppression may vary from asymptomatic reactivation to liver failure leading to death. HBV reactivation can hamper the course of planned therapies and diminish the effects of therapies; thus, it adversely affects the prognosis of the original disease and the survival of the patients. There is mounting evidence that HBV reactivation can be prevented and managed if patients are screened to determine their risk for HBV reactivation and are treated prophylactically before therapy with immunosuppressive agents or cytotoxic chemotherapy is initiated. In this article, we review the diagnostic criteria and clinical outcomes of HBV reactivation, discuss how immunosuppressive therapy may influence the risk of HBV reactivation, and outline strategies to prevent HBV reactivation. PMID- 29156045 TI - NOhep: Toward Global Control of Hepatitis B Virus Infection-An Introduction. PMID- 29156046 TI - Toward a Cure for Hepatitis B Virus Infection: Combination Therapy Involving Viral Suppression and Immune Modulation and Long-term Outcome. AB - Chronic hepatitis B virus (HBV) infection remains a major global health burden. Currently, the approved therapeutic regimens include nucleos(t)ide analogues (NAs) and either interferon or pegylated interferon. NA therapy is generally safe and well tolerated, but the rate of posttreatment virologic relapse is high, making NA treatment a lifetime commitment. The benefits of pegylated interferon treatment include a finite duration, more-durable response and absence of viral resistance. However, sustained response to interferon alone is achieved only in a minority of patients, and side effects are common, which limit its clinical use. Given that HBV covalently closed circular DNA and the integrated HBV genome persist stably in the nuclei of infected hepatocytes, elimination (complete cure) of HBV is rarely achieved. After completion of treatment, sustained HBV surface antigen loss, with or without seroconversion to HBV surface antibody positivity (ie, functional cure), is therefore recommended as the ideal end point for anti HBV treatment, despite the lack of complete eradication of HBV. Theoretically, combination of antiviral agents with differential mechanisms of actions on HBV, including viral suppression combined with immune modulation (as occurs during treatment with NA plus pegylated interferon), is an encouraging strategy to treat chronic hepatitis B. Recent studies have confirmed certain virological and serological advantages of simultaneous administration of NA and pegylated interferon (de novo combination therapy) or addition of pegylated interferon to ongoing NA therapy (sequential combination therapy) over monotherapy. Few data exist, however, on the long-term outcomes of patients receiving combination therapy. This review summarizes current combination therapy developed to cure chronic HBV infection. PMID- 29156047 TI - Immunopathogenesis of Hepatitis B Virus. AB - Chronic hepatitis B virus (HBV) infection is a global public health issue. There are >250 million people chronically infected with HBV, and these chronic carriers are at high risk of developing end-stage liver diseases and hepatocellular carcinoma. Patients with chronic hepatitis B (CHB) usually acquire the virus perinatally, while most patients infected during adulthood develop acute hepatitis B (AHB), which usually results in viral clearance. HBV infection is noncytopathic, and liver injury is mostly contributed by host immune responses. The virus is stealthy, since the infection rarely induces type I interferon response in the early phase. In AHB, viral infection is detected and restrained by the innate immune response, which is followed by a strong and robust adaptive immune response and accompanied by viral clearance. In patients with CHB, both innate and adaptive immune responses are weak and thus rarely lead to viral clearance. Interferon alpha and nucleos(t)ide analogues are 2 classes of approved antiviral therapies. The former treatment activates nature killer (NK) cells and NK T cells, which partially enhances the innate immune response, while the later treatment suppresses viral replication by inhibiting reverse transcriptase, which may restore the HBV-specific adaptive immune response. However, single or combined treatment are still far from achieving seroclearance of HBV surface antigen. Although the treatment response is unsatisfactory in current clinical trials using several immunomodulators for boosting antiviral immunity, immunotherapy that is able to induce immune surveillance is still the most promising modality for HBV cure in the future. PMID- 29156049 TI - Management of Pregnant Women and Children: Focusing on Preventing Mother-to Infant Transmission. AB - Hepatitis B virus (HBV) immunization has been effectively preventing chronic HBV infection with >90% efficacy in countries with universal neonatal immunization. Perinatal mother-to-infant transmission of HBV remains the major cause of chronic HBV infection despite immunization. Maternal hepatitis B e-antigen (HBeAg) and high viral load have been noted to be the most important risk factors for transmission. In recent years, short-term antiviral therapy for pregnant women in the third trimester has been shown to be highly effective in reducing 90% of vaccine failure in children. It is important to monitor maternal aminotransferase elevations postpartum. Long-term outcome of mothers and children is needed and awaits further investigations. Despite the above-mentioned preventive measures, it is also important to monitor high-risk children at 1 year of age with hepatitis B surface antigen and anti-hepatitis B to identify those with chronic HBV infection. Most of the children with chronic HBV infection were in the immune tolerant phase. The goals for antiviral treatment in children are to reduce severity of liver injury, achieve HBeAg seroconversion, and prevent development of liver fibrosis and cancer. Studies on antiviral therapy are undergoing to elucidate the optimal indication and drug treatment for children. The ideal future goal of treatment is to eradicate chronic HBV infection globally. PMID- 29156048 TI - Unmet Needs in Clinical and Basic Hepatitis B Virus Research. AB - Chronic hepatitis B (CHB) has become a treatable and controllable disease. The current nucleos(t)ide analogue (NUC) and pegylated interferon therapies effectively help slow disease progression and reduce the risk of cirrhosis, hepatocellular carcinoma (HCC), and CHB-associated mortality. Long-term viral suppression is easily achievable by NUC therapy, with limited adverse reactions. However, several unmet requirements still exist, including safety and risk stratified HCC surveillance among patients who received long-term NUC therapy. Criteria for determining which patients should receive finite-duration NUC therapy and which should receive combination therapy with both NUC and pegylated interferon remain unsettled. The management of hepatitis B virus (HBV) e antigen positive viremic patients with normal liver function and the incorporation of new biomarkers to help manage CHB require further exploration. To achieve functional cure (ie, HBV surface antigen seroclearance) and complete cure (ie, eradication of covalently closed circular DNA) of CHB, several challenges in basic research must be addressed, including the development of an efficient cell culture system and animal models for HBV investigation, development of treatment to eradicate covalently closed circular HBV DNA, and development of immunotherapy for CHB. This brief review focuses on unmet needs in both clinical and basic HBV research. PMID- 29156050 TI - Viral Factors Affecting the Clinical Outcomes of Chronic Hepatitis B. AB - Chronic hepatitis B (CHB) exhibits a variety of clinical outcomes, ranging from spontaneous resolution of hepatitis B to severe adverse consequences, including the development of cirrhosis, hepatic failure, and hepatocellular carcinoma. The heterogeneous clinical courses of chronic hepatitis B virus (HBV) infection reflect the complex host-virus interactions, and point to the difficulty and necessity of identifying the patients at risk. With the advance of HBV virology, several viral factors have been found to be associated with the long-term clinical outcomes of CHB patients. Different viral factors probe different aspects of CHB. Integration of these viral factors may help to determine the disease state of patients more accurately, and identify the patients who require timely antiviral therapy to prevent the development of detrimental clinical outcomes. In this article, we will introduce the conventional and emerging viral factors that are associated with clinical outcomes and discuss their utility in a clinical setting. PMID- 29156051 TI - Natural and Anthropogenic Influences on the Mating System of the Common Morning Glory. AB - Evolutionary biologists remain puzzled by the often dramatic variation of mating strategies within single species. Of particular interest is the extent to which environmental conditions shape patterns of variation of mating system components within mixed mating species, and how widespread anthropogenic manipulations may influence these associations. Here, we address this question in the common morning glory (Ipomoea purpurea) by combining a dataset of floral traits, estimates of the mating system, and relevant environmental factors compiled for 22 populations of this species distributed along a wide range of environments from the Southeastern and Midwestern United States. We identify a disparate set of environmental factors to influence population-level variation in selfing, inbreeding, and flower morphology. Although floral traits are primarily associated with climatic variation, the outcrossing rate and inbreeding coefficient are primarily influenced by the level of herbicide resistance. Furthermore, we find that populations with higher levels of herbicide resistance exhibit a stronger correlation between mating system-floral traits and mating system estimates (outcrossing rate and inbreeding coefficient). Altogether, these results demonstrate the dominant role that herbicide application plays in the determination of I. purpurea's mating system, and more generally uncover the complex and unforeseen evolutionary consequences of anthropogenic manipulations in natural systems. PMID- 29156052 TI - Primary Adrenal Insufficiency: Managing Mineralocorticoid Replacement Therapy. AB - Context: Mineralocorticoid (MC) replacement therapy in patients with primary adrenal insufficiency (PAI) was introduced more than 60 years ago. Still, there are limited data on how MC substitution should be optimized, because MC dosing regimens have only been systematically investigated in a few studies. We review the management of current standard MC replacement therapy in PAI and its plausible impact on outcome. Design: Using PubMed, we conducted a systematic review of the literature from 1939 to 2017, with the following keywords: adrenal insufficiency, MC deficiency, aldosterone, cardiovascular disease, hypertension, and heart failure. Results: The current standard treatment consists of fludrocortisone (FC) given once daily in the morning, aiming at normotension, normokalemia, and plasma renin activity in the upper normal range. Available data suggest that patients with PAI may be underreplaced with FC as symptoms and signs indicating chronic MC underreplacement, such as salt craving and postural dizziness persist, in many treated patients with PAI. Data acquired from large registry-based studies show that glucocorticoid doses for replacement in PAI are higher than those estimated from endogenous production. Glucocorticoid overreplacement may reduce the need of MC replacement but may also be a consequence of inadequate MC replacement. Conclusions: The commonly used MC replacement in PAI may not be adequate in some patients. Insufficient MC substitution may be responsible for poor cardiometabolic outcome and the failure to restore well-being adequately in patients with PAI. Well-designed studies oriented at optimizing MC replacement therapy are urgently needed. PMID- 29156053 TI - Propensity-matched analysis of outcomes after mitral valve surgery between trainees and consultants (institutional report). AB - OBJECTIVES: We aimed to determine whether early outcomes and long-term survival after mitral valve surgery performed by trainee residents are equivalent in terms of safety and efficacy when compared with consultant surgeons. METHODS: Between January 2000 and December 2015, a total of 1742 patients who underwent mitral valve surgery were identified. Of these, 1622 operations were performed by consultants (Group I) and 120 operations were performed by trainees (Group II). A propensity score-matched analysis has been used to minimize selection bias. Early postoperative outcomes were defined as in-hospital mortality, cerebrovascular accident, postoperative requirement of renal replacement therapy, reoperation for bleeding and postoperative length of hospital stay. Long-term outcomes were evaluated using late survival data after discharge. RESULTS: Before matching, the 2 groups differed significantly in terms of gender and reduced left ventricular ejection fraction, but these differences were solved after matching. Also, Group I included significantly more patients with mitral regurgitation (83% vs 62%; P < 0.01), but after matching, this difference was corrected (62% vs 59%; P = 0.71). Consultant group was associated with a higher in-hospital mortality (6% vs 2%; P = 0.04) in the unmatched population. Moreover, in the unmatched cohort, this group had longer cross-clamp time compared with the trainees group (91 +/- 38 vs 89 +/- 26 min; P = 0.47) and longer cardiopulmonary bypass time (132 +/- 58 vs 121 +/- 33 min; P = 0.27); these differences were not statistically significant. There were no significant differences in postoperative dialysis, cerebrovascular accident, reoperation for bleeding and length of hospital stay. Even after matching, no significant differences were found in terms of perioperative complications. The Kaplan-Meier survival curves at 1, 5 and 10 years were similar between the 2 groups. CONCLUSIONS: Mitral valve surgery can be safely performed by trainees and provides similar short- and long-term results compared with consultant surgeons. PMID- 29156054 TI - Hospice care, cancer-directed therapy, and Medicare expenditures among older patients dying with malignant brain tumors. AB - Background: End-of-life care for older adults with malignant brain tumors is poorly understood. The purpose of this study is to quantify end-of-life utilization of hospice care, cancer-directed therapy, and associated Medicare expenditures among older adults with malignant brain tumors. Methods: This retrospective cohort study included deceased Medicare beneficiaries age >=65 with primary malignant brain tumor (PMBT) or secondary MBT (SMBT) receiving care within a southeastern cancer community network including academic and community hospitals from 2012-2015. Utilization of hospice and cancer-directed therapy and total Medicare expenditures in the last 30 days of life were calculated using generalized linear and mixed effect models, respectively. Results: Late (1-3 days prior to death) or no hospice care was received by 24% of PMBT (n = 383) and 32% of SMBT (n = 940) patients. SMBT patients received late hospice care more frequently than PMBT patients (10% vs 5%, P = 0.002). Cancer-directed therapy was administered to 18% of patients with PMBT versus 25% with SMBT (P = 0.003). Nonwhite race, male sex, and receipt of any hospital-based care in the final 30 days of life were associated with increased risk of late or no hospice care. The average decrease in Medicare expenditures associated with hospice utilization for patients with PMBT was $-12,138 (95% CI: $-18,065 to $-6210) and with SMBT was $ 1,508 (95% CI: $-3,613 to $598). Conclusions: Receiving late or no hospice care was common among older patients with malignant brain tumors and was significantly associated with increased total Medicare expenditures for patients with PMBT. PMID- 29156055 TI - Analysis of an ADTKD family with a novel frameshift mutation in MUC1 reveals characteristic features of mutant MUC1 protein. AB - Background: Medullary cystic kidney disease Type 1 is an autosomal dominant tubulointerstitial kidney disease (ADTKD). Recently, mucin 1 (MUC1) was identified as a causal gene of medullary cystic kidney disease (ADTKD-MUC1). However, the MUC1 mutation was found to be a single cytosine insertion in a single copy of the GC-rich variable number of tandem repeats (VNTRs), which are very difficult to analyze by next-generation sequencing. To date, other mutations have not been detected in ADTKD-MUC1, and the mutant MUC1 protein has not been analyzed because of the difficulty of genetically modifying the VNTR sequence. Methods: We conducted whole-exome analyses of an ADTKD family by next-generation sequencing. We also performed histopathological analyses of a renal biopsy from a pedigree family member. We constructed a mutant protein expression vector based on the patient genome sequence and characterized the nature of the mutant protein. Results: We found a novel frameshift mutation before the VNTR in the MUC1 gene. The resulting mutant MUC1 protein had a very similar amino acid sequence and predicted 3D structure to the previously reported mutant protein. Notably, the recombinant mutant MUC1 protein was trapped in the cytoplasm and appeared to self-aggregate. The patient native mutant protein was also found in urine exosomes. Conclusions: This novel frameshift mutation in the MUC1 gene and consequent mutant protein may contribute to the future discovery of the pathophysiology of ADTKD-MUC1. The mutant MUC1 protein in urine exosomes may be used for non-DNA-related diagnosis. PMID- 29156056 TI - High doses of cholecalciferol alleviate the progression of hyperparathyroidism in patients with CKD Stages 3-4: results of a 12-week double-blind, randomized, controlled study. AB - Background: Calcidiol insufficiency may accelerate the development of secondary hyperparathyroidism (SHPT). We tested the effect of a substantial increase in calcidiol on mineral metabolism in patients with chronic kidney disease (CKD). Methods: Ninety-five patients with CKD Stages 3-4, parathyroid hormone (PTH) above 6.8 pmol/L and calcidiol below 75 nmol/L were randomized to receive either cholecalciferol 8000 IU/day or placebo for 12 weeks. The primary endpoint was difference in the mean change in iPTH after 12 weeks. The proportion of participants having a 30% reduction in PTH and the effect on hand grip strength, fatigue and different biochemical variables were also investigated. Results: Baseline calcidiol was 57.5 +/- 22 and 56.8 +/- 22 nmol/L in the cholecalciferol and placebo groups, respectively. The corresponding concentrations of PTH were 10.9 +/- 5 and 13.1 +/- 9 pmol/L. Calcidiol increased to 162 +/- 49 nmol/L in patients receiving cholecalciferol, and PTH levels remained constant at 10.5 +/- 5 pmol/L. In the placebo group, calcidiol remained stable and PTH increased to 15.2 +/- 11 pmol/L. The mean change in PTH differed significantly between the two groups (P < 0.01). The proportion of subjects reaching a 30% decrease in PTH did not differ. No effect on grip strength, fatigue, phosphate or fibroblast growth factor 23 was observed. Cholecalciferol treatment resulted in stable calcium concentrations and a substantial increase in calcitriol. Conclusion: Treatment with high daily doses of cholecalciferol in patients with CKD Stages 3-4 halts the progression of SHPT and does not cause hypercalcaemia or other side effects. PMID- 29156057 TI - PRGdb 3.0: a comprehensive platform for prediction and analysis of plant disease resistance genes. AB - The Plant Resistance Genes database (PRGdb; http://prgdb.org) has been redesigned with a new user interface, new sections, new tools and new data for genetic improvement, allowing easy access not only to the plant science research community but also to breeders who want to improve plant disease resistance. The home page offers an overview of easy-to-read search boxes that streamline data queries and directly show plant species for which data from candidate or cloned genes have been collected. Bulk data files and curated resistance gene annotations are made available for each plant species hosted. The new Gene Model view offers detailed information on each cloned resistance gene structure to highlight shared attributes with other genes. PRGdb 3.0 offers 153 reference resistance genes and 177 072 annotated candidate Pathogen Receptor Genes (PRGs). Compared to the previous release, the number of putative genes has been increased from 106 to 177 K from 76 sequenced Viridiplantae and algae genomes. The DRAGO 2 tool, which automatically annotates and predicts (PRGs) from DNA and amino acid with high accuracy and sensitivity, has been added. BLAST search has been implemented to offer users the opportunity to annotate and compare their own sequences. The improved section on plant diseases displays useful information linked to genes and genomes to connect complementary data and better address specific needs. Through, a revised and enlarged collection of data, the development of new tools and a renewed portal, PRGdb 3.0 engages the plant science community in developing a consensus plan to improve knowledge and strategies to fight diseases that afflict main crops and other plants. PMID- 29156058 TI - FEVR-like Presentation in an 11q Deletion Syndrome and 16p13.11 Microdeletion. AB - A 7-year-old boy was diagnosed and treated for familial exudative vitreoretinopathy. Genetic testing revealed a 16p13.11 microdeletion and unbalanced translocation causing 11q deletion syndrome. This is the first report describing retinal findings associated with this combination of genetic alterations. Patients with 11q deletion syndrome or 16p13 microdeletions should undergo ophthalmologic examination. [J Pediatr Ophthalmol Strabismus. 2017;54:e71 e74.]. PMID- 29156059 TI - Clinical Pearl: The "Rule of 8". AB - Preschool-aged children typically perform worse than 20/20 on visual acuity testing in the absence of ocular or visual pathway abnormalities due to non ocular issues, including concentration, cooperation, and/or confidence. As a result, vision screening for this age group can be a challenge. The "Rule of 8" is an easy-to-remember, highly effective mnemonic that clinicians can use to help differentiate children who are performing visual acuity testing at age appropriate levels from those who may need further evaluation. [J Pediatric Ophthalmol Strabismus. 2017;54:e75-e76.]. PMID- 29156060 TI - Three Cases of Associated Persistent Fetal Vasculature and Ocular Coloboma: Posterior Segment Dysgenesis. AB - The authors discuss the association of persistent fetal vasculature and ocular coloboma in three children. They explore the possibility of a cause-effect relationship between these disorders, and link them together as a broader posterior dysgenesis. [J Pediatr Ophthalmol Strabismus. 2017;54:e77-e80.]. PMID- 29156061 TI - Bilateral Superior Rectus Transposition With Bilateral Medial Rectus Recession for Mobius Syndrome. AB - Bilateral superior rectus transposition with bilateral medial rectus recession has been described successfully for treatment of Duane's syndrome but never for Mobius syndrome. The authors describe a child with Mobius syndrome who presented with large bilateral abduction deficits and esotropia. This surgical treatment resulted in marked improvement of said deficits. [J Pediatr Ophthalmol Strabismus. 2017;54:e81-e82.]. PMID- 29156062 TI - Surgical Technique for Pulled in Two Syndrome: Three Cases With Chronic Progressive External Ophthalmoplegia. AB - The authors describe three examples of "pulled in two syndrome" (PITS) from a series of 13 patients undergoing strabismus surgery with underlying chronic progressive external ophthalmoplegia (CPEO) and illustrate techniques for recovery of the "pulled in two" extraocular muscle should the complication arise. In all cases, a rectus muscle snapped under minimal tension while held on a strabismus hook during strabismus surgery. Two patients suffered from CPEO as a result of genetic mitochondrial disease, whereas one resulted from presumed mitochondrial toxicity induced by HAART. In cases 1 and 3, the proximal medial rectus segment was retrieved and reattached. In case 2, the fragmented superior rectus muscle was too friable to be reattached. All three patients were satisfied with the outcome, having reduced their angles of misalignment postoperatively. All three had improved cosmesis, and the two who had complained of diplopia preoperatively found their diplopia to be eliminated or improved. With anticipation of muscle friability in patients with previous extraocular surgery or degenerative muscle changes such as CPEO, the likelihood of the complication arising may be reduced. Should it occur, the loss of a snapped rectus muscle may be avoided through careful manipulation of the globe. [J Pediatr Ophthalmol Strabismus. 2017;54:e83-e87.]. PMID- 29156063 TI - Traumatic Ruptured Globe From a .22 Cartridge Casing in a 2-Year-Old Girl. AB - The authors report the case of a 2-year-old girl who presented with an acute ruptured globe secondary to penetration by the casing of a .22 caliber cartridge that was ignited by a car cigarette lighter. Although penetrating injuries are a common mechanism of ocular trauma, open globe induced by cartridge casing represents an unusual and preventable cause. [J Pediatr Ophthalmol Strabismus. 2017;54:e88-e90.]. PMID- 29156064 TI - Increasing Capacity for Family Care: A Research Opportunity. PMID- 29156065 TI - Examining Exercise in Older Adults Using the Theory of Planned Behavior and Temporal Discounting. AB - Exercise is one of the most important health behaviors to reduce and prevent the severity of many chronic diseases. The purpose of the current study was to determine if adding temporal discounting (TD) would affect the predictability of the Theory of Planned Behavior (TPB) in exercising among older adults. One hundred thirty-seven older adults were recruited from 11 churches in rural Arkansas using a cross-sectional design. Information regarding participants' exercise behavior, constructs of the TPB, TD rates, and demographics was collected. Path analysis was used to examine the relationships between and among each of the concepts of the TPB and TD. TD was not a significant predictor (p = 0.413) for exercise behavior after adjusting for intention. Adding TD to the existing TPB did not significantly affect the predictability of the model negatively or positively. [Res Gerontol Nurs. 2017; 10(6):252-259.]. PMID- 29156066 TI - Dehydration of Older Patients in Institutional Care and the Home Environment. AB - Dehydration in older adults is an important clinical problem associated with more comorbidities, longer hospital stays, and higher mortality rates. However, in daily clinical practice, no single gold standard marker of hydration status in older adults is available. The aim of the current study was to define the fluid balance status in older adults residing in institutional care or the home. Four hundred ten patients (192 from institutional care and 218 from home care) 65 and older from the region of lower Styria (Slovenia) were included in the study. Serum osmolality, electrolytes, and blood urea nitrogen to creatinine (BUN:Cr) ratio were used to identify dehydration. Statistically significant differences were found between groups in serum osmolality and BUN:Cr ratio. Moreover, dehydration (defined as increased serum osmolality) was significantly more common in patients in institutional care than home care (51% versus 41.3%, respectively). The results confirm that dehydration is a common clinical problem in older adults, especially in those from institutional care. Although many methods of determining hydration status in older adults have been proposed, no gold standard exists, making hydration evaluation difficult in this population. [Res Gerontol Nurs. 2017; 10(6):260-266.]. PMID- 29156067 TI - Pilot Testing a Coaching Intervention to Improve Certified Nursing Assistants' Dressing of Nursing Home Residents. AB - The purpose of the current study was to identify initial effects of a coaching training intervention using Level of Assistance (LoA) strategies compared with traditional lecture techniques on the appropriateness of LoA use by certified nursing assistants (CNAs) and independence of dressing of nursing home residents with dementia. Seventeen CNA-resident dyads participated in this pilot randomized controlled trial (RCT). Control and experimental group CNAs received a 25-minute traditional lecture. Experimental group CNAs also underwent three coaching sessions over 4 weeks. There were significant between-group differences in the percentage of dyads who had improved scores for appropriateness of LoA use and dressing independence from pretest to posttest (experimental: n = 9, 100%; control: n = 8, 50%; p = 0.029). However, there were no statistically significant median differences between groups in appropriateness of LoA use by CNAs and resident dressing independence scores. There were significant within-group median improvements in appropriateness of LoA use (p = 0.004) and independence of dressing scores (p = 0.004) between pretest and posttest in the experimental group, but not in the control group. This initial pilot RCT supports coach training as a method to improve appropriate use of LoA strategies by CNAs and independence of resident dressing. [Res Gerontol Nurs. 2017; 10(6):267-276.]. PMID- 29156068 TI - LMWF-5A for the Treatment of Severe Osteoarthritis of the Knee: Integrated Analysis of Safety and Efficacy. AB - The low-molecular-weight fraction of 5% human serum albumin (LMWF-5A) is being developed to treat the signs and symptoms of severe osteoarthritis of the knee. This study was a post hoc pooled analysis of 3 randomized placebo-controlled trials of a single intra-articular injection of LMWF-5A, focusing on the subset of patients with severe osteoarthritis of the knee (Kellgren-Lawrence grade 4). Patients were randomized 1:1 to receive a single 4-mL intra-articular knee injection of either LMWF-5A or saline. Safety was assessed as the incidence and severity of adverse events. Efficacy was assessed as the change from baseline to week 12 on the Western Ontario and McMaster Universities Osteoarthritis Index pain (primary outcome), stiffness, and physical function subscores and on patient global assessment scores and was presented as the least squares mean difference and 95% confidence interval. The proportion of responders was defined with the Outcome Measures in Rheumatology-Osteoarthritis Research Society International criteria for scenario D and examined with Pearson's chi-square test. For 417 patients with severe osteoarthritis of the knee, treatment with LMWF-5A resulted in a significant decrease in pain at 12 weeks compared with saline (mean difference, -0.19; 95% confidence interval, -0.34 to -0.04; P=.016), with improvements in function (mean difference, -0.15; 95% confidence interval, -0.31 to 0.01) and patient global assessment (mean difference, -0.30; 95% confidence interval, -0.49 to -0.12) and higher responder rates (64.25% vs 50.90%, P=.006). No drug-related serious adverse events and no deaths occurred, and the incidence and severity of adverse events were similar across treatment groups. This pooled analysis supports the use of LMWF-5A as a safe therapeutic agent for relief of the signs and symptoms of severe osteoarthritis of the knee. [Orthopedics. 2018; 41(1):e77-e83.]. PMID- 29156069 TI - The Role of Intraoperative Intermittent Pneumatic Compression Devices in Venous Thromboembolism Prophylaxis in Total Hip and Total Knee Arthroplasty. AB - Venous thromboembolism (VTE) is a common complication after total hip arthroplasty (THA) and total knee arthroplasty (TKA), occurring in up to 85% of patients who are not treated with prophylaxis. The initiation of VTE development may occur intraoperatively. This study investigated whether this gap in VTE prophylaxis can be addressed by the use of intraoperative intermittent pneumatic compression devices (IPCDs) and if intraoperative IPCDs have a meaningful benefit in preventing symptomatic VTE. The authors defined symptomatic VTE as deep venous thrombosis in either lower extremity or a pulmonary embolism. The authors evaluated the medical records of 3379 patients who underwent THA or TKA at their institution in 2014 and 2015. Effects of various factors, including age, sex, body mass index, and smoking status, were compared between these 2 cohorts. Patients who experienced a symptomatic VTE were also matched by age, sex, and procedure type with randomly selected controls. In the patient sample, 47 patients (1.4%) developed VTE. Forty (1.2%) of these patients underwent TKA, whereas 7 (0.2%) underwent THA. Venous thromboembolism occurred less frequently in patients who received intraoperative IPCDs (0.8%) than in patients who did not receive them (1.5%); however, this difference did not reach statistical significance. Total knee arthroplasty was associated with increased odds of VTE compared with THA, as was female sex. These results did not show a statistically significant benefit to the intraoperative use of IPCDs. Pneumatic compression remains a fast, easy, low-cost, low-risk, intuitive intervention that can supplement the postoperative multimodal approach and is worthy of further study. Intraoperative IPCD use should be considered for patients with a higher risk of VTE. [Orthopedics. 2018; 41(1):e98-e103.]. PMID- 29156070 TI - Medical Crowdfunding for Patients Undergoing Orthopedic Surgery. AB - Crowdfunding for medical expenses is growing in popularity. Through several websites, patients create public campaign profiles to which donors can contribute. Research on medical crowdfunding is limited, and there have been no studies of crowdfunding in orthopedics. Active medical crowdfunding campaigns for orthopedic trauma, total joint arthroplasty, and spine surgery were queried from a crowdfunding website. The characteristics and outcomes of crowdfunding campaigns were abstracted and analyzed. For this study, 444 campaigns were analyzed, raising a total of $1,443,528. Among the campaigns that received a donation, mean amount raised was $4414 (SE, $611). Multivariate analysis showed that campaigns with unspecified location (odds ratio, 0.26; P=.0008 vs West) and those for total joint arthroplasty (odds ratio, 0.35; P=.0003 vs trauma) had significantly lower odds of receipt of any donation. Description length was associated with higher odds of donation receipt (odds ratio, 1.13 per +100 characters; P<.0001). Among campaigns that received any donation, those with Southern location (-65.5%, P<.0001), international location (-68.5%, P=.0028), and unspecified location (-63.5%, P=.0039) raised lower amounts compared with campaigns in the West. Goal amount was associated with higher amount raised (+3.2% per +$1000, P<.0001). Resources obtained through crowdfunding may be disproportionately available to patients with specific diagnoses, those from specific regions, those who are able to craft a lengthy descriptive narrative, and those with access to robust digital social networks. Clinicians are likely to see a greater proportion of patients turning to crowdfunding as it grows in popularity. Patients may ask physicians for information about crowdfunding or request testimonials to support campaigns. Surgeons should consider their response to such requests individually. These findings shed light on the dynamics of medical crowdfunding and support robust personal and professional deliberation. [Orthopedics. 2018; 41(1):e58-e63.]. PMID- 29156071 TI - Arthroscopic Repair of Full-Thickness Rotator Cuff Tears in Active Patients Younger Than 40 Years: 2- to 5-Year Clinical Outcomes. AB - This study characterized injury patterns and reported clinical outcomes of all arthroscopic management of full-thickness rotator cuff tears among military patients younger than 40 years. A retrospective review was performed of prospective data for 42 patients younger than 40 years who underwent arthroscopic rotator cuff repair and, in some cases, concomitant labral repair. Preoperative and postoperative evaluations (minimum follow-up, 2 years; mean, 41 months; range, 24-66 months) included range of motion, visual analog scale (VAS) score, Subjective Shoulder Value (SSV), and American Shoulder and Elbow Surgeons (ASES) Shoulder Score. Of the patients, 97.6% (41 of 42) had improved VAS, SST, and ASES scores. Mean VAS score improved from 8.09+/-1.51 to 1.19+/-1.85 (P<.01). Mean SSV improved from 47.88+/-19.56 to 89.45+/-14.04 (P<.01). Mean ASES score improved from 38.97+/-12.70 to 89.88+/-14.26 (P<.01). No difference for VAS, SSV, and ASES scores was noted between (1) all 42 patients, (2) the 26 patients who had rotator cuff repair but not labral repair, and (3) the 16 patients who had both rotator cuff repair and labral repair. Complications (7.1%; 3 of 42) included 2 postoperatively frozen shoulders and 1 retear of the rotator cuff. Of the patients, 95.2% (40 of 42) returned to their preoperative level of recreational and military job activity. Military patients younger than 40 years who have a full-thickness rotator cuff tear have a high prevalence of concomitant shoulder injury, especially labral tear. For patients younger than 40 years, arthroscopic rotator cuff repair, with or without labral repair, resulted in excellent clinical outcomes, a low risk of complications, and a high rate of return to the preoperative level of recreational and military job activity. [Orthopedics. 2018; 41(1):e52-e57.]. PMID- 29156072 TI - Clinical and Radiologic Outcomes of Metatarsophalangeal Hemiarthroplasty: A Review of 12 Consecutive Cases. AB - This study examined function, pain, satisfaction, and radiologic outcomes among patients treated with first metatarsophalangeal hemiarthroplasty. Patients were invited to participate in an outcome study conducted with questionnaires on subjective and objective outcomes and clinical and radiographic follow-up. A total of 12 patients (12 feet; mean patient age, 58.8+/-12.3 years) agreed to participate. Mean follow-up was 22.3+/-19.8 months. Of these patients, 7 were satisfied with the postoperative result. The mean visual analog scale pain score decreased significantly from 7.0+/-2.3 preoperatively to 3.5+/-3.3 postoperatively (P=.024). Mean passive range of motion of the first metatarsophalangeal joint was 32 degrees +/-10 degrees preoperatively, 93 degrees +/-18 degrees intraoperatively after implantation of the prosthesis and closure of the joint capsule, and 38 degrees +/-19 degrees at final follow-up (P=.26). Mean American Orthopaedic Foot and Ankle Society forefoot score increased significantly from 47.3+/-14.7 preoperatively to 71.8+/-15.2 at last follow-up (P=.033). During the follow-up period, 6 patients underwent additional procedures: 5 therapeutic joint infiltrations and 1 arthrodesis. No patients had radiologic loosening of the implant at final follow-up. Osseous dysplastic changes at the base of the proximal phalanx were noted among 6 of 11 patients (12 total cases) at final follow-up. Although first metatarsophalangeal hemiarthroplasty provided significant pain reduction at mean follow-up of 22.3 months, range of motion of the first metatarsophalangeal joint was not restored to anticipated levels and there were high rates of patient dissatisfaction and secondary interventions. [Orthopedics. 2018; 41(1):e64-e69.]. PMID- 29156074 TI - Surgical Management of Brown Syndrome. PMID- 29156073 TI - Radiographic Underestimation of In Vivo Cup Coverage Provided by Total Hip Arthroplasty for Dysplasia. AB - The accuracy of using 2-dimensional anteroposterior pelvic radiography to assess acetabular cup coverage among patients with developmental dysplasia of the hip after total hip arthroplasty (THA) remains unclear in retrospective clinical studies. A group of 20 patients with developmental dysplasia of the hip (20 hips) underwent cementless THA. During surgery but after acetabular reconstruction, bone wax was pressed onto the uncovered surface of the acetabular cup. A surface model of the bone wax was generated with 3-dimensional scanning. The percentage of the acetabular cup that was covered by intact host acetabular bone in vivo was calculated with modeling software. Acetabular cup coverage also was determined from a postoperative supine anteroposterior pelvic radiograph. The height of the hip center (distance from the center of the femoral head perpendicular to the inter-teardrop line) also was determined from radiographs. Radiographic cup coverage was a mean of 6.93% (SD, 2.47%) lower than in vivo cup coverage for these 20 patients with developmental dysplasia of the hip (P<.001). However, both methods yielded highly correlated measurements for cup coverage (Pearson r=0.761, P<.001). The size of the acetabular cup (P=.001) but not the position of the hip center (high vs normal) was significantly associated with the difference between radiographic and in vivo cup coverage. Two-dimensional radiographically determined cup coverage conservatively reflects in vivo cup coverage and remains an important index (taking 7% underestimation errors and the effect of greater underestimation of larger cup size into account) for assessing the stability of the cup and monitoring for adequate ingrowth of bone. [Orthopedics. 2018; 41(1):e46-e51.]. PMID- 29156075 TI - "My Son Will Not Play Outside". PMID- 29156077 TI - Improving Resident Proficiency in Strabismus Surgery. PMID- 29156076 TI - Like an Old Married Couple. PMID- 29156078 TI - Correlation Between Clinical Examination and Diagnostic Imaging in Type II Peters Anomaly. PMID- 29156079 TI - The GARD platform for potency assessment of skin sensitizing chemicals. AB - Contact allergy induced by certain chemicals is a common health concern, and several alternative methods have been developed to fulfill the requirements of European legislation with regard to hazard assessment of potential skin sensitizers. However, validated methods, which provide information about the potency of skin sensitizers, are still lacking. The cell-based assay Genomic Allergen Rapid Detection (GARD), targeting key event 3, dendritic cell activation, of the skin sensitization AOP, uses gene expression profiling and a machine learning approach for the prediction of chemicals as sensitizers or non sensitizers. Based on the GARD platform, we here expanded the assay to predict three sensitizer potency classes according to the European Classification, Labelling and Packaging (CLP) Regulation, targeting categories 1A (strong), 1B (weak) and no cat (non-sensitizer). Using a random forest approach and 70 training samples, a potential biomarker signature of 52 transcripts was identified. The resulting model could predict an independent test set consisting of 18 chemicals, six from each CLP category and all previously unseen to the model, with an overall accuracy of 78%. Importantly, the model was shown to be conservative and only underestimated the class label of one chemical. Furthermore, an association of defined chemical protein reactivity with distinct biological pathways illustrates that our transcriptional approach can reveal information contributing to the understanding of underlying mechanisms in sensitization. PMID- 29156080 TI - Stereocontrolled Synthesis of Polypropionate Fragments based on a Building Block Assembly Strategy using Lithiation-Borylation Methodologies. AB - Polypropionates are important structural motifs in nature and are commonly made by iterative aldol or crotylation methodologies. Herein, an alternative strategy is presented in which stereochemically predefined building blocks, bearing appropriate functionality, are coupled together using a lithiation-borylation methodology with complete stereocontrol. The building blocks comprise lithiated carbamates acting as donors, and boronic esters acting as acceptors. The acceptor building blocks contain beta-hydroxyl groups masked as silyl groups to avoid elimination of the boronate intermediates. Subsequent oxidation of both the boron and silyl moieties can then deliver an array of polypropionate fragments with full stereochemical control, including the synthetically challenging anti-anti isomers. PMID- 29156081 TI - Cervical HPV prevalence and genotype distribution in immunosuppressed Danish women. AB - INTRODUCTION: Women receiving immunosuppressive treatment due to organ transplantation are at increased risk of Human papilloma virus (HPV)-related diseases, including cervical neoplasia. This pilot study aimed to describe the cervical HPV prevalence and genotype distribution in immunosuppressed Danish women. MATERIAL AND METHODS: We included women who underwent renal (RTR) or bone marrow transplantation (BMTR) in 2009-2012 or 2014 at Aarhus University Hospital, Denmark. Women undergoing transplantation in 2009-2012 had one cervical cytology performed, whereas women undergoing transplantation in 2014 had three, one before and two after transplantation. The samples were examined for cytological abnormalities and tested for HPV using Cobas(r) HPV Test and CLART(r) HPV2 Test. RESULTS: Of 94 eligible cases we included 60 RTR and BMTR. The overall prevalence of high-risk HPV was 15.0 [95% confidence interval (CI) 7.1-26.6] and the prevalence was higher among BMTR (29.4; 95% CI 10.3-56.0) than RTR (9.3%, 95% CI 2.6-22.1), although this was not statistically significant (p = 0.10). The distribution of high-risk HPV was broad, with HPV 45 as the most common genotype (3.3%). The prevalences of high-risk HPV types included in the bivalent/quadrivalent and the nonavalent vaccines were 1.7 and 8.3%, respectively. The prevalence of low-grade and high-grade cytological abnormalities was 6.7 and 5.0%, respectively. CONCLUSIONS: Immunosuppressed women were infected with a broad range of high-risk HPV genotypes and the prevalence of cytological abnormalities was higher than found in previous studies of the general population. The nonavalent HPV vaccine will offer immunosuppressed individuals a greater protection against HPV-related diseases compared with the bivalent/quadrivalent HPV vaccines. PMID- 29156082 TI - An unexpected but underestimated case of disseminated toxoplasmosis. AB - Toxoplasma gondii is a ubiquitous intracellular parasite that can cause disseminated infection following reactivation in immunocompromised hosts. We describe a 58-year-old man who died of refractory shock because of disseminated toxoplasmosis. The diagnosis was only made postmortem on autopsy. We discuss the importance of considering toxoplasmosis on the differential diagnosis in high risk patients, and review the role of screening and chemoprophylaxis in preventing infection. PMID- 29156084 TI - Role of Charge and Hydrophobicity in Liprotide Formation: A Molecular Dynamics Study with Experimental Constraints. AB - Bovine alpha-lactalbumin (aLA) and oleate (OA) form a complex that has been intensively studied for its tumoricidal activity. Small-angle X-ray scattering (SAXS) has revealed that this complex consists of a lipid core surrounded by partially unfolded protein. We call this type of complex a liprotide. Little is known of the molecular interactions between OA and aLA, and no technique has so far provided any high-resolution structure of a liprotide. Here we have used coarse-grained (CG) molecular dynamics (MD) simulations, isothermal titration calorimetry (ITC) and SAXS to investigate the interactions between aLA and OA during the process of liprotide formation. With ITC we found that the strongest enthalpic interactions occurred at a molar ratio of 12.0+/-1.4:1 OA/aLA. Liprotides formed between OA and aLA at several OA/aLA ratios in silico were stable both in CG and in all-atom simulations. From the simulated structures we calculated SAXS spectra that show good agreement with experimentally measured patterns of matching liprotides. The simulations showed that aLA assumes a molten globular (MG) state, exposing several hydrophobic patches involved in interactions with OA. Initial binding of aLA to OA occurs in an area of aLA in which a high amount of positive charge is located, and only later do hydrophobic interactions become important. The results reveal how unfolding of aLA to expose hydrophobic residues is important for complex formation between aLA and OA. Our findings suggest a general mechanism for liprotide formation and might explain the ability of a large number of proteins to form liprotides with OA. PMID- 29156083 TI - Toward ecologically realistic predictions of species distributions: A cross-time example from tropical montane cloud forests. AB - There is an urgent need for more ecologically realistic models for better predicting the effects of climate change on species' potential geographic distributions. Here we build ecological niche models using MAXENT and test whether selecting predictor variables based on biological knowledge and selecting ecologically realistic response curves can improve cross-time distributional predictions. We also evaluate how the method chosen for extrapolation into nonanalog conditions affects the prediction. We do so by estimating the potential distribution of a montane shrew (Mammalia, Soricidae, Cryptotis mexicanus) at present and the Last Glacial Maximum (LGM). Because it is tightly associated with cloud forests (with climatically determined upper and lower limits) whose distributional shifts are well characterized, this species provides clear expectations of plausible vs. implausible results. Response curves for the MAXENT model made using variables selected via biological justification were ecologically more realistic compared with those of the model made using many potential predictors. This strategy also led to much more plausible geographic predictions for upper and lower elevational limits of the species both for the present and during the LGM. By inspecting the modeled response curves, we also determined the most appropriate way to extrapolate into nonanalog environments, a previously overlooked factor in studies involving model transfer. This study provides intuitive context for recommendations that should promote more realistic ecological niche models for transfer across space and time. PMID- 29156085 TI - The association between burning mouth syndrome and sleep disturbance: A case control multicentre study. AB - OBJECTIVES: To investigate the quality of sleep and the psychological profiles of a large cohort of Italian patients with burning mouth syndrome (BMS) and to clarify the relationships between these variables and pain. METHODS: In this case control study, 200 patients with BMS vs an equal number of age- and sex-matched healthy controls, recruited in 10 universities, were enrolled. The Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), Numeric Pain Intensity Scale (NRS) and Total Pain Rating Index (T-PRI) were administered. Descriptive statistics, including the Mann-Whitney U test and hierarchical multiple linear regression analysis, were used. RESULTS: Poor sleep quality (PSQI >= 5) was present in 78.8% (160) patients with BMS. BMS patients had statistically higher scores in all items of the PSQI and ESS than the healthy controls (p < .001). A depressed mood and anxiety correlated positively with sleep disturbance. The Pearson correlations were 0.570 for the PSQI vs HAM-D (p < .001) and 0.549 for the PSQI vs HAM-A (p < .001). Pain intensity (NRS) poorly correlated to sleep quality; the Pearson correlation was 0.162 for the PSQI vs NRS (p = .021). CONCLUSIONS: The BMS patients showed a poor sleep quality, anxiety and depression, as compared with the controls, highlighting the relationships between oral burning, sleep and mood. PMID- 29156086 TI - Impact of low-level BK polyomavirus viremia on intermediate-term renal allograft function. AB - BACKGROUND: BK polyomavirus (BKPyV)-associated nephropathy (PyVAN) is a significant cause of premature renal transplant failure. High-level BKPyV viremia is predictive for PyVAN; however, low-level BKPyV viremia does not necessarily exclude the presence of PyVAN. As data are limited regarding whether or not low level BKPyV viremia has an effect on intermediate-term graft outcome, this study analyzes the impact of low-level BKPyV viremia on intermediate-term graft function and outcome compared with high-level viremia and non-viremic patients. METHODS: All renal transplant patients received follow-up examinations at the Department of Nephrology, University Hospital Essen. Patients were screened for BKPyV viremia and stratified into three groups according to their maximum BKPyV load in serum (low-level viremia, high-level viremia, and no viremia). RESULTS: In 142 of 213 (67%) patients, BKPyV was never detected in serum; 42 of 213 (20%) patients were found positive for low-level viremia (<=104 copies/mL); and 29 of 213 (13%) patients showed high-level viremia (>104 copies/mL). No significant differences regarding transplant function and graft failure were observed between patients without BKPyV viremia (delta estimated glomerular filtration rate [eGFR] +0.1 mL/min [month 1 vs last visit at month 44]) and patients with low-level BKPyV viremia (delta eGFR -1.7 mL/min). In patients with high-level viremia, transplant function was significantly restricted (delta eGFR -6.5 mL/min) compared with low-level viremia until the last visit at 44 +/- 9.7 months after transplantation. Although the graft function and graft loss were worse in the high-level viremia group compared with no viremia (eGFR 37 vs 45 mL/min), the difference was not significant. CONCLUSIONS: High-level viremia was associated with impaired graft function. In contrast, low-level BKPyV viremia had no significant impact on intermediate-term graft function. PMID- 29156087 TI - Fundamental nursing care: A systematic review of the evidence on the effect of nursing care interventions for nutrition, elimination, mobility and hygiene. AB - AIMS AND OBJECTIVES: To determine the effects of nursing interventions for people's nutrition, elimination, mobility and hygiene needs. BACKGROUND: Patient experience of health care is sensitive to nursing quality. A refocus on fundamental nursing care is undermined by lack of evidence of effectiveness for interventions in core areas such as elimination, nutrition, mobility and hygiene. DESIGN: Systematic review. METHODS: We searched for and included experimental studies on interventions by professionally qualified and unregistered nurses that addressed participants' nutrition, elimination, mobility and hygiene needs. We extracted data on scope, quality and results of studies followed by descriptive narrative synthesis of included study outcomes using a novel form of harvest plots. RESULTS: We included 149 studies, 35 nutrition, 56 elimination, 16 mobility, 39 hygiene and three addressing two or more areas simultaneously (67 randomised controlled trials, 32 non-randomised controlled trials and 50 uncontrolled trials). Studies into interventions on participant self-management of nutrition (n = 25), oral health (n = 26), catheter care (n = 23) and self management of elimination (n = 21) were the most prevalent. Most studies focussed their outcomes on observational or physiological measures, with very few collecting patient-reported outcomes, such as quality of life, experience or self reported symptoms. All but 13 studies were of low quality and at significant risk of bias. The majority of studies did not define primary outcomes, included multiple measures of identical concepts, used inappropriate analyses and did not conform to standard reporting quality criteria. CONCLUSIONS: The current evidence for fundamental nursing care interventions is sparse, of poor quality and unfit to provide evidence-based guidance to practising nurses. RELEVANCE TO CLINICAL PRACTICE: Researchers in nursing internationally should now undertake a programme of work to produce evidence for clinical practice in the fundamentals of care that is reliable, replicable and robust. PMID- 29156088 TI - Climate-mediated changes in marine ecosystem regulation during El Nino. AB - The degree to which ecosystems are regulated through bottom-up, top-down, or direct physical processes represents a long-standing issue in ecology, with important consequences for resource management and conservation. In marine ecosystems, the role of bottom-up and top-down forcing has been shown to vary over spatio-temporal scales, often linked to highly variable and heterogeneously distributed environmental conditions. Ecosystem dynamics in the Northeast Pacific have been suggested to be predominately bottom-up regulated. However, it remains unknown to what extent top-down regulation occurs, or whether the relative importance of bottom-up and top-down forcing may shift in response to climate change. In this study, we investigate the effects and relative importance of bottom-up, top-down, and physical forcing during changing climate conditions on ecosystem regulation in the Southern California Current System (SCCS) using a generalized food web model. This statistical approach is based on nonlinear threshold models and a long-term data set (~60 years) covering multiple trophic levels from phytoplankton to predatory fish. We found bottom-up control to be the primary mode of ecosystem regulation. However, our results also demonstrate an alternative mode of regulation represented by interacting bottom-up and top-down forcing, analogous to wasp-waist dynamics, but occurring across multiple trophic levels and only during periods of reduced bottom-up forcing (i.e., weak upwelling, low nutrient concentrations, and primary production). The shifts in ecosystem regulation are caused by changes in ocean-atmosphere forcing and triggered by highly variable climate conditions associated with El Nino. Furthermore, we show that biota respond differently to major El Nino events during positive or negative phases of the Pacific Decadal Oscillation (PDO), as well as highlight potential concerns for marine and fisheries management by demonstrating increased sensitivity of pelagic fish to exploitation during El Nino. PMID- 29156089 TI - Assessing the geographic dichotomy hypothesis with cacti in South America. AB - The Cactaceae is one of the most conspicuous and ecologically important plant families in the world. Its species may have specialist or generalist pollination systems that show geographic patterns, which are synthesised in the Geographic Dichotomy Hypothesis. Here, we assess this hypothesis in five countries in both tropical and extratropical regions, evaluating the pollinator visitation rate and pollinator identity and abundance. We calculate the Shannon diversity index (H') and evenness (J) and evaluate differences between latitude parameters with a Student t-test. Overall, we found more specialised pollination systems in all tropical sites; the richness, diversity and evenness of pollinators was reduced in comparison to extratropical regions, where the pollination system was generalised. Our results support the geographic dichotomy hypothesis in the cacti of South America, suggesting that environmental factors underlying the latitudinal patterns can help to explain differences in the pollination syndrome between tropical and extratropical regions. PMID- 29156090 TI - A case-control study: The association of serum paraoxonase 1 activity and concentration with the development of type 2 diabetes mellitus. AB - BACKGROUND: A longitudinal study assessed serum paraoxonase 1 (PON1) activity and concentration as affected by age and as associated with the development of type 2 diabetes (T2D). PON1's recently established physiological function is the hydrolysis of lipolactones in oxidized LDL particles. METHODS: Serum samples and clinical data collected and stored at different time points over a 20-year interval in the Air Force Health Study were analysed. PON1 activity and concentration and C-reactive protein concentration in samples from the same individuals 20 years apart were compared using a paired t test (n = 159). A case control study design and multivariable logistic regression analysis assessed the association of PON1's activity and concentration with the subsequent development of T2D (n = 222 and alpha = 0.10). RESULTS: No difference with age was found in PON1 activity assessed using 3 substrates, paraoxon (P = 0.897), phenyl acetate (P = 0.994), and dihydrocoumarin (P = 0.505), or PON1 serum concentration (P = 0.357). C-reactive protein concentration increased 0.7 mg/L (P = 0.004) over the 20-year interval. Lower PON1 activity assayed with phenyl acetate (P = 0.015, OR = 1.25 per 1000 U/L decrease) was associated with an increased risk of developing T2D as was a lower PON1 serum concentration (P = 0.004, OR = 1.72 per 2 MUmol/L decrease). PON1 activity assayed with paraoxon (P = 0.681) or dihydrocoumarin (P = 0.136) was not associated with the development of T2D. CONCLUSIONS: Lower PON1 activity and concentration were associated with an increased risk of developing T2D when adjusted for many of the common risk markers for T2D previously identified. Thus, PON1 may have merit as a biomarker for the development of T2D. PMID- 29156091 TI - Multifarious anchovy and sardine regimes in the Humboldt Current System during the last 150 years. AB - The Humboldt Current System (HCS) has the highest production of forage fish in the world, although it is highly variable and the future of the primary component, anchovy, is uncertain in the context of global warming. Paradigms based on late 20th century observations suggest that large-scale forcing controls decadal-scale fluctuations of anchovy and sardine across different boundary currents of the Pacific. We develop records of anchovy and sardine fluctuations since 1860 AD using fish scales from multiple sites containing laminated sediments and compare them with Pacific basin-scale and regional indices of ocean climate variability. Our records reveal two main anchovy and sardine phases with a timescale that is not consistent with previously proposed periodicities. Rather, the regime shifts in the HCS are related to 3D habitat changes driven by changes in upwelling intensity from both regional and large-scale forcing. Moreover, we show that a long-term increase in coastal upwelling translates via a bottom-up mechanism to top predators suggesting that the warming climate, at least up to the start of the 21st century, was favorable for fishery productivity in the HCS. PMID- 29156092 TI - Gingival cyst of the adult, lateral periodontal cyst, and botryoid odontogenic cyst: An updated systematic review. AB - The aim of the present review was to integrate the available data published on gingival cyst of the adult (GCA), lateral periodontal cyst (LPC), and botryoid odontogenic cyst (BOC) into a comprehensive analysis of their clinical/radiological features. An electronic search was undertaken in July/2017. Eligibility criteria included publications having enough clinical/radiological/histological information to confirm the diagnosis. A total of 146 publications (157 GCAs, 213 LPCs, 96 BOCs) were included. GCA and LPC presented highest prevalence in the sixth/fifth decades; BOC in the sixth/seventh decades. LPCs were larger lesions than GCAs and GCAs appeared at an older age than LPC. There was no statistically significant difference between them for other factors (location, symptoms, recurrence, follow-up time). In comparison with LPC, BOC lesions were larger, appeared more often in mandible and in older subjects, had more often a multilocular appearance, and presented a higher recurrence rate. Recurrence rates: GCA (3.2%), LPC (2.4%), BOC (21.7%). No factor seems to influence the recurrence rate of GCA or LPC. Multilocular radiological appearance seems to affect the recurrence rate of BOCs. Conservative surgical approaches seem to be enough for GCA/LPC. BOC presents a more aggressive behavior than GCA/LPC. Therefore, treatment of this lesion might involve some kind of adjunctive therapy after enucleation. PMID- 29156093 TI - Functional and molecular outcomes of the human masticatory muscles. AB - The masticatory muscles achieve a broad range of different activities such as chewing, sucking, swallowing, and speech. In order to accomplish these duties, masticatory muscles have a unique and heterogeneous structure and fiber composition, enabling them to produce their strength and contraction speed largely dependent on their motor units and myosin proteins that can change in response to genetic and environmental factors. Human masticatory muscles express unique myosin isoforms, including a combination of thick fibers, expressing myosin light chains (MyLC) and myosin class I and II heavy chains (MyHC) -IIA, IIX, alpha-cardiac, embryonic and neonatal and thin fibers, respectively. In this review, we discuss the current knowledge regarding the importance of fiber-type diversity in masticatory muscles versus supra- and infrahyoid muscles, and versus limb and trunk muscles. We also highlight new information regarding the adaptive response and specific genetic variations of muscle fibers on the functional significance of the masticatory muscles, which influences craniofacial characteristics, malocclusions, or asymmetry. These findings may offer future possibilities for the prevention of craniofacial growth disturbances. PMID- 29156094 TI - Multiple transmissions of chromosomally integrated human herpesvirus-6 in one family. AB - Chromosomally integrated human herpesvirus-6 (ciHHV-6) can be transmitted from parent to child or via allogeneic hematopoietic cell transplantation (HCT). We report a case of ciHHV-6 transmitted via syngeneic HCT, and vertically across 3 generations. ciHHV-6 was transmitted from a parent to the patient and her identical twin, and from the patient to her son. The patient underwent syngeneic HCT as rescue from chemotherapy-induced aplasia during which ciHHV-6 was re transmitted to her, this time from her identical twin. This is the first report, to our knowledge, of a patient acquiring ciHHV-6 once via germline from a parent and again via syngeneic HCT from an identical twin. PMID- 29156096 TI - Males that drop a sexually selected weapon grow larger testes. AB - Costly sexually selected weapons are predicted to trade off with postcopulatory traits, such as testes. Although weapons can be important for achieving access to females, individuals of some species can permanently drop (i.e. autotomize) their weapons, without regeneration, to escape danger. We capitalized on this natural behavior to experimentally address whether the loss of a sexually selected weapon leads to increased testes investment in the leaf-footed cactus bug, Narnia femorata Stal (Hemiptera: Coreidae). In a second experiment, we measured offspring production for males that lost a weapon during development. As predicted, males that dropped a hind limb during development grew significantly larger testes than the control treatments. Hind-limb autotomy did not result in the enlargement of other nearby traits. Our results are the first to experimentally demonstrate that males compensate for natural weapon loss by investing more in testes. In a second experiment we found that females paired with males that lost a hind limb had 40% lower egg hatching success than females paired with intact males, perhaps because of lower mating receptivity to males with a lost limb. Importantly, in those cases where viable offspring were produced, males missing a hind limb produced 42% more offspring than males with intact limbs. These results suggest that the loss of a hind-limb weapon can, in some cases, lead to greater fertilization success. PMID- 29156095 TI - Multiple role of 3-mercaptopyruvate sulfurtransferase: antioxidative function, H2 S and polysulfide production and possible SOx production. AB - Rat 3-mercaptopyruvate sulfurtransferase (MPST) is a 32 808 Da simple protein. Cys247 is a catalytic site, and Cys154 and Cys263 are on the enzyme surface. MPST is found in all tissues, particularly in the kidneys, although the localization of its activity differs in each tissue. In this review, four functions of MPST are reviewed: (i) antioxidative function: Cys247 is redox-sensitive and serves as a redox-sensing switch. It is oxidized to cysteine sulfenate, which has a low redox potential, upon which the enzyme is inactivated. Then, reduced thioredoxin (Trx) with a reducing system (Trx reductase and NADPH) reduces the sulfenate to restore activity; meanwhile, Cys154 and Cys263 form an intermolecular disulfide bond, which serves as another redox-sensing switch. Consequently, Trx specifically cleaves the intermolecular disulfide bond by converting it from the inactive form (dimer) to the active form (monomer). (ii) Hydrogen sulfide and polysulfide production: hydrogen sulfide is produced via reduction of the persulfurated sulfur-acceptor substrate by reduced Trx or Trx with a reducing system; as an alternative process, stable polysulfurated or persulfurated Cys247 as a reaction intermediate is reduced by Trx with a reducing system to release hydrogen sulfide and polysulfides. (iii) Possible sulfur oxide production: sulfur oxides (SO, SO2 and SO3 ) can be produced in the redox cycle of sulfane sulfur formed at the catalytic site Cys247 (Cys-SO- , Cys-SO2- and Cys-SO3- ) as reaction intermediates and released by reduced Trx or Trx with a reducing system. (iv) Possible anxiolytic-like effects: MPST-knockout mice exhibited anxiolytic like effects. PMID- 29156097 TI - 4-Aminopyridine: a pan voltage-gated potassium channel inhibitor that enhances Kv 7.4 currents and inhibits noradrenaline-mediated contraction of rat mesenteric small arteries. AB - BACKGROUND AND PURPOSE: Kv 7.4 and Kv 7.5 channels are regulators of vascular tone. 4-Aminopyridine (4-AP) is considered a broad inhibitor of voltage-gated potassium (KV ) channels, with little inhibitory effect on Kv 7 family members at mmol concentrations. However, the effect of 4-AP on Kv 7 channels has not been systematically studied. The aim of this study was to investigate the pharmacological activity of 4-AP on Kv 7.4 and Kv 7.5 channels and characterize the effect of 4-AP on rat resistance arteries. EXPERIMENTAL APPROACH: Voltage clamp experiments were performed on Xenopus laevis oocytes injected with cRNA encoding KCNQ4 or KCNQ5, HEK cells expressing Kv 7.4 channels and on rat, freshly isolated mesenteric artery smooth muscle cells. The effect of 4-AP on tension, membrane potential, intracellular calcium and pH was assessed in rat mesenteric artery segments. KEY RESULTS: 4-AP increased the Kv 7.4-mediated current in oocytes and HEK cells but did not affect Kv 7.5 current. 4-AP also enhanced native mesenteric artery myocyte K+ current at sub-mmol concentrations. When applied to NA-preconstricted mesenteric artery segments, 4-AP hyperpolarized the membrane, decreased [Ca2+ ]i and caused concentration-dependent relaxations that were independent of 4-AP-mediated changes in intracellular pH. Application of the Kv 7 channel blocker XE991 and BKCa channel blocker iberiotoxin attenuated 4-AP mediated relaxation. 4-AP also inhibited the NA-mediated signal transduction to elicit a relaxation. CONCLUSIONS AND IMPLICATIONS: These data show that 4-AP is able to relax NA-preconstricted rat mesenteric arteries by enhancing the activity of Kv 7.4 and BKCa channels and attenuating NA-mediated signalling. PMID- 29156098 TI - Technical Note: Penumbral width trimming in solid lung dose profiles for 0.9 and 1.5 T MRI-Linac prototypes. AB - PURPOSE: Longitudinal magnetic fields narrow beam penumbra and tighten lateral spread of secondary electrons in air cavities, including lung tissue. Gafchromic(r) EBT3 film was used to investigate differences between penumbra in solid water and solid lung, without a magnetic field (0 T) and with two field strengths (0.9 and 1.5 T). METHODS: The first prototype of the Australian MRI linac consisted of a 1.5 T Siemens Sonata MRI and Varian industrial linatron (nominal 4 MV). The second prototype replaced the Sonata with a 1.0 T Agilent split-bore magnet. Measurements were completed at 0.9 T to maintain the same source-to-surface distance between set-ups. Gammex-rmi(r) solid water with 50 mm of CIRS solid lung inserted as a lung cavity was positioned inside each magnet. This was compared to the same set-up with solid water only, where film measurements were completed at solid water equivalent depths corresponding to entrance interface/mid/exit interface positions of solid lung from the first set up. Multileaf collimator (MLC)-defined field sizes were set to 3 * 3 cm2 and 10 * 10 cm2 . The 80%-20% penumbral width was determined. RESULTS: Under 1.5 T conditions, penumbra narrowing occurred up to 4.4 +/- 0.1 mm compared to 0 T. As expected, the effect was less for 0.9 T, which resulted in a maximum narrowing of 2.5 +/- 0.1 mm. Exit profile penumbra were more affected than entrance penumbra by up to 2.6 +/- 0.2 mm. The 1.5 T field brought the solid water and lung penumbral widths more into alignment by a maximum difference of 0.4 +/- 0.1 mm. CONCLUSIONS: The trimming of penumbral widths due to magnetic fields in solid water and lung was demonstrated and compared to 0 T. The 0.9 and 1.5 T field trimmed the penumbra by up to 2.5 +/- 0.1 mm and 4.4 +/- 0.1 mm respectively. PMID- 29156099 TI - Mammalian Atg9 contributes to the post-Golgi transport of lysosomal hydrolases by interacting with adaptor protein-1. AB - Accumulating evidence has indicated a role for autophagy-related (Atgs) proteins in cell regulation which is independent of their autophagic activities. As the only known transmembrane protein essential for autophagy, Atg9 cycles between the trans-Golgi network (TGN) and endosomes. Here, we report a function for mammalian Atg9 (mAtg9) in the transport of lysosomal hydrolases which impacts the lysosomal degradation capacity. Depletion of mAtg9 inhibits the degradation of epidermal growth factor receptor and the maturation of cathepsin D and cathepsin L. mAtg9 interacts with adaptor protein-1 (AP1) and the cation-independent mannose-6 phosphate receptor, facilitating AP1 polymerization and the transport of cathepsin D from the TGN. These results suggest that mAtg9 may serve as a coreceptor of lysosomal hydrolases for their TGN export by cycling between the TGN and endosomes. PMID- 29156100 TI - Doctoral training in clinical psychology across 23 years: Continuity and change. AB - OBJECTIVE: Doctoral training in clinical psychology has undergone substantial changes in recent decades, especially with the increasing heterogeneity of training models and graduate students. To document these changes, we analyzed program, student, and faculty characteristics of American Psychological Association (APA)-accredited clinical psychology programs over a 23-year span. METHOD: We surveyed directors of clinical training about their doctoral programs every 2 years from 1991 to 2013, securing 90%-98% response rates. With minimal exceptions, the survey questions remained constant. RESULTS: Percentages of female and racial/ethnic minority students continued to grow, such that women now comprise about three quarters of trainees and ethnic minorities about one quarter. There has been a decisive shift in faculty theoretical orientation toward cognitive/cognitive-behavioral and away from psychodynamic/psychoanalytic. Internship match rates were relatively high and stable until the early 2010s but have recently rebounded. CONCLUSION: We discuss the limitations of these survey results and their implications for the future of doctoral training in clinical psychology. PMID- 29156101 TI - Primary extra-axial, para-articular chordoma of the knee. A case report and the review of literature. PMID- 29156104 TI - Correction. PMID- 29156102 TI - Decreasing trends in number of depot medroxyprogesterone acetate starters in Norway - a cross-sectional study. AB - INTRODUCTION: In this study, we examined changes in depot medroxyprogesterone acetate (DMPA) prescriptions over a time-period when new professions started prescribing, and when the method gained some negative media attention. MATERIAL AND METHODS: The Norwegian Prescription Database provided data on hormonal contraception from 2006 through 2012. We estimated the annual number of DMPA users by calculating doses sold per day/1000 women and calculated, for each contraceptive method on annual basis, a proportion of defined daily doses of all hormonal contraceptives in five-year age groups at reproductive age. All analyses were done in SPSS, version 22, with Chi-square test, t-test, and survival analysis with p < 0.05 as significance level. RESULTS: There were minor differences in overall DMPA use during the study years. The take-out rate was equivalent to 11-12/1000 women aged 15-49 years. DMPA sales amounted to nearly 4% of all daily doses of hormonal contraceptives sold. General practitioners and physicians without a specialty were the major prescribers. The number of starters decreased by nearly 40% during the study years and was consistent across age groups. The average use duration among starters was 17.7 (95% CI 17.5-17.9) months (range 0-90). There were minor changes in the relative proportion of long term users beyond 24 months during the study years. CONCLUSIONS: DMPA plays a minor role in the overall use of hormonal contraception in Norway, even among teenagers. The number of starters is decreasing, indicating a more restrictive attitude toward first use, especially among general practitioners. PMID- 29156108 TI - Optimizing quality of dental carving by preclinical dental students through anatomy theory reinforcement. AB - Knowledge of dental anatomy is of great importance in the practice of dentistry, especially in oral rehabilitation, because without this knowledge, professional practice is not possible. Dental carving plays a major role in training dental students as it develops their manual dexterity. This randomized controlled trial aimed to evaluate the influence of didactic-theoretical reinforcement on the theoretical and practical knowledge of dental anatomy of preclinical students by examining the quality of the anatomical restorations performed by these students before and after a didactic-theoretical reinforcement. For the evaluation of theoretical knowledge, a questionnaire with closed questions about dental anatomy was used. To evaluate the effect of didactic reinforcement on dental carvings, two groups of 15 preclinical students were assessed. Experimental group (G1) received a three-hour theoretical tutoring on dental anatomy, while the control group (G2) did not. The dental carving scores obtained by the two different groups were compared using Student's t-test. Cohen's d was used to estimate the effect sizes between groups. The frequency of correct answers given for each theoretical knowledge question was compared in each group using Fisher's exact test. T-test was also used to compare the means of the two groups' final scores of theoretical evaluations. To compare these final scores obtained in both carving and theoretical tests, a principal component analysis was performed with different items assessed in each test to obtain factor loading scores and a final weighted score, where factor loadings were considered for each item. Weighted scores were compared using t-test. Also, scores obtained during the head and neck course were assessed and compared using t-test. Spearman's correlation test was used to assess the correlation between scores obtained prior to the anatomy course and scores obtained in the dental carving exercise. The theoretical evaluation revealed no significant difference between the grades (mean +/- SD) of G1 (85.1 +/- 6.6%) and G2 (86.2 +/- 9.1%) with the grades of a baseline test that was previously obtained when students submitted to the study (P = 0.725). Regarding the tooth carving assessment, the dental carving quality by students of G1 has significantly improved, except for tooth #23 (P = 0.096). Theoretical reinforcement of dental anatomy seems to improve the students' carving performance but does not enhance their knowledge about dental anatomy. Anat Sci Educ 11: 377-384. (c) 2017 American Association of Anatomists. PMID- 29156107 TI - Hemodynamic force triggers rapid NETosis within sterile thrombotic occlusions. AB - : Essentials Neutrophil extracellular traps (NETs) are generated during thrombosis and sepsis. The effect of hemodynamics on NETosis during sterile thrombosis was studied using microfluidics. Pressure gradients > 70 mmHg per mm clot across sterile occlusions drive shear-induced NETosis. High interstitial hemodynamic forces trigger rapid NET release. SUMMARY: Background Neutrophil extracellular traps (NETs) are released when neutrophils encounter infectious pathogens, especially during sepsis. Additionally, NETosis occurs during venous and arterial thrombosis, disseminated intravascular coagulation, and trauma. Objective To determine whether hemodynamic forces trigger NETosis during sterile thrombosis. Methods NETs were imaged with Sytox Green during microfluidic perfusion of activated factor XII-inhibited or thrombin-inhibited human whole blood over fibrillar collagen (with or without tissue factor). Results For perfusions at initial inlet venous or arterial wall shear rates (100 s-1 or 1000 s-1 ), platelets rapidly accumulated and occluded microchannels with subsequent neutrophil infiltration under either flow condition; however, NETosis was detected only in the arterial condition. The level of shear-induced NETs (SINs) at 30 min was > 150-fold higher in the arterial condition in the absence of thrombin and > 80-fold greater in the presence of thrombin than the level in the venous condition. With or without thrombin, venous perfusion for 15 min generated no NETs, but an abrupt shift-up to arterial perfusion triggered NETosis within 2 min, NETs eventually reaching levels 15 min later that were 60-fold greater than that in microchannels without perfusion shift-up. SINs contained citrullinated histone H3 and myeloperoxidase, and were DNase-sensitive, but were not blocked by inhibitors of platelet-neutrophil adhesion, high-mobility group protein box 1 receptor for advanced glycation end products interaction, cyclooxygenase, ATP/ADP, or peptidylarginine deiminase 4. For measured pressure gradients exceeding 70 mmHg per millimeter of clot across NET-generating occlusions to drive interstitial flow, the calculated fluid shear stress on neutrophils exceeded the known lytic value of 150 dyne cm-2 . Conclusions High interstitial hemodynamic forces can drive physically entrapped neutrophils to rapidly release NETs during sterile occlusive thrombosis. PMID- 29156110 TI - Editor's Notes. PMID- 29156109 TI - A microfabricated 96-well wound-healing assay. AB - This article presents a microfabricated 96-well wound-healing assay enabling high throughput measurement of cellular migration capabilities. Within each well, the middle area is the wound region, made of microfabricated gold surface with self assembled PEG repellent for cell seeding. After the formation of a cellular confluent monolayer around the wound region, collagen solution was applied to form three-dimensional matrix to cover the PEG surface, initiating the wound healing process. By interpreting the numbers of migrated cells into the wound regions as a function of specific stimuli with different concentrations, EC50 (half-maximal effective concentration) was obtained. Using H1299 as a model, values of EC50 were quantified as 8% and 160 ng/ml for fetal bovine serum and CXCL12, respectively. In addition, the values of EC50 were demonstrated not to be affected by variations in compositions of extracellular matrix and geometries of wounds, which can thus be regarded as an intrinsic marker. Furthermore, the migration capabilities of a second cell type (HeLa) were characterized by the developed wound-healing assay, producing EC50 of 2% when fetal bovine serum was used as the stimuli. These results validated the proposed high-throughput wound healing assay, which may function as an enabling tool in studying cellular capabilities of migration and invasion. (c) 2017 International Society for Advancement of Cytometry. PMID- 29156111 TI - Utilizing Gamification to Foster Leadership Competency Development. AB - This chapter introduces gamification and a model for utilizing game design elements for leadership competency development. PMID- 29156112 TI - Using Leadership Competencies to Develop Talents into Strengths. AB - This chapter describes how to use a leadership competency approach to help students develop their five signature themes from the Clifton StrengthsFinder assessment into strengths. PMID- 29156113 TI - Using Leadership Competencies as a Framework for Career Readiness. AB - This chapter provides an overview of how a leadership competency approach grounded in emotional and social intelligence can help educators promote career readiness for students. Strategies and approaches for building leadership competencies will be reviewed. PMID- 29156114 TI - The Interaction of Efficacy and Leadership Competency Development. AB - This chapter covers the role of students' self-efficacy in developing their leadership competencies. Practical strategies and recommendations are provided. PMID- 29156115 TI - Aligning Instructional Strategies with Learning Outcomes and Leadership Competencies. AB - This chapter provides recommendations for aligning instructional strategies with learning outcomes and leadership competencies to foster intentional student leadership development. PMID- 29156116 TI - Building a Competency-Based Leadership Program with Campus-Wide Implementation. AB - This chapter outlines a process used by a large, public, research institution to create and implement a competency-based leadership development initiative across campus. PMID- 29156117 TI - Developing Leadership Competencies. AB - This chapter provides an overview of leadership competencies including the history of emergence, contemporary uses, common frameworks, challenges, benefits, and future implications. PMID- 29156118 TI - Strategies in Assessment of Leadership Competencies. AB - This chapter focuses on common pitfalls in assessing leadership competencies, simple strategies to avoid them, and innovative theoretical approaches and strategies in assessment. PMID- 29156119 TI - Cellular diagnosis for the clinicians. PMID- 29156120 TI - Combining Fragment-Ion and Neutral-Loss Matching during Mass Spectral Library Searching: A New General Purpose Algorithm Applicable to Illicit Drug Identification. AB - A mass spectral library search algorithm that identifies compounds that differ from library compounds by a single "inert" structural component is described. This algorithm, the Hybrid Similarity Search, generates a similarity score based on matching both fragment ions and neutral losses. It employs the parameter DeltaMass, defined as the mass difference between query and library compounds, to shift neutral loss peaks in the library spectrum to match corresponding neutral loss peaks in the query spectrum. When the spectra being compared differ by a single structural feature, these matching neutral loss peaks should contain that structural feature. This method extends the scope of the library to include spectra of "nearest-neighbor" compounds that differ from library compounds by a single chemical moiety. Additionally, determination of the structural origin of the shifted peaks can aid in the determination of the chemical structure and fragmentation mechanism of the query compound. A variety of examples are presented, including the identification of designer drugs and chemical derivatives not present in the library. PMID- 29156121 TI - The Toxmatrix: Chemo-Genomic Profiling Identifies Interactions That Reveal Mechanisms of Toxicity. AB - A chemical genomics "Toxmatrix" method was developed to elucidate mechanisms of cytotoxicity using neuronal models. Quantitative high-throughput screening (qHTS) was applied to systematically screen each toxicant against a panel of 70 modulators, drugs or chemicals that act on a known target, to identify interactions that either protect or sensitize cells to each toxicant. Thirty-two toxicants were tested at 10 concentrations for cytotoxicity to SH-SY5Y human neuroblastoma cells, with results fitted to the Hill equation to determine an IC50 for each toxicant. Thirty-three toxicant:modulator interactions were identified in SH-SY5Y cells for 14 toxicants, as modulators that shifted toxicant IC50 values lower or higher. The target of each modulator that sensitizes cells or protects cells from a toxicant suggests a mode of toxicant action or cellular adaptation. In secondary screening, we tested modulator-toxicant pairs identified from the SH-SY5Y primary screening for interactions in three differentiated neuronal human cell lines: dSH-SY5Y, conditionally immortalized dopaminergic neurons (LUHMES), and neural stem cells. Twenty toxicant-modulator pairs showed pronounced interactions in one or several differentiated cell models. Additional testing confirmed that several modulators acted through their primary targets. For example, several chelators protected differentiated LUHMES neurons from four toxicants by chelation of divalent cations and buthionine sulphoximine sensitized cells to 6-hydroxydopamine and 4-(methylamino)phenol hemisulfate by blocking glutathione synthesis. Such modulators that interact with multiple neurotoxicants suggest these may be vulnerable toxicity pathways in neurons. Thus, the Toxmatrix method is a systematic high-throughput approach that can identify mechanisms of toxicity and cellular adaptation. PMID- 29156122 TI - Preparation of Lignin/Sodium Dodecyl Sulfate Composite Nanoparticles and Their Application in Pickering Emulsion Template-Based Microencapsulation. AB - Lignin is a vastly underutilized biomass resource. The preparation of water dispersed lignin nanoparticles is an effective way to realize the high-value utilization of lignin. However, the currently reported preparation methods of lignin nanoparticles still have some drawbacks, such as the requirement for toxic organic solvent or chemical modification, complicated operation process, and poor dispersibility. Here, lignin/sodium dodecyl sulfate (SDS) composite nanoparticles (LSNPs) with outstanding water dispersibility and a size range of 70-200 nm were facilely prepared via acidifying the mixed basic solution of alkaline lignin and SDS. No harsh chemical was needed. The formation mechanism was systematically studied. Results indicated that the LSNPs were obtained by acid precipitation of the mixed micelles formed by the self-assembly of lignin and SDS. In addition, on the basis of the LSNP-stabilized Pickering emulsions, lignin/polyurea composite microcapsules combining the excellent chemical stability of a synthetic polyurea shell with the fantastic antiphotolysis and antioxidant properties of lignin were successfully prepared. PMID- 29156123 TI - Nanopore-Based, Label-Free, and Real-Time Monitoring Assay for DNA Methyltransferase Activity and Inhibition. AB - DNA methylation catalyzed by DNA methyltransferase plays an important role in many biological processes. However, conventional assays proposed for DNA methyltransferase activity are laborious and discontinuous. We have proposed a novel method for real-time monitoring of the activity and kinetics of Escherichia coli DNA adenine methyltransferase (Dam) using nanopore technique coupled with enzyme-linkage reactions. A double-stranded DNA probe AB having a recognition sequence 5'-GATC-3' for both Dam and MboI restriction endonuclease was prepared. Dam catalyzed the methylation of substrate probe AB, which blocked the cleavage reaction of MboI, while the absence of Dam resulted in cleavage of nonmethylated probe AB into four ssDNA fragments by MboI. When tested with nanopore, double stranded methylated probe AB generated long-lived events, distinguished clearly from MboI-cleavage-mediated ssDNA fragments that generated only spikelike events. The proposed method has a detection limit of 0.03 U/mL for Dam in a short assay time of about 150 min. This sensing system is easy to perform, simple to design and circumvents the use of radioactive substances, resulting in efficient detection of the activity of Dam even in complex matrixes like human serum sample. Furthermore, it has the potential to screen Dam-targeted inhibitor drugs which may assist in the discovery of new anticancer medicines. This method is general and could be extended easily for monitoring activity of a wide variety of methyltransferases by coupling with their corresponding methylation-sensitive endonucleases. PMID- 29156124 TI - Definition of Free O-H Groups of Water at the Air-Water Interface. AB - Free O-H groups of water are often found at the water-hydrophobic medium interface, e.g. for water contact with hydrophobic protein residues, or at the water-air interface. In surface-specific vibrational spectroscopic studies using sum-frequency generation (SFG) spectroscopy, free O-H groups are experimentally well characterized in the O-H stretch region by a sharp 3700 cm-1 peak. Although these free O-H groups are often defined as the O-H groups which are not hydrogen bonded to other water molecules, a direct correlation between such non-hydrogen bonded O-H groups and the 3700 cm-1 SFG response has been lacking. Our data show that commonly used hydrogen bond definitions do not adequately capture the free O H groups contributing to the 3700 cm-1 peak. We thus formulate a new definition for capturing the subensemble of the surface free O-H groups using the intermolecular distance and the angle formed by the water dimer, through the comparison of the ~3700 cm-1 SFG response and the responses from the selected free O-H groups at the HOD-air interface. Using these optimized free O-H group definitions, we infer the fraction of interfacial water molecules with free O-H groups of 28%, a vibrational lifetime of the free O-H groups of 1.3 ps, and the angle formed by the free O-H groups and the surface normal of 67 degrees at the water-air interface. We expect that this improved free O-H group definition can be helpful in exploring the structure and dynamics of the interfacial water. PMID- 29156125 TI - Validating a Coarse-Grained Voltage Activation Model by Comparing Its Performance to the Results of Monte Carlo Simulations. AB - Simulating the nature of voltage-activated systems is a problem of major current interest, ranging from the action of voltage-gated ion channels to energy storage batteries. However, fully microscopic converging molecular simulations of external voltage effects present a major challenge, and macroscopic models are associated with major uncertainties about the dielectric treatment and the underlying physical basis. Recently we developed a coarse-grained (CG) model that represents explicitly the electrodes, the electrolytes, and the membrane/protein system. The CG model provides a semimacroscopic way of capturing the microscopic physics of voltage-activated systems. Our method was originally validated by reproducing macroscopic and analytical results for key test cases and then used in modeling voltage-activated ion channels and related problems. In this work, we further establish the reliability of the CG voltage model by comparing it to the results of Monte Carlo (MC) simulations with a microscopic electrolyte model. The comparison explores different aspects of membrane, electrolyte, and electrode systems ranging from the Gouy-Chapman model to the determination of the electrolyte charge distribution in the solution between two electrodes (without and with a separating membrane), as well as the evaluation of gating charges. Overall the agreement is very impressive. This provides confidence in the CG model and also shows that the MC model can be used in realistic simulation of voltage activation of membrane proteins with sufficient computer time. PMID- 29156126 TI - Two-Dimensional Tantalum Carbide (MXenes) Composite Nanosheets for Multiple Imaging-Guided Photothermal Tumor Ablation. AB - MXenes, an emerging family of graphene-analogues two-dimensional (2D) materials, have attracted continuous and tremendous attention in many application fields because of their intrinsic physiochemical properties and high performance in versatile applications. In this work, we report on the construction of tantalum carbide (Ta4C3) MXene-based composite nanosheets for multiple imaging-guided photothermal tumor ablation, which has been achieved by rational choice of the composition of MXenes and their surface functionalization. A redox reaction was activated on the surface of tantalum carbide (Ta4C3) MXene for in situ growth of manganese oxide nanoparticles (MnOx/Ta4C3) based on the reducing surface of the nanosheets. The tantalum components of MnOx/Ta4C3 acted as the high-performance contrast agents for contrast-enhanced computed tomography, and the integrated MnOx component functionalized as the tumor microenvironment-responsive contrast agents for T1-weighted magnetic resonance imaging. The photothermal-conversion performance of MnOx/Ta4C3 composite nanosheets not only has achieved contrast enhanced photoacoustic imaging, but also realized the significant tumor-growth suppression by photothermal hyperthermia. This work broadens the biomedical applications of MXenes, not only by the fabrication of family members of biocompatible MXenes, but also by the development of functionalization strategies of MXenes for cancer-theranostic applications. PMID- 29156127 TI - Gas Separation through Bilayer Silica, the Thinnest Possible Silica Membrane. AB - Membrane-based gas separation processes can address key challenges in energy and environment, but for many applications the permeance and selectivity of bulk membranes is insufficient for economical use. Theory and experiment indicate that permeance and selectivity can be increased by using two-dimensional materials with subnanometer pores as membranes. Motivated by experiments showing selective permeation of H2/CO mixtures through amorphous silica bilayers, here we perform a theoretical study of gas separation through silica bilayers. Using density functional theory calculations, we obtain geometries of crystalline free-standing silica bilayers (comprised of six-membered rings), as well as the seven-, eight-, and nine-membered rings that are observed in glassy silica bilayers, which arise due to Stone-Wales defects and vacancies. We then compute the potential energy barriers for gas passage through these various pore types for He, Ne, Ar, Kr, H2, N2, CO, and CO2 gases, and use the data to assess their capability for selective gas separation. Our calculations indicate that crystalline bilayer silica, which is less than a nanometer thick, can be a high-selectivity and high-permeance membrane material for 3He/4He, He/natural gas, and H2/CO separations. PMID- 29156128 TI - Cyclic Peptide-Polymer Nanotubes as Efficient and Highly Potent Drug Delivery Systems for Organometallic Anticancer Complexes. AB - Functional drug carrier systems have potential for increasing solubility and potency of drugs while reducing side effects. Complex polymeric materials, particularly anisotropic structures, are especially attractive due to their long circulation times. Here, we have conjugated cyclic peptides to the biocompatible polymer poly(2-hydroxypropyl methacrylamide) (pHPMA). The resulting conjugates were functionalized with organoiridium anticancer complexes. Small angle neutron scattering and static light scattering confirmed their self-assembly and elongated cylindrical shape. Drug-loaded nanotubes exhibited more potent antiproliferative activity toward human cancer cells than either free drug or the drug-loaded polymers, while the nanotubes themselves were nontoxic. Cellular accumulation studies revealed that the increased potency of the conjugate appears to be related to a more efficient mode of action rather than a higher cellular accumulation of iridium. PMID- 29156129 TI - Small Molecule Mitochondrial Uncouplers and Their Therapeutic Potential. AB - Small molecule mitochondrial uncouplers transport protons from the mitochondrial inner membrane space into the mitochondrial matrix independent of ATP synthase, uncoupling nutrient metabolism from ATP generation. The therapeutic potential of mitochondrial uncouplers has been investigated for the treatment of metabolic diseases such as obesity and type 2 diabetes (T2D), ischemia-reperfusion injury, and neurodegenerative diseases. This communication will review the small molecule mitochondrial uncouplers reported to date and explore their potential as therapeutics. PMID- 29156130 TI - Theoretical and Experimental Evidence for the Carbon-Oxygen Group Enhancement of NO Reduction. AB - The relation between a catalytic center and the surrounding carbon-oxygen groups influences the catalytic activity in various reactions. However, the impact of this relation on catalysis is usually discussed separately. For the first time, we proved that carbon-oxygen groups increased the reducibility of Fe-C bonds toward NO reduction. Experimentally, we compared the reductive activities of materials with either one or both factors, i.e., carbon-oxygen groups and Fe-C bonds. As a result, graphene oxide-supported Fe (with both factors) showed the best activity, duration of activity, and selectivity. This material reduced 100% of NO to N2 at 300 degrees C. Moreover, theoretical calculations revealed that the adsorption energy of graphene for NO increased from -13.51 (physical adsorption) to -327.88 kJ/mol (chemical adsorption) after modification with Fe-C. When the graphene-supported Fe was further modified with carboxylic acid groups, the ability to transfer charge increased dramatically from 0.109 to 0.180 |e-|. Therefore, the carbon-oxygen groups increased the reducibility of Fe-C. The main results will contribute to the understanding of NO reduction and the design of effective catalysts. PMID- 29156131 TI - Development and Performance Characterization of a Polyimine Covalent Organic Framework Thin-Film Composite Nanofiltration Membrane. AB - Two-dimensional covalent organic frameworks (COFs) were used to create the first asymmetric, thin-film composite (TFC) nanofiltration (NF) membrane with a COF active layer. NF membrane active layers of polyimine COF were synthesized via the interfacial polymerization (IP) of terephthalaldehyde and tris(4 aminophenyl)benzene monomers on top of a poly(ether sulfone) (PES) ultrafiltration membrane support. Rutherford backscattering spectrometry and Fourier transform infrared spectroscopy analyses confirmed the presence of an imine-linked film with a thickness of ~10 nm that was formed reproducibly. The rejection efficiencies of the COF NF membrane for a model organic compound, Rhodamine-WT, and a background electrolyte, NaCl, were higher than those of the PES support without the COF film. This enhanced solute rejection is the first successful demonstration of a TFC membrane with a thin COF active layer. However, this work also demonstrates the need for COF NF membranes with smaller active layer pores and alternative support materials. The former should result in greater solute rejection, and the latter is key because the PES used for support in the COF membranes is incompatible with the organic solvents used for the COF IP process. PMID- 29156132 TI - PP1:Tautomycetin Complex Reveals a Path toward the Development of PP1-Specific Inhibitors. AB - Selective inhibitors for each serine/threonine phosphatase (PPP) are essential to investigate the biological actions of PPPs and to guide drug development. Biologically diverse organisms (e.g., cyanobacteria, dinoflagellates, beetles) produce structurally distinct toxins that are catalytic inhibitors of PPPs. However, most toxins exhibit little selectivity, typically inhibiting multiple family members with similar potencies. Thus, the use of these toxins as chemical tools to study the relationship between individual PPPs and their biological substrates, and how disruptions in these relationships contributes to human disease, is severely limited. Here, we show that tautomycetin (TTN) is highly selective for a single PPP, protein phosphatase 1 (PP1/PPP1C). Our structure of the PP1:TTN complex reveals that PP1 selectivity is defined by a covalent bond between TTN and a PP1-specific cysteine residue, Cys127. Together, these data provide key molecular insights needed for the development of novel probes targeting single PPPs, especially PP1. PMID- 29156134 TI - Organic Ice Resists. AB - Electron-beam lithography (EBL) is the backbone technology for patterning nanostructures and manufacturing nanodevices. It involves processing and handling synthetic resins in several steps, each requiring optimization and dedicated instrumentation in cleanroom environments. Here, we show that simple organic molecules, e.g. alcohols, condensed to form thin-films at low temperature demonstrate resist-like capabilities for EBL applications and beyond. The entire lithographic process takes place in a single instrument, and avoids exposing users to chemicals and the need of cleanrooms. Unlike EBL that requires large samples with optically flat surfaces, we patterned on fragile membranes only 5 nm thin, and 2 * 2 mm2 diamond samples. We created patterns on the nanometer to sub millimeter scale, as well as three-dimensional structures by stacking layers of frozen organic molecules. Finally, using plasma etching, the organic ice resist (OIR) patterns are used to structure the underlying material, and thus enable nanodevice fabrication. PMID- 29156133 TI - Harnessing Sphingosine-1-Phosphate Signaling and Nanotopographical Cues To Regulate Skeletal Muscle Maturation and Vascularization. AB - Despite possessing substantial regenerative capacity, skeletal muscle can suffer from loss of function due to catastrophic traumatic injury or degenerative disease. In such cases, engineered tissue grafts hold the potential to restore function and improve patient quality of life. Requirements for successful integration of engineered tissue grafts with the host musculature include cell alignment that mimics host tissue architecture and directional functionality, as well as vascularization to ensure tissue survival. Here, we have developed biomimetic nanopatterned poly(lactic-co-glycolic acid) substrates conjugated with sphingosine-1-phosphate (S1P), a potent angiogenic and myogenic factor, to enhance myoblast and endothelial maturation. Primary muscle cells cultured on these functionalized S1P nanopatterned substrates developed a highly aligned and elongated morphology and exhibited higher expression levels of myosin heavy chain, in addition to genes characteristic of mature skeletal muscle. We also found that S1P enhanced angiogenic potential in these cultures, as evidenced by elevated expression of endothelial-related genes. Computational analyses of live cell videos showed a significantly improved functionality of tissues cultured on S1P-functionalized nanopatterns as indicated by greater myotube contraction displacements and velocities. In summary, our study demonstrates that biomimetic nanotopography and S1P can be combined to synergistically regulate the maturation and vascularization of engineered skeletal muscles. PMID- 29156137 TI - Biologically Consistent Annotation of Metabolomics Data. AB - Annotation of metabolites remains a major challenge in liquid chromatography-mass spectrometry (LC-MS) based untargeted metabolomics. The current gold standard for metabolite identification is to match the detected feature with an authentic standard analyzed on the same equipment and using the same method as the experimental samples. However, there are substantial practical challenges in applying this approach to large data sets. One widely used annotation approach is to search spectral libraries in reference databases for matching metabolites; however, this approach is limited by the incomplete coverage of these libraries. An alternative computational approach is to match the detected features to candidate chemical structures based on their mass and predicted fragmentation pattern. Unfortunately, both of these approaches can match multiple identities with a single feature. Another issue is that annotations from different tools often disagree. This paper presents a novel LC-MS data annotation method, termed Biologically Consistent Annotation (BioCAn), that combines the results from database searches and in silico fragmentation analyses and places these results into a relevant biological context for the sample as captured by a metabolic model. We demonstrate the utility of this approach through an analysis of CHO cell samples. The performance of BioCAn is evaluated against several currently available annotation tools, and the accuracy of BioCAn annotations is verified using high-purity analytical standards. PMID- 29156136 TI - The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro 2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties. AB - The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28. PMID- 29156139 TI - Thermosensitive Phase Separation Behavior of Poly(benzyl methacrylate)/Solvate Ionic Liquid Solutions. AB - We report a lower critical solution temperature (LCST) behavior of binary systems consisting of poly(benzyl methacrylate) (PBnMA) and solvate ionic liquids: equimolar mixtures of triglyme (G3) or tetraglyme (G4) and lithium bis(trifluoromethanesulfonyl)amide. We evaluated the critical temperatures (Tcs) using transmittance measurements. The stability of the glyme-Li+ complex ([Li(G3 or G4)]+) in the presence of PBnMA was confirmed using Raman spectroscopy, pulsed field gradient spin-echo NMR (PGSE-NMR), and thermogravimetric analysis to demonstrate that the complex was not disrupted. The interaction between glyme-Li+ complex and PBnMA was investigated via 7Li NMR chemical shifts. Upfield shifts originating from the ring-current effect of the aromatic ring within PBnMA were observed with the addition of PBnMA, indicating localization of the glyme-Li+ complex above and below the benzyl group of PBnMA, which may be a reason for negative mixing entropy, a key requirement of the LCST. PMID- 29156138 TI - Plasmonic Sensing with 3D Printed Optics. AB - Three-dimensional (3D) printing has undergone an exponential growth in popularity due to its revolutionary and near limitless manufacturing capabilities. Recent trends have seen this technology utilized across a variety of scientific disciplines, including the measurement sciences, but precise fabrication of optical components for high-performance biosensing has not yet been demonstrated. We report here 3D printing of high-quality, custom prisms by stereolithography that enable Kretschmann-configured plasmonic sensing of bacterial toxins. Simple benchtop polishing procedures render a smooth surface that supports propagation of surface plasmon polaritons with a deposited gold layer, which exhibit high bulk refractive index sensitivities and are capable of discriminating trace levels of cholera toxin on a supported lipid membrane interface. Further evidence of the flexibility of this manufacturing technique is demonstrated with printed prisms of varied geometries and in situ monitoring of nanoparticle growth by total internal reflection spectroscopy. This work represents the first example of 3D printed light-guiding sensing platforms and demonstrates the versatility and broad perspective of 3D printing in optical detection. PMID- 29156135 TI - Fluorescent Probes of DNA Repair. AB - DNA repair is now understood to play a key role in a variety of disease states, most notably cancer. Tools for studying DNA have typically relied on traditional biochemical methods which are often laborious and indirect. Efforts to study the biology and therapeutic relevance of DNA repair pathways can be limited by such methods. Recently, specific fluorescent probes have been developed to aid in the study of DNA repair. Fluorescent probes offer the advantage of being able to directly assay for DNA repair activity in a simple, mix-and-measure format. This review will summarize the distinct classes of probe designs and their potential utility in varied research and preclinical settings. PMID- 29156140 TI - Automated Training of ReaxFF Reactive Force Fields for Energetics of Enzymatic Reactions. AB - Computational studies of the reaction mechanisms of various enzymes are nowadays based almost exclusively on hybrid QM/MM models. Unfortunately, the success of this approach strongly depends on the selection of the QM region, and computational cost is a crucial limiting factor. An interesting alternative is offered by empirical reactive molecular force fields, especially the ReaxFF potential developed by van Duin and co-workers. However, even though an initial parametrization of ReaxFF for biomolecules already exists, it does not provide the desired level of accuracy. We have conducted a thorough refitting of the ReaxFF force field to improve the description of reaction energetics. To minimize the human effort required, we propose a fully automated approach to generate an extensive training set comprised of thousands of different geometries and molecular fragments starting from a few model molecules. Electrostatic parameters were optimized with QM electrostatic potentials as the main target quantity, avoiding excessive dependence on the choice of reference atomic charges and improving robustness and transferability. The remaining force field parameters were optimized using the VD-CMA-ES variant of the CMA-ES optimization algorithm. This method is able to optimize hundreds of parameters simultaneously with unprecedented speed and reliability. The resulting force field was validated on a real enzymatic system, ppGalNAcT2 glycosyltransferase. The new force field offers excellent qualitative agreement with the reference QM/MM reaction energy profile, matches the relative energies of intermediate and product minima almost exactly, and reduces the overestimation of transition state energies by 27-48% compared with the previous parametrization. PMID- 29156141 TI - One-year unsupervised individualized exercise training intervention enhances cardiorespiratory fitness but not muscle deoxygenation or glycemic control in adults with type 1 diabetes. AB - Adaptations to long-term exercise training in type 1 diabetes are sparsely studied. We examined the effects of a 1-year individualized training intervention on cardiorespiratory fitness, exercise-induced active muscle deoxygenation, and glycemic control in adults with and without type 1 diabetes. Eight men with type 1 diabetes (T1D) and 8 healthy men (CON) matched for age, anthropometry, and peak pulmonary O2 uptake, completed a 1-year individualized training intervention in an unsupervised real-world setting. Before and after the intervention, the subjects performed a maximal incremental cycling test, during which alveolar gas exchange (volume turbine and mass spectrometry) and relative concentration changes in active leg muscle deoxygenated (Delta[HHb]) and total (Delta[tHb]) hemoglobin (near-infrared spectroscopy) were monitored. Peak O2 pulse, reflecting peak stroke volume, was calculated (peak pulmonary O2 uptake/peak heart rate). Glycemic control (glycosylated hemoglobin A1c (HbA1c)) was evaluated. Both T1D and CON averagely performed 1 resistance-training and 3-4 endurance-training sessions per week (~1 h/session at ~moderate intensity). Training increased peak pulmonary O2 uptake in T1D (p = 0.004) and CON (p = 0.045) (group * time p = 0.677). Peak O2 pulse also rose in T1D (p = 0.032) and CON (p = 0.018) (group * time p = 0.880). Training increased leg Delta[HHb] at peak exercise in CON (p = 0.039) but not in T1D (group * time p = 0.052), while no changes in leg Delta[tHb] at any work rate were observed in either group (p > 0.05). HbA1c retained unchanged in T1D (from 58 +/- 10 to 59 +/- 11 mmol/mol, p = 0.609). In conclusion, 1-year adherence to exercise training enhanced cardiorespiratory fitness similarly in T1D and CON but had no effect on active muscle deoxygenation or glycemic control in T1D. PMID- 29156142 TI - Cutaneous vasomotor adaptation following repeated, isothermal heat exposures: evidence of adaptation specificity. AB - Unequivocal enhancement of cutaneous vasomotor function has yet to be demonstrated following heat acclimation, possibly because the adaptation stimulus was not sustained, or because thermoeffector function was not assessed at equivalent deep-body temperatures. Therefore, forearm and local cutaneous vascular conductances were evaluated during exercise eliciting matched deep-body temperatures (37.5 degrees C, 38.5 degrees C), before and after isothermal heat acclimation. Both indices increased (21% and 25%), confirming cutaneous vasomotor adaptation can occur, provided those experimental design specifications are satisfied. PMID- 29156143 TI - Identification of nuclear localization signals in the human homeoprotein MSX1. AB - MSX1 is one of the homeoproteins with the homeodomain (HD) sequence, which regulates proliferation and differentiation of mesenchymal cells. In this study, we investigated the nuclear localization signal (NLS) in the MSX1 HD by deletion and amino acid substitution analyses. The web-based tool NLStradamus predicted 2 putative basic motifs in the N- and C-termini of the MSX1 HD. Green fluorescent protein (GFP) chimera studies revealed that NLS1 (161RKHKTNRKPR170) and NLS2 (216NRRAKAKR223) were independently insufficient for robust nuclear localization. However, they can work cooperatively to promote nuclear localization of MSX1, as was shown by the 2 tandem NLS motifs partially restoring functional NLS, leading to a significant nuclear accumulation of the GFP chimera. These results demonstrate a unique NLS motif in MSX1, which consists of an essential single core motif in helix-I, with weak potency, and an auxiliary subdomain in helix III, which alone does not have nuclear localization potency. Additionally, other peptide sequences, other than predicted 2 motifs in the spacer, may be necessary for complete nuclear localization in MSX1 HD. PMID- 29156144 TI - Breastfeeding Practices and Barriers to Implementing the Ten Steps to Successful Breastfeeding in Mississippi Hospitals. AB - BACKGROUND: Mississippi has the lowest rates of breastfeeding in the United States at 6 and 12 months. There is growing evidence that the rates and duration of infant breastfeeding improve after hospitals implement the Ten Steps to Successful Breastfeeding; moreover, the Ten Steps approach is considered the standard model for evaluation of breastfeeding practices in birthplaces. Research aim: This study aimed to examine the implementation level of the Ten Steps and identify barriers to implementing the Ten Steps in Mississippi hospitals. METHODS: A cross-sectional self-report survey was used to answer the research aim. Nurse managers of the birthing and maternity units of all 43 Mississippi hospitals that provided birthing and maternity care were recruited. A response rate of 72% ( N = 31) was obtained. Implementation of the Ten Steps in these hospitals was categorized as low, partial, moderate, or high. RESULTS: The researcher classified implementation in 29% of hospitals as moderate and in 71% as partial. The hospital level of implementation was significantly positively associated with the hospital delivery rate along with the hospital cesarean section rate per year. The main barriers for the implementation process of the Ten Steps reported were resistance to new policies, limited financial and human resources, and lack of support from national and state governments. CONCLUSION: Breastfeeding practices in Mississippi hospitals need to be improved. New policies need to be established in Mississippi to encourage hospitals to adopt the Ten Steps policies and practice in the maternity and birthing units. PMID- 29156146 TI - Effectiveness of a Staged US and Unenhanced MR Imaging Algorithm in the Diagnosis of Pediatric Appendicitis. AB - Purpose To establish, in a large cohort, the diagnostic performance of a staged algorithm involving ultrasonography (US) followed by conditional unenhanced magnetic resonance (MR) imaging for the imaging work-up of pediatric appendicitis. Materials and Methods A staged imaging algorithm in which US and unenhanced MR imaging were performed in pediatric patients suspected of having appendicitis was implemented at the authors' institution on January 1, 2011, with US as the initial modality followed by unenhanced MR imaging when US findings were equivocal. A search of the radiology database revealed 2180 pediatric patients who had undergone imaging for suspected appendicitis from January 1, 2011, through December 31, 2012. Of the 2180 patients, 1982 (90.9%) were evaluated according to the algorithm. The authors reviewed the electronic medical records and imaging reports for all patients. Imaging reports were reviewed and classified as positive, negative, or equivocal for appendicitis and correlated with surgical and pathology reports. Results The frequency of appendicitis was 20.5% (407 of 1982 patients). US alone was performed in 1905 of the 1982 patients (96.1%), yielding a sensitivity of 98.7% (386 of 391 patients) and specificity of 97.1% (1470 of 1514 patients) for appendicitis. Seventy-seven patients underwent unenhanced MR imaging after equivocal US findings, yielding an overall algorithm sensitivity of 98.2% (400 of 407 patients) and specificity of 97.1% (1530 of 1575 patients). Seven of the 1982 patients (0.4%) had false-negative results with the staged algorithm. The negative predictive value of the staged algorithm was 99.5% (1530 of 1537 patients). Conclusion A staged algorithm of US and unenhanced MR imaging for pediatric appendicitis appears to be effective. The results of this study demonstrate that this staged algorithm is 98.2% sensitive and 97.1% specific for the diagnosis of appendicitis in pediatric patients. (c) RSNA, 2017. PMID- 29156145 TI - Fractional Flow Reserve Estimated at Coronary CT Angiography in Intermediate Lesions: Comparison of Diagnostic Accuracy of Different Methods to Determine Coronary Flow Distribution. AB - Purpose To compare the diagnostic accuracy of different computed tomographic (CT) fractional flow reserve (FFR) algorithms for vessels with intermediate stenosis. Materials and Methods This cross-sectional HIPAA-compliant and human research committee-approved study applied a four-step CT FFR algorithm in 61 patients (mean age, 69 years +/- 10; age range, 29-89 years) with a lesion of intermediate diameter stenosis (25%-69%) at CT angiography who underwent FFR measurement within 90 days. The per-lesion diagnostic performance of CT FFR was tested for three different approaches to estimate blood flow distribution for CT FFR calculation. The first two, the Murray law and the Huo-Kassab rule, used coronary anatomy; the third used contrast material opacification gradients. CT FFR algorithms and CT angiography percentage diameter stenosis (DS) measurements were compared by using the area under the receiver operating characteristic curve (AUC) to detect FFRs of 0.8 or lower. Results Twenty-five lesions (41%) had FFRs of 0.8 or lower. The AUC of CT FFR determination by using contrast material gradients (AUC = 0.953) was significantly higher than that of the Huo-Kassab (AUC = 0.882, P = .043) and Murray law models (AUC = 0.871, P = .033). All three AUCs were higher than that for 50% or greater DS at CT angiography (AUC = 0.596, P < .001). Correlation of CT FFR with FFR was highest for gradients (Spearman rho = 0.80), followed by the Huo-Kassab rule (rho = 0.68) and Murray law (rho = 0.67) models. All CT FFR algorithms had small biases, ranging from -0.015 (Murray) to 0.049 (Huo-Kassab). Limits of agreement were narrowest for gradients (-0.182, 0.147), followed by the Huo-Kassab rule (-0.246, 0.149) and the Murray law ( 0.285, 0.256) models. Conclusion Clinicians can perform CT FFR by using a four step approach on site to accurately detect hemodynamically significant intermediate-stenosis lesions. Estimating blood flow distribution by using coronary contrast opacification variations may improve CT FFR accuracy. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29156147 TI - Electromagnetic Navigational Bronchoscopy versus CT-guided Percutaneous Sampling of Peripheral Indeterminate Pulmonary Nodules: A Cohort Study. AB - Purpose To compare the diagnostic yield and complication rates of electromagnetic navigational bronchoscopic (ENB)-guided and computed tomography (CT)-guided percutaneous tissue sampling of lung nodules. Materials and Methods Retrospectively identified were 149 patients sampled percutaneously with CT guidance and 146 patients who underwent ENB with transbronchial biopsy of a lung lesion between 2013 and 2015. Clinical data, incidence of complications, and nodule pathologic analyses were assessed through electronic medical record review. Lung nodule characteristics were reviewed through direct image analysis. Molecular marker studies and pathologic analyses from surgical excision were reviewed when available. Multiple-variable logistic regression models were built to compare the diagnostic yield and complication rates for each method and for different patient and disease characteristics. Results CT-guided sampling was more likely to be diagnostic than ENB-guided biopsy (86.0% [129 of 150] vs 66.0% [99 of 150], respectively), and this difference remained significant even after adjustments were made for patient and nodule characteristics (P < .001). Age, American Society of Anesthesiologists class, emphysema grade, nodule size, and distance from pleura were not significant predictors of increased diagnostic yield. Intraprocedural time for physicians was significantly lower with CT-guided sampling (P < .001). Similar yield for molecular analyses was noted with the two approaches (ENB-guided sampling, 88.9% [32 of 36]; CT-guided sampling, 82.0% [41 of 50]). The two groups had similar rates of major complications (symptomatic hemorrhage, P > .999; pneumothorax requiring chest tube and/or admission, P = .417). Conclusion CT-guided transthoracic biopsy provided higher diagnostic yield in the assessment of peripheral pulmonary nodules than navigational bronchoscopy with a similar rate of clinically relevant complications. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29156148 TI - CM-101: Type I Collagen-targeted MR Imaging Probe for Detection of Liver Fibrosis. AB - Purpose To evaluate the biodistribution, metabolism, and pharmacokinetics of a new type I collagen-targeted magnetic resonance (MR) probe, CM-101, and to assess its ability to help quantify liver fibrosis in animal models. Materials and Methods Biodistribution, pharmacokinetics, and stability of CM-101 in rats were measured with mass spectrometry. Bile duct-ligated (BDL) and sham-treated rats were imaged 19 days after the procedure by using a 1.5-T clinical MR imaging unit. Mice were treated with carbon tetrachloride (CCl4) or with vehicle two times a week for 10 weeks and were imaged with a 7.0-T preclinical MR imaging unit at baseline and 1 week after the last CCl4 treatment. Animals were imaged before and after injection of 10 umol/kg CM-101. Change in contrast-to-noise ratio (DeltaCNR) between liver and muscle tissue after CM-101 injection was used to quantify liver fibrosis. Liver tissue was analyzed for Sirius Red staining and hydroxyproline content. The institutional subcommittee for research animal care approved all in vivo procedures. Results CM-101 demonstrated rapid blood clearance (half-life = 6.8 minutes +/- 2.4) and predominately renal elimination in rats. Biodistribution showed low tissue gadolinium levels at 24 hours (<3.9% injected dose [ID]/g +/- 0.6) and 10-fold lower levels at 14 days (<0.33% ID/g +/ 12) after CM-101 injection with negligible accumulation in bone (0.07% ID/g +/- 0.02 and 0.010% ID/g +/- 0.004 at 1 and 14 days, respectively). DeltaCNR was significantly (P < .001) higher in BDL rats (13.6 +/- 3.2) than in sham-treated rats (5.7 +/- 4.2) and in the CCl4-treated mice (18.3 +/- 6.5) compared with baseline values (5.2 +/- 1.0). Conclusion CM-101 demonstrated fast blood clearance and whole-body elimination, negligible accumulation of gadolinium in bone or tissue, and robust detection of fibrosis in rat BDL and mouse CCl4 models of liver fibrosis. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29156149 TI - Quantitative Evaluation of Vertebral Microvascular Permeability and Fat Fraction in Alloxan-induced Diabetic Rabbits. AB - Purpose To determine longitudinal relationships between lumbar vertebral bone marrow permeability and marrow adipose tissue in a rabbit diabetes model by using quantitative dynamic contrast agent-enhanced (DCE) magnetic resonance (MR) imaging and iterative decomposition of water and fat with the echo asymmetry and least-squares estimation quantitation (IDEAL IQ) sequence. Materials and Methods Twenty rabbits were randomly assigned to the diabetic (n = 10) or control (n = 10) group. All rabbits underwent sagittal MR imaging of the lumbar region at fixed time points (0, 4, 8, 12, and 16 weeks after alloxan injection). A linear mixed-effects model was used to analyze fat fraction (FF) and permeability parameter changes for 16 months after baseline. These parameters were compared between the two groups by using an independent-samples t test. Correlation of DCE MR imaging parameters with FF and with microvessel density (MVD) was analyzed by using the Spearman correlation coefficient. All statistical analyses were performed with software. Results Twelve weeks after injection, transfer constant (Ktrans) and rate constant (Kep) were markedly and significantly increased, while fractional plasma volume (Vp) significantly decreased. The volume of extravascular extracellular space (Ve) decreased significantly after 16 weeks in the diabetic group. MVD was negatively correlated with Ktrans and Kep and positively correlated with Ve and Vp, while FF was positively correlated with Ktrans and Kep and negatively correlated with Ve and Vp (P < .05 for all). Conclusion DCE MR imaging and the IDEAL IQ sequence can be used for quantitative evaluation of changes in vertebral microvascular permeability and vertebral fat deposition in alloxan-induced diabetic rabbits. This variation is highly associated with increased vertebral fat deposition. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29156150 TI - Effect of Shift, Schedule, and Volume on Interpretive Accuracy: A Retrospective Analysis of 2.9 Million Radiologic Examinations. AB - Purpose To determine whether there is an association between radiologist shift length, schedule, or examination volume and interpretive accuracy. Materials and Methods This study was institutional review board approved and HIPAA compliant. A retrospective analysis of all major discrepancies from a 2015 quality assurance database of a teleradiology practice was performed. Board-certified radiologists provided initial preliminary interpretations. Discrepancies were identified during a secondary review by a practicing radiologist or through an internal quality assurance process and were vetted through a consensus radiology quality assurance committee. Unique anonymous radiologist identifiers were used to link the discrepancies to radiologists' shifts and schedules. Data were analyzed by using analysis of variance, t test, or chi2 test. Results A total of 4294 major discrepancies resulted from 2 922 377 examinations (0.15%). There was a significant difference for shift length (P < .0001) and volume (P < .0001) for shifts with versus those without discrepancies. On average, errors occurred a mean (+/- standard deviation) of 8.97 hours +/- 2.28 into the shift (median, 10 hours; interquartile range, 2.0 hours). Significantly more errors occurred late in shifts than early (P < .0001), peaking between 10 and 12 hours. The number of major discrepancies in a single shift ranged from one to four, with a significant difference in the number of discrepancies as a function of study volume (volume for all shifts, 67.60 +/- 60.24; volume for shifts with major discrepancies, 118.96 +/- 66.89; P < .001). Despite a trend for more discrepancies after more consecutive days worked, the difference was not significant (P = .0893). Conclusion Longer shifts and higher diagnostic examination volumes are associated with increased major interpretive discrepancies. These are more likely to occur later in a shift, peaking after the 10th hour of work. (c) RSNA, 2017. PMID- 29156151 TI - Limited evidence of fungicide-driven triazole-resistant Aspergillus fumigatus in Hamilton, Canada. AB - Aspergillus fumigatus is a ubiquitous opportunistic fungal pathogen that can cause aspergillosis in humans. Over the last decade there have been increasing global reports of treatment failure due to triazole resistance. An emerging hypothesis states that agricultural triazole fungicide use causes clinical triazole resistance. Here we test this hypothesis in Hamilton, Ontario, Canada, by examining a total of 195 agricultural, urban, and clinical isolates using 9 highly polymorphic microsatellite markers. For each isolate, the in vitro susceptibilities to itraconazole and voriconazole, 2 triazole drugs commonly used in the management of patients, were also determined. Our analyses suggested frequent gene flow among the agricultural, urban environmental, and clinical populations of A. fumigatus and found evidence for widespread sexual recombination within and among the different populations. Interestingly, all 195 isolates analyzed in this study were susceptible to both triazoles tested. However, compared with the urban population, agricultural and clinical populations showed significantly reduced susceptibility to itraconazole and voriconazole, consistent with ecological niche-specific selective pressures on A. fumigatus populations in Hamilton. Frequent gene flow and genetic recombination among these populations suggest greater attention should be paid to monitor A. fumigatus populations in Hamilton and other similar jurisdictions. PMID- 29156152 TI - Limited effect of omega-3 fatty acids on the quality of life in survivors of traumatic injury: A randomized, placebo-controlled trial. AB - Empirical evidence is divided on whether n-3 polyunsaturated fatty acid levels are associated with quality of life (QOL). This study investigated the effects of docosahexaenoic acid (DHA) supplementation on QOL in survivors of traumatic injury. In this secondary analysis of a double-blind, randomized controlled trial, we recruited 110 trauma patients (82% men; mean age, 39.6 years) in an intensive care unit. Fifty-three received DHA-rich supplements and 57 received placebo for 12 weeks. We used the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) to assess QOL at the end of intervention. DHA did not significantly affect any QOL domain on the SF-36 after 12 weeks. In the DHA group, changes in the erythrocyte levels of eicosapentaenoic acid (EPA) + DHA and EPA were positively correlated with the SF-36 mental component. DHA did not influence QOL of trauma patients, but increased EPA levels during the trial were associated with better QOL in patients receiving omega-3. PMID- 29156153 TI - Hyperbaric oxygen therapy is not associated with oxidative stress assessed using plasma F2-isoprostanes and isofurans. AB - BACKGROUND AND AIMS: Hyperbaric oxygen (HBO) therapy is increasingly used in medical practice as a means of enhancing the formation of collagen matrix and angiogenesis, thus promoting healing in wounds and necrotic tissue. However, there are concerns that oxygen can also associate with increased production of oxygen free radicals and oxidative stress. F2-Isoprostanes (F2-IsoPs) formed by non-enzymatic oxidation of arachidonic acid (AA) are reliable measures for assessing oxidative stress in vivo. In addition, under conditions of high oxygen tension isofurans (IsoFs) are preferentially formed from AA and are considered to better reflect oxidative stress in the setting of high oxygen tension. This study aimed to measure plasma IsoFs and F2-IsoP in patients receiving HBO therapy to treat osteonecrosis secondary to radiation therapy. Our hypothesis was that IsoFs would continue to rise with increasing oxygen pressures in contrast to F2-IsoPs whose synthesis would be reduced. METHODS: Twelve patients receiving hyperbaric therapy to treat osteonecrosis secondary to radiation therapy were studied during hyperbaric treatment. Blood samples were collected prior to, during and after cessation of HBO therapy that lasted for 119min. Seven serial blood samples were collected for measurement of plasma F2-IsoPs and IsoFs, blood gases and haemoglobin. RESULTS: Oxygen saturation and venous oxygen partial pressure (PvO2) rose significantly during hyperbaric therapy. However, there were no significant changes in plasma IsoFs or F2-IsoPs during the hyperbaric therapy session. CONCLUSION: In this study of patients with osteonecrosis, HBO therapy at a maximum pressure of 2.4atm with up to 100% oxygen did not worsen oxidative stress assessed using plasma F2- IsoFs and IsoPs. PMID- 29156154 TI - Coconut phytocompounds inhibits polyol pathway enzymes: Implication in prevention of microvascular diabetic complications. AB - Coconut oil (CO), the primary choice of cooking purposes in the south Asian countries, is rich in medium chain saturated fatty acids, especially lauric acid (50-52%). The oil has high medicinal use in Ayurvedic system and known to contain polyphenolic antioxidants. Studies have reported that CO improves insulin sensitivity and shows hypoglycemic effect. However, there is no information regarding its effect on chronic diabetic complications including retinopathy and nephropathy is available. The secondary diabetic complications are mediated by the activation of polyol pathway, where aldose reductase (AR) plays crucial role. In this study, in silico analysis has been used to screen the effect of CO as well as its constituents, MCFAs and phenolic compounds, for targeting the molecules in polyol pathway. The study revealed that lauric acid (LA) interacts with AR and DPP-IV of polyol pathway and inhibits the activity of these enzymes. Validation studies using animal models confirmed the inhibition of AR and SDH in wistar rats. Further, the LA dose dependently reduced the expression of AR in HCT 15 cells. Together, the study suggests the possible role of CO, particularly LA in reducing secondary diabetic complications. PMID- 29156156 TI - Effects of arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid on brain development using artificial rearing of delta-6-desaturase knockout mice. AB - This study focused on the effect of polyunsaturated fatty acids (PUFAs) during the lactation period of delta-6-desaturase knockout (D6D-KO) mice using an artificial rearing method. Newborn pups of D6D-KO male mice were separated from their dams within 48h and were fed artificial milk. Six formulations of milk were used: Control (Cont) milk (3.9% alpha-linolenic acid and 18% linoleic acid), + 1.3% arachidonic acid (ARA), + 1.2% docosahexaenoic acid (DHA), + 1.3% eicosapentaenoic acid (EPA), + 1.1% ARA + 1.3% DHA, and + 1.3% ARA + 1.3% EPA. After weaning, the mice were fed pelleted diets containing a similar fatty acid composition as during lactation. Brain function was measured using a behavioral approach including motor activity and the Morris water maze test at 9 weeks of age. The body weight of the KO Cont group was significantly lower than that of the wild-type (WT) group; however, the ARA, ARA+DHA and ARA+EPA groups were similar to the WT group. In the Morris water maze test, the DHA and ARA+DHA groups demonstrated learning and memory performance similar to the WT group; however, the Cont group exhibited quite poor learning performance. Interestingly, the ARA, EPA and ARA+EPA groups showed intermediate performance between the Cont and WT groups. These results suggested that the 18-C essential fatty acids linoleic and alpha-linolenic were not sufficient to support optimal growth and neural performance. ARA was the most critical long-chain PUFA for supporting body growth. In addition, DHA was clearly essential for brain function. Taken together, these results indicate that the combination of DHA and ARA is essential for optimal growth and development in early life. PMID- 29156158 TI - International Congress on Soldiers' Physical Performance 2017: Research priorities across the service members operational lifecycle. PMID- 29156157 TI - Continuous gradient temperature Raman spectroscopy from -100 to 40 degrees C yields new molecular models of arachidonic acid and 2-Arachidonoyl-1-stearoyl-sn glycero-3-phosphocholine. AB - Despite its biochemical importance, a complete Raman analysis of arachidonic acid (AA, 20:4n-6) has never been reported. Gradient temperature Raman spectroscopy (GTRS) applies the temperature gradients utilized in differential scanning calorimetry (DSC) to Raman spectroscopy, providing a straightforward technique to identify molecular rearrangements that occur near and at phase transitions. Herein we utilize the GTRS technique for AA and 1-18:0, 2-20:4n-6 phosphatidyl choline (AAPC) from cryogenic to mammalian body temperatures. 20Mb three dimensional data arrays with 0.2 degrees C increments and first/second derivatives allowed complete assignment of solid, liquid and transition state vibrational modes. The AA DSC shows a large exothermic peak at -60 degrees C indicating crystallization or a similar major structural change. No exothermic peak of this magnitude was observed in six other unsaturated lipids (DHA, n-3DPA, n-6DPA, LA, ALA, OA). Melting in AA occurs over a large range: (-60 to -35 degrees C): very large frequency offsets and intensity changes correlate with premelting initiating circa -60 degrees C, followed by melting (-37 degrees C). Novel, unique 3D structures for both molecules reveal that AA is not symmetric as a free fatty acid, and it changes significantly when in the sn-2 phospholipid position. Further, different CH and CH2 sites are unequally elastic and nonequivalent. PMID- 29156155 TI - Leukotriene B4 indicates lung injury and on-going inflammatory changes after severe trauma in a porcine long-term model. AB - BACKGROUND: Recognizing patients at risk for pulmonary complications (PC) is of high clinical relevance. Migration of polymorphonuclear leukocytes (PMN) to inflammatory sites plays an important role in PC, and is tightly regulated by specific chemokines including interleukin (IL)-8 and other mediators such as leukotriene (LT)B4. Previously, we have reported that LTB4 indicated early patients at risk for PC after trauma. Here, the relevance of LTB4 to indicating lung integrity in a newly established long-term porcine severe trauma model (polytrauma, PT) was explored. METHODS: Twelve pigs (3 months old, 30 +/- 5kg) underwent PT including standardized femur fracture, lung contusion, liver laceration, hemorrhagic shock, subsequent resuscitation and surgical fracture fixation. Six animals served as controls (sham). After 72h lung damage and inflammatory changes were assessed. LTB4 was determined in plasma before the experiment, immediately after trauma, and after 2, 4, 24 or 72h. Bronchoalveolar lavage (BAL)-fluid was collected prior and after the experiment. RESULTS: Lung injury, local gene expression of IL-8, IL-1beta, IL-10, IL-18 and PMN infiltration into lungs increased significantly in PT compared with sham. Systemic LTB4 increased markedly in both groups 4h after trauma. Compared with declined plasma LTB4 levels in sham, LTB4 increased further in PT after 72h. Similar increase was observed in BAL-fluid after PT. CONCLUSIONS: In a severe trauma model, sustained changes in terms of lung injury and inflammation are determined at day 3 post-trauma. Specifically, increased LTB4 in this porcine long-term model indicated a rapid inflammatory alteration both locally and systemically. The results support the concept of LTB4 as a biomarker for PC after severe trauma and lung contusion. PMID- 29156159 TI - Amnion: The Ideal Scaffold for Treating Full-Thickness Wounds of the Lower Extremity. AB - Amnion and amniotic tissue has been studied for more than 100 years in the treatment of acute and chronic wounds. Recent studies have focused on the use of amnion tissue in the management of full-thickness diabetic wounds, particularly of the lower extremities. With new harvesting, processing, and distribution technologies, amnion is increasingly available in treating these wounds. Current data and research show increased healing potential and decreased healing times, pain, drainage, and infection in wounds treated with amnion products. There are a variety of amnion products with varying differences and purposes, requiring additional research and comparison trials. PMID- 29156160 TI - Treating Charcot Arthropathy Is a Challenge: Explaining Why My Treatment Algorithm Has Changed. AB - Charcot deformity is a challenge that foot and ankle surgeons struggle to manage successfully. Despite the advances in knowledge, technology, and treatment modalities, limb loss is still greater than 10%. This article discusses the efficacy of conservative measures and traditional surgical approaches. It proposes a multidisciplinary team approach, medical optimization, and lifestyle modification to put the patient in the best position to heal. Also discussed is the authors' staged surgical treatment protocol to enhance outcomes and decrease the rate of limb loss. PMID- 29156161 TI - The Use of Particulated Juvenile Allograft Cartilage in Foot and Ankle Surgery. AB - Particulated juvenile allograft cartilage (PJAC) has significant promise and is currently supported by several studies. Potential benefits of this new technique include single-stage procedure, simplicity in the surgical technique, implantation of juvenile tissue, and a lack of donor site morbidity. This article discusses the imaging, surgical options, and postoperative management of PJAC. PMID- 29156162 TI - The Evolution of Limb Deformity: What Has Changed over the Past Ten Years? AB - Limb deformity correction has been widely discussed in orthopedic literature with an increasing interest in technologically based surgical strategies. However, principles described by Ilizarov and Paley still form the basis of these newly developing surgical systems. The recent advances and increased use of computers and mobile devices in the medical arena, along with the application of dynamic hexapod external fixation, have allowed for easier and more convenient strategies, leading to a greater outreach and more confidence in the newer surgeon when faced with addressing a patient with a limb deformity. PMID- 29156163 TI - The Role of Polyvinyl Alcohol in Cartilage Repair of the Ankle and First Metatarsophalangeal Joint. AB - The Cartiva implant (Cartiva, Alpharetta, GA) is an exciting option in dramatically diminishing patient symptoms in advanced stages of hallux rigidus as well as allowing continued joint motion. The procedure does not burn many bridges in case a future revision to an arthrodesis is necessary. This advantage is in contradistinction to other current implants whereby more bone resection is required for implant placement. PMID- 29156164 TI - Bone Marrow Aspirate Concentrate and Its Uses in the Foot and Ankle. AB - Bone marrow aspirate has been used for the adjunctive treatment of numerous pathologic conditions in orthopedics. Viable cells are found in aspiration from many different anatomic regions of the body. Concentration of these cells has been shown to improve healing due to the increased number of certain important cells. This article discusses the mechanisms involved and reviews the literature. PMID- 29156165 TI - Understanding Frontal Plane Correction in Hallux Valgus Repair. AB - Hallux-abducto-valgus or "bunion" surgery is one of the most common surgical procedures for the foot and ankle specialist. As our understanding of the hallux abducto-valgus deformity has grown, it is becoming clear that the anatomic CORA of the deformity may lie at the tarsometatarsal joint. There is also the component of the 3-dimensional nature of the deformity that may be best addressed at this CORA. With these issues in mind, it was necessary to address the shortcomings of the traditional Lapidus procedure and progress toward more consistent, instrumented steps that could address the 3-dimensional nature of the deformity. PMID- 29156166 TI - Allograft Bone: What Is the Role of Platelet-Derived Growth Factor in Hindfoot and Ankle Fusions. AB - Arthrodesis of the ankle or foot is a common procedure for chronic pain and disability. Nonunion remains a prevalent complication among arthrodesis procedures. Some patients present with an inherent risk of developing a nonunion. Allograft biologics have gained popularity in an effort to reduce complications such as nonunion. Various biologics bring unique properties while maintaining a singular purpose. Platelet-derived growth factor (PDGF) may be introduced into a fusion site to facilitate healthy bony consolidation. The purpose of this article is to review the benefits and modalities of PDGF and how it can improve patient outcomes in ankle and hindfoot fusions. PMID- 29156167 TI - Advancements in Bone Fixation Utilizing Novel Biointegrative Fixation Technology. AB - Advancement in orthopedics have been increasing rapidly. The most important advances have been in fixation. With time, metallic hardware will begin to be replaced by materials that become one with the body. This progress will not only aid in the repair process it will allow permanent and improved reinforcement of the fixated region. Biointegrative technology is a promising new generation of materials capable of achieving this goal. Over time, it is expected that plates, screws, pins, interference screws, and even possibly joint replacements will incorporate into patients' bodies, negating the need for hardware removal and adding structure and stability to an iatrogenically weakened area. PMID- 29156168 TI - New Fixation Methods for the Treatment of the Diabetic Foot: Beaming, External Fixation, and Beyond. AB - Surgical correction of complex foot and ankle deformities secondary to Charcot neuroarthropathy remains a significant surgical challenge. New technological advancements in hardware have allowed for the use of augmented fixation techniques in midfoot deformity correction, including the use of indication specific locking plates and beaming techniques that offer enhanced stability. Severe hindfoot deformity management can employ the use of internal fixation, including intramedullary hindfoot nails and circular external fixation frames for limb salvage. PMID- 29156169 TI - Next-Generation, Minimal-Resection, Fixed-Bearing Total Ankle Replacement: Indications and Outcomes. AB - Total ankle arthroplasty is an increasingly popular procedure to address tibiotalar joint arthritis. Implant design and the rationale behind it have changed throughout the years. Newer generation implants allow for minimal resection of bone and use fixed-bearing technology. Long-term follow-up multicenter studies will determine the lifetime of these devices and their effectiveness in addressing pain and improving function for patients with endstage tibiotalar arthritis. PMID- 29156170 TI - Computed Navigation Guidance for Ankle Replacement in the Setting of Ankle Deformity. AB - Total ankle replacement (TAR) has evolved over the past decade as a treatment for end-stage ankle arthritis with improved survivorship. Despite the improving outcomes, ankle deformity represents a challenge to the foot and ankle surgeon with increased risk of implant failure. The use of preoperative computer-assisted guidance has led to better understanding the 3-dimensional ankle anatomy and associated deformities and allows for reproducible, anatomic placement of the TAR components. PMID- 29156171 TI - The Use of Decellularized Human Placenta in Full-Thickness Wound Repair and Periarticular Soft Tissue Reconstruction: An Update on Regenerative Healing. AB - Prolonged or incomplete healing of the foot and ankle can pose significant challenges. Therefore, investigators have begun searching for alternative treatment strategies. With advances in tissue engineering, decellularized human placental connective tissue matrix has been suggested as a means to achieve more rapid and complete healing for various soft tissue and bone procedures. Basic science and clinical studies have shown that decellularized human placental connective tissue matrix can support regenerative healing through cellular migration, accelerated tissue remodeling, and the establishment of functional tissue. Additional research is needed to fully explore and evaluate clinical applications within the foot and ankle. PMID- 29156172 TI - New Technologies in Foot and Ankle Surgery. PMID- 29156173 TI - New Technologies in Foot and Ankle Reconstruction. PMID- 29156174 TI - Harvey Feigenbaum, MD, and the Creation of Clinical Echocardiography: A Conversation With Barry J. Maron, MD. PMID- 29156176 TI - Management of Patients With Left Ventricular Assist Devices Requiring Teeth Extraction: Is Halting Anticoagulation Appropriate? AB - PURPOSE: An increasing number of patients with end-stage heart failure are supported with left ventricular assist device (LVAD) implantation and must be maintained on a consistent anticoagulation regimen. Pre-emptive extraction of carious teeth in these patients is necessary to prevent seeding of the implanted device and endocarditis. Thus, the objective of this study was to evaluate bleeding complications after minor oral surgery, specifically teeth extractions, in this unique patient population requiring long-term anticoagulation. MATERIALS AND METHODS: This study was a retrospective single-center review. Adult patients supported on an implanted continuous-flow LVAD from January 1, 2007 to December 31, 2016 were included. Baseline characteristics were collected by retrospective chart review and the institutional LVAD registry. All extractions were performed in the operating room under local anesthesia with moderate sedation or general anesthesia with nasal intubation, and LVAD settings were monitored by a trained perfusionist. Preoperative and postoperative hematology laboratory values, such as hemoglobin and international normalized ratio (INR), were collected by chart review. Continuous variables were presented as mean +/- standard deviation and compared using the Student t test. Categorical variables were presented as proportion and percentage and compared using the chi2 test or Fisher exact test as appropriate. Statistical significance was established at a P value less than .05. RESULTS: After screening 798 patients, 32 (4%) were found to have undergone dental extractions after LVAD implantation. The sample was composed of 32 patients with a mean age of 60.13 years and 81.25% were men. The average time from LVAD implantation to extraction was 445.19 +/- 1,108.53 days. Average preoperative INR was 1.76 +/- 0.47. Preoperative fresh frozen plasma was not administered to any patients. Twenty-eight patients (87.5%) were on Coumadin (warfarin) preoperatively. In 11 of these 28 patients (39.3%), Coumadin was held preoperatively. The average postoperative change in hemoglobin level was -0.79 +/ 1.45. Only 1 patient (3%) required postoperative blood transfusion for a hemoglobin level of 7.6 that responded appropriately. There were no reoperations for bleeding. CONCLUSIONS: Minor oral surgical procedures can be performed safely for patients being supported on LVAD therapy. With primary closure of the gingiva at the site of extraction, dental extractions can be performed without the full reversal of anticoagulation. PMID- 29156177 TI - Proceedings of the American Association of Oral and Maxillofacial Surgeon's 2017 Clinical and Scientific Innovations in Oral and Maxillofacial Surgery (CSIOMS). AB - The sixth biennial Clinical and Scientific Innovations in Oral and Maxillofacial Surgery, formerly the Research Summit, of the American Association of Oral and Maxillofacial Surgeons and its Committee on Research Planning and Technology Assessment was held in Rosemont, Illinois from April 28 to 30, 2017. The goal of the symposium is to provide a forum for the latest clinical and scientific advances to be brought to the specialty. It also nurtures collaboration and the development of relationships between oral and maxillofacial surgeons and researchers to bridge the gap between clinical and basic science. The goal is to improve the care of oral and maxillofacial surgical patients through the advancement of translational and clinical research. PMID- 29156178 TI - Introduction: The State of Obesity in 2017. AB - Obesity continues to be a major national and global health challenge and a risk factor for an expanding set of chronic diseases. In 2015, high body mass index contributed to 4.0 million deaths globally, which represented 7.1% of the deaths from any cause. Obesity is now regarded as a disease, and multiple health care societies have begun to tackle obesity as a discrete target for assessment and treatment that is supported by several position statements and guidelines. Nonetheless, a perception and treatment gap continues to exist between health care providers and patients regarding the provision of obesity care. PMID- 29156180 TI - The Role of Behavioral Medicine in the Treatment of Obesity in Primary Care. AB - Behavioral medicine provides a framework for supporting patients to achieve changes in target health behaviors, such as dietary and physical activity changes. Behavioral medicine fits alongside traditional medical treatments, can minimize the need for more intensive medical treatments, improves outcomes of these treatments, and improves adherence to medication prescriptions or postsurgical recommendations. This article provides an overview of behavioral medicine counseling for obesity in primary care, rooted in the "5 As" approach to health behavior change, and the basic outline of behavioral skills interventions in which health care providers use self-regulatory and behavioral strategies to improve health-related behaviors among patients with obesity. PMID- 29156181 TI - Obesity as a Disease. AB - Obesity is a complex disease with many causal factors, associated with multiple comorbidities that contribute to significant morbidity and mortality. It is a highly prevalent disease that poses an enormous health and economic burden to society. This article reviews the mechanisms of obesity and its related comorbidities. PMID- 29156179 TI - Dietary Management of Obesity: Cornerstones of Healthy Eating Patterns. AB - Several dietary patterns, both macronutrient and food based, can lead to weight loss. A key strategy for weight management that can be applied across dietary patterns is to reduce energy density. Clinical trials show that reducing energy density is effective for weight loss and weight loss maintenance. A variety of practical strategies and tools can help facilitate successful weight management by reducing energy density, providing portion control, and improving diet quality. The flexibility of energy density gives patients options to tailor and personalize their dietary pattern to reduce energy intake for sustainable weight loss. PMID- 29156182 TI - Obesity Pharmacotherapy. AB - Although diet, physical activity, and behavioral modifications are the cornerstones of weight management, weight loss achieved by lifestyle modifications alone is often limited and difficult to maintain. Pharmacotherapy for obesity can be considered if patients have a body mass index (BMI) of 30 kg/m2 or greater or BMI of 27 kg/m2 or greater with weight-related comorbidities. The 6 most commonly used antiobesity medications are phentermine, orlistat, phentermine/topiramate extended release, lorcaserin, naltrexone sustained release (SR)/bupropion SR, and liraglutide 3.0 mg. Successful pharmacotherapy for obesity depends on tailoring treatment to patients' behaviors and comorbidities and monitoring of efficacy, safety, and tolerability. PMID- 29156183 TI - Medical Devices for Obesity Treatment: Endoscopic Bariatric Therapies. AB - Endoscopic bariatric therapies (EBTs) are effective tools for the management of obesity. By mimicking restrictive and bypass surgery physiology, they provide a safe and effective treatment option with the added capabilities of reaching a broader population. Multiple efficacious medical devices, such as intragastric balloons, endoscopic suturing/plication devices, and bypass liners, at various stages of development are available in the United States. EBTs represent the newest addition to a multidisciplinary approach in obesity management. This article reviews several devices' safety and efficacy for primary care providers in the era of evolving obesity treatment. PMID- 29156184 TI - Bariatric Surgery for Obesity. AB - In this review, the authors discuss the indications for and the published outcomes of commonly performed bariatric procedures, including weight loss, perioperative morbidity and mortality, late complications, as well as the impact of bariatric surgery on comorbidities, cardiovascular risk, and mortality. They also briefly discuss the mechanisms by which bariatric/metabolic surgery causes such significant weight loss and health gain. PMID- 29156186 TI - Treatment of Obesity in Primary Care. AB - This article outlines some of the behavioral, pharmacologic, and surgical interventions available to primary care physicians (PCPs) to help their patients with weight management. Studies on lifestyle modification, commercial weight loss programs, and medical and surgical options are reviewed. Several clinical suggestions on obesity management that PCPs can take back and use immediately in office practice are offered. PMID- 29156185 TI - Maintenance of Lost Weight and Long-Term Management of Obesity. AB - Weight loss can be achieved through a variety of modalities, but long-term maintenance of lost weight is much more challenging. Obesity interventions typically result in early weight loss followed by a weight plateau and progressive regain. This review describes current understanding of the biological, behavioral, and environmental factors driving this near-ubiquitous body weight trajectory and the implications for long-term weight management. Treatment of obesity requires ongoing clinical attention and weight maintenance specific counseling to support sustainable healthful behaviors and positive weight regulation. PMID- 29156187 TI - Guideline Recommendations for Obesity Management. AB - It is an obligation for all health care providers to participate in obesity management. This article discusses obesity guidelines from The Obesity Society; the Endocrine Society; and the American Association of Clinical Endocrinologists. It reviews and compares findings and recommendations across these guidelines, identifies areas of controversy and concordance, and suggests how primary care practices may make use of the most appropriate recommendations for their circumstances. PMID- 29156190 TI - In Search of the 70-kg Man. PMID- 29156191 TI - Obesity Medicine: A Core Competency for Primary Care Providers. PMID- 29156188 TI - Addressing Obesity in Aging Patients. AB - Obesity in older adults affects not only morbidity and mortality but, importantly, quality of life and the risk of institutionalization. Weight loss interventions can effectively lead to improved physical function. Diet-alone interventions can detrimentally affect muscle and bone physiology and, without interventions to affect these elements, can lead to adverse outcomes. Understanding social and nutritional issues facing older adults is of utmost importance to primary care providers. This article will also discuss the insufficient evidence related to pharmacotherapy as well as providing an overview of using physiologic rather than chronologic age for identifying suitable candidates for bariatric surgery. PMID- 29156192 TI - Editorial overview: Synthetic biology: Frontiers in synthetic biology. PMID- 29156193 TI - Editorial overview: Synthetic biomolecules: Biopolymers. PMID- 29156189 TI - Obesity in Pregnancy: Optimizing Outcomes for Mom and Baby. AB - Obesity is common in women of childbearing age, and management of this population around the time of pregnancy involves specific challenges. Weight and medical comorbidities should be optimized both before and during pregnancy. During pregnancy, gestational weight gain should be limited, comorbidities should be appropriately screened for and managed, and fetal health should be monitored. Consideration should be given to the optimal timing of delivery and to reducing surgical and anesthetic complications. In the postpartum period, breastfeeding and weight loss should be promoted. Maternal obesity is associated with adverse metabolic effects in offspring, promoting an intergenerational cycle of obesity. PMID- 29156194 TI - Editorial Special Supplement of the European Journal of Pharmaceutical Sciences on the occasion of the retirement of Professor Meindert Danhof as Professor of Pharmacology at Leiden University. PMID- 29156195 TI - AML in 2017: Advances in clinical practice. AB - Numerous advances have been made in the biology and treatment of acute myeloid leukemia (AML) in 2017. These include the integration of the assessment of minimal residual disease (MRD) into clinical practice, the approval and near approval of new agents, improvement in therapy for older patients, and the development of a number of promising new agents, including IDH inhibitors, a Hedgehog signaling pathway inhibitor, and a histone deacetylase inhibitor. In addition, the concept of chemotherapy manipulation is still valid and can increase efficacy in some AML populations, and transplant patterns have shifted, enabling more patients to receive a hematopoietic stem cell transplant. These and other advances are critical to improve the outcome for patients with AML. PMID- 29156196 TI - Familial myelodysplastic syndrome/acute myeloid leukemia. AB - A growing number of inherited genetic loci that contribute to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) development in both children as well as adults are rapidly being identified. In recognition of the clinical impact of this emerging field, the World Health Organization, National Comprehensive Cancer Network, and European LeukemiaNet have all added consideration of inherited predisposition to MDS/AML classification and management. Study of these disorders is providing unique insight into the biology of both sporadic and familial MDS/AML. International collaborative efforts to store germline tissue, document family histories, and pool data are essential to progress in diagnosing and treating both hereditary and sporadic forms of MDS/AML. PMID- 29156197 TI - Mutational complexity in myelodysplasia. AB - Myelodysplastic syndromes are characterized by genetic and clinical heterogeneity. Some mutations are able to drive clonal hematopoiesis without causing clinical consequences, while other mutations may have significant impact, including the transformation to leukemia. This review aims to describe the pathogenesis of myelodysplastic syndromes (MDS) by focusing on 3 aspects: combinatorial genetic events, environmental factors, and inherited genetic conditions. PMID- 29156198 TI - The evolving role of genomic testing in assessing prognosis of patients with myelodysplastic syndromes. AB - The introduction into routine hematology-oncology clinical practice of molecular genetic testing assays based on next-generation sequencing platforms is prompting reassessment of the importance of molecular assay results in comparison to existing disease-specific risk stratification tools based on clinical assessment and light microscopy. For patients with myelodysplastic syndromes (MDS), the most commonly used tools for prognostication currently include the International Prognostic Scoring System (IPSS) and the Revised IPSS (IPSS-R), which are based on marrow blast proportion, number and degree of cytopenias, and the metaphase karyotype. Integration of DNA sequencing data into an existing evidence-based practice approach inclusive of the IPSS or IPSS-R may be challenging, but the additional information provided by molecular genetic testing clearly can influence clinical decisions, such as determining patients' eligibility for clinical trials of novel targeted agents or helping assess which patients should be referred for allogeneic hematopoietic stem cell transplantation. This review discusses the prognostic and predictive value of mutation testing in the context of current clinical care of patients with MDS. PMID- 29156199 TI - How can one optimize induction therapy in AML? AB - Induction therapy for acute myeloid leukemia has not changed much since 1973, when the 7 + 3 regimen of cytarabine and daunorubicin was born. Since then, various strategies have been evaluated to improve patient response, including dose intensification, the incorporation of additional agents into the regimen, the development of novel agents, and modified approaches for older patients. Recently, two novel agents, CPX-351 and gemtuzumab ozogamicin, have been approved by the US Food and Drug Administration. This review discusses each of the induction strategies and their impact on patient outcomes. PMID- 29156200 TI - Do cytogenetics affect the post-remission strategy for older patients with AML in CR1? AB - Data have shown that intensified cytarabine in consolidation for treatment of acute myeloid leukemia (AML) does not equally benefit patients older than 60 years, and older patients experience significantly more neurotoxicity than younger patients. In addition, older patients are more likely to have abnormal or unfavorable cytogenetics, which also tend to confer limited efficacy with intensified cytarabine. This poses a treatment dilemma as to the best post remission therapy to treat older patients. This review explores some of the consolidation treatment strategies and options available for the older AML patient. PMID- 29156201 TI - Which new agents will be incorporated into frontline therapy in acute myeloid leukemia? AB - For 4 decades, new agents had not been permanently approved for use in treating acute myeloid leukemia (AML). The long dry spell was broken in 2017, however, with the approval of several agents: midostaurin for addition to chemotherapy in mutant FLT3 patients undergoing intensive chemotherapy, enasidenib in advanced mutant IDH2 patients, CPX-351 in secondary AML patients, and gemtuzumab ozogamicin in conjunction with standard chemotherapy in AML. This review surveys the use of tyrosine kinase inhibitors to treat patients with mutant FLT3 AML, mutant KIT AML, as well as IDH inhibitors and explores some questions regarding their integration into the treatment armamentarium for AML. PMID- 29156202 TI - Relapsed acute lymphoblastic leukemia: Is it crucial to achieve molecular remission prior to transplant? AB - In patients with acute lymphoblastic leukemia (ALL) the risk of recurrent leukemia influences the choice of treatment between chemotherapy and allogeneic hematopoietic cell transplantation. The evaluation of minimal residual disease (MRD) is now considered to be the greatest progress in risk stratification in regard to leukemia recurrence. Achieving molecular remission at the end of induction therapy after diagnosis or after relapse has influenced treatment choice. Failure to achieve molecular remission is considered "high risk" and allogeneic hematopoietic cell transplantation with a suitable donor, the accepted standard. Nevertheless, published reports support lower relapse and higher survival rates for those in molecular remission at transplantation compared to those in morphological remission. In the setting of relapsed ALL, the availability of targeted therapies offers an opportunity for molecular remission so that transplant recipients have the best possible option of attaining sustained remission upon completion of this treatment. PMID- 29156203 TI - Impact of allogeneic hematopoietic cell transplantation on the outcome of older patients with acute myeloid leukemia. AB - For younger patients with intermediate- or high-risk acute myeloid leukemia (AML) in first remission, allogeneic hematopoietic cell transplantation (HCT) offers the best chance of cure and therefore is the treatment of choice. The role of allogeneic HCT in the treatment of older patients is less well defined. In this review, four issues concerning the role of HCT in the treatment of older AML patients will be addressed: the frequency of allogeneic HCT in the older AML population in the US; the impact of age on the outcome of HCT; the comparative outcome of allogeneic HCT versus chemotherapy in older AML patients; and some of the barriers to the effective use of HCT in older AML patients. PMID- 29156204 TI - Autologous hematopoietic cell transplantation for adult acute myeloid leukemia: An obsolete or resurfacing concept? AB - Improving long-term outcomes of adult acute myeloid leukemia (AML) patients remains a challenge. Major scientific and clinical advances have led to a better understanding of the disease biology, and the majority of patients achieve a complete remission (CR) after induction therapy. Relapse risk, however, remains considerable and is the leading cause of death in this patient population. Significant efforts to improve outcomes emphasize use of post-remission therapies such as hematopoietic cell transplantation (HCT), an increasingly utilized modality. Improvement in transplantation techniques, understanding of donor:recipient histocompatibility, and increased availability of alternative donors have resulted in greater use of allogeneic HCT. Despite a graft-versus leukemia effect and lower post-HCT relapse rates, allogeneic HCT continues to be plagued by treatment-related mortality (TRM) and chronic graft-versus-host disease. Better understanding of AML risk stratification and issues relating to minimal residual disease (MRD) as well as extremely low TRM rates with autografts have prompted clinicians to re-explore use of autologous HCT in subsets of favorable and intermediate-risk CR1 AML patients. Herein, we highlight the evolving literature and treatment outcomes for autologous HCT in AML. We provide recommendations for considering this therapeutic modality for treatment intensification in AML. PMID- 29156205 TI - Which factors influence the development of GVHD in HLA-matched or mismatched transplants? AB - The sheer diversity of HLA alleles makes the probability of finding matched unrelated donors for patients requiring hematopoietic cell transplantation (HCT) a complex situation. New evidence suggests that mismatching at certain HLA loci may provide a greater benefit in terms of graft-versus-leukemia effect than other mismatches when HLA-matched donors are not available. This review summarizes the current understanding of HLA matching requirements for unrelated donor HCT. PMID- 29156206 TI - Cytokine release syndrome: Who is at risk and how to treat. AB - T-cell engaging therapies such as blinatumomab and anti-CD19 chimeric antigen receptor (CAR) T cells have revolutionized our approach to patients with relapsed and refractory acute lymphoblastic leukemia (ALL). However, the immune activation responsible for high remission rates is also responsible for the unique treatment related toxicity of cytokine release syndrome (CRS). The clinical signs of CRS include fever, hemodynamic instability, and capillary leak, which correlate with T-cell activation and elevated cytokine levels. Tocilizumab, an anti-IL-6 receptor antagonist, provides control of severe CRS induced by CAR T cells without being directly T cell toxic. With blinatumomab, the approach to CRS has been largely preventative with administration strategies that include disease cytoreduction, corticosteroid premedication, and dose titration. PMID- 29156207 TI - Intracellular protein degradation: From a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. AB - Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins, but how proteins are degraded has remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis is largely non-lysosomal, but the mechanisms involved remained obscure. The discovery of the ubiquitin proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs. PMID- 29156208 TI - From the Editor's desk...: December 2017. PMID- 29156209 TI - Changes in hemostasis in liver disease. PMID- 29156210 TI - Corrigendum to "Zika Virus Causes Persistent Infection in Porcine Conceptuses and May Impair Health in Offspring". PMID- 29156211 TI - Parents' Use of Nonpharmacologic Methods to Manage Procedural Pain in Infants. AB - OBJECTIVE: To describe parents' use of nonpharmacologic methods to manage infant procedural pain in the NICU and determine the demographic factors related to such use. DESIGN: A cross-sectional and descriptive study design. SETTING: Level III and Level II NICUs (seven units) of four University Hospitals in Finland. PARTICIPANTS: Parents (N = 178) whose infants were treated in Finnish NICUs. METHODS: Parents were asked to respond to a structured questionnaire during their infants' hospitalizations. We analyzed the data using the nonparametric Kruskal Wallis one-way analysis of variance and Mann-Whitney U test. RESULTS: Most parents reported that they used physical methods, such as touching, holding, and positioning, nearly always/always (86%, 76%, and 55%, respectively). However, less commonly used strategies included recorded music (2%), breastfeeding (2%), and non-nutritive sucking with oral sucrose (6%). Many characteristics of the infants, such as their gestational ages and their conditions, were significantly related to the implementation of nonpharmacologic methods. CONCLUSION: There is a clear need to extend parents' use of nonpharmacologic methods to manage their infants' procedural pain in the NICU. Because many methods were not considered as pain-relieving strategies, it is important to increase knowledge about the effectiveness of these interventions among parents and nurses. PMID- 29156212 TI - History and Purpose of Postpartum Support International. AB - Postpartum Support International provides training for professionals and supports families who experience perinatal mood and anxiety disorders. The purpose of this article is to describe Postpartum Support International, which was founded in 1987 to increase awareness among public and professional communities about the emotional difficulties women experience during and after pregnancy. We recommend strategies with which health care professionals can support families, reduce stigma, and offer resources for treatment and support. PMID- 29156213 TI - HOCl and the control of oncogenesis. AB - Sustained generation of extracellular superoxide anions by membrane-associated NADPH oxidase-1 is a hallmark of malignant transformation. The resulting H2O2 drives the proliferation of malignant cells and is converted to HOCl by a Dual oxidase-related peroxidase domain that acts analogously to myeloperoxidase. Whereas H2O2 induces apoptosis nonselectively in nontransformed and transformed cells, HOCl selectively affects malignant cells, as the interaction between HOCl and extracellular superoxide anions allows for site-specific generation of apoptosis-inducing hydroxyl radicals. Transformed cells (early stages of tumor progression) and bona fide tumor cells (representing late stages of tumor progression) respond to exogenous HOCl or HOCl generated by professional phagocytes with induction of apoptosis. In contrast, only transformed cells have the potential to synthesize HOCl through interaction between their superoxide anions/H2O2 and Dual oxidase-related peroxidase released by themselves or neighbouring nontransformed or transformed effector cells. Tumor cells prevent HOCl synthesis through membrane-associated catalase that decomposes H2O2, the substrate for peroxidase, and thus prevents HOCl synthesis. Elimination of malignant cells through HOCl signaling is prevented by Helicobacter pylori associated catalase and superoxide dismutase, whereas it is enhanced by low dose irradiation and by H2O2-producing lactobacilli in the presence of myeloperoxidase. Peroxidase and catalase that are involved in the control of HOCl signaling are also affecting apoptosis-inducing pathways based on reactive nitrogen species. Modification of tumor cell proteins by HOCl enhances the establishment of a T cell response and thus might be involved in immunogenic modulation. Therefore, targeting the control of HOCl signaling system should allow one to establish novel rational therapeutic approaches. PMID- 29156214 TI - Corrigendum to "Dynamics of EEG functional connectivity during statistical learning" [Neurobiol. Learn. Mem. 144 (2017) 216-229]. PMID- 29156215 TI - Gadolinium perturbs expression of skeletogenic genes, calcium uptake and larval development in phylogenetically distant sea urchin species. AB - Chelates of Gadolinium (Gd), a lanthanide metal, are employed as contrast agents for magnetic resonance imaging and are released into the aquatic environment where they are an emerging contaminant. We studied the effects of environmentally relevant Gd concentrations on the development of two phylogenetically and geographically distant sea urchin species: the Mediterranean Paracentrotus lividus and the Australian Heliocidaris tuberculata. We found a general delay of embryo development at 24h post-fertilization, and a strong inhibition of skeleton growth at 48h. Total Gd and Ca content in the larvae showed a time- and concentration-dependent increase in Gd, in parallel with a reduction in Ca. To investigate the impact of Gd on the expression of genes involved in the regulation of skeletogenesis, we performed comparative RT-PCR analysis and found a misregulation of several genes involved in the skeletogenic and left-right axis specification gene regulatory networks. Species-specific differences in the biomineralization response were evident, likely due to differences in the skeletal framework of the larvae and the amount of biomineral produced. Our results highlight the hazard of Gd for marine organisms. PMID- 29156216 TI - Covert retrieval in working memory impacts the phenomenological characteristics remembered during episodic memory. AB - Much research has investigated the qualitative experience of retrieving events from episodic memory (EM). The present study investigated whether covert retrieval in WM increases the phenomenological characteristics that participants find memorable in EM using tasks that distract attention from the maintenance of memoranda (i.e., complex span; Experiment 1) relative to tasks that do not (i.e., short or long list lengths of simple span; Experiments 1 and 2). Participants rated the quality of the phonological, semantic, and temporal-contextual characteristics remembered during a delayed memory characteristics questionnaire (MCQ). Whereas an advantage of the complex over simple span items was observed for each characteristic (Experiment 1), no such difference was observed between short and long trials of simple span (Experiment 2). These results are consistent with the view that covert retrieval in WM promotes content-context bindings that are later accessible from EM for both objective performance and subjective details of the remembered information. PMID- 29156217 TI - Characterization of UDP-glucosyltransferase from Indigofera tinctoria. AB - Indican is a secondary metabolite in Indigofera tinctoria; its synthesis from indoxyl and UDP-glucose is catalyzed by a UDP-glucosyltransferase (UGT). In this study, we partially purified UGT extracted from I. tinctoria leaves and analyzed the protein by peptide mass fingerprinting. We identified two fragments that were homologous to UGT after comparison with the transcriptomic data of I. tinctoria leaves. The fragments were named itUgt1 and itUgt2 and were amplified using rapid amplification of cDNA ends polymerase chain reaction to obtain full-length cDNAs. The resultant nucleotide sequences of itUgt1 and itUgt2 encoded peptides of 477 and 475 amino acids, respectively. The primary structure of itUGT1 was 89% identical to that of itUGT2 and contained an important plant secondary product glycosyltransferase (PSPG) box sequence and a UGT motif. The recombinant proteins expressed in Escherichia coli were found to possess high indican synthesis activity. Although the properties of the two proteins itUGT1 and itUGT2 were very similar, itUGT2 was more stable at high temperatures than itUGT1. Expression levels of itUGT mRNA and protein in plant tissues were examined by UGT assay, immunoblotting, and semi-quantitative reverse transcription polymerase chain reaction. So far, we presume that itUGT1, but not itUGT2, primarily catalyzes indican synthesis in I. tinctoria leaves. PMID- 29156218 TI - Use of luminescent gunshot residues markers in forensic context-Part II. AB - Gunshot residues (GSR) are important physical evidence in firearm-related crimes. Recently developed non-toxic ammunition, however, requires a new methodology for its characterization. To overcome this drawback, the introduction of noncommercial luminescent markers in ammunition was proposed. These markers, synthesized and added to the gunpowder, presented as a versatile tool for GSR analysis, since they require UV radiation alone to visualize the luminescent GSR (LGSR). This has opened up new perspectives for understanding GSR behavior at a crime scene. This work aims to expand previous studies performed with the luminescent markers in forensic contexts, exploring four different important aspects related to GSR behavior. Using LGSR amount/dispersion and a series of blind tests with marked ammunition, we tried to (1) identify the shooter position; (2) estimate the shooting distance; (3) evaluate the influence of the pistol type on the LGSR distribution on the shooter's hands and guns; and (4) study the transference of LGSR by a chain of handshaking. For this purpose, a portable UV lamp (lambda=254nm) and/or techniques such as video spectral comparator (VSC) and scanning electron microscopy with energy dispersive X-ray analysis (SEM/EDS) were used to visualize and analyze the residues. As a result, the observation of the LGSR enabled accurate determination of the shooter position and the firing distance without any chemicals. Besides, the LGSR were visualized on different kinds of pistols, regardless of firing mechanism. And finally, this study evidenced transference of residues from shaking hands with the shooter, which should be carefully considered when interpreting the results of a GSR analysis. PMID- 29156219 TI - Scapular upward rotation position is symmetrical in swimmers without current shoulder pain. AB - OBJECTIVES: A history of shoulder pain is common in swimmers and may influence scapular position, possibly increasing the risk of shoulder pain recurring. The aim of this study was to establish and compare bilateral static measures of scapular upward rotation in swimmers (14-20 years), some with a history of shoulder pain but all currently pain free, in two different elevated positions of shoulder abduction. DESIGN: Cross-sectional, observational study. PARTICIPANTS: Eighty-five swimmers without current shoulder pain. METHODS: Scapular upward rotation position was measured on both shoulders using a digital inclinometer in 90 degrees and 140 degrees shoulder abduction. Descriptive statistics were calculated for degrees of scapular upward rotation in both shoulder positions. Differences between shoulders (dominant, non-dominant, history and no history of pain) were explored using one-way ANOVA and paired t tests. RESULTS: A large range of values for scapular upward rotation was found at both positions of shoulder abduction but there were no significant differences between the shoulders: with and without a history of shoulder pain for the dominant and non dominant sides. CONCLUSIONS: A history of shoulder pain and arm dominance did not influence scapular upward rotation position when measured in shoulder abduction in swimmers without current shoulder pain. PMID- 29156220 TI - The epilepsy phenotype in adult patients with intellectual disability and pathogenic copy number variants. AB - PURPOSE: To characterize the electroclinical features of epilepsy associated with intellectual disability and pathogenic copy number variations (CNVs) METHODS: we prospectively investigated 61 adult patients with epilepsy and intellectual disability or other neurodevelopmental disorders. We performed high resolution SNP-Array analysis in order to detect clinical relevant chromosomal microdeletions and microduplications. An ordinal logistic regression model was fitted with 34 demographic, clinical and EEG-related variables in order to identify the epilepsy phenotype of patients with pathogenic CNVs. RESULTS: chromosome microarray analysis identify non-polymorphic CNVs in 33 patients analyzed: 11 had an established pathogenic microdeletion/microduplication, 22 were carriers of CNVs of unknown clinical significance. Univariate analysis revealed a significant association between pathogenic CNVs and 3 electroclinical variables considered, specifically atypical absence seizures (p<0.05), tonic seizures (p<0.05), epileptic spasms (p<0.01). CONCLUSIONS: high resolution SNP Array analysis should be evaluated in adult patients with intellectual disability and epilepsy with peculiar electroclinical features, specifically atypical absence seizures, tonic seizures, and epileptic spasms, resembling a Lennox Gastaut syndrome without a clear structural lesion. PMID- 29156221 TI - Novel recruitment models will drive Alzheimer's trial success. PMID- 29156222 TI - Cerebral small vessel disease in middle age and genetic predisposition to late onset Alzheimer's disease. AB - INTRODUCTION: Cerebral small vessel disease (CSVD) is associated with late-onset Alzheimer's disease (LOAD) and might contribute to the relationship between apolipoprotein E epsilon4 (APOE epsilon4) and LOAD, in older people. However, it is unclear whether CSVD begins in middle age in individuals genetically predisposed to LOAD. METHODS: We assessed the relationship between radiological markers of CSVD, white matter hyperintensities and microbleeds, and genetic predisposition to LOAD in a cross-sectional analysis of cognitively normal subjects aged 40-59 years recruited from the PREVENT Dementia study. RESULTS: Microbleed prevalence was 14.5%, and mean +/- standard deviation white matter hyperintensity percentage of total brain volume was 0.41 +/- 0.28%. There was no significant association between APOE epsilon4 carrier status or history of parental dementia and white matter hyperintensity volume (P = .713, .912 respectively) or microbleeds (P = .082, .562 respectively) on multiple regression. DISCUSSION: Genetic predisposition to LOAD, through APOE genotype or AD family history, is not associated with CSVD in middle age. PMID- 29156224 TI - Synthesis of 3-aminopropyl beta-(1 -> 6)-d-glucotetraoside and its biotinylated derivative. AB - 3-Aminopropyl beta-(1 -> 6)-d-glucotetraoside has been synthesized from 3 benzyloxycarbonylaminopropanol and 6-O-acetyl-2,3,4-tri-O-benzoyl-d glucopyranosyl trichloroacetimidate by successive attachment of one monosaccharide unit in total yield of 22%. Free aminopropyl glycoside was converted into a biotin derivative that can be used for controlled immobilization of the oligosaccharide on streptavidin-coated ELISA plates and for tracing carbohydrate binding molecules. PMID- 29156225 TI - Differences between auditory frequency-following responses and onset responses: Intracranial evidence from rat inferior colliculus. AB - A periodic sound, such as a pure tone, evokes both transient onset field potential responses and sustained frequency-following responses (FFRs) in the auditory midbrain, the inferior colliculus (IC). It is not clear whether the two types of responses are based on the same or different neural substrates. Although it has been assumed that FFRs are based on phase locking to the periodic sound, the evidence showing the direct relationship between the FFR amplitude and the phase-locking strength is still lacking. Using intracranial recordings from the rat central nucleus of inferior colliculus (ICC), this study was to examine whether FFRs and onset responses are different in sensitivity to pure-tone frequency and/or response-stimulus correlation, when a tone stimulus is presented either monaurally or binaurally. Particularly, this study was to examine whether the FFR amplitude is correlated with the strength of phase locking. The results showed that with the increase of tone-stimulus frequency from 1 to 2 kHz, the FFR amplitude decreased but the onset-response amplitude increased. Moreover, the FFR amplitude, but not the onset-response amplitude, was significantly correlated with the phase coherence between tone-evoked potentials and the tone stimulus. Finally, the FFR amplitude was negatively correlated with the onset-response amplitude. These results indicate that periodic-sound-evoked FFRs are based on phase-locking activities of sustained-response neurons, but onset responses are based on transient activities of onset-response neurons, suggesting that FFRs and onset responses are associated with different functions. PMID- 29156223 TI - Exploring APOE genotype effects on Alzheimer's disease risk and amyloid beta burden in individuals with subjective cognitive decline: The FundacioACE Healthy Brain Initiative (FACEHBI) study baseline results. AB - INTRODUCTION: Subjective cognitive decline (SCD) has been proposed as a potential preclinical stage of Alzheimer's disease (AD). Nevertheless, the genetic and biomarker profiles of SCD individuals remain mostly unexplored. METHODS: We evaluated apolipoprotein E (APOE) epsilon4's effect in the risk of presenting SCD, using the Fundacio ACE Healthy Brain Initiative (FACEHBI) SCD cohort and Spanish controls, and performed a meta-analysis addressing the same question. We assessed the relationship between APOE dosage and brain amyloid burden in the FACEHBI SCD and Alzheimer's Disease Neuroimaging Initiative cohorts. RESULTS: Analysis of the FACEHBI cohort and the meta-analysis demonstrated SCD individuals presented higher allelic frequencies of APOE epsilon4 with respect to controls. APOE dosage explained 9% (FACEHBI cohort) and 11% (FACEHBI and Alzheimer's Disease Neuroimaging Initiative cohorts) of the variance of cerebral amyloid levels. DISCUSSION: The FACEHBI sample presents APOE epsilon4 enrichment, suggesting that a pool of AD patients is nested in our sample. Cerebral amyloid levels are partially explained by the APOE allele dosage, suggesting that other genetic or epigenetic factors are involved in this AD endophenotype. PMID- 29156227 TI - Low physiological arousal and high impulsivity as predictors of self-injurious thoughts and behaviors among adolescents. AB - Self-injurious thoughts and behaviors are used to escape or regulate aversive physiological states during stress. Low sympathetic nervous system arousal during stress has been shown to confer risk. This risk may be exacerbated by trait impulsivity; adolescents high in impulsivity are more likely to rashly use maladaptive regulation strategies. We examined this relationship longitudinally in a sample of adolescents ages 10 to 14 (55.4% female) from the United States. Consistent with our hypothesis, low arousal during stress and high trait impulsivity interacted to predict the use of self-injurious thoughts and behaviors over a six-month period. This study extends and clarifies previous research findings regarding the relationship between physiological arousal and self-injurious thoughts and behaviors. PMID- 29156226 TI - Frequency of brain MRI abnormalities in neuromyelitis optica spectrum disorder at presentation: A cohort of Latin American patients. AB - BACKGROUND: Brain magnetic resonance imaging (BMRI) lesions were classically not reported in neuromyelitis optica (NMO). However, BMRI lesions are not uncommon in NMO spectrum disorder (NMOSD) patients. OBJECTIVE: To report BMRI characteristic abnormalities (location and configuration) in NMOSD patients at presentation. METHODS: Medical records and BMRI characteristics of 79 patients with NMOSD (during the first documented attack) in Argentina, Brazil and Venezuela were reviewed retrospectively. RESULTS: BMRI abnormalities were observed in 81.02% of NMOSD patients at presentation. Forty-two patients (53.1%) showed typical-NMOSD abnormalities. We found BMRI abnormalities at presentation in the brainstem/cerebellum (n = 26; 32.9%), optic chiasm (n = 16; 20.2%), area postrema (n = 13; 16.4%), thalamus/hypothalamus (n = 11; 13.9%), corpus callosum (n = 11; 13.9%), periependymal-third ventricle (n = 9; 11.3%), corticospinal tract (n = 7; 8.8%), hemispheric white matter (n = 1; 1.2%) and nonspecific areas (n = 49; 62.03%). Asymptomatic BMRI lesions were more common. The frequency of brain MRI abnormalities did not differ between patients who were positive and negative for aquaporin 4 antibodies at presentation. CONCLUSION: Typical brain MRI abnormalities are frequent in NMOSD at disease onset. PMID- 29156228 TI - Effect of abiotic and biotic stress factors analysis using machine learning methods in zebrafish. AB - In order to understand the mechanisms underlying stress responses, meta-analysis of transcriptome is made to identify differentially expressed genes (DEGs) and their biological, molecular and cellular mechanisms in response to stressors. The present study is aimed at identifying the effect of abiotic and biotic stress factors, and it is found that several stress responsive genes are common for both abiotic and biotic stress factors in zebrafish. The meta-analysis of micro-array studies revealed that almost 4.7% i.e., 108 common DEGs are differentially regulated between abiotic and biotic stresses. This shows that there is a global coordination and fine-tuning of gene regulation in response to these two types of challenges. We also performed dimension reduction methods, principal component analysis, and partial least squares discriminant analysis which are able to segregate abiotic and biotic stresses into separate entities. The supervised machine learning model, recursive-support vector machine, could classify abiotic and biotic stresses with 100% accuracy using a subset of DEGs. Beside these methods, the random forests decision tree model classified five out of 8 stress conditions with high accuracy. Finally, Functional enrichment analysis revealed the different gene ontology terms, transcription factors and miRNAs factors in the regulation of stress responses. PMID- 29156229 TI - Indirect tRNA aminoacylation during accurate translation and phenotypic mistranslation. AB - The fact that most bacteria do not contain a full set of aminoacyl-tRNA synthetases (aaRS) is often underappreciated. In the absence of asparaginyl-tRNA and/or glutaminyl-tRNA synthetase (AsnRS and GlnRS), Asn-tRNAAsn and/or Gln tRNAGln are produced by an indirect tRNA aminoacylation pathway that relies on misacylation of these two tRNAs by two different misacylating aaRSs, followed by transamidation by an amidotransferase (GatCAB in bacteria). This review highlights the central importance of indirect tRNA aminoacylation to accurate protein translation, mechanistic peculiarities that appear to be unique to this system, and the newly recognized connection between indirect tRNA aminoacylation and mistranslation as a strategy used by bacteria to respond to environmental stressors like antibiotics. PMID- 29156230 TI - Transport of a neonicotinoid pesticide, thiamethoxam, from artificial seed coatings. AB - Neonicotinoid insecticides coat the seeds of major crops worldwide; however, the high solubility of these compounds, combined with their toxicity to non-target organisms, makes it critical to decipher the processes by which they are transported through soils and into aquatic environments. Transport and distribution of a neonicotinoid (thiamethoxam, TMX) were investigated by growing TMX-coated corn seeds in coarse-textured and fine-textured soil columns (20 and 60cm lengths). To understand the influence of living plants, corn plants were terminated in half of the columns (no plant treatment) and allowed to grow to the V5 growth stage (33days of growth) in the other half (with plant treatment). TMX was analyzed in leachate 12 times over 33days and in bulk soil after 8, 19, and 33days of corn growth. All 20cm columns leached TMX at levels exceeding the United States Environmental Protection Agency benchmark for aquatic invertebrates (17.5MUgL-1). TMX migrated from seeds to adjacent bulk soil by the eighth day and reached deeper soil sections in later growth stages (e.g., 30-45cm depth by Day 33). Fine-particle soils transported over two orders of magnitude more TMX than coarse-textured soils (e.g., 29.9MUg vs 0.17MUg, respectively), which was attributed to elevated evapotranspiration (ET) rates in the sandy soil driving a higher net retention of the pesticide and to structural flow occurring in the fine-textured soil. Living plants increased TMX concentrations at depth (i.e., 30 60cm) compared to the no plant treatment, suggesting that corn growth may drive preferential transport of TMX from coated seeds. Altogether, this study showed that neonicotinoid seed coatings can be mobilized through soil leachate in concentrations considered acutely toxic to aquatic life. PMID- 29156231 TI - Acute Organoaxial gastric volvulus: A massive problem with a twist-case report. AB - INTRODUCTION: Gastric volvulus (GV) is a rare and life threatening condition if not treated promptly or wrongly diagnosed. The main complication of gastric volvulus is foregut obstruction. The extreme rotation can cut off blood supply to the stomach and even distal organs, which can lead to ischemia and necrosis of the affected area. PRESENTATION OF CASE: We report a case of a 41yo female that complained of severe abdominal pain, nausea and vomiting for approximately 3days after eating a large meal. The patient didn't have any flatus or bowel movements in the last 24h. CT of the abdomen and pelvis showed a dilatation of the stomach and esophageal hernia. Laparotomy confirmed an organoaxial volvulus at the level of the antrum and body of the stomach. Gastropexy was implemented and the stomach fixed to the posterior abdominal wall to prevent recurrence. DISCUSSION: GV may have a significant related morbidity and mortality rate. It can be missed easily on diagnosis. The presence of vomiting not responding to initial antiemetic treatment, as well as, the presence of a hiatal hernia on the imaging studies should trigger our thinking of gastric volvulus, regardless of the stable appearance of the patient. CONCLUSION: Chronic GV can manifests as atypical chest, abdomen and gastro intestinal symptoms. We recommend that everyone with these atypical symptoms seek medical attention to rule out GV. Early diagnosis and treatment will reduce the risk of developing chronic gastric volvulus to acute gastric volvulus. PMID- 29156232 TI - Use of negative pressure wound therapy after infection and flap dehiscence in radical vulvectomy: A case report. AB - INTRODUCTION: Vulvar cancer has a lower incidence in high income countries, but is rising, in part, due to the high life expectancy in these societies. Radical vulvectomy is still the standard treatment in initial stages. Wound dehiscence contitututes one of the most common postoperative complications. PRESENTATION OF CASE: A 76year old patient with a squamous cell carcinoma of the vulva, FIGO staged, IIIb is presented. Radical vulvectomy and bilateral inguinal lymph node dissection with lotus petal flaps reconstruction are performed as the first treatment. Wound infection and dehiscence of lotus petal flaps was seen postoperatively. Initial management consisted in antibiotics administration and removing necrotic tissue from surgical wound. After this initial treatment, negative wound pressure therapy was applied for 37days with good results. DISCUSSION: Wound dehiscence in radical vulvectomy remains the most frequent complication in the treatment of vulvar cancer. The treatment of this complications is still challenging for most gynecologic oncologist surgeons. CONCLUSION: The utilization of the negative wound pressure therapy could contribute to reduce hospitalization and the direct and indirect costs of these complications. PMID- 29156233 TI - Trans-cervical resection of a separate substernal goitre. AB - INTRODUCTION: A separate substernal goitre which is not continuous with the main cervical thyroid proves a unique challenge for resection. A trans-cervical approach is preferred but may be hazardous due to the possibility of ectopic thyroid tissue with alternate blood supply. PRESENTATION OF CASE: A 72year old female who had a previous left hemithyroidectomy presents with a symptomatic central substernal thyroid mass. Following radiological work-up, the separate goitre was carefully removed via a trans-cervical approach and avoidance of sternotomy. She had a rapid recovery without complication. DISCUSSION: The anatomy and embryology of substernal masses need to be carefully considered particularly if the mass is ectopic thyroid tissue. Careful pre-operative assessment may determine its nature and anatomical features. Intra-operative dissection requires consideration of blood supply and surrounding structures, but often may be and is best completed via a cervical approach to minimise morbidity. Review of the literature affirms the preference for a trans-cervical approach and offers criteria for successful resection via this method. CONCLUSION: Confirming the nature and anatomy of a separate substernal goitre enables successful removal of the mass via a trans-cervical approach with minimal morbidity. PMID- 29156235 TI - The pristine graphene produced by liquid exfoliation of graphite in mixed solvent and its application to determination of dopamine. AB - The pristine graphene can be easily prepared in isopropanol-water mixture with salts as assistant via liquid-phase exfoliation method. The concentration of graphene dispersion reaches as high as 0.565 mg/mL. The graphene film prepared by drop-casting method shows an excellent electrical conductivity (7.095 * 104 S/m). Furthermore, an electrochemical biosensor based on the pristine graphene shows high selectivity and sensitivity for the determination of dopamine. The linear detection range for dopamine is 2.5-1500 MUM with detection limit of 1.5 MUM. This method provides a potential process for preparing high-quality graphene ready-to-use in low-boiling point solvent. PMID- 29156236 TI - Nanozirconia supported ruthenium(0) nanoparticles: Highly active and reusable catalyst in hydrolytic dehydrogenation of ammonia borane. AB - Nanozirconia supported ruthenium(0) nanoparticles (Ru0/ZrO2) were prepared by impregnation of ruthenium(III) cations on the surface of zirconia followed by their reduction with sodium borohydride at room temperature. Ru0/ZrO2 was isolated from the reaction solution by centrifugation and characterized by ICP OES, XRD, TEM, SEM-EDS and XPS techniques. All the results reveal that ruthenium(0) nanoparticles were successfully supported on zirconia and the resulting Ru0/ZrO2 is a highly active and reusable catalyst for hydrogen generation from the hydrolysis of ammonia borane with a turnover frequency value of 173 min-1 at 25 degrees C. The reusability and catalytic lifetime tests reveal that Ru0/ZrO2 is still active in the subsequent runs of hydrolysis of ammonia borane preserving 67% of the initial catalytic activity even after the fifth run and Ru0/ZrO2 provides 72,500 turnovers (mol H2/mol Ru) before deactivation at 25 degrees C. Our report also includes the results of kinetic studies depending on the catalyst concentration and temperature to determine the activation energy (Ea = 58 +/- 2 kJ/mol) for hydrolytic dehydrogenation of AB. PMID- 29156234 TI - Candida albicans-epithelial interactions and induction of mucosal innate immunity. AB - Candida albicans is a human fungal pathogen that causes millions of mucosal and life-threatening infections annually. C. albicans initially interacts with epithelial cells, resulting in fungal recognition and the formation of hyphae. Hypha formation is critical for host cell damage and immune activation, which are both driven by the secretion of Candidalysin, a recently discovered peptide toxin. Epithelial activation leads to the production of inflammatory mediators that recruit innate immune cells including neutrophils, macrophages and innate Type 17 cells, which together work with epithelial cells to clear the fungal infection. This review will focus on the recent discoveries that have advanced our understanding of C. albicans-epithelial interactions and the induction of mucosal innate immunity. PMID- 29156237 TI - Skeleton/skin structured (RGO/CNTs)@PANI composite fiber electrodes with excellent mechanical and electrochemical performance for all-solid-state symmetric supercapacitors. AB - Polyaniline coated reduced graphene oxide/carbon nanotube composite fibers ((RGO/CNTs)@PANI, RCP) with skeleton/skin structure are designed as fiber-shaped electrodes for high performance all-solid-state symmetric supercapacitor. The one dimensional reduced graphene oxide/carbon nanotube composite fibers (RGO/CNTs, RC) are prepared via a simple in-situ reduction of graphene oxide in presence of carbon nanotubes in quartz glass pipes, which exhibit excellent mechanical performance of >193.4 MPa of tensile strength. Then polyaniline is coated onto the RC fibers by electrodepositing technique. The electrochemical properties of the RCP fiber-shaped electrodes are optimized by adjusting the feeding ratio of carbon nanotubes. The optimized one exhibits good electrochemical characteristic such as highest volumetric specific capacitance of 193.1 F cm-3 at 1 A cm-3, as well as excellent cyclic retention of 92.60% after 2000 cyclic voltammetry cycles. Furthermore, the all-solid-state symmetric supercapacitor, fabricated by using the final composite fiber as both positive and negative electrodes pre coated with the poly(vinyl alcohol)/H2SO4 gel polyelectrolyte, possesses volumetric capacitance of 36.7 F cm-3 at 0.2 A cm-3 and could light up a red light-emitting diode easily. The excellent mechanical and electrochemical performances make the designed supercapacitor as promising high performance wearable energy storage device. PMID- 29156238 TI - CO2 capture by nitrogen-doped porous carbons derived from nitrogen-containing hyper-cross-linked polymers. AB - The N-containing hyper-cross-linked polymers with different porosity and polarity were prepared from 4-vinylbenzyl chloride and 4-vinyl pyridine by the suspension polymerization and Friedel-Crafts reaction. A carbonization process by KOH chemical activation was carried out for the N-containing hyper-cross-linked polymers, and hence a series of N-doped porous carbons (NDPC) was easily fabricated. These porous materials were comparatively evaluated for CO2 adsorption. The NDPC were much more efficient than the N-containing hyper-cross linked polymers for the CO2 capture and the CO2 uptake had a linear correlation to the ultramicropore volume (d <= 0.8 nm) with R2 = 0.9737. NDPC-10% possessed the highest CO2 uptake around 270 mg/g, and had the sufficient CO2/N2 selectivity of 20.2 at 273 K and 1.0 bar. The CO2/N2 selectivity of the N-containing hyper cross-linked polymers was much higher than the NDPC due to the higher nitrogen content. The isosteric heat of adsorption on the N-containing hyper-cross-linked polymers ranged 29.0-41.2 kJ/mol while that on the NDPC was much lower (24.6-29.2 kJ/mol). The NDPC developed in this study may provide promising candidates for the CO2 capture. PMID- 29156240 TI - Mental files theory of mind: When do children consider agents acquainted with different object identities? AB - Mental files theory explains why children pass many perspective taking tasks like the false belief test around age 4 (Perner & Leahy, 2016). It also explains why older children struggle to understand that beliefs about an object depend on how one is acquainted with it (intensionality or aspectuality). If Heinz looks at an object that is both a die and an eraser, but cannot tell by looking that it is an eraser, he will not reach for it if he needs an eraser. Four- to 6-year olds find this difficult (Apperly & Robinson, 1998). We tested 129 35- to 86-month olds with a modified version of Apperly and Robinson's task. Each child faced four tasks resulting from two experimental factors, timing and mode of information. Timing: Children saw Heinz learn the die's location either before or after they learn that the die is an eraser. Mode of information: Heinz learns where the die is either perceptually or verbally. When Heinz' learning is verbal, he never perceives the die at all. We found that Apperly and Robinson's problem occurs only in the seen-after condition, where Heinz sees the die afterchildren had learnt that it was also an eraser. It vanishes when Heinz learns where the die is before children learn that it is also an eraser. The problem also vanishes when Heinz learns where the die is purely verbally (e.g., "The die is in the red box") and never sees it. This evidence lets us refine existing mental files theory, and eliminate several alternatives from the literature. PMID- 29156241 TI - Pre-linguistic segmentation of speech into syllable-like units. AB - Syllables are often considered to be central to infant and adult speech perception. Many theories and behavioral studies on early language acquisition are also based on syllable-level representations of spoken language. There is little clarity, however, on what sort of pre-linguistic "syllable" would actually be accessible to an infant with no phonological or lexical knowledge. Anchored by the notion that syllables are organized around particularly sonorous (audible) speech sounds, the present study investigates the feasibility of speech segmentation into syllable-like chunks without any a priori linguistic knowledge. We first operationalize sonority as a measurable property of the acoustic input, and then use sonority variation across time, or speech rhythm, as the basis for segmentation. The entire process from acoustic input to chunks of syllable-like acoustic segments is implemented as a computational model inspired by the oscillatory entrainment of the brain to speech rhythm. We analyze the output of the segmentation process in three different languages, showing that the sonority fluctuation in speech is highly informative of syllable and word boundaries in all three cases without any language-specific tuning of the model. These findings support the widely held assumption that syllable-like structure is accessible to infants even when they are only beginning to learn the properties of their native language. PMID- 29156239 TI - Examining the effects of alcohol on GABAA receptor mRNA expression and function in neural cultures generated from control and alcohol dependent donor induced pluripotent stem cells. AB - Factors influencing the development of alcohol-use disorder (AUD) are complex and heterogeneous. While animal models have been crucial to identifying actions of alcohol on neural cells, human-derived in vitro systems that reflect an individual's genetic background hold promise in furthering our understanding of the molecular and functional effects of alcohol exposure and the pathophysiology of AUD. In this report, we utilized induced pluripotent stem cell (iPSCs)-derived neural cell cultures obtained from healthy individuals (CTLs) and those with alcohol dependence (ADs) to 1) examine the effect of 21-day alcohol exposure on mRNA expression of three genes encoding GABAA receptor subunits (GABRA1, GABRG2, and GABRD) using quantitative PCR, and 2) examine the effect of acute and chronic alcohol exposure on GABA-evoked currents using whole-cell patch-clamp electrophysiology. iPSCs from CTLs and ADs were differentiated into neural cultures enriched for forebrain-type excitatory glutamate neurons. Following 21 day alcohol exposure, significant treatment effects were observed in GABRA1, GABRG2, and GABRD mRNA expression. A modestly significant interaction between treatment and donor phenotype was observed for GABRD, which was increased in cell cultures derived from ADs. No effect of acute or chronic alcohol was observed on GABA-evoked currents in neurons from either CTLs or ADs. This work extends findings examining the effects of alcohol on the GABAA receptor in human cell in vitro model systems. PMID- 29156242 TI - Optimization of PMAxx pretreatment to distinguish between human norovirus with intact and altered capsids in shellfish and sewage samples. AB - Shellfish contamination by human noroviruses (HuNoVs) is a serious health and economic problem. Recently an ISO procedure based on RT-qPCR for the quantitative detection of HuNoVs in shellfish has been issued, but these procedures cannot discriminate between inactivated and potentially infectious viruses. The aim of the present study was to optimize a pretreatment using PMAxx to better discriminate between intact and heat-treated HuNoVs in shellfish and sewage. To this end, the optimal conditions (30min incubation with 100MUM of PMAxx and 0.5% of Triton, and double photoactivation) were applied to mussels, oysters and cockles artificially inoculated with thermally-inactivated (99 degrees C for 5min) HuNoV GI and GII. This pretreatment reduced the signal of thermally inactivated HuNoV GI in cockles and HuNoV GII in mussels by >3 log. Additionally, this pretreatment reduced the signal of thermally-inactivated HuNoV GI and GII between 1 and 1.5 log in oysters. Thermal inactivation of HuNoV GI and GII in PBS, sewage and bioaccumulated oysters was also evaluated by the PMAxx-Triton pretreatment. Results showed significant differences between reductions observed in the control and PMAxx-treated samples in PBS following treatment at 72 and 95 degrees C for 15min. In sewage, the RT-qPCR signal of HuNoV GI was completely removed by the PMAxx pretreatment after heating at 72 and 95 degrees C, while the RT-qPCR signal for HuNoV GII was completely eliminated only at 95 degrees C. Finally, the PMAxx-Triton pretreatment was applied to naturally contaminated sewage and oysters, resulting in most of the HuNoV genomes quantified in sewage and oyster samples (12 out of 17) corresponding to undamaged capsids. Although this procedure may still overestimate infectivity, the PMAxx-Triton pretreatment represents a step forward to better interpret the quantification of intact HuNoVs in complex matrices, such as sewage and shellfish, and it could certainly be included in the procedures based on RT-qPCR. PMID- 29156243 TI - Isolation, identification and selection of antagonistic yeast against Alternaria alternata infection and tenuazonic acid production in wine grapes from Argentina. AB - Epiphytic isolates with yeast characteristics from grapes of the Malbec cultivar were obtained in order to find antagonists against Alternaria alternata. From a total of 111 isolates, 82% corresponded to the yeast-like organism Aureobasidium pullulans and the rest to the non-Saccharomyces yeasts Hanseniaspora uvarum (6.3%), Metschnikowia pulcherrima or spp. (5.4%), Cryptoccocus laurentti II (2.7%), Starmerella bacilaris or Candida zemplinina (2.7%) and Rhodotorula spp. (0.9%). The 22.4% (15 out of 67) of epiphytic yeasts and yeast-like organisms evaluated were able to reduce A. alternata infection from 0.0 to 4.4% when applied 2h previous to pathogen inoculation on wounds of grape berries. From these selected strains, 14 out of 15 strains completely prevented A. alternata infection (0.0%), which implies potential for field application. All Metschnikowia (pulcherrima or spp.), S. bacillaris and almost all H. uvarum evaluated strains showed antagonist capability against A. alternata. Meanwhile, none of the lesser nutritional requirement strains belonging to A. pullulans, Cr. laurenti II and Rhodotorula spp. did. All the yeasts with capacity to prevent A. alternata infection also reduced tenuazonic acid (TA) production by 81.2 to 99.8%, finding TA levels similar to negative controls. Therefore, the epiphytic yeasts selected are promising as biological control agents against Alternaria infection and toxin production in grapes for winemaking. PMID- 29156244 TI - Isolation and characterization of polyvalent bacteriophages infecting multi drug resistant Salmonella serovars isolated from broilers in Egypt. AB - In this study, we isolated and characterized three phages named as Salmacey1, Salmacey2 and Salmacey3, infecting multi drug resistant Salmonella serovars isolated from broilers in Egypt. The most prevalent Salmonella serovars were S. typhimurium, S. enteritidis, and S. kentucky. All these Salmonella serovars were found to be resistant to more than two of the ten antimicrobial agents tested. Only S. kentucky was found to be resistant to seven antimicrobial agents. Examination of these phage particles by transmission electron microscopy (TEM), demonstrated that two phages (Salmacey1, Salmacey2) were found to belong to family Siphoviridae, and Salmacey3 was assigned to the family Myoviridae. The results of host range assay revealed that these bacteriophages were polyvalent and thus capable of infecting four strains of Salmonella serovars and Citrobacter freundii. Moreover, the two phages (Salmacey1, Salmacey2) had a lytic effect on Enterobacter cloacae and Salmacey3 was able to infect E. coli. All phages could not infect S. para Typhi, Staphylococus aureus and Bacillus cereus. One-step growth curves of bacteriophages revealed that siphovirus phages (Salmacey1, Salmacey2) have burst size (80 and 90pfu per infected cell with latent period 35min and 40min respectively), and for the myovirus Salmacey3 had a burst size 110pfu per infected cell with latent period 60min. Molecular analyses indicated that these phages contained double-stranded DNA genomes. The lytic activity of the phages against the most multidrug resistant serovars S. kentucky as host strain was evaluated. The result showed that these bacteriophages were able to completely stop the growth of S. kentucky in vitro. These results suggest that phages have a high potential for phage application to control Salmonella serovars isolated from broilers in Egypt. PMID- 29156245 TI - Changes in activities of both photosystems and the regulatory effect of cyclic electron flow in field-grown cotton (Gossypium hirsutum L) under water deficit. AB - To clarify the influence of water deficit on the functionality of the photosynthetic apparatus of cotton plants, leaf gas exchange, chlorophyll a fluorescence, and P700 redox state were examined in field-grown cotton Gossypium hirsutum L. cv. Xinluzao 45. In addition, we measured changes in the P515 signal and analyzed the activity of ATP synthase and the trans-thylakoid proton gradient (DeltapH). With increasing water deficit, the net CO2 assimilation rate (AN) and stomatal conductance (gs) significantly decreased, but the maximum quantum efficiency of PSII photochemistry (Fv/Fm) did not change. The photochemical activity of photosystem II (PSII) was reflected by the photochemical quenching coefficient (qP), quantum efficiency of photosystem II [Y(II)], and electron transport rate through PSII [ETR(II)], while the activity of photosystem I (PSI) was reflected by the quantum efficiency of photosystem I [Y(I)] and the electron transport rate through PSI [ETR(I)]. Both activities were maintained under mild water deficit, but were slightly decreased under moderate water deficit. Under moderate water deficit, cyclic electron flow (CEF), the fraction of absorbed light dissipated thermally via the DeltapH- and xanthophyll-regulated process [Y(NPQ)], and the fraction of P700 oxidized under a given set of conditions [Y(ND)] increased. Our results suggest that the activities of both photosystems are stable under mild water deficit and decrease only slightly under moderate water deficit. Moderate water deficit stimulates CEF, and the stimulation of CEF is essential for protecting PSI and PSII against photoinhibition. PMID- 29156246 TI - The activation of shame following dissociation in the context of relationships: A vignette study. AB - BACKGROUND AND OBJECTIVES: Studies show experiences of negative affective states, such as shame, elevate dissociation. Using vignettes, this study aimed to investigate the reverse, whether experiences of dissociation in the context of varied interpersonal relationships elevate shame. METHODS: 269 adults completed online questionnaires (Dissociative Experiences Scale; Experiences of Shame Scale) and were randomly allocated to vignettes describing either dissociation or sadness in three different relationship contexts: (1) with an acquaintance, (2) with a close friend, or (3) when alone. Participants then completed six single item questions assessing discrete emotions, a five-item adaptation of the State Shame and Guilt Scale, and 8 items measuring behavioural responses to shame. RESULTS: Elevations of shame were evident when dissociation occurred in the presence of a close friend, but not in other contexts. Participants reported a greater inclination to stay with a close friend and discuss their experience of dissociation and sadness. LIMITATIONS: Limitations of this study are that a non clinical sample was used and that dissociative experiences were not induced experientially. CONCLUSION: Results did not suggest that shame is a generic reaction to experiences of dissociation or to specific relationship contexts. Rather, shame was uniquely evoked when dissociation occurred with a close friend. These findings suggest there is a contextualized bi-directional relationship between dissociation and shame, whereby shame appears to activate dissociation, and dissociation in the context of a close other seems to evoke shame. Knowledge about the activation of shame in response to dissociation may assist therapists in educating their clients about this connection. PMID- 29156247 TI - Humor doesn't retire: Improvisation as a health-promoting intervention for older adults. AB - As our population ages and aging in place continues to remain a priority of older adults, identifying novel ways to promote the wellbeing of older adults and reduce isolation is of the utmost importance. The Second City is a Chicago-based comedy improvisation organization that provides training in improvisation. One of their training courses, Humor Doesn't Retire, specifically teaches adults 55 and over, on improvisation. This study sought to explore the experiences of older adults enrolled in Humor Doesn't Retire, and to characterize any benefits that older adult participants perceived following participation in the comedy improvisation course. Qualitative analysis was used to identify and describe common themes that emerged in a survey of open-ended questions regarding benefits of the improvisation course on outlook and mood as well as behavior changes. Results for perceived benefits showed main themes of increased positivity, an increased sense of comfort and ease with the unexpected, a sense of self development and self-awareness, and a feeling of acceptance by their social group. Participants reported that these changes fed into their behaviors, and resulted in enhanced problem solving abilities, greater facility in social situations, and the tangible outcome of an expanded and closer-knit social circle. As the first study in our knowledge to examine the effect of improvisation comedy on healthy older adults, this exploratory analysis has suggested that improvisation comedy may be a mechanism by which to combat several geriatric syndromes, including depression, stress, and isolation - all of which are detrimental to older adults. PMID- 29156248 TI - The symbolic violence of 'outbreak': A mixed methods, quasi-experimental impact evaluation of social protection on Ebola survivor wellbeing. AB - Despite over 28,000 reported cases of Ebola virus disease (EVD) in the 2013-16 outbreak in West Africa, we are only beginning to trace the complex biosocial processes that have promoted its spread. Important questions remain, including the effects on survivors of clinical sequelae, loss of family and livelihood, and other psychological and social trauma. Another poorly understood question is what effect social protection and job creation programs have had on survivors' wellbeing. Several clinical and social protection programs have been developed to respond to the needs of EVD survivors; however, little in the way of impact evaluation has taken place. We enrolled 200 randomly selected EVD survivors from Port Loko, Kenema, and Kailahun districts in Sierra Leone and stratified them based on the amount of instrumental social protection received post-discharge from an Ebola Treatment Unit. We then conducted a survey and in-depth interviews to assess participants' wellbeing and food security. Social protection categories II-IV (moderate to extensive) were each significantly associated with ~15-22% higher wellbeing scores compared to minimal social protection (p < 0.001). Only social protection category IV (extensive) was significantly associated with being food secure (adjusted odds ratio 6.11; 95% confidence interval, 2.85-13.10) when compared to minimal social protection. Qualitative themes included having a sense of purpose during the crisis (work and fellowship helped survivors cope); using cash transfers to invest in business; the value of literacy and life-skills classes; loss of breadwinners (survivors with jobs were able to take over that role); and combating the consequences of stigma. We conclude that, for EVD survivors, short-term social protection during the vulnerable period post discharge can pay dividends two years later. Based on the empiric evidence presented, we discuss how terms such as "outbreak" and "epidemic" do symbolic violence by creating the illusion that social suffering ends when transmission of a pathogen ceases. PMID- 29156249 TI - Changing experience of adverse medical events in the National Health Service: Comparison of two population surveys in 2001 and 2013. AB - Care quality is important to patients and providers, but is hard to measure. This study aimed to examine changes in the frequency and severity of one quality measure - adverse events associated with medical care - in Great Britain over a 12-year period when available resources initially expanded and were subsequently constrained. Data on perceived adverse events, collected from two representative population surveys in 2001 and 2013, were analysed and compared. The samples consisted of 8202 adults aged 15 and over in 2001 and 19,746 adults aged 15 and over in 2013. The main outcome measures were self-reported illness, injury or impairment caused in the opinion of the respondent by medical treatment or care. Respondents were also asked about the perceived severity of harm in terms of health and work, and any actions taken in response. The proportion of all respondents reporting that over the last three years they had suffered some illness, injury or impairment that in their opinion was caused by their medical treatment or care was 2.5% (497/19746) in 2013, compared with 4.8% (391/8202) in 2001, a reduction of 33% after adjusting for age, gender, income and social class differences between the two surveys. Perceived impact on health and work of these events was similar in both surveys, as was the proportion of injured respondents who pursued a legal claim for financial compensation, at 11% (53/497) in 2013 and 10.5% (41/391) in 2001. We also report multivariate analyses of perceived harm rates and severity, and propensity to seek, and accept, compensation. Our results suggest that the NHS became significantly safer over this period when measured by patient perceived harm from medical care. Our survey method could provide a valuable contribution to the monitoring of trends in health-care related adverse events and the impact of patient safety initiatives. PMID- 29156250 TI - Fear, family and the placing of emotion: Black women's responses to a breast cancer awareness intervention. AB - This paper is based upon findings from the qualitative element of a mixed-methods study on the response of Black women aged 25-50 to a public health intervention related to breast cancer. The focus groups were conducted in the London Borough of Hackney, UK between 2013 and 2016, and were part of an evaluation of the effectiveness of a breast awareness DVD. While the content of the DVD was generally well-received by the participants, the focus group discussions revealed a complex and, at times, contradictory response to the women's construction as an 'at risk' community. As the paper highlights, for many of the women, breast cancer remains a disease of whiteness and the information provided in the DVD prompted a range of emotional responses; from anxiety and fear to a desire to become more knowledgeable and active in the promotion of self-care. As the paper argues, of particular importance to the women was the need to feel a much stronger emotional connection to the information presented in the DVD. The paper concludes by arguing that placing greater emphasis on feeling and emotion is an important dimension of future research in this area. PMID- 29156251 TI - Optically and thermally stimulated luminescence characteristics of LaAlO3:Pr3+ beta irradiated. AB - This paper reports on an investigation into the thermally stimulated luminescence (TL) and optically stimulated luminescence (OSL) characteristics of novel luminescent phosphor. A new Pr3+-doped, lanthanum aluminate (LaAlO3)-based luminescent phosphor is developed. Samples of LaAlO3:Pr3+ were irradiated to beta doses, in air, from 0.1Gy up to 50Gy and then were analyzed using both TL and continuous wavelength OSL (CW-OSL) techniques to determine their luminescent characteristics. This phosphor shows a TL glow curve, after its irradiation to beta radiation, with two TL peaks: one located around 160 degrees C and a second at 300 degrees C. CW-OSL response presented a fast decay into the first 20s of blue light stimulation. TL and CW-OSL response as a function of beta radiation dose were linear in the studied dose range. The high sensitivity of the CW-OSL and TL response will make this phosphor suitable for beta radiation detection. Finally, the kinetic parameters of activation energy, frequency factor and kinetic order were analyzed in the TL response using computerized glow curve deconvolution based on general order kinetic model. PMID- 29156253 TI - Exploring the impact of using measured or estimated values for height and weight on the relationship between BMI and acute hospital mortality. AB - PURPOSE: Studies have demonstrated an association between height and weight and mortality among patients in the Intensive Care Unit (ICU) and the optimal body mass index (BMI) might be well above the optimal values in the general population. Most of these studies have relied on estimated values, the validity of which is not known. MATERIAL AND METHODS: Admissions to adult general ICUs from 1 April 2009 to 31 March 2016 in the Case Mix Programme (CMP) Database were described by height and weight assessment methods (measured or estimated). A multilevel logistic regression model was built, which had acute hospital mortality as the outcome and included standard case mix adjustment, BMI, the assessment method and the interactions between BMI and assessment method. RESULTS: There were 690,405 eligible admissions and most patients (59.7%) had estimates of height and/or weight recorded. Patients with both height and weight measured had lower severity and mortality. The association between BMI and mortality was reverse J-shaped with the lowest mortality at BMI 34.3kg/m2. Whether height and weight were measured or estimated did not influence the association between BMI and mortality. CONCLUSIONS: For epidemiological comparisons of mortality among critically ill adults, estimated values of height and weight appear valid. PMID- 29156252 TI - Factors associated with physician self-efficacy in mental illness management and team-based care. PMID- 29156255 TI - Competitive adsorption of PPCP and humic substances by carbon nanotube membranes: Effects of coagulation and PPCP properties. AB - Natural organic matter (NOM) and pharmaceuticals and personal care products (PPCP) are known to compete for adsorption sites on carbon nanotubes (CNT), resulting in decreasing PPCP adsorption onto CNT. In this study, four types of PPCP, as such acetaminophen (AAP), caffeine (CAF), triclosan (TCS), and carbendazim (CBD) were used to investigate the effects of PPCP properties and NOM coagulation on the competitive adsorption of PPCP and NOM. Coagulation preferentially removed HS from a natural surface water, thereby increasing adsorption of AAP, CAF, TCS and CBD by 19%, 13%, 17% and 11%, respectively. Similar trends were obtained with synthetic natural waters, for which the adsorption of AAP, CAF, TCS, and CBD increased by 29%, 7%, 44% and 69%, respectively, as humic acid (HA) concentration decreased from 10mgL-1 to 0mgL-1. Furthermore, PPCP properties also affected their competition with NOM for adsorption by CNT membranes Because CAF existed in cationic form at pH ranging from 7 to 8.3, its adsorption was less affected by the presence/coagulation of NOM than AAP, CBD, and TCS. Based upon these findings, coagulation has the potential to be integrated with CNT adsorption for the removal of PPCP compounds during advanced drinking water treatment. PMID- 29156254 TI - Xenografted tissue models for the study of human endometrial biology. AB - The human endometrium undergoes extensive morphological, biochemical and molecular changes under the influence of female sex steroid hormones. Besides the fact that estrogen stimulates endometrial cell proliferation and progesterone inhibits this proliferation and induces differentiation, there is limited knowledge about precise molecular mechanisms underlying human endometrial biology. The importance of paracrine signaling in endometrial physiology explains why in vitro culture of endometrial cells has been challenging. Researchers, therefore, have developed alternative experimental in vivo models for the study of endometrial biology. The objective of this review is to summarize the recent developments and work on these in vivo endometrial research models. The in vivo recombinant tissue models in which wild-type endometrial cells are combined with endometrial cells from a gene-targeted mouse strain followed by xenografting to host mice have been critical in confirming the significance of paracrine signaling between the epithelium and stroma in the growth regulation of the endometrium. Additionally, these studies have uncovered differences between the mouse and human, emphasizing the need for the development of experimental models specifically of the human endometrium. Recently, xenotransplants of human endometrial fragments into the subcutaneous space of host mice and endometrial xenografts of dissociated and recombined epithelial and stromal cells beneath the kidney capsule of immunodeficient host mice have proven to be highly promising tools for in vivo research of endometrial functions. For the first time, the latter approach provides an immense opportunity for the application of genome engineering, such as targeted ablation of endometrial genes for example by using CRISPR/CAS9 system. This research will begin to elucidate the functional role of specific genes in this complex tissue. Another advantage of xenotransplantation and xenograft models of the human endometrium is their use to investigate endometrial effects of new compounds and drugs without needing to give them to women. Underpinning the molecular mechanisms underlying endometrial functions is critical to ultimately advance our understanding of endometrial pathophysiology and develop targeted therapies to prevent and cure endometrial pathologies as well as enhance endometrial function when it is desired for fertility. PMID- 29156256 TI - Effects of ambient temperature on lung function in patients with chronic obstructive pulmonary disease: A time-series panel study. AB - BACKGROUND: Limited evidence concerns the associations between ambient temperature and lung function and the results are mixed. OBJECTIVE: To evaluate the associations between temperature variations and daily fluctuations in pulmonary function in chronic obstructive pulmonary disease (COPD) patients. METHODS: We designed a time-series panel study of 28 male urban COPD patients with repeated daily lung function measurements from December 2012 to May 2013 in Shanghai, China. We used a linear mixed-effect model combined with a distributed lag model to estimate the cumulative effects of temperature on morning/evening pulmonary function tests (PFTs), including peak expiratory flow (PEF) and forced expiratory volume in 1-s (FEV1), while adjusting for within-subject correlations, individual characteristics, time trends and air pollution levels. RESULTS: We obtained a total of 8618 pairs of morning PFTs and 8528 pairs of evening PFTs. The associations between daily mean temperature and PEF were inverted U-shaped with both low and high temperatures significantly reducing morning and evening PEF. Compared with the referent temperature (16 degrees C), the low temperature (1st percentile, -1 degrees C) would result in cumulative decreases of 32.20L/min in morning PEF and 21.15L/min in evening PEF over lags of two weeks. The corresponding decrements at the same lag associated with high temperature (99th percentile, 25 degrees C) were 38.10L/min in morning PEF and 27.08L/min in evening PEF. There were no statistically significant changes in morning or evening FEV1. CONCLUSIONS: This time-series panel study provided robust evidence that both low and high temperatures were significantly associated with decrements in pulmonary function, particularly in PEF. PMID- 29156257 TI - Surrounding land cover types as predictors of palustrine wetland vegetation quality in conterminous USA. AB - The loss of wetland habitats and their often-unique biological communities is a major environmental concern. We examined vegetation data obtained from 380 wetlands sampled in a statistical survey of wetlands in the USA. Our goal was to identify which surrounding land cover types best predict two indices of vegetation quality in wetlands at the regional scale. We considered palustrine wetlands in four regions (Coastal Plains, North Central East, Interior Plains, and West) in which the dominant vegetation was emergent, forested, or scrub shrub. For each wetland, we calculated weighted proportions of eight land cover types surrounding the area in which vegetation was assessed, in four zones radiating from the edge of the assessment area to 2km. Using Akaike's Information Criterion, we determined the best 1-, 2- and 3-predictor models of the two indices, using the weighted proportions of the land cover types as potential predictors. Mean values of the two indices were generally higher in the North Central East and Coastal Plains than the other regions for forested and emergent wetlands. In nearly all cases, the best predictors of the indices were not the dominant surrounding land cover types. Overall, proportions of forest (positive effect) and agriculture (negative effect) surrounding the assessment area were the best predictors of the two indices. One or both of these variables were included as predictors in 65 of the 72 models supported by the data. Wetlands surrounding the assessment area had a positive effect on the indices, and ranked third (33%) among the predictors included in supported models. Development had a negative effect on the indices and was included in only 28% of supported models. These results can be used to develop regional management plans for wetlands, such as creating forest buffers around wetlands, or to conserve zones between wetlands to increase habitat connectivity. PMID- 29156258 TI - Developing an online tool for identifying at-risk populations to wildfire smoke hazards. AB - Wildfire episodes pose a significant public health threat in the United States. Adverse health impacts associated with wildfires occur near the burn area as well as in places far downwind due to wildfire smoke exposures. Health effects associated with exposure to particulate matter arising from wildfires can range from mild eye and respiratory tract irritation to more serious outcomes such as asthma exacerbation, bronchitis, and decreased lung function. Real-time operational forecasts of wildfire smoke concentrations are available but they are not readily integrated with information on vulnerable populations necessary to identify at-risk communities during wildfire smoke episodes. Efforts are currently underway at the Centers for Disease Control and Prevention (CDC) to develop an online tool that utilizes short-term predictions and forecasts of smoke concentrations and integrates them with measures of population-level vulnerability for identifying at-risk populations to wildfire smoke hazards. The tool will be operationalized on a national scale, seeking input and assistance from several academic, federal, state, local, Tribal, and Territorial partners. The final product will then be incorporated into CDC's National Environmental Public Health Tracking Network (http://ephtracking.cdc.gov), providing users with access to a suite of mapping and display functionalities. A real-time vulnerability assessment tool incorporating standardized health and exposure datasets, and prevention guidelines related to wildfire smoke hazards is currently unavailable for public health practitioners and emergency responders. This tool could strengthen existing situational awareness competencies, and expedite future response and recovery efforts during wildfire episodes. PMID- 29156259 TI - Biochar and nitrate reduce risk of methylmercury in soils under straw amendment. AB - There is growing evidence that incorporating crop straw into soils, which is being widely encouraged in many parts of the world, could increase net methylmercury (MeHg) production in soils and MeHg accumulation in crops. We explored the possibility of mitigating the risk of increased MeHg levels under straw amendment by transforming straw into biochar (BC). Greenhouse and batch experiments were conducted, in which soil MeHg concentrations, MeHg phytoavailability and accumulation in rice, dynamics of sulfate, nitrate and abundances of sulfate reducing bacteria (SRB) were compared in 'Control' (Hg contaminated soil), 'Straw' (soil with 1% rice straw), 'Straw+BC' (soil with 1% straw and 1% biochar), and 'Straw+BC+N' (soil with 1% straw, 1% biochar and 0.12% nitrate). Our results indicate that straw amendment increased MeHg concentrations in soils (28-136% higher) and rice plants (26% higher in grains, 'Straw' versus 'Control'), while co-application of biochar with straw reduced grain MeHg levels (60% lower, 'Straw+BC' versus 'Straw'). This could be mainly attributed to the reduced MeHg availability to rice plants (phytoavailability, extraction rates of MeHg by ammonium thiosulfate) under biochar amendment (64-99% lower, 'Straw+BC' versus 'Straw'). However, biochar amendment enhanced soil MeHg levels (5-75% higher, 'Straw+BC' versus 'Control'). Interestingly, nitrate addition helped reduce soil MeHg concentrations (11-41% lower, 'Straw+BC+N' versus 'Straw+BC') by facilitating nitrate reduction while inhibiting SRB activities. Subsequently, addition of nitrate with biochar, compared with biochar alone, further reduced grain MeHg levels by 34%. Therefore, straw biochar together with nitrate could possibly be effective in mitigating the risk of MeHg under straw amendment. Furthermore, the results evidence the impacts of straw management on the risk posed by MeHg in soils and emphasize the necessity to carefully consider the straw management policy in Hg-contaminated areas. PMID- 29156260 TI - Towards more ecological relevance in sediment toxicity testing with fish: Evaluation of multiple bioassays with embryos of the benthic weatherfish (Misgurnus fossilis). AB - The effects of sediment contamination on fish are of high significance for the protection of ecosystems, human health and economy. However, standardized sediment bioassays with benthic fish species, that mimic bioavailability of potentially toxic compounds and comply with the requirements of alternative test methods, are still scarce. In order to address this issue, embryos of the benthic European weatherfish (Misgurnus fossilis) were exposed to freeze-dried sediment (via sediment contact assays (SCA)) and sediment extracts (via acute fish embryo toxicity tests) varying in contamination level. The extracts were gained by accelerated solvent extraction with (i) acetone and (ii) pressurized hot water (PHWE) and subsequently analyzed for polycyclic aromatic hydrocarbons, polychlorinated biphenyls and polychlorinated dibenzodioxins and dibenzofurans. Furthermore, embryos of the predominately used zebrafish (Danio rerio) were exposed to extracts from the two most contaminated sediments. Results indicated sufficient robustness of weatherfish embryos towards varying test conditions and sensitivity towards relevant sediment-bound compounds. Furthermore, a compliance of effect concentrations derived from weatherfish embryos exposed to sediment extracts (96h-LC50) with both measured gradient of sediment contamination and previously published results was observed. In comparison to zebrafish, weatherfish embryos showed higher sensitivity to the bioavailability-mimicking extracts from PHWE but lower sensitivity to extracts gained with acetone. SCAs conducted with weatherfish embryos revealed practical difficulties that prevented an implementation with three of four sediments tested. In summary, an application of weatherfish embryos, using bioassays with sediment extracts from PHWE might increase the ecological relevance of sediment toxicity testing: it allows investigations using benthic and temperate fish species considering both bioavailable contaminants and animal welfare concerns. PMID- 29156261 TI - Soil water repellency of the artificial soil and natural soil in rocky slopes as affected by the drought stress and polyacrylamide. AB - Soil water repellency (SWR) causes reduced soil water storage, enhanced runoff and reduced ecosystem productivity. Therefore, characterization of SWR is a prerequisite for effective environmental management. SWR has been reported under different soils, land uses and regions of the world, particularly in forest land and after wildfires; however, the understanding of this variable in the artificial soil of rocky slope eco-engineering is still rather limited. This study presented the characterization of SWR in the artificial soil affected by the polyacrylamide (PAM) and drought stress. There were two molecular weights of PAM, and the CK was without PAM application. Three types of soil were studied: natural soil and two types of artificial soil which have been sprayed for 1y and 5y, respectively. The drought stress experiments had three drought gradients, lasted for three weeks. Water repellency index (WRI) and soil-water contact angle (beta) were determined using intrinsic sorptivity method by measuring the water sorptivity (SW) and ethanol sorptivity (SE) in all soil samples. The results showed that (1) Polyacrylamide treatments significantly increased SW by 3% to 38%, and reduced SE by 1% to 15%, WRI by 6% to 38%, beta by 3% to 23% compared to the control group. Polyacrylamide treatments also increased water-stable aggregates content and total porosity by 22% to 33%, 11% to 20% relative to the control, while PAM with a higher molecular weight performed best. (2) The interaction between PAM and drought stress had a significant effect on WRI and beta for all soil types (P<0.01) while it only had a significant effect on SW and SE for the artificial soil (P<0.01). (3) The artificial soil had a greater WRI and beta than the natural soil. PMID- 29156262 TI - Effect of biochar particle size on hydrophobic organic compound sorption kinetics: Applicability of using representative size. AB - Particle size of biochar may strongly affect the kinetics of hydrophobic organic compound (HOC) sorption. However, challenges exist in characterizing the effect of biochar particle size on the sorption kinetics because of the wide size range of biochar. The present study suggests a novel method to determine a representative value that can be used to show the dependence of HOC sorption kinetics to biochar particle size on the basis of an intra-particle diffusion model. Biochars derived from three different feedstocks are ground and sieved to obtain three daughter products each having different size distributions. Phenanthrene sorption kinetics to the biochars are well described by the intra particle diffusion model with significantly greater sorption rates observed for finer grained biochars. The time to reach 95% of equilibrium for phenanthrene sorption to biochar is reduced from 4.6-17.9days for the original biochars to <1 4.6days for the powdered biochars with <125MUm in size. A moderate linear correlation is found between the inverse square of the representative biochar particle radius obtained using particle size distribution analysis and the apparent phenanthrene sorption rates determined by the sorption kinetics experiments and normalized to account for the variation of the sorption rate determining factors other than the biochar particle radius. The results suggest that the representative biochar particle radius reasonably describes the dependence of HOC sorption rates on biochar particle size. PMID- 29156263 TI - Application of biochar from food and wood waste as green admixture for cement mortar. AB - Landfilling of food waste due to its low recycling rate is raising serious concerns because of associated soil and water contamination, and emission of methane and other greenhouse gases during the degradation process. This paper explores feasibility of using biochar derived from mixed food waste (FWBC), rice waste (RWBC) and wood waste (mixed wood saw dust, MWBC) as carbon sequestering additive in mortar. RWBC is prepared from boiled plain rice, while FWBC is prepared from combination of rice, meat, and vegetables in fixed proportion. Carbon content in FWBC, RWBC and MWBC were found to be 71%, 66% and 87% by weight respectively. Results show that addition of 1-2wt% of FWBC and RWBC in mortar results in similar mechanical strength as control mix (without biochar). 1wt% of FWBC led to 40% and 35% reduction in water penetration and sorptivity respectively, indicating higher impermeability of mortar. Biochar from mixed wood saw dust performed better in terms of mechanical and permeability properties. Increase in compressive strength and tensile strength by up to 20% was recorded, while depth of water penetration and sorptivity was reduced by about 60% and 38% respectively compared to control. Both FWBC and MWBC were found to act as reinforcement to mortar paste, which resulted in higher ductility than control at failure under flexure. This study suggests that biochar from food waste and mixed wood saw dust has the potential to be successfully deployed as additive in cement mortar, which would also promote waste recycling, and sequester high volume carbon in civil infrastructure. PMID- 29156264 TI - Examining the effects of socioeconomic development on fine particulate matter (PM2.5) in China's cities using spatial regression and the geographical detector technique. AB - The frequent occurrence of extreme smog episodes in recent years has begun to present a serious threat to human health. In addition to pollutant emissions and meteorological conditions, fine particulate matter (PM2.5) is also influenced by socioeconomic development. Thus, identifying the potential effects of socioeconomic development on PM2.5 variations can provide insights into particulate pollution control. This study applied spatial regression and the geographical detector technique for assessing the directions and strength of association between socioeconomic factors and PM2.5 concentrations, using data collected from 945 monitoring stations in 190 Chinese cities in 2014. The results indicated that the annual average PM2.5 concentrations is 61+/-20MUg/m3, and cites with more than 75MUg/m3 were mainly located in North China, especially in Tianjin and Hebei province. We also identified a marked seasonal variation in concentrations levels, with the highest level in winter due to coal consumption, lower temperatures, and less rainfall than in summer. Monthly variations followed a "U-shaped" pattern, with a down trend from January and an inflection point in September and then an increasing trend from October. The results of spatial regression indicated that population density, industrial structure, industrial soot (dust) emissions, and road density have a significantly positive effect on PM2.5 concentrations, with a significantly negative influence exerted only by economic growth. In addition, trade openness and electricity consumption were found to have no significant impact on PM2.5 concentrations. Using the geographical detector technique, the strength of association between the five significant drivers and PM2.5 concentrations was further analyzed. We found notable differences among the variables, with industrial soot (dust) emissions playing a greater role in the PM2.5 concentrations than the other variables. These results will be helpful in understanding the dynamics and the underlying mechanisms at work in PM2.5 concentrations in China at the city level, and thereby assisting the Chinese government in employing effective strategies to tackle pollution. PMID- 29156265 TI - Occurrence and fate of most prescribed antibiotics in different water environments of Tehran, Iran. AB - The presence of most prescribed antibiotic compounds from four therapeutic classes (beta-lactam, cephalosporins, macrolides, fluoroquinolones) were studied at two full-scale WWTPs, two rivers, thirteen groundwater resources, and five water treatment plants in Tehran. Analytical methodology was based on high performance liquid chromatography/tandem mass spectrometry after solid-phase extraction. Samples were collected at 33 sample locations on three sampling periods over four months from June to August 2016. None of the target antibiotics were detected in groundwater resources and water treatment plants, while seven out of nine target antibiotics were analyzed in two studied river waters as well as the influent and effluent of wastewater treatment plants at concentrations ranging from = 0.90), respectively. The adsorption kinetics depicted that pseudo-second order kinetics was followed simultaneously with intra-particle diffusion for both the dyes. Thermodynamic parameters such as DeltaG degrees , DeltaH degrees and DeltaS degrees were also calculated and confirmed the spontaneity, randomness and endothermic nature of the adsorption process. Further, the adsorbent exhibited good recyclability efficiency for the capture of Aur-O and EBT from aqueous solution with minimal activity decline after six and three cycles, respectively. So, the synthesized adsorbent could be used successfully by the textile industries for the treatment of dye contaminated water with excellent competency. PMID- 29156308 TI - Modulatory effects of green tea extract against the hepatotoxic effects of 4 nonylphenol in catfish (Clarias gariepinus). AB - The antioxidant role of the green tea (Camellia sinensis) extract (GTE) was examined to remedy the toxic effects of (0.2mgl-1) 4-nonylphenol(4-NP). Biochemical parameters, antioxidant enzymes, liver lipid peroxidation (LPO), DNA fragmentation, and apoptosis as well as histopathology of liver of African catfish Clarias gariepinus were considered. Catfishes were divided into four groups: first group (control), second group (0.2mgl-1 of 4-NP), third group (0.2mgl-1of 4-NP +100mg GTE l-1water), and fourth group (0.2mgl-1 of 4-NP +200mg GTE l-1water). The results showed that significant increments of serum glucose, AST, ALT, total protein, total lipids, cholesterol, G6PDH, and cortisol. Meanwhile, serum acetylcholinesterase, ALP, and LDH were significantly reduced. In addition, antioxidant enzymes (SOD, CAT, GST, and TAC) levels were reduced in 4-NP treated fish compared to control. Also, there were significant increments in hepatic LPO, DNA fragmentation, and apoptotic erythrocytes in 4-NP treated fish compared to control. Liver of 4-NP treated fish showed some histopathological alterations such as, vacuolization in hepatocytes, congestion in central vein, infiltration of mononuclear inflammatory cells, and necrosis as well as depletion of glycogen content of liver. Addition of green tea extract into the water restored the alterations in most of those biomarkers induced by 4-NP. We concluded that, GTE has a protective role against hepatic failure, depletion of antioxidant defense, and genotoxicity induced 4-NP in C. gariepinus. PMID- 29156309 TI - Recent development of computational resources for new antibiotics discovery. AB - Understanding a complex working mechanism of biosynthetic gene clusters (BGCs) encoding secondary metabolites is a key to discovery of new antibiotics. Computational resources continue to be developed in order to better process increasing volumes of genome and chemistry data, and thereby better understand BGCs. In this context, this review highlights recent advances in computational resources for secondary metabolites with emphasis on genome mining, compound identification and dereplication as well as databases. We also introduce an updated version of Secondary Metabolite Bioinformatics Portal (SMBP; http://www.secondarymetabolites.org), which we previously released as a curated gateway to all the computational tools and databases useful for discovery and engineering of secondary metabolites. PMID- 29156310 TI - Context and characteristics of illicit drug use in coastal and interior Tanzania. AB - BACKGROUND: An increase in heroin seizures in East Africa may signal wider local consumption of illicit drugs. Most information about drug use in Tanzania is from the economic capital, Dar es Salaam, and well-travelled Zanzibar. More data are needed on the extent, trends, and characteristics of illicit drug use in the vast coast and interior of the country. METHODS: The study was a rapid assessment, triangulating data from in-depth interviews of primary key informants (people who use drugs [PWUD]), secondary informants (police, community members, service providers), and ethnographic mapping of hotspots in 12 regions of Tanzania. RESULTS: We conducted 436 in-depth interviews from September 2013 to August 2014. Regions were categorized as (1) nascent: drug use is beginning to take root; (2) established: drug use has existed for some time; or (3) pervasive: drug use is spreading into new sub-groups/areas. Multiple sources corroborated that illicit drug use has been increasing in all regions. Most PWUD worked in the cash economy as bus touts, labourers, fishermen, miners, or sex workers, or stole to survive or support their habit. PWUD congregated around bus stops along transit corridors, in abandoned buildings, and in low-income residential areas. Informants described less visible PWUD among military, police, and working-class people. Cannabis was the most common, smoked alone or with tobacco and heroin ("cocktail"). Heroin was available in all regions. Cocaine was less common, likely due to high price and variable availability. Substances such as petrol, shoe polish, and glue were used as inhalants. CONCLUSIONS: Illicit drug use is widespread with variable features beyond cosmopolitan areas of Tanzania. Improving transportation infrastructure and economic opportunities combined with poverty and inequality appear key factors for increasing use. Findings call attention to increasing and widening drug use in Tanzania and the need to plan prevention, treatment, and harm-reduction measures nationally. PMID- 29156311 TI - Impacts from urban water systems on receiving waters - How to account for severe wet-weather events in LCA? AB - Sewage systems are a vital part of the urban infrastructure in most cities. They provide drainage, which protects public health, prevents the flooding of property and protects the water environment around urban areas. On some occasions sewers will overflow into the water environment during heavy rain potentially causing unacceptable impacts from releases of untreated sewage into the environment. In typical Life Cycle Assessment (LCA) studies of urban wastewater systems (UWS), average dry-weather conditions are modelled while wet-weather flows from UWS, presenting a high temporal variability, are not currently accounted for. In this context, the loads from several storm events could be important contributors to the impact categories freshwater eutrophication and ecotoxicity. In this study we investigated the contributions of these wet-weather-induced discharges relative to average dry-weather conditions in the life cycle inventory for UWS. In collaboration with the Paris public sanitation service (SIAAP) and Observatory of Urban Pollutants (OPUR) program researchers, this work aimed at identifying and comparing contributing flows from the UWS in the Paris area by a selection of routine wastewater parameters and priority pollutants. This collected data is organized according to archetypal weather days during a reference year. Then, for each archetypal weather day and its associated flows to the receiving river waters (Seine), the parameters of pollutant loads (statistical distribution of concentrations and volumes) were determined. The resulting inventory flows (i.e. the potential loads from the UWS) were used as LCA input data to assess the associated impacts. This allowed investigating the relative importance of episodic wet-weather versus "continuous" dry-weather loads with a probabilistic approach to account for pollutant variability within the urban flows. The analysis at the scale of one year showed that storm events are significant contributors to the impacts of freshwater eutrophication and ecotoxicity compared to those arising from treated effluents. At the rain event scale the wet-weather contributions to these impacts are even more significant, accounting for example for up to 62% of the total impact on freshwater ecotoxicity. This also allowed investigating and discussing the ecotoxicity contribution of each class of pollutants among the broad range of inventoried substances. Finally, with such significant contributions of pollutant loads and associated impacts from wet weather events, further research is required to better include temporally differentiated emissions when evaluating eutrophication and ecotoxicity. This will provide a better understanding of how the performance of an UWS system affects the receiving environment for given local weather conditions. PMID- 29156312 TI - Identifying health conditions, priorities, and relevant multilevel health promotion intervention strategies in African American churches: A faith community health needs assessment. PMID- 29156314 TI - Characterization of Northwest Africa 6286 and 7857 ordinary chondrites using X ray diffraction, magnetization measurements and Mossbauer spectroscopy. AB - Northwest Africa (NWA) 6286 and 7857 meteorites were studied in detail by using optical microscopy, scanning electron microscopy with energy dispersion spectroscopy, X-ray diffraction, magnetization measurements and 57Fe Mossbauer spectroscopy with a high velocity resolution. The main and the minor iron-bearing phases were identified in both meteorites. The unit cell parameters as well as Fe2+ and Mg2+ cation distribution were determined for the M1 and M2 sites in silicate microcrystals. Saturation magnetic moments were obtained for both meteorites. Mossbauer parameters for the main and the minor iron-bearing microcrystals were estimated and compared for NWA 6286 and NWA 7857 LL6 ordinary chondrites. The Fe2+ and Mg2+ cation partitioning, distribution coefficient and temperature of cation equilibrium distribution were estimated for silicate microcrystals using X-ray diffraction and Mossbauer spectroscopy. PMID- 29156313 TI - Synthesis, spectroscopic and TD-DFT quantum mechanical study of azo-azomethine dyes. A laser induced trans-cis-trans photoisomerization cycle. AB - This paper describes the synthesis, spectroscopic characterization and quantum mechanical calculations of three azo-azomethine dyes. The dyes were synthesized via condensation reaction between 4-(dimethylamino)benzaldehyde and three different 4-aminobenzene azo dyes. Quantum chemical calculations on the optimized molecular geometry and electron densities of the trans (E) and cis (Z) isomers and their vibrational frequencies have been computed by using DFT/B3LYP density functional theory with 6-311++G(d,p) basis set in vacuo. The thermodynamic parameters such as total electronic energy E (RB3LYP), enthalpy H298 (sum of electronic and thermal enthalpies), free Gibbs energy G298 (sum of electronic and thermal free Gibbs energies) and dipole moment MU were computed for trans (E) and cis (Z) isomers in order to estimate the DeltaEtrans->cis, DeltaMUtrans >cis,DeltaHtrans->cis, DeltaGtrans->cis and DeltaStrans->cis values. After molecular geometry optimization the electronic spectra have been obtained by TD DFT calculations at same basis set and correlated with the spectra of vapour deposited nanosized films of the dyes. The NBO analysis was performed in order to understand the intramolecular charge transfer and energy of resonance stabilization. Solvatochromism was investigated by UV-VIS spectroscopy in five different organic solvents with increasing polarity. The dynamic photoisomerization experiments have been performed in DMF by pump lasers lambda=355nm (mostly E->Z) and lambda=491nm (mostly Z->E) in spectral region 300nm - 800nm at equal concentrations and times of illumination in order to investigate the photodynamical trans-cis-trans properties of the CHN and NN chromophore groups of the dyes. PMID- 29156315 TI - Genus- and species-level identification of dermatophyte fungi by surface-enhanced Raman spectroscopy. AB - This paper demonstrates that surface-enhanced Raman spectroscopy (SERS) coupled with principal component analysis (PCA) can serve as a fast and reliable technique for detection and identification of dermatophyte fungi at both genus and species level. Dermatophyte infections are the most common mycotic diseases worldwide, affecting a quarter of the human population. Currently, there is no optimal method for detection and identification of fungal diseases, as each has certain limitations. Here, for the first time, we have achieved with a high accuracy, differentiation of dermatophytes representing three major genera, i.e. Trichophyton, Microsporum, and Epidermophyton. Two first principal components (PC), namely PC-1 and PC-2, gave together 97% of total variance. Additionally, species-level identification within the Trichophyton genus has been performed. PC 1 and PC-2, which are the most diagnostically significant, explain 98% of the variance in the data obtained from spectra of: Trichophyton rubrum, Trichophyton menatgrophytes, Trichophyton interdigitale and Trichophyton tonsurans. This study offers a new diagnostic approach for the identification of dermatophytes. Being fast, reliable and cost-effective, it has the potential to be incorporated in the clinical practice to improve diagnostics of medically important fungi. PMID- 29156316 TI - Neutral dipole-dipole dimers: A new field in science. AB - Dimer formation with dipole neutralization produces species such as low polarity water (LPW) compatible with hydrophobic surfaces (Phys. Chem. Chem. Phys. 2015, 17, 24895-24900) Dimerization and dipole neutralization occurs for N methylacetamide on polyethylene, a behavior drastically different from its contortions in acetonitrile on AgBr:AgCl planar crystals (AgX) (ChemPhysChem 2014, 15, 3598-3607). The weak infrared absorption of the amide dimer on polyethylene is shown experimentally. Dimerization of palmitic acid is shown along with some of the many ramifications for intracellular systems. Polyoligomers of water are present on polyethylene surfaces. Some high resolution spectra of three of the polyoligomers of water are shown along with a mechanistic scheme for polyoligomer formation and dissolution. The structures of some of the oligomers are known from spectroscopic studies of water on AgX. PMID- 29156317 TI - Benzimidazobenzothiazole-based highly-efficient thermally activated delayed fluorescence emitters for organic light-emitting diodes: A quantum-chemical TD DFT study. AB - Based upon two thermally activated delayed fluorescence (TADF) emitters 1 and 2, compounds 3-6 have been designed by replacing the carbazol group with the bis(4 biphenyl)amine one (3 and 4) and introducing the electron-withdrawing CF3 group into the acceptor unit of 3 and 4 (5 and 6). It is found that the present calculations predict comparable but relatively large energy differences (approximate 0.5eV) between the lowest singlet S1 and triplet T1 states (?EST) for the six targeted compounds. In order to explain the highly-efficient TADF behavior observed in compounds 1 and 2, the"triplet reservoir" mechanism has been proposed. In addition, the fluorescence rates of all six compounds are very large, in 107-108 orders of magnitude. According to the present calculations, it is a reasonable assumption that the newly designed compounds 3-6 could be considered as the potential TADF emitters, which needs to be further verified by experimental techniques. PMID- 29156318 TI - How host metabolism impacts on virus pathogenesis. PMID- 29156319 TI - Large-scale analysis of herpesviridae in epilepsy-patients with signs of autoimmune encephalitis. AB - PURPOSE: Epilepsy is one of the most common primary brain disorders. Nonparaneoplastic autoimmune encephalitis is increasingly recognized as an important cause of adult onset epilepsy. However, only in rare cases an initiating factor of the syndrome can be identified. Autoantibody detection after central nervous herpesvirus infection indicates a postviral etiology in a subgroup of patients. In order to analyze a possible underrecognition of postinfectious autoimmunity we performed a large-scale analysis of herpesvirus DNA in cerebrospinal fluid samples from patients with clinical signs of autoimmune encephalitis. METHODS: Real time PCR for HSV 1/2, CMV, EBV, VZV, HHV 6A, HHV-6B, HHV-7 and HHV-8 was performed in cerebrospinal fluid samples from 113 patients with epilepsy and suspected autoimmune encephalitis. Indirect immunofluorescence analysis was used for autoantibody analysis. RESULTS: Antineuronal autoantibodies could be identified in 48 patients with definite autoimmune encephalitis. No autoantibodies were detected in 65 additional patients with probable or possible autoimmune encephalitis. Real-time PCR analysis revealed in three autoantibody-negative patients positive results for HSV, but no evidence for further virus DNA. CONCLUSION: The findings argue against longstanding herpesvirus infection of the CNS as frequent trigger for autoimmunity. However, appearance of autoantibodies after a short period of active virus infection cannot be excluded. PMID- 29156320 TI - Localised sampling of myoelectric activity may provide biased estimates of cocontraction for gastrocnemius though not for soleus and tibialis anterior muscles. AB - Proper muscle activity quantification is highly relevant to monitor and treat spastic cocontraction. As activity may distribute unevenly within muscle volumes, particularly for pennate calf muscles, surface electromyograms (EMGs) detected by traditional bipolar montage may provide biased estimations of muscle activity. We compared cocontraction estimates obtained using bipolar vs grids of electrodes (high-density EMG, HD-EMG). EMGs were collected from medial gastrocnemius, soleus and tibialis anterior during isometric plantar and dorsi-flexion efforts at three levels (30%, 70% and 100% MVC), knee flexed and extended. Cocontraction index (CCI) was estimated separately for each electrode pair in the grid. While soleus and tibialis anterior CCI estimates did not depend on the detection system considered, for gastrocnemius bipolar electrodes provided larger cocontraction estimates than HD-EMG at highest effort levels, at both knee angles (ANOVA; P < .001). Interestingly, HD-EMG detected greater gastrocnemius EMGs distally during plantar flexions, and greater CCI values proximally during dorsiflexions. These results suggest that bipolar electrodes: (i) provide reliable estimates of soleus and tibialis anterior cocontraction; (ii) may under-or overestimate gastrocnemius cocontraction, depending on their distal or proximal position. PMID- 29156321 TI - Postural changes in orthodontic patients treated with clear aligners: A rasterstereographic study. AB - BACKGROUND: Correlation between malocclusions and body posture has been discussed in the last decades, but there is still a lack of consensus in existing literature. Rasterstereography allows tridimensional reconstruction of the spine, starting from the back surface analysis. So far studies which tested modifications of rasterstereographic parameters during orthodontic treatment, comparing with those obtained from untreated control group, are not available. Clear aligner treatment produces alteration of vertical height due to the occlusal coverage and, subsequently, a stimulation of periodontal receptors which causes an inhibition of the jaw closing muscles and, hypothetically, changes in mandibular posture. OBJECTIVES: Evaluate possible correlations between orthodontic treatment and posture. MATERIALS AND METHODS: Rasterstereographic values of 15 untreated patients and of 15 patients treated with clear aligners were compared at baseline, after 1, 3 and 6 months. Rasterstereographic parameters considered were the following: the kyphotic angle, the lordotic angle, the upper thoracic inclination, and the pelvic inclination. RESULTS: Correlations between Kyphosis Angle, Upper Toracic Inclination and Pelvic Inclination and body posture were found after 6 months of treatment with clear aligners. CONCLUSIONS: Occlusal coverage caused by aligners could influence body posture not only for upper spine sections but also lower spine sections. PMID- 29156322 TI - The development and importance of shared reality in the domains of opinion, morality, and religion. AB - The importance of shared reality emerges early in human development. Infants and young children notice when others share their beliefs, and information about shared beliefs influences their social judgments. This article reviews recent research on the importance of shared beliefs in three domains that have been widely investigated over the past several years-opinions, moral views, and religious beliefs. I argue that shared religious beliefs appear especially influential and suggest several reasons why this might be the case, including the perceived link between religion and morality as well as the strong role that religious beliefs play in personal identity. Future research can further test these possibilities. PMID- 29156324 TI - Influence of post-stroke spasticity on EMG-force coupling and force steadiness in biceps brachii. AB - BACKGROUND: Individuals with spasticity after stroke experience a decrease in force steadiness which can impact function. Alterations in the strength of EMG force coupling may contribute to the reduction in force steadiness observed in spasticity. The aim was to determine the extent to which force steadiness and EMG force coupling is affected by post-stroke spasticity. METHODS: This cross sectional study involved individuals with upper limb spasticity after stroke. Participants were required to generate and maintain isometric contractions of the elbow flexors at varying force levels. Coefficient of variation of force, absolute force, EMG-force cross-correlation function peak and peak latency was measured from both limbs with surface electromyography and isometric dynamometry. RESULTS: Statistically significant differences were observed between the affected and less affected limbs for all outcome measures. Significant main effects of force level were also observed. Force steadiness was not statistically significantly correlated with EMG-force coupling; however, both force steadiness and absolute force were associated with the level of impairment as measured by the Chedoke McMaster Stroke Assessment Scale. DISCUSSION: Spasticity after stroke uncouples the relationship between EMG and force and is associated with reduced force steadiness during isometric contractions; however, these features of control are not associated in individuals with spasticity. PMID- 29156325 TI - Differential partitioning of rumen-protected n-3 and n-6 fatty acids into muscles with different metabolism. AB - Bioavailability of polyunsaturated fatty acids (PUFA) in ruminants is enhanced by their protection from ruminal biohydrogenation. Both n-3 and n-6 PUFA fulfil important physiological functions. We investigated potentially different incorporation patterns of these functional PUFA into three beef muscles with different activity characteristics. We supplemented 33 Angus heifers with rumen protected oils characterized either by mainly C18:2 n-6 (linoleic acid (LA) in sunflower oil) or by C20:5 (eicosapentaenoic acid (EPA)) and C22:6 (docosahexaenoic acid (DHA)), both prevalent n-3 PUFA in fish oil. Contents and proportions of n-3 and n-6 PUFA of total fatty acids were elevated in the muscles of the respective diet group but they were partitioned differently into the muscles. For EPA and DHA, but not for LA, the diet effect was more distinct in the extensor carpi radialis compared to longissimus thoracis and biceps femoris. Partitioning of PUFA in metabolism could be related to muscle function. This has to be confirmed in other muscles, adipose tissues and organs. PMID- 29156323 TI - Early life exposure to per- and polyfluoroalkyl substances and mid-childhood lipid and alanine aminotransferase levels. AB - BACKGROUND: Growing evidence suggests that exposure to per- and polyfluoroalkyl substances (PFASs) may disrupt lipid homeostasis and liver function, but data in children are limited. OBJECTIVE: We examined the association of prenatal and mid childhood PFAS exposure with lipids and alanine aminotransferase (ALT) levels in children. METHODS: We studied 682 mother-child pairs from a Boston-area pre-birth cohort. We quantified PFASs in maternal plasma collected in pregnancy (median 9.7weeks gestation, 1999-2002) and in child plasma collected in mid-childhood (median age 7.7years, 2007-2010). In mid-childhood we also measured fasting total (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and ALT. We then derived low-density lipoprotein cholesterol (LDL-C) from TC, HDL-C, and TG using the Friedewald formula. RESULTS: Median (interquartile range, IQR) perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorodecanoate (PFDeA) concentrations in child plasma were 6.2 (5.5), 4.3 (3.0), and 0.3 (0.3) ng/mL, respectively. Among girls, higher child PFOS, PFOA, and PFDeA concentrations were associated with detrimental changes in the lipid profile, including higher TC and/or LDL-C [e.g., beta per IQR increment in PFOS=4.0mg/dL (95% CI: 0.3, 7.8) for TC and 2.6mg/dL (-0.5, 5.8) for LDL-C]. However, among both boys and girls, higher plasma concentrations of these child PFASs were also associated with higher HDL-C, which predicts better cardiovascular health, and slightly lower ALT, which may indicate better liver function. Prenatal PFAS concentrations were also modestly associated with improved childhood lipid and ALT levels. CONCLUSIONS: Our data suggest that prenatal and mid-childhood PFAS exposure may be associated with modest, but somewhat conflicting changes in the lipid profile and ALT levels in children. PMID- 29156326 TI - Monitoring lean meat percentage predictions from optical grading probes by a commercial cutting pattern. AB - The lean meat percentage (LMP) classification in Norwegian slaughterhouses is obtained by Hennessy Grading Probe 7 (HGP7), an optical tool. Even though the HGP7 method is validated frequently, there is industrial and legislative demand to reconsider the applied LMP equation, typically due to the introduction of new breeds. A deboning pilot plant generates precise yield data using cutting and deboning stratified pork carcasses by a specific commercial cutting pattern (CCP) at an annual rate of approximately 250 slaughter pigs. This paper shows how results obtained by CCP can be used to measure LMP in pork and how these results can be used for monitoring the quality of LMP predicted by HGP7. The effect of gender, maternal- and paternal lines on validity of HGP7 predictions was evaluated. The effect of introducing a new maternal line (TN70) seems to be substantial, whereas the effects of the tested paternal lines are small to negligible. PMID- 29156327 TI - Asiatic acid and maslinic acid attenuated kainic acid-induced seizure through decreasing hippocampal inflammatory and oxidative stress. AB - Seizure is a neurological disorder including hippocampal oxidative and inflammatory stress, and glutamate toxicity. Thus, any agent(s) that mitigate(s) these events in hippocampus might attenuate seizure severity. The effects of asiatic acid (AA) or maslinic acid (MA) pre-administration at 20 or 40mg/kg body weight/day upon inflammatory, oxidative and apoptotic injury in hippocampus of kainic acid (KA)-treated mice were examined. KA induced seizure-like behavioral patterns, which was attenuated by AA or MA pre-administration. KA stimulated the release of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and prostaglandin E2 in hippocampus of mice. AA or MA pre-administration decreased the production of these inflammatory factors. AA or MA also diminished KA-induced increase in hippocampal cyclooxygenase-2 activity and relative NF-kappaB p50/65 binding activity. KA depleted glutathione content and promoted reactive oxygen species generation. AA or MA pre-administration reversed these alterations. KA lowered Bcl-2 mRNA expression and increased Bax mRNA expression. AA or MA treatments reduced Bax mRNA expression. AA or MA pre-administration enhanced glutamine synthetase activity, decreased glutamate level and increased glutamine level in hippocampus of KA treated mice. In addition, AA or MA pre-treatments at 10 and 20MUM increased viability and decreased plasma membrane damage in KA treated nerve growth factor (NGF)-differentiated PC12 cells. Both agents also lowered the release of calcium ion induced by KA in NGF-treated PC12 cells. These findings support that asiatic acid and maslinic acid are potent nutraceutical agents for seizure alleviation. PMID- 29156328 TI - Role of hair pigmentation in drug incorporation into hair. AB - Hair analysis has notably expanded its application as a bio-monitor for drug or toxicant exposure. Hair pigmentation is proposed as a major factor affecting drug incorporation into hair; however, the mechanisms underlying the incorporation of drugs into hair are still unclear. In the present study, the effect of hair pigmentation on drug incorporation into hair was examined using rats carrying hair with different melanin status and human cells (SK-Mel-28 cells, HaCaT cells and the co-cultured HaCaT cells with SK-Mel-28 cells) representing the main pigmentary unit in hair. Tramadol, a synthetic opioid analgesic, was selected as a model drug. The distribution of tramadol and its phase I (O-desmethyltramadol [ODMT], N-desmethyltramadol [NDMT] and N,O-didesmethyltramadol [NODMT]) and phase II metabolites (ODMT-glucuronide and NODMT-glucuronide) was investigated in non pigmented and pigmented hair from Long-Evans rats. Moreover, the incorporation levels of ODMT and ODMT-glucuronide were compared in hair cells. The concentrations of tramadol and its phase I metabolites were significantly higher in pigmented rat hair while those of phase II metabolites did not showed any consistent significant difference depending on the status of hair pigmentation. ODMT was taken up to a greater extent than ODMT-glucuronide by SK-Mel-28 cells, HaCaT cells and the co-cultured HaCaT cells with SK-Mel-28 cells. Notably, the incorporated level of ODMT was higher in SK-Mel-28 cells than HaCaT cells and the concentration difference of ODMT was significantly larger than that of ODMT glucuronide. This study clearly demonstrated that hair pigmentation played a role as a facilitating factor for the incorporation of basic compounds and provided insight into the drug incorporation process into hair. PMID- 29156329 TI - Clinical outcomes of primary intracranial malignant melanoma and metastatic intracranial malignant melanoma. AB - OBJECTIVES: Primary intracranial malignant melanoma (PIMM) is extremely rare central nervous system (CNS) tumor and known for only composed 0.07% of the CNS tumors. PIMM composed only 1% of malignant melanoma and accordingly their clinical behavior and prognosis are not well documented. So, herein, we report our experience of pathologically proven PIMM, and compared their clinical characteristics and outcome with metastatic intracranial malignant melanoma (MIMM). PATIENTS AND METHODS: Our institutional database was reviewed for patients who diagnosed as PIMM and MIMM pathologically between 1996-2016. As a result, a total of 6 patients of PIMM and 18 patients of MIMM were identified and analyzed. All these patients' clinical, radiological, histopathological and surgical records were obtained and reviewed. RESULTS: The median age of PIMM patients at initial surgery was 54.5 years (range, 30-60 years). During the mean follow-up of 12.8 months (range: 9-21 months), tumor recurrence occurred in 5 patients (83.3%). The overall survival rates of PIMM at 6, 9, 12 and 18 months were 100%, 83%, 50% and 25%. The PFS rates of PIMM at 3,6,9 and 12 months were 66.7%, 50%, 16.7% and 16.7%. The overall survival rates and progression-free survival rate difference between PIMM and MIMM were not statistically significant. (p=0.723 and p=0.6, respectively). CONCLUSION: According to our experience, PIMM is very aggressive malignant tumor. Its median survival was less than 1year. We suggest that maximal safe resection plus adjuvant RT and CTX for intracranial malignant melanoma considering highly aggressive clinical course of this tumors. PMID- 29156330 TI - Hospital and demographic characteristics associated with inpatient neurological services in the United States. AB - OBJECTIVE: To determine nationwide availability and factors associated with inpatient neurological services. PATIENTS AND METHODS: Using the 2011 American Hospital Association survey, we determined the proportion of hospitals that provided inpatient neurological services. Demographic and household data from the 2010 national census and survey results were utilized to determine regional factors associated with the availability of inpatient neurologic services. Using rate ratios, the association was estimated using Poisson regression. Hospitals lacking emergency departments or with a bed size of less than 25 beds were excluded to focus on acute care facilities with the potential to have subspecialty services. RESULTS: Of 3969 hospitals that completed the survey, 2017 (65%) provided inpatient neurological services. Hospitals with Joint Commission (JC) accreditation were 1.35 times more likely (95% CI: 1.16-1.57) to have inpatient neurological services. Compared to small hospitals (bed size 25-36), large hospitals (bed size 246-2264) were 4.53 times more likely (95% CI: 2.79 7.35) to provide inpatient neurological services. Hospitals that were the sole community provider or were non-federal governmental hospitals had a lower probability of providing inpatient neurological services with rate ratio of 0.65 (95% CI: 0.5-0.84) and 0.81 (95% CI: 0.7-0.94), respectively. CONCLUSIONS: Approximately two-thirds of hospitals in this nationwide survey provided hospital based neurological services. Larger hospitals and those with JC accreditation were more likely to provide neurological services, whereas small hospitals, sole community providers, and non-federal governmental hospitals were less likely to provide them. PMID- 29156331 TI - May humic acids or mineral fertilisation mitigate arsenic mobility and availability to carrot plants (Daucus carota L.) in a volcanic soil polluted by As from irrigation water? AB - Carrot (Daucus carota L.) is a widely consumed root vegetable, whose growth and safety might be threatened by growing-medium arsenic (As) contamination. By this work, we evaluated the effects of humic acids from Leonardite and NPK mineral fertilisation on As mobility and availability to carrot plants grown for 60 days in a volcanic soil irrigated with As-contaminated water - representing the most common scenario occurring in As-affected Italian areas. As expected, the irrigation with As-contaminated water caused a serious toxic effect on plant growth and photosynthetic rate; the highest rate of As also inhibited soil enzymatic activity. In contrast, the organic and mineral fertilisation alleviated, at least partially, the toxicity of As, essentially by stimulating plant growth and promoting nutrient uptake. The mobility of As in the volcanic soil and thus its phytoavailability were differently affected by the organic and mineral fertilisers; the application of humic acids mitigated the availability of the contaminant, likely by its partial immobilisation on humic acid sorption sites - thus raising up the intrinsic anionic sorption capacity of the volcanic soil; the mineral fertilisation enhanced the mobility of As in soil, probably due to competition of P for the anionic sorption sites of the soil variable-charge minerals, very affine to available P. These findings hence suggest that a proper soil management of As-polluted volcanic soils and amendment by stable organic matter might mitigate the environmental risk of these soils, thus minimising the availability of As to biota. PMID- 29156332 TI - Effective flocculation of Microcystis aeruginosa with simultaneous nutrient precipitation from hydrolyzed human urine. AB - Mechanical harvest of massive harmful algal blooms is an effective measure for bloom mitigation. Yet subsequent processing of the resulting water from algae water separation after the harvesting becomes a new problem since individual algal cells or small algal aggregates are still present in the water. Here, we proposed a novel approach for effectively flocculating the cyanobacteria Microcystis aeruginosa with a removal efficiency of 97% in 6 h using hydrolyzed urine. Nitrogen and phosphorus were simultaneously reclaimed through struvite formation. The addition of Mg2+ promoted the flocculation efficiency and nutrient removal as well as the yield of struvite. Ca2+ could enhance the flocculation efficiency by forming calcium phosphate. During the flocculation process, no significant damage in algal cells was observed. This study provides a novel and sustainable potential for subsequent processing of the resulting water after algae water separation with simultaneous nutrient precipitation and reducing nutrient loads to wastewater treatment plants. PMID- 29156333 TI - Short- and long-term effects of manganese, zinc and copper ions on nitrogen removal in nitritation-anammox process. AB - This study provided a deep insight into the impacts of trace elements (Mn2+, Zn2+ and Cu2+) on nitritation-anammox process. For short-term exposure, all the three elements could improve the nitrogen removal rate (NRR) and the optimal concentrations were 2.0 mg/L, 2.0 mg/L and 0.5 mg/L for Mn2+, Zn2+ and Cu2+, respectively. Accordingly, the NRRs were enhanced 54.62%, 45.93% and 44.09%. The long-term experiments were carried out in lab-scale sequencing batch reactors. The surprising results showed that only Mn2+ addition could enhance the long-term nitritation-anammox process, and the NRR increased from 0.35 +/- 0.01 kg N/m3/d (control, no extra trace element addition) to 0.49 +/- 0.03 kg N/m3/d. Vice versa, the amendment of Zn2+ reduced the NRR to 0.28 +/- 0.02 kg N/m3/d, and Cu2+ had no significant effect on the NRR (0.36 +/- 0.01 kg N/m3/d). From the analysis of microbial community structure, it was explained by the increasing abundance of anaerobic ammonium oxidizing bacteria (AnAOB) only in Mn2+ treatment, whereas Zn2+ predominantly promoted ammonium oxidizing bacteria (AOB). Additionally, the majority of Mn2+ was identified inside AnAOB cells, and Zn2+ and Cu2+ were mainly located in AOB. Our results indicated the synergistic effects of trace elements on nitritation-anammox, both short-term encouraging activities of AnAOB and long term altering microbial community structure. This work implies the importance of trace elements addition in nitritation-anammox process. PMID- 29156334 TI - Applicability evaluation of advanced processes for elimination of neurophysiological activity of antidepressant fluoxetine. AB - Presence of the antidepressant fluoxetine in different water bodies has raised significant concerns due to its detrimental effects on non-targeted organisms, especially on fish. When seeking for an appropriate technology able to remove fluoxetine residue from a complex water matrix, special attention needs to be paid to the elimination of the neurophysiological activity that eventually lies behind the noxious effects of the parent compound. Our aim was to probe the applicability of advanced oxidation techniques for this purpose using in situ generated free radical system based on OH-initiated peroxyl radical-mediated processes. By performing product analysis experiments along with quantum chemical calculations, the most probable reaction paths were analyzed including aromatic hydroxylation, defluorination, O-dealkylation and C-dealkylation. The candidates for neurophysiological activity were further investigated by molecular docking. The hydroxylated derivatives are well accommodated in the binding pocket of the corresponding protein, suggesting that these compounds may retain the activity of the parent compound. From a worst-case perspective, we suggest that prolonged treatment needs to be applied to further transform hydroxylated derivatives. PMID- 29156335 TI - Thyroid disruption and reduced mental development in children from an informal e waste recycling area: A mediation analysis. AB - This paper aims to evaluate the effects of thyroid disruption on the mental development of children. A total of 258 three-year-old children in Guiyu (e-waste exposed group) and Nanao (reference group), China were examined. FT3, FT4, TSH, lead (BPb) and cadmium (BCd) in blood were determined, and cognitive and language scores of children were assessed based on the Bayley Scales of Infant Development III. Stepwise multiple regression was used to estimate the relationship between heavy metals and cognitive and language scores; mediation analysis was performed to determine whether thyroid disruption was mechanistically involved. Medians of BPb and BCd in Guiyu were higher than that of Nanao (11.30 +/- 5.38 vs. 5.77 +/- 2.51 MUg/dL BPb; 1.22 +/- 0.55 vs. 0.72 +/- 0.37 MUg/L BCd, both p < 0.001). Means of FT4 and TSH in Guiyu were also higher than those in Nanao (16.65 +/- 1.83 vs.16.06 +/- 1.66 pmol/L FT4, p = 0.007; 2.79 +/- 1.30 vs. 2.21 +/- 1.43 mIU/L TSH, p = 0.001). Guiyu children had lower cognitive scores (100.00 +/- 25.00 vs. 120.00 +/- 20.00, p < 0.001) and lower language scores (99.87 +/- 7.52 vs. 111.39 +/- 7.02, p < 0.001). Mediation analysis showed that Pb negatively correlated with both cognitive and language scores (both p < 0.001). However, FT3, FT4 and TSH did not significantly mediate the relationship between Pb and mental development of children (all p > 0.05). In contrast, Cd correlated with neither cognitive nor language scores (both p > 0.05). Results suggest exposure to heavy metal (Pb) reduces cognitive and language skills, and affects thyroid function, but fail to confirm that thyroid disruption is involved in the neurotoxicity induced by PbCd co-exposure. PMID- 29156336 TI - Magnesium lithospermate B loaded PEGylated solid lipid nanoparticles for improved oral bioavailability. AB - Magnesium lithospermate B (MLB) is an active polyphenol acid with multiple pharmacological activities and poor oral bioavailability. The present research aimed to construct MLB loaded solid lipid nanoparticles (MLB-SLNs) for oral delivery to enhance its bioavailability. MLB-SLNs were prepared by solvent diffusion method and subsequently modified with polyethylene glycol monostearate (PEG-SA) superficially. The particle sizes of MLB-SLNs varied from 82.57 to 53.50nm with an improved drug loading capacity (up to 16.18%) after PEG-SA modification. Pharmacokinetic study indicated that Cmax (peak plasma MLB concentration) and AUC (area under curve) of MLB-SLNs increased significantly compared to that of MLB solution in male SD rats. The relative bioavailability of MLB-SLNs with PEG-SA modification was 753.98% compared to MLB solution administered by tail intravenous injection. The enhanced transport mechanism could be further illustrated by the results that MLB-SLNs showed higher permeability across Madin-Daby canine kidney (MDCK) epithelial cell monolayer and MLB-SLNs with smaller particle size distribution and PEG-SA modification manifested stronger cellular internalization ability on MDCK cells. Thus, PEG-SA modified solid lipid nanoparticles confirmed with enhanced cellular transport and improved oral bioavailability can be a promising oral MLB delivery system. PMID- 29156337 TI - Facile preparation of core cross-linked nanomicelles based on graft copolymers with pH responsivity and reduction sensitivity for doxorubicin delivery. AB - To achieve passive targeting and controlled drug release at tumor sites trigged by low pH value and high level of glutathione (GSH), optimized delivery system for doxorubicin (DOX) based on core cross-linked nanomicelles was developed in this research. Particularly, methoxypoly(ethylene glycol)-nitrophenyl carbonate (mPEG-NPC) and 3,4-dihydroxyphenylaceticacid were grafted onto synthesized poly(N,N'-cystamine bisacrylamide-N-Boc-1,2-diaminoethane) (poly(CBA-DAE)) to give methoxypoly(ethylene glycol)-g-poly(N,N'-cystamine bisacrylamide-N-Boc-1, 2 diaminoethane)-g-3, 4-dihydroxyphenylaceticacid (mPEG-g-SS-PCD-DA). Core cross linked micelles (CCLMs/SS) with a decreased average particle size of 121nm were prepared by adding Fe3+ into uncross-linked micelles (UCLMs/SS) self-assembled from mPEG-g-SS-PCD-DA. DOX-loaded CCLMs/SS exhibited minimal drug leakage (17.3%) under simulated blood conditions compared to DOX-loaded UCLMs/SS (31.3%). Fast drug release (52.4%) of DOX-loaded CCLMs/SS was achieved compared to DOX-loaded CCLMs/CC (32.9%) without disulfide bonds under simulated lysosomes condition over 42h. The cytotoxicity of DOX-loaded CCLMs/SS against A549 cells pretreated with 40mM NH4Cl was decreased significantly compared to that without NH4Cl treatment, and it is higher than that of DOX-loaded CCLMs/CC, further confirmed DOX release was triggered by the low pH value and high level of reductive agents of lysosomes. Compared with free DOX, DOX-loaded CCLMs/SS showed enhanced cellular uptake ability during 24h of incubation through endocytosis. Besides, charge conversion of micelles happened when pH varied from 7.4 to 6.5, which facilitates the cellular uptake against A549 cells. In summary, all these results indicated that CCLMs/SS as a new type of intelligent nanocarriers exhibited excellent potential for drug delivery. PMID- 29156338 TI - Effect of Laminaria japonica polysaccharides on lipids monolayers at the air water surface. AB - In this paper, we examined the effect of Laminaria japonica polysaccharides (LJP) on cationic 1,2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP) and anionic 1,2 dipalmitoyl-sn-glycero-3-[phospho-rac-1-glycerol] (DPPG) monolayers at the air water interface by the pressure-area isotherms (pi-A), adsorption curves (pi-t) and morphology measurements with atomic force microscopy (AFM) technique. The pi A curves revealed that the isotherms shifted to larger mean molecular area with progressive addition of LJP into subphase for both DOTAP and DPPG monolayers. And the compression modulus Cs-1 obtained from pi-A curves showed that the elasticity of the films decreased with the addition of LJP. Adsorption curves were measured at the surface pressure of 10 and 20mN/m, which were fitted by the adsorption kinetics equation. It revealed that DOTAP monolayer changed into a mixed film with the insertion of polysaccharides molecules. However, there was no significant effect on the surface pressure for DPPG monolayer. Besides, surface morphology was observed by AFM, which was consistent with the results of fitted adsorption curves. PMID- 29156339 TI - Silicification process in diatom algae using different silicon chemical sources: Colloidal silicic acid interactions at cell surface. AB - The silicon transport and use inside cells are key processes for understanding how diatoms metabolize this element in the silica biogenic cycle in the ocean. A spin-probe electron paramagnetic resonance (EPR) study over time helped to investigate the interacting properties and the internalization mechanisms of silicic acid from different silicon sources into the cells. Diatom cells were grown in media containing biogenic amorphous substrates, such as diatomaceous earth and sponge spicules, and crystalline sodium metasilicate. It was found that the amorphous biogenic silicon slowed down the internalization process probably due to formation of colloidal particles at the cell surface after silicic acid condensation. Weaker interactions occurred with sponge spicules silicon source if compared to the other sources. The EPR results were explained by analyzing transcript level changes of silicon transporters (SITs) and silaffins (SILs) in synchronized Thalassiosira pseudonana cultures over time. The results indicated that the transport role of SITs is minor for silicic acid from both biogenic and crystalline substrates, and the role of SIT3 is linked to the transport of silicon inside the cells, mainly in the presence of sponge spicules. SIL3 transcripts were expressed in the presence of all silicon sources, while SIL1 transcripts only with sponge spicules. The data suggest that the transport of silicic acid from various silicon sources in diatoms is based on different physico-chemical interactions with the cell surface. PMID- 29156340 TI - Fabricating hierarchical micro and nano structures on implantable Co-Cr-Mo alloy for tissue engineering by one-step laser ablation. AB - Surface texturing is one of the effective strategies to improve bioactivity of implantable materials. In this study, hierarchical micro and nano structure (HMN) were fabricated on Co-Cr-Mo alloy substrate by a movable picosecond laser irradiation. Respectively, microgrooves with nano ripples and islands were produced on Co-Cr-Mo alloy by low and high laser power density. X-ray diffraction apparatus (XRD) phase analysis illustrated that substrate was in the phase of gamma- face-centered cubic structure (FCC) before laser treatment, while it was in epsilon-hexagonal closest packing structure (HCP) phase dominant after laser treatment. Cell adhesion and proliferation studies showed that the HMN surface exhibits enhanced adhesion of MC3TC-E1 osteoblast and promoted cell activity. Analyzing of the morphology of osteoblast cells indicated cells were in high ratio of elongation on the HMN surface, while they mainly kept in round shape on the polished surface. Results indicated the formation of hierarchical structure on Co-Cr-Mo alloy was able to improve biological performances, suggesting the potential application in cobalt based orthopedic implants. PMID- 29156341 TI - Urinary bisphenol A concentrations are associated with reproductive parameters in young men. AB - Bisphenol A (BPA) is a pervasive environmental toxicant with known reproductive effects on sperm parameters and hormone levels. Several observational studies have investigated the associations between BPA exposure and male reproductive function, but findings are inconsistent. The objective of this study was to assess the associations between urinary BPA concentrations and semen quality and reproductive hormone levels in a cross-sectional study with 215 healthy young university students (18-23 years old), investigated between 2010 and 2011 in Southern Spain (Murcia Region). All subjects provided urine, blood serum and semen samples on a single day. Urinary BPA concentrations were measured by dispersive liquid-liquid microextraction and ultra-high performance liquid chromatography with tandem mass spectrometry detection. Semen quality was evaluated by measuring volume, concentration, motility, morphology and total sperm count (TSC). Serum samples were analyzed for reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, inhibin B and estradiol. Relationships between urinary BPA concentrations and semen quality parameters and reproductive hormone levels were examined using linear regression, adjusting for potential confounders and covariates. Ninety-five percent of the men had detectable urinary BPA concentrations with unadjusted median (5th-95th) of 2.8 (0.16-11.5) ng/mL. After adjustment for important covariates, there was a significant positive association between urinary BPA concentrations and serum LH levels (beta = 0.07, 95%CI: 0.02;0.12, p-value < 0.01). Urinary BPA concentration was also significantly and inversely associated with sperm concentration (beta = - 0.04, 95%CI: - 0.07;- 0.02, p-value < 0.01) and TSC (beta = - 0.05, 95%CI: - 0.08;- 0.02, p-value < 0.01). No significant associations were found between BPA and other semen parameters or reproductive hormone levels. Our results support the hypothesis that BPA exposure may be associated with a reduction in Leydig cell capacity (increased LH levels) and decreased sperm counts in young men. PMID- 29156342 TI - A prospective cohort study of the association between bisphenol A exposure and the serum levels of liver enzymes in children. AB - BACKGROUND: Bisphenol A (BPA) is an endocrine disrupter that acts in an estrogen like manner. Few studies have investigated the association between urinary BPA concentrations and adverse liver function. Additionally, most studies were cross sectional in nature and included only adults. OBJECTIVES: We evaluated BPA exposure levels and prospectively explored the association between BPA exposure and liver function in children. METHODS: Data were retrieved from the ongoing prospective Ewha Birth and Growth Cohort Study. Urinary BPA concentrations were measured in 164 children at 3-5 and 7-9 years of age. At each visit, fasting blood and urine samples were collected, and questionnaires were completed. The associations between the BPA concentrations at these ages and the serum levels of liver enzymes measured at 10-13 years of age were analyzed (n = 113). Multiple regression analysis was performed with adjustment for covariates. We also explored whether the BPA level exhibited dose-response relationships with liver enzyme levels. RESULTS: The median urinary BPA concentrations were 0.76MUg/g creatinine at 3-5 years and 0.61MUg/g creatinine at 7-9 years of age. The urinary BPA concentrations at the two ages were correlated significantly (r = 0.23, p < 0.01). The urinary BPA concentrations at 7-9 years, but not that at 3-5 years, was associated significantly with the serum levels of liver enzymes at 10-13 years of age (p < 0.05). Those in the top tertile of urinary BPA concentration had higher levels of liver enzymes than did others. After adjustment for covariates, dose-response relationships of the BPA level with liver enzyme levels were evident at 7-9 years, but not at 3-5 years. Notably, the effect size was larger and the dose-response relationships were more evident in boys than in girls. CONCLUSIONS: Exposure of children to even low doses of BPA may adversely affect later liver function. PMID- 29156343 TI - Native and exotic oysters in Brazil: Comparative tolerance to hypercapnia. AB - Environmental hypercapnia in shallow coastal marine ecosystems can be exacerbated by increasing levels of atmospheric CO2. In these ecosystems organisms are expected to become increasingly subjected to pCO2 levels several times higher than those inhabiting ocean waters (e.g.: 10,000uatm), but still our current understanding on different species capacity to respond to such levels of hypercapnia is limited. Oysters are among the most important foundation species inhabiting these coastal ecosystems, although natural oyster banks are increasingly threatened worldwide. In the present study we studied the effects of hypercapnia on two important oyster species, the pacific oyster C. gigas and the mangrove oyster C. brasiliana, to bring new insights on different species response mechanisms towards three hypercapnic levels (ca. 1,000; 4,000; 10,000 uatm), by study of a set of biomarkers related to metabolic potential (electron transport system - ETS), antioxidant capacity (SOD, CAT, GSH), cellular damage (LPO) and energetic fitness (GLY), in two life stages (juvenile and adult) after 28 days of exposure. Results showed marked differences between each species tolerance capacity to hypercapnia, with contrasting metabolic readjustment strategies (ETS), different antioxidant response capacities (SOD, CAT, GSH), which generally allowed to prevent increased cellular damage (LPO) and energetic impairment (GLY) in both species. Juveniles were more responsive to hypercapnia stress in both congeners, and are likely to be most sensitive to extreme hypercapnia in the environment. Juvenile C. gigas presented more pronounced biochemical alterations at intermediate hypercapnia (4,000uatm) than C. brasiliana. Adult C. gigas showed biochemical alterations mostly in response to high hypercapnia (10,000uatm), while adult C. brasiliana were less responsive to this environmental stressor, despite presenting decreased metabolic potential. Our data bring new insights on the biochemical performance of two important oyster species, and suggest that the duration of extreme hypercapnia events in the ecosystem may pose increased challenges for these organisms as their tolerance capacity may be time limited. PMID- 29156344 TI - Neurotransmitter changes in rat brain regions following glyphosate exposure. AB - The effects of glyphosate oral exposure (35, 75, 150 and 800mg/kg bw, 6 days) on brain region monoamine levels of male Wistar rats were examined. Glyphosate treated rats (35, 75, 150 and 800mg/kg bw, 6 days), had no visible injury, i.e., no clinical signs of dysfunction were observed. After last dose of glyphosate, serotonin (5-HT), dopamine (DA) and norepinephrine (NE) and its metabolites levels were determined in the brain regions striatum, hippocampus, prefrontal, cortex, hypothalamus and midbrain, by HPLC. Glyphosate caused statistically significant changes in the 5-HT and its metabolite 5-hydroxy-3-indolacetic acid (5-HIAA), DA and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and NE and its metabolite 3-metoxy-4 hydroxyphenylethyleneglycol (MHPG) levels in a brain regional- and dose-related manner. Moreover, glyphosate, dose-dependent, evoked a statistically significant increase in 5-HT turnover in striatum and hypothalamus and in DA turnover in prefrontal cortex and hippocampus, and a statistically significant decrease in NE turnover in prefrontal cortex and hypothalamus. The present findings indicate that glyphosate significantly altered central nervous system (CNS) monoaminergic neurotransmitters in a brain regional- and dose-related manner, effects that may contribute to the overall spectrum of neurotoxicity caused by this herbicide. PMID- 29156345 TI - The extended production of UV-induced reactive oxygen species in L929 fibroblasts is attenuated by posttreatment with Arrabidaea chica through scavenging mechanisms. AB - Ultraviolet radiation (UVR) exposure causes various injurious effects to human skin by generating reactive oxygen species (ROS). Excessive ROS production can lead to oxidative stress which may damage cellular components like lipids and proteins and causing photoaging. The use of natural photochemopreventive agents with antioxidant properties is an important alternative to improve the effectiveness of sunscreens and reduce skin photodamage. A crude extract (CE) from the leaves of Arrabidaea chica underwent partition by a liquid-liquid method. The hexane fraction (FH), chloroform fraction (FC), and ethyl acetate fraction (FEA) were obtained. The antioxidant capacity of the CE, FH, FC, and FEA was studied in a cell-free system using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and the xanthine/luminol/xanthine oxidase system. The FC had the best antioxidant activity. We also evaluated the photochemoprotective effect of A. chica in protecting L929 fibroblasts against UV-A- and UV-B-induced cell damage. A. chica inhibited the extended production of ROS up to 3h. Posttreatment with the CE and FC attenuated UV-induced cell damage through scavenging mechanisms, including the quenching of intracellular ROS and mitochondrial O2- and preventing lipid peroxidation. These results suggest that A. chica may be a promising non sunscreen photoprotector that can improve the effectiveness of commercial sunscreens. PMID- 29156346 TI - ABCG2-mediated suppression of chlorin e6 accumulation and photodynamic therapy efficiency in glioblastoma cell lines can be reversed by KO143. AB - BACKGROUND: Photodynamic therapy (PDT) of malignant brain tumors is a promising adjunct to standard treatment, especially if tumor stem cells thought to be responsible for tumor progression and therapy resistance were also susceptible to this kind of treatment. However, some photosensitizers have been reported to be substrates of ABCG2, one of the membrane transporters mediating resistance to chemotherapy. Here we investigate, whether inhibition of ABCG2 can restore sensitivity to photosensitizer chlorin e6-mediated PDT. METHODS: Accumulation of chlorin e6 in wild type U87 and doxycycline-inducible U251 glioblastoma cells with or without induction of ABCG2 expression or ABCG2 inhibition by KO143 was analyzed using flow cytometry. In U251 cells, ABCG2 was inducible by doxycycline after stable transfection with a tet-on expression plasmid. Tumor sphere cultivation under low attachment conditions was used to enrich for cells with stem cell-like properties. PDT was done on monolayer cell cultures by irradiation with laser light at 665nm. RESULTS: Elevated levels of ABCG2 in U87 cells grown as tumor spheres or in U251 cells after ABCG2 induction led to a 6-fold lower accumulation of chlorin e6 and the light dose needed to reduce cell viability by 50% (LD50) was 2.5 to 4-fold higher. Both accumulation and PDT response can be restored by KO143, an efficient non-toxic inhibitor of ABCG2. CONCLUSION: Glioblastoma stem cells might escape phototoxic destruction by ABCG2-mediated reduction of photosensitizer accumulation. Inhibition of ABCG2 during photosensitizer accumulation and irradiation promises to restore full susceptibility of this crucial tumor cell population to photodynamic treatment. PMID- 29156347 TI - Creation of a 3Mn/1Fe cluster in the oxygen-evolving complex of photosystem II and investigation of its functional activity. AB - Extraction of Mn cations from the oxygen-evolving complex (OEC) of Ca-depleted PSII membranes (PSII[-Ca,4Mn]) by reductants like hydroquinone (H2Q) occurs with lower efficiency at acidic pH (2Mn/reaction center [RC] are extracted at pH5.7) than at neutral pH (3Mn/RC are extracted at pH6.5) [Semin et al. Photosynth. Res. 125 (2015) 95]. Fe(II) also extracts Mn cations from PSII(-Ca,4Mn), but only 2Mn/RC at pH6.5, forming a heteronuclear 2Mn/2Fe cluster [Semin and Seibert, J. Bioenerg. Biomembr. 48 (2016) 227]. Here we investigated the efficiency of Mn extraction by Fe(II) at acidic pH and found that Fe(II) cations can extract only 1Mn/RC from PSII(-Ca,4Mn) membranes at pH 5.7, forming a 3Mn/1Fe cluster. Also we found that the presence of Fe cations in a heteronuclear cluster (2Mn/2Fe) increases the resistance of the remaining Mn cations to H2Q action, since H2Q can extract Mn cations from homonuclear Mn clusters of PSII(-Ca,4Mn) and PSII( Ca,2Mn) membranes but not from the heteronuclear cluster in PSII(-Ca,2Mn,2Fe) membranes. H2Q also cannot extract Mn from PSII membranes obtained by incubation of PSII(-Ca,4Mn) membranes with Fe(II) cations at pH5.7, which suggests the formation of a heteronuclear 3Mn/1Fe cluster in the OEC. Functional activity of PSII with a 3Mn/1Fe cluster was investigated. PSII preparations with a 3Mn/1Fe cluster in the OEC are able to photoreduce the exogenous electron acceptor 2,6 dichlorophenolindophenol, possibly due to incomplete oxidation of water molecules as is the case with PSII(-Ca,2Mn,2Fe) samples. However, in the contrast to PSII( Ca,2Mn,2Fe) samples PSII(-Ca,3Mn,1Fe) membranes can evolve O2 at a low rate in the presence of exogenous Ca2+ (at about 27% of the rate of O2 evolution in native PSII membranes). The explanation for this phenomenon (either water splitting and production of molecular O2 by the 3Mn/1Fe cluster or apparent O2 evolution due to minor contamination of PSII(3Mn,1Fe) samples with PSII(-Ca,4Mn) membranes) is discussed. PMID- 29156348 TI - Development of photoprotective, antiphototoxic, and antiphotogenotoxic formulations of ocular drugs with fluoroquinolones. AB - The development of innovative solutions in photosafety of photolabile pharmaceutical products may help to reduce the adverse effects of these products, caused by light exposure. Providing new data in this area of study is particularly important in case of drugs applied topically on sensitive organs such as eyes. The main goal of this research is to investigate whether two potential excipients, namely: p-coumaric acid and benzophenone-4, affect the photodegradation, phototoxicity and photogenotoxicity of water solutions of four fluoroquinolones: ciprofloxacin, lomefloxacin, fleroxacin and clinafloxacin. We conducted a set of bioassays combined with the application of high-performance liquid chromatography and mass spectrometry techniques. The significant reduction of phototoxic and photogenotoxic abilities was evaluated in mixtures with ciprofloxacin and p-coumaric acid by using the umu test with Salmonella typhimurium TA1535/pSK1002, the methylthiazol tetrazolium reduction assay, and the micronucleus assay with the V79 cell line. In the bacterial assay the opposite effect was observed for the formulation with lomefloxacin and p-coumaric acid. This may be explained by the significant differences in the profile of the lomefloxacin photodegradation products. Further, the photoprotective and antiphotomutagenic abilities of ciprofloxacin mixed with benzophenone-4 were assessed. Promising results obtained in compositions with ciprofloxacin may be a basis for further research. Nevertheless, the increase in the DNA damage potential in mixtures with p-coumaric acid and two other antibiotics shows the importance of the safety evaluation of such innovative combinations. PMID- 29156349 TI - Biopolymer gelatin-coated zinc oxide nanoparticles showed high antibacterial, antibiofilm and anti-angiogenic activity. AB - The use of natural polymers in drug design plays an important role in biomedical applications. Combinations of nanoparticles (NPs) and biopolymers have been shown to be useful for many purposes. This study focused on gelatin-coated zinc oxide NPs synthesized by co-precipitation. The particles were characterized by UV-Vis spectrum, showing a main peak at 375nm. The stability and crystalline nature of the particles was evaluated by Zeta potential and X-ray diffraction analysis. Fourier transform infrared spectroscopy (FTIR) revealed the possible functional groups of Ge-ZnO NPs, with strong bands at 3851, 3447, and 2923cm-1. Moreover, transmission electron microscopy (TEM) highlighted the presence of spherically shaped Ge-ZnO NPs that were 20nm in size. Energy dispersive analysis X-ray (EDX) analysis showed that the zinc elemental content of Ge-ZnO NPs was 59.10%. The results of antibacterial activity assays revealed higher inhibition of Ge-ZnO NPs against Gram-negative Pseudomonas aeruginosa at 100MUg/ml over that against Gram positive Enterococcus faecalis. Greater inhibition of biofilm formation was observed for Gram-negative bacteria compared to Gram-positive bacteria. In addition, Ge-ZnO NPs effectively inhibited the biofilm growth of the fungus Candida albicans at 50MUg/ml. Ge-ZnO NPs reduced the viability of hepatocarcinoma cancer cell lines at 100MUg/ml. Moreover, in chick embryos, notable anti angiogenesis effects were observed for Ge-ZnO NPs and zinc acetate at 50MUg/ml compared to that observed testing gelatin. Overall, based on the results, Ge-ZnO NPs may be used as a novel agent for the control of biofilm-forming microbial pathogens. PMID- 29156350 TI - Photodynamic inactivation of Escherichia coli - Correlation of singlet oxygen kinetics and phototoxicity. AB - Photodynamic inactivation (PDI) of bacteria may play a major role in facing the challenge of the ever expanding antibiotic resistances. Here we report about the direct correlation of singlet oxygen luminescence kinetics and phototoxicity in E. coli cell suspension under PDI using the widely applied cationic photosensitizer TMPyP. Through direct access to the microenvironment, the time resolved investigation of singlet oxygen luminescence plays a key role in understanding the photosensitization mechanism and inactivation pathway. Using the homemade set-up for highly sensitive time resolved singlet oxygen luminescence detection, we show that the cationic TMPyP is localized predominantly outside the bacterial cells but in their immediate vicinity prior to photodynamic inactivation. Throughout following light exposure, a clear change in singlet oxygen kinetics indicates a redistribution of photosensitizer molecules to at least one additional microenvironment. We found the signal kinetics mirrored in cell viability measurements of equally treated samples from same overnight cultures conducted in parallel: A significant drop in cell viability of the illuminated samples and stationary viability of dark controls. Thus, for the system investigated in this work - a Gram-negative model bacteria and a well-known PS for its PDI - singlet oxygen kinetics correlates with phototoxicity. This finding suggests that it is well possible to evaluate PDI efficiency directly via time resolved singlet oxygen detection. PMID- 29156351 TI - Benzamide porphyrins with directly conjugated and distal pyridyl or pyridinium groups substituted to the porphyrin macrocycles: Study of the photosensitising abilities as inducers of apoptosis in cancer cells under photodynamic conditions. AB - Amphiphilic porphyrin photosensitisers (PSs) having combinations of directly substituted pyridyl group(s) at the meso-position of a porphyrin macrocycle, and/or indirectly linked pyridyl groups as benzamide derivatives are reported. The compounds 5,10,15,20-tetrakis-(4-pyridylbenzamide)porphyrin (A.2), 5,10,15,20 tetra[N-(pyridine-4-yl)benzamidium] porphyrin (A.3), 5-mono-(4-pyridyl)-10,15,20 tris-(4-pyridylbenzamide)porphyrin (B.2) and 5-mono-(4-methylpyridinium)-10,15,20 tris-(4-pyridiniumbenzamide)porphyrin (B.3) were synthesised. The compounds were successfully characterised through UV-Vis, Emission, 1H NMR, and ESI-HRMS techniques. To evaluate the effect of this combination of directly conjugated and non-conjugated pyridyl/cationic pyridinium groups on the porphyrin macrocycle, the efficacy of the synthesised compounds was compared to a known standard 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP). These compounds show better efficacy (IC50's ranging between 0.66+/-0.04MUM to 3.71+/-1.01MUM) against A549 (human epithelial adenocarcinoma lung cancer) cell line under in vitro photodynamic conditions in comparison to MDA-MB-231 (breast cancer) (IC50's ranging between 3.7+/-0.087MUM to 12.1+/-0.12MUM) and Pa-1 (ovarian cancer) (IC50's ranging between 17.9+/-0.01MUM to 42.45+/-0.02MUM) cell lines. It was found that B.3, having a pyridinium group attached to the meso-position of the macrocycle along with three distal cationic pyridinium groups, independent of the porphyrinic electron delocalisation cycle, showed better photocytotoxic efficacy (IC50=0.66+/-0.04MUM, A549 lung cancer cell line) and higher potential to promote apoptosis and hence better efficacy as PS towards cancer photodynamic therapy (PDT). The PDT activity of B.3 was further verified and established by various biological assays, viz. Annexin V assay, cell cycle assay, and reactive oxygen species (ROS) activity assay. PMID- 29156352 TI - A homogenization approach for the effective drained viscoelastic properties of 2D porous media and an application for cortical bone. AB - Closed-form solutions for the effective rheological properties of a 2D viscoelastic drained porous medium made of a Generalized Maxwell viscoelastic matrix and pore inclusions are developed and applied for cortical bone. The in plane (transverse) effective viscoelastic bulk and shear moduli of the Generalized Maxwell rheology of the homogenized medium are expressed as functions of the porosity and the viscoelastic properties of the solid phase. When deriving these functions, the classical inverse Laplace-Carson transformation technique is avoided, due to its complexity, by considering the short and long term approximations. The approximated results are validated against exact solutions obtained from the inverse Laplace-Carson transform for a simple configuration when the later is available. An application for cortical bone with assumption of circular pore in the transverse plane shows that the proposed approximation fit very well with experimental data. PMID- 29156353 TI - In-situ formation of textured TiN coatings on biomedical titanium alloy by laser irradiation. AB - The Ti-35Nb-7Zr-5Ta (TNZT) alloy has received much research attention among the biomedical titanium alloys for its low Young's modulus and outstanding biocompatibility. This paper provided an innovative technique for improving the wear and corrosion resistance of the TNZT alloy, by developing in-situ formed TiN coatings on the surface of the TNZT alloy through laser irradiation. The new technique combines the advantages of laser surface texturing and laser gas alloying. The experimental results showed that the phase compositions of the textured TNZT samples were beta-Ti, martensitic alpha'' phase and TiN after laser texturing in N2. The diameter of the surface dimples increased, when the width of laser pulse increased from 0.3ms to 0.7ms, and the depth decreased accordingly. In comparison to the samples without treatment, both the wear rate and the frictional coefficient of the TNZT samples with textured TiN coatings decreased significantly. The surface dimples served as micro-hydrodynamic bearing, which were able to keep liquid inside. As a result, the sample with a width of pulse of 0.3ms treated in N2 exhibited the lowest wear rate of 0.025 * 10-2m3/Nm, while the value of the sample without treatment was 0.351 * 10-2m3/Nm. The TiN contained surface coatings also exhibited higher electrochemical impedance, higher corrosion potential and lower corrosion current density. PMID- 29156354 TI - Anisotropic and nonlinear biaxial mechanical response of porcine small bowel mesentery. AB - Intestinal malrotation places pediatric patients at the risk of midgut volvulus, a complication that can lead to ischemic bowel, short gut syndrome, and even death. Even though the treatments for symptomatic patients of this complication are clear, it is still a challenge to identify asymptomatic patients who are at a higher risk of midgut volvulus and decide on a suitable course of treatment. Development of an accurate computerized model of this intestinal abnormality could help in gaining a better understanding of its integral behavior. To aid in developing such a model, in the current study, we have characterized the biaxial mechanical properties of the porcine small bowel mesentery. First, the tissue stress-strain response was determined using a biaxial tensile testing equipment. The stress-strain data were then fitted into a Fung-type phenomenological constitutive model to quantify the tissue material parameters. The stress-strain responses were highly nonlinear, showing more compliance at the lower strains following by a rapid transition into a stiffer response at higher strains. The tissue was anisotropic and showed more stiffness in the radial direction. The data fitted the Fung-type constitutive model with an average R-squared value of 0.93. An averaging scheme was used to produce a set of material parameters which can represent the generic mechanical behavior of the tissue in the models. PMID- 29156355 TI - Biomechanical evaluation of a personalized external aortic root support applied in the Ross procedure. AB - A commonly heard concern in the Ross procedure, where a diseased aortic valve is replaced by the patient's own pulmonary valve, is the possibility of pulmonary autograft dilatation. We performed a biomechanical investigation of the use of a personalized external aortic root support or exostent as a possibility for supporting the autograft. In ten sheep a short length of pulmonary artery was interposed in the descending aorta, serving as a simplified version of the Ross procedure. In seven of these cases, the autograft was supported by an external mesh or so-called exostent. Three sheep served as control, of which one was excluded from the mechanical testing. The sheep were sacrificed six months after the procedure. Samples of the relevant tissues were obtained for subsequent mechanical testing: normal aorta, normal pulmonary artery, aorta with exostent, pulmonary artery with exostent, and pulmonary artery in aortic position for six months. After mechanical testing, the material parameters of the Gasser-Ogden Holzapfel model were determined for the different tissue types. Stress-strain curves of the different tissue types show significantly different mechanical behavior. At baseline, stress-strain curves of the pulmonary artery are lower than aortic stress-strain curves, but at the strain levels at which the collagen fibers are recruited, the pulmonary artery behaves stiffer than the aorta. After being in aortic position for six months, the pulmonary artery tends towards aorta like behavior, indicating that growth and remodeling processes have taken place. When adding an exostent around the pulmonary autograft, the mechanical behavior of the composite artery (exostent + artery) differs from the artery alone, the non-linearity being more evident in the former. PMID- 29156356 TI - Limax extract ameliorates cigarette smoke-induced chronic obstructive pulmonary disease in mice. AB - Chronic obstructive pulmonary disease (COPD) is a chronic, progressive and lethal lung disease with few treatments. Limax, a mollusk with lung, has been widely used to control phlegm and cough in China, yet whether Limax has a positive effect on COPD is unknown. This study investigated the effects of water-soluble extract from Limax on COPD development and the underlying mechanisms. The results showed that Limax extract improved lung function, relieved emphysema and suppressed the inflammation in the lungs of CS-challenged mice, as evidenced by diminished release of IL-6, KC, TNF-alpha, IFN-gamma, Muc5AC, IL-17 and diminished mRNA expression of Muc5B. Moreover, Limax extract also inhibited phosphorylation of P38 and ERK and increased the expression of PPARgamma. More interestingly, Limax extract (0.1MUg/ml) inhibited CSE-induced release of IL-6 in vitro, which was substantially abrogated by heat treatment, and filtrate obtained from the deproteinized Limax extract with the 100KD ultrafiltration membrane, inhibited the secretion of IL-6. Taken together, these results suggest that, Limax extract prevents COPD development via inhibition of inflammation and mucus production, thus has a potential preventive and therapeutic application in COPD. PMID- 29156357 TI - Generation of complement molecular complex C5b-9 (C5b-9) in response to poly traumatic hemorrhagic shock and evaluation of C5 cleavage inhibitors in non-human primates. AB - Severe trauma initiates a systemic inflammatory cascade and that involves early activation of complement and cleavage of C5 into C5a (anaphylatoxin) and C5b (C5b 9 membrane attack complex). We examined activation of C5 in non-human primate (NHP) models of hemorrhagic shock. Blood plasma concentrations of C5b-9 were significantly increased in NHPs in response to hemorrhage alone and were further increased with the addition of tissue trauma. The onset of increased C5 cleavage was accelerated in NHPs that experienced decompensated poly-traumatic hemorrhagic shock. Next, to identify an effective inhibitor of NHP C5 cleavage in vitro, as a first step in the development of a potential therapy, three inhibitors of human C5 cleavage and hemolysis were tested in vitro. NHP C5 cleavage and complement mediated hemolysis were successfully inhibited by pre-treatment of serum samples with a small, inhibitory peptide RA101348. Commercially-available C5 inhibitory antibodies were found to exhibit species-specific efficacy in vitro. Quidel's A217 antibody demonstrated dose-dependent inhibition of C5 cleavage and hemolysis in NHP samples, whereas LGM-Eculizumab only inhibited complement-mediated hemolysis in human samples. This study shows that complement activation in NHPs following experimental poly-traumatic hemorrhagic shock is consistent with clinical reports, and that cleavage of C5 and complement-mediated hemolysis can be effectively inhibited in vitro using a small peptide inhibitor. Taken together, these findings offer a clinically-relevant vehicle and a potential strategy for treatment of hemorrhagic shock with poly-traumatic injury. PMID- 29156359 TI - Emotion regulation deficits in persons with body-focused repetitive behavior disorders. AB - BACKGROUND: Conceptualizations of emotion dysregulation (ED) and body-focused repetitive behavior disorders (BFRBDs) imply that ED may be a central component of BFRBDs as well as a factor that distinguishes BFRBDs from non-impairing, subclinical body-focused repetitive behaviors (BFRBs). The current study empirically tested these observations. METHODS: One hundred thirty-eight undergraduates (of 1900 who completed a screening survey) completed self-report measures assessing four emotion regulation (ER) deficits hypothesized to underlie ED (alexithymia, maladaptive emotional reactivity, experiential avoidance, and response inhibition when distressed); 34 of these participants had BFRBDs, 64 had subclinical BFRBs, and 42 were unaffected by BFRBs. RESULTS: Results indicated that participants with BFRBDs reported higher levels of maladaptive emotional reactivity, experiential avoidance, and response inhibition when distressed than participants with subclinical BFRBs and participants unaffected by BFRBs. These results held even when controlling for comorbidity and total number of reported BFRBs. Participants did not differ on alexithymia. LIMITATIONS: Limitations of the current study include the BFRB groups' different distributions of BFRB types (e.g., hair pulling versus skin picking), the sample's demographic uniformity, and the fact that negative affectivity was not controlled when exploring BFRB group differences on ER deficits. Future research should improve on these limitations. CONCLUSIONS: The current results suggest that ED is a factor that differentiates BFRBDs from subclinical BFRBs. Such results may be useful for generating hypotheses regarding mechanisms responsible for BFRBs' development into BFRBDs. Furthermore, these results may provide insight into factors that explain the efficacy of more contemporary behavioral treatments for BFRBDs. PMID- 29156358 TI - Peer norms moderate the association between mental health and sexual risk behaviors among young men living in Dar es Salaam, Tanzania. AB - BACKGROUND: Young men living in Dar es Salaam's informal settlements face environmental stressors that may expose them to multiple determinants of HIV risk including poor mental health and risky sexual behavior norms. We aimed to understand how these co-occurring risk factors not only independently affect men's condom use and sexual partner concurrency, but also how they interact to shape these risk behaviors. METHODS: Participants in the study were male members of 59 social groups known as "camps" in Dar es Salaam, Tanzania. We assessed moderation by changes in peer norms of the association between changes in symptoms of anxiety and depression and sexual risk behaviors (condom use and sexual partner concurrency) among 1113 sexually active men. Participants nominated their three closest friends in their camp and reported their perceptions of these friends' behaviors, attitudes, and encouragement of condom use and concurrency. Anxiety and depression were measured using the HSCL-25, and condom use and sexual partner concurrency were assessed through self-report. RESULTS: Perceptions of decreasing condom use among friends (descriptive norms) and decreasing encouragement of condom use were associated with lower levels of condom use. Perceptions of increasing partner concurrency and acceptability of partner concurrency (injunctive norms) among friends were associated with higher odds of concurrency. Changes in perceived condom use norms (descriptive norms and encouragement) interacted with changes in anxiety symptoms in association with condom use such that the negative relationship was amplified by norms less favorable for condom use, and attenuated by more favorable norms for condom use. CONCLUSIONS: These results provide novel evidence of the interacting effects of poor mental health and risky sexual behavior norms among a hard to reach population of marginalized young men in Dar es Salaam. Our findings provide important information for future norms-based and mental health promotion interventions targeting HIV prevention in this key population. PMID- 29156360 TI - Does the 15-item Geriatric Depression Scale function differently in old people with different levels of cognitive functioning? AB - BACKGROUND: The 15-item version of the Geriatric Depression Scale (GDS-15) is widely employed to screen depression among elderly but little is known about the scale functioning in cognitively impaired individuals when compared to normal ones. The aim of the current study is to investigate Differential Item Functioning (DIF) across groups of older people that differ in terms of cognitive functioning applying Item Response Theory (IRT)-based analyses. METHODS: Data from an Italian multi-centric clinical-based study on cognitive impairment and dementia in old people were employed (N = 1903; Age: M = 77.33, SD = 7.05, 62% women). All the participants underwent a comprehensive evaluation (including clinical examination, laboratory screening, neuroimaging, and cognitive and behavioral assessments) and they were assigned to three different groups on the basis of their cognitive functioning (normal, mild cognitive impairment, cognitive impairment) RESULTS: Two items showed uniform DIF but their differential functioning does not propagate to the GDS-15 total scores in such a way that a differential interpretation is needed LIMITATIONS: Whereas an advantage of the study is the large sample size, the relatively small size of the mild cognitive impairment group might reduce the stability of the present results CONCLUSIONS: Since a screening tool for elderly is intended to apply to everyone in the target population, the current findings support the clinical utility of the GDS-15 as screening tool for depression. PMID- 29156361 TI - Non suicidal self-injury in referred adolescents with mood disorders and its association with cyclothymic-hypersensitive temperament. AB - BACKGROUND: Non suicidal self-injuries (NSSIs) are deliberate self-harm behaviors without suicidal intent, usually starting in adolescence, with increasing rates of occurrence both in epidemiological and clinical samples. Several studies associated cyclothymic-hypersensitive temperament (CHT) with self-harm behaviors and suicidal risk. Aim of this study is to explore the association between NSSIs and CHT in a clinical sample of adolescents. We hypothesized that CHT may differentiate NSSI from non-NSSI adolescents with mood disorders, when other psychopathological features are controlled for. METHODS: A consecutive sample of 89 adolescents with mood disorders were assessed for presence and phenomenology of NSSIs, CHT, demographics, comorbid categorical psychiatric diagnoses, dimensional psychopathology, impairment and previous suicide attempts. RESULTS: NSSIs were reported in 52% of the sample, with higher rates in females and in bipolar disorder. Regression analyses showed that CHT, but not age, gender, bipolar vs depression diagnosis, functional impairment, was associated with NSSIs. DISCUSSION: CHT may be in close association with NSSIs in adolescents with mood disorders. An assessment of CHT in adolescents referred for mood disorder may help to detect specific psychological features of NSSIs, which may improve diagnostic and treatment strategies. LIMITATIONS: Given the cross-sectional design, a developmental relation between CHT and NSSIs cannot be determined. The small sample size and the selection bias of severely impaired patients limit the generalization of the results. More sophisticated measures of CHT may consent to explore other dimensions of the cyclothymic construct (i.e., emotional intensity, emotional reactivity, emotional stability, positive vs. negative emotions, interpersonal sensitivity, impulsivity). PMID- 29156362 TI - Test anxiety effects, predictors, and correlates: A 30-year meta-analytic review. AB - BACKGROUND AND OBJECTIVES: Since the 1988 publication of Hembree's seminal meta analysis on test anxiety, much has changed in the theoretical conceptualization of test anxiety, as well as the influences on test performance. The present study examined the influence of test anxiety on a variety of educational outcomes, in addition to demographic and intrapersonal correlates. DESIGN AND METHODS: Results of 238 studies from 1988 to the present, were synthesized via a meta-analytic framework to explicate predictors, correlates, and relationships with the test anxiety construct. Pooled effect sizes were calculated. RESULTS: Results indicated that test anxiety was significantly and negatively related to a wide range of educational performance outcomes, including standardized tests, university entrance exams, and grade point average. Results were most pronounced at the middle grades level. Self-esteem was a significant and strong predictor of test anxiety. Perceived difficulty of the test and the high-stakes nature or consequences of the test was also related to higher test anxiety. CONCLUSIONS: The magnitude of the relationship of test anxiety across a number of variables was in the small to moderate range. Implications for researchers and educators are discussed including the use of evidence-based assessment and interventions when warranted. PMID- 29156363 TI - Quality of life is associated with chronic inflammation in depression: A cross sectional study. AB - BACKGROUND: Inflammation may play a crucial role in the pathophysiology of depression. However, the association between chronic inflammation and health outcomes in depression remains unclear, particularly for patient-reported outcomes. METHODS: The aim of this study was to investigate the relationship between quality of life (QoL) (physical and mental health, assessed by the SF-36) and chronic inflammation assessed using C-reactive protein (CRP) in patients with current major depressive disorder. RESULTS: One hundred eighty-one patients with depression were enrolled in this study. After adjusting for key socio demographic, clinical and biological confounding factors, patients with high levels of CRP (> 3.0mg/L) had worse physical health than those with normal CRP levels (OR = 0.95, 95% CI = 0.92-0.99). Significant associations were found between a higher rate of metabolic syndrome (OR = 0.10, 95% CI = 0.02-0.41) and high CRP levels. LIMITATIONS: The cut-off point for high cardiovascular risk was used to define the two groups: normal CRP level and high CRP level. CRP was the sole marker of inflammation in this study and was collected at only one time point. The design of this study is cross-sectional and there are no conclusions about the directionality of the association between QoL and inflammation in depression. QoL was assessed only by SF-36 scores. CONCLUSION: This study found an association between SF-36 physical health score and CRP in patients with depression, thereby showing the need to consider physical well-being in depression. This paves the way for interventions to act both on inflammation and QoL in patients with depression. PMID- 29156365 TI - Antidepressant polypharmacy and the potential of pharmacokinetic interactions: Doxepin but not mirtazapine causes clinically relevant changes in venlafaxine metabolism. AB - BACKGROUND: To uncover pharmacokinetic interactions between venlafaxine and doxepin or mirtazapine in a naturalistic sample. METHODS: A therapeutic drug monitoring database containing plasma concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. We included 1067 of 1594 patients in the analysis. Three study groups were considered; a group of patients under venlafaxine without confounding medications, V0 (n = 905), a group of patients co-medicated with doxepin, VDOX (n = 25) and a second group, co medicated with mirtazapine, VMIR, n = 137. Plasma concentrations of VEN, ODVEN and the clinically relevant active moiety, sum of venlafaxine and O desmethylvenlafaxine (ODVEN) (AM), as well as dose-adjusted plasma concentrations (C/D) were compared. RESULTS: Median concentrations in the doxepin group showed 57.7% and 194.4% higher values for AM and VEN respectively; these differences were statistically significant (p < 0.001 for AM and p = 0.002 for VEN). Similar differences were detected for C/D concentrations of active moiety and VEN (p < 0.001 and p = 0.001) with higher values also in the doxepin group. The ratios ODVEN/VEN were lower in the doxepin group (p < 0.001). A co-medication with mirtazapine did not cause any changes in venlafaxine metabolism. CONCLUSIONS: Higher concentrations for VEN and AM imply an inhibiting effect of doxepin on the metabolism of venlafaxine, although the huge variability of concentrations has to be taken into account. It is recommended to monitor plasma concentrations in combination treatment to avoid problems in safety and efficacy. LIMITATIONS: Despite the large size of our study sample, the naturalistic nature of this data may arise some concerns of information bias potentially resulting from non standardized data recording. PMID- 29156364 TI - Pattern recognition of magnetic resonance imaging-based gray matter volume measurements classifies bipolar disorder and major depressive disorder. AB - BACKGROUND: Bipolar Disorder (BD) cannot be reliably distinguished from Major Depressive Disorder (MDD) until the first manic or hypomanic episode. Consequently, many patients with BD are treated with antidepressants without mood stabilizers, a strategy that is often ineffective and carries a risk of inducing a manic episode. We previously reported reduced cortical thickness in right precuneus, right caudal middle-frontal cortex and left inferior parietal cortex in BD compared with MDD. METHODS: This study extends our previous work by performing individual level classification of BD or MDD in an expanded, currently unmedicated, cohort using gray matter volume (GMV) based on Magnetic Resonance Imaging and a Support Vector Machine. All patients were in a Major Depressive Episode and a leave-two-out analysis was performed. RESULTS: Nineteen out of 26 BD subjects and 20 out of 26 MDD subjects were correctly identified, for a combined accuracy of 75%. The three brain regions contributing to the classification were higher GMV in bilateral supramarginal gyrus and occipital cortex indicating MDD, and higher GMV in right dorsolateral prefrontal cortex indicating BD. LIMITATIONS: This analysis included scans performed with two different headcoils and scan sequences, which limited the interpretability of results in an independent cohort analysis. CONCLUSIONS: Our results add to previously published data which suggest that regional gray matter volume should be investigated further as a clinical diagnostic tool to predict BD before the appearance of a manic or hypomanic episode. PMID- 29156366 TI - Triterpenoidal saponins from the fruits of Gleditsia caspica with proapoptotic properties. AB - Three previously undescribed oleanane-type triterpenoidal saponins named caspicaosides L-N were isolated from the fruits of Gleditsia caspica Desf. The aglycons of these saponins were echinocystic acid, erythrodiol and 12-oleanene 3,28,30-triol. Caspicaoside L is a bisdesmosidic saponin acylated with two monoterpenic acids. It has a disaccharide moiety made up of glucose and arabinose attached to C-3 and pentasaccharide moiety linked to C-28 made up of one glucose, 2 xyloses, one inner rhamnose and one terminal rhamnose which was acylated with two identical monoterpenic acids. Caspicaoside M is a monodesmosidic saponin with a trisaccharide moiety at C-3 made up of glucose, xylose and arabinose, while caspicaoside N has a disaccharide moiety at C-3 made up of glucose and arabinose. Their structures were determined by extensive 1D and 2D (DQF-COSY, HSQC, TOCSY, 1H-13C-HSQC-TOCSY, HMBC, ROESY, NOESY) NMR, HRESIMS analyses and chemical degradation. The cytotoxicity MTT-based assay showed that caspicaosides M, N and L, respectively, exhibited high cytotoxic activity with IC50 <= 10 MUM (72 h) at least against one of the three used cancer cell lines, MCF 7, A2780 and HT 29; and were 2-34 folds selective against the normal fibroblasts (MRC 5). All compounds also induced apoptosis and caused G2/M arrest in MCF 7 cells (24 h); thus showing pro-apoptotic properties. PMID- 29156367 TI - Action strategies for walking through multiple, misaligned apertures. AB - When avoiding obstacles, path selection is thought to be determined by the attraction of the end-goal. However for aperture crossing, it is unclear whether the attraction point originates in the center of the aperture or at the end-goal, as previous experiments align the aperture with the end-goal. The purpose of the current study was to decipher the possible location of the attraction point, by evaluating crossing behaviour for multiple, misaligned apertures. Participants were instructed to walk through three separate apertures while en route to an end goal. The first and last apertures were fixed such that they were both either 0.9* or 1.7* shoulder width (SW) while the second aperture was either 0.9, 1.3 or 1.7* SW and shifted 25, 50 or 75cm off the midline. Findings revealed that the attraction of the end-goal, and not the middle of the aperture, guided crossing behaviour. The spatial margin decreased as the size of the shift increased. Furthermore, the frequency of rotation increased as the aperture was shifted away from midline, regardless of the aperture size. Since rotations would not normally occur for all of these aperture sizes when aligned with the end-goal, these results suggest that rotations were produced in an attempt to keep one's trajectory as close to the midline as possible. Therefore, not only does the attraction of the goal guide path trajectory, but individuals will choose to reduce the spatial margin and rotate the shoulders when walking through misaligned apertures, likely in attempt to maintain the straightest possible path. PMID- 29156368 TI - Self and team prioritisation effects in perceptual matching: Evidence for a shared representation. AB - Previous research has demonstrated that in-group favouritism occurs not only in higher-level judgments such as reward allocation, but also in low-level perceptual and attentional tasks. Recently, Moradi, Sui, Hewstone, and Humphreys (2015) found a novel effect of in-group bias on a simple perceptual matching task in which football fans responded more efficiently to stimuli newly associated with their own football team than stimuli associated with rival or neutral teams. This result is consistent with a robust self-bias effect in which individuals show a large performance advantage in responding to stimuli associated with the self over stimuli associated with a close friend or a stranger (Sui, He, & Humphreys, 2012). The present research utilised a perceptual matching paradigm to investigate the relations between self and in-group prioritisation amongst a sample of college rowers. Across two experiments, we demonstrated a reliable performance advantage for self and team stimuli. We also found a relationship between the self and team advantage in RT, and demonstrated an overlap in the perception of self- and team-associated shapes that was stronger in participants who reported a greater sense of group identity with their team. Further, we found no relation between the team bias and positive valence implicitly associated with the team, showing that the team bias effects are unlikely to be driven by emotional significance. The results are consistent with an overlap between self and in-group representation, which may provide evidence for a common process driving both self and in-group perceptual advantage effects. PMID- 29156369 TI - Mixed bacterial culture mediated direct conversion of bio-glycerol to diols. AB - Direct and economic transformation of biodiesel derived crude glycerol is gaining more significance. During screening of bacterial cultures Klebsiella pneumoniae and Enterobacter aerogenes were able to convert crude bio-glycerol to 2,3 butanediol (2,3-BDO) and 1,3-propanediol (1,3-PDO), as major compounds, ethanol and acetoin as minor compounds, with a conversion of 69% and 79% respectively. Process optimization could achieve maximum conversion at pH 7.0, 37 degrees C, 30-40 g/L glycerol and 1.5 g of inoculum until 120 h. Mixed cultures led to complete glycerol conversion with optimal yield and productivity. An innovative approach of using crude glycerol for sustained growth and tolerance of bacteria as source of carbon and energy makes this study more significant. In addition to this, a mixed culture concept introduced here is expected to make impact in process economics for industrial scale synthesis for direct transformation of glycerol into C3 and specifically, C4 diols. PMID- 29156370 TI - A novel aerated surface flow constructed wetland using exhaust gas from biological wastewater treatment: Performance and mechanisms. AB - In this study, a novel aerated surface flow constructed wetland (SFCW) using exhaust gas from biological wastewater treatment was investigated. Compared with un-aerated SFCW, the introduction of exhaust gas into SFCW significantly improved NH4+-N, TN and COD removal efficiencies by 68.30 +/- 2.06%, 24.92 +/- 1.13% and 73.92 +/- 2.36%, respectively. The pollutants removal mechanism was related to the microbial abundance and the highest microbial abundance was observed in the SFCW with exhaust gas because of the introduction of exhaust gas from sequencing batch reactor (SBR), and thereby optimizing nitrogen transformation processes. Moreover, SFCW would significantly mitigate the risk of exhaust gas pollution. SFCW removed 20.00 +/- 1.23%, 34.78 +/- 1.39%, and 59.50 +/- 2.33% of H2S, NH3 and N2O in the exhaust gas, respectively. And 31.32 +/- 2.23% and 32.02 +/- 2.86% of bacterial and fungal aerosols in exhaust gas were also removed through passing SFCW, respectively. PMID- 29156371 TI - Bacterial microbiota of the nasal passages across the span of human life. AB - The human nasal passages host major human pathogens. Recent research suggests that the microbial communities inhabiting the epithelial surfaces of the nasal passages are a key factor in maintaining a healthy microenvironment by affecting both resistance to pathogens and immunological responses. The nasal bacterial microbiota shows distinct changes over the span of human life and disruption by environmental factors might be associated with both short- and long-term health consequences, such as susceptibility to viral and bacterial infections and disturbances of the immunological balance. Because infants and older adults experience a high burden of morbidity and mortality from respiratory tract infections, we review recent data on the bacterial nasal microbiota composition in health and acute respiratory infection in these age groups. PMID- 29156372 TI - Psychometric properties of the intuitive eating scale-2 (IES-2) in a culturally diverse Hispanic American sample. AB - BACKGROUND: Intuitive eating is an adaptive eating tendency consistently associated with positive physical and mental health outcomes, including lower risk for obesity and eating disorders (EDs). Obesity rates are disproportionately high in Hispanic American populations, yet the properties of intuitive eating remain to be examined in such samples. METHOD: The current study examined the psychometric properties of the Intuitive Eating Scale-2 (IES-2) in a Hispanic American sample of adult college students (N=482), and related IES-2 scores to levels of disordered eating, body mass index (BMI), fruit and vegetable consumption, and body shape satisfaction. RESULTS: The final confirmatory factor analysis supported a three factor, 11 item measure with the subscales of Eating for Physical Rather Than Emotional Reasons, Reliance on Hunger and Satiety Cues, and Body Food Choice Congruence. The Unconditional Permission to Eat subscale could not be replicated in the current sample. As predicted, scores on the revised measure differed by BMI category and body shape satisfaction, and correlated with disordered eating tendencies and fruit and vegetable consumption. CONCLUSION: The current findings demonstrate that the modified IES-2 is better tailored to assess the cultural nuances influencing intuitive eating and can advance understanding how intuitive eating is understood and practiced in Hispanic Americans, compared to the original measure. PMID- 29156373 TI - Mitochondria-targeted ubiquinone (MitoQ) enhances acetaldehyde clearance by reversing alcohol-induced posttranslational modification of aldehyde dehydrogenase 2: A molecular mechanism of protection against alcoholic liver disease. AB - Alcohol metabolism in the liver generates highly toxic acetaldehyde. Breakdown of acetaldehyde by aldehyde dehydrogenase 2 (ALDH2) in the mitochondria consumes NAD+ and generates reactive oxygen/nitrogen species, which represents a fundamental mechanism in the pathogenesis of alcoholic liver disease (ALD). A mitochondria-targeted lipophilic ubiquinone (MitoQ) has been shown to confer greater protection against oxidative damage in the mitochondria compared to untargeted antioxidants. The present study aimed to investigate if MitoQ could preserve mitochondrial ALDH2 activity and speed up acetaldehyde clearance, thereby protects against ALD. Male C57BL/6J mice were exposed to alcohol for 8 weeks with MitoQ supplementation (5mg/kg/d) for the last 4 weeks. MitoQ ameliorated alcohol-induced oxidative/nitrosative stress and glutathione deficiency. It also reversed alcohol-reduced hepatic ALDH activity and accelerated acetaldehyde clearance through modulating ALDH2 cysteine S nitrosylation, tyrosine nitration and 4-hydroxynonenol adducts formation. MitoQ ameliorated nitric oxide (NO) donor-mediated ADLH2 S-nitrosylation and nitration in Hepa-1c1c7 cells under glutathion depletion condition. In addition, alcohol increased circulating acetaldehyde levels were accompanied by reduced intestinal ALDH activity and impaired intestinal barrier. In accordance, MitoQ reversed alcohol-increased plasma endotoxin levels and hepatic toll-like receptor 4 (TLR4) NF-kappaB signaling along with subsequent inhibition of inflammatory cell infiltration. MitoQ also reversed alcohol-induced hepatic lipid accumulation through enhancing fatty acid beta-oxidation. Alcohol-induced ER stress and apoptotic cell death signaling were reversed by MitoQ. This study demonstrated that speeding up acetaldehyde clearance by preserving ALDH2 activity critically mediates the beneficial effect of MitoQ on alcohol-induced pathogenesis at the gut-liver axis. PMID- 29156374 TI - Genetic profiling and surface proteome analysis of human atrial stromal cells and rat ventricular epicardium-derived cells reveals novel insights into their cardiogenic potential. AB - Epicardium-derived cells (EPDC) and atrial stromal cells (ASC) display cardio regenerative potential, but the molecular details are still unexplored. Signals which induce activation, migration and differentiation of these cells are largely unknown. Here we have isolated rat ventricular EPDC and rat/human ASC and performed genetic and proteomic profiling. EPDC and ASC expressed epicardial/mesenchymal markers (WT-1, Tbx18, CD73, CD90, CD44, CD105), cardiac markers (Gata4, Tbx5, troponin T) and also contained phosphocreatine. We used cell surface biotinylation to isolate plasma membrane proteins of rEPDC and hASC, Nano-liquid chromatography with subsequent mass spectrometry and bioinformatics analysis identified 396 rat and 239 human plasma membrane proteins with 149 overlapping proteins. Functional GO-term analysis revealed several significantly enriched categories related to extracellular matrix (ECM), cell migration/differentiation, immunology or angiogenesis. We identified receptors for ephrin and growth factors (IGF, PDGF, EGF, anthrax toxin) known to be involved in cardiac repair and regeneration. Functional category enrichment identified clusters around integrins, PI3K/Akt-signaling and various cardiomyopathies. Our study indicates that EPDC and ASC have a similar molecular phenotype related to cardiac healing/regeneration. The cell surface proteome repository will help to further unravel the molecular details of their cardio regenerative potential and their role in cardiac diseases. PMID- 29156375 TI - Downregulation of the protein synthesis machinery is a major regulatory event during early adipogenic differentiation of human adipose-derived stromal cells. AB - Commitment of adult stem cells involves the activation of specific gene networks regulated from transcription to protein synthesis. Here, we used ribosome profiling to identify mRNAs regulated at the translational level, through both differential association to polysomes and modulation of their translational rates. We observed that translational regulation during the differentiation of human adipose-derived stromal cells (hASCs, also known as adipose-derived mesenchymal stem cells), a subset of which are stem cells, to adipocytes was a major regulatory event. hASCs showed a significant reduction of whole protein synthesis after adipogenic induction and a downregulation of the expression and translational efficiency of ribosomal proteins. Additionally, focal adhesion and cytoskeletal proteins were downregulated at the translational level. This negative regulation of the essential biological functions of hASCs resulted in a reduction in cell size and the potential of hASCs to migrate. We analyzed whether the inactivation of key translation initiation factors was involved in this observed major repression of translation. We showed that there was an increase in the hypo phosphorylated forms of 4E-BP1, a negative regulator of translation, during early adipogenesis. Our results showed that extensive translational regulation occurred during the early stage of the adipogenic differentiation of hASCs. PMID- 29156376 TI - Comparative transcriptomic analysis of endothelial progenitor cells derived from umbilical cord blood and adult peripheral blood: Implications for the generation of induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) offer the potential to generate tissues with ethnic diversity enabling toxicity testing on selected populations. Recently, it has been reported that endothelial progenitor cells (EPCs) derived from umbilical cord blood (CB) or adult peripheral blood (PB) afford a practical and efficient cellular substrate for iPSC generation. However, differences between EPCs from different blood sources have rarely been studied. In the current study, we derived EPCs from blood mononuclear cells (MNCs) and reprogrammed EPCs into iPSCs. We also explored differences between CB-EPCs and PB EPCs at the molecular and cellular levels through a combination of transcriptomic analysis and cell biology techniques. EPC colonies in CB-MNCs emerged 5-7days earlier, were 3-fold higher in number, and consistently larger in size than in PB MNCs. Similarly, iPSC colonies generated from CB-EPCs was 2.5-fold higher in number than from PB-EPCs, indicating CB-EPCs have a higher reprogramming efficiency than PB-EPCs. Transcriptomic analysis using microarrays found a total of 1133 genes differentially expressed in CB-EPCs compared with PB-EPCs, with 675 genes upregulated and 458 downregulated. Several canonical pathways were impacted, among which the human embryonic stem cell pluripotency pathway was of particular interest. The differences in the gene expression pattern between CB EPCs and PB-EPCs provide a molecular basis for the discrepancies seen in their derivation and reprogramming efficiencies, and highlight the advantages of using CB as the cellular source for the generation of iPSCs and their derivative tissues for ethnic-related toxicological applications. PMID- 29156377 TI - Establishment of induced pluripotent stem cell line (ZZUi010-A) from an Alzheimer's disease patient carrying an APP gene mutation. AB - Alzheimer's disease (AD) is one of the most common neurodegenerative disorders. Previous studies have identified mutations in several genes, such as amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), in patients with early-onset (<65years) familial AD. Recently, a patient with an APP gene mutation was identified; the dermal fibroblasts of the patient were obtained and a line of induced pluripotent stem cells (iPSCs) was successfully generated using the Sendai-virus (SeV) delivery system. The iPSC line will be useful for further study of the pathomechanism and drug screening for AD. PMID- 29156378 TI - Effect of robotic-assisted gait rehabilitation on dynamic equilibrium control in the gait of children with cerebral palsy. AB - Due to the intensity and repetition of movement, roboticassisted gait training therapy could have a beneficial effect on the recovery and improvement of postural and locomotor functions of the patient. This study sought to highlight the effects of robotic-assisted gait rehabilitation in gait of children with Cerebral Palsy (CP). We analyzed the different strategies before and after this rehabilitation which was used in order to generate forward motion while maintaining balance. Data were collected by a motion analysis system (Vicon(r) - Oxford Metrics, Oxford, UK). The children were divided into two groups in such a way as to obtain a randomized controlled population: i) a group of fourteen children (Treated Group) underwent 20 sessions of roboticassisted gait training therapy using the driven gait orthosis Lokomat(r)Pediatric (Hocoma AG, Volketswil, Switzerland) compared to ii) a group of sixteen children without sessions of Lokomat(r)Pediatric (Control Group). Significant differences are observed for the TG between the preand post-test values of the locomotor parameters and of the kinetic data of the propulsive forces of the Center of Mass (COM) and of the Center of Pressure (COP) dynamic trajectory. This first study, although performed on a limited number of patients, shows the usefulness of this robotic gait rehabilitation mainly in the balance control in gait. Indeed after this rehabilitation, these children improve their gait that is especially characterized by a more appropriate time lag between the time instant of COM-COP trajectory divergence and the time instant when the forward propulsive forces became apparent. PMID- 29156379 TI - Evaluating the immediate effects of wearing foot orthotics in children with Joint Hypermobility Syndrome (JHS) by analysis of temperospatial parameters of gait and dynamic balance: A preliminary study. AB - : Joint Hypermobility Syndrome (JHS) in children, presents with increased joint range of motion and can lead to altered gait strategies and reduced dynamic balance. Despite limited evidence foot orthoses are sometimes prescribed to patients with JHS with the aim to improve the stability of their gait pattern and theoretically reduce associated symptoms of fatigue and joint pain. The purpose of this study was therefore to analyse the immediate effects of 'off the shelf' orthoses on temporospatial parameters of gait and dynamic balance in this cohort. METHODS: A total of 21 patients were recruited for the study (13 female) with a median age of 10 years (IRQ = 4.12). Each patient had their gait analysed using the GAITRite walkway in their own footwear and immediately after being prescribed the orthoses. Gait was tested at both the patients' preferred speed and when asked to walk slower to challenge their dynamic balance. RESULTS: Gait appeared more synchronised, with a reduction in step length and width variability, when participants were provided with orthotics. The variation was greatest when participants were asked to walk slower. Double stance was significantly less at slower speeds when orthotics were added (1.61%, 95% CI = 0.34, 2.89, p = 0.015) CONCLUSION: Results of this study indicate that orthotics have a definite immediate influence on gait patterns in patients with JHS. Future studies should investigate the long-term effects of orthotics in this population and include outcome measures for symptoms such as pain. PMID- 29156380 TI - Structure-based design of hERG-neutral antihypertensive oxazalone and imidazolone derivatives. AB - Angiotensin II receptor type 1 (AT1) antagonists are the most recent drug class against hypertension. Recently first crystal structure of AT1 receptor is deposited to the protein data bank (PDB ID: 4YAY). In this work, several molecular screening methods such as molecular docking and de novo design studies were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor. A database consisting of 3500 fragments were used to enumerate de novo designed imidazolone and oxazolone derivatives and hereby more than 50000 novel small molecules were generated. These derivatives were then used in high throughput virtual screening simulations (Glide/HTVS) to find potent hit molecules. In addition, virtual screening of around 18 million small drug-like compounds from ZINC database were screened at the binding pocket of the AT1 receptor via Glide/HTVS method. Filtered structures were then used in more sophisticated molecular docking simulations protocols (i.e., Glide/SP; Glide/XP; Glide/IFD; Glide/QPLD, and GOLD). However, the K+ ion channel/drug interactions should also be considered in studies implemented in molecular level against their cardiovascular risks. Thus, selected compounds with high docking scores via all diverse docking algorithms are also screened at the pore domain regions of human ether-a-go-go-related gene (hERG1) K+ channel to remove the high affinity hERG1 blocking compounds. High docking scored compounds at the AT1 with low hERG1 affinity is considered for long molecular dynamics (MD) simulations. Post-processing analysis of MD simulations assisted for better understanding of molecular mechanism of studied compounds at the binding cavity of AT1 receptor. Results of this study can be useful for designing of novel and safe AT1 inhibitors. PMID- 29156381 TI - Structure-based methods to predict mutational resistance to diarylpyrimidine non nucleoside reverse transcriptase inhibitors. AB - Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) is a leading cause of HIV treatment failure. Often included in antiviral therapy, NNRTIs are chemically diverse compounds that bind an allosteric pocket of enzyme target reverse transcriptase (RT). Several new NNRTIs incorporate flexibility in order to compensate for lost interactions with amino acid conferring mutations in RT. Unfortunately, even successful inhibitors such as diarylpyrimidine (DAPY) inhibitor rilpivirine are affected by mutations in RT that confer resistance. In order to aid drug design efforts, it would be efficient and cost effective to pre evaluate NNRTI compounds in development using a structure-based computational approach. As proof of concept, we applied a residue scan and molecular dynamics strategy using RT crystal structures to predict mutations that confer resistance to DAPYs rilpivirine, etravirine, and investigational microbicide dapivirine. Our predictive values, changes in affinity and stability, are correlative with fold resistance data for several RT mutants. Consistent with previous studies, mutation K101P is predicted to confer high-level resistance to DAPYs. These findings were further validated using structural analysis, molecular dynamics, and an enzymatic reverse transcription assay. Our results confirm that changes in affinity and stability for mutant complexes are predictive parameters of resistance as validated by experimental and clinical data. In future work, we believe that this computational approach may be useful to predict resistance mutations for inhibitors in development. PMID- 29156382 TI - Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies. AB - Dengue virus is a major issue of tropical and sub-tropical regions. The proliferation of virus results in immense number of deaths each year because of unavailability of on-shelf drugs. This issue necessitates the design of novel anti-Dengue drugs. The protease enzyme pathway is the critical target for drug design due to its significance in the replication, survival and other cellular activities of Dengue virus. Keeping in mind the worsening situation regarding Dengue virus, approximately eighteen million drug-like compounds from the ZINC small molecule database have been screened against Nonstructural Protein 3 (NS3) previously by our group. In this study, in order to investigate the effect of extended time of molecular dynamics (MD) simulations on structural and dynamical profiles of used complexes, simulation run time is increased from 50-ns to 100-ns for the each system. In addition, a well-known Dengue virus inhibitor (MB21) from literature is used as reference structure (positive control) to compare the proposed molecules. Post-processing MD analyses including Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations were conducted to predict binding free energies of inhibitors from derived trajectory frames of MD simulations. Identified compounds are further directed to Quantum-Polarized Ligand Docking (QPLD), molecular fingerprint-based virtual screening of another small molecule database (Otava Drug Like small molecule database), and Structure based Pharmacophore Modeling (E-Pharmacophore). Finally, cell proliferation and cytotoxicity tests as well as pre- and post-treatment on HUH7 cells infected with DENV2 NGC strain are applied for four identified hit molecules (ZINC36681949, ZINC44921800, ZINC95518765 and ZINC39500661) to check whether these drugs inhibit DENV2 from entry and/or exit pathways. Based on cell-based Dengue quantification assays, there is no effect seen on pre-treatment of cells with these compounds indicating that the early infection processes of virus is not affected. In contrast, the post-treatment of cells with these compounds after Dengue virus infection has resulted in a significant 1 log PFU/ml reduction of the virus infectious titre. PMID- 29156383 TI - Diagnosis of Distant Metastasis of Lung Cancer: Based on Clinical and Radiomic Features. AB - OBJECTIVES: To analyze the distant metastasis possibility based on computed tomography (CT) radiomic features in patients with lung cancer. METHODS: This was a retrospective analysis of 348 patients with lung cancer enrolled between 2014 and February 2015. A feature set containing clinical features and 485 radiomic features was extracted from the pretherapy CT images. Feature selection via concave minimization (FSV) was used to select effective features. A support vector machine (SVM) was used to evaluate the predictive ability of each feature. RESULTS: Four radiomic features and three clinical features were obtained by FSV feature selection. Classification accuracy by the proposed SVM with SGD method was 71.02%, and the area under the curve was 72.84% with only the radiomic features extracted from CT. After the addition of clinical features, 89.09% can be achieved. CONCLUSION: The radiomic features of the pretherapy CT images may be used as predictors of distant metastasis. And it also can be used in combination with the patient's gender and tumor T and N phase information to diagnose the possibility of distant metastasis in lung cancer. PMID- 29156384 TI - Targeting FGFR pathway in breast cancer. AB - Developments in breast cancer biology over the last years have permitted deconstructing the molecular profile of the most relevant breast cancer subtypes. This has led to an increase in therapeutic options, including more effective personalized therapy for breast cancer and substantial improvements in patient outcomes. Although currently there are only a few targeted therapies approved for metastatic breast cancer, the discovery of druggable kinase gene alterations has radically changed cancer treatment by providing novel and successfully actionable drug targets. Fibroblast growth factors and their receptors (FGFRs) participate in different physiologic processes and also play an essential role in cancer cell proliferation, survival, differentiation, migration, and apoptosis. This article summarizes the main molecular alterations of FGFRs, as well as the available preclinical and clinical data with FGFR inhibitors in breast cancer, and discusses new opportunities for the clinical development of these agents in patients with breast cancer. PMID- 29156385 TI - Interaction with the GDF8/11 pathway reveals treatment options for adenocarcinoma of the breast. AB - Breast adenocarcinoma continues to be the most frequently diagnosed tumor entity. Despite established therapy options, mortality for breast cancer remains to be as high as 40,000 patients in the US annually. Thus, a need to develop a patient oriented, targeted therapy exists. In this study, we investigated the interaction of breast adenocarcinoma with the ubiquitously present protein Follistatin and subsequently the GDF8/11 pathway. We analyzed primary histological samples from adenocarcinoma patients for expression of Follistatin and GDF8/11. Furthermore, expression levels of Follistatin and GDF8/11 in MCF7 were compared with MCF10a cells. From the resulting data, GDF8 and Follistatin were used as chemotherapeutic agents in MCF7 cells and their migratory, proliferative behavior and viability were measured. From the experiments, we were able to detect a significantly increased expression of Follistatin and GDF8/11 in the low malignant breast adenocarcinoma (G1) as compared to benign breast fibroadenoma. Interestingly, a decrease was demonstrated in higher grade malignancies. These findings were accompanied by the clinical observation that increased expression of Follistatin and GDF8 is associated with a higher overall survival rate of breasts cancer patients. Substitution of GDF8 and Follistatin reduces the viability of the MCF7 cells and disrupts the migrative and proliferative potential. In summary, MCF7 cells show high chemosensitivity to Follistatin and especially GDF8 and both proteins might serve as targets to improve systemic treatment in breast cancer. In contrast to most established chemotherapy regimens Follistatin and GDF8 show no cytotoxicity to other organs. PMID- 29156386 TI - An innovative method for the solidification/stabilization of PAHs-contaminated soil using sulfonated oil. AB - Stabilization/solidification (S/S) has been successfully employed in many superfund sites contaminated with organic materials. However, this method's long term effectiveness has not been fully evaluated and the increase in soil volume following treatment is unfavorable to follow-up disposal. The present study developed a novel method for the S/S of PAHs-contaminated soil with the facilitation of sulfonated oil (SO). Adding SO significantly improved the unconfined compressive strength (UCS) values of Portland cement and activated carbon (PC-AC) treated soil samples, and the UCS values of the soil sample treated with 0.02% of SO were up to 2.3 times higher than without SO addition. When the soil was treated with PC-AC-SO, the PAHs leaching concentrations were 14%-25% of that in leachates of the control soil, and high molecular weight PAHs including benzo(a)pyrene were rarely leached. Freeze/thaw durability tests reveal that the leachability of PAHs was not influenced by freeze-thaw cycles. The UCS values of PC-AC-SO treated soil samples were 2.2-3.4 times greater than those of PC-AC treated soil samples after 12 freeze-thaw cycles. The PC-AC-SO treated soils resist disintegration better when compared to the PC-AC treated soils. The SEM micrographs reveal that the soils' compactness was significantly improved when treated with SO. PMID- 29156387 TI - Biotransformation and detoxification of selenite by microbial biogenesis of selenium-sulfur nanoparticles. AB - This study combines the interaction between the toxic oxyanions selenite and selenate and the plant growth promoting bacterium Azospirillum brasilense with a comprehensive characterization of the formed selenium particles. As selenium is an essential trace element, but also toxic in high concentrations, its state of occurrence in nature is of major concern. Growth of the bacterium was affected by selenite (1-5mM) only, observable as a prolonged growth lag-phase of 3days. Subsequently, selenite reduction occurred under aerobic conditions resulting in extracellularly formed insoluble Se0 particles. Complementary studies by microscopic and spectroscopic techniques revealed the particles to be homogeneous and stable Se8-nSn structured spheres with an average size of 400nm and highly negative surface charge of -18mV in the neutral pH range. As this is the first study showing Azospirillum brasilense being able to biotransform selenite to selenium particles containing a certain amount of sulfur, even if environmental waters supplemented with selenite were used, they may significantly contribute to the biogeochemical cycling of both elements in soil as well as to their soil plant transfer. Therefore, microbial biotransformation of selenite under certain circumstances may be used for various bio-remediation and bio-technological applications. PMID- 29156388 TI - The relationship of parental expressed emotion to co-occurring psychopathology in individuals with autism spectrum disorder: A systematic review. AB - Expressed emotion is a construct of the affective relationship between two people, with domains measuring criticism, hostility, warmth, relationship and emotional over-involvement. This review focuses on studies of Expressed Emotion in families of individuals with autism spectrum disorder and its association with co-occurring psychiatric disorders. A systematic search used the Psych-Info and Medline databases to identify articles available at or before September 2016. Eleven studies met the inclusion criteria. The included studies suggest that high levels of expressed emotion, including criticism, are associated with behavioural problems. However, the relationship between expressed emotion and emotional problems is presently unclear because findings were mixed. Also, there is presently little evidence regarding the impact of other components of expressed emotion on co-occurring disorders. PMID- 29156390 TI - The development and testing of the Nursing Student Perceptions of Dishonesty Scale. AB - BACKGROUND: Dishonesty in the classroom suggests dishonesty in practice. There is need to better understand nursing students' perceptions of dishonest behaviors in the classroom and clinical setting. There is currently no instrument to assess perceptions in the classroom and clinical setting. OBJECTIVE: The purpose of this study was to develop an instrument to assess nursing students' perceptions of academically dishonest behaviors in the classroom and clinical setting. DESIGN: Mixed Methods Instrument Development Study. PARTICIPANTS: 971 BSN students. METHOD: Using the results from a content synthesis of the literature and a small qualitative study, we created the Nursing Student Perceptions of Dishonesty Scale (NSPDS) and examined its psychometric properties. RESULTS: Factor analysis suggests strong loading of subscales in both settings with two comparable categories allow for correlation of perceptions in the classroom and clinical settings. Cronbach's alpha values begin to establish reliability and PAF with Promax rotation and correlational analysis begin to establish validity. CONCLUSION: This NSPDS can help researchers and educators understand more clearly nursing students' perceptions of dishonesty. This will allow for the creation of individualized, and therefore more effective, interventions to reduce dishonest behaviors of nursing students. Further work is needed to strengthen reliability and validity. PMID- 29156389 TI - Assessing working memory in children with ADHD: Minor administration and scoring changes may improve digit span backward's construct validity. AB - BACKGROUND: Pediatric ADHD is associated with impairments in working memory, but these deficits often go undetected when using clinic-based tests such as digit span backward. AIMS: The current study pilot-tested minor administration/scoring modifications to improve digit span backward's construct and predictive validities in a well-characterized sample of children with ADHD. METHODS AND PROCEDURES: WISC-IV digit span was modified to administer all trials (i.e., ignore discontinue rule) and count digits rather than trials correct. Traditional and modified scores were compared to a battery of criterion working memory (construct validity) and academic achievement tests (predictive validity) for 34 children with ADHD ages 8-13 (M=10.41; 11 girls). OUTCOMES AND RESULTS: Traditional digit span backward scores failed to predict working memory or KTEA-2 achievement (allns). Alternate administration/scoring of digit span backward significantly improved its associations with working memory reordering (r=.58), working memory dual-processing (r=.53), working memory updating (r=.28), and KTEA 2 achievement (r=.49). CONCLUSIONS AND IMPLICATIONS: Consistent with prior work, these findings urge caution when interpreting digit span performance. Minor test modifications may address test validity concerns, and should be considered in future test revisions. Digit span backward becomes a valid measure of working memory at exactly the point that testing is traditionally discontinued. PMID- 29156391 TI - Optimal allocation of physical water resources integrated with virtual water trade in water scarce regions: A case study for Beijing, China. AB - This study provides an innovative application of virtual water trade in the traditional allocation of physical water resources in water scarce regions. A multi-objective optimization model was developed to optimize the allocation of physical water and virtual water resources to different water users in Beijing, China, considering the trade-offs between economic benefit and environmental impacts of water consumption. Surface water, groundwater, transferred water and reclaimed water constituted the physical resource of water supply side, while virtual water flow associated with the trade of five major crops (barley, corn, rice, soy and wheat) and three livestock products (beef, pork and poultry) in agricultural sector (calculated by the trade quantities of products and their virtual water contents). Urban (daily activities and public facilities), industry, environment and agriculture (products growing) were considered in water demand side. As for the traditional allocation of physical water resources, the results showed that agriculture and urban were the two predominant water users (accounting 54% and 28%, respectively), while groundwater and surface water satisfied around 70% water demands of different users (accounting 36% and 34%, respectively). When considered the virtual water trade of eight agricultural products in water allocation procedure, the proportion of agricultural consumption decreased to 45% in total water demand, while the groundwater consumption decreased to 24% in total water supply. Virtual water trade overturned the traditional components of water supplied from different sources for agricultural consumption, and became the largest water source in Beijing. Additionally, it was also found that environmental demand took a similar percentage of water consumption in each water source. Reclaimed water was the main water source for industrial and environmental users. The results suggest that physical water resources would mainly satisfy the consumption of urban and environment, and the unbalance between water supply and demand could be filled by virtual water import in water scarce regions. PMID- 29156392 TI - Biofilms as a sink for antibiotic resistance genes (ARGs) in the Yangtze Estuary. AB - Biofilms are ubiquitous throughout aquatic environments and they are thought to promote the acquisition and dissemination of antibiotic resistant genes (ARGs). This study focused on the occurrence and distribution of five types of ARG in naturally-occurring biofilms, in comparison to associated sediment and water samples, from the Yangtze Estuary, which borders the meta-city of Shanghai, China. The detection frequency and abundances of most ARGs showed the following order: biofilm > sediment > water, which can be attributed to a high level of antibiotics and metals that can accelerate the generation and propagation of ARGs in biofilms. Most of ARG abundances were contributed by extracellular DNA (eDNA) in biofilm and sediment samples. ARGs (sul1, sul2, tetA and tetW) in eDNA were significantly correlated with TOC in both biofilm and sediment samples. Furthermore, both intracellular DNA-associated ARGs per gram of microbial biomass carbon (MBC) and eDNA-associated ARGs per gram of non-MBC and were higher in biofilms than sediments, and the partitioning coefficients of ARGs in eDNA between biofilm and water were higher than those between sediment and water. Our results provide new insight for evaluating the occurrence and abundance of ARGs in aquatic environments, confirming that biofilms are a significant sink for ARGs in the estuarine environment. PMID- 29156394 TI - Assessment of sampling strategies for estimation of site mean concentrations of stormwater pollutants. AB - The estimation of stormwater pollutant concentrations is a primary requirement of integrated urban water management. In order to determine effective sampling strategies for estimating pollutant concentrations, data from extensive field measurements at seven different catchments was used. At all sites, 1-min resolution continuous flow measurements, as well as flow-weighted samples, were taken and analysed for total suspend solids (TSS), total nitrogen (TN) and Escherichia coli (E. coli). For each of these parameters, the data was used to calculate the Event Mean Concentrations (EMCs) for each event. The measured Site Mean Concentrations (SMCs) were taken as the volume-weighted average of these EMCs for each parameter, at each site. 17 different sampling strategies, including random and fixed strategies were tested to estimate SMCs, which were compared with the measured SMCs. The ratios of estimated/measured SMCs were further analysed to determine the most effective sampling strategies. Results indicate that the random sampling strategies were the most promising method in reproducing SMCs for TSS and TN, while some fixed sampling strategies were better for estimating the SMC of E. coli. The differences in taking one, two or three random samples were small (up to 20% for TSS, and 10% for TN and E. coli), indicating that there is little benefit in investing in collection of more than one sample per event if attempting to estimate the SMC through monitoring of multiple events. It was estimated that an average of 27 events across the studied catchments are needed for characterising SMCs of TSS with a 90% confidence interval (CI) width of 1.0, followed by E.coli (average 12 events) and TN (average 11 events). The coefficient of variation of pollutant concentrations was linearly and significantly correlated to the 90% confidence interval ratio of the estimated/measured SMCs (R2 = 0.49; P < 0.01) as well as the number of events required to achieve certain accuracy, and hence could be a promising surrogate for determining the sampling frequency needed to accurately estimate SMCs of pollutants. PMID- 29156393 TI - Effect of TiO2 and CeO2 nanoparticles on the metabolic activity of surficial sediment microbial communities based on oxygen microelectrodes and high throughput sequencing. AB - Environmental concerns regarding the potential ecological risks of metallic oxide nanoparticles (MNPs) in aquatic ecosystems are increasing; sediment is considered a sink for these MNPs. Although several studies have studied the potential impact of MNPs on microbial communities in freshwater and estuarine sediments, limited information is available regarding the influence of MNPs on the metabolic activity of surficial sediment microbial communities and related biogeochemical conditions. To address these issues, a microcosm approach was established to study the metabolic response of surficial sediment microbial communities to a single addition of TiO2 or CeO2 NPs (5 mg/L) using oxygen microelectrodes, enzyme activity measurements, and high-throughput sequencing. Rapid sedimentation of MNPs (regardless of NP type) was observed in freshwater samples, and most (up to 85%) accumulated in surface sediments (<5 mm). Microelectrode profile measurements in pre-incubated sediments treated with MNPs showed that the oxygen concentration decreased at a slower rate with increasing sediment depth compared to that in untreated controls. Biological oxygen consumption in the uppermost sediment layer (0-1500 MUm) was significantly inhibited by MNPs, as calculated from steady-state microprofiles, with CeO2 NPs resulting in enhanced acute toxicity than TiO2 NPs. High-throughput sequencing showed that MNP exposure increased the bacterial diversity and altered the bacterial community structure, regardless of NP type. The abundance of three dominant bacterial genera, Methylotenera, Cytophagceae_uncultured (classified as an aerobic bacterium), and Cyanobacteria_norank (a facultative bacterium), was markedly reduced by MNPs, which was primarily responsible for inhibiting microbial-mediated oxygen consumption in surficial sediments. In summary, short-term exposure to MNPs negatively affected the metabolic activity of benthic microbial communities, which could influence the biogeochemical functions along the sediment-water interface. PMID- 29156395 TI - Validation of a multi-phase plant-wide model for the description of the aeration process in a WWTP. AB - This paper introduces a new mathematical model built under the PC-PWM methodology to describe the aeration process in a full-scale WWTP. This methodology enables a systematic and rigorous incorporation of chemical and physico-chemical transformations into biochemical process models, particularly for the description of liquid-gas transfer to describe the aeration process. The mathematical model constructed is able to reproduce biological COD and nitrogen removal, liquid-gas transfer and chemical reactions. The capability of the model to describe the liquid-gas mass transfer has been tested by comparing simulated and experimental results in a full-scale WWTP. Finally, an exploration by simulation has been undertaken to show the potential of the mathematical model. PMID- 29156396 TI - Determining code status on inpatient psychiatry. PMID- 29156397 TI - Composition determination of multinary III/V semiconductors via STEM HAADF multislice simulations. AB - Knowledge of the microscopic elemental composition of multinary III/V semiconductor materials is crucial to the development of functionalized opto electronic devices. Well-proven composition analysis methods, such as high resolution X-ray diffraction (HRXRD), fail to determine the elemental composition when more than three atomic species are involved. In this work we propose a procedure for the composition analysis of multinary III/V semiconductors at atomic resolution using high angle annular dark field (HAADF) scanning transmission electron microscopy (STEM) image simulations. Our method exploits the dependence of HAADF-STEM image intensities on the atomic number and static atomic displacements (SAD) at different detector inner angles. Here, we describe the proposed method in detail using Ga(NAsP) as an example multinary material. PMID- 29156398 TI - Spontaneous hair follicle germ (HFG) formation in vitro, enabling the large-scale production of HFGs for regenerative medicine. AB - Hair follicle morphogenesis is triggered by reciprocal interactions between hair follicle germ (HFG) epithelial and mesenchymal layers. Here, we developed a method for large-scale preparation of HFGs in vitro via self-organization of cells. We mixed mouse epidermal and mouse/human mesenchymal cells in suspension and seeded them in microwells of a custom-designed array plate. Over a 3-day culture period, cells initially formed a randomly distributed single cell aggregate and then spatially separated from each other, exhibiting typical HFG morphological features. These self-sorted hair follicle germs (ssHFGs) were shown to be capable of efficient hair-follicle and shaft generation upon intracutaneous transplantation into the backs of nude mice. This finding facilitated the large scale preparation of approximately 5000 ssHFGs in a microwell-array chip made of oxygen-permeable silicone. We demonstrated that the integrity of the oxygen supply through the bottom of the silicone chip was crucial to enabling both ssHFG formation and subsequent hair shaft generation. Finally, spatially aligned ssHFGs on the chip were encapsulated into a hydrogel and simultaneously transplanted into the back skin of nude mice to preserve their intervening spaces, resulting in spatially aligned hair follicle generation. This simple ssHFG preparation approach is a promising strategy for improving current hair-regenerative medicine techniques. PMID- 29156399 TI - Saliva of Ixodes ricinus enhances TBE virus replication in dendritic cells by modulation of pro-survival Akt pathway. AB - It has been suggested that tick saliva facilitates transmission of tick-borne encephalitis virus (TBEV) to vertebrates. The mechanism of this facilitation has not been elucidated yet. Since dendritic cells (DCs) are among first cells attacked by the virus, we examined the amount of virus and changes induced by saliva in TBEV-infected DCs. We found that virus replication was significantly increased by saliva of Ixodes ricinus tick. Next, saliva-induced enhancement of Akt pathway activation was observed in TBEV-infected DCs. Akt mediated pathway is known for its anti-apoptotic and pro-survival effects. Accordingly, apoptosis of TBEV-infected DCs was declined and cellular viability increased in the presence of tick saliva. Saliva-induced enhancement of STAT1 and NF-kappaB was also observed in TBEV-infected DCs. In conclusion, we suggest that tick saliva provides pro-survival and anti-apoptotic signals to infected DCs via upregulation of Akt, which may have positive consequences for TBEV replication and transmission. PMID- 29156400 TI - 'I have it just in case' - Naloxone access and changes in opioid use behaviours. AB - BACKGROUND: The past decade has seen over a four-fold increase in deaths from opioid overdose in the United States. To address this growing epidemic, many localities initiated policies to expand access to naloxone (a drug that reverses the effects of opioids); however, little is known how naloxone access affects opioid use behaviours. METHODS: The present qualitative study used semi structured, in-depth interviews with inpatients at a substance use treatment centre. All patients who met study inclusion criteria (in treatment for opioid use, between the ages of 18 and 40, able to speak and understand English, and had not previously completed an interview with the research team) were invited to participate. Interviews were conducted until thematic saturation was reached (N=20) and covered the participant's naloxone knowledge, access, and attitudes, as well as experience(s) with opioid use and opioid overdose, and their naloxone use in the context of opioid overdose. Thematic content analysis was used to analyze interview transcripts. RESULTS: Five main themes were uncovered during analysis; first, awareness about naloxone, including, content knowledge and source information for naloxone. Naloxone awareness was very common among opioid users; however, depth of knowledge varied; some participants did not make any efforts to have naloxone available, and others felt that it was "just as important as a clean needle." The second theme explored how naloxone access intersects with drug selling. The third theme explored naloxone availability while using, including attitudes about naloxone, occasions with no naloxone availability, when naloxone is "good to have," and when naloxone is a priority for users. The fourth theme examined changes in opioid use behaviours associated with naloxone access. Primarily, participants discussed changing how much heroin they used in a given situation to achieve a bigger high. The final theme explored naloxone behaviours that alter overdose mortality risk, such as how users distinguish when to use naloxone, dis-incentives to naloxone use, and solo opioid use. CONCLUSION: Results indicate that though naloxone awareness was high, there was great variation in the associated attitudes and practices. Participants generally described naloxone as an important resource, but not all were inclined to carry or use it appropriately. Future research needs to examine why different groups of opioid users access naloxone differently, particularly to identify those at risk for experimental opioid use while carrying naloxone. PMID- 29156401 TI - Nine reasons why ecstasy is not quite what it used to be. AB - This paper explores the recent resurgence in use of ecstasy/MDMA in Europe and highlights keys areas of continuity and divergence between the ecstasy market of the 1990s and the current MDMA market. Based on a scoping study involving a targeted multi-source data collection exercise on MDMA, it highlights nine areas that have undergone some level of change, linked with both supply and demand for the drug. Factors discussed include: innovation in production techniques; changes in precursor chemical availability; the role of online markets; competition with other stimulants and new psychoactive substances; the increased availability of high-strength MDMA; and the shift from subcultural towards more mainstream use of the drug. The paper proposes that the MDMA on Europe's contemporary market is in some respects a third generation product with a different consumer profile, with implications that responses developed at the time of the drug's earlier iteration, may be in need of a review and revamp. PMID- 29156402 TI - Effect of initiating drug treatment on the risk of drug-related poisoning death and acquisitive crime among offending heroin users. AB - BACKGROUND: A recent Cochrane review of randomised trials identified a lack of evidence for interventions provided to drug-using offenders. We use routine data to address whether contact with treatment services reduces heroin users' likelihood of a future acquisitive offence or drug-related poisoning (DRP) death. METHODS: Heroin-users were identified from probation assessments and linked to drug-treatment, mortality and offending records. The study cohort was selected to ensure that the subject was not: in prison, in treatment or had recently left treatment. Subjects were classed as initiators if they attended a triage appointment within two weeks of their assessment; non-initiators otherwise. Initiator and non-initiators were compared over a maximum of one year, with respect to their risk of recorded acquisitive offence or DRP-death. Balance was sought using propensity score matching and missing data were accounted for using multiple imputation. RESULTS: Nine percent of assessments identified for analysis were classed as initiators. Accounting for observed confounding and missing data, there was a reduction in DRPs associated with initiator assessments, however there was uncertainty around this estimate such that a null-effect could not be ruled out (HR: 0.42, 95% CI 0.17-1.04). There was no evidence of a decrease in the recidivism risk, in fact the analysis showed a small increase (HR: 1.10, 95% CI 1.02-1.18). CONCLUSION: For heroin-using offenders, initial contact with treatment services does not appear to reduce the likelihood of a future acquisitive offence. PMID- 29156403 TI - The role of trauma in the hormonal interplay of cortisol, testosterone, and oxytocin in adolescent aggression. AB - Although numerous studies have examined the neuroendocrinology of aggression, the findings are mixed and focused on cortisol and testosterone. We argue that past findings remain inconclusive partly because the key roles of oxytocin and trauma have not been systematically integrated yet. Oxytocin is associated with social behavior and interacts with cortisol and testosterone, whereas trauma is a crucial risk factor of aggression that strongly affects hormonal activity. In this review, we investigate the role of trauma in the hormonal interplay of cortisol, testosterone, and oxytocin in aggression during adolescence. We first discuss how these hormones interact with each other and how trauma influences these interactions and then we propose a model that highlights the role of trauma in the hormonal interplay in aggression. We suggest that the timing of trauma has a distinct effect on hormonal activity and it should be integrated into any comprehensive model. Current trauma is linked to different levels of oxytocin, cortisol, testosterone, and testosterone/cortisol ratio than childhood trauma, but this distinction is also influenced by gender and type of aggression. We conclude that in order to better understand the neuroendocrinology of aggression, it is crucial to incorporate the investigation of oxytocin and trauma in future research. PMID- 29156404 TI - Cascaded signal amplification via target-triggered formation of aptazyme for sensitive electrochemical detection of ATP. AB - The construction of reliable sensors for adenosine triphosphate (ATP) detection gains increasing interest because of its important roles in various enzymatic activities and biological processes. Based on a cascaded, significant signal amplification approach by the integration of the aptazymes and catalytic hairpin assembly (CHA), we have developed a sensitive electrochemical sensor for the detection of ATP. The target ATP leads to the conformational change of the aptazyme sequences and their association with the hairpin substrates to form active aptazymes, in which the hairpin substrates are cyclically cleaved by the metal ion cofactors in buffer to release the enzymatic sequences that can also bind the hairpin substrates to generate active DNAzymes. The catalytic cleavage of the hairpin substrates in the aptazymes/DNAzymes thus results in the generation of a large number of intermediate sequences. Subsequently, these intermediate sequences trigger catalytic capture of many methylene blue-tagged signal sequences on the electrode surface through CHA, producing significantly amplified current response for sensitive detection of ATP at 0.6nM. Besides, the developed sensor can discriminate ATP from analogous interference molecules and be applied to human serum samples, making the sensor a useful addition to the arena for sensitive detection of small molecules. PMID- 29156406 TI - Target-catalyzed hairpin assembly and metal-organic frameworks mediated nonenzymatic co-reaction for multiple signal amplification detection of miR-122 in human serum. AB - Herein, a new type of multifunctional iron based metal-organic frameworks (PdNPs@Fe-MOFs) has been synthesized by assembly palladium nanoparticles on the surface of Fe-MIL-88NH2 MOFs microcrystals, and first applied in electrochemical biosensor for ultrasensitive detection of microRNA-122 (miR-122, a biomarker of drug-induced liver injury). The nanohybrids have not only been utilized as ideal nanocarriers for immobilization of signal probes, but also used as redox probes and electrocatalysts. In this biosensor, two hairpin probes were designed as capture probes and signal probes, respectively. The nanohybrids conjugated with streptavidin and biotinylated signal probes were used as the tracer labels, target miR-122 was sandwiched between the tracer labels and thiol-terminated capture probes inserted in MCH monolayer on the gold nanoparticles-functionalized nitrogen-doped graphene sheets (AuNPs@N-G) modified electrode. Based on target catalyzed hairpin assembly, target miR-122 could trigger the hybridization of capture probes and signal probes to further be released to initiate the next reaction process resulted in numerous tracer indicators anchored onto the sensing interfaces. Thus, the detection signal could be dramatically enhanced towards the electrocatalytic oxidation of 3,3',5,5'-tetramethylbenzidine in the presence of H2O2 owing to the intrinsic and intriguing peroxidase-like activity of the nanohybrids. With the assist of target-catalyzed hairpin assembly and PdNPs@Fe MOFs mimetic co-reaction for signal amplification, a wide detection range from 0.01fM to 10pM was achieved with a low detection limit of 0.003fM (S/N =3). Furthermore, the proposed biosensor exhibited excellent specificity and recovery in spiked serum samples, and was successfully used for detecting miR-122 in real biological samples, which provided a rapid and efficient method for detecting drug-induced liver injury at an early stage. PMID- 29156405 TI - Effective immobilization of Au nanoparticles on TiO2 loaded graphene for a novel sandwich-type immunosensor. AB - A novel and sensitive sandwich immunosensor for amperometric determination of carcinoembryonic antigen (CEA) was designed using Au nanoparticles-titanium dioxide-graphene (AuNPs-TiO2-graphene) nanocomposites. Dopamine-functionalized graphene was firstly prepared by pi-stacking interaction, and TiO2 was then attached to the surface of dopamine-graphene by the specificity and high affinity of enediol ligands to Ti (IV). Afterwards, AuNPs-TiO2-graphene nanocomposites were synthesized with photo-reduction approach under ultraviolet irradiation. The morphology and conductivity of the as-prepared nanocomposites were characterized by transmission electron microscopy, Fourier transform infrared spectra, X-ray powder diffraction, cyclic voltammetry and electrochemical impedance spectroscopy. Taking the advantage of large specific surface area and excellent biocompatibility, AuNPs could covalently link horseradish peroxidase labeled secondary antibody (HRP-Ab2) through the interaction between AuNPs and mercapto or primary amine groups of HRP-Ab2 for sandwich-type immunosensor construction. Under optimum conditions, the modified electrode exhibited a linear current response to CEA concentration in a wide range of 0.005-200ngmL-1 (R2 = 0.994) with low detection limit of 3.33pgmL-1 (S/N = 3). PMID- 29156407 TI - Ultrasensitive detection of prostate specific antigen by electrochemical aptasensor using enzyme-free recycling amplification via target-induced catalytic hairpin assembly. AB - Based on the target-induced catalytic hairpin assembly and bimetallic catalyst, the enzyme-free recycling amplification strategy for sensitive detection of prostate specific antigen (PSA) has been designed. The aptamer and its complementary DNA (C-apt) are modified on the magnetic particles. The aptamer-PSA binding event can release the C-apt that triggers the catalytic assembly between hairpin capture DNA and hairpin help DNA. Then the catalytic hairpin assembly leads to cyclic reuse the C-apt and the generation of many opened hairpin capture DNA, which can associate with the prepared Au/Pt-polymethylene blue (PMB) probes to yield electrochemical signal. Meanwhile, the Au/Pt-PMB probes exhibit excellent electrocatalytic ability for H2O2 to magnify the response current. The designed sensor possesses a wide dynamic range of 10fgmL-1 to 100ngmL-1 and ultra low detection limit of 2.3fgmL-1. The present method has good performance in real serum sample analysis. This strategy is promising to be extended to provide a highly sensitive platform for various target analytes. PMID- 29156408 TI - Label-free electrochemical DNA biosensor for guanine and adenine by ds-DNA/poly(L cysteine)/Fe3O4 nanoparticles-graphene oxide nanocomposite modified electrode. AB - In this study, we aim to design a simple and effective electrochemical DNA biosensor based on a carbon paste electrode modified with ds-DNA/poly(L cysteine)/Fe3O4 nanoparticles-graphene oxide (ds-DNA/p(L-Cys)/Fe3O4 NPs-GO/CPE) for sensitive detection of adenine (A) and guanine (G). The electrocatalytic oxidation of A and G on the electrode was explored by differential pulse voltammetry (DPV) and cyclic voltammetry (CV). This sensor shows separated and well-defined peaks for A and G, by which one can determine these biological bases individually or simultaneously. The ds-DNA/p(L-Cys)/Fe3O4 NPs-GO/CPE exhibited an increase in peak currents and the electron transfer kinetics and decrease in the overpotential for the oxidation reaction of A and G. Under the optimal conditions a linear relationship is figured out between the peak current and the analytes' concentrations on a range of 0.01-30.0MUM and 0.01-25.0MUM for simultaneous determination of A and G, with detection limits of 3.48 and 1.59nM, respectively. As well as, individually determination is resulted two linear concentration ranges of 0.01-30.0MUM for A and 0.01-25.0MUM for G with detection limits of 3.90 and 1.58nM for A and G, respectively. The proposed biosensor exhibited some advantages in terms of simplicity, rapidity, high sensitivity, good reproducibility and long-term stability. Furthermore, the measurements of thermally denatured single-stranded DNA were carried out and the value of (G + C)/(A + T) of DNA was calculated as about 0.77 for various DNA samples. This study also ascertained that the proposed biosensor can be profitable to evaluate DNA bases damage. PMID- 29156409 TI - It's in the details: The role of selective discussion in forgetting of children's autobiographical memories. AB - This experiment investigated whether retrieval-induced forgetting (RIF) would be found in children's self-generated autobiographical memory recall. An adapted version of the RIF paradigm for adults' autobiographical memories was administered to 8- and 9-year-old children (N = 65). We hypothesized that RIF would be found in terms of both number of memories recalled and amount of memory detail reported. The relationship between memory detail at the retrieval practice phase and RIF magnitude was also investigated. Consistent with hypotheses, RIF was found for both the number of memories recalled and the amount of memory detail reported. In addition, memory detail at retrieval practice was associated with increased RIF magnitude. Findings extend the current literature in three ways. First, they indicate that selective discussion of autobiographical events with children can cause forgetting of similar non-discussed events. Second, even when these non-discussed events are recalled, they contain sparser memory detail. Finally, when events are selectively discussed in greater detail, forgetting of similar non-discussed events occurs to a greater extent. PMID- 29156410 TI - How do we learn to "kill" in volleyball?: The role of working memory capacity and expertise in volleyball motor learning. AB - This study examines young volleyball players' learning of increasingly complex attack gestures. The main purpose of the study was to examine the predictive role of a cognitive variable, working memory capacity (or "M capacity"), in the acquisition and development of motor skills in a structured sport. Pascual Leone's theory of constructive operators (TCO) was used as a framework; it defines working memory capacity as the maximum number of schemes that can be simultaneously activated by attentional resources. The role of expertise in motor learning was also considered. The expertise of each athlete was assessed in terms of years of practice and number of training sessions per week. The participants were 120 volleyball players, aged between 6 and 26 years, who performed both working memory tests and practical tests of volleyball involving the execution of the "third touch" by means of technical gestures of varying difficulty. We proposed a task analysis of these different gestures framed within the TCO. The results pointed to a very clear dissociation. On the one hand, M capacity was the best predictor of correct motor performance, and a specific capacity threshold was found for learning each attack gesture. On the other hand, experience was the key for the precision of the athletic gestures. This evidence could underline the existence of two different cognitive mechanisms in motor learning. The first one, relying on attentional resources, is required to learn a gesture. The second one, based on repeated experience, leads to its automatization. PMID- 29156411 TI - Relationship between carotid artery sclerosis and blood pressure variability in essential hypertension patients. AB - OBJECTIVES: This study aimed to investigate the relationship between the presence of carotid arteriosclerosis (CAS) and blood pressure variability (BPV) in patients with essential hypertension. METHODS: One hundred and forty four essential hypertension patients underwent ambulatory BP monitoring for 24h after hospitalization. Common BPV metrics were calculated. General clinical parameters, including age, gender, height, weight, history of coronary heart disease, stroke, diabetes, hypertension, smoking and drink, were recorded. Biochemical indices were obtained from a blood test. Carotid intima-media thickness (IMT) and carotid plaques were assessed to separate patients into a non-CAS group (IMT<=0.9mm; n=82) and a CAS group (IMT>0.9mm; n=62). BPV metrics and clinical parameters were analyzed and compared between the two groups. Multivariate logistic regression analysis was performed to determine the associated risk factors of CAS. RESULTS: Multivariate logistic regression analysis revealed that two BPV metrics, the standard deviation of daytime systolic blood pressure (SSD) (OR: 1.587, 95%CI: 1.242-2.028), the difference between average daytime SBP and nighttime SBP (OR: 0.914, 95%CI: 0.855-0.977), as well as three clinical parameters (age, OR: 1.098, 95%CI: 1.034-1.167; smoking, OR: 4.072, 95%CI: 1.466-11.310, and fasting blood glucose, OR: 2.029, 95%CI: 1.407-2.928), were significant factors of CAS in essential hypertension patients. CONCLUSION: SSD, in combination with the ageing, smoking and FBG, has been identified as risk factors for CAS in patients with essential hypertension. PMID- 29156412 TI - A system-level mathematical model of Basal Ganglia motor-circuit for kinematic planning of arm movements. AB - In this paper, a novel system-level mathematical model of the Basal Ganglia (BG) for kinematic planning, is proposed. An arm composed of several segments presents a geometric redundancy. Thus, selecting one trajectory among an infinite number of possible ones requires overcoming redundancy, according to some kinds of optimization. Solving this optimization is assumed to be the function of BG in planning. In the proposed model, first, a mathematical solution of kinematic planning is proposed for movements of a redundant arm in a plane, based on minimizing energy consumption. Next, the function of each part in the model is interpreted as a possible role of a nucleus of BG. Since the kinematic variables are considered as vectors, the proposed model is presented based on the vector calculus. This vector model predicts different neuronal populations in BG which is in accordance with some recent experimental studies. According to the proposed model, the function of the direct pathway is to calculate the necessary rotation of each joint, and the function of the indirect pathway is to control each joint rotation considering the movement of the other joints. In the proposed model, the local feedback loop between Subthalamic Nucleus and Globus Pallidus externus is interpreted as a local memory to store the previous amounts of movements of the other joints, which are utilized by the indirect pathway. In this model, activities of dopaminergic neurons would encode, at short-term, the error between the desired and actual positions of the end-effector. The short-term modulating effect of dopamine on Striatum is also modeled as cross product. The model is simulated to generate the commands of a redundant manipulator. The performance of the model is studied for different reaching movements between 8 points in a plane. Finally, some symptoms of Parkinson's disease such as bradykinesia and akinesia are simulated by modifying the model parameters, inspired by the dopamine depletion. PMID- 29156413 TI - Anterior-posterior gradient differences in lobar and cingulate cortex cerebral blood flow in late-life depression. AB - Vascular pathology is common in late-life depression, contributing to changes in cerebral function. We examined whether late-life depression was associated with differences in cerebral blood flow (CBF) and whether such differences were related to vascular risk and cerebrovascular pathology, specifically white matter hyperintensity (WMH) volumes. Twenty-three depressed elders and 20 age- and sex matched elders with no psychiatric history completed cranial 3T MRI. MRI procedures included a pseudo-continuous Arterial Spin Labeling (pcASL) acquisition obtained while on room air and during a hypercapnia challenge allowing for calculation of cerebrovascular reactivity (CVR). Brain segmentation identified frontal, temporal, parietal and cingulate sub-regions in which CBF and CVR were calculated. The depressed group exhibited an anterior-posterior gradient in CBF, with lower CBF throughout the frontal lobe but higher CBF in the parietal lobe, temporal lobe, thalamus and hippocampus. A similar anterior to posterior gradient was observed in the cingulate cortex, with anterior regions exhibiting lower CBF and posterior regions exhibiting higher CBF. We did not observe any group differences in CVR measures. We did not observe significant relationships between CBF and CVR with vascular risk or WMH volumes, aside from an isolated finding associating higher WMH volumes with lower CBF in the rostral anterior cingulate cortex. Decreased anterior CBF in depressed elders might reflect decreased metabolic activity in these regions, while increased posterior CBF may represent either compensatory processes or different activity of posterior intrinsic functional networks. Future work should examine how these findings are related to compensatory changes with aging. PMID- 29156414 TI - Schizophrenia heterogeneity revisited: Clinical, cognitive, and psychosocial correlates of statistically-derived negative symptoms subgroups. AB - Traditional efforts to delineate the clinical heterogeneity of schizophrenia have been unsuccessful because of the absence of a valid, stable, and meaningful subtyping scheme. A clinically-informed nosology supported by multivariate statistical classification methods may provide a better approach for classifying schizophrenia. The goals of the current study were to 1) use multivariate classification methods to validate a clinical subtyping scheme based on the profile of negative symptoms; and 2) following validation to contrast the statistically-derived subgroups to ascertain distinguishing demographic, clinical, cognitive, and functional characteristics. In the current study, 706 people with schizophrenia completed measures of positive and negative symptoms, premorbid adjustment, cognition, and psychosocial functioning. Latent class analysis served to identify the number of negative symptom subgroups in schizophrenia. Next, statistical classification methods-Bayes Theorem and the Base Rate Classification Technique-were used to assign participants into the identified subgroups. Subgroups were compared on external validation variables not used in the classification process via logistic regression and discriminant function analysis. Latent class analysis supported a three-class model of schizophrenia that included deficit, persistent, and transient negative symptom subgroups. Posthoc comparisons showed that demographic characteristics, positive symptoms, premorbid adjustment, and cognitive profiles can distinguish the schizophrenia subgroups with moderate accuracy. The deficit subgroup had the greatest impairments in psychosocial functioning and quality of life variables. Findings suggest that schizophrenia encapsulates qualitatively distinct negative symptom subgroups that differ in their demographic, symptomatic, neuropsychological, and functional profiles. Schizophrenia heterogeneity reflects a combination of non-arbitrary subgroups and severity-based differences in negative symptoms. PMID- 29156416 TI - The natural context of wellbeing: Ecological momentary assessment of the influence of nature and daylight on affect and stress for individuals with depression levels varying from none to clinical. AB - This paper explores how everyday encounters with two natural phenomena -natural elements and daylight- influence affect and stress levels for people differing in mental health. Nature and daylight exposure both have well-documented beneficial effects on mental health and affect but to what extent their exposure has beneficial effects in daily life is currently under investigated, as is the question whether lower mental health would make one more, or instead, less responsive. To this end, an ecological momentary assessment protocol was employed for a period of 6 days. Fifty-nine participants varying in level of depressive symptoms from none to clinical completed momentary assessments of affect, stress, and their physical environment. Results indicate beneficial effects of nature and daylight on affect and some effects on stress and stress-related outcomes. For nature exposure, but not for daylight exposure, effects were stronger for those in higher need of restoration, stressing the importance of our everyday environment for mental wellbeing. PMID- 29156415 TI - Patterns of food and physical activity environments related to children's food and activity behaviors: A latent class analysis. AB - Relationships between food and physical activity (PA) environments and children's related behaviors are complex. Latent class analyses derived patterns from proximity to healthy and unhealthy food outlets, PA facilities and parks, and counts of residential dwellings and intersections. Regression analyses examined whether derived classes were related to food consumption, PA, and overweight among 404 low-income children. Compared to children living in Low PA-Low Food environments, children in High Intersection&Parks-Moderate Density&Food, and High Density-Low Parks-High Food environments, had significantly greater sugar sweetened beverage consumption (ps<0.01) and overweight/obesity (ps<0.001). Children in the High Density-Low Parks-High Food environments were more likely to walk to destinations (p = 0.01) Recognizing and leveraging beneficial aspects of neighborhood patterns may be more effective at positively influencing children's eating and PA behaviors compared to isolating individual aspects of the built environment. PMID- 29156417 TI - The effect of magnesium hydroxide-containing dentifrice using an extrinsic and intrinsic erosion cycling model. AB - OBJECTIVE: To evaluate, in vitro, the effect of Mg(OH)2 dentifrice, and the influence of the number of experimental days, on the extrinsic (citric acid -CA) and intrinsic (hydrochloric acid -HCl) enamel erosion models. DESIGN: Human enamel slabs were selected according to surface hardness and randomly assigned to 3 groups (n=9) as follows: non-fluoridated (negative control), NaF (1450ppm F- positive control) and Mg(OH)2 (2%) dentifrices. The slabs were daily submitted to a 2-h period of pellicle formation and, over a period of 5days, submitted to cycles (3*/day) of erosive challenge (CA 0.05M, pH=3.75 or HCl 0.01M, pH=2 for 30s), treatment (1min -1:3w/w of dentifrice/distilled water) and remineralization (artificial saliva/120min). Enamel changes were determined by surface hardness loss (SHL) for each day and mechanical profilometry analysis. Data were analyzed by two-way ANOVA followed by Tukey's test to % SHL and one-way ANOVA to profilometry (p<0.05). RESULTS: The number of experimental days influenced the erosion process for the two types of erosion models (p<0.001). Mg(OH)2-containing dentifrices were effective in reducing enamel extrinsic acid erosion as determined by % SHL (p<0.001) when compared to the control group, being better than positive control (p<0.001); however, the dentifrices were not effective for the intrinsic model (p=0.295). With regards to surface wear, no statistically significant differences were found among the groups for CA (p=0.225) and HCl (p=0.526). CONCLUSION: The findings suggest that Mg(OH)2 dentifrices might protect enamel against slight erosion, but protection was not effective for stronger acid erosion. PMID- 29156418 TI - Characterization of domestic pig spermatogenesis using spermatogonial stem cell markers in the early months of life. AB - In pigs, spermatogonial stem cells (SSCs), which include gonocytes and undifferentiated spermatogonia, are classically defined as being present till up to 2 months of life. However, knowledge about this transition from gonocytes to undifferentiated spermatogonia in pigs is limited. In this study, we characterized pig SSCs in neonatal (n = 6), one-month-old (1-mo-old, n = 6), two month-old (2-mo-old, n = 6), and adult testes (n = 6) anatomically, histologically, and immunohistologically. Anatomically, testicular circumference (TC) was measured at each development stage. Histologically, the presence or absence of seminiferous lumen was confirmed, and seminiferous tubule diameter (SD) was measured. Immunohistologically, changes in expression of pluripotent markers: DBA, UCHL1, ZBTB16, and POU5F1, were evaluated. For the analyses, cells positive for DBA, ZBTB16, UCHL1, and Vimentin per 150 round seminiferous tubules of cross sections from each testis were counted to evaluate the total number of positive cells, and then the positive cells per 100 Sertoli cells (UCHL1+/Sertoli, DBA+/Sertoli, and ZBTB16+/Sertoli) were calculated to compare the four developmental stages. Anatomically, piglet testes became larger with increasing age. Histologically, there was no seminiferous lumen in piglet testes, and only a single layer of cells was observed within the seminiferous tubules. Immunohistologically, the average number of DBA+/Sertoli, which indicates the number of gonocytes, was significant lowerthan that of UCHL1+/Sertoli (P < 0.05), which indicates the number of total SSCs in neonatal testes, suggesting that spermatogenesis had already started at birth. In 2-mo-old testes, although the average number of UCHL1+/Sertoli was the same as that in neonatal and 1-mo-old testes, the average number of DBA+/Sertoli decreased rapidly to an undetectable level. Moreover, the numbers of ZBTB16+/Sertoli and DBA+/Sertoli in neonatal testes were similar, and the number of ZBTB16+/Sertoli in 1-mo-old testes was significantly lower than that of DBA+/Sertoli (P < 0.05). Since ZBTB16 may be a marker for stable gonocytes or spermatogonia, the multiplication of the SSCs in neonatal testes may not be very vigorous, and this may be accelerated around one month of age. Consequently, our study clarified that differentiation of pig SSCs starts during the fetal period; then, transition of SSCs from gonocytes to undifferentiated spermatogonia is accelerated at one month of age and finally completed at two months of age. PMID- 29156419 TI - Segmentation of the hippocampus by transferring algorithmic knowledge for large cohort processing. AB - The hippocampus is a particularly interesting target for neuroscience research studies due to its essential role within the human brain. In large human cohort studies, bilateral hippocampal structures are frequently identified and measured to gain insight into human behaviour or genomic variability in neuropsychiatric disorders of interest. Automatic segmentation is performed using various algorithms, with FreeSurfer being a popular option. In this manuscript, we present a method to segment the bilateral hippocampus using a deep-learned appearance model. Deep convolutional neural networks (ConvNets) have shown great success in recent years, due to their ability to learn meaningful features from a mass of training data. Our method relies on the following key novelties: (i) we use a wide and variable training set coming from multiple cohorts (ii) our training labels come in part from the output of the FreeSurfer algorithm, and (iii) we include synthetic data and use a powerful data augmentation scheme. Our method proves to be robust, and it has fast inference (<30s total per subject), with trained model available online (https://github.com/bthyreau/hippodeep). We depict illustrative results and show extensive qualitative and quantitative cohort-wide comparisons with FreeSurfer. Our work demonstrates that deep neural network methods can easily encode, and even improve, existing anatomical knowledge, even when this knowledge exists in algorithmic form. PMID- 29156420 TI - A concise synthesis of rhamnan oligosaccharides with alternating alpha-(1->2)/(1 >3)-linkages and repeating alpha-(1->3)-linkages by iterative alpha-glycosylation using disaccharide building blocks. AB - A concise synthetic route to rhamnan oligosaccharides with alternating alpha-(1 >2)/(1->3)-linkages and repeating alpha-(1->3)-linkages is reported. This synthesis was achieved by iterative alpha-glycosylation using disaccharide building blocks and through orthogonal coupling between thioglycosides of L rhamnose. To investigate the detailed structure-activity relationship of rhamnan sulfate from Monostroma nitidum against herpes simplex virus type 2, the synthesized oligosaccharides, bearing different orthogonal protecting groups (i.e., benzoyl, benzyl, 2-naphthylmethyl, and/or p-methoxybenzyl) are expected to be suitable for conversion into a range of rhamnan structures with diverse sulfation patterns. PMID- 29156421 TI - Impaired mitochondrial respiration in human carotid plaque atherosclerosis: A potential role for Pink1 in vascular smooth muscle cell energetics. AB - BACKGROUND AND AIMS: DNA damage and mitochondrial dysfunction are thought to play an essential role in ageing and the energetic decline of vascular smooth muscle cells (VSMCs) essential for maintaining plaque integrity. We aimed to better understand VSMCs and identify potentially useful compensatory pathways that could extend their lifespan. Moreover, we wanted to assess if defects in mitochondrial respiration exist in human atherosclerotic plaques and to identify the appropriate markers that may reflect a switch in VSMC energy metabolism. METHODS: Human plaque tissue and cells were assessed for composition and evidence of DNA damage, repair capacity and mitochondrial dysfunction. Fresh plaque tissue was evaluated using high resolution oxygen respirometry to assess oxidative metabolism. Recruitment and processing of the mitochondrial regulator of autophagy Pink1 kinase was investigated in combination with transcriptional and protein markers associated with a potential switch to a more glycolytic metabolism. RESULTS: Human VSMC have increased nuclear (nDNA) and mitochondrial (mtDNA) damage and reduced repair capacity. A subset of VSMCs within plaque cap had decreased oxidative phosphorylation and expression of Pink1 kinase. Plaque cells demonstrated increased glycolytic activity in response to loss of mitochondrial function. A potential compensatory glycolytic program may act as energetic switch via AMP kinase (AMPK) and hexokinase 2 (Hex2). CONCLUSIONS: We have identified a subset of plaque VSMCs required for plaque stability that have increased mitochondrial dysfunction and decreased oxidative phosphorylation. Pink1 kinase may initiate a cellular response to promote a compensatory glycolytic program associated with upregulation of AMPK and Hex2. PMID- 29156423 TI - Under pressure: evolutionary engineering of yeast strains for improved performance in fuels and chemicals production. AB - Evolutionary engineering, which uses laboratory evolution to select for industrially relevant traits, is a popular strategy in the development of high performing yeast strains for industrial production of fuels and chemicals. By integrating whole-genome sequencing, bioinformatics, classical genetics and genome-editing techniques, evolutionary engineering has also become a powerful approach for identification and reverse engineering of molecular mechanisms that underlie industrially relevant traits. New techniques enable acceleration of in vivo mutation rates, both across yeast genomes and at specific loci. Recent studies indicate that phenotypic trade-offs, which are often observed after evolution under constant conditions, can be mitigated by using dynamic cultivation regimes. Advances in research on synthetic regulatory circuits offer exciting possibilities to extend the applicability of evolutionary engineering to products of yeasts whose synthesis requires a net input of cellular energy. PMID- 29156422 TI - Syndecan-1 in mechanosensing of nanotopological cues in engineered materials. AB - The cells of the vascular system are highly sensitive to biophysical cues from their local cellular microenvironment. To engineer improved materials for vascular devices and delivery of cell therapies, a key challenge is to understand the mechanisms that cells use to sense biophysical cues from their environment. Syndecans are heparan sulfate proteoglycans (HSPGs) that consist of a protein core modified with heparan sulfate glycosaminoglycan chains. Due to their presence on the cell surface and their interaction with cytoskeletal and focal adhesion associated molecules, cell surface proteoglycans are well poised to serve as mechanosensors of the cellular microenvironment. Nanotopological cues have become recognized as major regulators of cell growth, migration and phenotype. We hypothesized that syndecan-1 could serve as a mechanosensor for nanotopological cues and can mediate the responsiveness of vascular smooth muscle cells to nanoengineered materials. We created engineered substrates made of polyurethane acrylate with nanogrooves using ultraviolet-assisted capillary force lithography. We cultured vascular smooth muscle cells with knockout of syndecan-1 on engineered substrates with varying compliance and nanotopology. We found that knockout of syndecan-1 reduced alignment of vascular smooth muscle cells to the nanogrooves under inflammatory treatments. In addition, we found that loss of syndecan-1 increased nuclear localization of Yap/Taz and phospho-Smad2/3 in response to nanogrooves. Syndecan-1 knockout vascular smooth muscle cells also had elevated levels of Rho-associated protein kinase-1 (Rock1), leading to increased cell stiffness and an enhanced contractile state in the cells. Together, our findings support that syndecan-1 knockout leads to alterations in mechanosensing of nanotopographical cues through alterations of in rho-associated signaling pathways, cell mechanics and mediators of the Hippo and TGF-beta signaling pathways. PMID- 29156424 TI - Blink reflex under external emotional-stimuli in bipolar I and II disorders. AB - Bipolar disorder types I (BD I) and II (BD II) might present different cortico brainstem circuit dysfunctions under external emotions, which might be reflected by the blink reflex. We therefore invited 32 BD I and 23 BD II patients, and 46 healthy volunteers to answer the Mood Disorder Questionnaire, the Hypomania Checklist-32, and the Plutchik - van Praag Depression inventory, and to undergo the blink reflex test under external emotions (emotional pictures plus sounds) of Disgust, Erotica, Fear, Happiness, and Sadness. Compared to healthy controls, BD I showed prolonged R2/R2' latencies under most emotions, and their PVP scores were negatively correlated with the areas under curve (AUCs) of R2 and R2' under Erotica; and BD II showed reduced R2/R2' AUCs under all emotions. Moreover, R2' AUCs under Disgust, Fear, and Happiness were significantly reduced in BD II than those in BD I. Our results have shown that, irrespective of patients' on-going affective states, the R2/R2' components were delayed in BD I but suppressed in BD II under most external emotions. Our study provides some hints to distinguish the two types of bipolar disorder, referring to the cortico-brainstem circuit dysfunctions under external emotions. PMID- 29156425 TI - Perceived provider stigma as a predictor of mental health service users' internalized stigma and disempowerment. AB - Despite increasing awareness of stigma from mental health service providers as a barrier to recovery, little research has directly examined how it might influence the service users' self-perceptions and treatment experience. The present study examined the association of service users' perceived provider stigma with their experience of internalized stigma and disempowerment, two psychosocial constructs known to hinder recovery. Mental health service users (N = 350) completed questionnaires assessing perceived stigma from mental health service providers, including perceptions of negative affective reactions towards individual users and desired social distance towards people with mental illnesses across various life domains, internalized stigma, and disempowerment (i.e., diminished self efficacy and mastery) in mental health treatment settings. Structural equation modeling showed that both perceived negative affective reactions and perceived social distance were positively associated with disempowerment. Furthermore, these associations were significantly mediated by internalized stigma. These findings illuminate how perceived stigma from providers can "get under the skin" of mental health service users and contribute to their overall sense of disempowerment in mental health settings. They also highlight the need for future stigma reduction interventions to specifically target the attitudes and beliefs held by mental health professionals. PMID- 29156427 TI - A longitudinal analysis of the effects of neuroticism and extraversion on subjective well-being in patients with schizophrenia. AB - One in five patients with a psychotic disorder has persistent low subjective well being (SWB), which is associated with a poorer prognosis. In schizophrenia patients, personality traits are associated with SWB. The present study aims to evaluate whether neuroticism and extraversion influence SWB in patients with a psychotic disorder and healthy controls over the course of time. In 186 patients and 126 healthy control subjects, SWB was measured with the Subjective Well-being under Neuroleptics-20 (SWN) scale at baseline, three years and six years. We used the Five-Factor Inventory to assess neuroticism and extraversion. Mixed model analyses were conducted to investigate moderating associations of positive, negative and depressive symptoms, cannabis use, illness insight, weak social support and antipsychotic medication in patients. Higher neuroticism and lower extraversion were associated with lower SWB over six years in both groups. Personality traits did not have a differential effect on the course of SWB over time. In patients, a stable low SWB was found in 15.1% of the subjects. This group scored highest on neuroticism and lowest on extraversion compared to subjects with an increase in SWB or a stable high SWB. Our findings underline that personality traits are correlated to subjective well-being regardless of psychotic or depressive symptoms. PMID- 29156426 TI - Theory of mind and schizophrenia in young and middle-aged patients: Influence of executive functions. AB - Theory of Mind (ToM) is compromised in schizophrenia, and responsible for social disability. We aim to study the correlation between ToM deficits and Executive Functions (EF), using the Faux Pas Test (FPT) for ToM evaluation, Behavioral Assessment of the Dysexecutive Syndrome (BADS) and Wisconsin Card Sorting Test (WCST) for EF assessment. Two groups of patients with schizophrenia were included: 22 young (18-35 years-old) and 18 middle-aged (>50 years-old) Patients, compared to age-matched Controls. We found worst FPT performances in both groups of patients, but with a more generalized pattern of dysfunction in the middle aged patient group. This group had worse EF scores than both controls and younger patients. The association of EF with FPT items was uneven. In young patients only empathy (Q6) remained significant after controlling for EF and level of education, while in middle-aged patients faux pas explanation (Q4), false belief (Q5) and total scores remained significant. In young patients only affective TOM was impaired. No correlation was found with clinical symptoms, nor age at onset of the disease. We conclude that ToM deficit arises early during the course of the illness (already present in young patients), increases in middle-aged patients, and relates only partially with EF. PMID- 29156428 TI - Involvement of the Mab21l1 gene in calvarial osteogenesis. AB - The Mab-21 gene family is crucial for animal development. A deficiency in the Mab 21 genes associates with several defects, including skeletal malformation in mice and humans. In this study, we observed that mice lacking Mab21l1 displayed an unclosed fontanelle, suggesting impaired calvarial bone development. Cells isolated from the calvaria of these mice showed a greater osteoblast differentiation potential as evidenced by the abundance of mineralized bone nodules and higher expression levels of osteogenic markers than wild-type cells. Mab21l1-/- osteoblasts also expressed higher levels of adipocyte genes and interferon-regulated genes at early stages of osteogenesis. Rankl/Opg expression levels were also higher in Mab21l1-/- osteoblasts than in wild-type cells. These data suggest that Mab21l1 is involved in either the regulation of mesenchymal cell proliferation and differentiation or the balance between bone formation and resorption. An alteration in these regulatory machineries, therefore, may lead to insufficient bone formation, causing the bone phenotype in Mab21l1-/- mice. PMID- 29156429 TI - Kinetics of biogas production and chemical oxygen demand removal from compost leachate in an anaerobic migrating blanket reactor. AB - In this study, laboratory anaerobic migrating blanket reactor (AMBR) with four units was used to reduce and remove COD leachate of composting process; it was also used to determine the kinetic coefficients of COD removal and biogas and methane gas production in several different OLRs. The maximum concentration of organic matter entering the reactor was 100,000 mg/L and the reactor was under operation for 319 days. The results showed that the COD removal efficiency of AMBR in all concentrations of substrate entering the reactor was above 80%. First order model and Stover-Kincannon were used to investigate the kinetics of COD removal via AMBR biological process; in addition, the two models of Modified Stover-Kincannon and Van der Meer and Heertjes were used to check the kinetic constants of biogas and methane gas production. The results obtained from the models showed that the experimental data on COD removal were more consistent with the results obtained from Stover-Kincannon model (R2 = 0.999) rather than with the First-order model (R2 = 0.926). Kinetic constants calculated via Stover Kincannon model were as follows: saturation value constant (KB) and maximum utilization rate constants (Umax), respectively, were 208,600 mg/L d and 172,400 mg/L d. We investigated the linear relationship between the experimental data and the values predicted by the models; as compared with the values predicted by the First-order model, the values predicted by Stover-Kincannon model were closer to the values measured via experiments. Based on the results of the evaluation of kinetic coefficients of Stover-Kincannon model, with the migration of the leachate flow from unit 1 to unit 4, Umax value has fallen significantly. The values of maximum specific biogas production rate (Gmax) and proportionality constant (GB) obtained from the Stover-Kincannon model, respectively, were 35,714 ml/L d and 42.85 (dimensionless) and value of kinetic constant of Van der Meer and Heertjes (ksg) was 0.0473 ml CH4/mg COD. PMID- 29156430 TI - Chromium tolerance, bioaccumulation and localization in plants: An overview. AB - In the current industrial scenario, chromium (Cr) as a metal is of great importance, but poses a major threat to the environment. Phytoremediation provides an environmentally sustainable, ecofriendly, cost effective approach for environmental cleanup of Cr. This review presents the current status of phytoremediation research with particular emphasis on cleanup of Cr contaminated soil and water systems. It gives a detailed account of the work done by different authors on the Cr bioavailability, uptake pathway, toxicity and storage in plants following the phytoextraction mechanism. This paper also describes recent findings related to Cr localization in hyperaccumulator plants. It gives an insight into the processes and mechanisms that allow plants to remove Cr from contaminated sites under varying conditions. These detailed knowledge of changes in plant metabolic pool in response to Cr stress would immensely help understand and improve the phytoextraction process. Further, this review provides a detailed understanding of Cr uptake and detoxification mechanism by plants that can be applied in developing a suitable approach for a better applicability of the process. PMID- 29156432 TI - The effects of human drugs in Corbicula fluminea. Assessment of neurotoxicity, inflammation, gametogenic activity, and energy status. AB - The constant release of pharmaceuticals products to aquatic environment even at low concentrations (ng L-1 to ug L-1) could lead to unknown chronic effects to non-target organisms. The aim of this study was to evaluate neurotoxic responses, inflammation, gametogenic activity and energy status on the fresh water clam C. fluminea after exposure to different concentrations of caffeine (CAF), ibuprofen (IBU), carbamazepine (CBZ), novobiocin (NOV) and tamoxifen (TMX) for 21 days under laboratory conditions. During the assay, water was spiked every two days with CAF (0; 0.1; 5; 15; 50ugL-1), IBU (0; 0.1; 5; 10; 50ugL-1), CBZ, NOV, and TMX (0.1, 1, 10, 50ugL-1). After the exposure period, dopamine levels (DOP), monoamine oxidase activity (MAO), arachidonic acid cyclooxygenase activity (COX), vitellogenin-like proteins (VTG), mitochondrial electron transport (MET), total lipids (TLP), and energy expenditure (MET/TLP) were determined in gonad tissues, and acetyl cholinesterase activity (AChE) was determined in digestive gland tissues. Results showed a concentration-dependence response on biomarkers tested, except for MAO. Environmental concentrations of pharmaceuticals induced significant changes (p < 0.05) in the neurotoxic responses analyzed (CAF, CBZ and NOV increased DOP levels and CBZ inhibited AChE activity), inflammation (CAF induced COX), and energy status (MET and TLP increased after exposure to CBZ, NOV and TMX). Responses of clams were related to the mechanism of action (MoA) of pharmaceuticals. Biomarkers applied and the model organism C. fluminea constituted a suitable tool for environmental risk assessment of pharmaceutical in aquatic environment. PMID- 29156431 TI - Pathway of oxfendazole from the host into the worm: Trichuris suis in pigs. AB - It is well known that the efficacy of a single oral dose of benzimidazoles against Trichuris spp. infections in humans and animals is poor, but is currently still used in control programmes against human trichuriasis. However, the route of the benzimidazoles from the treated host to Trichuris remains unknown. As parts of adult Trichuris are situated intracellularly in the caecum, they might be exposed to anthelmintic drugs in the intestinal content as well as the mucosa. In this study, the pathway of oxfendazole and its metabolites was explored using a T. suis-pig infection model, by simultaneously measuring drug concentrations within the worms and the caecal mucosa, caecal tissue, caecal content and plasma of pigs over time after a single oral dose of 5 mg/kg oxfendazole. Additionally, for comparison to the in vivo study, drug uptake and metabolism of oxfendazole by T. suis was examined after in vitro incubation. Oxfendazole and metabolites were quantified by High Performance Liquid Chromatography. Multivariate linear regression analysis showed a strong and highly significant association between OFZ concentrations within T. suis and in plasma, along with a weaker association between OFZ concentrations in caecal tissue/mucosa and T. suis, suggesting that oxfendazole reaches T. suis after absorption from the gastrointestinal tract and enters the worms by the blood-enterocyte pathway. The fenbendazole sulfone level in T. suis was highly affected by the concentrations in plasma. In addition, correlations between drug concentrations in the host compartments, were generally highest for this metabolite. In comparison to oxfendazole, the correlation between plasma and content was particularly high for this metabolite, suggesting a high level of drug movement between these compartments and the possible involvement of the enterohepatic circulation. PMID- 29156433 TI - Evaluating features of periphytic diatom communities as biomonitoring tools in fresh, brackish and marine waters. AB - The aims of this study were to assess the biodiversity of periphytic diatom assemblages in fresh, brackish and marine waterbodies of Korea, and to assess the effect of environmental and anthropogenic factors on parameters such as the quantity and biovolume of lipid bodies and deformations of diatoms as early warning measures of anthropogenic impact. Diatom samples were collected from 31 sites (14 freshwater, 10 brackish and 7 marine), which included less impacted (upstream) and impacted (downstream) sites in each water type. Our results showed higher abundance and biodiversity of periphytic diatoms at the less impacted sites in terms of species richness, Shannon index, cell count and biovolume of the communities than at the impacted sites for freshwater and estuarine sites, but not for marine sites. 84 diatom species were noted in freshwater, 80 in brackish water and 40 in marine waters. In comparison to diatoms of the impacted sites, those of less impacted freshwater, brackish and marine sites had less lipid bodies (also less biovolume) and a lower percentage of teratological frustules, and showed more mobile forms in the community. Principal component analysis (PCA) also showed clear segregation of impacted from less impacted sites by the extent of the presence of lipid bodies (higher both in number and biovolume) and deformities in diatom frustules. Pearson correlation analysis revealed that lipid body induction and deformities were positively correlated with metals (Cd, Co, Cr, Cu, Fe, Pb and Zn) and nutrients (total phosphorus and total nitrogen), whereas they showed negative correlation with salinity, dissolved oxygen, suspended solutes and pH. Life-forms, lipid bodies and deformities in diatoms may be an effective biomonitoring tool for assessing biological effects of pollutants in non-marine aquatic ecosystems in Korea. PMID- 29156434 TI - We prefer what we fear: A response preference bias mimics attentional capture in spider fear. AB - The extent to which emotionally significant stimuli capture visual attention remains elusive because a preference for reporting or choosing emotionally significant stimuli could mimic attentional capture by these stimuli. We conducted two prior-entry experiments to disentangle whether phobic and fear relevant stimuli capture attention or merely produce a response bias in spider fearful participants. Prior entry denotes the effect that attended stimuli are perceived earlier than unattended stimuli as indicated by temporal order judgments. We presented phobic (spiders), fear-relevant (snakes) and neutral stimuli in pairs with varying temporal onset. The participants' task was to indicate which stimulus was presented first (Experiment 1) or second (Experiment 2). In the first experiment, spider-fearful but not control participants indicated that they had perceived spiders as occurring earlier in time, suggesting a prior-entry effect for spiders in this group. But surprisingly, in the second experiment, spider-fearful participants indicated more frequently that they had seen spiders as being presented second. This finding rules out a genuine prior-entry effect and instead suggests a strong preference for the response option associated with the feared animal. This response bias may result from a hypervigilance toward the feared stimulus and contribute to maintaining avoidance behavior in individuals with specific phobias. PMID- 29156435 TI - More than A to B: Understanding and managing visitor spatial behaviour in urban forests using public participation GIS. AB - Planning and management needs up-to-date, easily-obtainable and accurate information on the spatial and social aspects of visitor behaviour in order to balance human use and impacts, and protection of natural resources in public parks. We used a web-based public participation GIS (PPGIS) approach to gather citizen data on visitor behaviour in Helsinki's Central Park in order to aid collaborative spatial decision-making. The study combined smartphone GPS tracking, route drawing and a questionnaire to examine differences between user groups in their use of formal trails, off-trail behaviour and the motivations that affect it. In our sample (n = 233), different activity types were associated with distinctive spatial patterns and potential extent of impacts. The density mapping and statistical analyses indicated three types of behaviour: predominantly on or close to formal trails (runners and cyclists), spatially concentrated off-trail behaviour confined to a few informal paths (mountain bikers), and dispersed off-trail use pattern (walkers and dog walkers). Across all user groups, off-trail behaviour was mainly motivated by positive attraction towards the environment such as scenic view, exploration, and viewing flora and fauna. Study findings lead to several management recommendations that were presented to city officials. These include reducing dispersion and the spatial extent of trampling impacts by encouraging use of a limited number of well established informal paths away from sensitive vegetation and protected habitats. PMID- 29156436 TI - Impact of changes in labor resources and transfers of land use rights on agricultural non-point source pollution in Jiangsu Province, China. AB - This study systematically explores the likely mechanisms driving the effect of the transfer of agricultural land use rights (ALURs) on agricultural non-point source pollution (ANSP) in the context of changing agricultural labor resources. It quantitatively estimates the direction and degree of this influence from a microeconomic perspective using data from rural households. The results reveal that economies of scale caused by ALURs transfers contribute to reducing both the ANSP and marginal costs of inputs. Changes in agricultural labor resources lead to reductions in agricultural labor supply and negatively impact on ANSP. Encouraging farmers to participate in ALURs transfers, therefore, helps to reduce ANSP. The government and related departments should implement policies that support farmers who decide to rent an entire village's land or the adjacent land to achieve economies of scale. Accelerating the development of small farm machinery that is suitable for smaller farm plots and the elderly can serve to reduce the use of chemical fertilizer and promote green production and sustainable agricultural development. PMID- 29156437 TI - Home composting using different ratios of bulking agent to food waste. AB - The negative environmental impacts associated with home composting may be due to the absence of a defined operation criteria for the degradation process. In addition to the potentially low environmental impact in terms of energy and water usage, which is minimal to the manufacture of the composting unit and avoiding the processing and transportation of waste or byproduct, composting at home can also promote a reduction in the emission of unpleasant gases. The proportion of the food waste and bulking agents in the composting mixture may be decisive to fulfill good practices of waste stabilization. The aim of this study was to investigate how different ratios of bulking agent and organic household waste can affect the progress and outcome of the composting process. Three treatments, varying in the ratio of rice husk: raw fruit and vegetable leftovers (70:30, 50:50, 30:70; v:v) were used in a home composting system on a pilot scale. Results show that the proportion of starting materials used in the composting mixture influenced the degradation of organic matter, nitrogen dynamics of the process and its toxicity on germinating plants. The proportions with greater amounts of food waste had higher concentrations of mineral matter, higher peak temperature, and a better initial carbon-to-nitrogen ratio, while the proportion containing 70% of bulking agent lacked odors and leachate generation and showed a low nitrogen loss. A higher proportion of food waste presented better conditions for microbiological development and less time to obtain characteristics of matured composts. A higher proportion of bulking agents resulted in favorable conditions for household handling and less potential for environmental impacts. PMID- 29156438 TI - Videolaryngoscope versus Macintosh laryngoscope for tracheal intubation in adults with obesity: A systematic review and meta-analysis. AB - STUDY OBJECTIVE: Videolaryngoscopy has become more common since the 2000s. Despite several anecdotal reports in the literature, it remains unclear whether videolaryngoscopy is superior to direct Macintosh laryngoscopy for tracheal intubation in adults with obesity. This systematic review and meta-analysis focused on prospective randomised trials comparing videolaryngoscopes with the Macintosh laryngoscope for tracheal intubation in adults with obesity. DESIGN: Systematic review, Meta-analysis SETTING: Operating room, Obesity patients MEASUREMENTS: Data on success rate, intubation time, and glottic visualisation during tracheal intubation were extracted from the identified studies. In a subgroup analysis, we also compared the parameters for videolaryngoscopes with a tracheal tube guide channel and those without a tracheal tube guide channel. Data from individual trials were combined, and the DerSimonian and Laird random-effect model was used to calculate either the pooled relative risk (RR) or the weighted mean difference (WMD) as well as the corresponding 95% confidence intervals (CI). MAIN RESULTS: Eleven articles describing 13 trials met the inclusion criteria. The performance of videolaryngoscopes was superior to that of the Macintosh laryngoscope for all outcomes. (Success rate; RR=1.11, 95% CI 1.04 to 1.18, p=0.001, I2=63%, Intubation time; WMD=-16.1, 95% CI -31.1 to -1.10, p=0.04, I2=97%, Glottic visualisation; RR=1.19, 95% CI 1.09 to 1.30, p<0.0001, I2=76%) In the subgroup analysis, the performance of both types of videolaryngoscopes (with and without a tracheal tube guide channel) was superior to that of the Macintosh laryngoscope, except for intubation time with the videolaryngoscopes without a tracheal tube guide channel. CONCLUSIONS: Videolaryngoscopes were superior to the Macintosh laryngoscope for tracheal intubation in adults with obesity. (GRADE score: low or very low.). PMID- 29156440 TI - Pharmaceutical and personal care products-induced stress symptoms and detoxification mechanisms in cucumber plants. AB - Contamination of agricultural soils by pharmaceutical and personal care products (PPCPs) resulting from the application of treated wastewater, biosolids and animal wastes constitutes a potential environmental risk in many countries. To date a handful of studies have considered the phytotoxicity of individual PPCPs in crop plants, however, little is known about the effect of PPCPs as mixtures at environmentally relevant levels. This study investigated the uptake and transport, physiological responses and detoxification of a mixture of 17 PPCPs in cucumber seedlings. All PPCPs were detected at higher concentrations in roots compared to leaves, with root activity inhibited in a dose-dependent manner. At 5 50 MUg/L, the mature leaves exhibited burnt edges as well as a reduction in photosynthesis pigments. Reactive oxygen species (ROS) production and lipid peroxidation increased with increasing PPCP concentrations; and their contents were greater in roots than in leaves for all PPCP treatments. Enzymes involved in various functions, including oxidative stress (superoxide dismutase and ascorbate peroxidase) and xenobiotic metabolism (peroxidase and glutathione S-transferase), were elevated to different levels depending on the PPCP concentration. Glutathione content gradually increased in leaves, while a maxima occurred at 0.5 MUg L-1 PPCPs in roots, followed by a decrease thereafter. This study illustrated the complexity of phytotoxicity after exposure to PPCP mixtures, and provided insights into the molecular mechanisms likely responsible for the detoxification of PPCPs in higher plants. PMID- 29156439 TI - Air pollution over the North China Plain and its implication of regional transport: A new sight from the observed evidences. AB - High concentrations of the fine particles (PM2.5) are frequently observed during all seasons over the North China Plain (NCP) region in recent years. In NCP, the contributions of regional transports to certain area, e.g. Beijing city, are often discussed and estimated by models when considering an effective air pollution controlling strategy. In this study, we selected three sites from southwest to northeast in NCP, in which the concentrations of air pollutants displayed a multi-step decreasing trend in space. An approach based on the measurement results at these sites has been developed to calculate the relative contributions of the minimal local emission (MinLEC) and the maximum regional transport (MaxRTC) to the air pollutants (e.g., SO2, NO2, CO, PM2.5) in Beijing. The minimal influence of local emission is estimated by the difference of the air pollutants' concentrations between urban and rural areas under the assumption of a similar influence of regional transport. Therefore, it's convenient to estimate the contributions of local emission from regional transport based on the selective measurement results instead of the complex numerical model simulation. For the whole year of 2013, the averaged contributions of MinLEC (MaxRTC) for NO2, SO2, PM2.5 and CO are 61.7% (30.7%), 46.6% (48%), 52.1% (40.2%) and 35.8% (45.5%), respectively. The diurnal variation of MaxRTC for SO2, PM2.5 and CO shows an increased pattern during the afternoon and reached a peak (more than 50%) around 18:00, which indicates that the regional transport is the important role for the daytime air pollution in Beijing. PMID- 29156441 TI - Modeling spray drift and runoff-related inputs of pesticides to receiving water. AB - Pesticides move to surface water via various pathways including surface runoff, spray drift and subsurface flow. Little is known about the relative contributions of surface runoff and spray drift in agricultural watersheds. This study develops a modeling framework to address the contribution of spray drift to the total loadings of pesticides in receiving water bodies. The modeling framework consists of a GIS module for identifying drift potential, the AgDRIFT model for simulating spray drift, and the Soil and Water Assessment Tool (SWAT) for simulating various hydrological and landscape processes including surface runoff and transport of pesticides. The modeling framework was applied on the Orestimba Creek Watershed, California. Monitoring data collected from daily samples were used for model evaluation. Pesticide mass deposition on the Orestimba Creek ranged from 0.08 to 6.09% of applied mass. Monitoring data suggests that surface runoff was the major pathway for pesticide entering water bodies, accounting for 76% of the annual loading; the rest 24% from spray drift. The results from the modeling framework showed 81 and 19%, respectively, for runoff and spray drift. Spray drift contributed over half of the mass loading during summer months. The slightly lower spray drift contribution as predicted by the modeling framework was mainly due to SWAT's under-prediction of pesticide mass loading during summer and over prediction of the loading during winter. Although model simulations were associated with various sources of uncertainties, the overall performance of the modeling framework was satisfactory as evaluated by multiple statistics: for simulation of daily flow, the Nash-Sutcliffe Efficiency Coefficient (NSE) ranged from 0.61 to 0.74 and the percent bias (PBIAS) < 28%; for daily pesticide loading, NSE = 0.18 and PBIAS = -1.6%. This modeling framework will be useful for assessing the relative exposure from pesticides related to spray drift and runoff in receiving waters and the design of management practices for mitigating pesticide exposure within a watershed. PMID- 29156442 TI - Charting a path towards non-destructive biomarkers in threatened wildlife: A systematic quantitative literature review. AB - Threatened species are susceptible to irreversible population decline caused by adverse sub-lethal effects of chemical contaminant exposure. It is therefore vital to develop the necessary tools to predict and detect these effects as early as possible. Biomarkers of contaminant exposure and effect are widely applied to this end, and a significant amount of research has focused on development and validation of sensitive and diagnostic biomarkers. However, progress in the use biomarkers that can be measured using non-destructive techniques has been relatively slow and there are still many difficulties to overcome in the development of sound methods. This paper systematically quantifies and reviews studies that have aimed to develop or validate non-destructive biomarkers in wildlife, and provides an analysis of the successes of these methods based on the invasiveness of the methods, the potential for universal application, cost, and the potential for new biomarker discovery. These data are then used to infer what methods and approaches appear the most effective for successful development of non-destructive biomarkers of contaminant exposure in wildlife. This review highlights that research on non-destructive biomarkers in wildlife is severely lacking, and suggests further exploration of in vitro methods in future studies. PMID- 29156443 TI - Ensuring quality pharmacokinetic analyses in antimicrobial drug development programs. AB - Pharmacokinetic studies and analyses can be expensive, time consuming, and labor intensive. However, it is crucial to understand that much of what happens in antimicrobial drug development, such as dose-selection and clinical study design, can be optimized with a strong understanding of the underlying pharmacokinetics of an agent. In this way, pharmacokinetics forms the bedrock of a pharmacometric approach to antimicrobial development. Thus, pharmacokinetic analyses must be considered an integral part of a drug's development strategy and studies must be planned and designed accordingly. This paper provides a brief overview of pharmacokinetic analysis methods, including best practices and their use in the context of a drug development program. In addition we will conclude with an overview of proper design and conduct of pharmacokinetic studies to optimize their use in evaluating clinical study data. PMID- 29156444 TI - Survival of microbes in Earth's stratosphere. AB - The remarkable survival of microorganisms high above the surface of the Earth is of increasing interest. At stratospheric levels, multiple stressors including ultraviolet and ionizing radiation, low temperatures, hypobaric conditions, extreme desiccation, and nutrient scarcity are all significant challenges. Our understanding of which microorganisms are capable of tolerating such stressful conditions has been addressed by stratospheric sample collection and survival assays, through launching and recovery, and exposure to simulated conditions in the laboratory. Here, we review stratospheric microbiology studies providing our current perspective on microbial life at extremely high altitudes and discuss implications for health and agriculture, climate change, planetary protection, and astrobiology. PMID- 29156445 TI - Autologous tenocyte implantation into shoulder tendon pathology in an elite swimmer. AB - INTRODUCTION: The use of novel bioengineer treatment techniques such as Autologous Tenocyte Implantation (ATI) have shown promising improvements in both pain ratings and functional outcomes in elbow, gluteal and shoulder tendon pathology. This case will review the injury timeline of ATI intervention in an elite male swimmer with subscapularis tendon pathology and investigate whether ATI has a concomitant healing effect associated with improved functional outcomes. METHODS: A palmaris longus tendon biopsy was performed and cells were expanded by in-vitro culture. Autologous tenocytes were injected into the subscapularis site identified. Three blinded radiologists reported on pre and post shoulder MRIs using the same 3T MRI protocol. A validated rating scale for severity of tendinopathy (0-3) and degree of tear (0-3) was used and hand-held Dynamometry (HHD) strength was recorded. RESULTS: Independent blinded radiology review demonstrated a significant reduction in tear size and improved tendon morphology. IR strength on HHD returned to baseline strength levels post ATI (231 253N) 6 weeks post intervention. The athlete returned to full training (volume and intensity) pain free and international level competition at 4 months post ATI. CONCLUSION: An athlete who had previously undergone unsuccessful conservative management demonstrated significant improvement in function and in tendon morphology post intervention. PMID- 29156446 TI - Who is watching user-generated alcohol posts on social media? AB - AIM: To examine students' exposure to user-generated alcohol content on social media, and identify characteristics (i.e. demographics, personality traits, alcohol use, alcohol-related cognitions, and social media factors) associated with monthly or more frequent exposure. METHOD: College/university students (N=11,236) in Bergen, Norway, completed a web-survey measuring exposure to alcohol on social media - both frequency and interpretations of alcohol content. The survey included questions regarding demographics, personality, alcohol related cognitions, and general use of social media and alcohol. Binary logistic regressions were run to identify characteristics associated with monthly or more frequent exposure to alcohol-related posts on social media. RESULTS: A total of 96.7% had been exposed to alcohol-related posts, exposure to posts with a positive valence of alcohol were more frequently reported than exposure to content with a negative valence of alcohol. Reports of monthly or more frequent exposure to alcohol on social media were associated with a range of characteristics, among these younger age, being native Norwegian, lower extroversion and higher agreeableness and self-monitoring scores, higher alcohol use, stronger descriptive norms for alcohol use among online-friends, and more frequent logins to social media. CONCLUSIONS: Students' potential inflated alcohol norms (originating from social media) should be addressed. The results suggest that exposure may be determined by high alcohol use and membership in demographical groups associated with high alcohol use, an increased attentiveness towards others' behavior, and excessive social media use. Future studies investigating the relationship between alcohol exposure on social media and later alcohol use should control for such factors. PMID- 29156447 TI - PD-1 blockade in advanced NSCLC: A focus on pembrolizumab. AB - Non-small cell lung cancer (NSCLC) is one of the most prevalent cancers and is responsible for a large proportion of all cancer-related deaths. Current treatment options are inadequate, reflecting a substantial unmet clinical need. Increasing knowledge regarding the mechanisms and genetic aberrations underlying tumor development and growth has heralded a new era of therapy in oncology, moving away from indiscriminate cytotoxic chemotherapy toward more finely focused, targeted medicine. The development of small-molecule drugs and monoclonal antibodies directed toward specific components of dysfunctional molecular or immune pathways, and mutated genes specific to particular cancer types, is leading the field to more personalized and less toxic treatment options, many of which have demonstrated greater efficacy and survival benefits than their chemotherapeutic counterparts. Particularly successful examples are agents that interfere with the programmed death 1 (PD-1) pathway, which many tumors can hijack to avoid immune surveillance and editing. Pembrolizumab, a monoclonal antibody directed at PD-1 that blocks the engagement between PD-1 and its ligands, has been explored as a treatment for solid tumors, and demonstrated survival benefits in several studies. The use of PD-1 inhibitors such as nivolumab and pembrolizumab in advanced cancers is widespread, and pembrolizumab is available in more than 60 countries for at least one of the following: advanced melanoma, PD-L1-expressing NSCLC, head and neck squamous cell carcinoma, and adult and pediatric patients with refractory classical Hodgkin's lymphoma. This work provides a brief overview of the role of pembrolizumab in the treatment of advanced (recurrent/metastatic) NSCLC. PMID- 29156448 TI - (De)hydratases-recent developments and future perspectives. AB - Hydratases have gained attention as alternative to chemical catalysts for their ability to add and eliminate water with high regio-selectivity, stereo selectivity and enantio-selectivity. Recently, especially cofactor-independent hydratases came into research focus as they are of particular interest for industrial application. The investigation of the substrate scope as well as mutagenesis studies combined with high-resolution crystal structures and bioinformatic methods shed light on this promising enzyme class. This review presents latest findings in the field of fatty acid hydratases, linalool dehydratase isomerase and carotenoid hydratases focusing on mechanistic und structural aspects as well as the expansion of the substrate scope and new applications in organic synthesis. PMID- 29156449 TI - Nutrition in the management of gastrointestinal diseases and disorders: the evidence for the low FODMAP diet. AB - A growing interest from both physicians and patients is fueling research in the interaction of symptoms related to irritable bowel syndrome (IBS) and diet, particularly the low FODMAP diet. Recent studies further define the role of these short-chain fermentable carbohydrates on IBS symptoms and their effects in different parts of the gastrointestinal tract. Mounting evidence supports the use of a low FODMAP diet in the clinical setting, but this dietary approach is not without potential drawbacks. This review illustrates the mechanisms by which the low FODMAP diet leads to improvement in IBS symptoms, summarizes the available clinical evidence, and offers practical advice regarding implementation of this dietary strategy. PMID- 29156450 TI - Current Indications and Outcome of Pulmonary Resections for Tuberculosis Complications in Ibadan, Nigeria. AB - OBJECTIVES: To review the current indications and outcome of pulmonary resections for tuberculosis (TB) at the Cardiothoracic Surgery Unit of the University College Hospital, Ibadan, Nigeria. SUBJECTS AND METHODS: A retrospective case series review of patients who had lung resections from January 2014 to January 2017 was performed. Data obtained from medical records included demographics, presenting symptoms, indication for surgery, preoperative evaluation and preparation, operative procedure, postoperative complications, and follow-up. The presence of TB in the patients was confirmed by detecting pathological changes suggestive of TB and/or past history of pulmonary TB associated with its anatomical complications such as cavitation and bronchiectasis. Data were analysed using descriptive statistics. RESULTS: Ten patients had pulmonary resections during this study period. The median age was 33.5 years (range: 3-50). The indication for lung resection was massive or persistent haemoptysis, and 2 patients also had aspergilloma. Six patients (60%) had lobectomy, 1 had a bilobectomy, and the remaining 3 had pneumonectomy. Complications included partial wound dehiscence in 2 patients, 1 of whom also had postoperative empyema thoracis. One patient died immediately due to haemorrhage. Follow-up ranged from 6 to 37 months. CONCLUSION: This study showed that the factors for a good outcome in patients presenting with massive or recurrent haemoptysis from TB complications were initial stabilization and multidisciplinary care. Hence, improved awareness of high-standard care to encourage inclusion of patients with TB complications in the surgical care protocol as part of national control programmes is recommended. PMID- 29156451 TI - Impact of Stressful Life Events on Patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: There is a general notion that stressful life events may cause mental and physical health problems. OBJECTIVES: We aimed to describe stressful life events reported by patients with chronic obstructive pulmonary disease (COPD) and to assess their impact on health outcomes and behaviors. METHODS: Two hundred and sixty-six primary care patients who participated in the ICE COLD ERIC cohort study were asked to document any stressful life events in the past 3 years. We assessed the before-after (the event) changes for symptoms of depression and anxiety, health status, dyspnea-related quality of life, exacerbations, cigarette use, and physical activity. We used linear regression analysis to estimate the crude and adjusted magnitude of the before-after changes. RESULTS: About 41% (110/266) of patients reported the experience of any stressful life events and "death of relatives/important persons" was most common (31%). After accounting for age, sex, living status, lung function, and anxiety/depression status at baseline, experiencing any stressful life events was associated with a 0.9-point increase on the depression scale (95% CI 0.3 to 1.4), a 0.8-point increase on the anxiety scale (95% CI 0.3 to 1.3), and a 0.8-point decrease in the physical activity score (95% CI -1.6 to 0). CONCLUSIONS: Experiencing stressful life events was associated with a small to moderate increase in symptoms of depression and anxiety in COPD, but no discernable effect was found for other physical outcomes. However, confirmation of these results in other COPD cohorts and identification of patients particularly vulnerable to stressful life events are needed. PMID- 29156452 TI - An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence. AB - This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Mullerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents. PMID- 29156453 TI - Use of Genetic Testing after Abnormal Screening Ultrasound: A Descriptive Cohort Study. AB - BACKGROUND/AIMS: The study aimed to characterize the use of genetic testing after abnormal screening ultrasound. METHODS: We performed a retrospective review of patients undergoing genetic testing after abnormal ultrasound. Genetic evaluation consisted of noninvasive prenatal screening (NIPS) or amniocentesis. Classification of ultrasound findings, type of genetic testing, and results were collected. RESULTS: A total of 139 subjects underwent genetic evaluation after abnormal screening ultrasound. Screening via NIPS was pursued by 61 (44%) patients while 78 (56%) proceeded directly to amniocentesis. Patients electing for amniocentesis had more cardiac, neurologic, and gastrointestinal malformations while soft markers for aneuploidy prompted more NIPS screening. Results were negative in 85% of the NIPS group compared to 60% of the amniocentesis group. Only 8% of patients who underwent NIPS proceeded to diagnostic testing. CONCLUSION: Patients pursuing NIPS after abnormal ultrasound had more soft markers of aneuploidy. Patients pursuing diagnostic testing were more likely to have major structural malformations and more total abnormalities identified. Patients who proceeded directly to amniocentesis were more likely to have abnormal genetic testing. PMID- 29156455 TI - [The Overrated Impact of Inhaled Substances (LABA, LAMA, ICS) on Exacerbation Rates in COPD]. AB - Numerous studies have shown that exacerbation rates in COPD can be significantly reduced by long acting beta-2-agonists (LABA), long acting anticholinergic agents (LAMA) and inhaled steroids (ICS). Elaborate and extensive investigations however failed to prove that the reduction in exacerbation rates leads to life prolongation. As opposed to this, numerous studies have shown a reduction in life expectancy with increasing number and severity of exacerbations.This review aimed at comparing these studies and to elaborate the relevance and reduction of exacerbations rates by LABA, LAMA and ICS application through effect size calculation by means of Cohens' d. These studies display a common pattern. The reduction of exacerbation rates is only being achieved for less severe exacerbations (Cohens' d max. 0.21). For more severe exacerbations and for the comparison of different substances Cohens' d remains below 0.1, indicating that the effect of the medications is practically irrelevant. The impact of LABA's, LAMA's and ICS on exacerbation rates in COPD patients is obviously overrated. PMID- 29156454 TI - Site-selective and stereoselective functionalization of non-activated tertiary C H bonds. AB - The synthesis of complex organic compounds usually relies on controlling the reactions of the functional groups. In recent years, it has become possible to carry out reactions directly on the C-H bonds, previously considered to be unreactive. One of the major challenges is to control the site-selectivity because most organic compounds have many similar C-H bonds. The most well developed procedures so far rely on the use of substrate control, in which the substrate has one inherently more reactive C-H bond or contains a directing group or the reaction is conducted intramolecularly so that a specific C-H bond is favoured. A more versatile but more challenging approach is to use catalysts to control which site in the substrate is functionalized. p450 enzymes exhibit C-H oxidation site-selectivity, in which the enzyme scaffold causes a specific C-H bond to be functionalized by placing it close to the iron-oxo haem complex. Several studies have aimed to emulate this enzymatic site-selectivity with designed transition-metal catalysts but it is difficult to achieve exceptionally high levels of site-selectivity. Recently, we reported a dirhodium catalyst for the site-selective functionalization of the most accessible non-activated (that is, not next to a functional group) secondary C-H bonds by means of rhodium carbene-induced C-H insertion. Here we describe another dirhodium catalyst that has a very different reactivity profile. Instead of the secondary C-H bond, the new catalyst is capable of precise site-selectivity at the most accessible tertiary C-H bonds. Using this catalyst, we modify several natural products, including steroids and a vitamin E derivative, indicating the applicability of this method of synthesis to the late-stage functionalization of complex molecules. These studies show it is possible to achieve site-selectivity at different positions within a substrate simply by selecting the appropriate catalyst. We hope that this work will inspire the design of even more sophisticated catalysts, such that catalyst-controlled C-H functionalization becomes a broadly applied strategy for the synthesis of complex molecules. PMID- 29156456 TI - Impact of Truncated Area on Point Estimate and Intra-Subject Variability in Bioequivalence of Dutasteride with Long Half-Life. AB - PURPOSE: To investigate the effect of using truncated area under the curve (AUC0 72) on bioequivalence of dutasteride with long half-life in point estimate and intra-subject variability. METHODS: Fifteen subjects were enrolled in this single dose, open-label, randomized two-way crossover design following an overnight fasting with five-week washout period. Plasma samples were collected to 72 h and 144 h following drug administration and dutasteride were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The pharmacokinetic parameters for bioequivalence assessment were AUC0-72 and AUC0-144. RESULTS: The estimated point and the 90% confidence intervals were 91.07% (84.54-98.11%) for AUC0-72 and 91.43% (84.65-98.75%) for AUC0-144, that is, within the ranges for acceptance of bioequivalence. The intra-subject variability's were 11.45% for AUC0-72 and 11.87% for AUC0-144. CONCLUSIONS: There was no statistically significant difference in point estimated and intra-subject variability between truncated AUC at 72 h and 144=h and the truncated AUC (AUC0-72) approach could be considered for bioequivalence assessment for dutasteride. PMID- 29156457 TI - Discovery of Novel Thiazol-2-Amines and Their Analogues as Bioactive Molecules: Design, Synthesis, Docking and Biological Evaluation. AB - A simple and highly efficient procedure for the synthesis of novel thiazol-2 amines, via Mannich reaction with secondary amines, is described. The newly synthesized derivatives 8(A-E): and 9(A-E): were characterized by 1H NMR, 13C NMR, IR, Mass spectroscopy and elemental analysis. All the derivatives were evaluated for their in-vitro anti-microbial activity against a panel of pathogenic strains of bacteria and fungi. The SAR showed that the secondary amines had a significant impact on the in-vitro antimicrobial activity of this class of agents. The most potent analogue N-((1H-benzo[d]imidazol-1-yl)methyl)-N (2(trifluoromethyl)phenyl)-4,5-dihydrothiazol-2-amine (8C): showed excellent inhibition with MIC (zoi) 6.25 (22.5), 25 (21.5) and 25 (18) ug/mL against E. coli, S. typhi and P. aeruginosa respectively as compared to the standard drug. Molecular docking results suggest that compound exhibited inhibitory activity by binding of the title compound within the active sites of the inhibiting Enoyl ACP reductase, Lipid A, Pyridoxal kinase and type I DHQase enzymes. The compound exhibited promising anti-microbial activity which can be further explored as potential lead for the development of cheaper, safe, effective and potent drugs against resistant microbial parasites. PMID- 29156459 TI - ? PMID- 29156458 TI - [Imaging in Rhabdomyolysis with Ectopic (dystrophic) Calcification]. PMID- 29156460 TI - ? PMID- 29156461 TI - ? PMID- 29156462 TI - ? PMID- 29156464 TI - [Spectacle Glasses - an Overview]. AB - This paper will give some support to choose the right spectacle lens. The question "what is the proper spectacle lens" cannot be answered exactly, the answer depends on many parameters. Depending on the visual task, the right spectacle lens is a compromise between lens properties. These properties are pointed out in the paper. PMID- 29156465 TI - [Pseudophacic additive lenses]. AB - Implantation of artificial intraocular lenses (IOL) after cataract removal today represents the standard of care in the field of anterior segment surgery. In refractive lens exchange cases the natural lens is replaced by an IOL to correct different types of refractive situations. In the majority of the operations the refractive result is satisfying with only few deviations from target refraction.But daily practice reveals some outliers from the intended corrections with the need for further refractive enhancements, respectively. Especially odd eyes with short or long axial length, corneal astigmatism, ceratoconus or after corneal laser vision correction are more or less candidates for refractive surprises. Laser corneal surgery and additional intraocular implants are both established surgical approaches to achieve this goal in pseudophacic eyes. In paediatric cataract surgery for congenital cataracts implantation of add-on lenses can be helpful to adjust refraction according to eyeball development and prevent amblyopia.This article presents an overview about currently available implants and techniques using additional lenses to correct residual refractive errors. Furthermore, new implants for special indications like macular degeneration are addressed. A thorough evaluation of risk and benefit for each patient group and materials used are provided. PMID- 29156466 TI - [Retinal Artery Occlusions]. AB - Retinal artery occlusions are acute vascular diseases. Very often they are caused by an embolisation. Rarely a thrombosis is caused by an arteriitis. In the acute phase diagnosis in most of the cases can be made by ophthalmoscopy due to the whitish retinal edema and in central retinal artery occlusion the cherry red spot. Difficulties in making the diagnosis can occur in the chronic stage, especially after reperfusion of the retinal vessels, when the fundus colour returned to normal again. Several diagnostic procedures help to make the diagnosis. Unfortunately there is no generally accepted therapeutic approach for retinal artery occlusions. The visual prognosis often is poor. It is very important to rule out underlying diseases because the patients have an increased risk for stroke or cardiovascular events. PMID- 29156467 TI - [Diagnosis and Therapy of Iris Lesions]. AB - The most common iris lesions are iris nevi, iris melanomas and iris pigment epithelium cysts. However, there is an abundance of rare differential diagnoses that have to be considered, including other melanocytic and non-melanocytic lesions. Diagnostic tools include the slit lamp examination, gonioscopy, tonometry, transillumination, ultrasound biomicroscopy (UBM), optical coherence tomography, fluorescein angiography and standardized photography-assisted documentation. The timely identification of malignant lesions (i.e. iris melanoma) is paramount. To assess malignancy criteria of iris nevi, the ABCDEF rule (age young, blood, clock hour inferior, diffuse growth, ektropion uveae, feathery margins) can be applied. Statistically, up to 11% of iris nevi may develop into iris melanomas within 20 years. TNM Staging follows the 2010 AJCC cancer staging manual and helps determine the optimal treatment strategy. Treatment options include radiotherapy, such as plaque brachytherapy and proton beam radiation therapy, as well as surgical excision. Both the surgical and the radiotherapeutic approaches show comparable local tumor control rates. However, the spectrum of therapy-related side effects and complications may differ amongst treatment modalities. After initial treatment, patients should be followed up every 3 - 6 months. Tumor-related mortality ranges between 0 - 11% and is significantly lower than in other uveal melanomas. A prognostic value of common genetic alterations, which have been identified as significant prognostic factors in posterior uveal melanoma, could not be shown for iris melanoma. PMID- 29156468 TI - Toxoplasma gondii-Associated Bilateral Panuveitis and Encephalitis after Bone Marrow Transplantation. PMID- 29156469 TI - [Efficacy of Vertical Muscle Transpositions with and without Simultaneous Rectus Muscle Recession for Unilateral Sixth Nerve Palsy]. AB - BACKGROUND: We report results of a modified vertical muscle transposition procedure according to the Hummelsheim principle - with and without simultaneous rectus muscle recession - for unilateral sixth nerve palsy. We examine the influence of the duration of the palsy, preoperative angle of squint and preoperative abductive capacity on surgical results of the procedures. PATIENTS AND METHODS: Retrospective study of 29 consecutive patients with unilateral abducens nerve palsy who underwent surgery between 2001 and 2012. 21 patients had a modified vertical rectus muscle transposition according to the Hummelsheim principle (HUM); 8 patients had this operation combined with simultaneous medial rectus muscle recession (HUM+I). Surgery was performed at least 9 months after onset of the palsy (HUM: 9 to 98, median 19, mean 30 months; HUM+I: 12 to 65, median 25, mean 29 months). RESULTS: The median preoperative angle of squint (far distance) for the HUM group was 27.0 degrees (20.0 to 45.0; mean 28.1 degrees ), and for the HUM+I group 30.5 degrees (21.8 to 50.0; mean 33.4 degrees ). The median preoperative abductive capacity was for - 1,6 mm before midline (- 8.0 to + 1.2; mean - 1.8 mm) for the HUM group, and - 3.0 mm before midline (- 10.0 to - 1.0; mean - 4.1 mm) for the HUM+I group. The median postoperative angle of squint (far distance) was 0 degrees (- 11.3 to + 20.0; mean 0.1 degrees ) for the HUM group, and - 2.3 degrees (- 11.3 to + 12.0; mean - 2.1 degrees ) for the HUM+I group. The median postoperative abductive capacity was 1.0 mm (0 to + 3.0; mean + 1.1 mm) for the HUM group, and 1.1 mm (- 1.2 to + 3.0; mean + 0.9 mm) for the HUM+I group. The median reduction of squint angle was 27.0 degrees (9.1 to 45.0; mean 28.0 degrees ) for the HUM group, and 36.8 degrees (25.2 to 41.4; mean 35.5 degrees ) for the HUM+I group. The median effect on abductive capacity was 2.5 mm (0 to 11.0; mean + 2.9 mm) for the HUM group, and 4.6 mm (2.4 to 8.8; mean + 5.0 mm) for the HUM+I group. In the HUM group, the effect on squint angle reduced with the duration of the palsy, whereas, in the HUM+I group, the effect improved with the duration of the palsy. CONCLUSIONS: For patients with unilateral sixth nerve palsy, simultaneous medial rectus recession increases the effect of modified vertical rectus muscle surgery according to the Hummelsheim principle. The duration of the palsy is a relevant parameter for the selection of a sole or combined intervention with medial rectus recession. PMID- 29156470 TI - [Functional and Anatomic Outcomes of Primary and Secondary Internal Limiting Membrane Transplantation in Large and Persistent Macular Holes]. AB - BACKGROUND: The gold standard therapy for full-thickness macular holes (FTMH) is vitrectomy (PPV) with peeling of the internal limiting membrane (ILM), gas tamponade of the vitreous cavity and postoperative face-down positioning. Nevertheless, eyes with large macular holes (> 400 um) and surgical failures remain difficult to manage. Recently, ILM transplantation (ILM-TX) techniques were developed with acceptable results, advocating different mechanisms of hole closure: in such a setting, the ILM could serve as a scaffold for neuronal tissue in the pedicle ILM flap technique or the ILM could induce a contraction of the FTMH rims through shrinking of a folded ILM plug. PATIENTS/MATERIAL AND METHODS: This retrospective study evaluates the functional and anatomic outcomes following ILM-TX for large FTMH and failed FMTH surgery. Large holes (group 1) were treated by the pedicle flap and the plug technique. Persistent holes following vitrectomy and ILM peeling (group 2) were treated with the plug technique. All ILM-TX were performed under perfluorocarbon liquid (PFCL) with a subsequent silicone oil tamponade. RESULTS: In group 1 (6 eyes), three eyes had a free ILM graft and three eyes underwent a pedunculated ILM-TX. The mean best corrected visual acuity (BCVA, LogMar) before primary ILM-TX was 1.18 +/- 0.54 with a mean initial hole size of 681 +/- 106 um and a photoreceptor defect (PRD) of 1829 +/- 474 um. Five of six eyes showed a postoperative anatomical macular hole closure (83%). The mean BCVA after a mean follow-up of 9.3 +/- 5.1 months was 0.83 +/- 0.31 after a free ILM graft and 0.95 +/- 0.79 after a pedunculated ILM flap. The PRD reduced to 1781 +/- 713 um after a free ILM graft and 1148 +/- 378 um after a pedunculated ILM flap. In group 2 (7 eyes), all patients had failed initial macular hole surgery closure. Prior to free ILM-TX BCVA was 1.05 +/- 0.41, the hole size was 433 +/- 183 um and PRD was 2012 +/- 718 um. After a mean of 9.6 +/- 4.1 months following ILM-TX, in six of seven eyes the FTMH hole was closed (86%), BCVA improved to 0.53 +/- 0.34 and the PRD shortened to 843 +/- 291 um. CONCLUSION: In most cases, with large FTMH or holes after failed vitrectomy plus ILM peeling, ILM-TX allows a hole closure. Functional outcomes show stabilization and sometimes even a slight improvement. PMID- 29156471 TI - ? PMID- 29156472 TI - ? PMID- 29156473 TI - [Calculations of Intraocular Lenses Implant Intended to Minimise Postoperative Vertical Anisometropia]. AB - Modern measuring instruments calculate the values of intraocular lenses implant preoperatively. This calculation is performed separately for each eye. No information is available on the postoperative binocular effect, especially in regard to vertical anisometropia (difference between the values of the vertical principial meridians of the right and the left spectacle lens). In this publication, a computer programme is introduced to calculate the values of intraocular lenses implant for both eyes together. With this program, vertical anisometropia is only 0.5 D. PMID- 29156474 TI - CT and MRI Findings in Cerebral Aspergilloma. AB - PURPOSE: Invasive aspergillosis usually affects immunocompromised patients. It carries a high risk of morbidity and mortality and usually has a nonspecific clinical presentation. Early diagnosis is essential in order to start effective treatment and improve clinical outcome. MATERIALS AND METHODS: In a retrospective search of the PACS databases from two medical centers, we identified 9 patients with histologically proven cerebral aspergilloma. We systematically analyzed CT and MRI imaging findings to identify typical imaging appearances of cerebral aspergilloma. RESULTS: CT did not show a typical appearance of the aspergillomas. In 100 % (9/9) there was a rim-attenuated diffusion restriction on MRI imaging. Multiple hypointense layers in the aspergillus wall, especially on the internal side, were detected in 100 % on T2-weighted imaging (9/9). Aspergillomas were T1 hypointense in 66 % of cases (6/9) and partly T1-hyperintense in 33 % (3/9). In 78 % (7/9) of cases, a rim-attenuated diffusion restriction was detected after contrast agent application. CONCLUSION: Nine cases were identified. Whereas CT features were less typical, we observed the following imaging features on MRI: A strong, rim-attenuated diffusion restriction (9/9); onion layer-like hypointense zones, in particular in the innermost part of the abscess wall on T2-weighted images (9/9). Enhancement of the lesion border was present in the majority of the cases (7/9). KEY POINTS: . There are typical MRI imaging features of aspergillomas.. . However, these findings could be affected by the immune status of the patient.. . Swift identification of aspergilloma imaging patterns is essential to allow for adequate therapeutic decision making.. CITATION FORMAT: . Gartner F, Forstenpointner J, Ertl-Wagner B et al. CT and MRI Findings in Cerebral Aspergilloma. Fortschr Rontgenstr 2018; 190: 967 - 970. PMID- 29156475 TI - Transient Severe Respiratory Motion Artifacts After Application of Gadoxetate Disodium: What We Currently Know. AB - BACKGROUND: Gadoxetate disodium is an intracellular contrast agent for magnetic resonance imaging (MRI) of the liver. Recent publications revealed that injection of gadoxetate disodium can lead to imaging artifacts due to transient severe motion (TSM) in the arterial phase of contrast-enhanced liver MRI. In this review we present and discuss published frequencies of TSM, contrast injection and image acquisition protocols, potential risk factors, and proposed strategies to avoid or minimize the effects of TSM. METHOD: Two reviewers independently searched the PubMed search engine for "transient severe motion artifact" and related terms. Reference lists of retrieved articles were also searched. The two reviewers selected in consensus nine studies that reported both frequencies of TSM and potential risk factors. Study data were extracted by both reviewers, and disagreement was resolved by consensus. RESULTS AND CONCLUSION: TSM is caused by impaired breath-hold ability after gadoxetate disodium injection and occurs in 5 22 % of patients. The dose of applied contrast agent, repeated exposure to gadoxetate disodium, high BMI and pulmonary disease have been described as potential risk factors for TSM. However, there are only few concordant results on this topic and the pathophysiology of TSM has not been identified. Proposed strategies for the prevention of TSM are slow injection rates and low doses of diluted gadoxetate disodium. Accelerated and free-breathing MRI sequence protocols and breath-hold training may minimize the effects of TSM. Further prospective studies are needed to confirm these strategies and to identify the underlying mechanism of TSM. KEY POINTS: . TSM occurs in 5 - 22 % of patients after gadoxetate disodium injection.. . Potential risk factors of TSM are dose, repeated exposure, BMI, pulmonary disease.. . The underlying mechanism for TSM has not been identified.. . Slow injection rates and diluted gadoxetate disodium may prevent TSM.. . Accelerated image acquisition or free-breathing sequences may mitigate the effects of TSM.. CITATION FORMAT: . Well L, Weinrich JM, Adam G et al. Transient Severe Respiratory Motion Artifacts After Application of Gadoxetate Disodium: What We Currently Know. Fortschr Rontgenstr 2018; 190: 20 - 30. PMID- 29156476 TI - Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome with Shoulder Joint Involvement: A Case Report with Literature Review. PMID- 29156477 TI - ? PMID- 29156479 TI - ? PMID- 29156478 TI - ? PMID- 29156480 TI - [Frailty: Prevalence in the Resident Population of Germany 70 - 79 Years of Age - a Population-Based Approach]. AB - In all countries life expectancy is rising, and many older persons spend a longer period in good health. Nevertheless, frailty is present in older people and can be considered as a risk factor for limitations. The "German Health Interview and Examination Survey for Adults" (DEGS1) 2008 - 2011 comprised interviews, examinations and tests. Data on 1110 community-dwelling people aged 70 to 79 years participating in DEGS1 with full records on frailty were analysed. Physical frailty was defined as exhaustion (SF-36 item), low grip strength, slowness (Timed Up-and-Go test > 15 seconds or unable to perform) and low physical activity (no sports or exertion). In men 36,6% (CI 32,2 - 41,2) were classified as pre-frail, 2,5% (CI 1,4 - 4,4) as frail; in women 41,8% (CI 37,3 - 46,5) were classified as pre-frail, and 2,9% (CI 1,9 - 4,5) as frail. Frail persons significantly show more polypharmacy, recurrent falls, receive more frequently nursing care financial benefits, are officially recognized disabled and have poor social support. This population-based information may help to identify frail people with high risk of adverse health outcomes. Prediction models in operative anaesthesiology for specific health care settings should be developed. PMID- 29156481 TI - [Why and How Should I Assess Frailty? A Guide for the Preoperative Anesthesia Clinic]. AB - Introduction: Frailty is a condition of decreased physiological reserves seen in approx. one third of elderly anesthesiological patients, and affecting many aspects of treatment as well as outcome. Although there are over 60 measurement instruments, frailty assessment is still poorly implemented. Understanding why and how to assess frailty is key to its implementation in preoperative anesthesia clinics. Method: After presenting the impact of perioperative frailty and the benefits of an early diagnosis on health related quality of life, we present an overview of the most important tools that can be used in the preoperative frailty assessment. Results: Early diagnosis offer several optimization opportunities for the perioperative period. The most efficient frailty assessment tools are presented and discussed, including physical, cognitive, and psychosocial aspects. Conclusion: Frailty assessments vary immensely in terms of required time, equipment, and expertise. We recommend at least one test for each domain of frailty, so as to obtain a more holistic view of the patient's physiological reserve. The implementation of an adequate and consistent preoperative frailty assessment has the potential to improve patient safety as well as short and long term outcomes. PMID- 29156482 TI - [How to Reduce the Rate of Postoperative Complications in Frail Patients?] AB - Frail patients are more prone to develop complications during and after surgery. As the syndrome becomes more common, recognition and special management of frail patients in the perioperative setting is becoming crucial to improve short- and long-term outcomes. Based on current literature and guidelines, we present a compilation of strategies that could be employed to reduce postoperative complication rates in frail patients. Due to their impaired response to stressors, potential perioperative hazards to frail patients are identified and discussed. This includes the risk of dehydration, hypothermia, cardiovascular decompensation, unusual drug reactions, and delirium. The benefits of early mobilization and nutritional support are also discussed. If frailty is detected preoperatively, thus alerting the team about the increased risk of complications, strategies can be implemented in the perioperative setting to improve the chances of successful recovery. PMID- 29156483 TI - [Interventions for Assisting Geriatric Patients with Frailty Before Surgery]. AB - Frailty is a complex syndrome leading to a higher vulnerability in elderly patients, especially during and after surgery. It is characterized by the simultaneous presence of at least three of five phenotypical symptoms: unintentional weight loss, exhaustion, muscle weakness, slow walking speed, and low activity levels. The presence of two of these symptoms is often labelled as pre-frailty.By identifying these symptoms of frailty, medical teams can plan and perform suitable interventions prior to a planned surgery in order to lower these risk factors and to avoid complications, such as delir, hospital re-admission, loss of independence, and increased mortality. Examples for these interventions are pre-surgery rehabilitation and Delirium Management Units (DMU).This article describes the frailty syndrome and its associated consequences for complications during and after surgery. Additionally, clinical assessments for identifying frailty symptoms as well as pre- and post-surgical interventions to reduce these risk factors are presented. PMID- 29156484 TI - [Perioperative Intravenous Fluid Therapy in Children]. AB - The objective of this consensus-based S1 Guideline for perioperative fluid therapy in children is to maintain or re-establish the child's homeostasis. Therefore, the perioperative fasting times should be as short as possible to prevent patient discomfort, dehydration, and ketoacidosis. For the intraoperative background infusion a physiologically composed balanced isotonic electrolyte solution (BS) with 1 - 2.5% glucose is recommended to maintain normal glucose concentrations and to avoid hyponatremia, hyperchloremia, and lipolysis. Additional BS without glucose can be used in patients with circulatory instability until the desired effect is achieved. The additional use of colloids is recommended to recover normovolemia and to avoid fluid overload when crystalloids alone are not sufficient and blood products are not indicated. Monitoring should be extended in cases with major surgery. PMID- 29156485 TI - [Cervical Plexus Blocks]. AB - Blockades of the cervical plexus are established anesthesia procedures, not only in the context of operative carotid revascularizations. Recent investigations define inner sonoanatomic landmarks as well as the importance of brain nerves for innervation in the neck region. The present practice-oriented article discusses current study results, alternative techniques (ultrasound- versus landmark guided) and fields of application (carotid desobliteration, surgery of the shoulder, ear and infraclavicular region). PMID- 29156486 TI - [Update in Obstetric Anesthesia - Tried and Trusted Methods, Controversies and New Perspectives]. AB - Since 1975, a plethora of lectures within the context of annual meetings relevant for the clinical care has been summarized in "what's new in obstetric anesthesia" by the society for Obstetric anesthesia and Perinatology which can be recommended to everyone interested in anaesthesiology in the delivery room. After the death of Gerard W. Ostheimer, Professor of Anaesthesiology at Brigham and Women's Hospital in Boston, Massachusetts, it became renamed the Gerard W. Ostheimer "what's new in obstetric anesthesia" lecture to honor his contributions to regional anesthesia and obstetric anaesthesia. Each year the event held by selected professional representatives and their imprint in leading anesthesia journals give insight into a critical appraisal of recent literature and the possible consequences for - but not only - the anaesthetic delivery room practice.A similar event has been established in Germany for more than 16 years (first event on April 1, 2000, most recently held on February 27, 2016, in Munich): the obstetrical anesthesia symposium of the academic working group "regional anesthesia and obstetrical anesthesia" [1], [2]."Evergreens" or "hot topics" with regard to anaesthesiological delivery room practice are presented and discussed regularly. The lectures often reveal the subtle change of the issues being debated much earlier than traditional textbook chapters do. This manuscript summarizes important findings from the last symposium held in 2016. Part I focuses on relevant causes for maternal morbidity and mortality as well as preventive measures, pregnancy in obese patients and sepsis in obstetric anaesthesia. Part II addresses established standards and new perspectives in the direct obstetric setting regarding epidural analgesia, post-dural puncture headache, anaesthesia and analgesia during and after caesarean section, haemodynamic monitoring during cesarean section and postpartum haemorrhage. PMID- 29156487 TI - Evolution and molecular mechanism of four-electron reducing ferredoxin-dependent bilin reductases from oceanic phages. AB - : Ferredoxin-dependent bilin reductases (FDBRs) are a class of enzymes reducing the heme metabolite biliverdin IXalpha (BV) to form open-chain tetrapyrroles used for light-perception and light-harvesting in photosynthetic organisms. Thus far, seven FDBR families have been identified, each catalysing a distinct reaction and either transferring two or four electrons from ferredoxin onto the substrate. The newest addition to the family is PcyX, originally identified from metagenomics data derived from phage. Phylogenetically, PcyA is the closest relative catalysing the reduction of BV to phycocyanobilin. PcyX, however, converts the same substrate to phycoerythrobilin, resembling the reaction catalysed by cyanophage PebS. Within this study, we aimed at understanding the evolution of catalytic activities within FDBRs using PcyX as an example. Additional members of the PcyX clade and a remote member of the PcyA family were investigated to gain insights into catalysis. Biochemical data in combination with the PcyX crystal structure revealed that a conserved aspartate-histidine pair is critical for activity. Interestingly, the same residues are part of a catalytic Asp-His-Glu triad in PcyA, including an additional Glu. While this Glu residue is replaced by Asp in PcyX, it is not involved in catalysis. Substitution back to a Glu failed to convert PcyX to a PcyA. Therefore, the change in regiospecificity is not only caused by individual catalytic amino acid residues. Rather the combination of the architecture of the active site with the positioning of the substrate triggers specific proton transfer yielding the individual phycobilin products. ENZYMES: Suggested EC number for PcyX: 1.3.7.6 DATABASES: The PcyX X-ray structure was deposited in the PDB with the accession code 5OWG. PMID- 29156488 TI - Association of programmed death ligand-1 (PD-L1) expression with treatment outcomes in patients with BRAF mutation-positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib. AB - The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1+ melanoma, with hazard ratios (HRs; PD-L1+ vs. PD-L1- ) of 0.70 (95% CI, 0.46-1.07) and 0.69 (95% CI, 0.42 1.13) for PFS and OS, respectively. However, in patients treated with cobimetinib plus vemurafenib, a similar trend was not observed with HRs (PD-L1+ versus PD-L1- ) of 1.04 (95% CI, 0.66-1.68) and 0.94 (95% CI, 0.57-1.57) for PFS and OS, respectively. The combination cobimetinib plus vemurafenib appears to overcome the poor prognosis associated with low PD-L1 expression. PMID- 29156490 TI - "The citizen is stepping into a new role"-Policy interpretations of patient and public involvement in Finland. AB - Involving patients and the public in healthcare decision-making is on the policy agenda in several countries. The aim of our study was to describe and analyse the development of patient and public involvement from a policy perspective. We argue that the language of health policies can influence both the aims and the development of involvement methods. In this study health policy documents, which have guided the development of patient and public involvement in Finland have been analysed using methods of Membership Categorisation Analysis. This has enabled us to explore how health policy documents categorise patients and the wider public in relation to involvement and orientate the involvement activities in which people are able to participate. Different set of abilities, expectations, responsibilities and opportunities is attached to the categories of patient, risk group, service user, customer and expert. Health policy documents often equate involvement with choice making by service users and customers; or as involvement in service development by experts. In both of these cases, involvement is depicted as an individual activity that requires personal responsibility and specialist knowledge. Although involvement opportunities have overall increased, they are primarily available to people that are "participation ready" and able to adopt roles promoted in policies. Health policy documents produce one interpretation of involvement, nevertheless it is important that diverse groups of patients, the public and health professionals participate in the discussion and express their views, which may differ from those of policy makers. PMID- 29156489 TI - An adherent mucus layer attenuates the genotoxic effect of colibactin. AB - The human gastrointestinal tract is a complex ecosystem in which epithelial cells and microorganisms of the intestinal microbiota live in symbiosis. Certain members of the microbiota, in particular Escherichia coli strains of the B2 phylotype, carry the polyketide synthase-island encoding the genotoxin colibactin. Colibactin is a nonribosomal peptide or polyketide-nonribosomal peptide hybrid of still unsolved structure, which induces DNA double strand breaks (DSBs) in eukaryotic cells. However, direct contact between live bacteria and host cell is required in order to elicit these genotoxic effects. In this study, we used a variety of cell culture models, among them, a 3D cell culture approach based on decellularised small intestinal submucosa, to investigate whether the intestinal mucus layer has the potential to interfere with colibactin activity. We demonstrate that the expression of mucins and the formation of an adherent mucus layer significantly increased with increasing complexity of cell culture. Moreover, we show that the presence of an adherent mucus layer on epithelial cells attenuates the genotoxic activity of colibactin, by preventing the induction of DNA-DSBs. Removal of the adherent mucus layer restored the occurrence of DNA-DSBs. PMID- 29156491 TI - Longterm calcineurin inhibitor therapy and brain function in patients after liver transplantation. AB - Calcineurin inhibitors (CNIs) frequently induce neurological complications early after orthotopic liver transplantation (OLT). We hypothesize that longterm CNI therapy after OLT causes dose-dependent cognitive dysfunction and alteration of brain structure. In this study, 85 OLT patients (20 with CNI-free, 35 with CNI low-dose, and 30 with standard-dose CNI immunosuppression) underwent psychometric testing and cerebral magnetic resonance imaging approximately 10 years after OLT to assess brain function and structural brain alterations. A total of 33 healthy patients adjusted for age, sex, and education served as controls. Patients receiving CNI showed a significantly worse visuospatial/constructional ability compared with controls (P <= 0.04). Furthermore, patients on low-dose CNI therapy had an overall impaired cognitive function compared with controls (P = 0.01). The tacrolimus total dose and mean trough level were negatively correlated to cognitive function. CNI doses had been adjusted in 91% of the patients in the low dose and CNI-free groups in the past due to CNI-induced kidney damage. Patients treated with CNI showed significantly more white matter hyperintensities (WMH) than patients on CNI-free immunosuppression and controls (P < 0.05). Both the mean cyclosporine A and tacrolimus trough levels correlated significantly with WMH. In conclusion, longterm CNI therapy carries a risk of cognitive dysfunction especially in patients who already showed nephrotoxic side effects indicating an increased susceptibility of these patients against toxic CNI effects. This subgroup of patients might benefit from a change to CNI-free immunosuppression. Liver Transplantation 24 56-66 2018 AASLD. PMID- 29156492 TI - Bayesian monotonic errors-in-variables models with applications to pathogen susceptibility testing. AB - Drug dilution (MIC) and disk diffusion (DIA) are the 2 most common antimicrobial susceptibility assays used by hospitals and clinics to determine an unknown pathogen's susceptibility to various antibiotics. Since only one assay is commonly used, it is important that the 2 assays give similar results. Calibration of the DIA assay to the MIC assay is typically done using the error rate bounded method, which selects DIA breakpoints that minimize the observed discrepancies between the 2 assays. In 2000, Craig proposed a model-based approach that specifically models the measurement error and rounding processes of each assay, the underlying pathogen distribution, and the true monotonic relationship between the 2 assays. The 2 assays are then calibrated by focusing on matching the probabilities of correct classification (susceptible, indeterminant, and resistant). This approach results in greater precision and accuracy for estimating DIA breakpoints. In this paper, we expand the flexibility of the model-based method by introducing a Bayesian 4-parameter logistic model (extending Craig's original 3-parameter model) as well as a Bayesian nonparametric spline model to describe the relationship between the 2 assays. We propose 2 ways to handle spline knot selection, considering many equally spaced knots but restricting overfitting via a random walk prior and treating the number and location of knots as additional unknown parameters. We demonstrate the 2 approaches via a series of simulation studies and apply the methods to 2 real data sets. PMID- 29156493 TI - Virtual reality for stroke rehabilitation. AB - BACKGROUND: Virtual reality and interactive video gaming have emerged as recent treatment approaches in stroke rehabilitation with commercial gaming consoles in particular, being rapidly adopted in clinical settings. This is an update of a Cochrane Review published first in 2011 and then again in 2015. OBJECTIVES: Primary objective: to determine the efficacy of virtual reality compared with an alternative intervention or no intervention on upper limb function and activity.Secondary objectives: to determine the efficacy of virtual reality compared with an alternative intervention or no intervention on: gait and balance, global motor function, cognitive function, activity limitation, participation restriction, quality of life, and adverse events. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (April 2017), CENTRAL, MEDLINE, Embase, and seven additional databases. We also searched trials registries and reference lists. SELECTION CRITERIA: Randomised and quasi randomised trials of virtual reality ("an advanced form of human-computer interface that allows the user to 'interact' with and become 'immersed' in a computer-generated environment in a naturalistic fashion") in adults after stroke. The primary outcome of interest was upper limb function and activity. Secondary outcomes included gait and balance and global motor function. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials based on pre-defined inclusion criteria, extracted data, and assessed risk of bias. A third review author moderated disagreements when required. The review authors contacted investigators to obtain missing information. MAIN RESULTS: We included 72 trials that involved 2470 participants. This review includes 35 new studies in addition to the studies included in the previous version of this review. Study sample sizes were generally small and interventions varied in terms of both the goals of treatment and the virtual reality devices used. The risk of bias present in many studies was unclear due to poor reporting. Thus, while there are a large number of randomised controlled trials, the evidence remains mostly low quality when rated using the GRADE system. Control groups usually received no intervention or therapy based on a standard-care approach. PRIMARY OUTCOME: results were not statistically significant for upper limb function (standardised mean difference (SMD) 0.07, 95% confidence intervals (CI) -0.05 to 0.20, 22 studies, 1038 participants, low-quality evidence) when comparing virtual reality to conventional therapy. However, when virtual reality was used in addition to usual care (providing a higher dose of therapy for those in the intervention group) there was a statistically significant difference between groups (SMD 0.49, 0.21 to 0.77, 10 studies, 210 participants, low-quality evidence). SECONDARY OUTCOMES: when compared to conventional therapy approaches there were no statistically significant effects for gait speed or balance. Results were statistically significant for the activities of daily living (ADL) outcome (SMD 0.25, 95% CI 0.06 to 0.43, 10 studies, 466 participants, moderate-quality evidence); however, we were unable to pool results for cognitive function, participation restriction, or quality of life. Twenty-three studies reported that they monitored for adverse events; across these studies there were few adverse events and those reported were relatively mild. AUTHORS' CONCLUSIONS: We found evidence that the use of virtual reality and interactive video gaming was not more beneficial than conventional therapy approaches in improving upper limb function. Virtual reality may be beneficial in improving upper limb function and activities of daily living function when used as an adjunct to usual care (to increase overall therapy time). There was insufficient evidence to reach conclusions about the effect of virtual reality and interactive video gaming on gait speed, balance, participation, or quality of life. This review found that time since onset of stroke, severity of impairment, and the type of device (commercial or customised) were not strong influencers of outcome. There was a trend suggesting that higher dose (more than 15 hours of total intervention) was preferable as were customised virtual reality programs; however, these findings were not statistically significant. PMID- 29156494 TI - Comparative analysis of vestibular ecomorphology in birds. AB - The bony labyrinth of vertebrates houses the semicircular canals. These sense rotational accelerations of the head and play an essential role in gaze stabilisation during locomotion. The sizes and shapes of the semicircular canals have hypothesised relationships to agility and locomotory modes in many groups, including birds, and a burgeoning palaeontological literature seeks to make ecological interpretations from the morphology of the labyrinth in extinct species. Rigorous tests of form-function relationships for the vestibular system are required to support these interpretations. We test the hypothesis that the lengths, streamlines and angles between the semicircular canals are related to body size, wing kinematics and flying style in birds. To do this, we applied geometric morphometrics and multivariate phylogenetic comparative methods to a dataset of 64 three-dimensional reconstructions of the endosseous labyrinth obtained using micro-computed tomography scanning of bird crania. A strong relationship between centroid size of the semicircular canals and body size indicates that larger birds have longer semicircular canals compared with their evolutionary relatives. Wing kinematics related to manoeuvrability (and quantified using the brachial index) explain a small additional portion of the variance in labyrinth size. We also find strong evidence for allometric shape change in the semicircular canals of birds, indicating that major aspects of the shape of the avian labyrinth are determined by spatial constraints. The avian braincase accommodates a large brain, a large eye and large semicircular canals compared with other tetrapods. Negative allometry of these structures means that the restriction of space within the braincase is intense in small birds. This may explain our observation that the angles between planes of the semicircular canals of birds deviate more strongly from orthogonality than those of mammals, and especially from agile, gliding and flying mammals. Furthermore, we find little support for relationships between labyrinth shape and flying style or wing kinematics. Overall, our results suggest that the topological problem of fitting long semicircular canals into a spatially constrained braincase is more important in determining the shape of the avian labyrinth than the specifics of locomotory style or agility. Our results tentatively indicate a link between visual acuity and proportional size of the labyrinth among birds. This suggests that the large labyrinths of birds compared with other tetrapods may result from their generally high visual acuities, and not directly from their ability to fly. The endosseous labyrinths of extinct birds and their close dinosaurian relatives may allow broad inferences about flight or vision, but so far provide few specific insights into detailed aspects of locomotion. PMID- 29156496 TI - Sensation, mechanoreceptor, and nerve fiber function after nerve regeneration. AB - OBJECTIVE: Sensation is essential for recovery after peripheral nerve injury. However, the relationship between sensory modalities and function of regenerated fibers is uncertain. We have investigated the relationships between touch threshold, tactile gnosis, and mechanoreceptor and sensory fiber function after nerve regeneration. METHODS: Twenty-one median or ulnar nerve lesions were repaired by a collagen nerve conduit or direct suture. Quantitative sensory hand function and sensory conduction studies by near-nerve technique, including tactile stimulation of mechanoreceptors, were followed for 2 years, and results were compared to noninjured hands. RESULTS: At both repair methods, touch thresholds at the finger tips recovered to 81 +/- 3% and tactile gnosis only to 20 +/- 4% (p < 0.001) of control. The sensory nerve action potentials (SNAPs) remained dispersed and areas recovered to 23 +/- 2% and the amplitudes only to 7 +/- 1% (P < 0.001). The areas of SNAPs after tactile stimulation recovered to 61 +/- 11% and remained slowed. Touch sensation correlated with SNAP areas (p < 0.005) and was negatively related to the prolongation of tactile latencies (p < 0.01); tactile gnosis was not related to electrophysiological parameters. INTERPRETATION: The recovered function of regenerated peripheral nerve fibers and reinnervated mechanoreceptors may differentially influence recovery of sensory modalities. Touch was affected by the number and function of regenerated fibers and mechanoreceptors. In contrast, tactile gnosis depends on the input and plasticity of the central nervous system (CNS), which may explain the absence of a direct relation between electrophysiological parameters and poor recovery. Dispersed maturation of sensory nerve fibers with desynchronized inputs to the CNS also contributes to the poor recovery of tactile gnosis. Ann Neurol 2017. Ann Neurol 2017;82:940-950. PMID- 29156495 TI - Multicenter study of endoscopic preoperative biliary drainage for malignant hilar biliary obstruction: E-POD hilar study. AB - BACKGROUND AND AIM: Endoscopic nasobiliary drainage (ENBD) is often recommended in preoperative biliary drainage (PBD) for hilar malignant biliary obstruction (MBO), but endoscopic biliary stent (EBS) is also used in the clinical practice. We conducted this large-scale multicenter study to compare ENBD and EBS in this setting. METHODS: A total of 374 cases undergoing PBD including 281 ENBD and 76 EBS for hilar MBO in 29 centers were retrospectively studied. RESULTS: Extrahepatic cholangiocarcinoma (ECC) accounted for 69.8% and Bismuth-Corlette classification was III or more in 58.8% of the study population. Endoscopic PBD was technically successful in 94.6%, and adverse event rate was 21.9%. The rate of post-endoscopic retrograde cholangiopancreatography pancreatitis was 16.0%, and non-endoscopic sphincterotomy was the only risk factor (odds ratio [OR] 2.51). Preoperative re-intervention was performed in 61.5%: planned re interventions in 48.4% and unplanned re-interventions in 31.0%. Percutaneous transhepatic biliary drainage was placed in 6.4% at the time of surgery. The risk factors for unplanned procedures were ECC (OR 2.64) and total bilirubin >= 10 mg/dL (OR 2.18). In surgically resected cases, prognostic factors were ECC (hazard ratio [HR] 0.57), predraiange magnetic resonance cholangiopancreatography (HR 1.62) and unplanned re-interventions (HR 1.81). EBS was not associated with increased adverse events, unplanned re-interventions, or a poor prognosis. CONCLUSIONS: Our retrospective analysis did not demonstrate the advantage of ENBD over EBS as the initial PBD for resectable hilar MBO. Although the technical success rate of endoscopic PBD was high, its re-intervention rate was not negligible, and unplanned re-intervention was associated with a poor prognosis in resected hilar MBO. PMID- 29156497 TI - Melanoma in patients with GATA2 deficiency. AB - GATA2 deficiency is a recently described genetic disorder affecting hematopoietic stem cells and is associated with immunodeficiency, hematologic malignancy, and various cutaneous pathologies including cutaneous tumors. To explore the incidence and clinical course of melanoma in patients with germline GATA2 deficiencies, we conducted a retrospective chart review of 71 such patients and identified two with invasive melanoma. One melanoma was diagnosed early because it was associated with pruritus due to a graft-versus-tumor effect following bone marrow transplantation. The other one, a lentigo maligna melanoma, was locally excised but progressed to widespread metastasis and death several years later. Our observations and published studies of melanoma biology suggest an association between decreased GATA2 expression and melanoma progression. These findings suggest that GATA2 deficient patients may have an increased risk of melanoma and should be observed closely for new or changing skin lesions. PMID- 29156499 TI - Risk assessment with newer statistical metrics. PMID- 29156498 TI - First things first: risk model performance metrics should reflect the clinical application. AB - Developing new measures of risk model performance is an active line of research, often motivated by the conventional wisdom that area under the ROC curve is an 'insensitive' measure of the additional predictive capacity offered by new biomarkers. Without endorsing area under the ROC curve, we argue that this charge is not substantiated. Three articles in this issue discuss alternative metrics of risk model performance: NRI(p) (two-category net reclassification index at the event rate), integrated discrimination index, and R-squared statistics. Guided by the principle that performance metrics should match the intended use of a risk prediction model, we argue that routine use of these indices is not justified. Instead, we recommend decision-theoretic measures to evaluate risk prediction models for applications in which clinically relevant risk thresholds have been established for classifying individuals. In the absence of established risk thresholds, additional research is needed to develop suitable metrics. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29156500 TI - The summary test tradeoff: a new measure of the value of an additional risk prediction marker. PMID- 29156501 TI - Event rate net reclassification index and the integrated discrimination improvement for studying incremental value of risk markers. PMID- 29156502 TI - Authors' response to comments. PMID- 29156503 TI - Editorial: Multiplicity issues in clinical trials. PMID- 29156504 TI - Clinical risk reclassification at 10 years. AB - Three papers in this issue focus on the role of calibration in model fit statistics, including the net reclassification improvement (NRI) and integrated discrimination improvement (IDI). This commentary reviews the development of such reclassification statistics along with more recent advances in our understanding of these measures. We show how the two-category NRI and the IDI are affected by changes in the event rate in theory and in an applied example. We also describe the role of calibration and how it may be assessed. Finally, we discuss the relevance of the event rate NRI for clinical use. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29156505 TI - Cross-Reactivity of Polyclonal Antibodies against Canavalia ensiformis (Jack Bean) Urease and Helicobacter pylori Urease Subunit A Fragments. AB - Overlapping decapeptide fragments of H. pylori urease subunit A (UreA) were synthesized and tested with polyclonal antibodies against Canavalia ensiformis (Jack bean) urease. The linear epitopes of UreA identified using the dot blot method were then examined using epitope mapping. For this purpose, series of overlapping fragments of UreA, frameshifted +/- four amino acid residues were synthesized. Most of the UreA epitopes which reacted with the Jack bean urease polyclonal antibodies had been recognized in previous studies by monoclonal antibodies against H. pylori urease. Fragments 11 - 24, 21 - 33, and 31 - 42 were able to interact with the Jack bean urease antibodies, giving stable immunological complexes. However, the lack of recognition by these antibodies of all the components in the peptide map strongly suggests that a non-continuous (nonlinear) epitope is located on the N-terminal domain of UreA. PMID- 29156506 TI - Lower gastrointestinal bleeding in patients with coronary artery disease on antithrombotics and subsequent mortality risk. AB - BACKGROUND: Lower gastrointestinal bleeding (LGIB) is a common complication for patients with coronary artery disease (CAD) due to the use of antithrombotic medications. Limited data exist describing which patients are at increased risk for mortality. AIM: This study aims to (i) determine whether patients on dual antiplatelet therapy (DAPT) or triple therapy are at higher risk of 90-day and 6 month mortality compared with patients on aspirin alone and (ii) evaluate risk factors for mortality in patients with CAD on antithrombotics hospitalized with LGIB. METHODS: We conducted a retrospective cohort study of patients hospitalized with LGIB and CAD while on aspirin at a single academic medical center from 2007 to 2015. Patients were identified using a validated, machine-learning algorithm and classified by use of aspirin, DAPT, or triple therapy. Univariate and multivariate Cox proportional hazards were used to determine mortality associated risk factors. RESULTS: Seven hundred sixteen patients were identified with LGIB and CAD. Four hundred seventy-two (65.9%) patients were on aspirin monotherapy, 179 (25%) on aspirin and thienopyridine (DAPT), and 65 (9.1%) on aspirin, thienopyridine, and systemic anticoagulant (triple therapy). On univariate analysis, triple therapy use was associated with increased risk of 90-day (hazard ratio [HR] 3.12, 95% confidence interval [CI] 1.52-5.92, P = 0.003) and 6-month (HR 2.46, 95%CI 1.29-4.35, P = 0.008) mortality. Holding anticoagulation was associated with higher mortality at 90 days (HR 2.30, 95%CI 1.27-4.07, P = 0.007). On multivariate analysis, after adjusting for confounding variables, the use of triple therapy remained associated with higher 90-day mortality (HR 3.23, 95%CI 1.56-6.16, P = 0.003). CONCLUSION: Triple therapy is associated with mortality at 90 days and at 6 months post discharge. PMID- 29156507 TI - Liver transplantation in adults with liver disease due to common variable immunodeficiency leads to early recurrent disease and poor outcome. AB - Common variable immunodeficiency (CVID) is the most common form of primary immunodeficiency characterized by antibody deficiency, recurrent bacterial infections, and autoimmunity. Advanced chronic liver disease occurs in a subset of patients with CVID and manifests with various histological features, such as nodular regenerative hyperplasia, inflammation, fibrosis, and cholangiopathy. We present a case series characterizing the outcomes in adult patients transplanted for primary CVID-related liver disease. We discuss the unique transplantation challenges faced in this primary immunodeficiency group including susceptibility to infections and early disease recurrence. There is a statistically significant decrease in 3-year and 5-year survival after liver transplantation in those with CVID-related liver disease (55% at 3 and 5 years) compared with all-comers (89% at 3 years, 81% at 5 years), prompting a need for discussion of suitability of transplantation in this group of patients as well as methods for reducing posttransplantation risk such as scrupulous search for infectious agents and reduction of immunosuppression. Liver Transplantation 24 171-181 2018 AASLD. PMID- 29156508 TI - Validity and reliability of the Turkish version of the readiness for hospital discharge scale/short form. AB - AIM: The aim of this study is to test the validity and reliability of the Turkish version of the readiness for hospital discharge scale/short form. BACKGROUND: Assessment of readiness for discharge from the patient's perspective is becoming increasingly important for patient safety, satisfaction and various patient outcomes such as readmission, health service utilization and mortality. The readiness for hospital discharge scale/short form allows health care providers to determine patients' discharge readiness. METHODS: Participants were 1,579 inpatients from internal medicine departments. The readiness for hospital discharge scale/short form was translated into Turkish via back-translation. We analyzed its reliability and validity via item analyses, an expert panel (content validity) and exploratory and confirmatory factor analyses (construct validity). RESULTS: The Cronbach's alpha of the whole scale was .74 and those for the subscales ranged from .79 to .93. The Spearman-Brown reliability coefficient was .92. The confirmatory factor analysis revealed good fit indices (chi2 /df = 2.6; RMSEA = .03; CFI = 1; GFI and AGFI = .99). The mean total score was 7.27 +/- 1.85, while the subscale means ranged from 6.62 +/- 3.41 to 7.69 +/- 2.24. CONCLUSION: The Turkish version of the readiness for hospital discharge scale/short form is a valid and reliable tool for assessing discharge readiness. The subscales with low means suggest opportunities for improvement. IMPLICATIONS FOR NURSING MANAGEMENT: If readiness for hospital discharge scale/short form is valid and reliable, patients who are unready for discharge can be determined with this scale. Thus, nurse managers can determine what kind of measures should be taken for patients who are not ready for discharge, can control nursing practices related to these patients and can provide cooperation between the nurses and other health professionals. PMID- 29156509 TI - The role of exosomes on colorectal cancer: A review. AB - Exosomes are extracellular microvesicles released from cells, which are involved in many biological and pathological processes, mainly because of their role in intercellular communication. Exosomes derived from colorectal cancer (CRC) cells are related to oncogenesis, tumor cell survival, chemo-resistance, and metastasis. The role of the exosomes in these processes involves the transfer of proteins, RNAs, or mutant versions of proto-oncogenes to the target cells. In recent years, great efforts have been made to identify useful biomarkers in CRC exosomes for diagnosis, prediction of prognosis, and treatment response. This review focuses on recent studies on CRC exosomes, considering isolation, cargo, biomarkers, and the effects of exosomes on the development and progression of CRC, including resistance to antitumor therapy. PMID- 29156510 TI - Isolation and Characterization of a Novel Broad-host-range Bacteriophage Infecting Salmonella enterica subsp. enterica for Biocontrol and Rapid Detection. AB - Bacteriophages have gained substantial attention as biocontrol and biorecognition agents, substituting antibodies. In this study, a Salmonella Enteritidis-specific bacteriophage, KFS-SE1, was isolated, identified, and characterized. This Siphoviridae phage infects S. Enteritidis with high specificity. This phage is highly stable under various pH (5-11), temperature (4-60 degrees C), and organic solvent conditions. The KFS-SE1 genome consisted of 59,715 bp with 73 predicted open reading frames and 57.14% GC content; it had a complete set of genes required for phage reconstruction. Comparative phylogenetic analysis of KFS-SE1 revealed that it was very similar to the other Salmonella phages in the Siphoviridae family. These characteristics suggest that KFS-SE1 with its high specificity and host lysis activity toward S. Enteritidis may have various potential applications. PMID- 29156511 TI - Molecular Epidemiology and Prevalence of Echovirus 30 in Zhejiang Province, China, from 2002 to 2015. AB - Echovirus serotype 30 (ECHO30) has been responsible for several recent worldwide outbreaks of viral meningitis. In Zhejiang Province, China, ECHO30 has been one of the main causes of viral meningitis for years. This study, using phylogenetic analysis of the VP1 gene, was performed to investigate the general molecular epidemiology and genetic patterns of ECHO30 circulating in Zhejiang Province between the years 2002 and 2015. The nucleotide sequences of ECHO30 VP1 showed that they were 64.8% identical with the prototype strain, Bastianni, while the amino acids were 84.9% identical. Phylogenetic analyses showed that ECHO30 in the Zhejiang area has diverged into two genotypes. Genotype I consists of strains isolated since 2002, whereas genotype II includes strains that were mainly isolated during the 2002 to 2004 outbreak. ECHO30 has been endemically circulating in both humans and the environment for a long period of time. Additionally, we evaluated the significance of recombination presented during the years 2005 to 2007 to demonstrate that recombination plays an important role in the prevalence of ECHO30 in the Zhejiang area. PMID- 29156512 TI - The Possible Mechanisms Involved in Citrinin Elimination by Cryptococcus podzolicus Y3 and the Effects of Extrinsic Factors on the Degradation of Citrinin. AB - Citrinin (CIT) is a toxic secondary metabolite produced by fungi belonging to the Penicillium, Aspergillus, and Monascus spp. This toxin has been detected in many agricultural products. In this study, a strain Y3 with the ability to eliminate CIT was screened and identified as Cryptococcus podzolicus, based on the sequence analysis of the internal transcribed spacer region. Neither uptake of CIT by cells nor adsorption by cell wall was involved in CIT elimination by Cryptococcus podzolicus Y3. The extracellular metabolites of Cryptococcus podzolicus Y3 stimulated by CIT or not showed no degradation for CIT. It indicated that CIT elimination was attributed to the degradation of intracellular enzyme(s). The degradation of CIT by C. podzolicus Y3 was dependent on the type of media, yeast concentration, temperature, pH, and initial concentration of CIT. Most of the CIT was degraded by C. podzolicus Y3 in NYDB medium at 42 h but not in PDB medium. The degradation rate of CIT was the highest (94%) when the concentration of C. podzolicus Y3 was 1 * 108 cells/ml. The quantity of CIT degradation was highest at 28 degrees C, and there was no degradation observed at 35 degrees C. The study also showed that acidic condition (pH 4.0) was the most favorable for CIT degradation by C. podzolicus Y3. The degradation rate of CIT increased to 98% as the concentration of CIT was increased to 20 MUg/ml. The toxicity of CIT degradation product(s) toward HEK293 was much lower than that of CIT. PMID- 29156513 TI - Production and Characterization of Keratinolytic Proteases by a Chicken Feather Degrading Thermophilic Strain, Thermoactinomyces sp. YT06. AB - Thermoactinomyces sp. strain YT06 was isolated from poultry compost and observed to degrade integral chicken feathers completely at 60 degrees C, resulting in the formation of 3.24 mg/ml of free amino acids from 50 ml of culture containing 10 g/l chicken feathers. Strain YT06 could grow and secrete keratinase using feather as the only carbon and nitrogen sources without other supplement, but complementation of 10 g/l sucrose and 4 g/l NaNO3 increased the production of the keratinolytic enzyme. The maximum protease activity obtained was 110 U/ml and for keratinase was 42 U/ml. The keratinase maintained active status over a broad pH (pH 8-11) and temperature (60-75 degrees C). It was inhibited by serine protease inhibitors and most metal ions; however, it could be stimulated by Mn2+ and the surfactant Tween-20. A reductive agent (beta-mercaptoethanol) was observed to cleave the disulfide bond of keratin and improve the access of the enzyme to the keratinaceous substrate. Zymogram analysis showed that strain YT06 primarily secreted keratinase with a molecular mass of approximately 35 kDa. The active band was assessed by MALDI-TOF mass spectrometry and was observed to be completely identical to an alkaline serine protease from Thermoactinomyces sp. Gus2-1. Thermoactinomyces sp. strain YT06 shows great potential as a novel candidate in enzymatic processing of hard-to-degrade proteins into high-value products, such as keratinous wastes. PMID- 29156514 TI - Esophageal Baseline Impedance Reflects Mucosal Integrity and Predicts Symptomatic Outcome With Proton Pump Inhibitor Treatment. AB - Background/Aims: Esophageal baseline impedance, which is decreased in gastroesophageal reflux disease (GERD) patients, is related to the severity of acid reflux and the integrity of the esophageal mucosa. The study aims to compare the baseline impedance and the dilated intercellular spaces (DIS) within patients with typical reflux symptoms and to evaluate the correlation of baseline impedance with DIS, esophageal acid exposure, as well as the efficacy of proton pump inhibitor (PPI) treatment. Methods: Ninety-two patients and 10 healthy controls were included in the study. Erosive esophagitis (EE) was defined by esophageal mucosal erosion under upper endoscopy. Patients without mucosa erosion were divided into groups with pathologic acid reflux (non-erosive reflux disease [NERD]) or with hypersensitive esophagus. The biopsies of esophageal mucosa were taken 2-4 cm above the gastroesophageal junction Z-line during upper endoscopy for DIS measurement. All the patients received esomeprazole 20 mg twice-daily treatment for 8 weeks. The efficacy of esomeprazole was evaluated among all patients. Results: The intercellular spaces were dilated in both EE and NERD patients (P < 0.05). The value 0.73 um could be used as the cut-off DIS value to distinguish patients from controls (area under the curve [AUC] = 0.849, P < 0.01). One thousand seven hundred sixty-four ohms could be used as the cut-off impedance values to distinguish patients from controls (AUC = 0.794, P < 0.01). The baseline impedance was decreased in both EE patients and NERD patients, and negatively correlated to the acid exposure time (r = -0.527, P < 0.05). There was a weak correlation between DIS and baseline impedance (r = -0.230, P < 0.05). "Baseline impedance > 1764 Omega" was an independent predictor for PPI failure (OR, 11.9; 95% CI, 2.4-58.9; P < 0.01). Conclusions: The DIS and decreased baseline impedance was observed in patients with mucosa erosion or pathological acid reflux. The baseline impedance reflected the mucosal integrity, it was more sensitive to esophageal acid exposure. Patients with high impedance might not benefit from the PPI treatment. PMID- 29156515 TI - Linc00152 promotes tumorigenesis by regulating DNMTs in triple-negative breast cancer. AB - Long noncoding RNA (lncRNA) is a significant factor that regulates various aspects of genome activity, including tumor development and progression. Linc00152, a member of lncRNA, is unregulated in various types of cancer. However, its role in breast cancer, especially in triple-negative breast cancer (TNBC), is unclear. In this study, we found that linc00152 was highly expressed in all basal-like cell lines and in the majority of TNBC tissues. Linc00152 suppression by shRNA significantly inhibited invasion and colony growth. Such suppression also triggered apoptosis in vitro and inhibited tumor growth in vivo. We also revealed that linc00152 partially enhanced breast cancer tumorigenesis by inactivation of the BRCA1/PTEN through DNA methyltransferases. This study provides new insight regarding linc00152 as a promising biomarker and therapeutic target for human TNBC treatment. PMID- 29156516 TI - Synergistic anticancer activity of 20(S)-Ginsenoside Rg3 and Sorafenib in hepatocellular carcinoma by modulating PTEN/Akt signaling pathway. AB - Sorafenib, a multikinase inhibitor for hepatocellular carcinoma treatment, inhibits the Raf/MAPK/ERK signaling pathway. However, PI3K/Akt signaling pathway is activated by Sorafenib and cross-talks with the Raf/MAPK/ERK signaling pathway, leading to drug resistance. 20(S)-Ginsenoside Rg3 has been reported with significant anticancer effect to numerous carcinomas by inhibition of PI3K-Akt signaling pathway. Hence, we aim to examine the synergistic anticancer activity of 20(S)-Ginsenoside Rg3 and Sorafenib via modulation of PTEN/Akt signaling pathway. Human hepatocellular carcinoma cell lines HepG2 and Huh7 were used. Cell viability, clonogenic assay, apoptosis assay, western blot analysis, xenograft treatment and immunohistochemistry were carried out. The viability of hepatocellular carcinoma cells significantly decreased by the treatment of Sorafenib combined with 20(S)-Ginsenoside Rg3, as well as the enhanced apoptotic rates. The levels of PTEN, Bax and cleaved caspase-3 expression increased, while the levels of phospho-PDK1 and phospho-Akt expression decreased by the treatment of Sorafenib combined with 20(S)-Ginsenoside Rg3. In vivo, the tumor volumes and weight decreased in the Sorafenib combined with 20(S)-Ginsenoside Rg3 group. The results demonstrated the synergistic anticancer activity of 20(S)-Ginsenoside Rg3 and Sorafenib in HCC by modulating PTEN/Akt signaling pathway. These findings suggest a promising strategy for HCC treatment, which could be performed in a sufficiently frequent manner. PMID- 29156517 TI - MiR-504 inhibits cell proliferation and invasion by targeting LOXL2 in non small cell lung cancer. AB - BACKGROUND: MicroRNAs (miRNAs) play crucial roles in tumor initiation and development. The aim of the study was to explore the clinicopathological role and functional effects of miR-504 in non small cell lung cancer (NSCLC). METHODS: Quantitative reverse transcription polymerase chain reaction (QRT-PCR) was applied to detect the expression of miR-504 in 55 cases of NSCLC tissues and matched adjacent normal tissues in NSCLC patients. MTT, colony formation and transwell invasion assays were performed to evaluate the effects of miR-504 on cell proliferation and invasion, respectively. Dual luciferase reporter assay was used to verify that LOXL2 was a direct target of miR-504. QRT-PCR and western blot analysis were performed to analyze mRNA and protein expression. RESULTS: In the study, we demonstrated that miR-504 was notably downregulated in NSCLC tissues compared with adjacent normal tissues. Lower miR-504 expression positively correlated with lymph node metastasis and advanced TNM stage in patients. Furthermore, upregulation of miR-504 significantly inhibited cell proliferation, cell invasion and EMT process of NSCLC. QRT-PCR, western blot and luciferase reporter assays confirmed that miR-504 could bind to LOXL2 3'UTR region and regulate its expression. Moreover, ectopic expression of LOXL2 could rescue the inhibiting effects on cell proliferation and invasion induced by miR 504 in NSCLC cells. CONCLUSIONS: Our results indicated that miR-504 functioned as a tumor suppressor in NSCLC and may serve as a target of NSCLC treatment. PMID- 29156518 TI - LINC00152/miR-139-5p regulates gastric cancer cell aerobic glycolysis by targeting PRKAA1. AB - Gastric cancer is one of the most common cancers in the world and glycolysis is a major feature of gastric cancer. MicroRNAs (miRNAs) involve in gastric cancer cell proliferation, glycolysis and other cellular processes. MiR-139-5p is reported as a tumor suppressor in cancers, however, the role of miR-139-5p including glycolytic metabolism is unclear in gastric cancer. So, the purpose of the present study is to elucidate the underlying mechanism in gastric cancer metabolism mediated by miR-139-5p. Our results revealed that miR-139-5p inhibited glycolysis by regulating AMP-activated, alpha 1 catalytic subunit (PRKAA1) expression in gastric cancer cells. We also found that miR-139-5p was down regulated by long intergenic non-coding RNA 152 (LINC00152) in gastric cancer cells. Our results indicate that LINC00152/miR-139-5p facilitates gastric cancer cell glycolysis by regulating PRKAA1 expression. PMID- 29156519 TI - In-vivo assessment of the osteo-protective effects of eugenol in alveolar bone tissues. AB - Estrogen deficiency following menopausal provokes alveolar bone loss, remodeling and inflammation. Eugenol is a phenolic compound with wide dental applications and anti-inflammatory properties. In the present study, the potential protective role of eugenol against alveolar bone deformities was investigated in an ovariectomized (OVX) rodent model. Two doses of eugenol (2.5 and 5 mg/kg/d) were administered to OVX animals for 12 weeks. In Serum, markers of bone metabolism and pro-inflammatory cytokines were estimated using ELISA. Alveolar bone morphometry was analyzed using high-resolution micro-computed tomography (CT). Bone histological analysis (H&E stain) was also performed. Alveolar bone expression of osteoclastogenesis modulating factors, such as osteoprotegerin (OPG), receptor activator of nuclear factor kappa-b ligand (RANKL) and inflammatory mediators, were measured using immunohistochemistry. Eugenol failed to correct elevated body weights and uterine atrophy in OVX rats. The significant elevation of bone metabolic markers and inflammatory cytokines in OVX animals were markedly improved by eugenol treatment, particularly the higher dose. Eugenol treatment considerably attenuated morphometric trabecular alterations of the alveolar bone and improved alveolar resorption and gingival infiltration. Alveolar bone of OVX animals showed augmented expression of RANKL, OPG and inflammatory cytokines, which were corrected by eugenol treatment. Alveolar bone loss and remodeling associated with estrogen insufficiency was ameliorated by eugenol owing to its anti-inflammatory properties, suggesting an extra dental impact for eugenol. PMID- 29156520 TI - Long noncoding RNA LINC00961 inhibits cell invasion and metastasis in human non small cell lung cancer. AB - Long noncoding RNAs (LncRNAs) expression has been found to be misregulated in multiple human cancers, and a growing number of studies have revealed that lncRNAs can function as important oncogenes or tumor suppressors. In this study, we identified a lncRNA-LINC00961, which was significantly down-regulated in human non-small cell lung cancer tissues. Decreased LINC00961 was associated with NSCLC patients advanced clinical stage, lymph node metastasis, and shorter survival time. Further experiments demonstrated that LSD1 could directly bind to LINC00961 promoter regions and epigenetically repress its transcription in NSCLC cells. Moreover, MTT assays showed that LINC00961 had no influence on NSCLC cell proliferation. Ectopic overexpression of LINC00961 inhibits NSCLC cell migration, invasion in vitro and metastasis in vivo. Finally, qRT-PCR and western blot assays revealed that LINC00961 could act as a tumor suppressor partially via affecting beta-catenin expression. Collectively, decreased LINC00961 might play a key role in NSCLC progression, and may serve as a novel prognostic marker in human NSCLC. PMID- 29156521 TI - MicroRNAs as novel biomarkers for colorectal cancer: New outlooks. AB - Colorectal cancer is one of the most prevalent cancers with high mortality in the world. MicroRNAs are a class of small non-coding RNAs that regulate gene expression through targeting mRNAs. MicroRNAs involve in many biological and pathological processes such as cell growth, differentiation, apoptosis. etc. Dysregulation of miRNAs expression patterns have been reported in many tumors including Colorectal Cancer. Various studies indicate that miRNAs can be utilized as diagnostic and prognostic biomarkers for evaluation of tumor initiation, development, invasion, metastasis and response to chemotherapeutic drugs. Numerous investigations have also shown dysregulation of miRNAs in tissue samples and body fluids such as serum, plasma and fecal samples from CRC patients. Recently, several studies have demonstrated that miRNAs have regulatory roles in response to anti-cancer drugs and suggested them as predictive factors for successful treatment. In this review, we highlight the facts concerning tumor suppressor miRNAs and oncomiRs in CRC; by emphasizing their importance in different signaling pathways such as the Wnt/beta catenin activation, EGFR pathway, (TGF-beta) and the TP53 network and then their potential as biomarker and targets for cancer treatment. PMID- 29156523 TI - Cancer-associated fibroblasts confer cisplatin resistance of tongue cancer via autophagy activation. AB - Cancer-associated fibroblasts (CAFs) play important roles in carcinogenesis and progression of tongue squamous cell carcinoma (TSCC). However, effect of CAFs on chemotherapy resistance of TSCC remains largely obscure. Here, we cultured the matched primary CAFs and normal fibroblasts (NFs) pairs and detected their roles in cisplatin sensitivity of TSCC, as well as autophagy-related protein LC3 and Beclin1 expressions. During exposure to cisplatin, TSCC with CAFs group exhibited significantly increased cell viability and IC50, but reduced apoptosis than that with NFs group. Meanwhile, cisplatin increased the LC3-II and Beclin1 levels of those TSCC co-cultured with CAFs. Activation of cisplatin-induced autophagic flux was inhibited by CQ, which can accumulate LC3-II protein and increase punctate distribution of LC3 localization. Beclin1 siRNA also decreased the cisplatin induced autophagy. Both CQ and Beclin1 siRNA increased cisplatin-induced apoptosis but inhibited viability of TSCC co-cultured with CAFs. In vivo, combination of cisplatin and CQ significantly inhibited the growth of xenografted tumors than cisplatin alone. Taken together, our findings highlight the important role of CAFs in cisplatin resistance of tongue cancer via autophagy activation, suggesting that inhibition of autophagy could be an optimal strategy for chemoresistance of TSCC. PMID- 29156522 TI - The prevention of TNF-alpha/IFN-gamma mixture-induced inflammation in human keratinocyte and atopic dermatitis-like skin lesions in Nc/Nga mice by mineral balanced deep sea water. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by environmental and chemical allergens. Despite the complexity of its pathogenesis, many investigations have shown that substances having anti-inflammatory activities alleviated the pathology of AD. Here, we evaluated the effects of mineral-balanced deep sea water (DSW) on AD-like skin damage in both in vitro and in vivo. The results showed that mineral-balanced DSW regressed inflammatory chemokines, such as macrophage-derived chemokine (MDC), thymus- and activation regulated chemokine (TARC) and regulated on activation, normal T-cell expressed and secreted (RANTES), and cytokines, interleukin (IL)-6 and granulocyte macrophage colony-stimulating factor (GM-CSF) mRNA expression in HaCaT immortal human keratinocyte treated with tumor necrosis factor (TNF)-alpha/ interferon (IFN)-gamma mixture. Furthermore, increased cyclooxygenase (COX)-2 protein expressions were also reversed, filaggrin gene expression was enhanced and decreased involucrin transcriptions was recovered by mineral-balanced DSW in TNF alpha/IFN-gamma mixture-treated HaCaT human keratinocyte. Moreover, we revealed that the inhibitory effects of mineral-balanced DSW were mediated with the suppression of signal transducer and activator of transcription (STAT) 1 phosphorylation. In animal experiments, we showed that hardness 2000 of mineral balanced DSW decreased the serum levels of IgE, IL-4, and histamine, and alleviated the severity score and numbers of scratching in dinitrochlorobezene (DNCB)-treated Nc/Nga mice. Furthermore, increased epidermal thickness and mast cell infiltration by DNCB treatment were reversed by the application of hardness 2000 mineral-balanced DSW. Taken together, the present investigation indicates that mineral-balanced DSW is a potent substance with anti-atopic dermatitis activity. PMID- 29156524 TI - KIF3A knockdown sensitizes bronchial epithelia to apoptosis and aggravates airway inflammation in asthma. AB - BACKGROUND: KIF3A expression was decreased in asthmatic child patients and animal. Impaired KIF3A expression resulted in increased Th2 inflammation in mice and apoptosis in renal tubular epithelium and photoreceptor cells. This work aimed to investigate the role of KIF3A in epithelium apoptosis and bronchial inflammation in asthma. METHODS: After establishment of ovalbumin induced asthma, the mice were infected with KIF3A adenovirus through nasal cavity inhalation. KIF3A expression and apoptosis in epithelia of nasal mucosa and bronchia were determined using qRT-PCR, western blotting, immunohistochemistry and TUNEL staining. The mRNA expression of COX-2, IL-4, IL-5, IL-13, IL-6, IL-10 and TNF alpha was also measured. In vitro, human bronchial epithelial cell line 16HBE 14o was stimulated with IL-4, IL-13 and TNF-alpha, accompanied by KIF3A knockdown or overexpression using siRNA or KIF3A adenovirus respectively. Apoptosis, mRNA expression of CCL17, CCL26, IL-5 and IL-8, and protein expression of COX-2 and beta-catenin were determined using flow cytometry, qRT-PCR and western blotting. RESULTS: KIF3A expression was reduced in epithelia of nasal mucosa and bronchia of asthmatic mice, and overexpression of KIF3A ameliorated epithelial cell apoptosis and bronchial inflammation in asthmatic mice. In vitro, KIF3A knockdown significantly promoted epithelium apoptosis, facilitated the transcription of CCL17, CCL26, IL-5 and IL-8, and increased the protein levels of COX-2 and beta catenin translocation, whereas overexpression of KIF3A exhibited the opposite effect. CONCLUSION: KIF3A plays an important role in epithelium apoptosis and bronchial inflammation in asthma, and may be a potential target for asthma treatment. PMID- 29156525 TI - Esomeprazole ameliorates CCl4 induced liver fibrosis in rats via modulating oxidative stress, inflammatory, fibrogenic and apoptotic markers. AB - BACKGROUND: Hepatic fibrosis is a major health problem that requires further medical attention. Proton pump inhibitors are proven to possess other therapeutic potentials apart of their acid anti-secretory actions. AIM OF THE WORK: To test possible anti-fibrotic effect of esomeprazole magnesium trihydrate in management of liver fibrosis compared to silymarin, the well-known hepatoprotective agent. MATERIALS & METHODS: 40 male albino rats were divided into 4 groups: normal control group; CCl4-treated group (1 mL/kg 40% CCl4, diluted in olive oil) I.P twice weekly for 6 weeks; esomeprazole-treated group (30 mg/kg body weight); and Silymarin-treated group (100 mg/kg body weight). Both esomeprazole and silymarin were given orally daily for two weeks after the last CCl4 dose. Serum and tissue samples were assessed for histopathological and biochemical analyses. RESULTS: Esomeprazole reversed hepatocellular damage, improved liver integrity, corrected major histopathological disturbances induced by CCl4 and lowered fibrosis scoring. It also improved anti-oxidant capacity and attenuated lipid peroxidation. Esomeprazole treatment resulted in down-regulation of hepatic pro apoptotic Bax and up-regulation of anti-apoptotic Bcl2 protein expressions. In addition, it resulted in inhibition of TNF-alpha, TGF-beta and IL-6 -mediated inflammatory responses, and retrieval of the epithelial marker e-cadherin. CONCLUSION: Esomeprazole confers significant anti-fibrotic actions. Further study is needed to elucidate other probable mechanisms for this effect and to test their anti-fibrotic potential clinically. PMID- 29156526 TI - Combined use of insoluble beta-glucan from the cell wall of Candida albicans and cyclophosphamide: Validation in S180 tumor-bearing mice. AB - BACKGROUND: Cyclophosphamide (CTX) is a widely used antitumor drug that can suppress the immune system. The effects of regulating immune response and antitumor of beta-glucan from the cell wall of Candida albicans (CAIBG) have been confirmed. However, the effects of the combined use of CAIBG and CTX remain unclear and warrant further investigation. METHODS: S180 tumor-bearing models were developed for CAIBG (100 mg/10 mL/kg) and CTX (30 mg/10 mL/kg) intervention. The weights of the body, tumor spleen, and Thymus were recorded to calculate the index of the spleen and Thymus. The spleen and Thymus were observed by hematoxylin and eosin staining, whereas the expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta was determined by Western blot. The survival times of mice were followed and recorded for analysis. RESULTS: CAIBG, CTX, and combined use of CAIBG and CTX could down-regulate the tumor growth and prolong the survival time. The spleen and Thymus index significantly increased in the CAIBG + CTX group than in the CTX group, but it was lower than that in the CAIBG group. Moreover, the Thymus index was significantly lower in the CAIBG + CTX group than in the CAIBG group. The lymphocytes of the spleen and Thymus decreased significantly in the CTX group but improved significantly in the CAIBG and CAIBG + CTX groups. The expression level of TNF-alpha and IL-1beta in the CTX+CAIBG group increased significantly compared with that in the CTX group. The survival time of the CAIBG group and CAIBG + CTX group was significantly higher than that of the CTX group. CONCLUSIONS: CAIBG has strong treatment potential in combating tumor growth and prolonging survival time of S180 tumor-bearing mice. Combined use of CAIBG and CTX can compensate the CTX-induced immunosuppression and provide antitumor effects. Future studies are necessary to elucidate the underlying mechanism. PMID- 29156527 TI - Synthesis and characterization of copper nanoparticles stabilized with Quisqualis indica extract: Evaluation of its cytotoxicity and apoptosis in B16F10 melanoma cells. AB - Green synthesis of metallic nanoparticles is a cost-effective environment friendly technique and Quisqualis indica has ethnomedicinal values. With this background in this study, the floral extract of Q. indica was used to fabricate copper nanoparticles (QCuNPs) from copper acetate. Biophysical analysis revealed the formation of spherical, monodisperse, crystalline QCuNPs. Significant cytotoxic potentials of the nanoformulation were determined by MTT and lactate dehydrogenase (LDH) assay on B16F10 melanoma cells. Estimation of GSH and ROS demonstrated that QCuNPs induced melanoma cell death by induction of oxidative stress. Gene transcript analysis showed up-regulation of caspase-dependent as well as caspase-independent (AIF) apoptotic genes in treated cells. Comparative proteomics study mostly showed the abundance of apoptotic and cell cycle arrest proteins in treated samples. The in vivo therapeutic efficacy was studied in mice bearing B16F10 melanoma tumor where a significant decrease in tumor growth was observed in nanoparticles treated animal model. In conclusion, QCuNPs caused cytotoxicity and apoptosis in melanoma cells and its mechanism was established from gene expression and proteomic studies. QCuNPs exhibited potential suppression of B16F10 melanoma cell proliferation and substantial inhibition of tumor growth in animals. As per our information, this is the first study exploring the potential of Q. indica for the formulation of eco-friendly copper nanoparticle which will have great future application in the medicinal field. PMID- 29156528 TI - Actein ameliorates hepatic steatosis and fibrosis in high fat diet-induced NAFLD by regulation of insulin and leptin resistant. AB - Insulin and leptin resistance are highly involved in metabolic syndrome and non alcoholic fatty liver disease (NAFLD). Presently, no approved treatment is available. Actein is isolated from the rthizomes of Cimicifuga foetida, a triterpene glycoside, exhibiting important biological properties, such as anti inflammatory, anti-cancer, and anti-oxidant activity. However, its effects on metabolic syndrome are poorly understood. The aims of the study were mainly to investigate the molecular mechanisms regulating insulin and leptin resistance, and lipogenic action of actein in high fat diet-fed mice. Our data indicated that actein-treated mice displayed lower body weight, epididymal and subcutaneous fat mass, as well as serum lipid levels. Also, improved insulin and leptin resistance were observed in actein-treated groups. Liver inflammation and fibrosis triggered by high fat diet were decreased for actein administration. Moreover, hepatic lipid accumulation was also reduced by actein along with reductions of hepatic de novo lipogenesis-linked signals in actein-treated rodents with high fat diet. High fat diet-induced activation of insulin receptor substrate 1/Forkhead box protein O1 (IRS1/FOXO1), Janus kinase 2 gene/signal transducer and activator of transcription (JAK2/STAT3) and Protein Kinase B/Glycogen synthase kinase 3 beta (AKT/GSK3beta) pathways in liver was inhibited by actein, a potential mechanism by which hyperinsulinemia, hyperleptindemia and dyslipidemia were attenuated. Thus, the findings above might be of nutritional and therapeutic importance for the treatment of NAFLD. PMID- 29156529 TI - Alpinetin improved high fat diet-induced non-alcoholic fatty liver disease (NAFLD) through improving oxidative stress, inflammatory response and lipid metabolism. AB - The non-alcoholic fatty liver disease (NAFLD) has become a serious medical problem and an increasing threat to public health. It is characterized by the abnormal fat accumulation in liver without excessive alcohol intake. The concurrent NAFLD might up-regulate the risk of chronic kidney disease as well as the mortality rate. Though various drugs have been investigated to attenuate NAFLD, further study is still necessary to find new therapeutic strategy and to reveal the underlying molecular mechanism. In the present study, NAFLD animal models were induced by feeding with high fat (HF) diet for 8 weeks. Alpinetin (ALP) was given to mice for another 8 weeks together with HF. Hepatic and renal function, oxidative stress, inflammatory response and lipid metabolism were calculated. And human liver cells of HL-7702 were cultured with high fructose (5mM) with or without ALP. The findings indicated that ALP down-regulated lipid accumulation in liver tissue samples. The higher inflammatory score induced by HF in liver and renal were reduced by ALP. HF-triggered oxidative stress was inhibited in ALP-treated groups, as evidenced by enhanced SOD1/HO-1/Nrf-2 expressions and reduced thioredoxin-interacting protein (TXNIP)/xanthine oxidase (XO) levels. ALP also suppressed inflammatory response by decreasing pro inflammatory cytokines through inactivating toll-like receptor 4-nuclear factor kappa B (TLR4-NF-kappaB) pathway. The anti-oxidant and anti-inflammatory effects of ALP were confirmed in HL-7702 cells. Further, abnormal lipid metabolism caused by HF was alleviated by ALP, which was associated with the decreased Stearoyl-CoA desaturase 1 (SCD1), fatty acid synthase (FAS), sterol element regulatory binding protein 1c (SREBP-1c), Liver X Receptor (LXR)-alpha, elongases of very long-chain fatty acids (Elovl)-2, p-insulin receptor substrate 1 (IRS1) expressions, and increased PPARalpha levels. Taken together, the results above indicated that ALP could suppress oxidative stress, reduce inflammatory response and attenuate lipid metabolism, preventing NAFLD. PMID- 29156530 TI - MicroRNA-373 facilitates HSV-1 replication through suppression of type I IFN response by targeting IRF1. AB - Herpes simplex virus type 1 (HSV-1) had led to kinds of clinical disorders and became an important cause of morbidity and mortality worldwide, such as herpetic gingivostomatitis in children. Previous studies reported that HSV-1 infection is common and has evolved a variety of mechanisms to evade the immune system, such as dysregulation of miRNAs. However, reports concerning the role of miRNA in HSV 1infection are limited. Here, we report that a host microRNA, miR-373, was significantly upregulated by HSV-1 infection in Hela cells and patients with herpetic gingivostomatitis and it facilitated HSV-1 replication in vitro. Subsequently, we demonstrated that miR-373 was a negative regulator of IFN-I response by directly targeting IRF1, resulting in the suppression of interferon stimulated gene (ISG) expression and enhancement of HSV-1 infection. Taken together, our findings provide new evidence of which HSV-1 hijacks the host miRNAs to promote its replication by negatively regulating the production of type I IFN and suggest a novel potential anti-HSV-1 therapeutic target. PMID- 29156531 TI - Heated naringin mitigate the genotoxicity effect of Mitomycin C in BALB/c mice through enhancing the antioxidant status. AB - A major problem with cancer chemotherapy is its severe toxic effects on non target tissues. Assessment of natural products for their protective effect against anticancer drugs induced toxicity is gaining importance in cancer biology. The aim of the present study was to evaluate the effect of native and thermal treated naringin on the protective effect against mitomycin C (MMC) induced genotoxicity. The genotoxicity in liver kidney and brain cells isolated from Balb/C mice were evaluated by performing the comet assay. Antioxidant and lipid peroxidation assays were carried out to understand the protective effects of these compounds. The comet assay showed that heated and native naringin were not genotoxic at the tested dose (40 mg/kg b.w) on liver, kidney and brain cells. A significant decrease in DNA damages was observed, at the tested doses (20 mg/kg b.w and 40 mg/kg b.w) suggesting a protective role of these molecules against the genotoxicity induced by mitomycin C on liver, kidney and brain cells. Moreover, administration of MMC (6 mg/kg b.w.) altered the activities of glutathione peroxidase and superoxide dismutase accompanied by a significant increase of lipid peroxidation. Pretreatment of mouse with heated and native naringin before MMC administration significantly raised the glutathione peroxidase and superoxide dismutase activities followed by a reduced MMC-induced lipid peroxidation. Our study demonstrated that heat treatment of naringin preserve activities of native naringin. The genoprotective properties of heated and native naringin against MMC could be attributed to its antioxidant activities and its inhibitory effect on lipid peroxidation. PMID- 29156532 TI - Paclitaxel alleviated liver injury of septic mice by alleviating inflammatory response via microRNA-27a/TAB3/NF-kappaB signaling pathway. AB - Excessive inflammatory response and apoptosis play an important role in the sepsis-induced liver injury. Paclitaxel, a diterpene alkaloid of Taxus brevifolia, is widely used as an anti-tumor drug and shows protective effects on acute lung and kidney injury. However, whether it has a protective effect against sepsis-induced liver injury has not been reported. The objective of this study was to investigate the protective effects of paclitaxel in septic liver injury in mice and associated molecular mechanisms. Our results showed that paclitaxel treatment improved LPS-induced liver injury, as evidenced by the reduced aminotransferase activity, histological scores and apoptosis in the liver tissues. This was accompanied by the alleviating of inflammation and oxidative stress, such as decreased levels of tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-6) interleukin-1beta (IL-1beta) and malondialdehyde (MDA) and increased levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH px) in serum and liver tissues. Subsequent microarray and qRT-PCR analysis further showed that miR-27a was significantly decreased in mice with sepsis, which was recovered by paclitaxel pretreatment. Antagomir-miR-27a suppressed the therapeutic effects of paclitaxel in mice liver injury model via promoting inflammatory response. Of note, TAB3, which participated in the activation of the NF-kappaB signaling pathway, was identified as a direct target of miR-27 by luciferase reporter gene assays. Then, we revealed a reverse relationship between miR-27a expression levels and TAB3 mRNA levels in liver tissues from septic mice. Furthermore, paclitaxel treatment significantly decreased the expression of NF kappaB p65, but increased inhibitor of nuclear factor-kappaB-alpha (IkappaBalpha) protein levels in septic mice, suggesting the inactivation of NF-kappaB signaling pathway. Notably, the inhibitory effects of paclitaxel on NF-kappaB signaling pathway were reversed by antagomir-miR-27a. Our data indicated that paclitaxel significantly attenuated septic induced liver injury through reducing inflammatory response via miR-27a/TAB3/NF-kappaB signaling pathway. PMID- 29156533 TI - Serotonin induces peripheral antinociception via the opioidergic system. AB - PURPOSE: Studies conducted since 1969 have shown that the release of serotonin (5 HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined. METHODS: The paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE2 (2 MUg). Serotonin (250 ng), administered locally to the right paw of animals, produces antinociception in this model. RESULTS: The selective antagonists for mu, delta and kappa opioid receptors, clocinnamox clocinnamox (40 MUg), naltrindole (60 MUg) and nor binaltorfimina (200 MUg), respectively, inhibited the antinociceptive effect induced by serotonin. Additionally, bestatin (400 MUg), an inhibitor of enkephalinases that degrade peptides opioids, enhanced the antinociceptive effect induced by serotonin (low dose of 62.5 ng). CONCLUSIONS: These results suggest that serotonin possibly induce peripheral antinociception through the release of endogenous opioid peptides, possible from immune cells or keratinocytes. PMID- 29156534 TI - Effects of standardized isopropanolic black cohosh and estrogen on salivary function in ovariectomized rats. AB - Oral dryness is a common feature in menopausal women. Estrogen therapy can relieve this symptom; however, the underlying mechanism was not clear. Standardized isopropanolic black cohosh (Actaea racemosa; Remifemin) can also relieve menopausal symptoms, such as hot flashes and sweating. Our previous study showed that standardized isopropanolic black cohosh could protect the submandibular gland structure. To investigate the effects and possible mechanisms of action of estrogen and standardized isopropanolic black cohosh on submandibular gland function in ovariectomized (OVX) rats, we measured body weight, daily water consumption, and blood flow in the submandibular glands. Immunohistochemistry and western blotting were used to detect the expression of muscarinic acetylcholine receptors 1 (M1) and 3 (M3), and aquaporin 5 (AQP5) in the submandibular gland. OVX increased daily water consumption and reduced vasodilation in the submandibular gland. It suggested that ovariectomy could damage the salviary function. Moreover, the expression of M1 and M3 receptors decreased, whereas that of AQP5 increased. These changes may explain the dysfunction of saliva secretion in menopause. Estrogen and standardized isopropanolic black cohosh treatment had the same effect on daily water consumption and vasodilation in the submandibular gland. It indicated that estrogen and standardized isopropanolic black cohosh could relieve oral dryness in menopause. However, the mechanism of the two treatments may differ because standardized isopropanolic black cohosh only protected against changes in M1 expression, whereas estrogen protected against variations in M1, M3, and AQP5 expression. PMID- 29156535 TI - HDACis (class I), cancer stem cell, and phytochemicals: Cancer therapy and prevention implications. AB - Epigenetics is independent of the sequence events that physically affect the condensing of chromatin and genes expression. The unique epigenetic memories of various cells trigger exclusive gene expression profiling. According to different studies, the aberrant epigenetic signatures and impaired gene expression profiles are master occurrences in cancer cells in which oncogene and tumor suppressor genes are affected. Owing to the facts that epigenetic modifications are performed earlier than expression and are reversible, the epigenetic reprogramming of cancer cells could be applied potentially for their prevention, control, and therapy. The disruption of the acetylation signature, as a master epigenetic change in cancers, is related to the expression and the activity of HDACs. In this context, class I HDACs play a significant role in the regulation of cell proliferation and cancer. More recently, cancer stem cell (CSC) has been introduced as a minority population of tumor that is responsible for invasiveness, drug resistance, and relapse of cancers. It is now believed that controlling CSC via epigenetic reprogramming such as targeting HDACs could be helpful in regulating the acetylation pattern of chromatin. Recently, a number of reports have introduced some phytochemicals as HDAC inhibitors. The use of phytochemicals with the HDAC inhibition property could be potentially efficient in overcoming the mentioned problems of CSCs. This review presents a perspective concerning HDAC-targeted phytochemicals to control CSC in tumors. Hopefully, this new route would have more advantages in therapeutic applications and prevention against cancer. PMID- 29156536 TI - A review on exudates detection methods for diabetic retinopathy. AB - The presence of exudates on the retina is the most characteristic symptom of diabetic retinopathy. As exudates are among early clinical signs of DR, their detection would be an essential asset to the mass screening task and serve as an important step towards automatic grading and monitoring of the disease. Reliable identification and classification of exudates are of inherent interest in an automated diabetic retinopathy screening system. Here we review the numerous early studies that used for automatic exudates detection with the aim of providing decision support in addition to reducing the workload of an ophthalmologist. PMID- 29156537 TI - Ursolic acid ameliorates oxidative stress, inflammation and fibrosis in diabetic cardiomyopathy rats. AB - Diabetic cardiomyopathy is a major and severe cardiovascular complication of diabetes mellitus. Ursolic acid, a pentacyclic triterpene compound widespread in fruits and plants, performs a variety of pharmacological activities including lowering blood glucose, anti-oxidation, anti-inflammation and anti-fibrosis. Our present study aimed to investigate the cardioprotective effects of ursolic acid on diabetic cardiomyopathy rats and uncover its underlying mechanism. Diabetes mellitus was induced by a single injection of STZ-only (40 mg/ kg, i.v.) in male SD rats. Animals were divided into three groups (n=10): control group (normal saline, i.g.), diabetic group (normal saline, i.g.) and diabetic+ursolic acid group (35 mg/kg UA + normal saline, i.g.). Rats were administered for 8 weeks from 5th to 12th week. After the last administration, cardiac function was evaluated; HWI was calculated; FBG, CK, LDH in serum and SOD, MDA in cardiac tissue were detected. HE staining and Masson trichrome staining were employed to observe pathological alterations. Immunohistochemistry and western blotting were taken to determine the expression levels of TNF-alpha, MCP-1, TGF-beta1 and MMP-2 in the heart. The results dramatically showed increased levels of FBG, CK, LDH, MDA and a decreased activity of SOD in diabetic group, in which left ventricular dysfunction, cardiac myocytes hypertrophy, inflammatory cell infiltration and myocardial interstitial fibrosis had also been found. What's more, the expressions of TNF-alpha, MCP-1 and TGF-beta1 were significantly up-regulated and the expression of MMP-2 was markedly down-regulated in myocardium. Interestingly, treatment with ursolic acid remarkably ameliorated these changes. Collectively, our study strongly showed that ursolic acid is capable of improving the cardiac structure and function in STZ-induced diabetic cardiomyopathy rats by attenuating oxidative stress, inflammation and fibrosis. PMID- 29156538 TI - Combined Effects of Simulated Microgravity and Radiation Exposure on Osteoclast Cell Fusion. AB - The loss of bone mass and alteration in bone physiology during space flight are one of the major health risks for astronauts. Although the lack of weight bearing in microgravity is considered a risk factor for bone loss and possible osteoporosis, organisms living in space are also exposed to cosmic radiation and other environmental stress factors. As such, it is still unclear as to whether and by how much radiation exposure contributes to bone loss during space travel, and whether the effects of microgravity and radiation exposure are additive or synergistic. Bone is continuously renewed through the resorption of old bone by osteoclast cells and the formation of new bone by osteoblast cells. In this study, we investigated the combined effects of microgravity and radiation by evaluating the maturation of a hematopoietic cell line to mature osteoclasts. RAW 264.7 monocyte/macrophage cells were cultured in rotating wall vessels that simulate microgravity on the ground. Cells under static 1g or simulated microgravity were exposed to gamma rays of varying doses, and then cultured in receptor activator of nuclear factor-kappaB ligand (RANKL) for the formation of osteoclast giant multinucleated cells (GMCs) and for gene expression analysis. Results of the study showed that radiation alone at doses as low as 0.1 Gy may stimulate osteoclast cell fusion as assessed by GMCs and the expression of signature genes such as tartrate resistant acid phosphatase (Trap) and dendritic cell-specific transmembrane protein (Dcstamp). However, osteoclast cell fusion decreased for doses greater than 0.5 Gy. In comparison to radiation exposure, simulated microgravity induced higher levels of cell fusion, and the effects of these two environmental factors appeared additive. Interestingly, the microgravity effect on osteoclast stimulatory transmembrane protein (Ocstamp) and Dcstamp expressions was significantly higher than the radiation effect, suggesting that radiation may not increase the synthesis of adhesion molecules as much as microgravity. PMID- 29156539 TI - Epidemiological Investigations of Four Cowpox Virus Outbreaks in Alpaca Herds, Germany. AB - Four cowpox virus (CPXV) outbreaks occurred in unrelated alpaca herds in Eastern Germany during 2012-2017. All incidents were initially noticed due to severe, generalized, and finally lethal CPXV infections, which were confirmed by testing of tissue and serum samples. As CPXV-infection has been described in South American camelids (SACs) only three times, all four herds were investigated to gain a deeper understanding of CPXV epidemiology in alpacas. The different herds were investigated twice, and various samples (serum, swab samples, and crusts of suspicious pox lesions, feces) were taken to identify additionally infected animals. Serum was used to detect CPXV-specific antibodies by performing an indirect immunofluorescence assay (iIFA); swab samples, crusts, and feces were used for detection of CPXV-specific DNA in a real-time PCR. In total, 28 out of 107 animals could be identified as affected by CPXV, by iIFA and/or PCR. Herd seroprevalence ranged from 16.1% to 81.2%. To investigate the potential source of infection, wild small mammals were trapped around all alpaca herds. In two herds, CPXV-specific antibodies were found in the local rodent population. In the third herd, CPXV could be isolated from a common vole (Microtus arvalis) found drowned in a water bucket used to water the alpacas. Full genome sequencing and comparison with the genome of a CPXV from an alpaca from the same herd reveal 99.997% identity, providing further evidence that the common vole is a reservoir host and infection source of CPXV. Only in the remaining fourth herd, none of the trapped rodents were found to be CPXV-infected. Rodents, as ubiquitous reservoir hosts, in combination with increasingly popular alpacas, as susceptible species, suggest an enhanced risk of future zoonotic infections. PMID- 29156540 TI - The New Old (and Old New) Medical Model: Four Decades Navigating the Biomedical and Psychosocial Understandings of Health and Illness. AB - The importance of how disease and illness are conceptualised lies in the fact that such definition is paramount to understand the boundaries and scope of responsibility associated with medical work. In this paper, we aim to provide an overview of the interplay of these understandings in shaping the nature of medical work, philosophically, and in practice. We first discuss the emergence of the biopsychosocial model as an attempt to both challenge and broaden the traditional biomedical model. Then, we outline the main criticisms associated with the biopsychosocial model and note a range of contributions addressing the shortcomings of the model as initially formulated. Despite recurrent criticisms and uneven uptake, the biopsychosocial model has gone on to influence core aspects of medical practice, education, and research across many areas of medicine. One of these areas is adolescent medicine, which provides a particularly good exemplar to examine the contemporary challenges associated with the practical application of the biopsychosocial model. We conclude that a more optimal use of existing bodies of evidence, bringing together evidence-based methodological advances of the biopsychosocial model and existing evidence on the psychosocial needs associated with specific conditions/populations, can help to bridge the gap between philosophy and practice. PMID- 29156541 TI - Effect of Alumina Incorporation on the Surface Mineralization and Degradation of a Bioactive Glass (CaO-MgO-SiO2-Na2O-P2O5-CaF2)-Glycerol Paste. AB - This study investigates the dissolution behavior as well as the surface biomineralization in simulated body fluid (SBF) of a paste composed of glycerol (gly) and a bioactive glass in the system CaO-MgO-SiO2-Na2O-P2O5-CaF2 (BG). The synthesis of the bioactive glass in an alumina crucible has been shown to significantly affect its bioactivity due to the incorporation of aluminum (ca. 1.3-1.4 wt %) into the glass network. Thus, the kinetics of the hydroxyapatite (HA) mineralization on the glass prepared in the alumina crucible was found to be slower than that reported for the same glass composition prepared in a Pt crucible. It is considered that the synthesis conditions lead to the incorporation of small amount of aluminum into the BG network and thus delay the HA mineralization. Interestingly, the BG-gly paste was shown to have significantly higher bioactivity than that of the as-prepared BG. Structural analysis of the paste indicate that glycerol chemically interacts with the glass surface and strongly alter the glass network architecture, thus generating a more depolymerized network, as well as an increased amount of silanol groups at the surface of the glass. In particular, BG-gly paste features early intermediate calcite precipitation during immersion in SBF, followed by hydroxyapatite formation after ca. seven days of SBF exposure; whereas the HA mineralization seems to be suppressed in BG, probably a consequence of the incorporation of aluminum into the glass network. The results obtained within the present study reveal the positive effect of using pastes based on bioactive glasses and organic carriers (here alcohols) which may be of interest not only due to their advantageous visco-elastic properties, but also due to the possibility of enhancing the glass bioactivity upon surface interactions with the organic carrier. PMID- 29156542 TI - Computational Approaches for Integrative Analysis of the Metabolome and Microbiome. AB - The study of the microbiome, the totality of all microbes inhabiting the host or an environmental niche, has experienced exponential growth over the past few years. The microbiome contributes functional genes and metabolites, and is an important factor for maintaining health. In this context, metabolomics is increasingly applied to complement sequencing-based approaches (marker genes or shotgun metagenomics) to enable resolution of microbiome-conferred functionalities associated with health. However, analyzing the resulting multi omics data remains a significant challenge in current microbiome studies. In this review, we provide an overview of different computational approaches that have been used in recent years for integrative analysis of metabolome and microbiome data, ranging from statistical correlation analysis to metabolic network-based modeling approaches. Throughout the process, we strive to present a unified conceptual framework for multi-omics integration and interpretation, as well as point out potential future directions. PMID- 29156543 TI - Efficiency of True-Green Light Emitting Diodes: Non-Uniformity and Temperature Effects. AB - External quantum efficiency of industrial-grade green InGaN light-emitting diodes (LEDs) has been measured in a wide range of operating currents at various temperatures from 13 K to 300 K. Unlike blue LEDs, the efficiency as a function of current is found to have a multi-peak character, which could not be fitted by a simple ABC-model. This observation correlated with splitting of LED emission spectra into two peaks at certain currents. The characterization data are interpreted in terms of non-uniformity of the LED active region, which is tentatively attributed to extended defects like V-pits. We suggest a new approach to evaluation of temperature-dependent light extraction and internal quantum efficiencies taking into account the active region non-uniformity. As a result, the temperature dependence of light extraction and internal quantum efficiencies have been evaluated in the temperature range mentioned above and compared with those of blue LEDs. PMID- 29156544 TI - Endogenous Sphingolipid Signaling Pathway Implicated in the Action of Croton membranaceus on the Prostate Gland in BPH Patients. AB - Background: Croton membranaceus extract has apoptotic effects on BPH-1 cells. This study determined if the apoptotic effects were created through the ceramide pathway. Methods: The study was a follow-up to a previous observational study of 30 histologically confirmed patients with benign prostatic hyperplasia (BPH) who were on C. membranaceus ethanolic extract at 20 mg t.i.d orally for 3 mo. Thereafter, total and free prostate-specific antigen (PSA), lipid profile plus Apo lipoprotein A and B, ceramide/Sphingophospho-kinase 1 (SphK1) and 2 (SphK2), sphingosine lyase (SPL), the cytotoxic adducts of oxidative stress 4-hydroxy-2 nonenal (4HNE) and malondialdehyde (MDA), were determined. Results: Total and free PSA were significantly (p < 0.05) different after treatment. Apo lipoprotein A was significantly different (p = 0.024). The SphK1/SphK2 ratio reduced significantly (p = 0.049). Furthermore, SPL, ceramide, and MDA increased significantly after treatment (p = 0.05, p = 0.004, and p = 0.007, respectively). A weak positive correlation was found between high-density lipoprotein (HDL) cholesterol and SphK1, and HDL and ceramide before treatment (p = 0.036, r = 0.3826; p = 0.018, r = 0.4286, respectively. Conclusions:C. membranaceus uses the ceramide pathway by modulating the SphK1/SphK2 ratio and increasing SPL to generate oxidative stress and consequently apoptosis. PMID- 29156545 TI - Ultrasonographic Evaluation of Botulinum Toxin Injection Site for the Medial Approach to Tibialis Posterior Muscle in Chronic Stroke Patients with Spastic Equinovarus Foot: An Observational Study. AB - The tibialis posterior muscle is a frequent target for injection of botulinum toxin during the management of spastic equinovarus foot in adults with post stroke spasticity. Although it is deep-seated, the needle insertion into the tibialis posterior muscle is usually performed using anatomical landmarks and safety information obtained from healthy subjects and cadavers. Our aim was to evaluate the botulinum toxin injection site for the medial approach to the tibialis posterior muscle in chronic stroke patients with spastic equinovarus foot. Forty-six patients were evaluated at the affected middle lower leg medial surface with ultrasonography according to the following parameters: tibialis posterior muscle depth, thickness, and echo intensity. As to the spastic tibialis posterior, we found a mean muscle depth of 26.5 mm and a mean muscle thickness of 10.1 mm. Furthermore we observed a median tibialis posterior muscle echo intensity of 3.00 on the Heckmatt scale. The tibialis posterior muscle thickness was found to be inversely associated with its depth (p < 0.001) and echo intensity (p = 0.006). Furthermore, tibialis posterior muscle depth was found to be directly associated with its echo intensity (p = 0.004). Our findings may usefully inform manual needle placement into the tibialis posterior for the botulinum toxin treatment of spastic equinovarus foot in chronic stroke patients. PMID- 29156546 TI - Systematic Review of Epigenetic Effects of Pharmacological Agents for Bipolar Disorders. AB - Epigenetic effects of medications are an evolving field of medicine, and can change the landscape of drug development. The aim of this paper is to systematically review the literature of the relationship between common medications used for treatment of bipolar disorders and epigenetic modifications. MedLine/PubMed searches were performed based on pre-specified inclusion criteria from inception to November 2017. Six animal and human studies met the inclusion criteria. These studies examined the epigenetic changes in the main classes of medications that are used in bipolar disorders, namely mood stabilizers and antipsychotics. Although these initial studies have small to moderate sample size, they generally suggest an evolving and accumulating evidence of epigenetic changes that are associated with several of the medications that are used in bipolar I and II disorders. In this manuscript, we describe the specific epigenetic changes that are associated with the medications studied. Of the studies reviewed, five of the six studies revealed epigenetic changes associated with the use of mood stabilizers or antipsychotic medications. This review contributes to future research directions. Further understanding of the complexities of the epigenome and the untangling of the effects and contributions of disease states versus medications is crucial for the future of drug design and the development of new therapeutics. Epigenetic therapeutics hold great promise for complex disease treatment and personalized interventions, including psychiatric diseases. PMID- 29156547 TI - Knowledge and Practices of Toxoplasmosis among Clinical Laboratory Professionals: A Cross-Sectional Study in Durango, Mexico. AB - Background: The aim of this study was to determine the level of knowledge and practices about toxoplasmosis in a sample of clinical laboratory professionals in Mexico. Methods: 192 clinical laboratory professionals were surveyed. They were asked about (1) Toxoplasma gondii; (2) clinical manifestations, diagnosis, treatment, and epidemiology of toxoplasmosis; and (3) their practices with respect to toxoplasmosis. Results: The range of animals infected by T. gondii was known by 44.8% of participants. Clinical aspects of toxoplasmosis were known by up to 44.3% of subjects. Correct answers about the interpretation of serological markers of T. gondii infection were provided by up to 32.8% of participants. A minority (32.2%) of participants knew about a high number of false positive results of anti-T. gondii IgM antibody tests. Most participants (90.1%) did not know what the anti-T. gondii IgG avidity test was. Up to 55.7% of participants provided incorrect answers about the interpretation of serology tests for the treatment of pregnant women. Common routes of T. gondii infection were known by <15% of participants. Most (84.4%) participants had not performed tests for detection T. gondii infection. Conclusions: Results indicate incomplete knowledge of T. gondii infection and toxoplasmosis and a limited practice of laboratory tests among the professionals surveyed. PMID- 29156548 TI - Patient-Provider Communication and Counseling about Gestational Weight Gain and Physical Activity: A Qualitative Study of the Perceptions and Experiences of Latinas Pregnant with their First Child. AB - Latina women in the United States (U.S.) are disproportionately affected by obesity and are more likely to begin pregnancy overweight and gain excessive weight during pregnancy. The prenatal care period represents a window of opportunity for women to access the healthcare system and receive preventive services, education, nutritional support, and other social services to improve pregnancy outcomes. Excessive gestational weight gain (GWG) has numerous negative short- and long-term consequences for both the mother and newborn. We explored nulliparous Latina women's perceptions about their experiences communicating with their primary healthcare provider about GWG and physical activity (PA) to identify possible intervention targets using in-depth, semi-structured interviews. Bilingual, trained research staff conducted 23 interviews with first time pregnant Latinas between 22 and 36 weeks of gestation. Interviews were transcribed verbatim and analyzed using content analysis. Salient text passages were extracted, shortened, coded, and grouped into categories. Women, including those who self-identified as being overweight or obese prior to pregnancy, reported receiving limited or no advice from their healthcare providers about GWG or PA. Additionally, analysis revealed that although participants value information received from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) program counselors, they would like to receive more information from their primary healthcare providers about adequate GWG. Furthermore, study findings indicate that some participants received conflicting information regarding PA during pregnancy. Study findings suggest the need for increased integration of communication and counseling about GWG and PA into prenatal care services to promote healthy weight gain and PA among low-income Latina women. PMID- 29156549 TI - New Tripentone Analogs with Antiproliferative Activity. AB - Tripentones represent an interesting class of compounds due to their significant cytotoxicity against different human tumor cells in the submicro-nanomolar range. New tripentone analogs, in which a pyridine moiety replaces the thiophene ring originating the fused azaindole system endowed with anticancer activity viz 8H thieno[2,3-b]pyrrolizinones, were efficiently synthesized in four steps with fair overall yields (34-57%). All tripentone derivatives were tested in the range of 0.1-100 MUM for cytotoxicity against two human tumor cell lines, HCT-116 (human colorectal carcinoma) and MCF-7 (human breast cancer). The most active derivative, with GI50 values of 4.25 uM and 20.73 uM for HCT-116 and MCF-7 cells, respectively, did not affect the viability of Caco-2 differentiated in normal intestinal-like cells, suggesting tumor cells as the main target of its cytotoxic action. The same compound was further investigated in order to study its mode of action. Results showed that it did not exert necrotic effects, while induced a clear shift of viable cells towards early apoptosis. Flow cytometric analysis demonstrated that this compound caused cell cycle alteration, inhibiting its progression in S and G2/M phases. PMID- 29156550 TI - Can Youthful Mesenchymal Stem Cells from Wharton's Jelly Bring a Breath of Fresh Air for COPD? AB - Chronic obstructive pulmonary disease (COPD) is a major global cause of morbidity and mortality, projected to become the 3rd cause of disease mortality worldwide by 2020. COPD is characterized by persistent and not fully reversible airflow limitation that is usually progressive and is associated with an abnormal chronic inflammatory response of the lung to noxious agents including cigarette smoke. Currently available therapeutic strategies aim to ease COPD symptoms but cannot prevent its progress or regenerate physiological lung structure or function. The urgently needed new approaches for the treatment of COPD include stem cell therapies among which transplantation of mesenchymal stem cells derived from Wharton's jelly (WJ-MSCs) emerges as a promising therapeutic strategy because of the unique properties of these cells. The present review discusses the main biological properties of WJ-MSCs pertinent to their potential application for the treatment of COPD in the context of COPD pathomechanisms with emphasis on chronic immune inflammatory processes that play key roles in the development and progression of COPD. PMID- 29156551 TI - Is All Urban Green Space the Same? A Comparison of the Health Benefits of Trees and Grass in New York City. AB - Living near vegetation, often called "green space" or "greenness", has been associated with numerous health benefits. We hypothesized that the two key components of urban vegetation, trees and grass, may differentially affect health. We estimated the association between near-residence trees, grass, and total vegetation (from the 2010 High Resolution Land Cover dataset for New York City (NYC)) with self-reported health from a survey of NYC adults (n = 1281). We found higher reporting of "very good" or "excellent" health for respondents with the highest, compared to the lowest, quartiles of tree (RR = 1.23, 95% CI = 1.06 1.44) but not grass density (relative risk (RR) = 1.00, 95% CI = 0.86-1.17) within 1000 m buffers, adjusting for pertinent confounders. Significant positive associations between trees and self-reported health remained after adjustment for grass, whereas associations with grass remained non-significant. Adjustment for air pollutants increased beneficial associations between trees and self-reported health; adjustment for parks only partially attenuated these effects. Results were null or negative using a 300 m buffer. Findings imply that higher exposure to vegetation, particularly trees outside of parks, may be associated with better health. If replicated, this may suggest that urban street tree planting may improve population health. PMID- 29156552 TI - Diversity of dsDNA Viruses in a South African Hot Spring Assessed by Metagenomics and Microscopy. AB - The current view of virus diversity in terrestrial hot springs is limited to a few sampling sites. To expand our current understanding of hot spring viral community diversity, this study aimed to investigate the first African hot spring (Brandvlei hot spring; 60 degrees C, pH 5.7) by means of electron microscopy and sequencing of the virus fraction. Microscopy analysis revealed a mixture of regular- and 'jumbo'-sized tailed morphotypes (Caudovirales), lemon-shaped virions (Fuselloviridae-like; salterprovirus-like) and pleiomorphic virus-like particles. Metavirome analysis corroborated the presence of His1-like viruses and has expanded the current clade of salterproviruses using a polymerase B gene phylogeny. The most represented viral contig was to a cyanophage genome fragment, which may underline basic ecosystem functioning provided by these viruses. Furthermore, a putative Gemmata-related phage was assembled with high coverage, a previously undocumented phage-host association. This study demonstrated that a moderately thermophilic spring environment contained a highly novel pool of viruses and should encourage future characterization of a wider temperature range of hot springs throughout the world. PMID- 29156554 TI - A High-Performance Liquid Chromatography Assay Method for the Determination of Lidocaine in Human Serum. AB - Here we report on the development of a selective and sensitive high-performance liquid chromatographic method for the determination of lidocaine in human serum. The extraction of lidocaine and procainamide (internal standard) from serum (0.25 mL) was achieved using diethyl ether under alkaline conditions. After liquid liquid extraction, the separation of analytes was accomplished using reverse phase extraction. The mobile phase, a combination of acetonitrile and monobasic potassium phosphate, was pumped isocratically through a C18 analytical column. The ultraviolet (UV) wavelength was at 277 nm for the internal standard, and subsequently changed to 210 for lidocaine. The assay exhibited excellent linearity (r2 > 0.999) in peak response over the concentration ranges of 50-5000 ng/mL lidocaine HCl in human serum. The mean absolute recoveries for 50 and 1000 ng/mL lidocaine HCl in serum using the present extraction procedure were 93.9 and 80.42%, respectively. The intra- and inter-day coefficients of variation in the serum were <15% at the lowest, and <12% at other concentrations, and the percent error values were less than 9%. The method displayed a high caliber of sensitivity and selectivity for monitoring therapeutic concentrations of lidocaine in human serum. PMID- 29156553 TI - Inclusion Complexes of Copaiba (Copaifera multijuga Hayne) Oleoresin and Cyclodextrins: Physicochemical Characterization and Anti-Inflammatory Activity. AB - Complexation with cyclodextrins (CDs) is a technique that has been extensively used to increase the aqueous solubility of oils and improve their stability. In addition, this technique has been used to convert oils into solid materials. This work aims to develop inclusion complexes of Copaifera multijuga oleoresin (CMO), which presents anti-inflammatory activity, with beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) by kneading (KND) and slurry (SL) methods. Physicochemical characterization was performed to verify the occurrence of interactions between CMO and the cyclodextrins. Carrageenan-induced hind paw edema in mice was carried out to evaluate the anti-inflammatory activity of CMO alone as well as complexed with CDs. Physicochemical characterization confirmed the formation of inclusion complex of CMO with both beta-CD and HP-beta-CD by KND and SL methods. Carrageenan-induced paw edema test showed that the anti inflammatory activity of CMO was maintained after complexation with beta-CD and HP-beta-CD, where they were able to decrease the levels of nitrite and myeloperoxidase. In conclusion, this study showed that it is possible to produce inclusion complexes of CMO with CDs by KND and SL methods without any change in CMO's anti-inflammatory activity. PMID- 29156555 TI - Identification of Major Flavone C-Glycosides and Their Optimized Extraction from Cymbidium kanran Using Deep Eutectic Solvents. AB - Cymbidium kanran, an orchid exclusively distributed in Northeast Asia, has been highly valued as a decorative plant and traditional herbal medicine. Here, C. kanran extracts were prepared in 70% aqueous methanol using ultrasound-assisted extraction (UAE) and subjected to liquid chromatography-photodiode array detection and ultra-high performance liquid chromatography-quadrupole-time-of flight-mass spectrometry analysis, which were used for quantitative and qualitative analysis, respectively. It was found that the extracts were rich in flavone C-glycosides including vicenin-2, vicenin-3, schaftoside, vitexin, and isovitexin. Ten deep eutectic solvents (DESs) were synthesized by combining choline chloride (hydrogen bond acceptor) with various polyols and diols (hydrogen bond donors) and were tested as a medium for the efficient production of extracts enriched with potentially bioactive flavone C-glycosides from C. kanran. A DES named ChCl:DPG, composed of choline chloride and dipropylene glycol at a 1:4 molar ratio, exhibited the best extraction yields. Then, the effects of extraction conditions on the extraction efficiency were investigated by response surface methodology. Lower water content in the extraction solvent and longer extraction time during UAE were desirable for higher extraction yields. Under the statistically optimized conditions, in which 100 mg of C. kanran powder were extracted in 0.53 mL of a mixture of ChCl:DPG and water (74:26, w/w) for 86 min, a total of 3.441 mg g-1 flavone C-glycosides including 1.933 mg g-1 vicenin-2 was obtained. This total yield was 196%, 131%, and 71% more than those obtained using 100% methanol, water, and 70% methanol, respectively. PMID- 29156556 TI - CDX2 Stimulates the Proliferation of Porcine Intestinal Epithelial Cells by Activating the mTORC1 and Wnt/beta-Catenin Signaling Pathways. AB - Caudal type homeobox 2 (CDX2) is expressed in intestinal epithelial cells and plays a role in gut development and homeostasis by regulating cell proliferation. However, whether CDX2 cooperates with the mammalian target of rapamycin complex 1 (mTORC1) and Wnt/beta-catenin signaling pathways to stimulate cell proliferation remains unknown. The objective of this study was to investigate the effect of CDX2 on the proliferation of porcine jejunum epithelial cells (IPEC-J2) and the correlation between CDX2, the mTORC1 and Wnt/beta-catenin signaling pathways. CDX2 overexpression and knockdown cell culture models were established to explore the regulation of CDX2 on both pathways. Pathway-specific antagonists were used to verify the effects. The results showed that CDX2 overexpression increased IPEC J2 cell proliferation and activated both the mTORC1 and Wnt/beta-catenin pathways, and that CDX2 knockdown decreased cell proliferation and inhibited both pathways. Furthermore, the mTORC1 and Wnt/beta-catenin pathway-specific antagonist rapamycin and XAV939 (3,5,7,8-tetrahydro-2-[4-(trifluoromethyl)]-4H thiopyrano[4,3-d]pyrimidin-4-one) both suppressed the proliferation of IPEC-J2 cells overexpressing CDX2, and that the combination of rapamycin and XAV939 had an additive effect. Regardless of whether the cells were treated with rapamycin or XAV939 alone or in combination, both mTORC1 and Wnt/beta-catenin pathways were down-regulated, accompanied by a decrease in CDX2 expression. Taken together, our data indicate that CDX2 stimulates porcine intestinal epithelial cell proliferation by activating the mTORC1 and Wnt/beta-catenin signaling pathways. PMID- 29156557 TI - The Invasive Region of Glioblastoma Defined by 5ALA Guided Surgery Has an Altered Cancer Stem Cell Marker Profile Compared to Central Tumour. AB - Glioblastoma, a WHO grade IV astrocytoma, is a highly aggressive and heterogeneous tumour that infiltrates deeply into surrounding brain parenchyma, making complete surgical resection impossible. Despite chemo-radiotherapy, the residual cell population within brain parenchyma post-surgery causes inevitable recurrence. Previously, the tumour core has been the focus of research and the basis for targeted therapeutic regimes, which have failed to improve survival in clinical trials. Here, we focus on the invasive margin as defined by the region with 5-aminolevulinic acid (5ALA) (GliolanTM) fluorescence at surgery beyond the T1 enhancing region on magnetic resonance imaging (MRI). This area is hypothesized to constitute unique microenvironmental pressures, and consequently be molecularly distinct to tumour core and enhancing rim regions. We conducted hematoxylin and eosin (H&E), array real time polymerase chain reaction (PCR), and immunohistochemistry staining on various intra-tumour regions of glioblastoma to determine molecular heterogeneity between regions. We analyzed 73 tumour samples from 21 patients and compared cellular density, cell proliferation, and the degree of vascularity. There is a statistically significant difference between the core, invasive margin and other regions for cell density (p < 0.001), cell proliferation (p = 0.029), and vascularity (p = 0.007). Aldehyde dehydrogenase 1 (ALDH1) and Nestin immunohistochemistry were used as a measure of stem-like properties, showing significantly decreased Nestin expression (p < 0.0001) in the invasive margin. Array PCR of the core, rim, and invasive regions showed significantly increased fibroblast growth factor (FGF) and ALDH1 expression in the invasive zone, with elevated hypoxia inducing factor 1-alpha (HIF1alpha) in the rim region, adjacent to the hypoxic core. The influence of varying microenvironments in the intra-tumour regions is a major key to understanding intra-tumour heterogeneity. This study confirms the distinct molecular composition of the heterogeneous invasive margin and cautions against purported therapy strategies that target candidate glioblastoma stem-like genes that are predominantly expressed in the tumour core. Full characterization of tumour cells in the invasive margin is critical, as these cells may more closely resemble the residual cell population responsible for tumour recurrence. Their unique nature should be considered when developing targeted agents for residual glioblastoma multiforme (GBM). PMID- 29156558 TI - Indoor Temperatures in Low Cost Housing in Johannesburg, South Africa. AB - Ambient and indoor temperature affects thermal comfort and human health. In a changing climate with a predicted change in temperature extremes, understanding indoor temperatures, both hot and cold, of different housing types is important. This study aimed to assess the hourly, daily and monthly variation in indoor temperatures in different housing types, namely formal houses, informal houses, flats, government-built low-cost houses and old, apartheid era low-cost housing, in five impoverished urban communities in Johannesburg, South Africa. During the cross-sectional survey of the Health, Environment and Development study data loggers were installed in 100 homes (20 per suburb) from February to May 2014. Indoor temperature and relative humidity were recorded on an hourly basis. Ambient outdoor temperatures were obtained from the nearest weather station. Indoor and outdoor temperature and relative humidity levels were compared; and an inter-comparison between the different housing types were also made. Apparent temperature was calculated to assess indoor thermal comfort. Data from 59 retrieved loggers showed a significant difference in monthly mean indoor temperature between the five different housing types (p < 0.0001). Low cost government-built houses and informal settlement houses had the greatest variation in temperature and experienced temperatures between 4 and 5 degrees C warmer than outdoor temperatures. Housing types occupied by poor communities experienced indoor temperature fluctuations often greater than that observed for ambient temperatures. Families living in government-built low-cost and informally constructed homes are the most at risk for indoor temperature extremes. These types of housing should be prioritised for interventions aimed at assisting families to cope with extreme temperatures, gaining optimal thermal comfort and preventing temperature-related health effects. PMID- 29156560 TI - System Modeling of a MEMS Vibratory Gyroscope and Integration to Circuit Simulation. AB - Recently, consumer applications have dramatically created the demand for low-cost and compact gyroscopes. Therefore, on the basis of microelectromechanical systems (MEMS) technology, many gyroscopes have been developed and successfully commercialized. A MEMS gyroscope consists of a MEMS device and an electrical circuit for self-oscillation and angular-rate detection. Since the MEMS device and circuit are interactively related, the entire system should be analyzed together to design or test the gyroscope. In this study, a MEMS vibratory gyroscope is analyzed based on the system dynamic modeling; thus, it can be mathematically expressed and integrated into a circuit simulator. A behavioral simulation of the entire system was conducted to prove the self-oscillation and angular-rate detection and to determine the circuit parameters to be optimized. From the simulation, the operating characteristic according to the vacuum pressure and scale factor was obtained, which indicated similar trends compared with those of the experimental results. The simulation method presented in this paper can be generalized to a wide range of MEMS devices. PMID- 29156559 TI - Tocotrienols: A Family of Molecules with Specific Biological Activities. AB - Vitamin E is a generic term frequently used to group together eight different molecules, namely: alpha-, beta-, gamma- and delta-tocopherol and the corresponding tocotrienols. The term tocopherol and eventually Vitamin E and its related activity was originally based on the capacity of countering foetal re absorption in deficient rodents or the development of encephalomalacia in chickens. In humans, Vitamin E activity is generally considered to be solely related to the antioxidant properties of the tocolic chemical structure. In recent years, several reports have shown that specific activities exist for each different tocotrienol form. In this short review, tocotrienol ability to inhibit cancer cell growth and induce apoptosis thanks to specific mechanisms, not shared by tocopherols, such as the binding to Estrogen Receptor-beta (ERbeta) and the triggering of endoplasmic reticulum (EndoR) stress will be described. The neuroprotective activity will also be presented and discussed. We propose that available studies strongly indicate that specific forms of tocotrienols have a distinct mechanism and biological activity, significantly different from tocopherol and more specifically from alpha-tocopherol. We therefore suggest not pooling them together within the broad term "Vitamin E" on solely the basis of their putative antioxidant properties. This option implies obvious consequences in the assessment of dietary Vitamin E adequacy and, probably more importantly, on the possibility of evaluating a separate biological variable, determinant in the relationship between diet and health. PMID- 29156561 TI - Adsorptive Stripping Voltammetric Determination of Amaranth and Tartrazine in Drinks and Gelatins Using a Screen-Printed Carbon Electrode. AB - A fast, sensitive, and selective method for the simultaneous determination of one pair of synthetic colorants commonly found mixed in food products, Amaranth (AM) and Tartrazine (TZ), based on their adsorption and oxidation on a screen-printed electrode (SPE) is presented. The variation of peak current with pH, supporting electrolyte, adsorption time, and adsorption potential were optimized using square wave adsorptive voltammetry. The optimal conditions were found to be: pH 3.2 (PBS), Eads 0.00 V, and tads 30 s. Under these conditions, the AM and TZ signals were observed at 0.56 and 0.74 V, respectively. A linear response were found over the 0.15 to 1.20 umol L-1 and 0.15 to 0.80 umol L-1 concentrations, with detection limits (3sigma/slope) of 26 and 70 nmol L-1 for AM and TZ, respectively. Reproducibility for 17.7 umol L-1 AM and TZ solutions were 2.5 and 3.0% (n = 7), respectively, using three different electrodes. The method was validated by determining AM and TZ in spiked tap water and unflavored gelatin spiked with AM and TZ. Because a beverage containing both AM and TZ was not found, the method was applied to the determination of AM in a kola soft drink and TZ in an orange jelly and a soft drink powder. PMID- 29156562 TI - Biodegradable Chitosan Decreases the Immune Response to Trichinella spiralis in Mice. AB - The purpose of this study was to evaluate the potential of chitosan units released during natural degradation of the polymer to activate the immune system against T. spiralis infection. High molecular weight chitosan was injected intraperitoneally into C57BL/6 mice. Flow cytometry and cytokine concentration, measured by ELISA, were used to characterize peritoneal cell populations during T. spiralis infection. The strong chemo-attractive properties of chitosan caused considerable infiltration into the peritoneal cavity of CD11b+ cells, with reduced expression of MHC class II, CD80, CD86, Dectin-1 or CD23 receptors in comparison to T. spiralis-infected mice. After prolonged chitosan biodegradation, cell populations expressing IL-4R, MR and Dectin-1 receptors were found to coexist with elevated IL-6, IL-10, TGF-beta and IgA production. IgA cross-reacted with T. spiralis antigen and chitosan. It was found that chitosan treatment attracted immune cells with low activity, which resulted in the number of nematodes increasing. The glucosamine and N-acetyl-D-glucosamine residues were recognized by wheat germ agglutinin (WGA) lectin and therefore any biodegradable chitosan units may actively downregulate the immune response to the parasite. The findings are relevant for both people and animals treated with chitosan preparations. PMID- 29156564 TI - Wireless Monitoring of Induction Machine Rotor Physical Variables. AB - With the widespread use of electric machines, there is a growing need to extract information from the machines to improve their control systems and maintenance management. The present work shows the development of an embedded system to perform the monitoring of the rotor physical variables of a squirrel cage induction motor. The system is comprised of: a circuit to acquire desirable rotor variable(s) and value(s) that send it to the computer; a rectifier and power storage circuit that converts an alternating current in a continuous current but also stores energy for a certain amount of time to wait for the motor's shutdown; and a magnetic generator that harvests energy from the rotating field to power the circuits mentioned above. The embedded system is set on the rotor of a 5 HP squirrel cage induction motor, making it difficult to power the system because it is rotating. This problem can be solved with the construction of a magnetic generator device to avoid the need of using batteries or collector rings and will send data to the computer using a wireless NRF24L01 module. For the proposed system, initial validation tests were made using a temperature sensor (DS18b20), as this variable is known as the most important when identifying the need for maintenance and control systems. Few tests have shown promising results that, with further improvements, can prove the feasibility of using sensors in the rotor. PMID- 29156563 TI - WNT Inhibitory Activity of Malus Pumila miller cv Annurca and Malus domestica cv Limoncella Apple Extracts on Human Colon-Rectal Cells Carrying Familial Adenomatous Polyposis Mutations. AB - Inhibitors of the Wingless-related Integration site (WNT)/beta-catenin pathway have recently been under consideration as potential chemopreventive agents against Familial Adenomatous Polyposis (FAP). This autosomal-dominant syndrome is caused by germline mutations in the gene coding for the protein APC and leads to hyperactivation of the WNT/beta-catenin signaling pathway, uncontrolled intestinal cell proliferation and formation of adenocarcinomas. The aim of the present work was to: (i) test, on in vitro cultures of cells carrying FAP mutations and on ex vivo biopsies of FAP patients, the WNT inhibitory activity of extracts from two common southern Italian apples, Malus pumila Miller cv. 'Annurca' and Malus domestica cv 'Limoncella'; (ii) identify the mechanisms underpinning their activities and; (iii) evaluate their potency upon gastrointestinal digestion. We here show that both Annurca and Limoncella apple extracts act as WNT inhibitors, mostly thanks to their polyphenolic contents. They inhibit the pathway in colon cells carrying FAP mutations with active dilutions falling in ranges close to consumer-relevant concentrations. Food-grade manufacturing of apple extracts increases their WNT inhibitory activity as result of the conversion of quercetin glycosides into the aglycone quercetin, a potent WNT inhibitor absent in the fresh fruit extract. However, in vitro simulated gastrointestinal digestion severely affected WNT inhibitory activity of apple extracts, as result of a loss of polyphenols. In conclusion, our results show that apple extracts inhibit the WNT pathway in colon cells carrying FAP mutations and represent a potential nutraceutical alternative for the treatment of this pathology. Enteric coating is advisable to preserve the activity of the extracts in the colon-rectal section of the digestive tract. PMID- 29156565 TI - Survey on the Performance of Source Localization Algorithms. AB - The localization of emitters using an array of sensors or antennas is a prevalent issue approached in several applications. There exist different techniques for source localization, which can be classified into multilateration, received signal strength (RSS) and proximity methods. The performance of multilateration techniques relies on measured time variables: the time of flight (ToF) of the emission from the emitter to the sensor, the time differences of arrival (TDoA) of the emission between sensors and the pseudo-time of flight (pToF) of the emission to the sensors. The multilateration algorithms presented and compared in this paper can be classified as iterative and non-iterative methods. Both standard least squares (SLS) and hyperbolic least squares (HLS) are iterative and based on the Newton-Raphson technique to solve the non-linear equation system. The metaheuristic technique particle swarm optimization (PSO) used for source localisation is also studied. This optimization technique estimates the source position as the optimum of an objective function based on HLS and is also iterative in nature. Three non-iterative algorithms, namely the hyperbolic positioning algorithms (HPA), the maximum likelihood estimator (MLE) and Bancroft algorithm, are also presented. A non-iterative combined algorithm, MLE-HLS, based on MLE and HLS, is further proposed in this paper. The performance of all algorithms is analysed and compared in terms of accuracy in the localization of the position of the emitter and in terms of computational time. The analysis is also undertaken with three different sensor layouts since the positions of the sensors affect the localization; several source positions are also evaluated to make the comparison more robust. The analysis is carried out using theoretical time differences, as well as including errors due to the effect of digital sampling of the time variables. It is shown that the most balanced algorithm, yielding better results than the other algorithms in terms of accuracy and short computational time, is the combined MLE-HLS algorithm. PMID- 29156566 TI - cGAS/STING Pathway in Cancer: Jekyll and Hyde Story of Cancer Immune Response. AB - The last two decades have witnessed enormous growth in the field of cancer immunity. Mechanistic insights of cancer immunoediting have not only enhanced our understanding but also paved the way to target and/or harness the innate immune system to combat cancer, called cancer immunotherapy. Cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon genes(STING) pathway has recently emerged as nodal player in cancer immunity and is currently being explored as potential therapeutic target. Although therapeutic activation of this pathway has shown promising anti-tumor effects in vivo, evidence also indicates the role of this pathway in inflammation mediated carcinogenesis. This review highlights our current understanding of cGAS/STING pathway in cancer, its therapeutic targeting and potential alternate approaches to target this pathway. Optimal therapeutic targeting and artificial tunability of this pathway still demand in depth understanding of cGAS/STING pathway regulation and homeostasis. PMID- 29156568 TI - Assessing Crop Coefficients for Natural Vegetated Areas Using Satellite Data and Eddy Covariance Stations. AB - The Food and Agricultural Organization (FAO) method for potential evapotranspiration assessment is based on the crop coefficient, which allows one to relate the reference evapotranspiration of well irrigated grass to the potential evapotranspiration of specific crops. The method was originally developed for cultivated species based on lysimeter measurements of potential evapotranspiration. Not many applications to natural vegetated areas exist due to the lack of available data for these species. In this paper we investigate the potential of using evapotranspiration measurements acquired by micrometeorological stations for the definition of crop coefficient functions of natural vegetated areas and extrapolation to ungauged sites through remotely sensed data. Pastures, deciduous and evergreen forests have been considered and lower crop coefficient values are found with respect to FAO data. PMID- 29156567 TI - The Role of Infected Cell Proliferation in the Clearance of Acute HBV Infection in Humans. AB - Around 90-95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans. We employed fitting of mathematical models to human acute infection data together with physiological constraints to investigate the role of these hypothesized mechanisms in the clearance of infection. Results suggest that cellular proliferation of infected cells resulting in two uninfected cells is required to minimize the destruction of the liver during the clearance of acute HBV infection. In contrast, we find that a cytokine-mediated cure of infected cells alone is insufficient to clear acute HBV infection. In conclusion, our modeling indicates that HBV clearance without lethal loss of liver mass is associated with the production of two uninfected cells upon proliferation of an infected cell. PMID- 29156570 TI - Random Access Performance of Distributed Sensors Attacked by Unknown Jammers. AB - In this paper, we model and investigate the random access (RA) performance of sensor nodes (SN) in a wireless sensor network (WSN). In the WSN, a central head sensor (HS) collects the information from distributed SNs, and jammers disturb the information transmission primarily by generating interference. In this paper, two jamming attacks are considered: power and code jamming. Power jammers (if they are friendly jammers) generate noises and, as a result, degrade the quality of the signal from SNs. Power jamming is equally harmful to all the SNs that are accessing HS and simply induces denial of service (DoS) without any need to hack HS or SNs. On the other hand, code jammers mimic legitimate SNs by sending fake signals and thus need to know certain system parameters that are used by the legitimate SNs. As a result of code jamming, HS falsely allocates radio resources to SNs. The code jamming hence increases the failure probability in sending the information messages, as well as misleads the usage of radio resources. In this paper, we present the probabilities of successful preamble transmission with power ramping according to the jammer types and provide the resulting throughput and delay of information transmission by SNs, respectively. The effect of two jamming attacks on the RA performances is compared with numerical investigation. The results show that, compared to RA without jammers, power and code jamming degrade the throughput by up to 30.3% and 40.5%, respectively, while the delay performance by up to 40.1% and 65.6%, respectively. PMID- 29156569 TI - New Insights into the Microbiota of Moth Pests. AB - In recent years, next generation sequencing (NGS) technologies have helped to improve our understanding of the bacterial communities associated with insects, shedding light on their wide taxonomic and functional diversity. To date, little is known about the microbiota of lepidopterans, which includes some of the most damaging agricultural and forest pests worldwide. Studying their microbiota could help us better understand their ecology and offer insights into developing new pest control strategies. In this paper, we review the literature pertaining to the microbiota of lepidopterans with a focus on pests, and highlight potential recurrent patterns regarding microbiota structure and composition. PMID- 29156571 TI - Studies for Improving a Rat Model of Alzheimer's Disease: Icv Administration of Well-Characterized beta-Amyloid 1-42 Oligomers Induce Dysfunction in Spatial Memory. AB - During the past 15 years, several genetically altered mouse models of human Alzheimer's disease (AD) have been developed. These costly models have greatly facilitated the evaluation of novel therapeutic approaches. Injecting synthetic beta-amyloid (Abeta) 1-42 species into different parts of the brain of non transgenic rodents frequently provided unreliable results, owing to a lack of a genuine characterization of the administered Abeta aggregates. Previously, we have published a new rat AD-model in which protofibrillar-fibrillar Abeta1-42 was administered into rat entorhinal cortex (Sipos 2007). In order to develop a more reliable model, we have injected well-characterized toxic soluble Abeta1-42 species (oligomers, protofibrils and fibrils) intracerebroventricularly (icv) into rat brain. Studies of the distribution of fluorescent-labeled Abeta1-42 in the brain showed that soluble Abeta-species diffused into all parts of the rat brain. After seven days, the Abeta-treated animals showed a significant decrease of spatial memory in Morris water maze test and impairment of synaptic plasticity (LTP) measured in acute hippocampal slices. The results of histological studies (decreased number of viable neurons, increased tau levels and decreased number of dendritic spines) also supported that icv administration of well-characterized toxic soluble Abeta species into rat brain provides a reliable rat AD-model. PMID- 29156572 TI - Assembly of the Cutin Polyester: From Cells to Extracellular Cell Walls. AB - Cuticular matrices covering aerial plant organs or delimiting compartments in these organs are composed of an insoluble hydrophobic polymer of high molecular mass, i.e., cutin, that encompass some cell wall polysaccharides and is filled by waxes. Cutin is a polyester of hydroxy and-or epoxy fatty acids including a low amount of glycerol. Screening of Arabidopsis and more recently of tomato (Solanum lycopersicum) mutants allowed the delineation of the metabolic pathway involved in the formation of cutin monomers, as well as their translocation in the apoplast. Furthermore, these studies identified an extracellular enzyme involved in the polymerization of these monomers, i.e., cutin synthase 1 (CUS1), an acyl transferase of the GDSL lipase protein family. By comparing the structure of tomato fruit cutins from wild type and down-regulated CUS1 mutants, as well as with the CUS1-catalyzed formation of oligomers in vitro, hypothetical models can be elaborated on the polymerization of cutins. The polymorphism of the GDSL lipase family raises a number of questions concerning the function of the different isoforms in relation with the formation of a composite material, the cuticle, containing entangled hydrophilic and hydrophobic polymers, i.e., polysaccharides and cutin, and plasticizers, i.e., waxes. PMID- 29156573 TI - Neuraminidase Inhibitory Activity and Constituent Characterization of Fagopyrum dibotrys. AB - This study aimed to identify a new biological activity of the widely distributed species Fagopyrum dibotrys. Four F. dibotrys extracts (ethyl acetate (EA), petroleum ether (P), ethanol (E), and water (W)) were explored for their anti neuraminidase (NA) activity. A total of 32 compounds were identified using UHPLC Q-Exactive Orbitrap HRMS in the EA extract, which had the best NA inhibitory effects. We used the docking data for supporting compounds' anti-neuraminidase activity. Among them, five compounds including one flavonoid, three organic acids, and one glucoside were discovered for the first time in F. dibotrys. Docking studies and NA activity assay revealed the remarkable NA inhibitory activity of eight components in EA extract, especially rutin, hesperidin, procyanidin B2, and quercitrin. Therefore, F. dibotrys could be used to develop anti-influenza drugs. PMID- 29156575 TI - Synthesis of Oxadiazole-Thiadiazole Hybrids and Their Anticandidal Activity. AB - In the field of infection management, it is a major challenge to discover a potent and safe antifungal agent due to the emergence of resistant strains. Hence, the goal of this paper is to design and synthesize novel oxadiazole thiadiazole hybrid compounds (6a-6s) and evaluate their antifungal activity. The structures of synthesized compounds were elucidated by various methods including FT-IR, 1H-NMR, 13C-NMR and HR-MS spectral data. Compounds were tested against four Candida species by broth microdilution assay. Compounds 6e, 6k and 6r, bearing a nitro group, showed significant antifungal activity against all fungi with minimum inhibitory concentration (MIC) in the range of 0.78-3.12 ug/mL. These compounds were also screened for their in vitro cytotoxic effects by MTT assay and detected as nontoxic at their active concentrations against Candida strains. To examine the effects of these compounds on ergosterol biosynthesis, the LC-MS-MS method, which is based on quantification of ergosterol level in C. krusei, was carried out. Finally, the most active molecule (6e) was docked in the active site of the lanosterol 14alpha-demethylase enzyme, and it was determined that there is a strong interaction between the compound and enzyme. PMID- 29156574 TI - Infectious Agents in Atherosclerotic Cardiovascular Diseases through Oxidative Stress. AB - Accumulating evidence demonstrates that vascular oxidative stress is a critical feature of atherosclerotic process, potentially triggered by several infectious agents that are considered as risk co-factors for the atherosclerotic cardiovascular diseases (CVDs). C. pneumoniae has been shown to upregulate multiple enzymatic systems capable of producing reactive oxygen species (ROS) such as NADPH oxidase (NOX) and cyclooxygenase in vascular endothelial cells, NOX and cytochrome c oxidase in macrophages as well as nitric oxide synthase and lipoxygenase in platelets contributing to both early and late stages of atherosclerosis. P. gingivalis seems to be markedly involved in the atherosclerotic process as compared to A. actinomycetemcomitans contributing to LDL oxidation and foam cell formation. Particularly interesting is the evidence describing the NLRP3 inflammasome activation as a new molecular mechanism underlying P. gingivalis-induced oxidative stress and inflammation. Amongst viral agents, immunodeficiency virus-1 and hepatitis C virus seem to have a major role in promoting ROS production, contributing, hence, to the early stages of atherosclerosis including endothelial dysfunction and LDL oxidation. In conclusion, oxidative mechanisms activated by several infectious agents during the atherosclerotic process underlying CVDs are very complex and not well-known, remaining, thus, an attractive target for future research. PMID- 29156576 TI - Stochastic Integration Hinfinity Filter for Rapid Transfer Alignment of INS. AB - The performance of an inertial navigation system (INS) operated on a moving base greatly depends on the accuracy of rapid transfer alignment (RTA). However, in practice, the coexistence of large initial attitude errors and uncertain observation noise statistics poses a great challenge for the estimation accuracy of misalignment angles. This study aims to develop a novel robust nonlinear filter, namely the stochastic integration H infinity filter (SIH infinity F) for improving both the accuracy and robustness of RTA. In this new nonlinear H infinity filter, the stochastic spherical-radial integration rule is incorporated with the framework of the derivative-free H infinity filter for the first time, and the resulting SIH infinity F simultaneously attenuates the negative effect in estimations caused by significant nonlinearity and large uncertainty. Comparisons between the SIH infinity F and previously well-known methodologies are carried out by means of numerical simulation and a van test. The results demonstrate that the newly-proposed method outperforms the cubature H infinity filter. Moreover, the SIH infinity F inherits the benefit of the traditional stochastic integration filter, but with more robustness in the presence of uncertainty. PMID- 29156577 TI - Magnetic Flux Distribution of Linear Machines with Novel Three-Dimensional Hybrid Magnet Arrays. AB - The objective of this paper is to propose a novel tubular linear machine with hybrid permanent magnet arrays and multiple movers, which could be employed for either actuation or sensing technology. The hybrid magnet array produces flux distribution on both sides of windings, and thus helps to increase the signal strength in the windings. The multiple movers are important for airspace technology, because they can improve the system's redundancy and reliability. The proposed design concept is presented, and the governing equations are obtained based on source free property and Maxwell equations. The magnetic field distribution in the linear machine is thus analytically formulated by using Bessel functions and harmonic expansion of magnetization vector. Numerical simulation is then conducted to validate the analytical solutions of the magnetic flux field. It is proved that the analytical model agrees with the numerical results well. Therefore, it can be utilized for the formulation of signal or force output subsequently, depending on its particular implementation. PMID- 29156579 TI - On the Piezoelectric Detection of Guided Ultrasonic Waves. AB - In order to quantify the wave motion of guided ultrasonic waves, the characteristics of piezoelectric detectors, or ultrasonic transducers and acoustic emission sensors, have been evaluated systematically. Such guided waves are widely used in structural health monitoring and nondestructive evaluation, but methods of calibrating piezoelectric detectors have been inadequate. This study relied on laser interferometry for the base displacement measurement of bar waves, from which eight different guided wave test set-ups are developed with known wave motion using piezoelectric transmitters. Both plates and bars of 12.7 and 6.4 mm thickness were used as wave propagation media. The upper frequency limit was 2 MHz. Output of guided wave detectors were obtained on the test set ups and their receiving sensitivities were characterized and averaged. While each sensitivity spectrum was noisy for a detector, the averaged spectrum showed a good convergence to a unique receiving sensitivity. Twelve detectors were evaluated and their sensitivity spectra determined in absolute units. Generally, these showed rapidly dropping sensitivity with increasing frequency due to waveform cancellation on their sensing areas. This effect contributed to vastly different sensitivities to guided wave and to normally incident wave for each one of the 12 detectors tested. Various other effects are discussed and recommendations on methods of implementing the approach developed are provided. PMID- 29156580 TI - Cellular Localization of Wheat High Molecular Weight Glutenin Subunits in Transgenic Rice Grain. AB - Rice (Oryza sativa L.) is a primary global food cereal. However, when compared to wheat, rice has poor food processing qualities. Dough that is made from rice flour has low viscoelasticity because rice seed lacks storage proteins that are comparable to gluten protein from wheat. Thus, current research efforts aim to improve rice flour processing qualities through the transgenic expression of viscoelastic proteins in rice seeds. In this study, we characterized the transgenic expression of wheat glutenin subunits in rice seeds. The two genes 1Dx5_KK and 1Dy10_JK, which both encode wheat high-molecular-weight glutenin subunits that confer high dough elasticity, were cloned from Korean wheat cultivars KeumKang and JoKyung, respectively. These genes were inserted into binary vectors under the control of the rice endosperm-specific Glu-B1 promoter and were expressed in the high-amylose Korean rice cultivar Koami (Oryza sativa L.). Individual expression of both glutenin subunits was confirmed by SDS-PAGE and immunoblot analyses performed using T3 generation of transgenic rice seeds. The subcellular localization of 1Dx5_KK and 1Dy10_JK in the rice seed endosperm was confirmed by immunofluorescence analysis, indicating that the wheat glutenin subunits accumulate in protein body-II and novel protein body types in the rice seed. These results contribute to our understanding of engineered seed storage proteins in rice. PMID- 29156581 TI - An Enhanced Non-Coherent Pre-Filter Design for Tracking Error Estimation in GNSS Receivers. AB - Tracking error estimation is of great importance in global navigation satellite system (GNSS) receivers. Any inaccurate estimation for tracking error will decrease the signal tracking ability of signal tracking loops and the accuracies of position fixing, velocity determination, and timing. Tracking error estimation can be done by traditional discriminator, or Kalman filter-based pre-filter. The pre-filter can be divided into two categories: coherent and non-coherent. This paper focuses on the performance improvements of non-coherent pre-filter. Firstly, the signal characteristics of coherent and non-coherent integration which are the basis of tracking error estimation-are analyzed in detail. After that, the probability distribution of estimation noise of four-quadrant arctangent (ATAN2) discriminator is derived according to the mathematical model of coherent integration. Secondly, the statistical property of observation noise of non-coherent pre-filter is studied through Monte Carlo simulation to set the observation noise variance matrix correctly. Thirdly, a simple fault detection and exclusion (FDE) structure is introduced to the non-coherent pre-filter design, and thus its effective working range for carrier phase error estimation extends from (-0.25 cycle, 0.25 cycle) to (-0.5 cycle, 0.5 cycle). Finally, the estimation accuracies of discriminator, coherent pre-filter, and the enhanced non coherent pre-filter are evaluated comprehensively through the carefully designed experiment scenario. The pre-filter outperforms traditional discriminator in estimation accuracy. In a highly dynamic scenario, the enhanced non-coherent pre filter provides accuracy improvements of 41.6%, 46.4%, and 50.36% for carrier phase error, carrier frequency error, and code phase error estimation, respectively, when compared with coherent pre-filter. The enhanced non-coherent pre-filter outperforms the coherent pre-filter in code phase error estimation when carrier-to-noise density ratio is less than 28.8 dB-Hz, in carrier frequency error estimation when carrier-to-noise density ratio is less than 20 dB-Hz, and in carrier phase error estimation when carrier-to-noise density belongs to (15, 23) dB-Hz ? (26, 50) dB-Hz. PMID- 29156582 TI - In Memoriam: Paolo Cappa. AB - Prof. Paolo Cappa passed away on 26 August 2016, at the age of 59, after a long and courageous fight against cancer. Paolo Cappa was a Professor in Mechanical and Thermal Measurements and Experimental Biomechanics in the Department of Mechanical and Aerospace Engineering of Sapienza University of Rome, where he had also served as the Head of the Department, and a Research Professor in the Department of Mechanical and Aerospace Engineering of New York University Tandon School of Engineering. During his intense, yet short, career, he made several significant scientific contributions within the discipline of Mechanical and Thermal Measurements, pioneering fundamental applications to Biomechanics. He co founded the Motion Analysis and Robotics Laboratory (MARLab) within the Neurorehabilitation Division of IRCCS Pediatric Hospital "Bambino Gesu", in Rome, to fuel transitional research from the laboratory to clinical practice. Through collaboration with neurologists and physiatrists at MARLab, Prof. Cappa led the development of a powerful array of novel mechanical solutions to wearable robotics for pediatric patients, addressing dramatic needs for children's health and contributing to the training of an entire generation of Mechanical Engineering students. PMID- 29156578 TI - Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells. AB - Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth most common cause of cancer related death and is the most lethal of common malignancies with a five-year survival rate of <10%. PDAC arises from different types of non-invasive precursor lesions: intraductal papillary mucinous neoplasms, mucinous cystic neoplasms and pancreatic intraepithelial neoplasia. The genetic landscape of PDAC is characterized by the presence of four frequently-mutated genes: KRAS, CDKN2A, TP53 and SMAD4. The development of mouse models of PDAC has greatly contributed to the understanding of the molecular and cellular mechanisms through which driver genes contribute to pancreatic cancer development. Particularly, oncogenic KRAS-driven genetically-engineered mouse models that phenotypically and genetically recapitulate human pancreatic cancer have clarified the mechanisms through which various mutated genes act in neoplasia induction and progression and have led to identifying the possible cellular origin of these neoplasias. Patient-derived xenografts are increasingly used for preclinical studies and for the development of personalized medicine strategies. The studies of the purification and characterization of pancreatic cancer stem cells have suggested that a minority cell population is responsible for initiation and maintenance of pancreatic adenocarcinomas. The study of these cells could contribute to the identification and clinical development of more efficacious drug treatments. PMID- 29156584 TI - Identification of Physiological Substrates and Binding Partners of the Plant Mitochondrial Protease FTSH4 by the Trapping Approach. AB - Maintenance of functional mitochondria is vital for optimal cell performance and survival. This is accomplished by distinct mechanisms, of which preservation of mitochondrial protein homeostasis fulfills a pivotal role. In plants, inner membrane-embedded i-AAA protease, FTSH4, contributes to the mitochondrial proteome surveillance. Owing to the limited knowledge of FTSH4's in vivo substrates, very little is known about the pathways and mechanisms directly controlled by this protease. Here, we applied substrate trapping coupled with mass spectrometry-based peptide identification in order to extend the list of FTSH4's physiological substrates and interaction partners. Our analyses revealed, among several putative targets of FTSH4, novel (mitochondrial pyruvate carrier 4 (MPC4) and Pam18-2) and known (Tim17-2) substrates of this protease. Furthermore, we demonstrate that FTSH4 degrades oxidatively damaged proteins in mitochondria. Our report provides new insights into the function of FTSH4 in the maintenance of plant mitochondrial proteome. PMID- 29156583 TI - New Paradigms for the Study of Ocular Alphaherpesvirus Infections: Insights into the Use of Non-Traditional Host Model Systems. AB - Ocular herpesviruses, most notably human alphaherpesvirus 1 (HSV-1), canid alphaherpesvirus 1 (CHV-1) and felid alphaherpesvirus 1 (FHV-1), infect and cause severe disease that may lead to blindness. CHV-1 and FHV-1 have a pathogenesis and induce clinical disease in their hosts that is similar to HSV-1 ocular infections in humans, suggesting that infection of dogs and cats with CHV-1 and FHV-1, respectively, can be used as a comparative natural host model of herpesvirus-induced ocular disease. In this review, we discuss both strengths and limitations of the various available model systems to study ocular herpesvirus infection, with a focus on the use of these non-traditional virus-natural host models. Recent work has demonstrated the robustness and reproducibility of experimental ocular herpesvirus infections in dogs and cats, and, therefore, these non-traditional models can provide additional insights into the pathogenesis of ocular herpesvirus infections. PMID- 29156585 TI - Pan-Cellulosomics of Mesophilic Clostridia: Variations on a Theme. AB - The bacterial cellulosome is an extracellular, multi-enzyme machinery, which efficiently depolymerizes plant biomass by degrading plant cell wall polysaccharides. Several cellulolytic bacteria have evolved various elaborate modular architectures of active cellulosomes. We present here a genome-wide analysis of a dozen mesophilic clostridia species, including both well-studied and yet-undescribed cellulosome-producing bacteria. We first report here, the presence of cellulosomal elements, thus expanding our knowledge regarding the prevalence of the cellulosomal paradigm in nature. We explored the genomic organization of key cellulosome components by comparing the cellulosomal gene clusters in each bacterial species, and the conserved sequence features of the specific cellulosomal modules (cohesins and dockerins), on the background of their phylogenetic relationship. Additionally, we performed comparative analyses of the species-specific repertoire of carbohydrate-degrading enzymes for each of the clostridial species, and classified each cellulosomal enzyme into a specific CAZy family, thus indicating their putative enzymatic activity (e.g., cellulases, hemicellulases, and pectinases). Our work provides, for this large group of bacteria, a broad overview of the blueprints of their multi-component cellulosomal complexes. The high similarity of their scaffoldin clusters and dockerin-based recognition residues suggests a common ancestor, and/or extensive horizontal gene transfer, and potential cross-species recognition. In addition, the sporadic spatial organization of the numerous dockerin-containing genes in several of the genomes, suggests the importance of the cellulosome paradigm in the given bacterial species. The information gained in this work may be utilized directly or developed further by genetically engineering and optimizing designer cellulosome systems for enhanced biotechnological biomass deconstruction and biofuel production. PMID- 29156586 TI - In-Depth Glyco-Peptidomics Approach Reveals Unexpected Diversity of Glycosylated Peptides and Atypical Post-Translational Modifications in Dendroaspis angusticeps Snake Venom. AB - Animal venoms represent a valuable source of bioactive peptides that can be derived into useful pharmacological tools, or even innovative drugs. In this way, the venom of Dendroaspis angusticeps (DA), the Eastern Green Mamba, has been intensively studied during recent years. It mainly contains hundreds of large toxins from 6 to 9 kDa, each displaying several disulfide bridges. These toxins are the main target of venom-based studies due to their valuable activities obtained by selectively targeting membrane receptors, such as ion channels or G protein coupled receptors. This study aims to demonstrate that the knowledge of venom composition is still limited and that animal venoms contain unexpected diversity and surprises. A previous study has shown that Dendroaspis angusticeps venom contains not only a cocktail of classical toxins, but also small glycosylated peptides. Following this work, a deep exploration of DA glycopeptidome by a dual nano liquid chromatography coupled to electrospray ionization mass spectrometry (nanoLC-ESI-MS) and Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) analyses was initiated. This study reveals unsuspected structural diversity of compounds such as 221 glycopeptides, displaying different glycan structures. Sequence alignments underline structural similarities with natriuretic peptides already characterized in Elapidae venoms. Finally, the presence of an S-cysteinylation and hydroxylation of proline on four glycopeptides, never described to date in snake venoms, is also revealed by proteomics and affined by nuclear magnetic resonance (NMR) experiments. PMID- 29156587 TI - A Subnano-g Electrostatic Force-Rebalanced Flexure Accelerometer for Gravity Gradient Instruments. AB - A subnano-g electrostatic force-rebalanced flexure accelerometer is designed for the rotating accelerometer gravity gradient instrument. This accelerometer has a large proof mass, which is supported inversely by two pairs of parallel leaf springs and is centered between two fixed capacitor plates. This novel design enables the proof mass to move exactly along the sensitive direction and exhibits a high rejection ratio at its cross-axis directions. Benefiting from large proof mass, high vacuum packaging, and air-tight sealing, the thermal Brownian noise of the accelerometer is lowered down to less than 0.2 ng / Hz with a quality factor of 15 and a natural resonant frequency of about 7.4 Hz . The accelerometer's designed measurement range is about +/-1 mg. Based on the correlation analysis between a commercial triaxial seismometer and our accelerometer, the demonstrated self-noise of our accelerometers is reduced to lower than 0.3 ng / Hz over the frequency ranging from 0.2 to 2 Hz, which meets the requirement of the rotating accelerometer gravity gradiometer. PMID- 29156588 TI - Cytotoxicity of Poly(Alkyl Cyanoacrylate) Nanoparticles. AB - Although nanotoxicology has become a large research field, assessment of cytotoxicity is often reduced to analysis of one cell line only. Cytotoxicity of nanoparticles is complex and should, preferentially, be evaluated in several cell lines with different methods and on multiple nanoparticle batches. Here we report the toxicity of poly(alkyl cyanoacrylate) nanoparticles in 12 different cell lines after synthesizing and analyzing 19 different nanoparticle batches and report that large variations were obtained when using different cell lines or various toxicity assays. Surprisingly, we found that nanoparticles with intermediate degradation rates were less toxic than particles that were degraded faster or more slowly in a cell-free system. The toxicity did not vary significantly with either the three different combinations of polyethylene glycol surfactants or with particle size (range 100-200 nm). No acute pro- or anti inflammatory activity on cells in whole blood was observed. PMID- 29156589 TI - Genome-Wide Development of MicroRNA-Based SSR Markers in Medicago truncatula with Their Transferability Analysis and Utilization in Related Legume Species. AB - Microsatellite (simple sequence repeats, SSRs) marker is one of the most widely used markers in marker-assisted breeding. As one type of functional markers, MicroRNA-based SSR (miRNA-SSR) markers have been exploited mainly in animals, but the development and characterization of miRNA-SSR markers in plants are still limited. In the present study, miRNA-SSR markers for Medicago truncatula (M. truncatula) were developed and their cross-species transferability in six leguminous species was evaluated. A total of 169 primer pairs were successfully designed from 130 M. truncatula miRNA genes, the majority of which were mononucleotide repeats (70.41%), followed by dinucleotide repeats (14.20%), compound repeats (11.24%) and trinucleotide repeats (4.14%). Functional classification of SSR-containing miRNA genes showed that all targets could be grouped into three Gene Ontology (GO) categories: 17 in biological process, 11 in molecular function, and 14 in cellular component. The miRNA-SSR markers showed high transferability in other six leguminous species, ranged from 74.56% to 90.53%. Furthermore, 25 Mt-miRNA-SSR markers were used to evaluate polymorphisms in 20 alfalfa accessions, and the polymorphism information content (PIC) values ranged from 0.39 to 0.89 with an average of 0.71, the allele number per marker varied from 3 to 18 with an average of 7.88, indicating a high level of informativeness. The present study is the first time developed and characterized of M. truncatula miRNA-SSRs and demonstrated their utility in transferability, these novel markers will be valuable for genetic diversity analysis, marker assisted selection and genotyping in leguminous species. PMID- 29156590 TI - Enhancement of Aggregation-Induced Emission by Introducing Multiple o-Carborane Substitutions into Triphenylamine. AB - The enhancement of aggregation-induced emission (AIE) is presented on the basis of the strategy for improving solid-state luminescence by employing multiple o carborane substituents. We synthesized the modified triphenylamines with various numbers of o-carborane units and compared their optical properties. From the optical measurements, the emission bands from the twisted intramolecular charge transfer (TICT) state were obtained from the modified triphenylamines. It was notable that emission efficiencies of the multi-substituted triphenylamines including two or three o-carborane units were enhanced 6- to 8-fold compared to those of the mono-substituted triphenylamine. According to mechanistic studies, it was proposed that the single o-carborane substitution can load the AIE property via the TICT mechanism. It was revealed that the additional o-carborane units contribute to improving solid-state emission by suppressing aggregation caused quenching (ACQ). Subsequently, intense AIEs were obtained. This paper presents a new role of the o-carborane substituent in the enhancement of AIEs. PMID- 29156591 TI - Plasmonic Spectral Splitting in Ring/Rod Metasurface. AB - We report spectral splitting behaviors based on Fano resonances in a novel simple planar metasurface composed of gold nanobars and nanorings. Multiple plasmonic modes and sharp Fano effects are achieved in a broadband transmittance spectrum by exploiting the rotational symmetry of the metasurface. The transmission properties are effectively modified and tuned by modulating the structural parameters. The highest single side Q-factor and FoM which reaches 196 and 105 are observed at Fano resonances. Our proposed design is relatively simple and can be applied for various applications such as multi-wavelength highly sensitive plasmonic sensors, switching, and slow light devices. PMID- 29156592 TI - Activation of TREK-1, but Not TREK-2, Channel by Mood Stabilizers. AB - Earlier studies have demonstrated that the tandem pore domain weak inward rectifying K+ channel (TWIK)-related K+ (TREK)-1 channel is inhibited by antidepressants and is associated with major depression. However, little is known about the effect of mood stabilizers that are commonly used for treatment of bipolar disorder on TREK channels, members of the two-pore domain K+ (K2P) channel family. This study sought to investigate the effect of mood stabilizers on TREK-1 and TREK-2 channels. HEK-293A cells were transfected with human TREK-1 or TREK-2 DNA. The effect of mood stabilizers on TREK-1 and TREK-2 was studied using the patch clamp technique. Changes in TREK protein expression by mood stabilizers were studied in the HT-22 mouse hippocampal neuronal cells using western blot analysis. Lithium chloride (LiCl, 1 mM), gabapentin (100 MUM), valproate (100 MUM), and carbamazepine (100 MUM) increased TREK-1 currents by 31 +/- 14%, 25 +/- 11%, 28 +/- 12%, and 72 +/- 12%, respectively, whereas they had no effect on TREK-2 channel activity. In addition, western blot analysis showed LiCl and carbamazepine slightly upregulated TREK-1 expression, but not TREK-2 in the HT-22 cells. These results suggest that TREK-1 could be a potential therapeutic target for treatment of bipolar disorders as well as depression, while TREK-2 is a target well suited for treatment of major depression. PMID- 29156593 TI - Site-Directed Mutagenesis of the Fibronectin Domains in Insulin Receptor-Related Receptor. AB - The orphan insulin receptor-related receptor (IRR), in contrast to its close homologs, the insulin receptor (IR) and insulin-like growth factor receptor (IGF IR) can be activated by mildly alkaline extracellular medium. We have previously demonstrated that IRR activation is defined by its extracellular region, involves multiple domains, and shows positive cooperativity with two synergistic sites. By the analyses of point mutants and chimeras of IRR with IR in, we now address the role of the fibronectin type III (FnIII) repeats in the IRR pH-sensing. The first activation site includes the intrinsically disordered subdomain ID (646-716) within the FnIII-2 domain at the C-terminus of IRR alpha subunit together with closely located residues L135, G188, R244, H318, and K319 of L1 and C domains of the second subunit. The second site involves residue T582 of FnIII-1 domain at the top of IRR lambda-shape pyramid together with M406, V407, and D408 from L2 domain within the second subunit. A possible importance of the IRR carbohydrate moiety for its activation was also assessed. IRR is normally less glycosylated than IR and IGF-IR. Swapping both FnIII-2 and FnIII-3 IRR domains with those of IR shifted beta-subunit mass from 68 kDa for IRR to about 100 kDa due to increased glycosylation and abolished the IRR pH response. However, mutations of four asparagine residues, potential glycosylation sites in chimera IRR with swapped FnIII-2/3 domains of IR, decreased the chimera glycosylation and resulted in a partial restoration of IRR pH-sensing activity, suggesting that the extensive glycosylation of FnIII-2/3 provides steric hindrance for the alkali induced rearrangement of the IRR ectodomain. PMID- 29156594 TI - Chemical Transformations in Proto-Cytoplasmic Media. Phosphorus Coupling in the Silica Hydrogel Phase. AB - It has been proposed that prebiotic chemical studies on the emergence of primitive life would be most relevant when performed in a hydrogel, rather than an aqueous, environment. In this paper we describe the ambient temperature coupling of phosphorus oxyacids [Pi] mediated by Fe(II) under aerobic conditions within a silica hydrogel (SHG) environment. We have chosen to examine SHGs as they have considerable geological precedence as key phases in silicification en route to rock formation. Following a description of the preparation and characterization studies on our SHG formulations, coupling experiments between Pi species are described across multiple permutations of (i) Pi compound; (ii) gel formulation; (iii) metal salt additive; and (iv) pH-modifying agent. The results suggest that successful Pi coupling, indicated by observation of pyrophosphate [PPi(V)] via 31P-NMR spectroscopy, takes place when the following components are present: (i) a mixture of mixture of Pi(III) and Pi(V) or pure PPi(III-V); (ii) Fe(II); (iii) acetic or formic acid (not hydrochloric acid); (iv) aerobic conditions or the presence of H2O2 as an oxidant; and (v) the presence of a gel system. On the basis of these, and aqueous control reactions, we suggest mechanistic possibilities. PMID- 29156595 TI - Two-Dimensional Micro-/Nanoradian Angle Generator with High Resolution and Repeatability Based on Piezo-Driven Double-Axis Flexure Hinge and Three Capacitive Sensors. AB - This study presents a two-dimensional micro-/nanoradian angle generator (2D-MNAG) that achieves high angular displacement resolution and repeatability using a piezo-driven flexure hinge for two-dimensional deflections and three capacitive sensors for output angle monitoring and feedback control. The principal error of the capacitive sensor for precision microangle measurement is analyzed and compensated for; so as to achieve a high angle output resolution of 10 nrad (0.002 arcsec) and positioning repeatability of 120 nrad (0.024 arcsec) over a large angular range of +/-4363 MUrad (+/-900 arcsec) for the 2D-MNAG. The impact of each error component, together with the synthetic error of the 2D-MNAG after principal error compensation are determined using Monte Carlo simulation for further improvement of the 2D-MNAG. PMID- 29156597 TI - Different Ways to Apply a Measurement Instrument of E-Nose Type to Evaluate Ambient Air Quality with Respect to Odour Nuisance in a Vicinity of Municipal Processing Plants. AB - This review paper presents different ways to apply a measurement instrument of e nose type to evaluate ambient air with respect to detection of the odorants characterized by unpleasant odour in a vicinity of municipal processing plants. An emphasis was put on the following applications of the electronic nose instruments: monitoring networks, remote controlled robots and drones as well as portable devices. Moreover, this paper presents commercially available sensors utilized in the electronic noses and characterized by the limit of quantification below 1 ppm v/v, which is close to the odour threshold of some odorants. Additionally, information about bioelectronic noses being a possible alternative to electronic noses and their principle of operation and application potential in the field of air evaluation with respect to detection of the odorants characterized by unpleasant odour was provided. PMID- 29156598 TI - Novel Montmorillonite/TiO2/MnAl-Mixed Oxide Composites Prepared from Inverse Microemulsions as Combustion Catalysts. AB - A novel design of combustion catalysts is proposed, in which clay/TiO2/MnAl-mixed oxide composites are formed by intermixing exfoliated organo-montmorillonite with oxide precursors (hydrotalcite-like in the case of Mn-Al oxide) obtained by an inverse microemulsion method. In order to assess the catalysts' thermal stability, two calcination temperatures were employed: 450 and 600 degrees C. The composites were characterized with XRF (X-ray fluorescence), XRD (X-ray diffraction), HR SEM (high resolution scanning electron microscopy, N2 adsorption/desorption at -196 degrees C, and H2 TPR (temperature programmed reduction). Profound differences in structural, textural and redox properties of the materials were observed, depending on the presence of the TiO2 component, the type of neutralization agent used in the titania nanoparticles preparation (NaOH or NH3 (aq)), and the temperature of calcination. Catalytic tests of toluene combustion revealed that the clay/TiO2/MnAl-mixed oxide composites prepared with the use of ammonia showed excellent activity, the composites obtained from MnAl hydrotalcite nanoparticles trapped between the organoclay layers were less active, but displayed spectacular thermal stability, while the clay/TiO2/MnAl mixed oxide materials obtained with the aid of NaOH were least active. The observed patterns of catalytic activity bear a direct relation to the materials' composition and their structural, textural, and redox properties. PMID- 29156599 TI - Illumination of a Vision-How Arthur Rimbaud Will Give Us Motivation to Find New Input into Bladder Cancer Biomarker Research. AB - Bladder cancer (BC) accounts for approximately 430,000 new cases and 165,000 deaths each year worldwide [...]. PMID- 29156596 TI - Microvesicle Involvement in Shiga Toxin-Associated Infection. AB - Shiga toxin is the main virulence factor of enterohemorrhagic Escherichia coli, a non-invasive pathogen that releases virulence factors in the intestine, causing hemorrhagic colitis and, in severe cases, hemolytic uremic syndrome (HUS). HUS manifests with acute renal failure, hemolytic anemia and thrombocytopenia. Shiga toxin induces endothelial cell damage leading to platelet deposition in thrombi within the microvasculature and the development of thrombotic microangiopathy, mostly affecting the kidney. Red blood cells are destroyed in the occlusive capillary lesions. This review focuses on the importance of microvesicles shed from blood cells and their participation in the prothrombotic lesion, in hemolysis and in the transfer of toxin from the circulation into the kidney. Shiga toxin binds to blood cells and may undergo endocytosis and be released within microvesicles. Microvesicles normally contribute to intracellular communication and remove unwanted components from cells. Many microvesicles are prothrombotic as they are tissue factor- and phosphatidylserine-positive. Shiga toxin induces complement-mediated hemolysis and the release of complement-coated red blood cell-derived microvesicles. Toxin was demonstrated within blood cell derived microvesicles that transported it to renal cells, where microvesicles were taken up and released their contents. Microvesicles are thereby involved in all cardinal aspects of Shiga toxin-associated HUS, thrombosis, hemolysis and renal failure. PMID- 29156600 TI - Fabrication of Semiconductor ZnO Nanostructures for Versatile SERS Application. AB - Since the initial discovery of surface-enhanced Raman scattering (SERS) in the 1970s, it has exhibited a huge potential application in many fields due to its outstanding advantages. Since the ultra-sensitive noble metallic nanostructures have increasingly exposed themselves as having some problems during application, semiconductors have been gradually exploited as one of the critical SERS substrate materials due to their distinctive advantages when compared with noble metals. ZnO is one of the most representative metallic oxide semiconductors with an abundant reserve, various and cost-effective fabrication techniques, as well as special physical and chemical properties. Thanks to the varied morphologies, size-dependent exciton, good chemical stability, a tunable band gap, carrier concentration, and stoichiometry, ZnO nanostructures have the potential to be exploited as SERS substrates. Moreover, other distinctive properties possessed by ZnO such as biocompatibility, photocatcalysis and self-cleaning, and gas- and chemo-sensitivity can be synergistically integrated and exerted with SERS activity to realize the multifunctional potential of ZnO substrates. In this review, we discuss the inevitable development trend of exploiting the potential semiconductor ZnO as a SERS substrate. After clarifying the root cause of the great disparity between the enhancement factor (EF) of noble metals and that of ZnO nanostructures, two specific methods are put forward to improve the SERS activity of ZnO, namely: elemental doping and combination of ZnO with noble metals. Then, we introduce a distinctive advantage of ZnO as SERS substrate and illustrate the necessity of reporting a meaningful average EF. We also summarize some fabrication methods for ZnO nanostructures with varied dimensions (0-3 dimensions). Finally, we present an overview of ZnO nanostructures for the versatile SERS application. PMID- 29156601 TI - Acute Toxicity and Ecological Risk Assessment of Benzophenone-3 (BP-3) and Benzophenone-4 (BP-4) in Ultraviolet (UV)-Filters. AB - Ultraviolet (UV)-absorbing chemicals (UV filters) are used in personal care products for the protection of human skin and hair from damage by UV radiation. Although these substances are released into the environment in the production and consumption processes, little is known about their ecotoxicology effects. The acute toxicity and potential ecological risk of UV filters benzophenone-3 (BP-3) and benzophenone-4 (BP-4) on Chlorella vulgaris, Daphnia magna, and Brachydanio rerio were analyzed in the present study. The EC50 values (96 h) of BP-3 and BP-4 on C. vulgaris were 2.98 and 201.00 mg/L, respectively. The 48 h-LC50 of BP-3 and BP-4 on D. magna were 1.09 and 47.47 mg/L, respectively. The 96 h-LC50 of BP-3 and BP-4 on B. rerio were 3.89 and 633.00 mg/L, respectively. The toxicity of a mixture of BP-3 and BP-4 on C. vulgaris, D. magna, and B. rerio all showed antagonistic effects. The induced predicted no-effect concentrations of BP-3 and BP-4 by the assessment factor method were 1.80 * 10-3 and 0.47 mg/L, respectively, by assessment factor (AF) method, which were both lower than the concentrations detected in the environment at present, verifying that BP-3 and BP 4 remain low-risk chemicals to the aquatic ecosystem. PMID- 29156602 TI - Assembled Cantilever Fiber Touch Trigger Probe for Three-Dimensional Measurement of Microstructures. AB - In this paper, an assembled cantilever fiber touch trigger probe was developed for three-dimensional measurements of clear microstructures. The probe consists of a shaft assembled vertically to an optical fiber cantilever and a probing sphere located at the free end of the shaft. The laser is emitted from the free end of the fiber cantilever and converges on the photosensitive surface of the camera through the lens. The position shift of the light spot centroid was used to detect the performance of the optical fiber cantilever, which changed dramatically when the probing sphere touched the objects being measured. Experimental results indicated that the sensing system has sensitivities of 3.32 pixels/MUm, 1.35 pixels/MUm, and 7.38 pixels/MUm in the x, y, and z directions, respectively, and resolutions of 10 nm, 30 nm, and 5 nm were achieved in the x, y, and z, respectively. An experiment on micro slit measurement was performed to verify the high aspect ratio measurement capability of the assembled cantilever fiber (ACF) probe and to calibrate the effective two-point diameter of the probing sphere. The two-point probe sphere diameter was found to be 174.634 MUm with a standard uncertainly of 0.045 MUm. PMID- 29156604 TI - Takamatsu, H. Comparison of Minimal Residual Disease Detection by Multiparameter Flow Cytometry, ASO-qPCR, Droplet Digital PCR, and Deep Sequencing in Patients with Multiple Myeloma Who Underwent Autologous Stem Cell Transplantation. J. Clin. Med. 2017, 6, 91. AB - The author wishes to make the following correction to this paper [...]. PMID- 29156603 TI - Adding an Artificial Tail-Anchor to a Peptide-Based HIV-1 Fusion Inhibitor for Improvement of Its Potency and Resistance Profile. AB - Peptides derived from the C-terminal heptad repeat (CHR) of human immunodeficiency virus type 1 (HIV-1) envelope protein transmembrane subunit gp41, such as T20 (enfuvirtide), can bind to the N-terminal heptad repeat (NHR) of gp41 and block six-helix bundle (6-HB) formation, thus inhibiting HIV-1 fusion with the target cell. However, clinical application of T20 is limited because of its low potency and genetic barrier to resistance. HP23, the shortest CHR peptide, exhibits better anti-HIV-1 activity than T20, but the HIV-1 strains with E49K mutations in gp41 will become resistant to it. Here, we modified HP23 by extending its C-terminal sequence using six amino acid residues (E6) and adding IDL (Ile-Asp-Leu) to the C-terminus of E6, which is expected to bind to the shallow pocket in the gp41 NHR N-terminal region. The newly designed peptide, designated HP23-E6-IDL, was about 2- to 16-fold more potent than HP23 against a broad spectrum of HIV-1 strains and more than 12-fold more effective against HIV 1 mutants resistant to HP23. These findings suggest that addition of an anchor tail to the C-terminus of a CHR peptide will allow binding with the pocket in the gp41 NHR that may increase the peptide's antiviral efficacy and its genetic barrier to resistance. PMID- 29156605 TI - Performance Indices in Wheat Chlorophyll a Fluorescence and Protein Quality Influenced by FHB. AB - Very little is known about the physiological interactions between wheat quality and Fusarium head blight (FHB), which substantially reduces wheat grain yield and quality worldwide. In order to investigate stress-induced changes in flag leaves from plants artificially inoculated with Fusarium, we screened for chlorophyll a fluorescence transient at 1, 2, 4, 7 and 14 days after Fusarium inoculation. Our results indicate that the maximum quantum yield of photochemistry (Fv/Fm) and the performance index (PI) were not affected by FHB, but there were significant differences in those two traits between different varieties and measurement times. FHB caused a significant reduction in the percentage of glutenins (GLU), high-molecular-weight (HMW), and low-molecular-weight (LMW) subunits in 'Kraljica' and 'Golubica', unlike 'Vulkan', where the percentage of GLU increased. PMID- 29156606 TI - Synthesis and In Vitro Cytotoxicity of the 4-(Halogenoanilino)-6 bromoquinazolines and Their 6-(4-Fluorophenyl) Substituted Derivatives as Potential Inhibitors of Epidermal Growth Factor Receptor Tyrosine Kinase. AB - Series of the 2-unsubstituted and 2-(4-chlorophenyl)-substituted 4-anilino-6 bromoquinazolines and their 6-(4-fluorophenyl)-substituted derivatives were evaluated for in vitro cytotoxicity against MCF-7 and HeLa cells. The 2 unsubstituted 4-anilino-6-bromoquinazolines lacked activity, whereas most of their 2-(4-chlorophenyl) substituted derivatives were found to exhibit significant cytotoxicity and selectivity against HeLa cells. Replacement of bromine with 4-fluorophenyl group for the 2-unsubstituted 4-anilinoquinazolines resulted in superior activity against HeLa cells compared to Gefitinib. The presence of a 4-fluorophenyl group in the 2-(4-chlorophenyl) substituted derivatives led to increased cytotoxicity against HeLa cells, except for the 3 chloroanilino derivative. The most active compounds, namely, 3g, 3l, and 4l, were found to exhibit a moderate to significant inhibitory effect against epidermal growth factor receptor tyrosine kinase (EGFR-TK). The EGFR molecular docking model suggested that these compounds are nicely bound to the region of EGFR. PMID- 29156607 TI - Calcium-Dependent Protein Kinases in Phytohormone Signaling Pathways. AB - Calcium-dependent protein kinases (CPKs/CDPKs) are Ca2+-sensors that decode Ca2+ signals into specific physiological responses. Research has reported that CDPKs constitute a large multigene family in various plant species, and play diverse roles in plant growth, development, and stress responses. Although numerous CDPKs have been exhaustively studied, and many of them have been found to be involved in plant hormone biosynthesis and response mechanisms, a comprehensive overview of the manner in which CDPKs participate in phytohormone signaling pathways, regulating nearly all aspects of plant growth, has not yet been undertaken. In this article, we reviewed the structure of CDPKs and the mechanism of their subcellular localization. Some CDPKs were elucidated to influence the intracellular localization of their substrates. Since little work has been done on the interaction between CDPKs and cytokinin signaling pathways, or on newly defined phytohormones such as brassinosteroids, strigolactones and salicylic acid, this paper mainly focused on discussing the integral associations between CDPKs and five plant hormones: auxins, gibberellins, ethylene, jasmonates, and abscisic acid. A perspective on future work is provided at the end. PMID- 29156609 TI - Green Routes for the Production of Enantiopure Benzylisoquinoline Alkaloids. AB - Benzylisoquinoline alkaloids (BIAs) are among the most important plant secondary metabolites, in that they include a number of biologically active substances widely employed as pharmaceuticals. Isolation of BIAs from their natural sources is an expensive and time-consuming procedure as they accumulate in very low levels in plant. Moreover, total synthesis is challenging due to the presence of stereogenic centers. In view of these considerations, green and scalable methods for BIA synthesis using fully enzymatic approaches are getting more and more attention. The aim of this paper is to review fully enzymatic strategies for producing the benzylisoquinoline central precursor, (S)-norcoclaurine and its derivatives. Specifically, we will detail the current status of synthesis of BIAs in microbial hosts as well as using isolated and recombinant enzymes. PMID- 29156611 TI - Immunodetection of Porcine Red Blood Cell Containing Food Ingredients Using a Porcine-Hemoglobin-Specific Monoclonal Antibody. AB - Monoclonal antibody (mAb) 24C12-E7 has been found to bind to a 12 kDa antigenic protein in the red blood cell (RBC) of porcine blood. The purpose of this study was to determine the identity of this 12 kDa protein and consequently examine its potential as a marker for monitoring porcine RBC-containing ingredients (PRBCIs) in foods. Proteomic techniques identified the 12 kDa antigenic protein to be a monomer of the tetrameric hemoglobin molecule. Further heat-processing of spray dried PRBCIs diminishes its detectability. Whereas mAb 24C12-E7-based indirect enzyme-linked immunosorbent assay (iELISA) could detect 1% (v/v) or less of PRBCIs in raw and cooked ground meats (beef, pork and chicken), the detection limits were 3 to 30 times higher for spiked cooked beef and pork. The assay is effective for monitoring the presence of PRBCIs in foods to protect the billions of people that avoid consuming blood. In situations where these PRBCIs are present as ingredients in foods that have undergone further heat processing, the assay, however, may not be as sensitive depending on the types of sample matrix, types of PRBCIs and the level of inclusion. PMID- 29156610 TI - Bevacizumab for Patients with Recurrent Multifocal Glioblastomas. AB - In patients with glioblastoma, antiangiogenic therapy with bevacizumab (BEV) has been shown to improve progression-free survival (PFS), but not overall survival (OS). Especially in patients with an unusual infiltrative phenotype as seen in multifocal glioblastoma, the use of BEV therapy is still more controversial. Therefore, we prepared a retrospective case series with 16 patients suffering from a multifocal glioblastoma treated with BEV. We compared these patients to a matched control cohort of 16 patients suffering from glioblastoma with a single lesion treated with BEV. The objective of this study was to evaluate whether the course of disease differs in glioblastoma patients with a multifocal disease pattern compared to those with a single lesion only. Patients were treated with BEV monotherapy or BEV in combination with irinotecan or lomustine (CCNU). Response rates and PFS were similar in both groups. There was a trend for an unfavorable OS in the patient group with multifocal glioblastoma, which was expected due to the generally worse prognosis of multifocal glioblastoma. We investigated whether BEV therapy affects the invasive growth pattern as measured by the appearance of new lesions on magnetic resonance imaging (MRI). Under BEV therapy, there was a trend for a lower frequency of new lesions both in multifocal and solitary glioblastoma. Based on these results, BEV therapy at relapse appears to be justified to no lesser extent in multifocal glioblastoma than in solitary glioblastoma. PMID- 29156608 TI - Fatty Acids, Antioxidants and Physical Activity in Brain Aging. AB - Polyunsaturated fatty acids and antioxidants are important mediators in the central nervous system. Lipid derivatives may control the production of proinflammatory agents and regulate NF-kappaB activity, microglial activation, and fatty acid oxidation; on the other hand, antioxidants, such as glutathione and ascorbate, have been shown to signal through transmitter receptors and protect against acute and chronic oxidative stress, modulating the activity of different signaling pathways. Several authors have investigated the role of these nutrients in the brains of the young and the aged in degenerative diseases such as Alzheimer's and Parkinson's, and during brain aging due to adiposity- and physical inactivity-mediated metabolic disturbances, chronic inflammation, and oxidative stress. Through a literature review, we aimed to highlight recent data on the role of adiposity, fatty acids, antioxidants, and physical inactivity in the pathophysiology of the brain and in the molecular mechanisms of senescence. Data indicate the complexity and necessity of endogenous/dietary antioxidants for the maintenance of redox status and the control of neuroglial signaling under stress. Recent studies also indicate that omega-3 and -6 fatty acids act in a competitive manner to generate mediators for energy metabolism, influencing feeding behavior, neural plasticity, and memory during aging. Finding pharmacological or dietary resources that mitigate or prevent neurodegenerative affections continues to be a great challenge and requires additional effort from researchers, clinicians, and nutritionists in the field. PMID- 29156612 TI - Leishmanicidal Activity of Biogenic Fe3O4 Nanoparticles. AB - Abstract: Due to the multiplicity of useful applications of metal oxide nanoparticles (ONPs) in medicine are growing exponentially, in this study, Fe3O4 (iron oxide) nanoparticles (IONPs) were biosynthesized using Rosemary to evaluate the leishmanicidal efficiency of green synthesized IONPs. This is the first report of the leishmanicidal efficiency of green synthesized IONPs against Leishmania major. The resulting biosynthesized IONPs were characterized by ultraviolet-visible spectroscopy (UV-Vis), X-ray diffraction (XRD), transmission electron microscopy (TEM), and Fourier transform infrared spectroscopy (FTIR). The leishmanicidal activity of IONPS was studied via 3-4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. The results showed the fabrication of the spherical shape of monodisperse IONPs with a size 4 +/- 2 nm. The UV visible spectrophotometer absorption peak was at 334 nm. The leishmanicidal activity of biogenic iron oxide nanoparticles against Leishmania major (promastigote) was also studied. The IC50 of IONPs was 350 ug/mL. In this report, IONPs were synthesized via a green method. IONPs are mainly spherical and homogeneous, with an average size of about 4 nm, and were synthesized here using an eco-friendly, simple, and inexpensive method. PMID- 29156613 TI - Synthesis and Swelling Behavior of pH-Sensitive Semi-IPN Superabsorbent Hydrogels Based on Poly(acrylic acid) Reinforced with Cellulose Nanocrystals. AB - pH-sensitive poly(acrylic acid) (PAA) hydrogel reinforced with cellulose nanocrystals (CNC) was prepared. Acrylic acid (AA) was subjected to chemical cross-linking using the cross-linking agent MBA (N,N-methylenebisacrylamide) with CNC entrapped in the PAA matrix. The quantity of CNC was varied between 0, 5, 10, 15, 20, and 25 wt %. X-ray diffraction (XRD) data showed an increase in crystallinity with the addition of CNC, while rheology tests demonstrated a significant increase in the storage modulus of the hydrogel with an increase in CNC content. It was found that the hydrogel reached maximum swelling at pH 7. The potential of the resulting hydrogels to act as drug carriers was then evaluated by means of the drug encapsulation efficiency test using theophylline as a model drug. It was observed that 15% CNC/PAA hydrogel showed the potential to be used as drug carrier system. PMID- 29156614 TI - A Loop All-Fiber Current Sensor Based on Single-Polarization Single-Mode Couplers. AB - Low current sensitivity and insufficient system stability are two key problems in all-fiber current sensor (AFCS) studies. In order to solve the two problems, a novel AFCS combining single-polarization single-mode (SPSM) couplers and a loop structure is presented in this paper with a design that incorporates the advantages of both SPSM couplers and a loop structure. SPSM couplers are shown to simplify the AFCS system and reduce the risk of interference, and the loop structure can enhance the current sensitivity. Both theory and experiment prove that the new AFCS can simultaneously overcome two prevalent obstacles of low current sensitivity and low stability. PMID- 29156615 TI - Clinical Significance of Measuring Global Hydroxymethylation of White Blood Cell DNA in Prostate Cancer: Comparison to PSA in a Pilot Exploratory Study. AB - This is the first study investigating the clinical relevance of 5 hydroxymethylcytosine (5hmC) in genomic DNA from white blood cells (WBC) in the context of prostate cancer (PCa) and other prostate pathologies. Using an enzyme linked immunosorbent assay, we identified significantly different distributions of patients with low and elevated 5hmC content in WBC DNA across controls and patients with prostate cancer (PCa), atypical small acinar proliferation (ASAP), and benign prostatic hyperplasia (BPH). The measured values were within the normal range for most PCa patients, while the latter category was predominant for ASAP. We observed a wider heterogeneity in 5hmC content in all of the prostate pathologies analyzed when compared to the healthy age-matched controls. When compared to blood levels of prostate-specific antigen (PSA), this 5hmC-based biomarker had a lower performance in PCa detection than the use of a PSA cut-off of 2.5 nanograms per milliliter (ng/mL). Above this threshold, however, it delineated almost three quarters of PCa patients from controls and patients with other prostate pathologies. Overall, genome-wide 5hmC content of WBC DNA appears to be applicable for detecting non-cancerous prostate diseases, rather than PCa. Our results also suggest a potential clinical usefulness of complementing PSA as a PCa marker by the addition of a set of hydroxymethylation markers in the blood, but further studies are necessary to confirm these findings. PMID- 29156616 TI - A Novel Mutation in the Fibrinogen Bbeta Chain (c.490G>A; End of Exon 3) Causes a Splicing Abnormality and Ultimately Leads to Congenital Hypofibrinogenemia. AB - We found a novel heterozygous mutation in the fibrinogen Bbeta chain (c.490G>A) of a 3-year-old girl with congenital hypofibrinogenemia. To clarify the complex genetic mechanism, we made a mini-gene including a FGB c.490G>A mutation region, transfected it into a Chinese Hamster Ovary (CHO) cell line, and analyzed reverse transcription (RT) products. The assembly process and secretion were examined using recombinant mutant fibrinogen. Direct sequencing demonstrated that the mutant RT product was 99 bp longer than the wild-type product, and an extra 99 bases were derived from intron 3. In recombinant expression, a mutant Bbeta-chain was weakly detected in the transfected CHO cell line, and aberrant fibrinogen was secreted into culture media; however, an aberrant Bbeta-chain was not detected in plasma. Since the aberrant Bbeta-chain was catabolized faster in cells, the aberrant Bbeta-chain in a small amount of secreted fibrinogen may catabolize in the bloodstream. FGB c.490G>A indicated the activation of a cryptic splice site causing the insertion of 99 bp in intron 3. This splicing abnormality led to the production of a Bbeta-chain possessing 33 aberrant amino acids, including two Cys residues in the coiled-coil domain. Therefore, a splicing abnormality may cause impaired fibrinogen assembly and secretion. PMID- 29156617 TI - Optimum Thermal Processing for Extended Shelf-Life (ESL) Milk. AB - Extended shelf-life (ESL) or ultra-pasteurized milk is produced by thermal processing using conditions between those used for traditional high-temperature, short-time (HTST) pasteurization and those used for ultra-high-temperature (UHT) sterilization. It should have a refrigerated shelf-life of more than 30 days. To achieve this, the thermal processing has to be quite intense. The challenge is to produce a product that has high bacteriological quality and safety but also very good organoleptic characteristics. Hence the two major aims in producing ESL milk are to inactivate all vegetative bacteria and spores of psychrotrophic bacteria, and to cause minimal chemical change that can result in cooked flavor development. The first aim is focused on inactivation of spores of psychrotrophic bacteria, especially Bacillus cereus because some strains of this organism are pathogenic, some can grow at <=7 degrees C and cause spoilage of milk, and the spores of some strains are very heat-resistant. The second aim is minimizing denaturation of beta-lactoglobulin (beta-Lg) as the extent of denaturation is strongly correlated with the production of volatile sulfur compounds that cause cooked flavor. It is proposed that the heating should have a bactericidal effect, B* (inactivation of thermophilic spores), of >0.3 and cause <=50% denaturation of beta-Lg. This can be best achieved by heating at high temperature for a short holding time using direct heating, and aseptically packaging the product. PMID- 29156618 TI - Optimized Lateral Flow Immunoassay Reader for the Detection of Infectious Diseases in Developing Countries. AB - Detection and control of infectious diseases is a major problem, especially in developing countries. Lateral flow immunoassays can be used with great success for the detection of infectious diseases. However, for the quantification of their results an electronic reader is required. This paper presents an optimized handheld electronic reader for developing countries. It features a potentially low-cost, low-power, battery-operated device with no added optical accessories. The operation of this proof of concept device is based on measuring the reflected light from the lateral flow immunoassay and translating it into the concentration of the specific analyte of interest. Characterization of the surface of the lateral flow immunoassay has been performed in order to accurately model its response to the incident light. Ray trace simulations have been performed to optimize the system and achieve maximum sensitivity by placing all the components in optimum positions. A microcontroller enables all the signal processing to be performed on the device and a Bluetooth module allows transmission of the results wirelessly to a mobile phone app. Its performance has been validated using lateral flow immunoassays with influenza A nucleoprotein in the concentration range of 0.5 ng/mL to 200 ng/mL. PMID- 29156620 TI - Stretchable, Highly Durable Ternary Nanocomposite Strain Sensor for Structural Health Monitoring of Flexible Aircraft. AB - Harmonious developments of electrical and mechanical performances are crucial for stretchable sensors in structural health monitoring (SHM) of flexible aircraft such as aerostats and morphing aircrafts. In this study, we prepared a highly durable ternary conductive nanocomposite made of polydimethylsiloxane (PDMS), carbon black (CB) and multi-walled carbon nanotubes (MWCNTs) to fabricate stretchable strain sensors. The nanocomposite has excellent electrical and mechanical properties by intensively optimizing the weight percentage of conducting fillers as well as the ratio of PDMS pre-polymer and curing agent. It was found that the nanocomposite with homogeneous hybrid filler of 1.75 wt % CB and 3 wt % MWCNTs exhibits a highly strain sensitive characteristics of good linearity, high gauge factor (GF ~ 12.25) and excellent durability over 105 stretching-releasing cycles under a tensile strain up to 25% when the PDMS was prepared at the ratio of 12.5:1. A strain measurement of crack detection for the aerostats surface was also employed, demonstrating a great potential of such ternary nanocomposite used as stretchable strain sensor in SHM. PMID- 29156619 TI - Standard vs. Calorie-Dense Immune Nutrition in Haemodynamically Compromised Cardiac Patients: A Prospective Randomized Controlled Pilot Study. AB - BACKGROUND: The aim of study was to test the hypothesis that early enteral nutrition (EN) with calorie-dense and protein rich enteral formula improves enteral energy and protein delivery in critically ill cardiac patients. METHODS: Prospective randomized pilot study of 40 ventilated adult patients undergoing elective cardiac surgery with use of cardiopulmonary bypass receiving inotropic support postoperatively. Patients were to receive either standard isocaloric (1000 Kcal/L and 38 g/L protein) early EN (n = 20) or calorie-dense and protein rich (1300 Kcal/L and 66.7 g/L protein) early EN (n = 20). RESULTS: The mean time to EN initiation was 27 +/- 11 h. Early EN with the calorie-dense formula provided significantly more energy and protein enteral delivery on the 2nd, (p < 0.0001), 5th (p = 0.036), and 7th days (p = 0.024), and was associated with higher levels of prealbumin concentration on the 14th day (0.13 +/- 0.01 g/L and 0.21 +/- 0.1 g/L; p = 0.04) and significantly increased levels of transferrin on the 3rd, 5th, and 7th day (p < 0.05) after surgery. CONCLUSION: Present findings support hypothesis that early EN using a calorie-dense and protein rich formula leads to better enteral energy and protein delivery and higher levels of short lived serum proteins. PMID- 29156621 TI - Influence of Shenxiong Glucose Injection on the Activities of Six CYP Isozymes and Metabolism of Warfarin in Rats Assessed Using Probe Cocktail and Pharmacokinetic Approaches. AB - Shenxiong glucose injection (SGI), a traditional Chinese medicine (TCM) preparation, has been widely used for the treatment of various cardiovascular and cerebrovascular diseases for many years. We assessed the potential influences of SGI on the activities of six CYP enzymes (CYP1A2, CYP2C11, CYP2C19, CYP2D4, CYP2E1, and CYP3A2) and on the pharmacokinetics of warfarin in rats. We compared plasma pharmacokinetics of six probe drugs (caffeine/CYP1A2, tolbutamide/CYP2C11, omeprazole/CYP2C19, metoprolol/CYP2D4, chlorzoxazone/CYP2E1, and midazolam/CYP3A2) and of warfarin between control and SGI-pretreated groups, to estimate the effect on the relative activities of the six isozymes and warfarin metabolism. There were no significant differences in the pharmacokinetic parameters of caffeine, omeprazole, metoprolol, chlorzoxazone, and midazolam between the SGI-pretreated and control groups. However, many pharmacokinetic parameters of tolbutamide in SGI-pretreated rats were affected significantly (p < 0.05), and indicated tolbutamide metabolism in the former group was markedly slower. Moreover, SGI reduced the clearance of warfarin. These results suggested SGI showed no effects on the enzyme activities of rat CYP1A2, CYP2C19, CYP2D4, CYP2E1, and CYP3A2, but inhibited the enzyme activity of CYP2C11, and improved the blood concentration of warfarin. This suggests that the dose of warfarin may need be adjusted when co-administrated with SGI. PMID- 29156622 TI - Advanced Glycation End Products in the Pathogenesis of Psoriasis. AB - Advanced glycation end products (AGEs) are extremely oxidant and biologically reactive compounds, which form through oxidation of sugars, lipids and amino acids to create aldehydes that bind covalently to proteins. AGEs formation and accumulation in human tissues is a physiological process during ageing but it is enhanced in case of persistent hyperglycemia, hyperlipidemia and oxidative or carbonyl stress, which are common in patients with moderate to severe psoriasis. Exogenous AGEs may derive from foods, UV irradiation and cigarette smoking. AGEs elicit biological functions by activating membrane receptors expressed on epithelial and inflammatory cell surface. AGEs amplify inflammatory response by favoring the release of cytokines and chemokines, the production of reactive oxygen species and the activation of metalloproteases. AGEs levels are increased in the skin and blood of patients with severe psoriasis independently of associated metabolic disorders. Intensified glycation of proteins in psoriasis skin might have a role in fueling cutaneous inflammation. In addition, AGEs released from psoriatic skin may increase metabolic and cardiovascular risk in patients with severe disease. PMID- 29156623 TI - OMI and Ground-Based In-Situ Tropospheric Nitrogen Dioxide Observations over Several Important European Cities during 2005-2014. AB - In this work we present the evolution of tropospheric nitrogen dioxide (NO2) content over several important European cities during 2005-2014 using space observations and ground-based in-situ measurements. The NO2 content was derived using the daily observations provided by the Ozone Monitoring Instrument (OMI), while the NO2 volume mixing ratio measurements were obtained from the European Environment Agency (EEA) air quality monitoring stations database. The European cities selected are: Athens (37.98 degrees N, 23.72 degrees E), Berlin (52.51 degrees N, 13.41 degrees E), Bucharest (44.43 degrees N, 26.10 degrees E), Madrid (40.38 degrees N, 3.71 degrees W), Lisbon (38.71 degrees N, 9.13 degrees W), Paris (48.85 degrees N, 2.35 degrees E), Rome (41.9 degrees N, 12.50 degrees E), and Rotterdam (51.91 degrees N, 4.46 degrees E). We show that OMI NO2 tropospheric column data can be used to assess the evolution of NO2 over important European cities. According to the statistical analysis, using the seasonal variation, we found good correlations (R > 0.50) between OMI and ground based in-situ observations for all of the cities presented in this work. Highest correlation coefficients (R > 0.80) between ground-based monitoring stations and OMI observations were calculated for the cities of Berlin, Madrid, and Rome. Both types of observations, in-situ and remote sensing, show an NO2 negative trend for all of locations presented in this study. PMID- 29156624 TI - Evaluation of Posaconazole Pharmacokinetics in Adult Patients with Invasive Fungal Infection. AB - Mortality and morbidity due to invasive fungal infections have increased over the years. Posaconazole is a second-generation triazole agent with an extended spectrum of activity, which shows a high interindividual variability in its plasma levels, rendering dosing in many patients inconsistent or inadequate. Hence, posaconazole therapeutic drug monitoring, which is easily available in clinical practice, may improve treatment success and safety. The aim of the study was to describe posaconazole pharmacokinetics, and to evaluate the utility of therapeutic drug monitoring for therapy and prophylaxis in a cohort of adult patients. A fully validated chromatographic method was used to quantify posaconazole concentration in plasma collected from adult patients at the end of the dosing interval. Associations between variables were tested using the Pearson test. The Mann-Whitney test was used to probe the influence of categorical variables on continuous ones. A high inter-individual variability was shown. Of the 172 enrolled patients, among those receiving the drug by the oral route (N = 170), gender significantly influenced drug exposure: males showed greater posaconazole concentration than females (p = 0.028). This study highlights the importance of therapeutic drug monitoring in those with invasive fungal infections and its significant clinical implications; moreover we propose, for the first time, the possible influence of gender on posaconazole exposure. PMID- 29156625 TI - Gene-Based Pathogen Detection: Can We Use qPCR to Predict the Outcome of Diagnostic Metagenomics? AB - In microbial food safety, molecular methods such as quantitative PCR (qPCR) and next-generation sequencing (NGS) of bacterial isolates can potentially be replaced by diagnostic shotgun metagenomics. However, the methods for pre analytical sample preparation are often optimized for qPCR, and do not necessarily perform equally well for qPCR and sequencing. The present study investigates, through screening of methods, whether qPCR can be used as an indicator for the optimization of sample preparation for NGS-based shotgun metagenomics with a diagnostic focus. This was used on human fecal samples spiked with 103 or 106 colony-forming units (CFU)/g Campylobacter jejuni, as well as porcine fecal samples spiked with 103 or 106 CFU/g Salmonella typhimurium. DNA was extracted from the samples using variations of two widely used kits. The following quality parameters were measured: DNA concentration, qPCR, DNA fragmentation during library preparation, amount of DNA available for sequencing, amount of sequencing data, distribution of data between samples in a batch, and data insert size; none showed any correlation with the target ratio of the spiking organism detected in sequencing data. Surprisingly, diagnostic metagenomics can have better detection sensitivity than qPCR for samples spiked with 103 CFU/g C. jejuni. The study also showed that qPCR and sequencing results may be different due to inhibition in one of the methods. In conclusion, qPCR cannot uncritically be used as an indicator for the optimization of sample preparation for diagnostic metagenomics. PMID- 29156626 TI - Surface Plasmon Resonance Sensing of Biorecognition Interactions within the Tumor Suppressor p53 Network. AB - Surface Plasmon Resonance (SPR) is a powerful technique to study the kinetics of biomolecules undergoing biorecognition processes, particularly suited for protein protein interactions of biomedical interest. The potentiality of SPR was exploited to sense the interactions occurring within the network of the tumor suppressor p53, which is crucial for maintaining genome integrity and whose function is inactivated, mainly by down regulation or by mutation, in the majority of human tumors. This study includes p53 down-regulators, p53 mutants and also the p53 family members, p63 and p73, which could vicariate p53 protective function. Furthermore, the application of SPR was extended to sense the interaction of p53 with anti-cancer drugs, which might restore p53 function. An extended review of previous published work and unpublished kinetic data is provided, dealing with the interaction between the p53 family members, or their mutants and two anticancer molecules, Azurin and its cell-penetrating peptide, p28. All the kinetic results are discussed in connection with those obtained by a complementary approach operating at the single molecule level, namely Atomic Force Spectroscopy and the related literature data. The overview of the SPR kinetic results may significantly contribute to a deeper understanding of the interactions within p53 network, also in the perspective of designing suitable anticancer drugs. PMID- 29156627 TI - Multichannel Discriminative Detection of Explosive Vapors with an Array of Nanofibrous Membranes Loaded with Quantum Dots. AB - The multichannel fluorescent sensor array based on nanofibrous membranes loaded with ZnS quantum dots (QDs) was created and demonstrated for the discriminative detection of explosives. The synergistic effect of the high surface-to-volume ratio of QDs, the good permeability of nanofibrous membranes and the differential response introduced by surface ligands was played by constructing the sensing array using nanofibrous membranes loaded with ZnS QDs featuring several surface ligands. Interestingly, although the fluorescence quenching of the nanofibrous membranes is not linearly related to the exposure time, the fingerprint of each explosive at different times is very similar in shape, and the fingerprints of the three explosives show different shapes. Three saturated vapors of nitroaromatic explosives could be reliably detected and discriminated by the array at room temperature. This work is the first step toward devising a monitoring system for explosives in the field of public security and defense. It could, for example, be coupled with the technology of image recognition and large data analysis for a rapid diagnostic test of explosives. This work further highlights the power of differential, multichannel arrays for the rapid and discriminative detection of a wide range of chemicals. PMID- 29156628 TI - Differentially Expressed tRNA-Derived Small RNAs Co-Sediment Primarily with Non Polysomal Fractions in Drosophila. AB - Recent studies point to the existence of poorly characterized small regulatory RNAs generated from mRNAs, rRNAs and tRNAs. To explore the subcellular location of tRNA-derived small RNAs, 0-1 and 7-8 h Drosophila embryos were fractionated on sucrose density gradients. Analysis of 12,553,921 deep-sequencing reads from unfractionated and fractionated Drosophila embryos has revealed that tRFs, which are detected mainly from the 5'ends of tRNAs, co-sediment with the non-polysomal fractions. Interestingly, the expression levels of a subset of tRFs change temporally following the maternal-to-zygotic transition in embryos. We detected non-polysomal association of tRFs in S2 cells as well. Differential tRF expression pattern points to developmental significance at the organismal level. These results suggest that tRFs are associated primarily with the non-polysomal complexes in Drosophila embryos and S2 cells. PMID- 29156631 TI - Morphology and Mechanical Properties of Polyimide Films: The Effects of UV Irradiation on Microscale Surface. AB - As an attractive dielectric material, polyimide has been widely used in the field of electronics, aerospace, and automobiles due to its useful mechanical properties and good chemical resistance. UV irradiation was considered to be the main factor related to the damage and failure of polyimide. Here the effects of UV irradiation on the surface morphology and microscale mechanical properties of polyimide films are characterized by atomic force microscopy (AFM). The surface roughness of the UV-irradiated samples developed and the mechanical properties degraded with the radiation dose increased. For comparison, uniaxial tensile test was performed to obtain the macroscale Young's modulus of polyimide film. The UV irradiated damaging depth was simulated with finite element method (FEM). PMID- 29156629 TI - Reconstruction of Craniomaxillofacial Bone Defects Using Tissue-Engineering Strategies with Injectable and Non-Injectable Scaffolds. AB - Engineering craniofacial bone tissues is challenging due to their complex structures. Current standard autografts and allografts have many drawbacks for craniofacial bone tissue reconstruction; including donor site morbidity and the ability to reinstate the aesthetic characteristics of the host tissue. To overcome these problems; tissue engineering and regenerative medicine strategies have been developed as a potential way to reconstruct damaged bone tissue. Different types of new biomaterials; including natural polymers; synthetic polymers and bioceramics; have emerged to treat these damaged craniofacial bone tissues in the form of injectable and non-injectable scaffolds; which are examined in this review. Injectable scaffolds can be considered a better approach to craniofacial tissue engineering as they can be inserted with minimally invasive surgery; thus protecting the aesthetic characteristics. In this review; we also focus on recent research innovations with different types of stem-cell sources harvested from oral tissue and growth factors used to develop craniofacial bone tissue-engineering strategies. PMID- 29156632 TI - Neurotropism In Vitro and Mouse Models of Severe and Mild Infection with Clinical Strains of Enterovirus 71. AB - Enterovirus 71 (EV71) is a common etiological agent of hand, foot, and mouth disease and fatal neurological diseases in children. The neuropathogenicity of severe EV71 infection has been documented, but studies comparing mouse models of severe and mild EV71 infection are lacking. The aim of the study was to investigate the neurovirulence of EV71 strains and the differences in serum cytokine and chemokine levels in mouse models of severe and mild EV71 infection. Nine EV71 isolates belonging to the C4 subgenogroup (proposed as genotype D) displayed infectivity in human neuroblastoma SK-N-SH cells; moreover, ultrastructural observation confirmed viral particle replication. The survival rate of the severe model was 71.43% (5/7), and 60% (3/5) of the surviving severe model mice displayed sequelae of paralysis, whereas the only symptom in mild model mice was ruffled fur. Dynamic detection of serum cytokine and chemokine levels demonstrated that interleukin (IL)-5, IL-13, IL-6, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-C motif) ligand 5 (also called Regulated upon Activation, Normal T-cell Expressed, and Secreted (CCL5/RANTES) were significantly up-regulated at the early period of infection, indicating that these factors might herald a severe outcome. Our findings suggest that elevated cytokines and chemokines may have potential value as prognostic markers in mouse models. PMID- 29156630 TI - Anti-Bacteria and Microecosystem-Regulating Effects of Dental Implant Coated with Dimethylaminododecyl Methacrylate. AB - The effects of dimethylaminododecyl methacrylate (DMADDM) modified titanium implants on bacterial activity and microbial ecosystem of saliva-derived biofilm were investigated for the first time. Titanium discs were coated with DMADDM solutions at mass fractions of 0 mg/mL (control), 1, 5 and 10 mg/mL, respectively. Biomass accumulation and metabolic activity of biofilms were tested using crystal violet assay and MTT (3-(4,5-Dimethyl-thiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay. 16S rRNA gene sequencing was performed to measure the microbial community. Live/dead staining and scanning electron microscopy (SEM) were used to value the structure of biofilm. The results showed that the higher mass fraction of DMADDM the coating solution had, the significantly lower the values of metabolic activity and accumulated biofilms got, as well as fewer live cells and less extracellular matrix. Moreover, 5 mg/mL of DMADDM was the most effective concentration, as well as 10 mg/mL. In microecosystem-regulation, the DMADDM modified titanium implant decreased the relative abundance of Neisseria and Actinomyces and increased the relative abundance of Lactobacillus, a probiotic for peri-implant diseases. In conclusion, via inhibiting growth and regulating microecosystem of biofilm, this novel titanium implant coating with DMADDM was promising in preventing peri-implant disease in an 'ecological manner'. PMID- 29156633 TI - Alcohol and Cancer Stem Cells. AB - Heavy alcohol consumption has been associated with increased risk of several cancers, including cancer of the colon, rectum, female breast, oral cavity, pharynx, larynx, liver, and esophagus. It appears that alcohol exposure not only promotes carcinogenesis but also enhances the progression and aggressiveness of existing cancers. The molecular mechanisms underlying alcohol tumor promotion, however, remain unclear. Cancer stem cells (CSC), a subpopulation of cancer cells with self-renewal and differentiation capacity, play an important role in tumor initiation, progression, metastasis, recurrence, and therapy resistance. The recent research evidence suggests that alcohol increases the CSC population in cancers, which may underlie alcohol-induced tumor promotion. This review discusses the recent progress in the research of alcohol promotion of CSC and underlying cellular/molecular mechanisms. The review will further explore the therapeutic potential of CSC inhibition in treating alcohol-induced tumor promotion. PMID- 29156634 TI - An Overview of Chitosan Nanoparticles and Its Application in Non-Parenteral Drug Delivery. AB - The focus of this review is to provide an overview of the chitosan based nanoparticles for various non-parenteral applications and also to put a spotlight on current research including sustained release and mucoadhesive chitosan dosage forms. Chitosan is a biodegradable, biocompatible polymer regarded as safe for human dietary use and approved for wound dressing applications. Chitosan has been used as a carrier in polymeric nanoparticles for drug delivery through various routes of administration. Chitosan has chemical functional groups that can be modified to achieve specific goals, making it a polymer with a tremendous range of potential applications. Nanoparticles (NP) prepared with chitosan and chitosan derivatives typically possess a positive surface charge and mucoadhesive properties such that can adhere to mucus membranes and release the drug payload in a sustained release manner. Chitosan-based NP have various applications in non parenteral drug delivery for the treatment of cancer, gastrointestinal diseases, pulmonary diseases, drug delivery to the brain and ocular infections which will be exemplified in this review. Chitosan shows low toxicity both in vitro and some in vivo models. This review explores recent research on chitosan based NP for non parenteral drug delivery, chitosan properties, modification, toxicity, pharmacokinetics and preclinical studies. PMID- 29156635 TI - Is School Type Associated with Objectively Measured Physical Activity in 15-Year Olds? AB - The main aims of this study were: (1) to determine the objectively assessed physical activity (PA) patterns in urban 15-year-old male and female adolescents according to school type and (2) to assess the differences in PA between school days and weekend days. In this cross-sectional study, participants were 187 secondary-school male and female adolescents (61.4% females) attending grammar and vocational schools. Patterns of PA were objectively evaluated using a multi sensor body monitor for 5 consecutive days. Confounders assessed included biological age, socio-economic status, sum of 4 skinfolds, maximal temperature and the amount of rainfall. Males and females from grammar schools achieved higher total daily energy expenditure (TEE) and active energy expenditure (AEE) compared to their peers from vocational schools (TEE: 50 +/- 12 kcal/kg/day vs. 47 +/- 12 kcal/kg/day, p = 0.02; AEE: 23 +/- 5 kcal/kg/day vs. vocational = 21 +/ 6 kcal/kg/day, p = 0.04). No differences in time spent in light (LPA), moderate (MPA) or vigorous (VPA) physical activity were noted between the two groups (p = 0.16-0.43). Next, a significant decline in TEE and MPA between school days and weekends was observed (p< 0.001 and p = 0.02, respectively), while VPA remained the same throughout the week (p = 0.76). Weekly patterns of PA did not show differences by school type or gender (p for interactions = 0.21-0.50). In addition, significantly lower amount of MPA was accumulated during weekends compared to school days, resulting in lower TEE, regardless of school type or gender. Policies and strategies on PA in adolescents should focus vocational schools and weekend days. PMID- 29156636 TI - Structural, Electrical, Magnetic and Resistive Switching Properties of the Multiferroic/Ferroelectric Bilayer Thin Films. AB - Bi0.8Pr0.2Fe0.95Mn0.05O3/Bi3.96Gd0.04Ti2.95W0.05O12 (BPFMO/BGTWO) bilayer thin films with Multiferroic/Ferroelectric (MF/FE) structures were deposited onto Pt(111)/Ti/SiO2/Si(100) substrates by using the sol-gel method with rapid thermal annealing. The BPFMO/BGTWO thin films exhibited well-saturated ferromagnetic and ferroelectric hysteresis loops because of the electro-magnetic coupling induced by the MF/FE structure. The remnant magnetization (2Mr) and remnant polarization (2Pr) were 4.6 emu/cm3 and 62 MUC/cm2, respectively. Moreover, the bipolar I-V switching curves of BPFMO/BGTWO bilayer thin films resistive random access memory (RRAM) devices were discussed, and investigated for LRS/HRS. PMID- 29156638 TI - Development of Evidence-Based Disease Education Literature for Pakistani Rheumatoid Arthritis Patients. AB - Rheumatoid arthritis affects 0.5% to 1% of the population globally and is one of the most common causes of disability. Patient education plays a key role in improving treatment outcomes. The purpose of this study was to discuss the process involved in designing an evidence-based disease education literature for rheumatoid arthritis patients of Pakistan in Urdu language with culturally relevant illustrations. A study was conducted to develop disease education literature using Delphi consensus, content validity, and patient feedback. A panel of experts comprised of university professors and health care experts, including health practitioners and pharmacists as well as a social scientist, was set up to assess the need. Eight patients were randomly selected and were asked to give their feedback. Their feedback was incorporated in the development process. The entire process was carried out in eight steps. A disease education literature for patients of rheumatoid arthritis was developed and edited in the form of a booklet. The booklet contained evidence-based information that must be provided to patients in both Urdu and English languages with culturally relevant illustrations. The availability of such literature is significant, as it enables the patients to seek knowledge at home at their convenience. This home-based knowledge support is as helpful as any other means of medical care. The developed literature is planned to be used in further studies which will evaluate its impact in improving knowledge of RA patients. PMID- 29156639 TI - Constructing an Indoor Floor Plan Using Crowdsourcing Based on Magnetic Fingerprinting. AB - A large number of indoor positioning systems have recently been developed to cater for various location-based services. Indoor maps are a prerequisite of such indoor positioning systems; however, indoor maps are currently non-existent for most indoor environments. Construction of an indoor map by external experts excludes quick deployment and prevents widespread utilization of indoor localization systems. Here, we propose an algorithm for the automatic construction of an indoor floor plan, together with a magnetic fingerprint map of unmapped buildings using crowdsourced smartphone data. For floor plan construction, our system combines the use of dead reckoning technology, an observation model with geomagnetic signals, and trajectory fusion based on an affinity propagation algorithm. To obtain the indoor paths, the magnetic trajectory data obtained through crowdsourcing were first clustered using dynamic time warping similarity criteria. The trajectories were inferred from odometry tracing, and those belonging to the same cluster in the magnetic trajectory domain were then fused. Fusing these data effectively eliminates the inherent tracking errors originating from noisy sensors; as a result, we obtained highly accurate indoor paths. One advantage of our system is that no additional hardware such as a laser rangefinder or wheel encoder is required. Experimental results demonstrate that our proposed algorithm successfully constructs indoor floor plans with 0.48 m accuracy, which could benefit location-based services which lack indoor maps. PMID- 29156637 TI - Synthesis and Improved Cross-Linking Properties of C5-Modified Furan Bearing PNAs. AB - Over the past decades, peptide nucleic acid/DNA (PNA:DNA) duplex stability has been improved via backbone modification, often achieved via introducing an amino acid side chain at the alpha- or gamma-position in the PNA sequence. It was previously shown that interstrand cross-linking can further enhance the binding event. In this work, we combined both strategies to fine-tune PNA crosslinking towards single stranded DNA sequences using a furan oxidation-based crosslinking method; for this purpose, gamma-l-lysine and gamma-l-arginine furan-PNA monomers were synthesized and incorporated in PNA sequences via solid phase synthesis. It was shown that the l-lysine gamma-modification had a beneficial effect on crosslink efficiency due to pre-organization of the PNA helix and a favorable electrostatic interaction between the positively-charged lysine and the negatively-charged DNA backbone. Moreover, the crosslink yield could be optimized by carefully choosing the type of furan PNA monomer. This work is the first to describe a selective and biocompatible furan crosslinking strategy for crosslinking of gamma-modified PNA sequences towards single-stranded DNA. PMID- 29156640 TI - Clinical Beneficial Effects of Using Crystalloid only in Recipients of Living Donor Liver Transplantation. AB - OBJECTIVE: Liver transplantation (LT) is a major surgery associated with intraoperative massive fluid shift, which is usually replaced by crystalloid, 5% albumin (colloid) and blood products. We studied 15 patients from 477 consecutive recipients of adult living donor liver transplantation. Each patient received crystalloid only during LT. Whether LT provides any clinical benefit is not clear and must be determined. METHODS AND PATIENTS: The anesthesia records of 477 adult LDLT were reviewed retrospectively. The patients were divided into three groups according to the fluids received. Group I (GI) had received blood products, 5% albumin and crystalloid, group II (GII) received 5% albumin and crystalloid, and group III (GIII) received crystalloid only. The characteristic intraoperative variable and postoperative acute rejection and survival rate were compared amongst groups by using One Way ANOVA post hoc with Bonferroni and by Ficher's Exact test and Chi-square chi2 test. RESULTS AND CONCLUSIONS: GIII had less intraoperative ascites and blood loss; they also had more stable hemodynamics. Furthermore, they could be extubated significantly earlier than GI, and the one- and three-year survival rates were excellent, with 100% in GIII, while that of GI and GII were 94.1%, 90.5% and 98.6%, 94.5%, respectively. PMID- 29156641 TI - Facile Control of the Porous Structure of Larch-Derived Mesoporous Carbons via Self-Assembly for Supercapacitors. AB - Mesoporous carbons have been successfully synthesized via self-assembly using larch-based resins as precursors and triblock copolymers as soft templates. The porous structure of mesoporous carbons can be tailored by adjusting the ratio of hydrophilic/hydrophobic (EO/PO) units owing to interfacial curvature. Interestingly, the porous structures show a distinct change from vortex-like to worm-like pores, to stripe-like pores, and to ordered two-dimensional hexagonal pores as the ratio of hydrophilic/hydrophobic units increases, indicating the significant effect of EO/PO ratio on the porous structure. The mesoporous carbons as supercapacitor electrodes exhibit superior electrochemical capacitive performance and a high degree of reversibility after 2000 cycles for supercapacitors due to the well-defined mesoporosity of the carbon materials. Meanwhile, the superior carbon has a high specific capacitance of 107 F.g-1 in 6 M KOH at a current density of 10 A.g-1. PMID- 29156642 TI - Is the Benefit-Risk Ratio for Patients with Transfusion-Dependent Thalassemia Treated by Unrelated Cord Blood Transplantation Favorable? AB - Transfusion-dependent thalassemia (TDT) is an inherited disorder characterized by absent or defective production of alpha- or beta-hemoglobin chains. If untreated, the disease invariably culminates in death in early infancy due to cardiac failure or overwhelming infection. Although there is clear evidence of good health-related quality of life and return to normal life style, the choice to undergo hematopoietic stem cell transplantation (HSCT) remains a challenge because of the potential risk of transplant-related mortality (TRM) in TDT. Successful hematopoietic stem cell transplantation may cure the hematological manifestations of TDT, but introduces risks of TRM and morbidity. The low incidence of graft-versus-host disease (GVHD) provides the major rationale for pursuing unrelated cord blood transplantation (CBT). Considerable evidence suggests a lower rate of recurrence after CBT than after transplantation from adult donors. As the TRM, overall survival, and thalassemia-free survival for CBT improve, the utility of this stem cell source will expand to indications that have hitherto rarely used unrelated CBT. This paper summarizes the current progress in understanding the advances in unrelated CBT for thalassemia. Although as yet only in a limited number of patients, the results of unrelated CBT for thalassemia are encouraging. PMID- 29156645 TI - The Short-Term Effects of Visibility and Haze on Mortality in a Coastal City of China: A Time-Series Study. AB - Few studies have been conducted to investigate the acute health effects of visibility and haze, which may be regarded as proxy indicators of ambient air pollution. We used a distributed lag non-linear model (DLNM) combined with quasi Poisson regression to estimate the relationship between visibility, haze and mortality in Ningbo, a coastal city of China. We found that the mortality risk of visibility was statistically significant only on the current day, while the risk of haze and PM10 peaked on the second day and could last for three days. When the visibility was less than 10 km, each 1 km decrease of visibility at lag 0 day was associated with a 0.78% (95% CI: 0.22-1.36%) increase in total mortality and a 1.61% (95% CI: 0.39-2.85%) increase in respiratory mortality. The excess risk of haze at lag 0-2 days on total mortality, cardiovascular and respiratory mortality was 7.76% (95% CI: 3.29-12.42%), 7.73% (95% CI: 0.12-15.92%) and 17.77% (95% CI: 7.64-28.86%), respectively. Greater effects of air pollution were observed during the cold season than in the warm season, and the elderly were at higher risk compared to youths. The effects of visibility and haze were attenuated by single pollutants. These findings suggest that visibility and haze could be used as surrogates of air quality where pollutant data are scarce, and strengthen the evidence to develop policy to control air pollution and protect vulnerable populations. PMID- 29156644 TI - Akt1 Stimulates Homologous Recombination Repair of DNA Double-Strand Breaks in a Rad51-Dependent Manner. AB - Akt1 is known to promote non-homologous end-joining (NHEJ)-mediated DNA double strand break (DSB) repair by stimulation of DNA-PKcs. In the present study, we investigated the effect of Akt1 on homologous recombination (HR)-dependent repair of radiation-induced DSBs in non-small cell lung cancer (NSCLC) cells A549 and H460. Akt1-knockdown (Akt1-KD) significantly reduced Rad51 protein level, Rad51 foci formation and its colocalization with gammaH2AX foci after irradiation. Moreover, Akt1-KD decreased clonogenicity after treatment with Mitomycin C and HR repair, as tested by an HR-reporter assay. Double knockdown of Akt1 and Rad51 did not lead to a further decrease in HR compared to the single knockdown of Rad51. Consequently, Akt1-KD significantly increased the number of residual DSBs after irradiation partially independent of the kinase activity of DNA-PKcs. Likewise, the number of residual BRCA1 foci, indicating unsuccessful HR events, also significantly increased in the irradiated cells after Akt1-KD. Together, the results of the study indicate that Akt1 seems to be a regulatory component in the HR repair of DSBs in a Rad51-dependent manner. Thus, based on this novel role of Akt1 in HR and the previously described role of Akt1 in NHEJ, we propose that targeting Akt1 could be an effective approach to selectively improve the killing of tumor cells by DSB-inducing cytotoxic agents, such as ionizing radiation. PMID- 29156643 TI - Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells. AB - Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells. PMID- 29156646 TI - Inhibition of bcl-2 and cox-2 Protein Expression after Local Application of a New Carmustine-Loaded Clinoptilolite-Based Delivery System in a Chemically Induced Skin Cancer Model in Mice. AB - Our research has focused on in vitro and in vivo evaluations of a new Carmustine (BCNU)-loaded clinoptilolite-based delivery system. Two clinoptilolite ionic forms-hydrogen form (HCLI) and sodium form (NaCLI)-were prepared, allowing a loading degree of about 5-6 mg BCNU/g of zeolite matrix due to the dual porous feature of clinoptilolite. Clinoptilolite-based delivery systems released 35.23% of the load in 12 h for the BCNU@HCLI system and only 10.82% for the BCNU@NaCLI system. The BCNU@HCLI system was chosen to develop gel and cream semisolid dosage forms. The cream (C_BCNU@HCLI) released 29.6% of the loaded BCNU after 12 h in the Nylon synthetic membrane test and 31.6% in the collagen membrane test, higher by comparison to the gel. The new cream was evaluated in vivo in a chemically induced model of skin cancer in mice. Quantitative immunohistochemistry analysis showed stronger inhibition of B-cell lymphoma-2 (bcl-2) and cyclooxygenase 2 (cox 2) protein expression, known markers for cancer survival and aggressiveness, after the treatment with C_BCNU@HCLI by comparison to all the control treatment types, including an off-label magistral formula commercially available Carmustine cream as reference, bringing evidence that a clinoptilolite-based delivery systems could be used as a cancer drug carriers and controlled release systems (skin-targeted topical delivery systems). PMID- 29156648 TI - Tuning the Photoluminescence of Graphene Quantum Dots by Photochemical Doping with Nitrogen. AB - Nitrogen-doped graphene quantum dots (NGQDs) were synthesized by irradiating graphene quantum dots (GQDs) in an NH3 atmosphere. The photoluminescence (PL) properties of the GQDs and the NGQDs samples were investigated. Compared with GQDs, a clear PL blue-shift of NGQDs could be achieved by regulating the irradiating time. The NGQDs obtained by irradiation of GQDs for 70 min had a high N content of 15.34 at % and a PL blue-shift of about 47 nm. This may be due to the fact that photochemical doping of GQDs with nitrogen can significantly enhance the contents of pyridine-like nitrogen, and also effectively decrease the contents of oxygen functional groups of NGQDs, thus leading to the observed obvious PL blue-shift. PMID- 29156647 TI - Effects of Nutritional Interventions during Pregnancy on Infant and Child Cognitive Outcomes: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Epidemiological studies have demonstrated that folate, iodine and iron intake during pregnancy impacts on foetal brain development and cognitive function. However, in human studies, the relationship with other dietary nutrients is less clear. OBJECTIVE: This systematic review aims to critically appraise the current literature and meta-analyses results from nutritional interventions during pregnancy that aimed to optimise infant and child cognitive outcomes. DESIGN: Ten electronic databases were searched for articles published up to August 2017. The search was limited to articles published in English. Randomised controlled trials (RCTs) testing the impact of any nutritional intervention (dietary counselling, education, nutrient supplementation, fortified foods and/or foods) during pregnancy on cognitive outcomes of children (<10 years old). Two independent reviewers assessed study eligibility and quality using the American Dietetic Association quality criteria checklist for primary research. Standardised mean differences were used for nine cognitive domains to measure effects for meta-analyses. RESULTS: A total of 34 RCTs were included (21 studies included children aged less than 35 months, 10 studies included children aged 36 60 months and 3 studies included children aged 61-119 months). The types of nutritional interventions included nutrient supplements, whole foods, fortified foods and nutrition education. The following nine cognition outcomes: attention, behaviour, crystallised intelligence, fluid intelligence, global cognition, memory, motor skills, visual processing, and problem solving were not significantly impacted by nutritional interventions, although 65% of studies conducted post-hoc data analyses and were likely to be underpowered. Although, long chain polyunsaturated fatty acids (LCPUFA) supplementation was associated with a marginal increase in crystallised intelligence (Effect size (ES): 0.25; 95% confidence interval (95% CI): -0.04, 0.53), the effect was not statistically significant (p = 0.09), with significant study heterogeneity (p = 0.00). CONCLUSIONS: LCPUFA supplementation may be associated with an improvement in child crystallised intelligence, however further research is warranted. The remaining eight cognition domains were not significantly impacted by maternal nutritional interventions. PMID- 29156649 TI - Short-Term Choriocapillaris Changes in Patients with Central Serous Chorioretinopathy after Half-Dose Photodynamic Therapy. AB - BACKGROUND: Although photodynamic therapy (PDT) has become the standard treatment for central serous chorioretinopathy (CSC), its mechanism of action remains unclear. It is assumed that PDT induces short-term choriocapillaris (CC) occlusion and long-term choroidal vascular remodeling. In this paper, we describe the short-term CC changes induced by Half-Dose PDT (HD-PDT) in chronic CSC using optical coherence tomography-angiography (OCTA). METHODS: This is a prospective interventional case series. Chronic CSC eyes underwent Spectral-Domain OCT, Fundus Autofluorescence, FA, ICGA (Heidelberg Spectralis, Heidelberg, Germany) and OCTA (RTVue XR Avanti with AngioVue; Optovue Inc., Fremont, CA, USA) before HD-PDT, with follow-up after one hour, one week, and one month. Vascular changes after PDT were analyzed within the CC layer. The CC vessel density was defined as the percentage of an area occupied by flow pixels, using Image J software to obtain measurements by applying a grey level threshold. All pixels with a grey level above the threshold were considered as indicators of blood flow. RESULTS: 20 eyes of 19 patients were included. At baseline the mean CC vessel density was 94.87 +/- 2.32%. It significantly differed from the density at 1 week and 1 month (92.79 +/- 3.16% and 95.55 +/- 2.05%, p < 0.001, respectively), but not with values at 1 h (94.8 +/- 2.28%, p = 0.516). CONCLUSIONS: CC vessel density was significantly reduced at 1 week as compared with baseline, suggesting a possible short-term effect of PDT on CC perfusion. After 1 month however, the CC vessel density was even higher than the baseline, probably due to a CC recovery. OCTA seems to be useful in the visualization of CC vessels and in confirming the mechanism of action of PDT treatment in eyes with chronic CSC. PMID- 29156650 TI - Nondestructive Evaluation of Carbon Fiber Bicycle Frames Using Infrared Thermography. AB - Bicycle frames made of carbon fibre are extremely popular for high-performance cycling due to the stiffness-to-weight ratio, which enables greater power transfer. However, products manufactured using carbon fibre are sensitive to impact damage. Therefore, intelligent nondestructive evaluation is a required step to prevent failures and ensure a secure usage of the bicycle. This work proposes an inspection method based on active thermography, a proven technique successfully applied to other materials. Different configurations for the inspection are tested, including power and heating time. Moreover, experiments are applied to a real bicycle frame with generated impact damage of different energies. Tests show excellent results, detecting the generated damage during the inspection. When the results are combined with advanced image post-processing methods, the SNR is greatly increased, and the size and localization of the defects are clearly visible in the images. PMID- 29156651 TI - Specific Effects of Chronic Dietary Exposure to Chlorpyrifos on Brain Gene Expression-A Mouse Study. AB - chlorpyrifos (CPF) is an organophosphate insecticide used to control pests on a variety of food and feed crops. In mammals, maternal exposure to CPF has been reported to induce cerebral cortex thinning, alteration of long-term brain cognitive function, and Parkinson-like symptoms, but the mechanisms of these processes are not fully understood. In this study, we aimed to gain a deeper understanding of the alterations induced in the brains of mice chronically exposed to CPF by dietary intake. For our purpose, we analysed F1 offspring (sacrificed at 3 and 8 months) of Mus musculus, treated in utero and postnatally with 3 different doses of CPF (0.1-1-10 mg/kg/day). Using RT2 Profiler PCR Arrays, we evaluated the alterations in the expression of 84 genes associated with neurodegenerative diseases. In the brains of exposed mice, we evidenced a clear dose-response relationship for AChE inhibition and alterations of gene expression. Some of the genes that were steadily down-regulated, such as Pink1, Park 2, Sv2b, Gabbr2, Sept5 and Atxn2, were directly related to Parkinson's onset. Our experimental results shed light on the possibility that long-term CPF exposure may exert membrane signalling alterations which make brain cells more susceptible to develop neurodegenerative diseases. PMID- 29156652 TI - Comparison of the Chemical Profiles and Antioxidant Activities of Different Parts of Cultivated Cistanche deserticola Using Ultra Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry and a 1,1-Diphenyl-2-picrylhydrazyl Based Assay. AB - In this study, a sensitive ultra-performance liquid chromatography-photodiode array coupled to quadruple time-of-flight mass (UPLC-PDA-Q/TOF-MS) method and a 1,1-diphenyl-2- picrylhydrazyl (DPPH)-based assay were used to determine the chemical constituents and screen the antioxidant activity profiles of the methanol extracts of different parts of cultivated Cistanche deserticola (C. deserticola). First, qualitative and quantitative chemical composition analyses of the different parts of cultivated C. deserticola were conducted. Obvious differences were observed between the chemical profiles and content distribution of phenylethanoid glycosides (PhGs) from the different cultivated C. deserticola parts. The average contents of the six PhGs parts varied from 4.91 to 72.56 mg/g DW (milligrams of extract per gram of plant dry weight) in the six different parts of Cistanche deserticola, displaying a significant decreasing trend from the bottom to the top of cultivated C. deserticola and the highest content in the stems. From the bottom to the top of the plant, the echinacoside and cistanoside A content decreased and the 2 ' -acetylacteoside content increased. Second, an offline DPPH assay revealed that the total scavenging activities of all parts within the range of 20-500 MU g/mL increased in a concentration-dependent manner and that good antioxidant activities were found in all plant parts, particularly in the stems, which could be related to their higher PhG content. Additionally, a DPPH-UPLC-PDA method was successfully applied to rapidly screen the antioxidant profiles and antioxidant components of the different cultivated C. deserticola parts. According to the antioxidant profiles before and after the DPPH reaction, there were wide variations in the antioxidant activities of different cultivated C. deserticola parts. Moreover, the antioxidant profiles revealed the presence of major free radical scavengers identified as PhGs using UPLC-Q/TOF-MS. Finally, the established DPPH-UPLC-PDA method was reagent saving, rapid and feasible for correlating the chemical profile of traditional chinese medicines (TCMs) with their bioactivities without isolation and purification and may be used for multicomponent analysis of active substances in other foods and herbs. Therefore, to better harness C. deserticola resources, using this method to evaluate cultivated C. deserticola, a promising herb material with obvious antioxidant activity, is crucial. PMID- 29156653 TI - Dual Competing Photovoltaic Supply Chains: A Social Welfare Maximization Perspective. AB - In the past decades, the inappropriate subsidy policies in many nations have caused problems such as serious oversupply, fierce competition and subpar social welfare in the photovoltaic (PV) industry in many nations. There is a clear shortage in the PV industry literature regarding how dual supply chains compete and the key decision issues regarding the competition between dual PV supply chains. It is critical to develop effective subsidy policies for the competing PV supply chains to achieve social welfare maximization. This study has explored the dual PV supply chain competition under the Bertrand competition assumption by three game-theoretical modeling scenarios (or supply chain strategies) considering either the public subsidy or no subsidy from a social welfare maximization perspective. A numerical analysis complemented by two sensitivity analyses provides a better understanding of the pricing and quantity decision dynamics in the dual supply chains under three different supply chain strategies and the corresponding outcomes regarding the total supply chain profits, the social welfare and the required total subsidies. The key findings disclose that if there are public subsidies, the dual PV supply chains have the strongest intention to pursue the decentralized strategy to achieve their maximal returns rather than the centralized strategy that would achieve the maximal social welfare; however, the government would need to pay for the maximal subsidy budget. Thus, the best option for the government would be to encourage the dual PV supply chains to adopt a centralized strategy since this will not only maximize the social welfare but also, at the same time, minimize the public subsidy. With a smart subsidy policy, the PV industry can make the best use of the subsidy budget and grow in a sustainable way to support the highly demanded solar power generation in many countries trying very hard to increase the proportion of their clean energy to combat the global warming effect. Several subsidy policies such as shared solar energy arrangements and performance-based incentive (PBI) are proposed to integrate the market users and the PV supply chains. This study serves as a pioneering study into the dual PV supply chain research which is very limited in the PV management and policy study literature. The findings and several untended issues provide a foundation for the future PV supply chain studies. PMID- 29156654 TI - A Dual Band Frequency Reconfigurable Origami Magic Cube Antenna for Wireless Sensor Network Applications. AB - In this paper, a novel dual band frequency reconfigurable antenna using an origami magic cube is proposed for wireless sensor network (WSN) applications. The proposed origami antenna consists of a meandered monopole folded onto three sides of the magic cube. A microstrip open-ended stub is loaded on the meandered monopole. The proposed origami magic cube can be mechanically folded and unfolded. The proposed antenna operates at 1.57 GHZ and 2.4 GHz in the folded state. In the unfolded state, the proposed antenna operates at 900 MHz and 2.3 GHz. The resonant frequency of the second band can be tunable by varying the length and position of the open stub. The origami magic cube is built on paper. Its performance is numerically and experimentally demonstrated from S-parameters and radiation patterns. The measured 10 dB impedance bandwidth of the proposed origami antenna is 18% (900-1120 MHz) and 15% (2.1-2.45 GHz) for the unfolded state and 20% (1.3-1.6 GHz) and 14% (2.3-2.5 GHz) for the folded state. The measured peak gain at 900 MHz and 2.3 GHz are 1.1 dBi and 2.32 dBi, respectively, in the unfolded state. The measured peak gain at 1.5 GHz and 2.4 GHz are 3.28 dBi and 1.98 dBi, respectively, in the folded state. PMID- 29156656 TI - VEGFR3 as a novel modulator for PAH. PMID- 29156657 TI - Moderate hypofractionation for prostate cancer. PMID- 29156658 TI - Unified promoter opening steps in eukaryotic gene expression. PMID- 29156659 TI - Targeted treatment of advanced NRAS-mutated melanoma. PMID- 29156655 TI - The Role of Glyoxalase-I (Glo-I), Advanced Glycation Endproducts (AGEs), and Their Receptor (RAGE) in Chronic Liver Disease and Hepatocellular Carcinoma (HCC). AB - Glyoxalase-I (Glo-I) and glyoxalase-II (Glo-II) comprise the glyoxalase system and are responsible for the detoxification of methylglyoxal (MGO). MGO is formed non-enzymatically as a by-product, mainly in glycolysis, and leads to the formation of advanced glycation endproducts (AGEs). AGEs bind to their receptor, RAGE, and activate intracellular transcription factors, resulting in the production of pro-inflammatory cytokines, oxidative stress, and inflammation. This review will focus on the implication of the Glo-I/AGE/RAGE system in liver injury and hepatocellular carcinoma (HCC). AGEs and RAGE are upregulated in liver fibrosis, and the silencing of RAGE reduced collagen deposition and the tumor growth of HCC. Nevertheless, data relating to Glo-I in fibrosis and cirrhosis are preliminary. Glo-I expression was found to be reduced in early and advanced cirrhosis with a subsequent increase of MGO-levels. On the other hand, pharmacological modulation of Glo-I resulted in the reduced activation of hepatic stellate cells and therefore reduced fibrosis in the CCl4-model of cirrhosis. Thus, current research highlighted the Glo-I/AGE/RAGE system as an interesting therapeutic target in chronic liver diseases. These findings need further elucidation in preclinical and clinical studies. PMID- 29156660 TI - Defining tissue resident vascular stem cells. PMID- 29156661 TI - TRPM2 channels in mitochondrial dynamics and cancer. PMID- 29156662 TI - Multiple arterial grafting and ostriches: let's all take heart! PMID- 29156663 TI - New concepts in fulminant myocarditis and risk of cardiac mortality. PMID- 29156664 TI - Molecular regulation of T-ALL cell infiltration into the CNS. PMID- 29156665 TI - New ideas in preventing castration-resistant prostate cancer. PMID- 29156666 TI - BETting on combination to overcome PARPi resistance. PMID- 29156667 TI - Maintenance of elderly AML patients with androgens. PMID- 29156668 TI - CLL kinetics in the tumor microenvironment. PMID- 29156669 TI - Transient targeting of the pancreatic cancer stroma as a 'fine-tuned' anti-tumor and anti-metastatic therapy. PMID- 29156670 TI - Chipping in on clonal hematopoiesis. PMID- 29156671 TI - Conditional survival estimates for cancer patients. PMID- 29156672 TI - Discovery of spermatogenic activators: a lesson from bone morphogenetic protein 8. PMID- 29156673 TI - Induction of DISE in ovarian cancer cells in vivo. AB - The death receptor CD95/Fas can be activated by immune cells to kill cancer cells. shRNAs and siRNAs derived from CD95 or CD95 ligand (CD95L) are highly toxic to most cancer cells. We recently found that these sh/siRNAs kill cancer cells in the absence of the target by targeting the 3'UTRs of critical survival genes through canonical RNAi. We have named this unique form of off-target effect DISE (for death induced by survival gene elimination). DISE preferentially kills transformed cells and cancer stem cells. We demonstrate that DISE induction occurs in cancer cells in vivo after introducing a lentiviral CD95L derived shRNA (shL3) into HeyA8 ovarian cancer cells grown as i.p. xenografts in mice, when compared to a scrambled shRNA. To demonstrate the possibility of therapeutically inducing DISE, we coupled siRNAs to templated lipoprotein nanoparticles (TLP). In vitro, TLPs loaded with a CD95L derived siRNA (siL3) selectively silenced a biosensor comprised of Venus and CD95L ORF and killed ovarian cancer cells. In vivo, two siRNA-TLPs (siL2-TLP and siL3-TLP) reduced tumor growth similarly as observed for cells expressing the shL3 vector. These data suggest that it is possible to kill ovarian cancer cells in vivo via DISE induction using siRNA TLPs. PMID- 29156674 TI - Novel combinations of PI3K-mTOR inhibitors with dacomitinib or chemotherapy in PTEN-deficient patient-derived tumor xenografts. AB - PTEN inactivation occurs commonly in human cancers and putatively activates the PI3K/AKT/ mTOR pathway. Activation of this pathway has been involved in resistance to chemotherapy or anti-EGFR/HER2 therapies. We evaluated the combination of PI3K-mTOR inhibitors with chemotherapy or the pan-HER inhibitor dacomitinib in PTEN-deficient patient-derived tumor xenografts (PDX). Three PDXs were selected for their lack of PTEN expression by immunohistochemistry: a triple negative breast cancer (TNBC), a KRAS G12R low-grade serous ovarian cancer (LGSOC), and KRAS G12C and TP53 R181P lung adenocarcinoma (LADC). Two dual PI3K mTOR inhibitors were evaluated-PF-04691502 and PF-05212384-in combination with cisplatin, paclitaxel, or dacomitinib. The addition of PI3K-mTOR inhibitors to cisplatin or paclitaxel increased the activity of chemotherapy in the TNBC and LGSOC models; whereas no added activity was observed in the LADC model. Pharmacodynamic modulation of pS6 and pAKT was observed in the group treated with PI3K-mTOR inhibitor. Our research suggests that the addition of a PI3K-mTOR inhibitor may enhance tumor growth inhibition when compared to chemotherapy alone in certain PTEN-deficient PDXs. However, this benefit was absent in the KRAS and TP53 mutant LADC model. The role of PTEN deficiency in the antitumor activity of these combinations should be further investigated in the clinic. PMID- 29156675 TI - Glioblastoma and glioblastoma stem cells are dependent on functional MTH1. AB - Glioblastoma multiforme (GBM) is an aggressive form of brain cancer with poor prognosis. Cancer cells are characterized by a specific redox environment that adjusts metabolism to its specific needs and allows the tumor to grow and metastasize. As a consequence, cancer cells and especially GBM cells suffer from elevated oxidative pressure which requires antioxidant-defense and other sanitation enzymes to be upregulated. MTH1, which degrades oxidized nucleotides, is one of these defense enzymes and represents a promising cancer target. We found MTH1 expression levels elevated and correlated with GBM aggressiveness and discovered that siRNA knock-down or inhibition of MTH1 with small molecules efficiently reduced viability of patient-derived GBM cultures. The effect of MTH1 loss on GBM viability was likely mediated through incorporation of oxidized nucleotides and subsequent DNA damage. We revealed that MTH1 inhibition targets GBM independent of aggressiveness as well as potently kills putative GBM stem cells in vitro. We used an orthotopic zebrafish model to confirm our results in vivo and light-sheet microscopy to follow the effect of MTH1 inhibition in GBM in real time. In conclusion, MTH1 represents a promising target for GBM therapy and MTH1 inhibitors may also be effective in patients that suffer from recurring disease. PMID- 29156676 TI - Uncoupling TORC2 from AGC kinases inhibits tumour growth. AB - Mammalian target of rapamycin (mTOR) is a central regulator of growth and metabolism. mTOR resides in two distinct multi-protein complexes - mTORC1 and mTORC2 - with distinct upstream regulators and downstream targets. While it is possible to specifically inhibit mTORC1 with rapamycin, or inhibit both mTOR complexes together with ATP pocket directed mTOR kinase inhibitors, it is not possible to assess the specific roles for mTORC2 pharmacologically. To overcome this, we have developed a novel, inducible, dominant negative system for disrupting substrate recruitment to mTORC2. Previously we identified the mTORC2 specific subunit Sin1 as a direct binding partner for AGC kinases Akt and PKC. Sin1 mutants, which retain the ability to bind Rictor and mTOR, but fail to recruit their AGC client kinases, inhibit AKT and PKC priming and block cell growth. In this study, we demonstrate that uncoupling mTORC2 from AGC kinases in DLD1 colon cancer cells inhibits Akt activation and blocks tumour growth in vivo. Further we demonstrate, using time resolved two-site amplified FRET (A-FRET) analysis of xenograft tumours, that inhibition of tumour growth correlates with the degree of mTORC2 uncoupling from its downstream targets, as demonstrated for Akt. These data add weight to the body of evidence that mTORC2 represents a pharmacological target in cancer independently of mTORC1. PMID- 29156677 TI - Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways. AB - Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies. We demonstrate effectiveness of multiple MEKi against diverse BRAF-fusions with novel N-terminal partners, with trametinib being the most potent. However, resistance to MEKi or PLX8394 develops via increased RTK expression causing activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones. To circumvent acquired resistance, we show potency of combinatorial targeting with trametinib and everolimus, an mTOR inhibitor (mTORi) against multiple BRAF fusions. While single-agent mTORi and MEKi PLGG clinical trials are underway, our study provides preclinical rationales for using MEKi and mTORi combinatorial therapy to stave off or prevent emergent drug-resistance in BRAF-fusion driven PLGGs. PMID- 29156678 TI - Epigenetic silencing of tumor suppressor candidate 3 confers adverse prognosis in early colorectal cancer. AB - Colorectal cancer (CRC) is a biologically and clinically heterogeneous disease. Even though many recurrent genomic alterations have been identified that may characterize distinct subgroups, their biological impact and clinical significance as prognostic indicators remain to be defined. The tumor suppressor candidate-3 (TUSC3/N33) locates to a genomic region frequently deleted or silenced in cancers. TUSC3 is a subunit of the oligosaccharyltransferase (OST) complex at the endoplasmic reticulum (ER) which catalyzes bulk N-glycosylation of membrane and secretory proteins. However, the consequences of TUSC3 loss are largely unknown. Thus, the aim of the study was to characterize the functional and clinical relevance of TUSC3 expression in CRC patients' tissues (n=306 cases) and cell lines. TUSC3 mRNA expression was silenced by promoter methylation in 85 % of benign adenomas (n=46 cases) and 35 % of CRCs (n =74 cases). Epidermal growth factor receptor (EGFR) was selected as one exemplary ER-derived target protein of TUSC3-mediated posttranslational modification. We found that TUSC3 inhibited EGFR-signaling and promoted apoptosis in human CRC cells, whereas TUSC3 siRNA knock-down increased EGFR-signaling. Accordingly, in stage I/II node negative CRC patients (n=156 cases) loss of TUSC3 protein expression was associated with poor overall survival. In sum, our data suggested that epigenetic silencing of TUSC3 may be useful as a molecular marker for progression of early CRC. PMID- 29156679 TI - Remote intracranial recurrence of IDH mutant gliomas is associated with TP53 mutations and an 8q gain. AB - Most IDH mutant gliomas harbor either 1p/19q co-deletions or TP53 mutation; 1p/19q co-deleted tumors have significantly better prognoses than tumors harboring TP53 mutations. To investigate the clinical factors that contribute to differences in tumor progression of IDH mutant gliomas, we classified recurrent tumor patterns based on MRI and correlated these patterns with their genomic characterization. Accordingly, in IDH mutant gliomas (N = 66), 1p/19 co-deleted gliomas only recurred locally, whereas TP53 mutant gliomas recurred both locally and in remote intracranial regions. In addition, diffuse tensor imaging suggested that remote intracranial recurrence in the astrocytomas, IDH-mutant with TP53 mutations may occur along major fiber bundles. Remotely recurrent tumors resulted in a higher mortality and significantly harbored an 8q gain; astrocytomas with an 8q gain resulted in significantly shorter overall survival than those without an 8q gain. OncoScan(r) arrays and next-generation sequencing revealed specific 8q regions (i.e., between 8q22 and 8q24) show a high copy number. In conclusion, only tumors with TP53 mutations showed patterns of remote recurrence in IDH mutant gliomas. Furthermore, an 8q gain was significantly associated with remote intracranial recurrence and can be considered a poor prognostic factor in astrocytomas, IDH-mutant. PMID- 29156680 TI - Vemurafenib-resistance via de novo RBM genes mutations and chromosome 5 aberrations is overcome by combined therapy with palbociclib in thyroid carcinoma with BRAFV600E. AB - Purpose: Papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor. BRAFV600E represents the PTC hallmark and is targeted with selective inhibitors (e.g. vemurafenib). Although there have been promising results in clinical trials using these inhibitors, most patients develop resistance and progress. Tumor clonal diversity is proposed as one mechanism underlying drug resistance. Here we have investigated mechanisms of primary and secondary resistance to vemurafenib in BRAFWT/V600E-positive PTC patient-derived cells with P16-/- (CDKN2A-/-). Experimental Design: Following treatment with vemurafenib, we expanded a sub population of cells with primary resistance and characterized them genetically and cytogenetically. We have used exome sequencing, metaphase chromosome analysis, FISH and oligonucleotide SNP-microarray assays to assess clonal evolution of vemurafenib-resistant cells. Furthermore, we have validated our findings by networks and pathways analyses using PTC clinical samples. Results: Vemurafenib-resistant cells grow similarly to naive cells but are refractory to apoptosis upon treatment with vemurafenib, and accumulate in G2-M phase. We find that vemurafenib-resistant cells show amplification of chromosome 5 and de novo mutations in the RBM (RNA-binding motifs) genes family (i.e. RBMX, RBM10). RBMX knockdown in naive-cells contributes to tetraploidization, including expansion of clones with chromosome 5 aberrations (e.g. isochromosome 5p). RBMX elicits gene regulatory networks with chromosome 5q cancer-associated genes and pathways for G2-M and DNA damage-response checkpoint regulation in BRAFWT/V600E-PTC. Importantly, combined therapy with vemurafenib plus palbociclib (inhibitor of CDK4/6, mimicking P16 functions) synergistically induces stronger apoptosis than single agents in resistant-cells and in anaplastic thyroid tumor cells harboring the heterozygous BRAFWT/V600E mutation. Conclusions: Critically, our findings suggest for the first time that targeting BRAFWT/V600E and CDK4/6 represents a novel therapeutic strategy to treat vemurafenib-resistant or vemurafenib-naive radioiodine-refractory BRAFWT/V600E-PTC. This combined therapy could prevent selection and expansion of aggressive PTC cell sub-clones with intrinsic resistance, targeting tumor cells either with primary or secondary resistance to BRAFV600E inhibitor. PMID- 29156681 TI - The histone demethylase Kdm3a is required for normal epithelial proliferation, ductal elongation and tumor growth in the mouse mammary gland. AB - Histone modification alters chromatin architecture to regulate gene transcription. KDM3A is a histone demethylase in the JmjC domain-containing protein family. It removes di- and mono- methyl residues from di- or mono methylated lysine 9 of histone H3 (H3K9me2/me1). Recent studies have shown that Kdm3a plays an important role in self-renewal of embryonic stem cells, spermatogenesis, metabolism, sex determination and tumor angiogenesis. However, its role in mammary gland development and breast carcinogenesis remains unclear. In this study, we found that Kdm3a is expressed in the mouse mammary gland epithelial cells. Knockout of Kdm3a significantly increased H3K9me2/me1 levels in these epithelial cells, which correlated with markedly decreased mammary gland ductal elongation and branching in the intact knockout virgin mice. Furthermore, estrogen replacement in the ovariectomized Kdm3a knockout mice couldn't rescue the retarded ductal growth. Moreover, transplantation of KO mammary gland pieces to wild type recipient mice showed slower ductal growth compared with that of WT gland pieces. Consistently, knockout of Kdm3a also reduced the proliferation rates and cyclin D1 expression in the mammary gland epithelial cells. In addition, Kdm3a knockout did not significantly change the latency of the polyoma middle T oncogene-induced mammary gland tumorigenesis. Tumor growth, however, was slowed which might be due to the decrease in cyclin D1 expression and tumor cell proliferation. We also found that Kdm3a binds and activates the cyclin D1 promoter. These results demonstrate that Kdm3a plays an important intrinsic role in promoting mammary gland ductal growth and tumor growth probably through enhancing cyclin D1 expression and cell proliferation. PMID- 29156682 TI - Pharmacologic inhibition of PI3K p110delta in mutant Shp2E76K-expressing mice. AB - Juvenile myelomonocytic leukemia is a childhood malignancy that lacks effective chemotherapies and thus has poor patient outcomes. PI3K p110delta has been found to promote hyperproliferation of cells expressing mutant Shp2. In this study, we tested the efficacy of a PI3Kdelta inhibitor in mice expressing the Shp2 gain-of function mutation, E76K. We found that in vivo treatment of mice led to significantly decreased splenomegaly, reduced frequency of bone marrow progenitor cells, and increased terminally differentiated peripheral blood myeloid cells. The survival of drug-treated mice was significantly prolonged compared to vehicle treated controls, although mice from both groups ultimately succumbed to a similar myeloid cell expansion. PI3Kdelta inhibitors are currently used to treat patients with relapsed lymphoid malignancies, such as chronic lymphocytic leukemia. The current findings provide evidence for using PI3Kdelta inhibitors as a treatment strategy for JMML and potentially other myeloid diseases. PMID- 29156683 TI - SHYCD induces APE1/Ref-1 subcellular localization to regulate the p53-apoptosis signaling pathway in the prevention and treatment of acute on chronic liver failure. AB - Background & Aims: San huang yin chi decoction(SHYCD) is derived from the yin chen hao decoction, a well-known and canonical Chinese medicine formula from the "Treatise on Febrile Diseases". Over the past decade, SHYCD has been used to treat and prevent the liver cirrhosis and liver failure. In the present study, we investigated the effects of SHYCD for acute on chronic liver failure(ACLF) and explored its potential mechanism. an ACLF rat model, which induced by carbon tetrachloride (CCl4) combined with D-galactosamine (D-GalN) and lipopolysaccharide(LPS), was used and confirmed by B-ultrasound analysis. Rats were randomly divided into control group, model group, SHYCD-H group, SHYCD-M group, SHYCD-L group, AGNHW group. Compared with the ACLF model group, High, medium, and low doses of SHYCD reduced ALT, AST, TBIL, NH3, IL-1beta, IL-6, and TNFalpha expression levels in the serum, Shorten PT and INR time,and increased Fbg content in the whole blood, increased survival rate of the rats, improved liver pathological changes. APE1 / Ref-1 was mainly expressed in the nucleus, but the nucleus and cytoplasm were co-expressed after hepatocyte injury. SHYCD significantly downregulated APE1/Ref-1 expression in the cytoplasm. Increased APE1/Ref-1, Bcl-2, reduced p53, caspase-3, Bax, and Cyt-c in the total protein. Base on the results, we conclused that High, medium, and low doses of SHYCD could be applied in prevention and treatment of ACLF, and dose-dependent. The possible mechanism is to promote the APE1 / Ref-1 from the cytoplasm to the nuclear transfer, regulation of p53 apoptosis signal pathway prevention and treatment of ACLF. PMID- 29156685 TI - Whole genome and transcriptome analysis reveal MALDI-TOF MS and SDS-PAGE have limited performance for the detection of the key outer membrane protein in carbapenem-resistant Klebsiella pneumoniae isolates. AB - To detect the outer membrane protein (OMP), which plays a key role in carbapenem resistance, whole-genome and transcriptome analysis of the clinical carbapenem resistant Klebsiella pneumoniae was carried out. The index strain lacked both OmpK35 and OmpK36, whereas the other strains lacked only OmpK35. After SDS-PAGE, the putative OMP bands were excised and identified as OmpA and OmpK36. MALDI-TOF MS showed peaks at ~36 and ~38 kDa that corresponded to OmpA and OmpK36, respectively. In all the strains except YMC2014/03/P345, the ~38 kDa peaks were present. The K. pneumoniae ATCC 13883 isolate showed three bands on SDS-PAGE and three corresponding peaks on MALDI-TOF MS. The additional third peak at ~37 kDa corresponding to OmpK35 was observed. To verify OmpK35 peak detection in other K. pneumoniae isolates by MALDI-TOF MS, we analyzed six strains from our laboratory's strain bank. Whole genome sequence indicated that only two isolates had intact OmpK35. Both MALDI-TOF MS and SDS-PAGE did not show a ~37 kDa peak or an OmpK35 band as observed in the K. pneumoniae ATCC 13883 isolate. Separation using SDS-PAGE showed a single peak representing OmpA. Therefore, both SDS-PAGE and MALDI-TOF MS were not completely reliable for OMP detection because they fail to detect OmpK35. To the best of our knowledge, this is the first report on the performance of SDS-PAGE and MALDI-TOF MS for the detection of OMP's using whole genome and RNA sequencing analyses. PMID- 29156684 TI - A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development. AB - Mental illnesses like schizophrenia (SCZ) and major depression disorder (MDD) are devastating brain disorders. The SCZ risk gene, disrupted in schizophrenia 1 (DISC1), has been associated with neuropsychiatric conditions. However, little is known regarding the long-lasting impacts on brain metabolism and behavioral outcomes from genetic insults on fetal NPCs during early life. We have established a new mouse model that specifically interrupts DISC1 functions in NPCs in vivo by a dominant-negative DISC1 (DN-DISC1) with a precise temporal and spatial regulation. Interestingly, prenatal interruption of mouse Disc1 function in NPCs leads to abnormal depression-like deficit in adult mice. Here we took a novel unbiased metabonomics approach to identify brain-specific metabolites that are significantly changed in DN-DISC1 mice. Surprisingly, the inhibitory neurotransmitter, GABA, is augmented. Consistently, parvalbumin (PV) interneurons are increased in the cingulate cortex, retrosplenial granular cortex, and motor cortex. Interestingly, somatostatin (SST) positive and neuropeptide Y (NPY) interneurons are decreased in some brain regions, suggesting that DN-DISC1 expression affects the localization of interneuron subtypes. To further explore the cellular mechanisms that cause this change, DN-DISC1 suppresses proliferation and promotes the cell cycle exit of progenitors in the medial ganglionic eminence (MGE), whereas it stimulates ectopic proliferation of neighboring cells through cell non-autonomous effect. Mechanistically, it modulates GSK3 activity and interrupts Dlx2 activity in the Wnt activation. In sum, our results provide evidence that specific genetic insults on NSCs at a short period of time could lead to prolonged changes of brain metabolism and development, eventually behavioral defects. PMID- 29156686 TI - Crosstalk between mismatch repair and base excision repair in human gastric cancer. AB - DNA repair gene expression in a set of gastric cancers suggested an inverse association between the expression of the mismatch repair (MMR) gene MLH1 and that of the base excision repair (BER) gene DNA polymerase beta (Polbeta). To gain insight into possible crosstalk of these two repair pathways in cancer, we analysed human gastric adenocarcinoma AGS cells over-expressing Polbeta or Polbeta active site mutants, alone or in combination with MLH1 silencing. Next, we investigated the cellular response to the alkylating agent methyl methanesulfonate (MMS) and the purine analogue 6-thioguanine (6-TG), agents that induce lesions that are substrates for BER and/or MMR. AGS cells over-expressing Polbeta were resistant to 6-TG to a similar extent as when MLH1 was inactivated while inhibition of O6-methylguanine-DNA methyltransferase (MGMT) was required to detect resistance to MMS. Upon either treatment, the association with MLH1 down regulation further amplified the resistant phenotype. Moreover, AGS cells mutated in Polbeta were hypersensitive to both 6-TG and MMS killing and their sensitivity was partially rescued by MLH1 silencing. We provide evidence that the critical lethal lesions in this new pathway are double strand breaks that are exacerbated when Polbeta is defective and relieved when MLH1 is silenced. In conclusion, we provide evidence of crosstalk between MLH1 and Polbeta that modulates the response to alkylation damage. These studies suggest that the Polbeta/MLH1 status should be taken into consideration when designing chemotherapeutic approaches for gastric cancer. PMID- 29156687 TI - Distribution of lymph node metastasis from lymphoepithelial-like carcinoma of the parotid. AB - Purpose: To explore the distribution of node spread from lymphoepithelial-like carcinoma (LELC) of the parotid gland based on the 2013 updated guidelines for neck node levels. Results: 42 (58.3%) cases had metastatic nodes, all were localized at the ipsilateral neck. The detailed distribution was: level Ia 0, level Ib 6(14.3%), level II 34 (80.1%), level III 16 (38.1%), level IV 9 (21.4%), level V 7 (16.7%), level VI 0, level VII 0, level VIII 37 (88.1%), level IX 0, level Xa 2 (4.8%), and level Xb 0. Lymphadenopathy in level Ib, V and Xa was always accompanied with level II or level VIII nodal metastasis. No statistical significance was found in the incidence of nodal involvement between T1-2 and T3 4 tumors (57.4% versus 61.1%, p = 0.78). Methods: We retrospectively reviewed the surgical and imaging documents of 72 cases of LELC from the parotid gland between January 2004 and November 2015. All patients received contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Parotid metastasis from nasopharyngeal cancer (NPC) was excluded. Nodal status and distribution was evaluated by both pathologic reports and imaging studies. Conclusions: This is the first description of topography of cervical nodal metastases from LELC of the parotid gland. Incidence of nodal involvement is high. Nodes at ipsilateral level VIII and II were most frequently involved, followed by level III, IV, V and Ib. Nodes in level Ia, VI and level VII were rarely seen. PMID- 29156688 TI - Frequency of expression and generation of T-cell responses against antigens on multiple myeloma cells in patients included in the GMMG-MM5 trial. AB - Background: Raising T-cell response against antigens either expressed on normal and malignant plasma cells (e.g. HM1.24) or aberrantly on myeloma cells only (e.g. cancer testis antigens, CTA) by vaccination is a potential treatment approach for multiple myeloma. Results: Expression by GEP is found for HM1.24 in all, HMMR in 318/458 (69.4%), MAGE-A3 in 209/458 (45.6%), NY-ESO-1/2 in 40/458 (8.7%), and WT-1 in 4/458 (0.8%) of samples with the pattern being confirmed by RNA-sequencing. T-cell-activation is found in 9/26 (34.6%) of patient samples, i.e. against HM1.24 (4/24), RHAMM-R3 (3/26), RHAMM1-8 (2/14), WT-1 (1/11), NY-ESO 1/2 (1/9), and MAGE-A3 (2/8). In 7/19 T-cell activation responses, myeloma cells lack respective antigen-expression. Expression of MAGE-A3, HMMR and NY-ESO-1/2 is associated with adverse survival. Experimental design: We assessed expression of HM1.24 and the CTAs MAGE-A3, NY-ESO-1/2, WT-1 and HMMR in CD138-purified myeloma cell samples of previously untreated myeloma patients in the GMMG-MM5 multicenter trial by gene expression profiling (GEP; n = 458) and RNA-sequencing (n = 152) as potential population regarding vaccination trials. We then validated the feasibility to generate T-cell responses (n = 72) against these antigens by IFN gamma EliSpot-assay (n = 26) related to antigen expression (n = 22). Lastly, we assessed survival impact of antigen expression in an independent cohort of 247 patients treated by high-dose therapy and autologous stem cell transplantation. Conclusions: As T-cell responses can only be raised in a subfraction of patients despite antigen expression, and the number of responses increases with more antigens used, vaccination strategies should assess patients' antigen expression and use a "cocktail" of peptide vaccines. PMID- 29156689 TI - Implications of PI3K/AKT inhibition on REST protein stability and neuroendocrine phenotype acquisition in prostate cancer cells. AB - Treatment-induced neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that arises as a consequence of rigorous androgen receptor (AR) pathway inhibition (ARPI) therapies. While the PI3K/AKT pathway has been investigated as a co-therapeutic target with ARPI for advanced PCa, whether this strategy can prevent tumor progression to t-NEPC remains unknown. Here, we report that PI3K/AKT inhibition alone reduces RE-1 silencing transcription factor (REST) protein expression and induces multiple NE markers in PCa cells. The loss of REST by PI3K/AKT inhibition is through protein degradation mediated by the E3-ubiquitin ligase beta-TRCP and REST phosphorylations at the S1024, S1027, and S1030 sites. Since AR inhibition can also deplete REST, the combinational inhibition of PI3K/AKT and AR further aggravated REST protein reduction. We profiled the transcriptomes of AKT and AR inhibitions in the LNCaP cells. The Gene Set Enrichment Analysis (GSEA) showed that these transcriptomes are highly correlated with the REST-regulated gene signature. Co-targeting AKT and AR resulted in a higher correlation comparing to those of single treatment. Comparing these transcriptomes to the t-NEPC gene signature in patients by GSEA, we observed that adding AKT inhibition to AR blockade enhanced the expression of neurogenesis-related genes and resulted in a stronger and broader upregulation of REST-regulated genes specific to t-NEPC. These results indicate that AKT pathway inhibition can induce neuroendocrine differentiation of PCa cells via REST protein degradation. It delineates a potential risk for the AR and PI3K/AKT co targeting strategy as it may further facilitate t-NEPC development. PMID- 29156690 TI - Abnormal amplitude of low-frequency fluctuations associated with rapid-eye movement in chronic primary insomnia patients. AB - Purpose: Chronic primary insomnia (CPI) is the most prevalent sleep disorder worldwide. CPI manifests as difficulties in sleep onset, maintaining sleep, prolonged sleep latency, and daytime impairment and is often accompanied by cognitive problems such as poor academic performance, poor attention, and decreased memory. The most popular explanation of insomnia is hyperarousal or increased activities of neurons. Rapid eye movement (REM) sleep detected by polysomnography (PSG) exhibits a positive relationship with brain homeostasis and can be helpful for optimally preparing an organism for emotional and social function. Limited work has been performed to explore brain function of insomnia patients in combination with PSG analysis. Results: We observed increased ALFF within areas related to hyperarousal such as the midbrain and bilateral extra nucleus, whereas decreased ALFF was observed within areas associated with memory and attention involving the parietal and occipital lobule and others. Furthermore, the altered ALFF was associated with the duration of insomnia, sleep efficiency, duration of REM, latency of RME and ratio of REM. Materials and Methods: In this study, we recruited twenty-five CPI patients and twenty-five normal sleep (NS) volunteers as a control group to investigate the amplitude of low-frequency fluctuations (ALFF) and the correlation between those altered ALFF regions through resting-state fMRI and PSG data. Conclusions: These findings suggest that hyperarousal reflected by ALFF abnormality within brain areas related to cognition and emotion in insomnia associated with REM sleep. PMID- 29156691 TI - Neutrophils in chronic lymphocytic leukemia are permanently activated and have functional defects. AB - A growing body of studies highlights involvement of neutrophils in cancer development and progression. Our aim was to assess the phenotypic and functional properties of circulating neutrophils from patients with chronic lymphocytic leukemia (CLL). The percentage of CD54+ and CD64+ neutrophils as well as CD54 expression on these cells were higher in CLL patients than in age-matched healthy controls. Neutrophils from CLL produced more reactive oxygen species (ROS) compared to controls in both resting and activated conditions. Lipopolysaccharide induced production of IL-1beta and TNF-a as well as reduced TLR2 expression in neutrophils from CLL than in neutrophils from controls suggesting their tolerant state. Finally, phenotypic alterations of neutrophils, particularly elevation of CD64 and CD54 markers, correlated with disease activity and treatment, and low percentage of neutrophils. Taken together, the alterations in percentage and functional characteristics of neutrophils reflect the clinical course of CLL. Our data provide first evidence that neutrophils in CLL are permanently primed and have functional defects. PMID- 29156692 TI - Increased transcriptional and metabolic capacity for lipid metabolism in the peripheral zone of the prostate may underpin its increased susceptibility to cancer. AB - The human prostate gland comprises three distinct anatomical glandular zones, namely the peripheral, central and transitional zones. Although prostate cancer can arise throughout the prostate, it is more frequent in the peripheral zone. In contrast, hyperplasia occurs most frequently in the transitional zone. In this paper, we test the hypothesis that peripheral and transitional zones have distinct metabolic adaptations that may underlie their different inherent predispositions to cancer and hyperplasia. In order to do this, we undertook RNA sequencing and high-throughput metabolic analyses of non-cancerous tissue from the peripheral and transitional zones of patients undergoing prostatectomy. Integrated analysis of RNAseq and metabolomic data revealed that transcription of genes involved in lipid biosynthesis is higher in the peripheral zone, which was mirrored by an increase in fatty acid metabolites, such as lysolipids. The peripheral zone also exhibited increased fatty acid catabolic activity and contained higher level of neurotransmitters. Such increased capacity for de novo lipogenesis and fatty acid oxidation, which is characteristic of prostate cancer, can potentially provide a permissive growth environment within the peripheral zone for cancer growth and also transmit a metabolic growth advantage to newly emerging clones themselves. This lipo-rich priming may explain the observed susceptibility of the peripheral zone to oncogenesis. PMID- 29156693 TI - CDK3, target of miR-4469, suppresses breast cancer metastasis via inhibiting Wnt/beta-catenin pathway. AB - Cyclin-dependent kinase 3 (CDK3), a member of CDK family, is involved in G0/G1 and G1/S cell cycle transitions. Although several researchers discovered that CDK3 related to cell growth in some kinds of cancer, the functions of CDK3 during tumor development remains unclear. Here, we first found that the expression of CDK3 was higher in primary tumors of non-metastatic breast cancer compared with those in metastatic breast cancer. Overexpression of CDK3 suppressed cell migration and invasion of breast cancer cells, and decreased the metastasis in nude mice. We further identified miR-4469 was a negative regulator of CDK3 by directly targeting its 3'-untranslated region (UTR). The increase of motility induced by miR-4469 could be abolished by CDK3 overexpression. Moreover, RNA-seq analysis revealed that Wnt pathway may be inhibited by CDK3 expression, which was subsequently confirmed by western blot. Moreover, Wnt3a treatment abolished the inhibitory role of CDK3 in cell motility, suggesting that Wnt signaling is the potential downstream of CDK3. In conclusion, these results support that CDK3 which is targeted by miR-4469 suppresses breast cancer metastasis by inhibiting Wnt/beta-catenin pathway. PMID- 29156694 TI - PDAC-derived exosomes enrich the microenvironment in MDSCs in a SMAD4-dependent manner through a new calcium related axis. AB - : Tumor genetics and escape from immune surveillance concur in the poor prognosis of PDAC. In this study an experimental model was set up to verify whether SMAD4, deleted in about 55% PDAC and associated with poor prognosis, is involved in determining immunosuppression through Exosomes (Exo). Potential mechanisms and mediators underlying SMAD4-dependent immunosuppression were evaluated by studying intracellular calcium (Fluo-4), Exo-miRNAs (microarray) and Exo-proteins (SILAC). Two PDAC cell lines expressing (BxPC3-SMAD4+) or not-expressing (BxPC3) SMAD4 were used to prepare Exo-enriched conditioned media, employed in experiments with blood donors PBMCs. Exo expanded myeloid derived suppressor cells (gMDSC and mMDSC, flow cytometry) and altered intracellular calcium fluxes in an SMAD4 dependent manner. BxPC3-SMAD4+, but mainly BxPC3 Exo, increased calcium fluxes of PBMCs (p = 0.007) and this increased intracellular calcium trafficking characterized mMDSCs. The analysis of de-regulated Exo-miRNAs and transfection experiments revealed hsa-miR-494-3p and has-miR-1260a as potential mediators of SMAD4-associated de-regulated calcium fluxes. Eleven main biological processes were identified by the analysis of SMAD4-associated de-regulated Exo-proteins, including translation, cell adhesion, cell signaling and glycolysis. A reverse Warburg effect was observed by treating PBMCs with PDAC-derived Exo: BxPC3 Exo induced a higher glucose consumption and lactate production than BxPC3-SMAD4+ Exo. CONCLUSION: PDAC-derived Exo from cells with, but mainly from those without SMAD4 expression, create an immunosuppressive myeloid cell background by increasing calcium fluxes and glycolysis through the transfer of SMAD4-related differentially expressed miRNAs and proteins. PMID- 29156695 TI - MiR-2964a-5p binding site SNP regulates ATM expression contributing to age related cataract risk. AB - This study was to explore the involvement of DNA repair genes in the pathogenesis of age-related cataract (ARC). We genotyped nine single nucleotide polymorphisms (SNPs) of genes responsible to DNA double strand breaks (DSBs) in 804 ARC cases and 804 controls in a cohort of eye diseases in Chinese population and found that the ataxia telangiectasia mutated (ATM) gene-rs4585:G>T was significantly associated with ARC risk. An in vitro functional test found that miR-2964a-5p specifically down-regulated luciferase reporter expression and ATM expression in the cell lines transfected with rs4585 T allele compared to rs4585 G allele. The molecular assay on human tissue samples discovered that ATM expression was down regulated in majority of ARC tissues and correlated with ATM genotypes. In addition, the Comet assay of cellular DNA damage of peripheral lymphocytes indicated that individuals carrying the G allele (GG/GT) of ATM-rs4585 had lower DNA breaks compared to individuals with TT genotype. These findings suggested that the SNP rs4585 in ATM might affect ARC risk through modulating the regulatory affinity of miR-2964a-5p. The reduced DSBs repair might be involved in ARC pathogenesis. PMID- 29156696 TI - Interaction of microRNA-21/145 and Smad3 domain-specific phosphorylation in hepatocellular carcinoma. AB - MicroRNAs 21 and 145 exhibit inverse expression in Hepatocellular carcinoma (HCC), but how they relate to Smad3 C-terminal and Link region phosphorylation (pSmad3C and pSmad3L) downstream of TGF-beta/MAPK signaling, remains inconclusive. Our results suggest microRNA-145 targets Smad3 in HepG2 cells. Decreased tumor volume and increased apoptosis were produced in both microRNA-21 antagomir and microRNA-145 agomir groups compared to controls. Inhibition of TbetaRI and MAPK (ERK, JNK, and p38) activation respectively produced decreased microRNA-21 but increased microRNA-145 expression. Correspondingly, the expression level of pSmad3C obviously increased while pSmad3L decreased in microRNA-145 agomir-group and the expression of pSmad3C/3L were not markedly changed but pERK, pJNK, pp38 decreased in microRNA-21 antagomir-group compared to controls. On the other hand, microRNA-145 and 21 increased respectively in xenografts of HepG2 cells transfected with Smad3 EPSM and 3S-A plasmid, and this correlated with the overexpression of pSmad3C and pSmad3L respectively compared to control. To conclude, microRNA-21 promotes tumor progression in a MAPK dependent manner while microRNA-145 suppresses it via domain-specific phosphorylation of Smad3 in HCC. Meanwhile, increased pSmad3C/3L lead to the up regulation of microRNA-145/21 respectively. The interaction between pSmad3C/3L and microRNA-145/21 regulates HCC progression and the switch of pSmad3C/3L may serve as an important target for HCC therapy. PMID- 29156697 TI - Exploring brusatol as a new anti-pancreatic cancer adjuvant: biological evaluation and mechanistic studies. AB - Pancreatic cancer is highly resistant to chemotherapeutic agents and is known to have a poor prognosis. The development of new therapeutic entities is badly needed for this deadly malignancy. In this study, we demonstrated for the first time that brusatol, a natural quassinoid isolated from a Chinese herbal medicine named Bruceae Fructus, possessed potent cytotoxic effect against different pancreatic adenocarcinoma cell lines. Its anti-pancreatic cancer effect was comparable to that of the first-line chemotherapeutic agents such as gemcitabine and 5-fluorouracil, with a more favorable safety profile. In addition, brusatol showed a synergistic anti-proliferative effect toward PANC-1 and Capan-2 cell lines when combined with gemcitabine or 5-fluorouracil. The results of flow cytometry suggested that brusatol combination treatment with gemcitabine or 5 fluorouracil was able to cause cell cycle arrest at G2/M phase, and accentuate apoptosis in PANC-1 cells. Moreover, brusatol deactivated gemcitabine/5 fluorouracil-induced NF-kappaB activation. Western blot analysis and qRT-PCR results showed that brusatol significantly down-regulated the expression of vimentin and Twist, and markedly stimulated the expression of E-cadherin, the key regulatory factors of the epithelial-mesenchymal transition process. Furthermore, treatment with combination of brusatol and gemcitabine or 5-fluorouracil significantly reduced in vivo tumor growth when compared with treatment of either brusatol or gemcitabine/5-fluorouracil alone. Taken together, these results have amply demonstrated that brusatol is a potent anti-pancreatic cancer natural compound, and the synergistic anti-pancreatic cancer effects of brusatol and gemcitabine/5-fluorouracil observed both in vitro and in vivo are associated with the suppression of epithelial-mesenchymal transition process, indicating that brusatol is a promising adjunct to the current chemotherapeutic regimen. PMID- 29156698 TI - Combined BRD4 and CDK9 inhibition as a new therapeutic approach in malignant rhabdoid tumors. AB - Rhabdoid tumors are caused by the deletion of SMARCB1, whose protein encodes the SMARCB1 subunit of the chromatin remodeling complex SWI/SNF that is involved in global chromatin organization and gene expression control. Simultaneously inhibiting the main players involved in the deregulated transcription machinery is a promising option for preventing exaggerated tumor cell proliferation and survival as it may bypass compensatory mechanisms. In support of this hypothesis, we report efficient impairment of cellular proliferation and strong induction of cell death elicited by inhibition of bromodomain protein BRD4 and transcription kinase CDK9 using small molecular compounds. Combination of both compounds efficiently represses antiapoptotic genes and the oncogene MYC. Our results provide a novel approach for the treatment of RT. PMID- 29156699 TI - Cell-specific regulation of proliferation by Ano1/TMEM16A in breast cancer with different ER, PR, and HER2 status. AB - The calcium-activated chloride channel Ano1 (TMEM16A) is overexpressed in many tumors. However, conflicting data exist regarding the role of Ano1 in cell proliferation. Here, we performed immunohistochemistry to investigate the expression of Ano1 and Ki67 in 403 patients with breast cancer, and analyzed the association between the expression of Ano1 and Ki67 in breast cancer subtypes categorized according to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Ano1 expression was negatively correlated with Ki67 expression. Ano1 overexpression more frequently occurred in ER-positive or HER2-negative patients with the low expression of Ki67. Ano1 overexpression was associated with longer overall survival (OS) in breast cancer with the low expression of Ki67, especially in ER-positive, PR-positive, and HER2 negative breast cancer. Multivariate Cox regression analysis showed that Ano1 overexpression was a prognostic factor for longer overall survival in ER positive, PR-positive, or HER2-negative patients with the low expression of Ki67. Furthermore, Ano1 promoted cell proliferation in ER-positive, PR-positive, and HER2-negative MCF7 cells, but inhibited cell proliferation in ER-negative, PR negative, and HER2-negative MDA-MB-435S cells. Our findings suggest that Ano1 may differentially regulate cell proliferation in a subtype of breast cancer defined by ER, PR, and HER2. Combined expression of Ano1 and Ki67 may be used for predicting clinical outcomes of breast cancer patients with different subtypes of ER, PR, and HER2. PMID- 29156700 TI - Linc00152 suppresses apoptosis and promotes migration by sponging miR-4767 in vascular endothelial cells. AB - Dysfunction of vascular endothelial cells (VECs), such as increased apoptosis and diminished migration, is closely connected with most cardiovascular diseases and angiogenesis-related events. LncRNAs have been involved in regulation of many pathological processes, but their roles in vascular endothelial function are hardly underreported. Here, we explore the role of a intergenic lncRNA named linc00152 in the apoptosis and migration of VECs. We found that linc00152 was downregulated in human umbilical vein VECs (HUVECs) in a dose- and time-dependent manner following treatment with oxLDL, which is a typical proinflammatory factor in the initiation and progression of vascular endothelial dysfunction. Gain- and loss-function experiments indicated that linc00152 distinctly inhibited apoptosis and improved migration in oxLDL-treated HUVECs. By sponging miR-4767, linc00152 positively regulated the expression of Bcl2L12 and EGFR proteins. Moreover, blocking miR-4767 rescued the decrease of Bcl2L12 and EGFR caused by linc00152 knockdown, as well as the changes in cell apoptosis and migration. Our findings propose a novel role of linc00152 in the improvement of vascular endothelial function and a potential target for the therapy of some cardiovascular diseases. PMID- 29156701 TI - Association of breast carcinoma growth with a non-canonical axis of IFNgamma/IDO1/TSP1. AB - Reciprocal interactions between cancers and the surrounding microenvironment have an important role in tumour evolution. In this study, our data suggested that through thrombospondin 1 (TSP1), tumour-associated microvessel provides a dormant niche to sustain inactive status of breast invasive ductal carcinoma (IDC) cells. TSP1 levels in the tumour stroma were negatively correlated with vascular indoleamine 2,3-dioxygenase 1 (IDO1) in IDC tissues. IDO1 is an intracellular enzyme initiating the first and rate-limited step of tryptophan breakdown. Lower stromal TSP1 levels and positive tumour vascular IDO1 staining seems to associate with poor survive of patients with IDC. IDC cells induced a significantly increase in IDO1 expression in endothelial cells (ECs). IFNgamma exerts a similar effect on ECs. We hypothesized a tryptophan starvation theory that since tryptophan is essential for the synthesis of TSP1, IDO1 induce a decrease in tryptophan availability and a reduction in TSP1 synthesis in ECs, leading to overcoming the dormancy state of IDC cells and exacerbating conditions such as tumour invasion and metastasis. These findings identify a non-canonical role of IFNgamma/IDO1/TSP1 axis in microvascular niche-dominated dormancy of breast invasive ductal carcinoma with a solid foundation for further investigation of therapeutic and prognostic relevance. PMID- 29156702 TI - Post-surgery fluids promote transition of cancer stem cell-to-endothelial and AKT/mTOR activity, contributing to relapse of giant cell tumors of bone. AB - Giant cell tumors of bone (GCTB) are rare sarcomas with a high rate of unpredictable local relapse. Studies suggest that surgical methods affect recurrence, supporting the idea that local disease develops from re-growth of residual cancer cells. To identify early prognostic markers of individual risk of recurrence, we evaluated the effect of post-surgery fluids from a cohort of GCTB patients on growth of primary and established sarcoma cell lines, and mice xenograph. Post-surgery fluids increased cell growth and enhanced expression of CD44++, the principal receptor for the extracellular matrix component hyaluronan and the mesenchymal stem marker CD117+. Cancer cells became highly invasive and tumorigenic, acquiring stemness properties, and activated AKT/mTOR pathway. Prolonged stimulation with post-surgery fluids down-regulated the mesenchymal gene TWIST1 and Vimentin protein, and transdifferentiated cells into tubule-like structures positive to the endothelial markers VE-Cadherin and CD31+. In mice, post-surgery fluids gave rise to larger and more vascularized tumors than control, while in patients AKT/mTOR pathway activation was associated with recurrence by logistic regression (Kaplan-Meier; P<0.001). These findings indicate that post-surgery fluids are an adjuvant in mechanisms of tumor regrowth, increasing stem cell growth and AKT/mTOR activity. PMID- 29156703 TI - Preclinical efficacy of the novel competitive NAMPT inhibitor STF-118804 in pancreatic cancer. AB - NAD salvage is one of the pathways used to generate NAD in mammals. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway, uses nicotinamide (NAM) to generate nicotinamide mononucleotide (NMN). NMN is one of the main precursors of NAD synthesis in cells. Our previous study showed the importance of NAMPT in maintaining NAD levels in pancreatic ductal adenocarcinoma cells (PDAC), and that the NAMPT inhibitor FK866 decreased pancreatic cancer growth. We now tested the effect of STF-118804, a new highly specific NAMPT inhibitor, in models of pancreatic ductal adenocarcinoma. STF-118804 reduced viability and growth of different PDAC lines, as well as the formation of colonies in soft agar. In addition, STF-118804 decreased glucose uptake, lactate excretion, and ATP levels, resulting in metabolic collapse. STF-118804 treatment activated AMPK and inhibited of mTOR pathways in these cells. This effect was significantly potentiated by pharmacological AMPK activation and mTOR inhibition. Exogenous NMN blocked both the activation of the AMPK pathway and the decrease in cell viability. Panc-1 cells expressing GFP-luciferase were orthotopically implanted on mice pancreas to test the in vivo effectiveness of STF-118804. Both STF-118804 and FK866 reduced tumor size after 21 days of treatment. Combinations of STF-118804 with chemotherapeutic agents such as paclitaxel, gemcitabine, and etoposide showed an additive effect in decreasing cell viability and growth. In conclusion, our preclinical study shows that the NAMPT inhibitor STF-118804 reduced the growth of PDAC in vitro and in vivo and had an additive effect in combination with main current chemotherapeutic drugs. PMID- 29156704 TI - ACKR3 expression on diffuse large B cell lymphoma is required for tumor spreading and tissue infiltration. AB - Diffuse large B cell lymphoma (DLBCL) is the most frequent lymphoma accounting for more than the 30% of the cases. Involvement of extranodal sites, such as bone marrow and central nervous system, is associated with poor prognosis. A contribution of the chemokine system in these processes is assumed as it is known as a critical regulator of the metastatic process in cancer. The atypical chemokine receptor 3 (ACKR3), which does not couple to G-proteins and does not mediate cell migration, acts as a scavenger for CXCL11 and CXCL12, interfering with the tumor homing CXCL12/CXCR4 axis. Here, functional expression of ACKR3 in DLBCL cells was necessary for colonization of the draining lymph node in an in vivo subcutaneous lymphoma model. Moreover, in a disseminated in vivo lymphoma model, ACKR3 expression was required for bone marrow and brain invasion and local tumor growth. The present data unveil ACKR3 as potential therapeutic target for the control of tumor dissemination in DLBCL. PMID- 29156705 TI - Upregulation of CD11b and CD86 through LSD1 inhibition promotes myeloid differentiation and suppresses cell proliferation in human monocytic leukemia cells. AB - LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells. Cell surface expression of CD11b and CD86 is significantly and dynamically increased in human AML cells upon sustained LSD1 inhibition. Chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) analyses of histone marks revealed that there is a specific increase of H3K4me2 modification and an accompanied increase of H3K4me3 modification at the respective CD11b and CD86 promoter region, whereas the global H3K4me2 level remains constant. Consistently, inhibition of LSD1 in vivo significantly blocks tumor growth and induces a prominent increase of CD11b and CD86. Taken together, our results demonstrate the anti-tumor properties of LSD1 inhibition on human AML cell line and mouse xenograft model. Our findings provide mechanistic insights into the LSD1 functions in controlling both differentiation and proliferation in AML. PMID- 29156706 TI - Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation. AB - Central precocious puberty (CPP) is attributed to the disorder of some trigger factors those can activate the hypothalamic-pituitary-gonadal axis controlled by GnRH neurons. Many recent studies reveal one of those trigger factors, Makorin ring finger protein 3 (Mkrn3), whose loss-of-function mutations are implicated in CPP. Although Mkrn3 contained zinc Ring finger domain is considered as a putative E3 ubiquitin ligase, its actual function is never reported. Here, our results demonstrated that in mice hypothalamus before and when puberty initiated, Mkrn3 expressed the reversed tendency with Nptx1, which is an important secreted protein for neuron development. Furthermore, our data manifested that Mkrn3 interacted and suppressed Nptx1 activity. And the Ring finger domain of Mkrn3 contained was determined to be essential for binding with Nptx1 for its polyubiquitination during the puberty initiation. Our study shed light on the molecular insights into the function of Mkrn3 in the events of puberty initiation. PMID- 29156707 TI - Infradiaphragmatic Hodgkin lymphoma: a large series of patients staged with PET CT. AB - Introduction: Infradiaphragmatic Hodgkin Lymphoma (IDHL) accounts for 3-11% of adult cases of stage I-II Hodgkin Lymphoma and the treatment strategy in IDHL is still heterogeneous. All previous published studies were conducted before the PET CT era. PET may provide a more accurate evaluation of IDHL stage. The aim of this study was to analyze the clinical and biological characteristics of IDHL patients staged by CT scan or PET-CT in eight French hematology departments and their impact on outcomes in these patients. Methods: Baseline clinical and biological data and outcomes in patients with a first diagnosis of stage I-II IDHL treated with ABVD +/- radiotherapy were retrospectively collected. Results: Among the 99 patients included, 65 (66%) were staged with PET-CT. These patients were older (53 years vs 46 years, p=0.043), had lower ESR (27 vs 58mm, p=0.022), higher hemoglobin level (13.6 vs 12.8g/dL, p=0.015), less frequent Ann Arbor stage II (74% vs 91%) and less central adenopathy involvement (60% vs 82%, p=0.024). Treatment was chemotherapy alone in 55% of patients and the remaining patients received chemo-radiotherapy (CRT). Five-year PFS and OS rates in PET-CT-staged patients were 78% (95% CI 64-87) and 88% (95% CI 73-95), respectively, compared with 65% (p=0.225) and 82% (p=0.352) in CT-staged patients. The CRT strategy was associated with fewer relapses (p=0.027). Conclusion: This study showed that the characteristics of CT-staged IDHL patients were less favorable than those of PET CT-staged patients and indicated that CRT provided better PFS than did chemotherapy alone. PMID- 29156708 TI - A preclinical evaluation of the MEK inhibitor refametinib in HER2-positive breast cancer cell lines including those with acquired resistance to trastuzumab or lapatinib. AB - Purpose: The MEK/MAPK pathway is commonly activated in HER2-positive breast cancer, but little investigation of targeting this pathway has been undertaken. Here we present the results of an in vitro preclinical evaluation of refametinib, an allosteric MEK1/2 inhibitor, in HER2-positive breast cancer cell lines including models of acquired resistance to trastuzumab or lapatinib. Methods: A panel of HER2-positive breast cancer cells were profiled for mutational status and also for anti-proliferative response to refametinib alone and in combination with the PI3K inhibitor (PI3Ki) copanlisib and the HER2-targeted therapies trastuzumab and lapatinib. Reverse phase protein array (RPPA) was used to determine the effect of refametinib alone and in combination with PI3Ki and HER2 inhibitors on expression and phosphorylation of proteins in the PI3K/AKT and MEK/MAPK pathways. We validated our proteomic in vitro findings by utilising RPPA analysis of patients who received either trastuzumab, lapatinib or the combination of both drugs in the NCT00524303/LPT109096 clinical trial. Results: Refametinib has anti-proliferative effects when used alone in 2/3 parental HER2 positive breast cancer cell lines (HCC1954, BT474), along with 3 models of these 2 cell lines with acquired trastuzumab or lapatinib resistance (6 cell lines tested). Refametinib treatment led to complete inhibition of MAPK signalling. In HCC1954, the most refametinib-sensitive cell line (IC50= 397 nM), lapatinib treatment inhibits phosphorylation of MEK and MAPK but activates AKT phosphorylation, in contrast to the other 2 parental cell lines tested (BT474-P, SKBR3-P), suggesting that HER2 may directly activate MEK/MAPK and not PI3K/AKT in HCC1954 cells but not in the other 2 cell lines, perhaps explaining the refametinib-sensitivity of this cell line. Using RPPA data from patients who received either trastuzumab, lapatinib or the combination of both drugs together with chemotherapy in the NCT00524303 clinical trial, we found that 18% (n=38) of tumours had decreased MAPK and increased AKT phosphorylation 14 days after treatment with HER2-targeted therapies. The combination of MEK inhibition (MEKi) with refametinib and copanlisib led to synergistic inhibition of growth in 4/6 cell lines tested (CI @ED75 = 0.39-0.75), whilst the combinations of lapatinib and refametinib led to synergistic inhibition of growth in 3/6 cell lines (CI @ED75 = 0.39-0.80). Conclusion: Refametinib alone or in combination with copanlisib or lapatinib could represent an improved treatment strategy for some patients with HER2-positive breast cancer, and should be considered for clinical trial evaluation. The direct down-regulation of MEK/MAPK but not AKT signalling by HER2 inhibition (e.g. by lapatinib or trastuzumab), which we demonstrate occurs in 18% of HER2-positive breast cancers may serve as a potential biomarker of responsiveness to the MEK inhibitor refametinib. PMID- 29156709 TI - Using molecular functional networks to manifest connections between obesity and obesity-related diseases. AB - Obesity is a primary risk factor for many diseases such as certain cancers. In this study, we have developed three algorithms including a random-walk based method OBNet, a shortest-path based method OBsp and a direct-overlap method OBoverlap, to reveal obesity-disease connections at protein-interaction subnetworks corresponding to thousands of biological functions and pathways. Through literature mining, we also curated an obesity-associated disease list, by which we compared the methods. As a result, OBNet outperforms other two methods. OBNet can predict whether a disease is obesity-related based on its associated genes. Meanwhile, OBNet identifies extensive connections between obesity genes and genes associated with a few diseases at various functional modules and pathways. Using breast cancer and Type 2 diabetes as two examples, OBNet identifies meaningful genes that may play key roles in connecting obesity and the two diseases. For example, TGFB1 and VEGFA are inferred to be the top two key genes mediating obesity-breast cancer connection in modules associated with brain development. Finally, the top modules identified by OBNet in breast cancer significantly overlap with modules identified from TCGA breast cancer gene expression study, revealing the power of OBNet in identifying biological processes involved in the disease. PMID- 29156710 TI - The synergistic antitumor effect of cinobufagin and cisplatin in human osteosarcoma cell line in vitro and in vivo. AB - Cisplatin (CDDP) has been shown to be a promising anticancer drug that is effective against many types of cancer, which include osteosarcoma (OS). However, its therapeutic application is restricted by its toxicity in normal tissues and by side effects caused in patients. Reduction of the toxicity of CDDP is necessary to improve cancer treatment. In the present study, we attempted to clarify how cinobufagin, a traditional Chinese medicine, enhances CDDP-induced cytotoxicity in OS cells. OS 143B cells were treated with cinobufagin and CDDP alone or in combination. After low dose combined treatments with cinobufagin and CDDP, the effects of these therapeutics on cell proliferation, apoptosis, cell cycle, migration, invasion, and involvement in Notch pathway, as well as tumor growth and metastatic capability were determined. It was found that the combination of low doses of cinobufagin and CDDP markedly inhibited cell activity, motility, and induced apoptosis and cell cycle arrest in S phase, as well as suppressing tumor growth, metastasis and prolonging longer survival of nude mice in OS xenograft models compared with the actions of either drug alone or vehicle. The results also demonstrated that cinobufagin plus CDDP significantly suppressed the Notch pathway. The anticancer mechanism of these two drugs may involve intervention in the Notch signaling, which may contribute to inhibit tumor growth. All of these results suggest that application of lower concentration cinobufagin plus CDDP could produce a synergistic antitumor effect and this finding warrants further investigation for its potential clinical applications in human OS patients. PMID- 29156711 TI - Multiple regulatory aspects of histone methyltransferase EZH2 in Pb-induced neurotoxicity. AB - Pb is a pervasive environmental threat to human health. Although remarkable progress has been made in its neurotoxicity, the precise molecular mechanisms underlying this widespread toxicant still remain elusive. In this study, the detailed roles of EZH2, a transcriptional repressor, in the regulation of Pb-led neurotoxicity were investigated, highlighting its sub-functionalization, compartmentalization, functional chaperones and downstream partners. Based on the findings, EZH2's protein levels were significantly reduced in response to Pb treatment; EZH2's gain-of-function trials recovered the dampened neurite outgrowth; EZH2' recruitment to ploycomb complex, as well as its interaction with cytosolic Vav1, was altered in a distinct manner, suggesting that EZH2's multiple roles were markedly redistributed in this context; EZH2's cytosolic and nuclear presence differed in their respective response towards Pb treatment; EZH2 directly occupied the promoters of EGR2, NGFR and CaMKK2, genes responsible for various nerve functions and repair mechanisms, and essentially contributed to their aberrant expression. It indicated that EZH2 mediated the dynamic changes of a cascade of key molecules and consequently the related neurological impairments. In summary, EZH2 emerges as a central player to regulate Pb-led neurotoxicity in a transcriptionally dependent and independent manner, and thereby provided a promising molecular target for medical intervention. PMID- 29156712 TI - Radiolabelled polymeric IgA: from biodistribution to a new molecular imaging tool in colorectal cancer lung metastases. AB - By radiolabelling monomeric (m) and polymeric (p) IgA with technetium 99m (99mTc), this study assessed IgA biodistribution and tumour-targeting potency. IgA directed against carcinoembryonic antigen (CEA), a colorectal cancer marker, was selected to involve IgA mucosal tropism. Ig was radiolabelled with 99mTc tricarbonyl after derivatisation by 2-iminothiolane. 99mTc-IgA was evaluated by in vitro analysis. The biodistributions of radiolabelled anti-CEA mIgA, pIgA and IgG were compared in normal mice. Anti-CEA pIgA tumour uptake was studied in mice bearing the WiDr caecal orthotopic graft. IgA radiolabelling was obtained with a high yield, was stable in PBS and murine plasma, and did not alter IgA binding functionality (Kd ~ 25 nM). Biodistribution studies in normal mice confirmed that radiolabelled pIgA - and to a lesser extent, mIgA - showed strong and fast mucosal tropism and a shorter serum half-life than IgG. In caecal tumour model mice, evaluation of the anti-CEA-pIgA biodistribution showed a high uptake in lung metastases, confirmed by histological analysis. However, no radioactivity uptake increase in the tumoural caecum was discerned from normal intestinal tissue, probably due to high IgA caecal natural tropism. In microSPECT/CT imaging, 99mTc-IgA confirmed its diagnostic potency of tumour in mucosal tissue, even if detection threshold by in vivo imaging was higher than post mortem studies. Contribution of the FcalphaRI receptor, studied with transgenic mouse model (Tsg SCID-CD89), did not appear to be determinant in 99mTc-IgA uptake. Pre clinical experiments highlighted significant differences between 99mTc-IgA and 99mTc-IgG biodistributions. Furthermore, tumoural model studies suggested potential targeting potency of pIgA in mucosal tissues. PMID- 29156713 TI - The prognostic impact of overall treatment time on disease outcome in uterine cervical cancer patients treated primarily with concomitant chemoradiotherapy: a nationwide Taiwanese cohort study. AB - The importance of the overall treatment time (OTT) has a paradoxical status in the current era of concomitant chemoradiotherapy. The main objective of this nationwide study was to evaluate the correlation between overall treatment duration and clinical outcome in cervical cancer patients treated primarily with curative concurrent chemoradiotherapy (CCRT). In this population-based cohort study, 2,594 patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I-IVA uterine cervical cancer were studied. Univariate and multivariate analyses of prognostic factors were analyzed using Cox's proportional hazards models. The median irradiation duration was 59 days. Significant prognostic factors related to poor cancer-specific survival (CSS) and overall survival (OS) included old age, non-squamous cell cancer type, high-grade histology, increased tumor size, advanced FIGO stage, and prolonged OTT. After multivariate analysis, prolonged treatment time remained as a significant factor for poor CSS (hazard ratio, HR = 1.33; p < 0.001) and OS (HR = 1.15; p = 0.05). Further subgroup analysis showed that the 5-year OS rates after a treatment time of <= 56 days compared with > 56 days in patients with FIGO stages I-IIB and III IVA were 70% and 65% (p = 0.002) compared with 43% and 42% (p = 0.67), respectively. Inconclusion, completion of CCRT within 8 weeks is recommended, particularly for patients with FIGO stage I-IIB disease. PMID- 29156714 TI - Investigation of factors affecting the efficacy of 3C23K, a human monoclonal antibody targeting MISIIR. AB - MISIIR is a potential target for ovarian cancer (OC) therapy due to its tissue specific pattern of expression. 3C23K is a novel therapeutic monoclonal anti MISIIR antibody designed to recruit effector cells and promote cell death through ADCC (antibody dependent cell-mediated cytotoxicity). Our objective was to determine the tolerability and efficacy of 3C23K in OC patient-derived xenografts (PDX) and to identify factors affecting efficacy. Quantitative RT-PCR, immunohistochemistry (IHC), and flow cytometry were used to categorize MISIIR expression in established PDX models derived from primary OC patients. We selected two high expressing models and two low expressing models for in vivo testing. One xenograft model using an MISIIR over-expressing SKOV3ip cell line (Z3) was a positive control. The primary endpoint was change in tumor size. The secondary endpoint was final tumor mass. We observed no statistically significant differences between control and treated animals. The lack of response could be secondary to a number of variables including the lack of known biomarkers of response, the low membrane expression of MISIIR, and a limited ability of 3C23K to induce ADCC in PDX models. Further study is needed to determine the magnitude of ovarian cancer response to 3C23K and also if there is a threshold surface expression to predict response. PMID- 29156715 TI - Connective tissue growth factor mediates TGF-beta1-induced low-grade serous ovarian tumor cell apoptosis. AB - Ovarian low-grade serous carcinoma (LGSC) is a rare disease and is now considered to be a distinct entity from high-grade serous carcinoma (HGSC), which is the most common and malignant form of epithelial ovarian cancer. Connective tissue growth factor (CTGF) is a secreted matricellular protein that has been shown to modulate many biological functions by interacting with multiple molecules in the microenvironment. Increasing evidence indicates that aberrant expression of CTGF is associated with cancer development and progression. Transforming growth factor beta1 (TGF-beta1) is a well-known molecule that can strongly up-regulate CTGF expression in different types of normal and cancer cells. Our previous study demonstrated that TGF-beta1 induces apoptosis of LGSC cells. However, the effect of TGF-beta1 on CTGF expression in LGSC needs to be defined. In addition, whether CTGF mediates TGF-beta1-induced LGSC cell apoptosis remains unknown. In the present study, we show that TGF-beta1 treatment up-regulates CTGF expression by activating SMAD3 signaling in two human LGSC cell lines. Additionally, siRNA mediated CTGF knockdown attenuates TGF-beta1-induced cell apoptosis. Moreover, our results show that the inhibitory effect of the CTGF knockdown on TGF-beta1 induced cell apoptosis is mediated by down-regulating SMAD3 expression. This study demonstrates an important role for CTGF in mediating the pro-apoptotic effects of TGF-beta1 on LGCS. PMID- 29156717 TI - Oligomer procyanidins (F2) repress HIF-1alpha expression in human U87 glioma cells by inhibiting the EGFR/ AKT/mTOR and MAPK/ERK1/2 signaling pathways in vitro and in vivo. AB - Hypoxia-inducible factor-1 (HIF-1) is over-expressed in gliomas and has become one of the most compelling tumor targets. In this study, we found that oligomer procyanidins (F2) can suppress the expressions of HIF-1alpha and its target genes in U87 cells, and also down-regulate the EGFR/PI3K/AKT/mTOR and MAPK/ERK1/2 pathways in vitro and in vivo. Furthermore, hypoxia-induced formation of tubular structures by human umbilical vascular endothelial cells and the migration and invasion of U87 cells could be inhibited by F2 in a HIF-1 dependent manner. Moreover, in a U87 xenograft tumor model, F2 significantly reduced intra-tumor vessel density and cell proliferation and finally retarded tumor growth, indicating that F2 may be a potential HIF-1 inhibitor and serve as one of candidates for glioma therapy. PMID- 29156716 TI - Using droplet digital PCR to analyze MYCN and ALK copy number in plasma from patients with neuroblastoma. AB - The invasive nature of surgical biopsies deters sequential application, and single biopsies often fail to reflect tumor dynamics, intratumor heterogeneity and drug sensitivities likely to change during tumor evolution and treatment. Implementing molecular characterization of cell-free neuroblastoma-derived DNA isolated from blood plasma could improve disease assessment for treatment selection and monitoring of patients with high-risk neuroblastoma. We established droplet digital PCR (ddPCR) protocols for MYCN and ALK copy number status in plasma from neuroblastoma patients. Our ddPCR protocol accurately discriminated between MYCN and ALK amplification, gain and normal diploid status in a large panel of neuroblastoma cell lines, and discrepancies with reported MYCN and ALK status were detected, including a high-level MYCN amplification in NB-1, a MYCN gain in SH-SY5Y, a high-level ALK amplification in IMR-32 and ALK gains in BE(2) C, Kelly, SH-SY5Y and LAN-6. MYCN and ALK status were also reliably determined from cell-free DNA derived from medium conditioned by the cell lines. MYCN and ALK copy numbers of subcutaneous neuroblastoma xenograft tumors were accurately determined from cell-free DNA in the mouse blood plasma. In a final validation step, we accurately distinguished MYCN and ALK copy numbers of the corresponding primary tumors using retrospectively collected blood plasma samples from 10 neuroblastoma patients. Our data justify the further development of molecular disease characterization using cell-free DNA in blood plasma from patients with neuroblastoma. This expanded molecular diagnostic palette may improve monitoring of disease progression including relapse and metastatic events as well as therapy success or failure in high-risk neuroblastoma patients. PMID- 29156718 TI - Interleukin-31 and thymic stromal lymphopoietin expression in plasma and lymph node from Hodgkin lymphoma patients. AB - Hodgkin Lymphoma (HL) is a tumor of B-cell origin characterized by Hodgkin and Reed-Stenberg (H/RS) cells embedded in an inflammatory tissue where numerous cytokines/chemokines contribute to shape the microenvironment, leading to the typical clinical symptoms. We investigated: i) the expression of Interleukin-IL 31 (IL-31) and Thymic Stromal Lymphopoietin (TSLP), two Th2-related cytokines with tumor-promoting and pruritogenic functions, and of the respective receptors in HL invaded lymph nodes by flow cytometry, and ii) the potential association of IL-31/TSLP plasma concentrations with clinical characteristics by ELISA. H/RS cells and the major immune cell types infiltrating HL lymph nodes expressed intracytoplasmic and surface IL-31/TSLP, and their receptors. A subgroup of patients showing at diagnosis elevated IL-31 and TSLP plasma levels had an International Prognostic Score>2, indicative of high risk of relapse, and a subsequent positive interim PET-scan, indicative of insufficient response to chemotherapy. No correlation was found between IL-31/TSLP plasma levels and overall or event-free survival. In conclusion, IL-31/TSLP and their receptors are expressed in HL cells and in immune cells infiltrating affected lymph nodes, where both cytokines may contribute to local immune suppression. The clinical impact of IL-31 and TSLP plasma levels has to be further defined in larger patient cohorts. PMID- 29156719 TI - The microRNAs miR-200b-3p and miR-429-5p target the LIMK1/CFL1 pathway to inhibit growth and motility of breast cancer cells. AB - Triple-negative breast cancer (TNBC) has the worst prognosis of all subtypes of breast cancer (BC), with limited options for conventional therapy and no targeted therapies. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. In this study, we aimed to determine whether two members of the miR-200 family, miR-200b-3p and miR-429-5p, are involved in BC cell proliferation and motility and to elucidate their target genes and pathways. We performed a meta-analysis that reveals down-regulated expression of miR-200b-3p and miR-429 5p in BC tissues and cell lines, consistent with a lower expression of miR-200b 3p and miR-429-5p in MDA-MB-231 and HCC1937 cells than in MCF-7 and MCF-10 cells. Overexpression of miR-200b-3p and miR-429-5p significantly inhibited the proliferation, migration, and invasion of TNBC cells; suppressed the expression of markers for proliferation and metastasis in TNBC cells. We next demonstrated that LIM domain kinase 1 (LIMK1) is a direct target gene of miR-200b-3p and miR 429-5p. Inhibition of LIMK1 reduced the expression and phosphorylation of cofilin 1 (CFL1), which polymerizes and depolymerizes F-actin and G-actin to reorganize cellular actin cytoskeleton. In addition, transfection with mimics for miR-200b 3p and miR-429-5p arrested G2/M and G0/G1 cell cycles respectively, suppressed the expression of the cell cycle-related complexes, cyclin D1/CDK4/CDK6 and cyclin E1/CDK2, in TNBC cells. In conclusion, miR-200b-3p and miR-429-5p suppress proliferation, migration, and invasion in TNBC cells, via the LIMK1/CFL1 pathway. These results provide insight into how specific miRNAs regulate TNBC progression and suggest that the LIMK1/CFL1 pathway is a therapeutic target for treating TNBC. PMID- 29156720 TI - Novel strategies of Raman imaging for brain tumor research. AB - Raman diagnostics and imaging have been shown to be an effective tool for the analysis and discrimination of human brain tumors from normal structures. Raman spectroscopic methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n= 5), low-grade astrocytoma (grades I-II WHO) (n =4), ependymoma (n=3) and metastatic brain tumors (n= 1) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma, low grade astrocytoma and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational features and Raman images we provide a real-time feedback method that is label free to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, proteins, DNA and RNA. Our results indicate marked metabolic differences between low and high grade brain tumors. We discuss molecular mechanisms causing these metabolic changes, particularly lipid alterations in malignant medulloblastoma and low grade gliomas that may shed light on the mechanisms driving tumor recurrence thereby revealing new approaches for the treatment of malignant glioma. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of beta-sheet conformation and down-regulated level of alpha-helix conformation when comparing against normal tissue. We have found that almost all tumors studied in the paper have increased Raman signals of nucleic acids. This increase can be interpreted as increased DNA/RNA turnover in brain tumors. We have shown that the ratio of Raman intensities I2930/I2845 at 2930 and 2845 cm-1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the different lipid and protein contents of cancerous brain tissue compared to the non-tumor tissue. We found that levels of the saturated fatty acids were significantly reduced in the high grade medulloblastoma samples compared with non tumor brain samples and low grade astrocytoma. Differences were also noted in the n-6/n-3 polyunsaturated fatty acids (PUFA) content between medulloblastoma and non-tumor brain samples. The content of the oleic acid (OA) was significantly smaller in almost all brain high grade brain tumors than that observed in the control samples. It indicates that the fatty acid composition of human brain tumors differs from that found in non-tumor brain tissue. The iodine number NI for the normal brain tissue is 60. For comparison OA has 87, docosahexaenoic acid (DHA) 464, alpha-linolenic acid (ALA) 274. The high grade tumors have the iodine numbers between that for palmitic acid, stearic acid, arachidic acid (NI=0) and oleic acid (NI=87). Most low grade tumors have NI similar to that of OA. The iodine number for arachidonic acid (AA) (NI=334) is much higher than those observed for all studied samples. PMID- 29156721 TI - A hemoglobin-based oxygen carrier sensitized Cisplatin based chemotherapy in hepatocellular carcinoma. AB - Background and Objective: Our previous study showed that liver graft injury not only promotes tumor recurrence, but also induces chemoresistance in recurrent HCC after liver transplantation. Recently, we found that the hemoglobin-based oxygen carrier"YQ23" significantly ameliorates hepatic IR injury and prevent tumor recurrence. Here, we intended to explore the novel therapeutic strategy using oxygen carrier "YQ23"to sensitize chemotherapy in HCC. Methods: To investigate the role of YQ23 combined with Cisplatin, the proliferation of HCC cells was examined under combined treatment by MTT and colony formation. To explore the effect of YQ23 on sensitization of Cisplatin based chemotherapy, the orthotopic liver cancer model was established. To characterize the delivery of YQ23 in tumor tissue, the intravital imaging system was applied for longitudinal observation in ectopic liver cancer model. The distribution of YQ23 was examined by IVIS spectrum. Results: YQ23 significantly suppressed the proliferation of HCC cells under Cisplatin treatment in a dose and time dependent manner. Moreover, YQ23 administration significantly sensitized Cisplatin based chemotherapy in orthotopic liver cancer model. Down-regulation of DHFR may be one of the reasons for YQ23 sensitizing Cisplatin based chemotherapy. Real-time intravital imaging showed that YQ23 accumulated in the tumor tissue and maintained as long as 3 days in ectopic liver cancer model. The IVIS spectrum examination showed that YQ23 distributed mainly at liver and bladder within the first 36 hours after administration in orthotopic liver cancer model. Conclusion: YQ23 treatment may be a potential therapeutic strategy to sensitize chemotherapy in HCC. PMID- 29156722 TI - Whole-exome sequencing reveals novel mutations and epigenetic regulation in hypopharyngeal carcinoma. AB - Hypopharyngeal cancer (HPC) frequently presents at an advanced stage, resulting in poor prognosis. Although combined surgical therapy and chemoradiotherapy have improved the survival for patients with HPC over the past 3 decades, the mortality rate in late-stage diagnosis of HPC is unsatisfactory. In this study, we performed whole-exome sequencing (WES) of 23 hypopharyngeal tumor and paired adjacent normal tissue to identify novel candidate driver genes associated with hypopharyngeal carcinoma. We identified several copy number variants (CNVs) and 15 somatic mutation genes that were associated with hypopharyngeal carcinoma. Mutations in nine new genes (PRB4, NSD1, REC8, ZNF772, ZNF69, EI24, CYFIP2, NEFH, KRTAP4-5) were also indentified. PRB4 and NSD1 expression were significantly upregulated in hypopharyngeal carcinoma, which was confirmed in an independent cohort using IHC. There was a positive relationship between PRB4 and NSD1. Downregulation of PRB4 by siRNA could inhibit cell growth, colony formation and cell invasion. Notably, we here demonstrate that NSD1 could bind to the promoter regions of PRB4 and activate promoter activity by reducing the binding of H3K27me2 and increasing the binding of H3K36me2 on PRB4 promoter. In summary, we pinpoint the predominant mutations in hypopharyngeal carcinoma by WES, highlighting the substantial genetic alterations contributing to hypopharyngeal carcinoma tumorigenesis. We also indentify a novel epigenetically regulatory between PRB4 and NSD1 that contribute to hypopharyngeal carcinoma tumorigenesis. They may become potential prognostic biomarkers and therapeutic target for hypopharyngeal carcinoma treatment. PMID- 29156723 TI - Effects of pharmacological gap junction and sodium channel blockade on S1S2 restitution properties in Langendorff-perfused mouse hearts. AB - Gap junctions and sodium channels are the major molecular determinants of normal and abnormal electrical conduction through the myocardium, however, their exact contributions to arrhythmogenesis are unclear. We examined conduction and recovery properties of regular (S1) and extrasystolic (S2) action potentials (APs), S1S2 restitution and ventricular arrhythmogenicity using the gap junction and sodium channel inhibitor heptanol (2 mM) in Langendorff-perfused mouse hearts (n=10). Monophasic action potential recordings obtained during S1S2 pacing showed that heptanol increased the proportion of hearts showing inducible ventricular tachycardia (0/10 vs. 5/8 hearts (Fisher's exact test, P < 0.05), prolonged activation latencies of S1 and S2 APs, thereby decreasing S2/S1 activation latency ratio (ANOVA, P < 0.05) despite prolonged ventricular effective refractory period (VERP). It did not alter S1 action potential duration at 90% repolarization (APD90) but prolonged S2 APD90 (P < 0.05), thereby increasing S2/S1 APD90 ratio (P < 0.05). It did not alter maximum conduction velocity (CV) restitution gradient or maximum CV reductions but decreased the restitution time constant (P < 0.05). It increased maximal APD90 restitution gradient (P < 0.05) without altering critical diastolic interval or maximum APD90 reductions. Pro arrhythmic effects of 2 mM heptanol are explicable by delayed conduction and abnormal electrical restitution. We concluded that gap junctions modulated via heptanol (0.05 mM) increased arrhythmogenicity through a delay in conduction, while sodium channel inhibition by a higher concentration of heptanol (2 mM) increased arrhythmogenicity via additional mechanisms, such as abnormalities in APDs and CV restitution. PMID- 29156724 TI - lncRNA PVT1 and its splicing variant function as competing endogenous RNA to regulate clear cell renal cell carcinoma progression. AB - Long non-coding RNAs (lncRNAs) exert critical regulatory roles in the development and progression of several cancers. Plasmacytoma variant translocation 1 (PVT1), an lncRNA, was shown to be upregulated in clear cell renal cell carcinoma (ccRCC) in our study, while Kaplan-Meier curve and Cox regression analysis showed that high expression of PVT1 was associated with poor overall survival (OS) and disease free survival (DFS) in ccRCC patients. In vitro experiments revealed that PVT1 promoted renal cancer cell proliferation, migration, and invasion, while in vivo studies confirmed its oncogenic roles in ccRCC. Further bioinformatic analysis and RNA immunoprecipitation revealed that PVT1 could function as an oncogenic transcript partly through sponging miR-200s to regulate BMI1, ZEB1 and ZEB2 expression. Besides, a novel splicing variant of PVT1 lacking exon 4 (PVT1DeltaE4) was found to have a higher expression in ccRCC and could also promote cell proliferation and invasion as the full-length transcript did. Besides, SRSF1 decreased the inclusion of exon 4 of full-length transcript and increased the relative expression of PVT1DeltaE4 in ccRCC. Mechanistic investigations indicated that PVT1DeltaE4 could also upregulate the expression of BMI1, ZEB1 and ZEB2 through interacting with miR-200s. Our study helps reveal new molecular events in ccRCC and provides promising diagnostic and therapeutic targets for this disease. PMID- 29156725 TI - Methylation of CpG sites in the upstream regulatory region, physical status and mRNA expression of HPV-6 in adult-onset laryngeal papilloma. AB - The methylation status of HPV-6 upstream regulatory region (URR) in adult-onset laryngeal papillomatosis (AO-LP) remains unclear. The purpose of this study was to investigate the methylation status of URR and the physical status of HPV-6, as well as the dynamic variations of viral load and mRNA expression in AO-LP. We examined 18 specimens from 11 patients with AO-LP by real-time polymerase chain reaction (PCR), bisulfite-sequencing PCR, and amplification of papilloma oncogene transcripts. HPV-6 was identified in 9 of 11 patients (81.8%), and all the 15 specimens derived from 9 HPV-6-positive cases contained only episomal HPV-6 transcripts with intact E2. Three HPV-6-positive patients developed recurrent lesions, and HPV-6 copy numbers and mRNA expression decreased after surgical treatment. Among the 96 CpG sites (16/case), 67 (69.8%) were unmethylated, while 23 (30.2%) were heterogeneous (>= 1 methylated CpG clone). High viral loads and episomal status of HPV-6 were frequently observed in AO-LP; thus, persistent E6/E7 mRNA expression of LR-HPV-6 may be associated with AO-LP recurrences. Hypomethylation and scattered patterns of methylated CpGs at the URR of HPV-6 were identified in AO-LP. PMID- 29156726 TI - Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth. AB - Obesity is a significant risk factor for pancreatic cancer, harboring a chronic inflammatory condition characterized by dysregulation of the adipokines, leptin and adiponectin, that in turn alter oncogenic signaling pathways. We and others have shown that leptin promotes the proliferation and an invasive potential of pancreatic cancer cells through STAT3 mediated signaling. However, the role of adiponectin on the tumorigenicity of pancreatic cancer has not been elucidated. Adiponectin represents an important negative regulator of cytokines, which acts through two receptors, ADIPOR1 and ADIPOR2, to elicit pro-apoptotic, anti inflammatory, and anti-angiogenic responses. We show that the level and expression of both adiponectin receptors are decreased in pancreatic tumors relative to normal pancreatic tissue. In vitro stimulation with adiponectin or a small molecule adiponectin receptor agonist, AdipoRon, increases apoptosis while inhibiting pancreatic cancer cell proliferation, colony formation, and anchorage independent growth. In addition, adiponectin receptor agonism inhibits leptin mediated STAT3 activation. In vivo, treatment of mice with AdipoRon inhibits orthotopic pancreatic tumor growth. These results demonstrate that adiponectin receptor activation is a key regulator of pancreatic cancer growth and AdipoRon provides a rational agent for the development of novel therapeutic strategies for pancreatic cancer. PMID- 29156727 TI - Bone marrow IRF4 level in multiple myeloma: an indicator of peripheral blood Th17 and disease. AB - Interferon regulator factor 4 (IRF4) is characterized to be a member of interferon regulatory family, which is predominantly expressed in bone marrow plasma cells of patients with multiple myeloma (MM). Recent studies indicated IRF4 is critical for T-help cells (Th17) differentiation and interleukin-17 (IL 17) secretion. Here, a total of 58 MM patients were enrolled in this study, the proportions of Th17 cells and T regulatory (Treg) cells in peripheral blood mononuclear cells (PBMCs) were determined by flow cytometric analysis. Immunohistochemistry was employed to detect the IRF4 expression in bone marrow. Herein, we observed a significant increase of IRF4 in bone marrow accompanied with a notable up-regulation of Th17 cells in PBMC within MM patients compared with healthy donors. Furthermore, the proportions of Th17 cells and serum IL-17 levels were higher in patients with stage III than stage I & II MM patients, and those parameters were positively correlated with the expression of IRF4 in these cases. These results for the first time indicate that a crosstalk between IRF4 and Th17 cells is associated with MM prognosis, and IRF4 may be served an important target for MM immunotherapy. PMID- 29156728 TI - Long non-coding RNA HOTAIR acts as a competing endogenous RNA to promote malignant melanoma progression by sponging miR-152-3p. AB - HOX transcript antisense RNA (HOTAIR) is associated with the growth and metastasis of many human tumors, but its biological roles in malignant melanoma remain unclear. In this study, we show that HOTAIR is overexpressed in melanoma tissues and cells, especially in metastatic melanoma. High HOTAIR levels correlate with poor prognosis in melanoma patients. We also determined that HOTAIR functions as a competing endogenous RNA (ceRNA) for miR-152-3p. miR-152-3p was decreased and acted as a tumor suppressor in melanoma, and c-MET was the functional target of miR-152-3p. Furthermore, HOTAIR promotes the growth and metastasis of melanoma cells by competitively binding miR-152-3p, which functionally liberates c-MET mRNA and results in the activation of the downstream PI3k/Akt/mTOR signaling pathway. We determined that HOTAIR acts as a ceRNA to promote malignant melanoma progression by sponging miR-152-3p. This finding elucidates a new mechanism for HOTAIR in melanoma development and provides a potential therapeutic target for melanoma patients. PMID- 29156729 TI - A RasGAP, DAB2IP, regulates lipid droplet homeostasis by serving as GAP toward RAB40C. AB - Lipid droplet (LD) homeostasis involves activities of various RAB small GTPases. Recently, we found RAB40C was one of the RAB proteins regulating LD homeostasis. RAB40C contains a unique SOCS domain that is required for clustering of LDs. However, its precise functional role in LD homeostasis and mechanism of regulation remain largely unknown. In this study, we observed over-accumulation of LDs in cells with RAB40C deleted by Crispr-Cas9 editing. RAB40C appeared to reduce LD accumulation after long term incubation of cells with oleic acid (24 hours). Unexpectedly, we found that Ras GTPase activating protein (GAP), DAB2IP, bound to RAB40C mainly via its GAP domain and could serve as RAB40C GAP. Studies involving overexpression of DAB2IP and its GAP defective mutant and siRNA depletion of DAB2IP all confirmed that DAB2IP negatively regulated the effect of RAB40C on LD homeostasis. These results provide a novel perspective on the regulation of RAB40C and implicate various signalling pathways regulated by DAB2IP, which may play a role in LD homeostasis via RAB40C. PMID- 29156730 TI - Generation of patient specific human neural stem cells from Niemann-Pick disease type C patient-derived fibroblasts. AB - Niemann-Pick disease type C (NPC) is a neurodegenerative and lysosomal lipid storage disorder, characterized by the abnormal accumulation of unesterified cholesterol and glycolipids, which is caused by mutations in the NPC1 genes. Here, we report the generation of human induced neural stem cells from NPC patient-derived fibroblasts (NPC-iNSCs) using only two reprogramming factors SOX2 and HMGA2 without going through the pluripotent state. NPC-iNSCs were stably expandable and differentiated into neurons, astrocytes, and oligodendrocytes. However, NPC-iNSCs displayed defects in self-renewal and neuronal differentiation accompanied by cholesterol accumulation, suggesting that NPC-iNSCs retain the main features of NPC. This study revealed that the cholesterol accumulation and the impairments in self-renewal and neuronal differentiation in NPC-iNSCs were significantly improved by valproic acid. Additionally, we demonstrated that the inhibition of cholesterol transportation by U18666A in WT-iNSCs mimicked the impaired self-renewal and neuronal differentiation of NPC-iNSCs, indicating that the regulation of cholesterol homeostasis is a crucial determinant for the neurodegenerative features of NPC. Taken together, these findings suggest that NPC-iNSCs can serve as an unlimited source of neural cells for pathological study or drug screening in a patient specific manner. Furthermore, this direct conversion technology might be extensively applicable for other human neurodegenerative diseases. PMID- 29156731 TI - miR-21 modulates the effect of EZH2 on the biological behavior of human lung cancer stem cells in vitro. AB - Non-small-cell lung cancer has a high mortality rate and poor prognosis. Therefore, novel therapeutic approaches are urgently needed to enhance patient survival rates. In this study, we investigated the effects of miR-21 and EZH2 on the biological behavior of human lung cancer stem cells in vitro. We found increased expression of EZH2 and miR-21 in LCSCs, and miR-21 overexpression increased EZH2 levels in LCSCs. In addition, EZH2 and miR-21 knockdown increased the sensitivity of LCSCs to chemo- and radiation therapy, and exogenous EZH2 expression rescued the effects of anti-miR-21. Cell proliferation was reduced by 39.2% and 69.7% in the presence of radio- or chemotherapy combined with anti-miR 21 transfection, respectively. The downstream molecules included Cdc2, cyclin B1, and Bcl-2, which are involved in the regulation of cell cycle and apoptosis and which could themselves be reduced or enhanced by changes in miR-21 and EZH2 levels in LCSCs. This study demonstrates the direct relationship between miR-21 and EZH2 which was increased by 43% after the application of the miR-21 mimic. Above data indicates that these two molecules can influence the biological behavior of LCSCs by altering their corresponding targets. Our findings support the potential roles of miR-21 and EZH2 in improving the therapeutic efficacy of clinical lung cancer treatments. PMID- 29156732 TI - Dietary inflammatory index and the risk of gastric cancer in a Korean population. AB - We aimed to investigate the association with the Dietary Inflammatory Index (DIITM) on the risk of gastric cancer and whether histological type modifies this association. From March 2011 to December 2014, 388 cases and 776 controls were enrolled at the National Cancer Center. Utilizing a food frequency questionnaire, thirty-five food components were used to score the DII. The tertile distribution of DII for controls was as follows: T1: <0.96, T2: 0.96-2.97, and T3: >=2.97. To investigate the association between DII and the gastric cancer risk, multivariable logistic models were constructed. In subgroup analyses, histological types including intestinal and diffuse types were examined. As the DII increased, gastric cancer risk increased (p-value for trend =0.007). Participants in the highest DII tertile had a greater gastric cancer risk compared to those in the lowest tertile [Odds Ratio (OR) =1.63, 95% Confidence Interval (CI) 1.15-2.29]. Stratification by sex revealed that men who were in the highest DII tertile showed a greater risk of intestinal type (OR=2.03, 95% CI 1.09-3.77). Participants positive for H. pylori infection had higher risk of intestinal type (OR=2.16, 95% CI 1.21-3.87). In this case-control study, we found a significantly positive association with a pro-inflammatory diet on gastric cancer risk, after adjusting for covariates. Future studies are suggested to prospectively examine the effect of a pro-inflammatory diet on gastric cancer risk. PMID- 29156733 TI - An integrated lncRNA, microRNA and mRNA signature to improve prognosis prediction of colorectal cancer. AB - Although the outcome of patients with colorectal cancer (CRC) has improved significantly, prognosis evaluation still presents challenges due to the disease heterogeneity. Increasing evidences revealed the close correlation between aberrant expression of certain RNAs and the prognosis. We envisioned that combined multiple types of RNAs into a single classifier could improve postoperative risk classification and add prognostic value to the current stage system. Firstly, differentially expressed RNAs including mRNAs, miRNAs and lncRNAs were identified by two different algorithms. Then survival and LASSO analysis was conducted to screen survival-related DERs and build a multi-RNA based classifier for CRC patient stratification. The prognostic value of the classifier was self-validated in the TCGA CRC cohort and further validated in an external independent set. Finally, survival receiver operating characteristic analysis was used to assess the performance of prognostic prediction. We found that the multi-RNA-based classifier consisted by 12 mRNAs, 1miRNA and 1 lncRNA, which could divide the patients into high and low risk groups with significantly different overall survival (training set: HR 2.54, 95%CI 1.67-3.87, p<0.0001; internal testing set: HR 2.54, 95%CI 1.67-3.87, p<0.0001; validation set: HR 5.02, 95% CI 2.2-11.6; p=0.0002). In addition, the classifier is not only independent of clinical features but also with a similar prognostic ability to the well-established TNM stage (AUC of ROC 0.83 versus 0.74, 95% CI = 0.608 0.824, P =0.0878). Furthermore, combination of the multi-RNA-based classifier with clinical features was a more powerful predictor of prognosis than either of the two parameters alone. In conclusion, the multi-RNA-based classifier may have important clinical implications in the selection of patients with CRC who are at high risk of mortality and add prognostic value to the current stage system. PMID- 29156734 TI - PAX3d mRNA over 2.76 copies/uL in the bloodstream predicts cutaneous malignant melanoma relapse. AB - Objective: The aim of this study was to evaluate if our molecular algorithm, based on tumor circulating transcripts, may predict relapse risk in cutaneous malignant melanoma (CMM). Results: The multi-marker panel was able to differentiate patients with CMM from HC with high diagnostic sensitivity and specificity, especially for MITF-m and TGFB2 (91-100%) whose levels decreased during follow-up of recurrence-free patients, and remained stable in the case of relapse. PAX3d higher than 2.76 copies/uL emerged as a promising biomarker [specificity = 75-93% and negative predictive value = 75-98%] to stratify subjects at high risk of CMM recurrence independently of age, gender and AJCC staging [OD = 9.5(3.2-28.0), p < 0.001]. The survival analysis confirmed PAX3d performance in relapse prediction with significant differences in recurrence risk 12 months after the basal time-point (p = 0.008). Materials and Methods: Peripheral blood was collected from 111 CMM patients and from 87 healthy controls (HC) randomly selected. Each specimen was examined by qRT-PCR analysis for the expression of 3 tumor-related transcripts (PAX3d, MITF-m and TGFB2) at diagnosis, and at the following 6 and 12 months during clinical monitoring. Conclusions: We demonstrated the usefulness of our molecular algorithm to indirectly detect circulating melanoma cells in blood, along with PAX3d capability to assess patients' progression and relapse prediction. PMID- 29156735 TI - Telomerase reverse transcriptase mediates EMT through NF-kappaB signaling in tongue squamous cell carcinoma. AB - Locoregional lymph nodes metastasis in oral tongue squamous cell carcinoma represents one of important and common prognostic factors for poor clinical outcome. The human Telomerase Reverse Transcriptase (hTERT) is one of key players in cancer metastasis and stemness, but its exact function in tongue squamous cell carcinoma remains unknown. Here, we aim to understand the role of hTERT by utilizing the CRISPR/Cas9 gene editing system to deplete hTERT in the SCC-15 cell line. Functional comparison of SCC-15 control and knockout cells (hTERT-/-) showed that loss of hTERT suppressed cell proliferation and migration/invasion. Furthermore, hTERT depletion significantly decreased tumorigenesis, including alterations in cellular morphology that areindicative for epithelial-mesenchymal transition (EMT). Mechanistically we demonstrated that the hTERT knockout attenuates NF-kappaB signaling via a negative feedback regulation in tumorprogression. From these results we propose a novel molecular mechanism of hTERT to promote SCC-15 invasion and metastasis via NF-kappaB activation. We conclude that targeting hTERT may represent a new therapeutic strategy to improve therapy and survival of tongue squamous cell carcinoma patients. PMID- 29156736 TI - Effects of sodium fluoride on blood cellular and humoral immunity in mice. AB - Exposure to high fluorine can cause toxicity in human and animals. Currently, there are no systematic studies on effects of high fluorine on blood cellular immunity and humoral immunity in mice. We evaluated the alterations of blood cellular immunity and humoral immunity in mice by using flow cytometry and ELISA. In the cellular immunity, we found that sodium fluoride (NaF) in excess of 12 mg/Kg resulted in a significant decrease in the percentages of CD3+, CD3+CD4+, CD3+CD8+ T lymphocytes in the peripheral blood. Meanwhile, serum T helper type 1 (Th1) cytokines including interleukin (IL)-2, interferon (IFN)-gamma, tumor necrosis factor (TNF), and Th2 cytokines including IL-4, IL-6, IL-10, and Th17 cytokine (IL-17A) contents were decreased. In the humoral immunity, NaF reduced the peripheral blood percentages of CD19+ B lymphocytes and serum immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM). The above results show that NaF can reduce blood cellular and humoral immune function in mice, providing an excellent animal model for clinical studies on immunotoxicity related fluorosis. PMID- 29156738 TI - Impact of mismatch-repair deficiency on the colorectal cancer immune microenvironment. AB - Colorectal cancer patients respond inconsistently to immunotherapies, likely due to the immune microenvironments around their tumors. We analyzed the relationship between deficient mismatch repair (dMMR) and the colorectal cancer immune microenvironment to identify predictors of effective immunotherapy. Colorectal cancer patients (n=113) who had undergone surgical resection were divided into dMMR and proficient mismatch repair (pMMR) groups. The levels of immune checkpoint proteins, including programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), indoleamine 2,3 dioxygenase and CD8 were assessed immunohistochemically. The percentage of tumor-infiltrating lymphocytes strongly positive for PD-1 (score=3) was higher in the dMMR than pMMR group (79.3% vs. 41.7%; p=0.003). The groups showed similar tumor cell PD-L1 positivity rates (34.5% vs. 35.7%, p=0.905) and PD-L1 intensity levels on immune cell infiltrates (86.2% vs. 84.5%, p=0.964). However, when a cut-off value of 80% was used for PD L1 positivity, the rate of PD-L1 positivity on immune cell infiltrates differed between the groups (51.7% vs. 22.6%, p=0.003). The rate of high indoleamine 2,3 dioxygenase expression was greater in the dMMR than pMMR group (55.2% vs. 36.9%, p=0.026). CD8+ T cells were elevated in the dMMR group in both compartments (p=0.017 for tumor-infiltrating lymphocytes and stroma; p=0.038 for invasive front). Thus the immune microenvironment of dMMR colorectal cancer differs from that of pMMR colorectal cancer. PMID- 29156737 TI - Combination treatment with recombinant methioninase enables temozolomide to arrest a BRAF V600E melanoma in a patient-derived orthotopic xenograft (PDOX) mouse model. AB - An excessive requirement for methionine termed methionine dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer cell growth can be selectively arrested by methionine deprivation such as with recombinant methioninase (rMETase). The present study used a previously established patient-derived orthotopic xenograft (PDOX) nude mouse model of BRAF V600E-mutant melanoma to determine the efficacy of rMETase in combination with a first-line melanoma drug, temozolomide (TEM). In the present study 40 melanoma PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n=10); TEM (25 mg/kg, oral 14 consecutive days, n=10); rMETase (100 units, intraperitoneal 14 consecutive days, n=10); combination TEM + rMETase (TEM: 25 mg/kg, oral rMETase: 100 units, intraperitoneal 14 consecutive days, n=10). All treatments inhibited tumor growth compared to untreated control (TEM: p=0.0081, rMETase: p=0.0037, TEM-rMETase: p=0.0024) on day 14 after initiation. However, the combination therapy of TEM and rMETase was significantly more efficacious than either mono-therapy (TEM: p=0.0051, rMETase: p=0.0051). The present study is the first demonstrating the efficacy of rMETase combination therapy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as melanoma, where rMETase may enhance first-line therapy. PMID- 29156739 TI - Electroacupuncture alleviates neuromuscular dysfunction in an experimental rat model of immobilization. AB - Immobilization-related skeletal muscle atrophy is a major concern to patients in Intensive Care Units and it has a profound effect on the quality of life. However, the underlying molecular events for the therapeutic effect of electroacupuncture to treat muscle atrophy have not been fully elucidated. Here we developed an immobilization mouse model and tested the hypothesis that skeletal muscle weakness may be caused by the increased expression of gamma and alpha7 nicotinic acetylcholine receptors (nAChRs) on muscle cell membranes, while electroacupuncture could decrease the expression of gamma and alpha7 nicotinic acetylcholine receptors. Compared with the rats in control, those treated with immobilization for 14 days showed a significant reduction of tibialis anterior muscle weight, muscle atrophy and dysfunction, which was associated with a significant decrease expression of neuregulin-1 and increased expression of gamma and alpha7-nAChR in tibialis anterior muscle. Electroacupuncture significantly enhanced the expression of neuregulin-1 and alleviated the muscle loss, while diminished the expression of gamma- and alpha7-nAChR. Taken together, the beneficial effect of electroacupuncture may be attributed to suppressing gamma- and alpha7-nAChR production, enhancing neuromuscular function and neuregulin-1 protein synthesis. These results suggest that electroacupuncture is a potential therapy for preventing muscle atrophy during immobilization. PMID- 29156740 TI - Improvement of therapeutic effects of mesenchymal stem cells in myocardial infarction through genetic suppression of microRNA-142. AB - Transplanted mesenchymal stem cells (MSCs) have been shown to contribute to myocardial repair after myocardial infarction (MI), primarily through production and secretion some growth factors and cytokines related to cell survival and regeneration. Further improvement of the therapeutic potential of MSCs appears to be an attractive strategy for MI treatment. CXC chemokine receptor (CXCR) 7 is the receptor for stromal cell-derived factor-1 (SDF-1), an important chemokine that is essential for tissue repair and angiogenesis. SDF-1/CXCR7 axis plays a critical role in the mobilization, recruitment and function of MSCs during tissue regeneration. Here, we depleted miR-142 that targets CXCR7 in MSCs cells through expression of antisense of miR-142, resulting in enhanced expression of CXCR7 in these miR-142-depleted MSCs (md-MSCs). In vitro, presence of md-MSCs reduced hypoxia-induced cardiac muscle cell apoptosis in a more pronounced manner than MSCs. In vivo, compared to transplantation of MSCs, transplantation of md-MSCs further enhanced cardiac re-vascularization and further improved cardiac functions after MI in mice. Together, our data suggest that depletion of miR-142 in MSCs may improve their therapeutic effects on MI. PMID- 29156741 TI - Screening epitopes on systemic lupus erythematosus autoantigens with a peptide array. AB - Systemic lupus erythematosus (SLE) is a common autoimmune disease. Many autoantibodies are closely associated with SLE. However, the specific epitopes recognized and bound by these autoantibodies are still unclear. This study screened the binding epitopes of SLE-related autoantibodies using a high throughput screening method. Epitope prediction on 12 SLE-related autoantigens was performed using the Immune Epitope Database and Analysis Resource (IEDB) software. The predicted epitopes were synthesized into peptides and developed into a peptide array. Serum IgG from 50 SLE patients and 25 healthy controls was detected using the peptide array. The results were then validated using an enzyme linked immunosorbent assay (ELISA). The diagnostic efficiency of each epitope was analyzed using a ROC curve. Seventy-three potential epitopes were screened for using the IEDB software after the epitopes on the 12 SLE-related autoantigens were analyzed. Peptide array screening revealed that the levels of the autoantibodies recognized and bound by 4 peptide antigens were significantly upregulated in the serum of SLE patients (P < 0.05). The ELISA results showed that the 4 antigens with significantly increased serum autoantibodies levels in SLE patients were acidic ribosomal phosphoprotein (P0)-4, acidic ribosomal phosphoprotein (P0)-11, DNA topoisomerase 1 (full length)-1, and U1-SnRNP 68/70 KDa-1 (P < 0.05), and the areas under the ROC curve for diagnosing SLE on the basis of these peptides were 0.91, 0.90, 0.93, and 0.91, respectively. Many autoantibodies specifically expressed in the serum of patients with SLE can be detected by specific peptide fragments and may be used as markers in clinical auxiliary diagnoses. PMID- 29156744 TI - Changes of alpha-fetoprotein levels could predict recurrent hepatocellular carcinoma survival after trans-arterial chemoembolization. AB - Background: There is paucity of information concerning whether AFP change is a predictor of prognosis for recurrent hepatocellular carcinoma (RHCC) patients after trans-arterial chemoembolization (TACE). Methods: A total of 177 RHCC patients who received TACE as first-line therapy were retrospectively analyzed. The patients were classified into three groups according to their pre-TACE and post-TACE AFP levels (group A: AFP decreased, group B: AFP consistent normal, and group C: AFP increased). The recurrence to death survival (RTDS) and overall survival (OS) were estimated by the Kaplan-Meier method, and compared by the log rank test. Multivariate analyses were performed to identify prognostic factors for OS and RTDS. Results: There was no significant difference among the three groups concerning the baseline characteristics. The median overall survival (OS) was 74.5 months in group A (95% confidence interval (CI): 63.5, 85.6), 64.0 months in group B (95% CI: 52.3, 75.7) and 29.0 months in group C (95% CI: 24.1, 33.9; P<0.001). The median recurrence to death survival (RTDS) was 66.5 months (95% CI: 53.4, 79.6) in group A, 50.4 months (95% CI: 39.5, 61.4) in group B and 17.7 months (95% CI: 13.4, 22.1; P<0.001) in group C. Multivariate analysis revealed that tumor size at resection stage, tumor number at recurrent stage, cycles of TACE, mRECIST response and AFP change after TACE were significant independent risk factors for RTDS and OS. Conclusions: AFP change could predict the prognoses of patients with RHCC who received trans-arterial chemoembolization, which may help clinicians make subsequent treatment decision. PMID- 29156742 TI - PRMDA: personalized recommendation-based MiRNA-disease association prediction. AB - Recently, researchers have been increasingly focusing on microRNAs (miRNAs) with accumulating evidence indicating that miRNAs serve as a vital role in various biological processes and dysfunctions of miRNAs are closely related with human complex diseases. Predicting potential associations between miRNAs and diseases is attached considerable significance in the domains of biology, medicine, and bioinformatics. In this study, we developed a computational model of Personalized Recommendation-based MiRNA-Disease Association prediction (PRMDA) to predict potential related miRNA for all diseases by implementing personalized recommendation-based algorithm based on integrated similarity for diseases and miRNAs. PRMDA is a global method capable of prioritizing candidate miRNAs for all diseases simultaneously. Moreover, the model could be applied to diseases without any known associated miRNAs. PRMDA obtained AUC of 0.8315 based on leave-one-out cross validation, which demonstrated that PRMDA could be regarded as a reliable tool for miRNA-disease association prediction. Besides, we implemented PRMDA on the HMDD V1.0 and HMDD V2.0 databases for three kinds of case studies about five important human cancers in order to test the performance of the model from different perspectives. As a result, 92%, 94%, 88%, 96% and 88% out of the top 50 candidate miRNAs predicted by PRMDA for Colon Neoplasms, Esophageal Neoplasms, Lymphoma, Lung Neoplasms and Breast Neoplasms, respectively, were confirmed by experimental reports. PMID- 29156743 TI - Hepatitis C virus Core overcomes all-trans retinoic acid-induced apoptosis in human hepatoma cells by inhibiting p14 expression via DNA methylation. AB - All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, is known to induce p14 expression via promoter hypomethylation to activate the p14-MDM2-p53 pathway, which leads to activation of the p53-dependent apoptotic pathway and subsequent induction of apoptosis in human hepatoma cells. In the present study, we found that hepatitis C virus (HCV) Core derived from ectopic expression or HCV infection overcomes ATRA-induced apoptosis in p53 positive hepatoma cells. For this effect, HCV Core upregulated both protein levels and enzyme activities of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b and thereby repressed p14 expression via promoter hypermethylation, resulting in inactivation of the pathway leading to p53 accumulation in the presence of ATRA. As a result, HCV Core prevented ATRA from activating several apoptosis-related molecules, including Bax, p53 upregulated modulator of apoptosis, caspase-9, caspase-3, and poly (ADP-ribose) polymerase. In addition, complementation of p14 in the Core-expressing cells by either ectopic expression or treatment with 5-Aza-2'dC almost completely abolished the potential of HCV Core to suppress ATRA-induced apoptosis. Based on these observations, we conclude that HCV Core executes its oncogenic potential by suppressing the p53-dependent apoptosis induced by ATRA in human hepatoma cells. PMID- 29156745 TI - Predictive value of preoperative inflammatory response biomarkers for metabolic syndrome and post-PCNL systemic inflammatory response syndrome in patients with nephrolithiasis. AB - Neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) were promising biomarkers used to predict diagnosis and prognosis in various inflammatory responses diseases and cancers. However, there have been no reports regarding these biomarkers in kidney stone patients. This study aimed to evaluate the predictive value of inflammatory biomarkers for metabolic syndrome (MetS) and post-PCNL SIRS in nephrolithiasis patients. We retrospectively enrolled 513 patients with nephrolithiasis and 204 healthy controls. NLR, dNLR, LMR and PLR in nephrolithiasis patients were significantly higher than control group. Patients with renal stone have higher NLR, dNLR, LMR and PLR than those without. ROC curve analysis indicated NLR, dNLR, LMR and PLR for predicting patients with nephrolithiasis and MetS, displayed AUC of 0.730, 0.717, 0.627 and 0.606. Additionally, ROC curves, using post-PCNL SIRS as the end-point for NLR, dNLR, LMR and PLR with AUC of 0.831, 0.813, 0.723 and 0.685. Multivariate analysis revealed that NLR, dNLR represented independent factors for predicting post-PCNL SIRS. While LMR independently associated with MetS. These resluts demonstrate preoperative NLR, dNLR and LMR appears to be effective predictors of post-PCNL SIRS and LMR of MetS in nephrolithiasis patients. PMID- 29156746 TI - TSSC3 represses self-renewal of osteosarcoma stem cells and Nanog expression by inhibiting the Src/Akt pathway. AB - Osteosarcoma is the most common type of bone cancer, and the second leading cause of cancer-related death in children and young adults. Osteosarcoma stem cells are essential for osteosarcoma initiation, metastasis, chemoresistance and recurrence. In the present study, we report that: 1) higher TSSC3 expression indicates a better prognosis for osteosarcoma patients, and; 2) overexpression of TSSC3 significantly decreases sphere-forming capacity, tumor initiation, stemness related surface markers and Nanog expression in osteosarcoma cells. We also discovered that higher Nanog expression correlates to a worse prognosis for osteosarcoma patients, and overexpression of Nanog increases the stem-related phenotype in osteosarcoma cells. Knockdown of Nanog suppresses these phenotypes. Inhibition of Nanog expression and self-renewal of osteosarcoma cells by TSSC3 overexpression appears to be mediated through inactivation of the Src/Akt pathway. In the clinical setting, expression of TSSC3, p-Src and Nanog is associated with recurrence, metastasis and surgical intervention. Lower TSSC3 expression, higher Nanog expression or higher p-Src expression indicate a poor prognosis for osteosarcoma patients. Overall, our study demonstrates that TSSC3 inhibits the stem-like phenotype and Nanog expression by inactivation of the Src/Akt pathway; this emphasizes the importance of Nanog in osteosarcoma stem cells. PMID- 29156747 TI - Lethality of inappropriate plasma exposure on chicken embryonic development. AB - In this study, we examined the effects of non-thermal dielectric barrier discharge plasma on embryonic development in chicken eggs in order to determine the optimal level of plasma exposure for the promotion of embryonic growth. We exposed developing chicken embryos at either Hamburger-Hamilton (HH) stage 04 or HH 20 to plasma at voltages of 11.7 kV to 27.6 kV. Our results show exposure at 11.7 kV for 1 min promoted chicken embryonic development, but exposure to more duration and intensity of plasma resulted in dose-dependent embryonic death and HH 20 stage embryos survive longer than those at stage HH 04. Furthermore, plasma exposure for 4 min increased the production of reactive oxygen species (ROS) and inactivated the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response signaling pathway, resulting in suppression of antioxidant enzymes in the skeletal muscle tissue of the dead embryos. We also found decreased levels of adenosine triphosphate production and reductions in the expression levels of several growth-related genes and proteins. These findings indicate that inappropriate plasma exposure causes dose-dependent embryonic death via excessive accumulation of ROS, NRF2-antioxidant signaling pathway disruption, and decreased growth factor expression. PMID- 29156748 TI - Association of melatonin membrane receptor 1A/1B gene polymorphisms with the occurrence and metastasis of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a prevalent primary neoplasm of the liver, whose heterogeneous global incidence suggests the likely impact of genetic variations among individuals on the susceptibility to this disease. Increasing evidence indicates that melatonin exhibits oncostatic properties in many cancer types at least in part mediated by its membrane-bound receptors, melatonin receptor 1A (encoded by MTNR1A) and 1B (MTNR1B). In this study, the effect of melatonin receptor gene polymorphisms on the risk and progression of hepatic tumors was evaluated between 335 HCC patients and 1196 cancer-free subjects. We detected a significant association of MTNR1A single nucleotide polymorphism (SNP), rs6553010, with the elevated risk of HCC (AOR, 1.587; 95% CI, 1.053-2.389; p = 0.027) after being adjusted for two potential confounders, age and alcohol use. In addition, patients who carry at least one polymorphic allele (heterozygote or homozygote) of MTNR1A rs2119882 or rs2375801 were more prone to develop distant metastasis (OR, 5.202; 95% CI, 1.163-23.270; p = 0.031, and OR, 7.782; 95% CI, 1.015-59.663; p = 0.048, for rs2119882 and rs2375801, respectively). Further analyses revealed that rs2119882 is located on the consensus binding site of GATA2 transcription factor within the promoter region of MTNR1A gene, and that a correlation between the levels of GATA2 and melatonin receptor 1A was observed in the TCGA (The Cancer Genome Atlas) dataset. Moreover, individuals bearing a specific haplotype of four MTNR1B SNPs were more prone to develop HCC. In conclusion, our data suggest an association of melatonin receptor gene polymorphisms with the risk of HCC and hepatic cancer metastasis. PMID- 29156749 TI - High uric acid (UA) downregulates bone alkaline phosphatase (BALP) expression through inhibition of its promoter activity. AB - Bone metastases often occur in prostate cancers, lung cancers and breast cancers. Bone alkaline phosphatase (BALP) is one of the most commonly used serological markers for clinical evaluation of bone metabolism. Here, we reported that high concentrations of uric acid (UA) caused decrease of BALP levels and revealed that the effect of high concentrations of UA on the BALP expression was through inhibition of its promoter activity. Our results suggested physicians to think about serum UA status of patients with advanced cancer to avoid misdiagnosis when BALP was used to diagnose or assess the extent of bone metastases. PMID- 29156750 TI - Somatic mutations in CDH1 and CTNNB1 in primary carcinomas at 13 anatomic sites. AB - Metastases are involved in most cancer deaths. Evidence has suggested that cancer cell detachment from primary tumors might occur largely via the mechanism of epithelial-mesenchymal transition (EMT) activated by epigenetic events, but data addressing other possible triggers of detachment, particularly genetic mutations, have been limited. Using the Profile study of cancer genomics at Dana-Farber Cancer Institute, we examined somatic mutations in the EMT genes CDH1 in 5,106 primary carcinomas and CTNNB1 in 7,578 primary carcinomas across 13 anatomic sites: urinary bladder, breast, colon/rectum, endometrium, esophagus, kidney, lung, ovary, pancreas, prostate, skin (non-melanoma), stomach, and thyroid. For each gene and anatomic site, we calculated the prevalence of primary carcinomas with at least one mutation. Across all anatomic sites, 4% of carcinomas had at least one CDH1 mutation and 4% of carcinomas had at least one CTNNB1 mutation. By anatomic site, the observed prevalence of carcinomas with at least one mutation was less than 5% at 10 sites for CDH1 and 12 sites for CTNNB1. Tumor stage data were available for a subset of breast, colorectal, lung, and prostate tumors. Among patients from this subset who were diagnosed with regional or distant disease, only 4% had a CDH1 mutation and 1% had a CTNNB1 mutation in the primary tumor. The low mutation prevalences, especially among those with diagnoses of regional or distant disease, suggest that somatic mutations in CDH1 and CTNNB1 are unlikely to explain a substantial proportion of cancer cell detachment from primary carcinomas originating at most anatomic sites. PMID- 29156751 TI - Identification of potential tissue-specific cancer biomarkers and development of cancer versus normal genomic classifiers. AB - Machine learning techniques for cancer prediction and biomarker discovery can hasten cancer detection and significantly improve prognosis. Recent "OMICS" studies which include a variety of cancer and normal tissue samples along with machine learning approaches have the potential to further accelerate such discovery. To demonstrate this potential, 2,175 gene expression samples from nine tissue types were obtained to identify gene sets whose expression is characteristic of each cancer class. Using random forests classification and ten fold cross-validation, we developed nine single-tissue classifiers, two multi tissue cancer-versus-normal classifiers, and one multi-tissue normal classifier. Given a sample of a specified tissue type, the single-tissue models classified samples as cancer or normal with a testing accuracy between 85.29% and 100%. Given a sample of non-specific tissue type, the multi-tissue bi-class model classified the sample as cancer versus normal with a testing accuracy of 97.89%. Given a sample of non-specific tissue type, the multi-tissue multi-class model classified the sample as cancer versus normal and as a specific tissue type with a testing accuracy of 97.43%. Given a normal sample of any of the nine tissue types, the multi-tissue normal model classified the sample as a particular tissue type with a testing accuracy of 97.35%. The machine learning classifiers developed in this study identify potential cancer biomarkers with sensitivity and specificity that exceed those of existing biomarkers and pointed to pathways that are critical to tissue-specific tumor development. This study demonstrates the feasibility of predicting the tissue origin of carcinoma in the context of multiple cancer classes. PMID- 29156752 TI - Early and late effects of aspirin and naproxen on microRNAs in the lung and blood of mice, either unexposed or exposed to cigarette smoke. AB - We recently showed that nonsteroidal anti-inflammatory drugs (NSAIDs) are able to inhibit the lung tumors induced by cigarette smoke, either mainstream (MCS) or environmental (ECS), in female mice. We used subsets of mice to analyze the expression of 1135 microRNAs in both lung and blood serum, as related to the whole-body exposure to smoke and/or oral administration of either aspirin or naproxen. In a first study, we evaluated early microRNA alterations in A/J mice exposed to ECS for 10 weeks, starting at birth, and/or treated with NSAIDs for 6 weeks, starting after weaning. At that time, when no histopathological change were apparent, ECS caused a considerable downregulation of pulmonary microRNAs affecting both adaptive mechanisms and disease-related pathways. Aspirin and naproxen modulated, with intergender differences, the expression of microRNAs having a variety of functions, also including regulation of cyclooxygenases and inflammation. In a second study, we evaluated late microRNA alterations in Swiss H mice exposed to MCS during the first 4 months of life and treated with NSAIDs after weaning until 7.5 months of life, when tumors were detected in mouse lung. Modulation of pulmonary microRNAs by the two NSAIDs was correlated with their ability to prevent preneoplastic lesions (microadenomas) and adenomas in the lung. In both studies, exposure to smoke and/or treatment with NSAIDs also modulated microRNA profiles in the blood serum. However, their levels were poorly correlated with those of pulmonary microRNAs, presumably because circulating microRNAs reflect the contributions from multiple organs and not only from lung. PMID- 29156753 TI - Candidate tumor suppressor ZNF154 suppresses invasion and metastasis in NPC by inhibiting the EMT via Wnt/beta-catenin signalling. AB - Background: Nasopharyngeal carcinoma (NPC) is especially prevalent in southeast Asia and southern China, but its molecular mechanisms remain poorly characterized. DNA methylation is associated with initiation and progression of tumors, including NPC. Through a genome-wide DNA methylation screening approach, we discovered ZNF154, but its methylation status and roles in NPC have not been investigated. Methods: The methylation status of ZNF154 in NPC was detected with Methylation specific-PCR (MSP) and Quantitative Sequenom MassARRAY. The invasion and migration capacities were examined by wound healing and transwell invasion assays. The role of ZNF154 in NPC metastasis was clarified with experimental metastasis assay in vivo. Western blotting analysis was used to investigate protein changes followed by ZNF154 over-expression. Kaplan-Meier analysis was performed to determine the association between ZNF154 methylation and prognosis in NPC. Results: Compared to immortalized nasopharyngeal tissues and cells, ZNF154 expression was frequently downregulated in NPC tissues and cell lines due to promoter methylation. Demethylation treatment with 5-aza-2-deoxycytidine (5 Aza) restored ZNF154 expression in NPC cell lines. Ectopic overexpression of ZNF154 in NPC cells inhibited cell migration and invasion in vitro and lung nodule formation in an in vivo tumor metastasis assay. Mechanistic investigations suggested ZNF154 inhibits Wnt/beta-catenin signalling pathway activation and prevents the EMT in NPC. Furthermore, Kaplan-Meier analysis showed hypermethylation of the ZNF154 promoter was associated with significantly poorer disease-free survival (P = 0.032) and distant metastasis-free survival (P = 0.040) among patients with locoregionally advanced NPC. Conclusions: Taken together, these findings define a novel role for ZNF154 as a tumor suppressor in NPC. PMID- 29156754 TI - Functional characterization of a novel transcript of ERCC1 in chemotherapy resistance of ovarian cancer. AB - Approximately 15-20% of ovarian cancer patients receiving platinum-based chemotherapy are primary platinum-resistant. Identification of these patients and transfer to other more effective therapy could reduce the morbidity of ovarian cancer. ERCC1 is a DNA repair gene which can complex with XPF to repair cisplatin induced DNA damage and cause chemotherapy resistance. In this study, we found a novel ERCC1 transcript initiated upstream of the normal transcription initiation site. The expression of this larger ERCC1 transcript dramatically increased following cisplatin treatment in ovarian cancer cells and was regulated by the MAPK pathway. This phenomenon conferred enhanced cisplatin resistance on ovarian cancer cells, and was confirmed with chemosensitive and chemoresistant patients' samples. Our data suggested that larger ERCC1 transcript levels correlated with the outcome of platinum-based chemotherapy. PMID- 29156755 TI - Escherichia coli Nissle 1917 engineered to express Tum-5 can restrain murine melanoma growth. AB - Tumor growth and metastasis depend on angiogenesis. Thus, inhibiting tumor angiogenesis has become promising cancer therapeutic strategy in recent years. Tumstatin is a more powerful angiogenesis inhibitor than endostatin. Anti angiogenic active fragment encoding amino acids 45-132 (Tum-5) of tumstatin was subcloned into four different inducible expression vectors and successfully solubly expressed in Escherichia coli BL21 (DE3) in this study. Subsequently, an anaerobic inducible expression vector was constructed under Vitreoscilla hemoglobin gene promoter Pvhb in E. coli Nissle 1917 (EcN). The secretory expression of Tum-5 in the engineered bacterium was determined in vitro and in vivo by Western blot or immunochemistry. The anti-tumor effect detection demonstrated that EcN could specifically colonize the tumor, and B16 melanoma tumor growth was remarkably restrained by EcN (Tum-5) in mice bearing B16 melanoma tumor. Abundant infiltrating inflammatory cells were observed in tumor areas of the EcN-treated group through hematoxylin and eosin staining, with a relatively reduced expression of endothelial marker platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) by immunofluorescence in tumor sections of EcN (Tum-5)-treated mice. No significant morphological differences were observed in the liver, kidney and spleen between EcN-treated mice and the control group, indicating that EcN was cleared by the immune system and did not cause systemic toxicity in mice. These findings demonstrated that the gene delivery of Tum-5 to solid tumors could be an effective strategy for cancer therapy. PMID- 29156756 TI - MiR-221-regulated KIT level by wild type or leukemia mutant RUNX1: a determinant of single myeloblast fate decisions that - collectively - drives or hinders granulopoiesis. AB - RUNX1, a master transcription factor of hematopoiesis, was shown to orchestrate both cell proliferation and differentiation during granulopoiesis by regulating microRNAs (miRs). In this study, taking advantage of the miR-ON reporter system, we monitored first, how the granulocyte colony stimulation factor (GCSF) temporally modulates the concomitant level variation of miR-221 and one of its prototypic targets, the stem cell factor receptor KIT, in single 32DmiR-ON-221 myeloblasts expressing wild type RUNX1. Second, with the same reporter system we assessed how these temporal dynamics are affected by the t(8;21)(q22;q22) acute myelogenous leukemia mutant RUNX1-MTG8 (RM8) in single 32D-RM8miR-ON-221 myeloblasts. Depending on either wild type, or mutant, RUNX1 transcriptional regulation, the cell-context specific miR-221-regulated KIT level translates into differential single cell fate decisions. Collectively, single cell fate choices translate into either initial expansion of undifferentiated myeloblasts followed by terminal granulocyte differentiation, as it happens in normal granulopoiesis, or aggressive growth of undifferentiated myeloblasts, as it happens in RUNX1-MTG8 positive acute myelogenous leukemia. Increasing knowledge of biological changes, due to altered miRNA dynamics, is expected to have relevant translational implications for leukemia detection and treatment. PMID- 29156757 TI - A PTEN-COL17A1 fusion gene and its novel regulatory role in Collagen XVII expression and GBM malignance. AB - Collagen XVII expression has recently been demonstrated to be correlated with the tumor malignance. While Collagen XVII is known to be widely distributed in neurons of the human brain, its precise role in pathogenesis of glioblastoma multiforme (GBM) is unknown. In this study, we identified and characterized a new PTEN-COL17A1 fusion gene in GMB using transcriptome sequencing. Although fusion gene did not result in measurable fusion protein production, its presence is accompanied with high levels of COL17A1 expression, revealed a novel regulatory mechanism of Collagen XVII expression by PTEN-COL17A1 gene fusion. Knocked down Collagen XVII expression in glioma cell lines resulted in decreased tumor invasiveness, along with significant reduction of MMP9 expression, while increased Collagen XVII expression promotes invasive activities of glioma cells and associated with GBM recurrences. Together, our results uncovered a new PTEN COL17A1 fusion gene and its novel regulatory role in Collagen XVII expression and GBM malignance, and demonstrated that COL17A1 could serve as a useful prognostic biomarker and therapeutic targets for GBM. PMID- 29156758 TI - Development of novel long noncoding RNA MALAT1 near-infrared optical probes for in vivo tumour imaging. AB - With the advent of next-generation sequencing technology, there is rapidly increasing interest in long noncoding RNAs (lncRNAs). The objectives of this study were to develop a novel lncRNA MALAT1 near-infrared optical probe, to evaluate the characteristics of this optical imaging probe in vitro and to determine whether it can be used for imaging MALAT1 expression in malignant tumours in vivo. Conjugation of Cy5.5 to MALAT1 ASO was accomplished using standard NHS (N-hydroxysuccinimide) ester procedures, and the labelled MALAT1 ASO was purified with a Glen-Pak DNA Purification Cartridge and reversed-phase high performance liquid chromatography (HPLC). The in vitro cellular uptake results showed that the percentage of cell binding increased with an increasing final concentration and increased with increasing incubation time for the MHCC-LM3 tumour cell flow cytometry analyses. in vivo optical imaging exhibited 5' (Cy5.5) MALAT1 ASO uptake in the tumour with a maximum at 30 min p.i. that slowly washed out over time. High contrast to normal tissue was gradually observed from 4 h to 48 h p.i. Tumour-to-normal ratios of fluorescence intensities were plotted as a function of time. The in vivo competition assay showed little uptake of the probe into the tumours at any time point, indicating effective competition, selectivity of probe binding and retention by tumours in vivo. Our proposed Cy5.5 labelling of MALAT1 ASO can serve as a potent optical probe for in vivo imaging of tumour expressing MALAT1. Importantly, the successful development of optical probes provides a basis for specific molecular diagnoses in the field of lncRNAs. PMID- 29156759 TI - Smoking and gender modify the effect of TWIST on patient survival in head and neck squamous carcinoma. AB - Purpose: TWIST is a critical factor for predicting prognosis in several human cancers. Here, we study the prognostic significance of TWIST1 and TWIST2 in Head and Neck squamous cell carcinoma (HNSCC) as well as interactions of TWISTs with both gender and smoking in patient survival. Methods: upper quartile normalized RNA-seq V2 RSEM values of TWIST1 and TWIST2 expressions were retrieved from a TCGA HNSCC dataset. Kaplan-Meier survival curves were used to assess the associations of TWIST1 and TWIST2 with patient survival, and multivariate Cox proportional hazards regression models were used to estimate the hazards ratios (HRs) and their 95% confidence intervals (CIs). Results: Survival analyses showed that high TWIST1 expression was associated with a poor overall survival at a borderline significance level, while a superior but not statistically significant overall survival was observed in high TWIST2 expression. The multivariate Cox proportional hazards regression model showed a significantly elevated risk of death (HR=1.37, p = 0.038) in patients with high TWIST1 compared to low TWIST1, and a borderline significantly decreased risk of death (HR = 0.74, p = 0.055) in patients with high TWIST2 compared to low TWIST2. Further stratification analyses showed that increased risks of death were found significantly in male and borderline significantly in smoker patients with high TWIST1 compared to low one, and a significantly decreased risk of death in non-smoker patients with high TWIST2 compared to low one. Conclusions: TWIST1 and TWIST2 are differentially associated with HNSCC patient survival. Gender and smoking could modify the effect of TWISTs on the risk of death in HNSCC patients. PMID- 29156760 TI - MicroRNA-29a increased the intestinal membrane permeability of colonic epithelial cells in irritable bowel syndrome rats. AB - Background: The whole pathogenesis of diarrhea-predominant irritable bowel syndrome(IBS-D) is poorly understood. Our goal was to evaluate the expression change of microRNA-29a(miR-29a) in colonic epithelial cells in IBS rats and clarify the mechanism of miR-29a increasing the intestinal membrane permeability through aquaporins(AQPs). Methods: The IBS-D rats models were induced by rectal distention pressure combining with extremities constraint. The colonic epithelial cells were divided into four groups. A: normal group. B: IBS-D control group. C: IBS-D +miR-29a NC. D: IBS-D + miR-29a antagomir. The expression of miR-29a, the concentration of the K+ and Lactate Dehydrogenase(LDH) and the expression of AQPs were detected. Results: The miR-29a expression increased in IBS-D control group(2.090+/-0.022) compared with the control group(1.00+/-0.031) (P<0.001) while it decreased in IBS-D+miR-29a antagomir group(1.403+/-0.042) compared with IBS-D control group(P<0.001). The K+ decreased in IBS-D control group(1.305+/ 0.289) compared with the control group(2.171+/-0.204)(P<0.05) while it increased in IBS-D+miR-29a antagomir group(1.813+/-0.102)(P<0.05) compared with IBS-D control group. The LDH increased in IBS-D control group(4153.440+/-177.365) compared with the control group(1434.573+/-96.111)(P<0.001) while it decreased in IBS-D+miR-29a antagomir group(2700.473+/-275.414) compared with IBS-D control group (P<0.01). The expression of AQP1, AQP3 and AQP8 decreased in IBS-D control group(0.132+/-0.010,0.110+/-0.005,0.108+/-0.007) compared with the control group (P<0.001) while it increased in IBS-D+miR-29a antagomir group(0.197+/ 0.005,0.182+/-0.011,0.194+/-0.003) compared with IBS-D control group(P<0.001). The IBS-D+miR-29a negative control(NC) group, a comparison with IBS-D+miR-29a antagomir group, each date showed the similar trend to the IBS-D control group. Conclusions: MiR-29a increased the intestinal membrane permeability of colonic epithelial cells by reducing the AQPs expression in IBS-D rats. PMID- 29156761 TI - Extracts from Hericium erinaceus relieve inflammatory bowel disease by regulating immunity and gut microbiota. AB - Hericium erinaceus (HE), a traditional edible mushroom, is known as a medicine food homology to ameliorate gastrointestinal diseases. To investigate whether HE is clinically effective in alleviating inflammatory bowel disease (IBD), HE extracts (polysaccharide, alcoholic extracts and whole extracts were prepared using solvent extraction methods) were administrated for 2 weeks in rats with IBD induced by trinitro-benzene-sulfonic acid (TNBS) enema (150 mg/kg). Significant clinical and histological changes in IBD rats were identified, including damage activity, common morphous and tissue damage index scores in colonic mucosa and myeloperoxidase (MPO) activity. The damage activity, common morphous and tissue damage index scores in colonic mucosa (P <0.05) were improved, MPO activities were decreased. Inflammatory factors were also differentially expressed in colonic mucosa in IBD rats, including serum cytokines, Foxp3 and interleukin (IL) 10 were increased while NF-kappaB p65 and tumor necrosis factor (TNF)-alpha were decreased (P <0.05), and T cells were activated (P <0.05), especially in the alcohol extracts-treated group. We also found that the structure of gut microbiota of the H. erinaceus extracts-treated groups changed significantly by compared with the model group. Further studies revealed that the polysaccharides in HE extracts may play a prebiotic role, whereas the alcoholic extracts show bactericidin-like and immunomodulatory effects. Taken together, we demonstrated that H. erinaceus extracts could promote the growth of beneficial gut bacteria and improve the host immunity in vivo IBD model, which shows clinical potential in relieving IBD by regulating gut microbiota and immune system. PMID- 29156762 TI - Glutaminase inhibition in multiple myeloma induces apoptosis via MYC degradation. AB - Multiple Myeloma (MM) is an incurable hematological malignancy affecting millions of people worldwide. As in all tumor cells both glucose and more recently glutamine have been identified as important for MM cellular metabolism, however there is some dispute as to the role of glutamine in MM cell survival. Here we show that the small molecule inhibitor compound 968 effectively inhibits glutaminase and that this inhibition induces apoptosis in both human multiple myeloma cell lines (HMCLs) and primary patient material. The HMCL U266 which does not express MYC was insensitive to both glutamine removal and compound 968, but ectopic expression of MYC imparted sensitivity. Finally, we show that glutamine depletion is reflected by rapid loss of MYC protein which is independent of MYC transcription and post translational modifications. However, MYC loss is dependent on proteasomal activity, and this loss was paralleled by an equally rapid induction of apoptosis. These findings are in contrast to those of glucose depletion which largely affected rates of proliferation in HMCLs, but had no effects on either MYC expression or viability. Therefore, inhibition of glutaminolysis is effective at inducing apoptosis and thus serves as a possible therapeutic target in MM. PMID- 29156763 TI - ELAS1 induces apoptotic death in adenocarcinoma DU145 and squamous-cell carcinoma SAS cancer cells, but not in normal KD cells. AB - We previously reported that an ELAS1 peptide containing 29 amino acids induces apoptotic death in U2OS human osteosarcoma cells following DNA double-strand break insults. Here, we show that ELAS1 also caused apoptosis in prostate adenocarcinoma DU145 cells and tongue squamous-cell carcinoma SAS cells. ELAS1 appears to be safe because it induced apoptosis only in cancer cells, not in normal KD cells. Because the effect of ELAS1 is dependent on increased stability of p53 and enhanced phosphorylation of p53-S46, we exogenously expressed wild type p53 protein to fully promote ELAS1-mediated induction of apoptosis in SAS cells. Interestingly, simultaneous expression of Myc-ELAS1 and FLAG-p53 mediated by an internal ribosome entry site efficiently induced apoptosis in SAS cells. Moreover, we prepared a recombinant adenovirus that simultaneously expressed Myc ELAS1 and FLAG-p53. This adenovirus also killed SAS cells, as determined by a cell viability assay, in the presence of camptothecin, an inducer of DNA double strand breaks. Moreover, nude mice harboring Myc-ELAS1-expressing SAS cells lived longer than mice harboring Myc-vector-expressing SAS cells, suggesting the usefulness of ELAS1 in vivo. Notably, Cy5-tagged ELAS1-t, which contained only ten amino acids, also efficiently induced apoptosis in both DU145 and SAS cells, suggesting the usefulness of ELAS1-t as a peptide. Taken together, our results suggest that ELAS1 is therapeutically useful as a peptide drug. PMID- 29156764 TI - The NEIL1 G83D germline DNA glycosylase variant induces genomic instability and cellular transformation. AB - Base excision repair (BER) is a key genome maintenance pathway. The NEIL1 DNA glycosylase recognizes oxidized bases, and likely removes damage in advance of the replication fork. The rs5745906 SNP of the NEIL1 gene is a rare human germline variant that encodes the NEIL1 G83D protein, which is devoid of DNA glycosylase activity. Here we show that expression of G83D NEIL1 in MCF10A immortalized but non-transformed mammary epithelial cells leads to replication fork stress. Upon treatment with hydrogen peroxide, we observe increased levels of stalled replication forks in cells expressing G83D NEIL1 versus cells expressing the wild-type (WT) protein. Double-strand breaks (DSBs) arise in G83D expressing cells during the S and G2/M phases of the cell cycle. Interestingly, these breaks result in genomic instability in the form of high levels of chromosomal aberrations and micronuclei. Cells expressing G83D also grow in an anchorage independent manner, suggesting that the genomic instability results in a carcinogenic phenotype. Our results are consistent with the idea that an inability to remove oxidative damage in an efficient manner at the replication fork leads to genomic instability and mutagenesis. We suggest that individuals who harbor the G83D NEIL1 variant face an increased risk for human cancer. PMID- 29156766 TI - Isobaric tags for relative and absolute quantification-based proteomic analysis of testis biopsies in rhesus monkeys treated with transient scrotal hyperthermia. AB - This study aimed to examine the cellular and molecular events that occur in rhesus monkey testes after scrotal hyperthermia. Eight male adult rhesus monkeys were subjected to scrotal hyperthermia at 43 degrees C for 30 min daily for 6 consecutive days. Sperm concentration, reproductive hormones, and testis histology were examined before hyperthermia (day 0), and at 8, 15, 30, 45, 60, 75, and 90 days after the initiation of hyperthermia. iTRAQ-based proteomic analysis was conducted on testicular tissues collected on days 0, 8, and 60 to identify differentially expressed proteins at the early and recovery stages of testicular damage. The sperm concentration was significantly decreased at days 30 and 45 after treatment (p < 0.01) and recovered to baseline at day 60. When compared with day 0, 101 and 24 differentially expressed proteins were identified at days 8 and 60 after heat treatment, respectively. The molecular functions of the differentially expressed proteins at day 8 were mainly nucleic acid binding, unfolded protein binding, nucleotide binding, and nucleoside phosphate binding. Spliceosome was enriched as the most significant pathway at day 8. CIRBP, PSIP1, Sam68, and Decorin were validated and found to be consistent with the proteomic data, indicating the reliability of the proteomic profiles identified in this study. In summary, we suggest that the proteins identified in this study may play important roles in heat-induced spermatogenic impairment. Some of these proteins, such as CIRBP, PSIP1, Sam68, and Decorin, may be early molecular targets responsible for spermatogenesis suppression induced by heat treatment. PMID- 29156765 TI - Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci. AB - Large-scale genome-wide association studies have identified multiple single nucleotide polymorphisms associated with risk of prostate cancer. Many of these genetic variants are presumed to be regulatory in nature; however, follow-up expression quantitative trait loci (eQTL) association studies have to-date been restricted largely to cis-acting associations due to study limitations. While trans-eQTL scans suffer from high testing dimensionality, recent evidence indicates most trans-eQTL associations are mediated by cis-regulated genes, such as transcription factors. Leveraging a data-driven gene co-expression network, we conducted a comprehensive cis-mediator analysis using RNA-Seq data from 471 normal prostate tissue samples to identify downstream regulatory associations of previously identified prostate cancer risk variants. We discovered multiple trans eQTL associations that were significantly mediated by cis-regulated transcripts, four of which involved risk locus 17q12, proximal transcription factor HNF1B, and target trans-genes with known HNF response elements (MIA2, SRC, SEMA6A, KIF12). We additionally identified evidence of cis-acting down-regulation of MSMB via rs10993994 corresponding to reduced co-expression of NDRG1. The majority of these cis-mediator relationships demonstrated trans-eQTL replicability in 87 prostate tissue samples from the Gene-Tissue Expression Project. These findings provide further biological context to known risk loci and outline new hypotheses for investigation into the etiology of prostate cancer. PMID- 29156767 TI - Enhancing conventional chemotherapy drug cisplatin-induced anti-tumor effects on human gastric cancer cells both in vitro and in vivo by Thymoquinone targeting PTEN gene. AB - Combination chemotherapy regimen with several anti-tumor drugs is a strategy to improve outcome. Thymoquinone (TQ) has been reported to exert biological activity on various types of human cancers without obvious toxicity. However, only few studies showed the anti-tumor effects of TQ combination with cisplatin on gastric cancer (GC). Here, we showed pretreatment with 5MUM TQ significantly increased the apoptotic effects induced by cisplatin on GC cell lines. Combined treatment of cisplatin with TQ represented a significantly superior tumor suppression effect than either agent alone in a xenograft tumor mouse model. Interestingly, TQ pretreatment following cisplatin caused a significant increase in the levels of PTEN, an obvious decrease in p-AKT, CyclinD1, P-glycoprotein (P-gp), meanwhile, TQ and cisplatin also led to an increase in Bax, Cyt C, AIF, cleaved caspase 9, and cleaved caspase 3, and a decrease in Bcl-2, procaspase-9, procaspase-3. Moreover, results in vitro, showed that a combination of TQ and cisplatin represents a more effective anti-tumor agent than either agent alone in a xenograft tumor mouse model. In conclusion, TQ significantly augments cisplatin induced anti-tumor effects on gastric cancer both in vitro and in vivo, through inhibiting PI3K/AKT signaling pathway, activating the mitochondrial pathway, and down-regulating P-glycoprotein by up-regulating PTEN gene. TQ might be as a promising candidate as a cancer chemopreventive or chemotherapeutic agent for antineoplastic combination therapy and merits further clinical investigation. PMID- 29156768 TI - Clinical significance of pre-surgical serum lipid levels in patients with glioblastoma. AB - Accumulating evidence demonstrates that pre-surgical serum lipid levels are linked to the clinical outcome of different types of human malignant tumors, but few studies have explored the prognostic value of these easily accessible parameters in glioblastoma. The aim of the current study was to validate the association between pre-surgical serum lipid levels and the clinical outcome of patients with glioblastoma. The pre-surgical serum lipid levels (triglycerides, total cholesterol, high-density lipoprotein [HDL] cholesterol, and low-density lipoprotein [LDL] cholesterol) of 125 patients with glioblastoma, who underwent surgery between January 2015 and May 2016, were retrospectively evaluated. The correlation between pre-surgical serum lipid levels and overall survival (OS) was examined using the Kaplan-Meier method and Cox proportional hazards regression model. Univariate analysis showed that lipids associated with OS were total cholesterol, HDL cholesterol, and LDL cholesterol levels. Results of multivariate analysis identified LDL cholesterol level as an independent prognostic factor for OS in patients with glioblastoma (hazard ratio: 0.412; 95% confidence interval: 0.211-0.801; P = 0.009). Total cholesterol and HDL cholesterol levels were predictive factors only in univariate analysis, but not in multivariate analysis. The current study demonstrated that pre-surgical serum LDL cholesterol level is an independent prognostic factor for clinical outcomes of patients with glioblastoma. Pre-surgical serum LDL cholesterol level might provide valuable prognostic information for patients with glioblastoma that could be applied in clinical practice. PMID- 29156770 TI - SCO-spondin oligopeptide inhibits angiogenesis in glioblastoma. AB - Angiogenesis plays a critical role in glioblastoma growth and progression. We therefore aimed at evaluating the anti-angiogenic properties of an oligopeptide originating from SCO-spondin (NX) on a model of human glioblastoma. To this end, we studied the impact of NX treatment on human brain endothelial cells (HBMECs) alone or co-cultured with glioblastoma cells (U87-MG) on apoptosis, proliferation, migration and release of angiogenic factors. We further investigated the anti-angiogenic potential of NX on human glioblastoma cells grown on chorio-allantoic membrane (CAM) or in glioblastoma xenografts. The results of our experiments showed that NX treatment impaired the microvascular network and induced a decrease in cell proliferation, vascularization and tumor growth in the CAM model as well as in xenotransplants. Interestingly, our in vitro experiments showed that NX impairs HBMECs migration but also regulates the release of angiogenic factors from U87-MG. These results are confirmed by the profiling of NX-treated U87-MG grown on CAM that highlighted modifications of several genes involved in angiogenesis. In conclusion, NX inhibits tumorigenesis by impairing the ability of glioblastoma cells to induce angiogenesis and by inhibiting endothelial cell migration. This molecule might therefore be an interesting candidate for future cancer therapies. PMID- 29156769 TI - Liraglutide activates autophagy via GLP-1R to improve functional recovery after spinal cord injury. AB - Therapeutics used to treat central nervous system (CNS) injury are designed to promote axonal regeneration and inhibit cell death. Previous studies have shown that liraglutide exerts potent neuroprotective effects after brain injury. However, little is known if liraglutide treatment has neuroprotective effects after spinal cord injury (SCI). This study explores the neuroprotective effects of liraglutide and associated underlying mechanisms. Our results showed that liraglutide could improve recovery after injury by decreasing apoptosis as well as increasing microtubulin acetylation, and autophagy. Autophagy inhibition with 3-methyladenine (3-MA) partially reversed the preservation of spinal cord tissue and decreased microtubule acetylation and polymerization. Additionally, siRNA knockdown of GLP-1R suppressed autophagy and reversed mTOR inhibition induced by liraglutide in vitro, indicating that GLP-1R regulates autophagic flux. GLP-1R knockdown ameliorated the mTOR inhibition and autophagy induction seen with liraglutide treatment in PC12 cells under H2O2 stimulation. Taken together, our study demonstrated that liraglutide could reduce apoptosis, improve functional recovery, and increase microtubule acetylation via autophagy stimulation after SCI. GLP-1R was associated with both the induction of autophagy and suppression of apoptosis in neuronal cultures. PMID- 29156771 TI - Novel post-transcriptional and post-translational regulation of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 determine the fate of breast cancer cells to survive or die. AB - Deregulation of apoptosis is central to cancer progression and a major obstacle to effective treatment. The Bcl-2 gene family members play important roles in the regulation of apoptosis and are frequently altered in cancers. One such member is pro-apoptotic protein Bcl-2-related Ovarian Killer (BOK). Despite its critical role in apoptosis, the regulation of BOK expression is poorly understood in cancers. Here, we discovered that miR-296-5p regulates BOK expression by binding to its 3'-UTR in breast cancers. Interestingly, miR-296-5p also regulates the expression of anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1), which is highly expressed in breast cancers. Our results reveal that Mcl-1 and BOK constitute a regulatory feedback loop as ectopic BOK expression induces Mcl-1, whereas silencing of Mcl-1 results in reduced BOK levels in breast cancer cells. In addition, we show that silencing of Mcl-1 but not BOK reduced the long-term growth of breast cancer cells. Silencing of both Mcl-1 and BOK rescued the effect of Mcl-1 silencing on breast cancer cell growth, suggesting that BOK is important for attenuating cell growth in the absence of Mcl-1. Depletion of BOK suppressed caspase-3 activation in the presence of paclitaxel and in turn protected cells from paclitaxel-induced apoptosis. Furthermore, we demonstrate that glycogen synthase kinase (GSK3) alpha/beta interacts with BOK and regulates its level post translationally in breast cancer cells. Taken together, our results suggest that fine tuning of the levels of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 may decide the fate of cancer cells to either undergo apoptosis or proliferation. PMID- 29156772 TI - STAT3 and STAT5A are potential therapeutic targets in castration-resistant prostate cancer. AB - Mechanisms of castration-resistant prostate cancer (CRPC) are not well understood, thus hindering rational-based drug design. Activation of STAT3/5A, key components of the JAK/STAT pathway, is implicated in aggressive PC, yet their clinical relevance in CRPC remains elusive. Here, we evaluated the possible role of STAT3/5A in CRPC using immunological, quantitative mRNA expression profiling, and pharmacological methods. We observed a strong nuclear immunoreactivity for STAT3 and STAT5A in 93% (n=14/15) and 80% (n=12/15) of CRPC cases, respectively, compared with benign prostatic hyperplasia (BPH). We demonstrated that PC cells express varying levels of STAT3 and STAT5A transcripts. In addition, we demonstrate that pimozide, a psychotropic drug and an indirect inhibitor of STAT5, attenuated PC cells growth, and induced apoptosis in a dose-dependent manner. Furthermore, our analysis of the PC public data revealed that the STAT3/5A genes were frequently amplified in metastatic CRPC. These findings suggest that STAT3/5A potentially serves as a predictive biomarker to evaluate the therapeutic efficacy of a cancer drug targeting the JAK/STAT pathway. Since the JAK/STAT and AR pathways are suggested to be functionally synergistic, inhibition of the JAK/STAT signaling alone or together with AR may lead to a novel treatment modality for patients with advanced PC. PMID- 29156773 TI - Association of ACYP2 and MPHOSPH6 genetic polymorphisms with the risk of hepatocellular carcinoma in chronic hepatitis B virus carriers. AB - Hepatocellular carcinoma (HCC) is the dominant histologic type of primary liver cancer, and hepatitis B virus (HBV) infection is one of the major causes of HCC in the chronic HBV. Our study was investigated the association between the polymorphisms of ACYP2 and MPHOSPH6 genes and the risk of HCC induced by HBV infection. A total of 490 subjects were divided into two groups: 248 HBV patients with HCC (Case group), and 242 HBV patients without HCC (Control group). Unconditional logistic regression analysis was used to evaluate the association. The genetic association analysis revealed variant of rs12621038 in ACYP2 gene had a significant association with increasing the risk of HBV-induced HCC based on the genotype, dominant and additive model (P<0.05). Moreover, our results also showed that minor allele "C" of rs3751862 was prevalent in cases than controls (P<0.05), and rs3751862 significantly increased the risk of HCC in chronic HBV carriers under genotype and dominant model (P<0.05). In addition, the haplotype "T-G-G" in MPHOSPH6 showed a harmful factor for the HBV-induced HCC (P<0.05). The results suggested that ACYP2 and MPHOSPH6 as the plausible candidate genes may predict the risk of HCC after chronic HBV infection in Chinese Han population, and further investigations in studies with a larger sample size and other races are needed to validate our findings. These data provide a theoretical foundation for future studies of this correlation between the polymorphisms of ACYP2 and MPHOSPH6 genes and the HCC in chronic HBV carriers. PMID- 29156775 TI - Monophosphoryl lipid a attenuates radiation injury through TLR4 activation. AB - Ionizing radiation causes severe damage to human body, and normal tissue toxicity in cancer radiotherapy also limits its further application. It is urgently required to develop safe and effective radioprotector. Our previous study has shown that toll like receptor 4 (TLR4) was dispensable for basal radiation resistance. However, severe toxicity of its traditional agonist lipopolysaccharide limits the clinical application. In present study, we demonstrated that monophosphoryl lipid A (MPLA), a potent TLR4 agonist with low toxicity, effectively attenuated radiation injury on in vitro and in vivo. MPLA increased cell survival and inhibited cell apoptosis after irradiation, and cell cycle arrest was also inhibited. Radiosensitive tissues including spleen, intestine, bone marrow and testis were protected from radiation damages in a TLR4 dependent manner. We also found that myeloid differentiation factor 88 (MyD88) accounted more than Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF) for the radioprotective effects of MPLA. In conclusion, our finding suggests TLR4 agonist MPLA as a safe and effective radioprotector for clinical application. PMID- 29156774 TI - MicroRNAs as predictors for CNS relapse of systemic diffuse large B-cell lymphoma. AB - Systemic diffuse large B-cell lymphoma (DLBCL) is a potentially curable disease using current regimen of immunochemotherapy. Central nervous system (CNS) relapse is a complication that occurs in approximately 5% of DLBCL patients and is associated with a high fatality rate. Early identification of molecular markers for CNS involvement may serve for the highly needed accurate stratification of patients into risk groups regarding CNS relapse. MicroRNAs (miRNAs) are small non coding RNA molecules that regulate gene expression at the post-transcriptional level and are known to be involved in DLBCL pathophysiology. In this study, we utilized miRNA multiplex reading of systemic newly diagnosed DLBCL samples obtained from patients with clinical risk factors for CNS involvement whose disease course was distinguished by the presence or absence of subsequent CNS relapse. The analysis detected two differentially expressed miRNAs, miR-20a and miR-30d, that predict for CNS involvement. Replication of these results in different samples was used for validation. We performed bioinformatics miRNA target enrichment analysis to reveal a number of putative mechanisms for these miRNAs regulation of CNS relapse, including neuronal plasticity and WNT signaling pathway. Altogether, we show that the expression level of two miRNAs may have valuable information that may refine stratification for patients-at-risk for relapse with CNS involvement in DLBCL. Further larger scale studies are needed to shed light on the pathways involved in this disease. PMID- 29156776 TI - UCHL1 expression and localization on testicular development and spermatogenesis of Chinese giant salamanders. AB - Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), which is extensively expressed in vertebrates, is a deubiquitinating enzymes that inhibits the degradation of proteins by reversing ubiquitination modification. Herein, a 1087-bp sequence encoding UCHL1 was identified from the Chinese giant salamander (CGS; Andrias davidianus). The coding sequences (CDS) of UCHL1 encoded a putative poly peptide of 222 amino acids. The CGS UCHL1 isoforms were more related to their human and mouse counterparts. The phylogenic tree of vertebrate UCHL1 indicated that CGS UCHL1 has the closest relationship with human UCHL1 (up to 73.99 %). Before the gonads of male CGSs matured, the peak level of UCHL1 expression in testes appeared in 3-year-old CGSs according to RT-qPCR and western blot. In adult testes, the level of UCHL1 protein was lower in the breeding period than in the post-breeding period, whereas the level of UCHL1 protein in interstitial fluid of adult CGS testes was higher during the breeding period than during the post breeding period. In testicular seminiferous lobules in the developmental stage of CGSs, immunohistochemistry displayed three kinds of localizing patterns of UCHL1, including nuclear localization at half year old, cytoplasmic localization from one year to three years old, and extracellular localization in adult. In testicular seminiferous lobules of adult CGS, the different developmental germ cells were separated by cysts containing UCHL1 protein, but UCHL1 did not localize on the mature sperm. The results showed that extracellular UCHL1 loaded on exosomes, as a component of the homogeneous germ cell cysts, could regulate the synchronous development of sperm in testes of adult CGS. PMID- 29156777 TI - Patients with NSCLC may display a low ratio of p.T790M vs. activating EGFR mutations in plasma at disease progression: implications for personalised treatment. AB - Introduction: NSCLC harboring activating mutations of EGFR is highly sensitive to first-line EGFR-tyrosine kinase inhibitors (TKIs), but drug resistance depending on the EGFR mutation p.T790M will occur in about 50-60% of patients. Detailed information on the amount of p.T790M plasmatic level associated with resistance to EGFR-TKIs and guidance to treatment with p.T790M-effective TKI depending on these levels, is lacking. Methods: This study enrolled p.T790M-positive patients (n=49) affected by EGFR-mutated NSCLC at progression to first-line EGFR-TKIs and, in selected cases (n=5), after second-line treatment with osimertinib. Cell-free circulating tumor DNA (cftDNA) was extracted from plasma and the quantitative analysis of EGFR ex19del, p.L858R and p.T790M was performed by digital droplet PCR. Results: The mean amount of mutated alleles at progression to first-line EGFR-TKIs was 108,492 copies/ml for ex19del, 97,336 copies/ml for p.L858R, but only 8,754 copies/ml for p.T790M. There was no significant correlation between progression-free survival and the ratio of p.T790M over EGFR activating mutations. The analysis of cftDNA in 5 patients treated with osimertinib revealed a marked decrease of all EGFR mutant alleles. Conclusions: The amount of p.T790M in plasma can be much lower than activating EGFR mutations. Despite this finding, osimertinib is effective in p.T790M-positive patients. These results indicate that clones driving resistance to EGFR-TKIs represent a minority among cells bearing activating EGFR-mutations. In addition, the identification of a threshold level of p.T790M is not a strict requirement for the selection of patients to be treated with osimertinib, since treatment showed a decrease in all EGFR mutated cells. PMID- 29156778 TI - Worse disease-free, tumor-specific, and overall survival in surgically-resected lung adenocarcinoma patients with ALK rearrangement. AB - Introduction: This study determined the prevalence of anaplastic lymphoma kinase (ALK) rearrangement, and identified the associations of ALK rearrangement with clinicopathologic characteristics and treatment outcomes in patients with surgically-resected stage I-III lung adenocarcinoma. Methods: A total of 534 surgically-resected lung adenocarcinoma patients were studied. The prevalence of ALK protein over-expression was determined by a fully-automated immunochemistry assay (with mouse monoclonal Ventana D5F3 antibody), and the associations of ALK rearrangement with clinicopathologic characteristics and treatment outcomes were analyzed. Results: Forty-two (7.9%) of the 534 lung adenocarcinoma patients were ALK IHC-positive. ALK rearrangement was significantly associated with younger age (P = 0.011), high T-stage (P = 0.025), high pathologic stage (P = 0.002), solid predominant adenocarcinoma with mucin production (P = 0.006), invasive mucinous adenocarcinoma (P = 0.009), and receipt of adjuvant therapy after surgery (P = 0.036), but no significant associations were found between the ALK rearrangement and sex or smoking status. ALK IHC-positivity was significantly associated with a shorter disease-free survival, tumor-specific survival, and overall survival (P = 0.001, 0.026, and 0.007, respectively). Multivariate analysis showed that ALK IHC positivity was an adverse prognostic factor for disease-free survival (HR, 1.80; 95% CI 1.18-2.77; P = 0.007), tumor-specific survival (HR, 2.59; 95% CI 1.35 4.97; P = 0.004), and overall survival (HR, 1.92; 95% CI 1.07-3.44; P = 0.030). Conclusion: The clinical characteristics of patients with ALK-positive lung adenocarcinoma were similar to those of EGFR-mutated patients. ALK rearrangement was an adverse prognostic factor in surgically-resected lung adenocarcinoma patients. PMID- 29156779 TI - Selecting lncRNAs in gastric cancer cells for directed therapy with bioactive peptides and chemotherapy drugs. AB - Selecting lncRNAs for directed therapy with bioactive peptides and chemotherapy drugs may be an effective approach to treating gastric cancer (GC). We show genome-scale identification and characterization of differentially expressed lncRNAs in GC cells treated with a novel anti-cancer bioactive peptide (ACBP) and the chemotherapy drug oxaliplatin (ASLB). A total of 17,897 lncRNAs were identified through pairwise comparison, including 2,074 novel lncRNAs. Of those, 1,386 lncRNAs were differentially expressed (over 1.5-fold change vs. control, q value < 0.05) in response to ACBP and ASLB treatment. These included 914 upregulated and 472 downregulated lincRNAs. Functional annotation of these lncRNAs through Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis revealed they activate metabolic pathways and protein-binding processes. Moreover, suppression of the DNA replication process and upregulation of AMP activated protein kinase (AMPK) signaling in MKN45 cells exposed to ACBP alone or in combination with ASLB was predicted by hierarchical clustering analysis. By providing new insight into the transcriptomic effects of ACBP and ASLB in GC cells, these results provide the first evidence of ACBP inhibition of lincRNAs and may provide new mechanisms of action for ACBP and ASLB. PMID- 29156780 TI - Baicalein inhibits progression of osteosarcoma cells through inactivation of the Wnt/beta-catenin signaling pathway. AB - Osteosarcoma is a very common type of malignant bone tumor in children and young adults and aberrant activation of Wnt/beta-catenin signaling pathway has been discovered in osteosarcoma. The traditional Chinese medicine baicalein was proved to have anti-proliferative and anti-metastatic properties in osteosarcoma, but the mechanism remained poorly understood. In the present study, we assessed the effects of baicalein on osteosarcoma and detected the potential molecular mechanism. We found that baicalein significantly suppressed the proliferation of osteosarcoma cells in a concentration- and time-dependent manner. In additional, baicalein could induce apoptosis and cell cycle arrest and reduce cell motility. Moreover, the level of beta-catenin and its target genes, including c-myc, cyclinD1, and survivin significantly decreased in baicalein-treated osteosarcoma cells, whereas exogenous expression of beta-catenin could reverse the anti proliferative and anti-metastatic effects of baicalein. Subsequently, we established a 143B xenograft tumor model and found that baicalein treatment significantly inhibited tumor growth accompanied with inhibiting Wnt/beta-catenin pathway. Thus, these findings suggest that baicalein may be a potentially effective Chinese herbal medicine for therapeutics of osteosarcoma and Wnt/beta catenin signaling pathway may serve as an efficient molecular marker or predictive target for osteosarcoma. PMID- 29156781 TI - Toxoplasma gondii Clp family protein: TgClpB1 plays a crucial role in thermotolerance. AB - Caseinolytic peptidase B (ClpB) plays a pivotal role in suppressing and reversing protein aggregation. Toxoplasma gondii is an intracellular parasitic protozoan that infects a wide variety of mammals and birds and therefore is exposed to a broad range of living condition. We screened ToxoDB (http://ToxoDB.org) and identified 10 putative T. gondii genes encoding members of the Clp superfamily of caseinolytic proteases and chaperones. Of these, we focused on characterizing the Class I ATP-dependent molecular chaperones TgClpB1, TgClpB2, and TgClpB3. We found that TgClpB1, the most divergent of the five T. gondii Class I Clp ATPases, is cytoplasmic, TgClpB2 is found in the mitochondria of the parasites, and TgClpB3 is a ClpB with novel apicoplast localization. Knockout strains of TgClpB1 and TgClpB2 were established by CRISPR/Cas9 mutagenesis, and their complementing strains were constructed with FLAG-tag. Although knockout of TgClpB1 or TgClpB2 did not affect growth under normal circumstances, TgClpB1 was required for T. gondii thermotolerance. The growth, replication, and invasion capabilities of TgClpB1-deficient mutants were significantly inhibited after extracellular parasites were pretreated at 45 degrees C. Moreover, TgClpB1 were observed at the poles of the DeltaTgClpB1 FLAG-tagged strain treated at 42 degrees C. PMID- 29156782 TI - Trends in neoadjuvant chemotherapy use and oncological outcomes for muscle invasive bladder cancer in Japan: a multicenter study. AB - Objective: Despite benefits of neoadjuvant chemotherapy (NAC), the adoption of guideline recommendations for NAC use in patients with muscle-invasive bladder cancer (MIBC) has been slow. We aimed to evaluate temporal trends in NAC use and oncological outcomes in a representative cohort of patients with MIBC. Methods: We included 532 patients from 4 hospitals who underwent radical cystectomy (RC) for >= cT2 MIBC in 1996-2017. We retrospectively evaluated temporal changes in NAC use and progression-free and overall survival. Candidates for NAC were administered with either cisplatin- or carboplatin-based regimens. The impact of NAC on oncological outcomes was examined using multivariate Cox regression analysis with inverse probability of treatment weighting (IPTW) models. Results: Of 532 patients, 336 underwent NAC followed by RC (NAC group) and 196 underwent RC alone (Ctrl group). NAC use significantly increased from 10% (1996-2004) to 83% (2005-2016). The number of patients administered with cisplatin- and carboplatin-based regimens was 43 and 280, respectively. Oncological outcomes in the NAC group were significantly improved compared to those in the Ctrl group. Multivariable analysis with IPTW models revealed that NAC significantly improved oncological outcomes in patients with MIBC. A nomogram for 5-year overall survival predicted 16% improvement in patients undergoing NAC. Conclusions: NAC use for MIBC increased after 2005. Platinum-based NAC for MIBC potentially improves oncological outcomes. PMID- 29156783 TI - Isolation of circulating tumor cells from pancreatic cancer by automated filtration. AB - It is now widely recognized that the isolation of circulating tumor cells based on cell surface markers might be hindered by variability in their protein expression. Especially in pancreatic cancer, isolation based only on EpCAM expression has produced very diverse results. Methods that are independent of surface markers and therefore independent of phenotypical changes in the circulating cells might increase CTC recovery also in pancreatic cancer. We compared an EpCAM-dependent (IsoFlux) and a size-dependent (automated Siemens Healthineers filtration device) isolation method for the enrichment of pancreatic cancer CTCs. The recovery rate of the filtration based approach is dramatically superior to the EpCAM-dependent approach especially for cells with low EpCAM expression (filtration: 52%, EpCAM-dependent: 1%). As storage and shipment of clinical samples is important for centralized analyses, we also evaluated the use of frozen diagnostic leukapheresis (DLA) as source for isolating CTCs and subsequent genetic analysis such as KRAS mutation detection analysis. Using frozen DLA samples of pancreatic cancer patients we detected CTCs in 42% of the samples by automated filtration. PMID- 29156784 TI - Marital status and survival of patients with kidney cancer. AB - Background: The relationship between marital status and prognosis of kidney cancer has not been explored in detail. In this study, we aimed to investigate the impact of marital status on survival outcomes in kidney cancer. Methods: We used the Surveillance, Epidemiology and End Results (SEER) program to identify 112860 patients with kidney cancer diagnosed in 2004 through 2013. Kaplan-Meier methods and multivariable Cox regression models were used to analyze the influence of marital status on overall survival (OS) and cancer-specific survival (CSS). Results: Married patients had better 5-year OS and CSS compared with patients who were divorced/separated, widowed, and single. After adjusting for known confounders, unmarried patients were at greater risk of overall and cancer specific mortality, especially the widowed. Moreover, subgroup analysis showed that married still had better prognosis across different SEER stages, ages and sexes. Conclusions: Our study revealed that marriage is associated with better outcomes of both OS and CSS in kidney cancer patients. PMID- 29156785 TI - In silico and in vitro identification of inhibitory activities of sorafenib on histone deacetylases in hepatocellular carcinoma cells. AB - Although sorafenib has been approved for treating hepatocellular carcinoma (HCC), clinical results are not satisfactory. Polypharmacology (one drug with multiple molecular targets) is viewed as an attractive strategy for identifying novel mechanisms of a drug and then rationally designing more-effective next-generation therapeutic agents. In this study, a polypharmacological study of sorafenib was performed by mining the next-generation Connectivity Map (CMap) database, CLUE (https://clue.io/). We found that sorafenib may act as a histone deacetylase (HDAC) inhibitor based on similar gene expression profiles. In vitro experimental analyses demonstrated that sorafenib indirectly inhibited HDAC activity in both sorafenib-sensitive and -resistant HCC cells. A cancer genomics analysis using the cBioPortal online tool showed the frequent upregulation of HDAC mRNAs. Furthermore, HCC patients with higher expressions of HDAC1 and HDAC2 had worse overall survival. Taken together, our study suggests that inhibition of HDAC by sorafenib may provide clinical benefits against HCC, and enhancement of HDAC inhibitory activity of sorafenib may improve its therapeutic efficacy. In addition, our study also provides a novel strategy to study polypharmacology. PMID- 29156786 TI - Suicidal ideation among Chinese methadone-maintained patients: prevalence and correlates. AB - Heroin users are at high risk for suicide. However, the epidemiological profile of suicidal behaviors in Chinese methadone-maintained patients remains largely unknown. This study determined the prevalence and correlates of suicidal ideation among Chinese methadone-maintained patients. A total of 603 methadone-maintained patients were consecutively recruited from three methadone maintenance treatment (MMT) clinics in Wuhan, China, and administered with standardized questionnaires to collect sociodemographic, clinical, and psychological data. Suicidal ideation was measured with a single self-report question "Have you ever thought about committing suicide?". Depression and anxiety were assessed with Zung's Self rating Depression Scale and Zung's Self-rating Anxiety Scale, respectively. The one-month and lifetime prevalence rates of suicidal ideation were 17.9% and 58.9%, respectively. In multiple logistic regression, lifetime suicidal ideation was significantly associated with female (OR: 1.69), an educational attainment of primary school and below (OR: 1.47), fair and poor interpersonal relationship (OR: 2.20), a history of injecting heroin (OR: 1.60), depression (OR: 1.38), and anxiety (OR: 4.00). Methadone-maintained patients of MMT clinics have a high prevalence of suicidal ideation and therefore at high risk for suicide. Suicide prevention efforts at MMT clinics should include periodic evaluation of suicidality, psychosocial supports, and, when necessary, psychiatric treatment and crisis intervention. PMID- 29156787 TI - Natural compound bavachalcone promotes the differentiation of endothelial progenitor cells and neovascularization through the RORalpha-erythropoietin-AMPK axis. AB - In cardiovascular diseases, endothelial function is impaired and the level of circulating endothelial progenitor cells (EPCs) is low. This study investigated whether the natural bioactive component bavachalcone (BavaC) induces the differentiation of EPCs and neovascularization in vivo; the underlying mechanisms were also examined. We observed that the treatment of rat bone marrow-derived cells with a very low dose of BavaC significantly promoted EPC differentiation. In our hindlimb ischemia models, low-dose BavaC administered orally for 14 days stimulated the recovery of ischemic hindlimb blood flow, increased circulating EPCs, and promoted capillary angiogenesis. The BavaC treatment of rat bone marrow cells for 24 h initiated the AMP-activated protein kinase (AMPK) activity required for the differentiation of EPCs. Further testing revealed that BavaC and CGP52608, a retinoic acid receptor-related orphan receptor alpha (RORalpha) activator, enhanced the activity of RORalpha1 and EPO luciferase reporter gene. BavaC treatment also elevated EPO mRNA and protein expression in vitro and in vivo and the circulating EPO levels in rats. By contrast, the RORalpha antagonist VPR66 inhibited BavaC-induced EPO reporter activity, and differentiation of bone marrow cells into endothelial progenitor cells. Overall, this study revealed that BavaC promotes EPC differentiation and neovascularization through a RORalpha-EPO AMPK axis. BavaC can be used as a promising angiogenesis agent for enhancing angiogenesis and tissue repair. PMID- 29156788 TI - Modulation of HIF-1alpha and STAT3 signaling contributes to anti-angiogenic effect of YC-1 in mice with liver fibrosis. AB - Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The aim of the study was to evaluate the mechanisms of HIF-1alpha inhibitor, YC-1, during bile duct ligation (BDL)-induced liver fibrosis in mice. Liver fibrosis was induced in mice, and YC-1 was then given intraperitoneally (50 mg/kg) once daily following 5 days. Liver injuries mice that were treated with YC 1 showed improved inflammatory response and diminished angiogenesis and hepatic fibrosis. YC-1 treatment inhibited liver neutrophil infiltration, while a decreased in TNF-alpha signaling as well as macrophage aggregation. In addition, YC-1 downregulates iNOS and COX-2 levels by inhibiting the activation of NF kappaB and STAT3 phosphorylation by negative regulation the expression of SOCS1 and SOCS3 signaling. On the other hand, YC-1 decreased angiogenesis, as shown by the downregulation of hypoxia-inducible cascade genes, i.e. VEGF. YC-1 treatment resulted in a significant decrease in hepatic fibrogenesis, alpha-SMA abundance, and TGF-betaR1 expression as well as hypoxia were assessed using VEGFR1, vWF and HIF-1alpha immunostaining. These results suggest that multi-targeted therapies directed against angiogenesis, hypoxia, and fibrosis. Therefore, it may be suggested that YC-1 treatment may be a novel therapeutic agent for the treatment of liver disease. PMID- 29156789 TI - XRCC1 mediated the development of cervival cancer through a novel Sp1/Krox-20 swich. AB - Cervical cancer is the second leading cause of mortality among women. Impairment of the base excision repair (BER) pathway is one of the major causes of the initiation and progression of cervical cancer. However, whether the polymorphisms of the BER pathway components (i.e., HOGG1, XRCC1, ADPRT, and APE1) can affect the risk of cervical cancer remains unknown. Herein, we applied a hospital-based case-control study covering two independent cohorts and a subsequent functional assay to determine the roles of the single nucleotide polymorphisms (SNPs) of the BER pathway genes in cervical cancer. Results indicated that the XRCC1 rs3213245 (-77TC) TT genotype was associated with an increased risk of cervical cancer. The immunohistochemistry assay showed that XRCC1 protein expression levels were upregulated in cervical cancer patients with the XRCC1 rs3213245 CC genotype compared with the CT or TT genotypes. Further, results from ChIP assay showed that Sp1 could bind to the -77 site and that the rs3213245 C genotype promoted the binding of Sp1 to the XRCC1 promoter. Moreover, ChIP/Re-ChIP assays revealed that transcription factor Krox-20 was recruited to the XRCC1 rs3213245 mutation region and regulated the transcription of the XRCC1 gene by interacting with Sp1, ultimately mediated cervical cancer development. In summary, the findings indicated that the functional XRCC1 SNP rs3213245 was associated with the risk of cervical cancer based on the Sp1/Krox-20 switch. PMID- 29156791 TI - The relationship between stromal cell derived SPARC in human gastric cancer tissue and its clinicopathologic significance. AB - Background: We aimed to investigate the cellular source of secreted protein acidic and rich in cysteine (SPARC) in gastric cancer tissues and the relationship between SPARC expression and its prognostic significance. Methods: The expression of SPARC in 365 primary advanced gastric adenocarcinomas and 39 non-cancerous tissues was evaluated by immunohistochemical staining. Double immunofluorescence staining was used to reveal the cellular source of SPARC in tumor tissues. Western blotting and immunofluorescence staining were applied for verifying the endogenous expression of SPARC in human cell lines of gastric cancer and fibroblast. Results: Higher positivity of SPARC was observed in gastric cancer tissues than non-cancerous gastric tissues (P=0.000). The positivity of SPARC was related to age (P=0.032), tumor location (P=0.018), depth of tumor invasion (P=0.011), nodal metastasis (P=0.023), TNM stage (P=0.034), the differentiation degree (P=0.006) and pathological type (P=0.002) of gastric cancer. SPARC in gastric cancer tissues was mainly expressed by cancer-associated fibroblasts. SPARC also appeared in neovascular endothelial cells and a few tumor associated macrophages. The endogenous expression of SPARC in fibroblasts was suppressed by mucus-producing gastric adenocarcinoma cells(MKN-45). Increased SPARC expression in gastric cancer tissue was suggestive of a shorter cumulative survival in the patients with gastric adenocarcinoma, though this difference was not statistically significant(P>0.05). Conclusion: SPARC in human gastric cancer tissue was derived from the stromal cells and was mainly produced by cancer associated fibroblasts. Production of SPARC in fibroblasts was reduced by the mucus-producing gastric adenocarcinoma cells. PMID- 29156790 TI - Kaempferol induces autophagic cell death of hepatocellular carcinoma cells via activating AMPK signaling. AB - In the present study, we demonstrate that Kaempferol inhibited survival and proliferation of established human hepatocellular carcinoma (HCC) cell lines (HepG2, Huh-7, BEL7402, and SMMC) and primary human HCC cells. Kaempferol treatment in HCC cells induced profound AMP-activated protein kinase (AMPK) activation, which led to Ulk1 phosphorylation, mTOR complex 1 inhibition and cell autophagy. Autophagy induction was reflected by Beclin-1/autophagy gene 5 upregulation and p62 degradation as well as light chain 3B (LC3B)-I to LC3B-II conversion and LC3B puncta formation. Inhibition of AMPK, via AMPKalpha1 shRNA or dominant negative mutation, reversed above signaling changes. AMPK inhibition also largely inhibited Kaempferol-induced cytotoxicity in HCC cells. Autophagy inhibition, by 3-methyaldenine or Beclin-1 shRNA, also protected HCC cells from Kaempferol. Kaempferol downregulated melanoma antigen 6, the AMPK ubiquitin ligase, causing AMPKalpha1 stabilization and accumulation. We conclude that Kaempferol inhibits human HCC cells via activating AMPK signaling. PMID- 29156792 TI - Liquid biopsy in colon cancer: comparison of different circulating DNA extraction systems following absolute quantification of KRAS mutations using Intplex allele specific PCR. AB - Non-invasive molecular analysis of circulating tumor DNA (ctDNA) is a promising application in personalized cancer management, although there is still much to learn about the biological characteristics of ctDNA. The present study compared absolute amounts of KRAS mutated ctDNA and total circulating cell-free DNA (cfDNA) in colorectal cancer (CRC) patients (n=50) from various stages and healthy controls (n=8) by Intplex allele-specific and digital droplet PCR. In addition, the impact of two prominent extraction techniques (silica-based membrane vs. magnetic beads) on cfDNA and ctDNA recovery was analyzed in 38 paired samples from CRC patients and specific spike-in DNA controls. CfDNA fragment size was assessed using the Agilent 2100 Bioanalyzer. Relative quantities of total cfDNA quantities were measured using the Qubit fluorometer. Statistical analysis on total cfDNA yield revealed a strong correlation (r=0.976) between Qubit and absolute Intplex allele-specific PCR measurements in cancer patients and healthy controls. Total cfDNA was significantly increased in cancer patients compared to healthy controls, with the highest yield in distant metastatic disease. In line, the highest amount of ctDNA (1.35 ng/MUL) was found in patients with distant organ metastasis. Of great interest, the silica-based membrane method significantly promoted extraction of long cfDNA fragments. In contrast, the magnetic bead system more efficiently recovered short cfDNA fragments in serum of cancer patients. Further, a decreased KRAS allele frequency was observed in serum compared to plasma. This study suggests that the source of cfDNA and choice of pre-analytical extraction systems needs to be more carefully validated in routine clinical practice. PMID- 29156794 TI - Salen-Mn compounds induces cell apoptosis in human prostate cancer cells through promoting AMPK activity and cell autophagy. AB - Currently only docetaxel has been approved to be used in the chemotherapy of prostate cancer and new drugs are urgent need. Salen-Mn is a novel type of synthetic reagent bionic and exerts remarkable anticancer activities. However, the effect of Salen-Mn on human prostate cancer has not been elucidated yet. In this study, we found that treatment of PC-3 and DU145 human prostate cancer cells with Salen-Mn inhibited cell growth in dose and time dependent manner. Moreover, Salen-Mn induced cell apoptosis, and increased the expression of apoptotic proteins, such as cleaved caspase-3, cleaved PARP, and Bax, in PC-3 and DU145 prostate cancer cells. Furthermore, we found that Salen-Mn induced expression of LC3-I/II, which is protein marker of cell autophagy, in both dose and time dependent manners; in addition, Salen-Mn increased the phosphorylation of AMPK, suggesting that Salen-Mn increase cell autophagy through activating AMPK pathway. On the other hand, when PC-3 and DU145 cells were treated with Salen-Mn and 3-MA, an inhibitor of cell autophagy, the inhibitory effect of Salen-Mn on cell growth and the induction of apoptotic proteins were decreased. In addition, we found that Salen-Mn inhibited the growth of PC-3 cell xenografts in nude mice. In summary, our results indicate that Salen-Mn suppresses cell growth through inducing AMPK activity and autophagic cell death related cell apoptosis in prostate cancer cells and suggest that Salen-Mn and its derivatives could be new options for the chemical therapeutics in the treatment of prostate cancer. PMID- 29156793 TI - Methylation of microRNA-129-5P modulates nucleus pulposus cell autophagy by targeting Beclin-1 in intervertebral disc degeneration. AB - MicroRNAs play an important role in the etiology and progression of many diseases, including intervertebral disc degeneration (IVDD). The miRNA miR-129-5P regulates autophagy in various cancers, but its role in human nucleus pulposus (NP) cells is unclear. The present study investigated whether miR-129-5p regulates the expression of Beclin-1 which is known to induce autophagy in NP cells by evaluating their levels in normal and degenerative disc tissues and human NP cells transfected with miR-129-5P mimic or inhibitor by quantitative real-time (qRT-)PCR, western blotting, flow cytometry, and immunofluorescence analysis. A bioinformatics analysis was used to predict the relationship between miR-129-5P and Beclin-1, which was confirmed by the dual luciferase assay. DNA methylation status was assessed by methylation-specific PCR, and the effect of demethylation on miR-129-5P level and autophagy was examined by qRT-PCR, western blotting, and flow cytometry. We found that miR-129-5P expression was downregulated while that of Beclin-1 and LC3-II was upregulated in degenerative disc NP cells. Meanwhile, autophagy was reduced in human NP cells transfected with miR-129-5P mimic, whereas the opposite result was observed upon treatment with miR-129-5P inhibitor. Bioinformatics analysis and the luciferase reporter assay revealed that Beclin-1 is a target of and is inhibited by miR-129-5P. We also found that CpG islands in the miR-129-5P promoter region were hypermethylated in degenerative as compared to normal disc tissue. Thus, miR-129 5P blocks NP cell autophagy by directly inhibiting Beclin-1, a process that is dependent on miR-129-5P promoter methylation. PMID- 29156795 TI - Prognostic evaluation of platelet to lymphocyte ratio in patients with colorectal cancer. AB - Growing evidence indicates that inflammation plays an important role in cancer progression and prognosis; however, the prognostic role of platelet to lymphocyte ratio (PLR) in colorectal cancer (CRC) is unknown. A cohort of 1845 CRC patients from the Department of Surgical Oncology at The First Hospital of China Medical University (CMU-SO) was retrospectively analyzed. Harrell's concordance index (c index) was used to determine the optimal cut-off value of PLR and evaluate its predictive ability. Our results from CMU-SO indicated that the overall survival (OS) rate was significantly lower in the high-PLR group compared with the low-PLR group (P = 0.001). A similar result was observed for the cancer-specific survival (CSS) rate between these two groups (P = 0.001). The multivariate analysis indicated that high PLR was an independent prognostic indicator of poor OS (hazard ratio [HR] = 1.356, 95% confidence interval [CI] = 1.117-1.647, P = 0.002) and CSS (HR = 1.364, 95% CI = 1.111-1.675, P = 0.003). In addition, the c indexes of TNM staging combined with PLR were greater than those of TNM staging alone (OS: 0.768 vs. 0.732; CSS: 0.785 vs. 0.746). In conclusion, elevated PLR is a negative prognostic indicator of CRC and may serve as an additional index of the current TNM staging system for predicting CRC. PMID- 29156796 TI - Downregulation of DNA repair proteins and increased DNA damage in hypoxic colon cancer cells is a therapeutically exploitable vulnerability. AB - Surgical removal of colorectal cancer (CRC) liver metastases generates areas of tissue hypoxia. Hypoxia imposes a stem-like phenotype on residual tumor cells and promotes tumor recurrence. Moreover, in primary CRC, gene expression signatures reflecting hypoxia and a stem-like phenotype are highly expressed in the aggressive Consensus Molecular Subtype 4 (CMS4). Therapeutic strategies eliminating hypoxic stem-like cells may limit recurrence following resection of primary tumors or metastases. Here we show that expression of DNA repair genes is strongly suppressed in CMS4 and inversely correlated with hypoxia-inducible factor-1 alpha (HIF1alpha) and HIF-2alpha co-expression signatures. Tumors with high expression of HIF signatures and low expression of repair proteins showed the worst survival. In human tumors, expression of the repair proteins RAD51, KU70 and RIF1 was strongly suppressed in hypoxic peri-necrotic tumor areas. Experimentally induced hypoxia in patient derived colonospheres in vitro or in vivo (through vascular clamping) was sufficient to downregulate repair protein expression and caused DNA damage. Hypoxia-induced DNA damage was prevented by expressing the hydroperoxide-scavenging enzyme glutathione peroxidase-2 (GPx2), indicating that reactive oxygen species mediate hypoxia-induced DNA damage. Finally, the hypoxia-activated prodrug Tirapazamine greatly augmented DNA damage and reduced the fraction of stem-like (Aldefluorbright) tumor cells in vitro, and in vivo following vascular clamping. We conclude that decreased expression of DNA repair proteins and increased DNA damage in hypoxic tumor areas may be therapeutically exploited with hypoxia-activated prodrugs, and that such drugs reduce the fraction of Aldefluorbright (stem-like) tumor cells. PMID- 29156797 TI - JQ1 synergizes with the Bcl-2 inhibitor ABT-263 against MYCN-amplified small cell lung cancer. AB - Small cell lung cancer (SCLC) is a clinically aggressive cancer with very poor prognosis. Amplification of MYC family genes and overexpression of Bcl-2 protein are common in SCLC, and they are likely therapeutic targets for SCLC. Previous clinical study showed that single agent targeting Bcl-2 with ABT-263 was of limited efficacy in SCLC. In this study, we demonstrated for the first time that co-targeting of N-Myc and Bcl-2 resulted in marked synergistic antitumor effects in MYCN-amplified SCLC. We found that MYCN-amplified SCLC cells were highly sensitive to a Bromodomain and Extra-Terminal domain (BET) inhibitor JQ1, which was able to inhibit N-Myc protein expression. The inhibition of N-Myc by JQ1 induced the expression of Bim, and thereby sensitizing MYCN-amplified SCLC cells to ABT-263. The knockdown on Bim by siRNA reduced this JQ1/ABT-263 induced cell death. ABT-263 and JQ1 co-treatment in MYCN-amplified SCLC cells markedly disrupted Bim/Bcl-2 interaction, and prevented Bim's interaction with Mcl-1. Importantly, this JQ1/ABT-263 co-targeting substantially inhibited the growth of MYCN-amplified SCLC xenografts in vivo. Our study demonstrates a new JQ-1/ABT-263 co-targeting strategy that can be employed for MYCN-amplified SCLC with high efficacy. PMID- 29156798 TI - ARHI is a novel epigenetic silenced tumor suppressor in sporadic pheochromocytoma. AB - Pheochromocytoma (PCC) is related to germline mutations in 12 susceptibility genes. Although comparative genomic hybridization array has revealed some putative tumor suppressor genes on the short arm of chromosome 1 that are likely to be involved in PCC tumorigenesis, the molecules involved, except for those encoded by known susceptibility genes, have not been found in the generation of sporadic tumors. In the present work, we first identified that the unmethylated allele of Aplasia Ras homolog member I (ARHI) was deleted in most PCC tumors which retained a hypermethylated copy, while its mRNA level was significantly correlated with the unmethylated copy. De-methylation experiments confirmed that expression of ARHI was also regulated by the methylation level of the remaining allele. Furthermore, ARHI overexpression inhibited cell proliferation, with cell cycle arrest and induction of apoptosis, in ARHI-negative primary human PCC cells, whereas knockdown of ARHI demonstrated the opposite effect in ARHI positive primary human PCC cells. Finally, we demonstrated that ARHI has the ability to suppress pAKT and pErK1/2, to promote the expression of p21Waf1/Cip1 and p27Kip1, and also to increase p27Kip1 protein stability. In summary, ARHI was silenced or downregulated in PCC tissues harboring only one hypermethylated allele. ARHI contributes to tumor suppression through inhibition of PI3K/AKT and MAKP/ERK pathways, to upregulate cell cycle inhibitors such as p27Kip1. We therefore reasoned that ARHI is a novel epigenetic silenced tumor suppressor gene on chromosome 1p that is involved in sporadic PCC tumorigenesis. PMID- 29156799 TI - Asiatic acid protects against hepatic ischemia/reperfusion injury by inactivation of Kupffer cells via PPARgamma/NLRP3 inflammasome signaling pathway. AB - Hepatic ischemia/reperfusion (I/R) contributes to major complications in clinical practice affecting perioperative morbidity and mortality. Recent evidence suggests the key role of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammaosme activation on the pathogenesis of I/R injury. Asiatic acid (AA) is a pentacyclic triterpene derivative presented with versatile activities, including antioxidant, anti inflammation and hepatoprotective effects. This study was designed to determine whether AA had potential hepatoprotective benefits against hepatic I/R injury, as well as to unveil the underlying mechanisms involved in the putative effects. Mice subjected to warm hepatic I/R, and Kupffer cells (KCs) or RAW264.7 cells challenged with lipopolysaccharide (LPS)/H2O2, were pretreated with AA. Administration of AA significantly attenuated hepatic histopathological damage, global inflammatory level, apoptotic signaling level, as well as NLRP3 inflammasome activation. These effects were correlated with increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma). Conversely, pharmacological inhibition of PPARgamma by GW9662 abolished the protective effects of AA on hepatic I/R injury and in turn aggravated NLRP3 inflammasome activation. Activation of NLRP3 inflammasome was most significant in nonparenchymal cells (NPCs). Depletion of KCs by gadolinium chloride (GdCl3) further attenuated the detrimental effects of GW9662 on hepatic I/R as well as NLRP3 activation. In vitro, AA concentration-dependently inhibited LPS/H2O2 induced NLRP3 inflammaosome activation in KCs and RAW264.7 cells. Either GW9662 or genetic knockdown of PPARgamma abolished the AA-mediated inactivation of NLRP3 inflammasome. Mechanistically, AA attenuated I/R or LPS/H2O2-induced ROS production and phosphorylation level of JNK, p38 MAPK and IkappaBalpha but not ERK, a mechanism dependent on PPARgamma. Finally, AA blocked the deleterious effects of LPS/H2O2-induced macrophage activation on hepatocyte viability in vitro, and improved survival in a lethal hepatic I/R injury model in vivo. Collectively, these data suggest that AA is effective in mitigating hepatic I/R injury through attenuation of KCs activation via PPARgamma/NLRP3 inflammasome signaling pathway. PMID- 29156800 TI - Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. AB - Tumor sidedness has emerged as an important prognostic and predictive factor in the treatment of colorectal cancer. Recent studies demonstrate that patients with advanced right-sided colon cancers have a worse prognosis than those with left sided colon or rectal cancers, and these patient subgroups respond differently to biological therapies. Historically, management of patients with metastatic colon and rectal cancers has been similar, and colon and rectal cancer patients have been grouped together in large clinical trials. Clearly, the differences in molecular biology among right-sided colon, left-sided colon, and rectal cancers should be further studied in order to account for disparities in clinical outcomes. We profiled 10,570 colorectal tumors (of which 2,413 were identified as arising from the left colon, right colon, or rectum) using next-generation sequencing, immunohistochemistry, chromogenic in-situ hybridization, and fragment analysis (Caris Life Sciences, Phoenix, AZ). Right-sided colon cancers had higher rates of microsatellite instability, more frequent aberrant activation of the EGFR pathway including higher BRAF and PIK3CA mutation rates, and increased mutational burden compared to left-sided colon and rectal cancers. Rectal cancers had higher rates of TOPO1 expression and Her2/neu amplification compared to both left- and right-sided colon cancers. Molecular variations among right-sided colon, left-sided colon, and rectal tumors may contribute to differences in clinical behavior. The site of tumor origin (left colon, right colon, or rectum) should certainly be considered when selecting treatment regimens and stratifying patients for future clinical trials. PMID- 29156801 TI - Genomic characterization of human papillomavirus-positive and -negative human squamous cell cancer cell lines. AB - Human cancer cell lines are the most frequently used preclinical models in the study of cancer biology and the development of therapeutics. Although anatomically diverse, human papillomavirus (HPV)-driven cancers have a common etiology and similar mutations that overlap with but are distinct from those found in HPV-negative cancers. Building on prior studies that have characterized subsets of head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESC) cell lines separately, we performed genomic, viral gene expression, and viral integration analyses on 74 cell lines that include all readily-available HPV-positive (9 HNSCC, 8 CESC) and CESC (8 HPV-positive, 2 HPV negative) cell lines and 55 HPV-negative HNSCC cell lines. We used over 700 human tumors for comparison. Mutation patterns in the cell lines were similar to those of human tumors. We confirmed HPV viral protein and mRNA expression in the HPV positive cell lines. We found HPV types in three CESC cell lines that are distinct from those previously reported. We found that cell lines and tumors had similar patterns of viral gene expression; there were few sites of recurrent HPV integration. As seen in tumors, HPV integration did appear to alter host gene expression in cell lines. The HPV-positive cell lines had higher levels of p16 and lower levels of Rb protein expression than did the HPV-negative lines. Although the number of HPV-positive cell lines is limited, our results suggest that these cell lines represent suitable models for studying HNSCC and CESC, both of which are common and lethal. PMID- 29156802 TI - Efficacy and safety of first-line pemetrexed plus carboplatin followed by single agent pemetrexed maintenance in elderly Chinese patients with non-squamous non small-cell lung cancer. AB - Chemotherapy with pemetrexed plus carboplatin followed by pemetrexed maintenance therapy is a first-line regimen for patients with advanced non-squamous non-small cell lung cancer. This phase II clinical study investigated the efficacy and safety of this regimen in older patients (aged >=65 years) with advanced non squamous non-small-cell lung cancer. All patients received 4 courses of induction therapy with pemetrexed (500 mg/m2) combined with carboplatin once every 3 weeks. If patients had stable disease or achieved a complete or partial tumor response after 4 courses of pemetrexed + carboplatin therapy, maintenance treatment with pemetrexed monotherapy was administered until either disease progression or intolerable toxicity occurred. The primary endpoint was progression-free survival, while secondary endpoints were the objective response rate, overall survival, and tolerability. A total of 105 elderly patients (median age, 71 years) with advanced lung adenocarcinoma were enrolled in the trial. The ORR with induction therapy was 36.2% and the disease control rate was 70.5%. Sixty-two patients (59.0%) subsequently received pemetrexed maintenance therapy. The median progression-free survival for all patients was 8.23 months (95% CI 5.85-10.62 months) and the median overall survival was 22.6 months (95% CI 20.09-25.11 months). Grade 3 or greater toxicities included neutropenia (15.3%), thrombocytopenia (9.5%), anemia (8.6%), leukopenia (4.8%), nausea (1.0%), vomiting (1.0%), and fatigue (1.0%). No treatment-related deaths occurred. These results indicate that pemetrexed combined with carboplatin therapy maintained by single-agent pemetrexed treatment of elderly patients with advanced non-squamous non-small-cell lung cancer was effective and tolerable. ClinicalTrials.gov identifier: NCT01860508. PMID- 29156803 TI - TET1 inhibits cell proliferation by inducing RASSF5 expression. AB - Tet methylcytosine dioxygenases (TETs) catalyze the oxidative reactions of 5 methylcytosine to 5-hydroxymethylcytosine (5hmC). However, TET1 roles in ovarian cancer cell growth are unknown. Here, we show that ectopic expression of TET1 increased 5hmC levels, and inhibited proliferation and colony formation in ovarian cancer cell lines. Furthermore, in vitro and in vivo functional studies demonstrated that TET1 overexpression is necessary for the suppression of ovarian cancer growth, whereas depletion of TET1 expression had the opposite effect. Furthermore, the results of RNA-seq and qRT-PCR analyses identified a tumor suppressor, Ras association domain family member 5 (RASSF5), as the key downstream target of TET1. TET1 promotes RASSF5 expression by demethylating a CpG site within RASSF5 promoter. Up-regulated RASSF5 expression leads to the suppression of ovarian cancer cells growth. Additionally, we demonstrated that inhibition of CUL4-DDB1 ubiquitin ligase complex decrease 5hmC levels in ovarian cancer cells. These results provide new insights into the understanding of how ovarian cancers develop and grow, and identify TET1 as a key player in this process. PMID- 29156804 TI - HOTAIR regulates HK2 expression by binding endogenous miR-125 and miR-143 in oesophageal squamous cell carcinoma progression. AB - Esophageal Squamous Cell Carcinoma (ESCC) is one of the most common malignant cancers worldwide with a high death rate worldwide. Long non-coding RNA (LncRNA) has been recently demonstrated to play a critical role in ESCC. LncRNA HOTAIR played important regulatory roles in ESCC. We highlight the molecular mechanisms by which HOTAIR could influence the expression of Hexokinase 2 (HK2) in ESCC through binding miR-125 and miR-143 directly. Taken together, this study identified a functional lncRNA HOTAIR involved with regulation of glycolysis via miRNA-125/miRNA-143-HK2 in ESCC cells. The "competitive endogenous RNA" (ceRNA) model of HOTAIR/miR-125 and miR143/HK2 interaction might serve as important targets for ESCC diagnosis and therapy. PMID- 29156805 TI - Circulating tumor DNA shows variable clonal response of breast cancer during neoadjuvant chemotherapy. AB - Circulating tumor DNA (ctDNA) correlates with tumor burden and provides early detection of treatment response and tumor genetic alterations in breast cancer (BC). In this study, we aimed to identify genetic alterations during the process of tumor clonal evolution and examine if ctDNA level well indicated clinical response to neoadjuvant chemotherapy (NAC) and BC recurrence. We performed targeted ultra-deep sequencing of plasma DNAs, matched germline DNAs and tumor DNAs from locally advanced BC patients. Serial plasma DNAs were collected at diagnosis, after the 1st cycle of NAC and after curative surgery. For the target enrichment, we designed RNA baits covering a total of ~202kb regions of the human genome including a total of 82 cancer-related genes. For ctDNA, 15 serial samples were collected and 87% of plasma SNVs were detected in 13 BC samples that had somatic alterations in tumor tissues. The TP53 mutation was most commonly detected in primary tumor tissues and plasma followed by BRCA1 and BRCA2. At BC diagnosis, the amount of plasma SNVs did not correlate with clinical stage at diagnosis. With respect to the therapeutic effects of NAC, we found two samples in which ctDNA disappeared after the 1st NAC cycle achieved a pathologic complete response (pCR). In addition, the amount of ctDNA correlated with residual cancer volume detected by breast MRI. This targeted ultra-deep sequencing for ctDNA analysis would be useful for monitoring tumor burden and drug resistance. Most of all, we suggest that ctDNA could be the earliest predictor of NAC response. PMID- 29156806 TI - Association between SNPs in microRNA machinery genes and gastric cancer susceptibility, invasion, and metastasis in Chinese Han population. AB - Objective: The present study investigates the influence of genetic variants in miRNA machinery genes (DROSHA, DICER, AGO1, and GEMIN4) on gastric cancer in Chinese Han population, further revealing the genetic mechanisms of gastric cancer occurrence and development. Methods: Genotyping of single nucleotide polymorphisms (SNPs) was performed in 628 patients with GC and 502 frequency matched (age and gender) controls by the high resolution melting (HRM) method. Results: The SNPs rs3742330 (DICER) and rs7813 (GEMIN4) were associated with susceptibility to gastric cancer (P = 0.002 and 0.010, respectively). Stratified analysis showed that the G allele of rs3742330 and genotype TT as well as T allele of rs7813 were associated with a later stage of gastric cancer (P=0.027, 0.032 and 0.018, respectively). Furthermore, the genotype TT and T allele of rs7813 appeared to be associated with a higher level of lymphatic metastasis of gastric cancer (P=0.021 and 0.030, respectively), while the genotype AA and A allele of rs636832 (AGO1) were correlated with a lower level of lymphatic metastasis of gastric cancer (P=0.016 and 0.041, respectively). There was no significant association between rs10719 (DROSHA) and gastric cancer. Conclusion: The present data demonstrated that genetic variants in miRNA machinery genes had a significant association with GC susceptibility (DICER and GEMIN4) and malignant behavior such as tumor stage (DICER and GEMIN4) and lymphatic metastasis of GC (GEMIN4 and AGO1) in Chinese Han population. PMID- 29156808 TI - Serum hepatitis B surface antigen levels predict insignificant fibrosis and non cirrhosis in hepatitis B e antigen positive patients with normal or mildly elevated alanine transaminase levels. AB - BACKGROUND/AIMS: We aimed to evaluate the diagnostic value of serum hepatitis B surface antigen (HBsAg) levels for liver fibrosis in hepatitis B e antigen positive [HBeAg (+)] chronic hepatitis B (CHB) patients with alanine transaminase (ALT)<=twice upper limit of normal (ULN). METHODS: 505 patients who underwent liver biopsies and HBsAg quantitative detections were included. Liver histology was scored using METAVIR scoring system. The area under the receiver-operator curve (AUROC) was used to determine the diagnostic accuracy. RESULTS: Of 505 CHB patients, 333 have HBeAg (+), and 172 have HBeAg (-). HBsAg levels and METAVIR fibrosis scores showed strong correlation (r=-0.50, p<0.001) in HBeAg (+) patients, but no correlation in HBeAg (-) patients (r=0.09, p=0.239). HBeAg (+) patients with insignificant fibrosis (F0-1) exhibited higher HBsAg levels than those with significant fibrosis (F2-4) (4.60 vs 4.12 log10IU/ml, p<0.001). HBeAg (+) patients with non-cirrhosis (F0-3) exhibited higher HBsAg levels than those with cirrhosis (F4) (4.48 vs 3.95 log10IU/ml, p<0.001). In this study, the AUROC of HBsAg was 0.86 for diagnosing insignificant fibrosis, and 0.91 for diagnosing non-cirrhosis in HBeAg (+) CHB patients. CONCLUSIONS: Serum HBsAg level can identify insignificant fibrosis and non-cirrhosis in HBeAg (+) CHB patients with ALT<=2 ULN, and thus avoid liver biopsy in this population. PMID- 29156807 TI - Halofuginone inhibits TGF-beta/BMP signaling and in combination with zoledronic acid enhances inhibition of breast cancer bone metastasis. AB - More efficient therapies that target multiple molecular mechanisms are needed for the treatment of incurable bone metastases. Halofuginone is a plant alkaloid derivative with antiangiogenic and antiproliferative effects. Here we demonstrate that halofuginone is an effective therapy for the treatment of bone metastases, through multiple actions that include inhibition of TGFbeta and BMP-signaling. Halofuginone blocked TGF-beta-signaling in MDA-MB-231 and PC3 cells showed by inhibition of TGF-beta-induced Smad-reporter, phosphorylation of Smad-proteins, and expression of TGF-beta-regulated metastatic genes. Halofuginone increased inhibitory Smad7-mRNA and reduced TGF-beta-receptor II protein. Proline supplementation but not Smad7-knockdown reversed halofuginone-inhibition of TGF beta-signaling. Halofuginone also decreased BMP-signaling. Treatment of MDA-MB 231 and PC3 cells with halofuginone reduced the BMP-Smad-reporter (BRE)4, Smad1/5/8-phosphorylation and mRNA of the BMP-regulated gene Id-1. Halofuginone decreased immunostaining of phospho-Smad2/3 and phospho-Smad1/5/8 in cancer cells in vivo. Furthermore, halofuginone decreased tumor-take and growth of orthotopic tumors. Mice with breast or prostate bone metastases treated with halofuginone had significantly less osteolysis than control mice. Combined treatment with halofuginone and zoledronic-acid significantly reduced osteolytic area more than either treatment alone. Thus, halofuginone reduces breast and prostate cancer bone metastases in mice and combined with treatment currently approved by the FDA is an effective treatment for this devastating complication of breast and prostate-cancer. PMID- 29156809 TI - Adipose-derived stem cells-seeded bladder acellular matrix graft-silk fibroin enhances bladder reconstruction in a rat model. AB - The unfavourable clinical outcomes of host cell-seeded scaffolds for bladder augmentation warrant improved bioactive biomaterials. This study aimed to examine the feasibility of adipose-derived stem cells (ASCs)-seeded bilayer bladder acellular matrix graft (BAMG)-silk fibroin (SF) scaffold in enhancing bladder reconstruction. Sprague Dawley rats were randomly divided into three groups: the BAMG-SF-ASCs group, the acellular BAMG-SF group and the cystotomy group. The BAMG SF-ASCs group was sampled at 2, 4 and 12 weeks, and compared with the other groups at 12 weeks. In the BAMG-SF-ASCs group, the normal bladder contour was reformed similar to that in the cystotomy group, with abundant urothelium and smooth muscle regeneration, as well as a suitable scaffold degradation speed, and trivial fibrosis and inflammation. The ASCs seeded in BAMG-SF were maintained in the regenerated region during the 12-week experimental period and significantly enhanced the vessel density, nerve regeneration and bladder function compared with acellular BAMG-SF. In addition, the BAMG-SF-ASCs group presented elevated levels of SDF-1alpha, VEGF and their receptors, with an obvious increase in ERK 1/2 phosphorylation. BAMG-SF is a promising biomaterial for ASCs seeding to facilitate bladder augmentation and demonstrated an enhanced angiogenic potential possibly related to the SDF-1alpha/CXCR4 pathway via ERK 1/2 activation. PMID- 29156810 TI - PSC-derived Galectin-1 inducing epithelial-mesenchymal transition of pancreatic ductal adenocarcinoma cells by activating the NF-kappaB pathway. AB - Galectin-1 has previously been shown to be strongly expressed in activated pancreatic stellate cells (PSCs) and promote the development and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms by which Galectin-1 promotes the malignant behavior of pancreatic cancer cells remain unclear. In this study, we examined the effects of Galectin-1 knockdown or overexpression in PSCs co-cultured with pancreatic cancer (PANC-1) cells. Immunohistochemical analysis showed expression of epithelial-mesenchymal transition (EMT) markers and MMP9 were positively associated with the expression of Galectin-1 in 66 human PDAC tissues. In addition, our in vitro studies showed PSC-derived Galectin-1 promoted the proliferation, invasion, and survival (anti apoptotic effects) of PANC-1 cells. We also showed PSC-derived Galectin-1 induced EMT of PANC-1 cells and activated the NF-kB pathway in vitro. Our mixed (PSCs and PANC-1 cells) mouse orthotopic xenograft model indicated that overexpression of Galectin-1 in PSCs significantly promoted the proliferation, growth, invasion, and liver metastasis of the transplanted tumor. Moreover, Galectin-1 overexpression in PSCs was strongly associated with increased expression of EMT markers in both the orthotopic xenograft tumor in the pancreas and in metastatic lesions of naked mice. We conclude that PSC-derived Galectin-1 promotes the malignant behavior of PDAC by inducing EMT via activation of the NF-kappaB pathway. Our results suggest that targeting Galectin-1 in PSCs could represent a promising therapeutic strategy for PDAC progression and metastasis. PMID- 29156811 TI - FcGBP was upregulated by HPV infection and correlated to longer survival time of HNSCC patients. AB - FcGBP was normally found in intestinal and colonic epithelia, gallbladder, cystic duct, bronchus, submandibular gland, cervix uteri and in fluids secreted by these cells in humans, and was down-regulated during colon carcinogenesis. We found FcGBP gene expression was decreased in HNSCC tissues compared to surgical safety border tissues while TGF-beta expression level increased in HNSCC tissues, and higher FcGBP expression level was correlated to longer OS time of HNSCC patients. FcGBP expression level was higher in HPV-positive HNSCC tissues compared to HPV negative HNSCC tissues, while TGF-beta expression level was lower in HPV-positive HNSCC tissues. Gene expression level of FcGBP and TGF-beta was negatively correlated in HNSCC tissues. FcGBP expression level increased after HPV E6 overexpression in HPV-negative HNSCC cells, and TGF-beta could inhibit the up regulation of FcGBP after HPV E6 or FcGBP overexpression in HPV-negative HNSCC cells. The migration capability was inhibited after FcGBP overexpression, and TGF beta could counteract the inhibition of migration caused by FcGBP overexpression. FcGBP gene expression level was correlated to the expression levels of EMT markers. In conclusion, FCGBP expression was upregulated by HPV infection while inhibited by TGF-beta, and was correlated to the prognosis of HNSCC patients. PMID- 29156812 TI - Correlation of DRD2 mRNA expression levels with deficit syndrome severity in chronic schizophrenia patients receiving clozapine treatment. AB - Schizophrenia is a complex, severe, chronic psychiatric disorder, and the associated deficit syndrome is widely regarded as an important clinical aspect of schizophrenia. This study analyzed the relationship of deficit syndrome severity with the mRNA levels of members of signaling pathways that associate with the pathophysiology of schizophrenia, including the dopamine D2 receptor (DRD2), protein kinase B (AKT1), and phosphoinositide-3 kinase (PI3KCB), in peripheral blood leukocytes (PBLs) of 20 healthy controls and 19 chronic schizophrenia patients with long-term clozapine treatment. The DRD2 expression levels in chronic schizophrenia group were statistically higher than those in controls (t=2.168, p=0.037). Moreover, in chronic schizophrenia group, correlations were observed between the expression levels of DRD2 and PI3KCB (r=0.771, p<0.001), DRD2 and AKT1 (r=0.592, p=0.008), and PI3KCB and AKT1 (r=0.562, p=0.012) and between the DRD2 mRNA levels and the Proxy for the Deficit Syndrome score (r=0.511, p=0.025). In control group, the correlation between PI3KCB expression levels and DRD2 expression levels was only observed (r=0.782, p<0.001). In conclusion, a correlation was observed between increased deficit syndrome severity and elevated expression levels of DRD2 in PBLs of chronic schizophrenia patients receiving long-term clozapine treatment. PMID- 29156813 TI - Association of variant in the ADIPOQ gene and functional study for its role in atherosclerosis. AB - The burden of atherosclerosis is heritable and associated with elevated risk of developing CVDs. Here, we evaluated genetic variants of adiponectin (ADIPOQ) gene, which has important role in anti- atherosclerosis, with risk of atherosclerosis among a large Chinese population. Our results show that rs74577862 was significantly associated with risk of atherosclerosis (OR=2.08; 95%CI=1.48-2.91; P=2.2*10-5). When stratified by atherosclerosis site, rs74577862 was associated with increased risk of both carotid atherosclerosis (OR=2.03; 95%CI=1.35-3.06; P=6.3*10-4) and coronary atherosclerosis (OR=2.11; 95%CI=1.44 3.09; P=1.1*10-4). In addition, we also carried out site-directed mutagenesis and dual-luciferase reporter assay to confirm the positive finding, which presents a significant decrease in luciferase expression for the reconstructed plasmid with rs74577862 A allele in comparison to the one with G allele (P<0.001). Real-time PCR also confirmed the findings above. These results strongly suggest that the functional SNP, ADIPOQ rs74577862 might contribute to atherosclerosis susceptibility. PMID- 29156814 TI - Screening circular RNA expression patterns following focal cerebral ischemia in mice. AB - Circular RNAs (circRNAs) have been demonstrated to act as microRNA (miRNA) sponges and they play important roles in regulating gene expression through a circRNA-miRNA-gene pathway. The specific roles of circRNAs in the pathogenesis of cerebral ischemia, however, are still unclear. Thus, the aim of this study is to determine circRNA expression profiles in the ischemic brain after stroke, which was induced by 45 min of transient middle cerebral artery occlusion (MCAO). The results from the circRNA microarrays revealed that 1027 circRNAs were significantly altered 48 hours after reperfusion in the ischemic brain compared with the sham group. Among them, 914 circRNAs were significantly upregulated, and the remaining 113 were significantly downregulated. In addition, the expressions of the three selected circRNAs, mmu_circRNA_40001, mmu_circRNA_013120, and mmu_circRNA_40806, were verified using quantitative real-time polymerase chain reaction (qRT-PCR). After predicting their target genes, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were further used to predict the associated significant cell signaling pathways and functions. The results show that the most enriched pathways are associated with the Rap1 signaling pathway and the Hippo signaling pathway, which regulate cell survival and death. Finally, we constructed an interaction network of circRNA-miRNA-target genes, including 13 miRNAs and their corresponding genes, indicating that changes in circRNA are associated with genes related with brain injury and recovery. In conclusion, circRNAs are complicated in the pathological development of brain injury after stroke, suggesting novel diagnostic and therapeutic targets for stroke therapy. PMID- 29156815 TI - The effect of aspirin on circulating netrin-1 levels in humans is dependent on the inflammatory status of the vascular endothelium. AB - In atherosclerotic animal models, the cyclo-oxygenase (COX)-inhibitor aspirin counteracts downregulation of endothelial-derived netrin-1, thus reducing arterial inflammation. We here explored the effect of aspirin on netrin-1 in healthy subjects undergoing influenza immunisation, which is an established experimental model of inflammation-related endothelial dysfunction. Our data showed that netrin-1 undergoes reduction (-29.25% from baseline; p=0.0017) in the presence of endothelial activation (VCAM-1 rose by 9.98% 2-days post-vaccination; p=0.0022). Aspirin counteracted vaccine-induced endothelial activation and reduction of netrin-1 in a dose-dependent manner (-3.06% and -17.03% from baseline at a dose of 300mg and 75mg respectively; p=0.0465 and p>0.05 vs untreated). Clopidogrel, which was used as a comparator due to its similar anti platelet activity, also reduced endothelial activation but, unlike aspirin, enhanced netrin-1 levels (+20.96% from baseline; p=0.0033 vs untreated). A correlation analysis incorporating cytokines, hs-CRP, VCAM-1, TXB2 and PGE2, showed that changes in netrin-1 were directly related to PGE2 variations only (r=0.6103; p=0.0002). In a separate population of 40 healthy unimmunised volunteers, 28-day treatment with aspirin 300mg reduced netrin-1 (-18.76% from baseline; p=0.0012) without affecting endothelial markers or hs-CRP; as expected, aspirin suppressed TXB2 and PGE2. Netrin-1 and PGE2 levels were directly related (r=0.358; p=0.0015), but other parameters including TXB2, hs-CRP and endothelial markers, were not. In conclusion, aspirin counteracts downregulation of netrin-1 following endothelial dysfunction due to its anti-inflammatory effect on the activated endothelium. However, inhibition of COX-dependent prostanoids negatively modulates netrin-1 synthesis in healthy subjects, and this could give rise to aspirin-dependent reduction in netrin-1 under steady state conditions. PMID- 29156816 TI - Mixed subtype thyroid cancer: A surveillance, epidemiology, and end results database analysis. AB - The prognosis of patients with mixed subtype thyroid cancer (MSTC) is unclear. The present study compared the prognoses of MSTC, papillary thyroid cancer (PTC), and follicular thyroid cancer (FTC) to provide a new perspective regarding the treatment guidelines for these diseases. We evaluated data from patients with thyroid cancer who were included in the Surveillance, Epidemiology, and End Results database between 2004 and 2013. Patient mortality was evaluated using Cox proportional hazards regression analyses and Kaplan-Meier analyses with log-rank tests. The univariate Cox regression analysis showed that the cancer-specific survival rate for MSTC was lower than that for PTC and FTC. However, in the multivariate Cox regression analysis, the cancer-specific survival rate for MSTC was similar to that for PTC and FTC. Before matching influence factors, the cancer-specific survival rate for MSTC was lower than that for PTC and FTC. However, after propensity score matching for relevant factors, the cancer specific survival rate for MSTC was also similar to that for PTC and FTC. Our result would be beneficial and provide a guideline for the understanding of MSTC. PMID- 29156817 TI - Near-infrared photothermal therapy using anti-EGFR-gold nanorod conjugates for triple negative breast cancer. AB - Current EGFR-targeted therapy for triple negative breast cancer (TNBC) has produced disappointing results. A rational therapeutic strategy to improve EGFR targeted treatment for TNBC is therefore needed. In this study we evaluated the feasibility of treating TNBC using photoacoustic imaging (PAI)-guided near infrared photothermal therapy (NIR-PTT) with anti-EGFR-conjugated gold nanorods (anti-EGFR-GN). NIR-PTT combined with anti-EGFR-GN exerted synergistic anti proliferative and apoptotic actions through upregulation of HSP70 and cleaved caspase-3, downregulation of Ki-67 and EGFR, and inhibition of several intracellular signaling molecules (mTOR, AKT, ERK1/2 and FAK). These combined effects give this approach significant efficacy. Our findings suggest PAI-guided NIR-PTT using anti-EGFR-GN represent a novel and effective strategy for EGFR targeted therapy in TNBC. PMID- 29156818 TI - A plasmid containing CpG ODN as vaccine adjuvant against grass carp reovirus in grass carp Ctenopharyngodon idella. AB - CpG oligodeoxynucleotides (ODNs) are proved to have strong immune stimulatory activity. Plasmids containing CpG ODNs could be conveniently and low-costly used as vaccine adjuvant. However, they are different among various plasmids, motif repeats, species, etc. In the present study, plasmid pcDNA3.1 (+) containing five repetitions of CpG ODN 1670A named pcDNA3.1-1670A*5 with strong immunostimulation was screened out from twelve recombinant plasmids and three empty vectors by cell proliferation activity, interferon promoter activities and immune related gene expressions in CIK cells. It works through TLR9-mediated signaling pathway, triggering the immune related genes expression. Furthermore, the potentiality of pcDNA3.1-1670A*5 as adjuvant was tested in vivo. pcDNA3.1-1670A*5 was co inoculated with inactivated GCRV vaccine on grass carp fingerlings. Immunoglobulins (IgM, IgD, IgZ), TLR9, IFNgamma2, IFN1, TNF-alpha, Mx2 and VP4 were examined. Ultimately, pcDNA3.1-1670A*5 significantly enhanced the expressions of IgM in serum, head kidney and spleen, recognition receptor TLR9 as well as antiviral effector molecule Mx2, and inhibited GCRV proliferation in head kidney and spleen tissues. The present study explored the application and mechanism of plasmid containing CpG ODN as high-efficient adjuvant to promote efficiency of vaccine and control disease in grass carp, which will contribute to the development of new type CpG ODN adjuvant in aquaculture industry. PMID- 29156820 TI - A water-soluble polysaccharide from Grifola frondosa induced macrophages activation via TLR4-MyD88-IKKbeta-NF-kappaB p65 pathways. AB - Here, the immunomodulatory effects of water-soluble polysaccharide from Grifola frondosa on RAW264.7 macrophages and its molecular mechanisms were investigated. G. frondosa polysaccharide could obviously enhance immunostimulatory activity such as the release of nitric oxide and cytokine production. Western blotting results showed that G. frondosa polysaccharide elevated the TLR4, which might act as an upstream regulator of MyD88 induced G. frondosa polysaccharide. MyD88 promoted IKKbeta in endochylema and translocate NF-kappaB p65 subunit into the nucleus which increased the NO production and cytokine/chemokines level. The results suggested that G. frondosa polysaccharide activated macrophages through TLR4-MyD88-IKKbeta-NF-kappaBp65 signaling pathways. PMID- 29156819 TI - miR-29a-3p suppresses cell proliferation and migration by downregulating IGF1R in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC), the most common primary tumor of the liver, has a poor prognosis and rapid progression. MicroRNAs (miRNAs) play important roles in carcinogenesis and tumor progression. Insulin-like growth factor 1 receptor (IGF1R) is a transmembrane heterotetrameric protein that has been reported to promote transformation to malignancy and cancer cell proliferation and survival. In this study, we found that the expression of miR-29a-3p was downregulated in HCC patients, resulting in poor survival rates. Contrastingly, the overexpression of miR-29a-3p significantly inhibited proliferation and migration in HepG2 cells. miR-29a-3p directly targeted IGF1R and down-regulated its expression. Moreover, knockdown of IGF1R led to the increased production of chemokine ligand 5 (CCL5). In tumor lesions, the local expression of CCL5 negatively affected the expression of IGF1R. Transwell analysis showed that CCL5 was important for the chemotactic movement of CD8+ T lymphocytes. The expression of CCL5 in HCC tissues positively correlated with the expression of CD8+ T lymphocyte surface marker, CD8. Patients with high CCL5 expression exhibited better survival. Our results revealed that miR-29a-3p is a tumor suppressor gene that acts by directly repressing the oncogene IGF1R, which takes part in immunoregulation in tumor microenvironments in HCC, implying that miR-29a-3p could be a potential target for HCC treatment. PMID- 29156821 TI - Prognostic significance of circulating tumor cells in non-small cell lung cancer patients undergoing chemotherapy. AB - The utility of circulating tumor cells (CTCs) as prognostic biomarkers in non small cell lung cancer (NSCLC) is inconclusive due to the limitations of current CTC detection methods. Using a novel high-efficiency detection method, we determined the ability of CTCs to predict survival and chemotherapeutic responses in NSCLC. In 127 patients with advanced NSCLC, CTCs were counted and analyzed at baseline and during follow-up. Median overall survival (OS) and progression-free survival (PFS) were longer in patients with baseline CTC counts <8 CTCs/3.2 mL (20.0 vs. 10.4 months [P = 0.009] and 7.2 vs. 5.5 months [P < 0.001], respectively). Patients with post-treatment increases in the CTC count had poorer OS and PFS than those without increases (12.0 vs. 13.3 months [P = 0.028] and 5.2 vs. 6.4 months [P = 0.022], respectively). There was no association between the baseline CTC count and chemotherapeutic response (P = 0.734). However, the rate of progressive disease in patients with and without post-treatment increases in the CTC count were 15.6% and 2.4% (P = 0.042), respectively. The baseline CTC count and the change in the CTC count during treatment were both valuable prognostic indicators for NSCLC. PMID- 29156822 TI - Circular RNA expression profiles reveal that hsa_circ_0018289 is up-regulated in cervical cancer and promotes the tumorigenesis. AB - Circular RNAs (circRNAs) are a type of non-coding RNAs that have been identified as critical regulators in various diseases, especially in cancers. However, the expression profiles and functions of circRNAs in cervical cancer are still unclear. In present study, human circRNAs microarray were performed to screen the circRNAs expression in cervical cancer tissue. Microarray analysis revealed 45 significantly expressed circRNAs with 4 fold change. Among these up-regulated circRNAs, hsa_circ_0018289 was validated to be significantly up-regulated in 35 pairs of cervical cancer tissue compared with adjacent normal tissue and cell lines. Loss-of-function experiments revealed that, in vitro and in vivo, hsa_circ_0018289 knockdown inhibited the proliferation, migration and invasion of cervical cancer cells. Via bioinformatics prediction program and luciferase reporter assays, hsa_circ_0018289 was observed to directly bind to miR-497. Taken together, the results indicate that hsa_circ_0018289 plays important role in cervical cancer proliferation, migration and invasion, suggesting the miRNA 'sponge' of hsa_circ_0018289 and its oncogenic role on cervical cancer tumorigenesis. PMID- 29156823 TI - Differential activation of Fyn kinase distinguishes saturated and unsaturated fats in mouse macrophages. AB - Diet-induced obesity is associated with increased adipose tissue activated macrophages. Yet, how macrophages integrate fatty acid (FA) signals remains unclear. We previously demonstrated that Fyn deficiency (fynKO) protects against high fat diet-induced adipose tissue macrophage accumulation. Herein, we show that inflammatory markers and reactive oxygen species are not induced in fynKO bone marrow-derived macrophages exposed to the saturated FA palmitate, suggesting that Fyn regulates macrophage function in response to FA signals. Palmitate activates Fyn and re-localizes Fyn into the nucleus of RAW264.7, J774 and wild type bone marrow-derived macrophages. Similarly, Fyn activity is increased in cells of adipose tissue stromal vascular fraction of high fat-fed control mice, with Fyn protein being located in the nucleus of these cells. We demonstrate that Fyn modulates palmitate-dependent oxidative stress in macrophages. Moreover, Fyn catalytic activity is necessary for its nuclear re-localization and downstream effects, as Fyn pharmacological inhibition abolishes palmitate-induced Fyn nuclear redistribution and palmitate-dependent increase of oxidative stress markers. Importantly, mono-or polyunsaturated FAs do not activate Fyn, and fail to re-localize Fyn to the nucleus. Together these data demonstrate that macrophages integrate nutritional FA signals via a differential activation of Fyn that distinguishes, at least partly, the effects of saturated versus unsaturated fats. PMID- 29156824 TI - 37 kDa LRP::FLAG enhances telomerase activity and reduces senescent markers in vitro. AB - One of the core regulators of cellular aging are telomeres, repetitive DNA sequences at the ends of chromosomes that are maintained by the ribonucleoprotein DNA polymerase complex, telomerase. Recently, we demonstrated that knockdown of the 37kDa/ 67kDa laminin receptor (LRP/LR), a protein that promotes cell viability in tumorigenic and normal cells, reduces telomerase activity. We therefore hypothesized that upregulating LRP/LR might increase telomerase activity and impede aging. Here we show that overexpression of LRP::FLAG resulted in significantly elevated hTERT levels, telomerase activity and telomere length, respectively, with concomitantly reduced levels of senescence markers. These data suggest a novel function of LRP/LR hampering the onset of senescence through elevating hTERT levels and telomerase activity, respectively. LRP::FLAG might therefore act as a potential novel anti-aging drug through the impediment of the cellular aging process. PMID- 29156825 TI - Targeting P-selectin blocks neuroblastoma growth. AB - Selectins and their ligands have been implicated in tumor growth and progression in carcinomas, but their role in neuroblastoma has not been systematically examined. In the current study we evaluated L-, P- and E-selectin binding to neuroblastoma cells and the expression of some of their known ligands, namely CD44, CD24 and P-selectin glycoprotein ligand-1 (PSGL-1). Genetic loss of PSGL-1 or CD24 and pharmacological inhibition of P-selectin reduced P-selectin binding to neuroblastoma cells in vitro. Targeting P-selectin using specific antibodies promoted a significant reduction in the growth of neuroblastoma tumors in vivo. In mechanistic studies binding of P-selectin to neuroblastoma cells activated Src and several other pro-survival kinases such as ERK1, AKT, FAK and p38. Interestingly, comparative mass single cell cytometry (CyTOF) analyses revealed considerable intra- and inter-cell line heterogeneity with respect to response to P-selectin binding. Additionally, the downstream response to all selectins showed general similarity. Our findings reported here not only provide pre-clinical evidence in support of therapeutic targeting of P-selectin, but also highlight the heterogeneity in response of tumor cells to P-selectin binding. These observations provide the basis for combining P-selectin inhibition with other targeted therapies for neuroblastoma. PMID- 29156826 TI - Protective effect of Ginkgo biloba leaves extract, EGb761, on myocardium injury in ischemia reperfusion rats via regulation of TLR-4/NF-kappaB signaling pathway. AB - Beneficial actions of EGb 761 against ischemia/reperfusion (I/R) injury in lung, brain and renal ischemia have been described. However, the relationship between EGb 761 and signal molecules in myocardial ischemia reperfusion has not been well elucidated. In this study, we investigated the effects and mechanism of EGb 761 preconditioning on anti-myocardial I/R injuries in vivo. Meanwhile, their potential anti-oxidative stress and anti-inflammation effect were assessed. Hemodynamic parameters were monitored as left ventricular systolic pressure, LV end-diastolic pressure and maximal rate of increase and decrease of left ventricular pressure (dP/dtmax). The oxidative stress indicators and inflammatory factors were also evaluated. Western blot method was used for analysis of toll like receptor 4 (TLR4), p-TLR4, nuclear factor-kappaB (NF-kappaB), p-NF-kappaB p65, Bax and Bcl-2 protein expressions. EGb 761 significantly improved cardiac function, decreased levels of creatine kinase, aspartate aminotransferase and lactate dehydrogenase. EGb 761 also restrained the oxidative stress related to myocardial ischemia injury as evidenced by decreased malondialdehyde, superoxide dismutase, catalase, glutathione-peroxidase, glutathione reductase activity. Meanwhile, the inflammatory cascade was inhibited as evidenced by decreased cytokines such as tumor necrosis factor-alpha, interleukin-6 and interleukin 1beta. Our results still showed that EGb 761 pretreatment significantly decrease the level of cleaved Bax, and increase the level of Bcl-2 in rats subjected to I/R injury. Simultaneously, the expressions of myocardial TLR4 and NF-kappaB were significantly decreased. It can be concluded that EGb 761 pretreatment was protected against myocardium I/R injury by decreasing oxidative stress, repressing inflammatory cascade in vivo and inhibiting TLR4/NF-kappaB pathway. PMID- 29156827 TI - Hepatitis C virus core protein potentiates proangiogenic activity of hepatocellular carcinoma cells. AB - Increased angiogenic activity has been demonstrated in hepatitis C virus (HCV) related hepatocellular carcinoma (HCC), but the mechanism was unclear. To study the role of HCV core protein, we used tube formation and Matrigel plug assays to assess the proangiogenic activity of an HCC cell line, HuH7, and 2 of its stable clones-HuH7-core-high and HuH7-core-low, with high and low HCV core protein expression, respectively. In both assays, HuH7-core-high and HuH7-core-low cells dose-dependently induced stronger angiogenesis than control cells. HuH7 cells with HCV core protein expression showed increased mRNA and protein expression of vascular endothelial growth factor (VEGF). VEGF inhibition by bevacizumab reduced the proangiogenic activity of HuH7-core-high cells. The promotor region of VEGF contains the binding site of activator protein-1 (AP-1). Compared with controls, HuH7-core-high cells had an increased AP-1 activity and nuclear localization of phospho-c-jun. AP-1 inhibition using either RNA knockdown or AP-1 inhibitors reduced the VEGF mRNA expression and the proangiogenic activity of HuH7-core-high cells. Among 131 tissue samples from HCC patients, HCV-related HCC revealed stronger VEGF expression than did hepatitis B virus-related HCC. In conclusion, increased VEGF expression through AP-1 activation is a crucial mechanism underlying the proangiogenic activity of the HCV core protein in HCC cells. PMID- 29156828 TI - The beta-glucan from Lentinus edodes suppresses cell proliferation and promotes apoptosis in estrogen receptor positive breast cancers. AB - Breast cancer is now the most common cancer in worldwide women, and novel interventions are needed to overcome the resistance occurring in the estrogen targeted endocrine therapy. Herein, we demonstrate that the beta-glucan from Lentinus edodes (LNT) exhibited a profound inhibition ratio of ~53% against estrogen receptor positive (ER+) MCF-7 tumor growth in nude mice similar to the positive control of cisplatin. Immunohistochemistry images showed that LNT evidently suppressed cell proliferation and promoted apoptosis in MCF-7 tumor tissues. The Western blotting analysis indicated that LNT up-regulated the tumor suppressor p53, phosphorylated extracellular signal-regulated kinase1/2 (p ERK1/2), cleaved-Caspase 3 and poly [ADP (ribose)] polymerase 1 (PARP 1) protein levels, and reduced the expression of mouse double minute 2 (MDM2), telomerase reverse transcriptase (TERT), nuclear factor-kappa B (NF-kappaB) p65, B-cell lymphoma-2 (Bcl-2), estrogen receptor alpha (ERalpha), etc. in tumor tissues. Moreover, LNT significantly suppressed phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt) and mammalian target of rapamycin (mTOR) protein levels. It was thus proposed that LNT inhibited MCF-7 tumor growth through suppressing cell proliferation and enhancing apoptosis possibly via multiple pathways such as PI3K/Akt/mTOR, NF-kappaB-, ERK-, ERalpha-, caspase- and p53-dependent pathways. Interestingly, the cell viability assay, siRNA transfection, Western blotting and flow cytometric analysis suggested that LNT targeted p53/ERalpha to only suppress cell proliferation via cell cycle arrest at G2/M phase without apoptosis in vitro. The big difference between in vivo and in vitro data suggested that the immune responses triggered by the polysaccharide should mainly contribute to the apoptotic effect in vivo. Overall, this work provides a novel strategy to treat ER+ breast cancers by using a naturally occurring beta-glucan from mushrooms. PMID- 29156829 TI - MDM4 genetic variants predict HPV16-positive tumors of patients with squamous cell carcinoma of the oropharynx. AB - The increasing incidence of squamous cell carcinoma of the oropharynx (SCCOP) is majorly attributed to the human papillomavirus (HPV) infection. Both HPV and MDM4 play a critical role in inhibition of p53 activity, thus affecting HPV tumor status of SCCOP. Three polymorphisms in MDM4 were genotyped from blood genomic DNA samples and HPV16 status in tumor specimens was examined. Odds ratio (OR) and 95% confidence intervals (CIs) in univariate and multivariable logistic regression models were calculated for the associations between these polymorphisms and HPV16 status. Three MDM4 variant genotypes were significantly associated with HPV16 tumor status among SCCOP patients compared with the common homozygous genotypes (OR, 0.6; 95% CI, 0.4-1.0 for rs10900598; OR, 1.6, 95% CI; 1.1-2.4 for rs1380576; and OR, 1.8, 95% CI, 1.1-2.9 for rs11801299; respectively). When we combined all risk genotypes of the 3 polymorphisms, the patients carrying 1-3 MDM4 risk genotypes were approximately 2.5 time as likely to have an HPV16-positive tumor than those with no risk genotypes (OR, 2.5, 95% CI, 1.6-3.9). Additionally, modifying effect of MDM4 risk genotypes was more pronounced among non-Hispanic white, never-smokers, and never-drinkers. Potential functional polymorphisms in MDM4 may serve as biomarkers for predicting tumor HPV16 status among SCCOP patients, particularly in non-Hispanic white, never smokers and never-drinkers. However, validation of these results in larger studies is needed. PMID- 29156830 TI - FBN3 gene involved in pathogenesis of a Chinese family with Bardet-Biedl syndrome. AB - Purpose: This study was designed to evaluate the molecular genetics of a Chinese family with Bardet-Biedl syndrome (BBS). Methods: All the family members underwent medical history evaluation, ophthalmologic and physical examinations. Whole exome sequencing was performed on two affected individuals and their parents. All variants were verified in all family members by PCR amplification and Sanger sequencing. Results: Patients in this family were diagnosed as Bardet Biedl syndrome, with an inheritance pattern of autosomal recessive. Compound heterozygous mutations of the FBN3 gene (c.3616G>A and c.6037C>T) were identified by whole exome sequencing. Results from Sanger sequencing showed co-segregation of these compound heterozygous mutations in the FBN3 gene with BBS disease in the family. Conclusion: Novel compound heterozygous mutations c.3616G>A and c.6037C>T of FBN3 were identified in all affected individuals but not in the unaffected family members. This is the first time to the best of our knowledge, that the FBN3 gene is involved in the pathogenesis of BBS. This study will expand our understanding about the gene spectrum related to this genetically heterogeneous disorder. PMID- 29156831 TI - Protective effect of NSA on intestinal epithelial cells in a necroptosis model. AB - Objective: This study aimed to investigate the protective effect of the necroptosis inhibitor necrosulfonamide (NSA) on intestinal epithelial cells using a novel in vitro necroptosis model that mimics inflammatory bowel disease (IBD). Methods: 2,4,6-trinitrobenzenesulfonic acid (TNBS) was perfused into the rectum of BALB/c mice to established a colitis model. Pathologic injury and cell death were evaluated. A novel in vitro model of necroptosis was established in Caco-2 cells using TNF-alpha and Z-VAD-fmk, and the cells were treated with or without NSA. Morphologic changes, manner of cell death and the levels of phosphorylation of receptor-interacting protein kinase 3 (p-RIPK3) and mixed-lineage kinase domain-like (p-MLKL) were detected. Results: In the TNBS-induced colitis in mice, TUNEL-positive and caspase-3-negative cells were observed in the intestinal mucosa, and p-RIPK3 was found to be elevated. Under the stimulation of TNF-alpha and Z-VAD-fmk, the morphologic damage in the Caco-2 cells was aggravated, the proportion of necrosis was increased, and the level of p-RIPK3 and p-MLKL were increased, confirming that the regulated cell death was necroptosis. NSA reversed the morphological abnormalities and reduced necrotic cell death induced by TNF alpha and Z-VAD-fmk. Conclusion: NSA can inhibit necroptosis in intestinal epithelial cells in vitro and might confer a potential protective effect against IBD. PMID- 29156832 TI - Associations of high altitude polycythemia with polymorphisms in EPAS1, ITGA6 and ERBB4 in Chinese Han and Tibetan populations. AB - High altitude polycythemia (HAPC) is a common chronic disease at high altitude, which is characterized by excessive erythrocytosis (females, hemoglobin >= 190 g/L; males, hemoglobin >= 210 g/L). It is the most common disease in chronic mountain sickness casued primarily by persistent arterial hypoxia and ventilatory impairment. However, the disease is still unmanageable and related molecular mechanisms remain largely unclear. This study aims to explore the genetic basis of HAPC in the Chinese Han and Tibetan populations. Subjects were screened for HAPC using the latest approved diagnostic criteria. To explore the hereditary basis of HAPC and investigate the association between three genes (EPAS1, ITGA6, ERBB4) and HAPC in Chinese Han and Tibetan populations. We enrolled 100 patients (70 Han, 30 Tibetan) with HAPC and 100 healthy control subjects (30 Han, 70 Tibetan). Subjects were screened for HAPC using the latest approved diagnostic criteria combined with excessive erythrocytosis and clinical symptoms. Analysis of variance was used to evaluate the impact of polymorphism on HAPC based on genetic variation. The Chi-squared test and analyses of genetic models, rs75591953 and rs75984373 in EPAS1, rs6744873 in ITGA6, rs17335043 in ERBB4 showed associations with reduced HAPC susceptibility in Han populations. Additionally, in Tibetan populations, rs3749148 in ITGA6, rs934607 and rs141267844 in ERBB4 showed a reduced risk of HAPC, whereas rs6710946 in ERBB4 increased the risk of HAPC. Our study suggest that the polymorphisms in the EPAS1, ITGA6 and ERBB4 correlate with susceptibility to HAPC. PMID- 29156833 TI - Targeting aggressive prostate cancer-associated CD44v6 using phage display selected peptides. AB - There is a crucial need to identify new biomarkers associated with aggressive prostate cancer (PCa) including those associated with cancer stem cells (CSCs). CD44v6, generated by alternative splicing of CD44, has been proposed as a CSC biomarker due to its correlation with aggressive PCa disease. We hypothesized that phage display selected peptides that target CD44v6 may serve as theranostic agents for aggressive PCa. Here, a 15 amino acid peptide ("PFT") was identified by affinity selection against a peptide derived from the v6 region of CD44v6. Synthesized PFT exhibited specific binding to CD44v6 with an equilibrium dissociation constant (Kd) of 743.4 nM. PFT also bound CD44v6 highly expressed on human PCa cell lines. Further, an aggressive form of PCa cells (v6A3) was isolated and tagged by a novel CSC reporter vector. The v6A3 cells had a CSC-like phenotype including enriched CD44v6 expression, enhanced clonogenicity, resistance to chemotherapeutics, and generation of heterogeneous offspring. PFT exhibited preferential binding to v6A3 cells compared to parental cells. Immunohistofluorescence studies with human PCa tissue microarrays (TMA) indicated that PFT was highly accurate in detecting CD44v6-positive aggressive PCa cells, and staining positivity was significantly higher in late stage, metastatic and higher-grade samples. Taken together, this study provides for the first time phage display selected peptides that target CD44v6 overexpressed on PCa cells. Peptide PFT may be explored as an aid in the diagnosis and therapy of advanced PCa disease. PMID- 29156834 TI - Oncolytic reovirus inhibits angiogenesis through induction of CXCL10/IP-10 and abrogation of HIF activity in soft tissue sarcomas. AB - The tumor-selective viral replication capacity and pro-apoptotic effects of oncolytic reovirus have been reported to be dependent on the presence of an activated RAS pathway in several solid tumor types. However, the mechanisms of selective anticancer efficacy of the reovirus-based formulation for cancer therapy (Reolysin, pelareorep) have not been rigorously studied in soft tissue sarcomas (STS). Here we report that Reolysin triggered a striking induction of the anti-angiogenic chemokine interferon-gamma-inducible protein 10 (IP 10)/CXCL10 (CXC chemokine ligand 10) in both wild type and RAS mutant STS cells. Further analysis determined that Reolysin treatment possessed significant anti angiogenic activity irrespective of RAS status. In addition to CXCL10 induction, Reolysin dramatically downregulated the expression of hypoxia inducible factor (HIF)-1alpha, HIF-2alpha and inhibited vascular endothelial growth factor (VEGF) secretion. CXCL10 antagonism significantly diminished the anti-angiogenic effects of Reolysin indicating that it is a key driver of this phenomenon. Xenograft studies demonstrated that Reolysin significantly improved the anticancer activity of the anti-angiogenic agents sunitinib, temsirolimus, and bevacizumab in a manner that was associated with increased CXCL10 levels. This effect was most pronounced following treatment with Reolysin in combination with temsirolimus. Further analysis in additional sarcoma xenograft models confirmed the significant increase in CXCL10 and increased anticancer activity of this combination. Our collective results demonstrate that Reolysin possesses CXCL10-driven anti angiogenic activity in sarcoma models, which can be harnessed to enhance the anticancer activity of temsirolimus and other agents that target the tumor vasculature. PMID- 29156835 TI - Indonesian herbal medicine prevents hypertension-induced left ventricular hypertrophy by diminishing NADPH oxidase-dependent oxidative stress. AB - Indonesian herbal medicine Centella asiatica, Justicia gendarussa and Imperata cylindrica decoction (CJID) are known to be efficacious for hypertension. Oxidative stress plays an important role in hypertension-induced left ventricular hypertrophy (H-LVH). This study evaluated whether CJID inhibit cardiac remodeling in spontaneously hypertensive rats (SHRs) through mechanism of oxidative stress related cardiac-NADPH oxidase (NOXs) pathway: NOX1, NOX2 and NOX4. Forty-weeks old SHRs and normotensive-WKY rats, were both randomly divided into 2 groups: CJID and control. All rats were treated for 5 weeks. Systolic blood pressure (SBP) and heart rate (HR) were measured. LV morphology, function and performance were assessed by histological staining and echocardiography. Serum and cardiac superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were assessed. Cardiac superoxide and hydrogen peroxide (H2O2) productions, protein expressions of SOD2, SOD3, NOX1, NOX2 and NOX4 were also determined. We found that SBP and HR were significantly decreased in SHRs-treated group. Echocardiography showed that CJID significantly improved LV morphometry and function. CJID decreased MDA level, but increased SOD activity. Cardiac superoxide and H2O2 generation were decreased in SHRs-treated group. CJID caused cardiac SODs expressions to be increased but NOXs expressions to be suppressed. In conclusion, CJID prevents H-LVH by reducing reactive oxygen species production via the NOXs-dependent pathway. PMID- 29156836 TI - The role of Rak in the regulation of stability and function of BRCA1. AB - BRCA1 is an important player in the DNA damage response signaling, and its deficiency results in genomic instability. A complete loss or significantly reduced BRCA1 protein expression is often found in sporadic breast cancer cases despite the absence of genetic or epigenetic aberrations, suggesting the existence of other regulatory mechanisms controlling BRCA1 protein expression. Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. In addition, Rak deficiency confers cellular sensitivity to DNA damaging agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Overall, our findings highlight a critical role of Rak in the maintenance of genomic stability, at least in part, through protecting BRCA1 and provide novel treatment strategies for patients with breast tumors lacking Rak. PMID- 29156837 TI - Meta-analysis of efficacy and adverse events of erlotinib-based targeted therapies for advanced/metastatic non-small cell lung cancer. AB - A network meta-analysis evaluating efficacy and adverse events of eight erlotinib based therapies (erlotinib+placebo, erlotinib+tivantinib, erlotinib+celecoxib, erlotinib+onartuzumab, erlotinib+sunitinib, erlotinib+entinostat, erlotinib+sorafenib, and erlotinib+bevacizumab) for advanced/metastatic non-small cell lung cancer (NSCLC) was performed. PubMed and Cochrane Library were reviewed, and ten randomized controlled trials were identified in which patients receiving at least one erlotinib-based therapy. Efficacy outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse outcomes were evaluated. Patients treated with erlotinib+tivantinib, or erlotinib+celecoxib had longer PFS than patients on erlotinib+placebo; patients on erlotinib+tivantinib had longer OS compared to erlotinib+placebo. For PFS, erlotinib+celecoxib had the highest value of surface under the cumulative ranking curve (SUCRA). For OS, erlotinib+tivantinib had the highest SUCRA. For ORR, erlotinib+bevacizumab had the highest SUCRA, while erlotinib+entinostat ranked the lowest. For DCR, erlotinib+sorafenib had the highest SUCRA. Erlotinib+onartuzumab had the highest SUCRA for diarrhea, nausea, vomiting, decreased appetite, and dyspnea. Erlotinib+sunitinib had the lowest SUCRA for diarrhea, nausea, vomiting, and decreased appetite. Erlotinib + entinostat had the lowest SUCRA for fatigue, asthenia, and dyspnea. Our study suggests erlotinib+tivantinib and erlotinib+celecoxib regimens have the best long-term efficacy, while erlotinib+sunitinib and erlotinib+entinostat have the fewest adverse effects in patients with advanced/metastatic NSCLC. PMID- 29156839 TI - The benefit of immunonutrition in patients undergoing hepatectomy: a systematic review and meta-analysis. AB - Perioperative immunonutrition in liver resection remains doubtful. A systematic review and meta-analysis was conducted to compare postoperative outcomes between patients undergoing hepatectomy who received perioperative immunonutrition and those who did not.A PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Knowledge database search was performed to retrieve all of the randomized controlled trials (RCTs) evaluating the value of perioperative immunonutrition in patients undergoing hepatectomy until the end of September 2016. Data extraction and quality assessment of RCTs were performed in accordance with PRISMA guidelines. The quality of evidence for each postoperative outcome was assessed using the GRADEpro analysis. A random-effects model was used to conduct a meta-analysis with RevMan 5.3.5 software. Eight RCTs including 805 patients (402 with and 403 without immunonutrition) were identified. Immunonutrition, mainly omega-3 fatty acids, significantly reduced the incidence of postoperative total complications (risk ratio [RR] = 0.59; 95% confidence interval [CI], 0.46-0.75; p < 0.0001) and infectious complications (RR = 0.46; 95% CI, 0.32-0.68; p < 0.0001), and shortened the length of hospital stay (standardized mean difference, -0.49; 95% CI, -0.81 to -0.16; p = 0.0004). There was no significant between-group difference in postoperative mortality (RR = 0.46; 95% CI, 0.16-1.31; p = 0.15). Immunonutrition, mainly omega-3 fatty acids, is potentially beneficial in reducing overall and infectious postoperative complications and in shortening the hospital stay for patients undergoing hepatectomy. PMID- 29156838 TI - Associations between dietary folate intake and risks of esophageal, gastric and pancreatic cancers: an overall and dose-response meta-analysis. AB - There are still some controversies on the association between dietary folate intake and the risk of upper gastrointestinal cancers including esophageal, gastric and pancreatic cancers. Hence, a comprehensive meta-analysis on all available literatures was performed to clarify the relationship between dietary folate intake and risks of upper gastrointestinal cancers. An electric search was performed up to December 12th, 2016 within the PubMed, MEDLINE AND EMBASE databases. Ultimately, a total of 46 studies which evaluated the association between folate intake and risks of upper gastrointestinal cancers were included. According to the data from included studies, the pooled results showed significant association between folate intake and esophageal (OR = 0.545, 95%CI = 0.432-0.658), gastric (OR=0.762, 95%CI=0.648-0.876) and pancreatic (OR=0.731, 95%CI=0.555-0.907) cancers. Linearity dose-response analysis indicated that with 100MUg/day increment in dietary folate intake, the risk of esophageal, gastric and pancreatic cancers would decrease by 9%, 1.5% and 6%, respectively. These findings indicated that higher level of dietary folate intake could help for preventing upper gastrointestinal cancers including esophageal, gastric and pancreatic cancers. PMID- 29156840 TI - Association between CYP2E1 genetic polymorphisms and urinary cancer risk: a meta analysis. AB - Objective: Studies investigating the contribution of Cytochrome P4502E1 (CYP2E1) polymorphisms to the etiology of urinary cancer draw inconsistent conclusions. Thus, we performed a meta-analysis to evaluate the association between CYP2E1 Rsa I/Pst I and Dra I polymorphisms and urinary cancer susceptibility. Materials and Methods: Meta-analysis based on the eligible case-control studies that assess the association of CYP2E1 Rsa I/Pst I and Dra I polymorphisms with urinary cancer was conducted. Subgroup analyses based on ethnicity and cancer type were also carried out. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the strength of the associations between the two polymorphisms. Funnel plot and Begg's test were used for publication bias diagnosis. Results: We found decreased urinary cancer risk among subjects carrying CYP2E1 RsaI/PstI c1c2 + c2c2 genotype and c2 allele (OR = 0.73, 95% CI = 0.68-0.79 and OR = 0.79, 95% CI = 0.74-0.85, respectively), with 3,301 cases and 3,786 controls from 14 studies. We also observed a significant difference in c1c2 + c2c2 vs. c1c1 and c2 vs. c1 among Asians (OR = 0.68, 95% CI = 0.60-0.78 and OR = 0.75, 95% CI = 0.66-0.85, respectively). However, the meta-analysis based on 5 eligible studies showed no significant association between CYP2E1 Dra I polymorphism and urinary cancer susceptibility in either dominant model or the allele model. Conclusions: Our meta-analysis concluded that CYP2E1 Rsa I/Pst I polymorphism correlates with urinary cancers risk in Asian population; while CYP2E1 Dra I polymorphism might be not significantly associated with the urinary cancer risks. Large and well designed studies are needed to confirm these results. PMID- 29156841 TI - Efficacy of intra-articular hyaluronic acid injections in hip osteoarthritis: a meta-analysis of randomized controlled trials. AB - There is less credible evidence of using of intra-articular injections of hyaluronic acid (HA) to treat hip osteoarthritis (OA). This study is to determine the therapeutic effects and risk of adverse events of HA administration for hip OA. The MEDLINE, Cochrane of Systematic Reviews, Cochrane Clinical Trial Register and EMBASE, were searched for articles published. Eligible studies were limited to trials of HA with a randomized design. A total of six studies were included in this the meta-analysis. The pooled effect size of improved pain scores from pretreatment was -0.72 (95%CI; -1.06 to -0.39; P < 0.05). The standardized mean difference (SMD) of improved Lequesne's index and McMaster Universities Osteoarthritis Index (WOMAC) was -0.74 (95%CI, -1.42 to -0.51; P < 0.05) and 7.75 (95%CI, -14.28 to -1.21; P < 0.05), respectively. The pooled effect size of improved pain scores compared HA with different controls was 0.03 (95%CI; -0.20 to 0.26; P < 0.05). The SMD of improved Lequesne's index and WOMAC was -0.24 (95%CI, -0.50 to 0.02; P > 0.05) and -0.13 (95%CI, 0.64 to 0.37; P > 0.05). There were no significant differences between HA and control group in adverse events (RR: 0.94; 95%CI, 0.41 to 2.20; P > 0.05). Intra-articular HA in hip OA can significantly reduce pain and improve functional recovery when compared with the condition before treatment. However, there seems no significant difference between HA and saline or other treatments. Currently, available evidence indicated that intra-articular HA in hip OA would not be increased risk of adverse events. PMID- 29156842 TI - Associations between EGFR gene polymorphisms and susceptibility to glioma: a systematic review and meta-analysis from GWAS and case-control studies. AB - The results of genome-wide association studies (GWAS) and case-control studies performed to investigate the associations between epidermal growth factor receptor (EGFR) gene polymorphisms and glioma risk are controversial. The aim of this systematic review and meta-analysis is to determine whether EGFR gene polymorphisms are associated with glioma risk by searching 'PubMed', 'EMBASE', 'Web of Science', 'Cochrane Library' and 'China WeiPu Library' to retrieve studies that investigated associations between EGFR gene polymorphisms and glioma risk. Four GWAS containing 35 studies and 7 case-control studies meeting the inclusion criteria were finally recruited, and 11 single-nucleotide polymorphisms (SNPs) were analyzed. The results showed a significant positive association between rs730437/rs845552 and glioma risk in Asians, and a significant negative association between them in Caucasians. In addition, rs11506105 was significantly associated with an increased risk of glioma in both Asians and Caucasians, and rs11979158 decreased the risk of glioma in Caucasians. However, no significant association was observed between rs12718945/rs17172432/rs4947492 and glioma risk in Asians, between rs2252586 and glioma risk in Caucasians, and between rs3752651 and glioma risk in either Asians or Caucasians. In conclusion, different SNPs in EGFR gene might have different impacts on the risk of glioma in various ethnicities, which offers new insights into the treatment with a target-oriented approach. PMID- 29156843 TI - Clinical efficacy of neoadjuvant chemotherapy regimens FLEEOX vs. XELOX in patients with initially unresectable advanced gastric cancer: a propensity score analysis. AB - Purpose: This study was designed to assess the effectiveness of FLEEOX (5-Fu, leucovorin, etoposide, oxaliplatin, and epirubicin) compared with XELOX (capecitabine and oxaliplatin) as neoadjuvant chemotherapy (NAC) for initially unresectable advanced gastric cancer (AGC). Methods: This study reviewed patients who underwent FLEEOX or XELOX for initially unresectable AGC. To reduce the bias in patient selection, we conducted propensity score match (PSM) with 1:1 ratio. Tumor and pathological response, surgical characteristics, chemotherapy-related toxicity and overall survival (OS) were analyzed. Results: From January 2004 to December 2012, 436 patients were enrolled; 99 pairs of patients were generated after PSM. The tumor response rates were 80.8% and 68.7% in FLEEOX and XELOX (P=0.018). 80 patients (80.8%) in FLEEOX and 63 (63.6%) in XELOX received radical resection (P<0.001). The pathological complete response rate and R0 rate were 11.1% and 69.7% in FLEEOX, respectively, while 4.8% and 38.4% in XELOX (P<0.001). Median OS time was longer in FLEEOX (30.0 vs. 25.1 months, P<0.001). In addition, more toxicities occurred in FLEEOX, including leukocytopenia (17.2% vs. 7.1%, P=0.024), nausea (17.2% vs. 6.1%, P=0.012) and vomiting (22.2% vs. 10.1%, P=0.016). The overall toxicity rate was higher in FLEEOX (71.7% vs. 35.4%, P<0.001). Conclusion: The FLEEOX regimen as NAC for patients with initially unresectable AGC can improve tumor response rate, radical resection rate, R0 rate, and OS as compared to XELOX regimen. More chemotherapy-related toxicity was observed in FLEEOX group, although no chemotherapy-related deaths and aborting were observed. Further randomized clinical trials on the FLEEOX regimen are necessary. PMID- 29156844 TI - A three-microRNA signature for lung squamous cell carcinoma diagnosis in Chinese male patients. AB - Various studies have demonstrated the diagnostic value of microRNA (miRNA) for lung cancer, but miRNA signatures varied between different subtypes. Whether serum miRNAs could be used as biomarkers in lung squamous cell carcinoma (SCC) remains unknown. Using quantitative real-time polymerase chain reaction (qRT-PCR) based Exiqon panel, 38 differentially expressed miRNAs were identified from 3 male lung SCC pool samples and 1 normal control (NC) pool in the initial screening phase. After the training (24 SCC VS. 15 NCs), testing (44 SCC VS. 57 NCs) and external validation (34 SCC VS. 36 NCs VS. 10 pulmonary hamartoma) processes via qRT-PCR, we identified a three-miRNA panel ((miR-106a-5p, miR-20a 5p and miR-93-5p) to be a potential diagnostic marker for male lung SCC patients. The areas under the receiver operating characteristic (ROC) curve of the three miRNA panel for the training, testing and validation phases were 0.969, 0.881 and 0.954 respectively. In addition, this signature could also differentiate lung SCC from pulmonary hamartoma (AUC=0.900). The 3 miRNAs were consistently up-regulated in lung SCC tissues (23 SCC VS. 23 NCs) and serum exosomes (17 SCC VS. 24 NCs). Moreover, expression of the 3 miRNAs was decreased in arterial serum (n = 3). In conclusion, we established a three-miRNA signature in the peripheral serum with considerable clinical value in the diagnosis of male lung SCC patients. PMID- 29156845 TI - Metastatic to negative lymph node ratio demonstrates significant prognostic value in patients with esophageal squamous cell carcinoma after esophagectomy. AB - Aims: The prognostic value of metastatic lymph node ratio (LNR) has been reported in some studies; however, there is no report on the prognostic significance of metastatic to negative lymph node ratio (MNLNR) in cancer patients. The aim of this study was to compare the prognostic value of pN, LNR and MNLNR on the survival of patients with esophageal squamous cell carcinoma (ESCC) after esophagectomy. Methods: The data of 290 patients with ESCC after curative esophagectomy was retrospectively analyzed. The optimal cut-point for LNR and MNLNR were set as 0, 01-0.2, and >0.2. Univariate and multivariate analyses were performed to identify prognostic factors for overall survival (OS). Results: Patients classified as LNR 0, 0.01-0.20, and 0.21-1.0, the observed 5-year OS rates were 46.6%, 26.0%, and 11.6%, respectively (P = 0.000). Patients classified as MNLNR 0, 0.01-0.20, and >0.2, the observed 5-year OS rates were 46.6%, 31.2%, and 7.4%, respectively, respectively (P = 0.000). The pN stage, LNR or MNLNR category was confirmed as a significant independent prognostic factor, respectively (P = 0.032, P = 0.011 and P = 0.003, respectively); However, only the MNLNR category (P = 0.003) remained as a significant prognostic factor when the pN stage, LNR and MNLNR category simultaneously included in the multivariate analysis models. Conclusions: The MNLNR was recognized as an independent prognostic factor in ESCC patients after curative esophagectomy. In addition, MNLNR showed better prognostic value than pN stage and LNR category. PMID- 29156846 TI - S100A14 rs11548103 G>A polymorphism is associated with a decreased risk of esophageal cancer in a Chinese population. AB - Objective: In China in 2009, esophageal cancer was the fifth most commonly diagnosed malignancy and the fourth leading cause of malignancy-related death. Accumulating evidence indicates that genetic factors might play an important role in esophageal squamous cell carcinoma (ESCC) carcinogenesis. Materials and Methods: In total, we recruited 629 ESCC patients and 686 controls. Genetic variations in the S100A14, MLH1, SMAD7 and CCL22/MDC genes were measured using the ligation detection reaction method. Results: When the S100A14 rs11548103 GG genotype was considered as the reference group, the GA genotype associated with decreased risk of ESCC (GA vs. GG: adjusted OR = 0.73, 95% CI = 0.57-0.93, p = 0.009). In the dominant model, GA/AA variants were associated with a significantly decreased risk of ESCC compared with the GG genotype (GA/AA vs. GG: adjusted OR = 0.76, 95% CI = 0.61-0.95, p = 0.018). Logistic regression analyses showed that the MLH1 rs1800734 C>T, SMAD7 rs12953717 C>T and CCL22/MDC rs4359426C>A polymorphisms were not associated with the risk of ESCC in any of the models tested. Conclusions: Our findings indicated that, in a Chinese population, rs11548103 might contribute to a decreased risk of ESCC. Further studies are need to confirm these data with results from a lager cohort and different ethnic origins. PMID- 29156847 TI - Longitudinal relationship between traumatic brain injury and the risk of incident optic neuropathy: A 10-year follow-up nationally representative Taiwan survey. AB - Accumulating evidences had shown that traumatic brain injury was associated with visual impairment or vision loss. However, there were a limited number of empirical studies regarding the longitudinal relationship between traumatic brain injury and incident optic neuropathy. We studied a cohort from the Taiwanese National Health Insurance data comprising 553918 participants with traumatic brain injury and optic neuropathy-free in the case group and 1107836 individuals without traumatic brain injury in the control group from 1st January 2000. After the index date until the end of 2010, Cox proportional hazards analysis was used to compare the risk of incident optic neuropathy. During the follow-up period, case group was more likely to develop incident optic neuropathy (0.24%) than the control group (0.11%). Multivariate Cox regression analysis demonstrated that the case group had a 3-fold increased risk of optic neuropathy (HR = 3.017, 95% CI = 2.767-3.289, p < 0.001). After stratification by demographic information, traumatic brain injury remained a significant factor for incident optic neuropathy. Our study provided evidence of the increased risk of incident optic neuropathy after traumatic brain injury during a 10-year follow-up period. Patients with traumatic brain injury required periodic and thorough eye examinations for incident optic neuropathy to prevent potentially irreversible vision loss. PMID- 29156848 TI - Nomograms for prognostic factors of spinal giant cell tumor combining traditional clinical characteristics with inflammatory biomarkers after gross total resection. AB - Giant cell tumor (GCT) of bone is a common primary bone tumor, which exhibits local aggressiveness and recurrent potential, especially for the spinal lesion. Increasing evidence indicates that inflammation plays a vital role in tumorigenesis and progression. The prognostic value of inflammatory biomarkers in GCT has not been established. A retrospective analysis was conducted in patients with spinal GCT in Changzheng Hospital Orthopedic Oncological Center (CHOOC) between January 2005 and October 2015 and 129 patients were identified eligible. Traditional clinical parameters and inflammatory indexes such as Neutrophil-to lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to monocyte ratio (LMR), and albumin/globulin ratio (AGR) were concluded and analyzed. Kaplan-Meier analysis was used to calculate the disease-free survival (DFS). Cox regression analysis was performed to assess the prognostic factors. Nomograms were established to predict DFS quantitatively for the first time, and Harrell's concordance index (c-index) was adopted to evaluate prediction accuracy. As results, the DFS was 78.3% in the cohort. Patients were stratified into 2 groups by NLR (<= 2.70 and > 2.70), PLR (<= 215.80 and > 215.80), LMR (<= 2.80 and >2.80) and AGR (< 1.50 and >= 1.50). Patients with NLR > 2.70, PLR > 215.80, LMR <= 2.80 and AGR < 1.50 were significantly associated with decreased DFS (p < 0.05). Multivariate analysis indicated that treatment history, tumor length, bisphosphonate treatment, NLR and PLR were independent factors of DFS (p < 0.05, respectively). In addition, nomogram on DFS was established according to all significant factors, and c-index was 0.728 (95% CI: 0.710-0.743). Nomograms based on DFS can be recommended as practical models to evaluate prognosis for spinal GCT patients. PMID- 29156851 TI - Cartilage reinforcement graft versus fascia graft in tympanoplasty AB - Background/aim: The purpose of this study was to compare cartilage reinforcement graft results with temporalis fascia graft alone in terms of hearing and anatomical outcomes in tympanoplasty. Materials and methods: Patients who underwent tympanoplasty with/without ossiculoplasty and/or mastoidectomy at a university hospital from 2006 through 2013 were reviewed retrospectively. The patients were divided into those grafted with temporalis muscle fascia alone and with fascia reinforced with cartilage. The postoperative air bone gap, gain in hearing thresholds, and graft status were evaluated for each group. Results: The study subjects included 179 patients. There were 82 patients in the fascia group and 97 patients in the cartilage group. Successful hearing results were elicited in 79.2% of the fascia group and 85.5% of the cartilage group. There was no significant difference in overall graft success. The graft was intact in 82.9% of the fascia group and 86.5% of the cartilage group. Conclusion: In this comparative study the use of cartilage to reinforce the temporalis muscle fascia was analyzed, showing better hearing and anatomical results than sole use of fascia in tympanoplasty both for primary and revision cases. Thus, in the light of our results, when performing tympanoplasty we recommend the use of cartilage reinforcement grafting whenever needed and indicated. PMID- 29156852 TI - Risk factors for recurrent central line-associated bloodstream infections in a pediatric intensive care unit AB - Background/aim: It is recommended that a central venous catheter (CVC) be removed if central line-associated bloodstream infection (CLABSI) has been diagnosed. The objective of this retrospective study was to evaluate the risk factors for recurrent CLABSI in reinserted catheters in a pediatric intensive care unit. Materials and methods: Patients with recurrent and nonrecurrent CLABSI were compared in terms of the catheter exchange interval, the interval between negative blood culture and reinsertion of the CVC, and the pre-/reinsertion treatment duration. Results: Thirty-one patients with initial CLABSI had reinserted CVCs, and 12 (38.7%) of these patients were diagnosed with recurrent CLABSI. In the recurrent group, the catheter exchange interval, the interval between negative blood culture and reinsertion of the second CVC, and pre /reinsertion treatment duration were found to be shorter. Logistic regression analysis revealed that if the interval between negative blood culture and reinsertion of the second CVC was shorter than 4 days, recurrent CLABSI risk increased by 1.7-fold (P = 0.021). Sterile gauze-dressed patients had shorter cumulative catheter surveys than the polyurethane-dressed patients (P = 0.005). Conclusion: Using transparent polyurethane dressings instead of sterile gauze for maintaining the CVC and delaying the reinsertion procedure for at least 4 days after the negative culture might be helpful in preventing recurrent CLABSI. PMID- 29156849 TI - Interest of integrins targeting in glioblastoma according to tumor heterogeneity and cancer stem cell paradigm: an update. AB - Glioblastomas are malignant brain tumors with dismal prognosis despite standard treatment with surgery and radio/chemotherapy. These tumors are defined by an important cellular heterogeneity and notably contain a particular subpopulation of Glioblastoma-initiating cells, which recapitulate the heterogeneity of the original Glioblastoma. In order to classify these heterogeneous tumors, genomic profiling has also been undertaken to classify these heterogeneous tumors into several subtypes. Current research focuses on developing therapies, which could take into account this cellular and genomic heterogeneity. Among these targets, integrins are the subject of numerous studies since these extracellular matrix transmembrane receptors notably controls tumor invasion and progression. Moreover, some of these integrins are considered as membrane markers for the Glioblastoma-initiating cells subpopulation. We reviewed here integrin expression according to glioblastoma molecular subtypes and cell heterogeneity. We discussed their roles in glioblastoma invasion, angiogenesis, therapeutic resistance, stemness and microenvironment modulations, and provide an overview of clinical trials investigating integrins in glioblastomas. This review highlights that specific integrins could be identified as selective glioblastoma cells markers and that their targeting represents new diagnostic and/or therapeutic strategies. PMID- 29156853 TI - The importance of routine bedside biliary ultrasonography in the management of patients admitted to the emergency department with isolated acute epigastric pain AB - Background/aim: The aim of our study was to emphasize the importance of routine bedside biliary ultrasonography (USG) for the differential diagnosis of biliary tract disorders in patients admitted with acute isolated epigastric pain. Materials and methods: Adult patients who were admitted to the emergency department with acute isolated epigastric pain were included in the study. Emergency residents (ERs) were asked whether they planned to perform biliary USG during the initial evaluation and following diagnosis/treatment (secondary evaluation) of these patients. Bedside biliary USG examinations were performed by a sonologist and a radiologist evaluated the video recordings. Results: A total of 103 patients were enrolled, 29 of whom were diagnosed with biliary tract disease (BTD). In the 29 patients diagnosed with BTD, 27 had gallstones (biliary colic, 18; acute cholecystitis, 7; acute pancreatitis, 2) and two had biliary sludge. USG was not ordered by the ERs for 44.8% of the 29 patients with a final diagnosis of BTD, 58.8% of 17 patients with normal liver function tests and BTD, and 35.3% of the 17 hospitalized patients. Conclusion: Emergency physicians should routinely use biliary USG along with clinical judgement and laboratory studies in order to rule out BTD in patients with acute isolated epigastric pain. PMID- 29156850 TI - Harness the synergy between targeted therapy and immunotherapy: what have we learned and where are we headed? AB - Since the introduction of imatinib for the treatment of chronic myelogenous leukemia, several oncogenic mutations have been identified in various malignancies that can serve as targets for therapy. More recently, a deeper insight into the mechanism of antitumor immunity and tumor immunoevasion have facilitated the development of novel immunotherapy agents. Certain targeted agents have the ability of inhibiting tumor growth without causing severe lymphocytopenia and amplifying antitumor immune response by increasing tumor antigenicity, enhancing intratumoral T cell infiltration, and altering the tumor immune microenvironment, which provides a rationale for combining targeted therapy with immunotherapy. Targeted therapy can elicit dramatic responses in selected patients by interfering with the tumor-intrinsic driver mutations. But in most cases, resistance will occur over a relatively short period of time. In contrast, immunotherapy can yield durable, albeit generally mild, responses in several tumor types via unleashing host antitumor immunity. Thus, combination approaches might be able to induce a rapid tumor regression and a prolonged duration of response. We examine the available evidence regarding immune effects of targeted therapy, and review preclinical and clinical studies on the combination of targeted therapy and immunotherapy for cancer treatment. Furthermore, we discuss challenges of the combined therapy and highlight the need for continued translational research. PMID- 29156854 TI - Endovascular embolization in the management of traumatic and postoperative abdominopelvic bleeding: a single-center experience AB - Background/aim: Endovascular embolization is widely used instead of surgery in the treatment of traumatic and postoperative abdominopelvic bleeding. The objective of this study is to evaluate the efficiency of computed tomography in the determination of active bleeding and the efficiency of endovascular embolization in traumatic and postoperative abdominopelvic bleeding. Materials and methods: Thirty-one patients admitted to our hospital with traumatic and postoperative abdominopelvic bleeding between January 2006 and September 2012 and treated with endovascular embolization were retrospectively enrolled in the study. In 15 hemodynamically stable patients, abdominal computed tomography was performed to detect the presence and/or localization of the hemorrhage. All 31 patients underwent digital subtraction angiography (DSA) and endovascular embolization. Results: Active hemorrhage was detected in all patients evaluated by computed tomography. Thirty-two embolization procedures were performed in 31 patients. Embolization was successful in all procedures. Two patients needed retreatment because of recurrent bleeding. One patient died 2 days after embolization as a result of concomitant multiorgan injury. Conclusion: Computed tomography is able to detect active bleeding, allowing it to take the place of diagnostic DSA. If careful patient selection is carried out, endovascular embolization may be the final treatment, despite high-grade visceral organ injury. PMID- 29156855 TI - Differences in leptin, ghrelin, and glucagon-like peptide-1 levels between religious fasting and normal fasting AB - Background/aim: Leptin, ghrelin, and glucagon-like peptide-1 (GLP-1) affect hunger, satiety feelings, and food intake. We hypothesized that during Ramadan, if the brain knows that the body will be hungry until sunset, there may be differences between leptin, ghrelin, and GLP-1 levels in Ramadan and non-Ramadan fasting. Materials and methods: This study had two phases. In the first phase, the participants were asked to skip the dawn meal of Ramadan (suhur), so that 12 h of fasting could be achieved. Participants ceased food intake at midnight, and at noon blood was drawn. Eight participants were selected as a subgroup. These participants gave blood three times a day to detect hormonal changes during Ramadan. Six months later, in the second phase, blood samples were obtained at noon from participants after 12 h of fasting. Results: Analysis was conducted on 30 patients [19 males (63.3%) and 11 females (36.7%)]. There was a significant difference in leptin, ghrelin, and GLP-1 levels between Ramadan fasting and non Ramadan fasting (P = 0.04, P = 0.02, and P < 0.001, respectively). In the subgroup analysis, there was no statistically significant difference in leptin, ghrelin, and GLP-1 levels over time. Conclusion: The results of this study suggest that the nervous and gastrointestinal systems may behave differently in religious fasting than in nonreligious fasting. PMID- 29156856 TI - Clinical and surgical outcomes of upper lumbar disc herniations: a retrospective study AB - Background/aim: Upper lumbar disc herniation (LDH), generally involving L1?L2 and L2?L3 level herniation, is less common than lower LDH and, in this retrospective study, the clinical and radiological findings of patients who suffered from upper LDH and were operated on due to this pathology were reviewed. Materials and methods: Data regarding neurological and radiological findings of patients operated on between January 2005 and December 2013 were retrospectively collected. During this period, 3494 patients had surgery for LDH, and 129 of these patients had disc herniation at the upper levels. Seventy-eight patients with proper follow-up and data were included in the study. Results: There were 39 males and 39 females enrolled in the study. Twenty-one patients (0.6%) were operated on due to L1?L2 disc herniation and 45 (1.2%) had L2?L3 disc herniation. Twelve (0.3%) patients had disc pathologies at both levels. The mean age of the population was 59.9 years old, and this was significantly higher than lower LDH averages previously described in the literature (42 years old). Cauda equina signs and urinary disturbances were frequently seen, in addition to symptoms related to back and leg pain, neurologic claudication, and weakness in lower extremities. Conclusion: Upper LDHs requiring surgical therapy are extremely rare, more so than other LDHs. They are more frequent among older patients and are often present along with signs of cauda equina and urinary dysfunction. PMID- 29156857 TI - A study of the chikungunya virus in humans in Turkey AB - Background/aim: The chikungunya virus (CHIKV) is a mosquito-borne disease and has recently been causing explosive outbreaks. The CHIKV has spread throughout all continents. Although the first chikungunya case imported from India to Turkey was reported in 2012, there is no detailed epidemiologic study in Turkey yet. The aim of this study was to investigate the seroprevalence of the CHIKV in Turkey. Materials and methods: ELISA was used to screen 500 random serum samples of healthy people collected from Kirikkale, which is located in central Anatolia in Turkey. The results were verified by indirect immunofluorescence test (IIFT). Results: The results showed that 0.4% samples were positive for CHIKV. In the verification study with IIFT, CHIKV IgG type antibodies were defined as negative. To the best of our knowledge, this is the first serological study on the CHIKV in Turkey. Conclusion: Further studies are needed to elucidate the epidemiological situation in patients that have fever and arthritis. PMID- 29156858 TI - Risk factors for colistin-associated nephrotoxicity and mortality in critically ill patients AB - Background/aim: Colistin is gaining popularity against multidrug-resistant bacteria. The primary concern with colistin is its nephrotoxicity (NT). The aim of this study was to evaluate the incidence and risk factors for NT and to evaluate the risk factors for mortality in the toxicity group. Materials and methods: NT was defined according to the RIFLE criteria. Data of patients who did or did not develop NT were compared. Positive and negative predictive values, risk ratio, and correlation coefficients were calculated. Results: NT was seen in 39 patients (70%). Hypoalbuminemia, old age, and the use of vasopressors (VPs) were associated with NT. The use of VPs had the highest positive predictive value, while age had the highest negative predictive value and risk ratio. The only variable that was associated with mortality in the toxicity group was VP use. Conclusion: Aging, hypoalbuminemia, and the use of VPs were shown to be risk factors for NT, while the last of these was the only significant risk factor for mortality in the toxicity group. PMID- 29156859 TI - Relationship of paratracheal lymph nodes with the progression of chronic autoimmune thyroiditis: 5-year follow-up results AB - Background/aim: To examine changes in paratracheal lymph nodes (PLNs) and the relationship with the course of the disease in patients with chronic autoimmune thyroiditis (CAT) 5 years after diagnosis. Materials and methods: A total of 169 patients with newly diagnosed CAT and 53 healthy subjects were included in the study. All patients underwent ultrasonographic (US) examinations of the thyroid, paratracheal regions, and examined thyroid function tests. Eighty-four patients who were euthyroid at baseline and who were contacted 5 years after the diagnosis were reevaluated by US and thyroid function tests. Results: The PLNs frequency was significantly higher in the CAT group than the controls (75.1 % vs. 30.1 %, P < 0.001). Among the 84 patients who were euthyroid at the time of diagnosis and were contacted again after 5 years, 15 developed hypothyroidism. Initially, PLNs were present in all patients who developed hypothyroidism and were significantly higher than in those who remained euthyroid (respectively 100% vs. 68.7%, P = 0.009). PLN presence and PLN volume in patients who were euthyroid at baseline predicted hypothyroidism at the end of 5 years. Conclusion: PLNs may be used as an indicator of disease progression. In addition, patient age and baseline TSH levels are other factors that predict the development of hypothyroidism in time. PMID- 29156860 TI - Decreased oxidative stress may contribute to the disease process in placenta accreta AB - Background/aim: The main aim of this study was to investigate serum total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and arylesterase levels in pregnant women with placenta accreta and to compare those with age-matched healthy pregnant women. Materials and methods: A total of 27 pregnant women who had clinically and pathologically proven placenta accreta and 30 age- and BMI- matched healthy pregnant women were enrolled in this case control study. Maternal serum TOS, TAS, OSI, and arylesterase levels were evaluated using logistic regression analysis to determine if there was an association with abnormal placental invasion or not. Results: Decreased OSI (OR= 0.999, 95%CI: 0.998-1.000, P = 0.035) and increased arylesterase levels (OR= 0.981, 95%CI: 0.970-0.993, P = 0.001) were significantly associated with the presence of placenta accreta. Maternal serum TOS, TAS, OSI, and arylesterase levels were not predictive for adverse perinatal outcomes (P > 0.05). Conclusions: Decreased OSI and increased arylesterase levels are significantly associated with placenta accreta and may contribute to the abnormal invasion process. PMID- 29156861 TI - Intraoperative boost radiation effects on early wound complications in breast cancer patients undergoing breast-conserving surgery AB - Background/aim: Intraoperative radiation therapy (IORT) may pose a risk for wound complications. All technical aspects of IORT regarding early wound complications were evaluated. Materials and methods: Ninety-three consecutive patients operated on with the same surgical technique and given (study group) or not given (control group) IORT were included. Wound complications were evaluated in two groups. Results: Forty-three patients were treated with boost dose IORT and 50 patients were treated with breast-conserving surgery without IORT. When both groups were compared in terms of early postoperative complications, there were 11 (25.5%) patients with seroma in the IORT group and 3 patients (6%) in the control group (P = 0.04). While 9 (21%) patients were seen to have surgical site infection (SSI) in the IORT group, there was 1 (2%) SSI in the control group (P = 0.005). There were 15 (35%) patients with delayed wound healing in the IORT group and 4 patients (8%) in the control group (P = 0.006). Conclusion: IORT could have a negative effect on seroma formation, SSI, and delayed healing. It should be kept in mind, however, that in centers with IORT implementation, the complication rate could also increase. Necessary measures for better sterilization in the operating room should be taken, while patient wound healing should be monitored closely. PMID- 29156862 TI - The prevalence of abdominal obesity is remarkable for underweight and normal weight adolescent girls AB - Background/aim: Obesity is a global public health challenge. This study was carried out in order to determine the prevalence of obesity and abdominal obesity in Turkish adolescent girls. Materials and methods: A cross-sectional study was conducted in a total of 1111 adolescent girls aged 12?18 years. The subjects were classified into four groups: underweight, normal, overweight, and obese. Abdominal obesity was defined according to waist circumference (WC) >= 90th percentile for Turkish adolescent population references (12-17 years) and waist to-height ratio (WHtR) >= 0.5. Results: The prevalence of underweight was 17.4%, normal weight 68.5%, overweight 12.1%, and obese 2.0%. A total of 16.9% subjects were abdominal obese based on WC and 10.4% based on WHtR. When the four groups were evaluated in terms of abdominal obesity status, prevalence was 6.4% and 2.6% in the underweight, 14.6% and 5.8% in the normal, 60.0% and 37.3% in the overweight, and 88.8% and 77.3% in the obese groups according to WC and WHtR, respectively. Both WC (r: 0.332) and WHtR (r: 0.156) were positively correlated with age (P < 0.05). Conclusion: The prevalence of abdominal obesity was found at high levels for overweight and obese adolescents. It should be emphasized that abdominal obesity is a condition that should be considered for underweight and normal adolescents as well. Therefore, abdominal obesity should be regularly assessed for nonobese adolescents to prevent cardiovascular risks, metabolic syndrome, and other related disease. PMID- 29156863 TI - Sleep quality, sleeping postures, and sleeping equipment in patients with ankylosing spondylitis AB - Background/aim: Inflammatory back pain, spinal stiffness, and limited spinal mobility are characteristic features of ankylosing spondylitis (AS). Sleeping postures can affect and/or reflect sleeping disturbances. The aim of the study was to evaluate sleeping postures and sleep disturbances in patients with AS. Materials and methods: Seventy-seven patients with AS and 49 healthy controls were enrolled. The Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) were applied to both groups. The most common sleeping postures were noted. Results: There was no significant difference between the groups in terms of sleeping postures. Total PSQI and ISI scores were higher in the AS group than in the controls (P = 0.004 and P = 0.038, respectively). The selection of sleeping postures of active and inactive patients were similar. The number of pillows used was not the same in the AS and control groups (P = 0.016). The frequency of customized bed use was higher in the AS group compared to the control group (P = 0.004). Conclusion: Sleep disturbances are more of a problem in patients with AS compared to healthy patients and in active AS patients compared to inactive ones. However, sleeping postures do not seem to affect either sleep disturbances or disease activity in patients with AS. PMID- 29156864 TI - Evaluation of lipid profiles in patients treated with capecitabine AB - Background/aim: Capecitabine is a prodrug of 5-fluorouracil and has shown significant antitumor activity. The main adverse effects are hand-foot syndrome, diarrhea, and dermatitis. In recent years, hypertriglyceridemia has been reported in patients treated with capecitabine. Dyslipidemia is a rare but important side effect of capecitabine. The aim of this study is to examine the changes in lipid levels during capecitabine treatment and to raise awareness of pharmacovigilance. Materials and methods: In this retrospective study, it was aimed to analyze lipid metabolism after capecitabine treatment and is intended to contribute to the formation of a pharmacoepidemiological database. For this purpose, triglyceride, cholesterol, HDL, LDL, ALT, AST, ALP, MCV, and Hb blood levels of 57 patients treated with capecitabine at the Department of Medical Oncology, Faculty of Medicine, Cukurova University, were examined before and after five cycles of treatment. Results: Blood triglyceride and cholesterol levels were significantly increased after capecitabine treatment. The increase in triglyceride levels was higher than the increase in cholesterol levels. Conclusion: In the light of these findings, monitoring of the lipid profile should be considered in cancer patients treated with capecitabine. PMID- 29156865 TI - Antibacterial resistance patterns and incidence of hospital-acquired Staphylococcus aureus bacteremia in a tertiary care educational hospital in Turkey: a perspective from 2001 to 2013 AB - Background/aim: Staphylococcus aureus is an important nosocomial pathogen and a successful antimicrobial-resistance developer. In this study we retrospectively evaluated the resistance patterns and incidence of microbiologically confirmed nosocomial bacteremia (MCNB) related S. aureus strains between 2001 and 2013. Materials and methods: Any patient in whom S. aureus was isolated in at least one set of blood cultures (sent to the bacteriology laboratory 72 h after hospital admission) was considered to have MCNB. Results: The methicillin-resistant S. aureus (MRSA) rate in 2001 was 73.8% whereas it was 36.2% in 2013. When the 2001 2003 and 2011?2013 periods were compared, resistance to oxacillin, levofloxacin, gentamicin, erythromycin, and clindamycin decreased significantly (P < 0.05). When we evaluated the total S. aureus, MRSA, and methicillin-sensitive S. aureus (MSSA) bacteremia rates per 1000 days and 1000 patients, there was an increase in the 2004?2005 period, which was followed by a slight decrease until 2013 (P < 0.05). There was a plateau in MCNB-related S. aureus rates between 2008 and 2011. Conclusion: There was a decrease in overall S. aureus and MRSA bacteremia incidence as well as MRSA rates except for a plateau between 2008 and 2011. This steady decrease in the resistance rates is most probably due to the 2003 budget application and application of antimicrobial stewardship. PMID- 29156866 TI - TLR2 (-196 to -174 Ins/Del) and TLR3 (1377C>T) as biomarkers for nasopharyngeal cancer in Tunisia AB - Background/aim: We evaluated the association of TLR2 (-196 to -174 Ins/Del) and TLR3 (1377 C>T) as potential risk factors for nasopharyngeal carcinoma (NPC) in Tunisians. Material and methods: The study subjects comprised 137 NPC patients and 164 cancer-free control subjects. TLR2 genotyping was done by PCR and TLR3 genotyping was performed by PCR-RFLP. Results: Minor allele frequency (MAF) and genotypes of TLR3 (1377 C>T) were comparable between NPC patients and controls. Significantly higher MAF and TLR2-containing Del allele genotypes of TLR2 (-196 to -174 Ins/Del) were seen in NPC patients compared to controls [OR (95% CI) = 2.10 (1.43-3.08), P < 0.001 and OR (95% CI) = 2.07 (1.27-3.37), P = 0.003]. In addition, higher increased NPC risk was associated with the TLR2-Del/Del genotype [OR (95% CI) = 2.74 (1.37-5.48), P = 0.004]. An increased frequency of the Del-T haplotype was seen in NPC cases compared to controls. Conclusion: Our results demonstrate an increased risk of NPC with the TLR2-Del/Del genotype and Del-T TLR2 and TLR3 haplotype, suggesting their potential use as biomarkers to evaluate NPC risk in Tunisians. PMID- 29156867 TI - Cross-cultural adaptation and psychometric assessment of the Turkish version of the Vulnerability to Abuse Screening Scale AB - Background/aim: The aim of this study was to evaluate the reliability and validity of the Turkish version of the Vulnerability to Abuse Screening Scale (VASS). Materials and methods: This was a methodological study. The sample included 140 elderly individuals. Data were collected by using a questionnaire form, the VASS, and the Geriatric Depression Scale (GDS). The Cronbach alpha value was calculated and test?retest reliability was tested for the reliability analyses. Results: The Cronbach alpha value calculated for the VASS (12 items) was 0.819. There was no difference between test and retest mean scores of the VASS. A statistically significantly positive and strong relationship was found between the test and retest scores of the individuals. A statistically significantly positive and moderate relationship was found between the VASS and GDS scores. Factor analysis revealed that a total of four factors accounted for 63.66% of the total variance with an eigenvalue of >1. These results show that the Turkish version of the VASS is a valid and reliable scale. Conclusion: This study showed that the adoption of the translated VASS in Turkey is reliable and valid to evaluate the risk of abuse in adults over the age of 65. PMID- 29156868 TI - A nationwide evaluation of off-label drug utilization in Turkey AB - Background/aim: Off-label drug use (OLDU) is under the control of the Turkish Medicines and Medical Devices Agency (TMMDA) in Turkey. It was aimed to investigate demographic and medical features of patients with OLDU applications in Turkey. Materials and methods: A total of 4426 electronic OLDU application records of the TMMDA were evaluated retrospectively. Information regarding patients? demographic characteristics, diagnoses, requested drugs, institutions, and specialties of the physicians were evaluated. Results: OLDU applications were mostly made by rheumatologists (21.5%) and 95.2% of them were approved by the TMMDA. The mean age of the patients was 35 years and 54.4% of them were female. Off-label drugs were mostly prescribed for patients aged 18?64 years (62.1%) and were most frequently prescribed by physicians from university medical centers (81.0%). Systemic lupus erythematosus (10.1%) was the most common diagnosis. Mycophenolate (16.1%) and rituximab (10.1%) were the most frequently prescribed off-label drugs. There were differences regarding some characteristics of patients and their physicians among most frequently prescribed off-label drugs (P < 0.05). Conclusion: It is noteworthy that OLDU applications showed demographical and institutional differences. It is expected that this study will provide important contributions to physicians working in the relevant area with respect to treatment alternatives of diseases with treatment challenges. PMID- 29156869 TI - Impact of GGCX polymorphisms on warfarin dose requirements in atrial fibrillation patients AB - Background/aim: Warfarin is a common anticoagulant with large interindividual differences and a narrow therapeutic range. The polymorphisms of gamma-glutamyl carboxylase (GGCX) are important genetic factors for warfarin dose requirements. Materials and methods: Polymerase chain reaction and direct sequencing methods were used to detect the GGCX rs699664 genotype in 215 atrial fibrillation (AF) patients with warfarin administration. The effects on warfarin dose by different genotypes were analyzed. A warfarin dosing algorithm was developed based on age, height, CYP2C9, VKORC1, and GGCX genotype. Results: In 215 AF patients, there were 104 cases of wild-type GG genotype (48.4%), 92 cases of GA genotype (42.8%), and 19 cases of AA genotype (8.8%). Patients with the GGCX rs699664 A allele (GA or AA genotypes) needed higher warfarin doses than those with the GG genotype (P < 0.05). A warfarin dosing algorithm showed that age, height, CYP2C9, VKORC1, and GGCX genotype were the best variables for estimating warfarin dose (R2 = 41.2%). Another independent cohort of 60 AF patients showed a significant linear correlation between predicted warfarin maintenance dose and actual dose (R = 0.660, P < 0.01). Conclusion: AF patients with the GA and AA genotypes in GGCX rs699664 required significantly higher warfarin doses. GGCX rs699664 is a potential predictor for the warfarin dose of AF patients. PMID- 29156870 TI - A fully liquid DTaP-IPV-HB-PRP-T hexavalent vaccine for primary and booster vaccination of healthy Turkish infants and toddlers AB - Background/aim: Immunogenicity and safety of a primary series of a fully liquid, hexavalent DTaP-IPV-HB-PRP-T vaccine given at 2, 3, and 4 months of age compared to licensed comparators and a DTaP-IPV-HB-PRP-T booster at 15?18 months were evaluated. Materials and methods: This was a Phase III, randomized, open-label trial. Primary series (no hepatitis B [HB] at birth) of DTaP-IPV-HB-PRP-T (N = 155) (group 1) or licensed control vaccines (DTaP-IPV//PRP-T and standalone HB: N = 155) (group 2) and DTaP-IPV-HB-PRP-T booster were administered. Noninferiority was evaluated 1 month postprimary series for anti-HB seroprotection (SP). All other analyses were descriptive. Safety was assessed from parental reports. Results: Postprimary series noninferiority of anti-HB >= 10 mIU/mL was demonstrated for the DTaP-IPV-HB-PRP-T vaccine (94.0%) compared to the licensed control (96.1%). Postprimary series primary SP and seroconversion (SC) rates were high and similar for both groups. Antibody persistence (prebooster) was high for each antigen and similar between groups except for HB, which was lower for DTaP IPV-HB-PRP-T than for standalone HB. For each antigen except HB, DTaP-IPV-HB-PRP T booster responses were high and similar in each group. Safety was good for primary and booster series and similar between groups. Conclusion: The DTaP-IPV HB-PRP-T vaccine is immunogenic and safe when administered in a challenging primary series schedule without HB vaccination at birth. PMID- 29156871 TI - Relationship of spinal curvature, mobility, and low back pain in women with and without urinary incontinence AB - Background/aim: This study aimed to investigate the relationship of sagittal spinal curvature, mobility, and low back pain (LBP) in women with and without urinary incontinence (UI). Materials and methods: Thirty-two women with UI (incontinence group) and 41 women without UI (control group) were included in this study. The sagittal spinal curvature and mobility were assessed with a Spinal Mouse device (IDIAG, Fehraltorf, Switzerland). Urogenital symptom distress, LBP, and disability caused by LBP were assessed using the Urogenital Distress Inventory-6 (UDI-6), a visual analog scale (VAS), and the Oswestry Disability Index (ODI), respectively. Results: It was seen that the sagittal thoracic curvature, lumbar curvature, and pelvic tilt were increased in the incontinence group in comparison to the control group (P < 0.05). An increase in sagittal lumbar mobility and pelvic mobility was found in the incontinence group (P < 0.05). It was observed that 71.9% of the women with UI and 12.2% of the women without UI had LBP. There were positive correlations of the UDI-6 with the VAS (r = 0.363, P = 0.041) and the ODI (r = 0.511, P = 0.003). Conclusion: The sagittal spinal alignment and lumbopelvic hypermobility should be taken into consideration in the existence of UI. PMID- 29156872 TI - Plasma human leukocyte antigen-G (HLA-G) in patients with thyroid cancer AB - Background/aim: A number of tumor markers detected in the serum or pathological specimens using immunohistochemical methods are used for early detection of malignancies and postoperative follow-up. Human leukocyte antigen-G (HLA-G) is a nonclassic HLA class I molecule. Recent studies suggested a relationship between HLA-G positivity and the stage or the phenotype of the malignancy. In this study, the relationship between serum HLA-G positivity and thyroid cancer was investigated. Materials and methods: Fifty patients with thyroid cancer and 45 healthy volunteers were included in this study. Serum HLA-G levels were measured using ELISA. Results: HLA-G was positive in only 3 out of 50 patients with thyroid cancer (2 papillary, 1 follicular type). On the other hand, HLA-G was positive in 20 out of 45 healthy subjects (P < 0.001). The prevalence of detectable levels of serum HLA-G was independent of sex and age in the whole study population. No correlation was found between serum HLA-G value and thyroid hormone profile, neither in papillary thyroid cancer nor follicular thyroid cancer patients. Conclusion: In this study, serum HLA-G was significantly less common in patients with thyroid cancer than in healthy controls. PMID- 29156873 TI - Prevention of propofol injection-related pain using pretreatment transcutaneous electrical acupoint stimulation AB - Background/aim: This study aimed to study the effect of pretreatment transcutaneous electrical acupoint stimulation (TEAS) in preventing propofol injection-related pain. Materials and methods: A total of 360 patients who were to undergo elective hysteroscopy surgery were randomly divided into the following three groups of 120 patients each: control (Group C), sham TEAS (Group F), and TEAS (Group T). Patients in Group C did not undergo any treatment before surgery; 30 min before the induction of anesthesia, patients in Groups F and T underwent electrical stimulation of the bilateral LI4-PC6 acupoint. Patients in Group F were subjected to 'feeling flow', while those in Group T were subjected to 'tolerance flow.' The stimulation frequency was 2/100 Hz and the duration of stimulation was 30 min. After the induction of anesthesia, propofol injection related pain scores, hemodynamic parameters, and adverse reactions were recorded. Results: Of the 360 patients, 324 completed the study. There were significant differences among the groups in terms of the incidence of moderate-to-severe pain. In terms of the four-point scaling method, the end of the radial vein, the cubital vein, and the 'back of the hand' vein differed significantly among the three groups (P = 0.05). Finally, using a numerical rating scale, a significant difference was observed among the three groups in terms of the pain scores in the different veins. Conclusions: Pretreatment TEAS effectively reduces the incidence and severity of propofol injection-related pain, the incidence of postoperative nausea and vomiting, and patient postoperative pain scores. PMID- 29156874 TI - Application of hemoperfusion in severe acute organophosphorus pesticide poisoning AB - Background/aim: The aim of this research is to investigate the clinical efficacy of hemoperfusion in the treatment of severe acute organophosphorus pesticide poisoning (AOPP). Materials and methods: Patients meeting the inclusion criteria were divided into Groups 1 and 2 according to whether hemoperfusion was applied or not. Group 2 was observed as the control group. Conventional therapy for AOPP was given to Groups 1 and 2. Besides conventional treatment, patients in Group 1 were also treated with hemoperfusion therapy. Cholinesterase activity and blood glucose concentration were tested before hemoperfusion and for the first 3 days afterwards. The recovery time of 50% cholinesterase was recorded. At the same time, the incidence and mortality of intermediate syndrome was observed and compared. Results: The incidence and mortality of intermediate syndrome in Group 1 was obviously decreased, and the recovery time of cholinesterase activity was significantly shortened compared with Group 2. Conclusion: Hemoperfusion, used for treating severe AOPP, contributes to the improvement of cholinesterase activity, low incidence and mortality of intermediate syndrome, and increase in curative rate. PMID- 29156875 TI - Sex-related differences in the efficacy of dexamethasone pretreatment for postoperative analgesia in patients undergoing laparoscopic cholecystectomy: a randomized controlled study AB - Background/aim: Sex-related differences in response to pain have become a topic of increasing interest. However, sex-related differences in the efficacy of dexamethasone for postoperative analgesia have not been previously addressed. Materials and methods: The study included 196 men and 196 women, aged between 18 and 45 years, who were scheduled for laparoscopic cholecystectomy. The patients were randomly allocated into dexamethasone (M/F: 98/98) and control (normal saline; M/F: 98/98) groups. Patients in the study group received intravenous dexamethasone at 0.1 mg/kg (dexamethasone group) 1 h before induction of anesthesia. Patients in the control group received normal saline. Changes in cumulative morphine-containing, patient-controlled analgesia consumption in both sexes, pain intensity using a visual analog scale 24 h after surgery, mean morphine consumption adjusted for body weight, and incidence of postoperative nausea or vomiting were measured. Results: Women in both groups had significantly higher pain scores at 1 and 6 h postoperatively, higher levels of patient controlled analgesia and mean morphine consumption, and more postoperative nausea and vomiting (P < 0.05). These effects were less severe in the dexamethasone group. Conclusion: The results suggest that women are less responsive than men to dexamethasone for postoperative analgesia and experience higher levels of postoperative pain. PMID- 29156876 TI - The comparison of various disinfectants? efficacy on Staphylococcus aureus and Pseudomonas aeruginosa biofilm layers AB - Background/aim: Because biofilms are resistant to antibiotics and biocides, they usually cause chronic persistent infections, which are arduous to cure and have high mortality and morbidity. Our study aimed to investigate the efficiency of orthophthalaldehyde, peracetic acid, hydrogen peroxide, and sodium hypochlorite on Pseudomonas aeruginosa and Staphylococcus aureus biofilm layers and live microbial cells. Materials and methods: Biofilm layers were determined by crystal violet assay and live microbial cells were determined using a resazurin assay. Results: For Pseudomonas aeruginosa, sodium hypochlorite showed the most influential disinfection because it diminished 83.6% of the biofilm layer and decreased 99.7% of live microbial cells. For Staphylococcus aureus, hydrogen peroxide was determined the most active disinfectant with 80.3% reduction of the biofilm layer. Sodium hypochlorite was also determined to be the most efficient disinfectant with 99.8% reduction of live microbial cells. Sodium hypochlorite was the most influential disinfectant on biofilm layers and live microbial cells of both microorganisms. Conclusion: We concluded that if we use sodium hypochlorite at a high level as a disinfectant for both surfaces and medical equipment, it is beneficial to prevent infections related to biofilms. More studies about prevention of biofilm occurrence and standardization of the methods for investigating disinfectants? effects are necessary. PMID- 29156877 TI - Comparison of microscopy, ELISA, and real-time PCR for detection of Giardia intestinalis in human stool specimens AB - Background/aim: This study included patients who had digestive system complaints between August 2015 and October 2015. The research was designed to compare conventional microscopy with an antigen detection ELISA kit and the TaqMan-based real-time PCR (RT-PCR) technique for detection of Giardia intestinalis in human stool specimens. Materials and methods: Samples were concentrated by formalin ether sedimentation technique and microscopic examinations were carried out on wet mount slides. A commercially available ELISA kit (Giardia CELISA, Cellabs, Brookvale, Australia) was used for immunoassay. DNA was extracted from fecal samples of about 200 mg using the QIAamp Fast DNA Stool Mini Kit (QIAGEN, Hilden, Germany) and the LightCycler Nano system (Roche Diagnostics, Mannheim, Germany) was used for the TaqMan-based RT-PCR assay. Results: A total of 94 stool samples, 38 of them diagnosed positive (40.4%) and 56 of them diagnosed negative by microscopy, were selected for evaluation by antigen detection and molecular assays. The prevalence of G. intestinalis infection was found as 46.8% (n: 44) and 79.8% (n: 75) by ELISA and RT-PCR, respectively. RT-PCR revealed by far the highest positivity rate compared to the other two methods. The difference between these methods was found to be statistically significant (P < 0.05). In comparison to PCR, the sensitivity and specificity of microscopy and ELISA were 50.7% and 100% and 53.3% and 79%, respectively. Conclusion: RT-PCR seems to be much more sensitive and beneficial for rapid and accurate diagnosis of G. intestinalis in human stools. PMID- 29156878 TI - Common SPINK-1 genetic mutations do not predispose to Crohn's Disease PMID- 29156879 TI - Pediatric pityriasis rosea PMID- 29156880 TI - A Pumpless Acoustofluidic Platform for Size-Selective Concentration and Separation of Microparticles. AB - We have designed a pumpless acoustofluidic device for the concentration and separation of different sized particles inside a single-layered straight polydimethylsiloxane (PDMS) microfluidic channel. The proposed device comprises two parallel interdigitated transducers (IDTs) positioned underneath the PDMS microchannel. The IDTs produce high-frequency surface acoustic waves that generate semipermeable virtual acoustic radiation force field walls that selectively trap and concentrate larger particles at different locations inside the microchannel and allow the smaller particles to pass through the acoustic filter. The performance of the acoustofluidic device was first characterized by injecting into the microchannel a uniform flow of suspended 9.9 MUm diameter particles with various initial concentrations (as low as 10 particles/mL) using a syringe pump. The particles were trapped with ~100% efficiency by a single IDT actuated at 73 MHz. The acoustofluidic platform was used to demonstrate the pumpless separation of 12.0, 4.8, and 2.1 MUm microparticles by trapping the 12 and 4.8 MUm particles using the two IDTs actuated at 73 and 140 MHz, respectively. However, most of the 2.1 MUm particles flowed over the IDTs unaffected. The acoustofluidic device was capable of rapidly processing a large volume of sample fluid pumped through the microchannel using an external syringe pump. A small volume of the sample fluid was processed through the device using a capillary flow and a hydrodynamic pressure difference that did not require an external pumping device. PMID- 29156881 TI - Mesoscale Graphene-like Honeycomb Mono- and Multilayers Constructed via Self Assembly of Coclusters. AB - Honeycomb structure endows graphene with extraordinary properties. But could a honeycomb monolayer superlattice also be generated via self-assembly of colloids or nanoparticles? Here we report the construction of mono- and multilayer molecular films with honeycomb structure that can be regarded as self-assembled artificial graphene (SAAG). We construct fan-shaped molecular building blocks by covalently connecting two kinds of clusters, one polyoxometalate and four polyhedral oligomeric silsesquioxanes. The precise shape control enables these complex molecules to self-assemble into a monolayer 2D honeycomb superlattice that mirrors that of graphene but on the mesoscale. The self-assembly of the SAAG was also reproduced via coarse-grained molecular simulations of a fan-shaped building block. It revealed a hierarchical process and the key role of intermediate states in determining the honeycomb structure. Experimental images also show a diversity of bi- and trilayer stacking modes. The successful creation of SAAG and its stacks opens up prospects for the preparation of novel self assembled nanomaterials with unique properties. PMID- 29156882 TI - Insights in the Diffusion Controlled Interfacial Flow Synthesis of Au Nanostructures in a Microfluidic System. AB - Continuous segmented flow interfacial synthesis of Au nanostructures is demonstrated in a microchannel reactor. This study brings new insights into the growth of nanostructures at continuous interfaces. The size as well as the shape of the nanostructures showed significant dependence on the reactant concentrations, reaction time, temperature, and surface tension, which actually controlled the interfacial mass transfer. The microchannel reactor assisted in achieving a high interfacial area, as well as uniformity in mass transfer effects. Hexagonal nanostructures were seen to be formed in synthesis times as short as 10 min. The wettability of the channel showed significant effect on the particle size as well as the actual shape. The hydrophobic channel yielded hexagonal structures of relatively smaller size than the hydrophilic microchannel, which yielded sharp hexagonal bipyramidal particles (diagonal distance of 30 nm). The evolution of particle size and shape for the case of hydrophilic microchannel is also shown as a function of the residence time. The interfacial synthesis approach based on a stable segmented flow promoted an excellent control on the reaction extent, reduction in axial dispersion as well as the particle size distribution. PMID- 29156883 TI - Low-Molecular-Weight Supramolecular Ionogel Based on Host-Guest Interaction. AB - Supramolecular ionogels were prepared by self-assembly of small molecules through host-guest interaction between beta-cyclodextrin (beta-CD) and a room-temperature ionic liquid (IL) 3-(1-methyl-3-imidazolio)propanesulfonate-lithium bis(trifluoromethanesulfonyl)imide (MIPS-LiTFSI) which contains zwitterion MIPS. 19F NMR and 2D ROESY 1H NMR have been used to prove that only TFSI- is involved in the complexation. 1H NMR, FT-IR, and comparative tests indicated that the electrostatic interaction between imidazole cation and TFSI- anion and intermolecular hydrogen bonding between three compounds also contribute to the formation of supramolecular ionogel. Ionogels with different gel-sol phase transition temperatures can be obtained by adjusting the molar ratio between beta CD and MIPS-LiTFSI. In addition, the supramolecular ionogels composed of "channel type" structural beta-CD have been constructed. The ionogel with high conductivity and low activation energy open a door to new fields for special applications. PMID- 29156884 TI - A Simple Method of Predicting Spin State in Solution. AB - A simple method, using density functional theory (DFT), of predicting spin-state in advance of synthesis is reported. Specifically, an excellent correlation is observed between the switching temperatures (T1/2) in CDCl3 solution of five spin crossover (SCO)-active [FeII(Lazine)2(NCBH3)2] complexes and the DFT-calculated (and observed) 15N NMR chemical shift (deltaNA) of the five different azine substituted 1,2,4-triazole ligands employed, Lazine = 4-(4-methylphenyl)-3-phenyl 5-(azine)-1,2,4-triazole, where azine = pyridine, pyridazine, 4-pyrimidine, pyrazine, and 2-pyrimidine. To test the generality of this finding, DFT was also employed to readily predict the deltaNA values for a family of 16 literature ligands, known as bppX,Y [X,Y-substituted 2,6-(pyrazol-1-yl)pyridines], which have produced 16 SCO-active [FeII(bppX,Y)2](Z)2 complexes (Z = BF4 or in one case PF6) in (CD3)2CO solution: again an excellent correlation was found between the computed deltaNA and the observed T1/2. These correlations represent a key advance in the field, as they allow a simple DFT calculation on a modified ligand to be used to reliably predict, before synthesis of the ligand or complex, the T1/2 that would result from that modification. Achieving such easily predictable tuning of T1/2, and hence of spin-state, is a significant step forward in the field of SCO and also has big implications in many other fields in which spin state is key, including catalysis, metallo-enzyme modeling studies, and host guest chemistry. PMID- 29156885 TI - Synthesis of Polyflourinated Biphenyls; Pushing the Boundaries of Suzuki-Miyaura Cross Coupling with Electron-Poor Substrates. AB - Polyfluorinated biphenyls are interesting and promising substrates for many different applications. Unfortunately, all current methods for the syntheses of these compounds only work for a hand full of molecules or only in very special cases. Thus, many of these compounds are still inaccessible to date. Here we report a general strategy for the synthesis of a wide range of highly fluorinated biphenyls. In our studies we investigated crucial parameters, such as different phosphine ligands and the influence of various nucleophiles and electrophiles with different degrees of fluorination. These results extend the scope of the already very versatile Suzuki-Miyaura reaction toward the synthesis of very electron-poor products, making these more readily accessible. The presented methodology is scalable and versatile without the need for elaborate phosphine ligands or Pd-precatalysts. PMID- 29156886 TI - Advocacy and pancreas cancer: a new world. PMID- 29156887 TI - Technical aspects of pancreaticoduodenectomy and their outcomes. AB - Pancreatic cancer is the fourth leading cause of cancer-related death in the Unites States and is rising in incidence. For the 15-25% of patients who do not have either metastatic or locally advanced disease, surgical resection with pancreaticoduodenectomy is the standard of care and results in improved 5-year survival of 15-25%. While mortality at high-volume centers is less than 5%, morbidity remains high at approximately 30-45%. This paper reviews technical aspects of pancreaticoduodenectomy and their outcomes. Specifically, we review technique and the outcome literature on vascular reconstruction, attempts to decrease delayed gastric emptying (DGE), including pylorus-preserving versus classic pancreaticoduodenectomy and gastrojejunostomy (GJ) technique, as well as attempts to decrease the rate of pancreatic fistula, including the use of pancreatic stents, fibrin sealant, and pancreaticojejunostomy (PJ) technique. Vascular resection and reconstruction have been associated with increased morbidity and mortality. However, the literature suggests that if it allows for an R0 resection, the survival is improved with comparable complication rates. DGE, one of the most common post-pancreaticoduodenectomy complications, has not been reliably decreased with various technical modifications of the GJ. The incidence of pancreatic fistula, one of the most morbid postoperative complications, is not definitively reduced by either the use of pancreatic stents or fibrin sealant. Additional research is needed to determine methods to further decrease rates of morbidity. PMID- 29156888 TI - Chimeric antigen receptor (CAR) T and other T cell strategies for pancreas adenocarcinoma. AB - Treatments in metastatic pancreas cancer remain based in cytotoxic chemotherapy, and novel treatment strategies are needed. Building on the emerging role of T cell therapy in hematologic malignancies and our understanding of the underlying biology of pancreas cancer, research is growing in the role of T cell therapy for patients with solid tumors in general and more specifically patients with pancreas cancer. This review will focus on describing the biology of T cell therapy and its current applications in pancreas cancer. PMID- 29156889 TI - Chemotherapy induced oral mucositis: prevention is possible. AB - BACKGROUND: Oral mucositis (OM) is an inflammation of the oral mucosa which occurs in 20-40% of patients receiving conventional chemotherapy (CM). Many different substances have been used separately to treat or prevent OM but no standard procedure has been settled as definitive. We conducted a prospective study to examine whether rinses with a mixture of soluble prednisolone, nystatin and salt water applied before the expected OM appears, would reduce the incidence of grade 2-3 OM in subsequent cycles of CM. METHODS: Prospective study of breast cancer patients undergoing neoadjuvant or adjuvant treatment with FEC (5 fluorouracil, epirubicin, cyclophosphamide) or docetaxel who developed OM grade 2 or 2-3 with the previous cycle. The specific mouthwash consisted of a combination of 100 mL of water, 5 mg of soluble prednisolone, 2 drops of nystatin and 2.300 mg of salt (1 teaspoon). Patients received clear instructions on how to use it. The primary end-point was the incidence of OM grade 2-3 with the following cycle of CM. Secondary end-points were the rate of CM dose reduction (DR) and the incidence of OM grade 0, 1 and 2 with the following treatment. RESULTS: Sixty eight patients were included. Twenty-three developed OM grade 2-3 after first cycle. After using this mouthwash, only two cases developed grade 2-3 OM. Only four cases needed a CM DR. CONCLUSIONS: Our study showed a significant reduction in the rate of OM grade 2-3 in patients using the especial mouthwash. This mouthwash is currently used as standard in our institution. Further evaluation in other centres to confirm these results is needed. PMID- 29156890 TI - Why the results of adjuvant pertuzumab in HER2-positive early breast cancer has been received as a mitigate success? PMID- 29156891 TI - Investigating the role of tumor-infiltrating lymphocytes in advanced HER2 positive breast cancer. PMID- 29156892 TI - Trastuzumab emtansine in HER2-positive metastatic breast cancer: what is the best sequence? PMID- 29156893 TI - Meditational spiritual intercession and recovery from disease in palliative care: a literature review. AB - Human body is a biological, open system and maintains itself in the changing environment. Disease state is cured by many medicinal systems for healing. Esoteric healing (through introspective hypnosis, meditation and spiritual intercession) is the system where its believers regard Supreme Being as Omnipotent, Omnipresent and Omniscient. Such persons take ill health as a boon and pray through meditation that He may by His Mercy grant health or if God wishes otherwise, they happily accept it so that they keep moving ahead on their spiritual path. This study is a review of literature, where results clearly point towards better psychological and spiritual healing in patients who believe in esoteric cures. Modern science in terms of cognitive psychology or neurophysiology has begun to emphasize the role of consciousness but, that is confined only to the physical world. It is only with the advent of Param Purush Puran Dhani Soami Ji Maharaj (200 years ago) that in the religion of Saints, the ultimate consciousness or the Super Consciousness of the highest order has been revealed. PMID- 29156894 TI - Clinical hypnosis, mindfulness and spirituality in palliative care. AB - In this article, I do not intend to present the many and well-known treatments for relieving pain and distress symptoms of the physical body, damaged by terminal diseases, such as cancer, AIDS, multiple sclerosis. In this article, I'd rather focus my attention on clinical hypnosis for subjects who, freed from physical pain, thanks to palliative care, are open to receiving comfort and support for their psychological and spiritual suffering. The intent of this article is to express how clinical hypnosis can harmoniously integrate psychological and spiritual aspects so that the terminal patient can make peace with his/her past, with the people who have hurt him/her, and with the people who will suffer because of his/her death. This article will present some hypnotic suggestions inspired by universal wisdom of the Stoics, by positive psychology of Mindfulness, by laws of nature regarding changes, differences and mysteries. The basic assumption of the suggestions presented is that, if disease is an enemy to fight, death is an inevitable part of life: it cannot be avoided, or postponed or exchanged with anybody. It arrives when we have finished living. When death is preceded by an incurable disease, palliative care can offer a mantle of compassion and acceptance of what cannot be avoided. The words palliative comes from the Latin pallium-mantle. This article also presents some suggestions I have utilized several times with my patients. These suggestions have demonstrated their efficacy in alleviating patients' suffering in coping with their disease and in facing death. PMID- 29156895 TI - Survival analysis of malignant epidural spinal cord compression after palliative radiotherapy using Tokuhashi scoring system and the impact of systemic therapy. AB - BACKGROUND: Previous studies have shown similar clinical outcomes of both single and multi-fraction (Fr) radiation therapy among malignant epidural spinal cord compression (MSCC) patients with poor prognosis; whereas, patients expected to have longer survival may require long-course radiotherapy to prevent local failure. However, such a poor prognosis risk group has not yet been clearly identified for use in daily clinical practice. We examined if the known predictive Tokuhashi scoring system could be adapted in MSCC patients treated with palliative radiation therapy. METHODS: A retrospective review of the treatment outcomes of MSCC patients who received palliative radiotherapy from January 2014 to May 2015 was conducted. The patients were stratified into two groups according to the Tokuhashi scoring system: group 1 (score <9), expected survival <6 months, and group 2 (score >8), expected survival >6 months. Their survival was tested against subsequent systemic therapy (chemotherapy, targeted or hormonal therapy) and other risk factors including age, primary site, visceral metastasis, baseline motor function, prior radiotherapy and radiotherapy fractionation (single or multiple). RESULTS: The outcomes of 119 patients were studied, 116 (97.5%) patients had already succumbed. The overall median survival was 55 days (range, 4-576 days). Ninety-three patients (78.2%) belonged to group 1. The median dose delivered was 25 Gy in 5 Frs [range, 7 Gy in 2 Frs-40 Gy in 10 Frs (to the cauda equina)]. Only nine patients (7.6%) received single-Fr radiotherapy, all belonging to Tokuhashi group 1. Patients belonging to group 1 had shorter median survival than group 2; 49 and 108 days, respectively (P=0.003). Among all the patients, subsequent systemic treatment [hazard ratio (HR) =0.407; 95% confidence interval (CI), 0.236-0.702; P=0.001], non-visceral metastasis (HR =0.608; 95% CI, 0.387-0.956; P=0.031) and primary lung or breast or prostate cancer (P=0.029) were associated with better survival in multivariate analysis. For patients in group 1, primary breast or prostate cancer (HR =0.264; 95% CI, 0.122-0.572; P=0.001) or lung cancer (HR =0.421; 95% CI, 0.246-0.719; P=0.002), non-visceral metastasis (HR =0.453; 95% CI, 0.264-0.777; P=0.004), multi-Fr (HR =0.455; 95% CI, 0.217-0.956; P=0.038) and subsequent systemic therapy (HR =0.460; 95% CI, 0.252-0.842; P=0.012) were associated with better survival. The survival of a subset of patients in group 1 without subsequent systemic therapy was dismal (median survival only 40 days) and not altered by radiotherapy schedule (P=0.189). CONCLUSIONS: MSCC comprises a very heterogenous group of patients, even under the Tokuhashi grouping. Systemic therapy or visceral metastasis may be more important prognostic factors. Further studies are necessary to better select the poor prognosis risk group. In clinical practice, single-Fr radiotherapy could be considered in Tokuhashi group 1 patients due to their expected short survival, especially for those without reasonable systemic treatment options. PMID- 29156896 TI - PROutine: a feasibility study assessing surveillance of electronic patient reported outcomes and adherence via smartphone app in advanced cancer. AB - BACKGROUND: In advanced cancer, quality of life (QoL) is a major treatment goal. In order to achieve this, the identification of suffering by screening for patient-reported-outcomes (PROs, i.e., symptoms) is of utmost importance. The use of paper-pencil questionnaires is associated with significant shortcomings due to missing data, recall bias and transcription errors. Other than that, the electronic recording of PROs by mobile Health (mHealth) offers a number of advantages. The aim of this study was to test whether the routine assessment of PROs via a newly developed smartphone application (MeQoL(r)) is feasible. METHODS: A prospective, uncontrolled, multi-center, feasibility trial was performed in adult outpatients with advanced, solid cancer. Patients under anti cancer therapy and with regular outpatient visits were eligible. Patients daily recorded the degree of perceived distress (NCCN Distress Thermometer(r)), pain intensity {average and worst [numerical rating scale (NRS), 0-10]}, the number of breakthrough pain episodes (BPE) and ten questions from a modified version of the Edmonton Symptom Assessment Scale (ESAS). Weekly, five questions concerning different domains of QoL from the short-form 8 (SF-8) questionnaire were obtained. Also, patients recorded the intake of their opioid rescue medication. According to the main scope of the trial (feasibility), no primary endpoint was defined. Rather, the following main feasibility criteria were assessed: missing data, drop-out- and acceptance-rate, patient satisfaction, patients' judgement of practicability, patients' and physicians' suggestions for improvement and basic clinical and demographic data of the participating patients. The study was registered in the German Clinical Trials Register (ID: DRKS00008761). RESULTS: In three German cancer centers, 40 patients {female: 28 (70%); average age, 57 years [range, 27-73 years; standard deviation (SD), 12]} were included. As three devices were lost on transport, 37 devices could be evaluated. The median investigation period per device was 99.5 days (SD, 31). Patient adherence in using the smartphone app to document their distress and symptoms was high and missing data were low: In median daily reviews were performed on 70 (SD, 29) of these days (70%) and median weekly recordings were 13 weeks (87%). Most often, patients recorded symptom intensity (89%, MIDOS) and distress (85%, NCCN thermometer). On feedback forms, patients reported a good to very good user friendliness of MeQoL(r) and a high motivation to use this tool again. CONCLUSIONS: Even though participants were asked to record PROs rather frequently (daily), missing data were low and patient satisfaction was high. Having in mind the findings of other working groups, such routine implementation of mHealth solutions may substantially improve outcomes of cancer therapy and increase the value of trials' findings. For the individual patient, MeQoL(r) allows for monitoring adherence to pharmacotherapy and can facilitate patient guidance. PMID- 29156897 TI - "Triggers" for referral to neurology palliative care service. AB - In neurology, many diseases are still incurable and have a fatal outcome. Palliative care (PC) definitely has a role in neurology. We discuss the screening criteria for PC referral, known as 'triggers' in different neurological diseases. Different clinical settings including in-patient and out-patient are covered. We hope this review can remind clinicians to involve PC in the appropriate patient group. Further clinical studies are expected to validate the triggers and trajectories of various neurological diseases. PMID- 29156898 TI - "More care, research and recognition" for neuro-palliative development. PMID- 29156899 TI - Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies. AB - Chemotherapy-induced neuropathic pain is a distressing and commonly occurring side effect of many commonly used chemotherapeutic agents, which in some cases may prevent cancer patients from being able to complete their treatment. Cannabinoid based therapies have the potential to manage or even prevent pain associated with this syndrome. Pre-clinical animal studies that investigate the modulation of the endocannabinoid system (endogenous cannabinoid pathway) are being conducted to better understand the mechanisms behind this phenomenon. Five recent pre-clinical studies identified from Medline published between 2013 and 2016 were selected for review. All studies evaluated the effect of small-molecule agonists or antagonists on components of the endocannabinoid system in rats or mice, using cisplatin or paclitax-el-induced allodynia as a model of chemotherapy induced neuropathic pain. Activation of the cannabinoid receptor-2 (CB-2) receptor by AM1710 blocked paclitaxel-induced mechanical and cold allodynia in one study. Four studies investigating the activation of both cannabinoid receptor 1 (CB-1) and CB-2 receptors by dual-agonists (WIN55,21 and CP55,940), or by the introduction of inhibitors of endocannabinoid metabolisers (URB597, URB937, JZL184, and SA-57) showed reduction of chemotherapy-induced al-lodynia. In addition, their results suggest that anti-allodynic effects may also be mediated by additional receptors, including TRPV1 and 5-hydroxytryptamine (5-HT1A). Pre clinical studies demon-strate that the activation of endocannabinoid CB-1 or CB-2 receptors produces physiological effects in animal models, namely the reduction of chemotherapy-induced allodynia. These studies also provide in-sight into the biological mechanism behind the therapeutic utility of cannabis compounds in managing chemotherapy-induced neuropathic pain, and provide a basis for the conduct of future clinical studies in patients of this population. PMID- 29156900 TI - Implementation of an advance directive focus in a Chronic Multi-Organ Rare Disease Clinic. AB - BACKGROUND: Education about an advance directive is frequently not addressed in the outpatient, ambulatory care setting. The objective of this study was to identify patients that do not have an advance directive in a Chronic Multi-Organ Rare Disease Clinic model, and define the role of a social worker in providing advance care planning (ACP). METHODS: The Chronic Multi-Organ Rare Disease Clinic in-corporates a multi-disciplinary team to provide outpatient care to over 600 patients. A review of advance directives filed in the electronic health record (EHR) prior to hiring a clinic social worker was examined in this high risk population. RESULTS: A total of 15 patients (2%) of this patient population were identified as having a completed, active advance directive filed with their EHR prior to hiring a clinic social worker. The clinic social worker began ACP discussions and inquiries about the status of patient advance directives with a total of 162 patients during September 2016-April 2017. Of these 162 patients, 14 patients (8.6%) submitted their completed advance directives for filing with their EHR after advanced care discussions were initiated by the clinic social worker. Two patients who completed an advance directive, died during this 7-month time period. Only three patients declined to complete advance directives during this same time period. CONCLUSIONS: Patient-centered care must incorporate ACP. A clinic social worker is an effective member of a multi-disciplinary team and can incorporate education about advance directives in order to improve health care quality. PMID- 29156902 TI - Symptomatic palliation with radiotherapy in extensive heterotopic ossifications. AB - Heterotopic ossification (HTO) is the dystrophic formation of mature lamellar bone outside the confines of normal osseous tissues. It is frequently a complication which occurs following traumatic insult, both iatrogenic and non iatrogenic, and neurological compromise. While mild degree of disease is often asymptomatic, significant pain and mobility limitations may result in reduced quality of life in advanced cases. Currently, the commonly accepted management for patients experiencing significant symptomatic HTOs is a combination therapy of surgical excision with prophylactic radiotherapy in the immediate perioperative period. In this article, we present a patient who achieved satisfactory pain relief and improvements in overall quality of life with the sole use of external beam radiation to illustrate the possibility of using radiotherapy alone for symptomatic management of HTO. PMID- 29156901 TI - Patient-centered family meetings in palliative care: a quality improvement project to explore a new model of family meetings with patients and families at the end of life. AB - BACKGROUND: Family meetings in palliative care can enhance communication with family members and identify unmet needs. However, the patient's voice may not be heard. METHODS: This pre and post-test quality improvement project was conducted from 2013-2014 and investigated a patient-centered family meeting, which is a different approach to palliative care family meetings, to determine its feasibility and acceptability for patients, family and the palliative care team. Newly admitted patients to an Australian in-patient specialist palliative care unit were invited to ask anyone they wished to join them in a meeting with the palliative care team and to identify issues they wished to discuss. Consenting inpatients were interviewed shortly after admission; participated in a family meeting and re-interviewed 2-3 days after the meeting. Family members provided feedback at the end of the meeting. A focus group was held with staff for feedback on this new approach for family meetings. Meetings were observed, documented and thematically analyzed. RESULTS: Thirty-one newly admitted patients were approached to participate in a family meeting. Eighty-four percent had family meetings and the majority (96%) was attended by the patient. Thematic analysis revealed 69% of patient-centered meetings raised end-of-life concerns and 54% were "family-focused". CONCLUSIONS: Patient-centered family meetings in palliative care were shown to be feasible and acceptable for staff, patients and family members. Many patients and families spontaneously shared end-of-life concerns. A patient-centered approach to family meetings that includes active patient involvement may provide additional and valued opportunities for patients and families to: express mutual concerns, deliver messages of comfort and appreciation, and prepare for death. Further investigation of this approach, including families' bereavement outcomes, is warranted. PMID- 29156903 TI - Gender differences in pain and patient reported outcomes: a secondary analysis of the NCIC CTG SC. 23 randomized trial. AB - BACKGROUND: Gender differences may contribute to variations in disease presentations and health outcomes. To explore the gender difference in pain and patient reported outcomes in cancer patients with bone metastases undergoing palliative radiotherapy on the National Cancer Institute of Canada (NCIC) SC.23 randomized trial. METHODS: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) bone metastases module (QLQ-BM22) and EORTC QOL Core-15-Palliative (QLQ-C15-PAL) before treatment and at days 10 and 42 after a single 8 Gy radiation treatment. Patient demographics, performance status, analgesic consumption, BM22 and C15 were compared between males and females using the 2-sample t-test for continuous variables or the Chi-squared test for categorical variables. Multiple linear regression models were used to check the difference between gender groups adjusting for the baseline demographics and primary disease sites. RESULTS: There were 298 patients (170 male, 128 female) with median age of 69 years. The most common primary cancer sites were lung, prostate and breast. At baseline, there were no differences in BM22 and C15 scores, except a worse nausea and vomiting score (P=0.03) in females on the C15. In patients with moderate baseline worst pain scores (WPS), females reported worse scores in painful sites of BM22. At day 42, there was no significant difference in response to radiotherapy. Among the responders, females reported better improvement in emotional aspect. CONCLUSIONS: In cancer patients with bone metastases undergoing palliative radiotherapy, the majority of symptom presentations, patient reported outcomes, and response to radiation was not significantly different between genders. TRIAL REGISTRATION: NCT01248585. PMID- 29156904 TI - Does gender affect self-perceived pain in cancer patients? -A meta-analysis. AB - BACKGROUND: Pain is reported in approximately 50-70% of cancer patients. Studies on gender differences in perceived pain generally report lower pain thresholds and increased pain prevalence in women, which may be attributed to gender specific behaviors, stereotypes, and unknown etiological factors. There are sparse and inconclusive results on gender differences in self-perceived pain in the cancer setting. The aim of this article was to examine the effect of gender on baseline perceived pain intensity in cancer patients through a meta-analysis. METHODS: A literature search was conducted using Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials [1947-2016] to identify observational studies and controlled trials that reported on gender-specific pain intensity in cancer patients. Using random-effects modeling, weighted mean differences and 95% confidence intervals (CI) were used to estimate the effect of gender on pain severity in cancer patients. A P value of less than 0.05 was considered statistically significant. RESULTS: Of the 1,911 search results reviewed, 13 studies were included. The weighted mean difference (95% CI) in pain intensity was as follows: -0.26 (95% CI: -0.57 to 0.04, P=0.09) for the 0-10 Numerical Rating Scale (NRS) group (n=3,752, 9 studies). When restricted to only patients with advanced cancer, the weighted mean difference was -0.08 (95% CI: 0.36 to 0.20, P=0.58) (n=2,762, 4 studies). The weighted mean difference in the Brief Pain Inventory scores between males and females was 0.03 (95% CI: -1.23 to 1.29, P=0.96) (n=521, 4 studies). CONCLUSIONS: Baseline perceived pain intensity in cancer patients did not significantly differ based on gender. PMID- 29156905 TI - I hurt so: hypnotic interventions and palliative care for traumatic brain injury. AB - This article presents a case study in which self-hypnosis, hypnosis-assisted psychotherapy, and palliative care strategies were provided within a multi-modal integrative treatment program for a 38-year-old woman with traumatic brain injury (TBI) secondary to motor vehicle accident. Self-hypnosis was helpful in anxiety reduction and pain management. Hypnosis-assisted psychotherapy was beneficial in de-sensitizing many post-traumatic memories, and in managing post-concussion pain, including neuropathic pain and post-traumatic migraine headaches. A variety of palliative care techniques and spiritual interventions were applied to enhance sleep, moderate cognitive deficits, and enhance quality of life. PMID- 29156906 TI - The development of neurology palliative care service for motor neuron disease (MND) patients: Hong Kong experience. AB - BACKGROUND: Motor neuron disease (MND) is a neurodegenerative disease characterized by loss of motor neurons in the spinal cord, brainstem and motor cortex. Clinically it is manifested as progressive decline in physical, respiratory, swallowing and communication function and ultimately death. Traditional model of care was fragmented and did not match with patients and carers multi-facet needs. METHODS: A special workgroup for MND patients that includes neurologist, respiratory physician, rehabilitation specialist and palliative care (PC) physician was formed in Hong Kong since year 2013. In various disease phase, each specialty team play a leading role in coordinated care of MND patients. RESULTS: From Apr 2013 to Mar 2015, 41 patients newly diagnosed with MND were cared in our model. 96.4% agreed to participate in the ACP discussion. Seventy-five percent of them opted for do-not-attempt cardiopulmonary resuscitation (DNACPR) and no intubation/mechanical ventilation. There were 16 (51.6%) of patients passed away within the review period. All of them succumbed with no CPR performed which was honoring their wish. The average duration under PC was 118 days. CONCLUSIONS: Strategies toward standardizing care delivery for MND patients and carers may help to address the physical, psychosocial and spiritual needs of MND patients. The experience shared from this article conceptualizes the roles of various multi-disciplinary team members, with emphasis paid on PC team position in taking care of advanced MND patients. PMID- 29156907 TI - The palliative care needs for those advanced neurology patients on mechanical ventilator support. AB - There are mainly two types of needs for the ventilator users with severe neurological diseases: respiratory related needs include mode of ventilation selection, mode of ventilator prescription, maintaining lung recruitment and good airway clearance; non-respiratory related needs include substantial nursing care, adequate nutrition, accessible communication and psychological support. All these are important to maintain the quality of life of these patients. PMID- 29156908 TI - Enhanced psychosocial support as important component of neuro-palliative service. AB - There are unmet palliative care (PC) needs for psychosocial and spiritual distress of neurology patients such as bad stroke as well as in chronic neurodegenerative diseases. As such, psychosocial support to both patients and their caregivers should be enhanced in order to provide comprehensive neuro-PC. The first step in developing this type of support/program was to recognize the main psychosocial care needs of the population. Once these were determined, a program was specifically devised to meet those needs as efficiently and effectively as possible. Several studies have shown the importance and value of psychosocial support for terminally ill patients. Generally, the psychosocial aspects of PC generally receive little or no attention in such studies due to financial limitations and, perhaps more importantly, because PC remains an evolving concept. Recent studies of psychological therapies have yielded relevant results in terms of effectiveness and have shown improvement regarding life meaning and well-being in end-of-life patients. However, there are still gaps in providing psychosocial support to the advanced neurology patients opted for PC. PMID- 29156909 TI - Genetic biomarkers associated with response to palliative radiotherapy in patients with painful bone metastases. AB - BACKGROUND: Palliative radiotherapy (RT) is effective in patients with painful bone metastases. Genetic factors may identify subgroup of patients who responded to RT. To identify DNA biomarkers associated with response to palliative RT. METHODS: Patients who received a single 8 Gy dose of RT for painful bone metastases were categorised into responders (n=36), non-responders (NR) (n=71). Saliva samples were sequenced to identify single-nucleotide variants (SNVs) in genes with known disease-causing variants from inflammation, radiation response, and DNA damage pathways. In univariate analysis, Cochran-Armitage trend tests were used to identify SNVs that associated with pain response (P<0.005), and the Penalized LASSO method with minimum Bayesian Information Criterion was used to identify multi-SNVs that jointly predict pain response to RT. The corresponding estimated effect of the multi-SNVs were used to drive the prognostic score for each patient. Based on it, patients were divided into 3 equal size risk groups. RESULTS: Forty-one significant variants were identified in univariate analysis. Multivariable analysis selected 14 variants to generate prognostic scores, adjusting for gender and primary cancer site. Eighty-nine percent of patients in the high prognostic group responded to palliative radiation therapy (P=0.0001). Estimated effect sizes of the variants ranged from 0.108-2.551. The most statistically significant variant was a deletion at position 111992032 in the ataxin gene ATXN2 (P=0.0001). Five variants were non-synonymous, including AOAH rs7986 (P=0.0017), ZAN rs539445 (P=0.00078) and rs542137 (P=0.00078), RAG1 rs3740955 (P=0.0014), and GBGT1 rs75765336 (P=0.0026). CONCLUSIONS: SNVs involved in mechanisms including DNA repair, inflammation, cellular adhesion, and cell signalling have significant associations with radiation response. SNVs with predictive power may stratify patient populations according to likelihood of responding to treatment, therefore enabling more efficient identification of beneficial strategies for pain management and improved resource utilisation. PMID- 29156911 TI - Prognostic indicators of neuromuscular disorders for palliative care referral. AB - BACKGROUND: Most of the neuromuscular disorders (NMDs) have poor prognosis and lead to various symptoms amendable to palliative care. However, the suitable time of referral is uncertain. METHODS: A retrospective study was conducted to describe the trajectories of NMDs. Early death within one year after NMD diagnosis was set as the outcome. Total of 86 adult NMD patients were recruited in a university hospital. Demographic variable including gender, age at diagnosis and early-onset symptoms including dyspnea, dysphagia, loss of mobility, constipation, mood and sleep disorders, and pain were correlated with the outcome. Prediction models for early death were tested. RESULTS: Age at NMD diagnosis, early-onsets dyspnea, dysphagia, constipation and impaired mobility were found to have statistically significant correlation with early death. A prediction model consisted of these four factors had area under receiver operating characteristic (ROC) curve of 0.919. CONCLUSIONS: Elder age at NMD diagnosis, early-onset dyspnea, dysphagia, constipation and impaired mobility within the first year after NMD diagnosis may predict mortality within the first year after diagnosis. It may provide guidance to clinicians for early palliative care referral in this patient group. PMID- 29156910 TI - Genetic biomarkers associated with changes in quality of life and pain following palliative radiotherapy in patients with bone metastases. AB - BACKGROUND: Patients with bone metastases undergoing palliative radiation therapy (RT) may experience changes in both the functional and symptomatic aspects of quality of life (QOL). The European Organization of Cancer Research and Treatment (EORTC) QOL Questionnaire Core-15 Palliative (QLQ-C15-PAL) is a validated questionnaire employed to assess QOL specifically in palliative patients. Our study aimed to identify single-nucleotide variant (SNV) genetic biomarkers associated with changes in QOL and pain. METHODS: Fifty-two patients who received a single 8-Gy RT for painful bone metastases completed the EORTC QOL-C15-PAL questionnaire prior to randomization and at 42-day post RT. Saliva samples obtained at day of RT were sequenced, and SNVs from genes involved in inflammation, radiation response, immune response, DNA damage, or QOL were assessed for association with changes in global QOL or the pain scale items using the Cochran-Armitage trend test. The penalized LASSO method with minimum Bayesian information criterion was used to select a multi-SNV model out of significant SNVs (P<0.005) and to produce prognostic scores for patients that categorized them into risk groups of low, middle, and high. RESULTS: The multivariable model predicting global QOL included 14 SNVs, of which HS1BP3 rs35579164 G:C and ABCA1 rs2230805 C>T had the largest positive and negative effect sizes, respectively (HS1BP3: 8.21, ABCA1: -3.44). The model for the response of QOL pain item included 8 SNVs, of which PLAUR rs4760 A>G and ELAC2rs11545302 had the largest positive and negative effect sizes, respectively (PLAUR: 5.23; ELAC: -3.84). The patients' risk groups were highly predictive of QOL response (P<0.0001) and pain item response (P<0.0001). In logistic regression analysis accounting for baseline factors of gender and primary cancer site, the global QOL risk group predicts pain response after RT [OR: 2.1, 95% confidence interval (CI): 1.2-3.9, P=0.015], but the QOL pain item risk group did not (OR: 0.93; 95% CI: 0.5-1.6, P=0.79). The multi-SNVs model included SNVs from genes involved in metabolism, membrane transport, cell cycle control, ciliary structure, and gene expression regulation. CONCLUSIONS: SNVs were significantly associated with changes in global QOL of global domain and pain item in patients with bone metastases. Identification of genetic biomarkers predictive of QOL items may allow patients and health care providers anticipate and better address the needs of the palliative cancer patient population. PMID- 29156913 TI - Symptom clusters using the Brief Pain Inventory in patients with breast cancer. AB - BACKGROUND: The purpose of this study was to assess symptom clusters in functional interference using the brief pain inventory (BPI) in patients with non metastatic breast cancer (BC) during and after chemotherapy. METHODS: A principal component analysis with varimax rotation was conducted on data from 228 patients to identify two clusters at baseline and two intervals following treatment. RESULTS: Physical (general activity, normal work, walking ability) and psychosocial (mood, relationships, sleep, enjoyment of life) interference clusters were present at baseline. Clusters were observed at 1-month (cluster 1: general activity, normal work, enjoyment of life; cluster 2: relationships, sleep) and 3-month (cluster 1: general activity, normal work, relationships; cluster 2: sleep, enjoyment of life) post-treatment. CONCLUSIONS: Results from our study suggest dynamic symptom clusters in this patient population, and encourage continued symptom management following completion of treatment. PMID- 29156912 TI - Genetic biomarkers associated with pain flare and dexamethasone response following palliative radiotherapy in patients with painful bone metastases. AB - BACKGROUND: In patients who receive palliative radiation therapy (RT) for painful bone metastases, 40% experience a transient increase in pain known as a pain flare. Prophylactic dexamethasone has been shown to reduce pain flare incidence to 25%. We aimed to identify DNA biomarkers associated with pain flare and dexamethasone response. METHODS: Daily pain levels were recorded by 81 patients who received a single 8 Gy RT for painful bone metastases, of which 50 also received prophylactic dexamethasone. To identify single-nucleotide variants (SNVs), patient saliva samples obtained at day of RT were sequenced for 4,813 disease-associated genes, then filtered for genes associated with inflammation, radiation or immune response, and DNA damage. Significant SNVs (P<0.005) identified by the Cochran-Armitage trend test underwent the Penalized LASSO method with minimum Bayesian Information Criterion to select a multi-SNV model that jointly predicted pain flare, and pain flare despite prophylactic dexamethasone (dexamethasone response). The corresponding estimated effects of the multi-SNVs were used to drive the prognostic score of developing pain flare for each patient, who were divided into three risk groups of roughly equal sizes. RESULTS: Risk groups were significantly predictive of pain flare (P<0.0001) and dexamethasone response (P<0.0001). The high-risk patient groups had a 78% chance of developing pain flare, and pain flare despite dexamethasone [OR =24.6, 95% confidence interval (CI): 1.8-342.7, P=0.02]. The multivariable model for pain flare included 15 variants, with effect sizes ranging from -4.97 (NBPF1 rs3872309 C>T) to 5.54 (DNM2 10940838 A>C). The multivariable model for dexamethasone response included 6 variants, with effect sizes ranging from -1.03 (NBPF1 rs3872309 C>T) to 0.85 (TSEN54 rs62088470 C>G). CONCLUSIONS: Significant SNVs associated with pain flare were found in genes with functions in biosynthesis (DHODH, PECR), lipid excretion and metabolism (UGT2A1/2, VLDLR), and intracellular signalling (DNM2, SEC23A). Significant SNVs associated with dexamethasone response were from genes involved in extracellular matrix (HAS1, ADAMTS16) and cytoskeleton regulation (GAS2L2). Identification of SNVs predictive of pain flare and dexamethasone response enables targeted prophylactic therapy according to a patient's predisposed response. PMID- 29156914 TI - Palliative radiotherapy utilization within a regional Australian palliative care unit. AB - BACKGROUND: Palliative radiotherapy has been demonstrated to be efficacious for symptom management in advanced malignancy however there are limited data investigating its use for inpatient palliative care patients. The aim of the current paper was to evaluate the utilization of radiotherapy amongst patients admitted to a regional Australian palliative care unit (PCU). METHODS: A retrospective cohort study was undertaken involving all Barwon Health PCU patients who received radiotherapy whilst an inpatient. A range of clinico demographic, radiotherapy-specific and outcome measures were evaluated. Changes in opioid consumption were used as a surrogate for radiotherapy effectiveness. Demographic variables were analyzed descriptively and Wilcoxon Signed Rank Tests were used to compare opioid consumption before and after radiotherapy at time points one week, two weeks and three weeks. RESULTS: Sixty episodes of radiotherapy were provided to 51 PCU patients during the study period with 54 admissions included in the final analysis. Pain management was the commonest reason for radiotherapy treatment and most courses were multi-fractionated. Using the proportion of patients whose opioid dose decreased following radiotherapy as a marker for response, response rates ranged from 32-42%. Fortyeight percent of patients died during their PCU admission and the median survival from radiotherapy commencement was 36 days. CONCLUSIONS: A small proportion of all patients admitted to PCU received radiotherapy. Almost half of patients died during their admission and radiotherapy response rates were lower than have been reported for all-comers. More research is needed to optimize the stratification of PCU patients for radiotherapy. PMID- 29156915 TI - Going beyond 'do no harm': a critical annotation. PMID- 29156916 TI - A critical evaluation of quality of life in clinical trials of breast cancer patients treated with radiation therapy. AB - The aim of this study was to investigate the extent to which health-related quality of life (HRQOL) parameters have been reported in phase III trials with breast cancer patients (BCPs) who received radiation therapy (RT). We also examine the frequency and correlates of significant HRQOL gains. A systematic review was conducted. When HRQOL was a study endpoint, we extracted data on the instruments used for HRQOL analysis, assessing if there was formal statistical comparison between study groups and the results of such comparisons as reported by the authors of the studies. In result, 182 trials were included. HRQOL was considered as endpoint in 38 (20.8%) of the studies and it was used as primary endpoint in 10.9% of them. Of 22 trials that had a positive primary endpoint, 18 had a significant benefit in HRQOL, in favor of the experimental arm. Of 13 trials that had a negative primary endpoint, there were no differences in HRQOL among the study groups. With respect to HRQOL assessment, statistical methods and definition of timing of evaluation were described in 32 (84.2%) and 36 (94.7%) trials, respectively. In conclusion, HRQOL has been infrequently investigated in trials in BCP who received RT. Statistical methods and timing of evaluation were infrequently described with sufficient detail to be informative. PMID- 29156917 TI - Advance care planning for patients with advanced neurology diseases. AB - BACKGROUND: Advanced neurology diseases including motor neuron disease (MND) are usually progressive life-limiting illness and could be devastating for patients, families and caregivers. Although medical technologies, such as enteral feeding and non-invasive ventilation, may prolong life expectancy of the patients, their utilization prompts important ethical questions in regard to their quality of life (QoL). Little attention had been paid on how ACP practice would practically help with patients suffering from different neurology diseases. We are unaware of any published studies on ACP practice among patients with different neurology diseases. In our study, we assessed end-of-life (EOL) care preferences, documentation, and communication in patients with various types of advanced neurology diseases. METHODS: This was a retrospective chart review of all patients referred to the neuro-palliative care team (NPCT) in a local acute hospital in Hong Kong. The study was approved by the institutional review board of the University of Hong Kong. NPCT consultation was hand abstracted from the electronic health record if there was a subspecialty palliative care (PC) consultation note during the study period. Hand abstraction of data also included any content related to advance care planning (ACP) [advance directive (AD), resuscitation order, ventilator support, artificial feeding, patient wishes, legacy]. RESULTS: For patient who signed AD, items including cardiopulmonary resuscitation (100%), mechanical ventilation (100%), artificial nutrition and hydration (80%) were mentioned more frequently than other EOL interventions. For patients who had ACP but without AD, the most common diagnosis is bad stroke (60%). Place of death, artificial nutrition and hydration were most mentioned EOL interventions. CONCLUSIONS: EOL decision making in patients with advanced neurology disease is often delayed. This study showed that MND patients are readier to discuss their EOL issues and signed their AD. The NPCT can play a valuable role in EOL discussions in patients with advanced neurology diseases under collaboration between the PC and the neurology teams. PMID- 29156918 TI - Challenges and ethical issues in the course of palliative care management for people living with advanced neurologic diseases. AB - In the recent years, there has been an increase in awareness with regards to the role of palliative care (PC) in management of neurologic diseases. In 1996, the need to incorporate PC in the care for patients with neurologic conditions was recognized by the American Academy of Neurology (AAN) Ethics and Humanities Subcommittee. The gaps in research, education and the ability to deliver adequate PC were then acknowledged by the National Academy of Sciences with their publication of "Approaching death: improving care at the end of life" and most recently, continued goals in improving PC was highlighted by another recent publication "Dying in America: improving quality and honoring individual preferences near the end of life". The complexity of managing neurologic patients brings about challenges and ethical issues in this setting. The aim of this review is to discuss and summarize the challenges and ethical issues in the context of PC management of patients with advanced acute, rapidly progressive, slowly-progressive or degenerative neurological conditions that are commonly encountered in practice. PMID- 29156920 TI - Supportive & palliative interventions in motor neurone disease: what we know from current literature? AB - Although there is no cure for motor neurone disease (MND), the advent of supportive interventions including multidisciplinary care (MDC) has improved treatment interventions and enhanced quality of life (QOL) for MND patients and their carers. Our integrative review showed evidence-based MDC, respiratory management and disease-modifying therapy that have improved the outcomes of patients diagnosed with MND. Supportive approaches to nutritional maintenance and optimization of symptomatic treatments, including management of communication and neuropsychiatric issues, improve the QOL for MND patients. Notwithstanding improvement to care and QOL, survival benefit has become evident with the advent of a MDC framework, early treatment with non-invasive ventilation (NIV). In addition, weight maintenance remains critical, as weight loss is associated with more rapid disease progression. The endof- life phase is poorly defined in MND patients and treatment remains challenging, yet effective symptom control through palliative care (PC) is achievable and essential. PMID- 29156921 TI - Sexual healthcare for cancer patients receiving palliative care: a narrative review. AB - Palliative care aims to improve quality of life (QoL) for patients and families and does so by addressing issues not limited to pathology, but other symptoms that may be debilitating to patient experience and QoL. Despite sexual health being an important aspect of life for many patients, it is often omitted in clinical practice. This review summarizes published primary studies to explore the prevalence and importance of incorporating sexual health in the symptom screening and assessments of palliative patients, to identify current interventions that are implemented to address sexual health issues, and identify the barriers that health care professionals (HCPs) and patients may encounter which may prevent sexual health discussions. A literature review was conducted on Medline and Embase databases using keywords including "cancer", "sexual health", "intimacy", and "palliative care". Eleven papers focusing on the sexual health and intimacy of terminally ill patients in hospice, palliative or terminal care settings were identified for inclusion. Discussions about sexual health, functioning, and intimacy were not common in patient care, despite being a service that both patients and their partners desired. Referrals to sexologists, or discussions with patients and partners about intimacy and sexuality over the course of the disease trajectory were shown to improve QoL as well as alleviate some of the stress of receiving palliative care services. HCPs cited a lack of training, their own life experiences, or discomfort with the topic as barriers to initiating conversations with patients. In conclusion, sexuality and intimacy remain important parts of many people's lives regardless of their health, and should be incorporated into the care of all patients including those in palliative care. There is a need for further research to evaluate different methods or procedures for educating and counselling patients and their partners on sexual health issues. HCPs should have specific training and education in sexual health care to enable them to initiate and direct these discussions. PMID- 29156922 TI - Changes in laser-evoked potentials during hypnotic analgesia for chronic pain: a pilot study. AB - BACKGROUND: Hypnotic analgesia is one of the most effective nonpharmacological methods for pain control. Hypnosis and distraction of attention from pain might share similar mechanisms by which brain responses to painful stimulation could be similarly reduced in both states. There is ample evidence for the efficacy of clinical hypnosis as a psychological intervention in the treatment of acute or chronic pain. Results are conflicting, however, with some studies showing an increase, others a reduction, and others still no change in the amplitude of event-related brain potentials during hypnosis as compared to control conditions. Here we compared the effects of clinical hypnosis to simple distraction of attention during recording of laser-evoked potentials (LEPs) in patients with chronic pain. METHODS: The dominant hand in ten patients with chronic pain was tested with LEPs during: (I) resting state; (II) clinical hypnosis, and (III) distraction of attention. Nociceptive responses elicited by LEPs were graded on a numerical rating scale (NRS), and the change in N2-P2 complex amplitude during the three experimental conditions was analyzed. RESULTS: N2-P2 amplitudes were significantly decreased during the hypnotic state as compared to the resting state and distraction of attention. CONCLUSIONS: Hypnosis is a modified state of consciousness that may differ from mental relaxation or distraction of attention from pain. A reduction in N2-P2 amplitude may result from the modulation of diverse brain networks, particularly the frontolimbic pathways, which could modify noxious stimuli input processing during hypnotic analgesia. Our findings indicate that several different brain mechanisms may act together in hypnosis and distraction of attention during pain processing and that clinical hypnosis may provide a useful non-invasive pain relief therapy. PMID- 29156923 TI - 4th Scientific Conferences UCM-ASEN "Functional and health benefits of the nutritional improvement" PMID- 29156924 TI - From infant to child. Feeding in different stages AB - Proper nutrition during childhood is necessary to: allow adequate growth and development, achieve optimal physical and psychic performance, maintain and improve health and recover more easily in disease processes.The first months of life (the infant stage) are a stage in which many rapid changes take place (anthropometric, body composition, maturation of organs and systems...), which suppose a high demand from nutritional point of view, in the quantitative aspect and especially in the qualitative aspect. After infant stage, preschool children feeding is an opportunity to acquire healthy habits and introduce new foods, textures, flavors, colors, etc., which will favor the autonomy and development of the individual, as well as being essential to maintain growth and development. PMID- 29156925 TI - New ingredients in infant formula. Health and functional benefits AB - There is an increasing body of evidence about the effect that early nutrition and lifestyle could have on the programming of later health and disease. Infant formula must cover all the nutritional needs to promote adequate infant growth and development. Currently, important research efforts have been made to supplement infant formulae with new bioactive ingredients with health benefits for the infant. The milk fat globule membrane is one of the new ingredients, which provides phospholipids and gangliosides, as well as bioactive proteins. In addition, ingredients such as probiotics and prebiotics modulate intestinal microbiota and contribute to improve gastrointestinal health. Other ingredients relevant in infant formulas are long chain polyunsaturated fatty acids, alpha lactalbumin and nucleotides. Recent research studies have demonstrated that adding these ingredients to infant formulas improves cognitive development and decreases the number of infections and allergies in infants. However, more studies are needed to find if these effects are long lasting and can be seen in childhood and adulthood. PMID- 29156926 TI - Oral feeding and nutritional improvement in hospitals and residential care homes. Industry innovations AB - OBJECTIVES: Inpatient and institutionalized elderly patients are population groups vulnerable from the nutritional point of view because oftheir greater risk of deficiencies and because in them the effects of imbalances are more serious than in other groups. Analyzing the possible usefulness of industry innovations offering solutions in the oral feeding of these population groups constitutes the objective of the present work. METHODS: Bibliographic search related to the topic. RESULTS: Patients with nutritional problems, prior to hospitalization, are at increased risk of complications, higher mortality and longer hospitalization. On the other hand, hospitalized or institutionalized individuals have different nutritional problems that increase their sanitary and functional risk. The most common nutritional problems can lead to sarcopenia, increased cardiovascular risk (by increased sodium intake or suffering from various deficiencies that impair lipid/homocysteine metabolism, blood pressure control, and promote oxidative stress, endothelial deterioration...), cataract disease, COPD, cognitive impairment and less defense against infections. Taking into account the most frequent problems, it is important that there are foods adapted (because of their texture and ease of swallowing), enriched (vitamins C, D, E, folic acid, calcium, zinc...), low sodium and in some cases are useful gluten-free, lactose-free and allergen-free products. In all cases they must guarantee a high nutritional value and achieve the best organoleptic qualities (taste, texture and color), so that they are appetizing and remind the individual (hospitalized or institutionalized) of the traditional cuisine. CONCLUSIONS: Diverse nutrition organizations and societies stand out that all individuals must have access to safe and adequate food for optimal nutritional status. The beneficial effect of proper nutrition on health promotion, disease risk reduction and impairment should be emphasized, especially in institutionalized/hospitalized subjects. Industry innovations can play an important role in enabling access to adequate food with nutritional benefits. PMID- 29156927 TI - The evolution of nutritional information and communication about food and beverages the last 50 years AB - INTRODUCTION: Nutritional information directed to consumers has evolved in some key aspects such as nutritional parameters, qualitative characteristics of the product and the necessary requirements for their communication. OBJECTIVES: To provide a general overview of legislative developments in nutrition communication in the last 50 years. MATERIALS AND METHODS: Literature review of available literature and European and Spanish Regulations. RESULTS: The main changes have occurred on the two key regulations. Regulation 1924/2006 covering for the first times in Europe the characteristics that must be declared by foods and beverages to make certain nutritional claims and their commercial communications. Additionally, Regulation 432/2012 provides a positive list of health claims. On the other hand, Regulation 1169/2011 offers an updated view of the information provided to the consumer, the compulsory and voluntary aspects of it and its application in the labeling, presentation and advertising of food and beverage products. In addition, there are other regulations and initiatives, at the non institutional level, to promote this communication with the consumer, such as GDAs or color schemes, based on the dietary reference intakes of different nutrients included in Regulation 1169/2011. CONCLUSION: Food legislation has tried to regulate the existing situation in the market by creating a harmonized framework to guarantee the consumer protection, offering nutritional information based in the scientific evidence and increasingly comprehensive and understandable. PMID- 29156929 TI - Role of the egg in the diet of athletes and physically active people AB - The practice of sport and medium-high intensity exercise increases the needs of energy and nutrients. Proper nutrition is very important for reaching the maximum performance, reducing the risk of injury, and ensuring the best recovery. It must also ensure the achievement of optimum nutritional status and prevent health problems at the present and in the future time. Eggs are a very nutritious food that can help athletes to achieve a correct diet. It contains proteins of high quality and bioavailability, a profile of fatty acids very favorable from the cardiovascular point of view, and vitamins and minerals involved in energy and protein metabolism, in defense against oxidative stress and inflammation, in cell growth and tissue repair. However, it is also a food subject to numerous myths that should be corrected, especially in relation to its cholesterol content. The egg, consumed in moderate amounts and properly handled, is a safe and adequate food for more active athletes and groups. PMID- 29156928 TI - Beyond the nutritional value of yogurt: a diet quality indicator? AB - Yogurt is a nutrient-dense probiotic food with unique properties. It has been associated with healthy dietary patterns and postulated as a marker of diet quality. In this report we describe the nutritional composition of yogurt as a good source of several micronutrients, which may help to improve diet quality and maintain metabolic well-being as part of a healthy dietary pattern. The results of this report indicate that yogurt consumers have overall higher diet quality. Increasing yogurt consumption may help to improve the intake of some shortfall vitamins and minerals, as part of a well energy-balanced diet. Further studies such as long-term intervention one, would be useful to explore the effect of yogurt consumption, on nutritional status and health. PMID- 29156930 TI - Benefits of soy in women's health AB - A great interest has been developed last decades on the role of phytoestrogens as an alternative to hormone replacement therapy. In fact, numerous studies have shown the effects of soy isoflavones on climacteric symptomatology by significantly reducing the frequency and intensity of hot flashes, as well on cardiovascular health. The aim of this paper was to review the last studies, mainly randomized controlled trials, on the effect of isoflavones on climacteric symptoms and their impact on women's quality of life, as well as on other health markers. Following a review of meta-analyzes and recent clinical trials, evidence has been obtained of the efficacy of isoflavones use in reducing hot flashes, improving the quality of life, lowering the cardiovascular risk by optimizing lipid profile, and Improving bone mineral density and other markers of bone resorption. Most of the authors concluded on the favorable effect of regular consumption of soy isoflavones on the health and quality of life of peri and postmenopausal women. PMID- 29156931 TI - Benefits of the beer polyphenols on the gut microbiota AB - Gut microbiota has a central role in the homeostasis of the host. Diet is one of the key factors affecting and modulating gut microbiota profile. Dietary polyphenols, which belongs to the non-digestible part of the diet, reach the colon almost unaltered. Polyphenols and gut microbiota put in contact within the colon, where gut microbiota transforms polyphenols to give their bioactivity. The moderate consumption of alcohol is associated with a lower cardiovascular risk and mortality, with the highest cardioprotective effects from the fermented beverages with a high amount of polyphenols. Beer, with a medium amount of polyphenols, is potentially classified within these beverages with a cardioprotective role. Beer sources and the production of the different varieties are going to change the amount and profiles of the beer polyphenols. Thus, the relationship with the gut microbiota could be different among the different types of beer, with different results for the host. In this manner, it could be said that the healthy benefits reported by the beer consumption could be mediated, at least partially, by the gut microbiota. However, more detailed studies are necessary. PMID- 29156932 TI - Adequacy of the dietary intake of total and added sugars in the Spanish diet to the recommendations: ANIBES study AB - INTRODUCTION: The WHO published in 2015 its recommendations for added sugars intake: < 10% of the total energy (TE) intake in both adults and children. No updated information is available in Spain. OBJECTIVES: To examine total sugar intake, mainly focused on added, and food and beverage sources. To analize fulfillment with WHO recommendations. METHODS: The ANIBES Study of a representative sample of the Spanish population (9-75 yr) was used. Food and beverage records were obtained by a three-day dietary record by using a tablet device. RESULTS: The median total sugar intake was 17% Total TE: 7.3% for added, and 9.6% for the intrinsic sugar intake. Differences were observed for added sugar which was much higher in children and adolescents. For the intrinsic sugar, however, a higher contribution to TE was observed in the elderly. A 58.2% of children fullfill WHO recommndations (< 10% TE), lower for the adolescents (52.6%),and higher for adults (76.7%) and the elderly (89,8%). The mayor sources of total sugar were milk and dairy products (23.2%), non-alcoholic beverages (18.6%), fruits (16.8%) and sugars and sweets (15.1%) and grains (12.0%). The major sources of intrinsic sugars were fruits (31.8%), milks (19.6%), juices and nectars (11.1%), vegetables (9.89%), yogurt and fermented milk (7.18%), low alcohol-content beverages (4.94%), bread (2.91%), and sugar soft drinks (2.24%). As for free sugars, sources were sugars and sweets (34.1%), non-alcoholic beverages (30.8%, mainly as sugar soft drinks, 25.5%) and grains (19.1%, principally as bakery and pastry, 15.2%). CONCLUSION: The present study demonstrates that only a moderate percentage of the Spanish population adhered to the present recommendations for total and added sugar intake, and urgent efforts are needed to improve diet quality in the youngest populations. PMID- 29156933 TI - Prevention of obesity from perinatal stage AB - Obesity is one of the major health problems and a determining factor in the prevalence of diseases such as metabolic syndrome, asthma, sleep apnea, infertility and various types of cancer. Its origin is multifactorial, involving genetic, socioeconomic and environmental factors. These last ones contribute mostly to explain the current epidemic growth of this disease. The sedentary lifestyle, inadequate diet, lack of sleep, alterations in intestinal microbiota and stress are factors related to its development. Since Barker presented his hypothesis about the "fetal origin of adult diseases", there are increasing number of studies that show the influence of an inadequate nutritional status and maternal weight in the development of chronic diseases, as obesity in offspring. The nutritional deficiencies of the pregnant mother cause epigenetic modifications and abnormal programming of the development oforgans and devices, adapting the fetus to this situation of deficiency and being able to adapt to an obesogenic environment after birth, increasing its propensity to obesity. Also, poor maternal nutritional status is related to intrauterine growth retardation and low birth weight infants, with a higher risk of childhood and adult central obesity. Currently, deficient intake of micronutrients and overweight or maternal obesity tend to overlap, and this combination may exacerbate the increase in obesity in the offspring. It is important to identify pregnant mothers at risk of suffering nutritional alterations and establish their improvement as a primary prevention strategy for overweight and obesity. PMID- 29156934 TI - Short chain fatty acids (butyric acid) and intestinal diseases AB - INTRODUCTION: Short chain fatty acids contain up to 6 carbon atoms. Among them, butyric acid stands out for its key role in pathologies with intestinal affectation. Butyric acid is the main energetic substrate of the colonocyte, it stimulates the absorption of sodium and water in the colon, and presents trophic action on the intestinal cells. OBJECTIVES: To review the clinical use of formulations for the oral use of butyric acid. METHODS: Review of published articles on oral supplementation with butyric acid in intestinal pathologies. RESULTS: The publications mainly deal with the use of oral butyric acid in pathologies involving inflammation and / or alterations of intestinal motility. Highlighting the clinical potential in inflammatory bowel diseases and irritable bowel syndrome. CONCLUSION: The use of oral supplementation with butyric acid is a promising strategy in pathologies such as inflammatory bowel diseases and irritable bowel syndrome. Bio-available butyric acid formulations with acceptable organoleptic characteristics are being advanced. PMID- 29156935 TI - Usefulness of plant sterols in the treatment of hypercholesterolemia AB - A consumption of 2 grams per day of plant sterols produces an inhibition of intestinal absorption of cholesterol and reduces the plasma concentration of c LDL (cholesterol associated with low-density lipoprotein) by around 10%, which has determined its incorporation into different food products like margarines or dairy. The plant sterols develop their action in the intestine, where they reduce the absorption of cholesterol increasing their elimination fecal. In clinical practice, the use of functional foods with plant sterols at the recommended doses can be considered as a complement to lifestyle modifications, in individuals with hypercholesterolemia and low cardiovascular risk but who do not require hypocholesterolemic pharmacological treatment, and also in those patients receiving pharmacological treatment with lipid-lowering drugs and who do not get the therapeutic goals of c-LDL. The hypocholesterolemic effect of plant sterols is additive to that achieved with changes in lifestyle and/or other lipid lowering agents. Coadministration with statins generates a hypocholesterolemic effect usually greater than that obtained when the statin dose is doubled. PMID- 29156936 TI - Nutrition and immune system disorders AB - INTRODUCTION: Energy and nutrients obtained through food play an important role in the development and preservation of the immune system therefore any nutritional imbalance affects its competence and integrity. OBJECTIVES: Knowing the nutritional approach on different disorders of the immune system. METHODS: A review has been carried out on the most prevalent immunological disorders in developed countries, the nutritional characteristics to which they are associated and their nutritional approach. RESULTS: Nutritional treatment for immune disorders has focused in recent years on the role of PUFA-omega3 and vitamin D. Maintaining body weight, preventing malnutrition and protein catabolism are key strategies for nutritional treatment. This should be adapted to each disease stage because it is a dynamic process. CONCLUSIONS: Nutritional treatment for immunological disorders, especially in autoimmune diseases, is not always clear because they present acute and remission states. Anorexia is one of the most characteristic symptoms derived mainly from pharmacological treatment and inflammatory processes. Diet should be dense in nutrients that prevent deterioration.Nutritional treatment of immunological disorders should aim to maintain an optimal state of nutrition during symptomatic periods, prevent their deterioration during acute episodes and improve during stable periods free of symptoms. PMID- 29156939 TI - Phenolic compounds as natural and multifunctional anti-obesity agents: A review. AB - Prevalence of obesity worldwide has reached pandemic proportions. Despite the increasing evidence in the implication of phenolic compounds in obesity management, the real effect is not completely understood. The available in vitro and in vivo studies have demonstrated the implication of phenolic compounds in: lowering food intake, decreasing lipogenesis, increasing lipolysis, stimulating fatty acids beta-oxidation, inhibiting adipocyte differentiation and growth, attenuating inflammatory responses and suppress oxidative stress. This review encompasses the most recent evidence in the anti-obesity effect of phenolic compounds from plants to different nutraceuticals and functional foods based on the in vitro, in vivo and clinical studies. For that, this review has been focused on popular plant-based products highly consumed today such as cocoa, cinnamon, and olive oil, beverages such as red wine, tea (green, white and black tea) and Hibiscus sabdariffa L. tea, among others. PMID- 29156941 TI - Supporting family dementia caregivers: testing the efficacy of dementia care management on multifaceted caregivers' burden. AB - OBJECTIVES: Current research suggests that dementia care management (DCM) can decrease burden and associated health impairments of caregivers. The objective of this secondary analysis is to investigate the impact of DCM on multifaceted caregivers' burden dimensions by differentiating between objective and subjective burden. METHODS: A sample of n = 317 dyads of caregivers and community-dwelling people with dementia (PwD) participated in a general practitioner-based, cluster randomized intervention trial (Identifier:NCT01401582) with two arms and comprehensive data assessment at baseline and 12-month follow-up. Data provided by the caregiver included an inventory with 88 items in 20 different dimensions. RESULTS: Caregivers in the intervention 'DCM' group showed decreased caregiver burden, especially in caregivers' objective burden due to caring (i.e. emotional support), caregivers' subjective burden due to behavior change (i.e. cognition, aggression and resistance, depression, late symptoms) and caregivers' subjective burden due to perceived conflicts between needs and responsibilities to care (i.e. financial losses) compared to caregivers in the control 'care as usual' group, which showed significant increased caregiver burden after 12 months. CONCLUSION: Our findings support evidence for the effectiveness of DCM to lower family dementia caregivers' burden in multifaceted dimensions. PMID- 29156943 TI - Assessment of Biochemical Bone Turnover Markers and Bone Mineral Density in Thin and Normal-Weight Children. AB - Objective There is scant research examining the prevalence of thinness in early childhood, despite its potential negative consequences for health and development across the life course. The objective of this study was to assess bone status through measurement of bone mineral density and biochemical bone turnover markers, with special attention paid to carboxylated (c-OC) as well as undercarboxylated (uc-OC) forms of osteocalcin, in the groups of thin and normal weight children. Design The study included 80 healthy prepubertal children (median age 7.0 years), who were divided (according to Cole's international cutoffs) into 2 subgroups: thin children ( n = 40, body mass index [BMI] = 13.5 kg/m2) and normal-weight children ( n = 40, BMI = 16.1 kg/m2). Bone mineral density (BMD) and bone mineral content (BMC) were assessed by dual-energy x-ray absorptiometry method. Serum concentrations of C-terminal telopeptide of collagen type I (CTX), total osteocalcin (OC), and c-OC, and uc-OC forms of osteocalcin were determined using enzyme-linked immunosorbent assays. Results In thin children, we observed higher levels of bone resorption marker CTX compared with normal-weight peers. Total osteocalcin concentrations were comparable in both groups of children; however, in thin children we observed higher median values of uc-OC (34.40 vs. 29.30 ng/mL, P < 0.05) and similar c-OC levels (25.65 vs. 28.80 ng/mL). The ratio of c-OC to uc-OC was significantly lower ( P < 0.05) in thin than in normal-weight children. Total BMD and BMC were significantly decreased ( P < 0.0001) in thin children compared with normal-weight peers (0.724 +/- 0.092 vs. 0.815 +/- 0.060 g/cm2 and 602.7 +/- 159.2 vs. 818.2 +/- 220.1 g, respectively). Conclusion Increased concentrations of CTX and uc-OC might lead to disturbances in bone turnover and a decrease in bone mineral density in thin children. PMID- 29156944 TI - alpha-Lipoic Acid Potentiates the Anti-Inflammatory Activity of Avocado/Soybean Unsaponifiables in Chondrocyte Cultures. AB - Objective Pro-inflammatory mediators such as prostaglandin E-2 (PGE2) play major roles in the pathogenesis of osteoarthritis (OA). Although current pharmacologic treatments reduce inflammation, their prolonged use is associated with deleterious side effects prompting the search for safer and effective alternative strategies. The present study evaluated whether chondrocyte production of PGE2 can be suppressed by the combination of avocado/soybean unsaponifiables (ASU) and alpha-lipoic acid (LA). Design Chondrocytes from articular cartilage of equine joints were incubated for 24 hours with: (1) control media, (2) ASU, (3) LA, or (4) ASU + LA combination. Cells were activated with lipopolysaccharide (LPS), interleukin 1beta (IL-1beta) or hydrogen peroxide (H2O2) for 24 hours and supernatants were immunoassayed for PGE2. Nuclear factor-kappa B (NF-kappaB) analyses were performed by immunocytochemistry and Western blot following 1 hour of activation with IL-1beta. Results LPS, IL-1beta, or H2O2 significantly increased PGE2 production. ASU or LA alone suppressed PGE2 production in LPS and IL-1beta activated cells. Only LA alone at 2.5 ug/mL was inhibitory in H2O2 activated chondrocytes. ASU + LA inhibited more than either agent alone in all activated cells. ASU + LA also inhibited the IL-1beta induced nuclear translocation of NF-kappaB. Conclusions The present study provides evidence that chondrocyte PGE2 production can be inhibited by the combination of ASU + LA more effectively than either ASU or LA alone. Inhibition of PGE2 production is associated with the suppression of NF-kappaB translocation. The potent inhibitory effect of ASU + LA on PGE2 production could offer a potential advantage for a combination anti-inflammatory/antioxidant approach in the management of OA. PMID- 29156945 TI - Modulation of Gene Expression in Infrapatellar Fat Pad-Derived Mesenchymal Stem Cells in Osteoarthritis. AB - Aim In the osteoarthritis (OA) disease, all structures of the joint are involved. The infrapatellar Hoffa fat pad is rich in macrophages and granulocytes, which also represents a source of adipose mesenchymal progenitor cells (ASC) cells. In our study, we analyze how OA affects the ability of ASC-derived from Hoffa's fat pad to differentiate into chondrocytes. Material and methodology We took knee Hoffa's pad samples and adipose tissue from the proximal thigh from 6 patients diagnosed with severe OA and from another 6 patients with an anterior cruciate ligament (ACL) rupture without OA. From all the patients, we took subcutaneous adipose tissue from the thigh, as the control group. Samples of synovial fluid (SF) were also extracted. The gene expression was analyzed by real-time quantitative polymerase chain reaction. Results PTH1R and MMP13 expression during chondrogenic differentiation were similar between OA and ACL groups, while the expression of OPG, FGF2, TGFbeta, MMP3 were significantly lower in the OA group. Exposure of differentiated ASC to OA SF induced an increase in the expression of OPG, PTH1R, and MMP13 and a decrease in the expression of FGF2 in cell culture of the ACL group. However, expression of none of these factors was altered by the OA synovial fluid in ASC cells of the OA group. Conclusion OA of the knee also affects the mesenchymal stem cells of Hoffa fat, suggesting that Hoffa fat is a new actor in the OA degenerative process that can contribute to the origin, onset, and progression of the disease. PMID- 29156947 TI - Off-label use of antipsychotics and associated factors in community living older adults. AB - BACKGROUND: Given the common off-label use of antipsychotics (AP), we aimed to assess the factors associated with this use in community living older adults. METHODS: The study sample consisted of a large representative sample of older adults (n = 4108), covered under a public drug insurance plan in Canada. Off label use of antipsychotics was defined by the absence of an approved indication for this use, according to Health Canada's drug product database. Multinomial logistic regression was used to assess the factors associated with off-label use. RESULTS: The prevalence of antipsychotics use was 2.5%, of which 78% was off label. Compared to non-use, off-label antipsychotics use was negatively associated with advanced age (>=75 vs. 65-74 years old) (OR: 0.46; 95%CI: 0.27 0.78); and positively associated with higher education level (OR: 2.68; 95% CI: 1.64-4.40), higher number of outpatient visits (>=6) (OR: 2.39; 95%CI: 1.34 4.25), antidepressant or benzodiazepine use (OR: 5.81; 95%CI: 3.31-10.21), and the presence of an organic brain syndrome & Alzheimer's (OR: 5.73; 95%CI: 1.74 18.89). Compared to labeled use, off-label use was less likely in those with major depression (OR: 0.02; 95%CI: <0.01-0.11) and with insomnia (OR: 0.13; 95%CI: 0.02-0.91). CONCLUSIONS: The majority of antipsychotics prescribed to community living older adults were off-label. This off-label use was more likely in complex clinical cases with multiple outpatient visits and other psychotropic drugs use. Further research should focus on the long-term effects associated with off-label use of antipsychotics. PMID- 29156946 TI - Chondroprotection in Models of Cartilage Injury by Raising the Temperature and Osmolarity of Irrigation Solutions. AB - Objectives During arthroscopic or open joint surgery, articular cartilage may be subjected to mechanical insults by accident or design. These may lead to chondrocyte death, cartilage breakdown and posttraumatic osteoarthritis. We have shown that increasing osmolarity of routinely used normal saline protected chondrocytes against injuries that may occur during orthopedic surgery. Often several liters of irrigation fluid are used during an orthopedic procedure, which is usually kept at room temperature, but is sometimes chilled. Here, we compared the effect of normal and hyperosmolar saline solution at different temperatures on chondrocyte viability following cartilage injury using in vitro and in vivo models of scalpel-induced injury. Design Cartilage injury was induced in bovine osteochondral explants and the patellar groove of rats in vivo by a single pass of a scalpel blade in the presence of normal saline (300 mOsm) or hyperosmolar saline solution (600 mOsm, sucrose addition) at 4 degrees C, 21 degrees C, or 37 degrees C. Chondrocytes were fluorescently labeled and visualized by confocal microscopy to assess cell death. Results Hyperosmolar saline reduced scalpel induced chondrocyte death in both bovine and rat cartilage by ~50% at all temperatures studied (4 degrees C, 21 degrees C, 37 degrees C; P < 0.05). Raising temperature of both irrigation solutions to 37 degrees C reduced scalpel-induced cell death ( P < 0.05). Conclusions Increasing the osmolarity of normal saline and raising the temperature of the irrigation solutions to 37 degrees C reduced chondrocyte death associated with scalpel-induced injury in both in vitro and in vivo cartilage injury models. A hyperosmolar saline irrigation solution at 37 degrees C may protect cartilage by decreasing the risk of chondrocyte death during mechanical injury. PMID- 29156948 TI - Perceived control among migrant live-in and local live-out home care workers in Israel. AB - OBJECTIVE: To examine perceived control among live-in and live-out home care workers and to identify factors that contribute to perceived control among both types of caregiving. METHOD: 338 migrant live-in home care workers and 185 local live-out home care workers were asked to report their perceived control. Burnout, satisfaction with the relationship with the care recipient and the care recipient's family, and satisfaction with social relationship were also gathered. RESULTS: Both types of caregivers reported high levels of perceived control, although live-in home care workers expressed more perceived control. Higher age, higher levels of satisfaction with the relationship with the care recipient and the care recipient's family and lower levels of burnout, predicted perceived control. Satisfaction with social relationship was a stronger predictor of one's perceived control among live-in home care workers. CONCLUSIONS: Promoting social relationships outside the home care context by allowing migrant live-in home care workers to take part in social gatherings is recommended as this can strengthen their sense of perceived control. PMID- 29156950 TI - Management of Moderate to Severe Plaque Psoriasis: The Emerging Role of IL-17 Inhibition. PMID- 29156953 TI - Understanding the experiences of people with disfigurements: An integration of four models of social and psychological functioning. AB - Both psychological (Cash, 1996; Partridge, 1998; Leary et al ., 1998) and sociological (Goffman, 1968) models have been used to explain the personal and social consequences of cosmetic blemishes. In this study, people with the skin disease vitiligo were asked to describe a situation in which their condition had recently affected their lives. Consistent with theories of body image disturbance, incidents usually involved a triggering event when concerns about appearance were raised due to bodily exposure or enacted stigma. These events led respondents to be vigilant to others' behaviour, to be self-conscious and to attribute the cause of the event to their appearance. Theories of social anxiety could be used to account for how the respondents used impression management strategies such as avoidance and concealment. Respondents described how they could be uncertain as to how to deal with others' behaviour, illustrating the relevance of social skills models. In addition, avoidance/concealment had a number of social and personal costs, including the loss of valued activities, reluctance to develop intimate relationships and continuing anxiety. Thus, theories of body image, social anxiety, social skills and the sociology of stigma could be used to understand the respondents' experiences. It seems likely that therapeutic interventions based on different models are useful because they influence different aspects of the above process. PMID- 29156952 TI - Duodenal infusions of isoleucine influence pancreatic exocrine function in dairy heifers. AB - Four healthy Holstein heifers (235 +/- 12 kg) fitted with duodenal and pancreatic cannulas were used to investigate infusion of isoleucine (Ile) on the pancreatic exocrine function in a 4 * 4 Latin square design. Three doses of Ile, 10, 20 and 30 g in 2500 ml water, respectively, were infused into the duodenum over a period of 12 h in Experiment (Exp) 1 and over 10 d in Exp 2. Hourly pancreatic juice and jugular blood were taken during the infusion period in Exp 1, and the blood samples were taken in 2-h intervals over the last 2 d in Exp 2. Compared with no Ile infusion, the Ile infusions in both experiments increased the concentration and secretion rate of the protein, activity of alpha-amylase and trypsin and plasma cholecystokinin. The secretion rate of alpha-amylase and the activity of trypsin linearly increased with the Ile doses. The pancreatic juice secretion linearly increased with Ile in Exp 2 but not in Exp 1. Isoleucine linearly increased plasma insulin in Exp 1, but not in Exp 2. No effects of Ile on pH of pancreatic juice, the activity of chymotrypsin and lipase and plasma glucose were found. In conclusion, duodenal Ile infusion could increase the pancreatic exocrine function of Holstein heifers, especially alpha-amylase, and the increment appeared to be dose and time dependent. PMID- 29156954 TI - The relation of health anxiety and attitudes to doctors and medicine to use of alternative and complementary treatments in general practice patients. AB - We investigated health anxiety and attitudes to doctors and medicine as determinants of use of 'alternative' practitioners and treatments in a sample of 200 general practice attenders. The Health Anxiety Questionnaire and the Attitudes to Doctors and Medicine Scale were used, as well as a schedule of non medical practitioners and treatments. Half those interviewed had ever used diet supplements, and about a quarter had ever used other nonmedical treatments such as herbal remedies and mega vitamins. 20% has been to a massage therapist, roughly 10% to a faith healer, acupuncturist or chiropractor. Health anxiety scores were unrelated to consultations except that those who had visited a faith healer or had taken dietary supplements were significantly more anxious. On the other hand, positive attitudes to doctors and medicine were positively correlated with almost all measures of use of alternative treatments. Rather than being a rejection of scientific medicine, it suggests that 'alternative' medicine is not distinguished from scientific medicine by Dublin GP attenders. PMID- 29156955 TI - Is there a role for compliance in the assessment of insight in chronic schizophrenia? AB - Current work on insight focuses on its assessment, a trend that is reflected in the inflation of newly-developed scales. Most scales assess compliance with treatment, recognition and acceptance of mental illness and relabeling of abnormal mental experience as pathological. A handful of studies indicate that compliance is weakly to moderately correlated with awareness of illness and relabelling of symptoms in acute samples. As the parameters of compliance differ between acute and chronic populations, this study investigated the relationship between the three components using the Schedule to Assess the Components of Insight in 78 outpatients with chronic schizophrenia. A weak positive correlation was found between acceptance of illness and relabelling. However, compliance was not reliably related to either the awareness or relabelling component. As the incidence of non-compliance in the present sample did not differ from comparable populations, it appears that non-compliance does not account for these findings. Non-compliance may be viewed as an evaluation of the costs and benefits of treatment on daily living rather than an insight deficit. The lack of a reliable relationship between compliance and insight suggests that the two phenomena should be viewed as distinct constructs and assessed separately in chronic schizophrenia. PMID- 29156956 TI - Catching the sun: An investigation of sun-exposure and skin protective behaviour. AB - This study, conducted at the end of a UK heatwave, used qualitative and quantitative questionnaire measures to investigate sun protection in the context of the potentially conflicting attractions of sun exposure. It examined attitudes to the good weather, beliefs about the benefits and harmful effects of the sun and perceptions of risk amongst a sample of students in the UK. Participants could think of more benefits than harmful effects of the sun for both their health and appearance. Most enjoyed sunbathing, protected themselves inadequately and did not intend to change this behaviour. Those who knew someone who had suffered skin cancer, who perceived higher risk and who wrote more about the harmful effects of skin cancer on their appearance (but not their health) were more likely to engage in skin protective behaviours. PMID- 29156957 TI - Representations of illness: Their relationship with an understanding of and adherence to homoeopathic treatment. AB - The aims of this study were twofold; to test the reliability of the illness Perception Questionnaire (IPQ; Weinman et al ., 1996) with a sample receiving homoeopathic treatment and to examine its predictive utility concerning the extent of understanding and adherence to treatment. Thirty adult patients presenting with 'chronic' conditions to homoeopathic practitioners completed the IPQ prior to their initial consultation. At their next consultation (4-6 weeks later), a further questionnaire was completed concerning their understanding of and the extent of adherence to the treatment. The IPQ yielded reliability coefficients of 0.89, 0.78 and 0.64 for time-line, consequences and control/cure, respectively. Causation beliefs appeared as the best predictors of both understanding and adherence. The severity and duration of the condition was associated with an understanding of the principles of homoeopathy and the extent of adherence to it. However, they were not associated with an understanding of the practitioners' explanations of the illness, awareness of its consequences and the extent of perceived efficacy of the treatment, the implications of which are discussed in relation to practice. PMID- 29156958 TI - A psychometric evaluation of the Hospital Anxiety and Depression Scale in coronary care patients following acute myocardial infarction. AB - The utility of the Hospital Anxiety and Depression Scale (HADS) as a screening instrument for coronary care patients following acute myocardial infarction (MI) was investigated. A maximum likelihood factor analysis was conducted on the HADS to determine its psychometric properties and utility in 194 patients. Though internal reliability estimations of the anxiety and depression sub-scales were found to be acceptable, the expected two-factor solution failed to emerge from the data set. The three-factor solution that emerged isolated dimensions representing depression and distinct factors of trait anxiety and state anxiety. The utility of the HADS in the routine assessment of the affective state of patients following acute MI may be extended by the use of the instrument in predicting mortality and morbidity. PMID- 29156959 TI - Hopelessness: The role of depression, future directed thinking and cognitive vulnerability. AB - Previous research has suggested that parasuicides are impaired in their ability to generate positive future experiences. This study aimed to look at the relationship between future experiences, cognitive vulnerability and hopelessness in parasuicides and matched hospital controls. Parasuicides ( N = 20) and matched hospital controls ( N = 20) were assessed the day following an episode of deliberate self-harm on measures of hopelessness, depression, anxiety, cognitive vulnerability and future directed thinking. The parasuicides differed from hospital controls on measures of depression, hopelessness and negative cognitive style in the predicted direction. Future positive thinking, depression and negative cognitive style explained 70.5% of the hopelessness variance. Future positive thinking was not correlated with either depression or negative cognitive style, whereas negative cognitive style was correlated with depression and hopelessness. Future directed thinking contributes to hopelessness independently of depression and does not seem to be associated with cognitive vulnerability. PMID- 29156960 TI - Coping style and psychological trauma after road accidents. AB - This prospective study aimed to follow a cohort of road accident victims for 6 months and to examine changes in psychological trauma and coping styles over this time. It also aimed to examine the relationship between initial coping style and subsequent psychological trauma. Seventy-two consecutive hospital attendees were assessed using the General Health Questionnaire, Impact of Event Scale, Posttraumatic Stress Disorder Interview and the Coping Inventory for Stressful Situations. Results showed that there was little change in reported coping style over the 6 months but there was a significant decrease in scores on trauma symptom measures. Initial emotion-focussed coping style and to a lesser extent avoidance had strong positive relationships with later trauma scores. PMID- 29156961 TI - Acting on one's intentions: Variations in condom use intentions and behaviours as a function of type of partner, gender, ethnicity and risk. AB - People may not take protective action (e.g. use condoms) either because they have no intention to engage in the protective behaviour, or because they have the appropriate intention but are unable to act upon it. This paper examines variations in intentions to use condoms for vaginal intercourse with main and casual partners as a function of gender, ethnicity and risk. Additionally, the paper examines the extent to which these different factors influence the degree to which people can (or cannot) act upon their intentions. While 68% of men and 81% of women report intentions to use condoms for vaginal sex with their casual partners, only 33% of men and 37% of women intend to use condoms for vaginal sex with their main partner. Men with positive intentions were able to carry out those intentions about 64% of the time with respect to both main and casual partners; women with positive intentions were able to act upon these intentions 53% of the time with their main partners, but almost 82%, of the time with their casual partners. Possible factors influencing the ability to act on one's intentions are explored and implications for interventions are discussed. PMID- 29156962 TI - Conference Diary. PMID- 29156963 TI - Social support in healthy and psychologically distressed French populations. AB - Social support is now recognized as a major determinant of physical and mental health. The purpose of the present study was to assess social support in two groups of French people, one consisting of apparently healthy adults recruited in the general population, the other of adults recruited in centres providing psychosocial therapy to people feeling lonely and isolated. Social support was measured using a French translation of the Sherbourne and Stewart social support scale. This scale measures the perceived availability of functional support in four dimensions (tangible, affectionate, emotional/informational and positive social interaction). The results indicate that the healthy adults have good social support, whereas those feeling lonely and isolated have poor social support. In addition, after six to 12 months of therapy, the centres' subjects showed significant improvement in their level of social support. These data could serve as references for studies on social support in different cultures. PMID- 29156965 TI - Keeping the child in focus while supporting the family: Swedish child healthcare nurses experiences of encountering families where child maltreatment is present or suspected. AB - Child maltreatment can lead to acute and long-term consequences, and it is important that at-risk children are identified early. Child healthcare (CHC) nurses in Sweden are in a position to identify child maltreatment, as they follow children and their parents from the child's birth to school age. Therefore, the aim was to describe CHC nurses' experiences when encountering families in which child maltreatment was identified or suspected. Individual open interviews with eight CHC nurses were performed and analysed using a qualitative content analysis. Findings revealed that keeping the child in focus, while supporting the family was essential for the nurses. This family-centred approach was assumed to benefit the child's interests. Meeting families where child maltreatment was identified or suspected influenced the nurses, emotionally in different ways. Nevertheless, it was important to keep an open mind and communication build on honesty. Furthermore, the nurses requested professional supervision in order to help them learn from the situation ahead of the next time. This knowledge about CHC nurses' experiences may form a basis for the development of interventions that aim to support the CHC nurses in their professional role, and thereby improve support to children and parents in the future. PMID- 29156966 TI - Chemical constituents from the fruits of Psoralea corylifolia and their protective effects on ionising radiation injury. AB - Two new flavonoids, corylifol F (1) and corylifol G (2), together with 19 known compounds, were isolated from the fruits of Psoralea corylifolia L.. The structures of these compounds were determined by interpretation of spectroscopic data and comparison with literature properties. The radioprotective effects of the isolated compounds against ionising radiation damage were also evaluated in vitro. The results showed that corylifol A exhibited radioprotective effects in both HBL-100 and MCF-7 cells, while psoralen, isopsoralen, corylifol C and bakuchiol showed obvious selective action to protect HBL-100 cells against damage caused by ionising radiation. PMID- 29156967 TI - Seed metabolite profiling of Vicia species from China via GC-MS. AB - In this study, we examined Vicia seeds using gas chromatography-mass spectrometry (GC-MS). The metabolic differences of seeds of twelve Vicia species were assessed. 184 metabolites were identified. Vicia species were classified via multivariate data analyses into four clusters. V. unijuga was most enriched in fatty acids and anthraquinones contents while highest levels of amino acids, alcohols and phenolic were in V. costata. Clustering analysis of biochemical profiles matched with the pervious phenotypic observation with all examined species from section Cracca grouped together under one sub-cluster, except for V. costata. PMID- 29156969 TI - Corrigendum. PMID- 29156968 TI - Cytotoxic monoterpenoid-type alkaloids from the aerial parts of Melodinus morsei. AB - Three new monoterpenoid alkaloids, melomorines A-C (1-3), along with melohemsine B (4), were isolated from the 70% ethanol extract of the aerial parts of Melodinus morsei. Structural elucidation of all the compounds was performed on the basis of spectral data. All the compounds were tested in vitro for cytotoxic activities. As a result, alkaloids 1, 2, and 4 exhibited cytotoxicities against all the five tested tumor cell lines with IC50 value of less than 20 MUM. PMID- 29156970 TI - 5'-Epi-SPA-6952A, a new insecticidal 24-membered macrolide produced by Streptomyces diastatochromogenes SSPRC-11339. AB - A new 24-membered macrolide, 5'-epi-SPA-6952A (1), was isolated from the cultured broth of Streptomyces diastatochromogenes. The structure was elucidated by means of spectroscopic methods and comparing with literature data of the known 24 membered macrolide SPA-6952A. Compound 1 was found to show significant insecticidal activity against oriental armyworm(Mythimna separata Walker) with LC50 value of 10.26 mg/L. PMID- 29156971 TI - New angular oxazole-fused coumarin derivatives: synthesis and biological activities. AB - Twelve angular oxazole-fused coumarin derivatives were designed, synthesised and characterised by 1H NMR, 13C NMR and HRMS. The structure of compound 4a was further confirmed by X-ray single-crystal diffraction. The bioassay experiment results indicated that compounds 4f and 4l have high antifungal activity on the mycelium growth of 4 plant disease fungi. Especially, compound 4l has a stronger antifungal activity compare to the commercial fungicide, Carbendazim. The herbicidal activity experiment showed that 4a and 4b can significantly inhibit the taproot and caulis development of Chenopodium album seedling and have better activities than the commercial herbicide, Acetochlor. PMID- 29156972 TI - Two new clerodane-type diterpenoids from Bornean liverwort Gottschelia schizopleura and their cytotoxic activity. AB - The Bornean liverwort Gottschelia schizopleura was investigated phytochemically for the first time. Two new and four previously known clerodane-type diterpenoids were isolated from the MeOH extract of G. schizopleura through a series of chromatographic techniques. The structures of the new metabolites were established by analyses of their spectroscopic data (1D NMR, 2D NMR, HRESIMS and IR). All the isolated compounds 1-6 were tested against human promyelocytic leukaemia (HL-60), human colon adenocarcinoma (HT-29) and Mus musculus skin melanoma (B16-F10). Compound 1 and 2 showed active inhibition against HL-60 and B16-F10 cells. PMID- 29156973 TI - Cartilage Defect Treatment Using High-Density Autologous Chondrocyte Implantation: Two-Year Follow-up. AB - OBJECTIVE: The aim of this work was to study the short- and mid-term effectiveness and safety of high-density autologous chondrocyte implantation (HD ACI) in the first 50 patients with knee cartilage damage treated in our unit. DESIGN: Fifty consecutive patients with cartilage lesions (Outerbridge grade III IV) in the knee treated with HD-ACI were included in this study. Chondrocytes were isolated from a nonbearing cartilage area biopsy and were cultured until 40 to 50 million cells were obtained. Five million chondrocytes per cm2 of a porcine collagen type I/III membrane were implanted covering the defect. Procedure effectiveness was assessed by evaluating pain, swelling, and range of mobility (flexion and extension) at 6-, 12-, and 24-month follow-up. The International Knee Documentation Committee (IKDC) subjective evaluation form was used to evaluate symptoms and functions of the knee. RESULTS: The percentage of patients with pain and swelling decreased progressively in the following visits, with differences being statistically significant ( P < 0.001 and P = 0.040, respectively). IKDC scores improved progressively throughout the 24-month follow up ( P < 0.001). Thus, the mean IKDC score improvement was 26.3 points (95% confidence interval [CI] = 18.2-34.4 points) at 12 months and 31.0 points (95% CI = 22.9-39 points) at 24 months. No significant differences were found when performing extension ( P = 0.112). Flexion significantly improved by 25.1 degrees at 24-month follow-up ( P = 0.013). CONCLUSIONS: HD-ACI is a safe and effective technique for the treatment of cartilage defects, improving clinical and subjective perception of knee functionality. These preliminary results encourage future studies comparing this technique with traditional ACI. PMID- 29156976 TI - Two new saponins from the leaves of Panax notoginseng. AB - Two new saponins, notoginsenosides Ng1 (1) and Ng2 (2), together with seven known compounds (3-9), were isolated from the leaves of Panax notoginseng. Their structures were elucidated by UV, IR, HRESIMS, and NMR experiments. Compounds 6 and 7 showed moderate cytotoxic activities against HCT-116, with IC50 values of 4.98 and 0.64 MUmol/L, respectively. PMID- 29156977 TI - Nurses' use of pliable and directed strategies when encountering children in child and school healthcare. AB - Nurses in Swedish child and school healthcare need to balance their assignment of promoting children's health and development based on the national health monitoring programme with their responsibility to consider each child's needs. In this balancing act, they encounter children through directed and pliable strategies to fulfil their professional obligations. The aim of this study was to analyse the extent to which nurses use different strategies when encountering children during their recurrent health visits throughout childhood. A quantitative descriptive content analysis was used to code 30 video recordings displaying nurses' encounters with children (3-16 years of age). A constructed observation protocol was used to identify the codes. The results show that nurses use pliable strategies (58%) and directed strategies (42%) in encounters with children. The action they use the most within the pliable strategy is encouraging (51%), while in the directed strategy, the action they use most is instructing (56%). That they primarily use these opposing actions can be understood as trying to synthesize their twofold assignment. However, they seem to act pliably to be able to fulfil their public function as dictated by the national health monitoring programme, rather than to meet each child's needs. PMID- 29156978 TI - Bone Marrow Progenitor Cells Isolated from Young Rabbit Trochlea Are More Numerous and Exhibit Greater Clonogenic, Chondrogenic, and Osteogenic Potential than Cells Isolated from Condyles. AB - OBJECTIVE: Bone marrow stimulation procedures initiate repair by fracturing or drilling subchondral bone at base of cartilaginous defect. Earlier studies have shown that defect location and animal age affect cartilage repair outcome, suggesting a strong influence of structural and biological characteristics of subchondral bone. Here, we analyzed comprehensive biological characteristics of bone marrow progenitor cells (BMPCs) in subchondral bone of young and old rabbit condyle and trochlea. We tested the hypothesis that in vitro biological properties of BMPCs are influenced by location, age of donor and method of their isolation. DESIGN: In vitro biological properties, including cell yield, colony forming unit fibroblasts (CFU-f), surface marker expression, and differentiation potential were determined. Comparisons were carried out between trochlea versus condyle and epiphyseal versus metaphyseal bone using old ( N = 5) and young animal knees ( N = 8) to generate collagenase and explant-derived BMPC cultures. RESULTS: CFU-f, cell yield, expression of stem cell markers, and osteogenic differentiation were significantly superior for younger animals. Trochlear subchondral bone yielded the most progenitors with the highest clonogenic potential and cartilaginous matrix expression. Trochlear collagenase-derived BMPCs had higher clonogenic capacity than explant-derived ones. Epiphyseal cells generated a larger chondrogenic pellet mass than metaphyseal-derived BMPCs. All older pellet cultures and one non-responder young rabbit failed to accumulate glycosaminoglycans (GAGs). CONCLUSION: Taken together, these results suggest that properties intrinsic to subchondral progenitors could significantly influence cartilage repair potential, and could partly explain variability in cartilage repair outcomes using same cartilage repair approach. PMID- 29156979 TI - Determination of lignans, phenolic acids and antioxidant capacity in transformed hairy root culture of Linum usitatissimum. AB - Hairy root culture is a promising alternative method for the production of secondary metabolites. In this study, transformed root of Linum usitatissimum was established using Agrobacterium rhizogenes A4 strain from root cultures for lignans, phenolic acids and antioxidant capacity determination. Total lignin content (secoisolariciresinol diglucoside, secoisolariciresinol and matairesinol) was 55.5% higher in transformed root cultures than in the non-transformed root culture. Secoisolariciresinol was detected in higher concentration (2.107 MUmol/g DM) in the transformed root culture than non-transformed culture (1.099 MUmol/g DM). Secoisolariciresinol diglucoside and matairesinol were exclusively detected in the transformed root culture, but were not found in the non-transformed root culture. The overall production of phenolic acids in transformed roots was approximately 3.5 times higher than that of the corresponding non-transformed culture. Free radical scavenging DPPH and ABTS+ assays showed 2.9-fold and 1.76 fold higher anti-oxidant activity in transformed root culture as compared to non transformed. PMID- 29156980 TI - Platelet-Rich Plasma and Hyaluronic Acid Are Not Synergistic When Used as Biological Adjuncts with Autologous Osteochondral Transplantation. AB - : Introduction Autologous osteochondral transplantation (AOT) is a treatment for osteochondral lesions with known concerns, including histological degradation of the graft and poor cartilage integration. Platelet-rich plasma (PRP) and hyaluronic acid (HA) have been described has having the potential to improve results. The aim of this study was to evaluate the effect of PRP and HA on AOT in a rabbit model. Methods Thirty-six rabbits underwent bilateral knee AOT treated with either the biological adjunct (PRP, n = 12; HA, n = 12; PRP + HA, n = 12) or saline (control). PRP and HA were administered as an intra-articular injection. The rabbits were euthanized at 3, 6, or 12 weeks postoperatively. The graft sections were assessed using the modified International Cartilage Repair Society (ICRS) scoring system. The results from the PRP alone group is from previously published data. Results The mean modified ICRS histological score for the PRP treated group was higher than its control ( P = 0.002). The mean modified ICRS histological score for the HA-treated group showed no difference compared with its control ( P = 0.142). The mean modified ICRS histological score for the PRP + HA-treated group was higher than its control ( P = 0.006). There was no difference between the mean modified ICRS scores of the PRP- and the PRP + HA treated grafts ( P = 0.445). Conclusion PRP may decrease graft degradation and improve chondral integration in an animal model. In this model, the addition of HA was not synergistic for the parameters assessed. LEVEL OF EVIDENCE: Basic science, Level V. CLINICAL RELEVANCE: PRP can be used as an adjunct to AOT, which may decrease graft degeneration and improve clinical outcomes. HA may not influence AOT. PMID- 29156982 TI - Cytotoxic ring A-seco triterpenoids from the stem bark of Dysoxylum lukii. AB - A chemical investigation of the 70% ethanol extract from the stem bark of Dysoxylum lukii afforded three new ring A-seco triterpenoids, dysoxylukiines A-C (1-3). Their structures were elucidated on the basis of extensive 1D and 2D NMR (COSY, HMQC, HMBC, and NOESY) analyses. The isolated compounds were evaluated in vitro for cytotoxic properties. Consequently, compound 3 exhibited modest cytotoxic activities against four osteosarcoma cell lines (SOSP-9607, MG-63, Saos 2, and M663) with IC50 values less than 10 MUM. PMID- 29156983 TI - Depressive symptoms and parental stress in mothers and fathers 25 months after birth. AB - The aim of this study was to determine the prevalence of depressive symptoms, feelings of incompetence and spouse relationship problems and their mutual relations. Data from a Swedish parent-infant population-based cohort 25 months after childbirth was used. A questionnaire containing Edinburgh Postnatal Depression Scale (EPDS) and a modified Swedish Parental Stress Questionnaire (SPSQ) regarding depression and parental stress was answered by 646 fathers and 700 mothers. Parents with depressive symptoms experienced more feelings of incompetence and spouse relationship problems than parents without depressive symptoms. The prevalence of depressive symptoms (EPDS >= 12) was more than11% for mothers and nearly 5% for fathers in the sample, 25 months after childbirth. The result indicated that feelings of incompetence and spouse relationship problems could be important constructs for understanding parental stress and depressive symptoms in the parents of young children. In conclusion, it is important that Child Health Care is attentive to both mothers' and fathers' depressive symptoms and parental stress after the first year. PMID- 29156985 TI - Isolated Lumbar Extension Resistance Training Improves Strength, Pain, and Disability, but Not Spinal Height or Shrinkage ("Creep") in Participants with Chronic Low Back Pain. AB - OBJECTIVE: Loss of disc height is commonly associated with chronic low back pain (CLBP). Isolated lumbar extension (ILEX) exercise for the lumbar extensors is recommended to treat CLBP and is suggested such exercise might promote disc healing and regeneration. This study examined a 12-week ILEX intervention on indirect determination of disc height and shrinkage through seated stadiometry, strength, pain, and disability. DESIGN: A quasi-experimental wait-list controlled design was used. Nine participants underwent pretesting (T1), a 12-week control period, retesting (T2), a 12-week intervention period, and finally posttesting (T3). Seated stadiometry, ILEX strength, pain, and disability were measured at each time point. RESULTS: No significant repeated-measures effects for any seated stadiometry variables occurred. Significant improvement across the intervention period (T2 to T3) was found for strength ( P <0.0001; effect size [ES] = 2.42). Change in pain was not significant for repeated effects ( P = 0.064); however, ES for the intervention period (T2 to T3) was moderate (ES = -0.77). Change in disability was significant between time point T1 and T3 ( P = 0.037) and ES for the intervention period (T2 to T3) was large (ES = -0.92). Pain and disability achieved minimal clinically important changes. CONCLUSIONS: This is apparently the first study to examine disc change in vivo after exercise in CLBP. Results of the present study, though supporting ILEX resistance training to improve strength, pain, and disability, did not find any effect on spinal height. PMID- 29156984 TI - Genkwalathins A and B, new lathyrane-type diterpenes from Daphne genkwa. AB - Screening for new natural anti-neuroinflammatory compounds was performed with the traditional folk medicine Genkwa Flos, which potently inhibited nitric oxide (NO) production by LPS-activated microglial BV-2 cells. Two new lathyrane-type diterpenes, genkwalathins A (1) and B (2), and 14 known daphnane-type diterpenes (3-16) were isolated. The lathyrane-type diterpenes were isolated for the first time from the Thymelaeaceae family in this study. Compounds 1 and 2 moderately inhibited LPS-induced NO production in BV-2 cells without affecting cell viability, while six daphnane-type diterpenes (3, 4, 6, 7, 9 and 10) potently reduced NO production with IC50 values less than 1 MUM, although they did display weak cytotoxicity. A structure-activity relationship study on the daphnane-type diterpenes indicated that the stereochemistry at C-19, the benzoate group at C 20, and the epoxide moiety could be important for their anti-neuroinflammatory effects. PMID- 29156986 TI - Microbial transformation of resveratrol by endophyte Streptomyces sp. A12 isolated from Polygonum cuspidatum. AB - Resveratrol (1) undergoes microbial transformation when fermented with Streptomyces sp. A12 to yield 3, 5, 4'-trimethoxy-trans-stilbene (2). The structure of the compound 2 was elucidated using the modern spectroscopic techniques. This is the first report of the microbial transformation of resveratrol to compound 2 using the endophyte isolated from Polygonum cuspidatum. PMID- 29156987 TI - Antiviral phenolics from Antenoron filiforme var. neofiliforme. AB - Two new phenolics, 1,3-di-O-p-coumaroyl-2',6'-di-O-acetylsucrose (1) and quercetin 3-O-beta-D-apiofuranoyl-(1->2)-alpha-L-rhamnopyranoside (2), along with nine known compounds (3-11), were isolated from the whole plants of Antenoron filiforme var. neofiliforme. Their chemical structures were characterized on the basis of various spectroscopic techniques. This is the first report of the isolation of phenylpropanoid sucrose (1, 3-4) from the genus Antenoron. The bioassay results showed that compound 11 exhibited antiviral activity against the Coxsackie virus B3 (CVB3). PMID- 29156988 TI - High-Definition transcranial direct current stimulation in early onset epileptic encephalopathy: a case study. AB - PRIMARY OBJECTIVE: Early onset epileptic encephalopathy is characterized by high daily seizure-frequency, multifocal epileptic discharges, severe psychomotor retardation, and death at infancy. Currently, there are no effective treatments to alleviate seizure frequency and high-voltage epileptic discharges in these catastrophic epilepsy cases. The current study examined the safety and feasibility of High-Definition transcranial direct current stimulation (HD-tDCS) in reducing epileptiform activity in a 30-month-old child suffering from early onset epileptic encephalopathy. DESIGN AND METHODS: HD-tDCS was administered over 10 intervention days spanning two weeks including pre- and post-intervention video-EEG monitoring. RESULTS: There were no serious adverse events or side effects related to the HD-tDCS intervention. Frequency of clinical seizures was not significantly reduced. However, interictal sharp wave amplitudes were significantly lower during the post-intervention period versus baseline. Vital signs and blood biochemistry remained stable throughout the entire study. CONCLUSIONS: These exploratory findings support the safety and feasibility of 4 * 1 HD-tDCS in early onset epileptic encephalopathy and provide the first evidence of HD-tDCS effects on paroxysmal EEG features in electroclinical cases under the age of 36 months. Extending HD-tDCS treatment may enhance electrographic findings and clinical effects. PMID- 29156989 TI - Survival and consciousness recovery are better in the minimally conscious state than in the vegetative state. AB - BACKGROUND: The prognosis value of early clinical diagnosis of consciousness impairment is documented by an extremely limited number of studies, whereas it may convey important information to guide medical decisions. OBJECTIVE: We aimed at determining if patients diagnosed at an early stage (<90 days after brain injury) as being in the minimally conscious state (MCS) have a better prognosis than patients in the vegetative state/Unresponsive Wakefulness syndrome (VS/UWS), independent of care limitations or withdrawal decisions. METHODS: Patients hospitalized in ICUs of the Pitie-Salpetriere Hospital (Paris, France) from November 2008 to January 2011 were included and evaluated behaviourally with standardized assessment and with the Coma Recovery Scale-Revised as being either in the VS/UWS or in the MCS. They were then prospectively followed until 1July 2011 to evaluate their outcome with the GOSE. We compared survival function and outcomes of these two groups. RESULTS: Both survival function and outcomes, including consciousness recovery, were significantly better in the MCS group. This difference of outcome still holds when considering only patients still alive at the end of the study. CONCLUSIONS: Early accurate clinical diagnosis of VS/UWS or MCS conveys a strong prognostic value of survival and of consciousness recovery. PMID- 29156990 TI - Psychological outcome after severe traumatic brain injury in adolescents and young adults: The chronic phase. AB - OBJECTIVES: Young individuals surviving severe traumatic brain injury (TBI) frequently experience a wide range of cognitive, emotional and behavioural consequences. This cross-sectional follow-up study investigated psychological outcome of young survivors in the chronic phase, and whether psychological outcome was associated with improvement of functional abilities during sub-acute admission. METHODS: Patients, who acquired a severe TBI during adolescence or early adulthood (n = 36) and received early intensive rehabilitation, were contacted for follow-up assessment concerning psychological outcome and completed the Adult Self Report 18-59 (ASR18-59). Demographic data, functional outcomes and severity measures were obtained from the local database. RESULTS: The participants had a mean age of 24.1 years (SD = 4.1) at follow-up, and the mean time since injury was 72.1 months (SD = 44.2). Results showed significantly higher scores compared with the normative reference population in relation to the subscales withdrawal/isolation (p = 0.013), attention problems (p = 0.008) and intrusive behaviour (p = 0.046). Pearson correlation analyses showed that young survivors experiencing more functional improvement during inpatient rehabilitation had fewer psychological problems during the chronic phase in the subscales: withdrawal/isolation, rule breaking, intrusive behaviour and total problems. CONCLUSION: Young patients reported psychological problems in several areas during the chronic phase of injury, which may hinder complete reintegration and participation in society. Larger functional improvement during sub-acute rehabilitation seemed to be associated with less psychological problems in the chronic phase. PMID- 29156991 TI - Repeated mild traumatic brain injury produces neuroinflammation, anxiety-like behaviour and impaired spatial memory in mice. AB - PRIMARY OBJECTIVE: Repeated traumatic brain injuries (rmTBI) are frequently associated with debilitating neuropsychiatric conditions such as cognitive impairment, mood disorders, and post-traumatic stress disorder. We tested the hypothesis that repeated mild traumatic brain injury impairs spatial memory and enhances anxiety-like behaviour. RESEARCH DESIGN: We used a between groups design using single (smTBI) or repeated (rmTBI) controlled cranial closed skull impacts to mice, compared to a control group. METHODS AND PROCEDURES: We assessed the effects of smTBI and rmTBI using measures of motor performance (Rotarod Test [RT]), anxiety-like behaviour (Elevated Plus Maze [EPM] and Open Field [OF] tests), and spatial memory (Morris Water Maze [MWM]) within 12 days of the final injury. In separate groups of mice, astrocytosis and microglial activation were assessed 24 hours after the final injury using GFAP and IBA-1 immunohistochemistry. MAIN OUTCOMES AND RESULTS: RmTBI impaired spatial memory in the MWM and increased anxiety-like behaviour in the EPM and OFT. In addition, rmTBI elevated GFAP and IBA-1 immunohistochemistry throughout the mouse brain. RmTBI produced astrocytosis and microglial activation, and elicited impaired spatial memory and anxiety-like behaviour. CONCLUSIONS: rmTBI produces acute cognitive and anxiety-like disturbances associated with inflammatory changes in brain regions involved in spatial memory and anxiety. PMID- 29156992 TI - Evaluation Fucoidan Extracts From Undaria pinnatifida and Fucus vesiculosus in Combination With Anticancer Drugs in Human Cancer Orthotopic Mouse Models. AB - OBJECTIVE: To determine the activity of fucoidan from Undaria pinnatifida (UPF) and Fucus vesiculosus (FVF) when given in combination of chemotherapy drugs using selected human breast or ovarian cancer orthotopic mouse models. METHODS: Mice were inoculated with 1 * 106 cells of TOV-112d, MCF-7, or ZR-75 subcutaneously or SKOV3-GFP-Luc intraperitoneally on day 0. MCF-7 and ZR-75 mice were administered with estradiol valerate 2 mg/kg in 0.2 mL castor oil subcutaneously two days prior to cell inoculation. Mice were randomized to one of six arms (N = 10/arm) paclitaxel, UPF/paclitaxel, FVF/paclitaxel, tamoxifen, UPF/tamoxifen, or FVF/tamoxifen. Tumors were measured three times per week for 28 days. RESULTS: Improved activity was observed with UPF or FVF in combination with tamoxifen in both the MCF-7 and ZR-75D breast cancer mouse models. Decreased activity of paclitaxel was observed when given in combination with UPF or FVF in both breast cancer mouse models. The combination of FVF/tamoxifen in the TOV-112d ovarian cancer mouse model had improved activity but no there was difference observed with the UPF/tamoxifen in either ovarian cancer mouse model. No difference was observed with combination of UPF or FVF with paclitaxel in human ovarian cancer SKOV3 or TOV-112d orthotopic mouse models. CONCLUSION: This study did confirm that UPF/FVF in combination with tamoxifen did not decrease tamoxifen activity in both breast and ovarian cancer, with some potential to improve activity compared to tamoxifen alone in breast cancers. Previous in vitro studies had suggested UPF and FVF had overall synergistic activity with paclitaxel; however, in the current in vivo human cancer mouse model studies there was no change in paclitaxel activity when given in combination with UPF or FVF in either of the two human ovarian cancer models. Furthermore, this study demonstrated that UPF or FVF given in combination with paclitaxel had a potential antagonistic effect in breast cancer models. Additional studies are warranted to delineate mechanisms contributing to variation in the in vivo activity when given in combination with paclitaxel. As a first step, a clinical pharmacokinetic study evaluating impact of FVF/UPF given in combination with chemotherapy in patients with solid tumors is underway. PMID- 29156993 TI - Phenolic compounds analysis, antioxidant, and hepatoprotective effects of Periploca angustifolia extract on cadmium-induced oxidative damage in HepG2 cell line and rats. AB - A total of five components (Catechin, Caffeic acid, Ferulic acid, Rosmarinic acid, and Amentoflavone) were identified in Periploca angustifolia leaf methanolic extract. This extract did not cause any cytotoxic effect on HepG2 cell line within the range of concentrations tested (0-400 ug mL-1). Thus, pre treatment with 100 ug mL-1 of P. angustifolia leaf methanolic extract (PAE) significantly (p < .05) protective HepG2 cells against cytotoxicity induced by cadmium exposure. However, Cd-intoxication significantly (p < .05) increased alanine and aspartate amino transferases serum activities (ALT and AST) and bilirubin content by 1.85-, 1.13-, and 3.55-fold, respectively. The levels of hepatic antioxidant parameters including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were significantly (p < .05) decreased in Cd-intoxicated rats with concomitant enhancement of lipid peroxidation. Our results showed that P. angustifolia leaf methanolic extract can induce antioxidant effects and also exerts beneficial effects for the treatment of Cd induced hepatotoxicity. PMID- 29156994 TI - Experimental diabetes impairs maternal reproductive performance in pregnant Wistar rats and their offspring. AB - : The aim of this study was to determine the effect of mild hyperglycemia on metabolism during pregnancy, the maternal reproductive performance, and the characteristics of the offspring in neonatal mild diabetic-induced Wistar rats. The experimental diabetes model was generated by neonatal streptozotocin administration (100 mg of streptozotocin/Kg bw/sc) in female Wistar rats. At adulthood, the control and diabetic group were mated. At the 20th day of gestation, a maternal and fetal blood sample were collected for biochemical measurement. The maternal livers, fetal livers, and placenta were removed for oxidative stress measurements. Maternal reproductive outcomes and fetal and placental morphometric measurements were analyzed. The fetuses were classified as small, appropriate, and large for pregnancy age, and examined for the presence of external anomalies. The diabetic group showed mild hyperglycemia, altered glucose tolerance, increased total cholesterol, triglycerides, and hemoglobin A1c during pregnancy. At the 20th day of gestation the diabetic mothers presented increased reabsorptions and embryonic losses before and after implantation, reduced corpora lutea number, litter size, implantation sites, live fetuses, and decreased efficiency of implantation rate. Similarly, the offspring showed reduced fetal, craniofacial, and placental dimensions, in addition to a higher proportion of small fetuses for pregnancy age. Mild hyperglycemia during pregnancy did not generate marked oxidative stress in the mother, and in fetal liver and placenta decreased antioxidant activity was evident by significant consumption of reduced glutathione. Mild diabetes led to a negative impact on maternal reproductive performance and characteristics of the offspring. This experimental model reproduced maternal and fetal outcomes of pregnant rats presenting controlled diabetes. ABBREVIATIONS: bw: body weight; sc: subcutaneous; DM: diabetes mellitus; STZ: streptozotocin; OGTT: oral glucose tolerance test; ITT: insulin tolerance test; GSH: glutathione; MDA: malondialdehyde; AOPPs: advanced oxidation protein products; TBARs: thiobarbituric acid reaction; SPA: small for pregancy age; APA: appropriate for pregnancy age; LPG: large for pregnancy age; ROS: reactive oxygen species. PMID- 29156995 TI - Combined repeated-dose and reproductive/developmental toxicity screening test of benzene, 1,1'-oxybis-, tetrapropylene derivs. in rats. AB - We have conducted animal toxicity tests of chemicals for a chemical safety program implemented by the Ministry of Economy, Trade and Industry of Japan. Here we conducted a combined repeated-dose and reproductive/developmental toxicity screening test of benzene, 1,1'-oxybis-, tetrapropylene derivs. (BOTD). BOTD was administered to 9-week-old Crl:CD(SD) male and female rats by gavage at 0, 40, 200, or 1000 mg/kg/day. Males were treated for 42 days including mating period. Females were treated for 42-53 days through the premating, mating, pregnancy, and until Day 4 of lactation periods. Increases in prothrombin time and activated partial thromboplastin time values were observed only in males at 200 and 1000 mg/kg/day. Hypertrophy of centrilobular hepatocytes was observed with increased liver weight in both sexes at 200 and 1000 mg/kg/day, but there was no histologic evidence of hepatotoxicity. Diffuse hypertrophy of follicular cells in thyroid glands was observed in females at 200 mg/kg/day and in both sexes at 1000 mg/kg/day, with an increased blood cholesterol level in females at 1000 mg/kg/day. The conception index was decreased for females at 1000 mg/kg/day; and no abnormalities were detected in the reproductive indices of implantation, delivery, or pups' condition, although a slight increase in the pups' body weight was noted at birth. Our data indicate a no-observed-adverse-effect level of 40 mg/kg/day for repeated-dose toxicity on the basis of the prolongation of blood coagulating time, and of 200 mg/kg/day for reproductive/developmental toxicity on the basis of the decreased conception index. PMID- 29156996 TI - Grouping of CoMPARA data with respect to compounds from the carcinogenic potency database. AB - Methods for clustering and measures of similarity of chemical structures have become an important supporting tool in chemoinformatics. They represent the basis for categorization of chemicals and read-across, where a molecular property is estimated from 'similar molecules'. This study proposes a clustering scheme within the given dataset with respect to a reference dataset. The scheme was applied on two datasets ToxCast_AR_Agonist and ToxCast_AR_Antagonists with 1654 and 1522 compounds, respectively. The compounds are tested to androgen receptor activity (AR) in 11 high throughput screening assays. The carcinogenic dataset was used as the reference set. PMID- 29156997 TI - Clinical manifestations and outcomes of severe warfarin overanticoagulation: from the EWA study. AB - INTRODUCTION: Severe warfarin overanticoagulation is a risk factor for bleeding, but there is little information on its manifestations, prognosis and factors affecting the outcome. We describe the manifestations and clinical outcomes of severe warfarin overanticoagulation in a large group of patients with atrial fibrillation (AF). MATERIAL AND METHODS: All international normalized ratio (INR) samples (n = 961,431) in the Turku University Hospital region between 2003 and 2015 were screened. A total of 412 AF patients with INR >=9 were compared to 405 patients with stable warfarin anticoagulation for AF. Electronic patient records were manually reviewed to collect comprehensive data. RESULTS: Of the 412 patients with INR >=9, bleeding was the primary manifestation in 105 (25.5%). Non bleeding symptoms were recorded in 165 (40.0%) patients and 142 (34.5%) had no symptoms. A total of 17 (16.2%) patients with a bleed and 67 (21.8%) without bleeding died within 30 days after the event. Intracranial haemorrhage strongly predicted death within 30 days. Other significant predictors were non-bleeding symptoms, active malignancies, recent bleed, history of myocardial infarction, older age, renal dysfunction and a recent treatment episode. CONCLUSIONS: Bleeds are not the major determinant of the poor prognosis in severe overanticoagulation, as coincidental INR >=9 findings also associate with high mortality. KEY MESSAGES Only a quarter of AF patients with INR >=9 suffered a bleeding event and the clinical manifestation of INR >=9 had a significant impact on patient outcome. The 30-day mortality rate in patients with INR >=9 was high ranging from 9.2 to 32.7%. Several significant predictors of 30-day mortality after INR >=9 were identified. PMID- 29156998 TI - Exposures to automatic dishwashing rinse aids reported to the United Kingdom National Poisons Information Service 2008-2016. AB - OBJECTIVE: To determine the toxicity of rinse aids which are used as drying aids to remove water from crockery. METHODS: Enquiries to the UK National Poisons Information Service (NPIS) were analysed retrospectively for the period January 2008 to December 2016. RESULTS: There were 855 enquiries relating to 828 patients; children aged 5 years or less accounted for 91.1%. Most exposures occurred from ingestion alone (n = 778, 94.0%), but 26 involved ingestion and other routes: 21 with skin contact, 3 with eye contact, and two with both skin and eye contact. There were a further 24 cases of eye contact alone (n = 20, 2.4%) or skin contact alone (n = 3, 0.4%) and a single case of inhalation alone. The World Health Organisation/International Programme on Chemical Safety/European Commission/European Association of Poison Centres and Clinical Toxicologists (WHO/IPCS/EC/EAPCCT) Poisoning severity score [PSS] was known in 824 of the 828 exposures: 425 of 824 (51.6%) patients did not develop clinical features, 381 (46.2%) had a PSS of 1 (minor toxicity), 15 (1.8%) developed moderate (PSS 2) and 3 (0.4%) severe (PSS 3) toxicity. Vomiting was the most common feature, occurring in over a third of all ingestions (n = 286, 35.8%), followed by coughing (n = 73, 9.1%). A higher proportion of adults than children developed clinical features (72.7% of 33 vs 46.0% of 767, p = .0026), although vomiting occurred significantly more frequently amongst children (p = .0315). Of the 25 eye contact cases, eye pain (n = 8) and/or eye irritation (n = 8) were reported, with or without abnormal vision (n = 7); there were two cases of corneal abrasion. Dermal contact rarely produced features; only 4 of 26 patients reported symptoms including skin rash or burning or numbness at the contact site. CONCLUSIONS: Severe clinical features were uncommon following rinse aid exposure; vomiting was the most frequently reported symptom following ingestion. PMID- 29156999 TI - Risk factors for intracranial lesions and mortality in older patients with mild traumatic brain injuries. AB - PRIMARY OBJECTIVE: To identify risk factors for intracerebral lesion (ICL) in older adults with mild traumatic brain injury (MTBI) and evaluate the influence of comorbidities on outcomes. RESEARCH DESIGN: Prospective cohort study. METHODS AND PROCEDURES: Information was gathered on clinical history/examination, cranial computed tomography, admission Glasgow Coma Scale (GCS) score, analytical and coagulation findings, and mortality at 1 week post-discharge. Bivariate and multivariate logistic regression analyses were performed, calculating odds ratios for ICL with 95% confidence interval. P < 0.05 was considered significant. MAIN OUTCOMES AND RESULTS: Data were analyzed on 504 patients with mean+/-SD age of 79.37 +/- 8.06 years. Multivariate analysis showed that traffic accident, GCS score of 14/15, transient consciousness loss, nausea, and receipt of antiplatelets were predictors of ICL, while SRRI and/or benzodiazepine intake was a protective factor. A score was assigned to patients by rounding OR values, and a score >=1 indicated moderate/high risk of ICL. CONCLUSIONS: MTBI management should be distinct in over-60 year-olds, who may not present typical symptoms, with frequent comorbidities. Knowledge of risk factors for post-MTBI ICL, associated with higher mortality, is important to support clinical decision making. Further research is warranted to verify our novel finding that benzodiazepines and/or SSRI inhibitors may act as neuroprotectors. PMID- 29157000 TI - Pre-injury psychosocial and demographic predictors of long-term functional outcomes post-TBI. AB - OBJECTIVE: To determine whether pre-injury psychosocial and demographic factors differentially influence long-term functional outcomes post-TBI. SETTING: Urban rehabilitation hospital. PARTICIPANTS: 149 individuals, ages 16-75, who sustained a mild complicated, moderate or severe TBI, were enrolled in a TBI Model System (TBIMS), and had functional outcome data five-15 years post-injury. DESIGN: Archival data were analysed with SPSS-18 using multiple regression to determine amount of variance accounted for in five functional domains. Predictors included age at injury, pre-injury education, Glasgow Coma Scale (GCS), pre-injury incarceration and psychiatric history. MEASURES: Craig Handicap Assessment and Reporting Technique (CHART), including Cognitive Independence, Physical Independence, Mobility, Occupation and Social Integration domains. RESULTS: Models were significant for Cognitive and Physical Independence, Mobility, and Occupation. Incarceration and psychiatric history accounted for the most variance in Cognitive and Physical Independence, over and above GCS and age at injury. Psychiatric history was also the strongest predictor of Occupation. Mobility was the only domain in which GCS accounted for the most variance. CONCLUSION: Pre injury psychosocial and demographic factors may be more important than injury severity for predicting some long-term functional outcomes post-TBI. It would likely be beneficial to assess these factors in the inpatient setting, with input from a multidisciplinary team, as an early understanding of prognostic indicators can help guide treatment for optimal functional outcomes. PMID- 29157001 TI - Screening of analgesic activity of Tunisian Urtica dioica and analysis of its major bioactive compounds by GCMS. AB - The present study was aimed to evaluate the analgesic properties of Urtica dioica (UD) and to profile phytochemicals by gas chromatography-mass spectrometry (GC MS). The ethanolic extracts were prepared by maceration method and extraction using rotary evaporator. The analgesic activity was analysed by hot plate method, formalin test, acetic acid-induced writhing test and the tail-flick test with different doses of the ethanolic extract. In all tests, the leaf's ethanolic extract exhibited significant analgesic activity (p < .001) at a dose of 400 mg/kg. Even with a low dose, we noticed an analgesic activity with many tests. The GC-MS analysis of the ethanol extract of leaf revealed many compounds; 2 methyltetradecane dodecane, 2,6,11-trimethyl-; 2,6,11-trimethyldodecane, and trimethylhexane which are pharmaceutically the most important. These findings justify that UD can be a valuable natural analgesic source which seemed to provide potential phototherapeutics against various ailments. The analysis of ethanolic extract of UD by GCMS revealed the presence of several compounds including polyphenols, flavonoids, triterpenes which can explain the analgesic effect of UD and its mechanism of action. Hence, UD could be another therapeutic alternative for relieving pain and for minimising the use of drugs that have long term secondary effects. PMID- 29157002 TI - Effects of circadian clock protein Per1b on zebrafish visual functions. AB - : The circadian clock is an endogenous and entrainable time-keeping mechanism with a period of approximately 24 h, operated by transcription/translation feedback loops composed of circadian clock genes and their proteins. The visual system displays robust circadian changes. Relatively little, however, is known about the mechanisms underlying visual circadian rhythmicity. Zebrafish period1b (per1b), as a canonical circadian clock gene, is involved in circadian regulation. Here, we observed that zebrafish per1b mutants exhibit visual defects including reduced behavioral contrast sensitivity and significant retinal dopaminergic deficiency. Further, partially damaged dopaminergic interplexiform cells in wild-type larvae also led to reduced behavioral contrast sensitivity, while exogenous dopamine administration effectively restored the contrast sensitivity of per1b mutants. Taken together, these results suggest that retinal dopaminergic deficiency derived from loss of per1b results in visual defects in zebrafish. ABBREVIATIONS: per1b, period1b; per, period; per1, period1; per2, period2; per3, period3; ERG, electroretinogram; DA-IPCs, dopaminergic interplexiform cells; IRBP, interphotoreceptor retinoid binding protein; MS-222, methane-sulfonate; USTC, University of Science and Technology of China; OKR, optokinetic response; dpf, day postfertilization; 6-OHDA, 6-hydroxydopamine; TH, tyrosine hydroxylase; DA, dopaminergic; INL, inner nuclear; IPL, innerplexiform layers; hpf, hours postfertilization; cpd, cycle per degree; ADHD, attention deficit and hyperactivity disorder. PMID- 29157003 TI - Chemical constituents from Epimedium koreanum Nakai and their chemotaxonomic significance. AB - In this study, 21 compounds were isolated from the aerial parts of Epimedium koreanum Nakai, including 6 phenols (1-5 and 10), 4 lignans (6-9) and 11 flavonoids (11-21). The chemical structures of those isolates were established after extensive one-and two-dimensional nuclear magnetic resonance and mass spectroscopy analyses. This is the first report of compounds 2, 3, 4 and 9 in E. koreanum and of compounds 5 and 7 in the family Berberidaceae. The chemotaxonomic significance of the isolated compounds is discussed. PMID- 29157004 TI - Vanadium inhalation induces retinal Muller glial cell (MGC) alterations in a murine model. AB - BACKGROUND: Vanadium (V) is a transition metal adhered to suspended particles. Previous studies demonstrated that V inhalation causes oxidative stress in the ependymal epithelium, the choroid plexus on brain lateral ventricles and in the retina. Inhaled-V reaches the eye's retina through the systemic circulation; however, its effect on the retina has not been widely studied. The Muller glial cell provides support and structure to the retina, facilitates synapses and regulates the microenvironment and neuronal metabolism. Hence, it is of great interest to study the effect of V exposure on the expression and localization of specific biomarkers on this cell. METHODS: Male CD-1 mice were exposed to V inhalation 1 h/twice/week for 4 and 8-Wk. Expression changes in the retina of Glial fibrillary acidic protein, highly expressed in Muller glial cell when retina is damaged, and Glutamine synthetase, important in preventing excitotoxicity in the retina, were analysed by immunohistochemistry. RESULTS: Glial fibrillary acidic protein expression increased at 4-Wk of V inhalation compared to the control and decreased at 8-Wk of exposure. A time-dependent gradual reduction in glutamine synthetase expression was observed. CONCLUSION: Changes in glial fibrillary acidic protein expression induced by V suggest retinal damage, whereas glutamine synthetase gradual reduction might indicate that photoreceptors, which produce most of the glutamine synthetase substrate in the retina, are degenerating, probably as a consequence of the oxidative stress induced by V. PMID- 29157005 TI - Quantitative structure-activity relationship of anti-HIV integrase and reverse transcriptase inhibitors using norm indexes. AB - The development of new and safe anti-human immunodeficiency virus (anti-HIV) drugs has been an urgent task for medical research recently. Herein, based on the norm-index descriptors proposed in this work and previous works, a couple of models were developed for investigating the quantitative structure activity/toxicity relationship (QSAR/QSTR) of dual-target anti-HIV integrase (IN) and reverse transcriptase (RT) inhibitors. The validation results proved that the developed models were stable and reliable, both in statistical quality and predictive capacity. Moreover, potential dual-target inhibitors with high activity and low toxicity were deduced from the developed models; molecular docking results indicated that these inhibitors could interact with some important residues of HIV IN and RT through H-bonding. Accordingly, the norm indexes descriptors proposed by this work might be helpful for the research and development of dual-target anti-HIV drugs. PMID- 29157006 TI - Chronotype description: In search of a solid subjective amplitude scale. AB - The term "subjective circadian amplitude" refers to the range or the distinctness of diurnal variations of arousal, that is, the awareness (or lack thereof) of difference between hyper- and hypo-activation phases, the ability to volitionally modulate one's own psychophysiological state, the strength of morning-evening preferences and flexibility of the rhythm or perceived stability of the circadian phase. The complexity of this construct is the source of difficulties in research and measurement. The psychometric features of distinctness subscales of the Chronotype Questionnaire and the Caen Chronotype Questionnaire are not satisfactory. In search of the solid subjective amplitude (AM) scale, the Rasch analysis was applied to test 12 behavioral descriptors of circadian rhythm distinctness. The results of the Rasch factor analysis showed unidimensionality of the construct. Rating scale diagnostics of the subjective amplitude scale indicated good fit. However, answer category 3 (neutral agreement on the Likert type, five-point scale) never emerged as modal and step calibrations negated the monotone incrementality of the scale. Rescoring the scale into a four-point category measure yielded satisfactory OUTFIT indices ranging from 0.90 to 1.10. The newly designed AM scale comprised four items referring to small and four to the large amplitude. The four-point answer option was adopted. The data from 234 subjects (53% women; mean age 31.63 +/- 12.99 years) were gathered and analyzed. Percent of the total variance explained in Component Analysis (PCA) reached 45.7% (morningness-eveningness (ME) scale - 26.5%, AM scale - 19.2%). There was no correlation between ME and AM scales (Pearsons's simple correlation coefficient r = -0.018). The internal reliability of the AM scale, as measured with Cronbach's alpha coefficient, proved to be satisfactory: 0.72 (for ME scale - 0.86). Item total correlations in the AM scale ranged from 0.433 to 0.774 and were significant at p < 0.001. Confirmatory factorial analysis of AM scale indicated mediocre fit: chi-square/degree of freedom = 3.00, root mean square error of approximation = 0.09, standardized root mean square residual = 0.08, comparative fit index = 0.87, Tucker-Lewis index = 0.82. However, the results of Rasch analysis showed good fit statistics for all items: OUTFIT mean squares range from 0.63 to 1.34 and INFIT mean square range from 0.64 to 1.40. All observed values were <=1.4, which confirmed the new scale as being unidimensional.f If to consider the chronotype in the context of the classical Borbely's two-process model of sleep regulation, it may be assumed that ME dimension relates to the tempo of increasing of sleep pressure during the day, that is, it reflects the homeostatic component of the diurnal rhythm of sleepiness. As to the amplitude, it may be supposed that more distinct rhythm (large amplitude) stands for greater vulnerability to the time of day - it resounds the circadian component of the sleep proneness. It seems that distinct diurnal changes of arousal indicate emotional lability and may be associated with emotional responsiveness, which in turn manifests itself in a characteristic style of coping with stressful situations. One may therefore consider the diurnal variability of arousal as a factor increasing individual susceptibility to mood swings and affective disorders. PMID- 29157008 TI - A comparative evaluation of migration sedimentation method for sperm preparation. AB - The effectiveness of semen preparation using the migration-sedimentation (MS) method was evaluated, and compared to density gradient centrifuge and swim-up combination (DGC+SU). Sperm selection using MS is based on motility, thus, deleterious effects for which centrifugation has been blamed, are believed to be avoided. Normozoospermic male patients who had more than 10% forward progressive motile sperm in their ejaculate were included in the study. Spermatozoa selected by two different methods were investigated and compared according to sperm motility, concentration, morphology, vitality, DNA fragmentation, and presence of persistent histones. The concentration and motility of sperm in the MS group was improved when compared to the DGC+SU group, but the difference between groups was not significant. The proportion of sperm with normal morphology was found to be 12.19 +/- 6.45% vs. 10.67 +/- 5.44%, vitality rate was 74.09 +/- 16.65% vs. 70.45 +/- 16.78%, DNA fragmentation rate was 3.91 +/- 3.96%, vs. 2.95 +/- 3.33%, presence of persistent histone proportion was 10.59 +/- 13.40%, vs. 8.86 +/- 7.89% in DGC+SU and MS groups respectively, without significance. The simple technique avoids centrifuge-based damage. PMID- 29157007 TI - Prognostic value of neuron-specific enolase (NSE) for prediction of post concussion symptoms following a mild traumatic brain injury: a systematic review. AB - BACKGROUND: This systematic review aimed to determine the prognostic value of neuron-specific enolase (NSE) to predict post-concussion symptoms following mild traumatic brain injury (TBI). METHODS: Seven databases were searched for studies evaluating the association between NSE levels and post-concussion symptoms assessed >= 3 months (persistent) or >= 7 days < 3 months (early) after mild TBI. Two researchers independently screened studies for inclusion, extracted data and appraised quality using the Quality in Prognostic Studies (QUIPS) tool. RESULTS: The search strategy yielded a total of 23,298 citations from which 8 cohorts presented in 10 studies were included. Studies included between 45 and 141 patients (total 608 patients). The outcomes most frequently assessed were post concussion syndrome (PCS, 12 assessments) and neuropsychological performance deficits (10 assessments). No association was found between an elevated NSE serum level and PCS. Only one study reported a statistically significant association between a higher NSE serum level and alteration of at least three cognitive domains at 2 weeks but this association was no longer significant at 6 weeks. Overall, risk of bias of the included studies was considered moderate. CONCLUSIONS: Early NSE serum level is not a strong independent predictor of post concussion symptoms following mild TBI. PMID- 29157011 TI - Reactive oxygen species modulate itraconazole-induced apoptosis via mitochondrial disruption in Candida albicans. AB - Itraconazole (ITC), a well-known fungistatic agent, has potent fungicidal activity against Candida albicans. However, its mechanism of fungicidal activity has not been elucidated yet, and we aimed to identify the mechanism of ITC against C. albicans. ITC caused cell shrinkage via potassium leakage through the ion channel. Since shrunken cells could indicate apoptosis, we investigated apoptotic features. Annexin V-FITC and TUNEL assays indicated that fungicidal activity of ITC was involved in apoptosis. Subsequently, we confirmed an intracellular factor that could cause apoptosis. ITC treatment caused reactive oxygen species (ROS) accumulation. To confirm whether ROS is related with ITC triggered cell death, cell viability was examined using the ROS scavenger N acetylcysteine (NAC). NAC pretreatment recovered ITC-induced cell death, indicating that antifungal activity of ITC is associated with ROS, which is also confirmed by impaired glutathione-related antioxidant system and oxidized intracellular lipids. Moreover, ITC-induced mitochondrial dysfunction, in turn, triggered cytochrome c release and metacaspase activation, leading to apoptosis. Unlike the only ITC-treatment group, cells with NAC pretreatment did not show significant damage to mitochondria, and attenuated apoptotic features. Therefore, our results suggest that ITC induces apoptosis as fungicidal mechanism, and intracellular ROS is major factor to trigger the apoptosis by ITC in C. albicans. PMID- 29157012 TI - Shift work and sleep disorder comorbidity tend to go hand in hand. AB - Taking into consideration that shift work has a wide-ranging impact on circadian and sleep functioning, it seems likely that shift work increases the risk of a general sleep disturbance, spread out over a multitude of comorbid sleep disorders. The aim of the present study is to analyze and present the sleep disorder data of 250 shift workers and 971 permanent day workers, taken from a nationally representative sample. Additional data concerning duration, timing, and quality of sleep, daytime functioning and social/family variables were added to the analyses. The results showed that the shift workers experienced significantly more difficulties with the variability of their sleep times, reported more napping and considered themselves more as poor sleepers than the day workers. Most importantly, shift work, in comparison with day work, appeared associated with a significantly higher prevalence of the clinical, International Classification of Sleep Disorders' defined symptoms of nearly all main sleep disorders (including shift work disorder). For shift workers, the prevalence of a general sleep disturbance was 39.0% (95%CI 33.2 - 45.2), significantly higher than for day workers (24.6%, 95%CI 22.0 - 27.4). Moreover, shift workers were characterized by high levels of sleep disorder comorbidity. In addition, exclusively for shift workers, the prevalence of disordered sleep systematically decreased across decades of life and was considerably higher for single versus partnered shift workers. This study adds to the insight into the interacting factors that determine shift work coping and may play a role in occupational health interventions aimed at reducing sleep problems and thus improving the resilience and tolerance of the shift worker. PMID- 29157009 TI - Nutritional Status and Physical Fitness of Tribal Adolescents in Ahmednagar District of Maharashtra. AB - We examined the influence of nutritional status, body fat, and anemia on the physical fitness (PFI) of tribal adolescents. Weight, height, skinfold thickness, PFI, and hemoglobin levels of 147 adolescents (11 to 16 years) were measured. The experience of cycling was recorded. Overall, 31.3% were mildly, 12.9% were moderately, and 10.9% were severely thin. The majority (81.6%) were nonanemic. All had "poor" PFI scores. Hemoglobin levels were significantly associated with PFI scores in boys and girls. Experience of cycling also predicted PFI in girls. Nutritional status, hemoglobin level, and physical activity were associated with the fitness levels of these adolescents. PMID- 29157013 TI - Prediction of metabolites of epoxidation reaction in MetaTox. AB - Biotransformation is a process of the chemical modifications which may lead to the reactive metabolites, in particular the epoxides. Epoxide reactive metabolites may cause the toxic effects. The prediction of such metabolites is important for drug development and ecotoxicology studies. Epoxides are formed by some oxidation reactions, usually catalysed by cytochromes P450, and represent a large class of three-membered cyclic ethers. Identification of molecules, which may be epoxidized, and indication of the specific location of epoxide functional group (which is called SOE - site of epoxidation) are important for prediction of epoxide metabolites. Datasets from 355 molecules and 615 reactions were created for training and validation. The prediction of SOE is based on a combination of LMNA (Labelled Multilevel Neighbourhood of Atom) descriptors and Bayesian-like algorithm implemented in PASS software and MetaTox web-service. The average invariant accuracy of prediction (AUC) calculated in leave-one-out and 20-fold cross-validation procedures is 0.9. Prediction of epoxide formation based on the created SAR model is included as the component of MetaTox web-service ( http://www.way2drug.com/mg ). PMID- 29157014 TI - Construction and cellular uptake evaluation of redox-responsive docetaxel prodrug self-assembled nanoparticles. AB - Docetaxel (DTX) solution has some serious adverse side effects. A redox responsive DTX prodrug synthesized in our laboratory was used to prepare DTX prodrug self-assembled nanoparticles (DSNPs) with the method of nanoprecipitation. This study aimed at optimizing the formulation to develop stable preparation for the delivery of DTX. Single-factor test was used to evaluate the effects of the preparation concentration of DTX prodrug, stirring speed, the types of stabilizers and temperature on the prescription process of DSNPs. The particle size and polydispersity index were selected as the evaluation indexes. The entrapment efficiency, drug-loading, size distribution and zeta potential were characterized by UPLC and Zetasizer, respectively. The stability and cellular behavior of DSNPs were investigated by Zetasizer, LC-MS/MS and confocal laser scanning microscope, respectively. The particle size, entrapment efficiency and drug-loading of DSNPs were 173.8 +/- 1.4 nm, 98.8% +/- 0.1%, and 47.8% +/- 0.9%, respectively. DSNPs showed good stability during the storage of 30 days, and were taken into the cells in a time-dependent and concentration dependent manner. The method of nanoprecipitation could be used to entrap DTX. The preparation method was simple, and the quality of DSNPs was stable and reliable. Through the optimization of the formulation, we obtained uniform and stable DSNPs, which could escape from lysosomes of tumor cells. The optimized formulations were stable for intravenous administration. This study could provide scientific support for the development of nano-drug delivery system of small anti tumor drug. PMID- 29157015 TI - Influence of selected antithrombotic treatment on thromboelastometric results. AB - Rotatory thromboelastometry (ROTEM(r)) is used for diagnosing and monitoring bleeding patients. Some of these patients receive antithrombotic treatment, thus having an increased risk of bleeding. Only sparse knowledge exists about whether the ROTEM(r) analysis is influenced by antithrombotic treatment. The objective of the present study was to examine if the ROTEM(r) results are affected in patients receiving antithrombotic treatment. This prospective observational study included patients receiving either vitamin K-antagonists (VKA), aspirin (ASA) or ASA combined with an adenosine diphosphate (ADP) receptor antagonist (ASA + ADP). ROTEM(r) analyses were performed using the standard assays EXTEM(r), INTEM(r) and FIBTEM(r). Furthermore, haemoglobin, platelet count, International Normalized Ratio (INR), activated partial thromboplastin time, fibrinogen (functional), creatinine, estimated glomerular filtration rate, and C-reactive protein were determined. The study included 231 patients receiving antithrombotic treatment and compared the results to ROTEM(r) previously collected data from 73 healthy subjects. The VKA (n = 73) patients had a consistently prolonged EXTEM clot initiation (p < .0001), which was significantly correlated to the INR (Spearman's r = 0.53, p < .0001). Additionally, the VKA patients had significantly reduced clot propagation [reduced maximum velocity, maximum velocity (MaxVel) and increased time to maximum velocity (MaxVelt)]. ASA (n = 80) and ASA + ADP patients (n = 78) revealed a prolonged clot initiation. ASA patients had decreased clot propagation (increased MaxVelt), whereas ASA + ADP patients had an inconsistent change in clot propagation (increased MaxVel and MaxVelt). In conclusion, VKA treatment was revealed by the ROTEM(r) analysis. On the contrary, ASA and ASA + ADP treatment were not consistently revealed by the analysis. PMID- 29157016 TI - On the new regulation of medical devices in Europe. PMID- 29157017 TI - Comprehensive assessment of shockwave intensity: Transcriptomic biomarker discovery for primary blast-induced mild traumatic brain injury using the mammalian hair follicle. AB - OBJECTIVE: Primary blast-induced mild traumatic brain injury (mTBI) is an injury experienced during modern warfare due to exposure to the pressure waves produced by the detonation of explosives. With virtually no apparent physical damage or symptoms presented, there is a need for more objective and accessible mTBI biomarkers posing minimal invasiveness risk. METHODS: We measured the transcriptomic sensitivity of the hair follicles in relation to the severity of primary blast-derived TBI. An Advanced Blast Simulator system was used to expose male rats to single pulse shock waves (intensities ranging from 15 to 30 psi) in a head-only fashion. Gene differential expression (DE) and gene set (GS) analyses were conducted in the rat whisker hair follicles and the whole blood samples. RESULTS: While shared cellular function, themes were found across the exposure groups, some gene sets under such themes were unique to the exposure conditions. Intensity-specific pathway enrichment patterns within shared GS themes were also identified. Furthermore, while exhibited shared pathways, the blood transcriptome showed substantially fewer enriched gene sets compared with the hair follicles across all exposure conditions. CONCLUSIONS: Accordingly, we demonstrate the potential of mammalian hair follicles serving as an additional source for biomarker discovery and for diagnosing mTBI with high accessibility. PMID- 29157018 TI - Progressive DNA and RNA damage from oxidation after aneurysmal subarachnoid haemorrhage in humans. AB - Free radical toxicity is considered as a key mechanism in the neuronal damage occurring after aneurysmal subarachnoid haemorrhage (SAH). We measured markers of DNA and RNA damage from oxidation (8-oxodG and 8-oxoGuo, respectively) in cerebrospinal fluid from 45 patients with SAH on day 1-14 after ictus and 45 age matched healthy control subjects. At baseline, both markers were significantly increased in patients compared to controls (p values < .001), and exhibited a progressive further increase (to >20-fold above control levels) from day 5-14. None of the markers predicted the occurrence of vasospasms or mortality, although there was a trend that the 8-oxoGuo marker was more strongly associated with mortality than the 8-oxodG marker. We conclude that SAH leads to a massive increase in damage to nucleic acids from oxidative stress, which is likely to play a role in neuronal dysfunction and death. As only patients in need of a ventriculostomy catheter were included in the study, the findings cannot necessarily be extrapolated to all patients with SAH. PMID- 29157019 TI - Patients' needs during a surgical intervention process for Dupuytren's disease. AB - PURPOSE: To explore and describe clients' needs during a surgical intervention process for Dupuytren's disease. MATERIALS AND METHODS: Design: Interview study with 21 men undergoing surgical intervention for Dupuytren's disease. Qualitative content analysis was performed with the model of Patient Evaluation Process as a theoretical framework. RESULTS: The primary reason for seeking medical care was to receive an intervention to improve hand function. The need for knowledge was evident during the care process, and was connected to involvement in decision making. During surgery and rehabilitation, participants needed support with pain relief, a sense of security, support for self-care, or sick leave. There was also a need for participation in the evaluation and improvement of care. Clients' life situations contributed to the occurrence of needs or were a resource for handling them. Depending on patient character, clients handled their perceived needs differently. CONCLUSIONS: Clients' needs during a surgical intervention process include needs for improvement of hand function, knowledge, and support during treatment, and participation in evaluation. Clients' needs change during the care process and can be influenced by their life situation or their character. The identified needs ought to be included in quality assessments from the carers' perspective, to ensure that important needs of the clients are met by the surgical intervention process. Communication and interaction between client and health care provider is a key aspect of fulfilling clients' needs. Implications for rehabilitation Patients have need for knowledge throughout the care process: about the disease, risk factors, treatment options, practical and medical information related to the treatment and recovery, and about the care process as a whole. Need for knowledge is closely connected to patients' experience of being involved in decision making. Patients need support with both general human and specific medical issues during surgery and rehabilitation. Patients' needs change during the care process and can be influenced by the patient's life situation or character. From the carers' perspective, the identified needs ought to be included in quality assessments to ensure that important needs of the clients are met by the surgical intervention process. PMID- 29157020 TI - Pharmacokinetic drug evaluation of mepolizumab for the treatment of severe asthma associated with persistent eosinophilic inflammation in adults. AB - INTRODUCTION: Mepolizumab is a humanized monoclonal antibody that binds to and inactivates IL-5. It is available as a subcutaneous preparation. The practical application of mepolizumab is as an add-on therapy in the treatment of severe eosinophilic asthma. Areas covered: This article was created from a comprehensive literature search with information taken from meta-analyses, systematic reviews, and clinical trials of adults. The articles that have been selected evaluate the use of mepolizumab and its role in eosinophilic asthma. Expert opinion: Mepolizumab is significantly more effective than placebo in reducing exacerbations and need for systemic corticosteroids in severe eosinophilic asthma. There is a lack of head to head studies comparing mepolizumab to other monoclonal anti-IL-5 inhibitors in severe eosinophilic asthma. Post marketing surveillance revealed risk of anaphylaxis that is below 1%. PMID- 29157021 TI - Gastroparesis: pharmacotherapy and cardiac risk. AB - BACKGROUND: Gastroparesis is characterized by abnormal gastric motility and delayed emptying with symptoms of early satiety, postprandial fullness, bloating, nausea, vomiting and abdominal pain. Pharmacological discovery has been lagging because potential drugs often are associated with abnormalities of electrical conduction of the myocardium due to interaction with cardiac ion channels leading to limited pharmaceutical options for development of new drugs. OBJECTIVE: Addresses the safety of drugs for gastroparesis in terms of cardiotoxicity related to the clinical use of prokinetics and antiemetics. METHODS: Survey of QT drugs List and review of current literature. RESULTS: Many prokinetic drugs are associated with cardiac adverse events and manifest as prolongation of ventricular repolarization, i.e., QT-interval prolongation of the electrocardiogram. This disturbance may develop into a potentially fatal polymorphic ventricular tachyarrhythmia; Torsade de Pointes. Co-administration of prokinetics with other drugs affecting the repolarization process, pharmacokinetic interactions leading to increased blood levels, or the presence of clinical risk factors could further increase the risk for cardiac arrhythmias. CONCLUSIONS: It is important that clinicians managing gastroparesis are aware of the arrhythmogenic potential of drugs used clinically and risk factors that contribute to QT prolongation to safeguard patients at risk for drug-induced cardiac arrhythmia. PMID- 29157022 TI - Phytochemical based nanomedicines against cancer: current status and future prospects. AB - Cancer continues to be one in all the leading reasons for death worldwide. The mean cancer survival through standard therapeutic strategies has not been significantly improved over the past few decades. Hence, alternate remedies are needed to treat this terrible disease. Recently, natural compounds present in the plants, i.e. phytochemicals have been widely exploited for their anticancer potential. Phytochemicals may exhibit their anticancer activity through targeting different cancer cell signalling pathways, promoting cell cycle arrest and apoptosis, regulating antioxidant status and detoxification. Despite their excellent anticancer activity, the phytochemicals are limited by their low aqueous solubility, poor bioavailability, and poor penetration into cells, hepatic disposition, narrow therapeutic index and rapid uptake by normal tissues. Therefore, to address these challenges, the scientific community has shifted its significant interests towards nanocarriers-based delivery of phytochemicals due to their ability to enhance aqueous solubility, and bioavailability, specific tumour cell/tissue targeting, improved cellular uptake, reducing doses of phytochemicals and achieving steady-state therapeutic levels of the phytochemicals over an extended period of time. Additional advantages include excellent blood stability, multifunctional design of nanocarriers and improvement in anticancer activities. This review aims to summarise recent progress in phytochemical based nanomedicines for effective treatment of cancer. PMID- 29157023 TI - The inconvenience due to women's monthly bleeding (ISY) survey: a study of premenstrual symptoms among 5728 women in Europe. AB - OBJECTIVES: The aim of the ISY study was to investigate the prevalence of menstrual-related symptoms prior to and/or during menstrual or withdrawal bleeding among women from 12 European countries. METHODS: A 15-min quantitative online survey was conducted in two waves from February to September 2015 among 5728 women aged between 18 and 45 years, with an equal distribution of women using a combined hormonal contraceptive, including regular combined oral contraceptives (COCs) (CHC group, n = 2739) and women using a non-hormonal contraceptive or no contraceptive (non-HC group, n = 2989). RESULTS: The prevalence of at least one menstrual-related symptom was high in CHC users (93%) and in non-HC users (95%) (p < .0001) and the average number of symptoms reported was 5.3 vs. 5.9, respectively, (p < .0001). Pelvic pain, bloating/swelling, irritability and mood swing were reported in more than half of the women in both groups. Although generally modest, symptom severity was higher in non-HC users, except for headache. Overall, during the last four cycles, 60-75% of women did not require a treatment for most symptoms but headaches and pelvic pain. Mood swings/irritability, water retention/weight gain, lack of energy/mood swings and lack of energy/irritability were common symptoms that frequently co-occurred. No associations were reported between symptoms and age, educational qualifications or women's desire to reduce the frequency of menstruation. CONCLUSIONS: Premenstrual and menstrual symptomatology was less frequent, less numerous and less severe (except for headache) in women using CHCs; however, it remains a common concern. Reducing the frequency of menstrual periods could reduce withdrawal-related symptoms. PMID- 29157024 TI - Critical limb ischemia update and the evolving role of drug-elution technologies. AB - INTRODUCTION: Critical limb ischemia (CLI) is a prevalent condition associated with cardiovascular mortality and limb loss. Areas covered: This review discusses the epidemiology of CLI, revascularization options, and drug-elution therapies. Expert commentary: Drug-eluting stents (DES) and drug-coated balloons (DCB) improve patency rates in the femoropopliteal segment, and are generally used as first-line therapies. For below-knee disease, angioplasty is the default strategy unless lesions are focal whereby DES can be used to reduce restenosis risk. PMID- 29157025 TI - Non-pharmacological rehabilitation interventions for concussion in children: a scoping review. AB - PURPOSE: To summarise the extent, nature, and quality of current scholarly literature related to non-pharmacological, rehabilitation interventions following concussion, or mild traumatic brain injury in children. METHODS: An electronic search was conducted from 1987 to 24 October 2017. Studies were included if they met the following criteria: (1) full text, peer reviewed, and written in English, (2) original research, (3) diagnosed concussion or mild traumatic brain injury, (4) described the evaluation of an intervention, (5) the outcome was a concussion impairment, and (6) the mean/median age was under 19. Quality assessment using the Down's and Black criteria was conducted. RESULTS: Twenty-six studies published between 2001 and 2017 were identified. Interventions included rest, active rehabilitation, exercise, vestibular, oculomotor, cervicospinal therapy, education, early intervention, telephone counselling, mobile health application, Web-based Self-Management program, multimodal physical therapy, cognitive behavioural therapy, transcranial direct current stimulation, and acupuncture. The quality assessments ranged from poor to good. CONCLUSIONS: The literature describing interventions following concussion in children is scarce. While both positive and negative results were obtained, there were methodological concerns in most studies limiting the ability to draw conclusions. Interventions incorporating aerobic exercise show promise as a concussion management strategy. Implications for rehabilitation Few studies have examined rehabilitation interventions for youth following concussion. Research ranging from rest to exercise highlights the uncertainty of the field. Low quality research limits the generalizability of results. The use of physical activity appears to be an emerging area of interest. Individualised, aerobic exercise should be used as part of clinical management. PMID- 29157026 TI - First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports. AB - BACKGROUND: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting. METHODS: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented. In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated. RESULTS: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were re-analysed using three categories. This demonstrated a better validity. CONCLUSION: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance. PMID- 29157027 TI - Urinary tract injuries during cesarean section in patients with morbid placental adherence: retrospective cohort study. AB - BACKGROUND/OBJECTIVE: The purpose of this study is to evaluate the cases of lower urinary tract injuries during cesarean section with or without hysterectomy in cases with morbid placental adherence. METHODS: This record based retrospective study was conducted at Ain Shams University Maternity Hospital in Cairo, Egypt during the period between January 2014 and December 2016. It included all patients who had urinary tract injuries during cesarean section with or without hysterectomy in the cases with morbid placental adherence and they were collected from files of pregnant women who were admitted at hospital planned for termination of pregnancy. Patients were enrolled in four groups, Group 1: cases without urinary tract injuries. Group 2: cases with injuries to the bladder. Group 3: cases with injuries of the ureter. Group 4: cases with injuries to the bladder and ureter. RESULTS: This study gave us new information about the incidence of urinary tract injuries during cesarean section with morbid adherence placenta was 21.7% (Bladder 11.7%, Ureter 4.7%, and bladder with ureter 5.3%). There were various types of repair of urinary tract injury, as the following, bladder repair 10.8%, ureteric catheterization 0.9%, ureterovesical repair or reimplantation 1.5%, bladder repair and ureterovesical 1.2%, bladder repair and ureteric catheterization 2.3%, ureteric catheterization and ureterovesical 1.5 and 6.4% of cases needed urologic consultations. There is a real relation between urinary tract injury and obesity (55.3%). Bladder invasion was found in only 26.9% of all cases according to sonography findings. Most of the cases were delivered by cesarean section in 67.5%, and the remainders were delivered by cesarean hysterectomy 32.5%. About 96.5% of cases needed a blood transfusion. CONCLUSIONS: The morbid adherent placenta is still a challenge, which faces us as obstetricians, due to high morbidity and mortality. A multidisciplinary team is mandatory to avoid complications. PMID- 29157028 TI - Enhanced selective cellular uptake and cytotoxicity of epidermal growth factor conjugated liposomes containing curcumin on EGFR-overexpressed pancreatic cancer cells. AB - Pancreatic cancer is one of the most malignant cancers with a high mortality rate. Some types of pancreatic cancer cells overexpress epidermal growth factor receptor (EGFR), which is a potential target for anticancer agents. In this study, we examined the effect of epidermal growth factor (EGF)-conjugated liposomes containing curcumin (EGF-LP-Cur) on three different EGFR-expressed human pancreatic cancer cell lines, BxPC-3, Panc-1 and Mia Paca-2. We have demonstrated that it is feasible to prepare liposomal vesicles of EGF-LP-Cur and that it is stable in the liquid vehicle at ambient conditions for three weeks. In addition, the formulation of curcumin had higher cytotoxicity on BxPC-3 than on any other cells. It is also shown that the cellular uptake of curcumin on BxPC-3, which is essential for the cytotoxicity, is associated with EGFR-mediated mechanism of action. In summary, our results have showed that targeting EGFR with EGF-conjugated curcumin liposomes enhanced the antitumor activity of curcumin against human pancreatic cancer cells. PMID- 29157029 TI - Corrigendum. PMID- 29157030 TI - One step versus two step approach for gestational diabetes screening: systematic review and meta-analysis of the randomized trials. AB - INTRODUCTION: To compare both the prevalence of gestational diabetes mellitus (GDM) as well as maternal and neonatal outcomes by either the one-step or the two step approaches. MATERIAL AND METHODS: Electronic databases were searched from their inception until June 2017. We included all randomized controlled trials (RCTs) comparing the one-step with the two-step approaches for the screening and diagnosis of GDM. The primary outcome was the incidence of GDM. RESULTS: Three RCTs (n = 2333 participants) were included in the meta-analysis. 910 were randomized to the one step approach (75 g, 2 hrs), and 1423 to the two step approach. No significant difference in the incidence of GDM was found comparing the one step versus the two step approaches (8.4 versus 4.3%; relative risk (RR) 1.64, 95%CI 0.77-3.48). Women screened with the one step approach had a significantly lower risk of preterm birth (PTB) (3.7 versus 7.6%; RR 0.49, 95%CI 0.27-0.88), cesarean delivery (16.3 versus 22.0%; RR 0.74, 95%CI 0.56-0.99), macrosomia (2.9 versus 6.9%; RR 0.43, 95%CI 0.22-0.82), neonatal hypoglycemia (1.7 versus 4.5%; RR 0.38, 95%CI 0.16-0.90), and admission to neonatal intensive care unit (NICU) (4.4 versus 9.0%; RR 0.49, 95%CI 0.29-0.84), compared to those randomized to screening with the two step approach. CONCLUSIONS: The one and the two step approaches were not associated with a significant difference in the incidence of GDM. However, the one step approach was associated with better maternal and perinatal outcomes. PMID- 29157031 TI - Early prenatal vitamin D concentrations and social-emotional development in infants. AB - BACKGROUND: Many pregnant women in the United States have suboptimal vitamin D, but the impact on infant development is unclear. Moreover, no pregnancy-specific vitamin D recommendations have been widely accepted. AIMS: Given the ubiquitous expression of vitamin D receptors in the brain, we investigated the association between early prenatal plasma 25-hydroxyvitamin D (25(OH)D) concentrations and children's social and emotional development in the Newborn Epigenetic Study, a prospective study of pregnancies from 2009 to 2011 in Durham, North Carolina. METHODS: We measured 25(OH)D concentrations in first or second trimester plasma samples and categorized 25(OH)D concentrations into quartiles. Covariates were derived from maternal questionnaires. Mothers completed the Infant Toddler Social Emotional Development Assessment when children were 12-24 months of age. We used multivariable linear regression to evaluate associations between 25(OH)D and specific behavior scores, adjusted for season of blood draw, maternal age, education, parity, smoking, marital status, prepregnancy BMI, and infant gender. We investigated effect-measure modification by race/ethnicity. RESULTS: Of the 218 mother-infant pairs with complete data, Black mothers had much lower 25(OH)D concentrations as compared to White and Hispanic mothers. After adjustment, lower prenatal 25(OH)D was associated with slightly higher (less favorable) Internalizing scores among White children, but lower (more favorable) Internalizing scores among Black and Hispanic children. Lower prenatal 25(OH)D also appears to be associated with higher (less favorable) dysregulation scores, though only among White and Hispanic children. CONCLUSIONS: Though imprecise, preliminary results warrant further investigation regarding a role for prenatal vitamin D on children's early social and emotional development. PMID- 29157032 TI - Pain, fatigue, function and participation among long-term manual wheelchair users partnered with a mobility service dog. AB - PURPOSE: To assess the effects of a mobility service dog (MSD) on pain, fatigue, wheelchair-related functional tasks, participation and satisfaction among manual wheelchair users over a nine-month period. METHOD: A longitudinal study with repeated assessment times before and three, six and nine months after intervention was achieved. Intervention consisted in partnering each participant with a MSD. The setting is a well-established provincial service dog training school and participants homes. A convenience sample of 24 long-term manual wheelchair users with a spinal cord injury was involved. Outcome measures were: Wheelchair User's Shoulder Pain Index (WUSPI), Rate of Perceived Exertion (RPE), vitality scale from the SF-36, grip strength, Wheelchair Skills Test (WST), Canadian Occupational Performance Measure (COPM), Reintegration to Normal Living Index (RNLI), Life Space Assessment, Psychosocial Impact of Assistive Devices Scale (PIADS) and Quebec User Evaluation of Satisfaction with assistive Technology (QUEST 2.0). RESULTS: Shoulder and wrist pain as well as fatigue decreased significantly over time with the use of a MSD as evidenced by scores from WUSPI, RPE and SF-36 (feeling less worn out). Manual wheelchair propulsion skills (steep slopes, soft surfaces and thresholds) improved significantly over time as confirmed by the WST. Participation increased significantly over time as revealed by the COPM (for five occupations) and the RNLI (for five items). Satisfaction with the MSD was high over time (QUEST: nine items) and with a high positive psychosocial impact (PIADS: 10 items). CONCLUSION: MSD represents a valuable mobility assistive technology option for manual wheelchair users. IMPLICATIONS FOR REHABILITATION For manual wheelchair users partenered with mobility service dog * Shoulder pain and fatigue significantly decreased and continued to decrease between the third and sixth month and the ninth month. * Performance with propelling the wheelchair up steep slopes increased from 41 to 88% and on soft surfaces increased from 53 to 100% after 3 months, respectively. * Occupational performance satisfaction was significantly increased for mobility in relation with the transfers, navigating in a natural environment and picking up objects. * High satisfaction towards psychosocial competency, psychosocial adequacy and self-esteem were reported at months three, six and nine. PMID- 29157033 TI - Alteration in methylation level at differential methylated regions of MEST and DLK1 in fetus of preeclampsia. AB - OBJECTIVES: Offspring born to preeclamptic women are at high risk for metabolic diseases in later life, but the mechanisms are not known. The purposes of the current investigation were to clarify the changes in DNA methylation at MEST and DLK1 DMRs in fetus of preeclampsia and to explore the possible mechanisms behind the high risk of adult diseases in the offspring of preeclampsia. METHODS: Fetal lymphocytes were isolated from umbilical cord blood of 78 women with preeclampsia and 95 women with normal pregnancy. Genomic DNA was extracted and then DNA methylation levels of MEST and DLK1 DMRs were determined by MassARRAY quantitative methylation analysis. RESULTS: The methylation levels were detected in 20 CpG sites of MEST DMR and 16 sites of DLK1 DMR. Methylation changes were significantly different at CPG1, 3, 4, 7.8, 15, 18.19, and 20 of MEST between preeclampsia and normal pregnancy (P = 0.014, 0.001, <0.001, <0.001, = 0.001, = 0.005, and = 0.003, respectively). Significant differences were also observed at CPG 3 and 9 of DLK1 (P = 0.002 and 0.027, respectively). However, overall methylation at these DMRs were not affected. CONCLUSION: We conclude methylation changes at some CpG sites of MEST and DLK DMRs in preeclamptic group. This may be among the mechanisms behind the high risk of adult diseases in the later life of offspring born to preeclamptic pregnancies. ABBREVIATIONS: DMR: Differentially Methylated Region; MEST: Mesoderm Specific Transcript. PMID- 29157034 TI - Effects of Single-Dose Preemptive Pregabalin and Intravenous Ibuprofen on Postoperative Opioid Consumption and Acute Pain after Laparoscopic Cholecystectomy. AB - PURPOSE: Non-opioid medications as a part of multimodal analgesia has been increasingly suggested in the management of acute post-surgical pain. The present study was planned to compare the efficacy of the combination of pregabalin plus iv ibuprofen. METHODS: 58 patients were included in this prospective, randomized, double-blinded study. The pregabalin group (Group P, n = 29) received 150 mg pregabalin, the pregabalin plus ibuprofen group (Gropu PI, n = 29) received 150 mg pregabalin and 400mg iv ibuprofen before surgery. Postoperative fentanyl consumption, additional analgesia requirements and PACU stay were recorded. Postoperative analgesia was performed with patient-controlled IV fentanyl. RESULTS: VAS scores in the group PI were statistically lower at PACU, 1and 2 hours at rest, at PACU, 1, 2, 4, 12 and 24 hours on movement compared to the group P (P < 0.05). Opioid consumption was statistically significantly higher in the group P compared to the group PI (130.17 +/- 60.27 vs 78.45 +/- 60.40 MUq, respectively, P < 0.001) and reduced in the 4th 24 hours by 55% in group PI. Rescue analgesia usage was statistically significantly higher in the group P than in the group PI (16/29 vs 7/29, respectively, P < 0.001). Four patient in the group PI did not need any opioid drug. Besides, PACU stay was shorter in the group PI than the group P (10.62 +/- 2.38 vs 15.59 +/- 2.11 min, respectively, P < 0.001). CONCLUSION: Preemptive pregabalin plus iv ibuprofen in laparoscopic cholecystectomy reduced postoperative opioid consumption. This multimodal analgesic aproach generated lower pain scores in the postoperative period. PMID- 29157035 TI - A new approach to fertility-preserving surgery in patients with placenta accreta. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of a novel combined surgical approach utilising: (1) two autonomous balloon Zhukovsky catheters (vaginal and uterine), (2) bilateral ligation of the descending uterine artery branches, (3) external supraplacental pleated sutures, and (4) either excision of a small area of placenta accreta or full metroplasty, for the management of uterine bleeding associated with placenta accreta of various severity. MATERIALS AND METHODS: The study included medical records of 92 pregnant women with placenta accreta undergoing a caesarean section. To evaluate the efficacy of the proposed management strategy, study participants were divided into three groups. In Group 1 (controls, n = 47), we utilised the combination of bilateral ligation, Barinov external supraplacental pleated sutures, and either excision of the tightly attached portion of placenta accreta or metroplasty. In Group 2 (n = 20), the abovementioned surgical techniques were additionally combined with balloon tamponade using an intrauterine Zhukovsky catheter. In Group 3 (n = 25), we additionally used an intravaginal Zhukovsky balloon catheter to enhance the efficacy of intrauterine tamponade. RESULTS: The use of an intrauterine balloon catheter combined with metroplasty was associated with a reduction in blood loss volume and blood transfusion rate by 1.9-fold, while the use of intravaginal balloon catheter reduced blood transfusion rate by 2.4-fold. The uterine balloon catheter reduced the risk of hysterectomy by 11-fold. CONCLUSION: Simultaneous use of two Zhukovsky balloon catheters (intravaginal and intrauterine) during caesarean section facilitates fertility-preserving surgery in patients with placenta accreta even in the cases of low-segment bleeding, thereby representing a promising approach to management of these patients. PMID- 29157036 TI - Epigallocatechin-3-O-gallate alleviates the malignant phenotype in A-431 epidermoid and SK-BR-3 breast cancer cell lines. AB - In this study, we evaluated the effects of epigallocatechin-3-O-gallate (EGCG) in two cancer cell lines, A-431 overexpressing ErbB1 and SK-BR-3, overexpressing ErbB2. EGCG treatment showed dose-dependent collapse of mitochondrial membrane potential (Deltapsim), increase in reactive oxygen species (ROS) production, changes in nuclear morphology and reduced viability. Flow cytometry data indicated that EGCG partially decreases the phosphorylation of several proteins involved in cell proliferation and survival: pErbB1(Y1173, Y1068), pAkt(S473) and pERK(Y204). EGCG affected the clonogenic growth in both cell lines with an EC50 of 2.5 and 5.4 uM for A-431 and SK-BR-3, respectively. Wound scratch assay demonstrated that EGCG inhibited the healing in dose-dependent manner and the effect was correlated with partial reduction in phosphorylation of pFAK(S910). Our data suggest that EGCG administration might reduce the unfavourable traits, particularly associated with ErbB1/EGFR overexpression. PMID- 29157037 TI - Fetal nuchal translucency in severe congenital heart defects: experiences in Northern Finland. AB - OBJECTIVE: To evaluate the performance of first-trimester measurement of fetal nuchal translucency (NT) in the detection of severe congenital heart defects (CHDs). METHODS: During the study period of 1 January 2008 - 31 December 2011, NT was measured in 31,144 women as a part of voluntary first-trimester screening program for Down's syndrome in Northern Finland. NT was measured by personnel trained on the job by the experienced staff. No certification or annual audits are required in Finland. However, the recommendation is that the examiner should perform 200 scans on average per year. Severe CHD was classified as a defect requiring surgery in the first year of life or a defect that led to the termination of the pregnancy. All severe CHDs diagnosed during the study period in Northern Finland could not be included in this study since all women did not participate in the first-trimester screening and some cases were missing important data. RESULTS: Fourteen (17.7%) out of 79 severe CHDs were found with NT cutoff of 3.5 mm. Amongst the 79 severe CHD cases, there were 17 chromosomal abnormalities. With NT cutoffs of 2.0 and 1.5 mm the detection rates would have increased to 25.3% (n = 20) and 46.8% (n = 37). Using a randomly selected control group of 762 women with normal pregnancy outcomes, false positive rates (FPRs) were calculated. For NT cutoffs of 1.5, 2.0 and 3.5 mm, the FPRs were, 18.5, 3.3 and 0.4%, respectively. CONCLUSIONS: A greater than 3.5 mm NT measurement in the first-trimester ultrasound is an indication to suspect a fetal heart defect but its sensitivity to detect severe CHD is poor. In our study, only 17.7% of severe CHDs would have been detected with an NT cutoff of 3.5 mm. PMID- 29157038 TI - Applying U.S. national guidelines for ototoxicity monitoring in adult patients: perspectives on patient populations, service gaps, barriers and solutions. AB - OBJECTIVES: To promote establishment of effective ototoxicity monitoring programs (OMPs), this report reviews the U.S. national audiology guidelines in relation to "real world" OMP application. Background is provided on the mechanisms, risks and clinical presentation of hearing loss associated with major classes of ototoxic medications. DESIGN: This is a non-systematic review using PubMed, national and international agency websites, personal communications between ototoxicity experts, and results of unpublished research. Examples are provided of OMPs in various healthcare settings within the U.S. civilian sector, Department of Defense (DoD), and Department of Veterans Affairs (VA). STUDY SAMPLE: The five OMPs compared in this report represent a convenience sample of the programs with which the authors are affiliated. Their opinions were elicited via two semi structured teleconferences on barriers and facilitators of OMP, followed by a self-administered questionnaire on OMP characteristics and practices, with responses synthesized herein. Preliminary results are provided from an ongoing VA clinical trial at one of these OMP sites. Participants were 40 VA patients who received cisplatin chemotherapy in 2014-2017. The study arms contrast access to care for OMP delivered on the treatment unit versus usual care as provided in the audiology clinic. RESULTS: Protocols of the OMPs examined varied, reflecting their diverse settings. Service delivery concerns included baseline tests missed or completed after the initial treatment, and monitoring tests done infrequently or only after cessation of treatment. Perceived barriers involved logistics related to accessing and testing patients, such as a lack of processes to help patients enter programs, patients' time and scheduling constraints, and inconvenient audiology clinic locations. Use of abbreviated or screening methods facilitated monitoring. CONCLUSIONS: The most effective OMPs integrated audiological management into care pathways of the clinical specialties that prescribe ototoxic medications. More OMP guidance is needed to inform evaluation schedules, outcome reporting, and determination of actionable ototoxic changes. Guidance is also lacking on the use of hearing conservation approaches suitable for the mass testing needed to support large-scale OMP efforts. Guideline adherence might improve with formal endorsement from organizations governing the medical specialty stakeholders in OMP such as oncologists, pulmonologists, infectious disease specialists, ototolaryngologists and pharmacists. PMID- 29157039 TI - Comparison of cesarean versus vaginal delivery of extremely preterm gestations in breech presentation: retrospective cohort study. AB - OBJECTIVE: As survival increases at earlier gestational ages, the optimal mode of delivery, especially in cases of breech presentation, is of increasing importance. The objective of this study was to compare outcomes of vaginal delivery (VD) and cesarean section (CS) births for infants in breech presentation at borderline viability. STUDY DESIGN: A retrospective chart review of live breech births between 23 + 0 and 25 + 6 weeks gestation at a tertiary university center from 2003 to 2013 was conducted. Those delivered vaginally were compared with those delivered by CS. Stillbirths and deliveries where no resuscitation was intended were removed from the analysis. Variables were compared using a Student t-test (continuous), Mann-Whitney U test (categorical), or a Chi-squared test (count). Logistic regression analysis was performed to further evaluate the results. Results with p < .05 were considered significant. RESULTS: One hundred seventy-six births were included, 36 VD and 140 CS. Baseline characteristics were similar between groups. Gestational age at delivery was significantly higher in CS deliveries (24.9 +/- 0.6 versus 24.5 +/- 0.7, p = .0007). The rate of neonatal death (23.6% versus 44.4%, p = .0127) was significantly lower in those born by CS. All other neonatal outcomes including Apgar scores at one and 5 min, cord gases, birth weight, length of stay in NICU, incidence of respiratory complications, and incidence of high-grade IVH demonstrated no significant differences. Logistic regression suggested that male sex, lower birth weight, and earlier gestational age are significantly associated with neonatal mortality. Thirty percent of uterine incisions were of the classical, high transverse or inverted-T types. The estimated blood loss was significantly higher in CS births (706.6 +/- 226.4 versus 327.4 +/- 174.1 mL, p < .0001), but there was no difference in the rate of blood transfusion. CONCLUSION: CS delivery of breech infants at borderline viability had a protective effect on neonatal mortality compared to VD depending on the regression model utilized. Infant sex, birth weight, and gestational age also contribute significantly to neonatal mortality. A prospective study of planned method of delivery is recommended to further explore this finding. PMID- 29157040 TI - IMI Platinum Award. PMID- 29157041 TI - Relation with postpartum maternal morbidity of different types of anesthesia in preeclamptic patients. AB - OBJECTIVE: The aim of this study is to investigate the effect of different anesthesia types administered to patients with preeclampsia on postoperative maternal morbidities. METHODS: Medical records of pregnant women complicated with preeclampsia delivered by cesarean from January 2010 to December 2016 in our clinic were retrospectively reviewed. RESULTS: There was not a statistically significant difference between patients receiving spinal anesthesia and general anesthesia in terms of additional parenteral analgesic requirement at postoperative period (p = 0.520). The length of stay in hospital and deltaHb (preoperative hemoglobin value minus postoperative hemoglobin value) were not different between spinal anesthesia and general anesthesia groups (p = 0.140 and 0.648, respectively). The rate of postoperative antihypertensive medication requirement was statistically significant in patients with severe preeclampsia who underwent general anesthesia (p = 0.009, x2 = 6.867, odds ratios = 4.276 (1.531-11.942)). The time passing to reach the first normal blood pressure level in patients with severe preeclampsia was 11.95 +/- 9.11 h in patients with spinal anesthesia, 10.55 +/- 4.95 h in patients with general anesthesia, and the difference was not statistically significant (p = 0.504). CONCLUSION: The need for antihypertensive medication is greater in patients with severe preeclampsia receiving general anesthesia. There is a need for comprehensive, prospective, and randomized controlled trials to establish the relationship between postpartum morbidity and the different types of anesthesia. PMID- 29157042 TI - Head-out immersion in hot water increases serum BDNF in healthy males. AB - PURPOSE: Brain-derived neurotrophic factor (BDNF) is an important neurotrophin. The present study investigated the effects of head-out water immersion (HOI) on serum BDNF concentrations. METHODS: Eight healthy men performed 20 min head-out water immersion at 42 degrees C (hot-HOI) and 35 degrees C (neutral-HOI). These experimental trials were administered in a randomised order separated by at least 7 days. Venous blood samples were withdrawn at rest, immediately after the 20-min HOI, as well as at 15 and 30 min after the end of the HOI. Serum BDNF and S100beta, plasma cortisol, platelet and monocyte counts, and core body temperature (Tcb) were measured. RESULTS: Tcb was higher at the end of the hot HOI and 15 min after hot-HOI (p < 0.01), but recovered to pre-HOI level at 30 min after hot-HOI. No change in Tcb was recorded during neutral-HOI. BDNF level was higher (p < 0.05) at the end of the hot-HOI and at 15 min after the end of hot HOI, and returned to the baseline at 30 min after hot-HOI. S100beta, platelet count and monocyte count remained stable throughout the study. Cortisol level was lower at the end of the hot-HOI and returned to pre-HOI level during the recovery period. BDNF and S100beta, cortisol, and platelet and monocyte counts did not change throughout the neutral-HOI study. CONCLUSIONS: The present findings suggested that the increase in BDNF during 20-min hot-HOI was induced by hyperthermia through enhanced production, rather than by changes in permeability of the blood-brain barrier (BBB), platelet clotting mechanisms or secretion from monocytes. PMID- 29157043 TI - Association of first-trimester maternal lipid profiles and triglyceride-glucose index with the risk of gestational diabetes mellitus and large for gestational age newborn. AB - OBJECTIVE: To evaluate the association of maternal first-trimester plasma lipid profiles, fasting plasma glucose (FPG), and triglyceride (TyG) index with the risk of gestational diabetes mellitus (GDM) and large for gestational age (LGA) infant in Iranian mothers. METHODS: Nine hundred and fifty-four healthy pregnant women were prospectively followed till after delivery. Maternal fasting lipids and glucose concentration were measured at nine-week gestation on average. We used generalized linear models to calculate the relative risks and 95% confidence intervals. RESULTS: The incidence of GDM and LGA infants among our participants was 18.4% and 26.1%, respectively. There was a significant correlation between the increase in FPG, triglyceride, TG/HDL-C ratio, as well as TyG index with the risk of GDM and LGA infant. After adjusting for potential confounders, the relative risk of GDM in women in the top tertile of FPG, triglyceride (TG), triglyceride/high-density lipoprotein-cholesterol (TG/HDL-C) and TyG index was 4.2-, 4.2-, 3.9-, and 4.9-folds of its risk in women in the bottom tertile, respectively. Also after adjusting for GDM, the relative risk of LGA infants in women in the top tertile of FPG, TG, TG/HDL-C ratio and TyG index was 3.9-, 4.3-, 4.8-, and 5.3-folds of its risk in women in the bottom tertile, respectively. CONCLUSIONS: Based on our findings, TyG index is more robust early predictors of GDM and LGA in Iranian women. PMID- 29157044 TI - Prenatal complications are associated with the postnatal airway host response and microbiota in intubated preterm infants. AB - PURPOSE: To prospectively examine the relationship between prenatal events, postnatal airway host response and microbiota, and clinical outcomes. MATERIALS AND METHODS: Tracheal aspirates collected at seven days of age from 71 mechanically ventilated infants (median gestational age (GA), 25 weeks [range 23 28]) were simultaneously processed for a 12-plex protein assay and bacterial identification by 16S rRNA sequencing. Phenotypes were determined by unsupervised clustering of the protein analytes. Subject characteristics, microbial communities and clinical factors and outcomes were compared across the phenotype groups. RESULTS: Three clusters were identified: 1 (high protein levels), 2 (high proinflammatory proteins and low anti-inflammatory proteins), and 3 (low protein levels), respectively. Antenatal hemorrhage was most common in cluster 1, while chorioamnionitis characterized cluster 2 and preeclampsia was most prevalent in cluster 3, which was characterized by a predominance of Staphylococcus and relative absence of Ureaplasma. There were higher rates of adverse clinical outcomes in cluster 1. CONCLUSIONS: Airway protein profiles in seven days old mechanically ventilated preterm infants are associated with important antenatal events and unique airway microbial communities. These relationships may reveal new mechanisms by which antenatal events impact the course and outcomes of preterm infants. PMID- 29157045 TI - From religious to existential issues: the implications for GPs. PMID- 29157046 TI - Authors reply: wide-reaching effects of and concerns regarding geographic localization of hospitalist units. PMID- 29157047 TI - Neurological development of children born to mothers after kidney transplantation. AB - BACKGROUND: Pregnancies after kidney transplantation are at high risk of complications such as preterm birth and foetal growth restriction. Until now, the impact of these factors on neurological development of children born to transplant mothers has not been established. AIMS: A comparison of neurological examinations performed in 36 children of kidney transplant women (study group) and 36 children born to healthy mothers (control group). The children from both groups were born at a similar gestational age and in the similar time period from 12/1996 to 09/2012. Neurological examinations were performed from 07/2010 to 11/2013. Each examination was adjusted to the patient's age and performed after the neonatal period. Three years later children were re-consulted, if they presented neurological deviations or were less than 12 months old at the time of the first examination. RESULTS: Normal neurological development was found in 86% of children in both groups (p = .999). Mild neurological deviations were observed in four (11%) children born to kidney transplant mothers and in five (14%) children born to healthy mothers (p = .999). Moderate deviations were diagnosed in one premature child born to transplant mother, whose pregnancy was complicated with a severe preeclampsia and foetal growth restriction. In the study population, no severe neurological disorders were found. Almost all (8/10) children with neurological deviations were born prematurely in good general conditions. The neurological deviations observed in the first year of life were mild and transient. In children over 1 year of age, deviations were more pronounced and continued to maintain. CONCLUSIONS: The neurological development of children of kidney transplant women is similar to that of the general population and possible deviations seem to be the result of intrauterine hypotrophy and prematurity. Therefore, in clinical practice, it is necessary to plan post-transplant pregnancies especially in women at high risk of these complications. PMID- 29157049 TI - Small for gestational age as an independent risk factor for long-term pediatric gastrointestinal morbidity of the offspring. AB - OBJECTIVE: The concept of neonatal programming has begun to emerge as an important component of adult health. Scarce data exist regarding perinatal risk factors for long-term gastrointestinal (GI) morbidity of the offspring. We aimed to evaluate the association between birthweight (BW) at term and long-term pediatric GI morbidity. STUDY DESIGN: A population-based cohort analysis was performed, comparing the risk of long-term GI morbidity (up to the age of 18 years) in children delivered at term according to their BW. The study included all term deliveries occurring between 1991 and 2014 at a single regional tertiary medical center. Multiple gestations and fetuses with congenital malformations were excluded. BW was subdivided into: small for gestational age (small for gestational age (SGA) - BW <= 5th centile), appropriate for gestational age (AGA 5th centile < BW < 95th centile), and large for gestational age (LGA - BW >=95th centile). Hospitalizations up to the age of 18 years involving GI morbidity were evaluated, using a predefined set of ICD-9 codes, as recorded in the hospital files. A Kaplan-Meier survival curve was used to compare cumulative GI morbidity incidence. A Cox proportional hazards model was constructed to control for confounders. RESULTS: During the study period, 225,600 term singleton deliveries met the inclusion criteria. Of them, 4.6% (n = 10,415) were SGA and 4.3% (n = 9796) were LGA. During the 18-years follow-up period, 11,791 (5.2%) children were hospitalized with GI morbidity. Hospitalizations were significantly more common in the SGA group, as compared with the AGA and LGA groups (6.6 versus 5.2 versus 4.5%, respectively, p < .001) Specifically, inflammatory bowel disease, celiac, hernia, hepatitis, and cholecystitis, were more common in the SGA group. The Kaplan-Meier survival curve demonstrated a significantly higher cumulative incidence of gastrointestinal morbidity in the SGA group (log rank p < .001). In the Cox proportional hazards model, controlled for relevant clinical confounders, SGA BW was found to be an independent risk factor for long-term GI morbidity (adjusted HR = 1.23, 95%CI 1.14-1.33, p < .001). CONCLUSIONS: SGA offspring are at an increased and independent risk for long-term pediatric GI morbidity. PMID- 29157050 TI - Pregnancy outcome and placental pathology in small for gestational age neonates in relation to the severity of their growth restriction. AB - PURPOSE: To investigate neonatal outcome and placental pathology in pregnancies complicated with small for gestational age neonates (SGA), in relation to the severity of growth restriction. METHODS: The medical records and placental histology reports of all neonates with a birth-weight (BW) <=10th percentile, born between 24-42 weeks, during 2010-2015, were reviewed. Placental lesions were classified into maternal and fetal vascular malperfusion (MVM and FVM) lesions. Results were compared between neonates with BW <5th percentile (severe SGA group), neonates with BW between 5th-10th percentile (mild SGA group) and a control group of appropriate for gestational age (AGA) neonates. Composite neonatal outcome was defined as one or more of early complications. RESULTS: Overall, 753 neonates were included, 238 in the severe SGA group, 266 in the mild SGA group, and 249 in the control group. The severe SGA group had higher rates of composite adverse neonatal outcome as compared with the mild SGA and control groups (37.2 versus 17.6%, versus 24.5%, respectively, p < .001). The SGA group was characterized by higher rates of placental MVM and FVM lesions, compared with controls (p < .001 for both). After controlling for confounders, using a multivariate regression analysis, the likelihood of detecting placental MVM and FVM lesions was increased as neonatal birthweight decreased. CONCLUSIONS: Worse neonatal outcome and more placental MVM and FVM lesions correlate with the severity of neonatal growth restriction in a "dose-dependent" manner. PMID- 29157048 TI - The Drosha rs10719 T>C polymorphism is associated with preeclampsia susceptibility. AB - PURPOSE: Drosha is a member of the micro RNA (miRNA) processing machinery that affects miRNA processing. Single-nucleotide polymorphisms (SNPs) in the Drosha gene might affect microRNA processing and the expression of various genes. The aim of this study is to investigate the association between SNPs in the Drosha gene and preeclampsia (PE) in the southeast of Iran. METHODS: Genotyping of Drosha rs10719 and rs6877842 was performed using blood samples from 219 PE women and 205 healthy control subjects by a polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The Drosha rs10719TC genotype was significantly associated with 1.6-fold higher risk of PE (odds ratio (OR, 1.6 [95% CI, 1.1-2.4], P = 0.026). In addition, the frequency of the Drosha rs10719CC genotype was significantly higher in PE women and was associated with threefold higher risk of PE (OR 3 [95% CI 1.4-6.3], P = 0.004). There was no association between the Drosha rs6877842 polymorphism and PE susceptibility. The CC-GG combined genotype was associated with 3.4-fold higher risk of PE (OR 3.4 [95% CI 1.4-8.1], P = 0.007). The haplotype-based association analysis showed higher frequency of C-G haplotype of Drosha rs10719 and rs6877842 polymorphisms with the increased risk of PE 1.5-fold (OR 1.5 [95% CI 1.1 - 2], P = 0.01). CONCLUSIONS: The Drosha rs10719TC and CC genotypes were associated with PE risk. The CC-GG combined genotype and C-G haplotype of Drosha rs10719 and rs6877842 polymorphisms may increase PE susceptibility. PMID- 29157051 TI - Cerebral NIRS patterns in late preterm and very preterm infants becoming late preterm. AB - BACKGROUND: Near Infrared Spectroscopy (NIRS) has been proposed as a useful, noninvasive monitoring technique providing reliable information about central nervous system (CNS) oximetry and function. Recently, brain damage has been reconsidered as a dynamic process evolving over the weeks of gestation. We therefore investigated NIRS cerebral pattern differences between healthy late preterm infants (LPTo) and very preterm infants becoming late preterm (LPT). METHODS: We conducted an observational study in 40 healthy late preterm infants, matched for gestational age at monitoring, of whom 20 where LPTo and 20 LPT. Clinical, diagnostic and laboratory monitoring procedures and cerebral oximetry (crSO2) and function (cFTOE) were recorded on admission into the study. RESULTS: No significant differences (p > .05, for all) were found between groups regarding clinical, diagnostic or laboratory parameters. Higher crSO2 and lower cFTOE (p < .001, for both) were found in the LPTo group. CONCLUSIONS: Our results, showing impaired oximetry and function of CNS in LPT, offer additional support to NIRS parameters as a useful tool for longitudinal CNS monitoring of very preterm infants becoming LPT. Future studies correlating NIRS variables and long-term neurological outcome in LPT are needed to elucidate the concept of dynamic brain damage pathogenesis. PMID- 29157052 TI - Population structure and patterns of geographic differentiation of Bactrocera oleae (Diptera: Tephritidae) in Eastern Mediterranean Basin. AB - The olive fly (Bactrocera oleae) is the most destructive pest of olives in most commercial olive-growing regions worldwide. Significant economic damage to olive production is caused by the larvae of this fly, which feed on the pulp of Olea fruits. Studying the genetic structure of insect pest populations is essential for the success of pest management strategies. Our primary goal in the present study was to examine the population structures of olive flies collected over a wide geographic area from Turkey, a representative of eastern Mediterranean region, using two mitochondrial DNA sequences as genetic markers. The data revealed a high level of genetic variability in olive fly populations and a moderate level of genetic differentiation between Mediterranean and Aegean populations in Turkey. We also merged the sequences obtained in the present study with previously published sequences from across the world into the data matrix. Strong population substructure and a significant correlation between genetic and geographic distances were detected in northern Mediterranean basin populations of B. oleae, indicating the possibility of a westward expansion of the species in the continent. In addition, our results revealed a very close genetic relationship between the Aegean and Iranian populations, which suggests that B. oleae was introduced to Iran from western parts of Turkey. However, additional markers and analytical approaches are required to determine the exact colonization route of olive fly. PMID- 29157053 TI - Impact of fluoroquinolone prophylaxis on documented infections in patients with febrile neutropenia. PMID- 29157054 TI - Genetic diversity and genetic structure of farmed and wild Chinese mitten crab (Eriocheir sinensis) populations from three major basins by mitochondrial DNA COI and Cyt b gene sequences. AB - The Chinese mitten crab, Eriocheir sinensis, is one of the important native crab species in East Asian region, which has been widely cultured throughout China, particularly in river basins of Yangtze, Huanghe and Liaohe. This study was designed to evaluate the genetic diversity and genetic structure of cultured and wild E. sinensis populations from the three river basins based on mitochondrial DNA (mtDNA) cytochrome oxidase subunit I (COI) and cytochrome b (Cyt b). The results showed that there were 62 variable sites and 30 parsimony informative sites in the 647 bp of sequenced mtDNA COI from 335 samples. Similarly, a 637 bp segment of Cyt b provided 59 variable sites and 26 parsimony informative sites. AMOVA showed that the levels of genetic differentiation were low among six populations. Although the haplotype diversity and nucleotide diversity of Huanghe wild population had slightly higher than the other populations, there were no significant differences. There was no significant differentiation between the genetic and geographic distance of the six populations, and haplotype network diagram indicated that there may exist genetic hybrids of E. sinensis from different river basins. The results of clustering and neutrality tests revealed that the distance of geographical locations were not completely related to their genetic distance values for the six populations. In conclusion, these results have great significance for the evaluation and exploitation of germplasm resources of E. sinensis. PMID- 29157055 TI - Haptotherapy as a new intervention for treating fear of childbirth: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of haptotherapy on severe fear of childbirth in pregnant women. DESIGN: Randomized controlled trial. SETTING: Community midwifery practices and a teaching hospital in the Netherlands. POPULATION OR SAMPLE: Primi and multigravida, suffering from severe fear of childbirth (N = 134). METHODS: Haptotherapy, psycho-education via Internet and care as usual were randomly assigned at 20-24 weeks of gestation and the effects were compared at 36 weeks of gestation and 6 weeks and 6 months postpartum. Repeated measurements ANOVA were carried out on the basis of intention to treat. Since there were crossovers from psycho-education via Internet and care as usual to haptotherapy, the analysis was repeated according to the as treated principle. MAIN OUTCOME MEASURES: Fear of childbirth score at the Wijma Delivery Expectancy/Experience Questionnaire. RESULTS: In the intention to treat analysis, only the haptotherapy group showed a significant decrease of fear of childbirth, F(2,99) = 3.321, p = .040. In the as treated analysis, the haptotherapy group showed a greater reduction in fear of childbirth than the other two groups, F(3,83) = 6.717, p < .001. CONCLUSION: Haptotherapy appears to be more effective in reducing fear of childbirth than psycho-education via Internet and care as usual. PMID- 29157056 TI - The intron landscape of the mtDNA cytb gene among the Ascomycota: introns and intron-encoded open reading frames. AB - Fungal mitochondrial genes are frequently noted for the presence of introns. These introns are self-splicing and can be assigned to either group I or II introns and they can encode open reading frames (ORFs). This study examines the introns present within the cytochrome b (cytb) gene of ascomycetes fungi. Cytochrome b gene sequences were sampled from GenBank and supplemented with our own data for species of Leptographium and Ophiostoma. Group I introns were encountered most frequently, many encoding either LAGLIDADG or GIY-YIG homing endonucleases (HEs). Numerous examples of different intron/ORF arrangements were observed including nested ORFs, multiple ORFs within a single intron and intron ORFs at various stages of erosion due to the accumulation of mutations. In addition, we noted one example of a nested intron and one complex group II intron that could potentially allow for alternative splicing. Documenting the distribution of introns within the same gene across a range of species allows for a better understanding of the evolution of introns and intronic ORFs. Intron landscapes also are a resource that can help in annotating genes and in bioprospecting for potentially active HEs, which are rare-cutting DNA endonucleases with applications in biotechnology. PMID- 29157057 TI - Radiofrequency ablation of osteoid osteoma in the atlas: A case report. AB - Osteoid osteoma of the atlas has previously been reported very rarely in the published literature. The traditional standard treatment has been a surgical resection of the nidus. Recently, computed tomography (CT)-guided radiofrequency ablation (RFA) has gained favor as a more precise alternative treatment. Here, we present a case of osteoid osteoma of the C1 lateral mass treated successfully using CT-guided RFA. A 30-year-old woman who presented with a four-month history of occipital and suboccipital pain was treated by CT-guided RFA. The visual analog scale (VAS) assessed the pain before and after RFA. The patient reported significant pain relief and normal activities. The VAS score reduced from 8/7 to 1/0 after the procedure. Therefore CT-guided percutaneous RFA of C1 vertebral osteoid osteoma is a safe and effective method. The technique might be contraindicated when the nidus is less than 2 mm away from the neural structures. PMID- 29157058 TI - Tramadol prescription patterns in patients followed by general practitioners and orthopedists in Germany in the year 2015. AB - OBJECTIVES: The aim of this study was to analyze tramadol prescription patterns in acute pain patients followed by general practitioners and orthopedists in Germany. METHODS: This study included patients >=18 years diagnosed with acute pain who received at least one tramadol prescription each in one of 1,129 general or 179 orthopedic practices in Germany between January and December 2015 (index date). Patients were excluded if they had received a prescription for another analgesic in the year prior to the index date, had a follow-up of less than 15 months after the index date, or were prescribed tramadol for a period of more than three months. The main outcome of this retrospective study was the share of patients receiving tramadol in combination therapy. Combination therapy was defined as the prescription of tramadol in conjunction with at least one other analgesic during the same medical visit. RESULTS: The present study included a total of 8,766 individuals. Overall, 1,492 (22.0%) of tramadol patients seen by general practitioners and 370 (18.7%) of those seen by orthopedists received tramadol in combination with other analgesics. Although this proportion was similar throughout the different subgroups in orthopedic practices, it was considerably higher in patients >80 years and in those with private health insurance coverage in general practices. CONCLUSIONS: Approximately one of five tramadol patients was prescribed tramadol in combination therapy. Further research is needed to gain a better understanding of the demographic and clinical factors that have an effect on tramadol prescription patterns in Germany. PMID- 29157059 TI - 90K immunostimulatory glycoprotein in children with juvenile idiopathic arthritis. AB - OBJECTIVES: To assess whether circulating levels of 90K glycoprotein are increased in children with juvenile idiopathic arthritis (JIA) at different stages of the disease, compared to healthy controls and to evaluate potential over time changes in its concentrations following treatment with the antitumor necrosis factor (TNF) drug etanercept. METHODS: 90K glycoprotein, C-reactive protein, erythrocyte sedimentation rate, TNF, antinuclear antibodies, rheumatoid factor and the Juvenile Arthritis Disease Activity Score were assessed in 71 children: 23 with newly diagnosed JIA, 23 with established and active JIA and 25 healthy controls. Patients, eligible for anti-TNF treatment, underwent a similar clinical/laboratory assessment after 6- and 12-month etanercept therapy. RESULTS: At baseline, significant differences were found in 90K levels between the three study groups: JIA at onset (157.7 [131.4-241.5] MUg/ml), JIA on treatment (90.0 [68.8-120.2] MUg/ml) and control group (58.0 [44.5-79.0] MUg/ml), (p for trend <.001), with the JIA at onset group showing the highest values. In the JIA on treatment group, following one-year etanercept treatment, a significant reduction in 90K was detected already at 6 months (74.3 [56.0-104.1] MUg/ml p = .001) and a further decline was observed at 12 months (49.3 [46.0-67.6] MUg/ml p < .001). CONCLUSION: Our study showed that 90K glycoprotein levels are increased in JIA children compared to healthy controls, suggesting a potential pathogenetic role in the JIA. Besides, 12 months of therapy with etanercept can reduce 90K levels. PMID- 29157060 TI - Mycobacterium genavense infections in non-HIV immunocompromised hosts: a systematic review. AB - BACKGROUND: Mycobacterium genavense is a non-tuberculous mycobacterium which can rarely cause disease in non-HIV immunocompromised hosts. We describe our experience with this unusual infection and perform a systematic review of the literature to describe the features of M. genavense infection in non-HIV immunocompromised hosts. METHODS: All cases of Mycobacterium genavense infection in non-HIV patients at our institution were reviewed. In addition, we conducted a systematic review of the literature to identify previously published cases of M. genavense infections in non-HIV hosts. FINDINGS: Two cases of M. genavense were identified at our center; a 51-year-old renal transplant recipient with a prosthetic knee joint infection and a 66-year-old woman with idiopathic CD4 lymphocytopenia with gastrointestinal tract disease. The systematic review identified 44 cases of M. genavense infection in non-HIV hosts. The most common underlying conditions were solid organ transplantation (40%), sarcoidosis (14%) and hematopoietic stem cell transplantation (7%). Disease most commonly involved the gastrointestinal tract, spleen, liver or bone marrow. Diagnosis was challenging with PCR required for identification in nearly all cases. Over one third of patients died, which may reflect the combination of infection and underlying comorbidities. Overall cure was achieved in 61% with a mean duration of antimycobacterial therapy of 15.5 months (range 10-24). CONCLUSION: M. genavense infection is a rare mycobacterial infection in non-HIV immunocompromised hosts. It should be suspected in immunocompromised patients presenting with disseminated mycobacterial infection, acid fast bacilli on smear or histopathologic examination, with poor or no growth in mycobacterial cultures. PMID- 29157061 TI - The DNA Pol epsilon stimulatory activity of Mrc1 is modulated by phosphorylation. AB - DNA replication checkpoint (Mec1-Mrc1-Rad53 in budding yeast) is an evolutionarily conserved surveillance system to ensure proper DNA replication and genome stability in all eukaryotes. Compared to its well-known function as a mediator of replication checkpoint, the exact role of Mrc1 as a component of normal replication forks remains relatively unclear. In this study, we provide in vitro biochemical evidence to support that yeast Mrc1 is able to enhance the activity of DNA polymerase epsilon (Pol epsilon), the major leading strand replicase. Mrc1 can selectively bind avidly to primer/template DNA bearing a single-stranded region, but not to double-stranded DNA (dsDNA). Mutations of the lysine residues within basic patch 1 (BP1) compromise both DNA binding and polymerase stimulatory activities. Interestingly, Mrc1-3D, a mutant mimicking phosphorylation by the Hog1/MAPK kinase during the osmotic stress response, retains DNA binding but not polymerase stimulation. The stimulatory effect is also abrogated in Mrc1 purified from cells treated with hydroxyurea (HU), which elicits replication checkpoint activation. Taken together with previous findings, these results imply that under unperturbed condition, Mrc1 has a DNA synthesis stimulatory activity, which can be eliminated via Mrc1 phosphorylation in response to replication and/or osmotic stresses. PMID- 29157062 TI - DNA barcoding techniques used to identify the shared ichthyofauna between the Pantanal floodplain and Upper Parana River. AB - The biological invasion process is widely debated topic, as the population depletion of some species and the extinction of others are related to this process. To accelerate the identification of species and to detect non-native forms, new tools are being developed, such as those based on genetic markers. This study aimed to use Barcode DNA methodology to identify fish species that had translocated between the Parana and Paraguay River Basins. Based on a database of two studies that were conducted in these regions, 289 sequences of Cytochrome Oxidase C subunit 1 (COI) were used for General Mixed Youle Coalecent (GMYC) analysis, including 29 morphospecies that were sampled in both river basins. As a result, we observed that while some morphospecies have low variation, demonstrating a recent occupation of the basins, other morphospecies probably represent species complexes. A third of the morphospecies had well-defined lineages but not enough to be treated as different Molecular Operational Taxonomic Units (MOTUs). These results demonstrate that human interventions possibly participated in the distribution of some lineages. However, biogeographical historical processes are also important for the morphospecies distribution. The data suggest that the number of species that are present in these two basins is underestimated and that human actions can irreversibly affect the natural history of the species in these regions. PMID- 29157063 TI - Effect of dentifrice containing fTCP, CPP-ACP and fluoride in the prevention of enamel demineralization. AB - OBJECTIVE: To evaluate the effect of different fluoride- and calcium- and/or phosphate-containing products on their ability to prevent enamel demineralization under pH cycling conditions. MATERIAL AND METHODS: Enamel bovine specimens were assigned to the following groups: G1-MPP (MI Paste Plus, 0.2% NaF, RecaldentTM, GC Corporation Tokyo, Japan); G2-FD (CrestTM Cavity Protection, 0.243% NaF, Procter & Gamble, USA); G3-CLP (ClinproTM 5000, 1.1% NaF, 3M ESPE, USA); and G4 CO (Control without fluoride, Silica-based dentifrice; Daudt Ltda, Brazil). The specimens were soaked in demineralizing solution for 6 h and remineralizing solution for 18 h alternatively for 10 days. The toothpaste was prepared with deionized water in a 1:3 ratio (w/v) for three minutes daily. The solutions were renewed every 48 h. After cycling, enamel changes were analysed by percentage change of SMH (%SMH) and energy-dispersive X-ray spectroscopy (EDS). The %SMH value observed for G3-CLP (2.9 +/- 39.2) was higher than that found in G4-CO ( 13.0 +/- 20.7), G1-MPP (-8.9 +/- 20.9) and G2-FD (-3.9 +/- 27.1). The %SMH was similar for all treatment groups (one-way ANOVA and Tukey's HSD; p < .05). The pH, Ca2+ and Ptotal in the remineralization solutions were not different among all groups (Kruskal-Wallis; p < .05). At 24 h, the Ca2+ concentration in the demineralization solution was significantly lower in G1-MPP. Ca2+ concentration increased in all groups after 48 h, except for G3-CLP. The EDX quantitative analysis showed that the atomic % of elements is lower level at G4-CO. CONCLUSIONS: The ClinproTM 5000 demonstrated having the most protective effect against demineralization; however, the % SMH was similar for all groups. PMID- 29157064 TI - Gender-related effects of vision impairment characteristics on depression in Korea. AB - PURPOSE: To investigate the gender-specific associations between perceived vision impairment and symptoms of depression. METHODS: We used the data from the 2012 Korean Longitudinal Study of Aging database of 7448 individuals aged 45 years and older. Questionnaires assessing depression symptoms and perceived visual impairment at near, distance, and in general were administered. Logistic regression analyses were used to evaluate if visual impairment could lead to depression, adjusting for the potential confounders of age, socioeconomic status (household income, education level, marital status, and employment status), and health behaviors (alcohol consumption, smoking, and physical activity level) after gender stratification. RESULTS: Perceived general and near vision impairment were significantly associated with symptoms of depression in males (odds ratio [OR] = 2.78 and 2.54; 95% confidence interval [CI], 1.91-4.04 and 1.78-3.63). Perceived general and distance vision impairment were significantly associated with symptoms of depression in females (OR = 2.16 and 2.08; 95% CI, 1.67-2.79 and 1.61-2.69). General sight with near vision impairment in males and general sight with distance vision impairment in females could be stronger predictors of depression than other vision impairment combinations (area under the receiver operating characteristic curve [AUROC], 0.6461; p = 0.0425 in males; AUROC, 0.6270; p = 0.0318 in females). Conclusion Gender differences were found in the characteristics of visual impairment on symptoms of depression. Ophthalmologists should be aware that near vision impairment in males and distance vision impairment in females have an adjunctive effect that might contribute to symptoms of depression. PMID- 29157065 TI - Small spotted bodies with multiple specific mitochondrial DNAs: existence of diverse and differentiated tigrina lineages or species (Leopardus spp: Felidae, Mammalia) throughout Latin America. AB - We analysed two sets of mitochondrial (mt) DNA data from tigrinas (traditionally, Leopardus tigrinus) we sampled in Costa Rica, Venezuela, Colombia, Ecuador, Peru, Bolivia, northwestern and northeastern Argentina and southern Brazil. Additionally, the analysis included some GenBank sequences from southern, central and northeastern Brazil. The first mt set (mt ATP8+mt 16S rRNA with 41 tigrina) revealed the existence of seven different tigrina-like haplogroups. They could represent, at least, 4-6 different tigrina species following the Phylogenetic Species Concept (PSC). In the second mt set (mitogenomics with 18 tigrinas), we detected six different tigrina-like haplogroups. They could represent 4-5 different tigrina species - including a possible full new species, which has gone previously unnoticed to the world of science both morphologic and molecularly. Coat patterns of several of these different tigrinas support the molecular differences. We also detected intense hybridization in many Andean tigrina with margays (Leopardus wiedii) and ocelots (Leopardus pardalis) as well as hybridization of one Bolivian tigrina with Leopardus geoffroyi. Similar hybridization was found for many of the southern Brazilian tigrina (Leopardus guttulus). All of the temporal split estimates for these tigrina haplogroups, together with those of the Leopardus species recognized to date, began in the late Pliocene but mostly occurred during the Pleistocene. In agreement with the existence of multiple species within the traditional L. tigrinus species, we detected strong and significant spatial structure in the two mt data sets. There were clear circular clines. A major part of the analyses detected more genetic resemblance between the Central American + trans Andean Colombian and Ecuadorian tigrina (L. oncilla) with the most geographically distant tigrina from central and southern Brazil (L. guttulus; pure individuals not hybridized with L. geoffroyi). In comparison, the Andean tigrina taxa had intermediate geographical origins but were highly genetically differentiated both from the Central American + trans Andean Colombian-Ecuadorian tigrina and from the central and southern Brazilian tigrina. PMID- 29157066 TI - Association between small for gestational age and low birth weight with attention deficit and impaired executive functions in 3-6 years old children. AB - BACKGROUND: Behavioral disorders and attention deficit hyperactivity disorder (ADHD) symptoms are frequently reported among children with history of small body size at birth and disproportionate intrauterine growth retardation. The current study aimed to investigate some factors like executive functions and attention deficit in children with history of Small for gestational age (SGA) and/or Low Birth Weight (LBW) at birth. METHODS: A historical cohort study was done and 3-6 years old preschool children (with past history of SGA/LBW) from some kindergartens and health centers were selected. Control group was randomly selected among children with history of normal birth weight and appropriate for gestational age at birth. All children were interviewed by an expert psychologist. Variables related to their attention, development, and executive functions were assessed by ASQ, Conner's, and Wisconsin Card Sorting Test. Completed questionnaires related Attention deficit and indexes of executive functions were evaluated between children in case groups and their counterparts in controls. RESULTS: Based on inclusion criteria, 229 preschool children entered the study. With regard to size for gestational age, 124 cases were categorized in the SGA/LBW group and the rest were assigned in the appropriate for gestational age (AGA) group. In the case group, NPE and Percent Perseverative Errors (PPE) scores were significantly lower than normal birth weight group (p = .0001, p = .015). Scores related B item of Conner's was significantly different between cases and their controls (p = .039, p = .035). CONCLUSIONS: Our results indicated that children with past history of some risks at birth may suffer from complications related attention and executive functions in their childhood. Recommendations for further research are strongly suggested. PMID- 29157067 TI - Role of Endoscopic Ultrasound in the Management of Tubercular Uveitis. AB - PURPOSE: To evaluate the role and safety of endoscopic ultrasound-guided fine needle aspiration cytology (EUS-FNAC) in patients of tubercular uveitis. DESIGN: Interventional case series Methods: Thirty patients suspected of tubercular uveitis that underwent EUS-FNAC were enrolled in the study. The patient details recorded were age, gender, systemic history, ocular complaints and clinical manifestations. The details of the investigations - skin test, X-Ray chest, CECT (contrast enhanced computed tomography) of chest and findings on EUS-FNAC were also recorded. RESULTS: Thirty patients with suspected tubercular uveitis showed mediastinal lymphadenopathy on CECT-chest and underwent EUS-FNAC. A total of 27 patients showed tubercular lymphadenitis and three patients showed reactive lymphadenopathy. Ziehl-Neelsen (ZN) staining was positive for acid-fast bacilli in four cases and culture was positive in one case. There were no noted complications of EUS-FNAC. CONCLUSION: EUS-FNAC is a safe and efficacious procedure for confirming the diagnosis of tubercular uveitis and should be routinely employed wherever available. PMID- 29157068 TI - Quadrivalent inactivated influenza vaccine (VaxigripTetraTM). AB - INTRODUCTION: VaxigripTetraTM (IIV4; Sanofi Pasteur) is a quadrivalent split virion influenza vaccine approved in Europe in 2016 for individuals >= 3 years of age. IIV4 builds on the well-established record of the trivalent split-virion influenza vaccine (Vaxigrip(r)). Areas covered: This literature review summarizes the rationale for developing quadrivalent influenza vaccines and discusses the phase III clinical trial results supporting the immunogenicity, safety, and tolerability of IIV4. Expert commentary: IIV4 is immunogenic and well tolerated. Adding a second B strain to the trivalent split-virion influenza vaccine provides a superior immune response for the additional strain but does not reduce the immune response for the three other strains or negatively affect the safety profile. By offering broader protection against co-circulating influenza B lineages, IIV4 has the potential to further reduce influenza-related morbidity and mortality beyond that achieved with trivalent vaccines. PMID- 29157069 TI - Tumor volume regression during preoperative chemoradiotherapy for rectal cancer: a prospective observational study with weekly MRI. AB - PURPOSE: Few data is available on rectal tumor shrinkage during preoperative chemoradiotherapy (CRT). This regression pattern is interesting to optimize timing of dose escalation on the tumor. METHODS: Gross tumor volumes (GTV) were contoured by two observers on magnetic resonance imaging (MRI) obtained before, weekly during, 2-4 weeks after, and 7-8 weeks after a 5-week course of concomitant CRT for rectal cancer. RESULTS: Overall, 120 MRIs were acquired in 15 patients. A statistically significant tumor volume reduction is seen from the first week, and between any two time points (p < .007). At the end of CRT, 46.3% of the initial tumor volume remained, and 32.4% at time of surgery. PTV measured 61.2% at the end of treatment. Tumor shrinkage is the fastest in the beginning of treatment (26%/week), slows down to 7%/week in the last 2 weeks of CRT, and finally to 1.3%/week in the last 5 weeks before surgery. CONCLUSIONS: The main rectal tumor regression occurs during CRT course itself, and mostly in the first half, with shrinking speed decreasing over the course. This suggests that a sequential boost is preferably done after the elective fields, yielding an average PTV-reduction of 39%. A simultaneous integrated boost strategy could benefit from adaptive planning during the course. PMID- 29157070 TI - Review of the literature examining the association between physical activity and retinopathy. AB - The main aim of this review was to evaluate the association between physical activity and retinopathy. Secondary aims included evaluating the association between sedentary behavior and retinopathy, and evaluating the association between physical activity/sedentary behavior on health outcomes among patients with existing retinopathy. Twenty-one articles met our criteria for inclusion in this review. Among the 19 studies evaluating the main aim (physical activity and retinopathy), 53% (n = 10/19) demonstrated evidence of a favorable (inverse) association between physical activity and retinopathy, 42% (n = 8/19) reported a null association physical activity and retinopathy, and 5% (n = 1/19) presented evidence for a detrimental association between physical activity and retinopathy. Regarding the secondary aims, one study demonstrated a detrimental association between sedentary behavior and retinopathy. Similarly, one study demonstrated that physical activity was protective against early mortality among those with mild retinopathy. This review identifies an 'indeterminate' association between physical activity and retinopathy. Too few studies evaluated the association between sedentary behavior and retinopathy or the effects of physical activity on health outcomes among those with existing retinopathy. PMID- 29157071 TI - Metabolism of metofluthrin in rats: II. Excretion, distribution and amount of metabolites. AB - 1. 14 C-Labelled E/Z isomers of a synthetic pyrethroid metofluthrin ((E/Z)-(1 R,3 R)-2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(1-propenyl) cyclopropanecarboxylate, abbreviated as RTE/RTZ, respectively) were used for rat metabolism studies. 14 C-RTE or RTZ labelled at the carbonyl-carbon [acid-14C] or the methoxymethylbenzyl-alpha-carbon [alcohol-14 C] was administered orally to rats at 1 and 20 mg/kg. 2. Dosed compounds were mostly absorbed, metabolised, and rapidly excreted. Dose-related increase in blood AUC suggested no saturation of absorption at the high dose. Blood 14 C was maximal at 3-8 h and decreased with a half-life of 52-163 h. Radioactivity in tissues, blood and plasma decreased basically at the same rate and the sum fell below 0.2% of the dose at 168 h. 3. Although the major metabolic pathways of the isomers, that is, ester cleavage, O demethylation and omega-oxidation, were similar, there was a notable difference. The RTZ double bond commonly undergoes epoxidation while RTE double bond mainly undergoes glutathione conjugation, which causes faster elimination from plasma and greater excretion into faeces on RTE. Faster urinary excretion and elimination from blood were observed for the alcohol moiety than the acid moiety. 4. In conclusion, this study described the overall metabolic profiles of metofluthrin and identified the differences in metabolic breakdown between the isomers. No marked sex-/dose-related differences were observed. PMID- 29157072 TI - Robustness versus evolvability analysis for regulatory feed-forward loops. AB - From the definition, it appears that phenotypic robustness and evolvability of an organism are inversely related to each other. However, a number of studies exploring this question have found conflicting evidences in this regard. This question motivated the current work where we explore the relationship between robustness and evolvability. As a model system, we pick the Feed Forward Loops (FFLs), and develop a framework to characterize their performance in terms of their ability to resist changes to steady state expression (robustness), and their ability to evolve towards novel phenotypes (evolvability). We demonstrate that robustness and evolvability are positively correlated in some FFL topologies. We compare this against other small regulatory topologies, and show that the same trend does not hold among them. We postulate that the ability to positively link robustness and evolvability could be an additional reason for over-representation of FFLs in living organisms, as compared to other regulatory topologies. PMID- 29157073 TI - Parental satisfaction with early intensive behavioral intervention. AB - Research related to parental satisfaction with early intensive behavioral intervention (EIBI) remains limited. A 35-item questionnaire called the parental satisfaction scale-EIBI (PSS-EIBI) was developed with four subdomains (child outcomes, family outcomes, quality of the model, and relationship with the team). Study 1 assessed levels of satisfaction for 48 parents with their child's EIBI program after approximately 1 year of intervention. Study 2 examined the relationship between parental satisfaction, length of child participation in EIBI, and the relationship between parental satisfaction and actual outcomes for their child as assessed by the Verbal Behavior Milestones Assessment and Placement Program after approximately 2 years. Results indicate that parental satisfaction with EIBI was consistently high in all four domains of the PSS-EIBI in both studies. Parental satisfaction was found to be associated with gains in child functioning after 1 year of intervention. PMID- 29157074 TI - Pain relief after a short course of palliative radiotherapy in pancreatic cancer, the Academic Medical Center (AMC) experience. PMID- 29157075 TI - Risk factors for mortality among tuberculosis patients co-infected with HIV. PMID- 29157076 TI - UHRF1 epigenetically down-regulates UbcH8 to inhibit apoptosis in cervical cancer cells. AB - UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is an important epigenetic regulator that plays a part in DNA methylation, protein methylation and ubiquitination. It is also frequently overexpressed in many types of cancers, including cervical cancer, which is caused by human papillomavirus (HPV). In this study, we showed that UHRF1 was up-regulated in HPV oncogene E7 expressing cells and HPV-positive cervical cancer cells. We demonstrated that UHRF1 down-regulated the expression of UBE2L6 gene that encodes the ISG15-conjugating enzyme UbcH8. Overexpression of UHRF1 reduced UBE2L6 while knockdown UHRF1 elevated the expression of UBE2L6. We showed that UHRF1 regulated UBE2L6 gene by promoter hypermethylation in cervical cancer cells. Consistent with the functions of UHRF1, restored expression of UbcH8 induced apoptosis. These findings establish UBE2L6 as a novel target of UHRF1 that regulates the apoptosis function of UHRF1. Our studies suggest that UHRF1/ UbcH8 can be manipulated for therapy in cervical cancer. PMID- 29157077 TI - How does early maternal separation and chronic stress in adult rats affect the immunoreactivity of serotonergic neurons within the dorsal raphe nucleus? AB - Vulnerability to emotional disorders like depression derives from interactions between early and late environments, including stressful conditions. The serotonin (5HT) system is strongly affected by stress and chronic unpredictable stress can alter the 5HT system. We evaluated the distribution of active serotonergic neurons in the dorsal raphe nucleus (DR) through immunohistochemistry in maternally separated and chronically stressed rats treated with an antidepressant, tianeptine, whose mechanism of action is still under review. Male Wistar rats were subjected to daily maternal separation (MS) for 4.5 h between postnatal days (PND) 1-21, or to animal facility rearing (AFR). Between (PND) days 50-74, rats were exposed to chronic unpredictable stress and were treated daily with tianeptine (10 mg/kg) or vehicle. We found an interaction between the effects of MS and chronic unpredictable stress on Fos-5HT immunoreactive cells at mid-caudal level of the DR. MS-chronically stressed rats showed an increase of Fos-5HT immunoreactive cells compared with AFR-chronically stressed rats. The ventrolateral (DRL/VLPAG) and dorsal (DRD) subdivisions of the DR were significantly more active than the ventral part (DRV). At the rostral level of the DR, tianeptine decreased the number of Fos-5HT cells in DR in the AFR groups, both unstressed and stressed. Overall, our results support the idea of a match in phenotype exhibited when the early and the adult environment correspond. PMID- 29157078 TI - Evolving paradigms for the biological response to low dose ionizing radiation; the role of epigenetics. AB - PURPOSE: In the late 1990s, it had become clear that the long-standing paradigm for the action of radiation on living cells and organisms did not have sufficient power to explain the observed effects of low dose ionizing radiation. The purpose of this commentary is to examine the experiments that lead up to the modification of the classic paradigm consequent on these observations, their historical precedents, and the development of our understanding of the role of epigenetics in low dose radiation effects. RESULTS AND CONCLUSIONS: We discuss how parallel advances in epigenetics from developmental biology and cancer studies, and the discovery of epigenetic modifications of chromatin, such as DNA methylation, impacted on the development of an epigenetic paradigm for low dose effects. We also assess the impact of technology development in supporting the paradigm shift. We then examine recent accumulated data on epigenetic modification in response to irradiation since that shift took place, and identify areas where bringing together data from developmental biology and cancer might answer some of the paradoxes and contradictions in this data. We predict that further paradigm shifts are imminent. PMID- 29157079 TI - ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage. AB - The ataxia-telangiectasia-mutated (ATM) and rad3-related (ATR) checkpoint pathway plays an essential role in modulating cellular responses to replication stress and DNA damage to maintain genomic stability. In various tumors, cancer cells have increased dependence on ATR signaling for survival, making ATR a promising target for cancer therapy. ATR inhibitors sensitize multiple tumor cell types to radiation and DNA-damaging agents, but application of an ATR inhibitor alone shows limited efficacy. In the present study, we investigated the role of epithelial-to-mesenchymal transition (EMT) and the EMT transcription factor ZEB1 in regulating cell sensitivity to the ATR inhibitor VE-821. We found that VE-821 induced EMT with concomitant ZEB1 upregulation and promoted migration in cells in which the anti-proliferative effect of VE-821 was limited. Knocking down ZEB1 using siRNA partially reversed VE-821-induced EMT, and sensitized cells to VE-821 via effective attenuation of migration and AKT/ERK signaling. Moreover, ZEB1 inhibition promoted Chk1 phosphorylation and induced S-phase arrest by enhancing TopBP1 expression, which suggests a distinctive modulatory effect of ZEB1 on Chk1. Finally, combining VE-821 with ZEB1 inhibition enhanced DNA damage accumulation. These results demonstrate that EMT represents a novel mechanism for limiting the effectiveness of an ATR inhibitor, and thus suggest that ZEB1 inhibition might represent a new approach to increasing the efficiency of, or reversing resistance to, ATR inhibitors. PMID- 29157080 TI - Secretory autophagy holds the key to lysozyme secretion during bacterial infection of the intestine. AB - In 2013, Dr. Lora Hooper and colleagues described the induction of antibacterial macroautophagy/autophagy in intestinal epithelial cells as a cytoprotective host defense mechanism against invading Salmonella enterica serovar Typhimurium (S. Typhimurium). Canonical autophagy functions in a primarily degradative capacity to safeguard cells and ensure survival during stress conditions, including pathogen infection. In contrast, secretory autophagy has emerged as an alternative nondegradative mechanism for cellular trafficking and unconventional protein secretion. More recently, a study by Bel et al. from Dr. Hooper's lab describes how intestinal Paneth cells exploit the endoplasmic reticulum (ER) stress response to release antibacterial lysozyme through secretory autophagy in response to S. Typhimurium infection. PMID- 29157081 TI - Regulation of BECN1-mediated autophagy by HSPB6: Insights from a human HSPB6S10F mutant. AB - HSPB6/Hsp20 (heat shock protein family B [small] member 6) has emerged as a novel cardioprotector against stress-induced injury. We identified a human mutant of HSPB6 (HSPB6S10F) exclusively present in dilated cardiomyopathy (DCM) patients. Cardiac expression of this mutant in mouse hearts resulted in remodeling and dysfunction, which progressed to heart failure and early death. These detrimental effects were associated with reduced interaction of mutant HSPB6S10F with BECN1/Beclin 1, leading to BECN1 ubiquitination and its proteosomal degradation. As a result, autophagy flux was substantially inhibited and apoptosis was increased in HSPB6S10F-mutant hearts. In contrast, overexpression of wild-type HSPB6 (HSPB6 WT) not only increased BECN1 levels, but also competitively suppressed binding of BECN1 to BCL2, resulting in stimulated autophagy. Indeed, preinhibition of autophagy attenuated the cardioprotective effects of HSPB6 WT. Taken together, these findings reveal a new regulatory mechanism of HSPB6 in cell survival through its interaction with BECN1. Furthermore, Ser10 appears to be crucial for the protective effects of HSPB6 and transversion of this amino acid to Phe contributes to cardiomyopathy. PMID- 29157083 TI - Folate: a possible role in erectile dysfunction? AB - A growing body of evidence suggests a role for homocysteine (Hcys) and folate (FA) in erectile function (EF): Hcys appears to impair EF affecting endothelium via several mechanism whereas the role of FA remains to be elucidated, besides decreasing Hcys. To assess correlation between erectile dysfunction (ED) and serum levels of FA, Hcys, and B12, we enrolled 31 patients affected by ED (Group A; age 52.83 +/- 11.89 years) and 31 healthy adults (Group B; age 49.14 +/- 13.63 years). Fasting blood samples were taken for each subject. ED was assessed by the International Index of Erectile Function-5 (IIEF-5). IIEF-5 mean score was significantly lower in Group A than in Group B (10.71 +/- 4.24 versus 23.32 +/- 1.33, p < .001). Compared to Group B, Group A also showed significantly lower serum FA levels (5.11 +/- 1.79 versus 7.9 +/- 3.55 ng/ml, p < .001) and significantly higher serum Hcys levels (13.61 +/- 3.55 versus 9.17 +/- 2.32 umol/L, p < .001). No significant correlation was observed between Hcys and FA both groups. Our results showed a significant association among ED, FA deficiency and hyperomocisteinemia. Lack of correlation between FA and Hcys suggests that FA deficit may directly impair EF. PMID- 29157082 TI - Radioprotective efficacy of Ginkgo biloba and Angelica archangelica extract against technetium-99m-sestamibi induced oxidative stress and lens injury in rats. AB - PURPOSE: Technetium-99m is a radioactive tracer that emits gamma rays. Its half life time is 6 h. Similar to other ionizing radiations, the main mechanism of radiation-induced effects is initiated through the production of reactive oxygen species (ROS). This study was designed to determine the possible protective effects of Ginkgo biloba and Angelica archangelica against oxidative organ damage that was induced by 99mTc-sestamibi. MATERIALS AND METHODS: The experiments were performed on thirty-six Wistar-rats which were subdivided into control groups and groups exposed to 99mTc-sestamibi. The irradiated groups were either untreated or pre-treated with G. biloba or A. archangelica. For all groups, the levels and/or activities of Catalase (CAT), Glutathione (GSH), Malondialdehyde (MDA) and Superoxide-dismutase (SOD) were measured in blood and lenses. The soluble/insoluble protein ratio was determined and lens-protein profiles were obtained via Sodium-Dodecyl-Sulfate Polyacrylamide Gel-Electrophoresis (SDS PAGE). RESULTS: There were no significant difference between the pre-treated and irradiated G. biloba group and control group, while both groups were significantly different (p < .05) from the untreated irradiated group. On the other hand, treatment with A. archangelica did not confer any significant protection against 99mTc-sestamibi induced toxicity. CONCLUSIONS: This study demonstrated that G. biloba, through its free radical scavenging and antioxidant properties, successfully attenuated 99mTc-sestamibi radiation-induced oxidative organ injury. The latter is a crucial factor of cataractogenesis in rats, suggesting that G. biloba may have a potential benefit in the protection against radiopharmaceuticals. PMID- 29157084 TI - Effects of task-irrelevant emotional information on deception. AB - Deception has been reported to be influenced by task-relevant emotional information from an external stimulus. However, it remains unclear how task irrelevant emotional information would influence deception. In the present study, facial expressions of different valence and emotion intensity were presented to participants, where they were asked to make either truthful or deceptive gender judgments according to the preceding cues. We observed the influence of facial expression intensity upon individuals' cognitive cost of deceiving (mean difference of individuals' truthful and deceptive response times). Larger cost was observed for high intensity faces compared to low intensity faces. These results provided insights on how automatic attraction of attention evoked by task irrelevant emotional information in facial expressions influenced individuals' cognitive cost of deceiving. PMID- 29157085 TI - Sequential occurrence of small cell and non-small lung cancer in a male patient: Is it a transformation? AB - Lung cancer is one of the leading causes of cancer-related mortality and is categorized into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). We present a patient with epidermal growth factor receptor (EGFR)-mutant NSCLC who developed metastatic SCLC after initial therapy with second-generation EGFR-tyrosine kinase inhibitor, afatinib. A 65-year-old male non-smoker was diagnosed with adenocarcinoma of the right lung, stage IVA (M1a). Due to tumor positivity for EGFR-Exon 19 deletion, the patient was started on oral afatinib, which resulted in a partial response. After ten months of treatment, he presented in the office with abdominal pain, distension, weight loss and jaundice. He had diffuse skeletal and hepatic metastases on PET/CT scan with interval progression of his cancer. Although the recurrence of lung adenocarcinoma was suspected, the patient was diagnosed with SCLC on liver biopsy. He received two cycles of chemotherapy and died due to pneumonia and sepsis. PMID- 29157086 TI - Abdominal aortic calcification score among several vascular calcification scores of plain radiograph is the most reliable predictor of severe coronary artery calcification in dialysis patients. AB - AIM: Coronary artery calcification (CAC) score on computed tomography (CT) or vascular calcification (VC) scores on plain radiographs are associated with cardiovascular events and fracture. We investigated which VC score among several VC scores on plain radiographs is predictor of CAC, and whether VC scores are related with bone mineral density (BMD) in dialysis patients. METHODS: We checked several plain radiographs (hands and pelvis [HP], feet and lateral lumbar spine), BMD and multidetector CT scans of 55 patients maintaining dialysis in this cross sectional study. We analyzed data to find predictors for severe CAC which was defined as CAC scores >400 on CT. RESULTS: Patients with severe CAC on CT had a higher proportion of abdominal aortic calcification (AAC) score >=5, HP score >=3 and feet >=1 than those without severe CAC. The CAC score on CT was positively correlated with all VC scores on plain radiographs. The AAC and CAC scores were negatively correlated with T-scores for the BMD at the forearm and positively correlated with osteoprotegerin levels. Among several VC scores on plain radiographs, the AAC >=5 were independently associated with severe CAC on CT. CONCLUSIONS: Several plain radiographs evaluating VC scores, including a lateral lumbar spine view at the very least, can replace CT checking CAC score in dialysis patients. The AAC score >=5 may not only reveal severe CAC but also give a hint of low bone mass at the forearm. PMID- 29157087 TI - THANATOS: an integrative data resource of proteins and post-translational modifications in the regulation of autophagy. AB - Macroautophagy/autophagy is a highly conserved process for degrading cytoplasmic contents, determines cell survival or death, and regulates the cellular homeostasis. Besides ATG proteins, numerous regulators together with various post translational modifications (PTMs) are also involved in autophagy. In this work, we collected 4,237 experimentally identified proteins regulated in autophagy and cell death pathways from the literature. Then we computationally identified potential orthologs of known proteins, and developed a comprehensive database of The Autophagy, Necrosis, ApopTosis OrchestratorS (THANATOS, http://thanatos.biocuckoo.org ), containing 191,543 proteins potentially associated with autophagy and cell death pathways in 164 eukaryotes. We performed an evolutionary analysis of ATG genes, and observed that ATGs required for the autophagosome formation are highly conserved across eukaryotes. Further analyses revealed that known cancer genes and drug targets were overrepresented in human autophagy proteins, which were significantly associated in a number of signaling pathways and human diseases. By reconstructing a human kinase-substrate phosphorylation network for ATG proteins, our results confirmed that phosphorylation play a critical role in regulating autophagy. In total, we mapped 65,015 known sites of 11 types of PTMs to collected proteins, and revealed that all types of PTM substrates were enriched in human autophagy. In addition, we observed multiple types of PTM regulators such as protein kinases and ubiquitin E3 ligases or adaptors were significantly associated with human autophagy, and again the results emphasized the importance of PTM regulations in autophagy. We anticipated THANATOS can be a useful resource for further studies. PMID- 29157088 TI - Examining the effect of the computer-based educational package on quality of life and severity of hypogonadism symptoms in males. AB - OBJECTIVE: The objective of this study was to determine the effect of the computer-based educational package on men's QoL and the severity of their hypogonadism symptoms. METHODS: A quasi-experimental study was conducted on 80 male employees. The data collection tool included the 'Aging Male Symptoms' (AMS) and 'Short Form-36' (SF36) questionnaires. Four sessions were held for the intervention group over a period of 4 weeks. Two months after training, QoL and the severity of hypogonadism symptoms were measured in both the intervention and control groups. The data were analyzed with SPSS 22 software and statistical tests, such as chi2, independent t-test, Fisher's exact test, and paired t-tests. RESULTS: Significant statistical changes were observed in the intervention group before and 2 months after the training in the QoL score in the overall dimensions of physical-psychological health and all its domains except for three domains of emotional role, social function, and pain. Furthermore, the paired t-tests showed significant differences between 2 months before and after the training in all the domains and the overall hypogonadism score in the intervention group. CONCLUSIONS: Based on our findings, the computer-based educational package has a positive effect on QoL and reduction of hypogonadism symptoms. PMID- 29157089 TI - The relationship between DNA single-stranded damage response and double-stranded damage response. AB - The damage response of DNA single-stranded breaks(SSBs) and double-stranded breaks(DSBs) are two relatively independent processes involving different signaling pathways and protein factors, but there are still many overlapping parts. All of them can activate p53 protein, then the activated p53 regulates the damage response of single-stranded breaks or double-stranded breaks in transcriptional regulation and non-transcriptional regulation. Especially, the two types of damage would compete for RPA and ATR resources in damage repair process. The research has been focused on damage response of DNA single-stranded breaks or DNA double-stranded breaks. However, when single-stranded breaks and double-stranded breaks exist simultaneously, the DNA damage response remains to be elucidated. Here, we present a hybrid numerical model of p53 response and a hybrid numerical model of DNA damage repair exploring DNA damage repair and apoptosis mechanisms when DNA single-stranded breaks and DNA double-stranded breaks exist simultaneously. Firstly, when two kinds of damage are present at the same time, the response of p53 is graded, it means that p53 responds to single stranded breaks preferentially; Secondly, DNA single-stranded breaks are repaired preferentially, and single-stranded breaks and double-stranded breaks can be repaired simultaneously after most of single-stranded breaks having been repaired; Moreover, single-stranded breaks are more likely to cause apoptosis, because the accumulation of p53 in DNA single-stranded breaks is faster than it in DNA double-stranded breaks and single-stranded breaks has lower threshold of apoptosis. PMID- 29157090 TI - A critical review of developmental exposure to particulate matter, autism spectrum disorder, and attention deficit hyperactivity disorder. AB - Autism spectrum disorder (ASD) and attention deficit (hyperactivity) disorder (ADD/ADHD) are key focuses of current health research due to their increasing prevalence. The objective of this systematic literature search and critical review was to evaluate whether the human epidemiologic data indicate a pattern of association between ASD or ADD/ADHD and developmental exposure to particulate matter (PM), with a focus on exposures encountered before the age of three. A MEDLINE and EMBASE search was conducted; following preliminary and full-text screening, 14 relevant articles were identified for review. Three of the 14 studies were prospective cohort studies evaluating exposure to PM10; 11 studies had a case-control design. There was no consistent association between developmental PM exposure and ASD across the three of the cohort studies. Seven of the case-control studies examined the relationship between PM2.5 and/or PM10 and ASD; four examined the relationship between developmental diesel PM exposure and ASD. Overall, there was low external consistency in results among studies of PM2.5/PM10 and ASD, with some reporting high internal consistency without significant associations, others showing associations with high internal consistency for specific exposure windows only (e.g., third trimester), and still others showing high consistency for moderate to strong associations between PM and ASD. The majority of studies reporting significant results had low effect sizes in conjunction with small sample sizes. The four studies of diesel PM and ASD also had low external consistency of results. Only one study evaluated associations with ADD/ADHD, and it found no significant associations with PM10. The inconsistent findings across studies of developmental exposure to PM and ASD may be attributed to differences in the study populations, exposure assessments, outcome assessments, or chance. Further research is needed to understand the underlying biological mechanisms that lead to ASD and ADD/ADHD and how PM might be involved in those mechanisms, if at all. High-quality epidemiologic studies are also needed to conclusively determine whether developmental PM exposure is a causal factor for ASD or ADD/ADHD, with focus on a well-developed exposure assessment. PMID- 29157091 TI - Corrigendum. PMID- 29157093 TI - Sample size for a noninferiority clinical trial with time-to-event data in the presence of competing risks. AB - The analysis and planning methods for competing risks model have been described in the literature in recent decades, and noninferiority clinical trials are helpful in current pharmaceutical practice. Analytical methods for noninferiority clinical trials in the presence of competing risks (NiCTCR) were investigated by Parpia et al., who indicated that the proportional sub-distribution hazard (SDH) model is appropriate in the context of biological studies. However, the analytical methods of the competing risks model differ from those appropriate for analyzing noninferiority clinical trials with a single outcome; thus, a corresponding method for planning such trials is necessary. A sample size formula for NiCTCR based on the proportional SDH model is presented in this paper. The primary endpoint relies on the SDH ratio. A total of 120 simulations and an example based on a randomized controlled trial verified the empirical performance of the presented formula. The results demonstrate that the empirical power of sample size formulas based on the Weibull distribution for noninferiority clinical trials with competing risks can reach the targeted power. PMID- 29157092 TI - Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies. AB - ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 uM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5 azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic. PMID- 29157094 TI - TEAD4 promotes colorectal tumorigenesis via transcriptionally targeting YAP1. AB - TEAD4 (TEA domain family member 4) was recently revealed as an oncogenic character in tumorigenesis. However, its role remains unclear in colorectal tumorigenesis. Here, we firstly found that the expression level of TEAD4 was significantly elevated in clinical samples of colorectal adenomas (CRA) and correlated with the size and histological type of CRA. Moreover, patients with higher TEAD4 expression in normal colon mucosa are more prone to be recurrent after polypectomy. TEAD4 knockdown significantly inhibited colorectal cell proliferation in vitro and suppressed tumor growth in vivo. RNA-seq and GSEA analysis reveals TEAD4 can probably regulate Hippo pathway and further experiment confirm the downstream target gene YAP1. The subsequent ChIP-qPCR and luciferase report assay indicated that TEAD4 regulated YAP1 by direct binding and transcriptional activation. In summary, our study reveals that TEAD4 plays an important tumor-promoting role in colorectal cancer by directly targeting the YAP1, thus we suggests TEAD4 may be used as a novel biomarker in colorectal tumorigenesis and provides TEAD4/YAP1 axis as a potential therapeutic option for colorectal cancer. PMID- 29157096 TI - Complementary and Alternative Medicine: The Mozart Effect on Childhood Epilepsy-A Systematic Review. AB - This systematic review examines the effectiveness of Mozart's music in decreasing seizures in children with epilepsy (Mozart Effect) using the Johns Hopkins Nursing Evidence-Based Practice rating scale(c). A search for articles with "Mozart Effect," "child*," and "epilepsy" was conducted in CINAHL Complete, Science Direct, Cochrane, and PubMed databases. Eight studies were selected based on the exclusion and inclusion criteria after removal of duplicates ( n = 17) and others ( n = 46). Studies included were English language, peer reviewed, published between April 2010 and February 2017, and available in full text with an abstract. Quasi-experimental studies demonstrate that the Mozart Effect May reduce epileptiform discharges or seizures in children and has potential as an adjunct to medical management of seizure activity or alone when medication or surgery is not accepted. A causal relationship between the music of Mozart and decreased seizure activity has yet to be demonstrated. PMID- 29157095 TI - Endothelial autophagic flux hampers atherosclerotic lesion development. AB - Blood flowing in arteries generates shear forces at the surface of the vascular endothelium that control its anti-atherogenic properties. However, due to the architecture of the vascular tree, these shear forces are heterogeneous and atherosclerotic plaques develop preferentially in areas where shear is low or disturbed. Here we review our recent study showing that elevated shear forces stimulate endothelial autophagic flux and that inactivating the endothelial macroautophagy/autophagy pathway promotes a proinflammatory, prosenescent and proapoptotic cell phenotype despite the presence of atheroprotective shear forces. Specific deficiency in endothelial autophagy in a murine model of atherosclerosis stimulates the development of atherosclerotic lesions exclusively in areas of the vasculature that are normally resistant to atherosclerosis. Our findings demonstrate that adequate endothelial autophagic flux limits atherosclerotic plaque formation by preventing endothelial apoptosis, senescence and inflammation. PMID- 29157097 TI - The Role of School Nurses, Challenges, and Reactions to Delegation Legislation: A Qualitative Approach. AB - Passage of new laws, national standards regarding delegation, and the recommendation for at least one full-time nurse in every school have provided more visibility to the role of school nurses. Recent legislative amendments in Kentucky presented an opportunity to examine how the role of the school nurse is changing. Aims were to describe the (1) role of school nurses in Kentucky, (2) impact of school nurses, (3) challenges faced by school nurses, and (4) impact of budget cuts and legislation. Three focus groups were conducted. School nurses faced challenges of limited time and resources, communication barriers, and multiple documentation requirements. Nurses' greatest impacts were their availability, recognition of psychosocial problems and health concerns, and connection with resources. Nurses had not yet encountered many changes due to new legislation that expanded delegation of diabetes-related tasks to unlicensed school personnel, but some had concerns about possible negative effects while others expressed support. PMID- 29157098 TI - Meanings of Living in Lodgings During Senior High School. AB - Studies show that senior high school students living in lodgings (away from home) when attending high school are vulnerable to stress and mental health problems. Moving away from home at the age of 15-16 is a transition that might affect adolescents' well-being. The aim of this study is to explore the experience of living in lodgings during senior high school. In-depth interviews were conducted with 21 Norwegian lodgers of both genders between the ages of 16-18. Interviews were analyzed according to a phenomenological hermeneutical approach. Four main themes were identified: (a) striving between controlling time and being controlled by time, (b) striving between finding comfort in being alone and feeling left alone, (c) striving between being independent and being taken care of, and (d) striving between leaving and finding home. The findings illuminate many challenges experienced by lodgers. A raised awareness and preventive initiatives from school nurses are recommended. PMID- 29157099 TI - The association of first trimester uterine arteries Doppler velocimetry with different clinical phenotypes of hypertensive disorders of pregnancy: a longitudinal study. AB - INTRODUCTION: Current classification of hypertensive disorders of pregnancy (HDP) is mostly based on temporal classification differentiating HDP according to early and late onset of the disease. However, epidemiological and clinical data suggest that there are two different clinical phenotypes of HDP that coexist at any gestational age: HDP associated to intrauterine growth restriction (HDP-IUGR) and HDP associated to appropriate for gestational age fetal growth (HDP-AGAf). The aim of the study was to evaluate the association of first trimester uterine arteries (UtA) by Doppler velocimetry, and maternal risk factors with HDP according to two different classifications: one based on gestational age at delivery (early- and late-HDP), and one based on longitudinal ultrasound evaluation of fetal growth (HDP-IUGR and HDP-AGAf), independently of the gestational age. METHODS: Maternal characteristics and mean pulsatility index (PI) of UtA were collected at 11-13 gestational weeks. A longitudinal ultrasound follow-up of fetal growth in each trimester and clinical outcome were obtained in 4290 singleton pregnancies. RESULTS: UtA-PI was significantly higher in women who developed HDP-IUGR (n = 22) and the odds ratio (OR) to develop HDP-IUGR from 25 to 39 weeks was 8.6 (p < .0001). HDP-AGAf (n = 112) was significantly associated with a higher BMI, multiparity, and maternal age, but not with UtA-PI (OR 1.3; p = .2). In women with an abnormal UtA-PI, the odds of developing early (n = 15) and late-HDP (n = 119) were 3.0 (p = .03) and 1.7 (p = .002), respectively. The AUCs for HDP-IUGR and early-HDP were 0.84 and 0.71, respectively. DISCUSSION: UtA Doppler velocimetry in the first trimester was strongly associated with HDP-IUGR all along gestation, as a proxy of placental insufficiency, and showed no association with HDP-AGAf. Our findings suggest an efficacy of first trimester UtA Doppler velocimetry to identify HDP-IUGR independently of the gestational age, and a limited value for HDP not associated with intrauterine growth restriction (IUGR). PMID- 29157100 TI - Imbalanced plasma ACE and ACE2 level in the uremic patients with cardiovascular diseases and its change during a single hemodialysis session. AB - BACKGROUND: The renin-angiotensin system (RAS) has significant influences on heart and renal disease progression. Angiotensin converting enzyme (ACE) and angiotensin converting enzyme II (ACE2) are major peptidases of RAS components and play counteracting functions through angiotensin II (Ang II)/ATIR and angiotensin-(1-7) (Ang-(1-7))/Mas axis, respectively. METHODS: There were 360 uremic patients on regular hemodialysis (HD) treatment (inclusive of 119 HD patients with cardiovascular diseases (CVD) and 241 HD patients without CVD and 50 healthy subjects were enrolled in this study. Plasma ACE, ACE2, Ang II and Ang (1-7) levels of the HD patients were determined. RESULTS: We compared pre-HD levels of plasma ACE, ACE2, Ang II and Ang-(1-7) in the HD patients with and without CVD to those of the controls. The HD patients, particularly those with CVD, showed a significant increase in the levels of ACE and Ang II, whereas ACE2 and Ang-(1-7) levels were lower than those in the healthy controls. Therefore, imbalanced ACE/ACE2 was observed in the HD patients with CVD. In the course of a single HD session, the plasma ACE, ACE/ACE2 and Ang II levels in the HD patients with CVD were increased from pre-HD to post-HD. On the contrary, ACE2 levels were decreased after the HD session. These changes were not detected in the HD patients without CVD. CONCLUSIONS: Pathogenically imbalanced circulating ACE/ACE2 was detected in the HD patients, particularly those with CVD. HD session could increase ACE/Ang II/AT1R axis and decrease ACE2/Ang-(1-7)/Mas axis activity in the circulation of HD patients with CVD. PMID- 29157101 TI - Expression and function of protein A in Staphylococcus pseudintermedius. AB - Staphylococcus pseudintermedius is an opportunistic pathogen in dogs and the most frequent cause of canine pyoderma. Protein A, a potent virulence factor in S. aureus is encoded by the spa gene. S. pseudintermedius possesses genes seemingly analogous to spa, but the expression and the characteristics of their products have not been directly determined. The purpose of this study was to test isolates from major clonal groups for the presence of spa gene orthologs, quantitate their expression levels, and to characterize protein A in S. pseudintermedius. From the data, it was observed that S. pseudintermedius isolates express genes analogous to spa in S. aureus. Isolates representing major clonal populations in the United States and Europe, ST68 and ST71 respectively, bound significantly higher amounts of canine IgG than isolates with other genetic backgrounds, suggesting that these isolates have a higher density of protein A on their surface. Also, canine IgG bound to protein A on S. pseudintermedius via its Fc region similar to protein A from S. aureus. The mRNA profile differed based on the bacterial sequence types and correlated to the density of protein A on the bacterial surface. Protein A was also found to be secreted during the exponential growth phase. Phagocytosis experiments with S. pseudintermedius show that blocking of protein A enhanced phagocytosis in whole blood, neutrophils and in DH82 canine macrophage-like cell line. Taken together, the results demonstrate that S. pseudintermedius produces protein A that shares S. aureus protein A's ability to bind the Fc region of immunoglobulins and may serve as a potential virulence factor by evading the host immune system. PMID- 29157103 TI - Multidisciplinary approaches to the study of eating disorders and obesity: Recent progress in research and development and future prospects. PMID- 29157104 TI - Using previous trial results to inform hypothesis testing of new interventions. AB - Results of industry-sponsored Phase III trials registered at clinicaltrials.gov include a rich amount of information on the efficacy of medical interventions. We propose that these results can be used to inform hypothesis testing of a new intervention through the Bayes principle. The posterior probability of positive efficacy offers an accessible interpretation of the uncertainty of efficacy and a convenient metric for global false-positive control. PMID- 29157102 TI - Chk1 inhibitor SCH 900776 enhances the antitumor activity of MLN4924 on pancreatic cancer. AB - MLN4924 inhibits the cullin-RING ligases mediated ubiquitin-proteasome system, and has showed antitumor activities in preclinical studies, but its effects and mechanisms on pancreatic cancer (PC) remains elusive. We found that MLN4924 inhibited the proliferation and clonogenicity of PC cells, caused DNA damage, particularly double-strand breaks, and leaded to Chk1 activation and cell-cycle arrest. Chk1 inhibitor SCH 900776 alone exhibited minimal cytotoxicity, and caused no DNA damage on PC cells. But in the combination therapy, SCH 900776 enhanced the cytotoxicity and DNA damage caused by MLN4924, likely by abrogating G2/M arrest and promoting DNA re-replication. In vivo study on a xenograft PC mouse model also showed that SCH 900776 increased the efficacy of MLN4924. We also evaluated the level of NEDD8-activating enzyme (NAE), the direct target of MLN4924, and found that NAE level was elevated in PC tissues compared with normal pancreas, but was irrelevant with prognosis. Our findings provide the preclinical evidence and the rationale of the combination therapy of MLN4924 with SCH 900776 or other Chk1 inhibitors to treat PC. PMID- 29157105 TI - mASKing cancer cells in a tumor microenvironment. PMID- 29157106 TI - Perception and use of complementary and alternative medicine for low back pain. AB - PURPOSE: To determine the prevalence of complementary and alternative medicine (CAM) use in patients with low back pain (LBP) and to identify its correlation with demographic factors, clinical condition and psychosocial factors. METHODS: A cross-sectional study was conducted with 278 LBP patients. Use of CAM, demographic parameters and disease duration were determined. Self-reported health status and self-rated scales assessed the effect of disease on quality of life and emotional well-being, respectively. Satisfaction with orthopaedic care and belief partiality towards CAM were assessed. RESULTS: In all, 72.3% patients sought CAM treatment. The most common choice of CAM was traditional Chinese medicine (TCM; n = 166), followed by massage therapy ( n = 114) and chiropractic treatment ( n = 45). Within TCM, acupuncture was the most popular treatment for LBP ( n = 127). Only 32.5% patients informed their doctors of their CAM use. In univariate analyses, factors positively associated with CAM use included duration of LBP (odds ratio (OR) = 1.45, 95% confidence interval (CI): 1.06-1.97), use of CAM in close social circles (OR = 1.98, 95% CI: 1.15-3.43) and summary score for belief partiality towards CAM (OR = 1.18, 95% CI: 1.13-1.23). Variables negatively and significantly associated with status of CAM use include age (OR = 0.97, 95% CI: 0.95-0.99) and summary score for satisfaction with orthopaedic care (OR = 0.93, 95% CI: 0.88-0.99). CONCLUSION: CAM use in patients with LBP is prevalent and largely unknown to their doctors. Personal beliefs and their satisfaction with conventional medical treatment both play a part in their decisions to use CAM. Future studies may aim at understanding the effect of CAM on patient adherence to conventional medical treatment and patients' perception of well-being and pain. PMID- 29157107 TI - The impact of surgery for trochanteric femur fracture on sexuality in men and their female partners. AB - PURPOSE: This study was aimed to investigate the effects of trochanteric femur fracture treatment methods on erectile functions of the patients and on sexual functions with their female partners. MATERIALS AND METHODS: A total of 43 patients with trochanteric femur fracture who underwent proximal femoral nail (PFN) or proximal femur locking compression plate (PF-LCP) surgery were included in the study. The PFN implant was applied to group 1 ( n = 23) and the PF-LCP implant to group 2 ( n = 20). All the patients and their female partners completed the 5-item version of the International Index of Erectile Function (IIEF-5) and the Female Sexual Function Index (FSFI) preoperatively and at 1 year postoperatively after the rehabilitation period. RESULTS: The mean preoperative IIEF-5 and FSFI score was 21.910.9 and 21.911.1, 72.319.7 and 70.516.2 for the PFN and PF-LCP treatment groups, respectively, and at postoperative 1 year after rehabilitation, change in IIEF-5 score and FSFI score of each group was -6.512.1 versus -3.811.6, ( p < 0.001) and -16110.7 versus -6.314, ( p = 0.001), respectively. CONCLUSION: These data show that trochanteric femur fractures treated with PFN or PF-LCP had a negative impact on sexual function. PF-LCP had a greater negative effect than PFN on sexual function. PMID- 29157108 TI - Morphological classification of anatomical variants of the intra-articular portion of the long head of the biceps brachii tendon and analysis of the incidence and the relationship with shoulder disease for each subtype. AB - PURPOSE: Although several cases of anatomical variants of the proximal portion of the long head of the biceps brachii tendon have been reported, most are case reports on single patients; few studies have investigated the classification and incidence of this phenomenon. We aimed to classify the variants of the long head of the biceps brachii tendon by their morphology and characterize them in regard to incidence, demography, and the relationship with biceps tendon or other shoulder diseases. METHODS: We retrospectively reviewed 760 arthroscopic images spanning 31 months from October 2008 and found 45 variations of the proximal portion of the long head of the biceps brachii tendon. We classified the variants using Dierickx classification system and calculated the incidence of each subtype. We investigated age, gender, bicipital morbidity rate, procedure rate, and the frequency of related shoulder disease among the variant groups using patient data and compared the groups to normal patients. RESULTS: The overall incidence of variants was 6.5% (67.4%, mesotenon; 32.6%, adherent; 0% split (SPL); and 0% absent (ABS) type). Morbidity and procedure rates of the long head of the biceps (LHB) tendon in the variant group (27.9% and 25.6%, respectively) were lower than in the normal group (40.5% and 38.9%, respectively), but the difference was not statistically significant ( p = 0.102 and 0.082, respectively). Rotator cuff tear was significantly less common in the mesotenon (44.8%) group than in the normal group (62.4%; p = 0.004). Shoulder joint instability was more prevalent in the mesotenon (27.6%) group than in the normal group (14.9%), but the difference was not significant ( p = 0.305). The distribution of other shoulder diseases in the adherent group was similar to that in the normal group. CONCLUSIONS: The incidence of variants of the long head of the biceps brachii tendon was 6.5%, and most variants were mesotenon or adherent type. The SPL and ABS types were rare. Morbidity and procedure rates of the LHB were not significantly different between the variant group and the normal group, and rotator cuff tear was less common in the mesotenon group. PMID- 29157109 TI - Comparison of patellar tracking according to different angles of external rotation of femoral component in varus knee of Asians. AB - PURPOSE: Racial difference in the femoral geometry may exist. Asian femurs may be more externally rotated. If anatomical differences in distal femur had existed between Caucasians and Asians, the group with 5 degrees external rotation of the femoral component should have shown better results than the group with 3 degrees external rotation of the femoral component have. METHODS: 598 patients underwent total knee arthroplasty in our institution, among whom 83 patients (115 knees) who had postoperative computed tomography (CT) were studied retrospectively. Sixty-two knees were set in 5 degrees of external rotation of femoral component relative to the posterior condylar axis (group A) while the others (53 knees) were set in 3 degrees (group B). The femoral component rotation (FCR) was measured and compared using CT. The patellar tilting (PT) and the lateral patellar displacement (LPD) were measured to evaluate the patellar tracking using Merchant view. And postoperative clinical scores were compared. RESULTS: The mean FCRs showed no significant difference between two groups ( p > 0.05). The mean PT and LPD showed no statistically significant difference either ( p > 0.05). There were no statistical differences in clinical scores. CONCLUSION: The difference in the patellar tracking between the two groups could not be demonstrated. There were no statistical differences in clinical scores either. We concluded there is no need to adhere to 5 degrees external rotation. PMID- 29157110 TI - Risk factors and clinical outcomes of delirium in osteoporotic hip fractures. AB - PURPOSE: This study is performed to identify risk factors for delirium in osteoporotic hip fractures and to evaluate the hospitalization cost and clinical outcomes of delirium in osteoporotic hip. METHODS: A total of 221 patients with osteoporotic hip fractures were assessed for eligibility between 2010 and 2014. Among them, 37 patients with delirium were allocated into the delirium group (group D) and 37 patients without delirium were allocated into the non-delirium group (group ND) by matching demographic factors. Risk factors such as time between admission and operation, body mass index, American Society of Anesthesiologists status, cognitive impairment, preoperative urinary catheter, electrolyte imbalance, preoperative hemoglobin, polymedication (medications > 5), pneumonia, anesthesia time, operation time, estimated blood loss, and total amount of transfusion were evaluated for correlation with incidence of delirium. The hospitalization cost was evaluated, and clinical outcomes such as readmission, mortality, and activity level at 1-year follow-up were evaluated. RESULTS: In multivariate analysis, polymedication ( p = 0.028) and preoperative indwelling urinary catheter insertion status ( p = 0.007) were related to the incidence of delirium in patients with osteoporotic hip fractures. Group D showed a significantly higher hospitalization cost compared to group ND. However, delirium did not have a significant effect on length of hospital stay, readmission rate, postoperative 1-year mortality, and activity level. CONCLUSIONS: Polymedication and preoperative urinary catheter were related to perioperative delirium. In addition, delirium in osteoporotic hip fractures may not have a detrimental effect on clinical outcomes; however, hospitalization cost seemed to be increased due to delirium. PMID- 29157113 TI - Assessing performance of sequential analysis methods for active drug safety surveillance using observational data. AB - The routine use of sequential methods is well established in clinical studies. Recently, there has been increasing interest in applying these methods to prospectively monitor the safety of newly approved drugs through accrual of real world data. However, the application to marketed drugs using real-world data has been limited and work is needed to determine which sequential approaches are most suited to such data. In this study, the conditional sequential sampling procedure (CSSP), a group sequential method, was compared with a log-linear model with Poisson distribution (LLMP) through a SAS procedure (PROC GENMOD) combined with an alpha-spending function on two large longitudinal US administrative health claims databases. Relative performance in identifying known drug-outcome associations was examined using a set of 50 well-studied drug-outcome pairs. The study finds that neither method correctly identified all pairs but that LLMP often provides better ability and shorter time for identifying the known drug outcome associations with superior computational performance when compared with CSSP, albeit with more false positives. With the features of flexible confounding control and ease of implementation, LLMP may be a good alternative or complement to CSSP. PMID- 29157111 TI - HMGA2 cooperates with either p27kip1 deficiency or Cdk4R24C mutation in pituitary tumorigenesis. AB - We have previously reported a critical role of HMGA proteins in pituitary tumorigenesis since either the Hmga1 or Hmga2 gene overexpression/activation induces the development of mixed growth hormone/prolactin cell pituitary adenomas by activating the E2F transcription factor 1, and then enhancing the G1/S transition of the cell cycle. Consistently, amplification and overexpression of the HMGA2 gene was found in human pituitary prolactinomas. Since impairment of the cell cycle control represents a feature of experimental and human pituitary adenomas, we have investigated the possible synergism between the alterations of other cell cycle regulators, such as p27 deficiency or Cdk4R24C mutation, with Hmga2 overexpression in pituitary tumorigenesis. Therefore, we crossed the Hmga2/T mice, overexpressing the truncated/active form of the Hmga2 gene, either with the knockout mice for p27kip1, or with the knockin mice for the Cdk4R24C mutation, both developing pituitary adenomas. Increased incidence and decreased latency in the development of pituitary lesions appeared in double mutant Hmga2/T;Cdk4R24C mice, and increased features of invasiveness and atypia were observed in pituitary tumors of both Hmga2/T;p27-ko and Hmga2/T;Cdk4R24C double mutant mice as compared with single mutant compounds. Interestingly, most of these mice develop pituitary adenomas with high Ki67 index, extrasellar expansion and brain tissue infiltration, representing good mouse models for human aggressive pituitary adenomas. Taken together, the results reported here indicate a cooperation between HMGA2 overexpression and either p27kip1 or CDK4 impairment in promoting pituitary tumor development and progression. PMID- 29157114 TI - Self-initiated object-location memory in young and older adults. AB - The present study explored self-initiated object-location memory in ecological contexts, as aspect of memory that is largely absent from the research literature. Young and older adults memorized objects-location associations they selected themselves or object-location associations provided to them, and elaborated on the strategy they used when selecting the locations themselves. Retrieval took place 30 min and 1 month after encoding. The results showed an age related decline in self-initiated and provided object-location memory. Older adults benefited from self-initiation more than young adults when tested after 30 min, while the benefit was equal when tested after 1 month. Furthermore, elaboration enhanced memory only in older adults, and only after 30 min. Both age groups used deep encoding strategies on the majority of the trials, but their percentage was lower in older adults. Overall, the study demonstrated the processes involved in self-initiated object-location memory, which is an essential part of everyday functioning. PMID- 29157115 TI - Subgroup analysis based on prognostic and predictive gene signatures for adjuvant chemotherapy in early-stage non-small-cell lung cancer patients. AB - In treating patients diagnosed with early Stage I non-small-cell lung cancer (NSCLC), doctors must choose surgery alone, Adjuvant Cisplatin-Based Chemotherapy (ACT) alone or both. For patients with resected stages IB to IIIA, clinical trials have shown a survival advantage from 4-15% with the adoption of ACT. However, due to the inherent toxicity of chemotherapy, it is necessary for doctors to identify patients whose chance of success with ACT is sufficient to justify the risks. This research seeks to use gene expression profiling in the development of a statistical decision-making algorithm to identify patients whose survival rates will improve from ACT treatment. Using the data from the National Cancer Institute, the lasso method in the Cox-Proportional-Hazards regression model is used as the main method to determine a feasible number of genes that are strongly associated with the treatment-related patient survival. Considering treatment groups separately, the patients are assigned a risk category based on the estimation of survival times. These risk categories are used to develop a Random Forests classification model to identify patients who are likely to benefit from chemotherapy treatment. This model allows the prediction of a new patient's prognosis and the likelihood of survival benefit from ACT treatment based on a feasible number of genomic biomarkers. The proposed methods are evaluated using a simulation study. PMID- 29157117 TI - Honor and harmed social-image. Muslims' anger and shame about the cartoon controversy. AB - Two studies examined anger and shame, and their associated appraisals and behavioral intentions, in response to harm to an in-group's social-image. In Study 1, 37 British Muslims (18 men, 19 women) reported incidents in which they were devalued as Muslims. In Study 2, 108 British Muslims (57 females, 50 males, 1 undisclosed) were presented with objective evidence of their in-group's devaluation: the controversial cartoons about Prophet Muhammad The appraisal of harm to social-image predicted anger and shame (Studies 1 and 2), whereas the appraisal of offense only predicted anger (Study 2). Anger was a more empowering response than shame, as anger predicted willingness for public confrontation (Studies 1 & 2), institutional punishment (Study 2), and written disapproval (Study 2). In contrast, shame only predicted written disapproval (Study 2). Furthermore, independent of individual differences in identification as Muslim, a mediation model showed that individual differences in honor orientation predicted anger and shame via the appraisals (Study 2). Implications for theory and research are discussed. PMID- 29157116 TI - Perinatal exposure to high dietary advanced glycation end products in transgenic NOD8.3 mice leads to pancreatic beta cell dysfunction. AB - The contribution of environmental factors to pancreatic islet damage in type 1 diabetes remains poorly understood. In this study, we crossed mice susceptible to type 1 diabetes, where parental male (CD8+ T cells specific for IGRP206-214; NOD8.3) and female (NOD/ShiLt) mice were randomized to a diet either low or high in AGE content and maintained on this diet throughout pregnancy and lactation. After weaning, NOD8.3+ female offspring were identified and maintained on the same parental feeding regimen for until day 28 of life. A low AGE diet, from conception to early postnatal life, decreased circulating AGE concentrations in the female offspring when compared to a high AGE diet. Insulin, proinsulin and glucagon secretion were greater in islets isolated from offspring in the low AGE diet group, which was akin to age matched non-diabetic C57BL/6 mice. Pancreatic islet expression of Ins2 gene was also higher in offspring from the low AGE diet group. Islet expression of glucagon, AGEs and the AGE receptor RAGE, were each reduced in low AGE fed offspring. Islet immune cell infiltration was also decreased in offspring exposed to a low AGE diet. Within pancreatic lymph nodes and spleen, the proportions of CD4+ and CD8+ T cells did not differ between groups. There were no significant changes in body weight, fasting glucose or glycemic hormones. This study demonstrates that reducing exposure to dietary AGEs throughout gestation, lactation and early postnatal life may benefit pancreatic islet secretion and immune infiltration in the type 1 diabetic susceptible mouse strain, NOD8.3. PMID- 29157118 TI - Efficient estimation of disease odds ratios for follow-up genetic association studies. AB - In the past decade, genome-wide association studies have identified thousands of susceptible variants associated with complex human diseases and traits. Conducting follow-up genetic association studies has become a standard approach to validate the findings of genome-wide association studies. One problem of high interest in genetic association studies is to accurately estimate the strength of the association, which is often quantified by odds ratios in case-control studies. However, estimating the association directly by follow-up studies is inefficient since this approach ignores information from the genome-wide association studies. In this article, an estimator called GFcom, which integrates information from genome-wide association studies and follow-up studies, is proposed. The estimator includes both the point estimate and corresponding confidence interval. GFcom is more efficient than competing estimators regarding MSE and the length of confidence intervals. The superiority of GFcom is particularly evident when the genome-wide association study suffers from severe selection bias. Comprehensive simulation studies and applications to three real follow-up studies demonstrate the performance of the proposed estimator. An R package, "GFcom", implementing our method is publicly available at https://github.com/JiyuanHu/GFcom . PMID- 29157119 TI - Biomarker combinations for diagnosis and prognosis in multicenter studies: Principles and methods. AB - Many investigators are interested in combining biomarkers to predict a binary outcome or detect underlying disease. This endeavor is complicated by the fact that many biomarker studies involve data from multiple centers. Depending upon the relationship between center, the biomarkers, and the target of prediction, care must be taken when constructing and evaluating combinations of biomarkers. We introduce a taxonomy to describe the role of center and consider how a biomarker combination should be constructed and evaluated. We show that ignoring center, which is frequently done by clinical researchers, is often not appropriate. The limited statistical literature proposes using random intercept logistic regression models, an approach that we demonstrate is generally inadequate and may be misleading. We instead propose using fixed intercept logistic regression, which appropriately accounts for center without relying on untenable assumptions. After constructing the biomarker combination, we recommend using performance measures that account for the multicenter nature of the data, namely the center-adjusted area under the receiver operating characteristic curve. We apply these methods to data from a multicenter study of acute kidney injury after cardiac surgery. Appropriately accounting for center, both in construction and evaluation, may increase the likelihood of identifying clinically useful biomarker combinations. PMID- 29157120 TI - Evaluating nurse understanding and participation in the informed consent process. AB - BACKGROUND: Informed consent is fundamental to the autonomous decision-making of patients, yet much is still unknown about the process in the clinical setting. In an evolving healthcare landscape, nurses must be prepared to address patient understanding and participate in the informed consent process to better fulfill their well-established role as patient advocates. RESEARCH OBJECTIVE: This study examines hospital-based nurses' experiences and understandings of the informed consent process. RESEARCH DESIGN: This qualitative descriptive study utilized a semi-structured interview approach identifying thematic concerns, experiences, and knowledge of informed consent across a selected population of clinically practicing nurses. Participants and research context: In all, 20 baccalaureate prepared registered nurses practicing in various clinical settings (i.e. critical care, oncology, medical/surgical) at a large northeastern academic medical center in the United States completed semi-structured interviews and a demographic survey. The mean age of participants was 36.6 years old, with a mean of 12.2 years of clinical experience. Ethical considerations: Participation in this study involved minimal risk and no invasive measures. This study received Institutional Review Board approval from the University of Pennsylvania. All participants voluntarily consented. FINDINGS: The majority of participants (N = 19) believe patient safety is directly linked to patient comprehension of the informed consent process. However, when asked if nurses have a defined role in the informed consent process, nearly half did not agree (N = 9). Through this qualitative approach, three major nursing roles emerged: the nurse as a communicator, the nurse as an advocate, and the clerical role of the nurse. DISCUSSION AND CONCLUSION: This investigation contributes to the foundation of ethical research that will better prepare nurses for patient engagement, advance current understanding of informed consent, and allow for future development of solutions. Nurses are at the forefront of patient-provider interactions and they are often presented opportunities to learn about and engage in the informed consent process. PMID- 29157121 TI - Signed family physician reminder letters to women overdue for screening mammography: A randomized clinical trial. AB - OBJECTIVE: To determine whether signed family physician reminder letters to women overdue for screening mammography prompts rescreening. METHODS: A randomized double-blind trial conducted in 2013 among women aged 51-73 and overdue for screening by 6-24 months. The study was carried out by the publicly funded British Columbia Cancer Agency Screening Mammography Program, which routinely sends standard reminder postcards to women who are due for mammography. Participating family physicians signed letters for the overdue women in their practices. The overdue women were mailed either the signed reminder letter and the standard reminder postcard, or the standard reminder postcard alone. The primary endpoint was the proportion of overdue women that attended a screening mammogram appointment within six months of mailing the study letters. The analysis was by intention to treat. RESULTS: In total, 822 family physicians participated and 5638 women were randomized. Mammography attendance by six months after mailing the reminders was 34.4% (947/2749) for women in the signed family physician letter arm, compared with 24.0% (660/2749) for women in the control arm (p < 0.0001). Adjusting for age, number of previous screening mammograms, and months overdue, women in the signed letter arm were significantly more likely to return for screening than women in the control arm (RR 1.41; 95% confidence interval: 1.30-1.54). CONCLUSION: A signed family physician reminder letter improved mammography attendance for women who were overdue for screening mammography. PMID- 29157124 TI - A Rare Case of Left Ventricular Pseudoaneurysm Due To Tuberculosis in a 13-Year Old Boy. PMID- 29157123 TI - Trichostatin A Induces NAG-1 Expression and Apoptosis in Human Endometriotic Stromal Cells. AB - To investigate the effects of trichostatin A (TSA) on nonsteroidal anti inflammatory drug-activated gene 1 (NAG-1) expression and apoptosis in human endometriotic stromal cells (HESCs), ectopic endometrial tissues were obtained from 15 patients with endometriotic cysts who underwent cystectomy. Human endometriotic stromal cells were isolated and cultured with different concentrations of TSA. Nonsteroidal anti-inflammatory drug-activated gene-1 messenger RNA (mRNA) and protein levels were evaluated by real-time polymerase chain reaction and Western blotting, respectively, and apoptosis was assessed by flow cytometry. Viability of HESCs was reduced in a dose-dependent manner by treatment with TSA. The percentage of early and late apoptotic HESCs was increased upon treatment with TSA. Nonsteroidal anti-inflammatory drug-activated gene-1 mRNA and protein expression was induced in a dose-dependent manner by TSA treatment. Gene knockdown experiments using small-interfering RNA confirmed an association between NAG-1 expression and TSA-induced apoptosis. Whether effects of TSA on NAG-1 gene expression are enhanced in the presence of 5-aza-2' deoxycytidine (5-aza-dC) are also investigated; however, TSA-induced apoptosis was unaffected by 5-aza-dC. In conclusion, TSA induced apoptosis in HESCs via induction of NAG-1 expression. These results suggest that upregulation of NAG-1 contributes to TSA-induced apoptosis in HESCs. PMID- 29157126 TI - Sample size calculations for blinding assessment. AB - Blinding is a critical component in randomized clinical trials along with treatment effect estimation and comparisons between the treatments. Various methods have been proposed for the statistical analyses of blinding-related data, but there is little guidance for determining the sample size for this type of data, especially if blinding assessment is done in pilot studies. In this paper, we try to fill this gap and provide simple methods to address sample size calculations for a "new" study with different research questions and scenarios. The proposed methods are framed in terms of estimation/precision or statistical testing to allow investigators to choose the best suited method for their goals. We illustrate the methods using worked examples with real data. PMID- 29157128 TI - Twenty-Four Months Follow-Up of Intravitreal Bevacizumab Injection versus Intravitreal Triamcinolone Acetonide Injection for the Management of Persistent Non-Infectious Uveitic Cystoid Macular Edema. AB - PURPOSE: To report the efficacy of intravitreal bevacizumab (IVB) injection versus intravitreal triamcinolone acetonide (IVT) for persistent non-infectious uveitic cystoid macular edema (CME). METHODS: Interventional retrospective comparative case series evaluated 37 consecutive patients (44 eyes) with completely controlled uveitis and recalcitrant CME. Patients received repeated injections of 1.25 mg of IVB or 4 mg of IVT. RESULTS: Best-corrected visual acuity (BCVA) at baseline and 24 months was logMAR 1 and 0.8 respectively, in the IVB group (p = 0.002) and; logMAR of 1.1 and 0.6, in the IVT group (p = 0.001). Central macular thickness at baseline and 24 months was 399.2 um and 333.7 um (p < 0.0009), respectively, for the IVB group and; 464.4 um and 316.5 um in the IVT group (p = 0.044). Postoperatively, IOP increased in the IVT group. CONCLUSIONS: Repeated injections with IVT improve BCVA as effectively as repeated injections with IVB in the long-term management of persistent uveitic CME. PMID- 29157127 TI - Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. AB - The gut microbiota is a contributing factor in obesity-related metabolic disorders. The effect of metformin on the gut microbiota has been reported; however, the relationship between the gut microbiota and the mechanism of action of metformin in elderly individuals is unclear. In this study, the effect of metformin on the gut microbiota was investigated in aged obese mice. The abundance of the genera Akkermansia, Bacteroides, Butyricimonas, and Parabacteroides was significantly increased by metformin in mice fed a high-fat diet. Metformin treatment decreased the expression of IL-1beta and IL-6 in epididymal fat, which was correlated with the abundance of various bacterial genera. In addition, both fecal microbiota transplantation from metformin-treated mice and extracellular vesicles of Akkermansia muciniphila improved the body weight and lipid profiles of the mice. Our findings suggest that modulation of the gut microbiota by metformin results in metabolic improvements in aged mice, and that these effects are associated with inflammatory immune responses. PMID- 29157129 TI - The impact of developmental dyslexia and dysgraphia on movement production during word writing. AB - This study investigated how deficits in orthographic processing affect movement production during word writing. Children with dyslexia and dysgraphia wrote words and pseudo-words on a digitizer. The words were orthographically regular and irregular of varying frequency. The group analysis revealed that writing irregular words and pseudo-words increased movement duration and dysfluency. This indicates that the spelling processes were active while the children were writing the words. The impact of these spelling processes was stronger for the children with dyslexia and dysgraphia. The analysis of individual performance revealed that most dyslexic/dysgraphic children presented similar writing patterns. However, selective lexical processing deficits affected irregular word writing but not pseudo-word writing. Selective poor sublexical processing affected pseudo word writing more than irregular word writing. This study suggests that the interaction between orthographic and motor processing constitutes an important cognitive load that may disrupt the graphic outcome of the children with dyslexia/dysgraphia. PMID- 29157130 TI - Positive Feedback From Male Authority Figures Boosts Women's Math Outcomes. AB - People often search for cues in the environment to determine whether or not they will be judged or treated negatively based on their social identities. Accordingly, feedback from gatekeepers-members of majority groups who hold authority and power in a field-may be an especially important cue for those at risk of experiencing social identity threat, such as women in math settings. Across a series of studies, women who received positive ("Good job!") versus objective (score only) feedback from a male (vs. female) authority figure in math reported greater confidence; belonging; self-efficacy; more favorable Science, Technology, Engineering, and Mathematics (STEM) attitudes/identification/interest; and greater implicit identification with math. Men were affected only by the type of math feedback they received, not by the source of feedback. A meta-analysis across studies confirmed results. Together, these findings suggest that positive feedback from gatekeepers is an important situational cue that can improve the outcomes of negatively stereotyped groups. PMID- 29157131 TI - Degradation of dye wastewater with a photoelectric integration process (MPEC): Microbial fuel cells-assisted dual electrodes thin-film photoelectrocatalytic. AB - A novel photoelectric integration process (MPEC) was developed to degrade Amaranth. In the MPEC, the output voltage of the microbial fuel cells (MFCs) was used to assist the dual slant-placed electrodes thin-film photocatalytic (PC). With two MFCs connected in series, the MPEC process realized the highest decolorization efficiency. It is close to that of the external bias photoelectrocatalytic (PEC), and 7% higher than that of the self-generated electric field-assisted photoelectrocatalytic (SPEC). The feasibility of MPEC pre treatment and MFC post-treatment of Amaranth was investigated. The results demonstrated that MPEC pre-treatment of Amaranth could improve its biodegradability. The higher MPEC decolorization efficiency indicated the stronger biodegradability of the obtained intermediates and the higher MFC output voltage. When the MPEC decolorization efficiency was gradually increased to 50%, the removal efficiencies of total Chemical Oxygen Demand (COD) by the MPEC and MFC increased; when the decolorization efficiency was increased above 50%, the removal efficiencies became stable. MPEC enhanced the biodegradability efficiently and was applicable to pre-treat textile wastewater. PMID- 29157132 TI - In planta functions of cytochrome P450 monooxygenase genes in the phytocassane biosynthetic gene cluster on rice chromosome 2. AB - In response to environmental stressors such as blast fungal infections, rice produces phytoalexins, an antimicrobial diterpenoid compound. Together with momilactones, phytocassanes are among the major diterpenoid phytoalexins. The biosynthetic genes of diterpenoid phytoalexin are organized on the chromosome in functional gene clusters, comprising diterpene cyclase, dehydrogenase, and cytochrome P450 monooxygenase genes. Their functions have been studied extensively using in vitro enzyme assay systems. Specifically, P450 genes (CYP71Z6, Z7; CYP76M5, M6, M7, M8) on rice chromosome 2 have multifunctional activities associated with ent-copalyl diphosphate-related diterpene hydrocarbons, but the in planta contribution of these genes to diterpenoid phytoalexin production remains unknown. Here, we characterized cyp71z7 T-DNA mutant and CYP76M7/M8 RNAi lines to find that potential phytoalexin intermediates accumulated in these P450-suppressed rice plants. The results suggested that in planta, CYP71Z7 is responsible for C2-hydroxylation of phytocassanes and that CYP76M7/M8 is involved in C11alpha-hydroxylation of 3-hydroxy-cassadiene. Based on these results, we proposed potential routes of phytocassane biosynthesis in planta. PMID- 29157133 TI - Reallocating sitting time to standing or stepping through isotemporal analysis: associations with markers of chronic low-grade inflammation. AB - Although high levels of sitting time are adversely related to health, it is unclear whether moving from sitting to standing provides a sufficient stimulus to elicit benefits upon markers of chronic low-grade inflammation in a population at high risk of type 2 diabetes (T2DM). Three hundred and seventy two participants (age = 66.8 +/- 7.5years; body mass index (BMI) = 31.7 +/- 5.5kg/m2; Male = 61%) were included. Sitting, standing and stepping was determined using the activPAL3TM device. Linear regression modelling employing an isotemporal substitution approach was used to quantify the association of theoretically substituting 60 minutes of sitting per day for standing or stepping on interleukin-6 (IL-6), C-reactive protein (CRP) and leptin. Reallocating 60 minutes of sitting time per day for standing was associated with a -4% (95% CI 7%, -1%) reduction in IL-6 (p = 0.048). Reallocating 60 minutes of sitting time for light stepping was also associated with lower IL-6 levels (-28% (-46%, -4%; p = 0.025)). Substituting sitting for moderate-to-vigorous (MVPA) stepping was associated with lower CRP (-41% (-75%, -8%; p = 0.032)), leptin (-24% (-34%, 12%; p <= 0.001)) and IL-6 (-16% (-28%, 10%; p = 0.036). Theoretically replacing 60 minutes of sitting per day with an equal amount of either standing or stepping yields beneficial associations upon markers of chronic-low grade inflammation. PMID- 29157136 TI - Blood transfusion versus hydroxyurea in beta-thalassemia in Iran: a cost effectiveness study. AB - INTRODUCTION: Thalassemia intermedia is a type of anemia which has several treatments modalities. We aimed to study the cost effectiveness of two treatments, including blood transfusion and hydroxyurea, in patients with beta thalassemia intermedia in south of Iran referred to a referral center affiliated to Iran, Shiraz University of Medical Sciences in 2015. MATERIALS AND METHODS: This was a cost-effectiveness study which was conducted on 122 patients with beta thalassemia intermedia. The indicator of effectiveness in this study was the reduction of growth disorder (normal BMI). Data analysis was done using SPSS 21, Excel 2010 and Treeage 2011. Finally, the one-way sensitivity analysis was performed to determine the robustness of the results. RESULTS: The average annual costs of blood transfusion and the use of hydroxyurea in 2015 were 20733.27 purchasing power parity (PPP)$ and 7040.29 PPP$, respectively. The effectiveness of blood transfusion was57.4% while in hydroxyurea group was 60.7%. CONCLUSION: The results showed that the cost effectiveness of using hydroxyurea was more than that of blood transfusion. Therefore, it is recommended that the use of hydroxyurea in the treatment of patients with beta-thalassemia intermedia would become the first priority, and more basic and supplementary insurance coverage for treating such patients using hydroxyurea should be considered. PMID- 29157137 TI - Taxonomising delusions: content or aetiology? AB - INTRODUCTION: Many theoretical treatments assume (often implicitly) that delusions ought to be taxonomised by the content of aberrant beliefs. A theoretically sound, and comparatively under-explored, alternative would split and combine delusions according to their underlying cognitive aetiology. METHODS: We give a theoretical review of several cases, focusing on monothematic delusions of misidentification and on somatoparaphrenia. RESULTS: We show that a purely content-based taxonomy is empirically problematic. It does not allow for projectability of discoveries across all members of delusions so delineated, and lumps together delusions that ought to be separated. We demonstrate that an aetiological approach is defensible, and further that insofar as content-based approaches are plausible, it is only to the extent that they implicitly link content to aetiology. CONCLUSIONS: We recommend a more explicit focus on cognitive aetiology as the grounds for delusion taxonomy, even when that would undermine traditional content-based boundaries. We also highlight the iterative and complex nature of evidence about aetiologically grounded taxonomies. PMID- 29157138 TI - Fast-cycling Rho GTPases. AB - The Rho GTPases were discovered more than 30 years ago, and they were for a long time considered to follow simple cycling between GDP-bound and GTP-bound conformations, as for the Ras subfamily of small GTPases. The Rho GTPases consist of 20 members, but at least 10 of these do not follow this classical GTPase cycle. Thus, based on their kinetic properties, these Rho GTPases can instead be classified as atypical. Some of these atypical Rho GTPases do not hydrolyze GTP, and some have significantly increased intrinsic GDP/GTP exchange activity. This review focuses on this latter category of atypical Rho GTPases, the so-called 'fast-cycling' Rho GTPases. The different members of these fast-cycling atypical Rho GTPases are described in more detail here, along with their potential regulatory mechanisms. Finally, some insights are provided into the involvement of the atypical Rho GTPases in human pathologies. PMID- 29157139 TI - Authors' response to letter to the editor: "Bar velocities capable of optimising the muscle power in strength-power exercises" by Loturco, Pereira, Abad, Tabares, Moraes, Kobal, Kitamura & Nakamura (2017). AB - Our study in the Journal of Sports Sciences was originally designed to test whether the bar-velocity is a precise indicator of the power training intensity (i.e., optimum loads) in different exercises commonly included in athletes' training programs. Furthermore, we presented secondary findings, related to the actual results obtained in our assessments. As a cross-sectional study with clear objectives, we focused on discussing issues and applications pertaining to neuromuscular training interventions, such as: (1) describing the advantages of using bar-velocities to control the power training intensity, (2) defining a range of loads capable of maximizing the power production in certain ballistic and traditional exercises, and (3) revealing the differences between these exercises and the respective implications for training. Fundamentally, we did not produce a mechanistic investigation and were very accurate and consistent in reporting our data, collected under rigorous and well-established experimental conditions. Here we provide our point-by-point comments to the concerns raised in the "Letter to the Editor", along with some theoretical explanations about the secondary findings reported by the authors of the Letter. To better understand the nature and purposes of our experiment, we also present a series of practical examples and review previous investigations involving the "bar-power" approach. PMID- 29157140 TI - How biomass growth mode affects ammonium oxidation start-up and NOB inhibition in the partial nitritation of cold and diluted reject water. AB - The inhibition of undesirable nitrite oxidizing bacteria (NOB) and desirable ammonium oxidizing bacteria (AOB) by free ammonia (FA) and free nitrous acid (FNA) in partial nitritation (PN) is crucially affected by the biomass growth mode (suspended sludge, biofilm, encapsulation). But, the limitations of these modes towards less concentrated reject waters (<=600 mg-N L-1) are unclear. Therefore, this work compares the start-up and stability of three PN sequencing batch reactors (SBRs) with biomass grown in one of the three modes: suspended sludge, biofilm and biomass encapsulated in polyvinyl alcohol (PVA) pellets. The SBRs were operated at 15 degrees C with influent total ammonium nitrogen (TAN) concentrations of 75-600 mg-TAN L-1. PN start-up was twice as fast in the biofilm and encapsulated biomass SBRs than in the suspended sludge SBR. After start-up, PN in the biofilm and suspended sludge SBRs was stable at 150-600 mg-TAN L-1. But, at 75 mg-TAN L-1, full nitrification gradually developed. In the encapsulated biomass SBR, full nitrification occurred even at 600 mg-TAN L-1, showing that NOB in this set-up can adapt even to 4.3 mg-FA L-1 and 0.27 mg-FNA L 1. Thus, PN in the biofilm was best for the treatment of an influent containing 150-600 mg-TAN L-1. PMID- 29157141 TI - Experimental study on effects of drilling parameters on respirable dust production during roof bolting operations. AB - Underground coalmine roof bolting operators exhibit a continued risk for overexposure to airborne levels of respirable coal and crystalline silica dust from the roof drilling operation. Inhaling these dusts can cause coal worker's pneumoconiosis and silicosis. This research explores the effect of drilling control parameters, specifically drilling bite depth, on the reduction of respirable dust generated during the drilling process. Laboratory drilling experiments were conducted and results demonstrated the feasibility of this dust control approach. Both the weight and size distribution of the dust particles collected from drilling tests with different bite depths were analyzed. The results showed that the amount of total inhalable and respirable dust was inversely proportional to the drilling bite depth. Therefore, control of the drilling process to achieve proper high-bite depth for the rock can be an important approach to reducing the generation of harmful dust. Different from conventional passive engineering controls, such as mist drilling and ventilation approaches, this approach is proactive and can cut down the generation of respirable dust from the source. These findings can be used to develop an integrated drilling control algorithm to achieve the best drilling efficiency as well as reducing respirable dust and noise. PMID- 29157142 TI - Experimental study on centerline velocities of a rectangular capture hood under realistic conditions. AB - Capture hoods are an important component of a local ventilation system designed to reduce exposures to airborne contaminants. The velocity at any point along the centerline of the hood (Vx) is currently estimated using one of many predictive equations developed since the 1930s. It is unproven that those predictive equations for Vx are accurate, despite the prodigious number of studies concerning them. Among other issues, almost all experimental verifications were conducted for conditions that were either unrealistically ideal without competing air currents (e.g., zero cross draft) or were not described. This study measured values of Vx along the midline using Particle Image Velocimetry (PIV) at distances of 1-14 inches in front of a rectangular capture hood. The experiments were conducted in a large wind tunnel (9' * 12' * 40', H * W * L) using a heated, breathing, anthropomorphically sized manikin. Three 0 degree draft velocities (Vdraft = 4, 14, and 50 ft/min) were tested, all directed toward the hood face and the back of the manikin (if present). For each value of Vdraft, the velocity fields were measured in a factorial design with and without the manikin, and with and without a worktable underneath the hood. An ideal condition was represented by a freestanding hood at the 4 fpm draft. Nonideal conditions included the presence of a worktable or manikin, and the combination of table and manikin. Each condition was tested at the three levels of Vdraft. The experimental results found significant effects (p < 0.001) for Vdraft, the presence of the manikin, the presence of the worktable, and all combinations of those factors. The effects of the independent variables were most pronounced at distances greater than 10 in (25.4 cm) from the hood face. It is concluded that none of the previously published models accurately predicted Vx under the realistic conditions tested in this study. A satisfactory model will have to include terms for Vdraft and the presence of a worktable and a worker. PMID- 29157143 TI - Stability of equilibria in quantitative genetic models based on modified-gradient systems. AB - Motivated by questions in biology, we investigate the stability of equilibria of the dynamical system [Formula: see text] which arise as critical points of f, under the assumption that [Formula: see text] is positive semi-definite. It is shown that the condition [Formula: see text], where [Formula: see text] is the smallest eigenvalue of [Formula: see text], plays a key role in guaranteeing uniform asymptotic stability and in providing information on the basis of attraction of those equilibria. PMID- 29157144 TI - Personal exposure of dairy workers to dust, endotoxin, muramic acid, ergosterol, and ammonia on large-scale dairies in the high plains Western United States. AB - Dairy workers experience a high degree of bioaerosol exposure, composed of an array of biological and chemical constituents, which have been tied to adverse health effects. A better understanding of the variation in the magnitude and composition of exposures by task is needed to inform worker protection strategies. To characterize the levels and types of exposures, 115 dairy workers grouped into three task categories on nine farms in the high plains Western United States underwent personal monitoring for inhalable dust, endotoxin, 3 hydroxy fatty acids (3-OHFA), muramic acid, ergosterol, and ammonia through one work shift. Eighty-nine percent of dairy workers were exposed to endotoxin at concentrations exceeding the recommended exposure guidelines (adjusted for a long work shift). The proportion of workers with exposures exceeding recommended guidelines was lower for inhalable dust (12%), and ammonia (1%). Ergosterol exposures were only measurable on 28% of samples, primarily among medical workers and feed handlers. Milking parlor workers were exposed to significantly higher inhalable dust, endotoxin, 3-OHFA, ammonia, and muramic acid concentrations compared to workers performing other tasks. Development of large modern dairies has successfully made progress in reducing worker exposures and lung disease prevalence. However, exposure to endotoxin, dust, and ammonia continues to present a significant risk to worker health on North American dairies, especially for workers in milking parlors. This study was among the first to concurrently evaluate occupational exposure to assayable endotoxin (lipid A), 3-hydroxy fatty acids or 3-OHFA (a chemical measure of cell bound and noncell-bound endotoxins), muramic acid, ergosterol, and ammonia among workers on Western U.S. dairies. There remains a need for cost-effective, culturally acceptable intervention strategies integrated in OHS Risk Management and production systems to further optimize worker health and farm productivity. PMID- 29157145 TI - Clostridium difficile treatment in neutropenic patients: Clinical outcomes of metronidazole, vancomycin, combinations, and switch therapy. AB - Background Clostridium difficile infection treatment guidelines exist for immunocompetent patients; however, there is a paucity of data evaluating clinical outcomes and time to C. difficile-associated diarrhea resolution in neutropenic patients. Objective To assess clinical outcomes in neutropenic patients treated with metronidazole, oral vancomycin, the combination of metronidazole plus oral vancomycin, and switch of metronidazole to oral vancomycin. Methods This retrospective, observational cohort study assessed adult neutropenic inpatients with C. difficile-associated diarrhea treated with metronidazole, oral vancomycin, combination (metronidazole and oral vancomycin), or switch therapy (metronidazole to oral vancomycin). The primary outcome was time to diarrhea resolution based on treatment regimen. Secondary outcomes included C. difficile associated diarrhea resolution of diarrhea by day 14, recurrence, and occurrence of major complications. Results Overall, 44 patients met full inclusion criteria (52.2% metronidazole monotherapy, 22.7% combination, and 25.0% switch therapy). Two patients on oral vancomycin monotherapy were excluded due to insufficient sample size. Overall time to C. difficile-associated diarrhea resolution was 9.1 +/- 10.7 days. The Cox regression results suggested both switch and combination therapy were associated with 65.5% (p = 0.002) and 65.9% (p = 0.046) longer time to C. difficile-associated diarrhea resolution compared to metronidazole monotherapy, respectively. An increasing absolute neutrophil count was associated with an increase in C. difficile-associated diarrhea resolution (p = 0.007). Conclusion Switch or combination therapy was associated with a prolonged time to C. difficile-associated diarrhea resolution. The decision to use switch or combination therapy may represent a surrogate marker for more severe disease and need for therapy escalation. It is unknown if initial therapy with oral vancomycin would provide better outcomes as this could not be assessed. PMID- 29157146 TI - Evaluation of rivaroxaban use in patients with gynecologic malignancies at an academic medical center: A pilot study. AB - Background Patients with gynecologic malignancies are at an increased risk for venous thromboembolism. National guidelines recommend treatment of an acute venous thromboembolism with low molecular weight heparin for 5-10 days followed by long-term secondary prophylaxis with low molecular weight heparin for at least six months. Non-vitamin K oral anticoagulants are not currently recommended to be used in cancer patients for the management of venous thromboembolism because robust data on their efficacy and safety have yet to become available in cancer patients. The objectives of this study were to determine the proportion of gynecologic oncology patients with venous thromboembolism using rivaroxaban compared to warfarin or low molecular weight heparin as well as compare the safety and efficacy of these anticoagulants. Methods This study was a retrospective pilot analysis of adult patients with gynecologic malignancies who received either rivaroxaban, warfarin or low molecular weight heparin for treatment of venous thromboembolism at Augusta University Medical Center from 1 July 2013 to 30 June 2015. Statistical comparisons between the enoxaparin and rivaroxaban group were made using T-tests and Chi-square or Fisher's exact tests, where appropriate. Results Out of the 49 patients, 37% (18) patients were on rivaroxaban, 53% (26) on enoxaparin, and 10% (5) on warfarin. Only one patient (4%) in the enoxaparin group experienced a recurrent deep vein thrombosis while there were no cases of recurrent venous thromboembolism in the rivaroxaban and warfarin group. The incidence of major bleeding was 17% ( n = 2), 20% ( n = 1), and 8% ( n = 2) in patients receiving rivaroxaban, enoxaparin, and warfarin, respectively. The rate of switching to a different anticoagulant than originally prescribed was 42% ( n = 14) in the enoxaparin arm, and 5.5% ( n = 1) in the rivaroxaban arm. Conclusion A high proportion of our gynecologic oncology patients received rivaroxaban for the management of venous thromboembolism. The sample size of this pilot analysis was too small to draw any conclusions regarding efficacy and safety of rivaroxaban compared with enoxaparin and warfarin. High rate of rivaroxaban use in gynecologic oncology patients at our institution highlights the need for larger, well-designed randomized controlled trials to confirm the safety and efficacy of its use in this population. PMID- 29157147 TI - A case of aseptic meningitis in a cetuximab-experienced patient with metastatic colon cancer. AB - Cetuximab is a monoclonal antibody against epidermal growth factor receptor and is used in the treatment of head and neck cancer, non-small cell lung cancer, and colorectal cancer. This case report describes a rare (<1% incidence) side effect of cetuximab administration: aseptic meningitis. We report a case which is, to our knowledge, the only case at the time of submission of this manuscript of aseptic meningitis in a patient being treated for metastatic colon cancer who was not cetuximab-naive. This case report may help inform clinicians about the identification and outcome of this adverse event. PMID- 29157148 TI - Implementation of clinical pharmacy services in an academic oncology practice in India. AB - Objective This study was conducted to investigate medication-related problems after implementation of clinical pharmacy services at a speciality oncology care setting. Methods It was a prospective interventional study conducted for a period of three years at a private academic oncology care setting. Paper-based medical records and medication orders were reviewed and patients and care givers were interviewed to understand the treatment plan. All the medication-related problems were identified by clinical pharmacists by performing drug therapy review. Patients were also followed up at ambulatory care and in-patient units to ensure appropriate administration of anti-cancer drugs by nurses. All the medication related problems were discussed with the concerned clinicians and then were resolved with the interventions of clinical pharmacists. Clinical significance of these interventions were assessed and classified as "Major", "Moderate "and "Minor". Educational, clinical and system-based interventions were developed and implemented to minimize medication-related problems at the study site. Results A total of 1359 medication-related problems were identified from 2120 medication orders reviewed of 1362 patients followed during the study period. The most common medication-related problems were lack of suboptimal supportive care (17.95%), inappropriate administration of medications (14.56%), untreated indication (14.20%), wrong dosing calculations (12.21%), drug-drug interactions (11.62%) and sub-therapeutic dose (11.11%). Clinical pharmacy interventions were made to resolve all the medication-related problems. Clinical significance of majority (n = 504, 37.08%) of medication-related problems was "Moderate" followed by "Major" (n = 434, 31.93%) and "Minor" (n = 421, 30.97%). Conclusion The study has demonstrated the importance of clinical pharmacy services in improving quality and safe use of medicines in oncology practice. Positive feedback of clinicians on clinical pharmacy services was a reflection of acceptance of clinical pharmacy interventions by clinicians. PMID- 29157149 TI - Stabilized landfill leachate treatment using Guadua amplexifolia bamboo as a source of activated carbon: kinetics study. AB - In the present study, the characteristics of leachate generated from dumpsite called 'Zapote' located in southern region of Tamaulipas, Mexico were evaluated. The adsorption of non-biodegradable organic matter measured as chemical oxygen demand (COD), color and heavy metals from leachate on activated carbon (AC) prepared in acid media from Guadua amplexifolia bamboo has been studied. In addition, the computation of kinetic parameters during the adsorption process as well as the most probable mechanisms was determined. The ACs were analyzed by using scanning electron microscopy and Fourier transform infrared spectroscopy. The experimental data showed that the ACs removed up to 81.4% of color and reduced COD up to 91.6% after 9 h of reaction at 60 degrees C. For heavy metals, the maximum adsorption uptake was achieved at pH = 8.0 within 20 min with removal percentages of 87.0% (Pb(II)), 43.0% (Cu(II)) and 30.5% (Ni(II)). A pseudo-second order model explained the adsorption kinetics most effectively for Pb, Ni and Cu, while a pseudo-first order was found for Zn. The AC synthesized from the G. amplexifolia species could be potentially used as an effective adsorbent in the reduction of COD, and removal of color and heavy metals. PMID- 29157150 TI - Assessment of urinary protein composition in response to consecutive days of wildland firefighting. AB - The purpose of this study was to examine the pattern of urinary protein excretion induced by 3 consecutive days of wildland firefighting. Eighteen male active-duty military personnel served as the participants. All testing on the 3 consecutive days was conducted at a Northwestern USA fire camp. All participants consumed military-based foods containing 2620-2864 kcal/day. The work activity was evaluated with an accelerometer in association with body weight and hydration markers over the experimental period. Urinary samples were collected pre and post workshift on days 1 and 3 to assess glomerular and tubular protein excretion (total protein, albumin, beta2-microglobulin, N-acetyl-beta-d-glucosaminidase and creatinine). The urinary levels of glomerular and tubular protein were not significantly different. The main findings of the present study indicate that similar alterations of urinary protein composition can be observed over consecutive days of wildland firefighting, which appears to be dependent on intensity rather than total work output. PMID- 29157151 TI - Health benefits of hard martial arts in adults: a systematic review. AB - Participation in organized sports is promoted as a means of increasing physical activity levels and reducing chronic disease risk in adults. Hard martial arts practice (i.e. using body contact techniques), has gained in popularity over time. This review explores the evidence for health benefits of "hard" martial arts practice within the adult population. A systematic electronic database search was conducted, and quality assessments applied the Effective Public Health Practice Project tool. Twenty-eight studies met the inclusion criteria, examining balance, cognitive function, muscular skeletal status, psychological, cardiovascular fitness, and metabolic effects. The majority of studies reported positive effects resulting from hard martial arts practice, showing some improvement and maintenance of balance, cognitive function and psychological health. Benefits may be obtained regardless of the age of practice commencement. However, quality of the evidence is affected by methodological weaknesses across the studies. "Hard" martial arts seem to have potential to improve balance and cognitive functions that decline with age, which can lead to poorer health outcomes among the elderly (e.g. cognitive decline, falls and fractures). Benefits should be further investigated with improved intervention studies, representative samples and longer follow-up periods in order to establish associations with morbidity and mortality in the long term. PMID- 29157152 TI - The compositional isotemporal substitution model: A method for estimating changes in a health outcome for reallocation of time between sleep, physical activity and sedentary behaviour. AB - How people use their time has been linked with their health. For example, spending more time being physically active is known to be beneficial for health, whereas long durations of sitting have been associated with unfavourable health outcomes. Accordingly, public health messages have advocated swapping strategies to promote the reallocation of time between parts of the time-use composition, such as "Move More, Sit Less", with the aim of achieving optimal distribution of time for health. However, the majority of research underpinning these public health messages has not considered daily time use as a composition, and has ignored the relative nature of time-use data. We present a way of applying compositional data analysis to estimate change in a health outcome when fixed durations of time are reallocated from one part of a particular time-use composition to another, while the remaining parts are kept constant, based on a multiple linear regression model on isometric log ratio coordinates. In an example, we examine the expected differences in Body Mass Index z-scores for reallocations of time between sleep, physical activity and sedentary behaviour. PMID- 29157153 TI - Evaluation of industrial by-products and natural minerals for phosphate adsorption from subsurface drainage. AB - Agricultural subsurface drainage has been recognized as an important pathway for phosphorus transport from soils to surface waters. Reactive permeable filters are a promising technology to remove phosphate from subsurface drainage. Three natural minerals (limestone, zeolite, and calcite) and five industrial by products (steel slag, iron filings, and three recycled steel by-products) were evaluated for phosphate removal from subsurface drainage using batch adsorption experiments. Phosphate adsorption onto these materials was characterized by Langmuir isotherm and second-order kinetic models. The adsorption capacities increased by factors of 1.2-2.5 when temperature was increased from 5 degrees C to 30 degrees C. Industrial by-products exhibited phosphate adsorption capacities that were one order of magnitude higher than natural minerals. Medium-sized steel chips exhibited high phosphate adsorption capacities (1.64-3.38 mg/g) across different temperatures, pH values, organic matter concentrations, and real drainage water matrixes. The strong chemical bonds between phosphate and steel by products prevented the release of adsorbed phosphate back to the solution. The steel by-product filter can be paired with a woodchip bioreactor for nitrate and phosphate removal. It is suggested that the phosphate filter be connected to a woodchip bioreactor after the startup phase to minimize the impact of dissolved organic matter on phosphate adsorption. The results of this study suggest that the low-cost steel by-products examined could be used as effective adsorption media for phosphate removal from subsurface drainage. PMID- 29157154 TI - Risk assessments using the Strain Index and the TLV for HAL, Part II: Multi-task jobs and prevalence of CTS. AB - The Strain Index (SI) and the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value for hand activity level (TLV for HAL) have been shown to be associated with prevalence of distal upper-limb musculoskeletal disorders such as carpal tunnel syndrome (CTS). The SI and TLV for HAL disagree on more than half of task exposure classifications. Similarly, time-weighted average (TWA), peak, and typical exposure techniques used to quantity physical exposure from multi-task jobs have shown between-technique agreement ranging from 61% to 93%, depending upon whether the SI or TLV for HAL model was used. This study compared exposure-response relationships between each model-technique combination and prevalence of CTS. Physical exposure data from 1,834 workers (710 with multi-task jobs) were analyzed using the SI and TLV for HAL and the TWA, typical, and peak multi-task job exposure techniques. Additionally, exposure classifications from the SI and TLV for HAL were combined into a single measure and evaluated. Prevalent CTS cases were identified using symptoms and nerve-conduction studies. Mixed effects logistic regression was used to quantify exposure-response relationships between categorized (i.e., low, medium, and high) physical exposure and CTS prevalence for all model-technique combinations, and for multi-task workers, mono-task workers, and all workers combined. Except for TWA TLV for HAL, all model-technique combinations showed monotonic increases in risk of CTS with increased physical exposure. The combined models approach showed stronger association than the SI or TLV for HAL for multi task workers. Despite differences in exposure classifications, nearly all model technique combinations showed exposure-response relationships with prevalence of CTS for the combined sample of mono-task and multi-task workers. Both the TLV for HAL and the SI, with the TWA or typical techniques, appear useful for epidemiological studies and surveillance. However, the utility of TWA, typical, and peak techniques for job design and intervention is dubious. PMID- 29157155 TI - Work environment and occupational risk assessment for small animal Portuguese veterinary activities. AB - The professional work of small animal veterinary staff encompasses a wide diversity of demanding tasks. This has prompted a number of studies covering physical, chemical, biological, ergonomic, or psychological hazards, as well as their health effects upon veterinary workers. However, such results were obtained from self-reported surveys (via paper or online). This study reports the identification of potential hazards and provides a risk assessment of 15 veterinary clinics based on data from walk-through surveys, interviews with workers, and quantification of indoor air quality parameters including concentration of volatile organic compounds (total, isoflurane, and glutaraldehyde). The risk arising from X-ray exposure was unacceptable in seven clinics; X-ray examination should be discontinued in the absence of isolated radiation rooms, poor safety practices, and lack of personal protective equipment. Ergonomic-related hazards and work practices should be revised as soon as possible, considering that improper postures, as well as moving and lifting heavy animals are major causes of musculoskeletal disorders. The risk levels were, in general, small or medium (acceptable) with regard to exposure to physical hazards (such as bites, scratches, cuts, and burns) and biological hazards. It was observed that the indoor air quality parameters including temperature, respirable particulate matter and total volatile organic compounds do not indicate a comfortable workplace environment, requiring clinics' attention to keep the safe environment. The veterinarians and nurses were exposed to isoflurane (above 2 ppm) during surgery if an extractor system for waste gas was used instead of a scavenging system. Finally, veterinary workers did not possess any type of training on occupational safety and health issues, even though they recognized its importance. PMID- 29157157 TI - Thank you to our referees. PMID- 29157156 TI - Editorial. PMID- 29157158 TI - Call for papers for a SPECIAL ISSUE in Palliative Medicine concerned with Haematology and Palliative Care. PMID- 29157159 TI - Quantitative weight of evidence assessment of risk to honeybee colonies from use of imidacloprid, clothianidin, and thiamethoxam as seed treatments: a postscript. AB - This paper is a postscript to the four companion papers in this issue of the Journal (Solomon and Stephenson 2017a , 2017b ; Stephenson and Solomon 2017a , 2017b ). The first paper in the series described the conceptual model and the methods of the QWoE process. The other three papers described the application of the QWoE process to studies on imidacloprid (IMI), clothianidin (CTD), and thiamethoxam (TMX). This postscript was written to summarize the utility of the methods used in the quantitative weight of evidence (QWoE), the overall relevance of the results, and the environmental implications of the findings. Hopefully, this will be helpful to others who wish to conduct QWoEs and use these methods in assessment of risks. PMID- 29157160 TI - Quantitative weight of evidence assessment of higher tier studies on the toxicity and risks of neonicotinoids in honeybees. 4. Thiamethoxam. AB - A quantitative weight of evidence (QWoE) methodology was used to assess several higher-tier studies on the effects of thiamethoxam (TMX) on honeybees. Assessment endpoints were population size and viability of commercially managed honeybee colonies and quantity of hive products. A higher-tier field toxicology study indicated a no-observed-adverse effect concentration (NOAEC) of 29.5 ug TMX/kg syrup, equivalent to an oral no-observed-adverse-effect-dose (NOAED) of 8.6 ng/bee/day for all responses measured. For exposures via deposition of dust, a conservative no-observed-adverse-effect-rate at the level of the colony was 0.1 g TMX/ha. There was minimal risk to honeybees from exposure to TMX via nectar and pollen from its use as a seed-treatment. For exposures via dust and dust/seed applications, there were no concentrations above the risk values for TMX in nectar and pollen. Although some risks were identified for potential exposures via guttation fluid, this route of exposure is incomplete; no apparent adverse effects were observed in field studies. For exposures via dust/seed and dust/foliar applications, few adverse effects were observed. Considering all lines of evidence, the quality of the studies included in this analysis was variable. However, the results of the studies were consistent and point to the same conclusion. The overall weight of evidence based on many studies indicates that TMX has no adverse effects on viability or survival of the colony. Thus, the overall conclusion is that the treatment of seeds with thiamethoxam, as currently used in good agricultural practices, does not present a significant risk to honeybees at the level of the colony. PMID- 29157161 TI - Modulation of hepcidin expression by normal control and beta0-thalassemia/Hb E erythroblasts. AB - OBJECTIVES: The inherited genetic disorder beta0-thalassemia/Hb E disease is associated with the over-suppression of the master regulator of iron homeostasis, the peptide hormone hepcidin. How developing erythroid cells mediate the suppression of hepcidin remains controversial, although a number of inhibitors have been proposed. METHODS: To investigate the ability of erythroid cells to suppress hepcidin expression in liver cells, conditioned media from the culture of in vitro differentiating erythroblasts (from normal controls and beta0 thalassemia/Hb E patients) was used to treat HepG2 cells, and the effects on hepcidin expression were assayed by real-time quantitative PCR and confocal microscopy. RESULTS: Early activation followed by later suppression of hepcidin expression was seen posttreatment. Markedly, however, no significant differences were observed between suppression of hepcidin as mediated by media from the culture of erythroblasts from normal controls and beta0-thalassemia/Hb E patients Discussion: Previous studies investigating the suppression of hepcidin expression in beta0-thalassemia/Hb E disease have used patient-derived serum samples, which are complex fluids with contributions from multiple cell types. This study has developed a simple in vitro system that allows investigation of how a single cell type mediates hepcidin expression. The results support proposals that over suppression of hepcidin seen in beta-thalassemia/Hb E patients is a consequence of the increased mass of erythropoiesis and not defects in the signaling process per se. CONCLUSION: The in vitro cell system developed here allows further investigation into the processes mediating erythroid cell suppression of liver hepcidin expression in both normal and pathological states. PMID- 29157162 TI - Discrete stochastic analogs of Erlang epidemic models. AB - Erlang differential equation models of epidemic processes provide more realistic disease-class transition dynamics from susceptible (S) to exposed (E) to infectious (I) and removed (R) categories than the ubiquitous SEIR model. The latter is itself is at one end of the spectrum of Erlang SE[Formula: see text]I[Formula: see text]R models with [Formula: see text] concatenated E compartments and [Formula: see text] concatenated I compartments. Discrete-time models, however, are computationally much simpler to simulate and fit to epidemic outbreak data than continuous-time differential equations, and are also much more readily extended to include demographic and other types of stochasticity. Here we formulate discrete-time deterministic analogs of the Erlang models, and their stochastic extension, based on a time-to-go distributional principle. Depending on which distributions are used (e.g. discretized Erlang, Gamma, Beta, or Uniform distributions), we demonstrate that our formulation represents both a discretization of Erlang epidemic models and generalizations thereof. We consider the challenges of fitting SE[Formula: see text]I[Formula: see text]R models and our discrete-time analog to data (the recent outbreak of Ebola in Liberia). We demonstrate that the latter performs much better than the former; although confining fits to strict SEIR formulations reduces the numerical challenges, but sacrifices best-fit likelihood scores by at least 7%. PMID- 29157163 TI - Taking risks for personal gain: An investigation of self-construal and testosterone responses to competition. AB - Recent research on testosterone and risk-taking behavior is beginning to focus on the role of context-dependent changes in testosterone. Extending this research, our study investigated the association between testosterone reactivity to competitive outcomes and risk-taking in the context of a video game based competition. The study also examined whether self-construal moderated this relationship. Results indicated that a rise in testosterone during competition did not predict subsequent risk-taking behavior. However, a rise in testosterone during competition predicted subsequent risk-taking behaviors within winners with independent self-construals. Nevertheless, results did not reveal an association between basal testosterone and risk-taking, nor did competitive outcomes modulate a differential testosterone response. Overall, we treat these findings as preliminary, as there were multiple analyses conducted and effect sizes were relatively small. We discuss these results in the context of recent animal findings that testosterone facilitates success at future competitions after winning a competition, as well as recent research suggesting self-construal moderates associations between testosterone and aggression. PMID- 29157164 TI - Concentrations and number size distribution of fine and nanoparticles in a traditional Finnish bakery. AB - In bakeries, high concentrations of flour dust can exist and ovens release particles into the air as well. Particle concentrations (mass, number) and number size distribution may vary considerably but the variation is not commonly studied. Furthermore, the role of the smallest size fractions is rarely considered in the exposure assessment due to their small mass. The objectives of this work were to find out how concentrations and number size distribution of fine and nanoparticles vary in a traditional Finnish bakery and to determine the exposure of a dough maker to the nanoparticle fraction of the inhalable dust. Two measurement campaigns were carried out in a traditional, small-scale bakery. Sampling was performed at the breathing zone of the dough maker and three stationary locations: baking area, oven area, and flour depository. Both real time measurements and conventional gravimetric sampling were conducted. Nanoparticle fraction of the inhalable dust was determined using an IOM sampler with a customized precyclone. Number concentration of fine and nanoparticles, and mass concentrations of both the inhalable dust and nanoparticles were high. The nanoparticle fraction was 9-15% of the inhalable dust at the breathing zone of the dough maker. Different sources, such as ovens and doughnut baking affected the number size distribution. Flour dust contained nanoparticles but most of the fine and nanoparticles were released into the air from the oven operations. However, nanoparticles are not a primary concern in bakeries compared to health effects linked to the large flour particles such as flour-induced sensitization or asthma and development of occupational rhinitis. PMID- 29157165 TI - Successful cochlear implantation in Langerhans cell histiocytosis: A rare case. AB - An 8-year-old girl presented with a 1-year history of bilateral progressive hearing loss and vertigo for 6 months. High-resolution computed tomography of the temporal bones demonstrated multiple lytic lesions. Histopathology examination confirmed a diagnosis of Langerhans cell histiocytosis (LCH). She underwent chemotherapy for 12 months. Following treatment, she was in remission. However, the bilateral profound sensorineural hearing loss persisted. She underwent right cochlear implantation with very good functional audiological outcomes. This is the first known reported case of successful auditory rehabilitation through cochlear implantation in a patient with bilateral profound hearing loss due to isolated bilateral temporal bone LCH. PMID- 29157166 TI - Sub-chronic boldine treatment exerts anticonvulsant effects in mice. AB - OBJECTIVES: Boldine is an aporphine alkaloid which is best known for its antioxidant, anti-inflammatory and cytoprotective characteristics. It seems that all these activities are related to boldine ability to scavenge reactive free radicals. As indicated by several pieces of evidence, free radicals generation are involved in initiation and propagation of epilepsy. METHODS: In this study, we investigated the sub-chronic effects of boldine on intraperitoneal and intravenous pentylenetetrazole (PTZ) models and electroshock-induced seizure in mice. Mice in treatment groups received different doses of boldine (once in a day for 8 days, ip.) and control group received solvent. We also evaluated the role of antioxidant activity of boldine as a part of its anti-seizure activity. RESULTS: The results demonstrated that sub-chronic administration of boldine increased time latencies to the onset of myoclonic and clonic seizure induced by intraperitoneal PTZ model and increased clonic seizure threshold in intravenous PTZ model. It also decreased tonic hind limb extension duration in the electroshock-induced seizure model. Co-administration of boldine with a non effective dose of vitamin C induced the anticonvulsant activity of vitamin C. Superoxide dismutase (SOD) activity in the brain tissue of animals was increased following sub-chronic administration of boldine which all indicated antioxidant activity of boldine may be a part of its anticonvulsant activity. DISCUSSION: The anticonvulsant effects of boldine in three different animal models of epilepsy have been indicated. We have also shown that the antioxidant role of boldine might be a part of its anticonvulsant effect. PMID- 29157167 TI - betaS globin gene haplotype and the stroke risk among Egyptian children with sickle cell disease. AB - BACKGROUND AND AIM OF WORK: Sickle cell disease (SCD) is an inherited disease of the beta globin gene. The betaS globin gene haplotypes are Senegal, Benin, Bantu, Cameroon, Arab-Indian and atypical haplotypes. In SCD, stroke is a life threatening event in both adults and children. In light of paucity of studies on betaS globin gene haplotypes in Egypt, we aimed to determine betaS globin gene haplotypes in children with SCD and study their impact on stroke risk. METHODS: Fifty-two SCD patients were included in the study, they were 26 males and 26 females with age range from 3 to 18 years old. The PCR-RFLP technique was used for the determination of betaS globin gene haplotypes. Transcranial Doppler (TCD) was done to identify patients at risk of stroke. RESULTS: Benin/Benin was the most prevalent haplotype detected in 50% followed by Benin/Bantu in 30.8% of studied patients. TCD study showed that 14/52 (26.9%) patients had abnormally high TCD flow velocities (TCD velocities >=170 cm/s) and thus considered high stroke risk group, whereas 38/52 (73.1%) patients had TCD flow velocities <170 cm/s and are considered low stroke risk group. Stroke risk was not found to be associated with betaS globin gene haplotype (p = .532). CONCLUSION: This study provides a relevant contribution to our understanding of the anthropological and historical background of the population in Egypt where Benin haplotype is the commonest betaS globin gene haplotype and homozygous Benin/Benin is associated with higher stroke risk than other haplotypes. PMID- 29157168 TI - Burkitt non-Hodgkin lymphoma presenting with mental neuropathy ('numb chin' syndrome) in an HIV-positive patient. AB - Mental nerve neuropathy is usually due to local trauma or dental causes, but may be a manifestation of malignancy. A patient with virologically controlled human immunodeficiency virus (HIV) infection presented with a 'numb chin' on the background of long-standing night sweats, malaise and weight loss, worsening respiratory symptoms, and lymphadenopathy. Burkitt non-Hodgkin lymphoma was diagnosed from histology of a lymph node. Imaging (magnetic resonance imaging and 18fluorodeoxyglucose [FDG]-positron emission tomography-computed tomography [PET CT]) showed abnormal intracranial enhancement of the right mandibular nerve and extensive 18FDG-avid lymphadenopathy above and below the diaphragm, focal lesions in the spleen and within the right mandible. The patient received chemotherapy and remains in clinical and radiological remission seven years later. This case highlights the need for clinicians to maintain a high index of suspicion for underlying malignancy when an HIV-infected patient presents with new onset of a 'numb chin'. Additionally, it demonstrates the importance of functional 18FDG-PET CT and neuroimaging in order to identify site(s) of pathology. PMID- 29157169 TI - Long-term persistence of human papillomavirus in the skin of the glans penis of elderly men above 80 years of age. AB - Investigations of human papillomavirus (HPV) in the glans penis are scarce, especially with regard to its natural history. To elucidate HPV prevalence among Japanese men attending urological clinics, 798 adult participants were recruited consecutively and stratified into groups by age based on 10-year intervals. The overall HPV prevalence among the participants was 24.8%, with 15.5% positive for high-risk HPV and 9.3% infected with other HPVs. The HPV positivity rate was sustained in those over 80 years of age at nearly the same level as those in the younger age groups. We also determined the age at last sexual intercourse of 15 HPV-positive participants in the 80+ years age group. In addition, six participants positive for HPV were re-examined for HPV and all showed nearly the same HPV types as those identified in their first examinations. The difference between the age at the first test and the age of last intercourse was 8.3 +/- 6.2 years. Except for the elderly group who reported sexual intercourse within the previous year, the duration was 10.0 +/- 5.1 years. Our data suggest an HPV persistence of at least eight years. Further investigation is necessary to elucidate the long-term persistence of HPV infection in the glans penis. PMID- 29157170 TI - Attitudes to, and experience of, pooled sampling for sexually transmitted infection testing: a web-based survey of English sexual health services. AB - Chlamydia trachomatis and Neisseria gonorrhoeae testing guidance recommends extragenital screening with locally validated nucleic acid amplification tests, with anatomical sites tested separately. Evidence supports multi-patient combined aliquot pooled sampling (PS) for population screening; evidence for within patient PS is sparse. Within-patient PS could be more cost-effective for triple site testing, but requires distinct clinical pathways and consideration over loss of information to guide risk assessments and treatment. We explored PS attitudes and practices amongst clinicians in England. A cross-sectional web-based survey was distributed to clinical leads of sexual health services throughout England in February 2016. Fifty-two (52/216, 23%) services responded. One service reported current within-patient PS and two were awaiting implementation. Of the 49 services not pooling, five were considering implementation. Concerns raised included the inability to distinguish infection site(s) (36/52, 69%), absence of national guidance (34/52, 65%) and reduced assay performance (18/52, 34%). Only 8/52 (15%) considered the current level of evidence sufficient to support PS, with 40/52 (77%) requesting further validation studies and 39/52 (77%) national guidance. PS was rarely used by respondents to this survey, although the response rate was low. The clinical challenges presented by PS need to be addressed through further development of the evidence base. PMID- 29157171 TI - Effect of changes in periodic limb movements under cpap on adherence and long term compliance in obstructive sleep apnea. AB - Purpose of the study Periodic leg movements (PLMs) are found in 30% of patients suffering from OSA. Under CPAP, we observed that PLMs can increase, decrease, or remain unchanged. The predictors of these changes are not well established. Objective To determine the predictors of PLMs change under CPAP and its impact on long-term adherence. Materials and method The patients were referred to the sleep laboratory for snoring or sleepiness. A single PSG night has been performed before and after CPAP treatment. Data on medication used, comorbidities and ferritin level were collected. Results A total of 160 patients were recruited with a severe OSA. About 32.5% (52/160) patients had emerging PLM i.e. that appeared after the disappearance of respiratory events. By comparing patients with emerging-PLMs to others, we found that only the blood ferritin level was significantly different between groups. Moreover, after one-year follow-up, a significant difference in adherence and long-term compliance was observed between patients without PLM at both screening and CPAP polysomnographies or emerging PLM at the second study (56%) vs. patients with baseline PLM, whether PLM remained stable or decreased under CPAP treatment (75%) (p-value 0.028). Serum ferritin and presence of diabetes mellitus predicted the evolution of PLM observed. Patients with low ferritin levels demonstrated an increase of PLM after initiation of nasal CPAP treatment. Conclusion The emergence of PLM negatively impacts long-term adherence to nasal CPAP treatment in OSA. Blood ferritin level is a predictor of the evolution of PLM under CPAP therapy. PMID- 29157174 TI - Erratum. PMID- 29157173 TI - Culiseta annulata - just a biting nuisance or a deadly foe? PMID- 29157175 TI - Interlaboratory comparison for the determination of the soluble fraction of metals in welding fume samples. AB - There is interest in the bioaccessible metal components of aerosols, but this has been minimally studied because standardized sampling and analytical methods have not yet been developed. An interlaboratory study (ILS) has been carried out to evaluate a method for determining the water-soluble component of realistic welding fume (WF) air samples. Replicate samples were generated in the laboratory and distributed to participating laboratories to be analyzed according to a standardized procedure. Within-laboratory precision of replicate sample analysis (repeatability) was very good. Reproducibility between laboratories was not as good, but within limits of acceptability for the analysis of typical aerosol samples. These results can be used to support the development of a standardized test method. PMID- 29157177 TI - Critical and systematic evaluation of data for estimating human exposures to 2,4 dichlorophenoxyacetic acid (2,4-D) - quality and generalizability. AB - The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) has been commercially available since the 1940's. Despite decades of data on 2,4-D in food, air, soil, and water, as well as in humans, the quality the quality of these data has not been comprehensively evaluated. Using selected elements of the Biomonitoring, Environmental Epidemiology, and Short-lived Chemicals (BEES-C) instrument (temporal variability, avoidance of sample contamination, analyte stability, and urinary methods of matrix adjustment), the quality of 156 publications of environmental- and biomonitoring-based 2,4-D data was examined. Few publications documented steps were taken to avoid sample contamination. Similarly, most studies did not demonstrate the stability of the analyte from sample collection to analysis. Less than half of the biomonitoring publications reported both creatinine-adjusted and unadjusted urine concentrations. The scope and detail of data needed to assess temporal variability and sources of 2,4-D varied widely across the reviewed studies. Exposures to short-lived chemicals such as 2,4-D are impacted by numerous and changing external factors including application practices and formulations. At a minimum, greater transparency in reporting of quality control measures is needed. Perhaps the greatest challenge for the exposure community is the ability to reach consensus on how to address problems specific to short-lived chemical exposures in observational epidemiology investigations. More extensive conversations are needed to advance our understanding of human exposures and enable interpretation of these data to catch up to analytical capabilities. The problems defined in this review remain exquisitely difficult to address for chemicals like 2,4-D, with short and variable environmental and physiological half-lives and with exposures impacted by numerous and changing external factors. PMID- 29157178 TI - Compliance and persistence with hydroxychloroquine in South Korean patients with systemic lupus erythematosus. AB - We aimed to analyze compliance and persistence with hydroxychloroquine (HCQ) in real practice and identify risk factors for poor adherence in South Korean patients with systemic lupus erythematosus (SLE). This retrospective longitudinal study evaluated 235 SLE patients in whom oral HCQ was newly started from 2002 to 2016 at a tertiary hospital in South Korea. Compliance was assessed using one year medication possession ratio (MPR) and non-compliance was defined as a one year MPR < 0.8. Persistence was determined as the time from HCQ treatment initiation to discontinuation without interruption for >=56 days. The mean one year MPR of HCQ was 0.88 and the frequency of non-compliance was 19.9%. During the study period, 115 (48.9%) patients discontinued HCQ and forgetfulness and/or carelessness (73%) were the most common reason for HCQ non-persistence, followed by adverse events (10.4%), unknown factors (10.4%), and pregnancy (6.1%). Median duration until HCQ discontinuation was 55.1 months and the one-year persistence rate to HCQ was 0.8. SLE Disease Activity Index 2000 (SLEDAI-2K) < 6 was a significant risk factor for non-compliance (OR = 2.98, p = 0.001) and non persistence (HR = 1.55, p = 0.046) with HCQ after adjusting confounding factors. However, HCQ adherence was not associated with the dose of HCQ or concomitant immunosuppressive medications. Our data showed that overall adherence to HCQ in SLE patients was suboptimal in real practice and SLEDAI-2K score < 6 was a risk factor for poor adherence, suggesting the need to improve adherence with HCQ treatment in SLE patients, especially in those with low disease activity. PMID- 29157176 TI - Separation of cell survival, growth, migration, and mesenchymal transdifferentiation effects of fibroblast secretome on tumor cells of head and neck squamous cell carcinoma. AB - Fibroblasts play a central role in tumor invasion, recurrence, and metastasis in head and neck squamous cell carcinoma. The aim of this study was to investigate the influence of tumor cell self-produced factors and paracrine fibroblast secreted factors in comparison to indirect co-culture on cancer cell survival, growth, migration, and epithelial-mesenchymal transition using the cell lines SCC 25 and human gingival fibroblasts. Thereby, we particularly focused on the participation of the fibroblast-secreted transforming growth factor beta-1.Tumor cell self-produced factors were sufficient to ensure tumor cell survival and basic cell growth, but fibroblast-secreted paracrine factors significantly increased cell proliferation, migration, and epithelial-mesenchymal transition related phenotype changes in tumor cells. Transforming growth factor beta-1 generated individually migrating disseminating tumor cell groups or single cells separated from the tumor cell nest, which were characterized by reduced E cadherin expression. At the same time, transforming growth factor beta-1 inhibited tumor cell proliferation under serum-starved conditions. Neutralizing transforming growth factor beta antibody reduced the cell migration support of fibroblast-conditioned medium. Transforming growth factor beta-1 as a single factor was sufficient for generation of disseminating tumor cells from epithelial tumor cell nests, while other fibroblast paracrine factors supported tumor nest outgrowth. Different fibroblast-released factors might support tumor cell proliferation and invasion, as two separate effects. PMID- 29157179 TI - Association between false-positive TORCH and antiphospholipid antibodies in healthy pregnant women. AB - The present study investigated: (a) the presence of antiphospholipid antibodies and (b) the obstetric outcome in healthy pregnant women showing false-positive TORCH-Toxoplasmosis, Other: syphilis, varicella-zoster, Rubella, Cytomegalovirus (CMV), and Herpes infections-results. Data from 23 singleton healthy pregnancies with false-positive TORCH results were collected. Each woman was systematically screened for TORCH IgG and IgM during the pre-conception assessment and/or at the beginning of pregnancy. In the presence of IgM positivity, when indicated (CMV, toxoplasmosis, rubella, herpes simplex virus), IgG avidity was evaluated and, if possible, polymerase chain reaction was performed on an amniotic fluid sample in order to distinguish between primary infection or false positivity. The antiphospholipid antibodies tests were: lupus anticoagulant, anticardiolipin antibodies IgG, IgM, and anti-beta2glicoprotein I IgG, IgM. The antiphospholipid antibodies tests, if positive, were repeated after 12 weeks to confirm the results. In pregnant women with false-positive TORCH, the overall prevalence of positive antiphospholipid antibodies for one or more tests was 52.2%. To clarify the correlation of false-positive TORCH results with clinical practice, obstetric outcome was analyzed in terms of live births, week of delivery, neonatal birth weight, and neonatal birth weight percentile. A statistically significant lower neonatal birth weight and neonatal birth weight percentile were observed in women with false-positive TORCH associated with antiphospholipid antibodies positivity (Group A) in comparison with those in women with false-positive TORCH without antiphospholipid antibodies positivity (Group B). No statistically significant difference was found for the week of delivery between the two groups. It is hoped that future studies will verify the life-long persistence of antiphospholipid antibodies positivity by follow-up of these women and identify who will develop a classical antiphospholipid syndrome or other autoimmune disorders. PMID- 29157180 TI - Voiding stimulation methods for collecting urine from young pre-continent children. PMID- 29157181 TI - Self-reported assistive technology outcomes and personal characteristics in college students with less-apparent disabilities. AB - The impact of assistive technology (AT) services for college students with less apparent disabilities is under-reported. Using the Canadian Occupational Performance Measure (COPM), we assessed student Performance and Satisfaction ratings of common academic tasks at the start and end of a semester during which 105 student-clients with less-apparent disabilities received AT services. We examined if COPM scores related to personal characteristics of gender, class level (e.g., Sophomore), and STEM education; if personal characteristics predicted a student's follow-through with an AT service referral (n=231); and if personal characteristics and initial COPM scores predicted dropout from AT services (n=187). COPM ratings significantly increased in all academic tasks (p<.001). Gender predicted initial Satisfaction (male ratings > female ratings; p=.01), and Performance changes (females were more likely to have a service meaningful change; p=.02). Higher class-level predicted better follow-through with a referral for AT services (p=.006). Increasing class-level (p=.05) and higher initial studying (p<.006) and reading (p<.029) ratings predicted a lower likelihood for dropout. These findings demonstrate that college students with less-apparent disabilities experience substantial improvements in their self ratings of academic performance and satisfaction following AT services. Gender, class-level, and initial self-perceived reading and studying abilities may influence if and how the student participates with AT services. PMID- 29157183 TI - Photobiology eye safety for horticultural LED lighting: Transmittance performance of eyewear protection using high-irradiant monochromatic LEDs. AB - Light emitting diodes have slowly gained market share as horticultural lighting systems in greenhouses due to their rapid improvement in color performances and light outputs. These advancements have increased the availability of the full spectrum of visible wavelengths and the corresponding irradiance outputs available to plants. However, light emitting diodes owners have limited information on the proper options for personal eyewear protection as the irradiance levels have increased. The objective of this study was to measure the light transmittance performance of 12 eyewear protection including welding goggles, safety goggles, polarized glasses, and sunglasses across the human visible spectrum (380-740 nm) up to an irradiance level of 1500 W.m-2 from high irradiant light emitting diodes assemblies. Based on the spectral measurements, certain transmitted spectra exhibited spectrum shifts or an alteration in the bimodal distribution which were different than the light emitting diodes spectra, due to the uneven transmittance efficiencies of the glasses. As for the measured transmittance percentages in two experiments, each type of eyewear protection showed distinct transmittance performances, and the performance of the tested eyewear protection was not impacted by irradiance but was dependent on the wavelength. The mean light transmittance was 1.77% for the welding glasses, 13.12% for the polarized glasses, 15.27% for the safety goggles, and 27.65% for the sunglasses. According to these measured results and the spectral weighting exposure limits from the International Electrotechnical Commission 62471 and EU directive 2006/25, consumers and workers using horticultural lighting can select welding goggles or polarized glasses, to limit the possible ocular impact of the high irradiance of monochromatic light in electrical lighting environment. Sunglasses and safety goggles would not be advised as protection, especially if infrared radiation was used. PMID- 29157182 TI - Do surveys with paper and electronic devices differ in quality and cost? Experience from the Rufiji Health and demographic surveillance system in Tanzania. AB - BACKGROUND: Data entry at the point of collection using mobile electronic devices may make data-handling processes more efficient and cost-effective, but there is little literature to document and quantify gains, especially for longitudinal surveillance systems. OBJECTIVE: To examine the potential of mobile electronic devices compared with paper-based tools in health data collection. METHODS: Using data from 961 households from the Rufiji Household and Demographic Survey in Tanzania, the quality and costs of data collected on paper forms and electronic devices were compared. We also documented, using qualitative approaches, field workers, whom we called 'enumerators', and households' members on the use of both methods. Existing administrative records were combined with logistics expenditure measured directly from comparison households to approximate annual costs per 1,000 households surveyed. RESULTS: Errors were detected in 17% (166) of households for the paper records and 2% (15) for the electronic records (p < 0.001). There were differences in the types of errors (p = 0.03). Of the errors occurring, a higher proportion were due to accuracy in paper surveys (79%, 95% CI: 72%, 86%) compared with electronic surveys (58%, 95% CI: 29%, 87%). Errors in electronic surveys were more likely to be related to completeness (32%, 95% CI 12%, 56%) than in paper surveys (11%, 95% CI: 7%, 17%).The median duration of the interviews ('enumeration'), per household was 9.4 minutes (90% central range 6.4, 12.2) for paper and 8.3 (6.1, 12.0) for electronic surveys (p = 0.001). Surveys using electronic tools, compared with paper-based tools, were less costly by 28% for recurrent and 19% for total costs. Although there were technical problems with electronic devices, there was good acceptance of both methods by enumerators and members of the community. CONCLUSIONS: Our findings support the use of mobile electronic devices for large-scale longitudinal surveys in resource-limited settings. PMID- 29157184 TI - Co-inheritance of HBB:c.-106G > C, a rare single nucleotide variation at position -56 relative to transcription initiation site, with other known mutations in the globin clusters. AB - OBJECTIVES: We performed molecular analysis to evaluate clinical implications of a rare nucleotide change, particularly when co-inherited with other known mutations in the globin clusters, in order to conduct an appropriate genetic counselling. METHODS: Complete blood cell counts and high-performance liquid chromatography were the routine first level analysis for patients referred to our Hospital Center in Palermo to undergo the screening test for haemoglobinopathies. Sequencing analysis was the selected method for the phenotypic characterization, especially in case of new or very rare mutations in globin genes. RESULTS: We report data of a rare single nucleotide variation at position -56 relative to transcription initiation site (NM_000518.4(HBB):c.-106G > C), identified in ten patients of Italian origin during the screening programme of the 'Sicilian population'. It was found in simple heterozygosity (n = 8), in association with beta haemoglobin variant Hb S (n = 1) and in heterozygosity with beta thalassaemic allele IVS-I-1 G->A [(HBB):c.92 + 1G > A] and alphaalphaalpha anti3.7 rearrangement (n = 1). DISCUSSION: Heterozygous subjects for this substitution showed normal haematological and electrophoretic features. Heterozygotes for this mutation and other defect in globin genes showed the classical phenotype of a healthy carrier, therefore it can be considered a benign variant that does not alter the production and function of haemoglobin. CONCLUSION: This is another example of rare or new nucleotide variations whose identification and characterization is crucial in order to carry out appropriate genetic counselling to a potential risk couple. PMID- 29157185 TI - Identification of two new species of Meliolinites associated with Lauraceae leaves from the middle Miocene of Fujian, China. AB - Several studies have investigated both the paleoclimate and the well-preserved fossil remains from the middle Miocene found in China's Fujian Province. This study describes two new species of Meliolinites, including their fungal hyphae, reproductive structures, and spores. The distribution of modern Meliolaceae indicates that they live in warm, humid, subtropical to tropical climates. Moreover, the fossil leaves and the epiphyllous fungal remains, indicate the prevalence of a warm, humid, subtropical to tropical climate in this area during the middle Miocene. In addition, it was observed that the surrounding cells of the fungi found on the uninfected host leaves were normal, whereas the infected host leaves themselves were abnormally dim. These features are a reflection of self-protection, and it can, therefore, be inferred that the host leaves were alive when they were infected. The present study used fossil angiosperm leaves with cuticles obtained from the Fotan sediments from Fujian to investigate not only the taxonomy of the fossils but also to interpret the paleoclimate and paleoecology. PMID- 29157186 TI - A high-caloric diet rich in soy oil alleviates oxidative damage of skeletal muscles induced by dexamethasone in chickens. AB - Objective Glucocorticoids (GCs) can induce oxidative damage in skeletal muscles. The purpose of this study was to demonstrate a high caloric (HC) diet rich in soy oil would change the oxidative stress induced by a GC. Methods The effect of dexamethasone (DEX) and HC diet on oxidative stress in plasma, skeletal muscles (M. pectoralis major, PM; M. biceps femoris, BF), and mitochondria were determined. The biomarkers of oxidative damage and antioxidative enzyme activity were determined. The fatty acid profile of muscles and the activities of complex I and II in mitochondria were measured. Results The results showed that DEX increased the concentrations of oxidative damage markers in plasma, muscles, and mitochondria. The activity of complex I was significantly suppressed by DEX. DEX chickens had higher proportions of polyunsaturated fatty acids and lower proportions of monounsaturated fatty acids in the PM. A HC diet decreased the levels of oxidative damage biomarkers in plasma, muscles, and mitochondria. The interaction between DEX and diet suppressed the activities of complex I and II in HC-chickens. Discussion Oxidative damage in skeletal muscles and mitochondria was the result of GC-induced suppression of the activity of mitochondrial complex I. A HC diet improved the antioxidative capacity and reduced the oxidative damage induced by the GC. PMID- 29157187 TI - Quantitative weight of evidence assessment of higher-tier studies on the toxicity and risks of neonicotinoid insecticides in honeybees 1: Methods. AB - A quantitative weight of evidence (QWoE) methodology was developed and used to assess many higher-tier studies on the effects of three neonicotinoid insecticides: clothianidin (CTD), imidacloprid (IMI), and thiamethoxam (TMX) on honeybees. A general problem formulation, a conceptual model for exposures of honeybees, and an analysis plan were developed. A QWoE methodology was used to characterize the quality of the available studies from the literature and unpublished reports of studies conducted by or for the registrants. These higher tier studies focused on the exposures of honeybees to neonicotinoids via several matrices as measured in the field as well as the effects in experimentally controlled field studies. Reports provided by Bayer Crop Protection and Syngenta Crop Protection and papers from the open literature were assessed in detail, using predefined criteria for quality and relevance to develop scores (on a relative scale of 0-4) to separate the higher-quality from lower-quality studies and those relevant from less-relevant results. The scores from the QWoEs were summarized graphically to illustrate the overall quality of the studies and their relevance. Through mean and standard errors, this method provided graphical and numerical indications of the quality and relevance of the responses observed in the studies and the uncertainty associated with these two metrics. All analyses were conducted transparently and the derivations of the scores were fully documented. The results of these analyses are presented in three companion papers and the QWoE analyses for each insecticide are presented in detailed supplemental information (SI) in these papers. PMID- 29157189 TI - Molecular dynamics of a far positioned SOD1 mutant V14M reveals pathogenic misfolding behavior. AB - Human superoxide dismutase (Cu/Zn SOD1) is a homodimeric enzyme. Mutations in Cu/Zn SOD1 causes a familial form of amyotrophic lateral sclerosis (fALS), and aggregation of mutant SOD1 has been proposed to play a role in neurodegeneration. Though a majority of the mutations are point substitutions, there are a few changes that result in amino acid deletions or truncations of the polypeptide. These pathogenic mutations are scattered throughout the three-dimensional structure of the dimeric enzyme, which creates a puzzling pattern to investigate the molecular determinants of fALS. The most common hypothesis proposed that the misfolding of SOD1 mutants are primarily triggered by decreased affinity for metal ions. However, this hypothesis is challenging, as a significant number of disease-causing mutations are located far away from the metal-binding site and dimer interface. So in the present study, we have investigated the influence of such a far positioned pathogenic mutation, V14M, in altering the stability and folding of the Cu/Zn SOD1. Though the location of Val14 is far positioned, it has a vital role in the stability of SOD1 by preserving its hydrophobic cluster at one end of the beta barrel domain. We have performed MD simulations of the V14M mutant for 80 ns timescale. The results reveal the fact that irrespective of its location, V14M mutation triggers a conformational change that is more similar to that of the metal-deficient holo form and could resemble an intermediate state in the folding reaction which results in protein misfolding and aggregation. PMID- 29157188 TI - Store owners as potential agents of change: energy drinks in the interior of Alaska. AB - Childhood obesity disproportionately impacts disadvantaged communities, including Alaska Native children. In part, lack of access to fresh fruits and vegetables and over consumption of sugar sweetened beverages including energy drinks contribute to excessive weight gain in Alaska Native youth. This commentary reports the possibility of storeowners and workers partnering with community members to limit sales of nutrient-poor energy drinks through point-of-sale counselling in rural communities in the interior of Alaska. This model of intervention may be useful to implement in areas where there are limited health workers or others that can serve as health educators. This study reports preliminary evidence from rural Alaska and from other Arctic communities that store workers may effectively improve community health status by limiting or promoting specific products. Storeowners or workers may be helpful partners in the fight against childhood obesity as they are present at the point of sale of high-risk beverages to Alaska Native youth. PMID- 29157190 TI - Mucopolysaccharidosis Type VI in a Great Dane Caused by a Nonsense Mutation in the ARSB Gene. AB - Mucopolysaccharidoses are inherited metabolic disorders that result from a deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans. Lysosomal glycosaminoglycan accumulation results in cell and organ dysfunction. This study characterized the phenotype and genotype of mucopolysaccharidosis VI in a Great Dane puppy with clinical signs of stunted growth, facial dysmorphia, skeletal deformities, corneal opacities, and increased respiratory sounds. Clinical and pathologic evaluations, urine glycosaminoglycan analyses, lysosomal enzyme assays, and ARSB sequencing were performed. The urine mucopolysaccharide spot test was strongly positive predominantly due to the accumulation of dermatan sulfate. Enzyme assays in leukocytes and tissues indicated a deficiency of arylsulfatase B (ARSB) activity. Histologic examination revealed cytoplasmic vacuoles in many tissues. Analysis of the exonic ARSB DNA sequences from the affected puppy compared to the published canine genome sequence revealed a homozygous nonsense mutation (c.295C>T) in exon 1, replacing glutamine with a premature stop codon (p.Gln99*), predicting no enzyme synthesis. A polymerase chain reaction-based restriction fragment length polymorphism test was established to assist with the clinical diagnosis and breeding of Great Danes. This genotyping test revealed that the clinically healthy parents and some other relatives of the puppy were heterozygous for the mutant allele, but all 200 clinically healthy dogs screened including 15 Great Danes were homozygous for the normal allele. This ARSB mutation is the fourth identified genetic variant causing canine mucopolysaccharidosis VI. Mucopolysaccharidosis VI is the first lysosomal storage disorder described in Great Danes but does not appear to be widespread in this breed. PMID- 29157191 TI - Neuronal Vacuolization in Feline Panleukopenia Virus Infection. AB - Feline panleukopenia virus (FPV) infections are typically associated with anorexia, vomiting, diarrhea, neutropenia, and lymphopenia. In cases of late prenatal or early neonatal infections, cerebellar hypoplasia is reported in kittens. In addition, single cases of encephalitis are described. FPV replication was recently identified in neurons, although it is mainly found in cells with high mitotic activity. A female cat, 2 months old, was submitted to necropsy after it died with neurologic deficits. Besides typical FPV intestinal tract changes, multifocal, randomly distributed intracytoplasmic vacuoles within neurons of the thoracic spinal cord were found histologically. Next-generation sequencing identified FPV-specific sequences within the central nervous system. FPV antigen was detected within central nervous system cells, including the vacuolated neurons, via immunohistochemistry. In situ hybridization confirmed the presence of FPV DNA within the vacuolated neurons. Thus, FPV should be considered a cause for neuronal vacuolization in cats presenting with ataxia. PMID- 29157192 TI - Neonatal and Juvenile Ocular Development in Sprague-Dawley Rats: A Histomorphological and Immunohistochemical Study. AB - As in many altricial species, rats are born with fused eyelids and markedly underdeveloped eyes. While the normal histology of the eyes of mature rats is known, the histomorphological changes occurring during postnatal eye development in this species remain incompletely characterized. This study was conducted to describe the postnatal development of ocular structures in Sprague-Dawley (SD) rats during the first month of age using histology and immunohistochemistry (IHC). Both eyes were collected from 51 SD rats at 13 time points between postnatal day (PND)1 and PND30. Histologic examination of hematoxylin and eosin stained sections was performed, as well as IHC for cleaved-caspase-3 and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) to evaluate apoptosis, and IHC for Ki-67 and phospho-histone-H3 to evaluate cell proliferation. Extensive ocular tissue remodeling occurred prior to the eyelid opening around PND14 and reflected the interplay between apoptosis and cell proliferation. Apoptosis was particularly remarkable in the maturing subcapsular anterior epithelium of the lens, the inner nuclear and ganglion cell layers of the developing retina, and the Harderian gland, and was involved in the regression of the hyaloid vasculature. Nuclear degradation in the newly formed secondary lens fibers was noteworthy after birth and was associated with TUNEL positive nuclear remnants lining the lens organelle-free zone. Cell proliferation was marked in the developing retina, cornea, iris, ciliary body and Harderian gland. The rat eye reached histomorphological maturity at PND21 after a rapid phase of morphological changes characterized by the coexistence of cell death and proliferation. PMID- 29157193 TI - Effect of ventilation velocity on hexavalent chromium and isocyanate exposures in aircraft paint spraying. AB - Exposure control system performance was evaluated during aircraft paint spraying at a military facility. Computational fluid dynamics (CFD) modeling, tracer gas testing, and exposure monitoring examined contaminant exposure vs. crossflow ventilation velocity. CFD modeling using the RNG k-epsilon turbulence model showed exposures to simulated methyl isobutyl ketone of 294 and 83.6 ppm, as a spatial average of five worker locations, for velocities of 0.508 and 0.381 m/s (100 and 75 fpm), respectively. In tracer gas experiments, observed supply/exhaust velocities of 0.706/0.503 m/s (136/99 fpm) were termed full-flow, and reduced velocities were termed 3/4-flow and half-flow. Half-flow showed higher tracer gas concentrations than 3/4-flow, which had the lowest time averaged concentration, with difference in log means significant at the 95% confidence level. Half-flow compared to full-flow and 3/4-flow compared to full flow showed no statistically significant difference. CFD modeling using these ventilation conditions agreed closely with the tracer results for the full-flow and 3/4-flow comparison, yet not for the 3/4-flow and half-flow comparison. Full flow conditions at the painting facility produced a velocity of 0.528 m/s (104 fpm) midway between supply and exhaust locations, with the supply rate of 94.4 m3/s (200,000 cfm) exceeding the exhaust rate of 68.7 m3/s (146,000 cfm). Ventilation modifications to correct this imbalance created a midhangar velocity of 0.406 m/s (80.0 fpm). Personal exposure monitoring for two worker groups sprayers and sprayer helpers ("hosemen")-compared process duration means for the two velocities. Hexavalent chromium (Cr[VI]) exposures were 500 vs. 360 ug/m3 for sprayers and 120 vs. 170 ug/m3 for hosemen, for 0.528 m/s (104 fpm) and 0.406 m/s (80.0 fpm), respectively. Hexamethylene diisocyanate (HDI) monomer means were 32.2 vs. 13.3 ug/m3 for sprayers and 3.99 vs. 8.42 ug/m3 for hosemen. Crossflow velocities affected exposures inconsistently, and local work zone velocities were much lower. Aircraft painting contaminant control is accomplished better with the unidirectional crossflow ventilation presented here than with other observed configurations. Exposure limit exceedances for this ideal condition reinforce continued use of personal protective equipment. PMID- 29157194 TI - Patient involvement in healthcare professional practice - a question about knowledge. AB - The concept of patient involvement is ambiguous and contested in the healthcare systems in Western Europe and North America. Current research indicates that patients only feel moderately involved in their treatment and care. This article builds on a study of chronically ill patients' perspectives on healthcare practice in Greenland. It discusses the significance of including in healthcare practice knowledge of patients' everyday lives with illness and their own views on their situations. Research was qualitative and ethnographic. Participants were followed with participant observations and qualitative interviews for 2.5 years during hospital stay in the capital Nuuk and in their homes in towns and settlements during 2010-2013. Results show that patients are concerned about how to manage their life with illness on a daily basis. Their everyday life activities demonstrate the resources they have to live with illness. However, procedures for healthcare practice concentrate on treatment of the physical disease. Knowledge about psychosocial needs for care and rehabilitation tend to be excluded. The study points to potential for improving professional practice through healthcare professionals' active investigation of patients' everyday lives and values, integration of this knowledge into their professional practice and developing structures for this kind of involvement. PMID- 29157195 TI - Management of transient ischemic attacks diagnosed by early-career general practitioners: A cross-sectional study. AB - Background Transient ischemic attack incurs a risk of recurrent stroke that can be dramatically reduced by urgent guideline-recommended management at the point of first medical contact. Aims This study describes the prevalence and associations of new transient ischemic attack presentations to general practice registrars and the management undertaken. Methods A cross-sectional analysis of the Registrar Clinical Encounters in Training cohort study. General practice registrars from five Australian states (urban to very remote practices) collected data on 60 consecutive patient encounters during each of their three six-month training terms. The proportion of problems managed being new transient ischemic attacks and proportion of transient ischemic attacks with guideline-recommended management were calculated. Univariate and multivariable logistic regression established associations of patient, registrar, and practice factors with a problem being a new transient ischemic attack. Results A total 1331 general practice registrars contributed data (response rate 95.8%). Of the 250,625 problems, there were 65 new transient ischemic attacks diagnosed (0.03% [95% confidence interval: 0.02-0.03%]). General practice registrars were more likely to seek help, generate learning goals, and spend more time for a new transient ischemic attack compared to other problems. Compliance with management guidelines was modest: 15.4% ordered brain and arterial imaging, 36.9% prescribed antiplatelet medication, and 3.1% prescribed antihypertensive medication. Conclusions Transient ischemic attack is a very infrequent presentation for general practice registrars, giving little clinical opportunity to reinforce training program education regarding guideline-recommended management. General practice registrars found transient ischemic attacks challenging and management was not ideal. Since most transient ischemic attacks first present to general practice and urgent management is essential, an enhanced model of care utilizing rapid access to specialist transient ischemic attack support and follow-up could improve guideline compliance. PMID- 29157196 TI - Perinatal outcomes of hypertensive disorders in pregnancy at a tertiary hospital in Ghana. AB - BACKGROUND: Hypertensive disorders in pregnancy remain a major global health issue not only because of the associated high adverse maternal outcomes but there is a close accompaniment of significant perinatal morbidity and mortality especially in Sub-Saharan Africa (SSA). However, the perinatal burden of HDP in Ghana has not been explored. We conducted this study to determine the perinatal outcomes of HDP at a tertiary hospital in Ghana. METHODS: A cross-sectional study conducted between January to February 2013 at Korle Bu Teaching Hospital (KBTH) in Accra, Ghana. Data collection involved baseline review of all the obstetric population who had just delivered to identify those with HDP. An informed consent was obtained after which a structured questionnaire was adminstered to the hypertensive mothers. The medical records of the mothers and their babies were also reviewed to determine the perinatal outcome indicators of relevance to the study. Data obtained were analyzed using SPSS version 20. RESULTS: We included 368 women with HDP and singleton births with a mean gestational age at delivery of 37.4 +/- 3.3 weeks. Adverse perinatal outcomes determined include the following: 91 (24.7%) neonates were admitted to the Neonatal Intensive Care Unit, 56 (15.2%) had neonatal respiratory distress/asphyxia with 14 (3.8%) requiring ventilatory support and 80 (21.7%) were delivered preterm. Also, stillbirth, early neonatal death, intrauterine growth restriction and low birth weight occurred in 25 (6.8%), 14 (3.8%), 23 (6.1%) and 91 (24.7%) respectively with a perinatal mortality rate of 106 per 1000 births. One and 5 minute APGAR scores <7 occurred in 125 (34.0%) and 55 (14.7%) neonates respectively. Most of the adverse perinatal outcomes were significantly more common in those with preeclampsia compared to the other hypertensive disorders. CONCLUSION: There is a significant burden of perinatal morbidity and mortality associated with HDP in the Ghanaian obstetric population and these adverse outcomes were more prevalent in preeclampsia compared to the other hypertensive disorders. Regular goal-oriented clinical audit into perinatal morbidity and mortality associated with HDP and an active multidisciplinary approach to the management of these disorders in the hospital might improve the clinical outcomes of women with maternal hypertension. PMID- 29157197 TI - Selection for female traits of high fertility affects male reproductive performance and alters the testicular transcriptional profile. AB - BACKGROUND: Many genes important for reproductive performance are shared by both sexes. However, fecundity indices are primarily based on female parameters such as litter size. We examined a fertility mouse line (FL2), which has a considerably increased number of offspring and a total litter weight of 180% compared to a randomly bred control line (Ctrl) after more than 170 generations of breeding. In the present study, we investigated whether there might be a parallel evolution in males after more than 40 years of breeding in this outbred mouse model. RESULTS: Males of the fertility mouse line FL2 showed reduced sperm motility performance in a 5 h thermal stress experiment and reduced birth rate in the outbred mouse line. Transcriptional analysis of the FL2 testis showed the differential expression of genes associated with steroid metabolic processes (Cyp1b1, Cyp19a1, Hsd3b6, and Cyp21a1) and female fecundity (Gdf9), accompanied by 150% elevated serum progesterone levels in the FL2 males. Cluster analysis revealed the downregulation of genes of the kallikrein-related peptidases (KLK) cluster located on chromosome 7 in addition to alterations in gene expression with serine peptidase activity, e.g., angiotensinogen (Agt), of the renin angiotensin system essential for ovulation. Although a majority of functional annotations map to female reproduction and ovulation, these genes are differentially expressed in FL2 testis. CONCLUSIONS: These data indicate that selection for primary female traits of increased litter size not only affects sperm characteristics but also manifests as transcriptional alterations of the male side likely with direct long-term consequences for the reproductive performance of the mouse line. PMID- 29157198 TI - Independent impacts of aging on mitochondrial DNA quantity and quality in humans. AB - BACKGROUND: The accumulation of mitochondrial DNA (mtDNA) mutations, and the reduction of mtDNA copy number, both disrupt mitochondrial energetics, and may contribute to aging and age-associated phenotypes. However, there are few genetic and epidemiological studies on the spectra of blood mtDNA heteroplasmies, and the distribution of mtDNA copy numbers in different age groups and their impact on age-related phenotypes. In this work, we used whole-genome sequencing data of isolated peripheral blood mononuclear cells (PBMCs) from the UK10K project to investigate in parallel mtDNA heteroplasmy and copy number in 1511 women, between 17 and 85 years old, recruited in the TwinsUK cohorts. RESULTS: We report a high prevalence of pathogenic mtDNA heteroplasmies in this population. We also find an increase in mtDNA heteroplasmies with age (beta = 0.011, P = 5.77e-6), and showed that, on average, individuals aged 70-years or older had 58.5% more mtDNA heteroplasmies than those under 40-years old. Conversely, mtDNA copy number decreased by an average of 0.4 copies per year (beta = -0.395, P = 0.0097). Multiple regression analyses also showed that age had independent effects on mtDNA copy number decrease and heteroplasmy accumulation. Finally, mtDNA copy number was positively associated with serum bicarbonate level (P = 4.46e-5), and inversely correlated with white blood cell count (P = 0.0006). Moreover, the aggregated heteroplasmy load was associated with blood apolipoprotein B level (P = 1.33e-5), linking the accumulation of mtDNA mutations to age-related physiological markers. CONCLUSIONS: Our population-based study indicates that both mtDNA quality and quantity are influenced by age. An open question for the future is whether interventions that would contribute to maintain optimal mtDNA copy number and prevent the expansion of heteroplasmy could promote healthy aging. PMID- 29157199 TI - Characterization of wheat MYB genes responsive to high temperatures. AB - BACKGROUND: Heat stress is one of the most crucial environmental factors, which reduces crop yield worldwide. In plants, the MYB family is one of the largest families of transcription factors (TFs). Although some wheat stress-related MYB TFs have been characterized, their involvement in response to high-temperature stress has not been properly studied. RESULTS: Six novel heat-induced MYB genes were identified by comparison with previously established de novo transcriptome sequencing data obtained from wheat plants subjected to heat treatment; genomic and complete coding sequences of these genes were isolated. All six TaMYBs were localized in the nucleus of wheat protoplasts. Transactivation assays in yeast revealed that all six proteins acted as transcriptional activators, and the activation domains were attributed to the C-termini of the six wheat MYB proteins. Phylogenetic analysis of the six TaMYBs and R2R3-MYBs from Arabidopsis revealed that all six proteins were in clades that contained stress-related MYB TFs. The expression profiles of TaMYB genes were different in wheat tissues and in response to various abiotic stresses and exogenous abscisic acid treatment. In transgenic Arabidopsis plants carrying TaMYB80 driven by the CaMV 35S promoter, tolerance to heat and drought stresses increased, which could be attributed to the increased levels of cellular abscisic acid. CONCLUSIONS: We identified six heat-induced MYB genes in wheat. We performed comprehensive analyses of the cloned MYB genes and their gene products, including gene structures, subcellular localization, transcriptional activation, phylogenetic relationships, and expression patterns in different wheat tissues and under various abiotic stresses. In particular, we showed that TaMYB80 conferred heat and drought tolerance in transgenic Arabidopsis. These results contribute to our understanding of the functions of heat-induced MYB genes and provide the basis for selecting the best candidates for in-depth functional studies of heat responsive MYB genes in wheat. PMID- 29157200 TI - Swellix: a computational tool to explore RNA conformational space. AB - BACKGROUND: The sequence of nucleotides in an RNA determines the possible base pairs for an RNA fold and thus also determines the overall shape and function of an RNA. The Swellix program presented here combines a helix abstraction with a combinatorial approach to the RNA folding problem in order to compute all possible non-pseudoknotted RNA structures for RNA sequences. The Swellix program builds on the Crumple program and can include experimental constraints on global RNA structures such as the minimum number and lengths of helices from crystallography, cryoelectron microscopy, or in vivo crosslinking and chemical probing methods. RESULTS: The conceptual advance in Swellix is to count helices and generate all possible combinations of helices rather than counting and combining base pairs. Swellix bundles similar helices and includes improvements in memory use and efficient parallelization. Biological applications of Swellix are demonstrated by computing the reduction in conformational space and entropy due to naturally modified nucleotides in tRNA sequences and by motif searches in Human Endogenous Retroviral (HERV) RNA sequences. The Swellix motif search reveals occurrences of protein and drug binding motifs in the HERV RNA ensemble that do not occur in minimum free energy or centroid predicted structures. CONCLUSIONS: Swellix presents significant improvements over Crumple in terms of efficiency and memory use. The efficient parallelization of Swellix enables the computation of sequences as long as 418 nucleotides with sufficient experimental constraints. Thus, Swellix provides a practical alternative to free energy minimization tools when multiple structures, kinetically determined structures, or complex RNA-RNA and RNA-protein interactions are present in an RNA folding problem. PMID- 29157201 TI - Phylogenetic and recombination analysis of the herpesvirus genus varicellovirus. AB - BACKGROUND: The varicelloviruses comprise a genus within the alphaherpesvirus subfamily, and infect both humans and other mammals. Recently, next-generation sequencing has been used to generate genomic sequences of several members of the Varicellovirus genus. Here, currently available varicellovirus genomic sequences were used for phylogenetic, recombination, and genetic distance analysis. RESULTS: A phylogenetic network including genomic sequences of individual species, was generated and suggested a potential restriction between the ungulate and non-ungulate viruses. Intraspecies genetic distances were higher in the ungulate viruses (pseudorabies virus (SuHV-1) 1.65%, bovine herpes virus type 1 (BHV-1) 0.81%, equine herpes virus type 1 (EHV-1) 0.79%, equine herpes virus type 4 (EHV-4) 0.16%) than non-ungulate viruses (feline herpes virus type 1 (FHV-1) 0.0089%, canine herpes virus type 1 (CHV-1) 0.005%, varicella-zoster virus (VZV) 0.136%). The G + C content of the ungulate viruses was also higher (SuHV-1 73.6%, BHV-1 72.6%, EHV-1 56.6%, EHV-4 50.5%) compared to the non-ungulate viruses (FHV 1 45.8%, CHV-1 31.6%, VZV 45.8%), which suggests a possible link between G + C content and intraspecies genetic diversity. Varicellovirus clade nomenclature is variable across different species, and we propose a standardization based on genomic genetic distance. A recent study reported no recombination between sequenced FHV-1 strains, however in the present study, both splitstree, bootscan, and PHI analysis indicated recombination. We also found that the recently sequenced Brazilian CHV-1 strain BTU-1 may contain a genetic signal in the UL50 gene from an unknown varicellovirus. CONCLUSION: Together, the data contribute to a greater understanding of varicellovirus genomics, and we also suggest a new clade nomenclature scheme based on genetic distances. PMID- 29157202 TI - Target proteins reprogrammed by As and As + Si treatments in Solanum lycopersicum L. fruit. AB - BACKGROUND: Arsenic is an important contaminant of many arable soils worldwide, while silicon, one of the most abundant elements in the earth's crust, interacts with As in the context of plant metabolism. As toxicity results largely from its stimulation of reactive oxygen species, and it is believed that Si can mitigate this process through reduction of the level of oxidative stress. Experiments targeting the proteomic impact of exposure to As and Si have to date largely focused on analyses of root, shoot and seed of a range of mainly non-solanaceous species, thus it remains unclear whether oxidative stress is the most important manifestation of As toxicity in Solanum lycopersicum fruit which during ripening go through drastic physiological and molecular readjustments. The role of Si also needs to be re-evaluated. RESULTS: A comparison was drawn between the proteomic responses to As and As + Si treatments of the fruit of two tomato cultivars (cvs. Aragon and Gladis) known to contrast for their ability to take up these elements and to translocate them into fruits. Treatments were applied at the beginning of the red ripening stage, and the fruit proteomes were captured after a 14 day period of exposure. For each cultivar, a set of differentially abundant fruit proteins (from non-treated and treated plants) were isolated by 2DGE and identified using mass spectrometry. In the fruit of cv. Aragon, the As treatment reprogrammed proteins largely involved in transcription regulation (growth- regulating factor 9-like), and cell structure (actin-51), while in the cv. Gladis, the majority of differentially expressed proteins were associated with protein ubiquitination and proteolysis (E3 ubiquitin protein, and hormones (1 aminocyclopropane 1-carboxylase). CONCLUSIONS: The present experiments were intended to establish whether Si supplementation can be used to reverse the proteomic disturbance induced by the As treatment; this reprogram was only partial and more effective in the fruit of cv. Gladis than in that of cv. Aragon. Proteins responsible for the protection of the fruits' quality in the face of As induced stress were identified. Moreover, supplementation with Si seemed to limit to a degree the accumulation of As in the tomato fruit of cv. Aragon. PMID- 29157203 TI - Survival time following resection of intracranial metastases from NSCLC development and validation of a novel nomogram. AB - BACKGROUND: Brain metastases (BM) from non-small cell lung cancer (NSCLC) are the most frequent intracranial tumors. To identify patients who might benefit from intracranial surgery, we compared the six existing prognostic indexes(PIs) and built a nomogram to predict the survival for NSCLC with BM before they intended to receive total intracranial resection in China. METHODS: First, clinical data of NSCLC presenting with BM were retrospectively reviewed. All of the patients had received total intracranial resection and were randomly distributed to developing cohort and validation cohort by 2:1. Second, we stratified the cohort using a recursive partitioning analysis(RPA), a score index for radiosurgery (SIR), a basic score for BM (BS-BM), a Golden Grading System (GGS), a disease specific graded prognostic assessment (DS-GPA) and by NSCLC-RADES. The predictive power of the six PIs was assessed using the Kaplan-Meier method and the log-rank test. Third, univariate and multivariate analysis were explored, and the nomogram predicting survival of BMs from NSCLC was constructed using R 3.2.3 software. The concordance index (C-index) was calculated to evaluate the discriminatory power of the nomogram in the developing cohort and validation cohort. RESULTS: BS-BM could better predict survival of patients before intracranial surgery compared with other PIs. In the final multivariate analysis, KPS at diagnosis of BM, metachronous or synchronous BM and the histology of lung cancer appeared to be the independent prognostic predictors for survival. The C-index in the developing cohort and validation cohort were 0.75 and 0.71 respectively, which was better than the C-index of the other six PIs. CONCLUSIONS: The new nomogram is a promising tool in further choosing the candidates for intracranial surgery among NSCLC with BM and in helping physicians tailor suitable treatment options before operation in clinical practice. PMID- 29157204 TI - Characterization of a novel splicing mutation in UNC13D gene through amplicon sequencing: a case report on HLH. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal disease caused by uncontrolled proliferation of activated lymphocytes and macrophages. Six genes including SH2D1A, PRF1, UNC13D, STX11, STXBP2 and XIAP were reported as causative genes in most cases. CASE PRESENTATION: Here we report a novel splicing mutation in UNC13D gene, which was identified in an 18-year-old female. Patient was diagnosed as HLH base on HLH-2004 guidelines, no history of inherited diseases was revealed in this family, parents were healthy and non consanguineous. Splenomegaly and hemophagocytosis in bone marrow were observed in clinical examination. Amplicon sequencing for the whole coding region of 6 HLH related genes was performed on Ion S5XL genetic analyzer. In all, four heterozygous mutations were detected, including 2 nonpathogenic SNPs (PRF1:c.900C > T, STX11:c.*70G > A) and 2 splicing mutations in UNC13D gene (UNC13D:c.1299 + 1G > A and UNC13D:c.2709 + 1G > A), both of which were predicted to be potentially pathogenic by human splicing finder (HSF3) tool. The result was confirmed by two-generation pedigree analysis base on sanger sequencing. CONCLUSIONS: Two compound heterozygous splicing mutations in UNC13D gene were identified and considered to be potential pathogenesis in a female patient of HLH. The mutation UNC13D:c.1299 + 1G > A was reported in HLH for the first time. The inheritance mode and source of the mutation in the proband was examined by family analysis. Our data suggest that further studies of the spectrum of HLH related mutations in China are warranted. PMID- 29157205 TI - The usefulness of chief complaints to predict severity, ventilator dependence, treatment option, and short-term outcome of patients with Guillain-Barre syndrome: a retrospective study. AB - BACKGROUND: It remains an urgent need for early recognition of disease severity, treatment option and outcome of Guillain-Barre syndrome (GBS). The chief complaint may be quickly obtained in clinic and is one of the candidates for early predictors. However, studies on the chief complaint are still lacking in GBS. The aim of the study is to describe the components of chief complaints of GBS patients, and to explore association between chief complaints and disease severity/treatment option/outcome of GBS, so as to aid the early prediction of the disease course and to assist the clinicians to prescribe an optimal early treatment. METHODS: A total of 523 GBS patients admitted to the First Hospital of Jilin University from 2003 to 2013 were enrolled for retrospective analysis. The data of chief complaints, clinical manifestations, and treatment options, etc. were collected. The clinical severity was evaluated by the Medical Research Council sum score and the Hughes Functional Grading Scale. The prognosis at 6 month after discharge was described by modified Erasmus GBS outcome score. The clinic GBS severity evaluation scale (CGSES), a newly established model in our study, was used to explore the role of chief complaints to predict intravenous immunoglobulin (IVIg). RESULTS: The major components of the chief complaints of GBS patients were weakness, numbness, pain, cranial nerve involvement, dyspnea, ataxia and autonomic dysfunction. Chief complaint of weakness was a predictor of severe disease course and poor short-term outcome, while chief complaint of numbness and cranial nerve involvement were promising predictors. Cranial nerve involvement was the predictor of ventilator dependence. The percentages of 366 GBS patients, who need IVIg treatment at nadir with CGSES ranging from 1 to 4, were 50.00, 67.34, 80.61, and 90.67%, respectively. CONCLUSIONS: Chief complaints are clinic predictors of disease severity, ventilator dependence and short-term outcome. IVIg treatment during hospitalisation could be predicted in clinic using CGSES score. PMID- 29157206 TI - Antifungal susceptibility testing of Candida species isolated from the immunocompromised patients admitted to ten university hospitals in Iran: comparison of colonizing and infecting isolates. AB - BACKGROUND: Antifungal susceptibility testing is a subject of interest in the field of medical mycology. The aim of the present study were the distributions and antifungal susceptibility patterns of various Candida species isolated from colonized and infected immunocompromised patients admitted to ten university hospitals in Iran. METHODS: In totally, 846 Candida species were isolated from more than 4000 clinical samples and identified by the API 20 C AUX system. Antifungal susceptibility testing was performed by broth microdilution method according to CLSI. RESULTS: The most frequent Candida species isolated from all patients was Candida albicans (510/846). The epidemiological cutoff value and percentage of wild-type species for amphotericin B and fluconazole in Candida albicans, Candida tropicalis, Candida glabrata and Candida krusei were 0.5 MUg/ml (95%) and 4 MUg/ml (96%); 1 MUg/ml (95%) and 8 MUg/ml (95%); 0.5 MUg/ml (99%) and 19 MUg/ml (98%); and 4 MUg/ml (95%) and 64 MUg/ml (95%), respectively. The MIC90 and epidemiological cutoff values to posaconazole in Candida krusei were 0.5 MUg/ml. There were significant differences between infecting and colonizing isolates of Candida tropicalis in MIC 90 values of amphotericin B, and isolates of Candida glabrata in values of amphotericin B, caspofungin, and voriconazole (P < 0.05). CONCLUSIONS: Our findings suggest that the susceptibility patterns of Candida species (colonizing and infecting isolates) in immunocompromised patients are not the same and acquired resistance was seen in some species. PMID- 29157207 TI - An ethnographic study of the effects of cognitive symptoms in patients with major depressive disorder: the IMPACT study. AB - BACKGROUND: The manifestation of major depressive disorder (MDD) may include cognitive symptoms that can precede the onset of MDD and persist beyond the resolution of acute depressive episodes. However, little is known about how cognitive symptoms are experienced by MDD patients and the people around them. METHODS: In this international (Brazil, Canada, China, France, and Germany) ethnographic study, we conducted semi-structured interviews and observations of remitted as well as symptomatic MDD patients (all patients self-reported being diagnosed by an HCP and self-reported being on an antidepressant) aged 18-60 years with self-reported cognitive symptoms (N = 34). In addition, participating depressed patients' close family or friends (N = 31) were interviewed. Separately recruited from depressed participants, work colleagues (N = 21) and healthcare providers (HCPs; N = 13) of depressed individuals were interviewed. RESULTS: Key insights were that: (1) patients were generally unaware that their cognitive symptoms were linked to their depression and, instead, attributed these symptoms to negative aspects of their person (e.g., age, separate disease, laziness, exhaustion); (2) cognitive symptoms in MDD appeared to negatively impact patients' social relationships and patients' ability to handle daily tasks at work and at home; (3) patients' cognitive symptoms also impacted relationships with family members and coworkers; (4) patients' cognitive symptoms increased stress and feelings of failure, which in turn seemed to worsen the cognitive symptoms, thereby creating a destructive cycle; and (5) although HCPs recommended that patients re-engage in everyday activities to help overcome their depression, cognitive symptoms seemed to impede such functional recovery. CONCLUSIONS: Taken together, these findings highlight a negative impact of patients' cognitive symptoms on their social functioning, work performance, and quality of life on the people close to them, and consequently on the degree of functional recovery after depression. PMID- 29157208 TI - Please sir, I want some more: an exploration of repeat foodbank use. AB - BACKGROUND: The sharp rise in foodbank use in Britain over the past five years suggests a proliferation of food insecurity that could herald a public health crisis. However, trends in foodbank use rely on imperfect figures that do not distinguish between single and repeat visits. Consequently, the true prevalence of foodbank use in Britain is unknown. By identifying repeat visits, this study provides the first estimate of the proportion of people using foodbanks. METHODS: Using data on referrals to West Cheshire Foodbank in the UK, this study offers a case study of 7769 referrals to one foodbank between 2013 and 2015. Foodbank use was explored in descriptive statistics, then negative binomial regression models were used to identify the household characteristics associated with the number of foodbank visits. RESULTS: Between 0.9 and 1.3% of people in West Cheshire sought assistance from West Cheshire Foodbank between 2013 and 2015. If scaled up nationally, this would equate to an estimated 850,000 people across Britain. The number of total recipients increased by 29% between 2013 and 2015, while the number of unique recipients rose by 14%. Multivariate analysis revealed that a larger number of visits were recorded in 2015 and among working-age and one person households, while households referred due to domestic abuse and unemployment made fewer visits. CONCLUSION: Food insecurity has emerged as a crucial challenge facing UK health professionals and policymakers. This study provides the first estimate of the proportion of individuals receiving emergency food in a single case study location, and demonstrates that foodbank use is becoming more prevalent, although headline figures overstate the scale of this growth. The potential nutrition and wider health consequences of reliance on emergency food - especially among those using foodbanks on multiple occasions - warns of an unfolding public health crisis. PMID- 29157209 TI - Transcriptome sequencing and analysis of zinc-uptake-related genes in Trichophyton mentagrophytes. AB - BACKGROUND: Trichophyton mentagrophytes is an important zoonotic dermatophytic (ringworm) pathogen; causing severe skin infection in humans and other animals worldwide. Fortunately, commonly used fungal skin disease prevention and treatment measures are relatively simple. However, T. mentagrophytes is primarily studied at the epidemiology and drug efficacy research levels, yet current study has been unable to meet the needs of clinical medicine. Zinc is a crucial trace element for the growth and reproduction of fungi and other microorganisms. The metal ions coordinate within a variety of proteins to form zinc finger proteins, which perform many vital biological functions. Zinc transport regulatory networks have not been resolved in T. mentagrophytes. The T. mentagrophytes transcriptome will allow us to discover new genes, particularly those genes involved in zinc uptake. RESULT: We found T. mentagrophytes growth to be restricted by zinc deficiency; natural T. mentagrophytes growth requires zinc ions. T. Mentagrophytes must acquire zinc ions for growth and development. The transcriptome of T. mentagrophytes was sequenced by using Illumina HiSeqTM 2000 technology and the de novo assembly of the transcriptome was performed by using the Trinity method, and functional annotation was analyzed. We got 10,751 unigenes. The growth of T. mentagrophytes is severely inhibited and there were many genes showing significant up regulation and down regulation respectively in T. mentagrophytes when zinc deficiency. Zinc deficiency can affect the expression of multiple genes of T. mentagrophytes. The effect of the zinc deficiency could be recovered in the normal medium. And we finally found the zinc-responsive activating factor (ZafA) and speculated that 4 unigenes are zinc transporters. We knocked ZafA gene by ATMT transformation in T. mentagrophytes, the result showed that ZafA gene is very important for the growth and the generation of conidia in T. mentagrophytes. The expression of 4 zinc transporter genes is potentially regulated by the zinc-responsive activating factor. The data of this study is also sufficient to be used as a support to study T. mentagrophytes. CONCLUSION: We reported the first large transcriptome study carried out in T. mentagrophytes where we have compared physiological and transcriptional responses to zinc deficiency, and analyzed the expression of genes involved in zinc uptake. The study also produced high-resolution digital profiles of global genes expression relating to T. mentagrophytes growth. PMID- 29157210 TI - Genome-wide identification of conserved and novel microRNAs in one bud and two tender leaves of tea plant (Camellia sinensis) by small RNA sequencing, microarray-based hybridization and genome survey scaffold sequences. AB - BACKGROUND: MicroRNAs (miRNAs) are important for plant growth and responses to environmental stresses via post-transcriptional regulation of gene expression. Tea, which is primarily produced from one bud and two tender leaves of the tea plant (Camellia sinensis), is one of the most popular non-alcoholic beverages worldwide owing to its abundance of secondary metabolites. A large number of miRNAs have been identified in various plants, including non-model species. However, due to the lack of reference genome sequences and/or information of tea plant genome survey scaffold sequences, discovery of miRNAs has been limited in C. sinensis. RESULTS: Using small RNA sequencing, combined with our recently obtained genome survey data, we have identified and analyzed 175 conserved and 83 novel miRNAs mainly in one bud and two tender leaves of the tea plant. Among these, 93 conserved and 18 novel miRNAs were validated using miRNA microarray hybridization. In addition, the expression pattern of 11 conserved and 8 novel miRNAs were validated by stem-loop-qRT-PCR. A total of 716 potential target genes of identified miRNAs were predicted. Further, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that most of the target genes were primarily involved in stress response and enzymes related to phenylpropanoid biosynthesis. The predicted targets of 4 conserved miRNAs were further validated by 5'RLM-RACE. A negative correlation between expression profiles of 3 out of 4 conserved miRNAs (csn-miR160a-5p, csn-miR164a, csn-miR828 and csn-miR858a) and their targets (ARF17, NAC100, WER and MYB12 transcription factor) were observed. CONCLUSION: In summary, the present study is one of few such studies on miRNA detection and identification in the tea plant. The predicted target genes of majority of miRNAs encoded enzymes, transcription factors, and functional proteins. The miRNA-target transcription factor gene interactions may provide important clues about the regulatory mechanism of these miRNAs in the tea plant. The data reported in this study will make a huge contribution to knowledge on the potential miRNA regulators of the secondary metabolism pathway and other important biological processes in C. sinensis. PMID- 29157211 TI - Alkaline peptone water enrichment with a dipstick test to quickly detect and monitor cholera outbreaks. AB - BACKGROUND: Detection, confirmation and monitoring of cholera outbreaks in many developing countries including Uganda is a big challenge due to lack of the required resources and the time the test takes. Culture method which takes 24-48 h to get the feedback and requires highly skilled laboratory staff plus other complex resources is the standard test. This study evaluated the new cholera rapid detection method that relies on Crystal VC dipsticks after enrichment with alkaline peptone water (APW) against the culture method for monitoring the progress of cholera outbreaks in rural setting. METHODS: We conducted the study between March and June 2015. Fresh stool samples and rectal swabs were incubated in 1% APW for 6 h at room temperature before testing with RDT following the manufacturer's instruction. The same stool sample was cultured to isolate V. cholerae in the standard manner. We also reviewed patient registers to epidemiologically describe the cholera epidemic. RESULTS: We tested stool from 102 consenting suspected cholera patients reporting during daytime at Bwera Hospital (n = 69), Kilembe Mines Hospital (n = 4) and Kinyabwama Health Centre (n = 29). Ninety one (91) samples were positive and nine samples were negative according to both methods. One (1) sample was positive only by dipstick and one sample was positive only by culture (sensitivity of 99%, specificity of 90%, Positive Predictive Value of 99% and Negative Predictive Value of 90%). Overall, 146 suspected cholera cases and two deaths, (case fatality rate of 1.36%) were recorded during the study period. Among the cases aged 1-9 years, 63% (50/79) were males while in those aged 20-49 years, 76% (34/45) were females. CONCLUSIONS: Our findings showed that the modified dipstick test after enrichment with 1% APW had high level of accuracy in detection of V. cholerae and is quick, affordable alternative cholera outbreak monitoring tool in resource constrained settings. However, culture method should remain for cholera epidemic confirmation, for monitoring of antibiotic sensitivity and for production of pure isolates for molecular characterization. Further studies should be done to better understand the observed age and sex case distribution, in Kasese district. PMID- 29157212 TI - Fine motor skills in a population of children in remote Australia with high levels of prenatal alcohol exposure and Fetal Alcohol Spectrum Disorder. AB - BACKGROUND: Many children in the remote Fitzroy Valley region of Western Australia have prenatal alcohol exposure (PAE). Individuals with PAE can have neurodevelopmental impairments and be diagnosed with one of several types of Fetal Alcohol Spectrum Disorder (FASD). Fine motor skills can be impaired by PAE, but no studies have developed a comprehensive profile of fine motor skills in a population-based cohort of children with FASD. We aimed to develop a comprehensive profile of fine motor skills in a cohort of Western Australian children; determine whether these differed in children with PAE or FASD; and establish the prevalence of impairment. METHODS: Children (n = 108, 7 to 9 years) were participants in a population-prevalence study of FASD in Western Australia. Fine motor skills were assessed using the Bruininks-Oseretsky Test of Motor Proficiency, which provided a Fine Motor Composite score, and evaluated Fine Manual Control (Fine Motor Precision; Fine Motor Integration) and Manual Coordination (Manual Dexterity; Upper-Limb Coordination). Descriptive statistics were reported for the overall cohort; and comparisons made between children with and without PAE and/or FASD. The prevalence of severe (<= 2nd percentile) and moderate (<=16th percentile) impairments was determined. RESULTS: Overall, Fine Motor Composite scores were 'average' (M = 48.6 +/- 7.4), as were Manual Coordination (M = 55.7 +/- 7.9) and Fine Manual Control scores (M = 42.5 +/- 6.2). Children with FASD had significantly lower Fine Motor Composite (M = 45.2 +/- 7.7 p = 0.046) and Manual Coordination scores (M = 51.8 +/- 7.3, p = 0.027) than children without PAE (Fine Motor Composite M = 49.8 +/- 7.2; Manual Coordination M = 57.0 +/- 7.7). Few children had severe impairment, but rates of moderate impairment were very high. CONCLUSIONS: Different types of fine motor skills should be evaluated in children with PAE or FASD. The high prevalence of fine motor impairment in our cohort, even in children without PAE, highlights the need for therapeutic intervention for many children in remote communities. PMID- 29157214 TI - Segmental ischaemic infarction of the iris after autologous fat injection into the lower eyelid tissue: a case report. AB - BACKGROUND: Autologous fat injection is getting popular in cosmetic procedures, however, still has a risk of fat embolism. Herein, we report the first case of segmental ischaemic infarction of the iris, which occurred after autologous fat injection into the lower eyelid. CASE PRESENTATION: A 28-year-old Korean woman complained of the discolouration of the iris after the fat injection. Slit-lamp biomicroscopy revealed segmental depigmented atrophic iris with sectoral sphincter palsy. CONCLUSIONS: We found that iris atrophy could be caused by autologous fat transplantation. The plastic surgeons should pay more attention to possibility of fat embolism-induced ocular complications in the procedure of fat injection. PMID- 29157213 TI - Phylogeny and maternal donors of Elytrigia Desv. sensu lato (Triticeae; Poaceae) inferred from nuclear internal-transcribed spacer and trnL-F sequences. AB - BACKGROUND: Elytrigia Desv. is a genus with a varied array of morphology, cytology, ecology, and distribution in Triticeae. Classification and systematic position of Elytrigia remain controversial. We used nuclear internal-transcribed spacer (nrITS) sequences and chloroplast trnL-F region to study the relationships of phylogenetic and maternal genome donor of Elytrigia Desv. sensu lato. RESULTS: (1) E, F, P, St, and W genomes bear close relationship with one another and are distant from H and Ns genomes. Ee and Eb are homoeologous. (2) In ESt genome species, E genome is the origin of diploid Elytrigia species with E genome, St genome is the origin of Pseudoroegneria. (3) Diploid species Et. elongata were differentiated. (4) Et. stipifolia and Et. varnensis sequences are diverse based on nrITS data. (5) Et. lolioides contains St and H genomes and belongs to Elymus s. l. (6) E genome diploid species in Elytrigia serve as maternal donors of E genome for Et. nodosa (PI547344), Et. farcta, Et. pontica, Et. pycnantha, Et. scirpea, and Et. scythica. At least two species act as maternal donor of allopolyploids (ESt and EStP genomes). CONCLUSIONS: Our results suggested that Elytrigia s. l. species contain different genomes, which should be divided into different genera. However, the genomes of Elytrigia species had close relationships with one another. Diploid species were differentiated, because of introgression and different geographical sources. The results also suggested that the same species and the same genomes of different species have different maternal donor. Further study of molecular biology and cytology could facilitate the evaluation of our results of phylogenetic in a more specific and accurate way. PMID- 29157215 TI - Integration of RNA-Seq data with heterogeneous microarray data for breast cancer profiling. AB - BACKGROUND: Nowadays, many public repositories containing large microarray gene expression datasets are available. However, the problem lies in the fact that microarray technology are less powerful and accurate than more recent Next Generation Sequencing technologies, such as RNA-Seq. In any case, information from microarrays is truthful and robust, thus it can be exploited through the integration of microarray data with RNA-Seq data. Additionally, information extraction and acquisition of large number of samples in RNA-Seq still entails very high costs in terms of time and computational resources.This paper proposes a new model to find the gene signature of breast cancer cell lines through the integration of heterogeneous data from different breast cancer datasets, obtained from microarray and RNA-Seq technologies. Consequently, data integration is expected to provide a more robust statistical significance to the results obtained. Finally, a classification method is proposed in order to test the robustness of the Differentially Expressed Genes when unseen data is presented for diagnosis. RESULTS: The proposed data integration allows analyzing gene expression samples coming from different technologies. The most significant genes of the whole integrated data were obtained through the intersection of the three gene sets, corresponding to the identified expressed genes within the microarray data itself, within the RNA-Seq data itself, and within the integrated data from both technologies. This intersection reveals 98 possible technology-independent biomarkers. Two different heterogeneous datasets were distinguished for the classification tasks: a training dataset for gene expression identification and classifier validation, and a test dataset with unseen data for testing the classifier. Both of them achieved great classification accuracies, therefore confirming the validity of the obtained set of genes as possible biomarkers for breast cancer. Through a feature selection process, a final small subset made up by six genes was considered for breast cancer diagnosis. CONCLUSIONS: This work proposes a novel data integration stage in the traditional gene expression analysis pipeline through the combination of heterogeneous data from microarrays and RNA-Seq technologies. Available samples have been successfully classified using a subset of six genes obtained by a feature selection method. Consequently, a new classification and diagnosis tool was built and its performance was validated using previously unseen samples. PMID- 29157217 TI - Genetics of Na+ exclusion and salinity tolerance in Afghani durum wheat landraces. AB - BACKGROUND: Selecting for low concentration of Na+ in the shoot provides one approach for tackling salinity stress that adversely affects crop production. Novel alleles for Na+ exclusion can be identified and then introduced into elite crop cultivars. RESULTS: We have identified loci associated with lower Na+ concentration in leaves of durum wheat landraces originating from Afghanistan. Seedlings of two F2 populations derived from crossings between Australian durum wheat (Jandaroi) and two Afghani landraces (AUS-14740 and AUS-14752) were grown hydroponically and evaluated for Na+ and K+ concentration in the third leaf. High heritability was found for both third leaf Na+ concentration and the K+/Na+ ratio in both populations. Further work focussed on line AUS-14740. Bulk segregant analysis using 9 K SNP markers identified two loci significantly associated with third leaf Na+ concentration. Marker regression analysis showed a strong association between all traits studied and a favourable allele originating from AUS-14740 located on the long arm of chromosome 4B. CONCLUSIONS: The candidate gene in the relevant region of chromosome 4B is likely to be the high affinity K+ transporter B1 (HKT1;5-B1). A second locus associated with third leaf Na+ concentration was located on chromosome 3BL, with the favourable allele originating from Jandaroi; however, no candidate gene can be identified. PMID- 29157216 TI - Breast cancer protection by genomic imprinting in close kin families. AB - Human inbreeding generally reduces breast cancer risk (BCR). When the parents are biologically related, their infants have a lower birth weight due to smaller body organs. The undersized breasts, because of fewer mammary stem cells, have a lower likelihood of malignant conversion. Fetal growth is regulated by genomically imprinted genes which are in conflict; they promote growth when derived from the father and suppress growth when derived from the mother. The kinship theory explicates that the intensity of conflict between these genes affects growth and therefore the size of the newborn. In descendants of closely related parents, this gene clash is less resulting in a smaller infant. In this review, we elucidate the different mechanisms by which human inbreeding affects BCR, and why this risk is dissimilar in different inbred populations. PMID- 29157218 TI - Brain medical image diagnosis based on corners with importance-values. AB - BACKGROUND: Brain disorders are one of the top causes of human death. Generally, neurologists analyze brain medical images for diagnosis. In the image analysis field, corners are one of the most important features, which makes corner detection and matching studies essential. However, existing corner detection studies do not consider the domain information of brain. This leads to many useless corners and the loss of significant information. Regarding corner matching, the uncertainty and structure of brain are not employed in existing methods. Moreover, most corner matching studies are used for 3D image registration. They are inapplicable for 2D brain image diagnosis because of the different mechanisms. To address these problems, we propose a novel corner-based brain medical image classification method. Specifically, we automatically extract multilayer texture images (MTIs) which embody diagnostic information from neurologists. Moreover, we present a corner matching method utilizing the uncertainty and structure of brain medical images and a bipartite graph model. Finally, we propose a similarity calculation method for diagnosis. RESULTS: Brain CT and MRI image sets are utilized to evaluate the proposed method. First, classifiers are trained in N-fold cross-validation analysis to produce the best theta and K. Then independent brain image sets are tested to evaluate the classifiers. Moreover, the classifiers are also compared with advanced brain image classification studies. For the brain CT image set, the proposed classifier outperforms the comparison methods by at least 8% on accuracy and 2.4% on F1 score. Regarding the brain MRI image set, the proposed classifier is superior to the comparison methods by more than 7.3% on accuracy and 4.9% on F1-score. Results also demonstrate that the proposed method is robust to different intensity ranges of brain medical image. CONCLUSIONS: In this study, we develop a robust corner-based brain medical image classifier. Specifically, we propose a corner detection method utilizing the diagnostic information from neurologists and a corner matching method based on the uncertainty and structure of brain medical images. Additionally, we present a similarity calculation method for brain image classification. Experimental results on two brain image sets show the proposed corner-based brain medical image classifier outperforms the state-of-the art studies. PMID- 29157220 TI - Combined effects of leaks, respiratory system properties and upper airway patency on the performance of home ventilators: a bench study. AB - BACKGROUND: Combined effects of leaks, mechanical property of respiratory system and upper airway (UA) patency on patient-ventilator synchrony (PVA) and the level of clinically "tolerable" leaks are not well established in home ventilators. METHODS: We comparatively assessed on a bench model, the highest leak level tolerated without inducing significant asynchrony ("critical leak") in three home ventilators (Astral 150, Trilogy 100 and Vivo 60; noted as A150, T100 and V60 respectively) subjected to three simulated diseased respiratory conditions: chronic obstructive pulmonary disease (COPD), obesity hypoventilation (OHS) and neuromuscular disorders (NMD), with both open and closed UA. Also, total leak values in the device reports were compared to the bench-measured values. RESULTS: With open UA, all ventilators were able to avoid asynchrony up to a 30 L/min leak and even to 55 L/min in some cases. UA closure and respiratory diseases especially OHS influenced PVA. With closed UA, the critical leak of A150 and T100 remained higher than 55 L/min in COPD and OHS, while for V60 decreased to 41 and 33 L/min respectively. In NMD with closed UA, only T100 reached a high critical leak of 69 L/min. Besides, inspiratory trigger sensitivity change was often necessary to avoid PVA. CONCLUSIONS: Home ventilators were able to avoid PVA in high-level leak conditions. However, asynchrony appeared in cases of abnormal mechanical properties of respiratory system or closed UA. In case of closed UA, the EPAP should be adjusted prior to the inspiratory trigger. TRIAL REGISTRATION: Not applicable. PMID- 29157219 TI - A new multiple trauma model of the mouse. AB - BACKGROUND: Blunt trauma is the most frequent mechanism of injury in multiple trauma, commonly resulting from road traffic collisions or falls. Two of the most frequent injuries in patients with multiple trauma are chest trauma and extremity fracture. Several trauma mouse models combine chest trauma and head injury, but no trauma mouse model to date includes the combination of long bone fractures and chest trauma. Outcome is essentially determined by the combination of these injuries. In this study, we attempted to establish a reproducible novel multiple trauma model in mice that combines blunt trauma, major injuries and simple practicability. METHODS: Ninety-six male C57BL/6 N mice (n = 8/group) were subjected to trauma for isolated femur fracture and a combination of femur fracture and chest injury. Serum samples of mice were obtained by heart puncture at defined time points of 0 h (hour), 6 h, 12 h, 24 h, 3 d (days), and 7 d. RESULTS: A tendency toward reduced weight and temperature was observed at 24 h after chest trauma and femur fracture. Blood analyses revealed a decrease in hemoglobin during the first 24 h after trauma. Some animals were killed by heart puncture immediately after chest contusion; these animals showed the most severe lung contusion and hemorrhage. The extent of structural lung injury varied in different mice but was evident in all animals. Representative H&E-stained (Haematoxylin and Eosin-stained) paraffin lung sections of mice with multiple trauma revealed hemorrhage and an inflammatory immune response. Plasma samples of mice with chest trauma and femur fracture showed an up-regulation of IL-1beta (Interleukin-1beta), IL-6, IL-10, IL-12p70 and TNF-alpha (Tumor necrosis factor- alpha) compared with the control group. Mice with femur fracture and chest trauma showed a significant up-regulation of IL-6 compared to group with isolated femur fracture. CONCLUSIONS: The multiple trauma mouse model comprising chest trauma and femur fracture enables many analogies to clinical cases of multiple trauma in humans and demonstrates associated characteristic clinical and pathophysiological changes. This model is easy to perform, is economical and can be used for further research examining specific immunological questions. PMID- 29157221 TI - The failure of suicide prevention in primary care: family and GP perspectives - a qualitative study. AB - BACKGROUND: Although Primary care is crucial for suicide prevention, clinicians tend to report completed suicides in their care as non-preventable. We aimed to examine systemic inadequacies in suicide prevention from the perspectives of bereaved family members and GPs. METHODS: Qualitative study of 72 relatives or close friends bereaved by suicide and 19 General Practitioners who have experienced the suicide of patients. RESULTS: Relatives highlight failures in detecting symptoms and behavioral changes and the inability of GPs to understand the needs of patients and their social contexts. A perceived overreliance on anti depressant treatment is a major source of criticism by family members. GPs tend to lack confidence in the recognition and management of suicidal patients, and report structural inadequacies in service provision. CONCLUSIONS: Mental health and primary care services must find innovative and ethical ways to involve families in the decision-making process for patients at risk of suicide. PMID- 29157222 TI - Comparative proteomics reveals the physiological differences between winter tender shoots and spring tender shoots of a novel tea (Camellia sinensis L.) cultivar evergrowing in winter. AB - BACKGROUND: A recently discovered tea [Camellia sinensis (L.) O. Kuntze] cultivar can generate tender shoots in winter. We performed comparative proteomics to analyze the differentially accumulated proteins between winter and spring tender shoots of this clonal cultivar to reveal the physiological basis of its evergrowing character during winter. RESULTS: We extracted proteins from the winter and spring tender shoots (newly formed two leaves and a bud) of the evergrowing tea cultivar "Dongcha11" respectively. Thirty-three differentially accumulated high-confidence proteins were identified by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF / TOF MS). Among these, 24 proteins had increased abundance while nine showed were decreased abundance in winter tender shoots as compared with the spring tender shoots. We categorized the differentially accumulated proteins into eight critical biological processes based on protein function annotation including photosynthesis, cell structure, protein synthesis & destination, transporters, metabolism of sugars and polysaccharides, secondary metabolism, disease/defense and proteins with unknown functions. Proteins with increased abundance in winter tender shoots were mainly related to the processes of photosynthesis, cytoskeleton and protein synthesis, whereas those with decreased abundance were correlated to metabolism and the secondary metabolism of polyphenolic flavonoids. Biochemical analysis showed that the total contents of soluble sugar and amino acid were higher in winter tender shoots while tea polyphenols were lower as compared with spring tender shoots. CONCLUSIONS: Our study suggested that the simultaneous increase in the abundance of photosynthesis-related proteins rubisco, plastocyanin, and ATP synthase delta chain, metabolism-related proteins eIF4 and protease subunits, and the cytoskeleton-structure associated proteins phosphatidylinositol transfer protein and profilin may be because of the adaptation of the evergrowing tea cultivar "Dongcha11" to low temperature and light conditions. Histone H4, Histone H2A.1, putative In2.1 protein and protein lin-28 homologs may also regulate the development of winter shoots and their response to adverse conditions. PMID- 29157223 TI - Tube feeding decreases pneumonia rate in patients with severe dementia: comparison between pre- and post-intervention. AB - BACKGROUND: It is widely supposed that there is no benefit, including extended survival and decreased rate of pneumonia, in patients with severe dementia receiving enteral tube feeding (TF). However, there have been few studies comparing the frequency of pneumonia before and after TF in severe dementia. METHODS: Nine psychiatric hospitals in Okayama Prefecture participated in this retrospective survey. All inpatients fulfilling the entry criteria were evaluated. All subjects suffered from difficulty in oral intake. Attending physicians thought that the patients could not live without long-term artificial nutrition, and they decided whether or not to make use of long-term artificial nutrition from January 1, 2014 to December 31, 2014. RESULTS: We evaluated 58 patients including 46 with TF and 12 without. The mean age of all patients was 79.6 +/- 9.0 years old. Patients with probable Alzheimer's disease (n = 38) formed the biggest group, and those with vascular dementia the second (n = 14). Median survival times were 23 months among patients with TF and two months among patients without TF. The start of TF decreased the frequency of pneumonia and the use of intravenous antibiotics. CONCLUSIONS: TF decreased pneumonia and antibiotic use, even in patients with severe dementia. The results of this study do not necessarily indicate that we should administer TF to patients with severe dementia. We should consider the quality of life of patients carefully before deciding the use or disuse of TF for patients with severe dementia. PMID- 29157224 TI - Shoulder MRI features with clinical correlations in subacromial pain syndrome: a cross-sectional and prognostic study. AB - BACKGROUND: Previous studies on shoulder patients have suggested that the prevalence of rotator cuff or bursa abnormalities are weakly related to symptoms and that similar findings are often found in asymptomatic persons. In addition, it is largely unknown whether structural changes identified by magnetic resonance imaging (MRI) affect outcome after treatment for shoulder pain. The purpose of this study was therefore to evaluate the presence of structural changes on MRI in patients with subacromial pain syndrome and to determine to what extent these changes are associated with symptoms and predict outcome after treatment (evaluated by the Shoulder Pain and Disability Index (SPADI)). METHODS: A prospective, observational assessment of a subset of shoulder patients who were included in a randomized study was performed. All participants had an MRI of the shoulder. An MRI total score for findings at the AC joint, subacromial bursa and rotator cuff was calculated. Multiple linear regression analysis was applied to examine the relationship between the MRI total score and the outcome measure at baseline and to examine to what extent the MRI total score was associated with the change in the SPADI score from baseline to the one year follow-up. RESULTS: There was a weak, inverse association between the SPADI score at baseline and the MRI total score (beta = -3.1, with 95% CI -5.9 to -0.34; p = 0.03), i.e. the SPADI score was higher for patients with a lower MRI total score. There was an association between the change in the SPADI score from baseline to the one year follow-up and the MRI total score (beta = 8.1, 95% CI -12.3 to -3.8; p < 0.001), with a poorer outcome for patients with a higher MRI total score. Both tendinosis (p = 0.01) and bursitis (p = 0.04) were associated with a poorer outcome after one year. CONCLUSIONS: In this study, MRI findings were significantly associated with the change in the SPADI score from baseline and to one year follow-up, with a poorer outcome after treatment for the patients with higher MRI total score, tendinosis and bursitis on MRI. TRIAL REGISTRATION: Clinicaltrials.gov no NCT01441830 . September 28, 2011. PMID- 29157225 TI - Identification of drought-responsive miRNAs and physiological characterization of tea plant (Camellia sinensis L.) under drought stress. AB - BACKGROUND: Drought stress is one of the major natural challenges in the main tea producing regions of China. The tea plant (Camellia sinensis) is a traditional beverage plant whose growth status directly affects tea quality. Recent studies have revealed that microRNAs (miRNAs) play key functions in plant growth and development. Although some miRNAs have been identified in C. sinensis, little is known about their roles in the drought stress response of tea plants. RESULTS: Physiological characterization of Camellia sinensis 'Tieguanyin' under drought stress showed that the malondialdehyde concentration and electrical conductivity of leaves of drought-stressed plants increased when the chlorophyll concentration decreased under severe drought stress. We sequenced four small-RNA (sRNA) libraries constructed from leaves of plants subjected to four different treatments, normal water supply (CK); mild drought stress (T1); moderate drought stress (T2) and severe drought stress (T3). A total of 299 known mature miRNA sequences and 46 novel miRNAs were identified. Gene Ontology enrichment analysis revealed that most of the differentially expressed-miRNA target genes were related to regulation of transcription. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the most highly enriched pathways under drought stress were D-alanine metabolism, sulfur metabolism, and mineral absorption pathways. Real-time quantitative PCR (qPCR) was used to validate the expression patterns of 21 miRNAs (2 up-regulated and 19 down-regulated under drought stress). The observed co-regulation of the miR166 family and their targets ATHB-14-like and ATHB-15-like indicate the presence of negative feedback regulation in miRNA pathways. CONCLUSIONS: Analyses of drought-responsive miRNAs in tea plants showed that most of differentially expressed-miRNA target genes were related to regulation of transcription. The results of study revealed that the expressions of phase-specific miRNAs vary with morphological, physiological, and biochemical changes. These findings will be useful for research on drought resistance and provide insights into the mechanisms of drought adaptation and resistance in C. sinensis. PMID- 29157226 TI - Remarkable spatial variation in the seroprevalence of Coxiella burnetii after a large Q fever epidemic. AB - BACKGROUND: Prior to the 2007-2010 Q fever epidemic in the Netherlands, the seroprevalence of antibodies against Coxiella burnetii in the general population was 1.5%, which is low compared to other countries. We aimed to determine the seroprevalence after the Q fever epidemic among people living in the affected area, compare the seroprevalence with the incidence of Q fever notifications during the 2007-2010 Q fever epidemic, and to identify farm exposures associated with having antibodies against C. burnetii. METHODS: During the period March 2014 February 2015, residents aged 18-70 years from two provinces were invited by general practitioners to complete a questionnaire on their symptoms and personal characteristics and to submit a blood sample. We used the mandatory provincial database of livestock licences to calculate distance to farms/farm animals for each participant. To compare ELISA-positive participants for C. burnetii antibodies with those who were negative, we calculated prevalence ratios (PR) using binominal regression. We compared the C. burnetii seroprevalence in the period March 2014-February 2015 with the incidence of Q fever notifications during the 2007-2010 Q fever epidemic at municipal level by calculating the Spearman correlation coefficient. RESULTS: Of the 2296 participants (response rate: 34%), 6.1% (n = 139, 95% CI 5.1-7.1%) had C. burnetii antibodies (range in municipalities: 1.7-14.1%). C. burnetii seroprevalence was higher in individuals living within 1000 m of goat farms (PR 3.0; 95% CI 1.4-6.4) or within 1000 m of > 50 goats (PR 1.9; 95% CI 1.2-3.0). Seroprevalence increased with decreasing distance to the closest goat farm that was infected during the epidemic years (< 500 m, PR 9.5, 95% CI 2.8-32; 500-1000 m, PR 4.5, 95% CI 2.6-7.7; 1000-1500 m, PR 2.2, 95% CI 1.1-4.3, 1500-2000 m, PR 1.2, 95% CI 0.6-2.5; > 2000 reference group). There was no significant correlation between C. burnetii seroprevalence and Q fever incidence during the 2007-2010 epidemic (r s = 0.42, p = 0.156). CONCLUSIONS: Results showed a remarkable spatial variation in C. burnetii seroprevalence in a relatively small livestock dense area. It confirms previous evidence that the Q fever epidemic was primarily the result of airborne C. burnetii transmission from Q fever affected goat farms. PMID- 29157227 TI - Metabolic adaptation of two in silico mutants of Mycobacterium tuberculosis during infection. AB - BACKGROUND: Up to date, Mycobacterium tuberculosis (Mtb) remains as the worst intracellular killer pathogen. To establish infection, inside the granuloma, Mtb reprograms its metabolism to support both growth and survival, keeping a balance between catabolism, anabolism and energy supply. Mtb knockouts with the faculty of being essential on a wide range of nutritional conditions are deemed as target candidates for tuberculosis (TB) treatment. Constraint-based genome-scale modeling is considered as a promising tool for evaluating genetic and nutritional perturbations on Mtb metabolic reprogramming. Nonetheless, few in silico assessments of the effect of nutritional conditions on Mtb's vulnerability and metabolic adaptation have been carried out. RESULTS: A genome-scale model (GEM) of Mtb, modified from the H37Rv iOSDD890, was used to explore the metabolic reprogramming of two Mtb knockout mutants (pfkA- and icl-mutants), lacking key enzymes of central carbon metabolism, while exposed to changing nutritional conditions (oxygen, and carbon and nitrogen sources). A combination of shadow pricing, sensitivity analysis, and flux distributions patterns allowed us to identify metabolic behaviors that are in agreement with phenotypes reported in the literature. During hypoxia, at high glucose consumption, the Mtb pfkA-mutant showed a detrimental growth effect derived from the accumulation of toxic sugar phosphate intermediates (glucose-6-phosphate and fructose-6-phosphate) along with an increment of carbon fluxes towards the reductive direction of the tricarboxylic acid cycle (TCA). Furthermore, metabolic reprogramming of the icl mutant (icl1&icl2) showed the importance of the methylmalonyl pathway for the detoxification of propionyl-CoA, during growth at high fatty acid consumption rates and aerobic conditions. At elevated levels of fatty acid uptake and hypoxia, we found a drop in TCA cycle intermediate accumulation that might create redox imbalance. Finally, findings regarding Mtb-mutant metabolic adaptation associated with asparagine consumption and acetate, succinate and alanine production, were in agreement with literature reports. CONCLUSIONS: This study demonstrates the potential application of genome-scale modeling, flux balance analysis (FBA), phenotypic phase plane (PhPP) analysis and shadow pricing to generate valuable insights about Mtb metabolic reprogramming in the context of human granulomas. PMID- 29157228 TI - Fellowship training: a qualitative study of scope and purpose across one department of medicine. AB - BACKGROUND: Fellowship training follows certification in a primary specialty or subspecialty and focusses on distinct and advanced clinical and/or academic skills. This phase of medical education is growing in prevalence, but has been an "invisible phase of postgraduate training" lacking standards for education and accreditation, as well as funding. We aimed to explore fellowship programs and examine the reasons to host and participate in fellowship training, seeking to inform the future development of fellowship education. METHODS: During the 2013 14 academic year, we conducted interviews and focus groups to examine the current status of fellowship training from the perspectives of division heads, fellowship directors and current fellows at the Department of Medicine, University of Ottawa, Canada. Descriptive statistics were used to depict the prevailing status of fellowship training. A process of data reduction, data analysis and conclusions/verifications was performed to analyse the quantitative data. RESULTS: We interviewed 16 division heads (94%), 15 fellowship directors (63%) and 8 fellows (21%). We identified three distinct types of fellowships. Individualized fellowships focus on the career goals of the trainee and/or the recruitment goals of the division. Clinical fellowships focus on the attainment of clinical expertise over and above the competencies of residency. Research fellowships focus on research productivity. Participants identified a variety of reasons to offer fellowships: improve academic productivity; improve clinical productivity; share/develop enhanced clinical expertise; recruit future faculty members/attain an academic position; enhance the reputation of the division/department/trainee; and enhance the scholarly environment. CONCLUSIONS: Fellowships serve a variety of purposes which benefit both individual trainees as well as the academic enterprise. Fellowships can be categorized within a distinct taxonomy: individualized; clinical; and research. Each type of fellowship may serve a variety of purposes, and each may need distinct support and resources. Further research is needed to catalogue the operational requirements for hosting and undertaking fellowship training, and establish recommendations for educational and administrative policy and processes in this new phase of postgraduate education. PMID- 29157229 TI - Computer model for the cardiovascular system: development of an e-learning tool for teaching of medical students. AB - BACKGROUND: This study combined themes in cardiovascular modelling, clinical cardiology and e-learning to create an on-line environment that would assist undergraduate medical students in understanding key physiological and pathophysiological processes in the cardiovascular system. METHODS: An interactive on-line environment was developed incorporating a lumped-parameter mathematical model of the human cardiovascular system. The model outputs were used to characterise the progression of key disease processes and allowed students to classify disease severity with the aim of improving their understanding of abnormal physiology in a clinical context. Access to the on-line environment was offered to students at all stages of undergraduate training as an adjunct to routine lectures and tutorials in cardiac pathophysiology. Student feedback was collected on this novel on-line material in the course of routine audits of teaching delivery. RESULTS: Medical students, irrespective of their stage of undergraduate training, reported that they found the models and the environment interesting and a positive experience. After exposure to the environment, there was a statistically significant improvement in student performance on a series of 6 questions based on cardiovascular medicine, with a 33% and 22% increase in the number of questions answered correctly, p < 0.0001 and p < 0.001 respectively. CONCLUSIONS: Considerable improvement was found in students' knowledge and understanding during assessment after exposure to the e learning environment. Opportunities exist for development of similar environments in other fields of medicine, refinement of the existing environment and further engagement with student cohorts. This work combines some exciting and developing fields in medical education, but routine adoption of these types of tool will be possible only with the engagement of all stake-holders, from educationalists, clinicians, modellers to, most importantly, medical students. PMID- 29157230 TI - Barriers and facilitators to implementing an evidence-based woman-focused intervention in South African health services. AB - BACKGROUND: Since the beginning of the HIV epidemic, numerous behavior change, risk-reduction, and biomedical interventions have been developed and tested. While some of these interventions have shown to be efficacious in randomized trials, it often takes almost two decades for an intervention to be translated into practice. Meanwhile, South Africa continues to have among the highest prevalence of HIV globally, with women of childbearing age bearing the burden of the epidemic. Given the urgency of the HIV epidemic among vulnerable women in South Africa, it is imperative that evidence-based interventions be implemented rapidly into practice. This study presents a first step toward examining the acceptability and feasibility of implementing the Women's Health CoOp (WHC) in clinics and substance abuse rehab settings in Cape Town, South Africa. METHODS: We conducted focus group discussions with women who use substances and with service providers, we also conducted in-depth interviews with health service planners. Our goal was to examine implementation and clinical outcomes associated with delivery of the WHC across clinics and substance abuse rehab programs. RESULTS: All participants agreed on the need for the WHC. Perceived facilitators to implementing the WHC included the recognizable need for programs to empower women and to build the capacity of staff to address issues of substance use, sexual risk, and intimate partner violence. Participants also identified potential barriers to women engaging with this program, including the stigma women experience when seeking services and the lack of person-centered care at healthcare facilities. CONCLUSIONS: In a country with the largest number of women of childbearing age living with HIV, an evidence-based woman-focused intervention that comprehensively addresses women's risk for suboptimal antiretroviral adherence may be essential for reducing HIV incidence. However, potential barriers to implementing the WHC successfully must be addressed before the program can be fully integrated into the services delivered by healthcare facilities. TRIAL REGISTRATION: Clinical trials NCT02733003 . Date of Registration: January 21, 2016, registered retroactively after participant enrollment. PMID- 29157231 TI - Risk factors for contralateral inguinal hernia repair after unilateral inguinal hernia repair in male adult patients: analysis from a nationwide population based cohort study. AB - BACKGROUND: To identify the rate of and risk factors for contralateral inguinal hernia (CIH) after unilateral inguinal hernia repair in adult male patients. METHODS: This retrospective cohort study identified from the Taiwan National Health Insurance Research Database (NHIRD). Information on all adult patients who underwent primary unilateral inguinal hernia repair without any other operation was collected using ICD-9 diagnostic and procedure codes. The exclusion criteria were laparoscopic hernia repair, non-primary repair, complicated hernia, other combined procedures, female and undetermined gender. RESULTS: A total of 170,492 adult male patients were included, with a median follow-up of 87 months. The overall CIH rate was 10.5%, with a median time of 48 months to a subsequent hernia operation. The 1-year, 2-year, 3-year and 5-year-recurrent rate was 2.6, 3, 4.3, and 6.7% respectively. Further, 3.7% patients who underwent CIH repair had a complicated inguinal hernia. Multivariate analysis demonstrated that age > 45 y, direct hernia, cirrhosis (HR = 1.564), severe liver disease (HR = 1.663), prostate disease (HR = 1.178), congestive heart failure (HR = 1.138), and history of malignancy (HR = 1.116) had a significantly higher risk of CIH repair. CONCLUSIONS: Among adult male patients undergoing long-term follow-up, we identified several significant risk factors for CIH repair. If these risk factors are presented, the surgeon should inform the following risk of CIH repair to patients so that it can be repaired as soon as possible. PMID- 29157232 TI - Implementation of an interprofessional team-based learning program involving seven undergraduate health and social care programs from two universities, and students' evaluation of their readiness for interprofessional learning. AB - BACKGROUND: Interprofessional learning is gaining momentum in revolutionizing healthcare education. During the academic year 2015/16, seven undergraduate-entry health and social care programs from two universities in Hong Kong took part in an interprofessional education program. Based on considerations such as the large number of students involved and the need to incorporate adult learning principles, team-based learning was adopted as the pedagogy for the program, which was therefore called the interprofessional team-based learning program (IPTBL). The authors describe the development and implementation of the IPTBL program and evaluate the effectiveness of the program implementation. METHODS: Eight hundred and one students, who are predominantly Chinese, participated in the IPTBL. The quantitative design (a pretest-posttest experimental design) was utilized to examine the students' gains on their readiness to engage in interprofessional education (IPE). RESULTS: Three instructional units (IUs) were implemented, each around a clinical area which could engage students from complementary health and social care disciplines. Each IU followed a team-based learning (TBL) process: pre-class study, individual readiness assurance test, team readiness assurance test, appeal, feedback, and application exercise. An electronic platform was developed and was progressively introduced in the three IUs. The students' self-perceived attainment of the IPE learning outcomes was high. Across all four subscales of RIPLS, there was significant improvement in student's readiness to engage in interprofessional learning after the IPTBL. A number of challenges were identified: significant time involvement of the teachers, difficulty in matching students from different programs, difficulty in making IPTBL count towards a summative assessment score, difficulty in developing the LAMS platform, logistics difficulty in managing paper TBL, and inappropriateness of the venue. CONCLUSIONS: Despite some challenges in developing and implementing the IPTBL program, our experience showed that TBL is a viable pedagogy to be used in interprofessional education involving hundreds of students. The significant improvement in all four subscales of RIPLS showed the effects of the IPTBL program in preparing students for collaborative practice. Factors that contributed to the success of the use of TBL for IPE are discussed. PMID- 29157233 TI - Integrating acute stroke telemedicine consultations into specialists' usual practice: a qualitative analysis comparing the experience of Australia and the United Kingdom. AB - BACKGROUND: Stroke telemedicine can reduce healthcare inequities by increasing access to specialists. Successful telemedicine networks require specialists adapting clinical practice to provide remote consultations. Variation in experiences of specialists between different countries is unknown. To support future implementation, we compared perceptions of Australian and United Kingdom specialists providing remote acute stroke consultations. METHODS: Specialist participants were identified using purposive sampling from two new services: Australia's Victorian Stroke Telemedicine Program (n = 6; 2010-13) and the United Kingdom's Cumbria and Lancashire telestroke network (n = 5; 2010-2012). Semi structured interviews were conducted pre- and post-implementation, recorded and transcribed verbatim. Deductive thematic and content analysis (NVivo) was undertaken by two independent coders using Normalisation Process Theory to explore integration of telemedicine into practice. Agreement between coders was M = 91%, SD = 9 and weighted average kappa = 0.70. RESULTS: Cross-cultural similarities and differences were found. In both countries, specialists described old and new consulting practices, the purpose and value of telemedicine systems, and concerns regarding confidence in the assessment and diagnostic skills of unknown colleagues requesting telemedicine support. Australian specialists discussed how remote consultations impacted on usual roles and suggested future improvements, while United Kingdom specialists discussed system governance, policy and procedures. CONCLUSION: Australian and United Kingdom specialists reported telemedicine required changes in work practice and development of new skills. Both groups described potential for improvements in stroke telemedicine systems with Australian specialists more focused on role change and the United Kingdom on system governance issues. Future research should examine if cross cultural variation reflects different models of care and extends to other networks. PMID- 29157234 TI - Zinc transporters and insulin resistance: therapeutic implications for type 2 diabetes and metabolic disease. AB - BACKGROUND: Zinc is a metal ion that is essential for growth and development, immunity, and metabolism, and therefore vital for life. Recent studies have highlighted zinc's dynamic role as an insulin mimetic and a cellular second messenger that controls many processes associated with insulin signaling and other downstream pathways that are amendable to glycemic control. MAIN BODY: Mechanisms that contribute to the decompartmentalization of zinc and dysfunctional zinc transporter mechanisms, including zinc signaling are associated with metabolic disease, including type 2 diabetes. The actions of the proteins involved in the uptake, storage, compartmentalization and distribution of zinc in cells is under intense investigation. Of these, emerging research has highlighted a role for several zinc transporters in the initiation of zinc signaling events in cells that lead to metabolic processes associated with maintaining insulin sensitivity and thus glycemic homeostasis. CONCLUSION: This raises the possibility that zinc transporters could provide novel utility to be targeted experimentally and in a clinical setting to treat patients with insulin resistance and thus introduce a new class of drug target with utility for diabetes pharmacotherapy. PMID- 29157235 TI - Telomere tracking from birth to adulthood and residential traffic exposure. AB - BACKGROUND: Telomere attrition is extremely rapid during the first years of life, while lifestyle during adulthood exerts a minor impact. This suggests that early life is an important period in the determination of telomere length. We investigated the importance of the early-life environment on both telomere tracking and adult telomere length. METHODS: Among 184 twins of the East Flanders Prospective Twin Survey, telomere length in placental tissue and in buccal cells in young adulthood was measured. Residential addresses at birth and in young adulthood were geocoded and residential traffic and greenness exposure was determined. RESULTS: We investigated individual telomere tracking from birth over a 20 year period (mean age (SD), 22.6 (3.1) years) in association with residential exposure to traffic and greenness. Telomere length in placental tissue and in buccal cells in young adulthood correlated positively (r = 0.31, P < 0.0001). Persons with higher placental telomere length at birth were more likely to have a stronger downward shift in telomere ranking over life (P < 0.0001). Maternal residential traffic exposure correlated inversely with telomere length at birth. Independent of birth placental telomere length, telomere ranking between birth and young adulthood was negatively and significantly associated with residential traffic exposure at the birth address, while traffic exposure at the residential address at adult age was not associated with telomere length. CONCLUSIONS: Longitudinal evidence of telomere length tracking from birth to adulthood shows inverse associations of residential traffic exposure in association with telomere length at birth as well as accelerated telomere shortening in the first two decades of life. PMID- 29157236 TI - Monitoring of nutrient limitation in growing E. coli: a mathematical model of a ppGpp-based biosensor. AB - BACKGROUND: E. coli can be used as bacterial cell factories for production of biofuels and other useful compounds. The efficient production of the desired products requires careful monitoring of growth conditions and the optimization of metabolic fluxes. To avoid nutrient depletion and maximize product yields we suggest using a natural mechanism for sensing nutrient limitation, related to biosynthesis of an intracellular messenger - guanosine tetraphosphate (ppGpp). RESULTS: We propose a design for a biosensor, which monitors changes in the intracellular concentration of ppGpp by coupling it to a fluorescent output. We used mathematical modelling to analyse the intracellular dynamics of ppGpp, its fluorescent reporter, and cell growth in normal and fatty acid-producing E. coli lines. The model integrates existing mechanisms of ppGpp regulation and predicts the biosensor response to changes in nutrient state. In particular, the model predicts that excessive stimulation of fatty acid production depletes fatty acid intermediates, downregulates growth and increases the levels of ppGpp-related fluorescence. CONCLUSIONS: Our analysis demonstrates that the ppGpp sensor can be used for early detection of nutrient limitation during cell growth and for testing productivity of engineered lines. PMID- 29157237 TI - Isolation and identification of culturable fungi from the genitals and semen of healthy giant pandas (Ailuropoda melanoleuca). AB - BACKGROUND: In order to better understand the possible role of fungi in giant panda reproduction and overall health, it is important to provide a baseline for the normal fungal composition in the reproductive system. Using morphology and internal transcribed spacer (ITS) sequence analysis, we systematically isolated and identified fungal species from the vagina, foreskin, and semen of 21 (11 males and 10 females) healthy giant pandas to understand the normal fungal flora of the genital tracts. RESULTS: A total of 76 fungal strains were obtained, representing 42 genera and 60 species. Among them 47 fungal strains were obtained from vaginal samples, 24 from foreskins, and 5 from semen samples. Several fungal strains were isolated from more than one sample. More fungal species were isolated from females from males. The predominant genera were Aspergillus, Trichosporon, and Penicillium, followed by Candida, Cladosporium, Sordariomycetes, and Diaporthe. The average number of strains in the female vagina was significantly higher than in the foreskin and semen of male. CONCLUSIONS: A total of 60 fungal species (belonging to 42 genera) were identified in the giant panda's genital tract. Some of the species were commonly shared in both males and females. These findings provide novel information on the fungal community in the reproductive tracts of giant pandas. PMID- 29157238 TI - Evaluation of normal swallowing functions by using dynamic high-density surface electromyography maps. AB - BACKGROUND: Swallowing is a continuous process with substantive interdependencies among different muscles, and it plays a significant role in our daily life. The aim of this study was to propose a novel technique based on high-density surface electromyography (HD sEMG) for the evaluation of normal swallowing functions. METHODS: A total of 96 electrodes were placed on the front neck to acquire myoelectric signals from 12 healthy subjects while they were performing different swallowing tasks. HD sEMG energy maps were constructed based on the root mean square values to visualize muscular activities during swallowing. The effects of different volumes, viscosities, and head postures on the normal swallowing process were systemically investigated by using the energy maps. RESULTS: The results showed that the HD sEMG energy maps could provide detailed spatial and temporal properties of the muscle electrical activity, and visualize the muscle contractions that closely related to the swallowing function. The energy maps also showed that the swallowing time and effort was also explicitly affected by the volume and viscosity of the bolus. The concentration of the muscular activities shifted to the opposite side when the subjects turned their head to either side. CONCLUSIONS: The proposed method could provide an alternative method to physiologically evaluate the dynamic characteristics of normal swallowing and had the advantage of providing a full picture of how different muscle activities cooperate in time and location. The findings from this study suggested that the HD sEMG technique might be a useful tool for fast screening and objective assessment of swallowing disorders or dysphagia. PMID- 29157239 TI - Does faculty development influence the quality of in-training evaluation reports in pharmacy? AB - BACKGROUND: In-training evaluation reports (ITERs) of student workplace-based learning are completed by clinical supervisors across various health disciplines. However, outside of medicine, the quality of submitted workplace-based assessments is largely uninvestigated. This study assessed the quality of ITERs in pharmacy and whether clinical supervisors could be trained to complete higher quality reports. METHODS: A random sample of ITERs submitted in a pharmacy program during 2013-2014 was evaluated. These ITERs served as a historical control (control group 1) for comparison with ITERs submitted in 2015-2016 by clinical supervisors who participated in an interactive faculty development workshop (intervention group) and those who did not (control group 2). Two trained independent raters scored the ITERs using a previously validated nine item scale assessing report quality, the Completed Clinical Evaluation Report Rating (CCERR). The scoring scale for each item is anchored at 1 ("not at all") and 5 ("exemplary"), with 3 categorized as "acceptable". RESULTS: Mean CCERR score for reports completed after the workshop (22.9 +/- 3.39) did not significantly improve when compared to prospective control group 2 (22.7 +/- 3.63, p = 0.84) and were worse than historical control group 1 (37.9 +/- 8.21, p = 0.001). Mean item scores for individual CCERR items were below acceptable thresholds for 5 of the 9 domains in control group 1, including supervisor documented evidence of specific examples to clearly explain weaknesses and concrete recommendations for student improvement. Mean item scores for individual CCERR items were below acceptable thresholds for 6 and 7 of the 9 domains in control group 2 and the intervention group, respectively. CONCLUSIONS: This study is the first using CCERR to evaluate ITER quality outside of medicine. Findings demonstrate low baseline CCERR scores in a pharmacy program not demonstrably changed by a faculty development workshop, but strategies are identified to augment future rater training. PMID- 29157240 TI - Automatic diagnosis of imbalanced ophthalmic images using a cost-sensitive deep convolutional neural network. AB - BACKGROUND: Ocular images play an essential role in ophthalmological diagnoses. Having an imbalanced dataset is an inevitable issue in automated ocular diseases diagnosis; the scarcity of positive samples always tends to result in the misdiagnosis of severe patients during the classification task. Exploring an effective computer-aided diagnostic method to deal with imbalanced ophthalmological dataset is crucial. METHODS: In this paper, we develop an effective cost-sensitive deep residual convolutional neural network (CS-ResCNN) classifier to diagnose ophthalmic diseases using retro-illumination images. First, the regions of interest (crystalline lens) are automatically identified via twice-applied Canny detection and Hough transformation. Then, the localized zones are fed into the CS-ResCNN to extract high-level features for subsequent use in automatic diagnosis. Second, the impacts of cost factors on the CS-ResCNN are further analyzed using a grid-search procedure to verify that our proposed system is robust and efficient. RESULTS: Qualitative analyses and quantitative experimental results demonstrate that our proposed method outperforms other conventional approaches and offers exceptional mean accuracy (92.24%), specificity (93.19%), sensitivity (89.66%) and AUC (97.11%) results. Moreover, the sensitivity of the CS-ResCNN is enhanced by over 13.6% compared to the native CNN method. CONCLUSION: Our study provides a practical strategy for addressing imbalanced ophthalmological datasets and has the potential to be applied to other medical images. The developed and deployed CS-ResCNN could serve as computer aided diagnosis software for ophthalmologists in clinical application. PMID- 29157241 TI - Organizational and provider level factors in implementation of trauma-informed care after a city-wide training: an explanatory mixed methods assessment. AB - BACKGROUND: While there is increasing support for training youth-serving providers in trauma-informed care (TIC) as a means of addressing high prevalence of U.S. childhood trauma, we know little about the effects of TIC training on organizational culture and providers' professional quality of life. This mixed methods study evaluated changes in organizational- and provider-level factors following participation in a citywide TIC training. METHODS: Government workers and nonprofit professionals (N = 90) who participated in a nine-month citywide TIC training completed a survey before and after the training to assess organizational culture and professional quality of life. Survey data were analyzed using multiple regression analyses. A subset of participants (n = 16) was interviewed using a semi-structured format, and themes related to organizational and provider factors were identified using qualitative methods. RESULTS: Analysis of survey data indicated significant improvements in participants' organizational culture and professional satisfaction at training completion. Participants' perceptions of their own burnout and secondary traumatic stress also increased. Four themes emerged from analysis of the interview data, including "Implementation of more flexible, less-punitive policies towards clients," "Adoption of trauma-informed workplace design," "Heightened awareness of own traumatic stress and need for self-care," and "Greater sense of camaraderie and empathy for colleagues." CONCLUSION: Use of a mixed-methods approach provided a nuanced understanding of the impact of TIC training and suggested potential benefits of the training on organizational and provider-level factors associated with implementation of trauma-informed policies and practices. Future trainings should explicitly address organizational factors such as safety climate and morale, managerial support, teamwork climate and collaboration, and individual factors including providers' compassion satisfaction, burnout, and secondary traumatic stress, to better support TIC implementation. PMID- 29157242 TI - Development and validation of a structured observation scale to measure responsiveness of physicians in rural Bangladesh. AB - BACKGROUND: Responsiveness of physicians is the social actions that physicians do to meet the legitimate expectations of service seekers. Since there is no such scale, this study aimed at developing one for measuring responsiveness of physicians in rural Bangladesh, by structured observation method. METHODS: Data were collected from Khulna division of Bangladesh, through structured observation of 393 patient-consultations with physicians. The structured observation tool consisted of 64 items, with four Likert type response categories, each anchored with a defined scenario. Inter-rater reliability was assessed by same three raters observing 30 consultations. Data were analyzed by exploratory factor analysis (EFA), followed by assessment of internal consistency by ordinal alpha coefficient, inter-rater reliability by intra-class correlation coefficient (ICC), concurrent validity by correlating responsiveness score with waiting time, and known group validity by comparing public and private sector physicians. RESULTS: After removing items with more than 50% missing values, 45 items were considered for EFA. Parallel analysis suggested a 5-factor model. Nine items were removed from the list owing to < 0.50 communality, <0.32 loading in un-rotated matrix, and <0.30 on any factor in rotated matrix. Since 34 items (i.e., the number of remaining items after removing nine items by EFA) were loaded neatly under five factors, explained 61.38% of common variance, and demonstrated high internal consistency with coefficient of 0.91, this was adopted as the Responsiveness of Physicians Scale (ROP-Scale). The five factors were named as 1) Friendliness, 2) Respecting, 3) Informing and guiding, 4) Gaining trust, and 5) Financial sensitivity. Inter-rater reliability was high, with an ICC of 0.64 for individual rater's reliability and 0.84 for average reliability scores. Positive correlation with waiting time (0.51), and higher score of private sector by 0.18 point denote concurrent, and known group validity, respectively. CONCLUSIONS: The ROP-Scale consists of 34 items grouped under five factors. One can apply this with confidence in comparable settings, as this scale demonstrated high internal consistency and inter-rater reliability. More research is needed to test this scale in other settings and with other types of providers. PMID- 29157243 TI - Factors influencing the use of malaria prevention strategies by women in Senegal: a cross-sectional study. AB - BACKGROUND: The World Health Organization (WHO) recommends the use of insecticide treated nets (ITNs) and intermittent preventive treatment in pregnancy (IPTp) as a cost-effective intervention for the prevention of malaria during pregnancy in endemic areas. This study was conducted to investigate: (1) the extent of use of both IPTp and ITNs, and (2) conduct multinomial regression to identify factors affecting the optimal usage of IPTp and ITNs among women with a recent pregnancy in Senegal. METHODS: Data was drawn from the 2013-2014 Demographic and Health Survey. A total of 4616 women aged 15-49 years old, who had a recent pregnancy were analyzed. Multinomial logistic regression model was used to assess factors associated with optimal uptake of malaria preventive strategies (both IPTp and ITN use). RESULTS: Amongst women who had a recent pregnancy, less than half of them used ITNs (46.84%) however, 80.35% reported taking IPTp during their last pregnancy. Overall, 37.51% reported using the optimal malaria preventive strategies. Women aged 35-49 years and living in the richer or middle wealth quintile were more likely to use optimal prevention methods. Pregnant women living in Diourbel, Saint-Louis, Thies, Louga, Fatick and Matam were more likely to use both IPTp-SP and ITNs compared to those living in Dakar. Additionally, women who initiated antenatal care in at least at 6 weeks of pregnancy or who attended four antenatal visits or more were more likely to use optimal malaria preventive methods during pregnancy. CONCLUSIONS: This study has shown important factors that influence the uptake of malaria prevention methods during pregnancy in Senegal. These findings highlight the need for targeted preventive strategies when designing and implementing policies aimed at improving the uptake of these measures during pregnancy in Senegal. PMID- 29157244 TI - Antimicrobial stewardship: a qualitative study of the development of national guidelines for antibiotic use in hospitals. AB - BACKGROUND: As effective antibiotics are becoming a scarce resource, governmental regulation is needed to promote responsible use. Implementation of antibiotic stewardship and practice guidelines in health care facilities seems to be crucial to this effort. Empirical studies suggest, however, that guidelines have limited influence on health professionals' behavior and practice. Barriers and facilitators to guideline implementability are much studied, but little attention has been given to health professionals' perceptions of normative acceptability of guidelines as a condition for compliance. The aim of the present study was first, to examine if and how aspects potentially promoting acceptability and compliance among clinical target users were addressed during development of Norwegian national guidelines for antibiotic use in hospitals and second, to identify procedural characteristics of the development process that were perceived by target users to yield legitimate guidelines. METHODS: Qualitative deductive thematic analysis was used. A theoretical framework inspired by the AGREE II Instrument and the Accountability for reasonableness framework assisted data gathering and interpretation. Archival data was collected and used to detail the guideline development process. Semi-structured, in-depth interviews with eight clinicians with extensive knowledge of the guidelines were carried out. RESULTS: Guideline development was characterized by i) broad agreement about scope and purpose, ii) broad involvement of stakeholders in the development process, iii) use of systematic methods to search for and apply evidence, iv) easily identifiable and specific recommendations, v) provision of tools on how to put recommendations into practice, and vi) editorial independence. Several procedural characteristics were perceived by the interviewees as promoting guideline legitimacy; i) diverse perspectives systematically involved in the process, ii) accessibility and transparency of the rationales for decision making, iii) opportunities for appeals and reconsiderations, and iv) regulative authority. CONCLUSIONS: This study provides insights as to how guidelines that are intended to promote responsible use of antibiotics in hospitals can be carefully developed to facilitate perceptions of relevance, transparency, and authority by health professionals. PMID- 29157245 TI - Low 1,5-anhydroglucitol levels are associated with long-term cardiac mortality in acute coronary syndrome patients with hemoglobin A1c levels less than 7.0. AB - BACKGROUND: Diabetes mellitus is considered an important risk factor for cardiovascular diseases. High hemoglobin A1c (HbA1c) levels, which indicate poor glycemic control, have been associated with occurrence of cardiovascular diseases. There are few parameters which can predict cardiovascular risk in patients with well-controlled diabetes. Low 1,5-anhydroglucitol (1,5-AG) levels are considered a clinical marker of postprandial hyperglycemia. We hypothesized that low 1,5-AG levels could predict long-term mortality in acute coronary syndrome (ACS) patients with relatively low HbA1c levels. METHODS: The present study followed a retrospective observational study design. We enrolled 388 consecutive patients with ACS admitted to the cardiac intensive care unit at the Juntendo University Hospital from January 2011 to December 2013. Levels of 1,5-AG were measured immediately before emergency coronary angiography. Patients with early stent thrombosis, no significant coronary artery stenosis, malignancy, liver cirrhosis, a history of gastrectomy, current steroid treatment, moderately to severely reduced kidney function (estimated glomerular filtration rate < 45 ml/min/1.73 m2; chronic kidney disease stage 3B, 4, and 5), HbA1c levels >= 7.0%, and those who received sodium glucose co-transporter 2 inhibitor therapy were excluded. RESULTS: During the 46.9-month mean follow-up period, nine patients (4.5%) died of cardiovascular disease. The 1,5-AG level was significantly lower in the cardiac death group compared with that in the survivor group (12.3 +/- 5.3 vs. 19.2 +/- 7.7 ug/ml, p < 0.01). Kaplan-Meier survival analysis showed that low 1,5-AG levels were associated with cardiac mortality (p = 0.02). Multivariable Cox regression analysis showed that 1,5-AG levels were an independent predictor of cardiac mortality (hazard ratio 0.76; 95% confidence interval 0.41-0.98; p = 0.03). CONCLUSION: Low 1,5-AG levels, which indicate postprandial hyperglycemia, predict long-term cardiac mortality even in ACS patients with HbA1c levels < 7.0%. PMID- 29157246 TI - Inferring gene regulatory networks from single-cell data: a mechanistic approach. AB - BACKGROUND: The recent development of single-cell transcriptomics has enabled gene expression to be measured in individual cells instead of being population averaged. Despite this considerable precision improvement, inferring regulatory networks remains challenging because stochasticity now proves to play a fundamental role in gene expression. In particular, mRNA synthesis is now acknowledged to occur in a highly bursty manner. RESULTS: We propose to view the inference problem as a fitting procedure for a mechanistic gene network model that is inherently stochastic and takes not only protein, but also mRNA levels into account. We first explain how to build and simulate this network model based upon the coupling of genes that are described as piecewise-deterministic Markov processes. Our model is modular and can be used to implement various biochemical hypotheses including causal interactions between genes. However, a naive fitting procedure would be intractable. By performing a relevant approximation of the stationary distribution, we derive a tractable procedure that corresponds to a statistical hidden Markov model with interpretable parameters. This approximation turns out to be extremely close to the theoretical distribution in the case of a simple toggle-switch, and we show that it can indeed fit real single-cell data. As a first step toward inference, our approach was applied to a number of simple two-gene networks simulated in silico from the mechanistic model and satisfactorily recovered the original networks. CONCLUSIONS: Our results demonstrate that functional interactions between genes can be inferred from the distribution of a mechanistic, dynamical stochastic model that is able to describe gene expression in individual cells. This approach seems promising in relation to the current explosion of single-cell expression data. PMID- 29157248 TI - Implementation and use of standardized outcome measures by physical therapists in Saudi Arabia: barriers, facilitators and perceptions. AB - BACKGROUND: The use of standardized outcome measures (SOMs) has been recommended in the physical therapy practice guidelines to improve the patient's management and encourage the evidence based practice. However, the extent of the use of SOMs by physical therapists (PTs) in Saudi Arabia was not investigated. The present study aimed to (1) evaluate the extent of the use of SOMs by PTs in routine daily practice in Saudi Arabia; (2) explore the barriers, facilitators and perceptions in the use of SOMs during physical therapy services; (3) examine the relationship between facility settings and the PTs characteristics and the use of SOMs. METHODS: The present study used an observational design. A survey based questionnaire used and distributed to 352 PTs who were working in Saudi Arabia and was commonly involved in the management of patients within different clinical settings, either private or public. RESULTS: One-hundred-eighty participants completed the questionnaires (response rate of 51%). One-hundred-eleven (62%) participants indicated that they used SOMs in their practice. The most common barriers to using the SOMs were time-consuming for patients and therapist and difficult to understand the outcome measures by the patients. Those with a Masters degree were 3.5 times more likely to use SOMs compared to PTs with diploma level qualification [Odd Ratio (95% CI) 3.5 (0.9-12.6)]. Participants with a clinical specialty were nearly 3 times more likely to use SOMs than those who do not have a specialty [Odd Ratio (95% CI) 2.9 (1.6-5.5)]. CONCLUSIONS: Nearly two-thirds of the participants indicated that they used SOMs in clinical practice. Time-consuming for patient and therapist, difficult to understand the SOMs by the patients were the main perceived barriers. Years of experience, professional degree, and clinical specialty had a high probability of using SOMs. The majority of the participants showed the willingness to use SOMs in the future. PMID- 29157247 TI - Effects of implant length and 3D bone-to-implant contact on initial stabilities of dental implant: a microcomputed tomography study. AB - BACKGROUND: The influences of potential bone-to-implant contact (BIC) area (pBICA), BIC area (BICA), and three dimensional (3D) BIC percentage (3D BIC%; defined as BICA divided by pBICA) in relation to the implant length on initial implant stability were studied. Correlations between these parameters were also evaluated. METHODS: Implants with lengths of 8.5, 10, 11.5, and 13 mm were placed in artificial bone specimens to measure three indexes of the initial implant stability: insertion torque value (ITV), Periotest value (PTV), and implant stability quotient (ISQ). The implants and bone specimens were also scanned by microcomputed tomography, and the obtained images were imported into Mimics software to reconstruct the 3D models and calculate the parameters of 3D bone-to implant contact including pBICA, BICA, and 3D BIC%. The Kruskal-Wallis test, Wilcoxon rank-sum test with Bonferroni adjustment, and Spearman correlations were applied for statistical and correlation analyses. RESULTS: The implant length affected ITV more than PTV and ISQ, and significantly affected pBICA, BICA, and 3D BIC%. A longer implant increased pBICA and BICA but decreased 3D BIC%. The Spearman coefficients were high (>0.78) for the correlations between the three 3D BIC parameters and the three indexes of the initial implant stability. CONCLUSIONS: pBICA, BICA, and 3D BIC% are useful when deciding on treatment plans related to various implant lengths, since these 3D BIC parameters are predictive of the initial implant stability. PMID- 29157249 TI - Biomechanical study of isolated radial head dislocation. AB - BACKGROUND: Isolated radial head dislocation is a rare injury with an unclear pathomechanism, and the treatment is controversial. The purpose of the present study was to investigate the biomechanical contributions of the annular ligament, quadrate ligament, interosseous membrane, and annular ligament reconstructions to proximal radioulnar joint stability. METHODS: Five fresh frozen cadaveric upper extremities were amputated above the elbow and solidly fixed on a customized jig. Radial head dislocation was reproduced by sequential sectioning of ligamentous structures and passive mobility testing. Radial head displacement during mobility testing was measured with an electromagnetic tracking device in three forearm rotation positions. The data were compared among different sectioning stages and between two types of simulated ligamentous reconstruction. RESULTS: Lateral displacement of the radial head significantly increased in the neutral forearm rotation after annular ligament sectioning (46 +/- 10%, p < 0.05). After quadrate ligament sectioning, we found significant posterior (67 +/- 36%, p < 0.05) and lateral (74 +/- 24%, p < 0.01) displacement in neutral forearm rotation and pronation. Significant radial head displacement was found in all directions and in all forearm positions after sequential sectioning of the proximal half of the interosseous membrane. Anatomical annular ligament reconstruction stabilized the proximal radioulnar joint except for anterior laxity in neutral forearm rotation (15 +/- 6%, p < 0.05). The radial head with Bell Tawse procedure was significantly displaced in all directions. CONCLUSION: The direction of radial head instability varied depending on the degree of soft tissue sectioning and specific forearm rotation. Anterior radial head dislocation may involve more severe ligament damage than other types of dislocation. Anatomical annular ligament reconstruction provided multidirectional radial head stability. PMID- 29157250 TI - Ozone exposure is associated with acute changes in inflammation, fibrinolysis, and endothelial cell function in coronary artery disease patients. AB - BACKGROUND: Air pollution is a major risk factor for cardiovascular disease, of which ozone is a major contributor. Several studies have found associations between ozone and cardiovascular morbidity, but the results have been inconclusive. We investigated associations between ozone and changes across biological pathways associated with cardiovascular disease. METHODS: Using a panel study design, 13 participants with coronary artery disease were assessed for markers of systemic inflammation, heart rate variability and repolarization, lipids, blood pressure, and endothelial function. Daily measurements of ozone and particulate matter (PM2.5) were obtained from central monitoring stations. Single (ozone) and two-pollutant (ozone and PM2.5) models were used to assess percent changes in measurements per interquartile ranges of pollutants. RESULTS: Per interquartile increase in ozone, changes in tissue plasminogen factor (6.6%, 95% confidence intervals (CI) = 0.4, 13.2), plasminogen activator inhibitor-1 (40.5%, 95% CI = 8.7, 81.6), neutrophils (8.7% 95% CI = 1.5, 16.4), monocytes (10.2%, 95% CI = 1.0, 20.1), interleukin-6 (15.9%, 95% CI = 3.6, 29.6), large-artery elasticity index (-19.5%, 95% CI = -34.0, -1.7), and the baseline diameter of the brachial artery (-2.5%, 95% CI = -5.0, 0.1) were observed. These associations were robust in the two-pollutant model. CONCLUSIONS: We observed alterations across several pathways associated with cardiovascular disease in 13 coronary artery disease patients following ozone exposures, independent of PM2.5. The results support the biological plausibility of ozone-induced cardiovascular effects. The effects were found at concentrations below the EPA National Ambient Air Quality Standards for both ozone and PM2.5. PMID- 29157251 TI - Slender women and overweight men: gender differences in the educational gradient in body weight in South Korea. AB - BACKGROUND: Little is known about the gender-specific mechanisms through which education is associated with weight status in societies that have experienced a rapid rise in their obesity rates. This study extends previous literature by examining how the link between education and weight status operates within the structure of gender relations in South Korea where huge gender differences have been observed in the educational inequalities in weight status. METHODS: Using the Korean National Health Survey (N = 17,947) conducted in 2008-2012 conditional quantile regression models were estimated to assess the associations between education and body weight distribution. The mean difference in the predicted probabilities of perceiving body image as average was compared by educational attainment for women and men while setting all other covariates at their means. RESULTS: Highly educated women were more likely to utilize their human capital to obtain slender body shape and the relationship was not mediated by economic resources. In contrast, education was positively associated with being overweight and obesity among men, for whom behaviors promoting healthy weight often conflict with a collective ideology at work that strongly supports long work hours and heavy alcohol consumption. Furthermore, Korean men were more likely to under perceive their body size than Korean women, that is, overweight men tend to consider themselves to be of 'average' weight, regardless of their educational attainment. CONCLUSIONS: Current study found that gender inequalities in social status in South Korea operate to affect the relationship between education and weight status among men and women in unique ways. Weight status can be socially patterned by the interplay between education, economic, and behavioral resources within the structure of gender relations. PMID- 29157252 TI - Diet quality and therapeutic targets in patients with type 2 diabetes: evaluation of concordance between dietary indexes. AB - BACKGROUND: This study aimed to evaluate the concordance between two dietary indexes, the Healthy Eating Index (HEI) and the Diabetes Healthy Eating Index (DHEI), in evaluating diet quality and its possible association with therapeutic targets in patients with type 2 diabetes. METHODS: Cross-sectional study of outpatients with type 2 diabetes mellitus treated at a university hospital. Dietary information was obtained from a quantitative food frequency questionnaire (previously validated for use in patients with type 2 diabetes) and converted into daily intakes. Diet quality was assessed using two dietary indexes: HEI (12 components, nine food groups and three moderation components) and DHEI (10 components, six food groups, three nutrient groups, and one for variety of diet). In both indexes, the sum of the scores for each component yields an overall score converted on a scale from 0 to 100%; diet quality is subsequently ranked as low (<51%), needing improvement (51-80%), or high (>80%). Patients underwent clinical and laboratory assessment. Those with fasting blood glucose values 70-130 mg/dL, A1c < 7%, total cholesterol <200 mg/dL, LDL-cholesterol <100 mg/dL, and triglycerides <150 mg/dL were considered to meet therapeutic targets. All analyses were conducted in PASW Statistics 18.0, and p < 0.05 deemed significant. RESULTS: We analyzed 148 patients with type 2 diabetes (73% white, mean age 63.2 +/- 9.4 years, median diabetes duration 10 [IQR 5-19] years, mean A1c% 8.4 +/- 2.0%, and mean BMI 30.5 +/- 4.2 kg/m2). Mean energy intake was 2114 +/- 649 kcal/day. DHEI scores were 17.0 (95%CI -6.8 to 41.0) points lower than HEI scores (55.9 +/- 14.2% vs. 72.9 +/- 10.7%, respectively; P < 0.001), suggesting there is no agreement (Bland-Altman method), and the Pearson correlation coefficient was 0.55 (P < 0.001). More patients were classified as having a low-quality diet by the DHEI than by the HEI (38.5% vs. 1.4%; P < 0.001). A higher proportion of patients (35.7%) with out-of-target total cholesterol levels had a low-quality diet evaluated by the DHEI (P = 0.03). We did not find associations between overall score of HEI and therapeutic targets. CONCLUSIONS: In its intended population of patients with type 2 diabetes, the DHEI seems to be a more rigorous tool to evaluate association between diet quality and changes in metabolic parameters. PMID- 29157253 TI - The no correlation argument: can the morality of conscientious objection be empirically supported? the Italian case. AB - BACKGROUND: The legitimacy of conscientious objection to abortion continues to fuel heated debate in Italy. In two recent decisions, the European Committee for Social Rights underlined that conscientious objection places safe, legal, and accessible care and services out of reach for most Italian women and that the measures that Italy has adopted to guarantee free access to abortion services are inadequate. Nevertheless, the Ministry of Health states that current Italian legislation, if appropriately applied, accommodates both the right to conscientious objection and the right to voluntary abortion. MAIN BODY: One empirical argument used to demonstrate that conscientious objection does not create barriers to abortion is the "no correlation" argument, which the Italian Committee for Bioethics employed to demonstrate that no association exists between conscientious objection and waiting times for voluntary abortion in Italy and to support the weak form of conventional comprise adopted by the Italian legislation to balance the conflict between women' autonomy and healthcare professionals' moral integrity. Conversely, we showed how the "no correlation" argument fails to demonstrate the absence of a relationship between the number of conscientious objectors and waiting times for voluntary abortion, and that the limitations of the "no correlation" argument itself demonstrate how it is still difficult to describe the real effect of conscientious objection on the access to abortion services and to evaluate the suitability of conventional compromise to effectively balance conflicting moral principles. CONCLUSION: Further studies are needed to better describe the relationship between conscientious objection and waiting times for voluntary abortion. If new evidence would show that the increasing proportion of objectors does undermine the efficacy of the Italian law and the right of a woman to freely obtain a voluntary abortion, new ways will need to be found to address the conflict between moral principles and restrict the protection accorded to the principle of moral integrity. This would inevitably imply the need to constrain and to redefine the terms and conditions for claiming conscientious objection. PMID- 29157254 TI - The implementation of medical revalidation: an assessment using normalisation process theory. AB - BACKGROUND: Medical revalidation is the process by which all licensed doctors are legally required to demonstrate that they are up to date and fit to practise in order to maintain their licence. Revalidation was introduced in the United Kingdom (UK) in 2012, constituting significant change in the regulation of doctors. The governing body, the General Medical Council (GMC), envisages that revalidation will improve patient care and safety. This potential however is, in part, dependent upon how successfully revalidation is embedded into routine practice. The aim of this study was to use Normalisation Process Theory (NPT) to explore issues contributing to or impeding the implementation of revalidation in practice. METHODS: We conducted seventy-one interviews with sixty UK policymakers and senior leaders at different points during the development and implementation of revalidation: in 2011 (n = 31), 2013 (n = 26) and 2015 (n = 14). We selected interviewees using purposeful sampling. NPT was used as a framework to enable systematic analysis across the interview sets. RESULTS: Initial lack of consensus over revalidation's purpose, and scepticism about its value, decreased over time as participants recognised the benefits it brought to their practice (coherence category of NPT). Though acceptance increased across time, revalidation was not seen as a legitimate part of their role by all doctors. Key individuals, notably the Responsible Officer (RO), were vital for the successful implementation of revalidation in organisations (cognitive participation category). The ease with which revalidation could be integrated into working practices varied greatly depending on the type of role a doctor held and the organisation they work for and the provision of resources was a significant variable in this (collective action category). Formal evaluation of revalidation in organisations was lacking but informal evaluation was taking place. Revalidation had not yet reached the stage where feedback was being used for improvement (reflexive monitoring category). CONCLUSIONS: Requiring all organisations to use the same revalidation model made revalidation easy to integrate into existing work for some but problematic for others. In order for revalidation to be fully embedded and successful, impeding factors, such as a lack of resources, need to be addressed. PMID- 29157255 TI - Effects of Antarctic krill oil on lipid and glucose metabolism in C57BL/6J mice fed with high fat diet. AB - BACKGROUND: Obesity and other metabolic diseases have become epidemic which greatly affect human health. Diets with healthy nutrition are efficient means to prevent this epidemic occurrence. Novel food resources and process technology were needed for these purpose. In this study, Antarctic krill oil (KO) extracted from a dry krill by a procedure of hot pump dehydration in combined with freezing drying was used to investigate health effect in animals including the growth, lipid and glucose metabolism. METHODS: C57BL/6J mice were fed with a lard based high fat (HF) diet and substituted with KO for a period of 12 weeks in comparison with low fat normal control (NC) diet. Mice body weight and food consumption were recorded. Serum lipid metabolism - of C57BL/6J mice serum was measured. A glucose tolerance tests (GTTs) and pathology analysis of mice were performed at the end of the experiment. RESULTS: The KO fed mice had less body weight gain, less fat accumulation in tissue such as adipose and liver. Dyslipidemia induced by high fat diet was partially improved by KO feeding with significant reduction of serum low density lipoprotein-cholesterol (LDL-C) content. Furthermore, KO feeding also improved glucose metabolism in C57BL/6J mice including a glucose tolerance of about 22% vs. 32% of AUC (area under the curve) for KO vs HF diet and the fast blood glucose level of 8.5 mmol/L, 9.8 mmol/L and 9.3 mmol/L for NC, HF and KO diet groups, respectively. In addition, KO feeding also reduced oxidative damage in liver with a decrease of malondialdehyde (MDA) content and increase of superoxide dismutase (SOD) content. CONCLUSION: This study provided evidence of the beneficial effects of KO on animal health from the processed technology, particularly on lipid and glucose metabolism. This study confirmed that as the Antarctic krill was extracted with a procedure of efficient energy, it might make it possible for Krill oil to be available for food industry. PMID- 29157256 TI - Identifying competitive strategies to improve the performance of hospitals in a competitive environment. AB - BACKGROUND: This study is based on competitive dynamics theory, and discusses competitive actions (including their implementation requirements, strategic orientation, and action complexity) that influence hospitals' performance, while also meeting the requirements of Taiwan's "global budget" insurance payment policy. METHODS: In order to investigate the possible actions of hospitals, the study was conducted in two stages. The first stage investigated the actions of hospitals from March 1 to May 31, 2009. Semi-structured questionnaires were used, which included in-depth interviews with senior supervisors of 10 medium- and large-scale hospitals in central Taiwan. This stage collected data related to the types of actions adopted by the hospitals in previous years. The second stage was based on the data collected from the first stage and on developed questionnaires, which were distributed from June 29 to November 1, 2009. The questionnaires were given to 20 superintendents, deputy superintendents, and supervisors responsible for the management of a hospital, and focused on medical centers and regional hospitals in central Taiwan in order to determine the types and number of competitive actions. RESULTS: First, the strategic orientation of an action has a significantly positive influence on subjective performance. Second, action complexity has a significantly positive influence on the subjective and the objective performance of a hospital. Third, the implementation requirements of actions do not have a significantly positive impact on the subjective or the objective performance of a hospital. CONCLUSION: Managers facing a competitive healthcare environment should adopt competitive strategies to improve the performance of the hospital. PMID- 29157257 TI - Patient safety culture in care homes for older people: a scoping review. AB - BACKGROUND: In recent years, there has been an increasing focus on the role of safety culture in preventing incidents such as medication errors and falls. However, research and developments in safety culture has predominantly taken place in hospital settings, with relatively less attention given to establishing a safety culture in care homes. Despite safety culture being accepted as an important quality indicator across all health and social care settings, the understanding of culture within social care settings remains far less developed than within hospitals. It is therefore important that the existing evidence base is gathered and reviewed in order to understand safety culture in care homes. METHODS: A scoping review was undertaken to describe the availability of evidence related to care homes' patient safety culture, what these studies focused on, and identify any knowledge gaps within the existing literature. Included papers were each reviewed by two authors for eligibility and to draw out information relevant to the scoping review. RESULTS: Twenty-four empirical papers and one literature review were included within the scoping review. The collective evidence demonstrated that safety culture research is largely based in the USA, within Nursing Homes rather than Residential Home settings. Moreover, the scoping review revealed that empirical evidence has predominantly used quantitative measures, and therefore the deeper levels of culture have not been captured in the evidence base. CONCLUSIONS: Safety culture in care homes is a topic that has not been extensively researched. The review highlights a number of key gaps in the evidence base, which future research into safety culture in care home should attempt to address. PMID- 29157258 TI - Impact of earplugs and eye mask on sleep in critically ill patients: a prospective randomized study. AB - BACKGROUND: Poor sleep is common in intensive care unit (ICU) patients, where environmental factors contribute to reduce and fragment sleep. The objective of this study was to evaluate the impact of earplugs and eye mask on sleep architecture in ICU patients. METHODS: A single-center randomized controlled trial of 64 ICU patients was conducted from July 2012 to December 2013. Patients were randomly assigned to sleep with or without earplugs and an eye mask from inclusion until ICU discharge. Polysomnography was performed on the first day and night following inclusion. The primary outcome was the proportion of stage N3 sleep over total sleep time. Secondary outcomes were other descriptors of sleep and major outcome variables. RESULTS: In the intervention group, nine (30%) patients did not wear earplugs all night long. The proportion of N3 sleep was 21 [7-28]% in the intervention group and 11 [3-23]% in the control group (p = 0.09). The duration of N3 sleep was higher among the patients in the intervention group who wore earplugs all night long than in the control group (74 [32-106] vs. 31 [7 76] minutes, p = 0.039). The number of prolonged awakenings was smaller in the intervention group (21 [19-26] vs. 31 [21-47] in the control group, p = 0.02). No significant difference was observed between the two groups in terms of clinical outcome variables. CONCLUSIONS: Earplugs and eye mask reduce long awakenings and increase N3 duration when they are well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02292134 . Registered on 21 Nov 2013. PMID- 29157259 TI - A qualitative exploration of perceptions and experiences of contraceptive use, abortion and post-abortion family planning services (PAFP) in three provinces in China. AB - BACKGROUND: The INPAC project aims to evaluate the effectiveness of integrated post-abortion family planning (PAFP) services into existing hospital based abortion services in China. A qualitative study was conducted in three provinces to contribute to developing effective PAFP services through understanding influences on contraceptive use, experiences of abortion and existing PAFP, and their effect on future contraceptive practices from the perspective of users, in the context of social and institutional change. METHODS: Twenty-nine in-depth interviews (IDIs) were undertaken with women who had experienced abortion between 1 and 6 months prior to interview, recruited from three urban and two rural facilities in each province. Thirteen IDIs were also conducted with male partners. Six focus group discussions (FGDs) were carried out with community members from different social groups, including unmarried and married women and men, urban residents and rural-to-urban migrants. RESULTS: Social networks and norms are important in shaping attitudes and behaviour towards abortion and contraception. Widespread concerns were expressed about side-effects, reliability and effects on future fertility of some modern contraceptives. The combination of limited information and choices and a lack of person-centred counselling in PAFP with anxieties about side effects underlies the widespread use of unreliable methods. Gendered power relations significantly influence contraceptive (non)use, with several examples illustrating women's relative lack of power to decide on a method, particularly in the case of condoms. Although the availability of contraceptive information from respected providers can offer impetus for individual behaviour change, social distance from providers reduces opportunities for clients to discuss their difficulties regarding contraceptive use; particularly, but not exclusively for young, unmarried clients. CONCLUSIONS: Increased access to non-commercial, reliable information on contraceptive methods is needed. PAFP services must go beyond simple information provision to ensure that providers take a more person-centred approach, which considers the most appropriate method for individual clients and probes for the underlying influences on contraceptive (non)use. More sensitive reflection on gender norms and relationships is required during counselling and, where women choose this, efforts should be made to include their male partners. Specific attention to provider positionality and skills for counselling young, unmarried clients is needed. PMID- 29157260 TI - High-resolution and accelerated multi-parametric mapping with automated characterization of vessel disease using intravascular MRI. AB - BACKGROUND: Atherosclerosis is prevalent in cardiovascular disease, but present imaging modalities have limited capabilities for characterizing lesion stage, progression and response to intervention. This study tests whether intravascular magnetic resonance imaging (IVMRI) measures of relaxation times (T1, T2) and proton density (PD) in a clinical 3 Tesla scanner could characterize vessel disease, and evaluates a practical strategy for accelerated quantification. METHODS: IVMRI was performed in fresh human artery segments and swine vessels in vivo, using fast multi-parametric sequences, 1-2 mm diameter loopless antennae and 200-300 MUm resolution. T1, T2 and PD data were used to train a machine learning classifier (support vector machine, SVM) to automatically classify normal vessel, and early or advanced disease, using histology for validation. Disease identification using the SVM was tested with receiver operating characteristic curves. To expedite acquisition of T1, T2 and PD data for vessel characterization, the linear algebraic method ('SLAM') was modified to accommodate the antenna's highly-nonuniform sensitivity, and used to provide average T1, T2 and PD measurements from compartments of normal and pathological tissue segmented from high-resolution images at acceleration factors of R <= 18 fold. The results were validated using compartment-average measures derived from the high-resolution scans. RESULTS: The SVM accurately classified ~80% of samples into the three disease classes. The 'area-under-the-curve' was 0.96 for detecting disease in 248 samples, with T1 providing the best discrimination. SLAM T1, T2 and PD measures for R <= 10 were indistinguishable from the true means of segmented tissue compartments. CONCLUSION: High-resolution IVMRI measures of T1, T2 and PD with a trained SVM can automatically classify normal, early and advanced atherosclerosis with high sensitivity and specificity. Replacing relaxometric MRI with SLAM yields good estimates of T1, T2 and PD an order-of magnitude faster to facilitate IVMRI-based characterization of vessel disease. PMID- 29157261 TI - Role of omics techniques in the toxicity testing of nanoparticles. AB - Nanotechnology is regarded as a key technology of the twenty-first century. Despite the many advantages of nanotechnology it is also known that engineered nanoparticles (NPs) may cause adverse health effects in humans. Reports on toxic effects of NPs relay mainly on conventional (phenotypic) testing but studies of changes in epigenome, transcriptome, proteome, and metabolome induced by NPs have also been performed. NPs most relevant for human exposure in consumer, health and food products are metal, metal oxide and carbon-based NPs. They were also studied quite frequently with omics technologies and an overview of the study results can serve to answer the question if screening for established targets of nanotoxicity (e.g. cell death, proliferation, oxidative stress, and inflammation) is sufficient or if omics techniques are needed to reveal new targets. Regulated pathways identified by omics techniques were confirmed by phenotypic assays performed in the same study and comparison of particle types and cells by the same group indicated a more cell/organ-specific than particle specific regulation pattern. Between different studies moderate overlap of the regulated pathways was observed and cell-specific regulation is less obvious. The lack of standardization in particle exposure, in omics technologies, difficulties to translate mechanistic data to phenotypes and comparison with human in vivo data currently limit the use of these technologies in the prediction of toxic effects by NPs. PMID- 29157262 TI - Immunoproteomic analysis of the excretory-secretory products of Trichinella pseudospiralis adult worms and newborn larvae. AB - BACKGROUND: The nematode Trichinella pseudospiralis is an intracellular parasite of mammalian skeletal muscle cells and exists in a non-encapsulated form. Previous studies demonstrated that T. pseudospiralis could induce a lower host inflammatory response. Excretory-secretory (ES) proteins as the most important products of host-parasite interaction may play the main functional role in alleviating host inflammation. However, the ES products of T. pseudospiralis early stage are still unknown. The identification of the ES products of the early stage facilitates the understanding of the molecular mechanisms of the immunomodulation and may help finding early diagnostic markers. RESULTS: In this study, we used two-dimensional gel electrophoresis (2-DE)-based western blotting coupled with matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF-MS/MS) to separate and identify the T. pseudospiralis adult worms ES products immunoreaction-positive proteins. In total, 400 protein spots were separated by 2-DE. Twenty-eight protein spots were successfully identified using the sera from infected pigs and were characterized to correlate with 12 different proteins of T. pseudospiralis, including adult-specific DNase II-10, poly-cysteine and histidine-tailed protein isoform 2, serine protease, serine/threonine-protein kinase ULK3, enolase, putative venom allergen 5, chymotrypsin-like elastase family member 1, uncharacterized protein, peptidase inhibitor 16, death-associated protein 1, deoxyribonuclease II superfamily and golgin-45. Bioinformatic analyses showed that the identified proteins have a wide diversity of molecular functions, especially deoxyribonuclease II (DNase II) activity and serine-type endopeptidase activity. CONCLUSIONS: Early candidate antigens from the ES proteins of T. pseudospiralis have been screened and identified. Our results suggest these proteins may play key roles during the T. pseudospiralis infection and suppress the host immune response. Further, they are the most likely antigen for early diagnosis and the development of a vaccine against the parasite. PMID- 29157263 TI - LDL receptor blockade reduces mortality in a mouse model of ischaemic stroke without improving tissue-type plasminogen activator-induced brain haemorrhage: towards pre-clinical simulation of symptomatic ICH. AB - BACKGROUND: Symptomatic intracerebral haemorrhage (sICH) following tissue-type plasminogen activator (rt-PA) administration is the most feared and lethal complication of thrombolytic therapy for ischaemic stroke, creating a significant obstacle for a broader uptake of this beneficial treatment. rt-PA also undermines cerebral vasculature stability in a multimodal process which involves engagement with LDL receptor-related protein 1 (LRP-1), potentially underlying the development of sICH. AIMS AND METHODS: We aimed to simulate rt-PA-induced haemorrhagic transformation (HT) in a mouse model of stroke and to assess if it drives symptomatic neurological deterioration and whether it is attenuated by LDL receptor blockade. rt-PA (10 mg/kg) or its vehicle, with or without the LDL receptor antagonist, receptor-associated protein (RAP; 2 mg/kg), were intravenously injected at reperfusion after 0.5 or 4 h of middle cerebral artery occlusion (MCAo). Albumin and haemoglobin content were measured in the perfused mouse brains 24 h post MCAo as indications of blood-brain barrier (BBB) compromise and HT, respectively. RESULTS: rt-PA did not elevate brain albumin and haemoglobin levels in sham mice or in mice subjected to 0.5 h MCAo. In contrast, administration of rt-PA after prolonged MCAo (4 h) caused a marked increase in HT (but similar changes in brain albumin) compared to vehicle, mimicking the clinical shift from a safe to detrimental intervention. Interestingly, this HT did not correlate with functional deficit severity at 24 h, suggesting that it does not play a symptomatic role in our mouse stroke model. Co-administration of RAP with or without rt-PA reduced mortality and neurological scores but did not effectively decrease brain albumin and haemoglobin levels. CONCLUSION: Despite the proven causative relationship between severe HT and neurological deterioration in human stroke, rt-PA-triggered HT in mouse MCAo does not contribute to neurological deficit or simulate sICH. Model limitations, such as the long duration of occlusion required, the type of HT achieved and the timing of deficit assessment may account for this mismatch. Our results further suggest that blockade of LDL receptors improves stroke outcome irrespective of rt-PA, blood-brain barrier breakdown and HT. PMID- 29157264 TI - Identifying "at-risk" patients for sub-optimal beta-lactam exposure in critically ill patients with severe infections. PMID- 29157265 TI - The impact of dual energy CT imaging on dose calculations for pre-clinical studies. AB - BACKGROUND: To investigate the feasibility of using dual-energy CT (DECT) for tissue segmentation and kilovolt (kV) dose calculations in pre-clinical studies and assess potential dose calculation accuracy gain. METHODS: Two phantoms and an ex-vivo mouse were scanned in a small animal irradiator with two distinct energies. Tissue segmentation was performed with the single-energy CT (SECT) and DECT methods. A number of different material maps was used. Dose calculations were performed to verify the impact of segmentations on the dose accuracy. RESULTS: DECT showed better overall results in comparison to SECT. Higher number of DECT segmentation media resulted in smaller dose differences in comparison to the reference. Increasing the number of materials in the SECT method yielded more instability. Both modalities showed a limit to which adding more materials with similar characteristics ceased providing better segmentation results, and resulted in more noise in the material maps and the dose distributions. The effect was aggravated with a decrease in beam energy. For the ex-vivo specimen, the choice of only one high dense bone for the SECT method resulted in large volumes of tissue receiving high doses. For the DECT method, the choice of more than one kind of bone resulted in lower dose values for the different tissues occupying the same volume. For the organs at risk surrounded by bone, the doses were lower when using the SECT method in comparison to DECT, due to the high absorption of the bone. SECT material segmentation may lead to an underestimation of the dose to OAR in the proximity of bone. CONCLUSIONS: The DECT method enabled the selection of a higher number of materials thereby increasing the accuracy in dose calculations. In phantom studies, SECT performed best with three materials and DECT with seven for the phantom case. For irradiations in preclinical studies with kV photon energies, the use of DECT segmentation combined with the choice of a low-density bone is recommended. PMID- 29157266 TI - Doxorubicin combined with low intensity ultrasound suppresses the growth of oral squamous cell carcinoma in culture and in xenografts. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) invades surrounding tissues by upregulating matrix metalloproteinases (MMPs) -2 and -9, which causes over expression of the Hedgehog signaling proteins Shh and Gli-1 and degradation of the extracellular matrix, thereby creating a "highway" for tumor invasion. We explored the potential of low intensity ultrasound (LIUS) and doxorubicin (DOX) to inhibit the formation of this "highway". METHODS: MTT assays were used to examine OSCC cell viability after exposure to LIUS and DOX. The cell morphological changes and ultrastructure were detected by scanning electron microscopy and transmission electron microscopy. Endogenous autophagy-associated proteins were analyzed by immunofluorescent staining and western blotting. Cell migration and invasion abilities were evaluated by Transwell assays. Collagen fiber changes were evaluated by Masson's trichrome staining. Invasion-associated proteins were analyzed by immunohistochemistry and western blotting. RESULTS: LIUS of 1 W/cm2 increased the in vitro DOX uptake into OSCC by nearly 3-fold in three different cell lines and induced transient autophagic vacuoles on the cell surface. The combination of LIUS and 0.2 MUg/ml DOX inhibited tumor cell viability and invasion, promoted tumor stromal collagen deposition, and prolonged the survival of mice. This combination also down-regulated MMP-2, MMP-9, Shh and Gli-1 in tumor xenografts. Collagen fiber expression was negatively correlated with the expression of these proteins in human OSCC samples. CONCLUSIONS: Our findings suggest that effective low dosages of DOX in combination with LIUS can inhibit cell proliferation, migration and invasion, which might be through MMP 2/9 production mediated by the Hedgehog signaling pathway. PMID- 29157267 TI - Transcriptomic analysis reveals the key immune-related signalling pathways of Sebastiscus marmoratus in response to infection with the parasitic ciliate Cryptocaryon irritans. AB - BACKGROUND: False kelpfish (Sebastiscus marmoratus) is one of the target species in artificial breeding in China, and is susceptible to infection by Cryptocaryon irritans, which is an obligate parasitic ciliate that lives in the epithelium of the fish gills, skin and fins. Here, we sought to understand the mechanisms of molecular immunity of S. marmoratus against C. irritans infection. METHODS: We carried out an extensive analysis of the transcriptome of S. marmoratus immune related tissues. A paired-end library was constructed from the cDNA synthesized using a Genomic Sample Prep Kit. Five normalized cDNA libraries were constructed using RNA from the control group and the four groups of C. irritans-infected fish. The libraries were sequenced on an Illumina Mi-Seq platform, and functional annotation of the transcriptome was performed using bioinformatics software. RESULTS: The data produced a total of 149,983,397 clean reads from five cDNA libraries constructed from S. marmoratus immune-related tissues. A total of 33,291 unigenes were assembled with an average length of 1768 bp. In eggNOG (Evolutionary Genealogy of Genes: non-supervised orthologous groups) categories, 333 unigenes (0.94%) were assigned to defense mechanisms. In the immune system process sub-categories of gene ontology (GO) enrichment analysis, with the passage of time post-infection, the number of differentially expressed genes (DEGs) was reduced from 24 h to 48 h but then increased from 72 h to 96 h. Specifically, the immune-related differentially expressed genes (IRDEGs), which belong to the KEGG (Kyoto encyclopedia of genes and genomes) pathways, such as the complement and coagulation cascades, chemokine signalling pathways and toll like receptor signalling pathways were mainly observed at 24 h post-infection. CONCLUSIONS: Infection with C. irritans resulted in a large number of DEGs in the immune-related tissues of S. marmoratus. The rapid and significant response of the S. marmoratus immune signalling pathways following C. irritans infection may be associated with their involvement in the immune process. PMID- 29157268 TI - The impact of signal-to-noise ratio, diffusion-weighted directions and image resolution in cardiac diffusion tensor imaging - insights from the ex-vivo rat heart. AB - BACKGROUND: Cardiac diffusion tensor imaging (DTI) is limited by scan time and signal-to-noise (SNR) restrictions. This invariably leads to a trade-off between the number of averages, diffusion-weighted directions (ND), and image resolution. Systematic evaluation of these parameters is therefore important for adoption of cardiac DTI in clinical routine where time is a key constraint. METHODS: High quality reference DTI data were acquired in five ex-vivo rat hearts. We then retrospectively set 2 <= SNR <= 97, 7 <= ND <= 61, varied the voxel volume by up to 192-fold and investigated the impact on the accuracy and precision of commonly derived parameters. RESULTS: For maximal scan efficiency, the accuracy and precision of the mean diffusivity is optimised when SNR is maximised at the expense of ND. With typical parameter settings used clinically, we estimate that fractional anisotropy may be overestimated by up to 13% with an uncertainty of +/ 30%, while the precision of the sheetlet angles may be as poor as +/-31 degrees . Although the helix angle has better precision of +/-14 degrees , the transmural range of helix angles may be under-estimated by up to 30 degrees in apical and basal slices, due to partial volume and tapering myocardial geometry. CONCLUSIONS: These findings inform a baseline of understanding upon which further issues inherent to in-vivo cardiac DTI, such as motion, strain and perfusion, can be considered. Furthermore, the reported bias and reproducibility provides a context in which to assess cardiac DTI biomarkers. PMID- 29157269 TI - Biodiversity, seasonal abundance, and distribution of blackflies (Diptera: Simuliidae) in six different regions of Thailand. AB - BACKGROUND: Blackflies are an important medical and veterinary group of small blood-sucking insects. Ninety-three blackfly species have been reported in Thailand. However, information on their biodiversity and population dynamics in each region is lacking. The main aim of this study was to assess the regional biodiversity, seasonal abundance and distribution of blackflies in six eco geographically different regions in the country. METHODS: Blackfly larvae and pupae were sampled monthly from 58 sites between May 2011 and April 2013. Diversity parameters, seasonal abundance, regional distribution and frequency of species occurrence in stream sites were analyzed. RESULTS: A total of 19,456 mature larvae representing 57 species, and belonging to six subgenera in the genus Simulium Latreille (s.l.), were found. The five predominant taxa were S. fenestratum (8.6%), the S. asakoae complex (8.3%), S. nakhonense (7.5%), the S. siamense complex (7.4%) and the S. doipuiense complex (6.7%). The most frequent taxa at all sites were the S. asakoae complex (84.5%), followed by S. fenestratum (82.8%), the S. siamense complex (75.9%), S. decuplum (60.3%), S. nakhonense (58.6%) and the S. tani complex (48.3%). The richness of regional species was highest (40 species) in the north and predominated in the cold season. However, blackflies in the south predominated during the hot season. The highest numbers of blackflies collected from central, northeastern, eastern and western regions of the country were observed in the rainy season. Overall, the mean number of blackflies collected across the six regions during the rainy and cold season had no statistically significant difference, but it differed significantly in the hot season. CONCLUSIONS: Blackflies in Thailand were surveyed in all three seasons across six geographical regions. These findings demonstrated that blackfly communities at each stream site varied with seasonality, and the regional relative abundance of blackflies differed markedly in the hot season. It was also found that the occurrence and distribution of blackflies in each region were associated strongly with elevation. PMID- 29157270 TI - Autologous platelet-rich plasma induces bone formation of tissue-engineered bone with bone marrow mesenchymal stem cells on beta-tricalcium phosphate ceramics. AB - BACKGROUND: The purpose of the study is to investigate whether autologous platelet-rich plasma (PRP) can serve as bone-inducing factors to provide osteoinduction and improve bone regeneration for tissue-engineered bones fabricated with bone marrow mesenchymal stem cells (MSCs) and beta-tricalcium phosphate (beta-TCP) ceramics. The current study will give more insight into the contradictory osteogenic capacity of PRP. METHODS: The concentration of platelets, platelet-derived growth factor-AB (PDGF-AB), and transforming growth factor-beta1 (TGF-beta1) were measured in PRP and whole blood. Tissue-engineered bones using MSCs on beta-TCP scaffolds in combination with autologous PRP were fabricated (PRP group). Controls were established without the use of autologous PRP (non-PRP group). In vitro, the proliferation and osteogenic differentiation of MSCs on fabricated constructs from six rabbits were evaluated with MTT assay, alkaline phosphatase (ALP) activity, and osteocalcin (OC) content measurement after 1, 7, and 14 days of culture. For in vivo study, the segmental defects of radial diaphyses of 12 rabbits from each group were repaired by fabricated constructs. Bone-forming capacity of the implanted constructs was determined by radiographic and histological analysis at 4 and 8 weeks postoperatively. RESULTS: PRP produced significantly higher concentration of platelets, PDGF-AB, and TGF beta1 than whole blood. In vitro study, MTT assay demonstrated that the MSCs in the presence of autologous PRP exhibited excellent proliferation at each time point. The results of osteogenic capacity detection showed significantly higher levels of synthesis of ALP and OC by the MSCs in combination with autologous PRP after 7 and 14 days of culture. In vivo study, radiographic observation showed that the PRP group produced significantly higher score than the non-PRP group at each time point. For histological evaluation, significantly higher volume of regenerated bone was found in the PRP group when compared with the non-PRP group at each time point. CONCLUSIONS: Our study findings support the osteogenic capacity of autologous PRP. The results indicate that the use of autologous PRP is a simple and effective way to provide osteoinduction and improve bone regeneration for tissue-engineered bone reconstruction. PMID- 29157271 TI - Comparison of neoadjuvant chemoradiation with carboplatin/ paclitaxel or cisplatin/ 5-fluoruracil in patients with squamous cell carcinoma of the esophagus. AB - PURPOSE: Neoadjuvant chemoradiation (nCRT) is the treatment of choice for patients with locally advanced squamous cell carcinoma of the esophagus (SCC). Today radiation oncologists can choose between two different therapy regimes including chemoradiation with cisplatin and 5-fluoruracil (CDDP/5FU) and chemoradiation analogue to the CROSS-regime with carboplatin and paclitaxel (Carb/TAX). However, there is a lack of studies comparing these regimes, especially for the subgroup of patients with SCC. In this study, we want to compare nCRT with CDDP/5FU and nCRT with Carb/TAX for patients with locally advanced SCC. PATIENTS AND METHODS: We retrospectively compared 20 patients who were scheduled for nCRT with a total radiation dose of 41.4 Gy (daily dose of 1.8 Gy) and weekly chemotherapy with carboplatin (Area under the curve 2) and Paclitaxel (50 mg per square meter of body-surface area) according to the CROSS regime to 31 patients who were scheduled for nCRT with a total radiation dose of 45 Gy (daily dose of 1.8 Gy) and simultaneous chemotherapy with cisplatin (20 mg/m2/d) and 5-fluoruracil (500 mg/m2/d) on day 1-5 and day 29-33. For the per protocol (PP) analysis, per protocol treatment was defined as either complete radiation with 41.4 Gy, at least three complete cycles of Carb/TAX and subsequent surgery or complete radiation with 45 Gy, at least one complete cycle of CDDP/5FU and subsequent surgery. RESULTS: Fifty-one patients (31 patients treated with CDDP/5FU and 20 patients treated with Carb/TAX) were evaluated for the intention to-treat (ITT) analysis and 44 patients (26 patients treated with CDDP/5FU and 18 patients treated with Carb/TAX) were evaluated for the PP analysis. No significant differences were seen for baseline and tumor characteristics like age, sex, TNM-stage, grading and tumor extension between patients treated with Carb/TAX and patients treated with CDDP/5FU. The most common tumor regression grade after nCRT was grade I as classified by Becker et al., which was observed in 84 and 79% of patients. No significant differences in tumor regression grades were seen between both regimes. Postoperative insufficiency of the anastomosis was seen in 6 patients (33%) who were treated with Carb/TAX and 4 patients (15%) who were treated with CDDP/5FU (p = 0.273). Patients treated with CDDP/5FU developed significantly more cumulative hematologic III degrees (CTCAE) toxicities (58% vs 20%; p = 0.010) than patients treated with Carb/TAX. In contrast to that, there was no significant difference for overall survival (OS) and freedom from relapse (FFR) between treatment groups. CONCLUSION: In this retrospective analysis, no significant difference was seen for OS and FFR between nCRT with CDDP/5FU and nCRT with Carb/TAX. However, the application of CDDP/5FU was associated with significantly more hematologic III degrees - toxicities compared to Carb/TAX. Future prospective trials should investigate if these results are reproducible in randomized patient cohorts. PMID- 29157273 TI - Effect of Daikenchuto (TJ-100) on gastrointestinal symptoms following laparoscopic colectomy in patients with colon cancer: study protocol for a randomized controlled trial. AB - BACKGROUND: Postoperative paralytic ileus can be a difficult complication for both surgeons and patients. Causes and treatments have been discussed for more than two centuries, but have not yet been fully resolved. Daikenchuto (TJ-100, DKT) is a traditional Japanese herbal medicine. Recently, some beneficial mechanisms of DKT to relieve paralytic ileus have been reported. DKT can suppress inflammation, increase intestinal blood flow, and accelerate bowel movements. Therefore, we have designed a randomized controlled trial to investigate the effects of DKT on postoperative gastrointestinal symptoms following laparoscopic colectomy in patients with left-sided colon cancer at a single institution. METHODS/DESIGN: As primary endpoints, the following outcomes will be evaluated: (i) grade of abdominal pain determined using the numeric rating scale (NRS), (ii) grade of abdominal distention determined using the NRS, and (iii) quality of life determined using the Gastrointestinal Quality Life Index (GIQLI). As secondary endpoints, the following will be evaluated: (i) postoperative nutritional status (Onodera's Prognostic Nutritional Index (PNI) and the Controlling Nutritional Status score (CONUT score)), (ii) duration to initial flatus, (iii) duration to initial defecation, (iv) bowel gas volume, (v) character of stool (Bristol Stool Form Scale), (vi) defecation frequency per day, (vii) postoperative complications (Clavien-Dindo classification), (viii) length of postoperative hospital stay, and (ix) metabolites in the stool and blood. This trial is an open-label study, and needs to include 40 patients (20 patients per group) and is expected to span 2 years. DISCUSSION: To our knowledge, this is the first randomized controlled trial to investigate the effects of DKT on postoperative subjective outcomes (i.e., postoperative quality of life) following laparoscopic colectomy as primary endpoints. Exploratory metabolomics analysis of metabolites in stool and blood will be conducted in this trial, which previously has only been performed in a few human studies. The study aims to guide a future full-scale pragmatic randomized trial to assess the overall effectiveness of DKT to improve the postoperative quality of life following laparoscopic colectomy. TRIAL REGISTRATION: UMIN-CTR (Japan), UMIN000023318 . Registered on 25 July 2016. PMID- 29157274 TI - Evaluating implementation of the World Health Organization's Strategic Approach to strengthening sexual and reproductive health policies and programs to address unintended pregnancy and unsafe abortion. AB - BACKGROUND: We conducted a process evaluation to assess how the World Health Organization's (WHO) Strategic Approach to strengthening sexual and reproductive health policies and programs ("the SA") was used in 15 countries that requested WHO's technical support in addressing unintended pregnancy and unsafe abortion. The SA is a three-stage planning, policy, and program implementation process. We used the social ecological model (SEM) to analyze the contextual factors that influenced SA implementation. METHODS: We used a two-phased sequential approach to data collection and analysis. In Phase A, we conducted a document and literature review and synthesized data thematically. In Phase B, we conducted interviews with stakeholders who used the SA in the countries of interest. We used a qualitative method triangulation technique to analyze and combine data from both phases to understand how the SA was implemented in each country. RESULTS: Data from 145 documents and 19 interviews described the SA process and activities in each country. All 15 countries completed Stage 1 activities. The activities of Stage 1 determined activities in subsequent stages and varied across countries. Following Stage 1, some countries focused on reforming policies to improve access to sexual and reproductive health (SRH) services whereas others focused on improving provider-level capacity to enhance SRH service quality and improving community-level SRH education. We identified factors across SEM levels that affected SA implementation, including individual- and community-level perceptions of using the SA and the recommendations that emerged from its use, organizational capacity to conduct SA activities, and how well these activities aligned with the existing political climate. Stakeholders perceived SA implementation to be country-driven and systematic in bringing attention to important SRH issues in their countries. CONCLUSION: We identified key success factors for influencing the individual, organization, and system change required for implementing the SA. These include sustaining stakeholder engagement for all SA stages, monitoring and reporting on activities, and leveraging activities and outputs from each SA stage to obtain technical and financial support for subsequent stages. Results may be used to optimize ongoing implementation efforts to improve access to and the quality of SRH services. PMID- 29157275 TI - The PREVENT study to evaluate the effectiveness and acceptability of a community based intervention to prevent childhood tuberculosis in Lesotho: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Effective, evidence-based interventions to prevent childhood tuberculosis (TB) in high TB/HIV-burden, resource-limited settings are urgently needed. There is limited implementation of evidence-based contact management strategies, including isoniazid preventive therapy (IPT), for child contacts of TB cases in Lesotho. METHODS/DESIGN: This mixed-methods implementation science study utilizes a two-arm cluster-randomized trial design with randomization at the health facility level. The study aims to evaluate the effectiveness and acceptability of a combination community-based intervention (CBI) versus standard of care (SOC) for the management of child TB contacts. The study includes three phases: (I) exploratory phase; (II) intervention implementation and testing phase; (III) post-intervention explanatory phase. Healthcare provider interviews to inform intervention refinement (phase I) were completed in December 2015. In phase II, 10 health facilities were randomized to deliver the CBI or SOC, with stratification by facility type (i.e., hospital vs. health center). CBI holistically addresses the complex provider-related, patient-related, and caregiver-related barriers to prevention of childhood TB through nurse training and mentorship; health education for caregivers and patients by village health workers; adherence support using text messaging and village health workers; and multidisciplinary team meetings, where programmatic data are reviewed and challenges and solutions are discussed. SOC sites follow country guidelines for child TB contact management. Routine TB program data will be abstracted for all adult TB cases newly registered during the study period and their child contacts from TB registers and cards. The anticipated sample size is 1080 child contacts. Primary outcomes are yield (number) of child contacts, including children < 5 years of age and HIV-positive children < 15 years of age; IPT initiation; and IPT completion. Secondary outcomes include HIV testing; yield of active prevalent TB among child contacts; and acceptability and utilization of CBI components. Intervention implementation began in February 2016 and is ongoing. Post intervention interviews with healthcare providers and caregivers (phase III) commenced in February 2017. DISCUSSION: The PREVENT study tests the effectiveness and acceptability of a novel combination CBI for child TB contact management in Lesotho. If effective, CBI will have important implications for addressing childhood TB in Lesotho and elsewhere. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02662829 . Registered on 15 January 2016. PMID- 29157276 TI - Impact of non-surgical periodontal therapy on OHRQoL in an obese population, a randomised control trial. AB - BACKGROUND: Oral Health Related Quality of Life (OHRQoL) is an important measure of disease and intervention outcomes. Chronic periodontitis (CP) is an inflammatory condition that is associated with obesity and adversely affects OHRQoL. Obese patients with CP incur a double burden of disease. In this article we aimed to explore the effect of Non-Surgical Periodontal Therapy (NSPT) on OHRQoL among obese participants with chronic periodontitis. MATERIALS AND METHODS: This was a randomised control clinical trial at the Faculty of Dentistry, University of Malaya. A total of 66 obese patients with chronic periodontitis were randomly allocated into the treatment group (n=33) who received NSPT, while the control group (n=33) received no treatment. Four participants (2 from each group) were non-contactable 12 weeks post intervention. Therefore, their data were removed from the final analysis. The protocol involved questionnaires (characteristics and OHRQoL (Oral Health Impact Profile-14; OHIP 14)) and a clinical examination. RESULTS: The OHIP prevalence of impact (PI), overall mean OHIP severity score (SS) and mean OHIP Extent of Impact (EI) at baseline and at the 12-week follow up were almost similar between the two groups and statistically not significant at (p=0.618), (p=0.573), and (p=0.915), respectively. However, in a within-group comparison, OHIP PI, OHIP SS, and OHIP EI showed a significant improvement for both treatment and control groups and the p values were ((0.002), (0.008) for PI), ((0.006) and (0.004) for SS) and ((0.006) and (0.002) for EI) in-treatment and control groups, respectively. CONCLUSION: NSPT did not significantly affect the OHRQoL among those obese with CP. Regardless, NSPT, functional limitation and psychological discomfort domains had significantly improved. TRIAL REGISTRATION: ( NCT02508415 ). Retrospectively registered on 2nd of April 2015. PMID- 29157272 TI - Mechanistic insight into the impact of nanomaterials on asthma and allergic airway disease. AB - Asthma is a chronic respiratory disease known for its high susceptibility to environmental exposure. Inadvertent inhalation of engineered or incidental nanomaterials is a concern for human health, particularly for those with underlying disease susceptibility. In this review we provide a comprehensive analysis of those studies focussed on safety assessment of different nanomaterials and their unique characteristics on asthma and allergic airway disease. These include in vivo and in vitro approaches as well as human and population studies. The weight of evidence presented supports a modifying role for nanomaterial exposure on established asthma as well as the development of the condition. Due to the variability in modelling approaches, nanomaterial characterisation and endpoints used for assessment in these studies, there is insufficient information for how one may assign relative hazard potential to individual nanoscale properties. New developments including the adoption of standardised models and focussed in vitro and in silico approaches have the potential to more reliably identify properties of concern through comparative analysis across robust and select testing systems. Importantly, key to refinement and choice of the most appropriate testing systems is a more complete understanding of how these materials may influence disease at the cellular and molecular level. Detailed mechanistic insight also brings with it opportunities to build important population and exposure susceptibilities into models. Ultimately, such approaches have the potential to more clearly extrapolate relevant toxicological information, which can be used to improve nanomaterial safety assessment for human disease susceptibility. PMID- 29157277 TI - A validated antibody panel for the characterization of tau post-translational modifications. AB - BACKGROUND: Tau is a microtubule-binding protein, which is subject to various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Aberrant PTMs such as hyperphosphorylation result in tau aggregation and the formation of neurofibrillary tangles, which are a hallmark of Alzheimer's disease (AD). In order to study the importance of PTMs on tau function, antibodies raised against specific modification sites are widely used. However, quality control of these antibodies is lacking and their specificity for particular modifications is often unclear. METHODS: In this study, we first designed an online tool called 'TauPTM', which enables the visualization of PTMs and their interactions on human tau. Using TauPTM, we next searched for commercially available antibodies against tau PTMs and characterized their specificity by peptide array, immunoblotting, electrochemiluminescence ELISA and immunofluorescence technologies. RESULTS: We demonstrate that commercially available antibodies can show a significant lack of specificity, and PTM-specific antibodies in particular often recognize non modified versions of the protein. In addition, detection may be hindered by other PTMs in close vicinity, complicating the interpretation of results. Finally, we compiled a panel of specific antibodies and show that they are useful to detect PTM-modified endogenous tau in hiPSC-derived neurons and mouse brains. CONCLUSION: This study has created a platform to reliably and robustly detect changes in localization and abundance of post-translationally modified tau in health and disease. A web-based version of TauPTM is fully available at http://www.tauptm.org . PMID- 29157278 TI - Ticks and the city - are there any differences between city parks and natural forests in terms of tick abundance and prevalence of spirochaetes? AB - BACKGROUND: Ixodes ricinus ticks are commonly encountered in either natural or urban areas, contributing to Lyme disease agents Borreliella [(Borrelia burgdorferi (sensu lato)] spp. and Borrelia miyamotoi enzootic cycles in cities. It is an actual problem whether urbanization affects pathogen circulation and therefore risk of infection. The aim of the study was to evaluate main tick-borne disease risk factors in natural, endemic areas of north-east (NE) Poland (Bialowieza) and urban areas of central Poland (Warsaw), measuring tick abundance/density, prevalence of infection with spirochaetes and diversity of these pathogens in spring-early summer and late summer-autumn periods between 2012 and 2015. METHODS: Questing I. ricinus ticks were collected from three urban sites in Warsaw, central Poland and three natural sites in Bialowieza, NE Poland. A total of 2993 ticks were analyzed for the presence of Borreliella spp. and/or Borrelia miyamotoi DNA by PCR. Tick abundance was analyzed by General Linear Models (GLM). Prevalence and distribution of spirochaetes was analyzed by Maximum Likelihood techniques based on log-linear analysis of contingency tables (HILOGLINEAR). Species typing and molecular phylogenetic analysis based on the sequenced flaB marker were carried out. RESULTS: Overall 4617 I. ricinus ticks were collected (2258 nymphs and 2359 adults). We report well established population of ticks in urban areas (10.1 +/- 0.9 ticks/100 m2), as in endemic natural areas with higher mean tick abundance (16.5 +/- 1.5 ticks/100 m2). Tick densities were the highest in spring-early summer in both types of areas. We observed no effect of the type of area on Borreliella spp. and B. miyamotoi presence in ticks, resulting in similar prevalence of spirochaetes in urban and natural areas [10.9% (95% CI: 9.7-12.2%) vs 12.4% (95% CI: 10.1-15.1%), respectively]. Prevalence of spirochaetes was significantly higher in the summer autumn period than in the spring-early summer [15.0% (95% CI: 12.8-17.5%) vs 10.4% (95% CI: 9.2-11.6%), respectively]. We have detected six species of bacteria present in both types of areas, with different frequencies: dominance of B. afzelii (69.3%) in urban and B. garinii (48.1%) in natural areas. Although we observed higher tick densities in forests than in maintained parks, the prevalence of spirochaetes was significantly higher in the latter [9.8% (95% CI: 8.6-11.0%) vs 17.5% (95% CI: 14.4-20.5%)]. CONCLUSIONS: Surprisingly, a similar risk of infection with Borreliella spp. and/or B. miyamotoi was discovered in highly- and low-transformed areas. We suggest that the awareness of presence of these disease agents in cities should be raised. PMID- 29157279 TI - Coinfection with Haemophilus parasuis serovar 4 increases the virulence of porcine circovirus type 2 in piglets. AB - BACKGROUND: Postweaning multisystemic wasting syndrome (PMWS) is an emerging disease in swine. Pigs with PMWS are often infected with a variety of other pathogens, including bacteria, viruses and mycoplasm, in addition to porcine circovirus type 2 (PCV2). PCV2 and Haemophilus parasuis serovar 4 (HPS4) coinfection remain epidemic in China. METHODS: Here we report construction of a three-week-old naturally farrowed, colostrum-deprived (NFCD) piglet's infection model and demonstrate that PCV2-infected piglets with the HPS4 coinfection increased the virulence of PCV2 and these pathogens interact acquired PMWS. RESULTS: All the single infected piglets were transiently bacteremic or viremic. All the PCV2/HPS4 coinfected piglets developed PMWS, characterized by dyspnea, anorexia, prostration and lose weight severely. Co-infection with PCV2 and HPS4 resulted in an increased amount of virus in serum and tissues, presented a slower generation and lower levels of antibodies against PCV2. Co-infection with PCV2 and HPS4 resulted in further reductions in total and differential peripheral blood leukocyte counts. Meantime, PCV2/ HPS4 coinfection potentiated the severity of lung and lymphoid lesions by PCV2-associated, increased the virulence of PCV2 antigen and enhanced the incidence of PMWS in piglets. CONCLUSION: Co-infection with PCV2 and HPS4 induce the exacerbation of system injuries and enhance the pathogenicity of PCV2 in piglets. PMID- 29157280 TI - The effects of progesterones on blood lipids in hormone replacement therapy. AB - The safety of progestogens as a class has drawn much attention after the publication of data from the Women's Health Initiative (WHI) trial, particularly with respect to cardiovascular disease. Depending on the chemical structure, pharmacokinetics, receptor affinity and potency of action, progestogens have a divergent range of properties that may translate to very different clinical effects. The purpose of this review is to describe the role of varied progestogens in hormone replacement therapy (HRT), especially focusing on blood lipids, which are the most important parameters for assessing cardiovascular disease risk. PMID- 29157282 TI - Updated molecular phylogenetic data for Opisthorchis spp. (Trematoda: Opisthorchioidea) from ducks in Vietnam. AB - BACKGROUND: An opisthorchiid liver fluke was recently reported from ducks (Anas platyrhynchos) in Binh Dinh Province of Central Vietnam, and referred to as "Opisthorchis viverrini-like". This species uses common cyprinoid fishes as second intermediate hosts as does Opisthorchis viverrini, with which it is sympatric in this province. In this study, we refer to the liver fluke from ducks as "Opisthorchis sp. BD2013", and provide new sequence data from the mitochondrial (mt) genome and the nuclear ribosomal transcription unit. A phylogenetic analysis was conducted to clarify the basal taxonomic position of this species from ducks within the genus Opisthorchis (Digenea: Opisthorchiidae). METHODS: Adults and eggs of liver flukes were collected from ducks, metacercariae from fishes (Puntius brevis, Rasbora aurotaenia, Esomus metallicus) and cercariae from snails (Bithynia funiculata) in different localities in Binh Dinh Province. From four developmental life stage samples (adults, eggs, metacercariae and cercariae), the complete cytochrome b (cob), nicotinamide dehydrogenase subunit 1 (nad1) and cytochrome c oxidase subunit 1 (cox1) genes, and near-complete 18S and partial 28S ribosomal DNA (rDNA) sequences were obtained by PCR-coupled sequencing. The alignments of nucleotide sequences of concatenated cob + nad1 + cox1, and of concatenated 18S + 28S were separately subjected to phylogenetic analyses. Homologous sequences from other trematode species were included in each alignment. RESULTS: Phylogenetic trees were inferred from concatenated (cob + nad1 + cox1) nucleotide sequences and combined 18S + 28S nucleotide sequences of five Opisthorchis sp. BD2013 samples and additional reference taxa. Both trees demonstrated the anticipated clustering of taxa within the superfamily Opisthorchioidea, the paraphyly of the genus Opisthorchis and the sister-species relationship of Opisthorchis sp. BD2013 with O. viverrini. CONCLUSIONS: While it is likely that Opisthorchis sp. BD2013 is distinct from O. viverrini, it is clearly a sister taxon of O. viverrini within the limited number of Opisthorchis species for which appropriate sequence data are available. The new sequences provided here will assist the diagnosis and the taxonomic clarification of the opisthorchiid species. PMID- 29157283 TI - The mouse viral outgrowth assay: avatars for the detection of HIV-1 reservoirs. AB - Sensitive assays are needed for the detection of residual viral reservoirs in HIV 1-infected subjects on suppressive combination antiretroviral therapy regimens to determine whether eradication strategies are effective. Mouse viral outgrowth assays have recently been developed and have the potential to be more sensitive than traditional in vitro quantitative viral outgrowth assays. In this article we describe these assays and review several studies that have used them to measure the latent reservoir. PMID- 29157281 TI - Identification of immunogenic proteins of the cysticercoid of Hymenolepis diminuta. AB - BACKGROUND: A wide range of molecules are used by tapeworm metacestodes to establish successful infection in the hostile environment of the host. Reports indicating the proteins in the cestode-host interactions are limited predominantly to taeniids, with no previous data available for non-taeniid species. A non-taeniid, Hymenolepis diminuta, represents one of the most important model species in cestode biology and exhibits an exceptional developmental plasticity in its life-cycle, which involves two phylogenetically distant hosts, arthropod and vertebrate. RESULTS: We identified H. diminuta cysticercoid proteins that were recognized by sera of H. diminuta-infected rats using two-dimensional gel electrophoresis (2DE), 2D-immunoblotting, and LC-MS/MS mass spectrometry. Proteomic analysis of 42 antigenic spots revealed 70 proteins. The largest number belonged to structural proteins and to the heat-shock protein (HSP) family. These results show a number of the antigenic proteins of the cysticercoid stage, which were present already in the insect host prior to contact with the mammal host. These are the first parasite antigens that the mammal host encounters after the infection, therefore they may represent some of the molecules important in host-parasite interactions at the early stage of infection. CONCLUSIONS: These results could help in understanding how H. diminuta and other cestodes adapt to their diverse and complex parasitic life-cycles and show universal molecules used among diverse groups of cestodes to escape the host response to infection. PMID- 29157284 TI - Malaria control in rural Malawi: implementing peer health education for behaviour change. AB - BACKGROUND: Interventions to reduce malaria burden are effective if communities use them appropriately and consistently. Several tools have been suggested to promote uptake and use of malaria control interventions. Community workshops on malaria, using the 'Health Animator' approach, are a potential behaviour change strategy for malaria control. The strategy aims to influence a change in mind-set of vulnerable populations to encourage self-reliance, using community volunteers known as Health Animators. The aim of the paper is to describe the process of implementing community workshops on malaria by Health Animators to improve uptake and use of malaria control interventions in rural Malawi. METHODS: This is a descriptive study reporting feasibility, acceptability, appropriateness and fidelity of using Health Animator-led community workshops for malaria control. Quantitative data were collected from self-reporting and researcher evaluation forms. Qualitative assessments were done with Health Animators, using three focus groups (October-December 2015) and seven in-depth interviews (October 2016 February 2017). RESULTS: Seventy seven health Animators were trained from 62 villages. A total of 2704 workshops were conducted, with consistent attendance from January 2015 to June 2017, representing 10-17% of the population. Attendance was affected by social responsibilities and activities, relationship of the village leaders and their community and involvement of Community Health Workers. Active discussion and participation were reported as main strengths of the workshops. Health Animators personally benefited from the mind-set change and were proactive peer influencers in the community. Although the information was comprehended and accepted, availability of adequate health services was a challenge for maintenance of behaviour change. CONCLUSION: Community workshops on malaria are a potential tool for influencing a positive change in behaviour towards malaria, and applicable for other health problems in rural African communities. Social structures of influence and power dynamics affect community response. There is need for systematic monitoring of community workshops to ensure implementation fidelity and strengthening health systems to ensure sustainability of health behaviour change. PMID- 29157285 TI - Map of biomedical research in Cameroon; a documentary review of approved protocols from 1997 to 2012. AB - BACKGROUND: Over the last decade, there has been a rapid increase in biomedical research in Cameroon. However, the question of whether these research projects target major health priorities, vulnerable populations and geographic locations at risk remains to be answered. The aim of this paper is to describe the state of biomedical research in Cameroon which is a key determinant that would guide future health care policies and promote equitable access to healthcare. METHODS: A documentary review of all approved protocols (proposals) of biomedical research projects, from 1997 through 2012, at the Cameroon National Ethics Committee. Protocols were reviewed systematically by independent reviewers and data were extracted on a grid. Data were analyzed by calculating proportions at 95% confidence interval, chi-square test (chi2) and p-values. RESULTS: Two thousand one hundred seventy two protocols were reviewed for data extraction. One thousand three hundred ninety-five (64.7%) were student projects, 369 (17.0%) projects had international sponsors, and 1528 (72.4%) were hospital-based studies. The most targeted domain was the fight against diseases 1323 (61.3%); mostly HIV 342 (25.8%) and Malaria 136 (10.3%). Over half of the studies were concentrated in the Centre region 1242 (57.2%), with the least projects conducted in the Northern region 15 (0.7%). There was strong evidence that international and local sponsors would influence the research site (p-value = 0.01) and population targets (p value = 0.00). CONCLUSION: Although biomedical research targets some important diseases that pose a great burden to Cameroonians, the most vulnerable populations are excluded from research. Biomedical research scarcely addresses other components of the health system and emerging diseases of vital public health importance. We recommend that the government should play a central role, between researchers from academic institutions, sponsors, NGOs and research institutions, to ensure that biomedical research addresses the health priorities of Cameroonians. It should include vulnerable populations, and address other components of the health system for a balance. These recommendations are critical to ensuring that future research informed health policies reflect the health needs of the populations and promote equity in healthcare access. PMID- 29157286 TI - Farmers' perception of termites in agriculture production and their indigenous utilization in Northwest Benin. AB - BACKGROUND: Although termites are considered as agricultural pests, they play an important role in maintaining the ecosystem. Therefore, it matters to investigate the farmers' perception of the impacts of the termites on the agriculture and their indigenous utilization. METHODS: A semi-structured questionnaire was used to interview 94 farmers through 10 villages of Atacora department, in the northwestern region of Benin, to obtain information for the development of successful strategies of termite management and conservation. Their perceptions on the importance and management of termites along with the indigenous nomenclature and utilization of termite mounds were assessed. Termite species identified by farmers were collected and preserved in 80% alcohol for identification. RESULTS: Eight crops were identified by farmers as susceptible to termites with maize, sorghum, and yam as being the most susceptible. According to farmers, the susceptibility to termites of these crops is due to their high-water content and sweet taste. A total of 27 vernacular names of termites were recorded corresponding to 10 species, Amitermes evuncifer, Macrotermes subhyalinus, and Trinervitermes oeconomus being the most damaging termite species. All the names given to termite species had a meaning. The drought was identified by farmers as the main factor favouring termite attacks. Demolition of termite mounds in the fields was the most commonly reported control method. Salt and other pesticides were commonly used by farmers to protect stored farm products. The lack of effective control methods is the main constraint for termite management. In northwestern Benin, farmers reported different purpose utilizations of termite mounds and termites. CONCLUSIONS: The study has shown that farmers perceived termites as pests of several agricultural crops and apply various indigenous control practices whose efficiency need to be verified. Utilization of termites and termite mound soil as food and medicinal resources underlines the need for a more focused approach to termite control for the conservation of non-pest termite species. The sensitization of farmers on the importance of termites as well as the development of an integrated control method to combat termite pests proved necessary. PMID- 29157287 TI - Safety in treatment of hepatocellular carcinoma with immune checkpoint inhibitors as compared to melanoma and non-small cell lung cancer. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a major health problem worldwide with increasing incidence rates. As HCC traditionally occurs in chronically inflamed livers, this inflammation aids to drive oncogenesis and often renders these lesions to be immunogenic and therefore potential targets for immunotherapy. As patients with HCC generally have underlying liver dysfunction, we sought to determine if immune checkpoint inhibitors were safe to use in patients with HCC as compared to melanoma and non-small cell lung cancer (NSCLC) in terms of the gastrointestinal side effects of elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and diarrhea as well as patients who drop out of the study due to drug toxicity and death secondary to drug toxicity. METHODS: A literature review was performed for clinical trials that have been completed with single agent immune checkpoint inhibitors for patients with HCC, melanoma, and NSCLC. Gastrointestinal related adverse events including elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and diarrhea were analyzed as well as those patients who were taken off therapy secondary to drug related toxicity and patients who died as a result of therapy. RESULTS: We found that although patients with HCC treated with immune checkpoint inhibitors have a substantial increase in AST/ALT as compared to patients with melanoma and NSCLC, this does not cause the patients to come off therapy or cause death secondary to drug toxicity. CONCLUSIONS: We propose immune checkpoint inhibitors are safe to pursue in the treatment of HCC. PMID- 29157288 TI - Development of a framework to improve the utilisation of malaria research for policy development in Malawi. AB - BACKGROUND: The existing gap between research evidence and public health practice has attributed to the unmet Millennium Development Goals in Africa and consequently, has stimulated the development of frameworks to enhance knowledge translation. These efforts aim at maximising health research utilisation in policy and practice to address the world's disease burdens, including malaria. This study aimed at developing a contextual framework to improve the utilisation of malaria research for policy development in Malawi. METHODS: The study used two approaches including: two case studies of policy analysis exploring the policy making process in Malawi, utilisation of local malaria research, and the role of key stakeholders in policy formulation process; and the assessment of facilitating factors and barriers to malaria research utilisation for policy making in Malawi. RESULTS: From the case studies' lessons and elements identified during the assessment of facilitating factors and barriers, a framework is developed to promote an integrated approach to knowledge translation. In this framework the Ministry of Health is considered as the main user of knowledge from research through the demand created by the research directorate and the National Malaria Control Programme. Key documents identified as being particularly relevant to the Ministry of Health for purposes of knowledge translation include the National Health Research Agenda, Guidelines for Policy Development and Analysis, and Guidelines for Evidence Use in Policy-making. Institutions conducting academic and policy-relevant malaria research in Malawi are identified and a consolidation of their linkages with the users of research is established through the Knowledge Translation Unit, the Evidence Informed decision-making Centre, and the African Institute for Development Policy. Equally, key players in this framework are the funding partners for both research and programmes that need to see accountability and impact of their support. Independent advisors, partners, and consultants also have their vital role in the process. CONCLUSION: The framework offers a practical basis for the factors identified and their linkages to promote a co-ordinated approach to malaria research utilisation in policy-making. Its applicability and success hinges on its wider dissemination and ownership by the government through the National Malaria Control Programme. PMID- 29157290 TI - Commentary on a participatory inquiry paradigm used to assess EOL simulation participant outcomes and design. AB - Care at the end-of-life has attracted global attention, as health care workers struggle with balancing cure based care with end-of-life care, and knowing when to transition from the former to the latter. Simulation is gaining in popularity as an education strategy to facilitate health care provider decision-making by improving communication skills with patients and family members. This commentary focuses on the authors' simulation evaluation process. When data were assessed using a participatory inquiry paradigm, the evaluation revealed far more than a formative or summative evaluation of participant knowledge and skills in this area of care. Consequently, this assessment strategy has ramifications for best practices for simulation design and evaluation. PMID- 29157289 TI - Vitamin C plus hydrogel facilitates bone marrow stromal cell-mediated endometrium regeneration in rats. AB - BACKGROUND: Intrauterine adhesion (IUA) is a common uterine cavity disease which can be caused by mechanical damage that may eventually lead to infertility and pregnancy abnormalities. Since the effect of therapeutic drugs appears disappointing, cell therapy has emerged as an alternative choice for endometrium regeneration. The aim of this study is to investigate whether the combination of hydrogel Pluronic F-127 (PF-127), Vitamin C (Vc), and a bone marrow stromal cell (BMSC) mixture could be a feasible strategy to improve the endometrial regeneration in a mechanical damage model of IUA in rats. METHODS: Firstly, PF 127 cytotoxicity and the effect of Vc was tested in vitro using the Annexin V/propidium iodide (PI) apoptosis test, cell count kit (CCK) growth test, and enzyme-linked immunosorbent assay (ELISA). For the establishment of the rat IUA model, a 2-mm transverse incision in the uterus was prepared at the upper end, and 1.5- to 2.0-cm endometrial damage was scraped. Rats were randomly assigned to five groups to investigate the combined strategy on IUA uterine regeneration: a sham group, an IUA control group, an IUA BMSC encapsulated in PF-127 plus Vc group, an IUA BMSC plus Vc group, and an IUA PF-127 plus Vc group. A cell mixture was injected into the uterine horn while making the IUA model. Eight weeks after cell transplantation, the rats were sacrificed and the uterine was dissected for analysis. Endometrial thickness, gland number, fibrosis area, and the expression of marker proteins for endometrial membrane were examined by hematoxylin and eosin staining, Masson's staining, and immunohistochemistry. RESULTS: Vc promoted the survival and health of PF-127-encapsulated BMSCs in vitro. When this combination was transplanted in vivo, the endometrium showed better restoration as the endometrium membrane became thicker and had more glands and less fibrosis areas. The expression of cytokeratin, von Willebrand Factor (vWF), was also restored. The proinflammatory cytokine interleukin-1beta (IL-1beta) was significantly lower compared with the control group. CONCLUSIONS: Vc alleviates the cytotoxic effect of PF-127 and promotes cell survival and growth in rat BMSC encapsulation. Thus, a cell therapy strategy containing biomaterial scaffold, BMSCs and the modulatory factor Vc promotes the restoration of damaged IUA endometrium. PMID- 29157291 TI - Vaccination with recombinant adenovirus expressing peste des petits ruminants virus-F or -H proteins elicits T cell responses to epitopes that arises during PPRV infection. AB - Peste des petits ruminants virus (PPRV) causes an economically important disease that limits productivity in small domestic ruminants and often affects the livestock of the poorest populations in developing countries. Animals that survive PPRV develop strong cellular and humoral responses, which are probably necessary for protection. Vaccination should thus aim at mimicking these natural responses. Immunization strategies against this morbillivirus using recombinant adenoviruses expressing PPRV-F or -H proteins can protect PPRV-challenged animals and permit differentiation of infected from vaccinated animals. Little is known of the T cell repertoire these recombinant vaccines induce. In the present work, we identified several CD4+ and CD8+ T cell epitopes in sheep infected with PPRV. We also show that recombinant adenovirus vaccination induced T cell responses to the same epitopes, and led to memory T cell differentiation. T cells primed by these recombinant adenovirus vaccines expanded after PPRV challenge and probably contributed to protection. These data validate the use of recombinant adenovirus expressing PPRV genes as DIVA strategies to control this highly contagious disease. PMID- 29157292 TI - Genotyping of polymorphic effectors of Toxoplasma gondii isolates from China. AB - BACKGROUND: Toxoplasma gondii is an opportunistic protozoan apicomplexan and obligate intracellular parasite that infects a wide range of animals and humans. Rhoptry proteins 5 (ROP5), ROP16, ROP18 and dense granules 15 (GRA15) are the important effectors secreted by T. gondii which link to the strain virulence for mice and modulate the host's response to the parasite. Little has been known about these molecules as well as GRA3 in type Chinese 1 strains that show polymorphism among strains of archetypical genotypes. This study examined the genetic diversity of these effectors and its correlated virulence in mice among T. gondii isolates from China. RESULTS: Twenty-one isolates from stray cats were detected, of which 15 belong to Chinese 1, and 6 to ToxoDB #205. Wh6 isolate, a Chinese 1 strain, has an avirulent phenotype. PCR-RFLP results of ROP5 and ROP18 presented few variations among the strains. Genotyping of GRA15 and ROP16 revealed that all the strains belong to type II allele except Xz7 which carries type I allele. ROP16 amino acid alignment at 503 locus demonstrated that 17 isolates are featured as type I or type III (ROP16I/III), and the other 4 as type II (ROP16II). The strains investigated may be divided into four groups based on GRA3 amino acid alignment, and all isolates of type Chinese 1 belong to the MU-1 allele except Wh6 which is identical to type II strain. CONCLUSIONS: PCR-RFLP and sequence alignment analyses of ROP5, ROP16, ROP18, GRA3, and GRA15 in T. gondii revealed that strains with the same genotype may have variations in some of their key genes. GRA3 variation exhibited by Wh6 strain may be associated with the difference in phenotype and pathogenesis. PMID- 29157293 TI - Effect of memantine on post-operative cognitive dysfunction after cardiac surgeries: a randomized clinical trial. AB - BACKGROUND: Post-operative cognitive dysfunction (POCD) is an important complication of cardiac surgeries. Glutamate plays a critical role in physiologic and pathologic conditions in the brain. Due to the role of glutamate in ischemia, this study is designed to identify the effect of memantine in prevention of POCD early and late after cardiac surgeries. METHODS: In this randomized clinical trial, 172 patients with ages 45-75 years old who underwent elective cardiac surgery were enrolled. For patients in memantine group, 5 mg of memantine per day administered at least 48 h before surgery and increased to 10 mg per day during the first 24 h after surgery and continued for 3 months. A brief Wechsler memory test (WMT) was administered before, three to 5 days after, and 3 months after surgery for both groups. RESULTS: Both groups demonstrate standard pattern of cognitive dysfunction after surgery and in follow up. Pre- and post-operative WMT score showed significant improvement in memantine compared to control group (P < 0.001) both in unadjusted and adjusted with confounding factor analysis. Unadjusted pre-, post-operative, and follow up WMT score improved significantly after 3 months in memantine group (P = 0.006). CONCLUSION: Pre-operative administration of memantine protects patients from POCD following cardiac surgeries. In addition, it improves cognitive function 3 months after surgery. TRIAL REGISTRATION: The trial was registered in the Iranian Registry of Clinical Trials (registration number: IRCT201303168698N12 ). Memantin effect on POCD. PMID- 29157294 TI - Isolated hepatoblastoma arising from the hepatogastric ligament: a case report. AB - BACKGROUND: Almost all hepatoblastomas are isolated to the liver. Hepatoblastoma arising from and limited to extrahepatic tissue is an extremely rare clinical entity. CASE PRESENTATION: Here we present a case of a 7-year-old Chinese boy of Han ethnicity with hepatoblastoma originating from the hepatogastric ligament. A complete resection was performed and the entire course was uneventful. He received six cycles of postoperative chemotherapy and had no signs of recurrence for 3 years after surgery. CONCLUSIONS: Hepatoblastoma arising from extrahepatic tissue is extremely rare. A pedunculated hepatoblastoma is prone to hemorrhage and tumor metastasis. The best treatment for a long-term cure is complete resection of the primary tumor combined with chemotherapy. PMID- 29157295 TI - Single-cell multiplexed cytokine profiling of CD19 CAR-T cells reveals a diverse landscape of polyfunctional antigen-specific response. AB - BACKGROUND: It remains challenging to characterize the functional attributes of chimeric antigen receptor (CAR)-engineered T cell product targeting CD19 related to potency and immunotoxicity ex vivo, despite promising in vivo efficacy in patients with B cell malignancies. METHODS: We employed a single-cell, 16-plex cytokine microfluidics device and new analysis techniques to evaluate the functional profile of CD19 CAR-T cells upon antigen-specific stimulation. CAR-T cells were manufactured from human PBMCs transfected with the lentivirus encoding the CD19-BB-z transgene and expanded with anti-CD3/anti-CD28 coated beads. The enriched CAR-T cells were stimulated with anti-CAR or control IgG beads, stained with anti-CD4 RPE and anti-CD8 Alexa Fluor 647 antibodies, and incubated for 16 h in a single-cell barcode chip (SCBC). Each SCBC contains ~12,000 microchambers, covered with a glass slide that was pre-patterned with a complete copy of a 16 plex antibody array. Protein secretions from single CAR-T cells were captured and subsequently analyzed using proprietary software and new visualization methods. RESULTS: We demonstrate a new method for single-cell profiling of CD19 CAR-T pre infusion products prepared from 4 healthy donors. CAR-T single cells exhibited a marked heterogeneity of cytokine secretions and polyfunctional (2+ cytokine) subsets specific to anti-CAR bead stimulation. The breadth of responses includes anti-tumor effector (Granzyme B, IFN-gamma, MIP-1alpha, TNF-alpha), stimulatory (GM-CSF, IL-2, IL-8), regulatory (IL-4, IL-13, IL-22), and inflammatory (IL-6, IL 17A) functions. Furthermore, we developed two new bioinformatics tools for more effective polyfunctional subset visualization and comparison between donors. CONCLUSIONS: Single-cell, multiplexed, proteomic profiling of CD19 CAR-T product reveals a diverse landscape of immune effector response of CD19 CAR-T cells to antigen-specific challenge, providing a new platform for capturing CAR-T product data for correlative analysis. Additionally, such high dimensional data requires new visualization methods to further define precise polyfunctional response differences in these products. The presented biomarker capture and analysis system provides a more sensitive and comprehensive functional assessment of CAR-T pre-infusion products and may provide insights into the safety and efficacy of CAR-T cell therapy. PMID- 29157296 TI - Biomarkers for immunotherapy in bladder cancer: a moving target. AB - Treatment options for metastatic urothelial carcinoma (mUC) remained relative unchanged over the last 30 years with combination chemotherapy as the mainstay of treatment. Within the last year the landscape for mUC has seismically shifted following the approval of five therapies targeting the programmed cell death protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis. Notably, the anti-PD 1 antibody pembrolizumab demonstrated improved OS relative to chemotherapy in a randomized phase III study for second line treatment of mUC; this level 1 evidence led to approval from the U.S. Food and Drug Administration (FDA). The PD 1 antibody nivolumab also demonstrated an overall survival benefit, in this case in comparison to historical controls. Similarly, antibodies targeting PD-L1 including atezolizumab, durvalumab, and avelumab have now received accelerated approval from the FDA as second line treatments for mUC, with durable response lasting more than 1 year in some patients. Some of these agents are approved in the first line setting as well - based on single-arm phase II studies atezolizumab and pembrolizumab received accelerated approval for first-line treatment of cisplatin ineligible patients. Despite these multiple approvals, the development of clinically useful biomarkers to determine the optimal treatment for patients remains somewhat elusive. In this review, we examine key clinical trial results with anti-PD1/PD-L1 antibodies and discuss progress towards developing novel biomarkers beyond PD-L1 expression. PMID- 29157297 TI - Smoldering myocarditis following immune checkpoint blockade. AB - BACKGROUND: Severe myocarditis associated with electrical conduction abnormalities and occasionally heart failure has been well documented following treatment with immune checkpoint blockade with an estimated incidence of less than 1%. However, the incidence, early detection, and management of less severe immune-related myocarditis are unknown since most immunotherapy trials have not included routine cardiac monitoring. Herein, we provide the first description of subclinical or smoldering myocarditis with minimal signs and symptoms following immune checkpoint blockade with a single dose of ipilimumab and nivolumab. CASE PRESENTATION: Our patient was diagnosed with immune checkpoint blockade-induced myocarditis based upon an acute rise in serum cardiac troponin I beginning 2 weeks after the initial dose of ipilimumab/nivolumab consistent with the reported median onset of clinical myocarditis at 17 days, as well as a lack of other causes despite extensive cardiac evaluation. The patient initially presented with intractable nausea with no known gastrointestinal etiology. High dose glucocorticoid therapy led to rapid resolution of nausea and a four-fold decrease in troponin I over 4 days. Serum troponin I spiked again following a steroid taper to 13 times the upper limit of normal with endomyocardial biopsy revealing collagen fibrosis and lymphocytic inflammation predominantly comprised of CD8+ T cells consistent with chronic smoldering myocarditis. Serum anti-striated muscle antibodies were also detected with no evidence of rhabdomyolysis. Serum cardiac troponin I levels as an indicator of ongoing myocyte damage gradually improved with chronic prednisone at 10 mg daily. Late addition of intravenous immunoglobulin was associated with rapid normalization of creatine kinase myocardial band. CONCLUSIONS: This case demonstrates that subclinical, smoldering myocarditis may occur following immune checkpoint blockade, with evidence of both humoral and cell-mediated immunity responsive to corticosteroid therapy. This experience supports early monitoring for myocarditis with serial electrocardiograms and serum troponin I determinations in large, prospective cohorts of patients receiving combination immune checkpoint blockade as early detection and initiation of immunosuppression may forestall fulminant presentation of this disease and limit myocardial damage. PMID- 29157298 TI - Impressive response to immunotherapy in a metastatic gastric cancer patient: could somatic copy number alterations help patient selection? AB - BACKGROUND: Metastatic gastric cancer (GC) is an incurable and aggressive disease with a poor prognosis. Immunotherapy is an attractive approach for treating patients with cancer, and studies using immunotherapy have shown promising results in melanoma, kidney and non-small cell lung cancers, among others. CASE PRESENTATION: We present a case of a 50-year-old woman with metastatic GC whose cancer had progressed after first-line chemotherapy and who received pembrolizumab as an experimental treatment. Molecular analyses showed that her tumor was negative for PD-L1 expression, contained microsatellite stability and several focal somatic copy number alterations. The patient experienced an almost complete response after eleven cycles of treatment. Her symptoms related to the disease disappeared, and the medication was well tolerated. CONCLUSIONS: Despite reports of promising responses in some patients, immunotherapy is not suitable for all patients; therefore, we explored the molecular characteristics that could explain the exceptional response and clinical benefits observed in our patient. PMID- 29157299 TI - The similarities between smDCs and regDCs in alleviating the immune injury caused by transplantation of hepatocytes differentiated from ESCs. AB - BACKGROUND: This study aimed to investigate the tolerogenic mechanisms induced by semimature dendritic cells (smDCs) and regulatory dendritic cells (regDCs) after transplantation of hepatocytes differentiated from mouse embryonic stem cells (ESCs) and to confirm the low immunogenicity of hepatocytes differentiated from ESCs. METHODS: Green fluorescent protein-labeled ESCs collected from 129 mice were cultured to differentiate into hepatocytes. smDCs and regDCs were cultured in vitro. The hepatocytes were cultured after being extracted from the livers of 129 mice. After injecting smDCs or regDCs 3 days in advance, these differentiated hepatocytes and normal hepatocytes were transplanted into the livers of BALB/c mice separately. Subsequently, the histopathological features and cytokines in transplant tissues as well as the Foxp3 expression in peripheral blood CD4+ T cells of the recipients were examined. RESULTS: The morphological phenotypes of smDCs and regDCs were similar. They both expressed medium levels of MHC-II, CD40, CD80, and CD86, high levels of TGF-beta and IL-10, and low levels of IL-2. The survival of differentiated hepatocytes was prolonged and inflammatory infiltration in transplant tissues was reduced in both the smDC and regDC groups. Foxp3 expression in peripheral blood CD4+ T cells of the smDC group increased to 5.38% and that of the regDC group also rose to 3.87%. Moreover, the inflammatory infiltration in the tissues receiving transplanted hepatocytes was more obvious. CONCLUSIONS: smDCs and regDCs were similar tolerogenic dendritic cells. They both could alleviate the immune injury by inducing CD4+CD25+Foxp3+ regulatory T cells through the medium expression of MHC-II, CD40, CD80, and CD86 and the appropriate secretion of cytokines. Hepatocytes differentiated from ESCs displayed low immunogenicity. PMID- 29157301 TI - Family support, discrimination, and quality of life among ART-treated HIV infected patients: a two-year study in China. AB - BACKGROUND: By September 2016, approximately 653,865 people in China were living with HIV/AIDS (PLWHA) and 492,725 people were receiving antiretroviral therapy (ART). PLWHA frequently experience discrimination in all domains of their personal and social lives. The World Health Organization includes discrimination in its list of social determinants of health factors that have been linked to poor physical and psychological health. This paper identifies the family support enjoyed and discrimination faced by people infected with HIV and examines the effect they have on patients' quality of life (QOL) as they undergo ART in China. METHODS: We conducted this observational cohort study of ART-treated patients with HIV in Guangxi Province using a questionnaire survey at baseline, 6, 12, and 24 months, starting in 2010. Descriptive analysis was used to describe the demographic characteristics (e.g., age, sex, educational level, marital status, and employment status) of participants. Generalized estimating equations (GEE) were employed to examine the relationships between family support, discrimination, and QOL. RESULTS: In the study, 90.4% (n = 281) of patients received family support at baseline, here defined as the initiation of ART, 91.8% (n = 244) received family support 6 months into ART, 95.5% (n = 220) at 12 months, and 94.3% (n = 230) at 24 months. The proportion of patients who did not feel discriminated against by their families was 87.2% (n = 274) at baseline, 90.4% (n = 229) 6 months into ART, 90.0% (n = 210) at 12 months, and 94.5% (n = 219) at 24 months. Patients' overall QOL scores were positively associated with having received family support (OR = 2.74, P = 0.040, 95% CI: 1.68-4.47), not feeling discriminated against by their families (OR = 1.3, P = 0.041, 95% CI: 1.07-1.59) or discrimination from patients themselves, including never experiencing fear of abandonment by family (OR = 2.05, P = 0.025, 95% CI: 1.49 2.82). CONCLUSIONS: Family support along with no or minimal discrimination was found to contribute to QOL among people infected with HIV. Their overall QOL tended to improve significantly as ART continued. This suggests that strategies meant to improve and strengthen family support, care for PLWHA, and promote HIV screening among high-risk populations should be explored by both policy makers and researchers. PMID- 29157303 TI - Promoting adherence to medicines: possible lessons for Canada? AB - Non-adherence to medication regimens is a major issue that can negatively impact patient health and wastes health care system resources. This commentary considers whether approaches to strategies undertaken in Israel to promote adherence could be viable in Canada. The structure of the Canadian health care system and budgetary constraints make new initiatives similar to those in Israel seem unlikely in Canada without some compelling stimulus. PMID- 29157302 TI - Prevalence of lactose intolerance in patients with diarrhea-predominant irritable bowel syndrome: data from a tertiary center in southern China. AB - BACKGROUND: Symptoms associated with lactose intolerance (LI) and diarrhea predominant irritable bowel syndrome (IBS-D) are almost the same. These disease entities are difficult to differentiate clinically. In practice, differential diagnosis depends on self-reported patient milk intolerance. However, there is limited data on the prevalence of LI in China. The aim of this study was to investigate the prevalence of LI in IBS-D patients and asymptomatic healthy controls. METHODS: Lactose malabsorption (LM) was diagnosed by a lactose hydrogen breath test (HBT) and was defined by peak breath H2 excretion over the baseline level of >= 20 ppm. LI-related symptoms were monitored for 8 h following lactose administration. LI was defined in LM patients with positive symptoms during the observation time. Patients with IBS-D were additionally asked if they were intolerant to milk. RESULTS: A total of 109 eligible IBS-D patients (Rome III criteria) and 50 healthy controls were enrolled in this study. Except for hydrogen non-producers, the prevalence of LM did not differ between IBS-D patients and the control group (85%, 82/96 vs 72%, 34/47; P = 0.061). There was, however, a higher LI prevalence in IBS patients than in healthy subjects (45%, 43/96 vs 17%, 8/47; P = 0.002). Sensitivity, specificity, and positive and negative predictive values of self-reported milk intolerance for detecting LI were 58, 58, 53, and 63%, respectively. CONCLUSIONS: Prevalence of LI is significantly higher in IBS-D patients than in healthy subjects. Self-reported milk intolerance is a poor diagnostic predictor of LI. PMID- 29157300 TI - Prospects for combined use of oncolytic viruses and CAR T-cells. AB - With the approval of talimogene laherparepvec (T-VEC) for inoperable locally advanced or metastatic malignant melanoma in the USA and Europe, oncolytic virotherapy is now emerging as a viable therapeutic option for cancer patients. In parallel, following the favourable results of several clinical trials, adoptive cell transfer using chimeric antigen receptor (CAR)-redirected T-cells is anticipated to enter routine clinical practice for the management of chemotherapy-refractory B-cell malignancies. However, CAR T-cell therapy for patients with advanced solid tumours has proved far less successful. This Review draws upon recent advances in the design of novel oncolytic viruses and CAR T cells and provides a comprehensive overview of the synergistic potential of combination oncolytic virotherapy with CAR T-cell adoptive cell transfer for the management of solid tumours, drawing particular attention to the methods by which recombinant oncolytic viruses may augment CAR T-cell trafficking into the tumour microenvironment, mitigate or reverse local immunosuppression and enhance CAR T cell effector function and persistence. PMID- 29157304 TI - A novel vector for transgenesis in the rat CNS. AB - The larger brain of the rat enables a much greater repertoire of complex behaviors than mice, likely making rats preferential for investigating neurodegeneration. Because molecular tools for specific expression of transgenes in the rat brain are sparse, we chose Prnp encoding the prion protein (PrP) to develop a novel vector to drive transgene expression in the rat brain. We compared the rat Prnp sequence with mouse and Syrian hamster Prnp sequences, identifying conserved genetic elements and hypothesizing that these elements would be able to drive neuronal transgene expression. We investigated this by generating a vector termed RaPrnp that encompasses portions of the rat Prnp gene. Importantly, we replaced the rat Prnp open reading frame (ORF) with a cloning site for rapid and seamless In-Fusion cloning. To validate the in vivo neuronal specificity of the RaPrnp vector in rats, we generated stable RaPrnp LacZ/enhanced green fluorescent protein (EGFP) transgenic (Tg) rat lines, which led to robust LacZ activity and high EGFP fluorescence in the central nervous system of embryos and adult animals. Next, we restored the rat Prnp ORF and generated multiple Tg(RaPrnp-PrP) lines, demonstrating that overexpression of Prnp accelerates the onset of scrapie. While the incubation time in wild-type (WT) rats was 175 +/- 3 days post inoculation (dpi), one line, Tg2919, overexpressed RaPrPC at 4.4-fold and exhibited a reduced incubation time of 149 +/- 2 dpi. The second line, Tg2922, overexpressed RaPrPC at 9.7-fold compared with WT animals and had an incubation time of 112 +/- 0 dpi. Tg2922 rats inoculated with rat RML showed extensive vacuolation of the brainstem in contrast to WT and Tg2919 animals in which vacuolation was most prominent in the hippocampus and striatum as well as the motor and sensory cortices. It is possible that construction of Tg rats with modified phenotypes will prove more advantageous than mice for neurodegeneration studies. PMID- 29157305 TI - Evaluation of the effect of a floxed Neo cassette within the dystroglycan (Dag1) gene. AB - OBJECTIVE: Dystroglycan (DG) is an adhesion complex formed by two subunits, alpha DG and beta-DG. In skeletal muscle, DG is part of the dystrophin-glycoprotein complex that is crucial for sarcolemma stability and it is involved in a plethora of muscular dystrophy phenotypes. Due to the important role played by DG in skeletal muscle stability as well as in a wide variety of other tissues including brain and the peripheral nervous system, it is essential to investigate its genetic assembly and transcriptional regulation. RESULTS: Herein, we analyze the effect of the insertion of a floxed neomycin (Neo) cassette within the 3' portion of the universally conserved IG1-intron of the DG gene (Dag1). We analyzed the transcription level of Dag1 and the expression of the DG protein in skeletal muscle of targeted mice compared to wild-type and we did not find any alterations that might be attributed to the gene targeting. However, we found an increase of the cross-sectional areas of tibialis anterior that might have some physiological significance that needs to be assessed in the future. Moreover, in targeted mice the skeletal muscle morphology and its regeneration capacity after injury did not show any evident alterations. We confirmed that the targeting of Dag1 with a floxed Neo-cassette did not produce any gross undesired effects. PMID- 29157306 TI - A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer. AB - BACKGROUND: Breast cancer remains a leading cause of cancer death worldwide. There is evidence that immunotherapy may play a role in the eradication of residual disease. Peptide vaccines for immunotherapy are capable of durable immune memory, but vaccines alone have shown sparse clinical activity against breast cancer to date. Toll-like receptor (TLR) agonists and helper peptides are excellent adjuvants for vaccine immunotherapy and they are examined in this human clinical trial. METHODS: A vaccine consisting of 9 MHC class I-restricted breast cancer-associated peptides (from MAGE-A1, -A3, and -A10, CEA, NY-ESO-1, and HER2 proteins) was combined with a TLR3 agonist, poly-ICLC, along with a helper peptide derived from tetanus toxoid. The vaccine was administered on days 1, 8, 15, 36, 57, 78. CD8+ T cell responses to the vaccine were assessed by both direct and stimulated interferon gamma ELIspot assays. RESULTS: Twelve patients with breast cancer were treated: five had estrogen receptor positive disease and five were HER2 amplified. There were no dose-limiting toxicities. Toxicities were limited to Grade 1 and Grade 2 and included mild injection site reactions and flu like symptoms, which occurred in most patients. The most common toxicities were injection site reaction/induration and fatigue, which were experienced by 100% and 92% of participants, respectively. In the stimulated ELIspot assays, peptide specific CD8+ T cell responses were detected in 4 of 11 evaluable patients. Two patients had borderline immune responses to the vaccine. The two peptides derived from CEA were immunogenic. No difference in immune response was evident between patients receiving endocrine therapy and those not receiving endocrine therapy during the vaccine series. CONCLUSIONS: Peptide vaccine administered in the adjuvant breast cancer setting was safe and feasible. The TLR3 adjuvant, poly ICLC, plus helper peptide mixture provided modest immune stimulation. Further optimization is required for this multi-peptide vaccine/adjuvant combination. TRIAL REGISTRATION: ClinicalTrials.gov (posted 2/15/2012): NCT01532960. Registered 2/8/2012. https://clinicaltrials.gov/show/NCT01532960. PMID- 29157307 TI - Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking. AB - BACKGROUND: Multidrug resistance-associated protein 4 (MRP4) is a member of the C subfamily of the ABC family of ATP-binding cassette (ABC) transporters. MRP4 regulates ATP-dependent efflux of various organic anionic substrates and bile acids out of cells. Since Clonorchis sinensis lives in host's bile duct, accumulation of bile juice can be toxic to the worm's tissues and cells. Therefore, C. sinensis needs bile transporters to reduce accumulation of bile acids within its body. RESULTS: We cloned MRP4 (CsMRP4) from C. sinensis and obtained a cDNA encoding an open reading frame of 1469 amino acids. Phylogenetic analysis revealed that CsMRP4 belonged to the MRP/SUR/CFTR subfamily. A tertiary structure of CsMRP4 was generated by homology modeling based on multiple structures of MRP1 and P-glycoprotein. CsMRP4 had two membrane-spanning domains (MSD1 & 2) and two nucleotide-binding domains (NBD1 & 2) as common structural folds. Docking simulation with nine bile acids showed that CsMRP4 transports bile acids through the inner cavity. Moreover, it was found that CsMRP4 mRNA was more abundant in the metacercariae than in the adults. Mouse immune serum, generated against the CsMRP4-NBD1 (24.9 kDa) fragment, localized CsMRP4 mainly in mesenchymal tissues and oral and ventral suckers of the metacercariae and the adults. CONCLUSIONS: Our findings shed new light on MRPs and their homologs and provide a platform for further structural and functional investigations on the bile transporters and parasites' survival. PMID- 29157308 TI - Characterization of the upper and lower respiratory tract microbiota in Piedmontese calves. AB - BACKGROUND: The microbiota of the bovine upper respiratory tract has been recently characterized, but no data for the lower respiratory tract are available. A major health problem in bovine medicine is infectious bronchopneumonia, the most common respiratory syndrome affecting cattle. With this study, we used 16S rRNA gene sequencing to characterize and compare the microbial community composition of the upper and lower respiratory tracts in calves. RESULTS: The microbiota of the upper (nasal swab [NS]) and the lower (trans-tracheal aspiration [TTA]) respiratory tracts of 19 post-weaned Piedmontese calves with (8/19) and without (11/19) clinical signs of respiratory disease, coming from six different farms, was characterized by 16S rRNA gene metabarcoding. A total of 29 phyla (29 in NS, 21 in TTA) and 305 genera (289 in NS, 182 in TTA) were identified. Mycoplasma (60.8%) was the most abundant genus identified in both the NS (27.3%) and TTA (76.7%) samples, followed by Moraxella (16.6%) in the NS and Pasteurella (7.3%) in the TTA samples. Pasteurella multocida (7.3% of total operational taxonomic units [OTUs]) was the most abundant species in the TTA and Psychrobacter sanguinis (1.1% of total OTUs) in the NS samples. Statistically significant differences between the NS and the TTA samples were found for both alpha (Shannon index, observed species, Chao1 index, and Simpson index; P = 0.001) and beta (Adonis; P = 0.001) diversity. Comparison of the NS and TTA samples by farm origin and clinical signs revealed no statistical difference (P > 0.05), except for farm origin for the NS samples when compared by the unweighted UniFrac metric (P = 0.05). CONCLUSIONS: Using 16S rRNA gene sequencing, we characterized the microbiota of the upper and lower respiratory tracts of calves, both healthy individuals and those with clinical signs of respiratory disease. Our results suggest that environmental factors may influence the composition of the upper airway microbiota in cattle. While the two microbial communities (upper and lower airways) differed in microbial composition, they shared several OTUs, suggesting that the lung microbiota may be a self-sustaining, more homogeneous ecosystem, influenced by the upper respiratory tract microbiota. PMID- 29157310 TI - Zooprophylaxis as a control strategy for malaria caused by the vector Anopheles arabiensis (Diptera: Culicidae): a systematic review. AB - BACKGROUND: Zooprophylaxis is the use of wild or domestic animals, which are not the reservoir host of a given disease, to divert the blood-seeking malaria vectors from human hosts. In this paper, we systematically reviewed zooprophylaxis to assess its efficacy as a malaria control strategy and to evaluate the possible methods of its application. METHODS: The electronic databases, PubMed Central(r), Web of Science, Science direct, and African Journals Online were searched using the key terms: "zooprophylaxis" or "cattle and malaria", and reports published between January 1995 and March 2016 were considered. Thirty-four reports on zooprophylaxis were retained for the systematic review. RESULTS: It was determined that Anopheles arabiensis is an opportunistic feeder. It has a strong preference for cattle odour when compared to human odour, but feeds on both hosts. Its feeding behaviour depends on the available hosts, varying from endophilic and endophagic to exophilic and exophagic. There are three essential factors for zooprophylaxis to be effective in practice: a zoophilic and exophilic vector, habitat separation between human and host animal quarters, and augmenting zooprophylaxis with insecticide treatment of animals or co-intervention of long-lasting insecticide-treated nets and/or indoor residual spraying. Passive zooprophylaxis can be applied only in malaria vector control if cattle and human dwellings are separated in order to avoid the problem of zoopotentiation. CONCLUSIONS: The outcomes of using zooprophylaxis as a malaria control strategy varied across locations. It is therefore advised to conduct a site-specific evaluation of its effectiveness in vector control before implementing zooprophylaxis as the behaviour of Anopheles arabiensis mosquitoes varies across localities and circumstances. PMID- 29157312 TI - Combating echinococcosis in China: strengthening the research and development. AB - Echinococcosis is a neglected zoonotic disease, causing great morbidity and mortality due to the wide distribution of its endemic areas. China holds a high percentage in the global burden of both cystic and alveolar echinococcosis. A national survey conducted between 2012 and 2016 showed that an estimated 50 million people are at risk of contracting the disease in western China, of whom about 0.17 million are cases with echinococcosis.Despite this, research and development on echinococcosis in China is greatly inadequate compared to that in other countries. In this paper, we argue that there is a need for more research and work to be conducted in China on echinococcosis, including researching techniques in regards to diagnosis, treatment, and vaccination, and developing products through technical transformation and piloting strategies to control and even elimination.However, great opportunities exist for China to strengthen the research and development on this disease through initiatives such as Health China 2030, the Belt and Road Initiative, the China-Africa cooperation, as well as through further cooperation between China and the World Health Organization. All of these can bring us closer to controlling echinococcosis in China as well as in other countries. One element of crucial importance will be the training and development of professionals, which can be strengthened through international cooperation. PMID- 29157311 TI - Peripheral and local predictive immune signatures identified in a phase II trial of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV melanoma. AB - BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a significant proportion of patients with metastatic melanoma. New approaches to increase survival and to predict which patients will benefit from treatment are needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP) to assess its safety, efficacy, and to search for peripheral and tumor-based predictive biomarkers. METHODS: Thirty patients with untreated unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse events (AEs) were monitored and response to treatment was evaluated. Tumor tissue and peripheral blood were collected at specified time points to characterize tumor immune markers by immunohistochemistry and systemic immune activity by multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed. Best Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%, respectively. Median overall survival was 16.2 months. Response to treatment was positively correlated with a higher tumor CD3+ infiltrate (immune score) at baseline. NRAS and BRAF mutations were less frequent in patients who experienced clinical benefit. Assessment of peripheral blood revealed that non-responders had elevated baseline levels of CXCL8 and CCL4, and a higher proportion of circulating late differentiated B cells. Pre-existing high levels of chemokines (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly associated with worse patient overall survival. Elevated proportions of circulating CD8+/PD-1+ T cells during treatment were associated with worse survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment. A pre-existing systemic inflammatory state characterized by elevation of selected chemokines and advanced B cell differentiation, was strongly associated with poor patient outcomes, revealing potential predictive circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 , registered on August 29, 2012. PMID- 29157313 TI - Calpain-5 gene expression in the mouse eye and brain. AB - OBJECTIVE: Our objective was to characterize CAPN5 gene expression in the mouse central nervous system. Mouse brain and eye sections were probed with two high affinity RNA oligonucleotide analogs designed to bind CAPN5 RNA and one scramble, control oligonucleotide. Images were captured in brightfield. RESULTS: CAPN5 RNA probes were validated on mouse breast cancer tumor tissue. In the eye, CAPN5 was expressed in the ganglion cell, inner nuclear and outer nuclear layers of the retina. Signal could not be detected in the ciliary body or the iris because of the high density of melanin. In the brain, CAPN5 was expressed in the granule cell layers of the hippocampus and cerebellum. There was scattered expression in pons. The visual cortex showed faint signal. Most signal in the brain was in a punctate pattern. PMID- 29157314 TI - Risk Factors for Staphylococcus aureus Acquisition in the Neonatal Intensive Care Unit: A Matched Case-Case-Control Study. AB - OBJECTIVE To determine risk factors independent of length of stay (LOS) for Staphylococcus aureus acquisition in infants admitted to the neonatal intensive care unit (NICU). DESIGN Retrospective matched case-case-control study. SETTING Quaternary-care referral NICU at a large academic children's hospital. METHODS Infants admitted between January 2014 and March 2016 at a level IV NICU who acquired methicillin resistant (MRSA) or susceptible (MSSA) S. aureus were matched with controls by duration of exposure to determine risk factors for acquisition. A secondary post hoc analysis was performed on the entire cohort of at-risk infants for risk factors identified in the primary analysis to further quantify risk. RESULTS In total, 1,751 infants were admitted during the study period with 199 infants identified as having S. aureus prevalent on admission. There were 246 incident S. aureus acquisitions in the remaining at-risk infant cohort. On matched analysis, infants housed in a single-bed unit were associated with a significantly decreased risk of both MRSA (P=.03) and MSSA (P=.01) acquisition compared with infants housed in multibed pods. Across the entire cohort, pooled S. aureus acquisition was significantly lower in infants housed in single-bed units (hazard ratio,=0.46; confidence interval, 0.34-0.62). CONCLUSIONS NICU bed design is significantly associated with S. aureus acquisition in hospitalized infants independent of LOS. Infect Control Hosp Epidemiol 2018;39:46-52. PMID- 29157309 TI - Recent knowledge on hepatitis E virus in Suidae reservoirs and transmission routes to human. AB - Hepatitis E virus (HEV) causes self-limiting acute hepatitis in humans that can eventually result in acute liver failures or progress to chronic infections. While in tropical and sub-tropical areas, HEV infections are associated with important waterborne epidemics, in Northern countries, HEV infections are autochthonous with a zoonotic origin. In the past decade, it has become clear that certain HEV genotypes are zoonotic and that swine, and more generally Suidae, are the main reservoir. Zoonotic transmissions of the virus may occur via direct contact with infected pigs, wild boars or consumption of contaminated meat. This review describes the current knowledge on domestic and wild Suidae as reservoirs of HEV and the evidence of the different routes of HEV transmission between these animals and humans. PMID- 29157315 TI - Botulinum Toxin Type A Injections as Monotherapy for Upper Limb Essential Tremor Using Kinematics. AB - BACKGROUND: There is a significant need for a targeted therapy for essential tremor (ET), as medications have not been developed specifically for ET, and the ones prescribed are often not well-tolerated, so that many patients remain untreated. Recent work has shown that, unlike previous experience, kinematically guided individualized botulinum toxin type A (BoNT-A) injections provide benefit along with minimal weakness. Ours is the first long-term (96-week) safety and efficacy study of BoNT-A as monotherapy for ET using kinematically driven injection parameters. METHODS: Ten ET patients were administered six serial BoNT A treatments every 16 weeks and were assessed at 6 weeks following treatment. During each study visit, the Fahn-Tolosa-Marin (FTM) scale, the Unified Parkinson's Disease Rating Scale, and the Quality of Life for Essential Tremor Questionnaire (QUEST) were administered along with kinematic assessment of the treated limb. Participants performed scripted tasks with motion sensors placed over each arm joint. Dosing patterns were determined using the movement disorder neurologist's interpretation of muscles contributing to the kinematically analyzed upper limb tremor biomechanics. RESULTS: There was a 33.8% (p<0.05) functional improvement (FTM part C) and a 39.8% (p<0.0005) improvement in QUEST score at week 96 compared to pretreatment scores at week 0. Although there was a 44.6% (p<0.0005) non-dose-dependent reduction in maximal grip strength, only 2 participants complained of mild weakness. Following the fourth serial treatment, mean action tremor score was reduced by 62.9% (p=0.001) in the treated and by 44.4% (p=0.03) in the untreated arm at week 96 compared to week 48. CONCLUSIONS: Individualized BoNT-A dosing patterns to each individual's tremor biomechanics provided an effective monotherapy for ET as function improved without functionally limiting muscle weakness. PMID- 29157316 TI - EVALUATION OF THE HTA CORE MODEL FOR NATIONAL HEALTH TECHNOLOGY ASSESSMENT REPORTS: COMPARATIVE STUDY AND EXPERIENCES FROM EUROPEAN COUNTRIES. AB - OBJECTIVES: The health technology assessment (HTA) Core Model(r) is a tool for defining and standardizing the elements of HTA analyses within several domains for producing structured reports. This study explored the parallels between the Core Model and a national HTA report. Experiences from various European HTA agencies were also investigated to determine the Core Model's adaptability to national reports. METHODS: A comparison between a national report on Genetic Counseling, produced by the Cellule d'expertise medicale Luxembourg, and the Core Model was performed to identify parallels in terms of relevant and comparable assessment elements (AEs). Semi-structured interviews with five representatives from European HTA agencies were performed to assess their user experiences with the Core Model. RESULTS: The comparative study revealed that 50 percent of the total number (n = 144) of AEs in the Core Model were relevant for the national report. Of these 144 AEs from the Core Model, 34 (24 percent) were covered in the national report. Some AEs were covered only partly. The interviewees emphasized flexibility in using the Core Model and stated that the most important aspects to be evaluated include characteristics of the disease and technology, clinical effectiveness, economic aspects, and safety. CONCLUSIONS: In the present study, the national report covered an acceptable number of AEs of the Core Model. These results need to be interpreted with caution because only one comparison was performed. The Core Model can be used in a flexible manner, applying only those elements that are relevant from the perspective of the technology assessment and specific country context. PMID- 29157317 TI - Entomopathogenic bacteria Photorhabdus luminescens as drug source against Leishmania amazonensis. AB - Leishmaniasis is a widely spread and zoonotic disease with serious problems as low effectiveness of drugs, emergence of parasite resistance and severe adverse reactions. In recent years, considerable attention has been given to secondary metabolites produced by Photorhabdus luminescens, an entomopathogenic bacterium. Here, we assessed the leishmanicidal activity of P. luminescens culture fluids. Initially, promastigotes of Leishmania amazonensis were incubated with cell free conditioned medium of P. luminescens and parasite survival was monitored. Different pre-treatments of the conditioned medium revealed that the leishmanicidal activity is due to a secreted peptide smaller than 3 kDa. The Photorhabdus-derived leishmanicidal toxin (PLT) was enriched from conditioned medium and its effect on mitochondrial membrane potential of promastigotes, was determined. Moreover, the biological activity of PLT against amastigotes was evaluated. PLT inhibited the parasite growth and showed significant leishmanicidal activity against promastigote and amastigotes of L. amazonensis. PLT also caused mitochondrial dysfunction in parasites, but low toxicity to mammalian cell and human erythrocytes. Moreover, the anti-amastigote activity was independent of nitric oxide production. In summary, our results highlight that P. luminescens secretes Leishmania-toxic peptide(s) that are promising novel drugs for therapy against leishmaniasis. PMID- 29157318 TI - Effect of Clinical Variables on the Volume of Blood Collected for Blood Cultures in an Adult Patient Population. AB - OBJECTIVE To identify clinical variables that influence blood culture volume recovery DESIGN Retrospective chart review and linear model analysis SETTING A 621-bed Academic Medical Center with a Clinical Laboratory that processes 20,000+ blood cultures annually and dedicated phlebotomy staff for venipuncture PATIENTS Consecutive patients requiring blood culture METHODS Over a 6-day period, blood volume was determined in 568 culture bottles from 128 unique adult patients, and clinical data from the time of phlebotomy were extracted from hospital electronic medical records. Conditional hierarchical linear models with random effects for patient and phlebotomy occasion were utilized to analyze correlations between values collected from the same patient and during the same phlebotomy occasion. RESULTS Blood samples obtained from a central venous catheter yielded, on average, 2.53 mL more blood (95% CI, 1.63-3.44 mL; P<.001) than those from peripheral venipuncture, and aerobic bottles contained 0.38 mL more blood (95% CI, 0.1-0.67 mL; P=.009) than the anaerobic bottles. The remaining clinical variables (eg, hospital department, patient age, body mass index, gender, mean arterial pressure, concomitant systemic antibiotic use, and Charlson comorbidity index score) failed to reach statistical significance (P<.05) in relation to volume. CONCLUSIONS Blood cultures obtained from central venous catheters contain significantly greater volume than those obtained via peripheral venipuncture. These data highlight the clinically significant issue of low culture volume recovery, indicate that diagnostic and prognostic tools that rely on volume dependent phenomena (ie, time to positivity) may require further validation under usual clinical practice circumstances, and suggest goals for future institutional performance improvement. Infect Control Hosp Epidemiol 2017;38:1493-1497. PMID- 29157319 TI - Reversible Ethyl Chloride Neurotoxicity: A Case Report. PMID- 29157320 TI - Comparison of high and low trans-fatty acid consumers: analyses of UK National Diet and Nutrition Surveys before and after product reformulation. AB - OBJECTIVE: The WHO encourages the virtual elimination of artificial trans-fatty acids (TFA), which increase CHD risk. Our UK analysis explores whether voluntary reformulation results in differential TFA intakes among socio-economic groups by determining characteristics of high TFA consumers before and after product reformulation. DESIGN: Food intake was collected by 7d weighed records pre reformulation and 4d diaries post-reformulation. Sociodemographic characteristics of TFA consumers above the WHO limit, and of the top 10 % of TFA consumers as a percentage food energy, were compared with those of lower TFA consumers. Multivariate logistic regression determined independent socio-economic predictors of being a top 10 % consumer. SUBJECTS: UK National Diet and Nutrition Surveys (NDNS) for adults aged 19-64 years pre-reformulation (2000/01; N 1724) and post reformulation (2010/11-2011/12; N 848). RESULTS: Post-reformulation 2.5 % of adults exceeded the WHO limit, v. 57 % pre-reformulation. In unadjusted analyses, high TFA consumption was associated with lower income, lower education and long term illness/disability pre- but not post-reformulation. In adjusted pre reformulation analyses, degree holders were half as likely as those without qualifications to be top 10 % consumers (OR=0.51; 95 % CI 0.28, 0.92). In adjusted post-reformulation analyses, those with higher income were 2.5-3.3 times more likely to be top 10 % consumers than lowest income households. Pre reformulation, high consumers consumed more foods containing artificial TFA, whereas ruminant TFA were more prominent post-reformulation. CONCLUSIONS: High TFA consumption was associated with socio-economic disadvantage pre reformulation, but evidence of this is less clear post-reformulation. Voluntary reformulation appeared effective in reducing TFA content in many UK products with mixed effects on dietary inequalities relating to income and education. PMID- 29157321 TI - Patient perception matters in weight management. AB - In a survey of 471 patients, we collected self-reported weight and height data and asked about self-perceptions of provider support toward weight loss and other weight management concerns. Multivariable analysis found that respondents with higher body mass index (BMI) were more likely to report that a physician had told them that they were overweight (OR=3.49, 95% CI 2.06-5.89, P<0.001). However, this conversation was less likely to change their personal view of their weight (OR=0.62 per 5 kg/m2, 95% CI 0.45-0.86, P=0.004), or motivate them to lose weight (OR=0.67 per 5 kg/m2, 95% CI 0.50-0.91, P=0.009). Higher BMI was associated with higher weight-loss goals (P<0.001), while anticipated time to achieve those goals was increased (P<0.001). Physician involvement in weight management was important, but the patients' needs and experiences differed by BMI. Approaches to addressing barriers and identifying resources for weight management should be tailored to individuals by considering BMI. PMID- 29157322 TI - Developmental relations between amygdala volume and anxiety traits: Effects of informant, sex, and age. AB - Although substantial human and animal evidence suggests a role for the amygdala in anxiety, literature linking amygdala volume to anxiety symptomatology is inconclusive, with studies finding positive, negative, and null results. Clarifying this brain-behavior relation in middle to late childhood is especially important, as this is a time both of amygdala structural maturation and the emergence of many anxiety disorders. The goal of the current study was to clarify inconsistent findings in previous literature by identifying factors moderating the relation between amygdala volume and anxiety traits in a large sample of typically developing children aged 6-13 years (N = 72). In particular, we investigated the moderating effects of informant (parent vs. child), age, and sex. We found that children's reports (i.e., self-reports) were related to amygdala volume; children who reported higher anxiety levels had smaller amygdalae. This negative relation between amygdala volume and anxiety weakened with age. There was also an independent effect of sex, such that relations were stronger in males than in females. These results indicate the importance of considering sample and informant characteristics when charting the neurobiological mechanisms underlying developmental anxiety. PMID- 29157323 TI - Prevalence and Factors Associated With Multidrug-Resistant Gram-Negative Organisms in Patients With Spinal Cord Injury. AB - OBJECTIVE Infections caused by multidrug-resistant gram-negative organisms (MDRGNOs) have been increasing every year. The objective of this study was to describe the prevalence of MDRGNOs and factors associated with MDRGNOs in patients with spinal cord injury or disorder (SCI/D). DESIGN Retrospective cohort study. METHODS Department of Veterans Affairs (VA) electronic health record data from 142 VA facilities were evaluated for 19,642 patients with SCI/D. Multivariable cluster-adjusted models were fit to identify factors associated with MDRGNO. RESULTS Gram-negative (GN) cultures occurred in 44% of patients with SCI/D receiving care at VA facilities, and 11,527 (41.3%) GN cultures had an MDRGNO. The most frequent GN organisms (GNOs) were Escherichia coli (28.5%), Klebsiella pneumoniae (17.0%), and Pseudomonas aeruginosa (16.0%). Two-thirds of GN cultures were from the outpatient setting, where MDRGNO prevalence was 37.6%. Significant geographic variation in the prevalence of MDRGNOs was identified (South, 44.7%; Northeast, 44.3%; West, 36.8%; Midwest, 34.4%). Other factors associated with an MDRGNO were older age, injury characteristics, comorbidities, specimen type, healthcare setting, and healthcare exposure. Black (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.39-1.78) and Hispanic race (OR, 1.58; 95% CI, 1.28-1.95), polymicrobial culture (OR, 2.67; 95% CI, 2.46-2.90), and antibiotic use in the previous 90 days (OR, 1.62; 95% CI, 1.50-1.76) were also associated with having an MDRGNO. CONCLUSIONS MDRGNOs were common in community and healthcare settings among veterans with SCI/D, with significant geographic variation. Health care and antibiotic exposures were significant factors associated with MDRGNOs. Priority should be given to controlling the spread of MDRGNOs in this special population, including a focus on judicious use of antibiotics. Infect Control Hosp Epidemiol 2017;38:1464-1471. PMID- 29157324 TI - Individual differences in anxiety trajectories from Grades 2 to 8: Impact of the middle school transition. AB - This study examined the impact of the middle school transition on general anxiety trajectories from middle childhood to middle adolescence, as well as how youths' individual vulnerability and exposure to contextual stressors were associated with anxiety trajectories. Participants were 631 youth (47% boys, M age = 7.96 years at Time 1), followed for 7 successive years from second to eighth grade. Teachers reported on youths' individual vulnerability to anxiety (anxious solitude) in second grade; youth reported on their anxiety in second to eighth grade and aspects of their social contexts particularly relevant to the school transition (school hassles, peer victimization, parent-child relationship quality, and friendship quality) in sixth to eighth grade. The results revealed two subgroups that showed either strongly increasing (5%) or decreasing (14%) levels of anxiety across the transition and two subgroups with fairly stable levels of either high (11%) or low (70%) anxiety over time. Youth in the latter two subgroups could be distinguished based on their individual vulnerability to anxiety, whereas youth with increasing anxiety reported more contextual stressors and less contextual support than youth with decreasing anxiety. In sum, findings suggest that the middle school transition has the potential to alter developmental trajectories of anxiety for some youth, for better or for worse. PMID- 29157325 TI - Childhood attachment and behavioral inhibition: Predicting intolerance of uncertainty in adulthood. AB - Intolerance of uncertainty (IU), the tendency to react negatively to uncertain situations, has been identified as an important cognitive component of anxiety disorders, yet little is known about its etiology. Links to temperament, particularly behavioral inhibition (BI), and insecure attachment have been proposed in the development of IU, but no prospective empirical investigation has been performed thus far. In the current study, attachment to caregiver and BI of 60 children were assessed at age 6, using observational measures. Mother's anxiety symptoms were assessed when participants were 14 years old. IU was reported by participants when they were 21 years old, as was neuroticism. Two types of insecure attachment (ambivalent and disorganized-controlling) and BI were positively related to IU over a 15-year span, even after controlling for participants' neuroticism and maternal anxiety. Attachment and BI had no significant interacting effect on the development of IU. Maternal anxiety was positively related to child BI and insecure attachment, but not IU. This study is the first to provide empirical support for a link between ambivalent and disorganized-controlling attachment and BI in preschool children to the development of IU in adulthood. Results have etiological and preventative implications not only for anxiety disorders but also for all disorders related to IU. PMID- 29157326 TI - Relative Resistance of the Emerging Fungal Pathogen Candida auris and Other Candida Species to Killing by Ultraviolet Light. AB - Mobile ultraviolet-C (UV-C) light room decontamination devices are frequently used as an adjunct to standard cleaning in healthcare facilities, but their efficacy in killing Candida species is not clear. In laboratory testing, the emerging multidrug-resistant Candida auris and 2 other Candida species were significantly less susceptible to killing by UV-C than methicillin-resistant Staphylococcus aureus. Infect Control Hosp Epidemiol 2018;39:94-96. PMID- 29157327 TI - Differences in the sodium content of bread products in the USA and UK: implications for policy. AB - OBJECTIVE: Americans consume Na in excess of daily recommendations. Most dietary Na comes from packaged foods, and bread is a major contributor. In the UK, national Na reduction strategies contributed to lower Na levels in packaged foods and lower population Na intake. Similar initiatives are emerging in the USA and require surveillance to assess effectiveness. We aimed to examine Na levels in bread products in the USA and compare levels with similar UK products. DESIGN: Na data for bread products were obtained from the US Label Insight Open Data Initiative (n 4466) and the FoodSwitch UK database (n 1651). Mean, median and range of Na content, and proportion of products meeting Na targets established by the National Salt Reduction Initiative (NSRI) and the UK Department of Health (DH) were calculated overall, by bread type and by country. RESULTS: Mean (sd) Na content in bread was 455 (170) mg/100 g in the USA and 406 (179) mg/100 g in the UK. In both countries, savoury bread had the highest mean Na (USA=584 mg/100 g, UK=543 mg/100 g) and fruit bread the lowest mean Na (USA=345 mg/100 g, UK=277 mg/100 g). Na content of US bread products was 12 % higher than in the UK, with 21 % of US bread products and 31 % of UK bread products meeting the NSRI and DH targets, respectively. CONCLUSIONS: US bread products have, on average, 12 % more Na than similar products in the UK. Variation in Na content within product categories, and between countries, suggests the feasibility of manufacturing products with lower Na to lower dietary Na intake. PMID- 29157329 TI - The Need for Rotavirus Vaccine Introduction in the National Immunization Program of More Than 100 Countries around the World. PMID- 29157328 TI - Peer effects on self-regulation in adolescence depend on the nature and quality of the peer interaction. AB - Adolescence is a critical period for the development of self-regulation, and peer interactions are thought to strongly influence regulation ability. Simple exposure to peers has been found to alter decisions about risky behaviors and increase sensitivity to rewards. The link between peer exposure and self regulation is likely to vary as a function of the type and quality of peer interaction (e.g., rejection or acceptance). Little is known about how the nature of interactions with peers influences different dimensions of self-regulation. We examined how randomization to acceptance or rejection by online "virtual" peers influenced multiple dimensions of self-regulation in a multisite community sample of 273 adolescents aged 16-17 years. Compared to a neutral condition, exposure to peers produced increases in cold cognitive control, but decreased hot cognitive control. Relative to peer acceptance, peer rejection reduced distress tolerance and increased sensitivity to losses. These findings suggest that different dimensions of adolescent self-regulation are influenced by the nature of the peer context: basic cognitive functions are altered by mere exposure to peers, whereas more complex decision making and emotion regulation processes are influenced primarily by the quality of that exposure. PMID- 29157330 TI - Easy and Fast Method for the Determination of Biogenic Amines in Fish and Fish Products with Liquid Chromatography Coupled to Orbitrap Tandem Mass Spectrometry. AB - A quantitative method for the determination of biogenic amines was developed. The method is characterized by the virtual absence of sample cleanup and does not require a derivatization reaction. Diluted extracts are centrifuged, filtrated, and directly injected into an ultra-HPLC column, which is coupled to a single stage high-resolution mass spectrometer (Orbitrap). The chromatography is based on a reversed-phase column and an eluent containing an ion-pairing agent (heptafluorobutyric acid). The high sensitivity of the instrument permits the injection of very diluted extracts, which ensures stable retention times and the virtual absence of signal suppression effects. In addition, the quantification of histamine (a regulated compound) is further aided by the use of an isotopically labeled internal standard. The method was validated for three fish-based matrixes. Both the sample processing and the analytical measurement are very fast; hence, the methodology is ideal for high-throughput work. In addition, the method is significantly more selective than conventional methods (i.e., derivatization followed by LC with UV/fluorescence (FL) detection) for biogenic amines. A comparison showed that LC-UV/FL methods can produce false-positive findings due to coeluting matrix compounds. PMID- 29157332 TI - The Gene Therapy Frontier in Aerospace Medicine. PMID- 29157333 TI - A Cohort Mortality Study Among Soviet and Russian Cosmonauts, 1961-2014. AB - INTRODUCTION: Over 500 people from different countries have been to space since the first manned spaceflight in 1961. Factors of space and spaceflights might cause functional and somatic disorders, leading to increased mortality. Our research goal was to assess cause-specific risk of death among Soviet and Russian cosmonauts who had at least one spaceflight. METHODS: The epidemiological cohort study included 115 male cosmonauts. The observation period was 54 yr (January 1, 1961-December 31, 2014) and 2707 person-years of follow-up were obtained. By the end of the period, 84 cosmonauts were still alive and 31 were deceased. The reference groups were the male population of Russia and of the Moscow Region, where Zvezdny City (Star City) is located. Mortality risk was assessed by standardized mortality ratio (SMR) with 95% confidence intervals (95% CI). RESULTS: Death risk in the cohort was significantly lower than that in both reference groups: for all causes (A00-Y98; SMR = 40), for diseases of the circulatory system (I00-I99; SMR = 37 and 35 compared to Russia and the Moscow Region, respectively), and for other causes, i.e., all causes except circulatory diseases, cancer, and accidents, (SMR = 8). Death risk for accidents (V01-Y98) in the cohort was 1.8-1.9 times lower than that in both reference groups: SMR = 52 (95% CI 19-139) and 56 (21-151), but was not statistically significant. SMR for cancer (C00-C97) was also below 100 (71 and 66), but insignificant. DISCUSSION: Our findings mainly characterize mortality among the first cosmonauts who have flown to space from 1961 through the 1970s, which indicates the necessity of continuing research.Ushakov IB, Voronkov YI, Bukhtiyarov IV, Tikhonova GI, Gorchakova TYu, Bryleva MS. A cohort mortality study among Soviet and Russian cosmonauts, 1961-2014. Aerosp Med Hum Perform. 2017; 88(12):1060-1065. PMID- 29157334 TI - In-Flight Decision-Making by General Aviation Pilots Operating in Areas of Extreme Thunderstorms. AB - BACKGROUND: General aviation (comprised mainly of noncommercial, light aircraft) accounts for 94% of civil aviation fatalities in the United States. Although thunderstorms are hazardous to light aircraft, little research has been undertaken on in-flight pilot decision-making regarding their avoidance. The study objectives were: 1) to determine if the thunderstorm accident rate has declined over the last two decades; and 2) assess in-flight (enroute/landing) airman decision-making regarding adherence to FAA separation minima from thunderstorms. METHODS: Thunderstorm-related accidents were identified from the NTSB database. To determine en route/arriving aircraft real-time thunderstorm proximity/relative position and airplane location, using a flight-tracking (Flight Aware(r)) website, were overlaid on a graphical weather image. Statistics employed Poisson and Chi-squared analyses. RESULTS: The thunderstorm-related accident rate was undiminished over the 1996-2014 period. In a prospective analysis the majority (enroute 77%, landing 93%) of flights violated the FAA recommended separation distance from extreme convection. Of these, 79 and 69% (en route and landing, respectively) selected a route downwind of the thunderstorm rather than a less hazardous upwind flight path. Using a mathematical product of binary (separation distance, relative aircraft-thunderstorm position) and nominal (thunderstorm-free egress area) parameters, airmen were more likely to operate in the thunderstorm hazard zone for landings than en route operations. DISCUSSION: The thunderstorm-related accident rate, carrying a 70% fatality rate, remains unabated, largely reflecting nonadherence to the FAA-recommended separation minima and selection of a more hazardous route (downwind) for circumnavigation of extreme convective weather. These findings argue for additional emphasis in ab initio pilot training/recurrency on thunderstorm hazards and safe practices (separation distance and flight path).Boyd DD. In-flight decision-making by general aviation pilots operating in areas of extreme thunderstorms. Aerosp Med Hum Perform. 2017; 88(12):1066-1072. PMID- 29157335 TI - Hyperoxia and Hypoxic Hypoxia Effects on Simple and Choice Reaction Times. AB - INTRODUCTION: Effects of exposure to hyperoxia (PiO2 > 105 mmHg), normoxia (PiO2 95-105 mmHg) and hypoxia (PiO2 < 95 mmHg) on simple and choice reaction performance tasks were evaluated. METHODS: Ten subjects performed simple and choice reaction time tests (SRT and CRT, respectively) at ground level for 40 min (20 min normoxic, 20 min hyperoxic, randomly assigned), 3048 m (10,000 ft) for 75 min (15 min hyperoxic, 60 min hypoxic), 4572 m (15,000 ft) for 60 min (15 min hyperoxic, 45 min hypoxic), and 6096 m (20,000 ft) for 35 min (15 min hyperoxic, 20 min hypoxic). SRT and CRT tests were also conducted at ground level 1 h after normoxic rest (recovery) to assess any recovery time effect on these psychomotor tasks. RESULTS: Total response time (TRT) significantly increased by 15 ms to 25 ms at all three altitudes for both the SRT and CRT tasks. At and below 4572 m, the performance changes were gradual over the duration of the exposures, whereas at 6096 m these changes were immediate. After 1 h, no performance decrement was measured. There was no statistical evidence that ground-level performance on these tasks was improved in hyperoxic vs. normoxic conditions. DISCUSSION: Results suggest mild decrements in reaction time due to hypoxia may occur as low as 3048 m (10,000 ft) while hyperoxia showed no positive effect on accuracy or reaction time at ground level or higher when performing simple and choice psychomotor reaction tasks.Dart T, Gallo M, Beer J, Fischer J, Morgan T, Pilmanis A. Hyperoxia and hypoxic hypoxia effects on simple and choice reaction times. Aerosp Med Hum Perform. 2017; 88(12):1073-1080. PMID- 29157336 TI - Dissociated Components of Executive Control in Acute Hypobaric Hypoxia. AB - INTRODUCTION: The neurocognitive effects of acute hypobaric hypoxia are still largely unknown. This study was designed to test the hypothesis that executive control, an important component of cognition, is especially vulnerable to hypoxia. METHODS: Subjects participated in a simulated hypobaric chamber flight to 5500 m. Four auditory tasks were presented before, during, and after hypoxia: 1) Voice, and 2) Name variant of the Stroop task (both measuring conflict resolution); 3) go/no-go task (GNG; measuring inhibition); and 4) two-choice reaction time task (CRT; which is a noninhibitory control task). RESULTS: The Stroop effect increased during hypoxia: in the Voice Stroop it increased from 49.4 to 83.6 ms for reaction time and from 4.1 to 12.3% for accuracy; in the Name Stroop from 43.5 to 82.9 ms for reaction time (accuracy remained unchanged). Accuracy declined from 82.3 to 75.0% in CRT, and from 85.8 to 77.5% (averaged over stimulus types) in the GNG task. Importantly, accuracy decreased similarly to go and no-go stimuli in the GNG task, revealing unaffected inhibition. DISCUSSION: The findings suggest that tasks requiring conflict resolution are more likely to be impaired than tasks requiring inhibition of response. Furthermore, our results provide evidence for the distinct nature of inhibitory control functions.Takacs E, Czigler I, Pato LG, Balazs L. Dissociated components of executive control in acute hypobaric hypoxia. Aerosp Med Hu Perform. 2017; 88(12):1081-1087. PMID- 29157337 TI - Simulated High Altitude Helium-Oxygen Diving. AB - BACKGROUND: Experience with commercial heliox diving at high altitude is limited. The purpose of this study was to evaluate the effects of acute high-altitude exposure on fitness to dive and the safety of decompression after heliox diving while using U.S. Navy heliox decompression tables with Cross correction. METHOD: Four professional male divers were consecutively decompressed in a hypo- and hyperbaric chamber to altitudes of 3000 m (9842.5 ft), 4000 m (13,123.4 ft), and 5200 m (17,060.4 ft) during the 8-d study. The dive profiles tested were to 30 m (98.4 ft) for 60 min at all three altitudes and, in addition, a dive to 50 m (164 ft) for 60 min at 5200 m altitude. The decompression followed the U.S. Navy heliox decompression table. The safety of decompression was evaluated by precordial Doppler venous gas emboli (VGE) monitoring during the decompression stages and postdive monitoring of the divers for symptoms of decompression sickness (DCS). Effects of altitude exposure were measured as subjective rating and EEG signs of sleepiness and fatigue, clinical symptoms of high altitude disease, and fitness to dive. RESULTS: A total of 24 person-dives were conducted. There were no VGE detected during the decompression and no postdive symptoms of decompression illness. Both the EEG findings and subjective evaluation indicated increased sleepiness and fatigue at 3000 m, 4000 m, and 5200 m, all compared with the sea level baseline. During the diving phase, both the EEG findings and subjective evaluation scores returned to the baseline and the divers successfully completed diving. DISCUSSION: Diving at high altitude with a short acclimatization period appears safe despite divers exhibiting clinical symptoms and EEG signs of impairment by hypoxia at high altitude. Despite a small number of dives, the results of this study indicate that our application of U.S. Navy standard heliox decompression tables with Cross correction is effective and could be used for underwater constructions up to 5200 m altitude, with due caution.Shi L, Zhang Y, Tetsuo K, Shi Z, Fang Y, Denoble PJ, Li Y. Simulated high altitude helium-oxygen diving. Aerosp Med Hum Perform. 2017; 88(12):1088-1093. PMID- 29157338 TI - One-Year Mission on ISS Is a Step Towards Interplanetary Missions. AB - BACKGROUND: in the 1990s Russian cosmonauts performed six long-duration missions on Mir that went from 312 to 438 d. In 2015 a mission on the International Space Station that continued for 340 d, 8 h, and 47 min was successfully accomplished. It was a joint U.S./Russian mission completed by Scott Kelly and Mikhail Kornienko (KM). METHODS: The intensity of in-flight physical exercises and postflight motor changes were measured in KM and in the six cosmonauts who made shorter flights (173.3 +/- 13.8 d) on ISS while using similar countermeasures against the adverse effects of microgravity. RESULTS: It was found that both parameters varied similarly in spite of the difference in the duration of ISS missions. KM maintained adequate physical performance throughout the entire flight; moreover, the level of postflight changes he displayed was comparable to that recorded in the group of cosmonauts who completed 6-mo missions on ISS. DISCUSSION: In summary, the 1-yr mission has clearly demonstrated the high efficacy of the countermeasures used by KM.Fomina EV, Lysova NYu, Kukoba TB, Grishin AP, Kornienko MB. One-year mission on ISS is a step towards interplanetary missions. Aerosp Med Hum Perform. 2017; 88(12):1094-1099. PMID- 29157339 TI - Concurrent Pilot Instrument Monitoring in the Automated Multi-Crew Airline Cockpit. AB - INTRODUCTION: Pilot instrument monitoring has been described as "inadequate," "ineffective," and "insufficient" after multicrew aircraft accidents. Regulators have called for improved instrument monitoring by flight crews, but scientific knowledge in the area is scarce. Research has tended to investigate the monitoring of individual pilots when in the pilot-flying role; very little research has looked at crew monitoring, or that of the "monitoring-pilot" role despite it being half of the apparent problem. METHODS: Eye-tracking data were collected from 17 properly constituted and current Boeing 737 crews operating in a full motion simulator. Each crew flew four realistic flight segments, with pilots swapping between the pilot-flying and pilot-monitoring roles, with and without the autopilot engaged. Analysis was performed on the 375 maneuvering segments prior to localizer intercept. RESULTS: Autopilot engagement led to significantly less visual dwell time on the attitude director indicator (mean 212.8-47.8 s for the flying pilot and 58.5-39.8 s for the monitoring-pilot) and an associated increase on the horizontal situation indicator (18-52.5 s and 36.4 50.5 s). DISCUSSION: The flying-pilots' withdrawal of attention from the primary flight reference and increased attention to the primary navigational reference was paralleled rather than complemented by the monitoring-pilot, suggesting that monitoring vulnerabilities can be duplicated in the flight deck. Therefore it is possible that accident causes identified as "inadequate" or "insufficient" monitoring, are in fact a result of parallel monitoring.Jarvis SR. Concurrent pilot instrument monitoring in the automated multi-crew airline cockpit. Aerosp Med Hum Perform. 2017; 88(12):1100-1106. PMID- 29157340 TI - Mindful Application of Aviation Practices in Healthcare. AB - INTRODUCTION: Evidence supports the efficacy of incorporating select recognized aviation practices and procedures into healthcare. Incident analysis, debrief, safety brief, and crew resource management (CRM) have all been assessed for implementation within the UK healthcare system, a world leader in aviation-based patient safety initiatives. Mindful application, in which aviation practices are specifically tailored to the unique healthcare setting, show promise in terms of acceptance and long-term sustainment. METHODS: In order to establish British healthcare applications of aviation practices, a PubMed search of UK authored manuscripts published between 2005-2016 was undertaken using search terms 'aviation,' 'healthcare,' 'checklist,' and 'CRM.' A convenience sample of UK authored aviation medical conference presentations and UK-authored patient safety manuscripts were also reviewed. RESULTS: A total of 11 of 94 papers with UK academic affiliations published between 2005-2016 and relevant to aviation modeled healthcare delivery were found. The debrief process, incident analysis, and CRM are the primary practices incorporated into UK healthcare, with success dependent on cultural acceptance and mindful application. CRM training has gained significant acceptance in UK healthcare environments. DISCUSSION: Aviation modeled incident analysis, debrief, safety brief, and CRM training are increasingly undertaken within the UK healthcare system. Nuanced application, in which the unique aspects of the healthcare setting are addressed as part of a comprehensive safety approach, shows promise for long-term success. The patient safety brief and aviation modeled incident analysis are in earlier phases of implementation, and warrant further analysis.Powell-Dunford N, Brennan PA, Peerally MF, Kapur N, Hynes JM, Hodkinson PD. Mindful application of aviation practices in healthcare. Aerosp Med Hum Perform. 2017; 88(12):1107-1116. PMID- 29157341 TI - Glaucoma in U.S. Civil Aviation: 2005-2014. AB - INTRODUCTION: Until recently, glaucoma requiring treatment was disqualifying for U.S. pilots and required an aeromedical special issuance waiver. Since 2013 Aerospace Medical Examiners (AMEs) have been authorized to evaluate third-class pilots with mild glaucoma using similar protocols and issue medical certificates without a waiver if these criteria specified in the AME Guide are met. METHODS: The FAA's medical database was searched for pilots with glaucoma between 2005 and 2014. The National Transportation Safety Board (NTSB) accident database was then searched to determine which pilots with glaucoma had aircraft accidents during that period. The odds of accidents in the glaucoma pilots were compared with the overall pilot accident odds. RESULTS: Of 5000 pilots being treated for glaucoma, 78 were involved in aircraft accidents; however, glaucoma was not cited as the probable cause or contributing factor in any of the accidents. A logistic regression model adjusted for age showed that glaucoma had a protective effect on accident odds. The crude accident rate for third-class pilots with glaucoma was estimated to be 7.2 per 100,000 flight hours, with a fatal accident rate of 1.8 per 100,000. Although these point estimates were slightly higher than the estimated general aviation accident rates, the differences were not statistically significant. DISCUSSION: These findings suggest that third-class pilots with glaucoma are not at significantly greater risk of an accident than the U.S. general aviation community. It also indicates that FAA certification protocols for certifying and following pilots with glaucoma provide an adequate level of flight safety.DeJohn CA, Mills WD. Glaucoma in U.S. civil aviation: 2005-2014. Aerosp Med Hum Perform. 2017; 88(12):1117-1122. PMID- 29157342 TI - Molecular Biological Effects of Weightlessness and Hypergravity on Intervertebral Disc Degeneration. AB - INTRODUCTION: The rate of intervertebral disc degeneration (IVDD) is influenced by environmental factors. Extracellular matrix (ECM) destruction and apoptosis of intervertebral disc cells are major characteristics of IVDD. ECM degradation is closely linked to up-regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMP). This study aimed to elucidate the molecular biological changes during IVDD under conditions of weightlessness and hypergravity. METHODS: A total of 120 rabbits were divided randomly into four groups: control group, weightlessness group, hypergravity group, and mixed (hypergravity + weightlessness) group. Tail-suspension was used to simulate a weightless environment, and an animal centrifuge (+7 Gz three times for 60 s) was used to mimic hypergravity conditions. After exposure to the above conditions for 30, 60, and 90 d, respectively, 10 rabbits were selected from each group for immunohistochemical determination of MMP-1, MMP-3, and TIMP-1 expression. TUNEL staining was also carried out to detect apoptotic cells in each group at each time point. RESULTS: MMP-1, MMP-3, and TIMP-1 were rarely expressed in the control group, but were positively expressed in the other three groups. The strongest expression was in the mixed group at every time point, followed by the hypergravity group, and then the weightlessness group. Cell apoptosis index followed a similar trend to MMPs and TIMP-1 expression. DISCUSSION: The results suggested that weightlessness and hypergravity may both aggravate IVDD over time, with hypergravity having a particularly marked effect.Wu D, Zheng C, Wu J, Huang R, Chen X, Zhang T, Zhang L. Molecular biological effects of weightlessness and hypergravity on intervertebral disc degeneration. Aerosp Med Hum Perform. 2017; 88(12):1123-1128. PMID- 29157344 TI - You're the Flight Surgeon. AB - Newbold PR. You're the flight surgeon: acute appendicitis. Aerosp Med Hum Perform. 2017; 88(12):1134-1137. PMID- 29157343 TI - Cross-Sectional Analysis of Commonly Prescribed Medications in Military Aviation. AB - BACKGROUND: Medication use by naval aviators, either prescription or over-the counter, is not always relayed to the flight surgeon, resulting in unsafe flying environments. Many medications have debilitating effects that prohibit their use during aviation. Education and availability of resources on approved medications for flight status personnel is lacking. METHODS: A retrospective search of the Department of Defense Composite Health Care System (DoD CHCS) was conducted from five geographic locations. Basic epidemiological information was obtained to determine the most common medications (N = 70) prescribed to active-duty flight status personnel. Analysis determined their medication category, flight status designation, and a generalized location comparison. A similar control medication list for nonflight status personnel was generated from one location. RESULTS: Analysis found that many medications prescribed to aviators are not approved for use in aviation and are similar to those of nonflight status personnel. There were 8 of the top 15 (53%) and 40 of the 70 (57%) most commonly prescribed medications of flight status personnel which were not approved. Similarly, 49% of total prescriptions (N = 15,652) were not approved. Little difference was found in medications among nonflight and flight status personnel, as 11 of the top 15 prescription medications (73%) were identical. DISCUSSION: This research demonstrates the need for education regarding certain medications and their prohibited use during flight. Results will provide the Flight Surgeon common medications prescribed to aviators to aid them in providing a safer flying environment.Ropp LG, Haight SP, Prudhomme MB, Ropp EL. Cross-sectional analysis of commonly prescribed medications in military aviation. Aerosp Med Hum Perform. 2017; 88(12):1129-1133. PMID- 29157345 TI - You're the Flight Surgeon. AB - Lusterio LR. You're the flight surgeon: Huntington's disease. Aerosp Med Hum Perform. 2017; 88(12):1137-1139. PMID- 29157346 TI - Dr. Sherman Vinograd and His Contributions to the Skylab Medical Program. PMID- 29157348 TI - Table of Contents to Indexes. PMID- 29157347 TI - This Month in Aerospace Medicine History. PMID- 29157349 TI - Volume Tables of Contents. PMID- 29157350 TI - Index to Subjects. PMID- 29157351 TI - Index to Authors. PMID- 29157353 TI - Index to Departments, News Subjects, and Names in the News. PMID- 29157354 TI - Identification of vulnerability within a child and family health service. AB - Objective The aims of the present study were to describe the prevalence of vulnerability in a cohort of newborns, identify the factors that increase the risk of vulnerability and examine whether those who are most vulnerable are receiving home visits.Methods A prospective cross-sectional study was performed using data collected from questionnaires completed by child and family health nurses and obstetric discharge summaries for each mother-baby dyad. Descriptive frequencies and percentages are used to describe the proportions of children who were vulnerable, offered services and had risk factors for vulnerability. Categorical data were compared using Pearson's Chi-squared analysis.Results In all, 1517 newborns were included in the present study. Of these, 40.5% were identified as vulnerable and 13.9% had two or more risk factors for vulnerability (95% confidence interval (CI) 12-16%). The most common risk factors were biological. Across all newborns, 33.7% were visited at home, and 74.6% of vulnerable newborns were offered a home visit. Children identified as vulnerable were more likely to have a home visit than those who were not (z for 95% CI=1.96; P<0.1).Conclusions Although the high reported prevalence of identified risk needs to be confirmed in further studies, identifying vulnerability allowed the offer of home visiting to be directed towards those most likely to benefit.What is known about the topic? Of the Australian child population, 10-20% are vulnerable to adverse health, developmental and wellbeing outcomes. Vulnerable infants are at a greater risk of becoming vulnerable children, adolescents and adults over the life course. Biological and psychosocial risk factors for vulnerability are well described. Families with the greatest need are often the least likely to access or receive support, and have lower utilisation of preventative health services despite evidence that support in the first few years of life can significantly improve long-term outcomes.What does this paper add? This paper provides a detailed description of vulnerabilities in a cohort of newborns and demonstrates that it is possible to assign risk of vulnerability within existing child and family health services using tools that identify biological and psychosocial risk factors. Identification of vulnerability risk allows prioritisation of services to those with the greatest need.What are the implications for practitioners? It is possible to identify vulnerability risk within child and family health services. This allows those families at risk of future adverse health, developmental and wellbeing outcomes to be prioritised to receive health services and supports. PMID- 29157355 TI - Hospital admissions and emergency department presentations for dental conditions indicate access to hospital, rather than poor access to dental health care in the community. AB - High rates of dental-related potentially preventable hospitalisations are thought to reflect poor access to non-hospital dental services. The association between accessibility (geographic and financial) to non-hospital dentists and potentially preventable hospitalisations was examined in Western Australia. Areas with persistently high rates of dental-related potentially preventable hospitalisations and emergency department (ED) presentations were mapped. Statistical models examined factors associated with these events. Persistently high rates of dental-related potentially preventable hospitalisations were clustered in metropolitan areas that were socioeconomically advantaged and had more dentists per capita (RR 1.06, 95% CI 1.04-1.08) after adjusting for age, sex, socioeconomics, and Aboriginality. Persistently high rates of ED presentations were clustered in socioeconomically disadvantaged areas near metropolitan EDs and with fewer dentists per capita (RR 0.91, 0.88-0.94). A positive association between dental-related potentially preventable hospitalisations and poor (financial or geographic) access to dentists was not found. Rather, rates of such events were positively associated with socioeconomic advantage, plus greater access to hospitals and non-hospital dental services. Furthermore, ED presentations for dental conditions are inappropriate indicators of poor access to non-hospital dental services because of their relationship with hospital proximity. Health service planners and policymakers should pursue alternative indicators of dental service accessibility. PMID- 29157356 TI - Effect of exogenous progesterone on embryo size and ewe uterine gene expression in an ovine 'dam size' model of maternal constraint. AB - Progesterone (P4), acting via its receptor, regulates uterine function and histotroph production, which are crucial to embryo growth. This study aimed to examine exogenous P4 effects on embryo size and differential endometrial gene expression at Day 19 of gestation using a 'dam size' sheep model of maternal constraint. Purebred Suffolk (S, genotypically large) embryos were transferred into recipient groups of Cheviot (C, genotypically small) or Suffolk ewes that had, or had not, been pre-treated with P4 from Days 0 to 6 of pregnancy. At Day 19S embryos were collected from four experimental groups: P4 pretreated S ewes (SP4; n=5), untreated S ewes (SnP4; n=15), P4 pretreated C ewes (CP4; n=7) and untreated C ewes (CnP4; n=21). Day-19 embryos from CP4 ewes were larger (P<0.05) than those from CnP4 ewes and similar in size (P>0.05) to embryos from SnP4 and SP4 ewes. Expression of mucin 1 (MUC1) and prostaglandin-endoperoxide synthase 2 (PTGS2) was upregulated in uterine horns ipsilateral to the corpus luteum from CP4 ewes. Prostaglandin receptor (PGR), MUC1 and PTGS2 expression was upregulated, whilst cathepsin L (CTSL) and radical S-adenosyl methionine domain containing 2 (RSAD2) expression was downregulated in the ipsilateral horn of SP4 ewes. This suggests that pretreating ewes with exogenous P4 may alleviate early pregnancy maternal constraint via mechanisms that alter uterine function. However, further research is required to investigate the timing of P4 administration and its impact on conception rates. PMID- 29157357 TI - Migration confers winter survival benefits in a partially migratory songbird. AB - To evolve and to be maintained, seasonal migration, despite its risks, has to yield fitness benefits compared with year-round residency. Empirical data supporting this prediction have remained elusive in the bird literature. To test fitness related benefits of migration, we studied a partial migratory population of European blackbirds (Turdus merula) over 7 years. Using a combination of capture-mark-recapture and radio telemetry, we compared survival probabilities between migrants and residents estimated by multi-event survival models, showing that migrant blackbirds had 16% higher probability to survive the winter compared to residents. A subsequent modelling exercise revealed that residents should have 61.25% higher breeding success than migrants, to outweigh the survival costs of residency. Our results support theoretical models that migration should confer survival benefits to evolve, and thus provide empirical evidence to understand the evolution and maintenance of migration. PMID- 29157358 TI - RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation. AB - Local regulation of synaptic efficacy is thought to be important for proper networking of neurons and memory formation. Dysregulation of global translation influences long-term memory in mice, but the relevance of the regulation specific for local translation by RNA granules remains elusive. Here, we demonstrate roles of RNG105/caprin1 in long-term memory formation. RNG105 deletion in mice impaired synaptic strength and structural plasticity in hippocampal neurons. Furthermore, RNG105-deficient mice displayed unprecedentedly severe defects in long-term memory formation in spatial and contextual learning tasks. Genome-wide profiling of mRNA distribution in the hippocampus revealed an underlying mechanism: RNG105 deficiency impaired the asymmetric somato-dendritic localization of mRNAs. Particularly, RNG105 deficiency reduced the dendritic localization of mRNAs encoding regulators of AMPAR surface expression, which was consistent with attenuated homeostatic AMPAR scaling in dendrites and reduced synaptic strength. Thus, RNG105 has an essential role, as a key regulator of dendritic mRNA localization, in long-term memory formation. PMID- 29157359 TI - Countercurrent heat exchange and thermoregulation during blood-feeding in kissing bugs. AB - Blood-sucking insects experience thermal stress at each feeding event on endothermic vertebrates. We used thermography to examine how kissing-bugs Rhodnius prolixus actively protect themselves from overheating. During feeding, these bugs sequester and dissipate the excess heat in their heads while maintaining an abdominal temperature close to ambient. We employed a functional morphological approach, combining histology, uCT and X-ray-synchrotron imaging to shed light on the way these insects manage the flow of heat across their bodies. The close alignment of the circulatory and ingestion systems, as well as other morphological characteristics, support the existence of a countercurrent heat exchanger in the head of R. prolixus, which decreases the temperature of the ingested blood before it reaches the abdomen. This kind of system has never been described before in the head of an insect. For the first time, we show that countercurrent heat exchange is associated to thermoregulation during blood feeding. PMID- 29157360 TI - Bugs battle stress from hot blood. AB - A heat exchange mechanism in the head of kissing bugs helps to prevent stress and regulate their temperature while they feed on warm blood. PMID- 29157361 TI - The Challenge of Detecting Glaucoma Progression. PMID- 29157362 TI - Detecting Visual Field Progression. AB - Timely detection of glaucomatous progression is crucial in the delivery of glaucoma care. Clinical judgment may be used to make this assessment, but relatively modest agreement among practitioners supports the use of complementary methods. Event-based analyses take into account expected localized test-retest variabilities in sensitivity, and trend-based analyses are helpful for determining and predicting overall visual function. Landmark clinical trials have used various visual field progression criteria as end points with variable performances. Short- and long-term fluctuations as well as inadequate testing frequency are limitations in visual field analysis for glaucomatous progression. Ongoing improvements in statistical techniques as well as incorporation of functional and structural measures into a single model likely will lead to an enhanced ability to detect glaucomatous progression and will allow for more timely and appropriate therapy. PMID- 29157363 TI - Detecting Structural Progression in Glaucoma with Optical Coherence Tomography. AB - Optical coherence tomography (OCT) is increasingly used to obtain objective measurements of the retinal nerve fiber layer (RNFL), optic nerve head, and macula for assessing glaucoma progression. Although OCT has been adopted widely in clinical practice, uncertainty remains concerning its optimal role. Questions include: What is the best structure to measure? What quantity of change is significant? Are structural changes relevant to the patient? How are longitudinal measurements affected by aging? How can changes resulting from aging be differentiated from true progression? How best should OCT be used alongside visual fields, and how often should OCT be performed? Recent studies have addressed some of these questions. Important developments include appreciation of the need to use a consistent point of reference for structural measurements, leading to the introduction of Bruch's membrane opening (BMO)-based measurements, including BMO-minimum rim width and BMO-minimum rim area. Commercially available OCT devices also permit analysis of macular changes over time, for example, changes in the ganglion cell and inner plexiform layers, the sites of the retinal ganglion cell bodies and dendrites, respectively. Several longitudinal studies have compared rates of change in RNFL and macular measurements, with some suggesting that the relative value of each parameter may differ at different stages of disease. In early disease, looking for change over time also may be useful for glaucoma diagnosis, with advantages over classifying eyes using cross sectional normative databases. Optimal glaucoma management requires information from imaging and visual fields, and efforts have been made to combine information, reducing the noise inherent in both tests to benefit from their different performances according to the stage of disease. Combining information from different structural measurements may also be useful. There is now substantial evidence that progressive structural changes are of direct clinical relevance, with progressive changes on OCT often preceding functional loss and patients with faster change on OCT at increased risk of worsening visual losses. Identification of such patients offers the possibility of commencing or escalating treatment at an earlier stage. This review appraises recent developments in the use of OCT for assessing glaucoma progression. PMID- 29157364 TI - The Evolving Role of the Relationship between Optic Nerve Structure and Function in Glaucoma. AB - The relationship between functional vision loss and structural changes of the optic nerve head and retinal ganglion cells is the hallmark of glaucoma diagnosis. Understanding and measuring this relationship has been the focus of numerous studies, the goal of which have been to improve glaucoma diagnosis and detection of glaucoma worsening. In this review, a historical perspective is used to understand structure-function relationships in glaucoma and their application to improve glaucoma diagnosis and monitoring. Initially, histologic studies that link visual field sensitivity to retinal ganglion cell count are discussed. Additionally, those studies that determined the mathematical relationship between visual field sensitivity and ganglion cell number are reviewed. Next, those studies that attempt to create a map of the structure-function relationship using fundus photography and visual field sensitivity are examined. Subsequently, studies that use more recent imaging technology, such as optical coherence tomography, confocal scanning laser ophthalmoscopy, or scanning laser perimetry, to measure structure quantitatively in vivo and to correlate these measures with automated perimetry are explored. Among these studies that use advanced imaging, those that use cross-sectional data to explore structure-function relationships to improve glaucoma diagnosis first are discussed. Second, those studies that use longitudinal data to improve detection of worsening are reviewed. Finally, areas of further research and steps needed to implement structure-function relationships clinically are explored. PMID- 29157366 TI - Culling from the actors' perspectives-Decision-making criteria for culling in Quebec dairy herds enrolled in a veterinary preventive medicine program. AB - The series of events leading to the decision to cull a cow is complex, involving both individual-level and herd-level factors. While the decision is guided by financial returns, it is also influenced by social and psychological factors. Research studies on the motivational and behavioural aspects of farmers' decision utility are sparse, and nonexistent regarding culling expectations and its decision process. Our goal was to identify shared criteria on culling decisions held by dairy producers and farm advisers, with the help of the Q-methodology. Forty-one dairy producers and 42 advisers (17 veterinarians, 13 feed mill advisers, and 12 dairy herd improvement (DHI) advisers) undertook a Q-sort with 40 statements that represented a range of views about cow and herd health, production performance, management issues, and material factors that might impact their culling decision-making process. The sorts were analysed by-person using factor analysis and oblimin rotation. A single view on culling could be identified among dairy producers that can be extended to dairy farm advisers, who showed two variations of the same well-structured, uni-dimensional decision making process. Udder health, milk production performance, and milk quota management were the key criteria for the culling decision. Farm management parameters (debts, amortization, employees, milking parlour capacity, herd size) did not play any role in the decision process. Three key differences were, however, identified between producers and the two types of advisers. One group of advisers followed the recommendations from mathematical models, where pregnancy is a major determinant of a cow's value. They assessed the cow in a more abstract way than did the other participants, still taking into account udder health and milk production, but adding economic considerations, like the availability of financial incentives and an evaluation of the post-partum health of the cow. Dairy producers were also more concerned about producing healthy and safe milk, which might reflect a different value given to dairy farming than by advisers. Very different degrees of importance were given to animal welfare by the three groups, which could represent different views on the attributed relationships between dairy farmers and their animals. Our findings suggest that dairy producers and their advisers hold a general common view regarding culling decision-making. However there are significant differences between producers and advisers, and among advisers. Understanding and managing these differences is important for assisting the change management processes required to increase farm profitability, and call for further investigation. PMID- 29157365 TI - The Future of Imaging in Detecting Glaucoma Progression. AB - Ocular imaging has been heavily incorporated into glaucoma management and provides important information that aids in the detection of disease progression. Longitudinal studies have shown that the circumpapillary retinal nerve fiber layer is an important parameter for glaucoma progression detection, whereas other studies have demonstrated that macular parameters, such as the ganglion cell inner plexiform layer and optic nerve head parameters, also are useful for progression detection. The introduction of novel technologies with faster scan speeds, wider scanning fields, higher resolution, and improved tissue penetration has enabled the precise quantification of additional key ocular structures, such as the individual retinal layers, optic nerve head, choroid, and lamina cribrosa. Furthermore, extracting functional information from scans such as blood flow rate and oxygen consumption provides new perspectives on the disease and its progression. These novel methods promise improved detection of glaucoma progression and better insight into the mechanisms of progression that will lead to better targeted treatment options to prevent visual damage and blindness. PMID- 29157367 TI - A multilevel study of the environmental determinants of swine ascariasis in England. AB - Ascariasis is considered a common parasitosis of swine worldwide. The disease causes significant economic losses due to its effect on feed conversion ratio and liver condemnations at slaughter (liver milk spots). This study aimed to characterise the between-farm and spatial variance in porcine ascariasis in England and to assess the association between the percentage of infected animals and potential environmental risk factors, including production system, socioeconomic deprivation, soil characteristics (pH, topsoil bulk density, topsoil organic matter, topsoil texture class, soil water regime, topsoil available water capacity, and elevation), and climatic conditions (relative humidity, air temperature, and rainfall) before slaughter. Post-mortem inspection results were provided by the Food Standards Agency and comprised information about the number of rejected livers, the number of animals sent to slaughter and the production system. All farms were georeferenced based on the postcode, which allowed the assessment of the area index of socioeconomic deprivation and the extraction of soil and climatic characteristics available in different online databases. Under a multilevel framework with adjustment for spatial autocorrelation, a standard linear mixed model was fitted to estimate the association between these determinants and the percentage of infected animals. From 2,513,973 English farmed pigs included in the study, 4.3% had their livers rejected due to milk spots. The percentage of infected pigs per batch ranged from 0% to 100%. The highest percentages were found in Surrey, East and West Sussex (8.9%) and lowest in Leicestershire, Rutland and Northamptonshire (2.0%). Significant associations were found at multivariable analysis between the proportion of infection and the number of animals sent to slaughter (beta=-0.005; 95%CI=-0.005, -0.004), soil texture (peat compared to coarse textured soils; beta=-0.516; 95%CI=-1.010, -0.063), relative humidity (beta=0.011; 95%CI=0.006, 0.015), mean temperature (beta=0.007; 95%CI=0.003, 0.012), and rainfall (beta=0.022; 95%CI=0.004, 0.037). In conclusion, our findings suggest that ascariasis can be influenced by a complex network of environmental factors. Future research needs to acknowledge these intermingled relationships to guide the development and application of control measures by the industry. PMID- 29157368 TI - Livestock as sentinels for an infectious disease in a sympatric or adjacent living wildlife reservoir host. AB - A central question to address in managing wildlife diseases is how much effort and resources are required to reduce infection prevalence to below a requisite threshold? This requires surveillance for infection in at least one species involved in the infection cycle, a process that is often expensive and time consuming but one which could be enhanced using additional sources of readily obtainable surveillance data. We demonstrate how surveillance data from ruminant livestock monitored for bovine tuberculosis (bTB) in New Zealand can be employed in spatially-explicit modelling to help predict the probability of freedom from Mycobacterium bovis infection in a sympatric wildlife reservoir species, the brushtail possum (Trichosurus vulpecula). We apply the model to a case study and compare resulting probabilities of freedom when utilizing (1) livestock data only, (2) wildlife data only, and (3) combined livestock-plus-wildlife surveillance data. Results indicated that the greatest probability of M. bovis eradication was achieved using wildlife monitoring data supplemented with livestock surveillance data. This combined approach lessened the time required for a confident (95% probability) declaration of regional eradication. However, the combined model was sensitive to the precision of the input parameters, and we describe ways to account for this. In a broad sense, this modelling approach is flexible in that any spatial arrangement of wildlife habitat and farms can be analysed, provided infection is readily detectable in both the wild and domestic animal(s) of interest. It is applicable to monitoring any communicable wildlife disease that affects regularly-tested livestock. The potential benefits to wildlife disease management include reduced surveillance costs and more rapid achievement of targeted reductions in disease prevalence. PMID- 29157369 TI - Risk factors associated with the A2C resistance pattern among E. coli isolates from broiler flocks in Canada. AB - The extra-label use of ceftiofur in Canadian hatcheries was cause for concern due to an increased prevalence of ceftiofur resistant Salmonella Heidelberg in chickens and humans in Quebec. Due to on-going concerns related to human health the use of ceftiofur was eventually phased out of the poultry production industry in 2014-2015. Simultaneous resistance to amoxicillin-clavulanic acid, ceftiofur and cefoxitin, a pattern known as A2C, caused by the presence of blaCMY-2 has become increasingly prevalent in broiler flocks worldwide. This study used data from the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) broiler farm surveillance program to examine the risk factors for A2C resistant Escherichia coli isolates (A2C-REI) from 1482 samples taken from 371 broiler flocks in Canada, between 2013 and 2015. Results of a mixed effects Poisson model with fixed effects at the flock level and random effects at the hatchery level indicated that the in ovo use of ceftiofur (Prevalence Ratio (PR): 1.91, 95% CI: 1.43-2.57), and the use of hydrogen peroxide to disinfect water lines during the growing period (PR: 1.52, 95% CI: 1.11-2.07), were risk factors for increased expected prevalence of A2C-REI, compared to farms not using these strategies. Controlling for wild birds (PR: 0.64, 95% CI: 0.48-0.84), use of avilamycin in feed (PR: 0.63, 95% CI: 0.41-0.98), and storage of manure on the farm (PR: 0.67, 95% CI: 0.51-0.89) were associated with a lower expected prevalence of A2C-REI, than farms that did not use these strategies. This study identified important management factors that were associated with the prevalence of A2C-REI on Canadian broiler farms. The findings of this study can be used as a baseline for the monitoring of the effects of the removal of ceftiofur from poultry production in Canada. PMID- 29157370 TI - Bayesian estimation of true prevalence, sensitivity and specificity of three diagnostic tests for detection of Escherichia coli O157 in cattle feces. AB - Cattle are a reservoir for Escherichia coli O157 and they shed the pathogen in their feces. Fecal contaminants on the hides can be transferred onto carcasses during processing at slaughter plants, thereby serving as a source of foodborne infection in humans. The detection of E. coli O157 in cattle feces is based on culture, immunological, and molecular methods We evaluated the diagnostic sensitivity and specificity of one culture- and two PCR-based tests for the detection of E. coli O157 in cattle feces, and its true prevalence using a Bayesian implementation of latent class models. A total of 576 fecal samples were collected from the floor of pens of finishing feedlot cattle in the central United States during summer 2013. Samples were enriched and subjected to detection of E. coli O157 by culture (immunomagnetic separation, plating on a selective medium, latex agglutination, and indole testing), conventional PCR (cPCR), and multiplex quantitative PCR (mqPCR). The statistical models assumed conditional dependence of the PCR tests and high specificity for culture (mode=99%; 5th percentile=97%). Prior estimates of test parameters were elicited from three experts. Estimated posterior sensitivity (posterior median and 95% highest posterior density intervals) of culture, cPCR, and mqPCR was 49.1% (44.8 53.4%), 59.7% (55.3-63.9%), and 97.3% (95.1-99.0%), respectively. Estimated posterior specificity of culture, cPCR, and mqPCR were 98.7% (96.8-99.8%), 94.1% (87.4-99.1%), and 94.8% (84.1-99.9%), respectively. True prevalence was estimated at 91.3% (88.1-94.2%). There was evidence of a weak conditional dependence between cPCR and mqPCR amongst test positive samples, but no evidence of conditional dependence amongst test negative samples. Sensitivity analyses showed that overall our posterior inference was rather robust to the choice of priors, except for inference on specificity of mqPCR, which was estimated with considerable uncertainty. Our study evaluates performance of three diagnostic tests for detection of E. coli O157 in feces of feedlot cattle which is important for quantifying true fecal prevalence and adjusting for test error in risk modeling. PMID- 29157371 TI - Australian horse owners and their biosecurity practices in the context of Hendra virus. AB - In recent years, outbreaks of exotic as well as newly emerging infectious diseases have highlighted the importance of biosecurity for the Australian horse industry. As the first potentially fatal zoonosis transmissible from horses to humans in Australia, Hendra virus has emphasised the need to incorporate sound hygiene and general biosecurity practices into day-to-day horse management. Recommended measures are widely publicised, but implementation is at the discretion of the individual owner. This cross-sectional study aimed to determine current levels of biosecurity of horse owners and to identify factors influencing the uptake of practices utilising data from an online survey. Level of biosecurity (low, medium, high), as determined by horse owners' responses to a set of questions on the frequency of various biosecurity practices performed around healthy (9 items) and sick horses (10 items), was used as a composite outcome variable in ordinal logistic regression analyses. The majority of horse owners surveyed were female (90%), from the states of Queensland (45%) or New South Wales (37%), and were involved in either mainly competitive/equestrian sports (37%) or recreational horse activities (35%). Seventy-five percent of owners indicated that they follow at least one-third of the recommended practices regularly when handling their horses, resulting in medium to high levels of biosecurity. Main factors associated with a higher level of biosecurity were high self-rated standard of biosecurity, access to personal protective equipment, absence of flying foxes in the local area, a good sense of control over Hendra virus risk, likelihood of discussing a sick horse with a veterinarian and likelihood of suspecting Hendra virus in a sick horse. Comparison of the outcome variable with the self-rated standard of biosecurity showed that over- as well as underestimation occurred. This highlights the need for continuous communication and education to enhance awareness and understanding of what biosecurity is and how it aligns with good horsemanship. Overall, strengthened biosecurity practices will help to improve animal as well as human health and increase preparedness for future disease outbreaks. PMID- 29157372 TI - Prevalence of antimicrobial resistance from bacterial culture and susceptibility records from horse samples in South Africa. AB - The continuous increase in prevalence of antimicrobial resistant bacteria presents a significant public health problem and is an indicator that antimicrobial prudent usage guidelines are not being followed, especially in developing countries. Despite trends being available from numerous countries, there is little published for South Africa. This study was aimed at estimating the prevalence and trends of antimicrobial resistance from bacterial isolates from equine clinical samples submitted for culture and susceptibility testing to the veterinary bacteriology laboratory of the University of Pretoria. The study covered a period of seven years from 2007. A total of 1505 bacterial isolates were included in this study comprising isolates from 2007 (n=447); 2008 (n=285); 2009 (n=258); 2010 (n=102); 2011 (n=89); 2012 (n=248) and 2013 (n=76). For this study, multiple drug resistance was above 50% for all the isolates. The Cochran Armitage test showed evidence of a significantly increasing trend in prevalence of resistance to several antimicrobial agents, including amikacin (E. coli, Staphylococcus), AMX/AMP (Corynebacteria, Lactobacillus and Salmonella), chloramphenicol (Enterococcus, E. coli, Pseudomonas, Streptococcus, Staphylococcus and Salmonella), enrofloxacin (E. coli, Staphylococcus, Salmonella and Pseudomonas) and gentamicin (Salmonella, Staphylococcus). The data obtained from this study is relevant to equine practitioners, as it helps enhance the body of veterinary knowledge pertaining to antimicrobial resistance in common equine pathogens in South Africa. PMID- 29157373 TI - Risk factors affecting length of stay of cats in an animal shelter: A case study at the Guelph Humane Society, 2011-2016. AB - There is a strong need for animal shelters to determine strategies to decrease the incidence of healthy animals being euthanized due to a lack of space. Thus, the Capacity for Care program was implemented at the Guelph Humane Society during August 2014. One objective of the Capacity for Care program is to decrease length of stay of cats within the shelter to improve individual welfare and increase the number of successful adoptions. The current study uses data collected from the Guelph Humane Society between 2011 and 2016. A Cox proportional hazards regression model was used to determine factors affecting a cat's time-to-adoption (length of stay). Cats' length of stay decreased by 24% after the implementation of the Capacity for Care program (p<0.001). Exotic breeds were found to have a length of stay 64% shorter than domestic shorthairs (p<0.01), while males had a length of stay 20% shorter than females (p<0.001). Adult cats' length of stay was 13% shorter than kittens (p<=0.01), which is expected as a result of calculating length of stay from date of admission rather than date available for adoption. This study provides evidence that the Capacity for Care program is associated with a reduced length of stay for cats; suggesting it is a suitable program to improve cat welfare and address cat overpopulation. PMID- 29157374 TI - Time series analysis based on two-part models for excessive zero count data to detect farm-level outbreaks of swine echinococcosis during meat inspections. AB - Echinococcus multilocularis is a parasite that causes highly pathogenic zoonoses and is maintained in foxes and rodents on Hokkaido Island, Japan. Detection of E. multilocularis infections in swine is epidemiologically important. In Hokkaido, administrative information is provided to swine producers based on the results of meat inspections. However, as the current criteria for providing administrative information often results in delays in providing information to producers, novel criteria are needed. Time series models were developed to monitor autocorrelations between data and lags using data collected from 84 producers at the Higashi-Mokoto Meat Inspection Center between April 2003 and November 2015. The two criteria were quantitatively compared using the sign test for the ability to rapidly detect farm-level outbreaks. Overall, the time series models based on an autoexponentially regressed zero-inflated negative binomial distribution with 60th percentile cumulative distribution function of the model detected outbreaks earlier more frequently than the current criteria (90.5%, 276/305, p<0.001). Our results show that a two-part model with autoexponential regression can adequately deal with data involving an excessive number of zeros and that the novel criteria overcome disadvantages of the current criteria to provide an earlier indication of increases in the rate of echinococcosis. PMID- 29157375 TI - Risk factors for race-day fatality, distal limb fracture and epistaxis in Thoroughbreds racing on all-weather surfaces in Great Britain (2000 to 2013). AB - The incidence of race-day injuries in Great Britain (GB) is higher on all-weather (AW) surfaces than on turf. However, to date no studies have focused on identifying risk factors for injury specific to AW racing. Therefore, the objective of the current study was to determine risk factors for fatality, distal limb fracture (DLF) and episodes of epistaxis in flat racing Thoroughbreds racing on AW surfaces in GB. Data included all flat racing starts on AW surfaces (n=258,193) and race-day veterinary events recorded between 2000 and 2013. Information on additional course-level variables was gathered during face-to-face interviews with racecourse clerks. Horse-, race- and course-level risk factors for each outcome were assessed using mixed-effects multivariable logistic regression including horse as a random effect. A classification tree method was used to identify potential interaction terms for inclusion in the models. During the study period, there were 233 fatalities resulting in a fatality incidence of 0.90 per 1000 starts; 245 DLF with a resultant DLF incidence of 0.95 per 1000 starts and 410 episodes of epistaxis resulting in an epistaxis incidence of 1.59 per 1000 starts. Risk factors varied for each outcome, although some factors were similar across models including the going, racing intensity, horse age, age at first race start, horse and trainer performance variables. Generally, older horses and those that had started racing at an older age were at higher risk of an adverse outcome, albeit with an interaction between the two variables in the fatality model. Faster going increased the odds of epistaxis and DLF but not fatality. Increasing race distance increased the odds of fatality but reduced the odds of epistaxis. Epistaxis was associated with type of AW surface (Fibresand versus Polytrack(r)), but DLF and fatality were not. This study provides further evidence of the association between the risk of race-day injuries and fatalities and current age, age at first start, race distance, going and horse performance. These findings provide the racing industry with information to develop strategies to reduce the occurrence of race-day events on AW surfaces. PMID- 29157376 TI - Epidemiological and partial budget analysis for treatment of subclinical Staphylococcus aureus intramammary infections considering microbiological and cytological scenarios. AB - An innovative method was investigated to aid in the elimination of Staphylococcus aureus (S. aureus) intramammary infections (IMI) from dairy herds. A stochastic model explore the economic benefit of three-day or eight-day treatment of subclinical IMI in all S. aureus infected cows or in only those with a somatic cell count (SCC) exceeding 200,000 cells/ml. An epidemiological model was developed to run parallel to the economic model that would predict the S. aureus IMI likely to persist, develop new infections and clinical mastitis. In the economic model a first algorithm was used to consider the low prevalence (LP) scenario and made use of S. aureus prevalence information provided by retrospective analysis of microbiological and cytological results in South Africa (2008-2012). The data used considered Staphylococcus aureus prevalence from [1.495; 1.595]95% to [6.72; 6.95]95% for SCC<=200,000 and SCC>200,000 cells/ml respectively. A second algorithm considered the high prevalence (HP) scenario to evaluate a simulated situation with a 5[U1] [R12] to 25% prevalence. Scenarios of low or high transmission ratio (TR) were included in the model according to the hygiene management on the farm. Probabilities and costs were calculated over 255days. The economic models predicted average cost indices for low S. aureus IMI and low TR to vary from -3179 ZAR (South African Rands) when subclinical cases with SCC higher than 200,000 cell/ml were treated for eight days, to -3663 ZAR when all subclinical S. aureus IMI were treated for three days. With a HP and high TR of S. aureus the average cost indices changed from -18,042 ZAR when none to -5433 ZAR per 255days when all S. aureus IMI were treated for eight days. The epidemiological model in this study predicted substantial benefit of treatment mainly in high TR scenarios. New IMI decreased up to77% in the three-day and up to 91% in the eight-day treatment scenarios. In the HP scenarios, persistent IMI were reduced by 94%. The number of clinical cases predicted with no treatment for subclinical infections was higher than the total number of clinical and subclinical cases in scenarios where cows were treated three or eight days. Initial prudent treatment of subclinical IMI resulted in less overall treatments and less new, persistent and clinical cases. Combined results of economic and epidemiological models indicated that the option that cost the least did not always have the best epidemiological outcome. Models may assist in optimising and balancing decisions relating to financial and IMI. PMID- 29157377 TI - Analyzing the Foot and Mouth Disease outbreak as from 2008 to 2014 in cattle and buffaloes in Sri Lanka. AB - Foot and Mouth Disease (FMD) is a highly contagious disease that affects all cloven hoofed animals and causes considerable economic losses to cattle and buffalo farmers worldwide. FMD is endemic to Sri Lanka. The objective of this study was to analyze the past situation of FMD from 2008 to 2014 in the country and to identify relevant risk factors associated with the 2014 outbreak. Outbreak data from the Department of Animal Production and Health, Sri Lanka from 2008 to 2014 were used to describe the spatial distribution and to determine associations between the frequency of outbreaks across the country (nine provinces) and factors including vaccination coverage and outbreak year. A questionnaire was used to collect the information on potential risk factors for FMD for the 2014 outbreak from case farms (n=83) and control farms (n=161). Seven focus group (FG) discussions with farmers and five in-depth interviews with veterinarians and livestock officers were conducted. A negative binomial regression model was constructed to determine the relationship between frequencies of outbreaks by province, year, vaccine coverage and bovine numbers per province. A logistic regression model was used to determine the association between potential risk factors and disease status of the farm. There was no association between vaccination coverage and outbreak frequencies at province level (Risk Ratio=1.02; 95% CI=0.09, 1.05). Based on our cases-control study there were five variables significantly associated with the FMD spread: cattle/buffalo contact with nearby villages (Odds Ratio=2.88; 95% CI: 1.23-6.72), cattle/buffalo grazing near water tank areas (OR=3.11;95% CI: 1.21-7.97), animals bought or sold during the outbreak (OR=3.3; 95% CI: 1.39-7.83), being near to a road where animal traders travel (OR=3.44 95% CI: 1.10-10.79), and being fed on the floor instead of feed troughs (OR=2.61,1.08-6.31). The major risk factor identified here was cattle/buffalo movement by means of grazing/trading. Both focus group discussions and the questionnaire ascertained that the vaccination had no effect in the most recent outbreak. Results from this study are expected to support veterinary services in developing effective control measures during future outbreaks. PMID- 29157378 TI - Monitoring breeding herd production data to detect PRRSV outbreaks. AB - Porcine reproductive and respiratory syndrome virus (PRRSv) causes substantial economic impact due to significant losses in productivity. Thus, measuring changes in farm productivity before and after PRRS infection enables quantifying the production and economic impact of outbreaks. This study assessed the application of exponentially weighted moving average (EWMA), a statistical process control method, on selected production data (number of abortions, pre weaning mortality rate and prenatal losses) to supplement PRRS surveillance programs by detecting significant deviations on productivity in a production system with 55,000 sows in 14 breed-to-wean herds in Minnesota, U.S.A. Weekly data from diagnostic monitoring program (available through the Morrison's Swine Health Monitoring Project) implemented on the same herds was used as reference for PRRS status. The time-to-detect, percentage of early detection of PRRSv associated productivity deviations, and relative sensitivity and specificity of the production data monitoring system were determined relative to the MSHMP. The time-to-detect deviations on productivity associated with PRRS outbreaks using the EWMA method was -4 to -1 weeks (interquartile range) for the number of abortions, 0-0 for preweaning mortality and -1 to 3 weeks for prenatal losses compared to the date it was reported in the MSHMP database. Overall, the models had high relative sensitivity (range 85.7-100%) and specificity (range 98.5% 99.6%) when comparing to the changes in PRRS status reported in the MSHMP database. In summary, the use of systematic data monitoring showed a high concordance compared to the MSHMP-reported outbreaks indicating that on-farm staff and veterinary oversight were efficient to detect PRRSv, but can be more efficient if they were monitoring closely the frequency of abortions. The systematic monitoring of production indicators using EWMA offers opportunity to standardize and semi-automate the detection of deviations on productivity associated with PRRS infection, offering opportunity to early detect outbreaks and/or to quantify the production losses attributed to PRRS infection. PMID- 29157379 TI - Incidence of fecal excretion of Mycobacterium avium subsp. paratuberculosis in dairy cows before and after the enrolment in the Quebec voluntary program. AB - Paratuberculosis is a chronic and contagious enteric disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). This disease of worldwide distribution is responsible for significant economic losses and the bacteria itself has been linked to human Crohn's disease. Paratuberculosis control programs focus on reducing MAP transmission by implementing better management practices that target infection routes. In Quebec, a Voluntary Paratuberculosis Prevention and Control Program (QVPPCP) was launched in 2007. The objectives of this prospective cohort study were threefold. The first was to describe the changes in the incidence of fecal excretion of MAP in cows born before and after farm enrolment in the QVPPCP. The second was to estimate the impact of the risk of within-herd transmission of MAP (measured by the risk assessment score (RAS)) on the incidence of fecal excretion of MAP. And the third was to evaluate the impact of calf rearing practices on the incidence of fecal excretion of MAP. Eighteen MAP-positive herds were visited annually from 2011 to 2015. At each visit, individual fecal samples from all adult cows were collected. MAP was cultured using liquid media and an automated system. A risk assessment questionnaire was completed upon enrolment in the QVPPCP and at each visit. The RAS of the farm was attributed to each cow according to its birthdate. Cox proportional hazards models were used to estimate the hazard ratios (HR) for the exposure variables. Herd clustering was taken into account using robust standard errors. A total of 2158 cows were included (cohort born before n=919; cohort born after n=1239). The incidence and hazard of fecal excretion were significantly lower for the cohort-after than the cohort-before (incidence rate ratio=0.38; 95% CI: 0.18-0.78 and HR=0.48; 95% CI: 0.23-0.98). The HR of fecal excretion for cows exposed to a high RAS was 2.20 times (95% CI: 1.21-3.99) that of cows exposed to a low RAS. Poor calving cow hygiene (HR=3.41; 95% CI: 1.40-8.31) and contact between pre-weaned heifers and adult cows or their feces were significantly associated with an increased hazard of fecal excretion of MAP (HR=2.66; 95% CI: 1.08-6.56). Our results suggest that enrolment in the QVPPCP reduces the risk of MAP fecal excretion. They support the hypothesis that contact between calves and adult cows or their feces increases MAP transmission. The incidence results also suggest that MAP prevalence could be reduced to low levels regardless of initial MAP prevalence. PMID- 29157380 TI - Staging of Non-Small-Cell Lung Cancer. AB - Staging of lung cancer serves 2 purposes; it attempts to classify patients into groups where particular treatments are appropriate and defines those groups based on expected prognosis. The eighth edition of the International Association for the Study of Lung Cancer staging system deals with the issues raised by screening with fine cut computed tomography. Each phase of staging is a legitimate dataset on its own. Molecular profiling of lung cancer has led to the development of an increasing number of novel agents to treat systemic disease. Prognosis is increasingly determined by genetic susceptibility of the specific cancer. PMID- 29157381 TI - Lung Neoplasms with Low F18-Fluorodeoxyglucose Avidity. AB - Some malignant lung neoplasms may demonstrate low or absent uptake on F18 fluorodeoxyglucose (FDG) PET/computed tomography. Pathologic type and clinical stage are independent factors associated with FDG avidity. Among lung malignancies with low FDG avidity, adenocarcinoma in situ and carcinoid are the most common. Early stage disease often has low FDG uptake. Small lesion size is another significant factor associated with negative FDG PET findings, which is due to a partial volume effect. Morphology of lung lesions on anatomic images may also affect FDG avidity. Subsolid pulmonary nodules, ground-glass nodules, or ground-glass opacity may be sources of false-negative PET. PMID- 29157382 TI - Diagnostic Imaging and Newer Modalities for Thoracic Diseases: PET/Computed Tomographic Imaging and Endobronchial Ultrasound for Staging and Its Implication for Lung Cancer. AB - Modalities to detect and characterize lung cancer are generally divided into those that are invasive [endobronchial ultrasound (EBUS), esophageal ultrasound (EUS), and electromagnetic navigational bronchoscopy (ENMB)] versus noninvasive [chest radiography (CXR), computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI)]. This chapter describes these modalities, the literature supporting their use, and delineates what tests to use to best evaluate the patient with lung cancer. PMID- 29157383 TI - 18F-Fluoro-2-Deoxy-d-Glucose PET/Computed Tomography Evaluation of Lung Cancer in Populations with High Prevalence of Tuberculosis and Other Granulomatous Disease. AB - Pulmonary tuberculosis infects one-third of world's population and is responsible for the high mortality and morbidity in developing countries. The presence of a high number of macrophages and lymphocytes in active tuberculosis granulomas is associated with high uptake of 18F-fluoro-2-deoxy-d-glucose on PET imaging mimicking lung cancer. In many cases, radiological features of pulmonary tuberculosis are undistinguishable from lung cancer, which makes the diagnosis difficult. Clinical history and computed tomographic (CT) findings on a hybrid PET/CT are as important as findings on a PET in the diagnosis of lung cancer. PMID- 29157384 TI - Genomic Characterization of Lung Cancer and Its Impact on the Use and Timing of PET in Therapeutic Response Assessment. AB - Significant advances in understanding the genomic landscape of non-small cell lung cancer (NSCLC) together with the coupling discovery of key oncogenic drivers and the development of effective targeted and immunotherapeutic agents have revolutionized the management of this malignancy. Although these therapies have resulted in improved outcomes for a subgroup of patients, their benefit may not necessarily be reflected by conventional response assessment criteria, because these therapeutic agents differ in their mechanism of action and response time compared with cytotoxic chemotherapy. Here the authors review available therapies in NSCLC and the utility of PET in therapeutic response assessment. PMID- 29157385 TI - Treatment Planning for Radiation Therapy. AB - PET scanning plays key roles in planning the management of patients with lung cancer who are candidates for curative-intent treatment with radiotherapy and has contributed to improvements in survival. 18F-fluorodeoxyglucose-PET is the most important modality for staging, patient selection, and radiotherapy target volume definition in patients with unresectable non-small cell lung cancer. Developments include the availability of alternative tracers, such as 18F-fluorothymidine, for imaging proliferation and a range of hypoxia imaging agents. The role of response adapted therapy, based on interim PET scans performed during the treatment course, is being explored as a way of improving local disease control. PMID- 29157386 TI - Prognostic Value of 18F-Fluorodeoxyglucose PET/Computed Tomography in Non-Small Cell Lung Cancer. AB - Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death with a poor prognosis. Numerous factors contribute to treatment outcome. 18F fluorodeoxyglucose (FDG) uptake reflects tumor metabolic activity and is an important prognosticator in patients with NSCLC. Volume-based FDG-PET parameters reflect the metabolic status of a malignancy more accurately than maximum standardized uptake value and thus are better prognostic markers in lung cancer. FDG-avid tumor burden parameters may help clinicians to predict treatment outcomes before and during therapy so that treatment can be adjusted to achieve the best possible outcomes while avoiding side effects. PMID- 29157387 TI - Non-Small-Cell Lung Cancer PET Imaging Beyond F18 Fluorodeoxyglucose. AB - F18 Flurodeoxyglucose (FDG) is a nonspecific PET tracer representing tumor energy metabolism, with common false-positive and false-negative findings in clinical practice. Non-small cell lung cancer is highly heterogeneous histologically, biologically, and molecularly. Novel PET tracers designed to characterize a specific aspect of tumor biology or a pathway-specific molecular target have the potential to provide noninvasive key information in tumor heterogeneity for patient stratification and in the assessment of treatment response. Non-FDG PET tracers, including 68Ga-somatostatin analogs, and some PET tracers targeting tumor proliferation, hypoxia, angiogenesis, and pathway-specific targets are briefly reviewed in this article. PMID- 29157388 TI - Future Directions in PET Imaging of Lung Cancer. AB - There is an ongoing and successful effort in developing new radiopharmaceuticals that coupled with new developments in chemistry and instrumentation offers the potential of rapidly defining imaging biomarkers and theranostic paradigms. The overarching challenge remains in funding and approving such agents; the Food and Drug Administration in the United States is making efforts to improve the process, but the time to release PET agents from the regulator shackles is surely now, to bring to patients the excellence of preclinical work that has already been done. PMID- 29157389 TI - Improved Detection of Small Pulmonary Nodules Through Simultaneous MR/PET Imaging. AB - Magnetic resonance (MR)/PET scanners provide an imaging platform that enables simultaneous acquisition of MR and PET data in perfect spatial and temporal registration. This feature allows improving image quality for the MR and PET images obtained during the course of an examination. In this work the authors demonstrate the use of prospective MR-based motion tracking information for removing motion blur in MR/PET images of small pulmonary nodules. The theoretical basis for the algorithms is presented alongside clinical examples of its use. PMID- 29157390 TI - Practical Considerations for Clinical PET/MR Imaging. AB - Clinical PET/MR imaging is currently performed at a number of centers around the world as part of routine standard of care. This article focuses on issues and considerations for a clinical PET/MR imaging program, focusing on routine standard-of-care studies. Although local factors influence how clinical PET/MR imaging is implemented, the approaches and considerations described here intend to apply to most clinical programs. PET/MR imaging provides many more options than PET/computed tomography with diagnostic advantages for certain clinical applications but with added complexity. A recurring theme is matching the PET/MR imaging protocol to the clinical application to balance diagnostic accuracy with efficiency. PMID- 29157391 TI - Lung Cancer. PMID- 29157392 TI - Multiple Sclerosis: Mechanisms of Disease and Strategies for Myelin and Axonal Repair. AB - Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system with a variety of presentations and unclear pathogenesis. Multiple sclerosis has been associated with the term autoimmunity as a surrogate for pathogenesis. Multiple sclerosis is an organ-specific disease with immune mediated myelin destruction. Understanding the complex etiology of multiple sclerosis and the importance of axon integrity is critical for clinicians who treat the disease. This review discusses the immune and autoimmune aspects of multiple sclerosis based on the current published data and novel evidence of strategies that promote remyelination and protect axons. PMID- 29157393 TI - New Concepts Related to Disease Appreciation in Multiple Sclerosis. AB - In the past several decades, MRI has become an indispensable tool in the field of multiple sclerosis (MS) for clinicians and researchers. However, the MS field still faces several challenges. This review focuses on 2 current areas of difficulty: 1) discriminating MS from other diseases when the clinical history and imaging features are atypical or nonspecific, and 2) the lack of quantitative imaging metrics with which to follow MS patients over time in clinical practice. This review highlights promising MRI and postprocessing techniques that have potential applications in these areas. With further study, these tools could be usefully integrated into clinical care. PMID- 29157394 TI - New Insights into Multiple Sclerosis Clinical Course from the Topographical Model and Functional Reserve. AB - Clinical course in multiple sclerosis (MS) is difficult to predict on group and individual levels. We discuss the topographical model of MS as a new approach to characterizing the clinical course, with the potential to personalize disability progression based on each individual patient's pattern of disease burden (eg, lesion location) and reserve. The dynamic clinical threshold depicted in this visual model may help clinicians to educate patients about clinical phenotype and disease burden, and foster an understanding of the difference between relapses and pseudoexacerbations. There is an emphasis on building reserve against cognitive and physical decline, encouraging agency among patients. PMID- 29157395 TI - Pediatric Multiple Sclerosis: From Recognition to Practical Clinical Management. AB - Pediatric-onset multiple sclerosis (MS) is a rare but increasingly recognized condition that both parallels and diverges from adult-onset MS. Exposure to key risk determinants for MS disease pathogenesis may occur during childhood. The diagnosis of pediatric MS can be challenging due to potential for atypical presentations and a broad differential diagnosis. MS disease-modifying therapies have not been rigorously studied in children and raise difficult questions on how to manage a chronic inflammatory neurologic disease in a population of patients with developing central nervous and immune systems. PMID- 29157396 TI - Ethnic Considerations and Multiple Sclerosis Disease Variability in the United States. AB - Minorities in the United States such as African Americans and Hispanics may have more severe disease than non-Hispanic whites. Factors contributing to these disparities are reviewed. The variations in disability from non-Hispanic whites may be the result of differences in clinical presentation, genetic underpinnings, and sociocultural factors. Creating awareness and increasing participation in research studies may improve our understanding. PMID- 29157397 TI - Progressive Forms of Multiple Sclerosis: Distinct Entity or Age-Dependent Phenomena. AB - In multiple sclerosis (MS), disease course is defined by a subclinical or clinical relapsing remitting phase, a progressive phase, and the overlapping phase in-between. Each phase can have intermittently active or inactive periods. Subclinical activity in radiologically isolated syndrome evolving to primary progressive MS is mostly indistinguishable from relapsing-remitting MS evolving to secondary-progressive MS. The onset of progressive-phase MS is age-dependent but time and pre-progressive phase agnostic. Pathologic hallmarks of progressive MS onset also appear to be age-dependent but pre-progressive phase agnostic. Onset of progressive MS is characterized by a peak in smoldering plaques. PMID- 29157398 TI - New Advances in Disease-Modifying Therapies for Relapsing and Progressive Forms of Multiple Sclerosis. AB - Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system in which inflammation, demyelination, and axonal loss occurs from early stages of the disease. It mainly affects people between 20 and 40 years old, with a female predominance. Treatment options have been increasingly growing in the past years and newer drugs, some with novel mechanisms of action, are being developed for treating patients with MS. There is an increasing interest in developing new drugs that will promote neuroprotection and/or myelin repair through different mechanisms of action that may target the most degenerative component of the disease. PMID- 29157399 TI - The Dynamics of the Gut Microbiome in Multiple Sclerosis in Relation to Disease. AB - Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease of unknown etiology, although genetic components and environmental triggers are thought to collude to commence pathogenesis. Numerous investigations are now demonstrating the role of the gut microbiota in neuroinflammation and how alterations in its content may be associated with MS disease. This article explores the studies using MS rodent models to determine the roles of gut bacteria in neuroinflammatory disease, evaluate the evidence linking gut bacterial dysbiosis and MS, and give insight into potential MS therapies targeting the gut microbiota currently under investigation. PMID- 29157400 TI - Advanced Symptom Management in Multiple Sclerosis. AB - Meaningful symptom management can have a profound impact on quality of life. It can challenge time parameters during clinic, and therefore thought should be given to strategies that can improve efficiency and thereby make the undertaking more tenable. For any given symptom, the building blocks of care, such as vitamin D status, exercise/physical therapy, nutrition, and stress management, and ensuring disease-modifying therapy coverage, should be maximized. For each symptom, there are pharmacologic and nonpharmacologic interventions. Patient expectations should be queried early in the encounter so that time can be budgeted accordingly. PMID- 29157401 TI - Multiple Sclerosis in the Contemporary Age: Understanding the Millennial Patient with Multiple Sclerosis to Create Next-Generation Care. AB - The average age of onset of multiple sclerosis (MS) is between 20 and 40 years of age. Therefore, most new patients diagnosed with MS within the next 10 to 15 years will be from the millennial generation, representing those born between 1982 and 2000. Certain preferences and trends of this contemporary generation will present new challenges to the MS physician and effective MS care. By first understanding these challenges, relevant and successful solutions can be created to craft a system of care that best benefits the millennial patient with MS. PMID- 29157402 TI - Effective Utilization of MRI in the Diagnosis and Management of Multiple Sclerosis. AB - MRI is the most important tool for diagnosis and management of patients with multiple sclerosis (MS). MRI shows high sensitivity for detection of white matter lesions in the central nervous system and specificity for lesion dissemination in space and time. MRI is also used for tracking disease activity, prognostic evaluation, and monitoring the efficacy and safety of disease-modifying treatments. Nonconventional MRI measures (eg, brain atrophy) and quantitative measures of advanced MRI can capture features of MS beyond WM lesions but are not currently implemented in clinical practice. Consensus guidelines on standardized MRI acquisition protocol have been recently published. PMID- 29157403 TI - Spinal Cord MRI in Multiple Sclerosis. AB - Spinal cord (SC) MRI in multiple sclerosis (MS) has significant usefulness in clinical and investigational settings. Conventional MRI of the SC is used in clinical practice, because it has both diagnostic and prognostic value. A number of advanced, quantitative SC MRI measures that assess the structural and functional integrity of the SC have been evaluated in investigational settings. These techniques have collectively demonstrated usefulness in providing insight into microstructural and functional changes relevant to disability in MS. With further development, these techniques may be useful in clinical trial settings as biomarkers of neurodegeneration and protection, and in day-to-day clinical practice. PMID- 29157404 TI - Anomalies Characteristic of Central Nervous System Demyelination: Radiologically Isolated Syndrome. AB - Radiologically isolated syndrome (RIS) was defined in 2009 for asymptomatic patients who presented incidentally identified white matter anomalies within the central nervous system suggestive of multiple sclerosis (MS). Approximately one third of RIS subjects will have a seminal clinical demyelinating event within 5 years of the identification of their abnormal MRI. Clinical evolution mirrors relapsing remitting or progressive forms of MS. Pejorative factors for clinical conversion are male gender, age younger than 35 years, and spinal cord lesions. PMID- 29157405 TI - Common Clinical and Imaging Conditions Misdiagnosed as Multiple Sclerosis: A Current Approach to the Differential Diagnosis of Multiple Sclerosis. AB - Multiple Sclerosis is increasing, so is the number of misdiagnosed cases as MS. One major source of misdiagnosis is misinterpretation of nonspecific clinical and imaging findings and misapplication of MS diagnostic criteria resulting in an overdiagnosis of MS! Since nonspecific white matter abnormalities on brain MRI and other imaging findings that may mimic MS, as well as MS-nonspecific lesions that are seen in people with MS, neurologists should be aware of all possibilities and should be able to interpret the clinical and MRI findings well and by their selves! The differential diagnosis of MS includes MS variants and inflammatory astrocytopathies and other atypical inflammatory-demyelinating syndromes, as well as a number of systemic diseases with CNS involvement. A detailed history, a through neurological examination and cerebrospinal fluid study are essential for MS diagnosis and MRI is one other tool that is most often confirmatory, but may cause confusion at times too. PMID- 29157406 TI - Contemporary Topics in Multiple Sclerosis. PMID- 29157407 TI - Oculomotor measures reveal the temporal dynamics of preparing for search. AB - Theories of visual search assume that selection is driven by an active template representation of the target object. Earlier studies suggest that template activation occurs prior to search, but the temporal dynamics of such preactivation remain unclear. Two experiments employed microsaccades to track both general preparation (i.e., anticipation of the search task as such) and template-specific preparation (i.e., anticipation of target selection) of visual search. Participants memorized a target color (i.e., the template) for an upcoming search task. During the delay period, we presented an irrelevant rapid serial visual presentation (RSVP) of lateralized colored disks. Crucially, at different time points into the RSVP, the template color was inserted, allowing us to measure attentional biases toward the template match as a function of time. Results showed a general suppression of saccades: the closer in time to the search display, the less saccades were produced. This suppression was stronger when a template-matching color was present compared to when absent. However, when microsaccades occurred, they were biased toward the template-matching color and more so just prior to the search display. We conclude that observers adapt search template activation to the anticipated moment of search, and that microsaccades reflect general as well as target-specific preparation effects. PMID- 29157408 TI - Fundamental computational constraints on the time course of perception and action. AB - A cognitive system faced with contingent events that cause rapid changes in sensory data may (i) incrementally incorporate new data into the ongoing perceptual and motor processing; or (ii) restart processing on each new event; or (iii) sample the data and hold onto the sample until its processing is complete, while disregarding any contingent changes. We offer a set of computational first principles arguments for a hypothesis, according to which any system that contends with certain classes of perception and behavioral control tasks must include the sample-and-hold option (possibly alongside the other two, which may be useful in other tasks). This hypothesis has implications for understanding the dynamics of perception and action. In particular, a sample-and-hold channel necessarily processes sensory data on some kind of cycle (which does not imply precise periodicity). Further, being prepared to face the world at all times requires that the sampling that initiates each cycle be triggered by every significant action on part of the agent itself, such as saccades. We survey a range of evidence for the sample-and-hold functionality, touching upon diverse phenomena such as attentional blink and backward masking, the yoking of olfaction to respiration, thalamocortical interactions, and metastable brain dynamics in perception and consciousness. PMID- 29157409 TI - Selecting multiple features delays perception, but only when targets are horizontally arranged. AB - Based on the finding that perception is lagged by attention split on multiple features (Lo et al., 2012), this study investigated how the feature-based lag effect interacts with the target spatial arrangement. Participants were presented with gratings the spatial frequencies of which constantly changed. The task was to monitor two gratings of the same or different colors and report their spatial frequencies right before the stimulus offset. The results showed a perceptual lag wherein the reported value was closer to the physical value some time prior to the stimulus offset. This lag effect was larger when the two gratings were of different colors than when they were the same color. Furthermore, the feature based lag effect was statistically significant when the two gratings were horizontally arranged but not when they were vertically or diagonally arranged. A model is proposed to explain the effect of target arrangement: When targets are horizontally arranged, selecting an additional feature delays perception. When targets are vertically or diagonally arranged, target selection for the lower field is prioritized. This prioritization on the lower target might prompt observers to only select the lower target and ignore the upper one, and this causes more perceptual errors without delaying perception. PMID- 29157410 TI - The maintenance and updating of representations of no longer visible objects and their parts. AB - When an object partially or completely disappears behind an occluding surface, a representation of that object persists. For example, fragments of no longer visible objects can serve as an input into mid-level constructive visual processes, interacting and integrating with currently visible portions to form perceptual units and global motion signals. Remarkably, these persistent representations need not be static and can have their positions and orientations updated postdictively as new information becomes visible. In this chapter, we highlight historical considerations, behavioral evidence, and neural correlates of this type of representational updating of no longer visible information at three distinct levels of visual processing. At the lowest level, we discuss spatiotemporal boundary formation in which visual transients can be integrated over space and time to construct local illusory edges, global form, and global motion percepts. At an intermediate level, we review how the visual system updates form information seen at one moment in time and integrates it with subsequently available information to generate global shape and motion representations (e.g., spatiotemporal form integration and anorthoscopic perception). At a higher level, when an entire object completely disappears behind an occluder, the object's identity and predicted position can be maintained in the absence of visual information. PMID- 29157411 TI - Choosing the speed of dynamic mental simulations. AB - The brain continuously maintains a current representation of its immediate surroundings. Perceptual representations are often updated when the world changes, e.g., when we notice an object move. However, we can also update representations internally, without incoming signals from the senses. In other words, we can run internal simulations of dynamic events. This ability is evident during mental object rotation. These uncontroversial observations lead to an obvious question that nevertheless remains to be answered: How does the brain control the speed of dynamic mental simulations? Is there a central rate controller or pacemaker module in the brain that can be temporarily coupled to sensory maps? We can refer to this as the common rate control theory. Alternatively, the primitive intelligence within each map could tune into the speed of recent changes and use this information to keep going after stimuli disappear. We can call this the separate rate control theory. Preliminary evidence from prediction motion experiments supports common rate control, although local predictive mechanisms may cover short gaps of <200ms. The putative rate controller might turn out to be the same thing as the velocity store described in smooth pursuit eye movement models and/or the pacemaker module proposed in the cognitive timing literature. Indirect neuroimaging evidence suggests rate control is a function of the core timing system in the dorsal striatum. PMID- 29157412 TI - Behavioral oscillation in face priming: Prediction about face identity is updated at a theta-band rhythm. AB - In order to deal with external world efficiently, the brain constantly generates predictions about incoming sensory inputs, a process known as "predictive coding." Our recent studies, by employing visual priming paradigms in combination with a time-resolved behavioral measurement, reveal that perceptual predictions about simple features (e.g., left or right orientation) return to low sensory areas not continuously but recurrently in a theta-band (3-4Hz) rhythm. However, it remains unknown whether high-level object processing is also mediated by the oscillatory mechanism and if yes at which rhythm the mechanism works. In the present study, we employed a morph-face priming paradigm and the time-resolved behavioral measurements to examine the fine temporal dynamics of face identity priming performance. First, we reveal classical priming effects and a rhythmic trend within the prime-to-probe SOA of 600ms (Experiment 1). Next, we densely sampled the face priming behavioral performances within this SOA range (Experiment 2). Our results demonstrate a significant ~5Hz oscillatory component in the face priming behavioral performances, suggesting that a rhythmic process also coordinates the object-level prediction (i.e., face identity here). In comparison to our previous studies, the results suggest that the rhythm for the high-level object is faster than that for simple features. We propose that the seemingly distinctive priming rhythms might be attributable to that the object level and simple feature-level predictions return to different stages along the visual pathway (e.g., FFA area for face priming and V1 area for simple feature priming). In summary, the findings support a general theta-band (3-6Hz) temporal organization mechanism in predictive coding, and that such wax-and-waning pattern in predictive coding may aid the brain to be more readily updated for new inputs. PMID- 29157413 TI - Incorporation of prosthetic limbs into the body representation of amputees: Evidence from the crossed hands temporal order illusion. AB - Understanding how we consciously experience our bodies is a fundamental issue in both psychology and neuroscience. To date, the incorporation of nonbody objects into the body representation has been investigated extensively, and the incorporation of prosthetic arms in amputees has been demonstrated using the rubber hand illusion. In this study, we investigated the incorporation of prosthetic arms in amputees using the crossed hands illusion, in which successive somatosensory stimuli are delivered, one to each arm, at intervals of 300ms or less, and where arm crossing often causes inversion of perceived tactile temporal order. The induced reversal illusion was greater with a prosthetic limb than without in three amputees. With a shorter prosthetic arm (i.e., one that did not reach the contralateral limb), the illusion induced by vision of the short prosthetic arm was significantly reduced as compared to that seen when the long prosthetic arm crossed over the other arm. These results therefore suggest that the somatosensory signals were referred to the spatial location of the tips of the prosthetic arm, which was incorporated into the body representation by the amputees. PMID- 29157414 TI - Synchronizing the tracking eye movements with the motion of a visual target: Basic neural processes. AB - In primates, the appearance of an object moving in the peripheral visual field elicits an interceptive saccade that brings the target image onto the foveae. This foveation is then maintained more or less efficiently by slow pursuit eye movements and subsequent catch-up saccades. Sometimes, the tracking is such that the gaze direction looks spatiotemporally locked onto the moving object. Such a spatial synchronism is quite spectacular when one considers that the target related signals are transmitted to the motor neurons through multiple parallel channels connecting separate neural populations with different conduction speeds and delays. Because of the delays between the changes of retinal activity and the changes of extraocular muscle tension, the maintenance of the target image onto the fovea cannot be driven by the current retinal signals as they correspond to past positions of the target. Yet, the spatiotemporal coincidence observed during pursuit suggests that the oculomotor system is driven by a command estimating continuously the current location of the target, i.e., where it is here and now. This inference is also supported by experimental perturbation studies: when the trajectory of an interceptive saccade is experimentally perturbed, a correction saccade is produced in flight or after a short delay, and brings the gaze next to the location where unperturbed saccades would have landed at about the same time, in the absence of visual feedback. In this chapter, we explain how such correction can be supported by previous visual signals without assuming "predictive" signals encoding future target locations. We also describe the basic neural processes which gradually yield the synchronization of eye movements with the target motion. When the process fails, the gaze is driven by signals related to past locations of the target, not by estimates to its upcoming locations, and a catch-up is made to reinitiate the synchronization. PMID- 29157415 TI - Attention in action and perception: Unitary or separate mechanisms of selectivity? AB - What is the relation between the two visual stream hypothesis and selective visual attention? In this chapter, we first consider this question at a theoretical level before presenting an example of work from our lab that examines the question: Under what conditions does the emotional content of a visual object influence visually guided action? Previous research has demonstrated that fear can influence perception, both consciously and unconsciously, but it is unclear when fear influences visually guided action. The study tested participants with varying degrees of spiderphobia on two visually guided pointing tasks, while manipulating the emotional valence of the target (positive and negative) and the cognitive load of the participant (single vs dual task). Participants rapidly moved their finger from a home position to a suddenly appearing target image on a touch screen. The images were emotionally negative (e.g., spiders and scorpions) or positive (e.g., flowers and food). In order to test the effect of emotional valence on the online control of the reach, the target either remained static or jumped to a new location. In both the single and dual tasks, a stream of digits were presented on the screen near the finger's starting location, but only in the dual task were participants asked to identify a letter somewhere in the stream. In the single task, increased fear of spiders reduced the speed and accuracy of the movement. In the dual task, increased fear impaired letter identification, but pointing actions were now equally efficient for low- and high-fear participants. These results imply that the finger's autopilot is influenced by emotional content only when attention can be fully devoted to the identification of the emotion-evoking images. As such, the results support the view that the mechanisms of selection are not the same in the two visual streams. PMID- 29157416 TI - The temporal dynamics involved in object representation updating to predict change. AB - The synchronization of cortically disparate neural assemblies at frequencies in the gamma-band range (30-70Hz) is considered to be involved in the perceptual organization of the environment. In support of this Elliott (2014) demonstrated improved detection of a target stimulus when this target was primed in a matrix that flickered at specific frequencies in the gamma-band range, each found to be separated by regular intervals which correspond with a 6.69Hz period. This can be explained in terms of the interaction of the stimulus (and stimulus-induced) rhythm with a slow endogenous theta rhythm. When the interaction is in phase between these rhythms and target presentation time is slightly ahead of the priming stimulus presentation, improved detection times are recorded indicating an anticipatory response. However, when these rhythms are out of phase and the target is presented during or slightly after priming stimulus presentation, improved responding also occurs, suggesting a retroactive response is facilitated. Research in the auditory domain supports these findings (Aksentijevic et al., 2011). The conclusions of this research suggest that synchronization of neural assemblies contributes to the temporal code necessary to facilitate representation updating in order to respond to a dynamic environment and anticipate the logical next event. PMID- 29157417 TI - Effect of emotions on temporal attention. AB - Emotions play a significant role in guiding everyday actions and strongly interact with attention. The processing of emotional information over time and the influence of attention on such processing has been studied through the phenomenon of attentional blink using rapid serial visual presentations (RSVP) tasks. This chapter discusses the interaction between temporal attention and the type of emotional information (words, scenes, and facial expressions) presented during or before the RSVP stream. The findings show that the affective content and the arousal value of the emotional stimuli presented as first target, second target, or both affects the magnitude and the duration of the blink window. In addition, modulation of emotional context or presentation of emotions in the RSVP stream as task irrelevant distractors also influenced attentional blink. Further, this chapter discusses different models and theories of attentional blink and attempts to explain the emotional effects. The chapter concludes with possible scope for future studies. PMID- 29157418 TI - Perceptual episodes, temporal attention, and the role of cognitive control: Lessons from the attentional blink. AB - The ability to identify a target is usually hindered if it appears shortly after another target. This simple and somewhat intuitive observation is qualified by a multitude of unexpected findings and conflicting theories that originate from the attentional blink paradigm. In this review, the major results, implications, and outstanding questions that stem from the paradigm are presented and discussed. The extant literature suggests that when the temporal domain is densely stacked with numerous stimuli, the entities that underlie attentional selection and cognitive control are brief perceptual episodes. Specifically, attention is deployed over an interval that frequently encompasses several stimuli. Most theories agree that the length and boundaries of this interval are influenced by cognitive control mechanisms. However, there is little agreement as to the extent and nature of this influence. Some theories suggest that control is needed in order to initiate a temporally limited attentional response. Other theories argue that cognitive control is actively suppressing attentional mechanisms in order to terminate the perceptual episode. Another formulation suggests that both ends of the interval are partially controlled and that the exertion of control corresponds to the focusing of attention on a narrow interval. The contents of perceptual episodes, as well as their deficiencies, can shed light on the features that guide attentional deployment, the goals that guide cognitive control, and the interactions between these mechanisms. Electrophysiological recordings are extremely useful when one tries to pinpoint the timing of attentional selection. Other neural indicators can elucidate the factors that define perceptual episodes. PMID- 29157419 TI - Accumulating visual information for action. AB - In this chapter, we discuss the way in which visual information is gathered and try to relate this to the task at hand. It is well established that people direct their gaze toward the places at which they expect to be able to gather the most useful information. Studies of gaze during goal-directed actions show that people also make sure to gather information precisely at the moment that they need it. We argue that the eye movements that people make during interception tasks and the precision that people achieve in such tasks suggest that people constantly update their estimates of the details that are needed to successfully hit the target. The updating predominantly consists of replacing the previously acquired information, rather than of adding to such information. PMID- 29157420 TI - Learning features in a complex and changing environment: A distribution-based framework for visual attention and vision in general. AB - What are the building blocks of our visual representations? Whatever we look at, the things we see will have some feature variability: even snow is not purely white but has a range of shades of white. However, in most studies investigating visual perception, homogeneous displays with all stimuli having a very limited range of features have been used. In contrast, recent studies using heterogeneous displays have shown that our perceptual system encodes surprisingly detailed information about stimuli, representing parameters such as the mean, variance, and most importantly the probability density functions of feature distributions. Learning the parameters of the distributions takes time as distribution representations are continuously updated with incoming information. However, the mechanisms guiding this process are not yet known. We will review current knowledge about the sampling and updating of representations of feature distributions in heterogeneous displays and will present new findings providing further insights into this process. Overall, the results show that representations of distributions can be remarkably detailed and shed light on how the information provided affects the learning of feature distributions. Observers' ability to quickly encode the probability density function of distributions in the environment may potentially provide novel interpretations of a number of well-known phenomena in visual perception. PMID- 29157421 TI - Preface. PMID- 29157422 TI - Toward the Miracle of Retinal Reanimation. PMID- 29157423 TI - Machine Learning Has Arrived! PMID- 29157424 TI - Endoscopic Vitrectomy for Microcornea, Posterior Megalolenticonus, Persistent Fetal Vasculature, Coloboma Syndrome. PMID- 29157425 TI - Wyburn-Mason Incidentally Diagnosed on Evaluation of Eye Redness. PMID- 29157426 TI - Amyloidosis Mimicking Temporal Arteritis in Multiple Myeloma. PMID- 29157427 TI - Long Eyebrow Hair Causing Corneal Ulcer. PMID- 29157428 TI - Progression of Dengue Maculopathy on OCT-Angiography and Fundus Photography. PMID- 29157429 TI - Bilateral Choroidal Metastases from Pancreatic Adenocarcinoma. PMID- 29157430 TI - Corrigendum. PMID- 29157432 TI - Corrigendum. PMID- 29157431 TI - Corrigendum. PMID- 29157433 TI - Reply. PMID- 29157434 TI - Re: Kitazawa et al.: Cystoid macular edema after Descemet's stripping automated endothelial keratoplasty (Ophthalmology. 2017;124:572-573). PMID- 29157435 TI - Re: Bressler et al.: Factors associated with worsening proliferative diabetic retinopathy in eyes treated with panretinal photocoagulation or ranibizumab (Ophthalmology. 2017;124:431-439). PMID- 29157436 TI - Reply. PMID- 29157437 TI - Re: Busin et al.: Large (9 mm) deep anterior lamellar keratoplasty with clearance of a 6-mm optical zone optimizes outcomes of keratoconus surgery (Ophthalmology. 2017;124:1072-1080). PMID- 29157438 TI - Reply. PMID- 29157439 TI - Re: Yamane et al.: Flanged intrascleral intraocular lens fixation with double needle technique (Ophthalmology. 2017;124:1136-1142). PMID- 29157440 TI - Reply. PMID- 29157441 TI - Special Issue on Biochar: Production, Characterization and Applications - Beyond Soil Applications. PMID- 29157442 TI - A deep learning-based multi-model ensemble method for cancer prediction. AB - BACKGROUND AND OBJECTIVE: Cancer is a complex worldwide health problem associated with high mortality. With the rapid development of the high-throughput sequencing technology and the application of various machine learning methods that have emerged in recent years, progress in cancer prediction has been increasingly made based on gene expression, providing insight into effective and accurate treatment decision making. Thus, developing machine learning methods, which can successfully distinguish cancer patients from healthy persons, is of great current interest. However, among the classification methods applied to cancer prediction so far, no one method outperforms all the others. METHODS: In this paper, we demonstrate a new strategy, which applies deep learning to an ensemble approach that incorporates multiple different machine learning models. We supply informative gene data selected by differential gene expression analysis to five different classification models. Then, a deep learning method is employed to ensemble the outputs of the five classifiers. RESULTS: The proposed deep learning based multi-model ensemble method was tested on three public RNA-seq data sets of three kinds of cancers, Lung Adenocarcinoma, Stomach Adenocarcinoma and Breast Invasive Carcinoma. The test results indicate that it increases the prediction accuracy of cancer for all the tested RNA-seq data sets as compared to using a single classifier or the majority voting algorithm. CONCLUSIONS: By taking full advantage of different classifiers, the proposed deep learning-based multi-model ensemble method is shown to be accurate and effective for cancer prediction. PMID- 29157443 TI - A benchmark study of automated intra-retinal cyst segmentation algorithms using optical coherence tomography B-scans. AB - (BACKGROUND AND OBJECTIVES): Retinal cysts are formed by accumulation of fluid in the retina caused by leakages from inflammation or vitreous fractures. Analysis of the retinal cystic spaces holds significance in detection and treatment of several ocular diseases like age-related macular degeneration, diabetic macular edema etc. Thus, segmentation of intra-retinal cysts and quantification of cystic spaces are vital for retinal pathology and severity detection. In the recent years, automated segmentation of intra-retinal cysts using optical coherence tomography B-scans has gained significant importance in the field of retinal image analysis. The objective of this paper is to compare different intra-retinal cyst segmentation algorithms for comparative analysis and benchmarking purposes. (METHODS): In this work, we employ a modular approach for standardizing the different segmentation algorithms. Further, we analyze the variations in automated cyst segmentation performances and method scalability across image acquisition systems by using the publicly available cyst segmentation challenge dataset (OPTIMA cyst segmentation challenge). (RESULTS): Several key automated methods are comparatively analyzed using quantitative and qualitative experiments. Our analysis demonstrates the significance of variations in signal to-noise ratio (SNR), retinal layer morphology and post-processing steps on the automated cyst segmentation processes. (CONCLUSION): This benchmarking study provides insights towards the scalability of automated processes across vendor specific imaging modalities to provide guidance for retinal pathology diagnostics and treatment processes. PMID- 29157444 TI - A tool to visualize and analyze perfusion data: Development and application of the R package "CTP". AB - BACKGROUND AND OBJECTIVE: Computed tomography perfusion (CTP) is a widely used imaging modality especially in neuroimaging. Despite this, CTP is often prohibitive due to the dearth of free/open-source software. This could have wide ranging implications for instruction and research. We have implemented an online available CTP tool built and run completely within the R computing environment. METHODS: Called from within R, the user can select one of four different methods to construct a cerebral blood flow (CBF) map: (1) max-slope (2) singular value decomposition (3) block circulant singular value decomposition or (4) oscillation minimization singular value decomposition. The four methods are compared against a digital CBF phantom. RESULTS: All four methods generate a CBF map, with the oscillation minimization technique giving the most accurate map. CONCLUSIONS: We have constructed an easily accessible teaching and research tool to create a CBF map and made it freely available. We hope this tool will help facilitate understanding of the methods involved in constructing perfusion maps and be a valuable resource to future researchers. PMID- 29157445 TI - An ensemble deep learning based approach for red lesion detection in fundus images. AB - BACKGROUND AND OBJECTIVES: Diabetic retinopathy (DR) is one of the leading causes of preventable blindness in the world. Its earliest sign are red lesions, a general term that groups both microaneurysms (MAs) and hemorrhages (HEs). In daily clinical practice, these lesions are manually detected by physicians using fundus photographs. However, this task is tedious and time consuming, and requires an intensive effort due to the small size of the lesions and their lack of contrast. Computer-assisted diagnosis of DR based on red lesion detection is being actively explored due to its improvement effects both in clinicians consistency and accuracy. Moreover, it provides comprehensive feedback that is easy to assess by the physicians. Several methods for detecting red lesions have been proposed in the literature, most of them based on characterizing lesion candidates using hand crafted features, and classifying them into true or false positive detections. Deep learning based approaches, by contrast, are scarce in this domain due to the high expense of annotating the lesions manually. METHODS: In this paper we propose a novel method for red lesion detection based on combining both deep learned and domain knowledge. Features learned by a convolutional neural network (CNN) are augmented by incorporating hand crafted features. Such ensemble vector of descriptors is used afterwards to identify true lesion candidates using a Random Forest classifier. RESULTS: We empirically observed that combining both sources of information significantly improve results with respect to using each approach separately. Furthermore, our method reported the highest performance on a per-lesion basis on DIARETDB1 and e-ophtha, and for screening and need for referral on MESSIDOR compared to a second human expert. CONCLUSIONS: Results highlight the fact that integrating manually engineered approaches with deep learned features is relevant to improve results when the networks are trained from lesion-level annotated data. An open source implementation of our system is publicly available at https://github.com/ignaciorlando/red-lesion-detection. PMID- 29157446 TI - Dynamic visualization of multi-level molecular data: The Director package in R. AB - BACKGROUND AND OBJECTIVE: High-throughput measurement technologies have triggered a rise in large-scale cancer studies containing multiple levels of molecular data. While there are a number of efficient methods to analyze individual data types, there are far less that enhance data interpretation after analysis. We present the R package Director, a dynamic visualization approach to linking and interrogating multiple levels of molecular data after analysis for clinically meaningful, actionable insights. METHODS: Sankey diagrams are traditionally used to represent quantitative flows through multiple, distinct events. Regulation can be interpreted as a flow of biological information through a series of molecular interactions. Functions in Director introduce novel drawing capabilities to make Sankey diagrams robust to a wide range of quantitative measures and to depict molecular interactions as regulatory cascades. The package streamlines creation of diagrams using as input quantitative measurements identifying nodes as molecules of interest and paths as the interaction strength between two molecules. RESULTS: Director's utility is demonstrated with quantitative measurements of candidate microRNA-gene networks identified in an ovarian cancer dataset. A recent study reported eight miRNAs as master regulators of signature genes in epithelial-mesenchymal transition (EMT). The Sankey diagrams generated with data from this study furthers interpretation of the miRNAs' roles by revealing potential co-regulatory behavior in the extracellular matrix (ECM). An additional analysis identified 32 genes differentially expressed between good and poor prognosis patients in four significant pathways (FDR <= 0.1), three of which support a complementary role of the ECM in ovarian cancer. The resulting diagram created with Director suggest elevated levels of COL11A1, INHBA, and THBS2 - a signature feature of metastasis [1] - and decreased levels of their targeting miRNAs define poor prognosis. CONCLUSION: We have demonstrated a visualization approach suitable for implementation in an analysis workflow, linking multiple levels of molecular data to gain novel perspective on candidate biomarkers in a complex disease. The diagrams are dynamic, easily replicable, and rendered locally as HTML files to facilitate sharing. The R package Director is simple to use and widely available on all operating systems through Bioconductor (http://bioconductor.org/packages/Director) and GitHub (http://kzouchka.github.io/Director). PMID- 29157447 TI - The usefulness and actual use of wearable devices among the elderly population. AB - BACKGROUND AND OBJECTIVE: Elderly populations are more prone to diseases and need continuous monitoring of parameters to ensure good health. Wearable devices (WDs) can be helpful in the early detection and management of medical conditions. However, less is known about the use of currently available WDs among elderly populations. The objectives of this study were to determine the usefulness and actual use of wearable devices among the elderly population. METHODS: Our methodology was based on a systematic review and a survey questionnaire. In the systematic review, search was conducted in four databases PubMed, MDPI, Sage, and Scopus with search terms "wearable device" and "elderly", "wearable sensor" and "elderly". The inclusion criteria were the studies which described health-related wearable devices, its use as the outcome, conducted on a minimum of ten participants and published in the last five years. The survey was conducted on the MOOCs (Massive Open Online Course) platform. The questionnaire was related to the use of technology, intention to use, security and privacy concerns, and willingness to pay. RESULTS: The review identified 4915 articles, of which, 31 studies eventually met the inclusion criteria. All studies reported positive impacts after assessing devices, despite certain drawbacks. The majority of the samples were males. The survey revealed responses from 233 individuals out of the 1100 participants of the course. The survey results were categorized into two age groups: 54.3% were elderly (>65 years) and 45.49% were non-elderly (<=65 years). Very few elderly people were currently using WD. More than 60% of elderly people were interested in the future use of wearable devices, and preferred future use to improve physical and mental activities. A majority of the respondents were female. CONCLUSIONS: This study suggests awareness should be created among elderly populations regarding the use of WDs for the early detection and prevention of complications and emergencies. Elderly populations are more prone to benefits from using WDs. The review concluded that devices should be tested on elderly groups as well, considering sex equality, and on both healthy and sick participants for better insights. The survey determined the elderly as frequent users of technology, but lack of knowledge of WD and demonstrated female interest in the use of WD. In future research on WDs, it is suggested that clinical studies be conducted for longer durations, and standard protocols such as age and sex equality should be considered. Requirements from both users and physicians should be acknowledged for better cognizance of WDs. PMID- 29157448 TI - Ab-initio conformational epitope structure prediction using genetic algorithm and SVM for vaccine design. AB - BACKGROUND AND OBJECTIVE: T-cell epitope structure identification is a significant challenging immunoinformatic problem within epitope-based vaccine design. Epitopes or antigenic peptides are a set of amino acids that bind with the Major Histocompatibility Complex (MHC) molecules. The aim of this process is presented by Antigen Presenting Cells to be inspected by T-cells. MHC-molecule binding epitopes are responsible for triggering the immune response to antigens. The epitope's three-dimensional (3D) molecular structure (i.e., tertiary structure) reflects its proper function. Therefore, the identification of MHC class-II epitopes structure is a significant step towards epitope-based vaccine design and understanding of the immune system. METHODS: In this paper, we propose a new technique using a Genetic Algorithm for Predicting the Epitope Structure (GAPES), to predict the structure of MHC class-II epitopes based on their sequence. The proposed Elitist-based genetic algorithm for predicting the epitope's tertiary structure is based on Ab-Initio Empirical Conformational Energy Program for Peptides (ECEPP) Force Field Model. The developed secondary structure prediction technique relies on Ramachandran Plot. We used two alignment algorithms: the ROSS alignment and TM-Score alignment. We applied four different alignment approaches to calculate the similarity scores of the dataset under test. We utilized the support vector machine (SVM) classifier as an evaluation of the prediction performance. RESULTS: The prediction accuracy and the Area Under Receiver Operating Characteristic (ROC) Curve (AUC) were calculated as measures of performance. The calculations are performed on twelve similarity-reduced datasets of the Immune Epitope Data Base (IEDB) and a large dataset of peptide binding affinities to HLA-DRB1*0101. The results showed that GAPES was reliable and very accurate. We achieved an average prediction accuracy of 93.50% and an average AUC of 0.974 in the IEDB dataset. Also, we achieved an accuracy of 95.125% and an AUC of 0.987 on the HLA-DRB1*0101 allele of the Wang benchmark dataset. CONCLUSIONS: The results indicate that the proposed prediction technique "GAPES" is a promising technique that will help researchers and scientists to predict the protein structure and it will assist them in the intelligent design of new epitope-based vaccines. PMID- 29157449 TI - Paroxysmal atrial fibrillation prediction based on HRV analysis and non-dominated sorting genetic algorithm III. AB - This paper presents a method that able to predict the paroxysmal atrial fibrillation (PAF). The method uses shorter heart rate variability (HRV) signals when compared to existing methods, and achieves good prediction accuracy. PAF is a common cardiac arrhythmia that increases the health risk of a patient, and the development of an accurate predictor of the onset of PAF is clinical important because it increases the possibility to electrically stabilize and prevent the onset of atrial arrhythmias with different pacing techniques. We propose a multi objective optimization algorithm based on the non-dominated sorting genetic algorithm III for optimizing the baseline PAF prediction system, that consists of the stages of pre-processing, HRV feature extraction, and support vector machine (SVM) model. The pre-processing stage comprises of heart rate correction, interpolation, and signal detrending. After that, time-domain, frequency-domain, non-linear HRV features are extracted from the pre-processed data in feature extraction stage. Then, these features are used as input to the SVM for predicting the PAF event. The proposed optimization algorithm is used to optimize the parameters and settings of various HRV feature extraction algorithms, select the best feature subsets, and tune the SVM parameters simultaneously for maximum prediction performance. The proposed method achieves an accuracy rate of 87.7%, which significantly outperforms most of the previous works. This accuracy rate is achieved even with the HRV signal length being reduced from the typical 30 min to just 5 min (a reduction of 83%). Furthermore, another significant result is the sensitivity rate, which is considered more important that other performance metrics in this paper, can be improved with the trade-off of lower specificity. PMID- 29157450 TI - Quantile planes without crossing via nonlinear programming. AB - BACKGROUND AND OBJECTIVE: In this note we propose a nonlinear programming approach for simultaneous fitting of quantile regression models for two or more quantiles. The approach is straightforward, flexible and practical. We apply this approach to a dataset of lactic acid values from a screening dataset in childhood malaria. METHODS: We carry out the fitting of simultaneous quantile regression models using a specific definition of a quantile as an expectation via nonlinear programming methods given certain monotonicity constraints. RESULTS: We illustrate through simulations and examples that are new approach to simultaneous quantile regression is practical and feasible. The approach is supplemented by providing a bootstrap framework for confidence interval estimation. CONCLUSIONS: Our nonlinear programming approach towards solving the simultaneous quantile regression fitting is shown to be a practical approach that should appeal to statistical practitioners. PMID- 29157451 TI - An integrated method for atherosclerotic carotid plaque segmentation in ultrasound image. AB - BACKGROUND AND OBJECTIVE: Carotid artery atherosclerosis is an important cause of stroke. Ultrasound imaging has been widely used in the diagnosis of atherosclerosis. Therefore, segmenting atherosclerotic carotid plaque in ultrasound image is an important task. Accurate plaque segmentation is helpful for the measurement of carotid plaque burden. In this paper, we propose and evaluate a novel learning-based integrated framework for plaque segmentation. METHODS: In our study, four different classification algorithms, along with the auto-context iterative algorithm, were employed to effectively integrate features from ultrasound images and later also the iteratively estimated and refined probability maps together for pixel-wise classification. The four classification algorithms were support vector machine with linear kernel, support vector machine with radial basis function kernel, AdaBoost and random forest. The plaque segmentation was implemented in the generated probability map. The performance of the four different learning-based plaque segmentation methods was tested on 29 B mode ultrasound images. The evaluation indices for our proposed methods were consisted of sensitivity, specificity, Dice similarity coefficient, overlap index, error of area, absolute error of area, point-to-point distance, and Hausdorff point-to-point distance, along with the area under the ROC curve. RESULTS: The segmentation method integrated the random forest and an auto-context model obtained the best results (sensitivity 80.4 +/- 8.4%, specificity 96.5 +/- 2.0%, Dice similarity coefficient 81.0 +/- 4.1%, overlap index 68.3 +/- 5.8%, error of area -1.02 +/- 18.3%, absolute error of area 14.7 +/- 10.9%, point-to point distance 0.34 +/- 0.10 mm, Hausdorff point-to-point distance 1.75 +/- 1.02 mm, and area under the ROC curve 0.897), which were almost the best, compared with that from the existed methods. CONCLUSIONS: Our proposed learning-based integrated framework investigated in this study could be useful for atherosclerotic carotid plaque segmentation, which will be helpful for the measurement of carotid plaque burden. PMID- 29157452 TI - Evolution of linear and nonlinear fetal heart rate indices throughout pregnancy in appropriate, small for gestational age and preterm fetuses: A cohort study. AB - BACKGROUND AND OBJECTIVES: To assess the evolution of linear and nonlinear fetal heart rate (FHR) analysis throughout pregnancy in appropriate (AGA), small for gestational age (SGA) and preterm (PTB) fetuses. METHODS: A prospective cohort study was carried out in 171 singleton pregnancies divided in three groups: AGA (n = 147), SGA (n = 13) fetuses and spontaneous PTB (n = 11). FHR was recorded with an external sensor from the 24th to the 40th week of gestation. Linear time- and frequency-domain and nonlinear FHR indices were computed on 10-min segments. Longitudinal analysis of indices throughout pregnancy was performed with generalized estimating equations, and receiver operating characteristic (ROC) curves were calculated for the prediction of SGA and PTB fetuses. RESULTS: Increasing gestational age significantly affected most FHR indices, with a general increase in variability and entropy indices, and a decrease in mean FHR. The PTB group exhibited a significantly lower short-term variation, and no monotonic increase in the sympatho-vagal balance as observed in the AGA group. The SGA group exhibited higher long-term irregularity and lower short-term irregularity than the AGA group throughout gestation. In prediction of SGA and PTB, the largest areas under the ROC curves obtained were 0.76 and 0.78, respectively. CONCLUSIONS: Linear and nonlinear FHR analysis provides useful information on the evolution of fetal autonomic nervous and complexity control systems throughout pregnancy, in relation with AGA, SGA and PTB fetuses, which may be helpful in clinical practice. PMID- 29157453 TI - Computer-Aided tumor diagnosis in 3-D breast elastography. AB - BACKGROUND AND OBJECTIVE: Breast cancer is the major cause of cancer-related mortality in women. However, the death rate can be effectively decreased if the breast cancer can be detected early and treated appropriately. In recent years, many studies have indicated that the elastography has the better diagnosis performance than conventional ultrasound (US). METHOD: In this study, the 3-D tumor contour is obtained by using the proposed segmentation methods and then the features containing texture information, shape information, ellipsoid fitting information are extracted respectively by using the segmented 3-D tumor contour and B-mode images, and the features containing elasticity information are calculated using the same contour and elastographic images. RESULTS: In this experiment, totally 40 biopsy-proved lesions containing 20 benign tumors and 20 malignant tumors are used to evaluate the proposed computer-aided diagnosis (CAD) system. From the experimental results, the combination of shape, ellipsoid fitting and elastographic features has the best performance with accuracy 90.50% (36/40), sensitivity 85.00% (17/20), specificity 95.00% (19/20), and the area under the ROC curve Az 0.987. CONCLUSION: The result shows that tumors can be diagnosed more precisely by using the elastography images. PMID- 29157454 TI - Developing a new intelligent system for the diagnosis of tuberculous pleural effusion. AB - BACKGROUND AND OBJECTIVE: In countries with high prevalence of tuberculosis (TB), clinicians often diagnose tuberculous pleural effusion (TPE) by using diagnostic tests, which have not only poor sensitivity, but poor availability as well. The aim of our study is to develop a new artificial intelligence based diagnostic model that is accurate, fast, non-invasive and cost effective to diagnose TPE. It is expected that a tool derived based on the model be installed on simple computer devices (such as smart phones and tablets) and be used by clinicians widely. METHODS: For this study, data of 140 patients whose clinical signs, routine blood test results, blood biochemistry markers, pleural fluid cell type and count, and pleural fluid biochemical tests' results were prospectively collected into a database. An Artificial intelligence based diagnostic model, which employs moth flame optimization based support vector machine with feature selection (FS-MFO-SVM), is constructed to predict the diagnosis of TPE. RESULTS: The optimal model results in an average of 95% accuracy (ACC), 0.9564 the area under the receiver operating characteristic curve (AUC), 93.35% sensitivity, and 97.57% specificity for FS-MFO-SVM. CONCLUSIONS: The proposed artificial intelligence based diagnostic model is found to be highly reliable for diagnosing TPE based on simple clinical signs, blood samples and pleural effusion samples. Therefore, the proposed model can be widely used in clinical practice and further evaluated for use as a substitute of invasive pleural biopsies. PMID- 29157455 TI - Identification of preterm birth based on RQA analysis of electrohysterograms. AB - BACKGROUND AND OBJECTIVE: Common methods for data analysis are mainly based on linear concepts, but in recent years nonlinear dynamics methods have been introduced. It is a well-known fact that In typical biological systems lack of stationarity and rather sudden changes of state are the properties distinguishing them from each other. There is an urgent need to better understand the mechanical activity of the myometrium (its contractility) to find a solution for preterm delivery problem, the largest cause of neonatal deaths and morbidity. The electrohysterographic signal (EHG) is a good non-linear, bioelectrical indicator for the detection and identification of term and preterm birth. METHODS: The material of the study consists of EHG signals, obtained from 20 patients between the 24th and the 28th week of pregnancy with threatened preterm labor. The women were divided into two groups: those delivering after more than 7 days - group A (n = 10) and women delivering within 7 days - group B (n = 10). In this paper, an analysis of bioelectrical signals was performed by recurrence quantification analysis (RQA) and principal component analysis (PCA) to distinguish particular patterns for term and preterm birth. To date, these methods have not been used for the evaluation of bioelectrical activity in the uterus. To train novel classifiers for the EHG signals Support Vectors Machine classifications (multiclass SVM) was used. Statistical analysis was performed by means of non parametric Mann-Whitney test. RESULTS: From among eleven parameters obtained from recurrence quantification analysis, five most appropriate were chosen: Recurrence Rate, Determinism, Laminarity, Entropy and Recurrence Period Density Entropy. Significant increase (p < .001) of Recurrence Rate was found in patients from group B, while increase of parameters, besides Laminarity, was found in patients from group A. The accuracy of classification obtained as a result of the analysis increased to 83,32%. CONCLUSION: We showed that the respectively selected recurrence quantificators obtained for that time series could be used to classify all those signals to the appropriate group. The proposed analysis could help in detecting preterm labor based on the EHG signal dynamics. PMID- 29157456 TI - Real-time deformation of human soft tissues: A radial basis meshless 3D model based on Marquardt's algorithm. AB - BACKGROUND: When the meshless method is used to establish the mathematical mechanical model of human soft tissues, it is necessary to define the space occupied by human tissues as the problem domain and the boundary of the domain as the surface of those tissues. Nodes should be distributed in both the problem domain and on the boundaries. Under external force, the displacement of the node is computed by the meshless method to represent the deformation of biological soft tissues. However, computation by the meshless method consumes too much time, which will affect the simulation of real-time deformation of human tissues in virtual surgery. METHODS: In this article, the Marquardt's Algorithm is proposed to fit the nodal displacement at the problem domain's boundary and obtain the relationship between surface deformation and force. When different external forces are applied, the deformation of soft tissues can be quickly obtained based on this relationship. RESULTS AND CONCLUSIONS: The analysis and discussion show that the improved model equations with Marquardt's Algorithm not only can simulate the deformation in real-time but also preserve the authenticity of the deformation model's physical properties. PMID- 29157458 TI - Robust breast cancer prediction system based on rough set theory at National Cancer Institute of Egypt. AB - BACKGROUND: Breast cancer is one of the major death causing diseases of the women in the world. Every year more than million women are diagnosed with breast cancer more than half of them will die because of inaccuracies and delays in diagnosis of the disease. High accuracy in cancer prediction is important to improve the treatment quality and the survivability rate of patients. OBJECTIVES: In this paper, we are going to propose a new and robust breast cancer prediction and diagnosis system based on the Rough Set (RS). Also, introducing the robust classification process based on some new and most effective attributes. Comparing and evaluating the performance of our proposed approach with the clinical, Radial Basis Function, and Artificial Neural Networks classification schemes. METHODS: The dataset used in our experiments consists of 60 samples obtained from the National Cancer Institute (NCI) of Egypt. We have used the RS theory to robustly find dependence relationships among data, and evaluate the importance of attributes through: Results: Conclusion: We have introduced the robustness of the RS theory in early predicting and diagnosing the breast cancer. This lay more importance to the contribution and efficiency of RS theory in the field of computational biology. PMID- 29157457 TI - The development and implementation of stroke risk prediction model in National Health Insurance Service's personal health record. AB - BACKGROUND AND OBJECTIVE: The purpose of this study was to build a 10-year stroke prediction model and categorize a probability of stroke using the Korean national health examination data. Then it intended to develop the algorithm to provide a personalized warning on the basis of each user's level of stroke risk and a lifestyle correction message about the stroke risk factors. METHODS: Subject to national health examinees in 2002-2003, the stroke prediction model identified when stroke was first diagnosed by following-up the cohort until 2013 and estimated a 10-year probability of stroke. It sorted the user's individual probability of stroke into five categories - normal, slightly high, high, risky, very risky, according to the five ranges of average probability of stroke in comparison to total population - less than 50 percentile, 50-70, 70-90, 90-99.9, more than 99.9 percentile, and constructed the personalized warning and lifestyle correction messages by each category. RESULTS: Risk factors in stroke risk model include the age, BMI, cholesterol, hypertension, diabetes, smoking status and intensity, physical activity, alcohol drinking, past history (hypertension, coronary heart disease) and family history (stroke, coronary heart disease). The AUC values of stroke risk prediction model from the external validation data set were 0.83 in men and 0.82 in women, which showed a high predictive power. The probability of stroke within 10 years for men in normal group (less than 50 percentile) was less than 3.92% and those in very risky group (top 0.01 percentile) was 66.2% and over. The women's probability of stroke within 10 years was less than 3.77% in normal group (less than 50 percentile) and 55.24% and over in very risky group. CONCLUSIONS: This study developed the stroke risk prediction model and the personalized warning and the lifestyle correction message based on the national health examination data and uploaded them to the personal health record service called My Health Bank in the health information website - Health iN. By doing so, it urged medical users to strengthen the motivation of health management and induced changes in their health behaviors. PMID- 29157459 TI - A computer-aided diagnosis system for breast ultrasound based on weighted BI-RADS classes. AB - BACKGROUND AND OBJECTIVE: Conventional computer-aided diagnosis (CAD) systems for breast ultrasound (BUS) are trained to classify pathological classes, that is, benign and malignant. However, from a clinical perspective, this kind of classification does not agree totally with radiologists' diagnoses. Usually, the tumors are assessed by using a BI-RADS (Breast Imaging-Reporting and Data System) category and, accordingly, a recommendation is emitted: annual study for category 2 (benign), six-month follow-up study for category 3 (probably benign), and biopsy for categories 4 and 5 (suspicious of malignancy). Hence, in this paper, a CAD system based on BI-RADS categories weighted by pathological information is presented. The goal is to increase the classification performance by reducing the common class imbalance found in pathological classes as well as to provide outcomes quite similar to radiologists' recommendations. METHODS: The BUS dataset considers 781 benign lesions and 347 malignant tumors proven by biopsy. Moreover, every lesion is associated to one BI-RADS category in the set {2, 3, 4, 5}. Thus, the dataset is split into three weighted classes: benign, BI-RADS 2 in benign lesions; probably benign, BI-RADS 3 and 4 in benign lesions; and malignant, BI RADS 4 and 5 in malignant lesions. Thereafter, a random forest (RF) classifier, denoted by RFw, is trained to predict the weighted BI-RADS classes. In addition, for comparison purposes, a RF classifier is trained to predict pathological classes, denoted as RFp. RESULTS: The ability of the classifiers to predict the pathological classes is measured by the area under the ROC curve (AUC), sensitivity (SEN), and specificity (SPE). The RFw classifier obtained AUC=0.872,SEN=0.826, and SPE=0.919, whereas the RFp classifier reached AUC=0.868,SEN=0.808, and SPE=0.929. According to a one-way analysis of variance test, the RFw classifier statistically outperforms (p < 0.001) the RFp classifier in terms of the AUC and SEN. Moreover, the classification performance of RFw to predict weighted BI-RADS classes is given by the Matthews correlation coefficient that obtained 0.614. CONCLUSIONS: The division of the classification problem into three classes reduces the imbalance between benign and malignant classes; thus, the sensitivity is increased without degrading the specificity. Therefore, the CAD based on weighted BI-RADS classes improves the classification performance of the conventional CAD systems. Additionally, the proposed approach has the advantage of being capable of providing a multiclass outcome related to radiologists' recommendations. PMID- 29157460 TI - Correlation analysis of respiratory signals by using parallel coordinate plots. AB - BACKGROUND AND OBJECTIVES: The understanding of the bonds and the relationships between the respiratory signals, i.e. the airflow, the mouth pressure, the relative temperature and the relative humidity during breathing may provide the improvement on the measurement methods of respiratory mechanics and sensor designs or the exploration of the several possible applications in the analysis of respiratory disorders. Therefore, the main objective of this study was to propose a new combination of methods in order to determine the relationship between respiratory signals as a multidimensional data. METHODS: In order to reveal the coupling between the processes two very different methods were used: the well-known statistical correlation analysis (i.e. Pearson's correlation and cross-correlation coefficient) and parallel coordinate plots (PCPs). Curve bundling with the number intersections for the correlation analysis, Least Mean Square Time Delay Estimator (LMS-TDE) for the point delay detection and visual metrics for the recognition of the visual structures were proposed and utilized in PCP. RESULTS: The number of intersections was increased when the correlation coefficient changed from high positive to high negative correlation between the respiratory signals, especially if whole breath was processed. LMS-TDE coefficients plotted in PCP indicated well-matched point delay results to the findings in the correlation analysis. Visual inspection of PCB by visual metrics showed range, dispersions, entropy comparisons and linear and sinusoidal-like relationships between the respiratory signals. CONCLUSION: It is demonstrated that the basic correlation analysis together with the parallel coordinate plots perceptually motivates the visual metrics in the display and thus can be considered as an aid to the user analysis by providing meaningful views of the data. PMID- 29157461 TI - Automated outcome scoring in a virtual reality simulator for endodontic surgery. AB - BACKGROUND AND OBJECTIVE: We address the problem of automated outcome assessment in a virtual reality (VR) simulator for endodontic surgery. Outcome assessment is an essential component of any system that provides formative feedback, which requires assessing the outcome, relating it to the procedure, and communicating in a language natural to dental students. This study takes a first step toward automated generation of such comprehensive feedback. METHODS: Virtual reference templates are computed based on tooth anatomy and the outcome is assessed with a 3D score cube volume which consists of voxel-level non-linear weighted scores based on the templates. The detailed scores are transformed into standard scoring language used by dental schools. The system was evaluated on fifteen outcome samples that contained optimal results and those with errors including perforation of the walls, floor, and both, as well as various combinations of major and minor over and under drilling errors. Five endodontists who had professional training and varying levels of experiences in root canal treatment participated as raters in the experiment. RESULTS: Results from evaluation of our system with expert endodontists show a high degree of agreement with expert scores (information based measure of disagreement 0.04-0.21). At the same time they show some disagreement among human expert scores, reflecting the subjective nature of human outcome scoring. The discriminatory power of the AOS scores analyzed with three grade tiers (A, B, C) using the area under the receiver operating characteristic curve (AUC). The AUC values are generally highest for the {AB: C} cutoff which is cutoff at the boundary between clinically acceptable (B) and clinically unacceptable (C) grades. CONCLUSIONS: The objective consistency of computed scores and high degree of agreement with experts make the proposed system a promising addition to existing VR simulators. The translation of detailed level scores into terminology commonly used in dental surgery supports natural communication with students and instructors. With the reference virtual templates created automatically, the approach is robust and is applicable in scoring the outcome of any dental surgery procedure involving the act of drilling. PMID- 29157462 TI - Recognition of pigment network pattern in dermoscopy images based on fuzzy classification of pixels. AB - BACKGROUND AND OBJECTIVE: One of the most relevant dermoscopic patterns is the pigment network. An innovative method of pattern recognition is presented for its detection in dermoscopy images. METHODS: It consists of two steps. In the first one, by means of a supervised machine learning process and after performing the extraction of different colour and texture features, a fuzzy classification of pixels into the three categories present in the pattern's definition ("net", "hole" and "other") is carried out. This enables the three corresponding fuzzy sets to be created and, as a result, the three probability images that map them out are generated. In the second step, the pigment network pattern is characterised from a parameterisation process -derived from the system specification- and the subsequent extraction of different features calculated from the combinations of image masks extracted from the probability images, corresponding to the alpha-cuts obtained from the fuzzy sets. RESULTS: The method was tested on a database of 875 images -by far the largest used in the state of the art to detect pigment network- extracted from a public Atlas of Dermoscopy, obtaining AUC results of 0.912 and 88%% accuracy, with 90.71%% sensitivity and 83.44%% specificity. CONCLUSION: The main contribution of this method is the very design of the algorithm, highly innovative, which could also be used to deal with other pattern recognition problems of a similar nature. Other contributions are: 1. The good performance in discriminating between the pattern and the disturbing artefacts -which means that no prior preprocessing is required in this method- and between the pattern and other dermoscopic patterns; 2. It puts forward a new methodological approach for work of this kind, introducing the system specification as a required step prior to algorithm design and development, being this specification the basis for a required parameterisation -in the form of configurable parameters (with their value ranges) and set threshold values- of the algorithm and the subsequent conducting of the experiments. PMID- 29157463 TI - Enhanced Wiener filter for ultrasound image restoration. AB - BACKGROUND AND OBJECTIVE: Speckle phenomenon strongly affects UltraSound (US) images. In the last years, several efforts have been done in order to provide an effective denoising methodology. Although good results have been achieved in terms of noise reduction effectiveness, most of the proposed approaches are not characterized by low computational burden and require the supervision of an external operator for tuning the input parameters. METHODS: Within this manuscript, a novel approach is investigated, based on Wiener filter. Working in the frequency domain, it is characterized by high computational efficiency. With respect to classical Wiener filter, the proposed Enhanced Wiener filter is able to locally adapt itself by tuning its kernel in order to combine edges and details preservation with effective noise reduction. This characteristic is achieved by implementing a Local Gaussian Markov Random Field for modeling the image. Due to its intrinsic characteristics, the computational burden of the algorithm is sensibly low compared to other widely adopted filters and the parameter tuning effort is minimal, being well suited for quasi real time applications. RESULTS: The approach has been tested on both simulated and real datasets, showing interesting performances compared to other state of art methods. CONCLUSIONS: A novel denoising method for UltraSound images is proposed. The approach is able to combine low computational burden with interesting denoising performances and details preservation. PMID- 29157464 TI - Characterization of coronary plaque regions in intravascular ultrasound images using a hybrid ensemble classifier. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to propose a hybrid ensemble classifier to characterize coronary plaque regions in intravascular ultrasound (IVUS) images. METHODS: Pixels were allocated to one of four tissues (fibrous tissue (FT), fibro-fatty tissue (FFT), necrotic core (NC), and dense calcium (DC)) through processes of border segmentation, feature extraction, feature selection, and classification. Grayscale IVUS images and their corresponding virtual histology images were acquired from 11 patients with known or suspected coronary artery disease using 20 MHz catheter. A total of 102 hybrid textural features including first order statistics (FOS), gray level co occurrence matrix (GLCM), extended gray level run-length matrix (GLRLM), Laws, local binary pattern (LBP), intensity, and discrete wavelet features (DWF) were extracted from IVUS images. To select optimal feature sets, genetic algorithm was implemented. A hybrid ensemble classifier based on histogram and texture information was then used for plaque characterization in this study. The optimal feature set was used as input of this ensemble classifier. After tissue characterization, parameters including sensitivity, specificity, and accuracy were calculated to validate the proposed approach. A ten-fold cross validation approach was used to determine the statistical significance of the proposed method. RESULTS: Our experimental results showed that the proposed method had reliable performance for tissue characterization in IVUS images. The hybrid ensemble classification method outperformed other existing methods by achieving characterization accuracy of 81% for FFT and 75% for NC. In addition, this study showed that Laws features (SSV and SAV) were key indicators for coronary tissue characterization. CONCLUSIONS: The proposed method had high clinical applicability for image-based tissue characterization. PMID- 29157465 TI - DIETOS: A dietary recommender system for chronic diseases monitoring and management. AB - BACKGROUND AND OBJECTIVE: Use of mobile and web-based applications for diet and weight management is currently increasing. However, the impact of known apps on clinical outcomes is not well-characterized so far. Moreover, availability of food recommender systems providing high quality nutritional advices to both healthy and diet-related chronic diseases users is very limited. In addition, the potentiality of nutraceutical properties of typical regional foods for improving app utility has not been exerted to this end. We present DIETOS, a recommender system for the adaptive delivery of nutrition contents to improve the quality of life of both healthy subjects and patients with diet-related chronic diseases. DIETOS provides highly specialized nutritional advices in different health conditions. METHODS: DIETOS was projected to provide users with health profile and individual nutritional recommendation. Health profiling was based on user answers to dynamic real-time medical questionnaires. Furthermore, DIETOS contains catalogs of typical foods from Calabria, a southern Italian region. Several Calabrian foods have been inserted because of their nutraceutical properties widely reported in several quality studies. DIETOS includes some well known methods for user profiling (overlay profiling) and content adaptation (content selection) coming from general purpose adaptive web systems. RESULTS: DIETOS has been validated for usability for both patients and specialists and for assessing the correctness of the profiling and recommendation, by enrolling 20 chronic kidney disease (CKD) patients at the Department of Nephrology and Dialysis, University Hospital, Catanzaro (Italy) and 20 age-matched healthy controls. Recruited subjects were invited to register to DIETOS and answer to medical questions to determine their health status. Based on our results, DIETOS has high specificity and sensitivity, allowing to determine a medical-controlled user's health profile and to perform a fine-grained recommendation that is better adapted to each user health status. The current version of DIETOS, available online at http://www.easyanalysis.it/dietos is not intended to be used by general users, but only for review purpose. CONCLUSIONS: DIETOS is a novel food recommender system for healthy people and individuals affected by diet-related chronic diseases. The proposed system builds a users health profile and, accordingly, provides individualized nutritional recommendations, also with attention to food geographical origin. PMID- 29157466 TI - Toward precise and preventive healthcare with computational tools. PMID- 29157468 TI - Homeopathy and intellectual honesty. PMID- 29157467 TI - Broad-spectrum immunoaffinity cleanup for the determination of aflatoxins B1, B2, G1, G2, M1, M2 in Ophiocordyceps sinensis and its pharmaceutical preparations by ultra performance liquid chromatography tandem mass spectrometry. AB - An ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous determination of aflatoxins B1, B2, G1, G2, M1 and M2 (AFB1, AFB2, AFG1, AFG2, AFM1 and AFM2) in Ophiocordyceps sinensis and its pharmaceutical preparations. A rapid and reliable immunoaffinity column containing a broad-spectrum monoclonal antibody for six aflatoxins was used for sample cleanup. Under the optimized conditions, the home made immunoaffinity column capacity were about 315, 319, 292, 102, 444 and 369ng/mL gel for AFB1, AFB2, AFG1, AFG2, AFM1 and AFM2, respectively. Recoveries for all tested aflatoxins ranged from 79.28% to 103.42% with relative standard deviation less than 8%. The limits of quantitation were in the range of 0.008 0.045MUg/kg. Among 31 real samples analyzed, one sample was contaminated with AFB1, AFB2 and AFM1 at levels of 0.483, 0.068 and 0.104MUg/kg, respectively. The established method is simple, accurate, and can be effectively used to determine the aflatoxins in Ophiocordyceps sinensis and its pharmaceutical preparations. PMID- 29157469 TI - Model validity of randomised placebo-controlled trials of non-individualised homeopathic treatment. AB - BACKGROUND: The comprehensive systematic review of randomised placebo-controlled trials (RCTs) in homeopathy requires examination of a study's model validity of homeopathic treatment (MVHT) as well as its risk of bias (extent of reliable evidence). OBJECTIVE: To appraise MVHT in those RCTs of non-individualised homeopathy that an associated investigation had judged as 'not at high risk of bias'. DESIGN: Systematic review. METHODS: An assessment of MVHT was ascribed to each of 26 eligible RCTs. Another 49 RCTs were ineligible due to their high risk of bias. MAIN OUTCOME MEASURES: MVHT and the prior risk of bias rating per trial were merged to obtain a single overall quality designation ('high', 'moderate', 'low'), based on the GRADE principle of downgrading. RESULTS: The trials were rated as 'acceptable MVHT' (N = 9), 'uncertain MVHT' (N = 10) and 'inadequate MVHT' (N = 7); and, previously, as 'reliable evidence' (N = 3) and 'non-reliable evidence' (N = 23). The 26 trials were designated overall as: 'high quality' (N = 1); 'moderate quality' (N = 18); 'low quality' (N = 7). CONCLUSION: Of the 26 RCTs of non-individualised homeopathy that were judged 'not at high risk of bias', nine have been rated 'acceptable MVHT'. One of those nine studies was designated 'high quality' overall ('acceptable MVHT' and 'reliable evidence'), and is thus currently the only reported RCT that represents best therapeutic practice as well as unbiased evidence in non-individualised homeopathy. As well as minimising risk of bias, new RCTs in this area must aim to maximise MVHT and clarity of reporting. PMID- 29157470 TI - Therapeutic potential of HIV nosode 30c as evaluated in A549 lung cancer cells. AB - OBJECTIVES: To examine if HIV nosode in 30c dilution (HIV 30c) has therapeutic potential against lung cancer cells (A549) as compared to WRL-68 normal cells and to elucidate its possible molecular mechanism of action on DNA replication and apoptosis. METHODS: Effects of HIV 30c were thoroughly tested for its possible anticancer potential on A549 cells (lung cancer); WRL-68 normal liver cells served as control. Three doses, one at LD50 and two below LD-50, were used. Proliferation, migration and senescence assays were made and generation of reactive oxygen species (ROS) studied by routine techniques. The ability of HIV 30c to induce apoptosis in A549 cells and its possible signalling pathway were determined using immunoblots of relevant signal proteins and confocal microscopy, including studies on telomerase reverse transcriptase (TERT) and topoisomerase II (Top II) activities, intimately associated with cell division and DNA replication. RESULTS: HIV 30c prevented cancer cell proliferation and migration, induced pre-mature senescence, enhanced pro-apoptotic signal proteins like p53, bax, cytochrome c, caspase-3 and inhibited anti-apoptotic signal proteins Bcl2, TERT and Top II, changed mitochondrial membrane potential and caused externalization of phosphatidyl serine. Thus, it induced apoptosis as also evidenced from increase in cells with distorted membrane morphology, nuclear condensation, DNA fragmentation, and ROS, typical of apoptosis in progress. CONCLUSION: HIV 30c nosode has therapeutic potential for inducing cytotoxic effects on A549 cells as manifested by changes in nuclear condensation, DNA fragmentation, ROS generation and MMP, and for its inhibitory action on cell proliferation, cell migration, expression of telomerase reverse transcriptase and Top II genes, and increasing expression of pro-apoptotic genes. PMID- 29157471 TI - Case reports on integrated management of tubercular disease. AB - BACKGROUND: Host immunity plays an important role in prevention of disease as is evident by the increased incidence of Tuberculosis (TB) in immuno-compromised population of HIV infected, diabetes inflicted, immune-suppressant therapy and elderly people. Rising incidence of antibiotic resistance has led to resurgence of TB of epidemic proportions. Integrated treatment with add on homeopathy in addition to anti-tuberculosis treatment (ATT) appears to improve outcome in TB. The intervention has been integrated treatment with homeopathy regime, which is using a patient specific, disease specific and supportive medicine simultaneously, all individualized for the patient and the disease. CASES: CASE 1: Pott's spine with paravertebral abscess, not responding to ATT. Addition of homeopathy led to fall in temperature, improved appetite, increase in weight and reduction of abscess. CASE 2: Recurrent sub-acute intestinal obstruction. The patient could not tolerate ATT but responded to homeopathy by reduction of abdominal pain and distension, vomiting, loose stools and queasiness. CASE 3: Pulmonary TB, treated with both ATT and homeopathy from beginning, led to rapid recovery and shortened treatment time. CONCLUSION: The addition of homeopathy to ATT is patient friendly, cost effective and appears to reduces the duration of treatment. Its role as immuno-modulatory therapy should be evaluated and explored. PMID- 29157472 TI - Nuclear Magnetic Resonance characterization of traditional homeopathically manufactured copper (Cuprum metallicum) and plant (Gelsemium sempervirens) medicines and controls. AB - BACKGROUND: NMR proton relaxation is sensitive to the dynamics of the water molecule H2O, through the interaction of the spin of the proton (1H) with external magnetic and electromagnetic fields. METHODS: We measured dilution and potentization processes through measurements of 1H spin-lattice T1 and spin-spin T2 relaxation times. In order to interpret the recorded fluctuations in T1- or T2 values, experimental data were linearized by investigating how the area under a fluctuating time = f(dilution) curve (dilution integral or DI) changes with dilution. Two kinds of fitting procedures were considered: chi-square fitting with a goodness-of-fit probability, and least absolute deviations criterion with Pearson's linear correlation coefficient. RESULTS: We showed that fluctuations are not attributable to random noise and/or experimental errors, evidencing a memory effect quantifiable by the slope of the DI = f(dilution) straight line. For all experiments, correlation coefficients were found to lie above 0.9999, against 0.999 for random noise. The discrimination between experimental slopes and slopes associated with random noise data was very good at a five-sigma level of confidence (i.e. probability 3 * 10-7). Discrimination between experimental slopes at a five-sigma level was possible in most cases, with three exceptions: gelsemium aqua pura v gelsemium dilution (four-sigma); copper aqua pura v gelsemium aqua pura (four-sigma) and copper simple dilution v gelsemium simple dilution (three-sigma). All potentized samples show very good discrimination (at least nine-sigma level) against aqua pura, lactose or simple dilution. It was possible to transform the associated relaxation times into a molecular rotational correlation time tauc and an average spin-spin distance d. Our experiments thus point to a considerable slowing down of molecular movements (tauc > 1300 ps or T = 224-225 K) around water molecules up to a distance of 3.7 A, values. It was also possible to rule out other possible mechanisms of relaxation (diffusive motion, 17O-1H relaxation or coupling with the electronic spin, S = 1, of dissolved dioxygen molecules). CONCLUSION: There is clear evidence that homeopathic solutions cannot be considered as pure water as commonly assumed. Instead, we have evidenced a clear memory effect upon dilution/potentization of a substance (water, lactose, copper, gelsemium) reflected by different rotational correlation times and average H?H distances. A possible explanation for such a memory effect may lie in the formation of mesoscopic water structures around nanoparticles and/or nanobubbles mediated by zero-point fluctuations of the vacuum electromagnetic field as suggested by quantum field theories. The existence of an Avogadro's 'wall' for homeopathically-prepared medicines is not supported by our data. Rather it appears that all dilutions have a specific material configuration determined by the potentized substance, also by the chemical nature of the containers, and dissolved gases and the electromagnetic environment. This sensitivity of homeopathically-prepared medicines to electromagnetic fields may be amplified by the highly non-linear processing routinely applied in the preparation of homeopathic medicines. Future work is needed in such directions. The time is now ripe for a demystification of the preparation of homeopathic remedies. PMID- 29157473 TI - A review of machines and devices to potentize homeopathic medicines. AB - BACKGROUND: Potentization, consisting of serial dilution and succussion, is a key step in the manufacture of homeopathic medicines. Originally prescribed as a manual process, several attempts at mechanization have been published, patented and even commercialised in order to remove the human element and introduce reproducibility without drudgery. Various machines have been used over the years to prepare homeopathic medicines. Although these machines follow the same principles, i.e. energetically mixing the medicines and diluting them significantly, their mode of operation is different from each other. METHODS: This review paper surveys the main methods of preparation of homeopathic medicines. The main machines discussed are: Boericke's potentizer, Tyler Kent's instrument, John Alphonse's machine and the fluxion potentizer, which were used in the past, as well as more recent potentizers like arm-and-weight instruments, the K-Tronic potentizer and Quinn's machine. We review the construction and operating principle of each of these machines, along with their advantages and limitations. A scheme for relative performance assessment of these machines is proposed based on the parameters mechanical efficiency, physico-chemical efficiency, turbulence generation, energy dissipation, and accuracy of dilution. RESULTS: Quinn's machine and the arm-and-weight potentizer perform well for generating turbulence due to high impaction forces, while John Alphonse's machine is much more accurate in diluting the homeopathic medicines at every step. CONCLUSIONS: Both the commercial potentizers, Quinn's machine and the K-Tronic potentizer, are completely automated and therefore reduce the manual labour and variation in succussive forces during each step, which may produce uniformity in physico-chemical changes within the resulting homeopathic medicines. PMID- 29157474 TI - Private and institutionalised patients' use of homeopathy in the early nineteenth century. AB - Medicine underwent a major crisis in the 18th century and several approaches, including homeopathy, were formulated to fill the void left by the fall of traditional Galenic medicine. While most of the literature deals with the reasons doctors had to shift to homeopathy, the patients' views became the focus of increasing scholarly attention along the past 20 years. In this article I present and discuss the current knowledge about the socio-demographic characteristics and medical complaints of patients who sought homeopathic care in the early 19th century in both private and institutional settings. The results show that not only patients from the higher and more educated classes sought homeopathic care, but a considerable number of individuals from the middle and lower strata did so too, even though they also had access to conventional hospitals. As to the clinical complaints, the reasons to seek homeopathic care were the typical ones for any general practice or hospital in the period considered. PMID- 29157475 TI - Corrigendum to "Generalisability of prognostic factor research: further analysis of data from the IIPCOS2 study" [Homeopathy 106 (3) (2017) 155-159]. PMID- 29157476 TI - Subhepatic Ectopic Pregnancy: Image-Guided Percutaneous Intervention. PMID- 29157477 TI - Spontaneous Dissection of Superior Mesenteric Artery: Long-Term Outcome of Stent Placement. AB - Stent placement was performed in 10 patients with symptomatic spontaneous dissection of the superior mesenteric artery (SMA). A stent was placed as first line treatment in 7 patients and as second-line treatment in 3 patients in whom conservative treatment had failed. Abdominal pain completely resolved within 2 days after stent placement, and follow-up (median 53 months; range, 11-99 months) CT angiography revealed complete obliteration of the false lumen and good stent patency in 9 patients. One patient showed asymptomatic stent occlusion at 99 month follow-up. Long-term patency of stent placement in patients with symptomatic SMA dissection seems to be acceptable. PMID- 29157478 TI - Treatment of Low-Flow Vascular Malformations of the Extremities Using MR-Guided High Intensity Focused Ultrasound: Preliminary Experience. AB - Five patients with painful vascular malformations of the extremities that were refractory to standard treatment and were confirmed as low-flow malformations on dynamic contrast-enhanced magnetic resonance (MR) imaging were treated with MR imaging-guided high intensity focused ultrasound. Daily maximum numeric rating scale scores for pain improved from 8.4 +/- 1.5 to 1.6 +/- 2.2 (P = .004) at a median follow-up of 9 months (range, 4-36 mo). The size of the vascular malformations decreased on follow-up MR imaging (median enhancing volume, 8.2 mL [0.7-10.1 mL] before treatment; 0 mL [0-2.3 mL] after treatment; P = .018) at a median follow-up of 5 months (range, 3-36 mo). No complications occurred. PMID- 29157479 TI - Selective Arterial Calcium Stimulation with Hepatic Venous Sampling in Patients with Recurrent Endogenous Hyperinsulinemic Hypoglycemia and Metastatic Insulinoma: Evaluation in Five Patients. AB - Selective arterial calcium stimulation (SACST) with hepatic venous sampling was performed in 5 patients (3 female, 2 male; age range, 53-73 y) with recurrent endogenous hyperinsulinemic hypoglycemia caused by metastatic insulinoma between January 2004 and December 2014. The biochemical results of SACST confirmed functional hepatic metastases alone (n = 3), peripancreatic lymph-node and hepatic metastases (n = 1), and occult insulinoma in the pancreatic bed (n = 1), thereby helping to guide management. SACST may be useful to determine the extent of functional metastatic insulinoma, particularly within the liver, and may provide clinicians with additional information to help guide the multidisciplinary management of patients with recurrent endogenous hyperinsulinemic hypoglycemia. PMID- 29157480 TI - Foreign Body in the Infrarenal Inferior Vena Cava: Is It a Filter? PMID- 29157481 TI - Characterizing IR Exposure at US Medical Schools with the Highest Percentage of Enrolled Underrepresented Minority Medical Students. PMID- 29157482 TI - Embolization of the Superior and Inferior Rectal Artery for Chronic Bleeding Caused by Hemorrhoidal Disease: A Case Report. PMID- 29157483 TI - Uterine Artery Embolization and Potassium Chloride Injection for Treatment of Cervical Pregnancy. PMID- 29157484 TI - ? AB - Parathormone (PTH), produced by parathyroid glands, is the main regulator of calcium homeostasis. Hypoparathyroidism (hypoPT), due to decrease of PTH production, is a rare disease. Symptoms are multiple, altering function of several organs and leading to a decrease of quality of life. Acquired etiologies, including thyroidectomy, the main cause of hypoPT, can be distinguished from congenital etiologies, including genetic defects. HypoPT, which is classically treated by supplementation by calcium and active vitamin D, can now be treated by recombinant injection in certain indications as a poor control under classical therapy. Here are summarized current knowledge on etiologies, epidemiology, clinical manifestations and management of hypoPT. PMID- 29157485 TI - ? AB - The 2017 Endocrine Society annual meeting included several communications and debates on the conservative adrenal surgery in bilateral hereditary pheochromocytomas (BHP), bilateral adrenal macronodular hyperplasia (BAMH) and primary hyperaldosteronism (PHA). The general principle is to preserve a part of the adrenal cortex to prevent the occurrence of a definitive adrenal insufficiency. In BHP, cortical sparing surgery allows more than 50% of patients to maintain normal corticotropic function at 10 years with a low recurrence rate (~ 10%). Since the adrenal medulla cannot be removed entirely, recurrence seems inevitable and long-term follow-up is essential. Individual risk of malignancy must be taken into account. In BAMH responsible for Cushing syndrome, unilateral adrenalectomy induces a normalization of urinary free cortisol in 92 to 100% of cases and even corticotropic insufficiency in 40 to 100% of cases. This is most often transient. Late recurrences of Cushing's syndrome may occur in 13 to 60% of cases. Prolonged patient monitoring is therefore essential. In PAH with lateralized aldosterone production, minimally invasive partial adrenal surgery, which consists of removing only the adrenal adenoma visualized at TDM, allows an improvement blood pressure in about 94% of patients. However, failure or recurrence may occur. Its place therefore remains marginal in the treatment of the lateralized PAHs. PMID- 29157486 TI - ? AB - Congenital adrenal hyperplasia is an autosomal recessive disease due to functional abnormalities of adrenal steroid enzymes. The most common form of the disease is due to a 21-hydroxylase deficiency. The classical forms (most severe) are characterized by a deficiency in cortisol and sometimes in aldosterone, which may compromise the vital prognosis of neonates, and by an increase in androgen synthesis, leading to the virilization of girls' external genitalia at birth, followed by clinical signs of hyperandrogenism during childhood and adolescence. Neonatal screening has improved management and reduced morbidity and mortality in the neonatal period, but its performance could be broadly optimised by adjusting the assay techniques or the biomarkers used. The genetic diagnosis is difficult owing to the large genetic heterogeneity of the 6p21.3 region, which contains the CYP21A2 gene, especially with respect to the use of new-generation techniques of sequencing. Prenatal diagnosis is now possible as early as 6 weeks of gestation, but prenatal treatment remains controversial, awaiting results from prospective cohorts evaluating its long-term impact. Since conventional therapies have limitations, new therapies are currently being developed to allow better control of androgen synthesis and a substitutive treatment that respects the physiological rhythm of cortisol secretion, which would limit the development of long-term complications. PMID- 29157487 TI - ? AB - The endocrine and exocrine functions of the gonads are controlled by the gonadotrope axis, whose master regulator is the hypothalamic decapeptide GnRH. The Kisspeptin/Neurokinin B (Kp/NkB) neuronendocrine system is the main physiologic regulator of GnRH neurons. The Kp/NkB system is currently considered the key mediator for the hypothalamic negative feedback exerted by sex steroids and prolactin, as well as by various metabolic signals. Intrinsic alterations or regulatory abnormalities of Kp/NkB system lead to various gonadotrope axis puberty and fertility dysfunctions. Molecular inactivations of Kp/NkB system actors are associated with some forms of congenital hypogonadotropic hypogonadism without anosmia. The Kp/NkB System is also involved in a few forms of precocious puberty. Finally, the Kp/NKB system is also implicated in gonadotrope axis alterations leading to functional hypothalamic amenorrhea or hyperprolactinemia. NkB is particularly and directly involved in vasomotor menopausal hot flushes mechanism. Various Kp/NkB agonist/antagonist compounds have been developed during the last ten years, and are currently being evaluated in humans. These molecules have potential applications not only in rare genetic diseases with Kp/NkB alterations, but also in various gonadotrope axis-related diseases or in vitro fertilization. The administration of NkB antagonists in menopausal women represents a real therapeutic advance because of their impressive effect in controlling vasomotor menopausal hot flushes. PMID- 29157488 TI - ? AB - Behaviour may be influenced by pituitary hormones or treatments. Dopamine agonist (DA) indicated in prolactinomas treatment can cause side effects, and especially impulse control disorders. In the context of prolactinomas treatment, impulse control disorders (ICD) have been reported like gambling, compulsive shopping, but mostly hypersexuality. These ICD can occur with low AD doses, and seem to be independent of type of molecule and psychiatric medical history. The main pathophysiologic hypothesis is a dysregulation of dopaminergic pathway involved in reward system. Given the possible devastating social impact of these ICD, they have to be screened in patients treated with DA. Our social behaviour can also be impacted by oxytocin. This hormone secreted on physiologic state at posterior pituitary, but also by others areas of brain and brainstem, has an impact on attachment in pair partners and in parent-child relationship, but also in empathy behaviour. Oxytocin affects as well eating behaviour with an anorexigenic impact. Studies on small populations assessed the relevance of an oxytocin treatment in several endocrine and nutritional pathologies like post-surgery craniopharyngioma, panhypopituitarism and obesity. Despite promising results, several pitfalls prevent yet the oxytocin use in clinical practice. PMID- 29157489 TI - NMR-based pharmacometabonomics: A new paradigm for personalised or precision medicine. AB - Metabolic profiling by NMR spectroscopy or hyphenated mass spectrometry, known as metabonomics or metabolomics, is an important tool for systems-based approaches in biology and medicine. The experiments are typically done in a diagnostic fashion where changes in metabolite profiles are interpreted as a consequence of an intervention or event; be that a change in diet, the administration of a drug, physical exertion or the onset of a disease. By contrast, pharmacometabonomics takes a prognostic approach to metabolic profiling, in order to predict the effects of drug dosing before it occurs. Differences in pre-dose metabolite profiles between groups of subjects are used to predict post-dose differences in response to drug administration. Thus the paradigm is inverted and pharmacometabonomics is the metabolic equivalent of pharmacogenomics. Although the field is still in its infancy, it is expected that pharmacometabonomics, alongside pharmacogenomics, will assist with the delivery of personalised or precision medicine to patients, which is a critical goal of 21st century healthcare. PMID- 29157490 TI - Dynamic nuclear polarization for sensitivity enhancement in modern solid-state NMR. AB - The field of dynamic nuclear polarization has undergone tremendous developments and diversification since its inception more than 6 decades ago. In this review we provide an in-depth overview of the relevant topics involved in DNP-enhanced MAS NMR spectroscopy. This includes the theoretical description of DNP mechanisms as well as of the polarization transfer pathways that can lead to a uniform or selective spreading of polarization between nuclear spins. Furthermore, we cover historical and state-of-the art aspects of dedicated instrumentation, polarizing agents, and optimization techniques for efficient MAS DNP. Finally, we present an extensive overview on applications in the fields of structural biology and materials science, which underlines that MAS DNP has moved far beyond the proof of-concept stage and has become an important tool for research in these fields. PMID- 29157491 TI - Monitoring protein folding through high pressure NMR spectroscopy. AB - High-pressure is a well-known perturbation method used to destabilize globular proteins. It is perfectly reversible, which is essential for a proper thermodynamic characterization of a protein equilibrium. In contrast to other perturbation methods such as heat or chemical denaturant that destabilize protein structures uniformly, pressure exerts local effects on regions or domains of a protein containing internal cavities. When combined with NMR spectroscopy, hydrostatic pressure offers the possibility to monitor at a residue level the structural transitions occurring upon unfolding and to determine the kinetic properties of the process. High-pressure NMR experiments can now be routinely performed, owing to the recent development of commercially available high pressure sample cells. This review summarizes recent advances and some future directions of high-pressure NMR techniques for the characterization at atomic resolution of the energy landscape of protein folding. PMID- 29157493 TI - Atomic resolution conformational dynamics of intrinsically disordered proteins from NMR spin relaxation. AB - Nuclear magnetic resonance (NMR) spectroscopy is one of the most powerful experimental approaches for investigating the conformational behaviour of intrinsically disordered proteins (IDPs). IDPs represent a significant fraction of all proteomes, and, despite their importance for understanding fundamental biological processes, the molecular basis of their activity still remains largely unknown. The functional mechanisms exploited by IDPs in their interactions with other biomolecules are defined by their intrinsic dynamic modes and associated timescales, justifying the considerable interest over recent years in the development of technologies adapted to measure and describe this behaviour. NMR spin relaxation delivers information-rich, site-specific data reporting on conformational fluctuations occurring throughout the molecule. Here we review recent progress in the use of 15N relaxation to identify local backbone dynamics and long-range chain-like motions in unfolded proteins. PMID- 29157494 TI - Plant metabolism as studied by NMR spectroscopy. AB - The study of plant metabolism impacts a broad range of domains such as plant cultural practices, plant breeding, human or animal nutrition, phytochemistry and green biotechnologies. Plant metabolites are extremely diverse in terms of structure or compound families as well as concentrations. This review attempts to illustrate how NMR spectroscopy, with its broad variety of experimental approaches, has contributed widely to the study of plant primary or specialized metabolism in very diverse ways. The review presents recent developments of one dimensional and multi-dimensional NMR methods to study various aspects of plant metabolism. Through recent examples, it highlights how NMR has proved to be an invaluable tool for the global characterization of sample composition within metabolomic studies, and shows some examples of use for targeted phytochemistry, with a special focus on compound identification and quantitation. In such cases, NMR approaches are often used to provide snapshots of the plant sample composition. The review also covers dynamic aspects of metabolism, with a description of NMR techniques to measure metabolic fluxes - in most cases after stable isotope labelling. It is mainly intended for NMR specialists who would be interested to learn more about the potential of their favourite technique in plant sciences and about specific details of NMR approaches in this field. Therefore, as a practical guide, a paragraph on the specific precautions that should be taken for sample preparation is also included. In addition, since the quality of NMR metabolic studies is highly dependent on approaches to data processing and data sharing, a specific part is dedicated to these aspects. The review concludes with perspectives on the emerging methods that could change significantly the role of NMR in the field of plant metabolism by boosting its sensitivity. The review is illustrated throughout with examples of studies selected to represent diverse applications of liquid-state or HR-MAS NMR. PMID- 29157492 TI - Biomolecular MRI reporters: Evolution of new mechanisms. AB - Magnetic resonance imaging (MRI) is a powerful technique for observing the function of specific cells and molecules inside living organisms. However, compared to optical microscopy, in which fluorescent protein reporters are available to visualize hundreds of cellular functions ranging from gene expression and chemical signaling to biomechanics, to date relatively few such reporters are available for MRI. Efforts to develop MRI-detectable biomolecules have mainly focused on proteins transporting paramagnetic metals for T1 and T2 relaxation enhancement or containing large numbers of exchangeable protons for chemical exchange saturation transfer. While these pioneering developments established several key uses of biomolecular MRI, such as imaging of gene expression and functional biosensing, they also revealed that low molecular sensitivity poses a major challenge for broader adoption in biology and medicine. Recently, new classes of biomolecular reporters have been developed based on alternative contrast mechanisms, including enhancement of spin diffusivity, interactions with hyperpolarized nuclei, and modulation of blood flow. These novel reporters promise to improve sensitivity and enable new forms of multiplexed and functional imaging. PMID- 29157495 TI - Calculation of 15N NMR chemical shifts: Recent advances and perspectives. AB - Recent advances in computation of 15N NMR chemical shifts are reviewed, concentrating mainly on practical aspects of computational protocols and accuracy factors. The review includes the discussion of the level of theory, the choice of density functionals and basis sets together with taking into account solvent effects, rovibrational corrections and relativistic effects. Computational aspects of 15N NMR are illustrated for the series of neutral and protonated open chain nitrogen-containing compounds and nitrogen heterocycles, coordination and intermolecular complexes. PMID- 29157496 TI - Medical Considerations in Children and Adolescents with Eating Disorders. AB - Eating disorders are a group of psychiatric disorders with potentially fatal medical complications. Early integrated care including the family as well as pediatric medicine, nutrition, psychology and psychiatry is critical for improving prognosis and limiting negative outcomes. Mental health services are a critical component of treatment; timely weight restoration maximizes efficacy. Despite being relatively common, there are many misperceptions about eating disorders, their severity, and the associated morbidity and mortality. Opportunities exist within the medical and psychiatric communities for a better understanding of the complexity of diagnosing and treating patients with eating disorders. PMID- 29157497 TI - Everywhere and Nowhere: Grief in Child and Adolescent Psychiatry and Pediatric Clinical Populations. AB - Grief is ubiquitous in the experience of children and adolescents with illness but not always recognized or named, and as a result grief is not always treated effectively by child/adolescent psychiatrists or pediatricians. Grief can be misinterpreted or treated as stress, anxiety, depression, adolescent moodiness, or behavioral concerns. Pediatricians and child/adolescent psychiatrists are often insufficiently educated on the topic of grief. PMID- 29157498 TI - The Medical Transition from Pediatric to Adult-Oriented Care: Considerations for Child and Adolescent Psychiatrists. AB - More adolescents and young adults are surviving previously fatal childhood illness and need support to transition from pediatric care to adult-oriented care. There are many barriers, but guidelines and tools assist providers with emphasis on gradually addressing transition with patients and families. Child and adolescent psychiatrists should be particularly attuned to the needs of adolescents with previously identified mental illness who are at high risk of falling out of regular care during transition. Providers are also uniquely suited to address the needs of adolescents and young adults with intellectual and developmental disabilities. PMID- 29157499 TI - Functional Abdominal Pain and Related Syndromes. AB - Functional gastrointestinal disorders are very common. They result from dysfunctional interaction in the brain-gut axis. Although the nature is benign, symptoms may be debilitating. The etiology is multifactorial; therefore, the diagnosis should be approached in a bio-psychosocial model. There are no biomarkers to characterize these conditions, but a solid understanding of the pathophysiology allows providers to present these disorders as a positive clinical diagnosis, rather than a diagnosis of exclusion. Effective management entails close collaboration between the medical and mental health providers. PMID- 29157500 TI - Unraveling Diagnostic Uncertainty Surrounding Lyme Disease in Children with Neuropsychiatric Illness. AB - Lyme disease is endemic in parts of the United States, including New England, the Atlantic seaboard, and Great Lakes region. The presentation has various manifestations, many of which can mimic psychiatric diseases in children. Distinguishing manifestations of Lyme disease from those of psychiatric illnesses is complicated by inexact diagnostic tests and misuse of these tests when they are not clinically indicated. This article aims to describe manifestations of Lyme disease in children with an emphasis on Lyme neuroborreliosis. Clinical scenarios will be presented and discussed. Finally, recommendations for clinical psychiatrists who encounter children with possible Lyme disease are presented. PMID- 29157501 TI - Evaluation and Management of Autoimmune Encephalitis: A Clinical Overview for the Practicing Child Psychiatrist. AB - Medical conditions that present with psychiatric symptoms are becoming increasingly well-recognized in response to the emergence of the field of neuroimmunology. As the availability of testing for novel antineuronal antibodies has increased, so too has the clinical awareness of this diagnostic spectrum. Psychiatrists may have little exposure to this area of expertise, yet may be called on to assist in the diagnosis and treatment of patients with complex neuropsychiatric syndromes secondary to autoimmune encephalitis. This article summarizes the evaluation and management of patients with autoimmune encephalitis and describes emerging patterns in phenotype recognition. PMID- 29157502 TI - Pediatric Psychogenic Nonepileptic Seizures: A Concise Review. AB - Psychogenic nonepileptic seizures is a complicated biopsychosocial disorder with significant morbidity and high cost in children's social, emotional, family, and academic functioning as well as health care service utilization. Misdiagnosis and diagnostic delay, resulting from both lack of access to approved standards for diagnosing and service providers comfortable with diagnosing and treating this disorder, impact prognosis. Treatment in close proximity to symptom onset is thought to provide the best chance for remission. PMID- 29157503 TI - A Review of the Prevention and Medical Management of Childhood Obesity. AB - Prevention and management of childhood obesity remains a public health priority and necessitates an integrated chronic care approach. Obesity prevention efforts should focus on healthy family-based lifestyle modifications. The United States Prevention Services Task Force recommends children older than age 6 of years be screened for obesity and, if clinically indicated, be referred for moderate to high intensity comprehensive behavioral interventions. Childhood obesity and its comorbidities affect most medical specialties. A shared understanding of prevention strategies, lifestyle recommendations, screening guidelines for comorbidities, and stages of treatment will allow for more integrated and collaborative care. PMID- 29157504 TI - Domestic Minor Sex Trafficking. AB - Commercial sexual exploitation of children and child sex trafficking is a major public health issue globally. Domestic minor sex trafficking has become increasingly recognized within the United States. Sexually exploited minors are commonly identified as having psychosocial risk factors, including histories of abuse or neglect, running away, substance use or abuse, and involvement with child protective services. Youth also suffer a variety of physical and mental health consequences, including posttraumatic stress disorder, depression, anxiety, and suicidality. Child psychiatrists and other medical providers have the opportunity to identify, interact, and intervene on behalf of involved and at risk youth. PMID- 29157506 TI - Co-occurring Medical Illnesses in Child and Adolescent Psychiatry: Updates and Treatment Considerations. PMID- 29157505 TI - Sports-Related Concussion: Acute Management and Chronic Postconcussive Issues. AB - Sports-related concussion (SRC) is a common problem in youth sports. Concussion may occur after a forceful hit to the body or head, resulting in transient neuropathological changes that spontaneously resolve with relative rest and activity modification in most patients. Most SRCs are effectively managed by primary care physicians and sports medicine specialists. In some cases, symptoms may persist and the child and adolescent psychiatrist may be consulted. This article reviews important background information regarding SRC and highlights a variety of pharmacologic and nonpharmacologic treatment options that consultant psychiatrists should know. PMID- 29157507 TI - Public attitudes towards involuntary admission and treatment by mental health services in Norway. AB - PURPOSE: The role of compulsory treatment of serious mental disorders has been the topic of ongoing public debate involving among others mental health professionals, service providers, service user advocates, relatives of service users, media commentators and politicians. However, relatively little is known about general public attitudes towards involuntary admission and compulsory treatment of people with various mental disorders. This article examines the attitudes in a representative sample of Norway's population towards the use of involuntary admission and treatment, and under which circumstances does the general public consider compulsory treatment to be justified in the Norwegian mental health care services. METHOD: Data were collected from a representative sample of the population in Norway aged 18 and older. The sample was stratified for gender, geographical region and age distribution (n=2001). The survey was performed in the months of May 2009 (n=1000) and May 2011 (n=1001), using Computer Assisted Telephone Interviews (CATI) by an independent polling company. All respondents were provided a general definition of coercive intervention before the interview was conducted. ANALYSIS: Univariate descriptions and bivariate analyses were performed by means of cross-tabulation, analysis of variance (one-way ANOVA) and comparing of group of means. Cohen's d was used as the measure for effect size. RESULTS: Between 87% and 97% of those surveyed expressed strong or partial agreement with the use of involuntary admissions or compulsory treatment related to specified cases and situations. The majority of interviewees (56%) expressed the opinion that overall, current levels are acceptable. A further, 34% were of the opinion that current levels are too low, while only 9.9% of respondents supported a reduction in the level of involuntary treatment. Lower levels of education were associated with a more positive attitude towards involuntary admission and treatment. There was stronger support for admission to prevent suicide than the possibility of violence by the mentally ill. CONCLUSION: The Norwegian adult population largely supports current legislation and practices regarding involuntary admission and compulsory treatment in the mental health services. PMID- 29157508 TI - Suicidal ideation while incarcerated: Prevalence and correlates in a large sample of male prisoners in Flanders, Belgium. AB - Prisoners constitute a high-risk group for suicide. As an early stage in the pathway leading to suicide, suicidal ideation represents an important target for prevention, yet research on this topic is scarce in general prison populations. Using a cross-sectional survey design, correlates of suicidal ideation while incarcerated were examined in a sample of 1203 male prisoners, randomly selected from 15 Flemish prisons. Overall, a lifetime history of suicidal ideation and attempts was endorsed by 43.1% and 20.3% of respondents, respectively. Approximately a quarter of all prisoners (23.7%) reported past-year suicidal ideation during their current incarceration, which was significantly associated with both imported vulnerabilities (psychiatric diagnoses and a history of attempted suicide) and variables unique to the prison experience (lack of working activity, exposure to suicidal behaviour by peers, and low levels of perceived autonomy, safety and social support) in the multivariate regression analysis. A first-ever period of imprisonment and a shorter length of incarceration (<=12months) were also associated with increased odds of recent suicidal ideation. Collectively, the current findings underscore the importance of both vulnerability factors and prison-specific stressors for suicidal ideation in prisoners, and hence the need for a multi-faceted approach to suicide prevention in custodial settings. In addition to the provision of appropriate mental health care, environmental interventions that target modifiable aspects of the prison regime could provide a substantial buffer for the onset and persistence of suicidal ideation in this at-risk population. PMID- 29157509 TI - Psychometric properties of Basic Empathy Scale among female juvenile delinquents and school youths. AB - Research on empathy often distinguishes between affective and cognitive empathy, but there is limited knowledge regarding the application or measurement of these two dimensions of empathy among female youth, especially forensic samples of female youth. The main aim of the present study was to examine the psychometric properties of the Basic Empathy Scale (BES) among a Portuguese sample of female youths (N=377), composed of incarcerated female juvenile offenders (n=103) and school youths (n=274). The two-factor structure of the BES obtained a good fit among the school sample, but the fit among the forensic sample was poor. Both samples demonstrated adequate psychometric properties in terms of Cronbach's alpha, omega coefficient, mean inter-item correlations, corrected item-total correlation range, and criterion validity. However, some caution is advised when using the BES with female youth involved in the juvenile justice system, particularly with incarcerated female youth. PMID- 29157510 TI - Euthanasia requests in a Canadian psychiatric emergency room: A case series: Part 1 of the McGill University euthanasia in psychiatry case series. AB - Euthanasia was decriminalized in Quebec in December 2015, and Canada-wide in June 2016. Both the Provincial and Federal legislation have limited the right to medical assistance in dying (MAID) to end-of-life cases; which makes MAID inaccessible to most patients solely suffering from psychiatric illness. While some end-stage anorexia nervosa or elderly patients may meet the end-of-life criterion because of their medical comorbidities or their age (Kelly et al., 2003), repeated suicide attempts or psychotic disorganization would not qualify since they would not be seen as elements of an illness leading to a foreseeable "natural death" (Canada, 2016). This is in contradiction to other jurisdictions, such as Belgium and the Netherlands as well as the eligibility criteria stated in the Supreme Court of Canada's decision in Carter v. Canada (Supreme Court of Canada, 2015). Here we analyze three cases of patients who presented to a psychiatric emergency department and requested MAID for psychiatric reasons. While none of the patients were eligible for MAID under Canadian law, we find that their demographics match closely that of patients granted MAID for psychiatric reasons in jurisdictions where that practice is allowed. Based on these cases, we comment on potentially negative consequences that may come from decriminalizing MAID for psychiatric reasons (such as an increased assessment burden on ED staff) and potentially positive consequences (such as encouraging suffering patients who had not consulted to seek care). While it is by no means our intention to take a political or moral stand on this important issue, or to conclusively weigh the negatives and positives of allowing MAID for psychiatric reasons, we do stress the importance of an active voice for psychiatry in this ongoing public debate. PMID- 29157511 TI - Subtypes of homicide offenders based on psychopathic traits. AB - The aim of the present study was to explore the subtypes of offenders based on psychopathic traits in a sample of 127 adult homicide offenders (n=40.3% convicted of murder, n=32.6% convicted of aggravated murder, n=27.1% convicted of attempted murder). A two-step cluster analysis of the four factors of psychopathy yielded three clusters, which were then compared on the general dimensions of personality defined by the HEXACO model, intelligence, sadism and psychopathology variables conceptualized by the MMPI-202. Cluster 1 was characterized by moderate scores on psychopathy factors, Agreeableness and aggressiveness. Cluster 2 was a psychopathic-like group with the highest scores on psychopathy factors, sadism, aggressiveness and paranoia, and with the lowest scores on Emotionality and Agreeableness. Cluster 3 was a non-psychopathic group with the lowest scores on psychopathy factors and aggressiveness, and with the highest scores on Agreeableness and Honesty-Humility. There were no significant differences between the clusters on intelligence, Openness to experience, Extraversion, Conscientiousness, and a number of psychopathological variables, including depression and anxiety. Present findings did not provide support for the distinction between primary and secondary psychopathy. The current study further contributes to the person-oriented research of psychopathy by emphasizing the differences between the individuals with high, moderate and low psychopathic traits. PMID- 29157512 TI - The closing of forensic psychiatric hospitals in Italy: Determinants, current status and future perspectives. A scoping review. AB - INTRODUCTION: Italy is the only country in the world to have closed forensic psychiatric hospitals and converted to fully-residential services. The international interest around this reform has not been matched by research. This scoping review aims to report the determinants of the reform, the most updated information on how the system operates, its benefits and its challenges. We further aim to discuss the implications for policy, research and practice. METHODS: 1. Selection of relevant sources through electronic search on four databases, Google, relevant printed materials and personal communication with practitioners currently working in REMS. 2. Study quality monitoring. 3. Data extraction onto NVivo 4. Data synthesis through content analysis. RESULTS: 43 papers were selected for inclusion in our review. Two main themes were identified: 1. Historical chronology of the closure of forensic psychiatric hospitals; 2. The current model of residential forensic psychiatric care. CONCLUSIONS: The closing down of Italian forensic psychiatric hospitals represented a fundamental step for human rights. Further work is required to improve the current service, including potential reforming of the penal code, improved referral/admission processes and consistent monitoring to reduce service inequality across regions. Further research is crucial to test the effectiveness of the Italian model of care against traditional ones. PMID- 29157513 TI - Antipsychotic augmentation for major depressive disorder: A review of clinical practice guidelines. AB - Clinical Practice Guidelines (CPGs) are seen as the gold standard of evidence based care. Because of their influence, these guidelines can have profound legal and economic effects. Despite their proliferation and influence, the trustworthiness and quality of guidelines have been seriously questioned and they have been implicated as drivers of overtreatment. In the U.S, augmentation with second generation antipsychotics (SGAs) is becoming an increasingly common strategy for treating major depressive disorder (MDD) when initial antidepressant treatment does not result in remission of symptoms. However, there is debate about the evidence for augmentation and whether this strategy is a form of overtreatment. We conducted a systematic search to identify treatment guidelines for MDD. Fourteen international guidelines met inclusion criteria and we reviewed them to determine: 1) if augmentation with SGAs was recommended for patients who did not respond to antidepressant medication; 2) what evidence was cited for the recommendation for or against augmentation; 3) the extent to which the guidelines addressed risk/benefit concerns when making their recommendations. There was significant variation among the CPGs regarding the recommendation to augment with antipsychotic medication for Major Depressive Disorder. Seven guidelines explicitly recommended augmentation with antipsychotics; 1 guideline reviewed the evidence but neither recommended for nor against; 1 guideline did not make a clear recommendation; 2 guidelines explicitly recommended against augmentation; and 3 guidelines did not address augmentation with antipsychotics as a potential treatment strategy. There was wide variation in terms of attention to risk/benefit issues and to the conditions under which augmentation should be considered. The results are discussed in terms of the implications for risk management and informed consent practices. PMID- 29157514 TI - A psycho-legal perspective on sexual offending in individuals with autism Spectrum disorder. AB - It is important to consider whether there are innate vulnerabilities that increase the risk of an individual with an autistic spectrum disorder (ASD), predominantly those defendants with a diagnosis of Asperger's Syndrome, being charged and convicted of a sexual offence. The significance of such can be readily seen in recent English case law, with judgments on appeal finding convictions unsafe where there have been a number of failings in the Judge's summing up. In this article, we will consider the gravity of Judges omitting to highlight a defendant's diagnosis of autism spectrum disorder and the necessity of detailed explanations to jury members regarding the condition and its effect upon thoughts and behaviour. Consideration will be specifically given to the necessity to prove sexual motivation in such offences and the judicial direction required in relation to whether the appellant's actions had been sexually motivated. Recognition of the social impairments inherent in ASDs are vital to this work and we shall consider whether the difficulty with the capacity to develop appropriate, consenting sexual relationships as a result of impaired social cognition may be one of the factors which increases the risk of sexual offending in individuals with ASD (Higgs & Carter, 2015). PMID- 29157515 TI - Legal capacity of persons with disabilities in Ethiopia: The need to reform existing legal frameworks. AB - The Convention on the Rights of Persons with Disabilities (CRPD) prohibited deprivation legal capacity of persons with disability based on assessment of mental capacity. The assertion is that, persons with disabilities shall exercise their legal capacity in all aspects of life without any restrictions that are based on mental incapacity (such as, unsoundness of mind, deficit in mental capacity, dotage, etc. This approach signifies a shift from substituted decision making, where another person act on behalf of persons with mental disabilities, to supported decision making where the person with mental disability is assisted in decision making. The rationale for the move lies on the recognition that the right to legal capacity embodies the inherent meaning of what it meant to be human. Without legal capacity a person cannot exercise all other rights and entitlements. Accordingly, States parties to CRPD are required to reform domestic legislations that are based on substituted decision making model and recognize full legal capacity of persons with disabilities in line with supported decision making model. As a Sate party to CRPD, Ethiopia assumed the same obligation. Nonetheless, in its initial report to the Committee on CRPD, the country denies existence of legislation that restricts legal capacity on the grounds of mental incapacity. This research found out that there are restrictions imposed on legal capacity of persons with disabilities on the basis of mental incapacity/disability. The research analyzed the approach employed to restrict legal capacity under the existing legal frameworks of Ethiopia vis-a-vis supported decision-making regime under CRPD. The research is doctrinal and, as such, limited to content analysis of general and specific legal capacity laws of the country (such as, marriage, divorce, will, work and employment, political participation, access to justice and others). PMID- 29157516 TI - Anatomy of the Tricuspid Valve, Pathophysiology of Functional Tricuspid Regurgitation, and Implications for Percutaneous Therapies. AB - The tricuspid valve is a complex dynamic apparatus made up of many different closely linked structures: the annulus, the three leaflets, the chordae, the papillary muscles and the right ventricle. Other nearby structures, such as the coronary sinus ostium, the conduction system, the membranous septum, and the right coronary artery must be taken into account when dealing with the tricuspid. Annulus dilation and leaflet tethering due to right ventricular remodeling are the 2 major mechanisms responsible for most tricuspid regurgitation cases. Precise knowledge of tricuspid anatomy and function, as well as careful preoperative planning, is fundamental for successful transcatheter tricuspid procedures. PMID- 29157517 TI - Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with several risk factors but is most frequently seen as a rare consequence of an acute pulmonary embolism. Surgical pulmonary thromboendarterectomy (PTE) is potentially curative for CTEPH with the best outcomes seen for the treatment of primarily proximal, accessible lobar or segmental disease. For surgically inoperable patients, percutaneous balloon pulmonary angioplasty (BPA) is feasible and has good short- to mid-term efficacy outcomes. This review focuses on the technique and outcomes associated with BPA which has emerged as a new therapeutic option for CTEPH. PMID- 29157518 TI - Mechanical Circulatory Support for High-Risk Pulmonary Embolism. AB - Temporary mechanical circulatory support (MCS) devices have a role in treating high-risk patients with pulmonary embolism with cardiogenic shock. Mechanical circulatory device selection should be made based on center experience and device specific features. All current devices are effective in decreasing right arterial pressure and providing circulatory support of 4 to 5 L/min. The pulmonary artery pulsatility index may prove to be an unreliable method to assess right ventricular function. Careful clinical evaluation on an individual patient basis should determine the need for MCS. PMID- 29157519 TI - Inferior Vena Cava Filters: Current and Future Concepts. AB - The inferior vena cava filter clinical environment is notable for the degree of controversy, uncertainty, and fear associated with these devices by both physicians and the public. This article reviews some of the more important current issues with these devices as well as emerging and future trends. PMID- 29157520 TI - Interventional Imaging of the Tricuspid Valve. AB - Nowadays, reasonable transcatheter tricuspid valve (TV) interventions are emerging as therapeutic options for functional tricuspid regurgitation (TR). The preprocedural planning is based on a multimodality imaging approach, which aims to (1) define the mechanisms of TR, (2) characterize TV morphology, (3) analyze the anatomic relationship between the TV apparatus and other structures, and (4) determine the size of the tricuspid annulus and vena cavae. Intraprocedural guidance is based mainly on transesophageal echocardiography (seldom transthoracic) and fluoroscopy, with the recent introduction of fusion imaging. PMID- 29157521 TI - Percutaneous Tricuspid Annuloplasty. AB - The tricuspid valve was ignored for a long time. The prevalence of severe tricuspid regurgitation is not negligible, however, and is associated with poor prognosis. In cases of primary tricuspid regurgitation, surgical options are limited by a high risk of mortality and morbidity. New percutaneous approaches are becoming available to meet this consistent unmet clinical need. This review presents the current available devices that reproduce both the complete and uncomplete surgical annuloplasty techniques. PMID- 29157522 TI - Tricuspid Clip: Step-by-Step and Clinical Data. AB - Symptomatic severe tricuspid regurgitation (TR), if untreated, carries a dismal prognosis. These patients are at very high risk for surgical repair or replacement and transcatheter options to treat TR are emerging. More than 300 transcatheter tricuspid repairs with the MitraClip system have been performed worldwide with promising results. The TriClip system, with the MitraClip NT delivered via a dedicated tricuspid steerable guide catheter, is currently under investigation. This article describes the step-by-step technique on using the MitraClip system to perform transcatheter tricuspid repair using echocardiographic and fluoroscopic guidance. The latest data on worldwide experience with tricuspid clipping are also discussed. PMID- 29157523 TI - The FORMA Repair System. AB - Significant tricuspid valve disease affects many patients with left-sided heart disease. Concomitant tricuspid valve surgery for at least moderate tricuspid insufficiency is undertaken far less frequently at the time of left-sided heart surgery. The burden of residual tricuspid disease in high-surgical-risk patients has spawned the evolution of several percutaneous treatment options. A dedicated percutaneously delivered tricuspid Spacer device (FORMA Repair System) has been developed and trialed in humans. This system anchors a Spacer to reduce the regurgitant orifice area, thereby providing a surface for valve leaflet coaptation. This article provides an overview of the FORMA Repair System to date. PMID- 29157524 TI - Caval Valve Implantation. AB - Recently, transcatheter therapy has expanded the treatment options for patients with heart valve disease. With the growing understanding of tricuspid regurgitation and its natural history, it becomes increasingly obvious that this patient population is a heterogeneous cohort presenting for treatment in different stages of a continuous disease process. It is still unclear which interventional approach will result in functional and clinical success and in which subtype of patient population. This article reviews the pathophysiologic background and current evidence for caval valve implantation and examines the potential role of this approach for the treatment of severe tricuspid regurgitation. PMID- 29157525 TI - Transcatheter Tricuspid Valve Replacement. AB - Tricuspid regurgitation (TR) is a common entity, most commonly functional in nature due to right-sided dysfunction in the setting of concomitant cardiac disease or pulmonary hypertension. Patients living with TR often experience numerous limitations as a result of right-sided heart failure symptoms, including functional decline, frequent hospitalizations, liver failure, and kidney failure. Furthermore, patients with significant TR demonstrate worse survival, although a cause-and-effect relationship has not been proven. For patients with a degenerated surgical bioprosthesis or valve ring, placement of a transcatheter aortic valve prosthesis in a valve-in-valve or valve-in-ring fashion may provide symptomatic benefit. For patients with native valve regurgitation, novel devices for treatment are currently under development. PMID- 29157526 TI - Systemic Thrombolysis for Pulmonary Embolism: Evidence, Patient Selection, and Protocols for Management. AB - Acute pulmonary embolism presents a clinical challenge for optimal risk stratification. Although associated with significant morbidity and mortality at the population level, the spectrum of presentation in an individual patient varies from mild symptoms to cardiac arrest. Treatment options include anticoagulation, systemic thrombolysis, catheter-based interventions, and surgical embolectomy. In this article, an attempt is made to optimally identify patients who, based on available evidence, may benefit from systemic thrombolytic therapy. The clinical efficacy of systemic thrombolysis must be balanced against increased risks of major bleeding and intracranial hemorrhage. PMID- 29157527 TI - Catheter-Directed Therapy for Pulmonary Embolism: Patient Selection and Technical Considerations. AB - Acute pulmonary embolism (PE) is the third most common cause of death among hospitalized patients. Treatment escalation beyond anticoagulation therapy is necessary in patients with cardiogenic shock and may be of benefit in select normotensive patients with right heart strain. Percutaneous catheter-based techniques (catheter-directed mechanical thrombectomy, clot maceration, and/or pharmacologic thrombolysis) as an alternative or adjunct to systemic thrombolysis can rapidly debulk central clot in patients with shock. Catheter-directed thrombolysis, which uses a low-dose intraclot prolonged thrombolytic infusion, is a promising but insufficiently studied therapy for patients presenting with acute intermediate-risk PE. PMID- 29157528 TI - Catheter-Based Embolectomy for Acute Pulmonary Embolism: Devices, Technical Considerations, Risks, and Benefits. AB - A significant number of patients with high-risk pulmonary embolism have contraindications to thrombolytic therapy. Catheter-based therapy may be helpful and consists of a multitude of catheters and techniques, some old and some new. Although there are few data supporting the use of any of these techniques, there has been a recent rise in interest and use of catheter-based pulmonary embolectomy. This text describes the contemporary devices used in pulmonary embolism treatment, discusses their challenges, and proposes some future directions. PMID- 29157529 TI - Transcatheter Tricuspid Valve Intervention: Addressing an Unmet Clinical Need. PMID- 29157530 TI - The Evolving State of Care for Acute Pulmonary Embolism. PMID- 29157531 TI - Survival of the Fittest-Promoting Fitness Throughout the Life Span. PMID- 29157532 TI - Clinical Manifestations and Outcomes of Fluoroquinolone-Related Acute Interstitial Nephritis. AB - OBJECTIVE: To describe the clinical presentation, diagnosis, and outcomes of patients with biopsy-proven acute interstitial nephritis (AIN) related to fluoroquinolone (FQ) therapy. PATIENT AND METHODS: We conducted a retrospective review of biopsy-proven AIN attributed to FQ use at Mayo Clinic's campus in Rochester, Minnesota, from January 1, 1993, through December 31, 2016. Cases were reviewed by a renal pathologist and attributed to FQ use by an expert nephrologist. We also reviewed and summarized all published case reports of biopsy-proven AIN that were attributed to FQ use. RESULTS: We identified 24 patients with FQ-related biopsy-proven AIN at our institution. The most commonly prescribed FQ was ciprofloxacin in 17 patients (71%), and the median antibiotic treatment duration was 7 days (interquartile range [IQR], 5-12 days). The median time from the initiation of FQ to the diagnosis of AIN was 8.5 days (IQR, 3.75 20.75 days). Common clinical manifestations included fever (12; 50%), skin rash (5; 21%), and flank pain (2; 8%), and 9 (38%) had peripheral eosinophilia. However, 4 (17%) of the patients were asymptomatic at the time of diagnosis and AIN was suspected on the basis of routine laboratory monitoring. Most patients (17; 71%) recovered after the discontinuation of antibiotic therapy, and renal function returned to baseline at a median of 20.5 days (IQR, 11.75-27.25 days). Six patients (25%) required temporary hemodialysis, and 14 patients (58%) received corticosteroid therapy. CONCLUSION: The onset of FQ-related AIN can be delayed, and a high index of suspicion is needed by physicians evaluating these patients. Overall outcomes are favorable, with recovery to baseline renal function within 3 weeks of discontinuing the offending drug. PMID- 29157533 TI - Cardiorespiratory Fitness Cutoff Points for Early Detection of Present and Future Cardiovascular Risk in Children: A 2-Year Follow-up Study. AB - OBJECTIVE: To examine the association between cardiorespiratory fitness (CRF) at baseline and cardiovascular disease (CVD) risk in 6- to 10-year-olds (cross sectional) and 2 years later (8- to 12-year-olds [longitudinal]) and whether changes with age in CRF are associated with CVD risk in children aged 8 to 12 years. PATIENTS AND METHODS: Spanish primary schoolchildren (n=236) aged 6 to 10 years participated at baseline. Of the 23 participating primary schools, 22% (n=5) were private schools and 78% (n=18) were public schools. The dropout rate at 2-year follow-up was 9.7% (n=23). The 20-m shuttle run test was used to estimate CRF. The CVD risk score was computed as the mean of 5 CVD risk factor standardized scores: sum of 2 skinfolds, systolic blood pressure, insulin/glucose, triglycerides, and total cholesterol/high-density lipoprotein cholesterol. RESULTS: At baseline, CRF was inversely associated with single CVD risk factors (all P<.05) and CVD risk score at baseline and follow-up (P<.001). Cardiorespiratory fitness cutoff points of 39.0 mL/kg per minute or greater in boys and 37.5 mL/kg per minute or greater in girls are discriminative to identify CVD risk in childhood (area under the curve, >0.85; P<.001) and to predict CVD risk 2 years later (P=.004). Persistent low CRF or the decline of CRF from 6-10 to 8-12 years of age is associated with increased CVD risk at age 8 to 12 years (P<.001). CONCLUSION: During childhood, CRF is a strong predictor of CVD risk and should be monitored to identify children with potential CVD risk. PMID- 29157534 TI - Moderate to High Levels of Cardiorespiratory Fitness Attenuate the Effects of Triglyceride to High-Density Lipoprotein Cholesterol Ratio on Coronary Heart Disease Mortality in Men. AB - OBJECTIVE: To examine the prospective relationships among cardiorespiratory fitness (CRF), fasting blood triglyceride to high density lipoprotein cholesterol ratio (TG:HDL-C), and coronary heart disease (CHD) mortality in men. METHODS: A total of 40,269 men received a comprehensive baseline clinical examination between January 1, 1978, and December 31, 2010. Their CRF was determined from a maximal treadmill exercise test. Participants were divided into CRF categories of low, moderate, and high fit by age group and by TG:HDL-C quartiles. Hazard ratios for CHD mortality were computed using Cox regression analysis. RESULTS: A total of 556 deaths due to CHD occurred during a mean +/- SD of 16.6+/-9.7 years (669,678 man-years) of follow-up. A significant positive trend in adjusted CHD mortality was shown across decreasing CRF categories (P for trend<.01). Adjusted hazard ratios were significantly higher across increasing TG:HDL-C quartiles as well (P for trend<.01). When grouped by CRF category and TG:HDL-C quartile, there was a significant positive trend (P=.04) in CHD mortality across decreasing CRF categories in each TG:HDL-C quartile. CONCLUSION: Both CRF and TG:HDL-C are significantly associated with CHD mortality in men. The risk of CHD mortality in each TG:HDL-C quartile was significantly attenuated in men with moderate to high CRF compared with men with low CRF. These results suggest that assessment of CRF and TG:HDL-C should be included for routine CHD mortality risk assessment and risk management. PMID- 29157536 TI - A Comparison of Techniques to Evaluate the Effectiveness of Genome Editing. AB - Genome editing using engineered nucleases (meganucleases, zinc finger nucleases, transcription activator-like effector nucleases) has created many recent breakthroughs. Prescreening for efficiency and specificity is a critical step prior to using any newly designed genome editing tool for experimental purposes. The current standard screening methods of evaluation are based on DNA sequencing or use mismatch-sensitive endonucleases. They can be time-consuming and costly or lack reproducibility. Here, we review and critically compare standard techniques with those more recently developed in terms of reliability, time, cost, and ease of use. PMID- 29157535 TI - CRISPR-Based Antibacterials: Transforming Bacterial Defense into Offense. AB - The development of antimicrobial-resistant (AMR) bacteria poses a serious worldwide health concern. CRISPR-based antibacterials are a novel and adaptable method for building an arsenal of antibacterials potentially capable of targeting any pathogenic bacteria. PMID- 29157537 TI - Special Issue: Mitochondria in Cancer. PMID- 29157538 TI - Mast cells in calcific aortic stenosis. AB - In developed countries, calcific aortic stenosis (CAS) has become the most common acquired valvular disease and reason for aortic valve replacement. It is considered a form of atherosclerosis and, like the latter, of inflammatory origin, with presence in the calcified aortic valves of blood vessels, lymphatics, lymphocytes, plasma cells, histiocytes, and sometimes also of metaplastic bone tissue. This study is aimed at examining the presence of CD117 - positive mast cells in CAS. In 56 examined calcified aortic valves excised by cardiac surgery, mast cells were constantly present as a part of the polymorphous cellular infiltrate; in individual cases, their numbers were 1-90 (median 24). The numbers were significantly higher in the congenitally malformed/bicuspid valves (median 40) than in the tricuspid ones (median 20). In valves with presence of metaplastic bone, mast cells were significantly more numerous (median 42) than in those without metaplasia (median 20). In 12 normal aortic valves obtained at autopsies, the numbers of mast cells were 4-21 (median 11). Discussed is a possible role of mast cells in pathogenesis of CAS. PMID- 29157539 TI - Physical Medicine and Rehabilitation Value in Bundled Payment for Total Joint Replacement and Cardiac Surgery: The Rusk Experience. PMID- 29157540 TI - Dental Anatomy and Nomenclature for the Radiologist. AB - Head and neck imaging studies frequently encompass the oral cavity and human dentition. Given the relatively wide prevalence of dental disease, the likelihood of detecting incidental dental pathology is high. This article provides an overview of dental terminology, anatomy, restorations, and associated computed tomography imaging artifacts necessary to more effectively interpret and communicate findings related to teeth. PMID- 29157541 TI - Imaging of Dentoalveolar and Jaw Trauma. AB - Prior to the invention of cone beam CT, use of 2-D plain film imaging for trauma involving the mandible was common practice, with CT imaging opted for in cases of more complex situations, especially in the maxilla and related structures. Cone beam CT has emerged as a reasonable and reliable alternative considering radiation dosage, image quality, and comfort for the patient. This article presents an overview of the patterns of dental and maxillofacial fractures using conventional and advanced imaging techniques illustrated with multiple clinical examples selected from the author's oral and maxillofacial radiology practice database. PMID- 29157542 TI - Alterations in Tooth Structure and Associated Systemic Conditions. AB - A variety of factors can affect the normal development of tissues and may lead to variation in the normal compliment of teeth and development of alterations in the shape and size of teeth. These anomalies can be congenital, developmental, or acquired. Dental anomalies can present as isolated traits or be associated with systemic conditions and syndromes for which early diagnosis and genetic testing may result in better treatment outcomes and quality of life. Dentists play an essential role in the multidisciplinary management of these abnormalities. This article discusses some of these tooth alterations and associated systemic and genetic conditions. PMID- 29157543 TI - Oral and Maxillofacial Anatomy. AB - This article deals with identification and descriptions of intraoral and extraoral anatomy of the dental and maxillofacial structures. The anatomic landmarks are highlighted and described based on their radiographic appearance and their clinical significance is provided. Cone beam CT-based images are described in detail using the multiplanar reconstructions. The skull views are depicted via line diagrams in addition to their normal radiographic appearance to make identification of anatomic structures easier for clinicians. The authors cover most of the anatomic structures commonly noted via radiographs and their descriptions. This article serves as a clinician's guide to oral and maxillofacial radiographic anatomy. PMID- 29157544 TI - Radiology of Implant Dentistry. AB - The article presents an overview of the goal of imaging at each stage of implant therapy and the usefulness and limitations of multidetector computed tomography (MDCT) in achieving those goals. Various MDCT protocols of use in implant imaging also are presented, with an emphasis on dose reduction and the use of iterative reconstruction techniques. Also discussed are options for viewing and analysis of CT images, issues related to appropriate image reformatting and interpretation, interactive treatment planning, and transfer of information from the images to the surgical field during implant surgery using surgical guides and CT-guided navigation systems. PMID- 29157545 TI - Temporomandibular Joint Imaging. AB - The temporomandibular joint (TMJ) is an anatomically and biomechanically complex structure. Understanding how this structure grows and functions is essential to accurate radiographic evaluation. This article discusses the anatomy, function, and growth and development of the TMJ and how growth changes can affect the morphology of the craniofacial structures. Accordingly, the radiographic appearance of the entities that may alter the TMJ are discussed, including developmental, degenerative, inflammatory, and traumatic changes. Both osseous imaging and soft tissue imaging are shown. PMID- 29157546 TI - Radiographic Evaluation of Sleep-Disordered Breathing. AB - Sleep-disordered breathing and obstructive sleep apnea are becoming more prevalent in today's population. Management of these conditions can be difficult and this diagnosis is often overlooked by clinicians. An increased awareness and understanding of craniofacial structures and anatomic relationships can aid the clinician in identifying at-risk patients, and improve treatment outcomes. An airway review of 3-dimensional computed tomography imaging can identify (1) anatomic variations that contribute to obstructive airway complications, and (2) measurable dimensions to identify at risk patients. This article provides instruction on the key anatomic landmarks and imaging protocols for radiographic airway evaluation. PMID- 29157547 TI - Imaging of Odontogenic Infections. AB - Odontogenic infections represent a common clinical problem in patients of all ages. The presence of teeth enables the direct spread of inflammatory products from dental caries, trauma, and/or periodontal disease into the maxilla and mandible. The radiographic changes seen depend on the type and duration of the inflammatory process and host body response. Imaging plays a central role in identifying the source of infection and the extent of the disease spread and in detecting any complications. Many different imaging modalities can be used. The radiographic features associated with acute and chronic inflammatory processes are discussed. PMID- 29157548 TI - Imaging of Benign Odontogenic Lesions. AB - Numerous benign cysts or solid tumors may present in the jaws. These arise from tooth-forming tissues in the dental alveolus or from nonodontogenic tissues in the basal bone of the mandible and maxilla. Radiologists provide 2 deliverables to assist in diagnosis and management: (1) appropriately formatted images demonstrating the location and extent of the lesion and (2) interpretive reports highlighting specific radiologic findings and an impression providing a radiologic differential diagnosis. This article provides guidance on essential image protocols for planning treatments, a radiologic differential diagnostic algorithm based on location and pattern recognition, and a summary of the main features of benign odontogenic lesions. PMID- 29157549 TI - Malignant Lesions in the Dentomaxillofacial Complex. AB - Malignancies in the maxillofacial region are rare but comprise a broad spectrum of lesions. Given the potential for malignancies to mimic dental/sinus/temporomandibular joint pathology or remain asymptomatic, the judicious radiologist will be familiar with the initial and unique malignant changes affecting the dentition, periodontium, and supporting osseous structures on conventional film, dental, and sinus imaging. This article is meant to serve as a complement to the many excellent texts dedicated to advanced imaging techniques for the staging of known malignancies. The lesions discussed are a representative sample of malignancies involving hard tissues of the maxillofacial complex but are far from complete. PMID- 29157550 TI - Imaging of Radiation- and Medication-Related Osteonecrosis. AB - Osteonecrosis is the devitalization of bone and consequent lytic changes. In the jaws, osteonecrosis is a pathologic consequence of prior radiation therapy (osteoradionecrosis) or certain antiresorptive medications. Herein, we review the pathogenesis and clinical manifestations of these lesions, and describe the spectrum of radiologic findings in these conditions, and highlight the similarities and differences between the imaging appearances of these 2 entities. PMID- 29157551 TI - Fibro-Osseous and Other Lesions of Bone in the Jaws. AB - Fibroosseous lesions in the jaws have similar histologic and radiographic features. Despite their similarity, management varies significantly. In this article, common fibroosseous lesions and key radiographic features are described. Many of the fibroosseous lesions are diagnosed radiographically, without performing histologic examinations. For some of the fibroosseous lesions, for example, periapical osseous dysplasia, histologic examination is contraindicated. Cherubism and fibrous dysplasia have specific radiographic findings; these conditions can be diagnosed radiographically. Accurate diagnosis conditions is essential; some conditions do not require any intervention, while others require surgical resection. Patient demographics, for example, age, gender, and race, play important roles in diagnosis. PMID- 29157552 TI - Oral and Maxillofacial Radiology. PMID- 29157553 TI - Editorial for 25th Anniversary Issue of Molecular Phylogenetics and Evolution. PMID- 29157554 TI - [Animal models for the study of cancer stem cells]. PMID- 29157555 TI - [Systemic therapy for advanced endometrial cancer]. AB - Endometrial cancer has generally a good prognosis when diagnosed at an early stage, but remains incurable at an advanced stage (recurrent or metastatic) with only few therapeutic options. Hormonal therapy is the treatment of choice in case of slow progressive disease with a tumor expressing hormonal receptors due to its favorable safety profile. Taxanes, anthracyclines and platinum compounds are the most active chemotherapy agents with greater response rates when combined, though at the price of a significant toxicity. Targeted therapies based on a better understanding of tumor biology are being evaluated with some promising results. A good knowledge of patients' comorbidities, and exact histologic characteristics of the tumor (type, grade, hormonal receptor expression, and MSI status) for a well adapted therapeutic decision. PMID- 29157557 TI - Corrigendum to Jhuang J-Y, Hsieh Y-C, Kuo C-C, Su Y-Z, Chuang S-S. Primary splenic low-grade follicular lymphoma presenting with leukaemia and large cell transformation in the marrow. Pathology 2017; 49: 649-52. PMID- 29157556 TI - [Epithelial-to-mesenchymal transition and cancer-initiating cells]. PMID- 29157558 TI - Cutaneous hyperpigmentation in vitamine B12 deficiency. PMID- 29157559 TI - ["Deciding wisely together" - an initiative of the Association of the Scientific Medical Societies in Germany: Mission, methodology and application]. AB - The question of how to improve healthcare quality and the need for patient empowerment and shared decision-making has been the subject of political and scientific debate for years. In addition to various quality initiatives, "top lists" summarizing selected recommendations to increase awareness of overuse, spread by means of public campaigns, has become popular on the international level - known as the "Choosing Wisely" initiative. However, the trustworthiness of "top lists", their impact on patient-relevant outcomes, their role in and integration into the context of the various pre-existing approaches to improve healthcare quality and the effects of neglecting under- and misuse are not clear. On the other hand, "top lists" may provide new opportunities to improve awareness and dissemination of carefully selected recommendations based on high-quality guidelines. Therefore, the Association of Scientific Medical Societies in Germany (AWMF) has established an ad hoc commission to design a system-specific initiative. The commission has the task to clarify goals, methods of development and concepts for implementation and evaluation, to address concerns and to build upon specific existing resources - e. g., the established quality management system for guidelines in Germany. The key goals defined by the commission include the systematization of the dialogue between healthcare practitioners and patients and the promotion of ethically founded decision-making as an answer to an increasing economic orientation of the healthcare system. To ensure the methodological quality of specific recommendations, the commission has developed a manual. To the best of our knowledge, this manual is the first detailed method paper aiming to guide developers of "Choosing Wisely" recommendations. More than 20 German medical scientific societies have already addressed the subject of "top lists". PMID- 29157560 TI - ? PMID- 29157561 TI - [Choosing Wisely: rationale, implementation, and evaluation]. AB - "Klug entscheiden" (Choosing Wisely) is an initiative launched by the German Society for Internal Medicine (DGIM) to boost the quality of medical indication by identifying both medical/therapeutic over- and underuse. Twelve specialist societies for internal medicine and DGIM associated societies develop corresponding recommendations which are subsequently evaluated and rejected or approved in a structured procedure by a multidisciplinary commission. Since 2016, 115 positive and negative recommendations have been developed and released for print media, radio and television. Physicians can obtain the DGIM/BDI* certificate "Klug entscheiden". First steps have been undertaken to implement "Klug entscheiden" in medical education. The wide dissemination and intense discussions give a reason to hope that positive and negative recommendations will be put into practice and that the awareness towards the relevance of the quality of medical indication will grow. And finally, specific recommendations are to be developed the implementation of which can be evaluated prospectively. * Professional organization of German specialists for internal medicine. PMID- 29157562 TI - ERK regulates mitochondrial membrane potential in fission deficient Drosophila follicle cells during differentiation. AB - Mitochondrial morphology regulatory proteins interact with signaling pathways involved in differentiation. In Drosophila oogenesis, EGFR signaling regulates mitochondrial fragmentation in posterior follicle cells (PFCs). EGFR driven oocyte patterning and Notch signaling mediated differentiation are abrogated when PFCs are deficient for the mitochondrial fission protein Drp1. It is not known whether fused mitochondrial morphology in drp1 mutant PFCs exerts its effects on these signaling pathways through a change in mitochondrial electron transport chain (ETC) activity. In this study we show that aggregated mitochondria in drp1 mutant PFCs have increased mitochondrial membrane potential. We perform experiments to assess the signaling pathway regulating mitochondrial membrane potential and how this impacts follicle cell differentiation. We find that drp1 mutant PFCs show increase in phosphorylated ERK (dpERK) formed downstream of EGFR signaling. ERK regulates high mitochondrial membrane potential in drp1 mutant PFCs. PFCs depleted of ERK and drp1 are able to undergo Notch mediated differentiation. Notably mitochondrial membrane potential decrease via ETC inhibition activates Notch signaling at an earlier stage in wild type and suppresses the Notch signaling defect in drp1 mutant PFCs. Thus, this study shows that the EGFR pathway maintains mitochondrial morphology and mitochondrial membrane potential in follicle cells for its functioning and decrease in mitochondrial membrane potential is needed for Notch mediated differentiation. PMID- 29157564 TI - Correction. PMID- 29157565 TI - State of Research on Simulation in Nursing Education Programs. PMID- 29157563 TI - Nr2f1a balances atrial chamber and atrioventricular canal size via BMP signaling independent and -dependent mechanisms. AB - Determination of appropriate chamber size is critical for normal vertebrate heart development. Although Nr2f transcription factors promote atrial maintenance and differentiation, how they determine atrial size remains unclear. Here, we demonstrate that zebrafish Nr2f1a is expressed in differentiating atrial cardiomyocytes. Zebrafish nr2f1a mutants have smaller atria due to a specific reduction in atrial cardiomyocyte (AC) number, suggesting it has similar requirements to Nr2f2 in mammals. Furthermore, the smaller atria in nr2f1a mutants are derived from distinct mechanisms that perturb AC differentiation at the chamber poles. At the venous pole, Nr2f1a enhances the rate of AC differentiation. Nr2f1a also establishes the atrial-atrioventricular canal (AVC) border through promoting the differentiation of mature ACs. Without Nr2f1a, AVC markers are expanded into the atrium, resulting in enlarged endocardial cushions (ECs). Inhibition of Bmp signaling can restore EC development, but not AC number, suggesting that Nr2f1a concomitantly coordinates atrial and AVC size through both Bmp-dependent and independent mechanisms. These findings provide insight into conserved functions of Nr2f proteins and the etiology of atrioventricular septal defects (AVSDs) associated with NR2F2 mutations in humans. PMID- 29157566 TI - Is health care payment reform impacting nurses' work settings, roles, and education preparation? AB - This study explores nurses' work settings and educational preparation in the five years before passage of the Affordable Care Act (ACA) and five years after ACA passage, with the aim of identifying areas for nurse educators' attention. The study setting was one small state undergoing rapid transition away from fee-for service service and thus provided the ideal laboratory to assess the impact of health reform on the nursing workforce. A secondary analysis of data gathered during relicensure compared the nursing workforce at an interval of one decade, with surveys in 2005 (n=4075; 65% response rate) and in 2015 (n=6723; 97% response rate). Findings demonstrated an increase in the proportion of nurses who reported working in ambulatory care and community settings (p=0.001). However, there was no associated decrease in the proportion of nurses who reported working in hospitals. Among respondents who reported employment in the ambulatory care/community settings in 2005, 34.3% had a BSN or higher, a proportion that increased to 41.2% in 2015 (p=0.010); nevertheless, the greatest proportional increase was among AD prepared nurses (34% to 48%). Although new nursing roles emerging as a result of health reform offer baccalaureate nurses the opportunity use the full complement of their knowledge and skills, these data suggest that BS prepared nurses are not fully accessing these opportunities. Implications for nursing education and further research are detailed. PMID- 29157567 TI - Expanding collaborative boundaries in nursing education and practice: The nurse practitioner-dentist model for primary care. AB - The purpose of this paper is to describe the design and implementation of a novel interprofessional collaborative practice education program for nurse practitioner and dental students, the Nurse Practitioner-Dentist Model for Primary Care (NPD Program). The NPD Program expands collaborative boundaries in advanced practice nursing by integrating primary care within an academic dental practice. The dental practice is located in a large, urban city in the Northeast United States and provides comprehensive dental services to vulnerable and underserved patients across the age spectrum. The NPD Program is a hybrid curriculum comprised of online learning, interprofessional collaborative practice-based leadership and teamwork training, and clinical rotations focused on the oral-systemic health connection. Practice-based learning promotes the development of leadership and team-based competencies. Nurse practitioners emerge with the requisite interprofessional collaborative practice competencies to improve oral and systemic health outcomes. PMID- 29157569 TI - A regional consortium for doctor of nursing practice education: Integrating improvement science into the curriculum. AB - The DNP curriculum prepares the graduate for evidence informed improvement translation through coursework integrating improvement, safety, and translation sciences. Innovative leadership skills are necessary to lead inter-professional unit-based and health system opportunities. Equipping the DNP with the necessary skills and competencies to accomplish any type of improvement translation requires exposure to the tools and techniques of these sciences with an emphasis in didactic content. With a foundational knowledge of the principles for improvement, translation and application will follow. It is imperative theoretical underpinnings of translational science are taught, and that the students be expected to apply these concepts in "real word" circumstances. Thus, the DNP student is afforded opportunities during their DNP program to participate in a "learning lab" for evidence informed improvement translation. In essence, the courses within the program are designed to allow conversion from theory into practice. PMID- 29157568 TI - Providing primary care using an interprofessional collaborative practice model: What clinicians have learned. AB - This article details a nurse-led, interprofessional collaborative practice (IPCP) model that was developed to provide primary care to a medically indigent population in Birmingham, Alabama. Funding to develop and implement this project came from a federal Nurse Education, Practice, Quality and Retention award to the University of Alabama at Birmingham (UAB) School of Nursing, with additional support coming from the UAB Hospital and Health System. The clinic is housed within a local community-based, non-profit organization and all services, including supplies and pharmaceuticals, are provided free of charge to this vulnerable population. The IPCP model that was developed includes three primary care teams and incorporates faculty clinicians from a variety of disciplines, including nursing, medicine, optometry, nutrition, mental health, social work and informatics. Evaluation of the project has included annual structured interviews of project personnel, a variety of survey instruments completed electronically at various intervals, and assessments by students as well as patients experiencing team-based care. The focus of this article is the qualitative data collected from structured interviews of clinician faculty annually over the three years of the funded project. The learning, understanding and growth that have taken place by the experienced clinicians from multiple disciplines regarding IPCP are detailed. PMID- 29157570 TI - Building clinical education training capacity in nurse practitioner programs. AB - Building clinical education training capacity in nurse practitioner programs is critical to build the primary care workforce and to address the access to care problem in the country. Challenges related to obtaining clinical sites and qualified preceptors are well reported, but few practical solutions are presented. Clinical sites and qualified preceptors willing to serve can be found, but nurse practitioner faculty must remove obstacles and strengthen resources by discovering untapped capacity. Nurse practitioner faculty can design, implement, and test innovative clinical models to maximize clinical training capacity. Clinical capacity development in geriatrics and long-term care, convenience care, distance immersions, correctional nursing, occupational health, and through interprofessional collaborations and faculty practice partnerships can be expanded. PMID- 29157571 TI - Using nurse managers' perceptions to guide new graduates toward positive nurse relationships. AB - One of the greatest challenges new graduates confront when transitioning to practice is establishing positive relationships with experienced nurses. Nursing faculty must prepare graduates for this challenge. However, nursing faculty are often removed from everyday practice and must rely on the perceptions of those entrenched in practice in order to ground teaching endeavors in authenticity. Nurse managers are well positioned to provide knowledgeable insights to nursing faculty regarding nurse relationships. The purpose of this qualitative, descriptive study was to explore nurse managers' perceptions regarding new graduates' relationships with more experienced nurses. Researcher-participant audiotaped interviews were conducted with 13 nurse managers. A content analysis revealed that all participants believed nurse relationships were significant, that factors such as perceived inequities and stressful occurrences triggered poor relationships, that new graduates were often targeted for negative relationships, and that reasons for targeting of new graduates included prolonged dependence on experienced nurses and either over or under confidence of the new graduate. Providing a supportive, protective environment and hiring practices that promote team unity were posed as strategies that could help to prevent targeting of new graduates. Findings provide real-life, practice based information that can underpin nurse educators' teaching regarding nurse relationships and relationship building. PMID- 29157572 TI - Long-term effects on nursing alumni: Assessing a course in public and global health. AB - The impact of a cultural awareness course among nursing students may affect the particular person for years to come. Cultural awareness can be taught via many methods, often requiring study abroad and/or extreme investment of time, money and effort. There is little research on sustained effects on nursing alumni from such a course. The purpose of this descriptive survey study was to determine the long term outcomes of a cultural awareness course and 2) compare the long term effects between alumni who went abroad and those who chose to complete the course locally. One hundred and twenty-one nursing alumni completed the International Education Survey (IES) (Zorn, 1996) with additional open-ended questions. Quantitative and qualitative results concluded: 1) nursing alumni were influenced long term by a course dedicated to public and global health and 2) all alumni had statistically significant IES scores but alumni who studied abroad had the greatest increase. PMID- 29157573 TI - Thirteen years and counting: Outcomes of a concurrent ASN/BSN enrollment program. AB - In their 2011 report, The Future of Nursing, the Institute of Medicine called for 80% of the nursing workforce to be comprised of baccalaureate prepared Registered Nurses by the year 2020. One suggested approach to achieve this goal is the creation of programs that allow students to progress through associate and baccalaureate nursing preparation simultaneously. This paper describes the University of Central Florida's 13-year experience after implementing a Concurrent Enrollment Program. Development and structure of the program, advisement and curriculum details, facilitators and barriers are described. Data on National Council Licensure Examination for Registered Nurses pass rates, completion rates, comparison with traditional RN-BSN students, and progression to graduate school are also included. The Concurrent Program model described here between a specific university and state college partners, demonstrated positive outcomes that support achievement of the Institute of Medicine's goals. PMID- 29157574 TI - Teaching evidence based practice to undergraduate nursing students. AB - Considering the heightened importance of evidence-based practice in healthcare settings, incorporating evidence-based practice into the nursing curriculum, especially in baccalaureate programs is essential because this is a first step to prepare students for their professional role as an RN, and the undergraduate nursing students are the ones who will spend the most time with patients at their bedside providing direct care. Teaching evidence-based practice at the undergraduate level, however, can be challenging. Creative and enjoyable teaching strategies are instrumental in order to promote students' engagement and learning about evidence-based practice. This paper describes useful strategies for teaching evidence-based practice in an undergraduate nursing research course. PMID- 29157575 TI - Effects of two different psychiatric nursing courses on nursing students' attitudes towards mental illness, perceptions of psychiatric nursing, and career choices. AB - This quasi-experimental study was carried out to compare the attitudes towards psychiatry patients of students educated with problem-based learning and students educated with a traditional method in western Turkey. The students' perceptions of psychiatric nursing and their career choices were also evaluated. The sample consisted of 202 students; 130 were educated with a problem-based learning model and 72 were educated with a traditional method. Students educated with the problem-based learning method developed more positive attitudes towards mental illness after the psychiatric nursing course in comparison with students educated with the traditional method. Students educated with the traditional method preferred psychiatric nursing in comparison with nursing students educated with problem-based learning. It is important that the psychiatric nursing curriculum includes topics and programs that will create awareness in students regarding stigmatization of mental illness and its effects. In addition, we suggest that studies are performed to determine the perceptions of students towards psychiatric nursing and the factors that affect their career choices. PMID- 29157576 TI - A professionalism and safety code of conduct designed for undergraduate nursing students. AB - Nationally, professionalism and safety are key concepts in nursing practice. Although they are traditionally viewed as individual concepts, we believe they are closely linked to and depend on one another. Herein, professionalism and safety are developed as a paired concept with specific indicators. The purpose of this paper is to describe the process used to develop and implement a professionalism and safety Code of Conduct for undergraduate nursing students and to share the end product of this process. Based on input from students, faculty, and health system partners in our academic-service partnership, the current definition and Code include six student behavioral domains: communication, self awareness, self-care, professional image, responsible learning, and personal accountability. Our Code of Conduct is now a program policy and published in both the Student Handbook and clinical syllabi. Compliance is expected. Still under development are progressive clinical grading rubrics for inclusion in every clinical course. PMID- 29157577 TI - Single-Molecule Imaging of GPCR Interactions. AB - G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and are of great interest as pharmacological targets. Although the occurrence of GPCR signaling nanodomains has long been hypothesized based on indirect evidence, this and other fundamental aspects of GPCR signaling have been difficult to prove. The advent of single-molecule microscopy methods, which allow direct visualization of individual membrane proteins with unprecedented spatiotemporal resolution, provides unique opportunities to address several of these open questions. Indeed, recent single-molecule studies have revealed that GPCRs and G proteins transiently interact with each other as well as with structural components of the plasma membrane, leading to the formation of dynamic complexes and 'hot spots' for GPCR signaling. Whereas we are only beginning to understand the implications of this unexpected level of complexity, single molecule approaches are likely to play a crucial role to further dissect the protein-protein interactions that are at the heart of GPCR signaling. PMID- 29157578 TI - Evaluation of the insulinotropic and glucose-lowering actions of zebrafish GIP in mammalian systems: Evidence for involvement of the GLP-1 receptor. AB - The insulinotropic properties of zebrafish GIP (zfGIP) were assessed in vitro using clonal pancreatic beta-cell lines and isolated mouse islets and acute effects on glucose tolerance and insulin release in vivo were evaluated in mice. The peptide produced a dose-dependent increase in the rate of insulin release from BRIN-BD11 rat clonal beta-cells at concentrations >=30nM. Insulin release from 1.1 B4 human clonal beta-cells and mouse islets was significantly increased by zfGIP (10nM and 1MUM). The in vitro insulinotropic activity of zfGIP was decreased after incubating BRIN-BD11 cells with the GLP-1 receptor antagonist, exendin-4(9-39) (p<0.001) and the GIP receptor antagonist, GIP (6-30) Cex K40[Pal] (p<0.05) but the glucagon receptor antagonist [des His1,Pro4,Glu9]glucagon amide was without effect. zfGIP (10nM and 1MUM) produced significant increases in cAMP concentration in CHL cells transfected with the human GLP-1 receptor but was without effect on HEK293 cells transfected with the human glucagon receptor. Conversely, zfGIP, but not human GIP, significantly stimulated insulin release from CRISPR/Cas9-engineered INS-1 clonal beta-cells from which the GIP receptor had been deleted. Intraperitoneal administration of zfGIP (25 and 75nmol/kg body weight) to mice together with an intraperitoneal glucose load (18mmol/kg body weight) produced a significant decrease in plasma glucose concentrations concomitant with an increase in insulin concentrations. The study provides evidence that the insulinotropic action of zfGIP in mammalian systems involves activation of both the GLP-1 and the GIP receptors but not the glucagon receptor. PMID- 29157579 TI - Sleep location and parent-perceived sleep outcomes in older infants. AB - OBJECTIVES: Initial studies indicate more independent and consolidated sleep in the first few months in infants who sleep separately. Little is known, however, about the relationship of sleep location (separate room, room-sharing, bed sharing) with sleep outcomes in older infants (ages 6-12 months). It was expected that those who sleep in a separate room would have better parent-perceived sleep outcomes and more positive sleep health behaviors. METHODS: Parents of 6236 infants (6-12 months) in the United States (US) and 3798 in an international sample (Australia, Brazil, Canada, Great Britain, and New Zealand) completed a smartphone app-based expanded version of the validated Brief Infant Sleep Questionnaire. RESULTS: A total of 37.2% of the infants in the US and 48.4% in the international sample slept in a separate room. In both samples, infants who slept in a separate room as opposed to room-sharing or bed-sharing had parent perceived sleep outcomes and sleep-related behaviors that reflected earlier bedtimes, shorter time to fall asleep, more nighttime and total sleep, and increased sleep consolidation. They were also more likely to have a consistent bedtime routine and to fall asleep independently, as well as less likely to feed to sleep at bedtime and during the night. In addition, parents of separate room sleepers perceived bedtime to be less difficult and sleep to be better overall. CONCLUSIONS: Overall, 6- to 12-month-old infants who slept in a separate room had better reported sleep outcomes and fewer parent-perceived disturbances at bedtime than infants who room-shared with their parents, as well compared to those who slept in their parents' bed. PMID- 29157580 TI - Obstructive sleep apnea and diet-controlled gestational diabetes. AB - BACKGROUND: Obstructive sleep apnea (OSA) was shown to be associated with gestational diabetes mellitus (GDM). However, prevalence of OSA in GDM women, its relationship to metabolic control, and predictive factors have not been studied. MATERIAL AND METHODS: Eighty-two obese pregnant women with diet-controlled GDM between 24 and 34 weeks of gestation participated. The Berlin questionnaire was used to assess OSA symptoms. OSA was diagnosed using an overnight monitor. Fasting glucose and hemoglobin A1c (HbA1c) were obtained. Those with OSA underwent meal tolerance test (MTT) to assess their metabolic parameters. Classification tree analysis was used to develop a screening tool for OSA. RESULTS: At a median gestational age of 29 weeks, OSA was diagnosed in 52.4% of the women, with a median apnea hypopnea index of 9.4 (interquartile range 6.4, 12.4). More severe OSA was significantly correlated with higher fasting glucose but not HbA1c. For those with OSA, sleep parameters related to oxygen desaturation significantly correlated with higher fasting insulin resistance and more severe beta-cell dysfunction, as evaluated by MTT. A screening tool involving two variables, neck circumference and Berlin Questionnaire score, was developed. The sensitivity and specificity were 86% and 51%, respectively. The overall accuracy was 70%. CONCLUSION: OSA is prevalent in obese pregnant women with diet-controlled GDM in the late second to early third trimester. OSA severity, especially the degree of oxygen desaturation, correlated with fasting glucose, insulin resistance, and beta-cell function. A simple screening tool involving the Berlin Questionnaire and neck circumference can aid in predicting OSA in this patient group. PMID- 29157581 TI - Sleep in children with type 1 diabetes and their parents in the T1D Exchange. AB - OBJECTIVES: Sleep has physiological and behavioral impacts on diabetes outcomes, yet little is known about the impact of sleep disturbances in children with type 1 diabetes. The current study sought to characterize sleep in children with type 1 diabetes and in their parents and to examine the associations between child sleep, glycemic control and adherence, parent sleep and well-being, parental fear of hypoglycemia, and nocturnal caregiving behavior. METHODS: Surveys were emailed to parents of 2- to 12-year-old participants in the Type 1 Diabetes (T1D) Exchange clinic registry. Clinical data were obtained from the registry for the 515 respondents. RESULTS: In our sample, 67% of children met criteria for poor sleep quality. Child sleep quality was related to glycemic control (HbA1c of 7.9% [63 mmol/mol] in children with poor sleep quality vs 7.6% [60 mmol/mol] in children with non-poor sleep quality; P < 0.001) but not mean frequency of blood glucose monitoring (BGM) (7.6 times/day vs 7.4 in poor/non-poor quality; P = 0.56). Associations were similar for sleep duration. Children with poor sleep quality were more likely to experience severe hypoglycemia (4% in children with poor sleep quality vs 1% in children with non-poor sleep quality; P = 0.05) and more likely to experience DKA (7% vs 4%, respectively; P < 0.001). Poorer child sleep quality was associated with poorer parental sleep quality, parental well being, and fear of hypoglycemia (P < 0.001 for all). Child sleep was not related to the use of diabetes-related technology (CGM, insulin pump). CONCLUSIONS: Sleep may be a modifiable factor to improve glycemic control and reduce parental distress. PMID- 29157583 TI - Sleep apneas trigger epilepsy. PMID- 29157582 TI - Serum lipid profile, sleep-disordered breathing and blood pressure in the elderly: a 10-year follow-up of the PROOF-SYNAPSE cohort. AB - OBJECTIVES: Dyslipidemia, sleep-disordered breathing (SDB) and hypertension are comorbid factors evidenced in adults, but poorly studied in old people. This study aimed to examine the long-term evolution of the serum lipid profile, and its relationships with SDB and blood pressure (BP) in the elderly. METHODS: A ten year follow-up of the prospective Prognostic Indicator of Cardiovascular and Cerebrovascular Events (PROOF) and the Autonomic Nervous System Activity, Aging and Sleep Apnea/Hypopnea (SYNAPSE) cohort, which initially included 1011 elderly subjects from the general population, and who were untreated by continuous positive airway pressure (CPAP). Serum lipid profile, respiratory polygraphy for SDB and ambulatory blood pressure monitoring were performed. RESULTS: A total of 266 subjects (male/female 150/116; age 66.2 +/- 0.8 years) were reassessed after 9.6 +/- 0.7 years (age 75.8 +/- 1.2 years). The prevalence of high-risk dyslipidemia decreased from 61.3 to 44.4%, and hypertension from 57.9 to 27.4%. The nocturnal oxygen desaturation index increased (mean + 2.3 +/- 6.7 events/hour; p < 0.001), while the mean SaO2 and minimal SaO2 decreased. These variations (Delta) of oxygen desaturation worsened whether or not elderly subjects took anti-hypertensive and lipid-lowering treatments, and were not associated with serum lipid variations. The decrease in diurnal diastolic BP was independently associated with aging, and with the lowering of the waist/hip ratio (DeltaW/H) and low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, while the decrease in diurnal systolic BP only depended on aging and DeltaW/H. CONCLUSIONS: The results suggested that the observed worsening of nocturnal oxygen desaturation after 10 years in the elderly was independent of the change in circulating lipids, and not influenced by lipid lowering treatments. However, the variation in blood pressure remained associated with aging, waist/hip and LDL-C/HDL-C ratios. TRIAL REGISTRY: NCT00759304 and NCT00766584 at clinicaltrials.gov. PMID- 29157584 TI - Impaired objective and subjective sleep in children and adolescents with inflammatory bowel disease compared to healthy controls. AB - OBJECTIVE: Poor sleep and higher inflammation markers are associated, and impaired sleep quality is common among patients with inflammatory bowel disease (IBD). However, information on sleep among children and adolescents with IBD is currently lacking. The aims of the present study were to compare subjective and objective sleep of children and adolescents with IBD with healthy controls and to shed more light on the relationship between sleep and inflammation. We expected that poor sleep, as assessed via sleep electroencephalography recordings, would be observed among participants with IBD, but particularly among participants in an active state of disease. Furthermore, we expected that poor sleep and higher inflammatory markers would be associated. METHODS: A total of 47 children and adolescents participated in the study; 23 were diagnosed with IBD (mean age: 13.88 years, 44% female). The IBD group was divided into a medically well adjusted "remission-group" (IBD-RE; n = 14) and a group with an "active state of disease" (IBD-AD; n = 8). Healthy controls (HC; n = 24) were age and gender matched. Participants completed self-rating questionnaires for subjective sleep disturbances. Anthropometric data, acute and chronic inflammatory markers (C reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and objective sleep were considered. RESULTS: Compared to HC and IBD-RE, IBD-AD patients showed impaired objective sleep patterns (eg, more awakenings, longer sleep latency, and reduced stage 3 sleep). Linear relationships described the correlation between higher ESR and more stage 4 (minutes, percentage) sleep. Nonlinear relationships described the relation between ESR and subjective sleep quality (inverse U shaped) and between CRP and sleep latency (U-shaped). CONCLUSION: In children and adolescents with an active IBD, objective sleep was impaired and overall sleep quality and inflammation indices were associated in a complex manner. It seems advisable to include assessment of subjective sleep quality in the care of pediatric IBD patients as an additional indicator for objective sleep disturbances and inflammation. TRIAL REGISTRATION NUMBER: NCT02264275. PMID- 29157585 TI - Cardiac autonomic control during sleep in patients with myotonic dystrophy type 1: the effects of comorbid obstructive sleep apnea. AB - OBJECTIVE: Myotonic dystrophy type 1 (DM1) is a hereditary myopathy characterized by an autosomal dominant inheritance with important cardiovascular and autonomic deregulation. DM1 patients have a high prevalence of obstructive sleep apnea (OSA), but the effects of this comorbidity on cardiovascular autonomic control (CAC) are unknown. The present study aimed to investigate CAC during sleep-wake cycle in DM1 patients, taking into account the effects of OSA comorbidity. METHOD: Twenty-three patients with a diagnosis of DM1, and a control group, underwent a complete polysomnographic study (PSG). Electrocardiogram and respiration were extracted from PSG, divided according to the sleep stages, and analyzed using spectral analysis (SpA) of heart rate variability (HRV). SpA identified three components: very low frequency (VLF), low frequency (LF), a marker of sympathetic modulation, and high frequency (HF), a marker of vagal modulation. RESULTS: The results showed that in DM1 patients, the sympathovagal balance shifted towards a vagal predominance during non-rapid eye movement (NREM) sleep and a sympathetic predominance during rapid eye movement (REM) sleep. Second, this preserved cardiac autonomic modulation was not affected by the comorbidity with obstructive sleep apnea syndrome (OSAS). Third, in DM1 patients, OSAS comorbidity was associated with a reduction in HRV during the whole sleep wake cycle. Lastly, in DM1 patients with OSA, cardiorespiratory coupling was reduced compared to controls. CONCLUSIONS: DM1 patients had preserved cardiac autonomic dynamics during NREM and REM sleep, and this phenomenon was not affected by the presence of OSA. However, the comorbidity with OSA was characterized by a reduction in total HRV, which is a marker of the ability of autonomic control to respond to stressors stimuli. PMID- 29157586 TI - Does comorbid obstructive sleep apnea impair the effectiveness of cognitive and behavioral therapy for insomnia? AB - AIMS: Comorbid insomnia and obstructive sleep apnea (OSA) represents a highly prevalent and debilitating condition; however, physicians and researchers are still uncertain about the most effective treatment approach. Several research groups have suggested that these patients should initially receive treatment for their insomnia before the sleep apnea is targeted. The current study aims to determine whether Cognitive and Behavioral Therapy for Insomnia (CBT-i) can effectively treat insomnia in patients with comorbid OSA and whether its effectiveness is impaired by the presence of OSA. METHODS: A retrospective chart review was conducted to examine 455 insomnia patients entering a CBT-i treatment program in a hospital out-patient setting. Three hundred and fourteen patients were diagnosed with insomnia alone and 141 with insomnia and comorbid OSA. Improvements in average sleep diary parameters, global insomnia severity, and several daytime functioning questionnaires from baseline, to post-treatment, to 3 month follow-up were compared between insomnia patients with and without comorbid OSA. RESULTS: Insomnia patients with comorbid OSA experienced significant improvements in insomnia symptoms, global insomnia severity, and other daytime functioning measures during and following treatment. Furthermore, improvements were no different between patients with or without comorbid OSA. Sleep apnea presence and severity were not related to rates of insomnia-remission or treatment-resistance following treatment. CONCLUSIONS: CBT-i is an effective treatment in the presence of comorbid OSA. This information offers support for the suggestion that patients with comorbid insomnia and OSA should be treated with CBT-i prior to the treatment of the OSA. PMID- 29157587 TI - Decreases in self-reported sleep duration among U.S. adolescents 2009-2015 and association with new media screen time. AB - STUDY OBJECTIVES: Insufficient sleep among adolescents carries significant health risks, making it important to determine social factors that change sleep duration. We sought to determine whether the self-reported sleep duration of U.S. adolescents changed between 2009 and 2015 and examine whether new media screen time (relative to other factors) might be responsible for changes in sleep. METHODS: We drew from yearly, nationally representative surveys of sleep duration and time use among adolescents conducted since 1991 (Monitoring the Future) and 2007 (Youth Risk Behavior Surveillance System of the Centers for Disease Control; total N = 369,595). RESULTS: Compared to 2009, adolescents in 2015 were 16%-17% more likely to report sleeping less than 7 h a night on most nights, with an increase in short sleep duration after 2011-2013. New media screen time (electronic device use, social media, and reading news online) increased over this time period and was associated with increased odds of short sleep duration, with a clear exposure-response relationship for electronic devices after 2 or more hours of use per day. Other activities associated with short sleep duration, such as homework time, working for pay, and TV watching, were relatively stable or reduced over this time period, making it unlikely that these activities caused the sudden increase in short sleep duration. CONCLUSIONS: Increased new media screen time may be involved in the recent increases (from 35% to 41% and from 37% to 43%) in short sleep among adolescents. Public health interventions should consider electronic device use as a target of intervention to improve adolescent health. PMID- 29157588 TI - Sleep spindles may predict response to cognitive-behavioral therapy for chronic insomnia. AB - BACKGROUND: While cognitive-behavioral therapy for insomnia constitutes the first line treatment for chronic insomnia, only few reports have investigated how sleep architecture relates to response to this treatment. In this pilot study, we aimed to determine whether pre-treatment sleep spindle density predicts treatment response to cognitive-behavioral therapy for insomnia. METHODS: Twenty-four participants with chronic primary insomnia participated in a 6-week cognitive behavioral therapy for insomnia performed in groups of 4-6 participants. Treatment response was assessed using the Pittsburgh Sleep Quality Index and the Insomnia Severity Index measured at pre- and post-treatment, and at 3- and 12 months' follow-up assessments. Secondary outcome measures were extracted from sleep diaries over 7 days and overnight polysomnography, obtained at pre- and post-treatment. Spindle density during stage N2-N3 sleep was extracted from polysomnography at pre-treatment. Hierarchical linear modeling analysis assessed whether sleep spindle density predicted response to cognitive-behavioral therapy. RESULTS: After adjusting for age, sex, and education level, lower spindle density at pre-treatment predicted poorer response over the 12-month follow-up, as reflected by a smaller reduction in Pittsburgh Sleep Quality Index over time. Reduced spindle density also predicted lower improvements in sleep diary sleep efficiency and wake after sleep onset immediately after treatment. There were no significant associations between spindle density and changes in the Insomnia Severity Index or polysomnography variables over time. CONCLUSION: These preliminary results suggest that inter-individual differences in sleep spindle density in insomnia may represent an endogenous biomarker predicting responsiveness to cognitive-behavioral therapy. Insomnia with altered spindle activity might constitute an insomnia subtype characterized by a neurophysiological vulnerability to sleep disruption associated with impaired responsiveness to cognitive-behavioral therapy. PMID- 29157589 TI - Overweight and obesity add to behavioral problems in children with sleep disordered breathing. AB - OBJECTIVE: This study aimed to determine whether overweight and obesity increased the detrimental effects of pediatric sleep-disordered breathing (SDB) on cognition, behavior, mood, and quality of life. METHODS: Children and adolescents (8-16 years) with clinically diagnosed SDB were categorized into two groups: healthy weight (Body Mass Index (BMI) z-score <1.04, N = 11) and overweight/obese (BMI z-score >= 1.04, N = 10). Age-matched healthy weight, non-snoring controls (N = 25) were recruited from the community. All participants underwent overnight laboratory polysomnography (PSG). Cognitive, behavioral, and quality of life assessments were conducted in the home following the PSG. Analysis of Covariance (ANCOVA) was used to assess group differences in cognitive outcomes, controlling for socio-economic status. Kruskal-Wallis ANOVA was used to determine group differences in behavior and quality of life. Where group differences were found, hierarchical linear regressions determined the effect of weight on outcomes. RESULTS: Children with SDB had significantly poorer behavior and quality of life than controls, with overweight/obese children with SDB having the greatest dysfunction. No group differences were found in cognitive outcomes. The obstructive apnea hypopnea index (OAHI) was a significant predictor of withdrawn behavior (R2 = 0.42), inattention (R2 = 0.43), and aggressive behavior (R2 = 0.30). BMI z-score added significantly to aggressive behavior (R2 = 0.22) and was an independent predictor of externalizing behaviors (R2 = 0.26). The OAHI predicted school functioning (R2 = 0.30). BMI z-score predicted social functioning (R2 = 0.38) and significantly added to physical functioning over the OAHI (OAHI R2 = 30; BMI z-score R2 = 0.37). CONCLUSIONS: Overweight and obesity comorbid with SDB increase the risk of externalizing behaviors such as aggression but do not affect other behavioral associates of SDB such as inattention and school functioning. PMID- 29157590 TI - Mechanisms influencing older adolescents' bedtimes during videogaming: the roles of game difficulty and flow. AB - A relationship between evening technology use and sleep has been established, and models suggest various mechanisms to explain this relationship. Recent updates to these models also suggest the influence of individual difference factors, such that the relationship between technology and sleep varies between young people. Flow is an experience of immersion and time distortion that could vary between adolescents when using technology. The aim of the present study was to investigate the effects of flow on the self-selected bedtimes of adolescents when videogaming. Seventeen older adolescent, experienced videogamers (age = 15.9 +/- 0.83 years), played a new videogame on two school-night evenings in a sleep laboratory. Game difficulty was set to "hard" one evening (flow condition) and "easy" on the other evening (disrupted flow). Trait and state flow were measured, along with heart rate during videogaming, and bedtime measured objectively with real-time cameras. An interaction effect for heart rate indicated an elevated heart rate in the easy condition after 150 min of gaming (p < 0.02). No significant differences were found in bedtimes between the easy and hard conditions (p = 0.77). Adolescents high on trait flow played for longer and selected significantly later bedtimes than their low trait flow peers but only for the hard (flow) condition (12:22 AM vs. 10:53 PM, p = 0.004). Similarly, adolescents with high state flow went to bed significantly later than those low on state flow (12:24 PM vs. 10:52 PM, p = 0.001), again only in the hard condition. These findings suggest that individual and situational characteristics may amplify the effects of technology use on the "sleep" of adolescents and provides support for the displacement of bedtime hypothesis. PMID- 29157591 TI - Telemonitoring in continuous positive airway pressure-treated patients improves delay to first intervention and early compliance: a randomized trial. AB - OBJECTIVE: Telemonitoring (TM) has been used in continuous positive airway pressure (CPAP)-treated patients to improve compliance, but results have been inconsistent. The purpose of this study was to assess the impact of TM on the delay to the first technical intervention after CPAP initiation. The impact of TM on mean compliance during the first 3 months of treatment was measured as a secondary outcome. METHODS: Patients diagnosed with moderate to severe obstructive sleep apnea syndrome were prospectively included and randomized to receive usual care (UC) or TM. In both arms, an educational session was scheduled 1 month after CPAP initiation, and medical visits were planned after 1.5 and 3 months. In the TM arm, we added a universal TM unit (T4P) to the CPAP device. RESULTS: Delay to first intervention was significantly shorter in the TM group (29 +/- 25 vs 47 +/- 30 days, p = 0.02). The first intervention in the TM group was motivated by detection of problems by the TM system in 39% of patients. Compliance at 3 months was significantly better in the TM group (5.7 +/- 1.6 vs 4.2 +/- 1.9 h/night, p = 0.018). CONCLUSION: This is the first randomized study showing that TM reduces delay to first technical intervention in CPAP-treated patients. This early activation of troubleshooting was associated with improved compliance at 3 months. Since CPAP side effects at 1 month have been shown to predict lower 12-month CPAP compliance, TM seems to be an excellent tool for improvement of long-term CPAP acceptance. PMID- 29157592 TI - The effects of continuous positive airway pressure therapy on Troponin-T and N terminal pro B-type natriuretic peptide in patients with obstructive sleep apnoea: a randomised controlled trial. AB - INTRODUCTION: Untreated obstructive sleep apnoea (OSA) is associated with increased risk of coronary artery disease (CAD) and heart failure. High sensitivity cardiac troponin (hs Trop-T) and B-type natriuretic peptide (NT-pro BNP) are sensitive biomarkers for myocardial injury and heart failure respectively. No randomised controlled trials have examined the treatment effect of continuous positive airway pressure (CPAP) in patients with OSA on these biomarkers. METHOD: Patients >21 years old with apnoea-hypopnoea index (AHI) >=25/h by overnight polysomnography were recruited. Main exclusion criteria were previous CPAP use and any significant comorbidities including CAD and heart failure. Eligible subjects were randomised to receive CPAP or sham CPAP for eight weeks each in a crossover design with a wash out period of one month between the treatments. Blood samples were collected at 8pm, 3am, and 8am during sleep studies conducted at the end of each eight-week treatment period. RESULTS: Of the 37 patients who were randomised, 28 patients had stored frozen samples available for analysis. In comparison to sham treatment, CPAP significantly lowered the NT pro-BNP level by 0.91 pmol/L (p = 0.0002). The reduction of 0.235 ng/L in hs Trop T on CPAP therapy was not statistically significant (p = 0.052). There were no overnight changes, across the three time points, in either biomarker with either treatment. CONCLUSION: Our study confirms CPAP therapy in patients with moderate severe OSA reduces NT-pro-BNP, but we did not confirm a significant effect on hs Trop-T. Future larger studies of longer duration incorporating biomarkers and cardiac functional measures are needed to better establish the benefit of OSA treatment. PMID- 29157593 TI - Immediate impact of positive airway pressure on atrial fibrillation. PMID- 29157594 TI - Short sleep duration, shift work, and actual days taken off work are predictive life-style risk factors for new-onset metabolic syndrome: a seven-year cohort study of 40,000 male workers. AB - BACKGROUND: This longitudinal study investigated the effects of various lifestyle related factors - including sleep duration, shift work, and actual days taken off work - on new-onset metabolic syndrome (MetS). METHODS AND RESULTS: A total of 39,182 male employees (mean age 42.4 +/- 9.8 years) of a local government organization in Japan were followed up for a maximum of seven years, between 1999 and 2006. Multivariate analysis (Cox proportional hazard method) identified seven high-risk lifestyle factors that were significantly associated with new-onset MetS or a range of metabolic factors (obesity, hypertension, hyperglycemia, dyslipidemia): (1) short sleep duration (<5 h/day), (2) shift work, (3) insufficient number of days off work, (4) always eating until satiety, (5) not trying to take every opportunity to walk, (6) alcohol intake >=60 g/day, and (7) smoking. In addition, a higher number of these high-risk lifestyle factors significantly promoted the onset of MetS. The hazard ratio for MetS associated with 0-1 high-risk lifestyle parameters per subject at the baseline was set at 1.00. Hazard ratios associated with the following numbers of high-risk lifestyle parameters were: 1.22 (95% CI 1.15-1.29) for 2-3 of these parameters; and 1.43 (1.33-1.54) for 4-7. CONCLUSION: An increase in the number of high-risk lifestyle factors - such as short sleep duration, shift work, and an insufficient number of days off work - increased the risk of MetS onset. Comprehensive strategies to improve a range of lifestyle factors for workers, such as sleep duration and days off work, could reduce the risk of MetS onset. PMID- 29157595 TI - Comorbidity of narcolepsy and depressive disorders: a nationwide population-based study in Taiwan. AB - OBJECTIVE: Narcolepsy is a chronic sleep disorder that is likely to have neuropsychiatric comorbidities. Depression is a serious mood disorder that affects individuals' daily activities and functions. The current study aimed to investigate the relationship between narcolepsy and depressive disorders. METHODS: The study consisted of patients diagnosed with narcolepsy between January 2002, and December 2011 (n = 258), and age-matched and gender-matched controls (n = 2580) from Taiwan's National Health Insurance database. Both the patients and the controls were monitored through December 31, 2011, to identify the occurrence of a depressive disorder. A multivariate logistic regression model was used to assess the narcolepsy's potential influence on the comorbidity of a depressive disorder. RESULTS: During the study period, 32.7%, 24.8%, and 10.9% of the narcoleptic patients were comorbid with any depressive disorder, dysthymic disorder, and major depressive disorder, respectively. When compared to the control subjects, the patients with narcolepsy were at greater risks of having any depressive disorder (aOR 6.77; 95% CI 4.90-9.37), dysthymic disorder (aOR 6.62; 95% CI 4.61-9.57), and major depressive disorder (aOR 6.83; 95% CI 4.06 11.48). Of the narcoleptic patients that were comorbid with depression, >50% had been diagnosed with depression prior to being diagnosed with narcolepsy. CONCLUSIONS: This nationwide data study revealed that narcolepsy and depression commonly co-occurred. Since some symptoms of narcolepsy overlapped with those of depressive disorders, the findings serve as a reminder that clinicians must pay attention to the comorbidity of narcolepsy and depression. PMID- 29157596 TI - Molecular epidemiology and phylogenetic analysis of human papillomavirus infection in women with cervical lesions and cancer from the coastal region of Ecuador. AB - The aim of the present study was to gather information regarding the molecular epidemiology of Human papillomavirus (HPV) and related risk factors in a group of women with low- and high-grade cervical lesions and cancer from the coastal region of Ecuador. In addition, we studied the evolution of HPV variants from the most prevalent types and provided a temporal framework for their emergence, which may help to trace the source of dissemination within the region. We analyzed 166 samples, including 57 CIN1, 95 CIN2/3 and 14 cancer cases. HPV detection and typing was done by PCR-sequencing (MY09/MY11). HPV variants and estimation of the time to most recent common ancestor (tMRCA) was assessed through phylogeny and coalescence analysis. HPV DNA was found in 54.4% of CIN1, 74.7% of CIN2/3 and 78.6% of cancer samples. HPV16 (38.9%) and HPV58 (19.5%) were the most prevalent types. Risk factors for the development of cervical lesions/cancer were the following: three or more pregnancies (OR=4.3), HPV infection (OR=3.7 for high risk types; OR=3.5 for HPV16), among others. With regard to HPV evolution, HPV16 isolates belonged to lineages A (69%) and D (31%) whereas HPV58 isolates belonged only to lineage A. The period of emergence of HPV16 was in association with human populations (tMRCA=91052 years for HPV16A and 27000 years for HPV16D), whereas HPV58A preceded Homo sapiens evolution (322257 years). This study provides novel data on HPV epidemiology and evolution in Ecuador, which will be fundamental in the vaccine era. PMID- 29157598 TI - Chinese, Vietnamese, and Asian Indian Parents' Perspectives About Well-Child Visits: A Qualitative Analysis. AB - OBJECTIVES: Well-child visits are a critical component of pediatric health care; however, disparities in attendance and quality of care exist for Asian children. Limited research has explored Asian immigrant parents' perspectives about their well-child visit experience. METHODS: Qualitative interviews were conducted with Chinese, Vietnamese, and Asian Indian immigrant parents. Participants were recruited from community-based organizations in the Boston area. Interviews focused on parents' perceptions about well-child visits, including individual attitudes, social and cultural factors affecting their opinions, perceived behavioral control, and improving visits for Asian immigrant families. Data were coded and analyzed using thematic analysis. RESULTS: Fifty-one parents participated. Although participants reported attending well-child visits, they thought language barriers and unfamiliarity with US preventive health care may limit attendance for other Asian immigrant families. Some reported high-quality visits, while others described them as "too simple," recollecting health care experiences from their countries of origin where more tests were completed. Participants described seeking advice about their children's preventive care from elder family members. Many expressed the importance of culturally concordant health care providers and culturally sensitive care, while others thought that culture was less relevant. Differences emerged among the 3 subgroups around culturally concordant care and traditional medicine. CONCLUSIONS: Querying parents about their past health care experiences and providing information about well-child visits may be useful when caring for immigrant families. Social influences on children's health outside of the parent-provider-child triad may also be important. Further work should explore how to deliver culturally sensitive care that considers not only a family's language preferences but also their unique cultural identity. PMID- 29157597 TI - Donor-specific HLA antibodies in predicting crossmatch outcome: Comparison of three different laboratory techniques. AB - The virtual crossmatch, which is based on single antigen bead technology, is used in the prediction of crossmatch results. However, this assay differs in sensitivity and specificity from crossmatch methods. In our study, the results of physical crossmatches, performed with three different methods, were assessed against virtual crossmatch results. The aim was to determine the potential cut off values for donor specific antibodies (DSA) that would predict the crossmatch results obtained by different methods. The results of different crossmatch techniques were correlated with the virtual crossmatch. The receiver operating characteristic (ROC) analysis revealed the Flow cytometric crossmatch (FCXM) and Luminex crossmatch (LXM) to be the most accurate, with area under curve (AUC) values of 0.861 and 0.805, respectively. While we found that the virtual crossmatch correlated well with all the crossmatch results, FCXM produced the best results (83% of the DSA detected). LXM outperformed the other tests in terms of the accuracy in separating class II DSA. PMID- 29157599 TI - Skin lesions of Birt-Hogg-Dube syndrome: Clinical and histopathological findings in 31 Japanese patients who presented with pneumothorax and/or multiple lung cysts. AB - BACKGROUND: Birt-Hogg-Dube syndrome (BHDS) (OMIM #135150) is an autosomal dominant disease, characterized by fibrofolliculomas (FFs) of the skin, pulmonary cysts with/without pneumothorax, and renal tumors. The prevalence of skin manifestations reported for Japanese BHDS patients is lower (<30%) compared with that of Western countries (75~90%), which appear to be underestimated. OBJECTIVE: To precisely examine the prevalence of skin lesions with dermoscopy and histopathology with reference to genetic analyses. METHODS: We studied 31 patients (47.0+/-13.2years old, range 15-71) consisting of 26 unrelated families consecutively from May 2013 to June 2015 specifically for skin-colored papules on their faces and cervicothoracic regions. Patients initially suspected of BHDS from multiple pulmonary cysts that resulted in pneumothorax (30/31; 96.8%) received dermoscopic examinations and skin biopsies if applicable. The diagnosis of BHDS was established by folliculin (FLCN) genetic testing, and the results were compared to the histopathological findings of FFs or trichodiscomas (TDs). RESULTS: FLCN germline mutation was demonstrated in 25/26 (96.2%) unrelated families tested and 28/29 patients (96.6%) tested. Skin lesions were recognized in 26/31 patients (83.9%); skin biopsies were performed in 23 patients of whom FFs and/or TDs were histologically demonstrated in 17 (73.9%). Although our study population included patients whose skin manifestations were evaluated prior to or after FLCN genetic testing, skin lesions were clearly prevalent and recognizable irrespective of whether genetic testing was or wasn't done. When examined with dermoscopy, distinct FFs appeared as well-demarcated areas of pallor with central follicular openings in 13 of 15 FF-bearing patients (86.7%); however, those manifestations were not recognized for TD. CONCLUSIONS: Skin lesions appear to be more prevalent than previously reported (<30% vs.73.9%) in Japanese BHDS patients. Dermoscopy is a useful diagnostic aid for finding FFs. PMID- 29157600 TI - Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91. AB - OBJECTIVE: Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools. METHODS AND RESULTS: Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed. Importantly, an empty side-pocket is identified next to the succinate binding site. All this information formed the basis for a substructure-based search query, which, combined with molecular docking, was used in virtual screening of the ZINC database to pick two serial mini-libraries of a total of only 245 compounds from which sub-micromolar, selective GPR91 agonists of unique structures were identified. The best compounds were backbone-modified succinate analogs in which an amide-linked hydrophobic moiety docked into the side-pocket next to succinate as shown by both loss- and gain-of-function mutagenesis. These compounds displayed GPR91-dependent activity in altering cytokine expression in human M2 macrophages similar to succinate, and importantly were devoid of any effect on the major intracellular target, succinate dehydrogenase. CONCLUSIONS: These novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91-mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflammation and diabetic complications such as retinopathy and nephropathy. PMID- 29157601 TI - Modulation of cognition and anxiety-like behavior by bone remodeling. AB - OBJECTIVE: That the bone-derived hormone osteocalcin is necessary to promote normal brain development and function, along with its recently described sufficiency in reversing cognitive manifestations of aging, raises novel questions. One of these is to assess whether bone health, which deteriorates rapidly with aging, is a significant determinant of cognition and anxiety-like behavior. METHODS: To begin addressing this question, we used mice haploinsufficient for Runx2, the master gene of osteoblast differentiation and the main regulator of Osteocalcin expression. Control and Runx2+/- mice were evaluated for the expression of osteocalcin's target genes in the brain and for behavioral parameters, using two assays each for cognition and anxiety-like behavior. RESULTS: We found that adult Runx2+/- mice had defects in bone resorption, reduced circulating levels of bioactive osteocalcin, and reduced expression of osteocalcin's target genes in the brain. Consequently, they had significant impairment in cognitive function and increased anxiety-like behavior. CONCLUSIONS: These results indicate that bone remodeling is a determinant of brain function. PMID- 29157603 TI - Ischemic stroke and subsequent thrombosis within a HeartMate 3 left ventricular assist system: A cautionary tale. PMID- 29157602 TI - Induction of fibroblast growth factor 21 does not require activation of the hepatic X-box binding protein 1 in mice. AB - OBJECTIVE: Fibroblast growth factor 21 (FGF21), a key regulator of the metabolic response to fasting, is highly induced by endoplasmic reticulum (ER) stress. The X-box binding protein 1 (Xbp1) is one of several ER stress proteins that has been shown to directly activate the FGF21 promoter. We aimed to determine whether hepatic Xbp1 is required for induction of hepatic FGF21 in vivo. METHODS: Mice bearing a hepatocyte-specific deletion of Xbp1 (Xbp1LKO) were subjected to fasting, pharmacologic ER stress, or a ketogenic diet, all potent stimuli of Fgf21 expression. RESULTS: Hepatocyte-specific Xbp1 knockout mice demonstrated normal induction of FGF21 in response to fasting or pharmacologic ER stress and enhanced induction of FGF21 in response to a ketogenic diet. Consistent with preserved induction of FGF21, Xbp1LKO mice exhibited normal induction of FGF21 target genes and normal ketogenesis in response to fasting or a ketogenic diet. CONCLUSION: Hepatic Xbp1 is not required for induction of FGF21 under physiologic or pathophysiologic conditions in vivo. PMID- 29157604 TI - The impact of nursing - a self-evident truth? PMID- 29157605 TI - Extraction of essential oil from Bunium Persicum (Boiss.) by instant controlled pressure drop (DIC). AB - Essential oils extraction from Bunium Persicum (Boiss) was performed using instant controlled pressure drop (in French: Detente Instantanee Controlee or DIC) thechnology and optimum extraction conditions were obtained. Response surface methodology (RSM) was used to determine the optimal conditions and the results were 20s heating time, 3.5bar pressure, 0.44mm particle diameter and 9 cycles. Essential oils extraction was also compared with Hydrodistillation (HD), ultrasound-assisted extraction (UAE) and Soxhlet (SOX) extraction. Results show higher efficiency of the DIC than other methods and more oxygenated components were observed. Impact of DIC, HD, UAE and SOX on the morphological structure of the plant was studied by SEM. Antioxidant activity and total phenolic content (TPC) of the extract were determined and comapred by HD. Results show that DIC facilitates achieving to higher TPC and more antioxidant activity. PMID- 29157606 TI - High-performance thin-layer chromatography HPTLC-direct bioautography as a method of choice for alpha-amylase and antioxidant activity evaluation in marine algae. AB - High-Performance Thin-layer chromatography (HPTLC) combined with DPPH free radical method and alpha-amylase bioassay was used to compare antioxidant and antidiabetic activities in ethanol and ethyl acetate extracts from 10 marine macroalgae species (3 Chlorophyta, 4 Phaeophyta and 3 Rhodophyta) from Blue Lagoon beach (Malaysia). Samples were also evaluated for their phenolic and stigmasterol content. On average, higher antioxidant activity was observed in the ethyl acetate extracts (55.1mg/100g gallic acid equivalents (GAE) compared to 35.0mg/100g GAE) while, as expected, phenolic content was higher in ethanol extracts (330.5mg/100g GAE compared to 289.5mg/100g GAE). Amounts of fucoxanthin, stigmasterol and alpha-amylase inhibitory activities were higher in ethyl acetate extracts. Higher enzyme inhibition is therefore related to higher concentrations of triterpenes and phytosterols (Note: these compounds are more soluble in ethyl acetate). Ethyl acetate extracts from Caulerpa racemosa and Padina minor, had the highest alpha-amylase inhibitory activity, and also showed moderately high antioxidant activities, stigmasterol content and polyphenolic content. Caulerpa racemose, being green algae, does not contain fucoxanthin, while Padina minor, being brown algae, contains high amounts of fucoxanthin. Therefore, it is very unlikely that fucoxanthin contributes to alpha-amylase inhibitory activity as previously reported. PMID- 29157607 TI - Is vacuum ultraviolet detector a concentration or a mass dependent detector? AB - The vacuum ultraviolet detector (VUV) is a very effective tool for chromatogram deconvolution and peak identification, and can also be used for quantification. To avoid quantitative issues in relation to time drift, such as variation of peak area or peak height, the detector response type has to be well defined. Due to the make-up flow and pressure regulation of make-up, the detector response (height of the peak) and peak area appeared to be dependent on experimental conditions such as inlet pressure and make-up pressure. Even if for some experimental conditions, VUV looks like mass-flow sensitive detector, it has been demonstrated that VUV is a concentration sensitive detector. PMID- 29157608 TI - Retention and effective diffusion of model metabolites on porous graphitic carbon. AB - The study of metabolites in biological samples is of high interest for a wide range of biological and pharmaceutical applications. Reversed phase liquid chromatography is a common technique used for the separation of metabolites, but it provides little retention for polar metabolites. An alternative to C18 bonded phases, porous graphitic carbon has the ability to provide significant retention for both non-polar and polar analytes. The goal of this work is to study the retention and effective diffusion properties of porous graphitic carbon, to see if it is suitable for the wide injection bands and long run times associated with long, packed capillary-scale separations. The retention of a set of standard metabolites was studied for both stationary phases over a wide range of mobile phase conditions. This data showed that porous graphitic carbon benefits from significantly increased retention (often >100 fold) under initial gradient conditions for these metabolites, suggesting much improved ability to focus a wide injection band at the column inlet. The effective diffusion properties of these columns were studied using peak-parking experiments with the standard metabolites under a wide range of retention conditions. Under the high retention conditions, which can be associated with retention after injection loading for gradient separations, Deff/Dm~0.1 for both the C18-bonded and porous graphitic carbon columns. As C18 bonded particles are widely, and successfully utilized for long gradient separations without issue of increasing peak width from longitudinal diffusion, this suggests that porous graphitic carbon should be amenable for long runtime gradient separations as well. PMID- 29157609 TI - Specific recognition of polyphenols by molecularly imprinted polymers based on a ternary deep eutectic solvent. AB - Typically, a target compound is selected as a template for a molecularly imprinted polymer (MIP); however, some target compounds are not suitable as templates because of their poor solubility. Using the tailoring properties of a deep eutectic solvent (DES), the insoluble target compound caffeic acid was transformed into a ternary choline chloride-caffeic acid-ethylene glycol (ChCl-CA EG) DES, which was then employed as a template to prepare MIPs. The ternary DES based MIPs were characterized by Fourier transform infrared spectroscopy, elemental analysis, scanning electron microscopy, and atomic force microscopy. The effects of time, temperature, ionic strength, and pH on the recognition processes for four polyphenols (caffeic acid, protocatechuic acid, catechin, and epicatechin) by 13 ChCl-CA-EG ternary DES-based MIPs was investigated using high performance liquid chromatography. The recognition specificity of the MIPs for CA was significantly better than that for the other polyphenols, and the MIPs exhibited obvious characteristics of chromatographic packing materials. In addition, the recognition processes mainly followed a second-order kinetics model and the Freundlich isotherm model, which together indicated that the MIPs mainly recognized the polyphenols by chemical interactions including ion exchange, electron exchange, and new bond formation. Furthermore, the specific recognition ability of the MIPs for polyphenols, which was better than those of C18, C8, or non-molecularly imprinted polymer adsorbents, was successfully applied to the recognition of polyphenols in a Radix asteris sample. The transformation of an insoluble target compound in a polymeric DES for MIP preparation and recognition is a novel and feasible strategy suitable for use in further MIP research developments. PMID- 29157610 TI - Chronic lung disorders and abdominal aortic aneurysms: An old clinical observation now proven? PMID- 29157611 TI - Epidemiology of Castleman Disease. AB - Castleman disease is a rare entity, including unicentric Castleman disease (UCD), human herpesvirus-8 plus Castleman disease (HHV-8+MCD), and idiopathic multicentric Castleman disease (iMCD). UCD is the most common at 16 per million person years and occurs at every age. HHV-8+MCD incidence varies widely, mostly affecting human immunodeficiency virus-positive men. iMCD is likely a more heterogeneous disease with an estimated incidence of 5 per million person years. Improved definitions should improve understanding of the epidemiology of Castleman disease and its subtypes. PMID- 29157612 TI - TAFRO Syndrome. AB - TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS). Lymph node biopsy is recommended to exclude other diseases and to diagnose TAFRO syndrome, which reveals characteristic histopathological findings similar to hyaline vascular type CD. TAFRO syndrome follows a more aggressive course, compared with iMCD-NOS, and there is no standard treatment. PMID- 29157613 TI - Castleman Disease Pathogenesis. AB - Castleman disease (CD) describes a group of heterogeneous disorders with common lymph node histopathologic features, including atrophic or hyperplastic germinal centers, prominent follicular dendritic cells, hypervascularization, polyclonal lymphoproliferation, and/or polytypic plasmacytosis. The cause and pathogenesis of the four subtypes of CD (unicentric CD; human herpesvirus-8-associated multicentric CD; polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes [POEMS]-associated multicentric CD; and idiopathic multicentric CD) vary considerably. This article provides a summary of our current understanding of the cause, cell types, signaling pathways, and effector cytokines implicated in the pathogenesis of each subtype. PMID- 29157614 TI - POEMS Syndrome: Diagnosis and Investigative Work-up. AB - POEMS syndrome is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Recognition of a combination of peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes, papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis, and Castleman disease is the first step in managing the disease. Increased blood levels of vascular endothelial growth factor are usually confirmatory. This rare disorder should not be missed, especially if the patient has a putative diagnosis of chronic inflammatory polyradiculoneuropathy, a lambda restricted monoclonal gammopathy, and thrombocytosis, and is not responding as expected to immunomodulatory therapy commonly used for chronic inflammatory polyradiculoneuropathy. PMID- 29157615 TI - POEMS Syndrome: Therapeutic Options. AB - Treatment of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome should be directed at the underlying plasma cell clone with risk-adapted therapy based on the extent of the plasma cell disorder. Radiation therapy is effective for patients with a localized presentation, without bone marrow involvement, and 1 to 3 bone lesions. Patients with disseminated disease should receive, preferably, high-dose chemotherapy with peripheral blood transplantation. Low-dose melphalan and dexamethasone or new agents used in myeloma are also effective. The most promising agent is lenalidomide, which could be given before high-dose therapy or radiation to get rapid neurologic responses. PMID- 29157616 TI - The Peripheral Neuropathies of POEMS Syndrome and Castleman Disease. AB - Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome is a rare paraneoplastic disorder. The polyneuropathy can be the presenting symptom and is typically a painful, motor predominant polyradiculoneuropathy often mimicking chronic inflammatory demyelinating polyradiculoneuropathy. The presence of a lambda monoclonal protein, elevated vascular endothelial growth factor, systemic features, and treatment resistance are clues to the diagnosis. Castleman disease (CD) is seen in a subset of these patients, and when present the neuropathy is similar but less severe. In contrast, in those patients with purely CD, the neuropathy is often a mild, painless distal sensory neuropathy. PMID- 29157617 TI - The Role of Interleukin-6 in Castleman Disease. AB - Since its discovery, improvements in treating Castleman disease and its variants have centered on interleukin-6 (IL-6). IL-6 was discovered from T-cell factors (BCDF or BSF-2), which induced B-cell maturation. Most symptoms of the plasma cell variant of Castleman disease are linked to the hyperfunction of IL-6, constitutively produced in the affected lymph nodes (1989), suggesting IL-6 is key in the pathogenesis of multicentric Castleman disease (MCD). The results of several studies have shown that most MCD symptoms and abnormal laboratory results are improved by anti-IL-6 MCD treatments, such as tocilizumab, a humanized anti IL-6 receptor antibody, and siltuximab, an anti-IL-6 antibody. PMID- 29157618 TI - Pathology of Castleman Disease. AB - The term Castleman disease encompasses several distinct lymphoproliferative disorders with different underlying disease pathogenesis, and clinical outcomes. It includes unicentric and multicentric diseases with limited versus significant systemic symptoms, respectively. Importantly, the histopathologic features encountered in the various forms of Castleman disease are diverse, and for the most part, lack specificity, because they are seen to varying degrees in different clinical variants of Castleman disease, and in reactive (autoimmune/infectious) and malignant (lymphoma) contexts. Accordingly, accurate clinical diagnosis of Castleman disease requires careful and thorough clinicopathologic correlation. An overview of the key histopathologic features of Castleman disease is presented. PMID- 29157619 TI - Diagnosis of Castleman Disease. AB - Castleman disease (CD) is a rare and heterogenous group of disorders sharing in common an abnormal lymph node pathology. CD comprises distinct subtypes with different prognoses. Unicentric CD and multicentric CD are featured by specific systemic manifestations and may be associated with Kaposi sarcoma, non-Hodgkin and Hodgkin lymphoma, and POEMS syndrome. Multicentric CD is classically associated with systemic symptoms and poorer prognosis. In this article, the authors review how to diagnose the disease, keeping in context the clinical findings, biochemical changes and complications associated with CD. PMID- 29157620 TI - Unicentric Castleman Disease. AB - Unicentric Castleman disease (UCD) is a rare lymphoproliferative disorder that manifests typically as proliferation of a single lymph node or region of lymph nodes. Histologically, hyaline vascular variant is found in a majority of UCDs. UCD commonly presents in younger patient populations. Patients with UCD may be asymptomatic or present with symptoms related to mass effects on surrounding structures. It is difficult to achieve a definitive diagnosis by imaging alone. Histologic examination of the lesion remains the gold standard for diagnosis. Complete surgical resection is the best primary treatment modality for UCD resulting in excellent long-term survival and low recurrence rates. PMID- 29157622 TI - Treatment of Idiopathic Castleman Disease. AB - Important progress has been made in the treatment of idiopathic multicentric Castleman disease (iMCD) with the introduction of interleukin-6 targeting monoclonal antibodies. This article describes the clinical results obtained with different treatment modalities and uses this evidence to provide treatment guidelines for the practicing clinician. Much is still to be learned about the pathophysiology of iMCD and further research is urgently needed to develop novel and curative treatment approaches for all patients. PMID- 29157623 TI - Castleman Disease. PMID- 29157621 TI - Treatment of Kaposi Sarcoma Herpesvirus-Associated Multicentric Castleman Disease. AB - Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a rare, polyclonal lymphoproliferative disorder characterized by flares of inflammatory symptoms, edema, cytopenias, lymphadenopathy, and splenomegaly. Diagnosis requires a lymph node biopsy. Pathogenesis is related to dysregulated inflammatory cytokines, including human and viral interleukin-6. Rituximab alone or in combination with chemotherapy, such as liposomal doxorubicin, has led to an overall survival of over 90% at 5 years. Experimental approaches to treatment include virus activated cytotoxic therapy with high-dose zidovudine and valganciclovir and targeting human interleukin-6 activity. Despite successful treatment of KSHV-MCD, patients remain at high risk for developing non-Hodgkin lymphomas. PMID- 29157624 TI - Language-specific strategy for programming hearing aids - A double-blind randomized controlled crossover study. AB - OBJECTIVE: Voice-aligned compression (VAC) is a method used in Oticon's hearing aids to provide more comfortable hearing without sacrificing speech discrimination. The complex, non-linear compression curve for the VAC strategy is designed based on the frequency profile of certain spoken Western languages. We hypothesized that hearing aids could be further customized for Japanese-speaking users by modifying the compression curve using the frequency profile of spoken Japanese. METHODS: A double-blind randomized controlled crossover study was performed to determine whether or not Oticon's modified amplification strategy (VAC-J) provides subjectively preferable hearing aids for Japanese-speaking hearing aid users compared to the same company's original amplification strategy (VAC). The participants were randomized to two groups. The VAC-first group received a pair of hearing aids programmed using the VAC strategy and wore them for three weeks, and then received a pair of hearing aids programmed using VAC-J strategy and wore them for three weeks. The VAC-J-first group underwent the same study, but they received hearing aids in the reverse sequence. A Speech, Spatial and Qualities (SSQ) questionnaire was administered before beginning to use the hearing aids, at the end of using the first pair of hearing aids, and at the end of using the second pair of hearing aids. RESULTS: Twenty-five participants that met the inclusion/exclusion criteria from January 1 to October 31, 2016, were randomized to two groups. Twenty-two participants completed the study. There were no statistically significant differences in the increment of SSQ scores between the participants when using the VAC- or the VAC-J-programmed hearing aids. However, participants preferred the VAC-J strategy to the VAC strategy at the end of the study, and this difference was statistically significant. CONCLUSION: Japanese-speaking hearing aid users preferred using hearing aids that were fitted with the VAC-J strategy. Our results show that the VAC strategy can be adjusted to the frequency profile of different languages and that participants expressed their subjective preference more clearly than was reflected in the SSQ scores. A similar language-specific strategy may improve user's satisfaction while using hearing devices, and this concept may be extended to implantable hearing devices. CLINICAL RESEARCH REGISTRATION NUMBER: R000023191. PMID- 29157625 TI - Pediatric type 1 cartilage tympanoplasty outcomes: A comparison of short and long term hearing results. AB - OBJECTIVE: Tympanoplasty is a commonly used procedure in children as in adults. The purposes of this study were to evaluate and report the long term results of type 1 cartilage tympanoplasty in pediatric population. Short term and long term hearing outcomes were compared according to age and perforation location. METHODS: We retrospectively evaluated a total of 76 of 93 patients who had regularly come to visits (38 male and 38 female) with chronic otitis media (COM) and who were younger than 16 years (range, 9-16 years) and underwent a primary type 1 tympanoplasty in tertiary medical center. We divided our population into 2 groups; a younger group (age <12 years) and an older group (age >=12 years). Age, gender, follow-up time, prior to surgery and at postoperative 6th and minimum 48th month follow-up pure tone audiometry (PTA) thresholds and if any residual perforation were noted. RESULTS: Successful closure occurred 74 in 76 patients and success rate was 97,03%. The mean 6th month follow-up bone conduction threshold values were 7,61+/-3,89 and 6,89+/-6,28 <12 years old and >=12 years old children, respectively. The mean 48th month follow-up bone conduction threshold values were 6,93+/-4,00 and 7,12+/-6,40, <12 years old and >=12 years old children, respectively. The mean 6th month follow-up air conduction threshold values were 23,75+/-8,38 and 24,73+/-10,41 <12 years old and >=12 years old children, respectively. The mean 48th month follow-up air conduction threshold values were 17,15+/-6,04 and 20,30+/-10,30, <12 years old and >=12 years old children, respectively. Among all children; preoperative mean air conduction differed significantly from postoperative 6th and 48th month follow-up mean air conduction thresholds (p<0.001). They had significant improvement in their ABG compared with their preoperative ABG scores. In addition according to groups, there was no significantly difference between pre and postoperative ABG improvement in both 6th and 48th month follow-up between <12 years old and >=12 years old patient group. CONCLUSION: In pediatric patients type 1 tympanoplasty with cartilage graft, gives statistically significant success in long term follow up. Long term hearing results of primary type 1 cartilage tympanoplasty is seem to be better than short term hearing results as well. We consider that cartilage graft could be the best graft material for pediatric tympanoplasty for long term success. PMID- 29157626 TI - Risk association of congenital anomalies in patients with ambiguous genitalia: A 22-year single-center experience. AB - BACKGROUND: Ambiguous genitalia refers to a form of differences of sex development (DSD) wherein the appearance of the external genitalia is atypical. This rare condition presents challenges in decision-making and clinical management. Review of historical data may reveal areas for clinical research to improve care for patients with ambiguous genitalia. OBJECTIVE: This chart review was performed to identify patients with ambiguous genitalia, and to classify them as having 46,XX DSD, 46,XY DSD, or sex chromosome DSD. Within these categories, we looked at establishment of specific diagnoses, type and frequency of other congenital anomalies and neoplasms, and gender assignment, as well as incidence of gender reassignment and transition. METHODS: We performed a retrospective chart review of patients diagnosed with DSD conditions from 1995 to 2016 using ICD9 codes. For the purpose of this study, review was limited to individuals assessed to have neonatal "ambiguous genitalia" or "indeterminate sex." RESULTS: Review identified 128 patients evaluated for ambiguous genitalia from 22 years of experience (Figure). Approximately half of these (53%) had 46,XY karyotype, 35% had 46,XX, and the remaining 12% had sex chromosome aberrations. Diagnostic rate for 46,XX DSD was higher at 64%, all of which were congenital adrenal hyperplasia, while diagnostic rate for 46,XY DSD was 11.7% for a molecularly confirmed diagnosis and 24% if clinical diagnoses were included. The most common anomalies included cardiac anomalies in 28/128 (22%), skeletal anomalies in 19/128 (15%), and failure to thrive or growth problems in 19/128 (15%). Additional congenital anomalies were found in 53 out of 128 patients (41%). There were three reported neoplasms in this group: gonadoblastoma, hepatoblastoma, and myelodysplastic syndrome with monosomy 7. Gender assignment was consistent with chromosomes in approximately 90% of XX and XY patients. There were three recorded gender reassignments or transitions. DISCUSSION: Diagnostic rate for ambiguous genitalia is low, especially in 46,XY DSD. Most neonates were assigned gender consistent with their chromosomes. Given the high rate of associated anomalies, screening for cardiac or other anomalies in patients with ambiguous genitalia may be beneficial. CONCLUSION: Patients with ambiguous genitalia often have additional congenital anomalies. Establishment of a specific diagnosis is uncommon in 46,XY patients. A few patients have gender reassignment outside of the newborn period. Ongoing collection of clinical data on this population may reveal new information regarding long-term health, quality of life, and establishment of more diagnoses with improved molecular techniques. PMID- 29157628 TI - Reply. PMID- 29157627 TI - Letrozole may be a valuable maintenance treatment in high-grade serous ovarian cancer patients. AB - OBJECTIVES: Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as maintenance in high-grade serous ovarian cancers (HGSOC). METHODS: We accessed the TCGA PANCAN dataset to evaluate the expression of ESR1. ESR1 expression data on all cancers (n=8901) and HGSOC (n=527) were followed by investigation of ER expression via immunohistochemistry (IHC) (n=4071). The same was performed in an independent cohort for matched primary and recurrent HGSOC (n=80). Finally, newly diagnosed ER+ HGSOC patients were offered a maintenance therapy with Letrozole. RESULTS: ESR1 was strongly expressed in similar levels in HGSOC as in breast cancer. We found a strong ER expression via IHC in both the primary and matched recurrent HGSOC, particularly in the Platinum-resistant subgroup. The additional use of Letrozole as maintenance treatment was associated with a significantly prolonged recurrence free interval (after 24months 60% when taking Letrozole versus 38.5% in the control group; p=0.035; RFS: IC50 reached by one subject versus 13.2months). This effect was also present in patients treated additionally with Bevacizumab; 20.8% of patients had no recurrence after 12months compared to 87.5% when taking Letrozole in addition to Bevacizumab (p=0.026). CONCLUSIONS: Primary HGSOC have a slightly higher ESR1 than and a similar ER expression breast cancer where aromatase inhibitor maintenance is routine for decades. Here we demonstrate evidence for the usefulness of Letrozole in HGSOC, particularly in patients with chemotherapy resistance or residual disease. PMID- 29157629 TI - MRI appearance in the early stage of Legg-Calve-Perthes disease to predict lateral pillar classification: A retrospective analysis of the labral horizontalization. AB - BACKGROUND: The Herring lateral pillar classification is widely used for the classification of Legg-Calve-Perthes disease, but is not applied at the early stage of Legg-Calve-Perthes disease because it is typically applied at the late fragmentation stage. The purpose of this study was to investigate the correlation between the early appearance on magnetic resonance imaging of the acetabular labrum and lateral pillar involvement in Legg-Calve-Perthes disease. METHODS: Non contrast magnetic resonance images of 26 hips in 25 children with early-stage Legg-Calve-Perthes disease were retrospectively reviewed. The extent of labral horizontalization was quantitatively evaluated with a new method, the labral angle, on T2*-weighted magnetic resonance images. A small labral angle indicates strong labral horizontalization. Calculation of the teardrop distance and acetabular head index on radiographs was modified for application to magnetic resonance imaging, and the extent of cartilaginous lateral subluxation (cartilaginous tear drop distance) and cartilaginous lateral extrusion (cartilaginous acetabular head index) were evaluated. The outcome measure was the lateral pillar classification. RESULTS: There were statistically significant correlations between the labral angle and the cartilaginous tear drop distance (p = 0.002, ? = -0.58) and the cartilaginous acetabular head index (p < 0.001, ? = 0.65) on magnetic resonance images. The labral angle was small in order of groups C, B, and A, and there were significant differences between groups A and C (p < 0.001) and B and C (p = 0.006). CONCLUSION: Greater labral horizontalization observed on magnetic resonance imaging at the early stage of Legg-Calve-Perthes disease correlated with strong cartilaginous lateral subluxation and extrusion, and with increased lateral pillar collapse at the maximum fragmentation stage. Our finding suggests that a quantitative evaluation of labral horizontalization using magnetic resonance imaging in the early-stage of Legg-Calve-Perthes disease can predict the later lateral pillar classification. PMID- 29157630 TI - The first postoperative-stimulated serum thyroglobulin is a prognostic factor for thyroid microcarcinomas. AB - INTRODUCTION: Endogenous thyroid-stimulating hormone-stimulated thyroglobulin collected after total thyroidectomy is a useful predictor of better prognosis in patients with differentiated thyroid carcinomas in general, but studies with microcarcinomas are scarce. OBJECTIVE: To assess whether the first postoperative stimulated thyroglobulin measurement is a prognostic factor in patients with microcarcinoma. METHODS: The medical data of 150 differentiated thyroid carcinoma patients were studied retrospectively, and 54 (36%) cases with microcarcinoma were selected. The first postoperative stimulated thyroglobulin (1st stimulated thyroglobulin), measured after thyroidectomy, initial presentation data, and microcarcinomas treatment were assessed regarding outcome. Worse prognosis was defined as neoplasm persistence/recurrence. RESULTS: Persistence/recurrence occurred in 27.6% of the cases. These patients were identified according to the following parameters: receiving more than one 131iodine dose (100% vs. 0%; p<0.0001); accumulated 131iodine dose (232.14+/-99.09 vs. 144+/-33.61mCi; p<0.0001); presented active disease in the last assessment (53.3% vs. 0%; p<0.0001); follow-up time (103.07+/-61.27 vs. 66.85+/-70.14 months; p=0.019); and 1st stimulated thyroglobulin (19.01+/-44.18 vs. 2.19+/-2.54ng/dL; p<0.0001). After multivariate logistic regression, only the 1stSTg [odds ratio=1.242; 95% confidence interval: 1.022-1.509; p=0.029] and follow-up time (odds ratio=1.027; 95% confidence interval: 1.007-1.048; p=0.007) were independent predictors of risk of persistence/recurrence. The cutoff point of 1.6ng/dL for the 1st stimulated thyroglobulin was significantly associated with disease persistence/recurrence [area under the curve=0.713 (p=0.019)]. CONCLUSION: The first stimulated thyroglobulin predicted disease persistence/recurrence in patients with microcarcinoma. PMID- 29157631 TI - Extreme gigantomastia. PMID- 29157632 TI - Appendicular Deciduosis as a Cause of Acute Abdomen. PMID- 29157633 TI - Painting a nightmare. PMID- 29157634 TI - The intersection between sleep science and policy: introduction to the special issue on school start times. PMID- 29157635 TI - Effects of school start time on students' sleep duration, daytime sleepiness, and attendance: a meta-analysis. AB - Research conducted over the past three decades finds that many children and adolescents do not meet recommended sleep guidelines. Lack of sleep is a predictor of a number of consequences, including issues at school such as sleepiness and tardiness. Considering the severity of this public health issue, it is essential to understand more about the factors that may compromise children's and adolescents' sleep. This meta-analysis examined the effects of school start time (SST) on sleep duration of students by aggregating the results of five longitudinal studies and 15 cross-sectional comparison group studies. Results indicated that later starting school times are associated with longer sleep durations. Additionally, later start times were associated with less daytime sleepiness (7 studies) and tardiness to school (3 studies). However, methodological considerations, such as a need for more longitudinal primary research, lead to a cautious interpretation. Overall, this systematic analysis of SST studies suggests that delaying SST is associated with benefits for students' sleep and, thus, their general well-being. PMID- 29157636 TI - Youth sleep durations and school start times: a cross-sectional analysis of the COMPASS study. AB - OBJECTIVES: This study explored school start times (SST) in relation to sleep duration and adherence to guidelines among Canadian youth. METHODS: Using Year 4 (2015/2016) data from the Cannabis, Obesity, Mental health, Physical activity, Alcohol use, Smoking, and Sedentary behaviour (COMPASS) study, the sample included 35,821 grade 9-12 students at 78 secondary schools in Ontario and Alberta, Canada. Random intercepts models tested student-reported sleep duration and whether students met sleep recommendations, as a function of SST, controlling for student- (race/ethnicity, grade, sex, travel mode to school) and school-level (school-area urbanicity and median household income) correlates. RESULTS: For each hour delay in SST, students reported an average of almost 7 minutes longer sleep and had 1.17 (adjusted odds ratio; 95% confidence interval, 1.04-1.31) higher odds of meeting the recommendations, with other factors held constant. CONCLUSIONS: Potential impacts on student sleep require consideration when deciding on school schedules. Delayed SST warrant further exploration as an intervention to help ameliorate the widespread sleep deprivation found among Canadian youth. PMID- 29157637 TI - A quasi-experimental study of the impact of school start time changes on adolescent sleep. AB - OBJECTIVE: To determine whether simultaneous school start time changes (delay for some schools; advance for others) impact adolescents' sleep. DESIGN: Quasi experimental study using cross-sectional surveys before and after changes to school start times in September 2015. SETTING: Eight middle (grades 7-8), 3 secondary (grades 7-12), and 8 high (grades 9-12) schools in Fairfax County (Virginia) public schools. PARTICIPANTS: A total of 2017 (6% of ~34,900) students were surveyed before start time changes, and 1180 (3% of ~35,300) were surveyed after. INTERVENTION: A 50-minute delay (7:20 to 8:10 am) in start time for high schools and secondary schools and a 30-minute advance (8:00 to 7:30 am) for middle schools. MEASUREMENTS: Differences before and after start time changes in self-reported sleep duration and daytime sleepiness. RESULTS: Among respondents, 57.5% were non-Hispanic white, and 10.3% received free or reduced-priced school meals. Before start time changes, high/secondary and middle school students slept a mean (SD) of 7.4 (1.2) and 8.4 (1.0) hours on school nights, respectively, and had a prevalence of daytime sleepiness of 78.4% and 57.2%, respectively. Adjusted for potential confounders, students with a 50-minute delay slept 30.1 minutes longer (95% confidence interval [CI], 24.3-36.0) on school nights and had less daytime sleepiness (-4.8%; 95% CI, -8.5% to -1.1%), whereas students with a 30 minute advance slept 14.8 minutes less (95% CI, -21.6 to -8.0) and had more daytime sleepiness (8.0%; 95% CI, 2.5%-13.5%). CONCLUSIONS: Both advances and delays in school start times are associated with changes in adolescents' school night sleep duration and daytime sleepiness. Larger changes might occur with later start times. PMID- 29157638 TI - High school start times after 8:30 am are associated with later wake times and longer time in bed among teens in a national urban cohort study. AB - OBJECTIVES: High school start times are a key contributor to insufficient sleep. This study investigated associations of high school start times with bedtime, wake time, and time in bed among urban teenagers. DESIGN: Daily-diary study nested within the prospective Fragile Families and Child Wellbeing Study. SETTING: Twenty US cities. PARTICIPANTS: Four hundred thirteen teenagers who completed >=1 daily diary report on a school day. MEASUREMENTS: Participating teens were asked to complete daily diaries for 7 consecutive days. School-day daily diaries (3.8+/-1.6 entries per person) were used in analyses (N=1555 school days). High school start time, the main predictor, was categorized as 7:00-7:29 am (15%), 7:30-7:59 am (22%), 8:00-8:29 am (35%), and 8:30 am or later (28%). Multilevel modeling examined the associations of school start times with bedtime, wake time, and time in bed. Models adjusted for age, sex, race/ethnicity, household income, caregiver's education, and school type. RESULTS: Teens with the earliest high school start times (7:00-7:29 am) obtained 46 minutes less time in bed on average compared with teens with high school start times at 8:30 am or later (P<.001). Teens exhibited a dose-response relationship between earlier school start times and shorter time in bed, primarily due to earlier wake times (P<.05). Start times after 8:30 am were associated with increased time in bed, extending morning sleep by 27-57 minutes (P<.05) when compared with teens with earlier school start times. CONCLUSION: Later school start times are associated with later wake times in our large, diverse sample. Teens starting school at 8:30 am or later are the only group with an average time in bed permitting 8 hours of sleep, the minimum recommended by expert consensus for health and well-being. PMID- 29157639 TI - The economic implications of later school start times in the United States. AB - Numerous studies have shown that later school start times (SST) are associated with positive student outcomes, including improvements in academic performance, mental and physical health, and public safety. While the benefits of later SST are very well documented in the literature, in practice there is opposition against delaying SST. A major argument against later SST is the claim that delaying SST will result in significant additional costs for schools due to changes in bussing strategies. However, to date, there has only been one published study that has quantified the potential economic benefits of later SST in relation to potential costs. The current study investigates the economic implications of later school start times by examining a policy experiment and its subsequent state-wide economic effects of a state-wide universal shift in school start times to 8.30AM. Using a novel macroeconomic modeling approach, the study estimates changes in the economic performance of 47 US states following a delayed school start time, which includes the benefits of higher academic performance of students and reduced car crash rates. The benefit-cost projections of this study suggest that delaying school start times is a cost-effective, population-level strategy, which could have a significant impact on public health and the US economy. From a policy perspective, these findings are crucial as they demonstrate that significant economic gains resulting from the delay in SST accrue over a relatively short period of time following the adoption of the policy shift. PMID- 29157640 TI - Early to bed, early to rise: sleep perceptions, patterns and related behaviors in ultra-orthodox Jewish adolescents in Israel. AB - OBJECTIVES: Studies have described biological and environmental mechanisms underlying adolescent sleep, yet the role of culture has received little attention. Ultra-orthodox (Haredi) Judaism adheres to a traditional lifestyle. To examine how culture and lifestyle are associated with sleep, this study compared sleep perceptions, habits, and patterns and related daytime behaviors among ultra orthodox and secular Jewish adolescents. METHODS: A sample of 178 healthy adolescents (116 ultra-orthodox, 77 males, ages 13-17) gathered via snowball sampling completed the School Sleep Habits Survey to assess sleep perceptions, habits, patterns (timing and duration), and related behaviors (sleepiness, mood, sleep-problem behaviors). Chi-square tests compared group sleep perceptions and habits. MANCOVAs tested GROUP, GENDER, and GROUP * GENDER interactions for sleep patterns and related behaviors, controlling for school start time, media devices, and habitual prayer. RESULTS: Compared with the secular group, ultra-orthodox adolescents perceived their sleep as more satisfactory (P<.05) and reported shorter sleep onset latency (P<.001). Ultra-orthodox males reported earlier bedtimes and longer sleep duration on school nights, earlier bed and wake times and shorter sleep duration on non-school nights, and less sleepiness and fewer sleep-problem behaviors (P<.05) than their group and gender counterparts. CONCLUSIONS: Ultra-orthodox males exhibited early and regular sleep timing that may be considered unique among healthy adolescents. Our comparison of sleep and related behaviors in adolescents having common hereditary backgrounds yet distinct cultural backgrounds provides insights into the cultural underpinnings of adolescent sleep. Professionals who work with adolescents should be aware of changes in sleep in the cultural context. PMID- 29157642 TI - Engaging the community in the process of changing school start times: experience of the Cherry Creek School District. AB - Despite growing evidence of the positive impact of later school start times on adolescent health and academic outcomes, relatively few districts have changed start times due to concerns about transportation, child care, and athletics/extracurricular activities. This paper provides a case study of the Cherry Creek School District's (CCSD) successful efforts to change start times. The CCSD is a diverse district with an enrollment of almost 55,000 students in suburban Denver. As part of CCSD's strategic plan, a multi-disciplinary task force was formed to examine the impact of start times on student achievement, and recommend a start time schedule driven by best practices on adolescent sleep patterns, balanced with family and community needs. Over 18 months the task force's work included engaging the community through meetings, as well as conducting a large survey (n = 24,574) of parents, teachers, and students, and gathering online feedback. An iterative process utilized feedback at every stage to refine the final recommendation given to the Board of Education. Survey results, implementation considerations, outcome evaluation plans, and lessons learned are discussed. PMID- 29157641 TI - A process-oriented model linking adolescents' sleep hygiene and psychological functioning: the moderating role of school start times. AB - OBJECTIVE: To examine a mediational model linking sleep hygiene to better mental health in adolescents via the mechanism of improved sleep quality, and to test the moderating role of school start times (SST) (before 8:30 AM vs. 8:30 AM or later) on that mediation model. DESIGN: Cross-sectional. SETTING: Online survey for high school students across the United States. PARTICIPANTS: A total of 197 adolescents aged 14-17 years old (Mage = 15.6 years, SD = 1.8; 53% female) completed a baseline survey and 7-day sleep diaries; their parents (Mage = 47.7 years, SD = 5.5; 79% female) reported on family socioeconomic status and high SST. MEASUREMENT: Adolescents reported on their sleep hygiene, circadian chronotype, daily levels of sleep quality and duration (morning diaries) and their depressive/anxiety symptoms (evening diaries) for 7 days. RESULTS: A moderated-mediation model suggested that baseline sleep hygiene was directly associated with lower average daily depressive/anxiety symptoms across all students, but that association was marginally stronger in students with later SST (8:30 AM or later). A mediated path emerged only for students with earlier start times, suggesting that, for those students, baseline sleep hygiene was indirectly associated with lower average daily psychological symptoms by improving average daily sleep quality. CONCLUSIONS: The current study is one of the first to demonstrate that SST might serve as a critical moderator in models of adolescent sleep and daily functioning. The findings provide additional evidence in the debate on how SST may affect adolescent health. PMID- 29157643 TI - Creating regional consensus for starting school later: a physician-driven approach in southern Maine. AB - In April 2016, several contiguous school districts and an independent high school academy in southern Maine voted simultaneously to start school later, beginning with the 2016-17 academic year. They became Maine's first school districts to implement the American Academy of Pediatrics'1 and the American Medical Association's2 health policy recommendations that middle and high schools should not start before 8:30 AM. Local physicians' presentations to school staff and parents on the medical evidence of the health benefits of a later start solidified early consensus. The action required special permission from the Maine Municipal Association to hold a joint school board vote, impacted approximately 6500 students across the region, resulted in no increase in busing costs, and took 8 months to implement after the first formal school board discussions. PMID- 29157644 TI - Applying behavioral insights to delay school start times. AB - Healthy People 2020 established a national objective to increase the proportion of 9th-to-12th-grade students reporting sufficient sleep. A salient approach for achieving this objective is to delay middle and high school start times. Despite decades of research supporting the benefits of delayed school start times on adolescent sleep, health, and well-being, progress has been slow. Accelerating progress will require new approaches incorporating strategies that influence how school policy decisions are made. In this commentary, we introduce four strategies that influence decision-making processes and demonstrate how they can be applied to efforts aimed at changing school start time policies. PMID- 29157645 TI - Law-based arguments and messages to advocate for later school start time policies in the United States. AB - The increasing scientific evidence that early school start times are harmful to the health and safety of teenagers has generated much recent debate about changing school start times policies for adolescent students. Although efforts to promote and implement such changes have proliferated in the United States in recent years, they have rarely been supported by law-based arguments and messages that leverage the existing legal infrastructure regulating public education and child welfare in the United States. Furthermore, the legal bases to support or resist such changes have not been explored in detail to date. This article provides an overview of how law-based arguments and messages can be constructed and applied to advocate for later school start time policies in US public secondary schools. The legal infrastructure impacting school start time policies in the United States is briefly reviewed, including descriptions of how government regulates education, what legal obligations school officials have concerning their students' welfare, and what laws and public policies currently exist that address adolescent sleep health and safety. On the basis of this legal infrastructure, some hypothetical examples of law-based arguments and messages that could be applied to various types of advocacy activities (eg, litigation, legislative and administrative advocacy, media and public outreach) to promote later school start times are discussed. Particular consideration is given to hypothetical arguments and messages aimed at emphasizing the consistency of later school start time policies with existing child welfare law and practices, legal responsibilities of school officials and governmental authorities, and societal values and norms. PMID- 29157647 TI - Preface. PMID- 29157646 TI - Self-report surveys of student sleep and well-being: a review of use in the context of school start times. AB - A large body of literature supports the need to delay high school starting times to improve student health and well-being by allowing students an opportunity to get sufficient and appropriately timed sleep. However, a dearth of uniform and standardized tools has hampered efforts to collect data on adolescent sleep and related health behaviors that might be used to establish a need for, or to evaluate outcomes of, bell time delays. To assess validated tools available to schools and contrast them with tools that schools have actually used, we identified and reviewed published, validated self-report surveys of adolescent sleep and well-being, as well as unpublished surveys, used to assess student sleep and related health measures in US high schools considering later high school start times. Only three of the surveys reviewed had adequate psychometric properties and covered an appropriately wide range of health and academic questions to allow for discernment of outcomes in pre-post educational settings. The surveys exhibited marked variability in numerous areas, including focus, terminology, calculation of sleep duration, mode of administration, context of administration, and follow-up procedures. Our findings provide sleep researchers and school administrators with an overview of surveys that school districts have used, along with a deeper understanding of the challenges of choosing, designing, and administering self-report surveys in the context of changing school schedules. They also highlight the opportunities presented by these instruments to assess outcomes of delaying bell times, compare communities meaningfully, and establish the need for later school start times in individual school districts. PMID- 29157648 TI - Falls and Delirium: Platypnea-Orthodeoxia Syndrome. PMID- 29157649 TI - Without Further Delay: Lyme Carditis. PMID- 29157650 TI - Appropriate Use of Proton Pump Inhibitors: A Double-Edged Sword. PMID- 29157651 TI - Is Science Important? A Recent Lecture. PMID- 29157652 TI - Chronic Pulmonary Aspergillosis in a Patient with Splenectomy. PMID- 29157653 TI - How to Use Desmopressin to Manage Severe Chronic Hyponatremia? PMID- 29157654 TI - An innovative lung model for multiple breath washout testing in health and disease. AB - BACKGROUND: Multiple breath washout (MBW) is a lung function test that identifies the degree of ventilation inhomogeneity (VI) in the lungs. In vitro validation of MBW devices is recommended. So far, plastic lung models for MBW validation ignored variable degrees of VI. Our primary aim was to create a plastic lung model applicable for physiological lung volumes and variable VI. METHODS: A plastic box divided in two chambers was filled with water and ventilated in various lung volumes and respiratory rates. A ventilator was used for efficient gas distribution (model with low VI). An additional divider was inserted to create a model with high VI. The model was connected to commercial MBW devices and measurements were performed using different tracer gases and conditions. Primary outcome was the precision of generated functional residual capacity (FRC) and the ability to generate variable VI. The latter was estimated by lung clearance index (LCI) and expiratory phase III slopes (SIII). LCI was also compared to a mathematical model. FINDINGS: The intra-test variability for FRC was minimal, mean(SD) coefficient of variation 0.96(0.63)%, using different tracer gases under different conditions. Compared to the model with low VI, in the model with high VI LCI and washout SIII were significantly increased. LCI compared well to the mathematical model. INTERPRETATION: This novel lung model shows excellent precision in lung volumes and VI estimates independent of tracer gases and conditions. The model can mimic the lungs of patients with uneven gas distribution. PMID- 29157655 TI - Roles of high apolipoprotein E blood levels and HDL in development of familial dysbetalipoproteinemia in epsilon2epsilon2 subjects. AB - OBJECTIVE: Familial dysbetalipoproteinemia (FD) or Type III hyperlipoproteinemia is a mixed hyperlipidemia closely associated with the epsilon2epsilon2 genotype of the common APOE polymorphism although not all homozygotes progress to FD. Unlike the polymorphism, few studies explore effects of apolipoprotein E (apoE) blood levels on FD development. Likewise, despite the known apoE2 lipoprotein binding preference for high-density lipoprotein (HDL); little work exists exploring HDL in FD. Accordingly, this study was undertaken to investigate potential roles in FD development for apoE and HDL. Additionally, insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were investigated in view of reports linking insulin resistance to FD. METHODS: APOE genotyping and levels of apoE, apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II), insulin, HOMA-IR, lipids, and NMR lipoprotein analysis were determined in a cohort of healthy individuals (N=7169). A lipid-based algorithm identified FD in 24 of 52 e2e2 subjects. Logistic regression modeling assessed associations of FD development with measured variables. RESULTS: Univariate models revealed associations with FD significant and positive for apoE, apoA-II/apoA-I, apoA I/HDL-C, apoA-II/HDL-C, and HOMA-IR. For HDL-C, association was significant but inverse. Results of multivariable models containing apoE with single parameters added revealed statistical significance only for the apoA-II/HDL-C ratio (OR 10.52, 95%CI 1.17-94.79, p=0.036) concurrent with significance for apoE (OR 2.21, 95%CI 1.06-4.65, p=0.035). Interaction was not demonstrated (p=0.36). NMR results revealed for FD versus nonFD subjects generally higher levels of VLDL and small HDL and for IDL few differences. CONCLUSION: High apoE and high apoA-II/HDL-C independently associate with FD development in epsilon2epsilon2 individuals. PMID- 29157656 TI - Diagnosis and medical treatment of breakthrough pain. PMID- 29157657 TI - How I cannulate the bile duct. PMID- 29157658 TI - Continuous ambulatory hand force monitoring during manual materials handling using instrumented force shoes and an inertial motion capture suit. AB - Hand forces (HFs) are commonly measured during biomechanical assessment of manual materials handling; however, it is often a challenge to directly measure HFs in field studies. Therefore, in a previous study we proposed a HF estimation method based on ground reaction forces (GRFs) and body segment accelerations and tested it with laboratory equipment: GFRs were measured with force plates (FPs) and segment accelerations were measured using optical motion capture (OMC). In the current study, we evaluated the HF estimation method based on an ambulatory measurement system, consisting of inertial motion capture (IMC) and instrumented force shoes (FSs). Sixteen participants lifted and carried a 10-kg crate from ground level while 3D full-body kinematics were measured using OMC and IMC, and 3D GRFs were measured using FPs and FSs. We estimated 3D hand force vectors based on: (1) FP+OMC, (2) FP+IMC and (3) FS+IMC. We calculated the root-mean-square differences (RMSDs) between the estimated HFs to reference HFs calculated based on crate kinematics and the GRFs of a FP that the crate was lifted from. Averaged over subjects and across 3D force directions, the HF RMSD ranged between 10-15N when using the laboratory equipment (FP + OMC), 11-18N when using the IMC instead of OMC data (FP+IMC), and 17-21N when using the FSs in combination with IMC (FS + IMC). This error is regarded acceptable for the assessment of spinal loading during manual lifting, as it would results in less than 5% error in peak moment estimates. PMID- 29157659 TI - Letter to the Editor regarding "Sprint mechanics return to competition follow-up after hamstring injury on a professional soccer player: A case study with an inertial sensor unit based methodological approach" by I. Setuain, P. Lecumberri, and M. Izquierdo. PMID- 29157660 TI - Encephalitis and myelitis in tropical countries: Report from the Task Force on Tropical Diseases by the World Federation of Societies of Intensive and Critical Care Medicine. AB - Tropical diseases are those that occur primarily or solely in the tropics, and as such include infectious diseases that are particularly prevalent in hot, humid conditions. The incidence of encephalitis in tropical countries is reported to be as high as 6.34/100,000/year. The term encephalitis implies inflammation of the brain and includes the presence of encephalopathy with two and more of the following features: fever, seizures and/or focal neurological findings; a cerebrospinal fluid pleocytosis; electroencephalographic findings or abnormal neuroimaging suggestive of encephalitis. Transverse myelitis (TM) is an inflammation of the spinal cord which has a wide variety of clinical presentations depending on the degree (severity of myelin and neuronal injury) and site of spinal cord involvement. In the present article we discuss the various forms of tropical, viral encephalitides and myelitis and the diagnosis and management. PMID- 29157661 TI - Analysis of codon usage pattern of mitochondrial protein-coding genes in different hookworms. AB - The phenomenon of unequal usage of synonymous codons encoding an amino acid in which some codons are more preferred to others is the codon usage bias (CUB) and it is species specific. Analysis of CUB helps in understanding evolution at molecular level and acquires significance in mRNA translation, design of transgenes and new gene discovery. In our current study, we analyzed synonymous codon usage pattern and the factors influencing it on mitochondrial protein coding genes of 6 different hookworms i.e. Ancylostoma ceylanicum, Ancylostoma duodenale, Necator americanus, Ancylostoma tubaeforme, Ancylostoma caninum and Uncinaria sanguinis as no work was reported yet. The effective number of codons for mitochondrial genes suggested that codon usage bias was high in most species. The GC content was lower than AT content i.e. genes were AT rich as indicated by nucleotide composition analysis. The overall nucleotide composition along with its composition at 3rd codon position and correspondence analysis suggested that both natural selection and mutation pressure might have affected the codon usage bias in mitochondrial genes. However, neutrality plot revealed that mutation pressure might have played a major role in A. ceylanicum while natural selection might have played the dominant role in Ancylostoma duodenale, Necator americanus, Ancylostoma tubaeforme, Ancylostoma caninum and Uncinaria sanguinis. PMID- 29157662 TI - Evaluation of Guideline Adherence in Colorectal Cancer Treatment in The Netherlands: A Survey Among Medical Oncologists by the Dutch Colorectal Cancer Group. AB - BACKGROUND: Clinical guidelines are generated to preserve high-quality evidence based care. Data on the implementation of guidelines into clinical practice are scarce, despite that guideline adherence prevents over- and undertreatment and correlates with survival. Therefore, we investigated guideline adherence for the systemic treatment in high-risk stage II and stage III colon cancer and metastatic colorectal cancer. PATIENTS AND METHODS: In all Dutch hospitals (n = 88) 1 medical oncologist involved in colorectal cancer care was approached to participate. An online survey was conducted regarding the local standard of care for adjuvant chemotherapy in high-risk stage II and stage III colon cancer and first-line treatment regimens in metastatic colorectal cancer. Frequency tables were provided for categorical variables and compared for differences in guideline adherence according to hospital type (academic/teaching/regional). RESULTS: The overall response rate was 70% (62 of 88). Reported guideline adherence was at least 60% of all presented settings. For high-risk stage II and stage III colon cancer, treatment strategies agreed with national guidelines in 66% and 84% of hospitals, and overtreatment patterns were identified in 28% and 13%, respectively. Targeted therapy was not routinely administered as first-line treatment in metastatic colorectal cancer (range from 63% to 71% in different settings). No differences in guideline adherence were observed among different hospital types. CONCLUSION: Guideline adherence as reported by medical oncologists in The Netherlands is suboptimal. Possible explanations include unawareness or disagreement with the guidelines, or local financial restrictions. Our results recommend additional support of guideline implementation and monitoring in clinical practice, and investigating underlying causes in case of nonadherence. PMID- 29157663 TI - Value of widespread use of multiplex PCR for diagnosis of viral respiratory tract infections in children. PMID- 29157664 TI - From the Editor. PMID- 29157666 TI - Cognitive flexibility in preschool children with and without stuttering disorders. AB - PURPOSE: Multifactorial explanations of developmental stuttering suggest that difficulties in self-regulation and weak attentional flexibility contribute to persisting stuttering. We tested this prediction by examining whether preschool age children who stutter (CWS) shift their attention less flexibly than children who do not stutter (CWNS) during a modified version of the Dimension Card Change Sort (DCCS), a reliable measure of attention switching for young children. METHODS: Sixteen CWS (12 males) and 30 children CWNS (11 males) participated in the study. Groups were matched on age (CWS: M=49.63, SD=10.34, range=38-80months; CWNS: M=50.63, SD=9.82, range=37-74months), cognitive ability, and language skills. All children completed a computer-based variation of the DCCS, in which they matched on-screen bivalent stimuli to response buttons based on rules that switched mid-task. RESULTS: Results showed increased slowing for CWS compared to controls during the postswitch phase, as well as contrasting patterns of speed accuracy tradeoff for CWS and CWNS as they moved from the preswitch to postswitch phase of the task. CONCLUSIONS: Group differences in performance suggest that early stuttering may be associated with difficulty shifting attention efficiently and greater concern about errors. Findings are consistent with a growing literature indicating links between weak attentional control and persisting developmental stuttering. PMID- 29157667 TI - A case of multiple system atrophy-parkinsonian type with stuttering- and palilalia-like dysfluencies and putaminal atrophy. AB - Both developmental and acquired stuttering are related to the function of the basal ganglia-thalamocortical loop, which includes the putamen. Here, we present a case of stuttering- and palilalia-like dysfluencies that manifested as an early symptom of multiple system atrophy-parkinsonian type (MSA-P) and bilateral atrophy of the putamen. The patient was a 72-year-old man with no history of developmental stuttering who presented with a stutter for consultation with our otorhinolaryngology department. The patient was diagnosed with MSA-P based on parkinsonism, autonomic dysfunction, and bilateral putaminal atrophy revealed by T2-weighted magnetic resonance imaging. Treatment with levodopa improved both the motor functional deficits related to MSA-P and stuttering-like dysfluencies while reading; however, the palilalia-like dysfluencies were much less responsive to levodopa therapy. The patient died of aspiration pneumonia two years after his first consultation at our hospital. In conclusion, adult-onset stuttering- and palilalia-like dysfluencies warrant careful examination of the basal ganglia thalamocortical loop, and especially the putamen, using neuroimaging techniques. Acquired stuttering may be related to deficits in dopaminergic function. PMID- 29157665 TI - Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression. AB - Lipopolysaccharides (LPSs) are a major component of the Gram-negative bacterial cell wall and play an important role in mediating intestinal inflammatory responses in inflammatory bowel disease. Although recent studies suggested that physiologically relevant concentrations of LPS (0 to 1 ng/mL) cause an increase in intestinal epithelial tight junction (TJ) permeability, the mechanisms that mediate an LPS-induced increase in intestinal TJ permeability remain unclear. Herein, we show that myosin light chain kinase (MLCK) plays a central role in the LPS-induced increase in TJ permeability. Filter-grown Caco-2 intestinal epithelial monolayers and C57BL/6 mice were used as an in vitro and in vivo intestinal epithelial model system, respectively. LPS caused a dose- and time dependent increase in MLCK expression and kinase activity in Caco-2 monolayers. The pharmacologic MLCK inhibition and siRNA-induced knock-down of MLCK inhibited the LPS-induced increase in Caco-2 TJ permeability. The LPS increase in TJ permeability was mediated by toll-like receptor 4 (TLR-4)/MyD88 signal transduction pathway up-regulation of MLCK expression. The LPS-induced increase in mouse intestinal permeability also required an increase in MLCK expression. The LPS-induced increase in intestinal permeability was inhibited in MLCK-/- and TLR-4-/- mice. These data show, for the first time, that the LPS-induced increase in intestinal permeability was mediated by TLR-4/MyD88 signal-transduction pathway up-regulation of MLCK. Therapeutic targeting of these pathways can prevent an LPS-induced increase in intestinal permeability. PMID- 29157668 TI - Iron induced RNA-oxidation in the general population and in mouse tissue. AB - Iron promotes formation of hydroxyl radicals by the Fenton reaction, subsequently leading to potential oxidatively generated damage of nucleic acids. Oxidatively generated damage to RNA, measured as 8-oxo-7,8-dihydroguanosine (8-oxoGuo) in urine, is increased in patients with genetic iron overload, which have led us to test the hypothesis that high iron status, assessed by iron biomarkers and genetic disposition, increases urinary excretion of 8-oxoGuo. In a general Danish population study we used a Mendelian randomization design with HFE genotypes as a proxy for iron status and supplemented with ex vivo experiments in mice muscle tissue exposed to iron(II) sulfate to attempt to clarify this hypothesis. The biomarkers ferritin, transferrin, and transferrin saturation (TS) were associated with 8-oxoGuo (in linear univariable and multivariable regression analyses: P < 0.001). Mendelian randomization indicated a causal pathway between genetically elevated iron biomarkers (assessed by ferritin and TS) and high levels of 8 oxoGuo. The ex vivo experiments showed a monotonically increase in 8-oxoGuo with increased iron concentration (ANOVA: P = 0.0008) that was prevented with iron chelation (P = 0.01). Our results indicate a causal relationship between iron biomarkers and 8-oxoGuo. Furthermore, the ex vivo experiment shows a mechanistic link between iron and 8-oxoGuo formation. Both iron overload and the biomarker 8 oxoGuo have been linked to e.g. diabetes, which merits future studies to investigate if iron induced 8-oxoGuo is involved in disease development. PMID- 29157669 TI - The combination of IL-6 and its soluble receptor is associated with the response of rheumatoid arthritis patients to tocilizumab. AB - BACKGROUND: IL-6 contributes significantly to the chronic inflammatory process of rheumatoid arthritis (RA). Tocilizumab, a humanized anti-human IL-6 receptor antibody that blocks the signaling originated by the IL-6/IL-6R complex, is an effective treatment. However, predictors of the response to tocilizumab are still required. We aimed to combine IL-6 and soluble IL-6R (sIL-6R) levels to identify groups of responses. METHODS: Heparinized blood and clinical data from 63 RA patients were collected before treatment and after 3 and 6 months. Two-step clustering (SPSS v.18) was used to establish the relationship between IL-6 and sIL-6R. Then, we compared European League Against Rheumatism (EULAR) response criteria with remission achievement in the groups of patients. RESULTS: Three statistical significant clusters of RA patients (i.e., g1, g2, and g3) were defined by serum concentrations of IL-6 and sIL-6R at baseline. All groups of RA patients had higher IL-6 and sIL-6R levels than healthy donors. The levels of IL 6 expressed as median (IQR) in g1 patients were 124(90-183)pg/ml, in g2 12.3(4.4 24)pg/ml, and in g3 60.1(30-146)pg/ml (p < 0.001). The levels of sIL-6R expressed as mean +/- sd in g1 patients were 250.5 +/- 72ng/ml, in g2 269.1 +/- 125ng/ml, and in g3 732.7 +/- 243ng/ml (p < 0.001). Disease activity score (DAS)28, C reactive protein, and erythrocyte sedimentation rate were comparable in the three groups at baseline. Disease duration in g3 was the longest (median(IQR) years: g1 = 11(5-15), g2 = 12(8-20), and g3 23(16-26); p = 0.006), with years of disease evolution being correlated with sIL-6R levels (R = 0.417, p < 0.001). Simple and Clinical Disease Activity Index (SDAI and CDAI) decreased significantly in the three groups. However, EULAR response criteria and remission achievement at 6m was different in the three groups (p = 0.03 and 0.04, respectively). In all. 17 out of the 18 patients in g1 had a good or moderate response to tocilizumab. Conversely, the percentage of patients with no response to tocilizumab was higher in g3 than in g1 and g2. We also observed different changing patterns of IL-6 and sIL-6R levels among the three groups. CONCLUSIONS: RA patients could be easily stratified prior to therapeutic intervention with two molecules related to the pathway blocked by tocilizumab. G1 patients, who had the best response to tocilizumab, had the highest level of IL-6 and the lowest level of sIL-6R. PMID- 29157670 TI - Presence of comorbidities and prognosis of clinical symptoms in knee and/or hip osteoarthritis: A systematic review and meta-analysis. AB - OBJECTIVE: (i) To determine the association between the presence of comorbidities and severity of pain and physical dysfunction in people with knee and/or hip osteoarthritis; (ii) to explore associations between specific comorbidities (cardiac disease and/or hypertension, diabetes, depression, and back pain) and symptom severity. METHODS: Studies were identified through systematic searches in four electronic databases and grey literature, and, subsequently, methodologically appraised. Eligible citations entailed cross-sectional or longitudinal studies as well as randomised controlled trials providing data of a direct association between comorbidity presence and the severity of self-reported and/or performance-based symptoms of pain and/or physical functioning, in people with knee and/or hip osteoarthritis. We performed random-effects meta-analysis if at least two citations of low-to-moderate risk of bias were available. The quality of the body of evidence was determined using Cochrane-recommended methods. RESULTS: Of all eligible citations (n = 26), 17 studies were entered in meta-analysis. Moderate quality evidence revealed an association between having >=1 general comorbidity and worsening of pain (regression coefficient (95% confidence interval (CI)): 0.18 (95% CI: 0.14,0.22)) and/or performance-based physical functioning (0.20 (95% CI: 0.10,0.29)). The presence of cardiac disease and/or hypertension (self-reported: 0.08 (95% CI: 0.01,0.16); performance-based: 0.11 (95% CI: 0.02,0.20)), or back pain (self-reported: 0.12 (95% CI: 0.04,0.20)) predicted deteriorated physical functioning. Co-existing diabetes was associated with worse pain (0.10 (95% CI: 0.02,0.17)). Other findings were non-significant and/or the evidence of poor quality. CONCLUSIONS: Greater comorbidity burden contributes to worse pain and performance-based physical function in people with knee and/or hip osteoarthritis. Suffering comorbid cardiac disease including hypertension, back pain or diabetes may have differential effects on symptom severity. PMID- 29157671 TI - Infectious Agents in Childhood Leukemia. AB - Acute leukemia is the most common pediatric cancer, representing one-third of all cancers that occurs in under 15 year olds, with a varied incidence worldwide. Although a number of advances have increased the knowledge of leukemia pathophysiology, its etiology remains less well understood. The role of infectious agents, such as viruses, bacteria, or parasites, in the pathogenesis of leukemia has been discussed. To date, several cellular mechanisms involving infectious agents have been proposed to cause leukemia following infections. However, although leukemia can be triggered by contact with such agents, they can also be beneficial in developing immune stimulation and protection despite the risk of leukemic clones. In this review, we analyze the proposed hypotheses concerning how infectious agents may play a role in the origin and development of leukemia, as well as in a possible mechanism of protection following infections. We review reported clinical observations associated with vaccination or breastfeeding, that support hypotheses such as early life exposure and the resulting early immune stimulation that lead to protection. PMID- 29157672 TI - Kruppel Like Factors Family Expression in Cervical Cancer Cells. AB - BACKGROUND AND AIMS: Kruppel Like Factors (KLF) refers to a family of seventeen members of transcription factors. Involved in several cellular processes. As other cancer types, Cervical Cancer (CC) presents molecular deregulations in transcription factors, but especially Human Papilloma Virus (HPV) sequences. Here in this work we analyzed the mRNA expression of all KLF family members in CC derived cell lines and CC tissues. METHODS: The cell lines used were HeLa, INBL, RoVa, C4-I, Ms751, ViPa, CaLo, SiHa, CaSki, C33a and ViBo and the non-tumorigenic HaCaT. mRNA expression was analyzed by means of expression microarray and RT-PCR, and KLF5 protein by immunofluorescence. RESULTS: The cell lines were grouped according to HPV genotype as HPV16, HPV18 positive or HPV negative cells. Heterogeneous expression was observed among the cell lines. Despite the heterogeneous expression profile, KLF3, -5, -12, -15 and -16 transcripts were present in all cell lines, KLF4 and -10 which were not expressed in CaSki; KLF11 and 13 were not expressed by Vipa and C4-I, and KLF7 was not expressed by C4-I and Rova. The CC tissue analysis shows expression of most of the KLF members, such as KLF5. KLF5 immunosignal was positive in the three cell lines analyzed. CONCLUSIONS: We suggest that KLF expression could not be related to HPV presence/genotype, at least at transcriptional level, and the expression of KLF family members may be necessary in the biology of the CC cells. PMID- 29157673 TI - Circulating microRNAs as Biomarkers for Pediatric Astrocytomas. AB - BACKGROUND AND AIMS: Since MicroRNAs (miRNAs) are potent regulators of gene expression, their expression and function alterations are associated with different types of cancer, including pediatric astrocytoma. Since the secretion of miRNAs by tumors into corporal fluids has made it possible to identify biomarkers in cancer, their deter mination in pediatric astrocytoma is vital. In order to gain insight into the mechanisms controlled by miRNAs in these neoplasms, we tested the expression of miRNAs 130a, 145, 335, 1303, and let-7g-3p by qPCR in tumors and blood serum from pediatric patients with astrocytoma. The data was analyzed with the DIANA-miRPath v3.0 platform. RESULTS: The data represented expression changes of all mirRNAs tested in both tumors and blood serum, which strongly suggest their use as circulating biomarkers for astrocytic tumors. The bioinformatic analysis -with DIANA-miRPath v3.0- showed the involvement of these miRNAs in extracellular matrix (ECM)-receptor interaction and proteoglycans in cancer, which control many hallmarks of cancer. In fact, the expression of the proteoglycan syndecan 4 (SDC4) and that of its biosynthetic enzymes, Exostosin Glycosyltransferase 1 (EXT1) and Xylosyltransferase 1 (XYLT1), were altered in pediatric astrocytoma. CONCLUSIONS: Our results highlight the role of microRNAs in the biology of pediatric astrocytoma and demonstrated for the first time the potential use of some circulating microRNAs as non-invasive biomarkers for this type of tumors, particularly miRs 130a, 145, and 335. PMID- 29157674 TI - Circulating Concentrations of Advanced Glycation end Products, its Association With the Development of Diabetes Mellitus. AB - BACKGROUND: Diabetes Mellitus (DM) is characterized by the production and accumulation of advanced glycation end products (AGEs), which are one of the key mechanisms in the development of its chronic complications. AIMS OF THE STUDY: To assess the serum AGEs concentration by a radioimmunoassay (RIA) developed in our laboratory, to establish reference values in healthy population and to evaluate the diagnostic potential of measuring longitudinal changes in circulating AGEs concentrations to predict the development of DM. METHODS: Clinical and metabolic parameters were obtained from a cohort of 781 Mexican people, initially and then seven years later. AGEs were quantified by a specific RIA. Associations of the changes in circulating levels of AGEs with the appearance of impaired fasting glucose (IFG), and the development of DM were evaluated. RESULTS: Diabetic subjects had higher circulating levels of AGEs than normoglycemic subjects or individuals with IFG in both samples studied (471 vs. 246 and 342 MUU/mL, p <0.001; and 912 vs. 428 and 519 MUU/mL, p <0.001; respectively). A multinomial logistic regression analysis showed that subjects who had AGEs concentration >=400 MUU/mL in the baseline sample had a relative risk ratio of 1.98 to develop IFG seven years later (p = 0.003). While the subjects who had AGEs concentration >=450 MUU/mL in the baseline sample had a relative risk ratio of 10.7 to develop DM seven years later (p <0.001). CONCLUSIONS: Circulating AGEs concentration is a good early marker to predict risk of developing DM. PMID- 29157675 TI - Corrigendum to ''Loperamide-induced Cardiac Depression Is Enhanced by Hyperglycemia: Evidence Relevant to Loperamide Abuse'' [Archives of Medical Research 48 (2017) 64-72]. PMID- 29157676 TI - Upregulation of Aedes aegypti Vago1 by Wolbachia and its effect on dengue virus replication. AB - Dengue infection along with its related disease conditions poses a significant threat to human health. The pathogen responsible for this infection is dengue virus (DENV) which is primarily transmitted to humans through the bites of Aedes aegypti mosquitoes. Unavailability of a potent vaccine has recently sparked renewed research endeavours aimed at vector control. To date, Wolbachia as an endosymbiotic bacterium has shown promise as a novel biocontrol agent to restrict DENV replication in the vector, although the underlying antiviral mechanism remains elusive. Recent studies have demonstrated the potential role of Vago as a novel secretory protein involved in cross-talk between the innate immune pathways in Culex quinquefasciatus mosquitoes to restrict West Nile virus replication. In this study, we have identified two homologs of the Vago protein in Ae. aegypti and looked into their modulation in the case of Wolbachia wMelPop strain infection. Furthermore, we have investigated the role of AeVago1, that is highly induced by Wolbachia, in the context of Wolbachia-mosquito-DENV interactions. Knockdown studies of the AeVago1 gene in Wolbachia-infected cells led to significant increases in DENV replication, with no effect on Wolbachia density. Our results suggest that the Wolbachia-induced AeVago1 in Ae. aegypti may function as a host factor to suppress DENV replication in the mosquito. PMID- 29157677 TI - DNA methylation affects the lifespan of honey bee (Apis mellifera L.) workers - Evidence for a regulatory module that involves vitellogenin expression but is independent of juvenile hormone function. AB - The canonic regulatory module for lifespan of honey bee (Apis mellifera) workers involves a mutual repressor relationship between juvenile hormone (JH) and vitellogenin (Vg). Compared to vertebrates, however, little is known about a possible role of epigenetic factors. The full genomic repertoire of DNA methyltransferases (DNMTs) makes the honey bee an attractive emergent model for studying the role of epigenetics in the aging process of invertebrates, and especially so in social insects. We first quantified the transcript levels of the four DNMTs encoding genes in the head thorax and abdomens of workers of different age, showing that dnmt1a and dnmt3 expression is up-regulated in abdomens of old workers, whereas dnmt1b and dnmt2 are down-regulated in heads of old workers. Pharmacological genome demethylation by RG108 treatment caused an increase in worker lifespan. Next, we showed that the genomic DNA methylation status indirectly affects vitellogenin gene expression both in vitro and in vivo in young workers, and that this occurs independent of caloric restriction or JH levels, suggesting that a non-canonical circuitry may be acting in parallel with the JH/Vg module to regulate the adult life cycle of honey bee workers. Our data provide evidence that epigenetic factors play a role in regulatory networks associated with complex life history traits of a social insect. PMID- 29157678 TI - Intensive mothering ideology in France: A pilot study. AB - OBJECTIVE: The aim of this pilot study was to adapt the intensive mothering ideology concept in a French sample and to get an assessment tool. METHOD: First, the Intensive Parenting Attitudes Questionnaire (IPAQ), a U.S. scale comprising 25 items, was translated and submitted online to French mothers and mothers-to-be (n=250). Structural validity was tested through confirmatory factor analysis with poor results. Secondly, to increase the cultural validity of a new tool, new items were derived from French women speech. French mothers and mothers-to-be (n=22) were asked about their views regarding motherhood and childcare (semi structured interviews). A thematic content analysis was performed with good inter judge agreement (0.53-0.86) and 27 items were created. Finally, the total set of 52 items was submitted online to French mothers and mothers-to-be (n=474). The structure was tested through exploratory factor analysis. RESULTS: A new tool called the Measure of Intensive Mothering Ideology (MIMI) was obtained. This 21 items scale with 6 dimensions (Essentialism, Consuming Fulfillment, Child centrism, Challenge, Sacrifice and Stimulation) explains 59.75% of variance. Internal consistencies were satisfactory (0.61-0.83) and most dimensions were positively and moderately correlated (0.17-0.38). CONCLUSION: The MIMI is the first French-language scale assessing IMI and offers interesting research avenues notably regarding perinatal parental adaptation. PMID- 29157680 TI - Immediate and late outcomes of endovascular therapy for lower extremity arteries in Buerger disease. AB - OBJECTIVE: Buerger disease is a rare inflammatory vasculopathy presenting with severe claudication or critical limb ischemia. In this study, we sought to evaluate the feasibility and clinical outcomes of endovascular therapy for Buerger disease involving arteries in the lower extremities. METHODS: Between January 2006 and May 2016, there were 44 Buerger disease patients (43 men; mean age, 40.4 +/- 9.6 years) with 50 target limbs treated by endovascular therapy at the Severance Cardiovascular Hospital. Baseline characteristics as well as both immediate and late clinical outcomes were retrospectively analyzed. RESULTS: The majority (86.4%) of patients presented with critical limb ischemia. A total of 88 target lesions in 50 limbs were treated with endovascular procedures. All limbs showed infrapopliteal artery occlusions, and multilevel diseases involving the iliac or femoropopliteal artery were found in 31 patients (62%). Technical success was achieved in 80% of subjects. We found that a lower serum level of C reactive protein, specifically the log C-reactive protein value (odds ratio, 0.03; 95% confidence interval [CI], 0.00-0.71; P = .030), was an independent predictor of technical failure. The median follow-up duration was 29 months. Major adverse limb event-free survival and reintervention- and amputation-free survival were 83.3% and 67.9% at 3 years, respectively. In a multivariate Cox proportional hazards analysis, previous endovascular treatment (hazard ratio, 3.70; 95% CI, 1.20-11.31; P = .022) and previous amputation (hazard ratio, 4.68; 95% CI, 1.37-15.96; P = .014) were identified as independent risk factors for reintervention- and amputation-free survival. CONCLUSIONS: In patients with Buerger disease, endovascular treatment achieved technical success in the majority of the cases and was associated with favorable immediate and late clinical outcomes. These findings indicate that endovascular therapy may be considered a first-line treatment option for severe symptomatic patients with Buerger disease. PMID- 29157679 TI - The Generalized Problematic Internet Use Scale-2 in a French sample: Psychometric evaluation of the theoretical model. AB - OBJECTIVES: The Generalized Problematic Internet Use Scale-2 (GPIUS-2) is a short self-report questionnaire assessing Internet addiction based on a cognitive behavioral model. Our main goal was to evaluate the psychometric properties of its French version among a sample of students and to appraise the relevance of the generalized problematic Internet use model. METHODS: A sample of 563 university students aged between 18 and 35 years (M=20.8; SD=2.7) completed several online self-report questionnaires including the GPIUS-2, the Internet Addiction Test (IAT) and the Center for Epidemiologic Study-Depression scale (CES D). RESULTS: Confirmatory Factorial Analyses revealed a poor but acceptable overall fit for the original five-factor model and the original four-factor model. Path analyses, testing Structural Equation Modeling provided showed a poor fit to the data, suggesting insufficient construct validity. Convergent and concurrent validities analyzed through correlational analyses revealed significant relationships between the GPIUS-2, its factors, the IAT, time spent online and the CES-D. CONCLUSIONS: This research highlights the insufficient psychometric properties of the GPIUS-2 in a French sample, similar to previous results. However, this French version appears to be a useful multidimensional tool for assessing problematic Internet use among students, and reveals promise for future research and clinical applications of the measure, given its solid theoretical basis and despite the results of this psychometric study. PMID- 29157681 TI - Endovascular treatment of the ascending aorta using a combined transapical and transfemoral approach. AB - In high-risk patients with diseases of the ascending aorta, endovascular repair might be a therapeutic alternative to surgical repair. We developed a combined access route with transapical and transfemoral externalization of the wire and report the operative technique as well as our initial experience of six patients treated with this method. Improved wire control resulted in precise deployment of endovascular prostheses, respecting the integrity of the coronary ostia and the supra-aortic vessels. Procedural success was 100%, and follow-up until 32 months postoperatively showed no need for reintervention or mortality. However, long term results of the presented technique are still unknown. PMID- 29157682 TI - Outcomes of thoracic endovascular aortic repair for chronic aortic dissections. AB - BACKGROUND: Open surgical repair remains the "gold standard" treatment for chronic type B aortic dissection (cTBD) with aneurysm. Thoracic endovascular aortic repair (TEVAR) has gained popularity in recent years for the treatment of thoracic aortic diseases, including cTBD. We assessed the effectiveness of TEVAR in the treatment of cTBD using the Vascular Quality Initiative (VQI) database. METHODS: The VQI registry identified 4713 patients treated with TEVAR from July 2010 to November 2015, including 125 repairs for cTBD. We analyzed TEVAR outcomes in this cohort per the Society for Vascular Surgery reporting standards for TEVAR. RESULTS: Median age was 65.0 years (interquartile range [IQR], 56.0-72.0 years), and 85 (68.0%) were male. Median aneurysm diameter was 5.5 cm (IQR, 4.8 6.3 cm). Sixty-two (49.6%) patients were asymptomatic on presentation, 57 (45.6%) were symptomatic, and 6 (4.8%) presented with rupture. Median length of stay was 8.0 days (IQR, 4.0-11.0 days). Fluoroscopy time was 17.3 minutes (IQR, 10.5-25.6 minutes). The distal landing zone was aortic zone 4 in 27 (21.6%) and aortic zone 5 and distal in 98 (78.4%) patients. Successful device delivery occurred in 123 (98.4%) patients. Conversion to open repair occurred in one (0.8%) patient. A type IA endoleak was present in 2 (1.6%), type IB endoleak in 2 (1.6%), and type II endoleak in 2 (1.6%) patients. Perioperative complications included stroke in 1 (0.8%), respiratory complications in 6 (4.8%), and spinal cord ischemia symptoms present at discharge in 3 (2.4%) patients. In-hospital mortality occurred in three (2.4%) patients. Reintervention was required in two (1.6%) patients for false lumen perfusion and in two (1.6%) patients for extension of the dissection. Follow-up was available for 43 patients at a median time of 239 days (IQR, 38-377 days). Median change in sac diameter was -0.2 cm (IQR, -0.5 to 0.1 cm). Sac shrinkage of 0.5 cm was noted in 12 (27.9%), with sac growth >0.5 cm in four (9.3%) patients. Extent of stent graft coverage did not affect sac shrinkage (P = .65). Patients with aneurysms >=5.5 cm compared with <5.5 cm were more likely to demonstrate shrinkage (-0.6 cm vs 0.0 cm; 95% confidence interval, 0.3-11.7; P = .04). CONCLUSIONS: TEVAR for cTBD may be performed with acceptable rates of morbidity and mortality. Changes in sac diameter in the midterm are promising. Long-term data are needed to determine whether this approach is durable. PMID- 29157683 TI - Unique Characteristics of High-Cost Users of Medical Care With Comorbid Mental Illness or Addiction in a Population-Based Cohort. AB - OBJECTIVE: To understand whether high-cost users of medical care with and without comorbid mental illness or addiction differ in terms of their sociodemographic and health characteristics. Unique characteristics would warrant different considerations for interventions and service design aimed at reducing unnecessary health care utilization and associated costs. METHODS: From the top 10% of Ontarians ranked by total medical care costs during fiscal year 2011/2012 (N = 314,936), prior 2-year mental illness or addiction diagnoses were determined from administrative data. Sociodemographics, medical illness characteristics, medical costs, and utilization were compared between those high-cost users of medical care with and without comorbid mental illness or addiction. Odds of being a frequent user of inpatient (>=3 admissions) and emergency (>=5 visits) services were compared between groups, adjusting for age, sex, socioeconomic status and medical illness characteristics. RESULTS: High-cost users of medical care with comorbid mental illness or addiction were younger, had a lower socioeconomic status, had greater historical medical morbidity, and had higher total medical care costs (mean excess of $2,031/user) than those without. They were more likely to be frequent users of inpatient (12.8% vs 10.2%; adjusted OR, 1.14; 95% CI: 1.12-1.17) and emergency (8.4% vs 4.8%; adjusted OR, 1.55; 95% CI: 1.50-1.59) services. Effect sizes were larger in major mood, psychotic, and substance use disorder subgroups. CONCLUSIONS: High-cost medical care users with mental illness or addiction have unique characteristics with respect to sociodemographics and service utilization patterns to consider in interventions and policies for this patient group. PMID- 29157684 TI - Resuscitation thoracotomy-technical aspects. PMID- 29157685 TI - Recent advances in the discovery of small molecule c-Met Kinase inhibitors. AB - c-Met is a prototype member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) and is the receptor for hepatocyte growth factor (HGF). Binding of HGF to its receptor c-Met, initiates a wide range of cellular signalling, including those involved in proliferation, motility, migration and invasion. Importantly, dysregulated HGF/c-Met signalling is a driving factor for numerous malignancies and promotes tumour growth, invasion, dissemination and/or angiogenesis. Dysregulated HGF/c-Met signalling has also been associated with poor clinical outcomes and resistance acquisition to some approved targeted therapies. Thus, c-Met kinase has emerged as a promising target for cancer drug development. Different therapeutic approaches targeting the HGF/c-Met signalling pathway are under development for targeted cancer therapy, among which small molecule inhibitors of c-Met kinase constitute the largest effort within the pharmaceutical industry. The review is an effort to summarize recent advancements in medicinal chemistry development of small molecule c-Met kinase inhibitors as potential anti-cancer agents which would certainly help future researchers to bring further developments in the discovery of small molecule c-Met kinase inhibitors. PMID- 29157686 TI - Unequal interactions: Examining the role of patient-centered care in reducing inequitable diffusion of a medical innovation, the human papillomavirus (HPV) vaccine. AB - RATIONALE: Studies of inequities in diffusion of medical innovations rarely consider the role of patient-centered care. OBJECTIVE: We used uptake of the human papillomavirus (HPV) vaccine shortly after its licensing to explore the role of patient-centered care. METHODS: Using a longitudinal multi-site survey of US parents and adolescents, we assessed whether patient-centered care ratings might shape racial/ethnic and socioeconomic gaps at two decision points in the HPV vaccination process: (1) Whether a medical provider recommends the vaccine and (2) whether a parent decides to vaccinate. RESULTS: We did not find evidence that the association of patient-centeredness with vaccination varies by parent education. In contrast, parent ratings of providers' patient-centeredness were significantly associated with racial/ethnic disparities in parents' reports of receiving a HPV vaccine recommendation from a provider: Among parents who rate patient-centered care as low, white parents' odds of receiving such a recommendation are 2.6 times higher than black parents' odds, but the racial/ethnic gap nearly disappears when parents report high patient centeredness. Moderated mediation analyses suggest that patient-centeredness is a major contributor underlying vaccination uptake disparities: Among parents who report low patient-centeredness, white parents' odds of vaccinating their child are 8.1 times higher than black parents' odds, while both groups are equally likely to vaccinate when patient-centeredness is high. CONCLUSION: The results indicate that patient-centered care, which has been a relatively understudied factor in the unequal diffusion of medical innovations, deserves more attention. Efforts to raise HPV vaccination rates should explore why certain patient groups may be less likely to receive recommendations and should support providers to consistently inform all patient groups about vaccination. PMID- 29157687 TI - Seven-Year-Old Girl With Forehead Swelling. PMID- 29157688 TI - Female With Neck Pain. PMID- 29157689 TI - Off the Monitor. PMID- 29157690 TI - The Last Turnover. PMID- 29157691 TI - Nonoperative Management of Appendicitis: A Paradigm Shift?: Answers to the July 2017 Journal Club Questions. PMID- 29157693 TI - Young Woman With a Blue, Painful and Swollen Arm. PMID- 29157692 TI - Male With Sudden Left Eye Vision Loss. PMID- 29157694 TI - Elderly Woman With Atrial Fibrillation. PMID- 29157695 TI - The Association Between Health Insurance and Emergency Department Use in Taiwan. PMID- 29157696 TI - Paraspinous Injections With Ropivacaine for Pediatric Headache Treatment. PMID- 29157697 TI - In reply. PMID- 29157698 TI - Fab Antivenom Controversy Continues. PMID- 29157699 TI - In reply. PMID- 29157700 TI - In Response to "The Efficacy of Crotalidae Polyvalent Immune Fab (Ovine) Antivenom Versus Placebo Plus Optional Rescue Therapy on Recovery from Copperhead Snake Envenomation". PMID- 29157701 TI - In reply. PMID- 29157702 TI - Academic Departments of Emergency Medicine in Medical Schools. PMID- 29157703 TI - Advocacy for Emergency Department Ultrasonographic Privilege and Practice. PMID- 29157704 TI - Blood-Borne Pathogens in Emergency Medicine. PMID- 29157705 TI - Boarding of Admitted and Intensive Care Patients in the Emergency Department. PMID- 29157706 TI - Emergency Department Utilization During Outbreaks of Influenza. PMID- 29157707 TI - External Cause of Morbidity Codes and Injury Surveillance Data Systems. PMID- 29157708 TI - Definition of Rural Emergency Medicine. PMID- 29157709 TI - Law Enforcement Information Gathering in the Emergency Department. PMID- 29157710 TI - EMS as an Essential Public Safety Service. PMID- 29157711 TI - Physician Medical Direction of Emergency Medical Services Dispatch Programs. PMID- 29157713 TI - Procedural Sedation in the Emergency Department. PMID- 29157712 TI - Reversal of Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) in the Presence of Major Life-Threatening Bleeding. PMID- 29157714 TI - Specialty Hospitals. PMID- 29157715 TI - Emergency Physician Shift Work. PMID- 29157716 TI - Support for Transition of Military Medics Into Civilian EMS Careers. PMID- 29157717 TI - When Anticoagulants Become a Bloody Mess. PMID- 29157718 TI - Male With Left Lower Quadrant Pain. PMID- 29157719 TI - Elderly Female With Dyspnea. PMID- 29157720 TI - Young Woman With Eye Pressure. PMID- 29157721 TI - Child With Generalized Weakness and Anorexia. PMID- 29157722 TI - Ca2+ leak-What is it? Why should we care? Can it be managed? AB - For arrhythmia triggers that are secondary to dysfunctional intracellular Ca2+ cycling, there are few, if any, agents that specifically target the Ca2+ handling machinery. However, several candidates have been proposed in the literature. Here we review the idea that these agents or their derivatives will prove invaluable in clinical applications in the future. PMID- 29157723 TI - Implantable cardioverter-defibrillator therapy in hypertrophic cardiomyopathy: A SIMPLE substudy. AB - BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) are considered to be at high risk for elevated defibrillation thresholds, periprocedural complications, and failed appropriate shocks. OBJECTIVE: The purpose of this study was to determine the value of defibrillation testing (DT) in HCM patients undergoing implantable cardioverter-defibrillator (ICD) insertion. METHODS: Defibrillation thresholds, perioperative complications, and long-term outcomes were compared between patients with HCM and those with ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) enrolled in the SIMPLE (Shockless IMPLant Evaluation) trial (Clinialtrials.gov Identifier: NCT00800384). In patients with HCM, outcomes were also compared between those randomized to DT vs no DT. RESULTS: Adequate defibrillation safety margin without system change was achieved in 46 of 52 (88.5%) HCM and 948 of 1047 (90.5%) ICM/DCM patients (P = .63). Perioperative complications occurred in 1 of 52 (1.9%) HCM patients with DT compared to 67 of 1047 (6.4%) ICM/DCM patients with DT (P = .37) or 3 of 42 (7.1%) HCM patients without DT (P = .32). During follow-up, there was no significant difference between HCM vs ICM/DCM patients in terms of all-cause mortality (adjusted hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.45 2.34), composite of arrhythmic death or failed appropriate shock (adjusted HR 0.33, 95% CI 0.04-2.42), inappropriate shocks (adjusted HR 1.64, 95% CI 0.69 3.89), or system complications (adjusted HR 1.93, 95% CI 0.88-4.27). All-cause mortality (HR 0.26, 95% CI 0.03-2.20), appropriate (HR 0.24, 95% CI 0.03-2.05), and inappropriate shocks (HR 2.13, 95% CI 0.51-8.94) were similar in HCM patients without or those with DT. CONCLUSION: We did not find any difference in intraoperative defibrillation efficacy, perioperative complications, and long term outcomes between patients with HCM and those with ICM/DCM. DT did not improve intraoperative or clinical shock efficacy in HCM patients. PMID- 29157724 TI - Differential N-glycan patterns identified in lung adenocarcinoma by N-glycan profiling of formalin-fixed paraffin-embedded (FFPE) tissue sections. AB - : N-glycan profiling is a powerful approach for analyzing the functional relationship between N-glycosylation and cancer. Current methods rely on either serum or fresh tissue samples; however, N-glycan patterns may differ between serum and tissue, as the proteins of serum originate from a variety of tissues. Furthermore, fresh tissue samples are difficult to ship and store. Here, we used a profiling method based on formalin-fixed paraffin-embedded (FFPE) tissue sections from lung adenocarcinoma patients. We found that our method was highly reproducible. We identified 58 N-glycan compositions from lung adenocarcinoma FFPE samples, 51 of which were further used for MSn-based structure prediction. We show that high mannose type N-glycans are upregulated, while sialylated N glycans are downregulated in our FFPE lung adenocarcinoma samples, compared to the control samples. Our receiver operating characteristic (ROC) curve analysis shows that high mannose type and sialylated N-glycans are useful discriminators to distinguish between lung adenocarcinoma and control tissue. Together, our results indicate that expression levels of specific N-glycans correlate well with lung adenocarcinoma, and strongly suggest that our FFPE-based method will be useful for N-glycan profiling of cancer tissues. SIGNIFICANCE: Glycosylation is one of the most important post-translational protein modifications, and is associated with several physiopathological processes, including carcinogenesis. In this study, we tested the feasibility of using formalin-fixed paraffin embedded (FFPE) tissue sections to identify changes in N-glycan patterns and identified the differentially expressed N-glycans of lung adenocarcinoma. Our study shows that the FFPE-based N-glycan profiling method is useful for clinical diagnosis as well as identification of potential biomarkers, and our data expand current knowledge of differential N-glycan patterns of lung adenocarcinoma. PMID- 29157725 TI - Nonsurgical lumbar radiculopathies treated with ultramicronized palmitoylethanolamide (umPEA): A series of 100 cases. AB - In this clinical/observational study we have reported the administration of Palmitoylethanolamide (PEA) in patients suffering from radicular lumbar spinal pathology, who had no indication for surgical treatment. We analyzed a series of 100 cases retrospectively, all undergoing clinical and diagnostic investigations, which had shown the presence of abnormalities of the vertebral body and intervertebral discs, mainly degenerative, such as spondyloarthrosis, spondylo discarthrosis, disc protrusion, excluding disc herniation, which fell within surgical cases. We then administered ultramicronized PEA (umPEA) to these patients, in combination with paracetamol and codeine, obtaining interesting results regarding the improvement of pain symptoms of the spine pathology, in the various checks carried out, through the administration of pain assessment scales. We also noted its safety due to the total absence of adverse effects. The obtained results encourage the use of PEA in degenerative spine pathologies. PMID- 29157726 TI - Adaptive and technology-independent architecture for fault-tolerant distributed AAL solutions. AB - Today's architectures for Ambient Assisted Living (AAL) must cope with a variety of challenges like flawless sensor integration and time synchronization (e.g. for sensor data fusion) while abstracting from the underlying technologies at the same time. Furthermore, an architecture for AAL must be capable to manage distributed application scenarios in order to support elderly people in all situations of their everyday life. This encompasses not just life at home but in particular the mobility of elderly people (e.g. when going for a walk or having sports) as well. Within this paper we will introduce a novel architecture for distributed AAL solutions whose design follows a modern Microservices approach by providing small core services instead of a monolithic application framework. The architecture comprises core services for sensor integration, and service discovery while supporting several communication models (periodic, sporadic, streaming). We extend the state-of-the-art by introducing a fault-tolerance model for our architecture on the basis of a fault-hypothesis describing the fault containment regions (FCRs) with their respective failure modes and failure rates in order to support safety-critical AAL applications. PMID- 29157727 TI - An opportunistic route to success: Towards a change of paradigm to fully exploit the potential of cell-penetrating peptides. AB - About 25years ago it was demonstrated that certain peptides possess the ability to cross the plasma membrane. This led to the development of cell-penetrating peptides (CPPs) as vectors to mediate the cellular entry of (macro-)molecules that do not show cell entry by themselves. Nonetheless, in spite of an early bloom of promising pre-clinical studies, not a single CPP-based drug has been approved, yet. It is a paradigm in CPP research that the peptides are taken up by virtually all cells. In exploratory research and early preclinical development, this assumption guides the choice of the therapeutic target. However, while this indiscriminatory uptake may be the case for tissue culture experiments, in an organism this is clearly not the case. Biodistribution analyses demonstrate that CPPs only target a very limited number of cells and many tissues are hardly reached at all. Here, we review biodistribution analyses of CPPs and CPP-based drug delivery systems. Based on this analysis we propose a paradigm change towards a more opportunistic approach in CPP research. The application of CPPs should focus on those pathophysiologies for which the relevant target cells have been shown to be reached in vivo. PMID- 29157728 TI - Organoselenium compounds from purines: Synthesis of 6-arylselanylpurines with antioxidant and anticholinesterase activities and memory improvement effect. AB - We describe here a simple method for the synthesis of 6-arylselanylpurines with antioxidant and anticholinesterase activities, and memory improvement effect. This class of compounds was synthesized in good yields by a reaction of 6 chloropurine with diaryl diselenides using NaBH4 as reducing agent and PEG-400 as solvent. Furthermore, the synthesized compounds were evaluated for their in vitro antioxidant and acetylcholinesterase (AChE) inhibitor activities. The best AChE inhibitor was assessed on the in vivo memory improvement. Our results demonstrated that the 6-((4-chlorophenyl)selanyl)-9H-purine and 6-(p tolylselanyl)-9H-purine presented in vitro antioxidant effect. In addition, 6-((4 fluorophenyl)selanyl)-9H-purine inhibited the AChE activity and improved memory, being a promising therapeutic agent for the treatment of Alzheimer's disease. PMID- 29157729 TI - Closer to the Source: Targeted-Release Corticosteroids for Immunoglobulin A Nephropathy. PMID- 29157730 TI - Donor and Recipient Perspectives on Anonymity in Kidney Donation From Live Donors: A Multicenter Survey Study. AB - BACKGROUND: Maintaining anonymity is a requirement in the Netherlands and Sweden for kidney donation from live donors in the context of nondirected (or unspecified) and paired exchange (or specified indirect) donation. Despite this policy, some donors and recipients express the desire to know one another. Little empirical evidence informs the debate on anonymity. This study explored the experiences, preferences, and attitudes of donors and recipients toward anonymity. STUDY DESIGN: Retrospective observational multicenter study using both qualitative and quantitative methods. SETTING & PARTICIPANTS: 414 participants from Dutch and Swedish transplantation centers who received or donated a kidney anonymously (nondirected or paired exchange) completed a questionnaire about anonymity. Participation was a median of 31 months after surgery. FACTORS: Country of residence, donor/recipient status, transplant type, time since surgery. OUTCOMES: Experiences, preferences, and attitudes toward anonymity. RESULTS: Most participants were satisfied with their experience of anonymity before and after surgery. A minority would have liked to have met the other party before (donors, 7%; recipients, 15%) or after (donors, 22%; recipients, 31%) surgery. Significantly more recipients than donors wanted to meet the other party. Most study participants were open to meeting the other party if the desire was mutual (donors, 58%; recipients, 60%). Donors agree significantly more with the principle of anonymity before and after surgery than recipients. Donors and recipients thought that if both parties agreed, it should be permissible to meet before or after surgery. There were few associations between country or time since surgery and experiences or attitudes. The pros and cons of anonymity reported by participants were clustered into relational and emotional, ethical, and practical and logistical domains. LIMITATIONS: The relatively low response rate of recipients may have reduced generalizability. Recall bias was possible given the time lag between transplantation and data collection. CONCLUSIONS: This exploratory study illustrated that although donors and recipients were usually satisfied with anonymity, the majority viewed a strict policy on anonymity as unnecessary. These results may inform policy and education on anonymity. PMID- 29157732 TI - RNase 7 Strongly Promotes TLR9-Mediated DNA Sensing by Human Plasmacytoid Dendritic Cells. AB - Plasmacytoid dendritic cells (pDCs) were described to accumulate in the skin of patients with psoriasis and to be recruited into the dermis upon allergen challenge in atopic dermatitis. Activation of pDCs in the skin has been identified as an important initiator of psoriasis development. Ribonuclease (RNase) 7 is one of the major antimicrobial peptides secreted by keratinocytes and is expressed in significantly higher amounts in lesional skin of patients with atopic dermatitis or psoriasis than in healthy individuals. The skin-derived antimicrobial peptides human beta-defensin 2 and LL-37 indirectly stimulate the activity of skin pDCs, but to our knowledge, an immunomodulatory potential of RNase 7 has not yet been reported. We show here that RNase 7 enables human pDCs to recognize self-DNA and promotes their rapid sensing of bacterial DNA. This very fast innate immune response was sufficient to up-regulate the expression of several antiviral IFN-stimulated genes in human peripheral blood mononuclear cells and to inhibit an infection of primary human keratinocytes with herpes simplex virus 1. RNase 7 was a markedly stronger trigger for IFN-alpha expression in human pDCs than the other antimicrobial peptides. Our data indicate that RNase 7 exhibits potent immunomodulatory functions and supports the efficient recognition of microbial infections by human skin-infiltrating pDCs. PMID- 29157733 TI - Using environmental isotopes along with major hydro-geochemical compositions to assess deep groundwater formation and evolution in eastern coastal China. AB - Hydrochemical analysis and environmental isotopic tracing are successfully applied to study groundwater evolution processes. Located in eastern China, the Jiangsu Coastal Plain is characterized by an extensively exploited deep groundwater system, and groundwater salinization has become the primary water environmental problem. This paper provides a case study on the use of a hydrochemical and environmental isotopic approach to assess possible mixing and evolution processes at Yoco Port, Jiangsu Province, China. Hydrochemical and isotopic patterns of deep groundwater allow one to distinguish different origins in deep water systems. HCO3- is the dominant anion in the freshwater samples, whereas Na+ and Cl- are the dominant major ions in the saline samples. According to delta18O, delta2H and 14C dating, the fresh water is derived from precipitation under a colder climate during the Glacial Maximum (Dali Glacial), while the saline groundwater is influenced by glacial-interglacial cycles during the Holocene Hypsithermal. The delta18O, delta2H and 3H data confirm that deep groundwater in some boreholes is mixed with overlying saline water. The deep groundwater reservoir can be divided into a saline water sector and a fresh water sector, and each show distinct hydrochemical and isotopic compositions. The saline groundwater found in the deep aquifer cannot be associated with present seawater intrusion. Since the Last Glacial Maximum in the Late Pleistocene, the deep groundwater flow system has evolved to its current status with the decrease in ice cover and the rising of sea level. However, the hydraulic connection is strengthened by continuous overexploitation, and deep groundwater is mixed with shallow groundwater at some points. PMID- 29157734 TI - Usefulness of the CHA2DS2-VASc Score to Predict Outcome in Patients Who Underwent Transcatheter Aortic Valve Implantation. AB - Risk assessment for transcatheter aortic valve implantation (TAVI) patients remains challenging, especially in elderly and high-risk candidates. Although several risk factors contribute to increased morbidity and mortality after TAVI, simple risk scores for routine use are lacking. Applying the CHA2DS2-VASC (congestive heart failure, hypertension, age >= 75 years, diabetes, prior stroke, vascular disease, age 65-74 years, sex [female] category) score as a novel risk stratification tool for conditions other than atrial fibrillation and stroke prevention has been previously examined; however, its usefulness in a population of patients with aortic stenosis after TAVI has not been established. Thus, we investigated 633 consecutive patients who underwent TAVI between November 2008 and May 2017, and calculated the CHA2DS2-VASC score. Patients were stratified according to their CHA2DS2-VASC score into 3 categories (0 to 3, 4 to 6, 7 to 9), and the association between CHA2DS2-VASC score and 1-year clinical outcomes (stroke, all-cause mortality, and combined outcome of stroke or mortality) was evaluated. We found that both stroke and mortality at 1 year were significantly more frequent with increasing CHA2DS2-VASC score (p = 0.012 and p = 0.025, respectively). Each single-point rise in CHA2DS2-VASC score was associated with a 38% increase in the 1-year combined outcome of mortality or stroke (p = 0.022; C index 0.615). In conclusion, CHA2DS2-VASC score can be used as a simple and effective tool to predict 1-year clinical outcomes including death and stroke in patients who underwent TAVI. PMID- 29157735 TI - Validation: a critical step in bringing biomarkers to clinical fruition. AB - Screening is vital to reducing morbidity and mortality due to cancer. A primary cause of poor survival is that many cancers are detected late and often after they have metastasized to distant sites. Therapies, therefore, become challenging for late-stage disease and are not successful for nearly all cancer types. The mortality rates from cancers where screening tools are available are lower than from cancers for which no viable screening tools exist. Even for cancers where screening tools currently exist, there is room for improvement, either in the accuracy of the tests or in increasing widespread use of screening by making the tests less invasive. For instance, despite widely available screening methods that can detect early-stage colon cancer or its precursors, only approximately 40% of newly diagnosed colon cancers are localized. It is a challenge to develop screening tests that are not only highly sensitive but also highly specific, to avoid putting patients through unnecessary biopsies and treatment. Biomarkers have great potential to improve the existing diagnostic accuracies of screening modalities and substitute invasive screening methods with noninvasive methodologies using bodily fluids such as plasma, serum, saliva, urine, etc. Biomarkers are defined by the National Institutes of Health as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention." In this commentary, we discuss important measures that could be taken to increase the chances of bringing biomarkers to clinical fruition. PMID- 29157731 TI - Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of Data From the TODAY Clinical Trial. AB - BACKGROUND: Diabetic kidney disease is a major cause of premature mortality in type 2 diabetes mellitus (T2DM). Worsening insulin sensitivity independent of glycemic control may contribute to the development of diabetic kidney disease. We investigated the longitudinal association of insulin sensitivity with hyperfiltration and increased albumin excretion in adolescents with T2DM. STUDY DESIGN: Observational prospective cohort study. SETTING & PARTICIPANTS: 532 TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) participants aged 12 to 17 years with T2DM duration less than 2 years at baseline. The TODAY Study was a multicenter randomized clinical trial that examined the efficacy of 3 treatment regimens (metformin monotherapy, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention program) to achieve durable glycemic control. PREDICTORS: Natural log-transformed estimated insulin sensitivity (reciprocal of fasting insulin), hemoglobin A1c concentration, age, race-ethnicity, treatment group, body mass index, loss of glycemic control, and hypertension. OUTCOMES: Hyperfiltration was defined as 99th percentile or higher of estimated glomerular filtration rate (>=140mL/min/1.73m2) when referenced to healthy adolescents (NHANES 1999-2002) and albumin-creatinine ratio >= 30MUg/mg at 3 consecutive annual visits. RESULTS: Hyperfiltration was observed in 7.0% of participants at baseline and in 13.3% by 5 years, with a cumulative incidence of 5.0% over 5 years. The prevalence of increased albumin excretion was 6% at baseline and 18% by 5 years, with a cumulative incidence of 13.4%. There was an 8% increase in risk for hyperfiltration per 10% lower estimated insulin sensitivity in unadjusted and adjusted models (P=0.01). Increased albumin excretion was associated with hemoglobin A1c concentration, but not estimated insulin sensitivity. LIMITATIONS: Longer follow-up is needed to capture the transition from hyperfiltration to rapid glomerular filtration rate decline in youth-onset T2DM. CONCLUSIONS: Lower estimated insulin sensitivity was associated with risk for hyperfiltration over time, whereas increased albumin excretion was associated with hyperglycemia in youth-onset T2DM. PMID- 29157736 TI - The influence of dosing on effect size of exercise therapy for musculoskeletal foot and ankle disorders: a systematic review. AB - OBJECTIVE: The purpose of this review was to identify doses of exercise therapy associated with greater treatment effect sizes in individuals with common musculoskeletal disorders of the foot and ankle, namely, achilles tendinopathy, ankle sprains and plantar heel pain. METHODS: AMED, EMBASE and MEDLINE were searched from 2005 to August 2017 for randomized controlled trials related to exercise for these three diagnoses. The Physiotherapy Evidence Database scale was used for methodological quality assessment. Exercise dosing variables and outcome measures related to pain and function were extracted from the studies, and standardized mean differences were calculated for the exercise groups. RESULTS: Fourteen studies met the final inclusion. A majority of the studies showed large effects and two small trends were identified. Patients with plantar heel pain may benefit more from a daily home exercise program than two supervised visits per week (SMD=3.82), but this recommendation is based on weak evidence. In achilles tendinopathy, a relationship was also seen when sets and repetitions of eccentric exercise were performed as tolerated (SMD=1.08 for function, -1.29 for pain). CONCLUSIONS: Session duration, frequency, total number of visits, and overall length of care may all be dosing variables with limited value for determining effective exercise prescription. However, the limited number of studies prevents any definitive conclusions. Further investigation is warranted to improve our understanding of the influence exercise dosing has on treatment effect sizes. Future randomized controlled trials comparing specific exercise dose variables should be conducted to clarify the impact of these variables. PMID- 29157737 TI - Predicting successful prosthetic rehabilitation in major lower-limb amputation patients: a 15-year retrospective cohort study. AB - OBJECTIVE: To determine and compare specific factors that could be associated and predictive with successful prosthetic rehabilitation in major lower-limb amputations. METHODS: A 15-year long (2000-2014) retrospective observational cohort study was conducted. Two different criteria were used to define successful prosthetic rehabilitation: (1) the ability to walk at least 45m, regardless of assistive devices; and (2) walking >45m without other ambulatory aids than one cane (if required). Age, gender, comorbidities, cause and level of amputation, stump characteristics, ulcers in the preserved limb, and time between surgery and physical therapy were examined as predictors of successful prosthetic rehabilitation. RESULTS: A total of 169 patients (61.60+/-15.9 years) were included. Regarding walking ability with or without walking aids, the presence of ulcers in the preserved limb was individually associated with failed prosthetic rehabilitation (p<0.001), while being male (OR=0.21; 95%CI=0.06-0.80) and transtibial level of amputation (OR=6.73; 95%CI=1.92-23.64) were identified as independent predictors of failure and success, respectively. Regarding the criterion of successful rehabilitation, a shorter time until rehabilitation was individually associated with improved walking ability (p<0.013), while failure could be predicted by comorbidities (OR=0.48; 95%CI=0.29-0.78) and age groups of 65-75 years old (OR=0.19; 95%CI=0.05-0.78) and over 75 years old (OR=0.19; 95%CI=0.04-0.91). CONCLUSIONS: Regarding walking ability with or without walking aids, male gender and transtibial level of amputation are independently associated with failure and success respectively, whereas older age and comorbidities can predict failed prosthetic rehabilitation when assistive walking devices are considered. Future prospective cohort studies are needed to confirm these findings. PMID- 29157738 TI - Do hip muscle weakness and dynamic knee valgus matter for the clinical evaluation and decision-making process in patients with patellofemoral pain? AB - BACKGROUND: Patellofemoral pain is a very common musculoskeletal condition. In the last years, evidence regarding this disease increased exponentially. Although widely investigated, this problem still frustrates patients and clinicians for having an unfavorable prognosis. Some gaps still exist in the understanding and managing of patellofemoral pain. Numerous cross-sectional association studies show an association between gluteus muscular strength and dynamic knee valgus in patients with patellofemoral pain. In spite of this biological plausibility, many evidences challenge the direct relationship between these factors. Recent studies have concluded that women with patellofemoral pain show muscular weakness of the hip based on the cross-sectional studies, however prospective studies indicate that hip weakness cannot be considered a risk for development of patellofemoral pain. In addition, some clinical trials have demonstrated that strength training of the gluteal muscles promotes significant improvement in symptoms but not alter the kinematics of the patients with patellofemoral pain. These findings cast doubt on whether the cause of this condition is really being treated, whether all individuals suffering from patellofemoral pain present dynamic knee valgus or if this is a disturbance present in only a subgroup of patients and whether the strengthening of the hip musculature is an option to consider for prevention of patellofemoral pain. CONCLUSION: Certainly, more studies should be conducted to clarify the influence of mechanical patterns on this condition, but with the existing evidence so far, the importance given to these issues in the evaluation and clinical decision on treatment of these patients seems questionable. Therefore, this masterclass explores the understanding about patellofemoral pain, highlighting mainly the importance of muscular strength and dynamic knee valgus, as well as other possible factors that must be consider during the evaluation and the decision making in these patients. PMID- 29157739 TI - Office-Based Spirometry: A New Model of Care in Preoperative Assessment for Low Risk Lung Resections. AB - BACKGROUND: Formal pulmonary function testing with laboratory spirometry (LS) is the standard of care for risk stratification before lung resection. LS and handheld office spirometry (OS) are clinically comparable for forced expiratory volume in 1 second and forced vital capacity. We investigated the safety of preoperative risk stratification based solely on OS. METHODS: Patients at low risk for cardiopulmonary complications were enrolled in a single-center prospective study and underwent preoperative OS. Formal LS was not performed when forced expiratory volume in 1 second was more than 60% by OS. Propensity score matching was used to compare patients in the OS group to low-risk institutional database patients (2008 to 2015) who underwent LS and lung resection. Standardized mean differences determined model covariate balance. The McNemar test and log-rank test were performed, respectively, for categorical and continuous paired outcome data. RESULTS: There were 66 prospectively enrolled patients who received OS and underwent pulmonary resection, and 1,290 patients received preoperative LS, resulting in 52 propensity score-matched pairs (83%). There were no deaths and two 30-day readmissions per group. The major morbidity risk was similar in each group (7.7%). All analyses of discordant pair morbidity had p exceeding 0.56. There was no association between length of stay and exposure to OS vs LS (p = 0.31). The estimated annual institutional cost savings from performing OS only and avoiding LS was $38,000. CONCLUSIONS: Low-risk patients undergoing lung resection can be adequately and safely assessed using OS without formal LS, with significant cost savings. With upcoming bundled care reimbursement paradigms, such safe and effective strategies are likely to be more widely used. PMID- 29157740 TI - Unplanned Readmissions After Open Thoracoabdominal Aortic Aneurysm Repair. AB - BACKGROUND: Although reducing the incidence of unplanned readmission after thoracoabdominal aortic aneurysm (TAAA) repair represents an important opportunity to improve outcomes, predictors of readmissions are not known. We sought to characterize and identify factors associated with unplanned readmission after discharge in survivors of open TAAA repair. METHODS: Through prospective phone contact and retrospective record review, we determined the frequency and characteristics of unplanned readmissions within 30 days of discharge in 363 patients who were discharged after open TAAA repair. We used univariate and multivariable analyses to identify factors associated with readmission. RESULTS: There were 44 unplanned readmissions in 40 patients (11%). After readmission, 11 patients underwent operations, and 17 underwent nonsurgical procedures, the most common of which was thoracentesis (n = 9). Readmitted patients tended to have lower preoperative estimated glomerular filtration rates (p = 0.045), higher frequencies of preoperative sleep apnea (p = 0.009) and postoperative pulmonary (p = 0.04) and infection (p = 0.02) complications, and longer hospital stays (p = 0.01) than patients without readmissions. Patient age, urgency of operation, and extent of TAAA repair were similar in patients with and without readmissions. Multivariable analysis identified sleep apnea (relative risk ratio [RRR] 3.21, 95% confidence interval [CI]: 1.51 to 6.82, p = 0.002), postoperative infection (RRR 4.34, 95% CI: 1.32 to 14.25, p = 0.02), renal failure necessitating dialysis (RRR 3.14, 95% CI: 1.04 to 9.46, p = 0.04), and visceral artery stenting (RRR 2.43, 95% CI: 1.09 to 5.44, p = 0.03) as significant predictors of readmission. CONCLUSIONS: Patients with renal dysfunction, sleep apnea, or postoperative infection were particularly likely to be readmitted; optimizing the management of these factors may reduce early readmission after TAAA repair. PMID- 29157741 TI - Biventricular Support With Intracorporeal, Continuous Flow, Centrifugal Ventricular Assist Devices. AB - BACKGROUND: The incidence of right ventricular dysfunction requiring right ventricular assist device after left ventricular assist device placement has been reported between 10% to 30%. The mortality rate is higher compared with patients who require left ventricular assist device only; the most effective and safest biventricular assist device remains unknown. We aimed to determine the survival outcomes and frequency of adverse events in patients with two durable, intracorporeal, continuous flow centrifugal pumps for support. METHODS: Between November 2012 and June 2015, 38 patients were identified from INTERMACS received durable, intracorporeal continuous flow centrifugal pumps for biventricular support. Pediatric patients were excluded. Mean age was 47 years, and 74% of patients were male. The common primary diagnoses in this cohort were dilated myopathy, idiopathic (37%) and ischemic (16%). RESULTS: Nineteen participating centers implanted devices in 38 patients; 11 patients died with device in place, 9 patients received a heart transplant, and 18 were alive on support with the right ventricular assist device in place. Survival outcomes were 68% at 6 months and 62% at 12 months. The left ventricular assist device was placed in the left ventricle apex in 91% of cases, and in 9%, the location was not specified. The right ventricular assist device was placed in the right ventricle in 50%, right atrium in 37%, and not specified in 13%. The adverse events included infection 50%, bleeding 44%, respiratory failure 31.6%, and malfunction 26.3%; neurologic dysfunction 26.3%; renal dysfunction 18.4%; and arrhythmia 18.4%. CONCLUSIONS: The use of durable, intracorporeal, continuous flow centrifugal pumps for management of advanced biventricular heart failure is associated with high morbidity and mortality. Further investigation of this device configuration is warranted. PMID- 29157742 TI - Phase 1 Trial Evaluating Safety of Pulmonary Artery Sealing With Ultrasonic Energy in VATS Lobectomy. AB - BACKGROUND: Energy-sealing devices may be useful to divide small pulmonary arteries (PAs) during video-assisted thoracoscopic surgery (VATS) lobectomy. We evaluated the safety of PA branch sealing with an ultrasonic energy vessel sealing device during VATS lobectomy. METHODS: The study consisted of a phase 1 trial. Patients planned to undergo VATS lobectomy were prospectively enrolled. Target sample size was 20 patients. Branches of 7 mm or less were sealed and cut with an ultrasonic energy vessel-sealing device. The remainder of the lobectomy was performed in a standard fashion. Intraoperative, in-hospital, and 30-day postoperative bleeding were prospectively recorded. RESULTS: Thirty-three patients were prospectively enrolled. Thirteen patients were not amenable to PA sealing with the vessel-sealing device because all PA branch diameters exceeded 7 mm (n = 10), conversion to thoracotomy (n = 2), and lobectomy not performed (n = 1). A minimum of one PA branch was sealed with the device in 20 patients. Fifty eight PA branches were divided in 20 patients: 31 with ultrasonic device, 24 with endostaplers, 2 with clips, and 1 with sutures. The mean vessel diameter sealed with the device was 4 mm. Two patients were converted to thoracotomy (1 with PA injury during dissection, 1 with PA tumor invasion). No intraoperative or postoperative bleeding was related to ultrasonic PA branch sealing. No postoperative deaths occurred. CONCLUSIONS: PA branch sealing for vessels 7 mm or less was safely achieved using an ultrasonic energy vessel-sealing device in VATS lobectomy. Large-scale, prospective, multi-institutional studies are necessary before widespread clinical application of energy for PA branch sealing in VATS lobectomy. PMID- 29157743 TI - Next generation microbiological risk assessment meta-omics: The next need for integration. AB - The development of a multi-omics approach has provided a new approach to the investigation of microbial communities allowing an integration of data, which can be used to better understand the behaviour of and interactions between community members. Metagenomics, metatranscriptomics, metaproteomics and metabolomics have the potential of producing a large amount of data in a very short time, however an important challenge is how to exploit and interpret these data to assist risk managers in food safety and quality decisions. This can be achieved by integrating multi-omics data in microbiological risk assessment. In this paper we identify limitations and challenges of the multi-omics approach, underlining promising potentials, but also identifying gaps, which should be addressed for its full exploitation. A view on how this new way of investigation will impact the traditional microbiology schemes in the food industry is also presented. PMID- 29157744 TI - Insufficient Sleep Is Associated with Obesity and Excessive Screen Time Amongst Ten-Year-Old Children in Sweden. AB - PURPOSE: This study investigated sleep, television, computer habits, and obesity in school-age children. DESIGN AND METHODS: This was a cross-sectional self report survey of 1260 children in grade 4 (mean age, 10.1) living in southern Sweden (49.1% boys). The heights and weights of 1097 (87.1%) of the children were recorded. Descriptive statistics, bivariate analyses, and multiple logistic regression were employed. RESULTS: The median length of self-reported sleep on weeknights was 9.5h. Approximately 40% of the children reported receiving <9h of sleep. The median bedtime was 9PM (21:00). On weekends, the median bedtime was 1 h later, and they delayed getting up by 1.5h. The median time spent watching TV and using a computer was 1 h each. The prevalence of being overweight (including obesity) was 18%. Insufficient sleep (<9h) was associated with being overweight, watching TV, or using a computer for two or more hours each day, difficulty falling asleep, and being tired at school. CONCLUSIONS: School-age children who receive less sleep are more likely to be overweight and report excessive television and computer use. A strong and urgent need exists to highlight the importance of healthy sleep and media habits. It is challenging for pediatric nurses and school nurses to teach children and their families about healthy sleep and media habits. PMID- 29157745 TI - Differential diagnosis of parkinsonian syndromes using dopamine transporter and perfusion SPECT. AB - OBJECTIVE: We aimed to assess whether a combined analysis of dopamine transporter (DAT)- and perfusion-SPECT images (or either) could: (1) distinguish atypical parkinsonian syndromes (APS) from Lewy body diseases (LBD; majority Parkinson disease [PD]), and (2) differentiate among APS subgroups (progressive supranuclear palsy [PSP], corticobasal syndrome [CBS], and multiple system atrophy [MSA]). METHODS: We recruited consecutive patients with neurodegenerative parkinsonian syndromes (LBD, n = 46; APS, n = 33). Individual [123I]FP-CIT- and [123I]iodoamphetamine-SPECT images were coregistered onto anatomical MRI segmented into brain regions. Striatal DAT activity and regional perfusion were extracted from each brain region for each patient and submitted to logistic regression analyses. Stepwise procedures were used to select predictors that should be included in the models to distinguish APS from LBD, and differentiate among the APS subgroups. Receiver-operating characteristic (ROC) analyses were performed to measure diagnostic power. Leave-one-out cross-validation (LOOCV) was performed to evaluate the diagnostic accuracy. RESULTS: The model to discriminate APS from LBD showed that the area under the ROC curve (AUC) was 0.923, while the total diagnostic accuracy (TDA) was 86.1% in LOOCV. In the model to distinguish PSP, CBS, and MSA from LBD, the AUC/TDA values were 0.978/94.6%, 0.978/87.0%, and 0.880/80.3%, respectively. In the model to differentiate between CBS and MSA, MSA and PSP, and PSP and CBS, the AUC/TDA values were 0.967/91.3%, 0.920/88.0%, 0.875/77.8%, respectively. CONCLUSION: An image-based automated classification using striatal DAT activity and regional perfusion patterns provided a good performance in the differential diagnosis of neurodegenerative parkinsonian syndromes without clinical information. PMID- 29157746 TI - Particle Filter-Based Target Tracking Algorithm for Magnetic Resonance-Guided Respiratory Compensation: Robustness and Accuracy Assessment. AB - PURPOSE: To assess overall robustness and accuracy of a modified particle filter based tracking algorithm for magnetic resonance (MR)-guided radiation therapy treatments. METHODS AND MATERIALS: An improved particle filter-based tracking algorithm was implemented, which used a normalized cross-correlation function as the likelihood calculation. With a total of 5 healthy volunteers and 8 patients, the robustness of the algorithm was tested on 24 dynamic magnetic resonance imaging (MRI) time series with varying resolution, contrast, and signal-to-noise ratio. The complete data set included data acquired with different scan parameters on a number of MRI scanners with varying field strengths, including the 1.5T MR linear accelerator. Tracking errors were computed by comparing the results obtained by the particle filter algorithm with experts' delineations. RESULTS: The ameliorated tracking algorithm was able to accurately track abdominal as well as thoracic tumors, whereas the previous Bhattacharyya distance based implementation failed in more than 50% of the cases. The tracking error, combined over all MRI acquisitions, is 1.1 +/- 0.4 mm, which demonstrated high robustness against variations in contrast, noise, and image resolution. Finally, the effect of the input/control parameters of the model was very similar across all cases, suggesting a class-based optimization is possible. CONCLUSIONS: The modified particle filter tracking algorithm is highly accurate and robust against varying image quality. This makes the algorithm a promising candidate for automated tracking on the MR linear accelerator. PMID- 29157747 TI - Multiplex Proximity Ligation Assay to Identify Potential Prognostic Biomarkers for Improved Survival in Locally Advanced Pancreatic Cancer Patients Treated With Stereotactic Body Radiation Therapy. AB - PURPOSE: To explore seromarker levels for associations with outcomes in locally advanced pancreatic cancer (LAPC) patients who received chemotherapy and stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Serum from LAPC patients in 2 prospective trials of hypofractionated SBRT (5-6.6 Gy * 5) was collected before SBRT. Proximity ligation assay quantified the expression levels of 36 pancreatic cancer-specific candidate seromarkers: Axl, BMP2, CA 125, CA 19 9, CEA, CXCL-1/6/9/10, EGFR, Gas6, Her2, IGF-2, IGFBP-2/3/7, IL-6/6Ra/7/8/12, mesothelin, MMP-1/2/3/7, osteopontin, PDGFRa, PDK1, PF4, RegIV, SPARC, TGF-beta, VEGF-A/D, and YKL40. Seromarker values were log transformed owing to log-normal distribution of the values, and Cox regression analysis was performed to assess for any association with overall survival. The Benjamini-Hochberg method was used to control for a false discovery rate (FDR) of only 10%. RESULTS: Sixty-four patients with LAPC were included. No clinical factors (including surgical resection, receipt of pre-SBRT chemotherapy, receipt of post-SBRT chemotherapy, performance status, and age) or potential biomarkers in the panel were associated with improved survival in this cohort after application of the FDR correction. Potential prognostic factors for improved survival for future investigation included surgical resection (P=.007, adjusted P=.153) and the serum expression of IL-8 (P=.006, adjusted P=.153), CA 19-9 (P=.031, adjusted P=.377), and MMP-1 (P=.036, adjusted P=.377). CONCLUSIONS: These data explore the expression of a panel of proteins in pre-SBRT serum of LAPC patients in the context of a conservative FDR correction. None of the clinical factors or expression levels of the serum proteins were found to be associated with survival; however, IL-8, CA 19-9, and MMP-1 were highlighted as possible candidates warranting inclusion in future seromarker studies in the ongoing efforts to identify tools for risk stratification and treatment allocation in LAPC. PMID- 29157748 TI - Consensus Contouring Guidelines for Postoperative Completely Resected Cavity Stereotactic Radiosurgery for Brain Metastases. AB - PURPOSE: To propose contouring guidelines based on consensus contours generated by 10 international experts for cavity stereotactic radiosurgery (SRS), an emerging treatment option after surgical resection of brain metastases. No guidelines for contouring the surgical cavity volume have been previously reported. METHODS AND MATERIALS: Ten postoperative completely resected cases with varying clinical scenarios and locations within the brain were selected. For each case, 10 experts independently contoured the surgical cavity clinical target volume (CTV). All the contours were analyzed, and agreement was calculated using the simultaneous truth and performance level estimation (STAPLE) with the kappa statistic. A follow-up survey was also completed by each investigator to summarize their contouring rationale for a number of different clinical scenarios. The results from the survey and the consensus STAPLE contours were both summarized to establish contouring guidelines. RESULTS: A high level of agreement was found between the expert CTV contours (mean sensitivity 0.75, mean specificity 0.98), and the mean kappa was 0.65. The agreement was statistically significant at P<.001 for all cases. From these results and analyses of the survey answers, the recommendations for CTV include fusion of the preoperative magnetic resonance imaging scan to aid in volume delineation; contouring the entire surgical tract regardless of the preoperative location of the tumor; extension of the CTV 5 to 10 mm along the dura overlying the bone flap to account for microscopic disease extension in cases with preoperative dural contact; and a margin of <=5 mm into the adjacent sinus when preoperative venous sinus contact was present. CONCLUSIONS: Consensus contouring guidelines for postoperative completely resected cavity SRS treatment were established using expert contours and clinical practice. However, in the absence of clinical data supporting these recommendations, these guidelines serve as a baseline for further study and refinement. PMID- 29157750 TI - Candida parapsilosis endophthalmitis after cataract surgery: A case report. PMID- 29157749 TI - Mithramycin A Enhances Tumor Sensitivity to Mitotic Catastrophe Resulting From DNA Damage. AB - PURPOSE: Specificity protein 1 (SP1) is involved in the transcription of several genes implicated in tumor maintenance. We investigated the effects of mithramycin A (MTA), an inhibitor of SP1 DNA binding, on radiation response. METHODS AND MATERIALS: Clonogenic survival after irradiation was assessed in 2 tumor cell lines (A549, UM-UC-3) and 1 human fibroblast line (BJ) after SP1 knockdown or MTA treatment. DNA damage repair was evaluated using gammaH2AX foci formation, and mitotic catastrophe was assessed using nuclear morphology. Gene expression was evaluated using polymerase chain reaction arrays. In vivo tumor growth delay was used to evaluate the effects of MTA on radiosensitivity. RESULTS: Targeting of SP1 with small interfering RNA or MTA sensitized A549 and UM-UC-3 to irradiation, with no effect on the BJ radiation response. MTA did not alter gammaH2AX foci formation after irradiation in tumor cells but did enhance mitotic catastrophe. Treatment with MTA suppressed transcription of genes involved in cell death. MTA administration to mice bearing A549 and UM-UC-3 xenografts enhanced radiation induced tumor growth delay. CONCLUSIONS: These results support SP1 as a target for radiation sensitization and confirm MTA as a radiation sensitizer in human tumor models. PMID- 29157751 TI - Preliminary evidence that digit length ratio (2D:4D) predicts neural response to delivery of motivational stimuli. AB - Reduced relative length of the 2nd to 4th digits (2D:4D) is thought to partially reflect fetal testosterone (FT) exposure, a process suspected to promote relatively permanent effects on the brain and behavior via structural and functional neuroadaptations. We examined the effect of 2D:4D on neural response - assessed by P2a and feedback-related negativity (FRN) event-related potentials (ERPs) - to motivational stimuli (reward or punishment) using two counterbalanced conditions of a passive S1/S2 outcome prediction design. P2a to expected and unexpected delivered rewards or punishments ($1 or white noise burst, respectively) and FRN to withheld rewards or punishments ($0 or silence, respectively) were observed in undergraduates. Lower left 2D:4D and greater 2D:4DR-L predicted amplified P2a to the delivery (but not FRN to the omission) of motivationally salient stimuli, regardless of valence and probability. These preliminary findings suggest that FT may organize dopamine neurons to respond more strongly to the delivery of motivational stimuli. PMID- 29157752 TI - Corrigendum to "Spousal resemblance for smoking: Underlying mechanisms and effects of cohort and age" [Drug Alcohol Depend. 153 (2015) 221-228]. PMID- 29157753 TI - [Validity and reproducibility of two direct observation assessment forms for evaluation of internal medicine residents' clinical skills]. AB - INTRODUCTION: The revision of the French medical studies' third cycle ought to be competency-based. In internal medicine, theoretical and practical knowledge will be assessed online with e-learning and e-portfolio. In parallel, a reflection about clinical skills assessment forms is currently ongoing. In this context, our aim was to assess the reproducibility and validity of two assessment forms based on direct clinical observation. METHOD: A prospective and multicentric study has been conducted from November 2015 to October 2016 aiming at evaluating the French translations of the MINI-Clinical Examination Exercice (MINI-CEX) and the Standardized Patient Satisfaction Questionnaire (SPSQ). Included residents have been assessed 2 times over a period of 6 months by the same binoma of judges. RESULTS: Nineteen residents have been included. The inter-judge reproducibility was satisfactory for the MINI-CEX: intraclass coefficients (ICC) between 0.4 and 0.8 and moderate for the SPSQ: ICC between 0.2 and 0.7 with a good internal coherence for both questionnaires (Cronbach between 0.92 and 0.94). Significant differences between the distributions of the scores given by the judges and a significant inter-center variability have been found. CONCLUSION: If the absolute value of the scores should not be taken into account in the evaluation process given its high variability, it could be of interest for the follow-up of the progression in the competencies. These forms could support the residents' debriefing based on the general trends given by the scores. PMID- 29157754 TI - [Should statin therapy be discontinued in the elderly?] PMID- 29157755 TI - [Acetaminophen induced 5-oxoproline acidosis: An uncommon case of high anion gap metabolic acidosis]. AB - The most common causes of high anion gap metabolic acidosis (HAGMA) are lactic acidosis, ketoacidosis, and intoxications. Nevertheless, clinicians can be faced with unexplained HAGMA, with a need to look for less common etiologies. We describe a case of 5-oxoproline (pyroglutamate) acidosis due to chronic acetaminophen ingestion at therapeutic dose in a 79-year-old inpatient. The pathophysiology of this condition is detailed, with abnormalities in the gamma glutamyl cycle due to acetaminophen ingestion and severe chronic morbidities, resulting in glutathione and cysteine deficiency and then accumulation of 5 oxoproline. In HAGMA, when usual causes have been excluded, 5-oxoproline acidosis should be suspected in patients with chronic morbidities and acetaminophen ingestion. This diagnosis should be kept in mind because it generally resolves quickly with cessation of acetaminophen and administration of intravenous fluids. PMID- 29157756 TI - Perianesthesia Nurses and the Family Caregiver. PMID- 29157757 TI - Letter to the Editor. PMID- 29157758 TI - Reply. PMID- 29157760 TI - The Use of Aromatherapy for Postoperative Pain Management: A Systematic Review of Randomized Controlled Trials. AB - PURPOSE: Aromatherapy (AT) is a complementary therapy recently used in the perianesthetic period. However, the scientific data on its effectiveness are limited. The aim of this systematic review is to present and analyze the results of all randomized controlled trials (RCTs) that studied the effectiveness of AT as a complementary treatment for postoperative pain. DESIGN: PubMed and Cochrane Library databases were searched from 1965 to December 2015. Nine randomized controlled trials that met the inclusion criteria were eventually included. METHODS: The studies included a total of 644 patients, who underwent various types of surgeries. The modified Jadad scale with eight items was used for the methodological evaluation of the RCTs. FINDINGS: Five RCTs support AT, which can alleviate postoperative pain, whereas four found no statistically significant differences between groups. CONCLUSIONS: Although AT is presented as an inexpensive complementary treatment with a low rate of adverse effects that improves patient satisfaction, it cannot be determined that there is sufficient evidence to conclude its effectiveness as a nonpharmacologic approach to the reduction of postoperative pain intensity. PMID- 29157759 TI - Effect of Preoperative Education on Postoperative Outcomes Among Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis. AB - PURPOSE: The objective of this review was to assess the effect of preoperative education on postoperative outcomes among patients undergoing cardiac surgery. DESIGN: Systematic review and meta-analysis. METHODS: A comprehensive literature search was made on PubMed, CINAHL, Ovid, ProQuest, ScienceDirect, Scopus, Web of Science, and the Cochrane database between 1995 and 2015. Fourteen randomized controlled trials were included. Data analysis was performed with RevMan software and created the Supplementary Appendix using the GRADE approach. FINDINGS: Meta analysis showed that preoperative education reduced anxiety scores (standardized mean difference = -0.96, 95% confidence interval: -1.37, -0.54; P < .0001). However, there was no significant effect of preoperative education on pain, depression, and length of hospital stay. There is low-quality evidence, and reasons for downgrading are due to study design limitations, inconsistency, and imprecision of effect estimates. CONCLUSIONS: The results show that preoperative education can effectively decrease anxiety in patients undergoing cardiac surgery. PMID- 29157761 TI - Competence Assessment Instruments in Perianesthesia Nursing Care: A Scoping Review of the Literature. AB - PURPOSE: To identify competence assessment instruments in perianesthesia nursing care and to describe the validity and reliability of the instruments. DESIGN: A scoping review in a systematic manner. METHODS: A search in CINAHL, MEDLINE, and ERIC was carried out to identify empirical studies from 1994 to 2015. A narrative synthesis approach was undertaken to analyze the data. FINDINGS: Nine competence assessment instruments in perianesthesia nursing care were identified. The instruments used three types of data collection methods: Self-report, observation, and written examinations. The most commonly reported validity method was content validity involving expert panels and reliability tests for internal consistency and inter-rater's consistency. CONCLUSIONS: Integrating more than one data collection method may give support to overcoming some of the limitations, such as lack of objectivity and misinterpretation of the assessment results. In an ever-changing environment, perianesthesia nursing competence requires constant reassessment from the perspective of content validity, scoring methods, and reliability. PMID- 29157762 TI - Postanesthesia Scoring Methods: An Integrative Review of the Literature. AB - PURPOSE: Internationally there is no consensus on the indicators essential for determining safe recovery from anesthesia and patient readiness for discharge from the postanesthesia care unit (PACU). DESIGN: Integrative review. METHODS: Using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) as a search strategy, the literature related to PACU discharge scores were evaluated and organized into themes. FINDINGS: The traditional components of airway support, oxygenation, sedation, and circulation are common within many first stage PACU discharge scores. However, there is strong support from the literature for components such as heart rate, temperature, pain, postoperative nausea and vomiting (PONV), urine output, and surgical site assessment to also be included. The review revealed that there is no standardized time frequency in applying a first stage PACU discharge score to patients within the PACU environment. CONCLUSIONS: There is a need for the development and trial of an evidence based first stage PACU discharge score. PMID- 29157763 TI - Does Site Matter? Comparing Accuracy and Patient Comfort of Blood Glucose Samples Taken From the Finger and Palm of the Perioperative Patient. AB - PURPOSE: This study compared two blood glucose (BG) point of care sampling methods to determine which is least painful yet accurate. DESIGN: The two-period, two-treatment crossover trial compared the traditional fingertip sampling method to a form of alternative site testing (AST), palm of the hand. METHODS: Subjects received both methods of BG sampling to compare comfort and accuracy. They were randomly assigned to determine which method was used first. Pain rating (0 to 10) and glucose results for both methods were documented. FINDING: Results indicated that pain rating was significantly lower with AST (1.65) than with the standard site (2.83) (P < .001). There was no significant difference in mean glucose measurements between standard care (150 mg/dL) and AST (149 mg/dL). The numbers were closely correlated (r = 0.9815). CONCLUSIONS: Findings support AST via the palm of the hand as an accurate and less painful method of obtaining BG results on diabetic patients. PMID- 29157764 TI - Perianesthesia Nurses Are My Second Family: A Qualitative Descriptive Study. AB - PURPOSE: Identify the perceptions of perianesthesia nurses regarding behaviors that promote or detract from sustaining a safe, efficient, and satisfying work environment. DESIGN: Two focus groups and seven individual interviews (n=14) were conducted exploring the perceptions regarding team behavior of registered nurses in one pediatric perianesthesia unit. METHODS: Qualitative descriptive data collection, inductive content analysis. FINDINGS: Nurses described a responsive, engaged health care team whose leadership is available and directive when needed, as creating an effective, satisfying work environment. Primary themes that emerged were Leadership Sets the Tone, Playing Fair, No One Gets Hurt, and Why We Stay. This nursing team acknowledged that inattentive, distracted team members cause frustration, work inequities, and care delays, potentially undermining patient safety. CONCLUSIONS: Results demonstrate the need to create and sustain consistently respectful perianesthesia work cultures. Research focusing on unit specific approaches to work distribution, communication, leadership, and technology use is needed. PMID- 29157765 TI - The Effect of Preoperative Oral Carbohydrate Solution Intake on Patient Comfort: A Randomized Controlled Study. AB - PURPOSE: The study was conducted to investigate the effect of preoperative oral carbohydrate loading on the preoperative discomforts and postoperative complications of patients undergoing elective thyroidectomy. DESIGN: A randomized controlled clinical trial. METHODS: Ninety patients scheduled for thyroidectomy were divided into three groups: (1) those receiving a carbohydrate-rich drink (CHD), (2) those receiving an overnight 5% glucose intravenous infusion, and (3) those fasting from midnight. The preoperative discomforts and postoperative complications of patients were evaluated using the Visual Analog Scale (VAS). The patients' vital signs and blood glucose levels were measured perioperatively. FINDINGS: In the preoperative assessment, hunger, thirst, mouth dryness, chill, and headache adjusted for age, gender, body mass index, and duration of the operation were all found to be significantly higher in the glucose and fasting groups than the CHD group (P < .01). In the postoperative period, the fasting group experienced more vomiting and pain compared with the CHD group (P < .05). A significant difference was found between the groups in terms of diastolic blood pressure and pulse rate in the preoperative and intraoperative periods (P < .05). CONCLUSIONS: The CHD treatment before thyroidectomy increases patient comfort by reducing preoperative discomfort (such as hunger, thirst, dry mouth, fatigue and headache) and early postoperative complications (vomiting and pain). PMID- 29157766 TI - Safety of Rolled and Folded Cotton Blankets Warmed in 130 degrees F and 200 degrees F Cabinets. AB - PURPOSE: In 2014, ECRI recommended that blanket warming cabinets be set at a maximum temperature of 130 degrees F because of safety concerns with warmed rolled and folded blankets. We could find no research to support this recommendation. The purpose of this study was to measure skin temperatures and thermal comfort in healthy volunteers before and after application of folded and rolled dry cotton blankets warmed in 130 degrees F or 200 degrees F cabinets. DESIGN: Randomized, descriptive, and comparative study. METHODS: Participants (n = 20) received two blankets (one rolled and one folded) from warming cabinets set at 130 degrees F or 200 degrees F. Folded blankets were applied to the back and rolled to the neck. Skin temperatures and thermal comfort were obtained at fixed time intervals. FINDINGS: Skin temperatures from blankets in the 200 degrees F cabinet were greater than those in the 130 degrees F cabinet. No skin temperatures reached temperature and/or duration thresholds for dermal injury. CONCLUSIONS: This study provides supportive evidence that warming cabinets may be set at a maximum of 200 degrees F without compromising patient safety. PMID- 29157767 TI - Nurses' Perceptions of Patient Care Continuity in Day Surgery. AB - PURPOSE: The increase in day surgery has brought about a significant change in patient care and care continuity. The purpose of this study was to analyze nurses' perceptions of the realization of continuity of care in day surgery. Continuity of care is examined from the perspectives of time, flow, co-ordination flow, caring relationship flow, and information flow. DESIGN: Descriptive study. METHODS: A questionnaire including demographics and questions about continuity of care was completed by 83 of the 120 eligible nurses (response rate, 69%) in one hospital district in Finland. FINDINGS: According to the nurses, continuity of patient care is mostly well realized. On the day of surgery, information flow was the domain that was best realized. In the opinion of the nurses, continuity of care was least realized at home before surgery and at home during the period after surgery. CONCLUSIONS: Based on nurses' perceptions, continuity of care was relatively well realized. PMID- 29157768 TI - Identifying Nurse Anesthetists' Professional Identity. AB - PURPOSE: To explore professional identity of registered nurse anesthetists (RNAs) and RNAs' expectations of their professional self and the expectations RNAs meet from interdisciplinary team members when preparing patients for general anesthesia. DESIGN: Focused ethnography was used for data collection. METHODS: Participant observations and interviews were conducted with patients scheduled for surgery and with RNAs in charge of the patients during the anesthetic procedures. Interviews with RNAs, anesthesiologists, and operation nurses with a specific focus on RNAs' professional identity were performed. The analysis was inspired by grounded theory. FINDINGS: A core variable of Identifying the professional self is presented, and two subcore variables are delineated: Gliding between tasks and structures and Depending on independence. CONCLUSIONS: RNAs are at risk of downsizing psychosocial and relational aspects of fundamentals of care in favor of performing technological procedures, and RNAs' professional values are influenced by the work culture in the Department of Anesthesiology. PMID- 29157769 TI - Rethinking Perianesthesia Orientation. AB - PURPOSE: To discover the best orientation method for perianesthesia nurses. DESIGN: Pilot study comparing two approaches to orientation. METHODS: Nurses in one group were each assigned to a single preceptor, whom they followed regardless of which of the three distinct areas-the preoperative unit, postanesthesia recovery unit, or Phase II discharge unit-the preceptor was scheduled to work. In the second group, trainees remained in one area, with various preceptors, until proficiency was achieved. All trainees (n = 25) were surveyed. FINDINGS: New registered nurses in the perianesthesia department prefer to remain in a single area until competency is achieved. CONCLUSIONS: Perianesthesia nursing has a distinct body of knowledge. Although conventional wisdom suggests that using a single preceptor for nursing orientation leads to better outcomes, our study indicates that allowing orientees to remain in one area until a level of competency is achieved may be more effective. PMID- 29157770 TI - The Prevention and Recognition of Ulnar Nerve and Brachial Plexus Injuries. AB - Perioperative peripheral nerve injury is a serious yet preventable perioperative complication. Since the inception of the American Association of Anesthesiologists Closed Claim Project, the incidence of peripheral nerve injury has remained constant with an overall reported prevalence rate of 15% to 16%. To date, the most frequent nerve injuries are ulnar nerve neuropathy and brachial plexus injury. This article will review the clinical presentation, pathophysiology, causative and risks factors, and preventive measures for the two most common nerve injuries. Knowledge of the anatomical structures and components of peripheral nerves prone to injuries during surgery can assist in defining precautionary actions in the perioperative setting. Positioning techniques in the operating room, early recognition of neuropathies, and use of a perioperative tool in the postoperative setting are keys to reduce significant clinical complications. PMID- 29157771 TI - Situational Awareness in Critical Care: An Aviation Approach to Reduce Error. PMID- 29157773 TI - The Culture of Kindness. PMID- 29157772 TI - Taking Bullying Out of Health Care: A Patient Safety Imperative. PMID- 29157774 TI - Erratum. PMID- 29157775 TI - Ketamine-What Is Old Is New Again. PMID- 29157776 TI - Dress Code in the Perianesthesia Setting. PMID- 29157777 TI - Considering the Literature. PMID- 29157778 TI - Reflecting on Racial Disparities in Pediatric Care: Can Perianesthesia Care Nurses Make a Difference? PMID- 29157779 TI - What's the Big Deal About Evidence-Based Practice? PMID- 29157780 TI - Hormonal response to a non-exercise stress test in athletes with overtraining syndrome: results from the Endocrine and metabolic Responses on Overtraining Syndrome (EROS) - EROS-STRESS. AB - OBJECTIVES: Overtraining syndrome (OTS) leads to worsened sports performance and fatigue. The pathophysiology of OTS has not been entirely elucidated, and there is a lack of accurate markers for its diagnosis. Changes in hormonal responses implicated in OTS were stimulated by exercise, which has limited their interpretation. Hence, we aimed to evaluate growth hormone (GH) and prolactin responses to a gold-standard and exercise-independent stimulation test, the insulin tolerance test (ITT). DESIGN: Volunteers were recruited and divided into OTS-affected athletes (OTS), healthy athletes (ATL), and healthy non-active subjects (NCS) groups, after general and specific inclusion and exclusion criteria. METHODS: We evaluated the responses of growth hormone (GH) and prolactin to the ITT, and compared between groups. RESULTS: A total of 51 subjects were included (OTS, n=14, ATL, n=25, and NCS, n=12). OTS disclosed significantly lower basal levels of GH (p=0.003) and prolactin (p=0.048), and GH (p=0.001) and prolactin (p<0.001) responses to ITT (p=0.001), compared to ATL, but similar to NCS. OTS showed a later rise in GH levels in response to hypoglycemia, compared to ATL, but not to NCS. We suggest cutoffs for GH and prolactin levels to aid in the diagnosis of OTS. CONCLUSIONS: OTS-affected athletes show reduced GH and prolactin basal levels and responses to a non exercise stress test compared to healthy athletes, but not to sedentary subjects. PMID- 29157781 TI - Infections by carbapenemase-producing enterobacteriaceae in a department of urology. A new challenge. AB - OBJECTIVES: To analyse infections by carbapenemase-producing enterobacteriaceae (CPE) and describe the characteristics and potential risk factors associated with patients of a department of urology. MATERIAL AND METHODS: Observational and retrospective study. The inclusion criterion was hospitalisation in our department of Urology between August 2013 and December 2016. We analysed those patients who were positive for CPE in at least 1 culture. We reviewed their baseline characteristics, risk factors and variables such as the presence of previous urinary tract infections, subsequent readmissions, the microorganism, type of CPE, treatment, origin (hospital or community) and mortality. RESULTS: Of the 5,657 patients who met the inclusion criterion, a CPE was isolated in 12 cases. CPE infections represented 3.6% of all healthcare-associated infections and 9.7% of those caused by enterobacteria. The analysed factors associated with CPE infection in our series were the presence of urinary catheters (100%), undergoing surgery (58.3%), previous ICU admission (8.3%) and immunosuppression (16.6%). In terms of mortality, 8.3% of the patients who presented CPE infection died during hospitalisation. CONCLUSIONS: Approximately 10% of enterobacteria present a carbapenemase-resistance pattern in urological patients in our setting. Carrying a urinary catheter and/or undergoing surgery are risk factors associated with the development of these infections in urological patients in our setting. CPE infections increase morbidity and mortality. PMID- 29157782 TI - Comparative Assessment of the Effect of Hyper-glycosylation on the Pattern and Kinetics of Degradation of Darbepoetin Alfa using a Stability-Indicating Orthogonal Testing Protocol. AB - Darbepoetin alfa (DA); hyper-glycosylated Erythropoietin alfa (EPO) is an essential treatment of anemia in patients with chronic kidney failure and cancer. In this study, DA and EPO were subjected to physicochemical stress factors that might be encountered during production, transport and storage (pH, temperature, agitation, repeated freeze-thaw and oxidation). An orthogonal stability indicating assay protocol comprised of SE-HPLC, RP-HPLC, ELISA and SDS-PAGE was developed and validated to investigate the effect of further glycosylation of DA on the pattern and kinetics of degradation. Results showed a relatively higher stability and lower tendency to form high molecular weight aggregates in the case of DA when compared to EPO, under equivalent stress conditions. Dimers and aggregates were formed for both drugs across the whole pH range and following incubation at temperatures higher than 2-8 degrees C or repeated freeze/thaw. The same observation was noted upon agitation of standard samples prepared in the formulation buffers at high speed and upon oxidation with hydrogen peroxide. The agreement between SE-HPLC, supported with spectral purity data and ELISA confirmed the specificity of both techniques for the intact drugs. Results of RP HPLC and SDS-PAGE indicated that dimerization occurred through disulfide and bi tyrosine covalent bonds in the case of pH and oxidation, respectively. It was evident that aggregation was significantly suppressed upon increasing the glycan size and under any of the studied stress factors loss of the glycan has not been observed. These observations supported with the slow kinetics of degradation confirmed the superiority of glyco-engineering over chemical pegylation to enhance the stability of EPO. Formation of such potentially immunogenic product related impurities at all tested stress factors confirmed the need for orthogonal testing protocols to investigate the complex pattern of degradation of such sensitive products. PMID- 29157783 TI - Effect of Push-Up Position on Wrist Joint Pressures in the Intact Wrist and Following Scapholunate Interosseous Ligament Sectioning. AB - PURPOSE: To determine the contact pressures between the scaphoid and lunate and the distal radius during 2 wrist push-up positions before and following scapholunate interosseous ligament (SLIL) sectioning. METHODS: Eight fresh cadaveric wrists were tested in a neutral flexion-extension (knuckle) push-up position and in an extended push-up position. Pressure measurements were acquired as each wrist was loaded with the wrist in extension and with the wrist in a neutral position. Data were acquired with the SLIL intact and following sectioning of its dorsal, volar, and proximal components. The wrist was disarticulated and a map drawn on each sensor to identify each joint fossa. RESULTS: A push-up performed with the wrist in extension caused a significantly greater peak pressure in the radioscaphoid fossa but not in the radiolunate fossa. Moving the wrist into extension caused a significant dorsal movement of the pressure centroid an average of 2.9 mm in the radiolunate fossa and an average of 5.7 mm in the radioscaphoid fossa. Sectioning the SLIL caused the centroid of pressure in the radioscaphoid fossa to significantly move an average 1.4 mm radially. CONCLUSIONS: A push-up with the wrist in extension causes a significant increase in the pressure in the radioscaphoid fossa but not in the radiolunate. This finding may help explain why degenerative arthritis first develops in the radioscaphoid fossa before involving the radiolunate fossa. As expected, gapping that occurs with SLIL injury was observed here as a radial translation of the scaphoid and not as a movement of the lunate. The new location of scaphoid contact may be an additional reason for the development of radioscaphoid arthritis occurring before radiolunate arthritis. CLINICAL RELEVANCE: This study provides a possible explanation as to why degenerative arthritis may first occur in the radioscaphoid fossa. PMID- 29157784 TI - Deriving muscle fiber diameter from recorded single fiber potential. AB - OBJECTIVE: The aim of the study was to estimate muscle fiber diameters through analysis of single muscle fiber potentials (SFPs) recorded in the frontalis muscle of a healthy subject. METHODS: Our previously developed analytical and graphic method to derive fiber diameter from the analysis of the negative peak duration and the amplitude of SFP, was applied to a sample of ten SFPs recorded in vivo. RESULTS: Muscle fiber diameters derived from the simulation method for the sample of frontalis muscle SFPs are consistent with anatomical data for this muscle. CONCLUSIONS: The results confirm the utility of proposed simulation method. Outlying data could be considered as the result of a contribution of other fibers to the potential recorded using an SFEMG electrode. Our graphic tool provides a rapid estimation of muscle fiber diameter. PMID- 29157785 TI - History of Breast Cancer Increases 90-Day Pulmonary Embolism Rates and Reimbursements After Total Hip Arthroplasty: A National Matched-Pair Analysis. AB - BACKGROUND: Rates of total hip arthroplasty (THA) are projected to increase in the coming decades. Multiple studies have focused on identifying risk factors for adverse events after joint arthroplasty, and recent attention has been directed toward cancer. Very limited data have been published examining the effects of history of malignancy on outcomes after THA. With a concomitant increase in breast cancer diagnosis and treatments in recent years, it is expected that orthopedic surgeons will likely see more breast cancer survivors in clinic. The purpose of this study is to examine the effects of a personal history of breast cancer on 90-day outcomes after THA. METHODS: We conducted a retrospective case control study of the entire Medicare records. The endpoints of this study included length of stay, medical complications, surgical complications, and costs (examined here as reimbursements). Patients were matched by age and gender in order to decrease confounding. A 1:1 matching was performed. RESULTS: After age and demographics matching, our findings demonstrated that patients with a history of breast cancer have increased rates of pulmonary embolism (0.59% vs 0.45%, P = .003), increased use of chest computed tomography (1.72% vs 1.18%, P < .001), and higher mean 90-day reimbursements (mean $15,432 vs mean $14,701, P = .011) in the 90 days following surgery. Other medical and surgical complications were equally distributed in both cohorts. CONCLUSION: Surgeons should be aware of the increased rate of pulmonary embolism and have a more aggressive thromboprophylaxis protocol in these patients. PMID- 29157786 TI - The Seasonal Variability of Surgical Site Infections in Knee and Hip Arthroplasty. AB - BACKGROUND: Surgical site infections (SSIs) after total knee (TKA) and total hip (THA) arthroplasty are devastating to patients and costly to healthcare systems. The purpose of this study is to investigate the seasonality of TKA and THA SSIs at a national level. METHODS: All data were extracted from the National Readmission Database for 2013 and 2014. Patients were included if they had undergone TKA or THA. We modeled the odds of having a primary diagnosis of SSI as a function of discharge date by month, payer status, hospital size, and various patient co-morbidities. SSI status was defined as patients who were readmitted to the hospital with a primary diagnosis of SSI within 30 days of their arthroplasty procedure. RESULTS: There were 760,283 procedures (TKA 424,104, THA 336,179) in our sample. Our models indicate that SSI risk was highest for patients discharged from their surgery in June and lowest for December discharges. For TKA, the odds of a 30-day readmission for SSI were 30.5% higher at the peak compared to the nadir time (95% confidence interval [CI] 20-42). For THA, the seasonal increase in SSI was 19% (95% CI 9-30). Compared to Medicare, patients with Medicaid as the primary payer had a 49% higher odds of 30-day SSI after TKA (95% CI 32-68). CONCLUSION: SSIs following TKA and THA are seasonal peaking in summer months. Payer status was also a significant risk factor for SSIs. Future studies should investigate potential factors that could relate to the associations demonstrated in this study. PMID- 29157787 TI - A Consultation Phone Service for Patients With Total Joint Arthroplasty May Reduce Unnecessary Emergency Department Visits. AB - BACKGROUND: Different measures for reducing costs after total joint arthroplasty (TJA) have gained attention lately. At our institution, a free-of-charge consultation phone service was initiated that targeted patients with TJA. This service aimed at reducing unnecessary emergency department (ED) visits and, thus, potentially improving the cost-effectiveness of TJAs. To our knowledge, a similar consultation service had not been described previously. We aimed at examining the rates and reasons for early postdischarge phone calls and evaluating the efficacy of this consultation service. METHODS: During a 2-month period, we gathered information on every call received by the consultation phone service from patients with TJAs within 90 days of the index TJA procedure. Patients were followed for 2 weeks after making a call to detect major complications and self initiated ED visits. Data were collected from electronic medical charts regarding age, gender, type of surgery, date of discharge, and length of hospital stay. RESULTS: We analyzed 288 phone calls. Calls were mostly related to medication (41%), wound complications (17%), and mobilization issues (15%). Most calls were resolved in the phone consultation. Few patients (13%) required further evaluation in the ED. The consultation service failed to detect the need for an ED visit in 2 cases (0.7%) that required further care. CONCLUSION: The consultation phone service clearly benefitted patients with TJAs. The service reduced the number of unnecessary ED visits and functioned well in detecting patients who required further care. Most postoperative concerns were related to prescribed medications, wound complications, and mobilization issues. PMID- 29157788 TI - A local survey of gastric lavage for gastrointestinal decontamination in a new century: The future marches on. PMID- 29157789 TI - Acute effects of the electromagnetic waves emitted by mobile phones on attention in emergency physicians. AB - STUDY OBJECTIVE: The purpose of this study was to investigate the acute effects of the electromagnetic waves (EMW) emitted by mobile phones on attention in emergency physicians. METHODS: This single-center, prospective, randomized, double-blinded clinical study was performed among emergency physicians in a tertiary hospital. Thirty emergency physicians were enrolled in the study. Initial d2 test was applied in the evaluation of attention and concentration of all the physicians, who were randomly assigned into one of two groups. The control group members hold mobile phones in 'off' mode to their left ears for 15min. The members of the intervention group hold mobile phones in 'on' mode to their left ears for 15min, thus exposing them to 900-1800MHz EMW. The d2 test was re-applied to both groups after this procedure. Differences in attention and concentration levels between the groups were compared. RESULTS: Difference between initial and final d2 test in total performance (TN-E, p=0.319), in total number of figures marked (TN, p=0.177), in test performance percentile (PR, p=0.619) and in attention fluctuation (FR, p=0.083) were similar between the groups. However, difference in the number of figures missed (E1 selective attention, p=0.025), difference between numbers of incorrectly marked figures (E2, p=0,018) and difference in focus levels (E, p=0.016) were significantly in favor of the intervention group. CONCLUSION: According to our study findings, the EMW emitted by mobile phones has no deleterious effect on the attention and concentration levels of emergency physicians, and even has a positive impact on selective attention levels. PMID- 29157790 TI - Improving the neurological prognosis following OHCA using real-time evaluation of cerebral tissue oxygenation. AB - BACKGROUND: The neurological prognosis is poor for patients suffering from out-of hospital cardiac arrest (OHCA), in the absence of bystander cardio pulmonary resuscitation (CPR), and showing asystole as the initial waveform. However, such patients have the potential of resuming social activity if cerebral tissue oxygen saturation can be preserved. CASE PRESENTATION: We recently encountered a 60-year old man who had suffered an OHCA in the absence of bystander CPR, and who successfully resumed complete social activity despite initial asystole and requiring at least 75min of chest compressions before return of spontaneous circulation (ROSC). In this case, chest compression was appropriately performed concurrently with real-time evaluation of cerebral tissue oxygenation using near infrared spectroscopy (NIRS). As a result, the cerebral tissue oxygenation was well maintained, leading to resumption of social activity. CONCLUSIONS: Improved neurological prognoses can be expected if OHCA patients with the potential for social activity resumption are identified, using NIRS, and effective cardiopulmonary and cerebral resuscitation is performed while visually checking CPR quality. PMID- 29157791 TI - Experience with dalbavancin for cellulitis in the emergency department and emergency observation unit. PMID- 29157792 TI - Reply to letter, "Potential pros and cons of the Kinect-based real-time audiovisual feedback device during in-hospital CPR". PMID- 29157793 TI - Analysis of K2 products sold as incense. PMID- 29157794 TI - Analgosedative interventions after rapid sequence intubation with rocuronium in the emergency department. AB - OBJECTIVES: The use of etomidate and rocuronium for rapid sequence intubation (RSI) results in a duration of paralysis that exceeds the duration of sedation. The primary objective of this study was to compare the number of analgosedative (AGS) interventions early versus late post-RSI, with this drug combination. The secondary objective was to descriptively assess time to first AGS intervention. METHODS: This was a retrospective cohort study conducted in an academic ED in the United States between January 2015 and June 2016. The study was conducted after a pharmacy-led education program. Consecutive adult patients who received the combination of etomidate and rocuronium for RSI were included. The primary outcome measure was the number of AGS interventions post-RSI. An AGS intervention was defined as initiation of an opioid or sedative, or a dose increase of an infusion rate. Interventions were categorized as early (0-30min post-RSI) or late (60-90min post-RSI). RESULTS: The sample (n=108) had a mean age of 58+/-19years, and the majority was male (n=62, 57%). The mean rocuronium dose was 1.1+/ 0.3mg/kg. There was a median of 2 interventions (IQR 1-3) that occurred early versus 0 interventions (IQR 0 to 1) that occurred late post-RSI (p<0.001). The median time to first AGS intervention was 7min (IQR 3 to 13min). CONCLUSIONS: When rocuronium was used for RSI in the ED there was no delay in provision of post-intubation sedation or analgesia, after a pharmacy-led educational program. PMID- 29157795 TI - Poor Reproducibility of Gallbladder Ejection Fraction by Biliary Scintigraphy for Diagnosis of Biliary Dyskinesia. AB - BACKGROUND: Twenty percent of cholecystectomies in the US are performed for a diagnosis of biliary dyskinesia. Diagnosis is made by measuring gallbladder ejection fraction (GbEF) using hepatobiliary scintigraphy. Our purpose was to evaluate the reproducibility of GbEF measurements. STUDY DESIGN: This is a retrospective review of patients referred for cholecystectomy, from 2010 to 2016, with a diagnosis of biliary dyskinesia based on a GbEF test, who then underwent a repeat GbEF test. Thirty consecutive patients were identified by hospital records. Re-testing of GbEF was performed at least 6 weeks after the initial test using Tc-99m and slow injection of sincalide at 0.02 mcg/kg. RESULTS: On re testing, 16 of 30 patients (53%) patients had a normal GbEF of >35%, ie the initial test result was not reproducible in them. Age, sex, days between testing, and initial GbEF did not differ between groups. The 14 patients who re-tested positive for biliary dyskinesia with reduced GbEF were significantly more likely to have episodic pain than steady pain. Re-testing frequently resulted in change in management in that most patients who re-tested in the normal range were not offered cholecystectomy. CONCLUSIONS: Hepatobiliary scintigraphy with GbEF is a poorly reproducible test. Re-testing resulted in a change in management in many patients who then avoided cholecystectomy. Strong consideration should be given to repeating hepatobiliary scintigraphy with GbEF before cholecystectomy in patients with an initial positive test. PMID- 29157796 TI - Neuropeptide S in the basolateral amygdala mediates an adaptive behavioral stress response in a rat model of posttraumatic stress disorder by increasing the expression of BDNF and the neuropeptide YY1 receptor. AB - Neuropeptide S (NPS) is a regulatory peptide that has anxiolytic and arousal promoting effects in rodents. We used an animal model of posttraumatic stress disorder (PTSD) to assess long-term behavioral effects of a single dose of NPS, microinjected into the basolateral amygdala (BLA) 1h following exposure to predator-scent stress (PSS). To elucidate the molecular mechanism by which NPS attenuates behavioral stress responses, expression levels of neuropeptide Y (NPY), NPY-Y1 receptor (NPY-Y1R), and brain-derived neurotrophic factor (BDNF) were evaluated in the hippocampus. The behavioral and molecular effects of NPS receptor antagonist (NPS-RA), NPY-Y1R antagonist (NPY-Y1RA), or both administered centrally were evaluated in the same manner. Circulating corticosterone levels were measured at different time points following PSS-exposure. Immediate post exposure treatment with NPS had a marked protective effect; BLA microinfusion of NPS completely abolished the extreme behavioral response to PSS, restored the decreased expression of BDNF and, unexpectedly, PY-Y1R, but didn't affect the decreased expression of NPY. BLA microinfusion of both NPY-Y1RA and NPS-RA together had an additive effect, which completely prevented the anxiolytic effects of NPS in rats exposed to PSS and disrupted the expression of NPY-Y1R in the hippocampus following NPS infusion. It may therefore be hypothesized that NPS acts, directly or indirectly, on both the NPY-Y1R and NPS receptors and that the cross-talk between NPS and NPY-Y1R may be necessary for the anxiolytic effects of NPS post-exposure. The NPS system might thus contribute to a potential endogenous mechanism underlying the shift towards adaptive behavioral response and thereby might be relevant as a pharmacological target for attenuating stress-related sequelae. PMID- 29157797 TI - Toxicity Outcomes in the Elderly Prostate Cancer Patient. PMID- 29157798 TI - Euglycemic Diabetic Ketoacidosis Secondary to Dapagliflozin Use: A Case Report. AB - BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a novel class of oral antihyperglycemic agents. They are associated with rare cases of euglycemic diabetic ketoacidosis (DKA), which presents a diagnostic challenge in the emergency department (ED) and potentially severe consequences if missed. CASE REPORT: A 53-year-old man with type 2 diabetes mellitus and a recent Roux-en-Y gastric bypass surgery presented to the ED with nausea, vomiting, and generalized abdominal pain. His medications included dapagliflozin. Work-up revealed anion gap acidosis, which prompted us to send serum ketone levels despite a blood glucose level of 9.8 mmol/L (162 mg/dL). The patient was ultimately diagnosed with euglycemic DKA. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients on SGLT2 inhibitors may present in DKA despite having normal blood glucose levels. It is important for emergency physicians to be aware of this phenomenon in all SGLT2-inhibitor users, as a delay in the diagnosis of DKA can be life threatening. PMID- 29157799 TI - Efficient generation of pink-fruited tomatoes using CRISPR/Cas9 system. PMID- 29157800 TI - Duchenne muscular dystrophy with platypnea-orthodeoxia from Chilaiditi syndrome. AB - INTRODUCTION: Chilaiditi syndrome is a rare pathophysiology in which the colon or other organs are interposed between the diaphragm and liver, and respiratory or digestive symptoms sometimes manifest. Although there have been some cases of Chilaiditi syndrome complicating neuromuscular disorders, none have described resulting respiratory or digestive symptoms. CASE PRESENTATION: Our patient was a 20-year-old man with DMD who had been receiving noninvasive positive-pressure ventilation during the night. He experienced respiratory distress when changing from a supine to sitting position. Ventilator adjustment did not relieve the respiratory distress. Abdominal computed tomography revealed marked constipation and interposition of the transverse colon between the diaphragm and liver, indicating Chilaiditi syndrome. The right side of the diaphragm was elevated by the interposed transverse colon when the respiratory distress was present on chest radiograph, but not when symptoms were absent. The patient was diagnosed with platypnea-orthodeoxia attributed to Chilaiditi syndrome. The respiratory distress was improved by the relief of constipation, in addition to the usage of the ventilator throughout the day. CONCLUSION: The rare symptoms and pathophysiology of DMD complicated by Chilaiditi syndrome are reported and discussed herein. PMID- 29157801 TI - Corrigendum to "Structure and pharmaceutical formulation development of a new long-acting recombinant human insulin analog studied by NMR and MS" [J. Pharm. Biomed. Anal. 135 (2017) 126-132]. PMID- 29157802 TI - Identification and in silico characterization of a novel peptide inhibitor of angiotensin converting enzyme from pigeon pea (Cajanus cajan). AB - BACKGROUND: Plants are important sources of bioactive peptides. Among these, angiotensin converting enzyme (ACE) inhibitory peptides have a major focus on their ability to prevent hypertension. Inhibition of ACE has been established as an effective approach for the treatment of ACE associated diseases. HYPOTHESIS/PURPOSE: Some synthetic ACE inhibitory drugs cause side effects and hence there is a constant interest in natural compounds as alternatives. STUDY DESIGN: The study was designed to identify and characterize a peptide molecule from pigeon pea which has the biological property to inhibit ACE and can be developed as a therapeutic approach towards hypertension. METHODS: Seeds of pigeon pea (Cajanus cajan (L.) Millsp.) was fermented with Aspergillus niger, a proteolytic fungus isolated from spoiled milk sweet. The extract was purified by size exclusion chromatography by FPLC system. The fractions that showed ACE inhibition was subjected to LC-MS/MS for sequence identification. The stability of the peptide was analyzed by molecular dynamic simulations and the interaction sites with ACE were identified by molecular docking. RESULTS: The study report a novel ACE inhibitory octapeptide Val-Val-Ser-Leu-Ser-Ile-Pro-Arg with a molecular mass of 869.53 Da. The Lineweaver-Burk plot indicated that the inhibition of ACE by this peptide is in competitive mode. Also, molecular docking and simulation studies showed a strong and stable interaction of the peptide with ACE. CONCLUSION: The results clearly show the inhibitory property of the peptide against ACE and hence it can be explored as a therapeutic strategy towards hypertension and other ACE associated diseases. PMID- 29157803 TI - Iridoid glycosides fraction from Picrorhiza kurroa attenuates cyclophosphamide induced renal toxicity and peripheral neuropathy via PPAR-gamma mediated inhibition of inflammation and apoptosis. AB - BACKGROUND: Picrorhiza kurroa Royle (Scrophulariaceae) is an important medicinal herb being widely used in variety of ailments. PURPOSE: The present study was envisaged to evaluate the effects of iridoid glycosides enriched fraction (IGs) from Picrorhiza kurroa rhizome against cyclophosphamide (CP) -induced renal toxicity and peripheral neuropathy. METHODS: Mice in different groups were pretreated with 25, 50 and 100 mg/kg; p.o. doses of IGs for 21 days, followed by cyclophosphamide intoxication for consecutive two days. Further, to identify the putative role of PPAR-gamma receptors for the protective effect of IGs, an additional group of mice were pretreated with PPAR-gamma antagonist BADGE (5 mg/kg; i.p.) followed by IGs (100 mg/kg; p.o.) for 21 days before CP intoxication. RESULTS: IGs pretreatment decreased the hyperalgesic responses toward acetone and heat in acetone drop and tail immersion tests. The abolition of intramyelin odema, cytoplasmic vacuolization and axonal degeneration of sciatic nerve were observed in IGs pretreated mice in a dose-dependent manner. IGs treatment also attenuated the altered serum biochemical markers for renal injury. Furthermore, the treatment prevented renal tubular swelling, granular degeneration and glomerular damage. The levels of IL-1beta and TNFalpha in different group revealed the anti-inflammatory effect of IGs, which was further confirmed by improvement in altered expressions of NF-kB in kidney and sciatic serve. Bax/Bcl-2 expressions and caspase 3/9 activity in renal tissues showed the anti-apoptotic effect of IGs. IGs pretreatment also improved the PPAR-gamma expression in the kidney tissues. All the observed protective effects of IGs were suppressed after pretreatment with BADGE. CONCLUSION: Present study concludes that IGs from Picrorhiza kurroa attenuates CP-induced renal toxicity and peripheral neuropathy via PPAR-gamma -mediated pathways. PMID- 29157805 TI - Position statement evidence generation in the paediatric population Extrapolation. PMID- 29157804 TI - Anti-Parkinsonian effects of beta-amyrin are regulated via LGG-1 involved autophagy pathway in Caenorhabditis elegans. AB - BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease that is associated with aging and is characterized as a movement disorder. Currently, there is still no complete therapy for PD. In recent years, the identification and characterization of medicinal plants to cure or treat PD has gained increasing scientific interest. PURPOSE: In this study, we investigated a pentacyclic triterpenoid compound, beta-amyrin, which is found in many medicinal plants for its anti-Parkinsonian effects, using Caenorhabditis elegans (C. elegans) disease models and their underlying mechanisms. METHODS: C. elegans treated or untreated with beta-amyrin were investigated for oxidative stress resistance, neurodegeneration, and alpha-synuclein aggregation assays. The C. elegans ortholog of Atg8/LC3, LGG-1 that is involved in the autophagy pathway was also evaluated by quantitative RT-PCR and transgenic strain experiments. RESULTS: beta-Amyrin exerted excellent antioxidant activity and reduced intracellular oxygen species in C. elegans. Using the transgenic strain BZ555, beta-amyrin showed a protective effect on dopaminergic neurons reducing cell damage induced by 6-hydroxydopamine (6-OHDA). In addition, beta-amyrin significantly reduced the alpha-synuclein aggregation in the transgenic strain NL5901. Moreover, beta amyrin up-regulated LGG-1 mRNA expression and increased the number of localized LGG-1 puncta in the transgenic strain DA2123. CONCLUSION: The results from this study suggest that the anti-Parkinsonian effects of beta-amyrin might be regulated via LGG-1 involved autophagy pathway in C. elegans. Therefore, beta amyrin may be useful for therapeutic applications or supplements to treat or slow the progression of PD. PMID- 29157806 TI - Trigonelline promotes auditory function through nerve growth factor signaling on diabetic animal models. AB - BACKGROUND: Protection of cochlear function and reconstruction of neuronal networks in damaged auditory sensory structures is crucial for therapeutic treatment of diabetic hearing loss. Nerve growth factor (NGF) has been used as a novel therapeutic target to protect against the neurodegenerative effects of Diabetes Mellitus (DM). PURPOSE: We aimed to evaluate the potential effect of trigonelline (TRG) on reducing auditory damage produced by DM using NGF as a potential marker. METHOD: Docking simulations were carried out using Autodock Vina software and visualized using Discovery Studio. Morphological analysis of hair cells and neuromasts was performed on alloxan-induced diabetic zebrafish by fluorescence and scanning electron microscopy. Blockage of NGF receptor phosphorylation with K-252a was used to evaluate TRG and NGF action. Further assessment of NGF by ELISA on a primary culture of spiral ganglion cells was performed as a marker of neuronal function on the hearing system. Finally, auditory function was assessed in LepR(db/db) mice using auditory brainstem response (ABR) and transient evoked otoacoustic emission (TEOAE) during 8 weeks. RESULTS: Docking simulations showed that TRG binds to the active site of NGF through molecular interactions with Lysine88 (Lys88) and Tyrosine52 (Tyr52). TRG treatment significantly reduced hair cell loss and neuromast damage in diabetic zebrafish (P < .05). Further evaluation revealed a significant increase in the number of neuromasts after NGF administration (P < .001). TRG and NGF action was suppressed during blockage of NGF receptor phosphorylation. Moreover, spiral ganglion cells revealed significant elevation on NGF values after TRG treatment (P < .05). In vivo evaluation of LepR(db/db) mice revealed a significant reduction in the auditory damage produced under diabetic progression, characterized by reduced ABR hearing threshold shifts and increased signal-to noise ratio in TEOAE (P < .05). CONCLUSIONS: This study suggests that the enhanced hearing function produced by TRG may be mediated by NGF, providing a potential therapeutic strategy for diabetic hearing loss. PMID- 29157807 TI - A comparative proteomic study of secretomes in kaempferitrin-treated CTX TNA2 astrocytic cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Kaempferitrin is extracted in significantly high quantities from the leaves of Cinnamomum osmophloeum (C.O) and Bauhinia forficata, and are used as an antidiabetic herbal remedy in China and Brazil. Commercial product using dry Cinnamomum osmophloeum leaves has been sold locally in Taiwan. Oral administration of kaempferitrin reduced blood sugar in diabetic rats. AIM OF THE STUDY: Though previously demonstrated to activate the classical insulin signaling pathways, a mechanism for kaempferitrin is still not fully understood. Also, studies on kaempferitrin on immune related cells have been inconclusive, and people consuming extract containing kaempferitrin often happen to be at high risk of diabetes and neurodegenerative diseases. Therefore, for kaempferitrin to be used every day, a comprehensive study is needed. MATERIALS AND METHODS: Astrocytic cell line was used as a model to test the differentially regulated secretomes, to test kaempferitrin effect on CNS glia, on pro inflammatory cytokines, and to test how different the mechanism of kaempferitrin is from that of insulin. CTX TNA2 astrocytic cells were differentially treated with and without 10 uM kaempferitrin for 24 h, and the conditioned medium was collected. For the proteomic study, protein in conditioned medium was trypsin digested, and resulting peptides in kaempferitrin/non-treated sample pair were differentially dimethyl labeled. The labeled peptides were further fractionated by StageTip-based strong-exchange method before LC-MS/MS analyses. Levels of interesting proteins were verified using Western or Eliza. C.O. leaf crude extract treated samples were included for a comparison of effects of purified kaempferitrin vs. kaempferitrin containing crude extract. RESULTS AND CONCLUSIONS: Data were obtained via ProteomeXchange with identifier PXD002814. It was found that no pro-inflammatory cytokines or inhibitory ECM were elevated upon treatment of kaempferitrin or a crude extract of C.O. leaves. This suggests that prolonged use of kaempferitrin containing herbs may not increase pro-inflammatory reaction. LDL-R trafficking between the cell membrane and the extracellular niche was regulated by kaempferitrin toward reduced secretion. Our proteomic study also demonstrated that molecules related to plasma membrane recycling were regulated by kaempferitrin. Our discoveries provide evidence that link kaempferitrin regulation for LDL-R and membrane recycling to the blood lipid regulation by the C.O. leaves extract. However, these proteins were differently regulated when cells were treated with crude extract. This demonstrates that the molecular interactions within crude extract of herbs are complex and may not act similar to the compound purified from the crude extract. PMID- 29157808 TI - A double-blind, randomized, placebo-controlled trial of saffron stigma (Crocus sativus L.) in mothers suffering from mild-to-moderate postpartum depression. AB - INTRODUCTION: Numerous adverse effects of antidepressants as well as the attitudes of breastfeeding mothers, who prefer to consume herbal medicine rather than chemical drugs, encouraged us to assess the effects of saffron (Crocus sativus L.) on mothers suffering from mild-to-moderate postpartum depressive disorder. METHODS: A double-blind, randomized, and placebo-controlled trial was conducted on 60 new mothers who had a maximum score of 29 on the Beck Depression Inventory-Second Edition (BDI-II). They were randomly assigned to the saffron (15 mg/Bid) or placebo group. The primary outcome was a change in the BDI-II scores 8 weeks after treatment compared to the baseline. The response and remission rates were considered to be secondary outcome measures. RESULTS: Saffron had a more significant impact on the BDI-II scores than the placebo. The mean BDI-II scores decreased from 20.3 +/- 5.7 to 8.4 +/- 3.7 for the saffron group (p < .0001) and from 19.8 +/- 3.2 to 15.1 +/- 5.4 for the placebo group (p < .01). In the final assessment, 96% of the saffron group were in remission compared to 43% of the placebo group (p < .01). The complete response rates were 6% for the placebo group and 66% for the saffron group. CONCLUSION: When administered to treat minor PPD in breastfeeding mothers, saffron had a more significant impact on the BDI-II than the placebo. PMID- 29157809 TI - The regulatory effect of oxymatrine on the TLR4/MyD88/NF-kappaB signaling pathway in lipopolysaccharide-induced MS1 cells. AB - BACKGROUND: Oxymatrine (OM), a major quinolizidine alkaloid extracted from the roots of Sophora flavescens, has been proved to regulate a variety of signaling pathways to produce a wide range of pharmacological effects. OBJECTIVES: The regulatory effects of OM on the TLR4/MyD88/NF-kappaB signaling pathway under the stimulation of lipopolysaccharide (LPS) in MS1 cells were explored to illuminate the potential anti-inflammatory mechanism of OM for pancreatitis treatment. METHODS: The signaling molecules related to the TLR4/MyD88/NF-kappaB pathway in MS1 cells were detected by Western blotting under different conditions, including OM pretreatment and LPS stimulation. The mRNA expression levels of TLR4, MyD88, NF-kappaB p65 and IkappaBalpha were detected by real-time PCR. The NF-kappaB p65 nuclear translocation in MS1 cells was measured by immunofluorescence, and the pro-inflammatory cytokine of IL-1beta was detected by ELISA. RESULTS: Increased levels of TLR4, MyD88 and NF-kappaB p65, induced by LPS stimulation, were significantly inhibited by OM pretreatment in MS1 cells. The decreased protein, but not mRNA, level of IkappaBalpha induced by LPS stimulation was increased by OM pretreatment. Meanwhile, LPS induced NF-kappaB p65 protein translocation to the nucleus as well as LPS increased expression of IL-1beta were also inhibited by OM pretreatment. CONCLUSION: Inhibitory effects of OM on molecules related to the TLR4/MyD88/NF-kappaB signaling pathway in pancreatic microvascular endothelial cells can alleviate inflammatory responses. PMID- 29157810 TI - Camptothecin-producing endophytic bacteria from Pyrenacantha volubilis Hook. (Icacinaceae): A possible role of a plasmid in the production of camptothecin. AB - BACKGROUND: Camptothecin (CPT), a quinoline alkaloid, is a potent inhibitor of eukaryotic topoisomerase I. Because of this property, several derivatives of CPT are used as chemotherapeutic agents. CPT is produced by several plant species belonging to the Asterid clade as well as by a number of endophytic fungal associates of these plants. In this study, we report the production of CPT by four bacterial endophytes and show the possible role of a plasmid in the biosynthesis of CPT. METHODS: Endophytic bacteria were isolated from leaves, stems and fruits of Pyrenacantha volubilis Hook. (Icacinanceae). The bacterial isolates were purified and analyzed for production of CPT by ESI-MS/MS and NMR analysis. Bacterial identity was established based on the morphology and 16s rRNA sequence analysis. Crude extracts of the bacterial endophytes were evaluated for their cytotoxicity using colon cancer cell lines. The role of plasmid in the production of CPT was studied by purging the plasmid, using acriflavine, as well as reconstituting the bacteria with the plasmid. RESULTS: Four bacterial isolates, Bacillus sp. (KP125955 and KP125956), Bacillus subtilis (KY741853) and Bacillus amyloliquefaciens (KY741854) were found to produce CPT in culture. Both based on ESI-MS/MS and NMR analysis, the identity of CPT was found to be similar to that produced by the host plant. The CPT was biologically active as evident by its cytotoxicity against colon cancer cell line. The production of CPT by the endophyte (Bacillus subtilis, KY741853) attenuated with sub-culture. A likely role of a plasmid in the production of CPT was established. A 5 kbp plasmid was recovered from the bacteria. Bacterial isolate cured of plasmid failed to produce CPT. CONCLUSION: Our study implies a possible role of a plasmid in the production of CPT by the endophytic bacteria and opens up further work to unravel the exact mechanisms that might be involved. PMID- 29157811 TI - Bud extracts from Salix caprea L. inhibit voltage gated calcium channels and catecholamines secretion in mouse chromaffin cells. AB - BACKGROUND: Salix caprea L. is an ornamental plant with prominent antioxidant activity. In the last decades Salix caprea bud extracts (SCBEs) have been used for the treatment of oxidative stress related disorders. PURPOSE: A large part of cellular functions depends on the amount of intracellular Ca2+ concentration which in turn is mainly determined by Ca2+ ions movements across plasma membrane as well as by Ca2+ released from the stores. For better evaluating the mechanism of action of SCBEs, we focused on the effect of SCBEs on voltage gated Ca2+ channels (VGCCs) functioning and related catecholamines secretion in mouse chromaffin cells (MCCs). These latter are neuroendocrine cells that share a wide variety of functions with neurons. They are particularly interesting for studying the relationship between VGCCs activation and catecholamines secretion both in control and under stressful conditions. STUDY DESIGN AND METHODS: We focused on the effect of SCBEs on VGCCs being these latter considered one of the main pathway of Ca2+ influx across plasma membrane. Ca2+ currents and capacitance changes were measured in patch clamp experiments performed in voltage clamp configuration. RESULTS: We show that SCBEs inhibited VGCCs in a dose dependent manner. On average, the saturating concentration of SCBEs (SCBEsmax) is able to block 36% of the maximum Ca2+ current amplitude (ICa) without selectivity for L (ICa, L) or non-L type (ICa, non-L) Ca2+ channels. Furthermore, ICa inhibition is not followed by alteration of VGCCs gating kinetics, but is responsible for a marked decrease of Ca2+ dependent catecholamines secretion. CONCLUSION: We conclude that the ability of SCBEs to inhibit VGCCs function, known to be potentiated during oxidative stress, could contribute to the already known antioxidant properties of Salix caprea L. We finally suggest that the inhibitory effect of SCBEs on catecholamines secretion may contribute to treat stress dependent cellular dysfunctions. PMID- 29157812 TI - The major Boswellia serrata active 3-acetyl-11-keto-beta-boswellic acid strengthens interleukin-1alpha upregulation of matrix metalloproteinase-9 via JNK MAP kinase activation. AB - BACKGROUND: Boswellia serrata gum resin has attracted pharmacological interest as an alternative antinflammatory. PURPOSE: We studied the application of an ethanolic extract of the resin and its main active 3-O-acetyl-11-keto-beta boswellic acid (AKBA) against inflammatory degeneration of skin extracellular matrix. STUDY DESIGN: We compared the effects of the extract and AKBA on the activity of MMP-2 and MMP-9 (72-kDa and 92-kDa type IV collagenases) in HaCaT keratinocytes exposed to interleukin-1alpha (IL-1alpha) as a skin inflammation model. METHODS: MMP activity in cell conditioned medium was assayed by gelatin zymography, while NF-kB and MAP kinase activations were evaluated by Western blotting. RESULTS: IL-1alpha (10 ng/ml) upregulated MMP-9 but not MMP-2 in HaCaT cells. The extract, used at 2.3, 4.6 and 9.3 ug/ml, had no effect, but in combination with IL-1alpha showed MMP-9 inhibition at the lowest dose and increased upregulation at the highest one. AKBA alone, at the same concentrations (corresponding to 5, 10, and 20 uM), did not stimulate MMP-9, but together with IL-1alpha induced an increased upregulation at the lowest dose that progressively disappeared at higher doses. WB analysis showed that IL-1alpha induced phosphorylation of NF-kappaB p65, while AKBA abolished this effect at 20 uM, but conversely increased it at 5 uM. Screening of MAP kinase phosphorylation showed a combined activation of IL-1alpha/AKBA on JNK, while the JNK inhibitor SP600125 abolished MMP-9 upregulation induced by IL-1alpha/AKBA. CONCLUSION: The enhancing effect of IL-1alpha/AKBA on MMP-9 at low AKBA concentration seems to involve the activation of JNK-mediated NF-kappaB pathway. Conversely, the extract inhibits the IL-1alpha effect at low doses, but not at higher ones, where AKBA and possibly other beta-boswellic acids reach concentrations that potentiate the effect of IL-1alpha. The extract at low doses could protect the skin against degenerative processes of extracellular matrix, while keto-beta-boswellic acids seem unsuitable for this purpose. PMID- 29157813 TI - Anti-inflammatory and antiviral activities of cynanversicoside A and cynanversicoside C isolated from Cynanchun paniculatum in influenza A virus infected mice pulmonary microvascular endothelial cells. AB - BACKGROUND: Outbreaks of the influenza A virus (IAV) often occur in various avian and mammalian species, including humans, causing serious respiratory injury worldwide. Therapeutic actions are limited to vaccines and a few antiviral drugs. Combination antiviral compounds and anti-inflammatory modulators to control the propagation of viruses would be more efficient therapeutic strategies for infectious diseases. PURPOSE: This study was designed to isolate anti inflammatory and antiviral compounds from Cynanchun paniculatum and elucidate their potential molecular mechanisms. METHODS/STUDY DESIGNS: Bioactivity-guided isolation (via in vitro anti-inflammatory assay) was performed on the ethanolic extract of C. paniculatum, the structures of active compounds were elucidated by comparing spectral data (ESI-MS, 1H NMR and 13C NMR) with literature values. The antiviral activity of active compounds against Influenza A virus (IAV) was determined using the cytopathic effect (CPE) inhibition assay. Inhibitory effects of active compounds on influenza A/FM1/1/47 (H1N1) virus infection were also determined by RT-PCR. Effect of active compounds on NF-kB and MAPK signaling pathways after virus infection was determined by ELISA. RESULTS: Two compounds that showed great anti-inflammatory activity were isolated from C. paniculatum and elucidated as cynanversicoside A and cynanversicoside C. Cytokine assay demonstrated that cynanversicoside A and cynanversicoside C can suppress the production of TNF-alpha, IL-6 and IL-1beta in Mice Pulmonary Microvascular Endothelial Cells (MPMEC) after Influenza virus A/FM/1/47 infection (p < .05) and also decreased the expressions of p-p65 and p-IkappaBalpha in infected cells. Furthermore, the phosphorylation of p38, ERK and JNK was also significantly attenuated. Subsequently, cynanversicoside A and cynanversicoside C treatment resulted in decreased viral replication and viral mRNA synthesis. CONCLUSIONS: These results indicate that cynanversicoside A isolated from C. paniculatum has potent anti-inflammatory and antiviral effects on IAV-infected MPMEC by the regulation of NF-kappaB and MAPK signaling pathways. PMID- 29157814 TI - Mistletoe (Viscum album) extract targets Axl to suppress cell proliferation and overcome cisplatin- and erlotinib-resistance in non-small cell lung cancer cells. AB - BACKGROUND: Mistletoe extract of Visucm album extract (VAE) contains many biologically active components and has been reported to be not only a complementary and alternative medicine, but also a potent therapeutic agent for many types of cancer. PURPOSE: In this study, we examined the effect of VAE on expression and activation of Axl and scrutinized the involvement of Axl in the anti-cancer activity of VAE in parental and chemo-resistant non-small cell lung cancer (NSCLC) cells. METHODS: The levels of Axl protein and mRNA were determined by Western blot analysis and RT-PCR, respectively. Phosphorylation of Axl upon Gas6 stimulation was observed by Western blot analysis. For ectopic expression or gene silencing of Axl, the recombinant plasmid, pcDNA3-Axl, or specific siRNA targeting Axl were transfected into A549 and H460 cells using Lipofectamine 2000, respectively. The anti-cancer activity of mistletoe extract was examined against the parental cells and each of their cisplatin- or erlotinib-resistant cells using trypan blue exclusion assays and colony formation assay. RESULTS: The levels of Axl mRNA were also reduced by VAE treatment, implying the transcriptional downregulation of Axl expression by VAE. In addition, the phosphorylation of Axl protein upon its ligand, Gas6, stimulation was found to be abrogated by VAE. We next found cytotoxic effect of VAE on both the parental NSCLC cells and their variants which are resistant to cisplatin (A549/CisR and H460/CisR) or erlotinib (H460/ER and H1975/ER). Treatment of these cells with VAE caused a dose-dependent decrease of cell viability and clonogenicity. This anti proliferative effect of VAE was attenuated in Axl-overexpressing cells, while it was augmented in cells transfected Axl specific siRNA. Next, we also found that in cisplatin-resistant cells and erlotinib-resistant cells, VAE treatment decreased Axl protein level, colonogenicity. The levels of several cell cycle regulator, p21 and apoptosis related protein, X-linked inhibitor of apoptosis, was found to be induced and reduced by VAE treatment, respectively. CONCLUSION: Taken together, our data provide that VAE targets Axl to suppress cell proliferation and to circumvent cisplatin- and erlotinib-resistance in NSCLC cells. PMID- 29157815 TI - An efflux pump (MexAB-OprM) of Pseudomonas aeruginosa is associated with antibacterial activity of Epigallocatechin-3-gallate (EGCG). AB - BACKGROUND: Pseudomonas aeruginosa is a notorious multidrug resistant nosocomial pathogen. An efflux pump (MexAB-OprM) is the main contributor to the multidrug resistance in clinical isolates of P. aeruginosa. Epigallocatechin-3-gallate (EGCG), a polyphenolic compound extracted from green tea, exhibits antibacterial activity. It is unclear that molecular details of the antibacterial activity of EGCG, EGCG-effect on antibiotic susceptibility, and clinical relevance of EGCG in bacteria. PURPOSE: This study aimed to determine the roles of the efflux pump and an efflux pump inhibitor (phenylalanine-arginine beta-naphthylamide; PAbetaN) in the antibacterial activity of EGCG and the EGCG-effect on antibiotic susceptibility. METHODS: Twenty-two multidrug resistant clinical isolates of P. aeruginosa and a wild type P. aeruginosa PAO1 were used to determine antibacterial activity of EGCG and EGCG-effect on antibiotic susceptibility. An efflux pump (MexAB-OPrM) mutant strain, its complemented strain carrying an intact mexAB-oprM, and their parental strain were used to determine roles of MexAB-OprM in the antibacterial activity of EGCG and EGCG-mediated antibiotic susceptibility. PAbetaN was also used to evaluate EGCG as a possible efflux pump inhibitor. RESULTS: EGCG inhibited cellular growth and killed 100% of cells at 64 512 ug/ml and at 256-1024 ug/ml, respectively, in all tested 22 clinical isolates including the wild type strain. A subinhibitory concentration of EGCG significantly enhanced susceptibility to antibiotics, unexceptionally to chloramphenicol and tetracyclines (>=4-fold) of the clinical isolates. Both the antibacterial activity of EGCG and the EGCG-mediated antibiotic susceptibility were enhanced more in the efflux pump mutant strain (mexB::Gm) than the parental strain, suggesting additionally accumulated-EGCG produced the more antibacterial activity in the mutant strain. EGCG was synergistically interacted with PAbetaN with enhancing susceptibility to all tested antibiotics (up to >500-fold) at higher levels than either EGCG alone or PAbetaN alone, suggesting EGCG may also inhibit the efflux pump with additional accumulation of the antibiotics. CONCLUSION: The results demonstrate that EGCG exhibits antibacterial activity and enhances antibiotic effects against clinical isolates of P. aeruginosa. EGCG may inhibit the efflux pump (MexAB-OprM) through which are associated with the antibacterial activity of EGCG and the EGCG-mediated antibiotic susceptibility in P. aeruginosa. PMID- 29157816 TI - Effect of Ipomoea aquatica ethanolic extract in streptozotocin (STZ) induced diabetic rats via1H NMR-based metabolomics approach. AB - BACKGROUND: Ipomoea aquatica (locally known as "kangkung") has previously been reported to have hypoglycemic activities on glucose level in diabetes patients. However, the effect of I. aquatica ethanolic extract on the metabolites in the body has remained unknown. PURPOSE: This study provides new insights on the changes of endogenous metabolites caused by I. aquatica ethanolic extract and improves the understanding on the therapeutic efficacy and mechanism of I. aquatica ethanolic extract. METHODS: By using a combination of 1H nuclear magnetic resonance (NMR) with multivariate analysis (MVDA), the changes of metabolites due to I. aquatica ethanolic extract administration in obese diabetic induced Sprague Dawley rats (OB+STZ+IA) were identified. RESULTS: The results suggested 19 potential biomarkers with variable importance projections (VIP) above 0.5, which include creatine/creatinine, glucose, creatinine, citrate, carnitine, 2-oxoglutarate, succinate, hippurate, leucine, 1-methylnicotinamice (MNA), taurine, 3-hydroxybutyrate (3-HB), tryptophan, lysine, trigonelline, allantoin, formiate, acetoacetate (AcAc) and dimethylamine. From the changes in the metabolites, the affected pathways and aspects of metabolism were identified. CONCLUSION: I. aquatica ethanolic extract increases metabolite levels such as creatinine/creatine, carnitine, MNA, trigonelline, leucine, lysine, 3-HB and decreases metabolite levels, including glucose and tricarboxylic acid (TCA) intermediates. This implies capabilities of I. aquatica ethanolic extract promoting glycolysis, gut microbiota and nicotinate/nicotinamide metabolism, improving the glomerular filtration rate (GFR) and reducing the beta-oxidation rate. However, the administration of I. aquatica ethanolic extract has several drawbacks, such as unimproved changes in amino acid metabolism, especially in reducing branched chain amino acid (BCAA) synthesis pathways and lipid metabolism. PMID- 29157817 TI - Cardioprotective action of the aqueous extract of Terminalia arjuna bark against toxicity induced by doxorubicin. AB - BACKGROUND: The aqueous extract of Terminalia arjuna (TA) bark (TAAqE) has been shown to have a direct inotropic effect on ventricular myocytes. Active constituents of TAAqE contain various flavonoids and proanthocyanidins, some of which are known to have antioxidant activities. Whether TAAqE affords a cardioprotective action against oxidative stress (OS) remains unclear. PURPOSE: Increased OS is one of the major mechanisms underlying cardiotoxicity induced by doxorubicin (DOX), a commonly-used anticancer agent. The aim of the present study was to investigate potential cardioprotective effect of TAAqE against DOX-induced OS and cardiac dysfunction. METHODS: OS and cytotoxicity were induced by 1 uM DOX for 24 h in H9c2 cells, a cardiac tissue-derived cell line, and left ventricular (LV) dysfunction was induced by intrapleural injection of DOX (accumulative 20 mg/kg body weight) to mice. Cellular oxidative levels and morphology were assessed using microscopy and oxidative-sensitive fluorescent dyes with and without co-treatment with TAAqE. LV function was monitored weekly with echocardiography. RESULTS: TAAqE reduced OS and preserved mitochondria and cell growth of H9c2 cells against DOX treatment. TAAqE (in drinking water) attenuated the decreased LV function and altered myocardial structure caused by DOX treatment. CONCLUSION: TAAqE exerts a protective action against cardiotoxicity caused by DOX in part via suppression of OS. Thus, TAAqE is a promising cardiotonic in adjuvant cancer chemotherapy. PMID- 29157818 TI - Biological characteristics, bioactive components and antineoplastic properties of sporoderm-broken spores from wild Cordyceps cicadae. AB - BACKGROUND: Cordyceps cicadae, an entomogenous fungus has been used as a dietary therapeutic in traditional Chinese medicine for several millennia, in the form of powders and decoction. However, wild C. cicadae is notably scarce. To date, there is still a lack of comprehensive and deep studies on the biological characteristics, chemical profiles and antineoplastic mechanisms of C. cicadae, especially its spores. AIM OF THE STUDY: This study aimed to identify wild C. cicadae using rDNA-ITS sequences. Active constituents and volatile ingredients of C. cicadae sporoderm-broken spore powders (CCBSP) were elucidated using UPLC-ESI Q-TOF-MS and GC-MS, respectively. The underlying anti-neoplastic mechanisms of CCBSP were further investigated in A549 lung carcinoma cells. RESULTS: Molecular phylogenetic analysis of nuclear rDNA sequences indicated that wild C. cicadae belonged to Paecilomyces cicadae. Eight primary compounds from CCBSP were identified by MS fragmentation ions including nucleosides, cordycepic acid, cordycepin, beauvericin and myriocin. In total, forty-nine volatile components representing 99.56% of CCBSP were clearly identified. CCBSP exhibited antiproliferative effects on A549 cells with IC50 value of 125.54 +/- 2.71 ug/ml, blocking the cell cycle in the G2/M phase. The nuclear morphology exhibited typical characteristics of apoptosis by Hoechst fluorescent stain. AnnexinV FITC/PI staining revealed that the number of apoptotic cells increased after CCBSP treatment. Furthermore, immunofluorescence experiments indicated that CCBSP lowered the expressions of beta-catenin and N-cadherin, which was accompanied by repressed Wnt/beta-catenin signalling and activation of caspase-mediated apoptosis pathways. CONCLUSIONS: rDNA-ITS sequencing enabled molecular identification of wild C. cicadae. Importantly, these findings provide the first evidence regarding the full-scale bioactive components and antineoplastic properties of CCBSP. These data highlight the significance of C. cicadae as a potential antineoplastic agent. PMID- 29157819 TI - Pro-angiogenic effects of Ilexsaponin A1 on human umbilical vein endothelial cells in vitro and zebrafish in vivo. AB - BACKGROUND: Ilexsaponin A1 is the major bioactive ingredient of Ilex pubescens Hook. et Arn. This plant has been conventionally used in Traditional Chinese Medicine for the treatment of cardiovascular diseases including stroke, coronary arterial disease, and peripheral vascular diseases. PURPOSE: To investigate the pro-angiogenic effect of Ilexsaponin A1 and its mechanism of action. STUDY DESIGN: Human umbilical vein endothelial cells (HUVECs) and transgenic zebrafish Tg(fli1:EGFP) were employed as an in vitro and in vivo model respectively. METHODS: Pro-angiogenic effects of Ilexsaponin A1 were examined by assessing endothelial cell proliferation, migration, invasion and tube formation. The mechanism of pro-angiogenic effects was investigated by measuring the expression level of various signalling proteins. Furthermore, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor II (VRI)-induced vascular insufficient transgenic zebrafish model was used to confirm the results of the HUVECs results in vivo. RESULTS: Ilexsaponin A1 significantly promoted cell proliferation, migration, invasion and tube formation in HUVECs, and rescued blood vessel loss in VRI-induced vascular insufficient zebrafish. Ilexsaponin A1 upregulated p-Akt, p-mTOR, p-Src, p-FAK, p-MEK, and p-Erk1/2 in HUVECs. CONCLUSION: This study showed that Ilexsaponin A1 exhibits pro-angiogenic activity in HUVECs and VRI induced vascular insufficient zebrafish, probably by activating Akt/mTOR, MAPK/ERK and Src- and FAK-dependent signalling pathways. The findings suggest that Ilexsaponin A1 and probably I. pubescens, a major source of Ilexsaponin A1, could be developed as a potential therapeutic agent for preventing or treating cardiovascular diseases and/or other diseases related to vascular insufficiency. PMID- 29157820 TI - Nymphaeol-C, a prenylflavonoid from Macaranga tanarius, suppresses the expression of fibroblast growth factor 18. AB - BACKGROUND: Fibroblast growth factor 18 (FGF18) is one of the key factors in human signaling pathways and has been reported to be associated with the formation of various tissues. Additionally, FGF18 has been reported to maintain the telogen stage of the hair cycle, and its over-expression has also been observed in cancer cells. HYPOTHESIS/PURPOSE: We searched for natural compounds that inhibit the expression of FGF18 expression in vitro and evaluated their inhibitory mechanisms. STUDY DESIGN: Various plant samples were screened using a luciferase assay targeting FGF18. One active compound was selected by the screening, isolated and identified. METHODS: The active compound was isolated using chromatographic techniques and identified by specific rotation measurements, LC-MS and NMR. Additionally, its inhibitory mechanism was evaluated using real-time RT-PCR and Western blotting. RESULTS: As a result of screening various plant leaf samples, Macaranga tanarius was identified as the most active plant and a prenylflavonoid nymphaeol-C was isolated as the active compound. Using real-time RT-PCR and Western blotting analysis, this compound was confirmed to strongly suppress the expression of FGF18. The compound lowered the beta catenin level in the Wnt/beta-catenin pathway. Thus, it was suggested that nymphaeol-C suppresses the expression of FGF18 by suppressing beta-catenin expression. Additionally, the compound lowered the extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation level in the mitogen-activated protein kinase cascade (MAPK cascade). Therefore, nymphaeol-C suppressed downstream signals of FGF18 by suppressing the expression of FGF18. CONCLUSION: We isolated and identified prenylflavonoid nymphaeol-C from M. tanarius. The compound suppresses the expression of FGF18 and affects FGF18 related signals. PMID- 29157821 TI - Poricoic acid ZA, a novel RAS inhibitor, attenuates tubulo-interstitial fibrosis and podocyte injury by inhibiting TGF-beta/Smad signaling pathway. AB - BACKGROUND: The pathogenesis of tubulo-interstitial fibrosis and glomerulosclerosisis was characterized by cellular hypertrophy, extracellular matrix accumulation and podocyte detachment. Poricoic acid ZA (PZA) is a tetracyclic triterpenoid compound extracted from the surface layer of Poria cocos (LPC), which have been used extensively for diuretic and renoprotective effects. METHODS: The anti-fibrotic effect of PZA is investigated in HK-2 cells and podocytes induced by TGF-beta1 and angiotensin II (ANGII). qRT-PCR, siRNA, immunofluorescence staining, co-immunoprecipitation and Western blot analyses are used to evaluate the expression of RAS signaling, TGF-beta/Smad pathway, epithelial-to-mesenchymal transition (EMT) and podocyte markers. RESULTS: PZA restores the mRNA and protein expression of EMT in HK-2 cells. Specific TGF-beta1 siRNA efficiently blocks ANGII-induced protein expression of TGF-beta1 and further inhibits activated Smad signaling. PZA significantly attenuates up regulation of angiotensinogen, renin, ACE and AT1. Further, PZA reverses up regulation of TGFbetaRII and suppresses Smad proteins. Simultaneously, PZA inhibits the protein interaction of TGF-beta receptor and Smads and PZA also inhibits activated RAS and TGF-beta/Smad signaling cascade and up-regulates protein expression of podocyte markers and mitigates podocyte injury. CONCLUSIONS: This study demonstrated the beneficial role of PZA in renal fibrosis and podocyte injury. Our study highlighted that PZA inhibits RAS and further suppresses TGF-beta/Smad pathway through inhibiting Smad2/3 phosphorylation via blocking Smad2/3-TGFbetaRI protein interaction. PZA is implicated in activation of RAS/TGF-beta/Smad axis in HK-2 cells and podocytes. PZA could be considered as a novel RAS inhibitor for treating CKD. PMID- 29157822 TI - Antibiofilm activities of norharmane and its derivatives against Escherichia coli O157:H7 and other bacteria. AB - BACKGROUND: Bacterial biofilms exhibit reduced sensitivity to conventional antibiotics and host defence systems and contribute to the persistence of chronic bacterial infections. HYPOTHESIS: The antibiofilm approach using plant alkaloids provides an alternative to antibiotic strategies. STUDY DESIGN: In this study, the antibiofilm activities of various plant alkaloids were investigated against enterohemorrhagic Escherichia coli O157:H7 and Pseudomonas aeruginosa. In the subsequent investigation, the effects of five norharmane derivatives were investigated. RESULT: Harmaline significantly inhibited biofilm formation by E. coli O157:H7, P. aeruginosa PAO1, P. aeruginosa PA14, and Klebsiella oxytoca, and norharmane (beta-carboline) was found to have antibiofilm activity. It was also found that functional groups at the C-1 and C-7 positions of norharmane could play important roles in its antibiofilm activity. Confocal and electron microscopic observations confirmed biofilm inhibition by harmaline and norharmane, and both reduced fimbriae production and swarming and swimming motilities. Furthermore, harmaline and norharmane attenuated the virulence of E. coli O157:H7 in a Caenorhabditis elegans nematode model. CONCLUSION: These findings strongly suggest that harmaline and norharmane could have potential use in antibiofilm strategy against persistent bacterial infections. PMID- 29157823 TI - Lespedeza bicolor ameliorates endothelial dysfunction induced by methylglyoxal glucotoxicity. AB - BACKGROUND: Lespedeza species have been used as a traditional medicine to treat nephritis, azotemia, inflammation, energy depletion, diabetes, and diuresis. PURPOSE: The purpose of this study is to screen the most potent Lespedeza species against methylglyoxal (MGO)-induced glucotoxicity, and to elucidate the mechanisms of action. Also, we will attempt to identify small chemical metabolites that might be responsible for such anti-glucotoxicity effects. METHODS: Firstly, the protective effect of 26 different Lespedeza species against MGO-induced toxicity in human umbilical vein endothelial cells was investigated. The chemical metabolites of the most potent species (Lespedeza bicolor 1 (LB1) were identified by high pressure liquid chromatography quadrupole time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS/MS), then quantified by HPLC. The effects of LB1 on MGO-induced apoptosis were measured by annexin V-FITC staining and western blot. Inhibitory effects of LB1 on MGO-induced ROS generation, and effect of LB1 on advanced glycation end products (AGEs) inhibitor or a glycated cross link breaker are also measured. RESULTS: Among different Lespedeza species, LB1 extract was shown to reduce intracellular reactive oxidative species, exhibit anti-apoptotic effects, strongly inhibit all the mitogen-activated protein kinase signals, inhibit MGO-induced AGEs formation, and break down preformed AGEs. We tentatively identified 17 chemical constituents of LB1 by HPLC-Q-TOF-MS/MS. Among those, some components, such as genistein and quercetin, significantly reduced the AGEs formation and increased the AGEs-breaking activity, resulting in the reduction of glucotoxicity. CONCLUSION: LB1 extract has shown to be effective in preventing or treating MGO-induced endothelial dysfunction. PMID- 29157824 TI - Fraxetin and ethyl acetate extract from Lawsonia inermis L. ameliorate oxidative stress in P. berghei infected mice by augmenting antioxidant defence system. AB - BACKGROUND: Lawsonia inermis L. is a well-documented plant for cosmetic as well as medicinal properties. It is used by local communities in India and Nigeria for the treatment of many parasitic diseases, including malaria. HYPOTHESIS/PURPOSE: Earlier studies on the plant's antiplasmodial activity were not assigned to any phytochemical with no quality assurance data. In this report, a recent chemically characterized extract and it's major constituent were investigated for in vitro antiplasmodial activity on chloroquine sensitive NF-54 strain. Furtherly, the potent extract and this constituent were assessed in vivo in Plasmodium berghei infected mice. The bioactive phytochemical and enriched extract were also monitored against various oxidative stress parameters. STUDY DESIGN/METHOD: The extract characterization was done by the quantitative analysis of eight phytochemicals using gradient reverse phase HPLC method. In vitro antiplasmodial activity was evaluated on chloroquine sensitive NF-54 strain by the determination of pfLDH activity. In vivo activity of the most potent extract and constituent were evaluated in P. berghei infected mice upon oral administration. The estimation of oxidative stress was done by monitoring various enzymatic and non enzymatic parameters. RESULTS: The ethyl acetate extract of leaves (IC50 9.00 +/- 0.68 ug/ml) and fraxetin (IC50 19.21 +/- 1.04 uM) were the most effective in in vitro assays therefore selected for in vivo tests. The administration of the ethyl acetate extract of leaves and fraxetin to the infected mice resulted in significant (p < .05) suppression of parasitaemia as evidenced by a 70.44 +/- 2.58% to 78.77 +/- 3.43% reduction compared to non-infected group. In addition, a two-fold increase in mean survival time, a significant (p < .05) reduction in lipid peroxidation and an elevation in glutathione, catalase and superoxide dismutase were also observed in treated mice. The post-infection treatment also led to an augmentation of endogenous antioxidant enzymes (GST, GR, GPx) with respect to the infected control. A significant (p < .05) elevation in serum Nrf2 antioxidant response element level responsible for the activation of endogenous enzymes was also observed. CONCLUSION: It was evident from the experiments that ethyl acetate extract of L. inermis and fraxetin were able to suppress the oxidative damage by augmenting endogenous antioxidant system and thus ameliorated the plasmodium infection in mice. PMID- 29157825 TI - 1, 6-di-O-caffeoyl-beta-D-glucopyranoside, a natural compound from Callicarpa nudiflora Hook impairs P2Y12 and thromboxane A2 receptor-mediated amplification of platelet activation and aggregation. AB - BACKGROUND: Platelet activation and subsequent accumulation at sites of vascular injury perform a central role in thrombus formation, which is believed to be the trigger of several cardiovascular diseases, such as atherosclerosis, myocardial infarction and strokes. In this sense, the search for agents that are capable of blocking platelets aggregation has important implications for these diseases. Callicarpa nudiflora (C. nudiflora) Hook is a traditional Chinese medicine herb for eliminating stasis to subdue swelling and hemostasis. Our previous study found several compounds extracted from this herb, including 1, 6-di-O-caffeoyl beta-D-glucopyranoside (CGP), showed inhibitory effects on adenosine diphosphate (ADP) induced platelet aggregation. PURPOSE: The aim of current study is confirmation of the anti-platelet effects and elucidation of the probable mechanisms. METHODS: The experiments were performed on platelet rich plasma freshly isolated from SD rat. ADP, U46619 or arachidonic acid (AA) induced platelet aggregation assay were performed to evaluate the anti-platelet properties of CGP. Activated alphaIIbbeta3 integrin abundance, serotonin (5-HT) secretion, thromboxane A2 (TXA2) synthesis was determined to assess the effects of CGP on platelet activation. Furthermore, RhoA and PI3K/Akt/GSK3beta signal transduction were analyzed by Western Blotting assay. In addition, radiolabelled ligand binding assay was involved to evaluate the ability of CGP binding to thromboxane prostanoid (TP) and P2Y12 receptors. RESULTS: CGP inhibited platelet aggregation induced by ADP, U46619 and arachidonic acid (AA), significantly. Furthermore, it is also found that LGP exhibited obvious inhibitory effects on alphaIIbbeta3 integrin activation, serotonin (5-HT) secretion from granule and thromboxane A2 (TXA2) synthesis. Next, we found that CGP suppressed RhoA and PI3K/Akt/GSK3beta signal transduction. Data from radiolabelled ligand binding assay showed that CGP displayed apparent competing effects on TP and P2Y12 receptors. CONCLUSION: Collectively, the data presented here demonstrated that CGP, a natural compound from Callicarpa nudiflora Hook, inhibited the development of platelet aggregation and amplification of platelet activation. These inhibitory effects may be associated with its dual-receptor inhibition on P2Y12 and TP receptors. PMID- 29157826 TI - Modulation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) activation by ursolic acid (UA) attenuates rifampin-isoniazid cytotoxicity. AB - BACKGROUND: Interactions between transcriptional inducers of cytochrome P450 (CYP450) enzymes and therapeutic drugs may be prevented by antagonizing the activation of a nuclear receptor (NR), pregnane X receptor (PXR, NR1I2), thus improving therapeutic efficacy. PURPOSE: In the present study, we aim to identify that ursolic acid (UA), a widely distributed pentacyclic triterpene, may act as an effective antagonist of PXR and its sister NR receptor, constitutive androstane receptor (CAR, NR1I3). METHODS: The hepatocellular carcinoma cell line, HepG2, was used to evaluate the promoter activity of PXR and CAR target genes, CYP3A4 and CYP2B6, respectively. Catalytic activities, mRNA, and protein expression of CYP3A4 and CYP2B6 were evaluated in a differentiated HepaRG cell line. Coregulation of PXR with coregulators on CYP3A4 promoter response elements was also been characterized. RESULTS: Transient transfection assays showed that UA effectively attenuated CYP3A4 and CYP2B6 promoter activities mediated by rifampin (RIF, human PXR agonist) and CITCO (human CAR agonist). These inhibitory effects were well correlated with the expression and catalytic activities of CYP3A4 and CYP2B6. Furthermore, the interaction of co-regulators with PXR and the transcriptional complexes in the CYP3A4 promoter activity and CYP3A4 promoter xenobiotic response element (everted repeat 6, ER6), respectively, were disrupted in the presence of UA. UA showed an antagonistic effect against PXR, and reversed the cytotoxic effects of isoniazid (INH) induced by RIF. Taken together, these results show that UA inhibits the transactivation effects of PXR and CAR, and reduces the expression and function of CYP3A4 and CYP2B6. CONCLUSION: The present study suggests that UA could be a powerful agent for reducing potentially dangerous interactions between transcriptional inducers of CYP enzymes and therapeutic drugs. PMID- 29157827 TI - Supplementation with tocotrienols from Bixa orellana improves the in vivo efficacy of daptomycin against methicillin-resistant Staphylococcus aureus in a mouse model of infected wound. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of skin and soft-tissue infection worldwide. An adequate immune response acts as a first line of defence against infections and therefore plays an essential role in the maintenance of health. Tocotrienols (T3s), the lesser known isomers of vitamin E, possess many biological properties and have been recognized as immunomodulators. PURPOSE: The aim of this study was to investigate whether the in vivo supplementation with a mixture of 87.1% delta- and 12.9% gamma-T3s extract from seeds of Bixa orellana, (T3s) could be effective in increasing the effect of daptomycin (DAP) in a mouse model of wound infection due to MRSA. STUDY DESIGN/METHODS: Bacteria were inoculated onto full-thickness wound on the dorsal side of BALB/c mice at 5 * 106 CFU per mouse. Mice were randomized into five groups: an uninfected group, an infected-untreated group, a T3s-pretreated group with no antibiotics given after challenge, a T3s-pretreated group plus DAP given after challenge, a group only given DAP after challenge. Main outcome measures were: bacterial load on the wounds, analysis of Natural Killer (NK) cytotoxicity, immunological phenotype and markers of tissue repair. RESULTS: Our results showed that bacterial load in wounds from mice receiving T3s or DAP alone was 1- or 3 log10 lower, respectively, compared with the infected-untreated group. T3s plus daptomycin showed the highest efficacy, achieving a 4-log10 decrease in bacterial load. This higher antimicrobial effect was associated with increased levels of NK cytotoxicity and markers of wound repair. CONCLUSION: These data suggest that treatment with T3s may be useful for the management of infected wounds as immune adjuvants in combination with DAP. PMID- 29157828 TI - Immune-related and adverse drug reactions to low versus high initial doses of Viscum album L. in cancer patients. AB - BACKGROUND: Immune-related adverse drug reactions (ADRs) to immunotherapy agents have been associated with beneficial clinical outcomes in oncology. Viscum album L. (VA, European mistletoe) is frequently used as an immunomodulatory agent alongside conventional cancer treatment in Europe. VA has been associated with improved quality of life and a reduction in chemotherapy-related ADRs. Beneficial effects of VA are believed to be related to its immunomodulatory properties. Current guidelines recommend commencing with a low dose and increasing slowly overtime, however, off-label prescribing of high initial doses is common. PURPOSE: We investigated ADR profiles related to subcutaneous VA therapy commencing with low, recommended doses versus higher than recommended doses. STUDY DESIGN: Retrospective cohort study. METHODS: Medical records of 1361 cancer patients treated between 2003 and 2013 were assessed. Patients were divided into two groups based on whether the dose of their first VA injection adhered to current guidelines. Patient characteristics and suspected VA-related ADRs were compared between dose groups. RESULTS: Of 1361 cancer patients, 516 (38%) started with a recommended, low dose of VA(<=0.02 mg) and 845 (62%) started with a higher dose(>0.02 mg). Groups did not differ by age or gender, but significant differences were observed for type (p < 0.001) and stage of cancer (p = 0.05). Starting with a high dose of VA was significantly associated with a higher incidence of VA-related ADRs compared to starting with a low dose (20.7% versus 0.8%, p < 0.001). Adjusting for age, gender, tumour type and stage of disease, produced an odds ratio of 37.5 (95% CI = 15.7-122.8, p < .001). Almost all ADRs, irrespective of the initial VA dose, were of mild or moderate intensity. Most ADRs were immune-related, general disorders and administration site conditions, many of which are desired reactions, such as pyrexia and local reactions. Overall, no serious ADRs occurred. CONCLUSIONS: Starting VA therapy with a higher than recommended dose was associated with a high frequency of ADRs, however, nearly all ADRs were expected, of mild to moderate intensity and most were desired reactions. Future research is necessary to investigate whether higher incidences of immune-related events are indicators of beneficial immunomodulation and better clinical outcomes. PMID- 29157830 TI - Ethnobotanical survey of medicinal plants in northeastern of Algeria. AB - BACKGROUND: In order to document medicinal uses of plants in the northeastern of Algeria, preserve traditional heritage and highlighted the risks of excessive human exploitation on flora and biodiversity of the region, an inventory of medicinal species existed in the traditional pharmacopoeia in Skikda region (north-east of Algeria) was made. The survey was carried out during the year (2015-2016), through face to face interviews, using pre-prepared questionnaire. The form contains: sociodemorgaphic profile of each respondent (sex, age, educational level and monthly income), local name of medicinal species used, uses, used parts and methods of preparations. RESULTS: A total of 90 species belonging to 42 botanical families, were listed. The analysis of the obtained results showed that the frequency of use of medicinal plants is related to the age, sex, educational level and monthly income of our respondents. It was recorded that the majority of remedies are prepared in the form of a decoctate from the leaves of the different species, in order to treat a wide range of diseases especially those of the digestive tract. CONCLUSION: Local population has a rich indigenous knowledge, but is always stays not adequately documented. It should be noted that some listed species are suffering from surexploitation which can subjects to the disappearance of the most vulnerable species. It will be urgent and essential to adopt a sustainable management strategy to avoid the degradation of biodiversity of the region. PMID- 29157829 TI - Sulfated galactans from the red seaweed Gracilaria fisheri exerts anti-migration effect on cholangiocarcinoma cells. AB - BACKGROUND: Seaweeds have a long history of use in Asian countries as functional foods, medicinal herbs, and the treatment of cancer. Polysaccharides from various seaweeds have shown anti-tumor activity. Cholangiocarcinoma (CCA), often with metastatic disease, is highly prevalent in Thailand as a consequence of liver fluke infection. Recently, we extracted sulfated galactans (SG) from Gracilaria fisheri (G. fisheri), a south east Asian seaweed, and found it exhibited anti proliferation effect on CCA cells. PURPOSE: In the present study, we evaluated the anti-migration activity of SG on CCA cells and its underlined mechanism. METHODS: CCA cells were treated with SG alone or drugs targeting to epidermal growth factor (EGF) receptor (EGFR) or pretreated with SG prior to incubation with EGF. Anti-migration activity was determined using a scratch wound-healing assay and zymography. Immunofluorescence staining and western blotting were used to investigate EGFR signaling mediators. RESULTS: Under basal condition, SG reduced the migration rate of CCA, which was correlated with a decrease in the active-form of matrix metalloproteinases-9. SG decreased expression of phosphorylated focal adhesion kinase (FAK), but increased expression of E cadherin to promote cells stasis. Moreover, phosphorylation of EGFR and extracellular signal-regulated kinases (ERK), known to stimulate growth of cancer cells, was blocked in a comparable way to EGFR inhibitors Cetuximab and Erlotinib. Pretreatment cells with SG attenuated EGF induced phosphorylation of EGFR, ERK and FAK. CONCLUSION: This study reveals that SG from G. fisheri retards migration of CCA cells, and its mechanism of inhibition is mediated, to some extent, by inhibitory effects on MAPK/ERK signal transduction pathway. Our findings suggest that there may be a therapeutic potential of SG in CCA treatment. PMID- 29157831 TI - Vitis labruscana leaf extract ameliorates scopolamine-induced impairments with activation of Akt, ERK and CREB in mice. AB - BACKGROUND: Grapes are among the most widely consumed plants and are used as a folk medicine. Vitis species have been traditionally used as anti-inflammatory, analgesic, and memory-enhancing agents, but, their biological activities of discarded grape leaves are not completely understood. PURPOSE: We investigated the effects of alcoholic aqueous leaf extract of Vitis labruscana (LEVL) in a mouse model of memory impairment and tried to ascertain its mechanism. We also evaluated its effects in SH-SY5Y cells. METHODS: LEVL (50, 100, and 150 mg/kg) was administered to ICR mice once daily for 7 days. Memory impairment was induced with intraperitoneal scopolamine injections (1 mg/kg) and measured with the Y maze test and a passive avoidance task. LEVL-induced signaling was evaluated in SH-SY5Y cells and mouse hippocampi. RESULTS: We first identified quercetin-3-O glucuronide as LEVL's major component. We then showed that LEVL promoted phosphorylation of Akt, extracellular regulated kinase (ERK), and cyclic AMP response element binding protein (CREB) and proliferation of SH-SY5Y cells. Oral LEVL administration (100 mg/kg) for 7 days significantly reversed scopolamine induced reductions of spontaneous alternation in the Y-maze test and scopolamine induced shortening of latency times in the passive avoidance task's retention trial. Consistent with the cell experiment results, LEVL restored scopolamine decreased phosphorylation of Akt, ERK, and CREB and scopolamine-reduced expression of brain-derived neuroprotective factor expression in mouse hippocampi. CONCLUSION: Our results suggest that LEVL promotes phosphorylation of Akt, ERK, and CREB in the hippocampus and ameliorates scopolamine-induced memory impairment in mice. PMID- 29157832 TI - Pachymic acid promotes induction of autophagy related to IGF-1 signaling pathway in WI-38 cells. AB - BACKGROUND: The insulin-like growth factor 1 (IGF-1) signaling pathway has spotlighted as a mechanism to elucidate aging associated with autophagy in recent years. Therefore, we have tried to screen an effective compound capable of inducing autophagy to delay aging process. PURPOSE: The aim of this study is to investigate whether pachymic acid, a main compound in Poria cocos, induces autophagy in the aged cells. METHODS: The aging of young cells was induced by treatment with IGF-1 at 50 ng/ml three times every two days. The effect of pachymic acid on cell viability was evaluated in human lung fibroblasts, WI-38 cells, using MTT assay. The induction of autophagy was detected using autophagy detection kit. The expression of proteins related to autophagy and IGF-1 signaling pathway was examined by western blot analysis and immunofluorescence assay. RESULTS: In this study, pachymic acid showed cytotoxic effect in a dose dependent manner and remarkably induced autophagy at the same time. Moreover, pachymic acid increased the expression of proteins related to autophagy such as LC3-II and Beclin1 and decreased the levels of mTor phosphorylation and p70S6K in the aged cells. In particular, pachymic acid increased the expression of p-PI3K, p-FoxO and Catalase. In addition, pachymic acid remarkably increased the expression of IGFBP-3. CONCLUSION: Above results suggest that pachymic acid could induce autophagy related to IGF-1 signaling pathway in the aged cells. PMID- 29157833 TI - Vasodilatory effect of asafoetida essential oil on rat aorta rings: The role of nitric oxide, prostacyclin, and calcium channels. AB - BACKGROUND: Asafoetida is an oleo-gum resin mainly obtained from Ferula assa foetida L. species in the apiaceae family. Previous studies have shown that it has antispasmodic effects on rat's and pig's ileums. PURPOSE: The main goals of this study were to assess the vasodilatory effect of asafoetida essential oil (AEO) on the contractile response of rat's aorta rings and to find the role of nitric oxide, cyclooxygenase, and calcium channels. Thoracic aorta rings were stretched under a steady-state tension of 1 g in an organ bath apparatus for 1 h and then precontracted by KCl (80 mM) in the presence and absence of AEO. L-NAME (blocker of nitric oxide synthase) and indomethacin (blocker of cyclooxygenase) were used to assess the role of nitric oxide (NO) and prostacyclin in the vasodilatory effect of AEO. Also, the effect of AEO on the influx of calcium through the cell membrane calcium channels was determined. RESULTS: Data showed that AEO had vasodilatory effects on aorta rings with both intact (IC50 = 1.6 ul/l) or denuded endothelium (IC50 = 19.2 ul/l) with a significantly higher potency in intact endothelium rings. The vasodilatory effects of AEO were reduced, but not completely inhibited, in the presence of L-NAME or indomethacin. Adding AEO to the free-calcium medium also significantly reduced the CaCl2 induced contractions. CONCLUSION: The results indicated that AEO has a potent vasodilatory effect that is endothelium-dependent and endothelium-independent. Also, it reduced the influx of calcium into the cell through plasma membrane calcium channels. PMID- 29157834 TI - 16-Hydroxycleroda-3, 13-dien-15, 16-olide inhibits the proliferation and induces mitochondrial-dependent apoptosis through Akt, mTOR, and MEK-ERK pathways in human renal carcinoma cells. AB - BACKGROUND: Renal cell carcinoma (RCC) is well known that it cannot be treated with traditional chemotherapy or radiotherapy. 16-Hydroxycleroda-3,13-dien-15,16 olide (CD), isolated from Polyalthia longifolia Benth. & Hook. f. var. pendula had been reported to display significant efficacy against cancer cell lines. PURPOSE: To determine the anti-tumour activities of CD in two clear cell type RCC (ccRCC) cell lines (A-498 and 786-O). In addition, the underlying mechanisms were also examined. METHODS: The cell viabilities of CD-treated ccRCC cells were examined by MTT assay. The apoptotic features were confirmed by acridine orange and ethidium bromide staining. 2',7'-dichlorofluorescin diacetate was used to check reactive oxygen species (ROS) involvement. Mitochondria membrane potential (MMP) were determined by using fluorescent dyes, rhodamine 123 and 5',6,6' tetrachloro-1,1',3,3'-tetraethyl benzimidazolylcarbocyanine iodide (JC-1). Proapoptotic, anti-apoptotic proteins and intracellular signaling molecules involved in CD-induced apoptosis were examined by Western blot analysis. RESULTS: CD inhibited both 786-O and A-498 cell proliferation and induced a series apoptotic characteristics expressions, ROS accumulation, caspase-3 activation as well as poly-(ADP-ribose) polymerase cleavage in both ccRCC cells. Additionally, CD caused MMP reduction and cytochrome c release from mitochondria as well as inhibition of anti-apoptotic proteins, including B cell lymphoma 2 and heat shock protein 70. Mechanically, we address that CD suppressed cell proliferation and induced apoptosis via induction of FOXO3a as well as decreased phosphorylation of Akt, mTOR, MEK/ERK and their downstream molecules, cMyc and hypoxia inducible factor 2alpha expression in a concentration- and time-dependent trend. CONCLUSION: CD caused cell death through ROS overproduction and induction of mitochondria-dependent apoptotic pathway in ccRCC cells that accompanied with multiple oncogenic signals inactivation. PMID- 29157835 TI - Corrigendum to "Intergenerational Transmission of Enhanced Seizure Susceptibility after Febrile Seizures" (EBioMedicine 17 (2017) 206-215). PMID- 29157836 TI - Elevated Neopterin Levels Predict Early Death in Older Hip-fracture Patients. AB - Our society faces a major challenge concerning management of the health and socio economic burden caused by acute physical stress in the older population (+75years). In particular, hip-fracture surgery (HFS) represents a major health care preoccupation, affecting 1.6 million patients worldwide, resulting in a significant drop in life quality and autonomy. The trauma is associated with 20 30% one-year mortality in the elderly. In the present study, we aim to identify factors, which influence and/or predict the outcome of elderly hip- fracture patients (HFP) post-surgery. Our objective was to identify biomarkers with a prognostic capacity of one-year mortality. We employed an observational cohort of HFP (n=60) followed-up longitudinally during the first year post fracture. Clinical and biological data (n=136), collected at arrival to hospital, were then compared to healthy controls (n=42) and analyzed using a regularized logistic regression model with lasso penalty followed by 10-fold cross-validation of variables. We show that plasmatic neopterin levels, a molecule released by IFN gamma-activated macrophages, is predictive of mortality in HFP (ROC-AUC=0.859). Moreover, neopterin measured at arrival to the hospital correlated negatively with the time of survival after HFS. Neopterin therefore represents a biomarker, which enables better follow-up of patients at risk of early death. PMID- 29157837 TI - Deguelin, a Novel Anti-Tumorigenic Agent in Human Esophageal Squamous Cell Carcinoma. PMID- 29157838 TI - Impaired Citric Acid Cycle in Nondiabetic Chronic Kidney Disease. PMID- 29157839 TI - Lifestyles guide and glaucoma (i). Sports and activities. AB - PURPOSES: The increase in quality and life expectancy, often leads to many patients asking the glaucoma specialist whether some sports, activities or hobbies would affect their illness. The aim of this article is to establish guidelines for patients, based on the scientific evidence of published papers. METHODS: Review of all published articles on glaucoma and sports or other activities. The papers were classified according to the level of scientific evidence based on the Oxford Centre for Evidence-Based Medicine classification. RESULTS: Aerobic sports are beneficial for the patient. Yoga indoor sports or relaxation techniques should be avoided if Valsalva manoeuvres are performed or the head is placed very low. Also, the patients must avoid sudden changes in height. Intense heat does not seem to lead to progression of glaucoma, but intense cold can affect patients with vascular dysregulation. Activities using the near vision slightly reduce the intraocular pressure. The use of wind instruments may raise intraocular pressure, depending on the technique used. CONCLUSIONS: Certain sports and activities may have an influence on the onset or progression of glaucoma. Glaucoma specialists should have adequate information about the scientific evidence in the publications, in order to properly advise the patients. PMID- 29157840 TI - The insular cortex and QTc interval in HIV+ and HIV- individuals: Is there an effect of sympathetic nervous system activity? PMID- 29157841 TI - Acute management of high-energy lisfranc injuries: A simple approach. AB - INTRODUCTION: The aims of this study were to (1) describe the use of the K-wire for the initial management of high-energy Lisfranc dislocations or fracture dislocations, (2) to evaluate whether this standalone technique allowed for adequate reduction of these injuries, (3) to evaluate whether reductions were maintained until definitive fixation was performed, (4) and to determine if it contributed to any increase in complications prior to or after definitive fixation. PATIENTS AND METHODS: A retrospective review was performed on all patients who presented with tarsometatarsal injuries from January 2005 through June 2015. Dislocations of the tarso-metatarsal joints were classified as either Type A (total incongruity, homolateral complex), Type B (partial incongruity, homolateral incomplete) or Type C (divergent, total or partial displacement) patterns, with or without associated fractures. For the purposes of this paper, high-energy injuries were defined as patients presenting with either a Type A or Type C (total displacement) dislocations or fracture-dislocation patterns. A total of 176 patients presented with a tarsometatarsal injury. Eighteen patients with divergent or homolateral patterns underwent a staged approach. Fifteen patients were managed exclusively with K-wire fixation. Wound complications, infections or the unexpected need to return to surgery were recorded. RESULTS: All patients demonstrated an improved alignment using K-wires. There were no compartment syndromes, vascular insufficiency, complications to the skin associated with traction or manipulation, or pin site infections. At definitive fixation, no patient demonstrated a loss in the alignment that had been obtained at the index procedure or had an unexpected return to surgery. DISCUSSION AND CONCLUSIONS: This study demonstrates that high-energy Lisfranc injuries are uncommon and that K-wires are a simple and adequate technique that can be used for initial staged approach of these injuries. The use of 2.0mm K-wires were sufficient to obtain and maintain the reduction until definitive fixation has been obtained, without producing any increase risk for complications. PMID- 29157842 TI - Femoral intertrochanteric nail (fitn): a new short version design with an anterior curvature and a geometric match study using post-operative radiographs. AB - OBJECTIVE: Femoral intertrochanteric fractures are usually fixed with short, straight cephalomedullary nails. However, mismatches between the nail and the femur frequently occur, such as tip impingement and tail protrusion. The authors designed a new type of short femoral intertrochanteric nail (fitn) with an anterior curvature (length=19.5cm, r=120cm) and herein report the geometric match study for the first of 50 cases. METHODS: A prospective case series of 50 geriatric patients suffering from unstable intertrochanteric fractures (AO/OTA 31 A2/3) were treated. There were 15 males and 35 females, with an average age of 82.3 years. Post-operatively, the nail entry point position in the sagittal greater trochanter (in three categories, anterior, central and posterior), the nail-tip position in the medullary canal (in 5-grade scale) and the nail-tail level to the greater trochanter (in 3-grade scale) were measured using X-ray films. RESULTS: For the nail entry point measurement, 5 cases were anterior (10%), 38 cases were central (76%), and 7 cases were posterior (14%). For the distal nail-tip position, 32 cases (64%) were located along the central canal axis, 13 cases (26%) were located anteriorly but did not contact the anterior inner cortex, 2 cases (4%) showed less than one-third anterior cortex thickness contact, and 3 cases (6%) were located posteriorly with no contact. For the proximal nail-tail level, there were no protrusions over the greater trochanter in 15 cases (30%), protrusion of less than 5mm in 29 cases (58%), and protrusion of more than 5mm in 6 cases (12%). The fitness was very high, as 96% cases showed no tip-cortex contact, and 88% cases showed less than 5mm proximal tail protrusion. CONCLUSION: The newly designed femoral intertrochanteric nail has a good geometric match with the femur medullary canal and the proximal length in the Chinese population. PMID- 29157843 TI - Predictors of osteoarthritis following operative treatment of medial tibial plateau fractures. AB - PURPOSE: To determine factors influencing the development of posttraumatic osteoarthritis (OA) following medial tibial plateau fractures and to evaluate concomitant injuries associated with these fractures. MATERIALS AND METHODS: A chart review of patients with operatively treated medial tibial plateau fractures admitted to our Level I trauma centre from 2002 to 2008 was performed. Of 63 patients, 41 participated in a clinical and radiographic examination. The mean age was 47 years (range 16-78) and the mean follow-up time was 7.6 (range 4.7 11.7) years. All patients had preoperative computed tomography (CT) scans and postoperative radiographs. At the end of follow-up, standing radiographs, mechanical axis, and CT scans were evaluated. RESULTS: Of the 41 patients, 24 had no or mild (Kellgren-Lawrence grade 0-2) OA and 17 had severe (grade 3-4) OA. Initial articular depression measured from preoperative CT scans was a significant predictor of OA (median 1.8mm vs 4.5mm, p=0.009). Fracture line extension to the lateral plateau (p=0.68) or fracture comminution (p=0.21) had no effect on the development of posttraumatic OA, nor did articular depression at the end of follow-up (p=0.68) measured from CT scans. Mechanical axis >4 degrees of varus and >=2mm articular depression or step-off were associated with worse WOMAC pain scores, but did not affect other functional outcome scores. Six patients (10%) had permanent peroneal nerve dysfunction. Ten patients (16%) required LCL reconstruction and nine (14%) ACL avulsions were treated at the time of fracture stabilisation. CONCLUSIONS: The amount of articular depression measured from preoperative CT scans seems to predict the development of posttraumatic OA, probably reflecting the severity of chondral injury at the time of fracture. Restoration of mechanical axis and articular congruence are important in achieving a good clinical outcome. PMID- 29157844 TI - Prevalence of asymptomatic femoroacetabular impingement in Turkey; cross sectional study. AB - OBJECTIVES: Femoroacetabular impingement (FAI) is one of the causes of hip pain in young-adult patients. The purpose of our study is to determine the prevalence of radiological FAI findings in asymptomatic population in Turkey. METHODS: Trauma patients aged 18-65 years who applied to the emergency service between September 2015 and September 2016 were retrospectively evaluated for this study. After a preliminary study and power analysis, 2152 hips of the 1076 previously asymptomatic patients were evaluated radiologically with pelvis antero-posterior and frog-leg radiographs. On radiographs of these patients; alpha angle, lateral central edge angle (LCEA), Tonnis angle (TA) and collodiaphyseal angle were measured. Alpha angle values higher than 55 degrees were noted as cam type FAI. TA values lower than 0 degrees or LCEA values higher than 39 degrees were noted as pincer type FAI. LCEA values lower than 25 degrees or TA values higher than 10 degrees were noted as acetabular dysplasia. RESULTS: Mean age of 1076 patients (602 female, 474 male) was 42.1 +/- 15.6 years. The assessment showed that 15.9% of the patients had cam type, 10.6% had pincer type, 3.1% had combined type FAI and 9.3% had findings of acetabular dysplasia. The prevalence of asymptomatic FAI is significantly more in males (46%) in comparison to females (17%) in Turkey. CONCLUSION: Even though FAI is considered to be a pathology associated with hip osteoarthritis; it is very common in asymptomatic population. In this respect, our study showed that prevalence of radiological FAI findings in asymptomatic adult population was 29.6% in Turkey. PMID- 29157846 TI - Definition of Traumatic Brain Injury, Neurosurgery, Trauma Orthopedics, Neuroimaging, Psychology, and Psychiatry in Mild Traumatic Brain Injury. AB - Traumatic brain injury (TBI) disrupts the normal function of the brain. This condition can adversely affect a person's quality of life with cognitive, behavioral, emotional, and physical symptoms that limit interpersonal, social, and occupational functioning. Although many systems exist, the simplest classification includes mild, moderate, and severe TBI depending on the nature of injury and the impact on the patient's clinical status. Patients with TBI require prompt evaluation and multidisciplinary management. Aside from the type and severity of the TBI, recovery is influenced by individual patient characteristics, social and environmental factors, and access to medical and rehabilitation services. PMID- 29157845 TI - Face Perception in Social Anxiety: Visuocortical Dynamics Reveal Propensities for Hypervigilance or Avoidance. AB - BACKGROUND: Theories of aberrant attentional processing in social anxiety, and anxiety disorders more broadly, have postulated an initial hypervigilance or facilitation to clinically relevant threats and consequent defensive avoidance. However, existing objective measurements utilized to explore this phenomenon lack the resolution to elucidate attentional dynamics, particularly covert influences. METHODS: We utilized a continuous measure of visuocortical engagement, the steady state visual evoked potential in response to naturalistic angry, fearful, happy, and neutral facial expressions. Participants were treatment-seeking patients with principal diagnoses of social anxiety circumscribed to performance situations (n = 21) or generalized across interaction contexts (n = 42), treatment-seeking patients with panic disorder with agoraphobia (n = 25), and 17 healthy participants. RESULTS: At the principal disorder level, only circumscribed social anxiety patients showed sustained visuocortical facilitation to aversive facial expressions. Control participants as well as patients with panic disorder with agoraphobia and generalized social anxiety showed no bias. More finely stratifying the sample according to clinical judgment of social anxiety severity and interference revealed a linear increase in visuocortical bias to aversive expressions for all but the most severely impaired patients. This group showed an opposing sustained attentional disengagement. CONCLUSIONS: Rather than shifts between covert vigilance and avoidance of aversive facial expressions, social anxiety appears to confer a sustained bias for one or the other. While vigilant attention reliably increases with social anxiety severity for the majority of patients, the most impaired patients show an opposing avoidance. These distinct patterns of attentional allocation could provide a powerful means of personalizing neuroscience-based interventions to modify attention bias and related impairment. PMID- 29157847 TI - Functional MR Imaging: Blood Oxygen Level-Dependent and Resting State Techniques in Mild Traumatic Brain Injury. AB - This article discusses mild traumatic brain injury (mTBI)-associated effects on brain functional connectivity assessed via resting-state functional MR (fMR) imaging. Several studies have reported acute post-injury default mode network hyperconnectivity, followed by a period of decreased connectivity before later connectivity normalization in some patients. Other studies have reported mTBI associated effects on connectivity that remain evident for up to 5-years or more. Discordance in the published literature regarding the direction of network connectivity changes (eg, increased versus decreased connectivity) may reflect differences in timing of data collection post-injury, as well as the need to standardize MR imaging acquisition protocols and processing methods. PMID- 29157848 TI - Diffusion MR Imaging in Mild Traumatic Brain Injury. AB - Remarkable advances have been made in the last decade in the use of diffusion MR imaging to study mild traumatic brain injury (mTBI). Diffusion imaging shows differences between mTBI patients and healthy control groups in multiple different metrics using a variety of techniques, supporting the notion that there are microstructural injuries in mTBI patients that radiologists have been insensitive to. Future areas of discovery in diffusion MR imaging and mTBI include larger longitudinal studies to better understand the evolution of the injury and unravel the biophysical meaning that the detected changes in diffusion MR imaging represent. PMID- 29157849 TI - Imaging of Chronic Concussion. AB - Conventional imaging findings in patients with cerebral concussion and chronic traumatic encephalopathy are absent or subtle in the majority of cases. The most common abnormalities include cerebral volume loss, enlargement of the cavum of the septum pellucidum, cerebral microhemorrhages, and white matter signal abnormalities, all of which have poor sensitivity and specificity. Advanced imaging modalities, such as diffusion tensor imaging (DTI), blood oxygen level dependent functional MR Imaging (BOLD fMRI), MR spectroscopy, perfusion imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetoencephalography detect physiologic abnormalities in symptomatic patients and, although currently in the investigation phase, may become useful in the clinical arena. PMID- 29157850 TI - Conventional Computed Tomography and Magnetic Resonance in Brain Concussion. AB - Conventional neuroimaging is still the mainstay in the assessment of the acute, follow-up, and chronic settings of concussion and mild traumatic brain injury (mTBI). Computed tomography (CT) is preferred for the initial assessment of acute mTBI, repeat evaluation in acute mTBI with neurologic deterioration, and cautious use in children with mTBI. Clinical rules have been developed to identify pediatric and adult patients with mTBI who can safely forego CT. Magnetic resonance (MR) imaging is mostly used in patients with acute mTBI when initial or follow-up CT is normal and there are persistent neurologic findings and in subacute or chronic mTBI. PMID- 29157851 TI - Multimodal Advanced Imaging for Concussion. AB - In the United States alone, 1.6 to 3.8 million people have sports-related concussions yearly. The patho-mechanisms of concussions may not be directly measured by conventional neuroimaging; advanced models may be needed to address the shortcomings of the current clinical protocols. Multimodal advanced imaging may provide more accurate diagnosis and predict the clinical course of concussion, assessing the efficacy of existing and emerging multifaceted therapies. In this article, the authors present an overview and pictorial display of conventional and advanced multimodal MR imaging methods that have been applied to identify the brain structures affected in traumatic brain injuries. PMID- 29157853 TI - Perfusion Imaging in Acute Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a significant problem worldwide and neuroimaging plays a critical role in diagnosis and management. Recently, perfusion neuroimaging techniques have been explored in TBI to determine and characterize potential perfusion neuroimaging biomarkers to aid in diagnosis, treatment, and prognosis. In this article, computed tomography (CT) bolus perfusion, MR imaging bolus perfusion, MR imaging arterial spin labeling perfusion, and xenon CT are reviewed with a focus on their applications in acute TBI. Future research directions are also discussed. PMID- 29157852 TI - Imaging of Concussion in Young Athletes. AB - Conventional neuroimaging examinations are typically normal in concussed young athletes. A current focus of research is the characterization of subtle abnormalities after concussion using advanced neuroimaging techniques. These techniques have the potential to identify biomarkers of concussion. In the future, such biomarkers will likely provide important clinical information regarding the appropriate time interval before return to play, as well as the risk for prolonged postconcussive symptoms and long-term cognitive impairment. This article discusses results from advanced imaging techniques and emphasizes imaging modalities that will likely become available in the near future for the clinical evaluation of concussed young athletes. PMID- 29157854 TI - PET and Single-Photon Emission Computed Tomography in Brain Concussion. AB - This article offers an overview of the application of PET and single photon emission computed tomography brain imaging to concussion, a type of mild traumatic brain injury and traumatic brain injury, in general. The article reviews the application of these neuronuclear imaging modalities in cross sectional and longitudinal studies. Additionally, this article frames the current literature with an overview of the basic physics and radiation exposure risks of each modality. PMID- 29157855 TI - Imaging the Role of Myelin in Concussion. AB - Myelin water imaging (MWI) provides mild traumatic brain injury (mTBI) researchers with a specific myelin biomarker and helps to further elucidate microstructural and microarchitectural changes of white matter after mTBI. Improvement of scanner hardware and software with the implementation of MWI across scanner platforms will likely result in increased research regarding the role of myelin in traumatic brain injury (TBI). Future research should include detailed investigation of myelin between 2 weeks and 2 months after injury, the use of MWI in moderate and severe TBI, and investigation of the role of myelin in chronic TBI. PMID- 29157857 TI - Imaging of Brain Concussion. PMID- 29157856 TI - Susceptibility-Weighted Imaging and Magnetic Resonance Spectroscopy in Concussion. AB - Although susceptibility-weighted imaging (SWI) studies have suggested an increased number of microhemorrhages in concussion, most show no significant differences compared with controls. There have been mixed results on using SWI to predict neurologic outcomes. Drawbacks include inability to time microhemorrhages and difficulty in attributing them to the concussion. Magnetic resonance spectroscopy (MRS) in concussion can identify metabolic abnormalities, with many studies showing correlations with clinical outcome. Applications in individual patients are impeded by conflicting data and lack of consensus on an optimal protocol. Therefore, currently MRS has most utility in group-level comparisons designed to reveal the pathophysiology of concussion. PMID- 29157858 TI - Imaging of Cerebral Concussion and Chronic Traumatic Encephalopathy. PMID- 29157859 TI - Adolescents' and Young Adults' Reports of Barriers to Confidential Health Care and Receipt of Contraceptive Services. AB - PURPOSE: The purpose of this study was to describe adolescents' and young adults' concerns about confidential reproductive health care and experience with time alone with a provider, and examine the association of these confidentiality issues with receipt of contraceptive services. METHODS: Data from the 2013 to 2015 National Survey of Family Growth were analyzed using Poisson regression to describe 15- to 25-year-olds' confidential reproductive health-care concerns and time alone with a provider at last health-care visit according to sociodemographic characteristics. We also assessed whether confidentiality issues were associated with obtaining contraceptive services among females. RESULTS: Concerns about confidential reproductive health care were less common among 15- to 17-year-olds who were covered by Medicaid compared to their parents' private insurance (adjusted risk ratio [ARR] = .61, confidence interval [CI] .41-.91) and had high-school graduate mothers compared to college-graduate mothers (ARR = .68, CI .47-.99), and were more common among those who lived with neither parent compared to living with both parents (ARR = 2.0, CI 1.27-3.16). Time alone with a provider was more common among black girls than white girls (ARR = 1.57, CI 1.11 2.22) and less common among girls covered by Medicaid than those with parents' private insurance (ARR = .72, CI .56-.92). Time alone was less common among boys living with neither parent compared to living with two parents (ARR = .48, CI .25 .91) and with high-school graduate mothers compared to college-graduate mothers (ARR = .59, CI .42-.84). Among sexually experienced girls and women, confidentiality concerns were associated with a reduced likelihood of having received a contraceptive service in the past year. CONCLUSIONS: Greater efforts are needed to support young Americans in receiving confidential care. PMID- 29157860 TI - Advances in rhinitis: Models and mechanisms. AB - OBJECTIVE: To summarize studies highlighting recent advances in rhinitis-related research in the past 2 years. DATA SOURCES: Original research articles were procured and examined from the Rhinitis and Upper Airway Disease section of the 2015 to 2017 Annals of Allergy, Asthma & Immunology issues. Additional original research articles were identified from PubMed and Google Scholar using the following search terms: allergic rhinitis, rhinitis, chronic rhinosinusitis, environmental exposure unit, and nasal allergen challenge. Only research articles published in the past 2 years were procured. STUDY SELECTIONS: Articles conducting research in allergic rhinitis (AR) or chronic rhinosinusitis or using controlled allergen challenge facilities or the nasal allergen challenge model were selected. RESULTS: Studies in the past 2 years have focused on using skin prick tests and early-life phenotyping to predict AR development in children. They also have elucidated the role of a subset of CD4+ T cells, basophils, and mast cells in non-eosinophilic chronic rhinosinusitis with nasal polyps, a relatively new chronic rhinosinusitis subtype in the Asian population. Several advances have been made in understanding the role of several cytokines and peripheral cell mitochondrial function in AR using controlled allergen challenge facilities and direct nasal allergen challenges. CONCLUSION: Findings from the recent literature highlight the utility of early-life predictors of AR in possibly targeting high-risk groups for prophylactic interventions. Studies also emphasize the use of controlled allergen challenge facilities and the nasal allergen challenge model as robust experimental models to study AR pathogenesis. PMID- 29157861 TI - Hydroxychloroquine as a steroid-sparing agent in an infant with chronic urticaria. PMID- 29157862 TI - Scutellarin inhibits Hela cell growth and glycolysis by inhibiting the activity of pyruvate kinase M2. AB - Scutellarin, one of natural flavonoids, is widely and clinically used for treating many diseases in China. Recently, scutellarin has demonstrated a broad spectrum of anti-proliferative activities against multiple cancer cell lines. However, the molecular mechanism of action remains to be investigated. We herein report the design and synthesis of biotinylated scutellareins as probes, which can be applied to discover scutellarein interacting proteins. Finally, we show that scutellarin directly targets pyruvate kinase M2 (PKM2) and inhibits its cytosolic activity to decrease glycolytic metabolism; on the other hand, scutellarin may also participate in regulating cell cycle and apoptotic proteins by activating MEK/ERK/PIN1 signaling pathway to promote the nuclear translocation of PKM2. PMID- 29157863 TI - Structure-activity relationship study of Aib-containing amphipathic helical peptide-cyclic RGD conjugates as carriers for siRNA delivery. AB - The conjugation of Aib-containing amphipathic helical peptide with cyclo(-Arg-Gly Asp-d-Phe-Cys-) (cRGDfC) at the C-terminus of the helix peptide (PI) has been reported to be useful for constructing a carrier for targeted siRNA delivery into cells. In order to explore structure-activity relationships for the development of potential carriers for siRNA delivery, we synthesized conjugates of Aib containing amphipathic helical peptide with cRGDfC at the N-terminus (PII) and both the N- and C-termini (PIII) of the helical peptide. Furthermore, to examine the influence of PI helical chain length on siRNA delivery, truncated peptides containing 16 (PIV), 12 (PV), and 8 (PVI) amino acid residues at the N-terminus of the helical chain were synthesized. PII and PIII, as well as PI, could deliver anti-luciferase siRNA into cells to induce the knockdown of luciferase stably expressed in cells. In contrast, all of the truncated peptides were unlikely to transport siRNA into cells. PMID- 29157864 TI - New Caspase-1 inhibitor by scaffold hopping into bio-inspired 3D-fragment space. AB - Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50 = 17 nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors. PMID- 29157865 TI - Peptide YY (3-36) modulates intracellular calcium through activation of the phosphatidylinositol pathway in hippocampal neurons. AB - Peptide YY (PYY) belongs to the neuropeptide Y (NPY) family, which also includes the pancreatic polypeptide (PP) and NPY. PYY is secreted by the intestinal L cells, being present in the blood stream in two active forms capable of crossing the blood brain barrier, PYY (1-36) and its cleavage product, PYY (3-36). PYY is a selective agonist for the Y2 receptor (Y2R) and these receptors are abundant in the hippocampus. Here we investigated the mechanisms by which PYY (3-36) regulates intracellular Ca2+ concentrations ([Ca2+]i) in hippocampal neurons by employing a calcium imaging technique in hippocampal cultures. Alterations in [Ca2+]i were detected by changes in the Fluo-4 AM reagent emission. PYY (3-36) significantly increased [Ca2+] from the concentration of 10-11M as compared to the controls (infusion of HEPES-buffered solution (HBS) solution alone). The PYY (3-36)-increase in [Ca2+]i remained unchanged even in Ca2+-free extracellular solutions. Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase pump (SERCA pump) inhibition partially prevent the PYY (3-36)-increase of [Ca2+]i and inositol 1,4,5-triphosphate receptor (IP3R) inhibition also decreased the PYY (3-36) increase of [Ca2+]i. Taken together, our data strongly suggest that PYY (3-36) mobilizes calcium from the neuronal endoplasmic reticulum (ER) stores towards the cytoplasm. Next, we showed that PYY (3-36) inhibited high K+-induced increases of [Ca2+]i, suggesting that PYY (3-36) could also act by activating G-protein coupled inwardly rectifying potassium K+ channels. Finally, the co-infusion of the Y2 receptor (Y2R) antagonist BIIE0246 with PYY (3-36) abolished the [Ca2+]i increase induced by the peptide, suggesting that PYY (3-36)-induced [Ca2+]i increase in hippocampal neurons occurs via Y2Rs. PMID- 29157867 TI - Challenges in assessing the health risks of consuming vegetables in metal contaminated environments. AB - A great deal of research has been devoted to the characterization of metal exposure due to the consumption of vegetables from urban or industrialized areas. It may seem comforting that concentrations in crops, as well as estimated exposure levels, are often found to be below permissible limits. However, we show that even a moderate increase in metal accumulation in crops may result in a significant increase in exposure. We also highlight the importance of assessing exposure levels in relation to a regional baseline. We have analyzed metal (Pb, Cd, As) concentrations in nearly 700 samples from 23 different vegetables, fruits, berries and mushrooms, collected near 21 highly contaminated industrial sites and from reference sites. Metal concentrations generally complied with permissible levels in commercial food and only Pb showed overall higher concentrations around the contaminated sites. Nevertheless, probabilistic exposure assessments revealed that the exposure to all three metals was significantly higher in the population residing around the contaminated sites, for both low-, median- and high consumers. The exposure was about twice as high for Pb and Cd, and four to six times as high for As. Since vegetable consumption alone did not result in exposure above tolerable intakes, it would have been easy to conclude that there is no risk associated with consuming vegetables grown near the contaminated sites. However, when the increase in exposure is quantified, its potential significance is harder to dismiss - especially when considering that exposure via other routes may be elevated in a similar way. PMID- 29157868 TI - Selective observation of charge storing ions in supercapacitor electrode materials. AB - Nuclear magnetic resonance (NMR) spectroscopy has emerged as a useful technique for probing the structure and dynamics of the electrode-electrolyte interface in supercapacitors, as ions inside the pores of the carbon electrodes can be studied separately from bulk electrolyte. However, in some cases spectral resolution can limit the information that can be obtained. In this study we address this issue by showing how cross polarisation (CP) NMR experiments can be used to selectively observe the in-pore ions in supercapacitor electrode materials. We do this by transferring magnetisation from 13C nuclei in porous carbons to nearby nuclei in the cations (1H) or anions (19F) of an ionic liquid. Two-dimensional NMR experiments and CP kinetics measurements confirm that in-pore ions are located within Angstroms of sp2-hybridised carbon surfaces. Multinuclear NMR experiments hold promise for future NMR studies of supercapacitor systems where spectral resolution is limited. PMID- 29157869 TI - Adapting and validating a measure of diabetes-specific self-compassion. AB - AIMS: Self-compassion (SC), or treating oneself with kindness when dealing with personal challenges, has not been rigorously examined in people with T1D. SC has been shown to buffer against negative emotions and to be linked to improved health outcomes, but diabetes-specific SC has not been studied. This study aimed to adapt the Self-Compassion Scale and validate it for a diabetes-specific population. METHODS: We developed and validated a diabetes-specific version of the Self-Compassion Scale (Neff, 2003) in a sample of adults with T1D (N=542; 65% female; 97% non-Hispanic White; M age 41, SD=15.7; M A1c=7.3, SD=1; 72% insulin pump users; 50% continuous glucose monitoring [CGM] users). Confirmatory factor analyses (CFA), and reliability and construct validity analyses were conducted. Validity measures included diabetes distress, diabetes empowerment, diabetes numeracy, and A1c. RESULTS: A two-factor bi-factor structure showed best fit, providing support for use of the adapted scale (SCS-D) as a unitary construct. The 19-item unidimensional SCS-D demonstrated excellent internal consistency (alpha=0.94; range of item-total correlations: 0.52-0.71) and construct validity. As hypothesized, higher SCS-D was associated with less distress, greater empowerment, and lower A1c, and was not associated with numeracy. CONCLUSIONS: The SCS-D is a reliable and valid measure of diabetes-specific self-compassion in adults with T1D. PMID- 29157870 TI - Cost-utility of empagliflozin in patients with type 2 diabetes at high cardiovascular risk. AB - AIMS: In the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG) trial, empagliflozin reduced cardiovascular and all-cause mortality in type 2 diabetes (T2D) patients at high cardiovascular risk. We sought to estimate the cost-effectiveness of empagliflozin versus standard treatment for the prevention of cardiovascular morbidity and mortality in patients with T2D. METHODS: A Markov model was developed to assess the cost effectiveness of empagliflozin (versus standard treatment) for the prevention of cardiovascular morbidity and mortality in patients with T2D using a 3-month cycle length and a lifetime horizon. Data sources included the EMPA-REG randomized clinical trial and other published epidemiological studies. Outcomes included treatment costs (in 2016 US$), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Probabilistic sensitivity analysis (PSA) was performed to test the robustness of conclusions. RESULTS: Empagliflozin use resulted in higher total lifetime treatment costs ($371,450 versus $272,966) but yielded greater QALYs (10.712 vs. 9.419) compared to standard treatment. This corresponded to an ICER of $76,167 per QALY gained. PSA suggested empagliflozin would be cost-effective in 96% of 10,000 iterations assuming a willingness-to-pay threshold of $100,000 per QALY gained. CONCLUSION: Empagliflozin may be cost effective compared to standard treatment in T2D patients at high cardiovascular risk. PMID- 29157866 TI - Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. AB - BACKGROUND: The efficacy of vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix has been questioned after publication of the OPPTIMUM study. OBJECTIVE: To determine whether vaginal progesterone prevents preterm birth and improves perinatal outcomes in asymptomatic women with a singleton gestation and a midtrimester sonographic short cervix. STUDY DESIGN: We searched MEDLINE, EMBASE, LILACS, and CINAHL (from their inception to September 2017); Cochrane databases; bibliographies; and conference proceedings for randomized controlled trials comparing vaginal progesterone vs placebo/no treatment in women with a singleton gestation and a midtrimester sonographic cervical length <=25 mm. This was a systematic review and meta-analysis of individual patient data. The primary outcome was preterm birth <33 weeks of gestation. Secondary outcomes included adverse perinatal outcomes and neurodevelopmental and health outcomes at 2 years of age. Individual patient data were analyzed using a 2-stage approach. Pooled relative risks with 95% confidence intervals were calculated. Quality of evidence was assessed using the GRADE methodology. RESULTS: Data were available from 974 women (498 allocated to vaginal progesterone, 476 allocated to placebo) with a cervical length <=25 mm participating in 5 high-quality trials. Vaginal progesterone was associated with a significant reduction in the risk of preterm birth <33 weeks of gestation (relative risk, 0.62; 95% confidence interval, 0.47 0.81; P = .0006; high-quality evidence). Moreover, vaginal progesterone significantly decreased the risk of preterm birth <36, <35, <34, <32, <30, and <28 weeks of gestation; spontaneous preterm birth <33 and <34 weeks of gestation; respiratory distress syndrome; composite neonatal morbidity and mortality; birthweight <1500 and <2500 g; and admission to the neonatal intensive care unit (relative risks from 0.47-0.82; high-quality evidence for all). There were 7 (1.4%) neonatal deaths in the vaginal progesterone group and 15 (3.2%) in the placebo group (relative risk, 0.44; 95% confidence interval, 0.18-1.07; P = .07; low-quality evidence). Maternal adverse events, congenital anomalies, and adverse neurodevelopmental and health outcomes at 2 years of age did not differ between groups. CONCLUSION: Vaginal progesterone decreases the risk of preterm birth and improves perinatal outcomes in singleton gestations with a midtrimester sonographic short cervix, without any demonstrable deleterious effects on childhood neurodevelopment. PMID- 29157871 TI - Using millet as substrate for efficient production of monacolin K by solid-state fermentation of Monascus ruber. AB - In this study, various grains such as rice, millet, corn, barley and wheat were used as raw materials for monacolin K production by solid-state fermentation of Monascus ruber. Among these substrates, millet was found to be the best one for monacolin K production, by which the yield reached 7.12 mg/g. For enhanced monacolin K production, the effects of fermentation time, charge amount, initial moisture content and inoculum volume were systematically investigated in the solid-state fermentation of M. ruber. Moreover, complementary carbon source and nitrogen source were added for further improving the production of monacolin K. Results showed that the maximum production of monacolin K (19.81 mg/g) could be obtained at the optimal conditions. Compared with the traditional red mold rice, using millet as substrate is promising for high production of monacolin K in the solid-state fermentation of M. ruber. PMID- 29157873 TI - Quantized filtering for T-S fuzzy networked systems with saturation nonlinearities: An output-dependent triggering method. AB - This paper addresses the problem of Hinfinity filter design for T-S fuzzy systems with saturation nonlinearities. For the purpose of reducing network burden, an output-dependent triggering scheme and a quantizer are introduced at the same time. The output-dependent triggering scheme is applied to determine whether or not the current instant information should be transmitted to the quantizer. Saturation nonlinearities, as a common phenomenon in networked systems due to the physical or technological constraints, is also considered here. Then a filtering error model with aforementioned characteristics is established. By using Lyapunov functional approach and stochastic analysis techniques, some matrix inequality based sufficient conditions for the existence of the fuzzy filter are obtained. Moreover, a co-design algorithm for solving the suitable filter and the event generator is derived. Finally, a numerical example is provided to demonstrate the effectiveness of the proposed approach. PMID- 29157872 TI - Effects of health education intervention on negative emotion and quality of life of patients with laryngeal cancer after postoperative radiotherapy. AB - PURPOSE: The study aimed to explore and analyze the effects of health education intervention on patients with laryngeal cancer and evaluate negative emotions and quality of life after receiving postoperative radiotherapy. Furthermore the relationship between health education intervention methods and its correlation to complications and relapse rates require greater understanding. MATERIAL AND METHODS: Patients with aryngeal cancer receiving surgery and postoperative radiotherapy were randomly divided into observation and control groups. A quality of life questionnaire was used to evaluate patients' current life quality as well as negative emotions experienced. The collected data was evaluated using the Self rating Anxiety Scale (SAS) as well as the Self-rating Depression Scale (SDS). At the time of discharge, patients' satisfaction on nursing and perception of health knowledge was assessed. Three and six months after discharge, patients were given follow-up visits and questionnaire surveys to evaluate their rehabilitation. This was done in relation with the Morningside Rehabilitation Stats Scale (MRSS), incidence of complications and recurrence. RESULTS: The scores of negative emotions, exhibited during the study, were lower in the observation group than in the control group. A month after discharge had a positive correlation to improved quality of life. This was highlighted in the observation group in comparison with the control group. The data collected following discharge revealed an improvement in quality of life, compared with that at the time of admission. Compared with the control group, the SAS and SDS scores in the observation group were decreased a month after discharge. Compared with the scores on admission, the SAS and SDS scores in both groups were decreased one month after discharge. The observation group had a lower incidence of complications than that of the control group. Six months after discharge, in the observation group, the MRSS score was lower than before discharge while in the control group, the MRSS score was higher than before discharge. CONCLUSIONS: Health education intervention can significantly improve the quality of life and reduce experiences relating to negative emotion in patients with laryngeal cancer. This improvement was seen following surgery and radiotherapy. Additionally effective reduction rates in the incidence of postoperative complications and recurrence were exhibited following methods of health education intervention. PMID- 29157874 TI - Air Travel and Postoperative Lymphedema-A Systematic Review. AB - Lymphedema is not uncommon after axillary dissection for breast cancer. Improved survival of patients with breast cancer from advances in adjuvant therapy has resulted in increased awareness of the quality of life for long-term survivors. Air travel has been postulated as 1 of the risk factors of lymphedema exacerbation. In the present systematic review, we sought to critically evaluate the current data on this topic. The present study was registered in the Research Registry. A systematic review of lymphedema and air travel was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. The Medline, EMBASE, CINAHL, and Cochrane databases were searched for English language studies up to June 2017 with a predefined strategy. The retrieved studies were independently screened and rated for relevance. Data were extracted by 2 of us. A total of 55 studies were identified using predefined keywords; 12 studies were included using the criteria stated in the study protocol. A pooled analysis of 2051 patients with a history of air travel revealed that <= 14.5% developed lymphedema after air flight. However, a subsequent analysis of 4 studies with a control arm showed that 107 of 1189 patients (9%) with a documented history of air travel developed lymphedema compared with 204 of 2356 patients (8.7%) who had not flown (chi2 test; P = .80). Two studies (1030 patients) evaluated the effect of lymphedema on patients' air travel patterns. Of the 1030 patients, 141 (13.7%) had totally avoided air travel after the development of lymphedema. However, air travel was not adversely associated with the development of lymphedema. PMID- 29157875 TI - Prostatic Calculi: Do They Matter? AB - INTRODUCTION: Prostatic calculi (PC) are frequently detected at computed tomography or ultrasound in men attending the health center or the urology outpatient department. PC have attracted more attention from urologists, but the clinical significance of PC is unknown. AIM: To review the available literature on the effects of PC on prostatic diseases and sexual function in men. METHODS: Relevant clinical trials were identified by searching the PubMed, Embase, and Cochrane Library databases. Results were classified, summarized, and analyzed. MAIN OUTCOME MEASURES: Transabdominal and rectal ultrasonography; urodynamics analysis; International Prostate Symptom Score; pathologic examination of prostatic tissue; prostate-specific antigen; and expressed prostatic secretion. RESULTS: PC can not only prolong the duration of bothersome symptoms but also decrease the cure rate of antibacterial therapy in patients with chronic prostatitis. Patients with PC usually have more severe lower urinary tract symptoms (LUTS), and some studies reported that moderate to marked PC are a predisposing factor for moderate to severe LUTS. Studies also reported that the serum level prostate-specific antigen is not influenced by PC. In addition, the presence of PC is not associated with an increased risk of prostate cancer. However, the correlation between PC in the peripheral zone and prostate cancer is statistically significant. In addition, the association between PC and Gleason scores is controversial. Some novel studies suggested that PC might play an important role in sexual impairment in middle-age men or men with chronic pelvic pain syndrome or chronic prostatitis. Recently, PC were found to increase the incidence of severe LUTS, urinary retention, and hematospermia after transrectal ultrasound-guided prostate biopsy. CONCLUSION: PC can aggravate LUTS, chronic prostatitis, and sexual dysfunction in men, but the association between PC and prostate cancer is still controversial. Cao J-J, Huang W, Wu H-S, et al. Prostatic Calculi: Do They Matter? Sex Med Rev 2018;6:482-491. PMID- 29157876 TI - Evaluating the effect of tariff on wastage and return of blood products in Kerman province. AB - BACKGROUND: In Iran blood products had been available to health care centers on free order to reduce the wastage they were tariffed in 2016. Thus, health care centers must pay for the blood products and take back the payment from the insurance. The aim of this study was to examine the effects of the tariff on consumption, wastage and return rates of blood products in health care centers in Kerman province. MATERIALS AND METHODS: In this retrospective cross-sectional study, demand, delivery and return rates of blood products (fresh frozen plasma, red blood cell and platelet) were examined in 23 health care centers and hospitals before and after the tariff. RESULTS: After the tariff in 2016, the return of unused units of fresh frozen plasma and platelet to the blood transfusion organization was increased and the increase was not statistically significant, but a significant increase was observed in red blood cell return rate and return/delivery ratio. CONCLUSION: Fresh frozen plasma and platelet return rates increased after the tariff resulting in less wastage of unused products but were not statistically meaningful. Tariff was highly effective on the wastage and return of red blood cell therefore it can be considered as a sparing action in the management of red blood cell. PMID- 29157877 TI - [Treatment of wrinkles of the upper lip by emulsified fat or "Nanofat": Biological and clinical study about 4 cases]. AB - OBJECTIVE: Emulsified fat injection showed its interest in aesthetic facial surgery. The adipose tissue harvested is mechanically emulsified and filtered. The suspension obtained is injected into the dermis through small diameter needles (27 to 30 gauges). The objective of our study was to evaluate the biological composition of emulsified fat and its clinical effectiveness in the treatment of peri-oral wrinkles in 4 patients aged 50 to 59 years. MATERIAL AND METHOD: Each patient received an intradermal injection of emulsified fat in the peri-oral wrinkles prepared from abdominal fat under local anesthesia. The cell viability, stromal vascular fraction (FVS) composition in emulsified fat and the adipocyte differentiation capacity of mesenchymal stem cells (MSC) were studied. The clinical results were evaluated by standardized photographs, 3D microphotography, confocal microscopy, and self-evaluation of patient satisfaction over a period of 4 months. RESULTS: The biological study of the emulsified fat found a lysis of all the adipocytes. The mean number of FVS cells was 126,330+/-2758 cells by cc of emulsified fat with preserved cell viability (85.1+/-6.84 %) and a good proportion of regeneratives cells (18.77+/-6.2 %). The clinical study found a tendency to decrease the volume of wrinkles on standardized photography and 3D microphotography no significative. Patients were satisfied with treatment with an average score of 7+/-1.15/10 to 4 months. CONCLUSION: Intradermal injection of emulsified fat seems to be an interesting treatment of face wrinkles. Our study has shown its safety, but additional studies seems necessary to confirm its clinical efficacy. PMID- 29157878 TI - [Septoplasty during primary unilateral cleft lip repair]. AB - Primary repair of cleft lip and palate has become a nasal and lip repair. In the aim to improve our nasal results on symmetry we perform an extensive septoplasty to put the nose in a good shape and a median axis. This septoplasty without resection of cartilage does not cause growth disorders to the nose and it promotes maxillary growth by improving early nasal breathing. It can prevent secondary rhinoplasty, source of new scars (externally, fork). But rhinoplasty will increase the incidence of scar contraction, thus shaping with a nasal conformer is essential. PMID- 29157879 TI - The snapping shrimp dactyl plunger: a thermomechanical damage-tolerant sandwich composite. AB - The dactyl plunger of Alpheus sp. was found to be a layered composite, with mineral-rich outer and inner layers and a chitin-rich middle layer of high porosity. The chitin-rich middle layer is itself composed of several porous chitin laminae. Modelling heat conduction through the plunger cross-section revealed that the chitin-rich layer is able to insulate heat and retard its progress through the material. Heat accumulates in the plunger after a series of successive snaps and as such, its thermally resistant design can be considered most useful under the conditions of successive snapping. The plunger has a concurrent mechanical damage-tolerant design with biogenic mineral layers, viscous (chitin-mineral) interfaces, energy-dissipating porous chitin, and sidewalls composed of ordered, layered aragonite. The snapping shrimp plunger has a design that may protect it and internal soft tissues from thermomechanical damage during plunger-socket compression prior to cavitation bubble release. PMID- 29157880 TI - Mechanical properties of harbor seal skin and blubber - a test of anisotropy. AB - The skin and blubber of marine mammals provides protection from the surrounding environment, whether that be temperature, microbes, or direct mechanical impacts. To understand the ability of harbor seals' (Phoca vitulina) skin and blubber to resist blunt force trauma, we tested the material properties of these tissues. We quantified two mechanical properties of the tissue: tensile strength and tensile stiffness, at two test speeds, three sample orientations, and two age groups. We found significant differences in material properties between test speeds, orientation, and age of the animal, but did not find a large difference with orientation. From this analysis, we conclude that harbor seal skin and blubber should be modeled as an isotropic non-linear elastic material with strain rate dependence. Moreover, we were interested in the effects of freezing on the biomechanical properties. The material was tested fresh and after being frozen for four months. Frozen data revealed an increase in stiffness and strength for the skin (epidermis and dermis), but did not show a conclusive trend in the blubber material properties. While the availability of frozen marine mammal tissue is greater than that of fresh material, frozen tissue of harbor seals, especially the skin, cannot serve as an accurate replacement for testing of fresh material. PMID- 29157881 TI - Deformation of avian middle ear structures under static pressure loads, and potential regulation mechanisms. AB - Static pressure changes can alter the configuration and mechanical behavior of the chain of ossicles, which may affect the acoustic transfer function. In mammals, the Eustachian tube plays an important role in restoring ambient middle ear pressure, hence restoring the acoustic transfer function and excluding barotrauma of the middle and inner ear. Ambient pressure fluctuations can be potentially extreme in birds and due to the simple structure of the avian middle ear (one ossicle, one muscle), regulation of the middle ear pressure via reflexive opening of the pharyngotympanic tube appears all the more important. In this study the deformations of the chicken (Gallus gallus domesticus) middle ear structures, as a result of middle ear pressure alterations, are quantified, using micro-CT scanning. It was experimentally tested whether reflexive opening of the pharyngotympanic tube to restore ambient middle ear pressure is present in chicken and mallard (Anas platyrhynchos) and whether this mechanism depends on sensing middle ear pressure indirectly via deformations of the middle ear components or sensing the middle ear pressure directly. A translation of the columella footplate was observed when middle ear pressure was kept at 1kPa and 1kPa relative to ambient pressure. Deformation of the tympanic membrane was larger than the columella footplate translation. Bending and deformation of the extracolumella was observed. Opening of the pharyngotympanic tube occurred at random pressure for both chicken and mallard when middle ear pressure was raised and lowered by 1.5kPa relative to ambient pressure. We also did not find a difference in middle ear venting rate when middle ear pressure was held constant at 0.5, 1, 1.5, -0.5, -1 and -1.5kPa for chickens and at 1, 2, 4, -1, -2 and 4kPa for mallards. As a result, no statement can be made about pressure within the avian middle ear being measured directly or indirectly. Our experiments do not support the presence of a short-loop reflexive control of pressure equilibration via the pharyngotympanic tube. However, it is still possible that triggering this loop requires additional sensorial input (e.g. visual, vestibular) or that it occurs voluntarily (being controlled at a higher brain level). PMID- 29157882 TI - Current perioperative care of infants with pyloric stenosis: comparison of survey results. AB - BACKGROUND: Considerable variation in the perioperative management of infants with pyloric stenosis (PS) led the authors to undertake a survey of pediatric anesthesiologists to determine if consensus-based guidelines could be developed. MATERIALS AND METHODS: Physicians who are members of the Society for Pediatric Anesthesia or the Association of Pediatric Anaesthetists of Great Britain and Ireland completed an online questionnaire through SurveyMonkey regarding current management of patients with PS. RESULTS: There were significant differences in the use of anticholinergic premedication, the selection of induction technique, and the use of adjuvant regional analgesia between the members of both organizations. CONCLUSIONS: The authors recommend creating an international multiinstitutional registry to prospectively record and track perioperative management of patients with PS to facilitate the development of clinical practice guidelines. PMID- 29157883 TI - As the guard changed, so it changes. PMID- 29157884 TI - CISNE or MASCC, which predictor is really the weakest in febrile neutropenia? PMID- 29157885 TI - Development and validation of a scoring system for the identification of pleural exudates of cardiac origin. AB - BACKGROUND: Light's criteria misclassify about 30% of cardiac effusions as exudates, possibly leading to unnecessary testing. Our purpose was to derive and validate a scoring model to effectively identify these falsely categorized cardiac effusions, in the setting of natriuretic peptide lacking data. METHODS: We retrospectively analyzed data from 3182 patients with exudative pleural effusions based on Light's criteria, of whom 276 had heart failure (derivation set). A scoring model was generated with those variables identified as independent predictors of cardiac effusions in a logistic regression analysis, and further evaluated in an independent population of 1165 patients. RESULTS: The score consisted of age >=75years (3 points), albumin gradient >1.2g/dL (3 points), pleural fluid lactate dehydrogenase <250U/L (2 points), bilateral effusions on chest radiograph (2 points), and protein gradient >2.5g/dL (1 point). At the best cutoff of >=7 points, the score yielded 92% diagnostic accuracy, a likelihood ratio positive of 12.7 and a likelihood ratio negative of 0.39 for labeling cardiac effusions in the derivation sample. The respective figures in the validation sample were 87%, 6.5 and 0.33. Notably, the score had higher discriminatory properties than protein and albumin gradients in both the derivation (respective area under the curve - AUC - of 0.925, 0.825, and 0.801) and validation (respective AUC of 0.908 0.862 and 0.802; all p<=0.01) cohorts. CONCLUSIONS: A simple scoring system can assist clinicians in accurately identifying false cardiac exudates when natriuretic peptides are not available. PMID- 29157886 TI - Prevalence of bendopnea in general population without heart failure. PMID- 29157887 TI - Spatial patterns of heavy metal accumulation in sediments and macrophytes of Bellandur wetland, Bangalore. AB - Heavy metals are one among the toxic chemicals and accumulation in sediments and plants has been posing serious health impacts. Wetlands aid as kidneys of the landscape and help in remediation through uptake of nutrients, heavy metals and other contaminants. The analyses of macrophytes and sediment samples help in evaluating pollution status in aquatic environment. In this study concentration of six heavy metals (Cadmium (Cd), Chromium (Cr), Copper (Cu), Nickel (Ni), Lead (Pb) and Zinc (Zn)) were assessed in sediment and dominant macrophyte samples collected from Bellandur Lake, largest Lake of Bangalore, India. Sediment samples reveal of heavy metals in the inlet regions and shore samples. The accumulation of metals in sediments were in the order of Zn > Cu > Cr > Pb > Ni > Cd. All metals exceeded the critical limits of metals in the sediment. Concentration of different metals in the macrophyte samples ranked as: Cr > Cu > Zn > Pb > Ni > Cd. Chromium and Copper were found to be more than critical range. Typha angustata had the higher accumulation of all metals except chromium. PMID- 29157888 TI - Quality measurement affecting surgical practice: Utility versus utopia. AB - The Triple Aim: improving healthcare quality, cost and patient experience has resulted in massive healthcare "quality" measurement. For many surgeons the origins, intent and strengths of this measurement barrage seems nebulous-though their shortcomings are noticeable. This article reviews the major organizations and programs (namely the Centers for Medicare and Medicaid Services) driving the somewhat burdensome healthcare quality climate. The success of this top-down approach is mixed, and far from convincing. We contend that the current programs disproportionately reflect the definitions of quality from (and the interests of) the national payer perspective; rather than a more balanced representation of all stakeholders interests-most importantly, patients' beneficence. The result is an environment more like performance management than one of valid quality assessment. Suggestions for a more meaningful construction of surgical quality measurement are offered, as well as a strategy to describe surgical quality from all of the stakeholders' perspectives. Our hope is to entice surgeons to engage in institution level quality improvement initiatives that promise utility and are less utopian than what is currently present. PMID- 29157889 TI - The effect of damage control laparotomy on major abdominal complications: A matched analysis. AB - INTRODUCTION: Damage control laparotomy (DCL) for trauma is thought to be associated with increased abdominal complications. The purpose of this study is to determine the effect of DCL on abdominal complications by comparing two groups of trauma patients: DCL patients who were prospectively adjudicated to potentially being closed at the primary laparotomy (potential DEF or pDEF) and those who underwent definitive laparotomy (DEF). METHODS: The pDEF group was matched to DEF patients according to mechanism of injury, abdominal injury severity, operating room transfusions, and performance of a colon resection. The primary outcome was major abdominal complications (MAC), a composite variable. RESULTS: No statistically significant difference in the primary outcome, major abdominal complications, were seen (pDEF 19% versus DEF 56%, p = 0.066). The pDEF group was more likely to have a fascial dehiscence (38% versus 0%, p = 0.018), and to be re-opened after fascial closure (38% versus 0%, p = 0.018). CONCLUSION: Damage control laparotomy was associated with clinically but not statistically significant increase in rates of MAC. Increased numbers of patients to analyze in this fashion is needed. PMID- 29157890 TI - Surgical clerkship or medical clerkship first: Does it make a difference? AB - INTRODUCTION: This study compares NBME surgical clerkship scores of students who completed their medicine clerkship before their surgical clerkship with the performance of those who had not previously completed their medical clerkship. METHODS: The study included 815 New York University School of Medicine students from the years 2014-2018 (571 students took medicine first, while 244 took surgery first). Performance on the surgical clerkship was assessed using the NBME SHELF examination. Statistical comparisons were performed via 2-tailed, independent-samples, unequal-variance t-tests. RESULTS: Mean NBME surgical SHELF scores of the students who had previously taken medicine were significantly higher than students who had not (mean 78.6 vs. 73.5, p < 0.001). Students who had solely medicine (as their first clerkship) before surgery also performed significantly better (mean 78.8 vs. 73.5, p < 0.001). Students who completed surgery later in the year did not perform better on the surgical SHELF, so long as both surgical clerkship cohorts had completed medicine. CONCLUSION: Students who completed their core medical clerkship prior to their surgical clerkship scored significantly better on the NBME surgical SHELF examination. PMID- 29157891 TI - Surgical resection improves median overall survival with marginal improvement in long-term survival when compared with definitive radiotherapy in Merkel cell carcinoma: A propensity score matched analysis of the National Cancer Database. AB - BACKGROUND: Definitive radiotherapy has been suggested as a treatment alternative to surgical resection in Merkel cell carcinoma (MCC). METHODS: Patients with MCC were identified from the National Cancer Database. Propensity score matching accounting for age, Charlson-Deyo score, grade, and AJCC stage was used to match patients in 1:1 fashion by primary treatment (surgery vs. radiotherapy). RESULTS: There were 1227 patients in each group. Median overall survival was improved with surgical resection in stage I/II (76 vs. 25 months, p < 0.001) and stage III disease (30 vs. 15 months, p < 0.001). For stage I/II, 5- and 8-year overall survival were 61% and 42%, in the surgical resection and 32% and 25% in the definitive radiotherapy groups, respectively. For stage III, 5- and 8-year overall survival were 34% and 21% for surgical resection and 19% and 16% in the radiotherapy group, respectively. CONCLUSIONS: Surgical resection for MCC improves median survival compared to definitive radiotherapy while marginally improving long-term survival. PMID- 29157892 TI - Is it safe to discharge geriatric trauma patients with anemia? AB - INTRODUCTION: The consequences of discharging anemic geriatric trauma patients are not well studied. We hypothesize that anemia at discharge is associated with adverse outcomes. METHODS: A 1-year retrospective review of patients >=65 years was performed. Hemoglobin levels at admission (HbA), discharge (HbD) and the lowest inpatient level (HbL) were recorded. Severity of anemia was categorized as mild (Hb >= 10.0 g/dl), moderate (Hb < 10.0 and >= 8.5 g/dl) and severe (Hb < 8.5 g/dl). The study endpoint was death or unplanned readmission 60 days following discharge. Univariate and multivariable analysis were used to determine if anemia predicted the outcome. A p value of 0.05 was considered significant. RESULTS: 550 patients were included. Moderate and severe anemia for HbA each predicted the study endpoint. Both HbD and HbL were highly correlated with HbA but did not predict the study endpoint. CONCLUSION: The degree of discharge anemia was not predictive of 60-day mortality or unplanned admissions in geriatric trauma patients. PMID- 29157893 TI - A surgical residency preparatory course for senior medical students leads to earlier independence in ACGME competencies. AB - BACKGROUND: It is unknown whether surgery residency preparatory courses lead to earlier independent practice. METHODS: A four-week surgical residency preparatory course was offered to graduating medical students. Upon entering residency, participants reported supervised and unsupervised performance of patient management and procedural competencies. Those who participated in the course (Group A) were compared with graduates from our institution who did not participate but entered surgery residency (Group B) and with residents from other medical schools in the same program as Group A (Group C). Time to independence was observed. RESULTS: Group A achieved independence earlier than Group B in 15/18 (83.3%), earlier than Group C in 14/18 (77.8%) and earlier than both in 12/16 (75%) competencies. Independence occurred 43.6 days earlier than Group B (range 6-112 days) and 49 days earlier than Group C (range 11.5-165 days). CONCLUSION: A surgical residency preparatory course led to earlier independent performance of the ACGME recommended patient management and procedural competencies compared to students from our institution and others who did not participate in such a course. PMID- 29157894 TI - Selective inhibition reveals cyclin-dependent kinase 2 as another kinase that phosphorylates the androgen receptor at serine 81. AB - Several studies have revealed that cyclin-dependent kinases (CDK) can mediate phosphorylation of steroid receptors at multiple sites, including serine 81 of the androgen receptor (AR). Phosphorylation of S81 is required for AR nuclear translocation, an association with chromatin and also regulates endogenous AR regulated transcription in response to hormones. Up to date, S81-phosphorylation has been studied using different CDK inhibitors. Nevertheless, most inhibitors are non-selective or have unknown selectivity. We investigated the selectivity of commercially available CDK inhibitors and identified compounds that will be suitable for further studies to identify the CDKs responsible for S81-AR phosphorylation. We confirmed the positive impact of CDK1 and CDK9 on phosphorylation of S81-AR and its transcriptional activity. Although CDK1 mediated phosphorylation was previously shown to occur during mitosis, our experiments did not confirm this finding. By using chemical and genetic inhibition techniques, we identified that CDK2 contributes to S81-AR phosphorylation and transactivation while CDK4 was not shown to be involved in this process. PMID- 29157896 TI - Facing a cancer diagnosis: empowering parents to speak with adolescents about sperm banking. PMID- 29157895 TI - A novel homozygous mutation in the FSHR gene is causative for primary ovarian insufficiency. AB - OBJECTIVE: To identify the potential FSHR mutation in a Chinese woman with primary ovarian insufficiency (POI). DESIGN: Genetic and functional studies. SETTING: University-based reproductive medicine center. PATIENT(S): A POI patient, her family members, and another 192 control women with regular menstruation. INTERVENTION(S): Ovarian biopsy was performed in the patient. Sanger sequencing was carried out for the patient, her sister, and parents. The novel variant identified was further confirmed with the use of control subjects. MAIN OUTCOME MEASURE(S): Sanger sequencing and genotype analysis to identify the potential variant of the FSHR gene; hematoxylin and eosin staining of the ovarian section to observe the follicular development; Western blotting and immunofluorescence to detect FSH receptor (FSHR) expression; and cyclic adenosine monophosphate (cAMP) assay to monitor FSH-induced signaling. RESULT(S): Histologic examination of the ovaries in the patient revealed follicular development up to the early antral stage. Mutational screening and genotype analysis of the FSHR gene identified a novel homozygous mutation c.175C>T (p.R59X) in exon 2, which was inherited in the autosomal recessive mode from her heterozygous parents but was absent in her sister and the 192 control women. Functional studies demonstrated that in vitro the nonsense mutation caused the loss of full-length FSHR expression and that p.R59X mutant showed no response to FSH stimulation in the cAMP level. CONCLUSION(S): The mutation p.R59X in FSHR is causative for POI by means of arresting folliculogenesis. PMID- 29157897 TI - Arteriopathy after transarterial chemo-lipiodolization for hepatocellular carcinoma. AB - OBJECTIVES: The purpose of this study was to investigate the incidence of and the risk factors for arteriopathy in hepatic arteries after transarterial chemo lipiodolization in patients with hepatocellular carcinoma and the subsequent treatment strategy changes due to arteriopathy. PATIENTS AND METHODS: A total of 365 arteries in 167 patients (126 men and 41 women; mean age, 60.4+/-15.0 [SD] years [range: 18-87 years]) were evaluated for the development of arteriopathy after chemo-lipiodolization with epirubicin- or doxorubicin-Lipiodol(r) emulsion. The development of arteriopathy after chemo-lipiodolization was assessed on arteriograms performed during subsequent transarterial treatments. The treatment strategy changes due to arteriopathy, including change in the chemo lipiodolization method and the application of alternative therapies was also investigated. Univariate and multivariate binary logistic regression models were used to identify risk factors for arteriopathy and subsequent treatment strategy change. RESULTS: One hundred two (27.9%) arteriopathies were detected in 62/167 (37.1%) patients (45 men, 17 women) with a mean age of 63.3+/-7.1 [SD] years (age range, 50-86 years). The incidence of arteriopathy was highly patient dependent, demonstrating significant correlation in a fully-adjusted multivariate regression model (P<0.0001). Multivariate-adjusted regression analysis with adjustment for the patient effect showed a statistically significant association of super selective chemo-lipiodolization (P=0.003) with the incidence of arteriopathy. Thirty of the 102 arteriopathies (29.4%) caused a change in treatment strategy. No factors were found to be significantly associated with the treatment strategy change. CONCLUSION: The incidence of arteriopathy after chemo-lipiodolization is 27.9%. Among them, 29.4% result in a change in treatment strategy. PMID- 29157898 TI - Radiologic and clinical evaluation of a bioabsorbable collagen implant to treat partial-thickness tears: a prospective multicenter study. AB - BACKGROUND: Treatment of partial-thickness cuff tears remains controversial. Although conservative therapy may treat symptoms, these defects do not spontaneously heal and conversion to a full-thickness lesion with subsequent repair may alter the tendon footprint. The ability to induce new tissue formation and limit tear progression in intermediate- and high-grade partial-thickness tears without surgical repair may represent a significant advancement in the treatment paradigm for these lesions. METHODS: We prospectively enrolled 33 patients with chronic, degenerative, intermediate-grade (n = 12) or high-grade (n = 21) partial-thickness tears (11 articular, 10 bursal, 4 intrasubstance, and 8 hybrid) of the supraspinatus tendon in a multicenter study. Following arthroscopic subacromial decompression without repair, a bioinductive implant was attached over the bursal surface of the tendon. Clinical outcomes were assessed using American Shoulder and Elbow Surgeons and Constant-Murley scores preoperatively and at 3 and 12 months postoperatively. Magnetic resonance imaging was performed to assess postoperative tendon healing and thickness at the original tear site. RESULTS: At 1-year follow-up, clinical scores improved significantly (P <.0001) and the mean tendon thickness increased by 2.0 mm (P <.0001). Magnetic resonance imaging evidence of complete healing was found in 8 patients and a considerable reduction in defect size was shown in 23, whereas 1 lesion remained stable. In 1 noncompliant patient with a high-grade articular lesion, progression to a full-thickness tear occurred while shoveling snow 1 month after surgery. No serious adverse events related to the implant were reported. CONCLUSIONS: Arthroscopic implantation of a bioinductive collagen scaffold is a safe and effective treatment for intermediate- to high-grade partial-thickness rotator cuff tears of the supraspinatus tendon. PMID- 29157899 TI - Epidemiology of diabetic foot infections in a reference tertiary hospital in India. AB - INTRODUCTION: The present study attempts to examine the microbial profile and antibiotic susceptibility of diabetic foot infections in the intensive care unit of a tertiary referral centre for diabetic foot. As part of the study, we also attempted to find the prevalence of blaNDM-like gene among carbapenem-resistant gram negative infections. METHODOLOGY: A prospective study of 261 patients with diabetic foot infections was performed during the period between January 2014 and June 2014. RESULTS: A total of 289 isolates were obtained from 178 tissue samples from 261 patients, 156 (59.7%) males and 105 (40.2%) females, with a mean age of 58 years (-15 years), having diabetic foot infection. No growth was seen in thirty eight (17.6%) tissue samples. Out of the total samples, 44.3% were monomicrobial and 55.7% were polymicrobial. Gram negative pathogens were predominant (58.5%). Seven of the total isolates were fungal; 0.7% showed pure fungal growth and 1.7% were mixed, grown along with some bacteria. The most frequently isolated bacteria were Staphylococcus aureus (26.9%), followed by Pseudomonas aeruginosa (20.9%). Of the 58.5% gram negative pathogens, 16.5% were Enterobacteriaceae resistant to carbapenems. Among these isolates, 4 (25%) were positive for blaNDM-like gene. Among the rest, 18.6% were carbapenem-resistant Pseudomonas, among which 4 (36.3%) were blaNDM. Among the Staphylococci, 23.7% were methicillin-resistant Staphylococcus aureus. CONCLUSIONS: Our results support the recent view that gram negative organisms, depending on the geographical location, may be predominant in DFIs. There is an increase in multidrug-resistant pathogens, especially carbapenem resistance and this is creeping rapidly. We need to be more judicious while using empiric antibiotics. PMID- 29157900 TI - A practical molecular identification of nonfermenting Gram-negative bacteria from cystic fibrosis. AB - Identification of nonfermenting Gram-negative bacteria (NFGNB) of cystic fibrosis patients is hard and misidentification could affect clinical outcome. This study aimed to propose a scheme using polymerase chain reaction to identify NFGNB. This scheme leads to reliable identification within 3 days in an economically viable manner when compared to other methods. PMID- 29157901 TI - Inducible cellulase production from an organic solvent tolerant Bacillus sp. SV1 and evolutionary divergence of endoglucanase in different species of the genus Bacillus. AB - Bacteria are important sources of cellulases with various industrial and biotechnological applications. In view of this, a non-hemolytic bacterial strain, tolerant to various environmental pollutants (heavy metals and organic solvents), showing high cellulolytic index (7.89) was isolated from cattle shed soil and identified as Bacillus sp. SV1 (99.27% pairwise similarity with Bacillus korlensis). Extracellular cellulases showed the presence of endoglucanase, total cellulase and beta-glucosidase activities. Cellulase production was induced in presence of cellulose (3.3 times CMCase, 2.9 times FPase and 2.1 times beta glucosidase), and enhanced (115.1% CMCase) by low-cost corn steep solids. An in silico investigation of endoglucanase (EC 3.2.1.4) protein sequences of three Bacillus spp. as query, revealed their similarities with members of nine bacterial phyla and to Eukaryota (represented by Arthropoda and Nematoda), and also highlighted of a convergent and divergent evolution from other enzymes of different substrate [(1,3)-linked beta-d-glucans, xylan and chitosan] specificities. Characteristic conserved signature indels were observed among members of Actinobacteria (7 aa insert) and Firmicutes (9 aa insert) that served as a potential tool in support of their relatedness in phylogenetic trees. PMID- 29157902 TI - Interaction of catecholamine precursor l-Dopa with lysozyme: A biophysical insight. AB - The current study comprises of an inclusive biophysical study, enlightening the binding of L-3, 4-dihydroxyphenylalanine (l-Dopa) with human lysozyme (HL) and hen egg white lysozyme (HEWL). Spectroscopic and molecular docking tools have been utilized to study the interaction of l-Dopa with both HL and HEWL. Spectrofluorimetric measurements exhibited that l-Dopa quenched the HL and HEWL intrinsic fluorescence. A binding constant (Kb) of ~104M-1 for both HL and HEWL was obtained, asserting a significant binding. Negative value of DeltaG affirmed that the reaction between proteins and l-Dopa was spontaneous. Far-UV CD spectra revealed a boost to the proteins helical content in the presence of l-Dopa. Furthermore, DLS measurements displayed the decrease in hydrodynamic radii (Rh) of HL and HEWL in the presence of l-Dopa. Molecular docking studies established that l-Dopa formed complexes with both the proteins through hydrogen bonding and hydrophobic interaction. The present study characterizing the l-Dopa interaction with lysozyme could be noteworthy in realizing both pharmaco-dynamics and/or kinetics of drugs used in various diseases. PMID- 29157903 TI - Enzymatic synthesis of quaternary ammonium chitosan-silk fibroin peptide copolymer and its characterization. AB - Free radicals are closely related to the occurrence and development of aging, cancer and inflammation. The aim of the present study was to improve the antioxidant effects of quaternary ammonium chitosan (QCS) by modified with silk fibroin peptide (SFP). The modification had been confirmed by FT-IR and 1H NMR spectroscopy. Degree of substitution (DS) of QCS-SFP could be controlled by adjusting the reaction conditions. In this paper, the results of moisture absorption and retention test showed that QCS-SFP had excellent moisture absorption and retention properties. In vitro antioxidant activity assays demonstrated that, with the DS and concentration increasing of QCS-SFP, the scavenging activity of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, hydroxyl radical and hydrogen peroxide (H2O2) increased. Furthermore, the methyl thiazolyl tetrazolium assay (MTT) was applied to evaluate the biocompatibility of QCS-SFP, and the result indicated that QCS-SFP with the DS of 0.32 displayed pronounced cell viability at 100ppm. These results suggested that QCS-SFP would appear to be a promising candidate for wound dressing application. PMID- 29157904 TI - Anti-fatigue activity of an arabinan-rich pectin from acerola (Malpighia emarginata). AB - A fraction composed of an arabinan-rich pectin was extracted from acerola fruit (Malpighia emarginata) and named ACWS. This fraction presented 93% of total carbohydrate, relative molecular weight of 7.5*104g/mol, galacturonic acid, arabinose, galactose, xylose and rhamnose in 52.1:32.4:7.2:4.8:3.5 molar ratio and had its structure confirmed by NMR analysis. The anti-fatigue activity of ACWS was evaluated using the weight load swim test on trained mice. ACWS was orally administered at doses of 50mg/kg, 100mg/kg and 200mg/kg for 28days. Plasma biochemical parameters, respiration of permeabilized skeletal muscle fibers, and GSH levels and lipoperoxidation in the brain (pre-frontal cortex, hippocampus, striatum and hypothalamus) were determined. ACWS could lengthen the swimming time, increase the plasma levels of glucose, triglycerides, lactate, and the GSH levels in the hippocampus at all tested doses. The mitochondrial respiratory capacity of the skeletal muscle was increased at middle and high ACWS doses. This study provides strong evidence that M. emarginata pectic polysaccharide supplementation has anti-fatigue activity, can modify the kinetics of energy substrates (carbohydrate and fat) mobilization and the respiratory capacity of the skeletal muscle, as well the antioxidant status in the hippocampus of ACWS treated animals. PMID- 29157905 TI - A new collagenase enzyme of the marine sponge pathogen Pseudoalteromonas agarivorans NW4327 is uniquely linked with a TonB dependent receptor. AB - The primary pathogen of the Great Barrier Reef sponge Rhopaloeides odorabile, recently identified as a novel strain (NW4327) of Pseudoalteromonas agarivorans, produced collagenase which degraded R. odorabile skeletal fibers. We now report the collagenase of P. agarivorans as a metalloprotease which required Ca2+ and Zn2+ as cofactors. The collagenase was a TonB dependent receptor (TBDR) having a carboxypeptidase regulatory like domain (CRLD) in the N-terminal along with an outer membrane (OM) channel superfamily domain. The genes for TBDR sub-components and collagenase formed one unified entity in the genome of P. agarivorans NW4327. This association of a collagenase with a TBDR distinguished it from all known functional collagenases till date and for the first time, established the enzymatic capability of TBDRs. Predicted TBDR model demonstrated only 15% identity with ferripyoverdin receptor and the CRLD displayed merely 24% identity with carboxypeptidase catalytic chain. Presence of signal peptide, lack of transmembrane helices, absence of N-terminal in the cytoplasmic side, extracellular localization and recovery from the culture supernatant implicated that the TBDR was secreted. Stronger binding of the collagenase with marine sponge type IV collagen than type I collagen, revealed through molecular docking, indicated higher specificity of the enzyme towards type IV collagen. PMID- 29157906 TI - Novel decellularized liver matrix-alginate hybrid gel beads for the 3D culture of hepatocellular carcinoma cells. AB - Developing reliable three-dimensional (3D) cell culture systems that can mimic native tumor microenvironments is necessary for investigating the mechanism of hepatocellular carcinoma (HCC) metastasis and screen therapeutic drugs. In the present study, we developed decellularized liver matrix-alginate (DLM-ALG) hybrid gel beads. DLM powder was prepared by optimized decellularization methods and liquid nitrogen grinding. DLM-ALG beads were generated by dropping alginate solution containing DLM powder into a gelling bath. DLM powder concentration in alginate solution was <=1% (w/v) and had no effect on the sphericity and mechanical stability of the beads. In addition, HCCLM3 cells cultured in 1% (w/v) DLM-ALG beads presented gradually enhanced viability during in vitro culture. The protein expression of urokinase plasminogen activator system and activity of matrix metalloproteinases (MMPs) of HCCLM3 cells, including MMP2 and MMP9, were more significantly promoted in DLM-ALG beads compared with that in conventional ALG beads without DLM powder. Moreover, the dose-dependent increase in HCCLM3 cell MMP activities was observed along with the DLM powder concentration in 0.5% and 1% DLM-ALG groups. Therefore, DLM-ALG beads might serve as a novel 3D culture system for exploring the mechanisms of HCC metastasis and screening therapeutic drugs. PMID- 29157907 TI - Expression and purification of plant fructan exohydrolases and their potential applications in fructose production. AB - Inulinases from microorganisms have been extensively studied for their role in the production of fructose from fructan. Fructan can also be hydrolyzed by plant fructan exohydrolases (FEHs), but these enzymes have not been used to produce fructose commercially. Two Ht1-FEHs (Ht1-FEH I and Ht1-FEH II) were recently characterized in Jerusalem artichoke. In this study, we cloned the third member of the Ht1-FEH family in Jerusalem artichoke (i.e., Ht1-FEH III). When heterologously expressed in Pichia pastoris X-33, Ht1-FEH III not only demonstrated hydrolysis activity towards beta (2, 1)-linked fructans and beta (2, 6)-linked levan, but also towards sucrose. To explore the potential industrial applications, we heterologously expressed and purified six plant 1-FEHs from two typical fructan plants (i.e., chicory and Jerusalem artichoke) and showed that chicory Ci1-FEH IIa had the highest hydrolysis capacity to fructan in vitro. Furthermore, we immobilized Ci1-FEH IIa on resin and optimized the immobilization conditions. We found that inulin-type fructan or the tuber extract from Jerusalem artichoke could be rapidly degraded into fructose and sucrose by immobilized Ci1 FEH IIa. The capacity of Ci1-FEH IIa to release fructose from fructans was comparable to that of some inulinases from microorganisms. Thus, plant FEHs have potential applications in fructose production. PMID- 29157908 TI - Recent trends on gellan gum blends with natural and synthetic polymers: A review. AB - Gellan gum (GG), a linear negatively charged exopolysaccharide,is biodegradable and non-toxic in nature. It produces hard and translucent gel in the presence of metallic ions which is stable at low pH. However, GG has poor mechanical strength, poor stability in physiological conditions, high gelling temperature and small temperature window.Therefore,it is blended with different polymers such as agar, chitosan, cellulose, sodium alginate, starch, pectin, polyanaline, pullulan, polyvinyl chloride, and xanthan gum. In this article, a comprehensive overview of combination of GG with natural and synthetic polymers/compounds and their applications in biomedical field involving drug delivery system, insulin delivery, wound healing and gene therapy, is presented. It also describes the utilization of GG based materials in food and petroleum industry. All the technical scientific issues have been addressed; highlighting the recent advancement. PMID- 29157909 TI - Effects of sulfated fucan from the sea cucumber Stichopus japonicus on natural killer cell activation and cytotoxicity. AB - The aqueous crude sulfated fucan (SF) from Stichopus japonicus was extracted and fractionated using anion-exchange chromatography to obtain four fractions (F1, F2, F3 and F4) and to investigate their NK cell activation and cytotoxicity. The most potent NK cell cytotoxicity (45% at 250MUg/mL) against HeLa cells was observed by F1 treatment, on the other hand, F3 and F4 treatment exhibited strong NK cell cytotoxicity (31-34% at 250MUg/mL) against HepG2 and HT-29 cells. The SF treatment enhanced the activation of NK cells through the mRNA expression of IFN gamma, an activating receptor (NKp30), lysing proteins (perforin and granzyme-B) as well as a death ligand (FasL). However, the treatment of the SF derivatives, deproteinated-F1 and desulfated-F3 (DP-F1 and DS-F3), markedly lowered the levels of NK cell cytotoxicity and mRNA expression of the activating factors, suggesting that the protein and sulfate were pivotal for the interaction between the SF and NK cells. The antibody neutralization test revealed that complement receptor-3 (CR3) may be a critical receptor involved in NK cell activation by the SF. PMID- 29157910 TI - Vigilin interacts with CTCF and is involved in the maintenance of imprinting of IGF2 through a novel RNA-mediated mechanism. AB - Accumulating evidence has revealed the imprinting of insulin-like growth factor-2 gene (IGF2) is maintained by binding of CCCTC binding factor (CTCF) to the unmethylated imprinting control region (ICR) between IGF2 and H19 genes. We have previously reported that high-density lipoprotein binding protein (HDLBP/vigilin), a multiKH-domain protein, interacts with CTCF and coexists with it at several CTCF-binding sites on the ICR to regulate general gene expression of IGF2. However, the impact of the interaction on imprinting of IGF2 remains unclear. Here, we demonstrate that cooperation of vigilin and CTCF protects IGF2 from losing of imprinting. Pull-down experiments show that KH1-7 domains of vigilin interact with zinc-finger domains of CTCF. We also display that some RNAs participate in the vigilin-CTCF interaction, one of which is H19 long noncoding RNA (lncRNA). Furthermore, we confirm that H19 lncRNA-knockdown alters the imprinting of IGF2. These data suggest that vigilin interacts with CTCF, mediated by H19 lncRNA, to keep the imprinting of IGF2. PMID- 29157911 TI - Enhanced activity and stability of industrial lipases immobilized onto spherelike bacterial cellulose. AB - This study focused on improving activity and stability of industrial lipases by means of enzymatic immobilization onto spherelike bacterial cellulose (SBC) newly synthesized by a particular bacterial strain (Gluconacetobacter xylinus, JCM 9730). The results revealed that immobilizing lipases onto aldehyde-modified SBC with a size of 6.10+/-0.50mm could lead to two optimal hydrolytic activities of lipases under both acidic (pH 5) and alkaline conditions (pH 8), which was superior to free lipases that only exhibited an alkaline activity at pH 9. In addition, immobilizing lipases onto SBC could also achieve an improved active temperature below 30 degrees C for lipases, which would help to reduce the energy consumption in the industrial production. Overall, this novel biomaterial has great potential as a green carrier for the immobilization of industrial lipases to enhance the recycling hydrolytic capability of oils and fats in various industrial divisions. PMID- 29157912 TI - New paradigm in ankyrin repeats: Beyond protein-protein interaction module. AB - Classically, ankyrin repeat (ANK) proteins are built from tandems of two or more repeats and form curved solenoid structures that are associated with protein protein interactions. These are short, widespread structural motif of around 33 amino acids repeats in tandem, having a canonical helix-loop-helix fold, found individually or in combination with other domains. The multiplicity of structural pattern enables it to form assemblies of diverse sizes, required for their abilities to confer multiple binding and structural roles of proteins. Three dimensional structures of these repeats determined to date reveal a degree of structural variability that translates into the considerable functional versatility of this protein superfamily. Recent work on the ANK has proposed novel structural information, especially protein-lipid, protein-sugar and protein protein interaction. Self-assembly of these repeats was also shown to prevent the associated protein in forming filaments. In this review, we summarize the latest findings and how the new structural information has increased our understanding of the structural determinants of ANK proteins. We discussed latest findings on how these proteins participate in various interactions to diversify the ANK roles in numerous biological processes, and explored the emerging and evolving field of designer ankyrins and its framework for protein engineering emphasizing on biotechnological applications. PMID- 29157913 TI - Evaluation of optimum conditions for Achyranthes bidentata polysaccharides encapsulated in cubosomes and immunological activity in vitro. AB - Cubosomes, as biocompatible carriers in drug delivery systems, consist of curved bicontinuous lipid bilayers. With a honeycombed structure divided into two internal aqueous channels, cubosomes could be used for many bioactive ingredients. Achyranthes bidentata polysaccharides (ABPs) are isolated from the roots of Achyranthes bidentata, used in Chinese herbal medicine, and present a noticeable effect as an immunomodulator. This study investigates the optimal preparation of combined cubosome-ABP (Cub-ABP) nanoparticles using response surface methodology and explores their characteristics and stability. The encapsulation efficiency of optimized Cub-ABPs was 72.59%. In-vitro stability studies demonstrated the stability of Cub-ABPs and cubosome nanoparticles without ABPs; both were stable for up to 25days. Safe concentrations of Cub-ABPs and cubosome nanoparticles without ABPs are 104.06MUg/mL and 208.13MUg/mL with comparatively low cytotoxicity against lymphocytes. Moreover, the feasible immunomodulatory effects of Cub-ABPs were determined by evaluating their proliferation and change of CD4+/CD8+ ratio on splenic lymphocytes in vitro. Proliferation and flow cytometry studies revealed that, compared with free ABPs and blank cubosomes, Cub-ABPs proved more effective in promoting lymphocyte proliferation and in triggering the transformation of T-lymphocytes into Th cells. PMID- 29157914 TI - Population sensitivities of animals to chronic ionizing radiation-model predictions from mice to elephant. AB - Model predictions of population response to chronic ionizing radiation (endpoint 'morbidity') were made for 11 species of warm-blooded animals, differing in body mass and lifespan - from mice to elephant. Predictions were made also for 3 bird species (duck, pigeon, and house sparrow). Calculations were based on analytical solutions of the mathematical model, simulating a population response to low-LET ionizing radiation in an ecosystem with a limiting resource (Sazykina, Kryshev, 2016). Model parameters for different species were taken from biological and radioecological databases; allometric relationships were employed for estimating some parameter values. As a threshold of decreased health status in exposed populations ('health threshold'), a 10% reduction in self-repairing capacity of organisms was suggested, associated with a decline in ability to sustain environmental stresses. Results of the modeling demonstrate a general increase of population vulnerability to ionizing radiation in animal species of larger size and longevity. Populations of small widespread species (mice, house sparrow; body mass 20-50 g), which are characterized by intensive metabolism and short lifespan, have calculated 'health thresholds' at dose rates about 6.5-7.5 mGy day 1. Widespread animals with body mass 200-500 g (rat, common pigeon) - demonstrate 'health threshold' values at 4-5 mGy day-1. For populations of animals with body mass 2-5 kg (rabbit, fox, raccoon), the indicators of 10% health decrease are in the range 2-3.4 mGy day-1. For animals with body mass 40-100 kg (wolf, sheep, wild boar), thresholds are within 0.5-0.8 mGy day-1; for herbivorous animals with body mass 200-300 kg (deer, horse) - 0.5-0.6 mGy day-1. The lowest health threshold was estimated for elephant (body mass around 5000 kg) - 0.1 mGy day-1. According to the model results, the differences in population sensitivities of warm-blooded animal species to ionizing radiation are generally depended on the metabolic rate and longevity of organisms, also on individual radiosensitivity of biological tissues. The results of 'health threshold' calculations are formulated as a graded scale of wildlife sensitivities to chronic radiation stress, ranging from potentially vulnerable to more resistant species. Further studies are needed to expand the scale of population sensitivities to radiation, including other groups of wildlife - cold-blooded species, invertebrates, and plants. PMID- 29157915 TI - A call to standardize our approach to fertility-sparing surgery in patients with gynecologic cancers. PMID- 29157916 TI - The effect of bariatric surgery on direct-acting oral anticoagulant drug levels. AB - OBJECTIVE: To determine direct-acting oral anticoagulant (DOAC) blood levels in post-bariatric surgery (BS) patients treated with long-term anticoagulation therapy. METHODS: We identified from medical records patients who underwent BS during 2005-2016 and who were treated with DOACs. We offered testing DOAC blood levels to these patients and to age, sex, body mass index, and serum creatinine matched individuals treated by DOACs who did not undergo BS. RESULTS: Overall, 36 individuals were enrolled, 18 post-BS patients and 18 control subjects. Of the post-BS patients, 12 underwent laparoscopic sleeve gastrectomy, 4 laparoscopic adjustable gastric banding and 2 laparoscopic Roux-en-Y gastric bypass surgery. Median time lapsed from surgery until study inclusion was 4.9years. Five post-BS patients had peak drug levels below expected levels compared to none of the control subjects (P=0.05). For patients who used apixaban (n=9) and dabigatran (n=2), peak drug levels were within the expected range. In contrast, for the 7 patients who used rivaroxaban, levels were below the expected range in 5, including all four who underwent sleeve gastrectomy and one following adjustable gastric banding. Peak rivaroxaban levels were significantly lower in the post-BS than the control group (P=0.02). CONCLUSION: This preliminary study suggests that all DOACs, particularly rivaroxaban, be cautiously used following BS, if used at all. Given that vitamin-K antagonists can be easily monitored, they may be a better choice, until more data on DOAC use in this patient population are available. PMID- 29157919 TI - PML nuclear bodies, membrane-less domains acting as ROS sensors? AB - PML Nuclear bodies (PML NBs) are spherical domains associated with a broad range of activities upon stress responses such as apoptosis, senescence DNA repair, epigenetic control, as well as control of oncogenesis. These bodies are considered as privileged sites for post-translational modifications, where sumoylation plays a key role. Here we summarize recent in vitro and in vivo findings on the link between PML NBs and ROS, in particular PML contributions to oxidative stress response. We discuss how it may regulate switch from cell protection against stress to cell arrest/cell death. PMID- 29157918 TI - Purpura Fulminans: Mechanism and Management of Dysregulated Hemostasis. AB - Purpura fulminans (PF) is a highly thrombotic subtype of disseminated intravascular coagulation that can accompany severe bacterial, and more rarely, viral infections. PF is associated with an extremely high mortality rate, and patients often die of overwhelming multisystemic thrombosis rather than septic shock. Survivors typically experience amputation of involved extremities and significant scarring in affected areas. Despite the devastating clinical course associated with this hemostatic complication of infection, the mechanism of PF remains poorly understood. Severe acquired deficiency of protein C and dysfunction of the protein C-thrombomodulin pathway as well as other systems that exert a negative regulatory effect on coagulation have been implicated. Management of PF involves treatment of the underlying infection, aggressive anticoagulation, and robust transfusion support aimed at correcting acquired deficiencies in natural anticoagulant proteins. In this review, we address the diagnosis and management of PF with a focus on a rational approach to this condition informed by the available data. Proposed mechanisms underlying the dysregulation of coagulation seen in PF are also covered, and implications for therapy are discussed. PMID- 29157917 TI - The mediator complex in genomic and non-genomic signaling in cancer. AB - Mediator is a conserved, multi-subunit macromolecular machine divided structurally into head, middle, and tail modules, along with a transiently associating kinase module. Mediator functions as an integrator of transcriptional regulatory activity by interacting with DNA-bound transcription factors and with RNA polymerase II (Pol II) to both activate and repress gene expression. Mediator has been shown to affect multiple steps in transcription, including chromatin looping between enhancers and promoters, pre-initiation complex formation, transcriptional elongation, and mRNA splicing. Individual Mediator subunits participate in regulation of gene expression by the estrogen and androgen receptors and are altered in a number of endocrine cancers, including breast and prostate cancer. In addition to its role in genomic signaling, MED12 has been implicated in non-genomic signaling by interacting with and activating TGF-beta receptor 2 in the cytoplasm. Recent structural studies have revealed extensive inter-domain interactions and complex architecture of the Mediator-Pol II complex, suggesting that Mediator is capable of reorganizing its conformation and composition to fit cellular needs. We propose that alterations in Mediator subunit expression that occur in various cancers could impact the organization and function of Mediator, resulting in changes in gene expression that promote malignancy. A better understanding of the role of Mediator in cancer could reveal new approaches to the diagnosis and treatment of Mediator-dependent endocrine cancers, especially in settings of therapy resistance. PMID- 29157920 TI - New genetic tools in the diagnosis of growth defects. AB - Growth is a complex biological process governed by thousands of genes. Genetic defects in a wide array of genes can cause severe growth disorders. Genomic technologies including chromosomal microarrays and whole exome sequencing have revolutionized our ability to diagnose growth disorders. In this brief review, we will discuss each of these technologies and how they have been applied in the field of growth disorders. PMID- 29157921 TI - Pooling of bronchoalveolar lavage in children with cystic fibrosis does not adversely affect the microbiological yield or sensitivity in detecting pulmonary inflammation. AB - BACKGROUND: Bronchoalveolar lavage (BAL) is a potentially useful outcome measure for clinical trials in children with CF but its use is limited by variations in approach internationally. We sought to determine if pooling adversely affected the diagnostic properties of BAL. METHODS: Children undergoing bronchoscopy for clinical reasons were included. A multi-step study protocol ensured BAL was collected and analysed both separately and as a pooled fluid. RESULTS: Eighty five children (53 CF, 32 control) were recruited. There was a high level of concordance between pooled and non-pooled samples in terms of organism identification (76%). There was good agreement (Bland Altman) between the two methods in terms of detection of inflammation independent of centre, microbiological concordance or disease status. Bi-directional variability in IL-8 levels between pooled and non-pooled samples was seen. Free neutrophil elastase (NE) was detected in 4 cases in pooled lavage when absent in non-pooled lavage. Levels of interleukin-8 (IL-8) were similar between the two groups with pooled samples showing a greater spread of values. CONCLUSIONS: Pooling of BAL in children does not negatively impact on either the detection of pulmonary infection or inflammation or the observed relationship between infection and inflammation. Intra-patient variability in BAL IL-8 levels suggests regional differences in inflammation. PMID- 29157922 TI - Development and electronic validation of the revised Cystic Fibrosis Questionnaire (CFQ-R Teen/Adult): New tool for monitoring psychosocial health in CF. AB - BACKGROUND: The Cystic Fibrosis Questionnaire-Revised (CFQ-R+14) is a disease specific, health-related quality of life instrument for cystic fibrosis (CF) patients >=14years. We have developed a Spanish electronic version of the CFQ-R (e-CFQ-R+14 Spain). Our aim was to compare the paper and electronic versions and to validate the electronic version. METHODS: Fifty CF patients completed the study. All answered the paper and electronic versions on day 1 and repeated the e CFQR version 15days later. RESULTS: Concordance between the electronic and paper copy versions was high, with correlations above 0.9 in all domains. Test-retest reliability of the e-CFQ-R results was strong, with coefficients ranging from 0.8 to 0.9. CONCLUSIONS: The e-CFQ-R version is reliable and valid and can replace the paper copy, thus simplifying the assessment of quality of life. It also provides immediate results with no errors in scoring. It is a useful new tool in CF care. PMID- 29157923 TI - Outcomes of laparoscopic and open surgery in children with and without congenital heart disease. AB - BACKGROUND: Children with congenital heart disease (CHD) often require noncardiac surgery. We compared outcomes following open and laparoscopic intraabdominal surgery among children with and without CHD. METHODS: We performed a retrospective cohort study using the 2013-2015 National Surgical Quality Improvement Project-Pediatrics. We matched 45,012 children <18years old who underwent laparoscopic surgery to 45,012 children who underwent open surgery. We determined the associations between laparoscopic (versus open) surgery and 30-day mortality, in-hospital mortality, 30-day morbidity, and postoperative length-of stay. RESULTS: Among children with minor CHD, laparoscopic surgery was associated with lower 30-day mortality (Odds Ratio [OR] 0.34 [95% Confidence Interval 0.15 0.79]), inhospital mortality (OR 0.42 [0.22-0.81]) and 30-day morbidity (OR 0.61 [0.50-0.73]). As CHD severity increased, this benefit of laparoscopic surgery decreased for 30-day morbidity (ptrend=0.01) and in-hospital mortality (ptrend=0.05), but not for 30-day mortality (ptrend=0.27). Length-of-stay was shorter for laparoscopic approaches for children at cost of higher readmissions. On subgroup analysis, laparoscopy was associated with lower odds of postoperative blood transfusion in all children. CONCLUSIONS: Intraabdominal laparoscopic surgery compared to open surgery is associated with decreased morbidity in patients with no CHD and lower morbidity and mortality in patients with minor CHD, but not in those with more severe CHD. LEVEL-OF-EVIDENCE: Level III: Treatment Study. PMID- 29157924 TI - Instrumental variable methods for a binary outcome were used to informatively address noncompliance in a randomized trial in surgery. AB - OBJECTIVES: Randomization can be used as an instrumental variable (IV) to account for unmeasured confounding when seeking to assess the impact of noncompliance with treatment allocation in a randomized trial. We present and compare different methods to calculate the treatment effect on a binary outcome as a rate ratio in a randomized surgical trial. STUDY DESIGN AND SETTING: The effectiveness of peeling versus not peeling the internal limiting membrane of the retina as part of the surgery for a full thickness macular hole. We compared the IV-based estimates (nonparametric causal bound and two-stage residual inclusion approach [2SRI]) with standard treatment effect measures (intention to treat, per protocol and treatment received [TR]). Compliance was defined in two ways (initial and up to the time point of interest). Poisson regression was used for the model-based approaches with robust standard errors to calculate the risk ratio (RR) with 95% confidence intervals. RESULTS: Results were similar for 1-month macular hole status across methods. For 3- and 6-month macular hole status, nonparametric causal bounds provided a narrower range of uncertainty than other methods, though still had substantial imprecision. For 3-month macular hole status, the TR estimate was substantially different from the other point estimates. CONCLUSION: Nonparametric causal bound approaches are a useful addition to an IV estimation approach, which tend to have large levels of uncertainty. Methods which allow RRs to be calculated when addressing noncompliance in randomized trials exist and may be superior to standard estimates. Further research is needed to explore the properties of different IV methods in a broad range of randomized controlled trial scenarios. PMID- 29157925 TI - Super-Fontan: Is it possible? PMID- 29157926 TI - The case for a pulmonary valve in neonatal and young infant primary tetralogy of Fallot repair: Does it make a difference? PMID- 29157927 TI - Addressing the imperative to evolve the hospital new product value analysis process. PMID- 29157928 TI - Staged endovascular followed by open repair of mycotic thoracic aneurysms: A bridge to success? PMID- 29157929 TI - Cardiac cysticercosis: A rare cause of myocardial infarction. PMID- 29157930 TI - Beating Clostridium difficile infection-Insights from the Cardiothoracic Surgery Trials Network. PMID- 29157931 TI - Alternatives to hysterectomy: The burden of fibroids and the quality of life. AB - Uterine fibroids are the most common benign tumor in reproductive-aged women. While the majority of women are asymptomatic, those with symptoms may suffer from abnormal uterine bleeding, infertility, pelvic pain or pressure, and urinary dysfunction. Fibroids represent a significant healthcare burden for women and society as a whole. Women with fibroids have compromised overall quality of life and impairment in many specific domains including work productivity, sexuality, self-image, relationships, and social emotional and physical well-being. Many women are reluctant to ask for help and delay seeking treatment. To date, myomectomy remains the gold standard for treating fibroid-related symptoms in reproductive-aged women. However, many less invasive uterine preserving approaches have been developed. Quality of life is improved in many women following treatment for fibroids. This article aims to provide an overview of the substantial impact of fibroids on health-related quality of life. PMID- 29157932 TI - [Find your 1%: prevalence and mortality of a community cohort of people with advanced chronic disease and palliative needs]. AB - OBJECTIVE: To determine the prevalence and profiles of people with advanced chronic diseases in Primary Care and to analyse the elements related to their mortality in order to orient strategies for improvement in this level of care. DESIGN: An observational, analytical and prospective study during 3 years conducted on a cohort of patients with palliative needs. LOCATION: Three Primary Care teams of Osona (Catalonia). PARTICIPANTS: A total of 251 people identified as advanced patients using a systematic population-based strategy that included the NECPAL tool. MAIN MEASUREMENTS: Basic demographic and clinical profile (age, gender, type of residence, health stratification level and main disease); date, place, and cause of eventual deaths. RESULTS: 1% of the adult Primary Care population suffer from advanced diseases, of which 56.6% are women, and with a median age of 85 years. Dementia or advanced frailty is observed in 49.3%, and only 13.7% have cancer. Just under one-quarter (24.3%) live in nursing homes. The accumulated mortality at 3 years is 62.1%, with a median survival of 23 months. Factors significantly associated with the likelihood of dying are cancer, female gender, and over-aging. Patients died at their home (47.3%), in an intermediate care hospital (37.2%), or in an acute care hospital (15.5%), depending on certain explanatory factors. CONCLUSIONS: The prevalence and characteristics of advanced community-based disease coincide with that reported in the literature. Potentially, Primary Care is the reference level of care for these patients, especially if it incorporates nursing homes as a usual field of practice. PMID- 29157933 TI - Predictive values in Forensic DNA Phenotyping are not necessarily prevalence dependent. PMID- 29157934 TI - Posttraumatic stress disorder onset and inflammatory and endothelial function biomarkers in women. AB - BACKGROUND: Research has linked posttraumatic stress disorder (PTSD) with higher circulating levels of inflammatory and endothelial function (EF) biomarkers, and effects may be bidirectional. We conducted the first investigation of new-onset PTSD and changes in inflammatory and EF biomarkers. METHODS: Data were from women in the Nurses' Health Study II. Biomarkers obtained at two blood draws, 10-16 years apart, included C-reactive protein (CRP), tumor necrosis factor-alpha receptor-II (TNFRII), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). PTSD was assessed via interview. Analyses compared biomarker levels in women with PTSD that onset between draws (n = 175) to women with no history of trauma (n = 175) and to women with history of trauma at draw 1 and no PTSD at either draw (n = 175). We examined if PTSD onset was associated with biomarker change over time and if pre-PTSD-onset biomarker levels indicated risk of subsequent PTSD using linear mixed models and linear regression, respectively. Biomarkers were log-transformed. RESULTS: Compared to women without trauma, women in the PTSD onset group had larger increases in VCAM 1 over time (b = 0.003, p = .068). They also had higher TNFRII (b = 0.05, p = .049) and ICAM-1 (b = 0.04, p = .060) levels at draw 1 (prior to trauma and PTSD onset). However, pre-PTSD-onset biomarker levels did not predict onset of more severe PTSD. CONCLUSIONS: PTSD onset (vs. no trauma) was associated with increases in one inflammation-related biomarker. Effects may be small and cumulative; longer follow-up periods with larger samples are needed. We did not observe strong support that pre-PTSD-onset biomarkers predicted risk of subsequent PTSD. PMID- 29157935 TI - A quiet space during rush hour: Quiescence in primordial germ cells. AB - Quiescence is a common character in stem cells. Low cellular activity in these cells may function to minimize the potential damaging effects of oxidative stress, reduce the number of cells needed for tissue replenishment, and as a consequence, perhaps occupy unique niches. Quiescent stem cells are found in many adult human tissues, the hematopoietic stem cells are paradigmatic, and more recently it appears that stem cell of the germ line in many animals display quiescence characters. Here we explore the diversity of quiescence phenotypes in primordial germ cells, leveraging the diverse mechanisms of germ cell formation to extract evolutionary significance to common processes. PMID- 29157936 TI - Short parietal lobe connections of the human and monkey brain. AB - The parietal lobe has a unique place in the human brain. Anatomically, it is at the crossroad between the frontal, occipital, and temporal lobes, thus providing a middle ground for multimodal sensory integration. Functionally, it supports higher cognitive functions that are characteristic of the human species, such as mathematical cognition, semantic and pragmatic aspects of language, and abstract thinking. Despite its importance, a comprehensive comparison of human and simian intraparietal networks is missing. In this study, we used diffusion imaging tractography to reconstruct the major intralobar parietal tracts in twenty-one datasets acquired in vivo from healthy human subjects and eleven ex vivo datasets from five vervet and six macaque monkeys. Three regions of interest (postcentral gyrus, superior parietal lobule and inferior parietal lobule) were used to identify the tracts. Surface projections were reconstructed for both species and results compared to identify similarities or differences in tract anatomy (i.e., trajectories and cortical projections). In addition, post-mortem dissections were performed in a human brain. The largest tract identified in both human and monkey brains is a vertical pathway between the superior and inferior parietal lobules. This tract can be divided into an anterior (supramarginal gyrus) and a posterior (angular gyrus) component in both humans and monkey brains. The second prominent intraparietal tract connects the postcentral gyrus to both supramarginal and angular gyri of the inferior parietal lobule in humans but only to the supramarginal gyrus in the monkey brain. The third tract connects the postcentral gyrus to the anterior region of the superior parietal lobule and is more prominent in monkeys compared to humans. Finally, short U-shaped fibres in the medial and lateral aspects of the parietal lobe were identified in both species. A tract connecting the medial parietal cortex to the lateral inferior parietal cortex was observed in the monkey brain only. Our findings suggest a consistent pattern of intralobar parietal connections between humans and monkeys with some differences for those areas that have cytoarchitectonically distinct features in humans. The overall pattern of intraparietal connectivity supports the special role of the inferior parietal lobule in cognitive functions characteristic of humans. PMID- 29157937 TI - Pure word deafness following left temporal damage: Behavioral and neuroanatomical evidence from a new case. AB - Pure Word Deafness (PWD) is a rare disorder, characterized by selective loss of speech input processing. Its most common cause is temporal damage to the primary auditory cortex of both hemispheres, but it has been reported also following unilateral lesions. In unilateral cases, PWD has been attributed to the disconnection of Wernicke's area from both right and left primary auditory cortex. Here we report behavioral and neuroimaging evidence from a new case of left unilateral PWD with both cortical and white matter damage due to a relatively small stroke lesion in the left temporal gyrus. Selective impairment in auditory language processing was accompanied by intact processing of nonspeech sounds and normal speech, reading and writing. Performance on dichotic listening was characterized by a reversal of the right-ear advantage typically observed in healthy subjects. Cortical thickness and gyral volume were severely reduced in the left superior temporal gyrus (STG), although abnormalities were not uniformly distributed and residual intact cortical areas were detected, for example in the medial portion of the Heschl's gyrus. Diffusion tractography documented partial damage to the acoustic radiations (AR), callosal temporal connections and intralobar tracts dedicated to single words comprehension. Behavioral and neuroimaging results in this case are difficult to integrate in a pure cortical or disconnection framework, as damage to primary auditory cortex in the left STG was only partial and Wernicke's area was not completely isolated from left or right-hemisphere input. On the basis of our findings we suggest that in this case of PWD, concurrent partial topological (cortical) and disconnection mechanisms have contributed to a selective impairment of speech sounds. The discrepancy between speech and non-speech sounds suggests selective damage to a language specific left lateralized network involved in phoneme processing. PMID- 29157938 TI - [Vascular adrenal cyst causing difficult to control high blood pressure]. AB - Hypertension is a prevalent disease in developed countries. Adrenal masses, and especially adrenal cysts, are a rare and usually asymptomatic finding, which can go unnoticed or be detected as incidental findings in imaging tests. These circumstances make the multidisciplinary approach mandatory. The case is presented on a 72 year-old woman with uncontrolled high blood pressure referred to the Urology Department due to the incidental finding of a right retroperitoneal mass. A functional and imaging study was performed, establishing a diagnosis of adrenal cyst causing hypertensive symptoms. A literature search was performed in order to assess diagnostic and therapeutic approaches. With the diagnosis of adrenal cyst causing uncontrolled high blood pressure, a right laparoscopic adrenalectomy was performed. After surgery the patient has maintained blood pressure within the normal range. A multidisciplinary approach is necessary for the management of rare diseases. The surgical approach, if possible, should be laparoscopic. PMID- 29157939 TI - Lymphadenopathy associated with IgG4-related disease: Diagnosis & differential diagnosis. AB - IgG4-related sclerosing disease, which now encompasses diverse organ-related disorders with various prior eponymic designations, may also present with solitary or multifocal lymph node enlargement. This review considers the histopathologic features of IgG4 lymphadenopathy (IgG4LAD), which has been subdivided by Cheuk & Chan into 5 microscopic subtypes. Those include variants that are typified by multicentric Castleman disease (MCD)-like changes, follicular hyperplasia, interfollicular lymphoplasmacytic proliferation, progressive transformation of germinal centers, and formation of inflammatory pseudotumor (IPT)-like lesions. All of them demonstrate an excess of IgG4 immunoreactive plasma cells in the inflammatory cell population. Differential diagnostic considerations for IgG4LAD include true MCD, true IPT, luetic lymphadenitis, Rosai-Dorfman disease, and inflammatory myofibroblastic tumor, among others. An interpretative distinction between malignant lymphoma and IgG4LAD is also crucial. PMID- 29157940 TI - Annular and Polycyclic Lesions on the Lower Limbs. PMID- 29157941 TI - Iso-Kikuchi Syndrome: A Clinically Diagnosed Condition Dermatologists Should Be Aware Of. PMID- 29157942 TI - Expression of two glycoprotein hormone receptors in larval, parasitic phase, and adult sea lampreys. AB - All jawed vertebrates have three canonical glycoprotein hormones (GpHs: luteinizing hormone, LH; follicle stimulating hormone, FSH; and thyroid stimulating hormone, TSH) with three corresponding GpH receptors (GpH-Rs: LH-R, FSH-R, and TSH-R). In contrast, we propose that the jawless vertebrate, the sea lamprey (Petromyzon marinus), only has two pituitary glycoprotein hormones, lamprey (l)GpH and l-thyrostimulin, and two functional glycoprotein receptors, lGpH-R I and II. It is not known at this time whether there is a specific receptor for lGpH and l-thyrostimulin, or if both GpHs can differentially activate the lGpH-Rs. In this report, we determined the RNA expression of lGpH-R I and II in the gonads and thyroids of larval, parasitic phase, and adult lampreys. A highly sensitive dual-label fluorescent in situ hybridization technique (RNAScopeTM) showed lGpH-R I expression in the ovaries of larval lamprey, and co-localization and co-expression of lGpH-R I and II in the ovaries of parasitic phase and adult lampreys. Both receptors were also highly co localized and co-expressed in the endostyle of larval lamprey and thyroid follicles of parasitic and adult lampreys. In addition, we performed in vivo studies to determine the actions of lamprey gonadotropin releasing hormones (lGnRHs) on lGpH-R I and II expression by real time PCR, and determined plasma concentrations of estradiol and thyroxine. Administration of lGnRH-III significantly (p <= 0.01) increased lGpHR II expression in the thyroid follicles of adult female lampreys but did not cause a significant increase in RNA expression of lGpH-R I and II in ovaries. Concomitantly, there was a significant increase (p <= 0.01) of plasma estradiol without any significant changes of plasma thyroxine concentrations in response to treatment to lGnRH-I, -II, or III. In summary, our results provide supporting evidence that the lamprey pituitary glycoprotein hormones may differentially activate the lamprey GpH-Rs in regulating both thyroid and gonadal activities during each of the three life stages of the sea lamprey. PMID- 29157943 TI - Editorial - Special issue of the 28th Conference of European Comparative Endocrinologists (CECE-2016) - Golden Jubilee of the European Society for Comparative Endocrinology (ESCE). PMID- 29157944 TI - Down-regulation of TYK2, CBLB and LMP7 genes expression in relapsing-remitting multiple sclerosis patients treated with interferon-beta. AB - This study aimed to examine the expression of TYK2, CBLB and LMP7 genes at both mRNA and protein levels in relapsing-remitting MS (RRMS) patients in compare with healthy controls. Seventy-eight RRMS patients treated with IFNbeta-1a and 79 age- and ethnic-matched healthy subjects were studied. The mRNA expression levels of TYK2, CBLB and LMP7 in PBMCs were quantified by real-time PCR and plasma concentrations of three molecules were measured by ELISA. Results were compared between patients and controls, IFNbeta-responders and non-responders. Forty-nine of 78 patients were classified as IFNbeta-responders and 29 cases were non responders. Significantly down-regulated expression of TYK2, CBLB and LMP7 genes was found in the patients group versus controls (P<0.001). Decreased plasma levels of three molecules were observed in patients compared to controls (P<0.001). IFNbeta-responders had significantly higher expressions for CBLB (P=0.001) and LMP7 (P=0.02) than non-responders. Also, we observed increased expressions of LMP7 (P=0.39) and CBLB (P=0.02) genes in patients under 30y and increased expression of TYK2 in patients >40years (P=0.002). Our results suggest that expression analysis of TYK2, CBLB and LMP7 genes could be useful for evaluation of T cells immunity and clinical response to IFNbeta-therapy in RRMS patients. PMID- 29157945 TI - Food allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention, and management. AB - This review provides general information to serve as a primer for those embarking on understanding food allergy and also details advances and updates in epidemiology, pathogenesis, diagnosis, and treatment that have occurred over the 4 years since our last comprehensive review. Although firm prevalence data are lacking, there is a strong impression that food allergy has increased, and rates as high as approximately 10% have been documented. Genetic, epigenetic, and environmental risk factors are being elucidated increasingly, creating potential for improved prevention and treatment strategies targeted to those at risk. Insights on pathophysiology reveal a complex interplay of the epithelial barrier, mucosal and systemic immune response, route of exposure, and microbiome among other influences resulting in allergy or tolerance. The diagnosis of food allergy is largely reliant on medical history, tests for sensitization, and oral food challenges, but emerging use of component-resolved diagnostics is improving diagnostic accuracy. Additional novel diagnostics, such as basophil activation tests, determination of epitope binding, DNA methylation signatures, and bioinformatics approaches, will further change the landscape. A number of prevention strategies are under investigation, but early introduction of peanut has been advised as a public health measure based on existing data. Management remains largely based on allergen avoidance, but a panoply of promising treatment strategies are in phase 2 and 3 studies, providing immense hope that better treatment will be imminently and widely available, whereas numerous additional promising treatments are in the preclinical and clinical pipeline. PMID- 29157946 TI - Endolysosomal protease susceptibility of Amb a 1 as a determinant of allergenicity. PMID- 29157947 TI - The vascular endothelial specific IL-4 receptor alpha-ABL1 kinase signaling axis regulates the severity of IgE-mediated anaphylactic reactions. AB - BACKGROUND: Severe IgE-mediated, food-induced anaphylactic reactions are characterized by pulmonary venous vasodilatation and fluid extravasation, which are thought to lead to the life-threatening anaphylactic phenotype. The underlying immunologic and cellular processes involved in driving fluid extravasation and the severe anaphylactic phenotype are not fully elucidated. OBJECTIVE: We sought to define the interaction and requirement of IL-4 and vascular endothelial (VE) IL-4 receptor alpha chain (IL-4Ralpha) signaling in histamine-abelson murine leukemia viral oncogene homology 1 (ABL1)-mediated VE dysfunction and fluid extravasation in the severity of IgE-mediated anaphylactic reactions in mice. METHODS: Mice deficient in VE IL-4Ralpha and models of passive and active oral antigen- and IgE-induced anaphylaxis were used to define the requirements of the VE IL-4Ralpha and ABL1 pathway in severe anaphylactic reactions. The human VE cell line (EA.hy926 cells) and pharmacologic (imatinib) and genetic (short hairpin RNA knockdown of IL4RA and ABL1) approaches were used to define the requirement of this pathway in VE barrier dysfunction. RESULTS: IL 4 exacerbation of histamine-induced hypovolemic shock in mice was dependent on VE expression of IL-4Ralpha. IL-4- and histamine-induced ABL1 activation in human VE cells and VE barrier dysfunction was ABL1-dependent. Development of severe IgE mediated hypovolemia and shock required VE-restricted ABL1 expression. Treatment of mice with a history of food-induced anaphylaxis with the ABL kinase inhibitor imatinib protected the mice from severe IgE-mediated anaphylaxis. CONCLUSION: IL 4 amplifies IgE- and histamine-induced VE dysfunction, fluid extravasation, and the severity of anaphylaxis through a VE IL-4Ralpha/ABL1-dependent mechanism. These studies implicate an important contribution by the VE compartment in the severity of anaphylaxis and identify a new pathway for therapeutic intervention of IgE-mediated reactions. PMID- 29157949 TI - Non-PCI/CABG therapies for refractory angina. AB - Angina persists for many patients despite modern medical therapy and/or revascularization, and this is referred to as refractory angina. All patients with refractory angina must be treated with aggressive risk factor modification plus optimized medical management. beta-Blockers and nitrates are usually first line agents; however most patients require multiple medications for refractory symptom control. Novel agents, such as ranolazine and ivabradine, as well as non pharmacologic therapies, such as enhanced external counterpulsation and cardiac rehabilitation, may provide relief or reduction of angina. Other standard treatments such as antiplatelet therapy, lipid reduction therapy, blood pressure control, diabetes control, smoking cessation, and wei1ght control should be part of the management of refractory angina as well. PMID- 29157948 TI - Neurturin is a PGC-1alpha1-controlled myokine that promotes motor neuron recruitment and neuromuscular junction formation. AB - OBJECTIVE: We examined whether skeletal muscle overexpression of PGC-1alpha1 or PGC-1alpha4 affected myokine secretion and neuromuscular junction (NMJ) formation. METHODS: A microfluidic device was used to model endocrine signaling and NMJ formation between primary mouse myoblast-derived myotubes and embryonic stem cell-derived motor neurons. Differences in hydrostatic pressure allowed for fluidic isolation of either cell type or unidirectional signaling in the fluid phase. Myotubes were transduced to overexpress PGC-1alpha1 or PGC-1alpha4, and myokine secretion was quantified using a proximity extension assay. Morphological and functional changes in NMJs were measured by fluorescent microscopy and by monitoring muscle contraction upon motor neuron stimulation. RESULTS: Skeletal muscle transduction with PGC-1alpha1, but not PGC-1alpha4, increased NMJ formation and size. PGC-1alpha1 increased muscle secretion of neurturin, which was sufficient and necessary for the effects of muscle PGC-1alpha1 on NMJ formation. CONCLUSIONS: Our findings indicate that neurturin is a mediator of PGC 1alpha1-dependent retrograde signaling from muscle to motor neurons. PMID- 29157950 TI - [Knowledge, beliefs and attitudes of the Roma population regarding colorectal cancer screening]. AB - OBJECTIVE: To identify predisposing, inhibitory and facilitating factors that may affect participation in colorectal cancer screening programs in the Roma population. METHOD: Qualitative and exploratory study by focus group technique. Three focus groups of men and three groups of women were carried out, with a total of 16 men and 18 women from the Roma population, aged 50-69 years, from the province of Alicante. A discourse analysis was performed with the PRECEDE model as an analysis framework. RESULTS: Several barriers to participation were identified, such as the aversion of the Roma population to talk about cancer, refusal to anticipate a diagnosis that can cause suffering to the person and their family, poor knowledge of the disease and the preventive programmes, refusal to collect and handle samples, fear and shame about the colonoscopy, acceptance of divine will, difficulties in understanding and reading, and the perception of being discriminated by their ethnicity in the health sector. However, predisposing factors to participate in the screening programme also were identified, for example willingness to receive relevant information through more appropriate pathways, as well as their confidence in professional counselling. CONCLUSION: A willingness to receive the recommendation to participate and understanding information from health professionals have been identified. This will enable us to envisage potential strategies for approaching this population group. This could contribute to improved participation of the Roma population in colorectal cancer screening programmes and to open up new ways to promote preventive behaviours. PMID- 29157952 TI - Caregiver burden regarding elderly with bipolar disorder: An underrecognized problem. PMID- 29157951 TI - [Evaluation of the autochthonous transmission risk of Zika virus and other emerging mosquito-borne viral diseases in Catalonia (Spain)]. AB - The recent Zika virus epidemic has highlighted the potential risk of introducing the arbovirosis to Europe, especially within the Mediterranean region where the vector, Aedes albopictus, has become established as an invasive species. In this context, a comprehensive evaluation of the risk of introducing the Zika virus and other mosquito-borne viruses of public health importance in Catalonia (Spain) was carried out. This article summarises the results of the preliminary assessment and the recommendations for the public health preparedness and response plan against the threat posed by these emerging diseases. PMID- 29157953 TI - Chromogenic detection procedure for the multidrug-resistant, neonatal sepsis associated clone Staphylococcus capitis NRCS-A. AB - The multiresistant Staphylococcus capitis clone NRCS-A is a major pathogen in neonates worldwide. We show that NRCS-A grows as mauve colonies with a cream color halo after a 5-day incubation on MRSA Brilliance 2 agar (Oxoid(r)). This innovative protocol will ease the screening of clinical and environmental niches of this clone. PMID- 29157954 TI - Activity of omadacycline tested against Streptococcus pneumoniae from a global surveillance program (2014). AB - The activity of omadacycline and comparators when tested against a subset of Streptococcus pneumoniae from US and European regions of a 2014 global surveillance program (304 isolates) are reported. These MIC results were compared to those obtained when testing S. pneumoniae from 2010 surveillance (1,834 isolates). The omadacycline MIC50/90 for S. pneumoniae (2014) was 0.06/0.06MUg/mL, similar to 2010 (MIC50/90, 0.06/0.12MUg/mL). The omadacycline MIC90 (0.06-0.12MUg/mL) was similar for the penicillin-susceptible, intermediate, -resistant, multidrug-resistance (MDR; >=3 classes), and ceftriaxone nonsusceptible subgroups. Omadacycline MIC90 values were 0.06 0.12MUg/mL for S. pneumoniae from the US and Europe. There was a high degree of resistance with doxycycline, erythromycin and trimethoprim-sulfamethoxazole in both US and EU. For penicillin-resistant S. pneumoniae, resistance to doxycycline and tetracycline in US/Europe was 64.2/61.0% and 63.8/60.5%, respectively, erythromycin 91.2/75.1, and ceftriaxone 7.3/4.0%. The potent activity of omadacycline against S. pneumoniae indicates that omadacycline merits further study in bacterial pneumonia, especially where MDR may be a concern. PMID- 29157955 TI - Development of a goat model for evaluation of withaferin A: Cervical implants for the treatment of cervical intraepithelial neoplasia. AB - Cervical cancer is caused by human papillomavirus (HPV). The disease develops over many years through a series of precancerous lesions. Cervical cancer can be prevented by HPV-vaccination, screening and treatment of precancer before development of cervical cancer. The treatment of high-grade cervical dysplasia (CIN 2+) has traditionally been by cervical conization. Surgical procedures are associated with increased risk of undesirable side effects including bleeding, infection, scarring (stenosis), infertility and complications in later pregnancies. An inexpensive, non-invasive method of delivering therapeutics locally will be favorable to treat precancerous cervical lesions without damaging healthy tissue. The feasibility and safety of a sustained, continuous drug releasing cervical polymeric implant for use in clinical trials was studied using a large animal model. The goat (Capra hircus), non-pregnant adult female Boer goats, was chosen due to similarities in cervical dimensions to the human. Estrus was induced with progesterone CIDR(r) vaginal implants for 14days followed by the administration of chorionic gonadotropins 48h prior to removal of the progesterone implants to relax the cervix to allow for the placement of the cervical implant. Cervical implants, containing 2% and 4% withaferin A (WFA), with 8 coats of blank polymer, provided sustained release for a long duration and were used for the animal study. The 'mushroom'-shaped cervical polymeric implant, originally designed for women required redesigning to be accommodated within the goat cervix. The cervical implants were well tolerated by the animals with no obvious evidence of discomfort, systemic or local inflammation or toxicity. In addition, we developed a new method to analyze tissue WFA levels by solvent extractions and LS/MS-MS. WFA was found to be localized to the target and adjacent tissues with 12-16ng WFA/g tissue, with essentially no detectable WFA in distant tissues. This study suggests that the goat is a good large animal model for the future development and evaluation of therapeutic efficacy of continuous local drug delivery by cervical polymeric implants to treat precancerous cervical lesions. PMID- 29157956 TI - Comparative analysis of fixation and embedding techniques for optimized histological preparation of zebrafish. AB - In recognition of the importance of zebrafish as a model organism for studying human disease, we have created zebrafish content for a web-based reference atlas of microanatomy for comparing histology and histopathology between model systems and with humans (http://bio-atlas.psu.edu). Fixation, decalcification, embedding, and sectioning of zebrafish were optimized to maximize section quality. A comparison of protocols involving six fixatives showed that 10% Neutral Buffered Formalin at 21 degrees C for 24h yielded excellent results. Sectioning of juveniles and adults requires bone decalcification; EDTA at 0.35M produced effective decalcification in 21-day-old juveniles through adults (>=~3Months). To improve section plane consistency in sets of larvae, we have developed new array casting molds based on the outside contours of larvae derived from 3D microCT images. Tissue discontinuity in sections, a common barrier to creating quality sections of zebrafish, was minimized by processing and embedding the formalin fixed zebrafish tissues in plasticized forms of paraffin wax, and by periodic hydration of the block surface in ice water between sets of sections. Optimal H&E (Hematoxylin and Eosin) staining was achieved through refinement of standard protocols. High quality slide scans produced from glass histology slides were digitally processed to maximize image quality, and experimental replicates posted as full slides as part of this publication. Modifications to tissue processing are still needed to eliminate the need for block surface hydration. The further addition of slide collections from other model systems and 3D tools for visualizing tissue architecture would greatly increase the utility of the digital atlas. PMID- 29157957 TI - Selection of vaccine strains for serotype O foot-and-mouth disease viruses (2007 2012) circulating in Southeast Asia, East Asia and Far East. AB - Foot-and-mouth disease (FMD) is endemic in Southeast Asia (SEA) and East Asia with circulation of multiple serotypes and multiple genotypes within each serotype of the virus. Although countries like Japan and South Korea in the Far East were free of FMD, in 2010 FMD serotype O (O/Mya-98) outbreaks were recorded and since then South Korea has experienced several FMD outbreaks despite regular vaccination. In this study a total of 85 serotype O FMD viruses (FMDV) isolated from 2007 to 2012 from SEA, East Asia and Far East were characterized by virus neutralisation tests using antisera to four existing (O/HKN/6/83, O/IND/R2/75, O/SKR/2010 and O/PanAsia-2) and one putative (O/MYA/2009) vaccine strains, and by full capsid sequencing. Serological studies revealed broad cross-reactivity with the vaccine strains; O/PanAsia-2 exhibited a good match with 95.3%, O/HKN/6/83 with 91.8%, O/IND/R2/75 with 80%, and the putative strain O/MYA/2009 with 89.4% isolates employed in this study. Similarly O/PanAsia-2 and O/IND/R2/75 vaccines showed a good match with all eight viruses belonging to O-Ind-2001d sublineage whereas the vaccines of O/Mya-98 lineage, O/MYA/2009 and O/SKR/2010 exhibited the lowest match indicating their unsuitability to protect infections from O-Ind 2001d viruses. A Bayesian analysis of the capsid sequence data indicated these circulating viruses (n = 85) to be of either SEA or Middle East-South Asian (ME SA) topotype. The ME-SA topotype viruses were mainly detected in Lao PDR, Vietnam, Myanmar and Thailand reflecting the trade links with the Indian subcontinent, and also within the SEA countries. Implications of these results in the context of FMD control in SEA and East Asian countries are discussed. PMID- 29157958 TI - U.S. pregnant women's knowledge and attitudes about behavioral strategies and vaccines to prevent Zika acquisition. AB - INTRODUCTION: Zika virus infection during pregnancy can cause significant infant morbidity. Little is known about pregnant women's attitudes regarding behavioral strategies and hypothetical vaccination to prevent Zika infections and sequelae. METHODS: Pregnant women across the United States (N = 362) completed an online questionnaire regarding attitudes about Zika, including six behavioral prevention strategies (i.e., abstaining from sex, using condoms, not traveling to an area with Zika, their partner not traveling into an area with Zika, using mosquito repellant, wearing long pants and sleeves) and vaccination. RESULTS: Most women (91%) were married/living with the baby's father, 65% were non-Hispanic White, and 71% had been pregnant. Seventy-four percent were worried about Zika, while 30% thought they were knowledgeable about Zika. The mean knowledge score was 5.0 out of 8 (SD = 2.09), and the mean behavioral strategies score was 4.9 out of 12 (SD = 3.7) with a range of 0 (none would be hard to do) to 12 (all would be hard to do). In a multivariable model, having had a sexually transmitted infection, living/traveling in an area with Zika, and worrying about Zika were significantly related to reporting behavioral strategies as hard to do. Seventy-two percent would be willing to be vaccinated. In the multivariable model, living/traveling in an area with Zika, believing they knew a lot about Zika, worrying about Zika, and considering Zika vaccine development as important were significantly associated with willingness to get vaccinated. CONCLUSIONS: Pregnant women were worried about Zika, yet had gaps in their factual knowledge. Most women reported they would get vaccinated if a vaccine was available. Pregnant women who reported themselves as vulnerable (being worried, having lived in or traveled to a Zika area) were more likely to view behavioral strategies as hard to do and to accept vaccination. PMID- 29157959 TI - The risk of lower respiratory tract infection following influenza virus infection: A systematic and narrative review. AB - BACKGROUND: Lower respiratory tract infections (LRTI) are a major cause of morbidity and mortality worldwide, particularly in young children and older adults. Influenza is known to cause severe disease but the risk of developing LRTI following influenza virus infection in various populations has not been systematically reviewed. Such data are important for estimating the impact specific influenza vaccine programs would have on LRTI outcomes in a community. We sought to review the published literature to determine the risk of developing LRTI following an influenza virus infection in individuals of any age. METHODS AND FINDINGS: We conducted a systematic review to identify prospective studies that estimated the incidence of LRTI following laboratory-confirmed influenza virus infection. We searched PubMed, Medline, and Embase databases for relevant literature. We supplemented this search with a narrative review of influenza and LRTI. The systematic review identified two prospective studies that both followed children less than 5 years. We also identified one additional pediatric study from our narrative review meeting the study inclusion criteria. Finally, we summarized recent case-control studies on the etiology of pneumonia in both adults and children. CONCLUSIONS: There is a dearth of prospective studies evaluating the risk of developing LRTI following influenza virus infection. Determining the burden of severe LRTI that is attributable to influenza is necessary to estimate the benefits of influenza vaccine on this important public health outcome. Vaccine probe studies are an efficient way to evaluate these questions and should be encouraged going forward. PMID- 29157960 TI - Immune responses to intradermal and intramuscular inactivated influenza vaccine among older age group. AB - BACKGROUD: Influenza viruses cause substantial morbidity, especially in older age groups. Thus, they are amongst high priority groups for routine vaccination. However, vaccine-induced immune responses and effectiveness were reported as relatively low. This study aims to systemically compare the immune responses elicited by intramuscular (IM) and intradermal (ID) injections with inactivated seasonal influenza vaccine among the older age group. METHODS: A prospective, open-label, randomized study with a total of 221 adults (>60 years) were enrolled and randomized into 2 groups. Group I (n = 111) received an IM inactivated seasonal influenza vaccine while Group II (n = 110) received the same vaccine ID. Demographics and co-morbidity were collected at baseline. Safety data was collected 3 days post-vaccination using diary card. HAI, NAb and NAI titers were assessed prior to vaccination and at 30, 45, and 60 days post-vaccination. Data was analyzed using SPSS 11.5. RESULTS: Both groups had similar BMI and co morbidity. For ID and IM groups, significant differences were observed for seroconversion rate measured using HAI against H1N1 and H3N2 (58/111 vs 44/110 and 68/111 vs 54/110, respectively) being higher for those aged 60-65 years. However, no differences in HI antibody against B/Phuket were seen. For ID route, history of hyperlipidemia and hypertension were factors associated with high seroconversion rate towards influenza A (p = .001). The seroconversion rate risk ratio were 1.31 and 1.25 (p < .05) against A/California/07/09(H1N1) and A/Songkha/308/13 (H3N2), respectively. Interestingly, the GMT (95% CI) of baseline NAI antibodies among both groups were high (56.57 and 54.01 in the ID and IM groups, respectively). A 4-fold increase measured by NAI against A/California/07/09 (H1N1) were detected in 16.67% and 20% of participants who received ID or IM vaccination, respectively. CONCLUSIONS: The seroconversion rates of HAI, NAb and NAI were modest, especially in those >65 years of age. However, it was higher in the ID group as compared to the IM group. CLINICAL TRIAL REGISTRATION: NCT02101749. PMID- 29157961 TI - Improvement of intestinal absorption of curcumin by cyclodextrins and the mechanisms underlying absorption enhancement. AB - Curcumin is known to possess a wide range of pharmacological activities for the treatment of chronic or inflammatory diseases, Alzheimer's disease, and various cancers. However, the therapeutic efficacy of curcumin is restricted by its poor bioavailability after oral administration. In this study, the effects of various cyclodextrins on the intestinal absorption of curcumin were evaluated in rat intestine by an in situ closed-loop method. Among the tested cyclodextrins, 50 mM alpha-cyclodextrin significantly enhanced the absorption of curcumin without inducing any intestinal toxicity. The analysis of cellular transport across Caco 2 cell monolayers showed that 50 mM alpha-cyclodextrin reduced the transepithelial electrical resistance value of cell monolayers and improved the permeability of 5(6)-carboxyfluorescein, a poorly absorbable drug, which is mainly transported via a paracellular pathway. Furthermore, the western blotting analysis showed that alpha-cyclodextrin decreased the expression of claudin-4, a tight junction-associated protein, in brush border membrane vesicles. Additionally, alpha-cyclodextrin increased the membrane fluidity of lipid bilayers in brush border membrane vesicles and may also have promoted the permeation of drug molecules via a transcellular pathway. These results suggested that alpha-cyclodextrin might enhance the intestinal absorption of curcumin via both paracellular and transcellular pathways. PMID- 29157962 TI - Current and novel approaches for control of dental biofilm. AB - Insights in oral demographics have revealed that a significant percentage of population faces chronic incidences of oral diseases. The innervation of these oral manifestations is required because untreated conditions may lead to bone loss in the oral cavity and systemic complications. Conventional treatments include surgery of the affected area followed by its management and/or treatment with antibiotics. However, widely used antibiotics like Triclosan have serious side effects including down-regulation of oral keratinocytes and fibroblasts. Thus, novel treatments with more targeted approaches have been under investigation. Treatment modalities like Viral mediated gene delivery, liposomes, nanoparticles, and nanobubbles not only help in management of oral diseases but also aid in reducing the biofilm formed due to bacterial bioburden in the areas less accessible through oral and conventional means. This review focuses on the limitation of conventional treatments and highlights the recent investigations in the use of the novel treatment approaches in order to increase the patient compliance and alleviation of side effects. The authors have also tried to emphasize on the future perspectives of glucansucrase inhibitors, photodynamic therapy and probiotics as targeted drug delivery systems. However, further investigations are necessary for implementation of these novel approaches in the clinical setup. PMID- 29157963 TI - Penta-block copolymer microspheres: Impact of polymer characteristics and process parameters on protein release. AB - Here, we aimed to develop protein loaded microspheres (MSs) using penta-block PLGA-based copolymers to obtain sustained and complete protein release. We varied MS morphology and studied the control of protein release. Lysozyme was used as a model protein and MSs were prepared using the solid-in-oil-in-water emulsion solvent extraction method. We synthesized and studied various penta-block PLGA based copolymers. Copolymer characteristics (LA/GA ratio and molecular weight of PLGA blocks) influenced MS morphology. MS porosity was influenced by process parameters (such as solvent type, polymer concentration, emulsifying speed), whereas the aqueous volume for extraction and stabilizer did not have a significant effect. MSs of the same size, but different morphologies, exhibited different protein release behavior, with porous structures being essential for the continuous and complete release of encapsulated protein. These findings suggest strategies to engineer the morphology of MSs produced from PLGA-based multi-block copolymers to achieve appropriate release rates for a protein delivery system. PMID- 29157964 TI - New insights on the influence of manufacturing conditions and molecular weight on phase-separated films intended for controlled release. AB - The aim of this work was to investigate how manufacturing conditions influence phase-separated films of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) with different molecular weights of HPC. Two HPC grades, SSL and M, with weight average molecular weights (Mw) of 30*103g/mol and 365*103g/mol, respectively, were combined with EC 10 cps (70:30w/w EC/HPC) and spray-coated from ethanol solutions onto a rotating drum under well-controlled process conditions. Generally, a low spray rate resulted in a more rapid film drying process and, consequently, in smaller HPC-rich domains in the phase-separated film structure. For EC/HPC films with the low Mw HPC (SSL) the most rapid drying process resulted in a shift from a HPC-discontinuous to a partly bicontinuous structure and an increase in the permeability for water. In contrast, films containing the high Mw HPC (M) all showed bicontinuous structures, which resulted in overall higher water permeabilities and polymer release compared to the low Mw films. Interestingly, a maximum in permeability was observed for the high Mw films at intermediate spray rates. Below this spray rate the permeability decreased due to a lower amount of polymer released and at higher spray rates, the permeability decreased due to a loss of pore connectivity (or increased tortuosity). To conclude, this study shows that different Mw systems of EC/HPC can respond differently to variations in manufacturing conditions. PMID- 29157965 TI - Polymer-based nanoparticles loaded with a TLR7 ligand to target the lymph node for immunostimulation. AB - Small-molecule agonists for the Toll-like receptors (TLR) 7 and 8 are effective for the immunotherapy of skin cancer when used as topical agents. Their systemic use has however been largely unsuccessful due to dose-limiting toxicity. We propose a polymer-based nanodelivery system to target resiquimod, a TLR7 ligand, to the lymph node in order to focus the immunostimulatory activity and to prevent a generalized inflammatory response. We demonstrate successful encapsulation of resiquimod in methoxypoly(ethylene glycol)-b-poly(DL-lactic acid) (mPEG-PLA) and mixed poly(DL-lactic-co-glycolic acid) (PLGA)/mPEG-PLA nanoparticles. We show that these particles are taken up mainly by dendritic cells and macrophages, which are the prime initiators of anticancer immune responses. Nanoparticles loaded with resiquimod activate these cells, demonstrating the availability of the immune-stimulating cargo. The unloaded particles are non-inflammatory and do not have cytotoxic activity on immune cells. Following subcutaneous injection in mice, mPEG-PLA and PLGA/mPEG-PLA nanoparticles are detected in dendritic cells and macrophages in the draining lymph nodes, demonstrating the targeting potential of these particles. Thus, polymer-based nanoparticles represent a promising delivery system that allows lymph node targeting for small-molecule TLR7 agonists in the context of systemic cancer immunotherapy. PMID- 29157966 TI - Antibiotic Killing through Incomplete DNA Repair. AB - Two recent studies show that incomplete repair of DNA damage due to oxidized nucleotides is crucial for reactive oxygen species (ROS)-related antimicrobial lethality. Using widely different experimental approaches they both reach the same conclusions on the role of downstream ROS production in cell killing upon exposure to bactericidal antimicrobials. PMID- 29157968 TI - Effects of pristine polyvinyl chloride fragments on whole body histology and protease activity in silver barb Barbodes gonionotus fry. AB - Silver barb Barbodes gonionotus fry were exposed to polyvinyl chloride (PVC) fragments at increasing concentrations of 0.2, 0.5 and 1.0 mg/L for 96 h, following which whole body histological evaluation and analysis of the digestive enzymes trypsin and chymotrypsin were performed. Whole body trypsin and chymotrypsin activities increased significantly in fish exposed to 0.5 and 1.0 mg/L PVC as compared those exposed to zero or 0.2 mg/L PVC. In fish exposed to all tested concentrations, PVCs were observed in both the proximal and distal intestine, and fish exposed to 0.5-1.0 and 1.0 mg/L PVC, respectively, and these particles were associated with localized thickening of the mucosal epithelium. No tissue damage was evident in any other internal organs or gills. This lack of damage may be attributed to the absence of contaminants associated with the PVC fragments and their relatively smooth surface. The increased whole body trypsin and chymotrypsin activities may indicate an attempt to enhance digestion to compensate for epithelial thickening of the intestine and/or to digest the plastics. PMID- 29157969 TI - Incorporating long-term satellite-based aerosol optical depth, localized land use data, and meteorological variables to estimate ground-level PM2.5 concentrations in Taiwan from 2005 to 2015. AB - Satellite-based aerosol optical depth (AOD) is now comprehensively applied to estimate ground-level concentrations of fine particulate matter (PM2.5). This study aimed to construct the AOD-PM2.5 estimation models over Taiwan. The AOD PM2.5 modeling in Taiwan island is challenging owing to heterogeneous land use, complex topography, and humid tropical to subtropical climate conditions with frequent cloud cover and prolonged rainy season. The AOD retrievals from the MODerate resolution Imaging Spectroradiometer (MODIS) onboard the Terra and Aqua satellites were combined with the meteorological variables from reanalysis data and high resolution localized land use variables to estimate PM2.5 over Taiwan island from 2005 to 2015. Ten-fold cross validation was carried out and the residuals of the estimation model at various locations and seasons are assessed. The cross validation (CV) R2 based on monitoring stations were 0.66 and 0.66, with CV root mean square errors of 14.0 MUg/m3 (34%) and 12.9 MUg/m3 (33%), respectively, for models based on Terra and Aqua AOD. The results provided PM2.5 estimations at locations without surface stations. The estimation revealed PM2.5 concentration hotspots in the central and southern part of the western plain areas, particularly in winter and spring. The annual average of estimated PM2.5 concentrations over Taiwan consistently declined during 2005-2015. The AOD-PM2.5 model is a reliable and validated method for estimating PM2.5 concentrations at locations without monitoring stations in Taiwan, which is crucial for epidemiological study and for the assessment of air quality control policy. PMID- 29157967 TI - The Role of Interferon in Persistent Viral Infection: Insights from Murine Norovirus. AB - Persistent viral infections result from evasion or avoidance of sterilizing immunity, extend the timeframe of virus transmission, and can trigger disease. Prior studies in mouse models of persistent infection have suggested that ineffective adaptive immune responses are necessary for persistent viral infection. However, recent work in the murine norovirus (MNV) model of persistent infection demonstrates that innate immunity can control both early and persistent viral replication independently of adaptive immune effector functions. Interferons (IFNs) are central to the innate control of persistent MNV, apart from a role in modulating adaptive immunity. Furthermore, subtypes of IFN play distinct tissue-specific roles in innate control of persistent MNV infection. Type I IFN (IFN-alpha/beta) controls systemic replication, and type III IFN (IFN lambda) controls MNV persistence in the intestinal epithelium. In this article, we review recent findings in the MNV model, highlighting the role of IFNs and innate immunity in clearing persistent viral infection, and discussing the broader implications of these findings for control of persistent human infections. PMID- 29157970 TI - Vertical characteristics of VOCs in the lower troposphere over the North China Plain during pollution periods. AB - In recent years, photochemical smog and gray haze-fog have frequently appeared over northern China. To determine the spatial distribution of volatile organic compounds (VOC) during a pollution period, tethered balloon flights were conducted over a suburban site on the North China Plain. Statistical analysis showed that the VOCs concentrations peaked at the surface, and decreased with altitude. A rapid decrease appeared from the surface to 400 m, with concnetrations of alkanes, alkenes, aromatics and halocarbons decreasing by 48.0%, 53.3%, 43.3% and 51.1%, respectively. At heights in the range of 500-1000 m, alkenes concnetrations decline by 40.2%; alkanes and halocarbons concnetrations only decreased by 24.8% and 6.4%, respectively; and aromatics increased slightly by 5.5%. High concentrations VOCs covered a higher range of height (400 m) on heavy pollution days due to lacking of diffusion power. The VOCs concentrations decreased by 50% at 200 m on light pollution days. The transport of air mass affected the composition and concentration of high-altitude VOCs, especially on lightly polluted days. These air masses originated in areas with abundant traffic and combustion sources. Reactive aromatics (kOH>20,000 ppm 1 min-1 and kOH<20,000 ppm-1 min-1) were the main contributor to the ozone formation, accounting for 37%, on the surface on light pollution days. The contribution increased to 52% with pollution aggravated, and increased to 64% with height. The contributions of reactive aromatics were influenced by the degree of air mass aging. Under the umbrella of aging air mass, the contribution of reactive aromatics increased with height. PMID- 29157971 TI - Health risk assessment of haloacetonitriles in drinking water based on internal dose. AB - To estimate the health risk of haloacetonitriles in different kinds of drinking water, the concentrations of haloacetonitriles in tap water, boiled water and direct drinking water were detected. The physiologically based pharmacokinetic (PBPK) model was used to calculate internal dose in the human body for haloacetonitriles through ingestion, and the probability distributions of the non carcinogenic risk of haloacetonitriles for human via drinking water were assessed. This study found that the mean concentrations of dichloroacetonitrile (DCAN) in tap water, boiled water and direct drinking water were 0.955 MUg/L, 0.207 MUg/L and 0.127 MUg/L, and those of dibromoacetonitrile (DBAN) were 0.221 MUg/L, 0.104 MUg/L, 0.089 MUg/L, respectively. In China, direct drinking water is used most frequently, so the concentrations of haloacetonitriles in direct drinking water were used to obtain data on the internal dose of haloacetonitriles. In addition, the simulation results for the PBPK model showed that the highest and lowest concentrations of DCAN occurred in the liver and venous blood, respectively. The peak concentrations of DBAN in each tissue were in the decreasing order liver > rapidly perfused tissue > kidney > slowly perfused tissues > fat > arterial blood (venous blood). In addition, the highest 95th percentile hazard quotients (HQ) value of haloacetonitriles via drinking water for humans was 8.89 * 10-3, much lower than 1. The 95th percentile hazard index (HI) was 0.046, which was also lower than 1, suggesting that there was no obvious non-carcinogenic risk. PMID- 29157972 TI - Phytofiltration of arsenic by aquatic moss (Warnstorfia fluitans). AB - This work investigates whether aquatic moss (Warnstorfia fluitans) originating from an arsenic (As)-contaminated wetland close to a mine tailings impoundment may be used for phytofiltration of As. The aim was to elucidate the capacity of W. fluitans to remove As from arsenite and arsenate contaminated water, how nutrients affect the As uptake and the proportion of As adsorption and absorption by the moss plant, which consists of dead and living parts. Arsenic removal from 0, 1, or 10% Hoagland nutrient solution containing 0-100 MUM arsenate was followed over 192 h, and the total As in aquatic moss after treatment was analysed. The uptake and speciation of As in moss cultivated in water containing 10 MUM arsenate or arsenite were examined as As uptake in living (absorption + adsorption) and dead (adsorption) plant parts. Results indicated that W. fluitans removed up to 82% of As from the water within one hour when 1 MUM arsenate was added in the absence of nutrients. The removal time increased with greater nutrient and As concentrations. Up to 100 MUM As had no toxic effect on the plant biomass. Both arsenite and arsenate were removed from the solution to similar extents and, independent of the As species added, more arsenate than arsenite was found in the plant. Of the As taken up, over 90% was firmly bound to the tissue, a possible mechanism for resisting high As concentrations. Arsenic was both absorbed and adsorbed by the moss, and twice as much As was found in living parts as in dead moss tissue. This study revealed that W. fluitans has potential to serve as a phytofilter for removing As from As-contaminated water without displaying any toxic effects of the metalloid. PMID- 29157973 TI - When the good go bad: Mutant NPM1 in acute myeloid leukemia. AB - Nucleophosmin 1 (NPM1) is a nucleolar phosphoprotein that performs diverse biological functions including molecular chaperoning, ribosome biogenesis, DNA repair, and genome stability. Acute myeloid leukemia (AML) is a heterogeneous disease, more than half of the AML cases exhibit normal karyotype (NK). Approximately 50-60 percent of patients with NK-AML carry NPM1 mutations which are characterized by cytoplasmic dislocation of the NPM1 protein. In AML, mutant NPM1 (NPM1c+) acts in a dominant negative fashion and also blocks the differentiation of myeloid cells through gain-of-function for the AML phenotype. Currently, there is limited knowledge on the gain-of-function mechanism of mutant NPM1. Here, we review the known mechanisms of mutant NPM1 in the pathogenesis of AML. We describe genetic abnormalities, the clinical significance of exon-12 mutations in the NPM1 gene, and chromosomal translocations including the recently discovered NPM1-TYK2, and NPM1-HAUS1. Also, we outline the possible therapeutic interventions for the treatment of AML by targeting NPM1. Overall, the review will summarize present knowledge on mutant NPM1 origin, pathogenesis, and therapy in AML. PMID- 29157974 TI - Stability of aerobic granules during long-term bioreactor operation. AB - Aerobic granular sludge technology has been extensively studied over the past 20 years and is regarded as the upcoming new standard for biological treatment of domestic and industrial wastewaters. Aerobic granules (AG) are dense, compact, self-immobilized microbial aggregates that allow better sludge-water separation and thereby higher biomass concentrations in the bioreactor than conventional activated sludge aggregates. This brings potential practical advantages in terms of investment cost, energy consumption and footprint. Yet, despite the relevant advances regarding the process of AG formation, instability of AG during long term operation is still seen as a major barrier for a broad practical application of this technology. This paper presents an up-to-date review of the literature focusing on AG stability, aiming to contribute to the identification of key factors for promoting long-term stability of AG and to a better understanding of the underlying mechanisms. Operational conditions leading to AG disintegration are described, including high organic loads, particulate substrates in the influent, toxic feed components, aerobic feeding and too short famine periods. These operational and influent wastewater composition conditions were shown to influence the micro-environment of AG, consequently affecting their stability. Granule stability is generally favored by the presence of a dense core, with microbial growth throughout the AG depth being a crucial intrinsic factor determining its structural integrity. Accordingly, possible practical solutions to improve granule long-term stability are described, namely through the promotion of minimal substrate concentration gradients and control of microbial growth rates within AG, including anaerobic, plug-flow feeding and specific sludge removal strategies. PMID- 29157975 TI - Crime, perceived safety, and physical activity: A meta-analysis. AB - Perceived safety from crime and objectively-measured crime rates may be associated with physical inactivity. The purpose of this meta-analysis is to estimate the odds of accumulating high levels of physical activity (PA) when the perception of safety from crime is high and when objectively-measured crime is high. Peer-reviewed studies were identified through PubMed, Web of Science, ProQuest Criminal Justice, and ScienceDirect from earliest record through 2016. Included studies measured total PA, leisure-time PA, or walking in addition to perceived safety from crime or objective measures of crime. Mean odds ratios were aggregated with random effects models, and meta-regression was used to examine effects of potential moderators: country, age, and crime/PA measure. Sixteen cross-sectional studies yielded sixteen effects for perceived safety from crime and four effects for objective crime. Those reporting feeling safe from crime had a 27% greater odds of achieving higher levels of physical activity (OR=1.27 [1.08, 1.49]), and those living in areas with higher objectively-measured crime had a 28% reduced odds of achieving higher levels of physical activity (OR=0.72 [0.61, 0.83]). Effects of perceived safety were highly heterogeneous (I2=94.09%), but explored moderators were not statistically significant, likely because of the small sample size. Despite the limited number of effects suitable for aggregation, the mean association between perceived safety and PA was significant. As it seems likely that perceived lack of safety from crime constrains PA behaviors, future research exploring moderators of this association may help guide public health recommendations and interventions. PMID- 29157976 TI - Loading dendritic cells with gold nanoparticles (GNPs) bearing HIV-peptides and mannosides enhance HIV-specific T cell responses. AB - Gold nanoparticles (GNPs) decorated with glycans ameliorate dendritic cells (DC) uptake, antigen-presentation and T-cells cross-talk, which are important aspects in vaccine design. GNPs allow for high antigen loading, DC targeting, lack of toxicity and are straightforward prepared and easy to handle. The present study aimed to assess the capacity of DC to process and present HIV-1-peptides loaded onto GNPs bearing high-mannoside-type oligosaccharides (P1@HM) to autologous T cells from HIV-1 patients. The results showed that P1@HM increased HIV-specific CD4+ and CD8+ T-cell proliferation and induced highly functional cytokine secretion compared with HIV-peptides alone. P1@HM elicits a highly efficient secretion of pro-TH1 cytokines and chemokines, a moderate production of pro-TH2 and significant higher secretion of pro-inflammatory cytokines such as TNF-alpha and IL-1beta. Thus, co-delivery of HIV-1 antigens and HM by GNPs is an excellent vaccine delivery system inducing HIV-specific cellular immune responses in HIV+ patients, being a promising approach to improve anti-HIV-1 vaccines. PMID- 29157978 TI - Stem cell-based gene delivery mediated by cationic niosomes for bone regeneration. AB - Bone morphogenetic protein-7(BMP-7) plays a pivotal role in the transformation of mesenchymal stem cells (MSCs) into bone. However, its impact is hampered due to its short half-life. Therefore, gene therapy may be an interesting approach to deliver BMP-7 gene to D1-MSCs. In this manuscript we prepared and characterized niosomes based on cationic lipid 2,3-di(tetradecyloxy)propan-1-amine, combined with polysorbate 80 for gene delivery purposes. Niosomes were characterized and combined initially with pCMS-EGFP reporter plasmid, and later with pUNO1-hBMP-7 plasmid to evaluate osteogenesis differentiation. Additionally, specific blockers of most relevant endocytic pathways were used to evaluate the intracellular disposition of complexes. MSCs transfected with niosomes showed increased growth rate, enhanced alkaline phosphatase activity (ALP) and extracellular matrix deposition which suggested the formation of osteoblast-like cells. We concluded that hBMP-7-transfected MSCs could be considered not only as an effective delivery tool of hBMP-7, but also as proliferating and bone forming cells for bone regeneration. PMID- 29157977 TI - Cell type-specific pharmacological kinase inhibition for cancer chemoprevention. AB - Safety is prerequisite for preventive medicine, but non-toxic agents are generally ineffective as clinical chemoprevention. Here we propose a strategy overcoming this challenge by delivering molecular-targeted agent specifically to the effector cell type to achieve sufficient potency, while circumventing toxicity in the context of cancer chemoprevention. Hepatic myofibroblasts drive progressive fibrosis that results in cirrhosis and liver cancer. In a rat model of cirrhosis-driven liver cancer, a small molecule epidermal growth factor receptor inhibitor, erlotinib, was delivered specifically to myofibroblasts by a versatile nanoparticle-based system, targeting platelet-derived growth factor receptor-beta uniquely expressed on their surface in the liver. With systemic administration of erlotinib, tumor burden was reduced to 31%, which was further improved to 21% by myofibroblast-targeted delivery even with reduced erlotinib dose (7.3-fold reduction with equivalent erlotinib dose) and less hepatocyte damage. These findings demonstrate a strategy, cell type-specific kinase inhibition, for more effective and safer precision cancer chemoprevention. PMID- 29157979 TI - Artificial apolipoprotein corona enables nanoparticle brain targeting. AB - Many potential therapeutic compounds for brain diseases fail to reach their molecular targets due to the impermeability of the blood-brain barrier, limiting their clinical development. Nanotechnology-based approaches might improve compounds pharmacokinetics by enhancing binding to the cerebrovascular endothelium and translocation into the brain. Adsorption of apolipoprotein E4 onto polysorbate 80-stabilized nanoparticles to produce a protein corona allows the specific targeting of cerebrovascular endothelium. This strategy increased nanoparticle translocation into brain parenchyma, and improved brain nanoparticle accumulation 3-fold compared to undecorated particles (119.8 vs 40.5 picomoles). Apolipoprotein decorated nanoparticles have high clinical translational potential and may improve the development of nanotechnology-based medicine for a variety of neurological diseases. PMID- 29157980 TI - Preparation and characterization of hydroxyapatite nanoparticles carrying insulin and gallic acid for insulin oral delivery. AB - Although nanoparticles carriers for oral delivery of insulin have been researched for many years, this method still fails to solve issues with toxicity, biocompatibility, and degradability in the organism. We therefore developed an innovative conjugation system to solve this problem. Nano hydroxyapatite (HAP) particles were used as the core, then polyethylene glycol (PEG) was wrapped onto the surface of hydroxyapatite, and, finally, insulin (INS) and gallic acid (GA) were conjugated with PEG. PEG functionalized HAP was increased the hydrophilicity of the nanoparticles, also protected them from degradation in the gastrointestinal (GI) tract. Most importantly, the in vivo absorption of nanoparticles in rat small intestines revealed that HAP-PEG-GA-INS was absorbed by the small intestine epithelium. The blood glucose of the type 1 diabetes (T1D) rats that were given intragastrically HAP-PEG-GA-INS showed an obvious downward trend. Overall, we synthesized a safe, non-toxic, and effective oral insulin delivery system. PMID- 29157982 TI - Who Truly Benefits From Pre-Publishing and Rushing Publishing?: Not Patients, Nor Clinicians. PMID- 29157981 TI - FoxO1 inhibition promotes differentiation of human embryonic stem cells into insulin producing cells. AB - Insulin-producing cells (IPCs) derived from human embryonic stem cells (hESCs) hold great potential for cell transplantation therapy in diabetes. Tremendous progress has been made in inducing differentiation of hESCs into IPCs in vitro, of which definitive endoderm (DE) protocol mimicking foetal pancreatic development has been widely used. However, immaturity of the obtained IPCs limits their further applications in treating diabetes. Forkhead box O1 (FoxO1) is involved in the differentiation and functional maintenance of murine pancreatic beta cells, but its role in human beta cell differentiation is under elucidation. Here, we showed that although FoxO1 expression level remained consistent, cytoplasmic phosphorylated FoxO1 protein level increased during IPC differentiation of hESCs induced by DE protocol. Lentiviral silencing of FoxO1 in pancreatic progenitors upregulated the levels of pancreatic islet differentiation related genes and improved glucose-stimulated insulin secretion response in their progeny IPCs, whereas overexpression of FoxO1 showed the opposite effects. Notably, treatment with the FoxO1 inhibitor AS1842856 displayed similar effects with FoxO1 knockdown in pancreatic progenitors. These effects were closely associated with the mutually exclusive nucleocytoplasmic shuttling of FoxO1 and Pdx1 in the AS1842856-treated pancreatic progenitors. Our data demonstrated a promising effect of FoxO1 inhibition by the small molecule on gene expression profile during the differentiation, and in turn, on determining IPC maturation via modulating subcellular location of FoxO1 and Pdx1. Therefore, we identify a novel role of FoxO1 inhibition in promoting IPC differentiation of hESCs, which may provide clues for induction of mature beta cells from hESCs and clinical applications in regenerative medicine. PMID- 29157983 TI - Blockade of NMDA receptors blocks the acquisition of cocaine conditioned approach in rats. AB - Conditioned stimuli (CSs) exert motivational effects on both adaptive and pathological reward-related behaviors, including drug taking and seeking. We developed a paradigm that allows us to investigate the neuropharmacology by which previously neutral stimuli acquire the capacity to function as CSs and elicit (intravenous) cocaine conditioned approach and used this paradigm to test the role of NMDA receptor stimulation in the acquisition of cocaine conditioned approach. Rats were injected systemically with the NMDA receptor antagonist, MK 801, before the start of 4 consecutive conditioning sessions, each of which consisted of 20 randomly presented light/tone (CS) presentations paired with cocaine infusion contingent upon nose pokes. Rats later were subjected to a CS only test. To test the role of NMDA receptor stimulation in the already established conditioned approach, rats were injected with MK-801 prior to the CS only test that occurred after 18 CS-cocaine conditioning sessions. Blockade of NMDA receptors significantly impaired the acquisition of cocaine-conditioned approach as indicated by the emission of significantly fewer nose pokes and significantly longer latencies to nose poke during CS presentations. When MK-801 treatment was applied after the acquisition of conditioned approach responding it had no effect on these measures. These results suggest that NMDA receptor stimulation plays an important role in the acquisition of reward-related conditioned responses driven by intravenous cocaine-associated CSs. PMID- 29157984 TI - Ropivacaine relieves pain and prevents chondrocyte degradation probably through Calcineurin/NFAT1 signaling pathway in osteoarthritis rats. AB - Calcineurin/NFAT1 signaling pathway plays critical roles in maintaining the homeostasis of articular chondrocytes and in regulating the pathogenesis of osteoarthritis (OA). A few studies demonstrate therapeutic values of ropivacaine (Rop) in OA, but the underlying mechanisms have not been defined. Here, we determined whether Calcineurin/NFAT1 signaling pathway mediates the benefits of Rop to OA. OA rat models were established by a single intra-articular injection of monosodium iodoacetate. The pathophysiology of OA was evaluated by measuring hyperalgesia behavior and the expression of NFAT1, calcineurin, catabolic enzymes in chondrocytes, and chondrogenic markers in affected articular cartilage and primary chondrocyte cultures treated with IL-1beta. ROP was applied both in vivo and in vitro to examine its effects on the pathophysiology of OA. Hyperalgesia in OA rats was improved by intra-articular injection of Rop. Moreover, Rop suppressed the overexpression of NFAT1, calcineurin, TNF-alpha, IL-6, MMP1 and MMP3, and reversed the diminution of collagen II and aggrecan, in affected cartilage of OA rats. Similar effects of Rop were also observed in mouse chondrocyte cultures treated with IL-1beta. In in vitro preparations, either activation (by increasing extracellular Ca2+) or inhibition (by cyclosporin A) of calcineurin blocked the effects of Rop. These results suggest that Rop may have therapeutic potential for OA in three aspects: analgesia, anti-inflammation, and anti-degradation of articular cartilage, probably via down-regulating calcineurin/NFAT1 signaling pathway. PMID- 29157985 TI - Evidence for autocrine and paracrine regulation of allergen-induced mast cell mediator release in the guinea pig airways. AB - Mast cells play an essential role in immediate type hypersensitivity reactions and in chronic allergic diseases of the airways, including asthma. Mast cell mediator release can be modulated by locally released autacoids and circulating hormones, but surprisingly little is known about the autocrine effects of mediators released upon mast cell activation. We thus set out to characterize the autocrine and paracrine effects of mast cell mediators on mast cell activation in the guinea pig airways. By direct measures of histamine, cysteinyl-leukotriene and thromboxane release and with studies of allergen-evoked contractions of airway smooth muscle, we describe a complex interplay amongst these autacoids. Notably, we observed an autocrine effect of the cysteinyl-leukotrienes acting through cysLT1 receptors on mast cell leukotriene release. We confirmed the results of previous studies demonstrating a marked enhancement of mast cell mediator release following cyclooxygenase inhibition, but we have extended these results by showing that COX-2 derived eicosanoids inhibit cysteinyl-leukotriene release and yet are without effect on histamine release. Given the prominent role of COX-1 inhibition in aspirin-sensitive asthma, these data implicate preformed mediators stored in granules as the initial drivers of these adverse reactions. Finally, we describe the paracrine signaling cascade leading to thromboxane synthesis in the guinea pig airways following allergen challenge, which occurs indirectly, secondary to cysLT1 receptor activation on structural cells and/ or leukocytes within the airway wall, and a COX-2 dependent synthesis of the eicosanoid. The results highlight the importance of cell-cell and autocrine interactions in regulating allergic responses in the airways. PMID- 29157986 TI - LncRNA myocardial infarction-associated transcript (MIAT) contributed to cardiac hypertrophy by regulating TLR4 via miR-93. AB - It has been reported that lncRNA myocardial infarction-associated transcript (MIAT) facilitated the pathological development in angiotensin II (AngII)-induced cardiac hypertrophy. Nevertheless, the underlying mechanism of MIAT involved in cardiac hypertrophy is largely unknown. In this study, AngII-treated cardiomyocytes were applied as a cardiac hypertrophy model in vitro. The expressions of MIAT and miR-93 were detected by qRT-PCR. The protein levels of toll-like receptor 4 (TLR4), atrial natriuretic factor (ANF), beta-myosin heavy chain (beta-MHC), phosphoinositide-3 kinase (PI3K), protein kinase B (Akt), phosphorylated Akt (p-Akt), mammalian target of rapamycin (mTOR), and phosphorylated mTOR (p-mTOR) were determined by western blot. Luciferase reporter assay and RNA immunoprecipitation (RIP) were performed to explore the relationship between MIAT, TLR4 and miR-93. Hypertrophic response was assessed by measuring cell surface area and quantifying the expressions of ANF and beta-MHC. The results demonstrated that MIAT was upregulated and miR-93 was downregulated in AngII-treated cardiomyocytes. MIAT functioned as a molecular sponge of miR-93 in cardiomyocytes. Additionally, TLR4 was identified as a target of miR-93 and MIAT promoted TLR4 expression by sponging miR-93. MIAT knockdown decreased cell surface area and the expression levels of ANF and beta-MHC in AngII-treated cardiomyocytes by modulating miR-93. Moreover, enforced expression of TLR4 partially reversed the protective effect of miR-93 overexpression on AngII induced cardiac hypertrophy. Furthermore, MIAT knockdown or miR-93 overexpression inactivated the PI3K/Akt/mTOR pathway via TLR4 in AngII-induced cardiac hypertrophy. Taken together, these data suggested that MIAT knockdown inhibited AngII-induced cardiac hypertrophy by regulating miR-93/TLR4 axis, highlighting a promising therapy target for cardiac hypertrophy. PMID- 29157987 TI - Corrigendum to "A biophysical approach to cancer dynamics: Quantum chaos and energy turbulence" [BioSystems 156-157 (June-July) (2017) 1-22]. PMID- 29157988 TI - De novo thrombotic microangiopathy after kidney transplantation. AB - Thrombotic microangiopathy (TMA) is a serious complication of transplantation that adversely affects kidney transplant recipient and allograft survival. Post transplant TMA is usually classified into two categories: 1) recurrent TMA and 2) de novo TMA. Atypical hemolytic uremic syndrome (aHUS) resulting from dysregulation and over-activation of the alternate complement pathway is a rare disease but the most common diagnosis associated with recurrence in the allografts. De novo TMA, on the other hand, represents an overwhelming majority of the cases of post-transplant TMA and is a substantially more heterogeneous entity than recurrent aHUS. Here, we review the etio-pathogenesis, diagnosis and treatment options for de novo post-transplant TMA. It is usually in the setting of calcineurin inhibitor use, mammalian target of rapamycin inhibitor use, or antibody mediated rejection; recently genetic mutations in complement regulatory genes for Factor H and Factor I similar to those described in aHUS have been reported in up to a third of these patients. Systemic signs of TMA are frequently absent, and a renal allograft biopsy is often needed to establish the diagnosis. Although withdrawal of the offending agents is usually the first line of treatment and resolution of laboratory abnormalities has been documented with this approach in several case reports and case series, available retrospective data demonstrate lack of benefit in long-term graft outcomes. Co-stimulation blockage with belatacept provides an effective alternate immunosuppressive strategy for these patients. Anti-complement therapy with eculizumab is effective in some cases; further work is required to define which patients with TMA (with and without concomitant antibody-mediated rejection) would benefit from receiving this treatment, and what biomarkers can be used to identify them. PMID- 29157989 TI - Do we publish what we preach? Analysis of Spanish Shoulder and Elbow Surgery Society publication rates. AB - INTRODUCTION: The purpose of this study is to analyse the publication rate of studies presented as podium presentations in the Spanish Society of Shoulder and Elbow Surgery (SECHC) congresses. METHODS: One hundred and twenty-two abstracts presented at the SECHC congresses held in 2007, 2009 and 2011 were included for the purpose of the study. The oral communications were categorized by study type, sample included and follow-up. In June 2017, possible publications of these studies were searched in PubMed. Type of study, delay in publication, journal and impact factor obtained were recorded. The concordance between the information presented at the congress and their subsequent full-text publications was analysed. RESULTS: The publication rate was 17.21% (21 of the 122 abstracts studied) after 6 years, with a mean time spent for publications of 36.71 months, and a mean impact factor of 1.51. There were no differences between results initially presented at the congresses and those subsequently published (P>0.05). DISCUSSION: The majority of papers presented at SECHC congresses do not end up with a publication. The papers that are published do not usually contain significant differences compared to the content delivered at the congress. PMID- 29157990 TI - New method for antibiotic release from bone cement (polymethylmethacrylate): Redefining boundaries. AB - INTRODUCTION: The increasing antimicrobial resistance is promoting the addition of antibiotics with high antistaphylococcal activity to polymethylmethacrylate (PMMA), for use in cement spacers in periprosthetic joint infection. Linezolid and levofloxacin have already been used in in-vitro studies, however, rifampicin has been shown to have a deleterious effect on the mechanical properties of PMMA, because it inhibits PMMA polymerization. The objective of our study was to isolate the rifampicin during the polymerization process using microencapsulation techniques, in order to obtain a PMMA suitable for manufacturing bone cement spacers. MATERIAL AND METHOD: Microcapsules of rifampicin were synthesized with alginate and PHBV, using Rifaldin(r). The concentration levels of rifampicin were studied by UV-visible spectrophotometry. Compression, hardness and setting time tests were performed with CMW(r)1 cement samples alone, with non-encapsulated rifampicin and with alginate or PHBV microcapsules. RESULTS: The production yield, efficiency and microencapsulation yield were greater with alginate (P = .0001). The cement with microcapsules demonstrated greater resistance to compression than the cement with rifampicin (91.26+/-5.13, 91.35+/-6.29 and 74.04+/-3.57 MPa in alginate, PHBV and rifampicin, respectively) (P = .0001). The setting time reduced, and the hardness curve of the cement with alginate microcapsules was similar to that of the control. DISCUSSION AND CONCLUSIONS: Microencapsulation with alginate is an appropriate technique for introducing rifampicin into PMMA, preserving compression properties and setting time. This could allow intraoperative manufacturing of bone cement spacers that release rifampicin for the treatment of periprosthetic joint infection. PMID- 29157991 TI - Percutaneous K wire fixation in pediatric lateral condylar fractures of humerus: A prospective study. AB - BACKGROUND: We evaluated the radiographic and clinical functional results of K wire fixation in the treatment of displaced lateral condyle fractures of the humerus. MATERIALS AND METHODS: A prospective longitudinal study was undertaken in our hospital during the period December 2010-December 2014. A total number of 85 children (18 girls and 67 boys) mean age 7.76 years; range 2-13 years with displaced (>2mm) lateral condyle fractures of the humerus. All the patients were treated by close reduction and internal fixation with two K-wires for three weeks. The fractures were classified according to the criteria by Milch and Badelon and functional results were evaluated according to the criteria by Hardacre et al. The mean follow-up period was 24 months (range: 20-28 months). RESULTS: All children achieved union in a mean time of 3 weeks (range: 2.5-6 weeks). Functional results were excellent in 91.75% children and good in 7.05% children. Full range of elbow motion was achieved in all the patients. None of the patients had instability postoperatively. Post-operatively, 5.88% children got pin tract infection, which was superficial and healed after removing pins and oral antibiotic administration. CONCLUSION: Percutaneous K-wire fixation is an effective treatment for unstable displaced lateral condylar fractures of the humerus in children. If fracture displacement after closed reduction exceeds 2mm, open reduction and internal fixation is recommended. PMID- 29157992 TI - Complications associated with the techniques for anterior cruciate ligament reconstruction in patients under 18 years old: a systematic review. AB - OBJECTIVE: Determine the complications related to the different techniques for anterior cruciate ligament reconstruction in patients under 18 years old. METHODOLOGY: Systematic review using the databases Medline, Cochrane Database of Systematic Reviews and Embase (until July 2016), additional studies were included conducting a search of the references of previous studies. The terms included in the search were: "cruciate", "ligament", "anterior", "immature", "complications", "outcome", "acl reconstruction"," cruciate ligament anterior reconstruction", "children", "child", "infants", "adolescent", "open physis", "growth plate" and "skeletally immature". RESULTS: A number of 73 studies were included; 1300 patients in total, average age 13 years, 70% were male, medial and lateral meniscal lesions in 26% and 30% respectively. Eleven cases of length discrepancy (0,8%): 4 cases were presented with physeal-sparing techniques (1,4%), 3 cases with partial physeal-sparing techniques (2.2%) and 4 cases were presented with transphyseal techniques (0.4%). There were 22 cases of axis deviation: 6 cases with physeal-sparing techniques (2%), 3 cases with partial physeal-sparing techniques and 13 cases with transphyseal techniques (1.4%). The use of allograft achilles tendon allograft and fascia lata was associated with increased length discrepancy and axis deviation (25%). There was no difference according to Tanner. CONCLUSIONS: The different anterior cruciate ligament reconstruction techniques in patients under 18 years old had low complications related to lower limb growth, arthrofibrosis and review. There was a higher percentage of cases of length discrepancy and axis deviation with physeal-sparing techniques than with the other surgical techniques. The evidence level studies cannot determine causality. PMID- 29157993 TI - Pronase independent flow cytometry crossmatching of rituximab treated patients. AB - ABO-incompatible (ABOi) kidney transplantation has become an established strategy to increase the number of available living donors. At our center, the conditioning protocol for ABOi patients is based on anti-A/B antibody removal and depletion of B cells with the anti-CD20 mAb rituximab (Mabthera(r)). It is known that even low amounts of remaining rituximab in serum of patients results in false positive B cell cross match results, masking detection of potentially harmful donor human leukocyte antigen (HLA) specific antibodies. Treatment of donor cells with high concentrations (>1 mg/mL) of pronase is currently standard procedure for elimination of rituximab (RIT) interference. It is, however, troublesome that recent reports indicate that pronase treatment per se can induce incorrect flow cytometry cross match (FCXM) results. The aim of this study was to evaluate an alternative pronase-free FCXM for crossmatching of patients treated with rituximab. FCXM with an anti-RIT monoclonal antibody (mAb) pre-blocking step were evaluated on normal human sera (NHS) and patient sera supplemented with RIT. NHS supplemented with RIT or patient sera, without donor specific antibodies (DSA), resulted in high B cell median channel shift (>200 IgG) above background. This shift was eliminated by a serum pre-blocking step with 2-fold excess of anti RIT (clone MB2A4). Blocking with anti-RIT did not influence the T cells crossmatch results. We present data supporting proof-of-concept that blocking with anti-RIT antibody prior to XM can enable reliable detection of anti-HLA class I and II donor specific antibodies without use of pronase treated donor cells. PMID- 29157994 TI - The importance of population differences: Influence of individual characteristics on the Australian public's preferences for emergency care. AB - A better understanding of the public's preferences and what factors influence them is required if they are to be used to drive decision-making in health. This is particularly the case for service areas undergoing continual reform such as emergency and primary care. Accordingly, this study sought to determine if attitudes, socio-demographic characteristics and healthcare experiences influence the public's intentions to access care and their preferences for hypothetical emergency care alternatives. A discrete choice experiment was used to elicit the preferences of Australian adults (n=1529). Mixed logit regression analyses revealed the influence of a range of individual characteristics on preferences and service uptake choices across three different presenting scenarios. Age was associated with service uptake choices in all contexts, whilst the impact of other sociodemographics, health experience and attitudinal factors varied by context. The improvements in explanatory power observed from including these factors in the models highlight the need to further clarify their influence with larger populations and other presenting contexts, and to identify other determinants of preference heterogeneity. The results suggest social marketing programs undertaken as part of demand management efforts need to be better targeted if decision-makers are seeking to increase community acceptance of emerging service models and alternatives. Other implications for health policy, service planning and research, including for workforce planning and the possible introduction of a system of co-payments are discussed. PMID- 29157996 TI - Longitudinal interactions between brain and cognitive measures on reading development from 6 months to 14 years. AB - Dyslexia is a neurobiological disorder impairing learning to read. Brain responses of infants at genetic risk for dyslexia are abnormal already at birth, and associations from infant speech perception to preschool cognitive skills and reading in early school years have been documented, but there are no studies showing predicting power until adolescence. Here we show that in at-risk infants, brain activation to pseudowords at left hemisphere predicts 44% of reading speed at 14 years, and even improves the prediction after taking into account neurocognitive preschool measures of letter naming, phonology, and verbal short term memory. The association between infant brain responses and reading speed is mediated by preschool rapid automatized naming ability. Therefore, we suggest that rapid naming and reading speed could share a similar cognitive process of automatized access to lexicon via phonological representations, and brain activation to speech sounds in infancy probably acts as an index of deficient development of the same process. PMID- 29157995 TI - In the ovine pituitary, CXCR4 is localized in gonadotropes and somatotropes and increases with elevated serum progesterone. AB - The pituitary is the central endocrine regulator of reproduction and in addition to various hormones regulating its actions, other molecules, such as chemokines, influence pituitary physiology as well. Despite reports over 2 decades ago that chemokines regulate the pituitary, much of the basic biology discerning chemokine action in the pituitary is unclear. A small number of chemokines and their receptors have been localized to the pituitary, yet chemokine ligand 12 (CXCL12) and its receptor, CXCR4, have received the most attention as both are increased in human pituitary adenomas. This chemokine duo was also reported in normal human and rat pituitary, suggestive of a functional role and that this chemokine axis might function in pituitaries from other mammalian species. To date, reports of CXCL12 and CXCR4 in pituitary from livestock are lacking, and research on pituitary during pregnancy in any mammalian species is limited. Moreover, progesterone regulates CXCR4 expression in a tissue-dependent manner, but whether differing concentrations of progesterone reaching the pituitary modulate CXCL12 or CXCR4 is not known. To address these gaps, our first objective was to determine if CXCL12 and CXCR4 expression and protein abundance differ in sheep pituitary during early gestation (days 20, 25, and 30 of gestation) compared to nonpregnant ewes. The second objective was to determine if CXCL12 or CXCR4 production was altered in the ovine pituitary when circulating progesterone concentrations are elevated. The expression of CXCL12 messenger RNA decreased on day 20 of gestation compared to nonpregnant ewes; CXCL12 protein was similar across all days tested. In nonpregnant and pregnant ewes, CXCR4 was localized to somatotropes and gonadotropes on all days tested. Abundance of CXCR4 increased in the pituitary tissue of pregnant ewes with elevated circulating progesterone compared with pregnant ewes with normal circulating progesterone concentrations (control). The present study details CXCL12 and CXCR4 in normal ovine pituitary and reveals that gonadotropes and somatotropes may be regulated by CXCL12/CXCR4, underscoring this signaling axis as a potential new class of modulator in endocrine functions. PMID- 29157997 TI - Smaller amygdala volume and increased neuroticism predict anxiety symptoms in healthy subjects: A volumetric approach using manual tracing. AB - Volume reductions in the amygdala (AMY) have been found in patients with anxiety disorders, but findings are mixed in subclinical participants with high trait anxiety scores, in whom both reductions and increases in AMY volume have been identified. One potential reason for such discrepancies could be the employment of different methods to determine the AMY volume (i.e., manual tracing in psychiatric research vs. automated methods), in non-patient research. In addition to trait anxiety, smaller AMY volume has also been linked to neuroticism, a personality trait consistently linked to increased vulnerability to anxiety. However, it is not clear how AMY volume and neuroticism together may contribute to anxiety symptoms in healthy functioning. These issues were investigated in a sample of 46 healthy participants who underwent anatomical MRI scanning and completed questionnaires measuring trait anxiety and neuroticism. AMY volume was assessed using manual tracing, based on anatomical landmarks identified in each participant's anatomical image. First, smaller left AMY volume was linked to higher levels of neuroticism (p = .013) and trait anxiety (p = .024), which in turn were positively correlated with each other. Moreover, AMY volume had a significant indirect effect on trait anxiety through neuroticism (ab = - .009, 95% CI [- .019, - .002]). This effect was not bidirectional, as trait anxiety did not predict AMY volume through neuroticism. Collectively, these findings provide support for a brain-personality-symptom framework of understanding affective dysregulation, which may help inform the development of prevention and intervention paradigms targeting preservation of AMY volume and reduction of neuroticism, to protect against anxiety symptoms. PMID- 29157998 TI - The developmental time course and topographic distribution of individual-level monkey face discrimination in the infant brain. AB - The ability to discriminate between faces from unfamiliar face groups has previously been found to decrease across the first year of life. Here, individual level discrimination of faces within a previously unfamiliar group was investigated by measuring neural responses to monkey faces. Six- and 9-month-old infants (n = 42) completed a Fast Periodic Visual Stimulation (FPVS) task while steady state visual evoked potentials (ssVEPs) were recorded. Using an oddball task design (e.g., infrequent changes in face identity) faces were presented at a 6Hz (1 face approximately every 167ms) stimulation rate and every 1.2Hz different individual monkey faces were presented. Significant SNRs at 1.2Hz in both 6- and 9-month-old infants suggest that neural responses, recorded over posterior scalp regions, remain sensitive to individual-level differences within an unfamiliar face group despite previous behavioral evidence of decreased discrimination. However, the topographic distribution of the 1.2Hz response varied by age, suggesting that 6- and 9-month-old infants are using different neural populations to discriminate unfamiliar faces at the individual level. PMID- 29157999 TI - Chromaticity separation and the alpha response. AB - Chromatic gratings can be uncomfortable to view and can evoke a large haemodynamic response. Both the discomfort and the amplitude of the haemodynamic response increase monotonically with the perceptual difference in the colour of the component bars of the grating, as registered by the separation in their chromaticity in the CIE 1976 UCS diagram. Individuals with photosensitive epilepsy exhibit epileptiform EEG activity in response to flickering light of alternate colours. The probability of the epileptiform response again increases monotonically with the separation of the colours in the CIE UCS diagram. We investigated whether alpha power, which is known to reflect the excitation of large populations of neurons, is similarly affected by the separation in chromaticity. Chromatic square-wave gratings with bars that differed in CIE UCS chromaticity were presented, together with a central fixation cross. In 18 non clinical participants, alpha responses were recorded over the visual cortex (O1, Oz, O2, PO3, POz, PO4, P1, P2) and compared to responses in prefrontal cortex (F1, F2). Gratings comprised bars of two alternate colours that either had a small difference in chromaticity (mean CIE UCS separation of 0.03), a medium difference (mean separation of 0.19), or a large difference (mean separation of 0.43). The colour pairs had chromaticities that lay on the red-green, red-blue, or blue-green borders of the screen gamut. Regardless of the hue, the larger the separation in chromaticity, the greater the alpha desynchronization and the lower the alpha power (p = 0.004), but only in posterior electrodes (p < 0.001). Together this indicates that differences in colour evoke a cortical excitation that increases monotonically with the colour difference. In this respect the alpha response resembles the haemodynamic response. PMID- 29158000 TI - Functional genomic fabrics are remodeled in a mouse model of Chagasic cardiomyopathy and restored following cell therapy. AB - We previously found that, in a mouse model of Chagas cardiomyopathy, 18% of the 9390 quantified unigenes were significantly regulated by Trypanosoma cruzi infection. However, treatment with bone marrow-derived mononuclear cells (MNCs) resulted in 84% transcriptomic recovery. We have applied new algorithms to reanalyze these datasets with respect to specific pathways [Chagas disease (CHAGAS), cardiac muscle contraction (CMC) and chemokine signaling (CCS)]. In addition to the levels of expression of individual genes we also calculated gene expression variability and coordination of expression of each gene with all others. These additional measures revealed changes in the control of transcript abundances and gene networking in CHAGAS and restoration following MNC treatment, not accessible using the conventional approach limited to the average expression levels. Moreover, our weighted pathway regulation analysis incorporated the contributions of all affected genes, eliminating the arbitrary cut-off criteria of fold-change and/or p-value for significantly regulated genes. The new analyses revealed that T. cruzi infection had large transcriptomic consequences for the CMC pathway and triggered a huge cytokine signaling. Remarkably, MNC therapy not only restored normal expression levels of numerous genes, but it also recovered most of the CHAGAS, CMC and CCS fabrics that were altered by the infection. PMID- 29158001 TI - Characterisation of sludge for pyrolysis conversion process based on biomass composition analysis and simulation of pyrolytic properties. AB - Pyrolytic behaviour of sludge is highly complex and obscure because of its heterogeneous and diverse composition. Therefore, an analytical procedure is proposed to categorise and quantify the main constituents in sludge. In addition, a simulation study of sludge characteristics is carried out to complement the composition analysis and to improve our understanding on the relationship between composition of sludge and its corresponding properties. Different types of sludge samples were collected at different treatment stages from four Water Reclamation Plants in Singapore in two separate batches. Model compounds are selected to represent components identified and are used in simulation of pyrolytic properties of sludge. Constituents of sludge are adequately categorised, quantified and characterised in this study. Qualitative similarities and quantitative variations on characteristics of different sludge samples were identified. Comparison among the samples collected with the simulation provided insights on how differences in organic composition of sludge affected its properties. PMID- 29158002 TI - SOFC single cells fed by biogas: Experimental tests with trace contaminants. AB - Biogas from biological treatments and from the waste degradation in landfills generally contains a wide range of trace impurities (e.g., sulphur compounds, siloxanes, halogens, tar compounds, etc.). This paper describes an experimental analysis performed with SOFC single cells fed by a synthetic gas polluted by H2S, HCl, D4 and a mixture of H2S + C2Cl4. The aim is to detect the threshold tolerance limit on different cell performance parameters. Results show how: hydrogen sulphide has a strong impact on the polarization losses due to the nickel sulphide formation on the electrode that causes a mass transfer resistance. Hydrogen chloride particularly limited the electrochemical processes. Octamethylcyclotetrasiloxane (D4) showed a high impact on SOFC performance even at ultra-low level (78-178 ppb(v)) as a consequence of the formation of silicon dioxide covering the anode porous sites. Sulphur added to C2Cl4, accelerated the deterioration of SOFC performance. In addition, current density variations and operating temperature are studied during sulphur poisoning. An opposite behaviour on SOFC performance was revealed by operating temperature and current density. PMID- 29158003 TI - Transportation fuel from plastic: Two cases of study. AB - Synthesis of liquid fuels from waste is a promising pathway for reducing the carbon footprint of transportation industry and optimizing waste management towards zero landfilling. The study of commercial plants that conduct pyrolysis of plastics from post-consumer recycled materials and directly mine from old landfills without any pre-treatment has revealed two cases that show the feasibility of manufacturing transportation fuels via these methods. Pyrolysis oil, consisting of almost 26% hydrocarbons within the gasoline range and almost 70% within the diesel range, is upgraded to transportation fuel in the existing refinery. A batch operating plant is able to deliver relatively good quality pyrolysis oil from post-consumer plastic waste, owing to the catalyst employed. Simple distillation was also evaluated as an alternative and cheaper upgrading process into transportation fuels, meeting EN590 diesel and ISO8217 marine fuel standards. Even though the two installations are outside the European Union, they represent good examples of the "circular economy" concept envisaged by the European Union via its ambitious "Circular Economy Package [1]", providing real world data for comparison with other experimental and lab results. PMID- 29158004 TI - Probing the interaction of copper cofactor and azachalcone substrate with G quadruplex of DNA based Diels-Alderase by site-specific fluorescence quenching titration. AB - DNAzymes have been widely used in biosensors, asymmetric synthesis and pharmaceuticals. Typically, metal cofactor and substrate interact with DNA by supramolecular interactions in DNAzyme based asymmetric catalysis. However, binding positions of cofactor and substrate with DNA scaffold are not well understood, which is an obstacle to reveal the assembly and catalysis mechanisms of DNAzyme. Herein, we report a method of site-specific fluorescence quenching titration to elucidate the assembly and catalysis processes of a G-quadruplex based Diels-Alderase DNAzyme. Titration data indicate that cofactor Cu(II) terpyridine stacked atop 5' and 3' external G-quartets with high and low binding affinities respectively, and induced the G-quadruplex to form a hybrid-1 topology. Substrate azachalcone interacted with 3' quartet exclusively, implicating that asymmetric Diels-Alder cycloaddition may occur at 3' G-quartet. In addition, enzyme kinetic analyses show that activity and enantioselectivity of the DNAzyme were substantially preserved after attaching the fluorophores. Overall, site-specific fluorescence quenching is a concise and efficient approach to probe the assembly processes of DNAzyme. PMID- 29158005 TI - 1,25(OH)2D3 induced apoptosis of human hepatocellular carcinoma cells in vitro and inhibited their growth in a nude mouse xenograft model by regulating histone deacetylase 2. AB - The aim of this study was to evaluate the effects of 1,25(OH)2D3 on the apoptosis of human hepatocellular carcinoma (HCC) cells. The effects of 1,25(OH)2D3 on the proliferation and apoptosis of human HCC cells by regulating histone deacetylase 2 (HDAC2) were assessed by MTT assay and flow cytometry. The effects of 1,25(OH)2D3 on the expressions of related proteins in the apoptosis pathway by regulating HDAC2 as well as the mechanism were studied by Western blot and quantitative real-time PCR. A nude mouse model of HCC xenograft was established. A control group, a 1,25(OH)2D3 treatment group, a 1,25(OH)2D3 + HDAC2 overexpression group, an HDAC2 interference group and an HDAC2 overexpression group were set. The tumor volume was recorded, and histopathological changes were observed by HE staining. 1,25(OH)2D3 inhibited the proliferation of HepG2 cells and induced their apoptosis. Overexpression of HDAC2 attenuated the inhibitory effects of 1,25(OH)2D3 on the proliferation of HepG2 cells and its ability to induce apoptosis. In the 1,25(OH)2D3 + HDAC2 overexpression group, the expressions of p53, Bax, DR5 and caspase 8 were significantly lower but the expression of Bcl-2 was significantly higher than those of the 1,25(OH)2D3 treatment group (P < 0.05). Compared with the control group, 1,25(OH)2D3 treatment and HDAC2 interference groups had significantly decreased tumor volumes and promoted apoptosis of HCC cells in tumor tissues. Overexpression of HDAC2 weakened the inhibitory effects of 1,25(OH)2D3 on tumor volume and its ability to induce apoptosis in tissues. A large area of tumor cells underwent necrosis in 1,25(OH)2D3 treatment and HDAC2 interference groups. In the 1,25(OH)2D3 + HDAC2 overexpression group, both the area of necrosis and cell volume decreased. In conclusion, 1,25(OH)2D3 inhibited the proliferation of HCC cells and induced their apoptosis by down-regulating the expression of HDAC2, up-regulating p53, and regulating its downstream mitochondria-mediated pathway and the exogenous DR mediated pathway. PMID- 29158006 TI - VDR independent induction of acid-sphingomyelinase by 1,23(OH)2 D3 in gastric cancer cells: Impact on apoptosis and cell morphology. AB - 1 alpha,25-dihydroxyvitamin D3 (1,23(OH)2 D3) is known to play a dual role in cancer, by promoting or inhibiting carcinogenesis via 1,23(OH)2 D3 receptor (VDR) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Fok I polymorphism of VDR may indirectly influence the receptor levels through autoregulation. The involvement of neutral sphingomyelinase in the non-classic VDR-mediated genomic pathway response to 1,23(OH)2 D3 treatment has been reported. Until now no information were reported about Fok I polymorphism of VDR in NCI-N87 human gastric cancer cells and the relation between acid sphingomyelinase and 1,23(OH)2 D3. Herein, we showed that NCI-N87 human gastric cancer cells are homozygous for the Fok I 'C' allele; resulting in a three amino acid-truncated protein form of the VDR. Surprisingly 1,23(OH)2 D3 treatments strongly down-regulated the expression of VDR whereas acid sphingomyelinase and PTEN expression were upregulated. No changes of neutral sphingomyelinase expression were observed after 1,23(OH)2 D3 treatment, whereas acid sphingomyelinase activity increased. Furthermore 1,23(OH)2 D3 induced over expression of caspase 8, CDKN2B, MAP3K5, cytochrome C apoptotic genes. Morphological analysis highlighted some very large round or oval cells and small cells with angular or fusiform extensions, confirmed by MIB-1 immunodetection and Hercep test. Taken together our results indicated that the action of 1,23(OH)2 D3 in gastric cancer cells was independent on 1,23(OH)2 D3 receptor and suggested the acid sphingomyelinase as a possible target to induce molecular events. PMID- 29158007 TI - Unmet needs in pulmonary embolism: Simplified anticoagulation and much more. PMID- 29158008 TI - The heart team approach to transcatheter aortic valve implantation: What has been done and what is to be expected. PMID- 29158009 TI - Effect of carbamazepine on expression of UDP-glucuronosyltransferase 1A6 and 1A7 in rat brain. AB - Because UDP-glucuronosyltransferase (Ugt) 1a6 and Ugt1a7 are highly expressed in the rat brain, changes in Ugt1a6 and Ugt1a7 expression may affect the pharmacokinetics of drugs and endogenous compounds in the brain. The present study aimed to elucidate the effect of carbamazepine (CBZ), a typical UGT inducer, on Ugt1a6 and Ugt1a7 expression in the rat brain. Sprague-Dawley rats were treated intraperitoneally for 7 d with CBZ (100 mg/kg/d). Ugt1a6 and Ugt1a7 mRNAs were induced by CBZ in the cerebellum, piriform cortex, and hippocampus (Ugt1a6: 3.1-, 2.4-, and 1.9-fold, respectively, Ugt1a7: 2.3-, 1.6-, and 3.1 fold, respectively); serotonin glucuronidation, which is catalyzed by Ugt1a6, was also increased by 2.8-, 1.7-, and 1.8-fold in these regions, respectively. The nuclear translocation of the constitutive androstane receptor was increased 1.4 fold in the cerebellum and piriform cortex, suggesting that brain Ugt1a6 and Ugt1a7 might be induced via the constitutive androstane receptor. However, the pregnane X receptor and nuclear factor erythroid 2-related factor 2 did not play decisive roles in the induction. Histone H3 lysine 9 acetylation, H3 lysine 4 pan methylation, and H3 lysine 9 mono-methylation may not be required for the induction. This study clarified that CBZ affected Ugt1a6 and Ugt1a7 in the brain. PMID- 29158010 TI - Complexity of intermittent letrozole adjuvant therapy. PMID- 29158012 TI - A randomized, double-blind, placebo-controlled proof of concept study to evaluate samidorphan in the prevention of olanzapine-induced weight gain in healthy volunteers. AB - Antipsychotic medications are associated with weight gain and adverse metabolic effects that complicate the treatment and management of schizophrenia. Olanzapine (OLZ) in particular is associated with significant weight gain and adverse metabolic effects. The present Phase 1, proof of concept, multicenter, randomized, double-blind, placebo-controlled study investigated the safety and effect on weight of a combination of OLZ (10mg) and the opioid modulator samidorphan (SAM; 5mg) in comparison to OLZ alone in healthy, male normal weight volunteers. Altogether, 106 male subjects with stable body weight and BMI 18 25kg/m2 were randomized to OLZ alone, OLZ+SAM, SAM alone, or placebo in a 2:2:1:1 ratio. The primary efficacy endpoint, mean (SD) body weight change from baseline to last assessment in the 3-week treatment period, was significantly less for OLZ+SAM vs. OLZ alone subjects [+2.2 (1.4) kg vs. +3.1 (1.9) kg; respectively; p=0.02]. In contrast, there was no significant difference in weight from baseline for either SAM or placebo [+0.1 (1.0) kg and +0.8 (1.4) kg, respectively]; p=0.09. Overall, OLZ+SAM compared to OLZ alone had similar safety and tolerability. In addition, less nausea was observed in subjects given OLZ+SAM compared to SAM alone. Thus, OLZ+SAM may offer effective treatment of schizophrenia with less weight gain and metabolic risk. Additional research exploring additional doses over longer durations in psychiatric populations is warranted. PMID- 29158013 TI - Association study of schizophrenia with variants in miR-137 binding sites. AB - There is strong cumulative evidence for the involvement of miR-137 and its targets in the aetiology of schizophrenia. Here we test whether variants, especially rare variants, in miR-137 binding sites are associated with schizophrenia in an exome-sequenced sample of 4225 cases and 5834 controls. Only a small proportion of binding sites were covered by the capture system which had been used. A weighted burden test using the 372 detected variants demonstrated an excess among cases significant at p=0.024. The sample size is too small to implicate individual variants or genes but overall this finding does provide some further support for the hypothesis that disruption of miR-137 binding sites can increase the risk of schizophrenia, perhaps by leading to over-expression of the target gene. We recommend that future exome sequencing studies should cover the untranscribed regions of genes, which contain the microRNA binding sites, in order that this potentially important pathogenic mechanism can be adequately investigated. PMID- 29158014 TI - Movement patterns in Entomopathogenic nematodes: Continuous vs. temporal. AB - To exploit resources, animals implement various foraging behaviors to increase their fitness. Entomopathogenic nematodes are obligate parasites of insects in nature. In previous studies, entomopathogenic nematodes were reported to exhibit group movement behavior in the presence and absence of insect hosts. However, it was not determined if group movement is continuous or temporal. For example, nematode movement behavior upon emergence from the host might start out in an independent fashion prior to aggregation, or group movement may be exhibited continuously. In the present study, we explored the propensity for innate group movement behavior of two insect parasitic nematodes in two families and genera: Heterorhabditis indica and Steinernema carpocapsae. We hypothesized the nematode populations would initially move independently from their origin and then come together for group movement. Movement patterns were investigated in sand when nematodes were applied in aqueous suspension (via filter paper) to a specific locus or when the nematodes emerged naturally from infected insect hosts. To compare nematode movement behavior over time and space, nematode dispersal was monitored at three distances (2.5, 4.5 and 8.0 cm) from the center (origin) and at two different time periods, 2 days and 3 days after nematode addition. We discovered that nematode dispersal continuously exhibited an aggregative pattern (independent movement was not observed). Results from both nematode species as well as the host-cadaver and filter paper (aqueous nematode suspension) application methods indicated a continuous aggregative pattern. The discovery of continuous aggregative movement patterns in steinernematid and heterorhabditid nematodes elucidates further the complexity of their foraging behavior and may serve as basis for exploring foraging behavior in other host-parasite systems. PMID- 29158015 TI - Acute bee paralysis virus occurs in the Asian honey bee Apis cerana and parasitic mite Tropilaelaps mercedesae. AB - Viruses, and especially RNA viruses, constantly change and adapt to new host species and vectors, posing a potential threat of new and reemerging infectious diseases. Honey bee Acute bee paralysis virus (ABPV) and Deformed wing virus (DWV) are two of the most common honey bee viruses found in European honey bees Apis mellifera and have been implicated in worldwide Varroa-associated bee colony losses. Previous studies have shown that DWV has jumped hosts several times in history causing infection in multiple host species. In the present study, we show that DWV infection could be detected in the Asian honey bee, A. cerana, and the parasitic mite Tropilaelaps mercedesae, confirming previous findings that DWV is a multi-host pathogen and supporting the notion that the high prevalence of DWV in honey bee host populations could be attributed to the high adaptability of this virus. Furthermore, our study provides the first evidence that ABPV occurs in both A. cerana and T. mercedesae in northern Thailand. The geographical proximity of host species likely played an important role in the initial exposure and the subsequent cross-species transmission of these viruses. Phylogenetic analyses suggest that ABPV might have moved from T. mercedesae to A. mellifera and to A. cerana while DWV might have moved in the opposite direction from A. cerana to A. mellifera and T. mercedesae. This result may reflect the differences in virus life history and virus-host interactions, warranting further investigation of virus transmission, epidemiology, and impacts of virus infections in the new hosts. The results from this study indicate that viral populations will continue to evolve and likely continue to expand host range, increasing the need for effective surveillance and control of virus infections in honey bee populations. PMID- 29158016 TI - Genetic hemochromatosis: Pathophysiology, diagnostic and therapeutic management. AB - The term hemochromatosis (HC) corresponds to several diseases characterized by systemic iron overload of genetic origin and affecting both the quality of life and life expectancy. Major improvement in the knowledge of iron metabolism permits to divide these diseases into two main pathophysiological categories. For most HC forms (types 1, 2, 3 and 4B HC) iron overload is related to cellular hepcidin deprivation which causes an increase of plasma iron concentration and the appearance of plasma non-transferrin bound iron. In contrast, iron excess in type 4A ferroportin disease is related to decreased cellular iron export. Whatever the HC type, the diagnosis rests on a non-invasive strategy, combining clinical, biological and imaging data. The mainstay of the treatment remains venesection therapy with the perspective of hepcidin supplementation for hepcidin deprivation-related HC. Prevention of HC is critical at the family level and, for type 1 HC, remains a major goal, although still debated, at the population level. PMID- 29158017 TI - Left Atrial Appendage Occlusion/Exclusion: Procedural Image Guidance with Transesophageal Echocardiography. AB - Atrial fibrillation is the most common arrhythmia worldwide and is a major risk factor for embolic stroke. In this article, the authors describe the crucial role of two- and three-dimensional transesophageal echocardiography in the pre- and postprocedural assessment and intraprocedural guidance of percutaneous left atrial appendage (LAA) occlusion procedures. Although recent advances have been made in the field of systemic anticoagulation with the novel oral anticoagulants, these medications come with a significant risk for bleeding and are contraindicated in many patients. Because thromboembolism in atrial fibrillation typically arises from thrombi originating in the LAA, surgical and percutaneous LAA exclusion/occlusion techniques have been devised as alternatives to systemic anticoagulation. Currently, surgical LAA exclusion is typically performed as an adjunct to other cardiac surgical procedures, which limits the number of eligible patients. Recently, several percutaneously delivered devices for LAA exclusion from the systemic circulation have been developed, some of which have been shown in clinical trials to reduce the risk for thromboembolism. These devices use an either purely endocardial LAA occlusion approach, such as the Watchman and Amulet procedures, or both an endocardial and a pericardial (epicardial) approach, such as the Lariat procedure. In the Watchman and Amulet procedures, a transseptally delivered structure composed of nitinol is placed in the LAA orifice, thereby excluding the LAA from the systemic circulation. In the Lariat procedure, a magnet link is created between a transseptally delivered endocardial wire and epicardially delivered pericardial wire, followed by epicardial suture ligation of the LAA. PMID- 29158018 TI - Centile Curves for Velocity-Time Integral Times Heart Rate as a Function of Ventricular Length: The Use of Minute Distance Is Advantageous to Enhance Clinical Reliability in Children. AB - BACKGROUND: The generation of velocity-time integrals (VTIs) from Doppler signals is an essential component of standard echocardiographic investigations. The most effective algorithm to compensate for growth in children has, however, not yet been identified. This study was initiated to establish pediatric reference values for VTI and to enhance the interpretability of those values, considering technical and physiological factors. METHODS: The echocardiographic data sets of healthy children and adolescents (N = 349; age range, 0-20 years) were recorded in a prospective approach and subsequently analyzed. In a pilot study, aortic and pulmonary VTIs were set in relation to the physiologic parameters of heart size as possible influencing parameters in a subgroup of children with comparable physical characteristics. The ratio with the smallest SD was taken as the base to generate centile curves using the LMS method. The clinical utility of the model was tested by examining patients (n = 80) with shunt lesions such as patent ductus arteriosus and atrial septal defect. RESULTS: Feasibility was 94.6% for aortic VTI and 92.8% for pulmonary VTI. The pilot study identified ventricular length and heart rate as suitable parameters with the lowest relative SDs and high correlations with VTI. Gender differences were not relevant for children <7 years of age, and with increasing age, SD increased because of higher stroke volume variations. The detection of increased aortic VTI was possible with sensitivity of 73% for patients with patent ductus arteriosus with moderate or large hemodynamically significant ductus arteriosus. Patients with atrial septal defects with enlarged right ventricles could be identified as having increased pulmonary VTI with sensitivity of 84%. CONCLUSIONS: These new reference values for VTI times heart rate as a function of ventricular length may be of specific clinical value to improve the assessment of cardiac function, therapeutic decision making, and follow-up in pediatric patients with heart disease. PMID- 29158019 TI - Impact of Significant Mitral Regurgitation on Assessing the Severity of Aortic Stenosis. AB - BACKGROUND: Significant mitral regurgitation (MR) may reduce a pressure gradient of aortic stenosis (AS) by decreasing forward stroke volume. The study objective was to evaluate whether significant MR can cause inconsistency when assessing the severity of AS. METHODS: Among 5,355 patients diagnosed with AS from 2000 to 2015, 68 were retrospectively found to have concomitant significant (moderate or greater) MR and normal left ventricular ejection fractions in normal sinus rhythm (AS with MR). As a control group, 136 patients with trivial or no MR were selected who were matched by age, gender, and left ventricular end-systolic volume (AS without MR). Nonlinear regression was performed for data pairs (aortic valve area [AVA] vs mean pressure gradient [MPG]) using the formula AVA = a + b/?MPG. Composite clinical events were defined as aortic valve surgery warranted by the development of symptoms or left ventricular dysfunction, admission because of heart failure, and death. RESULTS: The forward stroke volume index was significantly lower in the AS with MR group than in the AS without MR group (43.8 +/- 8.3 vs 49.2 +/- 10.2 mL/m2, P < .004). A significant group difference was found with respect to the relationship between (indexed) AVA and MPG (AVA, 0.02 + 4.43/?MPG vs -0.06 + 5.60/?MPG [P for interaction = .04]; indexed AVA, 0.03 + 2.66/?MPG vs -0.03 + 3.47/?MPG [P for interaction = .01]). An AVA of 1.0 cm2 corresponded to MPGs of 20.3 and 28.2 mm Hg for the groups with and without MR, respectively. Conversely, an MPG of 40 mm Hg corresponded to AVAs of 0.72 and 0.83 cm2 for the groups with and without MR, respectively. Among patients with MPGs < 40 mm Hg, clinical event rates were significantly higher in those with MR compared with those without MR (P = .009). CONCLUSIONS: This quantitative analysis demonstrated that AS severity assessed by MPG measurement may be underestimated, and thus AVA measurement is essential in patients with combined significant MR. PMID- 29158011 TI - Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial. AB - BACKGROUND: In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women. METHODS: We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2.5 mg/day orally for 5 years) or intermittent use of letrozole (2.5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2.5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing. FINDINGS: Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85.8% (95% CI 84.2-87.2) in the intermittent letrozole group compared with 87.5% (86.0-88.8) in the continuous letrozole group (hazard ratio 1.08, 95% CI 0.93-1.26; p=0.31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group). INTERPRETATION: In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them. FUNDING: Novartis and the International Breast Cancer Study Group. PMID- 29158020 TI - Head shape variation in cerambycid saproxylic beetles as a function of host plant selection. AB - Saproxylic insects depend on deadwood for larval development, and a certain degree of specialization may be involved in their choice of host plants and/or wood in a particular stage of degradation. The plant species chosen for oviposition in turn act as an environmental pressure on the head morphology of larvae and it is expected that head shape plasticity varies directly with the number of woody plant species used for larval development in each insect species. We analyzed head shape variation in saproxylic beetles with respect to host plant species, maximum time of larval emergence and season of the year when insects colonized branches. Generalist species in the use of host plants showed significant variation in head shape and size. Time of emergence and season did not appear to affect head shape, although season was a determinant factor of abundance and possibly head size variation. PMID- 29158021 TI - Gold nanoparticles potentiate CaV channel currents in rat tail artery myocytes. AB - This study was designed to unveil effects of 5-nm sized, polyvinylpyrrolidone coated gold nanoparticles (AuNPs) on vascular CaV1.2 and CaV3.1 channels. Ba2+ currents through both channels (IBa1.2 and IBa3.1) were recorded in single myocytes isolated from the rat tail main artery by means of the whole-cell patch clamp method. AuNPs increased IBa1.2 and IBa3.1 amplitude in a concentration- and Vh-dependent manner. Neither the voltage dependence of inactivation and activation curves nor inactivation and activation kinetics were affected by AuNPs. In conclusion, these findings warrant further investigation to clarify whether different types of NPs possess the same stimulatory activity and may represent a toxic hazard to humans. PMID- 29158022 TI - Activation of the Nrf2 signaling pathway and neuroprotection of nigral dopaminergic neurons by a novel synthetic compound KMS99220. AB - The transcription factor Nrf2 is known to induce gene expression of antioxidant enzymes and proteasome subunits. Because both oxidative stress and protein aggregation have damaging effects on neurons, activation of the Nrf2 signaling should be beneficial against neurodegeneration. In this study, we report a novel synthetic morpholine-containing chalcone KMS99220 that confers neuroprotection. It showed high binding affinity to the Nrf2 inhibitory protein Keap-1 and increased nuclear translocation of Nrf2 and gene expression of the antioxidant enzymes heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1, and the catalytic and modifier subunits of glutamate-cysteine ligase in dopaminergic CATH.a cells. KMS99220 also increased expression of the proteasome subunits PSMB5, PSMB7, PSMB8 and PSMA1, and the respective chymotrypsin and trypsin-like proteasomal enzyme activities, and reduced alpha-synuclein aggregate in GFP-alpha-syn A53T overexpressing cells. KMS99220 exhibited a favorable pharmacokinetic profile with excellent bioavailability and metabolic stability, did not interfere with activities of the cytochrome p450 isotypes, and showed no apparent in vivo toxicity when administered up to 2000 mg/kg. In 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-treated mice, oral administration of KMS99220 prevented degeneration of the nigral dopaminergic neurons, induced the Nrf2 target genes, and effectively prevented the associated motor deficits. These results suggest KMS99220 as a potential candidate for therapy against Parkinson's disease. PMID- 29158023 TI - Statin has more protective effects in AMI patients with higher plasma BNP or NT proBNP level, but not with lower left ventricular ejection fraction. AB - BACKGROUND: The benefit of statin therapy in patients with higher grades of heart failure has yet to be determined. The present study investigated whether statin therapy affects major composite outcomes (MCOs) and all-cause mortality in patients with acute myocardial infarction (AMI) within 1 year after AMI, according to their plasma natriuretic peptide (NP) levels and left ventricular ejection fraction (LVEF). METHODS: A total of 11,492 patients with AMI from two nationwide registry databases in Korea were analyzed. AMI patients were divided into quartiles by plasma levels of B-type NP (BNP) or N-terminal pro-BNP (NT proBNP) at admission. Patients with LVEF <40% on initial echocardiography were also evaluated. Total mortality and MCOs within 12 months of AMI, including death, nonfatal MI, and revascularization, were assessed. RESULTS: Among AMI patients, statin therapy was included in the discharge medications for 9075 (79.0%) patients, but not for the remaining 2417 patients (21.0%), and statin therapy was associated with a 27.8% lower risk of MCOs. After adjusting for risk factors, statin therapy was associated with lower hazard ratios for MCOs and all cause mortality in only the third and fourth NP quartile subgroups, being effective only with moderate- to high-intensity statin therapy. However, statins did not modify the outcomes in patients with LVEF <40%. CONCLUSIONS: Our results show that moderate- to high-intensity statin therapy was associated with a lower risk of major clinical outcomes and all-cause mortality in AMI patients with higher plasma NP, but not in AMI patients with decreased LVEF. PMID- 29158024 TI - Evaluation of the simplified therapeutic intervention scoring system: Chinese version. AB - OBJECTIVE: To prepare the Simplified Therapeutic Intervention Scoring System (TISS-28) to measure nursing workload in Intensive Care Units in Guangdong Province of China. METHODS: A non-experimental descriptive study was conducted in the intensive care units in the Province. TISS-28, TISS-76, Acute Physiology and Chronic Health Evaluation (APACHE II) were all measured. RESULTS: There were significant positive correlations between TISS-28 and APACHE II (n=91, r=0.432, p<0.001), TISS-76 scores (n=83, r=0.764, p<0.001). A significant difference was found between the mean TISS-28 score in the first day of the intensive care stay and the last day (30.76+/-6.86 vs 24.67+/-5.48, p<0.001). A significant intra class correlation was found between TISS-28 scores collected by the researcher and research associates (ICC=0.959, p<0.001). CONCLUSION: The reliability and validity of TISS-28 were shown in Chinese intensive care units. It is a practical tool for estimating the nursing workload and providing opportunities to compare the data between intensive care units in different facilities. The TISS-28 Chinese version is recommended to guide the allocation of nursing manpower in Chinese intensive care units. PMID- 29158025 TI - Oligomycins A and E, major bioactive secondary metabolites produced by Streptomyces sp. strain HG29 isolated from a Saharan soil. AB - An actinobacterial strain, HG29, with potent activity against pathogenic, toxigenic and phytopathogenic fungi was isolated from a Saharan soil sample of Algeria. On the basis of morphological and chemotaxonomic characteristics, the strain was classified in the genus Streptomyces. Analysis of the 16S rRNA gene sequence showed a similarity level of 99.3% with Streptomyces gancidicus NBRC 15412T. The comparison of its cultural and physiological characteristics with this species revealed significant differences. Moreover, the phylogenetic tree showed that strain HG29 forms a distinct phyletic line within the genus Streptomyces. Production of antifungal activity was investigated by following kinetics in shake broth. The highest antifungal activity was obtained after five days of fermentation, and in the dichloromethane extract. Two active compounds, NK1 and NK2, were purified by HPLC using a C18 column. Their chemical structures were identified through nuclear magnetic resonance experiments and mass spectrometry as oligomycins E and A, respectively, which have not been reported to be produced by S. gancidicus. The two bioactive compounds exhibited significant antifungal activity in vitro, showing minimal inhibitory concentrations (MICs) values between 2 and 75MUg/mL. PMID- 29158026 TI - The effects of exercise and calm interactions on in-kennel behavior of shelter dogs. AB - Over-activity, or excessive locomotion and barking in the kennel, may be unattractive to adopters and an indicator of poor welfare of kenneled dogs. The study assessed the efficacy of two common enrichment strategies, providing calm interaction and additional exercise, on in-kennel behavior in 16 shelter dogs. Both interventions resulted in appropriate behavior just prior to the sessions (t=2.10, df=7, p=0.03 and F [2216]=7.58, p=0.0007, respectively), but both also resulted in an increase of some undesirable behaviors immediately after the dogs were taken back to their kennels (F [3216]=7.77, p=0.0001 and F (5216)=10.1, p<0.0001 respectively). Right after receiving additional exercise, the dogs spent more time in back and forth motion in the kennel. Right after receiving the calm interaction, the dogs spent less time in the front of the kennel, less time facing forward, and more time engaging in back and forth motion. However, dogs also spent less time barking and jumping on the kennel door right after the calm interaction. The results suggest that both interventions may be useful, but shelter administrators and volunteers must take all of the behavioral changes into account when administering these interventions. PMID- 29158027 TI - A conditioned reinforcer did not help to maintain an operant conditioning in the absence of a primary reinforcer in horses. AB - The use of conditioned reinforcers is increasingly promoted in animal training. Surprisingly, the efficiency of their use remains to be demonstrated in horses. This study aimed to determine whether an auditory signal which had previously been associated with a food reward 288 times could be used as a conditioned reinforcer to replace the primary reinforcer in an unrelated operant conditioning procedure. Fourteen horses were divided into two groups of 7: No Reinforcement (NR) and Conditioned Reinforcement (CR). All horses underwent nine sessions of Pavlovian conditioning during which the word "good" was associated with food (32 associations/session). The horses then followed five sessions of operant conditioning (30 trials/session) during which they had to touch a cone signaled by an experimenter to receive a food reward. The last day, horses underwent one test session of the operant response: no reward was given, but the word "good" was said each time a CR horse touched the cone. Nothing was said in the NR group. CR horses did not achieve more correct trials than NR horses during the test. These findings again show that the conditioned reinforcement was ineffective when used instead of the primary reinforcement to maintain conditioning. PMID- 29158028 TI - Causation, constitution and context: Comment on "Seeing mental states: An experimental strategy for measuring the observability of other minds" by Cristina Becchio et al. PMID- 29158029 TI - Beyond blanket terms: Challenges for the explanatory value of variational (neuro )ethology: Comment on "Answering Schrodinger's question: A free-energy formulation" by Maxwell James Desormeau Ramstead et al. PMID- 29158030 TI - The role of Ayurveda management in preventing surgical site infections instead of surgical antibiotic prophylaxis. AB - It is probably for the first time in the history of modern surgery that Benign Prostate Hyperplasia (BPH) surgery which belongs to 'clean contaminated' class and requires at least 3 doses of prophylactic antibiotic as per recommendations by American Urology Association, was done without the use of any as the patient had a history of severe intolerance to them. The case was an 83 year old male patient presenting with acute urinary retention. He was a known case of BPH being managed continuously on Ayurvedic therapy for many years. It was a challenge to conduct the inevitable surgery without any antibiotic prophylaxis. Holmium laser enucleation of prostate (HOLEP) was done with Ayurvedic medicine support only without the use of any antibiotic. The post-operative recovery was uneventful. The long term recovery was unusually faster and remarkable. In view of rising antibiotic resistance and World Health Organisation (WHO) declaration of arrival of post-antibiotic era, the successful outcome of this case could open new channels of research into Ayurveda, to find out the solution to the worst ever antibiotic crisis of the present time. PMID- 29158031 TI - Robot-assisted renal transplantation using the retroperitoneal approach (RART) with more than one year follow up: Description of the technique and results. AB - OBJECTIVES: To describe the technique and report our first experience of robotic assisted renal transplantation (RART) with more than one year follow up. PATIENTS AND METHODS: In our center the first case of RART was realized in October 2013 with a cadaveric graft. We used the combined extra- and intraperitoneal robot assisted laparoscopic route with extraperitoneal positioning of the graft and intraperitoneal transplantation. The patient was placed in the supine position with arms along the body; the robot came from the right inferior part of the patient. Access to the retroperitoneal space was obtained using an Alexis trocar that permitted the insertion of the kidney with ice without losing the pneumoperitoneum. Ports included a 12-mm camera port (placed under the ombilicus), two 8-mm robotic ports (placed 6cms laterally from the previous port) and a 12-mm assistant port (placed between the upper port and the ombilic). All the pre-, per- and postoperative data were prospectively included in a database. We report the results of the initial experience of RART, performed with more than one year follow-up. RESULTS: This technique is the first described using the retroperitoneal approach that is the routine approach for conventional open renal transplantation. This approach permitted to perform excellent arterial, veinous and ureteral anastomosis. Eight cases of RART were conducted between October 2013 and November 2015 (five men and three women). The average age was 58 years (range 39-75years). The average body mass index was 28 (range 22-38). Five patients had history of abdominal surgery and were dialyzed for 30 months on average (range 3 63months). Three left and five right cadavers kidneys were transplanted in the right iliac fossa. The mean graft size was 109mm (range 90-130). The mean length of the incision for insertion of the graft was 60 mms (40-100mms). Mean warm ischemia time was 63minutes (range 46-84). The total operative time was 200minutes (149-245). No patient was transfused during surgery and two were transfused postoperatively. Median length of hospital stay was 14 days (range 10 30 days). Only one patient needed postoperative morphine, the pain visual analogic scale 12hours postoperatively was 2 (0-5). Mean serum creatinine at seven days, at three months and at one year was 400 (98-639micromol/L), 151 (80 235micromol/L) and 129 (86-194micromol/L) respectively. At one year follow-up, no patient had a wound infection or incisional hernia. One patient was re-operated for ureteral anastomosis stricture. CONCLUSION: The retroperitoneal approach for RART permits the kidney to be cooled and a direct access to the iliac vessels and bladder. This initial series with more than a year of post-monitoring RART shows promising results despite some initial technical difficulties. The procedure can still be improved and hoped to see an improvement in the results. A comparison to the results of the conventional route is necessary before diffusing the robot assisted technique. LEVEL OF PROOF: 3. PMID- 29158032 TI - Resolving taxonomic turbulence and uncovering cryptic diversity in the musk turtles (Sternotherus) using robust demographic modeling. AB - Accurate and consistent delimitation of species and their relationships provides a necessary framework for comparative studies, understanding evolutionary relationships, and informing conservation management. Despite the ever-increasing availability of genomic data, evolutionary dynamics can still render some relationships exceedingly difficult to resolve, including underlying speciation events that are rapid, recent, or confounded by post-speciation introgression. Here we present an empirical study of musk turtles (Sternotherus), which illustrates approaches to resolve difficult nodes in the Tree of Life that robust species-tree methods fail to resolve. We sequence 4430 RAD-loci from 205 individuals. Independent coalescent-based analyses, corroborated with morphology and geography, strongly support the recognition of cryptic species within Sternotherus, but with conflicting or weak support for some intraspecific relationships. To resolve species-tree conflict, we use a likelihood-based approach to test support for alternative demographic models behind alternative speciation scenarios and argue that demographic model testing has an important role for resolving systematic relationships in recent, rapid radiations. Species tree and demographic modeling strongly support the elevation of two nominal subspecies in Sternotherus to species and the recognition of a previously cryptic species (S. intermedius sp. nov.) described within. The evolutionary and taxonomic history of Sternotherus is discussed in the context of these new species and novel and well-supported systematic hypotheses. PMID- 29158033 TI - Resident fibroblast expansion during cardiac growth and remodeling. AB - Cardiac fibrosis, denoted by the deposition of extracellular matrix, manifests with a variety of diseases such as hypertension, diabetes, and myocardial infarction. Underlying this pathological extracellular matrix secretion is an expansion of fibroblasts. The mouse is now a common experimental model system for the study of cardiovascular remodeling and elucidation of fibroblast responses to cardiac growth and stress is vital for understanding disease processes. Here, using diverse but fibroblast specific markers, we report murine fibroblast distribution and proliferation in early postnatal, adult, and injured hearts. We find that perinatal fibroblasts and endothelial cells proliferate at similar rates. Furthermore, regardless of the injury model, fibroblast proliferation peaks within the first week after injury, a time window similar to the period of the inflammatory phase. In addition, fibroblast densities remain high weeks after the initial insult. These results provide detailed information regarding fibroblast distribution and proliferation in experimental methods of heart injury. PMID- 29158034 TI - Different Notch signaling in cells from calcified bicuspid and tricuspid aortic valves. AB - AIMS: Calcific aortic valve disease is the most common heart valve disease in the Western world. Bicuspid and tricuspid aortic valve calcifications are traditionally considered together although the dynamics of the disease progression is different between the two groups of patients. Notch signaling is critical for bicuspid valve development and NOTCH1 mutations are associated with bicuspid valve and calcification. We hypothesized that Notch-dependent mechanisms of valve mineralization might be different in the two groups. METHODS AND RESULTS: We used aortic valve interstitial cells and valve endothelial cells from patients with calcific aortic stenosis with bicuspid or tricuspid aortic valve. Expression of Notch-related genes in valve interstitial cells by qPCR was different between bicuspid and tricuspid groups. Discriminant analysis of gene expression pattern in the interstitial cells revealed that the cells from calcified bicuspid valves formed a separate group from calcified tricuspid and control cells. Interstitial cells from bicuspid calcified valves demonstrated significantly higher sensitivity to stimuli at early stages of induced proosteogenic differentiation and were significantly more sensitive to the activation of proosteogenic OPN, ALP and POSTIN expression by Notch activation. Notch-activated endothelial-to-mesenchymal transition and the corresponding expression of HEY1 and SLUG were also more prominent in bicuspid valve derived endothelial cells compared to the cells from calcified tricuspid and healthy valves. CONCLUSION: Early signaling events including Notch-dependent mechanisms that are responsible for the initiation of aortic valve calcification are different between the patients with bicuspid and tricuspid aortic valves. PMID- 29158035 TI - Infant chest compression quality: A video-based comparison of two-thumb versus one-hand technique in the emergency department. AB - AIM: To use video review to compare CC quality between 2-thumb encircling (2T) and one-hand anterior (1H) hand position in infants receiving CPR. METHODS: Events where an infant received >2min of CC using a CPR monitor device while videorecorded were included. CC were measured in segments provided by a single compressor; segment duration, identity of the compressor, and hand position (2T vs 1H) was determined from video review. CC rate and depth were measured by the monitor device. RESULTS: Seven infants received 111min of CCs from a total of 28 providers. 12/28 providers were assessed using both 2T and 1H; 6 providers used 2T and 1H in the same patient. 80 CC segments were analyzed; the median duration of CC segments was 74s (IQR 50-95s). Median CC rate across all segments was 127/min (IQR 115-142/min); median CC depth was 3.0cm (IQR 2.4-3.4cm). 2T position was used in 33/80 (41%) of segments. There was no significant difference in CC depth between 2T and 1H position (3.0+/-0.8 vs 3.0+/-0.6cm, p=0.81). 1H position was significantly associated with faster CC rate than 2T position (134+/-18 vs. 118+/-15 CC/min, p<0.001). CONCLUSIONS: During CC in infants, 1H position was associated with a greater prevalence of inappropriately fast CC rate compared to 2T. There was no significant difference in depth between 2T and 1H. Future studies should evaluate the effect of hand position on clinical outcomes. PMID- 29158036 TI - Paediatric weight estimation by age in the digital era: optimising a necessary evil. AB - BACKGROUND: Age-based weight estimation methods are regularly used in paediatric emergency medicine despite their well-established inaccuracy. AIM: Determine the potential improvement in accuracy achievable by the use of a new mobile application, based on CDC/WHO weight-for-age centile data, which incorporates a gender assignment, a body habitus assessment, and which is capable of an age-in months based calculation. METHODS: A theoretical, simulated validation study, comparing the performance of the widely used APLS/EPALS formulae against two contemporary habitus-adjusted methods, and the Helix Weight Estimation Tool. 1,070,743 children from the 2015/2016 UK National Child Measurement Program dataset, aged between 4 and 5 and 11 and 12 years, had age-based weight estimates made by all five methods. RESULTS: Primary outcomes were the percentage of weight estimations within 10%, 20%, and those greater than 20% discrepant from actual weight for each method. Our theoretical, gender-dependent, habitus-adjusted method performed better than all other methods across all error thresholds. The overall number of estimations within 10% was 70.4%, and within 20% was 95.45%. The mean percentage error was -1% compared to actual weight. CONCLUSION: The use of a digital tool incorporating a subjective assessment of body habitus, gender assignment, and the ability to estimate weight based on age-in-months might be able optimise the process of paediatric weight estimation by age, making this practice as safe and accurate as possible for the occasions when weight estimation by age is chosen over length-based methods. PMID- 29158037 TI - Quantitative imaging, dosimetry and metrology; Where do National Metrology Institutes fit in? AB - In External Beam Radiotherapy, National Metrology Institutes (NMIs) play a critical role in the delivery of accurate absorbed doses to patients undergoing treatment. In contrast for nuclear medicine the role of the NMI is less clear and although significant work has been done in order to establish links for activity measurement, the calculation of administered absorbed doses is not traceable in the same manner as EBRT. Over recent decades the use of novel radiolabelled pharmaceuticals has increased dramatically. The limitation of secondary complications due to radiation damage to non-target tissue has historically been achieved by the use of activity escalation studies during clinical trials and this in turn has led to a chronic under dosing of the majority of patients. This paper looks to address the difficulties in combining clinical everyday practice with the grand challenges laid out by national metrology institutes to improve measurement capability in all walks of life. In the life sciences it can often be difficult to find the correct balance between pure research and practical solutions to measurement problems, and this paper is a discussion regarding these difficulties and how some NMIs have chosen to tackle these issues. The necessity of establishing strong links to underlying standards in the field of quantitative nuclear medicine imaging is highlighted. The difficulties and successes of current methods for providing traceability in nuclear medicine are discussed. PMID- 29158038 TI - Sexual and Reproductive Health Services and Related Health Information on Pregnancy Resource Center Websites: A Statewide Content Analysis. AB - BACKGROUND: Pregnancy resource centers (PRCs) are nonprofit organizations with a primary mission of promoting childbirth among pregnant women. Given a new state grant program to publicly fund PRCs, we analyzed Georgia PRC websites to describe advertised services and related health information. METHODS: We systematically identified all accessible Georgia PRC websites available from April to June 2016. Entire websites were obtained and coded using defined protocols. RESULTS: Of 64 reviewed websites, pregnancy tests and testing (98%) and options counseling (84%) were most frequently advertised. However, 58% of sites did not provide notice that PRCs do not provide or refer for abortion, and 53% included false or misleading statements regarding the need to make a decision about abortion or links between abortion and mental health problems or breast cancer. Advertised contraceptive services were limited to counseling about natural family planning (3%) and emergency contraception (14%). Most sites (89%) did not provide notice that PRCs do not provide or refer for contraceptives. Two sites (3%) advertised unproven "abortion reversal" services. Approximately 63% advertised ultrasound examinations, 22% sexually transmitted infection testing, and 5% sexually transmitted infection treatment. None promoted consistent and correct condom use; 78% with content about condoms included statements that seemed to be designed to undermine confidence in condom effectiveness. Approximately 84% advertised educational programs, and 61% material resources. CONCLUSIONS: Georgia PRC websites contain high levels of false and misleading health information; the advertised services do not seem to align with prevailing medical guidelines. Public funding for PRCs, an increasing national trend, should be rigorously examined. Increased regulation may be warranted to ensure quality health information and services. PMID- 29158039 TI - Association between the American Board of Internal Medicine's General Internist's Maintenance of Certification Requirement and Mammography Screening for Medicare Beneficiaries. AB - BACKGROUND: Breast cancer is a leading cause of death in the United States. Continuing medical education programs such as the American Board of Internal Medicine's Maintenance of Certification (MOC) program can increase early detection of cancers by educating physicians about the benefits of screening. Did the imposition of American Board of Internal Medicine's MOC requirement affect guideline-compliant mammography screening? METHOD: To address this question, we took advantage of a natural experiment that occurred when one group of general internists was required to complete MOC by 2001 because they initially certified in 1991 (MOC required) and another group was grandfathered out of this requirement because they initially certified in 1989 (MOC grandfathers). To measure associations with the MOC requirement, we compared mammography screening in the 2 years before and the 3 years after the 2001 MOC requirement among beneficiaries treated by the MOC-required physicians and compared this difference with the same difference in mammography screening among a control group of beneficiaries treated by the MOC-grandfathered physicians. RESULTS: We found that the MOC requirement was associated with a regression adjusted 2.8% increase (p < .001) in annual screening and 1.7% increase (p < .001) in biennial screening. When we limited the sample to beneficiaries with no screening at baseline (1999 and 2000), these figures increased to 8.5% (p = .02) and 6.4% (p = .01), respectively. CONCLUSIONS: The MOC requirement was associated with an improvement in guideline-compliant mammography screening with the most pronounced improvements among women who were the least adherent at baseline and therefore might have benefited the most from screening. PMID- 29158040 TI - UK malaria guidelines - Dynamic changes for 2017. PMID- 29158041 TI - Mefloquine revisited. PMID- 29158042 TI - Development of an inhalation reference concentration for diethanolamine. AB - An inhalation reference concentration (RfC) was developed for diethanolamine (DEA), based principally on evaluation of three animal studies (Gamer et al., 1993, 1996, 2008). The RfC (25 MUg/m3) was based on statistically significantly increased relative liver weight in female rats in Gamer et al. (2008) as the critical effect. The lower confidence limit on the benchmark dose (BMDL10 of 5.5 mg/m3) was adjusted to a human equivalent concentration and to continuous exposure before dividing the final point of departure (2.3 mg/m3) by a total factor of 90 that considered standard key areas of uncertainty (intrahuman variability, potential interspecies toxicodynamic differences, database limitations). While laryngeal effects observed in Gamer et al. (2008) were also considered as candidate critical effects, evaluation of the adversity and human relevance of rat laryngeal squamous metaplasia and concomitant effects at the various exposure levels resulted in identifying a LOAEL for laryngeal squamous hyperplasia and chronic inflammation that was much higher than the liver weight LOAEL identified. The RfC of 25 MUg/m3 is considered health protective for the general population and can be used to evaluate the potential health effects of long-term environmental exposure of the general public (i.e., long-term, ambient air dispersion modelling or monitoring data). PMID- 29158043 TI - Six years after the NRC review of EPA's Draft IRIS Toxicological Review of Formaldehyde: Regulatory implications of new science in evaluating formaldehyde leukemogenicity. AB - Shortly after the International Agency for Research on Cancer (IARC) determined that formaldehyde causes leukemia, the United States Environmental Protection Agency (EPA) released its Draft IRIS Toxicological Review of Formaldehyde ("Draft IRIS Assessment"), also concluding that formaldehyde causes leukemia. Peer review of the Draft IRIS Assessment by a National Academy of Science committee noted that "causal determinations are not supported by the narrative provided in the draft" (NRC 2011). They offered recommendations for improving the Draft IRIS assessment and identified several important research gaps. Over the six years since the NRC peer review, significant new science has been published. We identify and summarize key recommendations made by NRC and map them to this new science, including extended analysis of epidemiological studies, updates of earlier occupational cohort studies, toxicological experiments using a sensitive mouse strain, mechanistic studies examining the role of exogenous versus endogenous formaldehyde in bone marrow, and several critical reviews. With few exceptions, new findings are consistently negative, and integration of all available evidence challenges the earlier conclusions that formaldehyde causes leukemia. Given formaldehyde's commercial importance, environmental ubiquity and endogenous production, accurate hazard classification and risk evaluation of whether exposure to formaldehyde from occupational, residential and consumer products causes leukemia are critical. PMID- 29158044 TI - Chemical analysis and in vitro toxicological evaluation of aerosol from a novel tobacco vapor product: A comparison with cigarette smoke. AB - The recent rapid increase in the prevalence of emerging tobacco- and nicotine containing products, such as e-cigarettes, is being driven in part by their reduced-risk potential compared to tobacco smoking. In this study, we examined emission levels for selected cigarette smoke constituents, so-called "Hoffmann analytes", and in vitro toxicity of aerosol from a novel tobacco vapor product (NTV). The NTV thermally vaporizes a nicotine-free carrier liquid to form an aerosol which then passes through tobacco, where it absorbs tobacco-derived flavors and nicotine. The NTV results were compared with those for 3R4F cigarette smoke. Chemical analysis of the NTV aerosol demonstrated that Hoffmann analyte levels were substantially lower than in 3R4F smoke and that the most were below quantifiable levels. Results from in vitro bacterial reverse mutation, micronucleus and neutral red uptake assays showed that, in contrast with 3R4F smoke, the NTV aerosol failed to demonstrate any measurable genotoxicity or cytotoxicity. The temperature of tobacco during NTV use was measured at approximately 30 degrees C, which may explain the lower Hoffmann analyte emission and in vitro toxicity levels. These results suggest that the aerosol from the NTV has a very different toxicological profile when compared with combustible cigarette smoke. PMID- 29158045 TI - [Primary Sjogren syndrome in a child]. AB - : Sjogren syndrome is uncommon in children and occurs most often in association with autoimmune diseases (secondary Sjogren syndrome). We describe the clinical and biological features of a 7-year-old girl with primary Sjogren syndrome revealed by recurrent parotiditis. CASE REPORT: A 7-year-old girl was referred for investigation of multiple episodes of parotid swelling since age 4 years, without systemic symptoms. The examination was unremarkable except for enlarged and painless parotid glands. Laboratory investigations and labial salivary gland biopsy revealed Sjogren syndrome without associated disease. Hydroxychloroquine was prescribed with clinical improvement. CONCLUSION: Recurrent parotiditis in children is an uncommon condition. The onset of parotid swelling at 5 years or over deserves screening for disimmune disorders, sarcoidosis, or Sjogren syndrome. Diagnosis of Sjogren syndrome is based on diagnostic criteria. PMID- 29158046 TI - [Rethinking birth: Ideas for pediatrician-coordinated care, from conception to the postnatal period]. PMID- 29158047 TI - [Fatal case of enterovirus A71 hand, foot, and mouth disease infection]. AB - Hand, foot, and mouth disease associated with enterovirus (EV) infections is a common pediatric pathology that is usually considered as benign. However, neurological complications of varying severity, sometimes fatal, are possible, particularly when EV-A71 is involved. Several Asian countries are regularly affected by large-scale epidemics of EV infections with substantial morbidity and mortality, where early screening and appropriate therapeutic management are a public health challenge. In 2016, Europe experienced an epidemic of unusual magnitude, associated with increasing cases of severe neurological complications in Spain and France, mainly affecting children. Virological diagnosis is based on EV genome detection in peripheral clinical specimens (vesicles or oral ulcerations, throat, nasopharyngeal aspirate, stool) in addition to cerebrospinal fluid and blood. EV-A71 is rarely detected in cerebrospinal fluid, which renders the diagnosis of EV-A71-associated encephalitis challenging. We report the case of a 27-month-old child with hand, foot, and mouth disease turning into rapidly progressive and fatal cardiopulmonary failure associated with EV-A71 infection, in France in 2016. EV infections associated with hand, foot, and mouth disease warrant specific epidemiological surveillance outside the Asian region. PMID- 29158048 TI - Enantiomer-specific positive allosteric modulation of CB1 signaling in autaptic hippocampal neurons. AB - The cannabinoid signaling system is found throughout the CNS and its involvement in several pathological processes makes it an attractive therapeutic target. Because orthosteric CB1 cannabinoid receptor ligands have undesirable adverse effects there has been great interest in the development of allosteric modulators - both negative (NAMs) and positive (PAMs) - of these receptors. NAMs of CB1 appeared first on the scene, followed more recently by PAMs. Because allosteric modulation can vary depending on the orthosteric ligand it is important to study their function in a system that employs endogenous cannabinoids. We have recently surveyed first generation NAMs using cultured autaptic hippocampal neurons. These neurons express depolarization induced suppression of excitation (DSE), a form of synaptic plasticity that is mediated by CB1 and 2-arachidonoyl glycerol (2-AG); they are therefore an excellent neuronal model of endogenous cannabinoid signaling in which to test CB1 modulators. In this study we find that while two related compounds, GAT211 and ZCZ011, each show PAM-like responses in autaptic hippocampal neurons, they also exhibit complex pharmacology. Notably we were able to separate the PAM- and agonist-like responses of GAT211 by examining the enantiomers of this racemic compound: GAT228 and GAT229. We find that GAT229 exhibits PAM-like behavior while GAT228 appears to directly activate the CB1 receptor. Both GAT229 and ZCZ011 represent the first PAMs that we have found to be effective in using this 2-AG utilizing neuronal model system. Because these compounds may exhibit both probe selectivity and biased signaling it will be important to test them with anandamide as well as other signaling pathways. PMID- 29158049 TI - Down regulation of pro-inflammatory pathways by tanshinone IIA and cryptotanshinone in a non-genetic mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a common form of dementia mainly characterized by the deposition of neurofibrillary tangles and beta-amyloid (Abeta) peptides in the brain. Additionally, increasing evidence demonstrates that a neuro-inflammatory state plays a key role in the development of this disease. Beside synthetic drugs, the use of natural compounds represents an alternative for the development of new potential drugs for the treatment of AD. Among these, the root of Salvia miltiorhiza Bunge (also known as Danshen) used for the treatment of cardiovascular, cerebrovascular disease and CNS functional decline in Chinese traditional medicine is one of the most representative examples. We therefore evaluated the effects of tanshinone IIA (TIIA) and cryptotanshinone (CRY) (the two major lipophilic compounds of Danshen) in a non-genetic mouse model of beta amyloid (Abeta)-induced AD, which is mainly characterized by reactive gliosis and neuro-inflammation in the brain. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Abeta1-42 peptide (3MUg/3MUl) and after with TIIA and CRY (1, 3, or 10mg/kg) intraperitoneally (i.p.) 3 times weekly for 21days following the induction of experimental AD. Spatial working memory was assessed as a measure of short-term memory in mice, whereas the level of GFAP, S100beta, COX-2, iNOS and NF-kBp65 monitored by western blot and ELISA assay, were selected as markers of reactive gliosis and neuro-inflammation. Finally, by docking studies, the modulation of key pro-inflammatory enzymes and pathways involved in the AD-related neuro-inflammation were also investigated. Results indicate that TIIA and CRY alleviate memory decline in Abeta1-42-injected mice, in a dose dependent manner. Moreover, the analysis of gliosis-related and neuro inflammatory markers in the hippocampal tissues reveal a remarkable reduction in the expression of GFAP, S100beta, COX-2, iNOS and NF-kBp65 after CRY (10mg/kg) treatment. These effects were less evident, but still significant, after TIIA (10mg/kg). Finally, in silico analysis also revealed that both compounds were able to interact with the binding sites of NF-kBp65 endorsing the data from biochemical analysis. We conclude that TIIA and CRY display anti-inflammatory and neuroprotective effect in a non-genetic mouse model of AD, thus playing a role in slowing down the course and onset of AD. PMID- 29158050 TI - Autoimmune thyroid diseases and Th17/Treg lymphocytes. AB - Years of researches have demonstrated that the imbalance of Th17 and Tregs contribute to the thyroid autoimmunity and the severity of autoimmune thyroid disease (AITD). The underlying mechanism comprises inherent genetic predisposition, abnormality of Th17 and Treg related biological molecules, and gut microbiota disorder. New therapeutic strategies have been developed to improve the Th17/Treg equilibrium, including regulation of intracellular signaling pathways, neutralization of Th17-related cytokines, as well as manipulation of Th17 and Treg specific transcription factors. Although a few of these agents are applied into AITD, the clinic prospect is promising. PMID- 29158051 TI - The regulation of FOXO1 and its role in disease progression. AB - Cell proliferation, apoptosis, autophagy, oxidative stress and metabolic dysregulation are the basis of many diseases. Forkhead box transcription factor O1 (FOXO1) changes in response to cellular stimulation and maintains tissue homeostasis during the above-mentioned physiological and pathological processes. Substantial evidences indicate that FOXO1's function depends on the modulation of downstream targets such as apoptosis- and autophagy-associated genes, anti oxidative stress enzymes, cell cycle arrest genes, and metabolic and immune regulators. In addition, oxidative stress, high glucose and other stimulations induce the regulation of FOXO1 activity via PI3k-Akt, JNK, CBP, Sirtuins, ubiquitin E3 ligases, etc., which mediate multiple signalling pathways. Subsequent post-transcriptional modifications, including phosphorylation, ubiquitination, acetylation, deacetylation, arginine methylation and O GlcNAcylation, activate or inhibit FOXO1. The regulation of FOXO1 and its role might provide a significant avenue for the prevention and treatment of diseases. However, the subtle mechanisms of the post-transcriptional modifications and the effect of FOXO1 remain elusive and even conflicting in the development of many diseases. The determination of these questions potentially has implications for further research regarding FOXO1 signalling and the identification of targeted drugs. PMID- 29158052 TI - Baicalin attenuates non-alcoholic steatohepatitis by suppressing key regulators of lipid metabolism, inflammation and fibrosis in mice. AB - AIMS: Baicalin (BA), an active flavonoid compound originating from the herb of Scutellaria baicalensis Georgi, has been previously shown to exert anti inflammation and anti-oxidant effects in liver diseases. However, the potential role of BA in the regulation of non-alcoholic steatohepatitis (NASH) remains elusive. In this study, we newly explored the hepatoprotective effects of BA in MCD diet-induced NASH by ameliorating hepatic steatosis, inflammation, fibrosis and apoptosis. MAIN METHODS: NASH was induced in mice fed a methionine and choline-deficient (MCD) diet for 4weeks. The mice were simultaneously treated with or without BA for 4weeks. Serum liver functional markers and inflammatory indicators were assessed by biochemical and ELISA methods, respectively. The livers were histologically examined using H&E, Oil Red O and Masson's trichrome staining methods. The qRT-PCR, IHC and Western blotting assays were applied to analyze mechanisms underlying BA protection. KEY FINDINGS: BA treatment significantly attenuated MCD diet-induced hepatic lipid accumulation partly through regulating the expression of SREBP-1c, FASN, PPARalpha and CPT1a. BA treatment dramatically suppressed MCD diet-induced hepatic inflammation, which was associated with decrease in serum TNF-alpha, IL-1beta and MCP-1 production, macrophage influx and suppression of nuclear factor-kappaB activation. Additionally, BA was proved to prevent liver fibrosis, which appears to be mediated by inhibition of alpha-SMA, TGF-beta1 and Col1A1. Furthermore, BA markedly inhibited hepatocyte apoptosis and cleaved caspase-3 protein expression in MCD diet-induced mice. SIGNIFICANCE: These results provide a possible basis of the underlying mechanism for the application of BA in the treatment of NASH. PMID- 29158054 TI - Early Outcomes for Valve-in-valve Transcatheter Aortic Valve Replacement in Degenerative Freestyle Bioprostheses. AB - Transcatheter aortic valve replacement (TAVR) is used increasingly to treat bioprosthetic valve failure. A paucity of data exists regarding valve-in-valve (ViV) TAVR in degenerated Freestyle stentless bioprostheses (FSBs). This study sought to evaluate the feasibility and short-term outcomes of ViV TAVR in previously placed FSB. From October 2014 to September 2016, 22 patients at a single institution underwent ViV TAVR with a self-expanding transcatheter valve for a failing FSB. Patient baseline characteristics and clinical outcomes data were collected retrospectively and entered into a dedicated database. The mean patient age was 74 +/- 9 years, and the mean Society of Thoracic Surgeons' Risk score was 9.0 +/- 7.4%. Ten patients presented with acute heart failure requiring urgent intervention. The most common mode of failure of the FSB was regurgitation caused by a flail or malcoapting leaflet. Seventeen (77%) patients had a modified subcoronary implantation, 3 (14%) had a full root replacement, and 2 (9%) had a root inclusion. Device success using a self-expanding transcatheter valve was 95%, all via transfemoral approach. The mean implant depth was 7 +/- 3 mm. Thirty day survival was 100%. No patient had more than mild paravalvular regurgitation at 30 days, and the permanent pacemaker rate was 9%. The mean hospital stay after intervention was 5 +/- 2 days. ViV TAVR using a self-expanding transcatheter valve is safe, feasible, and can be used successfully to treat a failed FSB. Procedural challenges suggest referral to valve centers of excellence. PMID- 29158053 TI - Transforming growth factor-beta1 promotes articular cartilage repair through canonical Smad and Hippo pathways in bone mesenchymal stem cells. AB - AIMS: Transforming growth factor-beta1 (TGF-beta1) is a chondrogenic factor and has been reported to be able to enhance chondrocyte differentiation from bone marrow mesenchymal stem cells (BMSCs). Here we investigate the molecular mechanism through which TGF-beta1 chronically promotes the repair of cartilage defect and inhibit chondrocyte hypertrophy. MAIN METHODS: Animal models of full thickness cartilage defects were divided into three groups: model group, BMSCs group (treated with BMSCs/calcium alginate gel) and BMSCs+TGF-beta1 group (treated with Lentivirus-TGF-beta1-EGFP transduced BMSCs/calcium alginate gel). 4 and 8weeks after treatment, macroscopic observation, histopathological study and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were done to analyze phenotypes of the animals. BMSCs were transduced with Lentivirus-TGF beta1-EGFP in vitro and Western blot analysis was performed. KEY FINDINGS: We found that TGF-beta1-expressiing BMSCs improved the repair of the cartilage defect. The impaired cartilage contained higher amount of GAG and type II collagen and was integrated to the surrounding normal cartilage and higher content of GAG and type II collagen. The major events include increased expression of type II collagen following Smad2/3 phosphorylation, and inhibition of cartilage hypertrophy by increasing Yes-associated protein-1 (YAP-1) and inhibiting Runx2 and Col10 after the completion of chondrogenic differentiation. SIGNIFICANCE: We conclude that TGF-beta1 is beneficial to chondrogenic differentiation of BMSCs via canonical Smad pathway to promote early-repairing of cartilage defect. Furthermore, TGF-beta1 inhibits chondrocyte hypertrophy by decreasing hypertrophy marker gene expression via Hippo signaling. Long-term rational use of TGF-beta1 may be an alternative approach in clinic for cartilage repair and regeneration. PMID- 29158055 TI - Do the Best Until We Know Better.... PMID- 29158056 TI - Factors Associated with Moyamoya Syndrome in a Kentucky Regional Population. AB - OBJECTIVES: Our study aimed to report both new and previously identified conditions associated with moyamoya syndrome in a Western population and to present our outcomes after surgical treatment with indirect bypass. METHODS: We performed a retrospective chart review of patients evaluated at our institution from June 2011 to June 2015 who were diagnosed with moyamoya. Data collected include patient demographics, presenting manifestations, vessels involved, comorbid conditions, abnormal laboratory values, treatments administered, and clinical outcomes. RESULTS: Thirty-one patients with moyamoya were enrolled (11 male and 20 female), with 84% Caucasian and 16% African-American. The most common comorbidity was hypertension in 61% of the patients. Coexisting autoimmune conditions were present in 26%, with another 13% having coexisting prothrombotic disorders. Diabetes mellitus was not found to correlate with the Suzuki grade of disease at presentation (P = .30). When noninvasive imaging was performed before the cerebral angiogram, the computed tomography angiography had a false-negative rate of 59%, and magnetic resonance angiography had a false-negative rate of 33%. Twenty-one patients underwent surgical intervention, 2 underwent intracranial stenting, and 19 underwent indirect bypass with encephaloduroarteriosynangiosis. At an average 28-month follow-up, all 15 patients who had an angiogram after intervention showed evidence of neovascularization. CONCLUSIONS: Autoimmune and prothrombotic disorders were found to be comorbid in patients with moyamoya at much higher rates than expected in the general population. Diabetes mellitus was not significantly correlated with Suzuki grade. Angiogram remains an important diagnostic modality when noninvasive imaging is negative for vasculopathy. We demonstrate excellent evidence of revascularization within 1 year with intracranial stenting and indirect bypass. PMID- 29158057 TI - The Wnt/beta-catenin pathway contributes to the regulation of adipocyte development induced by docosahexaenoic acid in grass carp, Ctenopharyngodon idellus. AB - Docosahexaenoic acid (DHA) has been suggested to inhibit adipogenesis in fish; the mechanism behind this observation remains largely unknown. The present study was to investigate the effects of DHA on the adipocyte differentiation of grass carp by using transcriptomic technology. Confluent primary cultured differentiating adipocytes were co-incubated with either 0MUM or 100MUM DHA for 2days (early phase of differentiation) and 7days (late phase). The results showed that 100MUM DHA promoted adipogenesis at 2days but decreased lipid accumulation at 7days of treatment compared to that of the control. Cells treated with DHA for 2days showed up-regulation of adipogenic genes, such as PPARgamma, C/EBPs, and FAS; 7day treatment showed down-regulation of these genes. Interestingly, beta catenin, which plays important roles in suppressing adipogenesis in mammals, was also up-regulated after 7days of treatment. To address this, administration of beta-catenin inhibitor FH535 was used and abolished the inhibition of the adipogenesis induced by DHA for 7days. However, FH535 did not rescue the inhibition of adipogenic gene expression (including that of PPARgamma, C/EBPbeta, and C/EBPgamma) in the presence of 100MUM DHA, but it attenuated the up regulation of beta-catenin downstream target genes, e.g. c-myc and cyc D1. This suggests that DHA might regulate the adipogenic junction through the beta-catenin pathway. Overall, our results demonstrate that continuous DHA treatment could promote the early step of adipocyte differentiation and suppress late phase adipogenesis in grass carp. Moreover, Wnt/beta-catenin might be a new potential signaling pathway by which DHA suppresses adipocyte development. PMID- 29158058 TI - Regional Cerebral Oxygen Saturation Level Predicts 30-Day Mortality Rate After Left Ventricular Assist Device Surgery. AB - OBJECTIVE: Left ventricular assist device (LVAD) surgery is complex, high risk, and expensive. The authors' hypothesis is baseline regional cerebral oxygen saturation (rSO2) might be a predictor of postoperative clinical outcomes. DESIGN: Retrospective review of 210 consecutive continuous flow LVAD patients between 2008 and 2014. The primary measure is 30-day mortality rate and secondary measures include modified major adverse cardiocerebral events (MACE), length of stay (LOS), and intensive care unit (ICU) stay. Multiple logistic regression models were applied to examine if a binary outcome variable, such as 30-day mortality and MACE, is associated with rSO2 at baseline. Log-linear model was used to examine whether LOS or ICU stay hours is associated with rSO2 at baseline. SETTING: Single institution, academic hospital. PARTICIPANTS: Patients who received LVAD surgery at Jewish Hospital, Louisville, KY. INTERVENTIONS: All patients received LVAD surgery. Cerebral oximetry monitoring was used in both the preoperative and intraoperative periods. MEASUREMENTS AND MAIN RESULTS: The authors found that higher rSO2 at baseline is associated with lower 30-day mortality with an odds ratio of 0.94 and 95% confidence interval (0.888, 0.995) for every 1% increase of rSO2. For secondary outcomes, baseline rSO2 was not significantly associated with MACE, requirement for postoperative renal failure/dialysis, reoperation for bleeding, and LOS or ICU hours. CONCLUSIONS: Regional cerebral oxygen saturation levels at baseline are significantly associated with 30-day mortality after LVAD surgeries. PMID- 29158059 TI - Iatrogenic Tracheal Rupture During Cardiac Arrest. PMID- 29158060 TI - Meta-Analysis of the Outcome After Postcardiotomy Venoarterial Extracorporeal Membrane Oxygenation in Adult Patients. AB - OBJECTIVE: This study was planned to pool existing data on outcome and to evaluate the efficacy of postcardiotomy venoarterial extracorporeal membrane oxygenation (VA-ECMO) in adult patients. DESIGN: Systematic review of the literature and meta-analysis. SETTING: Multi-institutional study. PARTICIPANTS: Adult patients with acute heart failure immediately after cardiac surgery. INTERVENTIONS: VA-ECMO after cardiac surgery. Studies evaluating only heart transplant patients were excluded from this analysis. MEASUREMENTS AND MAIN RESULTS: A literature search was performed to identify studies published since 2000. Thirty-one studies reported on 2,986 patients (mean age, 58.1 years) who required postcardiotomy VA-ECMO. The weaning rate from VA-ECMO was 59.5% and hospital survival was 36.1% (95% CI 31.5-40.8). The pooled rate of reoperation for bleeding was 42.9%, major neurological event 11.3%, lower limb ischemia 10.8%, deep sternal wound infection/mediastinitis 14.7%, and renal replacement therapy 47.1%. The pooled mean number of transfused red blood cell units was 17.7 (95% CI 13.3-22.1). The mean stay in the intensive care unit was 13.3 days (95% CI 10.2-16.4). Survivors were significantly younger (mean, 55.7 v 63.6 years, p = 0.015) and their blood lactate level before starting VA-ECMO was lower (mean, 7.7 v 10.7 mmol/L, p = 0.028) than patients who died. One-year survival rate was 30.9% (95% CI 24.3-37.5). CONCLUSIONS: Pooled data showed that VA-ECMO may salvage one-third of patients unresponsive to any other resuscitative treatment after adult cardiac surgery. PMID- 29158061 TI - Machine Learning in Radiology: Applications Beyond Image Interpretation. AB - Much attention has been given to machine learning and its perceived impact in radiology, particularly in light of recent success with image classification in international competitions. However, machine learning is likely to impact radiology outside of image interpretation long before a fully functional "machine radiologist" is implemented in practice. Here, we describe an overview of machine learning, its application to radiology and other domains, and many cases of use that do not involve image interpretation. We hope that better understanding of these potential applications will help radiology practices prepare for the future and realize performance improvement and efficiency gains. PMID- 29158062 TI - Effect of Change in Fluid Status Evaluated by Bioimpedance Techniques on Body Composition in Hemodialysis Patients. AB - OBJECTIVE: This prospective study uses calf bioimpedance spectroscopy (cBIS) to guide the attainment of dry weight (DWcBIS) in chronic hemodialysis (HD) patients. The primary aim of this study was to evaluate whether body composition is altered when fluid status is reduced to DWcBIS. METHODS: Target post-HD weight was gradually reduced from baseline (BL) until DWcBIS was achieved. DWcBIS was defined as the presence of both flattening of the curve of extracellular resistance and the attainment calf normalized resistivity in the normal range during the dialysis treatment. Extracellular volume (ECV), intracellular volume, and total body water (TBW) were measured using whole body BIS (Hydra 4200). Fluid overload, lean body mass, and fat mass were calculated according to a body composition model. RESULTS: Seventy-three patients enrolled and 60 completed the study (55 +/- 13 years, 49% male). Twenty-eight patients (25% diabetes) achieved DWcBIS, whereas 32 patients (47% diabetes) did not. Number of treatment measurements were 16 +/- 10 and 12 +/- 13 studies per patient in the DWcBIS and non-DWcBIS groups, respectively. Although significant decreases in body weight and ECV were observed, lean body mass and FM did not differ significantly in both groups from BL to the end of study. ECV, ECV/TBW, and fluid overload were higher in the non-DWcBIS than in the DWcBIS group both at BL and at the end of study. Ratios of intradialytic changes in calf normalized resistivity, ECV, and ECV/TBW to ultrafiltration volume were significantly lower in diabetic than in non diabetic patients. CONCLUSIONS: This study shows that decreasing fluid status by gradual reduction of post-HD weight in both DWcBIS and Non-DWcBIS groups did not affect body composition significantly over a period of about 4 weeks. PMID- 29158063 TI - Frailty and the Quality of Life in Hemodialysis Patients: The Importance of Waist Circumference. AB - OBJECTIVE: Frailty among the end-stage renal disease (ESRD) population is highly prevalent and has been associated with mortality. Little is known about the relation of different aspects of body composition, a modifiable risk factor, with the risk of frailty in ESRD population. DESIGN AND METHODS: One hundred and fifty one patients including 85 men and 66 women, aged >=18 years with ESRD who had been receiving conventional maintenance hemodialysis (HD) for at least 3 months were included. Body fat and muscle mass from both bioimpedance spectroscopy and skin-fold thickness and waist circumference as a surrogate of abdominal obesity were measured. Frailty was defined based on Fried's criteria. Health-related quality of life was collected using the RAND version of the Kidney Disease Quality of Life (KDQOL-36) Survey. RESULTS: We performed single and multiple predictor logistic regression analyses to determine factors associated with frailty. After adjustment for age, sex, and comorbidities, fat mass (both by bioimpedance spectroscopy and anthropometry) and waist circumference, but not muscle mass remained the main predictors of frailty. The odds ratio of frailty in the third tertile compared with the first was 4.97 (1.70-14.55) and 3.84 (1.39 10.61) for fat mass and waist circumference, respectively (P for trends for both <.05). The scores of physical health and kidney disease effect component of quality of life were lower in frail compared with nonfrail patients (40.7 +/- 9.2 vs. 33.7 +/- 10.2, P < .01 and 66.8 +/- 22.4 vs. 51.6 +/- 25.7, P < .05 for physical health and effects of disease, respectively). CONCLUSIONS: Frailty, which is associated with poor outcomes in chronic HD patients, is common and predicted by fat mass and waist circumference but not by body mass index and muscle mass. Interventions to modify abdominal obesity, reflected by waist circumference, could potentially lower the incidence of frailty and hence improve the quality of life in the HD population. PMID- 29158064 TI - miR-223 is repressed and correlates with inferior clinical features in mantle cell lymphoma through targeting SOX11. AB - Mantle cell lymphoma (MCL) is an aggressive lymphoid malignancy characterized by cytogenetic aberration of t(11;14), although it is not the prerequisite. Until now, the pathogenesis of MCL has not been fully interpreted. Our current study showed that microRNA (miR)-223 was downregulated in purified CD19+ lymphocytes from MCL patients (n = 21) compared with that of healthy donors (n = 20). In addition, patients with a high-risk Mantle Cell Lymphoma International Prognostic Index (MIPI) score, elevated lactate dehydrogenase, and Eastern Cooperative Oncology Group performance status >2 were more likely to have much lower miR-223 expression. Furthermore, low miR-223 expression predicted inferior overall survival regardless of treatment in our cohort of 21. To explore the role of miR 223 in MCL, we constructed an ectopic miR-223 MCL cell line and revealed that miR 223 inhibited cell proliferation and promoted G0/G1 accumulation and cell apoptosis. A database search showed that SOX11, a crucial transcription factor in MCL, is the putative target of miR-223. In support of this, we observed a much lower level of SOX11 protein in miR-223-overexpressing cells than in parental cells. Further, the luciferase reporter assay confirmed that miR-223 at the posttranscriptional level suppressed the wild-type 3'-untranslated region of SOX11 but not the mutated one. Finally, miR-223 was found to be negatively correlated with the mRNA level of SOX11 in clinical samples. Our work demonstrates for the first time that miR-223 is repressed and correlated with high-risk clinical features in MCL, which provides a potential molecule to target to optimize MCL management. PMID- 29158065 TI - Electrocardiographic Predictors of Morbidity and Mortality in Patients With Acute Myocarditis: The Importance of QRS-T Angle. AB - BACKGROUND: Acute myocarditis carries a variable prognosis. We evaluated the morbidity and mortality rates in patients with acute myocarditis and admission electrocardiographic predictors of outcome. METHODS AND RESULTS: Patients admitted to a tertiary hospital with a clinical diagnosis of acute myocarditis were evaluated; 193 patients were included. Median follow-up was 5.7 years, 82% were male, and overal median age was 30 years (range 21-39). The most common clinical presentations were chest pain (77%) and fever (53%). The 30-day survival rate was 98.9%. Overall survival during follow-up was 94.3%. The most common abnormalities observed on electrocardiography were T-wave changes (36%) and ST segment changes (32%). Less frequent changes included abnormal T-wave axis (>105 degrees or < -15 degrees ; 16%), abnormal QRS axis (12%), QTc >460 ms (11%), and QRS interval >=120 ms (5%). Wide QRS-T angle (>=100 degrees ) was demonstrated in 13% of the patients and was associated with an increased mortality rate compared with patients with a narrow QRS-T angle (20% vs 4%; P = .007). The rate of heart failure among patients with a wide QRS-T angle was significantly higher (36% vs 10%; P = .001). Cox regression analysis demonstrated that a wide QRS-T angle (>=100 degrees ) was a significant independent predictor of heart failure (hazard ratio [HR] 3.20, 95% confidence interval [CI] 1.35-7.59; P < .01) and of the combined end point of death or heart failure (HR 2.56, 95% CI 1.14-5.75; P < .05). CONCLUSIONS: QRS-T angle is a predictor of increased morbidity and mortality in acute myocarditis. PMID- 29158067 TI - Psoas Muscle Area as a Prognostic Factor for Survival in Patients with an Asymptomatic Infrarenal Abdominal Aortic Aneurysm: A Retrospective Cohort Study. AB - OBJECTIVES: Loss of muscle mass has been associated with poor survival in several surgical patient populations, including those with an abdominal aortic aneurysm (AAA). We wanted to replicate these findings and assess the association between psoas muscle area (PMA) and survival in patients with an asymptomatic AAA. METHODS: Patients with an asymptomatic infrarenal AAA who underwent computed tomography (CT) scanning between January 1, 2007, and December 31, 2013, were included in this single-centre retrospective cohort study. PMA was measured with thresholding on an axial image at the centre level of the third lumbar vertebra. The lowest tertile of PMA in all patients was used as a cutoff value for a low PMA. Then, in separate analyses for conservatively and surgically managed patients, survival was estimated with the Kaplan-Meier method. Differences in survival between patients with and without a low PMA were tested with the log rank test. RESULTS: Of 228 patients, 104 were managed conservatively and 124 underwent AAA repair. Seventy-seven patients (62%) had an endovascular repair. In these 228 patients, the median PMA was 16.83 cm2, while the cutoff value for low PMA was 14.56 cm2. Patients who were managed conservatively were more often classified as having low PMA (45/104, 43%, vs. 31/124, 25%; p = .004) and were significantly older (mean 73.44 +/- 9.05 years vs. 69.03 +/- 7.46 years; p < .001). Low PMA was not associated with survival, either in patients managed conservatively, or in those who underwent AAA repair (p = .512 and p = .311, respectively). CONCLUSIONS: The association between low PMA and poor survival could not be replicated; in this study, low PMA was not associated with survival in patients with an asymptomatic AAA. Further research is recommended before PMA can be used for pre-operative risk stratification. PMID- 29158069 TI - Intraosseous lipoma of the maxillary tuberosity: A case report. AB - Intraosseous lipoma appears less frequently in the maxilla than in the mandible. The initial phase of tumor development is characterized by asymptomatic growth, followed by the presence of pain and paresthesia in the later stage. We report the case of a 43-year-old female patient who contacted a doctor because of periodic pains and stupor in the left side of the upper jaw. The exostosis-like formation was found by palpation, subsequently raising suspicion of an odontogenic tumor on the basis of panoramic imaging (dental orthopan). The intraosseous lipoma was histopathologically diagnosed after surgical procedure and standardized treatment of removed tumefaction. Clinical features and x-ray findings of the intraosseous lipoma within the maxillary region are generally blurred. Surgery is the recommended treatment, and histopathology analysis is of utmost importance for the final diagnosis. PMID- 29158068 TI - New crystal forms of the integral membrane Escherichia coli quinol:fumarate reductase suggest that ligands control domain movement. AB - Quinol:fumarate reductase (QFR) is an integral membrane protein and a member of the respiratory Complex II superfamily. Although the structure of Escherichia coli QFR was first reported almost twenty years ago, many open questions of catalysis remain. Here we report two new crystal forms of QFR, one grown from the lipidic cubic phase and one grown from dodecyl maltoside micelles. QFR crystals grown from the lipid cubic phase processed as P1, merged to 7.5 A resolution, and exhibited crystal packing similar to previous crystal forms. Crystals grown from dodecyl maltoside micelles processed as P21, merged to 3.35 A resolution, and displayed a unique crystal packing. This latter crystal form provides the first view of the E. coli QFR active site without a dicarboxylate ligand. Instead, an unidentified anion binds at a shifted position. In one of the molecules in the asymmetric unit, this is accompanied by rotation of the capping domain of the catalytic subunit. In the other molecule, this is associated with loss of interpretable electron density for this same capping domain. Analysis of the structure suggests that the ligand adjusts the position of the capping domain. PMID- 29158070 TI - Assessment of carotid calcifications on digital panoramic radiographs: Retrospective analysis and review of the literature. AB - OBJECTIVES: To assess the validity of digital panoramic radiographs as an effective means of diagnosis for atherosclerosis and as a potential aid in the early detection of the disease. STUDY DESIGN: We reviewed 2014 digital panoramic radiographs taken throughout 2012 and 2013 to identify the presence of calcified atherosclerotic plaques of both female and male patients all aged over 18 years. In addition the medical records of these patients were reviewed in order to establish if there were any predisposing risk factors for atherosclerosis. Statistical analysis was performed to identify any possible link between radiographic atherosclerotic plaques and predisposing risk factors for atherosclerosis using univariate and multivariate models. Statistical significance criteria was defined as P<0.05. RESULTS: Out of 2014 patients (1149 female and 865 male), 191 (9.5%) were determined to have calcified atherosclerotic plaques on panoramic radiography. There was a statistically significant relationship between the presence of calcified atherosclerotic plaques and the established risk factors of atherosclerosis such as gender (OR=2.39, P<0.001), age (OR=1.5, P<0.001), stroke (OR=5.38, P<0.001) and hypertension (OR=2.11, P<0.001). CONCLUSION: To our knowledge this is the largest study investigating atherosclerotic plaques on digital panoramic radiographs ever carried out in Portugal. Dental practitioners need to be aware of these incidental findings and to consider referring these patients for further investigations to confirm diagnosis. PMID- 29158066 TI - The potential role of leptin in tumor invasion and metastasis. AB - The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin's association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor beta signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin's potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients. PMID- 29158071 TI - Frequency of and factors related to pro re nata (PRN) medication use in aged care services. AB - BACKGROUND: Little is known about the contribution of 'pro re nata' (PRN) medications to overall medication burden in residential aged care services (RACS). OBJECTIVES: To determine the frequency of, and factors associated with PRN medication administration in RACS. MEASUREMENTS: Details of all medications charted for regular or PRN use were extracted from medication charts for 383 residents of 6 Australian RACS. Records of medications administered over a 7 day period were also extracted. Factors associated with PRN medication administration among residents charted >=1 PRN were determined using multivariate logistic regression. RESULTS: Of the 360 (94%) residents charted >=1 PRN medication, 99 (28%) were administered PRN medication at least once. The most prevalent PRN medications were analgesics and laxatives. Residents with greater dependence with activities of daily living (ADL) (adjusted odds ratio (aOR) per additional point on Katz ADL scale: 0.80; 95% confidence interval (CI) 0.72-0.89; p < 0.001) and a greater number of regular medications (aOR per additional medication: 1.06; 95% CI 1.00-1.13; p = 0.042) were more likely to be administered PRN medication. CONCLUSIONS: Although most residents are charted PRN medications, rates of administration are relatively low, suggesting the contribution of PRNs to medication burden in RACS may be lower than previously thought. PMID- 29158072 TI - Test-retest reliability of longitudinal task-based fMRI: Implications for developmental studies. AB - Great advances have been made in functional Magnetic Resonance Imaging (fMRI) studies, including the use of longitudinal design to more accurately identify changes in brain development across childhood and adolescence. While longitudinal fMRI studies are necessary for our understanding of typical and atypical patterns of brain development, the variability observed in fMRI blood-oxygen-level dependent (BOLD) signal and its test-retest reliability in developing populations remain a concern. Here we review the current state of test-retest reliability for child and adolescent fMRI studies (ages 5-18 years) as indexed by intraclass correlation coefficients (ICC). In addition to highlighting ways to improve fMRI test-retest reliability in developmental cognitive neuroscience research, we hope to open a platform for dialogue regarding longitudinal fMRI study designs, analyses, and reporting of results. PMID- 29158073 TI - Methodological challenges in the comparison of infant fMRI across age groups. AB - Functional MRI (fMRI) in infants is rapidly growing and providing fundamental insights into the origins of brain functions. Comparing brain development at different ages is particularly powerful, but there are a number of methodological challenges that must be addressed if confounds are to be avoided. With development, brains change in composition in a way that alters their tissue contrast, and in size, shape, and gyrification, requiring careful image processing strategies and age-specific standard templates. The hemodynamic response and other aspects of physiology change with age, requiring careful paradigm design and analysis methods. Infants move more, particularly around the second year of age, and move in a different way to adults. This movement can lead to distortion in fMRI images, and requires tailored techniques during acquisition and post-processing. Infants have different sleep patterns, and their sensory periphery is changing macroscopically and in its neural pathways. Finally, once data have been acquired and analyzed, there are important considerations during mapping of brain processes and cognitive functions across age groups. In summary, new methods are critical to the comparison across age groups, and key to maximizing the rate at which infant fMRI can provide insight into the fascinating questions about the origin of cognition. PMID- 29158074 TI - A novel feature selection for RNA-seq analysis. AB - RNA-seq data are challenging existing omics data analytics for its volume and complexity. Although quite a few computational models were proposed from different standing points to conduct differential expression (D.E.) analysis, almost all these methods do not provide a rigorous feature selection for high dimensional RNA-seq count data. Instead, most or even all genes are invited into differential calls no matter they have real contributions to data variations or not. Thus, it would inevitably affect the robustness of D.E. analysis and lead to the increase of false positive ratios. In this study, we presented a novel feature selection method: nonnegative singular value approximation (NSVA) to enhance RNA-seq differential expression analysis by taking advantage of RNA-seq count data's non-negativity. As a variance-based feature selection method, it selects genes according to its contribution to the first singular value direction of input data in a data-driven approach. It demonstrates robustness to depth bias and gene length bias in feature selection in comparison with its five peer methods. Combining with state-of-the-art RNA-seq differential expression analysis, it contributes to enhancing differential expression analysis by lowering false discovery rates caused by the biases. Furthermore, we demonstrated the effectiveness of the proposed feature selection by proposing a data-driven differential expression analysis: NSVA-seq, besides conducting network marker discovery. PMID- 29158075 TI - Intermediate Care Unit After Cardiac Surgery: Impact on Length of Stay and Outcomes. AB - INTRODUCTION AND OBJECTIVES: Current postoperative management of adult cardiac surgery often comprises transfer from the intensive care unit (ICU) to a conventional ward. Intermediate care units (IMCU) permit hospital resource optimization. We analyzed the impact of an IMCU on length of stay (both ICU and in-hospital) and outcomes (in-hospital mortality and 30-day readmissions) after adult cardiac surgery (IMCU-CS). METHODS: From November 2012 to April 2015, 1324 consecutive patients were admitted to a university hospital for cardiac surgery. In May 2014, an IMCU-CS was established for postoperative care. For the purposes of this study, patients were classified into 2 groups, depending on the admission period: pre-IMCU-CS (November 2012-April 2014, n=674) and post-IMCU-CS (May 2014 April 2015, n=650). RESULTS: There were no statistically significant differences in age, sex, risk factors, comorbidities, EuroSCORE 2, left ventricular ejection fraction, or the types of surgery (valvular in 53%, coronary in 26%, valvular plus coronary in 11.5%, and aorta in 1.8%). The ICU length of stay decreased from 4.9+/-11 to 2.9+/-6 days (mean+/-standard deviation; P<.001); 2 [1-4] to 1 [0-3] (median [Q1-Q3]); in-hospital length of stay decreased from 13.5+/-15 to 12.7+/ 11 days (mean+/-standard deviation; P=.01); 9 [7-13] to 9 [7-11] (median [Q1 Q3]), in pre-IMCU-CS to post-IMCU-CS, respectively. There were no statistically significant differences in in-hospital mortality (4.9% vs 3.5%; P=.28) or 30-day readmission rate (4.3% vs 4.2%; P=.89). CONCLUSIONS: After the establishment of an IMCU-CS for postoperative cardiac surgery, there was a reduction in ICU and in hospital mean lengths of stay with no increase in in-hospital mortality or 30-day readmissions. PMID- 29158076 TI - Microcirculation and red cell transfusion in patients with sepsis. AB - Early identification of sepsis followed by diagnostic blood cultures and prompt administration of appropriate intravenous antibiotics covering all likely pathogen remains the corner stone in the initial management of sepsis. Source control, obtained by harvesting microbiological cultures and removal or drainage of the infected foci, is mandatory. However, optimization of hemodynamically unstable patients including volume support supplemented with vasopressor, inotropic and transfusion of red blood cells (RBCs) in case of persistent hypoperfusion have the potential to reduce morbidity and mortality. Given the imbalance between the ability of the cardiovascular system to deliver enough oxygen to meet the oxygen demand, transfusion of RBCs should theoretically provide the ideal solution to the challenge. However, both changes in the septic patients' RBCs induced by endogenous factors as well as the storage lesion affecting transfused RBCs have negative effects on the microcirculation. RBC morphology, distribution of fatty acids on the membrane surface, RBC deformability needed for capillary circulation and the nitrogen oxide (NO) signaling systems are involved. Although these deteriorating effects develop during storage, transfusion of fresh RBCs has not proven to be beneficial, possibly due to limitations of the studies performed. Until better evidence exists, transfusion guidelines recommend a restrictive strategy of RBC transfusion i.e. transfuse when hemoglobin (Hb)<7g/dL in septic patients. PMID- 29158077 TI - Mitral Regurgitation in the 21st Century. PMID- 29158078 TI - Self-Destructive Behavior among Full-Donor Blood and Marrow Grafts and the Association with Long-Term Graft Function. PMID- 29158079 TI - Bone Metastases as the Only Metastatic Site in Patients With Urothelial Carcinoma: Focus on a Special Patient Population. AB - BACKGROUND: Patients with exclusive bone metastatic spread from urothelial carcinoma (UC) throughout their disease course represent a rare subgroup with unique clinical features. These patients deserved special consideration in a retrospective multicenter study. PATIENTS AND METHODS: Analyses were made from a pool of 1911 patients with a diagnosis of metastatic UC, from 23 centers. Baseline characteristics, access to treatment, and outcomes were analyzed according to metastatic spread. Univariable and multivariable Cox analyses were performed. RESULTS: A total of 128 evaluable patients (6.7%), diagnosed between February 1997 and April 2013, were identified. Eastern Cooperative Oncology Group performance status (PS) was >= 2 in 33.3% versus 17.7% of the remaining patients. Seventy-three (57%) received first-line chemotherapy, that was platinum-based in 50 patients (69%). Twenty-eight (21.9%) received second-line chemotherapy (vs. 75.9% and 32.2%, respectively, of the remaining patients). In multivariable analyses, no clinical factor was significantly associated with overall survival (OS). Among platinum chemotherapy-treated patients (total evaluable n = 972), significantly different relapse-free survival (RFS) and OS were observed according to bone metastases status (no bone metastases vs. bone metastases only vs. bone and other sites, P < .001). In these groups, 2-year RFS was 37.4%, 28.8%, and 25.9%, respectively. Two-year OS was 35.5%, 15.8%, and 23%, respectively. CONCLUSION: Patients with metastatic UC and bone-only metastases are less likely to receive systemic therapy than those with other metastases, likely because of their lower PS. The prognostic effect of having exclusive bone metastases or additional sites seems to be equally poor. These patients deserve new effective and tolerable agents, and improvements in the knowledge of their disease. PMID- 29158080 TI - Risk-stratified management strategies for HBV reactivation in RA patients receiving biological and targeted therapy: A narrative review. AB - It is estimated that more than two billion people around the world have been infected by Hepatitis B virus (HBV). Reactivation of HBV (rHBV) is a potentially fatal complication after biological therapy. With the increasing use of biologics and targeted therapy in rheumatoid arthritis (RA) patients who are refractory to conventional synthetic disease-modifying anti-rheumatic drugs, rHBV in those with past infection has become increasingly problematic, especially in HBV-endemic regions. Among those receiving biological therapy, the risk of rHBV varies according to the status of HBV infection and the degree of biologic-related immunosuppression. As rHBV is largely preventable, it is imperative that the risk status of rHBV in RA patients receiving biological and targeted therapy be stratified. Therefore, the aim of this review was to summarize the reported data on rHBV, and propose management strategies for RA patients with different risks of rHBV based on evidence presented in the current literature. PMID- 29158081 TI - Streptococcus pyogenes nuclease A (SpnA) mediated virulence does not exclusively depend on nuclease activity. AB - BACKGROUND: Streptococcus pyogenes, or Group A Streptococcus (GAS), is a human pathogen that causes a wide range of diseases, including pharyngitis, necrotizing fasciitis and toxic shock syndrome. The bacterium produces a large arsenal of virulence factors, including the cell wall-anchored Streptococcus pyogenes nuclease A (SpnA), which facilitates immune evasion by degrading the DNA backbone of neutrophil extracellular traps. SpnA consists of a C-terminal endo/exonuclease domain and a N-terminal domain of unknown function. METHODS: Recombinant SpnA mutants were generated by alanine conversion of selected residues that were predicted to play a role in the enzymatic activity and tested for their ability to degrade DNA. A GAS spnA deletion mutant was complemented with a plasmid-borne catalytic site mutant and analyzed for virulence in a Galleria mellonella (wax moth) infection model. RESULTS: Several predicted residues were experimentally confirmed to play a role in SpnA enzymatic activity. These include Glu592, Arg696, His716, Asp767, Asn769, Asp810 and Asp842. Complementation of a GAS spnA deletion mutant with a spnA H716A mutant gene partially restored virulence in wax moth larvae, whereas complementation with the spnA wt gene completely restored activity. Furthermore, complementation with a secreted form of SpnA showed reduced virulence. CONCLUSION: Our results show that abolishing the enzymatic activity of SpnA only partially reduces virulence suggesting that SpnA has an additional virulence function, which might be located on the N-terminal domain. Furthermore, cell wall-anchoring of SpnA results in higher virulence compared to secreted SpnA, probably due to a higher local density of the enzyme. PMID- 29158082 TI - Successful treatment by fecal microbiota transplantation for Japanese patients with refractory Clostridium difficile infection: A prospective case series. AB - We prospectively enrolled four Japanese patients with refractory Clostridium difficile infection (CDI) and were treated with a single fecal microbiota transplantation (FMT). The average age of the patients was 83.7 years. All patients had a successful clinical course for up to 3 months without any adverse events. PMID- 29158083 TI - UNC-5 netrin receptor B mediates osteogenic differentiation by modulating bone morphogenetic protein signaling in human adipose-derived stem cells. AB - UNC-5 netrin receptor B (UNC5B) is a dependence receptor of netrin-1 that plays an essential role in mediating angiogenesis and tumorigenesis. Despite its significant roles, there is limited knowledge about the role played by UNC5B in osteogenesis. In the present study, we first demonstrated that UNC5B was required for osteogenic differentiation of human adipose-derived stem cells (hASCs), both in vitro and in vivo. We also found that mechanistically, UNC5B promotes osteogenic differentiation by activating bone morphogenetic protein signaling. These findings point to a new important function of UNC5B and provide a potential basis for hASCs-mediated bone regeneration. PMID- 29158084 TI - Distinct expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after myocardial infarction. AB - The coronary vascular system is critical for myocardial growth and cardiomyocyte survival. However, the molecular mechanism regulating coronary angiogenesis remains elusive. Vascular endothelial growth factor (VEGF) regulates angiogenesis by binding to the specific receptors Flk1 and Flt1, which results in different functions. Despite the importance of Flk1 and Flt1, their expression in the coronary vasculature remains largely unknown due to the lack of appropriate antibodies for immunostaining. Here, we analyzed multiple reporter mice including Flk1-GFP BAC transgenic (Tg), Flk1-LacZ knock-in, Flt1-DsRed BAC Tg, and Flk1 GFP/Flt1-DsRed double Tg animals to determine expression patterns in mouse hearts during cardiac growth and after myocardial infarction (MI). We found that Flk1 was expressed in endothelial cells (ECs) with a pattern of epicardial-to endocardial transmural gradients in the neonatal mouse ventricle, which was downregulated in adult coronary vessels with development. In contrast, Flt1 was homogeneously expressed in the ECs of neonatal mouse hearts and expression was maintained until adulthood. After MI, expression of both Flk1 and Flt1 was induced in the regenerating coronary vessels at day 7. Intriguingly, Flk1 expression was downregulated thereafter, whereas Flt1 expression was maintained in the newly formed coronary vessels until 30 days post-MI, recapitulating their expression kinetics during development. This is the first report demonstrating the spatiotemporal expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after MI; thus, this study suggests that these factors have distinct and important functions in coronary angiogenesis. PMID- 29158085 TI - Generation of branching ureteric bud tissues from human pluripotent stem cells. AB - Recent progress in kidney regeneration research is noteworthy. However, the selective and robust differentiation of the ureteric bud (UB), an embryonic renal progenitor, from human pluripotent stem cells (hPSCs) remains to be established. The present study aimed to establish a robust induction method for branching UB tissue from hPSCs towards the creation of renal disease models. Here, we found that anterior intermediate mesoderm (IM) differentiates from anterior primitive streak, which allowed us to successfully develop an efficient two-dimensional differentiation method of hPSCs into Wolffian duct (WD) cells. We also established a simplified procedure to generate three-dimensional WD epithelial structures that can form branching UB tissues. This system may contribute to hPSC based regenerative therapies and disease models for intractable disorders arising in the kidney and lower urinary tract. PMID- 29158086 TI - PFN2a, a new partner of RARalpha in the cytoplasm. AB - Retinoic acid receptors (RARs) are classically considered as nuclear ligand dependent regulators of transcription. Here we highlighted a novel face of the RARalpha subtype: RARalpha is present in low amounts in the cytoplasm of mouse embryonic fibroblasts (MEFs) where it interacts with profilin2a (PFN2A), a small actin-binding protein involved in filaments polymerization. The interaction involves the N-terminal proline-rich motif (PRM) of RARalpha and the SH3-like domain of PFN2a. When increased in the cytoplasm, RARalpha competes with other PFN2a-binding proteins bearing PRMs and involved in actin filaments elongation. Consequently, the actin filament network is altered and MEFs adhesion is decreased. This novel role opens novel avenues for the understanding of pathologies characterized by increased levels of cytoplasmic RARalpha. PMID- 29158087 TI - FABP4 induces asthmatic airway epithelial barrier dysfunction via ROS-activated FoxM1. AB - Functional abnormal airway epithelial cells, along with activated inflammatory cells, resulting in chronic airway inflammation, are considered as the characteristic of asthma. Fatty Acid Binding Protein 4 (FABP4) takes part in glucose and lipid homeostasis, and also have an important role in allergic airway inflammation. However, whether FABP4 influence barrier function of airway epithelial cells is unknown. In vivo, a HDM-induced murine model of asthma was obtained to assessed airway inflammation and protein expression of E-cadherin and Forkhead Box M1 (FoxM1). In vitro, 16-HBE was cultured and was treated with hrFABP4, siFABP4, FABPF4 inhibitor BMS, or FoxM1 inhibitor RCM-1. IL-4, IL-5, and IL-13 level was determined by ELISA. Transepithelial electrical resistance (TER), paracellular permeability and E-cadherin-special immunofluorescence were measured to value airway epithelial barrier function. Intracellular ROS production was determined by DCF-DA fluorescence. FABP4 inhibitor BMS alleviate airway inflammation and destruction of E-cad in allergic mouse. Treatment with HDM or hrFABP4 aggravated inflammatory response, damaged airway epithelial barrier, which could be inhibited by siFABP4 and BMS. Treatment with HDM or hrFABP4 also enhanced levels of FoxM1, and Inhibited FoxM1 suppressed HDM- and hrFABP4-induced inflammation and airway epithelial barrier dysfunction. In addition, H2O2 promoted FoxM1 expression, HDM and hrFABP4 induced-FoxM1 could be inhibited by NAC, leading to decreased inflammation and improved airway epithelial barrier. Upregulated ROS induced by FABP4 was of significance in activating FoxM1 leading to airway inflammation and epithelial barrier dysfunction. PMID- 29158088 TI - Interplay of adipocyte and hepatocyte: Leptin upregulates hepcidin. AB - Conflicting evidence concerning leptin, an adipocyte-derived hormone, in atherogenesis and non-alcoholic fatty liver disease (NAFLD) has been reported. Iron metabolism and iron-mediated oxidative stress should be taken into consideration for the clarification of the pathogenesis of these diseases. In this study, we demonstrate that leptin receptor activation directly affects iron metabolism by the finding that serum levels of hepcidin, the master regulator of iron in the whole body, were significantly lower in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice. The administration of recombinant leptin to ob/ob mice for two weeks showed a significant increase in serum hepcidin and hepatic Hamp mRNA levels. Hamp mRNA levels were significantly correlated with hepatic iron content and BMP6 mRNA levels. Hepatic iron content was associated with the increase in mRNA levels of divalent metal transporter 1 and transferrin receptor. Our data provide evidence that the interplay of these two hormones could help improve the understanding of the pathogenesis of atherosclerosis and NAFLD. PMID- 29158089 TI - Opportunities and difficulties for counseling at the margins of viability. AB - At the margins of viability, the interaction between physicians and families presents challenges but also opportunities for success. The counseling team often focuses on data: morbidity and mortality statistics and the course of a typical infant in the neonatal intensive care unit. Data that are generated on the population level can be difficult to align with the multiple facets of an individual infant's trajectory. It is also information that can be difficult to present because of framing biases and the complexities of intuiting statistical information on a personal level. Families also do not arrive as a blank slate but rather arrive with notions of prematurity generated from the culture they live in. Mothers and fathers often want to focus on hope, their changing role as parents, and in their desire to be a family. Multi-timepoint counseling provides the opportunity to address these goals and continue communication as the trajectories of infants, families and the counseling team change. PMID- 29158090 TI - The Developmental Switch in Bacteriophage lambda: A Critical Role of the Cro Protein. AB - Bacteriophage lambda of Escherichia coli has two alternative life cycles after infection-host survival with lysogen formation, or host lysis and phage production. In a lysogen, CI represses the two lytic promoters, pR and pL, and activates its own transcription from the auto-regulated pRM promoter. During induction from the lysogenic to lytic state, CI is inactivated, and the two lytic promoters are de-repressed allowing for expression of Cro from pR. Cro is known to repress transcription of CI from pRM to prevent lysogeny. We show here that when Cro and CI are both present but at low levels, the low level of Cro initially stimulates the lytic promoters while CI repressor is still present, stimulating the level of Cro to a concentration required for pRM repression. Cro has no stimulatory effect without the presence of CI. We propose that this early auto-activating role of Cro at lower concentrations is essential in the developmental switch to lytic growth, whereas pRM repression by Cro at relatively higher concentrations avoids restoring lysogeny. PMID- 29158091 TI - Observation of Effects of Different Surgical Treatments on Unilateral Masticatory Muscle Spasm. AB - BACKGROUND: Unilateral masticatory muscle spasm is a rare disease without a generally accepted and efficacious treatment plan. OBJECTIVE: We sought to compare the effects of different surgical treatments on unilateral masticatory muscle spasm. METHODS: A retrospective analysis of the surgical treatment and effects of 10 cases of unilateral masticatory muscle spasm occurred between February 2010 and September 2016. Three cases underwent complete amputation of the trigeminal motor branch, 3 cases underwent partial amputation of the trigeminal motor branch, and 4 cases received only vascular decompression. All patients were followed up by telephone interview after surgery. RESULTS: In the simple vascular decompression group, 3 cases were cured and 1 was cured after a delay. Of these 3 cases, 1 case became aggravated 2 years after the operation, 1 case became aggravated 5 years after the operation, and 1 case showed no change during the follow-up period. In the partial amputation group, 2 cases were cured and 1 case was alleviated. Of the 2 patients who were cured, 1 suffered recurrence 2 years later, while the other case showed no recurrence during the follow-up period. In the complete amputation group, 1 case was cured with a delay and 2 cases were cured immediately with no recurrence during the follow-up. Mild atrophy of the temporal muscle occurred gradually with no restriction of the mouth opening in 2 cases. CONCLUSIONS: Complete amputation of the trigeminal nerve did achieve better effects than pure microvascular decompression and partial amputation of the trigeminal motor branch, but it may lead to mild temporal muscle atrophy. PMID- 29158092 TI - Medical Malpractice in Neurosurgery: A Comprehensive Analysis. AB - BACKGROUND: Of all specialists, neurosurgeons have the highest probability of facing a medical malpractice claim. Here we report the first specialty-wide review of malpractice claims in neurosurgery performed using a well-established national online legal database. METHODS: The Westlaw legal research service (Thomson Reuters, Eagan, Minnesota, USA) was queried for jury verdicts and settlements related to neurosurgery and medical malpractice between 1985 and 2015. Case files were examined, and factors recorded included the age and sex of the patient, the state and year in which the verdict was reached, defendant specialties, award payouts, and alleged reasons for malpractice. Case files were sorted into neurosurgical subspecialties based on the nature of the condition and the type of treatment administered. RESULTS: A total of 516 cases were identified, and 343 cases were analyzed. A defendant's verdict was reached in 165 (48.1%) cases, and a plaintiff's verdict was reached in 93 (27.1%) cases. A settlement was reached in 81 cases (23.6%). The median payout for plaintiff's verdicts was $2,550,000 (range, $80,000-$216,849,187), and that for settlements was $1,300,000 (range, $100,000-$13,300,000). Procedural error (45.5%), a failure to diagnose (41.4%), or a failure to treat (42.9%) were the most commonly cited reasons for litigation. Neurosurgeons accounted for 21.1% of defendants. The median plaintiff award payout was highest for pediatric cases ($10,100,000). CONCLUSIONS: A defendant's verdict was reached in nearly one-half of the cases. In instances where a plaintiff's verdict was reached, large payouts were common, especially in pediatric and cerebrovascular cases. An emphasis on reducing procedural error, and making timely differential diagnoses, may reduce future litigation. PMID- 29158093 TI - Microsurgical Treatment of Ruptured Intracranial Aneurysms in Sub-Saharan Africa: A Series of 102 Consecutive Cases Treated in Senegal. AB - INTRODUCTION: In sub-Saharan Africa, the management of ruptured intracranial aneurysms (RIAs) is difficult for many reasons. In this retrospective, 3-year study, the authors will demonstrate the particularities of the management of RIAs in Senegal. METHODS: We analyzed retrospectively 102 consecutive cases of RIAs operated on between May 2013 and December 2016 in Neurosurgical Department of Fann Hospital in Dakar, Senegal. Patients characteristics, imaging results, aneurysms, treatment, and outcome were analyzed. RESULTS: One hundred two cases were operated in this 3-year period of a total of 129 cases of RIAs received in our department in the same period. A total of 65% of the patients were female. According to the World Federation of Neurosurgical Societies (WFNS) scale, 49% were WFNS I, and 33% WFNS III. Fisher scale showed 29% of Fisher 2 and 45% of Fisher 4. The aneurysms were located on anterior communicating complex in 38%, on the internal carotid artery in 28%, on the middle cerebral artery in 27% of cases and on posterior circulation in 9 cases. The pterional approach was used in 93 cases. According to the modified Rankin Scale, 67 patients (65.6%) had good outcome, 22 (21.5%) had poor outcome, and the mortality rate was 12.7% (13 patients) at last follow-up. CONCLUSIONS: This study demonstrates encouraging results if one refers to the global patient postoperative outcomes. However, the large number of patients not undergoing treatment also requires us to improve preoperative management conditions. PMID- 29158094 TI - Supernumerary Abducens Nerves: A Comprehensive Review. AB - BACKGROUND: Branching and/or replication of the abducens nerve is not an uncommon occurrence. Although numerous variations have been documented, the rarest forms are duplicated or triplicated nerves, where multiple nerve roots originate from the brainstem, travel intracranially, and attach to the lateral rectus as separate entities. METHODS: We conducted a systematic literature search on the topic of supernumerary abducens nerve, using PubMed and Google Scholar. RESULTS: After screening, 16 studies were included: 11 cadaveric studies and 6 case reports. CONCLUSIONS: In this paper, we review the literature on variations found, discuss current hypotheses and clinical relevance, and propose future studies. Neurosurgeons should be aware of such nerve variants when viewing imaging or operating in the regions traversed by the abducens nerve. PMID- 29158095 TI - Sagittal Alignment as Predictor of Adjacent Segment Disease After Lumbar Transforaminal Interbody Fusion. AB - OBJECTIVE: This study was carried out to explore the diagnostic value of sagittal measurements for adjacent segment disease after lumbar transforaminal interbody fusion (TLIF). METHODS: A total of 163 subjects who underwent TLIF for lumbar disease were initially enrolled in the study from July 2013 to August 2017. Sagittal alignment including thoracic inlet and spinopelvic parameters was measured by using preoperative full-length freestanding radiographs. Multivariate logistic regression analysis was performed to evaluate these parameters as the diagnostic index for adjacent segment disease (ASD). RESULTS: A total of 153 patients completed the final follow-up, and the mean follow-up period was 40.6 months. There were 53 (35.3%) cases with ASD found after the TLIF in the enrolled subjects. Logistic regression analysis and receiver operating characteristic analysis confirmed that preoperative pelvic tilt (PT) of more than 24.1 degrees and thoracic kyphosis (TK) of more than 23.3 degrees were significant risk factors of ASD after TLIF (P < 0.05). CONCLUSIONS: We confirmed that PT of more than 24.3 degrees and TK of more than 23.3 degrees could be regarded as predictors of ASD after lumbar TLIF. PMID- 29158096 TI - Cost-Effectiveness of Endoscopic Versus Microscopic Transsphenoidal Surgery for Pituitary Adenoma. AB - BACKGROUND: Endoscopic transsphenoidal surgery (ETPS) has become increasingly popular for resection of pituitary tumors, whereas microscopic transsphenoidal surgery (MTPS) also remains a commonly used approach. The economic sustainability of new techniques and technologies is rarely evaluated in the neurosurgical skull base literature. The aim of this study was to determine the cost-effectiveness of ETPS compared with MTPS. METHODS: A Markov model was constructed to conduct a cost-utility analysis of ETPS versus MTPS from a single-payer health care perspective. Data were obtained from previously published outcomes studies. Costs were based on Medicare reimbursement rates, considering covariates such as complications, length of stay, and operative time. The base case adopted a 2-year follow-up period. Univariate and multivariate sensitivity analyses were conducted. RESULTS: On average, ETPS costs $143 less and generates 0.014 quality adjusted life years (QALYs) compared with MTPS over 2 years. The incremental cost effectiveness ratio (ICER) is -$10,214 per QALY, suggesting economic dominance. The QALY benefit increased to 0.105 when modeled to 10 years, suggesting that ETPS becomes even more favorable over time. CONCLUSIONS: ETPS appears to be cost effective when compared with MTPS because the ICER falls below the commonly accepted $50,000 per QALY benchmark. Model limitations and assumptions affect the generalizability of the conclusion; however, ongoing efforts to improve rhinologic morbidity related to ETPS would appear to further augment the marginal cost savings and QALYs gained. Further research on the cost-effectiveness of ETPS using prospective data is warranted. PMID- 29158097 TI - Novel Minimally Invasive Treatment Strategy for Acute Traumatic Epidural Hematoma: Endovascular Embolization Combined with Drainage Surgery and Use of Urokinase. AB - BACKGROUND: Hematoma evacuation is regular treatment for acute traumatic epidural hematoma (ATEDH) patients meeting with surgery indications. However, it is an invasive approach performed under general anesthesia. Here, a novel minimally invasive method of endovascular embolization with subsequent drainage surgery and use of urokinase was established to treat ATEDH under local anesthesia. METHODS: A novel minimally invasive method of endovascular embolization with subsequent drainage surgery and use of urokinase was established to treat ATEDH under local anesthesia. Firstly, 23 ATEDH patients with hematomas in the temporal area underwent digital subtraction angiography detecting the bleeding point. Next, embolization was performed. After embolization, drainage surgery was taken and urokinase was injected into the hematoma cyst by drainage tube to lyse hematoma twice per day. RESULTS: The results showed that the middle meningeal artery was the bleeding source. Embolization immediately ceased bleeding. Most clots were resolved and drained after treatment. No recurrence of hematoma or infection was observed. CONCLUSION: The findings suggest that the combined treatments can be an alternative minimally invasive option for ATEDHs, especially for elderly patients or those contraindicated for general anesthesia. PMID- 29158098 TI - Risk Factors of Postoperative Sacroiliac Joint Pain for Posterior Lumbar Surgery: >=2-Year Follow-up Retrospective Study. AB - PURPOSE: A retrospective study was conducted to clarify the risk factors of postoperative sacroiliac joint pain (SIJP) for posterior open lumbar surgery. PATIENTS AND METHODS: A total of 472 patients who underwent posterior lumbar surgery between January 2011 and December 2014 were included in this analysis. We recorded basic characteristics, surgical characteristics, and SIJP information for each patient. RESULTS: The incidence of postoperative SIJP is 13.8% in our study. Comparison of the incidence of SIJP between diskectomy and posterior lumbar interbody fusion indicated that SIJP incidence tended to be higher in posterior lumbar interbody fusion patients (P = 0.029). Compared with the single segment group, SIJP occurred more frequently in the multiple operative segments group (P = 0.025). Comparing the incidence of SIJP among different types of lumbar diseases, SIJP incidence is significantly higher in the lumbar stenosis group (P = 0035). CONCLUSION: Lumbar fusion surgery and multiple operative segments are interdependent risk factors for the postoperative SIJP. The incidence of postoperative SIJP also increases in patients with lumbar stenosis compared with lumbar disk herniation and lumbar spondylolisthesis. PMID- 29158099 TI - A Novel Dissection Method Using a Flexible Neuroendoscope for Resection of Tumors Around the Aqueduct of Sylvius. AB - BACKGROUND: Flexible endoscopes have both a wide range of movement and a wide field of view and are therefore widely used for endoscopic third ventriculostomy and biopsy. However, tumor resection around the aqueduct of Sylvius using flexible endoscopes has scarcely been reported. CASE DESCRIPTION: We report 2 cases of tumor resection around the aqueduct of Sylvius. The first case is a 38 year-old man presenting with progressive headache, nausea, and diplopia. Magnetic resonance imaging (MRI) revealed a 1.4 cm nonenhancing mass at the entry of the aqueduct of Sylvius and occlusive hydrocephalus. We performed tumor resection and endoscopic third ventriculostomy (ETV) simultaneously. His symptoms disappeared after the operation. Final pathologic diagnosis was ancient schwannoma. The second case is a 78-year-old woman presenting with progressive disturbance of consciousness (coma). MRI showed 0.7 cm nonenhancing mass at the entry of the aqueduct of Sylvius and occlusive hydrocephalus. We performed tumor resection and ETV similarly. Her consciousness improved after the operation. Final tumor diagnosis was cavernous malformation. In both cases there was no additional neurologic deficit after the surgery. CONCLUSIONS: By using a flexible endoscope for tumor dissection, resection of a tumor without a neck, which cannot be removed through aspiration alone, becomes possible. To our knowledge, the presented cases are the first to describe the effectiveness of complete resection of a tumor in the third ventricle using flexible endoscopy. PMID- 29158100 TI - Stepping up HIV-1 low-level viraemia surveillance in South Africa. PMID- 29158101 TI - Effect of HIV-1 low-level viraemia during antiretroviral therapy on treatment outcomes in WHO-guided South African treatment programmes: a multicentre cohort study. AB - BACKGROUND: Antiretroviral therapy (ART) that enables suppression of HIV replication has been successfully rolled out at large scale to HIV-positive patients in low-income and middle-income countries. WHO guidelines for these regions define failure of ART with a lenient threshold of viraemia (HIV RNA viral load >=1000 copies per mL). We investigated the occurrence of detectable viraemia during ART below this threshold and its effect on treatment outcomes in a large South African cohort. METHODS: In this observational cohort study, we included HIV-positive adults registered between Jan 1, 2007, and May 1, 2016, at 57 clinical sites in South Africa, who were receiving WHO-recommended ART regimens and viral load monitoring. Low-level viraemia was defined as the occurrence of at least one viral load measurement of 51-999 copies per mL during ART. Outcomes were WHO-defined virological failure (one or more viral load measurement of >=1000 copies per mL) and switch to second-line ART. Risks were estimated with Cox proportional hazard models. FINDINGS: 70 930 patients were included in the analysis, of whom 67 644 received first-line ART, 1476 received second-line ART, and 1810 received both. Median duration of follow-up was 124 weeks (IQR 56-221) for patients on first-line ART and 101 weeks (IQR 51-178) for patients on second line ART. Low-level viraemia occurred in 16 013 (23%) of 69 454 patients, with an incidence of 11.5 per 100 person-years of follow-up (95% CI 11.4-11.7), during first-line ART. Virological failure during follow-up occurred in 14 380 (22%) of 69 454 patients on first-line ART. Low-level viraemia was associated with increased hazards of virological failure (hazard ratio [HR] 2.6, 95% CI 2.5-2.8; p<0.0001) and switch to second-line ART (HR 5.2, 4.4-6.1; p<0.0001]) compared with virological suppression of less than 50 copies per mL. Risk of virological failure increased further with higher ranges and persistence of low-level viraemia. INTERPRETATION: In this large cohort, low-level viraemia occurred frequently and increased the risk of virological failure and switch to second line ART. Strategies for management of low-level viraemia need to be incorporated into WHO guidelines to meet UNAIDS-defined targets aimed at halting the global HIV epidemic. FUNDING: None. PMID- 29158102 TI - Human papillomavirus types from infection to cancer in the anus, according to sex and HIV status: a systematic review and meta-analysis. AB - BACKGROUND: Data on carcinogenicity of human papillomavirus (HPV) types in the anus are needed to inform anal cancer prevention through vaccination and screening. This is particularly the case for people infected with HIV, who are at an increased risk of anal cancer. METHODS: We did a systematic review of studies published from January, 1986, to July, 2017, in MEDLINE, Embase, and the Cochrane Library on anal HPV infection, without any language restrictions. Eligible studies reported type-specific HPV prevalence by strata of cytopathological or histopathological anal diagnosis, sex, and HIV status. Data requests were made to authors when necessary. We did a meta-analysis of type-specific HPV prevalence across the full spectrum of anal diagnoses, from normal cytology to anal cancer. We assessed the main outcome of type-specific HPV prevalence ratios [PR], calculated across strata of anal diagnoses, gender, or HIV status, by use of generalised linear models. FINDINGS: 95 studies were identified from the search, published between 1992-2017, from which 18 646 individuals fulfilled the criteria for inclusion in the analyses: 8534 people with normal cytology, 5730 with low grade lesions, 2024 with high-grade lesions, and 2358 with anal cancer. HPV prevalence varied in normal cytology from 42% in HIV-negative women to 76% in HIV positive men and, for each diagnosis, was higher in individuals who were HIV positive than those who were HIV negative. HPV16 positivity increased with diagnosis severity, being the only HPV type accounting for more HPV infection in anal cancer than normal cytology, both in individuals who were HIV negative (PR 5.0, 95% CI 3.8-6.6, p<0.0001) and those who were HIV positive (2.3, 1.9-2.7, p<0.0001). HPV16 positivity increased even between high-grade lesions and anal cancer, whereas other high-risk HPV types accounted for high proportions of low grade or high-grade lesions but their prevalence decreased in anal cancer. However, HPV16 was less frequent in HIV-positive than HIV-negative anal cancer, both in men (PR 0.8, 95% CI 0.7-0.9, p<0.0001) and women (0.8, 0.6-1.0, p=0.063), and in HIV-positive versus HIV-negative high-grade lesions in women (0.6, 0.5 0.9, p=0.0077). Type-specific attribution of the non-HPV16 fraction of HIV positive anal cancer is hindered by a high prevalence of multiple HPV infections. INTERPRETATION: HPV16 is by far the most carcinogenic HPV type in the anus, with enrichment of HPV16 even from high-grade lesions to anal cancer, both in individuals who are HIV negative and those who are HIV positive. Nevertheless, the fraction of anal cancer attributable to HPV16 is smaller in the HIV-positive population. FUNDING: International Agency for Research on Cancer. PMID- 29158103 TI - The importance of HPV16 in anal cancer prevention. PMID- 29158104 TI - Impact of Primary Tumor Location on Survival from the European Organization for the Research and Treatment of Cancer Advanced Urothelial Cancer Studies. AB - PURPOSE: The prognostic relevance of primary location of urothelial carcinoma on survival has been poorly investigated. MATERIALS AND METHODS: We used prospectively collected data from 3 European Organization for the Research and Treatment of Cancer advanced urothelial carcinoma studies, including 30924 (methotrexate, vinblastine, doxorubicin and cisplatin vs high dose methotrexate, vinblastine, doxorubicin and cisplatin), 30986 (methotrexate, carboplatin and vinblastine vs gemcitabine and cisplatin in patients who were not candidates for cisplatin) and 30987 (gemcitabine and cisplatin-paclitaxel vs gemcitabine and cisplatin in candidates for cisplatin). Patients were grouped by primary tumor location as those with bladder cancer or upper tract urothelial carcinoma. Progression-free and overall survival was tested by tumor location using Cox proportional hazard regression stratified by study and treatment using 2-sided alpha = 0.05. RESULTS: Of the 1,039 patients 878 (85.3%) and 161 (14.7%) had bladder cancer and upper tract urothelial carcinoma, respectively. Patients with bladder cancer had better performance status and were more likely to be male (p = 0.008 and <0.074, respectively). By a median followup of 4.8 years (IQR 4.0-6.7) 733 patients had died and 925 had experienced disease progression. Overall and progression-free survival did not differ significantly between bladder and upper tract urothelial carcinoma cases (p = 0.3 and 0.7, respectively), even after adjusting for the effects of Bajorin risk group by each tumor location. When upper tract urothelial carcinoma was considered separately, patients with primary ureteral tumors had better overall survival than patients with primary bladder cancer (OR = 0.74, p = 0.047). However, this association did not remain significant after adjusting for Bajorin risk group (p = 0.05). CONCLUSIONS: Primary tumor location had no impact on progression-free or overall survival in patients with locally advanced or metastatic urothelial carcinoma treated with platinum based combination chemotherapy. PMID- 29158105 TI - The effect and associated factors of dispatcher recognition of stroke: A retrospective observational study. AB - BACKGROUND/PURPOSE: Details of the communication between the caller and dispatcher have not been reported previously in Taiwan. This study aimed to: (1) understand the details of the communication between the caller and dispatcher among the calls for stroke patients, (2) identify factors associated with stroke recognition by dispatchers, and (3) evaluate the association between stroke recognition by dispatchers and stroke management. METHODS: We conducted a retrospective observational study involving patients with stroke or transient ischemic stroke transported by the emergency medical service, and arriving at 9 hospitals in Taipei within 3 h of symptom onset from January 1, 2013 to February 28, 2014. Patients were excluded if tape-recording data or prehospital information were not available. Data of the enrolled patients were reviewed. We used stroke dispatch determination as the surrogate for stroke recognition by dispatchers. Multivariable logistic regression was used to identify the factors associated with stroke dispatch determination. RESULTS: A total of 507 patients were included. In approximately 50% of cases, callers were close family members. Ninety-one patients (17.9%) had stroke dispatch determination. After adjustment, stroke reported spontaneously, any symptom included in the Cincinnati Prehospital Stroke Scale reported spontaneously, and dispatcher adherence to the protocol, were associated with stroke dispatch determination significantly. Stroke dispatch determination was associated with receiving pre-arrival notification, shorter door-to-computed tomography time, and thrombolytic therapy. CONCLUSION: The dispatchers should spend more time identifying stroke patients by following the dispatch protocol. Recognition of stroke by dispatchers was associated with improved stroke care. PMID- 29158106 TI - Lipoma of the tongue. PMID- 29158108 TI - Signaling by Synaptic Zinc is Required for Whisker-Mediated, Fine Texture Discrimination. AB - Zinc-containing terminals are found throughout the neocortex, concentrated predominantly in layers II/III, V, and VI. Synaptic zinc is a potent neurotransmitter/modulator and, therefore, may mediate inter- or intra-cortical integration of sensory information. We have previously shown that levels of synaptic zinc are rapidly modulated in somatosensory (barrel) cortex, in an experience- and activity-dependent manner. Zinc transporter 3 (ZnT3) knockout (KO) mice lack synaptic zinc and provide us with a good model to examine the contribution of synaptic zinc to barrel cortex-dependent behavior. In the present study, we show that ZnT3 KO mice display a marked decrease in acuity for whisker dependent texture discrimination. ZnT3 KO mice were not able to discriminate between textures having an average particle diameter less than 300 MUm while control mice were able to discriminate between textures having particle diameters separated by as little as 25 MUm. This loss of texture discrimination acuity in ZnT3 KO mice was whisker-dependent and was observed in young (2 months-of-age) and older mice (12 months-of-age). These results show that zincergic signaling is necessary for the normal integration of somatosensory information. PMID- 29158107 TI - A Functional Role for the Epigenetic Regulator ING1 in Activity-induced Gene Expression in Primary Cortical Neurons. AB - Epigenetic regulation of activity-induced gene expression involves multiple levels of molecular interaction, including histone and DNA modifications, as well as mechanisms of DNA repair. Here we demonstrate that the genome-wide deposition of inhibitor of growth family member 1 (ING1), which is a central epigenetic regulatory protein, is dynamically regulated in response to activity in primary cortical neurons. ING1 knockdown leads to decreased expression of genes related to synaptic plasticity, including the regulatory subunit of calcineurin, Ppp3r1. In addition, ING1 binding at a site upstream of the transcription start site (TSS) of Ppp3r1 depends on yet another group of neuroepigenetic regulatory proteins, the Piwi-like family, which are also involved in DNA repair. These findings provide new insight into a novel mode of activity-induced gene expression, which involves the interaction between different epigenetic regulatory mechanisms traditionally associated with gene repression and DNA repair. PMID- 29158109 TI - Outcome Modulation Across Tasks in the Primate Dorsolateral Prefrontal Cortex. AB - Animals need to learn and to adapt to new and changing environments so that appropriate actions that lead to desirable outcomes are acquired within each context. The prefrontal cortex (PF) is known to underlie such function that directly implies that the outcome of each response must be represented in the brain for behavioral policies update. However, whether such PF signal is context dependent or it is a general representation beyond the specificity of a context is still unclear. Here, we analyzed the activity of neurons in the dorsolateral PF (PFdl) recorded while two monkeys performed two perceptual magnitude discrimination tasks. Both tasks were well known by the monkeys and unexpected changes did not occur but the difficulty of the task varied from trial to trial and thus the monkeys made mistakes in a proportion of trials. We show a context independent coding of the response outcome with neurons maintaining similar selectivity in both task contexts. Using a classification method of the neural activity, we also show that the trial outcome could be well predicted from the activity of the same neurons in the two contexts. Altogether, our results provide evidence of high degree of outcome generality in PFdl. PMID- 29158110 TI - Diabetes mellitus and Alzheimer's disease: GSK-3beta as a potential link. AB - It is well known that Alzheimer's disease (AD) is closely related to diabetes mellitus (DM), and AD is also regarded as Type 3 diabetes (T3D). However, the exact link between AD and DM is still unclear. Recently, more and more evidence has shown that glycogen synthase kinase-3beta (GSK-3beta) may be the potential link between DM and AD. In DM, GSK-3beta is the crucial enzyme of glycogen synthesis, which plays a key role in regulating blood glucose. More importantly, GSK-3beta is one of the key factors leading to insulin deficiency and insulin resistance, and insulin resistance is an important hallmark of the occurrence and development of DM. In AD, GSK-3beta plays an important role in hyperphosphorylation of microtubule-associated protein tau (tau), which is one of the pathological features in AD. GSK-3beta is one of the important kinases of tau phosphorylation and is involved in the insulin/phosphoinositide 3-kinase/protein kinase B (insulin/PI3K/Akt) signaling pathway. Dysfunction of the insulin/PI3K/Akt signaling pathway, which regulates glucose metabolism in the brain, can lead to tau hyperphosphorylation in the brain of AD patents. Additionally, insulin resistance in DM may cause beta-amyloid (Abeta) deposition, which will be cleared by tau, but excessive phosphorylation of tau will further aggravate the neurotoxicity; then damage the brain and affect the cognitive function. GSK-3beta is considered as a common kinase in insulin signaling transduction and tau protein phosphorylation, so we have reasons to believe that GSK-3beta is a potential link between DM and AD. PMID- 29158111 TI - Brain-derived neurotrophic factor (BDNF) determines a sex difference in cue conditioned alcohol seeking in rats. AB - Alcohol use disorder is a detrimental addictive disease that develops through prolonged ethanol exposure and regular intoxication. However, the changes in the underlying neurobiology leading to alcohol addiction remain unclear. Brain Derived Neurotrophic Factor (BDNF) is implicated in substance abuse disorders including alcoholism. As the vast majority of previous animal model studies have concentrated on males only, the aim of this study was to determine whether endogenous BDNF mediates alcohol seeking in a sex-specific manner. We used an operant self-administration paradigm where the animals were trained in operant chambers to self-administer a 10% ethanol solution, and compared male and female BDNF heterozygous (HET) and wildtype (WT) rats. Over several weeks, the animals progressed through acquisition, progressive ratio, extinction, and reinstatement phases. There were no significant sex or genotype differences in the number of alcohol-paired lever presses during acquisition, progressive ratio and extinction. However, a significant difference between male and female WT rats following alcohol-primed reinstatement was completely absent in BDNF HET rats suggesting a role of BDNF in sex differences in alcohol seeking after abstinence. Female BDNF HET rats showed significantly higher number of alcohol-paired lever presses during reinstatement than female WT controls. These findings suggest that BDNF regulatory pathways are involved in sex differences in reinstatement of alcohol intake and emphasize the need to include both male and female animals to explore sex-specific interactions in addiction neurocircuitry. PMID- 29158112 TI - Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL-G-F mice before prominent plaque deposition. AB - Amyloid-beta (Abeta) peptides occur in the brains of patients with Alzheimer's disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their use in preclinical research. We examined the occurrence of behavioral, cognitive and neuroimaging changes in APPNL-G-F knock-in mice that display Abeta42 amyloidosis in the absence of APP overexpression. Female APPNL-G-F mice (carrying Swedish, Iberian and Arctic APP mutations) were compared to APPNL mice (APP Swedish) at 3, 7 and 10 months. Mice were subjected to a test battery that referred to clinical AD symptoms, comprising cage activity, open field, elevated plus maze, social preference and novelty test, and spatial learning, reversal learning and spatial reference memory performance. Our assessment confirmed that behavior at these early ages was largely unaffected in these mice in accordance with previous reports, with some subtle behavioral changes, mainly in social and anxiety-related test performance. Resting-state functional MRI (rsfMRI) assessed connectivity between hippocampal and prefrontal regions with an established role in flexibility, learning and memory. Increased prefrontal-hippocampal network synchronicity was found in 3-month-old APPNL-G-F mice. These functional changes occurred before prominent amyloid plaque deposition. PMID- 29158113 TI - Contribution of M1 and M2 muscarinic receptor subtypes to convulsions in fasted mice treated with scopolamine and given food. AB - Treatment of fasted mice and rats with the nonselective muscarinic antagonist, scopolamine or atropine, causes convulsions after food intake. This study evaluated the effect of fasting on the expression of M1 and M2 muscarinic receptors in the brain regions, the relationship between receptor expression and seizure stages, and the muscarinic receptor subtype which plays a role in the occurrence of convulsions. Mice were grouped as allowed to eat ad lib (fed) and deprived of food for 24h (fasted). Fasted animals developed convulsions after being treated with scopolamine (60%) or the selective M1 receptor antagonist pirenzepine (10mg/kg; 20% and 60mg/kg; 70%) and given food. Fasting increased expression of M1 receptors in the frontal cortex and M2 receptors in the hippocampus, but produced no change in the expression of both receptors in the amygdaloid complex. Food intake after fasting decreased M1 receptor expression in the frontal cortex and M1 and M2 receptor expression in the hippocampus. Seizure severity was uncorrelated with muscarinic receptor expression in the brain regions. Taken together, these findings provide evidence for the role of M1 muscarinic receptor antagonism and fasting-induced increases in M1 and M2 expression possible underlying mechanism in the occurrence of convulsions in fasted animals. PMID- 29158114 TI - Early Relapse for Multiple Myeloma Patients Undergoing Single Autologous Stem Cell Therapy: A Single-center Experience. AB - INTRODUCTION: Multiple myeloma is a heterogeneous disease with diverse clinical courses and patient outcomes. Although the introduction of novel agents has improved the overall survival (OS) of multiple myeloma patients, reports have highlighted that a subset of patients persists who experience early relapse (ER) and whose prognosis is significantly poorer than that of patients with a longer therapy response. METHODS: The purpose of the present study was to understand the effect of ER on OS and identify other predictors of OS. We analyzed the outcomes of 257 patients who had undergone novel agent-based induction and single autologous stem cell therapy at our center from 2010 to 2016. RESULTS: ER occurred in 35 patients (13.6%), and the group had a greater percentage of high risk cytogenetics (48.5% vs. 23.3%; P = .0001), a lower percentage of a very good partial response or better (51.4% vs. 80.5%; P = .001), and a shorter median OS (17.8 months vs. not realized; P = .0001) compared with the non-ER group. Multivariate analysis showed that the presence of ER, high-risk cytogenetics, and lactate dehydrogenase > 350 UI/L are independent prognosticators for OS (P < .05). CONCLUSIONS: Our results have demonstrated that ER is an important clinical indicator of patients at high risk. As applications of novel agents evolve, further studies are required to tailor therapy for this patient group. PMID- 29158116 TI - Is intuitive eating related to resting state vagal activity? AB - Efferent and afferent fibers of the vagus nerve are involved in regulating hunger and satiety. Vagally-mediated heart rate variability (vmHRV) reflects vagal activity. Previously no study addressed a potential association between resting state vagal activity and intuitive eating. Self-reports on intuitive eating and measures of resting state vmHRV were obtained in 39 students (16 female, mean age: 19.64+/-1.44years). Hierarchical multiple regression models showed that, after controlling for gender, age, and body mass index, resting vagal activity was inversely related to the Unconditional Permission to Eat subscale of the Intuitive Eating scale. Individuals with higher resting vagal activity tend to be less willing to eat desired foods and are more likely to label certain foods as forbidden. Future studies should include measures of self-regulation and eating disorder symptomatology to identify potential mediators or moderators when attempting to replicate these preliminary findings in larger samples. PMID- 29158115 TI - Trace elements cause oxidative damage in the brain of rats with induced hypotension. AB - : Hypertension causes neuronal damage and apoptosis in the brain. Diazoxide is a drug used in the treatment of hypertension however, its effect on 5-hydroxyindole acetic acid (5-HIAA) and dopamine amines in adult animal models remains unclear. The purpose of this study was to determine the effect of oligoelements on 5-HIAA and dopamine in the brain of adult rats treated with diazoxide METHODS: Male Fisher rats (weight 250g) were treated as follows: Group I, NaCl 0.9% (control); group II, tracefusin(r) (1.5mL/rat); group III, diazoxide (20mg/rat) and group IV, tracefusin(r) (1.5mL/rat)+diazoxide (20mg/rat). All doses were intraperitoneally administered on daily basis for four consecutive days. After the last administration, the brain of the animals was obtained and dissected in cortex, hemispheres (striatum) and cerebellum/medulla oblongata to measure the levels of 5-HIAA, dopamine, lipid peroxidation and total ATPase activity through validated methods. RESULTS: Dopamine and 5-HIAA levels decreased significantly in the group that received trace elements and diazoxide in the hemisphere regions, while in cerebellum/medulla oblongata, dopamine levels increased significantly in the groups that received diazoxide alone in. Lipid peroxidation in all brain regions increased significantly in the groups that received trace elements and diazoxide. ATPase dependent of calcium and magnesium decreased in the groups that received diazoxide alone or combined with trace elements in cerebellum/medulla oblongata regions. CONCLUSION: The present results suggest that the use of trace elements and diazoxide alters metabolism of dopamine and 5-HIAA amines. Free radicals may be involved in this effect. PMID- 29158117 TI - Cold acclimation and cognitive performance: A review. AB - Athletes, occupational workers, and military personnel experience cold temperatures through cold air exposure or cold water immersion, both of which impair cognitive performance. Prior work has shown that neurophysiological pathways may be sensitive to the effects of temperature acclimation and, therefore, cold acclimation may be a potential strategy to attenuate cold-induced cognitive impairments for populations that are frequently exposed to cold environments. This review provides an overview of studies that examine repeated cold stress, cold acclimation, and measurements of cognitive performance to determine whether or not cold acclimation provides beneficial protection against cold-induced cognitive performance decrements. Studies included in this review assessed cognitive measures of reaction time, attention, logical reasoning, information processing, and memory. Repeated cold stress, with or without evidence of cold acclimation, appears to offer no added benefit of improving cognitive performance. However, research in this area is greatly lacking and, therefore, it is difficult to draw any definitive conclusions regarding the use of cold acclimation to improve cognitive performance during subsequent cold exposures. Given the current state of minimal knowledge on this topic, athletes, occupational workers, and military commands looking to specifically enhance cognitive performance in cold environments would likely not be advised to spend the time and effort required to become acclimated to cold. However, as more knowledge becomes available in this area, recommendations may change. PMID- 29158118 TI - Measuring physiological responses to the arts in people with a dementia. AB - The dementias are a group of progressive symptoms that have multiple causes, usually caused by disease or injury of the brain, affecting higher brain functions such as language, perception, memory, reasoning and mood; they can also be associated with changes in personality. Arts interventions and interaction with the arts can create meaningful, positive experiences for people with a dementia, as well as improve quality of life. Qualitative research in particular, has been able to describe the emotional responses the arts can produce, but quantifiable changes have not been well documented. Physiological measurements such as stress hormone levels and galvanic skin response show promise in being able to quantify such responses. When taken together, these can give a picture of the kinds of physiological outcomes that are associated with positive affect and improvements in mental wellbeing in the context of arts interventions. This review provides a critical overview of the studies which measure some form of physiological outcome in response to the arts or an arts intervention in people with dementia, and indicates how future research in this area can help to broaden our understanding of the effects of the arts in dementia research and care. PMID- 29158119 TI - Contrasting relationship between depression, quantitative gait characteristics and self-report walking difficulties in people with multiple sclerosis. AB - The purpose of this study was to examine the relationship between depression and walking in the multiple sclerosis (MS) community. This study included 132 people with MS (PwMS) (80 women), mean EDSS 2.9 (S.D. = 1.7). Depression was assessed by the Hospital Anxiety and Depression Scale questionnaire. Spatio-temporal parameters of gait were studied using an electronic walkway. Participants filled out a valid self-rated measure of walking ability, the Multiple Sclerosis Walking Scale (MSWS-12) questionnaire. Computerized cognitive scores were included in the analysis in a multivariable analysis. Forty PwMS (30.3%) were classified as suffering from depression. Individuals in the depressed group walked slower than those in the non-depressed group; 92.2 (S.D. = 30.5) vs. 107.9 (S.D. = 29.4)cm/s, respectively. However, after controlling for age, gender and EDSS, the difference between the groups was considered non-significant; p = 0.986. As for the MSWS-12 self-report questionnaire, regardless of the controlling factors (age, gender, EDSS), scores for participants in the depressed group were significantly elevated, indicating poor walking abilities, compared to scores in the non depressed group; 40.8 (S.D. = 15.9) vs. 26.6 (S.D. = 13.7); p = 0.002, respectively. Furthermore, according to the linear regression model, by utilizing the self-rated measure of walking ability, we were able to explain ~20% of the variance related to depression, while spatio-temporal parameters of gait were excluded from the model. In PwMS, depressive symptoms are related to self perception of walking, but not to quantitative gait parameters. PMID- 29158120 TI - Management of MS-relapse during alemtuzumab therapy: Is it really B-cell mediated? PMID- 29158121 TI - Systemic cytokines and chemokines on admission of children hospitalized with community-acquired pneumonia. AB - Community-acquired pneumonia (CAP) is the main cause of death in children under-5 years worldwide and Streptococcus pneumoniae is the most common bacterial agent. However, it is difficult to identify pneumococcal infection among children with CAP. We aimed to assess association between any cytokine/chemokine and pneumococcal infection in childhood CAP. Furthermore, we evaluated the diagnostic value of cytokine/chemokine for pneumococcal infection. This prospective study was conducted at an Emergency Room, in Salvador, Brazil. Children <5-years-old hospitalized with CAP in a 21-month period were evaluated. On admission, clinical and radiological data were collected along with biological samples to investigate 20 etiological agents and determine serum cytokines (interleukin (IL)-8, IL-6, IL 10, IL-1beta, IL-12, TNF-alpha, IL-2, IL-4, IL-5, gamma-interferon), and chemokines (CCL2, CCL5, CXCL9, CXCL10) concentration. From 166 patients with etiology detected, pneumococcal infection was detected in 38 (22.9%) cases among which the median IL-6(pg/ml) was 31.2 (IQR: 12.4-54.1). The other 128 cases had other causative agents detected (Haemophilus influenzae, Moraxella catarrhalis, atypical bacteria and viruses) with the median IL-6 concentration being 9.0 (IQR: 4.1-22.0; p < 0.001). The area under the ROC curve for IL-6 to predict pneumococcal CAP was 0.74 (95%CI: 0.65-0.83; p < 0.001). By multivariate analysis, with pneumococcal CAP as dependent variable, IL-6 was an independent predictor for pneumococcal infection (OR = 5.56; 95%CI: 2.42-12.75, cut-off point = 12.5 pg/ml; p = 0.0001). The negative predictive value of IL-6 under 12.5 pg/ml for pneumococcal infection was 90% (95%CI: 82-95%). Independently significant difference was not found for any other cytokines/chemokines. Serum IL-6 concentration on admission is independently associated with pneumococcal infection among children under-5 years hospitalized with CAP. PMID- 29158122 TI - Biomarkers distinguish HBeAg seroconverted from non-converted individuals in chronic hepatitis B patients treated with a therapeutic vaccine. AB - Cytokine assays of host immune responses to vaccination can indicate vaccine efficacy. Here we tested the hypothesis that assays of the cytokine status of infected individuals prior to therapeutic vaccination might provide a guide to vaccine therapeutic efficacy. If so, cytokine analysis might be used to select appropriate patients for therapeutic vaccination. Data were obtained from a panel of 14 cytokine/chemokine assays that were done during a phase III clinical trial of HBsAg-HBIG therapeutic vaccine (YIC) treatment of chronic hepatitis B (CHB) patients. Summarized assay results were compared between patients who responded by HBeAg-seroconversion and non-responders. Though no single cytokine or chemokine showed clear correlation with responsiveness, by bio-mathematical analysis with Boolean modelling, the combined results revealed that plasma IL-10, IL-33 and MIP-1alpha together correlated best with responsiveness. However, the difference between HBeAg seroconverted and non-converted YIC-treated CHB patients was maximized when results of all 14 cytokine/chemokine assays were included and showed a sensitivity around 0.59, and a specificity of 0.8. It suggested that the combined analysis of these elements may be useful to screen appropriate CHB patients for therapeutic vaccination with YIC. PMID- 29158123 TI - Efficacy and Safety of Necitumumab Continuation Therapy in the Phase III SQUIRE Study of Patients With Stage IV Squamous Non-Small-Cell Lung Cancer. AB - INTRODUCTION: In a retrospective analysis of the SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) study, we investigated the efficacy and safety of single-agent necitumumab continuation therapy in patients with stage IV squamous non-small-cell lung cancer and in a subpopulation of patients with epidermal growth factor receptor (EGFR)-expressing tumors. PATIENTS AND METHODS: Patients were randomized 1:1 for <= 6 cycles of gemcitabine and cisplatin either with or without necitumumab. Patients who received necitumumab continued receiving single-agent necitumumab until progressive disease (necitumumab continuation). Tissue collection was mandatory in SQUIRE. EGFR protein expression was assessed using immunohistochemistry in a central lab. In this subgroup analysis we compared patients treated with necitumumab monotherapy after completion of >= 4 cycles of chemotherapy with those in the chemotherapy arm who were progression-free and did not discontinue because of adverse events (AEs) after completion of >= 4 cycles of chemotherapy (gemcitabine-cisplatin nonprogressors). The same analysis was done for the subgroup of EGFR-expressing patients (EGFR > 0). RESULTS: Baseline characteristics and chemotherapy exposure were well balanced between the necitumumab continuation (n = 261) and gemcitabine cisplatin nonprogressor (n = 215) arms and in the EGFR-expressing population. Median overall survival (OS) from randomization in the necitumumab with gemcitabine-cisplatin versus gemcitabine-cisplatin nonprogressor arm was 15.9 versus 15.0 months (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69 1.05) and median progression-free survival (PFS) from randomization was 7.4 versus 6.9 months (HR, 0.86; 95% CI, 0.70-1.06). OS and PFS benefits were similar when assessed from the postinduction period and in EGFR-expressing patients. No new safety findings emerged. CONCLUSION: There was a consistent treatment effect in favor of necitumumab continuation versus that in gemcitabine-cisplatin nonprogressors, with no unexpected increases in AEs in intention-to-treat as well as EGFR-expressing populations. PMID- 29158124 TI - Improved Survival With Increased Time-To-Radiation and Sequential Chemotherapy After Surgery for pN2 Non-Small-cell Lung Cancer. AB - BACKGROUND: Currently, the ideal timing for postoperative radiotherapy (PORT) and chemotherapy is unknown. The present study evaluated their relative timing on overall survival (OS) using the National Cancer Database (NCDB). MATERIALS AND METHODS: The NCDB was queried for patients from 2004 to 2012 with resected non small-cell lung cancer (NSCLC), pathologically involved N2 (pN2) nodes, and negative margins. All patients underwent adjuvant chemotherapy and external beam radiotherapy. The time to radiation (TTR) was determined from the date of surgery to the start of PORT, with the exclusion of those receiving PORT < 4 weeks or > 24 weeks postoperatively. Early and late TTR was dichotomized at 8 weeks after receiver operating characteristic analysis. Multivariate Cox regression analysis was conducted to predict the variables significantly associated with survival. RESULTS: A total of 1629 patients were eligible for analysis. Of the 1629 patients, 703 had received PORT < 8 weeks and 926 had received PORT >= 8 weeks postoperatively. The receipt of PORT after 8 weeks was associated with better OS (P = .0044). No significant differences were found in survival in the concurrent group comparing early and later TTR (P = .9119). However, a significant OS benefit was found for sequential chemotherapy with an increased TTR (P = .0045). Older age, male sex, shorter distance traveled, increased nodal positivity, larger tumor size, higher Charlson/Deyo comorbidity score, and early TTR were associated with inferior survival on multivariate analysis. CONCLUSION: A TTR of >= 8 weeks with sequential chemotherapy in the setting of PORT was associated with improved survival in patients with NSCLC with pN2 nodes. PMID- 29158125 TI - Sex differences in nicotine intravenous self-administration: A meta-analytic review. AB - OBJECTIVE: This report reflects a meta-analysis that systematically reviewed the literature on intravenous self-administration (IVSA) of nicotine in female and male rats. The goal was to determine if sex differences in nicotine IVSA exist, estimate the magnitude of the effect, and identify potential moderators of the relationship between sex differences and nicotine consumption. METHODS: Extensive search procedures identified 20 studies that met the inclusion criteria of employing both female and male rats in nicotine IVSA procedures. The meta analysis was conducted on effect size values that were calculated from mean total intake or nicotine deliveries using the Hedges' unbiased gu statistic. RESULTS: A random effects analysis revealed that overall females self-administered more nicotine than males (weighted gu=0.18, 95% CI [0.003, 0.34]). Subsequent moderator variable analyses revealed that certain procedural conditions influenced the magnitude of sex differences in nicotine IVSA. Specifically, higher reinforcement requirements (>FR1) and extended-access sessions (23h) were associated with greater nicotine IVSA in females versus males. Females also displayed higher nicotine intake than males when the experiment included a light cue that signaled nicotine delivery. Sex differences were not influenced by the diurnal phase of testing, dose of nicotine, or prior operant training. CONCLUSION: Overall, the results revealed that female rats display higher levels of nicotine IVSA than males, suggesting that the strong reinforcing effects of nicotine promote tobacco use in women. PMID- 29158126 TI - Physiological and behavioral responses of an arboreal mammal to smoke and charcoal-ash substrate. AB - The recent observation that torpor plays a key role in post-fire survival has been mainly attributed to the reduced food resources after fires. However, some of these adjustments can be facilitated or amplified by environmental changes associated with fires, such as the presence of a charcoal-ash substrate. In a previous experiment on a small terrestrial mammal the presence of charcoal and ash linked to food restriction intensified torpor use. However, whether fire cues also act as a trigger of torpor use when food is available and whether they affect other species including arboreal mammals remains elusive. To evaluate whether smoke, charcoal and ash can act as proximate triggers for an impending period of food shortage requiring torpor for mammals, we conducted an experiment on captive sugar gliders (Petaurus breviceps), a small, arboreal marsupial, housed in outside aviaries under different food regimes and natural ambient conditions. When food was available, fire simulation via exposure to smoke and charcoal-ash substrate caused a significant earlier start of activity and a significant decrease in resting body temperature. In contrast, only when food was withheld, did smoke and charcoal-ash exposure significantly enhance torpor depth and duration. Thus, our study not only provides evidence that fire simulation does affect arboreal and terrestrial species similarly, but also suggests that smoke and ash were presumably selected as cues for torpor induction because they indicate an impending lack of food. PMID- 29158127 TI - Characterization of interactions of eggPC lipid structures with different biomolecules. AB - In this paper we study the interactions of two biomolecules (ascorbic acid and Annonacin) with a bilayer lipid membrane. Egg yolk phosphatidylcholine (eggPC) liposomes (in crystalline liquid state) were prepared in solutions of ascorbic acid (AA) at different concentration levels. On the other hand, liposomes were doped with Annonacin (Ann), a mono-tetrahydrofuran acetogenin (ACG), which is an effective citotoxic substance. While AA pharmacologic effect and action mechanisms are widely known, those of Ann's are only very recently being studied. Both Fourier Transformed Infrared (FTIR) and Raman spectroscopic techniques were used to study the participation of the main functional groups of the lipid bilayer involved in the membrane-solution interaction. The obtained spectra were comparatively analyzed, studying the spectral bands corresponding to both the hydrophobic and the hydrophilic regions in the lipid bilayer. Electrochemical experiments namely; impedance spectroscopy (EIS) and cyclic voltamperometry (CV) were used as the main characterization techniques to analyse stability and structural changes of a model system of supported EggPC bilayer in connection with its interactions with AA and Ann. At high molar ratios of AA, there is dehydration in both populations of the carbonyl group of the polar head of the lipid. On the other hand, Ann promotes the formation of hydrogen bonds with the carbonyl groups. No interaction between AA and phosphate groups is observed at low and intermediate molar ratios. Ann is expected to be able to induce the dehydration of the phosphate groups without the subsequent formation of H bonds with them. According to the electrochemical analysis, the interaction of AA with the supported lipid membrane does not alter its dielectric properties. This fact can be related to the conservation of structured water of the phosphate groups in the polar heads of the lipid. On the other hand, the incorporation of Ann into the lipid membrane generates an increase in the number of defects while changes the dielectric constant. This, in turn, can be associated with the induced dehydration of the phosphate groups. PMID- 29158128 TI - Fullerene-PAMAM(G5) composite modified impedimetric biosensor to detect Fetuin-A in real blood samples. AB - The aim of this study is to develop a nanomaterial-dendrimer composite modified biosensor to detect Fetuin-A (HFA) in real blood samples. For this purpose, we designed an Electrochemical Impedance Spectroscopy (EIS) based anti-Fetuin-A (Anti-HFA) modified biosensor system and tested in real blood samples. Chronoimpedance was also employed. The same samples were analyzed with ELISA and the results were compared for validation of the new system. Gold screen printed electrodes (AuSPE) were used as transducer. Firstly, a self-assembly monolayer (SAM) was formed on gold surface by 4-aminothiophenol (4-ATP), Fullerene and PAMAM-NH2 (G5), layers were formed, consecutively. Then Anti-HFA was immobilized on Au/4-ATP/Fullerene/PAMAM electrode via glutaraldehyde. The chronoimpedance test was employed to investigate the optimum analysis duration. According to the data of chronoimpedance, the total analysis time for EIS was chosen as 3 min. The new biosensor was compared with the ELISA method which required 150 min. The calibration curve was prepared electron transfer resistance of the electrode (DeltaRet) per minute as ohm and 1.66-134 ng/mL.min with a R2 = 0.9912. The LOD and LOQ of the biosensor was calculated as 0.48 ng/mL.min, 1.46 ng/mL.min, respectively. Linear regression analysis indicated that the novel developed biosensor results agreed well with that of the conventional ELISA assay. PMID- 29158129 TI - Mitochondrial transfer between cells: Methodological constraints in cell culture and animal models. AB - Interest in the recently discovered phenomenon of mitochondrial transfer between mammalian cells has gained momentum since it was first described in cell culture systems more than a decade ago. Mitochondria-targeting fluorescent dyes have been repurposed and are now widely used in these studies and in acute disease models, sometimes without due consideration of their limitations, while vectors containing mitochondrially-imported fluorescent proteins have complemented the use of mitochondria-targeting dyes. Genetic approaches that use mitochondrial DNA polymorphisms have also been used in some in vitro studies and in tumor models and are particularly useful where mtDNA is damaged or deleted. These approaches can also be used to study the long-term consequences of mitochondrial transfer such as in bone marrow and organ transplantation and in tumour biology where inherent mitochondrial damage is often a key feature. As research on intercellular mitochondrial transfer moves from cell culture into animal models and human diseases it will be important to understand the limitations of the various techniques in order to apply appropriate methodologies to address physiological and pathophysiological conditions. PMID- 29158130 TI - A new look at an old view of denaturant induced protein unfolding. AB - We re-examine a site-binding approach independently proposed by Schellman (Schellman, J.A. (1958) Compt. rend. Lab. Carlsberg Ser. Chim. 30, 439-449) and Aune and Tanford (Aune, K.C. and Tanford, D. (1969) Biochemistry, 8, 4586-4590) for explicitly including the denaturant concentration within the protein unfolding equilibrium. We extend and formalize the approach through development of a multi-dimensional analytical model in which the folding reaction coordinate is defined by the number of denaturant molecules bound to sites located on either the initially folded, or unfolded, states of the protein. We use the developed method to re-examine the mechanistic determinants underlying the sigmoidal shape of the unfolding transition. A natural feature of our method is that it presents a landscape picture of the denaturant induced protein unfolding reaction. PMID- 29158131 TI - Development of a low-cost paper-based ELISA method for rapid Escherichia coli O157:H7 detection. AB - Escherichia coli O157: H7 (E. coli O157: H7) has become one of the most dangerous foodborne pathogenic bacteria around the world. Currently, because of the tedious, high-cost and stringent laboratory conditions required, the conventional E. coli O157: H7 detection methods, such as culture-based methods and polymerase chain reaction (PCR), have much limitation. Thus, we developed a novel paper based enzyme-linked immunosorbent assay (p-ELISA) with shorter operation duration, lower cost, relatively higher sensitivity and wider application. This method required less than 3 h and 5 MUL of sample to complete the detection. The limit of detection (LOD) for E. coli O157: H7 reached 1 * 104 CFU/mL with high specificity. To be more suitable for on-site testing, the readout could be rapidly obtained without any expensive instruments. In this study, we chose E. coli O157:H7 as the representative, and our method could provide a platform for determination of other pathogenic bacteria. PMID- 29158132 TI - Evidence for the implication of the histone code in building the genome structure. AB - Histones are punctuated with small chemical modifications that alter their interaction with DNA. One attractive hypothesis stipulates that certain combinations of these histone modifications may function, alone or together, as a part of a predictive histone code to provide ground rules for chromatin folding. We consider four features that relate histone modifications to chromatin folding: charge neutralisation, molecular specificity, robustness and evolvability. Next, we present evidence for the association among different histone modifications at various levels of chromatin organisation and show how these relationships relate to function such as transcription, replication and cell division. Finally, we propose a model where the histone code can set critical checkpoints for chromatin to fold reversibly between different orders of the organisation in response to a biological stimulus. PMID- 29158133 TI - Characterization of heparan sulfate N-deacetylase/N-sulfotransferase isoform 4 using synthetic oligosaccharide substrates. AB - BACKGROUND: The final structure of heparan sulfate chains is strictly regulated in vivo, though the biosynthesis is not guided by a template process. N deacetylase/N-sulfotransferase (NDST) is the first modification enzyme in the HS biosynthetic pathway. The N-sulfo groups introduced by NDST are reportedly involved in determination of the susceptibility to subsequent processes catalyzed by C5-epimerse and 3-O-sulfotransferases. Understanding the substrate specificities of the four human NDST isoforms has become central to uncovering the regulatory mechanism of HS biosynthesis. METHODS: Highly-purified recombinant NDST-4 (rNDST-4) and a selective library of structurally-defined oligosaccharides were employed to determine the substrate specificity of rNDST-4. RESULTS: Full length rNDST-4 lacks obvious N-deacetylase activity, and displays only N sulfotransferase activity. Unlike NDST-1, NDST-4 did not show directional N sulfotransferase activity while the N-deacetylase domain was inactive. CONCLUSION AND GENERAL SIGNIFICANCE: Individual NDST-4 could not effectively assume the key role in the distribution of N-S domains and N-Ac domains in HS biosynthesis in vivo. PMID- 29158135 TI - Response to Letter to the Editor re 'Be cautious for exceptional results in evaluating the effect of adolescent booster of hepatitis B vaccine'. PMID- 29158134 TI - The inflammasome pathway is amplified and perpetuated in an autocrine manner through connexin43 hemichannel mediated ATP release. AB - BACKGROUND: Connexin43 hemichannels have been implicated in many inflammatory diseases including diabetic retinopathy (DR). Particularly, hemichannel-mediated ATP release has been associated with inflammasome pathway activation. Using an in vitro cell culture model, we evaluated hemichannel roles in response to inflammatory cytokines under high glucose (HG) conditions and propose a mechanism by which a connexin43 hemichannel-mediated autocrine ATP feedback loop augments chronic inflammatory disease. METHODS: Retinal pigment epithelial cells were exposed to HG, 10ng/mL pro-inflammatory cytokines IL-1beta and TNF-alpha, or a combination of both. Quantitative Cytometric Bead Array analysis was used to measure the release of inflammatory cytokines IL-6, IL-8, MCP-1, and sICAM-1, as well as VEGF and ATP. To determine the role of connexin43 hemichannels in the disease process, changes in cytokine and ATP release were evaluated following treatment with Peptide5, a connexin43 hemichannel blocker. Immunohistochemistry was used to compare NLRP3 inflammasome assembly under control and treatment conditions. RESULTS: Co-application of HG and cytokines increased the secretion of IL-6, IL-8, MCP-1, sICAM-1, VEGF and ATP, to significantly higher levels compared to cytokines alone. Peptide5 prevented cytokine release and prevented the increase in ATP release following co-application of HG and cytokines. Adding exogenous ATP negated Peptide5-mediated protection against inflammatory cytokine release in injury conditions. CONCLUSIONS: Our findings show that connexin43 hemichannels play an important role in the amplification and perpetuation of inflammation by mediating an ATP autocrine feedback loop in the inflammasome/inflammation cycle. GENERAL SIGNIFICANCE: Targeting connexin43 hemichannels offers a potential therapeutic strategy to break the inflammatory cycle in diseases such as DR, but also other chronic inflammatory indications. PMID- 29158136 TI - It's all about the perspective: Removing bias when co-managing patients with high grade T1 bladder cancer and localized prostate cancer-A competing risks analysis. AB - The risk connotation of terminology in influencing decision-making should not be underestimated. For example, "superficial" T1HG bladder cancer has the same poor cancer-specific survival as that conferred by the "highest risk" prostate cancer (Gleason 10, T3b). Co-management of concomitant prostate cancer and non-muscle invasive bladder cancer requires a careful competing risk analysis by both the physician and patient. Herein, we detail how patients and physicians should be careful not to underestimate the risk attributed to "non-muscle invasive" bladder cancer. PMID- 29158137 TI - Recent developments in the management of bladder cancer: Introduction. AB - An upsurge of advances in the management of bladder cancer has rapidly occurred over the past 2 years. In this issue, recent developments in the management of bladder cancer will be discussed, including the emerging role of immunotherapy, biomarkers, and advanced imaging. PMID- 29158138 TI - Different ecophysiological responses of freshwater fish to warming and acidification. AB - Future climate change scenarios predict threatening outcomes to biodiversity. Available empirical data concerning biological response of freshwater fish to climate change remains scarce. In this study, we investigated the physiological and biochemical responses of two Iberian freshwater fish species (Squalius carolitertii and the endangered S. torgalensis), inhabiting different climatic conditions, to projected future scenarios of warming (+3 degrees C) and acidification (DeltapH=-0.4). Herein, metabolic enzyme activities of glycolytic (citrate synthase - CS, lactate dehydrogenase - LDH) and antioxidant (glutathione S-transferase, catalase and superoxide dismutase) pathways, as well as the heat shock response (HSR) and lipid peroxidation were determined. Our results show that, under current water pH, warming causes differential interspecific changes on LDH activity, increasing and decreasing its activity in S. carolitertii and in S. torgalensis, respectively. Furthermore, the synergistic effect of warming and acidification caused an increase in LDH activity of S. torgalensis, comparing with the warming condition. As for CS activity, acidification significantly decreased its activity in S. carolitertii whereas in S. torgalensis no significant effect was observed. These results suggest that S. carolitertii is more vulnerable to climate change, possibly as the result of its evolutionary acclimatization to milder climatic condition, while S. torgalensis evolved in the warmer Mediterranean climate. However, significant changes in HSR were observed under the combined warming and acidification (S. carolitertii) or under acidification (S. torgalensis). Our results underlie the importance of conducting experimental studies and address species endpoint responses under projected climate change scenarios to improve conservation strategies, and to safeguard endangered freshwater fish. PMID- 29158139 TI - Expression and evaluation of recombinant P32 protein based ELISA for sero diagnostic potential of capripox in sheep and goats. AB - The study is aimed to develop and evaluate a recombinant P32 protein based ELISA for sero-monitoring and sero-surveillance using known and random/suspected serum samples for capripox infections from sheep and goats. Truncated P32 gene of goatpox virus (with an ORF of 750 bp) was expressed in E. coli BL-21 CodonPlus (DE3)-RIPL cells using pET32a vector and characterized by SDS-PAGE analysis and confirmed by western blotting as 48 kDa polyhistidine-tagged fusion protein. The protein was purified under denaturing conditions using 8M urea and characterized by SDS-PAGE and immunoblotting. The purified protein was used for optimizing ELISA in a chequerboard titration method using anti-GTPV serum as known positive. The optimized conditions were found to be 300 ng of protein/well, 1:10 dilution of antibody, 1:10000 dilution of rabbit anti-goat/sheep conjugate with 3% skim milk powder and 2% gelatin in phosphate buffer saline containing tween-20 as blocking buffer. The expressed protein was specific only for goatpox virus and sheeppox virus but did not react with related viruses of sheep and goats namely orf virus, peste de petits ruminants virus, bluetongue virus and foot and mouth disease virus. The optimized ELISA was evaluated using pre-vaccinated, post vaccinated and also post-challenge sera. The assay was found to have a diagnostic specificity of 100/98.7% and sensitivity of 97.1/98.1% when compared to whole virus antigen based ELISA/SNT by receiver operating characteristic (ROC) analysis. The optimized ELISA is able to determine the progression of antibody response against GTPV and SPPV following vaccination and challenge in sheep and goats. The rP32 protein based ELISA was evaluated using random field serum samples (n = 1008) suspected for sheeppox and goatpox and it has shown positivity rate as 24.4%. The rP32 protein based ELISA was found to be specific and sensitive for sero-evaluation of sheeppox virus and goatpox virus following vaccination and infection in sheep and goats. PMID- 29158140 TI - Consequences of an uncertain mass mortality regime triggered by climate variability on giant clam population management in the Pacific Ocean. AB - Despite actions to manage sustainably tropical Pacific Ocean reef fisheries, managers have faced failures and frustrations because of unpredicted mass mortality events triggered by climate variability. The consequences of these events on the long-term population dynamics of living resources need to be better understood for better management decisions. Here, we use a giant clam (Tridacna maxima) spatially explicit population model to compare the efficiency of several management strategies under various scenarios of natural mortality, including mass mortality due to climatic anomalies. The model was parameterized by in situ estimations of growth and mortality and fishing effort, and was validated by historical and new in situ surveys of giant clam stocks in two French Polynesia lagoons. Projections on the long run (100 years) suggested that the best management strategy was a decrease of fishing pressure through quota implementation, regardless of the mortality regime considered. In contrast, increasing the minimum legal size of catch and closing areas to fishing were less efficient. When high mortality occurred due to climate variability, the efficiency of all management scenarios decreased markedly. Simulating El Nino Southern Oscillation event by adding temporal autocorrelation in natural mortality rates increased the natural variability of stocks, and also decreased the efficiency of management. These results highlight the difficulties that managers in small Pacific islands can expect in the future in the face of global warming, climate anomalies and new mass mortalities. PMID- 29158141 TI - Patient-reported tolerance in treatments approved in neuroendocrine tumors: A national survey from the French Group of Endocrine Tumors. AB - BACKGROUND: Patients with advanced neuroendocrine tumors (NETs) benefit from an increasing number of treatments. The patient's preference could help physicians to choose among these options. Our patient-reported survey aims to compare the perceived tolerance of NETs treatments. METHODS: Patients treated by at least three different therapeutic options have evaluated their perceived tolerance from one (very good) to five (very poor) for each single treatment. Referent physician confirmed the type and ranking over time of each treatment. RESULTS: Two hundred and fourty two treatments have been evaluated by 54 patients. Among patients and NETs characteristics, only a female gender was associated with poor perceived tolerance. Median perceived tolerance increased from 1 (somatostatin analogs, peptide receptor radionuclide therapy (PRRT)), 2 (surgery, radiofrequency ablation and oral chemotherapy), 3 (interferon and everolimus), to 4 (liver embolization, sunitinib and intravenous chemotherapy). In taking somatostatin analogs as reference, the odd ratios for poor perceived tolerance were 1.7 [0.6 5.1] for oral chemotherapy, 2.2 [0.9-5.3] for surgery of the primary tumor, 2.4 [0.6-9.5] for radiofrequency ablation, 2.8 [1.1-7.3] for surgery of metastasis, 3.4 [1.4-7.9] for everolimus, 3.7 [1.6-8.5] for liver embolization, 4.9 [2.2 10.7] for intravenous chemotherapy and 5.9 [2.6-13.1] for sunitinib. Only PRRT had negative odd ratio. CONCLUSION: Our retrospective analysis suggests that perceived tolerance differ in between therapeutic options and may help physicians to sequence the therapeutic strategy. PMID- 29158142 TI - Can immunochromatographic tests for detecting Helicobacter pylori stools antigens replace urea breath test? PMID- 29158143 TI - Urinary concentrations and antimicrobial activity of tobramycin in healthy volunteers receiving a single oral dose of a novel formulation for improved absorption. AB - Oral antibiotics for the treatment of urinary tract infections are scarce. In this ex vivo phase 1 annex study, the clinical safety, urinary concentrations and bactericidal activity of a new formulation for improved oral absorption of tobramycin (TobrateTM) were evaluated. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of five test strains, one reference strain and four clinical uropathogenic strains were determined in cation-adjusted Mueller-Hinton broth (CA-MHB) and in pooled antimicrobial agent free subjects' urine at different pH values (5.5, 6.5, 7.5 and 8.5). Urinary concentrations and urinary bactericidal titres (UBTs) following single oral administration of 600 mg TobrateTM were measured in nine healthy volunteers up to 24 h. The MIC/MBC values in CA-MHB were 2-4/2-4 mg/L for two Escherichia coli strains, 2/2 mg/L for Klebsiella pneumoniae, 0.5/1 mg/L for Pseudomonas aeruginosa and 8/1 mg/L for Proteus mirabilis. MBCs in pooled alkaline urine were significantly lower than those in acidic urine. The mean maximum urinary concentration following 600 mg tobramycin was 83.9 mg/L (2-4 h collection period). The highest reciprocal median UBT values for each test strain were between 2 and 4 during the collection periods 2-4 h and 4-8 h, respectively. The new enteric oral tobramycin formulation significantly improved the very poor oral absorption of standard tobramycin salt. For all pathogens tested, maximum urinary concentrations of tobramycin were at least two times above the urinary MBC. A twice- or three-times daily dosage regimen and alkalising co-medication may further improve urinary bactericidal activity. PMID- 29158144 TI - Ceftolozane/tazobactam in the treatment of osteomyelitis and skin and soft-tissue infections due to extensively drug-resistant Pseudomonas aeruginosa: clinical and microbiological outcomes. AB - Infections due to multidrug-resistant bacteria (MDR) are currently a clinical challenge, mainly in elderly patients. The antimicrobial spectrum, safety and efficacy of ceftolozane/tazobactam (C/T) make it an attractive option for the treatment of MDR bacterial infections beyond the indications approved to date. Here we report our experience with C/T in four cases of osteomyelitis and three cases of skin and soft-tissue infections due to extensively-drug-resistant Pseudomonas aeruginosa. PMID- 29158145 TI - Intratumoural leukocyte infiltration is a prognostic indicator among pancreatic cancer patients with type 2 diabetes. AB - BACKGROUND: The life expectancy of pancreatic cancer patients remains minimal. The disease progression may be influenced by type 2 diabetes (T2D) and inflammatory status, although important gaps persist around their joint effects on disease outcome. The aim of this study was to investigate the clinical significance of the tumour immune microenvironment on pancreatic cancer prognosis in relation to T2D status. METHOD: Tumour-infiltrating macrophages, neutrophils and eosinophils were studied in primary pancreatic tumours and paired lymph node metastases in relation to patient and tumour characteristics, T2D status and overall survival in a retrospective cohort of patients with resectable pancreatic cancer in Sweden. RESULTS: Of the 80 included pancreatic cancer patients, 22 (27.2%) had T2D. The diabetic pancreatic cancer patients had significantly higher systemic high white blood cell count than those without diabetes (P = 0.028). Macrophage infiltration levels were higher in lymph node metastases compared with primary tumours (P = 0.040) among pancreatic cancer patients with diabetes. Type 2 diabetes or intra-tumoural leukocyte (macrophage, neutrophil or eosinophil) infiltration alone did not significantly influence pancreatic cancer prognosis. However, among cancer patients with T2D high macrophage or neutrophil tumour infiltration was associated with a significant reduction in overall survival (adjusted hazard ratio [HR] 7.2; 95% CI 1.5-35.0 and HR 5.4; 95% CI 1.1-26.3, respectively). CONCLUSION: These results demonstrate associations between T2D and enhanced inflammatory processes with significant implications on survival among pancreatic cancer patients with T2D. Validation in larger independent patient cohorts may identify additional prognostic tools and improved treatment strategies for specific patient subsets. PMID- 29158146 TI - Monitoring and predicting disease activity in autoimmune pancreatitis with the M ANNHEIM-AiP-Activity-Score. AB - BACKGROUND & OBJECTIVES: Autoimmune pancreatitis (AiP) is treated by immunosuppressive therapy. Exact description of disease activity of AiP is essential in clinical practice and research, but a score to describe the disease activity is missing. Thus, we aimed to establish an activity score of AiP. METHODS: We retrospectively studied long-term disease courses of 29 patients with AiP (Mannheim, Germany), receiving corticosteroid treatment (CST) by analyzing 613 treatment appointments. Two assumptions were made: First, disease activity is higher at emergency treatments; second, disease activity drops under CST. In all patients, we evaluated established activity- and classification-systems of chronic pancreatitis (cP). Based on the most suitable system, we established an activity score of AiP by including AiP-specific parameters identified from our long-term disease courses and the literature. The new AiP-specific activity score was validated in an external cohort of 14 patients with AiP (Stockholm, Sweden). RESULTS: Within published activity indexes of cP, the M-ANNHEIM-classification most significantly correlated with emergency- and treatment-dependent disease activities (p < 0.001 and p < 0.01, conditional-logistic-regression-analysis). Significant correlations of disease activity were found for several clinical parameters (biliary involvement, extrapancreatic lesions, acute pancreatitis, focal pancreatic mass, pancreatic sausage/mass, focal enlargement, ascites; p < 0.05, Wilcoxon-signed-rank-test). Based on these data and disease features from the literature, the M-ANNHEIM-AiP-Activity-Score (MAAS) was established. CST induced reduction of MAAS disease activity of more than 60% was associated with lower relapse rates (p < 0.05; Chi-Square-test). The results were validated in the external patient cohort. CONCLUSION: The MAAS might represent a useful tool to monitor AiP. PMID- 29158148 TI - Comparing escitaloipram with sertraline for obsessive and compulsive symptoms in patients with obsessive compulsive disorder: A comparative double blind clinical trial. AB - BACKGROUND: Escitalopram has some unique features among selective serotonin reuptake inhibitors. The aim of this survey is to compare the efficacy of escitalopram with sertraline on obsessive and compulsive symptoms in patients with Obsessive Compulsive Disorder (OCD). METHODS: In this 12-week double blind controlled randomized clinical trial, 57 patients with OCD were randomly allocated to receive escitalopram or sertraline. Yale Brown obsessive compulsive behavior scale (YBOCS) was used to assess the outcomes. Adverse effects were also recorded. RESULTS: 41 patients (20 in the escitalopram group and 21 in the sertraline group) completed the trial. In the escitalopram group 15 (70%) patients and in the sertraline group 16 (76.19%) patients showed more than 34% decrease in mean YBOCS score at the end of the trial (P=0.531). The two groups revealed significant decrease in YBOCS scores without significant difference (P=0.861) at week 12. No serious adverse effects were reported. CONCLUSIONS: Our results demonstrated that escitalopram is as effective as sertraline in treatment of obsessions and compulsions in patients with OCD. However, it needs to be noted that our study is preliminary and larger double blind controlled studies are needed to confirm the results. PMID- 29158147 TI - Joint analysis of cognitive and circadian variation in Schizophrenia and Bipolar I Disorder. AB - BACKGROUND: Impairment in cognitive variables and alterations in circadian function have been documented among patients with schizophrenia (SZ) and bipolar I disorder (BP1), but it is not known whether joint analysis of these variables can define clinically relevant sub-groups in either disorder. OBJECTIVES: To evaluate the pattern and relationship of cognitive and circadian function in SZ and BP1 patients with respect to diagnosis and indices of clinical severity. METHODS: Among patients with SZ and BP1, cognitive function was evaluated using the Penn Computerized Neurocognitive Battery and circadian function was assessed using the Composite Scale of Morningness/ Eveningness (CSM). Clinical severity was estimated using the Global Assessment of Function (GAF) scale, and age at onset of illness (AAO). The patients were compared with community based non psychotic control individuals and non-psychotic first degree relatives of the SZ patients. The cluster distributions of cognitive function, circadian function and clinical severity were investigated and identified clusters compared across diagnostic groups. RESULTS: Across participants, the cognitive domains could be separated into two clusters. Cluster 1 included the majority of control individuals and non-psychotic relatives, while SZ patients predominated in Cluster 2. BP1 patients were distributed across both clusters. The clusters could be differentiated by GAF scores, but not AAO. CSM scores were not significantly correlated with individual cognitive domains or with the clusters. CONCLUSIONS: Clusters based on levels of cognitive function can discriminate SZ patients from control individuals, but not BP1 patients. CSM scores do not contribute to such discrimination. PMID- 29158149 TI - The role of hydrogen sulfide in cyclic nucleotide signaling. AB - Hydrogen sulfide (H2S) is recognized as an endogenous gaseous transmitter alongside nitric oxide (NO) and carbon monoxide (CO). By integrating into multiple signaling pathways, H2S elicits biological functions in various mammalian systems. Among these pathways, cyclic nucleotide signaling has gradually gained attention in the past decade. Based on current evidence, it seems that H2S may differentially affect the activity of resting adenylyl cyclases (ACs) and activated ACs, therefore playing a dual role in the regulation of cyclic adenosine monophosphate (cAMP) mediated signaling. However, how H2S achieves the differential regulation on ACs remains unknown at molecular level. In the context of cyclic guanosine monophosphate (cGMP) regulation, H2S augments its downstream signaling at least through three different mechanisms: (1) H2S potentiates the response of soluble guanylyl cyclases (sGCs) to NO; (2) H2S inhibits activity of phosphodiesterases (PDEs); and (3) H2S enhances the production of NO. By regulating cyclic nucleotide signaling, H2S possesses therapeutic potentials particularly for hypertension and cardiac injury which have also been discussed in the current review. Nevertheless, a detailed portrayal of H2S mediated interaction with target proteins is still required for a better understanding of the role of this important gaseous mediator in regulating cyclic nucleotide signaling. PMID- 29158150 TI - Is repeated exposure the holy grail for increasing children's vegetable intake? Lessons learned from a Dutch childcare intervention using various vegetable preparations. AB - Children's failure to eat enough vegetables highlights the need for effective interventions encouraging this behaviour. The aim of this study was to investigate the effect of repeated exposure to three a priori unfamiliar vegetables, each prepared in two ways, on children's vegetable acceptance in a childcare setting. Two hundred fifty children (mean age 25 months; 57% boys) participated in a pre-test and a post-test, where they were offered pumpkin, courgette, and white radish. The intervention group (N = 125) participated in a 5 month exposure period, where they were exposed repeatedly (~12x) to the vegetables: pumpkin blanched and as a cracker spread; courgette blanched and as soup; white radish raw and as a cracker spread. The control group (N = 125) maintained their normal routine. Mixed model analyses were used to analyse intake data and Chi-square analyses for willingness to taste. At pre-test, children ate about 20 g of pumpkin and courgette, whereas white radish intake was approximately 10 g. There was a significant positive effect of the intervention for pumpkin (+15 g; p < 0.001) and white radish (+16 g; p = 0.01). Results for willingness to taste were in the same direction. There was no repeated exposure effect for courgette (p = 0.54); this may have been due to its less distinct taste profile or familiarity with boiled courgette. From our findings, we conclude that repeated exposure to multiple unfamiliar vegetable tastes within the daily routine of a childcare setting is effective in improving children's willingness to taste and intake of some of these vegetables. However, repeated exposure may not be sufficient for more familiar or blander tasting vegetables. This implies that one size does not fit all and that additional strategies are needed to increase children's intake of these vegetables. PMID- 29158151 TI - A novel liquid media mycobacteria extraction method for MALDI-TOF MS identification using VITEK(r) MS. AB - A low-cost identification method that can be performed directly from a positive liquid medium culture is needed for the diagnosis of mycobacterial infections. Here, we describe a novel, cost-effective, and validated method that allows for direct and rapid identification of mycobacteria from a positive liquid culture using VITEK(r) MS with a total process duration under 45min. From a liquid mycobacteria culture a 3.0mL aliquot is removed 24-72h post positivity and centrifuged to create a pellet. After decanting, the tube is blotted dry, the pellet is re-suspended in 0.5mL of 70% ethanol and then transferred into a 2.0mL tube containing glass beads. Mycobacteria are disrupted mechanically followed by a 10min. incubation at room temperature to complete inactivation. Inactivated material is pelleted by centrifugation and then re-suspended in 10MUL of 70% formic acid and 10MUL of acetonitrile. After centrifugation, 1MUL of supernatant (protein extract) is deposited onto target slide, allowed to dry, and then 1MUL CHCA matrix is added. A seeded study was conducted to demonstrate the reliability of the method, a total of 251 culture samples obtained from automated culture systems (BacT/ALERT(r) MP bottles, BACTEC MGITTM 960 tubes, and VersaTREK(r) Myco bottles), were tested and resulted in 98.8% correct identification. Reproducibility was shown by testing three organisms across three reagent lots, between four laboratory technicians, over the course of five days for three liquid media systems resulting in a total of 180 deposits with an overall correct identification of 98.9% with the remaining results giving no identification. Additional studies were performed including comparison of different mechanical disruption techniques, stability of frozen extracts, and stability of slide deposits to allow for flexibility in a routine clinical workflow. The described method proved to be safe while providing consistent and reproducible results for different species of mycobacteria and is compatible with the three most widely used liquid media medium detection systems. PMID- 29158152 TI - Early versus late surgery for infantile exotropia. AB - PURPOSE: To determine whether age at surgery influences postoperative outcome in infantile exotropia. METHODS: This longitudinal, retrospective study included children who underwent bilateral lateral rectus recession between 2004 and 2012 for an exotropia with onset by 12 months of age. Surgical outcomes were considered failures if recurrence with exodeviation of >8Delta or overcorrection with esodeviation of >5Delta developed during postoperative period. Univariate and multivariate analyses were conducted to compare the association of age at surgery with development of recurrence and overcorrection. RESULTS: A total of 93 children were included. Mean age at surgery was 3.2 years. At a mean follow-up of 3.6 years, 19 of 93 patients (20.4%) experienced recurrence and 3 (3.2%) had overcorrection. In the multivariate analyses, increased age at surgery was associated with higher risk for recurrence (OR = 1.031 per 1-month; 95% CI, 1.003 1.060). In subgroup analyses, the association was significant only in the constant exotropia group (OR = 1.410; 95% CI, 1.037-1.917) and not in the intermittent exotropia group (OR = 0.995; 95% CI, 0.938-1.056). In both groups, overcorrection was not associated with any factors, including age at surgery. CONCLUSIONS: Older age at surgery was associated with risk of recurrence in infantile exotropia with constant deviation, but it was not correlated with surgical outcomes for patients with intermittent exotropia in this study. PMID- 29158153 TI - M3 receptor is involved in the effect of penehyclidine hydrochloride reduced endothelial injury in LPS-stimulated human pulmonary microvascular endothelial cell. AB - LPS has been recently shown to induce muscarinic acetylcholine 3 receptor (M3 receptor) expression and penehyclidine hydrochloride (PHC) is an anticholinergic drug which could block the expression of M3 receptor. PHC has been demonstrated to perform protective effect on cell injury. This study is to investigate whether the effect of PHC on microvascular endothelial injury is related to its inhibition of M3 receptor or not. HPMVECs were treated with specific M3 receptor shRNA or PBS, and randomly divided into LPS group (A group), LPS+PHC group (B group), LPS + M3 shRNA group (C group) and LPS + PHC + M3 shRNA group (D group). Cells were collected at 60 min after LPS treatment to measure levels of LDH, endothelial permeability, TNF-alpha and IL-6 levels, NF-kappaB p65 activation, I kappaB protein expression, p38MAPK, and ERK1/2 activations as well as M3 mRNA expression. PHC could decrease LDH levels, cell permeability, TNF-alpha and IL-6 levels, p38 MAPK, ERK1/2, NF-kappaB p65 activations and M3 mRNA expressions compared with LPS group. When M3 receptor was silence, the changes of these indices were much more obvious. These findings suggest that M3 receptor plays an important role in LPS-induced pulmonary microvascular endothelial injury, which is regulated through NF-kappaB p65 and MAPK activation. And knockout of M3 receptor could attenuate LPS-induced pulmonary microvascular endothelial injury. Regulative effects of PHC on pulmonary microvascular permeability and NF-kappaB p65 as well as MAPK activations are including but not limited to inhibition of M3 receptor. PMID- 29158154 TI - Tiotropium inhibits mucin production stimulated by neutrophil elastase but not by IL-13. AB - Tiotropium, a muscarinic antagonist, is approved for the treatment of chronic obstructive pulmonary disease and poorly controlled asthma. Because mucus hypersecretion is characteristic of both of these diseases, and muscarinic agonists stimulate mucus secretion, we hypothesized that tiotropium would attenuate airway MUC5AC expression. We grew normal human bronchial epithelial (NHBE) cells to a goblet cell phenotype with 1 or 5 ng/mL of IL-13 and exposed these cells to 10 nM tiotropium or excipient for the full 14 days. Normally differentiated NHBE cells (without IL-13) were exposed to neutrophil elastase (NE) 1 * 10-7 or 5 * 10-7 M for 1 h. MUC5AC was measured by quantitative PCR and ELISA. Acetylcholine production by the epithelium was evaluated by quantitative PCR and by choline/acetylcholine quantification. Tiotropium had no effect on IL 13-stimulated MUC5AC, but attenuated MUC5AC stimulated by NE (p = 0.007 at 5 * 10 7 M). IL-13 increased CarAT mRNA (p < 0.001 at 5 ng/mL) and acetylcholine concentration in the medium (p = 0.018 at 5 ng/mL), while NE had no effect. Tiotropium had no direct effect on IL-13 or NE-induced CarAT or acetylcholine concentration. Tiotropium decreased MUC5AC stimulated by NE, but had no effect on MUC5AC stimulated by IL-13. These results may be due to IL-13, but not NE, increasing acetylcholine production. PMID- 29158155 TI - Reply to "Comments on associations between religiosity and anxiety, depressive symptoms, and well-being in Korean adults living with epilepsy". PMID- 29158156 TI - Anti-allergic effects of sesquiterpene lactones from Saussurea costus (Falc.) Lipsch. determined using in vivo and in vitro experiments. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea costus (Falc.) Lipsch. root has been used in Asian traditional medicine for the treatment of asthma, rheumatism, and other conditions. S. costus extracts were shown to alleviate house dust mite induced atopic-like dermatitis in Nc/Nga mice; besides, sesquiterpene lactones were isolated from S. costus extracts. AIMS OF THE STUDY: We aimed to investigate the effects of sesquiterpene lactones (alantolactone, costunolide, and dehydrocostuslactone) in allergic asthma using female Balb/c mice and rat RBL-2H3 mast cells. MATERIALS AND METHODS: Antigen-induced degranulation was assessed by measuring beta-hexosaminidase activity in vitro. In addition, a murine ovalbumin induced allergic asthma model was used to test the in vivo efficacy of sesquiterpene lactones. RESULTS: Sesquiterpene lactones inhibited antigen-induced degranulation, wherein dehydrocostuslactone > costunolide > alantolactone in potency. Administration of sesquiterpene lactones decreased the number of immune cells, particularly eosinophils, and reduced the expression and secretion of Th2 cytokines (IL-4 and IL-13) in the bronchoalveolar lavage fluid and lung tissues of mice with ovalbumin-induced allergic asthma. Histological studies showed that sesquiterpene lactones reduced inflammation and mucin production in the lungs. Similar to the in vitro study, dehydrocostuslactone showed the highest potency, followed by costunolide and alantolactone. CONCLUSION: These findings provide evidence that sesquiterpene lactones might be potential anti-allergic therapeutics. PMID- 29158157 TI - Nonalcoholic Fatty Liver Disease Associates With Increased Overall Mortality and Death From Cancer, Cardiovascular Disease, and Liver Disease in Women but Not Men. AB - BACKGROUND & AIMS: It is not clear whether women vs men have increased mortality from nonalcoholic fatty liver disease (NAFLD). We investigated whether NAFLD is associated with increased overall and cause-specific deaths in a Korean population using a large health study database. METHODS: We collected data on 318,224 subjects in Korea (165,131 men and 153,093 women) age 20 to 94 years (mean age, 39.3 y), enrolled in the Kangbuk Samsung Health Study cohort. All subjects underwent a comprehensive annual or biennial health examination in Seoul or Suwon, South Korea, from 2002 through 2012. The presence of NAFLD was ascertained by ultrasonography in the absence of other known liver diseases. Mortality (from 2002 through 2012) was determined by the nationwide death certificate data from the Korea National Statistical Office. RESULTS: During a median 5.7-year follow-up period, cumulative overall mortality was 0.51% (1613 deaths)-cancer was the leading cause of death. In men, NAFLD was not associated with increased mortality from any cause, except lower rate of death from cancer (hazard ratio, 0.79; 95% CI, 0.66-0.93; P = .005), after adjusting for age, body mass index, smoking status, daily alcohol consumption, and physical activity. In women, NAFLD was independently associated with death from all causes (hazard ratio, 1.79; 95% CI, 1.50-2.14; P < .0001), death from cancer (hazard ratio, 1.83; 95% CI, 1.42-2.35; P < .0001), death from cardiovascular disease (hazard ratio, 1.63; 95% CI, 1.00-2.66; P = .0498), and death from liver disease (hazard ratio, 5.58; 95% CI, 1.79-17.39; P = .003). In obese men, NAFLD was associated with a reduced risk of death from cancer. However, NAFLD was associated with increased risk of death from cardiovascular disease in nonobese men. In obese women, NAFLD did not increase risk of death compared with obesity alone. However, NAFLD was associated with increased overall risk of death and risk of death from cancer in nonobese women. CONCLUSIONS: Associations between NAFLD and mortality differ between men and women in Koreans. NAFLD was associated with increased overall mortality and death from cancer, cardiovascular disease, and liver disease in women, but these associations were not observed in men. PMID- 29158158 TI - Magnetic Resonance Enterography to Assess Multifocal and Multicentric Bowel Endometriosis. AB - STUDY OBJECTIVE: To prospectively determine the accuracy of magnetic resonance enterography (MRE) compared with conventional magnetic resonance imaging (MRI) for multifocal (i.e., multiple lesions affecting the same digestive segment) and multicentric (i.e., multiple lesions affecting several digestive segments) bowel endometriosis. DESIGN: A prospective study (Canadian Task Force classification II 2). SETTING: Tenon University Hospital, Paris, France. PATIENTS: Patients with MRI-suspected colorectal endometriosis scheduled for colorectal resection from April 2014 to February 2016 were included. INTERVENTIONS: Patients underwent both 1.5-Tesla MRI and MRE as well as laparoscopically assisted and open colorectal resections. MEASUREMENTS AND MAIN RESULTS: The diagnostic performance of MRI and MRE was evaluated for sensitivity, specificity, positive and negative predictive values, accuracy, and positive and negative likelihood ratios (LRs). The interobserver variability of the experienced and junior radiologists was quantified using weighted statistics. Forty-seven patients were included. Twenty two (46.8%) patients had unifocal lesions, 14 (30%) had multifocal lesions, and 11 (23.4%) had multicentric lesions. The sensitivity, specificity, positive LR, and negative LR for the diagnosis of multifocal lesions were 0.29 (6/21), 1.00 (23/24), 15.36, and 0.71 for MRI and 0.57 (12/21), 0.89 (23/25), 4.95, and 0.58 for MRE. The sensitivity, specificity, positive LR, and negative LR for the diagnosis of multicentric lesions were 0.18 (1/11), 1.00 (1/1), 15, and 0.80 for MRI and 0.46 (5/11), 0.92 (33/36), 5.45, and 0.60 for MRE. Lower accuracies for MRI compared with MRE to diagnose multicentric (p = .01) and multifocal lesions (p = .004) were noted. The interobserver agreement for MRE was good for both multifocality (kappa = 0.80) and multicentricity (kappa = 0.61). CONCLUSION: MRE has better accuracy for diagnosing multifocal and multicentric bowel endometriosis than conventional MRI. PMID- 29158159 TI - On the distributional and evolutionary nature of the obesity wage penalty. AB - The economics literature supports a link between labor market measures, such as earnings, and health conditions, such as obesity. There is reason to believe the effects of obesity on wages may vary for high- and low-earning individuals and that obesity wage effects may evolve over a lifecycle or from generation to generation. Drawing on data from two longitudinal surveys, we estimate quantile and fixed effect quantile regressions, among others, to further examine the obesity wage effect. Results suggest an increasingly severe penalty across the wage distribution for females. Specifically, the highest-earning women may be penalized as much as five times that of the lowest earners. Results for males suggest that penalties may be present at select wage levels, while prior research has generally found no male obesity penalty. We also provide evidence that the obesity penalty has increased across generations and limited evidence that it may slow earnings growth over one's lifetime. PMID- 29158160 TI - Glycoprotein M6a as a signaling transducer in neuronal lipid rafts. AB - Neuronal development is composed of the complex steps which involve many signaling proteins. On the other hand, there are many proteins highly expressed in the differentiated neurons at developmental stages, but of which physiological functions are not precisely known so far. Glycoprotein 6a (GPM6a) currently belongs to such proteins. This protein has four-transmembrane domains and is a member of proteolipid protein family. Recently, we demonstrated that GPM6a is highly concentrated in lipid rafts of the developing neuron with its palmitoylation, and that this molecule is involved in rapid determination of the neuronal polarity, in response to laminin, an extracellular matrix protein (Honda et al., J Neurosci 37: 4046-64 [2017]). Since lipid rafts are membrane domains enriched in sphingolipids and cholesterol, have lower fluidity than other membrane areas and are believed to be signaling "hot-spots", and here, we discuss the functions of this protein in neuronal lipid raft signaling for neuronal development. PMID- 29158161 TI - Extension of the transposable bacterial virus family: two genomic organisations among phages and prophages with a Tn552-related transposase. AB - Mu-like transposable phages and prophages have been isolated from, or predicted, in a wide range of bacterial phyla. However, related B3-like transposable phages, which differ in their genome organisation and the DDE transposase and transposition activator they code for have thus far been restricted to a very limited set of hosts. Through sequence similarity searches, we have now expanded the number of predicted B3-like prophages and uncovered a third genomic organisation. These new genomes, although only prophages, further illustrate the previously reported mosaicism existing in the proposed "Saltoviridae" family of Caudovirales, and further support the proposal to move morphology criteria (contractile vs. flexible or short tail, i.e. Myo-vs. Sipho- or Podoviridae) from the family to the subfamily level in the taxonomic classification of the Caudovirales. PMID- 29158162 TI - The gelatinases, MMP-2 and MMP-9, as fine tuners of neuroinflammatory processes. AB - This review focuses on the complementary roles of MMP-2 and MMP-9 in leukocyte migration into the brain in neuroinflammation, studied mainly in a murine model of experimental autoimmune encephalomyelitis (EAE) that has similarity to the human disease multiple sclerosis. We discuss the cellular sources of MMP-2/MMP-9 in EAE, their sites of activity, and how cleavage of the to-date identified MMP 2/MMP-9 substrates at the blood-brain barrier facilitate leukocyte filtration of the central nervous system (CNS). Where necessary, comparisons are made to inflammatory processes in the periphery and to other MMPs relevant to neuroinflammation. While the general principles concerning MMP-2 and MMP-9 function discussed here are relevant to all inflammatory situations, the details regarding substrates and molecular mechanisms of action are likely to be specific for neuroinflammation. PMID- 29158163 TI - Identification of tissue damage, extracellular matrix remodeling and bacterial challenge as common mechanisms associated with high-risk cutaneous squamous cell carcinomas. AB - In this study we used a genetic extracellular matrix (ECM) disease to identify mechanisms associated with aggressive behavior of cutaneous squamous cell carcinoma (cSCC). cSCC is one of the most common malignancies and usually has a good prognosis. However, some cSCCs recur or metastasize and cause significant morbidity and mortality. Known factors that are associated with aggressiveness of cSCCs include tumor grading, size, localization and microinvasive behavior. To investigate molecular mechanisms that influence biologic behavior we used global proteomic and histologic analyses of formalin-fixed paraffin-embedded tissue of primary human cSCCs. We compared three groups: non-recurring, non-metastasizing low-risk sporadic cSCCs; metastasizing sporadic cSCCs; and cSCCs from patients with recessive dystrophic epidermolysis bullosa (RDEB). RDEB is a genetic skin blistering and ECM disease caused by collagen VII deficiency. Patients commonly suffer from high-risk early onset cSCCs that frequently metastasize. The results indicate that different processes are associated with formation of RDEB cSCCs compared to sporadic cSCCs. Sporadic cSCCs show signs of UV damage, whereas RDEB cSCCs have higher mutational rates and display tissue damage, inflammation and subsequent remodeling of the dermal ECM as tumor initiating factors. Interestingly the two high-risk groups - high-risk metastasizing sporadic cSCCs and RDEB cSCCs - are both associated with tissue damage and ECM remodeling in gene-ontology enrichment and Search Tool for the Retrieval of Interacting Genes/Proteins analyses. In situ histologic analyses validate these results. The high-risk cSCCs also show signatures of enhanced bacterial challenge. Histologic analyses confirm correlation of bacterial colonization with worse prognosis. Collectively, this unbiased study - performed directly on human patient material reveals that common microenvironmental alterations linked to ECM remodeling and increased bacterial challenges are denominators of high-risk cSCCs. The proteins identified here could serve as potential diagnostic markers and therapeutic targets in high-risk cSCCs. PMID- 29158164 TI - LMO7 exerts an effect on mitosis progression and the spindle assembly checkpoint. AB - LMO7 (LIM domain only 7) is a transcription regulator for expression of many Emery-Dreifuss muscular dystrophy-relevant genes, and binds to alpha-actinin and AF6/afadin at adherens junctions for epithelial cell-cell adhesion. In this study, we found that human LMO7 interacted with the spindle assembly checkpoint (SAC) protein MAD1. LMO7 colocalized with actin filaments at the cell membrane but did not colocalize with MAD1 at kinetochores in prometaphase. Our observations reveal that overexpression but not depletion of LMO7 caused a SAC defect, and that the LIM domain of LMO7 was a determinant of its ability to interfere with kinetochore localization of the SAC proteins MAD2 and BUBR1 and cause a SAC defect though the LIM peptide itself did neither bind to MAD1, MAD2 and BUBR1 nor localize to the actin filaments. However, overexpression of LMO7 or the LIM peptide did not interfere with kinetochore localization of MAD1. Additionally, overexpression of the LIM peptide prolonged mitotic timing and interfered with chromosome congression whereas that of LMO7b did not. Taken together, we conclude that LMO7 via its LIM domain acts to control mitosis progression and exerts an effect on the SAC. PMID- 29158165 TI - Cardiac 3D printing for better understanding of congenital heart disease. PMID- 29158166 TI - The association between caspase-5 gene polymorphisms and rheumatoid arthritis in a Chinese population. AB - Genetic factors are widely recognized to have a substantial effect on the susceptibility to rheumatoid arthritis (RA). We examined the contribution of caspase-5 (CASP5) gene polymorphisms to RA risk in a Chinese population. We conducted a case-control study involving 500 RA patients and 500 controls and performed co-expression analysis to identify genes associated with CASP5. We attempted to analyze the functions of these genes by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. We carried out genotyping using a custom-by-design 48-Plex SNP (single nucleotide polymorphism) ScanTM Kit. The independent effects of these genetic loci were evaluated by creating genetic risk scores (GRS). Bioinformatics analysis confirmed that CASP5 was related to the development of inflammation, which is the main feature of RA. In addition, the CASP5 rs9651713 polymorphism was associated with an increased risk of RA, but there was no significant association between any other tested polymorphism (rs2276414, rs2282657, rs3181171, rs3181318, rs3181175, rs3181337, and rs552217) and RA risk. In addition, a high GRS was positively correlated with the risk of RA. In conclusion, CASP5 may contribute to the development of RA by mediating inflammation. Larger studies with more diverse ethnic populations are needed to confirm these results. PMID- 29158167 TI - ClC-3 chloride channel is involved in isoprenaline-induced cardiac hypertrophy. AB - Isoprenaline, an activator of beta-adrenergic receptor, has been found to induce cardiac hypertrophy in vivo and in vitro, but the exact mechanism is still unclear. ClC-3 is a member of the chloride channel family and is highly expressed in mammalian myocardium. In the present study, the role of ClC-3 in isopronaline induced cardiac hypertrophy was investigated. We found that ClC-3 expression was reduced in isoprenaline-induced hypertrophic H9c2 cells, primary rat neonatal cardiomyocytes and myocardium of C57/BL/6 mice, and this reduction was prevented by the pretreatment of propranolol. Adeno-associated virus 9 (AAV9)-mediated ClC 3 expression in myocardium decreased heart mass index, thinned interventricular septum and left ventricular wall and lowered the mRNA expression of natriuretic peptide type A (ANF) and beta-myosin heavy chain (beta-MHC). Our results showed that ClC-3 played an important role in beta-adrenergic cardiac hypertrophy which could be associated with ANF and beta-MHC, and all these findings suggested that ClC-3 may be a novel therapeutic target for the prevention or treatment of myocardiac hypertrophy. PMID- 29158168 TI - Identification and functional analysis of a novel mutation in the PAX3 gene associated with Waardenburg syndrome type I. AB - Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant genetic disorder of neural crest cells (NCC) characterized by congenital sensorineural hearing loss, dystopia canthorum, and abnormal iris pigmentation. WS1 is due to loss-of function mutations in paired box gene 3 (PAX3). Here, we identified a novel PAX3 mutation (c.808C>G, p.R270G) in a three-generation Chinese family with WS1, and then analyzed its in vitro activities. The R270G PAX3 retained nuclear distribution and normal DNA-binding ability; however, it failed to activate MITF promoter, suggesting that haploinsufficiency may be the underlying mechanism for the mild WS1 phenotype of the study family. PMID- 29158169 TI - Potential Benefit of Lymph Node Dissection During Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review by the European Association of Urology Guidelines Panel on Non-muscle-invasive Bladder Cancer. AB - CONTEXT: The oncological efficacy of routine lymphadenectomy (lymph node dissection [LND]) at the time of radical nephroureterectomy (RNU) remains controversial. OBJECTIVE: To systematically review the available literature assessing the impact of LND in upper tract urothelial carcinoma (UTUC) patients. EVIDENCE ACQUISITION: Embase, Medline, and Cochrane databases were searched for all studies comparing outcomes of patients undergoing RNU without LND versus any form of LND. We identified nine retrospective studies eligible for inclusion in this systematic review. We took cancer-specific survival (CSS) as the primary end point, and performed a narrative review and risk of bias assessment. EVIDENCE SYNTHESIS: Six studies compared outcomes of no LND versus LND. Three studies compared complete LND versus incomplete LND versus no LND. The incidence of pN+ in patients with high-stage (>=pT2) tumours ranged from 14.3% to 40%. Pre- and postoperative characteristics differed among the study groups, potentially biasing the results, as demonstrated by the risk of bias assessment, potentially favouring the LND group. Oncological outcomes such as cancer-specific, overall, recurrence-free, and metastasis-free survival were reviewed, demonstrating a survival benefit with LND in high-stage disease of the renal pelvis. CONCLUSIONS: Template-based and complete LND improves CSS in patients with high-stage (>=pT2) UTUC and reduces the risk of local recurrence. The impact of LND in ureteral tumours remains uncertain. PATIENT SUMMARY: Studies comparing radical nephroureterectomy with or without the removal of nodes (lymph node dissection [LND]) were analysed. LND improves survival in patients with high-stage disease of the renal pelvis, if it is performed according to an anatomical template-based approach. PMID- 29158170 TI - Suppressor of Runnerless Encodes a DELLA Protein that Controls Runner Formation for Asexual Reproduction in Strawberry. PMID- 29158171 TI - Pubourethral Stump Angle Measured on Preoperative Magnetic Resonance Imaging Predicts Urethroplasty Type for Pelvic Fracture Urethral Injury Repair. AB - OBJECTIVE: To examine whether the type of delayed urethroplasty required for pelvic fracture urethral injury, which is not easily predicted from conventional urethrography findings, can be predicted from preoperative magnetic resonance imaging (MRI) results. PATIENTS AND METHODS: Records of 74 male patients with pelvic fracture urethral injury who underwent MRI of the pelvis at least 3 months after injury and, subsequently, delayed anastomotic urethroplasty were retrospectively analyzed. Pubourethral stump length (PUL) was defined as the distance between the distal end of the proximal urethral stump and the lower border of the inferior pubic ramus. Pubourethral stump angle (PUA) was defined as the angle between the long axis of the pubis and the line between the distal end of the proximal urethral stump and the lower border of the inferior pubic ramus. Both PUL and PUA were measured in sagittal T2-weighted MRI. RESULTS: Delayed urethroplasty was performed by a simple perineal approach in the 28 patients requiring only bulbar urethral mobilization with or without corporal splitting and by elaborate approach in the 46 additionally requiring inferior pubectomy or an abdominoperineal approach with urethral rerouting. The overall success rate defined as no recurrent stricture on urethroscopy was 94.6%. Disruption at the prostate apex, greater urethral gap length, longer PUL, and lower PUA were in univariate analysis significantly associated with an elaborate approach. In multivariate analysis, only low PUA was an independent predictor of the need for an elaborate approach. CONCLUSION: PUA measured on MRI is useful for predicting the type of reconstruction needed for urethral repair. PMID- 29158172 TI - Estimated Minimal Residual Membranous Urethral Length on Preoperative Magnetic Resonance Imaging Can Be a New Predictor for Continence After Radical Prostatectomy. AB - OBJECTIVE: To identify a parameter predicting postoperative recovery of urinary continence after radical prostatectomy, associations between parameters on preoperative magnetic resonance imaging (MRI) and postoperative continence status were investigated. METHODS: This prospective study enrolled 113 patients with localized prostate cancer who underwent MRI before radical prostatectomy. Continence was evaluated using the Expanded Prostate Index Composite instrument before surgery and at 1, 3, 6, 12, 18, 24, and 36 months postoperatively. We developed a novel parameter, minimal residual membranous urethral length (mRUL), defined as the distance between the lower margins of the puboperinealis and bulbospongiosus muscles in a direction parallel with the urethra on preoperative MRI, which is supposed to represent the minimal intact residual part of the membranous urethra during RP. Thicknesses of the levator ani and periurethral sphincter complex were also estimated on MRI. RESULTS: Continence recovery was significantly faster in patients with longer mRUL (>=6.4 mm) than in patients with shorter mRUL (<6.4 mm; log-rank test, P = .003). Interestingly, incontinence rate before radical prostatectomy was significantly lower in patients with longer mRUL (2.0%) than in those with shorter mRUL (17.5%; P = .008). Multivariate analysis showed that longer mRUL was significantly related to superior continence recovery (hazard ratio, 0.78; P = .005). Thicknesses of the levator ani and periurethral sphincter complex were not associated with continence recovery. CONCLUSION: Preoperative mRUL offers an independent predictor of continence recovery after radical prostatectomy and is also associated with preoperative (baseline) continence status. PMID- 29158173 TI - Standardized and Simplified Retroperitoneal Lymph Node Dissection During Retroperitoneal Laparoscopic Radical Nephroureterectomy for Urothelial Carcinoma of the Upper Ureter or Renal Pelvis: En Bloc Resection Technique. AB - OBJECTIVE: To describe our en bloc technique of retroperitoneal lymph node dissection (RPLND) during retroperitoneal laparoscopic radical nephroureterectomy for upper urinary tract urothelial carcinoma and evaluate perioperative outcomes. METHODS: From 2002 to 2015, 114 patients with urinary tract urothelial carcinoma located at the pelvis or upper or middle ureter underwent retroperitoneal laparoscopic radical nephroureterectomy at 2 institutions. Performance of RPLND began in February 2009. The template of RPLND included the renal hilar and para aortic lymph nodes (left side) and the renal hilar, paracaval, retrocaval, and intra-aortocaval lymph nodes (right side). After incising Gerota fascia longitudinally, the aorta (left side) or inferior vena cava (right side) was exposed, and the lymphatic and surrounding fatty tissue in the template and kidney was dissected in a single monoblock. Preoperative data were compared between the RPLND and the no-RPLND groups using propensity score matching. RESULTS: In total, 32 matched pairs were evaluated. RPLND was successfully accomplished without open conversion in all cases. The operative time in the RPLND group was approximately 100 minutes longer than that in the no-RPLND group, but there was no significant difference in the blood loss volume or complication rate. The pathologic stages were similar in both groups. The mean number of retrieved lymph nodes was 10.7 (range 3-27), and lymph node metastasis was detected in 5 (16%) cases. CONCLUSION: Retroperitoneoscopic en bloc RPLND permits complete and radical removal of the lymphatic tissue contained in the RPLND template. Our en bloc technique is a safe and feasible procedure with comparable blood loss and complication rates. PMID- 29158174 TI - Impact of Cystectomy With Urinary Diversion Upon Tracked Receipt of Opioid Prescriptions Among Patients With Interstitial Cystitis/Bladder Pain Syndrome. AB - OBJECTIVE: To compare opioid requirements before and after cystectomy for end stage Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) using a statewide tracking system. METHODS: Narcotic prescriptions were captured using the North Carolina Controlled Substance Reporting System for patients at a single institute undergoing cystectomy with urinary diversion (CWUD) for refractory, end-stage IC/BPS between 2010 and 2017. Values were documented for the year before and the year after surgery (excluding 30 days postoperatively to account for surgical pain) and converted to morphine equivalents (ME). Values were compared using Student t test. RESULTS: Following CWUD, there was a mean decrease in opioid receipt per patient of 6535 ME/year (P = .321). 8/26 (31%) had not filled any opiate prescriptions for the preceding 3 months at time of manuscript writing. CONCLUSION: In certain patients with end-stage, refractory IC/BPS, CWUD can help reduce opioid requirements. PMID- 29158175 TI - Changes in gray and white matter in subgroups within the tinnitus population. AB - In this study, we investigated gray and white matter changes in subgroups within the larger tinnitus population related to differences in severity or duration of tinnitus symptoms. Tinnitus is the illusory perception of sound in the absence of an external source, most often experienced as a chronic condition. The psychological reaction to the sound constitutes the severity, or degree of discomfort experienced, and the duration refers to the time since onset of chronic tinnitus. We used voxel- and surface-based morphometry to investigate gray matter changes and diffusion tensor imaging (using fractional anisotropy, or FA, metrics) to assess changes in orientation of white matter tracts, using both whole brain and region of interest analyses. Whole brain analyses revealed decreased cortical thickness in the left parahippocampal gyrus in those with more severe tinnitus compared to a group with a milder reaction, and reduced gray matter volume in left anterior cingulate in those with mild tinnitus compared to a normal hearing control group without tinnitus. In the analysis based on FA, no significant differences were revealed between the subgroups or with respect to control groups in either whole brain or region of interest analyses. Our results suggest that these subgroups within the tinnitus population likely exhibit different anatomical alterations related to the disorder, which may explain the variable findings in the literature, particularly in terms of gray matter. PMID- 29158176 TI - Decreased Mcl-1 protein level in the striatum of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated mice. AB - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a well-known neurotoxicant that can selectively destroy dopaminergic neurons and MPTP-treated animals are often used as models for studying aspects of Parkinson's disease (PD). While apoptosis has been suggested as a possible mechanism underlying MPTP-induced cell death and several apoptosis-associated proteins have been implicated in MPTP animal models, relevant information regarding the possible involvement of Mcl-1 (myeloid cell leukemia 1) protein is missing. Mcl-l is an important member of the Bcl-2 family that is thought to be a highly regulated controller of cell death and survival. However, the expression level of Mcl-1 in response to MPTP treatment has not been examined in any area of the brain previously. In the present study, an acute MPTP treatment regimen was utilized with male C57BL/6 mice (10 mg/kg i.p. injections, 4 times with 2 h intervals) and several protein markers were examined 24-h after the initial injection. Dramatic decreases in the immunoreactivities of tyrosine hydroxylase and dopamine transporters were observed. Western-blot analysis and immunocytochemical labeling demonstrated an MPTP-induced decrease in Mcl-1 protein levels in the striatum. In addition, the two proteins BAX and ERK, both of which are also involved in apoptosis signaling, were examined. While the total BAX levels showed no significant difference between the control and MPTP-treated groups, levels of phosphorylated ERK were significantly increased following MPTP-treatment. Since Mcl-1 is an anti apoptotic protein, down-regulation of Mcl-1 following MPTP-treatment would be expected to lead to increased apoptotic activities processes, leading to increased neurodegeneration. PMID- 29158177 TI - Granger causal connectivity dissociates navigation networks that subserve allocentric and egocentric path integration. AB - Studies on spatial navigation demonstrate a significant role of the retrosplenial complex (RSC) in the transformation of egocentric and allocentric information into complementary spatial reference frames (SRFs). The tight anatomical connections of the RSC with a wide range of other cortical regions processing spatial information support its vital role within the human navigation network. To better understand how different areas of the navigational network interact, we investigated the dynamic causal interactions of brain regions involved in solving a virtual navigation task. EEG signals were decomposed by independent component analysis (ICA) and subsequently examined for information flow between clusters of independent components (ICs) using direct short-time directed transfer function (sdDTF). The results revealed information flow between the anterior cingulate cortex and the left prefrontal cortex in the theta (4-7 Hz) frequency band and between the prefrontal, motor, parietal, and occipital cortices as well as the RSC in the alpha (8-13 Hz) frequency band. When participants prefered to use distinct reference frames (egocentric vs. allocentric) during navigation was considered, a dominant occipito-parieto-RSC network was identified in allocentric navigators. These results are in line with the assumption that the RSC, parietal, and occipital cortices are involved in transforming egocentric visual-spatial information into an allocentric reference frame. Moreover, the RSC demonstrated the strongest causal flow during changes in orientation, suggesting that this structure directly provides information on heading changes in humans. PMID- 29158178 TI - Dissection-enabled scaffold-assisted resection (DeSCAR): a novel technique for resection of residual or non-lifting GI neoplasia of the colon (with video). AB - BACKGROUND AND AIMS: As a result of previous manipulation or submucosal invasion, GI lesions referred for EMR frequently have flat areas of visible tissue that cannot be snared. Current methods for treating residual tissue may lead to incomplete eradication or not allow complete tissue sampling for histologic evaluation. Our aim is to describe dissection-enabled scaffold-assisted resection (DeSCAR), a new technique combining circumferential ESD with EMR for removal of superficial non-lifting or residual "islands" with suspected submucosal involvement/fibrosis. METHODS: From 2015 to 2017, lesions referred for EMR were retrospectively reviewed. Cases were identified where lifting and/or snaring of the lesion was incomplete and the DeSCAR technique was undertaken. Cases were reviewed for location, previous manipulation, rates of successful hybrid resection, and adverse events. RESULTS: Twenty-nine lesions underwent DeSCAR because of non-lifting or residual "islands" of tissue. Fifty-two percent of the patients were male and 48% were female; average age was 66 years (standard deviation +/-9.9 years). Lesions were located in the cecum (n = 10), right side of the colon (n = 12), left side of the colon (n = 4), and rectum (n = 3). Average size was 31 mm (standard deviation +/-20.6 mm). Previous manipulation had occurred in 28 of 29 cases (83% biopsy, 34% resection attempt, 52% tattoo). The technical success rate for resection of non-lifting lesions was 100%. There was one episode of delayed bleeding but no other adverse events. CONCLUSIONS: DeSCAR is a feasible and safe alternative to argon plasma coagulation and avulsion for the endoscopic management of non-lifting or residual GI lesions, providing en bloc resection of tissue for histologic review. Further studies are needed to demonstrate long-term eradication and for comparison with other methods. PMID- 29158179 TI - Prognostic factors affecting outcomes in patients with malignant GI bleeding treated with a novel endoscopically delivered hemostatic powder. AB - BACKGROUND AND AIMS: Endoscopic hemostatic techniques remain poorly effective for GI tumor bleeding. We assessed Tc-325 (Hemospray, Cook Medical, Bloomington, Ind, USA) for this indication and determined possible predictors of decreased recurrent bleeding and improved 6-month survival in affected patients. METHODS: This retrospective study identified 99 patients with active malignant GI bleeding (primary or metastatic) treated with Tc-325. Eleven patients were excluded because of incomplete data. Data on patient characteristics and possible predictive factors of early (72-hour) and delayed (7-, 14-, and 30-day) recurrent bleeding, as well as 6-month survival, were collected. RESULTS: Overall, 70.5% were male (age, 65 +/- 14 years). Half had a high Eastern Cooperative Oncology Group (ECOG) score (3 or 4). An upper GI cancer was found in 56.8%, and 72.7% cancers were stage 4. Of those affected, 51.6% received at least 1 non-endoscopic additional definitive hemostatic treatment after Tc-325. Immediate hemostasis with Tc-325 was 97.7%, with recurrent bleeding noted in 15% (early) and 17% (delayed). Six-month survival was 53.4%. On multivariable analysis, no predictive factor for recurrent bleeding was identified, whereas ECOG score 0 to 2 (P = .001; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.47), cancer stage 1 to 3 (P = .04; HR, 0.31; 95% CI, 0.10-0.96), and receiving definite hemostatic treatment alone or in any combination with surgery, chemotherapy, radiotherapy, or radiologic embolization (P = .002; HR, 0.24; 95% CI, 0.09-0.59) were significant prognosticators of 6-month survival after adjusting for comorbidity, type of cancer bleeding, and presence of a coagulopathy. CONCLUSION: Before definitive therapy can be offered, Tc-325 provides effective initial hemostasis of tumoral GI bleeding. Good performance status, non-end-stage cancer, and receiving definite hemostatic treatment are independent predictors of 6-month survival. (Clinical trial registration number: NCT03066700.). PMID- 29158181 TI - Effects of noninvasive ventilation with bilevel positive airway pressure on exercise tolerance and dyspnea in heart failure patients. AB - BACKGROUND: Heart failure (HF) is a syndrome that results in inadequate blood supply, leading to a number of structural and functional changes. Noninvasive ventilatory support (NIVS) is used as an adjuvant treatment to improve the functional capacity of these patients. OBJECTIVE: To investigate the effect of NIVS with bilevel positive airway pressure ventilation (BiPAP) on exercise tolerance and dyspnea in HF patients. METHODS: Forty patients with New York Heart Association class I/II/III HF were randomly assigned either to a NIVS group (n = 20) or control group (n = 20). All patients underwent two 6-min walk tests (6MWT), with a 30-min interval between them. In the NIVS group, the patients performed the BiPAP with an inspiratory positive airway pressure of 12 cmH2O and expiratory positive airway pressure of 6 cmH2O for 30 min. At baseline, and after the first and second 6MWT, the heart rate, systolic and diastolic blood pressure, peripheral oxygen saturation (SaO2), and dyspnea were evaluated. RESULTS: Forty patients completed the study safely according to the randomization protocol, and no adverse events were reported during the tests. The NIVS group showed a significant improvement in the 6MWT distance (68.3 vs. 9.8 m) and dyspnea (1.3 vs. 3.1) compared with the control group. No serious adverse events were reported. CONCLUSIONS: NIVS/BiPAP showed beneficial effects on exercise tolerance and dyspnea. It was safe and well tolerated by HF patients and should be considered for inclusion in cardiac rehabilitation programs. PMID- 29158180 TI - Effect of left lateral tilt-down position on cecal intubation time: a 2-center, pragmatic, randomized controlled trial. AB - BACKGROUND AND AIMS: Colonoscopy insertion is technically challenging, time consuming, and painful, especially for the sigmoid. Several pilot studies indicated that the (left) tilt-down position could facilitate the insertion procedure, but no formal trials have been published to demonstrate its efficacy. We performed this study to verify the benefits of the left lateral tilt-down position (LTDP) on the insertion process. METHODS: This 2-center prospective trial randomized unsedated patients to the LTDP or left lateral horizontal position (LHP) to aid insertion. The primary outcome measure was cecal intubation time (CIT). Secondary outcome measures included decending colon intubation time (DIT), pain score of insertion, acceptance of unsedated colonoscopy for future examinations, difficulty score for insertion, and the adverse event rate of colonoscopy. RESULTS: Two hundred fifty-eight patients were randomized to the LTDP (128) or LHP (130) in 2 centers. The median CIT and DIT were shorter with patients positioned in LTDP than in LHP (CIT, 280.0 vs 339.5 s, P < .001; DIT, 53.0 vs 69.0 s, P < .001, respectively) and patients with high and low body mass index (BMI) benefited more from LTDP than from LHP, as opposed to patients with normal BMI. In addition, colonoscopy insertion in LTDP was less painful (3.4 +/- 1.6 vs 4.0 +/- 1.7, P = .02) and less difficult (3.1 +/- 1.9 vs 3.7 +/- 1.4, P < .001), showing a higher tendency to acceptance of unsedated colonoscopy (82.9% vs 73.8%, P = .08). The rates of adverse events were extremely low and did not differ significantly in the 2 groups. CONCLUSIONS: LTDP for colonoscopy insertion can reduce insertion time and pain, and potentially improves patients' acceptance of unsedated colonoscopy. (Clinical trial registration number: NCT02842489.). PMID- 29158182 TI - Confirmation of specificity of reactivity in a solid phase ELISA for the detection of hepatitis E viral antigen improves utility of the assay. AB - Genotype 3 hepatitis E virus (HEV) can lead to persistent infections in immunocompromised hosts. A recently available commercial assay for the detection of HEV antigen (HEV-Ag ELISA, Wantai diagnostics) may enable the study of HEV-Ag dynamics in such persistent infections, however currently there is no confirmatory test available. We generated a putative neutralising reagent from a pool of four convalescent blood donor samples and explored neutralising activity against HEV antigens from clinical samples, HEV tissue-culture and virus-like particles. Using this neutralisation method we were able to differentiate true reactivity from non-specific reactivity in plasma, stool and urine samples. This could also facilitate the introduction of HEV-Ag detection as a screening assay or the study of HEV-Ag in different body fluids. PMID- 29158183 TI - Serine prevented high-fat diet-induced oxidative stress by activating AMPK and epigenetically modulating the expression of glutathione synthesis-related genes. AB - Serine deficiency has been observed in patients with nonalcoholic fatty liver disease (NAFLD). Whether serine supplementation has any beneficial effects on the prevention of NAFLD remains unknown. The present study was conducted to investigate the effects of serine supplementation on hepatic oxidative stress and steatosis and its related mechanisms. Forty male C57BL/6J mice (9week-old) were randomly assigned into four groups (n=10) and fed: i) a low-fat diet; ii) a low fat diet supplemented with 1% (wt:vol) serine; iii) a high-fat (HF) diet; and iv) a HF diet supplemented with 1% serine, respectively. Palmitic acid (PA)-treated primary hepatocytes separated from adult mice were also used to study the effects of serine on oxidative stress. The results showed that serine supplementation increased glucose tolerance and insulin sensitivity, and protected mice from hepatic lipid accumulation, but did not significantly decreased HF diet-induced weight gain. In addition, serine supplementation protected glutathione (GSH) antioxidant system and prevented hypermethylation in the promoters of glutathione synthesis-related genes, while decreasing reactive oxygen species (ROS) in mice fed a HF diet. Moreover, we found that serine supplementation increased phosphorylation and S-glutathionylation of AMP-activated protein kinase alpha subunit (AMPKalpha), and decreased ROS, malondialdehyde and triglyceride contents in PA-treated primary hepatocytes. However, while AMPK activity or GSH synthesis was inhibited, the abovementioned effects of serine on PA-treated primary hepatocytes were not observed. Our results suggest that serine supplementation could prevent HF diet-induced oxidative stress and steatosis by epigenetically modulating the expression of glutathione synthesis-related genes and through AMPK activation. PMID- 29158184 TI - TGF-beta-mediated upregulation of Sox9 in fibroblast promotes renal fibrosis. AB - TGF-beta signaling plays a principal role in renal fibrosis, but the precise mechanisms and the downstream factors are still largely unknown. Sox9 exhibits diverse roles in regulating the production of extracellular matrix proteins. Here we found that Sox9 was induced by TGF-beta in the kidney fibroblast and acted as an important downstream mediator of TGF-beta signaling in promoting renal fibrosis. TGF-beta/Smad signaling mediated the upregulation of Sox9 in kidney fibroblast by binding to a conserved enhancer. In different mouse models of renal fibrosis, as well as in the kidney biopsy tissue from patients with renal fibrosis, Sox9 expression significantly increased. Immunostaining confirmed the upregulation of Sox9 in the kidney fibroblast during renal fibrosis. Delivery of Sox9 knockdown plasmid to the kidney by ultrasound microbubble-mediated gene transfer suppressed the unilateral ureteral obstruction (UUO) or folic acid induced mouse renal fibrosis, whereas ectopic expression of Sox9 aggravated renal fibrosis. In addition, we identified Sox9 as a direct target of miR-30. Notably, miR-30 expression was significantly inhibited by TGF-beta1 in the kidney fibroblast and the downregulation of miR-30 was observed in renal fibrosis. Mechanistically, inhibition of miR-30 independently strengthened the effect of TGF-beta/Smad signaling on Sox9 upregulation. Adenovirus-mediated ectopic expression of miR-30 in kidney fibroblast greatly reduced UUO-induced renal fibrosis by targeting Sox9. These findings link Sox9 to intrinsic mechanisms of TGF-beta signaling in renal fibrosis and may have therapeutic potential for tissue fibrosis. PMID- 29158185 TI - CDK5-mediated phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress. AB - Major depressive disorder (MDD) is a common, severe and recurrent psychiatric disorder worldwide; however, the underlying neuropathological mechanisms remain elusive. Histone deacetylases (HDACs) appear to play an essential role in depression. As the class III HDACs, Sirt1 and Sirt2 have attracted the most interest in the nervous system. Indeed, chronic stress decreased Sirt1 activity and down-regulated Sirt1 gene expression in MDD. Nevertheless, there is a paucity of literature on the role of Sirt2. To study the role of Sirt2 we established a MDD mouse model in wild type and Sirt2 knockout C57BL/6 mice using social defeat stress (SDS). We found that a lack of Sirt2 blocked the development of SDS induced depressive-like behavior. Moreover, SDS led to Sirt2 phosphorylation in the amygdala without changing total Sirt2 levels, and blocking the phosphorylation of Sirt2 by CDK5 at serine residues 368 and 372 prevented SDS induced depressive-like behavior and Sirt2 nuclear import. We also discovered that SDS-induced Sirt2 phosphorylation was involved in VTA-amygdala modulation using TetTag-pharmacogenetic method. These results suggest that CDK5 mediates phosphorylation of Sirt2 in the amygdala and contributes to the depressive-like behavior induced by SDS. This study highlights that inhibiting CDK5-dependent phosphorylation of Sirt2 at serine residues 368 and 372 by myristoylated membrane permeabilising peptide (Sirt2-p), rather than using non-specific sirtuin inhibitors, may be a novel strategy for treating depression. PMID- 29158186 TI - Diffusion kurtosis imaging with the breath-hold technique for staging hepatic fibrosis: A preliminary study. AB - PURPOSE: To evaluate the potential of diffusion kurtosis imaging (DKI) analysis with the breath-hold technique to assess the stage or classify hepatic fibrosis. MATERIALS AND METHODS: Patients (n=67) suspected of having a disease of the hepatobiliary system examined by diffusion-weighted imaging (DWI) using a 3.0-T magnetic resonance imaging unit were enrolled in this study. To evaluate hepatic fibrosis, mean kurtosis, Mean apparent diffusion (MD) and apparent diffusion coefficient (ADC) values were compared between groups with varying fibrosis; F0 F1, F2-F3, and F4. The Steel-Dwass test was used for overall comparisons. Correlations between the fibrosis stage and mean kurtosis, MD or ADC values were assessed using Spearman's rank correlation. Discriminative capacities of DKI were evaluated using receiver operating characteristic (ROC) analysis. RESULTS: There were significant differences in ADC, MD and mean kurtosis values between non cirrhosis and cirrhosis groups. Moreover, the mean kurtosis value was statistically different between the F0-F1 and F2-F3, F0-F1 and F4, and F2-F3 and F4 groups (all P<0.05). MD value was statistically different between the F0-F1 and F4 groups, and F2-F3 and F4 groups (all P<0.05). However, there was no significant difference in ADC values for all groups (all P>0.05). In addition, mean kurtosis and MD values significantly correlated with the extent of hepatic fibrosis staging (Spearman's rank correlation coefficient, rho=0.851 and -0.672; P<0.0001). However, ADC values did not reveal a correlation with the extent of hepatic fibrosis staging (rho=-0.227; P=0.078). According to the ROC analysis for the assessment of no fibrosis (F0), fibrosis (>=F1), and advanced fibrosis (>=F2) and liver cirrhosis, the DKI cut-off values were 0.923, 0.955, and 1.11, respectively. CONCLUSION: Using the DKI method with the breath-hold technique in the liver, the stage of hepatic fibrosis can be classified into normal and early hepatic fibrosis, substantial stages, and advanced hepatic fibrosis. PMID- 29158187 TI - White matter structural integrity and transcranial Doppler blood flow pulsatility in normal aging. AB - Cerebrovascular diseases underlie many forms of age-related cognitive impairment and the mechanism linking the two is hypothesized to involve adverse changes in white matter (WM) integrity. Despite being systemic, small vessel disease does not uniformly affect WM. We performed voxel-wise analysis of MRI images to examine the association between fractional anisotropy (FA) - a diffusion tensor measure of WM structural integrity - and pulsatility index (PI) - a transcranial Doppler ultrasound measure of abnormal arterial flow - in adults over the age of 70years who were free of stroke and dementia. We demonstrate that the relation of PI to microstructural changes in WM is artery specific and regional. We identified spatial clusters of significant correlations between elevated PI and reduced FA which cannot be explained by aging, supporting a vascular hypothesis of WM injury. These areas are not limited to the vascular territories of the vessels where PI is assessed, suggesting that the linkage between PI and FA is not likely a function of perfusion per se, but is consistent with injury caused by mechanical wave emanating from pulsating vessel walls. PMID- 29158188 TI - Experimental use of an acrolein-based primer as collagen cross-linker for dentine bonding. AB - OBJECTIVES: The objective of the present study was to investigate the long-term effect of 0.01% acrolein (ACR) aqueous solution, employed as an additional primer, on the mechanical durability and enzymatic activity of resin-dentine interfaces created with a simplified etch-and-rinse adhesive. METHODS: Dentine surfaces were etched with 35% phosphoric acid for 15s, rinsed and blot-dried. Specimens were then assigned to: Group 1: dentine pre-treated with 0.01% ACR aqueous solution for 1min and bonded with Adper Scotchbond 1 XT (SB1XT), a 2-step etch-and-rinse adhesive; Group 2: SB1XT was applied on untreated acid-etched dentine (control). Resin composite build-ups were made using Filtek Z250. Microtensile bond strength was tested by stressing sectioned specimens to failure immediately or after 1year of storage in artificial saliva at 37 degrees C. Zymography and in-situ zymography assays were performed for examining dentine matrix metalloproteinase (MMP) activities. RESULTS: The use of 0.01% ACR as conditioning primer appeared to have contributed better to preservation of bond strength over time without affecting immediate bond strength. Zymography and in situ zymography showed reduction in MMP activities after the application of ACR. CONCLUSION: Dentine collagen cross-linking produced by an ACR-based primer increases the longevity of resin-dentine bonds by reinforcement of the adhesive interface and reduction of dentine MMP activities. Further studies are required to evaluate the potential in vivo and in vivo cytotoxicity of ACR. CLINICAL SIGNIFICANCE: The acrolein-based primer is a potentially useful clinical bonding tool because it demonstrates good collagen cross-linking ability within a clinically-acceptable working time. Although a low ACR concentration was employed in the present study, the cytotoxicity of ACR should be tested prior to clinical use. PMID- 29158189 TI - Development of an oxygen-independent flavin mononucleotide-based fluorescent reporter system in Clostridium beijerinckii and its potential applications. AB - Clostridium beijerinckii is a predominant solventogenic clostridia with great attraction for renewable liquid biofuel and biochemical production. Metabolic engineering and synthetic biology can be employed to engineer the strain toward desirable phenotypes. However, current limited information such as promoter strength and gene regulation may hinder the efficient engineering of the strain. To investigate genetic information and complex cellular bioprocesses of C. beijerinckii, an in vivo fluorescence reporter system can be employed. In general, green fluorescence protein (GFP) and relative analogs have been widely used as real-time reporters. However, GFP-family proteins require molecular oxygen for fluorescence maturation. Considering the strict anaerobic growth requirement of the clostridia, an oxygen-independent fluorescence reporter such as a flavin mononucleotide-based fluorescent protein (FbFP) can be used as an alternative fluorescence reporter. In this study, we synthesized and expressed the codon-optimized FbFP gene for C. beijerinckii (CbFbFP) based on the nucleotide sequence of Bacillus subtilis YtvA variant EcFbFP in C. beijerinckii NCIMB 8052 wild-type. Protein expression and in vivo fluorescence of CbFbFP in C. beijeirnckii were confirmed under anaerobic growth conditions. Through fluorescence-activated cell sorting (FACS), we isolated the bright cells from the heterogenous population of C. beijerinckii cells expressing CbFbFP. Several mutations were found in the isolated plasmid which may be responsible for the high-level expression of CbFbFP in C. beijerinckii. The mutant plasmid and CbFbFP reporter were further utilized for strain selection, real-time fluorescence measurement, population analysis, and metabolic engineering in this study. PMID- 29158190 TI - Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas. AB - Microsatellite instability (MSI) caused by mismatch repair deficiency (dMMR) is detected in a small proportion of pancreatic ductal adenocarcinomas (PDACs). dMMR and MSI have been associated with responses of metastatic tumors, including PDACs, to immune checkpoint inhibitor therapy. We performed immunohistochemical analyses of a 445 PDAC specimens, collected from consecutive patients at multiple centers, to identify those with dMMR, based on loss of mismatch repair proteins MLH1, MSH2, MSH6, and/or PMS2. We detected dMMR in 1.6% of tumor samples; we found dMMR in a larger proportion of intraductal papillary mucinous neoplasms related tumors (4/58, 6.9%) than non- intraductal papillary mucinous neoplasms PDAC (5/385, 1.3%) (P = .02). PDACs with dMMR contained potentially immunogenic mutations because of MSI in coding repeat sequences. PDACs with dMMR or MSI had a higher density of CD8+ T cells at the invasive front than PDACs without dMMR or MSI (P = .08; Fisher exact test). A higher proportion of PDACs with dMMR or MSI expressed the CD274 molecule (PD-L1, 8/9) than PDACs without dMMR or MSI (4/10) (P = .05). Times of disease-free survival and overall survival did not differ significantly between patients with PDACs with dMMR or MSI vs without dMMR or MSI. Studies are needed to determine whether these features of PDACs with dMMR or MSI might serve as prognostic factors. PMID- 29158193 TI - EGFR Gene Copy Number by FISH May Predict Outcome of Necitumumab in Squamous Lung Carcinomas: Analysis from the SQUIRE Study. AB - INTRODUCTION: Necitumumab is a monoclonal antibody targeting EGFR. In the SQUIRE trial, the addition of necitumumab to chemotherapy for squamous cell lung cancer significantly improved overall survival (OS) (hazard ratio [HR] = 0.84); in a post hoc analysis, EGFR copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend toward improved OS (HR = 0.70) and progression-free survival (PFS) (HR = 0.71) with the addition of necitumumab. We present the analysis of granular EGFR FISH data from SQUIRE to examine the potential predictive role of high polysomy and gene amplification, as both were included in the FISH-positive category. METHODS: Available specimens from SQUIRE underwent FISH analysis in a central laboratory, and each sample was evaluated by using the Colorado EGFR scoring criteria. The correlation of granular FISH parameters with clinical outcomes was assessed. RESULTS: Samples were available for 557 of 1093 patients; 208 patients (37.3%) were FISH-positive, including 167 (30.0%) with high polysomy and 41 (7.4%) with gene amplification. In patients with high polysomy, the addition of necitumumab resulted in a statistically significant increase in PFS (6.08 versus 5.13 months [p = 0.044]) and nonstatistically significant increase in OS (12.6 versus 9.5 months [p = 0.133]); among patients with gene amplification, the addition of necitumumab did not significantly improve PFS (7.4 versus 5.6 months; [p = 0.334]) but did improve OS (14.8 versus 7.6 months; [p = 0.033]). CONCLUSIONS: EGFR copy number gain by FISH might have a role as a predictive biomarker for necitumumab in squamous cell lung cancer. In our opinion, these data encourage further studies to prospectively evaluate this potential biomarker. PMID- 29158194 TI - Recent advances in bacteriophage-based methods for bacteria detection. AB - Fast and reliable bacteria detection is crucial for lowering the socioeconomic burden related to bacterial infections (e.g., in healthcare, industry or security). Bacteriophages (i.e., viruses with bacterial hosts) pose advantages such as great specificity, robustness, toughness and cheap preparation, making them popular biorecognition elements in biosensors and other assays for bacteria detection. There are several possible designs of bacteriophage-based biosensors. Here, we focus on developments based on whole virions as recognition agents. We divide the review into sections dealing with phage lysis as an analytical signal, phages as capturing elements in assays and phage-based sensing layers, putting the main focus on development reported within the past three years but without omitting the fundamentals. PMID- 29158191 TI - Association Between Coffee Intake After Diagnosis of Colorectal Cancer and Reduced Mortality. AB - BACKGROUND & AIMS: Few studies have examined the association between coffee intake and survival after diagnosis of colorectal cancer (CRC). We performed a prospective study to investigate the association between coffee intake after a diagnosis of CRC and mortality. METHODS: We collected data from the Nurses' Health Study (1984-2012) and Health Professionals Follow-up Study (1986-2012), following 1599 patients diagnosed with stage 1, 2, or 3 CRC. CRC was reported on questionnaires and ascertained by review of medical records and pathology reports; intake of food and beverages was determined from responses to semi quantitative food frequency questionnaires. Participants were asked how often during the previous year that they consumed coffee, with 1 cup as the standard portion size. The first questionnaire response collected at least 6 months but not more than 4 years after diagnosis was used for assessment of post-diagnostic intake (median time from diagnosis to the dietary assessment, 2.2 years). The last semi-quantitative food frequency questionnaire prior to diagnosis was used to assess pre-diagnostic dietary intake. RESULTS: During a median of 7.8 years of follow-up, we documented 803 deaths, of which 188 were because of CRC. In the multivariable adjusted models, compared with nondrinkers, patients who consumed at least 4 cups of coffee per day had a 52% lower risk of CRC-specific death (hazard ratio [HR] 0.48; 95% CI, 0.28-0.83; P for trend=.003) and 30% reduced risk of all-cause death (HR, 0.70; 95% CI, 0.54-0.91; P for trend <.001). High intake of caffeinated and decaffeinated coffee (2 or more cups/day) was associated with lower risk of CRC-specific mortality and all-cause mortality. When coffee intake before vs after CRC diagnosis were examined, compared with patients consistently consuming low amounts (less than 2 cups/day), those who maintained a high intake (2 or more cups/day) had a significantly lower risk of CRC-specific death (multivariable HR, 0.63; 95% CI, 0.44-0.89) and death from any cause (multivariable HR, 0.71; 95% CI, 0.60-0.85). CONCLUSIONS: In an analysis data from the Nurses' Health Study and Health Professionals Follow-up Study, we associated intake of caffeinated and decaffeinated coffee after diagnosis of CRC with lower risk of CRC-specific death and overall death. Studies are needed to determine the mechanisms by which coffee might reduce CRC progression. PMID- 29158195 TI - Understanding missing proteins: a functional perspective. AB - A missing protein (MP) is an unconfirmed genetic sequence for which a protein product is not yet detected. Currently, MPs are tiered based on supporting evidence mainly in the form of protein existence (PE) classification. As we discuss here, this definition is overly restrictive because proteins go missing in day-to-day proteomics as a result of low abundance, lack of sequence specificity, splice variants, and so on. Thus, we propose a broader functional classification of MPs that complements PE classification, discuss major causes, and examine three corresponding solution tiers: biological, technical, and informatics. We assert that informatics-driven solutions would have a major role in resolving the MP problem (MPP). PMID- 29158196 TI - Stereoselective and domain-specific effects of ibuprofen on the thermal stability of human serum albumin. AB - Ibuprofen is one of the most used anti-inflammatory drugs, and it is transported in the blood by human serum albumin, a major plasmatic protein with a peculiar adaptability in the binding of several different ligands. We have characterized the interaction between albumin and ibuprofen, either in racemic mixture, or in the S(+) and R(-) enantiomeric forms, by using differential scanning calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, and molecular dynamics simulation. The results show that increasing concentrations of ibuprofen (up to sixfold drug/protein molar ratio) improve the protein resistance to thermal unfolding without altering the secondary structure. Deconvolution of the calorimetric thermal profiles at different albumin/ibuprofen molar ratios demonstrates a selective stability of the protein domains where the binding sites of the drug are localized. At the highest ibuprofen concentration, the melting temperature increased by about 10 degrees C with respect to the drug-free protein, whereas the unfolding enthalpy maintains an almost constant value. Furthermore, the degree of protein stabilization depends upon the chirality of the drug, and the R(-) enantiomer is more effective compared to the S(+) form. The stability is supported by molecular dynamics simulations, showing that ibuprofen maintains a stable coordination in the most favorable binding sites, leading to a more compact protein structure at high temperature. The overall results attest that the binding of ibuprofen determines on albumin a stereoselective and domain-specific stabilization with a predominantly entropic character, contributing to clarify significant aspects of the molecular mechanism of protein/drug interaction. PMID- 29158192 TI - Combination of Gene Expression Signature and Model for End-Stage Liver Disease Score Predicts Survival of Patients With Severe Alcoholic Hepatitis. AB - BACKGROUND & AIMS: Patients with severe alcoholic hepatitis (AH) have a high risk of death within 90 days. Corticosteroids, which can cause severe adverse events, are the only treatment that increases short-term survival. It is a challenge to predict outcomes of patients with severe AH. Therefore, we developed a scoring system to predict patient survival, integrating baseline molecular and clinical variables. METHODS: We obtained fixed liver biopsy samples from 71 consecutive patients diagnosed with severe AH and treated with corticosteroids from July 2006 through December 2013 in Brussels, Belgium (derivation cohort). Gene expression patterns were analyzed by microarrays and clinical data were collected for 180 days. We identified gene expression signatures and clinical data that are associated with survival without liver transplantation at 90 and 180 days after initiation of corticosteroid therapy. Findings were validated using liver biopsies from 48 consecutive patients with severe AH treated with corticosteroids, collected from March 2010 through February 2015 at hospitals in Belgium and Switzerland (validation cohort 1) and in liver biopsies from 20 patients (9 received corticosteroid treatment), collected from January 2012 through May 2015 in the United States (validation cohort 2). RESULTS: We integrated data on expression patterns of 123 genes and the model for end-stage liver disease (MELD) scores to assign patients to groups with poor survival (29% survived 90 days and 26% survived 180 days) and good survival (76% survived 90 days and 65% survived 180 days) (P < .001) in the derivation cohort. We named this assignment system the gene signature-MELD (gs-MELD) score. In validation cohort 1, the gs-MELD score discriminated patients with poor survival (43% survived 90 days) from those with good survival (96% survived 90 days) (P < .001). The gs-MELD score also discriminated between patients with a poor survival at 180 days (34% survived) and a good survival at 180 days (84% survived) (P < .001). The time-dependent area under the receiver operator characteristic curve for the score was 0.86 (95% confidence interval 0.73-0.99) for survival at 90 days, and 0.83 (95% confidence interval 0.71-0.96) for survival at 180 days. This score outperformed other clinical models to predict survival of patients with severe AH in validation cohort 1. In validation cohort 2, the gs-MELD discriminated patients with a poor survival at 90 days (12% survived) from those with a good survival at 90 days (100%) (P < .001). CONCLUSIONS: We integrated data on baseline liver gene expression pattern and the MELD score to create the gs-MELD scoring system, which identifies patients with severe AH, treated or not with corticosteroids, most and least likely to survive for 90 and 180 days. PMID- 29158197 TI - Modified mycotoxins: An updated review on their formation, detection, occurrence, and toxic effects. AB - Modified mycotoxins are metabolites that normally remain undetected during the testing for parent mycotoxin. These modified forms of mycotoxins can be produced by fungi or generated as part of the defense mechanism of the infected plant. In some cases, they are formed during food processing. The various processing steps greatly affect mycotoxin levels present in the final product (free and modified), although the results are still controversial regarding the increase or reduction of these levels, being strongly related to the type of process and the composition of the food in question. Evidence exists that some modified mycotoxins can be converted into the parent mycotoxin during digestion in humans and animals, potentially leading to adverse health effects. Some of these formed compounds can be even more toxic, in case they have higher bioaccessibility and bioavailability than the parent mycotoxin. The modified mycotoxins can occur simultaneously with the free mycotoxin, and, in some cases, the concentration of modified mycotoxins may exceed the level of free mycotoxin in processed foods. Even though toxicological data are scarce, the possibility of modified mycotoxin conversion to its free form may result in a potential risk to human and animal health. This review aims to update information on the formation, detection, occurrence, and toxic effects caused by modified mycotoxin. PMID- 29158199 TI - Male rat exposure to low dose of di(2-ethylhexyl) phthalate during pre-pubertal, pubertal and post-pubertal periods: Impact on sperm count, gonad histology and testosterone secretion. AB - Di (2-ethylhexyl) phthalate (DEHP) is the most ubiquitous endocrine disruptor in the environment. The present study aimed to investigate the low dose effects of DEHP on the male reproductive system of rats exposed during the pre-pubertal, pubertal and post-pubertal periods. Male Wistar rats were daily gavaged by DEHP from postnatal day (PND) 21 to PND 120 with 0.5, 50 and 5000MUg/kgBW/d. A decrease in sperm count of 41%, 24% and 46% was observed at 0.5, 50 and 5000MUg/kgBW/d respectively. A decrease of Sertoli cells number was observed at 50 and 5000MUg/kgBW/d (22% and 42%, respectively). Non-monotonic dose-response was observed for testosterone levels with a significant increase at 50MUg/kgBW/d associated to a notable enhancement of Leydig cells number (35%). In conclusion, our results showed that postnatal exposure to low doses of DEHP affects sperm count, Sertoli and Leydig cells number and testosterone level. PMID- 29158198 TI - Vitamin C exerts novel protective effects against cadmium toxicity in mouse spermatozoa by inducing the dephosphorylation of dihydrolipoamide dehydrogenase. AB - Cadmium (Cd) has been reported to inhibit mouse sperm motility by inducing the tyrosine phosphorylation of dihydrolipoamide dehydrogenase (DLD). This study aimed to assess the potential effects of vitamin C (Vc) on ameliorating Cd induced tyrosine phosphorylation of DLD and the specific underlying mechanism. Vc induced the dephosphorylation of DLD or inhibited the tyrosine phosphorylation of DLD. Accordingly, DLD activity, nicotinamide adenine dinucleotide hydrogen (NADH) levels, ATP levels and motility parameters were all restored to normal levels by Vc. Moreover, the effects of Vc on ameliorating these indicators had striking similarities to the effects of ethylenediaminetetraacetic acid (EDTA). In addition, neither the antioxidant melatonin nor the universal oxidant H2O2 influenced the tyrosine phosphorylation of DLD. Hence, the protective effects of Vc on the tyrosine phosphorylation of DLD might be attributed to its binding to Cd ions outside or inside sperm, and were not due to its antioxidant properties. PMID- 29158200 TI - Effects of diesel exhaust-derived secondary organic aerosol (SOA) on oocytes: Potential risks to meiotic maturation. AB - Particulate air pollution (PM 2.5) is a worldwide concern. Growing epidemiological evidence has shown pathophysiological effects of PM 2.5, not only on cardiovascular system but also on reproductive performance. The composition and physicochemical properties of PM 2.5 vary depending on the emission sources, climate conditions, and complex chemical reactions in the air. These factors make it difficult to understand the cause and mechanistic details of the adverse health effects of PM 2.5. Here, we show potential impacts of PM 2.5 on oocyte maturation in mice by utilizing diesel exhaust-derived secondary organic aerosol (SOA), a major component of urban PM 2.5. We found that the SOA destabilized microtubules of mouse oocytes and p-benzoquinone is one of the candidates for the microtubule-destabilizing compounds. We propose that some biologically reactive components of PM 2.5 should be prioritized for the regulation of atmospheric quality. PMID- 29158201 TI - The effect of prior knowledge on post-encoding brain connectivity and its relation to subsequent memory. AB - It is known that prior knowledge can facilitate memory acquisition. It is unclear, however, whether prior knowledge can affect post-encoding brain activity to facilitate memory consolidation. In this fMRI study, we asked participants to associate novel houses with famous/nonfamous faces and investigated how associative-encoding tasks with/without prior knowledge differentially affected post-encoding brain connectivity during rest. Besides memory advantages in the famous condition, we found that post-encoding hippocampal connectivity with the fusiform face area (FFA) and ventral-medial-prefrontal cortex (vmPFC) was stronger following encoding of associations with famous than non-famous faces. Importantly, post-encoding functional connectivity between the hippocampus (HPC) and FFA, and between the anterior temporal pole region (aTPL) and posterior perceptual regions (i.e., FFA and the parahippocampal place area), together predicted a large proportion of the variance in subsequent memory performance. This prediction was specific for face-house associative memory, not face/house item memory, and only in the famous condition where prior knowledge was involved. These results support the idea that when prior knowledge is involved, the HPC, vmPFC, and aTPL, which support prior episodic, social-evaluative/schematic, and semantic memories, respectively, continue to interact with each other and posterior perceptual brain regions during the post-encoding rest to facilitate off-line processing of the newly formed memory, and enhance memory consolidation. PMID- 29158202 TI - Dynamic effective connectivity in resting state fMRI. AB - Context-sensitive and activity-dependent fluctuations in connectivity underlie functional integration in the brain and have been studied widely in terms of synaptic plasticity, learning and condition-specific (e.g., attentional) modulations of synaptic efficacy. This dynamic aspect of brain connectivity has recently attracted a lot of attention in the resting state fMRI community. To explain dynamic functional connectivity in terms of directed effective connectivity among brain regions, we introduce a novel method to identify dynamic effective connectivity using spectral dynamic causal modelling (spDCM). We used parametric empirical Bayes (PEB) to model fluctuations in directed coupling over consecutive windows of resting state fMRI time series. Hierarchical PEB can model random effects on connectivity parameters at the second (between-window) level given connectivity estimates from the first (within-window) level. In this work, we used a discrete cosine transform basis set or eigenvariates (i.e., expression of principal components) to model fluctuations in effective connectivity over windows. We evaluated the ensuing dynamic effective connectivity in terms of the consistency of baseline connectivity within default mode network (DMN), using the resting state fMRI from Human Connectome Project (HCP). To model group-level baseline and dynamic effective connectivity for DMN, we extended the PEB approach by conducting a multilevel PEB analysis of between-session and between-subject group effects. Model comparison clearly spoke to dynamic fluctuations in effective connectivity - and the dynamic functional connectivity these changes explain. Furthermore, baseline effective connectivity was consistent across independent sessions - and notably more consistent than estimates based upon conventional models. This work illustrates the advantage of hierarchical modelling with spDCM, in characterizing the dynamics of effective connectivity. PMID- 29158204 TI - Definition of a SNOMED CT pathology subset and microglossary, based on 1.17 million biological samples from the Catalan Pathology Registry. AB - SNOMED CT terminology is not backed by standard norms of encoding among pathologists. The vast number of concepts ordered in hierarchies and axes, together with the lack of rules of use, complicates the functionality of SNOMED CT for coding, extracting, and analyzing the data. Defining subgroups of SNOMED CT by discipline could increase its functionality. The challenge lies in how to choose the concepts to be included in a subset from a total of over 300,000. Besides, SNOMED CT does not cover daily need, as the clinical reality is dynamic and changing. To adapt SNOMED CT to needs in a flexible way, the possibility exists to create extensions. In Catalonia, most pathology departments have been migrating from SNOMED II to SNOMED CT in a bid to advance the development of the Catalan Pathology Registry, which was created in 2014 as a repository for all the pathological diagnoses. This article explains the methodology used to: (a) identify the clinico-pathological entities and the molecular diagnostic procedures not included in SNOMED CT; (b) define the theoretical subset and microglossary of pathology; (c) describe the SNOMED CT concepts used by pathologists of 1.17 million samples of the Catalan Pathology Registry; and (d) adapt the theoretical subset and the microglossary according to the actual use of SNOMED CT. Of the 328,365 concepts available for coding the diagnoses (326,732 in SNOMED CT and 1576 in Catalan extension), only 2% have been used. Combining two axes of SNOMED CT, body structure and clinical findings, has enabled coding most of the morphologies. PMID- 29158203 TI - P2X7 receptor in spinal tuberculosis: Gene polymorphisms and protein levels in Chinese Han population. AB - Spinal tuberculosis (TB) accounts for 1%-5% of all TB infections. Host genetic variation influences susceptibility to Mycobacterium tuberculosis (MTB). P2X7 receptor (P2X7R) expressed on cells has been identified as a regulatory molecule in cell death/apoptosis, killing of intercellular pathogens, and bone turnover. This study investigated the P2X7 gene polymorphisms and protein levels in spinal TB. P2X7 gene -762C>T and 489C>T polymorphisms were genotyped. The expression of P2X7R in bone or intervertebral disc (ID) tissues was analyzed by Western blot assay. The -762C>T and 489C>T polymorphisms were associated with susceptibility to spinal TB. Having the -762CC genotype and -762C allele increased the risk of developing spinal TB (CC vs. TT: P=0.031, OR [95%CI]=1.865 [1.053-3.304]; C vs. T: P=0.028, OR [95%CI]=1.355 [1.034-1.775]). The presence of the 489T allele was associated with an increased risk of developing spinal TB (TT vs. CC: P=0.004, OR [95%CI]=2.248 [1.283-3.939]; CT vs. CC: P=0.044, OR [95%CI]=1.755 [1.011-3.047]; T vs. C: P=0.004, OR [95%CI]=1.482 [1.134-1.936]; TT+CT vs. CC: P=0.010, OR [95%CI]=1.967 [1.171-3.304]; TT vs. CT+CC: P=0.037, OR [95%CI]=1.489 [1.023 2.167]). The expression of P2X7R in TB-induced bone lesions increased significantly among spinal TB patients (t=0.011). Carrying the P2X7 -762CC genotype and 489T allele is associated with an increased risk of developing spinal TB in a Southern Chinese Han population. PMID- 29158205 TI - A molting-inhibiting hormone-like protein from Pacific white shrimp Litopenaeus vannamei is involved in immune responses. AB - The molting-inhibiting hormones (MIHs) from the crustacean hyperglycemic hormone (CHH) family are a group of neuropeptides that are implicated in regulation of molting and reproduction in crustaceans. In this study, a novel protein containing a typical crustacean neuropeptide domain was identified from Litopenaeus vannamei. The protein showed high homology with other shrimp MIHs and was then designated as a MIH-like protein (MIHL). Among the detected tissues, the heart expressed the highest level of MIHL. The expression of MIHL could be significantly up-regulated after infection with white spot syndrome virus (WSSV), gram-negative bacterium Vibro parahaemolyticus and gram-positive bacterium Staphylococcus aureus, indicating that MIHL could be involved in immune responses. The promoter of MIHL was predicted to contain two NF-kappaB binding sites and could be regulated by the NF-kappaB family protein Relish but not Dorsal, suggesting that MIHL could be an effector gene of the IMD/Relish pathway. Silencing of MIHL in vivo by RNAi strategy significantly down-regulated the expression of many immune effector genes and increased the mortalities of shrimp infected by V. parahaemolyticus and WSSV and their copy numbers in tissues. These confirmed that MIHL could play a role in antiviral and antibacterial immune responses in shrimp. PMID- 29158207 TI - School Counselors' Perspectives of a Web-Based Stepped Care Mental Health Service for Schools: Cross-Sectional Online Survey. AB - BACKGROUND: Mental health problems are common among youth in high school, and school counselors play a key role in the provision of school-based mental health care. However, school counselors occupy a multispecialist position that makes it difficult for them to provide care to all of those who are in need in a timely manner. A Web-based mental health service that offers screening, psychological therapy, and monitoring may help counselors manage time and provide additional oversight to students. However, for such a model to be implemented successfully, school counselors' attitudes toward Web-based resources and services need to be measured. OBJECTIVE: This study aimed to examine the acceptability of a proposed Web-based mental health service, the feasibility of providing this type of service in the school context, and the barriers and facilitators to implementation as perceived by school counselors in New South Wales (NSW), Australia. METHODS: This study utilized an online cross-sectional survey to measure school counselors' perspectives. RESULTS: A total of 145 school counselors completed the survey. Overall, 82.1% (119/145) thought that the proposed service would be helpful to students. One-third reported that they would recommend the proposed model, with the remaining reporting potential concerns. Years of experience was the only background factor associated with a higher level of comfort with the proposed service (P=.048). Personal beliefs, knowledge and awareness, Internet accessibility, privacy, and confidentiality were found to influence, both positively and negatively, the likelihood of school counselors implementing a Web-based school mental health service. CONCLUSIONS: The findings of this study confirmed that greater support and resources are needed to facilitate what is already a challenging and emotionally demanding role for school counselors. Although the school counselors in this study were open to the proposed service model, successful implementation will require that the issues outlined are carefully addressed. PMID- 29158208 TI - Syndromic Surveillance Models Using Web Data: The Case of Influenza in Greece and Italy Using Google Trends. AB - BACKGROUND: An extended discussion and research has been performed in recent years using data collected through search queries submitted via the Internet. It has been shown that the overall activity on the Internet is related to the number of cases of an infectious disease outbreak. OBJECTIVE: The aim of the study was to define a similar correlation between data from Google Trends and data collected by the official authorities of Greece and Europe by examining the development and the spread of seasonal influenza in Greece and Italy. METHODS: We used multiple regressions of the terms submitted in the Google search engine related to influenza for the period from 2011 to 2012 in Greece and Italy (sample data for 104 weeks for each country). We then used the autoregressive integrated moving average statistical model to determine the correlation between the Google search data and the real influenza cases confirmed by the aforementioned authorities. Two methods were used: (1) a flu score was created for the case of Greece and (2) comparison of data from a neighboring country of Greece, which is Italy. RESULTS: The results showed that there is a significant correlation that can help the prediction of the spread and the peak of the seasonal influenza using data from Google searches. The correlation for Greece for 2011 and 2012 was .909 and .831, respectively, and correlation for Italy for 2011 and 2012 was .979 and .933, respectively. The prediction of the peak was quite precise, providing a forecast before it arrives to population. CONCLUSIONS: We can create an Internet surveillance system based on Google searches to track influenza in Greece and Italy. PMID- 29158206 TI - Pulmonary Rehabilitation With Balance Training for Fall Reduction in Chronic Obstructive Pulmonary Disease: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. A growing body of evidence shows that individuals with COPD have important deficits in balance control that may be associated with an increased risk of falls. Pulmonary rehabilitation (PR) is a key therapeutic intervention for individuals with COPD; however, current international guidelines do not include balance training and fall prevention strategies. OBJECTIVE: The primary aim of this trial is to determine the effects of PR with balance training compared to PR with no balance training on the 12 month rate of falls in individuals with COPD. Secondary aims are to determine the effects of the intervention on balance, balance confidence, and functional lower body strength, and to estimate the cost-effectiveness of the program. METHODS: A total of 400 individuals from nine PR centers across Canada, Europe, and Australia will be recruited to participate in a randomized controlled trial. Individuals with COPD who have a self-reported decline in balance, a fall in the last 2 years, or recent near fall will be randomly assigned to an intervention or control group. The intervention group will undergo tailored balance training in addition to PR and will receive a personalized home-based balance program. The control group will receive usual PR and a home program that does not include balance training. All participants will receive monthly phone calls to provide support and collect health care utilization and loss of productivity data. Both groups will receive home visits at 3, 6, and 9 months to ensure proper technique and progression of home exercise programs. The primary outcome will be incidence of falls at 12-month follow-up. Falls will be measured using a standardized definition and recorded using monthly self-report fall diary calendars. Participants will be asked to record falls and time spent performing their home exercise program on the fall diary calendars. Completed calendars will be returned to the research centers in prepaid envelopes each month. Secondary measures collected by a blinded assessor at baseline (pre-PR), post-PR, and 12 month follow-up will include clinical measures of balance, balance confidence, functional lower body strength, and health status. The cost-effectiveness of the intervention group compared with the control group will be evaluated using the incremental cost per number of falls averted and the incremental cost per quality adjusted life years gained. RESULTS: Recruitment for the study began in January 2017 and is anticipated to be complete by December 2019. Results are expected to be available in 2020. CONCLUSIONS: Findings from this study will improve our understanding of the effectiveness and resource uses of tailored balance training for reducing falls in individuals with COPD. If effective, the intervention represents an opportunity to inform international guidelines and health policy for PR in individuals with COPD who are at risk of falling. TRIAL REGISTRATION: ClinicalTrials.gov NCT02995681; https://clinicaltrials.gov/ct2/show/NCT02995681 (Archived by WebCite at http://www.webcitation.org/6ukhxgAsg). PMID- 29158209 TI - Shaping an Effective Health Information Website on Rare Diseases Using a Group Decision-Making Tool: Inclusion of the Perspectives of Patients, Their Family Members, and Physicians. AB - BACKGROUND: Despite diverging definitions on rare conditions, people suffering from rare diseases share similar difficulties. A lack of experience by health professionals, a long wait from first symptoms to diagnosis, scarce medical and scientific knowledge, and unsatisfactory treatment options all trigger the search for health information by patients, family members, and physicians. Examining and systematically integrating stakeholder needs can help design information platforms that effectively support this search. OBJECTIVE: The aim of this study was to innovate on the group decision-making process involving patients, family members, and physicians for the establishment of a national rare disease Internet platform. We determined differences in the relevance of health information especially examining quantifiable preference weights-between these subgroups and elucidated the structure and distribution of these differences in people suffering from rare diseases, their family members, and physicians, thus providing information crucial to their collaboration. METHODS: The included items were identified using a systematic Internet research and verified through a qualitative interview study. The identified major information needs included medical issues, research, social help offers, and current events. These categories further comprised sublevels of diagnosis, therapy, general disease pattern, current studies, study results, registers, psychosocial counseling, self help, and sociolegal advice. The analytic hierarchy process was selected as the group decision-making tool. A sensitivity analysis was used to determine the stability and distribution of results. t tests were utilized to examine the results' significance. RESULTS: A total of 176 questionnaires were collected; we excluded some questionnaires in line with our chosen consistency level of 0.2. Ultimately, 120 patients, 24 family members, and 32 physicians participated in the study (48 men and 128 women, mean age=48 years, age range=17-87 years). Rankings and preference weights were highly heterogeneous. Global ranking positions of patients, family members, and physicians are shown in parentheses, as follows: medical issues (3/4, 4, 4), research (3/4, 2/3, 3), social help offers (1, 2/3, 2), and current events (2, 1, 1); diagnosis (6, 8, 9), therapy (5, 9, 7), general disease pattern (9, 4/5/6, 6), current studies (7, 4/5/6, 3), study results (8, 7, 8), registers (4, 1, 5), psychosocial counseling (1, 2, 4), self-help (3, 3, 2), and sociolegal advice (2, 4/5/6, 1). Differences were verified for patients for 5 information categories (P=.03), physicians for 6 information categories (P=.03), and family members for 4 information categories (P=.04). CONCLUSIONS: Our results offer a clear-cut information structure that can transparently translate group decisions into practice. Furthermore, we found different preference structures for rare disease information among patients, family members, and physicians. Some websites already address differences in comprehension between those subgroups. Similar to pharmaceutical companies, health information providers on rare diseases should also acknowledge different information needs to improve the accessibility of information. PMID- 29158210 TI - Longitudinal Influence of Pregnancy on Nicotine Metabolic Pathways. AB - Nicotine metabolism increases in pregnancy, which may contribute to the difficulties that pregnant women have in quitting smoking. We aimed to determine the extent and timing of changes in nicotine metabolic pathways, including C oxidation, N-glucuronidation, and the pregnancy-induced influences on the activity of enzymes mediating these pathways (CYP2A6 and UGT2B10, respectively). Current smoking pregnant women (n = 47) provided a urine sample during early pregnancy (12.5 weeks), late pregnancy (28.9 weeks), and 6 months postpartum. Concentrations of urinary nicotine and metabolites were analyzed using liquid chromatography tandem mass spectrometry and compared using general linear repeated measures analyses. Nicotine C-oxidation was 1.07-fold (P = 0.12) and 1.11-fold (P < 0.001) higher at early and late pregnancy, respectively, compared with postpartum. Nicotine N-glucuronidation was 1.33-fold (P = 0.06) and 1.67 fold (P = 0.003) higher at early and late pregnancy, respectively, compared with postpartum. The CYP2A6 phenotype ratio (total 3'-hydroxycotinine/cotinine) was significantly higher at early and late pregnancy compared with postpartum (all P < 0.05) and correlated with nicotine C-oxidation (all P < 0.001), suggesting CYP2A6 activity is induced during pregnancy. The UGT2B10 phenotype ratio (nicotine glucuronide/nicotine) was higher at early and late pregnancy compared with postpartum (P = 0.07 and P < 0.05, respectively) and correlated with a second UGT2B10 phenotype ratio (cotinine glucuronide/cotinine) (all P < 0.001), suggesting UGT2B10 activity is induced during pregnancy. In conclusion, pregnancy induced increases in nicotine metabolism start by 12 weeks gestation and continue as pregnancy progresses most likely due to induction of CYP2A6 and UGT2B10, resulting in potential reductions in the effectiveness of nicotine replacement therapies and an increase in metabolism of other CYP2A6 and UGT2B10 substrates during pregnancy. PMID- 29158213 TI - Risk Adjustment Tools in Congenital Heart Disease: A Consumer's View. PMID- 29158212 TI - Cardiac Toxicity of Immune Checkpoint Inhibitors: Cardio-Oncology Meets Immunology. PMID- 29158214 TI - Pulmonary Veno-Occlusive Disease: Welcome to the PAHty (Bostonian for Party). PMID- 29158216 TI - Gene Editing Could Help Pave the Way for Pig-to-Human Transplantations. PMID- 29158215 TI - Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and an increased risk of sudden cardiac death. Although structural abnormalities of the right ventricle predominate, it is well recognized that left ventricular involvement is common, particularly in advanced disease, and that left-dominant forms occur. The pathological characteristic of ARVC is myocyte loss with fibrofatty replacement. Since the first detailed clinical description of the disorder in 1982, significant advances have been made in understanding this disease. Once the diagnosis of ARVC is established, the single most important clinical decision is whether a particular patient's sudden cardiac death risk is sufficient to justify placement of an implantable cardioverter-defibrillator. The importance of this decision reflects the fact that ARVC is a common cause of sudden death in young people and that sudden death may be the first manifestation of the disease. This decision is particularly important because these are often young patients who are expected to live for many years. Although an implantable cardioverter defibrillator can save lives in individuals with this disease, it is also well recognized that implantable cardioverter-defibrillator therapy is associated with both short- and long-term complications. Decisions about the placement of an implantable cardioverter-defibrillator are based on an estimate of a patient's risk of sudden cardiac death, as well as their preferences and values. The primary purpose of this article is to provide a review of the literature that concerns risk stratification in patients with ARVC and to place this literature in the framework of the 3 authors' considerable lifetime experiences in caring for patients with ARVC. The most important parameters to consider when determining arrhythmic risk include electric instability, including the frequency of premature ventricular contractions and sustained ventricular arrhythmia; proband status; extent of structural disease; cardiac syncope; male sex; the presence of multiple mutations or a mutation in TMEM43; and the patient's willingness to restrict exercise and to eliminate participation in competitive or endurance exercise. PMID- 29158218 TI - Letter by Violi et al Regarding Article, "Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure". PMID- 29158217 TI - Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor Related Cardiotoxicity. PMID- 29158219 TI - Response by Sag et al to Letter Regarding Article, "Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure". PMID- 29158220 TI - Letter by Li et al Regarding Article, "Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling". PMID- 29158221 TI - Response by Du et al to Letter Regarding Article, "Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling". PMID- 29158222 TI - Trehalose metabolism genes render rice white tip nematode Aphelenchoides besseyi (Nematoda: Aphelenchoididae) resistant to an anaerobic environment. AB - After experiencing anaerobic environments, Aphelenchoides besseyi will enter a state of suspended animation known as anoxybiosis, during which it may use trehalose as an energy supply to survive. To explore the function of trehalose metabolism, two trehalose-6-phosphate synthase (TPS) genes (Ab-tps1 and Ab-tps2) encoding enzymes catalysing trehalose synthesis, and three trehalase (TRE) genes (Ab-ntre1, Ab-ntre2 and Ab-atre) encoding enzymes catalysing the hydrolysis of trehalose, were identified and investigated. Ab-tps1 and Ab-tps2 were active during certain periods of anoxybiosis for A. besseyi, and Ab-tps2, Ab-ntre1, Ab ntre2 and Ab-atre were active during certain periods of recovery. The results of RNA interference experiments suggested that TRE genes regulated each other and both TPS genes, while a single TPS gene only regulated the other TPS gene. However, two TPS genes together could regulate TRE genes, which indicated a feedback mechanism between these genes. All these genes also positively regulated the survival and resumption of active metabolism of the nematode. Genes functioning at re-aeration have a greater impact on nematode survival, suggesting that these genes could play roles in anoxybiosis regulation, but may function within restricted time frames. Changes in trehalose levels matched changes in TRE activity during the anoxybiosis-re-aeration process, suggesting that trehalose may act as an energy supply source. The observation of up-regulation of TPS genes during anoxybiosis suggested a possible signal role of trehalose. Trehalose metabolism genes could also work together to control trehalose levels at a certain level when the nematode is under anaerobic conditions. PMID- 29158223 TI - TGF-beta induces oncofetal fibronectin that, in turn, modulates TGF-beta superfamily signaling in endothelial cells. AB - Gene splicing profiles are frequently altered in cancer, and the splice variants of fibronectin (FN) that contain the extra-domains A (EDA) or B (EDB), referred to as EDA+FN or EDB+FN, are highly upregulated in tumor vasculature. Transforming growth factor beta (TGF-beta) signaling has been attributed a pivotal role in glioblastoma, with TGF-beta promoting angiogenesis and vessel remodeling. By using immunohistochemistry staining, we observed that the oncofetal FN isoforms EDA+FN and EDB+FN are expressed in glioblastoma vasculature. Ex vivo single-cell gene expression profiling of tumors by using CD31 and alpha-smooth muscle actin (alphaSMA) as markers for endothelial cells, and pericytes and vascular smooth muscle cells (VSMCs), respectively, confirmed the predominant expression of FN, EDA+FN and EDB+FN in the vascular compartment of glioblastoma. Specifically, within the CD31-positive cell population, we identified a positive correlation between the expression of EDA+FN and EDB+FN, and of molecules associated with TGF beta signaling. Further, TGF-beta induced EDA+FN and EDB+FN in human cerebral microvascular endothelial cells and glioblastoma-derived endothelial cells in a SMAD3- and SMAD4-dependent manner. In turn, we found that FN modulated TGF-beta superfamily signaling in endothelial cells via the EDA and EDB, pointing towards a bidirectional influence of oncofetal FN and TGF-beta superfamily signaling. PMID- 29158225 TI - Decompression surgery fails to relieve shoulder impingement in trial. PMID- 29158224 TI - A novel fluorescent reporter detects plastic remodeling of mitochondria-ER contact sites. AB - Mitochondria-ER contact sites (MERCs) enable communication between the ER and mitochondria and serve as platforms for many cellular events, including autophagy. Nonetheless, the molecular organization of MERCs is not known, and there is no bona fide marker of these contact sites in mammalian cells. In this study, we designed a genetically encoded reporter using split GFP protein for labeling MERCs. We subsequently analyzed its distribution and dynamics during the cell cycle and under stressful cellular conditions such as starvation, apoptosis and ER stress. We found that MERCs are dynamic structures that undergo remodeling within minutes. Mitochondrial morphology, but not ER morphology, affected the distribution of MERCs. We also found that carbonyl cyanidem-chlorophenyl hydrazone (CCCP) and oligomycin A treatment enhanced MERC formation. The stimulations that led to apoptosis or autophagy increased the MERC signal. By contrast, increasing cellular lipid droplet load did not change the pattern of MERCs. PMID- 29158226 TI - Adolescent Dating Violence and Nonmedical Prescription Drug Use. PMID- 29158227 TI - Physical and Sexual Dating Violence and Nonmedical Use of Prescription Drugs. AB - BACKGROUND: Little information is available on the associations between nonmedical use of prescription drugs (NMUPD) and dating violence victimization (DVV) among high school students and how associations vary by sex. METHODS: We used data from the 2015 national Youth Risk Behavior Survey, a cross-sectional survey of a nationally representative sample of students in grades 9 to 12. The sample was restricted to students who dated during the 12 months before the survey, resulting in a sample of 5136 boys and 5307 girls. Sex-stratified logistic regression models estimated adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) for associations between lifetime NMUPD and DVV. In our analyses, we examined a 4-level DVV measure: no DVV, physical only, sexual only, and both physical and sexual. RESULTS: Male students had a significantly lower prevalence of DVV compared with female students. By using the 4-level measure of DVV, after adjusting for covariates, sexual DVV only (aPR = 1.61, 95% CI: 1.21-2.12) and both physical and sexual DVV (aPR = 1.65, 95% CI: 1.26-2.17) were positively associated with NUMPD among boys, whereas among girls, physical DVV only (aPR = 1.42, 95% CI: 1.16-1.75) and both physical and sexual DVV (aPR = 1.43, 95% CI: 1.03-1.99) were positively associated with NMUPD. CONCLUSIONS: NMUPD was associated with experiences of DVV among both male and female students. Community- or school-based adolescent violence and substance use prevention efforts would be enhanced by considering the association between DVV and substance use, particularly NMUPD among both male and female adolescents, to address these public health problems. PMID- 29158228 TI - Stigma Experienced by Children and Adolescents With Obesity. AB - The stigmatization of people with obesity is widespread and causes harm. Weight stigma is often propagated and tolerated in society because of beliefs that stigma and shame will motivate people to lose weight. However, rather than motivating positive change, this stigma contributes to behaviors such as binge eating, social isolation, avoidance of health care services, decreased physical activity, and increased weight gain, which worsen obesity and create additional barriers to healthy behavior change. Furthermore, experiences of weight stigma also dramatically impair quality of life, especially for youth. Health care professionals continue to seek effective strategies and resources to address the obesity epidemic; however, they also frequently exhibit weight bias and stigmatizing behaviors. This policy statement seeks to raise awareness regarding the prevalence and negative effects of weight stigma on pediatric patients and their families and provides 6 clinical practice and 4 advocacy recommendations regarding the role of pediatricians in addressing weight stigma. In summary, these recommendations include improving the clinical setting by modeling best practices for nonbiased behaviors and language; using empathetic and empowering counseling techniques, such as motivational interviewing, and addressing weight stigma and bullying in the clinic visit; advocating for inclusion of training and education about weight stigma in medical schools, residency programs, and continuing medical education programs; and empowering families to be advocates to address weight stigma in the home environment and school setting. PMID- 29158229 TI - Obesogenic Behavior and Weight-Based Stigma in Popular Children's Movies, 2012 to 2015. AB - BACKGROUND: Obesity-promoting content and weight-stigmatizing messages are common in child-directed television programming and advertisements, and 1 study found similar trends in G- and PG-rated movies from 2006 to 2010. Our objective was to examine the prevalence of such content in more recent popular children's movies. METHODS: Raters examined 31 top-grossing G- and PG-rated movies released from 2012 to 2015. For each 10-minute segment (N = 302) and for movies as units, raters documented the presence of eating-, activity-, and weight-related content observed on-screen. To assess interrater reliability, 10 movies (32%) were coded by more than 1 rater. RESULTS: The result of Cohen's kappa test of agreement among 3 raters was 0.65 for binary responses (good agreement). All 31 movies included obesity-promoting content; most common were unhealthy foods (87% of movies, 42% of segments), exaggerated portion sizes (71%, 29%), screen use (68%, 38%), and sugar-sweetened beverages (61%, 24%). Weight-based stigma, such as a verbal insult about body size or weight, was observed in 84% of movies and 30% of segments. CONCLUSIONS: Children's movies include much obesogenic and weight stigmatizing content. These messages are not shown in isolated incidences; rather, they often appear on-screen multiple times throughout the entire movie. Future research should explore these trends over time, and their effects. PMID- 29158230 TI - Neoantigen Quality Predicts Immune Response, Survival. AB - A new mathematical model finds that tumor neoantigen quality trumps quantity when it comes to predicting response to immunotherapy and the likelihood of long-term survival among patients with cancer. PMID- 29158233 TI - Reflection is protection in abortion care-an essay by Sandy Goldbeck-Wood. PMID- 29158231 TI - Receptor-mediated Drp1 oligomerization on endoplasmic reticulum. AB - Drp1 is a dynamin guanosine triphosphatase important for mitochondrial and peroxisomal division. Drp1 oligomerization and mitochondrial recruitment are regulated by multiple factors, including interaction with mitochondrial receptors such as Mff, MiD49, MiD51, and Fis. In addition, both endoplasmic reticulum (ER) and actin filaments play positive roles in mitochondrial division, but mechanisms for their roles are poorly defined. Here, we find that a population of Drp1 oligomers is associated with ER in mammalian cells and is distinct from mitochondrial or peroxisomal Drp1 populations. Subpopulations of Mff and Fis1, which are tail-anchored proteins, also localize to ER. Drp1 oligomers assemble on ER, from which they can transfer to mitochondria. Suppression of Mff or inhibition of actin polymerization through the formin INF2 significantly reduces all Drp1 oligomer populations (mitochondrial, peroxisomal, and ER bound) and mitochondrial division, whereas Mff targeting to ER has a stimulatory effect on division. Our results suggest that ER can function as a platform for Drp1 oligomerization, and that ER-associated Drp1 contributes to mitochondrial division. PMID- 29158234 TI - Flu vaccine reduces children's admissions for respiratory complications, study shows. PMID- 29158232 TI - Development and validation of QDiabetes-2018 risk prediction algorithm to estimate future risk of type 2 diabetes: cohort study. AB - Objectives To derive and validate updated QDiabetes-2018 prediction algorithms to estimate the 10 year risk of type 2 diabetes in men and women, taking account of potential new risk factors, and to compare their performance with current approaches.Design Prospective open cohort study.Setting Routinely collected data from 1457 general practices in England contributing to the QResearch database: 1094 were used to develop the scores and a separate set of 363 were used to validate the scores.Participants 11.5 million people aged 25-84 and free of diabetes at baseline: 8.87 million in the derivation cohort and 2.63 million in the validation cohort.Methods Cox proportional hazards models were used in the derivation cohort to derive separate risk equations in men and women for evaluation at 10 years. Risk factors considered included those already in QDiabetes (age, ethnicity, deprivation, body mass index, smoking, family history of diabetes in a first degree relative, cardiovascular disease, treated hypertension, and regular use of corticosteroids) and new risk factors: atypical antipsychotics, statins, schizophrenia or bipolar affective disorder, learning disability, gestational diabetes, and polycystic ovary syndrome. Additional models included fasting blood glucose and glycated haemoglobin (HBA1c). Measures of calibration and discrimination were determined in the validation cohort for men and women separately and for individual subgroups by age group, ethnicity, and baseline disease status.Main outcome measure Incident type 2 diabetes recorded on the general practice record.Results In the derivation cohort, 178 314 incident cases of type 2 diabetes were identified during follow-up arising from 42.72 million person years of observation. In the validation cohort, 62 326 incident cases of type 2 diabetes were identified from 14.32 million person years of observation. All new risk factors considered met our model inclusion criteria. Model A included age, ethnicity, deprivation, body mass index, smoking, family history of diabetes in a first degree relative, cardiovascular disease, treated hypertension, and regular use of corticosteroids, and new risk factors: atypical antipsychotics, statins, schizophrenia or bipolar affective disorder, learning disability, and gestational diabetes and polycystic ovary syndrome in women. Model B included the same variables as model A plus fasting blood glucose. Model C included HBA1c instead of fasting blood glucose. All three models had good calibration and high levels of explained variation and discrimination. In women, model B explained 63.3% of the variation in time to diagnosis of type 2 diabetes (R2), the D statistic was 2.69 and the Harrell's C statistic value was 0.89. The corresponding values for men were 58.4%, 2.42, and 0.87. Model B also had the highest sensitivity compared with current recommended practice in the National Health Service based on bands of either fasting blood glucose or HBA1c. However, only 16% of patients had complete data for blood glucose measurements, smoking, and body mass index.Conclusions Three updated QDiabetes risk models to quantify the absolute risk of type 2 diabetes were developed and validated: model A does not require a blood test and can be used to identify patients for fasting blood glucose (model B) or HBA1c (model C) testing. Model B had the best performance for predicting 10 year risk of type 2 diabetes to identify those who need interventions and more intensive follow-up, improving on current approaches. Additional external validation of models B and C in datasets with more completely collected data on blood glucose would be valuable before the models are used in clinical practice. PMID- 29158235 TI - Coeliac biopsies: numbers are valid, alphabets not. PMID- 29158236 TI - Proton pump inhibitors and gastric cancer: a long expected side effect finally reported also in man. PMID- 29158238 TI - Margaret McCartney: Are physician associates just "doctors on the cheap"? PMID- 29158237 TI - Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations. AB - OBJECTIVE: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. DESIGN: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. RESULTS: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and >=80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (>=70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. CONCLUSION: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations. PMID- 29158239 TI - Comparative Genomics of Myxobacterial Chemosensory Systems. AB - Chemosensory systems (CSS) are among the most complex organizations of proteins functioning cooperatively to regulate bacterial motility and other cellular activities. These systems have been studied extensively in bacteria, and usually, they are present as a single system. Eight CSS, the highest number in bacteria, have been reported in Myxococcus xanthus DK1622 and are involved in coordinating diverse functions. Here, we have explored and compared the CSS in all available genomes of order Myxococcales. Myxococcales members contain 97 to 476 two component system (TCS) proteins, which assist the bacteria in surviving and adapting to varying environmental conditions. The number of myxobacterial CSS ranges between 1 and 12, with the largest number in family Cystobacteraceae and the smallest in Nannocystaceae CheA protein was used as a phylogenetic marker to infer evolutionary relatedness between different CSS, and six novel CSS ("extra CSS" [ECSS]) were thus identified in the myxobacteria besides the previously reported Che1 to Che8 systems from M. xanthus Che1 to Che8 systems are monophyletic to deltaproteobacteria, whereas the newly identified ECSS form separate clades with different bacterial classes. The comparative modular organization was concordant with the phylogeny. Four clusters lacking CheA proteins were also identified via CheB-based phylogenetic analysis and were categorized as accessory CSS (ACSS). In Archangium, an orphan CSS was identified, in which both CheA and CheB were absent. The novel, accessory, and orphan multimodular CSS identified here suggest the emergence of myxobacterial CSS and could assist in further characterizing their roles.IMPORTANCE This study is focused on chemosensory systems (CSS), which help the bacterium in directing its movement toward or away from chemical gradients. CSS are present as a single system in most of the bacteria except in some groups, including Myxococcus xanthus, which has 8 CSS, the highest number reported to date. This is the first comprehensive study carrying out a comparative analysis of the 22 available myxobacterial genomes, which suggests the evolutionary diversity of these systems. We are interested in understanding the distribution of CSS within all known myxobacteria and their probable evolution. PMID- 29158240 TI - Novel Genes and Regulators That Influence Production of Cell Surface Exopolysaccharides in Sinorhizobium meliloti. AB - Sinorhizobium meliloti is a soil-dwelling alphaproteobacterium that engages in a nitrogen-fixing root nodule symbiosis with leguminous plants. Cell surface polysaccharides are important both for adapting to stresses in the soil and for the development of an effective symbiotic interaction. Among the polysaccharides characterized to date, the acidic exopolysaccharides I (EPS-I; succinoglycan) and II (EPS-II; galactoglucan) are particularly important for protection from abiotic stresses, biofilm formation, root colonization, and infection of plant roots. Previous genetic screens discovered mutants with impaired EPS production, allowing the delineation of EPS biosynthetic pathways. Here we report on a genetic screen to isolate mutants with mucoid colonial morphologies that suggest EPS overproduction. Screening with Tn5-110, which allows the recovery of both null and upregulation mutants, yielded 47 mucoid mutants, most of which overproduce EPS-I; among the 30 unique genes and intergenic regions identified, 14 have not been associated with EPS production previously. We identified a new protein-coding gene, emmD, which may be involved in the regulation of EPS-I production as part of the EmmABC three-component regulatory circuit. We also identified a mutant defective in EPS-I production, motility, and symbiosis, where Tn5-110 was not responsible for the mutant phenotypes; these phenotypes result from a missense mutation in rpoA corresponding to the domain of the RNA polymerase alpha subunit known to interact with transcription regulators.IMPORTANCE The alphaproteobacterium Sinorhizobium meliloti converts dinitrogen to ammonium while inhabiting specialized plant organs termed root nodules. The transformation of S. meliloti from a free-living soil bacterium to a nitrogen-fixing plant symbiont is a complex developmental process requiring close interaction between the two partners. As the interface between the bacterium and its environment, the S. meliloti cell surface plays a critical role in adaptation to varied soil environments and in interaction with plant hosts. We isolated and characterized S. meliloti mutants with increased production of exopolysaccharides, key cell surface components. Our diverse set of mutants suggests roles for exopolysaccharide production in growth, metabolism, cell division, envelope homeostasis, biofilm formation, stress response, motility, and symbiosis. PMID- 29158241 TI - Polyphosphate Kinase Antagonizes Virulence Gene Expression in Francisella tularensis. AB - The alarmone ppGpp is a critical regulator of virulence gene expression in Francisella tularensis In this intracellular pathogen, ppGpp is thought to work in concert with the putative DNA-binding protein PigR and the SspA protein family members MglA and SspA to control a common set of genes. MglA and SspA form a complex that interacts with RNA polymerase (RNAP), and PigR functions by interacting with the RNAP-associated MglA-SspA complex. Prior work suggested that ppGpp indirectly exerts its regulatory effects in F. tularensis by promoting the accumulation of polyphosphate in the cell, which in turn was required for formation of the MglA-SspA complex. Here we show that in Escherichia coli, neither polyphosphate nor ppGpp is required for formation of the MglA-SspA complex but that ppGpp promotes the interaction between PigR and the MglA-SspA complex. Moreover, we show that polyphosphate kinase, the enzyme responsible for the synthesis of polyphosphate, antagonizes virulence gene expression in F. tularensis, a finding that is inconsistent with the notion that polyphosphate accumulation promotes virulence gene expression in this organism. Our findings identify polyphosphate kinase as a novel negative regulator of virulence gene expression in F. tularensis and support a model in which ppGpp exerts its positive regulatory effects by promoting the interaction between PigR and the MglA-SspA complex.IMPORTANCE In Francisella tularensis, MglA and SspA form a complex that associates with RNA polymerase to positively control the expression of key virulence genes. The MglA-SspA complex works together with the putative DNA-binding protein PigR and the alarmone ppGpp. PigR functions by interacting directly with the MglA-SspA complex, but how ppGpp exerts its effects was unclear. Prior work indicated that ppGpp acts by promoting the accumulation of polyphosphate, which is required for MglA and SspA to interact. Here we show that formation of the MglA-SspA complex does not require polyphosphate. Furthermore, we find that polyphosphate antagonizes the expression of virulence genes in F. tularensis Thus, ppGpp does not promote virulence gene expression in this organism through an effect on polyphosphate. PMID- 29158243 TI - Point-of-care lactate testing for sepsis at presentation to health care: a systematic review of patient outcomes. AB - BACKGROUND: Lactate is measured in hospital settings to identify patients with sepsis and severe infections, and to guide initiation of early treatment. Point of-care technology could facilitate measurement of lactate by clinicians in the community. However, there has been little research into its utility in these environments. AIM: To investigate the effect of using point-of-care lactate at presentation to health care on mortality and other clinical outcomes, in patients presenting with acute infections. DESIGN AND SETTING: Studies comparing the use of point-of-care lactate to usual care in initial patient assessment at presentation to health care were identified using a maximally sensitive search strategy of six electronic databases. METHOD: Two independent authors screened 3063 records for eligibility, and extracted data from eligible studies. Quality assessment for observational studies was performed using the ROBINS-I tool. RESULTS: Eight studies were eligible for inclusion (3063 patients). Seven studies were recruited from emergency departments, and one from a pre-hospital aeromedical setting. Five studies demonstrated a trend towards reduced mortality with point-of-care lactate; three studies achieved statistical significance. One study demonstrated a significant reduction in length of hospital stay, although another did not find any significant difference. Two studies demonstrated a significant reduction in time to treatment for antibiotics and intravenous fluids. CONCLUSION: This review identifies an evidence gap - there is no high quality evidence to support the use of point-of-care lactate in community settings. There are no randomised controlled trials (RCTs) and no studies in primary care. RCT evidence from community settings is needed to evaluate this potentially beneficial diagnostic technology. PMID- 29158242 TI - Mutations in Sugar-Nucleotide Synthesis Genes Restore Holdfast Polysaccharide Anchoring to Caulobacter crescentus Holdfast Anchor Mutants. AB - Attachment is essential for microorganisms to establish interactions with both biotic and abiotic surfaces. Stable attachment of Caulobacter crescentus to surfaces requires an adhesive polysaccharide holdfast, but the exact composition of the holdfast is unknown. The holdfast is anchored to the cell envelope by outer membrane proteins HfaA, HfaB, and HfaD. Holdfast anchor gene mutations result in holdfast shedding and reduced cell adherence. Translocation of HfaA and HfaD to the cell surface requires HfaB. The Wzx homolog HfsF is predicted to be a bacterial polysaccharide flippase. An hfsF deletion significantly reduced the amount of holdfast produced per cell and slightly reduced adherence. A DeltahfsF DeltahfaD double mutant was completely deficient in adherence. A suppressor screen that restored adhesion in the DeltahfsF DeltahfaD mutant identified mutations in three genes: wbqV, rfbB, and rmlA Both WbqV and RfbB belong to a family of nucleoside-diphosphate epimerases, and RmlA has similarity to nucleotidyltransferases. The loss of wbqV or rfbB in the DeltahfsF DeltahfaD mutant reduced holdfast shedding but did not restore holdfast synthesis to parental levels. Loss of wbqV or rfbB did not restore adherence to a DeltahfsF mutant but did restore adherence and holdfast anchoring to a DeltahfaD mutant, confirming that suppression occurs through restoration of holdfast anchoring. The adherence and holdfast anchoring of a DeltahfaA DeltahfaD mutant could be restored by wbqV or rfbB mutation, but such mutations could not suppress these phenotypes in the DeltahfaB mutant. We hypothesize that HfaB plays an additional role in holdfast anchoring or helps to translocate an unknown factor that is important for holdfast anchoring.IMPORTANCE Biofilm formation results in increased resistance to both environmental stresses and antibiotics. Caulobacter crescentus requires an adhesive holdfast for permanent attachment and biofilm formation, but the exact mechanism of polysaccharide anchoring to the cell and the holdfast composition are unknown. Here we identify novel polysaccharide genes that affect holdfast anchoring to the cell. We identify a new role for the holdfast anchor protein HfaB. This work increases our specific knowledge of the polysaccharide adhesin involved in Caulobacter attachment and the general knowledge regarding production and anchoring of polysaccharide adhesins by bacteria. This work also explores the interactions between different polysaccharide biosynthesis and secretion systems in bacteria. PMID- 29158244 TI - Post-traumatic knee MRI findings and associations with patient, trauma, and clinical characteristics: a subgroup analysis in primary care in the Netherlands. AB - BACKGROUND: The added value of magnetic resonance imaging (MRI) in primary care is still being debated. A high diagnostic yield can be expected in young and active patients with post-traumatic knee complaints. AIM: To determine the frequency of MRI abnormalities in young and active patients (aged 18-45 years) and the associations with patient, trauma, and clinical characteristics. DESIGN AND SETTING: A subgroup analysis of 174 patients, aged 18-45 years with knee trauma of <6 months, allocated to MRI in a randomised controlled trial on the yield of MRI in primary care. Patients were recruited by 150 GPs in the Netherlands from October 2012 to November 2015. METHOD: Associations were expressed using mean differences, odds ratio (OR) and predictive values. RESULTS: Sixty-seven out of 174 patients (39%) had a positive MRI finding, predominantly anterior cruciate ligament (ACL) ruptures (22%) and/or traumatic meniscal tears (15%). Patients with a pre-existing musculoskeletal comorbidity had a two-fold lower prevalence of positive MRI findings (21%), OR 3.0 (95% confidence interval [CI] = 1.3 to 7.0). A 'sports related trauma' showed the highest OR of 4.6 (95% CI = 2.2 to 9.3) for a positive MRI finding. Clinical scores were statistically, significantly worse in patients with positive MRI findings, with mean differences ranging from 10 to 20%. Furthermore, increasing duration of complaints was correlated with decreasing prevalence rates of positive MRI findings. Overall, a popping sound and direct swelling showed the highest positive predictive value of 65% for the presence of positive MRI findings. CONCLUSION: The results from this study enable a preselection of patients to increase the diagnostic yield of MRI in primary care. PMID- 29158245 TI - Variations in presentation, management, and patient outcomes of urinary tract infection: a prospective four-country primary care observational cohort study. AB - BACKGROUND: Regional variations in the presentation of uncomplicated urinary tract infection (UTI) and pathogen sensitivity to antibiotics have been cited as reasons to justify differences in how the infections are managed, which includes the prescription of broad-spectrum antibiotics. AIM: To describe presentation and management of UTI in primary care settings, and explore the association with patient recovery, taking microbiological findings and case mix into account. DESIGN AND SETTING: Prospective observational study of females with symptoms of uncomplicated UTI presenting to primary care networks in England, Wales, the Netherlands, and Spain. METHOD: Clinicians recorded history, symptom severity, management, and requested mid-stream urine culture. Participants recorded, in a diary, symptom severity each day for 14 days. Time to recovery was compared between patient characteristics and between countries using two-level Cox proportional hazards models, with patients nested within practices. RESULTS: In total, 797 females attending primary care networks in England (n = 246, 30.9% of cohort), Wales (n = 213, 26.7%), the Netherlands (n = 133, 16.7%), and Spain (n = 205, 25.7%) were included. In total, 259 (35.8%, 95% confidence interval 32.3 to 39.2) of 726 females for whom there was a result were urine culture positive for UTI. Pathogens and antibiotic sensitivities were similar. Empirical antibiotics were prescribed for 95.1% in England, 92.9% in Wales, 95.1% in Spain, and 59.4% in the Netherlands There were no meaningful differences at a country network level before and after controlling for severity, prior UTIs, and antibiotic prescribing. CONCLUSION: Variation in presentation and management of uncomplicated UTI at a country primary care network level is clinically unwarranted and highlights a lack of consensus concerning optimal symptom control and antibiotic prescribing. PMID- 29158246 TI - Self-taken vaginal swabs versus clinician-taken for detection of candida and bacterial vaginosis: a case-control study in primary care. AB - BACKGROUND: Vaginal discharge and vulvitis are common presenting symptoms in general practice. Few studies have specifically looked at the validity of self taken low vulvovaginal swabs (LVS) for the diagnosis of vulvovaginal candidiasis (VVC) and bacterial vaginosis (BV). AIM: To assess if patient self-taken LVS are a valid alternative to clinician-taken high vaginal swabs (HVS) for the detection of VVC and BV. DESIGN AND SETTING: Case-control study with the patient acting as their own control in an urban sexual health centre in Newcastle upon Tyne, UK. METHOD: Females aged 16-65 years attending with symptomatic vaginal discharge, vulval irritation, genital pain, and an offensive genital smell were recruited into the study. Participants took a self-taken LVS before vaginal examination, during which a clinician took an HVS (reference standard). Main outcome measures were the diagnosis of BV or VVC infection. RESULTS: A total of 104 females were enrolled. Of those, 45 were diagnosed with VVC and 26 with BV. The sensitivities of self-taken LVS for VVC and BV were 95.5% and 88.5% respectively. Cohen's kappa coefficient showed 'strong agreement' for the detection of both VVC and BV. Vulval itching was the most common symptom associated with VVC (69%), whereas 50% of females diagnosed with BV presented with an offensive discharge. Both symptoms had poor positive predictive values (0.63 and 0.50, respectively). CONCLUSION: Self-taken LVS appears to be a valid alternative to clinician-taken HVS for detecting VVC and BV infections. Symptoms were found to be a poor indicator of underlying infection. PMID- 29158247 TI - Predictive values of referrals for transient ischaemic attack from first-contact health care: a systematic review. AB - BACKGROUND: Over 150 000 cases of suspected transient ischaemic attack (TIA) are referred to outpatient clinics in England each year. The majority of referrals are made by GPs. AIM: This study aimed to identify how many patients referred to a TIA clinic actually have TIA (that is, calculate the positive predictive value [PPV] of first-contact healthcare referral) and to record the alternative diagnoses in patients without TIA, in order to determine the optimal service model for patients with suspected TIA. DESIGN AND SETTING: A systematic review of TIA clinic referrals from first-contact health professionals (GPs and emergency department [ED] doctors) was undertaken. METHOD: Four databases were searched using terms for TIA and diagnostic accuracy. Data on the number of patients referred to a TIA clinic who actually had a TIA (PPVs) were extracted. Frequencies of differential diagnoses were recorded, where reported. Study quality was assessed using the QUADAS-2 tool. RESULTS: Nineteen studies were included and reported sufficient information on referrals from GPs and ED doctors to derive PPVs (n = 15 935 referrals). PPVs for TIA ranged from 12.9% to 72.5%. A formal meta-analysis was not conducted due to heterogeneity across studies. Of those not diagnosed with TIA, approximately half of the final diagnoses were of neurological or cardiovascular conditions. CONCLUSION: This study highlights the variation in prevalence of true vascular events in patients referred to TIA clinics. For patients without a cerebrovascular diagnosis, the high prevalence of conditions that also require specialist investigations and management are an additional burden on a care pathway that is primarily designed to prevent recurrent stroke. Service commissioners need to assess whether the existing outpatient provision is optimal for people with pathologies other than cerebrovascular disease. PMID- 29158248 TI - Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation. AB - Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) that is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP's analgesic activity and 10 times BUP's respiratory depression effect. To optimize BUP's dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and nonpregnant mice by administering the same amount of NBUP through retro-orbital injection. We demonstrated that the systemic clearance (CL) of NBUP in pregnant mice increased ~2.5-fold compared with nonpregnant mice. Intrinsic CL of NBUP by glucuronidation in mouse liver microsomes from pregnant mice was ~2 times greater than that from nonpregnant mice. Targeted liquid chromatography tandem-mass spectrometry proteomics quantification revealed that hepatic Ugt1a1 and Ugt2b1 protein levels in the same amount of total liver membrane proteins were significantly increased by ~50% in pregnant mice versus nonpregnant mice. After scaling to the whole liver with consideration of the increase in liver protein content and liver weight, we found that the amounts of Ugt1a1, Ugt1a10, Ugt2b1, and Ugt2b35 protein in the whole liver of pregnant mice were significantly increased ~2-fold compared with nonpregnant mice. These data suggest that the increased systemic CL of NBUP in pregnant mice is likely caused by an induction of hepatic Ugt expression and activity. The data provide a basis for further mechanistic analysis of pregnancy induced changes in the disposition of NBUP and drugs that are predominately and extensively metabolized by Ugts. PMID- 29158249 TI - Objectively Measured Physical Activity and Sedentary Time Are Associated With Cardiometabolic Risk Factors in Adults With Prediabetes: The PREVIEW Study. AB - OBJECTIVE: The aim of the present cross-sectional study was to examine the association among physical activity (PA), sedentary time (ST), and cardiometabolic risk in adults with prediabetes. RESEARCH DESIGN AND METHODS: Participants (n = 2,326; 25-70 years old, 67% female) from eight countries, with a BMI >25 kg ? m-2 and impaired fasting glucose (5.6-6.9 mmol ? L-1) or impaired glucose tolerance (7.8-11.0 mmol ? L-1 at 2 h), participated. Seven-day accelerometry objectively assessed PA levels and ST. RESULTS: Multiple linear regression revealed that moderate-to-vigorous PA (MVPA) was negatively associated with HOMA of insulin resistance (HOMA-IR) (standardized beta = -0.078 [95% CI 0.128, -0.027]), waist circumference (WC) (beta = -0.177 [-0.122, -0.134]), fasting insulin (beta = -0.115 [-0.158, -0.072]), 2-h glucose (beta = -0.069 [ 0.112, -0.025]), triglycerides (beta = -0.091 [-0.138, -0.044]), and CRP (beta = 0.086 [-0.127, -0.045]). ST was positively associated with HOMA-IR (beta = 0.175 [0.114, 0.236]), WC (beta = 0.215 [0.026, 0.131]), fasting insulin (beta = 0.155 [0.092, 0.219]), triglycerides (beta = 0.106 [0.052, 0.16]), CRP (beta = 0.106 [0.39, 0.172]), systolic blood pressure (BP) (beta = 0.078 [0.026, 0.131]), and diastolic BP (beta = 0.106 [0.39, -0.172]). Associations reported between total PA (counts ? min-1), and all risk factors were comparable or stronger than for MVPA: HOMA-IR (beta = -0.151 [-0.194, -0.107]), WC (beta = -0.179 [-0.224, 0.134]), fasting insulin (beta = -0.139 [-0.183, -0.096]), 2-h glucose (beta = 0.088 [-0.131, -0.045]), triglycerides (beta = -0.117 [-0.162, -0.071]), and CRP (beta = -0.104 [-0.146, -0.062]). CONCLUSIONS: In adults with prediabetes, objectively measured PA and ST were associated with cardiometabolic risk markers. Total PA was at least as strongly associated with cardiometabolic risk markers as MVPA, which may imply that the accumulation of total PA over the day is as important as achieving the intensity of MVPA. PMID- 29158250 TI - Increased Liver Fatty Acid Uptake Is Partly Reversed and Liver Fat Content Normalized After Bariatric Surgery. AB - OBJECTIVE: Changes in liver fatty acid metabolism are important in understanding the mechanisms of diabetes remission and metabolic changes after bariatric surgery. RESEARCH DESIGN AND METHODS: Liver fatty acid uptake (LFU), blood flow, and fat content (LFC) were measured in 25 obese subjects before bariatric surgery and 6 months after using positron emission tomography/computed tomography and MRS; 14 lean individuals served as the control subjects. RESULTS: The increased LFU in obese subjects was associated with body adiposity. LFU was reduced postoperatively but was still high compared with the control subjects. LFC was normalized. Liver blood flow (per unit volume) was higher in obese subjects than in the control subjects at baseline and was further increased postoperatively; however, the total organ blood flow was unchanged as the liver volume decreased. CONCLUSIONS: The findings suggest that in a postoperative state, intrahepatic fatty acids are not stored in the liver but are used for oxidation to provide energy. Changes in perfusion may contribute to improved liver metabolism postoperatively. PMID- 29158251 TI - Role of Physical Activity and Exercise in Treating Patients with Overweight and Obesity. AB - BACKGROUND: Overweight and obesity are significant public health concerns that are linked to numerous negative health consequences. Physical activity is an important lifestyle behavior that contributes to body weight regulation. CONTENT: Physical activity is inversely associated with weight gain and the incidence of obesity. Physical activity also contributes to additional weight loss when coupled with dietary modification, and it can result in modest weight loss when not coupled with dietary modification. Moreover, physical activity is associated with improved long-term weight loss and prevention of weight gain following initial weight loss. Current evidence supports that physical activity should be moderate to vigorous in intensity to influence body weight regulation. There is also a growing body of evidence that physical activity can be accumulated throughout the day in shorter periods of time rather than being performed during a structured and longer period, and that physical activity performed in this manner can be important for body weight regulation. SUMMARY: The literature supports the inclusion of physical activity as an important lifestyle behavior for regulating body weight. There are multiple intervention approaches that may be effective for enhancing physical activity engagement within the context of weight control. PMID- 29158253 TI - The Burden of a Heavy Heart. PMID- 29158252 TI - Food Addiction, High-Glycemic-Index Carbohydrates, and Obesity. AB - BACKGROUND: Treatment success in obesity remains low, and recently food addiction has been delineated as an underlying etiologic factor with therapeutic relevance. Specifically, current treatment focuses on reduced food intake and increase of physical activity, whereas interventions for addiction encompass behavioral therapy, abstinence, and environmental interventions such as taxation, restrictions on advertising, and regulation of school menus. CONTENT: Here, we reviewed the pertinent literature on food addiction with a specific focus on the role of high-glycemic-index carbohydrates in triggering addictive symptoms. Three lines of evidence support the concept of food addiction: (a) behavioral responses to certain foods are similar to substances of abuse; (b) food intake regulation and addiction rely on similar neurobiological circuits; (c) individuals suffering from obesity or addiction show similar neurochemical- and brain activation patterns.High-glycemic-index carbohydrates elicit a rapid shift in blood glucose and insulin levels, akin to the pharmacokinetics of addictive substances. Similar to drugs of abuse, glucose and insulin signal to the mesolimbic system to modify dopamine concentration. Sugar elicits addiction-like craving, and self-reported problem foods are rich in high-glycemic-index carbohydrates. These properties make high-glycemic-index carbohydrates plausible triggers for food addiction. SUMMARY: We argue that food addiction is a plausible etiological factor contributing to the heterogeneous condition and phenotype of obesity. In at least a subset of vulnerable individuals, high-glycemic-index carbohydrates trigger addiction-like neurochemical and behavioral responses. PMID- 29158254 TI - Weight History and Subclinical Myocardial Damage. AB - BACKGROUND: Excess weight is associated with subclinical myocardial damage, as reflected by high-sensitivity cardiac troponin T (hs-cTnT) concentrations, which portends high heart failure risk. However, the association between weight history and myocardial damage is unknown. METHODS: We evaluated 9062 Atherosclerosis Risk in Communities (ARIC) visit 4 (1996-1999) participants with a body mass index (BMI) >= 18.5 kg/m2 and no previous cardiovascular disease. We cross-tabulated visit 4 ("current") BMI categories of normal weight, overweight, and obese with those at visit 1 (1987-1989) and with BMI categories calculated from self reported weight at age 25 years. Duration of obesity was calculated in years. A cumulative weight measure of "excess BMI-years" was also calculated [product of mean BMI (centered at 25 kg/m2) over all ARIC time points * follow-up duration]. We used logistic regression to estimate associations of weight history metrics with increased hs-cTnT (>=14 ng/L) at visit 4. RESULTS: Overall, 623 individuals (7%) had increased hs-cTnT at visit 4. Within each current BMI category, previous excess weight was associated with increased hs-cTnT, with the strongest associations for those with past and current obesity [odds ratio (OR), 3.85; 95% CI, 2.51-5.90 for obesity at age 25 years and visit 4]. Each 10-year longer obesity duration was associated with increased hs-cTnT (OR, 1.26; 95% CI, 1.17 1.35). Each 100 higher excess BMI-years was also progressively associated with increased hs-cTnT (OR, 1.21; 95% CI, 1.14-1.27). CONCLUSIONS: Previous obesity and greater cumulative weight from young adulthood increase the likelihood of myocardial damage, indicating long-term toxic effects of adiposity on the myocardium and the need for weight maintenance strategies targeting the entire life span. PMID- 29158255 TI - Nitro-fatty acid inhibition of triple-negative breast cancer cell viability, migration, invasion, and tumor growth. AB - Triple-negative breast cancer (TNBC) comprises ~20% of all breast cancers and is the most aggressive mammary cancer subtype. Devoid of the estrogen and progesterone receptors, along with the receptor tyrosine kinase ERB2 (HER2), that define most mammary cancers, there are no targeted therapies for patients with TNBC. This, combined with a high metastatic rate and a lower 5-year survival rate than for other breast cancer phenotypes, means there is significant unmet need for new therapeutic strategies. Herein, the anti-neoplastic effects of the electrophilic fatty acid nitroalkene derivative, 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO2-OA), were investigated in multiple preclinical models of TNBC. NO2-OA reduced TNBC cell growth and viability in vitro, attenuated TNFalpha induced TNBC cell migration and invasion, and inhibited the tumor growth of MDA MB-231 TNBC cell xenografts in the mammary fat pads of female nude mice. The up regulation of these aggressive tumor cell growth, migration, and invasion phenotypes is mediated in part by the constitutive activation of pro-inflammatory nuclear factor kappaB (NF-kappaB) signaling in TNBC. NO2-OA inhibited TNFalpha induced NF-kappaB transcriptional activity in human TNBC cells and suppressed downstream NF-kappaB target gene expression, including the metastasis-related proteins intercellular adhesion molecule-1 and urokinase-type plasminogen activator. The mechanisms accounting for NF-kappaB signaling inhibition by NO2-OA in TNBC cells were multifaceted, as NO2-OA (a) inhibited the inhibitor of NF kappaB subunit kinase beta phosphorylation and downstream inhibitor of NF-kappaB degradation, (b) alkylated the NF-kappaB RelA protein to prevent DNA binding, and (c) promoted RelA polyubiquitination and proteasomal degradation. Comparisons with non-tumorigenic human breast epithelial MCF-10A and MCF7 cells revealed that NO2-OA more selectively inhibited TNBC function. This was attributed to more facile mechanisms for maintaining redox homeostasis in normal breast epithelium, including a more favorable thiol/disulfide balance, greater extents of multidrug resistance protein-1 (MRP1) expression, and greater MRP1-mediated efflux of NO2 OA-glutathione conjugates. These observations reveal that electrophilic fatty acid nitroalkenes react with more alkylation-sensitive targets in TNBC cells to inhibit growth and viability. PMID- 29158256 TI - Heart failure-induced activation of phospholipase iPLA2gamma generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore. AB - Congestive heart failure typically arises from cardiac myocyte necrosis/apoptosis, associated with the pathological opening of the mitochondrial permeability transition pore (mPTP). mPTP opening decreases the mitochondrial membrane potential leading to the activation of Ca2+-independent phospholipase A2gamma (iPLA2gamma) and the production of downstream toxic metabolites. However, the array of enzymatic mediators and the exact chemical mechanisms responsible for modulating myocardial mPTP opening remain unclear. Herein, we demonstrate that human heart failure activates specific myocardial mitochondrial phospholipases that increase Ca2+-dependent production of toxic hydroxyeicosatetraenoic acids (HETEs) and attenuate the activity of phospholipases that promote the synthesis of protective epoxyeicosatrienoic acids (EETs). Mechanistically, HETEs activated the Ca2+-induced opening of the mPTP in failing human myocardium, and the highly selective pharmacological blockade of either iPLA2gamma or lipoxygenases attenuated mPTP opening in failing hearts. In contrast, pharmacological inhibition of cytochrome P450 epoxygenases opened the myocardial mPTP in human heart mitochondria. Remarkably, the major mitochondrial phospholipase responsible for Ca2+-activated release of arachidonic acid (AA) in mitochondria from non-failing hearts was calcium-dependent phospholipase A2zeta (cPLA2zeta) identified by sequential column chromatographies and activity-based protein profiling. In contrast, iPLA2gamma predominated in failing human myocardium. Stable isotope kinetics revealed that in non-failing human hearts, cPLA2zeta metabolically channels arachidonic acid into EETs, whereas in failing hearts, increased iPLA2gamma activity channels AA into toxic HETEs. These results mechanistically identify the sequelae of pathological remodeling of human mitochondrial phospholipases in failing myocardium. This remodeling metabolically channels AA into toxic HETEs promoting mPTP opening, which induces necrosis/apoptosis leading to further progression of heart failure. PMID- 29158257 TI - Structural dissection of an interaction between transcription initiation and termination factors implicated in promoter-terminator cross-talk. AB - Functional cross-talk between the promoter and terminator of a gene has long been noted. Promoters and terminators are juxtaposed to form gene loops in several organisms, and gene looping is thought to be involved in transcriptional regulation. The general transcription factor IIB (TFIIB) and the C-terminal domain phosphatase Ssu72, essential factors of the transcription preinitiation complex and the mRNA processing and polyadenylation complex, respectively, are important for gene loop formation. TFIIB and Ssu72 interact both genetically and physically, but the molecular basis of this interaction is not known. Here we present a crystal structure of the core domain of TFIIB in two new conformations that differ in the relative distance and orientation of the two cyclin-like domains. The observed extraordinary conformational plasticity may underlie the binding of TFIIB to multiple transcription factors and promoter DNAs that occurs in distinct stages of transcription, including initiation, reinitiation, and gene looping. We mapped the binding interface of the TFIIB-Ssu72 complex using a series of systematic, structure-guided in vitro binding and site-specific photocross-linking assays. Our results indicate that Ssu72 competes with acidic activators for TFIIB binding and that Ssu72 disrupts an intramolecular TFIIB complex known to impede transcription initiation. We also show that the TFIIB binding site on Ssu72 overlaps with the binding site of symplekin, a component of the mRNA processing and polyadenylation complex. We propose a hand-off model in which Ssu72 mediates a conformational transition in TFIIB, accounting for the role of Ssu72 in transcription reinitiation, gene looping, and promoter terminator cross-talk. PMID- 29158258 TI - A photo-cross-linking approach to monitor folding and assembly of newly synthesized proteins in a living cell. AB - Many proteins form multimeric complexes that play crucial roles in various cellular processes. Studying how proteins are correctly folded and assembled into such complexes in a living cell is important for understanding the physiological roles and the qualitative and quantitative regulation of the complex. However, few methods are suitable for analyzing these rapidly occurring processes. Site directed in vivo photo-cross-linking is an elegant technique that enables analysis of protein-protein interactions in living cells with high spatial resolution. However, the conventional site-directed in vivo photo-cross-linking method is unsuitable for analyzing dynamic processes. Here, by combining an improved site-directed in vivo photo-cross-linking technique with a pulse-chase approach, we developed a new method that can analyze the folding and assembly of a newly synthesized protein with high spatiotemporal resolution. We demonstrate that this method, named the pulse-chase and in vivo photo-cross-linking experiment (PiXie), enables the kinetic analysis of the formation of an Escherichia coli periplasmic (soluble) protein complex (PhoA). We also used our new technique to investigate assembly/folding processes of two membrane complexes (SecD-SecF in the inner membrane and LptD-LptE in the outer membrane), which provided new insights into the biogenesis of these complexes. Our PiXie method permits analysis of the dynamic behavior of various proteins and enables examination of protein-protein interactions at the level of individual amino acid residues. We anticipate that our new technique will have valuable utility for studies of protein dynamics in many organisms. PMID- 29158259 TI - Structural analyses of key features in the KANK1.KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex. AB - The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1.KIF21A complex at 2.1 A resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1.KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A. PMID- 29158260 TI - The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice. AB - Cardiac development and function require actin-myosin interactions in the sarcomere, a highly organized contractile structure. Sarcomere assembly mediated by formin homology 2 domain-containing 3 (Fhod3), a member of formins that directs formation of straight actin filaments, is essential for embryonic cardiogenesis. However, the role of Fhod3 in the neonatal and adult stages has remained unknown. Here, we generated floxed Fhod3 mice to bypass the embryonic lethality of an Fhod3 knockout (KO). Perinatal KO of Fhod3 in the heart caused juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development. Tamoxifen-induced conditional KO of Fhod3 in the adult heart neither led to lethal effects nor did it affect sarcomere structure and localization of sarcomere components. However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging. In addition to these age-related changes, systemic stimulation with the alpha1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3-deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart. We conclude that Fhod3 plays a crucial role in both postnatal cardiac development and functional maintenance of the adult heart. PMID- 29158261 TI - The biotin-ligating protein BPL-1 is critical for lipid biosynthesis and polarization of the Caenorhabditis elegans embryo. AB - Biotin is an essential cofactor for multiple metabolic reactions catalyzed by carboxylases. Biotin is covalently linked to apoproteins by holocarboxylase synthetase (HCS). Accordingly, some mutations in HCS cause holocarboxylase deficiency, a rare metabolic disorder that can be life-threatening if left untreated. However, the long-term effects of HCS deficiency are poorly understood. Here, we report our investigations of bpl-1, which encodes the Caenorhabditis elegans ortholog of HCS. We found that mutations in the biotin binding region of bpl-1 are maternal-effect lethal and cause defects in embryonic polarity establishment, meiosis, and the integrity of the eggshell permeability barrier. We confirmed that BPL-1 biotinylates four carboxylase enzymes, and we demonstrate that BPL-1 is required for efficient de novo fatty acid biosynthesis. We also show that the lack of larval growth defects as well as nearly normal fatty acid composition in young adult worms is due to sufficient fatty acid precursors provided by dietary bacteria. However, BPL-1 disruption strongly decreased levels of polyunsaturated fatty acids in embryos produced by bpl-1 mutant hermaphrodites, revealing a critical role for BPL-1 in lipid biosynthesis during embryogenesis and demonstrating that dietary fatty acids and lipid precursors are not adequate to support early embryogenesis in the absence of BPL 1. Our findings highlight that studying BPL-1 function in C. elegans could help dissect the roles of this important metabolic enzyme under different environmental and dietary conditions. PMID- 29158262 TI - The EPAC-Rap1 pathway prevents and reverses cytokine-induced retinal vascular permeability. AB - Increased retinal vascular permeability contributes to macular edema, a leading cause of vision loss in eye pathologies such as diabetic retinopathy, age-related macular degeneration, and central retinal vein occlusions. Pathological changes in vascular permeability are driven by growth factors such as VEGF and pro inflammatory cytokines such as TNF-alpha. Identifying the pro-barrier mechanisms that block vascular permeability and restore the blood-retinal barrier (BRB) may lead to new therapies. The cAMP-dependent guanine nucleotide exchange factor (EPAC) exchange-protein directly activated by cAMP promotes exchange of GTP in the small GTPase Rap1. Rap1 enhances barrier properties in human umbilical endothelial cells by promoting adherens junction assembly. We hypothesized that the EPAC-Rap1 signaling pathway may regulate the tight junction complex of the BRB and may restore barrier properties after cytokine-induced permeability. Here, we show that stimulating EPAC or Rap1 activation can prevent or reverse VEGF- or TNF-alpha-induced permeability in cell culture and in vivo Moreover, EPAC activation inhibited VEGF receptor (VEGFR) signaling through the Ras/MEK/ERK pathway. We also found that Rap1B knockdown or an EPAC antagonist increases endothelial permeability and that VEGF has no additive effect, suggesting a common pathway. Furthermore, GTP-bound Rap1 promoted tight junction assembly, and loss of Rap1B led to loss of junctional border organization. Collectively, our results indicate that the EPAC-Rap1 pathway helps maintain basal barrier properties in the retinal vascular endothelium and activation of the EPAC-Rap1 pathway may therefore represent a potential therapeutic strategy to restore the BRB. PMID- 29158263 TI - High-throughput screening identifies FAU protein as a regulator of mutant cystic fibrosis transmembrane conductance regulator channel. AB - In cystic fibrosis, deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel causes misfolding and premature degradation. One possible approach to reducing the detrimental health effects of cystic fibrosis could be the identification of proteins whose suppression rescues F508del-CFTR function in bronchial epithelial cells. However, searches for these potential targets have not yet been conducted, particularly in a relevant airway background using a functional readout. To identify proteins associated with F508del-CFTR processing, we used a high throughput functional assay to screen an siRNA library targeting 6,650 different cellular proteins. We identified 37 proteins whose silencing significantly rescued F508del-CFTR activity, as indicated by enhanced anion transport through the plasma membrane. These proteins included FAU, UBE2I, UBA52, MLLT6, UBA2, CHD4, PLXNA1, and TRIM24, among others. We focused our attention on FAU, a poorly characterized protein with unknown function. FAU knockdown increased the plasma membrane targeting and function of F508del-CFTR, but not of wild-type CFTR. Investigation into the mechanism of action revealed a preferential physical interaction of FAU with mutant CFTR, leading to its degradation. FAU and other proteins identified in our screening may offer a therapeutically relevant panel of drug targets to correct basic defects in F508del-CFTR processing. PMID- 29158264 TI - Azole resistance in a Candida albicans mutant lacking the ABC transporter CDR6/ROA1 depends on TOR signaling. AB - ATP-binding cassette (ABC) transporters help export various substrates across the cell membrane and significantly contribute to drug resistance. However, a recent study reported an unusual case in which the loss of an ABC transporter in Candida albicans, orf19.4531 (previously named ROA1), increases resistance against antifungal azoles, which was attributed to an altered membrane potential in the mutant strain. To obtain further mechanistic insights into this phenomenon, here we confirmed that the plasma membrane-localized transporter (renamed CDR6/ROA1 for consistency with C. albicans nomenclature) could efflux xenobiotics such as berberine, rhodamine 123, and paraquat. Moreover, a CDR6/ROA1 null mutant, NKKY101, displayed increased susceptibility to these xenobiotics. Interestingly, fluorescence recovery after photobleaching (FRAP) results indicated that NKKY101 mutant cells exhibited increased plasma membrane rigidity, resulting in reduced azole accumulation and contributing to azole resistance. Transcriptional profiling revealed that ribosome biogenesis genes were significantly up-regulated in the NKKY101 mutant. As ribosome biogenesis is a well-known downstream phenomenon of target of rapamycin (TOR1) signaling, we suspected a link between ribosome biogenesis and TOR1 signaling in NKKY101. Therefore, we grew NKKY101 cells on rapamycin and observed TOR1 hyperactivation, which leads to Hsp90 dependent calcineurin stabilization and thereby increased azole resistance. This in vitro finding was supported by in vivo data from a mouse model of systemic infection in which NKKY101 cells led to higher fungal load after fluconazole challenge than wild-type cells. Taken together, our study uncovers a mechanism of azole resistance in C. albicans, involving increased membrane rigidity and TOR signaling. PMID- 29158268 TI - CAR T-Cell Therapies in Glioblastoma: A First Look. AB - Glioblastoma is an aggressive malignancy with a poor prognosis. The current standard of care for newly diagnosed glioblastoma patients includes surgery to the extent, temozolomide combined with radiotherapy, and alternating electric fields therapy. After recurrence, there is no standard therapy and survival is less than 9 months. Recurrent glioblastoma offers a unique opportunity to investigate new treatment approaches in a malignancy known for remarkable genetic heterogeneity, an immunosuppressive microenvironment, and a partially permissive anatomic blood-brain barrier. Results from three first-in-man chimeric antigen receptor (CAR) T-cell trials targeting IL13Ralpha2, Her2/CMV, and EGFRvIII have recently been reported. Each one of these trials addresses important questions, such as T-cell trafficking to CNS, engraftment and persistence, tumor microenvironment remodeling, and monitoring of glioma response to CAR T cells. Objective radiologic responses have been reported. Here, we discuss and summarize the results of these trials and suggest opportunities for the field. Clin Cancer Res; 24(3); 535-40. (c)2017 AACR. PMID- 29158265 TI - Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5. AB - Diabetic foot ulcers (DFUs), a life-threatening complication of diabetes mellitus, have limited treatment options, often resulting in amputations. HMG-CoA reductase inhibitors such as statins are cholesterol-reducing agents that may provide a new therapeutic option. Statins target the cholesterol pathway and block the synthesis of the wound-healing inhibitors farnesyl pyrophosphate (FPP) and cortisol, ligands for the glucocorticoid receptor (GR). Here we demonstrate that the naturally occurring statin mevastatin reverses FPP's effects and promotes healing by using in vitro wound healing assays, human ex vivo and porcine in vivo wound models, and DFU tissue. Moreover, we measured cortisol levels by ELISA and found that mevastatin inhibited cortisol synthesis in keratinocytes and biopsies from patients with DFU. Of note, topical mevastatin stimulated epithelialization and angiogenesis in vivo Mevastatin also reversed FPP-mediated induction of the GR target, the transcription factor c-Myc (a biomarker of non-healing wounds), in porcine and human wound models. Importantly, mevastatin reversed c-Myc overexpression in DFUs. It induced expression of the long noncoding RNA Gas5 that blocks c-Myc expression, which was confirmed by overexpression studies. We conclude that topical mevastatin accelerates wound closure by promoting epithelialization via multiple mechanisms: modulation of GR ligands and induction of the long noncoding RNA Gas5, leading to c-Myc inhibition. In light of these findings, we propose that repurposing statin drugs for topical treatment of DFUs may offer another option for managing this serious condition. PMID- 29158267 TI - Methamphetamine increases HIV infectivity in neural progenitor cells. AB - HIV-1 infection and methamphetamine (METH) abuse frequently occur simultaneously and may have synergistic pathological effects. Although HIV-positive/active METH users have been shown to have higher HIV viral loads and experience more severe neurological complications than non-users, the direct impact of METH on HIV infection and its link to the development of neurocognitive alternations are still poorly understood. In the present study, we hypothesized that METH impacts HIV infection of neural progenitor cells (NPCs) by a mechanism encompassing NFkappaB/SP1-mediated HIV LTR activation. Mouse and human NPCs were infected with EcoHIV (modified HIV virus infectious to mice) and HIV, respectively, in the presence or absence of METH (50 or 100 MUm). Pretreatment with METH, but not simultaneous exposure, significantly increased HIV production in both mouse and human NPCs. To determine the mechanisms underlying these effects, cells were transfected with different variants of HIV LTR promoters and then exposed to METH. METH treatment induced transcriptional activity of the HIV LTR promotor, an effect that required both NFkappaB and SP1 signaling. Pretreatment with METH also decreased neuronal differentiation of HIV-infected NPCs in both in vitro and in vivo settings. Importantly, NPC-derived daughter cells appeared to be latently infected with HIV. This study indicates that METH increases HIV infectivity of NPCs, through the NFkappaB/SP1-dependent activation of the HIV LTR and with the subsequent alterations of NPC neurogenesis. Such events may underlie METH- exacerbated neurocognitive dysfunction in HIV-infected patients. PMID- 29158269 TI - The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy. AB - Purpose: The major obstacle in the management of advanced prostate cancer is the occurrence of resistance to endocrine therapy. Although the androgen receptor (AR) has been linked to therapy failure, the underlying escape mechanisms have not been fully clarified. Being closely related to the AR, the glucocorticoid receptor (GR) has been suggested to play a role in enzalutamide and docetaxel resistance. Given that glucocorticoids are frequently applied to prostate cancer patients, it is essential to unravel the exact role of the GR in prostate cancer progression.Experimental Design: Assessment of GR expression and functional significance in tissues from 177 prostate cancer patients, including 14 lymph node metastases, as well as in several human prostate cancer models, including androgen-dependent, androgen-independent, and long-term antiandrogen-treated cell lines.Results: Although GR expression is reduced in primary prostate cancer tissue, it is restored in metastatic lesions. Relapse patients with high GR experience shortened progression-free survival. GR is significantly increased upon long-term abiraterone or enzalutamide treatment in the majority of preclinical models, thus identifying GR upregulation as an underlying mechanism for cells to bypass AR blockade. Importantly, GR inhibition by RNAi or chemical blockade results in impaired proliferation and 3D-spheroid formation in all tested cell lines.Conclusions: GR upregulation seems to be a common mechanism during antiandrogen treatment and supports the notion that targeting the GR pathway combined with antiandrogen medication may further improve prostate cancer therapy. Clin Cancer Res; 24(4); 927-38. (c)2017 AACR. PMID- 29158266 TI - Stilbenoid prenyltransferases define key steps in the diversification of peanut phytoalexins. AB - Defense responses of peanut (Arachis hypogaea) to biotic and abiotic stresses include the synthesis of prenylated stilbenoids. Members of this compound class show several protective activities in human disease studies, and the list of potential therapeutic targets continues to expand. Despite their medical and biological importance, the biosynthetic pathways of prenylated stilbenoids remain to be elucidated, and the genes encoding stilbenoid-specific prenyltransferases have yet to be identified in any plant species. In this study, we combined targeted transcriptomic and metabolomic analyses to discover prenyltransferase genes in elicitor-treated peanut hairy root cultures. Transcripts encoding five enzymes were identified, and two of these were functionally characterized in a transient expression system consisting of Agrobacterium-infiltrated leaves of Nicotiana benthamiana We observed that one of these prenyltransferases, AhR4DT-1, catalyzes a key reaction in the biosynthesis of prenylated stilbenoids, in which resveratrol is prenylated at its C-4 position to form arachidin-2, whereas another, AhR3'DT-1, added the prenyl group to C-3' of resveratrol. Each of these prenyltransferases was highly specific for stilbenoid substrates, and we confirmed their subcellular location in the plastid by fluorescence microscopy. Structural analysis of the prenylated stilbenoids suggested that these two prenyltransferase activities represent the first committed steps in the biosynthesis of a large number of prenylated stilbenoids and their derivatives in peanut. In summary, we have identified five candidate prenyltransferases in peanut and confirmed that two of them are stilbenoid-specific, advancing our understanding of this specialized enzyme family and shedding critical light onto the biosynthesis of bioactive stilbenoids. PMID- 29158270 TI - In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, against Carbapenem-Nonsusceptible and Multidrug-Resistant Isolates of Gram-Negative Bacilli Collected Worldwide in 2014 to 2016. AB - The in vitro activity of the investigational siderophore cephalosporin, cefiderocol (formerly S-649266), was determined against a 2014-2016, 52-country, worldwide collection of clinical isolates of carbapenem-nonsusceptible Enterobacteriaceae (n = 1,022), multidrug-resistant (MDR) Acinetobacter baumannii (n = 368), MDR Pseudomonas aeruginosa (n = 262), Stenotrophomonas maltophilia (n = 217), and Burkholderia cepacia (n = 4) using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB), prepared according to a recently approved (2017), but not yet published, CLSI protocol, was used to test cefiderocol; all other antimicrobial agents were tested using CAMHB. The concentration of cefiderocol inhibiting 90% (MIC90) of isolates of carbapenem nonsusceptible Enterobacteriaceae was 4 MUg/ml; cefiderocol MICs ranged from 0.004 to 32 MUg/ml, and 97.0% (991/1,022) of isolates demonstrated cefiderocol MICs of <=4 MUg/ml. The MIC90s for cefiderocol for MDR A. baumannii, MDR P. aeruginosa, and S. maltophilia were 8, 1, and 0.25 MUg/ml, respectively, with 89.7% (330/368), 99.2% (260/262), and 100% (217/217) of isolates demonstrating cefiderocol MICs of <=4 MUg/ml. Cefiderocol MICs for B. cepacia ranged from 0.004 to 8 MUg/ml. We conclude that cefiderocol demonstrated potent in vitro activity against a 2014-2016, worldwide collection of clinical isolates of carbapenem nonsusceptible Enterobacteriaceae, MDR A. baumannii, MDR P. aeruginosa, S. maltophilia, and B. cepacia isolates as 96.2% of all (1,801/1,873) isolates tested had cefiderocol MICs of <=4 MUg/ml. PMID- 29158271 TI - In Vitro Activities of Ceftaroline and Comparators against Streptococcus pneumoniae Isolates from U.S. Hospitals: Results from Seven Years of the AWARE Surveillance Program (2010 to 2016). AB - We evaluated trends in Streptococcus pneumoniae antimicrobial susceptibility in United States hospitals in the 2010 to 2016 period. A total of 8,768 clinical isolates from 47 medical centers were tested for susceptibility by broth microdilution methods. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) rates decreased from 25.7% and 12.4%, respectively, in 2010 to 17.7% and 3.6%, respectively, in 2016. The susceptibilities to most comparator antimicrobial agents increased, whereas the susceptibilities to ceftaroline, levofloxacin, linezolid, and tigecycline remained stable. Ceftaroline retained potent activity against S. pneumoniae (>99.9%) with no marked variations. PMID- 29158272 TI - Combination Antibiotic Exposure Selectively Alters the Development of Vancomycin Intermediate Resistance in Staphylococcus aureus. AB - Invasive methicillin-resistant Staphylococcus aureus (MRSA) treated with vancomycin (VAN) is associated with reduced VAN susceptibility and treatment failure. VAN combination therapy is one strategy to improve response, but comprehensive assessments of combinations to prevent resistance are limited. This study identifies optimal combinations to prevent the emergence of VAN intermediate Staphylococcus aureus (VISA). Two standard MRSA and two heterogeneous VISA (hVISA) strains were exposed for 28 days in vitro to VAN alone, VAN with cefazolin (CFZ), fosfomycin, gentamicin, meropenem, rifampin, piperacillin-tazobactam (TZP), or trimethoprim-sulfamethoxazole. In addition to VAN susceptibility testing, cell wall thickness (CWT), carotenoid content, and membrane fluidity were determined for Mu3. VAN plus any beta-lactam limited the VAN MIC increase to 1 to 4 mg/liter throughout the 28-day exposure, with CFZ and TZP being the most effective agents (VAN MIC = 1 to 2 mg/liter). Similar MIC trends occurred with the lipo-/glycopeptide agents daptomycin and telavancin, where beta-lactam combinations with VAN prevented MIC increases to these agents as well. Combinations with non-beta-lactams were ineffective in preventing VAN MIC increases with VAN MICs of 4 to 16 mg/liter emerging during weeks 2 to 4 of treatment. VAN plus beta-lactam decreased CWT significantly, whereas VAN plus other antibiotics significantly increased the CWT. No correlation was observed between carotenoid content or membrane fluidity and antibiotic exposure. Only the combination exposures of VAN plus beta-lactam suppress the development of VISA. Rational selection of VAN plus beta-lactam should be further explored as a long term combination treatment of MRSA infections due to their ability to suppress VAN resistance. PMID- 29158273 TI - Revisiting Activation of and Mechanism of Resistance to Compound IQG-607 in Mycobacterium tuberculosis. AB - IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of Mycobacterium tuberculosis Unexpectedly, we found that INH-resistant clinical isolates were resistant to IQG 607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing, and all sequenced colonies carried alterations in the katG gene. The katG(S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages. Moreover, overexpression of the InhA(S94A) protein caused IQG-607's resistance. PMID- 29158274 TI - Dissemination of Multidrug-Resistant Proteus mirabilis Clones Carrying a Novel Integron-Borne blaIMP-1 in a Tertiary Hospital. AB - This study aimed to characterize multidrug-resistant Proteus mirabilis clones carrying a novel class 1 integron-borne blaIMP-1 In1359 was inserted into a large conjugative plasmid that also carried blaCTX-M-2 The production of carbapenemases in Enterobacteriaceae that are intrinsically resistant to polymyxins and tigecycline is very worrisome, representing a serious challenge to clinicians and infection control teams. PMID- 29158275 TI - A Simplified Derivative of Human Defensin 5 with Potent and Efficient Activity against Multidrug-Resistant Acinetobacter baumannii. AB - The increasing incidence of multidrug-resistant Acinetobacter baumannii (MDRAb) infections worldwide has necessitated the development of novel antibiotics. Human defensin 5 (HD5) is an endogenous peptide with a complex architecture and antibacterial activity against MDRAb In the present study, we attempted to simplify the structure of HD5 by removing disulfide bonds. We found that the Cys2 4 bond was most indispensable for HD5 to inactivate MDRAb, although the antibacterial activity of the derivative was significantly attenuated. We then replaced the noncationic and nonhydrophobic residues with electropositive Arg to increase the antibacterial activity of HD5 derivative that contains a Cys2-4 bond, obtaining another derivative termed HD5d5. The in vitro antibacterial assay and irradiation-wound-infection animal experiment both showed that HD5d5 was much more effective than HD5 at eliminating MDRAb Further investigations revealed that HD5d5 efficiently bound to outer membrane lipid A and penetrated membranes, leading to bacterial collapse and peptide translocation. Compared to HD5, more HD5d5 molecules were located in the cytoplasm of MDRAb, and HD5d5 was more efficient at reducing the activities of superoxide dismutase and catalase, causing the accumulation of reactive oxygen species that are detrimental to microbes. In addition, HD5 failed to suppress the pathogenic outer membrane protein A of Acinetobacter baumannii (AbOmpA) at concentrations up to 50 MUg/ml, whereas HD5d5 strongly bound to AbOmpA and exhibited a dramatic toxin neutralizing ability, thus expanding the repertoire of drugs that is available to treat MDRAb infections. PMID- 29158277 TI - High-Dose Daptomycin Is Effective as an Antibiotic Lock Therapy in a Rabbit Model of Staphylococcus epidermidis Catheter-Related Infection. AB - Long-term catheter-related bloodstream infections (CRBSIs) involving coagulase negative staphylococci are associated with poor patient outcomes, increased hospitalization, and high treatment costs. The use of vancomycin lock therapy has been an important step forward in treatment of these biofilms, although failures occur in 20% of patients. In this study, we report that a high dose of daptomycin lock therapy may offer a therapeutic advantage for these CRBSIs in just 24 h of treatment. PMID- 29158276 TI - Seventy-Five Years of Research on Protein Binding. AB - This review summarizes evidence that the impact of protein binding of the activity of antibiotics is multifaceted and more complex than indicated by the numerical value of protein binding alone. A plethora of studies has proven that protein binding of antibiotics matters, as the free fraction only is antibacterially active and governs pharmacokinetics. Several studies have indicated that independent from protein binding of immunoglobulin G, albumin, alpha1-acid-glycoprotein, and pulmonary surfactant acted synergistically with antibacterial agents, thus suggesting that some intrinsic properties of serum proteins may have mediated serum-antibiotic synergisms. It has been demonstrated that IgG and albumin permeabilized Gram-negative and Gram-positive bacteria and facilitated the uptake of poorly penetrating antibiotics. Alpha-1-acid glycoprotein and pulmonary surfactant also exerted a permeabilizing activity, but proof that this property results in a sensitizing effect is missing. The permeabilizing effect of serum proteins may explain why serum-antibiotic synergisms do not represent a general phenomenon but are limited to specific drug bug associations only. Although evidence has been generated to support the hypothesis that native serum proteins interact synergistically with antibiotics, systematic and well-controlled studies have to be performed to substantiate this phenomenon. The interactions between serum proteins and bacterial surfaces are driven by physicochemical forces. However, preparative techniques, storage conditions, and incubation methods have a significant impact on the intrinsic activities of these serum proteins affecting serum-antibiotic synergisms, so these techniques have to be standardized; otherwise, contradictory data or even artifacts will be generated. PMID- 29158278 TI - Characterization of Plasmodium Atg3-Atg8 Interaction Inhibitors Identifies Novel Alternative Mechanisms of Action in Toxoplasma gondii. AB - Protozoan parasites, including the apicomplexan pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis), infect millions of people worldwide and represent major human disease burdens. Despite their prevalence, therapeutic strategies to treat infections caused by these parasites remain limited and are threatened by the emergence of drug resistance, highlighting the need for the identification of novel drug targets. Recently, homologues of the core autophagy proteins, including Atg8 and Atg3, were identified in many protozoan parasites. Importantly, components of the Atg8 conjugation system that facilitate the lipidation of Atg8 are required for both canonical and parasite-specific functions and are essential for parasite viability. Structural characterization of the P. falciparum Atg3-Atg8 (PfAtg3 Atg8) interaction has led to the identification of compounds that block this interaction. Additionally, many of these compounds inhibit P. falciparum growth in vitro, demonstrating the viability of this pathway as a drug target. Given the essential role of the Atg8 lipidation pathway in Toxoplasma, we sought to determine whether three PfAtg3-Atg8 interaction inhibitors identified in the Medicines for Malaria Venture Malaria Box exerted a similar inhibitory effect in Toxoplasma While all three inhibitors blocked Toxoplasma replication in vitro at submicromolar concentrations, they did not inhibit T. gondii Atg8 (TgAtg8) lipidation. Rather, high concentrations of two of these compounds induced TgAtg8 lipidation and fragmentation of the parasite mitochondrion, similar to the effects seen following starvation and monensin-induced autophagy. Additionally, we report that one of the PfAtg3-Atg8 interaction inhibitors induces Toxoplasma egress and provide evidence that this is mediated by an increase in intracellular calcium in response to drug treatment. PMID- 29158280 TI - Proof-of-Principle Study in a Murine Lung Infection Model of Antipseudomonal Activity of Phage PEV20 in a Dry-Powder Formulation. AB - Bacteriophage therapy is a promising alternative treatment to antibiotics, as it has been documented to be efficacious against multidrug-resistant bacteria with minimal side effects. Several groups have demonstrated the efficacy of phage suspension in vivo to treat lung infections using intranasal delivery; however, phage dry-powder administration to the lungs has not yet been explored. Powder formulations provide potential advantages over a liquid formulation, including easy storage, transport, and administration. The purpose of this study was to assess the bactericidal activities of phage dry-powder formulations against multidrug-resistant (MDR) strain Pseudomonas aeruginosa FADDI-PA001 in a mouse lung infection model. Phage PEV20 spray dried with lactose and leucine produced an inhalable powder at a concentration of 2 * 107 PFU/mg. P. aeruginosa lung infection was established by intratracheal administration of the bacterial suspension to neutropenic mice. At 2 h after the bacterial challenge, the infected mice were treated with 2 mg of the phage powder using a dry-powder insufflator. At 24 h after the phage treatment, the bacterial load in the lungs was decreased by 5.3 log10 (P < 0.0005) in the phage-treated group compared with that in the nontreated group. Additionally, the phage concentration in the lungs was increased by 1 log10 at 24 h in the treated group. These results demonstrate the feasibility of a pulmonary delivery of phage PEV20 dry-powder formulation for the treatment of lung infection caused by antibiotic-resistant P. aeruginosa. PMID- 29158279 TI - KKL-35 Exhibits Potent Antibiotic Activity against Legionella Species Independently of trans-Translation Inhibition. AB - trans-Translation is a ribosome-rescue system that is ubiquitous in bacteria. Small molecules defining a new family of oxadiazole compounds that inhibit trans translation have been found to have broad-spectrum antibiotic activity. We sought to determine the activity of KKL-35, a potent member of the oxadiazole family, against the human pathogen Legionella pneumophila and other related species that can also cause Legionnaires' disease (LD). Consistent with the essential nature of trans-translation in L. pneumophila, KKL-35 inhibited the growth of all tested strains at submicromolar concentrations. KKL-35 was also active against other LD causing Legionella species. KKL-35 remained equally active against L. pneumophila mutants that have evolved resistance to macrolides. KKL-35 inhibited the multiplication of L. pneumophila in human macrophages at several stages of infection. No resistant mutants could be obtained, even during extended and chronic exposure. Surprisingly, KKL-35 was not synergistic with other ribosome targeting antibiotics and did not induce the filamentation phenotype observed in cells defective for trans-translation. Importantly, KKL-35 remained active against L. pneumophila mutants expressing an alternate ribosome-rescue system and lacking transfer-messenger RNA, the essential component of trans-translation. These results indicate that the antibiotic activity of KKL-35 is not related to the specific inhibition of trans-translation and its mode of action remains to be identified. In conclusion, KKL-35 is an effective antibacterial agent against the intracellular pathogen L. pneumophila with no detectable resistance development. However, further studies are needed to better understand its mechanism of action and to assess further the potential of oxadiazoles in treatment. PMID- 29158281 TI - Pharmacokinetics and Safety of Omadacycline in Subjects with Impaired Renal Function. AB - Many antibiotics require dose adjustments in patients with renal impairment and/or in those undergoing hemodialysis. Omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, displays activity against a broad spectrum of bacterial pathogens, including drug resistant strains. Data from completed phase 3 studies of omadacycline for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) showed intravenous (i.v.) to once daily oral omadacycline to be clinically effective and well tolerated. To determine if the dosing of omadacycline should be adjusted in patients with impaired renal function, a phase 1 study examining the pharmacokinetics (PK) and safety of i.v. omadacycline (100 mg) was conducted in subjects with end-stage renal disease (ESRD) on stable hemodialysis (n = 8) and in matched healthy subjects (n = 8). i.v. administration of omadacycline produced similar plasma concentration-time profiles in subjects with ESRD and healthy subjects. Further, in subjects with ESRD, similar values of the PK parameters were observed when omadacycline was administered i.v. after or before dialysis. The mean area under the concentration-time curve from time zero extrapolated to infinity in plasma was 10.30 MUg . h/ml when omadacycline was administered to ESRD subjects after dialysis, 10.20 MUg . h/ml when omadacycline was administered to ESRD subjects before dialysis, and 9.76 MUg . h/ml when omadacycline was administered to healthy subjects. The mean maximum observed concentration of omadacycline in plasma in ESRD subjects was 1.88 MUg/ml when it was administered after dialysis and 2.33 MUg/ml when it was administered before dialysis, and in healthy subjects it was 1.92 MUg/ml. The 100-mg i.v. dose of omadacycline was generally safe and well tolerated in both ESRD and healthy subjects. This study demonstrates that no dose adjustment is necessary for omadacycline in patients with impaired renal function or on days when patients are receiving hemodialysis. PMID- 29158282 TI - Fluconazole-Resistant Candida auris Is Susceptible to Salivary Histatin 5 Killing and to Intrinsic Host Defenses. AB - Candida auris is a newly identified species causing invasive candidemia and candidiasis. It has broad multidrug resistance (MDR) not observed for other pathogenic Candida species. Histatin 5 (Hst 5) is a well-studied salivary cationic peptide with significant antifungal activity against Candida albicans and is an attractive candidate for treating MDR fungi, since antimicrobial peptides induce minimal drug resistance. We investigated the susceptibility of C. auris to Hst 5 and neutrophils, two first-line innate defenses in the human host. The majority of C. auris clinical isolates, including fluconazole-resistant strains, were highly sensitive to Hst 5: 55 to 90% of cells were killed by use of 7.5 MUM Hst 5. Hst 5 was translocated to the cytosol and vacuole in C. auris cells; such translocation is required for the killing of C. albicans by Hst 5. The inverse relationship between fluconazole resistance and Hst 5 killing suggests different cellular targets for Hst 5 than for fluconazole. C. auris showed higher tolerance to oxidative stress than C. albicans, and higher survival within neutrophils, which correlated with resistance to oxidative stress in vitro Thus, resistance to reactive oxygen species (ROS) is likely one, though not the only, important factor in the killing of C. auris by neutrophils. Hst 5 has broad and potent candidacidal activity, enabling it to combat MDR C. auris strains effectively. PMID- 29158284 TI - Comparative In Vitro Activities of Relebactam, Imipenem, the Combination of the Two, and Six Comparator Antimicrobial Agents against 432 Strains of Anaerobic Organisms, Including Imipenem-Resistant Strains. AB - Relebactam is an important beta-lactamase inhibitor for certain aerobic organisms, but alone it has no antianaerobic activity, with most anaerobes having MICs of >=32 MUg/ml with the exception of a very few strains. There was no enhancement or antagonism of imipenem activity with the addition of relebactam, including activity against imipenem-resistant strains. The relebactam-imipenem combination had excellent overall activity against the anaerobes tested. PMID- 29158283 TI - Antimicrobial Octapeptin C4 Analogues Active against Cryptococcus Species. AB - Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen Cryptococcus neoformans is a significant contributor to mortality, and its growing resistance to current antifungals is an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with an MIC of 1.56 MUg/ml. Further testing of octapeptin C4 against 40 clinical isolates of C. neoformans var. grubii or neoformans showed an MIC of 1.56 to 3.13 MUg/ml, while 20 clinical isolates of C. neoformans var. gattii had an MIC of 0.78 to 12.5 MUg/ml. In each case, the MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule of C. neoformans influences the pathogen's sensitivity to octapeptin C4, whereas the degree of melanization had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents. PMID- 29158285 TI - Neoadjuvant palbociclib on ER+ breast cancer (N007): clinical response and EndoPredict's value. AB - The purpose of the study was to test the efficacy of neoadjuvant palbociclib therapy and to evaluate its impact on cell cycle arrest and changes in EndoPredict (EP) scores before and after treatment. Postmenopausal women with histologically proven ER+ve, HER2-ve invasive breast cancer, 2 cm or greater, were enrolled in an open-label, single-arm study. Twenty eligible patients were given letrozole 2.5 mg per day together with palbociclib 125 mg per day for 3 out of 4 weeks in repeated cycles for 16 weeks (4 cycles) before surgery. The primary end points were clinical response rates (cRR) and preoperative endocrine prognostic index (PEPI). The secondary end points were pathologic response and gene expression testing with EP test on collected tumor samples. The following results were obtained. 17 patients showed a clinical response of 50% or more, including 8 complete responses and 9 partial responses. There was significant reduction in area (P < 0.0001) and volume (P = 0.017) of the cancer. Pathologic complete response (pCR) was achieved in one patient; all cancers were downgraded after treatment. Ki67 (P = 0.044) and EP scores (P < 0.0001) were significantly reduced after treatment. Analysis of the relative gene expression levels showed that all proliferative genes, IL6ST and RBBP8 were decreased after palbociclib treatment. 6 patients with intermediate and three patients with high PEPI risk scores were found to have low EPclin scores. All patients with high PEPI relapse risk score had high EPclin score. In conclusion, effective clinical response was demonstrated by neoadjuvant letrozole in combination with palbociclib. Compared with PEPI, EPclin might be a better parameter to estimate prognosis after neoadjuvant therapy. PMID- 29158286 TI - Data Integrity: History, Issues, and Remediation of Issues. AB - Data integrity is critical to regulatory compliance, and the fundamental reason for 21 CFR Part 11 published by the U.S. Food and Drug Administration (FDA). FDA published the first guideline in 1963, and since then FDA and European Union (EU) have published numerous guidelines on various topics related to data integrity for the pharmaceutical industry. Regulators wanted to make certain that industry capture accurate data during the drug development lifecycle and through commercialization-consider the number of warning letters issued lately by inspectors across the globe on data integrity. This article discusses the history of regulations put forward by various regulatory bodies, the term ALCOA Plus adopted by regulators, the impact of not following regulations, and some prevention methods by using some simple checklists, self-audit, and self inspection techniques. FDA uses the acronym ALCOA to define its expectations of electronic data. ALCOA stands for Attributable, Legible, Contemporaneous, Original, and Accurate. ALCOA was further expanded to ALCOA Plus, and the Plus means Enduring, Available and Accessible, Complete, Consistent, Credible, and Corroborated. If we do not follow the regulations as written, then there is a huge risk. This article covers some of the risk aspects. To prevent data integrity, various solutions can be implemented such as a simple checklist for various systems, self-audit, and self-inspections. To do that we have to develop strategy, people, implement better business processes, and gain a better understanding of data lifecycle as well as technology.LAY ABSTRACT: If one does a Google search on "What is data integrity?" the first page will give the definition of data integrity, how to learn more about data integrity, the history of data integrity, risk management of data integrity, and at the top about various U.S. Food and Drug Administration (FDA) and European Union (EU) regulations. Data integrity is nothing but about accuracy of data. When someone searches Google for some words, we expect accurate results that we can rely on. The same principle applies during the drug development lifecycle. Pharmaceutical industry ensures that data entered for various steps of drug development is accurate so that we can have confidence that the drugs produced by the industry are within some parameters. The regulations put forward by FDA and EU are not new. The first regulation was published in 1963, and after that regulators published multiple guidelines. Inspectors from both regulatory bodies inspected the industry, and they found that the data was not accurate. If pharmaceutical industry produces drugs within the stated parameters, then it is approved and available in the market for patients. If inspectors find that the data is modified, then the drug is not approved. That means revenue loss for industry and drugs not available for patients. In this article, I explain some of the remediation plans for the industry that can be applied during the drug development lifecycle pathway. PMID- 29158287 TI - Development of a Premium Quality Plasma-derived IVIg (IQYMUNE(r)) Utilizing the Principles of Quality by Design-A Worked-through Case Study. AB - Polyvalent human normal immunoglobulins for intravenous use (IVIg), indicated for rare and often severe diseases, are complex plasma-derived protein preparations. A quality by design approach has been used to develop the Laboratoire Francais du Fractionnement et des Biotechnologies new-generation IVIg, targeting a high level of purity to generate an enhanced safety profile while maintaining a high level of efficacy. A modular approach of quality by design was implemented consisting of five consecutive steps to cover all the stages from the product design to the final product control strategy.A well-defined target product profile was translated into 27 product quality attributes that formed the basis of the process design. In parallel, a product risk analysis was conducted and identified 19 critical quality attributes among the product quality attributes. Process risk analysis was carried out to establish the links between process parameters and critical quality attributes. Twelve critical steps were identified, and for each of these steps a risk mitigation plan was established.Among the different process risk mitigation exercises, five process robustness studies were conducted at qualified small scale with a design of experiment approach. For each process step, critical process parameters were identified and, for each critical process parameter, proven acceptable ranges were established. The quality risk management and risk mitigation outputs, including verification of proven acceptable ranges, were used to design the process verification exercise at industrial scale.Finally, the control strategy was established using a mix, or hybrid, of the traditional approach plus elements of the quality by design enhanced approach, as illustrated, to more robustly assign material and process controls and in order to securely meet product specifications.The advantages of this quality by design approach were improved process knowledge for industrial design and process validation and a clear justification of the process and product specifications as a basis for control strategy and future comparability exercises. PMID- 29158288 TI - Time-Dependent Testing Evaluation and Modeling for Rubber Stopper Seal Performance. AB - Sufficient rubber stopper sealing performance throughout the entire sealed product life cycle is essential for maintaining container closure integrity in the parenteral packaging industry. However, prior publications have lacked systematic considerations for the time-dependent influence on sealing performance that results from the viscoelastic characteristics of the rubber stoppers. In this paper, we report results of an effort to study these effects by applying both compression stress relaxation testing and residual seal force testing for time-dependent experimental data collection. These experiments were followed by modeling fit calculations based on the Maxwell-Wiechert theory modified with the Kohlrausch-Williams-Watts stretched exponential function, resulting in a nonlinear, time-dependent sealing force model. By employing both testing evaluations and modeling calculations, an in-depth understanding of the time dependent effects on rubber stopper sealing force was developed. Both testing and modeling data show good consistency, demonstrating that the sealing force decays exponentially over time and eventually levels off because of the viscoelastic nature of the rubber stoppers. The nonlinearity of stress relaxation derives from the viscoelastic characteristics of the rubber stoppers coupled with the large stopper compression deformation into restrained geometry conditions. The modeling fit with capability to handle actual testing data can be employed as a tool to calculate the compression stress relaxation and residual seal force throughout the entire sealed product life cycle. In addition to being time-dependent, stress relaxation is also experimentally shown to be temperature-dependent. The present work provides a new, integrated methodology framework and some fresh insights to the parenteral packaging industry for practically and proactively considering, designing, setting up, controlling, and managing stopper sealing performance throughout the entire sealed product life cycle.LAY ABSTRACT: Historical publications in the parenteral packaging industry have lacked systematic considerations for the time-dependent influence on the sealing performance that results from effects of viscoelastic characteristic of the rubber stoppers. This study applied compression stress relaxation testing and residual seal force testing for time-dependent experimental data collection. These experiments were followed by modeling fit calculations based on the Maxwell-Wiechert theory modified with the Kohlrausch-Williams-Watts stretched exponential function, resulting in a nonlinear, time-dependent sealing force model. Experimental and modeling data show good consistency, demonstrating that sealing force decays exponentially over time and eventually levels off. The nonlinearity of stress relaxation derives from the viscoelastic characteristics of the rubber stoppers coupled with the large stopper compression deformation into restrained geometry conditions. In addition to being time-dependent stress relaxation, it is also experimentally shown to be temperature-dependent. The present work provides a new, integrated methodology framework and some fresh insights to the industry for practically and proactively considering, designing, setting up, controlling, and managing of the stopper sealing performance throughout the entire sealed product life cycle. PMID- 29158289 TI - Next-generation panel sequencing identifies NF1 germline mutations in three patients with pheochromocytoma but no clinical diagnosis of neurofibromatosis type 1. AB - OBJECTIVE: Our objective was to improve molecular diagnostics in patients with hereditary pheochromocytoma and paraganglioma (PPGL) by using next-generation sequencing (NGS) multi-gene panel analysis. Derived from this study, we here present three cases that were diagnosed with NF1 germline mutations but did not have a prior clinical diagnosis of neurofibromatosis type 1 (NF1). DESIGN: We performed genetic analysis of known tumor predisposition genes, including NF1, using a multi-gene NGS enrichment-based panel applied to a total of 1029 PPGL patients. We did not exclude genes known to cause clinically defined syndromes such as NF1 based on missing phenotypic expression as is commonly practiced. METHODS: Genetic analysis was performed using NGS (TruSight Cancer Panel/customized panel by Illumina) for analyzing patients' blood and tumor samples. Validation was carried out by Sanger sequencing. RESULTS: Within our cohort, three patients, who were identified to carry pathogenic NF1 germline mutations, attracted attention, since none of the patients had a clinical suspicion of NF1 and one of them was initially suspected to have MEN2A syndrome due to co-occurrence of a medullary thyroid carcinoma. In these cases, one splice site, one stop and one frameshift mutation in NF1 were identified. CONCLUSIONS: Since phenotypical presentation of NF1 is highly variable, we suggest analysis of the NF1 gene also in PPGL patients who do not meet diagnostic NF1 criteria. Co occurrence of medullary thyroid carcinoma and PPGL was found to be a clinical decoy in NF1 diagnostics. These observations underline the value of multi-gene panel NGS for PPGL patients. PMID- 29158290 TI - A Comparative Proteome Profile of Female Mouse Gonads Suggests a Tight Link between the Electron Transport Chain and Meiosis Initiation. AB - Generation of haploid gametes by meiosis is a unique property of germ cells and is critical for sexual reproduction. Leaving mitosis and entering meiosis is a key step in germ cell development. Several inducers or intrinsic genes are known to be important for meiotic initiation, but the regulation of meiotic initiation, especially at the protein level, is still not well understood. We constructed a comparative proteome profile of female mouse fetal gonads at specific time points (11.5, 12.5, and 13.5 days post coitum), spanning a critical window for initiation of meiosis in female germ cells. We identified 3666 proteins, of which 473 were differentially expressed. Further bioinformatics analysis showed that these differentially expressed proteins were enriched in the mitochondria, especially in the electron transport chain and, notably, 9 proteins in electron transport chain Complex I were differentially expressed. We disrupted the mitochondrial electron transport chain function by adding the complex I inhibitor, rotenone to 11.5 days post coitum female gonads cultured in vitro. This treatment resulted in a decreased proportion of meiotic germ cells, as assessed by staining for histone gammaH2AX. Rotenone treatment also caused decreased ATP levels, increased reactive oxygen species levels and failure of the germ cells to undergo premeiotic DNA replication. These effects were partially rescued by adding Coenzyme Q10. Taken together, our results suggested that a functional electron transport chain is important for meiosis initiation. Our characterization of the quantitative proteome of female gonads provides an inventory of proteins, useful for understanding the mechanisms of meiosis initiation and female fertility. PMID- 29158291 TI - RAD51C/XRCC3 Facilitates Mitochondrial DNA Replication and Maintains Integrity of the Mitochondrial Genome. AB - Mechanisms underlying mitochondrial genome maintenance have recently gained wide attention, as mutations in mitochondrial DNA (mtDNA) lead to inherited muscular and neurological diseases, which are linked to aging and cancer. It was previously reported that human RAD51, RAD51C, and XRCC3 localize to mitochondria upon oxidative stress and are required for the maintenance of mtDNA stability. Since RAD51 and RAD51 paralogs are spontaneously imported into mitochondria, their precise role in mtDNA maintenance under unperturbed conditions remains elusive. Here, we show that RAD51C/XRCC3 is an additional component of the mitochondrial nucleoid having nucleus-independent roles in mtDNA maintenance. RAD51C/XRCC3 localizes to the mtDNA regulatory regions in the D-loop along with the mitochondrial polymerase POLG, and this recruitment is dependent upon Twinkle helicase. Moreover, upon replication stress, RAD51C and XRCC3 are further enriched at the mtDNA mutation hot spot region D310. Notably, the absence of RAD51C/XRCC3 affects the stability of POLG on mtDNA. As a consequence, RAD51C/XRCC3-deficient cells exhibit reduced mtDNA synthesis and increased lesions in the mitochondrial genome, leading to overall unhealthy mitochondria. Together, these findings lead to the proposal of a mechanism for a direct role of RAD51C/XRCC3 in maintaining mtDNA integrity under replication stress conditions. PMID- 29158292 TI - Sphingomyelin metabolism is a regulator of KRAS function. AB - KRAS must localize to the plasma membrane (PM) for biological activity. We show here that multiple acid sphingomyelinase (ASM) inhibitors, including tricyclic antidepressants, mislocalized phosphatidylserine (PtdSer) and KRASG12V from the PM; resulting in abrogation of KRASG12V signaling and potent, selective growth inhibition of mutant KRAS transformed cancer cells. Concordantly, in nude mice, the ASM inhibitor fendiline decreased the rate of growth of oncogenic KRAS expressing MiaPaCa-2 tumors, but had no effect on the growth of the wild-type KRAS-expressing BxPC-3 tumors. ASM inhibitors also inhibited activated LET-60 (a KRAS ortholog) signaling in C.elegans as evidenced by suppression of the induced multi-vulva phenotype. Using RNAis against C.elegans genes encoding other enzymes in the sphingomyelin (SM) biosynthetic pathway, we identified 14 enzymes whose knockdown strongly or moderately suppressed the LET-60 multi-vulva phenotype. In mammalian cells, pharmacological agents that target these enzymes all depleted PtdSer from the PM and caused KRASG12V mislocalization. These effects correlated with changes in SM levels or subcellular distribution. Selected compounds, including sphingosine kinase inhibitors, potently inhibited the proliferation of oncogenic KRAS-expressing pancreatic cancer cells. In conclusion, these results show that normal SM metabolism is critical for KRAS function, which may present therapeutic options for the treatment of KRAS-driven cancers. PMID- 29158293 TI - GFZF, a glutathione S-transferase protein implicated in cell cycle regulation and hybrid inviability, is a transcriptional co-activator. AB - The core promoter of protein-encoding genes plays a central role in regulating transcription. M1BP is a transcriptional activator that associates with a core promoter element known as Motif 1 that resides at thousand of genes in Drosophila. To gain insight into how M1BP functions, we identified an interacting protein called GFZF. GFZF had been previously identified in genetic screens for factors involved in maintenance of hybrid inviability, the G2-M DNA damage checkpoint, and RAS/MAPK signaling but its contribution to these processes was unknown. Here, we show that GFZF resides in the nucleus and functions as a transcriptional co-activator. In addition, we show that GFZF is a glutathione S transferase(GST). Thus, GFZF is the first transcriptional co-activator with intrinsic GST activity, and its identification as a transcriptional co-activator provides an explanation for its role in numerous biological processes. PMID- 29158295 TI - Time to review the provision of addiction treatment for codeine dependence. PMID- 29158294 TI - The Actin-Binding Protein PPP1r18 Regulates Maturation, Actin Organization, and Bone Resorption Activity of Osteoclasts. AB - Osteoclasts resorb bone by attaching on the bone matrix and forming a sealing zone. In Src-deficient mice, osteoclasts cannot form the actin ring, a characteristic actin structure that seals the resorbed area, and resorb hardly any bone as a result. However, the molecular mechanism underlying the role of Src in the regulation and organization of the actin ring is still unclear. We identified an actin-regulatory protein, protein phosphatase 1 regulatory subunit 18 (PPP1r18), as an Src-binding protein in an Src-, Yes-, and Fyn-deficient fibroblast (SYF) cell line overexpressing a constitutively active form of Src. PPP1r18 was localized in the nucleus and actin ring. PPP1r18 overexpression in osteoclasts inhibited terminal differentiation, actin ring formation, and bone resorbing activity. A mutation of the protein phosphatase 1 (PP1)-binding domain of PPP1r18 rescued these phenotypes. In contrast, PPP1r18 knockdown promoted terminal differentiation and actin ring formation. In summary, we showed that PPP1r18 likely plays a role in podosome organization and bone resorption. PMID- 29158297 TI - Editors' Note. PMID- 29158296 TI - Quinidine-associated skin discoloration in KCNT1-associated pediatric epilepsy. PMID- 29158298 TI - Letter re: Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. PMID- 29158299 TI - Author response: Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. PMID- 29158300 TI - Letter re: Dementia risk in renal dysfunction: A systematic review and meta analysis of prospective studies. PMID- 29158301 TI - Author response: Dementia risk in renal dysfunction: A systematic review and meta analysis of prospective studies. PMID- 29158302 TI - Clinical Reasoning: An 82-year-old man with worsening gait. PMID- 29158303 TI - Teaching NeuroImages: Myeloperoxidase-anti-neutrophil cytoplasmic antibody positive hypertrophic pachymeningitis. PMID- 29158304 TI - ASHP Research and Education Foundation Pharmacy Forecast: A leader's resource to plan for the future. PMID- 29158306 TI - Jack E. Brown, researcher and AJHP contributing editor, dies at 48. PMID- 29158305 TI - ASHP Foundation Pharmacy Forecast 2018: Strategic Planning Advice for Pharmacy Departments in Hospitals and Health Systems. PMID- 29158307 TI - Extracellular vesicles in the tumour microenvironment. PMID- 29158308 TI - Glioblastoma multiforme-derived extracellular vesicles drive normal astrocytes towards a tumour-enhancing phenotype. AB - Glioblastoma multiforme (GBM) is a devastating tumour with abysmal prognoses. We desperately need novel approaches to understand GBM biology and therapeutic vulnerabilities. Extracellular vesicles (EVs) are membrane-enclosed nanospheres released locally and systemically by all cells, including tumours, with tremendous potential for intercellular communication. Tumour EVs manipulate their local environments as well as distal targets; EVs may be a mechanism for tumourigenesis in the recurrent GBM setting. We hypothesized that GBM EVs drive molecular changes in normal human astrocytes (NHAs), yielding phenotypically tumour-promoting, or even tumourigenic, entities. We incubated NHAs with GBM EVs and examined the astrocytes for changes in cell migration, cytokine release and tumour cell growth promotion via the conditioned media. We measured alterations in intracellular signalling and transformation capacity (astrocyte growth in soft agar). GBM EV-treated NHAs displayed increased migratory capacity, along with enhanced cytokine production which promoted tumour cell growth. GBM EV-treated NHAs developed tumour-like signalling patterns and exhibited colony formation in soft agar, reminiscent of tumour cells themselves. GBM EVs modify the local environment to benefit the tumour itself, co-opting neighbouring astrocytes to promote tumour growth, and perhaps even driving astrocytes to a tumourigenic phenotype. Such biological activities could have profound impacts in the recurrent GBM setting.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158309 TI - Why the need and how to approach the functional diversity of extracellular vesicles. AB - In the past decade, cell-to-cell communication mediated by exosomes has attracted growing attention from biomedical scientists and physicians, leading to several recent publications in top-tier journals. Exosomes are generally defined as secreted membrane vesicles, or extracellular vesicles (EVs), corresponding to the intraluminal vesicles of late endosomal compartments, which are secreted upon fusion of multi-vesicular endosomes with the cell's plasma membrane. Cells, however, were shown to release other types of EVs, for instance, by direct budding off their plasma membrane. Some of these EVs share with exosomes major biophysical and biochemical characteristics, such as size, density and membrane orientation, which impose difficulties in their efficient separation. Despite frequent claims in the literature, whether exosomes really display more important patho/physiological functions, or are endowed with higher potential as diagnostic or therapeutic tools than other EVs, is not yet convincingly demonstrated. In this opinion article, we describe reasons for this lack of precision knowledge in the current stage of the EV field, we review recently described approaches to overcome these caveats, and we propose ways to improve our knowledge on the respective functions of distinct EVs, which will be crucial for future development of well-designed EV-based clinical applications.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158310 TI - Functional role of extracellular vesicles and lipoproteins in the tumour microenvironment. AB - Cancer can be regarded as an invasive organ that exhibits unique plasticity provided by coordinated, cancer cell-stromal cell communication in the tumour microenvironment. Typical stress factors in the tumour niche, such as hypoxia and acidosis, are major drivers and modulators of these events. Recent findings reveal an important role of extracellular vesicles and lipoproteins in cancer cell adaption to exogenous stress. Adaptive mechanisms include stimulation of angiogenesis and increased metastasis. Here, we will discuss the similarities and distinct features of these endogenous nanoparticles and their roles as signalosomes and nutrient sources in cancer. We will focus on the accumulating evidence for a central role of cell-surface heparan sulphate proteoglycans in the uptake of extracellular vesicles and lipoproteins.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158311 TI - Cancer-derived extracellular vesicles: friend and foe of tumour immunosurveillance. AB - Extracellular vesicles (EVs) are important players of intercellular signalling mechanisms, including communication with and among immune cells. EVs can affect the surrounding tissue as well as peripheral cells. Recently, EVs have been identified to be involved in the aetiology of several diseases, including cancer. Tumour cell-released EVs or exosomes have been shown to promote a tumour supporting environment in non-malignant tissue and, thus, benefit metastasis. The underlying mechanisms are numerous: loss of antigen expression, direct suppression of immune effector cells, exchange of nucleic acids, alteration of the recipient cells' transcription and direct suppression of immune cells. Consequently, tumour cells can subvert the host's immune detection as well as suppress the immune system. On the contrary, recent studies reported the existence of EVs able to activate immune cells, thus promoting the tumour directed immune response. In this article, the immunosuppressive capabilities of EVs, on the one hand, and their potential use in immunoactivation and therapeutic potential, on the other hand, are discussed.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158312 TI - Organotypic three-dimensional assays based on human leiomyoma-derived matrices. AB - Alongside cancer cells, tumours exhibit a complex stroma containing a repertoire of cells, matrix molecules and soluble factors that actively crosstalk between each other. Recognition of this multifaceted concept of the tumour microenvironment (TME) calls for authentic TME mimetics to study cancer in vitro Traditionally, tumourigenesis has been investigated in non-human, three dimensional rat type I collagen containing organotypic discs or by means of mouse sarcoma-derived gel, such as Matrigel(r) However, the molecular compositions of these simplified assays do not properly simulate human TME. Here, we review the main properties and benefits of using human leiomyoma discs and their matrix Myogel for in vitro assays. Myoma discs are practical for investigating the invasion of cancer cells, as are cocultures of cancer and stromal cells in a stiff, hypoxic TME mimetic. Myoma discs contain soluble factors and matrix molecules commonly present in neoplastic stroma. In Transwell, IncuCyte, spheroid and sandwich assays, cancer cells move faster and form larger colonies in Myogel than in Matrigel(r) Additionally, Myogel can replace Matrigel(r) in hanging-drop and tube-formation assays. Myogel also suits three-dimensional drug testing and extracellular vesicle interactions. To conclude, we describe the application of our myoma-derived matrices in 3D in vitro cancer assays.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158313 TI - Extracellular vesicle-mediated cell-cell communication in haematological neoplasms. AB - Crosstalk between bone marrow tumour cells and surrounding cells, including bone marrow mesenchymal stromal cells (BM-MSCs), endothelial cells and immune cells, is important for tumour growth in haematological neoplasms. In addition to conventional signalling pathways, extracellular vesicles (EVs), which are endosome-derived vesicles containing proteins, mRNAs, lipids and miRNAs, can facilitate modulation of the bone marrow microenvironment without directly contacting non-tumourous cells. In this review, we discuss the current understanding of EV-mediated cell-cell communication in haematological neoplasms, particularly leukaemia and multiple myeloma. We highlight the actions of tumour and BM-MSC EVs in multiple myeloma. The origin of EVs, their tropism and mechanism of EV transfer are emerging issues that need to be addressed in EV mediated cell-cell communication in haematological neoplasms.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158315 TI - MicroRNAs and miRceptors: a new mechanism of action for intercellular communication. AB - MicroRNAs (miRs) are small non-coding RNAs (ncRNAs) that control the expression of target genes by modulating (usually inhibiting) their translation into proteins. This 'traditional' mechanism of action of miRs has been recently challenged by new discoveries pointing towards a role of miRs as 'hormones', capable of binding to proteic receptors (miRceptors) and triggering their downstream signalling pathways. These findings harbour particular significance within the tumour microenvironment (TME), defined as the variety of non-cancerous cells surrounding cancer cells, but are relevant also for other diseases. In recent years it has become clearer that the TME does not passively assist the growth of cancer cells but contributes to its biology. Some of the mediators of the intercellular communication between cancer cells and TME are miRs shuttled within exosomes, a subtype of cellular released extracellular vesicles. This article will highlight the most recent findings on the biological implications of miR-miRceptor interactions for the biology of the TME and other diseases, and will provide some perspectives on the future development of this fascinating research.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158314 TI - Tumour-adipose tissue crosstalk: fuelling tumour metastasis by extracellular vesicles. AB - During metastasis, tumour cells must communicate with their microenvironment by secreted soluble factors and extracellular vesicles. Different stromal cell types (e.g. bone marrow-derived cells, endothelial cells and fibroblasts) influence the growth and progression of tumours. In recent years, interest has extended to other cell types in the tumour microenvironment such as adipocytes and adipose tissue-derived mesenchymal stem cells. Indeed, obesity is becoming pandemic in some developing countries and it is now considered to be a risk factor for cancer progression. However, the true impact of obesity on the metastatic behaviour of tumours is still not yet fully understood. In this 'Perspective' article, we will discuss the potential influence of obesity on tumour metastasis, mainly in melanoma, breast and ovarian cancer. We summarize the main mechanisms involved with special attention to the role of extracellular vesicles in this process. We envisage that besides having a direct impact on tumour cells, obesity systemically preconditions the tumour microenvironment for future metastasis by favouring the formation of pro-inflammatory niches.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158316 TI - Role for extracellular vesicles in the tumour microenvironment. AB - Extracellular vesicles (EVs) are small-membrane vesicles secreted by most cells types with the role to provide intercellular communication both locally and systemically. The transfer of their content between cells, which includes nucleic acids, proteins and lipids, confers the means for these interactions and induces significant cellular behaviour changes in the receiving cell. EVs are implicated in the regulation of numerous physiological and pathological processes, including development and neurological and cardiovascular diseases. Importantly, it has been shown that EV signalling is essential in almost all the steps necessary for the progress of carcinomas, from primary tumours to metastasis. In this review, we will focus on the latest findings for EV biology in relation to cancer progression and the tumour microenvironment.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158317 TI - An apoptosis-driven 'onco-regenerative niche': roles of tumour-associated macrophages and extracellular vesicles. AB - The cell-death programme, apoptosis, is well established as a tumour suppressor mechanism. Paradoxically, high levels of apoptosis in tumours are closely coupled with poor prognosis. Indeed, where it has been studied, cell loss is a striking feature of high-grade cancers, illustrating the importance of considering malignant disease as an imbalance between cell gain and cell loss that favours cell gain rather than as a unidirectional disorder of cell gain alone. In addition to orchestrating cell loss, apoptosis can signal regenerative responses for example compensatory proliferation-in neighbouring cells. Accumulating evidence suggests that normal tissue repair and regenerative processes are hijacked in the malignant tissue microenvironment such that cancer may be likened to a 'wound that fails to stop repairing'. We have proposed that a critical requirement for the successful growth, progression and re-growth of malignant tumours is a complex milieu, conceptually termed the 'onco-regenerative niche', which is composed, in addition to transformed neoplastic cells, of a network of normal cells and factors activated as if in tissue repair and regeneration. Our work is based around the hypothesis that tumour cell apoptosis, macrophage activation and endothelial activation are key, interlinked elements of the onco regenerative niche and that apoptotic tumour cell-derived extracellular vesicles provide critical intercellular communication vehicles of the niche. In aggressive B-cell lymphoma, tumour cell apoptosis promotes both angiogenesis and the accumulation of pro-tumour macrophages in the lymphoma microenvironment. Furthermore, apoptotic lymphoma-derived extracellular vesicles have potent pro tumour potential. These findings have important implications for the roles of apoptosis in regulation of malignant diseases and for the efficacy of apoptosis inducing anti-cancer therapies.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158319 TI - Royal Society Scientific Meeting: Extracellular vesicles in the tumour microenvironment. AB - Cancer cells do not grow as an isolated homogeneous mass; tumours are, in fact, complex and heterogeneous collections of cancer and surrounding stromal cells, collectively termed the tumour microenvironment. The interaction between cancer cells and stromal cells in the tumour microenvironment has emerged as a key concept in the regulation of cancer progression. Understanding the intercellular dialogue in the tumour microenvironment is therefore an important goal. One aspect of this dialogue that has not been appreciated until recently is the role of extracellular vesicles (EVs). EVs are small vesicles released by cells under both normal and pathological conditions; they can transfer biological molecules between cells leading to changes in phenotype. EVs have emerged as important regulators of biological processes and can be dysregulated in diseases such as cancer; rapidly growing interest in their biology and therapeutic potential led to the Royal Society hosting a Scientific Meeting to explore the roles of EVs in the tumour microenvironment. This cross-disciplinary meeting explored examples of how aberrant crosstalk between tumour and stromal cells can promote cancer progression, and how such signalling can be targeted for diagnostic, prognostic and therapeutic benefit. In this review, and the special edition of Philosophical Transactions of the Royal Society B that follows, we will provide an overview of the content and outcomes of this exciting meeting.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158318 TI - Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells. AB - Ovarian cancer has a poor overall survival that is partly caused by resistance to drugs such as cisplatin. Resistance can be acquired as a result of changes to the tumour or due to altered interactions within the tumour microenvironment. Extracellular vesicles (EVs), small lipid-bound vesicles that are loaded with macromolecular cargo and released by cells, are emerging as mediators of communication in the tumour microenvironment. We previously showed that EVs mediate the bystander effect, a phenomenon in which stressed cells can communicate with neighbouring naive cells leading to various effects including DNA damage; however, the role of EVs released following cisplatin treatment has not been tested. Here we show that treatment of cells with cisplatin led to the release of EVs that could induce invasion and increased resistance when taken up by bystander cells. This coincided with changes in p38 and JNK signalling, suggesting that these pathways may be involved in mediating the effects. We also show that EV uptake inhibitors could prevent this EV-mediated adaptive response and thus sensitize cells in vitro to the effects of cisplatin. Our results suggest that preventing pro-tumourigenic EV cross-talk during chemotherapy is a potential therapeutic target for improving outcome in ovarian cancer patients.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'. PMID- 29158320 TI - Correction to 'Viral hepatitis and liver cancer'. PMID- 29158321 TI - Assembly and turnover of neurofilaments in growing axonal neurites. AB - Neurofilaments (NFs) are thought to provide stability to the axon. We examined NF dynamics within axonal neurites of NB2a/d1 neuroblastoma by transient transfection with green fluorescent protein-tagged NF-heavy (GFP-H) under the control of a tetracycline-inducible promoter. Immunofluorescent and biochemical analyses demonstrated that GFP-H expressed early during neurite outgrowth associated with a population of centrally-situated, highly-phosphorylated crosslinked NFs along the length of axonal neurites ('bundled NFs'). By contrast, GFP-H expressed after considerable neurite outgrowth displayed markedly reduced association with bundled NFs and was instead more evenly distributed throughout the axon. This differential localization was maintained for up to 2 weeks in culture. Once considerable neurite outgrowth had progressed, GFP that had previously associated with the NF bundle during early expression was irreversibly depleted by photobleaching. Cessation of expression allowed monitoring of NF turnover. GFP-H associated bundled NFs underwent slower decay than GFP-H associated with surrounding, less-phosphorylated NFs. Notably, GFP associated with bundled NFs underwent similar decay rates within the core and edges of this bundle. These results are consistent with previous demonstration of a resident NF population within axonal neurites, but suggest that this population is more dynamic than previously considered. PMID- 29158322 TI - Optogenetic activation of EphB2 receptor in dendrites induced actin polymerization by activating Arg kinase. AB - Erythropoietin-producing hepatocellular (Eph) receptors regulate a wide array of developmental processes by responding to cell-cell contacts. EphB2 is well expressed in the brain and known to be important for dendritic spine development, as well as for the maintenance of the synapses, although the mechanisms of these functions have not been fully understood. Here we studied EphB2's functions in hippocampal neurons with an optogenetic approach, which allowed us to specify spatial regions of signal activation and monitor in real-time the consequences of signal activation. We designed and constructed OptoEphB2, a genetically encoded photoactivatable EphB2. Photoactivation of OptoEphB2 in fibroblast cells induced receptor phosphorylation and resulted in cell rounding ------- a well-known cellular response to EphB2 activation. In contrast, local activation of OptoEphb2 in dendrites of hippocampal neurons induces rapid actin polymerization, resulting dynamic dendritic filopodial growth. Inhibition of Rac1 and CDC42 did not abolish OptoEphB2-induced actin polymerization. Instead, we identified Abelson tyrosine protein kinase 2 (Abl2/Arg) as a necessary effector in OptoEphB2-induced filopodia growth in dendrites. These findings provided new mechanistic insight into EphB2's role in neural development and demonstrated the advantage of OptoEphB as a new tool for studying EphB signaling. PMID- 29158323 TI - FGF8 morphogen gradients are differentially regulated by heparan sulphotransferases Hs2st and Hs6st1 in the developing brain. AB - Fibroblast growth factor (FGF) morphogen signalling through the evolutionarily ancient extracellular signalling-regulated kinase/mitogen activated protein kinase (ERK/MAPK) pathway recurs in many neural and non-neural developmental contexts, and understanding the mechanisms that regulate FGF/ERK function are correspondingly important. The glycosaminoglycan heparan sulphate (HS) binds to FGFs and exists in an enormous number of differentially sulphated forms produced by the action of HS modifying enzymes, and so has the potential to present an extremely large amount of information in FGF/ERK signalling. Although there have been many studies demonstrating that HS is an important regulator of FGF function, experimental evidence on the role of the different HS modifying enzymes on FGF gradient formation has been lacking until now. We challenged ex vivo developing mouse neural tissue, in which HS had either been enzymatically removed by heparanase treatment or lacking either the HS modifying enzymes Hs2st (Hs2st-/ tissue) or Hs6st1 (Hs6st1-/- tissue), with exogenous Fgf8 to gain insight on how HS and the function of these two HS modifying enzymes impacts on Fgf8 gradient formation from an exogenously supplied source of Fgf8 protein. We discover that two different HS modifying enzymes, Hs2st and Hs6st1, indeed differentially modulate the properties of emerging Fgf8 protein concentration gradients and the Erk signalling output in response to Fgf8 in living tissue in ex vivo cultures. Both Hs2st and Hs6st1 are required for stable Fgf8 gradients to form as rapidly as they do in wild-type tissue while only Hs6st1 has a significant effect on suppressing the levels of Fgf8 protein in the gradient compared to wild type. Next we show that Hs2st and Hs6st1 act to antagonise and agonise the Erk signalling in response to Fgf8 protein, respectively, in ex vivo cultures of living tissue. Examination of endogenous Fgf8 protein and Erk signalling outputs in Hs2st-/- and Hs6st1-/- embryos suggests that our ex vivo findings have physiological relevance in vivo Our discovery identifies a new class of mechanism to tune Fgf8 function by regulated expression of Hs2st and Hs6st1 that is likely to have broader application to the >200 other signalling proteins that interact with HS and their function in neural development and disease. PMID- 29158325 TI - MPs gather examples of GPs from outside Europe being unable to work in UK. PMID- 29158324 TI - Control of RAB7 activity and localization through the retromer-TBC1D5 complex enables RAB7-dependent mitophagy. AB - Retromer is an endosomal multi-protein complex that organizes the endocytic recycling of a vast range of integral membrane proteins. Here, we establish an additional retromer function in controlling the activity and localization of the late endosomal small GTPase RAB7. Surprisingly, we found that RAB7 not only decorates late endosomes or lysosomes, but is also present on the endoplasmic reticulum, trans-Golgi network, and mitochondrial membranes, a localization that is maintained by retromer and the retromer-associated RAB7-specific GAP TBC1D5. In the absence of either TBC1D5 or retromer, RAB7 activity state and localization are no longer controlled and hyperactivated RAB7 expands over the entire lysosomal domain. This lysosomal accumulation of hyperactivated RAB7 results in a striking loss of RAB7 mobility and overall depletion of the inactive RAB7 pool on endomembranes. Functionally, we establish that this control of RAB7 activity is not required for the recycling of retromer-dependent cargoes, but instead enables the correct sorting of the autophagy related transmembrane protein ATG9a and autophagosome formation around damaged mitochondria during Parkin-mediated mitophagy. PMID- 29158326 TI - Women and substance use: a qualitative study on sexual and reproductive health of women who use drugs in Delhi, India. AB - OBJECTIVES: To explore contextual factors that increase vulnerabilities to negative sexual and reproductive health (SRH) outcomes and possible differences in SRH-related behaviours and the needs of women who use drugs (WUD) through non injecting and injecting routes. DESIGN: Qualitative study design using semi structured in-depth interviews. PARTICIPANTS: Twenty women who injected drugs in the past 3 months and 28 women who reported using drugs through non-injecting routes in the past 1 month. SETTING: Interviews were conducted at community based, drop-in centres in Delhi, India. RESULTS: Study findings illustrate that WUD were sexually active and had multiple sex partners including clients of sex work. Transient relationships were reported and many participants engaged in unsafe sex. Factors which affected safe sex behaviours included: gender power imbalance, limited agency for decision-making, lack of accurate information for correct self-risk assessment, and being under the influence of drugs. Despite high awareness, low and inconsistent contraceptive use was reported. Some participants were coerced to conceive while a few others reported their inability to conceive. Violence was a key determinant for SRH outcomes. Perception of certain adverse health outcomes (such as infertility) to be 'common and expected among WUD' influenced access to healthcare. Further, healthcare providers' stigmatising attitudes and lack of women-centric services deterred women from uptake of healthcare services. CONCLUSION: Findings highlight that SRH-related behaviours and needs of this group are a complex interplay of multiple determinants which need to be addressed at all levels: individual, family, community and institutional. It is imperative to roll out a 'one-stop-shop' for a comprehensive package of health services. Expansion of existing drop-in-centres could be considered for setting-up community-based women-centric services with appropriate linkage to drug dependence treatment and reproductive health services. PMID- 29158327 TI - Early-onset group B Streptococcus (EOGBS) infection subsequent to cessation of screening-based intrapartum prophylaxis: findings of an observational study in West London, UK. AB - OBJECTIVES: To describe the impact on early-onset group B Streptococcus (EOGBS) infection rates following reversion from screening-based to risk-based intrapartum antimicrobial prophylaxis (IAP) for prevention. SETTING: Maternity services provided by secondary healthcare organisation in North West London. PARTICIPANTS: All women who gave birth in the healthcare organisation between April 2016 and March 2017. There were no exclusions. DESIGN: Observational study comparing EOGBS rates in the postscreening period (2016-2017) with prescreening (2009-2013) and screening periods (2014-2015). METHODS: Local guidelines for risk based IAP were reintroduced in April 2016. Compliance with guidelines was audited. Gestational age, mode of delivery, maternal demographics and EOGBS rates in three time periods were compared using Poisson regression analysis. EOGBS was defined through GBS being cultured from blood, cerebrospinal fluid or other sterile fluids within 6 days of birth. PRIMARY OUTCOME: EOGBS rates/1000 live births in prescreening, screening and postscreening periods RESULTS: Incremental changes in maternity population were observed throughout the study period (2009 onwards), in particular the ethnic profile of mothers. Of the 5033 live births in postscreening period, 9 babies developed EOGBS infection. Only one of the mothers of affected babies had a risk factor indicating use of IAP. Comparison of postscreening period with screening period showed a fivefold increase in EOGBS rates after adjustment for ethnicity (1.79 vs 0.33/1000 live births; risk ratio =5.67, p=0.009). There was no significant difference between prescreening and postscreening periods with rates of infection reverting to their prescreening level. CONCLUSIONS: This study provides further evidence of efficacy of screening based IAP compared with risk-based IAP in prevention of EOGBS in newborns in an area of high incidence. PMID- 29158328 TI - Prolines in Transit Peptides Are Crucial for Efficient Preprotein Translocation into Chloroplasts. AB - Chloroplasts import many preproteins that can be classified based on their physicochemical properties. The cleavable N-terminal transit peptide (TP) of chloroplast preproteins contains all the information required for import into chloroplasts through Toc/Tic translocons. The question of whether and how the physicochemical properties of preproteins affect TP-mediated import into chloroplasts has not been elucidated. Here, we present evidence that Pro residues in TP mediate efficient translocation through the chloroplast envelope membranes for proteins containing transmembrane domains (TMDs) or proteins prone to aggregation. By contrast, the translocation of soluble proteins through the chloroplast envelope membranes is less dependent on TP prolines. Proless TPs failed to mediate protein translocation into chloroplasts; instead, these mutant TPs led to protein mistargeting to the chloroplast envelope membranes or nonspecific protein aggregation during import into chloroplasts. The mistargeting of TMD-containing proteins caused by Pro-less TPs in wild-type protoplasts was mimicked by wild-type TPs in hsp93-V protoplasts, in which preprotein translocation is compromised. We propose that the physicochemical properties of chloroplast proteins affect protein translocation through the chloroplast envelope, and prolines in TP have a crucial role in the efficient translocation of TMD-containing proteins. PMID- 29158329 TI - Polysomes, Stress Granules, and Processing Bodies: A Dynamic Triumvirate Controlling Cytoplasmic mRNA Fate and Function. PMID- 29158330 TI - Regulation of Sucrose Transporters and Phloem Loading in Response to Environmental Cues. AB - Suc transporters (SUTs) play a key role in the allocation and partitioning of photosynthetically fixed carbon in plants. While a function could be assigned to many members of the SUT family, almost no information is available on their regulation. Here, the transcriptional regulation of SUTs in response to various environmental stimuli in the leaves of five dicots (Arabidopsis [Arabidopsis thaliana], soybean [Glycine max], potato [Solanum tuberosum], tomato [Solanumlycopersicum], and poplar [Populus spp.]) and four monocots (maize [Zeamays], rice [Oryza sativa], wheat [Triticum aestivum], and barley [Hordeum vulgare]) was investigated. Extensive data on expression of SUTs in relation to changes of environmental conditions were obtained through a global analysis of 168 transcriptomics data sets. Results were validated by quantitative PCR measurements and extended by the measurement of photosynthesis rate and phloem sugar content to draw insight on the correlation of SUT expression and sugar export from leaves. For the apoplasmic phloem loaders, a clear difference in transcriptional regulation in response to different environmental stimuli was observed. The consistent patterns of SUT expression under abiotic stress indicates which types of SUTs are involved in the regulation of leaf sugar status and in stress signaling. Furthermore, it is shown that down-regulation of phloem loading is likely to be caused by transcriptional regulation of SUTs, while up regulation depends on post-transcriptional regulation. In poplar, expression of PtaSUT4 was found to consistently respond to environmental stimuli, suggesting a significant role in the regulation of sugar export from leaves in this passive symplasmic phloem loader. PMID- 29158331 TI - Vessel-Specific Reintroduction of CINNAMOYL-COA REDUCTASE1 (CCR1) in Dwarfed ccr1 Mutants Restores Vessel and Xylary Fiber Integrity and Increases Biomass. AB - Lignocellulosic biomass is recalcitrant toward deconstruction into simple sugars due to the presence of lignin. To render lignocellulosic biomass a suitable feedstock for the bio-based economy, plants can be engineered to have decreased amounts of lignin. However, engineered plants with the lowest amounts of lignin exhibit collapsed vessels and yield penalties. Previous efforts were not able to fully overcome this phenotype without settling in sugar yield upon saccharification. Here, we reintroduced CINNAMOYL-COENZYME A REDUCTASE1 (CCR1) expression specifically in the protoxylem and metaxylem vessel cells of Arabidopsis (Arabidopsis thaliana) ccr1 mutants. The resulting ccr1 ProSNBE:CCR1 lines had overcome the vascular collapse and had a total stem biomass yield that was increased up to 59% as compared with the wild type. Raman analysis showed that monolignols synthesized in the vessels also contribute to the lignification of neighboring xylary fibers. The cell wall composition and metabolome of ccr1 ProSNBE:CCR1 still exhibited many similarities to those of ccr1 mutants, regardless of their yield increase. In contrast to a recent report, the yield penalty of ccr1 mutants was not caused by ferulic acid accumulation but was (largely) the consequence of collapsed vessels. Finally, ccr1 ProSNBE:CCR1 plants had a 4-fold increase in total sugar yield when compared with wild-type plants. PMID- 29158332 TI - Ethylene Receptors Signal via a Noncanonical Pathway to Regulate Abscisic Acid Responses. AB - Ethylene is a gaseous plant hormone perceived by a family of receptors in Arabidopsis (Arabidopsis thaliana) including ETHYLENE RESPONSE1 (ETR1) and ETR2. Previously we showed that etr1-6 loss-of-function plants germinate better and etr2-3 loss-of-function plants germinate worse than wild-type under NaCl stress and in response to abscisic acid (ABA). In this study, we expanded these results by showing that ETR1 and ETR2 have contrasting roles in the control of germination under a variety of inhibitory conditions for seed germination such as treatment with KCl, CuSO4, ZnSO4, and ethanol. Pharmacological and molecular biology results support a model where ETR1 and ETR2 are indirectly affecting the expression of genes encoding ABA signaling proteins to affect ABA sensitivity. The receiver domain of ETR1 is involved in this function in germination under these conditions and controlling the expression of genes encoding ABA signaling proteins. Epistasis analysis demonstrated that these contrasting roles of ETR1 and ETR2 do not require the canonical ethylene signaling pathway. To explore the importance of receptor-protein interactions, we conducted yeast two-hybrid screens using the cytosolic domains of ETR1 and ETR2 as bait. Unique interacting partners with either ETR1 or ETR2 were identified. We focused on three of these proteins and confirmed the interactions with receptors. Loss of these proteins led to faster germination in response to ABA, showing that they are involved in ABA responses. Thus, ETR1 and ETR2 have both ethylene-dependent and -independent roles in plant cells that affect responses to ABA. PMID- 29158333 TI - Transcription Factor OsTGA10 Is a Target of the MADS Protein OsMADS8 and Is Required for Tapetum Development. AB - This study aimed at elucidating regulatory components behind floral organ identity determination and tissue development. It remains unclear how organ identity proteins facilitate development of organ primordia into tissues with a determined identity, even though it has long been accepted that floral organ identity is genetically determined by interaction of identity genes according to the ABC model. Using the chromatin immunoprecipitation sequencing technique, we identified OsTGA10, encoding a bZIP transcription factor, as a target of the MADS box protein OsMADS8, which is annotated as an E-class organ identity protein. We characterized the function of OsTGA10 using genetic and molecular analyses. OsTGA10 was preferentially expressed during stamen development, and mutation of OsTGA10 resulted in male sterility. OsTGA10 was required for tapetum development and functioned by interacting with known tapetum genes. In addition, in ostga10 stamens, the hallmark cell wall thickening of the endothecium was defective. Our findings suggest that OsTGA10 plays a mediator role between organ identity determination and tapetum development in rice stamen development, between tapetum development and microspore development, and between various regulatory components required for tapetum development. Furthermore, the defective endothecium in ostga10 implies that cell wall thickening of endothecium is dependent on tapetum development. PMID- 29158334 TI - Global Transcriptome Sequencing Reveals Molecular Profiles of Summer Diapause Induction Stage of Onion Maggot, Delia antiqua (Diptera: Anthomyiidae). AB - The onion maggot, Delia antiqua, is a worldwide subterranean pest and can enter diapause during the summer and winter seasons. The molecular regulation of the ontogenesis transition remains largely unknown. Here we used high-throughput RNA sequencing to identify candidate genes and processes linked to summer diapause (SD) induction by comparing the transcriptome differences between the most sensitive larval developmental stage of SD and nondiapause (ND). Nine pairwise comparisons were performed, and significantly differentially regulated transcripts were identified. Several functional terms related to lipid, carbohydrate, and energy metabolism, environmental adaption, immune response, and aging were enriched during the most sensitive SD induction period. A subset of genes, including circadian clock genes, were expressed differentially under diapause induction conditions, and there was much more variation in the most sensitive period of ND- than SD-destined larvae. These expression variations probably resulted in a deep restructuring of metabolic pathways. Potential regulatory elements of SD induction including genes related to lipid, carbohydrate, energy metabolism, and environmental adaption. Collectively, our results suggest the circadian clock is one of the key drivers for integrating environmental signals into the SD induction. Our transcriptome analysis provides insight into the fundamental role of the circadian clock in SD induction in this important model insect species, and contributes to the in-depth elucidation of the molecular regulation mechanism of insect diapause induction. PMID- 29158335 TI - A Deconvolution Protocol for ChIP-Seq Reveals Analogous Enhancer Structures on the Mouse and Human Ribosomal RNA Genes. AB - The combination of Chromatin Immunoprecipitation and Massively Parallel Sequencing, or ChIP-Seq, has greatly advanced our genome-wide understanding of chromatin and enhancer structures. However, its resolution at any given genetic locus is limited by several factors. In applying ChIP-Seq to the study of the ribosomal RNA genes, we found that a major limitation to resolution was imposed by the underlying variability in sequence coverage that very often dominates the protein-DNA interaction profiles. Here, we describe a simple numerical deconvolution approach that, in large part, corrects for this variability, and significantly improves both the resolution and quantitation of protein-DNA interaction maps deduced from ChIP-Seq data. This approach has allowed us to determine the in vivo organization of the RNA polymerase I preinitiation complexes that form at the promoters and enhancers of the mouse (Mus musculus) and human (Homo sapiens) ribosomal RNA genes, and to reveal a phased binding of the HMG-box factor UBF across the rDNA. The data identify and map a "Spacer Promoter" and associated stalled polymerase in the intergenic spacer of the human ribosomal RNA genes, and reveal a very similar enhancer structure to that found in rodents and lower vertebrates. PMID- 29158336 TI - Severe Fertility Effects of sheepish Sperm Caused by Failure To Enter Female Sperm Storage Organs in Drosophila melanogaster. AB - In Drosophila, mature sperm are transferred from males to females during copulation, stored in the sperm storage organs of females, and then utilized for fertilization. Here, we report a gene named sheepish (shps) of Drosophila melanogaster that is essential for sperm storage in females. shps mutant males, although producing morphologically normal and motile sperm that are effectively transferred to females, produce very few offspring. Direct counts of sperm indicated that the primary defect was correlated to failure of shps sperm to migrate into the female sperm storage organs. Increased sperm motion parameters were seen in the control after transfer to females, whereas sperm from shps males have characteristics of the motion parameters different from the control. The few sperm that occasionally entered the female sperm storage organs showed no obvious defects in fertilization and early embryo development. The female postmating responses after copulation with shps males appeared normal, at least with respect to conformational changes of uterus, mating plug formation, and female remating rates. The shps gene encodes a protein with homology to amine oxidases, including as observed in mammals, with a transmembrane region at the C-terminal end. The shps mutation was characterized by a nonsense replacement in the third exon of CG13611, and shps was rescued by transformants of the wild-type copy of CG13611 Thus, shps may define a new class of gene responsible for sperm storage. PMID- 29158337 TI - A Single Residue Mutation in the Galphaq Subunit of the G Protein Complex Causes Blindness in Drosophila. AB - Heterotrimeric G proteins play central roles in many signaling pathways, including the phototransduction cascade in animals. However, the degree of involvement of the G protein subunit Galphaq is not clear since animals with previously reported strong loss-of-function mutations remain responsive to light stimuli. We recovered a new allele of Galphaq in Drosophila that abolishes light response in a conventional electroretinogram assay, and reduces sensitivity in whole-cell recordings of dissociated cells by at least five orders of magnitude. In addition, mutant eyes demonstrate a rapid rate of degeneration in the presence of light. Our new allele is likely the strongest hypomorph described to date. Interestingly, the mutant protein is produced in the eyes but carries a single amino acid change of a conserved hydrophobic residue that has been assigned to the interface of interaction between Galphaq and its downstream effector, PLC. Our study has thus uncovered possibly the first point mutation that specifically affects this interaction in vivo. PMID- 29158338 TI - Genes Integral to the Reproductive Function of Male Reproductive Tissues Drive Heterogeneity in Evolutionary Rates in Japanese Quail. AB - Early comparative genomics studies originally uncovered a nonintuitive pattern; genes involved in reproduction appeared to evolve more rapidly than other classes of genes. Currently, the emerging consensus is that genes encoding reproductive proteins evolve under variable selective pressures, producing more heterogeneous divergence patterns than previously appreciated. Here, we investigate a facet of that heterogeneity and explore the factors that drive male reproductive tissue based heterogeneity in evolutionary rates. In Japanese quail (Coturnix japonica), genes with enriched expression in the testes evolve much more rapidly than those enriched in the foam gland (FG), a novel gland that secretes an airy foam that males transfer to females during mating. We compared molecular evolutionary patterns among (1) genes with induced expression in breeding vs. wintering conditions for both tissues and (2) genes that encode foam proteins (FPs) vs. those with varying degrees of expression specificity in the FG. We report two major findings. First, genes upregulated in breeding condition testes evolve exceptionally rapidly, while those induced in breeding condition FGs evolve slowly. These differences hold even after correcting for hormonally-dependent gene expression and chromosomal location. Second, genes encoding FPs are extremely conserved in terms of gene identity and sequence. Together, these finding suggest that genes involved in the reproductive function of each tissue drive the marked rate of heterogeneity. PMID- 29158340 TI - Effects of Black Raspberry on Dibenzo[a,l]Pyrene Diol Epoxide Induced DNA Adducts, Mutagenesis, and Tumorigenesis in the Mouse Oral Cavity. AB - We previously showed that metabolic activation of the environmental and tobacco smoke constituent dibenzo[a,l]pyrene (DB[a,l]P) to its active fjord region diol epoxide (DB[a,l]PDE) is required to induce DNA damage, mutagenesis, and squamous cell carcinoma (SCC) in the mouse oral cavity. In contrast to procarcinogens, which were employed previously to induce SCC, DB[a,l]PDE does not require metabolic activation to exert its biological effects, and thus, this study was initiated to examine, for the first time, whether black raspberry powder (BRB) inhibits postmetabolic processes, such as DNA damage, mutagenesis, and tumorigenesis. Prior to long-term chemoprevention studies, we initially examined the effect of BRB (5% added to AIN-93M diet) on DNA damage in B6C3F1 mice using LC/MS-MS and on mutagenesis in the lacI gene in the mouse oral cavity. We showed that BRB inhibited DB[a,l]PDE-induced DNA damage (P < 0.05) and mutagenesis (P = 0.053) in the oral cavity. Tumor incidence in the oral cavity (oral mucosa and tongue) of mice fed diet containing 5% BRB was significantly (P < 0.05) reduced from 93% to 66%. Specifically, the incidence of benign tumor was significantly (P < 0.001) reduced from 90% to 31% (62% to 28% in the oral cavity and 28% to 2% in the tongue), a nonsignificant reduction of malignant tumors from 52% to 45%. Our preclinical findings demonstrate for the first time that the chemopreventive efficacy of BRB can be extended to direct-acting carcinogens that do not require phase I enzymes and is not just limited to procarcinogens. Cancer Prev Res; 11(3); 157-64. (c)2017 AACR. PMID- 29158341 TI - The (relative) importance of pollinator-mediated selection for evolution of flowers. PMID- 29158342 TI - Fates of angiosperm species following long-distance dispersal: Examples from American amphitropical Polemoniaceae. AB - PREMISE OF THE STUDY: Following establishment after long-distance dispersal, species may experience stasis, accumulate changes leading to new species identity, diversify into multiple species, interact with related species to form novel species, and even become extirpated. We examined each species of temperate Polemoniaceae in South America via the literature and new analyses to better understand the fates of species in this family after their dispersal from North America. METHODS: We reviewed literature for the 15 species of Polemoniaceae in South America amphitropically disjunct from their relatives in North America. We conducted DNA sequence analyses to infer relationships, timing of dispersal, and processes involved since dispersal in Microsteris gracilis, three Gilia, two Giliastrum, and three Collomia. Analyses included construction of haplotype networks and phylogenetic trees using maximum likelihood and Bayesian inference. KEY RESULTS: For all species examined in detail, origins in South America are compatible with dispersal via epizoochory from ca. 0.092-19.46 million years ago. Most species in South America are unique relative to their North American congeners, yet few have radiated into two or more species. Relative stasis, divergence, and hybridization with, and without, allopolyploid formation have occurred postdispersal in Polemoniaceae, as well as extirpation following at least brief establishment. CONCLUSIONS: Polemoniaceae that have established in South America share many features likely inherited from their North American progenitors, but some traits may have arisen in situ in specific taxa, such as cleistogamy, self-incompatibility, and the annual habit, evidencing the rich nature of diversification processes. PMID- 29158339 TI - Genome-Wide Mapping of Decay Factor-mRNA Interactions in Yeast Identifies Nutrient-Responsive Transcripts as Targets of the Deadenylase Ccr4. AB - The Ccr4 (carbon catabolite repression 4)-Not complex is a major regulator of stress responses that controls gene expression at multiple levels, from transcription to mRNA decay. Ccr4, a "core" subunit of the complex, is the main cytoplasmic deadenylase in Saccharomyces cerevisiae; however, its mRNA targets have not been mapped on a genome-wide scale. Here, we describe a genome-wide approach, RNA immunoprecipitation (RIP) high-throughput sequencing (RIP-seq), to identify the RNAs bound to Ccr4, and two proteins that associate with it, Dhh1 and Puf5 All three proteins were preferentially bound to lowly abundant mRNAs, most often at the 3' end of the transcript. Furthermore, Ccr4, Dhh1, and Puf5 are recruited to mRNAs that are targeted by other RNA-binding proteins that promote decay and mRNA transport, and inhibit translation. Although Ccr4-Not regulates mRNA transcription and decay, Ccr4 recruitment to mRNAs correlates better with decay rates, suggesting it imparts greater control over transcript abundance through decay. Ccr4-enriched mRNAs are refractory to control by the other deadenylase complex in yeast, Pan2/3, suggesting a division of labor between these deadenylation complexes. Finally, Ccr4 and Dhh1 associate with mRNAs whose abundance increases during nutrient starvation, and those that fluctuate during metabolic and oxygen consumption cycles, which explains the known genetic connections between these factors and nutrient utilization and stress pathways. PMID- 29158343 TI - Amphitropical disjunctions in New World Menthinae: Three Pliocene dispersals to South America following late Miocene dispersal to North America from the Old World. AB - PREMISE OF THE STUDY: The subtribe Menthinae (Lamiaceae), with 35 genera and 750 species, is among the largest and most economically important subtribes within the mint family. Most genera of Menthinae are found exclusively in the New World, where the group has a virtually continuous distribution ranging from temperate North America to southern South America. In this study, we explored the presence, timing, and origin of amphitropical disjuncts within Menthinae. METHODS: Our analyses were based on a data set consisting of 89 taxa and the nuclear ribosomal DNA markers ITS and ETS. Phylogenetic relationships were determined under maximum likelihood and Bayesian criteria, divergence times were estimated with the program BEAST, and ancestral range estimated with BioGeoBEARS. KEY RESULTS: A North Atlantic Land Bridge migration event at about 10.6 Ma is inferred from western Eurasia to North America. New World Menthinae spread rapidly across North America, and then into Central and South America. Several of the large speciose genera are not monophyletic with nuclear rDNA, a finding mirrored with previous chloroplast DNA results. Three amphitropical disjunctions involving North and southern South America clades, one including a southeastern South American clade with several genera, were inferred to have occurred within the past 5 Myr. CONCLUSIONS: Although three New World Menthinae genera occur in both North and South America, none exhibit an amphitropical disjunction. However, three clades exhibit amphitropical disjunctions, all dating to the early Pliocene, and all involve jump dispersals to either southeastern or southwestern South America from southeastern North America. PMID- 29158344 TI - Effects of walking in water on gut hormone concentrations and appetite: comparison with walking on land. AB - The effects of water exercise on gut hormone concentrations and appetite currently remain unclear. The aim of the present study was to investigate the effects of treadmill walking in water on gut hormone concentrations and appetite. Thirteen men (mean +/- s.d. age: 21.6 +/- 2.2 years, body mass index: 22.7 +/- 2.8 kg/m2, peak oxygen uptake (VO2peak): 49.8 +/- 7.8 mL/kg per min) participated in the walking in water and on land challenge. During the study period, ratings of subjective feelings of hunger, fullness, satiety and motivation to eat were reported on a 100-mm visual analog scale. A test meal was presented after walking, and energy intake (EI) was calculated. Blood samples were obtained during both trials to measure glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and acylated ghrelin (AG) concentrations. Hunger scores (How hungry do you feel?) were significantly lower during the water trial than during the land trial (P < 0.05). No significant differences were observed in EI between water and land trials. GLP-1 concentrations were significantly higher in the water trial than in the land trial (P < 0.05). No significant differences were observed in PYY concentrations between water and land trials. AG concentrations were significantly lower in the water trial than in the land trial (P < 0.01). In conclusion, changes in gut hormone concentrations during walking in water contribute to the exercise-induced suppression of appetite and provide novel information on the influence of walking in water on the acute regulation of appetite. PMID- 29158345 TI - Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients: Rescue by alpha-Ketoglutarate and TET-TDG Functional Reactivation. AB - RATIONALE: Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes. OBJECTIVE: To investigate the role of alpha-ketoglutarate (alphaKG) in the epimetabolic control of DNA demethylation in CMSCs. METHODS AND RESULTS: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5 methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high-fat diet (HFD), injected with streptozotocin, or both in combination (streptozotocin/HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of alphaKG synthesis in diabetic CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised TDG (thymine DNA glycosylase) and TET1 (ten-eleven translocation protein 1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that alphaKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatches or 5 formylcytosine. Accordingly, an exogenous source of alphaKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization, and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5-formylcytosine accumulation, thus partially mimicking the diabetic epigenetic landscape in cells of nondiabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of alphaKG dehydrogenase, increased the alphaKG level in diabetic CMSCs and in the heart of HFD and streptozotocin mice eliciting, in HFD, DNA demethylation, glucose uptake, and insulin response. CONCLUSIONS: Restoring the epimetabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes. PMID- 29158346 TI - Critical Functions of IRF4 in B and T Lymphocytes. PMID- 29158347 TI - Pillars Article: Requirement for the Transcription Factor LSIRF/IRF4 for Mature B and T Lymphocyte Function. Science. 1997. 275: 540-543. PMID- 29158348 TI - Galectin-1: A Jack-of-All-Trades in the Resolution of Acute and Chronic Inflammation. AB - Regulatory signals provide negative input to immunological networks promoting resolution of acute and chronic inflammation. Galectin-1 (Gal-1), a member of a family of evolutionarily conserved glycan-binding proteins, displays broad anti inflammatory and proresolving activities by targeting multiple immune cell types. Within the innate immune compartment, Gal-1 acts as a resolution-associated molecular pattern by counteracting the synthesis of proinflammatory cytokines, inhibiting neutrophil trafficking, targeting eosinophil migration and survival, and suppressing mast cell degranulation. Likewise, this lectin controls T cell and B cell compartments by modulating receptor clustering and signaling, thus serving as a negative-regulatory checkpoint that reprograms cellular activation, differentiation, and survival. In this review, we discuss the central role of Gal 1 in regulatory programs operating during acute inflammation, autoimmune diseases, allergic inflammation, pregnancy, cancer, and infection. Therapeutic strategies aimed at targeting Gal-1-glycan interactions will contribute to overcome cancer immunosuppression and reinforce antimicrobial immunity, whereas stimulation of Gal-1-driven immunoregulatory circuits will help to mitigate exuberant inflammation. PMID- 29158349 TI - Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice. AB - Teriparatide is a bone anabolic treatment for osteoporosis, modeled in animals by intermittent PTH (iPTH) administration, but the cellular and molecular mechanisms of action of iPTH are largely unknown. Here, we show that Teriparatide and iPTH cause a ~two-threefold increase in the number of regulatory T cells (Tregs) in humans and mice. Attesting in vivo relevance, blockade of the Treg increase in mice prevents the increase in bone formation and trabecular bone volume and structure induced by iPTH Therefore, increasing the number of Tregs is a pivotal mechanism by which iPTH exerts its bone anabolic activity. Increasing Tregs pharmacologically may represent a novel bone anabolic therapy, while iPTH-induced Treg increase may find applications in inflammatory conditions and transplant medicine. PMID- 29158351 TI - Conflicts of interest in scientific publishing. PMID- 29158350 TI - Cell fate decisions: emerging roles for metabolic signals and cell morphology. AB - Understanding how cell fate decisions are regulated is a fundamental goal of developmental and stem cell biology. Most studies on the control of cell fate decisions address the contributions of changes in transcriptional programming, epigenetic modifications, and biochemical differentiation cues. However, recent studies have found that other aspects of cell biology also make important contributions to regulating cell fate decisions. These cues can have a permissive or instructive role and are integrated into the larger network of signaling, functioning both upstream and downstream of developmental signaling pathways. Here, we summarize recent insights into how cell fate decisions are influenced by four aspects of cell biology: metabolism, reactive oxygen species (ROS), intracellular pH (pHi), and cell morphology. For each topic, we discuss how these cell biological cues interact with each other and with protein-based mechanisms for changing gene transcription. In addition, we highlight several questions that remain unanswered in these exciting and relatively new areas of the field. PMID- 29158353 TI - Blood Pressure Control by a Secreted FGFBP1 (Fibroblast Growth Factor-Binding Protein). AB - Fibroblast growth factors (FGFs) participate in organ development and tissue maintenance, as well as the control of vascular function. The paracrine-acting FGFs are stored in the extracellular matrix, and their release is controlled by a secreted FGF-binding protein (FGF-BP, FGFBP1, and BP1) that modulates FGF receptor signaling. A genetic polymorphism in the human FGFBP1 gene was associated with higher gene expression and an increased risk of familial hypertension. Here, we report on the effects of inducible BP1 expression in a transgenic mouse model. Induction of BP1 expression in adult animals leads to a sustained rise in mean arterial pressure by >30 mm Hg. The hypertensive effect of BP1 expression is prevented by candesartan, an angiotensin II (AngII) receptor antagonist, or by tempol, an inhibitor of reactive oxygen species. In vivo, BP1 expression sensitizes peripheral resistance vessels to AngII constriction by 20 fold but does not alter adrenergic vasoconstriction. FGF receptor kinase inhibition reverses the sensitization to AngII. Also, constriction of isolated renal afferent arterioles by AngII is enhanced after BP1 expression and blocked by FGF receptor kinase inhibition. Furthermore, AngII-mediated constriction of renal afferent arterioles is abolished in FGF2-/- mice but can be restored by add back of FGF2 plus BP1 proteins. In contrast to AngII, adrenergic constriction is not affected in the FGF2-/- model. Proteomics and gene expression analysis of kidney tissues after BP1 induction show that MAPK (mitogen-activated protein kinase) signaling via MKK4 (MAPK kinase 4), p38, and JNK (c-Jun N-terminal kinase) integrates the crosstalk of the FGF receptor and AngII pathways and thus impact vascular tone and blood pressure. PMID- 29158352 TI - Intracytoplasmic sperm injection: state of the art in humans. AB - Among infertile couples, 25% involve both male and female factors, while male factor alone accounts for another 25% due to oligo-, astheno-, teratozoospermia, a combination of the three, or even a complete absence of sperm cells in the ejaculate and can lead to a poor prognosis even with the help of assisted reproductive technology (ART). Intracytoplasmic sperm injection (ICSI) has been with us now for a quarter of a century and in spite of the controversy generated since its inception, it remains in the forefront of the techniques utilized in ART. The development of ICSI in 1992 has drastically decreased the impact of male factor, resulting in millions of pregnancies worldwide for couples who, without ICSI, would have had little chance of having their own biological child. This review focuses on the state of the art of ICSI regarding utility of bioassays that evaluate male factor infertility beyond the standard semen analysis and describes the current application and advances in regard to ICSI, particularly the genetic and epigenetic characteristics of spermatozoa and their impact on reproductive outcome. PMID- 29158354 TI - Confirmatory Tests for the Diagnosis of Primary Aldosteronism: A Prospective Diagnostic Accuracy Study. AB - The diagnosis of primary aldosteronism typically requires at least one confirmatory test. The fludrocortisone suppression test is generally accepted as a reliable confirmatory test, but it is cumbersome. Evidence from accuracy studies of the saline infusion test (SIT) and the captopril challenge test (CCT) has provided conflicting results. This prospective study aimed to evaluate the diagnostic accuracy of the SIT and CCT using fludrocortisone suppression test as the reference standard. One hundred thirty-five patients diagnosed with primary aldosteronism and 101 patients diagnosed with essential hypertension who completed the 3 confirmatory tests were included for the diagnostic accuracy analysis. The areas under the receiver-operator characteristics curves of the CCT and SIT were 0.96 (95% confidence interval [CI], 0.92-0.98) and 0.96 (95% CI, 0.92-0.98), respectively, using post-test plasma aldosterone concentration (PAC) for diagnosis. However, the areas under the receiver-operator characteristics curves of the CCT decreased to 0.71 (95% CI, 0.65-0.77) when the PAC suppression percentage was used to diagnose primary aldosteronism. The optimal cutoff of PAC post-CCT was set at 11 ng/dL, resulting in a sensitivity of 0.90 (95% CI, 0.84 0.95) and a specificity of 0.90 (95% CI, 0.83-0.95), which were not significantly different from those of SIT (with PAC post-SIT set at 8 ng/dL, sensitivity: 0.85 [95% CI, 0.78-0.91], P=0.192; specificity: 0.92 [95% CI, 0.85-0.97], P=0.551). In conclusion, both CCT and SIT are accurate alternatives to the more complex fludrocortisone suppression test. Because CCT is safe and much easier to perform, it may serve as a more feasible alternative. When interpreting the results of CCT, PAC post-CCT is highly recommended. PMID- 29158357 TI - Evidence for a Role of Vascular Endothelium in the Control of Arterial Wall Viscosity in Humans. AB - : Arterial wall viscosity (AWV) is a major cause of energy dissipation along the arterial tree. Its determinants remain controversial but an active endothelial regulation has been suggested. Our objective was to assess in humans the physiological role of endothelium-derived nitric oxide (NO), epoxyeicosatrienoic acids and the effect of modulating smooth muscle tone in the regulation of AWV. We simultaneously measured radial artery diameter, wall thickness, and arterial pressure in healthy volunteers during the local infusion of inhibitors of NO synthase (NG-monomethyl-l-arginine), epoxyeicosatrienoic acids synthesis by cytochrome P450 (fluconazole), the epoxyeicosatrienoic acids cellular targets calcium-activated potassium channels (tetraethylammonium), alone and in combination. AWV was estimated from the relative viscosity expressed as the ratio of the area of the hysteresis loop of the pressure-diameter relationship to the area under the loading phase. Arterial tone was assessed by measuring change in wall stiffness and midwall stress. NG-monomethyl-l-arginine paradoxically reduced relative viscosity (34.9+/-8.9%-28.9+/-8.6%). Conversely, relative viscosity was not modified by fluconazole (33.5+/-15.5%-32.0+/-13.6%) but increased by tetraethylammonium (31.7+/-6.6%-35.7+/-8.0%). This increase was more marked with NG-monomethyl-l-arginine+fluconazole (31.1+/-10.7%-43.3+/-13.2%) and NG monomethyl-l-arginine+tetraethylammonium (29.5+/-2.3%-41.5+/-11.1%) compared with inhibitors alone. Sodium nitroprusside decreased AWV (35.4+/-2.9%-28.7+/-2.0%). These effects were associated with parallel change in tone but of different magnitude for similar variations in viscosity, suggesting tone-dependent and independent mechanisms. In conclusion, this is the first demonstration that the endothelial factors, NO and epoxyeicosatrienoic acids, regulate AWV in humans and support the role of arterial tone in this regulation. CLINICAL TRIAL REGISTRATION: URL: https://eudract.ema.europa.eu. Unique identifier: RCB2007-A001 10-53. PMID- 29158356 TI - Cerebrovascular Reactivity and Vascular Activation in Postmenopausal Women With Histories of Preeclampsia. AB - Cerebrovascular reactivity (CVR) is reduced in patients with cognitive decline. Women with a history of preeclampsia are at increased risk for cognitive decline. This study examined an association between pregnancy history and CVR using a subgroup of 40 age- and parity-matched pairs of women having histories of preeclampsia (n=27) or normotensive pregnancy (n=29) and the association of activated blood elements with CVR. Middle cerebral artery velocity was measured by Doppler ultrasound before and during hypercapnia to assess CVR. Thirty-eight parameters of blood cellular elements, microvesicles, and cell-cell interactions measured in venous blood were assessed for association with CVR using principal component analysis. Middle cerebral artery velocity was lower in the preeclampsia compared with the normotensive group at baseline (63+/-4 versus 73+/-3 cm/s; P=0.047) and during hypercapnia (P=0.013-0.056). CVR was significantly lower in the preeclampsia compared with the normotensive group (2.1+/-1.3 versus 2.9+/-1.1 cm.s.mm Hg; P=0.009). Globally, the association of the 7 identified principal components with preeclampsia (P=0.107) and with baseline middle cerebral artery velocity (P=0.067) did not reach statistical significance. The interaction between pregnancy history and principal components with respect to CVR (P=0.084) was driven by a nominally significant interaction between preeclampsia and the individual principal component defined by blood elements, platelet aggregation, and interactions of platelets with monocytes and granulocytes (P=0.008). These results suggest that having a history of preeclampsia negatively affects the cerebral circulation years beyond the pregnancy and that this effect was associated with activated blood elements. PMID- 29158355 TI - Models and Molecular Mechanisms of World Health Organization Group 2 to 4 Pulmonary Hypertension. PMID- 29158358 TI - Obesity Paradox in Hypertension: Is This Because Sympathetic Activation in Obesity-Hypertension Takes a Benign Form? PMID- 29158359 TI - Are Cocaine-Seeking "Habits" Necessary for the Development of Addiction-Like Behavior in Rats? AB - Drug self-administration models of addiction typically require animals to make the same response (e.g., a lever-press or nose-poke) over and over to procure and take drugs. By their design, such procedures often produce behavior controlled by stimulus-response (S-R) habits. This has supported the notion of addiction as a "drug habit," and has led to considerable advances in our understanding of the neurobiological basis of such behavior. However, to procure such drugs as cocaine, addicts often require considerable ingenuity and flexibility in seeking behavior, which, by definition, precludes the development of habits. To better model drug-seeking behavior in addicts, we first developed a novel cocaine self administration procedure [puzzle self-administration procedure (PSAP)] that required rats to solve a new puzzle every day to gain access to cocaine, which they then self-administered on an intermittent access (IntA) schedule. Such daily problem-solving precluded the development of S-R seeking habits. We then asked whether prolonged PSAP/IntA experience would nevertheless produce "symptoms of addiction." It did, including escalation of intake, sensitized motivation for drug, continued drug use in the face of adverse consequences, and very robust cue induced reinstatement of drug seeking, especially in a subset of "addiction prone" rats. Furthermore, drug-seeking behavior continued to require dopamine neurotransmission in the core of the nucleus accumbens (but not the dorsolateral striatum). We conclude that the development of S-R seeking habits is not necessary for the development of cocaine addiction-like behavior in rats.SIGNIFICANCE STATEMENT Substance-use disorders are often characterized as "habitual" behaviors aimed at obtaining and administering drugs. Although the actions involved in consuming drugs may involve a rigid repertoire of habitual behaviors, evidence suggests that addicts must be very creative and flexible when trying to procure drugs, and thus drug seeking cannot be governed by habit alone. We modeled flexible drug-seeking behavior in rats by requiring animals to solve daily puzzles to gain access to cocaine. We find that habitual drug-seeking isn't necessary for the development of addiction-like behavior, and that our procedure doesn't result in transfer of dopaminergic control from the ventral to dorsal striatum. This approach may prove useful in studying changes in neuropsychological function that promote the transition to addiction. PMID- 29158360 TI - Chromatin modifying gene mutations in follicular lymphoma. AB - Follicular lymphoma (FL) is an indolent malignancy of germinal center B cells. Although the overall survival of FL patients has recently improved with the introduction of novel therapies, there is significant heterogeneity in patient outcome and a need for rationally designed therapeutic strategies that target disease biology. Next-generation sequencing studies have identified chromatin modifying gene (CMG) mutations as a hallmark of FL, highlighting epigenetic modifiers as an attractive therapeutic target in this disease. Understanding the complex roles of these mutations will be central to identifying and adaptively targeting associated vulnerabilities. Recent studies have provided insight into the functional consequences of the most frequently mutated CMGs (KMT2D, CREBBP, and EZH2) and point to a role for these events in modifying normal B-cell differentiation programs and impeding germinal center exit. However, the majority of FL tumors serially acquire multiple CMG mutations, suggesting that there is a level of cross talk or cooperation between these events that has not yet been defined. Here, I review the current state of knowledge on CMG mutations in FL, discuss their potential as therapeutic targets, and offer my perspective on unexplored areas that should be considered in the future. PMID- 29158361 TI - Prochemerin cleavage by factor XIa links coagulation and inflammation. AB - Chemerin is a chemoattractant and adipokine that circulates in blood as inactive prochemerin (chem163S). Chem163S is activated by a series of C-terminal proteolytic cleavages resulting in diverse chemerin forms with different levels of activity. We screened a panel of proteases in the coagulation, fibrinolytic, and inflammatory cascades to identify those that process prochemerin in plasma. Factor XIa (FXIa) cleaved chem163S, generating a novel chemerin form, chem162R, as an intermediate product, and chem158K, as the final product. Processing at Arg162 was not required for cleavage at Lys158 or regulation of chemerin bioactivity. Contact phase activation of human platelet-poor plasma by kaolin led to cleavage of chem163S, which was undetectable in FXI-depleted plasma and markedly enhanced in platelet-rich plasma (PRP). Contact phase activation by polyphosphate in PRP resulted in 75% cleavage of chem163S. This cleavage was partially inhibited by hirudin, which blocks thrombin activation of FXI. After activation of plasma, levels of the most potent form of chemerin, chem157S, as well as inactive chem155A, increased. Plasma levels of chem163S in FXI-deficient patients were significantly higher compared with a matched control group (91 +/- 10 ng/mL vs 58 +/- 3 ng/mL, n = 8; P < .01) and inversely correlated with the plasma FXI levels. Thus FXIa, generated on contact phase activation, cleaves chem163S to generate chem158K, which can be further processed to the most active chemerin form, providing a molecular link between coagulation and inflammation. PMID- 29158362 TI - CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies. AB - Pretargeted radioimmunotherapy (PRIT) has demonstrated remarkable efficacy targeting tumor antigens, but immunogenicity and endogenous biotin blocking may limit clinical translation. We describe a new PRIT approach for the treatment of multiple myeloma (MM) and other B-cell malignancies, for which we developed an anti-CD38-bispecific fusion protein that eliminates endogenous biotin interference and immunogenic elements. In murine xenograft models of MM and non Hodgkin lymphoma (NHL), the CD38-bispecific construct demonstrated excellent blood clearance and tumor targeting. Dosimetry calculations showed a tumor absorbed dose of 43.8 Gy per millicurie injected dose of 90Y, with tumor-to normal organ dose ratios of 7:1 for liver and 15:1 for lung and kidney. In therapy studies, CD38-bispecific PRIT resulted in 100% complete remissions by day 12 in MM and NHL xenograft models, ultimately curing 80% of mice at optimal doses. In direct comparisons, efficacy of the CD38 bispecific proved equal or superior to streptavidin (SA)-biotin-based CD38-SA PRIT. Each approach cured at least 75% of mice at the highest radiation dose tested (1200 uCi), whereas at 600 and 1000-uCi doses, the bispecific outperformed the SA approach, curing 35% more mice overall (P < .004). The high efficacy of bispecific PRIT, combined with its reduced risk of immunogenicity and endogenous biotin interference, make the CD38 bispecific an attractive candidate for clinical translation. Critically, CD38 PRIT may benefit patients with unresponsive, high-risk disease because refractory disease typically retains radiation sensitivity. We posit that PRIT might not only prolong survival, but possibly cure MM and treatment-refractory NHL patients. PMID- 29158363 TI - Phase I Pharmacokinetic Study of Nivolumab in Korean Patients with Advanced Solid Tumors. AB - LESSONS LEARNED: This pharmacokinetic study of nivolumab showed that there is little ethnic difference in the handling of nivolumab.Nivolumab was well tolerated in Korean patients. BACKGROUND: This phase I study of nivolumab, an anti-programmed cell death-1 (anti-PD-1) monoclonal antibody, investigated the pharmacokinetics and safety of nivolumab in Korean patients with advanced solid tumors. Findings were compared with results from Japan and the U.S. MATERIALS AND METHODS: In this two-part study, patients received a single dose of nivolumab (1, 3, and 10 mg/kg; ONO-4538-13) and were followed up for 3 weeks. Those who met the required criteria proceeded to the second part (ONO-4538-14), and received the same dose as in part one every 2 weeks. RESULTS: Six patients per dose level were enrolled (n = 18). The mean elimination half-life of nivolumab among the groups ranged from 15.0 to 19.1 days. The maximum serum concentration and area under serum concentration-time curve increased almost dose-proportionally at doses from 1 to 10 mg/kg. Adverse drug reactions (ADRs; mostly grade <=2) were reported in seven patients (38.9%). ADRs grade >=3 occurred in one patient (5.6%; pneumonitis). Three patients (16.7%) developed ADRs related to thyroid dysfunction. CONCLUSION: The pharmacokinetic parameters of nivolumab were similar among patients from Korea, Japan, and the U.S. The safety profile was consistent with findings from previous studies. PMID- 29158364 TI - Adverse Event Reporting in Clinical Trials: Time to Include Duration as Well as Severity. PMID- 29158365 TI - Phase II Trial Using a Combination of Oxaliplatin, Capecitabine, and Celecoxib with Concurrent Radiation for Newly Diagnosed Resectable Rectal Cancer. AB - LESSONS LEARNED: Colorectal cancers exhibit a high level of cyclooxygenase-2 (COX 2) expression with strong preclinical rationale for improved clinical outcomes with COX-2 inhibition. Celecoxib is a COX-2 inhibitor and we have shown that it can be safely combined with capecitabine and oxaliplatin as part of neoadjuvant treatment with radiation therapy (RT) in rectal cancer.There was a significant improvement in skin toxicity with this combination as compared with historical data. Considering the field has moved on to single-agent capecitabine, we believe future trials with capecitabine and celecoxib hold potential. BACKGROUND: Improved survival is seen among patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant therapy. Cyclooxygenase-2 (COX-2) expression is increased in gastrointestinal malignancies and it may serve as a target to enhance pathologic response. A trial combining chemoradiation and COX-2 inhibition was conducted to evaluate the pCR rate, surgical outcomes, survival, and treatment toxicity. METHODS: Patients with resectable (T3-4, N1-2) rectal cancer within 12 cm of the anal verge were included in this phase II clinical trial. The neoadjuvant treatment consisted of capecitabine 850 mg/m2 b.i.d. Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m2 intravenous (IV), celecoxib 200 mg b.i.d. daily, along with concurrent 45 gray radiation therapy in 25 fractions. RESULTS: Thirty-two patients were included in the final analysis. The primary endpoint was pCR: 31% (95% confidence interval [CI]: 16% 50%). Secondary endpoints were surgical downstaging (SD): 75% (95% CI: 57%-89%) and sphincter-sparing surgery (SSS): 56% (95% CI: 38%-74%). Common grade >3 toxicities were diarrhea and abnormal liver function tests (9% each). Grade 0 and 1 toxicities included radiation dermatitis (59% and 34%, respectively) and proctitis (63% and 28%, respectively). At 3 years, disease-free survival and overall survival (OS) were 84% (95% CI: 65%-93%) and 94% (95% CI: 77%-98%), respectively. CONCLUSION: Chemoradiation with celecoxib in rectal cancer was well tolerated and demonstrated high rates of pCR, SD, and SSS. Improvement in skin toxicity (34% grade 1 and no grade 3/4) as compared with historical results (43% 78% grade 3/4) seems to be a significant improvement with addition of celecoxib to neoadjuvant chemotherapy. PMID- 29158366 TI - Therapeutic Anticoagulation in Patients with Primary Brain Tumors or Secondary Brain Metastasis. AB - : Patients with primary or metastatic brain tumors are at increased risk of developing venous thromboses. However, the potential benefit of therapeutic anticoagulation in these patients must be weighed against the deadly complication of intracranial hemorrhage. In this review, we summarize available evidence and recent studies of intracranial bleeding risks in primary and metastatic tumors and the impact of therapeutic anticoagulation. We find that for the majority of primary and treated metastatic brain tumors, the risk of spontaneous bleeding is acceptable and not further increased by careful therapeutic anticoagulation with low molecular weight heparin or direct oral anticoagulants, although thrombocytopenia (platelet count less than 50,000/MUL) and other coagulopathies are relative contraindications. Patients with brain metastasis from melanoma, renal cell carcinoma, choriocarcinoma, thyroid carcinoma, and hepatocellular carcinoma have a higher tendency to bleed spontaneously than noted in patients with other malignancies, and thus warrant routine brain imaging and alternative strategies such as inferior vena cava filter placement in the acute setting of venous thromboembolism before consideration of therapeutic anticoagulation. IMPLICATIONS FOR PRACTICE: Malignant gliomas are associated with increased risks of both venous thromboses and intracranial hemorrhage, but the additional bleeding risk associated with therapeutic anticoagulation appears acceptable, especially after treatment of primary tumors. Most patients with treated brain metastasis have a low risk of intracranial hemorrhage associated with therapeutic anticoagulation, and low molecular weight heparin is currently the preferred agent of choice. Patients with untreated brain metastasis from melanoma, renal cell carcinoma, thyroid cancer, choriocarcinoma, and hepatocellular carcinoma have a higher propensity for spontaneous intracranial bleeding, and systemic anticoagulation may be contraindicated in the acute setting of venous thromboembolism. PMID- 29158368 TI - Anti-Hu-Associated Autoimmune Limbic Encephalitis in a Patient with PD-1 Inhibitor-Responsive Myxoid Chondrosarcoma. AB - Autoimmune encephalitis is an uncommon complication of immune checkpoint inhibitor therapy. This article reports a case of fatal anti-Hu-associated autoimmune limbic encephalitis presenting within 8 weeks following anti-PD1 therapy in a patient with myxoid chondrosarcoma and pre-existing anti-Hu antibodies. Although tumor reduction occurred in response to PD-1 inhibitor therapy, the patient had a rapidly progressive decline in neurologic function despite initial stabilization with immunosuppression. Considering the increasing use of immune checkpoint inhibitors for the treatment of various malignancies, an increase in the occurrence of neurologic adverse events is likely, requiring prompt intervention and enhanced pharmacovigilance in malignancies associated with onconeuronal antibodies. PMID- 29158367 TI - Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Necuparanib Combined with Nab-Paclitaxel and Gemcitabine in Patients with Metastatic Pancreatic Cancer: Phase I Results. AB - LESSONS LEARNED: Despite the compelling preclinical rationale of evaluating the genetically engineered heparin derivative, necuparanib, combined with standard therapy in metastatic pancreas adenocarcinoma, the results were ultimately disappointing.Safety was documented, although dose escalation was limited by the number of subcutaneous injections, the potential for skin toxicity (cellulitis), and low-level anticoagulant effect. Nonetheless, the hypothesis of targeting prothrombotic pathways in pancreas adenocarcinoma remains compelling. BACKGROUND: Necuparanib is derived from unfractionated heparin and engineered for reduced anticoagulant activity while preserving known heparin-associated antitumor properties. This trial assessed the safety, pharmacokinetics (PK), pharmacodynamics, and initial efficacy of necuparanib combined with gemcitabine +/- nab-paclitaxel in patients with metastatic pancreatic cancer. METHODS: Patients received escalating daily subcutaneous doses of necuparanib plus 1,000 mg/m2 gemcitabine (days 1, 8, 15, and every 28 days). The protocol was amended to include 125 mg/m2 nab-paclitaxel after two cohorts (following release of the phase III MPACT data). The necuparanib starting dose was 0.5 mg/kg, with escalation via a modified 3 + 3 design until the maximum tolerated dose (MTD) was determined. RESULTS: Thirty-nine patients were enrolled into seven cohorts (necuparanib 0.5, 1 mg/kg + gemcitabine; necuparanib 1, 2, 4, 6, and 5 mg/kg + nab-paclitaxel + gemcitabine). The most common adverse events were anemia (56%), fatigue (51%), neutropenia (51%), leukopenia (41%), and thrombocytopenia (41%). No deaths and two serious adverse events were potentially related to necuparanib. Measurable levels of necuparanib were seen starting at the 2 mg/kg dose. Of 24 patients who received at least one dose of necuparanib + nab-paclitaxel + gemcitabine, 9 (38%) achieved a partial response and 6 (25%) achieved stable disease (63% disease control rate). Given a cellulitis event and mild activated partial thromboplastin time increases at 6 mg/kg, the 5 mg/kg dose was considered the MTD and selected for further assessment in phase II. CONCLUSION: Acceptable safety and encouraging signals of activity in patients with metastatic pancreatic cancer receiving necuparanib, nab-paclitaxel, and gemcitabine were demonstrated. PMID- 29158369 TI - Trailblazing Precision Oncology for Rare Tumor Subtypes. PMID- 29158370 TI - Ovarian and Uterine Functions in Female Survivors of Childhood Cancers. AB - : Adult survivors of childhood cancers are more prone to developing poor reproductive and obstetrical outcomes than their siblings and the general population as a result of previous exposure to chemotherapy and radiation during childhood. Chemotherapy drugs exert cytotoxic effects systemically and therefore can damage the ovaries, leading to infertility, premature ovarian failure, and, to a lesser extent, spontaneous abortions. They have very limited or no deleterious effects on the uterus that can be recognized clinically. By contrast, radiation is detrimental to both the ovaries and the uterus, thereby causing a greater magnitude of adverse effects on the female reproductive function. These include infertility, premature ovarian failure, miscarriage, fetal growth restrictions, perinatal deaths, preterm births, delivery of small-for-gestational age infants, preeclampsia, and abnormal placentation. Regrettably, the majority of these adverse outcomes arise from radiation-induced uterine injury and are reported at higher incidence in the adult survivors of childhood cancers who were exposed to uterine radiation during childhood in the form of pelvic, spinal, or total-body irradiation. Recent findings of long-term follow-up studies evaluating reproductive performance of female survivors provided some reassurance to female cancer survivors by documenting that pregnancy and live birth rates were not significantly compromised in survivors, including those who had been treated with alkylating agents and had not received pelvic, cranial, and total-body irradiation. We aimed in this narrative review article to provide an update on the impact of chemotherapy and radiation on the ovarian and uterine function in female survivors of childhood cancer. IMPLICATIONS FOR PRACTICE: Adult survivors of childhood cancers are more prone to developing a number of poor reproductive and obstetrical outcomes than their siblings and the general population as a result of previous exposure to chemotherapy and radiation during childhood. The impact of radiation therapy on the female genital system is greater than chemotherapy regimens because radiation is detrimental to both the uterus and the ovaries, whereas toxic effects of chemotherapy drugs are confined to the ovaries. Therefore, radiation-induced uterine damage accounts for most poor obstetrical outcomes in the survivors. These include infertility, miscarriages, stillbirths, fetal growth restrictions, preeclampsia, and preterm deliveries. PMID- 29158371 TI - Perception of Curability Among Advanced Cancer Patients: An International Collaborative Study. AB - BACKGROUND: There are limited data on illness understanding and perception of cure among advanced cancer patients around the world. The aim of the study was to determine the frequency and factors associated with inaccurate perception of curability among advanced cancer patients receiving palliative care across the globe. MATERIALS AND METHODS: Secondary analysis of a study to understand the core concepts in end-of-life care among advanced cancer patients receiving palliative care from 11 countries across the world. Advanced cancer patients were surveyed using a Patient Illness Understanding survey and Control Preference Scale. Descriptive statistics and multicovariate logistic regression analysis were performed. RESULTS: Fifty-five percent (763/1,390) of patients receiving palliative care inaccurately reported that their cancer is curable. The median age was 58, 55% were female, 59% were married or had a partner, 48% were Catholic, and 35% were college educated. Sixty-eight percent perceived that the goal of therapy was "to get rid of their cancer," and 47% perceived themselves as "seriously ill." Multicovariate logistic regression analysis shows that accurate perception of curability was associated with female gender (odds ratio [OR] 0.73, p = .027), higher education (OR 0.37, p < .0001), unemployment status (OR 0.69, p = .02), and being from France (OR 0.26, p < .0001) and South Africa (OR 0.52, p = .034); inaccurate perception of curability was associated with better Karnofsky performance status (OR 1.02 per point, p = .0005), and being from Philippines (OR 15.49, p < .0001), Jordan (OR 8.43, p < .0001), Brazil (OR 2.17, p = .0037), and India (OR 2.47, p = .039). CONCLUSION: Inaccurate perception of curability in advanced cancer patients is 55% and significantly differs by gender, education, performance status, employment status, and country of origin. Further studies are needed to develop strategies to reduce this misperception of curability in advanced cancer patients. IMPLICATIONS FOR PRACTICE: The findings of this study indicate that inaccurate perception of curability among advanced cancer patients is 55%. Inaccurate perception of curability significantly differs by gender, education, performance status, employment status, and country of origin. There is great need to facilitate improved patient-physician communication so as to improve health care outcomes and patient satisfaction. PMID- 29158372 TI - Enhancing Next-Generation Sequencing-Guided Cancer Care Through Cognitive Computing. AB - BACKGROUND: Using next-generation sequencing (NGS) to guide cancer therapy has created challenges in analyzing and reporting large volumes of genomic data to patients and caregivers. Specifically, providing current, accurate information on newly approved therapies and open clinical trials requires considerable manual curation performed mainly by human "molecular tumor boards" (MTBs). The purpose of this study was to determine the utility of cognitive computing as performed by Watson for Genomics (WfG) compared with a human MTB. MATERIALS AND METHODS: One thousand eighteen patient cases that previously underwent targeted exon sequencing at the University of North Carolina (UNC) and subsequent analysis by the UNCseq informatics pipeline and the UNC MTB between November 7, 2011, and May 12, 2015, were analyzed with WfG, a cognitive computing technology for genomic analysis. RESULTS: Using a WfG-curated actionable gene list, we identified additional genomic events of potential significance (not discovered by traditional MTB curation) in 323 (32%) patients. The majority of these additional genomic events were considered actionable based upon their ability to qualify patients for biomarker-selected clinical trials. Indeed, the opening of a relevant clinical trial within 1 month prior to WfG analysis provided the rationale for identification of a new actionable event in nearly a quarter of the 323 patients. This automated analysis took <3 minutes per case. CONCLUSION: These results demonstrate that the interpretation and actionability of somatic NGS results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing could potentially improve patient care by providing a rapid, comprehensive approach for data analysis and consideration of up-to-date availability of clinical trials. IMPLICATIONS FOR PRACTICE: The results of this study demonstrate that the interpretation and actionability of somatic next-generation sequencing results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing can significantly improve patient care by providing a fast, cost-effective, and comprehensive approach for data analysis in the delivery of precision medicine. Patients and physicians who are considering enrollment in clinical trials may benefit from the support of such tools applied to genomic data. PMID- 29158373 TI - Revisiting Expectations in an Era of Precision Oncology. AB - As we enter an era of precision medicine and targeted therapies in the treatment of metastatic cancer, we face new challenges for patients and providers alike as we establish clear guidelines, regulations, and strategies for implementation. At the crux of this challenge is the fact that patients with advanced cancer may have disproportionate expectations of personal benefit when participating in clinical trials designed to generate generalizable knowledge. Patient and physician goals of treatment may not align, and reconciliation of their disparate perceptions must be addressed. However, it is particularly challenging to manage a patient's expectations when the goal of precision medicine-personalized response-exacerbates our inability to predict outcomes for any individual patient. The precision medicine informed consent process must therefore directly address this issue. We are challenged to honestly, clearly, and compassionately engage a patient population in an informed consent process that is responsive to their vulnerability, as well as ever-evolving indications and evidence. This era requires a continual reassessment of expectations and goals from both sides of the bed. PMID- 29158375 TI - NSD3 keeps IRF3 active. AB - In this issue of JEM, Wang et al. (https://doi.org/10.1084/jem.20170856) show a novel antiviral innate mechanism by which methyltransferase NSD3 directly monomethylates a transcription factor IRF3 and maintains IRF3 phosphorylation to enhance its transcriptional activity, consequently promoting antiviral innate immune responses. PMID- 29158374 TI - Maternal IgG immune complexes induce food allergen-specific tolerance in offspring. AB - The role of maternal immune responses in tolerance induction is poorly understood. To study whether maternal allergen sensitization affects offspring susceptibility to food allergy, we epicutaneously sensitized female mice with ovalbumin (OVA) followed by epicutaneous sensitization and oral challenge of their offspring with OVA. Maternal OVA sensitization prevented food anaphylaxis, OVA-specific IgE production, and intestinal mast cell expansion in offspring. This protection was mediated by neonatal crystallizable fragment receptor (FcRn) dependent transfer of maternal IgG and OVA immune complexes (IgG-IC) via breast milk and induction of allergen-specific regulatory T (T reg) cells in offspring. Breastfeeding by OVA-sensitized mothers or maternal supplementation with IgG-IC was sufficient to induce neonatal tolerance. FcRn-dependent antigen presentation by CD11c+ dendritic cells (DCs) in offspring was required for oral tolerance. Human breast milk containing OVA-IgG-IC induced tolerance in humanized FcRn mice. Collectively, we demonstrate that interactions of maternal IgG-IC and offspring FcRn are critical for induction of T reg cell responses and control of food specific tolerance in neonates. PMID- 29158376 TI - Leukemia-specific delivery of mutant NOTCH1 targeted therapy. AB - On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca2+ ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors. PMID- 29158377 TI - Evidence for rRNA 2'-O-methylation plasticity: Control of intrinsic translational capabilities of human ribosomes. AB - Ribosomal RNAs (rRNAs) are main effectors of messenger RNA (mRNA) decoding, peptide-bond formation, and ribosome dynamics during translation. Ribose 2'-O methylation (2'-O-Me) is the most abundant rRNA chemical modification, and displays a complex pattern in rRNA. 2'-O-Me was shown to be essential for accurate and efficient protein synthesis in eukaryotic cells. However, whether rRNA 2'-O-Me is an adjustable feature of the human ribosome and a means of regulating ribosome function remains to be determined. Here we challenged rRNA 2' O-Me globally by inhibiting the rRNA methyl-transferase fibrillarin in human cells. Using RiboMethSeq, a nonbiased quantitative mapping of 2'-O-Me, we identified a repertoire of 2'-O-Me sites subjected to variation and demonstrate that functional domains of ribosomes are targets of 2'-O-Me plasticity. Using the cricket paralysis virus internal ribosome entry site element, coupled to in vitro translation, we show that the intrinsic capability of ribosomes to translate mRNAs is modulated through a 2'-O-Me pattern and not by nonribosomal actors of the translational machinery. Our data establish rRNA 2'-O-Me plasticity as a mechanism providing functional specificity to human ribosomes. PMID- 29158378 TI - Kinship structures create persistent channels for language transmission. AB - Languages are transmitted through channels created by kinship systems. Given sufficient time, these kinship channels can change the genetic and linguistic structure of populations. In traditional societies of eastern Indonesia, finely resolved cophylogenies of languages and genes reveal persistent movements between stable speech communities facilitated by kinship rules. When multiple languages are present in a region and postmarital residence rules encourage sustained directional movement between speech communities, then languages should be channeled along uniparental lines. We find strong evidence for this pattern in 982 individuals from 25 villages on two adjacent islands, where different kinship rules have been followed. Core groups of close relatives have stayed together for generations, while remaining in contact with, and marrying into, surrounding groups. Over time, these kinship systems shaped their gene and language phylogenies: Consistently following a postmarital residence rule turned social communities into speech communities. PMID- 29158379 TI - Energy decomposition analysis of single bonds within Kohn-Sham density functional theory. AB - An energy decomposition analysis (EDA) for single chemical bonds is presented within the framework of Kohn-Sham density functional theory based on spin projection equations that are exact within wave function theory. Chemical bond energies can then be understood in terms of stabilization caused by spin-coupling augmented by dispersion, polarization, and charge transfer in competition with destabilizing Pauli repulsions. The EDA reveals distinguishing features of chemical bonds ranging across nonpolar, polar, ionic, and charge-shift bonds. The effect of electron correlation is assessed by comparison with Hartree-Fock results. Substituent effects are illustrated by comparing the C-C bond in ethane against that in bis(diamantane), and dispersion stabilization in the latter is quantified. Finally, three metal-metal bonds in experimentally characterized compounds are examined: a [Formula: see text]-[Formula: see text] dimer, the [Formula: see text]-[Formula: see text] bond in dizincocene, and the Mn-Mn bond in dimanganese decacarbonyl. PMID- 29158381 TI - Superhydrophobic diving flies (Ephydra hians) and the hypersaline waters of Mono Lake. AB - The remarkable alkali fly, Ephydra hians, deliberately crawls into the alkaline waters of Mono Lake to feed and lay eggs. These diving flies are protected by an air bubble that forms around their superhydrophobic cuticle upon entering the lake. To study the physical mechanisms underlying this process we measured the work required for flies to enter and leave various aqueous solutions. Our measurements show that it is more difficult for the flies to escape from Mono Lake water than from fresh water, due to the high concentration of Na2CO3 which causes water to penetrate and thus wet their setose cuticle. Other less kosmotropic salts do not have this effect, suggesting that the phenomenon is governed by Hofmeister effects as well as specific interactions between ion pairs. These effects likely create a small negative charge at the air-water interface, generating an electric double layer that facilitates wetting. Compared with six other species of flies, alkali flies are better able to resist wetting in a 0.5 M Na2CO3 solution. This trait arises from a combination of factors including a denser layer of setae on their cuticle and the prevalence of smaller cuticular hydrocarbons compared with other species. Although superbly adapted to resisting wetting, alkali flies are vulnerable to getting stuck in natural and artificial oils, including dimethicone, a common ingredient in sunscreen and other cosmetics. Mono Lake's alkali flies are a compelling example of how the evolution of picoscale physical and chemical changes can allow an animal to occupy an entirely new ecological niche. PMID- 29158380 TI - Anti-SIRPalpha antibody immunotherapy enhances neutrophil and macrophage antitumor activity. AB - Cancer immunotherapy has emerged as a promising therapeutic intervention. However, complete and durable responses are only seen in a fraction of patients who have cancer. A key factor that limits therapeutic success is the infiltration of tumors by cells of the myeloid lineage. The inhibitory receptor signal regulatory protein-alpha (SIRPalpha) is a myeloid-specific immune checkpoint that engages the "don't eat me" signal CD47 expressed on tumors and normal tissues. We therefore developed the monoclonal antibody KWAR23, which binds human SIRPalpha with high affinity and disrupts its binding to CD47. Administered by itself, KWAR23 is inert, but given in combination with tumor-opsonizing monoclonal antibodies, KWAR23 greatly augments myeloid cell-dependent killing of a collection of hematopoietic and nonhematopoietic human tumor-derived cell lines. Following KWAR23 antibody treatment in a human SIRPA knockin mouse model, both neutrophils and macrophages infiltrate a human Burkitt's lymphoma xenograft and inhibit tumor growth, generating complete responses in the majority of treated animals. We further demonstrate that a bispecific anti-CD70/SIRPalpha antibody outperforms individually delivered antibodies in specific types of cancers. These studies demonstrate that SIRPalpha blockade induces potent antitumor activity by targeting multiple myeloid cell subsets that frequently infiltrate tumors. Thus, KWAR23 represents a promising candidate for combination therapy. PMID- 29158382 TI - Active turbulence in a gas of self-assembled spinners. AB - Colloidal particles subject to an external periodic forcing exhibit complex collective behavior and self-assembled patterns. A dispersion of magnetic microparticles confined at the air-liquid interface and energized by a uniform uniaxial alternating magnetic field exhibits dynamic arrays of self-assembled spinners rotating in either direction. Here, we report on experimental and simulation studies of active turbulence and transport in a gas of self-assembled spinners. We show that the spinners, emerging as a result of spontaneous symmetry breaking of clock/counterclockwise rotation of self-assembled particle chains, generate vigorous vortical flows at the interface. An ensemble of spinners exhibits chaotic dynamics due to self-generated advection flows. The same chirality spinners (clockwise or counterclockwise) show a tendency to aggregate and form dynamic clusters. Emergent self-induced interface currents promote active diffusion that could be tuned by the parameters of the external excitation field. Furthermore, the erratic motion of spinners at the interface generates chaotic fluid flow reminiscent of 2D turbulence. Our work provides insight into fundamental aspects of collective transport in active spinner materials and yields rules for particle manipulation at the microscale. PMID- 29158383 TI - Optimal nutrient exchange and immune responses operate in partner specificity in the cnidarian-dinoflagellate symbiosis. AB - The relationship between corals and dinoflagellates of the genus Symbiodinium is fundamental to the functioning of coral ecosystems. It has been suggested that reef corals may adapt to climate change by changing their dominant symbiont type to a more thermally tolerant one, although the capacity for such a shift is potentially hindered by the compatibility of different host-symbiont pairings. Here we combined transcriptomic and metabolomic analyses to characterize the molecular, cellular, and physiological processes that underlie this compatibility, with a particular focus on Symbiodinium trenchii, an opportunistic, thermally tolerant symbiont that flourishes in coral tissues after bleaching events. Symbiont-free individuals of the sea anemone Exaiptasia pallida (commonly referred to as Aiptasia), an established model system for the study of the cnidarian-dinoflagellate symbiosis, were colonized with the "normal" (homologous) symbiont Symbiodinium minutum and the heterologous S. trenchii Analysis of the host gene and metabolite expression profiles revealed that heterologous symbionts induced an expression pattern intermediate between the typical symbiotic state and the aposymbiotic state. Furthermore, integrated pathway analysis revealed that increased catabolism of fixed carbon stores, metabolic signaling, and immune processes occurred in response to the heterologous symbiont type. Our data suggest that both nutritional provisioning and the immune response induced by the foreign "invader" are important factors in determining the capacity of corals to adapt to climate change through the establishment of novel symbioses. PMID- 29158384 TI - Trunk neural crest origin of dermal denticles in a cartilaginous fish. AB - Cartilaginous fishes (e.g., sharks and skates) possess a postcranial dermal skeleton consisting of tooth-like "denticles" embedded within their skin. As with teeth, the principal skeletal tissue of dermal denticles is dentine. In the head, cranial neural crest cells give rise to the dentine-producing cells (odontoblasts) of teeth. However, trunk neural crest cells are generally regarded as nonskeletogenic, and so the embryonic origin of trunk denticle odontoblasts remains unresolved. Here, we use expression of FoxD3 to pinpoint the specification and emigration of trunk neural crest cells in embryos of a cartilaginous fish, the little skate (Leucoraja erinacea). Using cell lineage tracing, we further demonstrate that trunk neural crest cells do, in fact, give rise to odontoblasts of trunk dermal denticles. These findings expand the repertoire of vertebrate trunk neural crest cell fates during normal development, highlight the likely primitive skeletogenic potential of this cell population, and point to a neural crest origin of dentine throughout the ancestral vertebrate dermal skeleton. PMID- 29158385 TI - Correction for Wang et al., Heterochronic truncation of odontogenesis in theropod dinosaurs provides insight into the macroevolution of avian beaks. PMID- 29158386 TI - Cholesterol-binding site of the influenza M2 protein in lipid bilayers from solid state NMR. AB - The influenza M2 protein not only forms a proton channel but also mediates membrane scission in a cholesterol-dependent manner to cause virus budding and release. The atomic interaction of cholesterol with M2, as with most eukaryotic membrane proteins, has long been elusive. We have now determined the cholesterol binding site of the M2 protein in phospholipid bilayers using solid-state NMR spectroscopy. Chain-fluorinated cholesterol was used to measure cholesterol proximity to M2 while sterol-deuterated cholesterol was used to measure bound cholesterol orientation in lipid bilayers. Carbon-fluorine distance measurements show that at a cholesterol concentration of 17 mol%, two cholesterol molecules bind each M2 tetramer. Cholesterol binds the C-terminal transmembrane (TM) residues, near an amphipathic helix, without requiring a cholesterol recognition sequence motif. Deuterium NMR spectra indicate that bound cholesterol is approximately parallel to the bilayer normal, with the rough face of the sterol rings apposed to methyl-rich TM residues. The distance- and orientation restrained cholesterol-binding site structure shows that cholesterol is stabilized by hydrophobic interactions with the TM helix and polar and aromatic interactions with neighboring amphipathic helices. At the 1:2 binding stoichiometry, lipid 31P spectra show an isotropic peak indicative of high membrane curvature. This M2-cholesterol complex structure, together with previously observed M2 localization at phase boundaries, suggests that cholesterol mediates M2 clustering to the neck of the budding virus to cause the necessary curvature for membrane scission. The solid-state NMR approach developed here is generally applicable for elucidating the structural basis of cholesterol's effects on membrane protein function. PMID- 29158388 TI - Mixed-order phase transition in a colloidal crystal. AB - Mixed-order phase transitions display a discontinuity in the order parameter like first-order transitions yet feature critical behavior like second-order transitions. Such transitions have been predicted for a broad range of equilibrium and nonequilibrium systems, but their experimental observation has remained elusive. Here, we analytically predict and experimentally realize a mixed-order equilibrium phase transition. Specifically, a discontinuous solid solid transition in a 2D crystal of paramagnetic colloidal particles is induced by a magnetic field [Formula: see text] At the transition field [Formula: see text], the energy landscape of the system becomes completely flat, which causes diverging fluctuations and correlation length [Formula: see text] Mean-field critical exponents are predicted, since the upper critical dimension of the transition is [Formula: see text] Our colloidal system provides an experimental test bed to probe the unconventional properties of mixed-order phase transitions. PMID- 29158387 TI - Retrograde inhibition by a specific subset of interpeduncular alpha5 nicotinic neurons regulates nicotine preference. AB - Repeated exposure to drugs of abuse can produce adaptive changes that lead to the establishment of dependence. It has been shown that allelic variation in the alpha5 nicotinic acetylcholine receptor (nAChR) gene CHRNA5 is associated with higher risk of tobacco dependence. In the brain, alpha5-containing nAChRs are expressed at very high levels in the interpeduncular nucleus (IPN). Here we identified two nonoverlapping alpha5 + cell populations (alpha5- Amigo1 and alpha5- Epyc ) in mouse IPN that respond differentially to nicotine. Chronic nicotine treatment altered the translational profile of more than 1,000 genes in alpha5- Amigo1 neurons, including neuronal nitric oxide synthase (Nos1) and somatostatin (Sst). In contrast, expression of few genes was altered in the alpha5- Epyc population. We show that both nitric oxide and SST suppress optically evoked neurotransmitter release from the terminals of habenular (Hb) neurons in IPN. Moreover, in vivo silencing of neurotransmitter release from the alpha5- Amigo1 but not from the alpha5- Epyc population eliminates nicotine reward, measured using place preference. This loss of nicotine reward was mimicked by shRNA-mediated knockdown of Nos1 in the IPN. These findings reveal a proaddiction adaptive response to chronic nicotine in which nitric oxide and SST are released by a specific alpha5+ neuronal population to provide retrograde inhibition of the Hb-IPN circuit and thereby enhance the motivational properties of nicotine. PMID- 29158389 TI - Burkholderia cenocepacia integrates cis-2-dodecenoic acid and cyclic dimeric guanosine monophosphate signals to control virulence. AB - Quorum sensing (QS) signals are used by bacteria to regulate biological functions in response to cell population densities. Cyclic diguanosine monophosphate (c-di GMP) regulates cell functions in response to diverse environmental chemical and physical signals that bacteria perceive. In Burkholderia cenocepacia, the QS signal receptor RpfR degrades intracellular c-di-GMP when it senses the QS signal cis-2-dodecenoic acid, also called Burkholderia diffusible signal factor (BDSF), as a proxy for high cell density. However, it was unclear how this resulted in control of BDSF-regulated phenotypes. Here, we found that RpfR forms a complex with a regulator named GtrR (BCAL1536) to enhance its binding to target gene promoters under circumstances where the BDSF signal binds to RpfR to stimulate its c-di-GMP phosphodiesterase activity. In the absence of BDSF, c-di-GMP binds to the RpfR-GtrR complex and inhibits its ability to control gene expression. Mutations in rpfR and gtrR had overlapping effects on both the B. cenocepacia transcriptome and BDSF-regulated phenotypes, including motility, biofilm formation, and virulence. These results show that RpfR is a QS signal receptor that also functions as a c-di-GMP sensor. This protein thus allows B. cenocepacia to integrate information about its physical and chemical surroundings as well as its population density to control diverse biological functions including virulence. This type of QS system appears to be widely distributed in beta and gamma proteobacteria. PMID- 29158390 TI - Additive effects of climate and fisheries drive ongoing declines in multiple albatross species. AB - Environmental and anthropogenic factors often drive population declines in top predators, but how their influences may combine remains unclear. Albatrosses are particularly threatened. They breed in fast-changing environments, and their extensive foraging ranges expose them to incidental mortality (bycatch) in multiple fisheries. The albatross community at South Georgia includes globally important populations of three species that have declined by 40-60% over the last 35 years. We used three steps to deeply understand the drivers of such dramatic changes: (i) describe fundamental demographic rates using multievent models, (ii) determine demographic drivers of population growth using matrix models, and (iii) identify environmental and anthropogenic drivers using ANOVAs. Each species was affected by different processes and threats in their foraging areas during the breeding and nonbreeding seasons. There was evidence for two kinds of combined environmental and anthropogenic effects. The first was sequential; in wandering and black-browed albatrosses, high levels of bycatch have reduced juvenile and adult survival, then increased temperature, reduced sea-ice cover, and stronger winds are affecting the population recovery potential. The second was additive; in gray-headed albatrosses, not only did bycatch impact adult survival but also this impact was exacerbated by lower food availability in years following El Nino events. This emphasizes the need for much improved implementation of mitigation measures in fisheries and better enforcement of compliance. We hope our results not only help focus future management actions for these populations but also demonstrate the power of the modelling approach for assessing impacts of environmental and anthropogenic drivers in wild animal populations. PMID- 29158391 TI - Maternal prolactin during late pregnancy is important in generating nurturing behavior in the offspring. AB - Although maternal nurturing behavior is extremely important for the preservation of a species, our knowledge of the biological underpinnings of these behaviors is insufficient. Here we show that the degree of a mother's nurturing behavior is regulated by factors present during her own fetal development. We found that Cin85-deficient (Cin85-/-) mother mice had reduced pituitary hormone prolactin (PRL) secretion as a result of excessive dopamine signaling in the brain. Their offspring matured normally and produced their own pups; however, nurturing behaviors such as pup retrieval and nursing were strongly inhibited. Surprisingly, when WT embryos were transplanted into the fallopian tubes of Cin85 /- mice, they also exhibited inhibited nurturing behavior as adults. Conversely, when Cin85-/- embryos were transplanted into the fallopian tubes of WT mice, the resultant pups exhibited normal nurturing behaviors as adults. When PRL was administered to Cin85-/- mice during late pregnancy, a higher proportion of the resultant pups exhibited nurturing behaviors as adults. This correlates with our findings that neural circuitry associated with nurturing behaviors was less active in pups born to Cin85-/- mothers, but PRL administration to mothers restored neural activity to normal levels. These results suggest that the prenatal period is extremely important in determining the expression of nurturing behaviors in the subsequent generation, and that maternal PRL is one of the critical factors for expression. In conclusion, perinatally secreted maternal PRL affects the expression of nurturing behaviors not only in a mother, but also in her pups when they have reached adulthood. PMID- 29158392 TI - High postural costs and anaerobic metabolism during swimming support the hypothesis of a U-shaped metabolism-speed curve in fishes. AB - Swimming performance is considered a key trait determining the ability of fish to survive. Hydrodynamic theory predicts that the energetic costs required for fishes to swim should vary with speed according to a U-shaped curve, with an expected energetic minimum at intermediate cruising speeds and increasing expenditure at low and high speeds. However, to date no complete datasets have shown an energetic minimum for swimming fish at intermediate speeds rather than low speeds. To address this knowledge gap, we used a negatively buoyant fish, the clearnose skate Raja eglanteria, and took two approaches: a classic critical swimming speed protocol and a single-speed exercise and recovery procedure. We found an anaerobic component at each velocity tested. The two approaches showed U shaped, though significantly different, speed-metabolic relationships. These results suggest that (i) postural costs, especially at low speeds, may result in J- or U-shaped metabolism-speed curves; (ii) anaerobic metabolism is involved at all swimming speeds in the clearnose skate; and (iii) critical swimming protocols might misrepresent the true costs of locomotion across speeds, at least in negatively buoyant fish. PMID- 29158393 TI - Dynamics and control of gold-encapped gallium arsenide nanowires imaged by 4D electron microscopy. AB - Eutectic-related reaction is a special chemical/physical reaction involving multiple phases, solid and liquid. Visualization of a phase reaction of composite nanomaterials with high spatial and temporal resolution provides a key understanding of alloy growth with important industrial applications. However, it has been a rather challenging task. Here, we report the direct imaging and control of the phase reaction dynamics of a single, as-grown free-standing gallium arsenide nanowire encapped with a gold nanoparticle, free from environmental confinement or disturbance, using four-dimensional (4D) electron microscopy. The nondestructive preparation of as-grown free-standing nanowires without supporting films allows us to study their anisotropic properties in their native environment with better statistical character. A laser heating pulse initiates the eutectic-related reaction at a temperature much lower than the melting points of the composite materials, followed by a precisely time-delayed electron pulse to visualize the irreversible transient states of nucleation, growth, and solidification of the complex. Combined with theoretical modeling, useful thermodynamic parameters of the newly formed alloy phases and their crystal structures could be determined. This technique of dynamical control aided by 4D imaging of phase reaction processes on the nanometer-ultrafast time scale opens new venues for engineering various reactions in a wide variety of other systems. PMID- 29158394 TI - Correction for Mann, News Feature: Lighting the way for dark matter. PMID- 29158395 TI - Histone methyltransferase MMSET promotes AID-mediated DNA breaks at the donor switch region during class switch recombination. AB - In B cells, Ig class switch recombination (CSR) is initiated by activation induced cytidine deaminase (AID), the activity of which leads to DNA double strand breaks (DSBs) within IgH switch (S) regions. Preferential targeting of AID mediated DSBs to S sequences is critical for allowing diversification of antibody functions, while minimizing potential off-target oncogenic events. Here, we used gene targeted inactivation of histone methyltransferase (HMT) multiple myeloma SET domain (MMSET) in mouse B cells and the CH12F3 cell line to explore its role in CSR. We find that deletion of MMSET-II, the isoform containing the catalytic SET domain, inhibits CSR without affecting either IgH germline transcription or joining of DSBs within S regions by classical nonhomologous end joining (C-NHEJ). Instead, we find that MMSET-II inactivation leads to decreased AID recruitment and DSBs at the upstream donor SMU region. Our findings suggest a role for the HMT MMSET in promoting AID-mediated DNA breaks during CSR. PMID- 29158397 TI - Wetter subtropics in a warmer world: Contrasting past and future hydrological cycles. AB - During the warm Miocene and Pliocene Epochs, vast subtropical regions had enough precipitation to support rich vegetation and fauna. Only with global cooling and the onset of glacial cycles some 3 Mya, toward the end of the Pliocene, did the broad patterns of arid and semiarid subtropical regions become fully developed. However, current projections of future global warming caused by CO2 rise generally suggest the intensification of dry conditions over these subtropical regions, rather than the return to a wetter state. What makes future projections different from these past warm climates? Here, we investigate this question by comparing a typical quadrupling-of-CO2 experiment with a simulation driven by sea surface temperatures closely resembling available reconstructions for the early Pliocene. Based on these two experiments and a suite of other perturbed climate simulations, we argue that this puzzle is explained by weaker atmospheric circulation in response to the different ocean surface temperature patterns of the Pliocene, specifically reduced meridional and zonal temperature gradients. Thus, our results highlight that accurately predicting the response of the hydrological cycle to global warming requires predicting not only how global mean temperature responds to elevated CO2 forcing (climate sensitivity) but also accurately quantifying how meridional sea-surface temperature patterns will change (structural climate sensitivity). PMID- 29158396 TI - EMT programs promote basal mammary stem cell and tumor-initiating cell stemness by inducing primary ciliogenesis and Hedgehog signaling. AB - Tissue regeneration relies on adult stem cells (SCs) that possess the ability to self-renew and produce differentiating progeny. In an analogous manner, the development of certain carcinomas depends on a small subset of tumor cells, called "tumor-initiating cells" (TICs), with SC-like properties. Mammary SCs (MaSCs) reside in the basal compartment of the mammary epithelium, and their neoplastic counterparts, mammary TICs (MaTICs), are thought to serve as the TICs for the claudin-low subtype of breast cancer. MaSCs and MaTICs both use epithelial-mesenchymal transition (EMT) programs to acquire SC properties, but the mechanism(s) connecting EMT programs to stemness remain unclear. Here we show that this depends on primary cilia, which are nonmotile, cell-surface structures that serve as platforms for receiving cues and enable activation of various signaling pathways. We show that MaSC and MaTIC EMT programs induce primary cilia formation and Hedgehog (Hh) signaling, which has previously been implicated in both MaSC and MaTIC function. Moreover, ablation of these primary cilia is sufficient to repress Hh signaling, the stemness of MaSCs, and the tumor-forming potential of MaTICs. Together, our findings establish primary ciliogenesis and consequent Hh signaling as a key mechanism by which MaSC and MaTIC EMT programs promote stemness and thereby support mammary tissue outgrowth and tumors of basal origin. PMID- 29158398 TI - Model-driven engineering of supramolecular buffering by multivalency. AB - A supramolecular system in which the concentration of a molecule is buffered over several orders of magnitude is presented. Molecular buffering is achieved as a result of competition in a ring-chain equilibrium of multivalent ureidopyrimidinone monomers and a monovalent naphthyridine molecule which acts as an end-capper. While we previously only considered divalent ureidopyrimidinone monomers we now present a model-driven engineering approach to improve molecular buffering using multivalent ring-chain systems. Our theoretical models reveal an odd-even effect where even-valent molecules show superior buffering capabilities. Furthermore, we predict that supramolecular buffering can be significantly improved using a tetravalent instead of a divalent molecule, since the tetravalent molecule can form two intramolecular rings with different "stabilities" due to statistical effects. Our model predictions are validated against experimental 1H NMR data, demonstrating that model-driven engineering has considerable potential in supramolecular chemistry. PMID- 29158399 TI - Nature and origins of the lexicon in 6-mo-olds. AB - Recent research reported the surprising finding that even 6-mo-olds understand common nouns [Bergelson E, Swingley D (2012) Proc Natl Acad Sci USA 109:3253 3258]. However, is their early lexicon structured and acquired like older learners? We test 6-mo-olds for a hallmark of the mature lexicon: cross-word relations. We also examine whether properties of the home environment that have been linked with lexical knowledge in older children are detectable in the initial stage of comprehension. We use a new dataset, which includes in-lab comprehension and home measures from the same infants. We find evidence for cross word structure: On seeing two images of common nouns, infants looked significantly more at named target images when the competitor images were semantically unrelated (e.g., milk and foot) than when they were related (e.g., milk and juice), just as older learners do. We further find initial evidence for home-lab links: common noun "copresence" (i.e., whether words' referents were present and attended to in home recordings) correlated with in-lab comprehension. These findings suggest that, even in neophyte word learners, cross-word relations are formed early and the home learning environment measurably helps shape the lexicon from the outset. PMID- 29158400 TI - Drosophila protein phosphatases 2A B' Wdb and Wrd regulate meiotic centromere localization and function of the MEI-S332 Shugoshin. AB - Proper segregation of chromosomes in meiosis is essential to prevent miscarriages and birth defects. This requires that sister chromatids maintain cohesion at the centromere as cohesion is released on the chromatid arms when the homologs segregate at anaphase I. The Shugoshin proteins preserve centromere cohesion by protecting the cohesin complex from cleavage, and this has been shown in yeasts to be mediated by recruitment of the protein phosphatase 2A B' (PP2A B'). In metazoans, delineation of the role of PP2A B' in meiosis has been hindered by its myriad of other essential roles. The Drosophila Shugoshin MEI-S332 can bind directly to both of the B' regulatory subunits of PP2A, Wdb and Wrd, in yeast two hybrid experiments. Exploiting experimental advantages of Drosophila spermatogenesis, we found that the Wdb subunit localizes first along chromosomes in meiosis I, becoming restricted to the centromere region as MEI-S332 binds. Wdb and MEI-S332 show colocalization at the centromere region until release of sister chromatid cohesion at the metaphase II/anaphase II transition. MEI-S332 is necessary for Wdb localization, but, additionally, both Wdb and Wrd are required for MEI-S332 localization. Thus, rather than MEI-S332 being hierarchical to PP2A B', these proteins reciprocally ensure centromere localization of the complex. We analyzed functional relationships between MEI-S332 and the two forms of PP2A by quantifying meiotic chromosome segregation defects in double or triple mutants. These studies revealed that both Wdb and Wrd contribute to MEI-S332's ability to ensure accurate segregation of sister chromatids, but, as in centromere localization, they do not act solely downstream of MEI-S332. PMID- 29158401 TI - Kinesin-dependent mechanism for controlling triglyceride secretion from the liver. AB - Despite massive fluctuations in its internal triglyceride content, the liver secretes triglyceride under tight homeostatic control. This buffering function is most visible after fasting, when liver triglyceride increases manyfold but circulating serum triglyceride barely fluctuates. How the liver controls triglyceride secretion is unknown, but is fundamentally important for lipid and energy homeostasis in animals. Here we find an unexpected cellular and molecular mechanism behind such control. We show that kinesin motors are recruited to triglyceride-rich lipid droplets (LDs) in the liver by the GTPase ARF1, which is a key activator of lipolysis. This recruitment is activated by an insulin dependent pathway and therefore responds to fed/fasted states of the animal. In fed state, ARF1 and kinesin appear on LDs, consequently transporting LDs to the periphery of hepatocytes where the smooth endoplasmic reticulum (sER) is present. Because the lipases that catabolize LDs in hepatocytes reside on the sER, LDs can now be catabolized efficiently to provide triglyceride for lipoprotein assembly and secretion from the sER. Upon fasting, insulin is lowered to remove ARF1 and kinesin from LDs, thus down-regulating LD transport and sER-LD contacts. This tempers triglyceride availabiity for very low density lipoprotein assembly and allows homeostatic control of serum triglyceride in a fasted state. We further show that kinesin knockdown inhibits hepatitis-C virus replication in hepatocytes, likely because translated viral proteins are unable to transfer from the ER to LDs. PMID- 29158403 TI - Beating the curse of dimension with accurate statistics for the Fokker-Planck equation in complex turbulent systems. AB - Solving the Fokker-Planck equation for high-dimensional complex dynamical systems is an important issue. Recently, the authors developed efficient statistically accurate algorithms for solving the Fokker-Planck equations associated with high dimensional nonlinear turbulent dynamical systems with conditional Gaussian structures, which contain many strong non-Gaussian features such as intermittency and fat-tailed probability density functions (PDFs). The algorithms involve a hybrid strategy with a small number of samples [Formula: see text], where a conditional Gaussian mixture in a high-dimensional subspace via an extremely efficient parametric method is combined with a judicious Gaussian kernel density estimation in the remaining low-dimensional subspace. In this article, two effective strategies are developed and incorporated into these algorithms. The first strategy involves a judicious block decomposition of the conditional covariance matrix such that the evolutions of different blocks have no interactions, which allows an extremely efficient parallel computation due to the small size of each individual block. The second strategy exploits statistical symmetry for a further reduction of [Formula: see text] The resulting algorithms can efficiently solve the Fokker-Planck equation with strongly non-Gaussian PDFs in much higher dimensions even with orders in the millions and thus beat the curse of dimension. The algorithms are applied to a [Formula: see text] dimensional stochastic coupled FitzHugh-Nagumo model for excitable media. An accurate recovery of both the transient and equilibrium non-Gaussian PDFs requires only [Formula: see text] samples! In addition, the block decomposition facilitates the algorithms to efficiently capture the distinct non-Gaussian features at different locations in a [Formula: see text]-dimensional two-layer inhomogeneous Lorenz 96 model, using only [Formula: see text] samples. PMID- 29158402 TI - Structural insights into enzymatic [4+2] aza-cycloaddition in thiopeptide antibiotic biosynthesis. AB - The [4+2] cycloaddition reaction is an enabling transformation in modern synthetic organic chemistry, but there are only limited examples of dedicated natural enzymes that can catalyze this transformation. Thiopeptides (or more formally thiazolyl peptides) are a class of thiazole-containing, highly modified, macrocyclic secondary metabolites made from ribosomally synthesized precursor peptides. The characteristic feature of these natural products is a six-membered nitrogenous heterocycle that is assembled via a formal [4+2] cycloaddition between two dehydroalanine (Dha) residues. This heteroannulation is entirely contingent on enzyme activity, although the mechanism of the requisite pyridine/dehydropiperidine synthase remains to be elucidated. The unusual aza cylic product is distinct from the more common carbocyclic products of synthetic and biosynthetic [4+2] cycloaddition reactions. To elucidate the mechanism of cycloaddition, we have determined atomic resolution structures of the pyridine synthases involved in the biosynthesis of the thiopeptides thiomuracin (TbtD) and GE2270A (PbtD), in complex with substrates and product analogs. Structure-guided biochemical, mutational, computational, and binding studies elucidate active-site features that explain how orthologs can generate rigid macrocyclic scaffolds of different sizes. Notably, the pyridine synthases show structural similarity to the elimination domain of lanthipeptide dehydratases, wherein insertions of secondary structural elements result in the formation of a distinct active site that catalyzes different chemistry. Comparative analysis identifies other catalysts that contain a shared core protein fold but whose active sites are located in entirely different regions, illustrating a principle predicted from efforts in de novo protein design. PMID- 29158404 TI - CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in TB granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells. PMID- 29158405 TI - Origin, evolution, and global transmission of community-acquired Staphylococcus aureus ST8. AB - USA300 is a pandemic clonal lineage of hypervirulent, community-acquired, methicillin-resistant Staphylococcus aureus (CA-MRSA) with specific molecular characteristics. Despite its high clinical relevance, the evolutionary origin of USA300 remained unclear. We used comparative genomics of 224 temporal and spatial diverse S. aureus isolates of multilocus sequence type (ST) 8 to reconstruct the molecular evolution and global dissemination of ST8, including USA300. Analyses of core SNP diversity and accessory genome variations showed that the ancestor of all ST8 S. aureus most likely emerged in Central Europe in the mid-19th century. From here, ST8 was exported to North America in the early 20th century and progressively acquired the USA300 characteristics Panton-Valentine leukocidin (PVL), SCCmec IVa, the arginine catabolic mobile element (ACME), and a specific mutation in capsular polysaccharide gene cap5E Although the PVL-encoding phage phiSa2USA was introduced into the ST8 background only once, various SCCmec types were introduced to ST8 at different times and places. Starting from North America, USA300 spread globally, including Africa. African USA300 isolates have aberrant spa-types (t112, t121) and form a monophyletic group within the clade of North American USA300. Large parts of ST8 methicillin-susceptible S. aureus (MSSA) isolated in Africa represent a symplesiomorphic group of ST8 (i.e., a group representing the characteristics of the ancestor), which are rarely found in other world regions. Isolates previously discussed as USA300 ancestors, including USA500 and a "historic" CA-MRSA from Western Australia, were shown to be only distantly related to recent USA300 clones. PMID- 29158407 TI - Dynamics of a rolling robot. AB - Equations describing the rolling of a spherical ball on a horizontal surface are obtained, the motion being activated by an internal rotor driven by a battery mechanism. The rotor is modeled as a point mass mounted inside a spherical shell and caused to move in a prescribed circular orbit relative to the shell. The system is described in terms of four independent dimensionless parameters. The equations governing the angular momentum of the ball relative to the point of contact with the plane constitute a six-dimensional, nonholonomic, nonautonomous dynamical system with cubic nonlinearity. This system is decoupled from a subsidiary system that describes the trajectories of the center of the ball. Numerical integration of these equations for prescribed values of the parameters and initial conditions reveals a tendency toward chaotic behavior as the radius of the circular orbit of the point mass increases (other parameters being held constant). It is further shown that there is a range of values of the initial angular velocity of the shell for which chaotic trajectories are realized while contact between the shell and the plane is maintained. The predicted behavior has been observed in our experiments. PMID- 29158406 TI - Transcriptome-wide characterization of human cytomegalovirus in natural infection and experimental latency. AB - The transcriptional program associated with herpesvirus latency and the viral genes regulating entry into and exit from latency are poorly understood and controversial. Here, we developed and validated a targeted enrichment platform and conducted large-scale transcriptome analyses of human cytomegalovirus (HCMV) infection. We used both an experimental hematopoietic cell model of latency and cells from naturally infected, healthy human subjects (clinical) to define the breadth of viral genes expressed. The viral transcriptome derived from experimental infection was highly correlated with that from clinical infection, validating our experimental latency model. These transcriptomes revealed a broader profile of gene expression during infection in hematopoietic cells than previously appreciated. Further, using recombinant viruses that establish a nonreactivating, latent-like or a replicative infection in CD34+ hematopoietic progenitor cells, we defined classes of low to moderately expressed genes that are differentially regulated in latent vs. replicative states of infection. Most of these genes have yet to be studied in depth. By contrast, genes that were highly expressed, were expressed similarly in both latent and replicative infection. From these findings, a model emerges whereby low or moderately expressed genes may have the greatest impact on regulating the switch between viral latency and replication. The core set of viral genes expressed in natural infection and differentially regulated depending on the pattern of infection provides insight into the HCMV transcriptome associated with latency in the host and a resource for investigating virus-host interactions underlying persistence. PMID- 29158408 TI - Correction for Wang et al., Assembly of silver Trigons into a buckyball-like Ag180 nanocage. PMID- 29158410 TI - Correction for Coghill et al., Neural correlates of interindividual differences in the subjective experience of pain. PMID- 29158409 TI - Hydrophobicity of proteins and nanostructured solutes is governed by topographical and chemical context. AB - Hydrophobic interactions drive many important biomolecular self-assembly phenomena. However, characterizing hydrophobicity at the nanoscale has remained a challenge due to its nontrivial dependence on the chemistry and topography of biomolecular surfaces. Here we use molecular simulations coupled with enhanced sampling methods to systematically displace water molecules from the hydration shells of nanostructured solutes and calculate the free energetics of interfacial water density fluctuations, which quantify the extent of solute-water adhesion, and therefore solute hydrophobicity. In particular, we characterize the hydrophobicity of curved graphene sheets, self-assembled monolayers (SAMs) with chemical patterns, and mutants of the protein hydrophobin-II. We find that water density fluctuations are enhanced near concave nonpolar surfaces compared with those near flat or convex ones, suggesting that concave surfaces are more hydrophobic. We also find that patterned SAMs and protein mutants, having the same number of nonpolar and polar sites but different geometrical arrangements, can display significantly different strengths of adhesion with water. Specifically, hydroxyl groups reduce the hydrophobicity of methyl-terminated SAMs most effectively not when they are clustered together but when they are separated by one methyl group. Hydrophobin-II mutants show that a charged amino acid reduces the hydrophobicity of a large nonpolar patch when placed at its center, rather than at its edge. Our results highlight the power of water density fluctuations-based measures to characterize the hydrophobicity of nanoscale surfaces and caution against the use of additive approximations, such as the commonly used surface area models or hydropathy scales for characterizing biomolecular hydrophobicity and the associated driving forces of assembly. PMID- 29158411 TI - Holocene fluctuations in human population demonstrate repeated links to food production and climate. AB - We consider the long-term relationship between human demography, food production, and Holocene climate via an archaeological radiocarbon date series of unprecedented sampling density and detail. There is striking consistency in the inferred human population dynamics across different regions of Britain and Ireland during the middle and later Holocene. Major cross-regional population downturns in population coincide with episodes of more abrupt change in North Atlantic climate and witness societal responses in food procurement as visible in directly dated plants and animals, often with moves toward hardier cereals, increased pastoralism, and/or gathered resources. For the Neolithic, this evidence questions existing models of wholly endogenous demographic boom-bust. For the wider Holocene, it demonstrates that climate-related disruptions have been quasi-periodic drivers of societal and subsistence change. PMID- 29158412 TI - Induced GnasR201H expression from the endogenous Gnas locus causes fibrous dysplasia by up-regulating Wnt/beta-catenin signaling. AB - Fibrous dysplasia (FD; Online Mendelian Inheritance in Man no. 174800) is a crippling skeletal disease caused by activating mutations of the GNAS gene, which encodes the stimulatory G protein Galphas FD can lead to severe adverse conditions such as bone deformity, fracture, and severe pain, leading to functional impairment and wheelchair confinement. So far there is no cure, as the underlying molecular and cellular mechanisms remain largely unknown and the lack of appropriate animal models has severely hampered FD research. Here we have investigated the cellular and molecular mechanisms underlying FD and tested its potential treatment by establishing a mouse model in which the human FD mutation (R201H) has been conditionally knocked into the corresponding mouse Gnas locus. We found that the germ-line FD mutant was embryonic lethal, and Cre-induced Gnas FD mutant expression in early osteochondral progenitors, osteoblast cells, or bone marrow stromal cells (BMSCs) recapitulated FD features. In addition, mosaic expression of FD mutant Galphas in BMSCs induced bone marrow fibrosis both cell autonomously and non-cell autonomously. Furthermore, Wnt/beta-catenin signaling was up-regulated in FD mutant mouse bone and BMSCs undergoing osteogenic differentiation, as we have found in FD human tissue previously. Reduction of Wnt/beta-catenin signaling by removing one Lrp6 copy in an FD mutant line significantly rescued the phenotypes. We demonstrate that induced expression of the FD Galphas mutant from the mouse endogenous Gnas locus exhibits human FD phenotypes in vivo, and that inhibitors of Wnt/beta-catenin signaling may be repurposed for treating FD and other bone diseases caused by Galphas activation. PMID- 29158413 TI - Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease. AB - The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-beta peptide (Abeta) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Abeta can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of beta-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Abeta nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Abeta plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Abeta-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Abeta among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Abeta conformation and clinical phenotype. PMID- 29158414 TI - Molecular basis of selective resistance of the bumblebee BiNav1 sodium channel to tau-fluvalinate. AB - Insecticides are widely used to control pests in agriculture and insect vectors that transmit human diseases. However, these chemicals can have a negative effect on nontarget, beneficial organisms including bees. Discovery and deployment of selective insecticides is a major mission of modern toxicology and pest management. Pyrethroids exert their toxic action by acting on insect voltage gated sodium channels. Honeybees and bumblebees are highly sensitive to most pyrethroids, but are resistant to a particular pyrethroid, tau-fluvalinate (tau FVL). Because of its unique selectivity, tau-FVL is widely used to control not only agricultural pests but also varroa mites, the principal ectoparasite of honeybees. However, the mechanism of bee resistance to tau-FVL largely remains elusive. In this study, we functionally characterized the sodium channel BiNav1-1 from the common eastern bumblebee (Bombus impatiens) in Xenopus oocytes and found that the BiNav1-1 channel is highly sensitive to six commonly used pyrethroids, but resistant to tau-FVL. Phylogenetic and mutational analyses revealed that three residues, which are conserved in sodium channels from 12 bee species, underlie resistance to tau-FVL or sensitivity to the other pyrethroids. Further computer modeling and mutagenesis uncovered four additional residues in the pyrethroid receptor sites that contribute to the unique selectivity of the bumblebee sodium channel to tau-FVL versus other pyrethroids. Our data contribute to understanding a long-standing enigma of selective pyrethroid toxicity in bees and may be used to guide future modification of pyrethroids to achieve highly selective control of pests with minimal effects on nontarget organisms. PMID- 29158415 TI - Long-term dopamine neurochemical monitoring in primates. AB - Many debilitating neuropsychiatric and neurodegenerative disorders are characterized by dopamine neurotransmitter dysregulation. Monitoring subsecond dopamine release accurately and for extended, clinically relevant timescales is a critical unmet need. Especially valuable has been the development of electrochemical fast-scan cyclic voltammetry implementing microsized carbon fiber probe implants to record fast millisecond changes in dopamine concentrations. Nevertheless, these well-established methods have only been applied in primates with acutely (few hours) implanted sensors. Neurochemical monitoring for long timescales is necessary to improve diagnostic and therapeutic procedures for a wide range of neurological disorders. Strategies for the chronic use of such sensors have recently been established successfully in rodents, but new infrastructures are needed to enable these strategies in primates. Here we report an integrated neurochemical recording platform for monitoring dopamine release from sensors chronically implanted in deep brain structures of nonhuman primates for over 100 days, together with results for behavior-related and stimulation induced dopamine release. From these chronically implanted probes, we measured dopamine release from multiple sites in the striatum as induced by behavioral performance and reward-related stimuli, by direct stimulation, and by drug administration. We further developed algorithms to automate detection of dopamine. These algorithms could be used to track the effects of drugs on endogenous dopamine neurotransmission, as well as to evaluate the long-term performance of the chronically implanted sensors. Our chronic measurements demonstrate the feasibility of measuring subsecond dopamine release from deep brain circuits of awake, behaving primates in a longitudinally reproducible manner. PMID- 29158417 TI - NOX2-Derived Reactive Oxygen Species Control Inflammation during Leishmania amazonensis Infection by Mediating Infection-Induced Neutrophil Apoptosis. AB - Reactive oxygen species (ROS) produced by NADPH phagocyte oxidase isoform (NOX2) are critical for the elimination of intracellular pathogens in many infections. Despite their importance, the role of ROS following infection with the eukaryotic pathogen Leishmania has not been fully elucidated. We addressed the role of ROS in C57BL/6 mice following intradermal infection with Leishmania amazonensis. Despite equivalent parasite loads compared with wild-type (WT) mice, mice deficient in ROS production by NOX2 due to the absence of the gp91 subunit (gp91phox-/-) had significantly more severe pathology in the later stages of infection. Pathology in gp91phox-/- mice was not associated with alterations in CD4+ T cell-mediated immunity but was preceded by enhanced neutrophil accumulation at the dermal infection site. Ex vivo analysis of infected versus uninfected neutrophils revealed a deficiency in infection-driven apoptosis in gp91phox-/- mice versus WT mice. gp91phox-/- mice presented with higher percentages of healthy or necrotic neutrophils but lower percentages of apoptotic neutrophils at early and chronic time points. In vitro infection of gp91phox-/- versus WT neutrophils also revealed reduced apoptosis and CD95 expression but increased necrosis in infected cells at 10 h postinfection. Provision of exogenous ROS in the form of H2O2 reversed the necrotic phenotype and restored CD95 expression on infected gp91phox-/- neutrophils. Although ROS production is typically viewed as a proinflammatory event, our observations identify the importance of ROS in mediating appropriate neutrophil apoptosis and the importance of apoptosis in inflammation and pathology during chronic infection. PMID- 29158416 TI - Tracking the genome-wide outcomes of a transposable element burst over decades of amplification. AB - To understand the success strategies of transposable elements (TEs) that attain high copy numbers, we analyzed two pairs of rice (Oryza sativa) strains, EG4/HEG4 and A119/A123, undergoing decades of rapid amplification (bursts) of the class 2 autonomous Ping element and the nonautonomous miniature inverted repeat transposable element (MITE) mPing Comparative analyses of whole-genome sequences of the two strain pairs validated that each pair has been maintained for decades as inbreds since divergence from their respective last common ancestor. Strains EG4 and HEG4 differ by fewer than 160 SNPs and a total of 264 new mPing insertions. Similarly, strains A119 and A123 exhibited about half as many SNPs (277) as new mPing insertions (518). Examination of all other potentially active TEs in these genomes revealed only a single new insertion out of ~40,000 loci surveyed. The virtual absence of any new TE insertions in these strains outside the mPing bursts demonstrates that the Ping/mPing family gradually attains high copy numbers by maintaining activity and evading host detection for dozens of generations. Evasion is possible because host recognition of mPing sequences appears to have no impact on initiation or maintenance of the burst. Ping is actively transcribed, and both Ping and mPing can transpose despite methylation of terminal sequences. This finding suggests that an important feature of MITE success is that host recognition does not lead to the silencing of the source of transposase. PMID- 29158418 TI - A Novel Pkhd1 Mutation Interacts with the Nonobese Diabetic Genetic Background To Cause Autoimmune Cholangitis. AB - We previously reported that NOD.c3c4 mice develop spontaneous autoimmune biliary disease (ABD) with anti-mitochondrial Abs, histopathological lesions, and autoimmune T lymphocytes similar to human primary biliary cholangitis. In this article, we demonstrate that ABD in NOD.c3c4 and related NOD ABD strains is caused by a chromosome 1 region that includes a novel mutation in polycystic kidney and hepatic disease 1 (Pkhd1). We show that a long terminal repeat element inserted into intron 35 exposes an alternative polyadenylation site, resulting in a truncated Pkhd1 transcript. A novel NOD congenic mouse expressing aberrant Pkhd1, but lacking the c3 and c4 chromosomal regions (NOD.Abd3), reproduces the immunopathological features of NOD ABD. RNA sequencing of NOD.Abd3 common bile duct early in disease demonstrates upregulation of genes involved in cholangiocyte injury/morphology and downregulation of immunoregulatory genes. Consistent with this, bone marrow chimera studies show that aberrant Pkhd1 must be expressed in the target tissue (cholangiocytes) and the immune system (bone marrow). Mutations of Pkhd1 produce biliary abnormalities in mice but have not been previously associated with autoimmunity. In this study, we eliminate clinical biliary disease by backcrossing this Pkhd1 mutation onto the C57BL/6 genetic background; thus, the NOD genetic background (which promotes autoimmunity) is essential for disease. We propose that loss of functional Pkhd1 on the NOD background produces early bile duct abnormalities, initiating a break in tolerance that leads to autoimmune cholangitis in NOD.Abd3 congenic mice. This model is important for understanding loss of tolerance to cholangiocytes and is relevant to the pathogenesis of several human cholangiopathies. PMID- 29158419 TI - Ultraviolet B-Induced Maturation of CD11b-Type Langerin- Dendritic Cells Controls the Expansion of Foxp3+ Regulatory T Cells in the Skin. AB - Skin dendritic cells (DCs) are divided into several subsets with distinctive functions. This study shows a previously unappreciated role of dermal CD11b-type Langerin- DCs in maintaining immunological self-tolerance after UVB exposure. After UVB exposure, dermal CD11b-type Langerin- DCs upregulated surface CD86 expression, induced proliferation of Foxp3+ regulatory T (Treg) cells without exogenous Ags, and upregulated a set of genes associated with immunological tolerance. This Treg-expansion activity was significantly hampered by CD80/CD86 blockade in vivo. These results indicate that CD11b-type Langerin- DCs from the UVB-exposed skin are specialized to expand Treg cells in the skin, which suppress autoimmunity. PMID- 29158420 TI - Superoxide Production by NADPH Oxidase Intensifies Macrophage Antiviral Responses during Diabetogenic Coxsackievirus Infection. AB - Coxsackievirus B infections are suspected environmental triggers of type 1 diabetes (T1D) and macrophage antiviral responses may provide a link to virus induced T1D. We previously demonstrated an important role for NADPH oxidase (NOX) derived superoxide production during T1D pathogenesis, as NOX-deficient NOD mice (NOD.Ncf1m1J ) were protected against T1D due, in part, to impaired proinflammatory TLR signaling in NOD.Ncf1m1J macrophages. Therefore, we hypothesized that loss of NOX-derived superoxide would dampen diabetogenic antiviral macrophage responses and protect from virus-induced diabetes. Upon infection with a suspected diabetogenic virus, Coxsackievirus B3 (CB3), NOD.Ncf1m1J mice remained resistant to virus-induced autoimmune diabetes. A concomitant decrease in circulating inflammatory chemokines, blunted antiviral gene signature within the pancreas, and reduced proinflammatory M1 macrophage responses were observed. Importantly, exogenous superoxide addition to CB3 infected NOD.Ncf1m1J bone marrow-derived macrophages rescued the inflammatory antiviral M1 macrophage response, revealing reduction-oxidation-dependent mechanisms of signal transducer and activator of transcription 1 signaling and dsRNA viral sensors in macrophages. We report that superoxide production following CB3 infection may exacerbate pancreatic beta cell destruction in T1D by influencing proinflammatory M1 macrophage responses, and mechanistically linking oxidative stress, inflammation, and diabetogenic virus infections. PMID- 29158421 TI - Urban-Rural Comparisons in Hospital Admission, Treatments, and Outcomes for ST Segment-Elevation Myocardial Infarction in China From 2001 to 2011: A Retrospective Analysis From the China PEACE Study (Patient-Centered Evaluative Assessment of Cardiac Events). AB - BACKGROUND: In response to urban-rural disparities in healthcare resources, China recently launched a healthcare reform with a focus on improving rural care during the past decade. However, nationally representative studies comparing medical care and patient outcomes between urban and rural areas in China during this period are not available. METHODS AND RESULTS: We created a nationally representative sample of patients in China admitted for ST-segment-elevation myocardial infarction in 2001, 2006, and 2011, using a 2-stage random sampling design in 2 urban and 3 rural strata. In China, evidence-based treatments were provided less often in 2001 in rural hospitals, which had lower volume and less availability of advanced cardiac facilities. However, these differences diminished by 2011 for reperfusion therapy (54% in urban versus 57% in rural; P=0.1) and reversed for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (66% versus 68%; P=0.04) and early beta-blockers (56% versus 60%; P=0.01). The risk-adjusted rate of in-hospital death or withdrawal from treatment was not significantly different between urban and rural hospitals in any study year, with an adjusted odds ratio of 1.13 (0.77-1.65) in 2001, 0.99 (0.77-1.27) in 2006, and 0.94 (0.74-1.19) in 2011. CONCLUSIONS: Although urban rural disparities in evidence-based treatment for myocardial infarction in China have largely been eliminated, substantial gaps in quality of care persist in both settings. In addition, urban hospitals providing more resource-intensive care did not achieve better outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01624883. PMID- 29158422 TI - Global Health and Circulation: Cardiovascular Quality & Outcomes. PMID- 29158423 TI - Are expanding disease definitions unnecessarily labelling women with polycystic ovary syndrome? PMID- 29158424 TI - The Spread of an Inversion with Migration and Selection. AB - We re-examine the model of Kirkpatrick and Barton for the spread of an inversion into a local population. This model assumes that local selection maintains alleles at two or more loci, despite immigration of alternative alleles at these loci from another population. We show that an inversion is favored because it prevents the breakdown of linkage disequilibrium generated by migration; the selective advantage of an inversion is dependent on the amount of recombination between the loci involved, as in other cases where inversions are selected for as a result of their effects on recombination. We derive expressions for the rate of spread of an inversion; when the loci covered by the inversion are tightly linked, these conditions deviate substantially from those proposed previously, and imply that an inversion can then have only a small advantage. PMID- 29158426 TI - Cohesin Function in Cohesion, Condensation, and DNA Repair Is Regulated by Wpl1p via a Common Mechanism in Saccharomyces cerevisiae. AB - Cohesin tethers DNA to mediate sister chromatid cohesion, chromosome condensation, and DNA repair. How the cell regulates cohesin to perform these distinct functions remains to be elucidated. One cohesin regulator, Wpl1p, was characterized in Saccharomyces cerevisiae as a promoter of efficient cohesion and an inhibitor of condensation. Wpl1p is also required for resistance to DNA damaging agents. Here, we provide evidence that Wpl1p promotes the timely repair of DNA damage induced during S-phase. Previous studies have indicated that Wpl1p destabilizes cohesin's binding to DNA by modulating the interface between the cohesin subunits Mcd1p and Smc3p Our results suggest that Wpl1p likely modulates this interface to regulate all of cohesin's biological functions. Furthermore, we show that Wpl1p regulates cohesion and condensation through the formation of a functional complex with another cohesin-associated factor, Pds5p In contrast, Wpl1p regulates DNA repair independently of its interaction with Pds5p Together, these results suggest that Wpl1p regulates distinct biological functions of cohesin by Pds5p-dependent and -independent modulation of the Smc3p/Mcd1p interface. PMID- 29158425 TI - Improving Metabolic Health Through Precision Dietetics in Mice. AB - The incidence of diet-induced metabolic disease has soared over the last half century, despite national efforts to improve health through universal dietary recommendations. Studies comparing dietary patterns of populations with health outcomes have historically provided the basis for healthy diet recommendations. However, evidence that population-level diet responses are reliable indicators of responses across individuals is lacking. This study investigated how genetic differences influence health responses to several popular diets in mice, which are similar to humans in genetic composition and the propensity to develop metabolic disease, but enable precise genetic and environmental control. We designed four human-comparable mouse diets that are representative of those eaten by historical human populations. Across four genetically distinct inbred mouse strains, we compared the American diet's impact on metabolic health to three alternative diets (Mediterranean, Japanese, and Maasai/ketogenic). Furthermore, we investigated metabolomic and epigenetic alterations associated with diet response. Health effects of the diets were highly dependent on genetic background, demonstrating that individualized diet strategies improve health outcomes in mice. If similar genetic-dependent diet responses exist in humans, then a personalized, or "precision dietetics," approach to dietary recommendations may yield better health outcomes than the traditional one-size fits-all approach. PMID- 29158427 TI - Do emotions related to alcohol consumption differ by alcohol type? An international cross-sectional survey of emotions associated with alcohol consumption and influence on drink choice in different settings. AB - OBJECTIVES: To examine the emotions associated with drinking different types of alcohol, explore whether these emotions differ by sociodemographics and alcohol dependency and whether the emotions associated with different drink types influence people's choice of drinks in different settings. DESIGN: International cross-sectional opportunistic survey (Global Drug Survey) using an online anonymous questionnaire in 11 languages promoted through newspapers, magazines and social media from November 2015 to January 2016. STUDY POPULATION: Individuals aged 18-34 years who reported consumption of beer, spirits, red and white wine in the previous 12 months and were resident in countries with more than 200 respondents (n=21 countries; 29 836 respondents). MAIN OUTCOME MEASURES: Positive and negative emotions associated with consumption of different alcoholic beverages (energised, relaxed, sexy, confident, tired, aggressive, ill, restless and tearful) over the past 12 months in different settings. RESULTS: Alcoholic beverages vary in the types of emotions individuals report they elicit, with spirits more frequently eliciting emotional changes of all types. Overall 29.8% of respondents reported feeling aggressive when drinking spirits, compared with only 7.1% when drinking red wine (p<0.001). Women more frequently reported feeling all emotions when drinking alcohol, apart from feelings of aggression. Respondents' level of alcohol dependency was strongly associated with feeling all emotions, with the likelihood of aggression being significantly higher in possible dependent versus low risk drinkers (adjusted OR 6.4; 95% CI 5.79 to 7.09; p<0.001). The odds of feeling the majority of positive and negative emotions also remained highest among dependent drinkers irrespective of setting. CONCLUSION: Understanding emotions associated with alcohol consumption is imperative to addressing alcohol misuse, providing insight into what emotions influence drink choice between different groups in the population. The differences identified between sociodemographic groups and influences on drink choice within different settings will aid future public health practice to further comprehend individuals' drinking patterns and influence behaviour change. PMID- 29158428 TI - The Borrelia burgdorferi Glycosaminoglycan Binding Protein Bgp in the B31 Strain Is Not Essential for Infectivity despite Facilitating Adherence and Tissue Colonization. AB - The Lyme disease-causing organism Borrelia burgdorferi is transmitted into the mammalian host by an infected-tick bite. Successful infection relies on the ability of this extracellular pathogen to persist and colonize different tissues. B. burgdorferi encodes a large number of adhesins that are able to interact with host ligands to facilitate adherence and tissue colonization. Multiple glycosaminoglycan binding proteins present in B. burgdorferi offer a degree of redundancy of function during infection, and this highlights the importance of glycosaminoglycans as host cell receptors for spirochete adherence. Of particular interest in this study is Borrelia glycosaminoglycan binding protein (Bgp), which binds to heparin-related glycosaminoglycans. The properties of a bgp transposon mutant and a trans-complemented derivative were compared to those of the wild type B. burgdorferi in the in vitro binding assays and in infection studies using a C3H/HeJ mouse infection model. We determined that the loss of Bgp impairs spirochete adherence, infectivity, and tissue colonization, resulting in a reduction of inflammatory manifestations of Lyme disease. Although Bgp is not essential for infectivity, it is an important virulence factor of B. burgdorferi that allows adherence and tissue colonization and contributes to disease severity. PMID- 29158429 TI - B Cell Presentation of Chlamydia Antigen Selects Out Protective CD4gamma13 T Cells: Implications for Genital Tract Tissue-Resident Memory Lymphocyte Clusters. AB - Surveillance and defense of the enormous mucosal interface with the nonsterile world are critical to protecting the host from a wide range of pathogens. Chlamydia trachomatis is an intracellular bacterial pathogen that replicates almost exclusively in the epithelium of the reproductive tract. The fallopian tubes and vagina are poorly suited to surveillance and defense, with limited immune infrastructure positioned near the epithelium. However, a dynamic process during clearing primary infections leaves behind new lymphoid clusters immediately beneath the epithelium. These memory lymphocyte clusters (MLCs) harboring tissue-resident memory (Trm) T cells are presumed to play an important role in protection from subsequent infections. Histologically, human Chlamydia MLCs have prominent B cell populations. We investigated the status of genital tract B cells during C. muridarum infections and the nature of T cells recovered from immune mice using immune B cells as antigen-presenting cells (APCs). These studies revealed a genital tract plasma B cell population and a novel genital tract CD4 T cell subset producing both gamma interferon (IFN-gamma) and interleukin-13 (IL-13). A panel of CD4 T cell clones and microarray analysis showed that the molecular fingerprint of CD4gamma13 T cells includes a Trm-like transcriptome. Adoptive transfer of a Chlamydia-specific CD4gamma13 T cell clone completely prevented oviduct immunopathology without accelerating bacterial clearance. Existence of a CD4gamma13 T cell subset provides a plausible explanation for the observation that human peripheral blood mononuclear cell (PBMC) Chlamydia-specific IFN-gamma and IL-13 responses predict resistance to reinfection. PMID- 29158430 TI - Characterization of Stress and Innate Immunity Resistance of Wild-Type and Deltap66 Borrelia burgdorferi. AB - Borrelia burgdorferi is a causative agent of Lyme disease, the most common arthropod-borne disease in the United States. B. burgdorferi evades host immune defenses to establish a persistent, disseminated infection. Previous work showed that P66-deficient B. burgdorferi (Deltap66) is cleared quickly after inoculation in mice. We demonstrate that the Deltap66 strain is rapidly cleared from the skin inoculation site prior to dissemination. The rapid clearance of Deltap66 bacteria is not due to inherent defects in multiple properties that might affect infectivity: bacterial outer membrane integrity, motility, chemotactic response, or nutrient acquisition. This led us to the hypothesis that P66 has a role in mouse cathelicidin-related antimicrobial peptide (mCRAMP; a major skin antimicrobial peptide) and/or neutrophil evasion. Neither wild-type (WT) nor Deltap66 B. burgdorferi was susceptible to mCRAMP. To examine the role of neutrophil evasion, we administered neutrophil-depleting antibody anti-Ly6G (1A8) to C3H/HeN mice and subsequently monitored the course of B. burgdorferi infection. Deltap66 mutants were unable to establish infection in neutrophil depleted mice, suggesting that the important role of P66 during early infection is through another mechanism. Neutrophil depletion did not affect WT B. burgdorferi bacterial burdens in the skin (inoculation site), ear, heart, or tibiotarsal joint at early time points postinoculation. This was unexpected given that prior in vitro studies demonstrated neutrophils phagocytose and kill B. burgdorferi These data, together with our previous work, suggest that despite the in vitro ability of host innate defenses to kill B. burgdorferi, individual innate immune mechanisms have limited contributions to controlling early B. burgdorferi infection in the laboratory model used. PMID- 29158431 TI - Salmonella enterica Serovar Typhimurium Alters the Extracellular Proteome of Macrophages and Leads to the Production of Proinflammatory Exosomes. AB - Salmonella enterica serovar Typhimurium is a Gram-negative bacterium, which can invade and survive within macrophages. Pathogenic salmonellae induce the secretion of specific cytokines from these phagocytic cells and interfere with the host secretory pathways. In this study, we describe the extracellular proteome of human macrophages infected with S Typhimurium, followed by analysis of canonical pathways of proteins isolated from the extracellular milieu. We demonstrate that some of the proteins secreted by macrophages upon S Typhimurium infection are released via exosomes. Moreover, we show that infected macrophages produce CD63+ and CD9+ subpopulations of exosomes at 2 h postinfection. Exosomes derived from infected macrophages trigger the Toll-like receptor 4-dependent release of tumor necrosis factor alpha (TNF-alpha) from naive macrophages and dendritic cells, but they also stimulate secretion of such cytokines as RANTES, IL-1ra, MIP-2, CXCL1, MCP-1, sICAM-1, GM-CSF, and G-CSF. Proinflammatory effects of exosomes are partially attributed to lipopolysaccharide, which is encapsulated within exosomes. In summary, we show for the first time that proinflammatory exosomes are formed in the early phase of macrophage infection with S Typhimurium and that they can be used to transfer cargo to naive cells, thereby leading to their stimulation. PMID- 29158432 TI - Identification and Characterization of Serotype-Specific Variation in Group A Streptococcus Pilus Expression. AB - Isolates of a given bacterial pathogen often display phenotypic variation, and this can negatively impact public health, for example, by reducing the efficacy of preventative measures. Here, we identify that the human pathogen group A Streptococcus (GAS; Streptococcus pyogenes) expresses pili on its cell surface in a serotype-specific manner. Specifically, we show that serotype M3 GAS isolates, which are nonrandomly associated with causing particularly severe and lethal invasive infections, produce negligible amounts of pili relative to serotype M1 and M49 isolates. Performance of an interserotype transcriptome comparison (serotype M1 versus serotype M3) was instrumental in this discovery. We also identified that the transcriptional regulator Nra positively regulates pilus expression in M3 GAS isolates and that the low level of pilus expression of these isolates correlates with a low level of nra transcription. Finally, we discovered that the phenotypic consequences of low levels of pilus expression by M3 GAS isolates are a reduced ability to adhere to host cells and an increased ability to survive and proliferate in human blood. We propose that an enhanced ability to survive in human blood, in part due to reduced pilus expression, is a contributing factor in the association of serotype M3 isolates with highly invasive infections. In conclusion, our data show that GAS isolates express pili in a serotype-dependent manner and may inform vaccine development, given that pilus proteins are being discussed as possible GAS vaccine antigens. PMID- 29158433 TI - Whole Genome Characterization of Bacillus cereus Associated with Specific Disease Manifestations. AB - Bacillus cereus remains an important cause of infections, particularly in immunocompromised hosts. While typically associated with enteric infections, disease manifestations can be quite diverse and include skin infections, bacteremia, pneumonia, and meningitis. Whether there are any genetic correlates of bacterial strains with particular clinical manifestations remains unknown. To address this gap in understanding we undertook whole genome analysis of B. cereus strains isolated from patients with a range of disease manifestations, including non-invasive colonizing disease, superficial skin infections, and invasive bacteremia. Interestingly, strains involved in skin infection tended to form a distinct genetic cluster compared to isolates associated with invasive disease. Other disease manifestations, despite not being exclusively clustered, nonetheless had unique genetic features. The unique features associated with the specific types of infections ranged from traditional virulence determinants, metabolic pathways, and gene regulators. These data represent the largest genetic analysis to-date of pathogenic B. cereus isolates with associated clinical parameters. PMID- 29158434 TI - High Levels of Cyclic Di-GMP in Klebsiella pneumoniae Attenuate Virulence in the Lung. AB - The bacterial second messenger bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) has been shown to influence the expression of virulence factors in certain pathogenic bacteria, but little is known about its activity in the increasingly antibiotic resistant pathogen Klebsiella pneumoniae Here, the expression in K. pneumoniae of a heterologous diguanylate cyclase increased the bacterial c-di-GMP concentration and attenuated pathogenesis in murine pneumonia. This attenuation remained evident in mice lacking the c-di-GMP sensor STING, indicating that the high c-di GMP concentration exerted its influence not on host responses but on bacterial physiology. While serum resistance and capsule expression were unaffected by the increased c-di-GMP concentration, both type 3 and type 1 pili were strongly upregulated. Importantly, attenuation of K. pneumoniae virulence by high c-di-GMP levels was abrogated when type 1 pilus expression was silenced. We conclude that increased type 1 piliation may hamper K. pneumoniae virulence in the respiratory tract and that c-di-GMP signaling represents a potential therapeutic target for antibiotic-resistant K. pneumoniae in this niche. PMID- 29158435 TI - Symptom Diary Use and Improved Survival for Patients With Heart Failure. AB - BACKGROUND: Attention to symptoms of weight gain and dyspnea are central tenets of patient education in heart failure (HF). However, it is not known whether diary use improves patient outcomes. The aims of this study were to compare mortality among rural patients with HF who completed versus did not complete a daily diary of weight and symptom self-assessment and to identify predictors of diary use. METHODS AND RESULTS: This is a secondary analysis of a 3-arm randomized controlled trial on HF education of self-care with 2 intervention groups versus control who were given diaries for 24 months to track daily weight, HF symptoms, and response to symptom changes. Mean age was 66+/-13, 58% were men, and 67% completed diaries (n=393). We formed 5 groups (no use, low, medium, high, and very high) based on the first 3 months of diary use and then analyzed time to event (cardiac mortality, all-cause mortality, and HF-related readmission) starting at 3 months. Compared with patients with no diary use, high and very high diary users were less likely to experience all-cause mortality (P=0.02 and P=0.01, respectively). Self-reported sedentary lifestyle was associated with less diary use in an adjusted model (odds ratio, 0.66; 95% confidence interval, 0.46 0.95; P=0.03). Depression and sex were not significant predictors of diary use in the adjusted model. CONCLUSIONS: In this study of 393 rural patients with HF, we found that greater diary use was associated with longer survival. These findings suggest that greater engagement in self-care behaviors is associated with better HF outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT00415545. PMID- 29158436 TI - Pathogenic Role of the Damage-Associated Molecular Patterns S100A8 and S100A9 in Coxsackievirus B3-Induced Myocarditis. AB - BACKGROUND: The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3) induced myocarditis. METHODS AND RESULTS: S100A8 and S100A9 mRNA expression was 13.0-fold (P=0.012) and 5.1-fold (P=0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3 mice. Exogenous application of S100A8 to S100A9 knockout CVB3 mice induced a severe myocarditis similar to wild type CVB3 mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3 infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3 S100A8 knockdown versus scrambled siRNA CVB3 cells. CONCLUSIONS: S100A8 and S100A9 aggravate CVB3 induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies. PMID- 29158438 TI - The Changing Face of Cardiac Inflammation: New Opportunities in the Management of Myocarditis. PMID- 29158437 TI - Cardiac Magnetic Resonance Imaging in Myocarditis Reveals Persistent Disease Activity Despite Normalization of Cardiac Enzymes and Inflammatory Parameters at 3-Month Follow-Up. AB - BACKGROUND: There is a major unmet need to identify high-risk patients in myocarditis. Although decreasing cardiac and inflammatory markers are commonly interpreted as resolving myocarditis, this assumption has not been confirmed as of today. We sought to evaluate whether routine laboratory parameters at diagnosis predict dynamic of late gadolinium enhancement (LGE) as persistent LGE has been shown to be a risk marker in myocarditis. METHODS AND RESULTS: Myocarditis was diagnosed based on clinical presentation, high-sensitivity troponin T, and cardiac magnetic resonance imaging, after exclusion of obstructive coronary artery disease by angiography. Cardiac magnetic resonance imaging was repeated at 3 months. LGE extent was analyzed with the software GT Volume. Change in LGE >20% was considered significant. Investigated cardiac and inflammatory markers included high-sensitivity troponin T, creatine kinase, myoglobin, N-terminal B-type natriuretic peptide, C-reactive protein, and leukocyte count. Twenty-four patients were enrolled. Absolute levels of cardiac enzymes and inflammatory markers at baseline did not predict change in LGE at 3 months. Cardiac and inflammatory markers had normalized in 21 patients (88%). LGE significantly improved in 16 patients (67%); however, it persisted to a lesser degree in 17 of them (71%) and increased in a small percentage (21%) despite normalization of cardiac enzymes. CONCLUSIONS: This is the first study reporting that cardiac enzymes and inflammatory parameters do not sufficiently reflect LGE in myocarditis. Although a majority of patients with normalizing laboratory markers experienced improved LGE, in a small percentage LGE worsened. These data suggest that cardiac magnetic resonance imaging might add value to currently existing diagnostic tools for risk assessment in myocarditis. PMID- 29158439 TI - Differential spatial distribution of miR165/6 determines variability in plant root anatomy. AB - A clear example of interspecific variation is the number of root cortical layers in plants. The genetic mechanisms underlying this variability are poorly understood, partly because of the lack of a convenient model. Here, we demonstrate that Cardamine hirsuta, unlike Arabidopsis thaliana, has two cortical layers that are patterned during late embryogenesis. We show that a miR165/6 dependent distribution of the HOMEODOMAIN LEUCINE ZIPPER III (HD-ZIPIII) transcription factor PHABULOSA (PHB) controls this pattern. Our findings reveal that interspecies variation in miRNA distribution can determine differences in anatomy in plants. PMID- 29158440 TI - Cohesin facilitates zygotic genome activation in zebrafish. AB - At zygotic genome activation (ZGA), changes in chromatin structure are associated with new transcription immediately following the maternal-to-zygotic transition (MZT). The nuclear architectural proteins cohesin and CCCTC-binding factor (CTCF) contribute to chromatin structure and gene regulation. We show here that normal cohesin function is important for ZGA in zebrafish. Depletion of the cohesin subunit Rad21 delays ZGA without affecting cell cycle progression. In contrast, CTCF depletion has little effect on ZGA, whereas complete abrogation is lethal. Genome-wide analysis of Rad21 binding reveals a change in distribution from pericentromeric satellite DNA and other locations, including the miR-430 locus (the products of which are responsible for maternal transcript degradation), to genes, as embryos progress through the MZT. After MZT, a subset of Rad21 binding overlaps the pioneer factor Pou5f3, which activates early expressed genes. Rad21 depletion disrupts the formation of nucleoli and RNA polymerase II foci, suggestive of global defects in chromosome architecture. We propose that Rad21/cohesin redistribution to active areas of the genome is key to the establishment of chromosome organization and the embryonic developmental program. PMID- 29158441 TI - Shep regulates Drosophila neuronal remodeling by controlling transcription of its chromatin targets. AB - Neuronal remodeling is crucial for formation of the mature nervous system and disruption of this process can lead to neuropsychiatric diseases. Global gene expression changes in neurons during remodeling as well as the factors that regulate these changes remain poorly defined. To elucidate this process, we performed RNA-seq on isolated Drosophila larval and pupal neurons and found upregulated synaptic signaling and downregulated gene expression regulators as a result of normal neuronal metamorphosis. We further tested the role of alan shepard (shep), which encodes an evolutionarily conserved RNA-binding protein required for proper neuronal remodeling. Depletion of shep in neurons prevents the execution of metamorphic gene expression patterns, and shep-regulated genes correspond to Shep chromatin and/or RNA-binding targets. Reduced expression of a Shep-inhibited target gene that we identified, brat, is sufficient to rescue neuronal remodeling defects of shep knockdown flies. Our results reveal direct regulation of transcriptional programs by Shep to regulate neuronal remodeling during metamorphosis. PMID- 29158442 TI - A novel role for sox7 in Xenopus early primordial germ cell development: mining the PGC transcriptome. AB - Xenopus primordial germ cells (PGCs) are determined by the presence of maternally derived germ plasm. Germ plasm components both protect PGCs from somatic differentiation and begin a unique gene expression program. Segregation of the germline from the endodermal lineage occurs during gastrulation, and PGCs subsequently initiate zygotic transcription. However, the gene network(s) that operate to both preserve and promote germline differentiation are poorly understood. Here, we utilized RNA-sequencing analysis to comprehensively interrogate PGC and neighboring endoderm cell mRNAs after lineage segregation. We identified 1865 transcripts enriched in PGCs compared with endoderm cells. We next compared the PGC-enriched transcripts with previously identified maternal, vegetally enriched transcripts and found that ~38% of maternal transcripts were enriched in PGCs, including sox7 PGC-directed sox7 knockdown and overexpression studies revealed an early requirement for sox7 in germ plasm localization, zygotic transcription and PGC number. We identified pou5f3.3 as the most highly expressed and enriched POU5F1 homolog in PGCs. We compared the Xenopus PGC transcriptome with human PGC transcripts and showed that 80% of genes are conserved, underscoring the potential usefulness of Xenopus for understanding human germline specification. PMID- 29158443 TI - FOX and ETS family transcription factors regulate the pigment cell lineage in planarians. AB - Many pigment cells acquire unique structural properties and gene expression profiles during animal development. The underlying differentiation pathways have been well characterized in cells formed during embryogenesis, such as the neural crest-derived melanocyte. However, much less is known about the developmental origins of pigment cells produced in adult organisms during tissue homeostasis and repair. Here we report a lineage analysis of ommochrome- and porphyrin producing cells in the brown, freshwater planarian Schmidtea mediterranea Using an RNA-sequencing approach, we identified two classes of markers expressed in sequential fashion when new pigment cells are generated during regeneration or in response to pigment cell ablation. We also report roles for FOXF-1 and ETS-1 transcription factors, as well as for an FGFR-like molecule, in the specification and maintenance of this cell type. Together, our results provide insights into mechanisms of adult pigment cell development in the strikingly colorful Platyhelminthes phylum. PMID- 29158444 TI - HNF1B controls epithelial organization and cell polarity during ureteric bud branching and collecting duct morphogenesis. AB - Kidney development depends crucially on proper ureteric bud branching giving rise to the entire collecting duct system. The transcription factor HNF1B is required for the early steps of ureteric bud branching, yet the molecular and cellular events regulated by HNF1B are poorly understood. We report that specific removal of Hnf1b from the ureteric bud leads to defective cell-cell contacts and apicobasal polarity during the early branching events. High-resolution ex vivo imaging combined with a membranous fluorescent reporter strategy show decreased mutant cell rearrangements during mitosis-associated cell dispersal and severe epithelial disorganization. Molecular analysis reveals downregulation of Gdnf-Ret pathway components and suggests that HNF1B acts both upstream and downstream of Ret signaling by directly regulating Gfra1 and Etv5 Subsequently, Hnf1b deletion leads to massively mispatterned ureteric tree network, defective collecting duct differentiation and disrupted tissue architecture, which leads to cystogenesis. Consistently, mRNA-seq analysis shows that the most impacted genes encode intrinsic cell-membrane components with transporter activity. Our study uncovers a fundamental and recurring role of HNF1B in epithelial organization during early ureteric bud branching and in further patterning and differentiation of the collecting duct system in mouse. PMID- 29158445 TI - PDGFRalpha/PDGFRbeta signaling balance modulates progenitor cell differentiation into white and beige adipocytes. AB - The relative abundance of thermogenic beige adipocytes and lipid-storing white adipocytes in adipose tissue underlie its metabolic activity. The roles of adipocyte progenitor cells, which express PDGFRalpha or PDGFRbeta, in adipose tissue function have remained unclear. Here, by defining the developmental timing of PDGFRalpha and PDGFRbeta expression in mouse subcutaneous and visceral adipose depots, we uncover depot specificity of pre-adipocyte delineation. We demonstrate that PDGFRalpha expression precedes PDGFRbeta expression in all subcutaneous but in only a fraction of visceral adipose stromal cells. We show that high-fat diet feeding or thermoneutrality in early postnatal development can induce PDGFRbeta+ lineage recruitment to generate white adipocytes. In contrast, the contribution of PDGFRbeta+ lineage to beige adipocytes is minimal. We provide evidence that human adipose tissue also contains distinct progenitor populations differentiating into beige or white adipocytes, depending on PDGFRbeta expression. Based on PDGFRalpha or PDGFRbeta deletion and ectopic expression experiments, we conclude that the PDGFRalpha/PDGFRbeta signaling balance determines progenitor commitment to beige (PDGFRalpha) or white (PDGFRbeta) adipogenesis. Our study suggests that adipocyte lineage specification and metabolism can be modulated through PDGFR signaling. PMID- 29158447 TI - Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve. AB - Although cardiac neural crest cells are required at early stages of arterial valve development, their contribution during valvular leaflet maturation remains poorly understood. Here, we show in mouse that neural crest cells from pre-otic and post-otic regions make distinct contributions to the arterial valve leaflets. Genetic fate-mapping analysis of Krox20-expressing neural crest cells shows a large contribution to the borders and the interleaflet triangles of the arterial valves. Loss of Krox20 function results in hyperplastic aortic valve and partially penetrant bicuspid aortic valve formation. Similar defects are observed in neural crest Krox20-deficient embryos. Genetic lineage tracing in Krox20-/- mutant mice shows that endothelial-derived cells are normal, whereas neural crest derived cells are abnormally increased in number and misplaced in the valve leaflets. In contrast, genetic ablation of Krox20-expressing cells is not sufficient to cause an aortic valve defect, suggesting that adjacent cells can compensate this depletion. Our findings demonstrate a crucial role for Krox20 in arterial valve development and reveal that an excess of neural crest cells may be associated with bicuspid aortic valve. PMID- 29158448 TI - Executive Function Declines in the First 6 Months After a Transient Ischemic Attack or Transient Neurological Attack. AB - BACKGROUND AND PURPOSE: Although by definition transient, both transient ischemic attack (TIA) and transient neurological attack (TNA) are associated with cognitive impairment. Determinants and course of cognitive function afterward are, however, unclear. We prospectively determined cognitive performance after TIA and TNA in relation to clinical diagnosis and diffusion-weighted imaging (DWI) results. METHODS: TIA and TNA patients aged >=45 years without prior stroke or dementia underwent comprehensive cognitive assessment and magnetic resonance imaging within 7 days after the qualifying event. Cognitive tests were repeated after 6 months. Domain-specific compound z scores based on the baseline mean and SD were calculated. Repeated-measures analysis was used to test for differences in domain-specific cognitive performance over time between DWI-positive and DWI negative patients, as well as between TIA and TNA patients. RESULTS: One hundred twenty-one patients were included (mean age (SD), 64.6 years (9.2 years), 60% TIA and 40% TNA) of whom 32 (26%) had a DWI lesion. Executive function performance decreased over time (mean change in compound score -0.23; P=0.01 adjusted for age, sex, education), whereas attention improved (0.11; P=0.02), and information processing speed and episodic memory remained unchanged. Patients with a DWI lesion had worse executive function at baseline than those without a DWI lesion (compound scores -0.26 versus 0.08; P=0.048), which persisted throughout the study period (P=0.04). Clinical diagnosis (TIA or TNA) was not related to cognitive function over time. CONCLUSIONS: Executive function declines during the first 6 months after TIA or TNA. Patients with an initial DWI lesion have persisting worse executive function than those without. PMID- 29158446 TI - Drosophila embryonic type II neuroblasts: origin, temporal patterning, and contribution to the adult central complex. AB - Drosophila neuroblasts are an excellent model for investigating how neuronal diversity is generated. Most brain neuroblasts generate a series of ganglion mother cells (GMCs) that each make two neurons (type I lineage), but 16 brain neuroblasts generate a series of intermediate neural progenitors (INPs) that each produce 4-6 GMCs and 8-12 neurons (type II lineage). Thus, type II lineages are similar to primate cortical lineages, and may serve as models for understanding cortical expansion. Yet the origin of type II neuroblasts remains mysterious: do they form in the embryo or larva? If they form in the embryo, do their progeny populate the adult central complex, as do the larval type II neuroblast progeny? Here, we present molecular and clonal data showing that all type II neuroblasts form in the embryo, produce INPs and express known temporal transcription factors. Embryonic type II neuroblasts and INPs undergo quiescence, and produce embryonic-born progeny that contribute to the adult central complex. Our results provide a foundation for investigating the development of the central complex, and tools for characterizing early-born neurons in central complex function. PMID- 29158449 TI - Induced Hypertension for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial. AB - BACKGROUND AND PURPOSE: Induced hypertension is widely used to treat delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but a literature review shows that its presumed effectiveness is based on uncontrolled case-series only. We here report clinical outcome of aneurysmal subarachnoid hemorrhage patients with DCI included in a randomized trial on the effectiveness of induced hypertension. METHODS: Aneurysmal subarachnoid hemorrhage patients with clinical symptoms of DCI were randomized to induced hypertension or no induced hypertension. Risk ratios for poor outcome (modified Rankin Scale score >3) at 3 months, with 95% confidence intervals, were calculated and adjusted for age, clinical condition at admission and at time of DCI, and amount of blood on initial computed tomographic scan with Poisson regression analysis. RESULTS: The trial aiming to include 240 patients was ended, based on lack of effect on cerebral perfusion and slow recruitment, when 21 patients had been randomized to induced hypertension, and 20 patients to no hypertension. With induced hypertension, the adjusted risk ratio for poor outcome was 1.0 (95% confidence interval, 0.6-1.8) and the risk ratio for serious adverse events 2.1 (95% confidence interval, 0.9-5.0). CONCLUSIONS: Before this trial, the effectiveness of induced hypertension for DCI in aneurysmal subarachnoid hemorrhage patients was unknown because current literature consists only of uncontrolled case series. The results from our premature halted trial do not add any evidence to support induced hypertension and show that this treatment can lead to serious adverse events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01613235. PMID- 29158450 TI - 70 years of the JCP-highly cited papers: The causal relation between human papillomavirus and cervical cancer. PMID- 29158451 TI - Correction: Aligning the flow cytometric evaluation with the diagnostic need: an evidence-based approach. PMID- 29158452 TI - A call for clarity and quality in medical writing. PMID- 29158453 TI - Healing racism in Canadian health care. PMID- 29158454 TI - Direct medical costs of motorcycle crashes in Ontario. AB - BACKGROUND: There is no reliable estimate of costs incurred by motorcycle crashes. Our objective was to calculate the direct costs of all publicly funded medical care provided to individuals after motorcycle crashes compared with automobile crashes. METHODS: We conducted a population-based, matched cohort study of adults in Ontario who presented to hospital because of a motorcycle or automobile crash from 2007 through 2013. For each case, we identified 1 control absent a motor vehicle crash during the study period. Direct costs for each case and control were estimated in 2013 Canadian dollars from the payer perspective using methodology that links health care use to individuals over time. We calculated costs attributable to motorcycle and automobile crashes within 2 years using a difference-in-differences approach. RESULTS: We identified 26 831 patients injured in motorcycle crashes and 281 826 injured in automobile crashes. Mean costs attributable to motorcycle and automobile crashes were $5825 and $2995, respectively (p < 0.001). The rate of injury was triple for motorcycle crashes compared with automobile crashes (2194 injured annually/100 000 registered motorcycles v. 718 injured annually/100 000 registered automobiles; incidence rate ratio [IRR] 3.1, 95% confidence interval [CI] 2.8 to 3.3, p < 0.001). Severe injuries, defined as those with an Abbreviated Injury Scale >= 3, were 10 times greater (125 severe injuries annually/100 000 registered motorcycles v. 12 severe injuries annually/100 000 registered automobiles; IRR 10.4, 95% CI 8.3 to 13.1, p < 0.001). INTERPRETATION: Considering both the attributable cost and higher rate of injury, we found that each registered motorcycle in Ontario costs the public health care system 6 times the amount of each registered automobile. Medical costs may provide an additional incentive to improve motorcycle safety. PMID- 29158455 TI - Acute strongyloidiasis in a child recently returned from vacation in Cuba. PMID- 29158456 TI - Subarachnoid hemorrhage. PMID- 29158457 TI - The importance of study design in the assessment of nonnutritive sweeteners and cardiometabolic health. PMID- 29158458 TI - Response to "The importance of study design in the assessment of nonnutritive sweeteners and cardiometabolic health". PMID- 29158459 TI - The timing of ingestion may influence the effect of nonnutritive sweeteners on cardiometabolic health: a potentially overlooked factor. PMID- 29158460 TI - Climate change is already making us sick. PMID- 29158461 TI - Facts not enough to change minds about health myths. PMID- 29158462 TI - Renewed support for surgical safety checklist. PMID- 29158463 TI - Celebrating more women leaders in global health. PMID- 29158464 TI - No quality health care without strong public health. PMID- 29158466 TI - Evolution of the species - the neurointerventional surgeon in 2017 and beyond. PMID- 29158465 TI - Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury. AB - Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function-related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury. PMID- 29158467 TI - Optimizing peer review: the JNIS approach. PMID- 29158468 TI - Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer. AB - BMI-1, also known as a stem cell factor, is frequently upregulated in several malignancies. Elevated expression of BMI-1 correlates with poor prognosis and is therefore considered a viable therapeutic target in a number of malignancies including ovarian cancer. Realizing the immense pathologic significance of BMI-1, small-molecule inhibitors against BMI-1 are recently being developed. In this study, we functionally characterize PTC-028, an orally bioavailable compound that decreases BMI-1 levels by posttranslational modification. We report that PTC-028 treatment selectively inhibits cancer cells in clonal growth and viability assays, whereas normal cells remain unaffected. Mechanistically, hyperphosphorylation-mediated depletion of cellular BMI-1 by PTC-028 coupled with a concurrent temporal decrease in ATP and a compromised mitochondrial redox balance potentiates caspase-dependent apoptosis. In vivo, orally administered PTC 028, as a single agent, exhibits significant antitumor activity comparable with the standard cisplatin/paclitaxel therapy in an orthotopic mouse model of ovarian cancer. Thus, PTC-028 has the potential to be used as an effective therapeutic agent in patients with epithelial ovarian cancer, where treatment options are limited. Mol Cancer Ther; 17(1); 39-49. (c)2017 AACR. PMID- 29158469 TI - Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab Resistance. AB - Acquired resistance to cetuximab, an antibody that targets the EGFR, impacts clinical benefit in head and neck, and colorectal cancers. One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA-approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab-resistant substitution, S468R (or S492R, depending on the amino acid numbering system). We determined an X-ray crystal structure to 2.8 A resolution of the necitumumab Fab bound to an S468R variant of EGFR domain III. The arginine is accommodated in a large, preexisting cavity in the necitumumab paratope. We predict that this paratope shape will be permissive to other epitope substitutions, and show that necitumumab binds to most cetuximab- and panitumumab resistant EGFR variants. We find that a simple computational approach can predict with high success which EGFR epitope substitutions abrogate antibody binding. This computational method will be valuable to determine whether necitumumab will bind to EGFR as new epitope resistance variants are identified. This method could also be useful for rapid evaluation of the effect on binding of alterations in other antibody/antigen interfaces. Together, these data suggest that necitumumab may be active in patients who are resistant to cetuximab or panitumumab through EGFR epitope mutation. Furthermore, our analysis leads us to speculate that antibodies with large paratope cavities may be less susceptible to resistance due to mutations mapping to the antigen epitope. Mol Cancer Ther; 17(2); 521-31. (c)2017 AACR. PMID- 29158470 TI - Comparative Oncology Evaluation of Intravenous Recombinant Oncolytic Vesicular Stomatitis Virus Therapy in Spontaneous Canine Cancer. AB - Clinical translation of intravenous therapies to treat disseminated or metastatic cancer is imperative. Comparative oncology, the evaluation of novel cancer therapies in animals with spontaneous cancer, can be utilized to inform and accelerate clinical translation. Preclinical murine studies demonstrate that single-shot systemic therapy with a vesicular stomatitis virus (VSV)-IFNbeta-NIS, a novel recombinant oncolytic VSV, can induce curative remission in tumor-bearing mice. Clinical translation of VSV-IFNbeta-NIS therapy is dependent on comprehensive assessment of clinical toxicities, virus shedding, pharmacokinetics, and efficacy in clinically relevant models. Dogs spontaneously develop cancer with comparable etiology, clinical progression, and response to therapy as human malignancies. A comparative oncology study was carried out to investigate feasibility and tolerability of intravenous oncolytic VSV-IFNbeta-NIS therapy in pet dogs with spontaneous cancer. Nine dogs with various malignancies were treated with a single intravenous dose of VSV-IFNbeta-NIS. Two dogs with high-grade peripheral T-cell lymphoma had rapid but transient remission of disseminated disease and transient hepatotoxicity that resolved spontaneously. There was no shedding of infectious virus. Correlative pharmacokinetic studies revealed elevated levels of VSV RNA in blood in dogs with measurable disease remission. This is the first evaluation of intravenous oncolytic virus therapy for spontaneous canine cancer, demonstrating that VSV-IFNbeta-NIS is well tolerated and safe in dogs with advanced or metastatic disease. This approach has informed clinical translation, including dose and target indication selection, leading to a clinical investigation of intravenous VSV-IFNbeta-NIS therapy, and provided preliminary evidence of clinical efficacy and potential biomarkers that correlate with therapeutic response. Mol Cancer Ther; 17(1); 316-26. (c)2017 AACR. PMID- 29158471 TI - Thoracic Epidural Hematoma Complicating Vertebroplasty. AB - BACKGROUND Percutaneous vertebroplasty procedures are commonly used to treat vertebral fractures. These techniques may be associated with major complications. CASE REPORT We present here a case of a 64-year-old female patient with T9 and T10 acute osteoporotic fractures, treated previously with vertebroplasty for four levels of osteoporotic vertebral fractures. The patient was treated by T9-T10 vertebroplasty. The post-operative neurological examination was normal. Two hours later, she progressively worsened and developed paraplegia. Magnetic resonance imaging (MRI) revealed a hyper-acute epidural hematoma over the T6 to T10 vertebrae. Evacuation of the epidural hematoma completely resolved her motor weakness. Previous literature reports one case with a thoracolumbar epidural hematoma over T11-L2 and another case with a L1 epidural hematoma after vertebroplasty. CONCLUSIONS Percutaneous vertebroplasty is generally a safe procedure but can have rare complications. Epidural hematoma after vertebroplasty is one of the uncommon complications. Before percutaneous vertebroplasty, patients should be informed about these rare complications. Prognosis is very good if early intervention is possible. PMID- 29158472 TI - Immediate Effects of Ankle Balance Taping with Kinesiology Tape for Amateur Soccer Players with Lateral Ankle Sprain: A Randomized Cross-Over Design. AB - BACKGROUND The objective of this study was to investigate the immediate effect on gait function when ankle balance taping is applied to amateur soccer players with lateral ankle sprain. MATERIAL AND METHODS A cross-over randomized design was used. Twenty-two soccer players with an ankle sprain underwent 3 interventions in a random order. Subjects were randomly assigned to ankle balance taping, placebo taping, and no taping groups. The assessment was performed using the GAITRite portable walkway system, which records the location and timing of each footfall during ambulation. RESULTS Significant differences were found in the velocity, step length, stride length, and H-H base support among the 3 different taping methods (p<0.05). The ankle balance taping group showed significantly greater velocity, step length, and stride length in comparison to the placebo and no taping group. The ankle balance taping group showed a statistically significant decrease (p<0.05) in the H-H base support compared to the placebo and no taping groups, and the placebo group showed significantly greater velocity in comparison to the no taping group (p<0.05). CONCLUSIONS We conclude that ankle balance taping that uses kinesiology tape instantly increased the walking ability of amateur soccer players with lateral ankle sprain. Therefore, ankle balance taping is a useful alternative to prevent and treat ankle sprain of soccer players. PMID- 29158473 TI - NOTCH1 is a mechanosensor in adult arteries. AB - Endothelial cells transduce mechanical forces from blood flow into intracellular signals required for vascular homeostasis. Here we show that endothelial NOTCH1 is responsive to shear stress, and is necessary for the maintenance of junctional integrity, cell elongation, and suppression of proliferation, phenotypes induced by laminar shear stress. NOTCH1 receptor localizes downstream of flow and canonical NOTCH signaling scales with the magnitude of fluid shear stress. Reduction of NOTCH1 destabilizes cellular junctions and triggers endothelial proliferation. NOTCH1 suppression results in changes in expression of genes involved in the regulation of intracellular calcium and proliferation, and preventing the increase of calcium signaling rescues the cell-cell junctional defects. Furthermore, loss of Notch1 in adult endothelium increases hypercholesterolemia-induced atherosclerosis in the descending aorta. We propose that NOTCH1 is atheroprotective and acts as a mechanosensor in adult arteries, where it integrates responses to laminar shear stress and regulates junctional integrity through modulation of calcium signaling. PMID- 29158475 TI - Universal model of individual and population mobility on diverse spatial scales. AB - Studies of human mobility in the past decade revealed a number of general scaling laws. However, to reproduce the scaling behaviors quantitatively at both the individual and population levels simultaneously remains to be an outstanding problem. Moreover, recent evidence suggests that spatial scales have a significant effect on human mobility, raising the need for formulating a universal model suited for human mobility at different levels and spatial scales. Here we develop a general model by combining memory effect and population-induced competition to enable accurate prediction of human mobility based on population distribution only. A variety of individual and collective mobility patterns such as scaling behaviors and trajectory motifs are accurately predicted for different countries and cities of diverse spatial scales. Our model establishes a universal underlying mechanism capable of explaining a variety of human mobility behaviors, and has significant applications for understanding many dynamical processes associated with human mobility. PMID- 29158474 TI - UNC93B1 interacts with the calcium sensor STIM1 for efficient antigen cross presentation in dendritic cells. AB - Dendritic cells (DC) have the unique ability to present exogenous antigens via the major histocompatibility complex class I pathway to stimulate naive CD8+ T cells. In DCs with a non-functional mutation in Unc93b1 (3d mutation), endosomal acidification, phagosomal maturation, antigen degradation, antigen export to the cytosol and the function of the store-operated-Ca2+-entry regulator STIM1 are impaired. These defects result in compromised antigen cross-presentation and anti tumor responses in 3d-mutated mice. Here, we show that UNC93B1 interacts with the calcium sensor STIM1 in the endoplasmic reticulum, a critical step for STIM1 oligomerization and activation. Expression of a constitutively active STIM1 mutant, which no longer binds UNC93B1, restores antigen degradation and cross presentation in 3d-mutated DCs. Furthermore, ablation of STIM1 in mouse and human cells leads to a decrease in cross-presentation. Our data indicate that the UNC93B1 and STIM1 cooperation is important for calcium flux and antigen cross presentation in DCs. PMID- 29158476 TI - Programmable DNA looping using engineered bivalent dCas9 complexes. AB - DNA looping is a ubiquitous and critical feature of gene regulation. Although DNA looping can be efficiently detected, tools to readily manipulate DNA looping are limited. Here we develop CRISPR-based DNA looping reagents for creation of programmable DNA loops. Cleavage-defective Cas9 proteins of different specificity are linked by heterodimerization or translational fusion to create bivalent complexes able to link two separate DNA regions. After model-directed optimization, the reagents are validated using a quantitative DNA looping assay in E. coli. Looping efficiency is ~15% for a 4.7 kb loop, but is significantly improved by loop multiplexing with additional guides. Bivalent dCas9 complexes are also used to activate endogenous norVW genes by rewiring chromosomal DNA to bring distal enhancer elements to the gene promoters. Such reagents should allow manipulation of DNA looping in a variety of cell types, aiding understanding of endogenous loops and enabling creation of new regulatory connections. PMID- 29158477 TI - Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells. AB - Sirolimus (rapamycin) is an immunosuppressive drug used in transplantation. One of its major side effects is the increased risk of diabetes mellitus; however, the exact mechanisms underlying such association have not been elucidated. Here we show that sirolimus impairs glucose-stimulated insulin secretion both in human and murine pancreatic islets and in clonal beta cells in a dose- and time dependent manner. Importantly, we demonstrate that sirolimus markedly depletes calcium (Ca2+) content in the endoplasmic reticulum and significantly decreases glucose-stimulated mitochondrial Ca2+ uptake. Crucially, the reduced mitochondrial Ca2+ uptake is mirrored by a significant impairment in mitochondrial respiration. Taken together, our findings indicate that sirolimus causes depletion of intracellular Ca2+ stores and alters mitochondrial fitness, eventually leading to decreased insulin release. Our results provide a novel molecular mechanism underlying the increased incidence of diabetes mellitus in patients treated with this drug. PMID- 29158478 TI - Structural basis for xenobiotic extrusion by eukaryotic MATE transporter. AB - Mulitidrug and toxic compound extrusion (MATE) family transporters export xenobiotics to maintain cellular homeostasis. The human MATE transporters mediate the excretion of xenobiotics and cationic clinical drugs, whereas some plant MATE transporters are responsible for aluminum tolerance and secondary metabolite transport. Here we report the crystal structure of the eukaryotic MATE transporter from Arabidopsis thaliana, at 2.6 A resolution. The structure reveals that its carboxy-terminal lobe (C-lobe) contains an extensive hydrogen-bonding network with well-conserved acidic residues, and their importance is demonstrated by the structure-based mutational analysis. The structural and functional analyses suggest that the transport mechanism involves the structural change of transmembrane helix 7, induced by the formation of a hydrogen-bonding network upon the protonation of the conserved acidic residue in the C-lobe. Our findings provide insights into the transport mechanism of eukaryotic MATE transporters, which is important for the improvement of the pharmacokinetics of the clinical drugs. PMID- 29158479 TI - Extremely high magnetoresistance and conductivity in the type-II Weyl semimetals WP2 and MoP2. AB - The peculiar band structure of semimetals exhibiting Dirac and Weyl crossings can lead to spectacular electronic properties such as large mobilities accompanied by extremely high magnetoresistance. In particular, two closely neighboring Weyl points of the same chirality are protected from annihilation by structural distortions or defects, thereby significantly reducing the scattering probability between them. Here we present the electronic properties of the transition metal diphosphides, WP2 and MoP2, which are type-II Weyl semimetals with robust Weyl points by transport, angle resolved photoemission spectroscopy and first principles calculations. Our single crystals of WP2 display an extremely low residual low-temperature resistivity of 3 nOmega cm accompanied by an enormous and highly anisotropic magnetoresistance above 200 million % at 63 T and 2.5 K. We observe a large suppression of charge carrier backscattering in WP2 from transport measurements. These properties are likely a consequence of the novel Weyl fermions expressed in this compound. PMID- 29158480 TI - Reversal of drug-resistance by noscapine chemo-sensitization in docetaxel resistant triple negative breast cancer. AB - Multidrug resistance (MDR) is a major impediment to cancer treatment. Here, for the first time, we investigated the chemo-sensitizing effect of Noscapine (Nos) at low concentrations in conjunction with docetaxel (DTX) to overcome drug resistance of triple negative breast cancer (TNBC). In vitro experiments showed that Nos significantly inhibited proliferation of TNBC wild type (p < 0.01) and drug resistant (p < 0.05) TNBC cells. Nos followed by DTX treatment notably increased the cell viability (~1.3 fold) markedly (p < 0.05) in 3D models compared to conventional 2D systems. In vivo oral administration of Nos (100 mg/kg) followed by intravenous DTX (5 mg/kg) liposome treatment revealed regression of xenograft tumors in both wild type (p < 0.001) and drug-resistant (p < 0.05) xenografts. In wild type xenografts, combination of Nos plus DTX group showed 5.49 and 3.25 fold reduction in tumor volume compared to Nos and DTX alone groups, respectively. In drug-resistant xenografts, tumor volume was decreased 2.33 and 1.41 fold in xenografts treated with Nos plus DTX significantly (p < 0.05) compared to Nos and DTX alone respectively and downregulated the expression of anti-apoptotic factors and multidrug resistance proteins. Collectively, chemo sensitizing effect of Nos followed by DTX regime provide a promising chemotherapeutic strategy and its significant role for the treatment of drug resistant TNBC. PMID- 29158481 TI - Female-specific myoinhibitory peptide neurons regulate mating receptivity in Drosophila melanogaster. AB - Upon mating, fruit fly females become refractory to further mating for several days. An ejaculate protein called sex peptide (SP) acts on uterine neurons to trigger this behavioural change, but it is still unclear how the SP signal modifies the mating decision. Here we describe two groups of female-specific local interneurons that are important for this process-the ventral abdominal lateral (vAL) and ventral abdominal medial (vAM) interneurons. Both vAL and vAM express myoinhibitory peptide (Mip)-GAL4. vAL is positive for Mip neuropeptides and the sex-determining transcriptional factor doublesex. Silencing the Mip neurons in females induces active rejection of male courtship attempts, whereas activation of the Mip neurons makes even mated females receptive to re-mating. vAL and vAM are located in the abdominal ganglion (AG) where they relay the SP signal to other AG neurons that project to the brain. Mip neuropeptides appear to promote mating receptivity both in virgins and mated females, although it is dispensable for normal mating in virgin females. PMID- 29158482 TI - Structural basis for the unique ganglioside and cell membrane recognition mechanism of botulinum neurotoxin DC. AB - Botulinum neurotoxins (BoNTs), the most potent toxins known, are potential bioterrorism agents. It is well established that all seven serotypes of BoNTs (BoNT/A-G) require complex gangliosides as co-receptors. Here, we report that BoNT/DC, a presumed mosaic toxin between BoNT/D and BoNT/C1, binds and enters efficiently into neurons lacking complex gangliosides and shows no reduction in toxicity in mice deficient in complex gangliosides. The co-crystal structure of BoNT/DC with sialyl-Thomsen-Friedenreich antigen (Sialyl-T) suggests that BoNT/DC recognizes only the sialic acid, but not other moieties in gangliosides. Using liposome flotation assays, we demonstrate that an extended loop in BoNT/DC directly interacts with lipid membranes, and the co-occurring sialic acid binding and loop-membrane interactions mediate the recognition of gangliosides in membranes by BoNT/DC. These findings reveal a unique mechanism for cell membrane recognition and demonstrate that BoNT/DC can use a broad range of sialic acid containing moieties as co-receptors. PMID- 29158483 TI - Noninvasive liquid diet delivery of stable isotopes into mouse models for deep metabolic network tracing. AB - Delivering isotopic tracers for metabolic studies in rodents without overt stress is challenging. Current methods achieve low label enrichment in proteins and lipids. Here, we report noninvasive introduction of 13C6-glucose via a stress free, ad libitum liquid diet. Using NMR and ion chromatography-mass spectrometry, we quantify extensive 13C enrichment in products of glycolysis, the Krebs cycle, the pentose phosphate pathway, nucleobases, UDP-sugars, glycogen, lipids, and proteins in mouse tissues during 12 to 48 h of 13C6-glucose feeding. Applying this approach to patient-derived lung tumor xenografts (PDTX), we show that the liver supplies glucose-derived Gln via the blood to the PDTX to fuel Glu and glutathione synthesis while gluconeogenesis occurs in the PDTX. Comparison of PDTX with ex vivo tumor cultures and arsenic-transformed lung cells versus xenografts reveals differential glucose metabolism that could reflect distinct tumor microenvironment. We further found differences in glucose metabolism between the primary PDTX and distant lymph node metastases. PMID- 29158484 TI - The HSF1-PARP13-PARP1 complex facilitates DNA repair and promotes mammary tumorigenesis. AB - Poly(ADP-ribose) polymerase 1 (PARP1) is involved in DNA repair, chromatin structure, and transcription. However, the mechanisms that regulate PARP1 distribution on DNA are poorly understood. Here, we show that heat shock transcription factor 1 (HSF1) recruits PARP1 through the scaffold protein PARP13. In response to DNA damage, activated and auto-poly-ADP-ribosylated PARP1 dissociates from HSF1-PARP13, and redistributes to DNA lesions and DNA damage inducible gene loci. Histone deacetylase 1 maintains PARP1 in the ternary complex by inactivating PARP1 through deacetylation. Blocking ternary complex formation impairs redistribution of PARP1 during DNA damage, which reduces gene expression and DNA repair. Furthermore, ternary complex formation and PARP1 redistribution protect cells from DNA damage by promoting DNA repair, and support growth of BRCA1-null mammary tumors, which are sensitive to PARP inhibitors. Our findings identify HSF1 as a regulator of genome integrity and define this function as a guarding mechanism for a specific type of mammary tumorigenesis. PMID- 29158485 TI - Cytoplasmic cleavage of DPPA3 is required for intracellular trafficking and cleavage-stage development in mice. AB - Degradation of maternal proteins by the ubiquitin-proteasome system (UPS) accompanies the maternal-to-zygotic transition. DPPA3/Stella/PGC7, encoded by a maternal effect gene, is present in the nucleus and cytoplasm of zygotes and has been associated with protecting the female pronucleus from TET3-mediated demethylation. We now report that cytoplasmic DPPA3 is partially cleaved by the ubiquitin-proteasome system and an N-terminus fragment remains in the cytoplasm where it associates with early and re-cycling endosomes. If DPPA3 is absent or if cleavage is prevented, multiple vesicles coalesce/aggregate and markers of lysosomes are decreased. Fertilized eggs develop poorly into blastocysts, which results in significantly decreased fecundity of Dppa3 R60A transgenic mice. This phenocopies aspects of Lamp1/2 knockdowns and Dppa3 KO embryos can be partially rescued in vitro by DPPA31-60 and to a lesser extent by LAMP1/2. Thus, the N terminus of DPPA3 has a significant role in cytoplasmic vesicular trafficking in addition to its previously reported nuclear function. PMID- 29158486 TI - BL-Hi-C is an efficient and sensitive approach for capturing structural and regulatory chromatin interactions. AB - In human cells, DNA is hierarchically organized and assembled with histones and DNA-binding proteins in three dimensions. Chromatin interactions play important roles in genome architecture and gene regulation, including robustness in the developmental stages and flexibility during the cell cycle. Here we propose in situ Hi-C method named Bridge Linker-Hi-C (BL-Hi-C) for capturing structural and regulatory chromatin interactions by restriction enzyme targeting and two-step proximity ligation. This method improves the sensitivity and specificity of active chromatin loop detection and can reveal the regulatory enhancer-promoter architecture better than conventional methods at a lower sequencing depth and with a simpler protocol. We demonstrate its utility with two well-studied developmental loci: the beta-globin and HOXC cluster regions. PMID- 29158487 TI - Genetic variants associated with physical performance and anthropometry in old age: a genome-wide association study in the ilSIRENTE cohort. AB - Unraveling the complexity of aging is crucial for understanding its mechanisms and its role as a risk factor for most chronic conditions. Advancements marked by genome-wide association studies (GWASs) have sparked interest in gene cataloguing in the context of aging and age-related conditions. Here, we used GWAS to explore whether single nucleotide polymorphisms (SNPs) were associated with functional and anthropometric parameters in a cohort of old community-dwellers enrolled in the ilSIRENTE study. Analyses were carried out in men and women aged 80+ years enrolled in the ilSIRENTE study (n = 286) and replicated in the inCHIANTI study (n = 1055). Genotyping was accomplished on Infinium Human610-QUAD version 1. In the ilSIRENTE population, genetic variants in ZNF295 and C2CD2 (rs928874 and rs1788355) on chromosome 21q22.3, were significantly associated with the 4-meter gait speed (rs928874, p = 5.61 * 10-8; rs1788355, p = 5.73 * 10-8). This association was not replicated in the inCHIANTI population. Our findings suggest that specific SNPs may be associated with a key measure of physical performance in older adults. GWASs using larger samples are needed to confirm these preliminary results to enhance our comprehension of complex age-associated phenomena. PMID- 29158488 TI - Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair. AB - Efficient cell membrane repair mechanisms are essential for maintaining membrane integrity and thus for cell life. Here we show that the Ca2+- and phospholipid binding proteins annexin A4 and A6 are involved in plasma membrane repair and needed for rapid closure of micron-size holes. We demonstrate that annexin A4 binds to artificial membranes and generates curvature force initiated from free edges, whereas annexin A6 induces constriction force. In cells, plasma membrane injury and Ca2+ influx recruit annexin A4 to the vicinity of membrane wound edges where its homo-trimerization leads to membrane curvature near the edges. We propose that curvature force is utilized together with annexin A6-mediated constriction force to pull the wound edges together for eventual fusion. We show that annexin A4 can counteract various plasma membrane disruptions including holes of several micrometers indicating that induction of curvature force around wound edges is an early key event in cell membrane repair. PMID- 29158489 TI - Yeast display biopanning identifies human antibodies targeting glioblastoma stem like cells. AB - Glioblastoma stem-like cells (GSC) are hypothesized to evade current therapies and cause tumor recurrence, contributing to poor patient survival. Existing cell surface markers for GSC are developed from embryonic or neural stem cell systems; however, currently available GSC markers are suboptimal in sensitivity and specificity. We hypothesized that the GSC cell surface proteome could be mined with a yeast display antibody library to reveal novel immunophenotypes. We isolated an extensive collection of antibodies that were differentially selective for GSC. A single domain antibody VH-9.7 showed selectivity for five distinct patient-derived GSC lines and visualized orthotopic GBM xenografts in vivo after conjugation with a near-infrared dye. These findings demonstrate a previously unexplored high-throughput strategy for GSC-selective antibody discovery, to aid in GSC isolation, diagnostic imaging, and therapeutic targeting. PMID- 29158490 TI - Long-lived unipotent Blimp1-positive luminal stem cells drive mammary gland organogenesis throughout adult life. AB - The hierarchical relationships between various stem and progenitor cell subpopulations driving mammary gland morphogenesis and homoeostasis are poorly understood. Conditional inactivation experiments previously demonstrated that expression of the zinc finger transcriptional repressor Blimp1/PRDM1 is essential for the establishment of epithelial cell polarity and functional maturation of alveolar cells. Here we exploit a Prdm1.CreERT2-LacZ reporter allele for lineage tracing experiments. Blimp1 expression marks a rare subpopulation of unipotent luminal stem cells that initially appear in the embryonic mammary gland at around E17.5 coincident with the segregation of the luminal and basal compartments. Fate mapping at multiple time points in combination with whole-mount confocal imaging revealed these long-lived unipotent luminal stem cells survive consecutive involutions and retain their identity throughout adult life. Blimp1+ luminal stem cells give rise to Blimp1- progeny that are invariably Elf5+ERalpha-PR-. Thus, Blimp1 expression defines a mammary stem cell subpopulation with unique functional characteristics. PMID- 29158491 TI - Gallstone Disease and the Risk of Type 2 Diabetes. AB - Gallstone disease (GSD) is related to several diabetes risk factors. The present study was to examine whether GSD was independently associated with type 2 diabetes in the China Kadoorie Biobank study. After excluding participants with prevalent diabetes and prior histories of cancer, heart disease, and stroke at baseline, 189,154 men and 272,059 women aged 30-79 years were eligible for analysis. The baseline prevalence of GSD was 5.7% of the included participants. During 4,138,687 person-years of follow-up (median, 9.1 years), a total of 4,735 men and 7,747 women were documented with incident type 2 diabetes. Compared with participants without GSD at baseline, the multivariate-adjusted hazard ratios (HRs) for type 2 diabetes for those with GSD were 1.09 (95% CI: 0.96-1.24; P = 0.206), 1.21 (95% CI: 1.13-1.30; P < 0.001), and 1.17 (95% CI: 1.10-1.25; P < 0.001) in men, women, and the whole cohort respectively. There was no statistically significant heterogeneity between men and women (P = 0.347 for interaction). The association between GSD and type 2 diabetes was strongest among participants who reported >=5 years since the first diagnosis and were still on treatment at baseline (HR = 1.48; 95% CI: 1.16-1.88; P = 0.001). The present study highlights the importance of developing a novel prevention strategy to mitigate type 2 diabetes through improvement of gastrointestinal health. PMID- 29158492 TI - Structural basis for the assembly of the Ragulator-Rag GTPase complex. AB - The mechanistic target of rapamycin complex 1 (mTORC1) plays a central role in regulating cell growth and metabolism by responding to cellular nutrient conditions. The activity of mTORC1 is controlled by Rag GTPases, which are anchored to lysosomes via Ragulator, a pentameric protein complex consisting of membrane-anchored p18/LAMTOR1 and two roadblock heterodimers. Here we report the crystal structure of Ragulator in complex with the roadblock domains of RagA-C, which helps to elucidate the molecular basis for the regulation of Rag GTPases. In the structure, p18 wraps around the three pairs of roadblock heterodimers to tandemly assemble them onto lysosomes. Cellular and in vitro analyses further demonstrate that p18 is required for Ragulator-Rag GTPase assembly and amino acid dependent activation of mTORC1. These results establish p18 as a critical organizing scaffold for the Ragulator-Rag GTPase complex, which may provide a platform for nutrient sensing on lysosomes. PMID- 29158493 TI - Structural and spatial chromatin features at developmental gene loci in human pluripotent stem cells. AB - Higher-order chromatin organization controls transcriptional programs that govern cell properties and functions. In order for pluripotent stem cells (PSCs) to appropriately respond to differentiation signals, developmental gene loci should be structurally and spatially regulated to be readily available for immediate transcription, even though these genes are hardly expressed in PSCs. Here, we show that both chromatin interaction profiles and nuclear positions at developmental gene loci differ between human somatic cells and hPSCs, and that changes in the chromatin interactions are closely related to the nuclear repositioning. Moreover, we also demonstrate that developmental gene loci, which have bivalent histone modifications, tend to colocalize in PSCs. Furthermore, this colocalization requires PRC1, PRC2, and TrxG complexes, which are essential regulatory factors for the maintenance of transcriptionally poised developmental genes. Our results indicate that higher-order chromatin regulation may be an integral part of the differentiation capacity that defines pluripotency. PMID- 29158495 TI - The prevalence of muscle wasting (sarcopenia) in peritoneal dialysis patients varies with ethnicity due to differences in muscle mass measured by bioimpedance. AB - BACKGROUND/OBJECTIVES: Sarcopenia is associated with increased mortality. European and North American recommended screening for low muscle mass uses gender specific cut points, with no adjustment for ethnicity. We wished to determine whether the prevalence of sarcopenia was altered by ethnicity in peritoneal dialysis (PD) patients. SUBJECTS/METHODS: We measured appendicular lean mass indexed to height (ALMI) in PD patients by segmental bioimpedance and determined sarcopenia using different cut off points for reduced muscle mass. RESULTS: We measured ALMI in 434 PD patients, 55.1% males, mean age 55.3 +/- 16.2 years, 32.3% diabetic, 54.1% white, 23.7% Asian, 19.1% black. ALMI was lower in Asian women, compared to white and black women (6.4 +/- 1.1 vs. 6.6 +/- 1.0 and 6.9 +/- 1.4 kg/m2), and lower in Asian men (7.5 +/- 1.3 vs. 8.5 +/- 1.2 and 8.7 +/- 1.3 kg/m2), p < 0.001. Depending on the ALM/ALMI cut point; the prevalence of sarcopenia was greater in Asian patients (25.6-41.2% using North American or European cut points) compared to white (12.3-18.7%) and black patients (3.8 15.7%), p < 0.001, but <11% when using Asian-specific cut points. The prevalence of sarcopenia obesity (BMI >= 30 kg/m2) was <3%, for all groups. There was no association with duration of PD, dialysis prescription, residual renal function or small solute clearances. CONCLUSIONS: There is no universally agreed consensus definition for loss of muscle mass (sarcopenia) and current European and North American recommended cut points for screening are adjusted only for gender. As body composition differs also with age and ethnicity, then ideally cut points should be based on age, gender and ethnicity normative values. PMID- 29158494 TI - Mrg15 stimulates Ash1 H3K36 methyltransferase activity and facilitates Ash1 Trithorax group protein function in Drosophila. AB - Ash1 is a Trithorax group protein that possesses H3K36-specific histone methyltransferase activity, which antagonizes Polycomb silencing. Here we report the identification of two Ash1 complex subunits, Mrg15 and Nurf55. In vitro, Mrg15 stimulates the enzymatic activity of Ash1. In vivo, Mrg15 is recruited by Ash1 to their common targets, and Mrg15 reinforces Ash1 chromatin association and facilitates the proper deposition of H3K36me2. To dissect the functional role of Mrg15 in the context of the Ash1 complex, we identify an Ash1 point mutation (Ash1-R1288A) that displays a greatly attenuated interaction with Mrg15. Knock-in flies bearing this mutation display multiple homeotic transformation phenotypes, and these phenotypes are partially rescued by overexpressing the Mrg15-Nurf55 fusion protein, which stabilizes the association of Mrg15 with Ash1. In summary, Mrg15 is a subunit of the Ash1 complex, a stimulator of Ash1 enzymatic activity and a critical regulator of the TrxG protein function of Ash1 in Drosophila. PMID- 29158496 TI - Diastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles using both aldonitrones and ketonitrones. AB - Optically active spirocyclic compounds play an important role in drug discovery, and new synthetic strategies for the efficient generation of spiro stereocenters are in much demand. Here we report a catalytic enantioselective cycloaddition using spirocyclic donor-acceptor cyclopropanes as a promising approach for the generation of spiro stereocenters. A diastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles with both aldonitrones and ketonitrones is developed. The key to reaction development is the activation of spirocyclopropyl oxindoles by a suitable electron-withdrawing N-protecting group. This activation approach offers the promise of a general solution to enable spirocyclopropyl oxindoles as synthons for catalytic enantioselective synthesis of spirocyclic oxindoles featuring a C3 spiro stereocenter, a prominent structural motif in drugs and pharmaceutically active compounds. This protocol also constitutes the catalytic enantioselective reaction using unactivated achiral ketonitrones to construct tetrasubstituted carbon stereocenters. PMID- 29158497 TI - Germline variation in ADAMTSL1 is associated with prognosis following breast cancer treatment in young women. AB - To identify genetic variants associated with breast cancer prognosis we conduct a meta-analysis of overall survival (OS) and disease-free survival (DFS) in 6042 patients from four cohorts. In young women, breast cancer is characterized by a higher incidence of adverse pathological features, unique gene expression profiles and worse survival, which may relate to germline variation. To explore this hypothesis, we also perform survival analysis in 2315 patients aged <= 40 years at diagnosis. Here, we identify two SNPs associated with early-onset DFS, rs715212 (P meta = 3.54 * 10-5) and rs10963755 (P meta = 3.91 * 10-4) in ADAMTSL1. The effect of these SNPs is independent of classical prognostic factors and there is no heterogeneity between cohorts. Most importantly, the association with rs715212 is noteworthy (FPRP <0.2) and approaches genome-wide significance in multivariable analysis (P multivariable = 5.37 * 10-8). Expression quantitative trait analysis provides tentative evidence that rs715212 may influence AREG expression (P eQTL = 0.035), although further functional studies are needed to confirm this association and determine a mechanism. PMID- 29158498 TI - Activity-dependent expression of Channelrhodopsin at neuronal synapses. AB - Increasing evidence points to the importance of dendritic spines in the formation and allocation of memories, and alterations of spine number and physiology are associated to memory and cognitive disorders. Modifications of the activity of subsets of synapses are believed to be crucial for memory establishment. However, the development of a method to directly test this hypothesis, by selectively controlling the activity of potentiated spines, is currently lagging. Here we introduce a hybrid RNA/protein approach to regulate the expression of a light sensitive membrane channel at activated synapses, enabling selective tagging of potentiated spines following the encoding of a novel context in the hippocampus. This approach can be used to map potentiated synapses in the brain and will make it possible to re-activate the neuron only at previously activated synapses, extending current neuron-tagging technologies in the investigation of memory processes. PMID- 29158500 TI - Use-dependent potentiation of voltage-gated calcium channels rescues neurotransmission in nerve terminals intoxicated by botulinum neurotoxin serotype A. AB - Botulinum neurotoxins (BoNTs) are highly potent toxins that cleave neuronal SNARE proteins required for neurotransmission, causing flaccid paralysis and death by asphyxiation. Currently, there are no clinical treatments to delay or reverse BoNT-induced blockade of neuromuscular transmission. While aminopyridines have demonstrated varying efficacy in transiently reducing paralysis following BoNT poisoning, the precise mechanisms by which aminopyridines symptomatically treat botulism are not understood. Here we found that activity-dependent potentiation of presynaptic voltage-gated calcium channels (VGCCs) underlies 3,4 diaminopyridine (3,4-DAP)-mediated rescue of neurotransmission in central nervous system synapses and mouse diaphragm neuromuscular junctions fully intoxicated by BoNT serotype A. Combinatorial treatments with 3,4-DAP and VGCC agonists proved synergistic in restoring suprathreshold endplate potentials in mouse diaphragms fully intoxicated by BoNT/A. In contrast, synapses fully intoxicated by BoNT serotypes D or E were refractory to synaptic rescue by any treatment. We interpret these data to propose that increasing the duration or extent of VGCC activation prolongs the opportunity for low-efficiency fusion by fusogenic complexes incorporating BoNT/A-cleaved SNAP-25. The identification of VGCC agonists that rescue neurotransmission in BoNT/A-intoxicated synapses provides compelling evidence for potential therapeutic utility in some cases of human botulism. PMID- 29158499 TI - Cardiac myocyte miR-29 promotes pathological remodeling of the heart by activating Wnt signaling. AB - Chronic cardiac stress induces pathologic hypertrophy and fibrosis of the myocardium. The microRNA-29 (miR-29) family has been found to prevent excess collagen expression in various organs, particularly through its function in fibroblasts. Here, we show that miR-29 promotes pathologic hypertrophy of cardiac myocytes and overall cardiac dysfunction. In a mouse model of cardiac pressure overload, global genetic deletion of miR-29 or antimiR-29 infusion prevents cardiac hypertrophy and fibrosis and improves cardiac function. Targeted deletion of miR-29 in cardiac myocytes in vivo also prevents cardiac hypertrophy and fibrosis, indicating that the function of miR-29 in cardiac myocytes dominates over that in non-myocyte cell types. Mechanistically, we found cardiac myocyte miR-29 to de-repress Wnt signaling by directly targeting four pathway factors. Our data suggests that, cell- or tissue-specific antimiR-29 delivery may have therapeutic value for pathological cardiac remodeling and fibrosis. PMID- 29158501 TI - Diverse landscapes beneath Pine Island Glacier influence ice flow. AB - The retreating Pine Island Glacier (PIG), West Antarctica, presently contributes ~5-10% of global sea-level rise. PIG's retreat rate has increased in recent decades with associated thinning migrating upstream into tributaries feeding the main glacier trunk. To project future change requires modelling that includes robust parameterisation of basal traction, the resistance to ice flow at the bed. However, most ice-sheet models estimate basal traction from satellite-derived surface velocity, without a priori knowledge of the key processes from which it is derived, namely friction at the ice-bed interface and form drag, and the resistance to ice flow that arises as ice deforms to negotiate bed topography. Here, we present high-resolution maps, acquired using ice-penetrating radar, of the bed topography across parts of PIG. Contrary to lower-resolution data currently used for ice-sheet models, these data show a contrasting topography across the ice-bed interface. We show that these diverse subglacial landscapes have an impact on ice flow, and present a challenge for modelling ice-sheet evolution and projecting global sea-level rise from ice-sheet loss. PMID- 29158502 TI - Competing tradeoffs between increasing marine mammal predation and fisheries harvest of Chinook salmon. AB - Many marine mammal predators, particularly pinnipeds, have increased in abundance in recent decades, generating new challenges for balancing human uses with recovery goals via ecosystem-based management. We used a spatio-temporal bioenergetics model of the Northeast Pacific Ocean to quantify how predation by three species of pinnipeds and killer whales (Orcinus orca) on Chinook salmon (Oncorhynchus tshawytscha) has changed since the 1970s along the west coast of North America, and compare these estimates to salmon fisheries. We find that from 1975 to 2015, biomass of Chinook salmon consumed by pinnipeds and killer whales increased from 6,100 to 15,200 metric tons (from 5 to 31.5 million individual salmon). Though there is variation across the regions in our model, overall, killer whales consume the largest biomass of Chinook salmon, but harbor seals (Phoca vitulina) consume the largest number of individuals. The decrease in adult Chinook salmon harvest from 1975-2015 was 16,400 to 9,600 metric tons. Thus, Chinook salmon removals (harvest + consumption) increased in the past 40 years despite catch reductions by fisheries, due to consumption by recovering pinnipeds and endangered killer whales. Long-term management strategies for Chinook salmon will need to consider potential conflicts between rebounding predators or endangered predators and prey. PMID- 29158503 TI - Krupple-like-factor 4 Attenuates Lung Fibrosis via Inhibiting Epithelial mesenchymal Transition. AB - Epithelial-mesenchymal transition (EMT) plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Krupple-like-factor 4 (KLF4), has been suggested to play an important role in the phenotype transition. However, its function in pulmonary fibrosis and EMT of human alveolar epithelial cells (AECs) remains unclear. This study aimed to examine the role of KLF4 in pulmonary fibrosis and EMT. Decreased expression of KLF4 was first observed in human IPF lung tissues and models of bleomycin-induced pulmonary fibrosis. Transgenic mice with overexpression of KLF4 were subjected to bleomycin-induced pulmonary fibrosis model and showed attenuated lung fibrosis and EMT compared to wild type group. Furthermore, the effects overexpression and knockdown of KLF4 on TGF-beta1-induced EMT were examined in AECs. Adenovirus-mediated overexpression of KLF4 attenuated TGF-beta1-induced EMT and activation of Smad2/3 and Dvl in AECs. Conversely, knockdown of KLF4 promoted the activation of pathways above mentioned and TGF-beta1-induced EMT. Our results demonstrates that KLF4 plays an important role in bleomycin-induced lung fibrosis through suppressing TGFbeta1 induced EMT. Thus, it may serve as a potential target for the treatment of pulmonary fibrosis. PMID- 29158504 TI - Computational design of fully overlapping coding schemes for protein pairs and triplets. AB - Gene pairs that overlap in their coding regions are rare except in viruses. They may occur transiently in gene creation and are of biotechnological interest. We have examined the possibility to encode an arbitrary pair of protein domains as a dual gene, with the shorter coding sequence completely embedded in the longer one. For 500 * 500 domain pairs (X, Y), we computationally designed homologous pairs (X', Y') coded this way, using an algorithm that provably maximizes the sequence similarity between (X', Y') and (X, Y). Three schemes were considered, with X' and Y' coded on the same or complementary strands. For 16% of the pairs, an overlapping coding exists where the level of homology of X', Y' to the natural proteins represents an E-value of 10-10 or better. Thus, for an arbitrary domain pair, it is surprisingly easy to design homologous sequences that can be encoded as a fully-overlapping gene pair. The algorithm is general and was used to design 200 triple genes, with three proteins encoded by the same DNA segment. The ease of design suggests overlapping genes may have occurred frequently in evolution and could be readily used to compress or constrain artificial genomes. PMID- 29158505 TI - Dynamic profile of differentiated thyroid cancer in male and female patients with thyroidectomy during 2000-2013 in China: a retrospective study. AB - The study aimed to investigate the gender-related differences of disease onset, age distribution, blood type, clinical characteristics, and malignant behaviors of differentiated thyroid carcinoma (DTC) in Chinese patients. A total of 7385 consecutive thyroid cancer patients who underwent thyroidectomy were retrospectively reviewed. 4087 (55.3%) were diagnosed as benign and the other (3298, 44.7%) were as malignant. DTC accounted for 97.6% in the malignant tumor. More single nodules turned out to be DTC in male compared to multiple nodules (46.9% vs. 40.4%, P = 0.004). The proportion increased along with the increase of year during 2000-2013, which was from 7.5% to 68.1% in males and from 16.2% to 66.7% in females. The level of preoperative TSH was significantly higher in patients with DTC compared to the patients with benign (1.97 vs. 1.57 mIU/L, P < 0.001). The proportion of thyroid cancer was dominated in blood type B and the lowest incidence in blood type A in male, the difference was not statistically significant. The results showed that age, nodule number, BMI and serum TSH were the related factors for DTC. More aggressive behaviors of DTC were observed in male patients, and more attention should be focused on the timely diagnosis and treatment of these patients. PMID- 29158507 TI - Dynamically controlled Purcell enhancement of visible spontaneous emission in a gated plasmonic heterostructure. AB - Emission control of colloidal quantum dots (QDs) is a cornerstone of modern high quality lighting and display technologies. Dynamic emission control of colloidal QDs in an optoelectronic device is usually achieved by changing the optical pump intensity or injection current density. Here we propose and demonstrate a distinctly different mechanism for the temporal modulation of QD emission intensity at constant optical pumping rate. Our mechanism is based on the electrically controlled modulation of the local density of optical states (LDOS) at the position of the QDs, resulting in the modulation of the QD spontaneous emission rate, far-field emission intensity, and quantum yield. We manipulate the LDOS via field effect-induced optical permittivity modulation of an ultrathin titanium nitride (TiN) film, which is incorporated in a gated TiN/SiO2/Ag plasmonic heterostructure. The demonstrated electrical control of the colloidal QD emission provides a new approach for modulating intensity of light in displays and other optoelectronics. PMID- 29158506 TI - The IKK/NF-kappaB signaling pathway requires Morgana to drive breast cancer metastasis. AB - NF-kappaB is a transcription factor involved in the regulation of multiple physiological and pathological cellular processes, including inflammation, cell survival, proliferation, and cancer cell metastasis. NF-kappaB is frequently hyperactivated in several cancers, including triple-negative breast cancer. Here we show that NF-kappaB activation in breast cancer cells depends on the presence of the CHORDC1 gene product Morgana, a previously unknown component of the IKK complex and essential for IkappaBalpha substrate recognition. Morgana silencing blocks metastasis formation in breast cancer mouse models and this phenotype is reverted by IkappaBalpha downregulation. High Morgana expression levels in cancer cells decrease recruitment of natural killer cells in the first phases of tumor growth and induce the expression of cytokines able to attract neutrophils in the primary tumor, as well as in the pre-metastatic lungs, fueling cancer metastasis. In accordance, high Morgana levels positively correlate with NF-kappaB target gene expression and poor prognosis in human patients. PMID- 29158508 TI - Switching between H- and J-type electronic coupling in single conjugated polymer aggregates. AB - The aggregation of conjugated polymers and electronic coupling of chromophores play a central role in the fundamental understanding of light and charge generation processes. Here we report that the predominant coupling in isolated aggregates of conjugated polymers can be switched reversibly between H-type and J type coupling by partially swelling and drying the aggregates. Aggregation is identified by shifts in photoluminescence energy, changes in vibronic peak ratio, and photoluminescence lifetime. This experiment unravels the internal electronic structure of the aggregate and highlights the importance of the drying process in the final spectroscopic properties. The electronic coupling after drying is tuned between H-type and J-type by changing the side chains of the conjugated polymer, but can also be entirely suppressed. The types of electronic coupling correlate with chain morphology, which is quantified by excitation polarization spectroscopy and the efficiency of interchromophoric energy transfer that is revealed by the degree of single-photon emission. PMID- 29158509 TI - Clinical utility of the Prostate Health Index (phi) for biopsy decision management in a large group urology practice setting. AB - BACKGROUND: Deciding when to biopsy a man with non-suspicious DRE findings and tPSA in the 4-10 ng/ml range can be challenging, because two-thirds of such biopsies are typically found to be benign. The Prostate Health Index (phi) exhibits significantly improved diagnostic accuracy for prostate cancer detection when compared to tPSA and %fPSA, however only one published study to date has investigated its impact on biopsy decisions in clinical practice. METHODS: An IRB approved observational study was conducted at four large urology group practices using a physician reported two-part questionnaire. Physician recommendations were recorded before and after receiving the phi test result. A historical control group was queried from each site's electronic medical records for eligible men who were seen by the same participating urologists prior to the implementation of the phi test in their practice. 506 men receiving a phi test were prospectively enrolled and 683 men were identified for the historical control group (without phi). Biopsy and pathological findings were also recorded for both groups. RESULTS: Men receiving a phi test showed a significant reduction in biopsy procedures performed when compared to the historical control group (36.4% vs. 60.3%, respectively, P < 0.0001). Based on questionnaire responses, the phi score impacted the physician's patient management plan in 73% of cases, including biopsy deferrals when the phi score was low, and decisions to perform biopsies when the phi score indicated an intermediate or high probability of prostate cancer (phi >=36). CONCLUSIONS: phi testing significantly impacted the physician's biopsy decision for men with tPSA in the 4-10 ng/ml range and non suspicious DRE findings. Appropriate utilization of phi resulted in a significant reduction in biopsy procedures performed compared to historical patients seen by the same participating urologists who would have met enrollment eligibility but did not receive a phi test. PMID- 29158511 TI - Anti-Stokes photoluminescence probing k-conservation and thermalization of minority carriers in degenerately doped semiconductors. AB - It has recently been found that anti-Stokes photoluminescence can be observed in degenerately n-doped indium phosphide nanowires, when exciting directly into the electron gas. This anti-Stokes mechanism has not been observed before and allows the study of carrier relaxation and recombination using standard photoluminescence techniques. It is important to know if this anti-Stokes photoluminescence also occurs in bulk semiconductors as well as its relation to carrier recombination and relaxation. Here we show that similar anti-Stokes photoluminescence can indeed be observed in degenerately doped bulk indium phosphide and gallium arsenide and is caused by minority carriers scattering to high momenta by phonons. We find in addition that the radiative electron-hole recombination is highly momentum-conserving and that photogenerated minority carriers recombine before relaxing to the band edge at low temperatures. These observations challenge the use of models assuming thermalization of minority carriers in the analysis of highly doped devices. PMID- 29158510 TI - Construction of developmental lineage relationships in the mouse mammary gland by single-cell RNA profiling. AB - The mammary epithelium comprises two primary cellular lineages, but the degree of heterogeneity within these compartments and their lineage relationships during development remain an open question. Here we report single-cell RNA profiling of mouse mammary epithelial cells spanning four developmental stages in the post natal gland. Notably, the epithelium undergoes a large-scale shift in gene expression from a relatively homogeneous basal-like program in pre-puberty to distinct lineage-restricted programs in puberty. Interrogation of single-cell transcriptomes reveals different levels of diversity within the luminal and basal compartments, and identifies an early progenitor subset marked by CD55. Moreover, we uncover a luminal transit population and a rare mixed-lineage cluster amongst basal cells in the adult mammary gland. Together these findings point to a developmental hierarchy in which a basal-like gene expression program prevails in the early post-natal gland prior to the specification of distinct lineage signatures, and the presence of cellular intermediates that may serve as transit or lineage-primed cells. PMID- 29158513 TI - Microscale cavitation as a mechanism for nucleating earthquakes at the base of the seismogenic zone. AB - Major earthquakes frequently nucleate near the base of the seismogenic zone, close to the brittle-ductile transition. Fault zone rupture at greater depths is inhibited by ductile flow of rock. However, the microphysical mechanisms responsible for the transition from ductile flow to seismogenic brittle/frictional behaviour at shallower depths remain unclear. Here we show that the flow-to-friction transition in experimentally simulated calcite faults is characterized by a transition from dislocation and diffusion creep to dilatant deformation, involving incompletely accommodated grain boundary sliding. With increasing shear rate or decreasing temperature, dislocation and diffusion creep become too slow to accommodate the imposed shear strain rate, leading to intergranular cavitation, weakening, strain localization, and a switch from stable flow to runaway fault rupture. The observed shear instability, triggered by the onset of microscale cavitation, provides a key mechanism for bringing about the brittle-ductile transition and for nucleating earthquakes at the base of the seismogenic zone. PMID- 29158512 TI - Wild bonobos host geographically restricted malaria parasites including a putative new Laverania species. AB - Malaria parasites, though widespread among wild chimpanzees and gorillas, have not been detected in bonobos. Here, we show that wild-living bonobos are endemically Plasmodium infected in the eastern-most part of their range. Testing 1556 faecal samples from 11 field sites, we identify high prevalence Laverania infections in the Tshuapa-Lomami-Lualaba (TL2) area, but not at other locations across the Congo. TL2 bonobos harbour P. gaboni, formerly only found in chimpanzees, as well as a potential new species, Plasmodium lomamiensis sp. nov. Rare co-infections with non-Laverania parasites were also observed. Phylogenetic relationships among Laverania species are consistent with co-divergence with their gorilla, chimpanzee and bonobo hosts, suggesting a timescale for their evolution. The absence of Plasmodium from most field sites could not be explained by parasite seasonality, nor by bonobo population structure, diet or gut microbiota. Thus, the geographic restriction of bonobo Plasmodium reflects still unidentified factors that likely influence parasite transmission. PMID- 29158514 TI - Large magneto-Seebeck effect in magnetic tunnel junctions with half-metallic Heusler electrodes. AB - Spin caloritronics studies the interplay between charge-, heat- and spin currents, which are initiated by temperature gradients in magnetic nanostructures. A plethora of new phenomena has been discovered that promises, e.g., to make wasted heat in electronic devices useable or to provide new read out mechanisms for information. However, only few materials have been studied so far with Seebeck voltages of only some microvolt, which hampers applications. Here, we demonstrate that half-metallic Heusler compounds are hot candidates for enhancing spin-dependent thermoelectric effects. This becomes evident when considering the asymmetry of the spin-split density of electronic states around the Fermi level that determines the spin-dependent thermoelectric transport in magnetic tunnel junctions. We identify Co2FeAl and Co2FeSi Heusler compounds as ideal due to their energy gaps in the minority density of states, and demonstrate devices with substantially larger Seebeck voltages and tunnel magneto-Seebeck effect ratios than the commonly used Co-Fe-B-based junctions. PMID- 29158516 TI - Prostate shapes on pre-treatment MRI between prostate cancer patients who do and do not undergo biochemical recurrence are different: Preliminary Findings. AB - Early identification of PCa patients at risk for biochemical recurrence (BCR) post-therapy will potentially complement definitive therapy with either neo- or adjuvant therapy to improve prognosis. BCR post definitive therapy is often associated with disease progression that might cause a bulge in the prostate gland. In this work we explored if an atlas-based comparison approach reveals shape differences in the prostate capsule as observed on pre-treatment T2 weighted MRI between prostate cancer patients who do (BCR +) and do not (BCR -) have BCR following definitive therapy. A single center IRB approved study included 874 patients. Complete image datasets, clinically localized PCa, availability of Gleason score, data available for post-treatment PSA and follow up for at least 3 years in patients without BCR were the inclusion criteria to select 77 patients out of the 874 patients. Further controlling for Gleason score, stage, age and to maintain equal number of cases for the BCR + and BCR - categories, the total number of cases was reduced to 50. Manually segmented prostate capsules were aligned to a BCR - template for statistical comparison between the BCR + and BCR - groups. Statistically significant shape difference between the two groups was observed towards the lateral and the posterior sides of prostate. PMID- 29158515 TI - A programmed cell division delay preserves genome integrity during natural genetic transformation in Streptococcus pneumoniae. AB - Competence for genetic transformation is a differentiation program during which exogenous DNA is imported into the cell and integrated into the chromosome. In Streptococcus pneumoniae, competence develops transiently and synchronously in all cells during exponential phase, and is accompanied by a pause in growth. Here, we reveal that this pause is linked to the cell cycle. At least two parallel pathways impair peptidoglycan synthesis in competent cells. Single-cell analyses demonstrate that ComM, a membrane protein induced during competence, inhibits both initiation of cell division and final constriction of the cytokinetic ring. Competence also interferes with the activity of the serine/threonine kinase StkP, the central regulator of pneumococcal cell division. We further present evidence that the ComM-mediated delay in division preserves genomic integrity during transformation. We propose that cell division arrest is programmed in competent pneumococcal cells to ensure that transformation is complete before resumption of cell division, to provide this pathogen with the maximum potential for genetic diversity and adaptation. PMID- 29158517 TI - Disentangling physical and biological drivers of phytoplankton dynamics in a coastal system. AB - This proof-of-concept study integrates the surface currents measured by high frequency coastal radars with plankton time-series data collected at a fixed sampling point from the Mediterranean Sea (MareChiara Long Term Ecological Research site in the Gulf of Naples) to characterize the spatial origin of phytoplankton assemblages and to scrutinize the processes ruling their dynamics. The phytoplankton community generally originated from the coastal waters whereby species succession was mainly regulated by biological factors (life-cycle processes, species-specific physiological performances and inter-specific interactions). Physical factors, e.g. the alternation between coastal and offshore waters and the horizontal mixing, were also important drivers of phytoplankton dynamics promoting diversity maintenance by i) advecting species from offshore and ii) diluting the resident coastal community so as to dampen resource stripping by dominant species and thereby increase the numerical importance of rarer species. Our observations highlight the resilience of coastal communities, which may favour their persistence over time and the prevalence of successional events over small time and space scales. Although coastal systems may act differently from one another, our findings provide a conceptual framework to address physical-biological interactions occurring in coastal basins, which can be generalised to other areas. PMID- 29158518 TI - miRNAs in bone tissue correlate to bone mineral density and circulating miRNAs are gender independent in osteoporotic patients. AB - We previously demonstrated the aberrant expression of nine specific miRNAs in serum from osteoporotic patients. In the present study, we further evaluated the expression of these miRNAs in bone tissue, osteoblasts, and osteoclasts from 28 patients. We hypothesize that miRNA expression in serum from osteoporotic patients may be gender-independent. A further hypothesis is that the miRNA expression in bone could be correlated with BMD values. Moreover, intracellular expression of these osteoporosis-related miRNAs may indicate the role of these molecules during osteoporosis. Our results indeed show that miRNA expression in serum was gender-independent except for miR125b-5p. A correlation with BMD was confirmed for miR-21-5p, miR-24-3p, miR-93-5p, miR-100-5p and miR125b-5p with linear correlation coefficients r > 0.9. Intracellular studies revealed a simultaneous up-regulation of miR-21-5p, miR-93-5p, miR-100-5p and miR125b-5p in osteoblasts and in osteoclasts. miR-148a-3p up-regulation in cells was specific for osteoporotic osteoclasts. Altogether, miR-21-5p, miR-93-5p, miR-100-5p, and miR-125b-5p showed significant upregulation in serum, tissue and bone cells of osteoporotic patients. All except miR-125b-5p showed gender independent expression and good correlation to BMD values. Our results suggest that these miRNAs may be important for an earlier diagnosis of osteoporosis. PMID- 29158519 TI - Biosynthesis of helvolic acid and identification of an unusual C-4-demethylation process distinct from sterol biosynthesis. AB - Fusidane-type antibiotics represented by helvolic acid, fusidic acid and cephalosporin P1 are a class of bacteriostatic agents, which have drawn renewed attention because they have no cross-resistance to commonly used antibiotics. However, their biosynthesis is poorly understood. Here, we perform a stepwise introduction of the nine genes from the proposed gene cluster for helvolic acid into Aspergillus oryzae NSAR1, which enables us to isolate helvolic acid (~20 mg L-1) and its 21 derivatives. Anti-Staphylococcus aureus assay reveals that the antibacterial activity of three intermediates is even stronger than that of helvolic acid. Notably, we observe an unusual C-4 demethylation process mediated by a promiscuous short-chain dehydrogenase/reductase (HelC) and a cytochrome P450 enzyme (HelB1), which is distinct from the common sterol biosynthesis. These studies have set the stage for using biosynthetic approaches to expand chemical diversity of fusidane-type antibiotics. PMID- 29158521 TI - Characterization and Separation Performance of a Novel Polyethersulfone Membrane Blended with Acacia Gum. AB - Novel polyethersulfone (PES) membranes blended with 0.1-3.0 wt. % of Acacia gum (AG) as a pore-former and antifouling agent were fabricated using phase inversion technique. The effect of AG on the pore-size, porosity, surface morphology, surface charge, hydrophilicity, and mechanical properties of PES/AG membranes was studied by scanning electron microscopy (SEM), Raman spectroscopy, contact angle and zeta potential measurements. The antifouling -properties of PES/AG membranes were evaluated using Escherichia coli bacteria and bovine serum albumine (BSA). The use of AG as an additive to PES membranes was found to increase the surface charge, hydrophilicity (by 20%), porosity (by 77%) and permeate flux (by about 130%). Moreover, PES/AG membranes demonstrated higher antifouling and tensile stress (by 31%) when compared to pure PES membranes. It was shown that the prepared PES/AG membranes efficiently removed lead ions from aqueous solutions. Both the sieving mechanism of the membrane and chelation of lead with AG macromolecules incorporated in the membrane matrix contributed to lead removal. The obtained results indicated that AG can be used as a novel pore-former, hydrophilizing and antifouling agent, as well as an enhancer to the mechanical and rejection properties of the PES membranes. PMID- 29158520 TI - MyD88 promotes myoblast fusion in a cell-autonomous manner. AB - Myoblast fusion is an indispensable step for skeletal muscle development, postnatal growth, and regeneration. Myeloid differentiation primary response gene 88 (MyD88) is an adaptor protein that mediates Toll-like receptors and interleukin-1 receptor signaling. Here we report a cell-autonomous role of MyD88 in the regulation of myoblast fusion. MyD88 protein levels are increased during in vitro myogenesis and in conditions that promote skeletal muscle growth in vivo. Deletion of MyD88 impairs fusion of myoblasts without affecting their survival, proliferation, or differentiation. MyD88 regulates non-canonical NF kappaB and canonical Wnt signaling during myogenesis and promotes skeletal muscle growth and overload-induced myofiber hypertrophy in mice. Ablation of MyD88 reduces myofiber size during muscle regeneration, whereas its overexpression promotes fusion of exogenous myoblasts to injured myofibers. Our study shows that MyD88 modulates myoblast fusion and suggests that augmenting its levels may be a therapeutic approach to improve skeletal muscle formation in degenerative muscle disorders. PMID- 29158522 TI - MiR-17-5p and miR-20a promote chicken cell proliferation at least in part by upregulation of c-Myc via MAP3K2 targeting. AB - The miR-17-92 cluster has been well studied in mammals but less extensively studied in birds. Here, we demonstrated that miR-17-92 cluster overexpression promoted the proliferation of DF1 cells and immortalized chicken preadipocytes (ICPA-1), and miR-17-5p and miR-20a, members of the miR-17-92 cluster, targeted MAP3K2. Further analysis showed that MAP3K2 overexpression reduced the proliferation of DF1 and ICPA-1 cells and attenuated the promotive effect of the miR-17-92 cluster on cell proliferation. Downstream gene expression analysis of the MAPK signalling pathway showed that MAP3K2 overexpression decreased c-Myc expression; in contrast, MAP3K2 knockdown using RNA interference and miR-17-92 cluster overexpression increased c-Myc expression. Furthermore, c-Myc overexpression promoted miR-17-92 cluster expression and DF1 cell proliferation. Taken together, these data indicated that miR-17-92 promotes chicken cell proliferation at least in part by the upregulation of c-Myc via targeting MAP3K2, and the miR-17-92 cluster, c-Myc and E2F1 form a complex regulatory network in chicken cell proliferation. PMID- 29158523 TI - Treatment of Myocardial Infarction with Gene-modified Mesenchymal Stem Cells in a Small Molecular Hydrogel. AB - The effect of transplanted rat mesenchymal stem cells (MSCs) can be reduced by extracellular microenvironment in myocardial infarction (MI). We tested a novel small-molecular hydrogel (SMH) on whether it could provide a scaffold for hepatocyte growth factor (HGF)-modified MSCs and alleviate ventricular remodeling while preserving cardiac function after MI. Overexpression of HGF in MSCs increased Bcl-2 and reduced Bax and caspase-3 levels in response to hypoxia in vitro. Immunocytochemistry demonstrated that cardiac troponin (cTnT), desmin and connexin 43 expression were significantly enhanced in the 5-azacytidine (5-aza) with SMH group compared with the 5-aza only group in vitro and in vivo. Bioluminescent imaging indicated that retention and survival of transplanted cells was highest when MSCs transfected with adenovirus (ad-HGF) were injected with SMH. Heart function and structure improvement were confirmed by echocardiography and histology in the Ad-HGF-SMHs-MSCs group compared to other groups. Our study showed that: HGF alleviated cell apoptosis and promoted MSC growth. SMHs improved stem cell adhesion, survival and myocardial cell differentiation after MSC transplantation. SMHs combined with modified MSCs significantly decreased the scar area and improved cardiac function. PMID- 29158524 TI - Mechanisms underlying the antiproliferative effects of a series of quinoxaline derived chalcones. AB - The present study aimed to characterize the effects of quinoxaline-derived chalcones, designed on the basis of the selective PI3Kgamma inhibitor AS605240, in oral cancer cells. Three lead compounds, namely N9, N17 and N23, were selected from a series of 20 quinoxaline-derived chalcones, based on an initial screening using human and rat squamous cell carcinoma lineages, representing compounds with at least one methoxy radical at the A-ring. The selected chalcones, mainly N9 and N17, displayed marked antiproliferative effects, via apoptosis and autophagy induction, with an increase of sub-G1 population and Akt inhibition. The three chalcones displayed marked in vitro antitumor effects in different protocols with standard chemotherapy drugs, with acceptable toxicity on normal cells. There was no growth retrieval, after exposure to chalcone N9 alone, in a long-term assay to determine the cumulative population doubling (CPD) of human oral cancer cells. A PCR array evaluating 168 genes related to cancer and inflammation, demonstrated striking actions for N9, which altered the expression of 74 genes. Altogether, our results point out quinoxalinic chalcones, mainly N9, as potential strategies for oral cancer treatment. PMID- 29158526 TI - Selective excitation of spin-polarized alkali atoms in different ground-state hyperfine levels. AB - A technique to selectively excite spin-polarized alkali atoms in one of the two ground-state hyperfine levels is demonstrated, which can separately create the transverse spin component of spin-polarized alkali atoms in either ground-state hyperfine level. The principle of this technique is analyzed, and the experimental results are found to be in good agreement with the theoretical predictions, thereby demonstrating the feasibility of this technique. This technique can be used to accurately measure spin relaxation and polarization of alkali atoms in either ground-state hyperfine level. An example of its applications to measure the transverse relaxation time is presented. PMID- 29158525 TI - Photoacoustic stimulation promotes the osteogenic differentiation of bone mesenchymal stem cells to enhance the repair of bone defect. AB - The aim of this study was to evaluate the direct photoacoustic (PA) effect on bone marrow mesenchymal stem cells (BMSCs) which is a key cell source for osteogenesis. As scaffold is also an indispensable element for tissue regeneration, here we firstly fabricated a composited sheet using polylactic-co glycolic acid (PLGA) mixing with graphene oxide (GO). BMSCs were seeded on the PLGA-GO sheets and received PA treatment in vitro for 3, 9 and 15 days, respectively. Then the BMSCs were harvested and subjected to assess alkaline phosphatase (ALP) activity, calcium content and osteopontin (OPN) on 3, 9 and 15 days. For in vivo study, PLGA-GO sheet seeded with BMSCs after in vitro PA stimulation for 9 days were implanted to repair the bone defect established in the femoral mid-shaft of Sprague-Dawley rat. PLGA-GO group with PA pretreatment showed promising outcomes in terms of the expression of ALP, OPN, and calcium content, thus enhanced the repair of bone defect. In conclusion, we have developed an alternative approach to enhance the repair of bone defect by making good use of the beneficial effect of PA. PMID- 29158527 TI - Azole sensitivity in Leptosphaeria pathogens of oilseed rape: the role of lanosterol 14alpha-demethylase. AB - Lanosterol 14-alpha demethylase is a key enzyme intermediating the biosynthesis of ergosterol in fungi, and the target of azole fungicides. Studies have suggested that Leptosphaeria maculans and L. biglobosa, the causal agents of phoma stem canker on oilseed rape, differ in their sensitivity to some azoles, which could be driving pathogen frequency change in crops. Here we used CYP51 protein modelling and heterologous expression to determine whether there are interspecific differences at the target-site level. Moreover, we provide an example of intrinsic sensitivity differences exhibited by both Leptosphaeria spp. in vitro and in planta. Comparison of homologous protein models identified highly conserved residues, particularly at the azole binding site, and heterologous expression of LmCYP51B and LbCYP51B, with fungicide sensitivity testing of the transformants, suggests that both proteins are similarly sensitive to azole fungicides flusilazole, prothioconazole-desthio and tebuconazole. Fungicide sensitivity testing on isolates shows that they sometimes have a minor difference in sensitivity in vitro and in planta. These results suggest that azole fungicides remain a useful component of integrated phoma stem canker control in the UK due to their effectiveness on both Leptosphaeria spp. Other factors, such as varietal resistance or climate, may be driving observed frequency changes between species. PMID- 29158529 TI - Accurate thermal conductivities from optimally short molecular dynamics simulations. AB - The evaluation of transport coefficients in extended systems, such as thermal conductivity or shear viscosity, is known to require impractically long simulations, thus calling for a paradigm shift that would allow to deploy state of-the-art quantum simulation methods. We introduce a new method to compute these coefficients from optimally short molecular dynamics simulations, based on the Green-Kubo theory of linear response and the cepstral analysis of time series. Information from the full sample power spectrum of the relevant current for a single and relatively short trajectory is leveraged to evaluate and optimally reduce the noise affecting its zero-frequency value, whose expectation is proportional to the corresponding conductivity. Our method is unbiased and consistent, in that both the resulting bias and statistical error can be made arbitrarily small in the long-time limit. A simple data-analysis protocol is proposed and validated with the calculation of thermal conductivities in the paradigmatic cases of elemental and molecular fluids (liquid Ar and H2O) and of crystalline and glassy solids (MgO and a-SiO2). We find that simulation times of one to a few hundred picoseconds are sufficient in these systems to achieve an accuracy of the order of 10% on the estimated thermal conductivities. PMID- 29158528 TI - Fine-mapping of genetic loci driving spontaneous clearance of hepatitis C virus infection. AB - Approximately three quarters of acute hepatitis C (HCV) infections evolve to a chronic state, while one quarter are spontaneously cleared. Genetic predispositions strongly contribute to the development of chronicity. We have conducted a genome-wide association study to identify genomic variants underlying HCV spontaneous clearance using ImmunoChip in European and African ancestries. We confirmed two previously reported significant associations, in the IL28B/IFNL4 and the major histocompatibility complex (MHC) regions, with spontaneous clearance in the European population. We further fine-mapped the association in the MHC to a region of about 50 kilo base pairs, down from 1 mega base pairs in the previous study. Additional analyses suggested that the association in MHC is stronger in samples from North America than those from Europe. PMID- 29158530 TI - mRNAs containing NMD-competent premature termination codons are stabilized and translated under UPF1 depletion. AB - mRNAs containing premature termination codons (PTCs) are rapidly degraded through nonsense-mediated mRNA decay (NMD). However, some PTC-containing mRNAs evade NMD, and might generate mutant proteins responsible for various diseases, including cancers. Using PTC-containing human genomic beta-globin constructs, we show that a fraction (~30%) of PTC-containing mRNAs expressed from NMD-competent PTC containing constructs were as stable as their PTC-free counterparts in a steady state. These PTC-containing mRNAs were monosome-enriched and rarely contributed to expression of mutant proteins. Expression of trace amounts of mutant proteins from NMD-competent PTC-containing constructs was not affected by inhibition of eIF4E-dependent translation and such expression was dependent on a continuous influx of newly synthesized PTC-containing mRNAs, indicating that truncated mutant proteins originated primarily in the pioneer round of translation. The generation of mutant proteins was promoted by UPF1 depletion, which induced polysome association of PTC-containing mRNAs, increased eIF4E-bound PTC containing mRNA levels, and subsequent eIF4E-dependent translation. Our findings suggest that PTC-containing mRNAs are potent and regulatable sources of mutant protein generation. PMID- 29158531 TI - Non-criticality of interaction network over system's crises: A percolation analysis. AB - Extraction of interaction networks from multi-variate time-series is one of the topics of broad interest in complex systems. Although this method has a wide range of applications, most of the previous analyses have focused on the pairwise relations. Here we establish the potential of such a method to elicit aggregated behavior of the system by making a connection with the concepts from percolation theory. We study the dynamical interaction networks of a financial market extracted from the correlation network of indices, and build a weighted network. In correspondence with the percolation model, we find that away from financial crises the interaction network behaves like a critical random network of Erdos Renyi, while close to a financial crisis, our model deviates from the critical random network and behaves differently at different size scales. We perform further analysis to clarify that our observation is not a simple consequence of the growth in correlations over the crises. PMID- 29158533 TI - High-injection effects in near-field thermophotovoltaic devices. AB - In near-field thermophotovoltaics, a substantial enhancement of the electrical power output is expected as a result of the larger photogeneration of electron hole pairs due to the tunneling of evanescent modes from the thermal radiator to the photovoltaic cell. The common low-injection approximation, which considers that the local carrier density due to photogeneration is moderate in comparison to that due to doping, needs therefore to be assessed. By solving the full drift diffusion equations, the existence of high-injection effects is studied in the case of a GaSb p-on-n junction cell and a radiator supporting surface polaritons. Depending on doping densities and surface recombination velocity, results reveal that high-injection phenomena can already take place in the far field and become very significant in the near field. Impacts of high injection on maximum electrical power, short-circuit current, open-circuit voltage, recombination rates, and variations of the difference between quasi-Fermi levels are analyzed in detail. By showing that an optimum acceptor doping density can be estimated, this work suggests that a detailed and accurate modeling of the electrical transport is also key for the design of near-field thermophotovoltaic devices. PMID- 29158532 TI - Recombinant Decorin Fusion Protein Attenuates Murine Abdominal Aortic Aneurysm Formation and Rupture. AB - Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflamed blood vessels and penetrates deep into the vessel wall. In the present study, the role of systemically-administered CAR-DCN in AAA progression and rupture was assessed in a murine model. Apolipoprotein E knockout (ApoE-KO) mice were infused with angiotensin II (AngII) for 28 days to induce AAA formation. CAR-DCN or vehicle was administrated systemically until day 15. Mortality due to AAA rupture was significantly reduced in CAR-DCN-treated mice compared to controls. Although the prevalence of AAA was similar between vehicle and CAR-DCN groups, the severity of AAA in the CAR-DCN group was significantly reduced. Histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels within the aortic wall as compared to vehicle controls. Taken together, these results suggest that CAR-DCN treatment attenuates the formation and rupture of Ang II-induced AAA in mice by reinforcing the aortic wall. PMID- 29158534 TI - Changes to Yucatan Peninsula precipitation associated with salinity and temperature extremes of the Caribbean Sea during the Maya civilization collapse. AB - Explanations of the Classic Maya civilization demise on the Yucatan Peninsula during the Terminal Classic Period (TCP; ~CE 750-1050) are controversial. Multiyear droughts are one likely cause, but the role of the Caribbean Sea, the dominant moisture source for Mesoamerica, remains largely unknown. Here we present bimonthly-resolved snapshots of reconstructed sea surface temperature (SST) and salinity (SSS) variability in the southern Caribbean from precisely dated fossil corals. The results indicate pronounced interannual to decadal SST and SSS variability during the TCP, which may be temporally coherent to precipitation anomalies on the Yucatan. Our results are best explained by changed Caribbean SST gradients affecting the Caribbean low-level atmospheric jet with consequences for Mesoamerican precipitation, which are possibly linked to changes in Atlantic Meridional Overturning Circulation strength. Our findings provide a new perspective on the anomalous hydrological changes during the TCP that complement the oft-suggested southward displacement of the Intertropical Convergence Zone. We advocate for a strong role of Caribbean SST and SSS condition changes and related ocean-atmosphere interactions that notably influenced the propagation and transport of precipitation to the Yucatan Peninsula during the TCP. PMID- 29158535 TI - The Triglycerides and Glucose Index rather than HOMA-IR is more associated with Hypogonadism in Chinese men. AB - Previous studies have reported that insulin resistant and low testosterone are related. The triglyceride and glucose index (TyG) well mirrors insulin sensitivity. No study investigated the application of TyG in male hypogonadism. We aimed to explore whether TyG was associated with hypogonadism, and also evaluate the ability of TyG compared to HOMA-IR as a possible hypogonadism predictor. A total of 4299 male subjects were enrolled from 22 sites in East China. Hypogonadism was defined as total testosterone <11.3 nmol/L. 695 (16.2%) hypogonadal men had significantly higher TyG index. The prevalence of hypogonadism stepwise increased across increasing TyG quartiles (P < 0.01). TyG was negatively associated with sex hormones and hypogonadism after adjustment for age, current smoking status, hypertension and overweight/obesity (all P for trend <0.01). The full-adjusted odds ratio was 6.1 for the highest quartile compared with the lowest quartile of TyG (95% CI 4.51, 8.25, P < 0.001). On ROC curve analysis, a larger area under the curve was found for TyG (0.71, 95% CI 0.69,0.73) than for HOMA-IR (0.68, 95% CI 0.66,0.70). Thus, the TyG was significantly associated with a higher prevalence of hypogonadism in Chinese men. TyG had a better predictive power for hypogonadism than HOMA-IR. PMID- 29158536 TI - Validation of methods for prediction of clinical output levels of active middle ear implants from measurements in human cadaveric ears. AB - Today, the standard method to predict output levels of active middle ear implants (AMEIs) before clinical data are available is stapes vibration measurement in human cadaveric ears, according to ASTM standard F2504-05. Although this procedure is well established, the validity of the predicted output levels has never been demonstrated clinically. Furthermore, this procedure requires a mobile and visually accessible stapes and an AMEI stimulating the ossicular chain. Thus, an alternative method is needed to quantify the output level of AMEIs in all other stimulation modes, e.g. reverse stimulation of the round window. Intracochlear pressure difference (ICPD) is a good candidate for such a method as it correlates with evoked potentials in animals and it is measurable in cadaveric ears. To validate this method we correlated AMEI output levels calculated from ICPD and from stapes vibration in cadaveric ears with outputs levels determined from clinical data. Output levels calculated from ICPD were similar to output levels calculated from stapes vibration and almost identical to clinical data. Our results demonstrate that both ICPD and stapes vibration can be used as a measure to predict AMEI clinical output levels in cadaveric ears and that ICPD as reference provided even more accurate results. PMID- 29158537 TI - Medicinal Plant Leaf Extract and Pure Flavonoid Mediated Green Synthesis of Silver Nanoparticles and their Enhanced Antibacterial Property. AB - The rewards of using plants and plant metabolites over other biological methods for nanoparticle synthesis have fascinated researchers to investigate mechanisms of metal ions uptake and bio-reduction by plants. Here, green chemistry were employed for the synthesis of silver nanoparticles (AgNPs) using leaf extracts of Ocimum Sanctum (Tulsi) and its derivative quercetin (flavonoid present in Tulsi) separately as precursors to investigate the role of biomolecules present in Tulsi in the formation of AgNPs from cationic silver under different physicochemical conditions such as pH, temperature, reaction time and reactants concentration. The size, shape, morphology, and stability of resultant AgNPs were investigated by optical spectroscopy (absorption, photoluminescence (PL), PL-lifetime and Fourier transform infrared), X-ray diffraction (XRD) analysis, and transmission electron microscopy (TEM). The enhanced antibacterial activity of AgNPs against E Coli gram-negative bacterial strains was analyzed based on the zone of inhibition and minimal inhibitory concentration (MIC) indices. The results of different characterization techniques showed that AgNPs synthesized using both leaf extract and neat quercetin separately followed the same optical, morphological, and antibacterial characteristics, demonstrating that biomolecules (quercetin) present in Tulsi are mainly responsible for the reduction of metal ions to metal nanoparticles. PMID- 29158538 TI - PinAPL-Py: A comprehensive web-application for the analysis of CRISPR/Cas9 screens. AB - Large-scale genetic screens using CRISPR/Cas9 technology have emerged as a major tool for functional genomics. With its increased popularity, experimental biologists frequently acquire large sequencing datasets for which they often do not have an easy analysis option. While a few bioinformatic tools have been developed for this purpose, their utility is still hindered either due to limited functionality or the requirement of bioinformatic expertise. To make sequencing data analysis of CRISPR/Cas9 screens more accessible to a wide range of scientists, we developed a Platform-independent Analysis of Pooled Screens using Python (PinAPL-Py), which is operated as an intuitive web-service. PinAPL-Py implements state-of-the-art tools and statistical models, assembled in a comprehensive workflow covering sequence quality control, automated sgRNA sequence extraction, alignment, sgRNA enrichment/depletion analysis and gene ranking. The workflow is set up to use a variety of popular sgRNA libraries as well as custom libraries that can be easily uploaded. Various analysis options are offered, suitable to analyze a large variety of CRISPR/Cas9 screening experiments. Analysis output includes ranked lists of sgRNAs and genes, and publication-ready plots. PinAPL-Py helps to advance genome-wide screening efforts by combining comprehensive functionality with user-friendly implementation. PinAPL-Py is freely accessible at http://pinapl-py.ucsd.edu with instructions and test datasets. PMID- 29158539 TI - Relaxation oscillation of borosilicate glasses in supercooled liquid region. AB - Most supercooled non-polymeric glass-forming melts exhibit a shear thinning phenomenon, i.e., viscosity decreases with increasing the strain rate. On compressing borosilicate glasses at high temperature, however, we discovered an interesting oscillatory viscous flow and identified it as a typical relaxation oscillation caused by the peculiar structure of borosilicate glass. Specifically, the micro-structure of borosilicate glass can be divided into borate network and silicate network. Under loading, deformation is mainly localized in the borate network via a transformation from the three coordinated planar boron to trigonal boron that could serve as a precursor for the subsequent formation of a BO4 tetrahedron, while the surrounding silicate network is acting as a stabilization/relaxation agent. The formation of stress oscillation was further described and explained by a new physics-based constitutive model. PMID- 29158540 TI - Calcium binding and voltage gating in Cx46 hemichannels. AB - The opening of connexin (Cx) hemichannels in the membrane is tightly regulated by calcium (Ca2+) and membrane voltage. Electrophysiological and atomic force microscopy experiments indicate that Ca2+ stabilizes the hemichannel closed state. However, structural data show that Ca2+ binding induces an electrostatic seal preventing ion transport without significant structural rearrangements. In agreement with the closed-state stabilization hypothesis, we found that the apparent Ca2+ sensitivity is increased as the voltage is made more negative. Moreover, the voltage and Ca2+ dependence of the channel kinetics indicate that the voltage sensor movement and Ca2+ binding are allosterically coupled. An allosteric kinetic model in which the Ca2+ decreases the energy necessary to deactivate the voltage sensor reproduces the effects of Ca2+ and voltage in Cx46 hemichannels. In agreement with the model and suggesting a conformational change that narrows the pore, Ca2+ inhibits the water flux through Cx hemichannels. We conclude that Ca2+ and voltage act allosterically to stabilize the closed conformation of Cx46 hemichannels. PMID- 29158541 TI - Dysregulation of mitochondrial function and biogenesis modulators in adipose tissue of obese children. AB - BACKGROUND/OBJECTIVES: We aimed to evaluate mitochondrial biogenesis (MB), structure, metabolism and dysfunction in abdominal adipose tissue from male pediatric patients with obesity. SUBJECTS/METHODS: Samples were collected from five children with obesity (percentile ?95) and five eutrophic boys (percentile ?5/?85) (8-12 years old) following parental informed consent. We analyzed the expression of key genes involved in MB (sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor-gamma (PPARgamma), PPARgamma coactivator-1alpha (PGC1alpha), nuclear respiratory factors 1 and 2 (NRF1, NRF2) and mitochondrial transcription factor A (TFAM) and surrogates for mitochondrial function/structure/metabolism (porin, TOMM20, complex I and V, UCP1, UCP2, SIRT3, SOD2) by western blot. Citrate synthase (CS), complex I (CI) activity, adenosine triphosphate (ATP) levels, mitochondrial DNA (mtDNA) content and oxidative stress end points were also determined. RESULTS: Most MB proteins were significantly decreased in samples from children with obesity except complex I, V and superoxide dismutase-2 (SOD2). Similarly, CS and CI activity showed a significant reduction, as well as ATP levels and mtDNA content. PPARgamma, PGC1alpha, complex I and V and SOD2 were hyperacetylated compared with lean samples. Concurrently, in samples from children with obesity, we found decreased SOD2 activity and redox state imbalance highlighted by decreased reduced glutathione/oxidized glutathione (GSH/GSSG) ratio and significant increases in protein carbonylation. CONCLUSIONS: Adipose tissue from children with obesity demonstrates a dysregulation of key modulators of MB and organelle structure, and displays hyperacetylation of key proteins and altered expression of upstream regulators of cell metabolism. PMID- 29158542 TI - Metabolic profiling of umbilical cord blood in macrosomia. AB - BACKGROUND/OBJECTIVE: The term macrosomia is used to describe neonates with a birth weight of 4000 g or more. Macrosomia is a potential risk factor for obesity and metabolic syndromes in postnatal and adult life, yet little is known about its associations with metabolic difference in the early age. We performed metabolic profiling of umbilical cord blood to discover differential metabolites of macrosomia. METHODS: We conducted a case-control study of full-term singletons with normal maternal glucose tolerance [50 cases (macrosomia, birth weight ?4000 g); 50 controls (normal weight, birth weight 2500-3999 g)]. Metabolites in umbilical cord blood were detected using an untargeted metabolomic approach based on gas chromatography/mass spectrometry. We performed logistic regression to evaluate the associations between metabolites and macrosomia. We also performed pathway analysis based on KEGG and MBRole. RESULTS: Compared with controls, the macrosomia cases had a greater male proportion, gestational age, paternal body mass index (BMI) and maternal pre-pregnancy BMI. Forty-two metabolites differed between the cases and controls. After multivariable adjustment, 2-methylfumarate [adjusted odds ratio (AOR)=1.232, 95% confidence interval (CI): 1.102-1.376], uracil (AOR=38.494, 95% CI: 5.635-262.951), elaidic acid (AOR=0.834, 95% CI: 0.761-0.915), ribose (AOR=0.089, 95% CI: 0.021-0.378), lactulose (AOR=0.815, 95% CI: 0.743-0.894) and 4-aminobutyric acid (AOR=0.835, 95% CI: 0.764-0.912) remained significantly associated with macrosomia. Pyrimidine metabolism and pentose and glucuronate interconversions were the two top-ranking pathways enriched with those metabolites (-log P-value=3.49 and 2.47, respectively). CONCLUSION: Levels of 2-methylfumarate, uracil, ribose, elaidic acid, lactulose and 4-aminobutyric acid were associated with the incidence of macrosomia. The alteration of pathways involving those factors might be linked with the incidence of macrosomia and relevant metabolic syndromes later in life, and further studies are needed to confirm it and verify the mechanisms. PMID- 29158543 TI - Genetic predisposition to obesity, restrained eating and changes in body weight: a population-based prospective study. AB - OBJECTIVES: There is no consensus on whether cognitive control over food intake (that is, restrained eating) is helpful, merely ineffective or actually harmful in weight management. We examined the interplay between genetic risk of obesity, restrained eating and changes in body weight and size. METHODS: Participants were Finnish aged 25-74 years who attended the DIetary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome study at baseline in 2007 and follow-up in 2014. At baseline (n=5024), height, weight and waist circumference (WC) were measured in a health examination and participants self-reported their weight at age 20 years. At follow-up (n=3735), height, weight and WC were based on measured or self-reported information. We calculated 7-year change in body mass index (BMI) and WC and annual weight change from age 20 years to baseline. Three-Factor Eating Questionnaire-R18 was used to assess restrained eating. Genetic risk of obesity was assessed by calculating a polygenic risk score of 97 known BMI-related loci. RESULTS: Cross-lagged autoregressive models indicated that baseline restrained eating was unrelated to 7-year change in BMI (beta=0.00; 95% confidence interval (CI)=-0.01, 0.02). Instead, higher baseline BMI predicted greater 7-year increases in restrained eating (beta=0.08; 95% CI=0.05, 0.11). Similar results were obtained with WC. Polygenic risk score correlated positively with restrained eating and obesity indicators in both study phases, but it did not predict 7-year change in BMI or WC. However, individuals with higher genetic risk of obesity tended to gain more weight from age 20 years to baseline, and this association was more pronounced in unrestrained eaters than in restrained eaters (P=0.038 for interaction). CONCLUSIONS: Our results suggest that restrained eating is a marker for previous weight gain rather than a factor that leads to future weight gain in middle-aged adults. Genetic influences on weight gain from early to middle adulthood may vary according to restrained eating, but this finding needs to be replicated in future studies. PMID- 29158545 TI - A potent Cas9-derived gene activator for plant and mammalian cells. AB - Overexpression of complementary DNA represents the most commonly used gain-of function approach for interrogating gene functions and for manipulating biological traits. However, this approach is challenging and inefficient for multigene expression due to increased labour for cloning, limited vector capacity, requirement of multiple promoters and terminators, and variable transgene expression levels. Synthetic transcriptional activators provide a promising alternative strategy for gene activation by tethering an autonomous transcription activation domain (TAD) to an intended gene promoter at the endogenous genomic locus through a programmable DNA-binding module. Among the known custom DNA-binding modules, the nuclease-dead Streptococcus pyogenes Cas9 (dCas9) protein, which recognizes a specific DNA target through base pairing between a synthetic guide RNA and DNA, outperforms zinc-finger proteins and transcription activator-like effectors, both of which target through protein-DNA interactions 1 . Recently, three potent dCas9-based transcriptional activation systems, namely VPR, SAM and SunTag, have been developed for animal cells 2-6 . However, an efficient dCas9-based transcriptional activation platform is still lacking for plant cells 7-9 . Here, we developed a new potent dCas9-TAD, named dCas9-TV, through plant cell-based screens. dCas9-TV confers far stronger transcriptional activation of single or multiple target genes than the routinely used dCas9-VP64 activator in both plant and mammalian cells. PMID- 29158546 TI - The Aegilops tauschii genome reveals multiple impacts of transposons. AB - Wheat is an important global crop with an extremely large and complex genome that contains more transposable elements (TEs) than any other known crop species. Here, we generated a chromosome-scale, high-quality reference genome of Aegilops tauschii, the donor of the wheat D genome, in which 92.5% sequences have been anchored to chromosomes. Using this assembly, we accurately characterized genic loci, gene expression, pseudogenes, methylation, recombination ratios, microRNAs and especially TEs on chromosomes. In addition to the discovery of a wave of very recent gene duplications, we detected that TEs occurred in about half of the genes, and found that such genes are expressed at lower levels than those without TEs, presumably because of their elevated methylation levels. We mapped all wheat molecular markers and constructed a high-resolution integrated genetic map corresponding to genome sequences, thereby placing previously detected agronomically important genes/quantitative trait loci (QTLs) on the Ae. tauschii genome for the first time. PMID- 29158547 TI - Keratoconus Detection Based on a New Corneal Volumetric Analysis. AB - There are numerous tomographic indices for the detection of keratoconus risk. When the indexes based on corneal volume are analyzed, two problems are presented: on the one hand, they are not very sensitive to the detection of incipient cases of keratoconus because they are not locally defined in the primary developmental region of the structural abnormalities; and on the other hand, they do not register the geometric decompensation driven by the asymmetry present during the disease progression. This work performed a morphogeometric modeling of the cornea by the aid of CAD tools and using raw topographic data (Sirius system, CSO, Firenze). For this method, four singular points present on the corneal surfaces were located and the following parameters based on corneal volume were calculated: VOLmct, defined by the points of minimal thickness; VOLaap, defined by the anterior corneal apex, and VOLpap, defined by the posterior corneal apex. The results demonstrate that a further reduction of corneal volume in keratoconus happens and significantly progresses along the disease severity level. The combination of optical and volumetric data, that collect the sensitivity of the asymmetry generated by the disease, allows an accurate detection of incipient cases and follow up of the disease progression. PMID- 29158548 TI - Synchronization enhancement of indirectly coupled oscillators via periodic modulation in an optomechanical system. AB - We study the synchronization behaviors of two indirectly coupled mechanical oscillators of different frequencies in a doublecavity optomechanical system. It is found that quantum synchronization is roughly vanishing though classical synchronization seems rather good when each cavity mode is driven by an external field in the absence of temporal modulations. By periodically modulating cavity detunings or driving amplitudes, however, it is possible to observe greatly enhanced quantum synchronization accompanied with nearly perfect classical synchronization. The level of quantum synchronization observed here is, in particular, much higher than that for two directly coupled mechanical oscillators. Note also that the modulation on cavity detunings is more appealing than that on driving amplitudes when the robustness of quantum synchronization is examined against the bath's mean temperature or the oscillators' frequency difference. PMID- 29158549 TI - Hypoxia inducible factor-1alpha mediates the profibrotic effect of albumin in renal tubular cells. AB - Proteinuria is closely associated with the progression of chronic kidney diseases (CKD) by producing renal tubulointerstitial fibrosis. Over-activation of hypoxia inducible factor (HIF)-1alpha has been implicated in the progression of CKD. The present study tested the hypothesis that HIF-1alpha mediates albumin-induced profibrotic effect in cultured renal proximal tubular cells. Incubation of the cells with albumin (40 MUg/ml) for 72 hrs significantly increased the protein levels of HIF-1alpha, tissue inhibitor of metalloproteinase (TIMP)-1 and collagen I, which were blocked by HIF-1alpha shRNA. Albumin also stimulated an epithelial mesenchymal transition (EMT) as indicated by the decrease in epithelial marker E cadherin, and the increase in mesenchymal markers alpha-smooth muscle actin and fibroblast-specific protein 1. HIF-1alpha shRNA blocked albumin-induced changes in these EMT markers as well. Furthermore, albumin reduced the level of hydroxylated HIF-1alpha, indicating an inhibition of the activity of prolyl hydroxylases, enzymes promoting the degradation of HIF-1alpha. An anti-oxidant ascorbate reversed albumin-induced inhibition of prolyl-hydroxylase activity. Overexpression of prolyl-hydroxylase 2 (PHD2) transgene, a predominant isoform of PHDs in renal tubules, to reduce HIF-1alpha level significantly attenuated albumin-induced increases in TIMP-1 and collagen-I levels. These results suggest that albumin-induced oxidative stress inhibits PHD activity to accumulate HIF 1alpha, which mediates albumin-induced profibrotic effects in renal tubular cells. PMID- 29158550 TI - Exome Pool-Seq in neurodevelopmental disorders. AB - High throughput sequencing has greatly advanced disease gene identification, especially in heterogeneous entities. Despite falling costs this is still an expensive and laborious technique, particularly when studying large cohorts. To address this problem we applied Exome Pool-Seq as an economic and fast screening technology in neurodevelopmental disorders (NDDs). Sequencing of 96 individuals can be performed in eight pools of 12 samples on less than one Illumina sequencer lane. In a pilot study with 96 cases we identified 27 variants, likely or possibly affecting function. Twenty five of these were identified in 923 established NDD genes (based on SysID database, status November 2016) (ACTB, AHDC1, ANKRD11, ATP6V1B2, ATRX, CASK, CHD8, GNAS, IFIH1, KCNQ2, KMT2A, KRAS, MAOA, MED12, MED13L, RIT1, SETD5, SIN3A, TCF4, TRAPPC11, TUBA1A, WAC, ZBTB18, ZMYND11), two in 543 (SysID) candidate genes (ZNF292, BPTF), and additionally a de novo loss-of-function variant in LRRC7, not previously implicated in NDDs. Most of them were confirmed to be de novo, but we also identified X-linked or autosomal-dominantly or autosomal-recessively inherited variants. With a detection rate of 28%, Exome Pool-Seq achieves comparable results to individual exome analyses but reduces costs by >85%. Compared with other large scale approaches using Molecular Inversion Probes (MIP) or gene panels, it allows flexible re-analysis of data. Exome Pool-Seq is thus well suited for large-scale, cost-efficient and flexible screening in characterized but heterogeneous entities like NDDs. PMID- 29158551 TI - The International Rare Diseases Research Consortium: Policies and Guidelines to maximize impact. AB - The International Rare Diseases Research Consortium (IRDiRC) has agreed on IRDiRC Policies and Guidelines, following extensive deliberations and discussions in 2012 and 2013, as a first step towards improving coordination of research efforts worldwide. The 25 funding members and 3 patient umbrella organizations (as of early 2013) of IRDiRC, a consortium of research funders that focuses on improving diagnosis and therapy for rare disease patients, agreed in Dublin, Ireland in April 2013 on the Policies and Guidelines that emphasize collaboration in rare disease research, the involvement of patients and their representatives in all relevant aspects of research, as well as the sharing of data and resources. The Policies and Guidelines provide guidance on ontologies, diagnostics, biomarkers, patient registries, biobanks, natural history, therapeutics, models, publication, intellectual property, and communication. Most IRDiRC members-currently nearly 50 strong-have since incorporated its policies in their funding calls and some have chosen to exceed the requirements laid out, for instance in relation to data sharing. The IRDiRC Policies and Guidelines are the first, detailed agreement of major public and private funding organizations worldwide to govern rare disease research, and may serve as a template for other areas of international research collaboration. While it is too early to assess their full impact on research productivity and patient benefit, the IRDiRC Policies and Guidelines have already contributed significantly to improving transparency and collaboration in rare disease research. PMID- 29158552 TI - Care and cost consequences of pediatric whole genome sequencing compared to chromosome microarray. AB - The clinical use of whole-genome sequencing (WGS) is expected to alter pediatric medical management. The study aimed to describe the type and cost of healthcare activities following pediatric WGS compared to chromosome microarray (CMA). Healthcare activities prompted by WGS and CMA were ascertained for 101 children with developmental delay over 1 year. Activities following receipt of non diagnostic CMA were compared to WGS diagnostic and non-diagnostic results. Activities were costed in 2016 Canadian dollars (CDN). Ongoing care accounted for 88.6% of post-test activities. The mean number of lab tests was greater following CMA than WGS (0.55 vs. 0.09; p = 0.007). The mean number of specialist visits was greater following WGS than CMA (0.41 vs. 0; p = 0.016). WGS results (diagnostic vs. non-diagnostic) modified the effect of test type on mean number of activities (p < 0.001). The cost of activities prompted by diagnostic WGS exceeded $557CDN for 10% of cases. In complex pediatric care, CMA prompted additional diagnostic investigations while WGS prompted tailored care guided by genotypic variants. Costs for prompted activities were low for the majority and constitute a small proportion of total test costs. Optimal use of WGS depends on robust evaluation of downstream care and cost consequences. PMID- 29158553 TI - The architecture of mutualistic networks as an evolutionary spandrel. AB - Mutualistic networks have been shown to involve complex patterns of interactions among animal and plant species, including a widespread presence of nestedness. The nested structure of these webs seems to be positively correlated with higher diversity and resilience. Moreover, these webs exhibit marked measurable structural patterns, including broad distributions of connectivity, strongly asymmetrical interactions and hierarchical organization. Hierarchical organization is an especially interesting property, since it is positively correlated with biodiversity and network resilience, thus suggesting potential selection processes favouring the observed web organization. However, here we show that all these structural quantitative patterns-and nestedness in particular can be properly explained by means of a very simple dynamical model of speciation and divergence with no selection-driven coevolution of traits. The agreement between observed and modelled networks suggests that the patterns displayed by real mutualistic webs might actually represent evolutionary spandrels. PMID- 29158554 TI - Genomic consequences of intensive inbreeding in an isolated wolf population. AB - Inbreeding (mating between relatives) is a major concern for conservation as it decreases individual fitness and can increase the risk of population extinction. We used whole-genome resequencing of 97 grey wolves (Canis lupus) from the highly inbred Scandinavian wolf population to identify 'identical-by-descent' (IBD) chromosome segments as runs of homozygosity (ROH). This gave the high resolution required to precisely measure realized inbreeding as the IBD fraction of the genome in ROH (F ROH). We found a striking pattern of complete or near-complete homozygosity of entire chromosomes in many individuals. The majority of individual inbreeding was due to long IBD segments (>5 cM) originating from ancestors <=10 generations ago, with 10 genomic regions showing very few ROH and forming candidate regions for containing loci contributing strongly to inbreeding depression. Inbreeding estimated with an extensive pedigree (F P) was strongly correlated with realized inbreeding measured with the entire genome (r 2 = 0.86). However, inbreeding measured with the whole genome was more strongly correlated with multi-locus heterozygosity estimated with as few as 500 single nucleotide polymorphisms, and with F ROH estimated with as few as 10,000 single nucleotide polymorphisms, than with F P. These results document in fine detail the genomic consequences of intensive inbreeding in a population of conservation concern. PMID- 29158555 TI - What genomic data can reveal about eco-evolutionary dynamics. AB - Recognition that evolution operates on the same timescale as ecological processes has motivated growing interest in eco-evolutionary dynamics. Nonetheless, generating sufficient data to test predictions about eco-evolutionary dynamics has proved challenging, particularly in natural contexts. Here we argue that genomic data can be integrated into the study of eco-evolutionary dynamics in ways that deepen our understanding of the interplay between ecology and evolution. Specifically, we outline five major questions in the study of eco evolutionary dynamics for which genomic data may provide answers. Although genomic data alone will not be sufficient to resolve these challenges, integrating genomic data can provide a more mechanistic understanding of the causes of phenotypic change, help elucidate the mechanisms driving eco evolutionary dynamics, and lead to more accurate evolutionary predictions of eco evolutionary dynamics in nature. PMID- 29158556 TI - Tetrad analysis in plants and fungi finds large differences in gene conversion rates but no GC bias. AB - GC-favouring gene conversion enables fixation of deleterious alleles, disturbs tests of natural selection and potentially explains both the evolution of recombination as well as the commonly reported intragenomic correlation between G+C content and recombination rate. In addition, gene conversion disturbs linkage disequilibrium, potentially affecting the ability to detect causative variants. However, the importance and generality of these effects is unresolved, not simply because direct analyses are technically challenging but also because previous within- and between-species discrepant results can be hard to appraise owing to methodological differences. Here we report results of methodologically uniform whole-genome sequencing of all tetrad products in Saccharomyces, Neurospora, Chlamydomonas and Arabidopsis. The proportion of polymorphic markers converted varies over three orders of magnitude between species (from 2% of markers converted in yeast to only ~0.005% in the two plants) with at least 87.5% of the variance in per tetrad conversion rates being between species. This is largely due to differences in recombination rate and median tract length. Despite three of the species showing a positive GC-recombination correlation, there is no significant net AT->GC conversion bias in any of the species, despite relatively high resolution in the two taxa (Saccharomyces and Neurospora) with relatively common gene conversion. The absence of a GC bias means that: (1) there should be no presumption that gene conversion is GC biased, or (2) that a GC-recombination correlation necessarily implies biased gene conversion, (3) K a/K s tests should be unaffected in these species and (4) it is unlikely that gene conversion explains the evolution of recombination. PMID- 29158557 TI - MiR-29b antagonizes the pro-inflammatory tumor-promoting activity of multiple myeloma-educated dendritic cells. AB - Dendritic cells (DCs) have a key role in regulating tumor immunity, tumor cell growth and drug resistance. We hypothesized that multiple myeloma (MM) cells might recruit and reprogram DCs to a tumor-permissive phenotype by changes within their microRNA (miRNA) network. By analyzing six different miRNA-profiling data sets, miR-29b was identified as the only miRNA upregulated in normal mature DCs and significantly downregulated in tumor-associated DCs. This finding was validated in primary DCs co-cultured in vitro with MM cell lines and in primary bone marrow DCs from MM patients. In DCs co-cultured with MM cells, enforced expression of miR-29b counteracted pro-inflammatory pathways, including signal transducer and activator of transcription 3 and nuclear factor-kappaB, and cytokine/chemokine signaling networks, which correlated with patients' adverse prognosis and development of bone disease. Moreover, miR-29b downregulated interleukin-23 in vitro and in the SCID-synth-hu in vivo model, and antagonized a Th17 inflammatory response. All together, these effects translated into strong anti-proliferative activity and reduction of genomic instability of MM cells. Our study demonstrates that MM reprograms the DCs functional phenotype by downregulating miR-29b whose reconstitution impairs DCs ability to sustain MM cell growth and survival. These results underscore miR-29b as an innovative and attractive candidate for miRNA-based immune therapy of MM. PMID- 29158559 TI - Carbon spheres@MnO2 core-shell nanocomposites with enhanced dielectric properties for electromagnetic shielding. AB - Carbon spheres (CS)@MnO2 core-shell nanocomposites, with MnO2 nanoflakes uniformly coating at the surface of CS cores, were successfully synthesized by a facile water-bathing method. MnO2 amounts is estimated to be 24.7 wt% in CS@MnO2 nanocomposites. A high dielectric loss value and an electromagnetic shielding effectiveness of 16-23 dB were observed for the CS@MnO2 in the frequency range of 8-18 GHz, which is mainly attributed to the enhanced absorption loss. The incorporation of the CS with MnO2 improves the electrical conductivity. Meanwhile, the electromagnetic impendence matching has been significantly ameliorated. Moreover, the increasing interfaces between the CS and MnO2 facilitate the microwave attenuation as well. Thus, the electromagnetic shielding performances were greatly enhanced. Our findings provide an effective methodology for the synthesis of the CS@MnO2 core-shell nanocomposite for potential electromagnetic applications. PMID- 29158558 TI - Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. AB - Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased progression free survival and overall survival. Either genetic knockdown or pharmacological inhibition of PRMT5 with the inhibitor EPZ015666 significantly inhibited growth of both cell lines and patient MM cells. Furthermore, PRMT5 inhibition abrogated NF-kappaB signaling. Interestingly, mass spectrometry identified a tripartite motif-containing protein 21 TRIM21 as a new PRMT5-partner, and we delineated a TRIM21-dependent mechanism of NF-kappaB inhibition. Importantly, oral administration of EPZ015666 significantly decreased MM growth in a humanized murine model of MM. These data both demonstrate the oncogenic role and prognostic relevance of PRMT5 in MM pathogenesis, and provide the rationale for novel therapies targeting PRMT5 to improve patient outcome. PMID- 29158561 TI - Using a Single VCSEL Source Employing OFDM Downstream Signal and Remodulated OOK Upstream Signal for Bi-directional Visible Light Communications. AB - In this work, we propose and demonstrate for the first time up to our knowledge, using a 682 nm visible vertical-cavity surface-emitting laser (VCSEL) applied in a bi-directional wavelength remodulated VLC system with a free space transmission distance of 3 m. To achieve a high VLC downstream traffic, spectral efficient orthogonal-frequency-division-multiplexing quadrature-amplitude-modulation (OFDM QAM) with bit and power loading algorithms are applied on the VCSEL in the central office (CO). The OFDM downstream wavelength is remodulated by an acousto optic modulator (AOM) with OOK modulation to produce the upstream traffic in the client side. Hence, only a single VCSEL laser is needed for the proposed bi directional VLC system, achieving 10.6 Gbit/s OFDM downstream and 2 Mbit/s remodulated OOK upstream simultaneously. For the proposed system, as a single laser source with wavelength remodulation is used, the laser wavelength and temperature managements at the client side are not needed; and the whole system could be cost effective and energy efficient. PMID- 29158560 TI - Field sampling marine plankton for biodiscovery. AB - Microalgae and plankton can be a rich source of bioactivity. However, induction of secondary metabolite production in lab conditions can be difficult. One simple way of bypassing this issue is to collect biomass in the field and screen for bioactivity. Therefore, bulk net samples from three areas along the coast of northern Norway and Spitsbergen were collected, extracted and fractionated. Biomass samples from a strain of a mass-cultivated diatom Porosira glacialis were used as a reference for comparison to field samples. Screening for bioactivity was performed with 13 assays within four therapeutic areas: antibacterial, anticancer, antidiabetes and antioxidation. We analysed the metabolic profiles of the samples using high resolution - mass spectroscopy (HR-MS). Principal component analysis showed a marked difference in metabolite profiles between the field samples and the photobioreactor culture; furthermore, the number of active fractions and extent of bioactivity was different in the field compared to the photobioreactor samples. We found varying levels of bioactivity in all samples, indicating that complex marine field samples could be used to investigate bioactivities from otherwise inaccessible sources. Furthermore, we hypothesize that metabolic pathways that would otherwise been silent under controlled growth in monocultures, might have been activated in the field samples. PMID- 29158562 TI - Highly expressed genes evolve under strong epistasis from a proteome-wide scan in E. coli. AB - Epistasis or the non-additivity of mutational effects is a major force in protein evolution, but it has not been systematically quantified at the level of a proteome. Here, we estimated the extent of epistasis for 2,382 genes in E. coli using several hundreds of orthologs for each gene within the class Gammaproteobacteria. We found that the average epistasis is ~41% across genes in the proteome and that epistasis is stronger among highly expressed genes. This trend is quantitatively explained by the prevailing model of sequence evolution based on minimizing the fitness cost of protein unfolding and aggregation. The genes with the highest epistasis are also functionally involved in the maintenance of proteostasis, translation and central metabolism. In contrast, genes evolving with low epistasis mainly encode for membrane proteins and are involved in transport activity. Our results highlight the coupling between selection and epistasis in the long-term evolution of a proteome. PMID- 29158563 TI - Vitamin D: missing link between hypertension and muscle mass. PMID- 29158564 TI - Long-read genome sequence assembly provides insight into ongoing retroviral invasion of the koala germline. AB - The koala retrovirus (KoRV) is implicated in several diseases affecting the koala (Phascolarctos cinereus). KoRV provirus can be present in the genome of koalas as an endogenous retrovirus (present in all cells via germline integration) or as exogenous retrovirus responsible for somatic integrations of proviral KoRV (present in a limited number of cells). This ongoing invasion of the koala germline by KoRV provides a powerful opportunity to assess the viral strategies used by KoRV in an individual. Analysis of a high-quality genome sequence of a single koala revealed 133 KoRV integration sites. Most integrations contain full length, endogenous provirus; KoRV-A subtype. The second most frequent integrations contain an endogenous recombinant element (recKoRV) in which most of the KoRV protein-coding region has been replaced with an ancient, endogenous retroelement. A third set of integrations, with very low sequence coverage, may represent somatic cell integrations of KoRV-A, KoRV-B and two recently designated additional subgroups, KoRV-D and KoRV-E. KoRV-D and KoRV-E are missing several genes required for viral processing, suggesting they have been transmitted as defective viruses. Our results represent the first comprehensive analyses of KoRV integration and variation in a single animal and provide further insights into the process of retroviral-host species interactions. PMID- 29158565 TI - Convergent evolution of plant and animal embryo defences by hyperstable non digestible storage proteins. AB - Plants have evolved sophisticated embryo defences by kinetically-stable non digestible storage proteins that lower the nutritional value of seeds, a strategy that have not been reported in animals. To further understand antinutritive defences in animals, we analysed PmPV1, massively accumulated in the eggs of the gastropod Pomacea maculata, focusing on how its structure and structural stability features affected its capacity to withstand passage through predator guts. The native protein withstands >50 min boiling and resists the denaturing detergent sodium dodecyl sulphate (SDS), indicating an unusually high structural stability (i.e., kinetic stability). PmPV1 is highly resistant to in vitro proteinase digestion and displays structural stability between pH 2.0-12.0 and 25 85 degrees C. Furthermore, PmPV1 withstands in vitro and mice digestion and is recovered unchanged in faeces, supporting an antinutritive defensive function. Subunit sequence similarities suggest a common origin and tolerance to mutations. This is the first known animal genus that, like plant seeds, lowers the nutritional value of eggs by kinetically-stable non-digestible storage proteins that survive the gut of predators unaffected. The selective pressure of the harsh gastrointestinal environment would have favoured their appearance, extending by convergent evolution the presence of plant-like hyperstable antinutritive proteins to unattended reproductive stages in animals. PMID- 29158566 TI - Graphene Quantum Dots for Cell Proliferation, Nucleus Imaging, and Photoluminescent Sensing Applications. AB - We report a simple one-pot microwave assisted "green synthesis" of Graphene Quantum Dots (GQDs) using grape seed extract as a green therapeutic carbon source. These GQDs readily self-assemble, hereafter referred to as "self assembled" GQDs (sGQDs) in the aqueous medium. The sGQDs enter via caveolae and clathrin-mediated endocytosis and target themselves into cell nucleus within 6-8 h without additional assistance of external capping/targeting agent. The tendency to self-localize themselves into cell nucleus also remains consistent in different cell lines such as L929, HT-1080, MIA PaCa-2, HeLa, and MG-63 cells, thereby serving as a nucleus labelling agent. Furthermore, the sGQDs are highly biocompatible and act as an enhancer in cell proliferation in mouse fibroblasts as confirmed by in vitro wound scratch assay and cell cycle analysis. Also, photoluminescence property of sGQDs (lifetime circa (ca.) 10 ns) was used for optical pH sensing application. The sGQDs show linear, cyclic and reversible trend in its fluorescence intensity between pH 3 and pH 10 (response time: ~1 min, sensitivity -49.96 +/- 3.5 mV/pH) thereby serving as a good pH sensing agent. A simple, cost-effective, scalable and green synthetic approach based sGQDs can be used to develop selective organelle labelling, nucleus targeting in theranostics, and optical sensing probes. PMID- 29158568 TI - Arc-induced Long Period Gratings in standard and speciality optical fibers under mixed neutron-gamma irradiation. AB - In this paper, for the first time, the effects of mixed neutron and gamma flux on the spectral and sensing responses of Long Period Gratings (LPGs) are thoroughly analyzed. Six LPGs written by means of Electric Arc Discharge (EAD) technique in standard and speciality fibers, including radiation-hardened ones, were tested. The EAD technique was chosen because it enables the writing of gratings both in standard and not photosensitive fibers. The experiments have been carried out in a "TRIGA" pulsed nuclear reactor and the LPGs were irradiated by a gamma-ray dose rate of 9 Gy/s and a mean 1.2?1012 n/(cm2s) neutron flux. Real time monitoring was performed for a comparative investigation of LPGs' response, in terms of radiation sensitivity and wavelength shift. Experiments show that LPG in a radiation-resistant fiber exhibits resonant wavelength shift higher than LPG in standard fiber. The changes of temperature sensitivity due to radiation were experimentally established by comparison of pre- and post-radiation characterization, indicating that radiation effects induce a slight increase of the temperature sensitivity, except for the LPG in pure-silica fiber. Theoretical and numerical analysis was combined with experimental data for evaluation LPGs' parameters changes, such as refractive index and thermo-optic coefficient, after exposure to radiation. PMID- 29158567 TI - Optogenetic silencing of nociceptive primary afferents reduces evoked and ongoing bladder pain. AB - Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) suffer from chronic pain that severely affects quality of life. Although the underlying pathophysiology is not well understood, inhibition of bladder sensory afferents temporarily relieves pain. Here, we explored the possibility that optogenetic inhibition of nociceptive sensory afferents could be used to modulate bladder pain. The light-activated inhibitory proton pump Archaerhodopsin (Arch) was expressed under control of the sensory neuron-specific sodium channel (sns) gene to selectively silence these neurons. Optically silencing nociceptive sensory afferents significantly blunted the evoked visceromotor response to bladder distension and led to small but significant changes in bladder function. To study of the role of nociceptive sensory afferents in freely behaving mice, we developed a fully implantable, flexible, wirelessly powered optoelectronic system for the long-term manipulation of bladder afferent expressed opsins. We found that optogenetic inhibition of nociceptive sensory afferents reduced both ongoing pain and evoked cutaneous hypersensitivity in the context of cystitis, but had no effect in uninjured, naive mice. These results suggest that selective optogenetic silencing of nociceptive bladder afferents may represent a potential future therapeutic strategy for the treatment of bladder pain. PMID- 29158569 TI - Section 1Tunable broadband terahertz absorbers based on multiple layers of graphene ribbons. AB - A novel metamaterial structure consisting of multiple graphene/dielectric layers and metallic substrate is proposed to achieve the broadband absorption response at terahertz (THz) frequencies. Utilizing the phase modulation effect generated by graphene ribbons, the bright-dark field is formed to suppress the reflection based on interference theory in a wide period. By irregularly stacking four graphene ribbons of varying widths on four dielectric layers with unequal thickness in a period, we merge successive absorption peaks into a broadband absorption spectrum successfully. The absorption decreases with fluctuations as the incident angle increases. The position of the absorption spectrum can be dynamically tuned by a small change in the Fermi level of graphene instead of re optimizing and re-fabricating the device. In addition, the bandwidth of the absorber can be further improved by means of increasing the graphene/dielectric layers. The structure proposed in this paper has potential applications in tunable terahertz photonic devices such as dynamic broadband filters, modulators and sensors. PMID- 29158570 TI - Expression of SRY-related HMG Box Transcription Factors (Sox) 2 and 9 in Craniopharyngioma Subtypes and Surrounding Brain Tissue. AB - Stem cells have been discovered as key players in the genesis of different neoplasms including craniopharyngioma (CP), a rare tumour entity in the sellar region. Sox2 and Sox9 are well-known stem cell markers involved in pituitary development. In this study we analysed the expression of both transcription factors using immunohistochemistry in a large cohort of 64 adamantinomatous (aCP) and 9 papillary CP (pCP) and quantitative PCR in 26 aCP and 7 pCP. Whereas immunohistochemically Sox2+ cells were verifiable in only five aCP (7.8%) and in 39.1% of the respective surrounding cerebral tissue, pCP specimens appeared always negative. In contrast, Sox9 was detectable in all tumours with a significantly higher expression in aCP compared to pCP (protein, p < 0.0001; mRNA p = 0.0484) This was also true for the respective tumour adjacent CNS where 63 aCP (98.4%) and six pCP (66.7%) showed Sox9+ cells. We further confirmed absence of Sox9 expression in nuclear beta-catenin accumulating cells of aCP. Our results point to the conclusion that Sox2 and Sox9, seem to play essential roles not only in the specific formation of aCP, but also in processes involving the cerebral tumour environment, which needs to be illuminated in the future. PMID- 29158572 TI - Systemic sclerosis: STAT3 - A key integrator of profibrotic signalling. PMID- 29158571 TI - Rheumatoid arthritis: Do TNF inhibitors influence lymphoma development? PMID- 29158575 TI - Inflammatory Myopathies: New classification criteria developed for research. PMID- 29158573 TI - Enthesitis: from pathophysiology to treatment. AB - Entheses are the insertion sites of tendons and ligaments to the bone surface and are essential structures for locomotion. Inflammation of the entheses (enthesitis) is a key feature of psoriatic arthritis and spondyloarthritis. To date, our conceptual understanding of enthesitis remains limited. This Review provides an insight into the pathophysiology of enthesitis, addressing the role of biomechanics, prostaglandin E2-mediated vasodilation and the activation of innate immune cells in the initiation phase of enthesitis, as well as the role of entheseal IL-23-responsive cells that augment inflammation by producing pro inflammatory mediators such as IL-17A, IL-22 and TNF. In addition, the molecular steps that translate inflammation into resident tissue responses, resulting in new bone formation, are discussed. The second part of the article summarizes the clinical features of enthesitis, and the role of clinical and imaging instruments in detecting enthesitis are discussed together with their challenges and limitations. Finally, the Review summarizes the current treatment possibilities for enthesitis based on the aforementioned pathophysiological concepts, focusing on the role of cytokine-blocking agents. PMID- 29158576 TI - Computational study on single molecular spectroscopy of tyrosin-glycine, tryptophane-glycine and glycine-tryptophane. AB - Quantum chemistry calculations play a fundamental role in revealing the molecular structures observed in gas-phase spectroscopic measurements. The supersonic jet cooling widely used in single molecular spectroscopy experiment is a non equilibrium process and often causes confusion on the theoretical and experimental comparison. A computational approach is proposed here to account for the effect of the non-equilibrium cooling on the experimental spectra and applied to the cases of tyrosin-glycine (YG), tryptophane-glycine (WG) and glycine tryptophane (GW). The low energy conformers of YG, WG and GW are obtained through thorough conformational searches. The structural features and equilibrium distributions of conformations and the energy barriers for conformer conversions are then determined. Three classes of transition energy barriers, high, medium and low, are found for the conversions among conformers with distinctly different, similar and the same structural types, respectively. The final conformation populations are determined by assuming an initial temperature of about 450 K and allowing for only the conformation conversion with a low energy barrier to occur during the rapid cooling process. The results provide a natural explanation for the numbers of YG, WG and GW conformations observed experimentally. The theoretical conformation assignments are also in good agreement with the experimental IR data. PMID- 29158574 TI - Immunogenicity and loss of response to TNF inhibitors: implications for rheumatoid arthritis treatment. AB - The availability of monoclonal antibodies has revolutionized the treatment of an increasingly broad spectrum of diseases. Inflammatory diseases are among those most widely treated with protein-based therapeutics, termed biologics. Following the first large-scale clinical trials with monoclonal antibodies performed in the 1990s by rheumatologists and clinical immunologists, the approval of these agents for use in daily clinical practice led to substantial progress in the treatment of rheumatic diseases. Despite this progress, however, only a proportion of patients achieve a long-term clinical response. Data on the use of agents blocking TNF, which were among the first biologics introduced into clinical practice, provide ample evidence of primary and secondary treatment inefficacy in patients with rheumatoid arthritis (RA). Important issues relevant to primary and secondary failure of these agents in RA include immunogenicity, methodological problems for the detection of antidrug antibodies and trough drug levels, and the implications for treatment strategies. Although there is no strong evidence to support the routine estimation of antidrug antibodies or serum trough levels during anti-TNF therapy, these assessments might be helpful in a few clinical situations; in particular, they might guide decisions on switching the therapeutic biologic in certain instances of secondary clinical failure. PMID- 29158578 TI - Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit. AB - Low doses of ketamine trigger rapid and lasting antidepressant effects after one injection in treatment-resistant patients with major depressive disorder. Modulation of AMPA receptors (AMPARs) in the hippocampus and prefrontal cortex is suggested to mediate the antidepressant action of ketamine and of one of its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). We have examined whether ketamine and (2R,6R)-HNK affect glutamatergic transmission and plasticity in the mesolimbic system, brain regions known to have key roles in reward-motivated behaviors, mood and hedonic drive. We found that one day after the injection of a low dose of ketamine, long-term potentiation (LTP) in the nucleus accumbens (NAc) was impaired. Loss of LTP was maintained for 7 days and was not associated with an altered basal synaptic transmission mediated by AMPARs and N-methyl-D aspartate receptors (NMDARs). Inhibition of mammalian target of rapamycin signaling with rapamycin did not prevent the ketamine-induced loss of LTP but inhibited LTP in saline-treated mice. However, ketamine blunted the increase in the phosphorylation of the GluA1 subunit of AMPARs at a calcium/calmodulin dependent protein kinase II/protein kinase C site induced by an LTP induction protocol. Moreover, ketamine caused a persistent increased phosphorylation of GluA1 at a protein kinase A site. (2R,6R)-HNK also impaired LTP in the NAc. In dopaminergic neurons of the ventral tegmental area from ketamine- or (2R,6R)-HNK treated mice, AMPAR-mediated responses were depressed, while those mediated by NMDARs were unaltered, which resulted in a reduced AMPA/NMDA ratio, a measure of long-term synaptic depression. These results demonstrate that a single injection of ketamine or (2R,6R)-HNK induces enduring alterations in the function of AMPARs and synaptic plasticity in brain regions involved in reward-related behaviors. PMID- 29158577 TI - VGF function in depression and antidepressant efficacy. AB - Brain-derived neurotrophic factor (BDNF) is a critical effector of depression like behaviors and antidepressant responses. Here, we show that VGF (non acronymic), which is robustly regulated by BDNF/TrkB signaling, is downregulated in hippocampus (male/female) and upregulated in nucleus accumbens (NAc) (male) in depressed human subjects and in mice subjected to chronic social defeat stress (CSDS). Adeno-associated virus (AAV)-Cre-mediated Vgf ablation in floxed VGF mice, in dorsal hippocampus (dHc) or NAc, led to pro-depressant or antidepressant behaviors, respectively, while dHc- or NAc-AAV-VGF overexpression induced opposite outcomes. Mice with reduced VGF levels in the germ line (Vgf+/-) or in dHc (AAV-Cre-injected floxed mice) showed increased susceptibility to CSDS and impaired responses to ketamine treatment in the forced swim test. Floxed mice with conditional pan-neuronal (Synapsin-Cre) but not those with forebrain (alphaCaMKII-Cre) Vgf ablation displayed increased susceptibility to subthreshold social defeat stress, suggesting that neuronal VGF, expressed in part in inhibitory interneurons, regulates depression-like behavior. Acute antibody mediated sequestration of VGF-derived C-terminal peptides AQEE-30 and TLQP-62 in dHc induced pro-depressant effects. Conversely, dHc TLQP-62 infusion had rapid antidepressant efficacy, which was reduced in BDNF floxed mice injected in dHc with AAV-Cre, and in NBQX- and rapamycin-pretreated wild-type mice, these compounds blocking alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling, respectively. VGF is therefore a critical modulator of depression-like behaviors in dHc and NAc. In hippocampus, the antidepressant response to ketamine is associated with rapid VGF translation, is impaired by reduced VGF expression, and as previously reported, requires coincident, rapid BDNF translation and release. PMID- 29158579 TI - Rare susceptibility variants for bipolar disorder suggest a role for G protein coupled receptors. AB - Bipolar disorder (BD) is a prevalent mood disorder that tends to cluster in families. Despite high heritability estimates, few genetic susceptibility factors have been identified over decades of genetic research. One possible interpretation for the shortcomings of previous studies to detect causative genes is that BD is caused by highly penetrant rare variants in many genes. We explored this hypothesis by sequencing the exomes of affected individuals from 40 well characterized multiplex families. We identified rare variants segregating with affected status in many interesting genes, and found an enrichment of deleterious variants in G protein-coupled receptor (GPCR) family genes, which are important drug targets. Furthermore, we showed targeted downstream GPCR dysregulation for some of the variants that may contribute to disease pathology. Particularly interesting was the finding of a rare and functionally relevant nonsense mutation in the corticotropin-releasing hormone receptor 2 (CRHR2) gene that tracked with affected status in one family. By focusing on rare variants in informative families, we identified key biochemical pathways likely implicated in this complex disorder. PMID- 29158580 TI - CK2 regulates 5-HT4 receptor signaling and modulates depressive-like behavior. AB - The serotonergic neurotransmitter system has been widely implicated in the pathophysiology of mood-related disorders such as anxiety and major depressive disorder (MDD). The onset of therapeutic efficacy of traditional antidepressants is delayed by several weeks. The 5-HT4 receptor has emerged as a new therapeutic target since agonists of this receptor induce rapid antidepressant-like responses in rodents. Here we show that the 5-HT4 receptor is regulated by CK2, at transcriptional and post-transcriptional levels. We present evidence, in two different CK2alpha knockout mouse lines, that this regulation is region-specific, with the 5-HT4 receptor upregulated in prefrontal cortex (PFC) but not striatum or hippocampus where CK2alpha is also ablated. 5-HT4 receptor signaling is enhanced in vitro, as evidenced by enhanced cAMP production or receptor plasma membrane localization in the presence of CK2 inhibitor or shRNA targeting CK2alpha. In vivo, 5-HT4 receptor signaling is also upregulated since ERK activation is elevated and sensitive to the inverse agonist, GR113808 in the PFC of CK2alpha KO mice. Behaviorally, KO mice as well as mice with AAV-mediated deletion of CK2alpha in the PFC show a robust 'anti-depressed-like' phenotype and display an enhanced response to antidepressant treatment when tested in paradigms for mood and anxiety. Importantly, it is sufficient to overexpress the 5-HT4 receptor in the mPFC to generate mice with a similar 'anti-depressed-like' phenotype. Our findings identify the mPFC as the region that mediates the effect of enhanced 5-HT4 receptor activity and CK2 as modulator of 5-HT4 receptor levels in this brain region that regulates mood-related phenotypes. PMID- 29158582 TI - The cAMP responsive element-binding (CREB)-1 gene increases risk of major psychiatric disorders. AB - Bipolar disorder (BPD), schizophrenia (SCZ) and unipolar major depressive disorder (MDD) are primary psychiatric disorders sharing substantial genetic risk factors. We previously reported that two single-nucleotide polymorphisms (SNPs) rs2709370 and rs6785 in the cAMP responsive element-binding (CREB)-1 gene (CREB1) were associated with the risk of BPD and abnormal hippocampal function in populations of European ancestry. In the present study, we further expanded our analyses of rs2709370 and rs6785 in multiple BPD, SCZ and MDD data sets, including the published Psychiatric Genomics Consortium (PGC) genome-wide association study, the samples used in our previous CREB1 study, and six additional cohorts (three new BPD samples, two new SCZ samples and one new MDD sample). Although the associations of both CREB1 SNPs with each illness were not replicated in the new cohorts (BPD analysis in 871 cases and 1089 controls (rs2709370, P=0.0611; rs6785, P=0.0544); SCZ analysis in 1273 cases and 1072 controls (rs2709370, P=0.230; rs6785, P=0.661); and MDD analysis in 129 cases and 100 controls (rs2709370, P=0.114; rs6785, P=0.188)), an overall meta-analysis of all included samples suggested that both SNPs were significantly associated with increased risk of BPD (11 105 cases and 51 331 controls; rs2709370, P=2.33 * 10 4; rs6785, P=6.33 * 10-5), SCZ (34 913 cases and 44 528 controls; rs2709370, P=3.96 * 10-5; rs6785, P=2.44 * 10-5) and MDD (9369 cases and 9619 controls; rs2709370, P=0.0144; rs6785, P=0.0314), with the same direction of allelic effects across diagnostic categories. We then examined the impact of diagnostic status on CREB1 mRNA expression using data obtained from independent brain tissue samples, and observed that the mRNA expression of CREB1 was significantly downregulated in psychiatric patients compared with healthy controls. The protein protein interaction analyses showed that the protein encoded by CREB1 directly interacted with several risk genes of psychiatric disorders identified by GWAS. In conclusion, the current study suggests that CREB1 might be a common risk gene for major psychiatric disorders, and further investigations are necessary. PMID- 29158581 TI - Improved ethical guidance for the return of results from psychiatric genomics research. AB - There is an emerging consensus that genomic researchers should, at a minimum, offer to return to individual participants clinically valid, medically important and medically actionable genomic findings (for example, pathogenic variants in BRCA1) identified in the course of research. However, this is not a common practice in psychiatric genetics research. Furthermore, psychiatry researchers often generate findings that do not meet all of these criteria, yet there may be ethically compelling arguments to offer selected results. Here, we review the return of results debate in genomics research and propose that, as for genomic studies of other medical conditions, psychiatric genomics researchers should offer findings that meet the minimum criteria stated above. Additionally, if resources allow, psychiatry researchers could consider offering to return pre specified 'clinically valuable' findings even if not medically actionable-for instance, findings that help corroborate a psychiatric diagnosis, and findings that indicate important health risks. Similarly, we propose offering 'likely clinically valuable' findings, specifically, variants of uncertain significance potentially related to a participant's symptoms. The goal of this Perspective is to initiate a discussion that can help identify optimal ways of managing the return of results from psychiatric genomics research. PMID- 29158583 TI - Patient-derived iPSCs show premature neural differentiation and neuron type specific phenotypes relevant to neurodevelopment. AB - Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC) derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human specific neurodevelopmental events. PMID- 29158585 TI - Child abuse associates with an imbalance of oligodendrocyte-lineage cells in ventromedial prefrontal white matter. AB - Child abuse (CA) is a major risk factor for depression, and strongly associates with suicidal behavior during adulthood. Neuroimaging studies have reported widespread changes in white matter integrity and brain connectivity in subjects with a history of CA. Although such observations could reflect changes in myelin and oligodendrocyte function, their cellular underpinnings have never been addressed. Using postmortem brain samples from depressed suicides with or without history of CA and matched controls (18 per group), we aimed to characterize the effects of CA on oligodendrocyte-lineage (OL) cells in the ventromedial prefrontal white matter. Using immunoblotting, double-labeling immunofluorescence and stereological estimates of stage-specific markers, we found that CA is associated with increased numbers of mature myelinating oligodendrocytes, accompanied by decreased numbers of more immature OL cells. This was paralleled by an increased expression of transcription factor MASH1, which is involved in the terminal differentiation of the OL, suggesting that CA may trigger an increased maturation, or bias the populations of OL cells toward a more mature phenotype. Some of these effects, which were absent in the brain of depressed suicides with no history of CA, were also found to recover with age, suggesting that changes in the balance of the OL may reflect a transient adaptive mechanism triggered by early-life adversity. In conclusion, our results indicate that CA in depressed suicides is associated with an imbalance of the OL in the ventromedial prefrontal white matter, an effect that could lead to myelin remodeling and long term connectivity changes within the limbic network. PMID- 29158584 TI - Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling. AB - Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism involves downstream activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells derived DA neurons. Sixty minutes exposure to ketamine elicited concentration dependent increases of dendritic arborization and soma size in both mouse and human cultures as measured 72 hours after application. These structural effects were blocked by mTOR complex/signaling inhibitors like rapamycin. Direct evidence of mTOR activation by ketamine was revealed by its induction of p70S6 kinase. All effects of ketamine were abolished by AMPA receptor antagonists and mimicked by the AMPA-positive allosteric modulator CX614. Inhibition of BDNF signaling prevented induction of structural plasticity by ketamine or CX614. Furthermore, the actions of ketamine required functionally intact dopamine D3 receptors (D3R), as its effects were abolished by selective D3R antagonists and absent in D3R knockout preparations. Finally, the ketamine metabolite (2R,6R) hydroxynorketamine mimicked ketamine effects at sub-micromolar concentrations. These data indicate that ketamine elicits structural plasticity by recruitment of AMPAR, mTOR and BDNF signaling in both mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. These observations are of likely relevance to the influence of ketamine upon mood and its other functional actions in vivo. PMID- 29158586 TI - Insights into gene expression profiles induced by Socs3 depletion in keratinocytes. AB - Specific deletion of suppressor of cytokine signaling 3 (Socs3) in keratinocytes can cause severe skin inflammation with infiltration of immune cells. The molecular mechanisms and key regulatory pathways involved in these processes remain elusive. To investigate the role of Socs3 in keratinocytes, we generated and analyzed global RNA-Seq profiles from Socs3 conditional knockout (cKO) mice of two different ages (2 and 10 weeks). Over 400 genes were significantly regulated at both time points. Samples from 2-week-old mice exhibited down regulation of genes involved in keratin-related functions and up-regulation of genes involved in lipid metabolism. At week 10, multiple chemokine and cytokine genes were up-regulated. Functional annotation revealed that the genes differentially expressed in the 2-week-old mice play roles in keratinization, keratinocyte differentiation, and epidermal cell differentiation. By contrast, differentially expressed genes in the 10-week-old animals are involved in acute immune-related functions. A group of activator protein-1-related genes were highly up-regulated in Socs3 cKO mice of both ages. This observation was validated using qRT-PCR by SOCS3-depleted human keratinocyte-derived HaCaT cells. Our results suggest that, in addition to participating in immune-mediated pathways, SOCS3 also plays important roles in skin barrier homeostasis. PMID- 29158588 TI - Immunotherapy: Gut bacteria modulate responses to PD-1 blockade. PMID- 29158589 TI - Lung cancer in 2017: Giant steps and stumbling blocks. PMID- 29158587 TI - Analysis of the gut microbiome and plasma short-chain fatty acid profiles in a spontaneous mouse model of metabolic syndrome. AB - Male Tsumura Suzuki obese diabetes (TSOD) mice spontaneously develop obesity and obesity-related metabolic syndrome. Gut dysbiosis, an imbalance of gut microbiota, has been implicated in the pathogenesis of metabolic syndrome, but its mechanisms are unknown. Short-chain fatty acids (SCFAs) are the main fermentation products of gut microbiota and a link between the gut microbiota and the host's physiology. Here, we investigated a correlation among gut dysbiosis, SCFAs, and metabolic syndrome in TSOD mice. We detected enriched levels of Gram positive bacteria and corresponding decreases in Gram-negative bacteria in 24-wk old metabolic syndrome-affected TSOD mice compared with age-matched controls. The abundance of Bacteroidetes species decreased, the abundance of Firmicutes species increased, and nine genera of bacteria were altered in 24-wk-old TSOD mice. The total plasma SCFA level was significantly lower in the TSOD mice than in controls. The major plasma SCFA-acetate-decreased in TSOD mice, whereas propionate and butyrate increased. TSOD mice had no minor SCFAs (valerate and hexanoate) but normal mice did. We thus concluded that gut dysbiosis and consequent disruptions in plasma SCFA profiles occurred in metabolic syndrome affected TSOD mice. We also propose that the TSOD mouse is a useful model to study gut dysbiosis, SCFAs, and metabolic syndrome. PMID- 29158590 TI - Disseminated breast tumour cells: biological and clinical meaning. PMID- 29158592 TI - Epidemiology, pathology and identification of Colletotrichum including a novel species associated with avocado (Persea americana) anthracnose in Israel. AB - Anthracnose disease caused by Colletotrichum species is a major constraint for the shelf-life and marketability of avocado fruits. To date, only C. gloeosporioides sensu lato and C. aenigma have been reported as pathogens affecting avocado in Israel. This study was conducted to identify and characterize Colletotrichum species associated with avocado anthracnose and to determine their survival on different host-structures in Israel. The pathogen survived and over-wintered mainly on fresh and dry leaves, as well as fresh twigs in the orchard. A collection of 538 Colletotrichum isolates used in this study was initially characterized based on morphology and banding patterns generated according to arbitrarily primed PCR to assess the genetic diversity of the fungal populations. Thereafter, based on multi-locus phylogenetic analyses involving combinations of ITS, act, ApMat, cal, chs1, gapdh, gs, his3, tub2 gene/markers; eight previously described species (C. aenigma, C. alienum, C. fructicola, C. gloeosporioides sensu stricto, C. karstii, C. nupharicola, C. siamense, C. theobromicola) and a novel species (C. perseae) were identified, as avocado anthracnose pathogens in Israel; and reconfirmed after pathogenicity assays. Colletotrichum perseae sp. nov. and teleomorph of C. aenigma are described along with comprehensive morphological descriptions and illustrations, for the first time in this study. PMID- 29158594 TI - Re-evaluation of the origin of relaxor ferroelectricity in vinylidene fluoride terpolymers: An approach using switching current measurements. AB - Relaxor-ferroelectric vinylidene fluoride (VDF)-based terpolymers have attracted increased attention for industrial applications because of their large dielectric constants, low voltage operation for nonvolatile memory, and energy storage capabilities. However, the origin of the relaxor ferroelectricity of VDF-based terpolymers is still under investigation. Here, we investigate the ferroelectric behaviour of thin films of terpolymers of VDF, trifluoroethylene (TrFE), and chlorofluoroethylene (CFE) (P(VDF-TrFE-CFE)) and terpolymers of VDF, TrFE, and chlorotrifluoroethylene (CTFE) (P(VDF-TrFE-CTFE)) using switching current - electric field (I-E) loop measurements. I-E loop measurements have substantial advantages because they directly provide information regarding the independent switching behaviour of dipoles. We show that the I-E loops of P(VDF-TrFE-CFE) are the summation of three pairs of Gaussian peak functions. Moreover, we provide definite proof of the presence of double hysteresis loop-like antiferroelectric behaviour and relaxor-ferroelectricity in the nanodomains of the dipoles when applying positive or negative sinusoidal electric fields to the sample films. PMID- 29158591 TI - Surgical oncology for gliomas: the state of the art. AB - Surgical resection remains the mainstay of treatment for patients with glioma of any grade. Maximal resection of the tumour is central to achieving long-term disease control; however, the relationship between the extent of glioma resection and actual clinical benefit for the patient is predicated on the balance between cytoreduction and neurological morbidity. For the neurosurgical oncologist, the clinical rationale for undertaking increasingly extensive resections has gained traction. In parallel, novel surgical techniques and technologies have been developed that help improve patient outcomes. During the past decade, neurosurgeons have leveraged advanced intraoperative imaging methods, fluorescence-based tumour biomarkers, and real-time mutational analyses to maximize the extent of tumour resection. In addition, approaches to minimizing the risk of perioperative morbidity continue to be improved through the combined use of stimulation-mapping techniques, corticospinal tract imaging, and stereotactic thermal ablation. Taken together, these modern principles of neurosurgical oncology bear little resemblance to historical therapeutic strategies for patients with glioma and have dramatically altered the approach to the treatment of patients with these brain tumours. Herein, we outline the state of the art in surgical oncology for gliomas. PMID- 29158593 TI - Facial Aesthetics in Young Adults after Cleft Lip and Palate Treatment over Five Decades. AB - Cleft Lip and Palate (CLP) - a common facial malformation in newborns - is typically corrected by surgical intervention to allow for normal speech development, psychosocial adjustment, and facial attractiveness. The long term treatment outcome can be evaluated after a number of years, possibly in adulthood. We investigated the aesthetics of the nasolabial region by subjective ratings. To compare various surgical approaches we recruited 12 raters to evaluate 429 patients. Expert and lay raters judged photographs from patients, who have completed treatment with one of three different surgical strategies performed in our institution over 50 years. Facial photographs were cropped, presented to the raters in a randomized sequence, and judged by the raters on a 5 point Likert scale. The subjective ratings between the raters revealed a fair to substantial inter-rater reliability. The average ratings of the surgical outcome improved continuously over the investigated 5 decades. Despite possible differences between raters and rater groups this overall result was consistently seen in the gender groups (male/female), or expertise related groups (expert/lay). Our analysis revealed that patients with bilateral CLP scored worse than patients with unilateral CLP when treated in the fifties; more recently treated patients of both groups scored similarly. PMID- 29158595 TI - Genome-wide identification of long non-coding RNA genes and their association with insecticide resistance and metamorphosis in diamondback moth, Plutella xylostella. AB - Long non-coding RNA (lncRNA) is a class of noncoding RNA >200 bp in length that has essential roles in regulating a variety of biological processes. Here, we constructed a computational pipeline to identify lncRNA genes in the diamondback moth (Plutella xylostella), a major insect pest of cruciferous vegetables. In total, 3,324 lncRNAs corresponding to 2,475 loci were identified from 13 RNA-Seq datasets, including samples from parasitized, insecticide-resistant strains and different developmental stages. The identified P. xylostella lncRNAs had shorter transcripts and fewer exons than protein-coding genes. Seven out of nine randomly selected lncRNAs were validated by strand-specific RT-PCR. In total, 54-172 lncRNAs were specifically expressed in the insecticide resistant strains, among which one lncRNA was located adjacent to the sodium channel gene. In addition, 63 135 lncRNAs were specifically expressed in different developmental stages, among which three lncRNAs overlapped or were located adjacent to the metamorphosis associated genes. These lncRNAs were either strongly or weakly co-expressed with their overlapping or neighboring mRNA genes. In summary, we identified thousands of lncRNAs and presented evidence that lncRNAs might have key roles in conferring insecticide resistance and regulating the metamorphosis development in P. xylostella. PMID- 29158596 TI - Efficient Cross-talk Reduction of Nanophotonic Circuits Enabled by Fabrication Friendly Periodic Silicon Strip Arrays. AB - Reduction of the crosstalk between adjacent photonic components has been regarded as one of the most effective, yet most challenging approaches for increasing the packing density of photonic integrated circuits. Recently, extensive efforts have been devoted to this field, leading to a number of elaborate designs, such as waveguide supperlattice and nanophotonic cloaking, among others. Here we develop a simple and efficient crosstalk reduction approach for silicon-based nanophotonic circuits by introducing a periodic array of silicon strips between adjacent waveguides. Studies indicate that the coupling lengths can be extended by more than two orders of magnitude for a waveguide pair with an edge-to-edge distance of ~lambda/3 at the telecommunication wavelength. Further investigations reveal that our method is effective for both strongly and weakly confined silicon photonic modes, and works well over a broad band of operational wavelengths. In addition, the crosstalk reduction technique is shown to be capable of improving the coupling lengths of other elements as well, such as vertical silicon slot waveguides. Our approach offers a promising platform for creating ultra-compact functional components that is fabrication friendly, thereby providing a feasible route toward the realization of photonic integrated circuits with ultra-high packing densities. PMID- 29158597 TI - A new paradigm in modelling the evolution of a stand via the distribution of tree sizes. AB - Our study focusses on investigating a modern modelling paradigm, a bivariate stochastic process, that allows us to link individual tree variables with growth and yield stand attributes. In this paper, our aim is to introduce the mathematics of mixed effect parameters in a bivariate stochastic differential equation and to describe how such a model can be used to aid our understanding of the bivariate height and diameter distribution in a stand using a large dataset provided by the Lithuanian National Forest Inventory (LNFI). We examine tree height and diameter evolution with a Vasicek-type bivariate stochastic differential equation and mixed effect parameters. It is focused on demonstrating how new developed bivariate conditional probability density functions allowed us to calculate the evolution, in the forward and backward directions, of the mean diameter, height, dominant height, assortments, stem volume of a stand and uncertainties in these attributes for a given stand age. We estimate the parameters by considering discrete samples of the diameter and height at a given age and by using an approximated maximum likelihood procedure. The model performance criteria for the height and diameter growth models include statistical indexes and an analysis of residuals. PMID- 29158598 TI - Influences of lone-pair electrons on directionality of hydrogen bonds formed by hydrophilic amino acid side chains in molecular dynamics simulation. AB - The influence of lone-pair electrons on the directionality of hydrogen bonds that are formed by oxygen and nitrogen atoms in the side chains of nine hydrophilic was investigated using molecular dynamics simulations. The simulations were conducted using two types of force fields; one incorporated lone-pair electrons placed at off-atom sites and the other did not. The density distributions of the hydration water molecules around the oxygen and nitrogen atoms were calculated from the simulation trajectories, and were compared with the empirical hydration distribution functions, which were constructed from a large number of hydration water molecules found in the crystal structures of proteins. Only simulations using the force field explicitly incorporating lone-pair electrons reproduced the directionality of hydrogen bonds that is observed in the empirical distribution functions for the deprotonated oxygen and nitrogen atoms in the sp 2 hybridization. The amino acids that include such atoms are functionally important glutamate, aspartate, and histidine. Therefore, a set of force field that incorporates lone-pair electrons as off-atom charge sites would be effective for considering hydrogen bond formation by these amino acids in molecular dynamics simulation studies. PMID- 29158601 TI - Write it as you like it. PMID- 29158599 TI - Application of genome editing technologies in rats for human disease models. AB - Laboratory rats and mice are representative experimental animals for models of human disease. The emergence of genome editing technologies has enabled us to produce a variety of genetically modified animals, including rats, as a means of elucidating the in vivo functions of the gene of interest and characterizing the molecular mechanisms of human disease. Several advanced techniques for knock-in methodologies in rats are currently in development, which permit researchers to introduce precise nucleotide modifications at target sites in the rat's genome. Furthermore, recent studies with knock-out rats have revealed that observed disease phenotypes are often more similar than mouse models to those of humans. In this article, we introduce the methodologies for efficient gene manipulation in rats using genome editing technologies, and describe the advances made using rats for human disease models. We also discuss the importance of gene manipulation in animal models for the better understanding of fundamental processes among different species. PMID- 29158600 TI - CRISPR/Cas9 library screening for drug target discovery. AB - CRISPR/Cas9-based tools have rapidly developed in recent years. These include CRISPR-based gene activation (CRISPRa) or inhibition (CRISPRi), for which there are libraries. CRISPR libraries for loss of function have been widely used to identify new biological mechanisms, such as drug resistance and cell survival signals. CRISPRa is highly useful in screening for gain of functions, and CRISPRi is a more powerful tool than RNA interference (RNAi) libraries in screening for loss of functions. Positive selection using a CRISPR library can detect survival cells with specific conditions, such as drug treatment, and it can easily clarify drug resistance mechanisms. Negative selection is capable of detecting dead or slow-growing cells efficiently, and it can identify survival-essential genes, which can be promising candidates for molecularly targeted drugs. In addition, negative selection can be applied for synthetic lethality interactions, where the perturbation of both genes simultaneously results in the loss of viability, but that of either gene alone does not affect viability. This mechanism is highly important to identifying the optimal combination of molecularly targeted drugs. Survival-co-essential genes in cancer cells can be identified using new methods, such as the paired guide RNA system and in combination with single-cell RNA sequencing techniques. These efficient methods can clarify interesting biological mechanisms and suggest candidates for molecularly targeted drugs. This review identifies what types of screenings were performed and suggests ideas for the next CRISPR screenings to develop new drugs. PMID- 29158602 TI - Radiative control of dark excitons at room temperature by nano-optical antenna tip Purcell effect. AB - Excitons, Coulomb-bound electron-hole pairs, are elementary photo-excitations in semiconductors that can couple to light through radiative relaxation. In contrast, dark excitons (XD) show anti-parallel spin configuration with generally forbidden radiative emission. Because of their long lifetimes, these dark excitons are appealing candidates for quantum computing and optoelectronics. However, optical read-out and control of XD states has remained challenging due to their decoupling from light. Here, we present a tip-enhanced nano-optical approach to induce, switch and programmably modulate the XD emission at room temperature. Using a monolayer transition metal dichalcogenide (TMD) WSe2 on a gold substrate, we demonstrate ~6 * 105-fold enhancement in dark exciton photoluminescence quantum yield achieved through coupling of the antenna-tip to the dark exciton out-of-plane optical dipole moment, with a large Purcell factor of >=2 * 103 of the tip-sample nano-cavity. Our approach provides a facile way to harness excitonic properties in low-dimensional semiconductors offering new strategies for quantum optoelectronics. PMID- 29158603 TI - Realization of ground state in artificial kagome spin ice via topological defect driven magnetic writing. AB - Arrays of non-interacting nanomagnets are widespread in data storage and processing. As current technologies approach fundamental limits on size and thermal stability, enhancing functionality through embracing the strong interactions present at high array densities becomes attractive. In this respect, artificial spin ices are geometrically frustrated magnetic metamaterials that offer vast untapped potential due to their unique microstate landscapes, with intriguing prospects in applications from reconfigurable logic to magnonic devices or hardware neural networks. However, progress in such systems is impeded by the inability to access more than a fraction of the total microstate space. Here, we demonstrate that topological defect-driven magnetic writing-a scanning probe technique-provides access to all of the possible microstates in artificial spin ices and related arrays of nanomagnets. We create previously elusive configurations such as the spin-crystal ground state of artificial kagome dipolar spin ices and high-energy, low-entropy 'monopole-chain' states that exhibit negative effective temperatures. PMID- 29158604 TI - Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice. AB - Zika virus (ZIKV) is an emerging, mosquito-borne RNA virus. The rapid spread of ZIKV within the Americas has unveiled microcephaly 1 and Guillain-Barre syndrome2,3 as ZIKV-associated neurological complications. Recent reports have also indicated other neurological manifestations to be associated with ZIKV, including myelitis 4 , meningoencephalitis 5 and fatal encephalitis 6 . Here, we investigate the neuropathogenesis of ZIKV infection in type I interferon receptor IFNAR knockout (Ifnar1 -/- ) mice, an infection model that exhibits high viral burden within the central nervous system. We show that systemic spread of ZIKV from the site of infection to the brain requires Ifnar1 deficiency in the haematopoietic compartment. However, spread of ZIKV within the central nervous system is supported by Ifnar1-deficient non-haematopoietic cells. Within this context, ZIKV infection of astrocytes results in breakdown of the blood-brain barrier and a large influx of CD8+ effector T cells. We also find that antiviral activity of CD8+ T cells within the brain markedly limits ZIKV infection of neurons, but, as a consequence, instigates ZIKV-associated paralysis. Taken together, our study uncovers mechanisms underlying ZIKV neuropathogenesis within a susceptible mouse model and suggests blood-brain barrier breakdown and T-cell mediated neuropathology as potential underpinnings of ZIKV-associated neurological complications in humans. PMID- 29158605 TI - Deep sequencing of HIV-1 reverse transcripts reveals the multifaceted antiviral functions of APOBEC3G. AB - Following cell entry, the RNA genome of HIV-1 is reverse transcribed into double stranded DNA that ultimately integrates into the host-cell genome to establish the provirus. These early phases of infection are notably vulnerable to suppression by a collection of cellular antiviral effectors, called restriction or resistance factors. The host antiviral protein APOBEC3G (A3G) antagonizes the early steps of HIV-1 infection through the combined effects of inhibiting viral cDNA production and cytidine-to-uridine-driven hypermutation of this cDNA. In seeking to address the underlying molecular mechanism for inhibited cDNA synthesis, we developed a deep sequencing strategy to characterize nascent reverse transcription products and their precise 3'-termini in HIV-1 infected T cells. Our results demonstrate site- and sequence-independent interference with reverse transcription, which requires the specific interaction of A3G with reverse transcriptase itself. This approach also established, contrary to current ideas, that cellular uracil base excision repair (UBER) enzymes target and cleave A3G-edited uridine-containing viral cDNA. Together, these findings yield further insights into the regulatory interplay between reverse transcriptase, A3G and cellular DNA repair machinery, and identify the suppression of HIV-1 reverse transcriptase by a directly interacting host protein as a new cell-mediated antiviral mechanism. PMID- 29158606 TI - Detecting macroecological patterns in bacterial communities across independent studies of global soils. AB - The emergence of high-throughput DNA sequencing methods provides unprecedented opportunities to further unravel bacterial biodiversity and its worldwide role from human health to ecosystem functioning. However, despite the abundance of sequencing studies, combining data from multiple individual studies to address macroecological questions of bacterial diversity remains methodically challenging and plagued with biases. Here, using a machine-learning approach that accounts for differences among studies and complex interactions among taxa, we merge 30 independent bacterial data sets comprising 1,998 soil samples from 21 countries. Whereas previous meta-analysis efforts have focused on bacterial diversity measures or abundances of major taxa, we show that disparate amplicon sequence data can be combined at the taxonomy-based level to assess bacterial community structure. We find that rarer taxa are more important for structuring soil communities than abundant taxa, and that these rarer taxa are better predictors of community structure than environmental factors, which are often confounded across studies. We conclude that combining data from independent studies can be used to explore bacterial community dynamics, identify potential 'indicator' taxa with an important role in structuring communities, and propose hypotheses on the factors that shape bacterial biogeography that have been overlooked in the past. PMID- 29158607 TI - Reiterative epoxide-based strategies for the synthesis of stereo-n-ads and application to polypropionate synthesis. A Personal Account. AB - The enantioselective synthesis of polypropionates continues to be an attractive realm for the synthetic chemists mostly due to the challenges presented by the number of consecutive stereogenic centers contained within the aliphatic chain. Over the years, our laboratory has developed an epoxide-based three-step reiterative methodology for the construction of these targets, with the ultimate goal that the approach could be extended to the synthesis of polypropionate containing natural products. The key steps include the diastereoselective epoxidation of allylic and homoallylic alcohols, and the regioselective cleavage of 2-methyl-3,4-epoxy alcohols. The choice of the organometallic reagent, and the cis/trans geometry of the chiral epoxide can be used to control both the relative and absolute configuration of the resulting propionate unit, allowing our approach to be applied in the synthesis of advanced fragments. Additionally, the combination of our first- and second-generation methodologies permits the incorporation of different variations at the methyl moiety. PMID- 29158608 TI - A fully coupled space-time multiscale modeling framework for predicting tumor growth. AB - Most biological systems encountered in living organisms involve highly complex heterogeneous multi-component structures that exhibit different physical, chemical, and biological behavior at different spatial and temporal scales. The development of predictive mathematical and computational models of multiscale events in such systems is a major challenge in contemporary computational biomechanics, particularly the development of models of growing tumors in humans. The aim of this study is to develop a general framework for tumor growth prediction by considering major biological events at tissue, cellular, and subcellular scales. The key to developing such multiscale models is how to bridge spatial and temporal scales that range from 10-3 to 103 mm in space and from 10-6 to 107 s in time. In this paper, a fully coupled space-time multiscale framework for modeling tumor growth is developed. The framework consists of a tissue scale model, a model of cellular activities, and a subcellular transduction signaling pathway model. The tissue, cellular, and subcellular models in this framework are solved using partial differential equations for tissue growth, agent-based model for cellular events, and ordinary differential equations for signaling transduction pathway as a network at subcellular scale. The model is calibrated using experimental observations. Moreover, this model is biologically-driven from a signaling pathway, volumetrically-consistent between cellular and tissue scale in terms of tumor volume evolution in time, and a biophysically-sound tissue model that satisfies all conservation laws. The results show that the model is capable of predicting major characteristics of tumor growth such as the morphological instability, growth patterns of different cell phenotypes, compact regions of the higher cell density at the tumor region, and the reduction of growth rate due to drug delivery. The predicted treatment outcomes show a reduction in proliferation at different rates in response to different drug dosages. Moreover, the results of several 3D applications to tumor growth and the evolution of cellular and subcellular events are presented. PMID- 29158609 TI - Three-way Interaction of Neuroticism, Extraversion, and Conscientiousness in the Internalizing Disorders: Evidence of Disorder Specificity in a Psychiatric Sample. AB - It is well-established that neuroticism, extraversion, and conscientiousness are individually associated with internalizing disorders, but research suggests that these main effects may be qualified by a three-way interaction when predicting depression. The current study was the first to examine this three-way interaction in a psychiatric sample (N=463) with a range of internalizing symptoms as the outcomes. Using two omnibus personality inventories and a diagnostic interview, the expected three-way interaction emerged most consistently for symptoms of major depression, and there was also evidence of synergistic effects for post traumatic stress disorder and generalized anxiety disorder. Findings indicate that, even in a clinically-distressed and currently-disordered sample, high levels of extraversion and conscientiousness protect against distress disorders for those with high levels of neuroticism. PMID- 29158610 TI - Cephalotrichum and related synnematous fungi with notes on species from the built environment. AB - A recent taxonomic revision of Microascaceae with an emphasis on synnematous fungi enabled re-identification of previously isolated indoor strains of Cephalotrichum. All available Cephalotrichum strains from the culture collection of the Westerdijk Institute were studied, 20 originating from the built environment. Phylogenetic relationships were inferred from DNA sequence data from the internal transcribed spacer 1 and 2 and intervening 5.8S nrDNA (ITS), and parts of beta-tubulin (tub2) and translation elongation factor 1-alpha (tef1) genes. Additionally, herbarium material of 14 Cephalotrichum species described from soil in China was studied, and the taxonomy of C. album, not considered in recent revisions, was reevaluated. Sixteen phylogenetic species in Cephalotrichum are distinguished, five described as new species: C. domesticum, C. lignatile, C. telluricum, C. tenuissimum and C. transvaalense. Five Cephalotrichum species occur in the built environment: C. domesticum, C. gorgonifer (formerly known as Trichurus spiralis), C. microsporum, C. purpureofuscum, and C. verrucisporum. Based on the number of isolates, C. gorgonifer (nine strains) is the most common indoor species. The study of the Chinese herbarium material resulted in the acceptance of three additional Cephalotrichum species: C. casteneum, C. ellipsoideum, and C. spirale. Four species are considered nomena dubia (C. cylindrosporum, C. macrosporum, C. ovoideum, and C. robustum), five are placed in synonymy with other Cephalotrichum species (C. acutisporum, C. inflatum, C. longicollum, C. oblongum, C. terricola) and one species, C. verrucipes, is probably a synonym of Penicillium clavigerum. Cephalotrichum columnare, former Doratomyces columnaris, is transferred to Kernia. Cephalotrichum album, formerly known as Doratomyces putredinis, is transferred to Acaulium and redescribed. PMID- 29158611 TI - Phylogeny of xerophilic aspergilli (subgenus Aspergillus) and taxonomic revision of section Restricti. AB - Aspergillus section Restricti together with sister section Aspergillus (formerly Eurotium) comprises xerophilic species, that are able to grow on substrates with low water activity and in extreme environments. We adressed the monophyly of both sections within subgenus Aspergillus and applied a multidisciplinary approach for definition of species boundaries in sect. Restricti. The monophyly of sections Aspergillus and Restricti was tested on a set of 102 isolates comprising all currently accepted species and was strongly supported by Maximum likelihood (ML) and Bayesian inferrence (BI) analysis based on beta-tubulin (benA), calmodulin (CaM) and RNA polymerase II second largest subunit (RPB2) loci. More than 300 strains belonging to sect. Restricti from various isolation sources and four continents were characterized by DNA sequencing, and 193 isolates were selected for phylogenetic analyses and phenotypic studies. Species delimitation methods based on multispecies coalescent model were employed on DNA sequences from four loci, i.e., ID region of rDNA (ITS + 28S), CaM, benA and RPB2, and supported recognition of 21 species, including 14 new. All these species were also strongly supported in ML and BI analyses. All recognised species can be reliably identified by all four examined genetic loci. Phenotype analysis was performed to support the delimitation of new species and includes colony characteristics on seven cultivation media incubated at several temperatures, growth on an osmotic gradient (six media with NaCl concentration from 0 to 25 %) and analysis of morphology including scanning electron microscopy. The micromorphology of conidial heads, vesicle dimensions, temperature profiles and growth parameters in osmotic gradient were useful criteria for species identification. The vast majority of species in sect. Restricti produce asperglaucide, asperphenamate or both in contrast to species in sect. Aspergillus. Mycophenolic acid was detected for the first time in at least six members of the section. The ascomata of A. halophilicus do not contain auroglaucin, epiheveadride or flavoglaucin which are common in sect. Aspergillus, but shares the echinulins with sect. Aspergillus. PMID- 29158612 TI - Detection of Pathological Changes in the Aorta during Thoracic Aortic Aneurysm Progression on Molecular Level. AB - The progression of thoracic aortic aneurysm depends on regulation of aortic wall homeostasis and on changes in the structural components of the extracellular matrix, which are affected by multiple molecular signalling pathways. We decided to correlate the diameter of ascending thoracic aneurysm with gene expression of inflammation markers (IL-6, CRP), cytokine receptors (IL-6R, TNFR1, and TNFR2), and extracellular matrix components (Emilin-1, MMP9, and TIMP) for detection of the degree of pathological process of TAA formation. The experimental group was divided into three groups according to the diameter of the aortic aneurysm. Whole blood and tissue samples were properly collected and used for nucleic acid, chromatin, and protein isolation. The mRNA levels were detected by qRT-PCR. For the detection of protein levels a Cytokine Array IV assay kit was used in combination with a biochip analyzer. In aortic tissue, significant positive correlations were found between increased mRNA levels of inflammatory cytokines (CRP and IL-6) on both mRNA levels in tissue and protein from the blood with maximum in stage 3. Changes of gene expression of selected genes can be used for the experimental study of the inflammatory receptor inhibitors during trials targeted on slowing down the progress of aortic wall aneurysm. PMID- 29158613 TI - Blood pressure, heart rate and perceived enjoyment after small-sided soccer games and repeated sprint in untrained healthy adolescents. AB - The purpose of this study was to examine systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), rating of perceived exertion (RPE) and perceived enjoyment responses to a repeated-sprint training session (RST) compared to a small-sided soccer game session (SSG) in untrained adolescents. Twelve healthy post-pubertal adolescent males (age 15.8+/-0.6 years, body mass 59.1+/-3.7 kg, height 1.7+/-0.1m) performed RST and SSG sessions in a randomized and counterbalanced order. Blood pressure and HR were measured at rest and at 10, 20 and 30 minutes after interventions, and RPE and enjoyment were assessed. RST and SSG elicited similar exercise HR (74.0% vs. 73.7% of HR peak during RST and SSG respectively, P>0.05). There was no significant change in SBP or DBP after the 2 interventions (all P>0.05, ES<0.5) with a trend to a decrease in SBP after SSG at 30 min after intervention (moderate effect, ES=0.6). Pearson's correlation analysis revealed a significant and large correlation between baseline BP values and magnitude of decline after both RST and SSG. Heart rate during recovery was higher compared with baseline at all times after both sessions (all P<0.05), with HR values significantly lower after SSG versus RST at 30 min after interventions (82.3+/-3.2 versus 92.4+/-3.2 beats/min, respectively, P=0.04). RPE was significantly lower (P=0.02, ES=1.1) after SSG than after RST, without significant differences in enjoyment. In conclusion, repeated sprint and small sided games elicited similar exercise intensity without a significant difference in perceived enjoyment. Post-exercise hypotension after the two forms of training may depend on resting BP of subjects. PMID- 29158614 TI - Evaluation of the external and internal workload in female futsal players. AB - Match analysis technology has been extensively used in football, but there is limited literature on its use in futsal. Despite its increased popularity, the female futsal game model has never been quantified. The aim of this study was to quantify locomotor and mechanical activities performed during a non-competitive female futsal match, measuring the differences between the first and second half. Sixteen female futsal players of the Italian 2nd division were enrolled (age 27+/ 5 years, height 1.65+/-0.09 m, body weight 56.9+/-7.7 kg, BMI 20.9+/-1.9, fat mass 21.5+/-2.9%). Locomotor and mechanical activities were recorded by means of the 10 Hz GPS StatSports system. Games were performed on a 38x18 m synthetic grass outdoor pitch. Significant differences were found between the first and second half in total distance (1424+/-114 and 1313+/-113 m, p<0.05), relative velocity (70+/-6 and 64+/-6 m min-1, p<0.05), high speed running (28+/-16 and 22+/-19 m, p<0.05) and high metabolic distance (80 +/- 29 and 69 +/- 28 m, p<0.05). The match analysis of female futsal matches provides useful information about its external load demands. Female futsal players decreased the workload in the second half compared to the first one during this non-competitive match. It was found that fatigue impairs the performance in the second part of the game. Coaches and physical trainers can obtain useful information to design training programmes taking into account the quantification of locomotor and mechanical activities performed in this study. PMID- 29158615 TI - Using lactate threshold to predict 5-km treadmill running performance in veteran athletes. AB - Measuring lactate threshold to predict endurance performance is difficult among veteran athletes, due to age-related decreases in net lactate concentration. The objective of this study was to determine whether lactate threshold, as assessed using the maximal deviation method (Dmax), which is not dependent on net values of lactate, could be used as a more valid measure of 5-km treadmill running performance than other methods of determining lactate threshold. Veteran runners (18 male and 18 female, aged 47.3+/-6.7 years) performed an incremental exercise test to establish mean treadmill velocity at lactate threshold using Dmax, a log log method, a visual method, and a 4-mmol.L-1 method, and, on a separate occasion, completed a 5-km time trial. Mean treadmill velocity at Dmax was 12.2+/ 1.8 km.h-1, not being significantly different to mean treadmill velocity (12.1+/ 1.8 km.h-1) attained during the 5-km time trial (p>0.05); velocities were also significantly correlated (r=0.92, p<0.001), and limits of agreement narrow (-1.61 to 1.35 km.h-1). Correlations were weaker and limits of agreement wider for the other methods of lactate threshold determination. Using a two-way, mixed-methods ANOVA, there was no significant effect of sex when using the different methods of determining Tlac (F4,136=3.70, p=0.15). Mean treadmill velocity, when using Dmax for determining lactate threshold, can be used to predict 5-km running performance among male and female veteran athletes. PMID- 29158616 TI - Validation of the VERT wearable jump monitor device in elite youth volleyball players. AB - This technical report aims to determine the validity and the accuracy of the VERT Wearable Jump Monitor. The participants of this study were all experienced volleyball players from the U18 category from the Brazilian National team. To assess jump performance, the VERT scores were compared to the VERTEC (jump and reach device). Each athlete performed 3 attack and 3 block jumps in a random, counterbalanced order, and the average score was registered. In the attack jumps, the VERTEC and VERT mean +/- SD scores were 70.9+/-8.2 and 76.3+/-7.5 cm, respectively, and the typical error of the estimate (TEE) as a coefficient of variation (CV) was 7.8% (90% CL 7.0 to 8.9%). VERTEC and VERT devices presented a very large Pearson's correlation for attack jumps (r=0.75; 90% CL 0.68 to 0.81). In addition, the mean+/-SD block jumps were 53.7+/-6.1 and 58.5+/-5.7 cm for the VERTEC and VERT, respectively and the TEE as a CV was 7.9% (90% CL 7.1 to 8.9%). Pearson's correlation coefficient was very large for block jumps (r=0.75; 90% CL 0.67 to 0.81). The VERT device was found to be a very practical tool to quantify jump performance in volleyball players. PMID- 29158617 TI - Pertussis outbreak in Polish shooters with adverse event analysis. AB - In addition to different injuries, infections are the most common reason for giving up training altogether or reducing its volume and intensity, as well as a lack of opportunities to participate in sports competitions. Nowadays, a slow but constant re-emergence of pertussis, especially among teenagers and young adults, including athletes, can be observed. This paper describes an outbreak of pertussis among professional Polish shooters, focusing on the transmission of Bordetella pertussis infection between members of the national team, its influence on performance capacity and adverse event analysis. From 9 June, 2015 to 31 July, 2015, a total of 4 confirmed and suspected cases of pertussis were reported among members of the Polish Sport Shooting National Team, their relatives and acquaintances. Pertussis significantly decreased exercise performance of the first athlete, a 35-year-old woman, interrupted her training, and finally resulted in failure to win a medal or quota place. Pertussis also significantly decreased performance of the second athlete, a 25-year-old shooter. The other cases emerged in their families. Whooping cough is a real threat to athletes and should be prevented. Preventive measures include appropriate immunization, constant medical supervision, as well as early isolation, diagnostic tests and treatment of all infected sport team members. Regular administration of booster doses of the acellular pertussis vaccine (Tdpa) every 5 years seems reasonable. PMID- 29158618 TI - Injury and illness epidemiology in soccer - effects of global geographical differences - a call for standardized and consistent research studies. AB - Soccer is the most popular sport in the world. While injuries and illnesses can affect the players' health and performance, they can also have a major economic impact on teams. Moreover, several studies have shown the favourable association between higher player availability and team success. Therefore, injury prevention could directly impact clubs' financial balance and teams' performance via increased player availability. To be able to develop effective methods of injury prevention, it is vital to first determine the scope and the degree of the problem: the mechanisms and types of injuries, their frequency and severity, etc. According to the most widely known prevention model, systematic injury surveillance is the first and most fundamental step towards injury prevention. Since epidemiological studies have shown that injuries and illnesses in soccer players differ from region to region, it is important to establish a specific injuries and illness database in order to guide specific preventive actions. Since Asia is the largest continent, with the highest number of soccer players, and in the light of the long-term research on injuries performed in UEFA clubs, the authors of the present article present the AFC surveillance. Some methodological issues related to this prospective design study are discussed. The definition of injury and illness and the methods to track players' exposure are described along with the potential challenges related to such a vast scale study. This article is also a call for action to have consistent and standardized epidemiological studies on soccer injuries and illnesses, with the aim to improve their prevention. PMID- 29158619 TI - The effect of mineral-based alkaline water on hydration status and the metabolic response to short-term anaerobic exercise. AB - Previously it was demonstrated that mineralization and alkalization properties of mineral water are important factors influencing acid-base balance and hydration in athletes. The purpose of this study was to investigate the effects of drinking different types of water on urine pH, specific urine gravity, and post-exercise lactate utilization in response to strenuous exercise. Thirty-six male soccer players were divided into three intervention groups, consuming around 4.0 l/day of different types of water for 7 days: HM (n=12; highly mineralized water), LM (n=12; low mineralized water), and CON (n=12; table water). The athletes performed an exercise protocol on two occasions (before and after intervention). The exercise protocol consisted of 5 bouts of intensive 60-s (120% VO2max) cycling separated by 60 s of passive rest. Body composition, urinalysis and lactate concentration were evaluated - before (t0), immediately after (t1), 5' (t2), and 30' (t3) after exercise. Total body water and its active transport (TBW - total body water / ICW - intracellular water / ECW - extracellular water) showed no significant differences in all groups, at both occasions. In the post hydration state we found a significant decrease of specific urine gravity in HM (1021+/-4.2 vs 1015+/-3.8 g/L) and LM (1022+/-3.1 vs 1008+/-4.2 g/L). We also found a significant increase of pH and lactate utilization rate in LM. In conclusion, the athletes hydrated with alkaline, low mineralized water demonstrated favourable changes in hydration status in response to high-intensity interval exercise with a significant decrease of specific urine gravity, increased urine pH and more efficient utilization of lactate after supramaximal exercise. PMID- 29158620 TI - Evaluation of different jumping tests in defining position-specific and performance-level differences in high level basketball players. AB - The importance of jumping ability in basketball is well known, but there is an evident lack of studies that have examined different jumping testing protocols in basketball players at advanced levels. The aim of this study was to assess the applicability of different tests of jumping capacity in identifying differences between (i) playing position and (ii) competitive levels of professional players. Participants were 110 male professional basketball players (height: 194.92+/-8.09 cm; body mass: 89.33+/-10.91 kg; 21.58+/-3.92 years of age; Guards, 49; Forwards, 22; Centres, 39) who competed in the first (n = 58) and second division (n = 52). The variables included anthropometrics and jumping test performance. Jumping performances were evaluated by the standing broad jump (SBJ), countermovement jump (CMJ), reactive strength index (RSI), repeated reactive strength ability (RRSA) and four running vertical jumps: maximal jump with (i) take-off from the dominant leg and (ii) non-dominant leg, lay-up shot jump with take-off from the (iii) dominant leg and (iv) non-dominant leg. First-division players were taller (ES: 0.76, 95%CI: 0.35-1.16, moderate differences), heavier (0.69, 0.29-1.10), had higher maximal reach height (0.67, 0.26-1.07, moderate differences), and had lower body fat % (-0.87, -1.27-0.45, moderate differences) than second-division players. The playing positions differed significantly in three of four running jump achievements, RSI and RRSA, with Centres being least successful. The first division players were superior to second-division players in SBJ (0.63, 0.23 1.03; 0.87, 0.26-1.43; 0.76, 0.11-1.63, all moderate differences, for total sample, Guards, and Forwards, respectively). Running vertical jumps and repeated jumping capacity can be used as valid measures of position-specific jumping ability in basketball. The differences between playing levels in vertical jumping achievement can be observed by assessing vertical jump scores together with differences in anthropometric indices between levels. PMID- 29158621 TI - Loaded and unloaded jump performance of top-level volleyball players from different age categories. AB - The aim of this study was to investigate the differences in loaded and unloaded jump performances between different age categories of top-level volleyball players from the same club. Forty-three volleyball players were divided into four age groups: under-17, under-19, under-21 and professional. Vertical jumping height for squat jump (SJ), countermovement jump (CMJ) and CMJ with arm swing (CMJa) and mean propulsive velocity (MPV) in the loaded jump squat exercise with 40% of the athlete's body mass were compared among the different age categories, considering body mass as a covariate. SJ and CMJ jump height values were higher for professional and under-21 players than under-17 players (p<0.05). CMJa height was higher for under-21 players than under-19 and under-17 players (p<0.05). MPV in the loaded jump squat was higher for under-21 players than under-17 players (p<0.05). From a general perspective, these results suggest that aging per se is not capable of substantially improving loaded and unloaded vertical jump performances across different age categories of top-level volleyball players. Therefore, to increase the vertical jumping ability of these team sport athletes throughout their long-term development, coaches and strength and conditioning professionals are encouraged to implement consistent neuromuscular training strategies, in accordance with the specific needs and physiological characteristics of each age group. PMID- 29158622 TI - Kinematic and Microphysical Significance of Lightning Jumps versus Non-Jump Increases in Total Flash Rate. AB - Thirty-nine thunderstorms are examined using multiple-Doppler, polarimetric and total lightning observations to understand the role of mixed phase kinematics and microphysics in the development of lightning jumps. This sample size is larger than those of previous studies on this topic. The principal result of this study is that lightning jumps are a result of mixed phase updraft intensification. Larger increases in intense updraft volume (>= 10 m s-1) and larger changes in peak updraft speed are observed prior to lightning jump occurrence when compared to other non-jump increases in total flash rate. Wilcoxon-Mann-Whitney Rank Sum testing yields p-values <=0.05, indicating statistical independence between lightning jump and non-jump distributions for these two parameters. Similar changes in mixed phase graupel mass magnitude are observed prior to lightning jumps and non-jump increases in total flash rate. The p-value for graupel mass change is p=0.096, so jump and non-jump distributions for graupel mass change are not found statistically independent using the p=0.05 significance level. Timing of updraft volume, speed and graupel mass increases are found to be 4 to 13 minutes in advance of lightning jump occurrence. Also, severe storms without lightning jumps lack robust mixed phase updrafts, demonstrating that mixed phase updrafts are not always a requirement for severe weather occurrence. Therefore, the results of this study show that lightning jump occurrences are coincident with larger increases in intense mixed phase updraft volume and peak updraft speed than smaller non-jump increases in total flash rate. PMID- 29158623 TI - Criterion Validity of the "HRQOLISP-E": A New Context-Specific Screening Tool for Poststroke Depression. AB - Objectives: The optimal tool for identifying postsroke depression (PSD) is yet to be identified. In the present study, we rely on the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) as a meaningful criterion to investigate the psychometric properties of the HRQOLISP-E, a new context-specific screening tool for PSD developed from a large cross-cultural sample. Methods: We assessed baseline data being collected as part of an intervention to improve one year blood pressure control among recent (<=one month) stroke survivors. Depression was measured using the HADS-D and the HRQOLISP-E. We determined sensitivity, specificity, likelihood ratios, and posttest probability. The area under a receiver operator curve (AUC) and the most appropriate HRQOLISP-E cut-off were also determined using standard procedures. Results: Using data derived from 387 recent stroke survivors, the HRQOLISP-E showed high agreement with the HADS D, sensitivity = 73.7%, specificity = 79.3%, and posterior test probability = 88% (95% CI = 84%-91%). The AUC was 0.81 (95% CI = 0.76-0.86). The HRQOLISP-E cut off, corresponding to HADS-D score >= 8, was 20/21 (out of a total score of 30). Conclusions: Within limitations of using the HADS-D as a referent criterion, the present results provide justification for further development of the HRQOLISP-E as the first stroke-specific screening tool for depression. PMID- 29158624 TI - Plant growth under water/salt stress: ROS production; antioxidants and significance of added potassium under such conditions. AB - Plants are confronted with a variety of environmenmtal stresses resulting in enhanced production of ROS. Plants require a threshold level of ROS for vital functions and any change in their concentration alters the entire physiology of plant. Delicate balance of ROS is maintained by an efficient functioning of intriguing indigenous defence system called antioxidant system comprising enzymatic and non enzymatic components. Down regulation of antioxidant system leads to ROS induced oxidative stress causing damage to important cellular structures and hence anomalies in metabolism. Proper mineral nutrition, in addition to other agricultural practices, forms an important part for growth and hence the yield. Potassium (K) is a key macro-element regulating growth and development through alterations in physiological and biochemical attributes. K has been reported to result into accumulation of osmolytes and augmentation of antioxidant components in the plants exposed to water and salt stress. In the present review an effort has been made to revisit the old findings and the current advances in research regarding the role of optimal, suboptimal and deficient K soil status on growth under normal and stressful conditions. Effect of K deficiency and sufficiency is discussed and the information about the K mediated antioxidant regulation and plant response is highlighted. PMID- 29158625 TI - Comparative genomic hybridization and transcriptome sequencing reveal that two genes, OsI_14279 (LOC_Os03g62620) and OsI_10794 (LOC_Os03g14950) regulate the mutation in the gamma-rl rice mutant. AB - We previously established the genetic locus of the rolled-leaf mutant, gamma-rl, to chromosome 3. In this study, we performed a comparative genomic hybridization (CGH) analysis to identify the genes responsible for the gamma-rl mutant phenotype. This was combined with RNA transcriptome sequencing (RNA-seq) to analyze differences in the mRNA expression in seeds 12 h after germination. Using the reference genome of the "indica type" rice from GenBank, we created a chip with 386,000 high density DNA probes designed to target chromosome 3. The genomic DNA from gamma-rl and Qinghuazhan (the wild-type) was used for hybridization against the chip to compare signal differences. We uncovered 49 regions with significant differences in hybridization signals including deletions and insertions. RNA-seq analysis between gamma-rl and QHZ identified 1060 differentially expressed genes, which potentially regulate numerous biological activities. Moreover, we identified 72 annotated genes in the 49 regions discovered in CGH. Among these, 44 genes showed differential expression in RNA seq. qRT-PCR validation of the candidate genes confirmed that seven of the 44 genes showed a significant change in their expression levels. Among these, four genes [OsI_10125 (LOC_Os03g06654), OsI_14045 (LOC_Os03g62490), OsI_14279 (LOC_Os03g62620) and OsI_14326 (LOC_Os03g63250)] were down regulated and three genes [(OsI_10794 (LOC_Os03g14950), OsI_11412 (LOC_Os03g21250) and OsI_14152 (LOC_Os03g61360)] were up regulated with a fold change >=2.0 and a P value <= 0.01. Finally, we constructed transgenic plants to study the in vivo functions of these genes. RNAi knock down of LOC_Os03g62620 resulted in rolled-leaf, lower seed-setting and decreased seed growth phenotypes. Transgenic plants with LOC_Os03g14950 over-expression showed dwarf plants with a shortened leaf phenotype. Our results, LOC_Os03g62620 and LOC_Os03g14950 as the essential genes responsible for creating the gamma-rl mutant phenotypes suggested that these genes may play crucial roles in regulating rice leaf development and seed growth. PMID- 29158626 TI - Genome scanning for identification and mapping of receptor-like kinase (RLK) gene superfamily in Solanum tuberosum. AB - Receptor-like kinases (RLKs) are a key class of genes that contribute to diverse phenomena from plant development to defense responses. The availability of completed potato genome sequences provide an excellent opportunity to identify and characterize RLK gene superfamily in this lineage. We identified 747 non redundant RLK genes in the potato genome that were classified into 52 subfamilies, of which 58% members organized into tandem repeats. Nine of potato RLK subfamilies organized into tandem repeats. Also, six subfamilies exhibited lineage-specific expansion compared to Arabidopsis. The majority of RLK genes were physically organized within heterogeneous and homogeneous clusters on chromosomes and were unevenly distributed on the genome. Chromosome 2, 3 and 7 contained the highest number of RLK genes and the most underrepresented chromosomes were chromosome 8, 10 and 11. Taken together, our results provide a framework for future efforts on comparative, evolutionary and functional studies of the members of RLK superfamily. PMID- 29158627 TI - Development of transcriptome based web genomic resources of yellow mosaic disease in Vigna mungo. AB - Vigna mungo (Urdbean) is cultivated in the tropical and sub-tropical continental region of Asia. It is not only important source of dietary protein and nutritional elements, but also of immense value to human health due to medicinal properties. Yellow mosaic disease caused by Mungbean Yellow Mosaic India Virus is known to incur huge loss to crop, adversely affecting crop yield. Contrasting genotypes are ideal source for knowledge discovery of plant defence mechanism and associated candidate genes for varietal improvement. Whole genome sequence of this crop is yet to be completed. Moreover, genomic resources are also not freely accessible, thus available transcriptome data can be of immense use. V. mungo Transcriptome database, accessible at http://webtom.cabgrid.res.in/vmtdb/ has been developed using available data of two contrasting varieties viz., cv. VM84 (resistant) and cv. T9 (susceptible). De novo assembly was carried out using Trinity and CAP3. Out of total 240,945 unigenes, 165,894 (68.8%) showed similarity with known genes against NR database, and remaining 31.2% were found to be novel. We found 22,101 differentially expressed genes in all datasets, 44,335 putative genic SSR markers, 4105 SNPs and Indels, 64,964 transcriptional factor, 546 mature miRNA target prediction in 703 differentially expressed unigenes and 137 pathways. MAPK, salicylic acid-binding protein 2-like, pathogenesis-related protein and NBS-LRR domain were found which may play an important role in defence against pathogens. This is the first web genomic resource of V. mungo for future genome annotation as well as ready to use markers for future variety improvement program. PMID- 29158628 TI - Identification and expression profiling analysis of TCP family genes involved in growth and development in maize. AB - The TCP family is a group of plant-specific transcription factors. TCP genes encode proteins harboring bHLH structure, which is implicated in DNA binding and protein-protein interactions and known as the TCP domain. TCP genes play important roles in plant development and have been evolutionarily and functionally elaborated in various plants, however, no overall phylogenetic analysis or expression profiling of TCP genes in Zea mays has been reported. In the present study, a systematic analysis of molecular evolution and functional prediction of TCP family genes in maize (Z. mays L.) has been conducted. We performed a genome-wide survey of TCP genes in maize, revealing the gene structure, chromosomal location and phylogenetic relationship of family members. Microsynteny between grass species and tissue-specific expression profiles were also investigated. In total, 29 TCP genes were identified in the maize genome, unevenly distributed on the 10 maize chromosomes. Additionally, ZmTCP genes were categorized into nine classes based on phylogeny and purifying selection may largely be responsible for maintaining the functions of maize TCP genes. What's more, microsynteny analysis suggested that TCP genes have been conserved during evolution. Finally, expression analysis revealed that most TCP genes are expressed in the stem and ear, which suggests that ZmTCP genes influence stem and ear growth. This result is consistent with the previous finding that maize TCP genes represses the growth of axillary organs and enables the formation of female inflorescences. Altogether, this study presents a thorough overview of TCP family in maize and provides a new perspective on the evolution of this gene family. The results also indicate that TCP family genes may be involved in development stage in plant growing conditions. Additionally, our results will be useful for further functional analysis of the TCP gene family in maize. PMID- 29158630 TI - Consequences of copper treatment on pigeon pea photosynthesis, osmolytes and antioxidants defense. AB - An attempt was made to explore the effect of copper sulphate treatment on growth, photosynthesis, osmolytes and antioxidants in 15 days old seedlings of C. cajan (Pigeonpea). C. cajan seedlings were grown in 0, 1, 5 and 10 mM concentrations of copper sulphate in petriplates lined with Whatman filter paper for 15 days. Root length and shoot length was decreased in a dose dependent manner with highest decrease of 82.80 and 45.92% in 10 mM Cu stress. Photosynthetic efficiency (qP, qN and Y) was decreased in a dose dependent manner whereas NPQ was increased in 1 and 5 mM and decreased in 10 mM Cu. Photosynthetic pigments viz total chlorophyll and carotenoids were increased in low concentrations and decreased in high concentrations of Cu. Osmolytes such as proline, glycine betaine and sugars were found to be increased in a dose dependent manner. Similarly antioxidants such as superoxide dismutase and catalase increased to 129.17 and 169.7%, respectively under Cu stress. Vitamin C and vitamin E was also increased in different concentrations of Cu to a significant level. It can be concluded from the present study that C. cajan can tolerate Cu stress up to 5 mM by adjusting the proportion of proline, glycine betaine, sugars and vitamins along with increasing the activity of some of the antioxidant enzymes. PMID- 29158629 TI - Overexpression of LhSorNPR1, a NPR1-like gene from the oriental hybrid lily 'Sorbonne', conferred enhanced resistance to Pseudomonas syringae pv. tomato DC3000 in Arabidopsis. AB - The non-expressor of the pathogenesis-related genes 1 (NPR1) is a master regulator in defense signaling of plants and plays a key role in basal and systemic acquired resistance. In this study, we isolated a NPR1-like gene from the oriental hybrid lily 'Sorbonne' (designated as LhSorNPR1) using rapid amplification of cDNA ends (RACE). The open reading frame of LhSorNPR1 consisted of 1854 bp, encoding a protein of 617 amino acids. Multiple sequence alignment revealed that LhSorNPR1 shares high similarity to NPR1-like proteins and characteristics of the BTB/POZ domain and ankyrin repeats. A comparison between the intron/exon organization of LhSorNPR1 and orthologs from other plant species demonstrated that NPR1 genomic fragments (including LhSorNPR1) are all composed of 4 exons and 3 introns. We also identified sequence motifs involved in hormone response and binding sites for RAV1 proteins and WRKY transcription factors through the prediction of cis-regulatory elements in the LhSorNPR1 promoter. Our gene expression analysis showed that LhSorNPR1 transcript levels significantly differed in various tissues, and that LhSorNPR1 expressions were induced by sodium salicylate, ethephon, and methyl jasmonate. Furthermore, we transformed LhSorNPR1 into Col-0 wild-type Arabidopsis to conduct function analysis, and we observed enhanced resistance to the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 in the Arabidopsis expressing LhSorNPR1 gene. The enhanced disease resistance of LhSorNPR1 expressing plants could correlate to elevated expression levels in pathogenesis-related genes (PR1, PR2, and PR5) in vivo. PMID- 29158631 TI - Mapping quantitative trait loci for heat tolerance at the booting stage using chromosomal segment substitution lines in rice. AB - High temperature stress is a major obstacle in rice productivity. Considerable progress has been made on studying heat tolerance (HT) at different stages. However, the genetic basis of HT at the booting stage is poorly understood. In this study, we analyzed the morphological features of a heat-sensitive japonica cultivar Sasanishiki under natural high temperature stress at the booting stage. The anthers became smaller and the number, and fertility, of pollen grains were decreased significantly. As a result, there was a dramatic reduction in spikelet fertility. In contrast, the indica cultivar Habataki showed high HT and normal spikelet fertility under high temperature stress. Additonally, a set of chromosome segment substitution lines, derived from Sasanishiki and Habataki, were evaluated for HT related quantitative trait loci (QTLs) across two environments in the natural field. A total of 12 QTLs associated with HT were detected, of which, 5 were identified in two environments, and 7 in one environment. Furthermore, one of the major-effect QTLs (qHTB3-3) detected on the long arm of chromosome 3, was confirmed using overlapping substituted lines. qHTB3-3 was finally mapped between the two markers RM3525 and 3-M95, approximately 2.8 Mb apart. These findings and further gene cloning of qHTB3-3 will help us better understand the molecular control of HT in rice, and may contribute to the development of high HT rice varieties. PMID- 29158632 TI - Impact of postharvest exogenous gamma-aminobutyric acid treatment on cucumber fruit in response to chilling tolerance. AB - Low-temperature storage is generally used to extend postharvest lifetime and to inhibit decay of cucumber fruit, but it also enhances the intensity of chilling injury. The capability of gamma-aminobutyric acid to enhance antioxidant enzyme activities and reduce chilling injury was studied in cucumber (Cucumis sativus L.) fruit stored at 1 degrees C for 5 weeks. The purpose of this study was to define if the GABA-induced modification in antioxidant system and phospholipase activity is linked to the reduced chilling injury in cold-stored cucumber fruit. Alleviation of chilling injury by GABA treatment was related to increased content of proline, endogenous GABA and enhanced activities of CAT and SOD, together with reduced activities of PLC, PLD and LOX. We suggest that PLC, LOX and PLD are associated with chilling injury initiation by involvement in a signaling pathway and membrane deterioration. Therefore the results obtained in this study suggest GABA's potential for postharvest applications for reducing chilling injury symptom in cucumber fruit. PMID- 29158633 TI - Comprehensive physiological analyses and reactive oxygen species profiling in drought tolerant rice genotypes under salinity stress. AB - Rice being a staple cereal is extremely susceptible towards abiotic stresses. Drought and salinity are two vital factors limiting rice cultivation in Eastern Indo-Gangetic Plains (EIGP). Present study has intended to evaluate the consequences of salinity stress on selected drought tolerant rice genotypes at the most susceptible seedling stage with an aim to identify the potential multi stress (drought and salt) tolerant rice genotype of this region. Genotypic variation was obvious in all traits related to drought and salt susceptibility. IR84895-B-127-CRA-5-1-1, one of the rice genotypes studied, exhibited exceptional drought and salinity tolerance. IR83373-B-B-25-3-B-B-25-3 also displayed enhanced drought and salt tolerance following IR84895-B-127-CRA-5-1-1. Variations were perceptible in different factors involving photosynthetic performance, proline content, lipid peroxidation, K+/Na+ ratio. Accumulation of reactive oxygen species (ROS) disintegrated cellular and sub-cellular membrane leading to decreased photosynthetic activities. Therefore, accumulation and detoxification of reactive oxygen species was also considered as a major determinant of salt tolerance. IR84895-B-127-CRA-5-1-1 showed improved ROS detoxification mediated by antioxidant enzymes. IR84895-B-127-CRA-5-1-1 seedlings also displayed significant recovery after removal of salt stress. The results established a direct association of ROS scavenging with improved physiological activities and salt tolerance. The study also recommended IR84895-B-127-CRA-5-1-1 for improved crop performance in both drought and saline environments of EIGP. These contrasting rice genotypes may assist in understanding the multiple stress associated factors in concurrent drought and salt tolerant rice genotypes. PMID- 29158634 TI - Aluminum exclusion from root zone and maintenance of nutrient uptake are principal mechanisms of Al tolerance in Pisum sativum L. AB - Our study aimed to evaluate intraspecific variability of pea (Pisum sativum L.) in Al tolerance and to reveal mechanisms underlying genotypic differences in this trait. At the first stage, 106 pea genotypes were screened for Al tolerance using root re-elongation assay based on staining with eriochrome cyanine R. The root re elongation zone varied from 0.5 mm to 14 mm and relationships between Al tolerance and provenance or phenotypic traits of genotypes were found. Tolerance index (TI), calculated as a biomass ratio of Al-treated and non-treated contrasting genotypes grown in hydroponics for 10 days, varied from 30% to 92% for roots and from 38% to 90% for shoots. TI did not correlate with root or shoot Al content, but correlated positively with increasing pH and negatively with residual Al concentration in nutrient solution in the end of experiments. Root exudation of organic acid anions (mostly acetate, citrate, lactate, pyroglutamate, pyruvate and succinate) significantly increased in several Al treated genotypes, but did not correlate with TI. Al-treatment decreased Ca, Co, Cu, K, Mg, Mn, Mo, Ni, S and Zn contents in roots and/or shoots, whereas contents of several elements (P, B, Fe and Mo in roots and B and Fe in shoots) increased, suggesting that Al toxicity induced substantial disturbances in uptake and translocation of nutrients. Nutritional disturbances were more pronounced in Al sensitive genotypes. In conclusion, pea has a high intraspecific variability in Al tolerance and this trait is associated with provenance and phenotypic properties of plants. Transformation of Al to unavailable (insoluble) forms in the root zone and the ability to maintain nutrient uptake are considered to be important mechanisms of Al tolerance in this plant species. PMID- 29158635 TI - Gene expression and activity of antioxidant enzymes in rice plants, cv. BRS AG, under saline stress. AB - The rice cultivar (Oryza sativa L.) BRS AG, developed by Embrapa Clima Temperado, is the first cultivar designed for purposes other than human consumption. It may be used in ethanol production and animal feed. Different abiotic stresses negatively affect plant growth. Soil salinity is responsible for a serious reduction in productivity. Therefore, the objective of this study was to evaluate the gene expression and the activity of antioxidant enzymes (SOD, CAT, APX and GR) and identify their functions in controlling ROS levels in rice plants, cultivar BRS AG, after a saline stress period. The plants were grown in vitro with two NaCl concentrations (0 and 136 mM), collected at 10, 15 and 20 days of cultivation. The results indicated that the activity of the enzymes evaluated promotes protection against oxidative stress. Although, there was an increase of reactive oxygen species, there was no increase in MDA levels. Regarding genes encoding isoforms of antioxidant enzymes, it was observed that OsSOD3-CU/Zn, OsSOD2-Cu/Zn, OsSOD-Cu/Zn, OsSOD4-Cu/Zn, OsSODCc1-Cu/Zn, OsSOD-Fe, OsAPX1, OsCATB and OsGR2 were the most responsive. The increase in the transcription of all genes among evaluated isoforms, except for OsAPX6, which remained stable, contributed to the increase or the maintenance of enzyme activity. Thus, it is possible to infer that the cv. BRS AG has defense mechanisms against salt stress. PMID- 29158636 TI - Chromosome segment detection for seed size and shape traits using an improved population of wild soybean chromosome segment substitution lines. AB - Size and shape of soybean seeds are closely related to seed yield and market value. Annual wild soybeans have the potential to improve cultivated soybeans, but their inferior seed characteristics should be excluded. To detect quantitative trait loci (QTLs)/segments of seed size and shape traits in annual wild soybean, its chromosome segment substitution lines (CSSLs) derived from NN1138-2 (recurrent parent, Glycine max) and N24852 (donor parent, Glycine soja) and then modified 2 iterations (coded SojaCSSLP3) were improved further to contain more lines (diagonal segments) and less heterozygous and missing portions. The new population (SojaCSSLP4) composed of 195 CSSLs was evaluated under four environments, and 11, 13, 7, 15 and 14 QTLs/segments were detected for seed length (SL), seed width (SW), seed roundness (SR), seed perimeter (SP) and seed cross section area (SA), respectively, with all 60 wild allele effects negative. Among them, 16 QTLs/segments were shared by 2-5 traits, respectively, but 0-3 segments for each of the 5 traits were independent. The non-shared Satt274 and shared Satt305, Satt540 and Satt239 were major segments, along with other segments composed of two different but related sets of genetic systems for SR and the other 4 traits, respectively. Compared with the literature, 7 SL, 5 SW and 2 SR QTLs/segments were also detected in cultivated soybeans; allele distinction took place between cultivated and wild soybeans, and also among cultivated parents. The present mapping is understood as macro-segment mapping, the segments may be further dissected into smaller segments as well as corresponding QTLs/genes. PMID- 29158637 TI - Marker-assisted identification of restorer gene(s) in iso-cytoplasmic restorer lines of WA cytoplasm in rice and assessment of their fertility restoration potential across environments. AB - Iso-cytoplasmic restorers possess the same male sterile cytoplasm as the cytoplasmic male sterile (CMS) lines, thereby minimizing the potential cyto nuclear conflict in the hybrids. Restoration of fertility of the wild abortive CMS is governed by two major genes namely, Rf3 and Rf4. Therefore, assessing the allelic status of these restorer genes in the iso-cytoplasmic restorers using molecular markers will not only help in estimating the efficiency of these genes either alone or in combination, in fertility restoration in the hybrids in different environments, but will also be useful in determining the efficacy of these markers. In the present study, the efficiency of molecular markers in identifying genotypes carrying restorer allele of the gene(s) Rf3 and Rf4, restoring male fertility of WA cytoplasm in rice was assessed in a set of 100 iso cytoplasmic rice restorers using gene linked as well as candidate gene based markers. In order to validate the efficacy of markers in identifying the restorers, a sub-set of selected 25 iso-cytoplasmic rice restorers were crossed with four different cytoplasmic male sterile lines namely, IR 79156A, IR 58025A, Pusa 6A and RTN 12A, and the pollen and spikelet fertility of the F1s were evaluated at three different locations. Marker analysis showed that Rf4 was the predominant fertility restorer gene in the iso-cytoplasmic restorers and Rf3 had a synergistic effect on fertility restoration. The efficiency of gene based markers, DRCG-RF4-14 and DRRM-RF3-10 for Rf4 (87%) and Rf3 (84%) genes was higher than respective gene-linked SSR markers RM6100 (80%) and RM3873 (82%). It is concluded that the gene based markers can be effectively used in identifying fertility restorer lines obviating the need for making crosses and evaluating the F1s. Though gene based markers are more efficient, there is a need to identify functional polymorphisms which can provide 100% efficiency. Three iso-cytoplasmic restorers namely, PRR 300, PRR 363 and PRR 396 possessing both Rf4 and Rf3 genes and good fertility restoration have been identified which could be used further in hybrid rice breeding. PMID- 29158638 TI - Genetic characterization of chayote [Sechium edule (Jacq.) Swartz.] landraces of North Eastern Hills of India and conservation measure. AB - Chayote or chow-chow is an underutilized cucurbit vegetable crop, widely cultivated by farmers in the backyards and Jhum lands for its tender leaves, fruits and tuberous root. In order to initiate crop improvement program in this crop, the present study was undertaken to assess the genetic variations in the 74 chow-chow landraces collected from the North Eastern Hill region of India. Wide variations for fruit colors, fruit length (6.5-21.5 cm), fruit width (4.2-10.7 cm), fruit weight (60-560 g), vitamin-C (2.6-13.8 mg/100 g), reducing sugar (0.18 2.77%), total sugar (1.09-2.94%) and phenol content (0.17-3.85 mg/100 g FW) were recorded among the landraces. All the landraces were also characterized using random amplified polymorphic DNA (RAPD) and inter simple sequence repeat (ISSR) markers. In RAPD analyses, out of 28 primers a total of 198 reproducible amplicons were formed at an average of 7.01 per primer and an overall polymorphism of 88.38%. Eight fragments were specific to landraces with light green fruits. Four fragments were observed to be specific to RCSC-22 (dark green fruits) and another four specific to a RCSC-30 (pale yellow fruits). Out of 30 ISSR, only 5 primers generated a total of 32 reproducible amplicons with an average of 6.4 per primer and overall polymorphism of 62.5%. The pair wise similarity coefficient values ranged from 0.55 to 0.96. The grouping of landraces in cluster analysis was found to be independent of their respective geographic locations. The cuttings of suckers and shoot top (2 months old) treated with indole-3-butyric acid (200 mg l-1) provide an alternative for the conservation of the diverse genetic materials to the researchers. PMID- 29158639 TI - Mining and characterization of EST-SSR markers for Zingiber officinale Roscoe with transferability to other species of Zingiberaceae. AB - Zingiber officinale is a model spice herb, well known for its medicinal value. It is primarily a vegetatively propagated commercial crop. However, considerable diversity in its morphology, fiber content and chemoprofiles has been reported. The present study explores the utility of EST-derived markers in studying genetic diversity in different accessions of Z. officinale and their cross transferability within the Zingiberaceae family. A total of 38,115 ESTs sequences were assembled to generate 7850 contigs and 10,762 singletons. SSRs were searched in the unigenes and 515 SSR-containing ESTs were identified with a frequency of 1 SSR per 25.21 kb of the genome. These ESTs were also annotated using BLAST2GO. Primers were designed for 349 EST-SSRs and 25 primer pairs were randomly picked for EST SSR study. Out of these, 16 primer pairs could be optimized for amplification in different accessions of Z. officinale as well as other species belonging to Zingiberaceae. GES454, GES466, GES480 and GES486 markers were found to exhibit 100% cross-transferability among different members of Zingiberaceae. PMID- 29158640 TI - A sucrose non-fermenting-1-related protein kinase 1 gene from potato, StSnRK1, regulates carbohydrate metabolism in transgenic tobacco. AB - Sucrose non-fermenting-1-related protein kinase 1 (SnRK1) has been shown to play an essential role in regulating saccharide metabolism and starch biosynthesis of plant. The regulatory role of StSnRK1 from potato in regulating carbohydrate metabolism and starch accumulation has not been investigated. In this work, a cDNA encoding the SnRK1 protein, named StSnRK1, was isolated from potato. The open reading frame contained 1545 nucleotides encoding 514 amino acids. Subcellular localization analysis in onion epidermal cells indicated that StSnRK1 protein was localized to the nucleus. The coding region of StSnRK1 was cloned into a binary vector under the control of 35S promoter and then transformed into tobacco to obtain transgenic plants. Transgenic tobacco plants expressing StSnRK1 were shown to have a significant increased accumulation of starch content, as well as sucrose, glucose and fructose content. Real-time quantitative PCR analysis indicated that overexpression of StSnRK1 up-regulated the expression of sucrose synthase (NtSUS), ADP-glucose pyrophosphorylase (NtAGPase) and soluble starch synthase (NtSSS III) genes involved in starch biosynthesis in the transgenic plants. In contrast, the expression of sucrose phosphate synthase (NtSPS) gene was decreased in the transgenic plants. Meanwhile, enzymatic analyses indicated that the activities of major enzymes (SUS, AGPase and SSS) involved in the starch biosynthesis were enhanced, whereas SPS activity was decreased in the transgenic plants compared to the wild-type. These results suggest that the manipulation of StSnRK1 expression might be used for improving quality of plants in the future. PMID- 29158641 TI - Development of an efficient and reproducible regeneration system in wheat (Triticum aestivum L.). AB - The availability of reproducible regeneration system through tissue culture is a major bottleneck in wheat improvement program. The present study has considered to develop an efficient callus induction and regeneration system using mature and immature embryos as explants in recently released agronomically superior spring wheat varieties. An efficient sterilization process was standardized using 0.1% HgCl2 and 70% ethanol for both seeds and embryos. The maximum possible combinations of plant growth regulators (PGRs) were evaluated for their effect on different wheat regeneration processes through tissue culture starting from callus to root induction. Picloram is found as an effective auxin with 87.63 98.67% callus induction efficiency in both explants. Supplementation of CuSO4 along with 2,4-D, zeatin in regeneration medium significantly enhanced the multiple shoot induction. The shoot development was achieved using full strength Murashige and Skoog's (MS) medium and root induction using half MS medium without PGRs. The optimized medium and method has resulted up to 100% regeneration irrespective of the genotype used with high reproducibility. Thus, the standardized regeneration system can be used in the regeneration of healthy plants from embryos rescued from interspecies crosses, transgenic production, induced mutation breeding and recently developed genome editing techniques for the procreation of wheat plants having novel traits. PMID- 29158642 TI - Insights into nuclear DNA content, hydrogen peroxide and antioxidative enzyme activities during transverse thin cell layer organogenesis and ex vitro acclimatization of Malaxis wallichii, a threatened medicinal orchid. AB - Malaxis wallichii (Lindl.) Deb, a small, perennial, monopodial, terrestrial orchid, is endemic to tropical Himalayas at an altitude of 1200-2000 m asl. The pseudobulbs are important ingredients of century old drug 'Ashtavarga' and a polyherbal energetic tonic 'Chyavanprash'. An efficient genetically stable in vitro propagation protocol using transverse thin cell layer culture system was established for M. wallichii. In the present report, meta-topolin alone proved to be three times more beneficial compared to other routinely used cytokinins in inducing highest number of shoot buds, plant height and growth of regenerated shoots. The highest regeneration frequency (89%) along with maximum number of adventitious shoots per explant (22.5 +/- 0.6) was observed in MS medium supplemented with 1.0 mg/l meta-topolin and 0.5 mg/l alpha-naphthalene acetic acid. Highest rooting frequency with highest number of roots (8.66 +/- 0.3) was achieved in half-strength MS medium fortified with 1.0 mg/l indole acetic acid. Clonal stability of in vitro-derived plantlets was evaluated and compared to donor plant using intron splice junction (ISJ) markers and flow cytometry. ISJ markers revealed 4.76% clonal variability indicating high degree of genetic stability amongst the in vitro-derived regenerants. The nuclear DNA content of M. wallichii (2n) was found to be 2C = 2.760 +/- 0.02 pg and therefore, 1349.64 Mbp (1C). Flow cytometry analysis of actively growing young and mature leaves from donor as well as in vitro-derived plantlets revealed presence of three peaks corresponding to 2C, 4C and 8C, while 2C was the most abundant. In the present investigation, there was no significant difference in the 2C DNA content between the mother and in vitro-derived plants; however, the frequency of endopolyploid cells varied in young and adult plants. An increased H2O2 content as well as lipid peroxidation activities were observed during early stages of acclimatization which declined afterwards. The enhanced activities of antioxidant enzymes like superoxide dismutase, catalase, ascorbate peroxidase and glutathione reductase in acclimatized plantlets as compared to in vitro-grown ones revealed their active involvement in growth and development against oxidative stress under external adverse environment. PMID- 29158643 TI - In vitro propagation, ex vitro rooting and leaf micromorphology of Bauhinia racemosa Lam.: a leguminous tree with medicinal values. AB - A micropropagation system for Bauhinia racemosa Lam. was developed involving axillary shoot proliferation and ex vitro rooting using nodal explants obtained from mature tree. MS medium with 3.0 mg l-1 BA (6-benzyladenine) was optimum for shoot bud induction. For shoot multiplication, mother explants were transferred repeatedly on medium containing low concentration of BA (0.75 mg l-1). Number of shoots was increased up to two passages and decreased thereafter. Shoot multiplication was further enhanced on MS medium containing 0.25 mg l-1 each of BA and Kin (Kinetin) with 0.1 mg l-1 of NAA (alpha-naphthalene acetic acid). Addition of 0.004 mg l-1 TDZ (thidiazuron) increased the rate of shoot multiplication and 21.81 +/- 1.26 shoots per culture vessel were obtained. In vitro regenerated shoots were rooted under ex vitro conditions treated with 400 mg l-1 IBA (indole-3-butyric acid) for 7 min on sterile soilrite. After successful hardening in greenhouse, ex vitro rooted plants were transferred to the field conditions with ~85% of survival rate. Micromorphological changes were observed on leaf surface i.e. development of vein density and trichomes and stomatal appearance, when plants were subjected to environmental conditions. This is the first report on in vitro regeneration of B. racemosa from mature tree. PMID- 29158644 TI - Injury mechanism, fracture characteristics and clinical treatment of pilon fracture with intact fibula-A retrospective study of 23 pilon fractures. AB - Objective: The effect of intact fibula on pilon fracture is not completely elucidated. We retrospectively analysed pilon fractures with intact fibula at our hospital over a 4 year period to understand the injury mechanism, fracture characteristics, treatment strategy and prognosis of this fracture. Methods: Pilon fracture patients with intact fibula treated in our hospital from January 2010 to December 2014 were observed. OA/ATO fracture type, Ruedi-Allgower classification and fracture characteristics were summarised. The following data were collected from the charts: operative time, operative approach, fixation, fracture healing time, ankle joint Mazur scores, Burwell-Charnley fracture reduction scores and postoperative complications. Results: Twenty-two patients were followed up with a mean follow-up time of 17.6 months (10-27 months). The examination results showed the existence of distal tibiofibular syndesmosis injuries, medial malleolus, posterior malleolar, and anterior tibial fractures, and talus-fibula relationship changes, which accounted for 65.2%, 69.3%, 73.9%, 100% and 26.1%, respectively. 19 cases underwent internal fixation, with an average operation time of 108 min. The mean fracture healing time was 6.74 months. The Mazur ankle score showed excellent and good ratings of 86.9%. The Burwell-Charnley fracture reduction score had good and fair ratings of 95.7%. Skin infection occurred in two cases. Conclusion: Pilon fracture with intact fibula is mostly caused by medium-low energy injury when the ankle is at neutral or varus position. Multi-part fractures commonly occur at the distal tibial articular surface because the energy is concentrated on the tibia. In general, one single anterior approach can complete open reduction and internal fixation operation with satisfactory clinical outcomes in most cases. PMID- 29158645 TI - Evaluation of functional outcome of pilon fractures managed with limited internal fixation and external fixation: A prospective clinical study. AB - Introduction: The management of pilon fractures is controversial primarily due to the high rate of complications irrespective of the mode of treatment. Limited internal fixation with external fixation is associated with minimal soft tissue handling. This may reduce the chances of wound dehiscence and infection. This study was designed to evaluate the functional and clinical outcomes in patients treated with limited internal fixation combined with external fixation in pilon fractures. Material and methods: This study was conducted as a prospective clinical study on 56 skeletally mature patients with closed fractures with poor skin condition, and with open grade 1 and grade 2 distal tibial intra-articular fractures. All patients were treated with combined limited internal fixation and ankle spanning external fixation. Results: All fractures in this series united with an average time period of union of 18.3weeks (ranging from 13 weeks to 30 weeks). There was no non-union in any case. There was malunion in 4 cases, varus malunion (>5 degree) in 2 cases and recurvatum in another 2 cases). Excellent to good functional results were observed in 88% cases based on the modified Ovadia and Beals score. The mean ankle dorsiflexion and planter flexion movements were 10.2+/-5.3 degrees and 27.4+/-7.2 degrees respectively. infections occurred in 6 patients which included 4 pin tract infections and 2 superficial wound infection, all 6 healed after removal of pin tract and with oral antibiotics. Conclusion: The technique of combined external fixation with internal fixation is safe and effective management option for intra-articular distal tibial fractures. PMID- 29158646 TI - Management of comminuted tibial end bony avulsion of posterior cruciate ligament by open posterior approach using suture bridge technique: A case series. AB - Background: Comminuted tibial end bony avulsion of posterior cruciate ligament (PCL) is a challenging problem in terms of accurate reduction, fixation and union to provide a stable knee. Arthroscopic reduction or a screw fixation is good option for a large fragment but comminuted fragment reduction remains a challenge. Suture bridge technique using two anchors can provide an accurate reduction and stable fixation. Method: 10 patients of isolated comminuted PCL avulsion with a mean age of 30 years were fixed by standard posterior approach using suture bridge technique. Results: Mean follow up was 12 months. All patients showed radiological union at 12 weeks with a mean Lysholm score of 92. Seven out of ten achieved IKDC grade A and remaining three had grade B. No complication of the procedure were noted. Conclusion: Suture bridge technique is an excellent option to fix a comminuted PCL avulsion fracture where arthroscopic reduction or open single screw fixation is not a viable due option due to comminution. PMID- 29158647 TI - Performance of physiology scoring systems in prediction of in-hospital mortality of traumatic children: A prospective observational study. AB - Background: This study is designed to compare the value of four physiologic scoring systems of rapid acute physiology score (RAPS), rapid emergency medicine score (REMS), Worthing physiology scoring system (WPSS) and revised trauma score (RTS) in predicting the in-hospital mortality of traumatic children brought to the emergency department. Method: We used the data gathered from six healthcare centers across Iran between the April-October 2016. Included patients were all children with trauma. Patients were assessed and followed until discharge. Moreover, patients were divided to two groups of died and alive, and discriminatory power and general calibration of models in prediction of in hospital mortality were compared. Results: Data was gathered from 814 children (average age of 11.65 +/- 5.36 years, 74.32% boys). Highest measured area under the curve was for RAPS and REMS with 0.986 and 0.986, respectively. Areas under the curve of WPSS and RTS were 0.920 and 0.949, respectively (p = 0.02). Sensitivity and specificity of RAPS were 100.0 and 95.05, respectively. These amounts for REMS were 100.0 and 94.04, respectively. Two models of RTS and WPSS had the same sensitivity of 84.62. Specificity of these two was 98.22 and 96.95, respectively. Three models of RAPS, REMS and RTS had proper calibrations in predicting mortality; however, it seems that WPSS overestimates the mortality in high risk patients. Conclusion: As calculations of RAPS is easier than REMS and their proper calibrations, it seems that RAPS is the best physiologic model in predicting in-hospital mortality and classifying in traumatic children based on severity of injury. However, further validation of the recommended score is essential before implementing them into routine clinical practice. PMID- 29158648 TI - Non-invasive repair of an iatrogenic tibial artery branch pseudoaneurysm after intramedullary nailing. AB - Tibial fractures are a commonly seen injury in orthopedic surgery. Intramedullary nailing is considered the standard of care, as complications are rare. Those of a vascular nature, including iatrogenically induced pseudoaneurysms of the tibial artery have been previously described in the literature, however each reported case has required surgical repair. In the current case, we describe a repair of a tibial artery branch pseudoaneurysm, after direct contact with an interlocking screw from tibial intramedullary nailing, via ultrasound-guided thrombin injection. To the authors' knowledge, this is the first reported case of a tibial artery pseudoaneurysm repaired non-surgically. This adds support to the promising literature on non-invasive repair of orthopedically related pseudoaneurysms. PMID- 29158649 TI - Life expectancy of osteoarthritic patients after primary total knee arthroplasty. AB - Background: Although an increased life expectancy has been previously reported in patients with osteoarthritis (OA) after undergoing total knee arthroplasty (TKA), the long-living Japanese population may provide a more accurate cohort for determining 10- and 15-year survival rates. The aims of the present study were to (1) determine the survival of patients after TKA, (2) identify the factors important for survival, and (3) compare the survival rate of the OA patients with that of the standardized general population. Methods: The 5-, 10-, and 15-year survival rates were assessed in 326 consecutive OA patients treated with TKA from January 1998 to December 2013. Eighty-six of the cases were staged bilateral TKAs. All patients were followed until December 31, 2014 or until the time of death. The survival rate of the patients was compared with that of the standardized general population using Kaplan-Meier survival curves. Results: Fifty-one of the patients died before the end of the follow-up. The cumulative 5 year patient survival was 93.5%, 10-year survival was 82.1%, and 15-year survival was 66.6%. The standardized mortality ratio was 0.916 (95% confidence interval: 0.682-1.204). A Cox proportional hazards model showed that increased age and unilateral TKA were factors related to higher patient mortality rates. Conclusions: These data suggest that patients undergoing TKA can expect similar life expectancy as the general population, with 66.6% of such patients surviving for at least 15-years. Additionally, patients undergoing bilateral TKAs may have a longer life expectancy than those undergoing unilateral TKA. PMID- 29158650 TI - Partial humeral replacement for peri-prosthetic fractures of the humerus. AB - Introduction: Treating peri-prosthetic fractures of the humerus can be very challenging, especially when there is poor bone stock and in the presence of adjacent joint prostheses. We discuss the option of a partial humeral replacement as a salvage procedure for such cases with some technical comments. Methods: This paper presents a technique which utilises a custom- made cemented connector to incorporate the existing well functioning elbow or shoulder replacement with a commercially available partial humeral replacement (PHR) or to an existing prosthetic humeral stem. Results: Our series involves 6 patients with severe rheumatoid arthritis, all female, with a mean age of 62.5 years. Their surgeries were performed over a span of 10 years, with an average follow up of 49 months. All had a well functioning implant at final follow-up, with a mean Mayo Elbow Performance score of 65. There were no cases of infection, nerve injury or dislocation in our patients. There were 2 deaths in our series, from unrelated medical causes at 2 and 4 years following their surgery. Conclusion: Although a partial humeral replacement connected to a well functioning implant is a rare procedure for salvage of a humeral peri-prosthetic fracture, it can be a viable option in certain patient populations. Every attempt should be made to maintain the secondary shoulder stabilisers at the proximal humerus as a functioning unit. PMID- 29158651 TI - Soft tissue complications in distal tibial fractures managed with medial locking plates: A myth or reality? AB - Background: Distal tibial fractures are common injuries that are prone to complications and require careful management. The use of medial periarticular locking plates is an established modality in the treatment if these fractures. These plates are inserted using the minimally invasive plate osteosynthesis (MIPO) or open technique. Our study looks at the soft tissue complications associated with the use of medial locking plates in the management of these fractures. Methods: This was a retrospective study carried out at a tertiary care university hospital in an urban setting. Forty four patients with distal tibia fractures treated with periarticular locking plates during a three year period were included in the study. Both closed and open fractures were included while those with an established non-union were excluded. Patient data related to inpatient stay, outpatient visits as well as readmissions was extracted from hospital records and analysed. Spanning external fixation was done if necessary and definitive fixation was done using medial locking plates with either MIPO technique or open reduction and internal fixation (ORIF) with biological technique. The sub cohort of patients with soft tissue complications was compared to the parent group. Results: The study group included 44 patients (28M:16F) with 45 fractures with a median age of 42.6 years (range 18-65 years) followed up for a mean of 9.2 months (range 5-20 months). Domestic falls were the cause of injury in 61.4% (n = 27) of the fractures. The average time to union was 26.2 weeks (range 12-66 weeks). Out of these 45 fractures, soft tissue complications were seen in 22.2% of cases (n = 10) with road side accidents seen in 60% (n = 6) of cases. In four patients, there was difficulty in achieving primary wound closure and in five other cases wound dehiscence with exposure of implant was seen within 12 to 30 days of surgery. One patient required secondary suturing after readjustment for malreduction. No statistically significant difference was found in the parent cohort and the sub cohort with soft tissue complications with respect to the use of spanning external fixator, MIPO/ORIF technique or fibular fixation. Conclusion: The incidence of soft tissue complications with the use of medial locking plates in distal tibial fractures may be more than what is currently reported in literature and further studies are required to shed more light on this subject. PMID- 29158652 TI - Foreword: Addressing the Social Determinants of Health through Academic-Community Partnerships. PMID- 29158653 TI - Incentivizing Fruit and Vegetable Purchasers at Fresh Markets in Lower 9th Ward, New Orleans. AB - Objective: Disparities in fruit and vegetable consumption have been observed across income and race-ethnicity and shown to be associated with both access to fresh food venues and price. This study assesses the feasibility of increasing produce consumption by incentivizing fruit and vegetable purchases at local markets. Design: We conducted analyses of a cross-sectional survey of program participants and point-of-sale reports on fruit and vegetable purchases at the fresh food markets. Setting: Five fresh food markets in the Lower Ninth Ward (LNW) of New Orleans, Louisiana. Participants: A total of 176 participants were enrolled in the "Veggie Dollars" program (VDP). Intervention: From January to July 2016, Sankofa, our community partner, recruited patrons at its markets into the VDP, a fresh food incentive program. Participants received coupons worth $4 per week for fruit and vegetables over a six-week period. Main Outcome Measures: Total monthly gross, VDP, and SNAP benefit sales at the markets measured program participation. A survey (N=96) assessed the demographics and fruit and vegetable purchasing practices of participants. Results: Participants were predominantly women (81%), African American (94%) and raising children at home (53%). Point-of sales data indicated that VDP sales nearly doubled over the intervention period. Total market sales and SNAP benefit purchases also increased. The majority (63%) of VDP participants reported their produce purchases increased and 89% reported increasing their consumption of fruit and vegetables since entering the program. Conclusions: Monetary incentives were associated with increased fruit and vegetable purchases at local fresh food markets in a low-income minority community. PMID- 29158654 TI - Farmers' Market Utilization among Supplemental Nutrition Assistance Program Recipients in New Orleans, Louisiana: Preliminary Findings. AB - Objective: Farmers' markets are increasingly being promoted as a means to provide fresh produce to poor and underserved communities. However, farmers' market (FM) use remains low among low-income patrons. The purpose of our study was to examine FM awareness and use, grocery shopping behaviors, and internet use among Supplemental Nutrition Assistance Program (SNAP) recipients. Design: A descriptive analysis of preliminary data was performed to evaluate quantitative baseline data among SNAP recipients between June and August 2016 in New Orleans, Louisiana (N=51). Data were collected via a 42-item online survey that included demographics, internet use, FM awareness and use, health information seeking behaviors and fruit and vegetable purchasing behaviors. Results: Less than half of the survey respondents (n=24) had ever been to a FM. Local grocery stores and Wal-Mart were most used for purchasing fruits and vegetables (88% and 84%, respectively). The most common sources of healthy eating information were Women, Infants and Children (WIC) and the internet, frequently accessed via smartphones. More than 80% of participants were not aware that local FMs accepted electronic benefit transfer payments as a form of payment. Conclusion: These results support the incorporation of promotional methodology that combines internet-based mobile technology and existing services (eg, WIC) as a viable strategy to improve farmers' market use among low-income populations. As most participants were not aware that participating FMs accept electronic benefit transfer payments, this fact should be emphasized in promotional material. PMID- 29158655 TI - Bikeshare Use in Urban Communities: Individual and Neighborhood Factors. AB - Objective: Bicycling is an affordable way to increase access to employment, schooling, and services and an effective measure against obesity. Bikeshare programs can make bicycling accessible to diverse populations, but little evidence exists on their adoption in low-resource neighborhoods. Our study examined factors associated with bikeshare use in a metropolitan area in the southern United States. Methods: We performed a retrospective cross-sectional analysis of a database of clients (N=815) who rented a bicycle from Zyp Bikeshare in Birmingham, Alabama between October 2015 and November 2016. Individual-level variables included bike use frequency, average speed, total miles traveled, total minutes ridden, bike type (traditional vs electricity-assisted pedelec), membership type, sex, and age. Area-level data aggregated to Census tracts, proxies for neighborhoods, were obtained from the 2010 US Census after geocoding clients' billing addresses. Using exploratory factor analysis, a neighborhood socioeconomic disadvantage index (SDI) was constructed. Bikeshare station presence in a tract was included as a covariate. Multivariate linear regression models, adjusted for clustering on Census tracts, were estimated to determine predictors of bikeshare use. Results: In a multivariate regression model of individual and neighborhood characteristics adjusted for clustering, each decile increase in the SDI was associated with a 9% increase in bikeshare use (P<.001). Bikeshare use was also positively associated with speed (.1, P<.001), total miles (.008, P<.001), and pedelec use (1.02, P<.01). Conclusion: Higher neighborhood socioeconomic disadvantage is associated with higher bikeshare use. Bikeshare is a viable transportation option in low-resource neighborhoods and may be an effective tool to improve the connectivity, livability, and health of urban communities. PMID- 29158656 TI - Translating the Birmingham Neighborhood Leaders Survey into Innovative Action through the Community Health Innovation Awards. AB - The Carnegie Foundation for the Advancement of Teaching describes community engagement as the collaboration between higher education institutions and their larger communities (local, regional/state, national, global) for the mutually beneficial exchange of knowledge and resources in a context of partnership. This article describes the development, implementation and outcomes of a community engaged grant-making program, the Community Health Innovation Awards (CHIA). The CHIA program was the by-product of a qualitative study jointly led by researchers at the University of Alabama at Birmingham and neighborhood leaders from the surrounding communities in Birmingham, AL. The competitive program provided funding to area organizations that proposed creative solutions to on-the-ground health challenges. Since its inception, CHIA has awarded $356,500 to 26 innovative projects between 2012 and 2017. These awards have supported novel programs that have connected academic and community partners in addressing health disparities and improving overall community well-being in the greater Birmingham area. PMID- 29158657 TI - Academic-Community Partnership Development to Enhance Program Outcomes in Underserved Communities: A Case Study. AB - Purpose: A community-academic partnership was developed to assess community needs and restructure a variety of community-based programs that provide services to underserved communities in New Orleans, Louisiana. Methods: The community and academic partners utilized five phases to assess community needs and restructure programs: 1) meetings; 2) narrowing the scope of community programs; 3) data collection and analysis; 4) emphasizing target programs; and 5) improving sustainability through grant submissions and grant development training. Results: Survey data were collected and analyzed pre- and post-community-academic partnership between November 2014-November 2016 in New Orleans, Louisiana. The data supported the need for community-based programs run by a community organization known as the Dillard University Office of Community and Church Relations (OCCR). The survey results showed that community members expressed interest in: screenings for chronic diseases, such as diabetes; attending exercise classes at local churches; attending financial management workshops; and health fairs run by the community organization. In the future, screenings, workshops, health fairs, as well as exercise and diet programs, will take place at all churches participating in the community-based, umbrella program, Churches in Unity program. Conclusion: A formal community-academic partnership, involving the assignment of an academic liaison, restructured programs for a community partner to better serve the needs of a community that is at-risk for a multitude of obesity-related health problems faced by underserved communities. PMID- 29158658 TI - Examining Neighborhood Social Cohesion in the Context of Community-based Participatory Research: Descriptive Findings from an Academic-Community Partnership. AB - Objective: The purpose of this article is to describe the process of conducting an assessment of neighborhood perceptions and cohesion by a community coalition academic team created in the context of community-based participatory research (CBPR), to guide the design of locally relevant health initiatives. Methods: Guided by CBPR principles, a collaborative partnership was established between an academic center and a local, urban, underserved neighborhood in Birmingham, Alabama to identify and address community concerns and priorities. A cross sectional survey was conducted in September 2016 among community residents (N=90) to examine perceptions of neighborhood characteristics, including social cohesion and neighborhood problems. Results: The major concerns voiced by the coalition were violence and lack of neighborhood cohesion and safety. The community survey verified the concerns of the coalition, with the majority of participants mentioning increasing safety and stopping the violence as the things to change about the community and the greatest hope for the community. Furthermore, results indicated residents had a moderate level of perceived social cohesion (mean = 2.87 [.67]). Conclusions: The Mid-South TCC Academic and Community Engagement (ACE) Core successfully partnered with community members and stakeholders to establish a coalition whose concerns and vision for the community matched the concerns of residents of the community. Collecting data from different groups strengthened the interpretation of the findings and allowed for a rich understanding of neighborhood concerns. PMID- 29158659 TI - The Value of Social Network Analysis for Evaluating Academic-Community Partnerships and Collaborations for Social Determinants of Health Research. AB - Objective: Community-based participatory research processes build healthy communities, as well as promote trust and genuine collaborative partnerships between stakeholders. Fostering relationships is essential to promoting these partnerships, which are necessary for collaborative, coordinated, and integrated efforts toward improving health outcomes in the community. The objective of our research was to demonstrate social network analysis as an evaluative tool to assess movement toward positive health outcomes through promoting relationships. Methods: Using the example of the Gulf States Health Policy Center Coalition based at Bayou Clinic in Bayou La Batre, Alabama, we demonstrate the ability of social network analysis (SNA) methods to measure and map the formation of relationships, as well as the level and frequency of these relationships. Data were collected via email using a survey of Gulf States Health Policy Center Coalition members (N=80, 87%) and analyzed using UCInet software for social network analysis in April 2016. Results: In this application of SNA to the community coalition of the Gulf States Health Policy Center, we find that, on average, coalition members doubled their own network within the coalition in a time period of <2 years and were working together more often and more collaboratively than they were before the coalition formed. Conclusions: The increased frequency and level of collaboration among the Coalition network was accompanied by a higher level of collaboration among the coalition members as posited by social network and capital theories. As such, the community engagement fostered through the Coalition has increased and thus, to date, the Gulf States Health Policy Center has been effective in promoting partnerships and collaboration. PMID- 29158660 TI - Empowering One Community at a Time for Policy, System and Environmental Changes to Impact Obesity. AB - Objective: This article describes Mayors Mentoring Mayors (3M), an initiative of the Arkansas Coalition for Obesity Prevention (ArCOP), which expanded to five states to become the signature community initiative of the Mid-South Transdisciplinary Collaborative Center (Mid-South TCC) for Health Disparities Research. Methods: The 3M program is an extension of the Growing Healthy Communities (GHC) program, which sought to build capacity within communities to reduce obesity by implementing policy, system and environmental (PSE) changes that support healthy living. GHC where the mayor was involved had the most significant changes toward better health. These mayors were recruited to share their successes, lessons learned, and best practices with their colleagues through a series of Lunch & Learns. Following the GHC and 3M models, a multi state approach to expand 3M to five additional states was developed. ArCOP partnered with the Mid-South TCC to recruit mayors in the five states. Results: Five Lunch & Learn events were held across Arkansas between March and May 2015, with a total of 98 participants (40 mayors, 37 community leaders, 21 guests). Each regional Lunch & Learn had 1-2 host mayor(s) in attendance, with a total of 9 host mayors. For the 3M regional expansion project, eight GHC Recognition Applications from five states were submitted. Five communities, designated as Emerging, were funded to implement GHC projects. Conclusion: ArCOP successfully engaged mayors, elected officials, and stakeholders who can influence policy across Arkansas as well as in an additional five states in the Mid-South TCC region to implement obesity PSE prevention strategies. PMID- 29158661 TI - Policy, System and Environmental Correlates of Fruit and Vegetable Consumption in a Low-Income African American Population in the Southeast. AB - Objective: The current study seeks to identify policy, system and environmental (PSE) correlates of fruit and vegetable consumption among a sample of low-income African Americans in two counties in Alabama (Jefferson and Mobile) and one county in Mississippi (Forrest). Design: A modified Behavioral Risk Factor Surveillance System (BRFFS) survey, which included multi-level ecological factors, was used to evaluate nutritional habits at the pre-intervention stage of a multi-state research study. We surveyed a total of 256 participants between May and August 2015. Local community coalitions established in each of the counties were instrumental in the planning and administration of the baseline survey. Results: Univariate analyses revealed that whether participants met the daily recommendation for fruit/vegetable consumption may be correlated with whether participants had children who attended schools/day care centers with health policies in place, received food assistance, and observed media campaigns related to nutrition. Further, results of multivariate analysis indicated that meeting fruit/vegetable recommendations was correlated with personally participating or having a family member who participated in a health policy meeting in the past two years. Conclusion: These findings suggest that policy-based interventions have the potential to improve health outcomes among priority populations, such as low-income African Americans, who are at high risk of developing chronic diseases. PMID- 29158662 TI - Medication Management Apps: Usable by Older Adults? AB - For older adults, managing medications can be a burden and could lead to medication non-adherence. To decrease risks associated with medication non adherence, healthcare providers may recommend medication reminder apps as an assistive tool. However, these apps are often not designed with consideration of older adults' needs, capabilities, and limitations. To identify whether available apps are suitable for older adults, we conducted an in-depth cognitive walkthrough and a heuristic evaluation of the most commonly downloaded medication reminder app. Findings revealed three main issues: 1) difficulty in navigation, 2) poor visibility, and 3) a lack of transparency. We also selected the top five downloaded medication reminder apps and categorized user reviews to assess app functionality and usability problems. The results of our analysis provide guidance for app design for older adult users to provide effective tools for managing medications and supporting patient/user health. PMID- 29158663 TI - A comparative pharmacokinetic and tolerability analysis of the novel orotic acid salt form of tenofovir disoproxil and the fumaric acid salt form in healthy subjects. AB - A novel orotic acid salt form of tenofovir disoproxil (DA-2802) was developed and is expected to replace the fumaric acid salt form. The pharmacokinetic (PK) characteristics and tolerability profiles of DA-2802 were compared to those of tenofovir disoproxil fumarate (TDF, Viread(r)) in healthy subjects. A randomized, open-label, single-dose study was conducted in 36 healthy subjects using a two treatment, two-period, and two-sequence crossover design. Subjects received a single oral dose of 319 mg DA-2802 or 300 mg TDF, during each period, with a 7 day washout. Serial blood samples were collected pre-dosing and up to 72 hours post-dosing in each period, for determination of serum tenofovir concentration, which was measured by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental method was used to obtain PK parameters of tenofovir. For comparison between the two tenofovir disoproxil salts, the 90% confidence intervals (90% CIs) of geometric mean ratios of DA-2802 to TDF for the maximum concentration (Cmax) and the area under the concentration-time curve to the last quantifiable concentration (AUC0-t) were determined. The tolerability profiles of tenofovir were assessed by evaluation of adverse events and vital signs, physical examination, ECG, and clinical laboratory tests. The serum tenofovir concentration-time profiles of DA-2802 or TDF were comparable in 32 subjects who completed the study. In both profiles, a two-compartmental elimination with first-order elimination kinetics in the terminal phase was reported in a few subjects, showing a secondary peak in the initial phase of elimination. The geometric mean ratio (90% CI) of DA-2802 to TDF was 0.898 (0.815 0.990) for Cmax and 0.904 (0.836-0.978) for AUC0-t. There were no clinically significant findings in the tolerability assessments. DA-2802 showed comparable PK characteristics and tolerability profiles to TDF. PMID- 29158664 TI - Impact of baseline blood pressure on the magnitude of blood pressure lowering by nifedipine gastrointestinal therapeutic system: refreshing the Wilder's principle. AB - Background: The objective of the study was to investigate the relationship between baseline blood pressure (BP) and the magnitude of BP reduction in patients with essential hypertension treated with nifedipine gastrointestinal therapeutic system (NGTS). Methods and patients: One hundred and thirty-eight patients with essential hypertension were enrolled in this prospective, single arm, open-label study. NGTS was administered for 24 weeks to achieve target BP of 140/90 mmHg. The dose could be uptitrated to 60 mg/d in case of unsatisfactory BP reduction after 4-week treatment. Home blood pressure measurement was recorded through the initial 1-14 days, and office BP and heart rate were evaluated at 2, 4, 8, 12, and 24 weeks. Results: One hundred and seventeen patients (84.8%) completed the study, and their average BP decreased by 19.0/11.3 mmHg after 24 weeks. The reduction of either systolic or diastolic BP was positively correlated with baseline BP at weeks 2, 4, or 24 after treatment (r=0.603-0.762, all p<0.05). The maximal BP reduction was observed in 83% of patients at 4 weeks of treatment even though the dose of nifedipine remained unchanged (30 mg/day). Conclusion: These findings show that BP reduction is greatly influenced by the baseline level. Patients with high baseline BP had maximum reduction after treatment with NGTS, and the maximal antihypertensive efficacy of NGTS could appear even at 4 weeks after treatment initiation. PMID- 29158665 TI - Pharmacokinetics and tolerability of MB12066, a beta-lapachone derivative targeting NAD(P)H: quinone oxidoreductase 1: two independent, double-blind, placebo-controlled, combined single and multiple ascending dose first-in-human clinical trials. AB - MB12066 is a molecule derived from beta-lapachone that shown effects on obesity in previous studies. The present studies were conducted to evaluate the tolerability and pharmacokinetics (PK) of MB12066 after the oral administration of single and multiple doses to healthy volunteers. The study comprised 2 independent, randomized, double-blind, placebo-controlled, combined single and multiple ascending dose first-in-human clinical trials to evaluate the safety, tolerability and PK of MB12066 in healthy Korean volunteers. Subjects were randomly assigned to receive a single 10, 30, 100, 150, 200, 300 or 400 mg of MB12066 and multiple 100 or 200 mg of MB12066. The subjects' vital signs, 12-lead electrocardiograms, clinical laboratory tests, adverse event statuses, and physical examinations were assessed during the study. Blood and urine samples were collected to determine the concentration of MB12066 from predose to 72 hours after the single administration and from predose to 96 hours postdose of day 7 after the multiple administration. NADH:quinone oxidoreductase 1 genotyping was performed to analyze the association between genetic polymorphisms and PK. MB12066 was well tolerated after oral administration of single and multiple doses. The systemic exposure to MB12066 after a single administration tended to increase in a dose-dependent manner in the dose range of 30-200 mg. The overall fraction of MB12066 excreted unchanged in urine was <1% of the administered dose. A significant relationship was observed between NADH:quinone oxidoreductase 1 polymorphisms and exposure to MB12066 after multiple administrations, but the result was not conclusive because of the small number of subjects. A single dose of MB12066 within the dose range of 10-400 mg and multiple doses of 100 and 200 mg of MB12066 were safe and tolerated in healthy subjects. Additionally, MB12066 was mainly eliminated through metabolism in humans. PMID- 29158666 TI - Tenofovir alafenamide in the treatment of chronic hepatitis B: design, development, and place in therapy. AB - Tenofovir alafenamide (TAF), a novel prodrug of tenofovir (TFV), has been approved for the treatment of chronic hepatitis B virus (HBV) infection. TAF has been shown to be a potent inhibitor of HBV replication at a low dose, with high intracellular concentration and more than 90% lower systemic TFV concentration than tenofovir disoproxil fumarate (TDF). In two randomized, double-blind, multinational, Phase 3, non-inferiority trials for hepatitis B e antigen (HBeAg) positive and -negative patients (primary analysis: 48 weeks), TAF 25 mg orally once-daily was not inferior to TDF 300 mg in achieving an HBV DNA level <29 IU/mL at week 48. No amino-acid substitutions associated with viral breakthrough were detected by deep sequencing, and no resistance to TAF was found through week 96. In addition, no difference in the frequency of HBeAg or hepatitis B surface antigen loss was observed. However, TAF was associated with a significantly higher ALT normalization rate than was TDF, based on the American Association for the Study of Liver Diseases criteria (male: ALT <=30 U/L and female: ALT <=19 U/L). An analysis of renal safety showed that patients treated with TAF had a significantly lower decrease in the estimated glomerular filtration rate level than did patients treated with TDF. Similarly, the declines of hip and spine bone mineral density were significantly less in the TAF group. These trends of efficacy and renal/bone safety continued through week 96. Longer term follow-up and real-world data will be required to determine if the differences in viral/biochemical response and renal/bone safety seen with TAF in comparison with TDF are clinically relevant. PMID- 29158668 TI - Reversal of cognitive impairment in a hypotensive elderly population using a passive exercise intervention. AB - Background: Cognitive decline in the elderly is strongly associated with cerebral hypoperfusion, a condition that can be reversed with exercise. Adhering to a traditional exercise regimen, however, is challenging for this population. Objective: In a pilot clinical study, we evaluated the ability of a "passive" exercise regimen (noninvasive calf muscle pump stimulation) to normalize blood pressure in a chronically hypotensive elderly population and enhance cognitive function. Participants and methods: Ten elderly (82.5+/-7.5 years) men and women volunteers, residing in a senior living facility in upstate New York, were divided into control (N=5) and intervention (N=5) groups based on initial diastolic blood pressure (DBP); participants with initial DBP <65 mmHg became intervention participants, and those with initial DBP >65 mmHg enrolled in the control group. Body mass, blood pressure, and executive function (using incongruent Stroop and Trailmaking B test) were evaluated weekly for 4 months. Results: At initiation of the study, time to complete the executive function tests in the hypotensive group was almost twice that of the control group. Daily calf muscle pump stimulation (passive exercise) for 1 hour/day, or less, was found to be sufficient to normalize DBP and significantly improve performance on the executive function tests. PMID- 29158667 TI - Different protocols for analyzing behavior and adaptability in obstacle crossing in Parkinson's disease. AB - Imbalance and tripping over obstacles as a result of altered gait in older adults, especially in patients with Parkinson's disease (PD), are one of the most common causes of falls. During obstacle crossing, patients with PD modify their behavior in order to decrease the mechanical demands and enhance dynamic stability. Various descriptions of dynamic traits of gait that have been collected over longer periods, probably better synthesize the underlying structure and pattern of fluctuations in gait and can be more sensitive markers of aging or early neurological dysfunction and increased risk of falls. This confirmation challenges the clinimetric of different protocols and paradigms used for gait analysis up till now, in particular when analyzing obstacle crossing. The authors here present a critical review of current knowledge concerning the interplay between the cognition and gait in aging and PD, emphasizing the differences in gait behavior and adaptability while walking over different and challenging obstacle paradigms, and the implications of obstacle negotiation as a predictor of falls. Some evidence concerning the effectiveness of future rehabilitation protocols on reviving obstacle crossing behavior by trial and error relearning, taking advantage of dual-task paradigms, physical exercise, and virtual reality have been put forward in this article. PMID- 29158669 TI - Minor positive effects of health-promoting senior meetings for older community dwelling persons on loneliness, social network, and social support. AB - Objective: The aim of this study was to evaluate the 1-year effect of the health promoting intervention "senior meetings" for older community-dwelling persons regarding loneliness, social network, and social support. Methods: Secondary analysis of data was carried out from two randomized controlled studies: Elderly Persons in the Risk Zone and Promoting Aging Migrants' Capabilities. Data from 416 participants who attended the senior meetings and the control group at baseline and the 1-year follow-up in the respective studies were included. Data were aggregated and analyzed with chi-square test and odds ratio (OR) to determine the intervention effect. Results: The senior meetings had a positive effect on social support regarding someone to turn to when in need of advice and backing (OR 1.72, p=0.01). No positive intervention effect could be identified for loneliness, social network, or other aspects of social support. Conclusion: Health-promoting senior meetings for older community-dwelling persons have a minor positive effect on social support. The senior meetings might benefit from a revision to reinforce content focused on loneliness, social network, and social support. However, the modest effect could also depend on the lack of accessible social resources to meet participants' identified needs, a possible hindrance for a person's capability. This makes it necessary to conduct further research to evaluate the effect of the senior meetings and other health-promoting initiatives on social aspects of older community-dwelling people's lives, since these aspects are of high importance for life satisfaction and well-being in old age. PMID- 29158670 TI - Interferential current sensory stimulation, through the neck skin, improves airway defense and oral nutrition intake in patients with dysphagia: a double blind randomized controlled trial. AB - Background: Neuromuscular electrical stimulation with muscle contraction, administered through the skin of the neck, improves a patient's swallowing ability. However, the beneficial effects of transcutaneous electrical sensory stimulation (TESS), without muscle contraction, are controversial. We investigated the effect of TESS, using interferential current, in patients undergoing dysphagia rehabilitation. Methods: This double-blind, randomized controlled trial involved 43 patients who were prescribed in-hospital dysphagia rehabilitation for >=3 weeks. Patients were randomly assigned to the sensory stimulation (SS) or sham groups; all received usual rehabilitative care plus 2 weeks of SS or sham intervention. Outcome measures included cough latency times against a 1% citric acid mist, functional oral intake scale (FOIS) scores, and oral nutritional intake - each determined after the second and third week following treatment initiation. Results: Mean patient age was 84.3+/-7.5 years; 58% were women. The SS and sham groups had similar baseline characteristics. Changes in cough latency time at 2 weeks (-14.1+/-14.0 vs -5.2+/-14.2 s, p=0.047) and oral nutrition intake at 3 weeks (437+/-575 vs 138+/-315 kcal/day, p=0.042) improved more in the SS group than in the sham group. Changes in cough frequency and FOIS scores indicated better outcomes in the SS group, based on substantial effect sizes. Conclusion: TESS, using interferential current through the neck, improved airway defense and nutrition in patients suffering from dysphagia. Further large-scale studies are needed to confirm the technique's effect on swallowing ability. PMID- 29158671 TI - Correlation and compatibility between surface respiratory electromyography and transesophageal diaphragmatic electromyography measurements during treadmill exercise in stable patients with COPD. AB - Purpose: To evaluate the compatibility and correlation between noninvasive surface respiratory electromyography and invasive transesophageal diaphragmatic electromyography measurements as facilitating indicators of neural respiratory drive (NRD) evaluation during treadmill exercise. Patients and methods: Transesophageal diaphragmatic electromyogram activity (EMGdi,es) and surface inspiratory electromyogram (EMG) activity, including surface diaphragmatic EMG activity (EMGdi,sur), surface parasternal intercostal muscle EMG activity (EMGpara), and surface sternocleidomastoid EMG activity (EMGsc), were detected simultaneously during increasing exercise capacity in 20 stable patients with COPD. EMGdi,es, EMGdi,sur, EMGpara, and EMGsc were quantified using the root mean square (RMS) and were represented as RMSdi,es, RMSdi,sur, RMSpara, and RMSsc, respectively. Results: There was a significant association between EMGdi,es and EMGdi,sur (r=0.966, p<0.01), EMGpara (r=0.967, p<0.01), and EMGsc (r=0.956, p<0.01) in the COPD patients during exercise. Bland-Altman plots showed that the lowest mean bias value was between EMGdi,es and EMGpara compared with the bias values between EMGdi,es and the other two EMG parameters. In comparing the estimation of EMGdi,es, we observed the lowest bias values (-1%) and the lowest limits of agreement values (-10% to -12%). Intraclass correlation coefficient (ICC) between EMGdi,es and EMGdi,sur was 0.978 (p<0.01), between EMGdi,es and EMGpara was 0.980 (p<0.01), and between EMGdi,es and EMGsc was 0.868 (p<0.01). Conclusion: RMSdi,sur, RMSpara, and RMSsc could provide useful physiological markers of NRD in COPD. RMSpara shows the best compatibility and correlation with transesophageal diaphragmatic electromyography during treadmill exercise in stable patients with COPD. PMID- 29158672 TI - Lung transplantation and survival outcomes in patients with oxygen-dependent COPD with regard to their alpha-1 antitrypsin deficiency status. AB - Background: Individuals with severe alpha-1 antitrypsin deficiency (AATD) have an increased risk of developing COPD. However, outcomes during long-term oxygen therapy (LTOT) in patients with severe AATD and hypoxemia are unknown. Patients and methods: This was a prospective, population-based, consecutive cohort study of patients on LTOT due to COPD in the period from January 1, 1987, to June 30, 2015, in the Swedish National Registry for Respiratory Failure (Swedevox). Severe AATD was identified using the Swedish AATD registry and confirmed by isoelectric focusing. Data on lung transplantation (LTx) were obtained from the two lung transplantation centers in Sweden. Mortality and causes of death were assessed based on the National Causes of Death Registry and analyzed using multivariable Cox regression. Results: A total of 14,644 patients who started LTOT due to COPD were included in this study. No patient was lost to follow up. Patients with AATD were younger, included more males and more never smokers, and had fewer comorbidities. During a median follow-up of 1.6 years (interquartile range [IQR], 2.7) on LTOT, patients without severe AATD had a higher mortality, hazard ratio [HR] 1.53 (95% CI, 1.24-1.88), adjusting for age, sex, smoking status, body mass index, performance status, level of hypoxemia, and comorbidities. Cardiovascular deaths were increased. A higher proportion of AATD patients underwent LTx, 53 (19%) vs 118 (1%). Survival after LTx was similar for AATD and non-AATD patients and was predicted by age. Conclusion: In oxygen-dependent COPD, patients with severe AATD have a longer survival time on LTOT, but they have a similar prognosis after lung transplantation compared with patients without AATD. PMID- 29158673 TI - Novel cationic lipid nanoparticles as an ophthalmic delivery system for multicomponent drugs: development, characterization, in vitro permeation, in vivo pharmacokinetic, and molecular dynamics studies. AB - The purpose of this study was to prepare, optimize, and characterize a cationic lipid nanoparticle (CLN) system containing multicomponent drugs using a molecular dynamics model as a novel method of evaluating formulations. Puerarin (PUE) and scutellarin (SCU) were used as model drugs. CLNs were successfully prepared using melt-emulsion ultrasonication and low temperature-solidification technique. The properties of CLNs such as morphology, particle size, zeta potential, entrapment efficiency (EE), drug loading (DL), and drug release behavior were investigated. The CLNs were evaluated by corneal permeation, preocular retention time, and pharmacokinetics in the aqueous humor. Additionally, a molecular dynamics model was used to evaluate the formulation. Electron microscopy results showed that the nanoparticles were approximately spherical in shape. The EE (%) and DL (%) values of PUE and SCU in the optimal formulation were 56.60+/-3.73, 72.31+/-1.96 and 1.68+/-0.17, 2.44+/-1.14, respectively. The pharmacokinetic study in the aqueous humor showed that compared with the PUE and SCU solution, the area under the concentration-time curve (AUC) value of PUE was enhanced by 2.33-fold for PUE-SCU CLNs (p<0.01), and the SCU AUC was enhanced by 2.32-fold (p<0.01). In the molecular dynamics model, PUE and SCU passed through the POPC bilayer, with an obvious difference in the free energy well depth. It was found that the maximum free energy required for PUE and SCU transmembrane movement was ~15 and 88 kJ.mol 1, respectively. These findings indicated that compared with SCU, PUE easily passed through the membrane. The diffusion coefficient for PUE and SCU were 4.1*10-3+/-0.0027 and 1.0*10-3+/-0.0006 e-5cm2.s-1, respectively. Data from the molecular dynamics model were consistent with the experimental data. All data indicated that CLNs have a great potential for ocular administration and can be used as an ocular delivery system for multicomponent drugs. Moreover, the molecular dynamics model can also be used as a novel method for evaluating formulations. PMID- 29158675 TI - Transplantation of bone mesenchymal stem cells promotes angiogenesis and improves neurological function after traumatic brain injury in mouse. AB - Traumatic brain injury (TBI) has emerged as a leading cause of mortality and morbidity worldwide. Transplantation of bone mesenchymal stem cells (BMSCs) has emerged as a promising treatment for various central nervous system diseases. This study aims to evaluate the effect of BMSCs transplantation by intravenous injection on neurological function and angiogenesis of the TBI mice. C57BL/6 male mice were randomly divided into four groups: control, sham, TBI, and BMSC. Functional neurological evaluation was performed 1, 4, 7, 14, and 21 days after TBI using neurological severity scores. The impairment of learning and memory in mice was evaluated 14 days after TBI by Morris water maze experiment. Mice were sacrificed 14 days after TBI, and then brain sections were stained by terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling staining to assess brain neuronal apoptosis. Immunohistochemistry was conducted to evaluate caspase-3 activity and identify vascular distribution and microvessel density. Protein and mRNA levels of vascular endothelial growth factor (VEGF) and angiogenin-1 (Ang-1) in brain tissues were analyzed by Western blot and quantitative real-time polymerase chain reaction, respectively. BMSCs transplantation promoted recovery of neurological function, ameliorated impairment of learning and memory, attenuated neuronal apoptosis, and diminished caspase-3 activation in mice after TBI. Also, BMSCs transplantation upregulated expressions of VEGF and Ang-1 and promoted the formation of microvessels in brain tissues after TBI. Our study demonstrated the important role of BMSCs transplantation in TBI mouse and indicated that the underlying mechanism was through promoting angiogenesis and improving neurological function. This provides a novel and effective strategy for cell-based therapy in the treatment of TBI. PMID- 29158674 TI - Skin-derived mesenchymal stem cells as quantum dot vehicles to tumors. AB - Purpose: Cell-mediated delivery of nanoparticles is emerging as a new method of cancer diagnostics and treatment. Due to their inherent regenerative properties, adult mesenchymal stem cells (MSCs) are naturally attracted to wounds and sites of inflammation, as well as tumors. Such characteristics enable MSCs to be used in cellular hitchhiking of nanoparticles. In this study, MSCs extracted from the skin connective tissue were investigated as transporters of semiconductor nanocrystals quantum dots (QDs). Materials and methods: Cytotoxicity of carboxylated CdSe/ZnS QDs was assessed by lactate dehydrogenase cell viability assay. Quantitative uptake of QDs was determined by flow cytometry; their intracellular localization was evaluated by confocal microscopy. In vitro tumor tropic migration of skin-derived MSCs was verified by Transwell migration assay. For in vivo migration studies of QD-loaded MSCs, human breast tumor-bearing immunodeficient mice were used. Results: QDs were found to be nontoxic to MSCs in concentrations no more than 16 nM. The uptake studies showed a rapid QD endocytosis followed by saturating effects after 6 h of incubation and intracellular localization in the perinuclear region. In vitro migration of MSCs toward MDA-MB-231 breast cancer cells and their conditioned medium was up to nine times greater than the migration toward noncancerous breast epithelial cells MCF 10A. In vivo, systemically administered QD-labeled MSCs were mainly located in the tumor and metastatic tissues, evading most healthy organs with the exception being blood clearance organs (spleen, kidneys, liver). Conclusion: Skin-derived MSCs demonstrate applicability in cell-mediated delivery of nanoparticles. The findings presented in this study promise further development of a cell therapy and nanotechnology-based tool for early cancer diagnostics and therapy. PMID- 29158676 TI - Role of 3-monthly long-acting injectable paliperidone in the maintenance of schizophrenia. AB - Aims: Paliperidone palmitate 3-month (PP3M) represents a new long-acting injectable antipsychotic therapeutic option. This review aims: 1) to summarize available data relating to efficacy, safety, tolerability and costs of PP3M; 2) to describe hospitalization rate, occupational status, treatment preference, satisfaction, adherence and caregiver burden of patients with schizophrenia who participate in PP3M clinical trials; 3) to examine ethical implications, pros and cons of PP3M use and 4) to propose study designs to further assess PP3M. Methods: On August 21, 2017, a search on PubMed about PPM3, without any filter restriction, was conducted and all available records were analyzed. Records written in a language other than English were excluded. Results: Twenty-two records were included in this review: 6 reviews, 1 report, 4 pharmacokinetic studies, 2 cost-effectiveness analyses, 1 open-label clinical trial, 2 randomized controlled trials (RCTs), 5 studies based on these 2 RCTs and 1 observational study. Discussion: According to these last 9 studies, when compared with placebo, PP3M showed a longer time to relapse and good safety and tolerability profiles. Furthermore, when compared with paliperidone palmitate 1 month (PP1M), PP3M treatment showed: 1) non-inferiority in terms of efficacy, safety, tolerability, rate of hospitalization, symptomatic and functional remission, treatment preference and variations of the occupational status; 2) a longer time to relapse after treatment discontinuation and 3) a similar reduction of the caregiver burden. Conclusion: PP3M is the only 3-monthly long-acting injectable antipsychotic available on the market. This makes it a unique option of treatment, which could be chosen both in early and advanced phases of illness. Nonetheless, longer naturalistic follow-up studies, two-arm head-to-head superiority trials and mirror studies, based on real-world samples of patients, are needed to further assess long-term safety and advantages of this new option of treatment and to define patients' sub-populations that would most beneficiate from it. PMID- 29158678 TI - Efficacy and safety of DFN-15, an oral liquid formulation of celecoxib, in adults with migraine: a multicenter, randomized, placebo-controlled, double-blind, crossover study. AB - Background: The objective of this proof-of-concept study was to assess the safety, efficacy, and potential for dose response of a new oral liquid formulation of celecoxib, DFN-15, in adults with migraine. Variability in patient identified most bothersome symptom (MBS) across 3 migraine attacks was also evaluated. Methods: This was a randomized, placebo-controlled, double-blind, 3 treatment, 6-sequence, 3-period, crossover study of 3 treatments (DFN-15 120 mg, DFN-15 240 mg, and placebo) administered at the onset of moderate to severe headache. Results: Of 63 randomized subjects, 56 (89%) took single doses of DFN 15 120 mg and 240 mg and completed all 3 treatment periods. Most subjects were female (75.0%) and white (86.7%), with a mean age of 43.6 years. Both doses of DFN-15 achieved a higher 2-hour pain-free response than placebo (29.1% for 120 mg, 26.1% for 240 mg, and 17.6% for placebo), but the differences were not statistically significant. Photophobia was most commonly reported as the MBS, but for 53% of subjects (27/51), their identified MBS varied across the 3 studied attacks. The most common treatment-emergent adverse events with DFN-15 were dysgeusia (<=11.8%) and nausea (<=5.9%). Conclusion: Both doses of DFN-15 outperformed placebo for the 2-hour pain-free end point, but due to a carryover effect with placebo, the differences were not statistically significant. Since response to both doses was similar, DFN-15 120 mg is being further developed for the management of acute migraine. Further study is needed to determine whether the current findings are altered by larger or different trial designs (ClinicalTrials.gov identifier: NCT02472418). PMID- 29158677 TI - A meta-analysis of effects of selective serotonin reuptake inhibitors on blood pressure in depression treatment: outcomes from placebo and serotonin and noradrenaline reuptake inhibitor controlled trials. AB - Background: Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) have been commonly prescribed for depression treatment. However, their effects on blood pressure are unclear. Materials and methods: Effects on blood pressure of depressive patients in two groups (SSRIs versus placebo and SSRIs versus SNRIs) were evaluated. A search was conducted for double-blind, randomized controlled trials (RCTs) in PubMed, EMBASE, ISI Web of Science, PsycNET, CCRCT, and DARE (up to March 2017). The outcomes were systolic blood pressure (SBP) changes and diastolic blood pressure (DBP) changes from baseline to endpoint or to a certain period of treatment duration. Weighted mean differences (WMDs) and 95% CIs were calculated and pooled using random effects models. The chi2 test and I2 statistics were used to assess heterogeneity. Funnel plots, Begg's test, and Egger's test were used to estimate publication bias. Results: A total of 23 RCTs involving 13,285 participants were included. Patients on SSRIs showed no significant differences in blood pressure changes compared with placebo. In the group of SSRIs versus SNRIs, overall SBP changes and DBP changes revealed statistical significances (WMD 1.5 mmHg, 95% CI 2.15, -0.84, Z=4.46, P<0.00001 and WMD 1.34 mmHg, 95% CI -1.92, -0.75, Z=6.18, P<0.00001). Subgroup analyses on treatment duration and age further evidenced these findings. Conclusion: It was established that SSRIs did not affect blood pressure, while SNRIs led to a modest increase in SBP and DBP with statistical significance compared with SSRIs. PMID- 29158679 TI - Treatment of pulmonary hypertension with left heart disease: a concise review. AB - Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure >= 25 mmHg, as determined by right heart catheterization. Pulmonary arterial hypertension (PAH) can no longer be considered an orphan disease given the increase in awareness and availability of new drugs. PH carries with it a dismal prognosis and leads to significant morbidity and mortality. Symptoms can range from dyspnea, fatigue and chest pain to right ventricular failure and death. PH is divided into five groups by the World Health Organization (WHO), based on etiology. The most common cause of PH in developed countries is left heart disease (group 2), owing to the epidemic of heart failure (HF). The data regarding prevalence, diagnosis and treatment of patients with group 2 PH is unclear as large, prospective, randomized controlled trials and standardized protocols do not exist. Current guidelines do not support the use of PAH-specific therapy in patients with group 2 PH. Prostacyclins, endothelin receptor antagonists, phosphodiesterase-5 inhibitors and guanylate cyclase stimulators have been tried in treatment of patients with HF and/or group 2 PH with mixed results. This review summarizes and critically appraises the evidence for diagnosis and treatment of patients with group 2 PH/HF and suggests directions for future research. PMID- 29158680 TI - Analysis of the factors affecting the safety of robotic stereotactic body radiation therapy for hepatocellular carcinoma patients. AB - Objective: The objective of this study was to investigate the safety of robotic stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) patients and its related factors. Methods: A total of 74 HCC patients with Child Turcotte-Pugh (CTP) Class A were included in a multi-institutional, single-arm Phase II trial (NCT 02363218) between February 2013 and August 2016. All patients received SBRT treatment at a dose of 45 Gy/3f. The liver function was compared before and after SBRT treatment by the analysis of adverse hepatic reactions and changes in CTP classification. Results: After SBRT treatment, eight patients presented with decreases in CTP classification and 13 patients presented with >= grade 2 hepatic adverse reactions. For patients presenting with >= grade 2 hepatic adverse reactions, the total liver volume of <=1,162 mL and a normal liver volume (total liver volume - gross tumor volume [GTV]) of <=1,148 mL were found to be independent risk factors and statistically significant (P<0.05). Conclusion: The total liver volume and normal liver volume are associated with the occurrence of >= grade 2 hepatic adverse reactions after SBRT treatment on HCC patients. Therefore, if the fractionated scheme of 45 Gy/3f is applied in SBRT for HCC patients, a total liver volume >1,162 mL and a normal liver volume >1,148 mL should be ensured to improve therapeutic safety. PMID- 29158681 TI - The associations between common SNPs of EFEMP1 gene and glioma risk in Chinese population. AB - Background: Although the associations between common single nucleotide polymorphisms (SNPs) of EFEMP1 gene and glioma risk have been investigated in Chinese population-based case-control studies, investigation results for several SNPs are inconsistent. In addition, the single-center study has a poor statistical power due to finite sample size. Therefore, a meta-analysis was conducted to comprehensively determine the associations. Methods: All eligible case-control studies were obtained by searching PubMed, EMBASE, Web of Science, and Chinese National Knowledge Infrastructure. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the associations in fixed- or random-effects model. Results: EFEMP1 rs1346787 polymorphism was significantly associated with glioma risk in Chinese population under all genetic models (GG vs AA, OR =2.22, 95% CI =1.46-3.36; AG vs AA, OR =1.54, 95% CI =1.27 1.87; (GG+AG) vs AA, OR =1.60, 95% CI =1.34-1.93; GG vs (AG+AA), OR =1.86, 95% CI =1.24-2.78; G vs A, OR =1.54, 95% CI =1.32-1.79). However, the significant association of EFEMP1 rs1346786 with glioma risk in Chinese population was observed only under heterozygous model of AG vs AA (OR =1.34, 95% CI =1.10-1.62), dominant model of (GG+AG) vs AA (OR =1.36, 95% CI =1.13-1.63), and allelic model of G vs A (OR =1.28, 95% CI =1.10-1.50). Conclusion: Our study demonstrated that EFEMP1 polymorphisms, especially rs1346787 and rs1346786, might predict glioma risk in Chinese population. However, high-quality case-control studies with larger sample sizes are warranted to confirm the above-mentioned findings. PMID- 29158682 TI - UNBS5162 inhibits proliferation of human retinoblastoma cells by promoting cell apoptosis. AB - Human retinoblastomas are malignant intraocular tumors and have a high incidence in children. Chemotherapy combined with local therapy is the principal means of retinoblastoma treatment, the application of which has saved the eye of many children and avoided external irradiation. UNBS5162, a naphthalimide, has broad prospects as a tumor treatment, with fewer toxic side effects and higher cancer suppression efficiency. However, the efficacy of UNBS5162 in human retinoblastomas is still not clear. In the present study, we investigated the specific mechanism of UNBS5162 in the human retinoblastoma cell lines WERIRb1 and Y79. Compared with a negative-control (NC) group, UNBS5162 treatment for 72 hours significantly decreased cell proliferation; meanwhile, more apoptotic cells were observed in the UNBS5162-treated group (27.1% in WERIRb1, 20.83% in Y79) than in the NC group (11.59% in WERIRb1, 12.89% in Y79). We also found caspase 3 p17 and Bax expression to be upregulated and Bcl2 downregulated significantly in UNBS5162 treated WERIRb1 and Y79 cells. The effects of UNBS5162 on human retinoblastoma cells may be regulated by the Akt-mTOR pathway. We found expression of the Akt pathway and key proliferation-related genes - those for p-Akt, p-mTOR, p70, and cyclin D1 - were downregulated significantly in the UNBS5162-treated group compared with the NC group in WERIRb1 and Y79. Therefore, for the first time, we demonstrated that UNBS5162 can inhibit proliferation and promote apoptosis of human retinoblastoma cells by regulating activity of the Akt-mTOR pathway in vitro, suggesting the potential value of UNBS5162 in treatment for human retinoblastoma. PMID- 29158684 TI - Right and left ventricular function in hospitalized children with respiratory syncytial virus infection. AB - Background: Extrapulmonary manifestations including cardiac dysfunction have been demonstrated in children with respiratory syncytial virus (RSV) infection requiring intensive care. The aim of this study was to examine cardiac function in hospitalized children with moderate RSV infection admitted to a regular pediatric ward. Methods: We used echocardiography to determine cardiac output, and right and left ventricular function in 26 patients (aged 2 weeks to 24 months) with RSV infection. The echocardiographic results were compared with s troponin, the need for supplementary oxygen or noninvasive respiratory support, and capillary refill time. Results: The number of measured s-troponins (ten [38%] of the included children) was too low to assess differences between children with elevated levels and those with normal levels. There were no differences in cardiac function between patients receiving oxygen treatment or respiratory support and those who did not. Capillary refill time did not correlate with any of the echocardiographic parameters. Both left and right ventricular output (mL/kg/min) was higher than published reference values. All other echocardiographic parameters were within the reference range. Conclusion: Children with moderate RSV infection had an increased left and right ventricular output, and cardiac function was well maintained. We conclude that routine cardiac ultrasound is not warranted in children with moderate RSV infection. The role of an elevated s-troponin in these patients remains to be determined. PMID- 29158683 TI - Animal models of asthma: utility and limitations. AB - Clinical studies in asthma are not able to clear up all aspects of disease pathophysiology. Animal models have been developed to better understand these mechanisms and to evaluate both safety and efficacy of therapies before starting clinical trials. Several species of animals have been used in experimental models of asthma, such as Drosophila, rats, guinea pigs, cats, dogs, pigs, primates and equines. However, the most common species studied in the last two decades is mice, particularly BALB/c. Animal models of asthma try to mimic the pathophysiology of human disease. They classically include two phases: sensitization and challenge. Sensitization is traditionally performed by intraperitoneal and subcutaneous routes, but intranasal instillation of allergens has been increasingly used because human asthma is induced by inhalation of allergens. Challenges with allergens are performed through aerosol, intranasal or intratracheal instillation. However, few studies have compared different routes of sensitization and challenge. The causative allergen is another important issue in developing a good animal model. Despite being more traditional and leading to intense inflammation, ovalbumin has been replaced by aeroallergens, such as house dust mites, to use the allergens that cause human disease. Finally, researchers should define outcomes to be evaluated, such as serum-specific antibodies, airway hyperresponsiveness, inflammation and remodeling. The present review analyzes the animal models of asthma, assessing differences between species, allergens and routes of allergen administration. PMID- 29158685 TI - Invasive Aspergillus terreus morphological transitions and immunoadaptations mediating antifungal resistance. AB - Background and aims: Aspergillus terreus Thom is a pathogen of public health and agricultural importance for its seamless abilities to expand its ecological niche. The aim of this study was holistically to investigate A. terreus morphological and immunoadaptations and their implication in antifungal resistance and proliferation during infection. Materials and methods: In-depth unstructured mining of relevant peer-reviewed literature was performed for A. terreus morphological, immune, resistance, and genetic diversity based on the sequenced calmodulin-like gene. Results: Accessory conidia and phialidic conidia produced by A. terreus confer discrete anti-fungal resistance that ensures survivability during therapies. Interestingly, by producing unique metabolites such as Asp-melanin and terretonin, A. terreus is capable of hijacking macrophages and scavenging iron, respectively. As such, A. terreus has established a rare mechanism to mitigate phagocytosis and swing the interaction dynamics in favor of its proliferation and survival in hosts. Conclusion: It is further unraveled that besides A. terreus genetic diversity, morphological, biochemical, and immunologic adaptations associated with conidia germination and discharge of chemical signals during infection enable masking of the host defense as an integral part of its strategy to survive and rapidly colonize hosts. PMID- 29158686 TI - Duodenal and jejunal Dieulafoy's lesions: optimal management. AB - Dieulafoy's lesions (DLs) are rare and cause gastrointestinal bleeding resulting from erosion of dilated submucosal vessels. The most common location for DL is the stomach, followed by duodenum. There is little information about duodenal and jejunal DLs. Challenges for diagnosis and treatment of Dieulafoy's lesions include the rare nature of the disease, asymptomatic patients, bleeding symptoms often requiring rapid diagnosis and treatment in symptomatic patients, variability in the diagnosis and treatment methods resulting from different lesion locations, and the risk of re-bleeding. For these reasons, there is no universal consensus about the diagnosis and treatment approach. There are few published case reports and case series recently published. Most duodenal DLs are not evaluated seperately in the studies, which makes it difficult to determine the optimal model. In this study, we summarize the general aspects and recent approaches used to treat duodenal DL. PMID- 29158687 TI - Novel mutation of FKBP10 in a pediatric patient with osteogenesis imperfecta type XI identified by clinical exome sequencing. AB - Osteogenesis imperfecta (OI) is a hereditary disease characterized by bone fragility caused by mutations in the proteins that support the formation of the extracellular matrix in the bone. The diagnosis of OI begins with clinical suspicion, from phenotypic findings at birth, low-impact fractures during childhood or family history that may lead to it. However, the variability in the semiology of the disease does not allow establishing an early diagnosis in all cases, and unfortunately, specific clinical data provided by the literature only report 28 patients with OI type XI. This information is limited and heterogeneous, and therefore, detailed information on the natural history of this disease is not yet available. This paper reports the case of a male patient who, despite undergoing multidisciplinary management, did not have a diagnosis for a long period of time, and could only be given one with the use of whole-exome sequencing. The use of the next-generation sequencing in patients with ultrarare genetic diseases, including skeletal dysplasias, should be justified when clear clinical criteria and an improvement in the quality of life of the patients and their families are intended while reducing economic and time costs. Thus, this case report corresponds to the 29th patient affected with OI type XI, and the 18th mutation in FKBP10, causative of this pathology. PMID- 29158688 TI - A time for new north-south relationships in global health. AB - The modern concept of globalization in health care and clinical research often carries a positive message for the "Global South" nations of Africa, South America and Southeast Asia. However, bioethical abuse of participants in clinical trials still exists in the Global South. Unethical studies directed by the "Global North", formed by the medically advanced nations in North America, Western Europe and Japan, have been hugely concerning. The issue between the Global North and South is a well-recognized socioeconomic phenomenon of globalization. Medical exploitation has its roots in the socioeconomic interactions of a postcolonial world, and solutions to reducing exploitation require a deeper understanding of these societal models of globalization. We explore the fundamental causes of imbalance and suggest solutions. Reflecting on the globalization model, there must be an effort to empower the Global South nations to direct and govern their own health care systems efficiently on the basis of equality. PMID- 29158689 TI - Assessment of chronic pain and access to pain therapy: a cross-sectional population-based study. AB - Background: Chronic pain (CP) has been shown as an important public health problem, and several studies emphasize the need to strengthen the health care and social systems to reduce its marginalization. This study aimed to: evaluate the epidemiology of CP in the general population in an Italian area; and assess the awareness of a specific law, unanimously approved in Parliament, which provides citizens the right to access pain management (Italian Law 38/2010). Methods: A cross-sectional population-based study carried out during the spring of 2014 at Narni, Umbria, Italy. All the citizens residing in that area, aged >18, were enrolled in the study. Outcome measures were: prevalence of CP and therapies. The awareness of the Italian Law 38/2010 was also recorded. Results: Data of 1293 questionnaires were analyzed. The prevalence of CP was 28.4%. In 51.5% of cases, pain was severe, with higher prevalence in females (p<0.001). Moreover, pain was generally increasing with age (p<0.001). The risk of suffering from severe pain was modeled using logistic regression. Significant predictors were female gender (OR 2.59; 95% CI: 1.77-3.79), living in an urban area (OR 0.63; 95% CI 0.45 0.88), and age (OR 1.06; 95% CI: 1.04-1.08). Among people with CP, 77.9% were receiving therapy; the proportion of individuals in therapy for severe pain significantly increased with age (OR 1.03; 95% CI: 1.02-1.05) and was smaller in individuals with light pain (OR 0.21; 95% CI: 0.07-0.66). The majority of subjects (61.9%) are not aware of the existence of a specific law stating their rights to receive pain management. Conclusion: CP, at least in the rural part of the community investigated in Italy, is not perceived as a chronic disease in its own right. A socio-cultural transformation in patients and in the health care system seems necessary. PMID- 29158690 TI - Pain aversion and anxiety-like behavior occur at different times during the course of chronic inflammatory pain in rats. AB - Pain is considered a multidimensional conscious experience that includes a sensory component and a negative affective-motivational component. The negative affective-motivational component of pain is different from the sensory component and amplifies the pain experience. Nowadays, a significant number of preclinical research groups have focused their attention on the affective symptoms of pain. In the present study, we investigated the pain aversion and anxiety-like behavior of the complete Freund's adjuvant (CFA)-induced chronic pain model. CFA rats experienced spontaneous pain during pain-paired conditioning (pain aversion) and spontaneous pain produces an affective response (anxiety-like behavior). Moreover, pain aversion was gradually attenuated, while the anxiety-like behavior increased in 4 weeks. Therefore, although the negative effect (including pain aversion and anxiety) is always associated with hyperalgesia, the manifestations of negative effect may follow different time courses, which may influence the progress of primary disease. The findings illustrate that targeted therapy should focus on a specific aspect in different stages of pain. Our study emphasizes the necessity of using multiple tests to study pain comorbidities. PMID- 29158691 TI - Project for the introduction of prehospital analgesia with fentanyl and morphine administered by specially trained paramedics in a rural service area in Germany. AB - Background: In patients with serious illness or trauma, reduction of severe pain is a key therapeutic goal of emergency medical service (EMS) teams. In Germany, only physicians are allowed to use opioid analgesics. In the rural EMS area studied, the mean arrival time for paramedics is 8 minutes, 23 seconds, and for the rescue physician between 10 minutes, 30 seconds and 16 minutes, 59 seconds, depending on EMS site. In cases of parallel callouts, rescue-physician arrival times may be considerably longer. Objective: During this project, we assessed the administration of the opioid analgesics morphine and fentanyl by specially trained paramedics with regard to analgesia quality and patient safety. Materials and methods: During the 18-month study period, specially trained paramedics administered morphine or fentanyl to patients with severe pain if indicated and if a rescue physician was not available in time. Besides basic documentation, pain intensity (using a numeric rating scale) and oxygen saturation were measured initially and at hospital handover. Results: During the 18 months, 4,285 emergency callouts were attended to by the 13 specially trained paramedics of the district (total callouts during this period 21,423). In 77 patients (1.8%), fentanyl (n=53/68.8%) or morphine (n=24/31.2%) was administered. Based on the measurements obtained with the numeric rating scale at the start of treatment (7.9) and upon hospital handover (3.3), pain reduction was 4.52 overall (41.5%, P<0.001): 4.64 with fentanyl (42.9%, P<0.001) and 4.25 with morphine (43.2%, P<0.001). None of the patients had an oxygen saturation <95% at the time of handover, and no patient developed opioid-induced respiratory depression requiring treatment. Conclusion: The results of this study indicate that the administration of opioid analgesics by specially trained and qualified paramedics is safe and effective. PMID- 29158692 TI - Pulsed radiofrequency of brachial plexus under ultrasound guidance for refractory stump pain: a case report. AB - The post-amputation (pain) syndrome, including stump pain, phantom limb sensation, and phantom limb pain is common but difficult to treat. Refractory stump pain in the syndrome is an extremely challenging and troublesome clinical condition. Patients respond poorly to drugs, nerve blocks, and other effective treatments like spinal cord stimulation and surgery. Pulsed radiofrequency (PRF) technique has been shown to be effective in reducing neuropathic pain. This report describes a patient with persistent and refractory upper limb stump pain being successfully relieved with PRF of brachial plexus under ultrasound guidance after a 6-month follow-up period, suggesting that PRF may be considered as an alternative treatment for refractory stump-neuroma pain. PMID- 29158693 TI - Adenocarcinoma arising from a gastric duplication cyst: a case report and literature review. AB - Introduction: Alimentary tract cystic duplication is a rare congenital anomaly predominantly affecting females, and diagnosed mostly in the early years of life. Case report: We present here a case of a 51-year-old man presenting with a 2-day history of melena. Gastroscopy showed fresh blood, as well as a mass lesion and cavity at the fundus. Biopsies of the mass edge reported the occurrence of moderately differentiated adenocarcinoma and mild chronic gastritis. Computed tomography imaging showed a 5.1*6.5 cm cystic mass in the gastric greater curvature. The patient received six cycles of epirubicin, capecitabine, and oxaliplatin, followed by uncomplicated total gastrectomy. Literature review: Data from all 11 reports of similar cases were reviewed and pooled. The result shows male predominance and variable symptoms, as well as a wide age range (25-76 years) at presentation. The cysts are commonly located along the greater curvature and are unilocular. Surgery was the treatment in most cases. Conclusion: Alimentary tract cystic duplication is rare and may predispose to malignancy. Early diagnosis and prompt surgical intervention is important for the best outcome. PMID- 29158694 TI - The art of removing nasal foreign bodies. AB - Objective: The removal of nasal foreign bodies (NFBs) can be a difficult task for the inexperienced physician, and the more unsuccessful attempts are made, the more difficult the extraction becomes. We have formulated this simple "four-step" approach to improve success, especially on the first try. Methods: A retrospective review of cases requiring NFB removal, seen by one registrar from 2012 to 2016 at Frankston Hospital, was performed. Results: From 2012 to 2016, 93 patients were referred, of whom 65 were confirmed to have NFBs. In all, 20 patients were first seen by the registrar and had the NFB removed successfully. Another 28 patients were referred to the registrar only after one failed attempt by another medical personnel, and the remaining 17 patients were referred after two failed attempts. All patients had the NFB removed locally in the emergency department using the "four-step" approach, except four patients who had the NFB removed under general anesthesia in the operating theater. Three of the latter had two failed attempts and had refused further attempts, and the fourth patient had developed epistaxis after a failed removal by his general practitioner. Conclusion: When performed correctly, the "four-step" approach will result in the successful removal of NFBs. Ideally, the removal of NFBs should only be performed by an experienced medical personnel, and any failed first attempt removals must be subsequently managed only by an experienced medical personnel. PMID- 29158696 TI - 65Plus: open-label study of bevacizumab in combination with pemetrexed or pemetrexed/carboplatin as first-line treatment of patients with advanced or recurrent nonsquamous non-small-cell lung cancer. AB - Background: The aim of the study was to investigate in terms of noninferiority the efficacy and safety of a monochemotherapy regimen of pemetrexed plus bevacizumab (BevPem) versus carboplatin/pemetrexed plus bevacizumab (BevCPem) in elderly patients as first-line treatment for advanced metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC). Materials and methods: 65Plus was a Phase III, randomized, open-label study. In total, 253 patients received BevPem (n=119) or BevCPem (n=134). The primary outcome measure was progression-free survival. Secondary end points were overall survival, tumor response, and safety outcomes. Evaluations were performed for the whole study population and stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS). Results: Noninferiority of BevPem in comparison to BevCPem could not be demonstrated for the overall population (P=0.7864). Significant superiority of the combined treatment BevCPem was seen in patients of ECOG PS 0-1 (median PFS 5.1 vs 6.9 months, HR 1.353, 95% CI 1.03-1.777), while the opposite tendency was observed in patients with ECOG PS 2 (median PFS 2.9 vs 1.5 months, HR 0.628, 95% CI 0.195-2.025). Overall, better tolerability was found for the BevPem group, irrespective of ECOG PS. Conclusion: Results from the 65plus study give evidence that BevPem and BevCPem treatments may exert differential effects on PFS, depending on the patients ECOG PS. It appears that patients with better ECOG PS (0-1) benefited more from the combined treatment with carboplatin, while the group comprising more severely impaired patients (ECOG PS 2) benefited more from the monochemotherapy. PMID- 29158695 TI - PNPLA3 expression and its impact on the liver: current perspectives. AB - A single-nucleotide polymorphism occurring in the sequence of the human patatin like phospholipase domain-containing 3 gene (PNPLA3), known as I148M variant, is one of the best characterized and deeply investigated variants in several clinical scenarios, because of its tight correlation with increased risk for developing hepatic steatosis and more aggressive part of the disease spectrum, such as nonalcoholic steatohepatitis, advanced fibrosis and cirrhosis. Further, the I148M variant is positively associated with alcoholic liver diseases, chronic hepatitis C-related cirrhosis and hepatocellular carcinoma. The native gene encodes for a protein that has not yet a fully defined role in liver lipid metabolism and, according to recent observations, seems to be divergently regulated among distinct liver cells type, such as hepatic stellate cells. Therefore, the aim of this review is to collect the latest data regarding PNPLA3 expression in human liver and to analyze the impact of its genetic variant in human hepatic pathologies. Moreover, a description of the current biochemical and metabolic data pertaining to PNPLA3 function in both animal models and in vitro studies is summarized to allow a better understanding of the relevant pathophysiological role of this enzyme in the progression of hepatic diseases. PMID- 29158697 TI - Revisions of Ruizodendron and Pseudephedranthus (Annonaceae) including a new species and an overview of most up-to-date revisions of Neotropical Annonaceae genera. AB - We present revisions of the Neotropical genera Ruizodendron and Pseudephedranthus (Annonaceae). Ruizodendron includes a single species R. ovale. Pseudephedranthus now comprises two species, with the description of the new species P. enigmaticussp. nov. extending the range of the genus beyond the Upper Rio Negro region of Brazil (Amazonas) and adjacent Venezuela (P. fragrans), to include Guyana, Suriname, and the Brazilian state of Para. An overview is provided of current revisions of Neotropical Annonaceae genera that will aid in accessing proper species information for this frequently encountered tropical rain forest family. PMID- 29158698 TI - Two new endemic tree species from Puerto Rico: Pisonia horneae and Pisonia roqueae (Nyctaginaceae). AB - In this paper, we describe two endemic tree species of Pisonia (Caryophyllales: Nyctaginaceae) from Puerto Rico that were erroneously catalogued under the single name Pisonia subcordata var. typica f. gigantophylla, misidentified as P. albida or P. subcordata, and informally named as "P. borinquena" and "P. woodburyana". The species here named as P. horneae is a rare to locally occasional tree from low elevations in the Northern Karst and the Sierra de Cayey. The other species, here named as P. roqueae, is a rare to locally common tree from mid to high elevations in the Central Mountain Range and the Luquillo Mountains. We provide an account of the taxonomical and nomenclatural history of both species, images, conservation notes, a distribution map, and a key to distinguish the species of Pisonia present in Puerto Rico. PMID- 29158699 TI - A new disjunct Dendrothrix (Euphorbiaceae, tribe Hippomaneae): a Guiana Shield element in sub-Andean cordilleras of Ecuador and Peru. AB - Dendrothrix condorensis K.Wurdack, sp. nov. from the sub-Andean cordilleras of Ecuador and Peru is described and illustrated. The new species is geographically widely separated from its likely closest relative, D. yutajensis, which is endemic to the Guiana Shield region of southern Venezuela and adjacent Brazil, and notably differs in leaf morphology. Vegetative (i.e., epidermal micropapillae, trichomes) and reproductive (i.e., cymule glands, flowers, pollen) micromorphological features were examined with SEM. Rare tristaminate flowers were documented among the typical bistaminate ones. Seeds and diagnostic features among the four species of Dendrothrix are compared. PMID- 29158700 TI - X-ray crystallographic and validated HPTLC analysis of the biomarker chromone glucoside (schumanniofioside A) isolated from Acalypha fruticosa growing in Saudi Arabia. AB - A chromone glucoside 2-methyl-5,7-dihydroxychromone 5-O-beta-D-glucopyranoside (schumanniofioside A, compound 1) was isolated from the methanol extract of Acalypha fruticosa. The structure of compound 1 was fully assigned based on nuclear magnetic resonance (NMR) (1H, 13C and 2D) spectra and electrospray ionization mass spectrum (ESI-MS) in addition to X-ray Crystallography. The molecules were packed in the crystal structure by eight intermolecular O-H?O and C-H?O interactions. The structure of compound 1 belongs to monoclinic, P21, a = 9.1989 (4) A, b = 4.6651 (2) A, c = 20.4042 (7) A, beta = 97.862 (3) degrees , V = 867.31 (6) A3, Z = 2, wRref(F2) = 0.101, T = 100 K. Thus, the bond angles, bond lengths and absolute structure of compound 1 were confirmed by its X-ray structure. A validated HPTLC method was developed for the quantitative analysis of compound 1 in chloroform and methanol extracts of A. fruticosa. It was found to furnish a compact and sharp band of compound 1 at Rf = 0.13 +/- 0.005 using chloroform, methanol and glacial acetic acid [17:3:0.5 (v/v/v)] as mobile phase. The LOD and LOQ for compound 1 were found to be 17.86 and 54.13 ng/band, respectively. Compound 1 was found in both chloroform and methanol extracts of the plant (0.03% w/w and 0.31% w/w, respectively). The proposed HPTLC method can be used for the further analysis of schumanniofioside A in different plant extracts, herbal formulations and biological samples as well as in process quality control. PMID- 29158701 TI - Study of DNA damage caused by dipyrone in presence of some transition metal ions. AB - The DNA damage in the presence of dipyrone (used as its sodium salt, NaDip) and some transition metal ions in an air saturated ([O2] ~ 0.25 mM) non-buffered solution at T = (25.0 +/- 0.5) degrees C was investigated by agarose gel electrophoresis. As metal ions Cu2+, Fe3+, Ni2+ and Mn3+ were selected and evaluated in the present study because of the important role they play in a biological system. pUC19 plasmid DNA damage-induced by NaDip (80-600 MUM) was observed in the presence of 100 MUM Cu2+. The damage was proportional to the NaDip concentration provided that the order of addition of reagents (pUC19 plasmid DNA + Cu2+ + NaDip) is obeyed. Addition in the reaction medium of ligands for Cu2+ and Cu+, respectively EDTA and neocuproine, promoted total inhibition or reduction of the pUC19 plasmid DNA damage suggesting the involvement of the Cu2+/Cu+ cycle. Besides, the decrease in the pUC19 plasmid DNA damage after addition of catalase (1.0 * 10-4 mg MUL-1) in the same reaction medium indicates that H2O2 is also involved in the damage process. In NaDip concentration range (80-600 MUM), and under same the experimental conditions, it was not possible to conclude whether there was pUC19 plasmid DNA damage caused by 10 MUM Fe3+. No damage was observed in the presence of Mn3+ or Ni2+. Although the technique used in this study is sensitive to detect the pUC19 plasmid DNA damage it was not possible to identify in which DNA base this damage occurs. Further studies with other techniques should be made to unambiguously identify the oxidative intermediates that are responsible for the DNA damage. As far as we know, this is the first study dealing with the pUC19 plasmid DNA damage-induced by NaDip in presence of copper, iron, nickel and manganese ions. PMID- 29158702 TI - Novel essential amino acid-sulfanilamide hybrid as safe anti-ulcerogenic agent with anti-helicobacter pylori activity. AB - A novel and safe essential amino acid (Leucine) incorporating sulfanilamide was synthesized, and evaluated for its anti-ulcerogenic activity and in vitro anti Helicobacter pylori activity. The new molecule showed a dose dependent activity against absolute ethanol-induced ulcer in rats, it produced percent protection of control ulcer by 66.7 at dose 100 mg/kg. In addition it showed a potent anti Helicobacter pylori activity in vitro against 7 clinically isolated strains. The minimum inhibitory concentration (MIC) ranged from 12.5 to 50 MUg/ml. The preliminary safety studies and toxicity profile are optimistic and encouraging. PMID- 29158703 TI - Vapour-phase method in the synthesis of polymer-ibuprofen sodium-silica gel composites. AB - The study discusses the synthesis of polymer-silica composites comprising water soluble drug (ibuprofen sodium, IBS). The polymers selected for this study were poly(TRIM) and poly(HEMA-co-TRIM) produced in the form of permanently porous beads via the suspension-emulsion polymerization method. The acid and base set ternary composites were prepared by the saturation of the solid dispersions of drug (poly(TRIM)-IBS and/or poly(HEMA-co-TRIM)-IBS) with TEOS, and followed by their exposition to the vapour mixture of water and ammonia, or water and hydrochloric acid, at autogenous pressure. The conducted analyses reveal that the internal structure and total porosity of the resulting composites strongly depend on the catalyst which was used for silica precursor gelation. The parameters characterizing the porosity of both of the acid set composites are much lower than the parameters of the base set composites. Moreover, the basic catalyst supplied in the vapour phase does not affect the ibuprofen sodium molecules, whereas the acid one causes transformation of the ibuprofen sodium into the sodium chloride and a derivative of propanoic acid, which is poorly water soluble. The release profiles of ibuprofen sodium from composites demonstrate that there are differences in the rate and efficiency of drug desorption from them. They are mainly affected by the chemical character of the polymeric carrier but are also associated with the restricted swelling of the composites in the buffer solution after precipitation of silica gel. PMID- 29158704 TI - A quality by design approach for the development of lyophilized liposomes with simvastatin. AB - Lyophilization is used to ensure an increased shelf-life of liposomes, by preserving them in dry state, more stable than the aqueous dispersions. When stored as aqueous systems, the encapsulated drugs are released and the liposomes might aggregate or fuse. The aim of this study was to develop and optimize a lyophilized formulation of simvastatin (SIM) loaded into long circulating liposomes using the Quality by Design (QbD) approach. Pharmaceutical development by QbD aims to identify characteristics that are critical for the final product quality, and to establish how the critical process parameters can be varied to consistently produce a product with the desired characteristics. In the case of lyophilized liposomes, the choice of the optimum formulation and technological parameters has to be done, in order to protect the integrity of the liposomal membrane during lyophilization. Thus, the influence of several risk factors (3 formulation factors: PEG proportion, cholesterol concentration, the cryoprotectant to phospholipids molar ratio, and 2 process parameters: the number of extrusions through 100 nm polycarbonate membranes and the freezing conditions prior lyophilization) over the critical quality attributes (CQAs) of lyophilized long circulating liposomes with simvastatin (lyo-LCL-SIM), i.e. the size, the encapsulated SIM concentration, the encapsulated SIM retention, the Tm change and the residual moisture content, was investigated within the current study using the design of experiments tool of QbD. Moreover, the design space for lyo-LCL-SIM was determined, in which the established quality requirements of the product are met, provided that the risk factors vary within the established limits. PMID- 29158705 TI - Melatonin attenuates thiocyanate-induced vasoconstriction in aortic rings. AB - Cigarette smoking not only has a carcinogenic effect but also leads to an increase in arterial blood pressure. Besides its main components, i.e. nicotine, tar, and carbon monoxide, cigarette smoke also contains thiocyanate. Thiocyanate anions (SCN-) arise from the detoxification of hydrogen cyanide and its plasma concentrations were found to correlate significantly with cigarette consumption. There is also evidence that atherosclerotic disease progression is much more rapid when serum SCN- levels are increased. Melatonin, a non-toxic indolamine with various physiologic functions, is believed to protect against inflammatory processes and oxidative stress. It has been demonstrated that melatonin serves as free radical scavenger and represents a potent antioxidant. Therefore, it is believed that melatonin with its atheroprotective effects may be useful either as a sole therapy or in conjunction with others. The aim of this study was to quantify the thiocyanate-induced vasomotor response in aortic tissue and further to examine the potential of melatonin in affecting the generated vasoreactivity. Aortic rings of adult male normotensive Wistar rats were cut into 4-mm rings. Following the administration of thiocyanate in various concentrations, vasomotor response of aortic vessel segments was measured. To assess the effect of melatonin on vasomotor activity, organ bath concentrations were modulated from 60 to 360 pM, which corresponds to physiologic plasma up to the levels of patients with regular oral intake of 3 mg of melatonin as a supplement. Thirty-six rat aortic rings were studied. When exposed to thiocyanate, vessel segments revealed vasoconstriction in a concentration-dependent manner. In rings which were preincubated with melatonin at a concentration of 360 pM, a 56.5% reduction of effect size could be achieved (4.09 +/- 1.22 mN versus 9.41 +/- 1.74 mN, P < 0.0001). Additionally, administration of 360 pM melatonin at a norepinephrine concentration of 80 mM resulted in a relaxation of 10.9 +/- 2.2%. The vasodilatatory effect of melatonin was significantly reduced to 1.3 +/- 0.5% when concentration of norepinephrine was doubled (P < 0.002). This study indicates that vessel segments that were exposed to thiocyanate responded with a dose dependent vasoconstriction. The effect could be markedly attenuated in segments preincubated in melatonin. PMID- 29158706 TI - Comparative study of free and liposome-entrapped chloramphenicol against biofilms of potentially pathogenic bacteria isolated from cooling towers. AB - This study aimed to investigate for the first time the in vitro antibiofilm effectiveness of two chloramphenicol liposome formulations against biofilms of potentially pathogenic bacteria associated to corrosion isolated from the water of cooling towers from a Brazilian industry. Antibiofilm assays with liposomes were performed in 96-wells microtiter plates, and data was compared to free chloramphenicol treatment. Chloramphenicol-loaded liposomes were successfully produced using the dehydration-rehydration method, with vesicle diameters of 131 nm (100 nm membrane extrusion) and 182 nm (200 nm membrane extrusion) assessed by dynamic light scattering. The liposomes obtained by 100 nm membrane extrusion were more effective than 200 nm membrane extrusion vesicles against the biofilms after overnight exposure, and the free drug had no antibiofilm effect. Our study open doors for more investigations on liposome entrapment of antimicrobial compounds such as biocides of industrial use, for controlling biofilm formation in aquatic environments. PMID- 29158707 TI - A novel monocyclic triterpenoid and a norsesquaterpenol from the aerial parts of Suaeda monoica Forssk. ex J.F. Gmel with cell proliferative potential. AB - Suaeda monoica Forssk. ex J.F. Gmel (Chenopodiaceae), a mangrove herb, is distributed in tropical Africa, Arabian Peninsula, India, Pakistan, Palestine and Jordan. The plant parts are used to treat sore throat, hepatitis, wounds, rheumatism, paralysis, asthma, snakebites, skin disease and ulcer. Two new phytoconstituents characterized as 13,17-octahydropentalene-4,4,10,23-tetramethyl 17,21-diisopropyl-tetradecahydrocyclo-[a]-phenanthrene-(14), 20(23), 21(30)-trien 5alpha-ol (SMC-3) and [1,4,4-trimethyl-cyclopent-1(5)-enyl]-9,10,17,21 tetramethyl-9alpha-ol-16alpha (17alpha)-epoxy heptadecan-6,10-dione (SMC-4) belong to the class norsesquaterpenol and monocyclic triterpenoid, respectively, along with two known compounds 3-epi-lupeol (SMC-1) and 4-cyclopentylpyrocatechol (SMC-2) have been isolated from the ethanol extract of aerial parts of S. monoica using normal and reverse phase column as well as planar chromatography. The spectroscopic studies including 1D, 2D NMR (DEPT, COSY, HMBC and HSQC) aided by EIMS mass and IR spectra were used to establish their structures. All the four compounds were tested for cytotoxicity on cultured HepG2 cells and for cell proliferation activities. The results revealed no cytotoxicity even at highest (6.25-50 MUg/ml) dose of all the four compounds. The compound SMC-1 showed prominent cell proliferative activity as compared to other SMC compounds. PMID- 29158708 TI - Medication safety officer preparatory course: Outcomes and experiences. AB - Purpose: Few hospitals employ a medication safety officer. A medication safety officer preparatory course was planned using a structured curriculum to prepare pharmacists with the knowledge and skills to start medication safety officer activities. The current study aims to assess the outcome, as change in knowledge, of a hospital medication safety officer preparatory course. Methods: We conducted a three-day course in February 2011 in Riyadh, Saudi Arabia. It was developed to provide attendees with the essential knowledge and skills to become a medication safety officer. Teaching methodologies included didactic teaching, group discussions, case presentations, and an independent study of medication safety materials. The content of the course focused on the various roles of a medication safety officer, the importance of medication safety in a health care setting, the incidence of adverse drug events in a hospital setting, strategies to identify and prevent adverse events, the use of root cause analysis and failure mode and effect analysis, the role of an officer in hospital accreditation, and ways for promoting safety culture. Assessment of the course outcome was accomplished by comparing scores of knowledge level before and after the course. The knowledge level was assessed by a 20-item exam which was developed and validated by course instructors. Results: Twenty-one participants attended the course and completed both the baseline and after-course assessment questionnaires. The majority was male (N = 14, % = 66.7) with a job experience of 1-5 five years (N = 10, % = 47.6). The knowledge score increased from 14.3 +/- 1.90 (mean +/- standard deviation) at baseline to 18.5 +/- 1.43 after successfully completing the course (P < 0.001). Conclusion: A three-day medication safety officer preparatory course has been shown to significantly improve attendee knowledge about medication safety. Educating health care professionals is an important tool to help ensure the safety of patients. PMID- 29158709 TI - Relationship between health literacy and body mass index among Arab women with polycystic ovary syndrome. AB - Background: Polycystic ovary syndrome (PCOS) puts patients at higher risk for obesity and diabetes. Poor health literacy is also associated with these conditions. Notably, weight loss is associated with improved ovulation and pregnancy rates for women with PCOS. In this study the association between health literacy and body mass index (BMI) among women with PCOS was examined. Methods: The health literacy of women with PCOS was measured using the Arabic version of the single item literacy screener (SILS) at a university medical center. Sociodemographic and medical information was collected by interviewing the participants and reviewing their medical records, respectively. The relationship between health literacy and BMI was assessed by multiple logistic regression analysis. Results: Health literacy was assessed in 127 women with PCOS from September 2015 to February 2016. Only 16.54% of participants had limited health literacy. The mean BMI for all participants was 30.57 (kg/m2), and the mean age was 27.40 years. Further, most of the participants (74%) had a high school diploma or a higher degree. Almost 56% of the participants were taking metformin, and 11.81% had hypothyroidism. After controlling for age, education, hypothyroidism diagnosis, and the use of metformin, participants with high BMI were 10% less likely to have a good health literacy level (OR = 0.904; 95% CI = 0.829-0.987; P = 0.0238). Conclusion: Improving the health literacy of patients with PCOS may have a positive impact on their BMI and eventually lead to favorable health outcomes. PMID- 29158710 TI - The impact of pharmacists providing direct patient care as members of interprofessional teams on diabetes management. AB - The purpose of this study was to evaluate the impact of pharmacist providing direct patient care as a member of interprofessional team on diabetes management. This study is a retrospective chart review of diabetes patients seen by a pharmacist in an endocrinology clinic affiliated with an academic medical center. The following patient outcomes were recorded pre and post the pharmacist intervention: glycemic control as measured by change in hemoglobin A1c (HbA1c), change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), statin use, and use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). 144 charts were reviewed, 28 of which were included in the study. A statistically significant improvement in HbA1c was observed in patients following the pharmacist intervention. The mean pre intervention HbA1c was 8.77% (+/-SD 2.48) while the post-intervention HbA1c was 7.59% (+/-SD 1.18), with a p-value of 0.040. A decrease in blood pressure was also observed; however, this decrease was not statistically significant. There was no statistically significant difference in use of ACEI/ARB and statins pre- and post-intervention. The results suggest that involvement of pharmacists in direct patient care as members of interprofessional team in our specialty ambulatory care clinic is associated with a positive impact on the glycemic control in patients with diabetes. PMID- 29158711 TI - Chemometric evaluation of the efficacy of locally administered chlorhexidine in patients with periodontal disease. AB - The process of assessment of drug efficacy produces multivariate data which are difficult to interpret. The interpretation and extraction of relevant data requires application of chemometric algorithms for multivariate data analysis. The aim of our study was evaluation of the efficacy of local treatment with chlorhexidine (CHX) in patients suffering from periodontal disease by chemometric algorithms for multivariate data analysis. Several algorithms were used: principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA). The PCA models identified the examined variables as suitable for monitoring the periodontal disease progression at the same time revealing mutual relationship among them. The developed PLS-DA model successfully distinguished patients treated with CHX from non-treated patients. The OPLS-DA model revealed differences in the mechanism of action of the two widely applied treatments in periodontal disease, local administration of CHX and local administration of doxycycline (DOX). The approach presented in this study opens the possibility of application of chemometric algorithms for multivariate data analysis for assessment of treatment efficacy. PMID- 29158712 TI - High resolution UHPLC-MS characterization and isolation of main compounds from the antioxidant medicinal plant Parastrephia lucida (Meyen). AB - High-resolution mass spectrometry is currently used to determine the mass of biologically active compounds in medicinal plants and food and UHPLC-Orbitrap is a relatively new technology that allows fast fingerprinting and metabolomics analysis. Forty-two metabolites including several phenolic acids, flavonoids, coumarines, tremetones and ent-clerodane diterpenes were accurately identified for the first time in the resin of the medicinal plant Parastrephia lucida (Asteraceae) a Chilean native species, commonly called umatola, collected in the pre-cordillera and altiplano regions of northern Chile, by means of UHPLC-PDA-HR MS. This could be possible by the state of the art technology employed, which allowed well resolved total ion current peaks and the proposal of some biosynthetic relationships between the compounds detected. Some mayor compounds were also isolated using HSCCC. The ethanolic extract showed high total polyphenols content and significant antioxidant capacity. Furthermore, several biological assays were performed that determined the high antioxidant capacity found for the mayor compound isolated from the plant, 11- p coumaroyloxyltremetone. PMID- 29158713 TI - Formulation and characterization of novel soft nanovesicles for enhanced transdermal delivery of eprosartan mesylate. AB - The objective of the present work was to formulate, optimize and evaluate the potential of novel soft nanovesicles i.e. nano-transfersomes, containing eprosartan mesylate (EM) for transdermal delivery. Nano-transfersomes of EM were developed using Phospholipon 90G, Span 80 (SP) and sodium deoxycholate (SDC) and characterized for vesicle size, shape, entrapment efficiency, in vitro skin permeation study and confocal laser scanning microscopy. The optimized nano transfersomes formulation showed vesicles size of 108.53 +/- 0.06 nm and entrapment efficiency of 63.00 +/- 2.76%. The optimized nano-transfersomes provided an improved transdermal flux of 27.22 +/- 0.29 ug/cm2/h with an enhancement ratio of 16.80 over traditional liposomes through Wistar rat skin. Confocal laser microscopy of rat skin treated with the optimized formulation showed that the formulation was eventually distributed and permeated deep into the rat skin. The present investigation has shown that the nature and concentration of surfactants (edge activators) influence immense control on the characteristics of nano-transfersomes. It was concluded that the developed nano transfersomes surmount the limitation of low penetration ability of the traditional liposomes across the rat skin. Improved drug delivery presented by nano-transfersomes establishes this system as an encouraging dosage form for the delivery of EM via skin route. PMID- 29158714 TI - Synthesis and anticancer activity of new quinazoline derivatives. AB - In this study, a new series of quinazoline derivatives (3-26) was synthesized and characterized via physicochemical and spectral means. Treatment of 2-amino-5 methylbenzoic acid with butyl isothiocyanate resulted in the new 2 thioxoquinazolin-4-one (3). Alkylation and hydrazinolysis of the inherent thioxo group in (1-3) afforded the corresponding thioethers (4-23) and hydrazine derivatives (24 and 25), then 24 was further transformed into tricyclic derivative 26 via cyclocondensation reaction. Compounds 1 and 2, which were previously synthesized, were found to exhibit anticancer activity. The cytotoxicity of all compounds was evaluated in vitro against the HeLa and MDA MB231 cancer cell lines, including 1 and 2 for comparison, using MTT assay. The treatment of the cells was performed with the synthesized compounds and gefitinib at 0, 1, 5, 10, 25, and 50 MUM and incubated for 24 h in 50% DMSO. The IC50 values of the target compounds were reported in MUM, using gefitinib as a standard. Our results indicated that all compounds exhibited significant in vitro cytotoxicity against both cell lines. While compounds 1-3 showed good activity, compounds 21-23 were found to be more potent than gefitinib. Thus, compounds 21 23 may be potential anticancer agents, with IC50 values ranging from 1.85 to 2.81 MUM in relation to gefitinib (IC50 = 4.3 and 28.3 MUM against HeLa and MDA-MB231 cells, respectively). PMID- 29158715 TI - Optimized furosemide taste masked orally disintegrating tablets. AB - Optimized orally disintegrating tablets (ODTs) containing furosemide (FUR) were prepared by direct compression method. Two factors, three levels (32) full factorial design was used to optimize the effect of taste masking agent (Eudragit E100; X1) and superdisintegarant; croscarmellose sodium (CCS; X2) on tablet properties. A composite was prepared by mixing ethanolic solution of FUR and Eudragit E100 with mannitol prior to mixing with other tablet ingredients. The prepared ODTs were characterized for their FUR content, hardness, friability and wetting time. The optimized ODT formulation (F1) was evaluated in term of palatability parameters and the in vivo disintegration. The manufactured ODTs were complying with the pharmacopeia guidelines regarding hardness, friability, weight variation and content. Eudragit E100 had a very slightly enhancing effect on tablets disintegration. However, the effects of both Eudragit E100 (X1) and CCS (X2) on ODTs disintegration time (Y1) were insignificant (p > 0.05). Moreover, X1 exhibited antagonistic effect on the dissolution after 5 and 30 min (D5 and D30, respectively), but only its effect on D30 is significant (p = 0.0004). Furthermore, the optimized ODTs formula showed good to acceptable taste in term of palatability, and in vivo disintegration time of this formula was about 10 s. PMID- 29158716 TI - New chroman-4-one/thiochroman-4-one derivatives as potential anticancer agents. AB - The synthesis of 3-[3/4-(2-aryl-2-oxoethoxy)arylidene]chroman/thiochroman-4-one derivatives (1-34) and evaluation of their anticancer activities were aimed in this work. Final compounds were obtained in multistep synthesis reactions using phenol/thiophenol derivatives as starting materials. For anticancer activity evaluation, all compounds were offered to National Cancer Institute (NCI), USA and selected ones were tested against sixty human tumor cell lines derived from nine neoplastic diseases. The activity results were evaluated according to the drug screening protocol of the institute. Compounds containing thiochromanone skeleton exhibited higher anticancer activity. PMID- 29158717 TI - Adverse drug reactions in high-risk pregnant women: A prospective study. AB - Background: Because pregnant women are often excluded from clinical trials, there is still very limited information about the risk and safety of prescription drugs during pregnancy. Objective: We aimed to determine the prevalence of Adverse Drug Reactions (ADRs) in high-risk pregnant women after hospital admission. A prospective study was carried out in a teaching maternity hospital in Brazil during six months. Causality of ADRs was assessed through the Naranjo Algorithm and Korean Algorithm for ADR Causality Assessment. Severity of ADRs was assessed using Hartwig's Severity Assessment Scale. Results: The prevalence of ADRs among the 294 inpatients studied was 8.8%. The mean age was 27.14 (+/-7.5) y.o. Patient's age was related to the presence of ADRs, while the manifestation of these events was not associated with any adverse pregnancy outcome. 75.9% of the ADRs reported in the study were of mild severity and 24.1% were of moderate severity. No ADR was caused by drug-drug interaction; however, a significant increase in blood pressure was observed in all patients using concurrent methyldopa and ferrous sulfate. Conclusion: Overall, ADRs were not common events among high-risk pregnant women and no adverse pregnancy outcomes following these events were observed. PMID- 29158718 TI - Effects of chronic Delta9-tetrahydrocannabinol treatment on Rho/Rho-kinase signalization pathway in mouse brain. AB - Delta9-Tetrahydrocannabinol (Delta9-THC) shows its effects by activating cannabinoid receptors which are on some tissues and neurons. Cannabinoid systems have role on cell proliferation and development of neurons. Furthermore, it is interesting that cannabinoid system and rho/rho-kinase signalization pathway, which have important role on cell development and proliferation, may have role on neuron proliferation and development together. Thus, a study is planned to investigate rhoA and rho-kinase enzyme expressions and their activities in the brain of chronic Delta9-THC treated mice. One group of mice are treated with Delta9-THC once to see effects of acute treatment. Another group of mice are treated with Delta9-THC three times per day for one month. After this period, rhoA and rho-kinase enzyme expressions and their activities in mice brains are analyzed by ELISA method. Chronic administration of Delta9-THC decreased the expression of rhoA while acute treatment has no meaningful effect on it. Administration of Delta9-THC did not affect expression of rho-kinase on both chronic and acute treatment. Administration of Delta9-THC increased rho-kinase activity on both chronic and acute treatment, however, chronic treatment decreased its activity with respect to acute treatment. This study showed that chronic Delta9-THC treatment down-regulated rhoA expression and did not change the expression level of rho-kinase which is downstream effector of rhoA. However, it elevated the rho-kinase activity. Delta9-THC induced down-regulation of rhoA may cause elevation of cypin expression and may have benefit on cypin related diseases. Furthermore, use of rho-kinase inhibitors and Delta9-THC together can be useful on rho-kinase related diseases. PMID- 29158719 TI - Medication discrepancies identified during medication reconciliation among medical patients at a tertiary care hospital. PMID- 29158720 TI - Propafenone HCl fast dissolving tablets containing subliming agent prepared by direct compression method. AB - Propafenone HCl (PPH), an antiarrhythmic drug, has a bitter taste, short half life, delayed drug dissolution and side effects. Thus, the purpose of this work is to develop orally fast dissolving tablets (OFDTs) containing PPH to provide a rapid drug dissolution and subsequently give rapid onset of action of PPH as an antiarrhythmic drug. Moreover, OFDTs of PPH reduce its side effects and improve its bioavailability. Propafenone HCl (PPH), an antiarrhythmic drug, has a bitter taste, short half-life, delayed drug dissolution and side effects. Direct compression method was used for the preparation of 15 formulations OFDTs containing PPH using directly compressible excipients, subliming agent and superdisintegrants. The prepared tablets were undergone physical characterization, in vitro dissolution and stability studies. All pre- and post compression tests met the pharmacopoeia specifications. In vitro dissolution of the prepared PPH OFDTs exhibited high dissolution rate than compared to the marketed tablets. It was found that the tablets prepared by using the higher concentration of crospovidone were found to dissolute the drug at a faster rate when compared to other concentrations. A formula containing croscarmellose sodium showed the higher present of PPH dissolved as compared to the other formulations. It was concluded that PPH OFDTs were formulated successfully with acceptable physical and chemical properties with rapid disintegration in the oral cavity, rapid onset of action, and enhanced patient compliance. It was found that F10 showed good stability upon storage at 25 and 40 degrees C for 3 months. Formulation of PPH OFDTs can result in a significant improvement in the PPH bioavailability since the first pass metabolism will be avoided. PMID- 29158721 TI - Knowledge of community pharmacists about the risks of medication use during pregnancy in central region of Saudi Arabia. AB - Background: Community pharmacists (CPs) are the most accessible health care provider to the public, and they have huge duties to improve medication use especially among the pregnant women in their community. The objective of this study was to evaluate knowledge of CPs about the medication safety during pregnancy. Methods: A prospective cross-sectional survey was carried out over practicing community pharmacists in a capital of Saudi Arabia (SA). Pharmacists were asked about the safety of each medicine during pregnancy. It involved both prescription-only medications (POM) and over-the-counter (OTC) medications. Both descriptive and analytic statistics were utilized. For descriptive analysis, results were expressed as numbers, percentages and mean (+/-SD and 95% CI). Results: The response rate was (71.1%). Most of the respondents (69.6%) believed that alprazolam is not safe while 22% of respondents believed that it is used on basis of risk-benefit assessment. Also, most of CPs (65.2%) said that amoxicillin is safe, but a very few of CPs (11.7%) knew that tetracycline should be used only if potential benefits may outweigh the risk. Among non-prescribed analgesics, majority of CPs (92.6%) knew that acetaminophen is safe. About dietary supplements, 48.4% of CPs reported that Vitamin A supplements are not safe. There was significant difference observed between age groups of CPs in scores of knowledge test (P = 0.001). Conclusion: Community Pharmacists are the most accessible health care providers who can help pregnant women with their medications use there are still gaps in knowledge where educational interventions are needed. PMID- 29158722 TI - Synthesis and investigation of antimicrobial activities of nitrofurazone analogues containing hydrazide-hydrazone moiety. AB - In this research we synthesized and tested for in vitro antimicrobial activity 21 nitrofurazone analogues. The compounds we obtained were identified on the basis of 1H NMR and 13C NMR spectroscopy. The in vitro screening of antimicrobial properties of synthesized compounds revealed a wide spectrum of antimicrobial activity. Compounds 28, 29, 32-43, and 45-48 showed very high bactericidal effect towards Staphylococcus spp. ATTC and Bacillus spp. ATTC (MIC = 0.002-7.81 ug/ml and MBC = 0.002-31.25 ug/ml). The levels of activity of several compounds were far better than those of nitrofurantoin, ciprofloxacin or cefuroxime. PMID- 29158723 TI - The usefulness of traditional birth attendants to women living with HIV in resource-poor settings: the case of Mfuwe, Zambia. AB - Background: Although there is increased attention on the role of trained traditional birth attendants (TBAs) in maternal care, most of the research has mainly focused on providing evidence of the relevance of trained TBAs to women in general without a specific focus on women who are HIV positive, despite them being most vulnerable. Therefore, the aim of this study is to fill this gap by assessing the relevance of trained TBAs to women living with HIV in resource-poor settings by using Zambia as a case study. Methods: Our data collection consisted of two focus group discussions, one involving HIV-positive women utilizing trained TBAs and the other with women not utilizing TBAs. Additionally, in-depth interviews were conducted with trained TBAs and health workers. Thematic analysis was used to analyze the data. Results: In general, women living with HIV positively characterized the services of TBAs. In the face of an inefficient health system, trained TBAs were seen to be useful in providing efficient, cheap and quality care, counseling, and referral and logistical support, including treatment adherence support. Conclusion: In Zambia, trained TBAs and professional care are not mutually exclusive but complementary. There is no doubt that HIV positive women need professionals to handle complications and offer antiretroviral treatment to ensure prevention of mother to child transmission (PMTCT). However, additional "soft" services offered by trained TBAs are equally important in the promotion of maternal health care among HIV-positive women. Thus, it seems there is more to gain by systematically allowing trained TBAs to work alongside professionals in a well-coordinated and complementary manner. PMID- 29158724 TI - Comparative proteomic analysis between nitrogen supplemented and starved conditions in Magnaporthe oryzae. AB - Background: Fungi are constantly exposed to nitrogen limiting environments, and thus the efficient regulation of nitrogen metabolism is essential for their survival, growth, development and pathogenicity. To understand how the rice blast pathogen Magnaporthe oryzae copes with limited nitrogen availability, a global proteome analysis under nitrogen supplemented and nitrogen starved conditions was completed. Methods: M. oryzae strain 70-15 was cultivated in liquid minimal media and transferred to media with nitrate or without a nitrogen source. Proteins were isolated and subjected to unfractionated gel-free based liquid chromatography tandem mass spectrometry (LC-MS/MS). The subcellular localization and function of the identified proteins were predicted using bioinformatics tools. Results: A total of 5498 M. oryzae proteins were identified. Comparative analysis of protein expression showed 363 proteins and 266 proteins significantly induced or uniquely expressed under nitrogen starved or nitrogen supplemented conditions, respectively. A functional analysis of differentially expressed proteins revealed that during nitrogen starvation nitrogen catabolite repression, melanin biosynthesis, protein degradation and protein translation pathways underwent extensive alterations. In addition, nitrogen starvation induced accumulation of various extracellular proteins including small extracellular proteins consistent with observations of a link between nitrogen starvation and the development of pathogenicity in M. oryzae. Conclusion: The results from this study provide a comprehensive understanding of fungal responses to nitrogen availability. PMID- 29158725 TI - Nutritional supplement practices of professional Ugandan athletes: a cross sectional study. AB - Background: The use of nutritional supplements (NS) places athletes at great risk for inadvertent doping. Due to the paucity of data on supplement use, this study aimed to determine the proportion of Ugandan athletes using nutritional supplements and to investigate the athletes' motivation to use these supplements. Methods: A cross-sectional study was conducted in which an interviewer administered questionnaire was used to collect data from 359 professional athletes participating in individual (boxing, cycling, athletics) and team (basketball, rugby, football, netball, and volleyball) sports. The data were categorized, and a Chi-square test was used for statistical analysis. Results: Of the 359 athletes, 48 (13.4%) used nutritional supplements. Carbohydrate supplements, energy drinks, vitamin and mineral supplements, fish oils, and protein supplements were the most common supplements used by athletes. NS use was significantly more common among athletes who played rugby and basketball (X2 = 61.101, p < 0.0001), athletes who had played the sport for 5-10 years (X2 = 7.460, p = 0.024), and athletes who had attained a tertiary education (X2 = 33.377, p < 0.0001). The athletes' occupation had no bearing on whether they used supplements. Nutritionists/dieticians, retail stores and pharmacies were the most common sources of NS products, whereas health practitioners, online media and teammates were the most common sources of information regarding NS. Most athletes used NS to improve their physical performance and health. Conclusions: Compared to NS use by athletes elsewhere, NS use among Ugandan athletes was low. However, determinants of athlete NS use in the current study (category of sport and duration of time spent playing the sport) are similar to those reported elsewhere. PMID- 29158727 TI - Near Complete Response in a Patient with Classical Hodgkin Lymphoma Treated with Brentuximab Vedotin Concurrent with Radiation Therapy. AB - Brentuximab vedotin, an antibody drug conjugate that delivers monomethyl auristatin E into CD-30 expressing cells is FDA approved for the treatment of patients with Hodgkin lymphoma after the failure of autologous stem cell transplantation or at least 2 prior multi-agent chemotherapy regiments. This approval was based on a study that showed an overall response rate of 75% and complete remission in 34%. We present a case of a 24-year-old male with classical nodular sclerosing Hodgkin lymphoma who achieved near complete remission following 5 cycles of brentuximab concurrent with ISRT (involved site radiation therapy) following progression of first-line ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) and subsequent second-line ICE (ifosfamide, carboplatin, etoposide) chemotherapy. This case not only reiterates the efficacy of brentuximab vedotin in the third-line setting but introduces the role of and need for further clinical trials of combined radiotherapy with brentuximab in Hodgkin lymphoma patients following failure of second-line options. PMID- 29158726 TI - Enhanced aerobic exercise performance in women by a combination of three mineral Chelates plus two conditionally essential nutrients. AB - Background: Certain essential and conditionally essential nutrients (CENs) perform functions involved in aerobic exercise performance. However, increased intake of such nutrient combinations has not actually been shown to improve such performance. Methods: For 1 mo, aerobically fit, young adult women took either a combination of 3 mineral glycinate complexes (daily dose: 36 mg iron, 15 mg zinc, and 2 mg copper) + 2 CENs (daily dose: 2 g carnitine and 400 mg phosphatidylserine), or the same combination with generic mineral complexes, or placebo (n = 14/group). In Trial 1, before and after 1 mo, subjects were tested for 3 mile run time (primary outcome), followed by distance covered in 25 min on a stationary bike (secondary outcome), followed by a 90 s step test (secondary outcome). To test reproducibility of the run results, and to examine a lower dose of carnitine, a second trial was done. New subjects took either mineral glycinates + CENs (1 g carnitine) or placebo (n = 17/group); subjects were tested for pre- and post-treatment 3 mile run time (primary outcome). Results: In Trial 1, the mineral glycinates + CENs decreased 3 mile run time (25.6 +/- 2.4 vs 26.5 +/- 2.3 min, p < 0.05, paired t-test) increased stationary bike distance after 25 min (6.5 +/- 0.6 vs 6.0 +/- 0.8 miles, p < 0.05, paired t-test), and increased steps in the step test (43.8 +/- 4.8 vs 40.3 +/- 6.4 steps, p < 0.05, paired t test). The placebo significantly affected only the biking distance, but it was less than for the glycinates-CENs treatment (0.2 +/- 0.4. vs 0.5 +/- 0.1 miles, p < 0.05, ANOVA + Tukey). The generic minerals + CENs only significantly affected the step test (44.1 +/- 5.2 vs 41.0 +/- 5.9 steps, p < 0.05, paired t-test) In Trial 2, 3 mile run time was decreased for the mineral glycinates + CENs (23.9 +/ 3.1 vs 24.7 +/- 2.5, p < 0.005, paired t-test), but not by the placebo. All changes for Test Formula II or III were high compared to placebo (1.9 to 4.9, Cohen's D), and high for Test Formula II vs I for running and biking (3.2 & 3.5, Cohen's D). Conclusion: In summary, a combination of certain mineral complexes plus two CENs improved aerobic exercise performance in fit young adult women. PMID- 29158728 TI - Corrigendum: Analysis of Correlation between an Accelerometer-Based Algorithm for Detecting Parkinsonian Gait and UPDRS Subscales. AB - [This corrects the article on p. 431 in vol. 8, PMID: 28919877.]. PMID- 29158729 TI - Evaluation of Deformable Image Registration for Three-Dimensional Temporal Subtraction of Chest Computed Tomography Images. AB - Purpose: To perform lung image registration for reducing misregistration artifacts on three-dimensional (3D) temporal subtraction of chest computed tomography (CT) images, in order to enhance temporal changes in lung lesions and evaluate these changes after deformable image registration (DIR). Methods: In 10 cases, mutual information (MI) lung mask affine mapping combined with cross correlation (CC) lung diffeomorphic mapping was used to implement lung volume registration. With advanced normalization tools (ANTs), we used greedy symmetric normalization (greedy SyN) as a transformation model, which involved MI-CC-SyN implementation. The resulting displacement fields were applied to warp the previous (moving) image, which was subsequently subtracted from the current (fixed) image to obtain the lung subtraction image. Results: The average minimum and maximum log-Jacobians were 0.31 and 3.74, respectively. When considering 3D landmark distance, the root-mean-square error changed from an average of 20.82 mm for Pfixed to Pmoving to 0.5 mm for Pwarped to Pfixed. Clear shadows were observed as enhanced lung nodules and lesions in subtraction images. The lesion shadows showed lesion shrinkage changes over time. Lesion tissue morphology was maintained after DIR. Conclusions: DIR (greedy SyN) effectively and accurately enhanced temporal changes in chest CT images and decreased misregistration artifacts in temporal subtraction images. PMID- 29158730 TI - Postoperative MR Defecography following Failed STARR Procedure for Obstructive Defecation Syndrome: A Three-Centre Experience. AB - Aim: To describe the abnormalities at MR imaging and related complaints in patients with poor outcome after STARR procedure. Materials and Methods: The medical records of 21 symptomatic patients from centre 1, 31 patients from centre 2, and 63 patients from centre 3 were reviewed with regard to findings at MR defecography and related symptoms. Results: Regardless of the centre, most relevant imaging features and related complaints were (a) impaired emptying (82.11%), related complaint ODS; (b) persistent rectocele >2 cm and intussusception (39.3%), split evacuation and digitation; (c) pelvic organ descent on straining (39.8%), prolapse sensation; (d) small neorectum and loss of contrast (32.5%), urgency and incontinence; (e) anastomotic stricture and granuloma (28.4%), pain; and (f) nonrelaxing puborectalis muscle (19.5%), tenesmus. Less frequent findings included rectal pocket formation (5.6%) and rectovaginal sinus tract (1.6%). Patients were referred to MR imaging with an average time interval of 5 +/- 2, 4 +/- 1, and 2 +/- 1 years in the three centres, respectively, and only rarely by the same surgeon who performed the operation: 1/21 (4.8%) in centre 1, 3/39 (7.7%) in centre 2, and 9/63 (14.3%) in centre 3. Conclusion: Most surgeons involved in STARR operation with subsequent poor outcome do not rely on MR imaging. PMID- 29158731 TI - Routine Drainage of Colorectal Anastomoses: An Evidence-Based Review of the Current Literature. AB - Background: The use of prophylactic drainage after colorectal anastomoses has been long debated. This report aimed to review the current literature discussing routine drainage of colorectal anastomoses highlighting two opposite perspectives (prodrainage and antidrainage) to demonstrate the clinical utility of prophylactic drainage and its proper indications. Methods: An organized literature search was conducted querying electronic databases and Google Scholar. Articles evaluating the role of routine prophylactic drainage after colorectal anastomosis were included and divided into two categories: articles supporting the use of drains (prodrainage) and articles disputing routine drainage (antidrainage). Results: There were seven systematic reviews and/or meta analyses, one Cochrane review, one randomized controlled trial, and six prospective or retrospective cohort studies. Six studies supported prophylactic drainage of colorectal anastomoses; the quality of these studies ranged between grade II and IV. Nine studies recommended against the use of prophylactic drainage, six studies were grade I, one was grade II, and two were grade IV. Conclusion: Since level I evidence studies including well-designed randomized trials and meta-analyses recommended against the use of pelvic drainage as a routine practice after colorectal anastomoses, we conclude no significant impact of routine drainage on the risk of anastomotic leakage after colorectal anastomoses. PMID- 29158732 TI - What Do Anesthesiologists Know about p Values, Confidence Intervals, and Correlations: A Pilot Survey. AB - Background: Statistical methods form the basis for clinical decision-making in evidence-based anesthesia. Data on the knowledge of anesthesiologists about statistics are lacking. This pilot study aims to provide a first impression of the anesthesiologists' understanding of commonly used concepts in statistics. Methods: A cross-sectional pilot survey was performed at a major international anesthesia conference. The questionnaire consisted of three basic multiple-choice questions on the topics "p value," "confidence interval," and "correlation." Results of the questions are reported as percentage of correct answers (95% confidence interval). Results: 65 questionnaires were analyzed. Forty participants were male, and mean age was 40 (standard deviation: 10) years. The question addressing the p value was correctly answered by 15% (95% CI: 8 to 27%) of respondents. The question concerning the 95% confidence interval was answered correctly by 28% (95% CI: 18 to 40%) of participants. For the question about correlation, a correct answer was given by 52% (95% CI: 40 to 64%). None of the participants answered all questions correctly, and 19 participants provided a wrong answer to all questions. Conclusions: Anesthesiologists seem to demonstrate a poor understanding of statistical key concepts. Further studies are needed to address statistical knowledge gaps among anesthesiologists more comprehensively. PMID- 29158734 TI - A Study of the Importance of Clonus Symptoms in Patients with Tramadol Poisoning. AB - Objectives: Clinical studies to reduce the side effects of tramadol, such as seizure, are necessary. Owing to the high prevalence of tramadol consumption and subsequent complications that result from seizures, the aim of the present study was to find a relationship between clonus and prediction of seizure outcome in patients with tramadol overdose. This can be used to determine the need for essential actions if a significant indicator of preventive medical measures is observed. Methods: In this case-control study, three groups of patients poisoned with tramadol and with marked ankle clonus were evaluated. A sample size of 50 patients per group was calculated using the Cohen first method. The data were analyzed using SPSS16 software. Results: All patients with ankle clonus were evaluated. Seizures occurred most commonly in patients aged 21-25 years or younger. The patients who received the preventive medication of magnesium sulfate were seizure-free for 72 h after admission. Conclusion: It is recommended that, for all patients referred with tramadol poisoning who have symptoms of ankle clonus, the administration of magnesium sulfate should be considered in addition to medication for the prevention of seizures and arrhythmias. PMID- 29158733 TI - Effect of Ultraviolet Light Irradiation Combined with Riboflavin on Different Bacterial Pathogens from Ocular Surface Infection. AB - In order to study Staphylococcus epidermis and Staphylococcus aureus in vitro viability after the exposure to ultraviolet (UV) light and riboflavin, twelve strains of Staphylococcus epidermis and twelve strains of Staphylococcus aureus were isolated from patients with bacterial keratitis. The growth situation of Staphylococcus epidermidis and Staphylococcus aureus under different experimental conditions was qualitatively observed. The number of colonies surviving bacteria was counted under different UV light power and different exposure time. The experiment showed that there was no inhibition effect on the growth of bacteria using riboflavin alone. In UV alone group and UV-riboflavin group, inhibition effect on the bacteria growth was found. The UV-riboflavin combination had better inhibition effect on bacteria than UV irradiation alone. The amount of bacteria in the UV-riboflavin group was decreased by 99.1%~99.5% and 54.8%~64.6% in the UV alone group, when the UV light power was 10.052 mW/cm2 and the irradiation time was 30 min. Moreover, with the increase of the UV power or irradiation time, the survival rates of bacteria were rapidly reduced. Compared with Staphylococcus aureus, Staphylococcus epidermis was more easily to be killed under the action of UV light combined with riboflavin. PMID- 29158735 TI - Correlation between Insulin Resistance and Thyroid Nodule in Type 2 Diabetes Mellitus. AB - Objective: The present study explored the association between insulin resistance (IR) and the clinical characteristics of thyroid nodules in patients with type 2 diabetes mellitus (T2DM). Methods: All the patients were newly diagnosed with T2DM. 201 patients with thyroid nodule disease and 308 patients without the nodular thyroid disease. The participants were evaluated by relevant examination. Correlation analyses and regression analyses were performed to examine the relationships between the two groups. Results: HOMA-IR values, serum FT4 (free thyroxine) levels, and age were higher in the thyroid nodule group than in the control group. The proportion of women in the thyroid nodule group is greater than the proportion of women in the control group. Logistic regression analysis showed that age, sex, FT4, and HOMA-IR were positive factors for thyroid nodule. The volume and size of the thyroid nodule were positively correlated with HOMA IR, irrespective of gender. The thyroid nodule volume and size and the TSH (thyroid stimulating hormone) were greater in females than in males, whereas FT3 (free triiodothyronine) was lower in females. Conclusion: IR might be a risk factor for thyroid nodule. Whether alleviating the IR might slow the growth, or diminish the volume and size of the thyroid nodules, is yet to be elucidated. PMID- 29158736 TI - Hollow-Fibre-Supported Dispersive Liquid-Liquid Microextraction for Determination of Atrazine and Triclosan in Aqueous Samples. AB - We report the application of the dispersive liquid-liquid microextraction coupled to hollow-fibre membrane-assisted liquid-phase microextraction and its application for extraction of atrazine and triclosan. Under optimum conditions, namely, 25 MUL of a 1 : 4 chlorobenzene : ethyl acetate mixture dispersed in 1 mL of aqueous sample, 10% (m/v) NaCl, a magnetic stirrer speed at 600 rpm, and 10 minutes' extraction time with toluene-filled fibre as the acceptor phase, the method demonstrates sufficient figures of merit. These include linearity (R2 >= 0.9975), intravial precision (%RSD <= 7.6), enrichment factors (127 and 142), limits of detection (0.0081 and 0.0169 ug/mL), and recovery from river water and sewerage (96-101%). The relatively high detection limits are attributed to the flame ionization detector which is less preferred than a mass spectrometer in trace analyses. This is the first report of a homogenous mixture of the dispersed organic solvent in aqueous solutions and its employment in extraction of organic compounds from aqueous solutions. It therefore adds yet another candidate in the pool of miniaturised solvent microextraction techniques. PMID- 29158737 TI - Herpes Simplex Virus and Human Papillomavirus Coinfections in Hyperimmunoglobulin E Syndrome Presenting as a Conjunctival Mass Lesion. AB - Hyperimmunoglobulin E syndrome (HIES) or Job's syndrome is a rare immunodeficiency disease with less than 200 cases reported worldwide, among which few cases are reported with lesions due to herpes simplex virus (HSV) or human papillomavirus (HPV). This case study presents a rare case of HIES with coinfection of HSV and HPV. A 12-year-old boy, previously diagnosed with HIES, presented with a large conjunctival mass lesion. The presence of HPV in the lesion was confirmed by biopsy and by using the line-probe assay method to detect the HPV genome. However, the mass lesion did not respond to anti-HPV therapy with topical interferon-alpha2b (IFN-alpha2b) and oral cimetidine but improved promptly after intravenous (IV) acyclovir, which is often administered for cutaneous herpetic lesions. This suggested the presence of HSV in the conjunctival mass. Review of pathology and HSV immunohistochemical staining confirmed the presence of HSV as a coinfection. The likelihood that the mass arose from an abnormal host response to HSV and HPV due to HIES was considered, but coexisting infection with these two viruses and HIES has not been reported in the literature; therefore, such cases require further investigation. PMID- 29158738 TI - Mitochondria: More than Just "Power Plants" in Stem Cells. PMID- 29158739 TI - Human ADMC-Derived Adipocyte Thermogenic Capacity Is Regulated by IL-4 Receptor. AB - Type two innate immune system is anti-inflammatory and may play an important role as the means whereby "browning" is induced in subcutaneous adipocytes. It was shown that IL-4 may influence the fate of adipose cell precursors by promoting differentiation towards more thermogenic adipocytes in mice. Here, we investigated the influence of IL-4 and IL-4 receptor, a type two immune cytokine pathway, on the metabolic activity and thermogenic potential of human adipocytes differentiated from adipose-derived mesenchymal stem cells (ADMSCs) obtained from subcutaneous samples of healthy women undergoing abdominoplasty. Western blot analysis, qPCR, and biochemical analyses were performed 10 days after ADMSC differentiation into mature adipocytes was induced. IL-4 receptor was expressed in both precursor and differentiated adipocytes, and IL-4 treatment increased phosphorylation Y641 of signal transducer and activator of transcription 6 (STAT6) in both cell types. IL-4 treatment also increased expression of thermogenic proteins PGC-1alpha, UCP-1, and CITED1. In addition, IL-4 increased the secretion of adiponectin, leptin, and FGF21 and promoted lipolysis in differentiated adipocytes. In conclusion, IL-4 may directly modulate differentiation of human adipocytes towards a beige phenotype acting through IL-4 receptors on both adipose precursors and differentiated human adipocytes, metabolic effect that must be considered in some antiallergic drugs. PMID- 29158740 TI - Xeno-Free Strategies for Safe Human Mesenchymal Stem/Stromal Cell Expansion: Supplements and Coatings. AB - Human mesenchymal stem/stromal cells (hMSCs) have generated great interest in regenerative medicine mainly due to their multidifferentiation potential and immunomodulatory role. Although hMSC can be obtained from different tissues, the number of available cells is always low for clinical applications, thus requiring in vitro expansion. Most of the current protocols for hMSC expansion make use of fetal bovine serum (FBS) as a nutrient-rich supplement. However, regulatory guidelines encourage novel xeno-free alternatives to define safer and standardized protocols for hMSC expansion that preserve their intrinsic therapeutic potential. Since hMSCs are adherent cells, the attachment surface and cell-adhesive components also play a crucial role on their successful expansion. This review focuses on the advantages/disadvantages of FBS-free media and surfaces/coatings that avoid the use of animal serum, overcoming ethical issues and improving the expansion of hMSC for clinical applications in a safe and reproducible way. PMID- 29158743 TI - Role of Epigenetic Modifications in Pathology of COPD. PMID- 29158742 TI - The First Symposium on COPD and Therapeutic Approaches 2016, Tehran, Iran. PMID- 29158741 TI - Polysaccharide Hydrogels Support the Long-Term Viability of Encapsulated Human Mesenchymal Stem Cells and Their Ability to Secrete Immunomodulatory Factors. AB - While therapeutically interesting, the injection of MSCs suffers major limitations including cell death upon injection and a massive leakage outside the injection site. We proposed to entrap MSCs within spherical particles derived from alginate, as a control, or from silanized hydroxypropyl methylcellulose (Si HPMC). We developed water in an oil dispersion method to produce small Si-HPMC particles with an average size of about 68 MUm. We evidenced a faster diffusion of fluorescein isothiocyanate-dextran in Si-HPMC particles than in alginate ones. Human adipose-derived MSCs (hASC) were encapsulated either in alginate or in Si HPMC, and the cellularized particles were cultured for up to 1 month. Both alginate and Si-HPMC particles supported cell survival, and the average number of encapsulated hASC per alginate and Si-HPMC particle (7102 and 5100, resp.) did not significantly change. The stimulation of encapsulated hASC with proinflammatory cytokines resulted in the production of IDO, PGE2, and HGF whose concentration was always higher when cells were encapsulated in Si-HPMC particles than in alginate ones. We have demonstrated that Si-HPMC and alginate particles support hASC viability and the maintenance of their ability to secrete therapeutic factors. PMID- 29158744 TI - Update Pathogenesis of COPD. PMID- 29158745 TI - "Mild" COPD: What Spirometry Conceals! PMID- 29158746 TI - Activity-Related Dyspnoea in Chronic Pulmonary Diseases: New Mechanistic Insights. PMID- 29158747 TI - Pulmonary Rehabilitation for COPD. PMID- 29158748 TI - Lung Volume Reduction in Advanced Emphysema. PMID- 29158749 TI - Impact of Air Pollution on COPD; Underlying Mechanisms. PMID- 29158750 TI - Does Noninvasive Ventilation Have a Role in Severe COPD? PMID- 29158752 TI - Does Noninvasive Ventilation Have a Role in Severe COPD? PMID- 29158751 TI - High Flow Nasal Cannula, Is There a Role in COPD? PMID- 29158753 TI - The Air We Breathe: Effect of Environmental Exposures on COPD. PMID- 29158754 TI - The Relationship between COPD and Cardiovascular Disease. PMID- 29158755 TI - Asthma, COPD & ACOS: -Omics Approach to Refine Treatable Traits in These Conditions. PMID- 29158756 TI - Mitochondrial Dysfunction as a Therapeutic Target in COPD. PMID- 29158757 TI - Neutrophil Priming in COPD Patients by Bronchitis Visualized by CT-Scans. PMID- 29158758 TI - Eosinophilic COPD: a Separate Disease Phenotype Warranting Specific Treatment. PMID- 29158759 TI - The Asthma COPD Overlap Syndrome: ACOS Epidemiology and Historical Perspective. PMID- 29158760 TI - Effect of Global Climate Change-Related Factors on COPD Morbidity. PMID- 29158761 TI - Eosinophilic COPD: a Separate Disease Phenotype Warranting Specific Treatment. PMID- 29158762 TI - The Asthma COPD Overlap Syndrome: ACOS. Epidemiology and Historical Perspective. PMID- 29158763 TI - Effect of Global Climate Change-Related Factors on COPD Morbidity. PMID- 29158764 TI - Fetal and preterm infant microbiomes: a new perspective of necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) is a devastating condition of hospitalized preterm infants. Numerous studies have attempted to identify the cause of NEC by examining the immunological features associated with pathogenic microorganisms. No single organism has proven responsible for the disease; however, immunological studies are now focused on the microbiome. Recent research has investigated the numerous bacterial species residing in the body and their role in diseases in preterm infants. The timing of initial microbial colonization is a subject of interest. The microbiome appears to transfer from the mother to the newborn, as well as to the fetus. Cross-talk between the fetus and fetal microbiome takes place continuously to generate a unique immune system. This review examined the transfer of the microbiome to the human fetus, and its potential relationship with NEC. PMID- 29158765 TI - Usefulness of the Korean Developmental Screening Test for infants and children for the evaluation of developmental delay in Korean infants and children: a single-center study. AB - Purpose: To evaluate the usefulness of the Korean Developmental Screening Test (K DST) for infants and children for developmental delay assessment. Methods: This study was based on retrospective studies of the results of the K-DST, Preschool Receptive-Expressive Language Scale (PRES), Sequenced Language Scale for Infants (SELSI), Childhood Autism Rating Scale (CARS), Modified Checklist for Autism in Toddlers (M-CHAT), electroencephalography, magnetic resonance imaging, and extensive tests conducted in 209 of 1,403 patients, of whom 758 underwent the K DST at the Korea University Guro Hospital between January 2015 and December 2016 and 645 were referred from local clinics between January 2015 and June 2016. Results: Based on the K-DST results, the male children significantly more frequently required further or follow-up examination than the female children in most test sections, except for gross motor. The male children had notably lower mean scores than the female children. The PRES/SELSI results showed that when more further or follow-up evaluations were required in the K-DST communication section, significantly more problems in language delay or disorder emerged. When further or follow-up evaluation was required in the cognitive section in the CARS/M-CHAT, the possibility of autism increased significantly. A child tended to score low in the CARS test and show autism when further or follow-up evaluation was recommended in the K-DST. Conclusion: This study demonstrated the usefulness of the K-DST as a screening test early in the development of infants and children in Korea. Data of normal control groups should be examined to determine the accuracy of this investigation. PMID- 29158766 TI - Local-food-based complementary feeding for the nutritional status of children ages 6-36 months in rural areas of Indonesia. AB - Purpose: This study aimed to evaluate a pilot project of the Nursing Feeding Center "Posyandu Plus" (NFCPP) through local food-based complementary feeding (LFCF) program designed to improve the nutritional status of children aged 6-36 months at community health centers in Indonesia. Methods: A quasi-experimental design was used to obtain data regarding the nutritional status of 109 children who participated in the project from 6 rural areas. The NFCPP was conducted for 9 weeks, comprising 2 weeks of preintervention, 6 weeks of intervention, and one week of postintervention. The LFCF intervention consisted of 12 sets of recipes to be made by mothers and given to their children 4 times daily over 6 weeks. The weight-for-age z score (WAZ), height-for-age z score (HAZ), weight-for-height z score (WHZ), and body mass index-for-age z score (BAZ) were calculated using World Health Organization Anthro Plus version 1.0.3. Results: LFCF intervention significantly increased WHZ, WAZ, and BAZ scores but decreased HAZ scores (P<0.001). Average scores of WHZ (0.96+/-0.97) and WAZ (0.45+/-0.72) increased; BAZ increased (1.12+/-0.93) after 6 weeks of LFCF. WAZ scores postintervention were 50.5% of normal, and WHZ scores were 77.1% of normal. However, the HAZ score decreased by 0.53+/-0.52, which indicated 57.8% had short stature. Conclusion: The NFCPP program with LFCF intervention can improve the nutritional status of children in rural areas. It should be implemented as a sustained program for better provision of complementary feeding during the period of lactation using local food made available at community health centers. PMID- 29158767 TI - Screening of SHOX gene sequence variants in Saudi Arabian children with idiopathic short stature. AB - Purpose: Short stature affects approximately 2%-3% of children, representing one of the most frequent disorders for which clinical attention is sought during childhood. Despite assumed genetic heterogeneity, mutations or deletions in the short stature homeobox-containing gene (SHOX) are frequently detected in subjects with short stature. Idiopathic short stature (ISS) refers to patients with short stature for various unknown reasons. The goal of this study was to screen all the exons of SHOX to identify related mutations. Methods: We screened all the exons of SHOX for mutations analysis in 105 ISS children patients (57 girls and 48 boys) living in Taif governorate, KSA using a direct DNA sequencing method. Height, arm span, and sitting height were recorded, and subischial leg length was calculated. Results: A total of 30 of 105 ISS patients (28%) contained six polymorphic variants in exons 1, 2, 4, and 6. One mutation was found in the DNA domain binding region of exon 4. Three of these polymorphic variants were novel, while the others were reported previously. There were no significant differences in anthropometric measures in ISS patients with and without identifiable polymorphic variants in SHOX. Conclusion: In Saudi Arabia ISS patients, rather than SHOX, it is possible that new genes are involved in longitudinal growth. Additional molecular analysis is required to diagnose and understand the etiology of this disease. PMID- 29158768 TI - Acute pancreatitis in hand, foot and mouth disease caused by Coxsackievirus A16: case report. AB - Coxsackievirus A16 (CA16), which primarily causes hand, foot, and mouth disease (HFMD), is associated with complications, such as encephalitis, acute flaccid paralysis, myocarditis, pericarditis, and shock. However, no case of pancreatitis associated with CA16 has been reported in children. We report a case of CA16 associated acute pancreatitis in a 3-year-old girl with HFMD. She was admitted because of poor oral intake and high fever for 1 day. Maculopapular rashes on both hands and feet and multiple vesicles on the soft palate were observed on physical examination. She was treated conservatively with intravenous fluids. On the fourth hospital day, she had severe abdominal pain and vomiting. The serum levels of amylase and lipase were remarkably elevated (amylase, 1,902 IU/L; reference range, 28-100 IU/L; lipase, >1,500 IU/L; reference range, 13-60 IU/L), and ultrasonography showed diffuse swelling of the pancreas with a small amount of ascites. The real-time reverse transcription polymerase chain reaction result from a stool sample was positive for CA16. CA16 can cause acute pancreatitis, and should be considered in the differential diagnosis of abdominal pain in children with HFMD. PMID- 29158769 TI - Physicians' duty to recontact and update genetic advice. AB - This perspective addresses whether physicians have a duty to recontact former or current patients to update clinical advice based on newly discovered genomic information. Genetic information is unique compared with other medical data in that the underlying data do not appreciably change during the patients' lifetime, but the clinical significance of that information will continue to evolve. Based on relevant case law and guidelines, there is no general, established legal duty for physicians to affirmatively recontact former or current patients to update clinical advice based on newly discovered genetic information. However, integration of genomics into clinical practice is advancing quickly, and there may be limited, specific situations where a physician may have a duty to provide updated genetic information. PMID- 29158770 TI - Does the enterolactone (ENL) affect fatty acid transporters and lipid metabolism in liver? AB - Background: NAFLD as a result of inappropriate diet and obesity, may progress to sever conditions such as: type 2 diabetes mellitus or steatohepatitis, and has recently become a prevalent topic of numerous investigations. Due to its dangerous aftermaths, finding new substances, such as polyphenols and their derivatives, which might reduce liver steatosis is the main target of research into NAFLD treatment. Hence, the aim of the present study was to evaluate the effect(s) of enterolactone (ENL), a metabolite of secoisolariciresinol (SECO), on lipid metabolism together with changes in the expression of fatty acid transporters in fatty liver. Methods: The experiments were conducted on HepG2 cells incubated with either ENL and/or palmitic acid during 16 h exposure. The expression of selected fatty acid transport proteins: FATP2, FATP5, CD36, FABPpm, ABCA1, MTP, ACBP and L-FABP, as well as the proteins directly involved in lipogenesis (FAS), oxidation pathway (CPT 1), and lipid metabolism (PPARalpha, LXR, SREBP1c, pAMPK) was estimated by Western Blot. Intra and extracellular lipid contents were assessed by Gas-Liquid Chromatography. The data was analyzed with two-way analysis of variance (ANOVA), and results were considered to be statistically significant at p <= 0.05. Results: ENL stimulated extracellular efflux of free fatty acids (FFA) and triacylglicerols (TAG) to the medium, while, it had no influence on FATP-family mediated intracellular fatty acid uptake. Moreover, ENL decreased the expression of CPT 1, pAMPK, PPARalpha, increased SREBP1c and had no effect on LXR, and FAS content. Conclusions: The findings of our study demonstrate that ENL had opposite effect on liver steatosis in comparison with other polyphenols what suggests that it may be an inactive metabolite. ENL did not affect significantly the intracellular accumulation of FFA, DAG and TAG, yet it promoted their extracellular efflux. Furthermore, it inhibited beta-oxydation and intracellular lipid metabolism what may contribute to the progression of NAFLD. PMID- 29158771 TI - Implementation and evaluation of community-based drop-in centres for breastfeeding support in Victoria, Australia. AB - Background: While Australia has high breastfeeding initiation, there is a sharp decline in the first weeks postpartum and this continues throughout the first year. Supporting breastfeeding In Local Communities (SILC) was a three-arm cluster randomised controlled trial to determine whether early home-based breastfeeding support by a maternal and child health nurse (SILC-MCHN), with or without access to a community-based breastfeeding drop-in centre, increased the proportion of infants receiving any breast milk at three, four and six months. The trial was conducted in ten Local Government Areas (LGAs) in Victoria, Australia.The primary aim of this paper is to describe the three drop-in centres established during the trial; and the profile of women who accessed them. The secondary aim is to explore the views and experiences of the drop-in centre staff, and the challenges faced in establishing and maintaining a breastfeeding drop-in centre in the community. Methods: Evaluation of the three LGAs with drop in centres was multifaceted and included observational visits and field notes; data collected from attendance log books from each drop-in centre; a written survey and focus groups with maternal and child health (MCH) nurses who ran the drop-in centres; and semi-structured interviews with MCH coordinators of the participating LGAs. Results: The three LGAs developed and ran different models of breastfeeding drop-in centres. They reported challenges in finding convenient, accessible locations. Overall, attendance was lower than expected, with an average of only one attendee per session. Two global themes were identified regarding staff views: implementation challenges, encompassing finding accessible, available space, recruiting volunteers to provide peer support, and frustration when women did not attend; and the work of SILC-MCHNs, including themes of satisfying and rewarding work, juggling roles, and benefits to women, babies and the community. Conclusion: Providing community-based breastfeeding support was satisfying for the drop-in centre staff but proved difficult to implement, reflected by the lower than anticipated attendances at all of the drop in centres. Interventions to increase breastfeeding in complex community settings require sufficient time to build partnerships with the existing services and the target population; to understand when and how to offer interventions for optimum benefit. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12611000898954. PMID- 29158772 TI - Correction to: Effects of early feeding on growth velocity and overweight/obesity in a cohort of HIV unexposed South African infants and children. AB - [This corrects the article DOI: 10.1186/s13006-015-0041-x.]. PMID- 29158773 TI - Construction of an miRNA-Regulated Pathway Network Reveals Candidate Biomarkers for Postmenopausal Osteoporosis. AB - We aimed to identify risk pathways for postmenopausal osteoporosis (PMOP) via establishing an microRNAs- (miRNA-) regulated pathway network (MRPN). Firstly, we identified differential pathways through calculating gene- and pathway-level statistics based on the accumulated normal samples using the individual pathway aberrance score (iPAS). Significant pathways based on differentially expressed genes (DEGs) using DAVID were extracted, followed by identifying the common pathways between iPAS and DAVID methods. Next, miRNAs prediction was implemented via calculating TargetScore values with precomputed input (log fold change (FC), TargetScan context score (TSCS), and probabilities of conserved targeting (PCT)). An MRPN construction was constructed using the common genes in the common pathways and the predicted miRNAs. Using false discovery rate (FDR) < 0.05, 279 differential pathways were identified. Using the criteria of FDR < 0.05 and |log?FC| >= 2, 39 DEGs were retrieved, and these DEGs were enriched in 64 significant pathways identified by DAVID. Overall, 27 pathways were the common ones between two methods. Importantly, MAPK signaling pathway and PI3K-Akt signaling pathway were the first and second significantly enriched ones, respectively. These 27 common pathways separated PMOP from controls with the accuracy of 0.912. MAPK signaling pathway and PI3K/Akt signaling pathway might play crucial roles in PMOP. PMID- 29158774 TI - Psychosocial Factors in Children's Obesity: Examples from an Innovative Line of Inquiry. AB - In recent years, researchers and policymakers have recognized that obesity in childhood is not simply a medical problem, but is a complex social and psychological phenomenon. Our research team used an interpersonal and intrapersonal risk model to examine the psychosocial aspects of obesity among rural children. In this article, we describe how the global study of children's obesity has broadened over the last 10 to 15 years, and we present our model of interpersonal and intrapersonal risk factors, which includes complex pathways with many psychosocial variables. We then describe a large prospective longitudinal study of children in grades 1 through 4, and highlight findings from five studies guided by this model. This work illustrates opportunities for developmental scientists and practitioners to join transdisciplinary teams to develop more effective prevention and intervention programs for children. PMID- 29158775 TI - Evaluation of microbial globin promoters for oxygen-limited processes using Escherichia coli. AB - Oxygen-responsive promoters can be useful for synthetic biology applications, however, information on their characteristics is still limited. Here, we characterized a group of heterologous microaerobic globin promoters in Escherichia coli. Globin promoters from Bacillus subtilis, Campylobacter jejuni, Deinococcus radiodurans, Streptomyces coelicolor, Salmonella typhi and Vitreoscilla stercoraria were used to express the FMN-binding fluorescent protein (FbFP), which is a non-oxygen dependent marker. FbFP fluorescence was monitored online in cultures at maximum oxygen transfer capacities (OTRmax) of 7 and 11 mmol L-1 h-1. Different FbFP fluorescence intensities were observed and the OTRmax affected the induction level and specific fluorescence emission rate (the product of the specific fluorescence intensity multiplied by the specific growth rate) of all promoters. The promoter from S. typhi displayed the highest fluorescence emission yields (the quotient of the fluorescence intensity divided by the scattered light intensity at every time-point) and rate, and together with the promoters from D. radiodurans and S. coelicolor, the highest induction ratios. These results show the potential of diverse heterologous globin promoters for oxygen-limited processes using E. coli. PMID- 29158776 TI - Genomics and prevalence of bacterial and archaeal isolates from biogas-producing microbiomes. AB - Background: To elucidate biogas microbial communities and processes, the application of high-throughput DNA analysis approaches is becoming increasingly important. Unfortunately, generated data can only partialy be interpreted rudimentary since databases lack reference sequences. Results: Novel cellulolytic, hydrolytic, and acidogenic/acetogenic Bacteria as well as methanogenic Archaea originating from different anaerobic digestion communities were analyzed on the genomic level to assess their role in biomass decomposition and biogas production. Some of the analyzed bacterial strains were recently described as new species and even genera, namely Herbinix hemicellulosilytica T3/55T, Herbinix luporum SD1DT, Clostridium bornimense M2/40T, Proteiniphilum saccharofermentans M3/6T, Fermentimonas caenicola ING2-E5BT, and Petrimonas mucosa ING2-E5AT. High-throughput genome sequencing of 22 anaerobic digestion isolates enabled functional genome interpretation, metabolic reconstruction, and prediction of microbial traits regarding their abilities to utilize complex bio polymers and to perform specific fermentation pathways. To determine the prevalence of the isolates included in this study in different biogas systems, corresponding metagenome fragment mappings were done. Methanoculleus bourgensis was found to be abundant in three mesophilic biogas plants studied and slightly less abundant in a thermophilic biogas plant, whereas Defluviitoga tunisiensis was only prominent in the thermophilic system. Moreover, several of the analyzed species were clearly detectable in the mesophilic biogas plants, but appeared to be only moderately abundant. Among the species for which genome sequence information was publicly available prior to this study, only the species Amphibacillus xylanus, Clostridium clariflavum, and Lactobacillus acidophilus are of importance for the biogas microbiomes analyzed, but did not reach the level of abundance as determined for M. bourgensis and D. tunisiensis. Conclusions: Isolation of key anaerobic digestion microorganisms and their functional interpretation was achieved by application of elaborated cultivation techniques and subsequent genome analyses. New isolates and their genome information extend the repository covering anaerobic digestion community members. PMID- 29158777 TI - Combined genome and transcriptome sequencing to investigate the plant cell wall degrading enzyme system in the thermophilic fungus Malbranchea cinnamomea. AB - Background: Genome and transcriptome sequencing has greatly facilitated the understanding of biomass-degrading mechanisms in a number of fungal species. The information obtained enables the investigation and discovery of genes encoding proteins involved in plant cell wall degradation, which are crucial for saccharification of lignocellulosic biomass in second-generation biorefinery applications. The thermophilic fungus Malbranchea cinnamomea is an efficient producer of many industrially relevant enzymes and a detailed analysis of its genomic content will considerably enhance our understanding of its lignocellulolytic system and promote the discovery of novel proteins. Results: The 25-million-base-pair genome of M. cinnamomea FCH 10.5 was sequenced with 225* coverage. A total of 9437 protein-coding genes were predicted and annotated, among which 301 carbohydrate-active enzyme (CAZyme) domains were found. The putative CAZymes of M. cinnamomea cover cellulases, hemicellulases, chitinases and pectinases, equipping the fungus with the ability to grow on a wide variety of biomass types. Upregulation of 438 and 150 genes during growth on wheat bran and xylan, respectively, in comparison to growth on glucose was revealed. Among the most highly upregulated CAZymes on xylan were glycoside hydrolase family GH10 and GH11 xylanases, as well as a putative glucuronoyl esterase and a putative lytic polysaccharide monooxygenase (LPMO). AA9-domain-containing proteins were also found to be upregulated on wheat bran, as well as a putative cutinase and a protein harbouring a CBM9 domain. Several genes encoding secreted proteins of unknown function were also more abundant on wheat bran and xylan than on glucose. Conclusions: The comprehensive combined genome and transcriptome analysis of M. cinnamomea provides a detailed insight into its response to growth on different types of biomass. In addition, the study facilitates the further exploration and exploitation of the repertoire of industrially relevant lignocellulolytic enzymes of this fungus. PMID- 29158779 TI - The treatment of acute bronchiolitis: past, present and future. AB - Acute bronchiolitis treatment: little has changed from late 19th century to nowadays, promising strategies incoming http://ow.ly/BmH230aWoXr. PMID- 29158780 TI - An interesting case of undiagnosed pleural effusion. AB - Pulmonary embolism is an important cause of undiagnosed pleural effusion http://ow.ly/HDLx30bVVa7. PMID- 29158778 TI - Helicobacter pylori and gut microbiota in multiple sclerosis versus Alzheimer's disease: 10 pitfalls of microbiome studies. AB - Alteration of microbiota has been associated with intestinal, inflammatory, and neurological diseases. Abundance of "good bacteria" such as Bifidobacterium, or their products have been generally believed to be beneficial for any diseases, while "bad bacteria" such as pathogenic Helicobacter pylori are assumed to be always detrimental for hosts. However, this is not the case when we compare and contrast the association of the gut microbiota with two neurological diseases, multiple sclerosis (MS) and Alzheimer's disease (AD). Following H. pylori infection, pro-inflammatory T helper (Th)1 and Th17 immune response are initially induced to eradicate bacteria. However, H. pylori evades the host immune response by inducing Th2 cells and regulatory T cells (Tregs) that produce anti inflammatory interleukin (IL)-10. Suppression of anti-bacterial Th1/Th17 cells by Tregs may enhance gastric H. pylori propagation, followed by a cascade reaction involving vitamin B12 and folic acid malabsorption, plasma homocysteine elevation, and reactive oxygen species induction. This can damage the blood-brain barrier (BBB), leading to accumulation of amyloid-beta in the brain, a hallmark of AD. On the other hand, this suppression of pro-inflammatory Th1/Th17 responses to H. pylori has protective effects on the hosts, since it prevents uncontrolled gastritis as well as suppresses the induction of encephalitogenic Th1/Th17 cells, which can mediate neuroinflammation in MS. The above scenario may explain why chronic H. pylori infection is positively associated with AD, while it is negatively associated with MS. Lastly, we list "10 pitfalls of microbiota studies", which will be useful for evaluating and designing clinical and experimental microbiota studies. PMID- 29158781 TI - Hypothalamic beta-endorphin neurons suppress preneoplastic and neoplastic lesions development in 1,2-dimethylhydrazine induced rat colon cancer model. AB - In recent years, experimental studies demonstrated negative impacts of impaired body stress response on colonic pathologies. In this study, we tested if reducing body stress response by the use of beta-endorphin (BEP) neuronal transplants in the hypothalamus suppresses pre-neoplastic and neoplastic lesions. Colon cancer was induced by injecting 1,2-dimethylhydrazine (DMH) for sixteen weeks in Sprague Dawley rats with BEP neuron transplants or control neuron transplants, and their colonic histopathologies, colon tissue levels of pro-inflammatory cytokines and epithelial-mesenchymal transition (EMT) proteins and splenic levels of cytotoxic proteins were measured. Our results revealed that DMH induced tumors in colon at 100% incidence in control rats but failed to induce colonic tumors in 70% of animal with BEP neuronal transplants. The mean volume of tumor at the colon was smaller in BEP neurons transplanted rats than those in controls. Histopathologies of colon tissues revealed that BEP neurons transplanted animals had lesser tissue lesions such as aberrant crypt foci (ACF) and adenocarcinoma development in the colon than those in control groups. Immunohistochemical and western blot analyses identified reduced expression of Ki-67, TNF-alpha and NF-kappaB nuclear translocation in colonic tissues of BEP neurons transplanted rats than those in controls. BEP neurons transplanted rats also showed reduced expressions of transcription factors linked to EMT like Snail, Twist, and N-cadherin, but increased the levels of an epithelial cell marker E-cadherin in colon tissue. Furthermore, splenic NK cells cytolytic proteins such as perforin, granzyme B and IFN-gamma levels in BEP neurons transplanted rats were higher than those in control rats. These data suggest that BEP neuron transplants suppress the growth and progression of colonic tumors possibly by decreasing inflammatory mileu and EMT via activation of innate immune responses. PMID- 29158782 TI - A phase II trial of preoperative concurrent chemotherapy and dose escalated intensity modulated radiotherapy (IMRT) for locally advanced rectal cancer. AB - Objectives: To determine the pathological response rates and toxicity and in patients with locally advanced rectal cancer treated with concurrent capecitabine and dose escalated intensity modulated radiotherapy (IMRT) Methods: Patients with stage II or III adenocarcinoma of the rectum were treated with preoperative concurrent capecitabine and IMRT. Dose of capecitabine was 825mg/m2, 5 days a week for 5 weeks. IMRT was used to deliver a dose of 45Gy in 25 fractions (1.8Gy per fraction daily, 5 days a week over 5 weeks) to the regional lymphatics and areas at risk of harbouring microscopic disease. A concomitant synchronous integrated boost (SIB) to the gross tumour with a margin to a total dose of 55Gy in 25 fractions was also delivered in the same period. TME surgery was performed 8 weeks after preoperative therapy. The primary endpoint is pathological complete response rate (pCR) and the secondary endpoint was downstaging rates, Sphincter preservation rates (SPR), disease free survival (DFS) at 2 years and toxicity graded using the CTCAE v3.0. Results: Twenty three patients were enrolled. Three were not evaluable; one did not complete treatment due to logistic issues and two declined surgery. The remaining 20 patients completed preoperative chemoIMRT followed by TME surgery. At a median follow-up of 38.2 months (17.5-53.2 months), 90% (18 of 20) patients were alive. The 2 year overall survival and DFS were 90% and 90% respectively. 35%(7/20) of patients had a pCR. 65% (13 of 20) patients had successful downstaging of their rectal tumours. There was no local recurrence. Sphincter preservation rate was 85%. Treatment was well tolerated with only one patient (5%) having Grade 3 radiation proctitis. Conclusions: Preoperative concurrent capecitabine and dose escalated IMRT is well tolerated and results in high rates of pCR. A randomized trial comparing this regimen with standard 3D conformal chemoradiotherapy is warranted. PMID- 29158783 TI - Fascin expression is inversely correlated with breast cancer metastasis suppressor 1 and predicts a worse survival outcome in node-negative breast cancer patients. AB - Background: Fascin is an actin-bundling protein that promotes cancer cell migration and invasion. By contrast, breast cancer metastasis suppressor 1 (BRMS1) inhibits cancer metastasis by targeting multiple steps of the metastatic cascade. We evaluated whether expression patterns of fascin and BRMS1 correlate with clinicopathological features and patient outcome. Methods: Immunohistochemistry for fascin and BRMS1 was performed using a tissue microarray constructed from 183 human breast cancer tissues. Fascin expression determined by the proportion of stained tumor cells (0: 0-5%, 1: 6-25%, 2: 26-50%, 3: 51-75%, or 4: >75%) and staining intensity (0: negative, 1: weak, 2: moderate, or 3: strong) were multiplied and defined as negative (0-3) or positive (4-12). BRMS1 expression was scored separately based on nuclear and cytoplasmic staining intensity (0: negative, 1: weak, 2: moderate, 3: strong). We obtained the BRMS1 H score by summing the nuclear and cytoplasmic scores and defined it as negative (0 2) or positive (3-6). Results: Expression of BRMS1 showed a significant inverse correlation with that of fascin. Fascin+ tumors were significantly associated with no lymph node metastasis, higher histological and higher nuclear grade, ER/PR/HER2 negativity, and triple-negative subtype (all ps < 0.05). These clinicopathological differences showed the same trend in a comparison of fascin /BRMS1+ and fascin+/BRMS1- tumors. Negative or weak BRMS1 cytoplasmic expression was significantly associated with shorter disease-free survival (DFS; p = 0.043). Fascin positivity was significantly associated with shorter DFS (p = 0.005) and overall survival (p = 0.020) when analyses were confined to node-negative patients. Conclusions: This study confirms an inverse correlation between expression of fascin and expression of BRMS1 using a quite large cohort of human breast cancer tissues. Fascin alone or combined with BRMS1 was a worse prognostic marker, particularly in node-negative breast cancer patients. PMID- 29158784 TI - Retraction: The Epstein-Barr Virus-encoded miR-BART22 targets MAP3K5 to promote host cell proliferative and invasive abilities in nasopharyngeal carcinoma. AB - [This retracts the article DOI: 10.7150/jca.15753.]. PMID- 29158785 TI - Breast Cancer Cell Line Classification and Its Relevance with Breast Tumor Subtyping. AB - Breast cancer cell lines have been widely used for breast cancer modelling which encompasses a panel of diseases with distinct phenotypical associations. Though cell lines provide unlimited homogenous materials for tumor studies and are relatively easy to culture, they are known to accumulate mutations duringthe initial establishment and subsequent series of cultivations. Thus, whether breast cancer cell line heterogeneity reflects that of carcinoma remains an important issue to resolve before drawing any reliable conclusion at the tumor level using cell lines. Inconsistent nomenclatures used for breast cancer cell line subtyping and the different number of subtypes grouped for cell lines and tumors make their direct matching elusive. By analyzing the molecular features of 92 breast cancer cell lines as documented by different literatures, we categorize 84 cell lines into 5 groups to be consistent with breast tumor classification. After combing through these cell lines, we summarized the molecular features, genetically and epigenetically, of each subtype, and manually documented 10 cell lines lacking explicit information on subtyping. Nine cell lines, either found inconsistent on their primary molecular features from different studies or being contaminated at the origin, are not suggested as the first choice for experimental use. We conclude that breast tumor cell lines, though having a high mutational frequency with many uncertainties and could not fully capture breast cancer heterogeneity, are feasible but crude models for tumors of the same subtype. New cell lines with enriched interferon regulated genes need to be established to enlarge the coverage of cell lines on tumor heterogeneity. PMID- 29158786 TI - FH535 Inhibits Proliferation and Motility of Colon Cancer Cells by Targeting Wnt/beta-catenin Signaling Pathway. AB - Aberrant Wnt/beta-catenin pathway activation is frequently observed in human colorectal cancer (CRC) and has become a promising target for CRC treatment. Our study aimed to evaluate the effect of FH535, a small molecule inhibitor of Wnt/beta-catenin pathway, on two colon cancer cell lines, HT29 and SW480. We found FH535 significantly inhibited colon cancer cell proliferation in vitro and induced cell cycle arrest. Moreover, FH535 inhibited colon cancer xenograft growth in vivo. Wound-healing assay and Transwell assay revealed that FH535 notably suppressed migration and invasion of SW480 cells. FH535 also repressed expression of cancer stem cell markers, CD24, CD44 and CD133 in HT29 cells. Real time-quantitative PCR and Western blotting revealed that targeting Wnt/beta catenin pathway using FH535 effectively downregulated target genes including cyclin D1 and survivin at mRNA and protein level, which contributed to the FH535 induced inhibitory effect on colon cancer cell proliferation. As mechanisms for suppressing cancer cell motility, FH535 downregulated expression of matrix metalloproteinase-7 and -9, Snail and vimentin. RNA sequencing revealed that FH535 prominently altered multiple biological pathways associated with DNA replication, cell cycle and metabolism. Our study highlights the anti-cancer effect of FH535 on colon cancer and presents its potential in colon cancer treatment. PMID- 29158787 TI - High Expression of FAM83B Predicts Poor Prognosis in Patients with Pancreatic Ductal Adenocarcinoma and Correlates with Cell Cycle and Cell Proliferation. AB - FAM83B (family with sequence similarity 83, member B) seems to emerge as a new class of players involved in the development of a variety of malignant tumors. Yet the molecular mechanisms are not well understood. The present study is intended to investigate the expression and function of FAM83B in pancreatic ductal adenocarcinoma (PDAC). In this study, we found that the expression of FAM83B was significantly increased both in PDAC cell lines and PDAC tumor tissues. FAM83B expression was positively related with advanced clinical stage and poor vital status. Higher FAM83B expression predicted shorter overall survival in PDAC patients, regardless of lymphatic metastasis status and histological differentiation. Actually, FAM83B may act as an independent prognostic indicator as well. What's more, down-regulation of FAM83B in PDAC cells contributed to G0/G1 phase arrest and inhibition of cell proliferation. Finally, a subcutaneous xenograft model indicated that knockdown of FAM83B significantly reduced the tumor volume in vivo. Our findings have provided supporting evidence for the potential molecular biomarker role of FAM83B in PDAC. It's of great interest and broad significance to target FAM83B in PDAC, which may conduce to develop a meaningful and effective strategy in the diagnosis and treatment of PDAC. PMID- 29158788 TI - Programmed Death Ligand 1 (PD-L1) Expression in Primary Angiosarcoma. AB - Angiosarcomas are rare malignant endothelial-cell tumors of vascular or lymphatic origin, and are among the most aggressive subtypes of soft-tissue sarcomas. The prognosis is poor and treatment is challenging in many cases. PD-1/PD-L1 pathway plays a critical role in immune escape of tumor cells. Recent studies described that PD-L1 is widely expressed in various types of cancer, providing the basis for the development of PD1/PD-L1 antibodies as anti-cancer immunotherapy. Despite the well-known potential of PD-L1 as prognostic and predictive biomarker, only few studies described its IHC expression in cancer subtypes for the extreme difficulty in developing standard protocol with the different antibody clones available. We analyzed the IHC expression of PD-L1 on a series of angiosarcomas at different body location, showing its aberrant expression in about 66% of samples with no relation with prognosis. Our study allowed us to correctly define PD-L1 staining in angiosarcoma tumor tissues with final purpose to stratify patients for immune checkpoint inhibitors therapies. PMID- 29158789 TI - Arecoline Increases Glycolysis and Modulates pH Regulator Expression in HA22T/VGH Hepatoma Cells, Leading to Increase of Intracellular Ca2+, Reactive Oxygen Species, and Anoikis. AB - Background: Cancer cells proliferate rapidly and are resistant to cell death, relying on aggravated glycolysis to satisfy their increased demand for energy and biosynthetic precursors. However, this process may create unfavorable microenvironments, such as increased acidity, leading to cytotoxicity. Our previous study demonstrated that arecoline induces anoikis of HA22T/VGH hepatoma cells. The present study aimed to examine if arecoline induced anoikis is related to the glycolytic pathway and explore the underlying mechanisms. Methods: HA22T/VGH cells were treated with arecoline and changes in the glycolytic end products lactate and ATP, glycolytic-related gene expression, intracellular and extracellular pH, pH-regulating gene expression, reactive oxygen species (ROS) levels, intracellular Ca2+ concentration ([Ca2+]i) and mitochondrial membrane potential were examined, relative to untreated cells. Cell viability and morphology were also assessed. Results: Arecoline increased lactate and ATP production through induction of glycolytic genes, including glucose transporter 3 (Glut3), hexokinase 1 (HK1), hexokinase 2 (HK2), and pyruvate kinase (PK). The intracellular pH was not changed, despite increased lactate levels, implying that intracellular H+ was exported out of the cells. mRNA expression of pH regulators including monocarboxylate transporter 1 and 4 (MCT 1 and 4), sodium bicarbonate cotransporter 1 (NBC1), carbonic anhydrases (CA) IX and XII and vacuolar ATPase (V-ATPase) were down-regulated. Na+/H+ exchanger 1 (NHE1) mRNA levels remained unchanged while Na+/Ca2+ exchanger (NCX) was up-regulated and eventually [Ca2+]i was increased. ROS generation was increased and mitochondrial membrane potential was decreased followed by cell detachment and death. Addition of 2-deoxy-d glucose, a glucose competitor that interferes with glycolysis, attenuated arecoline induction of lactate [Ca2+]i, ROS and cell detachment. Similarly, ROS scavengers could block the effects of arecoline. Conclusions: This study demonstrated that arecoline induced glycolysis and modulated the mRNA expression of pH-regulator genes in HA22T/VGH cells. This phenomenon led to the elevation of [Ca2+]i, ROS generation, and subsequent cell detachment. PMID- 29158790 TI - Synergy of purine-scaffold TLR7 agonist with doxorubicin on systemic inhibition of lymphoma in mouse model. AB - Chemo- and radio-therapy suffer from certain well-recognized drawbacks for lymphoma therapy. Passive immunotherapy with monoclonal antibody has improved outcome for patients with CD20+ B cell lymphoma, but not for T cell lymphoma. Therefore, novel treatment approaches are clearly required for T cell lymphoma. To date, the combined application targeting TLR7, 8 and 9 has established long term antitumor immunity. We previously synthesized a purine-scaffold TLR7 agonist named GD5. Here, we report that the intratumoral administration of GD5 combined with doxorubicin (DOX), a conventional chemotherapeutic agent in T cell lymphoma. This combined treatment made mice to produce more cytokines in blood, and generate more potent cytotoxic T lymphocyte response, then result in effective eradication of both local and distant tumors in tumor-bearing mice. Our findings demonstrate the potential for enhancing the efficacy of the current standard DOX therapy through combination with TLR7 agonist GD5 to improve antitumor immune responses and provide durable remissions for T cell lymphoma. PMID- 29158791 TI - Correlation of cancer stem cell markers and immune cell markers in resected non small cell lung cancer. AB - Background: Recent studies confirmed that immunotherapy showed prominent efficacy in non-small cell lung cancer (NSCLC). Cancer stem cells/cancer initiating cells are resistant to anticancer treatment. The purpose of the study was to analyze the correlation of cancer stem cells/cancer initiating cells and tumor infiltrating immune cells in NSCLC. Methods: CD133, octamer 4 (OCT-4), CD8, CD56, human leukocyte antigen (HLA) class I and programmed death ligand-1 (PD-L1) were assessed in 172 resected NSCLC samples. The staining was analyzed and scored by the pathologist who was blinded to the clinical pathological data of the patients. Results: High CD8+ T cell infiltration was correlated significantly with squamous cell carcinoma histology (p=0.008). High PD-L1 expression (>=10%) was associated with high tumor status (p=0.043). Pearson's correlation test showed that CD56+ cells were negatively correlated with CD133 expression (r= 0.361, p<0.001) and weakly correlated with negative OCT-4 expression (r=-0.180, p=0.018). There was a strong positive correlation between CD8 and HLA class I (r=0.573, p<0.001). In the survival analysis, high CD8+ T cell infiltration is an independent predictor of improved disease-free survival and overall survival. Patients with low CD133 expression and high CD56 expression had a longer overall survival than those with high CD133 expression and/or low CD56 expression (p=0.013). Conclusion: There is a negative correlation between CD56+ cells and cancer stem cell markers. This correlation may confirm the possibility that natural killer cells can target CD133+ cancer stem cells/cancer initiating cells in non-small cell lung cancer. PMID- 29158792 TI - Association between 8q24 Gene Polymorphisms and the Risk of Prostate Cancer: A Systematic Review and Meta-Analysis. AB - Though numerous studies have been conducted to investigate the associations between five 8q24 polymorphisms (rs6983267 T>G, rs1447295 C>A, rs16901979 C>A, rs6983561 A>C and rs10090154 C>T) and prostate cancer (PCa) risk, the available results remained contradictory. Therefore, we performed a comprehensive meta analysis to derive a precise estimation of such associations. We searched electronic databases PubMed, EMBASE, Web of Science and Wan Fang for the relevant available studies up to February 1st, 2017, and 39 articles were ultimately adopted in this meta-analysis. All data were extracted independently by two investigators and recorded in a unified form. The strength of association between 8q24 polymorphisms and PCa susceptibility was evaluated by the pooled odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analysis was conducted based on ethnicity, source of controls and genotypic method. Overall, a total of 39 articles containing 80 studies were adopted in this meta-analysis. The results of this meta-analysis indicated that five 8q24 polymorphisms above were all related to PCa susceptibility. Besides, in the subgroup analysis by ethnicity, all selected 8q24 polymorphisms were significantly associated with PCa risk in Asian population. In addition, stratification analysis by source of controls showed that significant results were mostly concentrated in the studies' controls from general population. Moreover, when stratified by genotypic method, significant increased PCa risks were found by TaqMan method. Therefore, this meta-analysis demonstrated that 8q24 polymorphisms (rs6983267 T>G, rs1447295 C>A, rs16901979 C>A, rs6983561 A>C and rs10090154 C>T) were associated with the susceptibility to PCa, which held the potential biomarkers for PCa risk. PMID- 29158794 TI - Association between Sumoylation-Related Gene rs77447679 Polymorphism and Risk of Gastric Cancer (GC) in a Chinese Population. AB - Purpose: Sumoylation plays a critical role in gene regulation and tumorigenesis, and is hypothesized to correlate with the development of various cancers. So far, there has been no reported association between sumoylation-related genes and the risk of gastric cancer (GC). Methods: A total of 17 tagging single-nucleotide polymorphisms (tag-SNPs) in 5 sumoylation-related genes were selected and genotyped by SNaPshot in a case-control study, including 1021 GC patients and 1304 controls. Odds ratio (OR) and 95% confidential interval (CI) were computed to evaluate the genetic association of the onset of GC. Results: We demonstrated that CBX4 rs77447679 polymorphism was significantly associated with GC risk (P= 0.017; adjusted OR: 1.71; 95% CI: 1.10-2.66). The patients with CC genotype had a lower risk of GC (CC vs. CA+AA, P= 0.017; adjusted OR: 1.24; 95% CI: 1.04-1.49). Conclusion: This study revealed that CBX4 rs77447679 polymorphism was positively associated with GC, and individuals with CC genotype had less risk of GC. The risky effects and functional effect of this polymorphism in GC require further investigation. PMID- 29158793 TI - Long non-coding RNAs in Colorectal Cancer: Progression and Future Directions. AB - Identification of the colorectal adenoma-carcinoma sequence with its corresponding genetic and epigenetic alterations has significantly increased our knowledge of the etiopathogenesis of colorectal cancer (CRC). However, the molecular mechanisms of colorectal carcinogenesis and metastasis haven't been clearly elucidated. Long non-coding ribonucleic acids (lncRNAs) are key participants of gene regulations rather than "noises". Accumulative studies have implicated that the aberrant expressions of lncRNAs are tightly corelated to CRC screening, diagnosis, prognosis and therapeutic outcomes. Our review focuses on recent findings on the involvement of lncRNAs in CRC oncogenesis and the lncRNA based clinical implications in patients with CRC. PMID- 29158795 TI - Mismatch Repair Protein hMLH1, but not hMSH2, Enhances Estrogen-Induced Apoptosis of Colon Cancer Cells. AB - BACKGROUND: Epidemiological studies suggest a protective role of estrogen against colon carcinogenesis; this effect appears to be dependent on mismatch repair (MMR) status. However, the underlying mechanism remains unclear. This study investigated the role of MMR proteins in apoptosis of colon cancer cells in the presence or absence of estrogen. METHODS: Two major MMR proteins, human mutL homolog 1 (hMLH1) and mutS homolog 2 (hMSH2), as well as estrogen receptor-beta (ERbeta), were transiently expressed in either hMLH1-deficient HCT116 cells or hMSH2-deficient LoVo cells. Effects of estradiol on cell viability and apoptosis were assessed. Furthermore, we examined the apoptotic status of epithelial cells in colonic mucosa taken from previous healthy female subjects with menopausal syndrome before and after 6-month hormone replacement therapy (HRT). RESULTS: In hMLH1-deficient HCT116 cells, re-expression of hMLH1 led to a significantly decreased cell viability and increased apoptosis, which were further enhanced by estradiol, including marked increase of activated caspase-3 and caspase-9, as well as Bax and P53. The effect of hMLH1 overexpression in LoVo cells resulted in a similar increase in apoptosis that was greatly stimulated by estradiol. The enhanced apoptosis by hMLH1 and estradiol was further validated by FACS analyses of Annexin V expression. Re-expression of hMSH2 or overexpression of ERbeta in HCT116 cells also enhanced apoptosis; however, the effects were independent of estradiol. Furthermore, studies on healthy menopausal women before and after 6 month HRT demonstrated a significant HRT-mediated upregulation of the hMLH1 expression, with concomitant elevation of caspase-3 and caspase-9 activation in the colonic mucosa. CONCLUSION: We present the first evidence that hMLH1 and hMSH2 have similar but distinct roles in the apoptosis of colon cancer cells: an increased expression of either one can promote apoptosis, while only the effect of hMLH1 but not hMSH2 is estradiol-dependent. Our data suggest that MMR status should be assessed before hormone replacement therapy or future application of estrogen-based chemoprevention. PMID- 29158796 TI - Radiotherapy Alone or Concurrent Chemoradiation for Esophageal Squamous Cell Carcinoma in Elderly Patients. AB - Purpose: The reported data of elderly ESCC are rather limited and there is a lack of information to guide treatment decisions for elderly patients with esophageal cancer. This study aims to identify the efficacy and factors for optimal treatment approaches for elderly esophageal squamous cell carcinoma (ESCC) treated with radiotherapy (RT) alone or concurrent chemoradiation (CCRT). Methods: This study included 184 I-III elderly ESCC patients aged >=70 years treated by oral single agent CCRT (sCCRT) or double agents CCRT (dCCRT) or RT alone at a single institution in China. RT was delivered with Intensity Modulated Irradiation Therapy (IMRT) or Volumetric-Modulated Arc Therapy (VMAT). Sequential or simultaneous integrated boost (SIB) approach was applied for GTV dose escalation. Toxicities were evaluated by criteria of Radiation Therapy Oncology Group. Statistical analyses were performed on survival and failure patterns. Results: At a median follow-up time of 15.5 months, the 2- and 3-year estimated overall survival (OS) were 43.5% and 35.2%, respectively. T and N stage, GTV dose (cutoff value 56Gy), simultaneous integrated boost (SIB) technique and CCRT were significant predictors for the outcomes. sCCRT was significantly associated with higher OS, LRFS, and DFS when compared with RT alone and no difference was observed between sCCRT and dCCRT. 44% patients experienced treatment failure, among whom 65.4% developed local failure. 81.3% local failure occurred in GTV and 70.6% regional failures occurred out of radiation field. dCCRT was the only independent prediction factor for grade >= 2 neutropenia and gastrointestinal reactions compared with sCCRT and RT alone. No significant difference of toxicities was observed between sCCRT and RT alone. Conclusions: Our results demonstrated that CCRT in elderly patients had significant survival benefit compared to RT alone, especially using Single oral agent. sCCRT had less toxicities compared to dCCRT, and the toxicity was similar to RT alone. GTV dose >= 56 Gy and SIB technique were optimal approaches for radiotherapy. PMID- 29158797 TI - PD-L1 is a Prognostic Biomarker in Resected NSCLC Patients with Moderate/high Smoking History and Elevated Serum SCCA Level. AB - Programmed cell death-1 (PD-1) -targeted immunotherapy has become a promising treatment paradigm for patients with advanced non-small cell lung cancer (NSCLC). Clinical responses to checkpoint inhibition therapy in NSCLC have been associated with programmed death-1 ligand 1 (PD-L1) expression. However, the association between the expression of PD-L1 and PD-L2 and the clinicopathological features and patient outcomes in NSCLC remain unclear. We retrospectively analyzed 364 patients (158 squamous cell carcinoma and 206 adenocarcinoma) who underwent complete resection between 2009 and 2012. Expression of PD-L1 and PD-L2 was determined by immunohistochemistry. Correlations between PD-L1/PD-L2 expression and the clinicopathological features and survival parameters were analyzed and prognostic factors were identified. PD-L1 expression was significantly associated with moderate/heavy smoking history and serum squamous cell carcinoma antigen (SCCA) levels. Multivariate analysis showed patients with high PD-L1 expression had significantly shorter disease free survival (DFS, HR 1.411, P = 0.025) and overall survival (OS, HR 1.659, P = 0.004) than those with low PD-L1 expression at a 50% cutoff value. No significant association was found between PD-L2 expression and patient postoperative survival. Further stratification analysis revealed that in patients with moderate/heavy smoking history, elevated serum SCCA level, and squamous cell carcinoma, PD-L1 expression was associated with significantly shorter DFS and OS. Therefore, PD-L1 expression was correlated with moderate/heavy smoking history and elevated serum SCCA level in NSCLC patients, and was an independently poor predictor of survival. PMID- 29158798 TI - Improvement in prediction of prostate cancer prognosis with somatic mutational signatures. AB - Prostate cancer is a leading male malignancy worldwide, while the prognosis prediction remains quite inaccurate. The study aimed to observe whether there was an association between the prognosis of prostate cancer and genetic mutation profile, and to build an accurate prognostic predictor based on the genetic signatures. The patients diagnosed of prostate cancer from The Cancer Genomic Atlas were used for prognostic stratification, while the somatic gene mutation profiles were compared between different prognostic groups. The genetic features were further used for training machine-learning models to predict prostate cancer prognosis. No significant gene with somatic mutation rate difference was found between prognostic groups of prostate cancer. Total 43 atypical genes were screened for building a support vector machine model to predict prostate cancer prognosis, with an average accuracy of 66% and 64% for 5-fold cross-validation or training-testing evaluation respectively. When combined with the National Institute for Health and Care Excellence (NICE) features, the model could be further improved, with the 5-fold cross-validation accuracy of ~71%, much better than NICE itself (62%). To our knowledge, for the first time, the research studied the relationship of genome-wide somatic mutations with prostate prognosis, and developed an effective prognostic prediction model with the atypical genetic signatures. PMID- 29158799 TI - Fluid intake-to-bed time, nocturia frequency and the risk of urothelial carcinoma of the bladder: a case-control study. AB - Objectives: To clarify the potential role of fluid intake-to-bed time and nocturia frequency on bladder cancer risk in a hospital-based case-control study with Chinese people. Materials and Methods: Four hundred and seven patients with histologically diagnosed bladder cancer and 400 matched controls were enrolled in this study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression model. Results: After adjustment for potential confounders, the fluid intake-to-bed time was associated with a decreased risk of BCa, with an OR of 0.586 (95% CI= 0.375-0.916, <=1h) and 0.257 (95% CI= 0.162-0.407, >1h). The adjusted OR of BCa for subjects with more nocturia frequency (>=2 times) was 2.268 (95 % CI= 1.481-3474), compared to those with no nocturia. Conclusion: We suggested strong protective effect of long fluid intake-to-bed time on BCa risk, especially in ones with >=2 times nocturia frequency. These results provide evidence for identifying high-risk individuals and modifying their behaviors and lifestyle. PMID- 29158800 TI - A Bottleneck in Understanding Metastatic Cancer Stem Cell of Peritoneal Seeding from Gastric Cancer: A Null Result in Brief. AB - The capture of peritoneal metastatic cancer stem cell of human gastric cancer (pMCSC-hGC) is important to further understand the mechanism of peritoneal metastasis in gastric cancer patients. Previously, cancer stem cells (CSCs) of gastric and rectal cancers were captured and identified. However, the bottleneck of capturing pMCSC-hGC may be the scarce surgical specimen and limited volume of peritoneal metastatic lesions from gastric cancer. Only 5.2% of patients were diagnosed of unpredictive peritoneal seeding intraoperatively, while none cell sphere were successfully formed through the identical culture approach based on peritoneal metastatic nodules. The attempt to enrich and capture pMCSC of transplanted gastric cancer (pMCSC-tGC) in immunodeficiency mice model through intraperitoneal injection of CSC-hGC may be a considerable and feasible alteration. PMID- 29158801 TI - Gambogenic Acid Exerts Antitumor Activity in Hypoxic Multiple Myeloma Cells by Regulation of miR-21. AB - Hypoxia is an inseparable component of the bone marrow (BM) microenvironment, accounting for aggressive tumor behavior and poor prognosis of multiple myeloma (MM). Gambogenic acid (GNA) has proven to be an attractive option for treatment of tumors due to its tumor suppressive activity. Herein, we found that GNA exhibits remarkable apoptotic activity against MM cells even under hypoxia. MicroRNA-21 (miR-21) has been found over-expressed in MM patients and associated with the occurrence and development of MM. Direct studies have shown that there is a functional link between hypoxia and miR-21 expression in multiple types of tumors. In the current study, we found that hypoxia increased miR-21 expression in U266 cells and miR-21 induced by hypoxia was associated with concurrent reductions in its target PTEN. After treatment with GNA, miR-21 expression in hypoxic U266 cells was strikingly downregulated in a dose-dependent manner. Besides, we identified that regulation of miR-21/PTEN by GNA under hypoxia is related with inhibition of HIF-1alpha accumulation and STAT3 phosphorylation. Furthermore, in vivo study revealed that intravenous GNA injection could significantly suppress tumor growth and the miR-21/PTEN pathway is involved in GNA's anti-tumor effects. Taken together, all these results indicated that GNA could be a highly potent therapeutic for human MM. PMID- 29158802 TI - Cytokine-Induced Killer Cells Modulates Resistance to Cisplatin in the A549/DDP Cell Line. AB - Background Cytokine-induced killer (CIK) cells can potentially enhance the tumor killing activity of chemotherapy. Objective This study aimed to evaluate the effects of CIK cells on cisplatin (DDP) resistance in the human lung adenocarcinoma cell line A549/DDP. Methods The detect resistance index, drug resistance related-genes and cytokine secretion of A549/DDP co-cultured with CIK cells were assayed in vitro. Results After A549/DDP co-culture with CIK cells, the DDP resistance of A549/DDP significantly decreased in a time-dependent manner. The DDP resistance of A549/DDP co-cultured with CIK cells for 20 h decreased 4.93-fold compared with that of A549/DDP cells cultured alone (P<0.05). The mRNA and protein expression levels of the glutathione-S-transferase (GST) -pi gene in A549/DDP significantly decreased after co-culture with CIK cells (P<0.05). The secretion of interferon (IFN)- gamma significantly increased along with the co-culture time of A549/DDP with CIK cells. The expression of GST-pi was restored by adding the neutralizing IFN-gamma. Conclusion CIK cells can reverse the drug resistance of A549/DDP in a time-dependent manner by reducing GST-pi expression to increase the accumulation of DDP. The effect of CIK cells on re sensitizing lung cancer cells to the chemotherapy drug was partially dependent on the secretion of IFN-gamma. PMID- 29158803 TI - Association between Mismatch-repair Genetic variation and the Risk of Multiple Primary Cancers: A Meta-Analysis. AB - Microsatellites instability (MSI) is a risk factor for multiple primary cancers (MPCs). However, a variety of studies focused on the risk in the hereditary non polyposis colorectal cancer (HNPCC) not the sporadic colorectal cancer (CRC) patients. The aim of this meta-analysis was to comprehensive overview and quantitative summary the association between MSI and risk of MPCs. A comprehensive literature search in MEDLINE, EMBASE, Web of science, ScienceDirect, Weily and OVID was conducted. Up to May 2016, we identified 22 observational studies. We calculated the summary relative risk (RR) for the risk of MPCs in MSI patients compared with microsatellites stability (MSS) patients using fixed- or random-effects models. The RR of the association between mismatch repair gene (MMR) genotype and MPCs was 2.59 (95% confidence interval [CI], 2.06 to 3.27); the RR was 2.14 (95% CI, 1.78 to 2.57) for sporadic CRC and 5.59 (95% CI, 2.69 to 11.59) for HNPCC for the MSI versus MSS category. The subgroup analyses showed different mutant gene, mutant locus, and mutant level of MMR with different influence on the patients susceptible to MPCs. In addition, MSI genotype increase the risk of MPC was not associated with an apparently specific in regard to site, timing, age and detection method. In conclusion, this meta analysis indicates that MSI is associated with an increased risk of MPCs both in the HNPCC and sporadic CRC patients. Our findings will form the backbone of the treatment for MSI genotype may be an important valuable strategy for MPCs prevention. PMID- 29158804 TI - Heparanase Contributes To Trans-Endothelial Migration of Hepatocellular Carcinoma Cells. AB - The overall outcome of patients with hepatocellular carcinoma (HCC) is still very poor due to its high metastasis and recurrence rate. During metastasis, trans endothelial migration (TEM) of HCC cells is a key step. Heparanase (HPSE) is an endo-beta-glucuronidase and exerts prometastatic properties for normal and tumor derived cells. However, it is remains unclear that HPSE contributes to TEM of HCC cells. In this study, human umbilical vein endothelial cells-C (HUVEC-C) was used to simulate vascular endothelial cells (VECs), and the HCCLM3 cells with high HPSE expression were chosen and used for in vitro TEM assay and in vivo experiment. As results, we found that HCCLM3 cells showed higher TEM rate compared with other HCC cells. Downregulation or inhibition of HPSE activity resulted in suppression of TEM of HCC cells both in vitro and in vivo. Our findings suggest that HPSE contributes to TEM of HCC cells, which may be a new biological function of HPSE. PMID- 29158805 TI - Histone Methyltransferase SETDB1 Promotes the Progression of Colorectal Cancer by Inhibiting the Expression of TP53. AB - SETDB1 is a novel histone methyltransferase associated with the functional tri methylation of histone H3K9. Although aberrant high expression of SETDB1 was experimentally obversed in a variety of solid tumors, its underlying mechanisms in human carcinogenesis are not well known. In this study, we investigated the expression of SETDB1 in a large cohort of colorectal cancer (CRC) samples and cell lines for the first time. Our findings showed that SETDB1 was highly expressed in majority CRC tissues and cell lines; moreover, up-regulation of SETDB1 was negatively correlated with the survival rate of CRC patients. Functionally, over-expression of SETDB1 significantly promoted the proliferation and migration of CRC cells in vitro and in vivo, while knocking down SETDB1 suppressed their growth. Mechanistically, we showed that over-expression of SETDB1 significantly inhibited the apoptosis induced by 5-Fluorouracil in CRC cells, which was closely related to the inhibition of TP53 and BAX expression. Furthermore, we confirmed that SETDB1 could be recruited to the promoter region of TP53, which might contribute its inhibition of apoptosis. For conclusion, our study indicated that SETDB1 is essential for colorectal carcinogenesis, and may be a newly target for treatment and prognostic evaluation in CRC. PMID- 29158806 TI - Correlation of ALDH1 and Notch3 Expression: Clinical implication in Ovarian Carcinomas. AB - Purpose : ALDH1 is a putative cancer stem cell marker, while the Notch signaling pathway is involved in regulation of cancer stem cell (CSC)s. This study aims to determine the expression of Notch signaling genes in ovarian CSCs, and to assess the clinical impact of expression of ALDH1 and Notch signaling genes in ovarian cancers. Methods : We examined expression of Notch signaling genes in FACS-sorted ALDH1(+) putative ovarian CSCs and expression of ALDH1 and Notch signaling genes in 86 ovarian epithelial tumors and various ovarian cancer cell lines by real time RT-PCR, including Notch receptors (Notch1-4), Notch ligands (Jagged1 and Jagged2), and the downstream molecule, Hes1. Furthermore, we correlated their expression with clinicopathological parameters and patient's survival in ovarian serous carcinoma (OSC)s, the most prevalent type of ovarian cancer. Results : The higher expression levels of ALDH1 and Notch related genes, especially Notch3 were associated with CSCs and with chemoresistant OSCs and paclitaxel-resistant SKpac ovarian cancer cells. Among the Notch signaling genes, high Notch3 expression was significantly associated with all the parameters of poor prognosis, i.e., advanced stage, lymph node and distant metastases, and chemoresistance, whereas other genes were less correlated with these parameters. A combined upregulation of ALDH1 and Notch3 was an independent poor prognostic factor in OSCs. Conclusions : ALDH1 correlates with Notch3 expression in ovarian carcinomas. ALDH1 and Notch3 overexpression is an independent poor prognostic indicator for worse patient's survival in this subset of OSCs. PMID- 29158807 TI - The Prognostic Value of Peripheral Benzodiazepine Receptor in Patients with Esophageal Squamous Cell Carcinoma. AB - Background: The peripheral benzodiazepine receptor (PBR) has previously been reported as an oncogene in prostate, breast and colorectal cancers, but its prognostic value, biological behavior and function in esophageal squamous cell carcinoma (ESCC) has not been investigated. Methods: qRT-PCR, western blotting and immunohistochemistry (IHC) were used to detect PBR expression in ESCC and matched non-cancerous tissues. Based on all of the significantly independent factors, a nomogram was established to predict the prognosis of ESCC patients. In addition, we performed comprehensive in vitro experiments to study the functions of PBR in cell growth, colony formation, and migration ability, as well as its relationship with epithelial-mesenchymal transition (EMT) related proteins in ESCC cells. Results: The mRNA and protein expression levels of PBR in ESCC were higher than those in adjacent non-tumor esophageal epithelial tissues. The IHC results demonstrated that PBR expression was an independent prognostic factor in ESCC survival, patients with higher PBR expression had a poorer survival than those with low expression, and PBR expression was significantly associated with lymphoid nodal status. Furthermore, a nomogram was established to reliably predict the probability of death in ESCC patients, with a Harrell's c-index of 0.696. In the vitro experiments, knocking down the expression of PBR inhibited proliferation, colony formation and migration of ESCC cells, and regulated EMT associated proteins (up-regulation of E-cadherin, ZO-1 and beta-catenin and concomitant with down-regulation of Fibronectin and N-cadherin). Conclusions: PBR is an independent prognostic factor in ESCC, and it promotes ESCC progression and metastasis. Basing on PBR expression level, a nomogram is established and performs a well in predicting survival of ESCC patients. PMID- 29158808 TI - Distant Metastasis and Survival Outcomes after Computed Tomography-Guided Needle Biopsy in Resected Stage I-III Non-Small Cell Lung Cancer. AB - Background and objective Several reports describe the needle-tract implantation after percutaneous needle lung biopsy. The present study evaluated whether preoperative computed tomography-guided needle biopsy (CTNB) affected the distant metastasis and overall survival in patients with early non-small cell lung cancer (NSCLC). Methods A total of 1667 patients with pathological stage I-III NSCLC were assimilated. Of these, 168 patients received preoperative CTNB, whereas 1499 patients were not subjected to any biopsy before surgical resection. Propensity score matching method was adopted to balance the observed covariates between the two groups. Cox regression analysis and Kaplan-Meier estimations were used for survival analysis. Subset analysis was performed in the p-stage <= II cases. Results The distant metastasis and mortality were not significantly increased for all patients with preoperative CTNB (P = 0.142 and P = 0.125, respectively). The subset analysis of p-stage <= II cases showed that CTNB increased the risk of distant metastasis (P = 0.032) while not increasing the risk of mortality (P = 0.086). Conclusion CTNB can increase the risk of distant metastasis in the p stage <= II patients. PMID- 29158809 TI - Alkaline Phosphatase-To-Albumin Ratio as a Prognostic Indicator in Pancreatic Ductal Adenocarcinoma after Curative Resection. AB - Background: The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor and the models for survival prediction in PDAC patients after curative resection are still limited. Preoperative alkaline phosphatase-to-albumin ratio (APAR), an original inflammation-based score, has been established to analyze the prognostic significance in PDAC. Therefore, in this study, we aim to formulate a valuable prognostic nomogram for PDAC following curative resection. Methods: A total of 354 patients with PDAC undergoing curative resection were retrospectively enrolled in this study. The prognostic value of APAR was analyzed in primary cohort containing 220 randomly selected PDAC patients with curative resection and prognostic nomogram incorporating APAR into the American Joint Commission on Cancer (AJCC) 8th edition was established to obtain superior discriminatory abilities. The predictive performance of APAR was further validated in another independent cohort of 134 PDAC patients. Results: Patients with higher serum APAR level were probable to sustain poorer overall survival (OS). Significant positive correlations were found between APAR and tumor site, and several serum biochemical indexes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), etc. The results of multivariate analysis showed, APAR was also identified as an independent prognostic indicator for OS in both primary and validation cohorts (P=0.004, P=0.038, respectively). Compared with the AJCC 8th edition, the nomogram consisting of APAR, pathological differentiation and the TNM staging system of AJCC 8th edition showed superior predictive accuracy for OS. All these results were further verified in the validation cohort. Conclusions: APAR can be considered as a novel independent prognostic biomarker for PDAC following curative resection. One more accurate and advanced predictive model will be achieved via the incorporation of APAR into nomogram. PMID- 29158810 TI - Phosphorylated Protein Kinase C (Zeta/Lambda) Expression in Colorectal Adenocarcinoma and Its Correlation with Clinicopathologic Characteristics and Prognosis. AB - Background: Protein kinase C zeta/lambda (PKCzeta/lambda) is a family of protein kinase enzymes that contributes to cell proliferation and regulation, which are important for cancer development. PKCzeta/lambda has been shown to be an important regulator of tumorigenesis in intestinal cancer. The phosphorylated form of PKCzeta/lambda, p-PKCzeta/lambda, is suggested as an active form of PKCzeta/lambda. However, p-PKCzeta/lambda expression and its clinicopathologic implication in colorectal adenocarcinoma (CRAC) are unclear. Methods: Seven whole tissue sections of malignant polyps containing both non-neoplastic and neoplastic mucosa, 11 adenomas with low-grade dysplasia, and 173 CRACs were examined by immunohistochemistry and western blot assay for p-PKCzeta/lambda protein expression. The association of p-PKCzeta/lambda expression with clinicopathologic factors including patient survival was studied. Results: In non-neoplastic epithelia, p-PKCzeta/lambda showed a weak cytoplasmic immunostaining. Adenomas and CRACs demonstrated up-regulated p-PKCzeta/lambda detection. Cytoplasmic p PKCzeta/lambda expression was higher in CRAC than in adenoma. In CRACs, p PKCzeta/lambda expression was inversely correlated with pathologic TNM stage (I II versus III-IV) and poor differentiation. Statistical correlations between low expression of p-PKCzeta/lambda with shortened overall survival and disease-free survival were seen (p=0.004 and p=0.034, respectively). Conclusions: P PKCzeta/lambda overexpression is implicated in tumorigenesis but down-regulation was a poor prognostic factor in CRAC. PMID- 29158811 TI - Transforming doxorubicin into a cancer stem cell killer via EpCAM aptamer mediated delivery. AB - Chemotherapy-resistant cancer stem cells (CSCs) are a major obstacle to the effective treatment of many forms of cancer. To overcome CSC chemo-resistance, we developed a novel system by conjugating a CSC-targeting EpCAM aptamer with doxorubicin (Apt-DOX) to eliminate CSCs. Incubation of Apt-DOX with colorectal cancer cells resulted in high concentration and prolonged retention of DOX in the nuclei. Treatment of tumour-bearing xenograft mice with Apt-DOX resulted in at least 3-fold more inhibition of tumour growth and longer survival as well as a 30 fold lower frequency of CSC and a prolonged longer tumourigenic latency compared with those receiving the same dose of free DOX. Our data demonstrate that a CSC targeting aptamer is able to transform a conventional chemotherapeutic agent into a CSC-killer to overcome drug resistance in solid tumours. PMID- 29158812 TI - Enhanced Radiotherapy using Bismuth Sulfide Nanoagents Combined with Photo thermal Treatment. AB - Nanotechniques that can improve the effectiveness of radiotherapy (RT) by integrating it with multimodal imaging are highly desirable. Results In this study, we fabricated Bi2S3 nanorods that have attractive features such as their ability to function as contrast agents for X-ray computed tomography (CT) and photoacoustic (PA) imaging as well as good biocompatibility. Both in vitro and in vivo studies confirmed that the Bi2S3 nanoagents could potentiate the lethal effects of radiation via amplifying the local radiation dose and enhancing the anti-tumor efficacy of RT by augmenting the photo-thermal effect. Furthermore, the nanoagent-mediated hyperthermia could effectively increase the oxygen concentration in hypoxic regions thereby inhibiting the expression of hypoxia inducible factor (HIF-1alpha). This, in turn, interfered with DNA repair via decreasing the expression of DNA repair-related proteins to overcome radio resistance. Also, RT combined with nanoagent-mediated hyperthermia could substantially suppress tumor metastasis via down-regulating angiogenic factors. Conclusion In summary, we constructed a single-component powerful nanoagent for CT/PA imaging-guided tumor radiotherapy and, most importantly, explored the potential mechanisms of nanoagent-mediated photo-thermal treatment for enhancing the efficacy of RT in a synergistic manner. PMID- 29158813 TI - Vascularized Tissue-Engineered Model for Studying Drug Resistance in Neuroblastoma. AB - : Neuroblastoma is a vascularized pediatric tumor derived from neural crest stem cells that displays vasculogenic mimicry and can express a number of stemness markers, such as SOX2 and NANOG. Tumor relapse is the major cause of succumbing to this disease, and properties attributed to cancer stem-like cells (CSLC), such as drug-resistance and cell plasticity, seem to be the key mechanisms. However, the lack of controllable models that recapitulate the features of human neuroblastoma limits our understanding of the process and impedes the development of new therapies. In response to these limitations, we engineered a perfusable, vascularized in vitro model of three-dimensional human neuroblastoma to study the effects of retinoid therapy on tumor vasculature and drug-resistance. METHODS: The in vitro model of neuroblastoma was generated using cell-sheet engineering and cultured in a perfusion bioreactor. Firstly, we stacked three cell sheets containing SKNBE(2) neuroblastoma cells and HUVEC. Then, a vascular bed made of fibrin, collagen I and HUVEC cells was placed onto a collagen-gel base with 8 microchannels. After gelling, the stacked cell sheets were placed on the vascular bed and cultured in the perfusion bioreactor (perfusion rate: 0.5 mL/min) for 4 days. Neuroblastoma models were treated with 10MUM isotretionin in single daily doses for 5 days. RESULTS: The bioengineered model recapitulated vasculogenic mimicry (vessel-like structure formation and tumor-derived endothelial cells TECs), and contained CSLC expressing SOX2 and NANOG. Treatment with Isotretinoin destabilized vascular networks but failed to target vasculogenic mimicry and augmented populations of CSLCs expressing high levels of SOX2. Our results suggest that CSLCs can transdifferentiate into drug resistant CD31+-TECs, and reveal the presence of an intermediate state STEC (stem tumor-derived endothelial cell) expressing both SOX2 and CD31. CONCLUSION: Our results reveal some roles of SOX2 in drug resistance and tumor relapse, and suggest that SOX2 could be a therapeutic target in neuroblastoma. PMID- 29158814 TI - DNA Methylation of miR-7 is a Mechanism Involved in Platinum Response through MAFG Overexpression in Cancer Cells. AB - One of the major limitations associated with platinum use is the resistance that almost invariably develops in different tumor types. In the current study, we sought to identify epigenetically regulated microRNAs as novel biomarkers of platinum resistance in lung and ovarian cancers, the ones with highest ratios of associated chemo-resistance. Methods: We combined transcriptomic data from microRNA and mRNA under the influence of an epigenetic reactivation treatment in a panel of four paired cisplatin -sensitive and -resistant cell lines, followed by real-time expression and epigenetic validations for accurate candidate selection in 19 human cancer cell lines. To identify specific candidate genes under miRNA regulation, we assembled "in silico" miRNAs and mRNAs sequences by using ten different algorithms followed by qRT-PCR validation. Functional assays of site-directed mutagenesis and luciferase activity, miRNAs precursor overexpression, silencing by antago-miR and cell viability were performed to confirm their specificity in gene regulation. Results were further explored in 187 primary samples obtained from ovarian tumors and controls. Results: We identified 4 candidates, miR-7, miR-132, miR-335 and miR-148a, which deregulation seems to be a common event in the development of resistance to cisplatin in both tumor types. miR-7 presented specific methylation in resistant cell lines, and was associated with poorer prognosis in ovarian cancer patients. Our experimental results strongly support the direct regulation of MAFG through miR-7 and their involvement in the development of CDDP resistance in human tumor cells. Conclusion: The basal methylation status of miR-7 before treatment may be a potential clinical epigenetic biomarker, predictor of the chemotherapy outcome to CDDP in ovarian cancer patients. To the best of our knowledge, this is the first report linking the regulation of MAFG by miRNA-7 and its role in chemotherapy response to CDDP. Furthermore, this data highlights the possible role of MAFG as a novel therapeutic target for platinum resistant tumors. PMID- 29158815 TI - Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury. AB - Increasing evidence indicates that interleukin-22 (IL-22) holds tremendous potential as a protective agent in preventing liver injury, but its pleiotropic effects and pathogenic role in carcinogenesis, rheumatoid arthritis and psoriasis restrict its systemic application. Here, we first developed a nanoparticle (liposIA) as a liver-targeted agent through IL-22 tethered to apolipoprotein A-I (ApoA-I) in a gene therapy vector. LiposIA was prepared using thin film dispersion method and the complexes exhibited desirable nanoparticle size, fine polydisperse index, highly efficient transfection, and excellent serum and storage stability. Biodistribution and hepatic STAT3 phosphorylation studies revealed that IL-22 tethered to ApoA-I led to highly efficient liver targeting. More importantly, our studies showed that a single-dose of liposIA was able to protect mice against acetaminophen-induced liver injury and did not initiate inflammatory response or systemic toxicity in vivo. During this process, activated STAT3/Erk and Akt/mTOR signaling transductions were observed, as well as inhibition of reactive oxygen species (ROS) generation, which prevented mitochondrial dysfunction. These studies demonstrated that IL-22 tethered to apolipoprotein A-I could target and ameliorate acetaminophen-induced acute liver injury, which highlighted that a targeted strategy for IL-22 delivery might have broad utility for the protection of hepatocellular damage. PMID- 29158816 TI - Dual-targeting Theranostic System with Mimicking Apoptosis to Promote Myocardial Infarction Repair via Modulation of Macrophages. AB - Currently unsatisfactory treatment of myocardial infarction (MI) is due to the unbridled inflammation and the delayed diagnosis at the early stage. To address these problems, firstly, phosphatidylserine (PS) was used to modulate the phenotypes of macrophages (MPhi) and resolve the early inflammation via binding to PS receptors (PSR) on macrophage surface. Secondly, highly-sensitive magnetic iron oxide nanocubes (MIONs) were adopted to realize the early visualization via magnetic resonance imaging (MRI). However, the major drawback for MIONs as contrast agents was their hydrophobic properties and insufficient delivery. Hence, zwitterionic biodegradable copolymer poly(lactide)-polycarboxybetaine (PLA PCB, PP), companied with PS, was used to provide a good colloidal stability and long blood circulation for the nanocubes. Given the above, a theranostic nanosystem (PP/PS@MIONs) was constructed for early treatment of MI. With external magnetic field-induced targeting and PS targeting, the nanosystem enhanced the accumulation in infarcted area, and accelerated the resolution of early inflammatory responses. Moreover, the nanocubes in system were promoted to escape from endosomes/lysosomes via protonation of PCB, which contributes to accurate MRI. This nanosystem showed good inflammation-resolving effects and imaging ability in MI model rats. Therefore, this theranostic nanosystem can realize accurate visualization and significantly improve the treatment efficacy of MI at early stage. PMID- 29158818 TI - Identifying and Characterizing circRNA-Protein Interaction. AB - Circular RNAs have been identified as naturally occurring RNAs that are highly represented in the eukaryotic transcriptome. Although a large number of circRNAs have been reported, circRNA functions remain largely unknown. CircRNAs can function as miRNA sponges, thereby reducing their ability to target mRNAs. We hypothesize that circRNAs may bind, store, sort, and sequester proteins to particular subcellular locations, and act as dynamic scaffolding molecules that modulate protein-protein interactions. Here, we review the biological implication and function of circRNA-protein interaction, and reveal a dynamic model of the interaction in various tissues, development stages and physiological conditions. Improved techniques to identify and characterize the dynamic RNA-protein interactions may elucidate the molecular mechanisms associated with the expression and functional diversity of circRNAs. PMID- 29158819 TI - Pro-Inflammatory CXCR3 Impairs Mitochondrial Function in Experimental Non Alcoholic Steatohepatitis. AB - : Mitochondrial dysfunction plays a crucial role in the development of non alcoholic steatohepatitis (NASH). However, the regulator of mitochondrial dysfunction in the pathogenesis of NASH is still largely unclear. CXCR3 is an essential pro-inflammatory factor in chronic liver diseases. We explored the significance of CXCR3 in regulating mitochondrial function during NASH development in animal models and cultured hepatocytes. METHODS: The effects of CXCR3 on mitochondrial function were evaluated by genetic knockout or pharmacological inhibition in mouse models and in vitro. The ultrastructural changes of mitochondria were assessed by transmission electron microscopy (TEM). Hepatic levels of mitochondrial reactive oxygen species (ROS), DNA damage, membrane potential and ATP were examined. RESULTS: CXCR3 ablation by genetic knockout or pharmacological inhibition in mice protected against NASH development by influencing mitochondrial function. Similarly, depletion of CXCR3 reduced steatohepatitis injury in cultured hepatocytes. TEM analysis revealed that liver mitochondrial integrity was much improved in CXCR3 knockout (CXCR3-/-) compared to wildtype (WT) mice. In agreement with this, impaired mitochondrial function was pronounced in WT mice compared to CXCR3-/- mice, evidenced by increased protein expression of dynamic-related protein-1 (DRP1) and fission-1 (FIS1) and decreased protein expression of mitofusin-1 (MFN1). Mitochondrial dysfunction was induced in AML-12 hepatocytes by methionine and choline deficient medium and in HepG2 cells by palmitic acid. The impaired mitochondrial function in both cell lines was evidenced by reduced membrane potential and ATP content, and by increased mitochondrial ROS accumulation and DNA damage. However, CXCR3 knockdown by siCXCR3 significantly diminished the mitochondrial dysfunction in both AML-12 and HepG2 hepatocytes. In addition, inhibition of CXCR3 by CXCR3 specific antagonists SCH546738 and AMG487 restored mitochondrial function and inhibited mitochondrial-dependent apoptosis in the liver of WT mice fed with methionine and choline deficient diet. CONCLUSION: CXCR3 induces mitochondrial dysfunction, which contributes to the pathogenesis of steatohepatitis. Pharmacologic blockade of CXCR3 prevents mitochondrial dysfunction and restores the severity of steatohepatitis, indicating a potential clinical impact for controlling the disease. PMID- 29158817 TI - Extracellular Vesicles in Cardiovascular Theranostics. AB - Extracellular vesicles (EVs) are small bilayer lipid membrane vesicles that can be released by most cell types and detected in most body fluids. EVs exert key functions for intercellular communication via transferring their bioactive cargos to recipient cells or activating signaling pathways in target cells. Increasing evidence has shown the important regulatory effects of EVs in cardiovascular diseases (CVDs). EVs secreted by cardiomyocytes, endothelial cells, fibroblasts, and stem cells play essential roles in pathophysiological processes such as cardiac hypertrophy, cardiomyocyte survival and apoptosis, cardiac fibrosis, and angiogenesis in relation to CVDs. In this review, we will first outline the current knowledge about the physical characteristics, biological contents, and isolation methods of EVs. We will then focus on the functional roles of cardiovascular EVs and their pathophysiological effects in CVDs, as well as summarize the potential of EVs as therapeutic agents and biomarkers for CVDs. Finally, we will discuss the specific application of EVs as a novel drug delivery system and the utility of EVs in the field of regenerative medicine. PMID- 29158820 TI - pH-Sensitive Nano-Complexes Overcome Drug Resistance and Inhibit Metastasis of Breast Cancer by Silencing Akt Expression. AB - The therapy of breast cancer is encumbered by drug resistance and metastasis, which can be due to a defective PI3K/AKT/mTOR signaling pathway. This study was aimed at improving the anti-cancer effect of the chemotherapeutic agent paclitaxel (PTX) on the drug resistant and metastatic breast cancer by co delivering PTX and a siRNA, siAkt, directed at silencing the Akt expression. Methods: The pH-sensitive amphiphilic polymer, poly [(1,4-butanediol)-diacrylate beta-N, N-diisopropylethylenediamine]-polyethyleneimine (BDP) was synthesized. The PTX-loaded BDP micelle/siAkt nano-complex (PMA) was prepared and characterized. The cellular uptake, cytotoxicity, RNA interference efficiency, biodistribution, pharmacokinetics, pharmacodynamics, and biocompatibility of PMA in the murine metastatic breast cancer 4T1 cells and the 4T1 tumor-bearing mice were evaluated. Results: PMA was stable at the neutral as well as tumor extracellular pH and released the drugs in the intra-endo/lysosome acidic environment. In 4T1 cells, the RNA interference against the Akt gene down regulated the expression of Akt and P-glycoprotein and up-regulated the expression of Caspase-3. The down-regulated P-gp inhibits the efflux of PTX thereby increasing its intracellular concentration, improving the cytotoxicity, and inhibiting the migration and invasion of 4T1 cells. In the 4T1 tumor-bearing mice, co-delivery of PTX and siAkt by PMA achieved a tumor inhibiting rate of 94.1% and suppressed 96.8% lung metastases. PMA did not cause pathological lesions in normal organs. Conclusion: PMA, by virtue of overcoming drug resistance and simultaneously restraining lung metastasis, might be an efficient drug delivery system for the therapy of breast cancer. PMID- 29158821 TI - Ultra-small pH-responsive Nd-doped NaDyF4 Nanoagents for Enhanced Cancer Theranostic by in situ Aggregation. AB - To achieve accurate tumor location and highly efficient cancer therapy effect, the properties of cancer theranostic agents should be optimized and enhanced. In this work, ultra-small Nd doped NaDyF4 were firstly reported as novel contrast agents for near-infrared second window downconversion luminescence (NIR II DCL) and magnetic resonance imaging. Based on the optimization strategy, gallic acid Fe(III) complex modified NaDyF4:10%Nd (NaDyF4:10%Nd-GA-Fe) was selected as the optimal agent with high transversal relaxivity, strong NIR II DCL, high photothermal conversion efficiency, and low toxicity. In vitro experiment found that it can be aggregated rapidly in low pH condition, leading to the particle size increasing. Due to the theranostic properties coupled in NaDyF4:10%Nd-GA-Fe are size dependent, properties enhancement was observed within the pH responsive aggregation progress. Further study in small animal model bearing tumor demonstrated the enhanced cancer theranostic by in situ aggregation. The optimized nanoagents have potential applications in medical and also provide a novel strategy for future study of cancer theranostic enhancement. PMID- 29158822 TI - Liposomal 64Cu-PET Imaging of Anti-VEGF Drug Effects on Liposomal Delivery to Colon Cancer Xenografts. AB - Liposomes (LP) deliver drug to tumors due to enhanced permeability and retention (EPR). LP were labeled with 64Cu for positron emission tomography (PET) to image tumor localization. Bevacizumab (bev), a VEGF targeted antibody, may modify LP delivery by altering tumor EPR and this change can also be imaged. Objective: Assess the utility of 64Cu-labeled LP for PET in measuring altered LP delivery early after treatment with bev. Methods: HT-29 human colorectal adenocarcinoma tumors were grown subcutaneously in SCID mice. Empty LP MM-DX-929 (Merrimack Pharmaceuticals, Inc. Cambridge, MA) were labeled with 64CuCl2 chelated with 4 DEAP-ATSC. Tumor-bearing mice received ~200-300 MUCi of 64Cu-MM-DX-929 and imaged with microPET. All mice were scanned before and after the treatment period, in which half of the mice received bev for one week. Scans were compared for changes in LP accumulation during this time. Initially, tissues were collected after the second PET for biodistribution measurements and histological analysis. Subsequent groups were divided for further treatment. Tumor growth following bev treatment, with or without LP-I, was assessed compared to untreated controls. Results: PET scans of untreated mice showed increased uptake of 64Cu-MM-DX-929, with a mean change in tumor SUVmax of 43.9%+/-6.6% (n=10) after 7 days. Conversely, images of treated mice showed that liposome delivery did not increase, with changes in SUVmax of 7.6%+/-4.8% (n=12). Changes in tumor SUVmax were significantly different between both groups (p=0.0003). Histology of tumor tissues indicated that short-term bev was able to alter vessel size. Therapeutically, while bev monotherapy, LP-I monotherapy, and treatment with bev followed by LP-I all slowed HT-29 tumor growth compared to controls, combination provided no therapeutic benefit. Conclusions: PET with tracer LP 64Cu-MM-DX-929 can detect significant differences in LP delivery to colon tumors treated with bev when compared to untreated controls. Imaging with 64Cu-MM-DX-929 is sensitive enough to measure drug-induced changes in LP localization which can have an effect on outcomes of treatment with LP. PMID- 29158823 TI - Engineered Zn(II)-Dipicolylamine-Gold Nanorod Provides Effective Prostate Cancer Treatment by Combining siRNA Delivery and Photothermal Therapy. AB - Combination cancer treatment has emerged as a critical approach to achieve remarkable anticancer effect. In this study, we prepared a theranostic nanoformulation that allows for photoacoustic imaging as well as combination gene and photothermal therapy. Gold nanorods (GNR) were coated with dipicolyl amine (DPA), which forms stable complexes with Zn2+ cations. The resulting nanoparticles, Zn(II)/DPA-GNR, recognize phosphate-containing molecules, including siRNA, because of the specific interaction between Zn(II) and the phosphates. We chose anti-polo-like kinase 1 siRNA (siPLK) as our example for gene silencing. The strong complexation between Zn(II)/DPA-GNR and siPLK provided high stability to the nano-complexes, which efficiently delivered siRNA into the targeted cancer cells in vitro and in vivo. The particle served as a theranostic agent because the GNRs of nano-complexes permitted effective photothermal therapy as well as photoacoustic imaging upon laser irradiation. This gene/photothermal combination therapy using siPLK/Zn(II)DPA-GNRs exhibited significant antitumor activity in a PC-3 tumor mouse model. The concept described in this work may be extended to the development of efficient delivery strategies for other polynucleotides as well as advanced anticancer therapy. PMID- 29158824 TI - Dioscin Exerts Protective Effects Against Crystalline Silica-induced Pulmonary Fibrosis in Mice. AB - : Inhalation of crystalline silica particles leads to pulmonary fibrosis, eventually resulting in respiratory failure and death. There are few effective drugs that can delay the progression of this disease; thus, patients with silicosis are usually only offered supportive care. Dioscin, a steroidal saponin, exhibits many biological activities and health benefits including its protective effects against hepatic fibrosis. However, the effect of dioscin on silicosis is unknown. METHODS: We employed experimental mouse mode of silicosis. Different doses of dioscin were gavaged to the animals 1 day after crystalline silica instillation to see the effect of dioscin on crystalline silica induced pulmonary fibrosis. Also, we used RAW264.7 and NIH-3T3 cell lines to explore dioscin effects on macrophages and fibroblasts. Dioscin was also oral treatment but 10 days after crystalline silica instillation to see its effect on established pulmonary fibrosis. RESULTS: Dioscin treatment reduced pro-inflammation and pro fibrotic cytokine secretion by modulating innate and adaptive immune responses. It also reduced the recruitment of fibrocytes, protected epithelial cells from crystalline silica injury, inhibited transforming growth factor beta/Smad3 signaling and fibroblast activation. Together, these effects delayed the progression of crystalline silica-induced pulmonary fibrosis. The mechanism by which dioscin treatment alleviated CS-induced inflammation appeared to be via the reduction of macrophage, B lymphocyte, and T lymphocte infiltration into lung. Dioscin inhibits macrophages and fibroblasts from secreting pro-inflammatory cytokines and may also function as a modulator of T helper cells responses, concurrent with attenuated phosphorylation of the apoptosis signal-regulating kinase 1-p38/c-Jun N-terminal kinase pathway. Also, dioscin could block the phosphorylation of Smad3 in fibroblast. Oral treatment of dioscin could also effectively postpone the progression of established silicosis. CONCLUSION: Oral treatment dioscin delays crystalline silica-induced pulmonary fibrosis and exerts pulmonary protective effects in mice. Dioscin may be a novel and potent candidate for protection against crystalline silica-induced pulmonary fibrosis. PMID- 29158825 TI - Noninvasive Imaging of CD206-Positive M2 Macrophages as an Early Biomarker for Post-Chemotherapy Tumor Relapse and Lymph Node Metastasis. AB - Tumor relapse after initial regression post-chemotherapy is a major challenge in cancer treatment, as it usually leads to local-regional recurrence or inoperable distant metastasis. M2 macrophages diminish the tumor-inhibitory effect of chemotherapy and correlate with distant metastasis and poor prognosis. In this study, we investigated whether molecular imaging of M2 macrophages could serve as an early biomarker for tumor relapse after chemotherapy and tumor lymph node metastasis in preclinical mouse models. Methods: We developed M2 macrophage targeted probes for near-infrared fluorescence (NIRF) imaging and single-photon emission computed tomography (SPECT) using an anti-CD206 monoclonal antibody. The specific targeting capacity and potential applications of the NIRF and SPECT probes were investigated in subcutaneous tumor and lymph node metastasis models of 4T1 murine breast cancer. Results: M2 macrophage infiltration was significantly increased in the 4T1 tumors that later underwent relapse but not in non-relapsing 4T1 tumors after cyclophosphamide treatment. Through NIRF imaging and SPECT using our synthesized probes, the infiltration of M2 macrophages in relapsing tumors and tumor lymph node metastasis could be sensitively detected. Importantly, early prediction of tumor relapse by molecular imaging of M2 macrophages resulted in an effective eradication of tumors upon combination with additional radiotherapy. Conclusion: Our findings demonstrate that M2 macrophage targeted imaging allows for noninvasively predicting post-chemotherapy tumor relapse and sensitively detecting the metastatic lymph nodes in vivo. This imaging strategy could provide a better understanding of cancer progression, enable early prediction of tumor resistance, and have implications on the rational design of cancer therapeutics. PMID- 29158826 TI - Label-Free Biochips for Accurate Detection of Prostate Cancer in the Clinic: Dual Biomarkers and Circulating Tumor Cells. AB - Purpose: Early diagnosis of prostate cancer (PCa) is essential for the prevention of metastasis and for early treatment; therefore, we aimed to develop a simple, accurate, and multi-analyte assay system for early PCa diagnosis in this study. Experimental design: We fabricated three kinds of biochips then integrated into microfluidic device for simultaneous detection of vascularendothelial growth factor (VEGF), prostate-specific antigen (PSA), and PCa circulating tumor cells (CTC) in human serum for accurate diagnosis of PCa. Then the integrated device can be put in the ELISA reader for signal analysis after sample incubation, no necessary of further fluorescence staining or microscopy counting. Result: The integrated device has wide liner detection ranges (0.05-25 ng/mL for both PSA and VEGF, and 5-300 cells/mL for PCa CTC), as well as high levels of sensitivity and selectivity, and demonstrated a high correlation with an enzyme-linked immunosorbent assay for sample detection in patients. Also, the presented biochips could maintain their stability when stored at 37 degrees C for 49 days without significant differences in the red-shift (<5%). Conclusions: We have successfully developed a multi-analyte sensing system for rapid and easy detection of PSA, VEGF, and PC3 cells in PCa samples using label-free glass-based chips. This method presents the advantages of a broad working range, high specificity, label-free, high-speed, stability, and low cost detection method for point-of-care testing of PCa. PMID- 29158827 TI - Long-term Effect of Biomineralized Insulin Nanoparticles on Type 2 Diabetes Treatment. AB - Intracellular insulin may exhibit a long-term effect in regulating protein synthesis, DNA synthesis, and gene transcription. However, the intracellular delivery of insulin is a great challenge. Here, we describe how a simple biomineralization modification of insulin can transport it into intact cells on a large scale, leading to a long-term therapeutic effect on diabetes mellitus. Using insulin-resistant HepG2 cell and diabetic KKAy mice as models, in vitro and in vivo assessments have demonstrated that biomineralized insulin nanoparticles can trigger glucose metabolism, and this improvement extends after the treatment. The potential exists to improve the current treatment of type 2 diabetes mellitus through biomineralized modifications of insulin. This study provides a new paradigm of biomimetic nanotechnology for biomedical applications. PMID- 29158828 TI - Oral Microbiome: A New Biomarker Reservoir for Oral and Oropharyngeal Cancers. AB - Current biomarkers (DNA, RNA and protein) for oral cavity and oropharyngeal cancers demonstrate biological variations between individuals, rendering them impractical for clinical translation. Whilst these biomarkers originate from the host, there is not much information in the literature about the influence of oral microbiota on cancer pathogenesis, especially in oral cancers. Oral microbiotas are known to participate in disease initiation and progression not only limited to the oral cavity, but also at other distant sites. Due to the close proximity of oral microbiota and oral cavity and oropharyngeal tumours, abundance changes in oral microbiota may provide useful information on tumourigenesis. This review aims to highlight information on the role of oral microbiota in oral cavity and oropharyngeal cancers. An in-depth analysis into the oral microbiota may provide a new avenue to diagnose and treat these patients. PMID- 29158829 TI - Past, Present, and Future: Development of Theranostic Agents Targeting Carbonic Anhydrase IX. AB - Theranostics is the integration of diagnostic information with pharmaceuticals to increase effectiveness and safety of cancer treatments. Nuclear medicine provides a non-invasive means to visualize drug target expression across primary and metastatic sites, and assess pharmacokinetics and efficacy of companion therapeutic agents. This is significant given the increasing recognition of the importance of clonal heterogeneity in treatment response and resistance. Carbonic anhydrase IX (CA-IX) has been advocated as an attractive diagnostic and therapeutic biomarker for targeting hypoxia in solid malignancies. CA-IX confers cancer cell survival under low oxygen tension, and is associated with increased propensity for metastasis. As such, CA-IX is overexpressed in a broad spectrum of cancers. Different classes of antigen recognition molecules targeting CA-IX including monoclonal antibodies, peptides, small molecule inhibitors, and antibody mimetics have been radiolabeled for imaging and therapeutic applications. cG250, a chimeric monoclonal antibody, has been labeled with an assortment of radionuclides (124I, 111In, 89Zr, 131I, 90Y, and 177Lu) and is the most extensively investigated CA-IX radiopharmaceutical. In recent years, there have been tremendous advancements made by the research community in developing alternatives to cG250. Although still in preclinical settings, several small molecule inhibitors and antibody mimetics hold great promise in improving the management of aggressive and resistant cancers. PMID- 29158830 TI - Sustained Release Talazoparib Implants for Localized Treatment of BRCA1-deficient Breast Cancer. AB - Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 ug) Talazoparib were fabricated and characterized. In vitro studies with Brca1-deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1Co/Co;MMTV-Cre;p53+/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and gamma-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro. Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and gamma-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors. PMID- 29158831 TI - Identification and Validation of a Salivary Protein Panel to Detect Heart Failure Early. AB - BACKGROUND: Over 26 million people suffer from heart failure (HF) globally. Current diagnosis of HF relies on clinical evaluation, blood assays and imaging techniques. Our aim is to develop a diagnostic assay to detect HF in at risk individuals within the community using human saliva as a medium, potentially leading to a simple, safe early warning system. METHODS: Saliva samples were collected from healthy controls (n=36) and HF patients (n=75). Salivary proteome profiles were analysed by Sequential Window Acquisition of All Theoretical fragment ion spectra - Mass Spectrometry (SWATH-MS). A total of 738 proteins were quantified and 177 proteins demonstrated significant differences between HF patients and healthy controls. Candidate biomarkers were chosen based on their abundance and difference between the two cohorts. A multi-protein panel was developed using logistic regression analysis. The diagnostic performance of the multi-protein panel was assessed using receiver operative characteristic curves. The candidate proteins were further confirmed, using western blot analysis, and validated technically, using an independent biological cohort. RESULTS: A group of six proteins were chosen in the discovery phase as potential candidates based on their differences in the abundance between the two cohorts. During the validation phase, two of the proteins were not detected with western blotting and as such were removed. The final panel consists of four proteins with sensitivity of 83.3%, specificity of 62.5% with an area under ROC curve of 0.78 in discriminating healthy controls from NYHA class I/II HF patients, and was validated in a second independent cohort study. CONCLUSION: Analysis of salivary proteome using SWATH-MS revealed novel HF-specific protein candidates yielding high diagnostic performance. A multi-centre longitudinal clinical trial will be the next step before clinical implementation of this panel. PMID- 29158832 TI - Clinical Translation and First In-Human Use of [44Sc]Sc-PSMA-617 for PET Imaging of Metastasized Castrate-Resistant Prostate Cancer. AB - BACKGROUND: Various trivalent radiometals are well suited for labeling of DOTA conjugated variants of Glu-ureido-based prostate-specific membrane antigen (PSMA) inhibitors. The DOTA-conjugate PSMA-617 has proven high potential in PSMA radioligand therapy (PSMA-RLT) of prostate cancer as well as PET imaging when labeled with lutetium-177 and gallium-68 respectively. Considering the relatively short physical half-life of gallium-68 this positron emitter precludes prolonged acquisition periods, as required for pre-therapeutic dosimetry or intraoperative applications. In this context, the positron emitter scandium-44 is an attractive alternative for PET imaging. We report the synthesis of [44Sc]Sc-PSMA-617 as radiopharmaceutical with generator produced scandium-44, its in vitro characterization and clinical translation as part of a first in-human study. METHODS: Scandium-44 was obtained from a 44Ti/44Sc radionuclide generator. PSMA 617 was labeled with 142.4+/-12.7 MBq of scandium-44 in analogy to [68Ga]Ga-PSMA 617 and evaluated in vitro and in cell studies using PSMA+ LNCaP cells. A first in-human investigation was subsequently carried out in a cohort of 4 patients (mean age 70+/-1.8 a) registered for [177Lu]Lu-PSMA-617 therapy. 50.5+/-9.3 MBq (40 ug, 38.4 nmol) [44Sc]Sc-PSMA-617 were applied via intravenous injection (i.v.), respectively. A Siemens Biograph 2 PET/CT system was used to acquire initial dynamic PET data (30 min) of abdomen in list mode followed by static PET/CT data (skull to mid-thigh) at 45 min, 2 and 18 h post-injection (p.i.). For quantitative analysis, dynamic images were reconstructed as 6 data sets of 300 s each. The noise ratio was measured in liver, lung and an additional region outside the body. SUV values in different organs and lesions were measured and compared to [68Ga]Ga-PSMA-11 data of the same patients. Residence times and organ absorbed doses were calculated using OLINDA/EXM software. RESULTS: Quantitative radiochemical yields of >=98 % were achieved using 18 nmol of PSMA-617 after 20 min at 95 degrees C with apparent molar activity of 6.69+/-0.78 MBq/nmol. Following purification, >99 % radiochemical purity was obtained. [44Sc]Sc-PSMA 617 showed high stability (>95 %) in serum for 24 h. The binding affinity and internalization fraction were determined in PSMA+ LNCaP cells (IC50 = 4.72+/-0.7 nM and internalization fraction: 15.78+/-2.14 % IA/106 LNCaP cells) and compared to [68Ga]Ga-PSMA-11 (12.0+/-2.8 nM and 9.47+/-2.56 % IA/106 LNCaP cells). Physiological tracer uptake was observed in kidneys, liver, spleen, small intestine, urinary bladder, and salivary glands and pathological uptake in both soft and skeletal metastases. SUV values were significantly lower in the kidneys (14.0) compared to [68Ga]Ga-PSMA-11 OET (30.5). All other measured SUV values did not show a statistically significant difference. Tumor to liver ratios were found to lie between 1.9 and 8.3 for [68Ga]Ga-PSMA-11 and between 2.5 and 8.8 for [44Sc]Sc-PSMA-617 after 120 min. For [44Sc]Sc-PSMA-617 the ratios were higher and no statistically significant differences were observed. Total and % activity were highest in liver followed by kidneys, spleen, small intestine and salivary glands. Rapid wash out was seen in liver and spleen and gradually over time in kidneys. Kidneys received the highest radiation absorbed dose of 0.354 (0.180 0.488) mSv/MBq. No adverse pharmacological effects were observed. CONCLUSION: In conclusion [44Sc]Sc-PSMA-617 PET is suitable for PET imaging of prostate cancer tissue. [44Sc]Sc-PSMA-617 shows promise to enable pre-therapeutic dosimetry in clinical settings. However, the clinical advantages for individual dosimetry or other applications like intraoperative applications have to be investigated in further studies. PMID- 29158833 TI - Human Umbilical Cord MSCs as New Cell Sources for Promoting Periodontal Regeneration in Inflammatory Periodontal Defect. AB - Human periodontal ligament stem cells (hPDLSCs) transplantation represents a promising approach for periodontal regeneration; however, the cell source is limited due to the invasive procedure required for cell isolation. As human umbilical cord mesenchymal stem cells (hUCMSCs) can be harvested inexpensively and inexhaustibly, here we evaluated the regenerative potentials of hUCMSCs as compared with hPDLSCs to determine whether hUCMSCs could be used as new cell sources for periodontal regeneration. Methods The characteristics of hUCMSCs, including multi-differentiation ability and anti-inflammatory capability, were determined by comparison with hPDLSCs. We constructed cell aggregates (CA) using hUCMSCs and hPDLSCs respectively. Then hPDLSCs-CA and hUCMSCs-CA were combined with beta-tricalcium phosphate bioceramic (beta-TCP) respectively and their regenerative potentials were determined in a rat inflammatory periodontal defect model. Results hPDLSCs showed higher osteogenic differentiation potentials than hUCMSCs. Meanwhile, hUCMSCs showed higher extracellular matrix secretion and anti inflammatory abilities than hPDLSCs. Similar to hPDLSCs, hUCMSCs were able to contribute to regeneration of both soft and hard periodontal tissues under inflammatory periodontitis condition. There were more newly formed bone and periodontal ligaments in hPDLSCs and hUCMSCs groups than in non-cell treated group. Moreover, no significant differences of regenerative promoting effects between hPDLSCs and hUCMSCs were found. Conclusion: hUCMSCs generated similar promoting effects on periodontal regeneration compared with hPDLSCs, and can be used as new cell sources for periodontal regeneration. PMID- 29158834 TI - Rational design of Polymeric Hybrid Micelles to Overcome Lymphatic and Intracellular Delivery Barriers in Cancer Immunotherapy. AB - Poor distribution of antigen/adjuvant to target sites and inadequate induction of T cell responses remain major challenges in cancer immunotherapy because of the lack of appropriate delivery systems. Nanocarrier-based antigen delivery systems have emerged as an innovative strategy to improve vaccine efficacy. Here we present polymeric hybrid micelles (PHMs) as a simple and potent antigen/adjuvant co-delivery system with highly tunable properties. PHMs consist of two amphiphilic diblock copolymers, polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethyleneglycol (PCL-PEG). PHMs with different proportions of cationic PCL-PEI were prepared and loaded with tyrosinase-related protein 2 (Trp2) peptide and adjuvant CpG oligodeoxynucleotide to generate the Trp2/PHM/CpG co-delivery system. Lymphatic and intracellular antigen delivery as a function of PCL-PEI proportion was evaluated in vitro and in vivo. PHMs containing 10% (w/w) PCL-PEI (Trp2/PHM10/CpG) showed the optimal balance of good distribution to lymph nodes, strong immunization effect after subcutaneous administration, and low toxicity to dendritic cells. In a mouse model of B16F10 melanoma, Trp2/PHM10/CpG showed significantly higher antigen-specific cytotoxic T lymphocyte activity and greater anticancer efficacy than Trp2/PHM0/CpG without PCL-PEI or a mixture of free Trp2 and CpG. These results provide new insights into how cationic segments affect the efficiency of antigen delivery by cationic nanocarriers. They also suggest that PHMs can serve as a structurally simple and highly tunable platform for co-delivery of antigen and adjuvant in cancer immunotherapy. PMID- 29158835 TI - Theranostic Role of 32P-ATP as Radiopharmaceutical for the Induction of Massive Cell Death within Avascular Tumor Core. AB - Drug inaccessibility to vast areas of the tumor parenchyma is amongst the major hurdles for conventional therapies. Treatment efficacy rapidly decreases with distance from vessels and most of the tumor cells survive therapy. Also, between subsequent cycles of treatment, spared cancer cells replace those killed near the vessels, improving their access to nutrients, boosting their proliferation rate, and thus enabling tumor repopulation. Because of their property of "acting at a distance," radioisotopes are believed to overcome the physical barrier of vascular inaccessibility. Methods A novel molecular imaging tool called Cerenkov Luminescence Imaging (CLI) was employed for the detection of Cerenkov radiation emitted by beta particles, allowing in vivo tracking of beta-emitters. More precisely we investigated using a xenograft model of colon carcinoma the potential use of 32P-ATP as a novel theranostic radiopharmaceutical for tracing tumor lesions while simultaneously hampering their growth. Results Our analyses demonstrated that 32P-ATP injected into tumor-bearing mice reaches tumor lesions and persists for days and weeks within the tumor parenchyma. Also, the high penetrating beta particles of 32P-ATP exert a "cross-fire" effect that induces massive cell death throughout the entire tumor parenchyma including core regions. Conclusion Our findings suggest 32P-ATP treatment as a potential approach to complement conventional therapies that fail to reach the tumor core and to prevent tumor repopulation. PMID- 29158836 TI - A Laser-Activated Biocompatible Theranostic Nanoagent for Targeted Multimodal Imaging and Photothermal Therapy. AB - : Multifunctional nanoparticles have been reported for cancer detection and treatment currently. However, the accurate diagnosis and efficient treatment for tumors are still not satisfied. Here we report on the development of targeted phase change multimodal polymeric nanoparticles for the imaging and treatment of HER2-positive breast cancer. METHODS: We evaluated the multimodal imaging capabilities of the prepared nanoparticles in vitro using agar-based phantoms. The targeting performance and cytotoxicity of the nanoparticles were examined in cell culture using SKBR3 (over-expressing HER2) and MDA-MB-231 (HER2 negative) cells. We then tested the magnetic resonance (MR)/ photoacoustic (PA)/ ultrasound (US)/ near-infrared fluorescence (NIRF) multimodal imaging properties and photothermal effect of the nanoparticles in vivo using a SKBR3 breast xenograft model in nude mice. Tissue histopathology and immunofluorescence were also conducted. RESULTS: Both in vitro and in vivo systematical studies validated that the hybrid nanoparticles can be used as a superb MR/US/PA/NIRF contrast agent to simultaneously diagnose and guide tumor photothermal therapy (PTT). When irradiated by a near infrared laser, the liquid PFP vaporizes to a gas, rapidly expelling the contents and damaging surrounding tissues. The resulting micro sized bubbles provide treatment validation through ultrasound imaging. Localization of DIR and SPIO in the tumor region facilitate photothermal therapy for targeted tumor destruction. The mice treated with HER2 targeted nanoparticles had a nearly complete response to treatment, while the controls showed continued tumor growth. CONCLUSION: This novel theranostic agent may provide better diagnostic imaging and therapeutic potential than current methods for treating HER2-positive breast cancer. PMID- 29158837 TI - Temperature-Sensitive Gold Nanoparticle-Coated Pluronic-PLL Nanoparticles for Drug Delivery and Chemo-Photothermal Therapy. AB - : Gold nanoparticle-coated Pluronic-b-poly(L-lysine) nanoparticles (Pluronic PLL@Au NPs) were synthesized via an easy one-step method and employed as carriers for the delivery of paclitaxel (PTX) in chemo-photothermal therapy, in which Pluronic-PLL acts as the reductant for the formation of AuNPs without the need for an additional reducing agent. METHODS: The deposition of AuNPs on the surface of Pluronic-PLL micelles and the thermal response of the system were followed via ultraviolet-visible spectroscopy and dynamic light scattering. Calcein-AM and MTT assays were used to study the cell viability of MDA-MB-231 cells treated with PTX loaded Pluronic-PLL@Au NPs, and we then irradiated the cells with NIR light. RESULTS: An obvious temperature response was observed for the Pluronic-PLL@Au NPs. Blood compatibility and in vitro cytotoxicity assays confirmed that the Pluronic-PLL@Au NPs have excellent biocompatibility. Compared to Taxol, the PTX loaded Pluronic-PLL@Au NPs exhibited higher cytotoxicity in MDA-MB-231 cells. All of these results and confocal laser scanning microscopy analysis results suggest that Pluronic-PLL@Au NPs greatly enhance the cellular uptake efficiency of the drug. CONCLUSION: As confirmed by in vitro and in vivo studies, the combination of chemotherapy and photothermal therapy can cause more damage than chemo- or photothermal therapy did alone, demonstrating the synergistic effect of chemo photothermal treatment. Thus, the as-prepared Pluronic-PLL@Au NPs are promising for chemo-photothermal therapy. PMID- 29158839 TI - Characterization of Cardiac Dynamics in an Acute Myocardial Infarction Model by Four-Dimensional Optoacoustic and Magnetic Resonance Imaging. AB - Extraction of murine cardiac functional parameters on a beat-by-beat basis is limited with the existing imaging modalities due to insufficient three dimensional temporal resolution. Faster volumetric imaging methods enabling in vivo characterization of functional parameters are poised to advance cardiovascular research and provide a better understanding of the mechanisms underlying cardiac diseases. We present a new approach based on analyzing contrast-enhanced optoacoustic (OA) images acquired at high volumetric frame rate without using cardiac gating or other approaches for motion correction. We apply an acute murine myocardial infarction model optimized for acquisition of artifact free optoacoustic imaging data to study cardiovascular hemodynamics. Infarcted hearts (n = 21) could be clearly differentiated from healthy controls (n = 9) based on a significantly higher pulmonary transit time (PTT) (2.25 [2.00-2.41] s versus 1.34 [1.25-1.67] s, p = 0.0235), while no statistically significant difference was observed in the heart rate (318 [252-361] bpm versus 264 [252-320] bpm, p = 0.3129). Nevertheless, nonlinear heartbeat dynamics was stronger in the healthy hearts, as evidenced by the third harmonic component in the heartbeat spectra. MRI data acquired from the same mice further revealed that the PTT increases with the size of infarction and similarly increases with reduced ejection fraction. Moreover, an inverse relationship between infarct PTT and time post-surgery was found, which suggests the occurrence of cardiac healing. In combination with the proven ability of optoacoustics to track targeted probes within the injured myocardium, our method can depict cardiac anatomy, function, and molecular signatures, with both high spatial and temporal resolution. Volumetric four-dimensional optoacoustic characterization of cardiac dynamics with supreme temporal resolution can capture cardiovascular dynamics on a beat-by beat basis in mouse models of myocardial ischemia. PMID- 29158838 TI - CRISPR Genome Engineering for Human Pluripotent Stem Cell Research. AB - The emergence of targeted and efficient genome editing technologies, such as repurposed bacterial programmable nucleases (e.g., CRISPR-Cas systems), has abetted the development of cell engineering approaches. Lessons learned from the development of RNA-interference (RNA-i) therapies can spur the translation of genome editing, such as those enabling the translation of human pluripotent stem cell engineering. In this review, we discuss the opportunities and the challenges of repurposing bacterial nucleases for genome editing, while appreciating their roles, primarily at the epigenomic granularity. First, we discuss the evolution of high-precision, genome editing technologies, highlighting CRISPR-Cas9. They exist in the form of programmable nucleases, engineered with sequence-specific localizing domains, and with the ability to revolutionize human stem cell technologies through precision targeting with greater on-target activities. Next, we highlight the major challenges that need to be met prior to bench-to-bedside translation, often learning from the path-to-clinic of complementary technologies, such as RNA-i. Finally, we suggest potential bioinformatics developments and CRISPR delivery vehicles that can be deployed to circumvent some of the challenges confronting genome editing technologies en route to the clinic. PMID- 29158840 TI - Inorganic Kernel-Reconstituted Lipoprotein Biomimetic Nanovehicles Enable Efficient Targeting "Trojan Horse" Delivery of STAT3-Decoy Oligonucleotide for Overcoming TRAIL Resistance. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in a variety of tumor cells, but not most normal cells. Nevertheless, its therapeutic potential is limited due to the frequent occurrence of resistance in tumor cells, especially hepatocellular carcinoma cell lines. Therefore, we investigated the reversal effect of STAT3-decoy oligonucleotides (ODNs) on TRAIL resistance. Methods. Considering that the drawback of poor cellular permeability and rapid degradation in vivo limited ODNs' further clinical applications, we developed a biomimetic calcium phosphate-reconstituted low density lipoprotein nanovehicle (CaP@LDL) that would serve as a "Trojan horse" to carry STAT3-decoy ODNs into tumor cells and then regulate TRAIL-induced apoptosis. Results. In comparison with native ODNs, the reconstituted CaP@LDL packaged ODNs showed significantly increased serum stability, cellular transfection, in vitro synergistic cytotoxicity and apoptosis in hepatoma cells, while there was no cytotoxicity to normal cells. The improved TRAIL sensitization is attributed to blocking of STAT3 signaling and consequent expression of the downstream target antiapoptotic gene. Following systemic administration, CaP@LDL displayed LDL-mimicking pharmacokinetic behavior such as attenuated blood clearance as well as enhanced accumulation in tumor and hepatorenal sites. With the synergistic combination of decoyODN/CaP@LDL, TRAIL dramatically inhibited hepatic tumor growth in a xenograft model and induced significant tumor apoptosis in vivo. Conclusion. These results suggested that CaP@LDL-mediated STAT3-decoy ODN delivery might be a promising new strategy for reversing TRAIL resistance in hepatocellular carcinoma therapy. PMID- 29158841 TI - Autophagy Maintains the Function of Bone Marrow Mesenchymal Stem Cells to Prevent Estrogen Deficiency-Induced Osteoporosis. AB - Rationale: The impaired function of endogenous bone marrow mesenchymal stem cells (BMMSCs) is a determinant in the development of osteoporosis (OP). Recent researches have proved that autophagy plays an important role in maintenance of skeletal phenotype. However, whether autophagy affects the development of OP through regulating the function of BMMSCs remains elusive. Methods: Ovariectomy (OVX)-induced OP model and sham model were established in 8-week-old C57 mice. The differentiation and immunoregulation properties of BMMSCs from two models were examined by osteogenic/adipogenic induction in vitro and treatment of a dextran sulfate sodium (DSS)-induced mice colitis model in vivo. We evaluated autophagy activity in sham and OVX BMMSCs by quantitative real time-polymerase chain reaction (qRT-PCR), western blotting, laser confocal microscopy and transmission electron microscopy (TEM). Finally, to testify the effects of rapamycin, short hairpin RNA (shRNA) -BECN1 (shBECN1) and shRNA-ATG5 (shATG5), we performed Alizarin Red staining and Oil Red O staining to detect lineage differentiations of BMMSCs, and carried out micro-CT, calcein staining and Oil Red O staining to assess the skeletal phenotype. Results: BMMSCs from OVX-induced OP model mice exhibited decreased osteogenic differentiation, increased adipogenic differentiation and impaired immunoregulatory capacity. Furthermore, autophagy decreased both in bone marrow and BMMSCs of osteoporotic mice. Importantly, regulation of autophagy directly affects the functions of BMMSCs, including differentiation and immunoregulatory capacities. Moreover, treatment with rapamycin rescued the function of endogenous BMMSCs and attenuated the osteoporotic phenotype in OVX mice. Conclusion: Our findings suggest that autophagy regulates the regenerative function of BMMSCs and controls the development of OP. The restoration of autophagy by rapamycin may provide an effective therapeutic method for osteoporosis. PMID- 29158842 TI - Locoregional Confinement and Major Clinical Benefit of 188Re-Loaded CXCR4 Targeted Nanocarriers in an Orthotopic Human to Mouse Model of Glioblastoma. AB - PURPOSE: Gold standard beam radiation for glioblastoma (GBM) treatment is challenged by resistance phenomena occurring in cellular populations well prepared to survive or to repair damage caused by radiation. Among signals that have been linked with radio-resistance, the SDF1/CXCR4 axis, associated with cancer stem-like cell, may be an opportune target. To avoid the problem of systemic toxicity and blood-brain barrier crossing, the relevance and efficacy of an original system of local brain internal radiation therapy combining a radiopharmaceutical with an immuno-nanoparticle was investigated. EXPERIMENT DESIGN: The nanocarrier combined lipophilic thiobenzoate complexes of rhenium-188 loaded in the core of a lipid nanocapsule (LNC188Re) with a function-blocking antibody, 12G5 directed at the CXCR4, on its surface. The efficiency of 12G5 LNC188Re was investigated in an orthotopic and xenogenic GBM model of CXCR4 positive U87MG cells implanted in the striatum of Scid mice. RESULTS: We demonstrated that 12G5-LNC188Re single infusion treatment by convection-enhanced delivery resulted in a major clinical improvement in median survival that was accompanied by locoregional effects on tumor development including hypovascularization and stimulation of the recruitment of bone marrow derived CD11b- or CD68-positive cells as confirmed by immunohistochemistry analysis. Interestingly, thorough analysis by spectral imaging in a chimeric U87MG GBM model containing CXCR4-positive/red fluorescent protein (RFP)-positive- and CXCR4 negative/RFP-negative-GBM cells revealed greater confinement of DiD-labeled 12G5 LNCs than control IgG2a-LNCs in RFP compartments. Main conclusion: These findings on locoregional impact and targeting of disseminated cancer cells in tumor margins suggest that intracerebral active targeting of nanocarriers loaded with radiopharmaceuticals may have considerable benefits in clinical applications. PMID- 29158843 TI - pH-Responsive Aerobic Nanoparticles for Effective Photodynamic Therapy. AB - RATIONALE: Photodynamic therapy (PDT), an O2-dependent treatment for inhibition of cancer proliferation, suffers from the low therapeutic effect in clinical application due to the hypoxic microenvironment in tumor cells. METHODS: To overcome this obstacle, a stimuli-responsive drug delivery system with O2 self sufficiency for effective PDT was developed. In this study, pH-responsive aerobic nanoparticles were prepared by the electrostatic interaction between the O2 evolving protein Catalase and Chitosan. Subsequently, the photosensitizer Chlorin e6 (Ce6) was encapsulated in the nanoparticles. RESULTS: The nanoparticles exhibited high stability in aqueous medium and efficient cellular uptake by tumor cells facilitating their accumulation in tumors by enhanced permeability and retention (EPR) effect. In acidic environment, irradiation caused disassembly of the nanoparticles resulting in the quick release of Catalase and the photosensitizer with continuous formation of cytotoxic singlet oxygen (1O2) greatly enhancing the PDT efficacy in hypoxic tumor tissues both in vitro and in vivo biological studies. CONCLUSION: Due to the unique O2 self-sufficiency, the nanoparticles, upon irradiation, exhibited higher anticancer activity than free Ce6 both in vitro and in vivo. Our work has identified a new pH-triggered strategy to overcome hypoxia for effective PDT against cancer cells. PMID- 29158844 TI - Quantitative Imaging for Targeted Radionuclide Therapy Dosimetry - Technical Review. AB - Targeted radionuclide therapy (TRT) is a promising technique for cancer therapy. However, in order to deliver the required dose to the tumor, minimize potential toxicity in normal organs, as well as monitor therapeutic effects, it is important to assess the individualized internal dosimetry based on patient specific data. Advanced imaging techniques, especially radionuclide imaging, can be used to determine the spatial distribution of administered tracers for calculating the organ-absorbed dose. While planar scintigraphy is still the mainstream imaging method, SPECT, PET and bremsstrahlung imaging have promising properties to improve accuracy in quantification. This article reviews the basic principles of TRT and discusses the latest development in radionuclide imaging techniques for different theranostic agents, with emphasis on their potential to improve personalized TRT dosimetry. PMID- 29158845 TI - In-Tether Chiral Center Induced Helical Peptide Modulators Target p53-MDM2/MDMX and Inhibit Tumor Growth in Stem-Like Cancer Cell. AB - Inhibition of the interaction between p53 and MDM2/MDMX has attracted significant attention in anticancer therapy development. We designed a series of in-tether chiral center-induced helical stabilized peptides, among which MeR/PhR effectively reactivated p53. The activation of p53 inhibits cell proliferation and induces apoptosis in both the MCF-7 normal tumor cell line and the PA-1 pluripotent cancer cell line with only minimal cellular toxicity towards normal cells or cancer cell lines with p53 mutations. The in vivo bioactivity study of the peptide in the ovarian teratocarcinoma (PA-1) xenograft model showed a tumor growth rate inhibition of 70% with a dosage of 10 mg/kg (one injection every other day). This is the first application of a stabilized peptide modulator targeting stem-like cancer cell both in vitro and in vivo and provides references to cancer stem cell therapy. PMID- 29158846 TI - Subcellular Localization of Survivin Determines Its Function in Cardiomyocytes. AB - Rationale: Reducing cardiomyocyte death and enhancing their proliferation after myocardial infarction is perhaps the single largest challenge for cardiac tissue regeneration. Survivin (SVV) is the smallest member of the inhibitor of apoptosis (IAP) family but plays two important roles; inhibiting caspase-9 activation in the intrinsic apoptosis pathway, and regulating microtubule dynamics and chromosome segregation during cell division. Genetic depletion of cardiac SVV leads to incomplete cardiomyocyte division and abnormal heart development. However, the function of SVV in adult hearts after myocardial infarction remains unclear. Methods: A homozygous inducible cardiomyocyte-specific SVV knockout transgenic mouse model was established through crossbreeding SVVflox/flox and alphaMHC-MCM transgenic mice. Adult mice received consecutive intraperitoneal injection of tamoxifen to induce genetic removal of SVV in cardiomyocytes. A SVV overexpressing model was established via local delivery of SVV in wild-type mouse hearts. Results: We found that 30.82% of cardiomyocytes in the peri-infarct region of SVV knockout mice were apoptotic, significantly higher than the 22.18% in control mice. In addition, ejection fraction was 29.00+/-0.40% in knockout mice compared to 38.04+/-0.50% in control mice 21 days after myocardial infarction. On the contrary, locally overexpressing SVV in the heart improved cardiac functions. Unexpectedly, we found that altering the subcellular localization of SVV overexpression produced different outcomes. Overexpression of SVV in the cytoplasm decreased cardiomyocyte apoptosis, whereas overexpression of SVV in the nucleus enhanced cardiac regeneration. The ejection fraction of mice overexpressing SVV was 36.58+/-0.91%, significantly higher than 28.18+/-1.70% in the GFP control group. Apoptotic cardiomyocytes were only 4.63% in mouse overexpressing cytosolic SVV, compared to 9.31% in the GFP group, and activation of caspase-3 was also reduced. Moreover, mice overexpressing NLS-SVV exhibited a better ejection fraction (36.19+/-1.02%,) than GFP controls (26.69+/-0.75%). NLS SVV enhanced H3P-positive cardiomyocytes in the border zone to 0.28%, compared to only 0.08% in GFP group, through interacting with Aurora B. Conclusions: We demonstrate the importance of SVV subcellular localization in regulating post-MI cardiac repair and regeneration. We hope that this will open new translational approaches through targeted delivery of SVV. PMID- 29158847 TI - Photoactive Poly(3-hexylthiophene) Nanoweb for Optoelectrical Stimulation to Enhance Neurogenesis of Human Stem Cells. AB - : Optoelectrical manipulation has recently gained attention for cellular engineering; however, few material platforms can be used to efficiently regulate stem cell behaviors via optoelectrical stimulation. In this study, we developed nanoweb substrates composed of photoactive polymer poly(3-hexylthiophene) (P3HT) to enhance the neurogenesis of human fetal neural stem cells (hfNSCs) through photo-induced electrical stimulation. METHODS: The photoactive nanoweb substrates were fabricated by self-assembled one-dimensional (1D) P3HT nanostructures (nanofibrils and nanorods). The hfNSCs cultured on the P3HT nanoweb substrates were optically stimulated with a green light (539 nm) and then differentiation of hfNSCs on the substrates with light stimulation was examined. The utility of the nanoweb substrates for optogenetic application was tested with photo-responsive hfNSCs engineered by polymer nanoparticle-mediated transfection of an engineered chimeric opsin variant (C1V1)-encoding gene. RESULTS: The nanoweb substrates provided not only topographical stimulation for activating focal adhesion signaling of hfNSCs, but also generated optoelectrical stimulation via photochemical and charge-transfer reactions upon exposure to 539 nm wavelength light, leading to significantly enhanced neuronal differentiation of hfNSCs. The optoelectrically stimulated hfNSCs exhibited mature neuronal phenotypes with highly extended neurite formation and functional neuron-like electrophysiological features of sodium currents and action potentials. Optoelectrical stimulation with 539 nm light simultaneously activated both C1V1-modified hfNSCs and nanoweb substrates, which upregulated the expression and activation of voltage-gated ion channels in hfNSCs and further increased the effect of photoactive substrates on neuronal differentiation of hfNSCs. CONCLUSION: The photoactive nanoweb substrates developed in this study may serve as platforms for producing stem cell therapeutics with enhanced neurogenesis and neuromodulation via optoelectrical control of stem cells. PMID- 29158848 TI - Biodegradable Core-shell Dual-Metal-Organic-Frameworks Nanotheranostic Agent for Multiple Imaging Guided Combination Cancer Therapy. AB - Metal-organic-frameworks (MOFs) possess high porosity, large surface area, and tunable functionality are promising candidates for synchronous diagnosis and therapy in cancer treatment. Although large number of MOFs has been discovered, conventional MOF-based nanoplatforms are mainly limited to the sole MOF source with sole functionality. In this study, surfactant modified Prussian blue (PB) core coated by compact ZIF-8 shell (core-shell dual-MOFs, CSD-MOFs) has been reported through a versatile stepwise approach. With Prussian blue as core, CSD MOFs are able to serve as both magnetic resonance imaging (MRI) and fluorescence optical imaging (FOI) agents. We show that CSD-MOFs crystals loading the anticancer drug doxorubicin (DOX) are efficient pH and near-infrared (NIR) dual stimuli responsive drug delivery vehicles. After the degradation of ZIF-8, simultaneous NIR irradiation to the inner PB MOFs continuously generate heat that kill cancer cells. Their efficacy on HeLa cancer cell lines is higher compared with the respective single treatment modality, achieving synergistic chemo thermal therapy efficacy. In vivo results indicate that the anti-tumor efficacy of CSD-MOFs@DOX+NIR was 7.16 and 5.07 times enhanced compared to single chemo therapy and single thermal-therapy respectively. Our strategy opens new possibilities to construct multifunctional theranostic systems through integration of two different MOFs. PMID- 29158849 TI - Enhanced antitumor efficacy of biocompatible magnetosomes for the magnetic hyperthermia treatment of glioblastoma. AB - In this study, biologically synthesized iron oxide nanoparticles, called magnetosomes, are made fully biocompatible by removing potentially toxic organic bacterial residues such as endotoxins at magnetosome mineral core surfaces and by coating such surface with poly-L-lysine, leading to magnetosomes-poly-L-lysine (M PLL). M-PLL antitumor efficacy is compared with that of chemically synthesized iron oxide nanoparticles (IONPs) currently used for magnetic hyperthermia. M-PLL and IONPs are tested for the treatment of glioblastoma, a dreadful cancer, in which intratumor nanoparticle administration is clinically relevant, using a mouse allograft model of murine glioma (GL-261 cell line). A magnetic hyperthermia treatment protocol is proposed, in which 25 ug in iron of nanoparticles per mm3 of tumor are administered and exposed to 11 to 15 magnetic sessions during which an alternating magnetic field of 198 kHz and 11 to 31 mT is applied for 30 minutes to attempt reaching temperatures of 43-46 degrees C. M PLL are characterized by a larger specific absorption rate (SAR of 40 W/gFe compared to 26 W/gFe for IONPs as measured during the first magnetic session), a lower strength of the applied magnetic field required for reaching a target temperature of 43-46 degrees C (11 to 27 mT compared with 22 to 31 mT for IONPs), a lower number of mice re-administered (4 compared to 6 for IONPs), a longer residence time within tumours (5 days compared to 1 day for IONPs), and a less scattered distribution in the tumour. M-PLL lead to higher antitumor efficacy with full tumor disappearances achieved in 50% of mice compared to 20% for IONPs. This is ascribed to better ability of M-PLL, at equal iron concentrations, to maintain tumor temperatures at 43-46 degrees C over a longer period of times. PMID- 29158851 TI - The Cuban Public Health System Focuses Research on Community Needs. PMID- 29158850 TI - MMPP Attenuates Non-Small Cell Lung Cancer Growth by Inhibiting the STAT3 DNA Binding Activity via Direct Binding to the STAT3 DNA-Binding Domain. AB - Rationale: Signal transducer and activator of transcription-3 (STAT3) plays a pivotal role in cancer biology. Many small-molecule inhibitors that target STAT3 have been developed as potential anticancer drugs. While designing small-molecule inhibitors that target the SH2 domain of STAT3 remains the leading focus for drug discovery, there has been a growing interest in targeting the DNA-binding domain (DBD) of the protein. Methods: We demonstrated the potential antitumor activity of a novel, small-molecule (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1 yl)phenol (MMPP) that directly binds to the DBD of STAT3, in patient-derived non small cell lung cancer (NSCLC) xenograft model as well as in NCI-H460 cell xenograft model in nude mice. Results: MMPP effectively inhibited the phosphorylation of STAT3 and its DNA binding activity in vitro and in vivo. It induced G1-phase cell cycle arrest and apoptosis through the regulation of cell cycle- and apoptosis-regulating genes by directly binding to the hydroxyl residue of threonine 456 in the DBD of STAT3. Furthermore, MMPP showed a similar or better antitumor activity than that of docetaxel or cisplatin. Conclusion: MMPP is suggested to be a potential candidate for further development as an anticancer drug that targets the DBD of STAT3. PMID- 29158852 TI - Curative Metatarsal Bone Surgery Combined with Intralesional Administration of Recombinant Human Epidermal Growth Factor in Diabetic Neuropathic Ulceration of the Forefoot: A Prospective, Open, Uncontrolled, Nonrandomized, Observational Study. AB - Background: Curative surgery is performed for a foot with ulcers and loss of protective sensation to heal the wound and prevent amputation. Evidence supports that patients with diabetes have decreased concentrations of growth factors in their tissues, notably epidermal growth factor (EGF). Injecting EGF deep into the bottom of the wound and its contours encourages a more effective response in terms of granulation tissue growth and wound closure. Objective: To assess the effectiveness and safety of curative metatarsal bone surgery combined with intralesional administration of human recombitant EGF in neuropathic diabetic forefoot ulceration. Methods: A prospective, open-label study of the effectiveness and safety of curative metatarsal bone surgery combined with intralesional administration of human recombitant EGF in neuropathic ulceration of the forefoot in patients with diabetes was conducted on a convenience sample of 212 patients with diabetes who had a total of 231 neuropathic ulcerations of the forefoot. The eligibility criteria included normal physical activity without a history of minor amputation and meeting the inclusion criteria without meeting any of the exclusion criteria in the Vascular Surgery Service of the Clinic Surgical Hospital "Jose R. Lopez Tabrane" from January 2009 to May 2015. The follow-up process ended in November 2015, which was based on nonprobability consecutive sampling of 128 patients with diabetes who had a total of 131 foot ulcers in the treatment group and 84 patients with diabetes who had a total of 100 foot ulcers in the control group. Results: The groups had comparable demographic and baseline characteristics. In the recombitant human EGF study group, there was a 2.1-fold shorter time of re-epithelization (healing), less recidivism, and a 2.3-fold decrease in lesions, which favored the selected treatment. The safety profile was appropriate according to the low frequency of complications and the light or moderate characteristics of the complications. Only shivering and fever were more frequent in the recombitant human EGF-treated group. Conclusions: The combination of curative metatarsal bone surgery with intralesional administration of recombinant human EGF resulted in a significant reduction in the re-epithelization time, recidivism, and development of new diabetic lesions. The safety profile was appropriate. However, more randomized, triple-blind, and placebo trials are needed to evaluate the efficacy and safety of this new therapy. PMID- 29158853 TI - Diagnosis and Treatment of Autoimmune Liver Diseases in a Tertiary Referral Center in Cuba. AB - Background: Autoimmune liver diseases (AILD) comprise a set of entities characterized by tissue damage as a result of the loss of self-tolerance. There are few reports of AILD from Caribbean countries. Objectives: The aim of our study was to investigate the clinical patterns, laboratory findings, and immunologic features, treatment responses, and prognoses of AILD in adult patients at a Cuban tertiary referral center. Methods: A prospective study was conducted at the National Institute of Gastroenterology in Havana, Cuba, from May 2012 to April 2016. Clinical, immunologic, and histologic features of autoimmune hepatitis (AIH), primary biliary cirrhosis, AIH/primary biliary cirrhosis overlap syndrome, autoimmune cholangiopathy, and primary sclerosing cholangitis were recorded. Response to therapy was assessed by serum alanine aminotransferase and bilirubin levels at 3, 6, 12, and 24 months after treatment initiation. Results: Of the 106 patients included in the study, 85.5% were women. The median age at presentation was 47 years. AIH was the most common AILD and was diagnosed in 60 patients (56.6%), 55 of whom had type 1 AIH. Primary biliary cirrhosis was diagnosed in 22 patients (20.7%), overlap syndrome in 16 patients (15%), autoimmune cholangiopathy in 5 patients (4.71%), and PSC in 3 patients (2.8%). Most patients were symptomatic; 48 patients (45.2%) presented with liver cirrhosis, 14.5% of whom had decompensated cirrhosis. Follow-up of treatment was between 6 and 24 months. Prednisone monotherapy was used in 22 AIH patients (36.6%) and a combination of prednisone and azathioprine was used in 28 (46.6%) AIH patients. Response to treatment was seen in 41 AIH patients (68.3%), 33 of whom (55%) had a complete response and 8 of whom (24.2%) relapsed after 12 months of maintenance therapy. No or incomplete response to treatment was seen in 18 patients (30%). In 46 patients with autoimmune cholestasis, ursodeoxycholic acid was used as monotherapy in 25 patients (54.3%). Conclusions: The clinical profile of AILD in a sample of the Cuban population is similar to that reported in South areas (Developing countries). AIH was more frequent than PBC, and usually presented with advanced liver disease that responded poorly to treatment. PMID- 29158854 TI - Current Condition of Chronic Hepatitis B Virus Infection in Cuban Adults. AB - Background: The reduction of the incidence of hepatitis B virus (HBV) infection in Cuba can be attributed to the effectiveness of the national immunization program. However, the number of patients with chronic HBV observed in clinical practice is not negligible. Objective: A cross-sectional study was conducted to describe the main clinical characteristics of patients with chronic hepatitis B virus infection. Methods: A total of 146 patients who had at least a 6-month history of hepatitis B surface antigen positivity were recruited between 2013 and 2015. Descriptive statistical analysis of the epidemiologic, clinical, biochemical, and virologic variables was performed. Results: Men accounted for 67.8% of patients, and the median age was 43 years. The median time since diagnosis of infection was 9 years. Among the patients, 59% had chronic hepatitis, 34% had liver cirrhosis, and 7% were inactive carriers. Concomitant diagnoses demonstrated that 16.4% of patients had malignancies, predominantly lymphoma. Only 64.4% of patients had received antiviral treatment, and lamivudine was the most commonly used (61.6%) drug. Moreover, 70% of patients were identified during an inactive phase. Conclusions: Patients with chronic HBV infection are still a health problem in the adult Cuban population, especially in patients with concomitant malignancies. PMID- 29158856 TI - Intralesional Administration of Human Recombinant Epidermal Growth Factor Improves Healing and Reduces Amputations in Patients with Severe Diabetic Foot Ulcers. PMID- 29158855 TI - Clinical Evaluation of Terap C Vaccine in Combined Treatment with Interferon and Ribavirin in Patients with Hepatitis C. AB - Background: An estimated 170 million individuals worldwide are infected with the hepatitis C virus (HCV). Although treatment options using a combination of pegylated interferon and ribavirin (P-IFN/RBV) are available, sustained clearance of the virus is only achieved in approximately 40% of individuals infected with HCV genotype 1. Recent advances in the treatment of HCV using directly acting antiviral agents have been achieved; however, treatment can be very expensive and is associated with substantial side effects. The development of a new treatment modality is needed. One possible modality could be specific immunotherapy. Terap C is a therapeutic vaccine candidate composed of pIDKE2, a plasmid expressing HCV structural antigens, with a recombinant HCV core protein, Co.120. Objective: To assess the safety and efficacy of concomitant therapy with the candidate vaccine, Terap C, IFN alpha-2b and ribavirin in untreated individuals with HCV genotype 1 infection. Methods: This was a Phase II randomized, placebo-controlled, double blind clinical trial evaluating the safety and efficacy of Terap C concomitant with IFN alpha-2b/RBV in 92 treatment-naive patients with HCV genotype 1 infection. The study was conducted at the Gastroenterology Institute in Havana, Cuba. Patients were randomly assigned to 1 of 5 groups. The control group (Group 1) received IFN alpha-2b/RBV and placebo for 48 weeks. Groups 2 and 3 were administered Terap C 6 and 9 times, respectively, in addition to standard IFN alpha-2b/RBV treatment. In groups 4 and 5, Terap C was introduced 12 weeks after the initiation of IFN alpha-2b/RBV and administered 6 and 9 times, respectively, concomitant with IFN alpha-2b/RBV. Results: All patients showed some adverse events. Out of 3615 adverse events, only 18.8% were considered to be probably associated with administration of Terap C. Most events (47.4%) were considered to be improbably associated with of administration Terap C. Only 33.8% were considered possibly temporarily associated with Terap C, and can be explained by the use of conventional IFN alpha-2b + RBV or by HCV itself. The most common adverse events (>=65%) observed were pain at the injection site, headache, asthenia, psychiatric disturbances, fever, and gastrointestinal symptoms. Regarding sustained virological response, a 20% superiority was observed in the patients who received concomitant Terap C treatments from the beginning of the study compared with those who started after Week 12. Conclusions: Vaccination with Terap C in patients with chronic HCV infection was safe and well tolerated. Clinical trial protocol code: IG/VHI/HC/0701; Public Register Code: RPCEC00000074. PMID- 29158857 TI - The BRCA2 variant c.68-7 T>A is associated with breast cancer. AB - Background: BRCA2 c.68-7T>A has been demonstrated to cause aberrant splicing and is possibly pathogenic. The population prevalence of the variant is 0.2%, which higher than usual for pathogenic BRCA2 variants. The pathogenicity of the variant is discussed. Methods: The outpatient genetic clinic at The Norwegian Radium Hospital, part of Oslo University Hospital, has invited breast cancer kindreds for genetic examinations and prospective follow-up of high risk patients since 1988. We have complete files of all activities and results, and we examined the files for association between BRCA2 c.68-7T>A and breast cancer. Results: Seventeen out of 714 (2.4%) breast cancer kindreds sequenced for BRCA2 carried the variant BRCA2 c.68-7T>A (p < 0.0001 compared to population controls). Segregation analysis was inconclusive (likelihood ratio 0.36) for pathogenicity. Two breast cancers were prospectively observed during 134 observation years (annual incidence rate 1.5% (95% CI 0.15% to 5.4%) and one additional breast cancer was diagnosed at first (prevalence) round. Conclusion: BRCA2 c.68-7T>A is associated with breast cancer. In the families selected due to aggregation of breast cancer, carriers of the BRCA2 c.68-7T>A variant have increased risk for breast cancer. It is, however, possible that the variant has lower penetrance than the average pathogenic BRCA2 variants, and that in the families selected for having known aggregation of breast cancer other (modifying) factors contributed to the observed results. PMID- 29158858 TI - Elastofibroma dorsi: case report and review of the literature. AB - Elastofibroma dorsi (ED) is an uncommon benign soft tissue tumor with an uncertain pathogenesis. It mostly occurs in the infrascapular region of elderly people with a female predominance. Typically bilateral, ED can also be unilateral. While many patients remain asymptomatic, ED can be responsible of a periscapular arch source of ache. The diagnosis of ED is set on magnetic resonance imaging, and the pathological study ensures the diagnosis after surgical excision and establishes the differential diagnosis with malignant neoplasic process. The prognosis is excellent with extremely rare recurrence cases. Herein we report a case of a 54-years-old woman with a bilateral painful ED. The diagnosis was based on clinical and MRI findings that revealed bilateral tumors. Surgery was decided due to the symptomatic nature of the tumors. Pathological study confirmed the diagnosis. The post operative course was uncomplicated. We update through a review of the literature aspects of the diagnostic and therapeutic care of Elastofibroma dorsi. PMID- 29158859 TI - Erratum: Food hygiene assessment in catering establishments in Hay Hassani district-Casablanca. AB - [This corrects the article DOI: 10.11604/pamj.2016.24.335.9171.]. PMID- 29158860 TI - Using equitable impact sensitive tool (EQUIST) and knowledge translation to promote evidence to policy link in maternal and child health: report of first EQUIST training workshop in Nigeria. AB - The Equitable Impact Sensitive Tool (EQUIST) designed by UNICEF and knowledge translation (KT) are important strategies that can help policymakers to improve equity and evidence-informed policy making in maternal, newborn and child health (MNCH). The purpose of this study was to improve the knowledge and capacity of an MNCH implementation research team (IRT) and policy makers to use EQUIST and KT. A modified "before and after" intervention study design was used in which outcomes were measured on the target participants both before the intervention (workshop) is implemented and after. A 5-point likert scale according to the degree of adequacy was employed. A three -day intensive EQUIST and KT training workshop was organized in Edo State, Nigeria with 45 participants in attendance. Some of the topics covered included: (i) Knowledge translation models, measures & tools; (ii) Policy review, analysis and contextualization; (iii) Policy formulation and legislation process; (iv) EQUIST Overview & Theory of change; (v) EQUIST's situation analysis, scenario analysis and scenario comparison. The pre-workshop mean of understanding of use of KT ranged from 2.02-3.41, while the post-workshop mean ranged from 3.24-4.30. Pre-workshop mean of understanding of use of EQUIST ranged from 1.66-2.41, while the post-workshop mean ranged from 3.56-4.54 on the 5point scale. The percentage increase in mean of KT and EQUIST at the end of the workshop ranged from 8.0%-88.1% and 65.6%-158.4% respectively. Findings of this study suggest that policymakers' and researchers KT and EQUSIT use competence relevant to evidence-informed policymaking can be enhanced through training workshop. PMID- 29158861 TI - [Bilateral macular retinoschisis associated with unilateral peripheral retinoschisis]. AB - X-linked juvenile retinoschisis is a hereditary disorder which usually occurs in boys rather than in girls, who are rarely affected. First clinical manifestations usually appear during the first decade. It is responsible for variable severity and slowly progressive vision loss. This progression can be characterized by vitreous hemorrhages and recurrent retinal detachments. We report the case of a 17-year old patient with stellar bilateral microcistic macular rearrangement of the eye-ground, centered on the foveola, associated with peripheral schisis with retinal detachment and unilateral tearing of internal and external layers. PMID- 29158862 TI - [Epidermoid cyst in the sella turcica: about a case]. AB - Epidermoid cyst (EC) or cholesteatoma is a benign tumor, often of congenital origin, occurring in the sub-arachnoidian spaces. Its treatment is based on surgery. We report the case of a 38 year-old patient presenting with progressive intracranial hypertension syndrome associated with anterior pituitary insufficiency signs of the corticotropic, thyrotropic, gonadotropic axis occurring 1 year before. Brain MRI showed a craniopharyngioma. Anatomopathologic evaluation of the specimen showed epidermoid cyst. PMID- 29158863 TI - South-South cooperation as a mechanism to strengthen public health services in Africa: experiences, challenges and a call for concerted action. AB - Implementation of new models of development cooperation have been on the increase lately. Coupled with this are calls for use of horizontal development cooperation mechanisms such as South-South Cooperation (SSC) as a way to enhance aid effectiveness in the health sector of developing countries. In this case series, we review recent experiences in the application of SSC initiatives to two public health situations in Africa to demonstrate the veracity of this new paradigm. Our review highlight the immense benefits associated with the use of SSC for health and provide evidence for increasing use of horizontal development coordination mechanisms to strengthen public health services delivery and socioeconomic development among African countries. Opportunities for SSC among African countries include in the areas of disease prevention and control, production of medical products and essential medicines, harmonization of regulatory processes, and health workforce development among others. However, pitfalls such as poor coordination, inadequate political commitment, lack of conducive policy environments, language barrier and inadequate financing opportunities for SSC initiatives present major dilemma for the use of SSC mechanisms. We conclude that the need for a paradigm shift from vertical to horizontal development cooperation needs no further proof but a call to action. We call on the concerned stakeholders to support the establishment of a systematic approach for use of SSC mechanisms in the health sector of Africa, designation of an African Centre of Excellence for SSC in public health and development of a regional mechanism for monitoring and evaluation of SSC initiatives in Africa. PMID- 29158864 TI - [Chronic kidney disease: associated factors, etiologies, clinical and biological parameters at Lubumbashi city in Democratic Republic of Congo]. AB - Introduction: Chronic kidney disease is fast becoming a worldwide public health problem due to the increase of hypertension and diabetes mellitus, its main risk factors. In countries like DRC where majority of population are in the low income bracket, very few studies about this disease, usually diagnosed at a very advanced stage have been conducted. As a result of such, cases are not always properly taken care of and managed. Methods: We opted for a descriptive cross sectional study and it was conducted during the period from July 2014 to July 2015 at CMDC dialysis service. Were included all patients with glomerular filtration rate lower than 60ml / min / 1,73 m2 or high level of creatinine longer than three months during the study period Goal. This study aims at describing the sociodemographic characteristics, risk factors and biological parameters of patients admitted for kidney failure. Results: We selected 60 patients. The average age was 51, 38 + / _ 13, 47 with the most affected included age group between 50-59 years. 51, 67% had completed secondary education and 40% higher. Risk factors of renal damage were the HTA 66, 64%, 25% diabetes mellitus, use of nephrotoxic products 35%, HIV infection 11, 67%, 10% obesity, sickle cell disease 3, 3%. The birth weight birth of our patients as well as existing renal disease in family were unknown factors. 85% of our patients had hemoglobin levels below 12 g%. Conclusion: From this observation, it appears that the age of our patients did not differ from that observed in other low-income communities. The level of education of our patients is higher compared to other studies. It would be better to develop strategies for early detection of kidney disease to avoid ending hemodialysis remains a very expensive treatment. PMID- 29158865 TI - [Anesthesiological aspects and complications of intracranial meningiomas operated at the Sylvanus Olympio University Hospital Center, Lome: about 21 cases]. AB - This study aimed to point to both the anesthesiological aspects and the perioperative complications of intracranial meningiomas operated at the Sylvanus Olympio University Hospital Center, Lome. We conducted a retrospective study by reviewing the medical records of patients with intracranial meningiomas undergoing surgery over the period December 2010-December 2015 (5 years) at the Sylvanus Olympio University Hospital Center, Lome. Out of 46 patients operated fo brain tumors, 21 (45.6%) had meningioma. The average age was 49 +/-20 years, with a male predominance (52.4%) and a sex ratio (M/F) of 1.1. Patients were classified according to ASA classification: 16 patients were classified as ASA II, 4 patients as ASA III and 1 patient as ASA IV. Patients underwent total intravenous anesthesia using hypnotic agent such as propofol (100%) and fentanyl (76.2%), which was the most available opioid. Perioperative complications were: bleeding, (mean blood loss: 1750 +/-584 ml), hypotension (mean arterial pressure (MAP) < 60 mmHg) in 10 (47.6%) patients; hemorrhagic shock in 2 (9.5%) patients, cardiovascular arrest: 01 (4.7%) patient successfully resuscitated. Postoperative complications were: convulsions in 5 (23.8%) cases, hyperthermia in 4 (19%) cases, hemorrhagic shock in 2 (9.5%) cases, death in 2 (9.5%) cases. Perioperative morbidity and mortality associated with intracranial meningioma surgery at the Sylvanus Olympio University Hospital Center, Lome remains high. Improvement of technical equipment and early consultation should reduce these complications. PMID- 29158866 TI - [TB/HIV co-infection associated with Kaposi's sarcoma under opioid substitution treatment using methadone: about a case]. AB - Late diagnosis of HIV infection can be fatal because it favors the appearance of opportunistic infections whose management requires the use of several molecules which can cause drug interactions. We report the case of a 45-year old female patient under heroin substitution treatment, using methadone and with HIV1 under antiretroviral treatment. This patient had nonspecific pulmonary appearance associated with dry nagging cough and progressive dyspnea evolving in a feverish context. Moreover, clinical examination showed left lower limb lymphedema with painless angiomatous nodules evolving over three years associated with plaques, angiomatous nodules occurred more recently at the level of the anterior face of the thorax. Sputum GeneXpert test allowed isolation of Mycobacterium tuberculosis. The diagnosis of pulmonary tuberculosis associated with Kaposi's sarcoma and immunosuppression caused by HIV was retained. PMID- 29158867 TI - Hepatic fascioliasis presenting with bile duct obstruction: a case report. AB - Fascioliasis is a zoonotic infection caused by a liver trematode: fasciola hepatica; which commonly affects cattle and sheep, humans are accidental hosts. Several cases have been reported in the literature worldwide with a large geographical distribution. We present a case of bile duct obstruction due to a hepatic fascioliasis, successfully treated with both a combined surgical and medical approaches. A high index of suspicion should be kept in mind for all cases of obstructive jaundice, especially in areas in which human fascioliasis infection is repeatedly reported. PMID- 29158868 TI - Prevalence of papular urticaria caused by flea bites and associated factors in children 1-6 years of age in Bogota, D.C. AB - Background: Papular urticaria is a chronic inflammatory disease caused by exposure to arthropod bites. The disease has been reported in children attending medical centers, but the causes as the risk factors associated with the disease have not been established. The objective of this study was to determine the prevalence of papular urticaria caused by flea bite and identify the risk factors in children between 1 to 6 years of age in Bogota D.C, between March 2009 and June 2011. Methods: A cross-sectional, two-stage, clustered study using random probability sampling and stratified with proportional allocation was carried out in children (1-6 years of age) in educational institutions in Bogota D.C. to determine the prevalence of the disease. Children underwent a dermatological examination by general practitioners with a previous training. Furthermore, digital photographs of skin lesions were taken for further confirmation of the diagnosis by dermatologists. A structured survey was completed by the parents or caregivers, and it was evaluated using an unconditional logistic regression to identify factors associated with the disease. Results: A total of 2437 children were included in the study. The prevalence of papular urticaria caused by flea bite in this population was 20.3% (CI 95%: 18.2 to 22.5%). The major risk factors associated with the disease were the presence of fleas in households (OR 1.74, CI 95%: 1.35 to 2.25), using mattresses without springs (OR 1.73, CI 95%: 1.20 to 2.50), the use of daily public transportation to carry the children to the educational institutions (OR 1.76, CI 95%: 1.07 to 2.89), having a soil/earth floor in the main bedroom (OR 6.81, CI 95%:1.16-39.96), and having siblings with a history of atopic dermatitis (OR 1.76 CI 95%: 1.07-2.89). Conclusions: A high prevalence of papular urticaria caused by flea bite was found in Bogota D.C. The main factors associated with the disease might be modified with the implementation of prevention, control strategies in housing, educational institutions, and public transportation. PMID- 29158869 TI - Otitis media with effusion and atopy: is there a causal relationship? AB - Otitis Media with Effusion (OME) is an inflammatory condition of the middle ear cleft, acute or chronic, with collection of fluid in the middle ear with an intact tympanic membrane. It is a very common disease in childhood, the most frequent cause of hearing loss in childhood and often requiring surgery. OME is called chronic when the fluid in the middle ear persists for more than three months or when the episodes recur six or more times in one year. The current article covers various aspects of OME including definition, epidemiology. Pathomechanisms, risk factors, role of allergy in OME, impact of upper airway disease on OME, eosinophilic otitis media and management of OME. PMID- 29158870 TI - Who has anaphylaxis in Brazil? Validation of a questionnaire for population studies. AB - Background: The incidence of anaphylaxis is increasing in several parts of the world; thus, determining the prevalence of the disease in a given region is important to understand the factors involved and to promote measures to avoid this type of allergic reaction. Aiming this objective, we validated an instrument for a population-basedstudy that assesses the prevalence of anaphylaxis in the Brazilian population. Methods: A questionnaire was generated in two variants - one for subjects seven years old or above (Group A) and another for children who were up to six years, 11 months and 29 days (Group B). The instrument was administered to patients with and without anaphylaxis. By allocating points, a score was calculated to differentiate subjects with and without the disease. After validation, the questionnaire was applied in the city of Botucatu (Sao Paulo state, Brazil), by randomly selecting houses and inviting residents to answer the questionnaire. Results: The questionnaire was reliable for identifying subjects with and without anaphylaxis in both groups, with a specificity and sensitivity above 90%. The prevalence of anaphylaxis in the pilot survey was 6.2% in Group A, however the evaluation was compromised in Group B by the low number of children below seven years of age due to random sampling of residences. Discussion: The prevalence of anaphylaxis in our pilot test (6.2%) was similar to major epidemiological surveys from several parts of the world, showing that anaphylaxis is not a rare disease. The instrument of the present work was suitable for this epidemiological survey and might be a good option for studying anaphylaxis in other populations. Conclusion: This instrument might be of particular value in places where researchers cannot access medical records to conduct similar epidemiological studies. PMID- 29158871 TI - Effects of Novel Nitric Oxide-Releasing Molecules against Oxidative Stress on Retinal Pigmented Epithelial Cells. AB - Oxidative stress is a hallmark of retinal degenerations such as age-related macular degeneration and diabetic retinopathy. Enhancement of heme oxygenase-1 (HO-1) activity in the retina would exert beneficial effects by protecting cells from oxidative stress, therefore promoting cell survival. Because a crosstalk exists between nitric oxide (NO) and HO-1 in promotion of cell survival under oxidative stress, we designed novel NO-releasing molecules also capable to induce HO-1. Starting from curcumin and caffeic acid phenethyl ester (CAPE), two known HO-1 inducers, the molecules were chemically modified by acylation with 4-bromo butanoyl chloride and 2-chloro-propanoyl chloride, respectively, and then treated in the dark with AgNO3 to obtain the nitrate derivatives VP10/12 and VP10/39. Human retinal pigment epithelial cells (ARPE-19) subjected to H2O2-mediated oxidative stress were treated with the described NO-releasing compounds. VP10/39 showed significant (p < 0.05) antioxidant and protecting activity against oxidative damage, in comparison to VP10/12, which in turn showed at 100 MUM concentration a slight but significant cell toxicity. Only VP10/39 significantly (p < 0.05) induced HO-1 in ARPE-19, most likely through covalent bond formation at Cys151 of the Keap1-BTB domain, as revealed from molecular docking analysis. In conclusion, the present data indicate VP10/39 as a promising candidate to protect ARPE-19 cells against oxidative stress. PMID- 29158872 TI - Neuroprotective and Cognitive-Enhancing Effects of Microencapsulation of Mulberry Fruit Extract in Animal Model of Menopausal Women with Metabolic Syndrome. AB - Currently, the neuroprotectant and memory-enhancing agent for menopausal women with metabolic syndrome is required. Based on the advantages of polyphenolics on numerous changes observed in menopause with metabolic syndrome and the encapsulation method, we hypothesized that microencapsulated mulberry fruit extract (MME) could protect brain damage and improve memory impairment in an animal model of menopause with metabolic syndrome. To test this hypothesis, MME at doses of 10, 50, and 250 mg/kg was given to female Wistar rats which were induced experimental menopause with metabolic syndrome by bilateral ovariectomy (OVX) and fed with high-carbohydrate high-fat (HCHF) diet for 8 weeks. Spatial memory together with neuron density, oxidative stress status, acetylcholinesterase, and phosphorylation of Erk in the hippocampus was assessed at the end of the study. It was found that MME decreased memory impairment, oxidative stress status, and AChE activity but increased neuron density and Erk phosphorylation in the hippocampus. Therefore, the neuroprotective and memory enhancing effects of MME might partly involve the enhanced cholinergic function and Erk phosphorylation but decreased oxidative stress status in hippocampus. Therefore, MME is the potential novel neuroprotectant and memory-enhancing agent for menopause with metabolic syndrome. However, further research especially clinical trial is still necessary. PMID- 29158873 TI - Contribution and Interactions of Hydroxycinnamic Acids Found in Bran and Wholegrain Sorghum (Sorghum bicolor L. Moench): Effects on the Antioxidant Capacity and Inhibition of Human Erythrocyte Hemolysis. AB - An imbalance between free radicals and antioxidants is known as oxidative stress, and it promotes cellular aging and the development of chronic noncommunicable diseases. The bioactive compounds present in food play an important role in preventing oxidative stress. The aim of this study was to determine the contributions and interactions of the hydroxycinnamic acids found in the bran and whole grain of sorghum and to evaluate their effects on the antioxidant capacity and inhibition of the hemolysis of human erythrocytes. Results showed that the caffeic acid, p-coumaric acid, and ferulic acid found in sorghum contributed to the scavenging of DPPH and ABTS radicals in various proportions. Ferulic acid, which was present in bound form in the bran and wholegrain sorghum, significantly inhibited the AAPH radical-induced oxidation of the erythrocyte membranes by 78.0 and 4.3%, respectively. Combinations of two, three, or four hydroxycinnamic acids may interact in an antagonistic or synergistic manner, thereby altering each other's bioactivities. The various interactions between the different sorghum bioactives can have a significant impact on their potential bioactivities. These results can be useful in the design of functional foods that aim to deliver bioactives to mitigate cellular aging or noncommunicable diseases. PMID- 29158874 TI - Mitochondria-Targeted Antioxidant SkQ1 Prevents Anesthesia-Induced Dry Eye Syndrome. AB - Dry eye syndrome (DES) is an age-related condition increasingly detected in younger people of risk groups, including patients who underwent ocular surgery or long-term general anesthesia. Being a multifactorial disease, it is characterized by oxidative stress in the cornea and commonly complicated by ocular surface inflammation. Polyetiologic DES is responsive to SkQ1, a mitochondria-targeted antioxidant suppressing age-related changes in the ocular tissues. Here, we demonstrate safety and efficacy of topical administration of SkQ1 at a dosage of 7.5 MUM for the prevention of general anesthesia-induced DES in rabbits. The protective action of SkQ1 improves clinical state of the ocular surface by inhibiting apoptotic and prenecrotic changes in the corneal epithelium. The underlying mechanism involves the suppression of the oxidative stress supported by the stimulation of intrinsic antioxidant activity and the activity of antioxidant enzymes, foremost glutathione peroxidase and glutathione reductase, in the cornea. Furthermore, SkQ1 increases antioxidant activity and stability of the tear film and produces anti-inflammatory effect exhibited as downregulation of TNF-alpha and IL-6 and pronounced upregulation of IL-10 in tears. Our data suggest novel features of SkQ1 and point to its feasibility in patients with DES and individuals at risk for the disease including those subjected to general anesthesia. PMID- 29158876 TI - Challenges in the Setup of Large-scale Next-Generation Sequencing Analysis Workflows. AB - While Next-Generation Sequencing (NGS) can now be considered an established analysis technology for research applications across the life sciences, the analysis workflows still require substantial bioinformatics expertise. Typical challenges include the appropriate selection of analytical software tools, the speedup of the overall procedure using HPC parallelization and acceleration technology, the development of automation strategies, data storage solutions and finally the development of methods for full exploitation of the analysis results across multiple experimental conditions. Recently, NGS has begun to expand into clinical environments, where it facilitates diagnostics enabling personalized therapeutic approaches, but is also accompanied by new technological, legal and ethical challenges. There are probably as many overall concepts for the analysis of the data as there are academic research institutions. Among these concepts are, for instance, complex IT architectures developed in-house, ready-to-use technologies installed on-site as well as comprehensive Everything as a Service (XaaS) solutions. In this mini-review, we summarize the key points to consider in the setup of the analysis architectures, mostly for scientific rather than diagnostic purposes, and provide an overview of the current state of the art and challenges of the field. PMID- 29158875 TI - A Gene Module-Based eQTL Analysis Prioritizing Disease Genes and Pathways in Kidney Cancer. AB - Clear cell renal cell carcinoma (ccRCC) is the most common and most aggressive form of renal cell cancer (RCC). The incidence of RCC has increased steadily in recent years. The pathogenesis of renal cell cancer remains poorly understood. Many of the tumor suppressor genes, oncogenes, and dysregulated pathways in ccRCC need to be revealed for improvement of the overall clinical outlook of the disease. Here, we developed a systems biology approach to prioritize the somatic mutated genes that lead to dysregulation of pathways in ccRCC. The method integrated multi-layer information to infer causative mutations and disease genes. First, we identified differential gene modules in ccRCC by coupling transcriptome and protein-protein interactions. Each of these modules consisted of interacting genes that were involved in similar biological processes and their combined expression alterations were significantly associated with disease type. Then, subsequent gene module-based eQTL analysis revealed somatic mutated genes that had driven the expression alterations of differential gene modules. Our study yielded a list of candidate disease genes, including several known ccRCC causative genes such as BAP1 and PBRM1, as well as novel genes such as NOD2, RRM1, CSRNP1, SLC4A2, TTLL1 and CNTN1. The differential gene modules and their driver genes revealed by our study provided a new perspective for understanding the molecular mechanisms underlying the disease. Moreover, we validated the results in independent ccRCC patient datasets. Our study provided a new method for prioritizing disease genes and pathways. PMID- 29158877 TI - Functional Brain Connectivity Differences Between Different ADHD Presentations: Impaired Functional Segregation in ADHD-Combined Presentation but not in ADHD Inattentive Presentation. AB - Introduction: Contrary to Diagnostic and Statistical Manual of Mental Disorders (DSM-5), fifth edition, some studies indicate that ADHD-inattentive presentation (ADHD-I) is a distinct diagnostic disorder and not an ADHD presentation. Methods: In this study, 12 ADHD-combined presentation (ADHD-C), 10 ADHD-I, and 13 controls were enrolled and their resting state EEG recorded. Following this, a graph theoretical analysis was performed and functional integration and segregation of brain network was calculated. Results: The results show that clustering coefficient of theta band was significantly different among three groups and significant differences were observed in theta global efficiency between controls and ADHD-C. Regarding the alpha band, a lower clustering coefficient was observed in control subjects. In the beta band, clustering coefficient was significantly different between the control and children with ADHD-C and also between ADHD-I and ADHD-C. The clustering coefficient, in the subjects with ADHD-C, demonstrated a rapid decline and was significantly lower than the subjects with ADHD-I and control. Conclusion: Decreased clustering, in high thresholds, may be associated with hyperactivity while increased segregation in low thresholds with inattentiveness. A different functional network occurs in the ADHD-C brain that is consistent with several studies that have reported ADHD-I as a distinct disorder. PMID- 29158878 TI - Molecular Analysis of rs2070744 and rs1799983 Polymorphisms of NOS3 Gene in Iranian Patients With Multiple Sclerosis. AB - Introduction: Multiple Sclerosis (MS) is a disease of central nervous system that mainly causes lesions or plaques in the spinal cord and brain. The purpose of this study was to analyze the relation between c.-813C>T (rs2070744) and c.894G>T (rs1799983) polymorphisms of NOS3 gene and MS in Iranian patients. Methods: A total of 78 patients with MS and 80 healthy controls were screened for NOS3 (rs2070744 and rs1799983) Single Nucleotide Polymorphisms (SNPs) by tetra-primer multiplex ARMS-PCR and PCR-RFLP. Results: Genotype frequencies of the c.-813C>T polymorphism in patients compared to controls were as follows: 53.8% to 80.0% for TT genotype, 41.0% to 18.8% for TC genotype, and 5.1% versus 1.2% for CC genotype (P=0.001). The frequencies of GG genotype was 57.7% and 78.8% and for GT genotype of c.894G>T polymorphism in patients compared to control subjects was 42.3% and 21.2%, respectively (P=0.004). Conclusion: Our results indicate that the studied NOS3 polymorphisms may be associated with MS in Iranian patients. PMID- 29158879 TI - Changes in Effective Connectivity Network Patterns in Drug Abusers, Treated With Different Methods. AB - Introduction: Various treatment methods for drug abusers will result in different success rates. This is partly due to different neural assumptions and partly due to various rate of relapse in abusers because of different circumstances. Investigating the brain activation networks of treated subjects can reveal the hidden mechanisms of the therapeutic methods. Methods: We studied three groups of subjects: heroin abusers treated with abstinent based therapy (ABT) method, heroin abusers treated with Methadone Maintenance Therapy (MMT) method, and a control group. They were all scanned with functional magnetic resonance imaging (fMRI), using a 6-block task, where each block consisted of the rest-craving-rest neutral sequence. Using the dynamic causal modeling (DCM) algorithm, brain effective connectivity network (caused by the drug craving stimulation) was quantified for all groups. In this regard, 4 brain areas were selected for this analysis based on previous findings: ventromedial prefrontal cortex (VMPFC), dorsolateral prefrontal cortex (DLPFC), amygdala, and ventral striatum. Results: Our results indicated that the control subjects did not show significant brain activations after craving stimulations, but the two other groups showed significant brain activations in all 4 regions. In addition, VMPFC showed higher activations in the ABT group compared to the MMT group. The effective connectivity network suggested that the control subjects did not have any direct input from drug-related cue indices, while the other two groups showed reactions to these cues. Also, VMPFC displayed an important role in ABT group. In encountering the craving pictures, MMT subjects manifest a very simple mechanism compared to other groups. Conclusion: This study revealed an activation network similar to the emotional and inhibitory control networks observed in drug abusers in previous works. The results of DCM analysis also support the regulatory role of frontal regions on bottom regions. Furthermore, this study demonstrates the different effective connectivity patterns after drug abuse treatment and in this way helps the experts in the field. PMID- 29158880 TI - Effect of Mild Cognitive Impairment and Alzheimer Disease on Auditory Steady State Responses. AB - Introduction: Mild Cognitive Impairment (MCI), a disorder of the elderly people, is difficult to diagnose and often progresses to Alzheimer Disease (AD). Temporal region is one of the initial areas, which gets impaired in the early stage of AD. Therefore, auditory cortical evoked potential could be a valuable neuromarker for detecting MCI and AD. Methods: In this study, the thresholds of Auditory Steady State Response (ASSR) to 40 Hz and 80 Hz were compared between Alzheimer Disease (AD), MCI, and control groups. A total of 42 patients (12 with AD, 15 with MCI, and 15 elderly normal controls) were tested for ASSR. Hearing thresholds at 500, 1000, and 2000 Hz in both ears with modulation rates of 40 and 80 Hz were obtained. Results: Significant differences in normal subjects were observed in estimated ASSR thresholds with 2 modulation rates in 3 frequencies in both ears. However, the difference was significant only in 500 Hz in the MCI group, and no significant differences were observed in the AD group. In addition, significant differences were observed between the normal subjects and AD patients with regard to the estimated ASSR thresholds with 2 modulation rates and 3 frequencies in both ears. A significant difference was observed between the normal and MCI groups at 2000 Hz, too. An increase in estimated 40 Hz ASSR thresholds in patients with AD and MCI suggests neural changes in auditory cortex compared to that in normal ageing. Conclusion: Auditory threshold estimation with low and high modulation rates by ASSR test could be a potentially helpful test for detecting cognitive impairment. PMID- 29158881 TI - Serum Proteomic Profiling of Obsessive-Compulsive Disorder, Washing Subtype: A Preliminary Study. AB - Introduction: Obsessive-Compulsive Disorder (OCD) is a disabling mental condition that its proteomic profiling is not yet investigated. Proteomics is a valuable tool to discover biomarker approaches. It can be helpful to detect protein expression changes in complex disorders such as OCD. Methods: Here, by the application of 2D gel electrophoresis (2DE), a pilot study of serum proteome profile of females with washing subtype of OCD was performed. Serum samples were obtained from females with washing subtype of OCD. Following the protein extraction from the serum with acetone perception, the samples were subjected to 2DE for separation based on pI and molecular weight (MW) with triple replications. Finally, the protein spots were visualized using Coomassie blue staining method and analyzed by Progenesis SameSpots software. Furthermore, protein-protein interaction (PPI) network analysis was handled by the application of Cytoscape software. Results: The results suggested that 41 matched spots demonstrated significant expression alterations among which 5 proteins including immunoglobulin heavy constant alpha-1 (IGHA1), apolipoprotein A-4 (APOA4), haptoglobin (HP), protein alpha-1-antitrypsin (SERPINA1), and component 3 (C3) were identified by database query. Additionally, PPI network analysis indicated the central role of SERPINA1 and C3 in the network integrity. However, albumin (ALB), amyloid precursor protein (APP), and protein alpha-1-antitrypsin (APOA1) proteins were important in OCD PPI network as well. The identified proteins were related to 3 processes: acute-phase response, hydrogen peroxide catabolic process, and regulation of triglyceride metabolic process. Conclusion: It was concluded that these proteins may have a fundamental role in OCD pathogenesis. Moreover, the dysregulation of inflammatory and antioxidant systems in OCD risk was suggested by the current study. However, evaluation of bigger sample sizes and application of mass spectrometry are essential requirements to confirm this preliminary evaluation. PMID- 29158882 TI - The Mediating Role of A2A Adenosine Receptors in the Mitochondrial Pathway of Apoptotic Hippocampal Cell Death, Following the Administration of MDMA in Rat. AB - Introduction: The 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug and a major source of substance abuse, which ultimately leads to sensations of well-being, elation and euphoria, moderate derealization/depersonalization, and cognitive disruptions, as well as intense sensory awareness. The mechanisms involved in memory impairment induced by MDMA are not completely understood. Methods: The current study used 40 Sprague-Dawley rats, weighted 200 to 250 g. Experiments were performed in four groups, each containing 10 rats. The first group of rats was used as the control, treated with dimethyl sulfoxide (DMSO). The second group was treated with MDMA. The third group was treated with MDMA and CGS (the adenosine A2A receptor agonist, 2-[p-(2 carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine) (CGS 21680) and the fourth group was treated with MDMA and SCH (the A2A receptor antagonist [7-(2 phenylethyl)-5-amino-2-(2-furyl-) pyrazolo-[4, 3-e]-1, 2, 4 triazolo [1,5-] pyrimidine]) (SCH 58261). The drugs in all groups were administrated intraperitoneally (i.p.) once a day for 7 days. In 5 rats of each group, following perfusion, samples were taken from hippocampi to investigate apoptosis. Accordingly, the samples were stained using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay kit, and studied by light microscopy. In other rats, fresh tissue was also removed to study the expression of bax and bcl-2 by Western blotting technique. Results: It was observed that the coadministration of MDMA with CGS reduced bax expression and prevented apoptosis of hippocampal cells. The coadministration of MDMA and SCH increased bax expression, and also increased the frequency of hippocampal cell apoptosis. Conclusion: The results of the current study showed that administration of CGS with MDMA decreased the common side effects associated with MDMA. PMID- 29158884 TI - A Mitochondrial Disorder in a Middle Age Iranian Patient: Report of a Rare Case. AB - Introduction: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) can involve multiple systems and cause stroke-like episodes and status epilepticus. Case Presentation: A 48-year-old female with history of early fatigability, migraine-type headaches, and bilateral sensory-neural hearing loss presented 3 episodes of serial seizures. On admission she was affected by Wernicke aphasia and, then, right hemiparesis. Investigations showed elevated arterial lactate and ragged red fibers on muscle biopsy. Conclusion: Though more commonly diagnosed during childhood, some cases of adult-onset MELAS syndrome are reported. This syndrome should be considered in patients with stroke-like events in adults without cerebrovascular risk factors and difficult-to-treat seizures. PMID- 29158883 TI - The Role of Protein Kinase B Signaling Pathway in Anti-Cancer Effect of Rolipram on Glioblastoma Multiforme: An In Vitro Study. AB - Introduction: The mechanism of putative cytotoxicity of 4-[3-(cyclopentyloxy)-4 methoxyphenyl]-2-pyrrolidone (rolipram), a specific phosphodiesterase-4 (PDE4) inhibitor, on glioblastoma multiforme (GBM) is almost unknown. This study aimed to investigate the role of protein kinase B (Akt) pathway in the cytotoxic effect of rolipram on human GBM U87 MG cell line and Tumor-Initiating Cells (TICs) isolated from patient's GBM specimen. Methods: TICs were characterized by using flow cytometry and quantitative real-time PCR. The cells were treated with rolipram at inhibitory concentration of 50% (IC50) in the presence or absence of SC79 (4MUg/mL), a specific AKT activator, for 48 hours. The cell viability and apoptosis were measured by MTT assay and TUNEL staining, respectively. The relative expression of Phospho-Akt (Ser473), matrix metalloproteinase 2 (MMP2), and vascular endothelial growth factor A (VEGFA) were detected using Western blotting. Results: The findings showed that rolipram could suppress cell viability in both U87MG and TICs, dose-dependently. Interestingly, the rolipram induced cytotoxicity was significantly reduced in the presence of SC79. Nevertheless, in rolipram-treated cells, the pretreatment with SC79 significantly led to increase in U87 MG cells and TICs apoptosis and decrease in viability of U87 MG cells but not TICs relative to corresponding control. In U87 MG and TICs, rolipram-induced reduction of Phospho-Akt (Ser473) and MMP2 levels were significantly suppressed by SC79. Conclusion: There is a cell type-specific mechanism of anti-proliferative action of rolipram on GBM cells. The reduction of intracellular level of MMP2 but not VEGFA by rolipram is conducted through the inhibition of Akt signal. Rolipram-induced apoptosis is mediated via Akt dependent/independent mechanisms. PMID- 29158885 TI - Taxonomy-Based Approaches to Quality Assurance of Ontologies. AB - Ontologies are important components of health information management systems. As such, the quality of their content is of paramount importance. It has been proven to be practical to develop quality assurance (QA) methodologies based on automated identification of sets of concepts expected to have higher likelihood of errors. Four kinds of such sets (called QA-sets) organized around the themes of complex and uncommonly modeled concepts are introduced. A survey of different methodologies based on these QA-sets and the results of applying them to various ontologies are presented. Overall, following these approaches leads to higher QA yields and better utilization of QA personnel. The formulation of additional QA set methodologies will further enhance the suite of available ontology QA tools. PMID- 29158886 TI - Noninvasive Evaluation of Portal Hypertension Using a Supervised Learning Technique. AB - Portal hypertension (PHT) is a key event in the evolution of different chronic liver diseases and leads to the morbidity and mortality of patients. The traditional reliable PHT evaluation method is a hepatic venous pressure gradient (HVPG) measurement, which is invasive and not always available or acceptable to patients. The HVPG measurement is relatively expensive and depends on the experience of the physician. There are many potential noninvasive methods to predict PHT, of which liver transient elastography is determined to be the most accurate; however, even transient elastography lacks the accuracy to be a perfect noninvasive diagnostic method of PHT. In this research, we are focusing on noninvasive PHT assessment methods that rely on selected best-supervised learning algorithms which use a wide set of noninvasively obtained data, including demographical, clinical, laboratory, instrumental, and transient elastography measurements. In order to build the best performing classification meta algorithm, a set of 21 classification algorithms have been tested. The problem was expanded by selecting the best performing clinical attributes using algorithm specific filtering methods that give the lowest error rate to predict clinically significant PHT. The suggested meta-algorithm objectively outperforms other methods found in literature and can be a good substitute for invasive PHT evaluation methods. PMID- 29158887 TI - Medical Imaging Lesion Detection Based on Unified Gravitational Fuzzy Clustering. AB - We develop a swift, robust, and practical tool for detecting brain lesions with minimal user intervention to assist clinicians and researchers in the diagnosis process, radiosurgery planning, and assessment of the patient's response to the therapy. We propose a unified gravitational fuzzy clustering-based segmentation algorithm, which integrates the Newtonian concept of gravity into fuzzy clustering. We first perform fuzzy rule-based image enhancement on our database which is comprised of T1/T2 weighted magnetic resonance (MR) and fluid-attenuated inversion recovery (FLAIR) images to facilitate a smoother segmentation. The scalar output obtained is fed into a gravitational fuzzy clustering algorithm, which separates healthy structures from the unhealthy. Finally, the lesion contour is automatically outlined through the initialization-free level set evolution method. An advantage of this lesion detection algorithm is its precision and its simultaneous use of features computed from the intensity properties of the MR scan in a cascading pattern, which makes the computation fast, robust, and self-contained. Furthermore, we validate our algorithm with large-scale experiments using clinical and synthetic brain lesion datasets. As a result, an 84%-93% overlap performance is obtained, with an emphasis on robustness with respect to different and heterogeneous types of lesion and a swift computation time. PMID- 29158888 TI - Initial evidence that non-clinical autistic traits are associated with lower income. AB - Among non-clinical samples, autistic traits correlate with a range of educational and social outcomes. However, previous work has not investigated the relationship between autistic traits and income, a key determinant of socio-economic status and well-being. In five studies (total N = 2491), we recruited participants without a diagnosis of autism from the general US population via an online platform and administered the short-form Autism Spectrum Quotient (AQ) as well as asked a range of demographic questions. We found a negative association between AQ and household income, which remained robust after controlling for age, gender, education, employment status, ethnicity, and socially desirable responding. The effect was primarily driven by the participant's own income and was mainly due to the social subscale of the AQ. These results provide initial evidence that income is negatively related to autistic traits among the general population, with potential implications for a range of social, psychological, and health outcomes. PMID- 29158889 TI - Non-canonical dorsoventral patterning in the moth midge Clogmia albipunctata. AB - Background: Bone morphogenetic proteins (BMPs) are of central importance for dorsal-ventral (DV) axis specification. They are core components of a signalling cascade that includes the BMP ligand decapentaplegic (DPP) and its antagonist short gastrulation (SOG) in Drosophila melanogaster. These components are very ancient, with orthologs involved in DV patterning in both protostomes and deuterostomes. Despite such strong conservation, recent comparative work in insects has revealed interesting differences in the way the patterning function of the DV system is achieved in different species. Results: In this paper, we characterise the expression patterns of the principal components of the BMP DV patterning system, as well as its signalling outputs and downstream targets, in the non-cyclorrhaphan moth midge Clogmia albipunctata (Diptera: Psychodidae). We previously reported ventral expression patterns of dpp in the pole regions of C. albipunctata blastoderm embryos. Strikingly, we also find ventral sog and posteriorly restricted tkv expression, as well as expanded polar activity of pMad. We use our results from gene knock-down by embryonic RNA interference to propose a mechanism of polar morphogen shuttling in C. albipunctata. We compare these results to available data from other species and discuss scenarios for the evolution of DV signalling in the holometabolan insects. Conclusions: A comparison of gene expression patterns across hemipteran and holometabolan insects reveals that expression of upstream signalling factors in the DV system is very variable, while signalling output is highly conserved. This has two major implications: first, as long as ligand shuttling and other upstream regulatory mechanisms lead to an appropriately localised activation of BMP signalling at the dorsal midline, it is of less importance exactly where the upstream components of the DV system are expressed. This, in turn, explains why the early-acting components of the DV patterning system in insects exhibit extensive amounts of developmental systems drift constrained by highly conserved downstream signalling output. PMID- 29158890 TI - Oxidation of Pyrrole by Dehaloperoxidase-Hemoglobin: Chemoenzymatic Synthesis of Pyrrolin-2-Ones. AB - The use of oxidoreductases as biocatalysts in the syntheses of functionalized, monomeric pyrroles has been a challenge owing to, among a number of factors, undesired polypyrrole formation. Here, we have investigated the ability of dehaloperoxidase (DHP), the coelomic hemoglobin from the terebellid polychaete Amphitrite ornata, to catalyze the H2O2-dependent oxidation of pyrroles as a new class of substrate for this enzyme. Substrate oxidation was observed for all compounds employed (pyrrole, N-methylpyrrole, 2-methylpyrrole, 3-methylpyrrole and 2,5-dimethylpyrrole) under both aerobic and anaerobic conditions. Using pyrrole as a representative substrate, only a single oxidation product, 4 pyrrolin-2-one, was observed, and notably without formation of polypyrrole. Reactivity could be initiated from all three biologically relevant oxidation states for this catalytic globin: ferric, ferrous and oxyferrous. Isotope labeling studies determined that the O-atom incorporated into the 4-pyrrolin-2 one product was derived exclusively from H2O2, indicative of a peroxygenase mechanism. Consistent with this observation, single- and double-mixing stopped flow UV-visible spectroscopic studies supported Compound I, but not Compounds ES or II, as the catalytically-relevant ferryl intermediate involved in pyrrole oxidation. Electrophilic addition of the ferryl oxygen to pyrrole is proposed as the mechanism of O-atom transfer. The results demonstrate the breadth of chemical reactivity afforded by dehaloperoxidase, and provide further evidence for establishing DHP as a multifunctional globin with practical applications as a biocatalyst. PMID- 29158892 TI - Correction to: Comparison of treatment outcomes in neck pain patients depending on the sex of the chiropractor: a prospective outcome study. AB - [This corrects the article DOI: 10.1186/s12998-017-0149-8.]. PMID- 29158891 TI - Overexpression of hypoxia-inducible factor and metabolic pathways: possible targets of cancer. AB - Cancer, the main cause of human deaths in the modern world is a group of diseases. Anticancer drug discovery is a challenge for scientists because of involvement of multiple survival pathways of cancer cells. An extensive study on the regulation of each step of these pathways may help find a potential cancer target. Up-regulated HIF-1 expression and altered metabolic pathways are two classical characteristics of cancer. Oxygen-dependent (through pVHL, PHDs, calcium-mediated) and independent (through growth factor signaling pathway, mdm2 pathway, HSP90) regulation of HIF-1alpha leads to angiogenesis, metastasis, and cell survival. The two subunits of HIF-1 regulates in the same fashion through different mechanisms. HIF-1alpha translation upregulates via mammalian target of rapamycin and mitogen-activated protein kinase signaling pathways, whereas HIF 1beta through calmodulin kinase. Further, the stabilized interactions of these two subunits are important for proper functioning. Also, metabolic pathways crucial for the formation of building blocks (pentose phosphate pathway) and energy generation (glycolysis, TCA cycle and catabolism of glutamine) are altered in cancer cells to protect them from oxidative stress and to meet the reduced oxygen and nutrient supply. Up-regulated anaerobic metabolism occurs through enhanced expression of hexokinase, phosphofructokinase, triosephosphate isomerase, glucose 6-phosphate dehydrogenase and down-regulation of aerobic metabolism via pyruvate dehydrogenase kinase and lactate dehydrogenase which compensate energy requirements along with high glucose intake. Controlled expression of these two pathways through their common intermediate may serve as potent cancer target in future. PMID- 29158893 TI - Evaluation of a Stenotrophomonas maltophilia bacteremia cluster in hematopoietic stem cell transplantation recipients using whole genome sequencing. AB - Background: Stenotrophomonas maltophilia ubiquitously occurs in the hospital environment. This opportunistic pathogen can cause severe infections in immunocompromised hosts such as hematopoietic stem cell transplantation (HSCT) recipients. Between February and July 2016, a cluster of four patients on the HSCT unit suffered from S. maltophilia bloodstream infections (BSI). Methods: For epidemiological investigation we retrospectively identified the colonization status of patients admitted to the ward during this time period and performed environmental monitoring of shower heads, shower outlets, washbasins and toilets in patient rooms. We tested antibiotic susceptibility of detected S. maltophilia isolates. Environmental and blood culture samples were subjected to whole genome sequence (WGS)-based typing. Results: Of four patients with S. maltophlilia BSI, three were found to be colonized previously. In addition, retrospective investigations revealed two patients being colonized in anal swab samples but not infected. Environmental monitoring revealed one shower outlet contaminated with S. maltophilia. Antibiotic susceptibility testing of seven S. maltophlia strains resulted in two trimethoprim/sulfamethoxazole resistant and five susceptible isolates, however, not excluding an outbreak scenario. WGS-based typing did not result in any close genotypic relationship among the patients' isolates. In contrast, one environmental isolate from a shower outlet was closely related to a single patient's isolate. Conclusion: WGS-based typing successfully refuted an outbreak of S. maltophilia on a HSCT ward but uncoverd that sanitary installations can be an actual source of S. maltophilia transmissions. PMID- 29158894 TI - Career planning for future surgeons. PMID- 29158896 TI - Factors associated with minimal meal frequency and dietary diversity practices among infants and young children in the predominantly agrarian society of Bale zone, Southeast Ethiopia: a community based cross sectional study. AB - Background: Poor infant and young child feeding (IYCF) practices in the first 2 years of age are among major causes of childhood malnutrition, in developing countries including Ethiopia. It results in irreversible outcomes of stunting, poor cognitive development, and significantly increases risks of many chronic and infectious diseases. This study was intended to assess factors associated with minimum meal frequency and minimum dietary diversity practice among children aged 6-23 months in the predominantly agrarian society of Bale zone, Southeast Ethiopia. Methods: A community based cross sectional study was employed from January to June 2016. An interviewer administered, pretested and structured questionnaire was used to collect data. Multi-stage sampling followed by a systematic random sampling technique was used to include study subjects. Data was entered using Epi info version 3.5.3 and analyzed by SPSS version 20. In the logistic regression, both bivariate and multivariate analyses were carried out to identify factors associated with minimum meal frequency and minimum dietary diversity scores. All variables with P-values of <0.2 in the bivariate were earmarked for the multivariate analysis. Both Crude Odds Ratio (COR) and Adjusted Odds Ratio (AOR) were computed at 95% Confidence Interval (CI) to determine the strength of associations. In the multivariate analysis, variables at P-Values of <0.05 were considered as statistically significant with minimum meal frequency and dietary diversity practice. Result: A total of 801 infants and young children aged 6-23 months and their mothers participated in the study. The overall prevalence of minimum meal frequency and minimum dietary diversity practice was 68.4% [95% CI: 0.652, 0.716] and 28.5% [95% CI: 0.254, 0.316], respectively. Child age (AOR = 0.29; 95% CI: 0.28, 0.94) and parity of mother (AOR = 2.8; 95% CI: 1.11, 7.50) were independently associated with minimal meal frequency. On the other hand, mothers educational level (AOR = 0.52; 95% CI: 0.28, 0.94), child illness in the past 1 week (AOR = 0.44; 95% CI: 0.26, 0.73) and maternal counselling on IYCF practice during postnatal care (PNC) visits (AOR = 2.6; 95% CI: 1.59, 4.45) were factors statistically associated with dietary diversity practice in the study area. Conclusion and recommendations: Compliance to recommended minimum meal frequency and diversified diets was low in this study community. Minimum meal frequency was associated with the age of child and parity of mother. But, mothers' education, child illness in the past 1 week, and maternal counseling on IYCF during PNC visits were factors associated with minimum dietary diversity practice. Improving the level of maternal and child health care utilization, increasing the educational level of mothers and providing health and nutrition counseling on IYCF during maternal PNC service visits are vital interventions to improve IYCF practices in the predominantly agrarian society of Bale zone, Southeast Ethiopia. PMID- 29158895 TI - A journey through liposuction and liposculture: Review. AB - Introduction: Nowadays, liposuction is the most frequently performed aesthetic surgery procedure in Western Countries. This technique has had rapid development since the 1970s, when it was experimented for the first time by A. and G. Fischer. It is currently widely used in clinical practice for many different situations in aesthetic, reconstructive and functional fields. Materials and methods: This review aims to describe the historical evolution of liposuction by analyzing the transformation of the method in function of the introduction of innovative ideas or instruments. We have also focused on reporting the major clinical applications of this surgical technique, applicable to almost the entire body surface. We finally analyzed the complications, both major and minor, associated with this surgical technique. Results: Liposuction is mainly used to correct deep and superficial fat accumulations and remodel the body contour. It has become an essential complementary technique to enhance the aesthetic result of many other aesthetic procedures such as reduction mammoplasty, abdominoplasty, brachioplasty, thigh lift and post bariatric body contouring. However, it can be largely used for the treatment of innumerable pathologies in reconstructive surgery such as lipomas, lipedema, lipodystrophies, pneudogynecomastia and gynecomastia, macromastia e gigantomastia, lymphedema and many others. The complication rate is very low, especially when compared with conventional excisional surgery and the major, complications are generally associated with improper performance of the technique and poor patient management before and after surgery. Conclusion: Liposuction is a safe, simple and effective method of body contouring. It has enormous potential for its application in ablative and reconstructive surgery, far from the most common aesthetic processes with a very low complication rate. PMID- 29158897 TI - Feminist approaches to Anorexia Nervosa: a qualitative study of a treatment group. AB - Background: Eating disorders (EDs) are now often approached as biopsychosocial problems. But it has been suggested by scholars interested in sociocultural factors that all is not equal within this biospsychosocial framework, with the 'social' aspects of the equation relegated to secondary factors within ED treatment contexts. Although sociocultural influences are well-established as risk factors for EDs, the exploration of whether or how such perspectives are useful in treatment has been little explored. In responding to this context, this article seeks to discuss and evaluate a 10 week closed group intervention based on feminist approaches to EDs at a residential eating disorder clinic in the East of England. Methods: The data was collected via one-to-one qualitative interviews and then analysed using thematic discourse analysis. Results: The participants suggested that the groups were helpful in enabling them to situate their problem within a broader cultural and group context, that they could operate as a form of 'protection' from ideologies regarding femininity, and that a focus on the societal contexts for EDs could potentially reduce feelings of self-blame. At the same time, the research pointed to the complexities of participants considering societal rather than individualised explanations for their problems, whilst it also confronted the implications of ambivalent responses toward feminism. Conclusions: Highly visible sociocultural factors in EDs - such as gender - may often be overlooked in ED clinical contexts. Although based on limited data, this research raises questions about the marginalisation of sociocultural factors in treatment, and the benefits and challenges including the latter may involve. PMID- 29158898 TI - An evaluation of the predictive validity of the URICA and ANSOCQ scales for weight gain in adults with AN in an outpatient eating disorders program: a prospective cohort study. AB - Background: The Transtheoretical Model (TTM) which focuses on stage of change has been the main conceptual model used in understanding the lack of motivation to change in patients with Anorexia Nervosa (AN). Whilst there is evidence to support the prognostic value of the TTM in AN, this evidence base sufferers from limitations including limited studies in adults and none in outpatient populations. The primary aim of this study was to clarify whether readiness to change, as measured by the University Rhode Island Change Assessment Scale (URICA) and the Anorexia Nervosa Stages of Change Questionnaire (ANSOCQ) could predict weight gain in adults with AN following treatment in an outpatient setting. Methods: This was a prospective cohort analysis, which selectively used data from an existing clinical database at an outpatient eating disorders service. 119 patients met eligibility criteria and were included in this study. This included all adult patients who had a diagnosis of AN and were assessed, but not necessarily treated at the outpatient eating disorders program (Group 1). A subgroup of 63 patients (Group 2) was also analysed which only included patients who had received treatment at the program. Baseline measures included the URICA score, the ANSOCQ score, the Eating Disorders Examination Questionnaire (EDE-Q) and body mass index (BMI). BMI was also measured on discharge. Results: The URICA scale had poor predictive validity for weight gain (r = 0.05, p = 0.725). The ANSOCQ had moderate predictive validity (Pearson's r = 0.57, p = 0.007), and accounted for 32.7% of variance in weight gain. The URICA and ANSOCQ were moderately correlated in both groups. The URICA was moderately predictive of symptom severity, measured by the EDE-Q in both groups. The ANSOCQ was moderately correlated with the EDE-Q scores in both Groups 1 and 2. Conclusions: To the authors' knowledge this is the only study evaluating stage of change, in an adult outpatient population with AN. The findings of this study suggest that while both the URICA and ANSOCQ were associated with eating disorder symptom severity, only the ANSOCQ was able to predict weight gain in outpatients with AN suggesting its greater utility in this context. PMID- 29158900 TI - Single measurement of plasminogen activator inhibitor-1 in sepsis: is it useful for evaluating the severity or prognosis of sepsis? PMID- 29158899 TI - Diaphragm thickening fraction to predict weaning-a prospective exploratory study. AB - Background: Diaphragm ultrasound (DUS) is a well-established point of care modality for assessment of dimensional and functional aspects of the diaphragm. Amongst various measures, diaphragmatic thickening fraction (DTf) is more comprehensive. However, there is still uncertainty about its capability to predict weaning from mechanical ventilation (MV). The present prospective observational exploratory study assessed the diaphragm at variable negative pressure triggers (NPTs) with US to predict weaning in ICU patients. Methods: Adult ICU patients about to receive their first T-piece were included in the study. Linear and curvilinear US probes were used to measure right side diaphragm characteristics first at pressure support ventilation (PSV) of 8 cmH2O with positive end expiratory pressure (PEEP) of 5 cmH2O against NPTs of 2, 4, and 6 cmH2O and then later during their first T-piece. The measured variables were then categorized into simple weaning (SW) and complicated weaning (CW) groups and their outcomes analyzed. Results: Sixty-four (M:F, 40:24) medical (55/64, 86%) patients were included in the study. Sepsis of lung origin (65.5%) was the dominant reason for MV. There were 33 and 31 patients in the SW and CW groups, respectively. DTf predicts SW with a cutoff >= 25.5, 26.5, 25.5, and 24.5 for 2, 4, and 6 NPTs and T-piece, respectively, with >= 0.90 ROC AUC. At NPT of 2, DTf had the highest sensitivity of 97% and specificity of 81% [ROC AUC (CI), 0.91 (0.84-0.99); p < 0.001]. Conclusions: DTf may successfully predict SW and also help identify patients ready to wean prior to a T-piece trial. PMID- 29158901 TI - Dosing of radioactive iodine in end-stage renal disease patient with thyroid cancer. AB - : We describe detailed administration of thyroidal and extrathyroidal doses of radioiodine to a patient with end-stage renal disease on hemodialysis. A thorough description of area under curve measurements in a patient with compromised renal function has rarely been described in the literature. Few publications have described thyroid cancer management of patients on hemodialysis, and we believe our management will aid in patient treatment in the future. Learning points: Scheduling of hemodialysis is important when administering radioactive iodine.Treatment of thyroid cancer with radioiodine in patients with end-stage renal disease requires multidisciplinary approach coordinating dialysis, nuclear medicine and endocrinologists care.Balancing ideal dosage of I131 and the timing of dialysis to insure maximal thyroidal uptake and minimal extra thyroidal I131 concentration is necessary. PMID- 29158902 TI - Hypernatraemic hypovolaemia with anaemia: an unusual presentation of primary testicular insufficiency. AB - : Hypogonadal men may experience intense vasomotor symptoms, and vasomotor sweating can occasionally be associated with profound fluid losses. We describe a 37-year-old male, who exhibited persistent hypovolaemic hypernatraemia that was challenging to treat despite a continuous high fluid input (>4-5 L/day). He was noted to have drenching sweats and normochromic anaemia. He had recent traumatic head injury, which resulted in neurocognitive dysfunction, so pituitary function tests were done which showed primary hypogonadism. After exclusion of all other possible causes of excess sweating, hypernatraemia and anaemia, a trial of testosterone therapy was instituted. Sweating dramatically ceased within hours of his first testosterone injection, hydration status normalised within days and anaemia and neurocognitive function progressively improved with continued testosterone replacement. This case demonstrates how, in a susceptible individual, hypovolaemic hypernatraemia can arise from insensible cutaneous fluid loss through eccrine sweating, mediated by vasomotor symptoms of untreated hypogonadism. Although this scenario has not been described in the literature, we felt it needed to be shared with the wider medical community because of how the diagnosis and treatment utterly transformed this patient's functional status and outcome. Learning points: Hypogonadal men may experience intense vasomotor symptoms and vasomotor sweating can occasionally be associated with profound fluid losses.Whether or not there is also hyperosmolar hypernatraemia, clinicians should always consider the possibility of underlying hypogonadism in men with normocytic anaemia and excessive sweating.Androgen (testosterone) replacement in hypogonadal men can have a dramatic effect on vasomotor sweating and hot flushes. PMID- 29158903 TI - Severe Cushing's syndrome and bilateral pulmonary nodules: beyond ectopic ACTH. AB - : Cushing's syndrome is a rare disease that results from prolonged exposure to supraphysiological levels of glucocorticoids. Severe and rapidly progressive cases are often, but not exclusively, attributable to ectopic ACTH secretion. Extreme hypercortisolism usually has florid metabolic consequences and is associated with an increased infectious and thrombotic risk. The authors report on a case of a 51-year-old male that presented with severe Cushing's syndrome secondary to an ACTH-secreting pituitary macroadenoma, whose diagnostic workup was affected by concurrent subclinical multifocal pulmonary infectious nodules. The case is noteworthy for the atypically severe presentation of Cushing's disease, and it should remind the clinician of the possible infectious and thrombotic complications associated with Cushing's syndrome. Learning points: Severe Cushing's syndrome is not always caused by ectopic ACTH secretion.Hypercortisolism is a state of immunosuppression, being associated with an increased risk for opportunistic infections.Infectious pulmonary infiltrates may lead to imaging diagnostic dilemmas when investigating a suspected ectopic ACTH secretion.Cushing's syndrome carries an increased thromboembolic risk that may even persist after successful surgical management.Antibiotic and venous thromboembolism prophylaxis should be considered in every patient with severe Cushing's syndrome. PMID- 29158904 TI - Follow-up and report on active trachoma in Zabol, Iran, prompted by Sharifi-Rad and Fallah's observations published in May 2016. PMID- 29158905 TI - Genome sequence and description of Mobilicoccus massiliensis sp. nov. isolated from the stool of a Nigerian boy with kwashiorkor. AB - Mobilicoccus massiliensis strain SIT2 (= CSUR P1306 = DSM 29065) is a new type strain of Mobilicoccus sp. nov. isolated from the stool of a 2-year-old Nigerian boy with kwashiorkor. M. massiliensis is Gram positive, facultatively anaerobic, nonsporulating and motile. The 3 842 438 bp long genome contains 3362 protein coding and 49 RNA genes, including one 5S rRNA gene, one 16S rRNA gene, one 23S rRNA gene and 46 tRNA genes. PMID- 29158906 TI - Molecular characterization of Panton-Valentine leukocidin (PVL) toxin-encoding phages from South India. AB - A total of 19 methicillin-resistant Staphylococcus aureus (MRSA) isolates were investigated for Panton-Valentine leukocidin (PVL) toxin, PVL gene sequence variation and PVL-encoding phages. Whole genome sequencing was performed for all isolates. Analysis of MRSA isolates (n = 19) confirmed that most MRSA (n = 11) were positive for the PVL gene and were multidrug resistant. ST772-MRSA-V was the predominant PVL-positive MRSA clone, although all of them were found to carry the PhiIND772PVL phage in the genome. This study provides insights into the evolution of a new lineage of PVL-MRSA and highlights the potential risk of the emergence of multidrug-resistant community-acquired MRSA with high virulence. PMID- 29158907 TI - Chikungunya outbreak in Delhi, India, 2016: report on coinfection status and comorbid conditions in patients. AB - Chikungunya fever is a major public health issue in India affecting billions. After 2010, the infection was in a decline until in 2016, when a massive outbreak affected the country. In this report, we present serologic and molecular investigations of 600 patient samples for chikungunya and dengue viruses along with clinical and comorbidity features. We recruited 600 patients during this outbreak and evaluated them for chikungunya and dengue virus antibodies and virus RNA through IgM, NS1 antigen and quantitative real-time PCR (qPCR). We further evaluated Zika virus RNA by qPCR. Additionally, we documented all clinical and comorbid features that were observed during the outbreak in the hospital. We report a total incidence rate of 58% of chikungunya during the outbreak in our hospital. Within the recruited patients, 70% of the patients were positive for chikungunya virus IgM whereas 24.17% were positive by qPCR. None of the samples was positive for Zika virus RNA. Additionally, coinfection of dengue and chikungunya was seen in 25.33% of patients. Analysis of clinical features revealed that 97% of patients had restricted movements of the joints with other features like swelling, itching and rashes of varying severity observed. Twelve patients presented with comorbid conditions, and two fatalities occurred among these comorbid patients. The high incidence of coinfection in the current outbreak warrants implementation of routine testing of both chikungunya and dengue virus in suspected patients for better patient management. The post-acute phase complications reported in the hospitals require in-depth studies to understand the actual impact of the current outbreak. PMID- 29158908 TI - Dairy production practices and associated risks for bovine vaccinia exposure in cattle, Brazil. AB - A cross-sectional serosurvey was performed to identify environmental features or practices of dairy farms associated with risk for exposure to vaccinia-like viruses in dairy cattle in Brazil. Sera from 103 cows from 18 farms in Minas Gerais state were examined for Orthopoxvirus-neutralizing antibodies. A database of 243 binary or multiple-selection categorical variables regarding the physical features and surrounding ecology of each property was obtained. Thirteen of 46 presumptive predictor variables were found to be significantly associated with Orthopoxvirus serostatus by univariate logistic regression methods. Use of teat sanitizer and having felids on the property were independently associated with virus exposure by multivariable analysis. Rodents have long been suspected of serving as maintenance reservoirs for vaccinia-like viruses in Brazil. Therefore, domestic felids are not only effective predators of small rodent pests, but also their urine can serve as a deterrent to rodent habitation in buildings such as stables and barns. These results corroborate previous evidence of the high significance of rodents in the Vaccinia virus transmission cycle, and they also raise questions regarding the common use of teat sanitizers in dairy production areas. PMID- 29158909 TI - First complete genome sequence of circulating dengue virus serotype 3 in Jeddah, Saudi Arabia. AB - Here we report the first full-length genome sequence of dengue virus serotype 3 (DENV-3) from a strain isolated from a patient in Jeddah, Saudi Arabia, in 2014. The genome consists of 10 635 bp and shows close similarity to circulating genotype III isolates from Singapore, suggesting possible importation, most probably during religious pilgrimages to Saudi Arabia. PMID- 29158910 TI - Association between working time quality and self-perceived health: analysis of the 3rd Korean working conditions survey (2011). AB - Background: Self-perceived health, a subjective assessment of one's health condition, is an important health indicator at the level of quality of life. In this study, working time quality refer to job factors with qualitative aspects of working time. This study was conducted to investigate the association between working time quality and self-perceived health in paid workers in Korea. Methods: In this study, 35,902 paid workers were analyzed based on the 3rd Korean working conditions survey. For independent variables, working time quality (working at night, working in the evenings, working on Sundays, working on Saturdays, and working more than 10 h a day) were set as major job-related variables. Other occupational characteristics were divided into 6 groups and general characteristics were divided into 6 groups, and univariate analysis was conducted with self-perceived health, a dependent variable. Variables that had significance in the univariate analysis were used for multivariate logistic regression analysis. Results: In the univariate analysis using Chi-square test, variables showing significance in self-perceived health were age, income, education, occupation, employment type, work hours per week, and shift work. Working time quality showed a significant association with self-perceived health. After adjusting for these variables using logistic regression analysis, working at night, working in the evening, working on Sundays, and working more than 10 h a day showed significant association with self-perceived health. Conclusions: This study showed a statistically significant association between working time quality of employees with self-perceived health. PMID- 29158911 TI - A retrospective evaluation of activity of gemcitabine/platinum regimens in the treatment of recurrent ovarian cancer. AB - Background: While many of these agents have been compared in prospective clinical trials, the gemcitabine/platinumbased regimens have not been compared in a prospective, randomized clinical trial. While bothgemcitabine/carboplatin and gemcitabine/cisplatin have a similar ORR in separate clinical trials, the tworegimens have never been directly been compared. With overlapping dose limiting toxicity of thrombocytopenia, the gemcitabine/carboplatin regimen has been challenging to employ in the clinical setting in previously treated ovarian cancer patients and is often associated with treatment delays and/or dose reductions. Gemcitabine/cisplatin can also be a challenge due to its dose limiting neuropathy and renal toxicity, especially in previously treated patients. In the absence of any prospective, head to head comparison this retrospective study was embarked upon to compare the response rate and toxicity profiles of gemcitabine/cisplatin verses gemcitabine/carboplatin for the treatment of platinum-sensitive verses platinum-resistant recurrent ovarian cancer. Methods: This was a retrospective chart review study that identified patients that had received either gemcitabine/cisplatin or gemcitabine/carboplatin for treatment of recurrent ovarian cancer and compared documented hematological and non-hematological toxicity and response based on RECIST (v1.1). Data was evaluated based upon platinum sensitivity/resistance as well. Results: A total of 93 patients were identified that had received a gemcitabine/platinum regimen with 48 with recurrent ovarian cancer that were included in the study. There were 21 patients in the gemcitabine/cisplatin arm and 27 patients identified in the gemcitabine/carboplatin arm. Objective response rate (ORR) was greater in platinum-sensitive patients that received gemcitabine/carboplatin compared to gemcitabine/cisplatin (8 (67%) vs 2 (25%), p < 0.05). Conversely, ORR was greater in platinum-resistant patients treated with gemcitabine/cisplatin (4 (57%) vs 1 (25%), NS). Mean time to progression was greater in gemcitabine/cisplatin patients (7.2 vs 5.1 months, p < 0.03). Patients treated with gemcitabine/carboplatin discontinued due to toxicity at a greater rate (8 (33%) vs 5 (24%)). Specifically gemcitabine/carboplatin had a greater incidence (85%) of grade 2 or greater leukopenia, thrombocytopenia, and neutropenia compared to gemcitabine/cisplatin (19%) However, there was no significant difference in dose reductions, treatment delays, or granulocyte colony stimulating factor (G-CSF) administration between regimens. Conclusions: Gemcitabine/cisplatin appears to have greater efficacy in platinum-resistant patients, while gemcitabine/carboplatin seems to have greater efficacy in platinum-sensitive patients. Overall, gemcitabine/carboplatin was associated with a greater incidence of myelosuppression and discontinuation due to toxicity. Similar to findings in endometrial cancer, gemcitabine/cisplatin may have benefit specifically in platinum-resistant ovarian cancer. PMID- 29158912 TI - A phase 2 quasi-experimental trial evaluating the feasibility, acceptability, and potential effectiveness of complex nursing intervention focused on QoL assessment on advanced cancer patients with palliative care needs: study protocol. AB - Background: Palliative care (PC) is an approach that improves the quality of life (QoL) of patients and their families facing the problem associated with incurable terminal disease. A number of QoL assessment tools have been validated in PC and their use described for research purposes, to support clinical practice, and as part of the quality improvement programs. There is a paucity of evidence on the implementation of a nursing intervention focused on QoL assessment in PC practice.The aim of this study is to model and determine the feasibility of a nursing complex intervention focused on QoL assessment in PC practice. Methods: The intervention will be evaluated through a quasi-experimental non-equivalent comparison group before-after study design. This project can be classified as phases 1-2, according to the Medical Research Council (MRC) framework for the development and evaluation of complex interventions.The study setting will take place in two inpatient hospice units in Italy. The study sample will be constituted of 39 multidisciplinary healthcare professionals and a sample of 46 advanced cancer patients admitted to hospices during the implementation of the intervention. Discussion: This study will generate information to address the implementation of QoL measurement in palliative care practice. Findings of this study will be used to inform a phase 3 trial according to the MRC framework. Trial registration: ISRCTN41201864 retrospectively registered. PMID- 29158913 TI - An implementation-effectiveness hybrid trial of video-based family therapy for peripartum depression in home visited mothers: a protocol for a pilot trial. AB - Background: The Federal Maternal, Infant, and Early Childhood Home Visiting (HV) Program serves over 100,000 vulnerable families at risk for child abuse in the USA and aims to improve many outcomes, including maternal mental health (HRSA's Federal Home Visiting Program: partnering with parents to help children succeed, 2017). Most clients are insured by Medicaid, and about 40% are adolescent mothers (pregnant and post-delivery) (The mother and infant home visiting program evaluation: early findings on the Maternal, Infant, and Early Childhood Home Visiting Program, 2015). Over a third of home-visited clients report peripartum depressive symptoms (The mother and infant home visiting program evaluation: early findings on the Maternal, Infant, and Early Childhood Home Visiting Program, 2015). Family conflict increases rates of peripartum depression in adolescent mothers (J Ped Health Care 21:289-98, 2007; J Emot Behav Disord 5:173 83, 1997; Fam Relat 47:395-402, 1998; Arch Ped Adolesc Med 150:64-9, 1996; Obstet Gynecol 110:134-40, 2007; Am Fam Physician 93:852-58, 2016). Although home visitors screen for depression and refer those with positive screens for treatment (The mother and infant home visiting program evaluation: early findings on the Maternal, Infant, and Early Childhood Home Visiting Program, 2015), home visited mothers infrequently obtain treatment or do not complete it if they do obtain it (Curr Probl Ped Adolesc Health Care 46:124-9, 2016; Making a difference in the lives of children and families: the impacts of Early Head Start Programs on infants and toddlers and their families, 2002; Depression and low-income women: challenges for TANF and welfare-to-work policies and programs, 2001; Aggress Violent Behav 15:191-200, 2010) due to many barriers (e.g., lack of child care, lack of transportation, geographical distance) (Arch Gen Psychiatry 68:627 36, 2011). There is a need for a video-based, family-oriented treatment for peripartum depression that is integrated into home visiting and would bypass these barriers. This article outlines a protocol for a pilot study that will explore the feasibility and acceptability of implementing a family-based treatment, using HIPAA-compliant video-based communication technology, for adolescents with peripartum depressive symptoms within the context of home visiting. Methods: This study protocol includes a description of an implementation-effectiveness hybrid trial design that will include 12 depressed adolescent mothers and their family members and a historical comparison group of 12 previously enrolled adolescent mothers. Discussion: The study results will provide a clearer understanding of whether or not video-based, family-oriented treatment is feasible and acceptable to implement within the context of home visiting and with home-visited adolescents with peripartum depressive symptoms. The findings from this pilot study could serve as a catalyst for future research that influences mental health practices and policies. Trial registration: NCT03282448, ClinicalTrials.gov date of registration 09/21/2017. PMID- 29158915 TI - Parafoveolar retinoblastoma regression with foveal preservation following intra arterial chemotherapy documented on hand-held optical coherence tomography in a newborn. AB - Background: Optical coherence tomography (OCT) has become an invaluable tool in retinoblastoma management, providing submillimeter visualization of tumor control following treatment. Herein, we document OCT-detection of a subtle tumor recurrence, allowing early intervention and achieving foveal microanatomy preservation. Case presentation: A 3-week-old girl was diagnosed with bilateral familial retinoblastoma, classified as group D in the right eye (OD) and group B in the left eye (OS), and treated with intravenous chemoreduction. At 6-months follow-up, the right eye was under control, but the left eye revealed a subtle juxtafoveal tumor recurrence, documented on handheld OCT (HH-OCT) and measuring 2750 um in diameter and 792 um in thickness. Treatment with intraarterial chemotherapy (IAC) using 1 cycle of melphalan 5 mg was performed and complete tumor control was achieved, leaving a flat, concave scar 663 um from the intact foveola and measuring 2750 um in diameter and 120 um in thickness. Foveal microanatomy OS was preserved on HH-OCT. The findings remained stable at 2 years following IAC. Conclusions: HH-OCT is an important tool in retinoblastoma management. In this case, HH-OCT allowed for early detection of retinoblastoma recurrence, before foveal invasion. Following treatment with IAC, complete tumor regression was noted and foveal microanatomy remained intact. PMID- 29158914 TI - Unsupervised progressive elastic band exercises for frail geriatric inpatients objectively monitored by new exercise-integrated technology-a feasibility trial with an embedded qualitative study. AB - Background: Frailty is a serious condition frequently present in geriatric inpatients that potentially causes serious adverse events. Strength training is acknowledged as a means of preventing or delaying frailty and loss of function in these patients. However, limited hospital resources challenge the amount of supervised training, and unsupervised training could possibly supplement supervised training thereby increasing the total exercise dose during admission. A new valid and reliable technology, the BandCizer, objectively measures the exact training dosage performed. The purpose was to investigate feasibility and acceptability of an unsupervised progressive strength training intervention monitored by BandCizer for frail geriatric inpatients. Methods: This feasibility trial included 15 frail inpatients at a geriatric ward. At hospitalization, the patients were prescribed two elastic band exercises to be performed unsupervised once daily. A BandCizer Datalogger enabling measurement of the number of sets, repetitions, and time-under-tension was attached to the elastic band. The patients were instructed in performing strength training: 3 sets of 10 repetitions (10-12 repetition maximum (RM)) with a separation of 2-min pauses and a time-under-tension of 8 s. The feasibility criterion for the unsupervised progressive exercises was that 33% of the recommended number of sets would be performed by at least 30% of patients. In addition, patients and staff were interviewed about their experiences with the intervention. Results: Four (27%) out of 15 patients completed 33% of the recommended number of sets. For the total sample, the average percent of performed sets was 23% and for those who actually trained (n = 12) 26%. Patients and staff expressed a general positive attitude towards the unsupervised training as an addition to the supervised training sessions. However, barriers were also described-especially constant interruptions. Conclusions: Based on the predefined criterion for feasibility, the unsupervised training was not feasible, although the criterion was almost met. The patients and staff mainly expressed positive attitudes towards the unsupervised training. As even a small training dosage has been shown to improve the physical performance of geriatric inpatients, the proposed intervention might be relevant if the interruptions are decreased in future large-scale trials and if the adherence is increased. Trial registration: ClinicalTrials.gov: NCT02702557, February 29, 2016. Data Protection Agency: 2016-42, February 25, 2016. Ethics Committee: No registration needed, December 8, 2015 (e-mail correspondence). PMID- 29158916 TI - The Involvement of beta-Catenin/COX-2/VEGF Axis in NMDA-Caused Retinopathy. AB - NMDA, a molecule that is capable of producing the loss of retinal ganglia cells (RGCs), has been widely studied; however, the detailed mechanism is not yet clarified. Previously, Wnt/beta-catenin signaling has been suggested to be involved in the NMDA-induced retinopathy. In addition, previous investigations in our group demonstrated the presence of a Wnt/beta-catenin/COX-2 axis in dorsal root ganglions (DRGs). Therefore, here in this paper, we tested whether there is an association of such axis with NMDA-induced RGC loss. Rat retinal damage models generated by intravitreal injection of NMDA were used to measure the expression levels of beta-catenin, COX-2, and VEGF in retinas, and the neuron numbers of the retinal GCL of rats were counted. Then, pharmacological tools (MK801, a NMDA receptor inhibitor; Dickkopf homolog 1, a specific inhibitor of the Wnt pathway; NS-398, a COX-2 inhibitor; and bevacizumab, IVB, a VEGF inhibitor) were introduced to evaluate the detailed roles of Wnt/beta-catenin, COX-2, and VEGF in retinopathy of rats. Results demonstrated that all three factors in sequence are positively regulated neuronal loss induced by NMDA. These observations indicated that the Wnt pathway/COX-2/VEGF axis plays a pathogenic role in retinopathy and represented novel therapeutic targets. PMID- 29158917 TI - Lipodystrophy among HIV-Infected Patients Attending Care and Treatment Clinics in Dar es Salaam. AB - Background: HIV infection and long-term HAART use are associated with metabolic and morphological changes. We assessed prevalence, types, and risk factors associated with lipodystrophy among HIV-infected adults attending CTC in Dar es Salaam, Tanzania. Methods: Analysis included 466 HIV-infected patients. Study protocol involved administration of structured questionnaire to collect sociodemographic and clinical information. Diagnosis of lipodystrophy was based on physician clinical assessment. Results: Lipodystrophy was present in 95 (20.4%) of the study participants, with lipoatrophy being the most common (49.5%) followed by mixed lipodystrophy (37.9%), and lipohypertrophy was the least prevalent (12.6%). Male gender, older age, long duration on HAART, and use of Stavudine containing regimen were associated with lipodystrophy (all p < 0.05). The risk for lipodystrophy was 1.6 times (AOR = 1.66, 95% CI = 1.01-2.72) for male participants and 13.3 times (AOR = 13.3, 95% CI = 6.4-27.7) for those on HAART. Long duration on HAART and use of Stavudine containing regimen were also associated with increased risk for lipodystrophy. Lipodystrophy was associated with poor perception about own body image and decreased social interactions. Conclusions: Lipodystrophy is common among HIV-infected patients in Tanzania, especially among male patients and those on HAART. Regular screening, monitoring, and patient awareness are needed for early identification and appropriate management. PMID- 29158918 TI - Challenges with Surveillance of Healthcare-Associated Infections in Intensive Care Units in South Africa. AB - Background: The incidence of healthcare-associated infections (HAIs) in the public health sector in South Africa is not known due to the lack of a surveillance system. We report on the challenges experienced in the implementation of a surveillance system for HAIs in intensive care units (ICUs). Methods: A passive, paper-based surveillance system was piloted in eight ICUs to measure the incidence of ventilator-associated pneumonia, catheter-associated urinary tract infection, and central line-associated bloodstream infection. Extensive consultation with the ICU clinical and nursing managers informed the development of the surveillance system. The Plan-Do-Study-Act method was utilized to guide the implementation of the surveillance. Results: The intended outputs of the surveillance system were not fully realized due to incomplete data. The organizational culture did not promote the collection of surveillance data. Nurses felt that the surveillance form added to their workload, and the infection control practitioners were unable to adequately supervise the process due to competing work demands. Conclusions: A manual system that adds to the administrative workload of nurses is not an effective method of measuring the burden of HAIs. Change management is required to promote an organizational culture that supports accurate data collection for HAIs. PMID- 29158919 TI - Antioxidant and Antiradical Properties of Selected Flavonoids and Phenolic Compounds. AB - Phenolic compounds and flavonoids are known by their antioxidant properties and one of the most important sources for humans is the diet. Due to the harmful effects of synthetic antioxidants such as BHA and BHT, natural novel antioxidants have become the focus of attention for protecting foods and beverages and reducing oxidative stress in vivo. In the current study, we investigated the total antioxidant, metal chelating, Fe3+ and Cu2+ reduction, and free radical scavenging activities of some phenolic and flavonoid compounds including malvin, oenin, ID-8, silychristin, callistephin, pelargonin, 3,4-dihydroxy-5 methoxybenzoic acid, 2,4,6-trihydroxybenzaldehyde, and arachidonoyl dopamine. The antioxidant properties of these compounds at different concentrations (10-30 MUg/mL) were compared with those of reference antioxidants such as BHA, BHT, alpha-tocopherol, and trolox. Each substance showed dose-dependent antioxidant activity. Furthermore, oenin, malvin, arachidonoyl dopamine, callistephin, silychristin, and 3,4-dihydroxy-5-methoxybenzoic acid exhibited more effective antioxidant activity than that observed for the reference antioxidants. These results suggest that these novel compounds may function to protect foods and medicines and to reduce oxidative stress in vivo. PMID- 29158920 TI - Enhancement in Tonically Active Glutamatergic Inputs to the Rostral Ventrolateral Medulla Contributes to Neuropathic Pain-Induced High Blood Pressure. AB - Neuropathic pain increases the risk of cardiovascular diseases including hypertension with the characteristic of sympathetic overactivity. The enhanced tonically active glutamatergic input to the rostral ventrolateral medulla (RVLM) contributes to sympathetic overactivity and blood pressure (BP) in cardiovascular diseases. We hypothesize that neuropathic pain enhances tonically active glutamatergic inputs to the RVLM, which contributes to high level of BP and sympathetic outflow. Animal model with the trigeminal neuropathic pain was induced by the infraorbital nerve-chronic constriction injury (ION-CCI). A significant increase in BP and renal sympathetic nerve activity (RSNA) was found in rats with ION-CCI (BP, n = 5, RSNA, n = 7, p < 0.05). The concentration of glutamate in the RVLM was significantly increased in the ION-CCI group (n = 4, p < 0.05). Blockade of glutamate receptors by injection of kynurenic acid into the RVLM significantly decreased BP and RSNA in the ION-CCI group (n = 5, p < 0.05). In two major sources (the paraventricular nucleus and periaqueductal gray) for glutamatergic inputs to the RVLM, the ION-CCI group (n = 5, p < 0.05) showed an increase in glutamate content and expression of glutaminase 2, vesicular glutamate transporter 2 proteins, and c-fos. Our results suggest that enhancement in tonically active glutamatergic inputs to the RVLM contributes to neuropathic pain-induced high blood pressure. PMID- 29158921 TI - A Nearly Lethal Screw: An Unusual Cause of Recurrent Bradycardia and Asystole Episodes after Fixation of the Cervical Spine. AB - We present a case of a 51-year-old man who was injured in a bicycle accident. His main injury was an unstable fracture of the cervical and thoracic vertebral column. Several hours after his arrival to the hospital the patient underwent open reduction and internal fixation (ORIF) of the cervical and thoracic spine. The patient was hospitalized in our critical care unit for 99 days. During this time patient had several episodes of severe bradycardia and asystole; some were short with spontaneous return to sinus and some required pharmacological treatment and even Cardiopulmonary Resuscitation (CPR). Initially, these episodes were attributed to the high cervical spine injury, but, later on, CT scan suggested that a fixation screw abutted on the esophagus and activated the vagus nerve by direct pressure. After repositioning of the cervical fixation, the bradycardia and asystole episodes were no longer observed and the patient was released to a rehabilitation ward. This case is presented in order to alert practitioners to the possibility that, after operative fixation of cervical spine injuries, recurrent episodes of bradyarrhythmia can be caused by incorrect placement of the fixation screws and might be confused with the natural history of the high cervical cord injury. PMID- 29158922 TI - Hypoxemic Respiratory Failure from Acute Respiratory Distress Syndrome Secondary to Leptospirosis. AB - Acute respiratory distress syndrome (ARDS), characterized by hypoxemic respiratory failure, is associated with a mortality of 30-50% and is precipitated by both direct and indirect pulmonary insults. Treatment is largely supportive, consisting of lung protective ventilation and thereby necessitating Intensive Care Unit (ICU) admission. The most common precipitant is community-acquired bacterial pneumonia, but other putative pathogens include viruses and fungi. On rare occasions, ARDS can be secondary to tropical disease. Accordingly, a history should include travel to endemic regions. Leptospirosis is a zoonotic disease most common in the tropics and typically associated with mild pulmonary complications. We describe a case of a 25-year-old male with undiagnosed leptospirosis, presenting with fever and severe hypoxemic respiratory failure, returning from a Costa Rican holiday. There was no other organ failure. He was intubated and received lung protective ventilation. His condition improved after ampicillin and penicillin G were added empirically. This case illustrates the rare complication of ARDS from leptospirosis, the importance of taking a travel history, and the need for empiric therapy because of diagnostic delay. PMID- 29158923 TI - Diffuse Subcutaneous Emphysema, Pneumomediastinum, and Pneumothorax following Robotic Assisted Laparoscopic Hysterectomy. AB - Robotic assisted laparoscopic surgery is becoming more widely available, but despite its multiple benefits, it is not without risk. This case is of a 62-year old female who presented to the emergency department for dyspnea two days after robotic assisted laparoscopic hysterectomy. Physical exam revealed diffuse facial, neck, upper extremity, torso, and lower extremity crepitus, which was diagnosed as diffuse subcutaneous air on computed tomography (CT). Imaging also revealed right apical pneumothorax and pneumomediastinum. The patient progressively improved over one month, with resolution of symptoms. PMID- 29158924 TI - Methylmalonic Acidemia with Novel MUT Gene Mutations. AB - A 5-year-old boy presented with recurrent episodes of fever, feeding problems, lethargy, from the age of 11 months, and poor weight gain. He was admitted and evaluated for metabolic causes and diagnosed as having methylmalonic acidemia (MMA). He was treated with vit B12 and carnitine supplements and has been on follow-up for the last 3 years. Mutation analysis by next generation sequencing (NGS), supplemented with Sanger sequencing, revealed two novel variants in the MUT gene responsible for MMA in exon 5 and exon 3, respectively. Recently he developed dystonic movements including orofacial dyskinesia. With advent of NGS, judicious use of NGS with Sanger sequencing can help identify causative possibly pathogenic mutations. PMID- 29158925 TI - Splenic Infarct and Pulmonary Embolism as a Rare Manifestation of Cytomegalovirus Infection. AB - Cytomegalovirus (CMV) is a type of herpes infection that has a characteristic feature of maintaining lifelong latency within the host cell. CMV manifestations can cover a broad spectrum from fever to as severe as pancytopenia, hepatitis, retinitis, meningoencephalitis, Guillain-Barre syndrome, pneumonia, and thrombosis. Multiple case reports of thrombosis associated with CMV have been reported. Deep vein thrombosis or pulmonary embolism is more common in immunocompetent patients while splenic infarct is more common in immunocompromised patients. However, here we report a female patient on low-dose methotrexate for rheumatoid arthritis who presented with both pulmonary embolism and splenic infarct. PMID- 29158926 TI - Acquired Elliptocytosis as a Manifestation of Myelodysplastic Syndrome with Ring Sideroblasts and Multilineage Dysplasia. AB - Acquired elliptocytosis is a known but rarely described abnormality in the myelodysplastic syndromes (MDS). Here we report the case of an elderly male who was admitted to the hospital with chest pain, dyspnea, and fatigue and was found to be anemic with an elliptocytosis that had only recently been noted on peripheral smears of his blood. After bone marrow biopsy he was diagnosed with MDS with ring sideroblasts and multilineage dysplasia and acquired elliptocytosis. Here we report a rare case of acquired elliptocytosis cooccurring with MDS with ring sideroblasts and multilineage dysplasia. PMID- 29158927 TI - Liver Metastases in Pancreatic Acinar Cell Carcinoma Treated with Selective Internal Radiation Therapy with Y-90 Resin Microspheres. AB - Background: Pancreatic acinar cell carcinoma (PACC) is a rare tumor. Surgical resection is the treatment of choice when feasible, but there are no clear recommendations for patients with advanced disease. Liver-directed therapy with Y 90 selective internal radiation therapy (SIRT) has been used to treat hepatic metastases from pancreatic tumors. We describe a case of PACC liver metastases treated with SIRT. Case Report: 59-year-old man was admitted with an infiltrative, solid lesion in pancreatic tail diagnosed as PACC. Lymph nodes in the hepatic hilum were enlarged, and many metastatic liver nodules were observed. After partial pancreatectomy, the left and right lobes of the liver were separately treated with Y-90 resin microspheres. Follow-up imaging revealed that all hepatic nodules shrank by at least 50%, and 3 nodules disappeared completely. Lipase concentration was 8407 U/L at baseline, rose to 12,705 U/L after pancreatectomy, and declined to 344 U/L after SIRT. Multiple rounds of chemotherapy in the subsequent year shrank the hepatic tumors further; disease then progressed, but a third line of chemotherapy shrank the tumors again, 16 months after SIRT treatment. Conclusion: SIRT had a positive effect on liver metastases from PACC. In conjunction with systemic therapy, SIRT can achieve sustained disease control. PMID- 29158928 TI - Discontinuation of Hemodialysis in a Patient with Anti-GBM Disease by the Treatment with Corticosteroids and Plasmapheresis despite Several Predictors for Dialysis-Dependence. AB - A 26-year-old man highly suspected of having antiglomerular basement membrane (GBM) disease was treated with corticosteroid pulse therapy 9 days after initial infection-like symptoms with high procalcitonin value. The patient required hemodialysis the next day of the treatment due to oliguria. In addition to corticosteroid therapy, plasmapheresis was introduced and the patient could discontinue hemodialysis 43 days after the treatment. Kidney biopsy after initiation of hemodialysis confirmed anti-GBM disease with 86.3% crescent formation. Physician should keep in mind that active anti-GBM disease shows even high procalcitonin value in the absence of infection. To pursue recovery of renal function, the challenge of the immediate and persistent treatment with high-dose corticosteroids plus plasmapheresis for highly suspected anti-GBM disease is vitally important despite the presence of reported predictors for dialysis dependence including oliguria and requiring hemodialysis at presentation. PMID- 29158929 TI - A Case Report of Isolated Bilateral Cerebral Peduncular Infarction. AB - Isolated bilateral cerebral peduncular infarctions (BCPI) presenting as acute pseudobulbar palsy are rarely reported and, to the best of our knowledge, most of the previous reports of BCPI were related to locked-in syndrome and disturbance of consciousness. Herein, we described a case of a 55-year-old man who presented with acute pseudobulbar palsy and mild tetraparesis, but preserved eye movements, with no consciousness disturbance. DWI revealed an acute infarction involving the central portion of the cerebral peduncle with a characteristic "traditional Chinese eight character" sign. The relationship between the infarcted range in the cerebral peduncle and the clinical manifestation was discussed in our report. PMID- 29158930 TI - Ectopic Breast Tissue of the Vulva in a Postmenopausal Woman. AB - Ectopic breast tissue is a rare condition caused by remnants of the mammary ridges that fail to involute during embryologic development. To date, only 39 cases have been reported in the literature worldwide. Here, we report the 40th case of a 69-year-old G3P2 postmenopausal Caucasian woman who presented with complaint of vulvar swelling. Biopsy of the mass revealed the presence of a benign mammary gland-like adenoma which was completely excised shortly thereafter. Clinical presentation of vulvar breast tissue is highly variable depending on the amount of breast tissue developed and its functionality. Diagnosis is ultimately made by tissue biopsy and histopathologic examination. Due to the scarce evidence that exists pertaining to supernumerary breast tissue located on the vulva, specific management guidelines are lacking. Since this ectopic tissue serves no function, but rather may provide a source for future malignancy, surgical excision is recommended. PMID- 29158931 TI - Atypical Distant Metastasis of Breast Malignant Phyllodes Tumors: A Case Report and Literature Review. AB - Malignant phyllodes tumors (MPT) are rare breast neoplasms. Preoperative diagnosis is often challenging due to the unspecific clinical, radiological, and histological characteristics of the tumor. Dissemination pathways are local with chest wall invasion, regional with lymph nodes metastasis, and distant, hematogenous, mostly to the lungs, bones, and brain. Distant metastasis (DM) can be synchronous or appear months to years after the diagnosis and initial management. The current report describes the case of a 57-year-old woman presenting with a giant/neglected MPT of the breast, with no DM at initial staging, treated by radical modified mastectomy. Motor disorders due to medullar compression by a paravertebral mass appeared at short follow-up, also treated surgically. The patient died from several DM of rapid evolution. To our knowledge, this is the only case described of MPT with metastases to soft tissue causing medullar compression. We present a literature review on unusual metastatic localizations of MPT. PMID- 29158932 TI - Gastric and Rectal Metastases from Malignant Melanoma Presenting with Hypochromic Anemia and Treated with Immunotherapy. AB - The authors present a case of an 80-year-old Caucasian male with multiple gastric and rectal metastases from malignant melanoma presenting with hypochromic anemia as the sole symptom of disease without evidence of cutaneous and ocular tumor localization. The patient had a medical history positive for malignant lentigo melanoma of the occipital region of the scalp and early stage laryngeal squamous cell carcinoma and prostatic carcinoma treated with radiation therapy. The authors make some considerations on intestinal involvement by metastatic melanoma and discuss the choice of not treating with endoscopic procedures the gastric metastatic lesions most likely responsible for the clinical sign present at diagnosis. The patient was referred to clinical oncologists and received immunotherapy with ipilimumab and pembrolizumab. PMID- 29158933 TI - Squamous Cell Carcinoma of the Thyroid as a Result of Anaplastic Transformation from BRAF-Positive Papillary Thyroid Cancer. AB - Papillary thyroid carcinoma (PTC) is the most common malignant neoplasm of the thyroid. Majority of the PTC carries an excellent prognosis. However, patients with tall cell variant (TCV) of papillary thyroid carcinoma have a worse prognosis than those with the classic variant. On the other hand, squamous cell carcinoma of the thyroid (SCT) is an unusual neoplasm thought to arise as a primary tumor or as a component of an anaplastic or undifferentiated carcinoma. We report a patient with TCV of PTC presenting years later with squamous transformation. In addition, the patient was found to have BRAF mutation. Such dedifferentiation is considered to be a rare phenomenon and has been reported only in the form of case reports in the literature. The relationship between BRAFV600E mutation and squamous cell transformation of papillary thyroid cancer is unknown at this time. Meticulous pathology is needed to identify such variants. Our patient responded to treatment with concurrent chemotherapy with carboplatin and paclitaxel along with radiation. PMID- 29158934 TI - Ocular Rosacea Causing Corneal Melt in an African American Patient and a Hispanic Patient. AB - Purpose: To discuss two rare presentations of ocular rosacea in a Hispanic patient and an African American patient with unusual ocular manifestations. Case Report: Case 1: a 43-year-old Hispanic woman presented with right eye corneal perforation. Her prior medical history was significant for rosacea only, diagnosed clinically by a dermatologist. Her eye exam showed signs of bilateral ocular rosacea. An emergent full thickness tectonic corneal patch graft was done. The patient's bilateral eye symptoms improved one month after initiating rosacea treatment. Case 2: a 51-year-old African American man with long standing history of untreated rosacea presented with bilateral peripheral corneal thinning with neovascularization that led to right eye corneal perforation. Glue and bandage contact lens were applied. The patient did well 4 weeks after starting antibacterial, oral steroids, and rosacea treatment. Discussion: Ocular rosacea can present in Hispanic and African American patients with severe manifestations such as corneal perforation. PMID- 29158935 TI - Synchronous HPV-Related Cancer of Bilateral Tonsils Detected Using Transoral Endoscopic Examination with Narrow-Band Imaging. AB - Background: The incidence of human papillomavirus- (HPV-) related oropharyngeal squamous cell carcinoma (OPSCC) has been rapidly increasing worldwide. HPV is reported in approximately 50% cases of OPSCC in Japan. However, there are few reports of synchronous bilateral HPV-positive tonsillar carcinoma, and, in almost all those cases, carcinoma was detected using positron emission tomography/computed tomography and/or bilateral tonsillectomy. Methods and Results: We report the case of a 63-year-old male with bilateral tonsillar carcinoma detected using transoral endoscopic examination with narrow-band imaging (NBI). A biopsy of the bilateral tonsils revealed squamous cell carcinoma, which was demonstrated to be HPV-related using in situ hybridization and p16 immunohistochemistry. The patient was diagnosed as synchronous bilateral tonsillar carcinoma: T1 (2) N2b M0. He was treated with induction chemotherapy, bilateral radical tonsillectomy with neck dissection, and radiotherapy. Conclusion: To our knowledge, this is the first report of a synchronous bilateral tonsillar carcinoma detected using transoral NBI in the outpatient setting. Early diagnosis without the inspection under general anesthesia is beneficial for the patients with lymph node metastasis from unknown primary lesion. PMID- 29158936 TI - SMARCA4-Deficient Carcinoma of Unknown Primary Presenting with Fatal Paraneoplastic Hypercalcemia in a Heart Transplant Recipient: First Report in a Male Patient. AB - Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare SMARCA4 driven aggressive malignancy of young age characteristically associated with paraneoplastic hypercalcemia. Comparable neoplasms/presentations have not been reported in males. A 39-year-old male heart transplant recipient (HTX 40 months previously) presented with multiple liver nodules and hypercalcemic crisis. The serum parathyroid hormone-related protein (PTHrp) was significantly elevated (241 pg/ml; reference value < 57). Liver biopsy showed poorly differentiated partially rhabdoid neoplasm expressing pancytokeratin, CK20, and focally GATA3, SATB2, p63, and SALL4. The tumor cells showed dual loss of SMARCA4 and SMARCA2. He died of irreversible multiorgan failure one week after admission. To our knowledge, this is the first report highlighting the rare occurrence of paraneoplastic hypercalcemia associated with SMARCA4-deficient malignancies in males. Although the immunophenotype suggests urothelial or upper gastrointestinal tract origin, the exact primary tumor site could not be ascertained due to rapid death of the patient. SMARCA4 immunohistochemistry should be included in the workup of neoplasms associated with hypercalcemia irrespective of gender and site. PMID- 29158937 TI - Connatal Urinary Ascites in a Female Preterm. AB - Background: Connatal urinary ascites is rare in females without associated malformations and occurs following bladder rupture. Case Presentation: A female very preterm was delivered by caesarean section because of abnormal Doppler findings. The mother suffered from viral pneumonia requiring intensive care in the third trimester of pregnancy. Serial fetal ultrasound examinations showed a megacystis and ascites. Postnatally, pronounced isolated ascites was drained and its urinary nature was confirmed. The bladder leak was demonstrated when blue dye, instilled via a Foley catheter, appeared in the ascitic drain. After removal of the catheter spontaneous micturition was unremarkable. A micturating cystourethrogram showed spontaneous closure of the bladder leak. Conclusion: The female infant experienced fetal bladder rupture and connatal urinary ascites due to maternal pneumonia and intensive care. The use of blue dye is an effective alternative method to any contrast media radiography and should be considered, especially in very preterm infants. PMID- 29158938 TI - Orthodeoxia without Platypnea in Hereditary Hemorrhagic Telangiectasia in the Presence of a Cerebral Abscess and Multiple Pulmonary Arteriovenous Malformations: Unusual Complications and Transcatheter Endovascular Treatment. AB - Hereditary hemorrhagic telangiectasia is a rare autosomal-dominant condition affecting visceral blood vessel development. Cerebral and most commonly pulmonary arteriovenous malformations are found in the majority of symptomatic patients. The most common complications include embolic strokes and cerebral abscesses, which have been attributed to abnormal vessel communications. Platypnea orthodeoxia is a rare condition that presents dyspnea and oxygen desaturation when adopting an upright position and is relieved on decubitus. The association between hereditary hemorrhagic telangiectasia, pulmonary arteriovenous malformations, and platypnea orthodeoxia has been described in medical literature; however, orthodeoxia as a single entity without platypnea has not been described yet, especially associated with complications of this hereditary condition. We present the case of a 38-year-old male with persistent headaches, in whom a cerebral lesion was detected. Orthostatic tachycardia and severe orthodeoxia without platypnea were evidenced during physical examination. The patient was subsequently diagnosed with hereditary hemorrhagic telangiectasia and underwent cerebral abscess drainage as well as transcatheter endovascular closure of multiple pulmonary arteriovenous malformations. For this reason, the concept of platypnea orthodeoxia syndrome needs further revision. Patients presenting refractory hypoxemia should warn physicians to initially evaluate their oxygen saturation measurements during standing and decubitus position, even though platypnea may not be present. PMID- 29158939 TI - Mediastinal Tracheostoma for Treatment of Tracheostenosis after Tracheostomy in a Patient with Mucopolysaccharidosis-Induced Tracheomalacia. AB - Background: Treatment of tracheostenosis after tracheostomy in pediatric patients is often difficult. Mucopolysaccharidosis is a lysosomal storage disease that may induce obstruction of the airways. Case Presentation: A 16-year-old male patient underwent long-term follow-up after postnatal diagnosis of type II mucopolysaccharidosis. At 11 years of age, tracheostomy was performed for mucopolysaccharidosis-induced laryngeal stenosis. One week prior to presentation, he was admitted to another hospital on an emergency basis for major dyspnea. He was diagnosed with tracheostenosis caused by granulation. The patient was then referred to our institution. The peripheral view of his airway was difficult because of mucopolysaccharidosis-induced tracheomalacia. For airway management, a mediastinal tracheostoma was created with extracorporeal membrane oxygenation. To maintain the blood flow, the skin incision for the mediastinal tracheal hole was sharply cut without an electrotome. The postoperative course was uneventful, and the patient was weaned from the ventilator on postoperative day 19. He was discharged 1.5 months postoperatively. Although he was referred to another institution because of respiratory failure caused by his primary disease 6 months postoperatively, his airway management remained successful for 1.5 years postoperatively. Conclusion: Mediastinal tracheostomy was useful for treatment of tracheostenosis caused by granulation tissue formation after a tracheostomy. PMID- 29158940 TI - Posttransplant Lymphoproliferative Disease Presenting as an Extracranial Mass. AB - Posttransplant lymphoproliferative disease is a serious complication following stem cell and solid organ transplantation. Early recognition of the disease is important in facilitating timely therapy and improving long-term outcomes. We report a renal transplant recipient presenting with an extracranial frontoparietal soft tissue mass that was subsequently diagnosed as a B-cell lymphoma. The patient was treated successfully with immunosuppression reduction, anti-CD20 monoclonal antibody therapy, and cytotoxic chemotherapy. Our case highlights the importance of recognizing soft tissue masses in the head and neck as a potential clinical manifestation of PTLD in solid organ transplant recipients. PMID- 29158941 TI - Corrigendum to "Falls and Fractures in the Elderly with Sinus Node Disease: The Impact of Pacemaker Implantation". AB - [This corrects the article DOI: 10.1155/2012/498102.]. PMID- 29158942 TI - The Single Nucleotide Polymorphism rs1014290 of the SLC2A9 Gene Is Associated with Uric Acid Metabolism in Parkinson's Disease. AB - Individuals with Parkinson's disease (PD) have lower uric acid levels than those without PD, and the CC genotype and C minor allele of a single nucleotide polymorphism (SNP), rs1014290 of SLC2A9, are associated with lower uric acid levels. We investigated the association of rs1014290 with uric acid metabolism in a cohort of PD cases (220) and controls (110) in a Han Chinese population. Uric acid levels were determined and rs1014290 was assayed using a mutation-sensitive on/off switch technology. PD uric acid levels (291.65 +/- 76.29 MUmol/L) were significantly lower than the controls (325.73 +/- 74.23 MUmol/L, P < 0.001, t test). Individuals with rs1014290 TT and CT genotypes had higher uric acid levels, and those with the CC genotype had the lowest uric acid levels among both control and PD cases. The CC genotype and the C minor allele were statistically more frequent in the PD group compared to the control group. Those with the CC genotype had a statistically significant higher risk of PD than those with the TT or TC genotype (odds ratio [OR] = 2.249, 95% confidence interval [CI]: 1.129 4.480, and P = 0.021). Thus, SLC2A9 rs1014290 is related to lower uric acid levels in PD patients and can be a risk factor for PD in the Han population. PMID- 29158943 TI - Depression in Parkinson's Disease: The Contribution from Animal Studies. AB - Besides being better known for causing motor impairments, Parkinson's disease (PD) can also cause many nonmotor symptoms, like depression and anxiety, which can cause significant loss of life quality and may not respond to regular drugs treatment. In this review, we discuss the depression in PD, based on data from studies in humans and rodents. Depression frequency seems higher in PD patients than in general population, despite high variation in data due to diagnosis disparities. Development of depression in PD seems more likely to be caused by the nigrostriatal pathway degeneration than as a consequence of the awareness of disease prognostic, and it seems to be related to dopaminergic, noradrenergic, and serotoninergic synapses deficits. The dopaminergic role could be more significant, since it can modulate the release of the others, and its depletion is progressive, due to the degenerative feature of PD. Highly regarded in major depression, serotonin can be depleted in rats after nigrostriatal damage, but data from human patients are more conflicting. Animal studies can help in understanding the neurobiological mechanisms of depression in PD and the pursuit for more effective drugs for its treatment, but they lack the complexity of the disease progression, especially the nondopaminergic degeneration. PMID- 29158944 TI - Comparative Metagenomic Analysis of Electrogenic Microbial Communities in Differentially Inoculated Swine Wastewater-Fed Microbial Fuel Cells. AB - Bioelectrochemical systems such as microbial fuel cells (MFCs) are promising new technologies for efficient removal of organic compounds from industrial wastewaters, including that generated from swine farming. We inoculated two pairs of laboratory-scale MFCs with sludge granules from a beer wastewater-treating anaerobic digester (IGBS) or from sludge taken from the bottom of a tank receiving swine wastewater (SS). The SS-inoculated MFC outperformed the IGBS inoculated MFC with regard to COD and VFA removal and electricity production. Using a metagenomic approach, we describe the microbial diversity of the MFC planktonic and anodic communities derived from the different inocula. Proteobacteria (mostly Deltaproteobacteria) became the predominant phylum in both MFC anodic communities with amplification of the electrogenic genus Geobacter being the most pronounced. Eight dominant and three minor species of Geobacter were found in both MFC anodic communities. The anodic communities of the SS inoculated MFCs had a higher proportion of Clostridium and Bacteroides relative to those of the IGBS-inoculated MFCs, which were enriched with Pelobacter. The archaeal populations of the SS- and IGBS-inoculated MFCs were dominated by Methanosarcina barkeri and Methanothermobacter thermautotrophicus, respectively. Our results show a long-term influence of inoculum type on the performance and microbial community composition of swine wastewater-treating MFCs. PMID- 29158946 TI - INTRODUCTION TO THE MOVEMENT SYSTEM AS THE FOUNDATION FOR PHYSICAL THERAPIST PRACTICE EDUCATION AND RESEARCH. AB - : In 2013, the American Physical Therapy Association (APTA) adopted an inspiring new vision, "Transforming society by optimizing movement to improve the human experience." This new vision for our profession calls us to action as physical therapists to transform society by using our skills, knowledge, and expertise related to the movement system in order to optimize movement, promote health and wellness, mitigate the progression of impairments, and prevent the development of (additional) disability. The guiding principle of the new vision is "identity," which can be summarized as "The physical therapy profession will define and promote the movement system as the foundation for optimizing movement to improve the health of society." Recognition and validation of the movement system is essential to understand the structure, function, and potential of the human body. As currently defined, the "movement system" represents the collection of systems (cardiovascular, pulmonary, endocrine, integumentary, nervous, and musculoskeletal) that interact to move the body or its component parts. By better characterizing physical therapists as movement system experts, we seek to solidify our professional identity within the medical community and society. The physical therapist will be responsible for evaluating and managing an individual's movement system across the lifespan to promote optimal development; diagnose impairments, activity limitations, and participation restrictions; and provide interventions targeted at preventing or ameliorating activity limitations and participation restrictions. Level of Evidence: 5. PMID- 29158947 TI - STATIC BALANCE MEASUREMENTS IN STABLE AND UNSTABLE CONDITIONS DO NOT DISCRIMINATE GROUPS OF YOUNG ADULTS ASSESSED BY THE FUNCTIONAL MOVEMENT SCREENTM (FMSTM). AB - Background: The Functional Movement ScreenTM (FMSTM) has been the focus of recent research related to movement profiling and injury prediction. However, there is a paucity of studies examining the associations between physical performance tasks such as balance and the FMSTM screening system. Purpose: The purpose of this study was to compare measures of static balance in stable and unstable conditions between different groups divided by FMSTM scores. A secondary purpose was to discern if balance indices discriminate the groups divided by FMSTM scores. Study Design: Cross-sectional study. Methods: Fifty-seven physically active subjects (25 men and 32 women; mean age of 22.9 +/- 3.1 yrs) participated. The outcome was unilateral stance balance indices, composed by: Anteroposterior Index; Medial lateral Index, and Overall Balance Index in stable and unstable conditions, as provided by the Biodex balance platform. Subjects were dichotomized into two groups, according to a FMSTM cut-off score of 14: FMS1 (score > 14) and FMS2 (score <= 14). The independent Students t-test was used to verify differences in balance indices between FMS1 and FMS2 groups. A discriminant analysis was applied in order to identify which of the balance indices would adequately discriminate the FMSTM groups. Results: Comparisons between FMS1 and FMS2 groups in the stable and unstable conditions demonstrated a higher unstable Anteroposterior index for FMS2 (p=0.017). No significant differences were found for other comparisons (p>0.05). The indices did not discriminate the FMSTM groups (p > 0.05). Conclusions: The balance indices adopted in this study were not useful as a parameter for identification and discrimination of healthy subjects assessed by the FMSTM. Level of evidence: 2c. PMID- 29158945 TI - NF-kappaB signaling in inflammation. AB - The transcription factor NF-kappaB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-kappaB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-kappaB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-kappaB activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of NF-kappaB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-kappaB inhibition. PMID- 29158948 TI - THE HOW AND WHY OF THE MOVEMENT SYSTEM AS THE IDENTITY OF PHYSICAL THERAPY. AB - : The Movement System was adopted as the identity of physical therapy as one of the 8 guiding principles accompanying the Vision Statement of 2013. At its inception physical therapy was considered more of a technical field rather than that of a professional field. Physicians were to diagnose the patient's problem and the therapist was to follow the prescription provided by the physician with the primary purpose being to relieve symptoms such as pain or muscle weakness. Even by the 1960's, the prescription became more of a referral and there was recognition that therapists were making decisions about the patient's treatment and discharge disposition. The role of the physical therapist in pathokinesiologic problems has been well accepted over the years but as insights are gained about the role of movement in musculoskeletal pain, the concept of kinesiopathologic problems is being defined. Whether the movement dysfunction is from a pathokinesiologic or a kinesiopathologic mechanisms, the underlying physiologic process is movement which is the composite action of the movement system. This article provides a brief discussion of the steps leading to promotion of the identity and the reasons that further defining and promoting the movement system as the body system for which physical therapists are responsible is necessary for the full recognition of the profession. As suggested by the kinesiopathologic concept of movement inducing pathology, physical therapists can address the cause of musculoskeletal problems and not just symptoms or consequences such as the pathoanatomic problem. Level of Evidence: 5. PMID- 29158949 TI - DIAGNOSIS DIALOG: RECAP AND RELEVANCE TO RECENT APTA ACTIONS. AB - For at least 40 years, physical therapists have been contemplating the issue of diagnosis. After the profession chose to require completion of doctoral-level training for entry into the profession, making some decisions about diagnosis became essential. In the 2004 Maley Lecture, Cynthia Coffin-Zadai called the profession to action on the question of diagnosis. One response to her call was the formation of a group of physical therapists from across the country to engage in an extended conversation about diagnosis. The Diagnosis Dialog group first met in St. Louis in 2006 and at the end of the meeting they decided to continue the discussion at another meeting. In fact, they met a total of 13 times over 10 years. The purposes of this article are to a) summarize briefly some of the topics that were discussed and b) demonstrate the relevance of those discussions to recent APTA actions regarding the adoption of the movement system as the core of physical therapist practice, education, and research. PMID- 29158951 TI - THE MOVEMENT SYSTEM IN EDUCATION. AB - : Although many physical therapists have begun to focus on movement and function in clinical practice, a significant number continue to focus on impairments or pathoanatomic models to direct interventions. This paradigm may be driven by the current models used to direct and guide curricula used for physical therapist education. The methods by which students are educated may contribute to a focus on independent systems, rather than viewing the body as a functional whole. Students who enter practice must be able to integrate information across multiple systems that affect a patient or client's movement and function. Such integration must be taught to students and it is the responsibility of those in physical therapist education to embrace and teach the next generation of students this identifying professional paradigm of the movement system. The purpose of this clinical commentary is to describe the current state of the movement system in physical therapy education, suggest strategies for enhancing movement system focus in entry level education, and envision the future of physical therapy education related to the movement system. Contributions by a student author offer depth and perspective to the ideas and suggestions presented. Level of Evidence: 5. PMID- 29158950 TI - CHANGING OUR DIAGNOSTIC PARADIGM: MOVEMENT SYSTEM DIAGNOSTIC CLASSIFICATION. AB - Proper diagnosis is a first step in applying best available treatments, and prognosticating outcomes for clients. Currently, the majority of musculoskeletal diagnoses are classified according to pathoanatomy. However, the majority of physical therapy treatments are applied toward movement system impairments or pain. While advocated within the physical therapy profession for over thirty years, diagnostic classification within a movement system framework has not been uniformly developed or adopted. We propose a basic framework and rationale for application of a movement system diagnostic classification for atraumatic shoulder pain conditions, as a case for the broader development of movement system diagnostic labels. Shifting our diagnostic paradigm has potential to enhance communication, improve educational efficiency, facilitate research, directly link to function, improve clinical care, and accelerate preventive interventions. PMID- 29158952 TI - THE IMPACT OF ATTENTIONAL FOCUS ON THE TREATMENT OF MUSCULOSKELETAL AND MOVEMENT DISORDERS. AB - : Treatment plans employed by physical therapists involved in musculoskeletal rehabilitation may follow a conventional medical-model approach, isolating care at the tissue level but neglecting consideration for neurocognitive contributions to recovery. Understanding and integration of motor learning concepts into physical therapy practice is integral for influencing the human movement system in the most effective manner. One such motor learning concept is the use of verbal instruction to influence the attentional focus of the learner. Evidence suggests that encouraging an external focus of attention through verbal instruction promotes superior motor performance, and more lasting effects of a learning experience than an internal focus of attention. Utilizing an external focus of attention when instructing a patient on a motor task may facilitate improved motor performance and improved functional outcomes in treatment plans devised to address musculoskeletal injury and movement disorders. The purpose of this review is to summarize the basic principles of motor learning and available evidence on the influence an external focus of attention has on motor learning and performance, including the benefits of an external focus of attention over an internal focus of attention and how therapists may inadvertently encourage the latter. Furthermore, the benefits of possessing greater awareness of neurocognitive mechanisms are discussed to exhibit how implementing such concepts into musculoskeletal rehabilitation can maximize treatment outcomes. Level of Evidence: 5. PMID- 29158953 TI - RETENTION OF MOVEMENT TECHNIQUE: IMPLICATIONS FOR PRIMARY PREVENTION OF ACL INJURIES. AB - Background: Retention of movement technique is crucial in anterior cruciate ligament (ACL) injury prevention programs. It is unknown if specific instructions or video instructions result in changes in kinematic and kinetic measures during a relatively short training session, and in a retention test one week later. Hypothesis/Purpose: The purpose was to determine the effects of verbal external focus (EF), verbal internal focus (IF) and video instructions (VI) on landing technique (i.e. kinematics and kinetics) during training and retention. Study Design: Randomized Controlled Trial. Methods: This study compared verbal EF, verbal IF, VI and CTRL group. Forty healthy athletes were assigned to the IF (n=10), EF (n=10), VI (n=10) or CTRL group (n=10). A jump-landing task was performed as a baseline, followed by two training blocks (TR1 and TR2) and a post test. Group specific instructions were offered in TR1 and TR2. In addition, subjects in the IF, EF and VI groups were free to ask for feedback after every jump in TR1 and TR2. One week later, a retention test was conducted without specific instructions or feedback. Kinematics and kinetics were captured using an 8-camera motion analysis system. Results: Males and females in the EF and VI instruction group showed beneficial results during and after the training session, in terms of improved landing technique. Retention was achieved after only a short training session. Conclusion: ACL injury prevention programs should include EF and/or VI instructions to improve kinematics and kinetics and achieve retention. Level of Evidence: 3b. PMID- 29158954 TI - THE RELATIONSHIP BETWEEN SEGMENTAL ROLLING ABILITY AND LUMBAR MULTIFIDUS ACTIVATION TIME. AB - Background: Segmental rolling has been utilized as an assessment and intervention tool to identify and affect dysfunction of the upper quarter, core, and lower quarter. One theory to explain dysfunctional segmental rolling is a lack of segmental spinal control / stabilization. Faulty muscle firing sequencing has been related to poor spinal stability, however to date, no assessment tool exists to evaluate a patient's motor coordination of local and global musculature. Purpose: The purpose of this study was to assess the temporal sequence of lumbar multifidus activation associated with anterior deltoid activation, and to determine if faulty sequencing was associated with the inability to segmentally roll in subjects without mobility restrictions. The authors hypothesized that in individuals who could not roll, a multifidus muscle onset latency relative to a prime mover activation would be present. In addition, a subset of the individuals with an inability to roll were utilized for a pilot study examining the ability to address the firing pattern with corrective exercise. Methods: Twenty healthy subjects (13 females, 7 males), ages 19-25, participated in the study. Each subject underwent an upper and lower quarter screen and assessment of thoracic spine mobility. Subjects were excluded from the study if they had previous spine surgery, or were currently experiencing back pain. In addition, subjects who had any disease, disorders, or pathology that would hinder participation in segmental rolling or who had spinal movement contraindications were excluded. Since shoulder flexion is performed during the study, participants who had shoulder pathology or contraindications to upper extremity movement were excluded as well. Subjects with less than 50 degrees of trunk rotation were excluded from the study due to a possible physical mobility limitation that would prevent proficient segmental rolling. Included subjects were assessed on their ability to segmentally roll. Subjects who could complete the rolling task were placed in cohort A ("can roll"), and subjects who could not roll were placed in cohort B ("can't roll").Electromyographic (EMG) activity of the multifidus was recorded adjacent to the lamina of the L4 vertebrae using intramuscular fine-wire electrodes. EMG activity of the anterior deltoid was also recorded with a surface electrode during a single arm movement into shoulder flexion. While in a standing position, subjects were instructed to move their right upper arm into flexion as quickly as possible. Subjects flexed their shoulder to 90 degrees for three trials while muscle activity was recorded. Data were high-pass filtered at 30 Hz to remove baseline artifact, and the onset EMG times was selected as the point at which EMG increased two SD above baseline levels. Onset of the multifidus muscle was reported relative to that of the prime mover (anterior deltoid). Muscle onset latency was defined as the time difference between the onset of contraction of the multifidus and the anterior deltoid. Results: Nine subjects were placed in cohort A, 11 subjects were placed in cohort B. The mean firing time of the lumbar multifidus for the cohort A was 16.67msec before the anterior deltoid, and the mean firing time of the lumbar multifidus for cohort B was 57.36msec after the anterior deltoid. There was a statistically significant difference (p<0.00) in the firing time between cohorts A and B. Conclusions: In subjects who could segmentally roll, the multifidus muscle activation always preceded that of the prime mover muscle activation. In subjects who could not segmentally roll, the results of this study confirm that there is a multifidus muscle onset latency relative to the activation of the anterior deltoid. The inability to segmentally roll may be related to faulty sequencing of lumbar multifidus firing. PMID- 29158955 TI - CORRELATION OF SELF-REPORTED OUTCOME MEASURES AND THE SELECTIVE FUNCTIONAL MOVEMENT ASSESSMENT (SFMA): AN EXPLORATION OF VALIDITY. AB - Background/Purpose: The Selective Functional Movement Assessment (SFMA) is a clinical model used to assist diagnosis and treatment of musculoskeletal disorders by identifying dysfunctions in movement patterns. Based on the premise that addressing movement dysfunction is associated with an improvement in patient outcomes, the validity of the SFMA would be strengthened by observed improvement in self-reported function being associated with change in movement patterns. The purpose of this study was to explore the validity of the SFMA by determining if a correlation exists between a change in self-reported outcome measures and attributes of the assessment. Methods: Eighty-five clinical subjects (20.3 +/- 1.6 years) were administered the Patient-Specific Functional Scale and one of four region-specific outcome measures followed by the SFMA top-tier movements. When deemed appropriate for discharge or following six weeks of therapy by an independent physical therapist, each subject repeated the outcome measures and was re-evaluated on the top-tier tests by the same initial assessor who was blinded to the subject's self-reported outcomes. Correlations between changes in outcome measures, number of painful movements and measures of movement quality (number of dysfunctional movements and criterion scores) were calculated with Spearman rank correlation coefficients. Subjects were analyzed as a consolidated group and by each region based on primary complaint. Results: Fair to good positive correlations between improvements in self-reported outcomes and decreases in the number of painful patterns were noted for the complete dataset and for those with shoulder girdle and lumbopelvic complaints (rs = 0.28, 0.52, and 0.41, respectively). Subjects with lumbopelvic complaints demonstrated fair positive correlations with improvements in self-reported outcomes and decreases in the number of dysfunctional patterns (rs = 0.41 and 0.46). No correlations between changes in outcome measures and criterion score were observed. Conclusion: Improvements in self-reported outcome measures were associated with fewer painful movement patterns of the SFMA. Improvements in self-reported function were not related to changes in movement quality, except for subjects presenting with lumbopelvic complaints. Level of Evidence: 2b. PMID- 29158956 TI - VALIDITY OF FUNCTIONAL SCREENING TESTS TO PREDICT LOST-TIME LOWER QUARTER INJURY IN A COHORT OF FEMALE COLLEGIATE ATHLETES. AB - Background: Lower quarter injuries account for more than 50% of all injuries in collegiate athletics. Neuromuscular screening tests could potentially identify athletes who are at risk for sustaining an injury. While previous research has studied individual tests, the authors of this paper are unaware of any study that has compared diagnostic accuracy of multiple neuromuscular screening tests within one study cohort. Hypothesis/Purpose: The purpose of this study was to examine the accuracy of three common neuromuscular screening tests to predict the occurrence of a lower quarter injury in female collegiate volleyball and basketball players. Study Design: Prospective Cohort. Methods: Thirty-five subjects underwent a pre-season screening by performing the Y-balance test, the Functional Movement ScreenTM, and Single Leg Hop test. Data were collected on lower quarter injury incidence, lost practice time, and lost competition time among subjects throughout the course of one season. Receiver operating characteristics curves were plotted and area under the curve was calculated to assess the relationship between lower extremity injury incidence and the scores of the functional tests. Results: Lost-time injuries occurred in 11 athletes (31.4%), of whom, six athletes (17.1%) lost 50 hours or greater. There were no significant relationships between occurrence of a lost-time lower extremity injury and scores on any of the three tests. Positive and negative likelihood ratios all included the value of 1.0. Conclusions: Although reliable, the screening tests under study did not appear to retain adequate validity to predict lower quarter injury risk within these female collegiate athletes. Level of Evidence: Level 2b. PMID- 29158957 TI - RELATIONSHIP OF PRESEASON MOVEMENT SCREENS WITH OVERUSE SYMPTOMS IN COLLEGIATE BASEBALL PLAYERS. AB - Background: The shoulder mobility screen of the Functional Movement ScreenTM (FMSTM) and the upper extremity patterns of the Selective Functional Movement Assessment (SFMA) assess global, multi-joint movement capabilities in the upper extremities. Identifying which assessment can most accurately determine if baseball players are at an increased risk of experiencing overuse symptoms in the shoulder or elbow throughout a competitive season may reduce throwing-related injuries requiring medical attention. Purpose: The purpose of this study was to determine if preseason FMSTM or SFMA scores were related to overuse severity scores in the shoulder or elbow during the preseason and competitive season. Study design: Cohort study. Methods: Sixty healthy, male, Division III collegiate baseball players (mean age = 20.1 +/- 2.0 years) underwent preseason testing using the FMSTM shoulder mobility screen, and SFMA upper extremity patterns. Their scores were dichotomized into good and bad movement scores, and were compared to weekly questionnaires registering overuse symptoms and pain severity in the shoulder or elbow during the season. Results: Poor FMSTM performance was associated with an increased likelihood of experiencing at least one overuse symptom during the preseason independent of grade and position (adjusted odds ratio [OR] = 5.14, p = 0.03). Poor SFMA performance was associated with an increased likelihood of experiencing at least one overuse symptom during the preseason (adjusted OR = 6.10, p = 0.03) and during the competitive season (adjusted OR = 17.07, p = 0.03) independent of grade and position. Conclusion: FMSTM shoulder mobility and SFMA upper extremity pattern performance were related to the likelihood of experiencing overuse symptoms during a baseball season. Participants with poor FMSTM performances may be more likely to experience at least one overuse symptom in their shoulder or elbow during the preseason. Additionally, individuals with poor SFMA performances may be more likely to report overuse symptoms during the preseason or competitive season. Level of evidence: Level 3. PMID- 29158958 TI - THE FUNCTIONAL MOVEMENT SCREEN (FMSTM) IN ELITE YOUNG SOCCER PLAYERS BETWEEN 14 AND 20 YEARS: COMPOSITE SCORE, INDIVIDUAL-TEST SCORES AND ASYMMETRIES. AB - Background: The Functional Movement Screen (FMSTM) is a widely used seven-test battery used by practitioners working in sport medicine. The FMSTM composite score (sum of seven tests) in soccer athletes from different competitive levels has been well explored in literature, but the specific movement deficits presented by young high competitive level players remains unclear. Purpose: The aim of the present study was to provide a detailed description of the performance of elite young soccer players (age 14-20 years) on the FMSTM testing battery. Study design: Cross-sectional observational study. Methods: One-hundred and three young soccer players (14-20 years) from a premier league club were assessed by two experienced raters using the FMSTM testing battery. FMSTM composite score, individual-test scores and asymmetries were considered for analysis, and comparisons between age categories were performed. Results: FMSTM composite scores ranged from 9 to 16 points (median=13 points). 82% of the athletes had a composite score <=14 points, and 91% were classified into the "Fail" group (score 0 or 1 in at least one test). Almost half of athletes (48%) had poor performance (i.e., individual score < 2) in "deep squat" test. Most of athletes in the younger categories (under-15 and under-16) had poor performance in the "trunk stability push-up" test (70%) and in the "rotary stability" test (74%). Asymmetry in at least one of five unilateral FMSTM tests was found in 65% of athletes. Conclusion: High-performance young soccer players have important functional deficits, especially in tasks involving deep squat and trunk stability, as well as high prevalence of asymmetry between right and left body side. Level of evidence: 3a. PMID- 29158959 TI - THE RELATIONSHIP BETWEEN PRE-OPERATIVE AND TWELVE-WEEK POST-OPERATIVE Y-BALANCE AND QUADRICEPS STRENGTH IN ATHLETES WITH AN ANTERIOR CRUCIATE LIGAMENT TEAR. AB - Background: Pre-operative quadriceps strength may have a positive influence on post-operative function and outcomes at time of return to sport. Little consideration has been given to quadriceps strength during the early post operative timeframes. Twelve-week post-operative anterior cruciate ligament reconstruction (ACL-R) is considered a critical time point for progression in the rehabilitation process. There is currently limited research looking at the relationship between clinical measurements pre-operatively and at 12-weeks following ACL-R. Purpose/Hypothesis: The primary purpose of this study was to examine the differences between Y-Balance Test Lower Quarter (YBT-LQ) and isokinetic quadriceps strength tested pre-operatively and post-operatively following ACL-R (12-weeks). Study Design: Within subject, repeated measures. Methods: Thirty-nine participants (15.6 +/- 1.5 y/o) were diagnosed with an ACL tear and were undergoing rehabilitation to return to a sport requiring cutting and pivoting were included. YBT-LQ and isokinetic quadriceps strength were assessed pre-operatively and at 12-weeks after ACL-R. YBT-LQ composite scores were calculated bilaterally and isokinetic quadriceps strength was tested using the Biodex Multi-Joint Testing and Rehabilitation System. Paired T-tests were used to determine mean group differences between YBT-LQ and isokinetic quadriceps strength scores pre-operatively and at 12-weeks post-operative. A Pearson Correlation was performed to determine relationships between variables at both time points. Results: There was a significant improvement in YBT-LQ composite scores from pre-operative to 12-weeks post-operative on both the involved (Pre operative: 89.0 +/- 7.7; 12-weeks: 94.1 +/- 7.1, p<0.001) and uninvolved (Pre operative: 92.6 +/- 6.2; 12-weeks: 97.6 +/- 6.8, p<0.001) limbs. Quadriceps strength decreased significantly from pre-operative to 12-weeks on the involved limb (Pre-operative: 82.3 ftlbs +/- 38.6; 12-weeks: 67.9 ftlbs+/-27.4, p<0.01), but no differences were found on the uninvolved limb (Pre-operative: 117.3ftlbs +/- 42.0; 12-weeks: 121.7ftlbs +/- 41.5, p = 0.226). Conclusions: Involved limb quadriceps strength decreases from time of pre-operative to 12-weeks following ACL-R. Level of Evidence: 3. PMID- 29158960 TI - A COMBINED TREATMENT APPROACH EMPHASIZING IMPAIRMENT-BASED MANUAL THERAPY AND EXERCISE FOR HIP-RELATED COMPENSATORY INJURY IN ELITE ATHLETES: A CASE SERIES. AB - Background/Purpose: Athletes experiencing hip, groin, and low back pain often exhibit similar clinical characteristics. Individuals with hip, groin and low back pain may have the presence of multiple concurrent pathoanatomical diagnoses. Regardless, similar regional characteristics and dysfunction may contribute to the patient's chief complaint, potentially creating a sub-group of individuals that may be defined by lumbopelvic and hip mobility limitations, motor control impairments, and other shared clinical findings. The purpose of this case series is to describe the conservative management of elite athletes, within the identified aforementioned sub-group, that emphasized regional manual therapy interventions, and therapeutic exercise designed to improve lumbopelvic and hip mobility, stability and motor control. Case Descriptions: Five elite athletes were clinically diagnosed by a physical therapist with primary pathologies including adductor-related groin pain (ARGP), femoral acetabular impingement (FAI) with acetabular labral lesion and acute, mechanical low back pain (LBP). Similar subjective, objective findings and overall clinical profiles were identified among all subjects. Common findings aside from the chief complaint included, but were not limited to, decreased hip range of motion (ROM), impaired lumbopelvic motor control and strength, lumbar hypomobility in at least one segment, and a positive hip flexion-adduction-internal rotation (FADIR) special test. A three-phase impairment-based physical therapy program was implemented to resolve the primary complaints and return the subjects to their desired level of function. Acute phase rehabilitation consisted of manual therapy and fundamental motor control exercises. Progression to the sub-acute and terminal phases was based on improved subjective pain reports and progress with functional impairments. As the subjects progress through the rehabilitation phases, the delivery of physical therapy interventions were defined by decreased manual therapies and an increased emphasis and priority on graded exercise. Outcomes: Significant reductions in reported pain (>2 points Numeric Pain Rating Scale), improved reported function via functional outcome measures (Hip and Groin Outcome Score), and continued participation in sport occurred in all five cases without the need for surgical intervention. Discussion: The athletes described in this case series make up a common clinical sub-group defined by hip and lumbopelvic mobility restrictions, lumbopelvic and lower extremity motor control impairments and potentially other shared clinical findings. Despite differences in pathoanatomic findings, similar objective findings were identified and similar treatment plans were applied, potentially affecting the movement system as a whole. Subjects were conservatively managed allowing continued participation in sport within their competitive seasons. Conclusion: Comprehensive conservative treatment of the athletes with shared impairments, as described in this case series, may be of clinical importance when managing athletes with hip, groin, and low back pain. Level of Evidence: Therapy, Level 4, Case Series. PMID- 29158961 TI - The Furvela tent-trap Mk 1.1 for the collection of outdoor biting mosquitoes. AB - Outdoor transmission of malaria and other vector borne diseases remains a problem. The WHO has recently recognized the need for suitable methods for assessing vector density outdoors and a number of tent-traps have been developed. Only one such trap, the Furvela tent-trap, does not require an 'entry' behavior on the part of the mosquito. It remains the cheapest and lightest tent-trap described. It takes less than two minutes to install and is the only trap that uses readily available components. Here we describe recent modifications to the trap, which make it even easier to set up in the field, provide a standard operating procedure (SOP) and describe some recent experiments examining the effect of the addition of light and door placement to working of the trap. The trap provides the closest approximation to CDC light-traps, widely used to collect indoor biting mosquitoes. This enables the effect of both indoor and outdoor interventions on mosquito density and behavior to be determined. PMID- 29158962 TI - Sediment tolerance mechanisms identified in sponges using advanced imaging techniques. AB - Terrestrial runoff, resuspension events and dredging can affect filter-feeding sponges by elevating the concentration of suspended sediments, reducing light intensity, and smothering sponges with sediments. To investigate how sponges respond to pressures associated with increased sediment loads, the abundant and widely distributed Indo-Pacific species Ianthella basta was exposed to elevated suspended sediment concentrations, sediment deposition, and light attenuation for 48 h (acute exposure) and 4 weeks (chronic exposure). In order to visualise the response mechanisms, sponge tissue was examined by 3D X-ray microscopy and scanning electron microscopy (SEM). Acute exposures resulted in sediment rapidly accumulating in the aquiferous system of I. basta, although this sediment was fully removed within three days. Sediment removal took longer (>2 weeks) following chronic exposures, and I. basta also exhibited tissue regression and a smaller aquiferous system. The application of advanced imaging approaches revealed that I. basta employs a multilevel system for sediment rejection and elimination, containing both active and passive components. Sponges responded to sediment stress through (i) mucus production, (ii) exclusion of particles by incurrent pores, (iii) closure of oscula and pumping cessation, (iv) expulsion of particles from the aquiferous system, and (v) tissue regression to reduce the volume of the aquiferous system, thereby entering a dormant state. These mechanisms would result in tolerance and resilience to exposure to variable and high sediment loads associated with both anthropogenic impacts like dredging programs and natural pressures like flood events. PMID- 29158963 TI - Grassland habitat restoration: lessons learnt from long term monitoring of Swanworth Quarry, UK, 1997-2014. AB - Habitat restoration projects are often conducted when prior use or extraction of natural resources results in land degradation. The success of restoration programmes, however, is variable, and studies that provide evidence of long term outcomes are valuable for evaluation purposes. This study focused on the restoration of vegetation within a limestone quarry in Dorset, UK between 1997 and 2014. Using a randomised block design, the effect of seed mix and seed rate on the development of community assemblage was investigated in comparison to a nearby target calcareous grassland site. We hypothesised that seed mix composition and sowing rate would influence both the trajectory of the grassland assemblage and final community composition. We found that species composition (in relation to both richness and community assemblage) was strongly influenced by time and to some extent by seed rate and seed mix. However, no treatments achieved strong resemblance to the calcareous grassland target vegetation; rather they resembled mesotrophic communities. We conclude that (as with previous studies) there is no "quick fix" for the establishment of a grassland community; long-term monitoring provides useful information on the trajectory of community development; sowing gets you something (in our case mesotrophic grassland), but, it may not be the target vegetation (e.g., calcicolous grassland) you want that is difficult to establish and regenerate; it is important to sow a diverse mix as subsequent recruitment opportunities are probably limited; post-establishment management should be explored further and carefully considered as part of a restoration project. PMID- 29158964 TI - Ginsenoside Rk1 bioactivity: a systematic review. AB - Ginsenoside Rk1 (G-Rk1) is a unique component created by processing the ginseng plant (mainly Sung Ginseng (SG)) at high temperatures. The aim of our study was to systematically review the pharmacological effects of G-Rk1. We utilized and manually searched eight databases to select in vivo and in vitro original studies that provided information about biological, pharmaceutical effects of G-Rk1 and were published up to July 2017 with no restriction on language or study design. Out of the 156 papers identified, we retrieved 28 eligible papers in the first skimming phase of research. Several articles largely described the G-Rk1 anti cancer activity investigating "cell viability", "cell proliferation inhibition", "apoptotic activity", and "effects of G-Rk1 on G1 phase and autophagy in tumor cells" either alone or in combination with G-Rg5. Others proved that it has antiplatelet aggregation activities, anti-inflammatory effects, anti-insulin resistance, nephroprotective effect, antimicrobial effect, cognitive function enhancement, lipid accumulation reduction and prevents osteoporosis. In conclusion, G-Rk1 has a significant anti-tumor effect on liver cancer, melanoma, lung cancer, cervical cancer, colon cancer, pancreatic cancer, gastric cancer, and breast adenocarcinoma against in vitro cell lines. In vivo experiments are further warranted to confirm these effects. PMID- 29158965 TI - Colour change of twig-mimicking peppered moth larvae is a continuous reaction norm that increases camouflage against avian predators. AB - Camouflage, and in particular background-matching, is one of the most common anti predator strategies observed in nature. Animals can improve their match to the colour/pattern of their surroundings through background selection, and/or by plastic colour change. Colour change can occur rapidly (a few seconds), or it may be slow, taking hours to days. Many studies have explored the cues and mechanisms behind rapid colour change, but there is a considerable lack of information about slow colour change in the context of predation: the cues that initiate it, and the range of phenotypes that are produced. Here we show that peppered moth (Biston betularia) larvae respond to colour and luminance of the twigs they rest on, and exhibit a continuous reaction norm of phenotypes. When presented with a heterogeneous environment of mixed twig colours, individual larvae specialise crypsis towards one colour rather than developing an intermediate colour. Flexible colour change in this species has likely evolved in association with wind dispersal and polyphagy, which result in caterpillars settling and feeding in a diverse range of visual environments. This is the first example of visually induced slow colour change in Lepidoptera that has been objectively quantified and measured from the visual perspective of natural predators. PMID- 29158966 TI - Mitochondrial genomes of three Tetrigoidea species and phylogeny of Tetrigoidea. AB - The mitochondrial genomes (mitogenomes) of Formosatettix qinlingensis, Coptotettix longjiangensis and Thoradonta obtusilobata (Orthoptera: Caelifera: Tetrigoidea) were sequenced in this study, and almost the entire mitogenomes of these species were determined. The mitogenome sequences obtained for the three species were 15,180, 14,495 and 14,538 bp in length, respectively, and each sequence included 13 protein-coding genes (PCGs), partial sequences of rRNA genes (rRNAs), tRNA genes (tRNAs) and a A + T-rich region. The order and orientation of the gene arrangement pattern were identical to that of most Tetrigoidea species. Some conserved spacer sequences between trnS(UCN) and nad1 were useful to identify Tetrigoidea and Acridoidea. The Ka/Ks value of atp8 between Trachytettix bufo and other four Tetrigoidea species indicated that some varied sites in this gene might be related with the evolution of T. bufo. The three Tetrigoidea species were compared with other Caelifera. At the superfamily level, conserved sequences were observed in intergenic spacers, which can be used for superfamily level identification between Tetrigoidea and Acridoidea. Furthermore, a phylogenomic analysis was conducted based on the concatenated data sets from mitogenome sequences of 24 species of Orthoptera in the superorders Caelifera and Ensifera. Both maximum likelihood and bayesian inference analyses strongly supported Acridoidea and Tetrigoidea as forming monophyletic groups. The relationships among six Tetrigoidea species were (((((Tetrix japonica, Alulatettix yunnanensis), Formosatettix qinlingensis), Coptotettix longjiangensis), Trachytettix bufo), Thoradonta obtusilobata). PMID- 29158967 TI - Bed site selection by a subordinate predator: an example with the cougar (Puma concolor) in the Greater Yellowstone Ecosystem. AB - As technology has improved, our ability to study cryptic animal behavior has increased. Bed site selection is one such example. Among prey species, bed site selection provides thermoregulatory benefits and mitigates predation risk, and may directly influence survival. We conducted research to test whether a subordinate carnivore also selected beds with similar characteristics in an ecosystem supporting a multi-species guild of competing predators. We employed a model comparison approach in which we tested whether cougar (Puma concolor) bed site attributes supported the thermoregulatory versus the predator avoidance hypotheses, or exhibited characteristics supporting both hypotheses. Between 2012 2016, we investigated 599 cougar bed sites in the Greater Yellowstone Ecosystem and examined attributes at two scales: the landscape (second-order, n = 599) and the microsite (fourth order, n = 140). At the landscape scale, cougars selected bed sites in winter that supported both the thermoregulatory and predator avoidance hypotheses: bed sites were on steeper slopes but at lower elevations, closer to the forest edge, away from sagebrush and meadow habitat types, and on southern, eastern, and western-facing slopes. In the summer, bed attributes supported the predator avoidance hypothesis over the thermoregulation hypothesis: beds were closer to forest edges, away from sagebrush and meadow habitat classes, and on steeper slopes. At the microsite scale, cougar bed attributes in both the winter and summer supported both the predator avoidance and thermoregulatory hypotheses: they selected bed sites with high canopy cover, high vegetative concealment, and in a rugged habitat class characterized by cliff bands and talus fields. We found that just like prey species, a subordinate predator selected bed sites that facilitated both thermoregulatory and anti-predator functions. In conclusion, we believe that measuring bed site attributes may provide a novel means of measuring the use of refugia by subordinate predators, and ultimately provide new insights into the habitat requirements and energetics of subordinate carnivores. PMID- 29158968 TI - Attribute amnesia is greatly reduced with novel stimuli. AB - Attribute amnesia is the counterintuitive phenomenon where observers are unable to report a salient aspect of a stimulus (e.g., its colour or its identity) immediately after the stimulus was presented, despite both attending to and processing the stimulus. Almost all previous attribute amnesia studies used highly familiar stimuli. Our study investigated whether attribute amnesia would also occur for unfamiliar stimuli. We conducted four experiments using stimuli that were highly familiar (colours or repeated animal images) or that were unfamiliar to the observers (unique animal images). Our results revealed that attribute amnesia was present for both sets of familiar stimuli, colour (p < .001) and repeated animals (p = .001); but was greatly attenuated, and possibly eliminated, when the stimuli were unique animals (p = .02). Our data shows that attribute amnesia is greatly reduced for novel stimuli. PMID- 29158969 TI - 5-Fluorouracil and irinotecan (SN-38) have limited impact on colon microbial functionality and composition in vitro. AB - Gastrointestinal mucositis is a debilitating side effect of chemotherapy treatment, with currently no treatment available. As changes in microbial composition have been reported upon chemotherapy treatment in vivo, it is thought that gut microbiota dysbiosis contribute to the mucositis etiology. Yet it is not known whether chemotherapeutics directly cause microbial dysbiosis, thereby increasing mucositis risk, or whether the chemotherapeutic subjected host environment disturbs the microbiome thereby aggravating the disease. To address this question, we used the M-SHIME(r), an in vitro mucosal simulator of the human intestinal microbial ecosystem, as an experimental setup that excludes the host factor. The direct impact of two chemotherapeutics, 5-fluorouracil (5-FU) and SN 38 (active metabolite of irinotecan), on the luminal and mucosal gut microbiota from several human donors was investigated through monitoring fermentation activity and next generation sequencing. At a dose of 10 uM in the mucosal environment, 5-FU impacted the functionality and composition of the colon microbiota to a minor extent. Similarly, a daily dose of 10 uM SN-38 in the luminal environment did not cause significant changes in the functionality or microbiome composition. As our mucosal model does not include a host-compartment, our findings strongly indicate that a putative microbial contribution to mucositis is initially triggered by an altered host environment upon chemotherapy. PMID- 29158970 TI - Snapshot recordings provide a first description of the acoustic signatures of deeper habitats adjacent to coral reefs of Moorea. AB - Acoustic recording has been recognized as a valuable tool for non-intrusive monitoring of the marine environment, complementing traditional visual surveys. Acoustic surveys conducted on coral ecosystems have so far been restricted to barrier reefs and to shallow depths (10-30 m). Since they may provide refuge for coral reef organisms, the monitoring of outer reef slopes and describing of the soundscapes of deeper environment could provide insights into the characteristics of different biotopes of coral ecosystems. In this study, the acoustic features of four different habitats, with different topographies and substrates, located at different depths from 10 to 100 m, were recorded during day-time on the outer reef slope of the north Coast of Moorea Island (French Polynesia). Barrier reefs appeared to be the noisiest habitats whereas the average sound levels at other habitats decreased with their distance from the reef and with increasing depth. However, sound levels were higher than expected by propagation models, supporting that these habitats possess their own sound sources. While reef sounds are known to attract marine larvae, sounds from deeper habitats may then also have a non negligible attractive potential, coming into play before the reef itself. PMID- 29158971 TI - The ultimate legs of Chilopoda (Myriapoda): a review on their morphological disparity and functional variability. AB - The arthropodium is the key innovation of arthropods. Its various modifications are the outcome of multiple evolutionary transformations, and the foundation of nearly endless functional possibilities. In contrast to hexapods, crustaceans, and even chelicerates, the spectrum of evolutionary transformations of myriapod arthropodia is insufficiently documented and rarely scrutinized. Among Myriapoda, Chilopoda (centipedes) are characterized by their venomous forcipules evolutionarily transformed walking legs of the first trunk segment. In addition, the posterior end of the centipedes' body, in particular the ultimate legs, exhibits a remarkable morphological heterogeneity. Not participating in locomotion, they hold a vast functional diversity. In many centipede species, elongation and annulation in combination with an augmentation of sensory structures indicates a functional shift towards a sensory appendage. In other species, thickening, widening and reinforcement with a multitude of cuticular protuberances and glandular systems suggests a role in both attack and defense. Moreover, sexual dimorphic characteristics indicate that centipede ultimate legs play a pivotal role in intraspecific communication, mate finding and courtship behavior. We address ambiguous identifications and designations of podomeres in order to point out controversial aspects of homology and homonymy. We provide a broad summary of descriptions, illustrations, ideas and observations published in past 160 years, and propose that studying centipede ultimate legs is not only essential in itself for filling gaps of knowledge in descriptive morphology, but also provides an opportunity to explore diverse pathways of leg transformations within Myriapoda. PMID- 29158972 TI - Short-term effects of CO2 leakage on the soil bacterial community in a simulated gas leakage scenario. AB - The technology of carbon dioxide (CO2) capture and storage (CCS) has provided a new option for mitigating global anthropogenic emissions with unique advantages. However, the potential risk of gas leakage from CO2 sequestration and utilization processes has attracted considerable attention. Moreover, leakage might threaten soil ecosystems and thus cannot be ignored. In this study, a simulation experiment of leakage from CO2 geological storage was designed to investigate the short-term effects of different CO2 leakage concentration (from 400 g m-2 day-1 to 2,000 g m-2 day-1) on soil bacterial communities. A shunt device and adjustable flow meter were used to control the amount of CO2 injected into the soil. Comparisons were made between soil physicochemical properties, soil enzyme activities, and microbial community diversity before and after injecting different CO2 concentrations. Increasing CO2 concentration decreased the soil pH, and the largest variation ranged from 8.15 to 7.29 (p < 0.05). Nitrate nitrogen content varied from 1.01 to 4.03 mg/Kg, while Olsen-phosphorus and total phosphorus demonstrated less regular downtrends. The fluorescein diacetate (FDA) hydrolytic enzyme activity was inhibited by the increasing CO2 flux, with the average content varying from 22.69 to 11.25 mg/(Kg h) (p < 0.05). However, the increasing activity amplitude of the polyphenol oxidase enzyme approached 230%, while the urease activity presented a similar rising trend. Alpha diversity results showed that the Shannon index decreased from 7.66 +/- 0.13 to 5.23 +/- 0.35 as the soil CO2 concentration increased. The dominant phylum in the soil samples was Proteobacteria, whose proportion rose rapidly from 28.85% to 67.93%. In addition, the proportion of Acidobacteria decreased from 19.64% to 9.29% (p < 0.01). Moreover, the abundances of genera Methylophilus, Methylobacillus, and Methylovorus increased, while GP4, GP6 and GP7 decreased. Canonical correlation analysis results suggested that there was a correlation between the abundance variation of Proteobacteria, Acidobacteria, and the increasing nitrate nitrogen, urease and polyphenol oxidase enzyme activities, as well as the decreasing FDA hydrolytic enzyme activity, Olsen-phosphorus and total phosphorus contents. These results might be useful for evaluating the risk of potential CO2 leakages on soil ecosystems. PMID- 29158973 TI - Science responses to IUCN Red Listing. AB - The IUCN Red List of Threatened Species is often advocated as a tool to assist decision-making in conservation investment and research focus. It is frequently suggested that research efforts should prioritize species in higher threat categories and those that are Data Deficient (DD). We assessed the linkage between IUCN listing and research effort in DD and Critically Endangered (CR) species, two groups generally advocated as research priorities. The analysis of the change in the research output following species classification indicated a listing effect in DD species, while such effect was observed in only a minority of CR species groups. DD species, while chronically understudied, seem to be recognized as research priorities, while research effort for endangered species appears to be driven by various factors other than the IUCN listing. Optimized conservation research focus would require international science planning efforts, harmonized through international mechanisms and promoted by financial and other incentives. PMID- 29158974 TI - Whole genome sequencing of Rhodotorula mucilaginosa isolated from the chewing stick (Distemonanthus benthamianus): insights into Rhodotorula phylogeny, mitogenome dynamics and carotenoid biosynthesis. AB - In industry, the yeast Rhodotorula mucilaginosa is commonly used for the production of carotenoids. The production of carotenoids is important because they are used as natural colorants in food and some carotenoids are precursors of retinol (vitamin A). However, the identification and molecular characterization of the carotenoid pathway/s in species belonging to the genus Rhodotorula is scarce due to the lack of genomic information thus potentially impeding effective metabolic engineering of these yeast strains for improved carotenoid production. In this study, we report the isolation, identification, characterization and the whole nuclear genome and mitogenome sequence of the endophyte R. mucilaginosa RIT389 isolated from Distemonanthus benthamianus, a plant known for its anti fungal and antibacterial properties and commonly used as chewing sticks. The assembled genome of R. mucilaginosa RIT389 is 19 Mbp in length with an estimated genomic heterozygosity of 9.29%. Whole genome phylogeny supports the species designation of strain RIT389 within the genus in addition to supporting the monophyly of the currently sequenced Rhodotorula species. Further, we report for the first time, the recovery of the complete mitochondrial genome of R. mucilaginosa using the genome skimming approach. The assembled mitogenome is at least 7,000 bases larger than that of Rhodotorula taiwanensis which is largely attributed to the presence of large intronic regions containing open reading frames coding for homing endonuclease from the LAGLIDADG and GIY-YIG families. Furthermore, genomic regions containing the key genes for carotenoid production were identified in R. mucilaginosa RIT389, revealing differences in gene synteny that may play a role in the regulation of the biotechnologically important carotenoid synthesis pathways in yeasts. PMID- 29158975 TI - Assessment of perioperative stress in colorectal cancer by use of in vitro cell models: a systematic review. AB - Background: The perioperative period is important for patient outcome. Colorectal cancer surgery can lead to metastatic disease due to release of disseminated tumor cells and the induction of surgical stress response. To explore the overall effects on surgically-induced changes in serum composition, in vitro model systems are useful. Methods: A systematic search in PubMed and EMBASE was performed to identify studies describing in vitro models used to investigate cancer cell growth/proliferation, cell migration, cell invasion and cell death of serum taken pre- and postoperatively from patients undergoing colorectal tumor resection. Results: Two authors (MG and TK) independently reviewed 984 studies and identified five studies, which fulfilled the inclusion criteria. Disagreements were solved by discussion. All studies investigated cell proliferation and cell invasion, whereas three studies investigated cell migration, and only one study investigated cell death/apoptosis. One study investigated postoperative peritoneal infection due to anastomotic leak, one study investigated mode of anesthesia (general anesthesia with volatile or intravenous anesthetics), and one study investigated preoperative intervention with granulocyte macrophage colony stimulating factor (GMCSF). In all studies an increased proliferation, cell migration and invasion was demonstrated after surgery. Anesthetics with propofol and intervention with GMCSF significantly reduced postoperative cell proliferation, whereas peritoneal infection enhanced the invasive capability of tumor cells. Conclusion: This study suggests that in vitro cell models are useful and reliable tools to explore the effect of surgery on colorectal cancer cell proliferation and metastatic ability. The models should therefore be considered as additional tests to investigate the effects of perioperative interventions. PMID- 29158976 TI - Intraspecific variation in the diet of the Mexican garter snake Thamnophis eques. AB - The Mexican Garter Snake (Thamnophis eques) is a terrestrial-aquatic generalist that feeds on both aquatic and terrestrial prey. We describe size-related variation and sexual variation in the diet of T. eques through analysis of 262 samples of identifiable stomach contents in snakes from 23 locations on the Mexican Plateau. The snake T. eques we studied consumed mostly fish, followed in lesser amounts by leeches, earthworms, frogs, and tadpoles. Correspondence analysis suggested that the frequency of consumption of various prey items differed between the categories of age but not between sex of snakes, and the general pattern was a reduction of prey item diversity with size of snake. Snake length was correlated positively with mass of ingested prey. Large snakes consumed large prey and continued to consume smaller prey. In general, no differences were found between the prey taxa of male and female snakes, although males ate two times more tadpoles than females. Males and females did not differ in the mass of leeches, earthworms, fishes, frogs and tadpoles that they ate, and males and females that ate each prey taxon were similar in length. We discuss proximate and functional determinants of diet and suggest that the observed intraspecific variation in T. eques could be explored by temporal variation in prey availability, proportions of snake size classes and possible sexual dimorphism in head traits and prey dimensions to assess the role of intersexual resource competition. PMID- 29158978 TI - Zebrafish swimming in the flow: a particle image velocimetry study. AB - Zebrafish is emerging as a species of choice for the study of a number of biomechanics problems, including balance development, schooling, and neuromuscular transmission. The precise quantification of the flow physics around swimming zebrafish is critical toward a mechanistic understanding of the complex swimming style of this fresh-water species. Although previous studies have elucidated the vortical structures in the wake of zebrafish swimming in placid water, the flow physics of zebrafish swimming against a water current remains unexplored. In an effort to illuminate zebrafish swimming in a dynamic environment reminiscent of its natural habitat, we experimentally investigated the locomotion and hydrodynamics of a single zebrafish swimming in a miniature water tunnel using particle image velocimetry. Our results on zebrafish locomotion detail the role of flow speed on tail beat undulations, heading direction, and swimming speed. Our findings on zebrafish hydrodynamics offer a precise quantification of vortex shedding during zebrafish swimming and demonstrate that locomotory patterns play a central role on the flow physics. This knowledge may help clarify the evolutionary advantage of burst and cruise swimming movements in zebrafish. PMID- 29158977 TI - The sensitivity of the yeast, Saccharomyces cerevisiae, to acetic acid is influenced by DOM34 and RPL36A. AB - The presence of acetic acid during industrial alcohol fermentation reduces the yield of fermentation by imposing additional stress on the yeast cells. The biology of cellular responses to stress has been a subject of vigorous investigations. Although much has been learned, details of some of these responses remain poorly understood. Members of heat shock chaperone HSP proteins have been linked to acetic acid and heat shock stress responses in yeast. Both acetic acid and heat shock have been identified to trigger different cellular responses including reduction of global protein synthesis and induction of programmed cell death. Yeast HSC82 and HSP82 code for two important heat shock proteins that together account for 1-2% of total cellular proteins. Both proteins have been linked to responses to acetic acid and heat shock. In contrast to the overall rate of protein synthesis which is reduced, the expression of HSC82 and HSP82 is induced in response to acetic acid stress. In the current study we identified two yeast genes DOM34 and RPL36A that are linked to acetic acid and heat shock sensitivity. We investigated the influence of these genes on the expression of HSP proteins. Our observations suggest that Dom34 and RPL36A influence translation in a CAP-independent manner. PMID- 29158979 TI - Response to "An exceptionally preserved 110 million years old praying mantis provides new insights into the predatory behaviour of early mantodeans". AB - Hornig, Haug & Haug (2017) published a description of a new specimen of Santanmantis axelrodi MB.I.2068, an extinct species of praying mantis from the Crato Formation of Brazil. According to Hornig, Haug & Haug (2017), the discovery of this new specimen brought with it implications for praying mantis character evolution and predatory behavior; it is with these lines of reasoning that we find fault. More specifically, we point to four flawed assumptions in their study that led to their unsubstantiated conclusion that S. axelrodi employed their mesothoracic legs in prey capture. PMID- 29158980 TI - North Atlantic Oscillation drives the annual occurrence of an isolated, peripheral population of the brown seaweed Fucus guiryi in the Western Mediterranean Sea. AB - The canopy-forming, intertidal brown (Phaeophyceae) seaweed Fucus guiryi is distributed along the cold-temperate and warm-temperate coasts of Europe and North Africa. Curiously, an isolated population develops at Punta Calaburras (Alboran Sea, Western Mediterranean) but thalli are not present in midsummer every year, unlike the closest (ca. 80 km), perennial populations at the Strait of Gibraltar. The persistence of the alga at Punta Calaburras could be due to the growth of resilient, microscopic stages as well as the arrival of few-celled stages originating from neighbouring localities, and transported by the permanent Atlantic Jet flowing from the Atlantic Ocean into the Mediterranean. A twenty-six year time series (from 1990 to 2015) of midsummer occurrence of F. guiryi thalli at Punta Calaburras has been analysed by correlating with oceanographic (sea surface temperature, an estimator of the Atlantic Jet power) and climatic factors (air temperature, rainfall, and North Atlantic Oscillation -NAO-, and Arctic Oscillation -AO- indexes). The midsummer occurrence of thalli clustered from 1990 1994 and 1999-2004, with sporadic occurrences in 2006 and 2011. Binary logistic regression showed that the occurrence of thalli at Punta Calaburras in midsummer is favoured under positive NAO index from April to June. It has been hypothesized that isolated population of F. guiryi should show greater stress than their congeners of permanent populations, and to this end, two approaches were used to evaluate stress: one based on the integrated response during ontogeny (developmental instability, based on measurements of the fractal branching pattern of algal thalli) and another based on the photosynthetic response. Although significant differences were detected in photosynthetic quantum yield and water loss under emersion conditions, with thalli from Punta Calaburras being more affected by emersion than those from Tarifa, the developmental instability showed that the population from Tarifa suffers higher stress during ontogeny than that from Punta Calaburras. In conclusion, this study demonstrates the teleconnection between atmospheric oscillations and survival and proliferation of marine macroalgae. PMID- 29158981 TI - Fitness implications of sex-specific catch-up growth in Nephila senegalensis, a spider with extreme reversed SSD. AB - Background: Animal growth is often constrained by unfavourable conditions and divergences from optimal body size can be detrimental to an individual's fitness, particularly in species with determinate growth and a narrow time-frame for life time reproduction. Growth restriction in early juvenile stages can later be compensated by means of plastic developmental responses, such as adaptive catch up growth (the compensation of growth deficits through delayed development). Although sex differences regarding the mode and degree of growth compensation have been coherently predicted from sex-specific fitness payoffs, inconsistent results imply a need for further research. We used the African Nephila senegalensis, representing an extreme case of female-biased sexual size dimorphism (SSD), to study fitness implications of sex-specific growth compensation. We predicted effective catch-up growth in early food-restricted females to result in full compensation of growth deficits and a life-time fecundity (LTF) equivalent to unrestricted females. Based on a stronger trade-off between size-related benefits and costs of a delayed maturation, we expected less effective catch-up growth in males. Methods: We tracked the development of over one thousand spiders in different feeding treatments, e.g., comprising a fixed period of early low feeding conditions followed by unrestricted feeding conditions, permanent unrestricted feeding conditions, or permanent low feeding conditions as a control. In a second experimental section, we assessed female fitness by measuring LTF in a subset of females. In addition, we tested whether compensatory development affected the reproductive lifespan in both sexes and analysed genotype-by-treatment interactions as a potential cause of variation in life-history traits. Results: Both sexes delayed maturation to counteract early growth restriction, but only females achieved full compensation of adult body size. Female catch-up growth resulted in equivalent LTF compared to unrestricted females. We found significant interactions between experimental treatments and sex as well as between treatments and family lineage, suggesting that family specific responses contribute to the unusually large variation of life-history traits in Nephila spiders. Our feeding treatments had no effect on the reproductive lifespan in either sex. Discussion: Our findings are in line with predictions of life-history theory and corroborate strong fecundity selection to result in full female growth compensation. Males showed incomplete growth compensation despite a delayed development, indicating relaxed selection on large size and a stronger trade-off between late maturation and size-related benefits. We suggest that moderate catch-up growth in males is still adaptive as a 'bet hedging' strategy to disperse unavoidable costs between life-history traits affected by early growth restriction (the duration of development and adult size). PMID- 29158982 TI - Genome-wide in silico identification of membrane-bound transcription factors in plant species. AB - Membrane-bound transcription factors (MTFs) are located in cellular membranes due to their transmembrane domains. In plants, proteolytic processing is considered to be the main mechanism for MTF activation, which ensures the liberation of MTFs from membranes and further their translocation into the nucleus to regulate gene expression; this process skips both the transcriptional and translational stages, and thus it guarantees the prompt responses of plants to various stimuli. Currently, information concerning plant MTFs is limited to model organisms, including Arabidopsis thaliana and Oryza sativa, and little is known in other plant species at the genome level. In the present study, seven membrane topology predictors widely used by the research community were employed to establish a reliable workflow for MTF identification. Genome-wide in silico analysis of MTFs was then performed in 14 plant species spanning the chlorophytes, bryophytes, gymnosperms, monocots and eudicots. A total of 1,089 MTFs have been identified from a total of 25,850 transcription factors in these 14 plant species. These MTFs belong to 52 gene family, and the top six most abundant families are the NAC (128), SBP (77), C2H2 (70), bZIP (67), MYB-related (65) and bHLH (63) families. The MTFs have transmembrane spans ranging from one to thirteen, and 71.5% and 21.1% of the MTFs have one and two transmembrane motifs, respectively. Most of the MTFs in this study have transmembrane motifs located in either N- or C terminal regions, indicating that proteolytic cleavage could be a conserved mechanism for MTF activation. Additionally, approximately half of the MTFs in the genome of either Arabidopsis thaliana or Gossypium raimondii could be potentially regulated by alternative splicing, indicating that alternative splicing is another conserved activation mechanism for MTFs. The present study performed systematic analyses of MTFs in plant lineages at the genome level, and provides invaluable information for the research community. PMID- 29158983 TI - Adult zebra finches rehearse highly variable song patterns during sleep. AB - Brain activity during sleep is fairly ubiquitous and the best studied possible function is a role in memory consolidation, including motor memory. One suggested mechanism of how neural activity effects these benefits is through reactivation of neurons in patterns resembling those of the preceding experience. The specific patterns of motor activation replayed during sleep are largely unknown for any system. Brain areas devoted to song production in the songbird brain exhibit spontaneous song-like activity during sleep, but single cell neural recordings did not permit detection of the specific song patterns. We have now discovered that this sleep activation can be detected in the muscles of the vocal organ, thus providing a unique window into song-related brain activity at night. We show that male zebra finches (Taeniopygia guttata) frequently exhibit spontaneous song like activity during the night, but that the fictive song patterns are highly variable and uncoordinated compared to the highly stereotyped day-time song production. This substantial variability is not consistent with the idea that night-time activity replays day-time experiences for consolidation. Although the function of this frequent activation is unknown, it may represent a mechanism for exploring motor space or serve to generate internal error signals that help maintain the high stereotypy of day-time song. In any case, the described activity supports the emerging insight that brain activity during sleep may serve a variety of functions. PMID- 29158985 TI - Coral-associated viral communities show high levels of diversity and host auxiliary functions. AB - Stony corals (Scleractinia) are marine invertebrates that form the foundation and framework upon which tropical reefs are built. The coral animal associates with a diverse microbiome comprised of dinoflagellate algae and other protists, bacteria, archaea, fungi and viruses. Using a metagenomics approach, we analysed the DNA and RNA viral assemblages of seven coral species from the central Great Barrier Reef (GBR), demonstrating that tailed bacteriophages of the Caudovirales dominate across all species examined, and ssDNA viruses, notably the Microviridae, are also prevalent. Most sequences with matches to eukaryotic viruses were assigned to six viral families, including four Nucleocytoplasmic Large DNA Viruses (NCLDVs) families: Iridoviridae, Phycodnaviridae, Mimiviridae, and Poxviridae, as well as Retroviridae and Polydnaviridae. Contrary to previous findings, Herpesvirales were rare in these GBR corals. Sequences of a ssRNA virus with similarities to the dinornavirus, Heterocapsa circularisquama ssRNA virus of the Alvernaviridae that infects free-living dinoflagellates, were observed in three coral species. We also detected viruses previously undescribed from the coral holobiont, including a virus that targets fungi associated with the coral species Acropora tenuis. Functional analysis of the assembled contigs indicated a high prevalence of latency-associated genes in the coral-associated viral assemblages, several host-derived auxiliary metabolic genes (AMGs) for photosynthesis (psbA, psbD genes encoding the photosystem II D1 and D2 proteins respectively), as well as potential nematocyst toxins and antioxidants (genes encoding green fluorescent-like chromoprotein). This study expands the currently limited knowledge on coral-associated viruses by characterising viral composition and function across seven GBR coral species. PMID- 29158984 TI - Virus like particles as a platform for cancer vaccine development. AB - Cancers have killed millions of people in human history and are still posing a serious health problem worldwide. Therefore, there is an urgent need for developing preventive and therapeutic cancer vaccines. Among various cancer vaccine development platforms, virus-like particles (VLPs) offer several advantages. VLPs are multimeric nanostructures with morphology resembling that of native viruses and are mainly composed of surface structural proteins of viruses but are devoid of viral genetic materials rendering them neither infective nor replicative. In addition, they can be engineered to display multiple, highly ordered heterologous epitopes or peptides in order to optimize the antigenicity and immunogenicity of the displayed entities. Like native viruses, specific epitopes displayed on VLPs can be taken up, processed, and presented by antigen presenting cells to elicit potent specific humoral and cell-mediated immune responses. Several studies also indicated that VLPs could overcome the immunosuppressive state of the tumor microenvironment and break self-tolerance to elicit strong cytotoxic lymphocyte activity, which is crucial for both virus clearance and destruction of cancerous cells. Collectively, these unique characteristics of VLPs make them optimal cancer vaccine candidates. This review discusses current progress in the development of VLP-based cancer vaccines and some potential drawbacks of VLPs in cancer vaccine development. Extracellular vesicles with close resembling to viral particles are also discussed and compared with VLPs as a platform in cancer vaccine developments. PMID- 29158986 TI - Comparative analysis of prophages in Streptococcus mutans genomes. AB - Prophages have been considered genetic units that have an intimate association with novel phenotypic properties of bacterial hosts, such as pathogenicity and genomic variation. Little is known about the genetic information of prophages in the genome of Streptococcus mutans, a major pathogen of human dental caries. In this study, we identified 35 prophage-like elements in S. mutans genomes and performed a comparative genomic analysis. Comparative genomic and phylogenetic analyses of prophage sequences revealed that the prophages could be classified into three main large clusters: Cluster A, Cluster B, and Cluster C. The S. mutans prophages in each cluster were compared. The genomic sequences of phismuN66-1, phismuNLML9-1, and phismu24-1 all shared similarities with the previously reported S. mutans phages M102, M102AD, and phiAPCM01. The genomes were organized into seven major gene clusters according to the putative functions of the predicted open reading frames: packaging and structural modules, integrase, host lysis modules, DNA replication/recombination modules, transcriptional regulatory modules, other protein modules, and hypothetical protein modules. Moreover, an integrase gene was only identified in phismuNLML9-1 prophages. PMID- 29158987 TI - Lowland extirpation of anuran populations on a tropical mountain. AB - Background: Climate change and infectious diseases threaten animal and plant species, even in natural and protected areas. To cope with these changes, species may acclimate, adapt, move or decline. Here, we test for shifts in anuran distributions in the Luquillo Mountains (LM), a tropical montane forest in Puerto Rico by comparing species distributions from historical (1931-1989)and current data (2015/2016). Methods: Historical data, which included different methodologies, were gathered through the Global Biodiversity Information Facility (GBIF) and published literature, and the current data were collected using acoustic recorders along three elevational transects. Results: In the recordings, we detected the 12 native frog species known to occur in LM. Over a span of ~25 years, two species have become extinct and four species suffered extirpation in lowland areas. As a consequence, low elevation areas in the LM (<300 m) have lost at least six anuran species. Discussion: We hypothesize that these extirpations are due to the effects of climate change and infectious diseases, which are restricting many species to higher elevations and a much smaller area. Land use change is not responsible for these changes because LM has been a protected reserve for the past 80 years. However, previous studies indicate that (1) climate change has increased temperatures in Puerto Rico, and (2) Batrachochytrium dendrobatidis (Bd) was found in 10 native species and early detection of Bd coincides with anurans declines in the LM. Our study confirms the general impressions of amphibian population extirpations at low elevations, and corroborates the levels of threat assigned by IUCN. PMID- 29158988 TI - A 16-gene signature predicting prognosis of patients with oral tongue squamous cell carcinoma. AB - Background: Oral tongue squamous cell carcinoma (OTSCC) is the most common subtype of oral cancer. A predictive gene signature is necessary for prognosis of OTSCC. Methods: Five microarray data sets of OTSCC from the Gene Expression Omnibus (GEO) and one data set from The Cancer Genome Atlas (TCGA) were obtained. Differentially expressed genes (DEGs) of GEO data sets were identified by integrated analysis. The DEGs associated with prognosis were screened in the TCGA data set by univariate survival analysis to obtain a gene signature. A risk score was calculated as the summation of weighted expression levels with coefficients by Cox analysis. The signature was used to distinguish carcinoma, estimated by receiver operator characteristic curves and the area under the curve (AUC). All were validated in the GEO and TCGA data sets. Results: Integrated analysis of GEO data sets revealed 300 DEGs. A 16-gene signature and a risk score were developed after survival analysis. The risk score was effective to stratify patients into high-risk and low-risk groups in the TCGA data set (P < 0.001). The 16-gene signature was valid to distinguish the carcinoma from normal samples (AUC 0.872, P < 0.001). Discussion: We identified a useful 16-gene signature for prognosis of OTSCC patients, which could be applied to clinical practice. Further studies were needed to prove the findings. PMID- 29158989 TI - Activation of Rho-kinase and focal adhesion kinase regulates the organization of stress fibers and focal adhesions in the central part of fibroblasts. AB - Specific regulation and activation of focal adhesion kinase (FAK) are thought to be important for focal adhesion formation, and activation of Rho-kinase has been suggested to play a role in determining the effects of FAK on the formation of stress fibers and focal adhesions. To clarify the role of FAK in stress fiber formation and focal adhesion organization, the author examined the formation of new stress fibers and focal adhesions by activation of Rho-kinase in FAK knockout (FAK-/-) fibroblasts. FAK-/- cells were elliptical in shape, and showed reduced numbers of stress fibers and focal adhesions in the central part of the cells along with large focal adhesions in the peripheral regions. Activation of Rho kinase in FAK-/- cells transiently increased the actin filaments in the cell center, but these did not form typical thick stress fibers. Moreover, only plaque like structures as the origins of newly formed focal adhesions were observed in the center of the cell. Furthermore, introduction of an exogenous GFP-labeled FAK gene into FAK-/- cells resulted in increased numbers of stress fibers and focal adhesions in the center of the cells, which showed typical fibroblast morphology. These results indicated that FAK plays an important role in the formation of stress fibers and focal adhesions as well as in regulation of cell shape and morphology with the activation of Rho-kinase. PMID- 29158990 TI - Increased risk of periodontitis in patients with psoriatic disease: a nationwide population-based retrospective cohort study. AB - Aims: Periodontitis and psoriatic disease, including psoriasis (PS) and psoriatic arthritis (PsA), share the common risk factors and co-morbidities. However, the risk of periodontitis in patients with psoriatic disease still needs further investigation. This study was a nationwide population-based retrospective cohort study assessing the risk of periodontitis from psoriatic disease exposure. Materials and Methods: Patients with newly diagnosed psoriatic disease from 2003 to 2012 were identified from the Taiwanese National Health Insurance Research Database. The 1:4 ratio propensity score matched controls were selected from no psoriatic disease participations. The subsequent risk of periodontitis was evaluated in exposure and comparison groups. Multiple Cox proportional hazard models were used for the estimation. Results: A total of 3,487 psoriatic disease patients and 13,948 controls were identified. Incidence rate of periodontitis was higher in patients with PsA. The adjusted hazard ratio (aHRs) for moderate/severe periodontitis were 0.85 (95% CI [0.65-1.11]) in PS group and 1.66 (95% CI [0.99 2.78]) in PsA group. The aHRs of PsA were increased over time, aHRs was changed from 0.65 (0-11 months from index date) to 1.34 (>=12 months from index date) in all types of periodontitis and from 1.09 to 1.79 in moderate/severe periodontitis group, respectively. Conclusions: The increased risk of periodontitis was observed, especially the association between PsA and moderate/severe periodontitis. The patients with psoriatic disease should receive regular periodontal evaluation. PMID- 29158991 TI - NDUFA4L2 is associated with clear cell renal cell carcinoma malignancy and is regulated by ELK1. AB - Background: Clear cell renal cell carcinoma (ccRCC) is the most common and lethal cancer of the adult kidney. However, its pathogenesis has not been fully understood till now, which hinders the therapeutic development of ccRCC. NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) was found to be upregulated and play an important role in ccRCC. We aimed to further investigate the underlying mechanisms by which NDUFA4L2 exerted function and its expression level was upregulated. Methods: The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data were mined to verify the change of NDUFA4L2 expression level in ccRCC tissues. The correlation between expression level of NDUFA4L2 and cell proliferation/apoptosis was explored by Gene Set Enrichment Analysis (GSEA). Protein-protein interaction (PPI) network of NDUFA4L2 was constructed. Biological process and involved pathways of NDUFA4L2 were analyzed by gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The transcription factors (TFs) which can induce the expression of NDUFA4L2 were explored in clinical samples by correlation analysis and its regulation on the expression of NDUFA4L2 was verified by knockdown experiment. Results: NDUFA4L2 was verified to be overexpressed in ccRCC tissues and its expression level was increased accordingly as the American Joint Committee on Cancer (AJCC) stage progressed. A high NDUFA4L2 level predicted the poor prognosis of ccRCC patients and correlated with enhanced cell proliferation and anti-apoptosis. NDUFA4L2 may interact with 14 tumor-related proteins, participate in growth and death processes and be involved in ccRCC-related pathways, such as insulin-like growth factor 1 (IGF-1), mammalian target of Rapamycin (mTOR) and phosphoinositide 3 kinase serine/threonine protein kinase (PI3K/AKT). ETS domain-containing protein ELK1 level positively correlated with the level of NDUFA4L2 in ccRCC tissues and ELK1 could regulate the expression of NDUFA4L2 in ccRCC cells. Discussion: NDUFA4L2 upregulation was associated with ccRCC malignancy. NDUFA4L2 expression was regulated by ELK1 in ccRCC cells. Our study provided potential mechanisms by which NDUFA4L2 affected ccRCC occurrence and progression. PMID- 29158992 TI - HRV-derived data similarity and distribution index based on ensemble neural network for measuring depth of anaesthesia. AB - Evaluation of depth of anaesthesia (DoA) is critical in clinical surgery. Indices derived from electroencephalogram (EEG) are currently widely used to quantify DoA. However, there are known to be inaccurate under certain conditions; therefore, experienced anaesthesiologists rely on the monitoring of vital signs such as body temperature, pulse rate, respiration rate, and blood pressure to control the procedure. Because of the lack of an ideal approach for quantifying level of consciousness, studies have been conducted to develop improved methods of measuring DoA. In this study, a short-term index known as the similarity and distribution index (SDI) is proposed. The SDI is generated using heart rate variability (HRV) in the time domain and is based on observations of data distribution differences between two consecutive 32 s HRV data segments. A comparison between SDI results and expert assessments of consciousness level revealed that the SDI has strong correlation with anaesthetic depth. To optimise the effect, artificial neural network (ANN) models were constructed to fit the SDI, and ANN blind cross-validation was conducted to overcome random errors and overfitting problems. An ensemble ANN was then employed and was discovered to provide favourable DoA assessment in comparison with commonly used Bispectral Index. This study demonstrated the effectiveness of this method of DoA assessment, and the results imply that it is feasible and meaningful to use the SDI to measure DoA with the additional use of other measurement methods, if appropriate. PMID- 29158993 TI - Antimicrobial consumption on Austrian dairy farms: an observational study of udder disease treatments based on veterinary medication records. AB - Background: Antimicrobial use in livestock production is an important contemporary issue, which is of public interest worldwide. Antimicrobials are not freely available to Austrian farmers and can only be administered to livestock by veterinarians, or by farmers who are trained members of the Animal Health Service. Since 2015, veterinarians have been required by law to report antimicrobials dispensed to farmers for use in food-producing animals. The study presented here went further than the statutory framework, and collected data on antimicrobials dispensed to farmers and those administered by veterinarians. Methods: Seventeen veterinary practices were enrolled in the study via convenience sampling. These veterinarians were asked to contact interested dairy farmers regarding participation in the study (respondent-driven sampling). Data were collected from veterinary practice software between 1st October 2015 and 30th September 2016. Electronic data (89.4%) were transferred via an online interface and paper records (10.6%) were entered by the authors. Antimicrobial treatments with respect to udder disease were analysed by number of defined daily doses per cow and year (nDDDvet/cow/year), based on the European Medicines Agency technical unit, Defined Daily Dose for animals (DDDvet). Descriptive statistics and the Wilcoxon rank sum test were used to analyse the results. Results: Antimicrobial use data from a total of 248 dairy farms were collected during the study, 232 of these farms treated cows with antibiotics; dry cow therapy was excluded from the current analysis. The mean number of DDDvet/cow/year for the antimicrobial treatment of all udder disease was 1.33 DDDvet/cow/year. Of these treatments, 0.73 DDDvet/cow/year were classed as highest priority critically important antimicrobials (HPCIAs), according to the World Health Organization (WHO) definition. The Wilcoxon rank sum test determined a statistically significant difference between the median number of DDDvet/cow/year for acute and chronic mastitis treatment (W = 10,734, p < 0.001). The most commonly administered antimicrobial class for the treatment of acute mastitis was beta lactams. Intramammary penicillin was used at a mean of 0.63 DDDvet/cow/year, followed by the third generation cephalosporin, cefoperazone, (a HPCIA) at 0.60 DDDvet/cow/year. Systemic antimicrobial treatments were used at a lower overall level than intramammary treatments for acute mastitis. Discussion: This study demonstrated that Austrian dairy cows in the study population were treated with antimicrobial substances for udder diseases at a relatively low frequency, however, a substantial proportion of these treatments were with substances considered critically important for human health. While it is vital that sick cows are treated, reductions in the overall use of antimicrobials, and critically important substances in particular, are still possible. PMID- 29158994 TI - Detection of bacterial contaminants and hybrid sequences in the genome of the kelp Saccharina japonica using Taxoblast. AB - Modern genome sequencing strategies are highly sensitive to contamination making the detection of foreign DNA sequences an important part of analysis pipelines. Here we use Taxoblast, a simple pipeline with a graphical user interface, for the post-assembly detection of contaminating sequences in the published genome of the kelp Saccharina japonica. Analyses were based on multiple blastn searches with short sequence fragments. They revealed a number of probable bacterial contaminations as well as hybrid scaffolds that contain both bacterial and algal sequences. This or similar types of analysis, in combination with manual curation, may thus constitute a useful complement to standard bioinformatics analyses prior to submission of genomic data to public repositories. Our analysis pipeline is open-source and freely available at http://sdittami.altervista.org/taxoblast and via SourceForge (https://sourceforge.net/projects/taxoblast). PMID- 29158995 TI - The role of biomaterials in the treatment of meniscal tears. AB - Extensive investigations over the recent decades have established the anatomical, biomechanical and functional importance of the meniscus in the knee joint. As a functioning part of the joint, it serves to prevent the deterioration of articular cartilage and subsequent osteoarthritis. To this end, meniscus repair and regeneration is of particular interest from the biomaterial, bioengineering and orthopaedic research community. Even though meniscal research is previously of a considerable volume, the research community with evolving material science, biology and medical advances are all pushing toward emerging novel solutions and approaches to the successful treatment of meniscal difficulties. This review presents a tactical evaluation of the latest biomaterials, experiments to simulate meniscal tears and the state-of-the-art materials and strategies currently used to treat tears. PMID- 29158996 TI - Anterior-posterior gene expression differences in three Lake Malawi cichlid fishes with variation in body stripe orientation. AB - Morphological differentiation among closely related species provides opportunities to study mechanisms shaping natural phenotypic variation. Here, we address variation in the orientation of melanin-colored body stripes in three cichlid species of the tribe Haplochromini. Melanochromis auratus displays a common pattern of dark, straight horizontal body stripes, whereas in Aristochromis christyi and Buccochromis rhoadesii, oblique stripes extend from the anterior dorsal to the posterior mid-lateral trunk. We first validated a stably reference gene, and then, investigated the chromatophore distribution in the skin by assessing the expression levels of the iridophore and melanophore marker genes, ltk and slc24a5, respectively, as well as pmel, a melanophore pigmentation marker gene. We found anterior-posterior differences in the expression levels of the three genes in the oblique-striped species. The higher anterior expression of ltk, indicates increased iridophore density in the anterior region, i.e., uneven horizontal distribution of iridophores, which coincides with the anterior dorsalization of melanophore stripe in these species. The obliqueness of the horizontal body stripes might be a result of distinct migratory or patterning abilities of melanophores in anterior and posterior stripe regions which could be reflected by variation in the expression of genes involved in melanophore patterning. To address this, we investigated anterior posterior expression levels of a primary set of candidate target genes with known functions in melanophore migration and stripe patterning in the adult zebrafish, and their related gene regulatory network. Among these genes, those with differences in anterior-posterior expression showed only species-specific differential expression, e.g., sdf1a, col14a1a, ifitm5, and agpat3, with the exception of fbxw4/hagoromo (differentially expressed in an oblique-and the straight-striped species). In summary, distinct anterior-posterior gradients in iridophore density found to be more similar characteristic between the two oblique-striped species. Furthermore, the species-specific differential expression of genes involved in stripe patterning might also implicate distinct molecular processes underlying the obliqueness of body stripe in two closely related cichlid species. PMID- 29158998 TI - Giant Cell Tumor of the Patellar Tendon Sheath: A Rare Case of Anterior Knee Pain. AB - Giant cell tumor of the tendon sheath (GCTTS) is a benign, proliferative lesion of the synovium of the joint, the bursa, and the tendon sheath. We report a case of intra-articular, localized GCTTS arising from the patellar tendon, which is a rare cause of anterior knee pain. The diagnosis may be delayed due to non specific symptoms and normal plain radiographic findings. Magnetic resonance imaging (MRI) is diagnostic to detect the lesion, but several other clinical entities and lesions should be evaluated in the differential diagnosis. The treatment of choice is a total excision of the lesion without leaving residual tumor tissue, in order to reduce the risk of recurrence. We present a patient with GCTTS of the patellar tendon and discuss its clinical and radiographic characteristics, differential diagnosis, pathology, and treatment. PMID- 29158999 TI - Recurrent Primary Suprahepatic Abscess Due to Providencia Stuartii: A Rare Phenomenon. AB - Gram-negative urease-producing bacilli, Providencia stuartii (P. stuartii), is reported in urinary tract infections, gastroenteritis, and bacteremia in humans but they rarely present with a hepatic abscess. We present a rare case of a recurrent suprahepatic cyst due to P. stuartii in a 45-year-old female, intravenous ( IV) heroin abuser with chronic hepatitis B and C. A 45-year-old female with 10 days status post right suprahepatic abscess drainage presented with recurrent, right, upper quadrant abdominal pain for one day. The pain was 7/10, sharp, radiated to the right back, and was associated with nausea, non bloody non-bilious vomiting, and right-sided pleuritic chest pain. She was discharged after interventional radiology (IR) drainage of the abscess and completed 14 days of levofloxacin and metronidazole. On palpation, mild tender hepatomegaly was noticed. Complete blood count showed leukocytosis of 17.1 with left shift but liver enzymes within normal limits. Aspirated fluid cultures from the abscess showed P. stuartii. Blood and urine cultures were negative. A human immunodeficiency virus (HIV) test was negative. Hepatitis B virus (HBV) deoxyribonucleic (DNA) polymerase chain reaction (PCR) showed > 17 million IU/ml and hepatitis C virus (HCV) Ab reactive. A right, upper quadrant sonogram showed 4.1x0.9x2.7 cm fluid collection anterior to the right liver lobe. A computed tomography (CT) abdomen showed a dominant 5.2x5.5x3.9 cm hypodense lesion consistent with an abscess above the right liver. Initially, she was treated empirically with IV piperacillin-tazobactam and anticoagulation for a pyogenic liver abscess (PLA). Clinical and laboratory improvement were achieved with intravenous antibiotics evidenced by the decreasing size of the abscess on repeat CT scan. The patient was discharged with continuing antibiotics after four weeks. Repeated CT scan showed complete resolving of the suprahepatic cyst. In conclusion, in our patient, long-term shelter residence, IV heroin use, and chronic hepatitis B and C might be precipitating factors for PLA. Managing a recurrent primary hepatic abscess caused by P. stuartii is similar to PLA from other bacterial causes: drainage and antibiotic therapy. However, in our case, she responded well to medical treatment without further surgical drainage. PMID- 29159000 TI - Umbilical Cord Prolapse in a Labouring Patient: A Multidisciplinary and Interprofessional Simulation Scenario. AB - This case is one of an eight-case multidisciplinary curriculum designed and implemented at the University of Ottawa by simulation educators with specialty training in obstetrics and gynecology (OB/GYN) and anesthesiology. Consultation from a nurse educator maintained quality and relevance of objectives for nursing participants. The curriculum was prepared to train OB/GYN and anesthesiology residents and nurses to hone crisis resource management skills and to recognize and manage rare/critical medical events in an obstetrical setting. Obstetricians, anesthesiologists, and nurses often work together in acute, high-stakes situations, and this curriculum provides a safe environment to practice team based management of such emergencies. Over an eight-year period, this curriculum has been executed in scenario couplets on a four-year cycle to allow OB/GYN and anesthesiology residents exposure to all scenarios during a five-year residency beginning in their second year. Prospective evaluative data has been positive. For example, over 90% of participants rated these simulations to be 5 out of 5 with comments, such as "Was an effective use of my educational time" and "Will influence/enhance my future practice". In this scenario, participants must recognize and manage fetal distress resulting from umbilical cord prolapse in a labouring patient and respond with urgent operative delivery. This scenario requires adult and fetal mannequins with presenting umbilical cord for pelvic examination as well as equipment for fetal monitoring, general anesthetic, and emergency cesarean section. This simulation case includes a case template, critical actions checklist, debriefing guide, summary of key medical content, and an evaluation form for learners to provide feedback. PMID- 29158997 TI - Presentation and Treatments for Mucopolysaccharidosis Type II (MPS II; Hunter Syndrome). AB - Introduction: Mucopolysaccharidosis Type II (MPS II; Hunter syndrome) is an X- linked lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS). IDS deficiency leads to primary accumulation of dermatan sulfate (DS) and heparan sulfate (HS). MPS II is both multi-systemic and progressive. Phenotypes are classified as either attenuated or severe (based on absence or presence of central nervous system impairment, respectively). Areas covered: Current treatments available are intravenous enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), anti-inflammatory treatment, and palliative care with symptomatic surgeries. Clinical trials are being conducted for intrathecal ERT and gene therapy is under pre-clinical investigation. Treatment approaches differ based on age, clinical severity, prognosis, availability and feasibility of therapy, and health insurance.This review provides a historical account of MPS II treatment as well as treatment development with insights into benefits and/or limitations of each specific treatment. Expert opinion: Conventional ERT and HSCT coupled with surgical intervention and palliative therapy are currently the treatment options available to MPS II patients. Intrathecal ERT and gene therapy are currently under investigation as future therapies. These investigative treatments are critical to address the limitations in treatment of the central nervous system (CNS). PMID- 29159001 TI - A Unique Case of Acute Cerebral Venous Sinus Thrombosis Secondary to Primary Varicella Zoster Virus Infection. AB - Primary varicella zoster virus (VZV) infection, predominantly in the pediatric population, presents with pyrexia and a classic pruritic vesicular rash. In adults, although less common, it is more severe and linked to more complications. Neurological complications, which account for less than 1% of all VZV complications, include meningitis, encephalitis, arterial vasculopathy, and venous thrombosis. We present a case of a 39-year-old male who developed extensive cerebral venous sinus thrombosis following primary VZV infection. Venous thrombosis in VZV has been suggested to be caused by autoantibodies against protein S, pre-existing hypercoagulability, or endothelial damage. The patient was acutely managed using intravenous acyclovir and heparin. Long-term anticoagulation therapy with warfarin was continued after discharge. We concluded that clinicians should be aware of the rare complications of this common pathology so that a timely diagnosis can be made, followed by prompt management. Further studies need to be done to better understand acute cerebral venous sinus thrombosis secondary to VZV. PMID- 29159002 TI - A Case Report of Fructosamine's Unreliability as a Glycemic Control Assessment Tool in Nephrotic Syndrome. AB - Fructosamine (FA) is a glycated primary amine widely used as an alternative method for the assessment of glycemic control when glycosylated hemoglobin (HbA1c) measurement is unreliable or if there is a need for short-term glycemic control monitoring. We report a case of a 36-year-old male patient with a six year history of poorly controlled type 2 diabetes mellitus and nephrotic syndrome. As the nephrotic syndrome progressed, we observed a decline in his serum FA levels that did not correlate with his increased HbA1c due to significant albuminuria. This case report highlights the unreliability of FA in patients with nephrotic syndrome and the significance of other glycemic markers. PMID- 29159003 TI - Toxic Adenoma in a Patient with Thyroid Hemiagenesis. AB - Thyroid hemiagenesis (TH) is a rare congenital anomaly that is usually asymptomatic. Functional disorders of the thyroid make the patient symptomatic. TH is usually and incidentally established during evaluation of patients with symptomatic thyroid pathology. We report the case of a patient of TH who became symptomatic with hyperactivity of the gland. The patient presented with signs and symptoms of thyrotoxicosis. Physical examination revealed asymmetric nodular goiter at the right lobe. Biochemical analysis established the diagnosis of hyperthyroidism. Ultrasound of the thyroid gland revealed the absence of the left lobe and a large, solitary hypoechoic solid nodule in the right lobe. Nuclear scan showed the absence of the left lobe and revealed a large, autonomous solitary nodule in the right lobe. The diagnosis was a toxic adenoma. After medical control of hyperthyroidism, the patient was surgically treated with hemithyroidectomy. We prescribed postoperative replacement medication with L thyroxin. Hyperthyroidism makes TH cases symptomatic. Thyroid ultrasound and scintigraphy incidentally discover agenesis of one lobe during evaluation of thyrotoxicosis. Hemithyroidectomy, including the autonomous nodule, is the procedure of choice for patients with toxic adenoma. Hemithyroidectomy in TH cases technically becomes a total thyroidectomy with a need for postoperative thyroid replacement therapy. PMID- 29159004 TI - Linear Malignant Melanoma In Situ: Reports and Review of Cutaneous Malignancies Presenting as Linear Skin Cancer. AB - Melanomas usually present as oval lesions in which the borders may be irregular. Other morphological features of melanoma include clinical asymmetry, variable color, diameter greater than 6 mm and evolving lesions. Two males whose melanoma in situ presented as linear skin lesions are described and cutaneous malignancies that may appear linear in morphology are summarized in this report. A medical literature search engine, PubMed, was used to search the following terms: cancer, cutaneous, in situ, linear, malignant, malignant melanoma, melanoma in situ, neoplasm, and skin. The 25 papers that were generated by the search and their references, were reviewed; 10 papers were selected for inclusion. The cancer of the skin typically presents as round lesions. However, basal cell carcinoma and squamous cell carcinoma may arise from primary skin conditions or benign skin neoplasms such as linear epidermal nevus and linear porokeratosis. In addition, linear tumors such as basal cell carcinoma can occur. The development of linear cutaneous neoplasms may occur secondary to skin tension line or embryonal growth patterns (as reflected by the lines of Langer and lines of Blaschko) or exogenous factors such as prior radiation therapy. Cutaneous neoplasms and specifically melanoma in situ can be added to the list of linear skin lesions. PMID- 29159005 TI - Field-Specific Intensity-modulated Proton Therapy Optimization Technique for Breast Cancer Patients with Tissue Expanders Containing Metal Ports. AB - This report aims to propose and present an evaluation of a robust pencil beam scanning proton multi-field optimized treatment planning technique for postmastectomy radiation of breast cancer patients with implanted tissue expanders containing an internal metal port. Field-specific split targets were created for optimization to prevent spots from traveling through the metal port, while providing uniform coverage of the target with the use of a multi-field intensity modulated optimization approach. Two beam angles were strategically selected to provide complementary target coverage and plan robustness. The plan was compared with an independently developed photon plan and evaluated for robustness with respect to isocenter shifts, range shifts, and variation of the water-equivalent thickness of the port. The proton plan resulted in clinically acceptable target coverage and dosage to neighboring normal tissues. The D95% coverage was 95.3% in the nominal proton plan, with a worst-case coverage of 90.1% (when considering 0.3 cm isocenter shifts combined with 3.5% range uncertainty), and the coverage varied less than 1% under a hypothetically extreme variation of the port density. The proton plan had improved dose homogeneity compared with the photon plan, and reduced ipsilateral lung and mean heart doses. We demonstrated that a practical, field-specific intensity-modulated proton therapy (IMPT) optimization technique can be used to deal with the challenge of metal port in breast cancer patients with tissue expanders. The resulting proton plan has superior dosimetric characteristics over the best-case scenario photon plan, and is also robust to setup and proton range uncertainties. PMID- 29159006 TI - The Sound Games: Introducing Gamification into Stanford's Orientation on Emergency Ultrasound. AB - Point-of-care ultrasound is a critical component of graduate medical training in emergency medicine. Innovation in ultrasound teaching methods is greatly needed to keep up with a changing medical landscape. A field-wide trend promoting simulation and technology-enhanced learning is underway in an effort to improve patient care, as well as patient safety. In an effort to both motivate students and increase their skill retention, training methods are shifting towards a friendly competition model and are gaining popularity nationwide. In line with this emerging trend, Stanford incorporated the Sound Games - an educational ultrasound event with a distinctly competitive thread - within its existing two day point-of-care ultrasound orientation course for emergency medicine interns. In this study, we demonstrate successful implementation of the orientation program, significant learning gains in participants, and overall student satisfaction with the course. PMID- 29159007 TI - Acute Brachial Artery Occlusion in an Elderly Patient With Acute Myocardial Ischemia. AB - We present a case of left upper extremity paresis secondary to acute brachial artery occlusion in an elderly female with active non-ST segment elevation myocardial ischemia (NSTEMI) in the setting of paroxysmal atrial fibrillation. The patient was initially suspected to have a cerebrovascular attack (CVA); however, computed tomography (CT) head was negative for acute stroke. The diagnosis was confirmed by computed tomographic angiography (CTA) of the upper extremity, confirming the diagnosis of acute left brachial artery occlusion. In evaluating a patient with concern for acute stroke with atypical presentation, it is essential to obtain a complete history and perform a rapid and thorough examination. Acute limb ischemia (ALI) should be considered in the differential diagnosis of CVA with atypical presentation. PMID- 29159008 TI - Caroli's Disease as a Cause of Chronic Epigastric Abdominal Pain: Two Case Reports and a Brief Review of the Literature. AB - Caroli's disease is a very rare congenital malformation, currently included in cystic diseases of the biliary tract, and is characterized by ectasia and dilatation of the intrahepatic bile ducts. Two clinical entities can be distinguished, Caroli's disease in which congenital hepatic impairment is limited to cystic dilatation and Caroli's syndrome in which congenital hepatic fibrosis coexists. We present two cases of atypical presentations of Caroli's disease. Case one was a 76-year-old man who was referred to our hospital for chronic non remitting epigastric pain prior to diagnosis. Magnetic resonance cholangiopancreatography (MRCP) was performed, which revealed findings consistent with Caroli's disease. Laboratory investigation disclosed a raised alpha fetoprotein. Left hepatectomy was performed due to suspected cholangiocarcinoma. Morphological findings were compatible with Caroli's disease and no evidence of malignancy was found. Case two was a 47-year-old man who presented with chronic epigastric pain and generalized abdominal discomfort. MRCP revealed findings compatible with Caroli's disease. The patient was discharged with ursodeoxycholic acid treatment and was later admitted twice due to inaugural episodes of cholangitis that were medically managed. Bisegmentectomies II and III were performed for suspected neoplasia after a gradual rise in alpha-fetoprotein and CA19-9 values were noted during follow-up. The surgical specimen confirmed Caroli's disease and there was no evidence of malignancy. Postoperative periods for both patients were favorable, and they remain asymptomatic and well to date. PMID- 29159009 TI - Myasthenia Gravis Induced by Nivolumab: A Case Report. AB - Nivolumab is a programmed cell death receptor (PD-1) inhibitor therapy for aggressive cancers; however, it poses a risk of immune-related adverse side effects. We present a 73-year-old male with renal cell carcinoma who developed myasthenia gravis (MG) after being treated with nivolumab, proven by acetylcholine receptor antibodies. Our patient presented with symptoms of fatigue and upper and lower extremity weakness, eventually resulting in respiratory failure as a result of MG. Nivolumab is an emerging therapy for advanced cancers but poses severe immune-related adverse events. Clinicians using PD-1 inhibitors should have a high index of suspicion of autoimmune diseases so that early discontinuation and treatment can be established to limit long-term morbidity and mortality. PMID- 29159010 TI - Multiple Myeloma Presenting as Acute Renal Failure in the Absence of Other Characteristic Features. AB - This case report describes a 54-year-old, asymptomatic man who presented with hyperkalemia on routine lab testing who was later found to have acute renal failure, unresponsive to fluid resuscitation, with minimal improvement after hemodialysis. After a comprehensive evaluation ruled out common causes of acute renal failure, the patient underwent testing with a bone survey, urine protein electrophoresis (UPEP), serum protein electrophoresis (SPEP), and immunoelectrophoresis for suspected plasma cell dyscrasia and received plasmapheresis for hyperviscosity syndrome and nephrotoxicity, which resulted in improved renal function. Lab results showed monoclonal gammopathy, elevated serum free light chains, and Bence Jones protein in the urine with a follow-up bone marrow biopsy indicating plasma cell dyscrasia. The patient received a diagnosis of multiple myeloma (MM) and was started on chemotherapy and immunosuppression. In patients presenting with acute renal failure with an evaluation ruling out prerenal and postrenal causes, multiple myeloma should be considered. PMID- 29159011 TI - Proton Therapy for Malignant Pleural Mesothelioma: A Three Case Series Describing the Clinical and Dosimetric Advantages of Proton-Based Therapy. AB - Malignant pleural mesothelioma (MPM) is a malignancy of the pleural cavity that typically presents at an advanced stage. Due to its large, circumferential clinical target volume (CTV) and proximity to major structures, including the heart and contralateral lung, delivering hemithoracic intensity-modulated radiotherapy (IMRT) with photon therapy to achieve loco-regional control following macroscopic complete resection is challenging. Intensity-modulated proton therapy (IMPT) has been shown to be a method for achieving higher therapeutic doses while limiting exposure to organs at risk (OARs), but patient outcomes after treatment have yet to be reported. We present three patients who received IMPT to 54 Gy after extrapleural pneumonectomy (EPP), with two patients receiving boosts to 66 and 60 Gy. All three tolerated treatment well and received doses to OARs markedly lower than those seen in comparison volumetric-modulated arc therapy (VMAT) IMRT photon plans. Radiation pneumonitis, a highly morbid and potentially fatal toxicity in patients receiving thoracic radiotherapy, was not observed even with boost treatments. In practice, IMPT appears to match dosimetric predictions as a feasible and safer alternative to photon IMRT-based radiotherapy. PMID- 29159012 TI - Robust Planning for a Patient Treated in Decubitus Position with Proton Pencil Beam Scanning Radiotherapy. AB - A challenging case was reported for a patient treated in decubitus position with proton pencil beam scanning. A regular robust plan with the consideration of the uncertainties of translational alignment and range accuracy cannot ensure the target coverage as revealed in two verification computed tomography (CT) scans during the first week of the treatment. The irreproducibility of daily alignment and anatomical variations in such a position is mainly due to patient's roll. To mitigate the interfractional effect on the target coverage, a novel robust optimization against the patient's angular setup uncertainties was implemented to improve the plan quality by introducing two artificial CT image sets by rolling the planning CT three degrees in both clockwise and counter-clockwise directions and adding them into robust optimization scenarios, which was shown to be an effective and simple way to mitigate target dose degradation with respect to interfractional variations. This method can be easily generalized and applied to other situations where angular variations in patient's setup can introduce large dosimetric effects. It is recommended that angularly robust optimization method should be integrated into the treatment planning system as an option particularly for patient's treatment subject to large angular variations, such as the one in the decubitus position reported here. PMID- 29159014 TI - Erratum: Transition Metal Carbides and Nitrides in Energy Storage and Conversion. AB - [This corrects the article DOI: 10.1002/advs.201500286.]. PMID- 29159013 TI - Computational and theoretical approaches for studies of a lipid recognition protein on biological membranes. AB - Many cellular functions, including cell signaling and related events, are regulated by the association of peripheral membrane proteins (PMPs) with biological membranes containing anionic lipids, e.g., phosphatidylinositol phosphate (PIP). This association is often mediated by lipid recognition modules present in many PMPs. Here, I summarize computational and theoretical approaches to investigate the molecular details of the interactions and dynamics of a lipid recognition module, the pleckstrin homology (PH) domain, on biological membranes. Multiscale molecular dynamics simulations using combinations of atomistic and coarse-grained models yielded results comparable to those of actual experiments and could be used to elucidate the molecular mechanisms of the formation of protein/lipid complexes on membrane surfaces, which are often difficult to obtain using experimental techniques. Simulations revealed some modes of membrane localization and interactions of PH domains with membranes in addition to the canonical binding mode. In the last part of this review, I address the dynamics of PH domains on the membrane surface. Local PIP clusters formed around the proteins exhibit anomalous fluctuations. This dynamic change in protein-lipid interactions cause temporally fluctuating diffusivity of proteins, i.e., the short-term diffusivity of the bound protein changes substantially with time, and may in turn contribute to the formation/dissolution of protein complexes in membranes. PMID- 29159015 TI - Meals for Good: An innovative community project to provide healthy meals to children in early care and education programs through food bank catering. AB - Innovative approaches to childhood obesity prevention are warranted in early care and education (ECE) settings, since intervening early among youth is recommended to promote and maintain healthy behaviors. The objective of the Meals for Good pilot was to explore feasibility of implementing a food bank-based catering model to ECE programs to provide more nutritious meals, compared to meals brought from home (a parent-prepared model). In 2014-2015, a 12-month project was implemented by a food bank in central Florida in four privately-owned ECE programs. An explanatory sequential design of a mixed-methods evaluation approach was utilized, including a pre-post menu analysis comparing parent-prepared meals to the catered meals, and stakeholder interviews to determine benefits and barriers. The menu analysis of lunches showed daily reductions in calories, fat, and saturated fat, but an increase in sodium in catered meals when compared to parent prepared meals. Interviews with ECE directors, teachers, parents, and food bank project staff, identified several benefits of the catered meals, including healthfulness of meals, convenience to parents, and the ECE program's ability to market this meal service. Barriers of the catered meals included the increased cost to parents, transportation and delivery logistics, and change from a 5 to a 2-week menu cycle during summer food service. This pilot demonstrated potential feasibility of a food bank-ECE program partnership, by capitalizing on the food bank's existing facilities and culinary programming, and interest in implementing strategies focused on younger children. The food bank has since leveraged lessons learned and expanded to additional ECE programs. PMID- 29159016 TI - Intimate partner violence discussions in the healthcare setting: A cross sectional study. AB - In 2013, the United States Preventive Services Task Force recommended routine intimate partner violence (IPV) screening for reproductive-age women. Given the increased attention paid to IPV on a national scale, and broader recognition of its social and physical implications, we sought to characterize the discussions resulting from routine IPV screening-specifically regarding provider response and patient perceptions. In a cross-sectional analysis, we implemented a survey to examine outcomes of IPV screening, including use of guideline-concordant discussion topics and interventions, as well as patient perception of the encounters. Women aged 18-65 with lifetime history of IPV and a past-year healthcare appointment were recruited from clinics and women's shelters in Pennsylvania. Data collection took place from May 2014-January 2015. Of 253 women, 39% were screened for IPV at a healthcare visit in the year prior to survey administration. Of women who were screened, guideline-concordant discussion topics were employed in 70% of encounters and guideline-concordant interventions were offered in 72% of encounters. 58% of women reported being "extremely" or "very satisfied," and 53% reported being "extremely" or "very comfortable" with IPV-related discussions. The low rate of screening in this population reiterates the importance of focusing efforts on educating providers on the importance of screening, promoting the availability of community resources, and developing systems-based practices that foster IPV screening, discussion, and referral following disclosure. PMID- 29159017 TI - Gardening and age-related weight gain: Results from a cross-sectional survey of Denver residents. AB - This study examined whether gardening modifies the association between age and body mass index (BMI). We used data from the Neighborhood Environments and Health Survey, which was conducted in Denver (N = 469) between 2006 and 2007. We fit two general linear mixed models. The base model had BMI in kg/m2 as the outcome, and age, an indicator variable for non-gardening status and the age-by-non-gardening status interaction as predictors. The adjusted model included as covariates the potential confounders of education, ethnicity and self-reported health. We assessed self-selection bias and confounding. BMI was 27.18 kg/m2 for non gardeners, 25.62 kg/m2 for home gardeners, and 24.17 kg/m2 for community gardeners. In the base model, a statistically significant association was observed between age and BMI for non-gardeners but not for the combined community and home gardening group (F = 9.27, ndf = 1, ddf = 441, p = 0.0025). In the adjusted model, the association between age and BMI in non-gardeners was not statistically significant (F = 1.72, ndf = 1, ddf = 431, p = 0.1908). Gardeners differed on social and demographic factors when compared to non-gardeners. The results from the base model are consistent with the hypothesis that gardening might offset age-related weight gain. However, the cross-sectional design does not permit differentiation of true causal effects from the possible effects of bias and confounding. As a follow-up study, to remove bias and confounding, we are conducting a randomized clinical trial of community gardening in Denver. PMID- 29159018 TI - The relationship between type of telephone service and smoking cessation among rural smokers enrolled in quitline tobacco dependence treatment. AB - Quitlines are successful tools for smoking cessation, but no known study has examined whether type of phone service (cell phone only (CPO) vs. landline (LL)) impacts quitline utilization, quit attempts, and sustained cessation. This report details an observational study examining the association between phone service and quitline utilization and cessation among Ohio Appalachian adults willing to quit smoking and enrolled in a cessation trial from 2010 to 2014. A secondary analysis was conducted with data obtained from smokers enrolled in the Ohio Tobacco Quitline arm of a group randomized trial (n = 345). The intermediate outcome variables included number of calls, cumulative total call length, average call length, verified shipments of NRT, and 24-hour quit attempt. The primary outcome measure was biologically confirmed 7-day point prevalence abstinence from tobacco at 3, 6, and 12 months post treatment. Participants with LL service, on average, made almost one more call to the quitline and spoke 17.2 min longer over the course of treatment than those with CPO service. Those with LL service were more likely to receive a second 4-week supply of NRT. Phone service status was not associated with average quitline call length, receiving at least one NRT shipment, having made one quit attempt at the end of treatment, or biochemically confirmed abstinence at 3, 6, or 12-month follow-up. Participants with LL services completed more counseling calls, accrued a longer cumulative length, and received more NRT when compared with CPO service participants. However, type of phone service did not deter abstinence outcomes. PMID- 29159019 TI - Introducing sit-stand desks increases classroom standing time among university students. AB - Excessive sedentary behavior has been associated with many negative health outcomes. While an understudied health topic, there is evidence that university students are excessively sedentary. Sit-stand desks have been shown to reduce sedentary time among pre-university students (ages 5-18 years) and sedentary workers but have not been tested in university classrooms. This study tested the effects of introducing sit-stand desks into a university classroom on student's classroom sitting and standing behaviors. Using a cross-over design, students received access to both traditional seated desks and sit-stand desks for six weeks. Data were collected between September and December, 2016. We recruited 304 healthy undergraduate university students enrolled in one of two small (25 seats) classrooms at a large Midwestern university during the fall of 2016. Average minutes of standing/hour/student, average percent class time spent standing, and the number of sit-stand transitions/student/hour were directly observed with video camera surveillance. Participants stood significantly more (p < 0.001) when provided access to sit-stand desks (7.2 min/h/student; 9.3% of class time spent standing) compared to when they had access to seated desks (0.7 min/h/student; 1.6% of class time spent standing) but no differences were observed for the number of sit-stand transitions (p = 0.47). Students reported high favorability for the sit-stand desks and improvements in several student engagement and affective outcomes while using the sit-stand desks. These findings support introducing sit-stand desks in university classrooms as an approach to reduce sedentary behaviors of university students. PMID- 29159021 TI - Mitochondrial uncoupler triclosan induces vasorelaxation of rat arteries. AB - Our previous studies found that mitochondrial uncouplers induced vasodilation. Triclosan, the broad spectrum antibacterial agent, is the active ingredient in soaps and toothpastes. It was reported that triclosan induced mitochondrial uncoupling, so we aim to investigate the effects of triclosan on vascular function of rat mesenteric arteries and aorta. The isometric tension of rat mesenteric artery and thoracic aorta was recorded by multi-wire myograph system. The cytosolic [Ca2+]i, mitochondrial reactive oxygen species (mitoROS), and mitochondrial membrane potential of smooth muscle cells (A10 cells) were measured using laser scanning confocal microscopy. Triclosan treatment relaxed phenylephrine (PE)- and high K+ (KPSS)-induced constriction, and pre-treatment with triclosan inhibited PE- and KPSS-induced constriction of rat mesenteric arteries. In rat thoracic aorta, triclosan also relaxed PE- and KPSS-induced constriction. Triclosan induces vasorelaxation without involving KATP channel activation in smooth muscle cells of arteries. Triclosan treatment increased cytosolic [Ca2+]i, mitochondrial ROS production and depolarized mitochondrial membrane potential in A10 cells. In conclusion, triclosan induces mitochondrial uncoupling in vascular smooth muscle cells and relaxes the constricted rat mesenteric arteries and aorta of rats. The present results suggest that triclosan would indicate vasodilation effect if absorbed excessively in vivo. PMID- 29159022 TI - Chinese herbal medicine compound Yi-Zhi-Hao pellet inhibits replication of influenza virus infection through activation of heme oxygenase-1. AB - As a leading cause of respiratory disease, influenza A virus (IAV) presents a pandemic threat in annual seasonal outbreaks. Given the limitation of existing anti-influenza therapies, there remains to be a requirement for new drugs. Compound Yi-Zhi-Hao pellet (CYZH) is a famous traditional Chinese medicine (TCM) used in the clinic, whose formula has been recorded in Complication of National Standard for Traditional Chinese Medicine to treat common cold. In this study, we found that CYZH exhibited a broad-spectrum anti-influenza activity and inhibited the expression of viral RNA and proteins in vitro. Mechanistically, CYZH had no inhibitory activities against viral protein hemagglutinin and IAV RNA-dependent RNA polymerase. Instead, it induced activation of erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-kappaB), which subsequently upregulated heme oxygenase-1 (HO-1) expression. Also, CYZH protected cells from oxidative damage induced by reactive oxygen series. In conclusions, CYZH inhibits IAV replication in vitro, at least partly by activating expression of the Nrf2/HO-1 pathway. PMID- 29159020 TI - The current agonists and positive allosteric modulators of alpha7 nAChR for CNS indications in clinical trials. AB - The alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR), consisting of homomeric alpha7 subunits, is a ligand-gated Ca2+-permeable ion channel implicated in cognition and neuropsychiatric disorders. Enhancement of alpha7 nAChR function is considered to be a potential therapeutic strategy aiming at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. Currently, a number of alpha7 nAChR modulators have been reported and several of them have advanced into clinical trials. In this brief review, we outline recent progress made in understanding the role of the alpha7 nAChR in multiple neuropsychiatric disorders and the pharmacological effects of alpha7 nAChR modulators used in clinical trials. PMID- 29159023 TI - 8,4'-Oxyneolignane glucosides from an aqueous extract of "ban lan gen" (Isatis indigotica root) and their absolute configurations. AB - Three pairs of glycosidic 8,4'-oxyneolignane diastereoisomers, named isatioxyneolignosides A-F (1-6), were isolated from an aqueous extract of Isatis indigotica roots. Their structures and absolute configurations were elucidated by comprehensive spectroscopic data analysis and enzyme hydrolysis. The validity of DeltadeltaC8-C7 values to distinguish threo and erythro aryl glycerol units and Cotton effects at 235+/-5 nm to determine absolute configurations at C-8 in 1-6 and their aglycones (1a-6a) are discussed. PMID- 29159024 TI - Application of 1H NMR-based metabolomics for discrimination of different parts and development of a new processing workflow for Cistanche deserticola. AB - Cistanche deserticola (CD) is one of the two authoritative source plants of Cistanches Herba, a well-known medicinal plant. Herein, 1H NMR spectroscopy was employed to characterize the chemical profile and to distinguish the different parts, as well as to propose a new processing workflow for CD. Signal assignment was achieved by multiple one and two dimensional NMR spectroscopic techniques in combination with available databases and authentic compounds. The upper parts of the plant were distinguished from the lower parts by combining 1H NMR spectroscopic dataset with multivariate statistical analysis. A new processing method that hyphenated steaming with freeze-drying, was demonstrated to be superior to either steaming coupled with oven-drying or direct freeze-drying via holistic 1H NMR-based metabolomic characterization. Phenylethanoid glycosides, mainly echinacoside and acteoside, were screened out and confirmed as the chemical markers responsible for exhibiting the superiority of the new processing workflow, whereas serial primary metabolites, especially carbohydrates and tricarboxylic acid cycle metabolites, were found as the primary molecules governing the discrimination between the upper and lower parts of the plant. Collectively, 1H NMR spectroscopy was demonstrated as a versatile analytical tool to characterize the chemical profile and to guide the in-depth exploitation of CD by providing comprehensive qualitative and quantitative information. PMID- 29159025 TI - Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1. AB - UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a key role in detoxification of many potentially harmful compounds and drugs. UGT1A1 inhibition may bring risks of drug-drug interactions (DDIs), hyperbilirubinemia and drug-induced liver injury. This study aimed to investigate and compare the inhibitory effects of icotinib and erlotinib against UGT1A1, as well as to evaluate their potential DDI risks via UGT1A1 inhibition. The results demonstrated that both icotinib and erlotinib are UGT1A1 inhibitors, but the inhibitory effect of icotinib on UGT1A1 is weaker than that of erlotinib. The IC50 values of icotinib and erlotinib against UGT1A1-mediated NCHN-O-glucuronidation in human liver microsomes (HLMs) were 5.15 and 0.68 MUmol/L, respectively. Inhibition kinetic analyses demonstrated that both icotinib and erlotinib were non-competitive inhibitors against UGT1A1-mediated glucuronidation of NCHN in HLMs, with the Ki values of 8.55 and 1.23 MUmol/L, respectively. Furthermore, their potential DDI risks via UGT1A1 inhibition were quantitatively predicted by the ratio of the areas under the concentration-time curve (AUC) of NCHN. These findings are helpful for the medicinal chemists to design and develop next generation tyrosine kinase inhibitors with improved safety, as well as to guide reasonable applications of icotinib and erlotinib in clinic, especially for avoiding their potential DDI risks via UGT1A1 inhibition. PMID- 29159026 TI - Highlights for the 6th International Ion Channel Conference: ion channel structure, function, disease and therapeutics. AB - To foster communication and interactions amongst international scholars and scientists in the field of ion channel research, the 6th International Ion Channel Conference (IICC-2017) was held between June 23-27, 2017 in the eastern coastal city of Qingdao, China. The meeting consisted of 450 attendees and 130 speakers and poster presenters. The program consisted of research progress, new findings and ongoing studies that were focused on (1) Ion channel structure and function; (2) Ion channel physiology and human diseases; (3) Ion channels as targets for drug discovery; (4) Technological advances in ion channel research. An insightful overview was presented on the structure and function of the mechanotransduction channel Drosophila NOMPC (No mechanoreceptor potential C), a member of the transient receptor potential (TRP) channel family. Recent studies on Transmembrane protein 16 or Anoctamin-1 (TMEM16A, a member of the calcium activated chloride channel [CaCC] family) were summarized as well. In addition, topics for ion channel regulation, homeostatic feedback and brain disorders were thoroughly discussed. The presentations at the IICC-2017 offer new insights into our understanding of ion channel structures and functions, and ion channels as targets for drug discovery. PMID- 29159027 TI - A case of paracoccidioidomycosis due to Paracoccidioides lutzii presenting sarcoid-like form. AB - Paracoccidioidomycosis (PCM) is a fungal disease caused by Paracoccidioides spp., which can cause a systemic granulomatous infection with tegumentary and visceral involvement. Sarcoid-like skin lesions are uncommon and can be misdiagnosed due to similarities with other granulomatous diseases. We report a case of a women presenting with erythematous infiltrated plaques on her face that was treated for leprosy and rosacea with no response and was later diagnosed with PCM, presenting positive serology for Paracoccidioides lutzii. PMID- 29159028 TI - Risk factors for bone metastasis from renal cell cancer. AB - Objective: The prognosis for renal cell carcinoma (RCC) is related to a high rate of metastasis, including 30% of bone metastasis. In this study, we investigate the correlation between diverse clinical factors and bone metastases secondary from renal cell cancer (RCC), and to identify potential risk factors for bone metastasis in newly diagnosed patients and those who have already received treatment. Methods: The clinical data of 372 patients with RCC were reviewed from January 2000 to August 2016. The correlations between age, gender, histopathologic types, alkaline phosphotase (ALP), CEA, AFP, CA-125, CA-153, CA 199, calcium, hemoglobin (HB) and bone metastases were analyzed. And the risk factors for bone metastases in RCC were identified by multivariate logistic regression analysis. The cutoff value, sensitivity and specificity of the independent correlation factors were calculated by receiver operating characteristic (ROC) curve. Results: The bone is the second to the lung as a distant metastasis target site in patients with RCC. Thirty eight individuals were identified with bone metastases. Of these patients, significantly higher levels of ALP, calcium, HB were found than those without bone metastasis (P < 0.05, respectively). No significant differences were detected in CEA, AFP, CA 125, CA-153, CA-199, age, gender and histopathologic types between patients with and without bone metastases (P > 0.05, respectively). Multivariate logistic regression analysis indicated that ALP, calcium and HB were independent risk factors correlated with bone metastasis (P < 0.05, respectively). ROC curves demonstrated these factors had comparable accuracy at predicting bone metastasis (AUC were 0.749, 0.633 and 0.665, respectively). The cutoff values of ALP, calcium and HB were 105.5 U/L, 2.615 mmol/L and 111.5 g/L, respectively. The sensitivities of them were 57.9%, 36.8% and 71.1% for predicting bone metastasis, with specificities of 83.5%, 95.2% and 65.3%, respectively. Conclusion: Based on our study, the concentrations of ALP, calcium and HB were potentially risk factors for bone metastasis in patients with RCC. For newly diagnosed patients, if the values of ALP>105.5 U/L, calcium>2.615 mmol/L and HB<111.5 g/L were detected, intensive monitoring and bone scanning are warranted for them. PMID- 29159029 TI - Case report: Unusual cause of difficulty in intubation and ventilation with asthmatic-like presentation of Endobronchial Tuberculosis. AB - Endobronchial Tuberculosis is hazardous in causing circumferential narrowing of tracheobronchial tree despite the eradication of tubercle bacilli in the initial insult from Pulmonary Tuberculosis. They may present as treatment resistant bronchial asthma and pose challenge to airway management in the acute setting. We present a 25 year-old lady who was newly diagnosed bronchial asthma with a past history of Pulmonary Tuberculosis that had completed treatment. She presented with sudden onset of difficulty breathing associated with noisy breathing for 3 days and hoarseness of voice for 6 months. Due to resistant bronchospasm, attempts were made to secure the airway which led to unanticipated difficult intubation and ventilation. Subsequent investigations confirmed the diagnosis of Endobronchial Tuberculosis and patient was managed successfully with anti TB medication, corticosteroids and multiple sessions of tracheal dilatation for tracheal stenosis. This case highlights the unusual cause of difficulty in intubation and ventilation due to Endobronchial Tuberculosis, which required medical and surgical intervention to improve the condition. PMID- 29159030 TI - Successful treatment of postoperative massive pulmonary embolism with paradoxal arterial embolism through extracorporeal life support and thrombolysis. AB - Pulmonary embolism is a common clinical entity related to high mortality. About 200,000 to 300,000 patients die every year due to pulmonary embolism. The purpose of this article is to describe a case of a patient who on the second postoperative day after undergoing thromboembolectomy of the left femoral artery, manifested a massive pulmonary embolism. Due to cardiorespiratory collapse a combined treatment via extracorporeal life support (ECLS) and parallel catheter thrombolysis was decided and performed. By cardiorespiratory improvement and final stabilization the patient was successfully weaned from ECLS and the system was successfully removed. After a reasonable postoperative time the patient was dismissed in good overall condition. PMID- 29159031 TI - Solitary fibrous tumor of the abdominal wall re-surfacing as unilateral pleural effusion and mass: A case report and review of the literature. AB - Background: Solitary fibrous tumors (SFTs) are rare fibroblastic mesenchymal neoplasms that were initially described in the pleura, but have been increasingly recognized to occur in other parts of the body. They have been traditionally regarded as indolent tumors that are rare to metastasize after surgical resection. Here, we describe a case of a Filipino female who initially presented with unilateral pleural effusion and mass, and was ultimately diagnosed with recurrent solitary fibrous tumor that originated from the abdominal wall. Then, we reviewed existing literature on intra- and extrathoracic SFTs with focus on pathological characteristics, recommendations for treatment as well as post treatment surveillance. Case presentation: A 79-year-old Filipino female with a history of solitary fibrous tumor of the abdominal wall status post complete surgical resection 3 years ago presented with unilateral pleural effusion and mass, and was diagnosed with recurrent solitary fibrous tumor that metastasized to the lung. She was not a candidate for systemic chemotherapy and ultimately died 1 year later from progressive respiratory failure. Conclusions: Solitary fibrous tumor are rare mesenchymal tumors that were initially described in the pleura, but have now been reported in many other sites. Complete surgical resection is the mainstay therapy for all cases; however, long-term monitoring and surveillance several years after initial presentation is crucial to prevent disease recurrence, and adjuvant treatment may be necessary for patients with high-risk features. Additional studies are needed to demonstrate the clinical utility of risk stratification models and to develop post-treatment surveillance guidelines for extrathoracic SFTs. PMID- 29159032 TI - Use of ceftolozane-tazobactam in a cystic fibrosis patient with multidrug resistant pseudomonas infection and renal insufficiency. AB - We report the successful use of ceftolozane/tazobactam (C/T) to treat a pulmonary exacerbation in a 35 year old female, post lung transplant, with cystic fibrosis (CF), malnutrition, chronic kidney disease, and multi-drug resistant Pseudomonas aeruginosa infection (MDR PSA). Given the complexity of the clinical profile, we measured drug levels of C/T during treatment of her current exacerbation to determine pharmacokinetics. The patient achieved an estimated ceftolozane peak of 174.1 MUg/mL and trough of 9.2 MUg/mL. Serum half-life was found to be slightly shorter than previously reported in normal subjects, (2.3 hr. vs. 2.6 hr.) despite the presence of renal insufficiency. Treatment resulted in improvement in serum inflammatory markers and symptoms and was well-tolerated. PMID- 29159033 TI - Interstitial pneumonia caused by dabigatran. AB - We describe the case of a 73-year-old man who experienced dry cough and exertional dyspnea after dabigatran administration. Chest radiographs revealed the development of bilateral consolidative and ground glass opacity, and transbronchial lung biopsy showed organized materials in the alveolar spaces with moderate inflammatory infiltrate and focal fibrosis. Lung opacity gradually disappeared after discontinuing dabigatran. To date, there has been only one report regarding dabigatran-induced lung injury, except for alveolar hemorrhage and eosinophilic pneumonia. Therefore, we should consider that any drug can cause various types of lung injuries. PMID- 29159035 TI - Tumor Lysis Syndrome (TLS) following intrathecal chemotherapy in a child with acute myelogenous leukemia (AML). AB - Tumor Lysis Syndrome (TLS) is a well-known complication of induction therapy for hematologic malignancies. It is characterized by rapid breakdown of malignant white blood cells (WBCs) leading to metabolic derangements and serious morbidity if left untreated. Most commonly, TLS is triggered by systemic chemotherapy, however, there have been case reports of TLS following intrathecal (IT) chemotherapy, all in patients with acute lymphoblastic leukemia (ALL)/lymphoma. Here, we report the first case of a patient with acute myelogenous leukemia (AML) who developed TLS following a single dose of IT cytosine arabinoside (Ara-C). PMID- 29159034 TI - Hamman-Rich syndrome. AB - INTRODUCTION: Acute interstitial pneumonia is a rare but important diagnosis, associated with a high mortality rate and important to identify early. CASE PRESENTATION: A 76 year-old individual presented to hospital with a two-week history of shortness of breath, fevers and a non-productive cough. Treatment initially was for lower respiratory tract infection but returned to hospital three days later as her shortness of breath and peripheral oedema was worsening despite diuretic treatment. Arterial blood gas showed Type 1 Respiratory Failure (p02 was only 10 kPa on 4 L per minute of oxygen). A computed tomography pulmonary angiography (CTPA) was performed to rule out a pulmonary embolism (PE), which showed multifocal diffuse areas of consolidations bilaterally involving all lobes. Bronchoalveolar lavage cellular analysis was also done. The patient was treated as nonspecific interstitial pneumonia. This case study highlights this rare condition presenting similarly to common pulmonary conditions. DISCUSSION: The disease is often preceded by a flu-like prodromal illness lasting one to two weeks prior to presentation. Acute respiratory failure develops in previously healthy individuals without pre-existing lung disease. Diagnosis is also supported by high-resolution computed tomography (HRCT). The effects of high flow ventilation in patients with idiopathic pulmonary fibrosis are associated with improvement in respiratory parameters, improving the efficiency of breathing. CONCLUSION: Acute interstitial pneumonitis can be a difficult diagnosis, associated with a high mortality rate up to 60%. It is also difficult to treat; however supportive treatment with high flow oxygen therapy along with pulsatile high dose Corticosteroids can aid recovery. PMID- 29159036 TI - EEG oscillations during word processing predict MCI conversion to Alzheimer's disease. AB - Only a subset of mild cognitive impairment (MCI) patients progress to develop a form of dementia. A prominent feature of Alzheimer's disease (AD) is a progressive decline in language. We investigated if subtle anomalies in EEG activity of MCI patients during a word comprehension task could provide insight into the likelihood of conversion to AD. We studied 25 amnestic MCI patients, a subset of whom developed AD within 3-years, and 11 elderly controls. In the task, auditory category descriptions (e.g., 'a type of wood') were followed by a single visual target word either semantically congruent (i.e., oak) or incongruent with the preceding category. We found that the MCI convertors group (i.e. patients that would go on to convert to AD in 3-years) had a diminished early posterior parietal theta (3-5 Hz) activity induced by first presentation of the target word (i.e., access to lexico-syntactic properties of the word), compared to MCI non convertors and controls. Moreover, MCI convertors exhibited oscillatory signatures for processing the semantically congruent words that were different from non-convertors and controls. MCI convertors thus showed basic anomalies for lexical and meaning processing. In addition, both MCI groups showed anomalous oscillatory signatures for the verbal learning/memory of repeated words: later alpha suppression (9-11 Hz), which followed first presentation of the target word, was attenuated for the second and third repetition in controls, but not in either MCI group. Our findings suggest that a subtle breakdown in the brain network subserving language comprehension can be foretelling of conversion to AD. PMID- 29159037 TI - Reorganization of the somatosensory cortex in hemiplegic cerebral palsy associated with impaired sensory tracts. AB - Functional neuroimaging studies argue that sensory deficits in hemiplegic cerebral palsy (HCP) are related to deviant somatosensory processing in the ipsilesional primary somatosensory cortex (S1). A separate body of structural neuroimaging literature argues that these deficits are due to structural damage of the ascending sensory tracts (AST). The relationship between the functional and structural integrity of the somatosensory system and the sensory performance is largely unknown in HCP. To address this relationship, we combined findings from magnetoencephalography (MEG) and probabilistic diffusion tractography (PDT) in 10 children with HCP and 13 typically developing (TD) children. With MEG, we mapped the functionally active regions in the contralateral S1 during tactile stimulation of the thumb, middle, and little fingers of both hands. Using these MEG-defined functional active regions as regions of interest for PDT, we estimated the diffusion parameters of the AST. Somatosensory function was assessed via two-point discrimination tests. Our MEG data showed: (i) an abnormal somatotopic organization in all children with HCP in either one or both of their hemispheres; (ii) longer Euclidean distances between the digit maps in the S1 of children with HCP compared to TD children; (iii) suppressed gamma responses at early latencies for both hemispheres of children with HCP; and (iv) a positive correlation between the Euclidean distances and the sensory tests for the more affected hemisphere of children with HCP. Our MEG-guided PDT data showed: (i) higher mean and radian diffusivity of the AST in children with HCP; (ii) a positive correlation between the axial diffusivity of the AST with the sensory tests for the more affected hemisphere; and (iii) a negative correlation between the gamma power change and the AD of the AST for the MA hemisphere. Our findings associate for the first time bilateral cortical functional reorganization in the S1 of HCP children with abnormalities in the structural integrity of the AST, and correlate these abnormalities with behaviorally-assessed sensory deficits. PMID- 29159038 TI - The cortical signature of impaired gesturing: Findings from schizophrenia. AB - Schizophrenia is characterized by deficits in gesturing that is important for nonverbal communication. Research in healthy participants and brain-damaged patients revealed a left-lateralized fronto-parieto-temporal network underlying gesture performance. First evidence from structural imaging studies in schizophrenia corroborates these results. However, as of yet, it is unclear if cortical thickness abnormalities contribute to impairments in gesture performance. We hypothesized that patients with deficits in gesture production show cortical thinning in 12 regions of interest (ROIs) of a gesture network relevant for gesture performance and recognition. Forty patients with schizophrenia and 41 healthy controls performed hand and finger gestures as either imitation or pantomime. Group differences in cortical thickness between patients with deficits, patients without deficits, and controls were explored using a multivariate analysis of covariance. In addition, the relationship between gesture recognition and cortical thickness was investigated. Patients with deficits in gesture production had reduced cortical thickness in eight ROIs, including the pars opercularis of the inferior frontal gyrus, the superior and inferior parietal lobes, and the superior and middle temporal gyri. Gesture recognition correlated with cortical thickness in fewer, but mainly the same, ROIs within the patient sample. In conclusion, our results show that impaired gesture production and recognition in schizophrenia is associated with cortical thinning in distinct areas of the gesture network. PMID- 29159039 TI - Disruption of default mode network dynamics in acute and chronic pain states. AB - It has been proposed that pain competes with other attention-demanding stimuli for cognitive resources, and many chronic pain patients display significant attention and mental flexibility deficits. These alterations may result from disruptions in the functioning of the default mode network (DMN) which plays a critical role in attention, memory, prospection and self-processing, and recent investigations have found alterations in DMN function in multiple chronic pain conditions. Whilst it has been proposed that these DMN alterations are a characteristic of pain that is chronic in nature, we recently reported altered oscillatory activity in the DMN during an acute, 5 minute noxious stimulus in healthy control subjects. We therefore hypothesize that altered DMN activity patterns will not be restricted to those in chronic pain but instead will also occur in healthy individuals during tonic noxious stimuli. We used functional magnetic resonance imaging to measure resting state infra-slow oscillatory activity and functional connectivity in patients with chronic orofacial pain at rest and in healthy controls during a 20-minute tonic pain stimulus. We found decreases in oscillatory activity in key regions of the DMN in patients with chronic pain, as well as in healthy controls during tonic pain in addition to changes in functional connectivity between the posterior cingulate cortex and areas of the DMN in both groups. The results show that similar alterations in DMN function occur in healthy individuals during acute noxious stimuli as well as in individuals with chronic pain. These DMN changes may reflect the presence of pain per se and may underlie alterations in attentional processes that occur in the presence of pain. PMID- 29159040 TI - Does the late positive component reflect successful reading acquisition? A longitudinal ERP study. AB - Developmental dyslexia is a reading disorder that is associated with deficits in phonological processing, where the exact neural basis for those processing deficits remains unclear. In particular, disagreement exists whether degraded phonological representations or an impaired access to the phonological representations causes these deficits. To investigate this question and to trace changes in neurophysiology during the process of reading acquisition, we designed a longitudinal study with event related potentials (ERPs) in children between kindergarten and second grade. We used an explicit word processing task to elicit the late positive component (LPC), which has been shown to reflect phonological processing. A brain-wide analysis of the LPC with an electrode-wise application of mixed effects models showed significantly attenuated amplitudes in the left temporo-parietal region in dyslexic children. Since these differences were only present in the word and not in the picture (i.e. control) condition, the attenuated amplitudes might reflect impaired access to the phonological representations of words. This was further confirmed by the longitudinal development, which showed a rapid increase in amplitude at the beginning of reading instruction and a decrease with continuing automatization, possibly pointing to a progression from grapheme-phoneme parsing to whole word reading. Our longitudinal study provides the first evidence that it is possible to detect neurophysiological differences in the LPC between children with dyslexia and control children in both preliterate and very early stages of reading acquisition, providing new insights about the neurophysiological development and a potential marker of later reading problems. PMID- 29159041 TI - White matter alterations and their associations with motor function in young adults born preterm with very low birth weight. AB - Very low birth weight (VLBW: <= 1500 g) individuals have an increased risk of white matter alterations and neurodevelopmental problems, including fine and gross motor problems. In this hospital-based follow-up study, the main aim was to examine white matter microstructure and its relationship to fine and gross motor function in 31 VLBW young adults without cerebral palsy compared with 31 term born controls, at mean age 22.6 +/- 0.7 years. The participants were examined with tests of fine and gross motor function (Trail Making Test-5: TMT-5, Grooved Pegboard, Triangle from Movement Assessment Battery for Children-2: MABC-2 and High-level Mobility Assessment Tool: HiMAT) and diffusion tensor imaging (DTI). Probabilistic tractography of motor pathways of the corticospinal tract (CST) and corpus callosum (CC) was performed. Fractional anisotropy (FA) was calculated in non-crossing (capsula interna in CST, body of CC) and crossing (centrum semiovale) fibre regions along the tracts and examined for group differences. Associations between motor test scores and FA in the CST and CC were investigated with linear regression. Tract-based spatial statistics (TBSS) was used to examine group differences in DTI metrics in all major white matter tracts. The VLBW group had lower scores on all motor tests compared with controls, however, only statistically significant for TMT-5. Based on tractography, FA in the VLBW group was lower in non-crossing fibre regions and higher in crossing fibre regions of the CST compared with controls. Within the VLBW group, poorer fine motor function was associated with higher FA in crossing fibre regions of the CST, and poorer bimanual coordination was additionally associated with lower FA in crossing fibre regions of the CC. Poorer gross motor function was associated with lower FA in crossing fibre regions of the CST and CC. There were no associations between motor function and FA in non-crossing fibre regions of the CST and CC within the VLBW group. In the TBSS analysis, the VLBW group had lower FA and higher mean diffusivity compared with controls in all major white matter tracts. The findings in this study may indicate that the associations between motor function and FA are caused by other tracts crossing the CST and CC, and/or by alterations in the periventricular white matter in the centrum semiovale. Some of the associations were in the opposite direction than hypothesized, thus higher FA does not always indicate better function. Furthermore, widespread white matter alterations in VLBW individuals persist into young adulthood. PMID- 29159042 TI - Evaluation of a deep learning approach for the segmentation of brain tissues and white matter hyperintensities of presumed vascular origin in MRI. AB - Automatic segmentation of brain tissues and white matter hyperintensities of presumed vascular origin (WMH) in MRI of older patients is widely described in the literature. Although brain abnormalities and motion artefacts are common in this age group, most segmentation methods are not evaluated in a setting that includes these items. In the present study, our tissue segmentation method for brain MRI was extended and evaluated for additional WMH segmentation. Furthermore, our method was evaluated in two large cohorts with a realistic variation in brain abnormalities and motion artefacts. The method uses a multi scale convolutional neural network with a T1-weighted image, a T2-weighted fluid attenuated inversion recovery (FLAIR) image and a T1-weighted inversion recovery (IR) image as input. The method automatically segments white matter (WM), cortical grey matter (cGM), basal ganglia and thalami (BGT), cerebellum (CB), brain stem (BS), lateral ventricular cerebrospinal fluid (lvCSF), peripheral cerebrospinal fluid (pCSF), and WMH. Our method was evaluated quantitatively with images publicly available from the MRBrainS13 challenge (n = 20), quantitatively and qualitatively in relatively healthy older subjects (n = 96), and qualitatively in patients from a memory clinic (n = 110). The method can accurately segment WMH (Overall Dice coefficient in the MRBrainS13 data of 0.67) without compromising performance for tissue segmentations (Overall Dice coefficients in the MRBrainS13 data of 0.87 for WM, 0.85 for cGM, 0.82 for BGT, 0.93 for CB, 0.92 for BS, 0.93 for lvCSF, 0.76 for pCSF). Furthermore, the automatic WMH volumes showed a high correlation with manual WMH volumes (Spearman's rho = 0.83 for relatively healthy older subjects). In both cohorts, our method produced reliable segmentations (as determined by a human observer) in most images (relatively healthy/memory clinic: tissues 88%/77% reliable, WMH 85%/84% reliable) despite various degrees of brain abnormalities and motion artefacts. In conclusion, this study shows that a convolutional neural network based segmentation method can accurately segment brain tissues and WMH in MR images of older patients with varying degrees of brain abnormalities and motion artefacts. PMID- 29159043 TI - Neuroimaging and other modalities to assess Alzheimer's disease in Down syndrome. AB - People with Down syndrome (DS) develop Alzheimer's disease (AD) at higher rates and a younger age of onset compared to the general population. As the average lifespan of people with DS is increasing, AD is becoming an important health concern in this group. Neuroimaging is becoming an increasingly useful tool in understanding the pathogenesis of dementia development in relation to clinical symptoms. Furthermore, neuroimaging has the potential to play a role in AD diagnosis and monitoring of therapeutics. This review describes major recent findings from in vivo neuroimaging studies analysing DS and AD via ligand-based positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG)-PET, structural magnetic resonance imaging (sMRI), and diffusion tensor imaging (DTI). Electroencephalography (EEG) and retinal imaging are also discussed as emerging modalities. The review is organized by neuroimaging method and assesses the relationship between cognitive decline and neuroimaging changes. We find that amyloid accumulation seen on PET occurs prior to dementia onset, possibly as a precursor to the atrophy and white matter changes seen in MRI studies. Future PET studies relating tau distribution to clinical symptoms will provide further insight into the role this protein plays in dementia development. Brain activity changes demonstrated by EEG and metabolic changes seen via FDG-PET may also follow predictable patterns that can help track dementia progression. Finally, newer approaches such as retinal imaging will hopefully overcome some of the limitations of neuroimaging and allow for detection of dementia at an earlier stage. PMID- 29159044 TI - A key role of the prefrontal cortex in the maintenance of chronic tinnitus: An fMRI study using a Stroop task. AB - Introduction: Since we recently showed in behavioural tasks that the top-down cognitive control was specifically altered in tinnitus sufferers, here we wanted to establish the link between this impaired executive function and brain alterations in the frontal cortex in tinnitus patients. Method: Using functional magnetic resonance imaging (fMRI), we monitored the brain activity changes in sixteen tinnitus patients (TP) and their control subjects (CS) while they were performing a spatial Stroop task, both in audition and vision. Results: We observed that TP differed from CS in their functional recruitment of the dorsolateral prefrontal cortex (dlPFC, BA46), the cingulate gyrus and the ventromedial prefrontal cortex (vmPFC, BA10). This recruitment was higher during interference conditions in tinnitus participants than in controls, whatever the sensory modality. Furthermore, the brain activity level in the right dlPFC and vmPFC correlated with the performance in the Stroop task in TP. Conclusion: Due to the direct link between poor executive functions and prefrontal cortex alterations in TP, we postulate that a lack of inhibitory modulation following an impaired top-down cognitive control may maintain tinnitus by hampering habituation mechanisms. This deficit in executive functions caused by prefrontal cortex alterations would be a key-factor in the generation and persistence of tinnitus. PMID- 29159045 TI - Identifying functional network changing patterns in individuals at clinical high risk for psychosis and patients with early illness schizophrenia: A group ICA study. AB - Although individuals at clinical high risk (CHR) for psychosis exhibit a psychosis-risk syndrome involving attenuated forms of the positive symptoms typical of schizophrenia (SZ), it remains unclear whether their resting-state brain intrinsic functional networks (INs) show attenuated or qualitatively distinct patterns of functional dysconnectivity relative to SZ patients. Based on resting-state functional magnetic imaging data from 70 healthy controls (HCs), 53 CHR individuals (among which 41 subjects were antipsychotic medication-naive), and 58 early illness SZ (ESZ) patients (among which 53 patients took antipsychotic medication) within five years of illness onset, we estimated subject-specific INs using a novel group information guided independent component analysis (GIG-ICA) and investigated group differences in INs. We found that when compared to HCs, both CHR and ESZ groups showed significant differences, primarily in default mode, salience, auditory-related, visuospatial, sensory motor, and parietal INs. Our findings suggest that widespread INs were diversely impacted. More than 25% of voxels in the identified significant discriminative regions (obtained using all 19 possible changing patterns excepting the no difference pattern) from six of the 15 interrogated INs exhibited monotonically decreasing Z-scores (in INs) from the HC to CHR to ESZ, and the related regions included the left lingual gyrus of two vision-related networks, the right postcentral cortex of the visuospatial network, the left thalamus region of the salience network, the left calcarine region of the fronto-occipital network and fronto-parieto-occipital network. Compared to HCs and CHR individuals, ESZ patients showed both increasing and decreasing connectivity, mainly hypo connectivity involving 15% of the altered voxels from four INs. The left supplementary motor area from the sensory-motor network and the right inferior occipital gyrus in the vision-related network showed a common abnormality in CHR and ESZ groups. Some brain regions also showed a CHR-unique alteration (primarily the CHR-increasing connectivity). In summary, CHR individuals generally showed intermediate connectivity between HCs and ESZ patients across multiple INs, suggesting that some dysconnectivity patterns evident in ESZ predate psychosis in attenuated form during the psychosis risk stage. Hence, these connectivity measures may serve as possible biomarkers to predict schizophrenia progression. PMID- 29159046 TI - Imaging of glia activation in people with primary lateral sclerosis. AB - Background: Glia activation is thought to contribute to neuronal damage in several neurodegenerative diseases based on preclinical and human post-mortem studies, but its role in primary lateral sclerosis (PLS) is unknown. Objectives: To localize and measure glia activation in people with PLS compared to healthy controls (HC). Methods: Ten participants with PLS and ten age-matched HCs underwent simultaneous magnetic resonance (MR) and proton emission tomography (PET). The radiotracer [11C]-PBR28 was used to obtain PET-based measures of 18 kDa translocator protein (TSPO) expression, a marker of activated glial cells. MR techniques included a structural sequence to measure cortical thickness and diffusion tensor imaging (DTI) to assess white matter integrity. Results: PET data showed increased [11C]-PBR28 uptake in anatomically-relevant motor regions which co-localized with areas of regional gray matter atrophy and decreased subcortical fractional anisotropy. Conclusions: This study supports a link between glia activation and neuronal degeneration in PLS, and suggests that these disease mechanisms can be measured in vivo in PLS. Future studies are needed to determine the longitudinal changes of these imaging measures and to clarify if MR PET with [11C]-PBR28 can be used as a biomarker for drug development in the context of clinical trials for PLS. PMID- 29159047 TI - Voxel-based comparison of brain glucose metabolism between patients with Cushing's disease and healthy subjects. AB - Cognitive impairment and psychiatric symptoms are common in patients with Cushing's disease (CD) owing to elevated levels of glucocorticoids. Molecular neuroimaging methods may help to detect changes in the brain of patients with CD. The aim of this study was to investigate the characteristics of brain metabolism and its association with serum cortisol level in CD. We compared brain metabolism, as measured using [18F]-fluorodeoxyglucose positron emission tomography (FDG PET), between 92 patients with CD and 118 normal subjects on a voxel-wise basis. Pearson correlation was performed to evaluate the association between cerebral FDG uptake and serum cortisol level in patients with CD. We demonstrated that certain brain regions in patients with CD showed significantly increased FDG uptake, including the basal ganglia, anteromedial temporal lobe, thalamus, precentral cortex, and cerebellum. The clusters that demonstrated significantly decreased uptake were mainly located in the medial and lateral frontal cortex, superior and inferior parietal lobule, medial occipital cortex, and insular cortex. The metabolic rate of the majority of these regions was found to be significantly correlated with the serum cortisol level. Our findings may help to explain the underlying mechanisms of cognitive impairment and psychiatric symptoms in patients exposed to excessive glucocorticoids and evaluate the efficacy of treatments during follow-up. PMID- 29159048 TI - Resting-state connectivity and executive functions after pediatric arterial ischemic stroke. AB - Background: The aim of this study was to compare the relationship between core executive functions and frontoparietal network connections at rest between children who had suffered an arterial ischemic stroke and typically developing peers. Methods: Children diagnosed with arterial ischemic stroke more than two years previously and typically developing controls were included. Executive function (EF) measures comprised inhibition (Go-NoGo task), fluency (category fluency task), processing speed (processing speed tasks), divided attention, working memory (letter-number sequencing), conceptual reasoning (matrices) and EF in everyday life (questionnaire). High-resolution T1-weighted magnetic resonance (MR) structural images and resting-state functional MR imaging were acquired. Independent component analysis was used to identify the frontoparietal network. Functional connections were obtained through correlation matrices; associations between cognitive measures and functional connections through Pearson's correlations. Results: Twenty participants after stroke (7 females; mean age 16.0 years) and 22 controls (13 females; mean age 14.8 years) were examined. Patients and controls performed within the normal range in all executive tasks. Patients who had had a stroke performed significantly less well in tests of fluency, processing speed and conceptual reasoning than controls. Resting-state functional connectivity between the left and right inferior parietal lobe was significantly reduced in patients after pediatric stroke. Fluency, processing speed and perceptual reasoning correlated positively with the interhemispheric inferior parietal lobe connection in patients and controls. Conclusion: Decreased interhemispheric connections after stroke in childhood may indicate a disruption of typical interhemispheric interactions relating to executive functions. The present results emphasize the relationship between functional organization of the brain at rest and cognitive processes. PMID- 29159049 TI - Pre-treatment EEG signal variability is associated with treatment success in depression. AB - Background: Previous work suggests that major depressive disorder (MDD) is associated with disturbances in global connectivity among brain regions, as well as local connectivity within regions. However, the relative importance of these global versus local changes for successful antidepressant treatment is unknown. We used multiscale entropy (MSE), a measure of brain signal variability, to examine how the propensity for local (fine scale MSE) versus global (coarse scale MSE) neural processing measured prior to antidepressant treatment is related to subsequent treatment response. Methods: We collected resting-state EEG activity during eyes-open and closed conditions from unmedicated individuals with MDD prior to antidepressant pharmacotherapy (N = 36) as well as from non-depressed controls (N = 36). Treatment response was assessed after 12 weeks of treatment using the Montgomery-Asberg Depression Rating Scale (MADRS), at which time participants with MDD were characterized as either responders (>= 50% MADRS decrease) or non-responders. MSE was calculated from baseline EEG, and compared between controls, future treatment responders and non-responders. Putative interactions with the well-documented age effect on signal variability (increased reliance on local neural communication with increasing age, indexed by greater finer-scale variability) were assessed. Results: Only in responders, we found that reduced MSE at fine temporal scales (especially fronto-centrally) and increased MSE diffusely at coarser temporal scales was related to the magnitude of the antidepressant response. In controls and MDD non-responders, but not MDD responders, there was an increase in MSE with age at fine temporal scales and a decrease in MSE with age at coarse temporal scales. Conclusion: Our results suggest that an increased propensity toward global processing, indexed by greater MSE at coarser timescales, at baseline appears to facilitate eventual antidepressant treatment response. PMID- 29159050 TI - Preliminary evidence for differential olfactory and trigeminal processing in combat veterans with and without PTSD. AB - Structural and functional changes in the olfactory system are increasingly implicated in the expression of PTSD. Still, very little is known about the neurobiological networks of trauma-related odor sensitivity or how they relate to other objective and subjective measures of olfaction and PTSD. The purpose of this study was to replicate prior findings and further characterize olfactory function in trauma-exposed combat veterans with and without PTSD. We also sought to extend this area of research by exploring the effects of time since the combat related index trauma (TST) on post-trauma olfactory function, as well as by correlating odor-elicited brain activity to general olfactory ability and odor elicited PTSD symptoms. Participants included combat veterans with PTSD (CV+PTSD; n = 21) or without any psychiatric disorder (CV-PTSD; n = 27). TST was coded as greater (n = 24) or less (n = 24) than 5 years. There were main effects and/or interaction for PTSD-status and TST across several parameters of olfactory function: odor detection, odor identification, ratings for trauma-related odor intensity and triggered PTSD symptoms, and trauma odor-elicited brain activation. Overall, results suggest olfactory impairment in chronic PTSD, but not necessarily in the earlier stages of the disorder, although some early-stage olfactory findings may be predictive of later olfactory impairment. Results also suggest that trauma-exposed individuals who never develop PTSD may demonstrate olfactory resiliency. Finally, results highlight a potentially unique role of trigeminal odor properties in the olfactory-PTSD relationship. PMID- 29159051 TI - Interactive versus additive relationships between regional cortical thinning and amyloid burden in predicting clinical decline in mild AD and MCI individuals. AB - The biological mechanisms that link Beta-amyloid (Abeta) plaque deposition, neurodegeneration, and clinical decline in Alzheimer's disease (AD) dementia, have not been completely elucidated. Here we studied whether amyloid accumulation and neurodegeneration, independently or interactively, predict clinical decline over time in a group of memory impaired older individuals [diagnosed with either amnestic mild cognitive impairment (MCI), or mild AD dementia]. We found that baseline Abeta-associated cortical thinning across clusters encompassing lateral and medial temporal and parietal cortices was related to higher baseline Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Baseline Abeta-associated cortical thinning also predicted CDR-SB over time. Notably, the association between CDR-SB change and cortical thickness values from the right lateral temporo-parietal cortex and right precuneus was driven by individuals with high Abeta burden. In contrast, the association between cortical thickness in the medial temporal lobe (MTL) and clinical decline was similar for individuals with high or low Abeta burden. Furthermore, amyloid pathology was a stronger predictor for clinical decline than MTL thickness. While this study validates previous findings relating AD biomarkers of neurodegeneration to clinical impairment, here we show that regions outside the MTL may be more vulnerable and specific to AD dementia. Additionally, excluding mild AD individuals revealed that these relationships remained, suggesting that lower cortical thickness values in specific regions, vulnerable to amyloid pathology, predict clinical decline already at the prodromal stage. PMID- 29159052 TI - Subcortical grey matter changes in juvenile myoclonic epilepsy. AB - Recent neuroimaging studies have provided converging evidence of structural and functional abnormalities of the thalamus in patients with juvenile myoclonic epilepsy (JME). There has also been limited evidence indicating involvement of the subcortical grey matter structures other than thalamus in JME, but with inconsistent findings across the studies. In the present study, we combined volumetric MRI and diffusion tensor imaging analyses to investigate macrostructural and microstructural alterations of the subcortical grey matter in 64 JME patients compared to 58 matched control subjects. Raw volume, fractional anisotropy (FA), and mean diffusivity (MD) of 6 subcortical grey matter structures (amygdala, hippocampus, caudate, pallidum, putamen, thalamus) were measured in both hemispheres. Between-group (controls versus patients) comparisons of normalized volume, FA, and MD, as well as within-group (patients) correlation analyses between structural changes and clinical variables were carried out. Compared to controls, JME patients exhibited significant volume reductions in left pallidum and bilateral putamen and thalamus. Duration of epilepsy negatively correlated with bilateral putamen volumes. Patients and controls did not differ in FA values of all structures. Compared to controls, JME patients showed significant MD increases in left pallidum and bilateral hippocampus, putamen, and thalamus. Significant positive correlations were found between duration of epilepsy and MD values of bilateral hippocampus and thalamus. We have provided evidence that macrostructural and microstructural abnormalities may not only be confined to the thalamus but also affect basal ganglia and hippocampus in JME. Our findings could further support the pathophysiological hypothesis of striato-thalamo-frontal network abnormality underlying JME, and may implicate disease progression. PMID- 29159053 TI - Using simultaneous PET/MRI to compare the accuracy of diagnosing frontotemporal dementia by arterial spin labelling MRI and FDG-PET. AB - Purpose: The clinical utility of FDG-PET in diagnosing frontotemporal dementia (FTD) has been well demonstrated over the past decades. On the contrary, the diagnostic value of arterial spin labelling (ASL) MRI - a relatively new technique - in clinical diagnosis of FTD has yet to be confirmed. Using simultaneous PET/MRI, we evaluated the diagnostic performance of ASL in identifying pathological abnormalities in FTD (FTD) to determine whether ASL can provide similar diagnostic value as FDG-PET. Methods: ASL and FDG-PET images were compared in 10 patients with FTD and 10 healthy older adults. Qualitative and quantitative measures of diagnostic equivalency were used to determine the diagnostic utility of ASL compared to FDG-PET. Sensitivity, specificity, and inter-rater reliability were calculated for each modality from scores of subjective visual ratings and from analysis of regional mean values in thirteen a priori regions of interest (ROI). To determine the extent of concordance between modalities in each patient, individual statistical maps generated from comparison of each patient to controls were compared between modalities using the Jaccard similarity index (JI). Results: Visual assessments revealed lower sensitivity, specificity and inter-rater reliability for ASL (66.67%/62.12%/0.2) compared to FDG-PET (88.43%/90.91%/0.61). Across all regions, ASL performed lower than FDG PET in discriminating patients from controls (areas under the receiver operating curve: ASL = 0.75 and FDG-PET = 0.87). In all patients, ASL identified patterns of reduced perfusion consistent with FTD, but areas of hypometabolism exceeded hypoperfused areas (group-mean JI = 0.30 +/- 0.22). Conclusion: This pilot study demonstrated that ASL can detect similar spatial patterns of abnormalities in individual FTD patients compared to FDG-PET, but its sensitivity and specificity for discriminant diagnosis of a patient from healthy individuals remained unmatched to FDG-PET. Further studies at the individual level are required to confirm the clinical role of ASL in FTD management. PMID- 29159054 TI - Delayed access to bilateral input alters cortical organization in children with asymmetric hearing. AB - Bilateral hearing in early development protects auditory cortices from reorganizing to prefer the better ear. Yet, such protection could be disrupted by mismatched bilateral input in children with asymmetric hearing who require electric stimulation of the auditory nerve from a cochlear implant in their deaf ear and amplified acoustic sound from a hearing aid in their better ear (bimodal hearing). Cortical responses to bimodal stimulation were measured by electroencephalography in 34 bimodal users and 16 age-matched peers with normal hearing, and compared with the same measures previously reported for 28 age matched bilateral implant users. Both auditory cortices increasingly favoured the better ear with delay to implanting the deaf ear; the time course mirrored that occurring with delay to bilateral implantation in unilateral implant users. Preference for the implanted ear tended to occur with ongoing implant use when hearing was poor in the non-implanted ear. Speech perception deteriorated with longer deprivation and poorer access to high-frequencies. Thus, cortical preference develops in children with asymmetric hearing but can be avoided by early provision of balanced bimodal stimulation. Although electric and acoustic stimulation differ, these inputs can work sympathetically when used bilaterally given sufficient hearing in the non-implanted ear. PMID- 29159055 TI - Neural correlates of working memory deficits and associations to response inhibition in obsessive compulsive disorder. AB - Previous research in patients with obsessive-compulsive disorder (OCD) has indicated performance decrements in working memory (WM) and response inhibition. However, underlying neural mechanisms of WM deficits are not well understood to date, and empirical evidence for a proposed conceptual link to inhibition deficits is missing. We investigated WM performance in a numeric n-back task with four WM load conditions during functional Magnetic Resonance Imaging (fMRI) in 51 patients with OCD and 49 healthy control participants who were matched for age, sex, and education. Additionally, a stop signal task was performed outside the MRI scanner in a subsample. On the behavioral level, a significant WM load by group interaction was found for both accuracy (p < 0.02) and reaction time measures (p < 0.03), indicating increased reaction times as well as reduced accuracy specifically at high WM load (3-back) in patients with OCD. Whole-brain analyses of fMRI-data identified neural correlates of a load-dependent WM decrement in OCD in the supplementary motor area (SMA) and the inferior parietal lobule (IPL). Within the OCD sample, SMA-activity as well as n-back performance were correlated with stop signal task performance. Results from behavioral and fMRI-analyses indicate a reduced WM load-dependent modulation of neural activity in OCD and suggest a common neural mechanism for inhibitory dysfunction and WM decrements in OCD. PMID- 29159056 TI - No association of cortical amyloid load and EEG connectivity in older people with subjective memory complaints. AB - Changes in functional connectivity of cortical networks have been observed in resting-state EEG studies in healthy aging as well as preclinical and clinical stages of AD. Little information, however, exists on associations between EEG connectivity and cortical amyloid load in people with subjective memory complaints. Here, we determined the association of global cortical amyloid load, as measured by florbetapir-PET, with functional connectivity based on the phase lag index of resting state EEG data for alpha and beta frequency bands in 318 cognitively normal individuals aged 70-85 years with subjective memory complaints from the INSIGHT-preAD cohort. Within the entire group we did not find any significant associations between global amyloid load and phase-lag index in any frequency band. Assessing exclusively the subgroup of amyloid-positive participants, we found enhancement of functional connectivity with higher global amyloid load in the alpha and a reduction in the beta frequency bands. In the amyloid-negative participants, higher amyloid load was associated with lower connectivity in the low alpha band. However, these correlations failed to reach significance after controlling for multiple comparisons. The absence of a strong amyloid effect on functional connectivity may represent a selection effect, where individuals remain in the cognitively normal group only if amyloid accumulation does not impair cortical functional connectivity. PMID- 29159057 TI - Gray matter atrophy patterns in multiple sclerosis: A 10-year source-based morphometry study. AB - Objectives: To investigate spatial patterns of gray matter (GM) atrophy and their association with disability progression in patients with early relapsing remitting multiple sclerosis (MS) in a longitudinal setting. Methods: Brain MRI and clinical neurological assessments were obtained in 152 MS patients at baseline and after 10 years of follow-up. Patients were classified into those with confirmed disability progression (CDP) (n = 85) and those without CDP (n = 67) at the end of the study. An optimized, longitudinal source-based morphometry (SBM) pipeline, which utilizes independent component analysis, was used to identify eight spatial patterns of common GM volume co-variation in a data-driven manner. GM volume at baseline and rates of change were compared between patients with CDP and those without CDP. Results: The identified patterns generally included structurally or functionally related GM regions. No significant differences were detected at baseline GM volume between the sub-groups. Over the follow-up, patients with CDP experienced a significantly greater rate of GM atrophy within two of the eight patterns, after correction for multiple comparisons (corrected p-values of 0.001 and 0.007). The patterns of GM atrophy associated with the development of CDP included areas involved in motor functioning and cognitive domains such as learning and memory. Conclusion: SBM analysis offers a novel way to study the temporal evolution of regional GM atrophy. Over 10 years of follow-up, disability progression in MS is related to GM atrophy in areas associated with motor and cognitive functioning. PMID- 29159059 TI - Triangulation of language-cognitive impairments, naming errors and their neural bases post-stroke. AB - In order to gain a better understanding of aphasia one must consider the complex combinations of language impairments along with the pattern of paraphasias. Despite the fact that both deficits and paraphasias feature in diagnostic criteria, most research has focused only on the lesion correlates of language deficits, with minimal attention on the pattern of patients' paraphasias. In this study, we used a data-driven approach (principal component analysis - PCA) to fuse patient impairments and their pattern of errors into one unified model of chronic post-stroke aphasia. This model was subsequently mapped onto the patients' lesion profiles to generate the triangulation of language-cognitive impairments, naming errors and their neural correlates. Specifically, we established the pattern of co-occurrence between fifteen error types, which avoids focussing on a subset of errors or the use of experimenter-derived methods to combine across error types. We obtained five principal components underlying the patients' errors: omission errors; semantically-related responses; phonologically-related responses; dysfluent responses; and a combination of circumlocutions with mixed errors. In the second step, we aligned these paraphasia-related principal components with the patients' performance on a detailed language and cognitive assessment battery, utilising an additional PCA. This omnibus PCA revealed seven unique fused impairment-paraphasia factors: output phonology; semantics; phonological working memory; speech quanta; executive-cognitive skill; phonological (input) discrimination; and the production of circumlocution errors. In doing so we were able to resolve the complex relationships between error types and impairments. Some are relatively straightforward: circumlocution errors formed their own independent factor; there was a one-to-one mapping for phonological errors with expressive phonological abilities and for dysfluent errors with speech fluency. In contrast, omission type errors loaded across both semantic and phonological working memory factors, whilst semantically-related errors had the most complex relationship by loading across four factors (phonological ability, speech quanta, executive-cognitive skills and circumlocution-type errors). Three components had unique lesion correlates: phonological working memory with the primary auditory region; semantics with the anterior temporal region; and fluency with the pre-central gyrus, converging with existing literature. In conclusion, the data-driven approach allowed derivation of the triangulation of deficits, error types and lesion correlates in post-stroke aphasia. PMID- 29159058 TI - Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease. AB - The relationships between beta-amyloid (Abeta), tau and neurodegeneration within Alzheimer's Disease pathogenesis are not fully understood. To explore these associations in vivo, we evaluated 30 Abeta PET-positive patients (mean +/- sd age 62.4 +/- 8.3) with mild probable AD and 12 Abeta PET-negative healthy controls (HC) (mean +/- sd age 77.3 +/- 6.9) as comparison. All participants underwent 3 T MRI, 11C-PiB (Abeta) PET and 18F-AV1451 (tau) PET. Multimodal correlation analyses were run at both voxel- and region-of-interest levels. 11C PiB retention in AD showed the most diffuse uptake pattern throughout association neocortex, whereas 18F-AV1451 and gray matter volume reduction (GMR) showed a progressive predilection for posterior cortices (p<0.05 Family-Wise Error-[FWE] corrected). Voxel-level analysis identified negative correlations between 18F AV1451 and gray matter peaking in medial and infero-occipital regions (p<0.01 False Discovery Rate-[FDR]-corrected). 18F-AV1451 and 11C-PiB were positively correlated in right parietal and medial/inferior occipital regions (p<0.001 uncorrected). 11C-PiB did not correlate with GMR at the voxel-level. Regionally, 18F-AV1451 was largely associated with local/adjacent GMR whereas frontal 11C-PiB correlated with GMR in posterior regions. These findings suggest that, in mild AD, tau aggregation drives local neurodegeneration, whereas the relationships between Abeta and neurodegeneration are not region specific and may be mediated by the interaction between Abeta and tau. PMID- 29159060 TI - Association between hippocampus volume and symptom profiles in obsessive compulsive disorder. AB - Background: The hippocampus has recently been identified to play a key role in the pathophysiology of adult obsessive-compulsive disorder (OCD). Surprisingly, there is only limited evidence regarding the potential relationships with symptom dimensions. Due to the heterogeneity of symptoms in OCD, we aimed at further examining, whether hippocampal volume differences might be related to symptom profiles instead of single symptom dimensions. Methods: In order to find out more about the potential association between clinical symptom profiles and alterations in hippocampal volume we categorized a large sample of OCD patients (N = 66) into distinct symptom profile groups using K-means clustering. In addition, hippocampal volumes of the different symptom profile groups were compared with hippocampal volumes in a sample of 66 healthy controls. Results: We found significant differences in hippocampal volume between the different symptom profile groups which remained significant after correcting for age, sex, total intracranial volume, OCI-total score, depression, medication, disease duration and scanner. The patient group characterized by overall lower symptom scores and without high symptom severity in any specific domain showed the highest hippocampal volume. Finally, the comparison with healthy controls demonstrated significantly lower hippocampal volumes in those patients whose symptom profile was characterized by a high severity of ordering and checking symptoms. Conclusions: Present results provide further confirmation for alterations in hippocampus structure in OCD and suggest that symptom profiles which take into account the multi-symptomatic character of the disorder should be given greater attention in this context. PMID- 29159061 TI - EEG coherence related to fMRI resting state synchrony in long-term abstinent alcoholics. AB - Recent work suggests that faulty co-activation or synchrony of multiple brain regions comprising "networks," or an imbalance between opposing brain networks, is important in alcoholism. Previous studies showed higher fMRI resting state synchrony (RSS) within the executive control (inhibitory control and emotion regulation) networks and lower RSS within the appetitive drive network in long term (multi-year) abstinent alcoholics (LTAA) vs. non substance abusing controls (NSAC). Our goal was to identify EEG networks that are correlated with the appetitive drive and executive function networks identified with fMRI in our previous alcohol studies. We used parallel ICA for multimodal data fusion for the 20 LTAA and 21 NSAC that had both usable fMRI and 64-channel EEG data. Our major result was that parallel ICA identified a pair of components that significantly separated NSAC from LTAA and were correlated with each other. Examination of the resting-state fMRI seed-correlation map component showed higher bilateral nucleus accumbens seed-correlation in the dorsolateral prefrontal cortex bilaterally and lower seed-correlation in the thalamus. This single component thus encompassed both the executive control and appetitive drive networks, consistent with our previous work. The correlated EEG coherence component showed mostly higher theta and alpha coherence in LTAA compared to NSAC, and lower gamma coherence in LTAA compared to NSAC. The EEG theta and alpha coherence results suggest enhanced top down control in LTAA and the gamma coherence results suggest impaired appetitive drive in LTAA. Our results support the notion that fMRI RSS is reflected in spontaneous EEG, even when the EEG and fMRI are not obtained simultaneously. PMID- 29159063 TI - Announcing Susan Kutz appointment as Co-Editor-in-Chief. PMID- 29159062 TI - Evaluation of factors influencing 18F-FET uptake in the brain. AB - PET using the amino-acid O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) is gaining increasing interest for brain tumour management. Semi-quantitative analysis of tracer uptake in brain tumours is based on the standardized uptake value (SUV) and the tumour-to-brain ratio (TBR). The aim of this study was to explore physiological factors that might influence the relationship of SUV of 18F-FET uptake in various brain areas, and thus affect quantification of 18F-FET uptake in brain tumours. Negative 18F-FET PET scans of 107 subjects, showing an inconspicuous brain distribution of 18F-FET, were evaluated retrospectively. Whole-brain quantitative analysis with Statistical Parametric Mapping (SPM) using parametric SUV PET images, and volumes of interest (VOIs) analysis with fronto parietal, temporal, occipital, and cerebellar SUV background areas were performed to study the effect of age, gender, height, weight, injected activity, body mass index (BMI), and body surface area (BSA). After multivariate analysis, female gender and high BMI were found to be two independent factors associated with increased SUV of 18F-FET uptake in the brain. In women, SUVmean of 18F-FET uptake in the brain was 23% higher than in men (p < 0.01). SUVmean of 18F-FET uptake in the brain was positively correlated with BMI (r = 0.29; p < 0.01). The influence of these factors on SUV of 18F-FET was similar in all brain areas. In conclusion, SUV of 18F-FET in the normal brain is influenced by gender and weakly by BMI, but changes are similar in all brain areas. PMID- 29159064 TI - Morphological keys to advance the understanding of protostrongylid biodiversity in caribou (Rangifer spp.) at high latitudes. AB - The Protostrongylidae is a diverse family of nematodes capable of causing significant respiratory and neuromuscular disease in their ungulate and lagomorph hosts. Establishing the species diversity and abundance of the protostrongylid fauna has been hindered because the first stage larvae, commonly referred as dorsal spined larvae (DSL), that are shed in the feces are morphologically very similar among several genera. We aimed to determine the protostrongylid diversity and distribution in caribou (Rangifer tarandus groenlandicus and R. t. pearyi) in the central and high Canadian Arctic. We first developed, tested and validated a morphological diagnostic guide for the DSL of two important protostrongylids, Parelaphostrongylus andersoni and Varestrongylus eleguneniensis, and then applied this guide to determine the prevalence and intensity of infection of these parasites in fecal samples from 242 caribou. We found that DSL of V. eleguneniensis and P. andersoni can be differentiated morphologically based on the structural differences at the caudal extremity. The presentation and morphology of the dorsal spine, and caudoventral bulging at the start of the tail extension were identified as the key identifying features. The two species were found in caribou on the arctic mainland and southern Victoria Island in single and co-infections, but the prevalence and intensity of infection was low. No protostrongylids were detected in caribou from the high arctic islands. Through this study, we provide a simple, efficient, and robust method to distinguish the DSL of the two protostrongylids, and present the current status of infection in different herds of caribou of the central Canadian Arctic. We report new geographic and host records for P. andersoni infection in Dolphin and Union caribou herd. PMID- 29159065 TI - Train of four stimulation artifact mimicking a seizure during computerized automated ICU EEG monitoring. AB - A 54-year-old man was admitted to the intensive care unit with an aneurysmal subarachnoid hemorrhage and subsequently underwent mechanical ventilation and received neuromuscular blocking drugs to control refractory elevated intracranial pressure. During quantitative EEG monitoring, an automated alert was triggered by the train of four peripheral nerve stimulation artifacts. Real-time feedback was made possible due to remote monitoring. This case illustrates how computerized, automated artificial intelligence algorithms can be used beyond typical seizure detection in the intensive care unit for remote monitoring to benefit patient care. PMID- 29159067 TI - Poor neurologic outcomes after cardiac arrest; a spectrum with individual implications. PMID- 29159066 TI - Six adult patients with septo-optic dysplasia and drug-resistant epilepsy: Clinical findings and course. AB - Septo-optic dysplasia (SOD) is a rare disorder associated with optic nerve hypoplasia, pituitary abnormalities and agenesis/dysgenesis of midline brain structures including the septum pellucidum and corpus callosum. Though sometimes associated with drug-resistant epilepsy, this association has not been well studied. We report six SOD patients with associated malformation of cortical development (MCD) and drug-resistant epilepsy who underwent video-EEG telemetry at our centre between 1998 and 2016 for drug-resistant epilepsy. ?Three then underwent surgery; right temporal neocortical resection, right functional hemispherectomy and placement of a vagus nerve stimulator. Clinical findings and the patients' ultimate courses are discussed. PMID- 29159068 TI - Transcriptome analysis of the Chinese giant salamander (Andrias davidianus) using RNA-sequencing. AB - The Chinese giant salamander (Andrias davidianus) is an economically important animal on academic value. However, the genomic information of this species has been less studied. In our study, the transcripts of A. davidianus were obtained by RNA-seq to conduct a transcriptomic analysis. In total 132,912 unigenes were generated with an average length of 690 bp and N50 of 1263 bp by de novo assembly using Trinity software. Using a sequence similarity search against the nine public databases (CDD, KOG, NR, NT, PFAM, Swiss-prot, TrEMBL, GO and KEGG databases), a total of 24,049, 18,406, 36,711, 15,858, 20,500, 27,515, 36,705, 28,879 and 10,958 unigenes were annotated in databases, respectively. Of these, 6323 unigenes were annotated in all database and 39,672 unigenes were annotated in at least one database. Blasted with KEGG pathway, 10,958 unigenes were annotated, and it was divided into 343 categories according to different pathways. In addition, we also identified 29,790 SSRs. This study provided a valuable resource for understanding transcriptomic information of A. davidianus and laid a foundation for further research on functional gene cloning, genomics, genetic diversity analysis and molecular marker exploitation in A. davidianus. PMID- 29159069 TI - Co-expression network analysis identified six hub genes in association with progression and prognosis in human clear cell renal cell carcinoma (ccRCC). AB - Human clear cell renal cell carcinoma (ccRCC) is one of the most common types of malignant adult kidney tumors. We constructed a weighted gene co-expression network to identify gene modules associated with clinical features of ccRCC (n = 97). Six hub genes (CCNB2, CDC20, CEP55, KIF20A, TOP2A and UBE2C) were identified in both co-expression and protein-protein interaction (PPI) networks, which were highly correlated with pathologic stage. The significance of expression of the hub genes in ccRCC was ranked top 4 among all cancers and correlated with poor prognosis. Functional analysis revealed that the hub genes were significantly enriched in cell cycle regulation and cell division. Gene set enrichment analysis suggested that the samples with highly expressed hub gene were correlated with cell cycle and p53 signaling pathway. Taken together, six hub genes were identified to be associated with progression and prognosis of ccRCC, and they might lead to poor prognosis by regulating p53 signaling pathway. PMID- 29159070 TI - Primary cytomegalovirus infection in immunocompetent adults in the United States A case series. AB - Primary Cytomegalovirus (CMV) infection is often not suspected as a cause of fever of unknown origin (FUO) in immune-competent adults. We present a case series of symptomatic primary CMV infection in immunocompetent adults presenting as fever of unknown origin (FUO). All patients with CMV serology tested between November 2008 and June 2016 underwent chart review. Cases were defined as those between 18 and 65 years of age with documented fever and elevated serum anti-CMV IgM. Exclusion criteria were organ specific CMV disease, positive serum anti-EBV IgM, or presence of any immunocompromising condition. Sixteen patients (69% male, mean age 42.2 +/- 11.7 years) met criteria. Mean duration of illness was 4.6 +/- 3.3 weeks. Common symptoms other than fever included fatigue (94%), night sweats (81%), malaise (75%), myalgias (63%), and headache (56%). Eleven patients (68.8%) had contact with young children; six (35.3%) patients had children in daycare. Twelve (75%) patients had extensive testing and multiple visits or hospitalizations prior to consulting with an infectious disease specialist. Peripheral smear was done in twelve (75%) patients and all had atypical lymphocytes. Five patients (31.3%) had a leukocytosis. Peak serum transaminases were: AST 115.25 +/- 50.5 IU/L and ALT 168.38 +/- 92.0 IU/L. One patient had splenic infarcts. In addition, two cases of hydrops fetalis were attributed to primary CMV infection. In summary, primary CMV infection can present as FUO in immunocompetent adults. Contact with young children in daycare may be a risk factor. Heightened clinical suspicion will promote earlier diagnosis and avoid unnecessary testing. PMID- 29159071 TI - First case report of infection caused by Cupriavidus gilardii in a non immunocompromised Chinese patient. AB - Cupriavidus gilardii was first identified as an aerobic, gram-negative, glucose nonfermenting rod. C. gilardii has been characterized as an organism with low pathogenicity that causes opportunistic infections and few case reports of infection caused by this organism previously. We encountered the first case of bloodstream infection caused in China by C. gilardii in a 87-year old man without obvious immunodeficiency. The isolate were identified as C. gilardii by 16S rRNA sequencing. The infected patient was treated according to the laboratory's antibiogram of this strain. Similar to the case report in Japan, this is the second report of an infection caused by this organism without obvious immunodeficiency, suggesting that C. gilardii exerts its pathogenicity both in immunodeficient and immunocompetent hosts. PMID- 29159072 TI - Adult retropharyngeal abscess. PMID- 29159073 TI - Home infusion with Elosulfase alpha (VimizimR) in a UK Paediatric setting. AB - Enzyme replacement therapy is the only available treatment for Mucopolysaccharidosis type IVA (MPS IVA, Morquio syndrome). The treatment is lengthy and invasive involving weekly intravenous infusions of 4-5 h. This can cause significant disruption to normal family life so the provision of a safe and effective homecare service is essential. In order to deliver a safe service, robust standards must be in place; this includes appropriately trained members of homecare staff, detailed management for infusion related reactions (IRR) and appropriate venous access. In this report we demonstrate the criteria required to ensure a successful home treatment programme and describe our experience thus far. PMID- 29159074 TI - Only some patients with bulbar and spinal muscular atrophy may develop cardiac disease. AB - Objectives: According to recent publications, some patients with spinal and bulbar muscular atrophy (BSMA) develop cardiac disease, manifesting as ST-segment abnormalities, Brugada-syndrome, dilative cardiomyopathy, or sudden cardiac death. Here we present neurological and cardiac data of a BSMA patient who was followed up for 10 y. Case report: In a male patient aged 47 y, BSMA was diagnosed at age 37 y upon the typical clinical presentation (postural tremor since age 12 y, dysarthria since age 15 y, muscle cramps since age 29 y, general myalgias since age 32 y, general fasciculations since age 34 y, myoclonic jerks, easy fatigability, dyspnea upon exercise since age 36 y) and a CAG-repeat expansion of 47 +/- 1 repeats in the androgen-receptor gene detected at age 37 y. During the next 10 y he additionally developed mild but slowly progressive diffuse weakness on the upper limbs and mild proximal weakness on the lower limbs. Cardiologic exam, ECG, and echocardiography were normal at ages 37 y, 41 y, 44 y, and 47 y. Conclusions: Cardiac involvement may only develop in some BSMA patients within 10 y, whereas neurologic abnormalities slowly progress within 10 y of observation. Cardiac disease may develop at a later stage with progression of age and disease. PMID- 29159075 TI - Enzyme replacement therapy in perinatal hypophosphatasia: Case report of a negative outcome and lessons for clinical practice. AB - Enzyme replacement therapy (ERT) is a newly approved disease-modifying treatment for hypophosphatasia (HPP), a rare metabolic bone disorder. With an orphan drug and ultra-rare disease, sharing information about responders and non-responders is particularly important, as any one centre's familiarity with its use will be limited. Nearly all published data in infants and very young children with life threatening HPP are from three small clinical trials that have reported generally positive outcomes. We describe in detail a patient with perinatal HPP for whom treatment with ERT was not successful. Lessons learned from this case can inform clinical decision-making and provide topics for the research agenda. We also discuss practical and ethical challenges related to treatment of an ultra-rare disease with an expensive new medication in a publicly funded healthcare system. PMID- 29159076 TI - Parkinson's disease prevalence in Fabry disease: A survey study. AB - Recent research has suggested a possible link between Parkinson's disease (PD) and Fabry disease. To test this relationship, we administered a self-report and family history questionnaire to determine the prevalence of PD in Fabry disease patients and family members with likely pathogenic alpha-galactosidase A (GLA) mutations. A total of 90 Fabry patients (77 from the online survey and 13 from the Icahn School of Medicine at Mount Sinai (ISMMS)) were included in the analysis. Two of the Fabry disease patients who completed the online survey were diagnosed with PD (2/90, 2.2%). Among probands older than 60, 8.3% (2/24) were diagnosed with PD. Using Kaplan Meier survival analysis, the age-specific risk of PD by age 70 was 11.1%. Family history was available on 72 Fabry families from the online study and 9 Fabry families from ISMMS. Among these 81 families, 6 (7.4%) had one first degree relative who fit the criteria for a conservative diagnosis of PD. The results of this study suggest that there may be an increased risk of developing PD in individuals with GLA mutations, but these findings should be interpreted with caution given the limitations of the study design. PMID- 29159077 TI - Long-term outcomes with agalsidase alfa enzyme replacement therapy: Analysis using deconstructed composite events. AB - This is a retrospective analysis of Fabry Outcome Survey data from children/adults (n = 677) receiving agalsidase alfa enzyme replacement therapy for a median of 3 years, examining cerebrovascular, cardiac, and renal morbidity endpoints separately. Cardiac events occurred at younger ages than cerebrovascular or renal events, cerebrovascular events were more frequent in females than males, and males were more likely to experience cardiac and renal events at a younger age than females. PMID- 29159078 TI - Conservative surgery using scrotal skin for invasive penile carcinoma: Case report and brief review of the literature. PMID- 29159079 TI - Translational Research in Endocrinology. PMID- 29159080 TI - Efficacy and safety of the glucagon-like peptide-1 receptor agonist lixisenatide versus the dipeptidyl peptidase-4 inhibitor sitagliptin in young (<50 years) obese patients with type 2 diabetes mellitus. AB - Objective: To compare the efficacy and safety of the once-daily prandial glucagon like peptide-1 receptor agonist lixisenatide with the dipeptidyl peptidase-4 inhibitor sitagliptin in patients aged <50 years affected by obesity and type 2 diabetes mellitus (T2DM). Materials and methods: This was a 24-week, double blind, randomized, parallel-group study. Obese patients with T2DM inadequately controlled on metformin were randomized to lixisenatide 20 MUg once-daily injection (n = 158) or once-daily oral sitagliptin 100 mg (n = 161). The primary endpoint was the proportion of patients with a glycated hemoglobin (HbA1c) <7% and >=5% weight loss at 24 weeks. Results: The proportion of patients that achieved the primary endpoint was 12.0% for lixisenatide versus 7.5% for sitagliptin; weighted average of proportion difference: 4.6%, p = 0.1696). A total of 40.7% of patients achieved HbA1c <7% with lixisenatide versus 40.0% with sitagliptin. Lixisenatide produced greater reductions in body weight (LS mean difference: -1.3 kg, p = 0.0006) and postprandial plasma glucose after a standardized meal test (LS mean difference: -34.4 mg/dL [-1.9 mmol/L], p = 0.0001) versus sitagliptin. There was a similar incidence of treatment-emergent adverse events (63.9% vs. 60.9%) and serious treatment-emergent adverse events (1.9% vs. 1.9%), with low rates of symptomatic hypoglycemia (0.6% vs. 1.9%) for lixisenatide and sitagliptin, respectively, and no cases of severe hypoglycemia. Conclusion: In obese patients aged <50 years with T2DM, the proportion of patients with an HbA1c <7% with weight loss >=5% was similar between groups. Lixisenatide, however, resulted in significantly greater reductions in body weight and postprandial plasma glucose excursions than sitagliptin. Tolerability was similar between groups. PMID- 29159081 TI - May diabetes patients have trouble sleeping despite not having obesity? AB - Obstructive sleep apnea (OSA) and periodic limb movements during sleep (PLMs) are sleep-related disorders with a high prevalence in type 2 diabetes. Commonly OSA is considered as a consequence of obesity, but several previous studies have shown the presence of OSA in non-obese diabetic patients. A previous study showed higher PLMs prevalence in patients with type 2 diabetes, compared to age-matched controls. We speculated that both OSA and PLMs may reflect the presence of diabetic autonomic neuropathy. To test this hypothesis, we compared a group of 112 non-obese patients with type 2 diabetes with 66 age-, sex-, and body mass index- matched nondiabetic patients. Both groups have been investigated through a set of tests including the Epworth Sleepiness Scale, polysomnography, and the Orthostatic Grading Scale (OGS), a questionnaire to assess the degree of autonomic dysfunction. Diabetic patients with OSA and PLMs scored higher on the OGS than controls. Our results confirm that both OSA and PLMs are related to dysautonomy and may be unrelated to obesity in type 2 diabetes patients. PMID- 29159082 TI - Longitudinal associations between lymphocyte count and LDL cholesterol in a health screening population. AB - Background: Longitudinal associations between leukocyte subtype counts and LDL cholesterol have not been reported. Methods and Results: This is a retrospective observational study in a health screening population. Spearman's correlation coefficients were calculated between leukocyte subtype counts and LDL cholesterol levels at baseline and after four years. Using Cox regression models, hazard ratios (HRs) of hyper-LDL cholesterolemia for leukocyte subtype counts during four years of follow-up were calculated adjusted for age, sex, high-sensitivity C reactive protein (hs-CRP) and other confounders. Spearman's correlation coefficients (p values) between changes in counts of neutrophil, lymphocyte, monocyte, basophil and eosinophil and changes in LDL cholesterol levels through 4 years were 0.02 (0.494), 0.12 (<0.001), 0.06 (0.016), 0.02 (0.524) and 0.03 (0.257), respectively among 1735 subjects who visited our medical check-up center, did not use anti-hyperlipidemic drugs and revisited after 4 years. Among 1992 followed subjects, 481 developed hyper-LDL cholesterolemia during four years (60.4 per 1000 person-years). The HRs (95% confidence intervals; p values) of hyper-LDL cholesterolemia for each one SD increase in counts of neutrophil, lymphocyte, monocyte, basophil and eosinophil were 1.08 (0.99-1.19; 0.085), 1.14 (1.04-1.25; 0.005), 1.05 (0.95-1.15; 0.339), 1.01 (0.92-1.11; 0.858) and 1.04 (0.95-1.14; 0.397), respectively. Conclusions: Lymphocyte count and LDL cholesterol were longitudinally positively correlated and lymphocyte count was associated with incidence of hyper-LDL cholesterolemia independently of hs-CRP in a health screening population. PMID- 29159083 TI - Efficacy and safety of twice-daily treatment with canagliflozin, a sodium glucose co-transporter 2 inhibitor, added on to metformin monotherapy in patients with type 2 diabetes mellitus. AB - Aim: To evaluate the efficacy/safety of canagliflozin twice daily (BID) compared with placebo in patients with type 2 diabetes mellitus (T2DM) on metformin. Methods: In this 18-week, randomized, double-blind, placebo-controlled study, patients (N = 279) at 60 centers in 7 countries received canagliflozin 50 or 150 mg or placebo BID. The pre-specified primary endpoint was change from baseline in HbA1c at Week 18. Pre-specified secondary endpoints included proportion of patients reaching HbA1c <7.0%, change in fasting plasma glucose (FPG), and percent change in body weight; changes in systolic blood pressure (BP) and fasting plasma lipids were also evaluated. Adverse events (AEs) were recorded throughout the study. Results: From a mean baseline HbA1c of 7.6% (60 mmol/mol), canagliflozin 50 and 150 mg BID significantly reduced HbA1c compared with placebo at Week 18 (-0.45%, -0.61%, -0.01% [-5, -7, -0.1 mmol/mol], respectively; P < 0.001). More patients achieved HbA1c <7.0% with canagliflozin than placebo (P < 0.05). Relative to placebo, both canagliflozin doses significantly lowered FPG and body weight (P < 0.001), and reduced systolic BP. Overall AE incidence was 35.5%, 40.9%, and 36.6% with canagliflozin 50 and 150 mg BID and placebo, respectively. Canagliflozin was associated with increased incidences of urinary tract infections, female genital mycotic infections, and osmotic diuresis-related AEs; these led to few discontinuations. The incidence of documented hypoglycemia was low across groups. Conclusions: Canagliflozin 50 and 150 mg BID provided significant glycemic efficacy and body weight reduction, and were generally well tolerated in patients with T2DM on background metformin.ClinicalTrials.gov Identifier: NCT01340664. PMID- 29159084 TI - Current controversies in turner syndrome: Genetic testing, assisted reproduction, and cardiovascular risks. AB - Patients with Turner syndrome (TS) require close medical follow-up and management for cardiac abnormalities, growth and reproductive issues. This review summarizes current controversies in this condition, including: 1) the optimal genetic testing for Turner syndrome patients, particularly with respect to identification of Y chromosome material that may increase the patient's risk of gonadoblastoma and dysgerminoma, 2) which patients should be referred for bilateral gonadectomy and the recommended timing of such referral, 3) options for assisted reproduction in these patients and associated risks, 4) the increased risk of mortality associated with pregnancy in this population, and 5) how best to assess and monitor cardiovascular risks. PMID- 29159085 TI - Autoimmune response to AGE modified human DNA: Implications in type 1 diabetes mellitus. AB - Aims: Non-enzymatic glycation of DNA both in vivo and in vitro results in generation of free radicals, known as glycoxidation. Glycoxidation leads to structural perturbation of DNA resulting in generation of neo-antigenic epitopes having implication in autoimmune disorders like diabetes mellitus. In this study human placental DNA was glycated with methylglyoxal (MG) and lysine (Lys) in the presence of Cu2+ and its auto-antibody binding was probed in Type 1 diabetes patients. Methods: Glycation was carried out by incubating DNA with MG, Lys and Cu2+ for 24 h at 37 degrees C. Carboxyethyl deoxyguanosine (CEdG) formed in glycation reaction was studied by LC-MS and the pathway for Amadori formation was studied by ESI-MS techniques. Furthermore, binding characteristics of auto antibodies in diabetes patients were assessed by direct binding, competitive ELISA and band shift assay. Results: DNA glycation with MG, Lys and Cu2+ results in the formation of CEdG (marker of DNA glycation) which was confirmed by LC-MS. The intermediate stages of glycation were confirmed by ESI-MS technique. Serum from diabetes patients exhibited enhanced binding and specificity for glycated DNA as compared to native form. Conclusions: Glycation of DNA has resulted in structural perturbation causing generation of neo-antigenic epitopes thus recognizing auto-antibodies in diabetes. PMID- 29159086 TI - Stigma of obesity: A major barrier to overcome. PMID- 29159087 TI - Factors associated with a diabetes diagnosis and late diabetes diagnosis for males and females. AB - Aims: To examine the factors associated with diabetes, a late diabetes diagnosis, and whether these factors are different for males and females. Methods: Cross sectional study including 7101 individuals aged >=25 years in Newfoundland and Labrador, Canada (466 with diabetes; 332 diagnosed late). Logistic regression analysis was used to determine the factors associated with a diabetes diagnosis and late diabetes diagnosis. Results: For males, overweight/obesity (HR, 1.35; 95% CI, 1.06-1.72) was positively associated with diabetes while being a regular/occasional drinker (HR, 0.53; 95% CI, 0.32-0.88) was inversely associated with diabetes. Living in a rural area (HR, 1.47; 95% CI, 1.01-2.15), receiving social assistance (HR, 2.80; 95% CI, 1.52-5.15), having poor self perceived health (HR, 2.06; 95% CI, 1.32-3.21), and considering most days stressful (HR, 1.45; 95% CI, 1.01-2.10) were positively associated with diabetes for females. No factors were significantly associated with a late diabetes diagnosis for males. Having a low education (OR, 0.33; 95% CI, 0.11-0.99) was inversely associated with a late diabetes diagnosis for females. Conclusions: Different factors are associated with diabetes for males and females. Disadvantaged females appear to be at the greatest risk. The factors associated with a late diabetes diagnosis were also different for males and females. Females with lower education levels are diagnosed with diabetes earlier than females with higher education levels. Certain risk factors appear to impact males and females differently and more research is needed on how males and females develop diabetes and when they are diagnosed. PMID- 29159088 TI - Metabolic bone disease of prematurity. AB - Metabolic bone disease (MBD) of prematurity remains a significant problem for preterm, chronically ill neonates. The definition and recommendations for screening and treatment of MBD vary in the literature. A recent American Academy of Pediatrics Consensus Statement may help close the gap in institutional variation, but evidence based practice guidelines remain obscure due to lack of normative data and clinical trials for preterm infants. This review highlights mineral homeostasis physiology, current recommendations in screening and monitoring, prevention and treatment strategies, and an added perspective of a bone health team serving a high volume referral neonatal intensive care center. PMID- 29159089 TI - Noninvasive skin fluorescence spectroscopy for detection of abnormal glucose tolerance. AB - The ENGINE study evaluated noninvasive skin fluorescence spectroscopy (SFS) for detection of abnormal glucose tolerance (AGT). The AGT detection performance of SFS was compared to fasting plasma glucose (FPG) and hemoglobin A1C (A1C). The study was a head-to-head comparison of SFS to FPG and A1C in an at-risk population of 507 subjects, with no prior diagnosis of diabetes, each of whom received a 75 g, two-hour oral glucose tolerance test (OGTT). Subjects were measured by SFS on multiple days in fasting and non-fasting states. SFS data were acquired and analyzed with the SCOUT DS(r) device (VeraLight, Albuquerque, NM, USA). Disease truth was AGT, defined as OGTT >= 7.8 mmol/L. Sensitivity, false positive rate (FPR), ROC area, and equal error rate (EER) for detection of AGT were computed. The reproducibility of SFS and FPG was assessed. The AGT sensitivity of SFS at the device's recommended screening threshold of 50 was 75.2%, higher than that of FPG (thresholds of 5.6 mmol/L or 6.1 mmol/L) and A1C (thresholds of 5.7% or 6.0%). The SFS FPR was 42.1%, comparable to an A1C threshold of 5.7% (FPR = 43.5%). The EERs of SFS, FPG and A1C were similar, as were the partial ROC areas for FPRs of 20-50%. The reproducibility of SFS was 7.7% versus 8.1% for FPG. SFS had similar AGT detection performance to FPG and A1C and is a viable alternative to screening individuals for AGT. PMID- 29159090 TI - Patient and parent perceptions of the diagnosis and management of cystic fibrosis related diabetes. AB - Background: Cystic Fibrosis Related Diabetes (CFRD) is an increasingly common complication in CF. CFRD introduces an additional complex chronic disease to individuals already attending to demanding treatment regimens. An improved understanding of the reaction to and coping mechanisms surrounding CFRD may facilitate management of CFRD. Methods: Semi-structured interviews completed by 10 children with CFRD, 10 adults with CFRD and 10 parents of children with CFRD in a single large CF Care Center were analyzed utilizing phenomenological analysis. Results: Patients and families reported having limited knowledge of CFRD prior to diagnosis. CFRD was considered an extension of their underlying CF and successful management depended upon integration into existing routines. Conclusions: Health care professionals caring for patients with CFRD should be informed of the specific challenges that arise in CFRD. Education in advance of CFRD diagnosis may facilitate management. PMID- 29159091 TI - Influence of aerobic exercise training on cardiovascular and endocrine inflammatory biomarkers in hypertensive postmenopausal women. AB - Given that few studies have examined the interaction between endocrine inflammatory mediators and aerobic exercise training in hypertensive postmenopausal women, the aim of this study was to investigate whether aerobic exercise training (AET) for twenty-four sessions would alter cortisol, leptin and interleukin-1beta (IL-1beta) levels. To further analyze endothelium function in response to AET, we also examined redox state as well as NO/cGMP pathway in this population. Eighteen hypertensive postmenopausal women finished this study. AET program consisted of 24 sessions in treadmill, 3 times per week, duration of 30 up to 40 min for each session, for 8 weeks at intensity of 100% of the MLSS according to previous incremental test. Heart rate was monitored in all studied time (resting and during exercise sessions). After 48 h of the last exercise session, blood samples were collected for biochemical analyses (levels of cortisol, leptin, IL-1beta, nitrite/nitrate (NOx-), cGMP, malondialdehyde (MDA) and asymmetric dimethylarginine (ADMA); superoxide and catalase activity). We also measured systolic and diastolic blood pressure. A significant reduction in body mass was observed. As expected, systolic and diastolic blood pressure values were significantly reduced after AET in hypertensive women. We also found a marked increase in NOx- levels as well as cGMP concentration in trained women, approximately 37.7 and 30.8%, respectively. No changes in cortisol, leptin, ADMA and IL-1beta levels were observed after AET. Similarly, MDA levels and catalase activity were not affected by AET. In contrast, a marked increase in SOD activity was found (86.6%). In conclusion, our findings show that aerobic exercise training for twenty-four sessions promoted a significant reduction in blood pressure by activating NO/cGMP pathway as well as by promoting an up-regulation of SOD activity without changing in cortisol/leptin levels in postmenopausal hypertensive women. PMID- 29159092 TI - Discriminatory metabolic and inflammatory parameters in serum and omental adipose tissue of obese patients with different insulin sensitivity. AB - Objective: Metabolically healthy obese phenotype is defined by high insulin sensitivity and lack of metabolic syndrome, parameters regulated by omental adipose tissue inflammation, ectopic fat deposition and adipose tissue dysfunction. Our study aimed to identify novel metabolic and inflammatory markers in serum and omental adipose tissue which characterize the "unhealthy" obese patients and distinguish them from obese patients with better metabolic profile. Design: Cross-sectional study. Patients: Subjects included 75 obese patients undergoing bariatric surgery at the Tel-Aviv Medical Center (mean age 43.9 +/- 13.9, mean BMI 41 +/- 8.4). The HOMA median value was used as a cut-off to differentiate between patients with better or worse insulin resistance. Measurements: Demographic data, fasting serum insulin, glucose, bile acids, serum metabolic and inflammatory markers were obtained. During the bariatric surgery, omental adipose tissue was harvested and analyzed for metabolic and inflammatory markers using qRT-PCR. Logistic regressions were used to calculate odds ratio and 95% confidence interval for the prediction of the metabolic profile. Results: Serum markers that were significantly higher among the obese with HOMA >6 were total bile acids. In the omental adipose tissue the inflammatory markers TNFalpha and ADAM17 were significantly higher among obese patients with HOMA >6. In multivariate analysis, the strongest predictor for insulin resistance was ADAM17 (OR = 1.82, 1.06-3.14, P = 0.031). Conclusions: The study highlighted the predictive value of serum bile acids in identifying obese patients at high risk. Secondly, omental adipose tissue ADAM17 was revealed as a novel and strongest independent predictor for higher insulin resistance in morbidly obese patients. PMID- 29159093 TI - Comparison of plantar pressure in three types of insole given to patients with diabetes at risk of developing foot ulcers - A two-year, randomized trial. AB - Background: Special insoles and shoes designed to prevent foot ulcers caused by repetitive high pressures are recommended for patients with diabetes who have any of the following risk factors: neuropathy; peripheral vascular disease; foot deformities; previous ulcers; amputation; and skin pathologies. However, there is a need for increased knowledge regarding: a) differences in the peak pressure (PP) and pressure time integral (PTI) for different types of insoles; and b) the properties of the pressure distribution for insoles used over a period of several months. We present the results of a randomized trial to compare the plantar pressures of three commonly used insoles. Objectives: The primary objective was to compare the PP and PTI between three types of insoles. The secondary objective was to explore the long-term pattern of peak plantar pressure distribution and variations in specific regions of interest (ROI). The tertiary objective was to investigate the impacts of insole adjustments, how much the insoles were used, and the levels of patient satisfaction. Methods: In a 2-year trial, 114 patients with type 1 (N = 31) or type 2 (N = 83) diabetes (62 men and 52 women; mean age, 57.7 +/- 15.4 years; duration of diabetes, 12.3 +/- 11.2 years; neuropathy, 38%), were randomized to be supplied with one of three different insoles. The ethylene vinyl acetate (EVA) insoles were used in outdoor walking shoes. The 35 EVA group (N = 39) received soft custom-made insoles composed of EVA of 35 shore A hardness, the 55 EVA group (N = 37) received custom-made insoles composed of EVA of 55 shore hardness, and the control group (N = 38) received prefabricated insoles composed of a hard core with a top layer of soft 12 shore hardness microfiber. Using F-Scan(r), the in-shoe plantar pressures were measured at seven ROI (hallux, metatarsal head 1, metatarsal head 2, metatarsal head 4, metatarsal head 5, lateral aspect of the mid-foot, heel) on five occasions during the study period. The plantar-pressure variables used were PP (main outcome) and PTI. The plantar patterns of load were explored, satisfaction and usage of the insoles were rated by the participants, and insole adjustments were recorded. Results: A mixed model analysis estimated lower PP values in the heel regions for the 35 EVA and 55 EVA insoles (171 +/- 13 and 161 +/- 13 kPa, respectively) than for the prefabricated insoles (234 +/- 10 kPa) (p < 0.001). Also for some of the other six ROI indications of difference in PP or PTI could be observed. The redistribution of peak plantar pressure for all of the insoles, was stable at the mid-foot, while the proportion of load on the distal area changed during the study period According to the self-reported answers (scale, 0-100), the average usage of the insoles was rated as 79 and satisfaction was rated as 85 (N = 75). Thirty-two percent of the subjects had not received foot care. Fourteen adjustments to insoles were made during the study period, and 86 pairs of insoles were exchanged due to wear, with 49% being exchanged in the 35 EVA group. Conclusions: Custom-made insoles used in combination with stable walking shoes gave lower pressures at the heel region. The variation makes it difficult to detect a systematic difference in plantar pressure for the 6 ROI, if such a difference indeed exists. The levels of satisfaction and usage for all the insoles tested were high. The insoles maintained their pressure redistribution properties over long periods, and few adjustments were needed. PMID- 29159094 TI - The value of neck circumference (NC) as a predictor of non-alcoholic fatty liver disease (NAFLD). AB - Aims: To analyze the correlation between neck circumference (NC) and non alcoholic fatty liver disease (NAFLD) and compare the predictive value of NC for NAFLD with that of other simple anthropometric measures and other biochemical profiles. Methods: 2761 subjects, undergoing a medical check-up at the Changhai Hospital between October 01, 2012 and November 30, 2012, were recruited to the study. NC, other simple anthropometric measures, and biochemical profiles were analyzed. Results: NC in NAFLD subjects with or without elevated ALT were 38.94 +/- 2.62 cm and 37.21 +/- 3.06 cm respectively, which was significantly higher than that in subjects with other metabolic disorders (NC: 35.33 +/- 3.03 cm) and in normal controls (NC: 32.60 +/- 2.37) (both P < 0.001). NC in women with NAFLD increased by 1 cm and fasting insulin (FINS) and homeostasis model assessment insulin resistance (HOMA-IR) increased by 1.87 mIU/L and 1.43, respectively. Compared with other anthropometric measures, neck circumference-height ratio (NHtR) had a significant impact both on the incidence of NAFLD. After adjustment for sex, abdominal obesity and other influencing factors, the incidence of NAFLD still tended to positively correlate with NC. Optimal cut-off points of NC and NHtR for predicting NAFLD in males were 37.25 cm and 0.224, respectively, and such points in females were 32.90 cm and 0.208, respectively. Conclusion: NC was wider in NAFLD patients than in healthy subjects and other metabolic disorder sufferers. NC and NHtR could be used as simple predictive tools for NAFLD. PMID- 29159095 TI - Optimizing insulin injection technique and its effect on blood glucose control. AB - Purpose: The purpose of the study is to assess whether proper Injection Technique (IT) is associated with improved glucose control over a three month period. Methods: Patients (N = 346) with diabetes from 18 ambulatory centers throughout northern Italy who had been injecting insulin >= four years answered a questionnaire about their IT. The nurse then examined the patient's injection sites for the presence of lipohypertrophy (LH), followed by an individualized training session in which sub-optimal IT practices highlighted in the questionnaire were addressed. All patients were taught to rotate sites correctly to avoid LH and were begun on 4 mm pen needles to avoid intramuscular (IM) injections. They were instructed not to reuse needles. Results: Nearly 49% of patients were found to have LH at study entry. After three months, patients had mean reductions in HbA1c of 0.58% (0.50%-0.66%, 95% CI), in fasting blood glucose of 14 mg/dL (10.2-17.8 mg/dL, 95% CI) and in total daily insulin dose of 2.0 IU (1.4-2.5 IU, 95% CI) all with p < 0.05. Follow-up questionnaires showed significant numbers of patients recognized the importance of IT and were performing their injections more correctly. The majority found the 4 mm needle convenient and comfortable. Conclusions: Targeted individualized training in IT, including the switch to a 4 mm needle, is associated with improved glucose control, greater satisfaction with therapy, better and simpler injection practices and possibly lower consumption of insulin after only a three month period. PMID- 29159096 TI - Use of an integrated strip-free blood glucose monitoring system increases frequency of self-monitoring and improves glycemic control: Results from the ExAct study. AB - Aims: We investigated the impact of using an integrated, strip-free system compared to the use of single-strip systems on testing frequency and glycemic control in individuals with insulin-treated diabetes. Methods: This multinational, comparative, cluster-randomized, observational study included 311 patients with type 1 and insulin-treated type 2 diabetes who were performing SMBG at suboptimal frequencies. Sites were cluster-randomized to "integrated strip free" system (EXP group) or any "single-strip" system (CNL group). Testing frequency and HbA1c were measured at baseline, 12 weeks and 24 weeks. Results: At week 24, the EXP group showed an increase in SMBG frequency from baseline of 4.17 tests/week (95% CI 2.76, 5.58) compared with an increase of 0.53 tests/week (95% CI -0.73, 1.79) among CNL patients, resulting in a between-group difference of 3.63 tests/week (p < 0.0002). Mixed-effects models for repeated measurements (MMRM) controlling for baseline frequency of testing, country and clinical site confirmed a higher SMBG testing frequency in the EXP group compared to the CNL group, with a between-group difference of 2.70 tests/week (p < 0.01). Univariate analysis showed greater HbA1c reductions in the EXP group than CNL group: -0.44% (95% CI -0.59, -0.29) vs. -0.13% (95% CI -0.27, 0.01), respectively, p < 0.0002. MMRM analyses confirmed these HbA1c reductions. A greater percentage of EXP than CNL patients achieved HbA1c reductions of >=0.5%: 45.1% vs. 29.1%, respectively, p < 0.01. Conclusions: The use of an integrated, strip-free SMBG system improved testing adherence and was associated with improvements in glycemic control. PMID- 29159097 TI - The role of vitamin D in tuberculosis. PMID- 29159098 TI - Inpatient hyperglycemia: Clinical management needs in teaching hospital. PMID- 29159099 TI - Cancer, sunlight and vitamin D. AB - The sunshine vitamin has been associated with reduced risk for many chronic illnesses including cancer and cancer mortality. Epidemiologic and ecological studies have suggested that living at higher latitudes and having lower blood levels of 25-hydroxyvitamin D are associated with increased risk for up to 15 cancers including breast, colon, lung, lymphoma, pancreatic, ovarian and prostate cancer. Most randomized controlled trials using appropriate doses of vitamin D have suggested that improvement in vitamin D status reduces risk for several cancers. Although the exact mechanism by which enhanced vitamin D status reduces risk for cancer is not completely understood, there is evidence that by raising blood levels of 25-hydroxyvitamin D this metabolite can enter a wide variety of cells in the body and then be converted to 1,25-dihydroxyvitamin D3. The vitamin D metabolite, 1,25-dihydroxyvitamin D3, has been demonstrated to markedly reduce cellular proliferation especially of malignant cells that have a vitamin D receptor. It also induces terminal differentiation. 1,25-dihydroxyvitamin D3 is also anti-angiogenic and pro-apoptotic which also plays a role in reducing the growth and spread of malignant cells. Thus improvement in vitamin D status with sensible sun exposure, vitamin D supplementation and ingesting foods containing vitamin D is a reasonable strategy to reduce risk of malignancy. PMID- 29159100 TI - Outcomes of hospitalized diabetic foot patients in a multi-disciplinary team setting: Thailand's experience. AB - Aims: The aims of this study were to evaluate the outcomes of treatment among hospitalized patients with diabetic foot ulcers, the risk factors for non-healing ulcers, and the rate of major amputation among Thai patients. Methods: A retrospective study of hospitalized diabetic foot patients treated at Theptarin Hospital during the period of 2009-2013. The complete healing rate was assessed at 12 months after admission. Results: During the study period, 232 patients (123 males and 109 females) with 262 admissions were included (mean age 65.6 +/- 11.9 years, mean duration of diabetes 17.2 +/- 9.9 years) with a mean follow-up of 17.5 +/- 16.7 months. Major amputations were performed in 4.2% of the patients and peripheral vascular disease (PVD) was a predictive factor (OR 5.25; 95% CI [1.43-19.29]; p-value 0.006). Complete healing (including minor amputations) was achieved in 82.1% of the admissions. Only DFU of the heel was a statistically significant (OR 3.34; 95% CI [1.11-10.24]; p-value 0.041) predictor of non healing ulcers. Three patients (1.1%) died during hospitalization. Conclusions: Management of diabetes-related foot ulcers with a multidisciplinary approach resulted in a limb salvage rate that was greater than 90% and a complete healing rate that was greater than 80%. Successful management of diabetic foot ulcers might be possible in Thailand utilizing this approach. PMID- 29159101 TI - Declining beta-cell function is associated with the lack of long-range negative correlation in glucose dynamics and increased glycemic variability: A retrospective analysis in patients with type 2 diabetes. AB - Objective: To determine whether characteristics of glucose dynamics are reflections of beta-cell function or rather of inadequate diabetes control. Materials/methods: We analyzed historical liquid meal tolerance test (LMTT) and continuous glucose monitoring (CGM) data, which had been obtained from 56 non insulin treated type 2 diabetic outpatients during withdrawal of antidiabetic drugs. Computed CGM parameters included detrended fluctuation analysis (DFA) based indices, autocorrelation function exponent, mean amplitude of glycemic excursions (MAGE), glucose SD, and measures of glycemic exposure. The LMTT-based disposition index (LMTT-DI) calculated from the ratio of the area-under-the insulin-curve to the area-under-the-glucose-curve and Matsuda index was used to assess relationships among beta-cell function, glucose profile complexity, autocorrelation function, and glycemic variability. Results: The LMTT-DI was inverse linearly correlated with the short-range alpha1 and long-range scaling exponent alpha2 (r = -0.275 and -0.441, respectively, p < 0.01) such that lower glucose complexity was associated with better preserved insulin reserve, but it did not correlate with the autocorrelation decay exponent gamma. By contrast, the LMTT-DI was strongly correlated with MAGE and SD (r = 0.625 and 0.646, both p < 0.001), demonstrating a curvilinear relationship between beta-cell function and glycemic variability. On stepwise regression analyses, the LMTT-DI emerged as an independent contributor, explaining 20, 38, and 47% (all p < 0.001) of the variance in the long-range DFA scaling exponent, MAGE, and hemoglobin A1C, respectively, whereas insulin sensitivity failed to contribute independently. Conclusions: Loss of complexity and increased variability in glucose profiles are associated with declining beta-cell reserve and worsening glycemic control. PMID- 29159102 TI - Effects of carbohydrate and protein supplementation during resistance exercise on respiratory exchange ratio, blood glucose, and performance. AB - Introduction: Athletes must determine whether they will benefit most from exercise in the fasted or fed state when discussing variables such as substrate oxidation, muscle anabolism, and performance. Objective: To determine the effects of a carbohydrate plus protein (C + P) beverage consumed during resistance exercise on respiratory exchange ratio (RER), blood glucose, and performance. Methods: Ten resistance trained male subjects completed two bouts of exercise consisting of seven sets of squats and bench presses using 60% of their one repetition maximum (1RM). Subjects consumed C + P during one trial, and a non caloric placebo (P) in the other. Six sets of each exercise were performed for a predetermined number of repetitions, followed by a seventh set of each exercise for as many repetitions as possible, performed as explosively as possible. Power was measured during the final set of each exercise. Glucose was measured pre, during, and post exercise. RER was measured seven times during each session. Results: No significant difference in power was found. C + P resulted in significantly greater work in the bench press (p < 0.05), with no difference in the squat (p = 0.10). Post-exercise glucose was significantly greater (p < 0.05) in C + P vs. placebo. In C + P, post-exercise glucose was significantly greater (p < 0.05) than before or during exercise. For RER, a significant effect was found for time (p < 0.05), with no difference between conditions. Conclusion: In active males, C + P ingestion during resistance exercise improved bench press performance and increased blood glucose, but does not appear to affect RER. PMID- 29159103 TI - Additive effects of lupin protein and phytic acid on aortic calcification in ApoE deficient mice. AB - Lupin proteins have repeatedly been shown to exhibit lipid lowering properties and reduce aortic calcification in atherosclerosis models. Despite many efforts on its identification, the component which is responsible for the observed effects is still under debate. Phytic acid which is generally associated with lupin protein isolates has currently been described as bioactive plant compound. The objective of the study was to determine the role of associated phytic acid for the described lupin protein effects. A two-factorial study with ApoE knockout mice was conducted in which mice received lupin protein isolate or casein with or without phytase. Phytic acid was added to the casein diets to a final concentration identical to the lupin protein diets. Here we show that the serum concentrations of cholesterol, lathosterol and desmosterol were lower and the faecal bile acid excretion was higher in the groups fed lupin proteins than in the groups fed casein (p < 0.05). Mice that received the lupin protein diet containing phytic acid were characterized by a lower aortic calcification than mice of the other three groups (p < 0.05). In conclusion, our results show that the cholesterol lowering properties of lupin protein isolate were not caused by phytic acid. However, the hypocalcific action of lupin proteins appears to depend on the combination of lupin proteins and phytic acid. PMID- 29159104 TI - Calcitriol treatment in metabolic bone disease of prematurity with elevated parathyroid hormone: A preliminary study. AB - Objective: To describe the association of calcitriol treatment with the change in parathyroid hormone (PTH) and biochemical markers of bone disease in infants with metabolic bone disease of prematurity (MBD) and secondary hyperparathyroidism. Study design: This retrospective chart review examined serum intact PTH, serum calcium (Ca), serum phosphorus (P), serum alkaline phosphatase (APA), urine calcium/creatinine (UCa/Cr), and tubular reabsorption of phosphate (TRP) in 32 infants prior to and following calcitriol treatment for MBD with PTH >100 pg/ml. 25-hydroxyvitamin D concentrations were recorded. Results: Following calcitriol treatment, PTH decreased from median (min/max) 220 (115/593) to 25 (3/259) pg/ml, p < 0.001; Ca increased from 9.9 (8.9/10.7) to 10.3 (9.7/11.3) mg/dl, p < 0.001; P increased from 4.3 (2.7/6.4) to 5.4 (2.9/7.4) mg/dl, p = 0.001; and TRP increased from 81 (59/98) to 91.5 (78/98) %, p = 0.03. APA did not differ pre treatment: 616 (209/1193) vs. post-treatment 485 (196/1229) U/L, p = 0.12. Vitamin D deficiency was not present. Hypercalcemia with hypercalciuria occurred in 3/32 subjects, all normalized after dose reduction. Conclusion: Improvements in MBD markers and lack of serious adverse effects suggest calcitriol may be a treatment option in infants with MBD and secondary hyperparathyroidism. PMID- 29159105 TI - Role of HbA1c in post-partum screening of women with gestational diabetes mellitus. AB - Aim: To compare the performance of HbA1c with established glucose criteria during an oral glucose tolerance test (OGTT) and to assess HbA1c as a screening test for undiagnosed diabetes and pre-diabetes after gestational diabetes mellitus (GDM). Methods: Glucose homeostasis was re-evaluated 1-5 years after delivery in 140 women with previous GDM, by means of OGTT and simultaneous HbA1c measurement. Glucose tolerance was defined according to World Health Organisation criteria. HbA1c >=6.5% (>=48 mmol/mol) was used for diabetes diagnosis and HbA1c >=5.7% (>=39 mmol/mol) to define abnormal glucose homeostasis. Results: HbA1c had low sensitivity (14.3%) and high specificity (99.1%) in diabetes diagnosis. Sensitivity and specificity of HbA1c to detect abnormal glucose tolerance were 29.5% and 95.2%, respectively. The consistency in classifying abnormal glucose tolerance between HbA1c and OGTT criteria was 59% (kappa = 0.227) and the area under the receiver operating characteristic curve was 0.708. The combined use of HbA1c and fasting glucose criteria showed similar performance to that of fasting glucose criteria alone. The latter identified 63% of the women with pre-diabetes or diabetes in the study cohort. However, by lowering the cut-point of HbA1c to >=5.0% (>=31 mmol/mol), an additional proportion (27%) with isolated post-glucose load hyperglycaemia was identified. Conclusion: Proposed thresholds of HbA1c had low diagnostic sensitivity. Combined with a fasting glucose test, the performance was no better than with using a fasting glucose test alone. Combining a fasting glucose test with a lower HbA1c cut-point may be an alternative approach for selection of women for an OGTT. PMID- 29159107 TI - The relationship between self-efficacy and diabetic foot self-care. AB - Aims: Research has shown that the ongoing rate of diabetes-related amputations remains significant despite the existence of prevention methods and that amputation in most cases can be prevented. The purpose of the study was to assess the relationship between the level of self-efficacy and performance of foot self care in those with diabetes as they relate to the prevention of lower extremity amputation (LEA). Methods: A descriptive correlational study was conducted using the theoretical framework of Bandura's social cognitive theory. The Foot Care Confidence Scale (FCCS) and the Nottingham Assessment of Functional Footcare (NAFF) survey instruments were distributed to individuals over 18 years old with diabetes Type 1 and 2 in the lower peninsula of Michigan (N = 223). Results: No significant correlation was identified between the level of self-efficacy and performance of foot self-care behaviors. Statistical significance was found between foot self-care behaviors and gender with males scoring higher than females. Conclusions: This study adds to the body of knowledge regarding self efficacy and diabetic foot self-care behaviors. Further research is needed to explore the relationship of gender, diabetes education attendance, and foot self care behaviors as influencing factors in LEA prevention. PMID- 29159106 TI - Methods and initial findings from the Durham Diabetes Coalition: Integrating geospatial health technology and community interventions to reduce death and disability. AB - Objective: The Durham Diabetes Coalition (DDC) was established in response to escalating rates of disability and death related to type 2 diabetes mellitus, particularly among racial/ethnic minorities and persons of low socioeconomic status in Durham County, North Carolina. We describe a community-based demonstration project, informed by a geographic health information system (GHIS), that aims to improve health and healthcare delivery for Durham County residents with diabetes. Materials and Methods: A prospective, population-based study is assessing a community intervention that leverages a GHIS to inform community based diabetes care programs. The GHIS integrates clinical, social, and environmental data to identify, stratify by risk, and assist selection of interventions at the individual, neighborhood, and population levels. Results: The DDC is using a multifaceted approach facilitated by GHIS to identify the specific risk profiles of patients and neighborhoods across Durham County. A total of 22,982 patients with diabetes in Durham County were identified using a computable phenotype. These patients tended to be older, female, African American, and not covered by private health insurance, compared with the 166,041 persons without diabetes. Predictive models inform decision-making to facilitate care and track outcomes. Interventions include: 1) neighborhood interventions to improve the context of care; 2) intensive team-based care for persons in the top decile of risk for death or hospitalization within the coming year; 3) low intensity telephone coaching to improve adherence to evidence-based treatments; 4) county-wide communication strategies; and 5) systematic quality improvement in clinical care. Conclusions: To improve health outcomes and reduce costs associated with type 2 diabetes, the DDC is matching resources with the specific needs of individuals and communities based on their risk characteristics. PMID- 29159108 TI - Insulin resistance in Saudi postmenopausal women with and without metabolic syndrome and its association with vitamin D deficiency. AB - Background: There is increasing interest in the non-skeletal effects of vitamin D and the relationship between vitamin D deficiency and chronic conditions such as diabetes mellitus. We aimed to investigate the relationship between surrogate indices of insulin resistance (IR), and vitamin D deficiency/insufficiency in postmenopausal Saudi women with and without metabolic syndrome. Methods: The study population consisted of 300 postmenopausal women aged 46-88 years enrolled consecutively from women attending the Outpatient Clinics of King Abdulaziz University Hospital. Demographic, anthropometric, and biochemical parameters were recorded. Data were analyzed for women with and without metabolic syndrome. Results: Abdominal obesity, IR, and hypovitaminosis D were highly prevalent within our population sample. Of the components used to define metabolic syndrome; waist circumference, serum triglycerides (TG), high density lipoprotein cholesterol, and fasting blood glucose (FBG) were significantly related with all surrogate measures of IR. Significant inverse correlations were found between serum vitamin D and serum TG, FBG, and diastolic blood pressure, within the study cohort. Conclusions: These observations suggest that hypovitaminosis D may be associated with the risk of developing metabolic syndrome. Interrelationships between IR, metabolic syndrome, and hypovitaminosis D are of particular interest in Saudi population, given the high prevalence of these conditions in this region. PMID- 29159109 TI - Vitamin D deficiency in Thailand. PMID- 29159110 TI - Symptoms of depression among patients attending a diabetes care clinic in rural western Kenya. AB - Objective: The prevalence of diabetes in sub-Saharan Africa is rising, but its relationship to depression is not well-characterized. This report describes depressive symptom prevalence and associations with adherence and outcomes among patients with diabetes in a rural, resource-constrained setting. Methods: In the Webuye, Kenya diabetes clinic, we conducted a chart review, analyzing data including medication adherence, hemoglobin A1c (HbA1c), clinic attendance, and PHQ-2 depression screening results. Results: Among 253 patients, 20.9% screened positive for depression. Prevalence in females was higher than in males; 27% vs 15% (p = 0.023). Glycemic control trends were better in those screening negative; at 24 months post-enrollment mean HbA1c was 7.5 for those screening negative and 9.5 for those screening positive (p = 0.0025). There was a nonsignificant (p = 0.269) trend toward loss to follow-up among those screening positive. Conclusions: These findings suggest that depression is common among people with diabetes in rural western Kenya, which may profoundly impact diabetes control and treatment adherence. PMID- 29159112 TI - Relationship of treatment satisfaction to health-related quality of life among Palestinian patients with type 2 diabetes mellitus: Findings from a cross sectional study. AB - Objectives: The aims of the current study were to assess the association between health-related quality of life (HRQoL) and treatment satisfaction in a sample of diabetic patients from Palestine, and to determine the influence of socio demographic and clinical factors on HRQoL. Methods: It was a cross-sectional study performed during the period June 2013 to October 2013. The Arabic version of Treatment Satisfaction Questionnaire for Medication (TSQM 1.4) was used to assess treatment satisfaction, and the Arabic version of European Quality of Life scale (EQ-5D-5L) was used to assess HRQoL. Multiple linear regression was used to estimate which variables were the most important related to HRQoL. Results: A total of 385 diabetic patients were included. There were modest positive correlations between the total score on the Overall Satisfaction domain and EQ-5D 5L (r = 0.14; p = 0.005). After adjusting multiple covariates by multiple linear regression, the association between the Overall Satisfaction and HRQoL was not statistically significant (p = 0.075); (R = 0.495; adjusted R2 = 0.245; F = 10.3; df = 12; p < 0.001). The results showed that elderly patients, being unemployed, and number of comorbid diseases, were significantly associated with HRQoL. Conclusions: Overall, these results indicate that elderly patients, being unemployed, and those with comorbid diseases, are independent risk factors for poor HRQoL. Furthermore, it emerges that HRQoL and treatment satisfaction are both probably influenced by socio-demographic and clinical characteristics. In fact, to improve diabetic patients' quality of life, elderly patients were recommended to receive more attention in their health and economic status. PMID- 29159113 TI - Effect of intermittent sitting time on acute postprandial lipemia in children. AB - Objective: To investigate the effect of interrupting sitting time with intermittent moderate exercise on acute postprandial plasma triglyceride (TG) in healthy children following high-fat meal consumption. Methods: Twelve participants (8 girls; 4 boys), aged 12 +/- 2 years (mean +/- SD), completed two trials in the laboratory. On Day 1 (d1), sitting was interrupted with moderate intensity exercise every 30 min, and compared with day 2, (d2), where participants remained sedentary. On each testing day, participants consumed four high fat meals. Blood was sampled in a fasted state and 2-hourly for 6 h with the last sample taken on the 7th hour. Results: Overall, there were no significant differences in the area under the concentration-time curve between day 1 and day 2, for the 12 participants combined (p = 0.98). However, in eight of the 12 participants, triglyceride concentrations remained high on d2 at two, four and 6 h after baseline compared with d1 (p = 0.03). Conclusion: When sitting was interrupted by short bouts of moderate intensity exercise there was a reduction in triglyceride concentrations in eight out of 12 participants. Possible reasons to account for the difference in response may include sexual maturation, gender differences, genetic conditions, or the rate of digestion and intestinal absorption. PMID- 29159114 TI - Further insight into data interpretation and conclusions. PMID- 29159111 TI - Normal menstrual cycle steroid hormones variation does not affect the blood levels of total adiponectin and its multimer forms. AB - Objective: Plasma total adiponectin reveals a sexual dimorphism indicating that gonadal steroids may be involved in its secretion and/or metabolism. However, results from previous reports are conflicting and data regarding the influence of ovarian steroids on adiponectin's multimer forms are scarce. The objective of the study was to assess if total adiponectin and its isoforms are affected by the changes of estradiol and progesterone during the normal menstrual cycle and the association of total adiponectin and its isoforms with the gonadal steroid levels. Materials/methods: Quantitative determination of plasma adiponectin and its multimers was conducted in the three phases of an ovulatory cycle in 13 premenopausal women, in the follicular phase of 10 more premenopausal women, in 20 postmenopausal women and in 21 men. Moreover, serum levels of FSH, LH, prolactin, estradiol, progesterone, and testosterone, sex hormone binding globulin, glucose, and insulin were measured. Results: The circulating levels of total adiponectin and its multimers were not affected by the normal variation of estradiol and progesterone across the ovulatory menstrual cycle. In the whole number of participants, the total adiponectin and high molecular weight adiponectin levels were significantly different between genders and associated positively with age and sex hormone binding globulin levels, and negatively with testosterone and progesterone levels and the waist/hip ratio. In the multiple logistic regression analysis, after adjustment for age, gender, and sex hormone binding globulin and progesterone levels, significant predictors of total adiponectin levels were the waist/hip ratio and testosterone levels, and of high molecular weight adiponectin the testosterone levels. Conclusions: Normal menstrual cycle ovarian steroids are not involved directly in the regulation of secretion and/or metabolism of total adiponectin and its multimers. Testosterone seems to be responsible for the adiponectin's sexual dimorphism. PMID- 29159115 TI - Reply to "Further insight into data interpretation and conclusions". PMID- 29159117 TI - ENDO 2015 - Meeting report. PMID- 29159116 TI - Prevalence of diabetic nephropathy in Type 2 Diabetes Mellitus in rural communities of Guanajuato, Mexico. Effect after 6 months of Telmisartan treatment. AB - Objective: To determine the prevalence of Diabetic Nephropathy (DN) in patients with type 2 Diabetes Mellitus (T2DM) with over 5 years of evolution in rural communities of Guanajuato, Mexico, and evaluate the effects of an ARB treatment over 6 months in patients with DN. Materials and methods: Patients of both sexes, 38-86 years, T2DM over 5 years of evolution and diagnosed with arterial hypertension (HT) after T2DM incidence. Monthly determination of microalbuminuria (MA), lipids, glucose, serum creatinine, and glycated hemoglobin (HbA1c). Estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease (MDRD) formula. A dose of 80 mg of Telmisartan was administered daily over 6 months. Results: The total adult population of two rural communities (3609 subjects) was studied, 335 subjects had T2DM, among them 80 (with a prevalence of 24%) had DN and HT. Sixty-seven patients received Telmisartan, and showed significant improvement in all parameters studied. Conclusions: A higher prevalence of DN than that reported in the Mexican National Health Survey (ENSANUT) was found. Further research is required in a larger population sample in order to confirm the results of Telmisartan treatment. PMID- 29159118 TI - Impaired hepatic counterregulatory response to insulin-induced hypoglycemia in hepatic denervated pigs. AB - Objective: The liver reacts to hypoglycemia by increasing its glucose output. This response is assumed to depend both on glucose sensing at the liver and the brain, as well as efferent impulses from the brain to the liver. We tested the importance of this signaling pathway by studying the hepatic response to insulin induced hypoglycemia in hepatic complete denervated pigs. Materials/methods: Two weeks prior to the metabolic study, 36-kg pigs underwent either total hepatic denervation (DN; n = 12) or sham operation (sham; n = 12). On the metabolic study day, measurements were performed at baseline conditions and during a hypoglycemic hyperinsulinemic (5 mU/kg/min) clamp. Endogenous insulin and glucagon secretions were inhibited by somatostatin, and glucagon was replaced at baseline levels. Endogenous glucose production (EGP) and glucose utilization (Rd) were determined by [3-3H] glucose infusion. Results: Baseline plasma concentrations of glucose, insulin, EGP and Rd did not differ significantly between the two groups of animals. During insulin infusion, the plasma glucose concentration was clamped at ~3 mmol/L in both groups of animals resulting in an increase in plasma concentrations of epinephrine and norepinephrine in sham pigs (both P < 0.05), while this effect was abolished in DN pigs. While insulin action (P = 0.09) and glucose utilization (P = 0.44) were similar, EGP was markedly decreased in the DN pigs (P < 0.05). Conclusion: The findings indicate a blunted hepatic counterregulatory response to hypoglycemia following complete hepatic denervation. This implies that intact neural impulses to and from the liver are necessary to maintain the increase in EGP that protects the organism against hypoglycemia. PMID- 29159119 TI - Levothyroxine treatment generates an abnormal uterine contractility patterns in an in vitro animal model. AB - Objective: Abnormal uterine contraction patterns were recently demonstrated in uterine strips from pregnant women treated with Levothyroxine (T4). These abnormalities were correlated with an increased risk of C-section delivery and associated surgical complications. To date, no study has investigated whether uterine contractility is modified by hypothyroidism or T4 treatment. Herein, we analyze the physiological role of T4 on uterine contractions. Study design: Female non-pregnant Sprague-Dawley rats (N = 22) were used and divided into four groups: 1) control, 2) hypothyroidism, 3) hypothyroidism treated with low T4 doses (20 MUg/kg/day) and 4) with high T4 doses (100 MUg/kg/day). Hypothyroidism was induced by an iodine-deficient diet. Isometric tension measurements were performed in vitro on myometrium tissues in isolated organ baths. Contractile activity parameters were quantified (amplitude, duration, frequency and area under the curve) using pharmacological tools to assess their effect. Results: Screening of thyroid function confirmed a hypothyroid state for all rats under iodine-free diet to which T4 was subsequently administered to counterbalance hypothyroidism. Results demonstrate that hypothyroidism significantly decreased contractile duration (-17%) and increased contractile frequency (+26%), while high doses of T4 increased duration (+200%) and decreased frequency (-51%). These results thus mimic the pattern of abnormal contractions previously observed in uterine tissue from T4-treated hypothyroid pregnant women. Conclusion: Our data suggest that changes in myometrial reactivity are induced by T4 treatment. Thus, in conjunction with our previous observations on human myometrial strips, management of hypothyroidism should be improved to reduce the rate of C-sections in this group of patients. PMID- 29159120 TI - Psycholosocial factors associated with psychological insulin resistance in primary care patients in Hong Kong. AB - Aim: Patients with diabetes mellitus (DM) often delay the initiation of insulin treatment and titration due to psychological factors. This phenomenon is called psychological insulin resistance (PIR). The insulin treatment appraisal scale (ITAS) that was initially developed for Western populations has been translated and validated to measure PIR in Taiwanese populations (C-ITAS). This study aims to estimate the prevalence of PIR in primary care patients with DM in Hong Kong and to examine the relationship between PIR and psychosocial factors. Method: 402 DM patients from a government-funded general outpatient clinic completed the C ITAS and a health questionnaire (the Patient Health Questionnaire-9, PHQ-9). Patient demographics were recorded and associations among C-ITAS scores, PHQ-9 scores and demographic data were evaluated. Results: There was no relationship between the presence of depression and PIR. Furthermore, the prevalence of PIR was 47.2% in insulin-naive patients but only 8.7% in current insulin users. Tools such as the C-ITAS may help clinicians understand the etiology of PIR, which this study suggests is likely the result of multiple risk factors. Factors associated with a lower prevalence of PIR included current insulin use, a family history of insulin use, a high education level, male sex, and having received counseling from a physician about insulin within the previous 6 months. PMID- 29159121 TI - Role of omentin-1 and C-reactive protein in obese subjects with subclinical inflammation. AB - Background: While chronic subclinical inflammation is now considered to be a predisposing risk factor of cardiovascular diseases, the extent by which adipokines induce metabolic abnormalities in humans is not fully resolved. The purpose of this study was to examine the relationship between insulin resistance and serum inflammatory markers in obese subjects. Methods: One hundred and five subjects without any clinically evident CVD were classified into 3 coronary risk levels according to Framingham risk score. Demographic and anthropometric variables were estimated. Serum levels of lipid profile, blood glucose, insulin, omentin-1 and high sensitivity-C reactive protein (hs-CRP) were measured in fasting blood samples. Insulin resistance indices were also calculated. Results: 29% and 62% of the study population were overweight and obese respectively by body mass index (BMI) measures. Almost half of the study population was considered diabetic. There was a tendency for a fall in serum omentin-1 concentrations with increasing coronary risk with a significant increase in hs CRP levels in the same direction (p < 0.05). Age and fasting blood glucose were found to be independently associated with serum omentin-1 levels. BMI and fasting blood glucose were independent determinants of serum hs-CRP levels. Conclusions: Omentin-1 might be associated with the development of diabetes mellitus indirectly via insulin activity and obesity. These findings may have important implications for the pathophysiology and therapy of diabetes mellitus by further longitudinal studies. PMID- 29159122 TI - Unique obstacles to establishing thyroid cancer registries. PMID- 29159123 TI - Pharmacokinetics and pharmacodynamics of insulin glargine-insulin glulisine basal bolus and twice-daily premixed analog insulin in type 1 diabetes mellitus patients during three standardized meals. AB - Aims: To evaluate the pharmacokinetics and pharmacodynamics of basal insulin glargine with mealtime insulin glulisine or twice daily 75/25 premixed neutral protamine insulin lispro and insulin lispro in individuals with type 1 diabetes during three standardized meals over a 24 hour duration and compare to physiologic insulin and glucose responses in healthy non-diabetic individuals. Methods: Twelve healthy (4 male/8 female) and thirteen individuals with type 1 diabetes (8 male/5 female) were studied during three sequential standardized meals. Individuals with type 1 diabetes received either glargine and glulisine injected 5 minutes subcutaneously before each meal or premixed insulin lispro injected 5 minutes before breakfast and dinner in a randomized fashion separated by eight weeks. Results: The incremental systemic insulin AUC, maximal insulin concentration, and rate of rise of systemic insulin (0-30 minutes) during all three meal intervals were similar between glargine/glulisine and healthy controls. Incremental glucose AUC with glargine/glulisine was similar to controls at lunch and dinner. With premix 75/25 insulin, insulin AUC was lower and incremental glucose AUC was greater at lunch compared to the healthy and glargine/glulisine. Hypoglycemic events before lunch were greater with premix insulin group than with glargine/glulisine (p < 0.0001). Conclusions: Glargine/glulisine pharmacokinetics in type 1 diabetes can closely approximate physiologic insulin responses in healthy individuals during a day in which three standardized meals are consumed. Additionally, when glulisine is dosed only five minutes pre-meal, systemic insulin concentration rises as rapidly as prandial endogenous insulin levels. This present study compared glargine and glulisine administered in an approximate 50/50 proportion. Future studies of alternate meal times, meal content and differing premixed insulin preparations are indicated. PMID- 29159124 TI - Diagnostic values of glycated haemoglobin and diagnosis of diabetes: Results of a cross-sectional survey among general practitioners in the province of Reggio Emilia, Italy. AB - Aims: The aim of this study was to investigate whether subjects included in the diabetes register solely because their HbA1c was over the diagnostic threshold received a diagnosis of diabetes from their general practitioner (GP). Methods: The study included all registered cases in 2009-2010 aged 18 or over that were identified only by the laboratory database because they had one or more HbA1c over the 6.5% threshold and for whom we did not find any information in the search of full electronic clinical records. Multilevel logistic regression was used to examine the influence of GP and patient characteristics. Results: There were 228 participating GPs (76.3% of those invited) and 832 assessed subjects (68.8% of study population). There was a strong clustering among the GPs (residual intraclass correlation = 0.52, 95% CI 0.40-0.64). About one in two (55.5%) subjects with two or more HbA1c > =6.5% has been diagnosed as diabetic and the percentage declined - unless zeroing - in case the abnormal value was only one (28.3%). The likelihood of being labelled 'no diabetes' was greater in subjects aged less than 65 or over 74 with respect to the reference age group (OR 1.89, 95% CI 1.13-3.15; OR 1.55 95% CI 0.94-2.53). The same likelihood consistently decreased when HbA1c test was accompanied by abnormal fasting plasma glucose (FPG) assay (OR 0.20, 95% CI 0.12-0.32). Conclusions: A permanent exchange of information between the diabetes register and GPs should be maintained to improve the care of patients and the awareness of criteria for diabetes diagnosis among GPs. PMID- 29159125 TI - Annual all-cause mortality rate for patients with diabetic kidney disease in Singapore. AB - Background: The prognosis of diabetic kidney disease is poor because epidemiological data have shown that all-cause mortality increases with declining renal function. This study aims to estimate the annual mortality rate of diabetic kidney disease stratified by chronic kidney disease (CKD) stages and to identify the predictors of mortality. Methods: Patients with Stage 3-5 CKD (estimated glomerular filtration rate [eGFR] less than 60 mL/min per 1.73 m2) with diabetic kidney disease from the National Healthcare Group CKD Registry from 1 January 2007 to 31 December 2007 were included in this study. The patients were followed up till 30 November 2013. Cox's proportional hazards regression modelling was used to assess the factors associated with all-cause mortality. Results: Over a median follow up period of 6.0 years, 985 out of 3008 patients (32.8%) died. Of those who died, 363 (36.9%) died from cardiovascular causes. The annual mortality rate was 64.1 per 1000 individuals (95% confidence interval [CI] 60.2-68.3) and the mortality rate increased with severity of CKD [Stage 3A (37.0), Stage 3B (57.5), Stage 4 (98.3) and Stage 5 (198.5)]. Predictors of mortality were age, male gender, CKD stages, albuminuria, comorbid conditions such as peripheral vascular disease, neuropathy, retinopathy and the use of antiplatelet agents. Conclusion: Our study estimated the annual all-cause mortality rate for Singaporean patients with diabetic kidney disease by CKD stages and identified predictors of all-cause mortality. This study has affirmed the poor prognosis of these patients and an urgency to intervene early so as to retard the progression to later stages of CKD. PMID- 29159126 TI - Hypoglycemia-related information seeking among informal caregivers of type 2 diabetes patients: Implications for health education. AB - Aims: To examine information seeking and knowledge about hypoglycemia among partners and family of type 2 diabetes patients and to identify associations between information seeking, knowledge and demographic, and disease-related characteristics. Methods: Caregivers of adults with type 2 diabetes (N = 488) completed surveys assessing information seeking, knowledge of hypoglycemia symptoms and treatment, perceived competence, demographic information, and diabetes-related characteristics. Hierarchical and logistic regressions were used for data analysis. Results: Nearly two thirds of family members and friends actively sought information about hypoglycemia, while health professionals and print media were reported as the main sources. Many respondents (74.5%) were able to identify at least one correct warning sign. But 32% could not state any correct treatment measures. Health professionals were the main and most helpful source of their knowledge. Education, past experience with hypoglycemia, and comprehension of information were associated with knowledge about treatment. Caregivers' perceived competence about hypoglycemia correlated with medical education, information-seeking, and comprehension of information. Conclusions: Our results indicate the importance of the hypoglycemia-related information seeking of caregivers in managing incidents of hypoglycemia. These findings suggest the need to consider caregivers' health knowledge when developing health education programs in diabetes care. More attention must be focused on providing interventions that motivate information seeking and improve the comprehension of information. Interventions should inform caregivers about hypoglycemia to enhance their knowledge. PMID- 29159127 TI - Fear of hypoglycaemia and self-management in type 1 diabetes. AB - Aims: We studied the association between fear of hypoglycaemia (FoH) and various diabetes self-management practices. Methods: Data from 798 individuals with type 1 diabetes participating in the FinnDiane Study were included. Self-reported questionnaires were used to assess FoH and self-management practices (e.g. dietary intake, insulin administration, physical activity). For glycaemic control, we used both the latest HbA1c measurements and the serial HbA1c measurements from the medical files. Factor analysis was used to reveal underlying constructs within the food frequency section of the diet questionnaire. Results: In all, 44% and 63% of men and women reported FoH, respectively. In men, FoH was associated with higher mean serial HbA1c levels, higher number of reported self-monitoring of blood glucose (SMBG), higher carbohydrate intake, and lower scores in the "high-fat" factor. In women, FoH was associated with a higher number of reported SMBGs and higher energy intake. No difference was observed in physical activity and insulin administration. Conclusions: FoH has various implications for the self-management of diabetes. More studies are however needed to assess on one hand the association between FoH and diabetes self-management, and on the other hand, FoH and its long term consequences, such as the emergence of diabetic complications and mortality. PMID- 29159128 TI - Comparing metabolic control and complications in type 2 diabetes in two Pacific Islands at baseline and following diabetes care intervention. AB - Aim: To compare metabolic control and complications in people with type 2 diabetes in Nauru and the Solomon Islands before and after a project intervention. Methods: This follow-up study compared metabolic control and complications in a cohort of 216 people with diabetes (81 from Nauru and 135 from the Solomon Islands) at baseline and 15 months following a project intervention (upgrading and equipping the existing diabetes centres, and providing training and clinical support systems) aimed at improving the quality of clinical diabetes care. Subjects were screened using a standardised protocol which gathered information on demographics, treatment, physical and biochemical parameters and their outcomes. Results: At follow-up, glycaemic control had improved and mean HbA1c had decreased in study participants in both Nauru (mean difference (MD) = 0.9 +/- 2.3%) and the Solomon Islands (MD = -0.6 +/- 1.4%), P < 0.001. Mean blood pressure was reduced in the Solomon Islands (systolic MD = -11.6 +/- 19.2 mmHg and diastolic MD = -5.4 +/- 10.5 mmHg), P < 0.001. There were no significant changes in mean blood lipids or albumin-creatinine ratio. Overall the percentage of subjects achieving recommended clinical targets increased. However these percentages remained low, e.g. 23.5% of participants in Nauru and 20.7% in the Solomon Islands achieved an HbA1c target <7% (53 mmol/mol). A trend towards lower complications rates of foot problems was observed but there were no significant changes in the prevalence of other diabetes complications. Conclusions: This study indicates improved metabolic control but little change in diabetes complications 15 months after intervention. Efforts to improve and evaluate the ongoing quality and accessibility of diabetes care in Pacific Island settings need to be further strengthened. PMID- 29159129 TI - Volunteer peer support, diabetes, and depressive symptoms: Results from the ENCOURAGE trial. AB - Aims: Depression in diabetes mellitus (DM) is common and is associated with poor health outcomes. Peer support DM interventions include encouraging interactions that could improve depressive symptoms. We examined intervention effects for those with and without depressive symptoms in a peer support trial. Methods: The 1-year ENCOURAGE trial included 424 persons with DM living in rural Alabama. Intervention participants worked with community volunteers who encouraged participants to engage in daily self-management; control arm participants received usual care. Outcomes included HbA1c, body mass index (BMI) and quality of life (QoL) with EuroQuol-5D (range 0.0-1.0). Depressive symptoms were assessed with the Patient Health Questionnaire (PHQ-8, range 0-24). Generalized Additive Models (GAM) examined control-intervention differences in changes in HbA1c, BMI, and QoL for those with PHQ-8 >= 5 and PHQ-8 < 5. Results: Of the 424 participants enrolled at baseline, 355 completed follow-up and had data were that could be included into the study; they were aged 60.2 +/- 12.1 years, 87% African American, 75% female, and 39% insulin-treated. In an overall GAM adjusting for imbalance across trial arms and time-related covariates, depressive symptoms improved for all, but after 15 months of follow-up intervention, participants experienced greater reduction in PHQ-8 score than control participants (p = 0.01). In stratified analyses, those with PHQ-8 >= 5 had unchanged HbA1c, lost weight (p = 0.03) and improved QoL (p = 0.04). Those with PHQ-8 < 5 also had unchanged HbA1c and lost weight, but did not improve QoL (p = 0.06). Conclusions: Peer support improved depressive symptoms for all, but resulted in greater weight loss and gains in QoL for those with baseline depressive symptoms compared to those without. PMID- 29159130 TI - The impact of a low glycaemic index (GI) diet on simultaneous measurements of blood glucose and fat oxidation: A whole body calorimetric study. AB - Objective: Low glycaemic index (GI) foods are known to minimize large fluctuations in blood glucose levels and have been suggested to increase fat oxidation. The objective of this study was to simultaneously investigate glucose excursion and substrate oxidation in a whole body calorimetre when Chinese male subjects were provided a low or high GI meal. Materials/Methods: In a randomized, controlled crossover non blind design, 12 healthy Chinese male adults (BMI 21.8 +/- 1.3 kgm-2) attended two sessions consisting of either four low or high glycaemic meals (LGI vs HGI). Breakfast, lunch and snack were consumed in a whole body calorimetre while dinner was consumed at home. Daily changes in glycaemic response (GR) and postprandial GR responses were measured using a continuous glucose monitoring system. The GR was further calculated to obtain the incremental area under the curve (iAUC) for glucose concentrations. Glycaemic variability was calculated as mean amplitude of glycaemic excursion (MAGE). Substrate oxidation was calculated by measuring respiratory quotient and urine nitrogen excretion. Results: After LGI meals in the whole body calorimetre, iAUC for glucose (P = 0.008) was lower compared to the HGI session. The HGI treatment produced a significantly greater MAGE than the LGI treatment over the 24 hour period (P < 0.001). Additionally, higher fat oxidation and lower carbohydrate oxidation were observed following breakfast and lunch when comparing LGI to HGI (P < 0.05). Conclusions: Consumption of LGI meals was capable of attenuating 24 hour blood glucose profiles and decreasing postprandial glucose excursions in healthy Asian males. Additionally, LGI mixed meals were able to promote fat oxidation over carbohydrate oxidation when compared to HGI mixed meals. The consumption of low GI meals may be a strategic approach in improving overall glycaemia and increasing fat oxidation in Asians consuming a high carbohydrate diet. PMID- 29159131 TI - The chlorite-based drug WF10 constantly reduces hemoglobin A1c values and improves glucose control in diabetes patients with severe foot syndrome. AB - Aims: The intravenous application of the chlorite-based drug solution WF10 is known to improve wound healing in patients with diabetic foot syndrome. In this retrospective study, we addressed the question, which effects are caused by this drug in patients with diabetic foot ulcers on the hemoglobin A1c value. Methods: Patients received five consecutive daily infusions of WF10. Three patients received a second cycle of WF10, and one patient a third cycle. Results: On a group of twelve patients with diabetic foot syndrome, WF10 gradually reduced the HbA1c values from a high-risk range (9.1 +/- 1.6% (76 +/- 13 mmol/mol)) into a low-risk range in all patients but one. These values remain low over at least 8 to 12 weeks after the administration of WF10. This drug improved also considerably wound healing processes in eleven patients. Conclusions: The chlorite component of WF10 is known to inactivate efficiently free cytotoxic hemoglobin forms that might accumulate in peripheral blood after hemolysis and induces the removal of pre-damaged red blood cells from circulation. By these mechanisms WF10 diminished toxic effects of hemolysis, improved microcirculation and glucose consumption in affected tissues, and prevented, thus, below knee amputation. PMID- 29159132 TI - The expanding world of diabetes in this month's JCTE. PMID- 29159133 TI - Integration of novel approaches demonstrates simultaneous metabolic inactivation and CAR-mediated hepatocarcinogenesis of a nitrification inhibitor. AB - Nitrapyrin, a nitrification inhibitor, produces liver tumors in mice at high doses. Several experiments were performed to investigate molecular, cellular, and apical endpoints to define the key events leading to the tumor formation. These data support a mode-of-action (MoA) characterized by constitutive androstane receptor (CAR) nuclear receptor activation, increased hepatocellular proliferation leading to hepatocellular foci and tumor formation. Specifically, nitrapyrin induced a dose-related increase in the Cyp2b10/CAR-associated transcript and protein. Interestingly, the corresponding enzyme activity (7 pentoxyresorufin-O-dealkylase (PROD) was not enhanced due to nitrapyrin-mediated suicide inhibition of PROD activity. Nitrapyrin exposure elicited a clear dose responsive increase in hepatocellular proliferation in wild-type mice, but not in CAR knock-out mice, informing that CAR activation is an obligatory key event in this test material-induced hepatocarcinogenesis. Furthermore, nitrapyrin exposure induced a clear, concentration-responsive increase in cell proliferation in mouse, but not human, hepatocytes in vitro. Evaluation of the data from repeat dose and MoA studies by the Bradford Hill criteria and a Human Relevance Framework (HRF) suggested that nitrapyrin-induced mouse liver tumors are not relevant to human health risk assessment because of qualitative differences between these two species. PMID- 29159136 TI - Determination of the critical values of flow parameters characteristic of the alignment of cylindrical nano-objects in suspensions. AB - A method for determining the critical values of the flow speed and the flow constriction degree characteristic of the alignment of cylindrical nano-objects in a flowing suspension is proposed. Previously, the alignment process of cylindrical nano-objects in suspensions was investigated by using birefringence of the polarized light and the small-angle X-ray scattering. While both methods are suitable for measuring the alignment degree of cylindrical nano-objects in suspensions diluted down to low concentrations, they are restricted for the application to undiluted concentrated suspensions because of non-transparency and multiple scattering of X-rays. In addition, the use of the second method requires an expensive synchrotron equipment. We present a simple and faster method based on the direct ultrasound attenuation measurements of longitudinal viscosity of a suspension containing cylindrical nano-objects, which decreases monotonically, approaching its asymptotic value with increase in the flow speed and the flow constriction degree. The principle and advantages of the proposed method are as follows: *The cylindrical nano-objects align along an accelerated flow at overcritical values of the flow speed and the constriction degree.*The critical values correspond to the state of a suspension possessing viscosity close to the asymptotic value.*The method is applicable to undiluted concentrated suspensions, including opaque ones. PMID- 29159134 TI - Model selection and prediction of outcomes in recent onset schizophrenia patients who undergo cognitive training. AB - Predicting treatment outcomes in psychiatric populations remains a challenge, but is increasingly important in the pursuit of personalized medicine. Patients with schizophrenia have deficits in cognition, and targeted cognitive training (TCT) of auditory processing and working memory has been shown to improve some of these impairments; but little is known about the baseline patient characteristics predictive of cognitive improvement. Here we use a model selection and regression approach called least absolute shrinkage and selection operator (LASSO) to examine predictors of cognitive improvement in response to TCT for patients with recent onset schizophrenia. Forty-three individuals with recent onset schizophrenia randomized to undergo TCT were assessed at baseline on measures of cognition, symptoms, functioning, illness duration, and demographic variables. We carried out 10-fold cross-validation of LASSO for model selection and regression. We followed up on these results using linear models for statistical inference. No individual variable was found to correlate with improvement in global cognition using a Pearson correlation approach, and a linear model including all variables was also found not to be significant. However, the LASSO model identified baseline global cognition, education, and gender in a model predictive of improvement on global cognition following TCT. These findings offer guidelines for personalized approaches to cognitive training for patients with schizophrenia. PMID- 29159137 TI - Optimum efficiency of treatment plants discharging wastewater into river, case study: Tigris river within the Baghdad city in Iraq. AB - The present study aims to manage and determine the most economical efficiency of five wastewater treatment plants discharging wastewater into the Tigris River in Iraq. The management system was based on ensuring the five-day biological oxygen demand concentration in the river is <30 mg/L according to the Iraqi standards. In many cases, the determined optimized efficiencies were found to be lower than the present working efficiencies. Although this was good for the environment, it was not cost-effective. This study revealed that the variation of river flow rates was not an important factor that effects on the results obtained. It was found that the variation of organic decomposition value in the river and the minimum efficiency limit of the first upstream plant greatly affected the operating efficiency of the downstream plants. Furthermore, no constant rank was recorded for the effects of the natural decomposition on the operating efficiency of each plant. Three points were highlighted from this study: *The optimization methods were used to determine the most economical efficiency of multi wastewater treatment plants.*The effects of the BOD decomposition value, the river flow, and the minimum efficiency limit were also investigated.*This study presents the linear modeling method in detail and has a scientific impact for similar studies. PMID- 29159135 TI - The influence of schizotypal traits on attention under high perceptual load. AB - Schizophrenia Spectrum Disorders (SSD) are known to be characterised by abnormalities in attentional processes, but there are inconsistencies in the literature that remain unresolved. This article considers whether perceptual resource limitations play a role in moderating attentional abnormalities in SSD. According to perceptual load theory, perceptual resource limitations can lead to attenuated or superior performance on dual-task paradigms depending on whether participants are required to process, or attempt to ignore, secondary stimuli. If SSD is associated with perceptual resource limitations, and if it represents the extreme end of an otherwise normally distributed neuropsychological phenotype, schizotypal traits in the general population should lead to disproportionate performance costs on dual-task paradigms as a function of the perceptual task demands. To test this prediction, schizotypal traits were quantified via the Schizotypal Personality Questionnaire (SPQ) in 74 healthy volunteers, who also completed a dual-task signal detection paradigm that required participants to detect central and peripheral stimuli across conditions that varied in the overall number of stimuli presented. The results confirmed decreasing performance as the perceptual load of the task increased. More importantly, significant correlations between SPQ scores and task performance confirmed that increased schizotypal traits, particularly in the cognitive-perceptual domain, are associated with greater performance decrements under increasing perceptual load. These results confirm that attentional difficulties associated with SSD extend sub-clinically into the general population and suggest that cognitive-perceptual schizotypal traits may represent a risk factor for difficulties in the regulation of attention under increasing perceptual load. PMID- 29159138 TI - Paternal inheritance of plastid-encoded transgenes in Petunia hybrida in the greenhouse and under field conditions. AB - As already demonstrated in greenhouse trials, outcrossing of transgenic plants can be drastically reduced via transgene integration into the plastid. We verified this result in the field with Petunia, for which the highest paternal leakage has been observed. The variety white 115 (W115) served as recipient and Pink Wave (PW) and the transplastomic variant PW T16, encoding the uidA reporter gene, as pollen donor. While manual pollination in the greenhouse led to over 90% hybrids for both crossings, the transgenic donor resulted only in 2% hybrids in the field. Nevertheless paternal leakage was detected in one case which proves that paternal inheritance of plastid-located transgenes is possible under artificial conditions. In the greenhouse, paternal leakage occurred in a frequency comparable to published results. As expected natural pollination reduced the hybrid formation in the field from 90 to 7.6% and the transgenic donor did not result in any hybrid. PMID- 29159139 TI - Task-shifting point-of-care CD4+ testing to lay health workers in HIV care and treatment services in Namibia. AB - Introduction: Access to CD4+ testing remains a common barrier to early initiation of antiretroviral therapy among persons living with HIV/AIDS in low- and middle income countries. The feasibility of task-shifting of point-of-care (POC) CD4+ testing to lay health workers in Namibia has not been evaluated. Methods: From July to August 2011, Pima CD4+ analysers were used to improve access to CD4+ testing at 10 selected public health facilities in Namibia. POC Pima CD4+ testing was performed by nurses or lay health workers. Venous blood samples were collected from 10% of patients and sent to centralised laboratories for CD4+ testing with standard methods. Outcomes for POC Pima CD4+ testing and patient receipt of results were compared between nurses and lay health workers and between the POC method and standard laboratory CD4+ testing methods. Results: Overall, 1429 patients received a Pima CD4+ test; 500 (35.0%) tests were performed by nurses and 929 (65.0%) were performed by lay health workers. When Pima CD4+ testing was performed by a nurse or a lay health worker, 93.2% and 95.2% of results were valid (p = 0.1); 95.6% and 98.1% of results were received by the patient (p = 0.007); 96.2% and 94.0% of results were received by the patient on the same day (p = 0.08). Overall, 97.2% of Pima CD4+ results were received by patients, compared to 55.4% of standard laboratory CD4+ results (p < 0.001). Conclusions: POC CD4+ testing was feasible and effective when task shifted to lay health workers. Rollout of POC CD4+ testing via task-shifting can improve access to CD4+ testing and retention in care between HIV diagnosis and antiretroviral therapy initiation in low- and middle-income countries. PMID- 29159140 TI - Debate on human aging and lifespan. AB - The issue of human lifespan has long been a matter of controversy among scientists. In spite of the recent claim by Dong et al that human lifespan is limited to 115 years, with the mounting improvements in biotechnology and scientific understanding of aging, we may be confident that aging will slow down over the course of the current century extending human longevity much longer than 115 years. PMID- 29159141 TI - The effect of cell penetrating peptides on transfection activity and cytotoxicity of polyallylamine. AB - Introduction: Cationic polymers have the potential to be modified to achieve an ideal gene vector lacking viral vector defects. The aim of the present study was to improve polyallylamine (PAA) transfection efficiency and to reduce cytotoxicity by incorporating of cell-penetrating peptides (CPPs). Methods: To prepare the peptide-based polyplexes, PAA (15 kDa) was modified with 2 peptides (TAT and CyLoP-1) by covering the 0.5% and 1% of amines. Buffer capacity and DNA condensation ability of modified polymer, particle size and zeta potential of nanoparticles, cell viability, and transfection activity of vectors were evaluated. Results: In low carrier to plasmid (C/P) weight ratios such as 0.5 and 1, the unmodified polymer was more capable to condense the DNA compared to the synthesized vectors. In C/P ratio of 2, the plasmid was fully condensed in all vectors. The size of polyplexes ranged from 195 to 240 nm. The zeta potential was almost as the same as PAA and varied from 25 to 27 mV. All polyplexes increased the buffer capacity compared to PAA. The transfection efficiency was improved compared to unmodified polymer especially in the vectors modified with 1% of TAT or CyLoP-1 peptides in C/P ratio of 2. The cytotoxicity of prepared vectors was less than PAA. In most ratios, the cytotoxicity of the CyLoP-1 modified samples was less than the TAT modified ones. Conclusion: Modification of PAA with CPPs improved the transfection activity of vector. PMID- 29159142 TI - Investigation of the binding mechanism and inhibition of bovine liver catalase by quercetin: Multi-spectroscopic and computational study. AB - Introduction: The study on the side effects of various drugs and compounds on enzymes is a main issue for monitoring the conformational and functional changes of them. Quercetin (3,5,7,3',4'-pentahydroxyflavone, QUE), a polyphenolic flavonoid, widely found in fruits, vegetables and it is used as an ingredient in foods and beverages. The interaction of bovine liver catalase (BLC) with QUE has been studied in this research by using different spectroscopic methods. Methods: In this work, the interaction of QUE with BLC was investigated using different spectroscopic methods including ultraviolet-visible (UV-vis) absorption, circular dichroism (CD) and fluorescence spectroscopy and molecular docking studies. Results: Fluorescence data at different temperatures, synchronous fluorescence and CD studies revealed conformational changes in the BLC structure in the presence of different concentration of QUE. Also, the fluorescence quenching data showed that QUE can form a non-fluorescent complex with BLC and quench its intrinsic emission by a static process. The binding constant (Ka) for the interaction was 104, and the number of binding site was obtained ~1. The ?H, ?S and ?G changes were obtained, indicating that hydrophobic interactions play a main role in the complex formation. In vitro kinetic studies revealed that QUE can inhibit BLC activity through non-competitive manner. Molecular docking study results were in good agreement with experimental data, confirming only one binding site on BLC for QUE at a cavity among the wrapping domain, threating arm and beta-barrel. Conclusion: Inhibition of BLC activity upon interaction with QUE demonstrated that in addition to their beneficial effects, they should not be overlooked for their side effects. PMID- 29159143 TI - "Grafting-from" synthesis and characterization of poly (2-ethyl-2-oxazoline)-b poly (benzyl L-glutamate) micellar nanoparticles for potential biomedical applications. AB - Introduction: Recent advances in the field of poly (2-oxazolines) as bio-inspired synthetic pseudopeptides have proven their potential biomedical applications such as drug delivery and tissue engineering. Methods: In order to fabricate a biodegradable micellar nanoparticle of poly (2-ethyl 2-oxazoline)-b-poly (benzyl L-glutamate) or pEOx-b-pBLG, "grafting-from" synthesis approach was used involving consecutive steps of cationic ring-opening polymerization of 2-ethyl-2 oxazoline, amine functionalization of pEOx using 1-Boc-piperazine and N carboxyanhydride polymerization of gamma-benzyl- L-glutamate. Following hydrolysis of the copolymer, the protecting gamma-benzyl groups were removed yielding a double-hydrophilic block ionomer of pEOx-b-poly (L-glutamic acid). The polymers were characterized by FTIR, 1H-NMR, size exclusion chromatography and differential scanning calorimetry (DSC). Aqueous assembly of the polymers was investigated by pyrene assay, dynamic light scattering, and transmission electron microscopy. MTT cytotoxicity assay was also performed to determine the cytocompatibility in various tumor cell lines. Results: The polymeric micelles presented a uni-modal size distribution with mean hydrodynamic diameter of 149.8 +/- 10.6 nm and critical aggregation concentration of 60 ug/mL. The average molecular weight of pEOx increased from ~ 14 to 20 kDa for pEOx-b-poly (L glutamic acid) as determined by light scattering (Debye plot), indicating a successful copolymerization. MTT assay showed little to no practical cytotoxicity at concentrations below 1 mg/mL. Conclusion: Multi-step synthesis of pEOx-b-pBLG and subsequent alkaline hydrolysis were performed to obtain the block ionomer pEOx-b-poly (L-glutamic acid). Both pEOx-based copolymers can be considered for various potential applications such as loading and delivery of drugs, genes, and contrast agents either by chemical conjugation or physical loading. PMID- 29159144 TI - Thermoresponsive graphene oxide - starch micro/nanohydrogel composite as biocompatible drug delivery system. AB - Introduction: Stimuli-responsive hydrogels, which indicate a significant response to the environmental change (e.g., pH, temperature, light, ...), have potential applications for tissue engineering, drug delivery systems, cell therapy, artificial muscles, biosensors, etc. Among the temperature-responsive materials, poly (N-isopropylacrylamide) (PNIPAAm) based hydrogels have been widely developed and their properties can be easily tailored by manipulating the properties of the hydrogel and the composite material. Graphene oxide (GO), as a multifunctional and biocompatible nanosheet, can efficiently improve the mechanical strength and response rate of PNIPAAm-based hydrogels. Here, hydrogel composites (HCs) of PNIPAAm with GO was developed using the modified starch as a biodegradable cross linker. Methods: Micro/nanohydrogel composites were synthesized by free radical polymerization of NIPAAm in the suspension of different feed ratio of GO using maleate-modified starch (St-MA) as cross-linker and Tetrakis (hydroxymethyl) phosphonium chloride (THPC) as a strong oxygen scavenger. The HCs were characterized by FT-IR, DSC, TGA, SEM, and DLS. Also, the phase transition, swelling/deswelling behavior, hemocompatibility and biocompatibility of the synthesized HCs were investigated. Results: The thermal stability, phase transition temperature and internal network crosslinking of HCs increases with increasing of the GO feed ratio. Also, the swelling/deswelling, hemolysis, and MTT assays studies confirmed that the HCs are a fast response, hemocompatible and biocompatible materials. Conclusion: The employed facile approach for the synthesis of HCs yields an intelligent material with great potential for biomedical applications. PMID- 29159145 TI - pH responsive cross-linked polymeric matrices based on natural polymers: effect of process variables on swelling characterization and drug delivery properties. AB - Introduction: The current work was aimed to design and synthesize novel crosslinked pH-sensitive gelatin/pectin (Ge/Pec) hydrogels using different polymeric ratios and to explore the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and in vitro release behavior of the model drug (Mannitol). Methods: The Ge/Pec based hydrogels were prepared using glutaraldehyde as the crosslinker. Various structural parameters that affect their release behavior were determined, including swelling study, porosity, sol gel analysis, average molecular weight between crosslinks (Mc), volume fraction of polymer (V2,s), solvent interaction parameter (chi) and diffusion coefficient. The synthesized hydrogels were subjected to various characterization tools like Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and DSC differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Results: The hydrogels show highest water uptake and release at lower pH values. The FTIR spectra showed an interaction between Ge and Pec, and the drug-loaded samples also showed the drug-related peaks, indicating proper loading of the drug. DSC and TGA studies confirmed the thermal stability of hydrogel samples, while SEM showed the porous nature of hydrogels. The drug release followed non Fickian diffusion or anomalous mechanism. Conclusion: Aforementioned characterizations reveal the successful formation of copolymer hydrogels. The pH sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and drug diffusion from these hydrogels are comparable which also predicts their possible use for site-specific drug delivery. PMID- 29159146 TI - Lactobacillus plantarum induces apoptosis in oral cancer KB cells through upregulation of PTEN and downregulation of MAPK signalling pathways. AB - Introduction: The oral tumor is the sixth most prevalent type of cancer worldwide and the second leading cause of cancer-related mortality. Although chemotherapy and immunotherapy are the main strategies for the treatment of oral cancer, an emergence of inevitable resistance to these treatment modalities is the major drawback that causes recurrence of the disease. Nowadays, probiotics have been suggested as adjunctive and complementary treatment modalities for improving the impacts of chemotherapy and immunotherapy agents. Probiotics, the friendly microflora in our bodies, contribute to the production of useful metabolites with positive effects on the immune system against various diseases such as cancer. Methods:Lactobacillus plantarum is one of the most important bacteria, which commensally live in the human oral system. In the current study, the impacts of L. plantarum on maintaining oral system health were investigated, and the molecular mechanisms of inhibition of oral cancer KB cells mediated by L. plantarum were evaluated using real-time polymerase chain reaction (PCR) and FACS flow cytometry analyses. Results: Our findings showed that L. plantarum is effective in the signal transduction of the oral cancer cells through upregulation and downregulation of PTEN and MAPK pathways, respectively. Conclusion: Based on the biological effects of oral candidate probiotics candidate bacterium L. plantarum on functional expression of PTEN and MAPK pathways, this microorganism seems to play a key role in controlling undesired cancer development in the oral system. Taken all, L. plantarum is proposed as a potential candidate for probiotics cancer therapy. PMID- 29159147 TI - Osmotic conditions could promote scFv antibody production in the Escherichia coli HB2151. AB - Introduction: Single chain variable fragment (scFv) antibodies are reduced forms of the whole antibodies that could be regarded as an alternative tool for diagnostic and therapeutic purposes. The optimization of processes and environmental conditions is necessary to increase the production yields and enhance the productivity. This can result in a cost-effective process and respond to the high demand for these antibodies. Methods: In this research, physical and chemical factors influencing the batch fermentation was investigated in 50 mL batch tubes using minimum media to find the optimum conditions for production of a single chain variable fragment antibody in the Escherichia coli HB2151. Experimental designs were used to screen the effective parameters and to optimize the main factors. Results: Arabinose was used instead of IPTG as a cheaper and nontoxic inducer and its optimum concentration was determined 0.1% (w/w). Induction duration time and filling volume fraction were set on the relatively better states 24 hours and 1/10 respectively. Regarding our previous study, stationary phase of the cell growth was selected as induction start time that showed higher specific scFv production yields (YP/X) in the minimum media. Finally, a statistical experimental design was extended to a central composite design (CCD) and analysis was performed based on sucrose and sorbitol concentrations producing osmotic condition for induction. The optimum region in the contour plot for the periplasmic scFv production was an osmotic circle area with total sugar molarity 0.8 to 0.9. Conclusion: Sugars such as sucrose and sorbitol producing osmotic conditions could lead to periplasmic scFv concentrations up to 2.85 mg/L of culture media improving scFv concentration near to five times of the average of the screening step (0.59 mg/L). PMID- 29159148 TI - Endovascular Treatment of Symptomatic Vasospasm after Aneurysmal Subarachnoid Hemorrhage: A Three-year Experience. AB - Objective: The cause of severe clinical vasospasm after aneurysmal subarachnoid hemorrhage remains unknown, despite extensive research over the past 30 years. However, the intra-arterial administration of vasodilating agents and balloon angioplasty have been successfully used in severe refractory cerebral vasospasm. Materials and Methods: We retrospectively analyzed the data of 233 patients admitted to our institute with aneurysmal subarachnoid hemorrhage (SAH) over the past 3 years. Results: Of these, 27 (10.6%) developed severe symptomatic vasospasm, requiring endovascular therapy. Vasospasm occurred at an average of 5.3 days after SAH. A total of 46 endovascular procedures were performed in 27 patients. Endovascular therapy was performed once in 18 (66.7%) patients, 2 times in 4 (14.8%) patients, 3 or more times in 5 (18.5%) patients. Intra-arterial vasodilating agents were used in 44 procedures (27 with nimodipine infusion, 17 with nicardipine infusion). Balloon angioplasty was performed in only 2 (7.4%) patients. The Average nimodipine infusion volume was 2.47 mg, and nicardipine was 3.78 mg. Most patients recovered after the initial emergency room visit. Two patients (7.4%) worsened, but there were no deaths. Conclusion: With advances in endovascular techniques, administration of vasodilating agents and balloon angioplasty reduces the morbidity and mortality of vasospasm after aneurysmal SAH. PMID- 29159149 TI - Procedure-related Complications during Endovascular Treatment of Intracranial Saccular Aneurysms. AB - Objective: We evaluate the rates and outcomes of major procedure-related complications during coiling. Materials and Methods: Between 2007 and 2015, 436 intracranial saccular aneurysms were treated. Complications are categorized as three types: intraprocedural aneurysm rupture (IAR), thromboembolism (TE), and post-procedural early rebleeding (PER). And we evaluated the risk factors of procedure related complications by multivariate analysis. Results: Complications occurred in 61 aneurysms (14%). The overall incidence of complications in subarachnoid hemorrhage (SAH) was significantly higher than in unruptured intracranial aneurysm (UIA) (20% vs. 6%). The incidence of IAR and TE were higher in SAH than in UIA (IAR 12% vs. 4%, TE 7% vs. 3%, p < 0.05). Five PER occurred only in SAH. In 34 UIA which were treated with balloon-assisted coiling (BAC), all these patients had good recovery despite 3 patients had the IAR. The incidence of IAR and TE were not different between BAC and non-BAC groups (p > 0.05). All 7 patients who had IAR during BAC had good recovery. In multiple logistic regression analysis, female gender, SAH, and intraventricular hemorrhage were associated with procedure related complication (p < 0.05). Conclusion: Endovascular coil embolization is a minimally invasive procedure, but incidence of its complication is not low, especially in SAH. BAC can be a good tool to avoid poor outcome from unexpected IAR during coiling. While IA tirofiban injection is a useful therapy in TE during coiling, sometimes we are aware of the risk of the early rebleeding in SAH patients. PMID- 29159150 TI - The Blood Blister Like-aneurysm: Usefulness of Sundt Clip. AB - Objective: Blood blister-like aneurysm (BBA) is a kind of dorsal wall aneurysm and it is small, sessile, fragile and hazardous because of its high mortality and morbidity. Many challenges tried to establish the management or strategy. But so far, there is no optimal treatment of choice for the BBA. In this article, 17 cases of the ruptured BBA in one institute were analyzed retrospectively. The operative options were correlated with surgical and clinical outcomes. Materials and Methods: During 14 years between October, 2002 and October, 2016, 23 patients were treated for subarachnoid hemorrhage with ruptured dorsal wall aneurysms. There were various strategies for treatment and different outcomes revealed. BBA were 17 (74%) cases and 6 (26%) cases were saccular aneurysm. By excluding saccular aneurysm, BBA was sorted and classified with its morphological characteristics, and the outcome of treatment in each case investigated retrospectively. Results: Among 17 BBA-cases, 8 cases get microsurgical operation by Sundt clip. 5 cases get operation by conventional Yasargil clip, 1 case treated by Yasargil clip with wrapping, and 2 cases underwent endovascular management with coiling, and 1 case was managed by endovascular trapping of involved internal cerebral artery. Clinical outcomes were analyzed with modified Rankin Scale, Glasgow outcome scale and post-operative complications. Conclusion: As the optimal management, operation using Sundt clip had much significance in treatment BBA. And, a thorough analysis of the angiography is essential to prepare for the treatment of BBA. PMID- 29159151 TI - A Case of Unusual Presentation of Contrast-induced Encephalopathy after Cerebral Angiography Using Iodixanol. AB - Contrast-induced encephalopathy after cerebral angiography is a rare complication and until now, only few cases have been reported. This paper reports on contras induced encephalopathy mimicking meningoencephalitis after cerebral angiography by using iodixanol, an iso-osmolar non-ionic contrast agent. A 58-year-old woman underwent cerebral angiography for the evaluation of multiple intracranial aneurysms. A few hours later, she had persistent headache, vomiting, fever, and seizures. Brain computed tomography (CT) showed sulcal obliteration of right cerebral hemisphere and cerebrospinal fluid profile was unremarkable. The next day, she developed left side hemiparesis, sensory loss, and left-sided neglect with drowsy mentality. Brain magnetic resonance imaging (MRI) showed cerebral swelling with leptomeningeal enhancement in the right parieto-occipital lobe without sign of ischemia or hemorrhage. The patient was managed with intravenous dexamethasone, mannitol and anticonvulsant. There was a progressive neurological improvement with complete resolution of the symptoms at day 6. This observation highlights that contrast-induced encephalopathy can be caused by an iso-osmolar non-ionic contrast agent. This rare entity should be suspected if neurologic deterioration after cerebral angiography is not explained by other frequent causes such as acute infarction or hemorrhage. PMID- 29159152 TI - Cranial Nerve Palsy after Onyx Embolization as a Treatment for Cerebral Vascular Malformation. AB - The Onyx liquid embolic system is a relatively safe and commonly used treatment for vascular malformations, such as arteriovenous fistulas and arteriovenous malformations. However, studies on possible complications after Onyx embolization in patients with vascular malformations are limited, and the occurrence of cranial nerve palsy is occasionally reported. Here we report the progress of two different types of cranial nerve palsy that can occur after embolization. In both cases, Onyx embolization was performed to treat vascular malformations and ipsilateral oculomotor and facial nerve palsies were observed. Both patients were treated with steroids and exhibited symptom improvement after several months. The most common types of neuropathy that can occur after Onyx embolization are facial nerve palsy and trigeminal neuralgia. Although the mechanisms underlying these neuropathies are not clear, they may involve traction injuries sustained while extracting the microcatheter, mass effects resulting from thrombi and edema, or Onyx reflux into the vasa nervorum. In most cases, the neuropathy spontaneously resolves several months following the procedure. PMID- 29159153 TI - Endovascular Treatment of a Fusiform Aneurysm Involving a Premammillary Artery Originating from the Internal Carotid Artery: A Case Report. AB - The premammillary artery (PMA) is a branch of the posterior communicating artery (PCoA). While the PMA is known to originate from the PCoA as demonstrated by most anatomical studies, it originates directly from the internal carotid artery in approximately 1% of patients. Cerebral aneurysms associated with the PMA have rarely been reported. We report an extremely rare case of a ruptured PMA aneurysm that was managed using endovascular treatment. PMID- 29159154 TI - Horizontal Stent Assisted Coiling of Wide Neck Basilar Tip Aneurysm: Comparison of Two Cases. AB - Currently, endovascular coiling is a popular treatment for basilar tip aneurysms, which usually involve a wide neck. Serious complications can occur when the posterior cerebral artery (PCA) originating from a wide neck is not properly preserved. Accordingly, various adjunctive procedures using stents or a balloon have been introduced. Herein we report two cases of basilar tip aneurysms in which retrograde horizontal (from one PCA to the other PCA) stent-assisted coiling was successful, and we provide a summary of the important technical points. PMID- 29159155 TI - How to Escape Stentriever Wedging in an Open-cell Carotid Stent during Mechanical Thrombectomy for Tandem Cervical Internal Carotid Artery and Middle Cerebral Artery Occlusion. AB - We present 2 cases of complicated mechanical thrombectomy involving tandem cervical internal carotid artery and middle cerebral artery occlusion using the Solitaire FR stent and simultaneous carotid stent angioplasty. During the procedures, the Solitaire stents containing the thrombus were wedged into the open-cell carotid stents, which were already deployed for proximal flow restoration. We describe the methods used to avoid and overcome such complications. PMID- 29159156 TI - Self-expandable Graft Stenting in an Iatrogenic Fistula between Common Carotid Artery and Internal Jugular Vein. AB - A 47-year-old woman with stage IV chronic kidney disease developed a fistula between common carotid artery (CCA) and internal jugular vein (IJV) during central catheterization of the right IJV. The patient was treated with a self expandable graft stent, which achieved successful closure of the carotid-jugular fistula. As demonstrated in our case, self-expandable graft stents could be a feasible treatment option for CCA-IJV fistulas without additional interventional procedures such as balloon angioplasty. PMID- 29159157 TI - Surgical Removal of a Ruptured Radiculomedullary Artery Aneurysm: A Case Report. AB - Subarachnoid hemorrhage due to a solitary spinal aneurysm is extremely rare, and diagnosis and treatment are challenging. We report a rare case of a ruptured radiculomedullary artery aneurysm in a patient with Behcet disease. A 49-year-old man presented with severe lower abdominal and leg pain. Magnetic resonance imaging was performed and an enhanced intradural-extramedullary lesion at the T12 spinal level with subarachnoid hemorrhage was identified. Diagnostic spinal angiography was performed to evaluate the vascular lesion, and a radiculomedullary artery aneurysm at the T12 level was identified. We performed surgical resection of the aneurysm and a good neurological outcome was obtained. PMID- 29159158 TI - Transarterial Balloon-assisted Onyx Embolization of Intracranial Arteriovenous Malformations Using a Dual-lumen Balloon Microcatheter: Two Case Reports. AB - The Onyx system has been well established in recent years as a very important material in the treatment of arteriovenous malformations (AVMs). When using the Onyx, it is essential to wait for the creation of a plug around the tip of the catheter, which enables the effective forward penetration of Onyx. Recent reports have shown that the introduction of a dimethyl sulfoxide compatible dual-lumen balloon microcatheter improves the efficiency of AVM embolization. We report our recent experience of two cases of intracranial AVM embolization using Onyx and the transarterial balloon-assisted technique. In both cases, the procedures were successfully performed and the nidus of the AVM was totally occluded in a relatively short time. This technique may enable immediate forward flow and penetration of Onyx without concern about reflux. It may also reduce the procedure time and increase the angiographic occlusion rate. Navigation of the dual-lumen balloon microcatheter nevertheless remains a challenge. PMID- 29159159 TI - Corrigendum: Genome Reduction for Niche Association in Campylobacter Hepaticus, A Cause of Spotty Liver Disease in Poultry. AB - [This corrects the article on p. 354 in vol. 7, PMID: 28848714.]. PMID- 29159160 TI - Lactose Intolerance and Colorectal Cancer. PMID- 29159161 TI - Correlation Between Anastomotic Configuration and Long-term Outcomes in Surgery for Crohn Disease. PMID- 29159163 TI - Association of LCT-13910 C/T Polymorphism and Colorectal Cancer. AB - Purpose: The activity of epithelial lactase (LCT) is associated with a polymorphism 13910 bp upstream in the lactase encoding gene. Because the association between the LCT-13910 polymorphism and the risk for colorectal cancer is not clear, we investigated the role of the LCT-13910 polymorphism as a potential risk factor for colorectal cancer and colorectal polyps in the Turkish population. Methods: One hundred sixty-six subjects (74 with polyps, 44 with colorectal cancer, 48 controls), who had undergone a total colonoscopy between January 2012 and November 2012 in our endoscopy unit were genotyped for the LCT 13910 polymorphism by using the polymerase chain reaction and minisequencing. Results: The CC genotype in the lactose gene 13910 locus, which is accepted as the genetic indicator of lactase deficiency, was determined as 83.7%. The CC genotype rate was determined as 89.1% in patients who had a history of lactose intolerance and 81.5% in those without a history of lactose intolerance (P = 0.236). No difference was detected between the patients who had colorectal polyp(s) and/or cancer and the controls with regard to the LCT-13910 polymorphism. No differences were determined between groups when they were compared with regard to the C or the T allele. Conclusion: No differences were detected between the patients who had colorectal polyp(s) and/or cancer and those with normal colonoscopy findings with regard to lactase gene polymorphisms. No differences were determined between the groups when they were compared with regard to the C or the T allele. PMID- 29159162 TI - Electrophysiological Basis of Fecal Incontinence and Its Implications for Treatment. AB - The majority of patients with neuropathic incontinence and other pelvic floor conditions associated with straining at stool have damage to the pudendal nerves distal to the ischial spine. Sacral nerve stimulation appears to be a promising innovation and has been widely adopted and currently considered the standard of care for adults with moderate to severe fecal incontinence and following failed sphincter repair. From a decision-to-treat perspective, the short-term efficacy is good (70%-80%), but the long-term efficacy of sacral nerve stimulation is around 50%. Newer electrophysiological tests and improved anal endosonography would more effectively guide clinical decision making. PMID- 29159164 TI - Does Anastomosis Configuration Influence Long-term Outcomes in Patients With Crohn Disease? AB - Purpose: In this study, we evaluated the role of various anastomoses in surgical recurrence for patients with Crohn disease (CD). Methods: We analyzed data retrospectively from consecutive laparotomy cases involving complicated CD between 1991 and 2008. Clinical data were compared in terms of reoperation-free survival (RFS) according to the types of anastomoses, the materials used for the anastomoses, and the operating surgeon. Results: Of 233 patients with entero enteric or entero-colic anastomoses, 199 (85%), 11 (5%), and 23 (10%) experienced side-to-side (SS), side-to-end (SE), and end-to-end (EE) anastomoses, respectively. The SS group had the following characteristics: more extensive bowel involvement, frequent obstruction, and greater stapler use; the SS anastomoses were also frequently made by specialized surgeons (P < 0.001-0.004). EE anastomoses were frequently made by general surgeons using a hand-sewing technique (P < 0.001). No differences in RFS were noted among the 3 groups according to the type of anastomosis and the operating surgeon. However, the hand sewn group showed better RFS than the stapler group (P = 0.04). Conclusion: The roles of the anastomotic configuration, the material used, and the operating surgeon were not significantly correlated with reoperations or complications in our retrospective CD cohort, irrespective of the higher risk of anastomosis site stricture for EE anastomoses. PMID- 29159165 TI - Clinical Features and Factors Associated With Surgical Treatment in Patients With Complicated Colonic Diverticulitis. AB - Purpose: Colonic diverticulitis is uncommon in Korea, but the incidence is rapidly increasing nowadays. The clinical features and the factors associated with complications of diverticulitis are important for properly treating the disease. Methods: A retrospective review of the medical records of 225 patients that were prospectively collected between October 2007 and September 2016 was conducted. Results: Diverticulitis was detected mainly in men and women aged 30 to 50 years. Diverticulitis more frequently affected the right colon (n = 194, 86.2%), but age was higher in case of left colonic involvement (42 years vs. 57 years, P < 0.001). Percentages of comorbidities (65.6% vs. 23.8%, P < 0.001), complications (65.6% vs. 6.2%, P < 0.001), and surgical treatment (50.0% vs. 4.1%, P < 0.001) were significantly higher in patients with left colonic diverticulitis. In the multivariate analysis, a risk factor for complicated diverticulitis was left colonic involvement (P < 0.001; relative risk [RR], 47.108; 95% confidence interval [CI], 12.651-175.413). In complicated diverticulitis, age over 50 was the only significant risk factor for surgical treatment (P = 0.024; RR, 19.350; 95% CI, 1.474-254.023). Conclusion: In patients over 50 years of age with left colonic diverticulitis, a preventive colectomy should be reconsidered as one of the options for treatment. PMID- 29159166 TI - Laparoscopic and Robotic Surgeries for Patients With Colorectal Cancer Who Have Had a Previous Abdominal Surgery. AB - Purpose: The impact of previous abdominal surgery (PAS) on surgical outcomes from laparoscopic and robot surgeries is inconclusive. This study aimed to investigate the impact of PAS on perioperative outcomes from laparoscopic and robotic colorectal surgeries. Methods: From March 2007 to February 2014, a total of 612 and 238 patients underwent laparoscopic and robotic surgeries, respectively. Patients were divided into 3 groups: those who did not have a PAS (NPAS), those who had a major PAS, and those who had a minor PAS. We further divided the patients so that our final groups for analysis were: patients with NPAS (n = 478), major PAS (n = 19), and minor PAS (n = 115) in the laparoscopy group, and patients with NPAS (n = 202) and minor PAS (n = 36) in the robotic surgery group. Results: In the laparoscopy group, no differences in the conversion rates between the 3 groups were noted (NPAS = 1.0% vs. major PAS = 0% vs. minor PAS = 1.7%, P = 0.701). In the robotic surgery group, the conversion rate did not differ between the NPAS group and the minor PAS group (1.0% vs. 2.8%, P = 0.390). Among the groups, neither the operation time, blood loss, days to soft diet, length of hospital stay, nor complication rate were affected by PAS. Conclusion: PAS did not jeopardize the perioperative outcomes for either laparoscopic or robotic colorectal surgeries. Therefore, PAS should not be regarded as an absolute contraindication for minimally invasive colorectal surgeries. PMID- 29159167 TI - Accuracy of Preoperative Local Staging of Primary Colorectal Cancer by Using Computed Tomography: Reappraisal Based on Data Collected at a Highly Organized Cancer Center. AB - Purpose: In patients with colorectal cancer, preoperative staging using various imaging technologies is important for establishing the treatment plan and predicting the prognosis. Although computed tomography (CT) has been used most widely, the versatility of CT accuracy was primarily because of the lack of specialization. In this study, we aimed to identify whether any advancement in abdominal CT accuracy in the prediction of local staging has occurred. Methods: Between December 2014 and November 2015, patients with colorectal cancer were retrospectively enrolled. All CT findings were retrospectively reported. A total of 285 patients were included, and their retrospectively collected data were retrospectively reviewed, focusing on a comparison between preoperative and postoperative staging. Results: The overall prediction accuracy of the T stage was 55.1%, with overstaging occurring in 63 (22.1%) and understaging in 65 patients (22.8%). The sensitivity and specificity were 90.0% and 68.4%, respectively. The overall prediction accuracy of the N stage was 54.7%, with overstaging occurring in 89 (31.2%) and understaging in 40 patients (14.1%). The sensitivity and specificity were 71.9% and 63.2%, respectively. The CT accuracies by pathologic stage were 0%, 62.2%, 25.3%, and 81.2% for stages 0 (Tis N0), I, II, and III, respectively. Conclusion: CT has good sensitivity for detecting colon cancers with tumor invasion beyond the bowel wall. However, detection of nodal involvement using CT is unreliable. In our opinion, abdominal CT alone has limitations in predicting the local staging of colorectal cancer, and additional technologies, such as CT plus positron emission tomography and/or colonography, will improve its accuracy. PMID- 29159168 TI - Incidental Mesenteric Paraganglioma: A Case Report and Literature Review. AB - Mesenteric paragangliomas are a rare entity; consequently, only 12 cases have been reported to date. Although considered benign and often found incidentally, they have the potential to metastasize and are an important diagnosis to consider for patients with a mesenteric tumor. We report the case of a 71-year-old woman who was found on magnetic resonance imaging to have an incidental, large, complex, intra-abdominal mass that had initially been misdiagnosed as ovarian in origin. She underwent an open resection of the tumor and adjacent small bowel with no perioperative complications; histology confirmed the mass to be a mesenteric paraganglioma. This case report highlights several important key issues regarding paraganglioma, including diagnosis, imaging, genetic testing, and surgical resection. The results of a literature review are also discussed. PMID- 29159169 TI - Salmonella enteritis: A Rare Cause of Adult Intussusception. AB - Intussusception is a relatively rare condition in the adult population and is commonly secondary to a malignant process. Eight to twenty percent of cases of adult intussusception are thought to be idiopathic. In children, infection has been proven to precipitate intussusception in the absence of any other cause. We present a rare case of intussusception in a healthy adult patient secondary to salmonella infection and discuss infection as a potential explanation for a proportion of the cases of adult intussusception that are thought to be idiopathic. We recommend testing for infective causes of intussusception in adults when more common causes, such as malignancy, have been excluded. PMID- 29159170 TI - A case of dystrophic calcification in the masseter muscle. AB - Background: Dystrophic calcification can occur in any soft tissue with the absence of a systemic mineral imbalance and is often associated with trauma, infection, or inflammation. It is easily found in the site of the heart and skeletal muscles and rarely appears in the head and neck area. Case report: We present a rare case of multiple calcified masses in the left masseter muscle of a 26-year-old female with a history of trauma in the area. In computed tomography, multiple radiopaque masses were observed inside the left masseter muscle and blood test results were normal. The calcified masses were diagnosed as dystrophic calcification and removed by surgery without any complications. Conclusion: Different types of calcifications may occur in the cheek area, and they need to be distinguished from dystrophic calcification. Thorough clinical examination and history taking is required together with blood testing and radiographic examinations. PMID- 29159171 TI - Recent advances in dental implants. AB - Dental implants are a common treatment for the loss of teeth. This paper summarizes current knowledge on implant surfaces, immediate loading versus conventional loading, short implants, sinus lifting, and custom implants using three-dimensional printing. Most of the implant surface modifications showed good osseointegration results. Regarding biomolecular coatings, which have been recently developed and studied, good results were observed in animal experiments. Immediate loading had similar clinical outcomes compared to conventional loading and can be used as a successful treatment because it has the advantage of reducing treatment times and providing early function and aesthetics. Short implants showed similar clinical outcomes compared to standard implants. A variety of sinus augmentation techniques, grafting materials, and alternative techniques, such as tilted implants, zygomatic implants, and short implants, can be used. With the development of new technologies in three-dimension and computer aided design/computer-aided manufacturing (CAD/CAM) customized implants can be used as an alternative to conventional implant designs. However, there are limitations due to the lack of long-term studies or clinical studies. A long-term clinical trial and a more predictive study are needed. PMID- 29159173 TI - Corrigendum: Dogs with Acute Myeloid Leukemia Have Clonal Re-arrangements in T and B Cell Receptors. AB - [This corrects the article on p. 76 in vol. 4, PMID: 28620611.]. PMID- 29159174 TI - Prevalence and Association of Obesity with Self-Reported Comorbidity: A Cross Sectional Study of 1321 Adult Participants in Lasbela, Balochistan. AB - Association of fatness with chronic metabolic diseases is a well-established fact, and a high prevalence of risk factors for these disorders has increasingly been reported in the third world. In order to incorporate any preventive strategies for such risk factors into clinical practice, decision-makers require objective evidence about the associated burden of disease. A cross-sectional study of 1321 adults from one of the districts of Balochistan, among the most economically challenged areas of Pakistan, was carried out for the measures of fatness and self-reported comorbidities. Body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) were measured and demographic information and self-reported comorbidities were documented. The prevalence of obesity was 4.8% (95% CI: [3.8, 6.1]) and 21.7% (95% CI: [19.5, 24.0]), as defined by the World Health Organization (WHO) international and Asia/Asia Pacific BMI cut-offs, respectively. The proportion exhibiting comorbidity increased with increasing levels of fatness in a dose-response relationship (p value < .001). An interaction of weight status with gender was observed to produce a significantly (p = .033) higher comorbidity among overweight women (odds ratio (OR) = 6.1 [1.2, 31.7]) compared with overweight men (OR = 1.1 [0.48, 2.75], p = .762). PMID- 29159172 TI - Examining the Link between Biofilm Formation and the Ability of Pathogenic Salmonella Strains to Colonize Multiple Host Species. AB - Salmonella are important pathogens worldwide and a predominant number of human infections are zoonotic in nature. The ability of strains to form biofilms, which is a multicellular behavior characterized by the aggregation of cells, is predicted to be a conserved strategy for increased persistence and survival. It may also contribute to the increasing number of infections caused by ingestion of contaminated fruits and vegetables. There is a correlation between biofilm formation and the ability of strains to colonize and replicate within the intestines of multiple host species. These strains predominantly cause localized gastroenteritis infections in humans. In contrast, there are salmonellae that cause systemic, disseminated infections in a select few host species; these "invasive" strains have a narrowed host range, and most are unable to form biofilms. This includes host-restricted Salmonella serovar Typhi, which are only able to infect humans, and atypical gastroenteritis strains associated with the opportunistic infection of immunocompromised patients. From the perspective of transmission, biofilm formation is advantageous for ensuring pathogen survival in the environment. However, from an infection point of view, biofilm formation may be an anti-virulence trait. We do not know if the capacity to form biofilms prevents a strain from accessing the systemic compartments within the host or if loss of the biofilm phenotype reflects a change in a strain's interaction with the host. In this review, we examine the connections between biofilm formation, Salmonella disease states, degrees of host adaptation, and how this might relate to different transmission patterns. A better understanding of the dynamic lifecycle of Salmonella will allow us to reduce the burden of livestock and human infections caused by these important pathogens. PMID- 29159175 TI - Multilocus Sequencing of Corynebacterium pseudotuberculosis Biotype Ovis Strains. AB - Thirteen Corynebacterium pseudotuberculosis biotype ovis strains isolated from clinical cases of caseous lymphadenitis in Hungary were characterised using multilocus sequencing and their phylogenetic comparison was carried out on the basis of four housekeeping genes (groEL1, infB, dnaK, and leuA). The in silico analysis of the 16 frequently studied housekeeping genes showed that C. pseudotuberculosis strains could be readily distinguished from C. diphtheriae and C. ulcerans strains; however, sequences of the same genes in the two biotypes of the C. pseudotuberculosis were highly similar; the heterogeneity values were low. Genes dnaK, infB, groEL1, and leuA showed marked genetic variation within C. pseudotuberculosis, and strains of the two biotypes of C. pseudotuberculosis could be differentiated. Analysis of the individual genes showed a fairly conservative nature of C. pseudotuberculosis biotype ovis strains. The greatest genetic differentiation was seen in the dnaK and infB genes and concatenations of these two genes were very useful in the genetic separation of the studied strains. PMID- 29159176 TI - Effect of Alternate Nostril Breathing Exercise on Experimentally Induced Anxiety in Healthy Volunteers Using the Simulated Public Speaking Model: A Randomized Controlled Pilot Study. AB - A randomized controlled pilot study was carried out to determine the effect of a 15-minute practice of ANB exercise on experimentally induced anxiety using the simulated public speaking model in yoga-naive healthy young adults. Thirty consenting medical students were equally divided into test and control groups. The test group performed alternate nostril breathing exercise for 15 minutes, while the control group sat in a quiet room before participating in the simulated public speaking test (SPST). Visual Analog Mood Scale and Self-Statements during Public Speaking scale were used to measure the mood state at different phases of the SPST. The psychometric scores of both groups were comparable at baseline. Repeated-measures ANOVA showed a significant effect of phase (p < 0.05), but group and gender did not have statistically significant influence on the mean anxiety scores. However, the test group showed a trend towards lower mean scores for the anxiety factor when compared with the control group. Considering the limitations of this pilot study and the trend seen towards lower anxiety in the test group, alternate nostril breathing may have potential anxiolytic effect in acute stressful situations. A study with larger sample size is therefore warranted. This trial is registered with CTRI/2014/03/004460. PMID- 29159177 TI - Effectiveness of Chinese Herbal Medicine Combined with Antibiotics for Extensively Drug-Resistant Enterobacteria and Nonfermentative Bacteria Infection: Real-Life Experience in a Retrospective Cohort. AB - Chinese herbal medicines (CHMs) have been successfully used in the treatment of infectious diseases, yet the effectiveness of CHMs for extensively drug-resistant enterobacteria (XDRE) infection remains unclear. Herein we developed a retrospective multicenter study including 766 patients with XDRE and nonfermentative bacteria (NFB) infection to investigate the effectiveness of CHMs combined with antibiotics in the treatment of XDRE infections in clinical daily practice in a cohort of patients and compared the regular antibiotics monotherapy. After 14-day treatment, the 547 patients accepted CHMs combined with antibiotics therapy indicating a more desirable effectiveness compared to the 219 patients treated with antibiotics monotherapy. The primary evaluation indexes included white blood cell count (WBC) and percentage of neutrophil (N%) in blood test. Secondary evaluation indexes consisted of body temperature, breath, heart rate, platelets, hemoglobin, red blood cell, albumin, creatinine, glucose, and 28 day survival rates. Briefly speaking, in our experience, CHMs combined with antibiotics therapy achieved more desirable effectiveness in treating XDRE infections compared with antibiotics monotherapy, and CHMs might be a potential huge resource in the field of XDRE infection management and enlighten the new antibiotics research and development. This trial is registered with ChiCTR-ORC 17011760. PMID- 29159178 TI - Zinc-Containing Hydroxyapatite Enhances Cold-Light-Activated Tooth Bleaching Treatment In Vitro. AB - Cold-light bleaching treatment has grown to be a popular tooth whitening procedure in recent years, but its side effect of dental enamel demineralization is a widespread problem. The aim of this study was to synthesize zinc-substituted hydroxyapatite as an effective biomaterial to inhibit demineralization or increase remineralization. We synthesized zinc-substituted hydroxyapatite containing different zinc concentrations and analysed the product using X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and energy dispersive spectrometer (EDS). The biological assessment of Zn-HA was conducted by CCK-8 assay and bacterial inhibition tests. pH cycling was performed to estimate the effect of Zn-HA on the enamel surface after cold-light bleaching treatment. The XRD, FTIR, and EDS results illustrated that zinc ions and hydroxyapatite combined in two forms: (1) Zn2+ absorbed on the surface of HA crystal and (2) Zn2+ incorporated into the lattice of HA. The results indicated that 2% Zn-HA, 4% Zn-HA, and 8% Zn-HA effectively inhibited the growth of bacteria yet showed poor biocompatibility, whereas 1% Zn-HA positively affected osteoblast proliferation. The XRD and scanning electron microscopy (SEM) results showed that the use of Zn-HA in pH cycling is obviously beneficial for enamel remineralization. Zinc-substituted hydroxyapatite could be a promising biomaterial for use in cold-light bleaching to prevent enamel demineralization. PMID- 29159179 TI - miR-31 Functions as an Oncomir Which Promotes Epithelial-Mesenchymal Transition via Regulating BAP1 in Cervical Cancer. AB - MicroRNA-31 (miR-31) functions as tumor suppressors or oncogenes that are involved in tumor behavior. However, the function of miR-31 in cervical carcinogenesis remains unclear. The aim of this study was to validate the potential role of miR-31 and BRCA1-associated protein-1 (BAP1) on regulating epithelial-mesenchymal transition (EMT) in cervical cancer. In the present study, qRT-PCR assay revealed that the expression of miR-31 was upregulated in human cervical cancer cells and clinical tissues. Results of wound healing and cell migration assay revealed that knockdown of miR-31 inhibited cell metastasis and migration. Bioinformatic and dual-luciferase reporter gene assay showed that BAP1 was the direct target of miR-31. Furthermore, the results revealed that miR-31 promoted proliferation and EMT in cervical cancer cells and accelerated the development of tumor growth in vivo xenograft experiment by inhibiting BAP1 expression. Overall, these results highlight an important role of miR-31 functioning as an oncomir which could promote EMT in cervical cancer via downregulating BAP1 expression. Thus, downregulation of miR-31 could be a novel approach for the molecular treatment of cervical cancers and other malignancies. PMID- 29159180 TI - The Influence of Serum Prostate-Specific Antigen on the Accuracy of Magnetic Resonance Imaging Targeted Biopsy versus Saturation Biopsy in Patients with Previous Negative Biopsy. AB - Objective: We compared the prostate cancer (PCa) detection rates of targeted biopsy (TB) and saturation biopsy (SB) in patients with previous negative biopsy and the accuracy of TB and SB stratified by different serum prostate-specific antigen (PSA) levels. Materials and Methods: Overall 185 patients were enrolled. In the magnetic resonance imaging (MRI) group, 65 men underwent TB and SB. In the control group, 120 men underwent SB alone. The primary outcome was the difference in PCa detection rate between the MRI group and control group. The secondary outcome was the difference in accuracy between TB and SB in detecting clinically significant PCa by stratifying the patients in the MRI group into those with PSA < 10 ng/ml and PSA >= 10 ng/ml. Results: The detection rates for overall and clinically significant PCa were higher in the MRI group than in the control group (46.2% versus 20.9% and 43.1% versus 16.7%, both p < 0.001). In the MRI group, the accuracy of TB was higher than SB (94.7% versus 84.2%, p = 0.001) for the patients with PSA >= 10 ng/mL. Conclusions: Combining TB and SB achieved the best cancer detection rate. The accuracy of TB was better than SB in the patients with serum PSA >= 10 ng/mL. PMID- 29159181 TI - Living Conditions and Helicobacter pylori in Adults. AB - Introduction: Infection by the bacterium Helicobacter pylori (H. pylori) is transmissible and is considered a public health issue which affects people of all ages. The objective of this study was to identify factors (lifestyles, dietary factors, and hygiene conditions) related to the prevalence of H. pylori infection. Methods: We carried out an observational cross-sectional study with a community sample of adults from the municipalities of Viseu and Satao, Portugal. The final sample resulted in 166 adults. The data were collected through a self administered questionnaire with questions regarding sociodemographic aspects and lifestyles. H. pylori infection was identified using the 13C-urea breath test. Results: No association was found between the prevalence of H. pylori infection and the use of tobacco, alcohol, or coffee or dietary factors. The prevalence of H. pylori infection was higher in adults who reported higher consumption of fried food and lower consumption of vegetables and fruit. H. pylori infection was significant for the variables of lower frequency of handwashing before going to the bathroom (p = 0.02) and well water consumption (p = 0.05). Conclusion: A significant association was found for H. pylori infection with the lower frequency of handwashing before going to the bathroom and the consumption of well water. PMID- 29159182 TI - A Psychological Perspective on Preterm Children: The Influence of Contextual Factors on Quality of Family Interactions. AB - Preterm birth has a critical influence on interactive, communicative, and expressive child behaviour, particularly during the first years of life. Few studies have stressed the assessment of mother-father-child interaction in families with preterm children, generating contradictory results. The present study wished to develop these fields: (i) comparing the quality of family interactions between families with preterm children and families with children born at full term; (ii) observing the development of family interactions after six months in the families with children born preterm; (iii) assessing family and contextual factors, as parental stress and social support, in parents of preterm children in order to observe their influence on the quality of family interactions. 78 families are recruited: 39 families with preterm children (M = 19,8 months, SD = 11,05) and 39 families with full-term children (M = 19,66 months; SD = 13,10). Results show that families with preterm children display a low quality of mother-father-child interactions. After six months, family interactions result is generally stable, except for some LTP-scales reflecting a hard adjustment of parenting style to the evolution of the child. In families with preterm children, the parenting stress seemed to be correlated with the quality of mother-father-child interactions. PMID- 29159183 TI - Patients Affected by Unmethylated O(6)-Methylguanine-DNA Methyltransferase Glioblastoma Undergoing Radiochemotherapy May Benefit from Moderately Dose Escalated Radiotherapy. AB - Purpose: To compare the therapeutic results of two radiotherapy (RT) dose schedules in combined temozolomide- (TMZ-) RT treatment in newly diagnosed glioblastoma (GB), according to the O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status. Material and Method: Patients received either standard (60 Gy) or moderately escalated dose (70 Gy) radiotherapy (RT) with concomitant and adjuvant TMZ between June 2006 and October 2013. We retrospectively evaluated the therapeutic effectiveness of RT schedules in terms of Overall Survival (OS) and Progression-Disease Free Survival (PDFS) analyzing the MGMT methylation status. Results: One hundred and seventeen patients were selected for the present analysis. Seventy-two out of the selected cases received the standard RT-TMZ course (SDRT-TMZ) whereas the remaining 45 underwent the escalated schedule (HDRT TMZ). The analysis according to the MGMT promoter methylation status showed that, in unmethylated-MGMT GB patients, HDRT-TMZ and SDRT-TMZ groups had different median OS (p = 0,01) and PDFS (p = 0,007), that is, 8 months and 5 months for the SDRT-TMZ group and 14 months and 9 months for the HDRT-TMZ group, respectively. No difference in survival outcomes was found in methylated MGMT patients according to the two RT schedules (p = 0,12). Conclusions: In our experience, unmethylated-MGMT GB patients benefited from a moderately escalated dose of RT plus TMZ. PMID- 29159184 TI - Acute Asthma in the Pediatric Emergency Department: Infections Are the Main Triggers of Exacerbations. AB - Background: Asthma exacerbations are a common reason for Emergency Department (ED) visits in children. Aim: To analyze differences among age groups in terms of triggering factors and seasonality and to identify those with higher risk of severe exacerbations. Methods: We retrospectively revised the files of children admitted for acute asthma in 2016 in our Pediatric ED. Results: Visits for acute asthma were 603/23197 (2.6%). 76% of the patients were <6 years old and 24% >=6. Infections were the main trigger of exacerbations in both groups; 33% of the school-aged children had a triggering allergic condition (versus 3% in <6 years; p < .01). 191 patients had a previous history of asthma; among them, 95 were >=6 years, 67% of whom were not using any controller medication, showing a higher risk of a moderate-to-severe exacerbation than those under long-term therapy (p < .01). Exacerbations peaked in autumn and winter in preschoolers and in spring and early autumn in the school-aged children. Conclusions: Infections are the main trigger of acute asthma in children of any age, followed by allergy in the school aged children. Efforts for an improved management of patients affected by chronic asthma might go through individualized action plans and possibly vaccinations and allergen-avoidance measures. PMID- 29159185 TI - Design and Testing of an Experimental Steam-Induced Burn Model in Rats. AB - Background: Most of the current models for experimental burns pose difficulties in ensuring consistency and standardization. Aim of Study: We aimed to develop an automated, reproducible technique for experimental burns using steam-based heat transfer. Methods: The system developed for steam exposure was based on a novel, integrated, computer-controlled design. Three groups of rats were exposed to steam for 1, 3, and 7 seconds. The lesions were evaluated after 20 minutes, 48 hours, and 72 hours after burn induction. Results: One-second steam application produced a superficial second-degree burn; three-second application induced deep second-degree burn; and seven-second application led to a third-degree burn. Conclusion: The high level of automation of our integrated, computer-controlled system makes the difference between our system and other models, by ensuring the control of the duration of exposure, temperature, and pressure and eliminating as many potential human generated errors as possible. The automated system can accurately reproduce specific types of burns, according to histological assessment. This model could generate the reproducible data needed in the study of burn pathology and in order to assess new treatments. PMID- 29159186 TI - Protective Effects of Ophiocordyceps lanpingensis on Glycerol-Induced Acute Renal Failure in Mice. AB - Objective: Oxidative stress and immune response are associated with acute renal failure (ARF). Ophiocordyceps lanpingensis (OL) might be an antioxidant and immunopotentiator. In this study, we explored the protective effects of OL on glycerol-induced ARF. Methods: Male mice were randomly divided into four groups, specifically, glycerol-induced ARF model group, low-dose OL-treated group (1.0 g/kg/d), high-dose OL-treated group (2.0 g/kg/d), and control group. Renal conditions were evaluated using kidney index, serum creatinine (Cr), blood urea nitrogen (BUN), and histological analysis. Rhabdomyolysis was monitored using creatine kinase (CK) level. Oxidative stress was determined using kidney tissue glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. Immune status was evaluated using immune organ indices and immunoglobulin G (IgG) level. Results: OL could relieve renal pathological injury and decrease the abnormal levels of kidney index, serum Cr, CK, BUN, and MDA, as well as increase the immune organ indices and the levels of IgG, GSH, and SOD. Treatment with a high dose of OL had more positive therapeutic effects on ARF than using a low dose of OL. Conclusion: OL could ameliorate renal dysfunction in glycerol-induced ARF in mice by inhibiting oxidative stress and enhancing immune response. PMID- 29159188 TI - Correction to: The impact of dysfunctional tear films and optical aberrations on chronic migraine. AB - [This corrects the article DOI: 10.1186/s40662-017-0070-1.]. PMID- 29159187 TI - The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation. AB - Pig-to-human xenotransplantation offers a potential bridge to the growing disparity between patients with end-stage organ failure and graft availability. Early studies attempting to overcome cross-species barriers demonstrated robust humoral immune responses to discordant xenoantigens. Recent advances have led to highly efficient and targeted genomic editing, drastically altering the playing field towards rapid production of less immunogenic porcine tissues and even the discussion of human xenotransplantation trials. However, as these humoral immune barriers to cross-species transplantation are overcome with advanced transgenics, cellular immunity to these novel xenografts remains an outstanding issue. Therefore, understanding and optimizing immunomodulation will be paramount for successful clinical xenotransplantation. Costimulation blockade agents have been introduced in xenotransplantation research in 2000 with anti-CD154mAb. Most recently, prolonged survival has been achieved in solid organ (kidney xenograft survival > 400 days with anti-CD154mAb, heart xenograft survival > 900 days, and liver xenograft survival 29 days with anti-CD40mAb) and islet xenotransplantation (>600 days with anti-CD154mAb) with the use of these potent experimental agents. As the development of novel genetic modifications and costimulation blocking agents converges, we review their impact thus far on preclinical xenotransplantation and the potential for future application. PMID- 29159189 TI - NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody. AB - Objective: Autoimmune encephalitis is most frequently associated with anti-NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody-producing clones, and characterize their antibody signatures in recombinant form. Methods: Patients with recent onset typical anti-NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy- (IgH) and light chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance. Results: Intrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen-driven intrathecal immune response. Consistently, a single recombinant human GluN1-specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo. Interpretation: A CNS-specific humoral immune response is present in anti-NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti-NMDAR encephalitis as a humorally mediated autoimmune disease. PMID- 29159190 TI - Divergent neural responses to narrative speech in disorders of consciousness. AB - Objective: Clinical assessment of auditory attention in patients with disorders of consciousness is often limited by motor impairment. Here, we employ intersubject correlations among electroencephalography responses to naturalistic speech in order to assay auditory attention among patients and healthy controls. Methods: Electroencephalographic data were recorded from 20 subjects with disorders of consciousness and 14 healthy controls during of two narrative audio stimuli, presented both forwards and time-reversed. Intersubject correlation of evoked electroencephalography signals were calculated, comparing responses of both groups to those of the healthy control subjects. This analysis was performed blinded and subsequently compared to the diagnostic status of each patient based on the Coma Recovery Scale-Revised. Results: Subjects with disorders of consciousness exhibit significantly lower intersubject correlation than healthy controls during narrative speech. Additionally, while healthy subjects had higher intersubject correlation values in forwards versus backwards presentation, neural responses did not vary significantly with the direction of playback in subjects with disorders of consciousness. Increased intersubject correlation values in the backward speech condition were noted with improving disorder of consciousness diagnosis, both in cross-sectional analysis and in a subset of patients with longitudinal data. Interpretation: Intersubject correlation of neural responses to narrative speech audition differentiates healthy controls from patients and appears to index clinical diagnoses in disorders of consciousness. PMID- 29159191 TI - Soluble CD163 in intracerebral hemorrhage: biomarker for perihematomal edema. AB - Objective: Patients with intracerebral hemorrhage (ICH) may elaborate varying degrees of perihematomal edema (PHE), requiring closer monitoring and a higher intensity of treatment. Here, we explore whether the soluble form of CD163, a scavenger receptor responsible for hemoglobin sequestration, can serve as a prognostic biomarker of PHE development and poor outcome after ICH. Methods: Our study cohort was comprised of 51 primary age- and sex-matched ICH patients with moderate-sized, hypertensive deep hemorrhages. Patients were part of a prospective ICH registry cataloguing admission data along with functional outcomes. We measured sCD163 levels in serial serum and cerebrospinal fluid (CSF) samples obtained at prespecified timepoints. Descriptive statistics, including a generalized estimating equation for longitudinal data, were used to analyze sCD163 in relation to ICH outcomes. Results: Acute serum sCD163 (<48 h postictus) was significantly elevated in ICH patients compared to both acute neurological event controls (P = <0.001) and healthy controls (P = 0.003). As predicted, acute serum sCD163 levels were significantly associated with both hematoma volume expansion (P = 0.009) and PHE expansion (P = 0.002). Further examination determined that patients with high PHE expansion had poorer modified Rankin Scale scores at discharge (P = 0.024), and circulating sCD163 levels were found to be significantly lower in patients with high-level PHE expansion. Interpretation: Acute sCD163 levels may be a useful biomarker for the acute identification of patients at risk for hematoma expansion, perihematomal edema expansion and poorer short-term outcomes. PMID- 29159192 TI - Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease. AB - Objective: To evaluate sex differences and the relative effect of G2019S LRRK2 mutations in Parkinson's disease (PD). Methods: 530 LRRK2 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and LRRK2 PD; and features were compared between IPD and LRRK2 PD separately for men and women. Results: Among IPD: men had higher levodopa equivalency dose (LED), worse activities of daily living and motoric severity but lower complications of therapy (UPDRS-IV). IPD women had higher olfaction and thermoregulatory scores and were more likely to report family history of PD. Among LRRK2 PD: Male predominance was not observed among G2019S LRRK2 cases. Women had worse UPDRS-IV but better olfaction. Among same sex:LRRK2 men and women had better olfaction than IPD counterparts. LRRK2 men demonstrated lower motor and higher cognitive, RBD and thermoregulation scores than IPD men and LRRK2 women had greater UDPRS-IV and rates of dyskinesia. Interpretation: There were clinical differences between sexes with a more severe phenotype in IPD men and more complications of therapy in women. The more severe male phenotype was moderated by LRRK2, with LRRK2 men and women showing less diversity of phenotype. Our study supports that both genetics and sex drive phenotype, and thus trials in LRRK2 and IPD should consider gender stratification in design or analysis. PMID- 29159193 TI - PREP2: A biomarker-based algorithm for predicting upper limb function after stroke. AB - Objective: Recovery of motor function is important for regaining independence after stroke, but difficult to predict for individual patients. Our aim was to develop an efficient, accurate, and accessible algorithm for use in clinical settings. Clinical, neurophysiological, and neuroimaging biomarkers of corticospinal integrity obtained within days of stroke were combined to predict likely upper limb motor outcomes 3 months after stroke. Methods: Data from 207 patients recruited within 3 days of stroke [103 females (50%), median age 72 (range 18-98) years] were included in a Classification and Regression Tree analysis to predict upper limb function 3 months poststroke. Results: The analysis produced an algorithm that sequentially combined a measure of upper limb impairment; age; the presence or absence of upper limb motor evoked potentials elicited with transcranial magnetic stimulation; and stroke lesion load obtained from MRI or stroke severity assessed with the NIHSS score. The algorithm makes correct predictions for 75% of patients. A key biomarker obtained with transcranial magnetic stimulation is required for one third of patients. This biomarker combined with NIHSS score can be used in place of more costly magnetic resonance imaging, with no loss of prediction accuracy. Interpretation: The new algorithm is more accurate, efficient, and accessible than its predecessors, which may support its use in clinical practice. While further work is needed to potentially incorporate sensory and cognitive factors, the algorithm can be used within days of stroke to provide accurate predictions of upper limb functional outcomes at 3 months after stroke. www.presto.auckland.ac.nz. PMID- 29159194 TI - Multigeneration family with dominant SPG30 hereditary spastic paraplegia. AB - Autosomal recessive KIF1A missense mutations cause hereditary spastic paraplegia (HSP) type SPG30, while recessive truncations lead to sensory and autonomic neuropathy (HSN2C) and many de novo missense mutations are associated with cognitive impairment. Here, we describe family members across three generations with pure HSP. A heterozygous p.Ser69Leu KIF1A mutation segregates with those afflicted. The same variant was previously reported in a Finnish father and son with pure HSP as well as four members of a Sicilian kindred with more intrafamilial phenotypic variability. This further validates the pathogenicity of the p.Ser69Leu mutation and suggests that it may represent a mutation hot spot. PMID- 29159195 TI - CD4+ T cells from multiple sclerosis patients respond to a commensal-derived antigen. AB - Multiple sclerosis, an immune-mediated disease of the central nervous system, is characterized by the impaired function of regulatory cells that fail to suppress self-reactive effector cells. We have previously found that polysaccharide A, a capsular antigen derived from the human gut commensal Bacteroides fragilis, can induce a population of regulatory T cells. Herein, we demonstrate that naive T cells isolated from patients with multiple sclerosis have the capacity to acquire regulatory characteristics when stimulated in vitro with polysaccharide A. This study demonstrates the amplification of a regulatory T cell response by a gut derived commensal antigen in those with multiple sclerosis. PMID- 29159196 TI - Botulinum toxin treatment for hypersalivation in anti-NMDA receptor encephalitis. AB - Hypersalivation is one of the intractable symptoms of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. While anticholinergic medications partially improve the hypersalivation, they can aggravate the autonomic dysfunctions associated with anti-NMDAR encephalitis. Thus, we investigated the efficacy and safety of botulinum toxin type A injection on hypersalivation refractory to anticholinergics in six patients with anti-NMDAR encephalitis. Hypersalivation was well-controlled without remarkable adverse reaction over 16 weeks after botulinum toxin type A, although two patients were reinjected at 12 weeks due to reaggravation of hypersalivation. Our findings suggest that botulinum toxin type A might be a better choice than anticholinergics for management of hypersalivation in patients with anti-NMDAR encephalitis. PMID- 29159197 TI - Donepezil enhances understanding of degraded speech in Alzheimer's disease. AB - Auditory dysfunction under complex, dynamic listening conditions is a clinical hallmark of Alzheimer's disease (AD) but challenging to measure and manage. Here, we assessed understanding of sinewave speech (a paradigm of degraded speech perception) and general cognitive abilities in 17 AD patients, before and following a 10 mg dose of donepezil. Relative to healthy older individuals, patients had impaired sinewave speech comprehension that was selectively ameliorated by donepezil. Our findings demonstrate impaired perception of degraded speech in AD but retained perceptual learning capacity that can be harnessed by acetylcholinesterase inhibition, with implications for designing communication interventions and acoustic environments in dementia. PMID- 29159198 TI - Perceptions of Safety Among LGBTQ People Following the 2016 Pulse Nightclub Shooting. AB - The goals of this manuscript are two-fold. First, we provide a brief reaction to this journal's "Special Section: Reflections on the Orlando Massacre on its First Anniversary." Second, we present findings from a study on perceptions of safety among LGBTQ individuals following the Pulse shooting. These issues are discussed within the historical context of hate crimes experienced by the LGBTQ population (Herek), media coverage following the shooting (Hancock & Halderman), and the immediate reaction of LGBTQ graduate students to the event (Jackson). Our study sought to examine differences in perceptions of personal and peer safety by race/ethnicity, gender identity, and sexual orientation among a large, diverse sample of LGBTQ people. Findings from our study indicate that there were differences in perceptions of personal safety by gender identity, and differences in perceptions of peer safety by gender identity and sexual orientation. These findings also suggest that subgroups of the LGBTQ community with more marginalized gender and sexual identities (e.g., female, transgender, genderqueer, bisexual, queer respondents) perceived more concerns related to safety, on average, than subgroups with relatively more privilege (e.g., gay, male). Elevated safety concern may exacerbate multiple minority stress burden, a known driver of poor health outcomes among LGBTQ people. These findings are a call to action to healthcare providers to be well informed and trained to provide the appropriate care and counseling referrals that can address the safety-related concerns of LGBTQ individuals in the aftermath of identity-related attacks. PMID- 29159199 TI - DNA-Mediated Gene Therapy in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. AB - Mutations in the gene for dysferlin cause a degenerative disorder of skeletal muscle known as limb girdle muscular dystrophy 2B. To achieve gene delivery of plasmids encoding dysferlin to hind limb muscles of dysferlin knockout mice, we used a vascular injection method that perfused naked plasmid DNA into all major muscle groups of the hind limb. We monitored delivery by luciferase live imaging and western blot, confirming strong dysferlin expression that persisted over the 3-month time course of the experiment. Co-delivery of the follistatin gene, which may promote muscle growth, was monitored by ELISA. Immunohistochemistry documented the presence of dysferlin in muscle fibers in treated limbs, and PCR confirmed the presence of plasmid DNA. Because dysferlin is involved in repair of the sarcolemmal membrane, dysferlin loss leads to fragile sarcolemmal membranes that can be detected by permeability to Evan's blue dye. We showed that after gene therapy with a plasmid encoding both dysferlin and follistatin, statistically significant reduction in Evan's blue dye permeability was present in hamstring muscles. These results suggest that vascular delivery of plasmids carrying these therapeutic genes may lead to simple and effective approaches for improving the clinical condition of limb girdle muscular dystrophy 2B. PMID- 29159200 TI - Analyzing the Genotoxicity of Retroviral Vectors in Hematopoietic Cell Gene Therapy. AB - Retroviral vectors, including those derived from gammaretroviruses and lentiviruses, have found their way into the clinical arena and demonstrated remarkable efficacy for the treatment of immunodeficiencies, leukodystrophies, and globinopathies. Despite these successes, gene therapy unfortunately also has had to face severe adverse events in the form of leukemias and myelodysplastic syndromes, related to the semi-random vector integration into the host cell genome that caused deregulation of neighboring proto-oncogenes. Although improvements in vector design clearly lowered the risk of this insertional mutagenesis, analysis of potential genotoxicity and the consequences of vector integration remain important parameters for basic and translational research and most importantly for the clinic. Here, we review current assays to analyze biodistribution and genotoxicity in the pre-clinical setting and describe tools to monitor vector integration sites in vector-treated patients as a biosafety readout. PMID- 29159202 TI - A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I. AB - Antibodies against recombinant proteins can significantly reduce their effectiveness in unanticipated ways. We evaluated the humoral response of mice with the lysosomal storage disease mucopolysaccharidosis type I treated with weekly intravenous recombinant human alpha-l-iduronidase (rhIDU). Unlike patients, the majority of whom develop antibodies to recombinant human alpha-l iduronidase, only approximately half of the treated mice developed antibodies against recombinant human alpha-l-iduronidase and levels were low. Serum from antibody-positive mice inhibited uptake of recombinant human alpha-l-iduronidase into human fibroblasts by partial inhibition compared to control serum. Tissue and cellular distributions of rhIDU were altered in antibody-positive mice compared to either antibody-negative or naive mice, with significantly less recombinant human alpha-l-iduronidase activity in the heart and kidney in antibody-positive mice. In the liver, recombinant human alpha-l-iduronidase was preferentially found in sinusoidal cells rather than in hepatocytes in antibody positive mice. Antibodies against recombinant human alpha-l-iduronidase enhanced uptake of recombinant human alpha-l-iduronidase into macrophages obtained from MPS I mice. Collectively, these results imply that a humoral immune response against a therapeutic protein can shift its distribution preferentially into macrophage-lineage cells, causing decreased availability of the protein to the cells that are its therapeutic targets. PMID- 29159201 TI - Interactions between Retroviruses and the Host Cell Genome. AB - Replication-defective retroviral vectors have been used for more than 25 years as a tool for efficient and stable insertion of therapeutic transgenes in human cells. Patients suffering from severe genetic diseases have been successfully treated by transplantation of autologous hematopoietic stem-progenitor cells (HSPCs) transduced with retroviral vectors, and the first of this class of therapies, Strimvelis, has recently received market authorization in Europe. Some clinical trials, however, resulted in severe adverse events caused by vector induced proto-oncogene activation, which showed that retroviral vectors may retain a genotoxic potential associated to proviral integration in the human genome. The adverse events sparked a renewed interest in the biology of retroviruses, which led in a few years to a remarkable understanding of the molecular mechanisms underlying retroviral integration site selection within mammalian genomes. This review summarizes the current knowledge on retrovirus host interactions at the genomic level, and the peculiar mechanisms by which different retroviruses, and their related gene transfer vectors, integrate in, and interact with, the human genome. This knowledge provides the basis for the development of safer and more efficacious retroviral vectors for human gene therapy. PMID- 29159203 TI - Varicella zoster virus-infected cerebrovascular cells produce a proinflammatory environment. AB - Objective: To test whether varicella zoster virus (VZV) infection of human brain vascular cells and of lung fibroblasts directly increases proinflammatory cytokine levels, consistent with VZV as a causative agent in intracerebral VZV vasculopathy and giant-cell arteritis (GCA). Methods: Conditioned supernatant from mock- and VZV-infected human brain vascular adventitial fibroblasts (HBVAFs), human perineurial cells (HPNCs), human brain vascular smooth muscle cells (HBVSMCs), and human fetal lung fibroblasts (HFLs) were collected at 72 hours postinfection and analyzed for levels of 30 proinflammatory cytokines using the Meso Scale Discovery Multiplex ELISA platform. Results: Compared with mock infection, VZV infection led to significantly increased levels of the following: interleukin-8 (IL-8) in all cell lines examined; IL-6 in HBVAFs, HPNCs, and HFLs, with no change in HBVSMCs; and vascular endothelial growth factor A in HBVAFs, HBVSMCs, and HFLs, with a significant decrease in HPNCs. Other cytokines, including IL-2, IL-4, IL-15, IL-16, TGF-b, Eotaxin-1, Eotaxin-3, IP-10, MCP-1, and granulocyte macrophage colony-stimulating factor, were also significantly altered upon VZV infection in a cell type-specific manner. Conclusions: VZV infection of vascular cells can directly produce a proinflammatory environment that may potentially lead to prolonged arterial wall inflammation and vasculitis. The VZV-mediated increase in IL-8 and IL-6 is consistent with that seen in the CSF of patients with intracerebral VZV vasculopathy, and the VZV-mediated increase in IL-6 is consistent with the cytokine's elevated levels in temporal arteries and plasma of patients with GCA. PMID- 29159204 TI - Immune response to vaccines is maintained in patients treated with dimethyl fumarate. AB - Objectives: To investigate the immune response to vaccinations in patients with relapsing forms of MS treated with delayed-release dimethyl fumarate (DMF) vs nonpegylated interferon (IFN). Methods: In this open-label, multicenter study, patients received 3 vaccinations: (1) tetanus-diphtheria toxoid (Td) to test T cell-dependent recall response, (2) pneumococcal vaccine polyvalent to test T cell-independent humoral response, and (3) meningococcal (groups A, C, W-135, and Y) oligosaccharide CRM197 conjugate to test T-cell-dependent neoantigen response. Eligible patients were aged 18-55 years, diagnosed with relapsing-remitting MS (RRMS), and either treated for >=6 months with an approved dose of DMF or for >=3 months with an approved dose of nonpegylated IFN. Primary end point was the proportion of patients with >=2-fold rise in antitetanus serum IgG levels from prevaccination to 4 weeks after vaccination. Results: Seventy-one patients (DMF treated, 38; IFN treated, 33) were enrolled. The mean age was 45.3 years (range 27-55); 86% were women. Responder rates (>=2-fold rise) to Td vaccination were comparable between DMF- and IFN-treated groups (68% vs 73%). Responder rates (>=2 fold rise) were also similar between DMF- and IFN-treated groups for diphtheria antitoxoid (58% vs 61%), pneumococcal serotype 3 (66% vs 79%), pneumococcal serotype 8 (95% vs 88%), and meningococcal serogroup C (53% vs 53%), all p > 0.05. In a post hoc analysis, no meaningful differences were observed between groups in the proportion of responders when stratified by age category or lymphocyte count. Conclusions: DMF-treated patients mount an immune response to recall, neoantigens, and T-cell-independent antigens, which was comparable with that of IFN-treated patients and provided adequate seroprotection. ClinicalTrialsgov identifier: NCT02097849. Classification of evidence: This study provides Class II evidence that patients with RRMS treated with DMF respond to vaccinations comparably with IFN-treated patients. PMID- 29159205 TI - Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker. AB - Objective: To compare brain metabolism patterns on fluorodeoxyglucose (FDG) PET/CT in anti-NMDA receptor and other definite autoimmune encephalitis (AE) and to assess how these patterns differ between anti-NMDA receptor neurologic disability groups. Methods: Retrospective review of clinical data and initial dedicated brain FDG-PET/CT studies for neurology inpatients with definite AE, per published consensus criteria, treated at a single academic medical center over a 10-year period. Z-score maps of FDG-PET/CT were made using 3-dimensional stereotactic surface projections in comparison to age group-matched controls. Brain region mean Z scores with magnitudes >=2.00 were interpreted as significant. Comparisons were made between anti-NMDA receptor and other definite AE patients as well as among patients with anti-NMDA receptor based on modified Rankin Scale (mRS) scores at the time of FDG-PET/CT. Results: The medial occipital lobes were markedly hypometabolic in 6 of 8 patients with anti-NMDA receptor encephalitis and as a group (Z = -4.02, interquartile range [IQR] 2.14) relative to those with definite AE (Z = -2.32, 1.46; p = 0.004). Among patients with anti-NMDA receptor encephalitis, the lateral and medial occipital lobes were markedly hypometabolic for patients with mRS 4-5 (lateral occipital lobe Z = 3.69, IQR 1; medial occipital lobe Z = -4.08, 1) compared with those with mRS 0-3 (lateral occipital lobe Z = -0.83, 2; p < 0.0005; medial occipital lobe Z = 1.07, 2; p = 0.001). Conclusions: Marked medial occipital lobe hypometabolism by dedicated brain FDG-PET/CT may serve as an early biomarker for discriminating anti-NMDA receptor encephalitis from other AE. Resolution of lateral and medial occipital hypometabolism may correlate with improved neurologic status in anti NMDA receptor encephalitis. PMID- 29159206 TI - Influence of patient position and other inherent factors on image quality in two different cone beam computed tomography (CBCT) devices. AB - Objectives: The aim of this in vitro study was to evaluate how a deviation from the horizontal plane, affects the image quality in two different CBCT-devices. Methods: A phantom head SK150 (RANDO, The Phantom Laboratory, Salem, NY, USA) was examined in two CBCT-units: Accuitomo 80 and Veraviewepocs 3D R100 (J. Morita Mfg. Corp. Kyoto, Japan). The phantom head was placed with the hard palate parallel to the horizontal plane and tilted 20 degrees backwards. Exposures were performed with different field of views (FOVs), voxel sizes, slice thicknesses and exposure settings. Effective dose was calculated using PCXMC 2.0 (STUK, Helsinki, Finland). Image quality was assessed using contrast-to-noise ratio (CNR). Region of interest (ROI) was set at three different levels of the mandibular bone and soft tissue, uni- and bilaterally in small and large FOVs, respectively. CNR values were calculated by CT-value and standard deviation for each ROI. Factor analysis was used to analyze the material. Results: Tilting the phantom head backwards rendered significantly higher mean CNR values regardless of FOV. The effective dose was lower in small than in large FOVs and varied to a larger extent between CBCT-devices in large FOVs. Conclusions: Head position can affect the image quality. Tilting the head backward improved image quality in the mandibular region. However, if influenced by other variables e.g. motion artifacts in a clinical situation, remains to be further investigated. Advances in knowledge: Image quality assessed using CNR values to investigate the influence of different patient positions and FOVs. PMID- 29159207 TI - Primary breast chondrosarcoma: Imaging and pathological findings. AB - We present the case of a 62 year-old woman who was admitted to our institute of radiological sciences for a breast mass developed in the last few months. The final diagnosis was primary breast chondrosarcoma and the surgical treatment performed, based on imaging and pathological findings, was the mastectomy. PMID- 29159208 TI - A rare presentation of Spigelian hernia involving the appendix. AB - Spigelian hernia (SH) is a rare entity accounting for 1-2% of ventral abdominal wall hernias. Elusive clinical signs and symptoms pose a diagnostic challenge and a consequent risk of strangulation. We present an emergent case of a Spigelian hernia involving the appendix. PMID- 29159209 TI - Dynamics of Pulicat Lake mouth analysis using geospatial data, east coast of India: Implications to socio-economic scenarios. AB - Pulicat Lake is one of the major wetlands in India. It is the second largest brackish water lagoon in India next to Chilika Lake in Orissa state. Pulicat Lake sits beside the Bay of Bengal so, the study on the mouth is vital. The investigations were carried out by using multi-temporal satellite imageries of IRS P6, LISS III data for four years viz., 2009, 2011, 2012 and 2013. Subsequent changes in the width of the lake at the southern side were measured. It is found that the lake mouth is not static but dynamic predominantly fluctuating year by year. Obviously, this poses threat to the lake biodiversity. Hence, it is high time to mitigate, manage, monitor and protect the existing width of the sea mouth to keep the lake biological, ecological, economically active. This paper noticed a considerable change in the mouth of the lake studied using satellite imageries and socio-economic settings. PMID- 29159210 TI - Dataset on ground radiometric survey in part of the Eastern Dahomey Basin, SW Nigeria. AB - The dataset for this article contains the measured activity concentration of radionuclides and gamma-radiation dose rate obtained from the radiometric survey in Ota, Ado-Odo Local Government Area, Ogun State, Nigeria. The data were manually collected in fifty (50) locations using the Super SPEC RS-125 spectrometer for about three (3) weeks in January, 2017. The descriptive statistical analysis of the data were equally explored for possible statistical relationships. The field dataset is made available publicly for further extended analyses that can provide insights into the safety status of the study area from radiological health concerns. The dataset could also serve as a significant baseline radiometric data for future epidemiology researches and monitoring initiative in Ota and its environs. PMID- 29159211 TI - The relationship between knowledge of leadership and knowledge management practices in the food industry in Kurdistan province, Iran. AB - The aim of this study was to identify the relationship between the knowledge of leadership and knowledge management practices. This research strategy, in terms of quantity, procedure and obtain information, is descriptive and correlational. Statistical population, consist of all employees of a food industry in Kurdistan province of Iran, who were engaged in 2016 and their total number is about 1800 people. 316 employees in the Kurdistan food industry (Kurdistan FI) were selected, using Cochran formula. Non-random method and valid questions (standard) for measurement of the data are used. Reliability and validity were confirmed. Statistical analysis of the data was carried out, using SPSS 16. The statistical analysis of collected data showed the relationship between knowledge-oriented of leadership and knowledge management activities as mediator variables. The results of the data and test hypotheses suggest that knowledge management activities play an important role in the functioning of product innovation and the results showed that the activities of Knowledge Management (knowledge transfer, storage knowledge, application of knowledge, creation of knowledge) on performance of product innovation. PMID- 29159212 TI - Data on the expression of PEPCK in HepG2 hepatocytes transfected with miR-195. AB - Dietary fats rich in saturated fatty acid (SFA) increase the risk of metabolic diseases, and certain microRNAs (miRNAs) dysregulated by SFA are associated with the pathogenesis of insulin resistance and type 2 diabetes. A previous study found that miR-195 is increased by SFA and impairs hepatic insulin signaling through the suppression of INSR (Yang et al., 2014) [1]. This article reports accompanying data to determine the effect of miR-195 on the expression of PEPCK, a key player in hepatic gluconeogenesis. The transfection of miR-195 in HepG2 hepatocytes was found to increase the mRNA and protein expression of PEPCK. Moreover, the insulin-stimulated reduction of PEPCK expression was attenuated drastically by miR-195. More detailed analysis and understanding of the role of miR-195 in diet-induced hepatic insulin resistance can be found in "Saturated fatty acid-induced miR-195 impairs insulin signaling and glycogen metabolism in HepG2 cells" (Yang et al., 2014) [1]. PMID- 29159213 TI - Dataset generated for Dissection of mechanisms of Trypanothione Reductase and Tryparedoxin Peroxidase through dynamic network analysis and simulations in leishmaniasis. AB - Leishmaniasis is the second largest parasitic killer disease caused by the protozoan parasite Leishmania, transmitted by the bite of sand flies. It's endemic in the eastern India with 165.4 million populations at risk with the current drug regimen. Three forms of leishmaniasis exist in which cutaneous is the most common form caused by Leishmania major. Trypanothione Reductase (TryR), a flavoprotein oxidoreductase, unique to thiol redox system, is considered as a potential target for chemotherapy for trypanosomatids infection. It is involved in the NADPH dependent reduction of Trypanothione disulphide to Trypanothione. Similarly, is Tryparedoxin Peroxidase (Txnpx), for detoxification of peroxides, an event pivotal for survival of Leishmania in two disparate biological environment. Fe-S plays a major role in regulating redox balance. To check for the closeness between human homologs of these proteins, we have carried the molecular clock analysis followed by molecular modeling of 3D structure of this protein, enabling us to design and test the novel drug like molecules. Molecular clock analysis suggests that human homologs of TryR i.e. Glutathione Reductase and Txnpx respectively are highly diverged in phylogenetic tree, thus, they serve as good candidates for chemotherapy of leishmaniasis. Furthermore, we have done the homology modeling of TryR using template of same protein from Leishmania infantum (PDB ID: 2JK6). This was done using Modeller 9.18 and the resultant models were validated. To inhibit this target, molecular docking was done with various screened inhibitors in which we found Taxifolin acts as common inhibitors for both TryR and Txnpx. We constructed the protein-protein interaction network for the proteins that are involved in the redox metabolism from various Interaction databases and the network was statistically analysed. PMID- 29159214 TI - Many-body interactions in the Al-Cu system. AB - The article contains computational data of many-body interactions in Al-Cu alloys, obtained using PAW-VASP calculations. Pairwise, three-site, and four-site interactions are presented. Mentioned data are relevant to the research article "Many-body mechanism of Guinier-Preston zones stabilization in Al-Cu alloys" (Gorbatov et al., 2017) [1]. PMID- 29159216 TI - Data on the decreased expression of FOXO1 by miR-1271 in HepG2 hepatocytes. AB - Obesity and metabolic diseases are closely associated with insulin resistance. Obesity-induced miRNAs are also considered to be potential contributors to the development of insulin resistance and type 2 diabetes. Previously, the expression of miR-1271 was reported to be upregulated in the liver of diet-induced obese mice (Yang et al., 2016) [1]. In this data article, multiple in silico analysis predicted FOXO1 gene to be a direct target of miR-1271. Dual luciferase reporter gene analysis showed that miR-1271 suppressed FOXO1 expression by direct binding to 3'UTR. The overexpression of miR-1271 reduced the protein expression of FOXO1, thereby reducing the transcription of PEPCK, a downstream target of FOXO1. The data is related to a research article entitled "MiR-1271 upregulated by saturated fatty acid palmitate provokes impaired insulin signaling by repressing INSR and IRS-1 expression in HepG2 cells" (Yang et al., 2016) [1]. PMID- 29159215 TI - Nfs1 cysteine desulfurase protein complexes and phosphorylation sites as assessed by mass spectrometry. AB - Fe-S clusters are cofactors that participate in diverse and essential biological processes. Mitochondria contain a complete machinery for Fe-S cluster assembly. Cysteine desulfurase (Nfs1) is required generation of a form of activated sulfur and is essential for the initial Fe-S cluster assembly step. Using mass spectometry we identified proteins that were copurified with Nfs1 using a pull down strategy, including a novel protein kinase. Furthermore, we were able to identify phosphorylation sites on the Nfs1 protein. These data and analyses support the research article "Cysteine desulfurase is regulated by phosphorylation of Nfs1 in yeast mitochondria" by Rocha et al. (in press) [1]. PMID- 29159217 TI - Data on strategically located land and spatially integrated urban human settlements in South Africa. AB - In developing countries like South Africa processed geographic information systems (GIS) data on land suitability, is often not available for land use management. Data in this article is based on a published article "The strategically located land index support system for humans settlements land reform in South Africa" (Musakwa et al., 2017) [1]. This article utilities data from Musakwa et al. (2017) [1] and it goes on a step further by presenting the top 25th percentile of areas in the country that are strategically located and suited to develop spatially integrated human settlements. Furthermore the least 25th percentile of the country that are not strategically located and spatially integrated to establish human settlements are also presented. The article also presents the processed spatial datasets that where used to develop the strategically located land index as supplementary material. The data presented is meant to stir debate on spatially integrated human settlements in South Africa. PMID- 29159218 TI - Geoexploration of radioelement's datasets in a flood plain of crystalline bedrock. AB - The data in this article contains statistical analysis of radioelement in Odo-Oba flood plain of crystalline bedrock, Southwestern Nigeria. The data were acquired along twenty-two traverses. The length of each traverse is a function of its accessibility in the study area. The traverses covered the area used for agricultural practices and the area where these farm products are being sold to either the retailers or the consumers. Descriptive and multivariate statistical analyses were used to explore the measured emitted gamma radiation in Odo-Oba flood plain. The dataset can provide insights into the risks involved in exposure to outdoor radiation in a commercial centre when the average outdoor gamma radiation levels are compared to the global threshold values from the regulatory bodies such as World Health Organization, National Research Council, United States Environmental Protection Agency, Federal Environmental Protection Agency, International Commission on Radiological Protection, the United Nations Scientific Committee on the Effects of Atomic Radiation, and Federal Radiation Protection Service among others. PMID- 29159219 TI - Concentration and size distribution data of silicon nitride nanoparticles measured using nanoparticle tracking analysis. AB - This article refers to the paper "A novel method for isolation and recovery of ceramic nanoparticles and metal wear debris from serum lubricants at ultra-low wear rates" (Lal et al., 2016) [1] and describes the concentration and size distribution data of silicon nitride nanoparticles measured using nanoparticle tracking analysis (NTA). A NanoSight LM10 instrument was used to capture the video data of silicon nitride nanoparticles moving under Brownian motion in the water. The video data was then analyzed using the NanoSight NTA software. This article also describes a methodology for calculating the percentage recovery of a nanoparticle isolation process. PMID- 29159220 TI - Data on atherosclerosis specific antibody conjugation to nanoemulsions. AB - This article present data related to the publication entitled "Iron oxide core oil-in-water nanoemulsion as tracer for atherosclerosis MPI and MRI imaging" (Prevot et al., 2017) [1]. Herein we describe the engineering in the baculovirus insect cell system and purification processes of the human scFv-Fc TEG4-2C antibody, specific of platelets within the atheroma plaque. For molecular targeting purpose, atheroma specific antibody was conjugated to nanoemulsions (NEs) using a heterobifunctional linker (DSPE-PEG-maleimide). Atheroma labelling was assayed by immunochemistry on arterial sections from rabbits. PMID- 29159221 TI - Geoelectrical resistivity data sets for subsurface characterisation and aquifer delineation in Iyesi, southwestern Nigeria. AB - This article consists of geoelectrical resistivity data sets for thirty (30) vertical electrical sounding (VES) and four (4) traverses of 2D electrical resistivity imaging (ERI) collected within Iyesi, Ota, southwestern Nigeria for about five (5) weeks between December, 2016 and January, 2017 using an ABEM Terrameter (SAS1000/4000). The observed apparent resistivity data sets for the VES were processed using WinResist to obtain geoelectric layer parameters while those of the 2D ERI were processed with RES2DINV to obtain 2D inverse model resistivity images. The geoelectric parameters for the VES and the inverse models for the 2D ERI were integrated to characterise the subsurface and delineate the underlying aquifer units. PMID- 29159222 TI - Data on metagenomic profiles of activated sludge from a full-scale wastewater treatment plant. AB - The data in this article mainly present the sequences of activated sludge from a full-scale municipal wastewater treatment plant (WWTP) carrying out simultaneous nitrogen and phosphorous removal in Beijing, China. Data include the operational conditions and performance, dominant microbes and taxonomic analysis in this WWTP, and function annotation results based on SEED, Clusters of Orthologous Groups (COG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Sequencing data were generated by using Illumina HiSeq. 2000 platform according to the recommendations of the manufacturer. The sequencing data have been deposited in MG-RAST server (project ID: mgm4735473.3). For more information, see "Unraveling microbial structure and diversity of activated sludge in a full-scale simultaneous nitrogen and phosphorus removal plant using metagenomic sequencing" by Guo et al. (2017) [1]. PMID- 29159223 TI - Programs for the calculation of the spinodal decomposition growth rate and the spinodal gap in nanoparticles. AB - This data article contains the programs for the calculation of the spinodal decomposition growth rate and for the modeling of the spinodal gap and concentration profiles in nanoparticles which were used in our article (Pogorelov et al., 2017) [1]. The modeling is based on the mathematical model of spinodal phase decomposition with intercalation rate conditions on the boundaries (Singh et al., 2008) [2]. The maximal growth rate and the parameters of the concentration wave function can be evaluated for a fixed mean composition and intercalation rate. Furthermore, the maximal growth rate as a function of concentration and particle site can be evaluated for various intercalation rates. PMID- 29159224 TI - Data on iron oxide core oil-in-water nanoemulsions for atherosclerosis imaging. AB - The data presented in this article are related to the publication entitled "Iron oxide core oil-in-water nanoemulsion as tracer for atherosclerosis MPI and MRI imaging" (Prevot et al., 2017) [1]. Herein we describe the synthesis and the characteristics of the Superparamagnetic Iron Oxide Nanoparticles (SPION) loaded inside nanoemulsions (NEs). Focus was set on obtaining SPION with narrow size distribution and close to superparamagnetic limit (20 nm) in order to reach a reasonable magnetic signal. Nanoparticles (NPs) of three different sizes were obtained (7, 11 and 18 nm) and characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), diffuse reflectance infrared Fourier transform (DRIFT) and thermogravimetric analysis (TGA). SPION were coated with oleic acid (OA) in order to load them inside the oily core of NEs droplets. SPION loaded NEs were magnetically sorted using MACS(r) MS Column (Miltenyi Biotec) and iron quantification was performed by UV-spectrometry measurements. PMID- 29159225 TI - Data on the effect of miR-15b on the expression of INSR in murine C2C12 myocytes. AB - The ectopic expression of miR-15b is linked causally to impaired insulin signaling in human HepG2 hepatocytes through the suppression of INSR (Yang et al., 2015) [1]. In this data article, we further examined the effect of miR-15b on insulin signaling in a murine skeletal muscle cells, C2C12 myocytes. Although the 3'UTR of mouse INSR mRNA has an appropriate binding site for miR-15b based on TargetScan analysis, the ectopic expression of miR-15b did not suppress the expression and insulin-stimulated phosphorylation of insulin signaling intermediates in C2C12 myocytes. A more detailed understanding of the effects of miR-15b on hepatic insulin resistance can be found in "Obesity-induced miR-15b is linked causally to the development of insulin resistance through the repression of the insulin receptor in hepatocytes" (Yang et al., 2015) [1]. PMID- 29159226 TI - Experimental data on adsorption of Cr(VI) from aqueous solution using nanosized cellulose fibers obtained from rice husk. AB - The aim of this study was to evaluate the efficiency of nano-sized cellulose obtained from rice husk for Cr(VI) adsorption. The effect of operational parameters including initial pH (3-10), contact time (0-120 min), adsorbent dosage (0.2-1.5 g/L), and initial Cr(VI) concentration (5-50 mg/L) were investigated according to one factor at time method. The results showed, in pH=6, contact time=100 min, adsorbent dose=1.5 g/L and 30 mg/L initial chromium concentration, the adsorption efficiency reached to 92.99%. Also Langmuir isotherm with (R2=0.998 at 303 degrees K) and pseudo-first-order kinetic model (R2=0.993) were the best models for describing the Cr(VI) adsorption reactions. The negative values of [Formula: see text] and positive value of [Formula: see text] showed that, the Cr(VI) adsorption on NCFs was endothermic and spontaneously process. Therefore, it can be concluded that the application this method is recommended for removing Cr(VI) from aqueous solutions. PMID- 29159227 TI - Draft genome and sequence variant data of the oomycete Pythium insidiosum strain Pi45 from the phylogenetically-distinct Clade-III. AB - Pythium insidiosum is a unique oomycete microorganism, capable of infecting humans and animals. The organism can be phylogenetically categorized into three distinct clades: Clade-I (strains from the Americas); Clade-II (strains from Asia and Australia), and Clade-III (strains from Thailand and the United States). Two draft genomes of the P. insidiosum Clade-I strain CDC-B5653 and Clade-II strain Pi-S are available in the public domain. The genome of P. insidiosum from the distinct Clade-III, which is distantly-related to the other two clades, is lacking. Here, we report the draft genome sequence of the P. insidiosum strain Pi45 (also known as MCC13; isolated from a Thai patient with pythiosis; accession numbers BCFM01000001-BCFM01017277) as a representative strain of the phylogenetically-distinct Clade-III. We also report a genome-scale data set of sequence variants (i.e., SNPs and INDELs) found in P. insidiosum (accessible online at the Mendeley database: http://dx.doi.org/10.17632/r75799jy6c.1). PMID- 29159228 TI - Data on water quality index for the groundwater in rural area Neyshabur County, Razavi province, Iran. AB - Public health is at risk from physical and chemical contaminants in the drinking water which may have immediate health consequences. The data from the current study was evaluated for groundwater quality in the rural villages of Neyshabur County in Iran. For determination of the essential physicochemical parameters, water samples were collected from 30 randomly-selected water wells during 2013 and 2014. The samples were tested in situ to measure physical parameters of pH and electrical conductivity and chemical parameters of total dissolved solids, total hardness and levels of calcium, magnesium, carbonates, bicarbonates, sodium, potassium, chloride and sulfates. The APHA method was applied to determine the physicochemical parameters of the water samples. PMID- 29159229 TI - Interactions of manganese with iron, zinc, and copper in neonatal C57BL/6J and parkin mice following developmental oral manganese exposure. AB - High dose manganese (Mn) exposure can result in changes in tissue concentrations of other essential metals due to Mn-induced alterations in metal absorption and competition for metal transporters and regulatory proteins. We evaluated responses in mice with a Parkin gene defect (parkin mice) and a wildtype strain (C57BL/6J) following neonatal Mn exposure. Neonatal parkin and C57BL/6J littermates were randomly assigned to 0, 11, or 25 mg Mn/kg-day dose groups with oral exposures occurring from postnatal day (PND) 1 through PND 28. We report liver, femur, olfactory bulb, striatum, and frontal cortex iron, copper, and zinc concentrations and changes in hepatic gene expression of different metal transporters in PND 29 parkin and C57BL/6J mice. A companion manuscript (Foster et al., 2017) [1] describes the primary study findings. This data provides insights into strain differences in the way Mn interacts with other trace metals in mice. PMID- 29159230 TI - Dataset on the spent filter backwash water treatment by sedimentation, coagulation and ultra filtration. AB - During operation of most water treatment plants, spent filter backwash water (SFBW) is generated, which accounts about 2-10% of the total plant production. By increasing world population and water shortage in many countries, SFBW can be used as a permanent water source until the water treatment plant is working. This data article reports the practical method being used for water reuse from SFBW through different method including pre-sedimentation, coagulation and flocculation, second clarification, ultra filtration (UF) and returned settled SFBW to the beginning of water treatment plant (WTP). Also, two coagulants of polyaluminum ferric chloride (PAFCl) and ferric chloride (FeCl3) were investigated with respect to their performance on treated SFBW quality. Samples were collected from Isfahan's WTP in Iran during spring and summer season. The acquired data indicated that drinkable water can be produced form SFBW by applying hybrid coagulation-UF process (especially when PAFCl used as coagulant). PMID- 29159231 TI - Techno-economic data for a multi-model approach to decarbonisation of the Irish private car sector. AB - These data and analyses support the research article "From technology pathways to policy roadmaps to enabling measures - A multi-model approach" Mulholland et al. (2017) [1]. This article uses 3 models - an optimization model of the Irish energy system (Irish TIMES), a simulation model of the Irish private transport sector (CarSTOCK), and a market share algorithm used to provide a behavior rich representation into the multi-modelling process. Each of these models are linked to provide a technology pathway, policy roadmap, and finally identify the enabling measures of the private transport sector in a low-carbon Ireland moving toward 2050. The article is organized in the same order, firstly providing the key modelling assumptions and operability of Irish TIMES, secondly for CarSTOCK, and finally for the market share algorithm. All data is supplied within this article. PMID- 29159232 TI - Application of bi-clustering of gene expression data and gene set enrichment analysis methods to identify potentially disease causing nanomaterials. AB - This article contains data related to the research article 'Application of bi clustering of gene expression data and gene set enrichment analysis methods to identify potentially disease causing nanomaterials' (Williams and Halappanavar, 2015) [1]. The presence of diverse types of nanomaterials (NMs) in commerce has grown significantly in the past decade and as a result, human exposure to these materials in the environment is inevitable. The traditional toxicity testing approaches that are reliant on animals are both time- and cost- intensive; employing which, it is not possible to complete the challenging task of safety assessment of NMs currently on the market in a timely manner. Thus, there is an urgent need for comprehensive understanding of the biological behavior of NMs, and efficient toxicity screening tools that will enable the development of predictive toxicology paradigms suited to rapidly assessing the human health impacts of exposure to NMs. In an effort to predict the long term health impacts of acute exposure to NMs, in Williams and Halappanavar (2015) [1], we applied bi clustering and gene set enrichment analysis methods to derive essential features of altered lung transcriptome following exposure to NMs that are associated with lung-specific diseases. Several datasets from public microarray repositories describing pulmonary diseases in mouse models following exposure to a variety of substances were examined and functionally related bi-clusters showing similar gene expression profiles were identified. The identified bi-clusters were then used to conduct a gene set enrichment analysis on lung gene expression profiles derived from mice exposed to nano-titanium dioxide, carbon black or carbon nanotubes (nano-TiO2, CB and CNTs) to determine the disease significance of these data-driven gene sets. The results of the analysis correctly identified all NMs to be inflammogenic, and only CB and CNTs as potentially fibrogenic. Here, we elaborate on the details of the statistical methods and algorithms used to derive the disease relevant gene signatures. These details will enable other investigators to use the gene signature in future Gene Set Enrichment Analysis studies involving NMs or as features for clustering and classifying NMs of diverse properties. PMID- 29159233 TI - Data for the homology modelling of the red pigment-concentrating hormone receptor (Dappu-RPCHR) of the crustacean Daphnia pulex, and docking of its cognate agonist (Dappu-RPCH). AB - The data presented in this article are related to the publication "Interaction of the red pigment-concentrating hormone of the crustacean Daphnia pulex, with its cognate receptor, Dappu-RPCHR: A nuclear magnetic resonance and modeling study" (Jackson et al., 2017) [1]. This article contains the data for homology modeling of the red pigment-concentrating hormone (RPCH) receptor of the water flea, Daphnia pulex (Dappu-RPCHR), which was constructed from its primary sequence. This is the first 3D model of a crustacean G-protein coupled receptor. Docking of the agonist, pGlu-Val-Asn-Phe-Ser-Thr-Ser-Trp amide (Dappu-RPCH), was used to find a binding pocket on the receptor and compared to the binding pocket of the adipokinetic hormone (AKH) receptor from the malaria mosquito. Data for the receptor, with and without loop refinement, together with the docked agonist, are presented. PMID- 29159234 TI - Gene expression microarray data from mouse cerebrum treated with rTMS for 30 days. AB - This data article contains complementary tables related to the research article entitled, 'Effects of repetitive transcranial magnetic stimulation on ER stress related genes and glutamate, gamma-aminobutyric acid, and glycine transporter genes in mouse brain' (Ikeda et al. (2017) [1]), which showed that rTMS modulates glutamate, GABA and glycine transporters and regulates ER stress-related genes. Here we provide accompanying data collected using Affymetrix GeneChip microarrays to identify changes in gene expression in mouse cerebrum treated with rTMS for 30 days (Tables 1-10). PMID- 29159235 TI - Trimethylation of Histone 3 lysine 27 (H3K27me3) ChIP-PCR and transcriptional expression data of Ef1-alpha, cyp26A, HoxC10, HoxD10 and HoxD11 in the Xenopus XTC cell line. AB - Trimethylation of Histone 3 lysine 27 (H3K27me3) is a chromatin modification that is associated with transcriptional repression (Cao et al., 2002; Sarma et al., 2008; Pengelly et al., 2013) [1], [2], [3]. In this article we performed anti H3K27me3 Chromosomal Immunoprecipitation (ChIP-PCR), to detect the abundance of H3K27me3 marks on Ef1-alpha, cyp26A, HoxC10, HoxD10 and HoxD11 in the Xenopus XTC cell line. We also performed RT-PCR for these genes to determine whether their expression is detectable in the XTC cell culture. The data we present here are the fold enrichment of Ef1-alpha, cyp26A, HoxC10, HoxD10 and HoxD11 on anti H3K27me3 ChIP compared to no antibody controls. We also present RT-PCR data on the above listed genes. PMID- 29159236 TI - Data of drowning related deaths with reference to entomological evidence from Haryana. AB - Most often the newspapers and bulletin come out with voluminous cases of deaths due to drowning. At the same time an ample section of such cases encompass entomological evidences, that can be scrutinized as a very useful parameter in estimating post mortem interval (PMI). This research database is an outcome of a 2 years reflective study, based on an assessment of records related to human deaths due to drowning. The drowned bodies from various districts of Haryana are sent to PGIMS (Post Graduate Institute of Medical Sciences), Rohtak. The study took the data of year 2015-2016 into consideration. All the cases were reviewed and summarized in terms of monthly occurrence of total cases, age differentiation, gender differentiation and month wise occurrence of entomological evidences on the dead bodies through detailed study of post mortem findings. This data will lead to an insight into the magnitude of drowning deaths in Haryana along with the usage of entomological data for determining Post Mortem Submersion Intervals (PMSI). PMID- 29159238 TI - Data on optimum recycle aggregate content in production of new structural concrete. AB - This data presented herein are the research summary of "mechanical behavior and durability performance of concrete containing recycled concrete aggregate" (Paul, 2011) [1]. The results reported in this article relate to an important parameter of optimum content of recycle concrete aggregate (RCA) in production of new concrete for both structural and non-structural applications. For the purpose of the research various types of physical, mechanical and durability tests are performed for concrete made with different percentages of RCA. Therefore, this data set can be a great help of the readers to understand the mechanism of RCA in relates to the concrete properties. PMID- 29159237 TI - Motion database of disguised and non-disguised team handball penalty throws by novice and expert performers. AB - This article describes the motion database for a large sample (n = 2400) of 7-m penalty throws in team handball that includes 1600 disguised throws. Throws were performed by both novice (n = 5) and expert (n = 5) penalty takers. The article reports the methods and materials used to capture the motion data. The database itself is accessible for download via JLU Web Server and provides all raw files in a three-dimensional motion data format (.c3d). Additional information is given on the marker placement of the penalty taker, goalkeeper, and ball together with details on the skill level and/or playing history of the expert group. The database was first used by Helm et al. (2017) [1] to investigate the kinematic patterns of disguised movements. Results of this analysis are reported and discussed in their article "Kinematic patterns underlying disguised movements: Spatial and temporal dissimilarity compared to genuine movement patterns" (doi:10.1016/j.humov.2017.05.010) [1]. PMID- 29159239 TI - The urban features of informal settlements in Jakarta, Indonesia. AB - This data article contains the urban features of three informal settlements in Jakarta: A. Kampung Bandan; B. Kampung Luar Batang; And C. Kampung Muara Baru. The data describes the urban features of physical structures, infrastructures, and public services. These data include maps showing locations of these settlements, photography of urban status, and examples of urban fabric. The data are obtained from the statistical records and field surveys of three settlements cases. PMID- 29159240 TI - Dataset reporting the perceiver identification rates of basic emotions expressed by male, female and ambiguous gendered walkers in full-light, point-light and synthetically modelled point-light walkers. AB - This data set describes the experimental data collected and reported in the research article "Walking my way? Walker gender and display format confounds the perception of specific emotions" (Halovic and Kroos, in press) [1]. The data set represent perceiver identification rates for different emotions (happiness, sadness, anger, fear and neutral), as displayed by full-light, point-light and synthetic point-light walkers. The perceiver identification scores have been transformed into Ht rates, which represent proportions/percentages of correct identifications above what would be expected by chance. This data set also provides Ht rates separately for male, female and ambiguously gendered walkers. PMID- 29159241 TI - Ex-situ X-ray computed tomography data for a non-crimp fabric based glass fibre composite under fatigue loading. AB - The data published with this article are high resolution X-ray computed tomography (CT) data obtained during an ex-situ fatigue test of a coupon test specimen made from a non-crimp fabric based glass fibre composite similar to those used for wind turbine blades. The fatigue test was interrupted four times for X-ray CT examination during the fatigue life of the considered specimen. All the X-ray CT experiments were performed in the region where unidirectional fibre fractures first became visible, and thereby include the damage progression in 3D in this specific region during fatigue loading of the specimen. PMID- 29159242 TI - Data on spatiotemporal patterns of the foundation of Japanese companies in China from 1980-2016. AB - This data article provides spatiotemporal patterns of the foundation of Japanese companies in China. The data for companies in the food manufacturing, wholesaling, and service industries were collected from published lists of Chinese companies founded through the investment of Japanese companies. The data are provided in a matrix heatmap format, a two-dimensional visualization of data using color to represent the magnitude of two variables: year of foundation and area in China where the company is located. PMID- 29159243 TI - Data on people's interests related to entry into the Chinese market based on Internet activity corresponding to real-world statistical data in the period 2004 2015 in Japan. AB - This data article describes Internet activities in Japan related to entry into the Chinese market from 2004 to 2015 using data obtained from mining Google Trends. The search volumes were processed and correlated with statistical annual data on the number of Chinese companies founded by investment from Japanese companies. Relative search volumes generated by Google Trends reflect the increase and decrease in the number of Chinese companies founded by Japanese companies in the "real world." The correlation between relative search volumes generated by Google Trends and foundation of companies in the "real world" in the study period (2004-2015) was statistically significant. PMID- 29159244 TI - Clinical, pathological, and molecular data concerning Coenurus cerebralis in Sheep in Egypt. AB - This article contains information related to a recent study "Prevalence and Identity of Taenia multiceps cysts "Coenurus cerebralis" in Sheep in Egypt" (Amer et al., 2017) [1]. Specifically, affected sheep showed neurological disorders manifested as depression, head shaking and circling, altered head position, incoordination and paralysis in some cases. Brain-derived cysts were molecularly identified by PCR-sequence analysis at mitochondrial 12S rRNA gene marker. Cyst induced pathological changes included degenerative changes and demyelination in brain tissue, infiltration of lymphocytes and histiocytes. Cystic fluids were biochemically analyzed for protein, lipids and electrolytes. The data of this study provides more understanding on phylogeny, epidemiology and pathology of coenurosis in sheep. PMID- 29159245 TI - Data on evolutionary relationships of Aeromonas hydrophila and Serratia proteamaculans that attach to water tanks. AB - Here the data on evolutionary relationships of persistent bacteria from water tanks and their close relatives are shown. Curated sequences of the hypervariable region of ribosomal ribonucleic acid (rRNA) obtained from a strain of Aeromonas hydrophila and two strains of Serratia proteamaculans after searches in the GenBank(r) database were analyzed. The analysis which included 104 other bacteria strains, was carried out using molecular evolutionary genetic analysis (MEGA 7.0) software. PMID- 29159246 TI - Integrating clinical, dermoscopy, and reflectance confocal microscopy findings into correctly identifying a nevoid melanoma. PMID- 29159247 TI - Infliximab therapy for Netherton syndrome: A case report. PMID- 29159248 TI - Massive perianal ulceration: Entamoeba histolytica and Candida albicans co infection. PMID- 29159249 TI - Visual impairment reversal with oral acitretin therapy in keratitis-ichthyosis deafness (KID) syndrome. PMID- 29159250 TI - Secretory carcinoma of the skin: Case report and review of the literature. PMID- 29159251 TI - Hair repigmentation associated with the use of brentuximab. PMID- 29159252 TI - Granulomatous hepatitis in a healthy adult after bacillus Calmette-Guerin injection into a plantar wart. PMID- 29159253 TI - Hidradenitis suppurativa after radiotherapy for uterine adenocarcinoma: A typical example of an isoradiotopic response. PMID- 29159254 TI - Radiation-induced inflammatory dermatosis: Another facet of the immunocompromised cutaneous district. PMID- 29159255 TI - Comparative Diagnostic Performance of the Granulocyte and Neutrophil Counts. AB - Objectives: Use of point-of-care testing is increasing, however many haematology analysers can only determine granulocyte count without further differentiation into neutrophils, eosinophils and basophils. Since the diagnosis of life threatening neutropenia in cancer patients requires a distinct neutrophil count, this study aimed to determine the comparative performance between the neutrophil and granulocyte count. Design and methods: A database of 508 646 venous full blood count results measured on a laboratory reference analyser was mined from a large oncology unit. The relationship between granulocyte and neutrophil counts was assessed. Multinomial logistic regression was used to classify results into neutropenia grades using an equivalent granulocyte count. Results: Granulocyte to neutrophil count correlation was 0.997. The accuracy for classification into neutropenia grades using the derived equivalent granulocyte count ranges was 96.4%. Identification of results with a neutrophil count <1.5*109 cells/L using an equivalent granulocyte count of <1.69*109 cells/L resulted in sensitivity, specificity, positive and negative predictive values of 98.0%, 99.5%, 97.8% and 99.5%, respectively. Conclusions: These results describe the relationship between granulocyte and neutrophil counts, measured on a laboratory analyser, in a large population of patients with malignancies and receiving anti-cancer therapies. However, this relationship must be established using a point of care testing system with a three-part differential count before considering the possibility that a granulocyte count can guide clinical decisions in the absence of a definitive neutrophil count, to reduce the frequency and severity of neutropenic complications in patients receiving cancer treatments. PMID- 29159256 TI - Cirrhosis of liver: Interference of serpins in quantification of SERPINA4 - A preliminary study. AB - Background: Cirrhosis of liver is a pathological condition, wherein functions of liver are impaired by chronic liver exploitations. Due to decrease in synthetic capacity, expressions of plasma proteins tend to decrease in blood stream. Serpins (Serine protease inhibitors) are class of plasma proteins expressed from liver with structural similarities and diverse functions. SERPINA4 (Kallistatin) is a multifunctional serpin clade A protein expressed from liver and concentration in serum is the reflection of extent of liver dysfunction. Objective: To identify interference of other serpins by immunological cross reactivity with SERPINA4 in cirrhotic liver and healthy subjects. Materials and methods: Blood samples were collected from 20 subjects (10 cirrhotic liver, 10 healthy) from R.L. Jalappa Hospital and Research Centre, Kolar, Karnataka, India. Separation of proteins was carried out by SDS-PAGE. Cross reactivity study was analyzed using western blot. Results: Proteins present in cirrhotic liver and healthy subject's serum were separated by SDS PAGE. There was no band detection on both (cirrhotic liver and healthy) PVDF (polyvinylidene diflouride) membranes. However, a significant band was observed with recombinant kallistatin. Conclusion: Structurally similar serpins with minor amino acid sequence similarities did not show any immunological cross reactivity with SERPINA4 due to non identical epitope in cirrhotic liver and healthy subjects. Present study revealed that there is no interference of serpins for immunological reactions in quantitative estimation of kallistatin which needs further validation. PMID- 29159257 TI - Development and analytical performance of a new ARCHITECT automated dipeptidyl peptidase-4 immunoassay. AB - Background: Dipeptidyl peptidase-4 (DPP-4) may be a suitable biomarker to identify people with severe asthma who have greater activation of the interleukin 13 (IL-13) pathway and may therefore benefit from IL-13-targeted treatments. We report the analytical performance of an Investigational Use Only immunoassay and provide data on the biological range of DPP-4 concentrations. Methods: We assessed assay performance, utilising analyses of precision, linearity and sensitivity; interference from common endogenous assay interferents, and from asthma and anti-diabetic medications, were also assessed. The assay was used to measure the range of serum DPP-4 concentrations in healthy volunteers and subjects with diabetes and severe, uncontrolled asthma. Results: The total precision of DPP-4 concentration measurement (determined using percentage coefficient of variation) was <=5% over 20 days. Dilution analysis yielded linear results from 30 to 1305 ng/mL; the limit of quantitation was 19.2 ng/mL. No notable endogenous or drug interferences were observed at the expected therapeutic concentration. Median DPP-4 concentrations in healthy volunteers and subjects with asthma or Type 1 diabetes were assessed, with concentrations remaining similar in subjects with diabetes and asthma across different demographics. Conclusion: These analyses indicate that the ARCHITECT DPP-4 Immunoassay is a reliable and robust method for measuring serum DPP-4 concentration. PMID- 29159258 TI - Spontaneous tumor lysis syndrome occurring in untreated uterine cancer. AB - *Tumor lysis syndrome is rare in solid tumors.*Tumor lysis syndrome is an oncologic emergency.*We present two cases of spontaneous tumor lysis syndrome arising in uterine cancer. PMID- 29159259 TI - Primary, non-germinal center, double-expressor diffuse large B cell lymphoma confined to a uterine leiomyoma: A case report. AB - *Primary lymphoma of the female genital tract accounts for 1% of extranodal lymphomas.*Approximately 13% are diffuse large B cell lymphoma of the uterus, most often involving the endometrial stroma or cervix.*The first double-expressor diffuse large B cell lymphoma confined to a uterine leiomyoma is described. PMID- 29159260 TI - Public health approach to prevent cervical cancer in HIV-infected women in Kenya: Issues to consider in the design of prevention programs. AB - Women living with HIV in Africa are at increased risk to be co-infected with Human Papilloma Virus (HPV), persistent high risk (HR) HPV infection and bacterial vaginosis (BV), which compounds HPV persistence, thereby increasing the risk for cervical dysplasia. New guidance from WHO in 2014 advocating for a "screen and treat" approach in resource poor settings is becoming a more widely recommended screening tool for cervical cancer prevention programs in such contexts. This review article summarizes the risk factors to be considered when designing a primary and secondary cervical prevention program in a post vaccination era for HIV-infected women in Kenya. This review article is based on our prior research on the epidemiology of pHR/HR-HPV genotypes in HIV-infected women and CIN 2 + in Kenya and other sub-Saharan contexts. In order to contextualize the findings, a literature search was carried out in March 2017 by means of four electronic databases: PUBMED, EMBASE, SCOPUS, and PROQUEST. Risk factors for potential (pHR)/HR HPV acquisition, including CD4 count, HAART initiation, Female Sex Worker status (FSW) and BV need to be considered. Furthermore, there may be risk factors for abnormal cytology, including FSW status, multiple potential (p)HR/HR HPV genotypes, which may require that HIV infected women be subjected to screening at more frequent intervals than the three year recommended by the WHO. The quadruple synergistic interaction between HIV, HPV and BV and its related cervicitis may need to be reflected within a larger prevention framework at the community level. The opportunities brought forth by the roll out of HAART could lead to task shifting of HIV-HPV-BV care to nurses, which may increase access in poorly-served areas. PMID- 29159261 TI - A case of pure-type ovarian squamous cell carcinoma producing granulocyte-colony stimulating factor. AB - *Pure-type ovarian squamous cell carcinoma (POSCC) is extremely rare.*This is the first report of G-CSF-producing POSCC.*This case was successfully treated with primary surgery and standard chemotherapy.*A tumor with uninfected neutrophilia may be a G-CSF-producing tumor.*18F-FDG-PET/CT and MRI may be useful for diagnosing G-CSF-producing tumors. PMID- 29159262 TI - Tumor lysis syndrome in a patient with ovarian yolk sac tumor. AB - *Tumor lysis syndrome is an oncologic emergency with profound metabolic derangements.*Germ cell tumors with large disease burden increase the risk for tumor lysis syndrome.*Herein we present a case of tumor lysis syndrome prior to initiation of cytotoxic chemotherapy for ovarian yolk sac tumor. PMID- 29159263 TI - Influence of age and body condition on astrovirus infection of bats in Singapore: An evolutionary and epidemiological analysis. AB - Bats are unique mammals that are reservoirs of high levels of virus diversity. Although several of these viruses are zoonotic, the majority are not. Astroviruses, transmitted fecal-orally, are commonly detected in a wide diversity of bat species, are prevalent at high rates and are not thought to directly infect humans. These features make astroviruses useful in examining virus evolutionary history, epidemiology in the host, and temporal shedding trends. Our study screened for the presence of astroviruses in bats in Singapore, reconstructed the phylogenetic relations of the polymerase genes and tested for population characteristics associated with infection. Of the seven species screened, astroviruses were detected in Rhinolophus lepidus and Eonycteris spelaea. The R. lepidus sequences grouped with other Rhinolophus astrovirus sequences from China and Laos, while the Eoncyteris sequences formed a distinct clade with astroviruses from Rousettus spp. in Laos and Pteropus giganteus in Bangladesh, but not with other E. spelaea sequences. Longitudinal collections of Eonycteris feces demonstrated variable shedding. Juvenile status of bats was a risk factor for astroviruses. This study highlights the diversity of astroviruses in nectivorous and insectivorous bats in Singapore and provides a predictive framework for understanding astrovirus infection in these bats. It also suggests that in addition to host phylogenetic relatedness, host ecology, such as roosting behavior, may drive co-infections, virus maintenance and spillover. PMID- 29159264 TI - The effects of apolipoprotein E genotype, alpha-synuclein deficiency, and sex on brain synaptic and Alzheimer's disease-related pathology. AB - Introduction: Alzheimer's disease (AD) and synucleinopathies share common pathological mechanisms. Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for AD, also increases the risk for dementia in pure synucleinopathies. We presently examined the effects of alpha-synuclein deficiency (alpha-syn-/-) and sex on apoE4-driven pathologies. Methods: AD related, synaptic, and vascular markers were analyzed in female and male alpha syn-/- and alpha-syn+/+ apoE4, apoE3, and apoE3/E4 mice. Results: ApoE4 was hypolipidated, and this effect was unchanged by alpha-syn-/- and sex. The levels of synaptic markers were lower, and the levels of AD-related parameters were higher in female alpha-syn-/- apoE4 mice compared with the corresponding apoE3 mice. By comparison, apoE4 had small effects on the AD parameters of male and female alpha-syn+/+ apoE4 mice. Discussion: Although alpha-syn-/- does not affect the upstream lipidation impairment of apoE4, it acts as a "second hit" enhancer of the subsequent apoE4-driven pathologies. PMID- 29159265 TI - Characterizing biomarker features of cognitively normal individuals with ventriculomegaly. AB - Introduction: The clinical significance of ventriculomegaly in cognitively normal elderly individuals remains unclear. Methods: We selected cognitively normal individuals (n = 425) from the Alzheimer's Disease Neuroimaging Initiative database and calculated Evans index (EI) based on the ratio of the frontal horn and skull diameter. We defined ventriculomegaly as EI >= 0.30, and the participants were stratified into EI >= 0.30 group and EI < 0.30 group. Neuropsychological, imaging, and fluid biomarker profiles between the two groups were then compared using regression models. Results: A total of 96 (22.5%) individuals who had ventriculomegaly performed worse on the cognitive tests; showed smaller hippocampal volume but larger caudate, cingulate, and paracentral gyrus volumes; and displayed lower positron emission tomography [18F]fluorodeoxyglucose standardized uptake value ratio but higher amyloid burden represented by higher [18F]florbetapir standardized uptake value ratio and lower cerebrospinal fluid amyloid beta 1-42 levels compared to those without ventriculomegaly. Discussion: Asymptomatic ventriculomegaly might be an early imaging signature of preclinical Alzheimer's disease and/or normal pressure hydrocephalus. PMID- 29159266 TI - Analysis of macrolinguistic aspects of narratives from individuals with Alzheimer's disease, mild cognitive impairment, and no cognitive impairment. AB - Introduction: The depiction of features in discourse production promotes accurate diagnosis and helps to establish the therapeutic intervention in cognitive impairment and dementia. We aimed to identify alterations in the macrolinguistic aspects of discourse using a new computational tool. Methods: Sixty individuals, aged 60 years and older, were distributed in three different groups: mild Alzheimer's disease (mAD), amnestic mild cognitive impairment, and healthy controls. A narrative created by individuals was analyzed through the Coh-Metrix Dementia program, extracting the features of interest automatically. Results: mAD showed worse overall performance compared to the other groups: less informative discourse, greater impairment in global coherence, greater modalization, and inferior narrative structure. It was not possible to discriminate between amnestic mild cognitive impairment and healthy controls. Discussion: Our results are in line with the literature, verifying a pathological change in the macrostructure of discourse in mAD. PMID- 29159267 TI - Long-term impact of intensive lifestyle intervention on cognitive function assessed with the National Institutes of Health Toolbox: The Look AHEAD study. AB - Introduction: This study sought to determine whether 10 years of assignment to intensive lifestyle intervention (ILI) relative to diabetes support and education leads to better cognition. We examine intervention effects overall and among clinical subgroups, and report correlations between computer-administered and interviewer-administered cognitive batteries. Methods: The Action for Health in Diabetes (Look AHEAD) was a 16-site randomized controlled trial with overweight/obese individuals (aged 45-76) who had type 2 diabetes. The NIH Toolbox Cognition Battery tests developed to measure cognition across the lifespan were used to evaluate cognition. Results were compared with standard paper-and-pencil tests. The Toolbox and paper-and-pencil tests were administered an average of 10.9 years after randomization to 1002 participants. Results: Toolbox measures significantly correlated with interviewer-administered measures, with the strongest correlations between the Toolbox Fluid Cognition Composite and Trails B (r = -0.64, P < .0001) and Digit Symbol Coding (r = 0.63, P < .0001), and between the Toolbox Dimensional Change Card Sort (r = 0.55, P < .0001) and the Digit Symbol Coding test. Overall, ILI and diabetes support and education groups had similar adjusted mean cognitive outcomes (P > .05 for all). Subgroup analyses identified different intervention effects within baseline body mass index groups for Picture Sequence Memory (P = .01), within baseline cardiovascular disease groups for Picture Vocabulary (P = .01) and Fluid Cognition Composite (P = .02) measures, and within baseline age groups for Picture Vocabulary (P = .02). Discussion: Correlations between Toolbox and interviewer-administered outcomes provide a measure of internal validity. Findings suggest no overall effect of the intervention on cognition and that an ILI resulting in weight loss may have negative implications for cognition in individuals aged >=60, with previous history of cardiovascular disease, and those with body mass index >=40. PMID- 29159268 TI - Olfactory identification in subjective cognitive decline and mild cognitive impairment: Association with tau but not amyloid positron emission tomography. AB - Introduction: We investigated the association between olfactory identification and Alzheimer's disease biomarkers, including amyloid, tau, and neurodegeneration. Methods: Thirty-four older adults, including 19 cognitively normal (CN), 10 subjective cognitive decline (SCD), and 5 mild cognitive impairment, underwent amyloid positron emission tomography, magnetic resonance imaging, and the University of Pennsylvania Smell Identification Test (UPSIT). Twenty-six also underwent tau positron emission tomography. Associations between the UPSIT and regionally sampled amyloid, tau, and temporal atrophy were evaluated. Voxel-wise regression models were also utilized. Analyses were conducted with the full sample and only CN/SCD. Results: Lower UPSIT scores were associated with increased temporal and parietal tau burden in regional and voxel wise analyses in the full sample and in CN and SCD only. Temporal lobe atrophy was associated with lower UPSIT score. Amyloid was not associated with the UPSIT. Discussion: Impairment on the UPSIT may be a good marker for tau and neurodegeneration in preclinical or prodromal Alzheimer's disease. PMID- 29159269 TI - Pulmonary artery dysfunction in chronic thromboembolic pulmonary hypertension. AB - Background: Unresolved thromboemboli in the pulmonary arteries (PA) is known to cause chronic thromboembolic pulmonary hypertension (CTEPH). However, it remains unknown if vascular dysfunction in pulmonary arteries exists in patients with CTEPH. Methods and results: We enrolled 7 female patients with CTEPH in this study, who have stable pulmonary hemodynamics after balloon pulmonary angioplasty (age; 73.6 +/- 3.0 years old, mean right atrial pressure; 4.1 +/- 0.4 mm Hg, mean pulmonary arterial pressure; 29.4 +/- 2.7, mean pulmonary artery wedge pressure; 8.1 +/- 1.2, pulmonary vascular resistance; 397.3 +/- 51.7 dynes, cardiac index; 3.1 +/- 0.2 L/min/m2). Pulmonary artery vascular function was evaluated by measuring pulmonary artery vasomotion in response to acetylcholine (Ach) at 10 month follow-up after balloon pulmonary angioplasty. All pulmonary vasoactive drugs were discontinued on the day of the procedures. The endothelium-dependent vasomotor response was evaluated by intra-pulmonary artery infusion of Ach at the dose of 10- 8 mol/l, and the vaso-spastic response was at 10- 6 mol/l. We evaluated vasomotor responses at the same segment in each patient, by measuring % changes of luminal area detected by quantitative pulmonary arterial optical frequency-domain imaging (OFDI), where OFDI catheter was fixed during the procedure. Endothelial dysfunction was observed at the dose of Ach at 10- 8 mol/l and vasoconstriction was also confirmed at the dose of Ach at 10- 6 mol/l in the diseased pulmonary arteries in CTEPH. Conclusions: These results indicated that the pulmonary artery dysfunction exists in patients with CTEPH, which may be involved in the pathogenesis and progression of CTEPH. PMID- 29159270 TI - The circular RNA MICRA for risk stratification after myocardial infarction. AB - Background: A significant proportion of patients develop heart failure (HF) after acute myocardial infarction (MI). Predicting this development with novel biomarkers would allow tailoring healthcare to each individual. We recently identified a circular RNA called MICRA which was associated with HF development after MI. Here, we tested whether MICRA was able to risk stratify MI patients. Methods: MICRA was assessed in whole blood samples collected at reperfusion in 472 patients with acute MI. Left ventricular ejection fraction (EF) was evaluated by echocardiography at 4 months. Multivariable analyses with ordinal regression were conducted to determine the ability of MICRA to classify patients into 3 EF groups: reduced EF (<= 40%), mid-range EF (4149%) and preserved EF (>= 50%). Results: Eighty seven patients (18%) had a reduced EF, 106 (22%) had a mid-range EF and 279 (59%) had a preserved EF at 4 months. MICRA classified patients into EF groups with an adjusted odds ratio [95% confidence interval] of 0.78 [0.64 0.95]. MICRA improved the predictive value of a multivariable clinical model as attested by a decrease of the Akaike Information Criteria (p = 0.012). Bootstrap internal validation confirmed the incremental prognostic value of MICRA. Conclusion: We report that the circRNA MICRA improves risk classification after MI, supporting the added value of this novel biomarker in future prognostication strategies. PMID- 29159271 TI - Is there any tip that makes performing EUS-guided drainage easier and safer? PMID- 29159272 TI - Reply to Paik WH and colleague: "Is there any tip to perform EUS-guided drainage easier and safer?" PMID- 29159273 TI - A health economic evaluation of needle-based confocal laser endomicroscopy for the diagnosis of pancreatic cysts. AB - Background and study aims: The low sensitivity of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), especially for the diagnosis of serous cystadenomas (SCAs), can be associated with diagnostic uncertainty that can regularly lead to unnecessary surgical procedures. Needle-based confocal laser endomicroscopy (nCLE) used with EUS-FNA improves diagnostic accuracy, helping to reduce unnecessary surgery and patient follow-up. This study was conducted to evaluate the economic benefit of EUS-FNA + nCLE. Patients and methods: Probabilities used were derived from two studies representative of the two diagnostic strategies: a retrospective analysis of patients diagnosed by EUS-FNA alone and a prospective study of patients diagnosed by EUS-FNA + nCLE. Costs were based on French healthcare system rates; both private and public sector rates were included. A decision tree structure model used these probabilities and costs for two hypothetical cohorts of 1000 patients. Results: EUS-FNA + nCLE resulted in a reduction of 23 % in the total rate of surgical intervention, which translated to a reduction in clinical costs of 13 % (public sector) and 14 % (private sector). Additionally, the reduced rate of surgery would save the lives of 4 in 1000 patients. A stochastic sensitivity analysis using 100 simulations showed that in all cases the number of interventions was less for EUS-FNA + nCLE than for EUS-FNA. There was also a reduction in the incidence of false negatives using EUS-FNA + nCLE. Conclusions: EUS-FNA + nCLE results in significant economic benefits by reducing the incidence of misdiagnosis through improved diagnostic accuracy. PMID- 29159274 TI - Novel investigative modalities for evaluation of pancreatic cystic lesions: Does increased diagnostic accuracy justify the high costs? PMID- 29159275 TI - Comparative analysis of avascular areas in superficial esophageal squamous cell carcinomas using in vivo and ex vivo magnifying endoscopy. AB - Background and study aims: An avascular area (AVA), one of the microvasculature changes in superficial esophageal cancers, appears when a tumor demonstrates a bulky growth pattern. We aimed to compare endoscopic and histopathological findings by observing formalin-fixed AVA specimens using magnifying endoscopy. Patients and methods: A prospective analysis was conducted on 16 patients with superficial esophageal cancer, including AVA, who underwent endoscopic submucosal dissection (ESD). Magnifying endoscopy and blue laser imaging were used to identify AVAs. After the ESD, the AVA width was measured on formalin-fixed specimens using magnifying endoscopy, and AVA thickness and depth were determined after hematoxylin and eosin staining using microscopy. Results: Mean AVA widths of M1, M2, and M3/SM-lesions were 0.434, 0.578, and 0.835 mm, respectively (M1 vs. M2, P = 0.16; M2 vs. M3/SM-, P = 0.07). Mean AVA thicknesses of M1, M2, and M3/SM-lesions were significantly different (0.176, 0.518, and 0.800 mm; M1 vs. M2, P < 0.01; M2 vs. M3/SM-, P < 0.05). There was a significant correlation between AVA width and thickness. Conclusions: AVA size can be measured accurately on formalin-fixed specimens with magnifying endoscopy. AVA thickness can be useful for determining tumor depth. PMID- 29159276 TI - Linked color imaging (LCI), a novel image-enhanced endoscopy technology, emphasizes the color of early gastric cancer. AB - Background and study aims: Linked color imaging (LCI) and blue laser imaging (BLI) are novel image-enhanced endoscopy technologies with strong, unique color enhancement. We investigated the efficacy of LCI and BLI-bright compared to conventional white light imaging (WLI) by measuring the color difference between early gastric cancer lesions and the surrounding mucosa. Patients and methods: Images of early gastric cancer scheduled for endoscopic submucosal dissection were captured by LCI, BLI-bright, and WLI under the same conditions. Color values of the lesion and surrounding mucosa were defined as the average of the color value in each region of interest. Color differences between the lesion and surrounding mucosa (DeltaE) were examined in each mode. The color value was assessed using the CIE L*a*b* color space (CIE: Commission Internationale d'Eclairage). Results: We collected images of 43 lesions from 42 patients. Average DeltaE values with LCI, BLI-bright, and WLI were 11.02, 5.04, and 5.99, respectively. The DeltaE was significantly higher with LCI than with WLI ( P < 0.001). Limited to cases of small DeltaE with WLI, the DeltaE was approximately 3 times higher with LCI than with WLI (7.18 vs. 2.25). The DeltaE with LCI was larger when the surrounding mucosa had severe intestinal metaplasia ( P = 0.04). The average color value of a lesion and the surrounding mucosa differed. This value did not have a sufficient cut-off point between the lesion and surrounding mucosa to distinguish them, even with LCI. Conclusion: LCI had a larger DeltaE than WLI. It may allow easy recognition and early detection of gastric cancer, even for inexperienced endoscopists. PMID- 29159277 TI - Development of a porcine model for assessment of mucosal repair following endoscopic resection of the lower gastrointestinal tract. AB - Background and aims: Endoscopic mucosal resection (EMR) is widely performed for the treatment of colorectal polyps. However, the pathophysiological mechanisms of mucosal repair, including in situations at high risk of post-polypectomy bleeding, remain largely unknown. The objective of our study was to develop a porcine model of EMR in the lower gastrointestinal tract to monitor mucosal wound healing over time. Methods: Under general anesthesia, five large wounds were created in the lower gastrointestinal tract at different times, i. e. at day 0, 3, 7, 10, and 14, by multiband EMR, in each of the six pigs in the study. A colorectal resection was performed at day 14 and the animal euthanized. Repeated endoscopic and endomicroscopic examination, and histological analysis were performed. Results: No complications occurred and all animals reached the study end point. The endoscopic aspect of wound healing evolved into different phases with first a fibrin deposit covering the wounds which then gave way to granulomatous tissue. The size of the wound regressed significantly as early as day 3. Re-epithelialization of the wound started from day 7, and neo-mucosal crypts appeared from day 10. The endomicroscopic analysis described a 'ground glass appearance' from day 3 and irregular crypts from day 10, which was consistent with histological data. Good agreement between macroscopic, endomicroscopic, and histological parameters of mucosal wound healing was observed in vivo. Conclusion: This study demonstrates for the first time the feasibility of an experimental in vivo porcine model of lower gastrointestinal endoscopic resections to monitor tissue repair. This model might be helpful to document pharmacological approaches for preventing complications of endoscopic procedures performed in humans. PMID- 29159278 TI - Comparative evaluation of two porcine ex vivo models for training in endoscopic ultrasound-guided drainage of pancreatic fluid collections. AB - Introduction: EUS-guided cystoenterostomy (EUCE), a technique used for the drainage of pancreatic pseudocysts and peri-enteric collections, requires specific skills for which dedicated models are needed. Based on a compact EASIE model (Erlangen Active Simulator for Interventional Endoscopy), we developed two ex vivo porcine models of retrogastric cysts and evaluated learning performance within the frame of a structured training program. Material and methods: The first model was made of porcine colon (i. e. "natural cyst"), the second one with an ostomy bag (i. e. "artificial cyst"). All procedures were achieved with an EUS scope under fluoroscopy. Both models were evaluated prospectively over a 2-day session involving 14 students and five experts. The primary end point was overall satisfaction with each model. Results: The "natural cyst" and "artificial cyst" were prepared within 10 and 16.5 minutes ( P = 0.78), respectively. Model grading showed a non-significant trend for overall satisfaction in favor of the artificial model ( P = 0.06). As secondary end points, difference was not significant for impression of realism ( P = 0.75) whereas the "artificial cyst" was graded significantly better by experts and students in terms of ability to teach procedural steps ( P = 0.01) and ease of puncture ( P = 0.03). Moreover, experts considered the ability to improve students' proficiency to be superior with the "artificial cyst" ( P = 0.008). Conclusion: Both "artificial" and "natural cysts" are efficient for EUCE training in terms of overall satisfaction. However, the "artificial cyst" model appears to make the procedure easier with a higher ability to teach procedural steps and improve the students' proficiency. Larger applications of this model are needed to validate as a standard of training. PMID- 29159279 TI - Auditory processing enhancements in the TS2-neo mouse model of Timothy Syndrome, a rare genetic disorder associated with autism spectrum disorders. PMID- 29159280 TI - Insertion of the Type-I IFN Decoy Receptor B18R in a miRNA-Tagged Semliki Forest Virus Improves Oncolytic Capacity but Results in Neurotoxicity. AB - Oncolytic Semliki Forest virus (SFV) has been suggested as a potential candidate for the treatment of glioblastoma and neuroblastoma. However, the oncolytic capacity of SFV is restricted by the anti-viral type-I interferon (IFN) response. The aim of this study was to increase the oncolytic capacity of a microRNA target tagged SFV against glioblastoma by arming it with the Vaccinia-virus-encoded type I IFN decoy receptor B18R (SFV4B18RmiRT) to neutralize type-I IFN response. Expression of B18R by SFV4B18RmiRT aided neutralization of IFN-beta, which was shown by reduced STAT-1 phosphorylation and improved virus spread in plaque assays. B18R expression by SFV4 increased its oncolytic capacity in vitro against murine glioblastoma (CT-2A), regardless of the presence of exogenous IFN-beta. Both SFV4B18RmiRT and SFV4miRT treatments controlled tumor growth in mice with syngeneic orthotopic gliomablastoma (CT-2A). However, treatment with SFV4B18RmiRT induced severe neurological symptoms in some mice because of virus replication in the healthy brain. Neither neurotoxicity nor virus replication in the brain was observed when SFV4miRT was administered. In summary, our results indicate that the oncolytic capacity of SFV4 was improved in vitro and in vivo by incorporation of B18R, but neurotoxicity of the virus was increased, possibly due to loss of microRNA targets. PMID- 29159281 TI - The Role of the Gustatory System in the Coordination of Feeding. AB - To survive, all animals must find, inspect, and ingest food. Behavioral coordination and control of feeding is therefore a challenge that animals must face. Here, we focus on how the gustatory system guides the precise execution of behavioral sequences that promote ingestion and suppresses competing behaviors. We summarize principles learnt from Drosophila, where underlying sensory neuronal mechanisms are illustrated in great detail. Moreover, we compare these principles with findings in other animals, where such coordination plays prominent roles. These examples suggest that the use of gustatory information for feeding coordination has an ancient origin and is prevalent throughout the animal kingdom. PMID- 29159282 TI - Ultrafast direct electron transfer at organic semiconductor and metal interfaces. AB - The ability to control direct electron transfer can facilitate the development of new molecular electronics, light-harvesting materials, and photocatalysis. However, control of direct electron transfer has been rarely reported, and the molecular conformation-electron dynamics relationships remain unclear. We describe direct electron transfer at buried interfaces between an organic polymer semiconductor film and a gold substrate by observing the first dynamical electric field-induced vibrational sum frequency generation (VSFG). In transient electric field-induced VSFG measurements on this system, we observe dynamical responses (<150 fs) that depend on photon energy and polarization, demonstrating that electrons are directly transferred from the Fermi level of gold to the lowest unoccupied molecular orbital of organic semiconductor. Transient spectra further reveal that, although the interfaces are prepared without deliberate alignment control, a subensemble of surface molecules can adopt conformations for direct electron transfer. Density functional theory calculations support the experimental results and ascribe the observed electron transfer to a flat-lying polymer configuration in which electronic orbitals are found to be delocalized across the interface. The present observation of direct electron transfer at complex interfaces and the insights gained into the relationship between molecular conformations and electron dynamics will have implications for implementing novel direct electron transfer in energy materials. PMID- 29159283 TI - Structural rearrangements governing Johari-Goldstein relaxations in metallic glasses. AB - The Johari-Goldstein secondary (beta) relaxations are an intrinsic feature of supercooled liquids and glasses. They are crucial to many properties of glassy materials, but the underlying mechanisms are still not established. In a model metallic glass, we study the atomic rearrangements by molecular dynamics simulations at time scales of up to microseconds. We find that the distributions of single-particle displacements exhibit multiple peaks, whose positions quantitatively match the pair distribution function. These are identified as the structural signature of cooperative string-like excitations. Furthermore, the most probable time of the string-like motions coincides with the beta-relaxation time as probed by dynamical mechanical simulations over a wide temperature range and is consistent with a theoretical model. Our results provide insights into the long-standing puzzle regarding the structural origin of beta relaxations in glassy metallic materials. PMID- 29159284 TI - Measuring quantitative effects of methylation on transcription factor-DNA binding affinity. AB - Methylation of CpG (cytosine-phosphate-guanine) dinucleotides is a common epigenetic mark that influences gene expression. The effects of methylation on transcription factor (TF) binding are unknown for most TFs and, even when known, such knowledge is often only qualitative. In reality, methylation sensitivity is a quantitative effect, just as changes to the DNA sequence have quantitative effects on TF binding affinity. We describe Methyl-Spec-seq, an easy-to-use method that measures the effects of CpG methylation (mCPG) on binding affinity for hundreds to thousands of variants in parallel, allowing one to quantitatively assess the effects at every position in a binding site. We demonstrate its use on several important DNA binding proteins. We calibrate the accuracy of Methyl-Spec seq using a novel two-color competitive fluorescence anisotropy method that can accurately determine the relative affinities of two sequences in solution. We also present software that extends standard methods for representing, visualizing, and searching for matches to binding site motifs to include the effects of methylation. These tools facilitate the study of the consequences for gene regulation of epigenetic marks on DNA. PMID- 29159285 TI - Reactive oxygen species leave a damage trail that reveals water channels in Photosystem II. AB - Photosystem II (PSII), a unique membrane-bound oxidoreductase, catalyzes light driven oxidation of water to molecular oxygen. Although high-resolution structures of PSII are known, the exact path of the substrate water molecules to the catalytic Mn4CaO5 center within the PSII complex remains poorly understood. PSII produces reactive oxygen species (ROS), responsible for the frequent damage and turnover of this megacomplex that occur under physiological conditions. Such ROS are known to specifically modify PSII proteins. Using high-resolution tandem mass spectrometry, we identified oxidative modifications on 36 amino acid residues on the lumenal side of PSII, in the core PSII proteins D1, D2, and CP43 of the cyanobacterium Synechocystis sp. PCC 6803. Remarkably, these oxidized residues clustered into three nearly continuous formations, tracking the pathways of ROS diffusion from the manganese center all the way out to the surface of PSII. We suggest that these profiles of oxidized residues reveal the locations of water channels within PSII. Our results provide the most comprehensive experimental evidence to date of physiologically relevant oxidized residues in PSII and illuminate three possible channels for water between the catalytic Mn cluster in the PSII complex and the bulk medium around it. PMID- 29159286 TI - Tailor-made temperature-dependent thermal conductivity via interparticle constriction. AB - Managing heat is a major challenge to meet future demands for a sustainable use of our energy resources. This requires materials, which can be custom-designed to exhibit specific temperature-dependent thermal transport properties to become integrated into thermal switches, transistors, or diodes. Common crystalline and amorphous materials are not suitable, owing to their gradual changes of the temperature-dependent thermal conductivity. We show how a second-order phase transition fully controls the temperature-dependent thermal transport properties of polymer materials. We demonstrate four major concepts based on a colloidal superstructure: (i) control of transition temperature, (ii) width of phase transition regime, (iii) multistep transitions, and (iv) step height of the transition. Most importantly, this unique control over thermal conductivity is only governed by the interparticle constriction, the particle composition, and its mesostructure. Our concept is therefore also applicable to a wide variety of other particulate materials. PMID- 29159287 TI - Strained hybrid perovskite thin films and their impact on the intrinsic stability of perovskite solar cells. AB - Organic-inorganic hybrid perovskite (OIHP) solar cells have achieved comparable efficiencies to those of commercial solar cells, although their instability hinders their commercialization. Although encapsulation techniques have been developed to protect OIHP solar cells from external stimuli such as moisture, oxygen, and ultraviolet light, understanding of the origin of the intrinsic instability of perovskite films is needed to improve their stability. We show that the OIHP films fabricated by existing methods are strained and that strain is caused by mismatched thermal expansion of perovskite films and substrates during the thermal annealing process. The polycrystalline films have compressive strain in the out-of-plane direction and in-plane tensile strain. The strain accelerates degradation of perovskite films under illumination, which can be explained by increased ion migration in strained OIHP films. This study points out an avenue to enhance the intrinsic stability of perovskite films and solar cells by reducing residual strain in perovskite films. PMID- 29159288 TI - Extreme enrichment in atmospheric 15N15N. AB - Molecular nitrogen (N2) comprises three-quarters of Earth's atmosphere and significant portions of other planetary atmospheres. We report a 19 per mil (0/00) excess of 15N15N in air relative to a random distribution of nitrogen isotopes, an enrichment that is 10 times larger than what isotopic equilibration in the atmosphere allows. Biological experiments show that the main sources and sinks of N2 yield much smaller proportions of 15N15N in N2. Electrical discharge experiments, however, establish 15N15N excesses of up to +230/00. We argue that 15N15N accumulates in the atmosphere because of gas-phase chemistry in the thermosphere (>100 km altitude) on time scales comparable to those of biological cycling. The atmospheric 15N15N excess therefore reflects a planetary-scale balance of biogeochemical and atmospheric nitrogen chemistry, one that may also exist on other planets. PMID- 29159290 TI - Erratum for the Research Article: "Coordinated infraslow neural and cardiac oscillations mark fragility and offline periods in mammalian sleep" by S. Lecci, L. M. J. Fernandez, F. D. Weber, R. Cardis, J.-Y. Chatton, J. Born, A. Luthi. AB - [This corrects the article e1602026 in vol. 3, PMID: 28246641.]. PMID- 29159289 TI - Atomically engineered electron spin lifetimes of 30 s in silicon. AB - Scaling up to large arrays of donor-based spin qubits for quantum computation will require the ability to perform high-fidelity readout of multiple individual spin qubits. Recent experiments have shown that the limiting factor for high fidelity readout of many qubits is the lifetime of the electron spin. We demonstrate the longest reported lifetimes (up to 30 s) of any electron spin qubit in a nanoelectronic device. By atomic-level engineering of the electron wave function within phosphorus atom quantum dots, we can minimize spin relaxation in agreement with recent theoretical predictions. These lifetimes allow us to demonstrate the sequential readout of two electron spin qubits with fidelities as high as 99.8%, which is above the surface code fault-tolerant threshold. This work paves the way for future experiments on multiqubit systems using donors in silicon. PMID- 29159292 TI - Focusing on Transgender Healthcare. PMID- 29159291 TI - Continuum Reconfigurable Parallel Robots for Surgery: Shape Sensing and State Estimation with Uncertainty. AB - This paper examines shape sensing for a new class of surgical robot that consists of parallel flexible structures that can be reconfigured inside the human body. Known as CRISP robots, these devices provide access to the human body through needle-sized entry points, yet can be configured into truss-like structures capable of dexterous movement and large force application. They can also be reconfigured as needed during a surgical procedure. Since CRISP robots are elastic, they will deform when subjected to external forces or other perturbations. In this paper, we explore how to combine sensor information with mechanics-based models for CRISP robots to estimate their shapes under applied loads. The end result is a shape sensing framework for CRISP robots that will enable future research on control under applied loads, autonomous motion, force sensing, and other robot behaviors. PMID- 29159293 TI - Fit to Serve? Exploring Mental and Physical Health and Well-Being Among Transgender Active-Duty Service Members and Veterans in the U.S. Military. AB - Purpose: Although transgender people are currently excluded from enlistment and discharged from service based on medical and psychological fitness policies, the current mental and physical health of transgender active-duty U.S. military personnel and veterans is poorly understood. The purpose of the current study was to investigate the military histories, lifetime mental and physical health diagnoses, and transgender transition-related health of transgender active-duty service members (ADSM) and veterans. Methods: Participants were recruited through private LGBT military and veteran organizational listservs, snowball sampling, and in-person recruitment to complete an anonymous and confidential self administered online questionnaire. Results: A total of 106 transgender ADSM (n=55) and veterans (n=51) completed the questionnaire. Transgender veterans were significantly older (44 mean years vs. 29.5 mean years, t=-6.23, p<0.001). A greater percentage of veterans than ADSM reported depression (64.6% vs. 30.9%, chi2=11.68, p=0.001) and anxiety (41.3% vs. 18.2%, chi2=6.54, p=0.011). In addition, 15.9% of veterans versus 1.8% of ADSM (chi2=6.53, p=0.011) had been diagnosed with a substance abuse disorder. There were no significant differences in lifetime physical health conditions; however, veterans reported a higher body mass index than ADSM (28.4 vs. 24.9, t=-3.85, p<0.001). For both groups, mental and physical health problems were positively correlated with age and years of military service (r=0.37-0.84, p<0.01). There were no significant differences between groups in transgender transition-related health. Conclusion: Our data represent the first descriptive statistics of lifetime mental and physical health issues among transgender ADSM and veterans. Data indicate that transgender ADSM report fewer lifetime mental and physical health problems than transgender veterans. Taken together, our findings suggest that more research, specifically among transgender ADSM, is needed to challenge the exclusion of transgender persons from U.S. military service based on the presumption of poor mental or physical health. PMID- 29159295 TI - Gender Confirmation Surgery: An Update for the Primary Care Provider. AB - Increased advocacy efforts and expanded third-party insurance coverage have improved access to healthcare for transgender individuals. In conjunction with mental health and medical professionals, gender surgeries offer an important step in allowing individuals to realize their true selves. To provide quality multidisciplinary care, primary care doctors need to understand challenges facing transgender individuals and treatment options available to them. In this article, we will review the role of the surgeon and the goals of various gender confirming surgeries. In addition, we will provide an overview of the available surgical options. PMID- 29159294 TI - Mental Health Disparities Within the LGBT Population: A Comparison Between Transgender and Nontransgender Individuals. AB - Purpose: This study assessed within a Midwestern LGBT population whether, and the extent to which, transgender identity was associated with elevated odds of reported discrimination, depression symptoms, and suicide attempts. Methods: Based on survey data collected online from respondents who self-identified as lesbian, gay, bisexual, and/or transgender persons over the age of 19 in Nebraska in 2010, this study performed bivariate t- or chi-square tests and multivariate logistic regression analysis to examine differences in reported discrimination, depression symptoms, suicide attempts, and self-acceptance of LGBT identity between 91 transgender and 676 nontransgender respondents. Results: After controlling for the effects of selected confounders, transgender identity was associated with higher odds of reported discrimination (OR=2.63, p<0.01), depression symptoms (OR=2.33, p<0.05), and attempted suicides (OR=2.59, p<0.01) when compared with nontransgender individuals. Self-acceptance of LGBT identity was associated with substantially lower odds of reporting depression symptoms (OR=0.46, p<0.001). Conclusion: Relative to nontransgender LGB individuals, transgender individuals were more likely to report discrimination, depression symptoms, and attempted suicides. Lack of self-acceptance of LGBT identity was associated with depression symptoms among transgender individuals. PMID- 29159296 TI - Preservation of Fertility Potential for Gender and Sex Diverse Individuals. AB - Gender and sex diverse individuals-transgender individuals and those with disorders of sex development (DSD)-both face medical treatments that may impair biological fertility potential. Young DSD patients also often have abnormal gonadal development. Fertility preservation for these populations has historically been poorly understood and rarely addressed. Future fertility should be discussed with gender and sex diverse individuals, particularly given recent advances in fertility preservation technologies and evolving views of fertility potential. Key ethical issues include parental proxy decision-making and uncertainty regarding prepubertal fertility preservation technologies. Many opportunities exist for advancing fertility-related care and research for transgender and DSD patients. PMID- 29159297 TI - Implementation and Evaluation of a Pilot Training to Improve Transgender Competency Among Medical Staff in an Urban Clinic. AB - Purpose: Transgender individuals (TGI), who identify their gender as different from their sex assigned at birth, continue facing widespread discrimination and mistreatment within the healthcare system. Providers often lack expertise in adequate transgender (TG) care due to limited specialized training. In response to these inadequacies, and to increase evidence-based interventions effecting TG affirmative healthcare, we implemented and evaluated a structural-level intervention in the form of a comprehensive Provider Training Program (PTP) in TG health within a New York City-based outpatient clinic serving primarily individuals of color and of low socioeconomic status. This pilot intervention aimed to increase medical staff knowledge of TG health and needs, and to support positive attitudes toward TGI. Methods: Three 2-h training sessions were delivered to 35 clinic staff across 4 months by two of the authors experienced in TG competency training; the training sessions included TG-related identity and barriers to healthcare issues, TG-specialized care, and creating TG-affirmative environments, medical forms, and billing procedures. We evaluated changes through pre-post intervention surveys by trainees. Results: Compared to pre-training scores, post-training scores indicated significant (1) decreases in negative attitudes toward TGI and increases in TG-related clinical skills, (2) increases in staff's awareness of transphobic practices, and (3) increases in self-reported readiness to serve TGI. The clinic increased its representation of general LGBT related images in the waiting areas, and the staff provided highly positive training evaluations. Conclusion: This PTP in TG health shows promise in leading to changes in provider attitudes and competence, as well as clinic systems, especially with its incorporation in continuing education endeavors, which can, in turn, contribute to health disparities reductions among TG groups. PMID- 29159298 TI - Interdisciplinary Transgender Veteran Care: Development of a Core Curriculum for VHA Providers. AB - Purpose: The Veteran's Health Administration (VHA) has created a training program for interdisciplinary teams of providers on the unique treatment needs of transgender veterans. An overview of this program's structure and content is described along with an evaluation of each session and the program overall. Methods: A specialty care team delivered 14 didactic courses supplemented with case consultation twice per month over the course of 7 months through video teleconferencing to 16 teams of learners. Each team, consisting of at least one mental health provider (e.g., social worker, psychologist, or psychiatrist) and one medical provider (e.g., physician, nurse, physician assistant, advanced practice nurse, or pharmacist), received training and consultation on transgender veteran care. Results: In the first three waves of learners, 111 providers across a variety of disciplines attended the sessions and received training. Didactic topics included hormone therapy initiation and adjustments, primary care issues, advocacy within the system, and psychotherapy issues. Responses were provided to 39 veteran-specific consult questions to augment learning. Learners reported an increase in knowledge plus an increase in team cohesion and functioning. As a result, learners anticipated treating more transgender veterans in the future. Conclusion: VHA providers are learning about the unique healthcare needs of transgender veterans and benefitting from the training opportunity offered through the Transgender Specialty Care Access Network-Extension of Community Healthcare Outcomes program. The success of this program in training interdisciplinary teams of providers suggests that it might serve as a model for other large healthcare systems. In addition, it provides a path forward for individual learners (both within VHA and in the community) who wish to increase their knowledge. PMID- 29159299 TI - Assessing Residency Program Approaches to the Transgender Health CREOG Objective. AB - Purpose: The transgender population is a small yet distinctive portion of the gynecology patient population, requiring both primary care and specialty services. Recognizing the need for increased education, the Council on Resident Education in Obstetrics and Gynecology (CREOG) developed objectives specific to the care of transgender patients. This study is to assess residency program directors' knowledge about the transgender health CREOG objectives, describe how objectives are being implemented in training programs, and identify what types of educational materials would be useful if available. Methods: In May 2014, an 11 item anonymous survey was sent through e-mail to all eligible program directors of accredited obstetrics and gynecology residency programs. The short questionnaire contained questions about program demographics, approach to training residents with regard to the CREOG objectives, and opinions on tools they would like to use to train their residents on the transgender CREOG objectives. Results: Just under half (47%) of the 86 geographically diverse respondents were from hospital-based programs. The majority reported that the transgender health objectives were important (82%); however, only 70% were familiar with the objectives themselves. Most respondents (96%) felt that providing an educational activity in their training program would be beneficial for their residents' education. Conclusions: Most program directors support the CREOG transgender health objectives and are in favor of implementing educational tools to meet the objectives, suggesting that development of new tools to meet this need would be useful. Future endeavors will be made toward build a training module to facilitate obstetrics and gynecology (Ob-Gyn) programs meeting the CREOG objectives. PMID- 29159300 TI - Gender Affirmation and Resiliency Among Black Transgender Women With and Without HIV Infection. AB - Purpose: Among black transgender women (transwomen) at high risk of HIV acquisition or already living with HIV/AIDS, the study examined whether medical or socially based gender affirming factors may contribute differentially to selected measures of resiliency, perceived stress, and a scale measure of mental health outcomes. This question has implications for clinical care and counseling of this population. Methods: Seventy-seven black transwomen were recruited to participate in a private, face-to-face structured interview. Two index measures of gender affirmation (GA) were constructed from the data. One comprised medical aspects only and the other comprised social aspects of GA. Assessed outcomes were personal competence and acceptance of self and life (resiliency), perceived stress and recent anxiety, depression, and suicide ideation (mental health). Associations between GA variables and outcomes were first assessed using bivariate level correlations. Significant bivariate associations were then tested in multivariable regression models adjusting for age and HIV status. Results: Mean age of the sample was 34.5 years. More than one-half of the sample (62.3%) indicated being HIV-infected. None of the bivariate or multivariable associations pertaining to GA medical factors were significant. Conversely, the social GA factors were significant and protective with all four outcomes. In the presence of age and HIV status, greater social GA was significantly associated with greater personal competence, acceptance of self and life, and positive mental health outcome. HIV status had an independent effect on personal competence, acceptance of self and life, with HIV-positive transwomen scoring higher on both measures. Conclusion: Among black transwomen at high risk of HIV acquisition or already HIV-infected, study findings suggest the possibility that socially based GA may play a prominent role in strengthening the resiliency and mental health of black transwomen. This same protective effect may not occur as a consequence of gender affirming body modification practices. PMID- 29159301 TI - Anogenital Human Papillomavirus Infection and HIV Infection Outcomes Among Peruvian Transgender Women: Results from a Cohort Study. AB - Latin American transgender women are highly vulnerable to HIV infection, and although much is known about factors associated with HIV infection in this population, little is known about the association of human papilloma virus (HPV) with HIV infection. We investigated anogenital HPV and cumulative HIV incidence among 68, initially HIV uninfected, Peruvian transgender women enrolled into a 2 year, prospective cohort study: 95.6% had at least one anogenital HPV genotype at baseline, 19.1% had visible anogenital warts, and 6.0% became infected with HIV over the course of the study. Due to the high anogenital HPV prevalence, this population would likely benefit from early immunization with the HPV vaccine. PMID- 29159302 TI - Transgender Veterans and the Veterans Health Administration: Exploring the Experiences of Transgender Veterans in the Veterans Affairs Healthcare System. AB - Purpose: The Veterans Health Administration (VHA) has provided transgender transition-related care to veterans since 2011. However, little is known about the experiences of transgender veteran patients accessing transgender transition related healthcare at Veterans Affairs (VA) clinics since the establishment of this care. The purpose of this study was to explore transgender veterans' experiences accessing and utilizing transition-related healthcare through the VA healthcare system. Methods: Eleven transgender veterans were recruited using in person recruitment at the 2013 Southern Comfort Conference (Atlanta, GA). In depth semistructured interviews were conducted with participants using a qualitative inquiry methodological perspective and experience-centered approach. Interviews were digitally recorded and transcribed verbatim. The transcripts were coded by two independent researchers using ATLAS.ti.(c) Results: Five inter related themes were identified as key factors impacting the accessibility and quality of care transgender veterans receive through the VA: (1) long delays in receiving care; (2) needing to travel to receive care; (3) lack of patient knowledge regarding the coverage of transition-related care; (4) insensitivity, harassment, and violence among providers; and (5) a general lack of knowledge about transgender patients and care among providers. Conclusion: To our knowledge, this study is one of the first to explore the experiences of transgender veterans in accessing and utilizing transgender transition-related care at the VA after the 2011 VHA directive. Our findings suggest that although transgender healthcare coverage is available, additional patient-centered and healthcare system-level interventions are needed to improve the uptake and implementation of the VHA transgender protections and care coverage. PMID- 29159303 TI - Choosing a Surgeon: An Exploratory Study of Factors Influencing Selection of a Gender Affirmation Surgeon. AB - Purpose: Selecting a healthcare provider is often a complicated process. Many factors appear to govern the decision as to how to select the provider in the patient-provider relationship. While the possibility of changing primary care physicians or specialists exists, decisions regarding surgeons are immutable once surgery has been performed. This study is an attempt to assess the importance attached to various factors involved in selecting a surgeon to perform gender affirmation surgery (GAS). It was hypothesized that owing to the intimate nature of the surgery, the expense typically involved, the emotional meaning attached to the surgery, and other variables, decisions regarding choice of surgeon for this procedure would involve factors other than those that inform more typical healthcare provider selection or surgeon selection for other plastic/reconstructive procedures. Methods: Questionnaires were distributed to individuals who had undergone GAS and individuals who had undergone elective plastic surgery to assess decision-making. Results: The results generally confirm previous findings regarding how patients select providers. Conclusion: Choosing a surgeon to perform gender-affirming surgery is a challenging process, but patients are quite rational in their decision-making. Unlike prior studies, we did not find a preference for gender-concordant surgeons, even though the surgery involves the genital area. Providing strategies and resources for surgical selection can improve patient satisfaction. PMID- 29159304 TI - An Intersectional Perspective on Access to HIV-Related Healthcare for Transgender Women. AB - Transgender women experience decreased access to HIV-related healthcare relative to cisgender people, in part due to pervasive transphobia in healthcare. This perspective describes intersectionality as a salient theoretical approach to understanding this disparity, moving beyond transphobia to explore how intersecting systems of oppression, including cisnormativity, sexism/transmisogyny, classism, racism, and HIV-related, gender nonconformity, substance use, and sex work stigma influence HIV-related healthcare access for transgender women living with HIV. This perspective concludes with a discussion of how intersectionality-informed studies can be enhanced through studying underexplored intersections and bringing attention to women's resiliency and empowerment. PMID- 29159305 TI - Gaps in Transgender Medicine Content Identified Among Canadian Medical School Curricula. AB - Purpose: The transgender community is a diverse group that requires unique consideration in the healthcare setting. However, several studies have suggested that their needs are not currently being met by our medical system. Although the reason for this discrepancy is likely multifactorial, inadequate training of healthcare professionals to manage this population has been cited as a contributing factor. Methods: To evaluate the role that Canadian medical schools play in addressing these proposed deficits, program administrators were invited to provide curricular information detailing their delivery of transgender health, and medical students were surveyed to assess the impact of current curricula on their knowledge, attitudes, and experiences with regard to transgender health. Results: Six of fourteen schools provided curricular information about their instruction in transgender health and wide variation was found; 255/1152 University of British Columbia (UBC) students and 155/2358 students from eight other Canadian medical schools responded to the survey. Greater than 95% of responders agreed that transgender issues are important and should be addressed by physicians. However, fewer than 10% of students felt that they were sufficiently knowledgeable to do so. At UBC, there was no significant improvement in the self-reported knowledge levels after receiving the transgender-related curricula, and only 24% of students felt the topic was proficiently taught. Conclusion: This study showed that the majority of students who responded do not feel comfortable addressing the needs of transgender individuals in a healthcare setting and suggests that a reevaluation of related curricula may be warranted. PMID- 29159306 TI - Expecting Rejection: Understanding the Minority Stress Experiences of Transgender and Gender-Nonconforming Individuals. AB - Purpose: Transgender and gender-nonconforming (TGNC) individuals often are the target of enacted or external (i.e., distal) experiences of stigma, discrimination, and violence, which are linked to adverse health, particularly psychological distress. There is limited research, however, examining felt or internal (i.e., proximal) stressors faced by TGNC individuals. This study sought to examine one type of internal stressor, expecting rejection, and aimed to (1) identify how and to what extent rejection expectations operate day-to-day for TGNC individuals and (2) explore how TGNC individuals respond to expectations of rejection. Methods: In-depth interviews were conducted with 30 participants from 2014 to 2015 who identified as TGNC (mean age=30.4; 60% people of color); data were analyzed using a consensual qualitative research method. Results: Four thematic categories emerged about expecting rejection: (1) where to expect rejection; (2) thoughts and feelings associated with expectations of rejection; (3) coping strategies used to manage the expectation of rejection; and (4) the intersection of race and ethnicity with rejection expectations. Conclusion: Findings from this study suggest that expecting rejection is a frequent and salient internal stressor for TGNC individuals. We discuss the psychological and cumulative potential health impact of minority stress, and the applicability of Meyer's Minority Stress Model. Therapeutic interventions are needed to address the specific cognitive, emotional, and behavioral responses TGNC individuals experience as a result of the stress associated with expecting rejection, including fear, anxiety, and situational avoidance. PMID- 29159307 TI - Transwomen and the Metabolic Syndrome: Is Orchiectomy Protective? AB - Background: Male-to-female transsexual women or transwomen who undergo cross-sex hormone treatments experience increased health-related risks (e.g., increased rates of cardiovascular disease and premature death). Yet, the exact mechanism by which altering biochemistry leads to metabolic impairment remains unclear. While much attention has been paid to cross-sex hormone therapy, little is known about the metabolic risk associated with orchiectomy. Methods: To address the above limitation, we prospectively enrolled 12 transwomen: 4 who had undergone bi lateral orchiectomy and 8 who had not. Both groups were using cross-sex hormones. Glucose tolerance was assessed using a standard 75g oral glucose tolerance test. Hepatic steatosis was assessed by 1H magnetic resonance spectroscopy. The amount of subcutaneous and visceral abdominal fat was determined from a single abdominal axial image at the level between the vertebral L2 and L3 bodies. Baseline venous fasting blood sampling was performed for measurement of hemoglobin A1c, glucose, insulin, sex hormones, and sex hormone binding globulin. Results: The major novel findings were: (1) orchiectomy and cross-sex hormone therapy is associated with less hepatic steatosis and insulin resistance; (2) orchiectomy may be metabolically protective, and (3) circulating concentrations of sex hormones may be a major determinant of metabolic health in transwomen. Conclusions: To our knowledge, this is the first study to suggest an independent and protective role of orchiectomy on the metabolic health of transwomen. PMID- 29159308 TI - Transgender and Gender Nonconforming Youths' Public Facilities Use and Psychological Well-Being: A Mixed-Method Study. AB - Purpose: In this study, we explored experiences and feelings of safety in public facilities in relation to psychological well-being among transgender and gender nonconforming (TGNC) youth in the Midwest in the summer of 2016, in the context of ongoing legislative proposals and regulations regarding school and public bathroom use in the United States. Methods: We used a mixed-method approach, with (1) a self-administered, paper-and-pencil survey of 120 TGNC youth, focusing on differences of self-esteem, resilience, quality of life (QoL), perceived stigma, feelings of safety, and experiences of public facility use and (2) two focus group interviews (n=9) in which TGNC youth discussed individual perceptions, attitudes, and experiences of bathroom use outside participants' homes. The samples consisted predominantly of individuals assigned female at birth and currently of trans-masculine identity. Results: TGNC youth in our sample who reported that they had felt unsafe in bathrooms due to appearance or gender identity had significantly lower levels of resilience (mean(felt safe)=125.7 vs. mean(felt unsafe)=116.1; p=0.03, Cohen's d=0.44) and QoL (mean(felt safe)=59.1 vs. mean(felt unsafe)=51.9; p=0.04, Cohen's d=0.39), compared to those who felt safe. Meanwhile, feeling unsafe in bathrooms was associated with a greater level of perceived LGBT stigma (mean(felt safe)=2.3 vs. mean(felt unsafe)=2.6; p=0.03, Cohen's d=0.41) and problematic anxiety in the past year (chi2 (1)=4.06; p=0.04). Individuals in the focus groups provided specific examples of their experiences of and concerns about locker room or bathroom use in public facilities, and on the impact of school bathroom-related policies and legislation on them. Conclusion: Perceptions of safety related to bathroom use are related to psychological well-being among TGNC youth. Our predominantly trans-masculine youth sample indicated that choice of bathroom and locker room use is important and that antiharassment policies need to support students' use of their choice of bathrooms. This is particularly important information given debate of so-called bathroom bills, which attempt to restrict public bathroom use for TGNC youth, creating less choice and more stress and fear among these individuals. PMID- 29159309 TI - HIV Testing in Urban Transgender Individuals: A Descriptive Study. AB - HIV testing is considered the initial component of HIV eradication strategies. This study aimed to describe HIV testing in urban, transgender individuals in western New York. The study uses HIV testing intake data from a sample of self identified transgender males and females volunteering for an HIV test at a community-based healthcare organization. Transgender individuals with some characteristics were found to have more HIV tests including female gender, black, HIV status (positive), a history of incarceration, sex worker, housing situation, and self-referral. The findings can be used to tailor future interventions to encourage HIV testing in transgender populations. PMID- 29159310 TI - Factors Associated with Gender-Affirming Surgery and Age of Hormone Therapy Initiation Among Transgender Adults. AB - Purpose: Gender-affirming surgeries and hormone therapy are medically necessary treatments to alleviate gender dysphoria; however, significant gaps exist in the research and clinical literature on surgery utilization and age of hormone therapy initiation among transgender adults. Methods: We conducted a retrospective review of electronic health record data from a random sample of 201 transgender patients of ages 18-64 years who presented for primary care between July 1, 2010 and June 30, 2015 (inclusive) at an urban community health center in Boston, MA. Fifty percent in our analyses were trans masculine (TM), 50% trans feminine, and 24% reported a genderqueer/nonbinary gender identity. Regression models were fit to assess demographic, gender identity-related, sexual history, and mental health correlates of gender-affirming surgery and of age of hormone therapy initiation. Results: Overall, 95% of patients were prescribed hormones by their primary care provider, and the mean age of initiation of masculinizing or feminizing hormone prescriptions was 31.8 years (SD=11.1). Younger age of initiation of hormone prescriptions was associated with being TM, being a student, identifying as straight/heterosexual, having casual sexual partners, and not having past alcohol use disorder. Approximately one-third (32%) had a documented history of gender-affirming surgery. Factors associated with increased odds of surgery were older age, higher income levels, not identifying as bisexual, and not having a current psychotherapist. Conclusion: This study extends our understanding of prevalence and factors associated with gender affirming treatments among transgender adults seeking primary care. Findings can inform future interventions to expand delivery of clinical care for transgender patients. PMID- 29159311 TI - The Response of the Menstrual Cycle to Initiation of Hormonal Therapy in Transgender Men. AB - Purpose: Transition from female to male gender after initiation of hormonal therapy involves both phenotypic and physiological changes. The response to treatment can vary widely from person to person. In this study, we looked at the response of the menstrual cycle after the initiation of testosterone therapy and we wished to determine the time period and dose of testosterone leading to the cessation of menses in transgender men. Methods: A retrospective chart review of 114 transgender men (individuals assigned female gender at birth but later identify themselves as males) seen for hormonal therapy in our transgender clinic from 2006 through 2016. Results: Forty patients were excluded from the study as they were either not menstruating (19), started therapy elsewhere (13), had incomplete data (6), or were treated with transdermal testosterone (2). Of the 74 patients begun on low dose (20-40 mg weekly) intramuscular testosterone, 55% had cessation of menses within 6 months, 32% took more than 6 to 12 months, and 7% had not had complete cessation by 1 year and were prescribed progesterone (5% were given progesterone after menses had not ceased by 4 months for personal preference). The dose of testosterone correlated only loosely with the time of cessation (mean dose 40.1+/-8.1 mg/week for those <6 months and 56.1+/-12.0 mg/week for those who took 6-12 months). Conclusion: The initiation of low to moderate testosterone was sufficient in leading to menstrual cessation in the majority of patients by 6 months and nearly all by 1 year. There was individual variability in the time to cessation with little correlation to testosterone dose. PMID- 29159312 TI - Perceived Parental Attitudes of Gender Expansiveness: Development and Preliminary Factor Structure of a Self-Report Youth Questionnaire. AB - Purpose: Parental acceptance of gender identity/expression in lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ+) youth moderates the effects of minority stress on mental health outcomes. Given this association, mental health clinicians of gender-expansive adolescents often assess the degree to which these youth perceive their parents/primary caregivers as accepting or nonaffirming of their gender identity and expression. While existing measures may reliably assess youth's perceptions of general family support, no known tool aids in the assessment an adolescent's perceived parental support related to adolescent gender-expansive experiences. Methods: To provide both clinicians and researchers with an empirically derived tool, the current study used factor analysis to explore an underlying factor structure of a brief questionnaire developed by subject-matter experts and pertaining to multiple aspects of perceived parental support in gender-expansive adolescents and young adults. Respondents were gender-expansive adolescents and young adults seeking care in an interdisciplinary gender-health clinic within a pediatric academic medical center in the Midwestern United States. Results: Exploratory factor analysis resulted in a 14-item questionnaire comprised of two subscales assessing perceived parental nonaffirmation and perceived parental acceptance. Internal consistency and construct validity results provided support for this new questionnaire. Conclusion: This study provides preliminary evidence of the factor structure, reliability and validity of the Parental Attitudes of Gender Expansiveness Scale for Youth (PAGES-Y). These findings demonstrate both the clinical and research utility of the PAGES-Y, a tool that can yield a more nuanced understanding of family-related risk and protective factors in gender-expansive adolescents. PMID- 29159313 TI - Fibrosis and Atrial Fibrillation: Computerized and Optical Mapping; A View into the Human Atria at Submillimeter Resolution. AB - Recent studies strongly suggest that the majority of atrial fibrillation (AF) patients with diagnosed or subclinical cardiac diseases have established or even pre-existing fibrotic structural remodeling, which may lead to conduction abnormalities and reentrant activity that sustain AF. As conventional treatments fail to treat AF in far too many cases, an urgent need exists to identify specific structural arrhythmogenic fibrosis patterns, which may maintain AF, in order to identify effective ablation targets for AF treatment. However, the existing challenge is to define what exact structural remodeling within the complex 3D human atrial wall is arrhythmogenic, as well as linking arrhythmogenic fibrosis to an underlying mechanism of AF maintenance in the clinical setting. This review is focused on the role of 3D fibrosis architecture in the mechanisms of AF maintenance revealed by submillimeter, high-resolution ex-vivo imaging modalities directly of human atria, as well as from in-silico 3D computational techniques that can be able to overcome in-vivo clinical limitations. The systematic integration of functional and structural imaging ex-vivo may inform the necessary integration of electrode and structural mapping in-vivo. A holistic view of AF driver mechanisms may begin to identify the defining characteristics or "fingerprints" of reentrant AF drivers, such as 3D fibrotic architecture, in order to design optimal patient-specific ablation strategies. PMID- 29159314 TI - Vasoconstriction triggered by hydrogen sulfide: Evidence for Na+,K+,2Cl cotransport and L-type Ca2+ channel-mediated pathway. AB - Objectives: This study examined the dose-dependent actions of hydrogen sulfide donor sodium hydrosulphide (NaHS) on isometric contractions and ion transport in rat aorta smooth muscle cells (SMC). Methods: Isometric contraction was measured in ring aortas segments from male Wistar rats. Activity of Na+/K+-pump and Na+,K+,2Cl-cotransport was measured in cultured endothelial and smooth muscle cells from the rat aorta as ouabain-sensitive and ouabain-resistant, bumetanide sensitive components of the 86Rb influx, respectively. Results: NaHS exhibited the bimodal action on contractions triggered by modest depolarization ([K+]o=30 mM). At 10-4 M, NaHS augmented contractions of intact and endothelium-denuded strips by ~ 15% and 25%, respectively, whereas at concentration of 10-3 M it decreased contractile responses by more than two-fold. Contractions evoked by 10 4 M NaHS were completely abolished by bumetanide, a potent inhibitor of Na+,K+,2Cl-cotransport, whereas the inhibition seen at 10-3 M NaHS was suppressed in the presence of K+ channel blocker TEA. In cultured SMC, 5*10-5 M NaHS increased Na+,K+,2Cl- - cotransport without any effect on the activity of this carrier in endothelial cells. In depolarized SMC, 45Ca influx was enhanced in the presence of 10-4 M NaHS and suppressed under elevation of [NaHS] up to 10-3 M. 45Ca influx triggered by 10-4 M NaHS was abolished by bumetanide and L-type Ca2+ channel blocker nicardipine. Conclusions: Our results strongly suggest that contractions of rat aortic rings triggered by low doses of NaHS are mediated by activation of Na+,K+,2Cl-cotransport and Ca2+ influx via L-type channels. PMID- 29159315 TI - L-arginine biosensors: A comprehensive review. AB - Arginine has been considered as the most potent nutraceutics discovered ever, due to its powerful healing property, and it's been known to scientists as the Miracle Molecule. Arginine detection in fermented food products is necessary because, high level of arginine in foods forms ethyl carbamate (EC) during the fermentation process. Therefore, L-arginine detection in fermented food products is very important as a control measure for quality of fermented foods, food supplements and beverages including wine. In clinical analysis arginine detection is important due to their enormous inherent versatility in various metabolic pathways, topmost in the synthesis of Nitric oxide (NO) and tumor growth. A number of methods are being used for arginine detection, but biosensors technique holds prime position due to rapid response, high sensitivity and high specificity. However, there are many problems still to be addressed, including selectivity, real time analysis and interference of urea presence in the sample. In the present review we aim to emphasize the significant role of arginine in human physiology and foods. A small attempt has been made to discuss the various techniques used for development of arginine biosensor and how these techniques affect their performance. The choice of transducers for arginine biosensor ranges from optical, pH sensing, ammonia gas sensing, ammonium ion-selective, conductometric and amperometric electrodes because ammonia is formed as a final product. PMID- 29159316 TI - In-vitro starch hydrolysis of chitosan incorporating whey protein and wheat starch composite gels. AB - The study examined the influence of chitosan, incorporated into whey protein and wheat starch thermo gels, on the in-vitro hydrolysis of the polysaccharide. Gels were subjected to the following external conditions containing alpha-amylase at constant incubation temperature of 37 degrees C: In the first procedure, they were immersed in phosphate buffer (0.05 M) and maintained at pH 6.9 throughout the entire digestion. In the second instance, they were introduced into a salt solution, with pH and total volume adjusted at times in sync with the human gastrointestinal tract. Results indicate that low and medium molecular weight chitosan, in combination with whey protein, were effective at enhancing the protective barrier against starch degradation. Less maltose was liberated from gels containing medium molecular weight chitosan, as opposed to the low molecular weight counterpart, and results compare favorably with the outcome of the in vitro digestion of binary whey protein and wheat starch composites. PMID- 29159317 TI - The impact of dark tetrad traits on political orientation and extremism: an analysis in the course of a presidential election. AB - Previous research on personality and political attitudes has been conducted in countries where political parties from the center dominate the political system. In the present research (N = 675), we focus on the relationship between the dark side of human personality and political orientation and extremism, respectively, in the course of a presidential election where the two candidates represent either left-wing or right-wing political policies. Narcissism, Machiavellianism, psychopathy, and everyday sadism were associated with right-wing political orientation, whereas narcissism and psychopathy were associated with political extremism. Moreover, the relationships between personality and right-wing political orientation and extremism, respectively, were relatively independent from each other. PMID- 29159318 TI - Young donor white blood cell immunotherapy induces extensive tumor necrosis in advanced-stage solid tumors. AB - Background: In the past decade, a variety of immunotherapy approaches focused predominantly on the adaptive immune system have shown unprecedented responses in patients with advanced-stage malignancies. However, studies in spontaneous regression/complete resistance (SR/CR) mice and humans have shown a novel innate cancer-killing activity mediated by granulocytes, which is completely transferable for prevention or therapy against established malignancies. Methods: Three patients with advanced, relapsed or refractory solid tumors for which no standard therapy was available or was refused were enrolled into this ongoing combined phase I/II open label clinical trial testing the safety, dose tolerance, and possible antineoplastic efficacy of sequential infusions of HLA-mismatched non-irradiated allogeneic white cells (68-91% granulocytes) collected by leukapheresis from young, healthy donors (age 18-35) following mobilization with granulocyte colony stimulating factor (G-CSF) and dexamethasone. Results: Besides fevers and flushing, no infusional toxicities were observed. All patients remained clinically stable following infusions with mild cytokine release syndrome and no evidence of transfusion-associated graft-versus-host disease, acute tumor lysis syndrome,or transfusion-associated acute lung injury. Pathological examination of all cases post-mortem revealed extensive tumor necrosis up to 80% in patients 1-2, 40-50% in patient 3, and leukocyte infiltration in all cases, which could not be attributed to disease progression. Conclusions: Allogeneic white cell immunotherapy (AWIT) from young, healthy donors is well tolerated with minimal side effects and shows antitumor activity against advanced-stage solid tumors. AWIT represents a novel, safe, and cost effective immunotherapy that can be administered in an outpatient cancer clinic. PMID- 29159319 TI - Co-circulation of Crimean-Congo Hemorrhagic Fever virus strains Asia 1 and 2 between the border of Iran and Pakistan. AB - Crimean-Congo Hemorrhagic Fever (CCHF) is a tick-borne viral disease that is transmitted by numerous species of ticks, which serve both as a reservoir and vector of CCHF virus (CCHFV). Molecular and serological tests were undertaken on hard ticks (Ixodidae spp.) and samples from livestock were collected in 2015 from Chabahar County in Southeast Iran. Using RT-PCR, the ticks were tested for the presence of CCHFV. In addition, seven livestock were serologically tested for the presence of IgG antibodies using an ELISA test. IgG antibodies against CCHFV were detected in one of 7 of the livestock that were tested. In total, 49 ticks including five species: Rhipicephalus sanguineus, Hyalomma anatolicum, Hy. asiaticum, Hy. dromedarii and Hy. marginatum with a prevalence of 46.9%, 32.7%, 4.1%, 4.1% and 2.1% respectively were identified. CCHFV was detected in three ticks among 49 collected ticks. The ticks infected with CCHFV belonged to the genus Hyalomma and Rhipicephalus. Phylogenetic analysis demonstrated that two sequences clustered in clade IV (Asia-1) and one sequence was located within clade IV (Asia-2). Most of the animal and human CCHF cases of the country are reported from Sistan and Baluchistan provinces. Regular monitoring programs in the tick population and livestock are needed in the future. PMID- 29159320 TI - Immunogenicity and persistence of the 13-valent Pneumococcal Conjugate Vaccine (PCV13) in patients with untreated Smoldering Multiple Myeloma (SMM): A pilot study. AB - Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder that frequently progress to multiple myeloma (MM), a disease at high risk of pneumococcal infections. Moreover, if the polysaccharide vaccine is poorly immunogenic in MM, the 13-valent conjugated vaccine has never been tested in clonal plasma cell disorders. We evaluated its immunogenicity for 7 serotypes in 20 patients >= 50 years of age with smoldering multiple myeloma (SMM) pre and post routine-vaccination with PCV13. Concentrations of IgG specific for 7 serotypes were measured at baseline, 1, 6, and 12 months after vaccination by standardized ELISA and an Opsonophagocytic Assay (OPA). The primary endpoint was the proportion of patients responding to at least 5 of the 7 serotypes by ELISA at one month. At 1 month post vaccination, 12 patients (60%) were responders by ELISA, among whom 8 were also responders by OPA. At 6 months, 6 (30% of total) of the 12 responders had persistent immunity, and only 2 (10% of total) at 12 months. These results suggested a partial response in this population and a rapid decrease in antibody levels in the first months of vaccination. Although one injection of the 13-valent pneumococcal conjugate vaccine is immunogenic in some patients with SMM, the response is transient. Repeated injections are likely to be needed for effective and sustained protection. PMID- 29159321 TI - Lie group analysis of magnetohydrodynamic tangent hyperbolic fluid flow towards a stretching sheet with slip conditions. AB - In this paper, we studied MHD two dimensional flow of an incompressible tangent hyperbolic fluid flow and heat transfer towards a stretching sheet with velocity and thermal slip. Lie group analysis is used to develop new similarity transformation, using these similarity transformation the governing nonlinear partial differential equation are reduced into a system of coupled nonlinear ordinary differential equation. The obtained system is solved numerically by applying shooting method. Effects of pertinent parameters on the velocity and temperature profiles, skin friction, local Nusselt number are graphically presented and discussed. Comparison between the present and previous results are shown in special cases. PMID- 29159322 TI - Demonstration of entanglement assisted invariance on IBM's quantum experience. AB - Quantum entanglement is among the most fundamental, yet from classical intuition also most surprising properties of the fully quantum nature of physical reality. We report several experiments performed on IBM's Quantum Experience demonstrating envariance - entanglement assisted invariance. Envariance is a recently discovered symmetry of composite quantum systems, which is at the foundational origin of physics and a quantum phenomenon of pure states. These very easily reproducible and freely accessible experiments on Quantum Experience provide simple tools to study the properties of envariance, and we illustrate this for several cases with "quantum universes" consisting of up to five qubits. PMID- 29159323 TI - Summer and winter habitat suitability of Marco Polo argali in southeastern Tajikistan: A modeling approach. AB - We modeled summer and winter habitat suitability of Marco Polo argali in the Pamir Mountains in southeastern Tajikistan using these statistical algorithms: Generalized Linear Model, Random Forest, Boosted Regression Tree, Maxent, and Multivariate Adaptive Regression Splines. Using sheep occurrence data collected from 2009 to 2015 and a set of selected habitat predictors, we produced summer and winter habitat suitability maps and determined the important habitat suitability predictors for both seasons. Our results demonstrated that argali selected proximity to riparian areas and greenness as the two most relevant variables for summer, and the degree of slope (gentler slopes between 0 degrees to 20 degrees ) and Landsat temperature band for winter. The terrain roughness was also among the most important variables in summer and winter models. Aspect was only significant for winter habitat, with argali preferring south-facing mountain slopes. We evaluated various measures of model performance such as the Area Under the Curve (AUC) and the True Skill Statistic (TSS). Comparing the five algorithms, the AUC scored highest for Boosted Regression Tree in summer (AUC = 0.94) and winter model runs (AUC = 0.94). In contrast, Random Forest underperformed in both model runs. PMID- 29159324 TI - DNA repair after oxidative stress: current challenges. AB - Reactive oxygen and nitrogen species damage cellular macromolecules including DNA. Cells have a robust base excision repair pathway to deal with this damage in both nuclear and mitochondrial genomes. However, mitochondria lack nucleotide excision repair. Evidence suggests that chronic oxidative stress can induce protective pathways lowering genotoxicity. Understanding oxidant injury to DNA and its repair is critical for our understanding the pathophysiology of a wide range of human disorders. PMID- 29159326 TI - Overexpression of ID1 reverses the repression of human dental pulp stem cells differentiation induced by TWIST1 silencing. AB - : Multiple studies showed that the cessation of TWIST1 expression is the prerequisite for osteoblasts' maturation. However, recent reports revealed that the function of TWIST1 is different in the dental pulp stem cells (DPSCs), where a high level of TWIST1 expression promoted DPSCs' differentiation. The aim of the study was to investigate the impact of TWIST1 and ID1 on the differentiation process in the human DPSCs. METHODS: TWIST1 and ID1 expression in the DSPCs was modulated by lentivirus transduction. Genes expression was assessed with qRT-PCR. The proteins level was evaluated by Western blot. The DPSCs differentiation was assessed with the proliferation, alkaline phosphatase (ALP) activity, and calcium concentration assays. RESULTS: TWIST1 silencing suppressed the expression of ID1 and both the early and late markers of odontoblasts' differentiation detected at the transcript and protein level. The forced overexpression of ID1 increased the expression of the late markers of odontoblasts differentiation but diminished the expression of the early markers. DPCSs with the silenced TWIST1 and subsequent ID1 overexpression displayed an increase in the expression of the late markers of odontoblasts differentiation. Cells with silenced TWIST1 and overexpressing ID1 had increased activity of ALP, higher calcium concentration and decreased proliferation rate. The high level of ID1 expression might be a critical factor stimulating DPSCs differentiation and it might compensate the repressed differentiation of DPSCs caused by TWIST1 silencing. CONCLUSION: The mutual correlation between the expression level of TWIST1 and ID1 might be a critical factor driving the process of the human odontoblasts' differentiation. PMID- 29159328 TI - Efficient cross-coupling of aryl/alkenyl triflates with acyclic secondary alkylboronic acids. AB - Aryl-secondary alkyl cross-coupling with aryl sulfonate esters as coupling partners remains a significant challenge. Efficient cross-coupling between aryl/alkenyl triflates and acyclic secondary alkylboronic acids is realized for the first time to provide a series of sterically congested acyclic secondary alkyl arenes/olefins in good to excellent yields. The employment of sterically bulky P,P[double bond, length as m-dash]O ligand L1/L2 is crucial for the high yields and selectivities. The method has enabled a concise and 4-step synthesis of a key intermediate of male contraceptive agent and PAF antagonist gossypol. PMID- 29159329 TI - Self-assembly of Au@Ag core-shell nanocuboids into staircase superstructures by droplet evaporation. AB - Plasmonic nanomaterials, along with their assemblies, provide numerous applications due to their profound optical properties. In this work, we report the self-assembly of Au@Ag core-shell nanocuboids (NCs) into staircase superstructures in both vertical and horizontal orientations through two-stage droplet evaporation. Each stair is composed of a uniform well-aligned monolayer of NCs. The gap distance between NCs can be greatly shrunk to boost the corresponding surface-enhanced Raman scattering (SERS) performance using an ethanol wash method. The SERS performance of the assembled NCs is calculated by finite-difference time-domain (FDTD) simulation, and studied against the step number using 4-mercaptobenzoic acid as a Raman reporter molecule. The increasing EF with the increase of layer number proves that the plasmon mode propagates well in our uniformly aligned assemblies. PMID- 29159325 TI - Role of Aramchol in steatohepatitis and fibrosis in mice. AB - : Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) which sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits including oxidative stress, mitochondrial dysfunction, inflammation and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Aramchol (arachidyl-amido cholanoic acid) is presently in a phase IIb NASH study. The aim of this study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine- and choline-deficient (MCD) diet model of NASH. We collected liver and serum from mice fed a MCD diet containing 0.1% methionine (0.1MCD) for four weeks, which developed steatohepatitis and fibrosis, as well as mice receiving a control diet; the metabolomes and proteomes were determined. 0.1MCD fed mice were given Aramchol (5mg/kg/day for the last 2 weeks); liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD fed mice. Aramchol downregulated stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in triglyceride biosynthesis whose loss enhances fatty acid beta-oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and GSH/GSSG ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of serum metabolomic pattern between 0.1MCD fed mice and NAFLD patients showed a substantial overlap. Conclusions: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing SCD1, and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in about 50% of NAFLD patients, which supports the potential use of Aramchol in NASH treatment. PMID- 29159330 TI - Taking advantage of Co(ii) induced enhanced VCD for the fast and sensitive determination of enantiomeric excess. AB - Co(ii) induces a large VCD signal enhancement, which overcomes the low sensitivity of VCD and opens new perspectives in quantitative VCD. We used a stereodynamic system, where the analyte determines the chirality of the Co(ii) coordination sphere. The strong VCD signals stand out the baseline, which allows for their rapid and accurate quantitation. This lends itself to the first general method for the ee determination of alpha-amino acids based on vibrational circular dichroism and constitutes a model for the design of sensitive quantitative assays based on VCD. PMID- 29159331 TI - Computational insights into crystal plane dependence of thermal activity of anion (C and N)-substituted titania. AB - Geometry optimizations of anion (C and N) doped anatase TiO2 were carried out by using DFT+U calculations. Various anion vacancy sites were examined to study the synergistic effects of anion doping accompanied with anion vacancy formation on lattice oxygen activation. Two non-identical crystal planes (0 0 1) and (1 0 0) were chosen for C and N substitutions. Energetically favoured N-vacancy pairs were identified on TiO2 surfaces. Substitution of N along with anion vacancies at various sites was energetically more favoured than that of C-doping in bulk TiO2 while the energies were comparable for surface substitutions. Bond length distributions due to the formation of differential bonds were determined. Net oxygen activation and accompanying reversible oxygen exchange capacities were compared for TiO2-2xCx and TiO2-3xN2x. Substitution of C in the surface exposed (1 0 0) plane of TiO2 resulted in 47.6% and 23.8% of bond elongation and compression, respectively, resulting in 23.8% of net oxygen activation which was higher when compared to N substitution in the (1 0 0) plane of TiO2 resulting in a net oxygen activation of 17%. PMID- 29159333 TI - New phenazine based AIE probes for selective detection of aluminium(iii) ions in presence of other trivalent metal ions in living cells. AB - Phenazine fluorophore based imidazole derivatives (S1 and S2) were synthesized and sensor studies were carried out with various cations. Aggregation induced emission (AIE) was observed selectively for Al3+ among other cations under study in case of both sensors. 1H NMR titration supported the aggregation induced emission of S2 with Al3+. ESI mass spectra successfully confirmed the aggregate formation. SEM images clearly showed the aggregation of receptor induced by Al3+ in a flower-like fashion. AIE probe was successfully applied for bio-imaging of RAW264.7 cells. PMID- 29159334 TI - Low-temperature benchtop-synthesis of all-inorganic perovskite nanowires. AB - A facile, low-temperature precipitation-based method is utilized for the synthesis of ultra-thin and highly uniform cesium lead bromide perovskite nanowires (NWs). The reactions facilitate the NWs' crystalline nature over micron size lengths, while they impart tailored nanowire widths that range from the quantum confinement regime (~7 nm) down to 2.6 nm. This colloidal synthesis approach is the first of its kind that is carried out on the work-bench, without demanding chemical synthesis equipment. Importantly, the NWs' photoluminescence is shown to improve over time, with no requirement for tedious post-synthesis surface treatment. PMID- 29159332 TI - A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance. AB - Traditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform in depth, leaving a gap in understanding how extracellular signals such as stiffness, dimensionality, and cell-cell contacts act independently or are integrated within a cell to affect either drug sensitivity or resistance. This is critically important, as adaptive resistance is mediated, at least in part, by the extracellular matrix (ECM) of the tumor microenvironment. We developed an approach to screen drug responses in cells cultured on 2D and in 3D biomaterial environments to explore how key features of ECM mediate drug response. This approach uncovered that cells on 2D hydrogels and spheroids encapsulated in 3D hydrogels were less responsive to receptor tyrosine kinase (RTK)-targeting drugs sorafenib and lapatinib, but not cytotoxic drugs, compared to single cells in hydrogels and cells on plastic. We found that transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance to sorafenib. However, a systems biology analysis of phospho-kinome data uncovered that variation in MEK phosphorylation was associated with RTK-targeted drug resistance. Using sorafenib as a model drug, we found that co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone. In sum, we provide a novel strategy for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments. PMID- 29159335 TI - Protective effects of lipoic acid against acrylamide-induced neurotoxicity: involvement of mitochondrial energy metabolism and autophagy. AB - Acrylamide (ACR) is a chronic neurotoxin that is generated in high-starch foods during heat processing. Alpha-lipoic acid (LA) is an antioxidant that occurs in most plants and animals. The objective of this study was to reveal the mechanism of ACR-triggered neurotoxicity and identify the protective role of LA in SH-SY5Y cells. In this study, LA restored ACR-stimulated depletion of glutathione content and mitochondrial membrane potential, moderated the activation of inflammatory pathways, and recovered the Keap1/Nrf2 pathway. Moreover, LA upregulated the activities of oxidative phosphorylation complexes and diminished ACR-induced variation in AMPK/GSK3beta, Ca2+ disturbance, and ATP depletion. The Sirt1/PGC 1alpha pathway was inhibited by ACR. Notably, autophagy was activated in the mitochondria-mediated apoptosis induced by ACR, which was also blocked by LA. Overall, our study demonstrated the pivotal roles of the mitochondrial energy metabolism and autophagy in the protective effects of LA and cytotoxicity of ACR in SH-SY5Y cells. PMID- 29159336 TI - Retraction: The reductive phase of Rhodobacter sphaeroides cytochrome c oxidase disentangled by CO ligation. AB - Retraction of 'The reductive phase of Rhodobacter sphaeroides cytochrome c oxidase disentangled by CO ligation' by Hendrik Mohrmann et al., Phys. Chem. Chem. Phys., 2017, DOI: . PMID- 29159337 TI - Alkyl radical triggered in situ SO2-capture cascades. AB - An unprecedented in situ SO2-capture cascade triggered by alkyl radicals has been documented herein. Mechanistic investigations suggest that, triggered by alkyl radicals, SO2 was released in situ and subsequently fixed into polycyclic small molecules. A wide range of alkylsulfonyl substituted polycyclic compounds were easily prepared with high yields and good functional group tolerability. PMID- 29159339 TI - Correction: Direct N-H/alpha,alpha,beta,beta-C(sp3)-H functionalization of piperidine via an azomethine ylide route: synthesis of spirooxindoles bearing 3 substituted oxindoles. AB - Correction for 'Direct N-H/alpha,alpha,beta,beta-C(sp3)-H functionalization of piperidine via an azomethine ylide route: synthesis of spirooxindoles bearing 3 substituted oxindoles' by Yanlong Du et al., Chem. Commun., 2017, 53, 1684-1687. PMID- 29159340 TI - Bonding and optical properties of spirocyclic-phosphazene derivatives. A DFT approach. AB - The bonding properties of phosphazenes and spirocyclophosphazenes containing tris 2,2'-dioxybiphenyl groups and their derivatives were investigated by means of different computational techniques. Electronic delocalization and phosphazene ligand bonding were studied in terms of natural bond orbitals (NBOs) and energy decomposition (EDA) analysis in combination with the natural orbital for chemical valence (NOCV), which showed the dependency of the charge transfer with the electron delocalization. TD-DFT calculations were employed to study the absorption profile of the studied molecules and to contrast the redshift and change in intensities of the lambdamax. An assessment of second-order stabilization energies, DeltaE2, within the NBO analysis revealed clear differences between the cyclic-phosphazene arrays. The EDA-NOCV showed that the ligand-phosphazene charge transfer is stronger in phosphazene with amine substituents (4c), which is due to the donor character of the substituent over the phenyl ring. The NBO analysis confirmed either the inflow or outflow of charge due to the influence of the electron donor or electron withdrawing groups. PMID- 29159343 TI - An insight into intrinsic interfacial properties between Li metals and Li10GeP2S12 solid electrolytes. AB - Density functional theory simulations and experimental studies were performed to investigate the interfacial properties, including lithium ion migration kinetics, between lithium metal anode and solid electrolyte Li10GeP2S12(LGPS). The LGPS[001] plane was chosen as the studied surface because the easiest Li+ migration pathway is along this direction. The electronic structure of the surface states indicated that the electrochemical stability was reduced at both the PS4- and GeS4-teminated surfaces. For the interface cases, the equilibrium interfacial structures of lithium metal against the PS4-terminated LGPS[001] surface (Li/PS4-LGPS) and the GeS4-terminated LGPS[001] surface (Li/GeS4-LGPS) were revealed based on the structural relaxation and adhesion energy analysis. Solid electrolyte interphases were expected to be formed at both Li/PS4-LGPS and Li/GeS4-LGPS interfaces, resulting in an unstable state of interface and large interfacial resistance, which was verified by the EIS results of the Li/LGPS/Li cell. In addition, the simulations of the migration kinetics show that the energy barriers for Li+ crossing the Li/GeS4-LGPS interface were relatively low compared with the Li/PS4-LGPS interface. This may contribute to the formation of Ge-rich phases at the Li/LGPS interface, which can tune the interfacial structures to improve the ionic conductivity for future all-solid-state batteries. This work will offer a thorough understanding of the Li/LGPS interface, including local structures, electronic states and Li+ diffusion behaviors in all-solid-state batteries. PMID- 29159344 TI - Regioselective and enantiospecific synthesis of the HSP co-inducer arimoclomol from chiral glycidyl derivatives. AB - A new efficient chiral synthesis of enantiopure arimoclomol (2) is reported from (R)-(-)-glycidyl nosylate (11) with complete retention of chiral integrity. Off target pharmacology of arimoclomol (2) was evaluated against a representative set of drug targets and showed modest binding to a few kinases. Pharmacokinetic data was generated in vivo in mouse and showed a low brain : plasma ratio. These studies will be helpful towards a better understanding of the PK-PD relationship of 2 in disease models. PMID- 29159345 TI - Multiplexed electrochemical immunoassay for two immunoglobulin proteins based on Cd and Cu nanocrystals. AB - Herein, a simple and feasible electrochemical immunosensing method for simultaneous voltammetric detection of two immunoglobulin proteins, human IgG (HIgG) and rabbit IgG (RIgG), was developed using two distinguishable signal generation tags on the same electrode. The immunosensor was prepared by immobilizing two Fab antibody fragments on a gold electrode. After this, Cu and Cd nanocrystals, as nanotags, were synthesized and functionalized with identical detection antibodies. Transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR) were employed to characterize the Cu and Cd nanocrystals. The covalently modified electrode with the Fab antibody fragments through the Au-thiolate bond (to dispel the non-specific adsorption) was investigated via scanning electron microscopy (SEM). After the sandwiched immunoreaction, the antibody-modified nanocrystals were captured on the immunosensor, which could be interrogated in pH 3.5 HCl using square-wave anodic stripping voltammetry. Experimental results also indicated that the multiplexed immunoassay enabled the simultaneous detection of HIgG and RIgG in a single run with the similar linear range from 0.01 to 10 ng mL-1, and the limits of detection (LODs) towards two analytes could be as low as 3.4 pg mL-1 (at 3sigma). Acceptable assay results on precision, reproducibility, specificity, and method accuracy were also acquired. Importantly, the newly designed strategy avoided cross-talk and enzymatic introduction as compared to conventional electrochemical immunoassays, thus exhibiting a promising potential in clinical applications. PMID- 29159346 TI - Peramivir analogues bearing hydrophilic side chains exhibit higher activities against H275Y mutant than wild-type influenza virus. AB - Peramivir is an effective anti-influenza drug in the clinical treatment of influenza, but its efficacy toward the H275Y mutant is reduced. The previously reported cocrystal structures of inhibitors in the mutant neuraminidase (NA) suggest that the hydrophobic side chain should be at the origin of reduced binding affinity. In contrast, zanamivir having a hydrophilic glycerol side chain still possesses high affinity toward the H275Y NA. We thus designed five peramivir analogues (5-9) carrying hydrophilic glycol or glycerol side chains, and evaluated their roles in anti-influenza activity, especially for the H275Y mutant. The synthetic sequence involves a key step of (3 + 2) cycloaddition reactions between alkenes and nitrile oxides to construct the scaffold of peramivir carrying the desired hydrophilic side chains and other appropriate functional groups. The molecular docking experiments reveal that the hydrophilic side chain can provide extra hydrogen bonding with the translocated Glu-276 residue in the H275Y NA active site. Thus, the H275Y mutant may be even more sensitive than wild-type virus toward the peramivir analogues bearing hydrophilic side chains. Notably, the peramivir analogue bearing a glycerol side chain inhibits the H275Y mutant with an IC50 value of 35 nM, which is better than the WSN virus by 9 fold. PMID- 29159347 TI - How do the interfacial properties of zwitterionic sulfobetaine micelles differ from those of cationic alkyl quaternary ammonium micelles? An excited state proton transfer study. AB - Zwitterionic surfactants (e.g. sulfobetaine), comprising both positive and negative groups in their headgroups, are essentially electro-neutral as monomers, but their micelles preferentially uptake anions similar to cationic surfactant micelles. How do the interfacial properties (e.g. interfacial hydration or headgroup packing) of a zwitterionic micelle differ from those of a cationic micelle? For this, we investigated excited-state proton transfer (ESPT) and fluorescence anisotropy decay of an interface-localized negative fluorophore, 8 hydroxypyrene-1,3,6-trisulphonate (HPTS), and its methyl analogue, 8 methoxypyrene-1,3,6-trisulfonate (MPTS), within the micellar interfaces. Two sulfobetaine surfactants (SB-12 and SB-16) and two cationic surfactants (DTAB and CTAB) with matching alkyl tails were selected for an effective comparison. The ESPT dynamics was observed to be significantly suppressed inside the zwitterionic micelle interface compared to that of the cationic micelle. This is attributed to a less hydrated interface of the zwitterionic micelles compared to that of the cationic one. Fluorescence anisotropy decay inside the zwitterionic micellar interface was also slower compared to that of the cationic one indicating a better packing of the zwitterionic surfactants at the interface. PMID- 29159348 TI - Hydrogen evolution from water based on plasmon-induced charge separation at a TiO2/Au/NiO/Pt system. AB - Metal-semiconductor plasmonic nanostructures are capable of converting light energy through plasmon-induced charge separation (PICS), providing fruitful new strategies to utilize solar energy in various fields, including photocatalysis. Here, we enhance the PICS efficiencies for hydrogen evolution from water at a Pt cathode coupled with a TiO2/Au photoanode by coating the TiO2/Au with a p-type NiO layer on which a Pt co-catalyst is deposited. PICS occurs at the Au-TiO2 interface under visible light. The electrons injected from the Au nanoparticles into TiO2 are transported to the Pt cathode and cause hydrogen evolution from water, the action spectrum of which matches the plasmonic extinction spectrum of the Au nanoparticles. The NiO layer extracts the separated positive charges from the Au nanoparticles, accumulates the charges and drives methanol oxidation at the Pt co-catalyst on NiO with the positive charges. As a result of the introduction of the Pt-modified NiO layer, the rates of methanol oxidation and accompanying hydrogen evolution at zero bias voltage were improved by ~3.5 times. The NiO layer may also protect the Au nanoparticles from self-oxidation. PMID- 29159349 TI - Near-field chemical mapping of gold nanostructures using a functionalized scanning probe. AB - We report on photochemical and photophysical properties produced by Surface Plasmon Resonance (SPR) on metallic nanograins by means of high resolution Functionalized Tip-Enhanced Raman Spectroscopy (F-TERS). This technique relies on a sharp gold tip functionalized with Raman-active molecules to be scanned relatively to plasmonic hot-spots on a surface. We describe the local variation of plasmon-induced Raman enhancement on the surface of nanostructures that also affects the photochemistry while the quantitative interpretation of peak intensities requires the consideration of surface topography near the tip apex. Our F-TERS maps show Raman modes of hot electron reduction of 4-nitrothiophenol (4-NTP) molecules on the tip and indicate at least partial photochemical dimerization. An apparent photo-induced reversibility of this dimerization can be conservatively explained by a local topography feature that we simulate in a finite element environment. Our experimental results reveal a spatial resolution of approximately 10 nm, corresponding to a few hundred 4-NTP molecules exposed to the near-field. PMID- 29159350 TI - Mucopenetrating micelles with a PEG corona. AB - Crossing the intestinal mucus layer is a long-standing challenge for orally delivered nanoparticles carrying therapeutic cargo. We report the assembly of mucopenetrating cargo-loaded micelles using block copolymers consisting of either linear poly(ethylene glycol) (PEG) or bottle-brush poly(oligo(ethylene glycol)methacrylate) (PEGb) as the hydrophilic block and poly(caprolactone) (PCL) or poly(cholesteryl methacrylate) (PCMA) as the hydrophobic extension. The micelles were shown to preserve their stability and retain ~50% of their cargo in simulated gastric fluid. The ability of micelles to diffuse through reconstituted porcine mucus was assessed in a microfluidic set-up. Finally, the delivery of Nile Red as a hydrophobic model cargo across a mucus layer produced by epithelial cells was demonstrated. These engineered mucopenetrating micelles have potential to be developed into efficient absorption enhancers, contributing a nanotechnology solution to oral drug delivery. PMID- 29159351 TI - A quantitative analysis of the supercontraction-induced molecular disorientation of major ampullate spider silk. AB - Spider silks exhibit remarkable properties, among which the so-called supercontraction, a physical phenomenon by which fibers undergo a longitudinal shrinkage and a radial swelling when exposed to water. The process is marked by a significant decrease in chain orientation resulting from plasticisation of the amorphous phase. Despite several studies that determined the Hermans orientation function, more quantitative data are required to be able to describe theoretically the macroscopic water-induced shrinkage from molecular reorganization. Here, we have examined the supercontraction of the major ampullate silk single fibers of Nephila clavipes (Nc) and Araneus diadematus (Ad) using polarized Raman spectromicroscopy. We determined the order parameters, the orientation distribution and the secondary structure content. Our data suggest that supercontraction induces a slight increase in beta-sheet content, consistently with previous works. The beta-sheet orientation is slightly affected by supercontraction compared to that of the amorphous phase, which becomes almost isotropic with shrinkage. Despite an initially lower orientation level, the Ad fiber shows a larger orientation decrease than Nc, consistently with its higher shrinkage amplitude. Although they share similar trends, absolute values of the orientation parameters from this work differ from those found in the literature. We took advantage of having determined the distribution of orientation to estimate the amplitude of shrinkage from changes in macromolecular size resulting from molecular disorientation. Our calculations show that more realistic models are needed to correlate molecular reorientation/refolding to macroscopic shrinkage. This work also underlines that more accurate data relative to molecular orientation are necessary. PMID- 29159352 TI - Improved Li-storage performance with PEDOT-decorated MnO2 nanoboxes. AB - In this paper, MnO2 nanoboxes coated with poly(3,4-ethylenedioxythiophene) film (denoted as MnO2@PEDOT) are investigated as an anode material in lithium-ion batteries. The MnO2 nanoboxes are developed through the surface chemical oxidation decomposition of MnCO3 cubes and the subsequent removal of their remaining cores. PEDOT is coated on the surface of MnO2 nanoboxes via in situ polymerization of 3,4-ethylenedioxythiophene. The charge-discharge tests demonstrate that this special configuration endows the resulting MnO2@PEDOT with remarkable electrochemical performances, that is a reversible capacity of 628 mA h g-1 after 850 cycles at a current density of 1000 mA g-1 and a rate capacity of 367 mA h g-1 at 3000 mA g-1. The results indicate that the nanoboxes provide the paths for Li-ion diffusion, the reaction sites for Li-ion intercalation/deintercalation and the space to buffer the volume change during the charge-discharge process, while the conductive polymer ensures the structural stability and improves the electronic conductive property of MnO2. PMID- 29159353 TI - Kinetically-enhanced DNA detection via multiple-pass exonuclease III-aided target recycling. AB - One of the promising approaches to address the challenge of detecting dilute nucleic acid analytes is exonuclease III-aided target recycling. In this strategy, the target DNA self-assembles with the reactant DNA probes and displays itself as a reactant and product at the same time. This provides an autonomous mechanism to release and reuse the analyte from each round of reactions for repetitive cycles, which amplifies the signal without amplifying the analyte itself. However, for very low amounts of the analyte, it takes a considerably long time before a detectable signal is generated. Thus, in this paper, we report a kinetically-enhanced target recycling strategy by designing two more target recycling sub-reactions that are triggered by the byproducts of the first reaction involving the target analyte. In this manner, concentrations of up to 0.5 pM of target DNA can be detected in 15 minutes. PMID- 29159354 TI - Self-assembled nano-leaf/vein bionic structure of TiO2/MoS2 composites for photoelectric sensors. AB - Inspired by the leaf/vein structure of leaves which effectively supports the photosynthesis of green plants, a nano-leaf/vein bionic structure of self assembled TiO2/MoS2 composites is applied to induce the reversible photochromic reactions of methylene blue (MB) for the first time. This reversible photochromic phenomenon gives a novel performance for the TiO2/MoS2 composites and expands their applications. Similar to the case where the natural vein network in leaves ensures the efficient material transfer and energy exchange for photosynthesis, the bionic internal MoS2 vein network in the composites ensures the efficient separation and directional transfer of photo-generated carriers to restrain the photocatalytic degradation reactions and to enhance the reversible photochromic reactions. Furthermore, the photosensitive applications of the TiO2/MoS2/MB systems with such a self-assembled nano-leaf/vein bionic structure are discussed with two typical photoelectric sensory models for both controllers and detectors. PMID- 29159355 TI - Aggregation-induced visible light absorption makes reactant 1,2-diisocyanoarenes act as photosensitizers in double radical isocyanide insertions. AB - The joint computational and experimental efforts reveal that the organic molecule 1,2-diisocyano-4,5-dimethylbenzene (1) acts as both a reactant and a photosensitizer (PS) in a metal-free reaction with perfluoroalkylhalide (2) to produce 2-perfluoroalkyl quinoxalines (3) under visible light. Both the pi-pi stacking aggregation in crystals and the solvation in various solvents of PS 1 exhibited visible-light absorption at 466 nm in spite of its smaller coefficient than that of the ultraviolet-light absorption. Such an aggregation-assisted visible-light absorption phenomenon is rationalized by theoretical calculations of the condensed-phase properties with the consideration of the explicit polarization effect from the neighboring molecules. Upon irradiation with different wavelengths, the emission colors changed from navy to bright yellow. Fluorescence lifetime measurements show that the emission of 1 comes from its singlet excited state. The aggregation induced emission when excited at 420 nm has a shorter lifetime (0.45 ns) than that of the emission from isolated molecules (2.71 ns) when excited at 381 nm. It is conceived that the aggregation assisted visible light absorption properties may be general in other photo reactive molecules, such as 1,4-diisocyano-2,5-dimethylbenzene (4), 1,4 dicyanobenzene (5), and 1,4-diisocyanobenzene (6), which are widely used in many photochemical reactions in the absence of any external photosensitizer. PMID- 29159356 TI - Influence of the anatase/rutile ratio on the charge transport properties of TiO2 NTs arrays studied by dual wavelength opto-electrochemical impedance spectroscopy. AB - The modification of photo-generated charge transport properties in aligned titanium dioxide nanotubes (TiO2-NTs) regarding the anatase/rutile ratio was studied by photo-electrochemical methods. TiO2-NTs obtained by anodization were thermally treated under air flux at different temperatures to significantly modify the proportion of TiO2 anatase and rutile phases in the tubular structure. Material characterisation methods (XRD, SEM, UV-visible spectroscopy) were used to determine the characteristics of the different TiO2-NT electrodes in terms of dimensions, proportion of each phase and optical properties. The solar to chemical energy conversion efficiency of these electrodes during an oxidation process was investigated in basic aqueous solution, using methanol as a sacrificial agent, by cyclic voltametry and Incident Photon to Current conversion Efficiency (IPCE) measurements. TiO2-NTs with a high rutile content absorb photons of higher wavelengths, but despite this red shifted optical band gap, they exhibit the lowest photo-electrochemical conversion efficiency. To further investigate the transport properties in these photoelectrodes, Intensity Modulated Photocurrent Spectroscopy (IMPS) was used with two different irradiation wavelengths to determine the transport and recombination properties of anatase and rutile separately. The results obtained by this set of experiments indicate that the presence of the rutile at the bottom of the nanotubes is the major factor limiting the photo-generated electron transfer. PMID- 29159357 TI - Characterizing the interplay of Pauli repulsion, electrostatics, dispersion and charge transfer in halogen bonding with energy decomposition analysis. AB - The halogen bond is a class of non-covalent interaction that has attracted considerable attention recently. A widespread theory for describing them is the sigma-hole concept, which predicts that the strength of the interaction is proportional to the size of the sigma-hole, a region of positive electrostatic potential opposite a sigma bond. Previous work shows that in the case of CX3I, with X equal to F, Cl, Br, and I, the sigma-hole trend is exactly opposite to the trend in binding energy with common electron pair donors. Using energy decomposition analysis (EDA) applied to a potential energy scan as well as the recent adiabatic EDA technique, we show that the observed trend is a result of charge transfer. Therefore a picture of the halogen bond that excludes charge transfer cannot be complete, and permanent and induced electrostatics do not always provide the dominant stabilizing contributions to halogen bonds. Overall, three universally attractive factors, polarization, dispersion and charge transfer, together with permanent electrostatics, which is usually attractive, drive halogen bonding, against Pauli repulsion. PMID- 29159358 TI - Optical manipulation of individual strongly absorbing platinum nanoparticles. AB - Nanostructures with exceptional absorption in the near infrared (NIR) regime are receiving significant attention due to their ability to promote controlled local heating in biological material upon irradiation. Also, such nano-structures have numerous applications in nano-electronics and for bio-exploration. Therefore, significant effort is being put into controlling and understanding plasmonic nanostructures. However, essentially all focus has been on NIR resonant gold nanoparticles and remarkably little attention has been given to nanoparticles of other materials that may have superior properties. Here, we demonstrate optical control and manipulation of individual strongly absorbing platinum nanoparticles in three dimensions using a single focused continuous wave NIR laser beam. Also, we quantify how the platinum nanoparticles interact with light and compare to similarly sized absorbing gold nanoparticles, both massive gold and gold nanoshells. By finite element modeling, we find the scattering and absorption cross sections and the polarizability of all particles. The trapping experiments allow for direct measurements of the interaction between the nanoparticles and NIR light which compares well to the theoretical predictions. In the NIR, platinum nanoparticles are stronger absorbers than similarly sized massive gold nanoparticles and scatter similarly. Compared to NIR resonant gold nanoshells, platinum nanoparticles absorb less, however, they also scatter significantly less, thus leading to more stable optical trapping. These results pave the way for nano-manipulation and positioning of platinum nanoparticles and for using these for to enhance spectroscopic signals, for localized heating, and for manipulation of biological systems. PMID- 29159359 TI - Highly selective and sensitive chromogenic detection of nerve agents (sarin, tabun and VX): a multianalyte detection approach. AB - A novel strategy using ferrocenyl dye (1) was developed for highly selective chromogenic detection of all nerve agents. The protocol was first established with nerve agent mimics (DFP, DCNP, and malaoxon) and then implemented on real agents, i.e. sarin, tabun and VX. The developed chemosensor showed no interferences from the most probable interferents such as acetyl chloride, sulfur mustard, oxygen mustard and DMMP. Real-time visual detection with a lower limit of detection (below LD50) made the present protocol highly appealing and versatile. PMID- 29159360 TI - Integration of molecular machines into supramolecular materials: actuation between equilibrium polymers and crystal-like gels. AB - In this article, the dynamic structure of complex supramolecular polymers composed of bistable [c2]daisy chain rotaxanes as molecular machines that are linked by ureidopyrimidinones (Upy) as recognition moieties was studied. pH actuation of the integrated mechanically active rotaxanes controls the contraction/extension of the polymer chains as well as their physical reticulation. Small-angle neutron and X-ray scattering were used to study in depth the nanostructure of the contracted and extended polymer aggregates in toluene solution. The supramolecular polymers comprising contracted nanomachines were found to be equilibrium polymers with a mass that is concentration dependent in dilute and semidilute regimes. Surprisingly, the extended polymers form a gel network with a crystal-like internal structure that is independent of concentration and reminiscent of a pearl-necklace network. PMID- 29159361 TI - Ultraflexible and tailorable all-solid-state supercapacitors using polyacrylamide based hydrogel electrolyte with high ionic conductivity. AB - Hydrogels with high ionic conductivity consisting of a cross-linked polymer network swollen in water are very promising to be used as an electrolyte for all solid-state supercapacitors. However, there are rather few flexible supercapacitors using ionic conducting hydrogel electrolytes reported to date. In this work, highly flexible and ionic conducting polyacrylamide hydrogels were synthesized through a simple approach. On using the ionic hydrogels as the electrolyte, the resulting supercapacitors not only exhibited a high specific capacitance but also showed a long self-discharge time (over 10 hours to the half of original open-circuit voltage) and a low leakage current. These newly developed all-solid-state supercapacitors can be bent, knot, and kneaded for 5000 cycles without performance decay, suggesting excellent flexibility and mechanical stability. These all-solid-state supercapacitors can also be easily tailored into strip-like supercapacitors without a short circuit, which provides an efficient approach to fabricate wearable energy storage devices. PMID- 29159362 TI - From helix to helical pores: solid-state crystalline conversions triggered by gas solid reactions. AB - Two one-dimensional (1D) helical coordination polymers, CuBIm-Cl and CuBIm-Br (BIm = 1,2-bis((5H-imidazol-4-yl)-methylene)hydrazine), are constructed from Cu2+ ions, halides and mono-deprotonated BIm. Solid-state crystalline conversions of CuBIm-Cl and CuBIm-Br to a gyroidal metal-organic framework (MOF) STU-3 which is composed of Cu ions and Bim ligands are observed through a gas-solid reaction, where the gas is methylamine. PMID- 29159363 TI - Measuring Patient Safety in Real Time: An Essential Method for Effectively Improving the Safety of Care. PMID- 29159364 TI - Rubella Vaccine-A Tale of Appropriate Caution and Remarkable Success. PMID- 29159366 TI - Bortezomib for Neuromyelitis Optica Spectrum Disorder: A New Therapeutic Option for the More Severe Forms?-Reply. PMID- 29159365 TI - Novel Stool-Based Protein Biomarkers for Improved Colorectal Cancer Screening: A Case-Control Study. AB - Background: The fecal immunochemical test (FIT) for detecting hemoglobin is used widely for noninvasive colorectal cancer (CRC) screening, but its sensitivity leaves room for improvement. Objective: To identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRC and advanced adenomas. Design: Case-control study. Setting: Colonoscopy-controlled referral population from several centers. Participants: 315 stool samples from one series of 12 patients with CRC and 10 persons without colorectal neoplasia (control samples) and a second series of 81 patients with CRC, 40 with advanced adenomas, and 43 with nonadvanced adenomas, as well as 129 persons without colorectal neoplasia (control samples); 72 FIT samples from a third independent series of 14 patients with CRC, 16 with advanced adenomas, and 18 with nonadvanced adenomas, as well as 24 persons without colorectal neoplasia (control samples). Measurements: Stool samples were analyzed by mass spectrometry. Classification and regression tree (CART) analysis and logistic regression analyses were performed to identify protein combinations that differentiated CRC or advanced adenoma from control samples. Antibody-based assays for 4 selected proteins were done on FIT samples. Results: In total, 834 human proteins were identified, 29 of which were statistically significantly enriched in CRC versus control stool samples in both series. Combinations of 4 proteins reached sensitivities of 80% and 45% for detecting CRC and advanced adenomas, respectively, at 95% specificity, which was higher than that of hemoglobin alone (P < 0.001 and P = 0.003, respectively). Selected proteins could be measured in small sample volumes used in FIT-based screening programs and discriminated between CRC and control samples (P < 0.001). Limitation: Lack of availability of antibodies prohibited validation of the top protein combinations in FIT samples. Conclusion: Mass spectrometry of stool samples identified novel candidate protein biomarkers for CRC screening. Several protein combinations outperformed hemoglobin in discriminating CRC or advanced adenoma from control samples. Proof of concept that such proteins can be detected with antibody-based assays in small sample volumes indicates the potential of these biomarkers to be applied in population screening. Primary Funding Source: Center for Translational Molecular Medicine, International Translational Cancer Research Dream Team, Stand Up to Cancer (American Association for Cancer Research and the Dutch Cancer Society), Dutch Digestive Foundation, and VU University Medical Center. PMID- 29159367 TI - Promoting High-Value Practice by Reducing Unnecessary Transfusions With a Patient Blood Management Program. AB - Although blood transfusion is a lifesaving therapy for some patients, transfusion has been named 1 of the top 5 overused procedures in US hospitals. As unnecessary transfusions only increase risk and cost without providing benefit, improving transfusion practice is an effective way of promoting high-value care. Most high quality clinical trials supporting a restrictive transfusion strategy have been published in the past 5 to 10 years, so the value of a successful patient blood management program has only recently been recognized. We review the most recent transfusion practice guidelines and the evidence supporting these guidelines. We also discuss several medical societies' Choosing Wisely campaigns to reduce or eliminate overuse of transfusions. A blueprint is presented for developing a patient blood management program, which includes discussion of specific methods for optimizing transfusion practice. PMID- 29159368 TI - Palliative Care Eligibility, Symptom Burden, and Quality-of-Life Ratings in Nursing Home Residents. PMID- 29159369 TI - Rubella Vaccine-Reply. PMID- 29159372 TI - Bortezomib for Neuromyelitis Optica Spectrum Disorder: A New Therapeutic Option for the More Severe Forms? PMID- 29159371 TI - Care Planning for Inpatients Referred for Palliative Care Consultation. AB - Importance: Care planning is a critical function of palliative care teams, but the impact of advance care planning and goals of care discussions by palliative care teams has not been well characterized. Objective: To describe the population of patients referred to inpatient palliative care consultation teams for care planning, the needs identified by palliative care clinicians, the care planning activities that occur, and the results of these activities. Design, Setting, and Participants: This was a prospective cohort study conducted between January 1, 2013, and December 31, 2016. Seventy-eight inpatient palliative care teams from diverse US hospitals in the Palliative Care Quality Network, a national quality improvement collaborative. Standardized data were submitted for 73 145 patients. Exposures: Inpatient palliative care consultation. Results: Overall, 52 571 of 73 145 patients (71.9%) referred to inpatient palliative care were referred for care planning (range among teams, 27.5%-99.4% of patients). Patients referred for care planning were older (73.3 vs 67.9 years; F statistic, 1546.0; P < .001), less likely to have cancer (30.0% vs 41.1%; P < .001), and slightly more often had a clinical order of full code at the time of referral (54.6% vs 52.1%; P < .001). Palliative care teams identified care planning needs in 52 825 of 73 145 patients (72.2%) overall, including 42 467 of 49 713 patients (85.4%) referred for care planning and in 10 054 of 17 475 patients (57.5%) referred for other reasons. Through care planning conversations, surrogates were identified for 10 571 of 11 149 patients (94.8%) and 9026 patients (37.4%) elected to change their code status. Substantially more patients indicated that a status of do not resuscitate/do not intubate was consistent with their goals (7006 [32.1%] preconsultation to 13 773 [63.1%] postconsultation). However, an advance directive was completed for just 2160 of 67 955 patients (3.2%) and a Physicians Orders for Life-Sustaining Treatment form was completed for 8359 of 67 955 patients (12.3%) seen by palliative care teams. Conclusions and Relevance: Care planning was the most common reason for inpatient palliative care consultation, and care planning needs were often found even when the consultation was for other reasons. Surrogates were consistently identified, and patients' preferences regarding life-sustaining treatments were frequently updated. However, a minority of patients completed legal forms to document their care preferences, highlighting an area in need of improvement. PMID- 29159373 TI - Bortezomib for Neuromyelitis Optica Spectrum Disorder: A New Therapeutic Option for the More Severe Forms? PMID- 29159374 TI - Characteristics of U.S. Physician Marriages, 2000-2015: An Analysis of Data From a U.S. Census Survey. PMID- 29159375 TI - The 2017 Clinical Practice Guideline for High Blood Pressure. PMID- 29159376 TI - Guideline: Recommendations for THA or TKA perioperative antirheumatic drugs in patients with rheumatic diseases. PMID- 29159377 TI - Review: Continuous compression and 30:2 compression-to-ventilation CPR ratio do not differ for survival. PMID- 29159379 TI - In localized prostate cancer, radical prostatectomy and observation did not differ for mortality at 13 years. PMID- 29159378 TI - In stable CVD, rivaroxaban plus aspirin reduced CV events and increased bleeding compared with aspirin alone. PMID- 29159380 TI - Review: In adults with sleep apnea, positive airway pressure does not reduce cardiovascular events or death. PMID- 29159381 TI - Review: In obstructive sleep apnea, continuous positive airway pressure does not reduce cardiovascular outcomes. PMID- 29159382 TI - Review: Antioxidant vitamin or mineral supplements do not prevent age-related macular degeneration. PMID- 29159383 TI - Review: In age-related macular degeneration, antioxidant multivitamins and zinc supplements each decrease progression. PMID- 29159384 TI - In patients with proteinuric IgA nephropathy, benefits of methylprednisolone were offset by harms. PMID- 29159385 TI - In suspected PE, 2% of patients with a Wells score > 4 and negative CT pulmonary angiography had VTE at 3 months. PMID- 29159386 TI - Antibiotic Prescribing for Nonbacterial Acute Upper Respiratory Infections in Elderly Persons. PMID- 29159387 TI - Antibiotic Prescribing for Nonbacterial Acute Upper Respiratory Infections in Elderly Persons. PMID- 29159388 TI - Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus. PMID- 29159389 TI - Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus. PMID- 29159390 TI - 2:32 a.m. PMID- 29159391 TI - Web Exclusives. Annals for Hospitalists Inpatient Notes - The Other Catheter-the Mighty Peripheral IV. PMID- 29159392 TI - Web Exclusives. Annals Consult Guys - Fasting Before Anesthesia: A Cappucino On Call? PMID- 29159395 TI - Error in Author Name. PMID- 29159397 TI - Extracellular Mitochondria for Therapy and Diagnosis in Acute Central Nervous System Injury. AB - Objective: Acute central nervous system (CNS) injury after stroke and trauma remains a clinical challenge with limited diagnostic and therapeutic approaches. In this article, we review studies suggesting that after CNS injury, mitochondria can be released into extracellular space as a "help-me" signal to augment recovery. Results are taken from experimental studies in cell and animal models and an initial proof-of-concept analysis in humans suggesting the functional relevance of extracellular mitochondria after acute CNS injury. Observations: After acute CNS injury, (1) mitochondria may be released into extracellular space, (2) mitochondria may be transferred between cells, and (3) levels of extracellular mitochondria may serve as potential biomarkers for recovery. Conclusions and Relevance: Further translational and clinical studies are warranted to assess the overall hypothesis of using extracellular mitochondria as a therapy and biomarker in the CNS after stroke and trauma. PMID- 29159396 TI - Association of Nonalcoholic Fatty Liver Disease With Lower Brain Volume in Healthy Middle-aged Adults in the Framingham Study. AB - Importance: Nonalcoholic fatty liver disease (NAFLD) is a common condition that is most often asymptomatic. It is associated with metabolic syndrome, incident diabetes, carotid atherosclerosis, and endothelial dysfunction, conditions that in turn are strongly linked with brain damage and cognitive impairment. However, it is not known whether NAFLD is associated with structural brain measures in humans. Objective: To assess the association between prevalent NAFLD and brain magnetic resonance imaging (MRI) measures. Design, Setting, and Participants: The cross-sectional association between NAFLD and brain MRI measures was assessed from November 6, 2002, to March 16, 2011, in 766 individuals from the Offspring cohort of the Framingham Study. Participants were included if they did not have excessive alcohol intake and were free of stroke and dementia. Data analysis was conducted from December 30, 2015, to June 15, 2016. Exposures: Nonalcoholic fatty liver disease was assessed by multidetector computed tomographic scans of the abdomen. Main Outcomes and Measures: Linear or logistic regression models were used to evaluate the cross-sectional association between NAFLD and brain MRI measures, adjusting for age, sex, alcohol consumption, visceral adipose tissue, body mass index, menopausal status, systolic blood pressure, hypertension, current smoking, high-density lipoprotein and low-density lipoprotein cholesterol levels, lipid treatment, type 2 diabetes, cardiovascular disease, physical activity, insulin resistance, C-reactive protein levels, and plasma homocysteine values. Brain MRI measures included total cerebral brain volume, hippocampal and white matter hyperintensity volumes, and presence or absence of covert brain infarcts. Results: Of the 766 individuals in the study sample (410 women and 356 men; mean [SD] age at the time of brain MRI, 67 [9] years), 137 (17.9%) had NAFLD. Nonalcoholic fatty liver disease was significantly associated with smaller total cerebral brain volume even after adjustment for all the covariates included in the study (beta [SE], -0.26 [0.11]; P = .02). Differences in total cerebral brain volume between those with and without NAFLD corresponded to 4.2 years of brain aging in the general sample and to 7.3 years in individuals younger than 60 years of age. No statistically significant associations were observed between NAFLD and hippocampal or white matter hyperintensity volumes or covert brain infarcts. Conclusions and Relevance: Nonalcoholic fatty liver disease is associated with a smaller total cerebral brain volume, independent of visceral adipose tissue and cardiometabolic risk factors, pointing to a possible link between hepatic steatosis and brain aging. PMID- 29159398 TI - Cost-Effectiveness of Publicly Funded Treatment of Opioid Use Disorder in California. AB - Background: Only 1 in 5 of the nearly 2.4 million Americans with an opioid use disorder received treatment in 2015. Fewer than half of Californians who received treatment in 2014 received opioid agonist treatment (OAT), and regulations for admission to OAT in California are more stringent than federal regulations. Objective: To determine the cost-effectiveness of OAT for all treatment recipients compared with the observed standard of care for patients presenting with opioid use disorder to California's publicly funded treatment facilities. Design: Model-based cost-effectiveness analysis. Data Sources: Linked population level administrative databases capturing treatment and criminal justice records for California (2006 to 2010); published literature. Target Population: Persons initially presenting for publicly funded treatment of opioid use disorder. Time Horizon: Lifetime. Perspective: Societal. Intervention: Immediate access to OAT with methadone for all treatment recipients compared with the observed standard of care (54.3% initiate opioid use disorder treatment with medically managed withdrawal). Outcome Measures: Discounted quality-adjusted life-years (QALYs) and discounted costs. Results of Base-Case Analysis: Immediate access to OAT for all treatment recipients costs less (by $78 257), with patients accumulating more QALYs (by 0.42) than with the observed standard of care. In a hypothetical scenario where all Californians starting treatment of opioid use disorder in 2014 had immediate access to OAT, total lifetime savings for this cohort could be as high as $3.8 billion. Results of Sensitivity Analysis: 99.6% of the 2000 simulations resulted in lower costs and more QALYs. Limitation: Nonrandomized delivery of OAT or medically managed withdrawal. Conclusion: The value of publicly funded treatment of opioid use disorder in California is maximized when OAT is delivered to all patients presenting for treatment, providing greater health benefits and cost savings than the observed standard of care. Primary Funding Source: National Institute on Drug Abuse. PMID- 29159399 TI - More Beds or More Chairs? Using a Science-Based Approach to Address the Opioid Epidemic. PMID- 29159400 TI - Hepatitis B Vaccination, Screening, and Linkage to Care. PMID- 29159401 TI - Comparison of Observational Data and the ONTARGET Results for Telmisartan Treatment of Hypertension: Bull's-eye or Painting the Target Around the Arrow? PMID- 29159402 TI - Communicating Through a Patient Portal to Engage Family Care Partners. PMID- 29159403 TI - Not Your Typical ST-Elevation Myocardial Infarction. PMID- 29159404 TI - Variation in the 12-Month Treatment Trajectories of Children and Adolescents After a Diagnosis of Depression. AB - Importance: Depression during childhood and adolescence is heterogeneous. Treatment patterns are often examined in aggregate, yet there is substantial variability across individual treatment trajectories. Understanding this variability can help identify treatment gaps among youths with depression. Objective: To characterize heterogeneity in 12-month trajectories of psychotherapy and antidepressant treatment in youths with depression. Design, Setting, and Participants: This is a longitudinal-cohort study of youths 18 years or younger with a new diagnosis of depression and at least 12 months of follow-up following diagnosis, as determined from commercial insurance claims filed from 2007 to 2014. Latent class models were fit to summary measures of psychotherapy and antidepressant use in the 12 months following the index diagnosis. We examined variation in baseline health, health care utilization, and health outcomes across classes with similar patterns of psychotherapy and antidepressant use. Data analysis took place between June 2016 and March 2017. Main Outcomes and Measures: Psychotherapy and antidepressant use. Results: The cohort included 84 909 individuals with a mean (SD) age at index diagnosis of 15.0 (2.6) years, of whom 49 995 (59%) were female. Attention-deficit/hyperactivity disorder (n = 14 625; 17%) and anxiety (n = 12 358; 15%) were the most common comorbid diagnoses. During the assessment period, 59 023 individuals (70%) received psychotherapy at any point, and 33 997 individuals (40%) were dispensed antidepressants at any point. Eight classes with distinct treatment trajectories were identified, which we classified into 4 broad groups: 3 classes that received dual therapy (n = 18 710; 22%), 2 classes that received antidepressant monotherapy (n = 15 287; 18%), 2 classes that received psychotherapy monotherapy (n = 40 313; 48%) and 1 class that received no treatment (n = 10 599; 13%). The most common class received psychotherapy monotherapy (n = 35 243; 42%) and had the lowest incidence of attempted suicide (0.8 per 100 person-years [PY]) and inpatient hospitalization (3.5 per 100 PY) during the assessment period and postassessment period (0.5 per 100 PY and 1.3 per 100 PY, respectively). The group receiving dual therapy had the highest incidence of attempted suicide during the assessment period (4.7-7.1 per 100 PY, depending on the class) and postassessment period (1.5-1.7 per 100 PY). Conclusions and Relevance: In our sample, 13% of youths received no treatment, and 18% received antidepressants without concomitant psychotherapy. Summary measures of treatment can mask informative patterns of psychotherapy and antidepressant use. Latent class analysis can be used to identify subgroups of individuals with similar treatment trajectories and help identify treatment gaps under current practice patterns. PMID- 29159406 TI - Promise of Salivary MicroRNA for Assessing Concussion. PMID- 29159408 TI - Public Health Interventions for Decreasing Dementia Risk. PMID- 29159405 TI - Management of Tiny Unruptured Intracranial Aneurysms: A Comparative Effectiveness Analysis. AB - Importance: Unruptured intracranial aneurysms (UIAs) are relatively common in the general population and are being increasingly diagnosed; a significant proportion are tiny (<=3 mm) aneurysms. There is significant heterogeneity in practice and lack of clear guidelines on the management of incidental, tiny UIAs. It is important to quantify the implications of different management strategies in terms of health benefits to patients. Objective: To evaluate the effectiveness of routine treatment (aneurysm coiling) vs 3 strategies for imaging surveillance compared with no preventive treatment or routine follow-up of tiny UIAs. Design, Setting, and Participants: A decision-analytic model-based comparative effectiveness analysis was conducted from May 1 to June 30, 2017, using inputs from the medical literature. PubMed searches were performed to identify relevant literature for all key model inputs, each of which was derived from the clinical study with the most robust data and greatest applicability. Analysis included 10 000 iterations simulating adult patients with incidental detections of UIAs 3 mm or smaller and no history of subarachnoid hemorrhage. Interventions: The following 5 management strategies for tiny UIAs were evaluated: annual magnetic resonance angiography (MRA) screening, biennial MRA screening, MRA screening every 5 years, aneurysm coiling and follow-up, and no treatment or preventive follow-up. Main Outcomes and Measures: A Markov decision model for lifetime rupture was constructed from a societal perspective per 10 000 patients with incidental, tiny UIAs. Outcomes were assessed in terms of quality-adjusted life years. Probabilistic, 1-way, and 2-way sensitivity analyses were performed. Results: In this analysis of 10 000 iterations simulating adult patients with a mean age of 50 years, the base-case calculation shows that the management strategy of no treatment or preventive follow-up has the highest health benefit (mean [SD] quality-adjusted life-years, 19.40 [0.31]). Among the management strategies that incorporate follow-up imaging, MRA every 5 years is the best strategy with the next highest effectiveness (mean [SD] quality-adjusted life years, 18.05 [0.62]). The conclusion remains robust in probabilistic and 1-way sensitivity analyses. No routine follow-up remains the optimal strategy when the annual growth rate and risk of rupture of growing aneurysms are varied. When the annual risk of rupture of nongrowing UIAs is less than 1.7% (0.23% in base case scenario), no follow-up is the optimal strategy. If annual risk of rupture is more than 1.7%, coiling should be performed directly. Conclusions and Relevance: Given the current literature, no preventive treatment or imaging follow-up is the most effective strategy in patients with aneurysms that are 3 mm or smaller, resulting in better health outcomes. More aggressive imaging surveillance for aneurysm growth or preventive treatment should be reserved for patients with a high risk of rupture. Given these findings, it is important to critically evaluate the appropriateness of current clinical practices, and potentially determine specific guidelines to reflect the most effective management strategy for patients with incidental, tiny UIAs. PMID- 29159407 TI - Association of Salivary MicroRNA Changes With Prolonged Concussion Symptoms. AB - Importance: Approximately one-third of children who experience a concussion develop prolonged concussion symptoms. To our knowledge, there are currently no objective or easily administered tests for predicting prolonged concussion symptoms. Several studies have identified alterations in epigenetic molecules known as microRNAs (miRNAs) following traumatic brain injury. No studies have examined whether miRNA expression can detect prolonged concussion symptoms. Objective: To evaluate the efficacy of salivary miRNAs for identifying children with concussion who are at risk for prolonged symptoms. Design, Setting, and Participants: This prospective cohort study at the Penn State Medical Center observed 52 patients aged 7 to 21 years presenting for evaluation of concussion within 14 days of initial head injury, with follow-up at 4 and 8 weeks. Exposures: All patients had a clinical diagnosis of concussion. Main Outcomes and Measures: Salivary miRNA expression was measured at the time of initial clinical presentation in all patients. Patients with a Sport Concussion Assessment Tool (SCAT3) symptom score of 5 or greater on self-report or parent report 4 weeks after injury were designated as having prolonged symptoms. Results: Of the 52 included participants, 22 (42%) were female, and the mean (SD) age was 14 (3) years. Participants were split into the prolonged symptom group (n = 30) and acute symptom group (n = 22). Concentrations of 15 salivary miRNAs spatially differentiated prolonged and acute symptom groups on partial least squares discriminant analysis and demonstrated functional relationships with neuronal regulatory pathways. Levels of 5 miRNAs (miR-320c-1, miR-133a-5p, miR-769-5p, let 7a-3p, and miR-1307-3p) accurately identified patients with prolonged symptoms on logistic regression (area under the curve, 0.856; 95% CI, 0.822-0.890). This accuracy exceeded accuracy of symptom burden on child (area under the curve, 0.649; 95% CI, 0.388-0.887) or parent (area under the curve, 0.562; 95% CI, 0.219 0.734) SCAT3 score. Levels of 3 miRNAs were associated with specific symptoms 4 weeks after injury; miR-320c-1 was associated with memory difficulty (R, 0.55; false detection rate, 0.02), miR-629 was associated with headaches (R, 0.47; false detection rate, 0.04), and let-7b-5p was associated with fatigue (R, 0.45; false detection rate, 0.04). Conclusions and Relevance: Salivary miRNA levels may identify the duration and character of concussion symptoms. This could reduce parental anxiety and improve care by providing a tool for concussion management. Further validation of this approach is needed. PMID- 29159409 TI - Marijuana, Secondhand Smoke, and Social Acceptability. PMID- 29159411 TI - Long-Acting Reversible Contraceptives for Adolescents: More Complex Than "First Line". PMID- 29159410 TI - Use of Health Care Databases to Support Supplemental Indications of Approved Medications. AB - Importance: Manufacturers of US Food and Drug Administration-approved prescription drugs often apply for additional indications based on randomized clinical trials. Real-world database analyses on a medication's use and outcomes in routine settings of care might help to inform decision making regarding such supplemental indications. Objective: To examine whether longitudinal data from a health care database can support the results of a randomized clinical trial that led to a supplemental indication for telmisartan. Design, Setting, and Participants: This cohort study of patients newly prescribed telmisartan or ramipril used insurance claims data from a nationwide health care database from January 1, 2003, through September 30, 2009, to compare patient outcomes. This study replicated the inclusion and exclusion criteria used in the Ongoing Telmisartan Alone and in Combination with Ramipril Global End-point Trial (ONTARGET) and used propensity score matching to balance 74 patient characteristics. Data analysis was performed from February 15, 2017, to May 24, 2017. Exposures: Telmisartan use vs ramipril use. Main Outcomes and Measures: The primary outcome was a composite of myocardial infarction, stroke, or hospitalization for congestive heart failure. Results: Of the 640 951 patients included in the study, 48 053 were newly prescribed ramipril (mean [SD] age, 68.29 [9.52] years; 31 940 male [66.5%]) and 4665 were newly prescribed telmisartan (mean [SD] age, 69.43 [9.60] years; 2413 male [51.7%]). After propensity score matching, a total of 4665 patients were newly prescribed telmisartan (mean [SD] age, 69.43 [9.60] years; 2413 [51.7%]), and 4665 patients were newly prescribed ramipril (mean [SD] age, 69.36 [9.67] years; 2343 male [50.2%]). As seen in ONTARGET, the composite risk of stroke, myocardial infarction, and hospitalization for congestive heart failure was similar for the 2 medications (hazard ratio, 1.0; 95% CI, 0.9-1.1). In addition, the study found that telmisartan was associated with a substantially decreased risk of angioedema (hazard ratio, 0.1; 95% CI, 0.03-0.56) compared with ramipril. Conclusions and Relevance: Real-world data analyses of patients receiving routine care provided findings similar to those found in the randomized clinical trial that established telmisartan's supplemental indication. In certain situations, database studies may support supplemental applications for effectiveness for already approved medications. PMID- 29159412 TI - Leaving Tiny, Unruptured Intracranial Aneurysms Untreated: Why Is It So Hard? PMID- 29159413 TI - The Achilles Heel of Medical Cannabis Research-Inadequate Blinding of Placebo Controlled Trials. PMID- 29159415 TI - Omitted Funding Information. PMID- 29159414 TI - Hepatitis B Vaccination, Screening, and Linkage to Care: Best Practice Advice From the American College of Physicians and the Centers for Disease Control and Prevention. AB - Background: Vaccination, screening, and linkage to care can reduce the burden of chronic hepatitis B virus (HBV) infection. However, recommendations vary among organizations, and their implementation has been suboptimal. The American College of Physicians' High Value Care Task Force and the Centers for Disease Control and Prevention developed this article to present best practice statements for hepatitis B vaccination, screening, and linkage to care. Methods: A narrative literature review of clinical guidelines, systematic reviews, randomized trials, and intervention studies on hepatitis B vaccination, screening, and linkage to care published between January 2005 and June 2017 was conducted. Best Practice Advice 1: Clinicians should vaccinate against hepatitis B virus (HBV) in all unvaccinated adults (including pregnant women) at risk for infection due to sexual, percutaneous, or mucosal exposure; health care and public safety workers at risk for blood exposure; adults with chronic liver disease, end-stage renal disease (including hemodialysis patients), or HIV infection; travelers to HBV endemic regions; and adults seeking protection from HBV infection. Best Practice Advice 2: Clinicians should screen (hepatitis B surface antigen, antibody to hepatitis B core antigen, and antibody to hepatitis B surface antigen) for HBV in high-risk persons, including persons born in countries with 2% or higher HBV prevalence, men who have sex with men, persons who inject drugs, HIV-positive persons, household and sexual contacts of HBV-infected persons, persons requiring immunosuppressive therapy, persons with end-stage renal disease (including hemodialysis patients), blood and tissue donors, persons infected with hepatitis C virus, persons with elevated alanine aminotransferase levels (>=19 IU/L for women and >=30 IU/L for men), incarcerated persons, pregnant women, and infants born to HBV-infected mothers. Best Practice Advice 3: Clinicians should provide or refer all patients identified with HBV (HBsAg-positive) for posttest counseling and hepatitis B-directed care. PMID- 29159416 TI - Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. PMID- 29159417 TI - The New 2017 ACC/AHA Guidelines "Up the Pressure" on Diagnosis and Treatment of Hypertension. PMID- 29159418 TI - Reliability and convergent validity of the five-step test in people with chronic stroke. AB - OBJECTIVES: (i) To estimate the intra-rater, inter-rater and test-retest reliabilities of the Five-Step Test (FST), as well as the minimum detectable change in FST completion times in people with stroke. (ii) To estimate the convergent validity of the FST with other measures of stroke-specific impairments. (iii) To identify the best cut-off times for distinguishing FST performance in people with stroke from that of healthy older adults. DESIGN: A cross-sectional study. SETTING: University-based rehabilitation centre. PARTICIPANTS: Forty-eight people with stroke and 39 healthy controls. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The FST, along with (for the stroke survivors only) scores on the Fugl-Meyer Lower Extremity Assessment (FMA-LE), the Berg Balance Scale (BBS), Limits of Stability (LOS) tests, and Activities specific Balance Confidence (ABC) scale were tested. RESULTS: The FST showed excellent intra-rater (intra-class correlation coefficient; ICC = 0.866-0.905), inter-rater (ICC = 0.998), and test-retest (ICC = 0.838-0.842) reliabilities. A minimum detectable change of 9.16 s was found for the FST in people with stroke. The FST correlated significantly with the FMA-LE, BBS, and LOS results in the forward and sideways directions (r = -0.411 to -0.716, p < 0.004). The FST completion time of 13.35 s was shown to discriminate reliably between people with stroke and healthy older adults. CONCLUSION: The FST is a reliable, easy-to administer clinical test for assessing stroke survivors' ability to negotiate steps and stairs. PMID- 29159419 TI - Implementation of Clinical Quality Management for Rehabilitation in Malaysia. AB - In February 2017, the World Health Organization (WHO) launched its historic "Rehabilitation 2030: A Call for Action". Scaling up rehabilitation in health systems requires concerted action across all 6 components of WHO's Health Systems Framework. For rehabilitation, information about functioning is essential, as it is required for effective rehabilitation at all levels of the health system. What is missing is a countrywide demonstration project involving the implementation of a clinical quality management system for the continuous improvement of rehabilitation, both at the level of clinical care for individual patients and at the level of rehabilitation service provision. Consequently, the Department of Rehabilitation Medicine at the University of Malaya and University Malaya Medical Centre, together with the Cheras Rehabilitation Hospital of the Ministry of Health, and the Social Security Organisation (SOCSO) Rehabilitation Centre in Malacca, Malaysia, initiated a project to develop a Malaysian-wide clinical quality management system for rehabilitation (CQM-R Malaysia). The objective of this paper is to describe CQM-R Malaysia. First, a conceptual description of a CQM-R based on the International Classification of Functioning, Disability and Health (ICF) is set out. The methods, results and conclusions of a situation analysis conducted in January 2017 are then reported. Finally, the building blocks and implementation action plan developed for CQM-R Malaysia are presented. PMID- 29159420 TI - Smoothness of stimulus motion can affect vection strength. AB - We examined the effect of the smoothness of motion on vection strength. The smoothness of stimulus motion was modulated by varying the number of frames comprising the movement. In this study, a horizontal grating translated through 360 degrees of phase in 1 s divided into steps of 3, 4, 6, 12, 20, 30, or 60 frames. We hypothesized that smoother motion should induce stronger vection because the smoother stimulus is more natural and contains more motion energy. We examined this effect of frame number on vection for both downward (Experiment 1) and expanding (Experiment 2) optical flow. The results clearly showed that vection strength increased with increasing frame rate, however, the rates of increase in the vection strength with frame rate are not constant, but rapidly increase in the low frame-rate range and appear to asymptote in the high range. The strength estimates saturated at lower frame rates for expanding flow than for downward flow. This might be related to the fact that to process expanding flow it is necessary to integrate motion signals across the visual field. We conclude that the smoothness of the motion stimulus highly affects vection induction. PMID- 29159421 TI - QTL mapping of downy and powdery mildew resistances in PI 197088 cucumber with genotyping-by-sequencing in RIL population. AB - KEY MESSAGE: Host resistances in PI 197088 cucumber to downy and powdery mildew pathogens are conferred by 11 (3 with major effect) and 4 (1 major effect) QTL, respectively, and three of which are co-localized. The downy mildew (DM) and powdery mildew (PM) are the two most important foliar diseases of cucurbit crops worldwide. The cucumber accession PI 197088 exhibits high-level resistances to both pathogens. Here, we reported QTL mapping results for DM and PM resistances with 148 recombinant inbred lines from a cross between PI 197088 and the susceptible line 'Coolgreen'. Phenotypic data on responses to natural DM and PM infection were collected in multi-year and multi-location replicated field trials. A high-density genetic map with 2780 single nucleotide polymorphisms (SNPs) from genotyping-by-sequencing and 55 microsatellite markers was developed, which revealed genomic regions with segregation distortion and mis-assemblies in the '9930' cucumber draft genome. QTL analysis identified 11 and 4 QTL for DM and PM resistances accounting for more than 73.5 and 63.0% total phenotypic variance, respectively. Among the 11 DM resistance QTL, dm5.1, dm5.2, and dm5.3 were major effect contributing QTL, whereas dm1.1, dm2.1, and dm6.2 conferred susceptibility. Of the 4 QTL for PM resistance, pm5.1 was the major-effect QTL explaining 32.4% phenotypic variance and the minor-effect QTL pm6.1 contributed to disease susceptibility. Three PM QTL, pm2.1, pm5.1, and pm6.1, were co localized with DM QTL dm2.1, dm5.2, and dm6.1, respectively, which was consistent with the observed linkage of PM and DM resistances in PI 197088. The genetic architecture of DM resistance in PI 197088 and another resistant line WI7120 (PI 330628) was compared, and the potential of using PI 197088 in cucumber breeding for downy and powdery mildew resistances is discussed. PMID- 29159422 TI - Fine-mapping of QTLs for individual and total isoflavone content in soybean (Glycine max L.) using a high-density genetic map. AB - KEY MESSAGE: Fifteen stable QTLs were identified using a high-density soybean genetic map across multiple environments. One major QTL, qIF5-1, contributing to total isoflavone content explained phenotypic variance 49.38, 43.27, 46.59, 45.15 and 52.50%, respectively. Soybeans (Glycine max L.) are a major source of dietary isoflavones. To identify novel quantitative trait loci (QTL) underlying isoflavone content, and to improve the accuracy of marker-assisted breeding in soybean, a valuable mapping population comprised of 196 F7:8-10 recombinant inbred lines (RILs, Huachun 2 * Wayao) was utilized to evaluate individual and total isoflavone content in plants grown in four different environments in Guangdong. A high-density genetic linkage map containing 3469 recombination bin markers based on 0.2 * restriction site-associated DNA tag sequencing (RAD-seq) technology was used to finely map QTLs for both individual and total isoflavone contents. Correlation analyses showed that total isoflavone content, and that of five individual isoflavone, was significantly correlated across the four environments. Based on the high-density genetic linkage map, a total of 15 stable quantitative trait loci (QTLs) associated with isoflavone content across multiple environments were mapped onto chromosomes 02, 05, 07, 09, 10, 11, 13, 16, 17, and 19. Further, one of them, qIF5-1, localized to chromosomes 05 (38,434,171 39,045,620 bp) contributed to almost all isoflavone components across all environments, and explained 6.37-59.95% of the phenotypic variance, especially explained 49.38, 43.27, 46.59, 45.15 and 52.50% for total isoflavone. The results obtained in the present study will pave the way for a better understanding of the genetics of isoflavone accumulation and reveals the scope available for improvement of isoflavone content through marker-assisted selection. PMID- 29159423 TI - Characterizing pediatric surgical capacity in the Eastern Democratic Republic of Congo: results of a pilot study. AB - PURPOSE: Characterize pediatric surgical capacity in the eastern Democratic Republic of Congo (DRC) to identify areas of potential improvement. METHODS: The Pediatric Personnel, Infrastructure, Procedures, Equipment, and Supplies (PediPIPES) survey was used in two representative eastern DRC provinces to assess existing surgical infrastructure and capacity. We compared our results to previously published reports from other sub-Saharan African countries. RESULTS: Fourteen hospitals in the eastern DRC and 37 in 19 sub-Saharan African (SSA) countries were compared. The average PediPIPES index for the DRC was 7.7 compared to 13.5 for SSAs. The greatest disparities existed in the areas of personnel and infrastructure. Running water was reportedly available to 57.1% of the hospitals in the DRC, and the majority of hospitals (78.6%) were dependent on generators and solar panels for electricity. Only two hospitals in the DRC (14.3%) reported a pediatric surgeon equivalent on staff, compared to 86.5% of facilities sampled in SSA reporting >= 1 pediatric surgeon. CONCLUSIONS: Significant barriers in personnel, infrastructure, procedures, equipment, and supplies impede the provision of adequate surgical care to children. Further work is needed to assess allocation and utilization of existing resources, and to enhance training of personnel with specific attention to pediatric surgery. PMID- 29159424 TI - Visualizing translational errors: one cell at a time. AB - Physiological heterogeneity among single cells with identical genetic information has been observed in a large number of bacterial phenotypes, including growth, stress responses, cell size, and antibiotic tolerance. Despite the widespread observation of this phenomenon in bacterial populations, not much is known about the molecular mechanisms behind phenotypic heterogeneity. Currently, our understanding is primarily limited to transcriptional profile of single cells using fluorescence reporters. Although the development of these tools has been extremely informative, it cannot fully explain the heterogeneity seen in populations. In a recent publication, Fan et al. have developed a dual fluorescent reporter system that is capable of quantitatively measuring translational fidelity in single cells. It is shown that translational fidelity is heterogeneous and affects the growth characteristics of single cells. The development of tools for analysis of molecular heterogeneity downstream of transcription may play an important role in advancing our understanding of the physiology of bacterial populations. PMID- 29159425 TI - Novel biosynthetic pathway for sulfur amino acids in Cryptococcus neoformans. AB - We elucidated a unique feature of sulfur metabolism in Cryptococcus neoformans. C. neoformans produces cysteine solely by the O-acetylserine pathway that consists of serine-O-acetyl transferase and cysteine synthase. We designated the gene encoding the former enzyme CYS2 (locus tag CNE02740) and the latter enzyme CYS1 (locus tag CNL05880). The cys1Deltamutant strain was found to be avirulent in a murine infection model. Methionine practically does not support growth of the cys1Delta strain, and cysteine does not serve as a methionine source, indicating that the transsulfuration pathway does not contribute to sulfur amino acid synthesis in C. neoformans. Among the genes encoding enzymes catalyzing the reactions from homoserine to methionine, the gene corresponding to the Saccharomyces cerevisiae MET17 encoding O-acetylhomoserine sulfhydrylase (Met17p) had remained to be identified in C. neoformans. By genetic analysis of Met- mutants obtained by Agrobacterium tumefaciens-mediated mutagenesis, we concluded that Cnc01220, most similar to Str2p (36% identity), cystathionine-gamma synthase, in the Saccharomyces genome, is the C. neoformans version of O acetylhomoserine sulfhydrylase. We designated CNC01220 as MET17. The C. neoformans met3Delta mutant defective in the first step of the sulfate assimilation pathway, sulfate adenylyltransferase, barely uses methionine as a sulfur source, whereas it uses cysteine efficiently. The poor utilization of methionine by the met3Delta mutant is most probably due to the absence of the transsulfuration pathway, causing an incapability of C. neoformans to produce cysteine and hydrogen sulfide from methionine. When cysteine is used as a sulfur source, methionine is likely produced de novo by using hydrogen sulfide derived from cysteine via an unidentified pathway. Altogether, the unique features of sulfur amino acid metabolism in C. neoformans will make this fungus a valuable experimental system to develop anti-fungal agents and to investigate physiology of hydrogen sulfide. PMID- 29159426 TI - An initial cost-effectiveness analysis of intraoperative magnetic resonance imaging (iMRI) in pediatric epilepsy surgery. AB - PURPOSE: Previous studies have illustrated the clinical utility of the addition of intraoperative magnetic resonance imaging (iMRI) to conventional microsurgical resection. While iMRI requires initial capital cost investment, long-term reduction in costly follow-up management and reoperation costs may prove economically efficacious. The objective of this study is to investigate the cost effectiveness of the addition of iMRI utilization versus conventional microsurgical techniques in focal cortical dysplasia (FCD) resection in pediatric patients with medically refractory epilepsy. METHODS: We retrospectively reviewed the medical records of pediatric subjects who underwent surgical resection of FCD at the Children's National Health System between March 2005 and April 2015. Patients were assigned to one of three cohorts: iMRI-assisted resection, conventional resection with iMRI-assisted reoperation, or conventional resection. Direct costs included preoperative, operative, postoperative, long-term follow up, and antiepileptic drug (AED) costs. The cost-effectiveness was calculated as the sum total of all direct medical costs over the quality-adjusted life years (QALYs). We also performed sensitivity analysis on numerous variables to assess the validity of our results. RESULTS: Fifty-six consecutive pediatric patients underwent resective surgery for medically intractable FCD. Ten patients underwent iMRI-assisted resection; 7 underwent conventional resection followed by iMRI assisted reoperation; 39 patients underwent conventional microsurgical resection. Taken over the lifetime of the patient, the cumulative discounted QALY of patients in the iMRI-assisted resection cohort was about 2.91 years, versus 2.61 years in the conventional resection with iMRI-assisted reoperation cohort, and 1.76 years for the conventional resection cohort. Adjusting for inflation, iMRI assisted surgeries have a cost-effectiveness ratio of $16,179 per QALY, versus $28,514 per QALY for the conventional resection with iMRI-assisted reoperation cohort, and $49,960 per QALY for the conventional resection cohort. Sensitivity analysis demonstrated that no one single variable significantly altered cost effectiveness across all three cohorts compared to the baseline results. CONCLUSION: The addition of iMRI to conventional microsurgical techniques for resection of FCD in pediatric patients with intractable epilepsy resulted in increased seizure freedom and reduction in long-term direct medical costs compared to conventional surgeries. Our data suggests that iMRI may be a cost effective addition to the surgical armamentarium for epilepsy surgery. PMID- 29159427 TI - Shunt revision rates in myelomeningocele patients in the first year of life: a retrospective study of 52 patients. AB - PURPOSE: Shunt placement indications are stringent and require confirmation of clinical and radiological evidence of hydrocephalus (HC). The aim of this study was to determine the rate of shunting and discuss the outcome in the first year of life in patients with myelomeningocele (MMC) on the basis of review of the literature. METHODS: All patients who underwent postnatal repair of MMC at our institution between March 2014 and March 2015 were evaluated. Patients were only included if they underwent both MMC repair and ventriculoperitoneal (VP) shunt insertion at our institution and were followed up for at least 12 months. The mean ages for repair of MMC, MMC levels, timing of VP shunt placement, shunt revisions, and causes of shunt revisions were documented. RESULTS: Fifty-two patients with MMC were included in this study. The average gestational age at birth was 38 weeks. The level of MMC was thoracolumbar in 13 cases, 11 times lumbar, 21 times lumbosacral, and 7 times sacral. Thirty-one patients (59.61%) suffered from hydrocephalus and required placement of a shunt. When we evaluate the lesion levels of patients who require shunting, 13 cases were thoracolumbar, 6 cases were lumbar, and 11 cases were lumbosacral. None of the sacral cases needed VP shunt. Seven patients (13.4%) had shunt revision within the first year of life. The cause of shunt revision was wound problem in one patient (1.9%), underdrainage in two patients (3.8%), infection in three patients (5.7%), and mechanical obstruction in another one patient (1.9%). CONCLUSION: MMC closure and management of the associated HC are one of the most basic, but never simple, legs of the pediatric neurosurgery around the world. As clinicians and neurosurgeons, we are obligated to analyze recent evidences and evaluate present approaches to achieve optimization in this subject until further technologies or approaches became more advantageous for our patients. PMID- 29159428 TI - Expert's comment concerning Grand Rounds case entitled "Rheumatoid arthritis associated spinal neuroarthropathy with double-level isthmic spondylolisthesis" by S. I. Kim et al. (Eur Spine J; 2017: doi:10.1007/s00586-017-5220-6). PMID- 29159429 TI - Phenolic constituents from Alisma plantago-aquatica Linnaeus and their anti chronic prostatitis activity. AB - BACKGROUND: The plant Alisma plantago-aquatica Linnaeus, which is widely distributed in southwest of China, is the main material of traditional Chinese medicine "Zexie". It was used as folk medicine for immune-modulation, anti-tumor, anti-inflammatory and antibacterial. Previous chemical studies on A. plantago aquatica reported the identification of triterpenes, diterpenes, sesquiterpenes, steroids, alkaloids and phenolic acid. Terpenes and phenolic acid were regard as major secondary metabolites from this medicine plant. RESULTS: A new phenolic acid, plantain A (1), along with four known compounds (2-5) were isolated and identified from A. plantago-aquatica by extensive chromatographic and spectrometric methods. In the present study, the levels of TNF-alpha, IL-1beta, COX-2, PEG2 and TGF-beta1 were increased in model group rats, whereas on treatment with the isolated compound (1 and 4) at 50 mg/kg, there was a significant decrease in the cytokine levels. Therefore, the anti-CNP effect of 1 and 4 may be related to their anti-inflammatory properties. CONCLUSIONS: A new phenolic acid and four known phenolic compounds were isolated from A. plantago aquatica. Moreover, compounds 1 and 4 shows significant anti-chronic prostatitis activity in rats. PMID- 29159431 TI - Invited comment to: Laparoscopic inguinal hernioplasty after robot-assisted laparoscopic radical prostatectomy. Sakon M, Sekino Y, Okada M, Seki H, Munakata Y. PMID- 29159430 TI - Radiation therapy-induced metastasis: radiobiology and clinical implications. AB - Radiation therapy is an effective means of achieving local control in a wide range of primary tumours, with the reduction in the size of the tumour(s) thought to mediate the observed reductions in metastatic spread in clinical trials. However, there is evidence to suggest that the complex changes induced by radiation in the tumour environment can also present metastatic risks that may counteract the long-term efficacy of the treatment. More than 25 years ago, several largely theoretical mechanisms by which radiation exposure might increase metastatic risk were postulated. These include the direct release of tumour cells into the circulation, systemic effects of tumour and normal tissue irradiation and radiation-induced changes in tumour cell phenotype. Here, we review the data that has since emerged to either support or refute these putative mechanisms focusing on how the unique radiobiology underlying modern radiotherapy modalities might alter these risks. PMID- 29159432 TI - Comparison of the neuroprotective effects of brimonidine tartrate and melatonin on retinal ganglion cells. AB - PURPOSE: We aimed to compare the neuroprotective effects of brimonidine tartrate (BRT) and melatonin (MEL) on retinal ganglion cells (RGCs) in a rat glaucoma model. METHODS: Thirty-six adult Wistar albino rats were allocated into six groups: control (C), glaucoma (G), BRT, MEL, G + BRT and G + MEL. After establishing the glaucoma model, intraocular pressure (IOP) of all animals measured at day 4 and day 30 was compared statistically with day 0 and day 4, respectively. Prior to sacrification at day 30 for histological evaluation and TUNEL analysis, retrograde labeling of non-apoptotic RGCs with 3% Fluorogold was performed and RGCs were evaluated under fluorescein microscope. RESULTS: IOP measurements at day 4 were significantly higher than basal measurements in all glaucoma groups. BRT alone induced a time-dependent decrease in IOP (p < 0.05), while MEL alone failed to reduce IOP. However, both BRT and MEL reduced IOP in the presence of glaucoma at day 30 (p < 0.05). BRT treatment significantly reversed the reduced non-apoptotic RGC counts (p < 0.01) and increased TUNEL positive RGCs (p < 0.001) to control group levels in the presence of glaucoma. However, no statistical significance was found between groups G and G + MEL considering 3% Fluorogold-labeled cell counts and apoptotic index values. CONCLUSION: Our study revealed that systemic administration of BRT also has an IOP reducing effect. MEL has no neuroprotective effect on RGCs; on the other hand, BRT acts as a neuroprotective agent against glaucomatous injury, when applied systemically. PMID- 29159433 TI - Effects of rainfall intensity and slope gradient on runoff and sediment yield characteristics of bare loess soil. AB - Soil erosion is a universal phenomenon on the Loess Plateau but it exhibits complex and typical mechanism which makes it difficult to understand soil loss laws on slopes. We design artificial simulated rainfall experiments including six rainfall intensities (45, 60, 75, 90, 105, 120 mm/h) and five slopes (5 degrees , 10 degrees , 15 degrees , 20 degrees , 25 degrees ) to reveal the fundamental changing trends of runoff and sediment yield on bare loess soil. Here, we show that the runoff yield within the initial 15 min increased rapidly and its trend gradually became stable. Trends of sediment yield under different rainfall intensities are various. The linear correlation between runoff and rainfall intensity is obvious for different slopes, but the correlations between sediment yield and rainfall intensity are weak. Runoff and sediment yield on the slope surface both presents an increasing trend when the rainfall intensity increases from 45 mm/h to 120 mm/h, but the increasing trend of runoff yield is higher than that of sediment yield. The sediment yield also has an overall increasing trend when the slope changes from 5 degrees to 25 degrees , but the trend of runoff yield is not obvious. Our results may provide data support and underlying insights needed to guide the management of soil conservation planning on the Loess Plateau. PMID- 29159434 TI - Mineralogical and geochemical characterization of waste rocks from a gold mine in northeastern Thailand: application for environmental impact protection. AB - Waste rocks from gold mining in northeastern Thailand are classified as sandstone, siltstone, gossan, skarn, skarn-sulfide, massive sulfide, diorite, and limestone/marble. Among these rocks, skarn-sulfide and massive sulfide rocks have the potential to generate acid mine drainage (AMD) because they contain significant amounts of sulfide minerals, i.e., pyrrhotite, pyrite, arsenopyrite, and chalcopyrite. Moreover, both sulfide rocks present high contents of As and Cu, which are caused by the occurrence of arsenopyrite and chalcopyrite, respectively. Another main concern is gossan contents, which are composed of goethite, hydrous ferric oxide (HFO), quartz, gypsum, and oxidized pyroxene. X ray maps using electron probe micro-analysis (EPMA) indicate distribution of some toxic elements in Fe-oxyhydroxide minerals in the gossan waste rock. Arsenic (up to 1.37 wt.%) and copper (up to 0.60 wt.%) are found in goethite, HFO, and along the oxidized rim of pyroxene. Therefore, the gossan rock appears to be a source of As, Cu, and Mn. As a result, massive sulfide, skarn-sulfide, and gossan have the potential to cause environmental impacts, particularly AMD and toxic element contamination. Consequently, the massive sulfide and skarn-sulfide waste rocks should be protected from oxygen and water to avoid an oxidizing environment, whereas the gossan waste rocks should be protected from the formation of AMD to prevent heavy metal contamination. PMID- 29159435 TI - Determination of selected elements in canned food sold in Jordan markets. AB - In this study, the concentrations of seven heavy metals including As, Cd, Cr, Cu, Ni, Pb, and Zn in imported canned food samples of different brands including tuna, beef, sardines, and mushroom were determined. Samples were collected from popular Jordanian market, Irbid city, Northern Jordan (44 samples of each type). The metal concentrations in canned food samples were found to be in the range of 1.85-4.50 MUg/g for As, 0.42-0.58 MUg/g for Cd, 0.47-1.67 MUg/g for Cr, 0.73-0.90 MUg/g for Cu, 1.08-2.77 MUg/g for Ni, 2.5-3.0 MUg/g for Pb, and 0.43-2.25 MUg/g for Zn. Results revealed that As and Pb have the highest concentrations in all samples analyzed, whereas, the lowest concentrations obtained were in Cd. For example, in canned sardine, the mean concentrations of heavy metals are 0.43 MUg/g for Zn, 2.50 MUg/g for Pb, 1.74 MUg/g for Ni, 0.80 MUg/g for Cu, 0.47 MUg/g for Cr, 0.42 MUg/g for Cd, and 1.85 MUg/g for As. Whereas, the mean concentrations in canned tuna were 3.48 MUg/g for As, 0.47 MUg/g for Cd, 0.53 MUg/g for Cr, 0.73 MUg/g for Cu, 2.77 MUg/g for Ni, 2.80 MUg/g for Pb, and 1.63 MUg/g for Zn. The results of this study indicated that the concentration of the tested elements including As, Cd, Cr, Ni, and Pb in canned food samples sold in Jordanian markets exceeded the permissible limits set by health organizations such as FAO/WHO. The results were compared with the literature values. PMID- 29159436 TI - Comparison of bioaccumulation and elimination of Escherichia coli and male specific bacteriophages by ascidians and bivalves. AB - Levels of Escherichia coli and male-specific bacteriophages (MSBs) were determined in the filter feeders obtained from retail markets, commercial farms, and wild beds in Korea. The accumulation and elimination of E. coli and MSBs were compared between ascidians and bivalves (oysters and mussels) during relaying and depuration. E. coli concentrations in ascidians from retail markets ranged between < 20 and 460 most probable number/100 g while MSBs were not detected. E. coli levels in bivalves from commercial farms and wild beds were not significantly different but bacterial levels in ascidians were consistently lower. Ascidians exhibited much lower ability than bivalves to accumulate E. coli and MSBs during relaying in a polluted coastal area. This study also shows that an equilibrium was developed between levels of microbes in water and ascidians and shellfish during relaying. E. coli and MSBs in ascidians decreased quickly during depuration in a clean seawater tank. However, after 1 day, E. coli in bivalves decreased by only 1.1-1.6 logs, and the elimination of MSBs was negligible. Therefore, depuration is an effective means to reduce the health risk of contaminated ascidians. PMID- 29159438 TI - Polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDEs in human serum from Shanghai, China: a study on their presence and correlations. AB - Polybrominated diphenyl ethers (PBDEs) are becoming a public health concern because of their potential toxicity, from endocrine disruption system to neurodevelopmental impairments. Nonetheless, information on their levels in human blood is scarce. In this study, human serum samples collected in Shanghai, China, were analyzed for the concentrations of PBDEs and their hydroxylated metabolites (OH-PBDEs). Eight PBDE congeners and six OH-PBDE congeners were quantified in serum samples by gas chromatography with mass spectrometry (GC-MS) and high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). As a result, total PBDE concentration ranged from 0.280 to 12.330 ng g-1 on a lipid weight basis lw (median: 1.100 ng g-1 lw) and the total OH-PBDE level ranged from 0.045 to 0.363 ng g-1 (lw) (median: 0.187 ng g-1 lw). Among them, BDE-47 and 6-OH BDE-47 were the predominant PBDEs and OH-PBDEs, respectively. In addition, based on the results of the Bartelett X 2 test, BDE-47 significantly (p < 0.05) correlated with BDE-28, BDE-100, BDE-85, and BDE-154, whereas 3'-OH-BDE-7 significantly (p < 0.01) correlated with 3-OH-BDE-47, 2-OH-BDE-68, and 6'-OH-BDE 99. Among all donors, no significant association between age and PBDEs (or OH PBDEs) was found. Further research on the exposure routes in the environment and metabolic processing of PBDEs in human blood is necessary. PMID- 29159437 TI - Exploring the potential relationship between indoor air quality and the concentration of airborne culturable fungi: a combined experimental and neural network modeling study. AB - Indoor airborne culturable fungi exposure has been closely linked to occupants' health. However, conventional measurement of indoor airborne fungal concentration is complicated and usually requires around one week for fungi incubation in laboratory. To provide an ultra-fast solution, here, for the first time, a knowledge-based machine learning model is developed with the inputs of indoor air quality data for estimating the concentration of indoor airborne culturable fungi. To construct a database for statistical analysis and model training, 249 data groups of air quality indicators (concentration of indoor airborne culturable fungi, indoor/outdoor PM2.5 and PM10 concentrations, indoor temperature, indoor relative humidity, and indoor CO2 concentration) were measured from 85 residential buildings of Baoding (China) during the period of 2016.11.15-2017.03.15. Our results show that artificial neural network (ANN) with one hidden layer has good prediction performances, compared to a support vector machine (SVM). With the tolerance of +/- 30%, the prediction accuracy of the ANN model with ten hidden nodes can at highest reach 83.33% in the testing set. Most importantly, we here provide a quick method for estimating the concentration of indoor airborne fungi that can be applied to real-time evaluation. PMID- 29159439 TI - Isolation of lead-resistant Arthrobactor strain GQ-9 and its biosorption mechanism. AB - In this study, lead-resistant bacterium Arthrobacter sp. GQ-9 with a resistant capability to cadmium, zinc, and copper was isolated from a heavy metal polluted soil. Microcalorimetry analysis was applied to assess the strain's microbial activity under Pb(II) stress and suggested that GQ-9's microbial activities under Pb(II) stress were stronger than a non-resistant strain. Biosorption batch experiments revealed that the optimal condition for adsorption of Pb(II) by GQ-9 was pH 5.5, a biomass dosage of 1.2 g L-1, and an initial Pb(II) concentration of 100 mg L-1 with a maximum biosorption capacity of 17.56 mg g-1.Adsorption desorption experiments and Fourier transform infrared spectroscopy (FTIR) analysis were applied to elucidate the biosorption mechanisms. Adsorption desorption analysis showed that GQ-9 cells could sequester 56.60% of the adsorbed Pb(II) ions on the cell wall. FTIR analysis suggested that hydroxyl, carboxyl, amino, nitrile, and sulfhydryl groups and amide I, amide II bands on the GQ-9 cell wall participated in the complexation of Pb(II) ions. The present study illustrates that the lead-resistant bacteria GQ-9 has the potential for further development of an effective and ecofriendly adsorbent for heavy metal bioremediation. PMID- 29159440 TI - Identifying and assessing human activity impacts on groundwater quality through hydrogeochemical anomalies and NO3-, NH4+, and COD contamination: a case study of the Liujiang River Basin, Hebei Province, P.R. China. AB - In the face of rapid economic development and increasing human activity, the deterioration of groundwater quality has seriously affected the safety of the groundwater supply in eastern China. Identifying and assessing the impact of human activities is key to finding solutions to this problem. This study is an effort to scientifically and systematically identify and assess the influence of human activities on groundwater based on irregularities in hydrochemical properties and water contamination, which are considered to directly result from anthropogenic activity. The combination of the hydrochemical anomaly identification (HAI) and the contaminant identification (CI) was proposed to identify the influence of human activities on groundwater quality. And the degree of abnormality was quantified by the background threshold value. The principal component analysis (PCA) and land use map were used to verify the reliability of the identification result. The final result show that the strong influence areas mainly distributed in the south of the basin and the affected indicators contained the major elements and NO3-, NH4+, COD. Impacts from anthropogenic activities can be divided into two types: mine drainage that disrupts natural water-rock interaction processes, agricultural cultivation, and sewage emissions that contribute to nitrate pollution. PMID- 29159442 TI - From the New Editors' Desk: A Taste of What's to Come. PMID- 29159443 TI - Persistence of Opioid Prescribing after a Forearm or Lower Leg Fracture. PMID- 29159441 TI - A Meta-Analysis of the Association Between Birth Weight and Attention Deficit Hyperactivity Disorder. AB - A large body of work has investigated the association between birth weight and ADHD and has resulted in mixed findings with regard to the direction and magnitude of this association. Despite the vast amount of research on this topic, a comprehensive and systematic quantification of the association between birth weight and ADHD has yet to be undertaken. A meta-analysis of 88 unique studies (N = 4,645,482) was conducted to quantify the overall effect size of birth weight on ADHD symptoms. Several variables were examined as moderators that may contribute to systematic variation in effect sizes. Overall, birth weight was found to have a small, but significant, association with ADHD symptoms such that individuals born at lower birth weights manifested greater symptoms of ADHD (r = -0.15). Sample type, mean birth weight of the sample, geographic region, the informant of ADHD symptoms, ADHD symptom measurement method, and race were all found to contribute significantly to heterogeneity in effect sizes. Notably, several early life risk factors previously found to be associated with both ADHD and birth weight, gestational age and prenatal smoking exposure, were not found to contribute to heterogeneity in effect sizes. The findings of the current analyses align with the growing recognition that early life adversity contributes to neurodevelopmental difficulties, and the findings highlight the importance of a better understanding of the mechanisms underlying the association between early life risk factors and adverse neurodevelopmental sequela, such as that observed in ADHD. PMID- 29159444 TI - Are Demographic Characteristics Associated with Advance Directive Completion? A Secondary Analysis of Two Randomized Trials. PMID- 29159445 TI - Probiotic Properties and Cellular Antioxidant Activity of Lactobacillus plantarum MA2 Isolated from Tibetan Kefir Grains. AB - Lactobacillus plantarum MA2 was isolated from traditional Chinese Tibetan kefir grains. Its antioxidant properties had been demonstrated in vitro and in vivo previously. In the present study, the probiotic characteristics of this strain were further evaluated by investigating its acid and bile salt tolerances, cell surface hydrophobicity, and autoaggregation, respectively. In addition, the cellular antioxidant activity (CAA) assay was applied to test the antioxidant capacity of the isolate in different growth phases. Same method was also used to evaluate the antioxidant capacity of its fermentation supernatant, cell-free extract, and intact cell quantitatively. The results of probiotic characteristic tests showed that MA2 could survive at pH 2.5 and 0.3% bile salt. Meanwhile, the measurements of cell surface hydrophobicity and autoaggregation were 45.29 +/- 2.15 and 6.30 +/- 0.34%, respectively. The results of cellular antioxidant activity tests indicated that MA2 had high antioxidant potential. The CAA value of logarithmic phase cell-free extract of MA2 (39,450.00 +/- 424.05 MUmol quercetin equivalents/100 g sample) was significantly higher than that in stationary phase cell-free extract (3395.98 +/- 126.06 MUmol quercetin equivalents/100 g sample) and that of fermentation supernatant in logarithmic phase (2174.41 +/- 224.47 MUmol quercetin equivalents/100 g sample) (p < 0.05). The CAA method was successively applied to evaluate the antioxidant capacity of MA2 in this study, which suggests that it could be used as a useful method for lactic acid bacteria antioxidant potential evaluation. PMID- 29159446 TI - Reflecting Before Testing : Comment on "Personal Genomic Testing, Genetic Inheritance, and Uncertainty". AB - This response is a comment on the case of Jordan presented by Mason (2017). A key perspective we can take from this case is a consideration of: consumer motivations for testing, whether they have enough information and time to make a decision, and if the test they seek is entirely appropriate for them at their current stage of life. PMID- 29159448 TI - Laudation for Professor Alexander Berghaus. PMID- 29159447 TI - Transcriptome sequencing of the long-nosed bandicoot (Perameles nasuta) reveals conservation and innovation of immune genes in the marsupial order Peramelemorphia. AB - Bandicoots are omnivorous marsupials of the order Peramelemorphia. Conservation concerns and their unique biological characteristics suggest peramelomorphs are worthy research subjects, but knowledge of their genetics and immunology has lagged behind that of other high-profile marsupials. Here, we characterise the transcriptome of the long-nose bandicoot (Perameles nasuta), the first high throughput data set from any peramelomorph. We investigate the immune gene repertoire of the bandicoot, with a focus on key immune gene families, and compare to previously characterised marsupial and mammalian species. We find that the immune gene complement in bandicoot is often conserved with respect to other marsupials; however, the diversity of expressed transcripts in several key families, such as major histocompatibility complex, T cell receptor MU and natural killer cell receptors, appears greater in the bandicoot than other Australian marsupials, including devil and koala. This transcriptome is an important first step for future studies of bandicoots and the bilby, allowing for population level analysis and construction of bandicoot-specific immunological reagents and assays. Such studies will be critical to understanding the immunology and physiology of Peramelemorphia and to inform the conservation of these unique marsupials. PMID- 29159449 TI - Handling the phosphorus paradox in agriculture and natural ecosystems: Scarcity, necessity, and burden of P. AB - This special issue of Ambio compiles a series of contributions made at the 8th International Phosphorus Workshop (IPW8), held in September 2016 in Rostock, Germany. The introducing overview article summarizes major published scientific findings in the time period from IPW7 (2015) until recently, including presentations from IPW8. The P issue was subdivided into four themes along the logical sequence of P utilization in production, environmental, and societal systems: (1) Sufficiency and efficiency of P utilization, especially in animal husbandry and crop production; (2) P recycling: technologies and product applications; (3) P fluxes and cycling in the environment; and (4) P governance. The latter two themes had separate sessions for the first time in the International Phosphorus Workshops series; thus, this overview presents a scene setting rather than an overview of the latest research for these themes. In summary, this paper details new findings in agricultural and environmental P research, which indicate reduced P inputs, improved management options, and provide translations into governance options for a more sustainable P use. PMID- 29159450 TI - Lower dietary phosphorus supply in pigs match both animal welfare aspects and resource efficiency. AB - Dietary phosphorus frequently exceeds age-specific requirements and pig manure often contains high phosphorus load which causes environmental burden at regional scales. Therefore, feeding strategies towards improved phosphorus efficiency and reduced environmental phosphorus load have to be developed. A 5-week feeding trial was conducted: piglets received medium, lower (-25%), or higher (+25%) amounts of phosphorus and calcium. Dietary responses were reflected by performance parameters, bone characteristics, and molecular data retrieved from serum, intestinal mucosa, and kidney cortex (p < 0.05). Transcripts associated with vitamin D hydroxylation (Cyp24A1, Cyp27A1, Cyp27B1) were regulated by diet at local tissue sites. Low-fed animals showed attempts to maintain mineral homoeostasis via intrinsic mechanisms, whereas the high-fed animals adapted at the expense of growth and development. Results suggest that a diet containing low phosphorus and calcium levels might be useful to improve resource efficiency and to reduce phosphorus losses along the agricultural value chain. PMID- 29159451 TI - Re-evaluation of the yield response to phosphorus fertilization based on meta analyses of long-term field experiments. AB - Phosphorus (P) fertilizer recommendations in most European countries are based on plant-available soil P contents and long-term field experiments. Site-specific conditions are often neglected, resulting in excessive P fertilizer applications. P fertilization experiments including relevant site and soil parameters were evaluated in order to analyze the yield response. The database comprises about 2000 datasets from 30 field experiments from Germany and Austria. Statistical evaluations using a classification and regression tree approach, and multiple linear regression analysis indicate that besides plant-available soil P content, soil texture and soil organic matter content have a large influence on the effectiveness of P fertilization. This study methodology can be a basis for modification and specification of existing P fertilization recommendations and thus contribute to mitigate environmental impacts of P fertilization. PMID- 29159452 TI - Saprotrophic soil fungi to improve phosphorus solubilisation and release: In vitro abilities of several species. AB - Modern agriculture is dependent on phosphate rock (PR), which is a nonrenewable resource. Improvement of phosphorus (P) availability for crops in agricultural soils represents a key strategy to slow down the depletion of PR. The aim of this study was to identify potential P biofertilisers among saprotrophic fungal species. We tested 30 fungal strains belonging to 28 taxa (4 Zygomycota and 24 Ascomycota) and with different life strategies. The study showed that many saprotrophic fungi have the ability to mobilise P from insoluble forms according to a variety of mechanisms. Our results expand the pool of P solubilising fungal species, also suggesting a new solubilisation index and shedding light on parameters that could be basic in the selection of efficient soil P biofertilisers fungi. Rhizopus stolonifer var. stolonifer, Aspergillus niger and Alternaria alternata were found to be the best performing strains in terms of amounts of TCP solubilisation. PMID- 29159453 TI - Performance of secondary P-fertilizers in pot experiments analyzed by phosphorus X-ray absorption near-edge structure (XANES) spectroscopy. AB - A pot experiment was carried out with maize to determine the phosphorus (P) plant availability of different secondary P-fertilizers derived from wastewater. We analyzed the respective soils by P K-edge X-ray absorption near-edge structure (XANES) spectroscopy to determine the P chemical forms that were present and determine the transformation processes. Macro- and micro-XANES spectroscopy were used to determine the chemical state of the overall soil P and identify P compounds in P-rich spots. Mainly organic P and/or P adsorbed on organic matter or other substrates were detected in unfertilized and fertilized soils. In addition, there were indications for the formation of ammonium phosphates in some fertilized soils. However, this effect was not seen in the maize yield of all P fertilizers. The observed reactions between phosphate from secondary P fertilizers and co-fertilized nitrogen compounds should be further investigated. Formation of highly plant-available compounds such as ammonium phosphates could make secondary P-fertilizers more competitive to commercial phosphate rock-based fertilizers with positive effects on resources conservation. PMID- 29159454 TI - Phosphorus transformations in plant-based and bio-waste materials induced by pyrolysis. AB - Strategies are needed to increase the sustainability of phosphorus (P) fertiliser management in agriculture. This paper reports on the potential of pyrolysis treatment to recycle P from renewable materials previously regarded as wastes. The study used K-edge X-ray absorption near-edge structure (XANES) spectroscopy to examine chemical forms of P in the waste feedstock materials and corresponding biochars (pyrolysis at 480-500 degrees C) of four ligno-cellulosic, plant-based residues and five relatively P-rich livestock and water-treatment by-products, to acquire information on changes in potential P fertiliser value. Pyrolysis enriched P in the biochars by factors of 1.3-4.3, thus offering wide-ranging P fertiliser potential. XANES spectroscopy revealed hydroxyapatite (HAP) as one of the dominant chemical P compounds in the feedstocks, ranging from 14% (rice husks) to 98% (animal bone) of total P. For most materials, pyrolysis increased the proportion of HAP, and pyrophosphates were generated in several cases. These alterations possibly lead to diversity in the P solubility characteristics of the biochars if used as soil amendments; this is an important property of environmentally sound P fertilisers. PMID- 29159455 TI - Plant available phosphorus in soil as predictor for the leaching potential: Insights from long-term lysimeter studies. AB - This study aimed to demonstrate the impact of phosphorus (P) mineral fertilization on topsoil P content and P leaching. We evaluated 83 datasets from 25 years from lysimeter experiments involving different cropping systems (winter crop, summer crop and autumn tillage, harvested grass) or unfertilized fallow, four types of soil texture, and three levels of applied mineral P fertilizer. A positive monotonic and significant correlation was indicated between P in the topsoil determined by the double lactate method (P DL) and the yearly flow-weight total (TP) concentrations in leachates with Spearman rank correlations r s (r s > 0.183) and probability (p) < 0.05. The present German recommended rates of P mineral fertilization are proposed insufficient to protect fresh and marine waters from undesired P pollution and eutrophication. A long-term reduction of excess soil P is urgent along with other measures to mitigate high P inputs to surface and ground waters. PMID- 29159456 TI - Assessing strategies to mitigate phosphorus leaching from drained clay soils. AB - Assessing mitigation of phosphorus (P) leaching from subsurface drainage systems is challenging due to high spatial and temporal variation in leaching. Mean measured total P leaching from a clayey soil in an eight-year study period (four replicates per treatment) was (kg ha-1 year-1): 1.21 from shallow autumn tillage (ShT), 0.84 from unfertilised fallow (UF), 0.81 from conventional autumn ploughing (CT) and 0.57 from structure liming (SL-CT). Treatment was not significant using Richards-Baker flow index or a distance factor as covariate (p = 0.084 and 0.057). A tendency for lower leaching was obtained comparing SL-CT with ShT (p adjusted = 0.060 and 0.009 respectively). A combination of measures adapted to drainage conditions and clay content in different parts of the field is proposed since P leaching was approximately halved from an adjacent field (4.3 ha) in a three-year post-period compared with a three-year pre-period for structure liming the entire field and drainage system renovation plus structure lime drain backfilling. PMID- 29159457 TI - Ertugliflozin in Patients with Stage 3 Chronic Kidney Disease and Type 2 Diabetes Mellitus: The VERTIS RENAL Randomized Study. AB - INTRODUCTION: Ertugliflozin is a sodium-glucose cotransporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The safety and efficacy of ertugliflozin were evaluated over 52 weeks in patients with chronic kidney disease (CKD). METHODS: In this double-blind randomized study (NCT01986855), patients with glycated hemoglobin (A1C) 7.0-10.5% and stage 3 CKD [estimated glomerular filtration rate (eGFR) >= 30 to < 60 mL/min/1.73 m2] who were undergoing treatment with standard diabetes therapy (or therapies) including insulin and/or sulfonylureas were randomized to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Patients on metformin underwent a pre-randomization >= 10-week wash-off period. The primary endpoint was change from baseline in A1C at week 26 in the overall cohort. Secondary efficacy endpoints were assessed in the stage 3A CKD cohort (eGFR >= 45 to < 60 mL/min/1.73 m2) at weeks 26 and 52. Safety was assessed in the overall cohort. RESULTS: 468 patients were randomized (baseline mean A1C 8.2%). At week 26, reductions from baseline in A1C were observed across groups in the overall cohort [least squares mean changes (95% confidence interval) - 0.3% (- 0.4, - 0.1), - 0.3% (- 0.4, - 0.1), and - 0.4% (- 0.6, - 0.3) for placebo and for ertugliflozin 5 mg and 15 mg, respectively]. Prohibited use of metformin was identified in ~ 17% of patients and impacted evaluation of the primary endpoint. Greater reductions from baseline in body weight, fasting plasma glucose, and systolic blood pressure were observed with ertugliflozin versus placebo at week 26 (stage 3A CKD cohort). The incidences of urinary tract infections, genital mycotic infections, and hypoglycemia adverse events were not meaningfully different between groups. The incidence of hypovolemia-related adverse events was higher with ertugliflozin relative to placebo. CONCLUSION: Although surreptitious metformin use impacted the primary analysis, reductions in blood glucose and body weight were observed with ertugliflozin in patients with T2DM and stage 3 CKD; ertugliflozin had an acceptable safety profile. FUNDING: Merck Sharp & Dohme Corp. a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Pfizer Inc. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01986855. PMID- 29159458 TI - Cardiopulmonary Exercise Testing Reflects Improved Exercise Capacity in Response to Treatment in Morquio A Patients: Results of a 52-Week Pilot Study of Two Different Doses of Elosulfase Alfa. AB - OBJECTIVE: To assess impact of a 52-week elosulfase alfa enzyme replacement therapy (ERT) on exercise capacity in Morquio A patients and analyze cardiorespiratory and metabolic function during exercise to uncover exercise limitations beyond skeletal abnormalities. METHODS: Morquio A patients aged >=7 years, able to walk >200 m in the 6-minute walk test (6MWT), received elosulfase alfa 2.0 mg/kg/week (N = 15) or 4.0 mg/kg/week (N = 10) for 52 weeks in the randomized, double-blind MOR-008 study ( ClinicalTrials.gov NCT01609062) and its extension. Exercise capacity was assessed by 6MWT, 3-minute stair climb test (3MSCT), and cardiopulmonary exercise test (CPET; N = 15 dosage groups combined). RESULTS: Changes over 52 weeks in 6MWT and 3MSCT were minimal. Baseline CPET results showed impaired weight-adjusted peak oxygen uptake (VO2), partly attributable to inability to increase tidal volume during exercise. CPET measures of exercise function showed significant improvement at 25 and/or 52 weeks in exercise duration, peak workload, O2 pulse, and peak tidal volume (% increases in duration, 16.9 (P = 0.0045) and 9.4 (P = 0.0807); peak workload, 26.5 (P = 0.0026) and 21.2 (P = 0.0132); O2 pulse, 10.7 (P = 0.0187) and 2.3 (P = 0.643); peak tidal volume, 11.7 (P = 0.1117) and 29.1 (P = 0.0142)). In addition, decreased VO2/work ratio was noted (% decrease -7.6 [-11.9, 1.3] and -9.2 [-25.7, 5.1]), indicating performance of work at reduced oxygen cost. CONCLUSIONS: CPET uncovers limitation in exercise capacity in Morquio A related to reduced lung function. ERT improves exercise capacity and efficiency of oxygen utilization, not attributable to changes in cardiac or pulmonary function. Further study of the long-term impact of ERT on exercise capacity and the clinical relevance of the observed changes is warranted. PMID- 29159459 TI - EPG5-Related Vici Syndrome: A Primary Defect of Autophagic Regulation with an Emerging Phenotype Overlapping with Mitochondrial Disorders. AB - Vici syndrome is a rare, under-recognised, relentlessly progressive congenital multisystem disorder characterised by five principal features of callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and oculocutaneous hypopigmentation. In addition, three equally consistent features (profound developmental delay, progressive failure to thrive and acquired microcephaly) are highly supportive of the diagnosis. Since its recognition as a distinct entity in 1988, an extended phenotype with sensorineural hearing loss, skeletal myopathy and variable involvement of virtually any organ system, including the lungs, thyroid, liver and kidneys, have been described.Autosomal recessive mutations in EPG5 encoding ectopic P-granules autophagy protein 5 (EPG5), a key autophagy regulator implicated in the formation of autolysosomes, were identified as the genetic cause of Vici syndrome. The eight key features outlined above are highly predictive of EPG5 involvement, with pathogenic EPG5 mutations identified in >90% of cases where six or more of these features are present. The manifestation of all eight features has a specificity of 97% and sensitivity of 89% for EPG5 related Vici syndrome. Nevertheless, substantial clinical overlap exists with other multisystem disorders, in particular congenital disorders of glycosylation and mitochondrial disorders. Clinical and pathological findings suggest Vici syndrome as a paradigm of congenital disorders of autophagy, a novel group of inherited neurometabolic conditions linking neurodevelopment and neurodegeneration due to primary autophagy defects.Here we describe the diagnostic odyssey in a 4-year-old boy whose clinical presentation with multisystem manifestations including skeletal myopathy mimicked a mitochondrial disorder. A genetic diagnosis of Vici syndrome was made through whole genome sequencing which identified compound heterozygous variants in EPG5. We also review the myopathic presentation and morphological characterisation of previously reported cases. PMID- 29159460 TI - Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib Pair. AB - Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ10 production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q10 deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ10, and the siblings were subsequently established on a therapeutic dose of CoQ10 with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes. PMID- 29159461 TI - Severe Hyperammonemic Encephalopathy Requiring Dialysis Aggravated by Prolonged Fasting and Intermittent High Fat Load in a Ramadan Fasting Month in a Patient with CPTII Homozygous Mutation. AB - BACKGROUND: Carnitine palmitoyltransferase II (CPTII) deficiency is a mitochondrial fatty acid oxidation disorder that can present antenatally as congenital brain malformations, or postnatally with lethal neonatal, severe infantile, or the most common adult myopathic forms. No case of severe hyperammonemia without liver dysfunction has been reported. CASE PRESENTATION: We described a 23-year-old man who presented to the emergency department with seizures and was found to have markedly elevation of serum ammonia. Continuous renal replacement therapy was initiated with successfully decreased ammonia to a safety level. He had a prolonged history of epilepsies and encephalopathic attacks that was associated with high ammonia level. Molecular diagnosis revealed a homozygous mutation in CPTII. The plasma acylcarnitine profile was consistent with the diagnosis. Failure to produce acetyl-CoA, the precursor of urea cycle from fatty acid in prolonged fasting state in Ramadan month, worsening mitochondrial functions from circulating long chain fatty acid and valproate toxicities were believed to contribute to this critical metabolic decompensation. CONCLUSION: Fatty acid oxidation disorders should be considered in the differential diagnosis of hyperammonemia even without liver dysfunction. To our knowledge, this is the first case of CPTII deficiency presented with severe hyperammonemic encephalopathy required dialysis after prolonged religious related fasting. PMID- 29159462 TI - [Ulnar collateral ligament reconstruction of the elbow in posttraumatic and chronic ligament instability]. AB - OBJECTIVE: Restoration of ulnar elbow stability in cases of posttraumatic and chronic ulnar ligament instability. INDICATIONS: Symptomatic therapy-resistant ulnar ligament instability of the elbow. CONTRAINDICATIONS: Arthrofibrosis and high-grade elbow arthrosis. SURGICAL TECHNIQUE: Anatomical reconstruction of the ulnar collateral ligament (UCL) with autologous tendon graft (tendons of the palmaris longus muscle and gracilis muscle) in implant-free docking technique. POSTOPERATIVE MANAGEMENT: A cast for 1 week, then 5 weeks orthesis with limitation of complete extension and flexion; full weight bearing after 3 months. RESULTS: After 2 years 90% of the patients are able to return at an equal level of activity. The overall complication rate is 10.4%. The most common complication is ulnar nerve neurapraxia in 7.8% of the patients. PMID- 29159463 TI - A nationwide survey of the influence of month of birth on the risk of developing multiple sclerosis in Sweden and Iceland. AB - Previous studies have shown that the risk of multiple sclerosis (MS) is associated with season of birth with a higher proportion of MS patients being born in spring. However, this relationship has recently been questioned and may be due to confounding factors. Our aim was to assess the influence from season or month of birth on the risk of developing MS in Sweden and Iceland. Information about month of birth, gender, and phenotype of MS for patients born 1940-1996 was retrieved from the Swedish MS registry (SMSR), and their place of birth was retrieved from the Swedish Total Population Registry (TPR). The corresponding information was retrieved from medical journals of Icelandic MS patients born 1981-1996. The control groups consisted of every person born in Sweden 1940-1996, their gender and county of birth (TPR), and in Iceland all persons born between 1981 and 1996 and their gender (Statistics Iceland). We calculated the expected number of MS patients born during each season and in every month and compared it with the observed number. Adjustments were made for gender, birth year, and county of birth. We included 12,020 Swedish and 108 Icelandic MS patients in the analyses. There was no significant difference between expected and observed MS births related to season or month of birth in Sweden or Iceland. This was even the results before adjustments were made for birth year and birth place. No significant differences were found in subgroup analyses including data of latitude of birth, gender, clinical phenotype, and MS onset of 30 years or less. Our results do not support the previously reported association between season or month of birth and MS risk. Analysis of birth place and birth year as possible confounding factors showed no major influence of them on the seasonal MS risk in Sweden and Iceland. PMID- 29159464 TI - Anti-MAG associated cerebellar ataxia and response to rituximab. AB - BACKGROUND: Myelin-associated glycoprotein (MAG) is a glycoprotein specific to Schwann cells. Schwann cells produce myelin for nerve cells in the peripheral nervous system. MAG also plays a role in the central nervous system (CNS) by maintaining myelin integrity and inhibiting axonal regeneration from cerebellar neurons. There is a well-established link between distal demyelinating neuropathy and anti-MAG antibodies in patients with monoclonal gammopathy of unknown significance. We describe a series of five patients with anti-MAG antibodies with evidence of cerebellar rather than just sensory ataxia and our experience of treatment with rituximab. METHODS: Cerebellar ataxia was clinically suspected and confirmed using magnetic resonance spectroscopy (MRS) of the cerebellum. All patients underwent detailed nerve conduction studies. RESULTS: Four patients were males. The ages ranged from 64 to 82 years. All patients were anti-MAG positive and also had IgM monoclonal gammopathy. Four patients had neuropathy, whilst one had no evidence of neuropathy. All patients were treated with rituximab and showed improvement in the MRS parameters of the cerebellum. CONCLUSION: Anti-MAG antibodies might be involved in the pathogenesis of idiopathic sporadic ataxias, even in the absence of peripheral neuropathy. Rituximab seems to be a promising therapeutic intervention for those cases. PMID- 29159465 TI - Changes in disability in people with multiple sclerosis: a 10-year prospective study. AB - BACKGROUND: Little is known about the long-term course of disability in relation with disease severity in people with multiple sclerosis (PwMS). OBJECTIVE: To explore changes in a broad spectrum of disability over 10 years in relation with disease severity in PwMS. METHODS: We conducted a longitudinal study of 155 PwMS who attended the MS Centre at Karolinska University Hospital, Stockholm. Disease severity was determined by the use of the Expanded Disability Status Scale (EDSS) and classified as mild MS (EDSS score 0-3.5) or moderate/severe MS (EDSS score 4 9.5). Ten-year changes in perceived physical and psychological impacts of MS, walking, cognition, manual dexterity, participation in social/lifestyle activities, and signs of depression were compared between PwMS with mild and moderate/severe MS at baseline. RESULTS: Although walking, manual dexterity, and cognition declined in both groups, only the moderate/severe group demonstrated that long-term increased physical impact of MS, increased wheel-chair dependency, and reduced participation in social/lifestyle activities. Perceived psychological impact of MS declined in both groups, while signs of depression were experienced by fewer in the mild group and remained unaltered in the moderate/severe group. CONCLUSION: We found a more pronounced increase in disability across 10 years in individuals with moderate/severe MS compared to mild MS. These findings accentuate the importance of developing a variety of interventions that can be applied across the spectrum of disease severity. PMID- 29159466 TI - Efficacy and safety of perampanel in Parkinson's disease. A systematic review with meta-analysis. AB - BACKGROUND: L-Dopa represents the mainstay of therapy of Parkinson's disease (PD), but its effectiveness is reduced with continued treatment and disease progression. Accordingly, there remains a need to explore novel treatment strategies to manage the signs and symptoms of the later disease stages. The aim of the study was to evaluate the efficacy and safety of adjunctive perampanel (PER) in patients with PD through a meta-analysis of existing trials. METHODS: Randomized, placebo-controlled, double- or single-blind, add-on studies of PER in patients with PD were identified through a systematic literature search. The following outcomes were assessed: changes from baseline to final efficacy visit in total daily OFF time, activities of daily living during OFF time and motor function during ON time, incidence of adverse events (AEs), and treatment withdrawal. RESULTS: Four trials were included involving 2266 participants, 1449 and 817 for PER and placebo treatment groups, respectively. Four PER daily doses were tested, namely 0.5, 1, 2 and 4 mg. There were no significant differences in any efficacy outcome between PER and placebo treated patients. The risk ratios (RRs) for AEs, severe AEs and treatment withdrawal were similar between placebo and PER at 0.5, 1 and 2 mg; the 4 mg daily dose was associated with an increased risk of AEs [RR 1.118 (1.047-1.193)], and withdrawal for AEs [RR 1.345 (1.034 1.749)] and for any reason [RR 1.197 (1.020-1.406)]. CONCLUSIONS: In PD patients experiencing motor fluctuations, adjunctive PER did not improve the motor state and was well-tolerated at the lower doses. PMID- 29159467 TI - The use of multiparametric quantitative magnetic resonance imaging for evaluating visually assigned lesion groups in patients with multiple sclerosis. AB - In multiple sclerosis (MS), inflammatory lesions present a broad spectrum of histopathologic processes. For a better discrimination, lesions are visually defined into different lesion groups according to their appearance on conventional magnetic resonance imaging (MRI). The aim of this study was to investigate the properties of different MS lesion groups using multiparametric quantitative MRI. 35 patients diagnosed with relapsing-remitting MS received 3 Tesla MRI including magnetization-prepared 2 rapid acquisition gradient echo, diffusion tensor imaging and magnetization transfer imaging. Lesion segmentation was performed for T2 lesions, black holes and contrast-enhancing lesions. A subtraction mask was created including only T2 lesions that did not correspond to a black hole or contrast-enhancing lesion. T1 relaxation time (T1-RT), magnetization transfer ratio (MTR), mean diffusivity (MD) and fractional anisotropy (FA) were determined for every lesion and in normal-appearing white matter. Only MD differed significantly between all lesion groups and NAWM (p < 0.05), while FA differed between all lesion groups but not NAWM. T1-RT and MTR were not useful imaging biomarkers to distinguish between lesion groups. A lack of sensitivity and specificity and unproportional alterations of quantitative MRI measures, due to heterogenous histopathologic processes within lesions, may be a possible explanation for missing discrimination. Thus, not only interpretation of visually defined MS lesion but also interpretation of quantitative MRI measures remains challenging and should be conducted carefully. PMID- 29159469 TI - [Acne inversa/hidradenitis suppurativa: An update]. AB - Acne inversa (AI)/hidradenitis suppurativa is a chronic, recurrent, immune mediated dermatosis characterized by deep inflammatory nodules, abscesses, fistulas, and undermined scars in skin areas bearing apocrine glands. In addition to the cutaneous manifestation, numerous AI patients show metabolic changes, spondyloarthritis, and depression. AI leads to a strong reduction in the quality of life and an impairment of the sexual life of affected individuals and often culminates in social withdrawal, stigmatization, unemployment, and suicidal thoughts. In this overview, we summarized the most important facts about AI and propose a simple algorithm for therapy. PMID- 29159468 TI - HbA1c is associated with altered expression in blood of cell cycle- and immune response-related genes. AB - AIMS/HYPOTHESIS: Individuals with type 2 diabetes are heterogeneous in their glycaemic control as tracked by blood HbA1c levels. Here, we investigated the extent to which gene expression levels in blood reflect current and future HbA1c levels. METHODS: HbA1c levels at baseline and 1 and 2 year follow-up were compared with gene expression levels in 391 individuals with type 2 diabetes from the Hoorn Diabetes Care System Cohort (15,564 genes, RNA sequencing). The functions of associated baseline genes were investigated further using pathway enrichment analysis. Using publicly available data, we investigated whether the genes identified are also associated with HbA1c in the target tissues, muscle and pancreas. RESULTS: At baseline, 220 genes (1.4%) were associated with baseline HbA1c. Identified genes were enriched for cell cycle and complement system activation pathways. The association of 15 genes extended to the target tissues, muscle (n = 113) and pancreatic islets (n = 115). At follow-up, expression of 25 genes (0.16%) associated with 1 year HbA1c and nine genes (0.06%) with 2 year HbA1c. Five genes overlapped across all time points, and 18 additional genes between baseline and 1 year follow-up. After adjustment for baseline HbA1c, the number of significant genes at 1 and 2 years markedly decreased, suggesting that gene expression levels in whole blood reflect the current glycaemic state and but not necessarily the future glycaemic state. CONCLUSIONS/INTERPRETATION: HbA1c levels in individuals with type 2 diabetes are associated with expression levels of genes that link to the cell cycle and complement system activation. PMID- 29159470 TI - Biogeochemical assessment of the urban area in Moscow. AB - The biogeochemical and ecological assessment of the industrial city territory including urban soils and trees was carried out. Chemical (macroelement and microelement) composition of the city soils, morphological and biochemical properties of the linden leaves, possible impact of de-icing salts on soil and tree state, the correlation between the content of trace elements, and the S containing plant compounds (phytochelatins) were included in the assessment. It was found that concentrations of trace elements in the soils near road with intensive traffic are changed from the soils, located at a distance of 40-50 m from the road. They have higher concentrations of As, Fe, Mn, Se, and Sr and lower concentration of Zn. The linden leaves from the roadside were characterized by the increase in As, Cu, Fe, Zn, and Cr and sharp decrease in the Mn and Sr concentrations. The analysis of soil water extracts showed a slight decrease of pH and low content of Ca, Mg, K, and Na for the distant sites. The phytochelatin test of linden leaves was weakly effective as well as asymmetry degree study of leaf lamina. The main differences were observed in the damage symptoms of leaves (chlorosis and necrosis) and the content of pigments (chlorophyll and carotenoids). The biochemical and ecological assessment of soils and trees showed relatively satisfactory ecological state of the investigated area in Moscow. The data obtained shows the weak local impact of the application of de-icing salts and automobile emissions. PMID- 29159471 TI - Evidence for genetic overlap between adult onset Still's disease and hereditary periodic fever syndromes. AB - OBJECTIVE: Adult onset Still's disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD. METHODS: We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants (n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD. RESULTS: We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant (p c = 2.34E- 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A (p c = 2.40E- 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment. CONCLUSION: Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients. PMID- 29159473 TI - Two rare cases of abdominal tumor in children: Questions. PMID- 29159474 TI - Two rare cases of abdominal tumor in children: Answers. PMID- 29159475 TI - Correction to: A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men. AB - The article [A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men]. PMID- 29159472 TI - Current strategies to predict and manage sequelae of posterior urethral valves in children. AB - Posterior urethral valves (PUV) constitute a significant urological cause of chronic kidney disease (CKD) in children. The condition is characterised by the unique pathophysiology of the evolution of bladder dysfunction after relief of obstruction, which contributes to CKD. Improvements in prenatal diagnosis followed by selective foetal intervention have not yet produced improvement in long-term renal outcomes, although better patient selection may alter this in the future. Proactive management with surveillance, pharmacotherapy, timed voiding, double voiding, and/or assisted bladder-emptying, is being increasingly offered to those with severe bladder dysfunction and has the potential of reducing the burden of renal disease. Clinicians are currently able to counsel regarding the prognosis using serum creatinine and other emerging markers. However, much of this work remains to be validated. Satisfactory graft survival rates are now reported with aggressive management of bladder dysfunction in children who are candidates for renal transplantation. Knowledge gaps exist in identifying early markers of renal injury, risk stratification, and in understanding patient and carer perspectives in PUV. PMID- 29159476 TI - The impact of skeletal muscle on the pharmacokinetics and toxicity of 5 fluorouracil in colorectal cancer. AB - PURPOSE: Great heterogeneity exists in the ability of adults with cancer to tolerate chemotherapy. Variability in body composition may affect rates of metabolism of cytotoxic agents and contribute to the variable chemotherapy toxicity observed. The objective of this exploratory study was to examine the association of low skeletal muscle, commonly known as sarcopenia, on the pharmacokinetics (PKs) of 5-fluorouracil (5FU) in patients receiving FOLFOX for colorectal cancer. METHODS: We performed a secondary analysis of a completed multicenter trial that investigated PK-guided 5FU dosing in patients receiving mFOLFOX6 +/- bevacizumab for colorectal cancer. Cycle 1 PK samples were obtained 2-44 h after the start of the 5FU infusion (steady state). RESULTS: No significant differences in first cycle 5FU area-under-the-concentration-time curve (AUC) were found between sarcopenic and non-sarcopenic patients (17.3 vs. 19.3 AUC, p = 0.43). Patients with grade 3/4 toxicity had a higher dose of 5FU per kg lean body mass (LBM) (105 vs. 93 mg/kg, p = 0.06), most notably for hematological toxicities (110 vs. 94 mg/kg, p = 0.002); however, no correlation between the dose/LBM and 5FU AUC was found. CONCLUSIONS: Although our results did not confirm the impact of low skeletal muscle on PKs of 5FU, further research exploring the impact of body composition on chemotherapy PKs and related toxicities is warranted with the potential for alternative dosing strategies in sarcopenic patients to reduce unnecessary toxicities while maintaining efficacy. PMID- 29159477 TI - Factors Influencing Uptake of Sylvatic Plague Vaccine Baits by Prairie Dogs. AB - Sylvatic plague vaccine (SPV) is a virally vectored bait-delivered vaccine expressing Yersinia pestis antigens that can protect prairie dogs (Cynomys spp.) from plague and has potential utility as a management tool. In a large-scale 3 year field trial, SPV-laden baits containing the biomarker rhodamine B (used to determine bait consumption) were distributed annually at a rate of approximately 100-125 baits/hectare along transects at 58 plots encompassing the geographic ranges of four species of prairie dogs. We assessed site- and individual-level factors related to bait uptake in prairie dogs to determine which were associated with bait uptake rates. Overall bait uptake for 7820 prairie dogs sampled was 70% (95% C.I. 69.9-72.0). Factors influencing bait uptake rates by prairie dogs varied by species, however, in general, heavier animals had greater bait uptake rates. Vegetation quality and day of baiting influenced this relationship for black-tailed, Gunnison's, and Utah prairie dogs. For these species, baiting later in the season, when normalized difference vegetation indices (a measure of green vegetation density) are lower, improves bait uptake by smaller animals. Consideration of these factors can aid in the development of species-specific SPV baiting strategies that maximize bait uptake and subsequent immunization of prairie dogs against plague. PMID- 29159479 TI - Operative treatment of pelvic apophyseal avulsions in adolescent and young adult athletes: a follow-up study. AB - INTRODUCTION: Pelvic apophyseal avulsion can limit young athletes' performance for months and may result in permanent disability. Nonoperative treatment is most commonly preferred, while surgical management with reduction and fixation is reserved for selected cases. Our aim was to evaluate outcomes of operative management of pelvic apophyseal avulsions in a series of adolescents and young adult athletes. MATERIALS AND METHODS: Operative room registries and medical records were reviewed to identify patients who received surgical treatment for pelvic apophyseal avulsions who were younger than 24 years and with a minimum of 12 month follow-up. RESULTS: Thirty-two patients (16.8 years +/- 2.6) were identified. The most common avulsion sites were anterior inferior iliac spine (34.4%, N = 11) and ischial tuberosity (34.4%, N = 11). Other avulsions were five cases (15.6%) of the pubic apophysis, four cases (12.5%) of the anterior superior iliac spine apophysis and one case of the iliac crest apophysis. Seventeen cases (53.1%) underwent surgery early, i.e., during the first 3 months after the acute injury. Twenty-two cases (68.8%) involved reduction with internal fixation, and six cases (18.8%) involved resection of the fragment. Twenty-six athletes (81.3%, N = 26) reported good outcomes and were able to return to preinjury sports level. Six patients (18.8%) had moderate outcome and reported activity limitations during high-level sports. Large displacement (> 20 mm) or delayed (> 3 months) surgery was not associated with inferior outcomes (P = 0.690 and P = 0.392, respectively). Injury side (P = 0.61) or gender (P = 0.345) did not affect outcomes. CONCLUSIONS: Operative management of pelvic apophyseal avulsion results in return to the preinjury sports level in more than 80% of the cases. However, while both acute surgery for large displacement and delayed intervention for failed nonoperative treatment are generally successful in improving sports function in these cases, comparative studies are required to refine criteria for surgery. LEVEL OF EVIDENCE: Case series, IV. PMID- 29159480 TI - Electrochemical behavior and in-vitro antimicrobial screening of some thienylazoaryls dyes. AB - BACKGROUND: A series of recently reported phenolic azo dyes 7a-e were prepared by coupling the thienyl diazonium sulfate of 3-Amino-4H-benzo[f]thieno[3,4 c](2H)chromen-4-one with selected diversely substituted phenolic and naphtholic derivatives. These compounds were evaluated for their antibacterial and antifungal activities. Furthermore their voltammetric behavior was compared at a glassy carbon electrode. RESULTS: The voltammetric behavior of the five recently reported azo dyes has been compared at a glassy carbon electrode. It is shown that the azo dyes 7a-e with a hydroxyl group in the ortho position with respect to the azo bridge give rise to well defined, irreversible peaks for the oxidation and reduction process within a pH range of 2-7. The mechanisms of electrochemical oxidation of compound 7a-c and 7e are proposed. For the hydroxyl-substituted dyes, re-oxidation peaks were obtained in the subsequent scan. The antimicrobial activities of the reported compounds 7a-e along with the entire precursors 1-4 and 6a-e were performed against selected bacterial and fungal species and their activities compared to those of nystatin, griseofulvin and ciprofloxacin used as reference drugs. CONCLUSIONS: The present study showed significant antimicrobial activity of compounds 6d, 7a and 7c,e against the tested microorganisms; this result confirms the antimicrobial potency of azo compounds and some of their precursors. PMID- 29159481 TI - Effects of Multi-Component Mixtures from Sewage Treatment Plant Effluent on Common Carp (Cyprinus carpio) under Fully Realistic Condition. AB - This study characterized changes in biomarker responses in common carp (Cyprinus carpio) upon exposure to effluent water discharged from a sewage treatment plant (STP) under real conditions. Fish were exposed to contamination in Cezarka pond, which receives all of its water input from the STP in the town of Vodnany, Czech Republic. Five sampling events were performed at day 0, 30, 90, 180, and 360 starting in April 2015. In total, 62 pharmaceutical and personal care products (PPCPs) were detected in the polar organic chemical integrative sampler. Compared to a control pond, the total concentration of PPCPs was 45, 16, 7, and 7 times higher in Cezarka pond at day 30, 90, 180, and 360, respectively. The result of oxidative stress and antioxidant enzyme biomarkers indicated alterations in the liver and intestine tissues of fish from Cezarka pond at day 30 and 360, respectively. High plasma vitellogenin levels were observed in both exposed females (180 and 360 days) and males (360 days) compared with their respective controls. However, only exposed female fish had higher vitellogenin mRNA expression than the control fish in these periods. Exposed female fish showed irregular structure of the ovary with scattered oocytes, which further developed to a vitellogenic stage at day 360. Low white blood cell levels were indicated in all exposed fish. Despite numerous alterations in exposed fish, favorable ecological conditions including high availability of food resulted in a better overall condition of the exposed fish after 1 year of exposure compared to the controls. PMID- 29159482 TI - Characterizing the Breadth and Depth of Volunteer Water Monitoring Programs in the United States. AB - A survey of 345 volunteer water monitoring programs in the United States was conducted to document their characteristics, and perceived level of support for data to inform natural resource management or policy decisions. The response rate of 86% provided information from 46 states. Programs represented a range of ages, budgets, objectives, scopes, and level of quality assurance, which influenced data uses and perceived support by sponsoring agency administrators and external decision makers. Most programs focused on rivers, streams, and lakes. Programs had not made substantial progress to develop EPA or state-approved quality assurance plans since 1998, with only 48% reporting such plans. Program coordinators reported feeling slightly more support for data to be used for management as compared to policy decisions. Programs with smaller budgets may be at particular risk of being perceived to lack credibility due to failure to develop quality assurance plans. Over half of programs identified as collaborative, in that volunteers assisted scientists in program design, data analysis and/or dissemination of results. Just under a third were contributory, in which volunteers primarily collected data in a scientist-defined program. Recommendations to improve perceived data credibility, and to augment limited budgets include developing quality assurance plans and gaining agency approval, and developing partnerships with other organizations conducting monitoring in the area to share resources and knowledge. Funding agencies should support development of quality assurance plans to help ensure data credibility. Service providers can aid in plan development by providing training to program staff over time to address high staff turnover rates. PMID- 29159483 TI - Obestatin can potentially differentiate Wharton's jelly mesenchymal stem cells into insulin-producing cells. AB - In vitro-generation of beta-cells from Wharton's jelly mesenchymal stem cells (WJ MSCs) could provide a potential basis for diabetes mellitus cell therapy. However, the generation of functional insulin-producing cells (IPCs) from WJ-MSCs remains a challenge. Recently, obestatin, a gut hormone, was found to promote beta-cell generation from pancreatic precursor cells. Accordingly, we hypothesize that obestatin can induce the differentiation of WJ-MSCs into IPCs. Therefore, the purpose of the current study is to examine the ability of obestatin to generate IPCs in comparison to well-known extrinsic factors that are commonly used in IPCs differentiation protocols from MSCs, namely exendin-4 and glucagon like peptide-1 (GLP-1). To achieve our aims, WJ-MSCs were isolated, cultured and characterized by immunophenotyping and adipocytes differentiation. Afterwards, WJ MSCs were induced to differentiate into IPCs using two differentiation protocols incorporating either exendin-4, GLP-1 or obestatin. The pancreatic progenitor marker, nestin and beta-cell differentiation markers were assessed by qRT-PCR, while the functionality of the generated IPCs was assessed by glucose-stimulated insulin secretion (GSIS). Our results showed that WJ-MSCs exhibit all the characteristics of MSCs. Interestingly, using obestatin in both the short and long differentiation protocols managed to induce the expression of beta-cell markers, similar to exendin-4. In GSIS, IPCs generated using either GLP-1 or obestatin showed higher secretion of insulin as compared to those generated using exendin-4 under low-glucose conditions but failed to show a significant response to increased glucose. These results indicate obestatin can be considered as a novel potential factor to consider for generation of IPCs from WJ-MSCs. PMID- 29159484 TI - Correction to: Laminin-derived Ile-Lys-Val-ala-Val: a promising bioactive peptide in neural tissue engineering in traumatic brain injury. AB - There is only one problem with Table 3. The references mentioned in this table were wrong in the final proof. PMID- 29159485 TI - Beriberi Outbreak Among Unauthorised Immigrants in a Detention Camp in Malaysia. AB - In February 2012, a district health authority received three inmates with bilateral leg swelling and difficulty in breathing from a detention camp for unauthorized immigrants. A case control study was conducted. Fasting blood samples of case and control groups were collected according to instructions of the laboratory for determining thiamine level, and their 1 week dietary intake was analyzed. 9% (21/226) of inmates had bilateral leg swelling, and 75% (6/8) of them had low thiamine level (< 66 mmol/L). Their diet contained mainly polished rice and other items with low thiamine contents. Bilateral leg swelling was associated with history of no meat consumption during past 3 months (OR 8.4; CI 2.2-32.1). Patients were treated with 100 mg thiamine intravenously and 5 mg orally per day for 6 weeks. All patients responded well. The management was advised to provide vitamin B complex daily, and encouraged to provide thiamine rich foods. PMID- 29159486 TI - Program Components of Psychosocial Interventions in Foster and Kinship Care: A Systematic Review. AB - Foster children frequently experience early trauma that significantly impacts their neurobiological, psychological and social development. This systematic review examines the comparative effectiveness of foster and kinship care interventions. It examines the components within each intervention, exploring their potential to benefit child and carer well-being, particularly focussing on child behaviour problems, and relational functioning. Systematic searches of electronic databases included PsycINFO, MEDLINE, Web of Science Core Collection, the Cochrane Collaborations Register of Controlled Trials (CENTRAL) and Scopus to identify randomised or quasi-randomised trials of psychosocial foster/kinship care interventions, published between 1990 and 2016. Seventeen studies describing 14 interventions were included. Eleven studies reported comparative benefit compared to control. Overall, effective interventions had clearly defined aims, targeted specific domains and developmental stages, provided coaching or role play, and were developed to ameliorate the effects of maltreatment and relationship disruption. Interventions effective in reducing behaviour problems included consistent discipline and positive reinforcement components, trauma psychoeducation, problem-solving and parent-related components. Interventions effective in improving parent-child relationships included components focussed on developing empathic, sensitive and attuned parental responses to children's needs. Given the prevalence of both behaviour problems and relational difficulties in foster families, targeting these needs is essential. However, interventions have tended to measure outcomes in either behavioural or relational terms. A more coordinated and collaborative research approach would provide a better understanding of the association between parent-child relationships and child behaviour problems. This would allow us to develop, deliver and evaluate programs that combine these components more effectively. Protocol Registration Number: PROSPERO CRD42016048411. PMID- 29159487 TI - Management of cardiopulmonary assist devices in critically ill patients using point-of-care transthoracic echocardiography: a case series. AB - Point-of-care transthoracic echocardiography is increasingly being utilized by the intensive care physicians in the management of hemodynamically unstable patients. However, its use in the management of critically ill patients requiring cardiopulmonary mechanical device support remains to be well described. In this case series, we present two case reports where point-of-care echocardiography was successfully used by the intensive care team in diagnosing and managing problems related to cardiopulmonary assist device malposition. PMID- 29159488 TI - Inter-rater reliability of STOPPFrail [Screening Tool of Older Persons Prescriptions in Frail adults with limited life expectancy] criteria amongst 12 physicians. AB - PURPOSE: STOPPFrail is an explicit tool, developed by Delphi consensus, to assist physicians with deprescribing medications in frail older adults with poor survival prognosis. This study aimed to determine the inter-rater reliability (IRR), amongst physicians, of STOPPFrail application. METHODS: Twenty clinical cases were collated to represent frail older patients. Eighteen cases met STOPPFrail inclusion criteria. They had a mean age of 79.5 (SD6) years and a median of 7 (IQR6-8.25) comorbidities and were prescribed a median of 9 (IQR7.75 11.25) medications. Two of the STOPPFrail originators reached complete agreement (gold standard) in determining 91 of 165 medications (55.2%) as inappropriate. Twelve physicians (6 geriatricians, 3 general practitioners and 3 palliative care physicians) independently applied STOPPFrail criteria. IRR between physicians and gold standard (GS) assessment was determined using Cohen's kappa statistic. RESULTS: Eighteen of the 20 cases that met STOPPFrail inclusion criteria were correctly identified by 9 of 12 physicians (75%). The average time taken per clinical case was 2.7 (SD0.94) minutes. The kappa co-efficient between physicians and GS assessment ranged from 0.71 (substantial) to 0.86 (good), with a mean kappa value of 0.758 (SD0.059). The Fleiss kappa coefficients between GS assessment and geriatricians, GPs and palliative care physicians were 0.80 (SD0.6), 0.77 (SD0.9) and 0.75 (SD0.1), respectively. No significant difference was noted, between groups or between participants within groups, as determined by one-way ANOVA, (df (2, 9) = 0.712, p = 0.516). CONCLUSIONS: IRR of STOPPFrail criteria between physicians, practising in different specialties, is substantial, despite no prior knowledge of the criteria. PMID- 29159489 TI - In response to: "Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning". PMID- 29159490 TI - [Prewarming according to the AWMF S3 guidelines on preventing inadvertant perioperative hypothermia 2014 : Retrospective analysis of 7786 patients]. AB - BACKGROUND: Inadvertent perioperative hypothermia, which is defined as a core body temperature of less than 36.0 degrees C, can have serious consequences in surgery patients. These include cardiac complications, increased blood loss, wound infections and postoperative shivering; therefore, the scientific evidence that inadvertent perioperative hypothermia should be avoided is undisputed and several national guidelines have been published summarizing the scientific evidence and recommending specific procedures. The German AWMF guidelines were the first to emphasize the importance of prewarming for surgery patients to avoid inadvertant perioperative hypothermia; however, in contrast to intraoperative warming, prewarming is so far not sufficiently implemented in clinical practice in many hospitals. Furthermore, a recent study has questioned the effectiveness of prewarming. OBJECTIVE: The aim of this retrospective investigation was to evaluate the hypothermia rates that can be achieved when prewarming in the anesthesia induction room is introduced into the clinical practice and performed in addition to intraoperative warming. MATERIAL AND METHODS: The ethics committee of the Medical Faculty of the Martin Luther University Halle Wittenberg gave approval for data storage and retrospective data analysis from the anesthesia database. According to the existing local standard operating procedure, prewarming with forced air was performed in addition to intraoperative warming in the anesthesia induction room in 3899 patients receiving general anesthesia with a duration of 30 min or longer from January 2015 to December 2016. The results were compared with a control group of 3887 patients from July 2012 to August 2014 who received intraoperative warming but were not subjected to prewarming. Tracheal intubation was carried out in all patients and temperature measurements after the induction of anesthesia were performed using esophageal, urinary catheter or intra-arterial temperature probes. RESULTS: The mean duration of prewarming was 25 min in the treatment group. Patients subjected to prewarming showed an intraoperative hypothermia rate of 15.8% and a postoperative hypothermia rate of 5.1%. Patients without prewarming showed an intraoperative hypothermia rate of 30.4% and a postoperative hypothermia rate of 12.4%. This means a 52% reduction of the intraoperative hypothermia rate and a 41% reduction of the postoperative hypothermia rate for patients who received prewarmimg (p < 0.0001). Multivariate logistic regression revealed that the lack of prewarming was independently associated with intraoperative hypothermia with an odds ratio of 2.5 (95% confidence interval CI 2.250-2.841; p < 0.0001) and postoperative hypothermia with an odds ratio of 2.8 (95% CI 2.316-3.277; p < 0.0001). CONCLUSION: Prewarming, as recommended in the AWMF guidelines, resulted in a significant and clinically relevant reduction in the incidence of inadvertent perioperative hypothermia; therefore, prewarming can still be regarded as an effective method to avoid perioperative hypothermia. Hypothermia rates of 15.8% intraoperatively and 5.1% postoperatively can be achieved in clinical practice, when prewarming is performed in addition to intraoperative warming in the anesthesia induction room directly before the start of surgical procedures. PMID- 29159491 TI - [Algorithm for securing an unexpected difficult airway : User analysis on a simulator]. AB - BACKGROUND: Critical incidents in difficult airway management are still a main contributory factor for perioperative morbidity and mortality. Many national associations have developed algorithms for management of these time critical events. For implementation of these algorithms the provision of technical requirements and procedure-related training are essential. Severe airway incidents are rare events and clinical experience of the individual operators is limited; therefore, simulation is an adequate instrument for training and evaluating difficult airway algorithms. OBJECTIVE: The aim of this observational study was to evaluate the application of the institutional difficult airway algorithm among anesthetists. MATERIAL AND METHODS: After ethics committee approval, anesthetists were observed while treating a "cannot intubate" (CI) and a "cannot intubate, cannot ventilate" (CICV) situation in the institutional simulation center. As leader of a supportive team the participants had to deal with an unexpected difficult airway after induction of anesthesia in a patient simulator. The following data were recorded: sequence of the applied airway instruments, time to ventilation after establishing a secured airway using any instrument in the CI situation and time to ventilation via cricothyrotomy in the CICV situation. Conformity to the algorithm was defined by the sequence of the applied instruments. Analysis comprised conformity to the algorithm, non parametric tests for time to ventilation and differences between junior and senior anesthetists. RESULTS: Out of 50 participants 45 were analyzed in the CI situation. In this situation 93% of the participants acted in conformity with the algorithm. In 62% the airway was secured by flexible intubation endoscopy, in 38% with another device. Data from 46 participants were analyzed in the CICV situation. In this situation 91% acted in conformity with the algorithm. The last device used prior to the decision for cricothyrotomy was flexible intubation endoscopy in 39%, a laryngeal mask in 22% and other instruments in 39%. Of the 50 participants 38 had already been institutionally trained in difficult airway management during the previous 2 years. For cricothyrotomy the participants needed a median time of 63 s and there was no difference between junior and senior anesthetists (p = 0.46). The cricothyrotomy was performed faster using a surgical approach than a transtracheal puncture approach using a Melker emergency cricothyrotomy set (52 s vs. 73 s, p = 0.014). CONCLUSION: The conformity to the algorithm of over 90% indicates a good training level of the participants concerning the difficult airway algorithm. In the observed sample flexible intubation endoscopy tended to be of high significance even in the unanticipated difficult airway. Cricothyrotomy was performed faster surgically than by the use of the transtracheal puncture approach, while no differences between junior and senior anesthetists were observed. For the successful management of an unexpected difficult airway, specific training of these special and rare events is crucial. A standardized provision of special airway instruments stored in a special trolley and frequent application of this trolley in the clinical routine is recommended. PMID- 29159492 TI - Blood pressure variability in primary hyperparathyroidism: more data needed. PMID- 29159493 TI - The Intestinal Microbiota of Tadpoles Differs from Those of Syntopic Aquatic Invertebrates. AB - Bacterial communities associated to eukaryotes play important roles in the physiology, development, and health of their hosts. Here, we examine the intestinal microbiota in tadpoles and aquatic invertebrates (insects and gastropods) to better understand the degree of specialization in the tadpole microbiotas. Samples were collected at the same time in one pond, and the V4 region of the bacterial 16S rRNA gene was sequenced with Illumina amplicon sequencing. We found that bacterial richness and diversity were highest in two studied snail individuals, intermediate in tadpoles, and lowest in the four groups of aquatic insects. All groups had substantial numbers of exclusive bacterial operational taxonomic units (OTUs) in their guts, but also shared a high proportion of OTUs, probably corresponding to transient environmental bacteria. Significant differences were found for all pairwise comparisons of tadpoles and snails with the major groups of insects, but not among insect groups or between snails and tadpoles. The similarity between tadpoles and snails may be related to similar feeding mode as both snails and tadpoles scratch biofilms and algae from surfaces; however, this requires confirmation due to low sample sizes. Overall, the gut microbiota differences found among syntopic aquatic animals are likely shaped by both food preferences and host identity. PMID- 29159495 TI - Lifetime Trauma and Depressive Symptomatology Among Older American Indians: The Native Elder Care Study. AB - We examined the association between lifetime traumatic events with or without trauma response symptoms and depressive symptomatology in American Indians aged >= 55 years from a tribe in the Southeastern US (N = 362). Twenty-three percent of the sample experienced a traumatic event without trauma-response symptoms, whereas 14% experienced a traumatic event with at least one trauma-response symptom. After adjustment for sociodemographic characteristics and social support, participants who experienced a traumatic event with one or more trauma response symptoms had higher odds of clinically relevant depressive symptomatology compared to (1) those who never experienced a traumatic event [odds ratio (OR) 3.2, p < 0.05], (2) and those who experienced a traumatic event without further symptoms (OR 3.7, p < 0.05). Our results suggest that mental health providers who serve older American Indians should consider the experience of traumatic events followed with response symptoms as a potential risk factor for further disruptions in psychological functioning. PMID- 29159494 TI - The nucleocapsid protein of hantaviruses: much more than a genome-wrapping protein. AB - The nucleocapsid (N) protein of hantaviruses represents an impressive example of a viral multifunctional protein. It encompasses properties as diverse as genome packaging, RNA chaperoning, intracellular protein transport, DNA degradation, intervention in host translation, and restricting host immune responses. These functions all rely on the capability of N to interact with RNA and other viral and cellular proteins. We have compiled data on the N protein of different hantavirus species together with information of the recently published three dimensional structural data of the protein. The array of diverse functional activities accommodated in the hantaviral N protein goes far beyond to be a static structural protein and makes it an interesting target in the development of antiviral therapeutics. PMID- 29159496 TI - A Comparison of Vocational Engagement Among Young People with Psychosis, Depression and Borderline Personality Pathology. AB - Poor vocational engagement is well documented among young people experiencing first-episode psychosis (FEP). The aim of the present study was to establish and compare rates of vocational engagement across young people with first-episode psychosis, depression, and borderline personality pathology. A file audit was used to collect vocational data of young people aged 15-25 entering tertiary mental health treatment in 2011. Rates of vocational engagement were similar across groups, indicating that like those with FEP, young people with depression and borderline personality pathology experience impaired vocational engagement and are in need of targeted vocational interventions. Post hoc analysis indicated that that the depression group had significantly more people who were partially vocationally engaged compared with the psychosis group, suggesting that vocational interventions might need to be targeted differently across different diagnostic groups. Future research should explore risk factors for vocational disengagement across diagnostic groups in order to inform intervention development. PMID- 29159497 TI - Correction to: Superior biomechanical properties and tying time with the modified Prusik knot and Wittstein suture loop to the Krackow stitch. AB - Due to an error during the production process, the legend. PMID- 29159498 TI - Pooled analysis of the reports of carfilzomib/ixazomib combinations for relapsed/refractory multiple myeloma. AB - We sought to evaluate the activity and safety of carfilzomib-/ixazomib-containing combinations for patients with relapsed/refractory multiple myeloma (RRMM). We searched published reports including carfilzomib-/ixazomib-containing combinations for RRMM. Finally, we identified 11 prospective studies covering 2845 relapsed/refractory patients. Carfilzomib- and ixazomib-containing combinations respectively resulted in an impressive overall response rate (ORR 77 vs. 64%, P = 0.14), very good partial response or better (>= VGPR 48 vs. 21%, P = 0.001), complete response or better (>= CR 14 vs. 7%, P = 0.23), and clinical benefit rate (CBR 84 vs. 59%, P = 0.0002). Subgroup analysis showed that the carfilzomib (CFZ) +lenalidomide (LEN) + dexamethasone (DEX) triplet regimen resulted into similar response outcomes to those from CFZ + DEX doublet regimen in ORR (77 vs. 78%, P = 0.91), >=VGPR (50 vs. 53%, P = 0.84), and >= CR (13 vs. 12%, P = 0.96) analysis in these previously heavily pretreated population. And, there were no statistically significant differences between IXA + LEN + DEX triplet regimen and CFZ + LEN + DEX triplet regimen in ORR (85 vs. 78%, P = 0.55), >= VGPR (37 vs. 53%, P = 0.19), and >= CR (18 vs. 12%, P = 0.70) analysis. There were favorable trend towards proteasome inhibitors (PIs) + IMiDs + DEX in comparison with PIs + alkylating agent + Dex in ORR (79 vs 49%, P < 0.00001), >= VGPR analysis (36 vs. 16%, P = 0.008), and >= CR (16 vs. 3%, P < 0.00001). Compared with current standard chemotherapy, carfilzomib containing combinations clearly improved overall survival (HR, 0.79; P = 0.01), progression free survival (HR, 0.61; P = 0.0001). Carfilzomib-/ixazomib-containing combinations produced clinical benefit for patients with R/RMM. PIs + IMiDs + DEX triplet regimens could be good options for such relapsed/refractory patients. PMID- 29159499 TI - Redistribution of cell cycle by arsenic trioxide is associated with demethylation and expression changes of cell cycle related genes in acute promyelocytic leukemia cell line (NB4). AB - PML-RARalpha perturbs the normal epigenetic setting, which is essential to oncogenic transformation in acute promyelocytic leukemia (APL). Transcription induction and recruitment of DNA methyltransferases (DNMTs) by PML-RARalpha and subsequent hypermethylation are components of this perturbation. Arsenic trioxide (ATO), an important drug in APL therapy, concurrent with degradation of PML RARalpha induces cell cycle change and apoptosis. How ATO causes cell cycle alteration has remained largely unexplained. Here, we investigated DNA methylation patterns of cell cycle regulatory genes promoters, the effects of ATO on the methylated genes and cell cycle distribution in an APL cell line, NB4. Analysis of promoter methylation status of 22 cell cycle related genes in NB4 revealed that CCND1, CCNE1, CCNF, CDKN1A, GADD45alpha, and RBL1 genes were methylated 60.7, 84.6, 58.6, 8.7, 33.4, and 73.7%, respectively, that after treatment with 2 MUM ATO for 48 h, turn into 0.6, 13.8, 0.1, 6.6, 10.7, and 54.5% methylated. ATO significantly reduced the expression of DNMT1, 3A, and 3B. ATO induced the expression of CCND1, CCNE1, and GADD45alpha genes, suppressed the expression of CCNF and CDKN1A genes, which were consistent with decreased number of cells in G1 and S phases and increased number of cells in G2/M phase. In conclusion, demethylation and alteration in the expression level of the cell cycle related genes may be possible mechanisms in ATO-induced cell cycle arrest in APL cells. It may suggest that ATO by demethylation of CCND1 and CCNE1 and their transcriptional activation accelerates G1 and S transition into the G2/M cell cycle arrest. PMID- 29159500 TI - Comparative analysis of molecular activity in dermal mesenchymal stem cells from different passages. AB - Mesenchymal stem cells (MSCs) are used for tissue regeneration in several pathological conditions, including autoimmune diseases. However, the optimal sources and culture requirements for these cells are still under investigation. Here, we compared mRNA expression in dermal MSCs (DMSCs) at passage (P) 3 and P5 to provide a reference for future studies related to DMSCs expansion. In normal DMSCs, the expression of three of eight genes associated with basic cellular activity were different at P5 compared to that at P3: PLCB4 and SYTL2 were upregulated by 4.30- and 6.42-fold, respectively (P < 0.05), whereas SATB2 was downregulated by 39.25-fold (P < 0.05). At the same time, genes associated with proliferation, differentiation, inflammation, and apoptosis were expressed at similar levels at P3 and P5 (P > 0.05). In contrast, in DMSCs isolated from psoriatic patients we observed differential expression of three inflammation associated genes at P5 compared to P3; thus IL6, IL8, and CXCL6 mRNA levels were upregulated by 16.02-, 31.15-, and 15.04-fold, respectively. Our results indicate that normal and psoriatic DMSCs showed different expression patterns for genes related to inflammation and basic cell activity at P3 and P5, whereas those for genes linked to proliferation, differentiation, and apoptosis were mostly similar. PMID- 29159501 TI - A fundamental study of photoluminescence modulation from DNA-wrapped single walled carbon nanotubes. AB - In this study, we investigated the interaction of base sequence-assigned single stranded DNA (ssDNA) molecules with the surfaces of single-walled carbon nanotube (SWNT)-thymine (T30)/cytosine (C30) hybrids (T30/C30-SWNT), by measuring the modulation of near-infrared (NIR) photoluminescence (PL). Significant PL shifts were observed when T30/C30-SWNTs were reacted with 30-mers of adenine (A30)/guanine (G30). In contrast, when non-complementary ssDNA was used, no significant energy shift was observed in the PL modulation except when T30-SWNTs were reacted with G30. Furthermore, atomic force microscopy (AFM) measurements revealed that the average heights of the T30-SWNTs and C30-SWNTs, after reaction with A30 were 2 +/- 0.6 and 1.1 +/- 0.3 nm, respectively. This result was in good agreement with the results of PL measurements. Our data reveal that DNA hybridization could be detected by measuring PL from SWNTs, without the use of fluorescent molecules. This leads to the possibility of developing nanotube-based photoelectric conversion or optical switch devices driven by organic molecules. PMID- 29159502 TI - Antifungal activity of Myrtus communis against Malassezia sp. isolated from the skin of patients with pityriasis versicolor. AB - The increasing incidence of fungal infections and antifungal resistance has prompted the search for novel antifungal drugs and alternative agents. We explored the antifungal activity of Myrtus communis essential oil (EO) against Malassezia sp. isolated from the skin of patients with pityriasis versicolor. These broad-spectrum antimicrobial activities of M. communis EO and its potent inhibiting activity on Malassezia growth deserve further research with aim to considerate this EO as candidate for topical use in treatment of skin diseases. PMID- 29159503 TI - Discovering the individual brain: brain stimulation in psychiatry : Editorial I to the supplement from the 2nd European conference on brain stimulation in psychiatry. PMID- 29159504 TI - There is no magic in speaker policies: creating gender equality at brain stimulation conferences : Editorial II to the supplement from the 2nd European Conference on brain stimulation in psychiatry. PMID- 29159505 TI - Biochemical stress evaluation after medial parapatellar and subvastus approach in total knee replacement. AB - INTRODUCTION: Even if different surgical approaches for total knee arthroplasty are well known since decades, the standard medial parapatellar incision remains the most common one; general agreement about significant advantages with minimally invasive techniques is lacking. Furthermore, the surgical stress effect on the organism has always been analyzed through blood inflammatory parameters. This study aim was to compare the standard and subvastus approaches, using the salivary cortisol in particular as measure for systemic surgery-related stress. METHODS: Fifteen operations were performed in a consecutive series; clinical (Knee Society Knee Scoring System., a questionnaire score, range of motion, tourniquet time, intra-operative bleeding) and biochemical factors (salivary and hematic cortisol, C-reactive protein, muscular creatine phosphokinase levels) were evaluated. The final follow-up was at two months after the operation. RESULTS: No significant differences were observed in most of the parameters; however, the subvastus group had a sharper and earlier functional improvement trend than the standard one. On the other side, it increased the CPK levels significantly. CONCLUSIONS: In our experience, the medial subvastus approach, firstly associated with greater surgical stress, has then been characterized by a more favorable functional improvement trend. Moreover, the salivary cortisol measurement has proved to be a non-invasive and reliable method to evaluate the systemic surgery-related stress. PMID- 29159507 TI - STAT3 as a common signal of ischemic conditioning: a lesson on "rigor and reproducibility" in preclinical studies on cardioprotection. AB - Ischemic conditioning before (ischemic preconditioning, IPC) or after (ischemic postconditioning, POCO) sustained myocardial ischemia/reperfusion (I/R), induced locally or remotely from the heart (remote IPC, RIPC), reduces infarct size. However, none of the identified signaling steps of ischemic conditioning was robust across models and species to be successfully translated to humans. In prior separate studies in pigs, activation of signal transducer and activator of transcription 3 (STAT3) was causal for infarct size reduction by IPC, POCO, and RIPC but it remains unclear whether or not STAT3 is truly a common denominator of cardioprotective signaling. We therefore, now analyzed the phosphorylation of STAT3 and other signaling proteins in left ventricular biopsies from our prior studies on IPC, POCO and RIPC in one approach. We developed a strategy for the quantification of protein phosphorylation in multiple samples from many experiments on different gels/membranes by Western blot. Along with reduced infarct size, the ratio of STAT3tyr705 phosphorylation/total STAT3 protein at early reperfusion was significantly increased by IPC (IPC 2.0 +/- 0.3 vs. I/R 1.2 +/- 0.2 arbitrary units), but only trendwise by POCO and RIPC (1.3 +/- 0.2; 1.4 +/- 0.2 arbitrary units); storage time for IPC samples was shorter than for POCO and RIPC samples. No other signaling protein phosphorylation was associated with reduced infarct size. We confirmed STAT3 phosphorylation with IPC. For POCO and RIPC we could not reproduce the findings from our earlier more focused studies. At this point, we can not distinguish between lack of robustness of the biological signal and methodological issues of our retrospective approach. PMID- 29159506 TI - A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk. AB - DNA methylation (DNAm) has been found to show robust and widespread age-related changes across the genome. DNAm profiles from whole blood can be used to predict human aging rates with great accuracy. We sought to test whether DNAm-based predictions of age are related to phenotypes associated with type 2 diabetes (T2D), with the goal of identifying risk factors potentially mediated by DNAm. Our participants were 43 women enrolled in the Women's Health Initiative. We obtained methylation data via the Illumina 450K Methylation array on whole blood samples from participants at three timepoints, covering on average 16 years per participant. We employed the method and software of Horvath, which uses DNAm at 353 CpGs to form a DNAm-based estimate of chronological age. We then calculated the epigenetic age acceleration, or Deltaage, at each timepoint. We fit linear mixed models to characterize how Deltaage contributed to a longitudinal model of aging and diabetes-related phenotypes and risk factors. For most participants, Deltaage remained constant, indicating that age acceleration is generally stable over time. We found that Deltaage associated with body mass index (p = 0.0012), waist circumference (p = 0.033), and fasting glucose (p = 0.0073), with the relationship with BMI maintaining significance after correction for multiple testing. Replication in a larger cohort of 157 WHI participants spanning 3 years was unsuccessful, possibly due to the shorter time frame covered. Our results suggest that DNAm has the potential to act as a mediator between aging and diabetes-related phenotypes, or alternatively, may serve as a biomarker of these phenotypes. PMID- 29159508 TI - Comparative genomics and transcriptome analysis of Lactobacillus rhamnosus ATCC 11443 and the mutant strain SCT-10-10-60 with enhanced L-lactic acid production capacity. AB - Mechanisms for high L-lactic acid production remain unclear in many bacteria. Lactobacillus rhamnosus SCT-10-10-60 was previously obtained from L. rhamnosus ATCC 11443 via mutagenesis and showed improved L-lactic acid production. In this study, the genomes of strains SCT-10-10-60 and ATCC 11443 were sequenced. Both genomes are a circular chromosome, 2.99 Mb in length with a GC content of approximately 46.8%. Eight split genes were identified in strain SCT-10-10-60, including two LytR family transcriptional regulators, two Rex redox-sensing transcriptional repressors, and four ABC transporters. In total, 60 significantly up-regulated genes (log2fold-change >= 2) and 39 significantly down-regulated genes (log2fold-change <= - 2) were identified by a transcriptome comparison between strains SCT-10-10-60 and ATCC 11443. KEGG pathway enrichment analysis revealed that "pyruvate metabolism" was significantly different (P < 0.05) between the two strains. The split genes and the differentially expressed genes involved in the "pyruvate metabolism" pathway are probably responsible for the increased L-lactic acid production by SCT-10-10-60. The genome and transcriptome sequencing information and comparison of SCT-10-10-60 with ATCC 11443 provide insights into the anabolism of L-lactic acid and a reference for improving L lactic acid production using genetic engineering. PMID- 29159509 TI - The role of socio-demographic factors in depression and anxiety of patients on hemodialysis: an observational cross-sectional study. AB - PURPOSE: Depression and anxiety have high prevalence in patients on hemodialysis and are strongly associated with socio-economic factors. The aim of this study was to evaluate the prevalence of depression and anxiety in hemodialyzed patients in Greece and its association with socio-demographic factors. METHODS: Four hundred and fourteen (414) patients on hemodialysis (262 males and 152 females) from 24 dialysis centers in Greece participated in this observational cross sectional study. Mean age was 63.54 (54.06-72.41), and mean time of dialysis treatment was 36 (16-72) months. Depression and anxiety were assessed by the state-trait anxiety inventory (STAI), the beck depression inventory (BDI) and the hospital anxiety and depression scale (HADS). Multinomial logistic regression was performed to estimate the factors being independently associated with anxiety and depression levels (HADS scale). Multiple linear regression was performed to estimate the factors being independently associated with BDI and STAI. RESULTS: From a total of 414 participants, (29.4%, n = 122) had depression and 35.9% (n = 149) had anxiety. Depression and anxiety were significantly associated with females, low level of education, increased patients' age, retirement, poor financial situation, marital status and co-morbidities. CONCLUSION: The overall study findings indicated a significant correlation between the levels of anxiety and depression in patients on hemodialysis. Patients with high levels of anxiety had higher levels of depression and those with high depression scores had higher anxiety scores. PMID- 29159510 TI - Differences in sampling techniques on total post-mortem tryptase. AB - BACKGROUND: The measurement of mast cell tryptase is commonly used to support the diagnosis of anaphylaxis. In the post-mortem setting, the literature recommends sampling from peripheral blood sources (femoral blood) but does not specify the exact sampling technique. Sampling techniques vary between pathologists, and it is unclear whether different sampling techniques have any impact on post-mortem tryptase levels. AIM: The aim of this study is to compare the difference in femoral total post-mortem tryptase levels between two sampling techniques. METHODS: A 6-month retrospective study comparing femoral total post-mortem tryptase levels between (1) aspirating femoral vessels with a needle and syringe prior to evisceration and (2) femoral vein cut down during evisceration. RESULTS: Twenty cases were identified, with three cases excluded from analysis. There was a statistically significant difference (paired t test, p < 0.05) between mean post-mortem tryptase by aspiration (10.87 ug/L) and by cut down (14.15 ug/L). The mean difference between the two methods was 3.28 ug/L (median, 1.4 ug/L; min, - 6.1 ug/L; max, 16.5 ug/L; 95% CI, 0.001-6.564 ug/L). CONCLUSIONS: Femoral total post-mortem tryptase is significantly different, albeit by a small amount, between the two sampling methods. The clinical significance of this finding and what factors may contribute to it are unclear. When requesting post-mortem tryptase, the pathologist should consider documenting the exact blood collection site and method used for collection. In addition, blood samples acquired by different techniques should not be mixed together and should be analyzed separately if possible. PMID- 29159511 TI - Application of 3D models of palatal rugae to personal identification: hints at identification from 3D-3D superimposition techniques. AB - Palatal rugae are known in literature as individualizing anatomical structures with a strong potential for personal identification. However, a 3D assessment of their uniqueness has not yet been performed. The present study aims at verifying the uniqueness of 3D models of the palate. Twenty-six subjects were recruited among the orthodontic patients of a private dental office; from every patient, at least two dental casts were taken in different time periods, for a total of 62 casts. Dental casts were digitized by a 3D laser scanner (iSeries, Dental Wings(c), Montreal, Canada). The palatal area was identified, and a series of 250 superimpositions was then performed automatically through VAM(c)software in order to reach the minimum point-to point distance between two models. In 36 matches the models belonged to the same individual, whereas in 214 mismatches they came from different subjects. The RMS (root mean square) of point-to-point distances was then calculated by 3D software. Possible statistically significant differences were assessed through Mann-Whitney test (p < 0.05). Results showed a statistically significant difference in RMS mean point-to-point distance between matches (mean 0.26 mm; SD 0.12) and mismatches (mean 1.30; SD 0.44) (p < 0.0001).All matches reached an RMS value below 0.50 mm. This study first provided an assessment of uniqueness of palatal rugae, based on their anatomical 3D conformations, with consequent applications to personal identification. PMID- 29159512 TI - Cell sheet-based multilayered liver tumor models for anti-cancer drug screening. AB - OBJECTIVE: To fabricate in vitro cell-dense, three-dimensional (3D) tumor models by employing a cell sheet technology for testing anti-cancer drug efficacy. RESULTS: The stratified liver tumor models were fabricated by stacking contiguous HepG2 cell sheets. Triple-layer (3L), double-layer (2L), single-layer (1L) cell sheet-based liver tumor models (CSLTMs) demonstrated 106, 96, 85% cell viability, respectively, after 3 days treatment of 10 uM doxorubicin hydrochloride (DOX), while cell viability in two-dimensional (2D) conventional culture (control) was 27%. After 7 days of DOX treatment, the viabilities of 3L, 2L, 1L, control were 24, 14, 3 and 4%, respectively. Probable explanations were blocked diffusion of DOX by the intact and multilayered structure and also hypoxia in the bottom of multilayered cell sheets. CONCLUSION: CSLTMs showed a thickness-dependent cytotoxic efficacy of DOX and greater drug resistance than the control, thereby providing useful information toward the development of improved biomimetic tumor models. PMID- 29159513 TI - Molybdenum coated SU-8 microneedle electrodes for transcutaneous electrical nerve stimulation. AB - Electrophysiological devices are connected to the body through electrodes. In some applications, such as nerve stimulation, it is needed to minimally pierce the skin and reach the underneath layers to bypass the impedance of the first layer called stratum corneum. In this study, we have designed and fabricated surface microneedle electrodes for applications such as electrical peripheral nerve stimulation. We used molybdenum for microneedle fabrication, which is a biocompatible metal; it was used for the conductive layer of the needle array. To evaluate the performance of the fabricated electrodes, they were compared with the conventional surface electrodes in nerve conduction velocity experiment. The recorded signals showed a much lower contact resistance and higher bandwidth in low frequencies for the fabricated microneedle electrodes compared to those of the conventional electrodes. These results indicate the electrode-tissue interface capacitance and charge transfer resistance have been increased in our designed electrodes, while the contact resistance decreased. These changes will lead to less harmful Faradaic current passing through the tissue during stimulation in different frequencies. We also compared the designed microneedle electrodes with conventional ones by a 3-dimensional finite element simulation. The results demonstrated that the current density in the deep layers of the skin and the directivity toward a target nerve for microneedle electrodes were much more than those for the conventional ones. Therefore, the designed electrodes are much more efficient than the conventional electrodes for superficial transcutaneous nerve stimulation purposes. PMID- 29159514 TI - Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in the perioperative setting. PMID- 29159515 TI - The effect of low-level laser therapy (660 nm) on the gene expression involved in tissue repair. AB - The effect of low-level laser therapy (LLLT) on the healing of skin lesions has been evaluated in many studies; however, the molecular mechanisms involved in the biostimulatory effects resulting from this treatment need to be better understood. The paper aims to analyze the effects of LLLT (660 nm) at doses of 1 and 5 J/cm2 on cell viability and expression of vascular endothelial growth factor (VEGF) and interleukin (IL6) genes in L929 fibroblast cells. The dose response curve was performed with the GaInAlAs (660 nm) laser-treated cells at energy rates of 1 and 5 J/cm2. Cell viability was quantified at 24, 48, and 72 h after irradiation and the effects of TLBP on the cytoskeleton and endoplasmic reticulum were evaluated by fluorescence microscopy and the RT-qPCR method was used for the analysis of gene expression. It was observed that the 72 h group had a statistically significant increase in cell viability compared to the 48 h group (p < 0.01) and when compared to the 72 h control (p = 0.03). In 72 h, a greater distribution of the cytoskeleton filaments and the more evident endoplasmatic reticulum was verified, indicating an increase in the protein synthesis when compared with the control group. In the expression of the VEGF gene, a significant increase of 1.98 times (p < 0.05) in the number of transcripts was observed; whereas for the IL6 gene, a decrease of the transcripts was 4.05 times (p < 0.05), both occurring within 72 h after irradiation at 5 J/cm2. The LLLT (660 nm) at the dose of 5 J/cm2 should modulate cellular viability, upregulated VEGF, and downregulated IL6 expression of messenger RNA in culture of L929 fibroblast cells. PMID- 29159516 TI - Second Hip Fracture: Incidence, Trends, and Predictors. AB - Older persons who have suffered a hip fracture (HFx) are at increased risk of subsequent hip fractures. The cumulative incidence of a second hip fracture (SHFx) has been estimated in 8.4%; however, no studies have been carried out in our country, and the information on risk markers of SHFx is limited. The aim of this study was to estimate the incidence, explore trends, and examine predictors of SHFx in a suburban population of Spain. An observational longitudinal retrospective study was performed in a universal health coverage setting (Alcorcon, 1999-2011). Data were obtained from the area hospital discharge database. Annual incidence of HFx was estimated over 100,000 population (general and persons with HFx), and median time to SHFx by Kaplan-Meier tables. Cox regression was used for the analysis of association between SHFx and baseline predictors, measured by hazard ratio (HR). Among the 3430 patients who suffered a first HFx in the study period, 255 (7.4%) experienced a SHFx (4.5% of men and 8.5% of women). Median time between the first and second HFx was 3.7 years (SD 3.2). Annual incidence of HFx in population over 45 was 290.5 per 100,000 inhabitants (131.03 in men and 433.11 in women). Annual incidence of SHFx among persons with a HFx was 956.7 per 100,000 (1052.1 in women and 595.5 in men). There was a decline trend along the study period with an annual reduction of 10.4% (95% CI 7.7-13.0%; p < 0.001) in both sexes. The following associations were found: female sex (HR 1.41, 95% CI 0.97-2.02), age (HR 1.03, 95% CI 1.01 1.04), living in a nursing house (HR 1.46, 95% CI 1.10-1.94), and moderate to severe liver disease (HR 4.96, 95% CI 1.23-20.06). In our environment the occurrence of a SHFx is 7.4%, three-fold risk compared to no previous HFx. Being woman, elderly, living in a nursing home, and having severe to moderate liver disease may be important predictors of a SHFx. There seems to be adequate time between the first and the SHFx for interventions that may reduce the risk. PMID- 29159517 TI - Correction to: Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study. AB - The article "Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study", written by Masaya Hattori, Hiroshi Ishiguro, Norikazu Masuda, Akiyo Yoshimura, Shoichiro Ohtani, Hiroyuki Yasojima, Satoshi Morita, Shinji Ohno, and Hiroji Iwata, was originally published electronically on the publisher's Internet portal (currently SpringerLink) on 31 August 2017 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on [9 November 2017] to PMID- 29159518 TI - Uniaxial Magnetization Performance of Textured Fe Nanowire Arrays Electrodeposited by a Pulsed Potential Deposition Technique. AB - Textured ferromagnetic Fe nanowire arrays were electrodeposited using a rectangular-pulsed potential deposition technique into anodized aluminum oxide nanochannels. During the electrodeposition of Fe nanowire arrays at a cathodic potential of - 1.2 V, the growth rate of the nanowires was ca. 200 nm s-1. The aspect ratio of Fe nanowires with a diameter of 30 +/- 5 nm reached ca. 2000. The long axis of Fe nanowires corresponded with the <200> direction when a large overpotential during the on-time pulse was applied, whereas it orientated to the <110> direction under the potentiostatic condition with a small overpotential. By shifting the on-time cathode potential up to - 1.8 V, the texture coefficient for the (200) plane, TC200, reached up to 1.94. Perpendicular magnetization performance was observed in Fe nanowire arrays. With increasing TC200, the squareness of Fe nanowire arrays increased up to 0.95 with the coercivity maintained at 1.4 kOe at room temperature. This research result has opened a novel possibility of Fe nanowire arrays that can be applied for a new permanent magnetic material without rare-earth metals. PMID- 29159519 TI - Full-wafer in-situ fabrication and packaging of microfluidic flow cytometer with photo-patternable adhesive polymers. AB - Integration of microelectronics with microfluidics enables sophisticated lab-on-a chip devices for sensing and actuation. In this paper, we investigate a novel method for in-situ microfluidics fabrication and packaging on wafer level. Two novel photo-patternable adhesive polymers were tested and compared, PA-S500H and DXL-009. The microfluidics fabrication method employs photo lithographical patterning of spin coated polymer films of PA or DXL and direct bonding of formed microfluidics to a top glass cover using die-to-wafer level bonding. These new adhesive materials remove the need for additional gluing layers. With this approach, we fabricated disposable microfluidic flow cytometers and evaluated the performance of those materials in the context of this application. DXL-009 exhibits lower autofluorescence compared to PA-S500H which improves detection sensitivity of fluorescently stained cells. Results obtained from the cytotoxicity test reveals that both materials are biocompatible. The functionality of these materials was demonstrated by detection of immunostained monocytes in microfluidic flow cytometers. The flexible, fully CMOS compatible fabrication process of these photo-patternable adhesive materials will simplify prototyping and mass manufacturing of sophisticated microfluidic devices with integrated microelectronics. PMID- 29159520 TI - Moral dilemmas of community pharmacists: a narrative study. AB - Background Pharmacists are increasingly involved in patient care. This new role in a complex healthcare system with demanding patients may lead to moral dilemmas. There has been little research into pharmacy ethics, and existing data are limited by their retrospective nature and small sample sizes. A thematic overview of the moral dilemmas experienced by community pharmacists is still missing. Objective To make a thematic overview of moral dilemmas experienced in daily pharmacy practice. Setting Dutch community pharmacy. Methods Dutch community pharmacists wrote a narrative about a moral dilemma they had experienced in clinical practice. The narratives were analysed using qualitative content analysis to identify underlying themes. Main outcome measure Themes of moral dilemmas. Results Twenty-two themes were identified in 128 narratives. These moral dilemmas arose predominantly during pharmacists' contact with patients and other health professionals. The relationship between the pharmacist, patient and other health professionals was complicated by other parties, such as legal representatives, health insurance companies, and regulators. Conclusion The moral dilemmas experienced by community pharmacists are more diverse than previously reported. The main dilemmas arose in their professional contacts, frequently when their professional autonomy was challenged by the behaviour of patients and other health professionals. PMID- 29159522 TI - The "Bladder ear". PMID- 29159521 TI - Discovery of small molecules binding to the normal conformation of prion by combining virtual screening and multiple biological activity evaluation methods. AB - Conformational conversion of the normal cellular prion protein, PrPC, into the misfolded isoform, PrPSc, is considered to be a central event in the development of fatal neurodegenerative diseases. Stabilization of prion protein at the normal cellular form (PrPC) with small molecules is a rational and efficient strategy for treatment of prion related diseases. However, few compounds have been identified as potent prion inhibitors by binding to the normal conformation of prion. In this work, to rational screening of inhibitors capable of stabilizing cellular form of prion protein, multiple approaches combining docking-based virtual screening, steady-state fluorescence quenching, surface plasmon resonance and thioflavin T fluorescence assay were used to discover new compounds interrupting PrPC to PrPSc conversion. Compound 3253-0207 that can bind to PrPC with micromolar affinity and inhibit prion fibrillation was identified from small molecule databases. Molecular dynamics simulation indicated that compound 3253 0207 can bind to the hotspot residues in the binding pocket composed by beta1, beta2 and alpha2, which are significant structure moieties in conversion from PrPC to PrPSc. PMID- 29159523 TI - Quantitating whole lesion tumor biology in rectal cancer MRI: taking a lesson from FDG-PET tumor metrics. AB - PURPOSE: To determine the value of novel whole tumor metrics in DWI-MRI and DCE MRI of rectal cancer treatment assessment. MATERIALS AND METHODS: This retrospective study included 24 uniformly treated patients with rectal adenocarcinoma who underwent MRI including diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) sequences, before and after chemoradiotherapy. Two experienced readers independently measured tumor volume and apparent diffusion coefficient (ADC) on DWI-MRI and tumor volume and transfer constant K trans on DCE-MRI. In addition, we explored and defined Total Lesion Diffusion (TLD) as Total DWI tumor volume multiplied by mean volumetric ADC and Total Lesion Perfusion (TLP) as the total DCE tumor volume multiplied by the mean volumetric K trans. These metrics were correlated with histopathologic percent tumor regression in the resected specimen (%TR). Inter-reader agreement was assessed using the concordance correlation coefficient (CCC). RESULTS: For both readers, post-treatment TLP revealed comparable correlations with %TR compared with K trans (reader 1; Spearman's rho = - 0.36 vs. - 0.32, reader 2; Spearman's rho = - 0.32 vs. - 0.28). In addition, TLP afforded the highest inter-reader agreement at post-treatment among TLP, DCE vol, and K trans (CCC: 0.64 vs. 0.36 vs. 0.35). Post-treatment TLD showed similar correlation with %TR as DWI volume in reader 1 and superior correlation with %TR for reader 2 (reader 1; Spearman's rho - 0.56 vs. - 0.57, reader 2; Spearman's rho - 0.59 vs. - 0.45). CONCLUSION: The novel tumor metrics TLD and TLP revealed similar results to established metrics for correlation with tumor response with equivalent or superior inter-reader agreements and we recommend that these be studied in larger trials. PMID- 29159524 TI - A retrospective analysis of complication and adequacy rates of ultrasound-guided native and transplant non-focal renal biopsies. AB - PURPOSE: To assess non-focal ultrasound (US)-guided renal biopsy complication and adequacy rates at our institution. METHODS: A retrospective analysis of 1067 non focal renal biopsy cases between 2012 and 2015. Information collected including type of US-guided procedure (US-localized by nephrology vs. real-time US-guided by radiology), sample adequacy, complications, blood work, and histologic data. RESULTS: 602 biopsies were performed by radiology (56.4%) and 465 (43.6%) by nephrology. The overall adequacy rate was 96.1%, with an US-localized rate of 95.7% and real-time US-guided rate of 96.3% (p = 0.58). A lower adequacy rate was noted for 1 biopsy core but there were no differences between 2 and 6 cores (p = 0.001). A lower adequacy rate was found for transplant biopsies vs. native biopsies (p = 0.03). Complication rates were as follows-minor 5.9%, major 4.3%, and life-threatening 0.8%. There were no differences in complication rates between the US-localized and real-time US-guided techniques (p = 0.63). Complications were more likely in patients with a lower hemoglobin, higher serum creatinine, and lower albumin (p < 0.05). No differences were found between the number of cores performed and the complication rates. The complication rate was similar between transplant biopsies vs. native biopsies (p = 0.2). The adequacy rate was lower in trainees (p = 0.01) than experienced radiologists. CONCLUSIONS: No significant differences were found between US-localized vs. real-time US guided techniques. A lower adequacy rate was found for trainee radiologists and for transplant biopsies. A lower adequacy rate was also observed when only 1 biopsy pass was performed. PMID- 29159525 TI - Hepatic tumors of vascular origin: imaging appearances. AB - A number of benign and malignant neoplasms may arise from the vascular elements within the liver parenchyma. Lesions discussed in this article include angiosarcoma, epithelioid hemangioendothelioma, solitary fibrous tumor (hemangiopericytoma), infantile, and cavernous hemangiomas. Despite a common theme of vascular origin, the pathologic and imaging appearance of these entities can be heterogeneous. Angiosarcomas are bizarrely enhancing, highly aggressive tumors, which often present with metastatic disease. When solitary, epithelioid hemangioendothelioma lesions can exhibit a concentric ring or target appearance on contrast-enhanced CT and at MR and when numerous may be indistinguishable from angiosarcoma except for a more slowly advancing course. Primary solitary fibrous tumors of the liver are exceedingly rare solid masses and most often initially diagnosed on imaging as other entities such as cholangiocarcinoma. Infantile hemangiomas consist of benign proliferation of the vascular endothelium and in the absence of flow-related complications, are usually clinically silent, and may be detected incidentally as T1 hypointense, T2 hyperintense, centripetally enhancing lesions. Cavernous hemangiomas are extremely common hepatic lesions and when classic rarely offer a challenge in diagnosis, though atypical variants may mimic more serious diseases. The purpose of this review is to provide an overview of important vascular tumors of the liver in order to aid the radiologist in providing a broad differential diagnosis for focal liver lesions, and when classic, suggest specific uncommonly seen diagnoses in order to more accurately guide clinical management. PMID- 29159526 TI - Cardiovascular disease in kidney transplant recipients: Japan Academic Consortium of Kidney Transplantation (JACK) cohort study. AB - BACKGROUND: The number of kidney transplant recipients (KTRs) from diabetic nephropathy (DN) and with cardiovascular disease (CVD) history has increased worldwide. Nevertheless, epidemiologic evidence of CVD in KTRs remains limited. METHODS: We investigated post-transplant CVD in 1614 adult KTRs between 1990 and 2014. CVD was defined according to the international classification of diseases (ICD-10). All-cause mortality was also investigated. Final follow-up was performed in March 2016. The KTRs were categorized into four groups according to DN and CVD at surgery. RESULTS: During the follow-up period, 309 KTRs experienced CVDs and 124 KTRs died. The 15-year cumulative CVDs rate was 87% in KTRs with both DN and CVD history, and the rate in KTRs without those was 22.3%. DN and CVD were associated with increased risk of post-transplant CVD [hazard ratio (HR), 3.44; 95% confidence interval (CI), 2.03-5.82; P < 0.001], and the impact marked increased after 7.5 years follow-up period (HR, 16.56; 95% CI, 6.56-41.8; P < 0.001). DN and CVD in KTRs were associated with mortality (HR, 3.32; 95% CI, 1.34 8.22; P = 0.009), and post-transplant CVD was the leading cause (35.5%) of overall death. However, DN and CVD were not associated with increased graft failure rate. CONCLUSIONS: The risk of post-transplant CVDs incidence in KTRs with DN and CVD history is high, and it increases during the late transplant period. Appropriate routine cardiovascular screening and evaluation are needed to reduce late-onset CVD incidence. PMID- 29159527 TI - Melatonin ameliorates intrarenal renin-angiotensin system in a 5/6 nephrectomy rat model. AB - BACKGROUND: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. It has been reported that reactive oxygen species (ROS) are important components of intrarenal RAS activation. Melatonin is recognized as a powerful antioxidant, and we recently reported that impaired nighttime melatonin secretion correlates negatively with urinary angiotensinogen excretion, the surrogate marker of intrarenal RAS activity in patients with CKD. However, whether melatonin supplementation ameliorates the augmentation of intrarenal RAS in CKD has remained unknown. We aimed to clarify whether exogenous melatonin ameliorates intrarenal RAS activation via the reduction of ROS production. METHODS: 5/6 Nephrectomized (Nx) rats were used as a chronic progressive CKD model and compared with sham-operated control rats. The Nx rats were divided into untreated Nx rats and melatonin-treated Nx rats. The levels of intrarenal RAS, ROS components, and renal injury were evaluated after 4 weeks of treatment. RESULTS: Compared with the control rats, the untreated Nx rats exhibited significant increases in intrarenal angiotensinogen, angiotensin II (AngII) type 1 receptors, and AngII, accompanied by elevated blood pressure, higher oxidative stress (8-hydroxy-2'-deoxyguanosine), lower antioxidant (superoxide dismutase) activity, and increased markers of interstitial fibrosis (alpha-smooth muscle actin, Snail, and type I collagen) in the remnant kidneys. Treatment with melatonin significantly reversed these abnormalities. CONCLUSION: Antioxidant treatment with melatonin was shown to ameliorate intrarenal RAS activation and renal injury in a 5/6 Nx rat model. PMID- 29159528 TI - Death with graft function after kidney transplantation: a single-center experience. AB - BACKGROUND: Death with graft function (DWGF) is an important cause of long-term loss of grafts and patients. In this study, we investigated clinical characteristics and causes of DWGF in kidney transplant recipients. METHODS: We recruited kidney allograft recipients who underwent surgery during 1973-2016 at Seoul National University Hospital in Korea (n = 2137). We divided recipients into four groups: alive with graft function (AWGF), alive with graft loss (AWGL), DWGF, and death with graft loss (DWGL). RESULTS: Among 455 recipients with graft loss, 88 (19.3%) lost graft function due to death. DWGF was responsible for 38.6% of a total of 228 deaths. Recipients with DWGF were older, more often diabetic, and experienced delayed graft function more often compared to patients with AWGF, AWGL, and DWGL. Additionally, they had fewer episodes of acute rejection than AWGF and AWGL patients. The majority of DWGF developed because of infection (40.9%), malignancy (28.4%), and cardiovascular disease (11.4%). Infection related mortality was highest within the first year after transplantation. Death due to malignancy was lowest within the first year, but increased thereafter. CONCLUSIONS: In our center, DWGF was a significant cause of graft loss. Infection and malignancy were the leading causes of DWGF during the overall post transplantation period. Therefore, close monitoring for infection and malignancy should be instituted to lessen the burden of graft loss. PMID- 29159530 TI - Introduction to topical issue on myocardial classification. PMID- 29159529 TI - Plasma p-cresol lowering effect of sevelamer in non-dialysis CKD patients: evidence from a randomized controlled trial. AB - BACKGROUND: The accumulation of p-cresol, a metabolic product of aromatic amino acids generated by intestinal microbiome, increases the cardiovascular risk in chronic kidney disease (CKD) patients. Therefore, therapeutic strategies to reduce plasma p-cresol levels are highly demanded. It has been reported that the phosphate binder sevelamer (SEV) sequesters p-cresol in vitro, while in vivo studies on dialysis patients showed controversial results. Aim of our study was to evaluate the effect of SEV on p-cresol levels in non-dialysis CKD patients. METHODS: This was a single-blind, randomized placebo-controlled trial (Registration number NCT02199444) carried on 69 CKD patients (stage 3-5, not on dialysis), randomly assigned (1:1) to receive either SEV or placebo for 3 months. Total p-cresol serum levels were evaluated at baseline (T0), and 1 (T1) and 3 months (T3) after treatment start. The primary end-point was to evaluate the effect of SEV on p-cresol levels. RESULTS: Compared to baseline (T0, 7.4 +/- 2.7 mg/mL), p-cresol mean concentration was significantly reduced in SEV patients after one (- 2.06 mg/mL, 95% CI - 2.62 to - 1.50 mg/mL; p < 0.001) and 3 months of treatment (- 3.97 mg/mL, 95% CI - 4.53 to - 3.41 mg/mL; p < 0.001); no change of plasma p-cresol concentration was recorded in placebo-treated patients. Moreover, P and LDL values were reduced after 3 months of treatment by SEV but not placebo. CONCLUSIONS: In conclusion, our study represents the first evidence that SEV is effective in reducing p-cresol levels in CKD patients in conservative treatment, and confirms its beneficial effects on inflammation and lipid pattern. PMID- 29159531 TI - Very early neointimal coverage of new biodegradable polymer drug-eluting stent compared with durable polymer everolimus-eluting stent evaluated by optical frequency domain imaging. AB - Polymeric component is associated with the increased risk of delayed vessel healing and stent endothelialization. We aimed to clarify neointimal coverage within 1 month after implantation of the new-generation abluminal biodegradable polymer (BP) drug-eluting stent (DES) compared with the second-generation durable polymer (DP) everolimus-eluting stent (EES). Between November 2015 and October 2016, 32 BP-DES and 25 DP-EES were evaluated by optical frequency domain imaging (OFDI) within 1 month after the procedure. The average interval to follow-up OFDI was not significantly different between the groups (16.3 +/- 7.7 days in BP-DES vs. 15.4 +/- 7.4 days in DP-EES, P = 0.75). Neointimal coverage was significantly superior in BP-DES in both apposed and malapposed strut (apposed: 53.9% in BP-DES vs. 28.0% in DP-EES, P < 0.001; malapposed: 22.9% in BP-DES vs. 7.5% in DP-EES, P = 0.001). When the follow-up period was divided into < 2 and > 2 weeks, neointimal coverage was also significantly superior in BP-DES (< 2 weeks: 47.7% in BP-DES vs. 19.2% in DP-EES, P < 0.001; > 2 weeks: 60.1% in BP-DES vs. 37.4% in DP-EES, P = 0.001). The new-generation BP-DES showed excellent early neointimal coverage compared with the second-generation DP-EES in both apposed and malapposed struts. PMID- 29159532 TI - A multiphysics approach for modeling early atherosclerosis. AB - This work is devoted to the development of a mathematical model of the early stages of atherosclerosis incorporating processes of all time scales of the disease and to show their interactions. The cardiovascular mechanics is modeled by a fluid-structure interaction approach coupling a non-Newtonian fluid to a hyperelastic solid undergoing anisotropic growth and a change of its constitutive equation. Additionally, the transport of low-density lipoproteins and its penetration through the endothelium is considered by a coupled set of advection diffusion-reaction equations. Thereby, the permeability of the endothelium is wall-shear stress modulated resulting in a locally varying accumulation of foam cells triggering a novel growth and remodeling formulation. The model is calibrated and applied to an murine-specific case study, and a qualitative validation of the computational results is performed. The model is utilized to further investigate the influence of the pulsatile blood flow and the compliance of the artery wall to the atherosclerotic process. The computational results imply that the pulsatile blood flow is crucial, whereas the compliance of the aorta has only a minor influence on atherosclerosis. Further, it is shown that the novel model is capable to produce a narrowing of the vessel lumen inducing an adaption of the endothelial permeability pattern. PMID- 29159533 TI - Reduced bone mineral density in human immunodeficiency virus-infected individuals: a meta-analysis of its prevalence and risk factors. AB - : A meta-analysis was conducted to evaluate the prevalence of osteopenia/osteoporosis in human immunodeficiency virus (HIV)-infected individuals. The prevalence of osteopenia/osteoporosis in HIV-infected and antiretroviral therapy (ART)-treated individuals was significantly higher than respective controls. Evidence regarding bone loss within first year of HIV infection or ART initiation was preliminary. PURPOSE: The aim of the study is to systematically review published literature on the prevalence of osteopenia/osteoporosis and its associated risk factors in HIV-infected individuals. METHODS: A literature search was conducted from 1989 to 2015 in six databases. Full text, English articles on HIV-infected individuals >= 18 years, which used dual X-ray absorptiometry to measure BMD, were included. Studies were excluded if the prevalence of osteopenia/osteoporosis was without a comparison group, and the BMD/T-score were not reported. RESULTS: Twenty-one cross sectional and eight longitudinal studies were included. The prevalence of osteopenia/osteoporosis was significantly higher in both HIV-infected [odds ratio (OR) = 2.4 (95%Cl: 2.0, 2.8) at lumbar spine, 2.6 (95%Cl: 2.2, 3.0) at hip] and ART-treated individuals [OR = 2.8 (95%Cl: 2.0, 3.8) at lumbar spine, 3.4 (95%Cl: 2.5, 4.7) at hip] when compared to controls. PI-treated individuals had an OR of 1.3 (95%Cl: 1.0, 1.7) of developing osteopenia/osteoporosis compared to controls. A higher proportion of tenofovir-treated individuals (52.6%) had lower BMD compared to controls (42.7%), but did not reach statistical significance (p = 0.248). No significant difference was found in the percent change of BMD at the lumbar spine, femoral neck, or total hip from baseline to follow-up between HIV infected, PI-treated, tenofovir-treated, and controls. Older age, history of bone fracture, low BMI, low body weight, being Hispanic or Caucasian, low testosterone level, smoking, low CD4 cell count, lipodystrophy, low fat mass, and low lean body mass were associated with low BMD. CONCLUSIONS: The prevalence of osteopenia/osteoporosis in HIV-infected and antiretroviral therapy (ART)-treated individuals was two times more compared to controls. However, evidence concerning bone loss within the first year of HIV infection and ART initiation was preliminary. PMID- 29159534 TI - Concise clinical reviews. PMID- 29159536 TI - Physics of epi-thermal boron neutron capture therapy (epi-thermal BNCT). AB - The physics of epi-thermal neutrons in the human body is discussed in the effort to clarify the nature of the unique radiologic properties of boron neutron capture therapy (BNCT). This discussion leads to the computational method of Monte Carlo simulation in BNCT. The method is discussed through two examples based on model phantoms. The physics is kept at an introductory level in the discussion in this tutorial review. PMID- 29159537 TI - Relationship between empowerment and wealth: trends and predictors in Kenya between 2003 and 2008-2009. AB - OBJECTIVES: This study aimed to examine the association between women's empowerment and wealth over time in Kenya. METHODS: Kenya Demographic and Health Surveys (DHS) for 2003 and 2008-2009 were used. Eligible women and men were either married or living with a partner. Two scales were used for empowerment: female participation in decision-making, and attitudes toward domestic violence against female partners. Hierarchical linear models were used based on theoretical blocks of covariates. RESULTS: In a sample of 9847 women and 3207 men, results showed empowerment increased over time. After adjustment, female partners' reporting greater empowerment on either scale remained significantly associated with increased wealth, (urban: beta = 0.04, p value < 0.05; beta = - 0.06, p value < 0.01) and (rural: beta = 0.04, p value < 0.01, beta = - 0.07, p value < 0.01). Based on male partners' responses, female partners' participation in decision-making was associated with increased wealth in rural regions (beta = 0.04, p value < 0.01), and agreement with domestic violence towards a female partner was significantly associated with a decrease in wealth in urban regions (beta = - 0.08, p value < 0.01). CONCLUSIONS: Women's empowerment has increased over time in Kenya and is associated with increased family wealth. The association varies by gender of respondent and rural/urban residence. PMID- 29159538 TI - Neuroinflammation, cortical activity, and fatiguing behaviour during self-paced exercise. AB - The present study aimed to identify whether or not the release of interleukin (IL)-6 and soluble (s) IL-6 receptor (R) is associated with fatiguing behaviour and changes in cortical activity during self-paced exercise. Relationships between the IL-6 and its soluble receptors, total work, reductions in power output, and changes in slow, alpha (alpha) and fast, beta (beta) brain waves during self-paced exercise were evaluated. Different intensities and environments were used to manipulate the release of IL-6, whereby seven active males cycled for 60 min in heat stress (HS) or thermoneutral (TN) environments at a clamped rating of perceived exertion (RPE) equating to low intensity (RPE = 12) or high intensity (RPE = 16). IL-6 and sIL-6R were positively associated with total work, but not with reductions in power output. There was greater alpha activity in high intensity conditions, which was associated with the reduction in power output. Both high-intensity conditions appeared to have greater beta activity, and there was a positive correlation between beta activity and total work and beta activity and sIL-6R. We conclude that IL-6 and sIL-6R may contribute to perturbations in cortical activity and are associated with total work output, but reductions in power output are likely influenced greater by other internal and external factors. PMID- 29159540 TI - Is fertility-preservation safe for adult non-metastatic gynecologic rhabdomyosarcoma patients? Systematic review and pooled survival analysis of 137 patients. AB - PURPOSE: Recently, conservative approaches such as wide local excisions and neoadjuvant chemotherapy are being considered to select young adult females with gynecologic RMS who have strong desire to preserve fertility. This analysis aims to identify prognosticators affecting survival outcomes and defining potential candidacy for fertility-preservation. Another focus is to explore the role of chemotherapy in reducing the need for aggressive surgery and the role of radiotherapy in decreasing rates of local failure. METHODS: A comprehensive database search identified 137 females > 16 years old with primary non-metastatic gynecologic RMS, who were included in a multivariate survival analysis. RESULTS: 5-year overall survival rate was 65%. Patients < 50 years old, with cervix uteri primaries, well-defined/polypoid presentations, embryonal histology and superficial tumors were more likely to survive. Deeply invasive disease and alveolar/pleomorphic histology significantly increased risks of treatment failure and tumor recurrence. Chemotherapy use was a significant multivariate predictor of better overall and metastasis-free survival. Radical surgery did not add local control or overall survival benefit for patients with superficial lesions (minimal/no cervical stromal invasion and no myometrial invasion). CONCLUSIONS: While high-quality clinical trial evidence is missing, existing evidence seems to support holding back on radical surgery for selected candidates with well defined, polypoid, superficial, embryonal cervical/endometrial RMS lesions that could be completely excised with conservative surgery; further local resections with/without radiotherapy are then warranted based on margin status. Experience on the use of neoadjuvant chemotherapy in the conservative management of uterine RMS in adults is very limited, though this approach is golden-standard in pediatrics. A suggested scheme is introduced for the management of uterine RMS. PMID- 29159539 TI - The Importance of Assessing for Childhood Abuse and Lifetime PTSD in Bariatric Surgery Candidates. AB - For bariatric surgery candidates, history of child abuse and PTSD may be under recognized or under-reported at pre-surgical evaluation. On a range of clinically relevant factors, we studied 3045 candidates for bariatric surgery: (1) those with a history of childhood abuse compared to those without such history; and (2) among candidates with a history of abuse, those with a lifetime diagnosis of PTSD compared to those without that diagnosis. We compared them on current and lifetime eating disorders, physical health problems, health behaviors, physical functioning, psychosocial functioning, psychiatric disorders, emotional wellness, body satisfaction, and self-esteem. We hypothesized that patients with a history of childhood abuse, and within that group, those with a lifetime PTSD diagnosis, would display greater overall impairment. Patients were interviewed with semi structured interviews and completed self-report questionnaires. Results showed that (1) patients with a history of childhood abuse exhibited significantly greater impairment than those without abuse; and (2) among candidates with a history of abuse, those with a lifetime history of PTSD displayed significantly greater impairment than those without a PTSD diagnosis. The findings suggest that a history of both childhood abuse and lifetime PTSD should be thoroughly assessed for at pre-surgical evaluation, and that greater attention be paid to the experience of PTSD symptoms in abuse survivors presenting for bariatric surgery. PMID- 29159541 TI - Automated detection of exudative age-related macular degeneration in spectral domain optical coherence tomography using deep learning. AB - PURPOSE: Our purpose was to use deep learning for the automated detection of age related macular degeneration (AMD) in spectral domain optical coherence tomography (SD-OCT). METHODS: A total of 1112 cross-section SD-OCT images of patients with exudative AMD and a healthy control group were used for this study. In the first step, an open-source multi-layer deep convolutional neural network (DCNN), which was pretrained with 1.2 million images from ImageNet, was trained and validated with 1012 cross-section SD-OCT scans (AMD: 701; healthy: 311). During this procedure training accuracy, validation accuracy and cross-entropy were computed. The open-source deep learning framework TensorFlowTM (Google Inc., Mountain View, CA, USA) was used to accelerate the deep learning process. In the last step, a created DCNN classifier, using the information of the above mentioned deep learning process, was tested in detecting 100 untrained cross section SD-OCT images (AMD: 50; healthy: 50). Therefore, an AMD testing score was computed: 0.98 or higher was presumed for AMD. RESULTS: After an iteration of 500 training steps, the training accuracy and validation accuracies were 100%, and the cross-entropy was 0.005. The average AMD scores were 0.997 +/- 0.003 in the AMD testing group and 0.9203 +/- 0.085 in the healthy comparison group. The difference between the two groups was highly significant (p < 0.001). CONCLUSIONS: With a deep learning-based approach using TensorFlowTM, it is possible to detect AMD in SD-OCT with high sensitivity and specificity. With more image data, an expansion of this classifier for other macular diseases or further details in AMD is possible, suggesting an application for this model as a support in clinical decisions. Another possible future application would involve the individual prediction of the progress and success of therapy for different diseases by automatically detecting hidden image information. PMID- 29159542 TI - Evaluation of the Removal of Potassium Cyanide and its Toxicity in Green Algae (Chlorella vulgaris). AB - To evaluate the removal of potassium cyanide (KCN) and its toxicity in algae, an initial comprehensive analysis was performed with Chlorella vulgaris. The algae showed potential removal capability for KCN, with the maximal removal rate of 61%. Moreover, effects of KCN on growth, cellular morphology and antioxidant defense system of C. vulgaris were evaluated. Cell number and chlorophyll a content decreased in most cases, with the maximal inhibition rates of 48% and 99%, respectively. The 100 mg L- 1 KCN seriously damaged the algal cell membrane. Additionally, activity of superoxide dismutase (SOD) was promoted by KCN exposure among 0.1-50 mg L- 1 and inhibited by 100 mg L- 1 KCN, while the malondialdehyde (MDA) content gradually decreased in C. vulgaris with increasing exposure concentration compared to the control. The present study reveals that C. vulgaris is useful in bio-treatment of cyanide-contaminated aquatic ecosystem, except in high concentrations which would cause overwhelming effects. PMID- 29159543 TI - Endosulfan is toxic to the reproductive health of male freshwater fish, Cyprinion watsoni. AB - Endosulfan is an organochlorine pesticide that is toxic to aquatic life. Endosulfan might hamper the reproductive health of indigenous fish in agricultural areas of Pakistan where this pesticide is sprayed widely. The aim of the current study is to investigate the toxic effects of endosulfan on selected reproductive parameters of male freshwater fish, Cyprinion watsoni. Two concentrations of endosulfan (0.5 and 1 ppb for 30 days exposure) were tested for their effects on body weight, body length, and testicular weight, length, and width. Testicular testosterone was assayed from tissue extracts using enzyme immunoassay (EIA). A significant increase in the mortality rate was observed in both treated groups during both spawning and quiescent seasons. The overall behavior of fish in the aquarium was normal in all control and treated groups. However, the treated fish exhibited anxiety after treatment with endosulfan. The body weight and length, and testicular weight, length and width were not significantly different to the control group. The testicular testosterone concentrations were significantly lower in both endosulfan-treated groups compared to the control. The decrease was dose-dependent, with a significant difference between the two treated groups. The histomorphological results demonstrated various testicular alterations in the treated groups. These alterations included an increase in interlobular areas and clumping patterns in spermatocytes/spermatids. Because spermatids eventually differentiate into sperms, their low count will directly result in lower sperm count. Taken together, these results suggest that endosulfan is a toxicant that at least disturbs testosterone levels (possibly others) and negatively impacts the reproductive health of male freshwater fish. PMID- 29159544 TI - "Yeah that Made a Big Difference!": The Importance of the Relationship between Health Professionals and Fathers Who Have a Child with Down Syndrome. AB - Evidence suggests that medical services do not reflect the increased involvement of fathers in childcare, a discrepancy that can often lead to feelings of exclusion and inequality. Fathers who have a child with Down syndrome may encounter many different health professionals during their child's life, therefore it is important to consider this relationship, and investigate the factors that influence their experiences. This is particularly important because the limited research focusing on fathers suggest that those who have a child with Down syndrome can experience increased stress levels and lasting feelings of loss and grief. It is therefore important to address their relationships with health professionals, as these may be a significant resource to prevent these feelings. This study used interpretative phenomenological analysis (IPA) to explore the experiences of seven fathers who have a child with Down syndrome, focusing on their interactions with health professionals. The analysis showed that the major factors associated with negative experiences were feelings of exclusion, receiving overly negative information about the condition and a perceived lack of on-going support. Positive experiences were associated with being made to feel like an equal parent, being given direct/clear information and being congratulated on the birth of their child. These results provide an insight into what fathers expect in terms of their own and their child's care and highlight that health professionals have an important and extensive role in influencing fathers' experiences of Down syndrome. PMID- 29159545 TI - Clinician-Stakeholders' Perspectives on Using Patient Portals to Return Lynch Syndrome Screening Results. AB - Test results for genetic conditions, such as Lynch Syndrome (LS), have traditionally been returned by genetic counselors or other providers who can explain results implications and provide psychosocial support. Returning genetic results through an Electronic Health Record's patient portal may increase the efficiency of returning results and could activate patient follow-up; however, stakeholder input is necessary to determine acceptability and appropriate implementation for LS. Twenty interviews were conducted with clinicians from six specialties involved in LS screening that represent a range of settings. Data were analyzed using directed content analysis and thematic analysis across content categories. Participants felt that patient portals could supplement personal calls, but the potential sensitive nature of LS screening results indicated the need for caution. Others felt that LS results could be returned through portals if there were clear explanations of the result, reputable additional information available within the portal, urging follow up confirmatory testing, and a referral to a genetics specialist. Patient portals were seen as helpful for prompting patient follow-up and providing resources to notify at-risk family members. There is potential for patient portals to return LS screening and other genetic results, however we raise several issues to resolve before implementation is warranted. PMID- 29159547 TI - Correction to: Current Methodologies and Implications of Phase Identification of the Vertical Jump: A Systematic Review and Meta-analysis. AB - Pages 1313-5, table 1, column 1: The cell entries in the 'Reference' column, which previously read. PMID- 29159546 TI - Sport-Related Concussion and Mental Health Outcomes in Elite Athletes: A Systematic Review. AB - BACKGROUND: Elite athletes can experience a diverse range of symptoms following post-concussive injury. The impact of sport-related concussion on specific mental health outcomes is unclear in this population. OBJECTIVE: The aim was to appraise the evidence base regarding the association between sport-related concussion and mental health outcomes in athletes competing at elite and professional levels. METHODS: A systematic search of PubMed, EMBASE, SPORTDiscus, PsycINFO, Cochrane, and Cinahl databases was conducted. RESULTS: A total of 27 studies met inclusion criteria for review. Most of the included studies (67%, n = 18) were published in 2014 or later. Study methodology and reporting varied markedly. The extant research has been conducted predominantly in North America (USA, n = 23 studies; Canada, n = 3), often in male only (44.4%, n = 12) and college (70.4%, n = 19) samples. Depression is the most commonly studied mental health outcome (70.4%, n = 19 studies). Cross-sectional retrospective studies and studies including a control comparison tend to support an association between concussion exposure and depression symptoms, although several studies report that these symptoms resolved in the medium term (i.e. 1 month) post-concussion. Evidence for anxiety is mixed. There are insufficient studies to draw conclusions for other mental health domains. CONCLUSION: Consistent with current recommendations to assess mood disturbance in post-concussive examinations, current evidence suggests a link between sports-related concussion and depression symptoms in elite athletes. Causation cannot be determined at this stage of enquiry because of the lack of well-designed, prospective studies. More research is required that considers a range of mental health outcomes in diverse samples of elite athletes/sports. PMID- 29159548 TI - Applicability of the AAOS appropriate-use criteria for distal radius fractures in surgical practice. AB - PURPOSE: The appropriate-use criteria (AUC) for distal radius fracture (DRF) was developed by the American Academy of Orthopedic Surgeons (AAOS) to aid surgeons in making evidence-based treatment decisions for DRFs. The aim of our study was to cross-reference the management of operatively treated DRFs with the web-based AAOS published AUC recommendations. METHODS: The AUC for DRF evaluates the appropriateness of ten treatment options for each of 240 mutually exclusive patient scenarios based on the combination of five factors. For every scenario, each treatment is classified as appropriate, maybe appropriate or rarely appropriate. We retrospectively reviewed the medical charts and radiographs of all adult patients >=19 years who underwent surgery for DRFs between 1 January and 31 December 2014 and determined the rate of appropriateness of treatment in this consecutive series of patients. RESULTS: Over the study period, 108 patients (83.3% men; mean age 39.8 years) with 113 DRFs (five bilateral) were treated surgically. The most frequent scenario was represented by a type C fracture, high energy mechanism, normal functional demand, American Society Anesthesiologists (ASA) status 1-3 and no associated injuries. The most frequently used treatment was volar locking plate (54.0%). Based on the AUC, treatment was appropriate for 96 cases (85.0%), maybe appropriate for 15 (13.2%), and rarely appropriate for two (1.8%). CONCLUSIONS: A web-based electronic AUC application can be an attractive and easy decision-making aid for orthopaedic surgeons. Application of the AUC to clinical data was relatively simple, and most operatively treated DRFs were managed appropriately. LEVEL OF EVIDENCE: IV. PMID- 29159550 TI - Comment on "Effects of Laparoscopic Roux-en-Y Gastric Bypass for Type 2 Diabetes Mellitus: Comparison of BMI > 30 and < 30 kg/m2". PMID- 29159549 TI - [Diagnostics of Wilson's disease]. AB - Wilson's disease is a rare genetic but treatable metabolic disorder which has a favorable prognosis when diagnosed early and treated adequately. Therefore, knowledge of this rare clinical condition and a reliable diagnosis are indispensable. The diagnostic work-up is initiated in cases of unexplained acute or chronic liver disease and/or an extrapyramidal motor disturbance occurring mostly between the 5th and 45th years of life. Manifestations with initial symptoms have occasionally been observed at an age younger than 1 year and later than 70 years. Immediate biochemical and genetic examinations for early diagnosis are essential. Further test methods, such as liver and transcranial sonography, cerebral magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET), 123I-beta-CIT and 123I-iodobenzamide (IBZM) single photon emission computed tomography (SPECT), electrophysiology as well as fine motor tests are unspecific but can be used to test for organ damage and for monitoring of progress. Immediate initiation of a therapy is required and justified on the basis of a confirmed diagnosis. PMID- 29159551 TI - Long-Term (over 10 Years) Retrospective Follow-up of Laparoscopic Adjustable Gastric Banding. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) placements have progressively decreased in recent years. This is related to poor long-term weight loss outcomes and necessity for revision or removal of these bands. Long-term outcome results following LAGB are limited. The aim of our study was to determine the long-term outcome after LAGB at our institution. OBJECTIVES: The aim of our study was to determine the long-term outcome after LAGB at our institution. SETTING: The setting of this is Academic Center, Israel. METHODS: Patients who underwent LAGB between 1999 and 2004 were reviewed. Patient comorbidities and weight loss parameters were collected preoperatively and at defined postoperative periods. Improvement in weight loss was defined as percent excess weight lost, and improvement in comorbidities was defined based on standardized reporting definitions. RESULTS: In total, 74 (80%) patients who underwent LAGB met inclusion criteria. The mean age at LAGB placement was 50.5 +/- 9.6 years, and the mean body mass index (BMI) was 45.5 +/- 4.8 kg/m2. Preoperative comorbidities were diabetes mellitus (13.5%), hypertension (32%), hyperlipidemia (12.1%), obstructive sleep apnea (5.4%), joints disease (10.8%), mood disorders (5.4%), and gastro-esophageal reflux disease (GERD) symptoms (8.1%). The mean follow-up was 162.96 +/- 13.9 months; 44 patients (59.4%) had their band removed, and 22 (30%) had another bariatric surgery. The follow-up BMI was 35.7 +/- 6.9 (p < 0.001), and the % total weight loss was 21.0 +/- 0.13. There was no improvement in any of the comorbidities. GERD symptoms worsened at long-term follow-up (p < 0.001). Undergoing another bariatric procedure was associated with a higher weight loss (OR 12.8; CI 95% 1.62-23.9; p = 0.02). CONCLUSION: LAGB required removal in the majority of our patients and showed poor resolution of comorbidities with worsening of GERD-related symptoms. Patients who go on to have another bariatric procedure have more durable weight loss outcomes. PMID- 29159552 TI - The Effect of Helicobacter pylori on Postoperative Outcomes in Patients Undergoing Bariatric Surgery: a Systematic Review and Meta-analysis. AB - Helicobacter pylori (HP) occurs in 50% of people worldwide with higher rates reported in the bariatric population. HP has been associated with adverse outcomes following bariatric surgery; however, its true impact has not yet been defined. We aimed to systematically review the effect of HP on bariatric surgery outcomes. A comprehensive literature review was conducted yielding seven studies with 255,435 patients. Meta-analysis found comparable rates of bleeding, leak, hospital length of stay, and weight loss between HP-positive and HP-negative patients. HP was, however, found to be the largest independent predictor of marginal ulceration in those undergoing RYGB, with a tenfold increase versus HP negative patients. Overall, HP is associated with increased marginal ulceration rates, but has little impact on other bariatric surgery outcomes. PMID- 29159553 TI - Revisional Malabsorptive Bariatric Surgery: 29-Year Follow-up in a Brazilian Public Hospital. AB - BACKGROUND: This study aimed to evaluate the outcomes of 67 patients who underwent revisional bariatric surgeries over a 29-year period in a Brazilian public hospital. METHODS: The records of all patients who underwent revisional bariatric surgery from January 1987 to December of 2016 at our hospital were analyzed for weight loss and complications. Descriptive statistics and paired t tests were computed. RESULTS: Sixty-seven patients were included in the study. The primary surgeries previously performed on these patients were biliopancreatic diversion with duodenal switch (BPD-DS) (37 cases, 55.2%), jejunoileal bypass (JIB) (24 cases, 35.8%), sleeve gastrectomy (4 cases, 5.9%), Roux-en-Y gastric bypass (RYGB) (1 case, 1.5%), and laparoscopic adjustable gastric band (1 case, 1.5%). The indications for revisional surgery were as follows: malnutrition in 29 cases (43.3%), failure to lose weight in 27 cases (40.3%), weight regain in 5 cases (7.5%), and untreatable diarrhea in 6 cases (9.2%). Most revisional surgeries were performed using JIB or BPD-DS. Operative mortality was higher after the revisional procedures compared with that following the primary bariatric surgeries. CONCLUSIONS: Most patients requiring a revisional surgery had undergone a primary BPD-DS or JIB. Severe and untreatable malnutrition and diarrhea were the main indications for the revisional procedures. RYGB produced significant and sustainable weight loss and exhibited a low risk of malnutrition or requiring revisional surgery. PMID- 29159554 TI - Detailed Description of Change in Serum Cholesterol Profile with Incremental Weight Loss After Restrictive Bariatric Surgery. AB - INTRODUCTION: Dyslipidemia affects up to 75% of morbidly obese individuals and is a key driver of cardiovascular disease. Weight loss is an established strategy to improve metabolic risk, including dyslipidemia. We aimed to determine weight loss goals for resolution of serum lipid abnormalities, by measuring improvements during progressive weight loss in obese individuals. METHODS: We performed a prospective cohort study of obese individuals with the metabolic syndrome undergoing adjustable gastric banding. Lipid levels were monitored monthly for 9 months, then three monthly until 24 months. RESULTS: There were 101 participants included, age 47.4 +/- 10.9 years with body mass index 42.6 +/- 5.9 kg/m2. At 24 months, total body weight loss (TBWL) was 18.3 +/- 7.9%. This was associated with significant improvements in high-density lipoprotein (HDL) (1.18 vs 1.47, p < 0.001), triglyceride (2.0 vs 1.4, p < 0.001), and total cholesterol to HDL ratio (TC:HDL) (4.6 vs 3.6, p < 0.001). Over this time, progressive and linear improvements in HDL, triglycerides, and TC:HDL were seen with incremental weight loss (observed at 2.5% TBWL intervals). Significant improvements occurred after a threshold weight loss of 7.5-12.5% TBWL was achieved, with odds ratio (OR) 1.48 2.50 for normalization. These odds improved significantly with increasing weight loss (OR 18.2-30.4 with > 25% TBWL). Despite significant weight loss, there was no significant change in low-density lipoprotein (LDL). CONCLUSION: Significant improvements in triglycerides, HDL, and TC:HDL occur after 7.5-12.5% TBWL, with ongoing benefit after greater weight loss. LDL needs to be addressed independently, as this was not observed to respond to weight loss alone. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Registry (ACTRN12610000049077). PMID- 29159555 TI - Use of a Hands Free, Instantaneous, Closed-Loop Communication Device Improves Perception of Communication and Workflow Integration in an Academic Teaching Hospital: A Pilot Study. AB - Efficient and effective communication between providers is critical to quality patient care within a hospital system. Hands free communication devices (HFCD) allow instantaneous, closed-loop communication between physicians and other members of a multidisciplinary team, providing a communication advantage over traditional pager systems. HFCD have been shown to decrease emergency room interruptions, improve nursing communication, improve speed of information flow, and eliminate health care waste. We evaluated the integration of an HFCD with an existing alphanumeric paging system on an acute inpatient medicine service. We conducted a prospective, observational, survey-based study over twenty-four weeks in an academic tertiary care center with attending physicians and residents. Our intervention involved the implementation of an HFCD alongside the existing paging system. Fifty-six pre and post surveys evaluated the perception of improvement in communication and the integration of the HFCD into existing workflow. We saw significant improvements in the ability of an HFCD to help physicians communicate thoughts clearly, communicate thoughts effectively, reach team members, reach ancillary staff, and stay informed about patients. Physicians also reported better workflow integration during admissions, rounds, discharge, and teaching sessions. Qualitative data from post surveys demonstrated that the greatest strengths of the HFCD included the ability to reach colleagues and staff quickly, provide instant access to individuals of the care team, and improve overall communication. Integration of an instantaneous, hands free, closed loop communication system alongside the existing pager system can provide improvements in the perceptions of communication and workflow integration in an academic medicine service. Future studies are needed to correlate these subjective findings with objective measures of quality and safety. PMID- 29159556 TI - Effects of Arsenic Trioxide on INF-gamma Gene Expression in MRL/lpr Mice and Human Lupus. AB - Arsenic trioxide (As2O3; ATO), a traditional Chinese medicine, is used to treat patients with acute promye-locytic leukemia, while its application for treatment of systemic lupus erythematosus (SLE) is still under evaluation. The high expression of INF-gamma (INF-gamma) is a primary pathogenic factor in SLE. It is found that ATO can reduce INF-gamma expression levels in lupus-prone mice, whereas it is not clear whether ATO has the same effect on SLE patients. Therefore, this study was to investigate the underlying mechanism of the effects of ATO on the expression of INF-gamma in splenocytes of MRL/lpr mice and PBMCs of human lupus. The mRNA and protein expression levels of INF-gamma were assessed by real-time RT-PCR and ELISA, respectively. The histone acetylation status of the INF-gamma promoter and the binding of RNA polymerase II (RNA Pol II) to the INF gamma promoter were detected using a chromatin immunoprecipitation (ChIP) technique. The mRNA and protein expression levels of INF-gamma decreased in both splenocytes of MRL/lpr mice and PBMCs of SLE patients with ATO treatment, which were accompanied by reduced histone H4 and H3 acetylation in INF-gamma promoter and decreased combination of RNA Pol II to the INF-gamma promoter. Therefore, ATO may reduce the expression level of the INF-gamma by altering the levels of INF gamma promoter acetylation and the combination of RNA Pol II to the INF-gamma promoter in splenocytes of MRL/lpr mice and PBMCs of SLE patients. PMID- 29159557 TI - Correction to: Potentiometric Determination of Fluoride Concentration in Beers. AB - The original version of the article unfortunately contained a mistake. The first author Inmaculada Gutierrez was omitted. PMID- 29159558 TI - Theoretical investigation of the safety of nitroguanidine-based PBXs containing the nonpolar desensitizing agent polytetrafluoroethylene. AB - In order to elucidate why the inclusion of a nonpolar desensitizing agent in polymer-bonded explosives (PBXs) affects their sensitivity and safety, the intermolecular interactions between nitroguanidine (NQ: a high-energy-density compound used as a propellant and in explosive charges) and F2C=CF2 were investigated theoretically at the B3LYP/6-311++G(2df,2p) and M06-2X/6 311++G(2df,2p) levels of theory, focusing especially on the influence of intermolecular interactions on the strength of the trigger bond in NQ. The binding energies and mechanical properties of various beta NQ/polytetrafluoroethylene PBXs were also studied via molecular dynamics simulation. The results indicated that the weak intermolecular interactions between NQ and F2C=CF2 have almost no effect on the strength of the trigger bond or the energy barrier to the intramolecular hydrogen-transfer isomerization of NQ, as also confirmed by an AIM (atoms in molecules) analysis. However, the mechanical properties of the beta-NQ/polytetrafluoroethylene PBXs were found to be significantly different from those of pure beta-NQ: the PBXs showed reduced rigidity and brittleness, greater elasticity and plasticity, and-in particular better ductility. Thus, beta-NQ-based PBXs with polytetrafluoroethylene are predicted to be less sensitive to external mechanical stimuli, leading to reduced explosive sensitivity and increased safety. Only mechanical properties influence the safety of nitroguanidine-based PBXs. PMID- 29159559 TI - Cerberus, an Access Control Scheme for Enforcing Least Privilege in Patient Cohort Study Platforms : A Comprehensive Access Control Scheme Applied to the GENIDA Project - Study of Genetic Forms of Intellectual Disabilities and Autism Spectrum Disorders. AB - Cohort Study Platforms (CSP) are emerging as a key tool for collecting patient information, providing new research data, and supporting family and patient associations. However they pose new ethics and regulatory challenges since they cross the gap between patients and medical practitioners. One of the critical issues for CSP is to enforce a strict control on access privileges whilst allowing the users to take advantage of the breadth of the available data. We propose Cerberus, a new access control scheme spanning the whole life-cycle of access right management: design, implementation, deployment and maintenance, operations. Cerberus enables switching from a dual world, where CSP data can be accessed either from the users who entered it or fully de-identified, to an access-when-required world, where patients, practitioners and researchers can access focused medical data through explicit authorisation by the data owner. Efficient access control requires application-specific access rights, as well as the ability to restrict these rights when they are not used. Cerberus is implemented and evaluated in the context of the GENIDA project, an international CSP for Genetically determined Intellectual Disabilities and Autism Spectrum Disorders. As a result of this study, the software is made available for the community, and validated specifications for CSPs are given. PMID- 29159560 TI - What's new in prognostication after cardiac arrest: microRNAs? PMID- 29159561 TI - High prevalence of sleep apnea syndrome in patients admitted to ICU for acute hypercapnic respiratory failure: a preliminary study. PMID- 29159562 TI - Recommendations on infrastructure and organization of adult ICUs in resource limited settings. PMID- 29159563 TI - Lack of concordance between ECDC and CDC systems for surveillance of ventilator associated pneumonia. PMID- 29159564 TI - Headache in immigrant patients: similarities and differences with Italian population. AB - Headache is one of the most common neurological diseases. It is well known that there are differences in the perception and in the management of pain in various populations. Immigrants represent a growing portion between neurology outpatients. We analyzed the epidemiological characteristic of headache in immigrants come to our attention, in comparison with Italians. Data collected included age at immigration, age of onset of headache, headache's type (HIS criteria), and psychiatric comorbidities. There were not substantial differences in the incidence of headache subtypes: migraine was the most frequent diagnosis in both groups, followed by tension-type headache. The incidence of depression was similar, while anxiety was significantly less frequent in immigrants. Studies on neurological diseases in immigrants are few. The data available seem to show no differences in the incidence, but rather in treatment. Our study confirms the evenness of two populations, local and foreign, afferent in a Headache Unit, according to the single similar study, except for anxiety, maybe related to language difficulties or cultural background. PMID- 29159565 TI - A Comprehensive Review on Mustard-Induced Allergy and Implications for Human Health. AB - Mustard is widely used in a variety of foods/food products to enhance the flavor and nutritional value that subsequently raise the risk of hypersensitivity reactions. Mustard allergy has been reported for many years and is increasing gradually especially in the areas where its consumption is comparatively higher, and it may be considered among the most important food allergies. A number of relevant clinical studies focused on mustard-induced allergic manifestations are summarized in the current review. In addition, the knowledge regarding the immunological as well as biochemical characteristics of mustard allergens that have been known till date and their cross-reactivity with other food allergens have also been discussed here. Notably, mustard may also be present as a hidden allergen in foods; therefore, it is important to recognize food products that may contain mustard as it may pose potential risk for the allergic individuals. Additionally, the better understanding of the underlying mechanism in mustard allergy is a prerequisite for the development of specific therapeutic procedures. Conclusively, mustard sensitivity should be routinely tested in patients with idiopathic anaphylaxis for the safety of the allergic patients. PMID- 29159566 TI - Editorial: epigenetic regulation of plant development and stress responses. PMID- 29159567 TI - Correction to: Abstracts : 29th European Congress of Pathology. AB - Due to an error with the registration system, the following abstract was regrettably omitted from the Poster Sessions. The abstract should have been included as PS-13-128 and displayed on page S201. PMID- 29159568 TI - A cross-sectional and longitudinal study between association of n-3 polyunsaturated fatty acids derived from fish consumption and high-density lipoprotein heterogeneity. AB - Decreased high-density lipoprotein (HDL) particle size, cholesterol poor, apolipoprotein A-I-rich HDL particles leading to smaller HDL particle size, may be associated with an anti-atherosclerotic effect. The data are sparse regarding the relationship between n-3 polyunsaturated fatty acids [n-3 PUFAs: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] and HDL particle size. This study was designed as a hospital-based cross-sectional study to investigate the relationship between the serum levels of n-3 PUFAs and the HDL cholesterol/apolipoprotein A-1 ratio, as estimated by the HDL particle size, in patients with the presence of one or more risk factors for atherosclerotic cardiovascular disease (ASCVD). Six hundred and forty sequential patients were enrolled in this study. The serum levels of EPA and DHA showed a strong correlation (r = 0.736, p < 0.0001). However, in a multivariate regression analysis after adjustment for ASCVD risk factors, increased serum DHA (beta = - 0.745, p = 0.021), but not serum EPA (beta = - 0.414, p = 0.139) or EPA + DHA (beta = 0.330, p = 0.557) level, was identified as an independent indicator of decreased HDL particle size. In 476 patients followed up for at least 6 months, the absolute change (Delta) in the HDL-cholesterol/apolipoprotein A-1 ratio decreased significantly as the quartile of the Delta DHA level increased (p = 0.014), whereas no significant difference in the Delta HDL cholesterol/apolipoprotein A-1 ratio was noted with the increase in the quartile of the Delta EPA level. Moreover, a multivariate regression analysis identified increased DHA level and decreased estimated low-density lipoprotein (LDL) particle size measured relative to the mobility value of LDL with polyacrylamide gel electrophoresis (i.e., relative LDL migration: LDL-Rm value), as independent predictors of decreased HDL-cholesterol/apolipoprotein A-1 ratio (beta = - 0.171, p = 0.0003 and beta = - 0.142, p = 0.002). The results suggest that increased serum DHA level, but not EPA level, might be associated with decreased HDL cholesterol/apolipoprotein A-1 ratio, an indicator of estimated HDL particle size. Further studies are needed to investigate the useful clinical indices and outcomes of these patients. Clinical Trial Registration Information UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010603. PMID- 29159569 TI - Determinants of short and long door-to-balloon time in current primary percutaneous coronary interventions. AB - Primary percutaneous coronary interventions (PCI) have been developed to improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). In primary PCI, the door-to-balloon time (DTBT) is closely associated with mortality and morbidity. The purpose of this study was to find determinants of short and long DTBT. From our hospital record, we included 214 STEMI patients, and divided into the short DTBT group (DTBT < 60 min, n = 60), the intermediate DTBT group (60 min <= DTBT <= 120 min, n = 121) and the long DTBT group (DTBT > 120 min, n = 33). In-hospital mortality was highest in the long DTBT group (24.2%), followed by the intermediate DTBT group (5.8%), and lowest in the short DTBT group (0%) (< 0.001). Transfers from local clinics or hospitals (OR 3.43, 95% CI 1.72-6.83, P < 0.001) were significantly associated with short DTBT, whereas Killip class 3 or 4 (vs. Killip class 1 or 2: OR 0.20, 95% CI 0.06-0.64, P = 0.007) was inversely associated with short DTBT in multivariate analysis. In conclusion, transfer from local clinics/hospitals was associated with short DTBT. Our results may suggest the current limitation of ambulance system, which does not include pre-hospital ECG system, in Japan. The development of pre-hospital ECG system would be needed for better management in STEMI. PMID- 29159570 TI - Multi-timescale analysis of a metabolic network in synthetic biology: a kinetic model for 3-hydroxypropionic acid production via beta-alanine. AB - A biosustainable production route for 3-hydroxypropionic acid (3HP), an important platform chemical, would allow 3HP to be produced without using fossil fuels. We are interested in investigating a potential biochemical route to 3HP from pyruvate through [Formula: see text]-alanine and, in this paper, we develop and solve a mathematical model for the reaction kinetics of the metabolites involved in this pathway. We consider two limiting cases, one where the levels of pyruvate are never replenished, the other where the levels of pyruvate are continuously replenished and thus kept constant. We exploit the natural separation of both the time scales and the metabolite concentrations to make significant asymptotic progress in understanding the system without resorting to computationally expensive parameter sweeps. Using our asymptotic results, we are able to predict the most important reactions to maximize the production of 3HP in this system while reducing the maximum amount of the toxic intermediate compound malonic semi aldehyde present at any one time, and thus we are able to recommend which enzymes experimentalists should focus on manipulating. PMID- 29159571 TI - Comparing eye movements during position tracking and identity tracking: No evidence for separate systems. AB - There is an ongoing debate as to whether people track multiple moving objects in a serial fashion or with a parallel mechanism. One recent study compared eye movements when observers tracked identical objects (Multiple Object Tracking-MOT task) versus when they tracked the identities of different objects (Multiple Identity Tracking-MIT task). Distinct eye-movement patterns were found and attributed to two separate tracking systems. However, the same results could be caused by differences in the stimuli viewed during tracking. In the present study, object identities in the MIT task were invisible during tracking, so observers performed MOT and MIT tasks with identical stimuli. Observer were able to track either position and identity depending on the task. There was no difference in eye movements between position tracking and identity tracking. This result suggests that, while observers can use different eye-movement strategies in MOT and MIT, it is not necessary. PMID- 29159572 TI - Comparison of positron emission tomography/computed tomography and magnetic resonance imaging for posttherapy evaluation in patients with advanced cervical cancer receiving definitive concurrent chemoradiotherapy. AB - PURPOSE: Our purpose was to assess the diagnostic performance of positron emission tomography/computed tomography (PET/CT) and pelvic/abdominal magnetic resonance imaging (MRI) after concurrent chemoradiotherapy (CCRT) for posttherapy evaluation in patients with advanced cervical cancer. METHODS: Patients with cervical squamous cell carcinoma, either with advanced FIGO stage or with positive pelvic or para-aortic lymph node (PALN), received PET/CT using [18F]fluorodeoxyglucose and MRI including diffusion-weighted imaging between 2 and 3 months after CCRT completion. PET/CT were interpreted independently by two nuclear medicine physicians and MRI by two radiologists using the same scoring system. Active residual tumor was proven by pathological confirmation or disease progression on imaging studies within one year after CCRT and the disease regions were classified as local, regional, PALN, or distant. Patient-based and region based comparison was performed using the receiver operating characteristic curve analysis. RESULTS: The study included 55 patients and 15 (27%) patients had active residual tumor. The diagnostic performance of PET/CT is significantly superior to that of MRI in patient-based analysis (P = 0.025) and in the detection of local (P = 0.045) and regional (P = 0.014) disease. The patient based sensitivity, specificity, and accuracy of PET/CT are 60%, 100%, and 89% while those of MRI are 27%, 100%, and 80%. CONCLUSIONS: PET/CT is superior to MRI for posttherapy evaluation in patients with advanced cervical cancer 2-3 months after definitive CCRT, mainly for the detection of residual local and regional disease. Patients with negative or equivocal results should be followed up regularly due to suboptimal sensitivities of imaging. PMID- 29159573 TI - Low baseline and subsequent higher aortic abdominal aneurysm FDG uptake are associated with poor sac shrinkage post endovascular repair. AB - PURPOSE: The growth phases of medically treated abdominal aortic aneurysms (AAA) are frequently associated with an 18F-fluorodesoxyglucose positron emission tomography (FDG-PET) pattern involving low baseline and subsequent higher FDG uptake. However, the FDG-PET patterns associated with the endovascular aneurysm repair (EVAR) of larger AAA are presently unknown. This study aimed to investigate the relationship between serial AAA FDG uptake measurements, obtained before EVAR and 1 and 6 months post-intervention and subsequent sac shrinkage at 6 months, a well-recognized indicator of successful repair. METHODS: Thirty-three AAA patients referred for EVAR (maximal diameter: 55.4 +/- 6.0 mm, total volume: 205.7 +/- 63.0 mL) underwent FDG-PET/computed tomography (CT) before EVAR and at 1 and 6 months thereafter, with the monitoring of AAA volume and of a maximal standardized FDG uptake [SUVmax] averaged between the axial slices encompassing the AAA. RESULTS: Sac shrinkage was highly variable and could be stratified into three terciles: a first tercile in which shrinkage was absent or very limited (0 29 mL) and a third tercile with pronounced shrinkage (56-165 mL). SUVmax values were relatively low at baseline in the 1st tercile (SUVmax: 1.69 +/- 0.33), but markedly increased at 6 months (2.42 +/- 0.69, p = 0.02 vs. baseline). These SUV max values were by contrast much higher at baseline in the 3rd tercile (SUVmax: 2.53 +/- 0.83 p = 0.009 vs. 1st tercile) and stable at 6 months (2.49 +/- 0.80), while intermediate results were documented in the 2nd tercile. Lastly, the amount of sac shrinkage, expressed in absolute values or in percentages of baseline AAA volumes, was positively correlated with baseline SUVmax (p = 0.001 for both). CONCLUSION: A low pre-EVAR FDG uptake and increased AAA FDG uptake at 6 months are associated with reduced sac shrinkage. This sequential FDG-PET pattern is similar to that already shown to accompany growth phases of medically treated AAA. PMID- 29159574 TI - Reply to comments on "Brain abscess due to Nocardia infection in an immunocompetent patient with asymptomatic pulmonary alveolar proteinosis". Acta Neurol Belg DOI 10.1007/s13760-017-0815-6. PMID- 29159575 TI - [DOG and BVA guideline no. 24b : Noninfectious uveitis posterior]. PMID- 29159576 TI - An experience of second-trimester anhydramnios salvaged by single amnioinfusion. AB - Second-trimester anhydramnios, which is primarily caused by ruptured membranes, placental dysfunction, or congenital renal malformations, is associated with high perinatal morbidity and mortality. Although amnioinfusion temporarily increases amniotic fluid volume, it does not generally provide a fundamental solution. We describe a case of second-trimester anhydramnios with an umbilical cord factor, wherein single amnioinfusion may have successfully broken a vicious circle involving non-reassuring fetal status. A 34-year-old primigravid woman was referred to our hospital because of anhydramnios at 22 weeks' gestation. Single amnioinfusion improved the fetal circulatory failure, and the patient delivered a healthy full-term newborn. Single amnioinfusion may be a therapeutic approach to improve the prognosis of pregnancy when second-trimester anhydramnios results from umbilical cord factors. PMID- 29159577 TI - Core curriculum case illustration: a rare case of an isolated fallopian tube torsion. AB - This is the 46th installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at: http://www.erad.org/page/CCIP_TOC . PMID- 29159578 TI - Assessing Quality of Program Environments for Children and Youth with Autism: Autism Program Environment Rating Scale (APERS). AB - The purpose of this study was to examine the psychometric properties of the Autism Program Environment Rating Scale (APERS), an instrument designed to assess quality of program environments for students with autism spectrum disorder. Data sets from two samples of public school programs that provided services to children and youth with autism spectrum disorder were utilized. Cronbach alpha analyses indicated high coefficients of internal consistency for the total APERS and moderate levels for item domains for the first data set, which was replicated with the second data set. A factor analysis of the first data set indicated that all domain scores loaded on one main factor, in alignment with the conceptual model, with this finding being replicated in the second data set. Also, the APERS was sensitive to changes resulting from a professional development program designed to promote program quality. PMID- 29159579 TI - Examining the Effectiveness of Naturalistic Social Skills Training in Developing Social Skills and Theory of Mind in Preschoolers with ASD. AB - We compared the effectiveness of two programs for developing social skills, 'Play Time/Social Time' (PT/ST) and 'I Can Problem Solve' (ICPS), in improving the social skills and theory of mind (ToM) of preschoolers with ASD. The experiment took place in a classroom setting. Fifty-two children attended and data were analyzed with latent growth curve models. Comparison with a control group indicated that both programs were effective in developing social skills. The PT/ST program was more effective than ICPS in developing interaction skills; both programs improved children's ability to cope with difficult social situations. The ICPS program was marginally effective in developing ToM when compared with PT/ST and control condition. These results are relevant to children with ASD and their teachers. PMID- 29159580 TI - Low left amygdala volume is associated with a longer duration of unipolar depression. AB - The amygdala plays a crucial role in the pathogenesis of major depressive disorder (MDD). While robust findings support a negative impact of illness duration on hippocampal volume in MDD, morphometric studies of the amygdala have yielded inhomogeneous results. Considering the methodical problems of automatic segmentation methods, a standardized segmentation protocol with proven inter- and intra-rater reliability was employed using high-resolution magnetic resonance imaging. To identify the effect of MDD on amygdala morphometry, 23 unipolar depressed patients who responded to antidepressant medication and 30 age-matched healthy controls (HC) were enrolled. First, gray matter volumes (GMV) of the bilateral amygdala were delineated manually in 3D by three blinded experts using the MultiTracer. The whole brain GMV was determined by using voxel-based morphometry. Second, the differences of the whole brain and the bilateral amygdala GMV values between MDD and HC were calculated with t-statistics. The GMV of the whole brain and the amygdala did not differ between HC and MDD patients. Third, MDD characteristics were correlated with amygdala GMV. Within the normal range, the left amygdala GMV was larger in patients with later onset and smaller in cases of prolonged depression. In line with prior reports of depressed patients responding to antidepressant treatment, amygdala GMV was negatively related to illness duration, suggesting volume loss with disease progression. It remains unclear as to whether the association between illness duration and GMV reduced left amygdala volume indicates a neurotoxic effect of prolonged MDD or is rather a negative predictor of chronic depression. PMID- 29159581 TI - Inhibition of salivary secretion by tolterodine transdermal patch. AB - Tolterodine, a nonselective muscarinic antagonist available only as immediate release (IR) or extended release (ER) oral formulations, is used for the treatment of overactive bladder (OAB). This study aimed to compare the efficacy and extent of dry mouth adverse effects of tolterodine transdermal patch to the oral formulation. The two formulations have been examined through the muscarinic receptor binding tests conducted in bladder and salivary gland tissues and the salivary secretion tests conducted in rats. Comparable average tolterodine blood concentration levels were obtained 3 h after oral administration of tolterodine 25 mg/kg and 12 h after transdermal application of tolterodine patch 6 mg/8 cm2. While Kd in the bladder tissue increased to a similar degree in both formulations of tolterodine, Kd in the salivary gland increased to a greater degree in the oral formulation. These results indicate that similar degree of inhibitory effects were observed in the bladder for both formulations while less inhibitory effects were observed in the salivary gland with tolterodine transdermal formulation compared to the oral formulation. For assessment of salivary secretion, tolterodine transdermal patch 6 mg/8 cm2 application resulted in significantly less inhibitory effects than oral tolterodine 25 mg/kg. Therefore, this study suggests that tolterodine transdermal patch could be a useful formulation that provides uniform and consistent inhibitory effects to effectively control OAB symptoms with reduced severity of dry mouth in comparison to the oral formulation. PMID- 29159582 TI - Development of taladegib as a sonic hedgehog signaling pathway inhibitor. PMID- 29159584 TI - Correction to: Optimized synthesis of novel prenyl ferulate performed by feruloyl esterases from Myceliophthora thermophila in microemulsions. AB - After publication of the original article, authors found that there has been a minor mistake in the units of kcat and kcat/Km in Table 2. The units should be 103 min-1 g-1 FAE for kcat and mM-1 min-1 g-1 FAE for kcat/Km. This correction does not affect any conclusions drawn within the article. PMID- 29159583 TI - The Association Between Artificial Sweeteners and Obesity. AB - PURPOSE OF REVIEW: The purpose of this paper is to review the epidemiology of obesity and the evolution of artificial sweeteners; to examine the latest research on the effects of artificial sweeteners on the host microbiome, the gut brain axis, glucose homeostasis, and energy consumption; and to discuss how all of these changes ultimately contribute to obesity. RECENT FINDINGS: Although artificial sweeteners were developed as a sugar substitute to help reduce insulin resistance and obesity, data in both animal models and humans suggest that the effects of artificial sweeteners may contribute to metabolic syndrome and the obesity epidemic. Artificial sweeteners appear to change the host microbiome, lead to decreased satiety, and alter glucose homeostasis, and are associated with increased caloric consumption and weight gain. Artificial sweeteners are marketed as a healthy alternative to sugar and as a tool for weight loss. Data however suggests that the intended effects do not correlate with what is seen in clinical practice. Future research should focus on the newer plant-based sweeteners, incorporate extended study durations to determine the long-term effects of artificial sweetener consumption, and focus on changes in the microbiome, as that seems to be one of the main driving forces behind nutrient absorption and glucose metabolism. PMID- 29159585 TI - KfoA, the UDP-glucose-4-epimerase of Escherichia coli strain O5:K4:H4, shows preference for acetylated substrates. AB - Capsule of Escherichia coli O5:K4:H4 is formed of a chondroitin-repeat disaccharide unit of glucuronic acid (GlcA)-N-acetylgalactosamine (GalNAc). This polysaccharide, commonly referred to as K4CP, is a potentially important source of precursors for chemoenzymatic or bioengineering synthesis of chondroitin sulfate. KfoA, encoded by a gene from region 2 of the K4 capsular gene cluster, shows high homology to the UDP-glucose-4-epimerase (GalE) from E. coli. KfoA is reputed to be responsible for uridine 5'-diphosphate-N-acetylgalactosamine (UDP GalNAc) supply for K4CP biosynthesis in vivo, but it has not been biochemically characterized. Here, we probed the substrate specificity of KfoA by a capillary electrophoresis (CE)-based method. KfoA could epimerize both acetylated and non acetylated substrates, but its k cat/K m value for UDP-GlcNAc was approximately 1300-fold that for UDP-Glc. Recombinant KfoA showed a strong preference for acetylated substrates in vitro. The conclusion that KfoA is a higher efficiency UDP-GalNAc provider than GalE was supported by a coupled assay developed based on the donor-acceptor combination specificity of E. coli K4 chondroitin polymerase (KfoC). Furthermore, residue Ser-301, located near the UDP-GlcNAc binding pocket, plays an important role in the determination of the conversion ratio of UDP GlcNAc to UDP-GalNAc by KfoA. Our results deepen the understanding of the mechanism of KfoA and will assist in the research into the metabolic engineering for chondroitin sulfate production. PMID- 29159586 TI - Extensive hydrolysis of raw rice starch by a chimeric alpha-amylase engineered with alpha-amylase (AmyP) and a starch-binding domain from Cryptococcus sp. S-2. AB - Recombinant chimeric alpha-amylase (AmyP-Cr) was constructed by a catalytic core of alpha-amylase (AmyP) from a marine metagenomic library and a starch-binding domain (SBDCr) of alpha-amylase from Cryptococcus sp. S-2. The molecular fusion did not alter optimum pH, optimum temperature, hydrolysis products, and an ability of preferential and rapid degradation towards raw rice starch, but catalytic efficiency and thermostability were remarkably improved compared with those of the wild-type AmyP. AmyP-Cr achieved the final hydrolysis degree of 61.7 +/- 1.2% for 10% raw rice starch and 47.3 +/- 0.8% for 15% raw rice starch after 4 h at 40 degrees C with 1.0 U per mg of raw starch. The catalytic efficiency was very high, with 3.6-4.0 times higher than that of AmyP. The enhanced catalytic efficiency was attributed to the better thermostability and the higher adsorption and disruption to raw rice starch caused by SBDCr. The properties of AmyP-Cr open a new way in terms of a new design of raw rice starch processing. PMID- 29159587 TI - Teaching an old pET new tricks: tuning of inclusion body formation and properties by a mixed feed system in E. coli. AB - Against the outdated belief that inclusion bodies (IBs) in Escherichia coli are only inactive aggregates of misfolded protein, and thus should be avoided during recombinant protein production, numerous biopharmaceutically important proteins are currently produced as IBs. To obtain correctly folded, soluble product, IBs have to be processed, namely, harvested, solubilized, and refolded. Several years ago, it was discovered that, depending on cultivation conditions and protein properties, IBs contain partially correctly folded protein structures, which makes IB processing more efficient. Here, we present a method of tailored induction of recombinant protein production in E. coli by a mixed feed system using glucose and lactose and its impact on IB formation. Our method allows tuning of IB amount, IB size, size distribution, and purity, which does not only facilitate IB processing, but is also crucial for potential direct applications of IBs as nanomaterials and biomaterials in regenerative medicine. PMID- 29159588 TI - Arabidopsis thaliana MLO genes are expressed in discrete domains during reproductive development. AB - KEY MESSAGE: MLOs in Plant Reproduction. The MILDEW RESISTANCE LOCUS-O (MLO) protein family, comprised of 15 members, plays roles in diverse cell-cell communication processes such as powdery mildew susceptibility, root thigmomorphogenesis, and pollen tube reception. The NORTIA (NTA, AtMLO7) gene is expressed in the synergid cells of the female gametophyte where it functions in intercellular communication with the pollen tube. Discrepancies between previously published promoter::GUS and promoter::gene-GUS constructs expression patterns led us to explore the regulation of NTA expression. Here we found via NTApro::gNTA-GUS truncations that sequences within the NTA gene negatively regulate its expression in the stomata and carpel walls. This led to the hypothesis that other MLO family members may also have additional regulatory sequences within the gene. MLOpro::gMLO-GUS constructs were examined for each family member focusing specifically on flowers in order to determine whether other MLOs could play a role in reproductive cell-cell communication. Notably, several MLOs were expressed in the pollen, in the stigma, in the pollinated style, and in the synergids and central cell. These findings indicate that other MLOs in addition to NTA could play a role in reproduction. Previous studies on the MLO family showed that phylogenetically related MLOs had redundant functions in powdery mildew infection and root thigmomorphogenesis; however, MLO expression in reproductive tissues did not strictly follow phylogenetic relationships, indicating that MLOs from different evolutionary origins may have been recruited for function in sexual reproduction. PMID- 29159589 TI - The effect of Mindfulness-Based Stress Reduction on wound healing: a preliminary study. AB - Psychological factors have been shown to influence the process of wound healing. This study examined the effect of Mindfulness-Based Stress Reduction (MBSR) on the speed of wound healing. The local production of pro-inflammatory cytokines and growth factors was studied as potential underlying mechanism. Forty-nine adults were randomly allocated to a waiting-list control group (n = 26) or an 8 week MBSR group (n = 23). Pre- and post-intervention/waiting period assessment for both groups consisted of questionnaires. Standardized skin wounds were induced on the forearm using a suction blister method. Primary outcomes were skin permeability and reduction in wound size monitored once a day at day 3, 4, 5, 6, 7, and 10 after injury. Secondary outcomes were cytokines and growth factors and were measured in wound exudates obtained at 3, 6, and 22 h after wounding. Although there was no overall condition effect on skin permeability or wound size, post hoc analyses indicated that larger increases in mindfulness were related to greater reductions in skin permeability 3 and 4 days after wound induction. In addition, MBSR was associated with lower levels of interleukin (IL) 8 and placental growth factor in the wound fluid 22 h after wound induction. These outcomes suggest that increasing mindfulness by MBSR might have beneficial effects on early stages of wound healing. Trial Registration NTR3652, http://www.trialregister.nl. PMID- 29159590 TI - Nanovirus-alphasatellite complex identified in Vicia cracca in the Rhone delta region of France. AB - Nanoviruses are multi-component plant-infecting single-stranded DNA viruses. Using a viral metagenomics-informed approach, a new nanovirus and two associated alphasatellite molecules have been identified in an uncultivated asymptomatic Vicia cracca plant in the Rhone region of France. This novel nanovirus genome includes eight genomic components (named DNA-R, DNA-S, DNA-M, DNA-C, DNA-N, DNA U1, DNA-U2 and DNA-U4) and, across all components, shares < 66% pairwise sequence identity with other nanovirus genomes. The two associated alphasatellites share 62% identity with each other and < 81% identity will all other nanovirus associated alphasatellites. PMID- 29159591 TI - Evaluation of the associations between endothelial dysfunction, inflammation and coagulation in Crimean-Congo hemorrhagic fever patients. AB - Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne zoonotic viral disease. The aim of this study was to evaluate the association between inflammation, coagulation and endothelial dysfunction in CCHF. The study population consisted of 40 patients and 50 healthy controls. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), endocan, high sensitive C-reactive protein (hsCRP), international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (aPTT) and platelets values were determined in blood samples. Median hsCRP (p < 0.0001), ALT (p < 0.001), AST (p < 0.001) and aPTT (p < 0.001) values were found to be higher in CCHF patients than in the healthy control subjects. In contrast, median endocan (p = 0.0006) and platelet (p < 0.001) concentrations were found to be lower in CCHF patients than in healthy controls. Serum hsCRP concentrations positively correlated with PT, aPTT and INR in CCHF patients, whereas serum endocan levels were not correlated with hsCRP, PT, aPTT and INR. In conclusion, endothelial dysfunction is one of the key steps in CCHF disease development and serum endocan may be used as a biomarker to evaluate endothelial dysfunction in patients. There is no relationship between increased inflammation and endothelial dysfunction. Coagulation abnormalities might be related to the impaired hepatic synthetic function of coagulation factors. Increased hsCRP concentrations may have a compensatory role in restoring impaired hemostasis in CCHF. Further research is needed to confirm these findings and to examine possible explanations. PMID- 29159593 TI - High Burden of HIV, Syphilis and HSV-2 and Factors Associated with HIV Infection Among Female Sex Workers in Tanzania: Implications for Early Treatment of HIV and Pre-exposure Prophylaxis (PrEP). AB - This paper estimates population-based prevalence of HIV, syphilis, HSV-2 and factors influencing HIV infection using a national sample of 1914 female sex workers (FSWs) in 7 regions in Tanzania. Additionally, HIV incidence was estimated by comparing biological HIV results with self-reported HIV status. The average HIV prevalence among FSWs in all 7 regions was 28%, ranging from 14% in Tabora to 38% in Shinyanga. HIV incidence was found to be 13 per 100 person years. Syphilis prevalence was 8% with significantly higher burden found in Iringa (11%), Mbeya (13%), and Shinyanga (12%). Nearly 60% of the study population was infected with HSV-2. The high HIV prevalence and incidence coupled with suboptimal condom use indicate an urgent need to roll out the "Treat-All" approach and provide antiretroviral therapy to FSWs living with HIV regardless of their CD4 count. In addition, antiretroviral-based prevention technologies such as oral pre-exposure prophylaxis and microbicides should be piloted and evaluated. PMID- 29159592 TI - Uptake of a Partner Notification Model for HIV Among Men Who Have Sex With Men and Transgender Women in Tijuana, Mexico. AB - Undiagnosed HIV infection is common among men who have sex with men (MSM) and transgender women (TW) in Latin America. We examined uptake of a partner notification (PN) model among MSM and TW in Tijuana, Mexico. Forty-six HIV positive MSM/TW enrolled as index patients, and reported 132 MSM/TW sexual partners for PN. Of notified partners (90/132), 39% declined eligibility screening or participation, 39% tested for HIV, and of those 28% were newly diagnosed HIV-positive. Partners who were seen by the index patient more than once in the past 4 months and those who primarily had sex with the index patient in one of their homes were more likely to be notified via PN (76% vs. 50%; p = 0.01 and 86% vs. 64%, p = 0.02, respectively). Lower than expected PN uptake was associated with problems identifying index patients, obtaining reliable partner contact information, and engaging notified partners. PMID- 29159594 TI - Structural Interventions in HIV Prevention: A Taxonomy and Descriptive Systematic Review. AB - One of the four national HIV prevention goals is to incorporate combinations of effective, evidence-based approaches to prevent HIV infection. In fields of public health, techniques that alter environment and affect choice options are effective. Structural approaches may be effective in preventing HIV infection. Existing frameworks for structural interventions were lacking in breadth and/or depth. We conducted a systematic review and searched CDC's HIV/AIDS Prevention Research Synthesis Project's database for relevant interventions during 1988 2013. We used an iterative process to develop the taxonomy. We identified 213 structural interventions: Access (65%), Policy/Procedure (32%), Mass Media (29%), Physical Structure (27%), Capacity Building (24%), Community Mobilization (9%), and Social Determinants of Health (8%). Forty percent targeted high-risk populations (e.g., people who inject drugs [12%]). This paper describes a comprehensive, well-defined taxonomy of structural interventions with 7 categories and 20 subcategories. The taxonomy accommodated all interventions identified. PMID- 29159595 TI - Resilience and Physical and Mental Well-Being in Adults with and Without HIV. AB - Resilience has been related to improved physical and mental health, and is thought to improve with age. No studies have explored the relationship between resilience, ageing with HIV, and well-being. A cross sectional observational study performed on UK HIV positive (N = 195) and HIV negative adults (N = 130). Associations of both age and 'time diagnosed with HIV' with resilience (RS-14) were assessed, and the association of resilience with depression, anxiety symptoms (PHQ-9 and GAD-7), and problems with activities of daily living (ADLs) (Euroqol 5D-3L). In a multivariable model, HIV status overall was not related to resilience. However, longer time diagnosed with HIV was related to lower resilience, and older age showed a non-significant trend towards higher resilience. In adults with HIV, high resilience was related to a lower prevalence of depression, anxiety, and problems with ADLs. It may be necessary to consider resilience when exploring the well-being of adults ageing with HIV. PMID- 29159596 TI - Human monoclonal antibodies as candidate therapeutics against emerging viruses. AB - The emergence of new pathogens, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and Ebola virus, poses serious challenges to global public health and highlights the urgent need for novel antiviral approaches. Monoclonal antibodies (mAbs) have been successfully used to treat various diseases, particularly cancer and immunological disorders. Antigen-specific mAbs have been isolated using several different approaches, including hybridoma, transgenic mice, phage display, yeast display, and single B-cell isolation. Consequently, an increasing number of mAbs, which exhibit high potency against emerging viruses in vitro and in animal models of infection, have been developed. In this paper, we summarize historical trends and recent developments in mAb discovery, compare the advantages and disadvantages of various approaches to mAb production, and discuss the potential use of such strategies for the development of antivirals against emerging diseases. We also review the application of recently developed human mAbs against SARS-CoV, MERS-CoV, and Ebola virus and discuss prospects for the development of mAbs as therapeutic agents against emerging viral diseases. PMID- 29159597 TI - Universal influenza virus vaccines: what can we learn from the human immune response following exposure to H7 subtype viruses? AB - Several universal influenza virus vaccine candidates based on eliciting antibodies against the hemagglutinin stalk domain are in development. Typically, these vaccines induce responses that target group 1 or group 2 hemagglutinins with little to no cross-group reactivity and protection. Similarly, the majority of human anti-stalk monoclonal antibodies that have been isolated are directed against group 1 or group 2 hemagglutinins with very few that bind to hemagglutinins of both groups. Here we review what is known about the human humoral immune response to vaccination and infection with H7 subtype influenza viruses on a polyclonal and monoclonal level. It seems that unlike vaccination with H5 hemagglutinin, which induces antibody responses mostly restricted to the group 1 stalk domain, H7 exposure induces both group 2 and cross-group antibody responses. A better understanding of this phenomenon and the underlying mechanisms might help to develop future universal influenza virus vaccine candidates. PMID- 29159598 TI - eTOX ALLIES: an automated pipeLine for linear interaction energy-based simulations. AB - BACKGROUND: Computational methods to predict binding affinities of small ligands toward relevant biological (off-)targets are helpful in prioritizing the screening and synthesis of new drug candidates, thereby speeding up the drug discovery process. However, use of ligand-based approaches can lead to erroneous predictions when structural and dynamic features of the target substantially affect ligand binding. Free energy methods for affinity computation can include steric and electrostatic protein-ligand interactions, solvent effects, and thermal fluctuations, but often they are computationally demanding and require a high level of supervision. As a result their application is typically limited to the screening of small sets of compounds by experts in molecular modeling. RESULTS: We have developed eTOX ALLIES, an open source framework that allows the automated prediction of ligand-binding free energies requiring the ligand structure as only input. eTOX ALLIES is based on the linear interaction energy approach, an efficient end-point free energy method derived from Free Energy Perturbation theory. Upon submission of a ligand or dataset of compounds, the tool performs the multiple steps required for binding free-energy prediction (docking, ligand topology creation, molecular dynamics simulations, data analysis), making use of external open source software where necessary. Moreover, functionalities are also available to enable and assist the creation and calibration of new models. In addition, a web graphical user interface has been developed to allow use of free-energy based models to users that are not an expert in molecular modeling. CONCLUSIONS: Because of the user-friendliness, efficiency and free-software licensing, eTOX ALLIES represents a novel extension of the toolbox for computational chemists, pharmaceutical scientists and toxicologists, who are interested in fast affinity predictions of small molecules toward biological (off-)targets for which protein flexibility, solvent and binding site interactions directly affect the strength of ligand-protein binding. PMID- 29159599 TI - Delayed Gastric Emptying Following Laparoscopic Repair of Very Large Hiatus Hernias Impairs Quality of Life. AB - BACKGROUND: Delayed gastric emptying (DGE) following hiatus hernia surgery may affect a substantial number of patients with adverse clinical consequences. Here, we aim to evaluate the impact of DGE following laparoscopic repair of very large hiatus hernias on patients' quality of life, gastrointestinal symptomatology, and daily function. METHODS: Analysis of data collected from a multicenter prospective randomised trial of patients who underwent laparoscopic mesh versus sutured repair of very large hiatus hernias (>50% of stomach in chest). DGE was defined as gastric food retention visualised at endoscopy after 6 h of fasting at 6 months post-surgery. Quality of life (QOL), gastrointestinal symptomatology, and daily function were assessed with the SF-36 questionnaire, Visick scoring and structured surveys administered prior to surgery and at 1, 3, 6 and 12 months after surgery. RESULTS: Nineteen of 102 (18.6%) patients had DGE 6 months after surgery. QOL questionnaires were completed in at least 80% of patients across all time points. Compared with controls, the DGE group demonstrated significantly lower SF-36 physical component scores, delayed improvement in health transition, more adverse gastrointestinal symptoms, higher Visick scores and a slower rate of return to normal daily activities. These differences were still present 12 months after surgery. CONCLUSIONS: DGE following large hiatus hernia repair is associated with a negative impact on quality of life at follow-up to 12 months after surgery. PMID- 29159600 TI - Early Seizure Prophylaxis in Traumatic Brain Injuries Revisited: A Prospective Observational Study. AB - INTRODUCTION: Pharmacological prophylaxis for early seizures following traumatic brain injury (TBI) is a recommendation in the Brain Trauma Foundation Guidelines. However, several studies have challenged the efficacy and safety of this practice, resulting in varied practice across centers around the world. The purpose of the present study was to compare the incidence of early clinical seizures following TBI, between two large centers, a US Center that practises routine seizure prophylaxis and a Chinese Center that does not use seizure prophylaxis following TBI. PATIENTS AND METHODS: This was a prospective observational study including an urban level I trauma center in the USA and a large hospital in Shenzhen, China. At the US Center, all patients received seizure prophylaxis with levetiracetam. At the Chinese Center, no seizure prophylaxis was given. All patients with blunt TBI and positive computed tomography findings for epidural hematoma, subdural hematoma, subarachnoid hemorrhage, intracerebral hemorrhage or diffuse axonal injury were included. Patients who died within 24 h of admission were excluded. The study population was monitored daily for clinical seizures for the first 7 post-injury days. Data collected included demographics, mechanism of injury, vital signs upon arrival, injury severity and emergency interventions. Primary outcome was the incidence of early seizures, defined as those occurring within 7 days of injury. RESULTS: A total of 522 patients were included in the analysis: 272 patients at the US Center who received seizure prophylaxis and 250 patients at the Chinese Center who did not receive prophylaxis. Overall, 3.7% of patients who received seizure prophylaxis developed early seizures, compared to 2.8% of patients who did not receive any prophylaxis (p = 0.573). Decompressive craniectomy was associated with the highest incidence of early seizure (9.2%). In this subgroup, the seizure rate was 10.4% in the prophylaxis group and 7.1% in the no-prophylaxis group (p = 0.738). Patients with admission GCS < 9 had an overall early seizure incidence of 7.0%: 4.3% in the prophylaxis group and 14.3% in the no-prophylaxis group (p = 0.062). Analysis of the subgroup with isolated blunt TBI showed an incidence of early seizures of 3.4% in the prophylaxis group versus 2.4% in the no-prophylaxis group (p = 0.593). Further analyses of outcomes according to head AIS 3, 4 and 5 showed no significant difference in the seizure rate between the two groups: head AIS 3: 6.1% in the prophylaxis group versus 2.6% in the no-prophylaxis group, p = 0.329; head AIS 4: 0 versus 2.7%, p = 0.302; head AIS 5: 8.7 versus 4.0%, p = 0.601. CONCLUSIONS: The present study failed to show any benefit of routine early seizure prophylaxis following blunt TBI. This practice should be reexamined in a large randomized clinical study. PMID- 29159601 TI - Activating FGFR1 Mutations in Sporadic Pheochromocytomas. AB - INTRODUCTION: Pheochromocytomas are neuroendocrine tumors of the adrenal glands. Up to 40% of the cases are caused by germline mutations in one of at least 15 susceptibility genes, making them the human neoplasms with the highest degree of heritability. Recurrent somatic alterations are found in about 50% of the more common sporadic tumors with NF1 being the most common mutated gene (20-25%). In many sporadic tumors, however, a genetic explanation is still lacking. MATERIALS AND METHODS: We investigated the genomic landscape of sporadic pheochromocytomas with whole-exome sequencing of 16 paired tumor and normal DNA samples and extended confirmation analysis in 2 additional cohorts comprising a total of 80 sporadic pheochromocytomas. RESULTS: We discovered on average 33 non-silent somatic variants per tumor. One of the recurrently mutated genes was FGFR1, encoding the fibroblast growth factor receptor 1, which was recently revealed as an oncogene in pediatric brain tumors. Including a subsequent analysis of a larger cohort, activating FGFR1 mutations were detected in three of 80 sporadic pheochromocytomas (3.8%). Gene expression microarray profiling showed that these tumors clustered with NF1-, RET,- and HRAS-mutated pheochromocytomas, indicating activation of the MAPK and PI3K-AKT signal transduction pathways. CONCLUSION: Besides RET and HRAS, FGFR1 is only the third protooncogene found to be recurrently mutated in pheochromocytomas. The results advance our biological understanding of pheochromocytoma and suggest that somatic FGFR1 activation is an important event in a subset of sporadic pheochromocytomas. PMID- 29159602 TI - Competitive Advantage of MBA for Physician Executives: A Systematic Literature Review. AB - In response to systemic challenges facing the US healthcare system, many medical students, residents and practicing physicians are pursuing a Master in Business Administration (MBA) degree. The value of such proposition remains poorly defined. The aim of this review is to analyze current literature pertaining to the added value of MBA training for physician executives (PEs). We hypothesized that physicians who supplement their clinical expertise with business education gain a significant competitive advantage. A detailed literature search of four electronic databases (PubMed, SCOPUS, Embase and ERIC) was performed. Included were studies published between Jan 2000 and June 2017, focusing specifically on PEs. Among 1580 non-duplicative titles, we identified 23 relevant articles. Attributes which were found to add value to one's competitiveness as PE were recorded. A quality index score was assigned to each article in order to minimize bias. Results were tabulated by attributes and by publication. We found that competitive domains deemed to be most important for PEs in the context of MBA training were leadership (n = 17), career advancement opportunities (n = 12), understanding of financial aspects of medicine (n = 9) and team-building skills (n = 10). Among other prominent factors associated with the desire to engage in an MBA were higher compensation, awareness of public health issues/strategy, increased negotiation skills and enhanced work-life balance. Of interest, the learning of strategies for reducing malpractice litigation was less important than the other drivers. This comprehensive systemic review supports our hypothesis that a business degree confers a competitive advantage for PEs. Physician executives equipped with an MBA degree appear to be better equipped to face the challenge of the dynamically evolving healthcare landscape. This information may be beneficial to medical schools designing or implementing combined dual-degree curricula. PMID- 29159603 TI - Prophylactic Intraperitoneal Onlay Mesh Reinforcement Reduces the Risk of Incisional Hernia, Two-Year Results of a Randomized Clinical Trial. AB - BACKGROUND: Incisional hernias still are a major concern after laparotomy and are causing substantial morbidity. This study examines the feasibility, safety and incisional hernia rate of the use of a prophylactic intraperitoneal onlay mesh stripe (IPOM) to prevent incisional hernia following midline laparotomy. METHODS: This prospective, randomized controlled trial randomly allocated patients undergoing median laparotomy either to mass closure of the abdominal wall with a PDS-loop running suture reinforced by an intraperitoneal composite mesh stripe (Group A) or to the same procedure without the additional mesh stripe (Group B). Primary endpoint was the incidence of incisional hernias at 2 years following midline laparotomy. Secondary endpoints are were the feasibility, the safety of the mesh stripe implantation including postoperative pain, and the incidence of incisional hernias at 5 years. RESULTS: A total of 267 patients were included in this study. Follow-up data 2 years after surgery was available from 210 patients (Group A = 107; Group B = 103). An incisional hernia was diagnosed in 18/107 (17%) patients in Group A and in 40/103 (39%) patients in Group B (p < 0.001). A surgical operation due to an incisional hernia was conducted for 12/107 (11%) patients in Group A and for 24/103 (23%) patients in Group B (p = 0.039). In both groups, minor and major complications as well as postoperative pain are reported with no statistically significant difference between the groups, even in contaminated situations. CONCLUSIONS: This first randomized clinical trial indicates that the placement of a non-absorbable IPOM-stripe with prophylactic intention may significantly reduce the risk for a midline incisional hernia. TRIAL REGISTRATION: Ref. NCT01003067 (clinicaltrials.gov). PMID- 29159604 TI - It's Complicated: How Often are Patients with Primary Aldosteronism Cured After Adrenalectomy? PMID- 29159605 TI - Outcomes of Emergency Laparotomy (EL) Care Protocol at Tertiary Care Center from Low-Middle-Income Country (LMIC). AB - BACKGROUND: Emergency laparotomy mortality ranges between 10 and 20% in best of Western healthcare systems and is currently a major focus for quality improvement programs. In contrast, emergency surgery scenario in LMIC is largely undefined, often neglected and complex (large burden of diseases but only limited capacity for adequate treatment). We evaluated the efficacy of 'EL care protocol' aimed at cost-effective optimal utilization of best available local expertise and infrastructure. METHODS: One hundred and two consecutive adult patients (>=16 years) who underwent EL from December 2012-December 2015 at a private tertiary hospital were retrospectively analyzed. The patients who underwent emergency laparoscopic procedures were excluded from the analysis. The EL care protocol included. (1) Admission to surgical intensive care unit for pre- and postoperative optimization. (2) Preferred radiologic investigation: abdominal computed tomography (CT) scan. (3) Surgery and critical care by senior surgical gastroenterologists and internists/anesthesiologists, respectively. Outcome measures were procedure-related complications (Clavien-Dindo classification), readmissions and costs. RESULTS: Of the 102 patients, there were 62 males and 40 females with median age of 60 (range 16-93) years. There were no complications in 22 (21.6%) patients, while Clavien-Dindo complications grade I or II occurred in 48 (47%) patients. Grade V Clavien-Dindo complications and the 30-day mortality were similar of 19 (18.6%). The readmission rate was 8 (7.8%). The expected mortality for the study group by P-POSSUM score was 31.2 (30.6%). The ratio (O/E) of observed to expected mortality was 0.61. The all inclusive median cost of treatment was INR 379,255 ($5590). CONCLUSIONS: LMIC centers should develop their own center-specific EL care protocols to improve outcomes of EL. PMID- 29159607 TI - High-resolution melting analysis (HRM) for mutational screening of Dnajc17 gene in patients affected by thyroid dysgenesis. AB - BACKGROUND: Congenital hypothyroidism is a frequent disease occurring with an incidence of about 1/1500 newborns/year. In about 75% of the cases, CH is caused by alterations in thyroid morphogenesis, defined "thyroid dysgenesis" (TD). TD is generally a sporadic disease but in about 5% of the cases a genetic origin has been demonstrated. Previous studies indicate that Dnajc17 as a candidate modifier gene for hypothyroidism, since it is expressed in the thyroid bud, interacts with NKX2.1 and PAX8 and it has been associated to the hypothyroid phenotype in mice carrying a single Nkx2.1 and Pax8 genes (double heterozygous knock-out). PURPOSE: The work evaluates the possible involvement of DNAJC17 in the pathogenesis of TD. METHODS: High-resolution DNA melting analysis (HRM) and direct sequencing have been used to screen for mutations in the DNAJC17 coding sequence in 89 patients with TD. RESULTS: Two mutations have been identified in the coding sequence of DNAJC17 gene, one in exon 5 (c.350A>C; rs79709714) and one in exon 9 (c.610G>C; rs117485355). The last one is a rare variant, while the rs79709714 is a polymorphism. Both are present in databases and the frequency of the alleles is not different between TD patients and controls. CONCLUSIONS: DNAJC17 mutations are not frequently present in patients with TD. PMID- 29159606 TI - Preoperative 68Ga-DOTA-Somatostatin Analog-PET/CT Hybrid Imaging Increases Detection Rate of Intra-abdominal Small Intestinal Neuroendocrine Tumor Lesions. AB - BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are the most common form of neoplasm in the small bowel. Radiological identification of primary tumors (PT), which may be multiple, is difficult, and therefore palpation of the entire small bowel is routinely performed during laparotomy. The aim was to determine detection rates of PT and peritoneal carcinomatosis (PC) with 68Ga DOTATOC/TATE-PET/CT in comparison with i.v. contrast-enhanced computed tomography (CE-CT) and thus to clarify whether modern functional imaging can mitigate the need for palpation of bowel during surgery enabling oncologically adequate laparoscopic resection. METHODS: A total of 28 patients with SI-NET who preoperatively underwent both 68Ga-DOTATOC/TATE-PET/CT and CE-CT were included. The detection rates of PT and PC for PET/CT and CE-CT were compared to the findings in the surgical and histopathological reports. Appropriate statistical tests were used, and significance was set to p < 0.05. RESULTS: Out of 82 PT, 43 PT were not detected by any imaging modality. More PT lesions were detected with PET/CT (n = 39 [47.5%]) than with CE-CT (n = 10 [12.2%], p < 0.001). Also, PET/CT identified significantly more PC lesions than CE-CT (78 and 38%, p = 0.004, respectively). CONCLUSION: PET/CT detected more PT and PC lesions than CE-CT. Some PTs and PC lesions were only detected by one of the modalities, and CT performed in conjunction with PET/CT should therefore be performed as a fully diagnostic CE-CT for optimal results. Palpation of the small bowel remains crucial during surgery in these patients because several PTs escaped detection by both PET/CT and CE-CT. PMID- 29159608 TI - [Four reasons for the bloated abdomen of your patient]. PMID- 29159609 TI - ? PMID- 29159610 TI - ? PMID- 29159611 TI - ? PMID- 29159612 TI - ? PMID- 29159614 TI - ? PMID- 29159613 TI - ? PMID- 29159615 TI - [Hypertension during epistaxis - cause or consequence?] PMID- 29159616 TI - [Atopic eczema in childhood or primary immunodeficiency - what needs to be considered?] PMID- 29159618 TI - ? PMID- 29159617 TI - [Medical aid at sea]. PMID- 29159620 TI - ? PMID- 29159619 TI - [Life style and male fertility]. PMID- 29159621 TI - ? PMID- 29159622 TI - ? PMID- 29159623 TI - ? PMID- 29159624 TI - ? PMID- 29159625 TI - ? PMID- 29159626 TI - ? PMID- 29159628 TI - ? PMID- 29159627 TI - ? PMID- 29159629 TI - ? PMID- 29159631 TI - ? PMID- 29159630 TI - ? PMID- 29159632 TI - ? PMID- 29159633 TI - ? PMID- 29159635 TI - ? PMID- 29159634 TI - ? PMID- 29159636 TI - ? PMID- 29159637 TI - ? PMID- 29159638 TI - ? PMID- 29159639 TI - ? PMID- 29159640 TI - ? PMID- 29159641 TI - ? PMID- 29159642 TI - ? PMID- 29159643 TI - ? PMID- 29159644 TI - ? PMID- 29159645 TI - ? PMID- 29159646 TI - ? PMID- 29159647 TI - ? PMID- 29159648 TI - ? PMID- 29159649 TI - ? PMID- 29159650 TI - ? PMID- 29159651 TI - ? PMID- 29159653 TI - ? PMID- 29159654 TI - ? PMID- 29159655 TI - ? PMID- 29159656 TI - ? PMID- 29159657 TI - Polysaccharides from Dolichos biflorus Linn and Trachyspermum ammi Linn seeds: isolation, characterization and remarkable antimicrobial activity. AB - Polysaccharides are structurally complex and essential constituents of life, and therefore, studies directed to these kinds of molecules have received scientific attention. Despite an easy availability of Dolichos biflorus Linn and Trachyspermum ammi (Linn) seeds isolation, characterization and antimicrobial studies of polysaccharides derived from these two natural sources have not been investigated. Therefore, we report here isolation of polysaccharides, their purification and characterization from Dolichos biflorus Linn and Trachyspermum ammi (Linn) seeds. Gel permeation chromatography, GC-MS, SEM, XRD, EDX and FT-IR analyses show the presence of three pentose sugar such as D-ribose, D-arabinose, D-xylose and hexose sugar such as D-mannose, D-galactose and D-glucose. Unprecedented antimicrobial activity of these polysaccharides against Gram positive bacteria such as Staphylococcus aureus and Bacillus subtilis and Gram negative bacteria such as Escherichia coli and Pseudomonas aeruginosa are established. PMID- 29159658 TI - Lung necrosectomy in pediatric patients with necrotizing pneumonia. AB - INTRODUCTION: Necrotizing pneumonia is the consolidation of lung parenchyma with destruction and necrosis, forming solitary or multiloculated radiolucent foci. When antibiotic treatment fails and clinical course does not improve, patients might need lung tissue resection: segmentectomy, lobectomy or bilobectomy. We have performed a more conservative surgical approach in pediatric patients with necrotizing pneumonia, lung necrosectomy: resection of unviable necrotic tissue, to preserve more healthy and potentially recoverable lung parenchyma. The objective of this study is to present the results of our experience with lung necrosectomy. METHODS: Retrospective review of clinical charts of children with necrotizing pneumonia. The diagnosis was based on physical examination, laboratory data and contrast CT scan. Lung necrosectomy technique includes resection of necrotic tissue with careful debridement technique; air leaks were sutured and/or tissue imbrication. RESULTS: Twenty-four children were surgically treated for necrotizing pneumonia (18 girls and 6 boys). The mean age was 31.5 +/ 13.5 months. All the patients presented productive cough, fever and dyspnea; chest X-rays showed consolidated areas with intraparenchymal cavities and hypoperfusion on the contrasted CT. Surgical treatment included: Lung necrosectomy 17 (70%); lobectomy 3 (12.5%); wedge resection 2 (8.3%); lobectomy + lung necrosectomy 1 (4.1%), and wedge resection + lung necrosectomy 1 (4.1%). The postoperative course was uneventful in 23 patients; mean postoperative hospital stay was 6.3. One patient died because of sepsis. CONCLUSIONS: Lung necrosectomy is a conservative, effective surgical treatment, which solves lung necrotizing infection avoiding resection of healthy lung parenchyma. PMID- 29159659 TI - Identification determinant factors on willingness to pay for health services in Iran. AB - BACKGROUND: A common method used to examine the relationship between internal preferences and caring externalities is willingness to pay (WTP) approach. We aimed to estimate WTP for health status with different severity level and identify determinant factors on WTP. METHODS: For determining main factors in WTP, a cross-sectional study was conducted in Shiraz in the southeast of Iran, in March to April 2015. The open-ended method was used to estimate monthly WTP in private and altruistic section. Multivariate regression analyses using ordinary least squares were applied to examine the effect of Scio-demographic factors on WTP using SPSS software 21. RESULTS: Participants were willing to pay an average amount of $ 295 in health status 1 and an average amount of $ 596 in health status 6 (worst status) for internal preferences. Altruistic WTP for health status 1 was $ 294 and participants were willing to pay an average amount of $ 416 in health status 6. Multiple regression analysis identified monthly income as the key determinant of WTP for internal preferences and caring externalities (P < 0.01). With an increase of 1% in income, private WTP increase 1.38% in health status 1. CONCLUSIONS: The finding indicates that the mean of WTP increases at severe health status; therefore, health policy maker should allocate resources toward severe health status. PMID- 29159660 TI - Opinion: Paracoccidioidomycosis and HIV Immune Recovery Inflammatory Syndrome. AB - Two distinct patterns of immune recovery inflammatory syndrome (IRIS) are recognized, paradoxical and unmasking IRIS. Here we raise some concerns regarding the first case of neuroPCM-IRIS published to date, as recently proposed by Almeida and Roza (Mycopathologia 177:137-141, 2017) for a patient originally described by Silva-Vergara et al. (Mycopathologia 182:393-396, 2014), taking in account the different case definitions for IRIS and the cases of neuroparacoccidioidomycosis already described in the literature. We are concerned that data from the case report have been misinterpreted and that no regard has been given to the possibility that the development of manifestations of neuroPCM after starting antiretroviral therapy and antifungal treatments could represent the predicted course of a missed neuroPCM diagnosis at presentation whose treatment failed. We hypothesize that diagnosis of the neuroPCM would not have been missed if careful screening for opportunistic infection of the central nervous system was performed prior to antiretroviral therapy initiation. Currently, there is no definitive diagnostic test for IRIS and diagnostic suspicion, as well as its management, are based on image studies and non-specific clinical signs and symptoms of inflammation. IRIS remains a diagnosis of exclusion, after considering drug toxicity, microbiologic treatment failure and the expected course of newly or previously diagnosed opportunistic infections. PMID- 29159661 TI - Safety of clomiphene citrate: a literature review. AB - Clomiphene citrate (CC) is a nonsteroidal compound and induces ovulation indirectly. The wide usage of the CC raises a question; is it safe or not? In the light of this question, this review aimed to highlight all researches and insights into the association between the use of CC and risk of genotoxicity, cytotoxicity, embryotoxicity, teratogenicity and risk of different cancer types. We conducted a MEDLINE/PubMed, Scopus, Web of Science, Google Scholar search. After a careful screening process of all authors, 32 of these articles were considered as appropriate, and reviewed. Our evaluations showed that CC has genotoxic, cytotoxic, embryotoxic and teratogenic properties. There is no association between the use of CC and risk of ovarian, breast, uterine, cervix, endometrium, lung, colorectal cancer, and lymphoma. However, risk increased especially after 6 cycles of use and especially in nulligravid women. The use of CC should be restricted to 6 cycles. Moreover, malignant melanoma and thyroid cancer risk was found to be higher among CC treated women in almost all studies. Further works should be conducted especially in animal models to assess its risk features. PMID- 29159662 TI - Correction to: Traumatic inferior shoulder dislocation: a review of management and outcome. AB - The original version of this article unfortunately contained mistakes. The presentation of the author names was incorrect. PMID- 29159663 TI - Infrapatellar vs. suprapatellar approach to obtain an optimal insertion angle for intramedullary nailing of tibial fractures. AB - BACKGROUND: During intramedullary nailing of tibial fractures, the insertion angle of the nail is of great importance. When the nail impacts the posterior cortex due to a large insertion angle with a dorsal target course, higher insertion forces are needed, and the danger of iatrogenic fractures increases. Accordingly, the insertion direction should be as parallel as possible to the longitudinal axis of the tibia. We aimed to confirm the hypothesis that intramedullary nailing of tibial fractures can be performed with smaller insertion angles via a suprapatellar approach rather than infrapatellar approach. METHODS: In 19 human bodies of donors with intact tibiae, we performed intramedullary nailing by both a suprapatellar and an infrapatellar approach. The correct entry point was determined by fluoroscopy. Subsequently, the medullary canal was reamed up to a diameter of 10 mm, and a 9 mm polytetrafluorethylen tube was inserted instead of a tibia nail. The angle between the proximal aspect of the tube and the longitudinal axis of the tibia was measured using a computer assisted surgery system. RESULTS: The angle between the proximal aspect of the inserted tube, simulating the tibial nail, and the longitudinal tibial axis was significantly larger when using the infrapatellar approach. CONCLUSIONS: We achieved an insertion angle significantly more parallel to the longitudinal axis when using a suprapatellar approach for intramedullary nailing of tibial fractures. Thereby, both the risk of iatrogenic fracture of the posterior cortex and apex anterior angulation of the short proximal fragment can be reduced during intramedullary nailing of tibial fractures. PMID- 29159664 TI - Dual roles of the hippocampus and intraparietal sulcus in network integration and segregation support scene recognition. AB - Effectively recognizing surroundings is a critical ability in human navigation. Previous neuroimaging studies have depicted distributed brain regions underpinning spatial navigation, but little is known about how these regions are formed into the navigation network (NN) supporting scene recognition. In this study, we addressed this issue by using a voxel-based global functional connectivity method to characterize the integration (i.e., within-network connectivity, WNC) of the NN and its segregation (i.e., between-network connectivity, BNC) from non-NN networks. We found that the majority of the voxels in the NN showed a stronger WNC than BNC, indicating the encapsulation of the NN. Importantly, individuals with stronger WNC and weaker BNC in the left hippocampus (Hipp) and intraparietal sulcus (IPS) performed better in scene recognition, suggesting that the left Hipp and IPS were involved in scene recognition by both integrating regions in the NN and separating the NN from non-NN networks. Further analyses showed that the integration of these two regions in the NN serves different functions, that is, while the WNC of the left Hipp was only related to scene recognition, the WNC of the left IPS was also related to the general executive control function of attention. In short, our study demonstrated the dual roles of the Hipp and IPS in integration and segregation of the NN to support scene recognition, suggesting that scene recognition involves not only regions specialized in spatial navigation, but also those with general functions. PMID- 29159666 TI - [Polymorphic and itchy rash in a 21-year-old woman]. AB - Pityriasis lichenoides et varioliformis acuta (PLEVA) is a common inflammatory disease which usually occurs in children and young adults. Characteristic is a polymorph clinical picture with papules, erosions, ulcers and haemorrhagic crusts compatible with many differential diagnoses. We report about a patient with PLEVA and describe possible differential diagnoses. PMID- 29159665 TI - Functional rostro-caudal gradient in the human posterior lateral frontal cortex. AB - The present study examined the hypothesis that the posterior motor/premotor region of the lateral frontal cortex is functionally organized along a rostro caudal axis. During functional magnetic resonance imaging scanning, the subjects performed various tasks assessing basic saccadic eye or hand actions and also tasks requiring the cognitive selection between competing hand or eye movements based on previously learned conditional relations (if A, select movement X, but if B select movement Y). Subject-by-subject analysis demonstrated precise relationships between the foci of functional activity and specific sulci. In agreement with previous reports, basic eye movements activated the Frontal Eye Field (FEF) in the ventral branch of the superior precentral sulcus, but the high level selection of saccadic eye movements was localized systematically anterior to this region in the superior frontal sulcus. Similarly, basic performance of hand movements activated the primary motor cortex, but the region involved in the high-level selection between competing hand movements was systematically localized within the dorsal branch of the superior precentral sulcus, anterior to the primary motor region. Importantly, there was no overlap between the anterior cognitive selection regions, suggesting an effector specific organization. These results demonstrate a functional rostro-caudal gradient within the posterior lateral frontal cortex reflecting a hierarchical organization of action control. PMID- 29159667 TI - Uterus-sparing vaginolaparoscopic sacrocolpopexy for apical pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: Our aim was to evaluate the safety, feasibility, and effectiveness of a vaginolaparoscopic sacrocolpopexy (VLS) technique for treating apical pelvic organ prolapse (POP). MATERIALS AND METHODS: This was a prospective interventional case series (design classification: Canadian Task Force II3) performed in the endoscopic unit of a tertiary care referral facility and university hospital. We assessed 15 symptomatic parous women with stage >=2 apical POP according to the POP Quantification (POP-Q) classification. Interventions comprised posterior colpotomy with mesh fixation to the uterosacral ligaments and the back of the uterus that was further fixed to the anterior longitudinal ligament of the sacrum using a tacker via laparoscopy. RESULTS: The main outcome was a significant postoperative improvement in prolapse and resultant improvement in quality of life (QoL) after VLS. Six patients required concomitant reconstructive procedures. Mean operative time for the vaginal phase was 8.54 +/- 3.10 (7-12) min and 32.36 +/- 8.2 (27-41) min. for the laparoscopic phase Mean duration of VLS ranged from 30 to 50 min. At the 6-months follow-up, the procedure was successful in 14 of 15 patients (93.34%); one woman (6.66%) presented with recurrence at a lower stage. Neither mesh complications nor sacral ostitis were encountered. There was significant improvement in vaginal symptoms, sexual well-being, QoL, and clinical staging after the procedure. CONCLUSION: By eliminating all forms of intraperitoneal suturing, performing a posterior colpotomy, and the advent of tackers without evidence of sacral ostitis, VLS seems to be a simple, feasible, effective, and fast approach for treating POP. PMID- 29159668 TI - New pulmonary hypertension model in conscious dogs to investigate pulmonary selectivity of acute pharmacological interventions. AB - PURPOSE: Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively. METHODS: Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs. A hypoxic chamber was constructed in which the animals were placed in a conscious state. By reducing the inspired oxygen fraction (FiO2) to 10%, a hypoxic pulmonary vasoconstriction was induced leading to PH. The PDE-5 inhibitor sildenafil, the current standard of care was compared to atrial natriuretic peptide (ANP). RESULTS: The new hypoxic chamber provided a stable hypoxic atmosphere during all experiments. The mean PAP under normoxic conditions was 15.8 +/- 1.8 mmHg. Hypoxia caused a reliable increase in mean PAP (+ 12.2 +/- 3.2 mmHg, p < 0.0001). Both, sildenafil (- 6.8 +/- 4.4 mmHg) and ANP (- 6.4 +/- 3.8 mmHg) significantly (p < 0.05) decreased PAP. Furthermore sildenafil and ANP showed similar effects on systemic hemodynamics. In subsequent studies, the in vitro effects and gene expression pattern of the two pathways were exemplified. CONCLUSIONS: By combining the hypoxic environment with the telemetric approach, we could successfully establish a new acute PH model. Sildenafil and ANP demonstrated equal effects regarding pulmonary selectivity. This non-invasive model could help to rapidly screen pulmonary vasodilators with decreased animal burden. PMID- 29159669 TI - Thyroid hormones and commonly cited symptoms of overtraining in collegiate female endurance runners. AB - PURPOSE: Overtraining syndrome (OTS) is reported in endurance sports. Thyroid hormones (TH) regulate metabolism, mood, and energy production, and may play a role in OTS of endurance athletes. The purpose of this study was to investigate relationships in TH and symptoms of OTS in track and field endurance runners (ER). METHODS: Sixteen female track and field middle distance (MD; n = 9; age: 20.2 +/- 1.5 years; ht: 167.86 +/- 5.04 cm; body-mass: 57.97 +/- 5.05 kg; VO2MAX: 53.62 +/- 6.04 ml/kg/min) and long distance (LD; n = 7; age: 20.5 +/- 1.5 years; ht: 162.48 +/- 6.11 cm; body-mass: 56.15 +/- 5.99 kg; VO2MAX: 61.94 +/- 3.29 ml/kg/min) ER participated in this descriptive study (15-weeks). Thyroid stimulating hormone (TSH), triiodothyronine (T 3), and thyroxine (T 4), were collected at pre-(PRE) and post-season (POST). A fatigue scale was administered weekly, and percent change (PDelta) in race time (season best vs. championship performance) was calculated. Wilcoxon-sign ranked tests and Spearman's rho correlations were used to determine changes and relationships between TH and performance. RESULTS: TSH, T 3 and T 4 did not change from PRE to POST. The percent change (PDelta) in T 3 from PRE to POST was correlated with running performance at the end of the season (rho = - 0.70, p = 0.036). Fatigue at week 12 correlated with running performance at the end of the season (rho = - 0.74, p = 0.004). CONCLUSION: TH may be valuable in assessing the overall training state of ER. TH concentrations change too slowly to be a frequent marker of monitoring OTS, but are related to markers of decreased performance. Monitoring dietary intake, and fatigue may be predictive markers to assess OTS and training status of female ER. PMID- 29159671 TI - Janice Britton-Davidian (1950-2017). PMID- 29159670 TI - Analysis of B chromosome nondisjunction induced by the r-X1 deficiency in maize. AB - The maize B chromosome typically undergoes nondisjunction during the second microspore division. For normal A chromosomes, the r-X1 deficiency in maize can induce nondisjunction during the second megaspore and first microspore divisions. However, it is not known whether the r-X1 deficiency also induces nondisjunction of the maize B chromosome during these cell divisions. To answer this question, chromosome numbers were determined in the progeny of r-X1/R-r female parents carrying two B chromosomes. Some of the r-X1-lacking progeny (21.2%) contained zero or two B chromosomes. However, a much higher percentage of the r-X1 containing progeny (43.4%) exhibited zero or two B chromosomes, but none displayed more than two B chromosomes. Thus, the results indicated that the r-X1 deficiency could also induce nondisjunction of the B chromosome during the second megaspore division; moreover, the B chromosome in itself could undergo nondisjunction during the same division. In addition, pollen grains from plants with two B chromosomes lacking or exhibiting the r-X1 deficiency were compared via pollen fluorescence in situ hybridization (FISH) using a B chromosome specific probe. The results revealed that the r-X1 deficiency could induce the occurrence of B chromosome nondisjunction during the first microspore division and that the B chromosome in itself could undergo nondisjunction during the same division at a lower frequency. Our data shed more light on the behavior of the maize B chromosome during cell division. PMID- 29159672 TI - Patellar tracking should be taken into account when measuring radiographic parameters for recurrent patellar instability. AB - PURPOSE: To date, many radiographic parameters on patellar instability have their measurements taken statically, and have not been studied in various degrees of flexion according to the patellar tracking. There are also limited data regarding the use of these parameters in predicting recurrent patellar dislocation. The current study aims to review the radiographic parameters of the patellofemoral joint in different degrees of knee flexion and to correlate them with the presence of recurrent instability. METHODS: A 10-year retrospective study was conducted on all patients who had computed tomography patellar-tracking scan done for patellar instability when aged 18 years or younger. The computed tomography patellar-tracking scans were performed with the knee in extension, 10 degrees flexion, and 20 degrees flexion. The axial radiographic parameters were evaluated at the patellar equator, roman arch, and distal patellar pole. Sagittal and coronal parameters were noted. Radiographic parameters were then correlated with recurrent patellar instability. RESULTS: The femoral sulcus angle and trochlear groove depth at the distal patellar pole in 10 degrees knee flexion (p value 0.04 and 0.03, respectively) and patellar equator in 20 degrees knee flexion (p value 0.02 and 0.03, respectively) had the most significant clinical correlations with recurrent instability on multivariate analysis. Other radiographic parameters found to have significant clinical correlation on univariate analysis include the patellar tilt angle, congruence angle, femoral sulcus angle, trochlear groove depth, and Wiberg's classification. CONCLUSIONS: As per the knee dynamics, axial radiographic parameters had the most significant correlation with recurrent patellar instability when measured at the distal patellar pole in 10 degrees knee flexion and at the patellar equator in 20 degrees knee flexion. Future axial radiographic evaluation of patellofemoral instability should then be performed at these degrees of knee flexion and axial cuts. Trochlear dysplasia, as measured by the femoral sulcus angle and trochlear groove depth, was the most significant predictor of recurrent patellar instability in the skeletally immature. Wiberg's classification was also a novel factor found to have clinical correlation with patellofemoral instability. LEVEL OF EVIDENCE: III. PMID- 29159673 TI - Double-bundle anterior cruciate ligament reconstruction is better than single bundle reconstruction in terms of objective assessment but not in terms of subjective score. AB - PURPOSE: A comparison of clinical outcomes between double-bundle (DB) and single bundle (SB) anterior cruciate ligament (ACL) reconstruction for patients with ACL injury. METHODS: Sixty patients were treated with either SB (n = 30) or DB (n = 30) ACL reconstruction between 2011 and 2012. The hamstring tendons were autografted with suspensory fixation on the femoral side, while a bio-absorbable interference screw was used for fixation on the tibial side. These patients were evaluated using Lysholm score, International Knee Documentation Committee (IKDC) forms (both objective and subjective), Lachman test, pivot shift test, and KT 1000 arthrometer. RESULTS: After a median follow-up duration of 35.5 months (ranging between 30 and 42 months), the frequency of patients who had high objective IKDC scores was significantly higher in the DB group than those in the SB group. In terms of DB, the Lachman test was normal in 26 patients (86.7%), nearly normal in three patients (10%), and abnormal in one patient (3.3%); comparatively, in terms of SB, the Lachman test was normal in 20 patients (66.7%), nearly normal in eight patients (26.7%) and abnormal in two patients (6.6%). The pivot shift test was negative in 29 patients (96.7%) and 21 patients (70%) for DB and SB, respectively. The average KT-1000 side-to-side difference was 1.0 mm for DB and 1.5 mm for SB. The subjective IKDC and Lysholm score showed non-significant differences between both techniques. CONCLUSION: Double-bundle ACL reconstruction was found to have a significant advantage in anterior and rotational stability as well as objective IKDC than that of SB reconstruction. However, subjective measurements showed no statistical differences between the techniques. LEVEL OF EVIDENCE: II. PMID- 29159674 TI - The quadrant method measuring four points is as a reliable and accurate as the quadrant method in the evaluation after anatomical double-bundle ACL reconstruction. AB - PURPOSE: The quadrant method was described by Bernard et al. and it has been widely used for postoperative evaluation of anterior cruciate ligament (ACL) reconstruction. The purpose of this research is to further develop the quadrant method measuring four points, which we named four-point quadrant method, and to compare with the quadrant method. METHODS: Three-dimensional computed tomography (3D-CT) analyses were performed in 25 patients who underwent double-bundle ACL reconstruction using the outside-in technique. The four points in this study's quadrant method were defined as point1-highest, point2-deepest, point3-lowest, and point4-shallowest, in femoral tunnel position. Value of depth and height in each point was measured. Antero-medial (AM) tunnel is (depth1, height2) and postero-lateral (PL) tunnel is (depth3, height4) in this four-point quadrant method. The 3D-CT images were evaluated independently by 2 orthopaedic surgeons. A second measurement was performed by both observers after a 4-week interval. Intra- and inter-observer reliability was calculated by means of intra-class correlation coefficient (ICC). Also, the accuracy of the method was evaluated against the quadrant method. RESULTS: Intra-observer reliability was almost perfect for both AM and PL tunnel (ICC > 0.81). Inter-observer reliability of AM tunnel was substantial (ICC > 0.61) and that of PL tunnel was almost perfect (ICC > 0.81). The AM tunnel position was 0.13% deep, 0.58% high and PL tunnel position was 0.01% shallow, 0.13% low compared to quadrant method. CONCLUSIONS: The four point quadrant method was found to have high intra- and inter-observer reliability and accuracy. This method can evaluate the tunnel position regardless of the shape and morphology of the bone tunnel aperture for use of comparison and can provide measurement that can be compared with various reconstruction methods. The four-point quadrant method of this study is considered to have clinical relevance in that it is a detailed and accurate tool for evaluating femoral tunnel position after ACL reconstruction. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 29159675 TI - Diffusion weighted imaging demystified: the technique and potential clinical applications for soft tissue imaging. AB - Diffusion-weighted imaging (DWI) is a fast, non-contrast technique that is readily available and easy to integrate into an existing imaging protocol. DWI with apparent diffusion coefficient (ADC) mapping offers a quantitative metric for soft tissue evaluation and provides information regarding the cellularity of a region of interest. There are several available methods of performing DWI, and artifacts and pitfalls must be considered when interpreting DWI studies. This review article will review the various techniques of DWI acquisition and utility of qualitative as well as quantitative methods of image interpretation, with emphasis on optimal methods for ADC measurement. The current clinical applications for DWI are primarily related to oncologic evaluation: For the assessment of de novo soft tissue masses, ADC mapping can serve as a useful adjunct technique to routine anatomic sequences for lesion characterization as cyst or solid and, if solid, benign or malignant. For treated soft tissue masses, the role of DWI/ADC mapping in the assessment of treatment response as well as recurrent or residual neoplasm in the setting of operative management is discussed, especially when intravenous contrast medium cannot be given. Emerging DWI applications for non-neoplastic clinical indications are also reviewed. PMID- 29159676 TI - The posterior-anterior flexed view is better than the anterior-posterior view for assessing osteoarthritis of the knee. AB - OBJECTIVE: The aim of this study is to determine whether the posterior-anterior (PA)-flexed view improves the radiographic assessment of patients with knee pain compared with the standard standing anterior-posterior radiograph. MATERIALS AND METHODS: Three hundred and sixty-five patients with knee pain underwent anterior posterior (AP), PA flexed, lateral, and Merchant radiographs of the knee. Knees were grouped as mild (Kellgren and Lawrence [K-L] 1-2) or severe (K-L 3-4) osteoarthritis (OA) and either varus (medial compartment), valgus (lateral compartment), or patellofemoral OA. RESULTS: In knees with mild valgus OA on AP view (K-L 1-2), the PA flexed view was more sensitive than the AP view. The measured lateral minimal joint space width (minJSW) decreased more than 2 mm in 68% of the patients, resulting in an increase in K-L grade (3 or 4). In patients with severe valgus OA and in all patients with varus and patellofemoral OA, there was no difference between AP and PA flexed view with regard to radiographic measurements or KL grade. Based on the Medicare reimbursement rate using the PA flexed view alone instead of both views reduced imaging costs by 47%. CONCLUSION: The PA flexed view better classifies the severity of lateral compartment disease in patients with mild valgus OA and provides comparable diagnostic sensitivity for joint space narrowing in varus- and patellofemoral OA. Using the PA flexed view alone was more cost effective than using the combination of AP and PA flexed imaging. PMID- 29159677 TI - Not all sagittal band tears come with extensor instability: a case report with radiological and operative correlation. AB - The sagittal bands are a component of the extensor hood. They serve an important role in stabilizing the extensor tendon by forming a "check-rein" to radial-ulnar translation of the tendon over the metacarpal head, and extending the metacarpophalangeal (MCP) joint by virtue of attaching the extensor tendon to the palmar plate. Injury to the sagittal band is thought to cause extensor instability and subluxation to the contralateral side by disruption of this "check-rein" function, although recent evidence from cadaver studies suggests that ulnar sagittal band tear may be spared of extensor instability. As a case in point, we encountered a patient with surgically proven ulnar sagittal band tear, who did not have any extensor tendon subluxation or any limitation in motion. Intraoperative findings demonstrated a chronic-appearing ulnar sagittal band tear, indicating that chronic injury with fibrosis may stabilize the central band. Therefore, in patients with metacarpophalangeal pain without central tendon subluxation or limitation of motion, it remains important to raise the concern of sagittal band tear for appropriate treatment. We present the clinical course of this case, with radiological and operative findings, followed by a review of the relevant literature. PMID- 29159678 TI - On the predictability of event boundaries in discourse: An ERP investigation. AB - When reading a text describing an everyday activity, comprehenders build a model of the situation described that includes prior knowledge of the entities, locations, and sequences of actions that typically occur within the event. Previous work has demonstrated that such knowledge guides the processing of incoming information by making event boundaries more or less expected. In the present ERP study, we investigated whether comprehenders' expectations about event boundaries are influenced by how elaborately common events are described in the context. Participants read short stories in which a common activity (e.g., washing the dishes) was described either in brief or in an elaborate manner. The final sentence contained a target word referring to a more predictable action marking a fine event boundary (e.g., drying) or a less predictable action, marking a coarse event boundary (e.g., jogging). The results revealed a larger N400 effect for coarse event boundaries compared to fine event boundaries, but no interaction with description length. Between 600 and 1000 ms, however, elaborate contexts elicited a larger frontal positivity compared to brief contexts. This effect was largely driven by less predictable targets, marking coarse event boundaries. We interpret the P600 effect as indexing the updating of the situation model at event boundaries, consistent with Event Segmentation Theory (EST). The updating process is more demanding with coarse event boundaries, which presumably require the construction of a new situation model. PMID- 29159679 TI - The location-, word-, and arrow-based Simon effects: An ex-Gaussian analysis. AB - Task-irrelevant spatial information, conveyed by stimulus location, location word, or arrow direction, can influence the response to task-relevant attributes, generating the location-, word-, and arrow-based Simon effects. We examined whether different mechanisms are involved in the generation of these Simon effects by fitting a mathematical ex-Gaussian function to empirical response time (RT) distributions. Specifically, we tested whether which ex-Gaussian parameters (MU, sigma, and tau) show Simon effects and whether the location-, word, and arrow-based effects are on different parameters. Results show that the location based Simon effect occurred on mean RT and MU but not on tau, and a reverse Simon effect occurred on sigma. In contrast, a positive word-based Simon effect was obtained on all these measures (including sigma), and a positive arrow-based Simon effect was evident on mean RT, sigma, and tau but not MU. The arrow-based Simon effect was not different from the word-based Simon effect on tau or sigma but was on MU and mean RT. These distinct results on mean RT and ex-Gaussian parameters provide evidence that spatial information conveyed by the various location modes are different in the time-course of activation. PMID- 29159680 TI - Vitamin D3 Versus Gliadin: A Battle to the Last Tight Junction. PMID- 29159681 TI - Advanced Strategies for Eliminating the cccDNA of HBV. AB - Persistent hepatitis B virus (HBV) infection of hepatocytes is associated with a covalently closed circular DNA (cccDNA) episome. Although serologic hepatitis B surface antigen tests are negative, the presence of cccDNA is obviously increased in HBeAg-positive patients compared with that in HBeAg-negative patients, inactive carriers and patients. Moreover, trace cccDNA levels can also be found in the liver cells of patients with resolved hepatitis B infections. Therefore, clearance of cccDNA in hepatocytes could be an effective cure for HBV. In this review, we summarize the strategies that have been employed to eliminate cccDNA in recent years and discuss the future development of treatments for chronic hepatitis B. PMID- 29159682 TI - Physiological and Biomechanical Responses of Highly Trained Distance Runners to Lower-Body Positive Pressure Treadmill Running. AB - BACKGROUND: As a way to train at faster running speeds, add training volume, prevent injury, or rehabilitate after an injury, lower-body positive pressure treadmills (LBPPT) have become increasingly commonplace among athletes. However, there are conflicting evidence and a paucity of data describing the physiological and biomechanical responses to LBPPT running in highly trained or elite caliber runners at the running speeds they habitually train at, which are considerably faster than those of recreational runners. Furthermore, data is lacking regarding female runners' responses to LBPPT running. Therefore, this study was designed to evaluate the physiological and biomechanical responses to LBPPT running in highly trained male and female distance runners. METHODS: Fifteen highly trained distance runners (seven male; eight female) completed a single running test composed of 4 * 9-min interval series at fixed percentages of body weight ranging from 0 to 30% body weight support (BWS) in 10% increments on LBPPT. The first interval was always conducted at 0% BWS; thereafter, intervals at 10, 20, and 30% BWS were conducted in random order. Each interval consisted of three stages of 3 min each, at velocities of 14.5, 16.1, and 17.7 km.h-1 for men and 12.9, 14.5, and 16.1 km.h-1 for women. Expired gases, ventilation, breathing frequency, heart rate (HR), rating of perceived exertion (RPE), and stride characteristics were measured during each running speed and BWS. RESULTS: Male and female runners had similar physiological and biomechanical responses to running on LBPPT. Increasing BWS increased stride length (p < 0.02) and flight duration (p < 0.01) and decreased stride rate (p < 0.01) and contact time (p < 0.01) in small-large magnitudes. There was a large attenuation of oxygen consumption (VO2) relative to BWS (p < 0.001), while there were trivial-moderate reductions in respiratory exchange ratio, minute ventilation, and respiratory frequency (p > 0.05), and small-large effects on HR and RPE (p < 0.01). There were trivial-small differences in VE, respiratory frequency, HR, and RPE for a given VO2 across various BWS (p > 0.05). CONCLUSIONS: The results indicate the male and female distance runners have similar physiological and biomechanical responses to LBPPT running. Overall, the biomechanical changes during LBPPT running all contributed to less metabolic cost and corresponding physiological changes. PMID- 29159683 TI - Interaction rates, vital rates, background fitness and replicator dynamics: how to embed evolutionary game structure into realistic population dynamics. AB - In this paper we are concerned with how aggregated outcomes of individual behaviours, during interactions with other individuals (games) or with environmental factors, determine the vital rates constituting the growth rate of the population. This approach needs additional elements, namely the rates of event occurrence (interaction rates). Interaction rates describe the distribution of the interaction events in time, which seriously affects the population dynamics, as is shown in this paper. This leads to the model of a population of individuals playing different games, where focal game affected by the considered trait can be extracted from the general model, and the impact on the dynamics of other events (which is not neutral) can be described by an average background fertility and mortality. This leads to a distinction between two types of background fitness, strategically neutral elements of the focal games (correlated with the focal game events) and the aggregated outcomes of other interactions (independent of the focal game). The new approach is useful for clarification of the biological meaning of concepts such as weak selection. Results are illustrated by a Hawk-Dove example. PMID- 29159684 TI - Early Experience with a New Concept of Angioplasty Nitinol-Constrained Balloon Catheter (Chocolate(r)) in Severely Claudicant Patients. AB - BACKGROUND: To report our experience in treating severely claudicant patients, employing a "nitinol-constrained" balloon (Chocolate, TriReme Medical Inc., Pleasanton, CA-USA) before drug-coated balloon (DCB) in a standardized protocol. METHODS: Eighty-one (84 limbs) consecutive Rutherford category (RC) 3 patients treated between December 2014 and December 2016 for superficial femoral artery (SFA) and popliteal arterial (PA) disease by nitinol-constrained balloon followed by DCB were enrolled. Bailout stenting was performed by Zilver PTX implantation. Intraoperative technical success and bailout-stenting rates were assessed as well as clinical improvement, ankle-brachial index (ABI) modification, primary patency (PP), and secondary patency (SP) rates at follow-up. RESULTS: Sixty-eight patients (83.9%) were male and 31 (38.2%) diabetics. Fifty-five limbs (65.5%) presented occlusion (CTO); in 18 limbs CTO was longer than 150 mm. Bailout stenting rate was 9.5% (8/84). All patients completed 30-day follow-up: PP 100%, 61 patients completely asymptomatic (RC = 0). Mean follow-up was 12.3 +/- 5.6 months; overall PP was 98.8%, and SP was 98.8%. At mid-term analysis, no differences in outcomes were recorded between stenosis and CTOs with a PP of 96.5 and 96%, respectively (p = 0.725). CTO length impacted early results: in cases of CTOs < 150 mm, PP was 100%, while in CTOs > 150 mm, it was 83.3% (p = 0031). ABI at 12-month was significantly higher with respect to preoperative values (p < 0.001). CONCLUSIONS: In this preliminary experience, our protocol seems to be safe and effective in treating SFA and PA lesions in claudicant patients with satisfactory early and 12-month results. PMID- 29159685 TI - Performance of a Robotic Assistance Device in Computed Tomography-Guided Percutaneous Diagnostic and Therapeutic Procedures. AB - PURPOSE: To evaluate a commercially available robotic assistance device for computed tomography-guided diagnostic and therapeutic interventions, compared to regular, manually performed CT scan-guided interventions in terms of precision, exposure to radiation to the patient and intervention time. MATERIALS AND METHODS: Over a period of 6 months, 55 consecutive patients were recruited and treated using robotic assistance and compared to a control group of 101 patients previously treated with a regular CT scan-guided, manual approach. Evaluated parameters were precision (deviation from planned target and number of needle replacements), radiation exposure to the patient and intervention time. Evaluations were performed with regard to complexity (in-plane vs out-of-plane interventions) and type of anesthesia (general vs local). RESULTS: Parameters related to precision were in general significantly better in the robotic assistance group (p < 0.01) with a mean deviation of 1.2 mm (+/- 1.6 mm) compared to 2.6 mm (+/- 1.1 mm) in the comparison group. Compared to manual procedure, the mean intervention time was reduced by 15 min (+/- 5.4 min) on average for an out of-plane needle placement in the robotic group. There was no increase of exposure to radiation to the patient while radiation exposure for the physician was reduced to zero when the navigation system was used. CONCLUSION: Compared to manual placement, the use of a robotic assistance device in out-of-plane CT guided interventions under general anesthesia allows for probe placement with high precision. Intervention time is reduced with no increase of exposure to radiation to the patient. PMID- 29159686 TI - New cyclic sulfides extracted from Allium sativum: garlicnins P, J2, and Q. AB - Two atypical cyclic-type sulfides, garlicnin P (1) and garlicnin J2 (2), and one thiabicyclic-type sulfide, garlicnin Q (3), were isolated from the acetone extracts of garlic, Allium sativum, bulbs cultivated in the Kumamoto city area, and their structures characterized. Their production pathways are also discussed. PMID- 29159687 TI - AU-1 from Agavaceae plants downregulates the expression of glycolytic enzyme phosphoglycerate mutase. AB - The spirostanol saponin AU-1 from Agavaceae plants stimulates the expression of the glycolytic enzyme phosphoglycerate mutase (PGAM) in ACHN cells. We hypothesized that this may arise from the downregulation of the NAD+-dependent deacetylase SIRT1. In this article, we showed that, unlike in renal adenocarcinoma cells, AU-1 does not affect the expression of SIRT1 in the normal renal cell-derived cell line HK-2. Consistent with the lack of a downregulation of SIRT1, AU-1 did not upregulate, but rather decreased PGAM expression. Moreover, AU-1 inhibited the increase in PGAM levels that results from the knock down of SIRT1. Our results suggest that AU-1 may prevent carcinogenesis caused by increased cellular PGAM. PMID- 29159688 TI - Correction to: Sphenopalatine Ganglion Block in the Management of Chronic Headaches. AB - The original version of this article contains an error in an author's first name. The spelling of Dr. Mojica's first name should read "Jeffrey" instead of "Jeffery." PMID- 29159689 TI - Antibacterial and Antioxidant Metabolites of Diaporthe spp. Isolated from Flowers of Melodorum fruticosum. AB - Fifty-two strains of endophytic fungi were isolated from flowers of the medicinal plant Melodorum fruticosum. Seven genera were identified including Alternaria, Aspergillus, Colletotrichum, Diaporthe, Fusarium, Greeneria and Nigrospora. All strains were cultured for 30 days and further macerated in ethyl acetate solvent for 3 days. The obtained fungal extracts were examined for antibacterial activity using agar disc diffusion against nine pathogenic bacteria: Staphylococcus aureus, Bacillus subtilis, B. cereus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Shigella flexneri, Vibrio cholerae and V. parahaemolyticus. Forty-three fungal extracts exhibited antibacterial activity against at least one tested pathogen. The antioxidant properties of all extracts were also investigated by DPPH scavenging assay. Sixteen extracts displayed high antioxidant capacity (IC50 ranging from 10 to 50 ug/mL) when compared to the gallic acid and trolox standards (IC50 of 12.46 and 2.55 ug/mL, respectively). The crude extracts of Diaporthe sp. MFLUCC16-0682 and Diaporthe sp. MFLUCC16-0693 exhibited notable antibacterial and antioxidant activities. Analysis of chemical composition using gas chromatography-mass spectrometry suggested that the observed antibacterial activity of the two Diaporthe spp. was possibly due to the presence of abienol, 4-methoxy stilbene, phenethyl cinnamate and 2Z,6Z-farnesal, while their potential antioxidant activity could be attributed to phenolic compounds, such as benzene acetaldehyde, benzyl benzoate, salicylaldehyde, benzoin and benzyl cinnamate. The results suggest that the genus Diaporthe is a potential source of metabolites that can be used in a variety of applications. PMID- 29159690 TI - Fungal Endophyte Communities in Begonia Species from the Brazilian Atlantic Rainforest. AB - Tropical plants represent hotspots of endophytic fungal species diversity. Based on culture-dependent methods, we evaluated the endophytic fungal communities in leaves of three plant species found in the Brazilian Atlantic Rainforest: Begonia fischeri, Begonia olsoniae, and Begonia venosa. These species are found in two distant sites: a continental region and an insular area. A total of 426 fungal endophytes in 19 genera were isolated in pure culture including Colletotrichum (51.6% of isolates) and Diaporthe (22.5%) as the most abundant, followed by Phyllosticta (3.5%), Neopestalotiopsis (1.8%), Stagonospora (1.8%), and Nigrospora (1.6%) among the genera found in minor abundance. The diversity and composition of fungal taxa differed across plant hosts. Richness and diversity of fungi were higher in B. fischeri in comparison to B. olsoniae and B. venosa. Discriminatory analysis revealed that fungal communities are structured according to hosts, which means that each plant species had its distinct endophytic communities, but dominated by common fungal taxa. This is the first study to report fungal endophytes in begonia leaves and characterize their communities. PMID- 29159691 TI - Potential treatment of atopic dermatitis: tolerability and safety of cream containing nanoparticles loaded with hydrocortisone and hydroxytyrosol in human subjects. AB - Hydrocortisone (HC), topical glucocorticoid along with hydroxytyrosol (HT), and anti-microbial- and anti-oxidant-loaded chitosan nanoparticles (CSNPs) were prepared in large scale and analyzed for their adverse effects on healthy human skin followed by repeated applications. Ten subjects were randomized to receive test (HC-HT CSNPs) and vehicle samples (aqueous (AQ) cream). They were applied on the arms for 28 days, and transepidermal water loss (TEWL), erythema intensity, and irritation score were measured. Blood samples were analyzed for blood hematology, blood biochemistry, and adrenal cortico-thyroid hormone (ACTH) levels. Skin biopsy was obtained to assess histopathological changes in the skin. HC-HT CSNP AQ cream was stored at 4, 25, and 45 degrees C for a period of 1 year, and its stability was assessed by monitoring their physical appearances, particle size, and pH. Spherical-shaped NPs were successfully upscaled using spinning-disc technology, with insignificant changes in particle size, zeta potential, and incorporation of drugs as compared to the well-established laboratory method. Particle size of HC-HT CSNPs was < 250 nm, and HC-HT CSNPs AQ cream remained stable when stored at 25 degrees C. TEWL and erythema intensity for 28-day application did not indicate any signs of local irritation, redness, and toxicity, which were confirmed by normal Draize skin irritation scoring system and skin hematoxylin and eosin (H&E) staining results. Comparative results of blood hematology, blood biochemistry, and adrenal cortico-thyroid hormone level at day 0 and day 28 were not significant, indicating non-systemic toxicity. In conclusion, HC-HT CSNP AQ cream is safe, well-tolerated, and non-toxic, which may be useful in treating atopic dermatitis. PMID- 29159692 TI - Germacrone and sesquiterpene-enriched extracts from Curcuma aeruginosa Roxb. increase skin penetration of minoxidil, a hair growth promoter. AB - Minoxidil is approved for topical treatment of androgenic alopecia but hampered by poor cutaneous absorption. Recently, the randomized control trial showed that hair loss treatment of minoxidil was improved by co-application of the anti androgen, Curcuma aeruginosa Roxb. extract. Here, we aimed to show that the apparent synergism arises from improved cutaneous penetration of minoxidil by bioactive compound, germacrone or C. aeruginosa (as an n-hexane extract, or essential oil). The partition coefficient of germacrone was determined by HPLC. Skin penetration was measured ex vivo on Franz diffusion cells using full thickness human foreskin as membranes. The receiver solution was sampled hourly for 8 h after which the skin was removed, the stratum corneum separated, and minoxidil assayed in this and in the remaining viable skin layer by HPLC. Skin penetration of minoxidil with 0.2 and 2% extract was increased ~ 4-fold (accumulated amount in receiver + skin viable layer after 8 h). Furthermore, germacrone enhanced minoxidil flux by ~ 10-fold and C. aeruginosa essential oil by ~ 20-fold. This work suggests three clinical consequences: (i) minoxidil efficacy is promoted, (ii) lower doses of minoxidil suffice, and (iii) C. aeruginosa extract/essential oil or germacrone can supplement treatment outcomes by acting as anti-androgen, thereby introducing a more effective topical treatment strategy for androgenic alopecia. PMID- 29159693 TI - Betahistine dihydrochloride transdermal delivery via optimized thermosensitive gels: percutaneous absorption evaluation using rat growth as a biomarker. AB - The aim of this study was to develop and optimize a betahistine dihydrochloride (BH) thermoreversible bioadhesive gel intended for transdermal delivery. The gels were obtained via cold method. A full factorial design was employed to investigate the joint effect of Poloxamer 407 concentration (18 and 20%), adhesive polymer type (Polyvinyl pyrolidone, Hydroxypropyl methylcellulose, and Carbopol 934), and adhesive polymer concentration (0.5 and 1.5%) on gelling temperature, viscosity at 37 degrees C, and adhesion strength. Data collected were analyzed using multiple linear regression. A desirability index approach with relative importance weight was used to choose the most desirable formulation. F4 (20% Poloxamer+1.5% Carbopol) was selected for further characterization. F4 released 96.97% drug in 12 h across hairless rat skin. F4 gelation temperature and time were 36 +/- 0.35 degrees C, and 6 +/- 0.7 min, respectively. F4 adhesive force was 8835.68 dyne/cm2. F4 was tested for its appetite suppressing effect in a rat model and it was evaluated histopathologically. Rats' chow intake and weight gain was significantly decreased with no signs of inflammation or lipolysis when the optimized BH gel formulation, F4, was compared with untreated animals and animals treated with BH free gel. The results suggest that BH is percutaneously absorbed from the gel base and that the BH gel is tolerable. The desirability index approach with relative importance weight of responses was effective in determination of the optimum formulation. BH is systemically effective and well-tolerated when applied topically in hydrogel-based systems. The Carbopol-Poloxamer gel is a promising modality for transdermal delivery of BH. PMID- 29159694 TI - Urinary excretion of ciprofloxacin after administration of extended release tablets in healthy volunteers. Swellable drug-polyelectrolyte matrix versus bilayer tablets. AB - This paper builds on a previous paper in which new ciprofloxacin extended-release tablets were developed based on a ciprofloxacin-based swellable drug polyelectrolyte matrix (SDPM-CIP). The matrix contains a molecular dispersion of ciprofloxacin ionically bonded to the acidic groups of carbomer, forming the polyelectrolyte-drug complex CB-CIP. This formulation showed that the release profile of the ciprofloxacin bilayer tablets currently commercialised can be achieved with a simpler strategy. Thus, since ciprofloxacin urine concentrations are associated with the clinical cure of urinary tract infections, the goal of this work was to compare the urinary excretion of SDPM-CIP tablets with those of the CIPRO XR(r) bilayer tablets. A batch of SDPM-CIP tablets was manufactured by the wet granulation method and the CB-CIP ionic complex was obtained in situ. Fasted healthy volunteers received a single oral dose of 500 mg ciprofloxacin of either formulation in a randomised crossover study. Urinary concentrations were assessed by HPLC at intervals up to 36 h. Pharmacokinetic parameters (rate of urinary excretion, maximum urine excretion rate, tmax, area under the curve, amount and percentage of the ciprofloxacin dose excreted in urine) showed no statistical differences between both formulations at any of the time intervals of collection. The processing conditions to obtain SDPM-CIP tablets are easy to scale up since they involve technology currently employed in the pharmaceutical industry and the process is less challenging to implement. In addition, SDPM-CIP tablets met pharmacopoeial quality specifications. PMID- 29159695 TI - A novel lignin-based nanofibrous dressing containing arginine for wound-healing applications. AB - Nanofiber-based wound dressings have attracted much attention in wound care owing to their unique properties such as high aspect ratio and three-dimensional structure. Arginine is a precursor of nitric oxide that plays an important role in the wound-healing process. Therefore, in this study, we have developed a gel which contains lignin nanofibers (Lig-NFs) that were surface modified by arginine molecules via electrostatic interaction (Arg-Lig-NF gel). The effect of pH on the amount of arginine attached on Lig-NF surface was evaluated at three different pH values-5, 6, and 7. Fourier transform infrared spectroscopy and zeta potential of Lig-NFs before and after surface modification confirmed the surface modification of Lig-NFs with arginine molecules. The optimum gel composed of uniform Arg-Lig NFs with diameter ranging from 100 to 250 nm. There was 184.60 +/- 4.85 mg arginine in each gram of optimum gel. The release of arginine from Arg-Lig-NF gel showed a sustained release manner, and about 86.28 +/- 3.50% of attached arginine were released after 24 h. Moreover, the optimum gel presented suitable viscosity and spreadability for topical application. The in vivo full thickness wound healing assay carried out in rats demonstrated that the optimum Arg-Lig-NF gel can accelerate wound closure and increase re-epithelialization, collagen deposition, and angiogenesis significantly in Arg-Lig-NF gel-treated wounds compared to Lig-NF gel and arginine solution. Overall, these findings demonstrate that Arg-Lig-NF gel can be a promising material for the future development of effective hydrocolloid wound dressings used in the treatment of acute and chronic wounds. PMID- 29159696 TI - Reflex testing of speckled cytoplasmic patterns observed in routine ANA HEp-2 indirect immunofluorescence with a multiplex anti-synthetase dot-blot assay: a multicentric pilot study. AB - Immunofluorescence on HEp2-cells is the standard diagnostic assay for the detection of anti-nuclear antibodies (ANA). Cytoplasmic speckled patterns are a common finding, and are associated with various antibodies, including anti synthetase antibodies. However, classic ENA testing generally identifies only anti-Jo-1. Moreover, anti-synthetase syndrome is increasingly recognized as a pleomorphic entity, possibly presenting as isolated arthritis or interstitial lung disease. Sera referred for routine ANA testing were selected on the basis of the presence of a fine dense speckled cytoplasmic pattern (254 samples) and compared to control sera with negative cytoplasm (239 samples). All 493 samples were tested with a commercial synthetase profile dot-blot (D TEK - Alphadia Alifax) including anti-Jo1, anti-PL7, anti-PL12, anti-EJ, anti-OJ, anti-KS, anti ZO, anti-HA, anti-SRP, and anti-Ribosome P0. Retrospective clinical data was searched for positive patients. Dot-blot identified 18/254 (7.1%) positive sera in the samples with a cytoplasmic fluorescence pattern and 4/239 (1.7%) in the control group (chi2 = 8.4627; p = 0.003625). Blot intensity was more intense in samples with concordant cytoplasmic staining (cytoplasmic negative 27 +/- 12.4; cytoplasmic positive 53.9 27 +/- 27.7; p = 0.0027). In the positive samples, 8/18 had a highly compatible diagnosis (myositis, interstitial lung disease, arthritis), 7/18 an uncharacterized connective tissue disease, and 3 a diagnosis not associated with the presence of anti-synthetase antibodies. We evaluated the performance of a dot-blot assay for anti-cytoplasmic antibodies in a serologic cohort presenting a cytoplasmic speckled pattern found during routine ANA testing. This algorithm enabled the identification of a significant quota of patients with rare anti-synthetase antibodies and an incomplete or atypical clinical picture. Reflex testing strategies of speckled cytoplasmic patterns with multiplex assays containing cytoplasm-specific antigens, as opposed to standard ENA testing, may yield important data and for this reason should be implemented in routine ANA testing. PMID- 29159699 TI - Fleeting reliability in the dot-probe task. AB - In a dot-probe task, two cues-one emotional and one neutral-are followed by a probe in one of their locations. Faster responses to probes co-located with the emotional stimulus are taken as evidence of attentional bias. Several studies indicate that such attentional bias measures have poor reliability, even though ERP studies show that people reliably attend to the emotional stimulus. This inconsistency might arise because the emotional stimulus captures attention briefly (as indicated by ERP), but cues appear for long enough that attention can be redistributed before the probe onset, causing RT measures of bias to vary across trials. We tested this hypothesis by manipulating SOA (stimulus onset asynchrony between onset of the cues and onset of the probe) in a dot-probe task using angry and neutral faces. Across three experiments, the internal reliability of behavioural biases was significantly greater than zero when probes followed faces by 100 ms, but not when the SOA was 300, 500, or 900 ms. Thus, the initial capture of attention shows some level of consistency, but this diminishes quickly. Even at the shortest SOA internal reliability estimates were poor, and not sufficient to justify the use of the task as an index of individual differences in attentional bias. PMID- 29159698 TI - Analysis of Biosignals During Immersion in Computer Games. AB - The number of computer game users is increasing as computers and various IT devices in connection with the Internet are commonplace in all ages. In this research, in order to find the relevance of behavioral activity and its associated biosignal, biosignal changes before and after as well as during computer games were measured and analyzed for 31 subjects. For this purpose, a device to measure electrocardiogram, photoplethysmogram and skin temperature was developed such that the effect of motion artifacts could be minimized. The device was made wearable for convenient measurement. The game selected for the experiments was League of LegendsTM. Analysis on the pulse transit time, heart rate variability and skin temperature showed increased sympathetic nerve activities during computer game, while the parasympathetic nerves became less active. Interestingly, the sympathetic predominance group showed less change in the heart rate variability as compared to the normal group. The results can be valuable for studying internet gaming disorder. PMID- 29159697 TI - Subepidermal autoimmune bullous diseases: overview, epidemiology, and associations. AB - Subepidermal autoimmune bullous diseases of the skin and mucosae comprise a large group of chronic diseases, including bullous pemphigoid, pemphigoid gestationis, mucous membrane pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, and anti-p200 pemphigoid. These diseases are characterized by an antibody response toward structural components of the basement membrane zone, resulting in subepidermal blistering. The epidemiological features of these diseases vary substantially in different regions of the world. Observational studies investigating comorbidities and associations among patients with these diseases are inconsistent and sometimes inconclusive. This review provides a brief overview regarding each one of the subepidermal autoimmune bullous diseases. In addition, it summarizes the most recent understanding of the epidemiological features and associations of this group of organ-specific autoimmune diseases. PMID- 29159700 TI - Expression and distribution patterns of spermine, spermidine, and putrescine in rat hair follicle. AB - No expression and distribution patterns of polyamines (PAs), spermine, spermidine, and their precursor putrescine in mammalian hair follicle are available, although polyamines are known to correlate well with hair growth and epidermal tumor genesis. Immunohistochemistry (IHC) using our original two monoclonal antibodies (mAbs) ASPM-29 specific for spermine or spermidine, and APUT-32 specific for putrescine allowed us to detect immunoreactivity for polyamines in hair follicles from normal adult rats. A wide range of immunoreactivity for the total spermine and spermidine was observed in the compartments of hair follicle: The highest degree of immunoreactivity for polyamines was observed in the matrix, in the Huxley's layer, in the deeper Henle's layer, and in the cuticle of the inner root sheath/the hair cuticle, while moderate immunoreactivity existed in the lower-to-mid cortex and the companion layer, followed by lower immunoreactivity in the outer root sheath, including the bulge region and in the deeper medulla, in which the immunoreactivity was also evident in their nuclei. In addition, somewhat surprisingly, with IHC by APUT-32 mAb, we detected significant levels of putrescine in the compartments, in which the immunostaining pattern was the closely similar to that of the total spermine and spermidine. Thus, among these compartments, the cell types of the matrix, the Huxley's layer, the deeper Henle's layer, and the cuticle of the inner root sheath/the hair cuticle seem to have the biologically higher potential in compartments of anagen hair follicle, maybe suggesting that they are involved more critically in the biological event of hair growth. In addition, we noted sharp differences of immunostaining by IHCs between ASPM-29 mAb and APUT-32 mAb in the epidermis cells and fibroblast. ASPM 29 mAb resulted in strong staining in both the cell types, but APUT-32 mAb showed only very light staining in both types. Consequently, the use of the two IHCs could be extremely useful in further studies on hair cycle and epidermal tumor genesis experimentally or clinically. PMID- 29159701 TI - Residues of Diclofenac in Tissues of Vultures in India: A Post-ban Scenario. AB - Populations of three resident Gyps species (Indian white-backed vulture Gyps bengalensis, Indian vulture Gyps indicus, and Slender-billed vulture Gyps tenuirostris) in India have decreased by more than 90% since mid 1990s, and they continue to decline. Experimental studies showed the mortality of vultures to be due to renal failure caused by diclofenac, a nonsteroidal anti-inflammatory drug. India, Pakistan, and Nepal banned the veterinary usage of diclofenac in 2006 to prevent further decline in vulture population. This study was performed to know the current status of the impact of diclofenac on vultures in India. Between 2011 and 2014, 44 vultures comprising two species, namely Indian white-backed vulture (32) and Himalayan griffon Gyps himalayensis (12) were collected dead from Gujarat, Assam, and Tamil Nadu on an opportunistic basis. Kidney and liver tissues and gut content were analysed for diclofenac. Of the 32 dead white-backed vultures analysed, 68.75% of them had diclofenac ranging from 62.28 to 272.20 ng/g. Fourteen white-backed vultures had diclofenac in kidney in toxic range (70 908 ng/g). Of 12 Himalayan griffon studied, 75% of them had diclofenac in the range of 139.69 to 411.73 ng/g. Himalayan griffon had significantly higher levels of diclofenac in tissues than Indian white-backed vultures. It is possible that 14 of 29 white-backed vultures and 9 of 12 Himalayan griffon included in this study died due to diclofenac poisoning. Studies have indicated that diclofenac can continue to kill vultures even after its ban in India for veterinary use. PMID- 29159702 TI - Evaluation of Levels, Sources and Health Hazards of Road-Dust Associated Toxic Metals in Jalalabad and Kabul Cities, Afghanistan. AB - This study was designed to investigate selected road-dust associated heavy metals, their relations with natural and anthropogenic sources, and potential human and environmental health risks. For this purpose, 42 and 36 road-dusts samples were collected from Jalalabad and Kabul cities (Afghanistan), respectively. The following elements were found in descending concentrations: Mn, Zn, Pb, Ni, Cu, Cr, Co, and Cd in Jalalabad; and Mn, Zn, Ni, Cu, Cr, Pb, Co, and Cd in Kabul. Except for Ni, all the elemental contents were less than the Canadian permissible limits in residential/parkland soils. Principle Component Analysis and enrichment of Cd, Cu, Ni, Pb, and Zn pointed to anthropogenic sources, whereas Co, Cr, and Mn indicated crustal inputs. Broadly, Cd monomial risk index ([Formula: see text]) was considerable; however, one site each in both cities showed high risk ([Formula: see text] >= 350). The potential ecological risk (RI) is mostly low; however, at some sites, the risk was considerable. Ingestion appeared to be the main exposure route (99%) for heavy metals and contributed > 90% to noncancerous (all residents), as well as 92% (children) and 75-89% (adults) cancerous risks. The noncancerous risks of all metals and their integrated risks for all residents were within acceptable levels. Moreover, potential cancer risks in children from Ni and Cr were slightly higher than the US-EPA safe levels but were within acceptable levels for adults. This study found higher risks to children and therefore recommends proper management and ways to control metals pollution load in these areas to decrease human health and RIs. PMID- 29159703 TI - Ambrosia pollen source inventory for Italy: a multi-purpose tool to assess the impact of the ragweed leaf beetle (Ophraella communa LeSage) on populations of its host plant. AB - Here, we produce Ambrosia pollen source inventories for Italy that focuses on the periods before and after the accidental introduction of the Ophraella communa beetle. The inventory uses the top-down approach that combines the annual Ambrosia pollen index from a number of monitoring stations in the source region as well as Ambrosia ecology, local knowledge of Ambrosia infestation and detailed land cover information. The final inventory is gridded to a 5 * 5-km resolution using a stereographic projection. The sites with the highest European Infection levels were recorded in the north of Italy at Busto Arsizio (VA3) (European Infection level 2003-2014 = 52.1) and Magenta (MI7) (European Infection level 2003-2014 = 51.3), whereas the sites with the lowest (i.e. around 0.0) were generally located to the south of the country. Analysis showed that the European Infection level in all of Italy was significantly lower in 2013-2014 compared to 2003-2012, and this decrease was even more pronounced at the sites in the area where Ophraella communa was distributed. Cross-validations show that the sensitivity to the inclusion of stations is typically below 1% (for two thirds of the stations) and that the station Magenta (MI7) had the largest impact compared to all other stations. This is the first time that pollen source inventories from different temporal periods have been compared in this way and has implications for simulating interannual variations in pollen emission as well as evaluating the management of anemophilous plants like Ambrosia artemisiifolia. PMID- 29159704 TI - Neuroimmune Regulation of JC Virus by Intracellular and Extracellular Agnoprotein. AB - JC virus (JCV) is a human polyomavirus and the etiologic agent of the demyelinating disease progressive multifocal leukoencephalopathy (PML). PML is observed in patients with underlying immunocompromising conditions, suggesting that neuro-immune interactions between peripheral immune cells and neuro-glia play an important role in controlling viral reactivation in the brain. There is little known about the immunobiology of JCV reactivation in glial cells and the role of immune, glial, and viral players in this regulation. We have previously showed that agnoprotein, a small JCV regulatory protein, is released from infected cells and internalized by neighboring bystander cells. Here we have investigated the possible role of extracellular and intracellular agnoprotein in the neuroimmune response to JC virus. Our findings suggest that glial cells exposed to agnoprotein secrete significantly less GM-CSF, which is mediated by agnoprotein induced suppression of GM-CSF transcription. Likewise, monocytes treated with agnoprotein showed altered differentiation and maturation. In addition, monocytes and microglial cells exposed to agnoprotein showed a significant reduction in their phagocytic activities. Moreover, when an in vitro blood-brain barrier model was used, agnoprotein treatment resulted in decreased monocyte migration through the endothelial cell layer in response to activated astrocytes. All together, these results have revealed a novel immunomodulatory function of agnoprotein during JCV infection within theCNS and open a new avenue of research to better understand the mechanisms associated with JCV reactivation in patients who are at risk of developing PML. PMID- 29159705 TI - Isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives induce regulated necrosis-like cell death on Leishmania (Leishmania) mexicana. AB - Leishmaniasis is a neglected tropical disease caused by the parasite of the genus Leishmania. About 13 million people are infected worldwide, and it is estimated that 350 million are at risk of infection. Clinical manifestations depend on the parasite species and factors related to the host such as the immune system, nutrition, housing, and financial resources. Available treatments have severe side effects; therefore, research currently focuses on finding more active and less toxic compounds. Quinoxalines have been described as promising alternatives. In this context, 17 isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives were evaluated as potential leishmanicidal agents. Their effect on the cell metabolism of Leishmania mexicana promastigotes and their cytotoxic effects on the J774.A1 cell line and on erythrocytes were evaluated, and their selectivity index was calculated. Compounds T-069 (IC50 = 1.49 MUg/mL), T-070 (IC50 = 1.71 MUg/mL), T-072 (IC50 = 6.62 MUg/mL), T-073 (IC50 = 1.25 MUg/mL), T 085 (IC50 = 0.74 MUg/mL), and T-116 (IC50 = 0.88 MUg/mL) were the most active against L. mexicana promastigotes and their mechanism of action was characterized by flow cytometry and microscopy. Compound T-073, the most selective quinoxaline derivative, induced cell membrane damage, phosphatidylserine exposition, reactive oxygen species production, disruption of the mitochondrion membrane potential, and DNA fragmentation, all in a dose-dependent manner, indicating the induction of regulated necrosis. Light and transmission electron microscopy showed the drastic morphological changes induced and the mitochondrion as the most sensitive organelle in response to T-073. This study describes the mechanism by which active isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide quinoxalines affect the parasite. PMID- 29159706 TI - Alcoholism Detection by Data Augmentation and Convolutional Neural Network with Stochastic Pooling. AB - Alcohol use disorder (AUD) is an important brain disease. It alters the brain structure. Recently, scholars tend to use computer vision based techniques to detect AUD. We collected 235 subjects, 114 alcoholic and 121 non-alcoholic. Among the 235 image, 100 images were used as training set, and data augmentation method was used. The rest 135 images were used as test set. Further, we chose the latest powerful technique-convolutional neural network (CNN) based on convolutional layer, rectified linear unit layer, pooling layer, fully connected layer, and softmax layer. We also compared three different pooling techniques: max pooling, average pooling, and stochastic pooling. The results showed that our method achieved a sensitivity of 96.88%, a specificity of 97.18%, and an accuracy of 97.04%. Our method was better than three state-of-the-art approaches. Besides, stochastic pooling performed better than other max pooling and average pooling. We validated CNN with five convolution layers and two fully connected layers performed the best. The GPU yielded a 149* acceleration in training and a 166* acceleration in test, compared to CPU. PMID- 29159707 TI - Propionyl-CoA carboxylase pcca-1 and pccb-1 gene deletions in Caenorhabditis elegans globally impair mitochondrial energy metabolism. AB - : Propionic acidemia (PA) is a classical inborn error of metabolism with high morbidity that results from the inability of the propionyl-CoA carboxylase (PCC) enzyme to convert propionyl-CoA to methylmalonyl-CoA. PA is inherited in an autosomal recessive fashion due to functional loss of both alleles of either PCCA or PCCB. These genes are highly conserved across evolutionarily diverse species and share extensive similarity with pcca-1 and pccb-1 in the nematode, Caenorhabditis elegans. Here, we report the global metabolic effects of deletion in a single PCC gene, either pcca-1 or pccb-1, in C. elegans. Animal lifespan was significantly reduced relative to wild-type worms in both mutant strains, although to a greater degree in pcca-1. Mitochondrial oxidative phosphorylation (OXPHOS) capacity and efficiency as determined by direct polarography of isolated mitochondria were also significantly reduced in both mutant strains. While in vivo quantitation of mitochondrial physiology was normal in pccb-1 mutants, pcca 1 deletion mutants had significantly increased mitochondrial matrix oxidant burden as well as significantly decreased mitochondrial membrane potential and mitochondrial content. Whole worm steady-state free amino acid profiling by UPLC revealed reduced levels in both mutant strains of the glutathione precursor cysteine, possibly suggestive of increased oxidative stress. Intermediary metabolic flux analysis by GC/MS with 1,6-13C2-glucose further showed both PCC deletion strains had decreased accumulation of a distal tricarboxylic acid (TCA) cycle metabolic intermediate (+1 malate), isotopic enrichment in a proximal TCA cycle intermediate (+1 citrate), and increased +1 lactate accumulation. GC/MS analysis further revealed accumulation in the PCC mutants of a small amount of 3 hydroxypropionate, which appeared to be metabolized in C. elegans to oxalate through a unique metabolic pathway. Collectively, these detailed metabolic investigations in translational PA model animals with genetic-based PCC deficiency reveal their significantly dysregulated energy metabolism at multiple levels, including reduced mitochondrial OXPHOS capacity, increased oxidative stress, and inhibition of distal TCA cycle flux, culminating in reduced animal lifespan. These findings demonstrate that the pathophysiology of PA extends well beyond what has classically been understood as a single PCC enzyme deficiency with toxic precursor accumulation, and suggest that therapeutically targeting the globally disrupted energy metabolism may offer novel treatment opportunities for PA. SUMMARY: Two C. elegans model animals of propionic acidemia with single-gene pcca-1 or pccb-1 deletions have reduced lifespan with significantly reduced mitochondrial energy metabolism and increased oxidative stress, reflecting the disease's broader pathophysiology beyond a single enzyme deficiency with toxic precursor accumulation. PMID- 29159708 TI - Mainstreaming genetics in palliative care: barriers and suggestions for clinical genetic services. AB - Palliative healthcare professionals (PHCPs) frequently do not refer their eligible patients for genetic testing. After the death of the affected individual, clinically relevant information for family members is lost. In previous research, PHCPs stated that the end-of-life setting is not appropriate to discuss genetic issues. It is unclear if this has changed due to increasing awareness of genetics in the media and efforts to mainstream genetic testing. Semi-structured interviews of PHCPs were analysed by thematic analysis. Seven PHCPs (four nurses, two consultants, and one clinical psychologist) were interviewed. Participants reported feeling unfamiliar with the role of clinical genetics services, and did not feel confident in addressing genetic issues with their patients. A lack of scientific knowledge and unawareness of existing infrastructure to support their patients were cited. Many stated that palliative patients are interested in exploring a potential hereditary component to their disease, and acknowledged the potential for psychological benefit for their patients and their families. Most stated that addressing genetics fits within their skill set, but expressed concern about issues of consent, logistical difficulties, and ethical dilemmas. These perceptions differ considerably from those reported in existing literature. Importantly, each participant stated that the potential benefits of addressing genetic issues outweighed the potential for harm in most cases. These results suggest a need for clinical genetics staff to develop closer links with their local PHCPs and to provide education. Clinical psychologists may also be a helpful resource to address PHCPs' concerns. PMID- 29159709 TI - 12th International HHT Scientific Conference : June 8-11, 2017, Dubrovnik, Croatia. PMID- 29159710 TI - Prediction of Free from Total Mycophenolic Acid Concentrations in Stable Renal Transplant Patients: A Population-Based Approach. AB - BACKGROUND: A population pharmacokinetic (PK) protein-binding model was developed to (1) predict free mycophenolic acid (fMPA) based on total MPA (tMPA) concentrations in renal transplant patients, to establish the therapeutic range of fMPA through pharmacokinetic-pharmacodynamic studies; and (2) provide a guideline for dosing mycophenolate mofetil (MMF). METHODS: Full PK profiles of 56 patients (from five different occasions) during the first year after transplantation who were treated with oral MMF and cyclosporine, or macrolides (either tacrolimus or sirolimus), were analysed. fMPA protein-binding was modelled using nonlinear mixed effects modelling (NONMEM). The influence of physiological factors and coadministered immunosupressant was studied. RESULTS: A two-compartment model with first-order absorption and elimination, linear protein binding and enterohepatic circulation (EHC) best described the PK of MPA. Different recycling rate constants were considered depending on the coadministered immunosuppressant. The protein-binding rate constant (KB [relative standard error, RSE%]) increased nonlinearly with renal function according to K B = 43.1 (3.13).(CLCR/59.51)0.394(10.66) h-1. Furthermore, fMPA plasma clearance, given by clearance of the free mycophenolic acid (CLfMPA), CLfMPA = 410 (RSE%3.00).(1+CsA.0.594 (22.39)) L/h, was 59.4% greater in cyclosporine-treated patients than in macrolide-treated patients, leading to lower MPA exposures. External evaluation proved acceptable area under the plasma concentration-time curve and trough concentration predictions. CONCLUSIONS: A reliable protein binding population PK model was developed for prediction of fMPA or tMPA from each other and for dose guiding in stable renal transplant recipients. PMID- 29159711 TI - Treatment of Richter's Syndrome. AB - OPINION STATEMENT: Based on the available literature, mostly derived from retrospective or non-randomized phase I or II studies, it is difficult to define an optimized treatment approach for patients developing Richter's syndrome (RS). Early recognition of chronic lymphocytic leukemia (CLL) patients presenting clinical features suspected for a transformation is useful to avoid exposing them to multiple lines of therapy that, being targeted to CLL progression, have poor efficacy against RS. Because of the low specificity (~ 50-60%) of clinical signs of RS (such as rapid and discordant bulky localized lymphadenopathies, elevated LDH levels, emergent physical deterioration, and/or fever in the absence of infection), a 18FDG PET/CT and a biopsy are recommended to confirm RS. A 18FDG PET/CT showing low uptake is helpful to rule out RS and avoid unnecessary risks and costs of performing a biopsy. A 18FDG PET/CT showing a high uptake is not diagnostic of RS but may help in the choice of the site where the biopsy is to be performed. In the setting of the diffuse large B-cell lymphoma (DLBCL) variant of RS, the definition of a clonal relationship between RS and the underlying CLL may guide the choice of treatment. If a clonal relationship is confirmed (the most common situation), rituximab-CHOP-like treatment does not guarantee long-lasting remissions, and should be used as induction therapy followed by consolidation with a stem cell transplant in physically fit patients. If the CLL and RS are clonally unrelated (the less common situation), the management should be that of a de novo DLBCL. In the setting of the rare Hodgkin lymphoma variant of RS, which is usually clonally unrelated to the CLL, ABVD with or without radiotherapy may be curative of the aggressive lymphoma. PMID- 29159712 TI - Effect of Kaempferol isolated from seeds of Eruca sativa on changes of pain sensitivity in Streptozotocin-induced diabetic neuropathy. AB - Generation of excessive reactive oxygen species (ROS) and advanced glycation end products (AGEs), and cellular apoptosis are implicated in the pathogenesis of diabetic neuropathy. Present study was aimed to explore the effect of Eruca sativa and Kaempferol (KP) on hyperalgesia (thermal and mechanical); tactile allodynia, motor nerve conduction velocity (MNCV) and oxidative-nitrosative stress in streptozotocin (STZ) induced experimental diabetes. Neuropathy developed in diabetic rats was evident from a marked hyperalgesia and allodynia; reduced MNCV associated with excess formation of AGEs and ROS. Chronic treatment with E. sativa hydroalcoholic extract (EHA; 100, 200 and 400 mg/kg) and KP (5 and 10 mg/kg) for 30 days starting from the 60th day of STZ administration significantly ameliorated behavioral and biochemical changes linked to diabetic neuropathy. Present study suggested that EHA and KP corrected hyperglycemia and reversed the pain response partially in diabetic rats along via modulating oxidative and nitrosative stress along with reduction of AGEs formation in diabetic rats. Thus E. sativa might be beneficial in chronic diabetes, ameliorate the progression of diabetic neuropathy and may also find application in diabetic neuropathic pain. PMID- 29159713 TI - TMEM88 mediates inflammatory cytokines secretion by regulating JNK/P38 and canonical Wnt/beta-catenin signaling pathway in LX-2 cells. AB - Recent data have shown that Transmembrane protein 88 (TMEM88), a newly discovered protein localized on the cell membrane, interacts with the PDZ domain of disheveled-1 (Dvl-1) in Xenopus embryos. Indeed, TMEM88 might inhibit the canonical Wnt/beta-catenin signaling pathway by competing with LRP5/6 for interaction with Dvl-1. TMEM88 plays a crucial role in regulating human stem cell differentiation and embryonic development. Until recently, the function of TMEM88 has been a matter of debate. In this study, we explore the role of TMEM88 in cytokine secretion and the role of the MAPK and Wnt/beta-catenin signaling pathway in tumor necrosis factor-alpha (TNF-alpha)-induced TMEM88 expression in LX-2 cells. We demonstrated that overexpression of TMEM88 results in an upregulation of IL-6 and IL-1beta secretion. On the other hand, knockdown of TMEM88 by transfecting siRNA decreased IL-6 and IL-1beta secretion in LX-2 cells. Meanwhile, the results showed that TMEM88 silencing could increase the expression levels of canonical Wnt/beta-catenin accompanied with upregulated phosphorylation of wnt3a, wnt10b and beta-catenin protein levels in response to TNF-alpha. In conclusion, these results indicated that TMEM88 plays a significant role in TNF alpha-enhanced cytokine (IL-6 and IL-1beta) secretion of LX-2 cells via regulating JNK/P38 and canonical Wnt/beta-catenin signaling pathway. PMID- 29159714 TI - Regulatory effects of dexamethasone on NK and T cell immunity. AB - Glucocorticoids (GCs) act via the intracellular glucocorticoid receptor (GR), which can regulate the expression of target genes. With regard to the immune system, GCs may affect both innate and adaptive immunity. Our study analyzed the immunoregulatory effects of dexamethasone (Dex) treatment on splenic T, Treg, NK and NKT cells by treating C57Bl6 mice with various doses of Dex. We observed that treatment with Dex decreased the number of NK cells in the spleen and suppressed their activity. In particular, the expression of both Ly49G and NKG2D receptors was decreased by Dex. However, Dex did not affect the population of NKT cells. With regard to splenic T cells, our results show a dose-dependent reduction in CD3+, CD4+, CD8+, CD44+ and CD8+CD122+ T cells, but a stimulatory effect on CD4+CD25+ regulatory T cells by Dex treatment. In addition, treatment with Dex suppressed anti-tumor immune response in a mouse EG7 tumor model. We conclude that Dex may suppress both T- and NK-mediated immunity. PMID- 29159715 TI - Does the administration of melatonin during post-traumatic brain injury affect cytokine levels? AB - Increased levels of inflammatory cytokines after traumatic brain injury (TBI) can lead to brain edema and neuronal death. In this study, the effect of melatonin on pro-inflammatory (IL-1beta, IL-6, and TNF-alpha) and anti-inflammatory (IL-10) cytokines following TBI was investigated considering anti-inflammatory effect of melatonin. Male Wistar rats were divided into five groups: Sham, TBI, TBI + VEH (vehicle), TBI + 5 mg dose of melatonin (MEL5), TBI + 20 mg dose of melatonin (MEL20). Diffuse TBI was induced by Marmarou method. Melatonin was administered 1, 24, 48 and 72 h after TBI through i.p. Brain water content and brain levels of pro-inflammatory (IL-1beta, IL-6 and TNF-alpha) and anti-inflammatory (IL-10) cytokines were measured 72 h after TBI. The IL-1beta levels decreased in the TBI + MEL5 and TBI + MEL20 groups in comparison to TBI + VEH group (p < 0.001). The levels of IL-6 and TNF-alpha also decreased in melatonin-treated groups compared to control group (p < 0.001). The amount of IL-10 decreased after TBI. But melatonin administration increased the IL-10 levels in comparison with TBI + VEH group (p < 0.001). The results showed that melatonin administration affected the brain levels of pro-inflammatory and anti-inflammatory cytokines involving in brain edema led to neuronal protection after TBI. PMID- 29159716 TI - Rotula aquatica Lour attenuates secretion of proinflammatory mediators and cytokines in lipopolysaccharide-induced inflammatory responses in murine RAW 264.7 macrophages. AB - Rotula aquatica belongs to the family Boraginaceae, and is reported to contain baunerol, steroids and alkaloids. In Ayurveda, R. aquatica has been used for the treatment of various diseases such as diabetes, treatment of piles, venereal disease, and cancer. The current study aims to investigate the anti-inflammatory effect of methanolic extract of R. aquatica (MERA) in RAW 264.7 cells. The cytotoxicity of MERA was analyzed by MTT assay. The total cyclooxygenase (COX) activity, 5-lipoxygenase (5-LOX) activity, myeloperoxidase activity, inducible nitric oxide synthase activity, nitrate level and reactive oxygen species production were studied in LPS-stimulated RAW 264.7 cells. The gene level expression of cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were also evaluated in this study. The MERA did not show any cytotoxicity at different concentrations (6.25-100 ug/ml). MERA (100 MUg/ml) inhibited total COX and 5-LOX activity at 50.53 and 62.03%, respectively, besides significantly (p < 0.05) diminished nitrate and ROS generation, when compared with LPS control. Moreover, MERA down-regulated the mRNA expressions of inflammatory marker genes like TNF-alpha, IL-6, and COX-2 against LPS stimulation. Our results demonstrate that MERA is able to attenuate inflammatory response, possibly via ROS and NO suppression, inhibiting the production of arachidonic acid metabolites and modulation of proinflammatory mediators and cytokines release. PMID- 29159717 TI - Analgesic, anti-inflammatory and anticancer activities of Combretin A and Combretin B isolated from Combretum fragrans F. HOFFM (Combretaceae) leaves. AB - Previous pharmacological and phytochemical studies showed that, Combretum fragrans F. HOFFM (Combretaceae) is a Cameroonian medicinal plant possessing numerous therapeutic virtues and rich in various active secondary metabolites. In this study, we investigate in vivo anti-nociceptive and anti-inflammatory activity and, in vitro anticancer, anti-TNFalpha, ROS and NO-inhibitory activities of Combretum A and Combretin B, two triterpenes cycloartane-type isolated from the leaves of Combretum fragrans. The effect on ROS, TNF-alpha and NO production, anticancer activity and cytotoxicity assay were done using chemiluminescence technique, ELISA kit, colorimetric method, MCF-7 cells and MTT assay, respectively. Antinociceptive and anti-inflammatory activities were estimated using a model of acetic acid, formalin and carrageenan. Combretin A and Combretin B significantly (p < 0.001) inhibited extracellular ROS production. These compounds also significantly (p < 0.001) reduced TNF-alpha and NO production. Moreover, these compounds decreased cell viability of MCF-7 cell lines. For acetic acid- or formalin-induced pain, as well as carrageenan-induced acute inflammation, Combretin A and Combretin B exhibited significant (p < 0.001) anti-nociceptive and anti-inflammatory activities. Anti-nociceptive, anti inflammatory and anticancer potential associated with inhibitory effects on ROS, TNFalpha and NO production in this study show that, Combretin A and Combretin B could be considered as the promising chemotherapeutic agents in breast cancer treatment and inflammatory disease. PMID- 29159718 TI - Genetics and epigenetics in the pathogenesis of primary biliary cholangitis. AB - Primary biliary cholangitis (PBC) is a chronic, slowly progressive cholestatic autoimmune liver disease predominantly afflicting women. PBC is characterized by the presence of disease-specific antimitochondrial antibodies and the histological destruction of intrahepatic bile ducts, which eventually lead to cirrhosis and hepatic failure. Fortunately, ursodeoxycholic acid therapy has improved the outcome of the vast majority of PBC cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. PBC patients may also have genetically determined risk factors in non-HLA regions. Meanwhile, exposure to environmental factors, such as infectious diseases and harmful chemicals, can produce epigenetic alterations in some individuals and subsequent PBC onset. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies on this disease and its future prospects in terms of epigenetics. PMID- 29159719 TI - Effect of a Real-Time Electronic Dashboard on a Rapid Response System. AB - A rapid response system (RRS) may have limited effectiveness when inpatient providers fail to recognize signs of early patient decompensation. We evaluated the impact of an electronic medical record (EMR)-based alerting dashboard on outcomes associated with RRS activation. We used a repeated treatment study in which the dashboard display was successively turned on and off each week for ten 2-week cycles over a 20-week period on the inpatient acute care wards of an academic medical center. The Rapid Response Team (RRT) dashboard displayed all hospital patients in a single view ranked by severity score, updated in real time. The dashboard could be seen within the EMR by any provider, including RRT members. The primary outcomes were the incidence rate ratio (IRR) of all RRT activations, unexpected ICU transfers, cardiopulmonary arrests and deaths on general medical-surgical wards (wards). We conducted an exploratory analysis of first RRT activations. There were 6736 eligible admissions during the 20-week study period. There was no change in overall RRT activations (IRR = 1.14, p = 0.07), but a significant increase in first RRT activations (IRR = 1.20, p = 0.04). There were no significant differences in unexpected ICU transfers (IRR = 1.15, p = 0.25), cardiopulmonary arrests on general wards (IRR = 1.46, p = 0.43), or deaths on general wards (IRR = 0.96, p = 0.89). The introduction of the RRT dashboard was associated with increased initial RRT activations but not overall activations, unexpected ICU transfers, cardiopulmonary arrests, or death. The RRT dashboard is a novel tool to help providers recognize patient decompensation and may improve initial RRT notification. PMID- 29159720 TI - Spontaneous rotation of the monorail-type guide extension support catheter during advancement of a curved guiding catheter: the potential hazard of twisting with the coronary guidewire. AB - The extension support guiding catheter has been used to perform complex percutaneous coronary intervention to increase back-up support for the guiding catheter or to ensure deep intubation for device delivery. However, because of its monorail design, advancement of the stent into the distal extension tubing segment is sometimes problematic. Although this problem is considered due to simple collision of the stent, operators have observed tangling between a monorail extension catheter and coronary guidewire in some patients. To examine movement of the collar of the extension guide catheter during advancement of the guiding catheter, we set up an in vitro model in which the guiding catheter had two curves. Rotation of the extension guide catheter was examined by both fluoroscopic imaging and movement of the hub of the proximal end of the catheter. During advancement in the first curve, the collar moved toward the outer side of the curve of the guiding catheter as the operator pushed the shaft of the extension guiding catheter, which overrode the guidewire. After crossing the first curve, the collar moved again to the outer side of the second curve (the inner side of the first curve) of the mother catheter, and then, another clockwise rotation was observed in the proximal hub. Consequently, the collar and tubing portion of the extension guide catheter rotated 360 degrees around the coronary guidewire, and the monorail extension catheter and guidewire became tangled. There is a potential risk of unintentional twisting with the guidewire during advancement into the curved guiding catheter because of its monorail design. PMID- 29159721 TI - Design, synthesis, in silico and in vitro antimicrobial screenings of novel 1,2,4 triazoles carrying 1,2,3-triazole scaffold with lipophilic side chain tether. AB - BACKGROUND: 1,2,4-Triazoles and 1,2,3-triazoles have gained significant importance in medicinal chemistry. RESULTS: This study describes a green, efficient and quick solvent free click synthesis of new 1,2,3-triazole-4,5 diesters carrying a lipophilic side chain via 1,3-dipolar cycloaddition of diethylacetylene dicarboxylate with different surfactant azides. Further structural modifications of the resulting 1,2,3-triazole diesters to their corresponding 1,2,4-triazole-3-thiones via multi-step synthesis has been also investigated. The structures of the newly designed triazoles have been elucidated based on their analytical and spectral data. These compounds were evaluated for their antimicrobial activities. Relative to the standard antimicrobial agents, derivatives of 1,2,3-triazole-bis-4-amino-1,2,4-triazole-3-thiones were the most potent antimicrobial agents with compound 7d demonstrating comparable antibacterial and antifungal activities against all tested microorganisms. Further, the selected compounds were studied for docking using the enzyme, Glucosamine-6-phosphate synthase. CONCLUSIONS: The in silico study reveals that all the synthesized compounds had shown good binding energy toward the target protein ranging from - 10.49 to - 5.72 kJ mol-1 and have good affinity toward the active pocket, thus, they may be considered as good inhibitors of GlcN-6-P synthase. PMID- 29159722 TI - Inbreeding in Southeastern Spain : The Impact of Geography and Demography on Marital Mobility and Marital Distance Patterns (1900-1969). AB - In this paper, the structure of a southeastern Spanish population was studied for the first time with respect to its inbreeding patterns and its relationship with demographic and geographic factors. Data on consanguineous marriages (up to second cousins) from 1900 to 1969 were taken from ecclesiastic dispensations. Our results confirm that the patterns and trends of inbreeding in the study area are consistent with those previously observed in most non-Cantabrian Spanish populations. The rate of consanguineous marriages was apparently stable between 1900 and 1935 and then sharply decreased since 1940, which coincides with industrialization in Spain. A marked departure from Hardy-Weinberg expectations (0.25) in the ratio of first cousin (M22) to second cousin (M33) marriages in the study population (0.88) was observed. The high levels of endogamy (>80%) and its significant steadiness throughout the twentieth century is noteworthy. Accordingly, our results show that exogamous marriages were not only poorly represented but also that this reduced mobility (<6 km) suggests that the choice of a mate was preferentially local. We found higher mobility in M22 with respect to M33 cousin mating. The relationships between population size and consanguinity rates and inbreeding fit power-law distributions. A significant positive correlation was observed between inbreeding and elevation. Many Spanish populations have experienced a prolonged and considerable isolation across generations, which has led to high proportions of historical and local endogamy that is associated, in general, with high [Formula: see text] values. Thus, assessing genomic inbreeding using runs of homozygosity (ROH) in current Spanish populations could be an additional pertinent strategy for obtaining a more refined perspective regarding the population history inferred from the extent and frequency of ROH regions. PMID- 29159724 TI - Turkish case of ethylmalonic encephalopathy misdiagnosed as short chain acyl-CoA dehydrogenase deficiency. AB - Ethylmalonic encephalopathy is a very rare autosomal recessively inherited inborn error of metabolism; characterized by encephalopathy, recurrent petechiae without bleeding diathesis, chronic diarrhea, and orthostatic acrocyanosis. Here, we describe a case of ethylmalonic encephalopathy with late onset neurologic symptoms and a confusing family history of two deceased brothers with the wrong suspicion of short chain acyl-CoA dehydrogenase deficiency. PMID- 29159723 TI - Anatomical and diffusional determinants inside leaves explain the difference in photosynthetic capacity between Cypripedium and Paphiopedilum, Orchidaceae. AB - Comparing with other angiosperms, most members within the family Orchidaceae have lower photosynthetic capacities. However, the underlying mechanisms remain unclear. Cypripedium and Paphiopedilum are closely related phylogenetically in Orchidaceae, but their photosynthetic performances are different. We explored the roles of internal anatomy and diffusional conductance in determining photosynthesis in three Cypripedium and three Paphiopedilum species, and quantitatively analyzed their diffusional and biochemical limitations to photosynthesis. Paphiopedilum species showed lower light-saturated photosynthetic rate (A N), stomatal conductance (g s), and mesophyll conductance (g m) than Cypripedium species. A N was positively correlated with g s and g m. And yet, in both species A N was more strongly limited by g m than by biochemical factors or g s. The greater g s of Cypripedium was mainly affected by larger stomatal apparatus area and smaller pore depth, while the less g m of Paphiopedilum was determined by the reduced surface area of mesophyll cells and chloroplasts exposed to intercellular airspace per unit of leaf area, and much thicker cell wall thickness. These results suggest that leaf anatomical structure is the key factor affecting g m, which is largely responsible for the difference in photosynthetic capacity between those two genera. Our findings provide new insight into the photosynthetic physiology and functional diversification of orchids. PMID- 29159725 TI - ECAP Editorial. PMID- 29159726 TI - Liquid Chromatography-Mass Spectrometry (LC-MS)-Based Analysis of Molecular Lipids in Algae Samples. AB - In this paper, an analytical method for the analysis of molecular lipids in algae samples is reported. The sample preparation is based on a modified Folch extraction, and the analysis is carried out with ultrahigh performance liquid chromatography combined with mass spectrometry (UPLC-MS). For further characterization of lipids, MS/MS analyses are carried out utilizing either a separate instrument (e.g., LTQ-Orbitrap mass spectrometer) or simultaneous fragmentation with the same instrument. Throughput of the method is over 100 samples/d. The repeatability is good, and the relative standard deviation of spiked samples is <15%. PMID- 29159727 TI - Determining Inorganic and Organic Phosphorus. AB - Phosphorus (P) is a macronutrient for all microalgal species, and the main form of uptake is orthophosphate (PO4). In this chapter we present a colorimetric method for determining the PO4 concentration and dissolved organic phosphorus (DOP) based on total phosphorus (TP) measurements. We also describe a method for determining particulate organic phosphorus (POP) based on the same principles. PMID- 29159728 TI - In-Lab Manufacturing of Decellularized Rat Renal Scaffold for Kidney Bioengineering. AB - Whole-organ decellularization is recently gaining interest in the transplantation field as strategy to obtain acellular scaffold only composed by extracellular matrix. These structures, that still remain organ-specific in terms of biological cues and tridimensional morphology could be then recellularized with patient's autologous cells. The final result should be a nwe transplantable autologous organ that should by-pass, at the same time, the problem of organ shortage and secondly the consequences related to the immunosuppression need. Herein we describe the protocol to manufacture a whole-organ transplantable rat kidney scaffold by a dual-detergent (Triton X-100 and SDS) arterial peristaltic perfusion. Final results show whole-renal acellular scaffold with contextual preservation of tridimensional architecture and biological properties deriving from the extracellular matrix composition. PMID- 29159729 TI - Determining Inorganic and Organic Carbon. AB - Carbon is the element which makes up the major fraction of lipids and carbohydrates, which could be used for making biofuel. It is therefore important to provide enough carbon and also follow the flow into particulate organic carbon and potential loss to dissolved organic forms of carbon. Here we present methods for determining dissolved inorganic carbon, dissolved organic carbon, and particulate organic carbon. PMID- 29159730 TI - UPLC-ELSD Analysis of Algal Lipid Classes and Derivatization of Bound and Free Fatty Acids and Sterols for GC-MS Methods. AB - Constituents of microalgae and sample preparation for UPLC-ELSD and GC-MS analyses are described. Bound fatty acids from acylglycerols, alkylacylglycerols, galactosyldiacylglycerols, glycerophospholipids, and sterol esters are derivatized by using transesterification with sodium methoxide to form fatty acid methyl esters. Compounds containing free hydroxyl groups, either present originally or formed during previous step, like free fatty acids, sterols, alpha tocopherol, phytol, and nonesterified alkoxyglycerols, are trimethylsilylated. The compounds in algal lipid extract are subsequently derivatized by these two steps. PMID- 29159731 TI - Effects of Population Variability on Knee Loading During Simulated Human Gait. AB - Cadaveric simulation models allow researchers to study native tissues in situ. However, as tests are conducted using donor specimens with unmatched kinematics, techniques that impose population average motions are subject to deviation from true physiologic conditions. This study aimed to identify factors which explain the kinetic variability observed during robotic simulations of a single human gait motion using a sample of human cadaver knees. Twelve human cadaver limbs (58 +/- 16 years) were subjected to tibiofemoral geometrical analysis and cyclical stiffness testing in each anatomical degree of freedom. A simulated gait motion was then applied to each specimen. Resulting kinetics, specimen geometries, and various representations of tissue stiffness were reduced to functional attributes using principal component analysis and fit to a generalized linear prediction model. The capacity of knee topography to generate force was the largest contributor to kinetic variation in compression. Overall joint size, femoral notch height, translational laxity, and ad/abduction stiffness significantly contributed to kinetic variation in medial/lateral and anterior/posterior forces and associated torques. Future studies will investigate customizing kinematic paths to better simulate native conditions and reduce sampling variation, improving biomechanical test methods and evaluation strategies for future orthopedic techniques. PMID- 29159732 TI - The PGC-1alpha Activator ZLN005 Ameliorates Ischemia-Induced Neuronal Injury In Vitro and In Vivo. AB - Oxidative stress is a great challenge to neurons following cerebral ischemia. PGC 1alpha has been shown to act as a potent modulator of oxidative metabolism. In this study, the effects of ZLN005, a small molecule that activate PGC-1alpha, against oxygen-glucose deprivation (OGD)- or ischemia-induced neuronal injury in vitro and in vivo were investigated. Transient middle cerebral artery occlusion (tMCAO) was performed in rats and ZLN005 was administered intravenously at 2 h, 4 h, or 6 h after ischemia onset. Infarct volume and neurological deficit score were detected to evaluate the neuroprotective effects of ZLN005. Well differentiated PC12 cells, which were subjected to OGD for 2 h followed by reoxygenation for 22 h, were used as an in vitro ischemic model. Changes in expression of PGC-1alpha, its related genes, and antioxidant genes were determined by real-time quantitative PCR. The results showed that ZLN005 reduced cerebral infarct volume and improved the neurological deficit in rat with tMCAO, and significantly protected OGD-induced neuronal injury in PC12 cells. Furthermore, ZLN005 enhanced expression of PGC-1alpha in PC12 cells and in the ipsilateral hemisphere of rats with tMCAO. Additionally, ZLN005 increased antioxidant genes, including SOD1 and HO-1, and significantly prevented the ischemia-induced decrease in SOD activity. Taking together, the PGC-1alpha activator ZLN005 exhibits neuroprotective effects under ischemic conditions and molecular mechanisms possibly involve activation of PGC-1alpha signaling pathway and cellular antioxidant systems. PMID- 29159734 TI - Reply: Global Cancer Consortiums: Moving from Consensus to Practice. PMID- 29159733 TI - Management of Hemophilia in Older Patients. AB - In recent decades, several improvements in hemophilia care have resulted in increased quality of life and life expectancy for those affected by this inherited hemorrhagic condition. Nowadays, individuals with hemophilia enjoy a life expectancy at birth close to that of males in the general population. As a consequence of the increasing age of the hemophilia population, a growing number of these patients develop age-related co-morbidities, such as cardiovascular disease and cancer, the management of which represents a new challenge for caregivers at hemophilia treatment centers. This narrative review focuses on the clinical problems arising in older people with hemophilia, with particular attention to the optimal therapeutic strategies. PMID- 29159735 TI - Pre-SN Ultrasound-FNAC can be Sensitive for Lymph Node Metastases in Melanoma Patients if Performed with the Use of the Berlin Criteria. PMID- 29159737 TI - Reply: "Adjuvant" Hyperthermic Intraperitoneal Chemotherapy: A Call to Action. PMID- 29159736 TI - Long-Term Results of Thoraco-Pleuro-Pneumonectomy (TPP) for Recurrent Thoracic Sarcomas. PMID- 29159738 TI - Prospective Assessment of First-Year Quality of Life After Pelvic Exenteration for Gynecologic Malignancy: A French Multicentric Study. AB - BACKGROUND: Pelvic exenteration remains one of the most mutilating procedures, with important postoperative morbidity, an altered body image, and long-term physical and psychosocial concerns. This study aimed to assess quality of life (QOL) during the first year after pelvic exenteration for gynecologic malignancy performed with curative intent. METHODS: A French multicentric prospective study was performed by including patients who underwent pelvic exenteration. Quality of life by measurement of functional and symptom scales was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (version 3.0) and the EORTC QLQ-OV28 questionnaires before surgery, at baseline, and 1, 3, 6, and 12 months after the procedure. RESULTS: The study enrolled 97 patients. Quality of life including physical, personal, fatigue, and anorexia reported in the QLQ-C30 was significantly reduced 1 month postoperatively and improved at least to baseline level 1 year after the procedure. Body image also was significantly reduced 1 month postoperatively. Global health, emotional, dyspnea, and anorexia items were significantly improved 1 year after surgery compared with baseline values. Unlike younger patients, elderly patients did not regain physical and social activities after pelvic exenteration. CONCLUSIONS: Therapeutic decision on performing a pelvic exenteration can have a severe and permanent impact on all aspects of patients' QOL. Deterioration of QOL was most significant during the first 3 months after surgery. Elderly patients were the only group of patients with permanent decreased physical and social function. Preoperative evaluation and postoperative follow-up evaluation should include health-related QOL instruments, counseling by a multidisciplinary team to cover all aspects concerning stoma care, sexual function, and long-term concerns after surgery. PMID- 29159739 TI - Video-Assisted Thoracic Surgery for Patients with Advanced Stage Non-small Cell Lung Cancer. PMID- 29159740 TI - Port-Site Resection in Surgical Management of Incidental Gallbladder Cancer: A Still Unresolved Question. PMID- 29159741 TI - Sized Influences Nodal Status in Women Aged #70 with Endocrine Responsive Breast Cancer. PMID- 29159742 TI - Validation of the Recent PSOGI Pathological Classification of Pseudomyxoma Peritonei in a Single-Center Series of 265 Patients Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. AB - BACKGROUND: Controversies still persist regarding the terminology and pathologic classification of appendiceal mucinous neoplasms and associated pseudomyxoma peritonei (PMP). We assessed reproducibility and prognostic significance of the classification recently proposed by the Peritoneal Surface Oncology Group International (PSOGI). METHODS: A prospective database of 265 PMP patients uniformly treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) from 1995 to 2017 was reviewed. According to the PSOGI, peritoneal disease was retrospectively classified into three categories: low grade (LG-PMP), high-grade (HG-PMP), and signet-ring cells (SRC-PMP). Acellular mucin (AC) was classified separately. The extent of peritoneal involvement was quantified by the peritoneal cancer index (PCI). RESULTS: Twenty-six patients were diagnosed with AC (9.8%), 197 with LG-PMP (74.4%), 38 with HG-PMP (14.3%), and 4 with SRC-PMP (1.5%). In the overall series, median follow-up was 65.5 months (95% confidence interval 53.7-78.8) and 10-year overall survival was 62.9% (median 148.7 months). Operative death occurred in 10 patients (3.8%) and major complications occurred in 89 patients (33.6%). Ten-year survival was 89.6% for AC, 63.2% for LG-PMP, 40.1% for HG-PMP, and 0 for SRC-PMP. In a multivariate model, the World Health Organization (WHO) pathological classification independently correlated with survival (p = 0.028). In a separate model, the PSOGI classification did not reach statistical significance (p = 0.149). Completeness of cytoreduction and PCI > 22 correlated with prognosis in both models. CONCLUSIONS: AC and SRC-PMP pathological categories of the PSOGI classification identified two subsets of patients with favorable and exceedingly dismal prognosis, respectively. It remains unclear whether the PSOGI classification might provide better prognostic stratification than the current WHO classification. Further studies in larger prospective series are needed. PMID- 29159743 TI - Morbidity and Outcomes Following Axillary Lymphadenectomy for Melanoma: Weighing the Risk of Surgery in the Era of MSLT-II. AB - BACKGROUND: Limited data exist characterizing complications after axillary lymphadenectomy for melanoma. With high rates of complications reported after dissection for breast cancer and data suggesting that completion lymphadenectomy may have limited therapeutic benefit, this study characterized morbidity to facilitate clinical decision-making. METHODS: Using a broad definition for complications, patients who underwent axillary dissection for melanoma at a single center (from 2003 to 2015) were assessed through retrospective chart review. Patients were stratified by potential risk factors for complications; outcomes were compared. RESULTS: Two hundred fifty-four axillary dissections in 239 patients were identified. Assessed risk factors for complications included age > 55 years (n = 133, 52%), body mass index (BMI) >= 30 kg/m2 (n = 90, 40%), diabetes (n = 40, 16%), smoking (n = 81, 32%), extremity primary (n = 71, 28%), therapeutic lymphadenectomy (n = 105, 41%), and adjuvant radiation (n = 33, 13%). Wound complications were observed in 51 patients with 38 (15%) seromas, 3 (1%) dehiscences, and 10 (4%) hematomas. There were 5 (2%) reoperations, all for hematoma. Thirty-day readmission rate was 6% (n = 14). Importantly, lymphedema occurred in only 13 (5%) patients. Wound dehiscence occurred only in smokers (p = 0.03) and was associated with adjuvant radiation (p = 0.04). Twenty-eight (11%) patients developed frozen shoulder, which was related to smoking (p = 0.02). Lymphedema was more likely in patients after therapeutic dissection (p = 0.04). All other risk factors were not associated with increased complications. CONCLUSIONS: This analysis supports historical data that axillary dissection for melanoma is a low-risk procedure, with smoking, therapeutic lymphadenectomy, and adjuvant radiation associated with increased morbidity. Although morbidity of lymphadenectomy is often cited as a reason to alter surgical approach or even forgo intervention, this may be less of a concern for axillary dissection. PMID- 29159744 TI - Treatment and Outcome of Synchronous Colorectal Carcinomas: A Nationwide Study. AB - BACKGROUND: Synchronous colorectal carcinomas (CRC) occur in 1-8% of patients diagnosed with CRC. This study evaluated treatment patterns and patient outcomes in synchronous CRCs compared with solitary CRC patients. METHODS: All patients diagnosed with primary CRC between 2008 and 2013, who underwent elective surgery, were selected from the Netherlands Cancer Registry. Using multivariable regressions, the effects of synchronous CRC were assessed for both short-term outcomes (prolonged postoperative hospital admission, anastomotic leakage, postoperative 30-day mortality, administration of neoadjuvant or adjuvant treatment), and 5-year relative survival (RS). RESULTS: Of 41,060 CRC patients, 1969 patients (5%) had synchronous CRC. Patients with synchronous CRC were older (mean age 71 +/- 10.6 vs. 69 +/- 11.4 years), more often male (61 vs. 54%), and diagnosed with more advanced tumour stage (stage III-IV 54 vs. 49%) compared with solitary CRC (all p < 0.0001). In 50% of the synchronous CRCs, an extended surgery was conducted (n = 934). Synchronous CRCs with at least one stage II-III rectal tumour less likely received neoadjuvant (chemo)radiation [78 vs. 86%; adjusted OR 0.6 (0.48-0.84)], and synchronous CRCs with at least one stage III colon tumour less likely received adjuvant chemotherapy [49 vs. 63%; adjusted OR 0.7 (0.55-0.89)]. Synchronous CRCs were independently associated with decreased survival [RS 77 vs. 71%; adjusted RER 1.1 (1.01-1.23)]. CONCLUSIONS: The incidence of synchronous CRCs in the Dutch population is 5%. Synchronous CRCs were associated with decreased survival compared with solitary CRC. The results emphasize the importance of identifying synchronous tumours, preferably before surgery to provide optimal treatment. PMID- 29159745 TI - Prognostic Value of Tumor Volume in Glioblastoma Patients: Size Also Matters for Patients with Incomplete Resection. AB - BACKGROUND: Incomplete resection of glioblastoma is discussed controversially in the era of combined radiochemotherapy. OBJECTIVE: The aim of this study was to analyze the benefit of subtotal tumor resection for glioblastoma patients as this was recently questioned in the era of radiochemotherapy. METHODS: Overall, 209 patients undergoing surgery for newly diagnosed WHO grade IV gliomas were retrospectively analyzed, and pre- and postoperative tumor volumes were manually segmented (cm3). Survival analyses were performed, including prognostic factors such as age, Karnofsky performance score (KPS), O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and adjuvant treatment regimen. RESULTS: Pre- and postoperative tumor volume is significantly associated with pre- and postoperative KPS, as well as age (p < 0.001). Postoperative tumor volume remained a significant prognostic factor in a multivariate analysis, independent of other prognostic factors (hazard ratio 1.0365, 95% confidence interval 1.0235-1.0497, p < 0.001). CONCLUSIONS: In the era of molecularly-driven radiochemotherapy, glioblastoma surgery remains a major prognostic factor. Even in situations in which a gross total resection cannot be achieved, maximum safe reduction of tumor burden should be attempted. PMID- 29159746 TI - Microsurgical Reconstruction of the Oral Cavity with Free Flaps from the Anterolateral Thigh and Radial Forearm: Example of Confounding by Indication? PMID- 29159747 TI - Correction to: Reply to ''Complications in DIEP Flap Breast Reconstruction After Mastectomy for Breast Cancer: A Prospective Cohort Study Comparing Unilateral Versus Bilateral Reconstructions". AB - In the original article Justin C. R. Wormald's middle initials were incorrect. They are correct as reflected in this erratum. The original article has also been corrected. PMID- 29159748 TI - Molecular Genomic Testing for Breast Cancer: Utility for Surgeons. AB - Molecular genomic testing provides clinicians with both prognostic and (sometimes) predictive information that can help individualize treatment and decrease the risk of over- or under-treatment. We review the genomic tests that are currently available for clinical use in management of breast cancer, discuss ongoing research related to validating and expanding their utility in different patient populations, and explain why it is important for surgeons to know how to incorporate these tools into their clinical practice in order to individualize patient treatment, reduce unnecessary morbidity, and, accordingly, improve outcomes. PMID- 29159749 TI - Fullerenol-Based Intracellular Delivery of Methotrexate: A Water-Soluble Nanoconjugate for Enhanced Cytotoxicity and Improved Pharmacokinetics. AB - Derivatization of fullerenes to polyhydroxylated fullerenes, i.e., fullerenols (FLU), dramatically decreases their toxicity and has been reported to enhance the solubility as well as cellular permeability. In this paper, we report synthesis of FLU as nanocarrier and subsequent chemical conjugation of Methotrexate (MTX) to FLU with a serum-stable and intracellularly hydrolysable ester bond between FLU and MTX. The conjugate was characterized for physiochemical attributes, micromeritics, drug-loading, and drug-release and evaluated for cancer cell toxicity, cellular-uptake, hemocompatibility, protein binding, and pharmacokinetics. The developed hemocompatible FL-MTX offered lower protein binding vis-a-vis naive drug and substantially higher drug loading. The conjugate offered pH-dependent release of 38.20 +/- 1.19% at systemic pH and 85.67 +/- 3.39% at the cancer cell pH. FLU-MTX-treated cells showed significant reduction in IC50 value vis-a-vis the cells treated with pure MTX. Analogously, the results from confocal scanning laser microscopy also confirmed the easy access of the dye tagged FLU-MTX conjugate to the cell interiors. In pharmacokinetics, the AUC of MTX was enhanced by approx. 6.15 times and plasma half-life was enhanced by 2.45 times, after parenteral administration of single equivalent dose in rodents. FLU MTX offered enhanced availability of drug to the biological system, meanwhile improved the cancer-cell cytotoxicity, sustained the effective plasma drug concentrations, and offered substantial compatibility to erythrocytes. PMID- 29159750 TI - General health-related quality of life scores from head and neck squamous cell carcinoma patients obtained throughout the first year following diagnosis predicted up to 10-year overall survival. AB - OBJECTIVES: To evaluate the 5- and 10-year survival prediction of health-related quality of life (HRQoL) scores obtained at diagnosis and at 6, 9 and 12 months after diagnosis in a cohort of curable head and neck squamous cell carcinoma (HNSCC) patients. MATERIALS AND METHODS: HNSCC patients (n = 109) reported their HRQoL measured by the EORTC Quality of Life Questionnaire (QLQ) general (C30) questionnaire. At diagnosis, the included patients were below 78 years of age and at diagnosis planned treated with curative intent. Clinical variables and self reported smoking, alcohol consumption and socio-demographic information were registered. From diagnostic blocks, we found 22 patients to be human papillomavirus (HPV) positive. New HRQoL scores were not obtained if the patient treatment changed from curative to palliative throughout the HRQoL data acquisition. Survival was determined from the National Population Register of Norway. RESULTS: Decreased survival with low HRQoL scores from EORTC QLQ scores was demonstrated with HRQoL scores obtained from different time points of the four time points studied. These survival predictions were mostly independent of HPV status, gender, age, TNM stage, tumor site, alcohol consumption, present smoking status and whether comorbidities were present at diagnosis; as well as to some extent with an adjustment of the same HRQoL score/index obtained at diagnosis. The specific indices "physical function", "general pain" and "sleep disturbance" were in particular predictive of survival. CONCLUSION: HRQoL scores obtained throughout the first year after diagnosis contained prognostic power to overall survival when measured both at 5 and 10 years of observation. PMID- 29159752 TI - Response to Commentaries: Recognizing Hypersexuality as a Psychosexual Behavioral Problem and Advancing the Sexhavior Cycle of Hypersexuality. PMID- 29159751 TI - Septal and turbinate surgery: is overnight essential? AB - INTRODUCTION: The performance of septoplasty and turbinate surgery in an outpatient basis is an increasingly established practice, although is still a controversial topic. METHODS: Retrospective analysis of 227 patients who underwent septoplasty +/- inferior and/or middle turbinoplasty. Demographic, clinical, surgical, and anesthetic data were collected. Our primary outcomes were rates of perioperative complications, prolongation of hospital stay (PHS), unexpected hospital revisits (UHR), or readmissions within 30 days of surgery. RESULTS: The UHR rate was 4.8 and 6.6% in the first 48 h and 30 postoperative days, respectively. The main reasons were nasal obstruction, self-limited epistaxis, and gastrointestinal intolerance to the prescribed antibiotic. Four patients required PHS due to nausea or vomiting and asthenia. There were no intraoperative complications, readmissions to the operative room, or hospital readmissions after discharge. The addiction of turbinate procedures was not associated with higher risk of complications. Patients with PHS were younger than those discharged as scheduled. There was no association between complications and comorbidities, gender, ASA classification, revision surgery, surgeon's grading, technique of inferior turbinoplasty, type of nasal packing, duration of anesthesia, and operative time. CONCLUSION: The UHR rate of septoplasty performed at our unit is above that recommended for ambulatory procedures, but is within the range previously published and no major complications were seen. Septoplasty and turbinate surgery, including middle turbinate surgery, have a great potential to be undertaken as a day-case procedure, being patient selection the cornerstone of safe and efficient perioperative care. PMID- 29159753 TI - Homosexual Sons and the Fraternal Birth Order Effect: The Role of Elevated Maternal Intrauterine Testosterone. PMID- 29159754 TI - The Fraternal Birth Order Effect Is Robust and Important. PMID- 29159755 TI - Emotions and Cognitions Associated with the Stigma of Non-Offending Pedophilia: A Vignette Experiment. AB - Cognitive and affective antecedents of the desire to avoid or punish non offending pedophilic individuals are not well understood. In this article, we examined the effects of non-offending motivation (internal vs. external) and sexual orientation (pedophilic vs. teleiophilic) on cognitive apprehensions (amorality, dangerousness, abnormality), emotions (fear, anger, disgust), punitive attitudes, and social distance toward a man experiencing a sexually transgressive impulse. A total of 205 U.S.-based MTurk workers were randomly assigned to one of four groups in this 2 * 2 factorial vignette study. As expected, pedophilic orientations and extrinsic non-offending motivations led to stronger negative apprehensions and emotions, as well as higher social distance and punitive attitudes. When controlling for the other emotions, disgust mediated the effect of pedophilic orientation on social distance, while anger and fear mediated the effect of non-offending motivation on punitive attitudes. Disgust, fear, and anger were furthermore differentially associated with perceived amorality, dangerousness, and abnormality. This research helps clarify why desires to punish or avoid non-offending pedophilic men are so strong, even when they never commit sexual crimes. PMID- 29159756 TI - Patient-Provider Communication and Health Outcomes Among Individuals with Hepato Pancreato-Biliary Disease in the USA. AB - BACKGROUND: Patient-provider communication (PPC) is utilized as a value-based metric in pay-for-performance programs. We sought to evaluate the association of PPC with patient-reported health outcomes, as well as healthcare resource utilization among a nationally representative cohort of patients with hepato pancreato-biliary (HPB) diagnoses. METHODS: Patients with HPB diseases were identified from the 2008-2014 Medical Expenditure Panel Survey cohort. A weighted PPC composite score was categorized using the responses from the CAHPS (Consumer Assessment of Healthcare Providers and Systems) survey as optimal, average, or poor. Multivariate analysis was performed using logistic regression. RESULTS: Among 1951 adult-patients, representing 21.7 million HPB patients, reported PPC was optimal (33.4%), average (46.3%), or poor (15.3%). Patients who were older and patients with low income were more likely to report poor PPC (both p < 0.05). Statin use, a quality of care measure, was associated with optimal PPC (OR 1.70, 95% CI 1.10-2.64; p = 0.01). In contrast, patients who reported poor PPC were more likely to have a poor physical (20.8%) or mental (8.8%) health component on their SF12 (both p < 0.05). Furthermore, patients with poor PPC were more likely to report poor mental status (OR 2.97, 95% CI 1.60-5.52), as well as higher emergency department visits (OR 1.95, 95% CI 1.25-3.05) and hospitalizations (OR 1.90, 95% CI 1.02-3.55) (both p < 0.05). Reported PPC was not associated with differences in overall healthcare expenditures or out-of-pocket expenditures. CONCLUSIONS: PPC was associated with a wide spectrum of patient-specific demographic and health utilization factors. Self-reported patient satisfaction with provider communication may be impacted by other considerations than simply the patient-provider interaction. PMID- 29159757 TI - Correlation Between Postoperative Early Recurrence of Hepatocellular Carcinoma and Mesenchymal Circulating Tumor Cells in Peripheral Blood. AB - BACKGROUND: Circulating tumor cells (CTCs) have been actively studied for their functions in hepatocellular carcinoma (HCC) recurrence. However, the relationship between circulating tumor cells subtypes and hepatocellular carcinoma recurrence is still unclear. METHODS: CTCs were collected from the peripheral blood of 62 postoperative HCC patients. The CTCs were isolated with a filtration-based method. Multiplex fluorescence in situ hybridization was used to characterize the CTCs based on mRNA expression levels of epithelial and mesenchymal markers. RESULTS: Of the 62 HCC patients, 26 were diagnosed with early recurrence (ER) and 36 did not experience recurrence. Comparison between the recurrence group and the non-recurrence group showed the total number of CTCs, mesenchymal CTCs, and mixed CTCs in the recurrence group was significantly higher than in the non-recurrence group. Receiver operator characteristic (ROC) curve analysis was performed to define the positive cutoff values as follows: total number of CTCs >= 4, mesenchymal CTCs >= 1, and mixed CTCs >= 3. Analysis showed that portal vein tumor thrombus (hazard ratio [HR] = 2.905, P = 0.023) and mesenchymal CTC positivity (HR = 3.453, P = 0.007) were independent risk factors for ER. The correlation between the presence of mesenchymal CTCs and time to recurrence was further examined, and the results showed significantly shortened postoperative disease-free survival in patients positive for mesenchymal CTCs (P < 0.001). CONCLUSIONS: HCC patients with positive peripheral mesenchymal CTCs have a more serious risk of ER, which could be a potential biomarker in HCC prognosis monitoring. PMID- 29159758 TI - Left Paraduodenal Hernia. AB - Left paraduodenal hernia is an entrapment of the small bowel into the Landzert fossa, an unusual congenital peritoneal defect behind the descending mesocolon that results from failure of part of the descending mesocolon to fuse with the posterior parietal peritoneum (Doishita et al. in Radiographics, 36(1): 88-106, 2016). This fossa is reported to be present in approximately 2% of autopsy bodies. The authors present a case of a left paraduodenal hernia in a young woman. PMID- 29159759 TI - Phylogenetic Classification of Seed Plants of Taiwan. AB - BACKGROUND: Biological classification, the hierarchical arrangement of scientific names of organisms, constitutes the core infrastructure of biological databases. For an efficient management of biological databases, adopting a stable and universal biological classification system is crucial. Currently in Taiwan Biodiversity Information Facility (TaiBIF; http://taibif.tw/ ), the national portal website that integrates Taiwan's biodiversity information databases, angiosperms are arranged according to Cronquist's System of Classification, which is not compatible with current trend of the Angiosperm Phylogeny Group (APG) classification. To consolidate the function and management of the database, TaiBIF is moving to adopt the APG IV classification and Christenhusz et al. (Phytotaxa 19:55-70, 2011)'s classification of gymnosperms, which we summarize as the Phylogenetic Classification of Seed Plants of Taiwan. RESULTS: The Phylogenetic Classification of Seed Plants of Taiwan places gymnosperms in five families [vs. eight families in the Flora of Taiwan (FOT)] and angiosperms in 210 families (vs. 193 families in FOT). Three FOT gymnosperm families are synonymized in current treatment. Of the 210 APG IV families, familial circumscriptions of 114 families are identical with FOT and 50 families are recircumscription of FOT, with 46 families newly added. Of the 29 FOT families not included in current classification, two families are excluded and 27 families are synonymized. CONCLUSIONS: The adoption of the Phylogenetic Classification of Seed Plants of Taiwan in TaiBIF will provide better service and efficient management of the nation's biodiversity information databases. PMID- 29159760 TI - Body mass index, age at breast cancer diagnosis, and breast cancer subtype: a cross-sectional study. AB - PURPOSE: Evidence suggests that premenopausal obesity decreases and postmenopausal obesity increases breast cancer risk. Because it is not well known whether this is subtype dependent, we studied the association between body mass index (BMI) and age at breast cancer diagnosis, or the probability of being diagnosed with a specific breast cancer phenotype, by menopausal status. METHODS: All patients with non-metastatic operable breast cancer from the University Hospital Leuven diagnosed between January 1, 2000 and December 31, 2013 were included (n = 7020) in this cross-sectional study. Linear models and logistic regression were used for statistical analysis. Allowing correction for age related BMI-increase, we used the age-adjusted BMI score which equals the difference between a patient's BMI score and the population-average BMI score corresponding to the patient's age category. RESULTS: The quadratic relationship between the age-adjusted BMI and age at breast cancer diagnosis (p = 0.0207) interacted with menopausal status (p < 0.0001); increased age at breast cancer diagnosis was observed with above-average BMI scores in postmenopausal women, and with below-average BMI scores in premenopausal women. BMI was linearly related to the probabilities of Luminal B and HER2-like breast cancer phenotypes, but only in postmenopausal women. The relative changes in probabilities between both these subtypes mirrored each other. CONCLUSION: BMI associates differently before and after menopause with age at breast cancer diagnosis and with the probability that breast cancer belongs to a certain phenotype. The opposite effect of increasing BMI on relative frequencies of Luminal B and HER2-like breast cancers suggests a common origin. PMID- 29159761 TI - Nestin expression in breast cancer: association with prognosis and subtype on 3641 cases with long-term follow-up. AB - BACKGROUND: Basal-like breast cancers, originally recognized by gene expression profiling, can be clinically identified using immunohistochemical (IHC) definitions that require estrogen receptor (ER) negativity. However, some basal cases are ER positive and are mistakenly considered to be luminal by standard IHC approaches, leading to suboptimal treatment choices. Nestin, an intermediate filament expressed in many stem cells, is a recently identified positive marker of basal-like phenotype independent of ER status. In this study, we evaluated its clinical associations and prognostic capacity in a large breast cancer cohort. METHODS: A tissue microarray series of clinically annotated invasive breast cancers with 12.6-year median follow-up was assessed for nestin expression by IHC. Kaplan-Meier and Cox regression models were used to evaluate the prognostic significance of nestin status, for the primary endpoint of breast cancer-specific survival (BCSS). RESULTS: Among 3641 cases interpretable for nestin by IHC, positive staining was found in 371 cases (10%) and was significantly associated with poor prognostic factors including other markers of basal-like differentiation. Patients with nestin-positive tumors had a significantly lower 10 year BCSS (HR 1.97, 95% CI 1.62-2.40; P < 0.001). Importantly, within the large group of 2323 ER+ cases, nestin positivity identified a subgroup of 120 patients (5%) with a significantly inferior 10-year BCSS (HR 1.50, 95% CI 1.10 2.13; P = 0.02). CONCLUSIONS: Nestin IHC positivity is associated with the poor clinical outcomes and reduced survival rates that characterize the gene expression basal-like subtype. This easily applicable tool identifies ER+ poor prognosis basal phenotype patients that are currently being missed by "Triple negative" or "Core basal" IHC definitions. PMID- 29159763 TI - Chinese Learners of English See Chinese Words When Reading English Words. AB - The present study examines when second language (L2) learners read words in the L2, whether the orthography and/or phonology of the translation words in the first language (L1) is activated and whether the patterns would be modulated by the proficiency in the L2. In two experiments, two groups of Chinese learners of English immersed in the L1 environment, one less proficient and the other more proficient in English, performed a translation recognition task. In this task, participants judged whether pairs of words, with an L2 word preceding an L1 word, were translation words or not. The critical conditions compared the performance of learners to reject distractors that were related to the translation word (e.g., , pronounced as /bei 1/) of an L2 word (e.g., cup) in orthography (e.g., , bad in Chinese, pronounced as /huai 4/) or phonology (e.g., , sad in Chinese, pronounced as /bei 1/). Results of Experiment 1 showed less proficient learners were slower and less accurate to reject translation orthography distractors, as compared to unrelated controls, demonstrating a robust translation orthography interference effect. In contrast, their performance was not significantly different when rejecting translation phonology distractors, relative to unrelated controls, showing no translation phonology interference. The same patterns were observed in more proficient learners in Experiment 2. Together, these results suggest that when Chinese learners of English read English words, the orthographic information, but not the phonological information of the Chinese translation words is activated. In addition, this activation is not modulated by L2 proficiency. PMID- 29159762 TI - P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2',3'-dideoxycytidine. AB - The direct neurotoxicity of HIV and neurotoxicity of combination antiretroviral therapy medications both contribute to the development of neuropathic pain. Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in mechanical and thermal hyperalgesia. The P2Y12 receptor expressed in SGCs of the DRG is involved in pain transmission. In this study, we explored the role of the P2Y12 receptor in neuropathic pain induced by HIV envelope glycoprotein 120 (gp120) combined with ddC (2',3'-dideoxycytidine). A rat model of gp120+ddC-induced neuropathic pain was used. Peripheral nerve exposure to HIV-gp120+ddC increased mechanical and thermal hyperalgesia in gp120+ddC-treated model rats. The gp120+ddC treatment increased expression of P2Y12 receptor mRNA and protein in DRG SGCs. In primary cultured DRG SGCs treated with gp120+ddC, the levels of [Ca2+]i activated by the P2Y12 receptor agonist 2 (Methylthio) adenosine 5'-diphosphate trisodium salt (2-MeSADP) were significantly increased. P2Y12 receptor shRNA treatment inhibited 2-MeSADP induced [Ca2+]i in primary cultured DRG SGCs treated with gp120+ddC. Intrathecal treatment with a shRNA against P2Y12 receptor in DRG SGCs reduced the release of pro-inflammatory cytokines, decreased phosphorylation of p38 MAPK in the DRG of gp120+ddC-treated rats. Thus, downregulating the P2Y12 receptor relieved mechanical and thermal hyperalgesia in gp120+ddC-treated rats. PMID- 29159764 TI - Establishing IAEA TRS-457 diagnostic X-ray beam qualities at the Australian primary standard dosimetry laboratory. AB - This paper reports the process and findings in establishing the diagnostic beam qualities for the calibration of diagnostic dose meters in the Australian primary standard dosimetry laboratory at the Australian Radiation Protection and Nuclear Safety Agency, ARPANSA. A novel iterative method to achieve the RQR beam quality requirements described by IEC 61267 is presented. The correction factors for the primary standard free-air chamber and their uncertainties are reported. The calibration procedure with detailed uncertainty budget of a typical diagnostic ionisation chamber (model PTW 34060) is reported. Beam profile measurements and details of the use of an external monitor chamber (model PTW 34014) are also reported. The uncertainty in the ARPANSA calibration coefficients is estimated to be 1.2% at k = 2 for both RQR and RQA beam qualities. The laboratory is now able to provide calibration services for radiation detectors used in general X-ray radiography. PMID- 29159765 TI - Characteristic Comparison of Meningitis and Non-meningitis of Streptococcus suis in an Experimentally Infected Porcine Model. AB - This study tested the differences of meningitis and non-meningitis of Streptococcus suis (SS). In this study, an infected pig model of streptococcal meningitis was established. Compared with the non-meningitis Streptococcus suis group (JZLQ001 group), the meningitis Streptococcus suis group (JZLQ022) exhibited neurological symptoms, such as ataxia and foaming at the mouth, and the brain showed a large area of congestion at 5 days post-infection (p.i.). Moreover, bacterial counts, white blood cells (WBCs), neutrophils, and blood glucose in the blood reached a peak and were significantly higher than those of the JZLQ001 group at 3 days p.i. These values then decreased at 5 days p.i. However, the content of total protein in the blood was lower in the JZLQ022 group than that in the JZLQ001 group, and the difference was most significant at 5 days p.i. When neurological symptoms appeared on 5 days p.i., the bacterial counts in the brain in the JZLQ022 group were significantly higher than those in the JZLQ001 group. The levels of cytokines in the peripheral blood and cerebrospinal fluid (CSF) were an important indicator of inflammation. By ELISA detection, the secretion levels of IL-6, IL-8, and IL-17 in the peripheral blood in the JZLQ022 group were significantly higher than those in the JZLQ001 group at 12 and 24 h and 3 days p.i.; however, TNF-alpha showed no difference. At 5 days p.i., the secretion levels of IL-6, IL-8, and IL-17 in the JZLQ022 group were significantly lower than those in the JZLQ001 group. The results were similar in CSF. HE staining revealed that the JZLQ022 group exhibited neuronophagia and hyperemia in the brain, but no change was found in the JZLQ001 group. A further study investigating the impact of meningitis Streptococcus suis on blood-brain barrier (BBB) integrity found that the brain tissue content of endogenous IgG in the JZLQ022 group was significantly higher than that in the JZLQ001 group. The present study demonstrated that pigs infected with meningitis and non-meningitis Streptococcus suis exhibit significant differences in immunological aspects such as bacterial counts, WBCs, neutrophils, blood glucose and total protein in the peripheral blood, the secretion levels of IL-6, IL-8, and IL-17, and BBB integrity. These data provide the necessary evidence to better understand SS meningitis. PMID- 29159766 TI - Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience. AB - Background Immunotherapy is emerging as the cornerstone for treatment of patients with advanced cancer, but significant toxicity (immune-related adverse events [irAEs]) associated with unbridled T cell activity remains a concern. Patients and methods A retrospective review of the electronic medical records of 290 patients with advanced cancer treated on an immunotherapy-based clinical trial in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center between February 2010 and September 2015 was performed. Clinical and laboratory parameters were collected to determine the incidence of irAEs, risk factors, and their association with treatment outcomes. Results Ninety eight of 290 patients (34%) experienced any grade irAEs. Among the 15 (5.2%) patients with grade >= 3 irAEs, the most common irAEs were dermatitis and enterocolitis. Although 80% of the patients with grade >= 3 irAEs required systemic corticosteroids, all the 15 patients recovered from the irAEs. On re challenge, 4 of the 5 patients who had received systemic corticosteroids for irAE continued to respond. There were no irAE-related deaths. Importantly, patients with grade >= 3 irAEs had improved overall response rate (25 vs. 6%; p = 0.039) and longer median time to progression (30 weeks vs. 10 weeks; p = 0.0040) when compared to those without grade >= 3 irAEs. Conclusion Incidence of irAEs with immunotherapeutic agents indicates an active immune status, suggestive of potential clinical benefit to the patient. Further validation of this association in a large prospective study is warranted. PMID- 29159767 TI - Development and Validation of the Health of the Nation Outcome Scales-Residential Facility (HoNOS-RF). AB - The Health of the Nation Outcome Scale (HoNOS) (Lora et al. Epidemiol Psichiatr Soc 10(3):198-212, 2001) is widely used. However, clinicians have expressed concerns about its ability to describe severe mentally ill patients, as it does not consider some relevant clinical aspects. This study aims to develop and validate the HoNOS-Residential Facility (HoNOS-RF) in order to pursue a thorough assessment of patients admitted to psychiatric residential facilities (RFs). The final version of the HoNOS-RF was administered to 409 patients admitted to four RFs. Exploratory factor analysis, Cronbach' alpha (alpha), Intraclass Correlation Coefficients (ICC) were used to assess construct validity, internal consistency and reliability, respectively. Concurrent criterion validity was assessed through correlations with the Brief Psychiatric Rating Scale-Expanded Version (BPRS-E) (Roncone et al. Acta Psychiatric Scand 100(3):229-36, 1999), Personal and Social Performance Scale (PSP) (Morosini et al. Acta Psychiatric Scand 101(4): 323-29, 2000), and comparisons across diagnostic groups. The final version of the HoNOS RF consisted of 31 items, grouped into the following eight factors (overall explaining 55% of the total variability): personal and interpersonal functioning; environment; behavior and burden of care; cognitive function; somatic problems; anxiety-depression symptoms; psychotic symptoms; and other psychiatric symptoms. The scale showed high internal consistency (alpha = .807), and the correlations with PSP and BPRS-E ranged from adequate to moderate. The ICCs were in the excellent range for almost all items. These findings support the validity and the reliability of the HoNOS-RF, thus it may be a useful tool for the assessment of patients admitted to RFs, as it addresses clinical aspects that were mostly not included in the original version. PMID- 29159768 TI - The Impact of Dealing with the Late Effects of National Socialist Terror on West German Psychiatric Care. AB - Health damages and the late effects of NS trauma were largely ignored in German speaking countries. This paper describes how dealing with the late effects of Nazi terror influenced post-war psychiatry in West Germany and thus the development of the psychiatric reform. As part of a greater overview study of the impulses and framework conditions of the reform-orientated development of post war psychiatry in West Germany, this analysis is based on a thorough literary and documentary analysis. The sources show that publications by Helmut Paul and Herberg [81] as well as Baeyer et al. [12] can be considered as remarkable milestones. The awareness of psychological late effects of NS persecution was only reluctantly taken up by the scientific community. Nevertheless, this discussion was an essential component of the reform-orientated psychiatry in West Germany in the late 1960s to 1970s. PMID- 29159769 TI - Diversity effect of capsaicin on different types of skeletal muscle. AB - Capsaicin is a major pungent content in green and red peppers which are widely used as spice, and capsaicin may activate different receptors. To determine whether capsaicin has different effects on different types of skeletal muscle, we applied different concentrations (0, 0.01, and 0.02%) of capsaicin in the normal diet and conducted a four-week experiment on Sprague-Dawley rats. The fiber type composition, glucose metabolism enzyme activity, and different signaling molecules' expressions of receptors were detected. Our results suggested that capsaicin reduced the body fat deposition, while promoting the slow muscle related gene expression and increasing the enzyme activity in the gastrocnemius and soleus muscles. However, fatty acid metabolism was significantly increased only in the soleus muscle. The study of intracellular signaling suggested that the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptors in the soleus muscle were more sensitive to capsaicin. In conclusion, the distribution of TRPV1 and cannabinoid receptors differs in different types of muscle, and the different roles of capsaicin in different types of muscle may be related to the different degrees of activation of receptors. PMID- 29159770 TI - JIP3 localises to exocytic vesicles and focal adhesions in the growth cones of differentiated PC12 cells. AB - The JNK-interacting protein 3 (JIP3) is a molecular scaffold, expressed predominantly in neurons, that serves to coordinate the activation of the c-Jun N terminal kinase (JNK) by binding to JNK and the upstream kinases involved in its activation. The JNK pathway is involved in the regulation of many cellular processes including the control of cell survival, cell death and differentiation. JIP3 also associates with microtubule motor proteins such as kinesin and dynein and is likely an adapter protein involved in the tethering of vesicular cargoes to the motors involved in axonal transport in neurons. We have used immunofluorescence microscopy and biochemical fractionation to investigate the subcellular distribution of JIP3 in relation to JNK and to vesicular and organelle markers in rat pheochromocytoma cells (PC12) differentiating in response to nerve growth factor. In differentiated PC12 cells, JIP3 was seen to accumulate in growth cones at the tips of developing neurites where it co localised with both JNK and the JNK substrate paxillin. Cellular fractionation of PC12 cells showed that JIP3 was associated with a subpopulation of vesicles in the microsomal fraction, distinct from synaptic vesicles, likely to be an anterograde-directed exocytic vesicle pool. In differentiated PC12 cells, JIP3 did not appear to associate with retrograde endosomal vesicles thought to be involved in signalling axonal injury. Together, these observations indicate that JIP3 may be involved in transporting vesicular cargoes to the growth cones of PC12 cells, possibly targeting JNK to its substrate paxillin, and thus facilitating neurite outgrowth. PMID- 29159771 TI - CLDN6 enhances chemoresistance to ADM via AF-6/ERKs pathway in TNBC cell line MDAMB231. AB - Claudin-6 (CLDN6), a critical tight junction protein acting as a tumor suppressor in breast cancer, is also considered to be a stem cell marker. Triple-negative breast cancer (TNBC) is a subtype of claudin-low and stem cell-like breast cancer which is chemoresistant to multiple anti-cancer drugs. The aim of our study was to determine whether CLDN6 plays a role in chemoresistance of TNBC. We found that overexpression of CLDN6 in TNBC cell line MDAMB231 significantly inhibited cell growth, migration, and invasion. The expression of CLDN6 increased the IC50 of adriamycin (ADM) and promoted the clonogenic survival. CLDN6 inhibited ADM induced apoptosis and senescence in MDAMB231 cells. However, P-gp, a resistance related protein highly associated with chemoresistance, was downregulated by CLDN6 overexpression in MDAMB231 cells. Epithelial mesenchymal transition (EMT) marker E-cadherin was increased, and vimentin was decreased by CLDN6. In addition, stem cell markers OCT4, SOX2, and Nanog were dramatically increased. CLDN6 colocalized and interacted with AF-6. Overexpression of CLDN6 increased the expression of afadin (AF-6) and hampered the activation of ERK signaling. PMA, a specific ERK activator, reversed the expression of EMT and stem cell markers, and decreased chemoresistance of MDAMB231 cells to ADM with a decreased IC50 and an increased apoptosis resulting from CLDN6. Together, we conclude that CLDN6 enhances the chemoresistance to ADM via activating the AF-6/ERK signaling pathway and up-regulating cancer stem cell characters in MDAMB231 cells. PMID- 29159772 TI - Total Pancreatectomy with Islet Autotransplantation for the Ampullary Cancer. A Case Report. PMID- 29159774 TI - Pharmacokinetics, Pharmacodynamics, and Safety of Rasagiline Transdermal Patch: A Preliminary Study in Healthy Chinese Subjects. AB - BACKGROUND AND OBJECTIVES: Rasagiline tablet is an oral MAO-B inhibitor applied in early or advanced Parkinson's disease (PD). However, when patients with PD cannot take their usual oral medications, a rasagiline transdermal patch can be used as a way to offer continuous rasagiline while avoiding plasma concentration peaks and troughs. The objectives of this study were to investigate the pharmacokinetics, pharmacodynamics, and safety of the rasagiline transdermal patch in healthy Chinese subjects. METHODS: This single-dose, open-label, randomized, parallel-group study was conducted in 15 healthy subjects. Fasted subjects received a single dose of rasagiline (either by transdermal patch-1.25 mg/24 h, 1.25 mg/48 h, 2.5 mg/48 h, or 2.5 mg/72 h, or orally-in the form of a 1 mg tablet) and were monitored over a 168-h observation period to assess pharmacokinetics, pharmacodynamics, and safety. RESULTS: After administration of a single-dose rasagiline transdermal patch, the mean terminal elimination half life (t 1/2) was 6.06-9.41 h, which was longer than with the 1-mg tablet dose (2.32 +/- 0.28 h). The mean dose-normalized maximum plasma concentration (C max,norm(dose)) of the 1-mg tablet dose was twofold higher than that of the transdermal patch groups. The mean dose-normalized areas under the concentration time curve (AUCnorm(dose)) of 1.25 and 2.5 mg for the rasagiline transdermal patch doses were fourfold and sevenfold higher than that of the 1-mg tablet dose, respectively. Cumulative urinary excretion was about 0.2% of the total dose. Inhibition of MAO-B activity was dose dependent, and the maximal inhibition was 73.9-94.1% at doses ranging from 1.25 to 2.5 mg. The reported adverse events were mild or moderate. CONCLUSION: The prolonged t 1/2, increased AUC0-t , and more stable plasma drug concentration of the rasagiline patch may permit a longer dosing interval compared to the oral tablet. The rasagiline transdermal patch was safe and well tolerated in healthy Chinese subjects. PMID- 29159775 TI - Toxic effects of phytol and retinol on human glioblastoma cells are associated with modulation of cholesterol and fatty acid biosynthetic pathways. AB - Glioblastoma (GBM) is the most common primary brain tumor. Genetic mutations may reprogram the metabolism of neoplastic cells. Particularly, alterations in cholesterol and fatty acid biosynthetic pathways may favor biomass synthesis and resistance to therapy. Therefore, compounds that interfere with those pathways, such as phytol (PHY) and retinol (RET), may be appropriate for cytotoxic approaches. We tested the effect of PHY or RET on the viability of human GBM cell lines (U87MG, A172 and T98G). Since the compounds showed a dose-dependent cytotoxic effect, additional analyses were performed with IC50 values. Transcriptome analyses of A172 cells treated with PHY IC50 or RET IC50 revealed down-regulated genes involved in cholesterol and/or fatty acid biosynthetic pathways. Thus, we investigated the expression of proteins required for cholesterol and/or fatty acid synthesis after treating all lineages with PHY IC50 or RET IC50 and comparing them with controls. Sterol regulatory element-binding protein 1 (SREBP-1) expression was reduced by PHY in U87 and T98G cells. However, fatty acid synthase (FAS) protein expression, which is regulated by SREBP-1, was down-regulated in all lineages after both treatments. Moreover, farnesyl diphosphate farnesyltransferase (FDFT1) levels, a protein associated with cholesterol synthesis, were reduced in all lineages by PHY and in U87MG and A172 cells by RET. Our results suggest that SREBP-1, FAS and FDFT1 are potential target(s) for future in vivo approaches against GBM and support the use of inhibitors of their synthesis, including PHY and RET, for such approaches. PMID- 29159776 TI - Non-pharmacological interventions in patients with spinal cord compression: a systematic review. AB - Spinal cord compression is a complex and challenging condition that greatly affects the quality of life. Non-pharmacological techniques have only been studied to a very lesser extent; although they are evidence to be beneficial. We performed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) analysis of the scientific literature in several databases (Medline, Cochrane, Scopus, Cuiden, Pubmed, Lilacs and Embase); using the following keywords: spinal cord compression, spine compression, mobilization, positioning, brace and bracing. Eleven studies met the inclusion criteria and were finally included in the systematic review. 3 of them were related to metastatic spinal cord compression, 5 to spinal cord compression due to other causes and the last 3 of them regarded the health professional's knowledge in oncology patients. In all cases, it seems possible to manage spinal cord compression by using external mobilization and braces and that this treatment is beneficial to patients. Positioning plays a massive role in the disease and can improve or worsen the condition when used improperly; the supine position is overused and can have a negative impact both physically and psychologically. Non-pharmacological interventions could be useful for pain management, cardiovascular alterations and patients' well-being. One randomized clinical trial demonstrated that massage therapy, using either broad compression massage or light contact touch massage improved pain control. There is an urgent need of randomized clinical trials with these interventions in order to achieve an improved care of these patients. PMID- 29159773 TI - Japan Society of Gynecologic Oncology guidelines 2015 for the treatment of vulvar cancer and vaginal cancer. AB - BACKGROUND: Vulvar cancer and vaginal cancer are relatively rare tumors, and there had been no established treatment principles or guidelines to treat these rare tumors in Japan. The first version of the Japan Society of Gynecologic Oncology (JSGO) guidelines for the treatment of vulvar cancer and vaginal cancer was published in 2015 in Japanese. OBJECTIVE: The JSGO committee decided to publish the English version of the JSGO guidelines worldwide, and hope it will be a useful guide to physicians in a similar situation as in Japan. METHODS: The guideline was created according to the basic principles in creating the guidelines of JSGO. RESULTS: The guidelines consist of five chapters and five algorithms. Prior to the first chapter, basic items are described including staging classification and history, classification of histology, and definition of the methods of surgery, radiation, and chemotherapy to give the reader a better understanding of the contents of the guidelines for these rare tumors. The first chapter gives an overview of the guidelines, including the basic policy of the guidelines. The second chapter discusses vulvar cancer, the third chapter discusses vaginal cancer, and the fourth chapter discusses vulvar Paget's disease and malignant melanoma. Each chapter includes clinical questions, recommendations, backgrounds, objectives, explanations, and references. The fifth chapter provides supplemental data for the drugs that are mentioned in the explanation of clinical questions. CONCLUSION: Overall, the objective of these guidelines is to clearly delineate the standard of care for vulvar and vaginal cancer with the goal of ensuring a high standard of care for all women diagnosed with these rare diseases. PMID- 29159777 TI - Prognostic factors for survival in adult patients with recurrent glioblastoma: a decision-tree-based model. AB - We assessed prognostic factors in relation to OS from progression in recurrent glioblastomas. Retrospective multicentric study enrolling 407 (training set) and 370 (external validation set) adult patients with a recurrent supratentorial glioblastoma treated by surgical resection and standard combined chemoradiotherapy as first-line treatment. Four complementary multivariate prognostic models were evaluated: Cox proportional hazards regression modeling, single-tree recursive partitioning, random survival forest, conditional random forest. Median overall survival from progression was 7.6 months (mean, 10.1; range, 0-86) and 8.0 months (mean, 8.5; range, 0-56) in the training and validation sets, respectively (p = 0.900). Using the Cox model in the training set, independent predictors of poorer overall survival from progression included increasing age at histopathological diagnosis (aHR, 1.47; 95% CI [1.03-2.08]; p = 0.032), RTOG-RPA V-VI classes (aHR, 1.38; 95% CI [1.11-1.73]; p = 0.004), decreasing KPS at progression (aHR, 3.46; 95% CI [2.10-5.72]; p < 0.001), while independent predictors of longer overall survival from progression included surgical resection (aHR, 0.57; 95% CI [0.44-0.73]; p < 0.001) and chemotherapy (aHR, 0.41; 95% CI [0.31-0.55]; p < 0.001). Single-tree recursive partitioning identified KPS at progression, surgical resection at progression, chemotherapy at progression, and RTOG-RPA class at histopathological diagnosis, as main survival predictors in the training set, yielding four risk categories highly predictive of overall survival from progression both in training (p < 0.0001) and validation (p < 0.0001) sets. Both random forest approaches identified KPS at progression as the most important survival predictor. Age, KPS at progression, RTOG-RPA classes, surgical resection at progression and chemotherapy at progression are prognostic for survival in recurrent glioblastomas and should inform the treatment decisions. PMID- 29159778 TI - Risk of leptomeningeal carcinomatosis in patients with brain metastases treated with stereotactic radiosurgery. AB - There is limited available literature examining factors that predispose patients to the development of LMC after stereotactic radiosurgery (SRS) for brain metastases. We sought to evaluate risk factors that may predispose patients to LMC after SRS treatment in this case-control study of patients with brain metastases who underwent single-fraction SRS between 2011 and 2016. Demographic and clinical information were collected retrospectively for 19 LMC cases and 30 controls out of 413 screened patients with brain metastases. Risk factors of interest were evaluated by univariate and multivariate logistic regression analyses and overall survival rates were evaluated by Kaplan-Meier survival analysis. About 5% of patients with brain metastases treated with SRS developed LMC. Patients with LMC (median 154 days, 95% CI 33-203 days) demonstrated a poorer overall survival than matched controls (median 417 days, 95% CI 121-512 days, p = 0.002). The most common primary tumor histologies that lead to the development of LMC were non-small cell lung cancer (36.8%), breast cancer (26.3%), and melanoma (21.1%). No association was found between the risk of LMC and the location of the brain lesion or total volume of brain metastases. Prior surgical resection of brain metastases before SRS was associated with a 6.5 times higher odds (95% CI 1.45-29.35, p = 0.01) of developing LMC post-radiosurgery compared to those with no prior resections of brain metastases. Additionally, adjuvant WBRT may help to reduce the risk of LMC and can be considered in decision-making for patients who have had brain metastasectomy. PMID- 29159780 TI - PermacolTM collagen paste for treating a rectovaginal fistula following anterior rectal prolapsectomy. PMID- 29159779 TI - Simultaneous whole-body and breast 18F-FDG PET/MRI examinations in patients with breast cancer: a comparison of apparent diffusion coefficients and maximum standardized uptake values. AB - PURPOSE: To compare standardized uptake value (SUV) and apparent diffusion coefficient (ADC) values acquired using a PET/MRI scanner in breast cancer patients. MATERIALS AND METHODS: Whole-body PET/MRI and breast PET/MRI were performed in 108 consecutive patients. Ninety-four patients who had a total of 100 breast cancers were analyzed. SUVmax and ADCmean acquired using breast PET/MRI were compared with pathologic prognostic factors. RESULTS: All the lesions were visually detectable using PET and diffusion-weighted imaging (DWI) on breast PET/MRI; however, lesions were visually undetectable on whole-body DWI in 13 patients (13%) or on whole-body PET in 7 patients (7%). An analysis of ADCmean and SUVmax demonstrated a statistically significant correlation between whole-body imaging and breast imaging (rho = 0.613, p < 0.001 and rho = 0.928, p < 0.001, respectively). In a univariate analysis, SUVmax was significantly correlated with HER2 status (p < 0.001), Ki-67 (p = 0.014), tumor size (p = 0.0177), and nuclear grade (p = 0.0448). In multiple regression analysis, only tumor size (p = 0.00701) was shown to independently influence SUVmax. CONCLUSION: Prone breast imaging was more sensitive than whole-body PET/MRI for detection of breast cancers. Both SUVmax and ADCmean showed limited correlation with pathologic prognostic factors. PMID- 29159781 TI - Outcomes of GatekeeperTM prosthesis implantation for the treatment of fecal incontinence: a multicenter observational study. AB - BACKGROUND: The implantation of Gatekeeper TM (GK) represents a new option for the treatment of fecal incontinence (FI). The aim of this study was to analyze the postoperative morbidity associated with GK and to determine its clinical efficacy after at least 1 year of follow-up. METHODS: This was a multicenter, retrospective and longitudinal study of patients with FI who were treated with GK at our institutions between January 2010 and December 2015. Patients with FI without sphincter lesions or with sphincter injuries < 120 degrees and with low anterior resection syndrome were included. Postoperative complications, long-term adverse effects and migration were recorded. FI severity was assessed using the Vaizey score. Patients were classified as responders or non-responders according to the improvement of the Vaizey score (>= than 50 and < 50%, respectively) during the first 6 months after implantation. RESULTS: Forty-nine consecutive patients treated with GK between 2010 and 2015 were included (11 males and 38 females, mean age 63.3 years, SD 13.5). No postoperative and long-term complications were observed. Prosthesis migration was observed in 51% of patients. Twenty-three patients (48%) were classified as responders and 25 (52%) as non-responders. The mean Vaizey score at baseline, 6, 12 months and last visit post-surgery in the responder group was, respectively, 13.3 (SD 3.8), 4.3 (SD 2.1), 4.2 (SD 3.6) and 5.7 (SD 5.3). Significant differences were observed between the mean baseline Vaizey score and the mean 6, 12 and last follow-up Vaizey score values (p < 0.001). In long-term follow-up (2.7 years (SD 1.1)), responders maintained an improvement of more than 50% of the baseline Vaizey score. In the non-responder group the mean number of migrated prostheses was higher than in the responder group (2.4 SD 2.5 vs. 1.0 SD 1.6; p = 0.040). CONCLUSIONS: GK is a safe and effective procedure in more than 50% of the patients for at least 1 year after the implantation. PMID- 29159783 TI - In Vitro Study of the Effects of Denosumab on Giant Cell Tumor of Bone: Comparison with Zoledronic Acid. AB - Giant cell tumor of bone (GCTB) is a locally aggressive primary bone tumor that contains numerous osteoclasts formed from marrow-derived precursors through receptor activator of nuclear factor kappa-B ligand (RANKL), an osteoclast differentiation factor expressed in neoplastic cells of GCTB. Denosumab, a fully human monoclonal antibody targeting RANKL, has recently been used for the treatment of GCTB, and superior treatment effects have been reported. The aim of this work was to elucidate the mechanism of action of denosumab, and the differences between denosumab and zoledronic acid at the level of GCTB cells. We isolated GCTB cells from 3 patients and separated them into osteoclasts, osteoclast precursors and proliferating spindle-shaped stromal cells (the true neoplastic component), and examined the action of denosumab on differentiation, survival and bone resorption activity of osteoclasts. Denosumab and zoledronic acid inhibited osteoclast differentiation from mononuclear cells containing osteoclast precursors. Zoledronic acid inhibited osteoclast survival, whereas an inhibitory effect of denosumab on osteoclast survival was not observed. The inhibitory effect on bone resorption by both agents was confirmed in culture on dentin slices. Furthermore, zoledronic acid showed dose-dependent inhibition of cell growth of neoplastic cells whereas denosumab had no inhibitory effect on these cells. Denosumab has an inhibitory effect on osteoclast differentiation, but no inhibitory effects on survival of osteoclasts or growth of neoplastic cells in GCTBs. PMID- 29159782 TI - Cecal bascule: a systematic review of the literature. AB - BACKGROUND: Cecal volvulus is a rare clinical entity with an average incidence of 2.8-7.1 per million people per year, accounting for 1-2% of all large bowel obstructions. Cecal bascule is the rarest type of cecal volvulus, accounting for 5-20% of all cases. Although several case reports have been published, there is no consensus regarding its diagnosis and treatment. The aim of this study was to review the literature on cecal bascule in order to summarize the etiopathogenesis, clinical features, diagnosis, and treatment options. METHODS: The PubMed, MEDLINE, and Scopus databases were systematically searched by two independent authors. Cecal bascule was defined as anterior displacement of the distended cecum on the ascending colon without any torsion. The etiopathogenesis, clinical features, diagnosis, and treatment options were analyzed. RESULTS: Nineteen previously published papers reporting on 26 patients were included. The mean age of patients from previously reported cases was 55.1 +/- 19.2 years, and 54% of all patients were males. Presenting symptoms included abdominal pain in 16 (61%), distension in 22 (84%), and vomiting in eight patients (30%). The mean time to diagnosis was 3.6 +/- 2.6 days. The extent of surgery varied from cecopexy to right colectomy. There was no postoperative mortality. Cecal bascule recurred one 1 year after index surgery in one patient. CONCLUSIONS: Cecal bascule is a rare clinical entity, which is mostly encountered in patients with peritoneal adhesions, mobile cecum, bowel dysfunction, and cecal displacement. In patients with recurrent or persistent abdominal pain and distension, cecal bascule should be considered. The majority of these patients require surgical management. PMID- 29159784 TI - G2A as a Threshold Regulator of Inflammatory Hyperalgesia Modulates Chronic Hyperalgesia. AB - Tissue injury, pathogen infection, and diseases are often accompanied by inflammation to release mediators that sensitize nociceptors and further recruit immune cells, which can lead to chronic hyperalgesia and inflammation. Tissue acidosis, occurring at the inflammatory site, is a major factor contributing to pain and hyperalgesia. The receptor G2 accumulation (G2A), expressed in neurons and immune cells, responds to protons or oxidized free fatty acids such as 9 hydroxyoctadecadienoic acid produced by injured cells or oxidative stresses. We previously found increased G2A expression in mouse dorsal root ganglia (DRG) at 90 min after complete Freund's adjuvant (CFA)-induced inflammatory pain, but whether G2A is involved in the inflammation or hyperalgesia remained unclear. In this study, we overexpressed or knocked-down G2A gene expression in DRG to explore the roles of G2A. G2A overexpression reduced the infiltration of acute immune cells (granulocytes) and attenuated hyperalgesia at 90 to 240 min after CFA injection. G2A knockdown increased the number of immune cells before CFA injection and prolonged the inflammatory hyperalgesia after CFA injection. G2A may serve as a threshold regulator in neurons to attenuate the initial nociceptive and inflammatory signals, modulating the chronic state of hyperalgesia. PMID- 29159785 TI - Improving the Hospital Quality of Care during Winter Periods by Optimizing Budget Allocation Between Rotavirus Vaccination and Bed Expansion. AB - BACKGROUND: During each winter the hospital quality of care (QoC) in pediatric wards decreases due to a surge in pediatric infectious diseases leading to overcrowded units. Bed occupancy rates often surpass the good hospital bed management threshold of 85%, which can result in poor conditions in the workplace. This study explores how QoC-scores could be improved by investing in additional beds and/or better vaccination programs against vaccine-preventable infectious diseases. METHODS: The Cobb-Douglas model was selected to define the improvement in QoC (%) as a function of two strategies (rotavirus vaccination coverage [%] and addition of extra hospital beds [% of existing beds]), allowing improvement-isocurves to be produced. Subsequently, budget minimization was applied to determine the combination of the two strategies needed to reach a given QoC improvement at the lowest cost. Data from Jessa Hospital (Hasselt, Belgium) were chosen as an example. The annual population in the catchment area to be vaccinated was 7000 children; the winter period was 90 days with 34 pediatric beds available. Rotavirus vaccination cost per course was ?118.26 and the daily cost of a pediatric bed was ?436.53. The target QoC increase was fixed at 50%. The model was first built with baseline parameter values. RESULTS: The model predicted that a combination of 64% vaccine coverage and 39% extra hospital beds (~ 13 extra beds) in winter would improve QoC-scores by 50% for the minimum budget allocation. CONCLUSION: The model allows determination of the most efficient allocation of the healthcare budget between rotavirus vaccination and bed expansion for improving QoC-scores during the annual epidemic winter seasons. PMID- 29159786 TI - Nitazoxanide May Modify the Course of Progressive Multifocal Leukoencephalopathy. PMID- 29159787 TI - How can an Education Workshop Serve as an Intervention for American Indian Screening Participation. AB - American Indians (AIs) continue to have elevated cancer incidence and mortality, and most have issues accessing cancer screening services. During 2013-2014, Mayo and its partners created Native Cancer 101 Module 10 "Prevention and Early Cancer Detection" education workshop. A community-based AI organization implemented nine of these workshops during 2014-2015 via diverse venues. Nearly all participants eligible for at least one type of cancer screening participated in a workshop and consented to follow-up within 3 to 6 months to determine if screenings had been completed or scheduled. Native Cancer 101 Module 10 workshops were conducted with 150 community members of whom 6 had recently completed cancer screening (n = 144). The workshops had a 25.20% increase in knowledge, and 97.1% of subjects responded that they would recommend the workshop to their friends and family. Most (136 of 144) submitted a consent form to be contacted 3 to 6 months following the workshop. Patient navigators reached 86 (63.2%) of the consented participants in the follow-up calls after the workshop, and 63 (46.3%) self reported that they had completed at least one cancer screening test for which they were eligible. The single implementation of the workshop influenced community participants' completion of cancer screening. PMID- 29159788 TI - The Fight Against Tuberculosis in the Mid-nineteenth Century: The Pivotal Contribution of Edoardo Maragliano (1849-1940). AB - The second half of the nineteenth century saw the development of new medical "specialties", which, like the idea of constitutional disease, had a profound influence on medical practice. Against this lively "backdrop", Edoardo Maragliano played a central role in medicine's "renaissance" in Italy. Having graduated in medicine in 1870 at the University of Naples, he worked as an assistant in the University Medical Clinic. After beginning his academic career as professor of pathology at the Faculty of Medicine in Genoa in 1877, he became full professor of internal medicine in 1881. While he studied all fields of internal medicine, his research focused mainly on tuberculosis.His experiments in the medical clinic enabled Maragliano to announce the possibility of immunization against Mycobacterium tuberculosis. Although criticized for using an inactivated vaccine, Maragliano continued to advocate vaccination with any type of vaccine.In the Senate of the Kingdom of Italy, Maragliano actively debated social, economic and sanitary questions, without neglecting his duties as a physician and professor. As an officer during the First World War, he organized military health services and taught medicine at the Military University of Padua.In 1924, Maragliano created the first Italian specialty school in the study of tuberculosis, which provided physicians with specific training in the diagnosis, therapy and prevention of the disease. His scientific zeal and his vision of modern medicine prompted the introduction of new specializations, such as radiology and, especially, pneumology, which led to the creation of one of Europe's most renowned medical schools. PMID- 29159789 TI - Heart Failure and Kidney Disease. AB - Kidney disease is commonly found in heart failure (HF) patients. They share many risk factors and common pathophysiological pathways which often lead to mutual dysfunction. Both haemodynamic and non-haemodynamic mechanisms are involved in the development of renal impairment in heart failure patients. Moreover, the presence of a chronic kidney disease is a significant independent predictor of worse outcome in chronic as well as in acute decompensated HF. As a consequence, an accurate evaluation of renal function plays a key role in the management of HF patients. Serum creatinine levels and glomerular filtration rate (GFR) estimates are the corner stones of renal function evaluation in clinical practice. However, to overcome their limits, several emerging glomerular and tubular biomarkers have been proposed over the last years. Alongside the renal biomarkers, imaging techniques could complement the laboratory data exploring different pathophysiological pathways. In particular, Doppler evaluation of renal circulation is a highly feasible technique that can effectively identify HF patients prone to develop renal dysfunction and with a worse outcome. Finally, some classes of drugs currently used in heart failure treatment can affect renal function and their use can be influenced by the presence of chronic kidney disease. PMID- 29159790 TI - Vitamin D supplementation in pregnancy-a survey of compliance with recommendations. AB - BACKGROUND: Vitamin D deficiency in pregnancy has important maternal and fetal implications, with increased risk of developing gestational diabetes, preeclampsia, preterm birth and small for gestational age birthweight. It is recommended that every pregnant woman should take 5 MUg (200 IU) of vitamin D per day during pregnancy and lactation. AIMS: This study aimed to determine the prevalence of women taking vitamin D supplementation and to identify the reasons for patients not taking supplementation within women attending an antenatal clinic in Dublin. METHODS: Survey of women attending the antenatal clinic of the National Maternity Hospital Dublin during 2 weeks in January 2017. Women were asked to record demographics, medical comorbidities and use of vitamin D supplementation or any other supplements in pregnancy, as well as reasons for non use if appropriate. RESULTS: Three hundred women were invited to participate and 175 completed the questionnaire (58%). Overall, 38.9% (n = 68) reported to be taking vitamin D supplementation. Of the women that reported not to be taking vitamin D supplementation, 57.9% (n = 62) were taking a pregnancy multivitamin that contained vitamin D, and 28.0% (n = 30) did not know that it was recommended in pregnancy. Therefore, a total of 45 women (25.7%) in our cohort were taking no vitamin D supplementation during pregnancy. There was no difference in non-use based on maternal age, BMI, parity, or country of origin. CONCLUSIONS: Of the women surveyed, 74.3% reported supplementation with vitamin D, either knowingly or unknowingly. Public health initiatives need to utilize this relatively safe, low-cost intervention to maximize maternal and fetal health. This could reduce the rates of antenatal conditions with associated high morbidity and healthcare burden such as gestational diabetes and preeclampsia. PMID- 29159791 TI - Determining personalized treatment by gene expression profiling in metastatic breast carcinoma patients: a pilot study. AB - PURPOSE: The present study evaluates the massive study of gene expression in metastatic breast carcinoma (MBC) patients using microarray gene expression profiling (MAGE) complemented with conventional sequencing, immunohistochemistry (IHC) and fluorescent "in situ" hybridization (FISH), seeking to optimize the treatment in a subset of heavily pretreated patients and with limited life expectancy. PATIENTS, MATERIAL AND METHODS: MBC patients in hormone therapy progression with survival expectancy of at least 3 months (m) have been included. The MAGE contains gene probes representing genes known to potentially interact with available drugs as cited in the literature. RESULTS: Thirty-nine procedures were performed from October 2010 to April 2016. Within the 30 evaluable procedures, considering all hormonal manipulations as a single line, the patients had received a median of 4 treatment lines prior to MAGE (range 1-7). Progression was observed in 6 cases, stable disease (SD) in 7 cases and partial response (PR) in 16 cases, which implies a clinical benefit rate (SD + PR) of 76%. Actuarial median progression-free survival (PFS) was 6 m (95% CI 2.5-9.5) in patients with clinical benefit. The median overall survival (OS) for the entire series was 11 m (95% CI 2.2-19.8). CONCLUSION: Data presented here indicate that the use of MAGE provides relevant information to establish personalized treatment in frail patients with limited life expectancy in which therapeutic futility is a particularly difficult burden to assume. PMID- 29159792 TI - SEOM clinical guidelines for the treatment of head and neck cancer (2017). AB - Head and neck cancer (HNC) is defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2013 publication, Spanish Society of Medical Oncology (SEOM) presents an update of HNC diagnosis and treatment guideline. The eighth edition of TNM classification, published in January 2017, introduces important changes for p16-positive oropharyngeal tumours, for lip and oral cavity cancer and for N3 category. In addition, there are new data about induction chemotherapy and the role of immunotherapy in HNC. PMID- 29159793 TI - Curative radiation therapy for very elderly bladder cancer patients with localized disease. AB - PURPOSE: To report the outcomes of a cohort of very elderly muscle-invasive bladder cancer (MIBC) patients treated with contemporary 3D-conformal radiation therapy (3D-CRT) with or without concurrent chemotherapy, after transurethral resection of bladder tumor (TURBT). METHODS: From February 2010 to January 2014, a total of 41 patients older than 75 years, with T2-3 N0-1 high-grade MIBC, a Karnofsky index (KI) of at least 90% and/or a Barthel scale score of at least 95, were treated with TURBT followed by radiotherapy (RT) with or without chemotherapy, and were prospectively followed-up. RESULTS: The mean age of patients was 82 years (range 76-88). Median follow-up was 47 months for surviving patients. Mean Charlson Comorbidity Index (CCI) score was 5 points. 28 patients (68.29%) were T2N0. All received 3D-CRT to a mean dose of 60 Gy (range 48.6-66 Gy), and chemotherapy was delivered to 34 patients (83%). Cause-specific survival (CSS) was 86 and 78.8% at 1 and 5 years, respectively. Patients achieving a complete response lived longer (48 vs 14 m, p = 0.036) than those with a progressive disease, who were more likely to die from cancer than from other causes (HR 3.865, IC95% 1.562-9.562). Dead patients had a longest treatment time (mean 56.78 vs 48.91 days, p = 0.019) than survivors. CONCLUSION: RT with contemporary 3D-CRT techniques after TURBT for MIBC in elderly patients is feasible and well-tolerated. Achieving a maximal response and shortening the total radiation treatment time may improve outcomes and quality of life. PMID- 29159794 TI - High-Fat, High-Sugar Diet-Induced Subendothelial Matrix Stiffening is Mitigated by Exercise. AB - Consumption of a high-fat, high-sugar diet and sedentary lifestyle are correlated with bulk arterial stiffening. While measurements of bulk arterial stiffening are used to assess cardiovascular health clinically, they cannot account for changes to the tissue occurring on the cellular scale. The compliance of the subendothelial matrix in the intima mediates vascular permeability, an initiating step in atherosclerosis. High-fat, high-sugar diet consumption and a sedentary lifestyle both cause micro-scale subendothelial matrix stiffening, but the impact of these factors in concert remains unknown. In this study, mice on a high-fat, high-sugar diet were treated with aerobic exercise or returned to a normal diet. We measured bulk arterial stiffness through pulse wave velocity and subendothelial matrix stiffness ex vivo through atomic force microscopy. Our data indicate that while diet reversal mitigates high-fat, high-sugar diet-induced macro- and micro-scale stiffening, exercise only significantly decreases micro scale stiffness and not macro-scale stiffness, during the time-scale studied. These data underscore the need for both healthy diet and exercise to maintain vascular health. These data also indicate that exercise may serve as a key lifestyle modification to partially reverse the deleterious impacts of high-fat, high-sugar diet consumption, even while macro-scale stiffness indicators do not change. PMID- 29159795 TI - Impact of chemotherapy-induced neurotoxicities on adult cancer survivors' symptom burden and quality of life. AB - PURPOSE: Limited information is available on the impact of chemotherapy (CTX) induced neurotoxicity on adult survivors' symptom experience and quality of life (QOL). Purposes were to describe occurrence of hearing loss and tinnitus and evaluate for differences in phenotypic characteristics and measures of sensation, balance, perceived stress, symptom burden, and QOL between survivors who received neurotoxic CTX and did (i.e., neurotoxicity group) and did not (i.e., no neurotoxicity group) develop neurotoxicity. Neurotoxicity was defined as the presence of chemotherapy-induced neuropathy (CIN), hearing loss, and tinnitus. Survivors in the no neurotoxicity group had none of these conditions. METHODS: Survivors (n = 609) completed questionnaires that evaluated hearing loss, tinnitus, stress, symptoms, and QOL. Objective measures of sensation and balance were evaluated. RESULTS: Of the 609 survivors evaluated, 68.6% did and 31.4% did not have CIN. Of the survivors without CIN, 42.4% reported either hearing loss and/or tinnitus and 48.1% of the survivors with CIN reported some form of ototoxicity. Compared to the no neurotoxicity group (n = 110), survivors in the neurotoxicity group (n = 85) were older, were less likely to be employed, had a higher comorbidity burden, and a higher symptom burden, higher levels of perceived stress, and poorer QOL (all p < .05). CONCLUSIONS: Findings suggest that CIN, hearing loss, and tinnitus are relatively common conditions in survivors who received neurotoxic CTX. IMPLICATIONS FOR CANCER SURVIVORS: Survivors need to be evaluated for these neurotoxicities and receive appropriate interventions. Referrals to audiologists and physical therapists are warranted to improve survivors' hearing ability, functional status, and QOL. PMID- 29159796 TI - Host Preferences of Telenomus podisi (Hymenoptera: Scelionidae): Parasitism on Eggs of Dichelops melacanthus, Euschistus heros, and Podisus nigrispinus (Hemiptera: Pentatomidae). AB - Successful biological control requires detailed knowledge about host preferences of the released parasitoid, because the presence of alternative hosts may affect the control of the target pest. The objective of this work was therefore to evaluate host preferences of Telenomus podisi Ashmead among the eggs of three stink bug species: Dichelops melacanthus Dallas, Euschistus heros Fabricius, and Podisus nigrispinus Dallas (Heteroptera: Pentatomidae). Three independent experiments were carried out to study host preferences among the following: (1) E. heros, D. melacanthus dallas, and P. nigrispinus (bioassay 1); (2) E. heros and D. melacanthus (bioassay 2); and (3) D. melacanthus and P. nigrispinus (bioassay 3). A single bioassay (bioassay 4) was carried out to evaluate the egg size of E. heros, D. melacanthus, and P. nigrispinus. Two more bioassays were carried out: bioassay 5 to study the biological characteristics of T. podisi reared on E. heros, D. melacanthus, and P. nigrispinus eggs, and bioassay 6 to study the morphological characters of T. podisi reared on those different host eggs. Overall, T. podisi consistently preferred eggs of D. melacanthus to those of the other studied hosts, due to probably their better nutritional value; hypothesis that is supported by the fast T. podisi development and bigger parasitoids when reared on D. melacanthus and P. nigrispinus eggs. This allows suggesting that neither pre-imaginal conditioning nor associative learning nor alpha-conditioning are relevant to T. podisi parasitism. Thus, E. heros eggs could be successfully used for mass rearing of this parasitoid for successive generations since it would not affect its parasitism on other species of the Pentatomidae family in the field. PMID- 29159797 TI - Correlation of Opioid Mortality with Prescriptions and Social Determinants: A Cross-sectional Study of Medicare Enrollees. AB - BACKGROUND: The opioid epidemic is an escalating health crisis. We evaluated the impact of opioid prescription rates and socioeconomic determinants on opioid mortality rates, and identified potential differences in prescription patterns by categories of practitioners. METHODS: We combined the 2013 and 2014 Medicare Part D data and quantified the opioid prescription rate in a county level cross sectional study with data from 2710 counties, 468,614 unique prescribers and 46,665,037 beneficiaries. We used the CDC WONDER database to obtain opioid related mortality data. Socioeconomic characteristics for each county were acquired from the US Census Bureau. RESULTS: The average national opioid prescription rate was 3.86 claims per beneficiary that received a prescription for opioids (95% CI 3.86-3.86). At a county level, overall opioid prescription rates (p < 0.001, Coeff = 0.27) and especially those provided by emergency medicine (p < 0.001, Coeff = 0.21), family medicine physicians (p = 0.11, Coeff = 0.008), internal medicine (p = 0.018, Coeff = 0.1) and physician assistants (p = 0.021, Coeff = 0.08) were associated with opioid-related mortality. Demographic factors, such as proportion of white (p white < 0.001, Coeff = 0.22), black (p black < 0.001, Coeff = - 0.19) and male population (p male < 0.001, Coeff = 0.13) were associated with opioid prescription rates, while poverty (p < 0.001, Coeff = 0.41) and proportion of white population (p white < 0.001, Coeff = 0.27) were risk factors for opioid-related mortality (p model < 0.001, R 2 = 0.35). Notably, the impact of prescribers in the upper quartile was associated with opioid mortality (p < 0.001, Coeff = 0.14) and was twice that of the remaining 75% of prescribers together (p < 0.001, Coeff = 0.07) (p model = 0.03, R 2 = 0.03). CONCLUSIONS: The prescription opioid rate, and especially that by certain categories of prescribers, correlated with opioid-related mortality. Interventions should prioritize providers that have a disproportionate impact and those that care for populations with socioeconomic factors that place them at higher risk. PMID- 29159798 TI - Tasks determine what is learned in visual statistical learning. AB - Visual statistical learning (VSL), the unsupervised learning of statistical contingencies across time and space, may play a key role in efficient and predictive encoding of the perceptual world. How VSL capabilities vary as a function of ongoing task demands is still poorly understood. VSL is modulated by selective attention and faces interference from some secondary tasks, but there is little evidence that the types of contingencies learned in VSL are sensitive to task demands. We found a powerful effect of task on what is learned in VSL. Participants first completed a visual familiarization task requiring judgments of face gender (female/male) or scene location (interior/exterior). Statistical regularities were embedded between stimulus pairs. During a surprise recognition phase, participants showed less recognition for pairs that had required a change in response key (e.g., female followed by male) or task (e.g., female followed by indoor) during familiarization. When familiarization required detection of "flicker" or "jiggle" events unrelated to image content, there was weaker, but uniform, VSL across pair types. These results suggest that simple task manipulations play a strong role in modulating the distribution of learning over different pair combinations. Such variations may arise from task and response conflict or because the manner in which images are processed is altered. PMID- 29159799 TI - Memory for retinotopic locations is more accurate than memory for spatiotopic locations, even for visually guided reaching. AB - To interact successfully with objects, we must maintain stable representations of their locations in the world. However, their images on the retina may be displaced several times per second by large, rapid eye movements. A number of studies have demonstrated that visual processing is heavily influenced by gaze centered (retinotopic) information, including a recent finding that memory for an object's location is more accurate and precise in gaze-centered (retinotopic) than world-centered (spatiotopic) coordinates (Golomb & Kanwisher, 2012b). This effect is somewhat surprising, given our intuition that behavior is successfully guided by spatiotopic representations. In the present experiment, we asked whether the visual system may rely on a more spatiotopic memory store depending on the mode of responding. Specifically, we tested whether reaching toward and tapping directly on an object's location could improve memory for its spatiotopic location. Participants performed a spatial working memory task under four conditions: retinotopic vs. spatiotopic task, and computer mouse click vs. touchscreen reaching response. When participants responded by clicking with a mouse on the screen, we replicated Golomb & Kanwisher's original results, finding that memory was more accurate in retinotopic than spatiotopic coordinates and that the accuracy of spatiotopic memory deteriorated substantially more than retinotopic memory with additional eye movements during the memory delay. Critically, we found the same pattern of results when participants responded by using their finger to reach and tap the remembered location on the monitor. These results further support the hypothesis that spatial memory is natively retinotopic; we found no evidence that engaging the motor system improves spatiotopic memory across saccades. PMID- 29159800 TI - Effects of combined helium pre/post-conditioning on the brain and heart in a rat resuscitation model. AB - BACKGROUND: The noble gas helium induces cardio- and neuroprotection by pre- and post-conditioning. We investigated the effects of helium pre- and post conditioning on the brain and heart in a rat resuscitation model. METHODS: After approval by the Animal Care Committee, 96 Wistar rats underwent cardiac arrest for 6 min induced by ventricular fibrillation. Animals received 70% helium and 30% oxygen for 5 min before cardiac arrest and for 30 min after restoration of spontaneous circulation (ROSC). Control animals received 70% nitrogen and 30% oxygen. Hearts and brains were excised after 2, 4 h or 7 days. Neurological degeneration was evaluated using TUNEL and Nissl staining in the hippocampal CA-1 sector. Cognitive function after 7 days was detected with the tape removal test. Molecular targets were measured by infrared western blot. Data are shown as median [Interquartile range]. RESULTS: Helium treatment resulted in significantly less apoptosis (TUNEL positive cells/100 pixel 73.5 [60.3-78.6] vs.78.2 [70.4 92.9] P = 0.023). Changes in Caveolin-3 expression in the membrane fraction and Hexokinase-II in the mitochondrial fraction were observed in the heart. Caveolin 1 expression of treated animals significantly differed from control animals in the membrane fraction of the heart and brain after ROSC. CONCLUSION: Treatment with helium reduced apoptosis in our resuscitation model. Differential expression levels of Caveolin-1, Caveolin-3 and Hexokinase II in the heart were found after helium pre- and post-conditioning. No beneficial effects were seen on neurofunctional outcome. PMID- 29159801 TI - Real-life clinical use of natalizumab and fingolimod in Austria. AB - OBJECTIVES: To compare the efficacy of natalizumab or fingolimod in a nationwide observational cohort using prospectively collected data. MATERIALS AND METHODS: We included all patients starting treatment with natalizumab or fingolimod documented in the Austrian MS Treatment Registry (AMSTR) from 2011 and staying on therapy for at least 24 months. We used propensity scores for several matching methods and as a covariate in multivariate models to correct for the bias of this non-randomized registry study. RESULTS: The study cohort includes 588 patients with RRMS. Ten patients did not produce a propensity score in the common support region, thus leaving 578 cases for final analyses, 332 in the fingolimod and 246 in the natalizumab group. Mean annualized relapse rates (ARR) during the 24 months observation period were 0.19 under fingolimod and 0.12 under natalizumab treatment (P = .005). No statistical significant differences were found analysing the log-transformed ARR, probability for experiencing a relapse, EDSS progression and EDSS regression. The hazard ratio for switching treatment from fingolimod comparing with natalizumab was 0.36 (95% CI: 0.247-0.523), P < .001. CONCLUSIONS: The generalized linear model (GLM) for relapse count as Poisson distributed dependent variable and propensity score as covariate showed a statistically significant reduction for the mean relapse count in the natalizumab group compared with fingolimod. This effect was smaller in the analyses of log transformed ARR with propensity score matching, loosing statistical significance although showing the same direction for the effect. We assume that the GLM was the more sensitive model analysing this question. PMID- 29159803 TI - A note on the expected value of the Rand index. AB - Two expectations of the adjusted Rand index (ARI) are compared. It is shown that the expectation derived by Morey and Agresti (1984, Educational and Psychological Measurement, 44, 33) under the multinomial distribution to approximate the exact expectation from the hypergeometric distribution (Hubert & Arabie, 1985, Journal of Classification, 2, 193) provides a poor approximation, and, in some cases, the difference between the two expectations can increase with the sample size. Proofs concerning the minimum and maximum difference between the two expectations are provided, and it is shown through simulation that the ARI can differ significantly depending on which expectation is used. Furthermore, when compared in a hypothesis testing framework, multinomial approximation overly favours the null hypothesis. PMID- 29159802 TI - Adenovirus vector-based prime-boost vaccination via heterologous routes induces cervicovaginal CD8+ T cell responses against HPV16 oncoproteins. AB - Recent advances in immunotherapy against cancer underscore the importance of T lymphocytes and tumor microenvironment, but few vaccines targeting cancer have been approved likely due in part to the dearth of common tumor antigens, insufficient immunogenicity and the evolution of immune evasion mechanisms during the progression to malignancy. Human papillomaviruses (HPVs) are the primary etiologic agents of cervical cancer and progression from persistent HPV-infection to cervical intraepithelial lesions and eventually cancer requires persistent expression of the oncoproteins E6 and E7. This offers the opportunity to specifically target these virus-specific antigens for vaccine-induced clearance of infected cells before cancers develop. Here we have evaluated the immunogenicity of Adenovirus Types 26 and 35 derived vectors expressing a fusion of HPV16 E6 and E7 oncoproteins after intramuscular (IM) and/or intravaginal (Ivag) immunization in mice. The adenovirus vectors were shown to transduce an intact cervicovaginal epithelium. IM prime followed by Ivag boost maximized the induction and trafficking of HPV-specific CD8+ T cells producing IFN-gamma and TNF-alpha to the cervicovaginal tract. Importantly, the cervicovaginal CD8+ T cells expressed CD69 and CD103; hallmarks of intraepithelial tissue-resident memory CD8+ T cells. This prime-boost strategy targeting heterologous locations also induced circulating HPV-specific CD8+ T cell responses. Our study prompts further evaluation of Ivag immunization with adenoviral vectors expressing modified E6 and E7 antigens for therapeutic vaccination against persistent HPV infection and cervical intraepithelial neoplasia. PMID- 29159804 TI - Antibodies against human papillomaviruses as diagnostic and prognostic biomarker in patients with neck squamous cell carcinoma from unknown primary tumor. AB - Treatment of patients with neck lymph node metastasis of squamous cell carcinoma (SCC) from unknown primary tumor (NSCCUP) is challenging due to the risk of missing occult tumors or inducing toxicity to unaffected sites. Human papillomavirus (HPV) is a promising biomarker given its causal link to oropharyngeal SCC and superior survival of patients with HPV-driven oropharyngeal SCC and NSCCUP. Identification of HPV-driven NSCCUP could focus diagnostic work up and treatment on the oropharynx. For the first time, we assessed HPV antibodies and their prognostic value in NSCCUP patients. Antibodies against E6 and E7 (HPV16/18/31/33/35), E1 and E2 (HPV16/18) were assessed in 46 NSCCUP patients in sera collected at diagnosis, and in follow-up sera from five patients. In 28 patients, HPV tumor status was determined using molecular markers (HPV DNA, mRNA and cellular p16INK4a ). Thirteen (28%) NSCCUP patients were HPV seropositive for HPV16, 18, 31, or 33. Of eleven patients with HPV-driven NSCCUP, ten were HPV-seropositive, while all 17 patients with non-HPV-driven NSCCUP were HPV-seronegative, resulting in 91% sensitivity (95% CI: 59-100%) and 100% specificity (95% CI: 80-100%). HPV antibody levels decreased after curative treatment. Recurrence was associated with increasing levels in an individual case. HPV-seropositive patients had a better overall and progression-free survival with hazard ratios of 0.09 (95% CI: 0.01-0.42) and 0.03 (95% CI: 0.002 0.18), respectively. For the first time, seropositivity to HPV proteins is described in NSCCUP patients, and high sensitivity and specificity for HPV-driven NSCCUP are demonstrated. HPV seropositivity appears to be a reliable diagnostic and prognostic biomarker for patients with HPV-driven NSCCUP. PMID- 29159805 TI - The anatomy of the infrarenal lumbar splanchnic nerves in human cadavers: implications for retroperitoneal nerve-sparing surgery. AB - Injury to the nerves of the aortic- and superior hypogastric plexuses during retroperitoneal surgery often results in significant post-operative complications, including retrograde ejaculation and/or loss of seminal emission in males. Although previous characterizations of these plexuses have done well to provide a basis for understanding the typical anatomy, additional research into the common variations of these plexuses could further optimize nerve-sparing techniques for retroperitoneal surgery. To achieve this, the present study aimed to document the prevalence and positional variability of the infrarenal lumbar splanchnic nerves (LSNs) through gross dissection of 26 human cadavers. In almost all cases, two LSNs were observed joining each side of the aortic plexus, with 48% (left) and 33% (right) of specimens also exhibiting a third joining inferior to the left renal vein. As expected, the position of the LSNs varied greatly between specimens. That said, the vast majority (98%) of LSNs joining the aortic plexus were found to originate from the lumbar sympathetic trunk above the level of the inferior mesenteric artery. It was also found that, within specimens, adjacent LSNs often coursed in parallel. In addition to these nerves, 85% of specimens also demonstrated retroaortic LSN(s) that were angled more inferior compared with the other LSNs (P < 0.05), and exhibited a unique course between the aorta/common iliac arteries and the left common iliac vein before joining the superior hypogastric plexus below the aortic bifurcation. These findings may have significant implications for surgeons attempting nerve-sparing procedures of the sympathetic nerves in the infrarenal retroperitoneum such as retroperitoneal lymphadenectomies. We anticipate that the collective findings of the current study will help improve such retroperitoneal nerve-sparing surgical procedures, which may assist in preserving male ejaculatory function post-operatively. PMID- 29159806 TI - The evolution of bite force in horned lizards: the influence of dietary specialization. AB - Dietary specialization is an important driver of the morphology and performance of the feeding system in many organisms, yet the evolution of phenotypic specialization has only rarely been examined within a species complex. Horned lizards are considered primarily myrmecophagous (ant eating), but variation in diet among the 17 species of horned lizards (Phrynosoma) makes them an ideal group to examine the relationship between dietary specialization and the resultant morphological and functional changes of the feeding system. In this study, we perform a detailed analysis of the jaw adductor musculature and use a biomechanical model validated with in vivo bite force data to examine the evolution of bite force in Phrynosoma. Our model simulations demonstrate that bite force varies predictably with respect to the gape angle and bite position along the tooth row, with maximal bite forces being attained at lower gape angles and at the posterior tooth positions. Maximal bite forces vary considerably among horned lizards, with highly myrmecophagous species exhibiting very low bite forces. In contrast, members of the short-horned lizard clade are able to bite considerably harder than even closely related dietary generalists. This group appears to be built for performing crushing bites and may represent a divergent morphology adapted for eating hard prey items. The evolutionary loss of processing morphology (teeth, jaw and muscle reduction) and bite force in ant specialists may be a response to the lack of prey processing rather than a functional adaptation per se. PMID- 29159807 TI - Experimental investigation of GafChromic(r) EBT3 intrinsic energy dependence with kilovoltage x rays, 137 Cs, and 60 Co. AB - PURPOSE: To determine experimentally the intrinsic energy response, kbq , of EBT3 GafChromic(r) radiochromic film with kilovoltage x rays, 137 Cs, and 60 Co in therapeutic and diagnostic dose ranges through direct measurement with an accompanying mathematical approach to describe the physical processes involved. METHODS: The EBT3 film was irradiated with known doses using 60 Co, 137 Cs, and 13 NIST-matched kilovoltage x-ray beams. Seven dose levels, ranging from 57 to 7002 mGy, were chosen for this work. Monte Carlo methods were used to convert air kerma rates to dose rates to the film active layer for each energy. A total of 738 film dosimeters, each measuring (1.2 * 1.2) cm2 , were cut from three film sheets out of the same lot of the latest version of EBT3 film, to allow for multiple dosimeters to be irradiated by each target dose and beam quality as well as unirradiated dosimeters to be used as controls. Net change in optical density in excess of the unirradiated controls was measured using the UWMRRC Laser Densitometry System (LDS). The dosimeter intrinsic energy response, kbq , for each dose level was determined relative to 60 Co, as the ratio of dosimeter response to each beam quality relative to the absorbed dose to the film active volume at the same dose level. A simplified, single-hit mathematical model was used to derive a single-free-parameter, beta, which is a proportionality constant that is dependent on beam quality and describes the microdosimetric interactions within the active layer of film. The response of beta for each beam quality relative to 60 Co was also determined. RESULTS: kbq was determined for a wide range of doses and energies. The results show a unique variation of kbq as a function of energy, and agree well with results from other investigations. There was no measurable dose dependence for kbq within the 500-7002 mGy range outside of the expanded measurement uncertainty of 3.65% (k = 2). For doses less than 500 mGy, the signal-to-noise ratio was too low to determine kbq accurately. The single-free-parameter, beta, fit calculations derived from the single-hit model show a correlation with kbq that suggests that beta, at least in part, characterizes the microdosimetric interactions that determine kbq . CONCLUSIONS: For the beam qualities investigated, a single energy-dependent kbq correction can be used for doses between 500 and 7002 mGy. Using the single-hit model with the single-free-parameter fit to solve for beta shows promise in the determination of the intrinsic energy response of film, with beta being the mathematical analog of the measured kbq . PMID- 29159808 TI - Association between height and periodontitis in Korean adults: Results from KNHANES IV and V. AB - BACKGROUND AND OBJECTIVE: Evidence shows that a short stature in adulthood is associated with chronic diseases. However, few studies have investigated the association between height and periodontitis. The purpose of this study was to examine the relationship between adult height and periodontitis and to assess the roles of covariates in different birth cohorts of Korea. MATERIAL AND METHODS: This was a cross-sectional study using the data from the 4th and 5th Korea National Health and Nutritional Examination Survey. The subjects were grouped into 2 birth cohorts based on their historical and social context: born from 1946 to 1962 and from 1963 to 1978. The dependent variables were periodontitis and severe periodontitis, while the independent variable was the height quartile. Demographic factors (age and gender), socioeconomic position (own education, region and income), health behaviors (frequency of daily tooth brushing and smoking) and medical status (diabetes) were included. Logistic regression analyses estimated the association of adult height with periodontitis after sequential adjustments. RESULTS: The sample size of the final analysis was 18 010. The shortest quartile was associated with severe periodontitis (OR = 1.55, 95% CI 1.11-2.16) in the 1963-1978 birth cohort. The association remained after full adjustment in the 1963-1978 birth cohort (OR = 1.41, 95% CI 1.01-1.97). CONCLUSION: Our study shows that there is an inverse association between height and severe periodontitis only in the younger Korean birth cohort. Our results support the impact of height, as an early childhood environmental indicator, on severe periodontitis in adulthood. PMID- 29159810 TI - Usefulness of Doppler waveform analysis before performing a complex procedure using femoral venous access. AB - Ultrasonography is a well-defined and widely accepted technique in the settings of interventional procedures requiring peripheral venous access, either for the confirmation of the vein patency (with the compression test) or for guiding needle insertion. This report describes a case of unsuccessful guidewire passage through the right iliac vein in spite of successful ultrasonography-guided puncture of the femoral vein. On repeat duplex ultrasonography, the Doppler waveform showed a continuous pattern without respiratory phasicity, which was consistent with proximal venous occlusion. Venous Doppler signal waveform analysis can be helpful for ensuring downstream patency when planning long distance catheterization via femoral venous access. PMID- 29159809 TI - Shoulder joint synovial chondromatosis presenting as multiple axillary masses: A case report. AB - Synovial chondromatosis is a rare, benign, proliferative cartilaginous lesion arising from the synovial tissue, tenosynovium, or bursal lining. We describe the case of a patient who initially presented with multiple axillary masses. Breast ultrasound (US) was requested due to the concern of a breast tumor with axillary lymph node metastases. US study was helpful and provided adequate information to suggest the diagnosis. PMID- 29159812 TI - The I in autism: Severity and social functioning in autism are related to self processing. AB - It is well established that children with autism spectrum disorder (ASD) show impaired understanding of others and deficits within social functioning. However, it is still unknown whether self-processing is related to these impairments and to what extent self impacts social functioning and communication. Using an ownership paradigm, we show that children with ASD and chronological- and verbal age-matched typically developing (TD) children do show the self-referential effect in memory. In addition, the self-bias was dependent on symptom severity and socio-communicative ability. Children with milder ASD symptoms were more likely to have a high self-bias, consistent with a low attention to others relative to self. In contrast, severe ASD symptoms were associated with reduced self-bias, consistent with an 'absent-self' hypothesis. These findings indicate that deficits in self-processing may be related to impairments in social cognition for those on the lower end of the autism spectrum. Statement of contribution What is already known on this subject? Impaired self-processing in autism is linked to social and cognitive deficits. There are discrepancies across the literature, with reports of both intact and impaired self-processing in autism. Ownership tasks are developmentally appropriate and have shown to induce self-memory bias in young children. What does this study add? Using an ownership task, children with autism showed a significant self-memory bias, greater than typical peers. Severity was negatively correlated with level of self-bias, potentially explaining the previous discrepancies. Severe autism symptoms are associated with an 'absent self', and mild autism symptoms reduce attention to others. PMID- 29159811 TI - A deep learning method for classifying mammographic breast density categories. AB - PURPOSE: Mammographic breast density is an established risk marker for breast cancer and is visually assessed by radiologists in routine mammogram image reading, using four qualitative Breast Imaging and Reporting Data System (BI RADS) breast density categories. It is particularly difficult for radiologists to consistently distinguish the two most common and most variably assigned BI-RADS categories, i.e., "scattered density" and "heterogeneously dense". The aim of this work was to investigate a deep learning-based breast density classifier to consistently distinguish these two categories, aiming at providing a potential computerized tool to assist radiologists in assigning a BI-RADS category in current clinical workflow. METHODS: In this study, we constructed a convolutional neural network (CNN)-based model coupled with a large (i.e., 22,000 images) digital mammogram imaging dataset to evaluate the classification performance between the two aforementioned breast density categories. All images were collected from a cohort of 1,427 women who underwent standard digital mammography screening from 2005 to 2016 at our institution. The truths of the density categories were based on standard clinical assessment made by board-certified breast imaging radiologists. Effects of direct training from scratch solely using digital mammogram images and transfer learning of a pretrained model on a large nonmedical imaging dataset were evaluated for the specific task of breast density classification. In order to measure the classification performance, the CNN classifier was also tested on a refined version of the mammogram image dataset by removing some potentially inaccurately labeled images. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to measure the accuracy of the classifier. RESULTS: The AUC was 0.9421 when the CNN model was trained from scratch on our own mammogram images, and the accuracy increased gradually along with an increased size of training samples. Using the pretrained model followed by a fine-tuning process with as few as 500 mammogram images led to an AUC of 0.9265. After removing the potentially inaccurately labeled images, AUC was increased to 0.9882 and 0.9857 for without and with the pretrained model, respectively, both significantly higher (P < 0.001) than when using the full imaging dataset. CONCLUSIONS: Our study demonstrated high classification accuracies between two difficult to distinguish breast density categories that are routinely assessed by radiologists. We anticipate that our approach will help enhance current clinical assessment of breast density and better support consistent density notification to patients in breast cancer screening. PMID- 29159813 TI - An overview of cleaner fish use in Ireland. AB - Sea lice infestations represent one of the most significant challenges facing the salmon farming industry, giving rise to lost production, additional costs of treatment and potential negative interactions with wild stocks. At present, cleaner fish, which actively remove lice from salmon, are an effective, biological, long-term option which has been adopted by many countries. In Ireland, several key studies were conducted in the 1990s on the use of wild caught wrasse (corkwing, goldsinny and rock cook) as cleaner fish in experimental and commercial scale trials. More recently, the National University of Ireland Galway (NUIG), at their marine research facility in Carna (CRS), has undertaken applied research on ballan wrasse and lumpsucker. Currently, CRS is providing lumpsucker juveniles and research and development for the Irish salmon industry with support from BIM (Ireland's Seafood Development Agency) and Marine Harvest Ireland. There is a large amount of research currently being carried out in this area in all countries that are utilizing cleaner fish technology. The current focus in Ireland is the development of a native lumpsucker broodstock to facilitate its sustainable production. The aim of this article was to provide an overview of the research, challenges and use of cleaner fish in Ireland. PMID- 29159814 TI - CERES: An ab initio code dedicated to the calculation of the electronic structure and magnetic properties of lanthanide complexes. AB - We have developed and implemented a new ab initio code, Ceres (Computational Emulator of Rare Earth Systems), completely written in C++11, which is dedicated to the efficient calculation of the electronic structure and magnetic properties of the crystal field states arising from the splitting of the ground state spin orbit multiplet in lanthanide complexes. The new code gains efficiency via an optimized implementation of a direct configurational averaged Hartree-Fock (CAHF) algorithm for the determination of 4f quasi-atomic active orbitals common to all multi-electron spin manifolds contributing to the ground spin-orbit multiplet of the lanthanide ion. The new CAHF implementation is based on quasi-Newton convergence acceleration techniques coupled to an efficient library for the direct evaluation of molecular integrals, and problem-specific density matrix guess strategies. After describing the main features of the new code, we compare its efficiency with the current state-of-the-art ab initio strategy to determine crystal field levels and properties, and show that our methodology, as implemented in Ceres, represents a more time-efficient computational strategy for the evaluation of the magnetic properties of lanthanide complexes, also allowing a full representation of non-perturbative spin-orbit coupling effects. (c) 2017 Wiley Periodicals, Inc. PMID- 29159815 TI - Effectiveness of Interventions for Breast Cancer Screening in African American Women: A Meta-Analysis. AB - OBJECTIVE: The purpose of this study was to report the results of a meta-analysis conducted on the effects of clinical trials in breast cancer screening for African American women between 1997 and 2017. DATA SOURCES: Articles published in English and in the United States, between January 1997 and March 2017, were eligible for inclusion if they (1) conducted psychosocial, behavioral, or educational interventions designed to increase screening mammography rates in predominantly African American women of all ages; (2) utilized a randomized, controlled trial (RCT) design; and (3) reported quantitative screening rates following the intervention. STUDY DESIGN: Randomized clinical trials on breast cancer screening in African American women, published between January 1997 and March 2017, were selected from database searches. DATA COLLECTION METHODS: Data collected included effect size of screening versus comparison interventions, intervention characteristics, and a number of study characteristics to explore potential moderators. Search results yielded 327 articles, of which 14 met inclusion criteria and were included in analyses. PRINCIPAL FINDINGS: Findings indicated that screening interventions for African American women were significantly more likely to result in mammography than control (OR = 1.56 [95 percent CI = 1.27-1.93], p < .0001). Although no patient or study characteristics significantly moderated screening efficacy, the most effective interventions were those specifically tailored to meet the perceived risk of African American women. CONCLUSIONS: Screening interventions are at least minimally effective for promoting mammography among African American women, but research in this area is limited to a small number of studies. More research is needed to enhance the efficacy of existing interventions and reduce the high morbidity and mortality rate of this underserved population. PMID- 29159816 TI - On the isotropy of induced multipole moments in heavy ion complexes. AB - Polarization effects have been proven to play an important role in the theoretical description of chemical processes. With this respect, we report ab initio calculations describing multiconfigurational and relativistic effects as well as electron correlation to determine dipole- and quadrupole polarizabilities for all trivalent actinide and lanthanide ions. The results are used in an iterative point-multipole model to compute polarization interaction for different metal compounds. Significant differences between the usage of isotropic polarizabilities for the coordinating ligands compared to the full tensor representation is found. Quadrupole contributions are found to be negligible for symmetric geometries but can contribute up to 30 kJ/mol to the polarization energy in specific cases. The employed method allows a parameter free study of multipole interactions for a wide variety of systems. (c) 2017 Wiley Periodicals, Inc. PMID- 29159817 TI - Long-term safety of adalimumab in clinical trials in adult patients with Crohn's disease or ulcerative colitis. AB - BACKGROUND: Adalimumab is used to treat moderate to severe Crohn's disease (CD) and ulcerative colitis (UC) when conventional therapies fail. AIM: To update long term adalimumab safety from CD and UC trials; the previous report was CD only, 3160 patients/3402 patient-years (PYs). METHODS: Treatment-emergent adverse events (AEs; first dose to 70 days after last dose/December 31, 2015) in adults in phase 2/3 and 3/3b trials and open-label extensions were coded using Medical Dictionary for Regulatory Activities (MedDRA-v18.1). Rates were assessed as events/100 (E/100 PYs). RESULTS: The database (16 trials; CD, N = 3606; UC, N = 1739) represented 4145 and 3397 PYs of exposure, respectively. For CD, incidences of any AEs with adalimumab were 60.8%-65.1%, depending on dose, and 71.5% with placebo; for UC, the incidences were 53.5%-54.8% and 56.1%, respectively. Rates of any AEs (CD, 605 E/100 PYs; UC, 361 E/100 PYs), serious AEs (CD, 36.1 E/100 PYs; UC, 18.9 E/100 PYs), and malignancies (CD, 1.2 E/100 PYs; UC, 1.0 E/100 PYs) were similar between current and prior analyses. Apparent rate of opportunistic infections was lowered to 0.3 and 0.2 E/100 PYs for CD and UC, respectively, by recent MedDRA changes excluding oral candidiasis and tuberculosis. Standardised incidence ratios for malignancies were similar to the general population (CD, 1.45 [95% CI, 0.90-2.22]; UC, 1.36 [95% CI, 0.84-2.07]). Demyelinating disorders were uncommon (CD, 0.1 E/100 PYs; UC, <0.1 E/100 PYs). CONCLUSIONS: Patients with moderately to severely active Crohn's disease or ulcerative colitis continued to experience acceptable safety with adalimumab, without new safety signals. PMID- 29159818 TI - C/EBPalpha-dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer. AB - : Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while hepatocellular carcinoma (HCC) is caused by the dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. In both cases of liver cancer, the dephosphorylation of tumor suppressor protein CCAAT/enhancer binding protein alpha (C/EBPalpha) at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C/EBPalpha-S193A, in a large cohort of human HBL samples, and in Pten/p53 double knockout mice and found that these cancers are characterized by elevation of C/EBPalpha that is dephosphorylated at Ser190/193. We found that dephosphorylated C/EBPalpha creates preneoplastic foci with cancer stem cells that give rise to HCC and aggressive HBL. C/EBPalpha-dependent dedifferentiation of hepatocytes into cancer stem cells includes increased proliferation of hepatocytes, followed by generation of multinucleated hepatocytes and subsequent appearance of hepatocytes with delta-like 1 homolog-positive intranuclear inclusions. We further isolated C/EBPalpha-dependent multinucleated hepatocytes and found that they possess characteristics of tumor-initiating cells, including elevation of stem cell markers. C/EBPalpha-dependent cancer stem cells are observed in patients with aggressive HBL and in patients with a predisposition for liver cancer. CONCLUSION: The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include conversion of the tumor suppressor C/EBPalpha into an oncogenic isoform, which further creates preneoplastic foci where hepatocytes dedifferentiate into cancer cells, giving rise to liver cancer. (Hepatology 2018;67:1857-1871). PMID- 29159820 TI - Prevalence of type I sensitization to alpha-gal in forest service employees and hunters: Is the blood type an overlooked risk factor in epidemiological studies of the alpha-Gal syndrome? PMID- 29159819 TI - Focal Nodular Hyperplasia of the Liver: Contrast-Enhanced Ultrasonographic Features With Sonazoid. AB - OBJECTIVES: To investigate ultrasonographic features of focal nodular hyperplasia of the liver with contrast-enhanced ultrasonography (CEUS) using Sonazoid (perflubutane; GE Healthcare, Oslo, Norway). METHODS: Thirty-one patients with 31 focal nodular hyperplasia nodules who underwent CEUS using Sonazoid between July 2012 and February 2015 were included in this study. After the microbubble contrast agent was injected, intermittent CEUS images were obtained during the following 4 phases: arterial (10-40 seconds), portal venous (60-90 seconds), delayed (3 minutes), and Kupffer (>10 minutes). Three abdominal radiologists retrospectively reviewed the images and achieved consensus for vascular (central artery, stellate vascularity, and centrifugal enhancement) and dynamic enhancement patterns during the late arterial, portal venous, delayed, and Kupffer phases. RESULTS: The patients included 12 men and 19 women (age range, 21 82 years; mean, 47 years). The mean diameter of the lesions +/- SD was 2.2 +/- 0.9 cm (range, 1.0-4.0 cm). On CEUS, 24 of 31 lesions (77.4%) showed central artery and stellate vascularity in the early arterial phase, and 25 (80.6%) showed centrifugal enhancement. Twenty-six lesions (83.9%) were hyperechoic during the late arterial phase and showed hyperenhancement or isoenhancement during the serial dynamic phases. Kupffer-phase images indicated that only 2 lesions (6.5%) were hypoechoic compared with surrounding liver parenchyma, whereas 29 (93.5%) remained either hyperechoic (2 [6.5%]) or isoechoic (27 [87.1%]). CONCLUSIONS: Contrast-enhanced US using Sonazoid for focal nodular hyperplasia showed typical vascular patterns of central artery vascularity, stellate vascularity, and centrifugal enhancement. Most cases were either hyperenhanced or isoenhanced on serial dynamic- and Kupffer-phase imaging. Based on these results, CEUS can provide useful information for noninvasive focal nodular hyperplasia diagnoses. PMID- 29159821 TI - The D0-14/D ratio: A new paleodemographic index and equation for estimating total fertility rates. AB - OBJECTIVES: The objectives of this study were to develop a new subadult-adult ratio for application to sites with good infant representation and to produce an equation to estimate the total fertility rate for a population based on the age at-death ratio. A new approach is required as current methods exclude the 0-4 years age category due to presumed underenumeration of infants. While this is true for some skeletal samples, others experience good infant representation. MATERIALS AND METHODS: Using age-at-death data and total fertility rates for 52 countries from the United Nations database for the year 1960, we examined the correlation between three age-at-death ratios and the fertility rate. We also utilized linear regression to determine an equation for calculating total fertility rate from the ratio. RESULTS: We achieved a correlation of 0.848 between our D0-14/D Ratio and actual fertility rates. This correlation was significantly higher (p < .05) than the other ratios examined, including the d5 14/d20+ by Bocquet-Appel and Masset () and the 15 P5 index by Bocquet-Appel (). DISCUSSION: The exclusion of infants can result in inaccurate demographic measures, particularly where subadults aged over 5 years of age experience robust survivorship. In addition to providing a solution for sites with good infant representation, this study indicates that the 0-4 years of age category possesses great predictive power when compared to other age categories. The regression equation provides a total fertility rate which is comparable with data regardless of their temporal origin. This method will provide more accurate demographic measures for bioarcheological sites with good infant preservation. PMID- 29159822 TI - Everyday police work during mental health encounters: A study of call resolutions in Chicago and their implications for diversion. AB - In recent decades, there has been sustained focus on police responses to persons experiencing mental health crises. The Crisis Intervention Team (CIT) model has been a seminal effort to improve safety, reduce arrests and enhance the use of emergency psychiatric assessment. With CIT well established, new discussions have emerged around how to further enhance the police-public health interface, including diversion from hospital emergency departments. In this context, this article takes stock of current police practices, utilizing descriptive data on 428 mental health-related calls addressed by Chicago Police over 3 years triangulated with insights from 21 in-depth officer interviews. During these calls, hospital transports were conducted more often than arrests. Moreover, informal interventions - without any legal action or hospitalization - were used most often, speaking to the "gray zone" nature of mental health-related encounters. Taken together, the data reveal the need for non-crisis diversion options that address chronic vulnerabilities. PMID- 29159823 TI - Constrained optimization for position calibration of an NMR field camera. AB - PURPOSE: Knowledge of the positions of field probes in an NMR field camera is necessary for monitoring the B0 field. The typical method of estimating these positions is by switching the gradients with known strengths and calculating the positions using the phases of the FIDs. We investigated improving the accuracy of estimating the probe positions and analyzed the effect of inaccurate estimations on field monitoring. METHODS: The field probe positions were estimated by 1) assuming ideal gradient fields, 2) using measured gradient fields (including nonlinearities), and 3) using measured gradient fields with relative position constraints. The fields measured with the NMR field camera were compared to fields acquired using a dual-echo gradient recalled echo B0 mapping sequence. Comparisons were done for shim fields from second- to fourth-order shim terms. RESULTS: The position estimation was the most accurate when relative position constraints were used in conjunction with measured (nonlinear) gradient fields. The effect of more accurate position estimates was seen when compared to fields measured using a B0 mapping sequence (up to 10%-15% more accurate for some shim fields). The models acquired from the field camera are sensitive to noise due to the low number of spatial sample points. CONCLUSION: Position estimation of field probes in an NMR camera can be improved using relative position constraints and nonlinear gradient fields. Magn Reson Med 80:380-390, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29159824 TI - The external phenotype-skeleton link in post-hatch farmed Chinook salmon (Oncorhynchus tshawytscha). AB - Skeletal deformities in farmed fish are a recurrent problem. External malformations are easily recognized, but there is little information on how external malformations relate to malformations of the axial skeleton: the external phenotype-skeleton link. Here, this link is studied in post-hatch to first-feed life stages of Chinook salmon (Oncorhynchus tshawytscha) raised at 4, 8 and 12 degrees C. Specimens were whole-mount-stained for cartilage and bone, and analysed by histology. In all temperature groups, externally normal specimens can have internal malformations, predominantly fused vertebral centra. Conversely, externally malformed fish usually display internal malformations. Externally curled animals typically have malformed haemal and neural arches. External malformations affecting a single region (tail malformation and bent neck) relate to malformed notochords and early fusion of fused vertebral centra. The frequencies of internal malformations in both externally normal and malformed specimens show a U-shaped response, with lowest frequency in 8 degrees C specimens. The fused vertebral centra that occur in externally normal specimens represent a malformation that can be contained and could be carried through into harvest size animals. This study highlights the relationship between external phenotype and axial skeleton and may help to set the framework for the early identification of skeletal malformations on fish farms. PMID- 29159826 TI - Pharmacological and molecular approaches for the treatment of beta-hemoglobin disorders. AB - beta-hemoglobin disorders, such as beta-thalassemia and sickle cell anemia are among the most prevalent inherited genetic disorders worldwide. These disorders are caused by mutations in the gene encoding hemoglobin-beta (HBB), a vital protein found in red blood cells (RBCs) that carries oxygen from lungs to all parts of the human body. As a consequence, there has been an enduring interest in this field in formulating therapeutic strategies for the treatment of these diseases. Currently, there is no cure available for hemoglobin disorders, although, some patients have been treated with bone marrow transplantation, whose scope is limited because of the difficulty in finding a histocompatible donor and also due to transplant-associated clinical complications that can arise during the treatment. On account of these constraints, reactivation of fetal hemoglobin (HbF) synthesis holds immense promise and is a viable strategy to alleviate the symptoms of beta-hemoglobin disorders. Development of new genomic tools has led to the identification of important natural genetic modifiers of hemoglobin switching which include BCL11A, KLF1, HBSIL-MYB, LRF, LSD1, LDB1, histone deacetylases 1 and 2 (HDAC1 and HDAC2). miRNAs are also promising therapeutic targets for development of more effective strategies for the induction of HbF production. Many new small molecule pharmacological inducers of HbF production are already under pre-clinical and clinical development. Furthermore, recent advancements in gene and cell therapy includes targeted genome editing and iPS cell technologies, both of which utilizes a patient's own cells, are emerging as extremely promising approaches for significantly reducing the burden of beta hemoglobin disorders. PMID- 29159825 TI - Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. AB - : Alcoholic liver disease (ALD) is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to ALD. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an over-representation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine. Bile acid analysis confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower farnesoid X receptor (FXR) activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (Cyp)-7a1 protein expression and circulating bile acid levels. Depletion of the commensal microbiota with nonabsorbable antibiotics attenuated hepatic Cyp7a1 expression and reduced ALD in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal FXR activity, we used a pharmacological intervention with the intestine-restricted FXR agonist fexaramine, which protected mice from ethanol-induced liver injury. Whereas bile acid metabolism was only minimally altered, fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial metabolic effect to FGF15, a nontumorigenic FGF19 variant-a human FGF15 ortholog-was overexpressed in mice using adeno associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis. CONCLUSION: Taken together, alcohol associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions improve bile acid-FXR-FGF15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, and reduce ethanol-induced liver disease in mice. (Hepatology 2018;67:2150-2166). PMID- 29159827 TI - Family-based tests for associating haplotypes with general phenotype data: Improving the FBAT-haplotype algorithm. AB - For family-based association studies, Horvath et al. proposed an algorithm for the association analysis between haplotypes and arbitrary phenotypes when the phase of the haplotypes is unknown, that is, genotype data is given. Their approach to haplotype analysis maintains the original features of the TDT/FBAT approach, that is, complete robustness against genetic confounding and misspecification of the phenotype. The algorithm has been implemented in the FBAT and PBAT software package and has been used in numerous substantive manuscripts. Here, we propose a simplification of the original algorithm that maintains the original approach but reduces the computational burden of the approach substantially and gives valuable insights regarding the conditional distribution. With the modified algorithm, the application to whole-genome sequencing (WGS) studies becomes feasible; for example, in sliding window approaches or spatial clustering approaches. The reduction of the computational burden that our modification provides is especially dramatic when both parental genotypes are missing. For example, for eight variants and 441 nuclear families with mostly offspring-only families, in a WGS study at the APOE locus, the running time decreased from approximately 21 hr for the original algorithm to 0.11 sec after our modification. PMID- 29159828 TI - Crystal structure of the Legionella effector Lem22. AB - Legionella pneumophila is a pathogen causing severe pneumonia in humans called Legionnaires' disease. Lem22 is a previously uncharacterized effector protein conserved in multiple Legionella strains. Here, we report the crystal structure of Lem22 from the Philadelphia strain, also known as lpg2328, at 1.40 A resolution. The structure shows an up-and-down three-helical bundle with a significant structural similarity to a number of protein-binding domains involved in apoptosis and membrane trafficking. Sequence conservation identifies a putative functional site on the interface of helices 2 and 3. The structure is an important step toward a functional characterization of Lem22. PMID- 29159829 TI - Calcium hydroxide regulates transcription of the bone sialoprotein gene via a calcium-sensing receptor in osteoblast-like ROS 17/2.8 cells. AB - Bone sialoprotein (BSP) is a glycoprotein associated with mineralized tissues. In this study, we investigated the regulation of Bsp transcription by calcium hydroxide [Ca(OH)2 ] in rat osteosarcoma-derived osteoblast-like ROS 17/2.8 cells and stromal bone marrow cells. Application of Ca(OH)2 (0.4 mM) increased the levels of runt-related transcription factor 2 (Runx2) and BspmRNAs at 3 and 6 h and the level of BSP protein at 12 h. Transient transfection analyses were performed using chimeric constructs encompassing different regions of the rat Bsp gene promoter ligated to a luciferase reporter gene. It was found that Ca(OH)2 increased the luciferase activities of the pLUC3 and pLUC4 constructs. Introduction of 2-bp mutations to the luciferase construct showed that the effects of Ca(OH)2 were mediated by cAMP response-element (CRE) and fibroblast growth factor 2 (FGF2) response element (FRE). Luciferase activities induced by Ca(OH)2 were blocked by protein kinase C (PKC), protein kinase A (PKA), phosphoinositide-3-kinase (PI3-K), and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors and by calcium-sensing receptor (CASR) antagonists. Gel-shift analyses showed that Ca(OH)2 increased binding of nuclear protein to CRE and FRE. Dexamethasone-induced mineralization in stromal bone marrow cells was abrogated by CASR antagonists. These studies demonstrate that Ca(OH)2 regulates Bsp transcription via the CASR by targeting CRE and FRE in the rat Bsp gene promoter. PMID- 29159830 TI - ERK5 plays an essential role in gestational beta-cell proliferation. AB - OBJECTIVES: Restoring a functional beta-cell mass is a fundamental goal in treating diabetes. A complex signalling pathway network coordinates the regulation of beta-cell proliferation, although a role for ERK5 in this network has not been reported. This question was addressed in this study. MATERIALS AND METHODS: We studied the activation of extracellular-signal-regulated kinase 5 (ERK5) in pregnant mice, a well-known mouse model of increased beta-cell proliferation. A specific inhibitor of ERK5 activation, BIX02189, was intraperitoneally injected into the pregnant mice to suppress ERK5 signalling. Beta-cell proliferation was determined by quantification of Ki-67+ beta cells. Beta-cell apoptosis was determined by TUNEL assay. The extent of beta-cell proliferation was determined by beta-cell mass. The alteration of ERK5 activation and CyclinD1 levels in purified mouse islets was examined by Western blotting. RESULTS: Extracellular-signal-regulated kinase 5 phosphorylation, which represents ERK5 activation, was significantly upregulated in islets from pregnant mice. Suppression of ERK5 activation by BIX02189 in pregnant mice significantly reduced beta-cell proliferation, without affecting beta-cell apoptosis, resulting in increases in random blood glucose levels and impairment of glucose response of the mice. ERK5 seemed to activate CyclinD1 to promote gestational beta-cell proliferation. CONCLUSIONS: Extracellular-signal-regulated kinase 5 plays an essential role in the gestational augmentation of beta-cell proliferation. ERK5 may be a promising target for increasing beta-cell mass in diabetes patients. PMID- 29159831 TI - Design and development of low cost polyurethane biopolymer based on castor oil and glycerol for biomedical applications. AB - In the current study, we present the synthesis of novel low cost bio-polyurethane compositions with variable mechanical properties based on castor oil and glycerol for biomedical applications. A detailed investigation of the physicochemical properties of the polymer was carried out by using mechanical testing, ATR-FTIR, and X-ray photoelectron spectroscopy (XPS). Polymers were also tested in short term in-vitro cell culture with human mesenchymal stem cells to evaluate their biocompatibility for potential applications as biomaterial. FTIR analysis confirmed the synthesis of castor oil and glycerol based PU polymers. FTIR also showed that the addition of glycerol as co-polyol increases crosslinking within the polymer backbone hence enhancing the bulk mechanical properties of the polymer. XPS data showed that glycerol incorporation leads to an enrichment of oxidized organic species on the surface of the polymers. Preliminary investigation into in vitro biocompatibility showed that serum protein adsorption can be controlled by varying the glycerol content with polymer backbone. An alamar blue assay looking at the metabolic activity of the cells indicated that castor oil based PU and its variants containing glycerol are non-toxic to the cells. This study opens an avenue for using low cost bio-polyurethane based on castor oil and glycerol for biomedical applications. PMID- 29159832 TI - Expression and localisation of RXFP3 in human spermatozoa and impact of INSL7 on sperm functions. AB - Insulin-like peptide 7 (INSL7) or relaxin-3 is a member of the insulin superfamily that is recently discovered. This hormone interacts with relaxin family peptide receptor 3 (RXFP3). Although recent studies of INSL7 have focused on its function in the brain as a neuropeptide, spermatozoa may be a candidate target of INSL7 due to its detection in testes and contains binding sites. Therefore, this study aims to analyse the expression and localisation of RXFP3 on human spermatozoa and to assess the effect of INSL7 on human sperm motility. We have incubated normal semen samples in different doses of INSL7. Sperm motility was analysed by Computer Assisted Sperm Analysis. Moreover, localisation and expression of RXFP3 were assessed in human spermatozoa by immunofluorescence and RT-PCR respectively. This study indicated that RXFP3 mainly localised in the post acrosomal region of sperm head and neck. However, we did not observe expression of RXFP3 mRNA in human spermatozoa. This study showed that INSL7 alleviated the natural decline in sperm motility after a 4-hr incubation period. This was particularly observed in the 1.8 pmol/L treated samples. These data suggested that most likely expression of RXFP3 arrested in spermiogenesis, but the RXFP3 peptide existed on the surface of mature spermatozoa. PMID- 29159833 TI - Maternal hypothyroidism in the perinatal period and childhood asthma in the offspring. AB - BACKGROUND: There is increasing interest in the possible link between maternal hypothyroidism in the perinatal period and childhood asthma risk. We explored this in this study while accounting for the timing of hypothyroidism diagnosis. Further, we evaluated whether the risk was moderated by thyroid hormone treatment during pregnancy. METHODS: We conducted a population-based cohort study using Danish national registers. All live-born singletons in Denmark from 1998 to 2007 were identified. Maternal hypothyroidism and asthma in the children were defined by data from the Patient Register and Prescription Registry. We estimated incidence rate ratios (IRRs) of asthma among children born to hypothyroid mothers versus children born to mothers with no recorded thyroid dysfunction using Poisson regression models. RESULTS: Of 595 669 children, 3524 children were born to mothers with hypothyroidism diagnosed before delivery and 4664 diagnosed after delivery. Overall, 48 990 children received treatment for asthma. The IRRs of asthma was 1.16 (95% confidence interval (CI): 1.03-1.30) and 1.12 (95% CI: 1.02 1.24) for children born to mothers with hypothyroidism diagnosed before and after delivery, compared to children born to mothers with no thyroid dysfunction. The highest risk was observed among children born to mothers with hypothyroidism diagnosed before delivery who did not receive thyroid hormone treatment during pregnancy (IRR=1.37, 95% CI: 1.04-1.80). CONCLUSION: Our findings suggest that maternal hypothyroidism, especially when it is untreated, increases childhood asthma risk. Early detection and appropriate treatment of hypothyroidism in pregnant women may be an area for possible prevention of childhood asthma. PMID- 29159834 TI - LINC00473 antagonizes the tumour suppressor miR-195 to mediate the pathogenesis of Wilms tumour via IKKalpha. AB - OBJECTIVES: Although dramatic improvements of overall survival has achieved in patients with favourable histology Wilms tumour, disease recurrence is still the main cause of cancer-related death in childhood. Long non-coding RNAs (lncRNAs) as oncogenes or tumour suppressors are dysregulated during carcinogenesis. However, the role of lncRNAs in the pathogenesis of Wilms tumour is unknown. Here, an lncRNA LINC00473 signature that functioned as oncogene was identified in Wilms tumour. METHODS: Wilms tumour (n = 15) and relative normal tissues were collected. The LINC00473 expression and function in Wilms tumour was determined. The LncRNA-miRNA network of LINC00473 was analysed in vitro and vivo. RESULTS: We uncovered that the expression of LINC00473 was elevated in tumour tissues than that in relative normal tissues. Higher LINC00473 levels correlated to higher stage and unfavourable histology Wilms tumour. Mechanistically, knockdown of LINC00473 inhibited cell vitality and induced Bcl-2-dependent apoptosis and G1/S arrest via CDK2 and cyclin D1. Moreover, LINC00473 harboured binding sites for miR-195 and limited miR-195 availability in a dose-dependent manner. Forced expression of miR-195 impaired tumour survival and metastasis, which, however, could be restored by LINC00473. Furthermore, IKKalpha was the downstream of LINC00473/miR-195 signals and could be directly targeted by miR-195 to participate LINC00473-induced tumour progression. Loss-of-function of LINC00473 in vivo effectively promoted the regression of Wilms tumour via miR-195/IKKalpha mediated growth inhibition. CONCLUSION: LINC00473 as an oncogene is up-regulated to participate into the molecular pathogenesis of Wilms tumour via miR 195/IKKalpha. PMID- 29159835 TI - Precarious schedules linked with workplace aggression in a high-risk occupation. AB - INTRODUCTION: Night work and prolonged work hours increase the risk for workplace aggression, however, the risk related to precarious schedules remains unknown. METHODS: Cross-sectional study among Parole Probation Officers (PPOs) (n = 35). A precarious schedules index was created including the following indicators (a) experiencing one or more unexpected shifts during the last 4 weeks; (b) having minimal control over work hours; and (c) shifts notifications of less than a week. Generalized Poisson Regressions estimated the association between precarious schedules and self-reported client-based aggressive incidents (verbal, threating, property, or physical) during the last 12 months. RESULTS: Workplace aggression was highly prevalent (94.3%). PPOs who experienced precarious schedules (74.3% prevalence) had an adjusted rate of workplace aggression 1.55 times greater than PPOs without precarious schedules (IRR = 1.55, 95% CI 1.25, 1.97, P < 0.001). CONCLUSIONS: Precarious schedules were associated with workplace aggression. Further research ought to examine whether improving schedule predictability may reduce client-based aggression. PMID- 29159836 TI - Mechanisms of calcium sequestration by isolated Malpighian tubules of the house cricket Acheta domesticus. AB - Hemolymph calcium homeostasis in insects is achieved by the Malpighian tubules, primarily by sequestering excess Ca2+ within internal calcium stores (Ca-rich granules) most often located within type I (principal) tubule cells. Using both the scanning ion-selective electrode technique and the Ramsay secretion assay this study provides the first measurements of basolateral and transepithelial Ca2+ fluxes across the Malpighian tubules of an Orthopteran insect, the house cricket Acheta domesticus. Ca2+ transport was specific to midtubule segments, where 97% of the Ca2+ entering the tubule is sequestered within intracellular calcium stores and the remaining 3% is secreted into the lumen. Antagonists of voltage-gated (L-type) calcium channels decreased Ca2+ influx >=fivefold in adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated tubules, suggesting basolateral Ca2+ influx is facilitated by voltage-gated Ca2+ channels. Increasing fluid secretion through manipulation of intracellular levels of cAMP or Ca2+ had opposite effects on tubule Ca2+ transport. The adenylyl cyclase-cAMP-PKA pathway promotes Ca2+ sequestration whereas both 5-hydroxytryptamine and thapsigargin inhibited sequestration. Our results suggest that the midtubules of Acheta domesticus are dynamic calcium stores, which maintain hemolymph calcium concentration by manipulating rates of Ca2+ sequestration through stimulatory (cAMP) and inhibitory (Ca2+ ) regulatory pathways. PMID- 29159837 TI - Protein structure modeling and refinement by global optimization in CASP12. AB - For protein structure modeling in the CASP12 experiment, we have developed a new protocol based on our previous CASP11 approach. The global optimization method of conformational space annealing (CSA) was applied to 3 stages of modeling: multiple sequence-structure alignment, three-dimensional (3D) chain building, and side-chain re-modeling. For better template selection and model selection, we updated our model quality assessment (QA) method with the newly developed SVMQA (support vector machine for quality assessment). For 3D chain building, we updated our energy function by including restraints generated from predicted residue-residue contacts. New energy terms for the predicted secondary structure and predicted solvent accessible surface area were also introduced. For difficult targets, we proposed a new method, LEEab, where the template term played a less significant role than it did in LEE, complemented by increased contributions from other terms such as the predicted contact term. For TBM (template-based modeling) targets, LEE performed better than LEEab, but for FM targets, LEEab was better. For model refinement, we modified our CASP11 molecular dynamics (MD) based protocol by using explicit solvents and tuning down restraint weights. Refinement results from MD simulations that used a new augmented statistical energy term in the force field were quite promising. Finally, when using inaccurate information (such as the predicted contacts), it was important to use the Lorentzian function for which the maximal penalty arising from wrong information is always bounded. PMID- 29159838 TI - EYS mutation update: In silico assessment of 271 reported and 26 novel variants in patients with retinitis pigmentosa. AB - Mutations in Eyes shut homolog (EYS) are one of the most common causes of autosomal recessive (ar) retinitis pigmentosa (RP), a progressive blinding disorder. The exact function of the EYS protein and the pathogenic mechanisms underlying EYS-associated RP are still poorly understood, which hampers the interpretation of the causality of many EYS variants discovered to date. We collected all reported EYS variants present in 377 arRP index cases published before June 2017, and uploaded them in the Leiden Open Variation Database (www.LOVD.nl/EYS). We also describe 36 additional index cases, carrying 26 novel variants. Of the 297 unique EYS variants identified, almost half (n = 130) are predicted to result in premature truncation of the EYS protein. Classification of all variants using the American College of Medical Genetics and Genomics guidelines revealed that the predicted pathogenicity of these variants cover the complete spectrum ranging from likely benign to pathogenic, although especially missense variants largely fall in the category of uncertain significance. Besides the identification of likely benign alleles previously reported as being probably pathogenic, our comprehensive analysis underscores the need of functional assays to assess the causality of EYS variants, in order to improve molecular diagnostics and counseling of patients with EYS-associated RP. PMID- 29159839 TI - Increased Renal Echogenicity in Children With Appendicitis. AB - OBJECTIVES: Ultrasound (US) is an important modality for the detection of acute appendicitis in children but has limited sensitivity and specificity. Therefore, additional US findings may contribute to the diagnosis. In our experience, children with acute appendicitis often have increased renal cortical echogenicity on US imaging. The purpose of this study was to examine the association of increased renal cortical echogenicity with appendicitis. METHODS: This study included 240 consecutive pediatric patients with no renal or liver disease who underwent US examinations for suspected appendicitis between February 2014 and January 2016. Ultrasound images of the liver and right kidney were retrospectively reviewed, and the echogenicity of the renal cortex was classified as less than the liver, equal to the liver, or greater than the liver. RESULTS: The renal cortex was abnormally hyperechoic in 38 (50%) of all of the patients who had appendicitis according to US (P < .001) and in 47% of patients who underwent appendectomy (P = .002). Overall, 36% of patients with increased renal cortical echogenicity had a diagnosis of appendicitis. After correction for variables, patients with renal hyperechogenicity had a 2.5 times chance of appendicitis (odds ratio, 2.5). CONCLUSIONS: There is a statistically significant association between increased renal cortical echogenicity and appendicitis. In the absence of hepatic or renal disease, this finding may increase the accuracy of the US diagnosis of appendicitis. Increased renal cortical echogenicity may be added to the list of US findings accompanying acute appendicitis in children. PMID- 29159840 TI - Cognitive Outcomes After Transcatheter Aortic Valve Implantation: A Metaanalysis. AB - OBJECTIVES: To quantitatively summarize changes in cognitive performance in individuals with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI). DESIGN: Metaanalysis. PARTICIPANTS: Individuals undergoing TAVI (N = 1,065 (48.5% male) from 18 studies, average age >=80). MEASUREMENTS: The MEDLINE, EMBASE, and Cochrane Central databases were searched for original peer-reviewed reports assessing cognitive performance using standardized cognitive tests before and after TAVI. Data were extracted for cognitive scores before TAVI; perioperatively (within 7 days after TAVI); 1, 3, and 6 months after TAVI, and 12 to 34 months after TAVI (over the long term). Standardized mean differences (SMDs) were generated using random-effects models for changes in cognition at each time point. Metaregression analyses were conducted to assess the association between population and procedural characteristics and cognitive outcomes. Risk of bias was assessed. RESULTS: There were no significant changes from baseline in perioperative cognitive performance (SMD = 0.05, 95% confidence interval (CI) = -0.08-0.18; z = 0.75, P = .46), although overall cognitive performance had improved significantly 1 month after TAVI (SMD = -0.33, 95% CI = 0.50 to -0.16; z = 3.83, P < .001). There were no differences in cognitive performance 3 and 6 months after TAVI or over the long term. Cognitive outcomes were not associated with any covariates in regression analyses. CONCLUSION: Cognitive performance is preserved after TAVI, suggesting TAVI is not detrimental to cognition. PMID- 29159841 TI - Trends in hepatitis C-related mortality in Switzerland. AB - In order to accurately assess the burden of hepatitis C (HCV) and develop effective interventions, we must understand the magnitude and trends of mortality related to the disease. In the United States, HCV-related mortality is continuously increasing. We have no comparable data for Switzerland and other European countries, although a modelling study predicted a similar increase. We analysed time trends (1 January 1995-31 December 2014) in HCV-specific mortality rates in the Swiss general population using the death registry of the Swiss Federal Statistical Office (SFSO). We compared HCV-related mortality to HIV related and hepatitis B (HBV)-related mortality. To determine potential under reporting in HCV-related mortality, we probabilistically linked the SFSO data to persons who died in the Swiss Hepatitis C Cohort Study (SCCS). SFSO data showed that HCV-related mortality more than doubled between 1995 and 2003, but has since stabilized at ~2.5/100 000 person-years. Since 2000, HCV-related mortality has been higher than HIV-related mortality and was about fivefold higher in 2014. HBV related mortality remained low at ~0.5/100 000 person-years. Of 4556 persons in the SCCS, 421 have died and 86.2% could be linked to the death registry. According to the SCCS, 133 deaths were HCV-related. HCV was not mentioned on the SFSO death certificate of 45% of these (n = 60/133). In conclusion, HCV-related mortality remained constant, possibly because quality of care was high, or because of under-reporting or because mortality has not yet increased. However, HCV-related mortality is now much higher than HIV- and HBV-related mortality, and under-reporting was common. PMID- 29159842 TI - Struggle and failure on clinical placement: a critical narrative review. AB - BACKGROUND: Clinical placements are crucial to the development of skills and competencies in speech-language pathology (SLP) education and, more generally, a requirement of all health professional training programmes. Literature from medical education provides a context for understanding how the environment can be vital to all students' learning. Given the increasing costs of education and demands on health services, students who struggle or fail on clinical placement place an additional burden on educators. Therefore, if more is known or understood about these students and their experience in relation to the clinical learning environment, appropriate strategies and support can be provided to reduce the burden. However, this literature does not specifically explore marginal or failing students and their experience. AIMS: To review existing research that has explored failing and struggling health professional students undertaking clinical placements and, in particular, SLP students. METHODS & PROCEDURES: A critical narrative review was undertaken. Three electronic databases, ProQuest, CINAHL and OVID (Medline 1948-), were searched for papers exploring marginal and failing students in clinical placement contexts across all health professions, published between 1988 and 2017. Data were extracted and examined to determine the breadth of the existing research, and publications were critically appraised and major research themes identified. MAIN CONTRIBUTION: Sixty-nine papers were included in the review. The majority came from medicine and nursing in the United States and United Kingdom, with other allied health disciplines less well represented. The review identified key themes with the majority of papers focused on identification of at risk students and support and remediation. The review also highlighted the absence of literature relating to the student voice and in the allied health professions. CONCLUSIONS & IMPLICATIONS: This review highlighted the limited research related to failing/struggling student learning in clinical contexts, and only a handful of papers have specifically addressed marginal or failing students in allied health professions. The complexity of interrelated factors in this field has been highlighted in this review. Further research needs to include the student's voice to develop greater understanding and insights of struggle and failure in clinical contexts. PMID- 29159843 TI - Vocational outcome in cerebral venous thrombosis: Long-term follow-up study. AB - OBJECTIVES: Few studies have investigated long-term functional outcome in patients with cerebral venous thrombosis (CVT). We aimed to evaluate return to work (RTW) after CVT and its association with self-reported life satisfaction, quality of life, health, participation, fatigue, depression, and anxiety. METHODS: From hospital records, we identified all patients diagnosed with CVT in Sahlgrenska University Hospital between 1996 and 2016 and invited all survivors to a clinical follow-up visit >1 year after onset. Primary outcome was RTW within the follow-up period which was defined as >=50% of gainful work or equivalent activity. Patients that were >62 years when they developed CVT were excluded. Cox regression analyses identified associated factors to RTW and Mann-Whitney U tests compared distributions of self-reported questionnaires on life satisfaction and health. RESULTS: Of 62 eligible and consenting patients (median age: 41.5 years (28.75-51.0); 61.3% female), 44 (71.0%) did RTW within the follow-up period (median 135 months, IQR 64-197). Median time to RTW was 7.0 months (IQR 1.4 12.7). Female sex (HR = 0.50, 95% CI = 0.25-0.99, P = .049) and parenchymal lesion detected during acute hospital stay (HR = 0.45, 95% CI = 0.24-0.82, P = .009) were significantly associated with no RTW. Patients with RTW reported significantly higher life satisfaction, quality of life, health, participation and lesser impact of fatigue, depression, and anxiety. CONCLUSIONS: Return to work after CVT is associated with higher life satisfaction, participation, and health. Parenchymal lesion in acute phase and female sex were associated with no RTW. Despite the young age of the patients, a significant portion did not regain working ability. PMID- 29159844 TI - Incidence and predictors of 30-day postoperative readmission in children. AB - BACKGROUND: Hospital readmissions are being used as a quality metric for hospital reimbursement without a clear understanding of the factors that contribute to readmission. OBJECTIVE: The objective of this study was to report the incidence of 30-day postsurgical readmission in children, identify the predictors for readmission, and create an algorithm to identify high-risk children. METHODS: Data from the 2012-2014 Pediatric database of the American College of Surgeons National Surgical Quality Improvement Program were analyzed using univariable and multivariable logistical regression analysis. RESULTS: Among 182 589 children included in the 2012-2014 American College of Surgeons National Surgical Quality Improvement Program Pediatric database, 4.8% (8815/182 589) experienced a readmission within 30 days. Four significant predictors were retained in the multivariable logistic regression model: American Society of Anesthesiologists physical status >= 3 (OR: 1.9, 95% CI: 1.8-2.0), presence of congenital heart disease (OR: 1.66, 95% CI: 1.31-2.11), inpatient status at time of surgery (OR: 3.5, 95% CI: 3.3-3.7), and at least 1 postoperative complication (neurologic, renal, wound, cardiac, bleeding, or pulmonary) (OR: 3.14, 95% CI: 2.92-3.34). The multivariable logistic regression model showed reasonably good discrimination in predicting 30-day readmissions with receiver operating characteristic area under the curve of 0.747 (95% CI: 0.73-0.75) and good calibration (Brier score: 0.044). We created a predictive algorithm of 30-day readmission based on the 4 significant predictors. CONCLUSION: Children with congenital heart disease, high American Society of Anesthesiologist physical class, inpatient status, and at least 1 postoperative complication of any kind are at high risk for postsurgical readmissions. We provide an algorithm for quantifying this risk with the goal of reducing the number of readmissions, improving the care of patients with complex chronic illnesses, and reducing hospital costs. PMID- 29159845 TI - A diuretic-sparing strategy to facilitate deactivation of vasopressin secretion. PMID- 29159846 TI - Horizontal and vertical distribution of sea lice larvae (Lepeophtheirus salmonis) in and around salmon farms in the Bay of Fundy, Canada. AB - The sea louse, Lepeophtheirus salmonis, is parasitic to salmonid species in the Northern Hemisphere and has become a widespread biological and economic problem for the salmon farming industry. A better understanding is needed of their spatial distribution and early life history to disrupt the life cycle of the sea louse. In this study, sea lice larval densities within salmon farms, between salmon farms and reference sites, and at various depths were quantified using both plankton pumps and plankton nets. Farm sites exhibited significantly higher densities than reference sites; however, these densities dropped an order of magnitude at a distance of 100 m from the cages. The majority of the larvae captured in the study were nauplii (93%), and densities ranged from 0 to 10 larvae/m3 . Free-swimming sea lice larvae were found to exhibit a diel cycle where nauplii larvae were in deeper waters (10-17 m) during the day and in surface waters (1-6 m) during the night. The results of this study suggest that the early life-history stages of sea lice originate from and may remain close to active salmon farms, creating a self-sustaining population. PMID- 29159847 TI - More or less likely to offend? Young adults with a history of identified developmental language disorders. AB - BACKGROUND: There is now substantial literature demonstrating that a disproportionate number of young people who come into contact with youth justice services evidence unidentified language difficulties. These young people, therefore, have received little or no professional input in this area. Conversely, there is a dearth of research pertaining to criminality outcomes among those individuals with identified developmental language disorders (DLD) who have received such interventions. AIMS: To examine police-initiated contact and substance use outcomes of young adults with a history of identified DLD versus age-matched peers (AMP). Additionally, self-reported rule breaking behaviours and aggression are considered. We hypothesize that early identification/intervention reduces engagement with risky behaviour such as substance and alcohol use as well as offending-related behaviours. METHODS & PROCEDURES: Adversarial police-initiated contacts were examined in 84 young adults with a history of DLD and 88 AMP. Rule-breaking and aggression were evaluated using the Achenbach Adult Self-Report for ages 18-59 years. OUTCOMES & RESULTS: Adults with a history of DLD who received targeted intervention during their school years reported less contact with their local police service compared with AMPs at age 24. Comparable proportions of both groups reported current alcohol consumption, but group differences were found relating to alcohol use. No group differences in rule-breaking behaviours were found, but the DLD group was found to have a statistically significant higher raw score on the aggressive behaviour scale. CONCLUSIONS & IMPLICATIONS: There is a need for early identification of children with DLD. Early intervention aimed at ameliorating such difficulties could possibly have distal outcomes in relation to offending. PMID- 29159848 TI - Speech deterioration in amyotrophic lateral sclerosis (ALS) after manifestation of bulbar symptoms. AB - BACKGROUND: The symptoms and their progression in amyotrophic lateral sclerosis (ALS) are typically studied after the diagnosis has been confirmed. However, many people with ALS already have severe dysarthria and loss of adequate speech at the time of diagnosis. Speech-and-language therapy interventions should be targeted timely based on communicative need in ALS. AIMS: To investigate how long natural speech will remain functional and to identify the changes in the speech of persons with ALS. METHODS & PROCEDURES: Altogether 30 consecutive participants were studied and divided into two groups based on the initial type of ALS, bulbar or spinal. Their speech disorder was evaluated on severity, articulation rate and intelligibility during the 2-year follow-up. OUTCOME & RESULTS: The ability to speak deteriorated to poor and necessitated augmentative and alternative communication (AAC) methods with 60% of the participants. Their speech remained adequate on average for 18 months from the first bulbar symptom. Severity, articulation rate and intelligibility declined with nearly all participants during the study. To begin with speech deteriorated more in the bulbar group than in the spinal group and the difference remained during the whole follow-up with some exceptions. CONCLUSIONS & IMPLICATIONS: The onset of bulbar symptoms indicated the time to loss of speech better than when assessed from ALS diagnosis or the first speech therapy evaluation. In clinical work, it is important to take the initial type of ALS into consideration when determining the urgency of AAC measures as people with bulbar-onset ALS are more susceptible to delayed evaluation and AAC intervention. PMID- 29159849 TI - Spoken sentence production in college students with dyslexia: working memory and vocabulary effects. AB - BACKGROUND: Individuals with dyslexia demonstrate syntactic difficulties on tasks of language comprehension, yet little is known about spoken language production in this population. AIMS: To investigate whether spoken sentence production in college students with dyslexia is less proficient than in typical readers, and to determine whether group differences can be attributable to cognitive differences between groups. METHODS & PROCEDURES: Fifty-one college students with and without dyslexia were asked to produce sentences from stimuli comprising a verb and two nouns. Verb types varied in argument structure and morphological form and nouns varied in animacy. Outcome measures were precision (measured by fluency, grammaticality and completeness) and efficiency (measured by response times). Vocabulary and working memory tests were also administered and used as predictors of sentence production performance. OUTCOMES & RESULTS: Relative to non-dyslexic peers, students with dyslexia responded significantly slower and produced sentences that were significantly less precise in terms of fluency, grammaticality and completeness. The primary predictors of precision and efficiency were working memory, which differed between groups, and vocabulary, which did not. CONCLUSIONS & IMPLICATIONS: College students with dyslexia were significantly less facile and flexible on this spoken sentence-production task than typical readers, which is consistent with previous studies of school-age children with dyslexia. Group differences in performance were traced primarily to limited working memory, and were somewhat mitigated by strong vocabulary. PMID- 29159850 TI - From two to three dimensions: The importance of the third dimension for evaluating the limits to neuronal miniaturization in insects. AB - Most studies dealing with the limits to miniaturization in insect brains have until now relied on information based on data collected in two dimensions: either histological sections imaged by light microscopy, or electron micrographs of single ultrathin sections imaged by transmission electron microscopy (TEM). To test the validity of transferring information gained from two-dimensional images to the third dimension, we examined a 3D image stack from serial-section TEM (ssTEM) of the optic neuropiles of the miniature parasitic wasp Trichogramma brassicae (Bezdenko, 1968). We reinvestigated the proposed lower limit of 2 um for the diameters of neuronal somata and found average volumes of 6.5 MUm3 for lamina cells and 3.8 MUm3 for medulla cells. We likewise found a limiting factor for the volume of nuclei, which averages 41.9% and 49.2% of the cell body volume, respectively, but that in turn the compactness of heterochromatin was not a limiting factor in the minimal volume of the nuclei. Finally, we also found a minimum axon diameter of 98 nm that could nevertheless accommodate axoplasmic mitochondria. Incorporating the third dimension thus proves critically important in avoiding volumetric misinterpretations of these values. We discuss the limitations of analyzing the effects of miniaturization from profile data of neurons and demonstrate that miniaturization within the nervous system can lie beyond previously described limits and in some cases is already present in the optic lobe neurons of T. brassicae. PMID- 29159851 TI - Comparison of three fixation methods in treatment of tibial fracture in adolescents. AB - BACKGROUND: Tibial fractures are the most common musculoskeletal injury in adolescents. The optimal management of tibial fractures in adolescents is controversial. In this study, we compared the outcomes including complications of three fixation methods in tibial fractures of adolescents and explored the factors associated with the complications. METHODS: A retrospective cohort study about 83 diaphyseal tibial fractures in 79 children and adolescents, who were treated with plate fixation (PF), elastic stable intramedullary nail fixation (ESINF), or external fixation (EF), was conducted. After adjustment for age, weight, energy of the injury, polytrauma, fracture level and pattern, and extent of comminution, treatment outcomes were compared in accordance with the length of the hospital stay, time to union, and complication rates including many factors. RESULTS: The mean age of the patients was 13.4 years, and their mean weight was 44.2 kg. There was a loss of reduction in two of 33 fractures treated with ESINF and four of 13 treated with EF (P < 0.001). At the time of final follow-up, three patients (two treated with EF and one treated with ESINF) had >=2.0 cm of shortening. Four of the 32 patients (33 fractures) treated with ESINF underwent a reoperation (two due to loss of reduction and one each because of delayed union and nonunion). Six patients treated with EF required a reoperation (four due to loss of reduction, one for malunion and one for replacement of a pin complicated by infection). Two fracture treated with PF required refixation attributing to nonunion and malunion. A multivariate analysis with adjustment for baseline differences showed that EF was associated with a 7.56-times (95% confidence interval 3.74-29.87) greater risk of loss of reduction and/or malunion than ESINF. CONCLUSIONS: All three treatments had satisfactory outcomes, and EF was correlated with the highest rate of complications in our series of adolescents treated with a tibial fracture. However, we cannot currently recommend that all fractures might be suitable for ESINF. The choice of fixation will remain influenced by surgeon preference in term of expertise and experience, patient and fracture characteristics, and patients and family preferences. PMID- 29159852 TI - Orbital invasive squamous cell carcinoma with adnexal involvement clinically mimicking feline restrictive orbital myofibroblastic sarcoma: 19 cases (1990 2016). AB - OBJECTIVE: To describe the clinical presentations of patients diagnosed with ocular adnexal or orbital squamous cell carcinoma (SCC), which possess features similar to feline restrictive orbital myofibroblastic sarcoma (FROMS). PROCEDURES: A retrospective review of adnexal and/or orbital SCC was performed. Cases were collected from the University of Georgia College of Veterinary Medicine and the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) (1990-2016). Data included signalment, ophthalmic clinical signs, nonophthalmic history and clinical signs, clinician suspicion of FROMS, advanced imaging results, and subsequent histopathologic diagnosis. FROMS cases from the COPLOW over the same time span were reviewed and compared statistically to the SCC cases with a significance threshold of 0.05. RESULTS: Nineteen cases (20 eyes) were identified with adnexal SCC with features similar to FROMS, including keratitis and eyelid/third eyelid restriction and/or thickening. There were no statistically significant differences between clinical findings in the SCC cases and the identified and compared FROMS cases (57 cases; 67 eyes), except for exophthalmos and/or resistance to retropulsion, which was less common in SCC cases (20%) than in FROMS cases (47.8%) (P = 0.027); and clinical or imaged presence of an overt eyelid or orbital mass, which was more common in the SCC cases (30%) than in the FROMS cases (4.5%) (P = 0.0010). CONCLUSIONS: SCC with adnexal involvement has many features similar to FROMS. In addition to FROMS, SCC should be considered a differential diagnosis in cats with restrictive adnexal or orbital signs and corneal changes. PMID- 29159853 TI - The use of cell conditioned medium for musculoskeletal tissue regeneration. AB - Tissue regenerative medicine combines the use of cells, scaffolds, and molecules to repair damaged tissues. Different cell types are employed for musculoskeletal diseases, both differentiated and mesenchymal stromal cells (MSCs). In recent years, the hypothesis that cell-based therapy is guided principally by cell secreted factors has become increasingly popular. The aim of the present literature review was to evaluate preclinical and clinical studies that used conditioned medium (CM), rich in cell-factors, for musculoskeletal regeneration. Thirty-one were in vitro, 12 in vivo studies, 1 was a clinical study, and 2 regarded extracellular vesicles. Both differentiated cells and MSCs produce CM that induces reduction in inflammation and increases synthetic activity. MSC recruitment and differentiation, endothelial cell recruitment and angiogenesis have also been observed. In vivo studies were performed with CM in bone and periodontal defects, arthritis and muscle dystrophy pathologies. The only clinical study was performed with CM from MSCs in patients needing alveolar bone regeneration, showing bone formation and no systemic or local complications. Platelet derived growth factor receptor beta, C3a, vascular endothelial growth factor, monocyte chemoattractant protein-1 and -3, interleukin 3 and 6, insulin like growth factor-I were identified as responsible of cell migration, proliferation, osteogenic differentiation, and angiogenesis. The use of CM could represent a new regenerative treatment in several musculoskeletal pathologies because it overcomes problems associated with the use of cells and avoids the use of exogenous GFs or gene delivery systems. However, some issues remain to be clarified. PMID- 29159854 TI - The effect of impaired glucose metabolism on weight loss in multidisciplinary childhood obesity treatment. AB - OBJECTIVE: To investigate whether children and adolescents exhibiting an impaired glucose metabolism are more obese at treatment entry and less likely to reduce their degree of obesity during treatment. METHODS: The present study is a longitudinal observational study, including children and adolescents from the Children's Obesity Clinic, Holbaek, Denmark. Anthropometrics, pubertal development, socioeconomic status (SES), and fasting concentrations of plasma glucose, serum insulin, serum C-peptide, and whole blood glycosylated hemoglobin (HbA1c) were collected at treatment entry and at follow-up. Proxies of Homeostasis Model Assessment 2-insulin sensitivity (HOMA2-IS) and Homeostasis Model Assessment 2-beta-cell function (HOMA2-B) were calculated with the Homeostasis Model Assessment 2 program. RESULTS: In total, 569 (333 boys) patients, median 11.5 years of age (range 6-22 years), and median body mass index (BMI) z-score 2.94 (range 1.34-5.54) were included. The mean BMI z-score reduction was 0.31 (+/-0.46) after 13 months (range 6-18) of treatment. At treatment entry, patients with impaired estimates of glucose metabolism were more obese than normoglycemic patients. Baseline concentration of C-peptide was associated with a lower weight loss during treatment in girls (P = .02). Reduction in the insulin concentrations was associated with reduction in BMI z score in both sexes (P < .0001, P = .0005). During treatment, values of glucose, HbA1c, HOMA2-IS, and HOMA2-B did not change or impact the treatment outcome, regardless of age, sex, SES, or degree of obesity at treatment entry. CONCLUSION: The capability to reduce weight during multidisciplinary treatment in children and adolescents with overweight/obesity is not influenced by an impaired glucose metabolism at study entry or during the course of treatment. PMID- 29159855 TI - B1 artifact reduction in abdominal DCE-MRI using kT -points: First clinical assessment of dynamic RF shimming at 3T. AB - BACKGROUND: The excitation inhomogeneity artifact occurring at 3T in the abdomen can lead to dramatic loss of signal and contrast, thereby hampering diagnosis. PURPOSE: To assess excitation homogeneity and image quality achieved by nonselective prototypical kT -points pulses, compared to tailored static RF shimming, in clinical routine on a commercial dual-transmit scanner. STUDY TYPE: Retrospective study with Institutional Review Board approval; informed consent was waived. POPULATION: Fifty consecutive patients referred for liver MRI at a single hospital. FIELD STRENGTH/SEQUENCE: 3D breath-hold dynamic contrast enhanced (DCE) MRI at 3T. ASSESSMENT: Flip angle homogeneity was estimated via numerical simulation based on measured static and RF field maps. In all, 20 of the 50 patients underwent DCE-MRI while a pulse designer was present. The effect of RF shimming and kT -point pulses could be compared by repeating the acquisition with each transmit scheme before injection and in the late phase. Signal homogeneity, T1 contrast, enhancement quality, structure details, and global image quality were assessed on a 4-level scale (0 to 3) by two radiologists. STATISTICAL TESTS: Means were compared using Wilcoxon signed-rank tests. RESULTS: Normalized root mean square flip angle error was significantly reduced with kT -points compared to static RF shimming (8.5% +/- 1.5% [mean +/- standard deviation, SD] vs. 20.4% +/- 9.8%; P < 0.0001). The worst case (heavy ascites) led to 13.0% (kT -points) vs. 54.9% (RF shimming). Global image quality was significantly higher for kT -points (2.3 +/- 0.5 vs. 1.9 +/- 0.6; P = 0.008). One subject's examination was judged unusable with RF shimming by one reader, none with kT -points. 85% of kT -points acquisitions were graded at least 2/3, and only 55% for static RF shimming. DATA CONCLUSION: KT -points reduce excitation inhomogeneity quantitatively and qualitatively, especially in patients with ascites and prone to B1 shading. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1562-1571. PMID- 29159856 TI - Color Doppler Sonography Accompanied by Dynamic Scanning for the Diagnosis of Ankle and Foot Fractures. AB - Sonography is conventionally used to diagnose fractures by identifying cortical discontinuity of the bone. In this study, fracture sonography in addition to color Doppler and dynamic scanning was performed in settings with limited or no access to radiography. We describe 5 cases of ankle and foot fractures with the use of sonography to identify changes in the fractured site. The width of the fracture space increased on dynamic scanning, and the Doppler signals were generated inside the fracture space on dynamic scanning. In conclusion, color Doppler sonography accompanied by dynamic scanning is a useful adjunctive diagnostic tool in addition to previously described sonographic fracture findings. PMID- 29159857 TI - Methylphenidate for children and adolescents with autism spectrum disorder. AB - BACKGROUND: Children with autistic spectrum disorder (ASD) frequently present with inattention, impulsivity and hyperactivity, which are the cardinal symptoms of attention deficit hyperactivity disorder (ADHD). The effectiveness of methylphenidate, a commonly used ADHD treatment, is therefore of interest in these children. OBJECTIVES: To assess the effects of methylphenidate for symptoms of ADHD (inattention, impulsivity and hyperactivity) and ASD (impairments in social interaction and communication, and repetitive, restricted or stereotypical behaviours) in children and adolescents aged 6 to 18 years with ASD. SEARCH METHODS: In November 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 11 other databases and two trials registers. We also checked reference lists and contacted study authors and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) that investigated the effect of methylphenidate versus placebo on the core symptoms of ASD or ADHD-like symptoms, or both, in children aged 6 to 18 years who were diagnosed with ASD or pervasive developmental disorder. The primary outcome was clinical efficacy, defined as an improvement in ADHD-like symptoms (inattention, impulsivity and hyperactivity) and in the core symptoms of ASD (impaired social interaction, impaired communication, and stereotypical behaviours), and overall ASD. Secondary outcomes examined were: rate of adverse events; caregiver well-being; need for institutionalisation, special schooling or therapy to achieve learning outcomes; and overall quality of life. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We combined outcome measures that used different psychometric scales, where clinically appropriate. We used a coefficient of 0.6 to calculate standard deviations and adjust for the studies' cross-over design. We considered a standardised mean difference (SMD) of 0.52 as the minimum clinically relevant inter-treatment difference. We applied the GRADE rating for strength of evidence for each outcome. MAIN RESULTS: The studies: we included four cross-over studies, with a total of 113 children aged 5 to 13 years, most of whom (83%) were boys. We included two studies with five-year-old children since we were unable to obtain the disaggregated data for those aged six years and above, and all other participants were in our target age range. All participants resided in the USA. The duration of treatment in the cross-over phase was one week for each dose of methylphenidate. Studies used a range of outcome scales, rated by parents, teachers or both; clinicians; or programme staff. We report parent-rated outcomes separately. Risk of bias: we considered three trials to be at high risk of bias due to selective reporting and all trials to be at unclear risk of bias for blinding of participants and assessors, due to the potential for recognising the side effects of methylphenidate. We judged all trials to be at low or unclear risk of bias for other items. Primary outcomes: the meta-analysis suggested that high-dose methylphenidate (0.43 mg/kg/dose to 0.60 mg/kg/dose) had a significant and clinically relevant benefit on hyperactivity, as rated by teachers (SMD -0.78, 95% confidence interval (CI) 1.13 to -0.43; 4 studies, 73 participants; P < 0.001; low-quality evidence) and parents (mean difference (MD) -6.61 points, 95% CI -12.19 to -1.03, rated on the hyperactivity subscale of the Aberrant Behviour Checklist, range 0 to 48; 2 studies, 71 participants; P = 0.02; low-quality evidence). Meta-analysis also showed a significant but not clinically relevant benefit on teacher-rated inattention (MD -2.72 points, 95% CI -5.37 to -0.06, rated on the inattention subscale of the Swanson, Nolan and Pelham, Fourth Version questionnaire, range 0 to 27; 2 studies, 51 participants; P = 0.04; low-quality evidence). There were inadequate data to conduct a meta-analysis on the symptom of impulsivity. There was no evidence that methylphenidate worsens the core symptoms of ASD or benefits social interaction (SMD -0.51, 95% CI -1.07 to 0.05; 3 studies, 63 participants; P = 0.07; very low-quality evidence), stereotypical behaviours (SMD -0.34, 95% CI -0.84 to 0.17; 3 studies, 69 participants; P = 0.19; low-quality evidence), or overall ASD (SMD -0.53, 95% CI -1.26 to 0.19; 2 studies, 36 participants; P = 0.15; low-quality evidence), as rated by teachers. There were inadequate data to conduct a meta-analysis on the symptom of impaired communication. SECONDARY OUTCOMES: no data were available for the secondary outcomes of caregiver well being; need for institutionalisation, special schooling options or therapy to achieve learning outcomes; or overall quality of life. No trials reported serious adverse events. The only adverse effect that was significantly more likely with treatment was reduced appetite as rated by parents (risk ratio 8.28, 95% CI 2.57 to 26.73; 2 studies, 74 participants; P < 0.001; very low-quality evidence). Subgroup analysis by dose did not identify any significant differences in effect on our primary outcomes between low-, medium- or high-dose ranges. AUTHORS' CONCLUSIONS: We found that short-term use of methylphenidate might improve symptoms of hyperactivity and possibly inattention in children with ASD who are tolerant of the medication, although the low quality of evidence means that we cannot be certain of the true magnitude of any effect. There was no evidence that methylphenidate has a negative impact on the core symptoms of ASD, or that it improves social interaction, stereotypical behaviours, or overall ASD. The evidence for adverse events is of very low quality because trials were short and excluded children intolerant of methylphenidate in the test-dose phase. Future RCTs should consider extending the duration of treatment and follow-up. The minimum clinically important difference also needs to be confirmed in children with ASD using outcome scales validated for this population. PMID- 29159858 TI - Nonlinear effect of irradiance on photoheterotrophic activity and growth of the aerobic anoxygenic phototrophic bacterium Dinoroseobacter shibae. AB - Aerobic anoxygenic photosynthetic bacteria are an important component of marine microbial communities. They produce energy in light using bacteriochlorophyll a containing photosystems. This extra energy provides an advantage over purely heterotrophic bacteria. One of the most intensively studied AAP bacteria is Dinoroseobacter shibae, a member of the environmentally important Roseobacter clade. Light stimulates its growth and metabolism, but the effect of light intensity remains unclear. Here, we show that an increase in biomass along an irradiance gradient followed the exponential rise to the maximum curve, with saturation at about 300 umol photons m-2 s-1 , without any inhibition at light intensities up to 600 umol photons m-2 s-1 . The cells adapted to higher irradiance by reducing pigmentation and increasing the electron transfer rate. This additional energy allowed D. shibae to redirect the metabolism of organic carbon sources such as glucose, leucine, glutamate, acetate and pyruvate toward anabolism, resulting in a twofold increase of their assimilation rates. We provide equations that can be feasibly incorporated into the existing model of D. shibae metabolism to further advance our understanding of the role of photoheterotrophy in the ocean. PMID- 29159859 TI - Identifiability in N-mixture models: a large-scale screening test with bird data. AB - Binomial N-mixture models have proven very useful in ecology, conservation, and monitoring: they allow estimation and modeling of abundance separately from detection probability using simple counts. Recently, doubts about parameter identifiability have been voiced. I conducted a large-scale screening test with 137 bird data sets from 2,037 sites. I found virtually no identifiability problems for Poisson and zero-inflated Poisson (ZIP) binomial N-mixture models, but negative-binomial (NB) models had problems in 25% of all data sets. The corresponding multinomial N-mixture models had no problems. Parameter estimates under Poisson and ZIP binomial and multinomial N-mixture models were extremely similar. Identifiability problems became a little more frequent with smaller sample sizes (267 and 50 sites), but were unaffected by whether the models did or did not include covariates. Hence, binomial N-mixture model parameters with Poisson and ZIP mixtures typically appeared identifiable. In contrast, NB mixtures were often unidentifiable, which is worrying since these were often selected by Akaike's information criterion. Identifiability of binomial N-mixture models should always be checked. If problems are found, simpler models, integrated models that combine different observation models or the use of external information via informative priors or penalized likelihoods, may help. PMID- 29159860 TI - Assessment of sedation level prior to neonatal intubation: A systematic review. AB - BACKGROUND: Adequate premedication before neonatal endotracheal intubation reduces pain, stress, and adverse physiological responses, diminishes duration and number of attempts at intubation, and prevents traumatic airway injury. Therefore, intubation should not be started until an adequate level of sedation is reached. It is not clear how this should be measured in the clinical situation. OBJECTIVES: The aim of this study is to provide a systematic review of the usability and validity of scoring systems or other objective parameters to evaluate the level of sedation before intubation in neonates. Secondary aims were to describe parameters that are used to determine the level of sedation and criteria on which the decision to proceed with intubation is based. METHODS: Literature was searched (January 2017) in the following electronic databases: Embase, Medline, Web of Science, Cochrane Central Registrar of Controlled Trials, Pubmed Publisher, and Google Scholar. RESULTS: From 1653 hits, 20 studies were finally included in the systematic review. In 7 studies, intubation was started after a predefined time period; in 1 study, preoxygenation was the criterion to start with intubation; and in 12 studies, intubation was started in case of adequate sedation and/or relaxation. Only 4 studies described the use of 3 different objective scoring system, all in the neonatal intensive care unit, which are not validated. CONCLUSION: No validated scoring systems to assess the level of sedation prior to intubation in newborns are available in the literature. Three objective sedation assessment tools seem promising but need further validation before they can be implemented in research and clinical settings. PMID- 29159861 TI - Promoting high standards of care for women living with HIV: position statement from the Women Against Viruses in Europe Working Group. AB - OBJECTIVES: Gender-related factors can influence management decisions, treatment outcomes and the overall long-term wellbeing of people living with HIV (PLWH). The Women Against Viruses in Europe (WAVE) Working Group was established to promote the health and wellbeing of women living with HIV (WLWH). WAVE is part of the European AIDS Clinical Society (EACS) and organizes annual workshops to discuss different issues in the management of WLWH. METHODS: In 2016, 34 WAVE members including community representatives, HIV clinicians and researchers met to discuss standards of care for WLWH and to review current guidelines. Participants focused on three different themes: (1) access to and engagement and retention in care; (2) monitoring of women on antiretroviral therapy and management of comorbidities; and (3) review of EACS treatment guidelines. RESULTS: Five priority areas for optimizing the care of WLWH were identified: (1) psychosocial aspects of HIV diagnosis and care; (2) mental health and wellbeing; (3) pharmacokinetics, toxicity and tolerability of antiretroviral therapy; (4) coinfections and comorbidities; and (5) sexual and reproductive health. WAVE recommendations are provided for each of these areas, and gaps in knowledge and needs for changes in currently existing standards are discussed. CONCLUSIONS: This position statement provides an overview of the key recommendations to optimize the care of WLWH that emerged during the 2016 WAVE workshop. PMID- 29159862 TI - Mass media interventions for smoking cessation in adults. AB - BACKGROUND: Mass media tobacco control campaigns can reach large numbers of people. Much of the literature is focused on the effects of tobacco control advertising on young people, but there are also a number of evaluations of campaigns targeting adult smokers, which show mixed results. Campaigns may be local, regional or national, and may be combined with other components of a comprehensive tobacco control policy. OBJECTIVES: To assess the effectiveness of mass media interventions in reducing smoking among adults. SEARCH METHODS: The Cochrane Tobacco Addiction Group search strategy was combined with additional searches for any studies that referred to tobacco/smoking cessation, mass media and adults. We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) and a number of electronic databases. The last search was carried out in November 2016. SELECTION CRITERIA: Controlled trials allocating communities, regions or states to intervention or control conditions; interrupted time series.Adults, 25 years or older, who regularly smoke cigarettes. Studies which cover all adults as defined in studies were included.Mass media are defined here as channels of communication such as television, radio, newspapers, billboards, posters, leaflets or booklets intended to reach large numbers of people, and which are not dependent on person-to-person contact. The purpose of the mass media campaign must be primarily to encourage smokers to quit. They could be carried out alone or in conjunction with tobacco control programmes.The primary outcome was change in smoking behaviour. This could be reported as changes in prevalence, changes in cigarette consumption, quit rates, or odds of being a smoker. DATA COLLECTION AND ANALYSIS: Two authors independently assessed all studies for inclusion criteria and for study quality (MB, LS, RTM). One author (MB) extracted data, and a second author (LS) checked them.Results were not pooled due to heterogeneity of the included studies and are presented narratively and in table form. MAIN RESULTS: Eleven campaigns met the inclusion criteria for this review. Studies differed in design, settings, duration, content and intensity of intervention, length of follow-up, methods of evaluation and also in definitions and measures of smoking behaviour used. Among seven campaigns reporting smoking prevalence, significant decreases were observed in the California and Massachusetts statewide tobacco control campaigns compared with the rest of the USA. Some positive effects on prevalence in the whole population or in the subgroups were observed in three of the remaining seven studies. Three large-scale campaigns of the seven presenting results for tobacco consumption found statistically significant decreases. Among the eight studies presenting abstinence or quit rates, four showed some positive effect, although in one of them the effect was measured for quitting and cutting down combined. Among the three that did not show significant decreases, one demonstrated a significant intervention effect on smokers and ex-smokers combined. AUTHORS' CONCLUSIONS: There is evidence that comprehensive tobacco control programmes which include mass media campaigns can be effective in changing smoking behaviour in adults, but the evidence comes from a heterogeneous group of studies of variable methodological quality. One state-wide tobacco control programme (Massachusetts) showed positive results up to eight years after the campaign. Another (California) showed positive results during the period of adequate funding and implementation and in final evaluation since the beginning of the programme. Six of nine studies carried out in communities or regions showed some positive effects on smoking behaviour and at least one significant change in smoking prevalence (Sydney). The intensity and duration of mass media campaigns may influence effectiveness, but length of follow-up and concurrent secular trends and events can make this difficult to quantify. No consistent relationship was observed between campaign effectiveness and age, education, ethnicity or gender. PMID- 29159864 TI - Effects of music during daytime rest in the intensive care unit. AB - BACKGROUND: Sleep is essential to the recovery of patients in the intensive care unit. Patients in the intensive care unit frequently experience poor sleep, characterized by sleep deprivation, sleep fragmentation and abnormal sleep architecture. Factors affecting sleep are multifactorial. AIM: To investigate the effects of music on self-reported quality of sleep during daytime rest among patients in the intensive care unit. STUDY DESIGN: A randomized controlled trial. METHODS: The study was conducted between February and April 2016 in two Danish multidisciplinary intensive care units. The study sample consisted of 37 patients (19 in the control group and 18 in the intervention group) who complied with the criteria of inclusion for the study. Patients were randomly assigned to either an intervention group or a control group. The intervention group listened to music for 30 min during daytime rest while the control group rested without music. The Richards-Campbell Sleep Questionnaire was used to measure the subjective quality of sleep. RESULTS: Significant differences in the mean scores of the subjective quality of sleep were found between the intervention group and the control group (p < 0.02). Significant differences were also found between groups in three items of sleep scores: sleep depth (p < 0.02), awakenings (p < 0.00) and the overall perceived quality of sleep (p < 0.01). The perceived noise level score was higher in the intervention group compared with the control group, although not statistically significant (p < 0.67). CONCLUSION: Listening to music during daytime rest improves subjective sleep in patients in the intensive care unit. Furthermore, there are indications that listening to music reduces the subjective experience of noise in some patients. RELEVANCE TO CLINICAL PRACTICE: The result of this study implies that music can be an effective practice for nurses to improve sleep among patients in the intensive care unit. PMID- 29159865 TI - Delayed allergic hypersensitivity to hyaluronidase during the treatment of granulomatous hyaluronic acid reactions. AB - Hyaluronic acid (HA) is now extensively employed for esthetic concerns. In the majority of cases, HA is considered to be safe, but mild-to-severe complications can occur in a few cases. Hyaluronidase is enzymes that degrade HA, also being suggested for the treatment of HA filler-induced complications. However, hyaluronidase has been reported to be a potential cause of allergic responses in some anesthetic and ophthalmic literature. However, there are few reports of allergic reactions to hyaluronidase in cosmetic medicine. We herein report on a 39-year-old Asian woman who developed a delayed allergic hypersensitivity to hyaluronidase in the treatment process of HA-related granulomatous reaction. PMID- 29159863 TI - Genome-wide gene-environment interaction in depression: A systematic evaluation of candidate genes: The childhood trauma working-group of PGC-MDD. AB - Gene by environment (GxE) interaction studies have investigated the influence of a number of candidate genes and variants for major depressive disorder (MDD) on the association between childhood trauma and MDD. Most of these studies are hypothesis driven and investigate only a limited number of SNPs in relevant pathways using differing methodological approaches. Here (1) we identified 27 genes and 268 SNPs previously associated with MDD or with GxE interaction in MDD and (2) analyzed their impact on GxE in MDD using a common approach in 3944 subjects of European ancestry from the Psychiatric Genomics Consortium who had completed the Childhood Trauma Questionnaire. (3) We subsequently used the genome wide SNP data for a genome-wide case-control GxE model and GxE case-only analyses testing for an enrichment of associated SNPs. No genome-wide significant hits and no consistency among the signals of the different analytic approaches could be observed. This is the largest study for systematic GxE interaction analysis in MDD in subjects of European ancestry to date. Most of the known candidate genes/variants could not be supported. Thus, their impact on GxE interaction in MDD may be questionable. Our results underscore the need for larger samples, more extensive assessment of environmental exposures, and greater efforts to investigate new methodological approaches in GxE models for MDD. PMID- 29159867 TI - Computing sleep deficiency. AB - Sleep deficiency is a major public health concern. Since epidemiological studies play an important role in public health evaluations, this theoretical paper pursues answers to the question: 'How can we compute sleep deficiency as informative measures of exposures or doses in observational research?' Starting from the social jetlag concept and based on the chronodisruption rationale, we illustrate and discuss five approaches (one established and four untested, each with unique strengths and limitations) to quantify sleep deficiency by focusing on the timing and duration of sleep. Hitherto, social jetlag and chronodisruption rationale were neither explicitly proposed nor developed as assessments of sleep deficiency but, as we suggest, could potentially be utilized to this end. This first foray into computing sleep deficiency in epidemiological studies makes clear that laboratory, field and epidemiological collaboration is pre-requisite to elucidating potential (co-)causal roles of sleep deficiency in disease endpoints. PMID- 29159866 TI - Administration of adjuvant chemotherapy for stage II-III colon cancer patients: An European population-based study. AB - The advantage of adjuvant chemotherapy (ACT) for treating Stage III colon cancer patients is well established and widely accepted. However, many patients with Stage III colon cancer do not receive ACT. Moreover, there are controversies around the effectiveness of ACT for Stage II patients. We investigated the administration of ACT and its association with overall survival in resected Stage II (overall and stratified by low-/high-risk) and Stage III colon cancer patients in three European countries including The Netherlands (2009-2014), Belgium (2009 2013) and Sweden (2009-2014). Hazard ratios (HR) for death were obtained by Cox regression models adjusted for potential confounders. A total of 60244 resected colon cancer patients with pathological Stages II and III were analyzed. A small proportion (range 9-24%) of Stage II and over half (range 55-68%) of Stage III patients received ACT. Administration of ACT in Stages II and III tumors decreased with higher age of patients. Administration of ACT was significantly associated with higher overall survival in high-risk Stage II patients (in The Netherlands (HR; 95%CI = 0.82 (0.67-0.99), Belgium (0.73; 0.59-0.90) and Sweden (0.58; 0.44-0.75)), and in Stage III patients (in The Netherlands (0.47; 0.43 0.50), Belgium (0.46; 0.41-0.50) and Sweden (0.48; 0.43-0.54)). In Stage III, results were consistent across subgroups including elderly patients. Our results show an association of ACT with higher survival among Stage III and high-risk Stage II colon cancer patients. Further investigations are needed on the selection criteria of Stages II and III colon cancer patients for ACT. PMID- 29159868 TI - Tarsal-carpal coalition syndrome: Report of a novel missense mutation in NOG gene and phenotypic delineation. AB - We report a family of Indian origin presenting with Tarsal-carpal coalition syndrome (TCC), which is a rare genetic disorder of skeletal abnormalities, inherited in autosomal dominant manner. In this family, three individuals (mother and two children) were found to be similarly affected with slight intrafamilial individual variability in the phenotype. Sanger sequencing revealed a novel heterozygous missense mutation in NOG gene (NM_005450.4:c.611G>A) in all the affected individuals of the family. Until now only six mutations have been reported in different families affected with TCC syndrome worldwide. This report further delineates the phenotypic spectrum of this rare disorder with the addition of a new variant to the mutation spectrum. PMID- 29159869 TI - Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor-dependent sensory long-term facilitation in naive carotid bodies. AB - KEY POINTS: Activity-dependent plasticity can be induced in carotid body (CB) chemosensory afferents without chronic intermittent hypoxia (CIH) preconditioning by acute intermittent hypoxia coincident with bouts of hypercapnia (AIH-Hc). Several properties of this acute plasticity are shared with CIH-dependent sensory long-term facilitation (LTF) in that induction is dependent on 5-HT, angiotensin II, protein kinase C and reactive oxygen species. Several properties differ from CIH-dependent sensory LTF; H2 O2 appears to play no part in induction, whereas maintenance requires purinergic P2X2/3 receptor activation and is dependent on transient receptor potential vanilloid type 1 (TRPV1) receptor sensitization. Because P2X2/3 and TRPV1 receptors are located in carotid sinus nerve (CSN) terminals but not presynaptic glomus cells, a primary site of the acute AIH-Hc induced sensory LTF appears to be postsynaptic. Our results obtained in vivo suggest a role for TRPV1-dependent CB activity in acute sympathetic LTF. We propose that P2X-TRPV1-receptor-dependent sensory LTF may constitute an important early mechanism linking sleep apnoea with hypertension and/or cardiovascular disease. ABSTRACT: Apnoeas constitute an acute existential threat to neonates and adults. In large part, this threat is detected by the carotid bodies, which are the primary peripheral chemoreceptors, and is combatted by arousal and acute cardiorespiratory responses, including increased sympathetic output. Similar responses occur with repeated apnoeas but they continue beyond the last apnoea and can persist for hours [i.e. ventilatory and sympathetic long-term facilitation (LTF)]. These long-term effects may be adaptive during acute episodic apnoea, although they may prolong hypertension causing chronic cardiovascular impairment. We report a novel mechanism of acute carotid body (CB) plasticity (sensory LTF) induced by repeated apnoea-like stimuli [i.e. acute intermittent hypoxia coincident with bouts of hypercapnia (AIH-Hc)]. This plasticity did not require chronic intermittent hypoxia preconditioning, was dependent on P2X receptors and protein kinase C, and involved heat-sensitive transient receptor potential vanilloid type 1 (TRPV1) receptors. Reactive oxygen species (O2 .-) were involved in initiating plasticity only; no evidence was found for H2 O2 involvement. Angiotensin II and 5-HT receptor antagonists, losartan and ketanserin, severely reduced CB responses to individual hypoxic hypercapnic challenges and prevented the induction of sensory LTF but, if applied after AIH-Hc, failed to reduce plasticity-associated activity. Conversely, TRPV1 receptor antagonism had no effect on responses to individual hypoxic-hypercapnic challenges but reduced plasticity-associated activity by ~50%. Further, TRPV1 receptor antagonism in vivo reduced sympathetic LTF caused by AIH-Hc, although only if the CBs were functional. These data demonstrate a new mechanism of CB plasticity and suggest P2X-TRPV1-dependent sensory LTF as a novel target for pharmacological intervention in some forms of neurogenic hypertension associated with recurrent apnoeas. PMID- 29159871 TI - Immunodeficiency in CHARGE syndrome. AB - Immunodeficiency can occur in CHARGE syndrome, with immunophenotypes including reduction in T-cell counts, combined T-B cell defects rarely requiring antibiotic prophylaxis or immunoglobulin replacement, and severe combined immunodeficiency, which is fatal without immune reconstitution. However, the prevalence of immunodeficiency in CHARGE syndrome remains unclear with few prospective studies. In this review, we examine the existing literature covering immunodeficiency associated with CHARGE syndrome, compare these with immunodeficiencies reported in 22q11.2 deletion syndrome (a condition that shares many phenotypic characteristics with CHARGE syndrome) and suggest future research priorities. PMID- 29159870 TI - Predictive hyperglycemia and hypoglycemia minimization: In-home double-blind randomized controlled evaluation in children and young adolescents. AB - OBJECTIVE: The primary objective of this trial was to evaluate the feasibility, safety, and efficacy of a predictive hyperglycemia and hypoglycemia minimization (PHHM) system vs predictive low glucose suspension (PLGS) alone in optimizing overnight glucose control in children 6 to 14 years old. RESEARCH DESIGN AND METHODS: Twenty-eight participants 6 to 14 years old with T1D duration >=1 year with daily insulin therapy >=12 months and on insulin pump therapy for >=6 months were randomized per night into PHHM mode or PLGS-only mode for 42 nights. The primary outcome was percentage of time in sensor-measured range 70 to 180 mg/dL in the overnight period. RESULTS: The addition of automated insulin delivery with PHHM increased time in target range (70-180 mg/dL) from 66 +/- 11% during PLGS nights to 76 +/- 9% during PHHM nights (P<.001), without increasing hypoglycemia as measured by time below various thresholds. Average morning blood glucose improved from 176 +/- 28 mg/dL following PLGS nights to 154 +/- 19 mg/dL following PHHM nights (P<.001). CONCLUSIONS: The PHHM system was effective in optimizing overnight glycemic control, significantly increasing time in range, lowering mean glucose, and decreasing glycemic variability compared to PLGS alone in children 6 to 14 years old. PMID- 29159872 TI - The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas? AB - One of the hallmarks of cancer cells is the increased ability to acquire nutrients, particularly glucose and glutamine. Proliferating cells need precursors for cell growth and NADPH reducing equivalents for survival. The principal responsible for glucose uptake is facilitative glucose transporters (GLUTs), which usually are overexpressed in cancer cells. Besides their role in glucose uptake, GLUT transporters are able to transport other compounds such as dehydroascorbic acid or uric acid. They play a major role in tumor progression and cellular processes such as regulated cell death. The prostate gland has the particular characteristic of being more glycolytic than other non-pathological tissues given an accumulation of citrate in the seminal fluid and the inhibition of m-aconitase that affects to tricarboxylic acid cycle. In prostate cancer (PCa), androgens increase glucose uptake, upregulate GLUT transporters such as GLUT1 and GLUT3 and stimulate AMP-activated protein kinase pathway, suggesting a possible connection between glycolytic and androgenic signaling. Interestingly, diabetes is not a risk factor for PCa, as it is in other cancers, while insulin stimulates progression and insulin-like growth factor 1 pathway plays an important role in PCa progression. It was recently found that PCa cells overexpress GLUT4 and, more importantly, that it seems to be related to the castration-resistant prostate cancer (CRPC) phenotype, although little is known about its participation in tumor progression. This review will focus on the role of GLUT transporters along with PCa progression, and the involvement of GLUT4 on CRPC phenotype transition would be considered. PMID- 29159873 TI - Orthopaedic manifestations within the 22q11.2 Deletion syndrome: A systematic review. AB - The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome with an estimated prevalence of 1:4,000 live births. 22q11.2DS is known to have wide phenotypic variability, including orthopaedic manifestations. The purpose of this systematic review is to increase the awareness of orthopaedic manifestations associated with 22q11.2DS. This systematic review was performed according to the PRISMA Guidelines. Original epidemiological studies on the prevalence of orthopaedic manifestations within 22q11.2DS were systematically searched for in PubMed and EMBASE. The included articles were scored according to a risk-of-bias tool, a best-evidence synthesis was performed and the prevalence data was extracted. Sixty-nine published manuscripts described 58 orthopaedic manifestations in a total of 6,055 patients. The prevalence of at least one cervical or occipital anomaly is 90.5-100% (strong evidence). Fourteen studies (n = 2,264) revealed moderate evidence for a wide scoliosis prevalence of 0.6-60%. Two studies demonstrated that 5-6.4% of all 22q11.2DS patients required surgical scoliosis correction. Fifteen studies (n = 2,115) reported a 1.1-13.3% prevalence of clubfoot with moderate evidence. Other reported orthopaedic manifestations are patellar dislocation (10-20%), juvenile rheumatic arthritis (3.75%), impaired growth and skeletal anomalies like polydactyly (1.0-3.7%), syndactyly (11-11.8%), butterfly vertebrae (11.1%) and 13 ribs (2-19%). Orthopaedic findings are important manifestations of the 22q11.2DS, both in bringing patients to diagnostic attention and in requiring surveillance and appropriate intervention. Data on these manifestations are scattered and incomprehensive. Routinely screening for cervical anomalies, scoliosis, and upper and lower limb malformations is recommended in this vulnerable group of patients. PMID- 29159874 TI - Meta-Synthesis on Migraine Management. AB - BACKGROUND: Migraine is one of the top 10 most disabling conditions among adults worldwide. Most migraine research is quantitative and indicates concerns about medication adherence, stigma, and more. Qualitative studies might reveal an improved understanding of migraine patients' perspectives regarding migraine treatment. OBJECTIVE: The aim of this study was to synthesize the qualitative research on migraine patients' perspectives regarding migraine treatment to (a) identify common patterns across various types of migraine treatment studies and (b) inform future research. METHODS: A systematic search for qualitative studies in the HA (HA) literature was conducted in Medline (PubMed), PsycINFO, EMBASE, CINAHL, Web of Science, Joanna Briggs Institute EBP Database, and The Cochrane Library. Search terms (subject headings and keywords) were HA, HA disorders, migraine, qualitative studies, and qualitative research. Qualitative studies were systematically identified by using published qualitative search filters recommended by The InterTASC Information Specialists' Sub-Group (ISSG). The search was limited to English only, peer reviewed publications, and studies published between 1996 and 2016. For screening, additional inclusion criteria were (1) adult migraine patients; (2) must mention treatment in the title or study design of the abstract. Ten studies met the inclusion criteria. The Critical Appraisal Skills Program tool was applied to appraise study quality. Thematic analysis produced the codes and themes. Two authors read articles separately and individually created codes. Code lists were synthesized and themes emerged iteratively from the process. RESULTS: Study sample sizes ranged from 10 to 33 participants, with our findings representing 161 participants. Data were collected either using interviews or focus groups. The more common methodologies were grounded theory and phenomenology. Few (3) studies described the number of headache (HA) days for inclusion in the study. Eight out of 10 used International Classification of Headache Disorders (ICHD) criteria. Our synthesis produced five major themes. The first theme was "Migraine patients' difficulties with health care utilization," and it included issues surrounding the cost of migraine treatment (seeing providers and prescription medications). The second theme was "Migraine patients' perceived relationships with their providers," which included the role and relationship with the provider, as well as trust in the provider and the providers' knowledge in managing HAs. The third theme was "Thoughts about the various migraine treatments." It was based on patients' comments indicating an aversion to prescription medications, the use of non-pharmacological interventions for treatment, behavioral modification as a form of treatment, and the need for additional treatment options. The fourth and fifth themes were "Understanding diagnosis/triggers" and "Societal implications," respectively. The latter theme included feelings of not being taken seriously and issues surrounding quality of life. DISCUSSION: The metasynthesis revealed several key commonalities regarding patients' perspectives on migraine treatment and identified new areas for research using a qualitative approach. Researchers conducting qualitative research with patients experiencing migraines might consider using and reporting more of the inclusion and exclusion criteria commonly used in migraine research, for example, reporting whether the ICHD criteria were used and the number of HA days for patients to be in a study. Future studies might be done to determine how the role of allied health care providers, for example, pharmacists, physical therapists, and psychologists, might be expanded to help with migraine treatment and ultimately to improve patient outcomes. PMID- 29159875 TI - Renal hypoxia in kidney disease: Cause or consequence? AB - Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute kidney injury (AKI), initiating and propagating a vicious cycle of tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (i) Is kidney disease always associated with tissue hypoxia? (ii) Does tissue hypoxia drive signalling cascades that lead to tissue damage and dysfunction? (iii) Does tissue hypoxia per se lead to kidney disease? (iv) Does tissue hypoxia precede pathology? (v) Does tissue hypoxia colocalize with pathology? (vi) Does prevention of tissue hypoxia prevent kidney disease? We conclude that tissue hypoxia is a common feature of both AKI and CKD. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signalling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. colocalization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a "common pathway" to both AKI and CKD still remains to be adequately tested. PMID- 29159876 TI - Work-related injuries in the Alaska logging industry, 1991-2014. AB - BACKGROUND: Although loggers in Alaska are at high risk for occupational injury, no comprehensive review of such injuries has been performed since the mid-1990s. We investigated work-related injuries in the Alaska logging industry during 1991 2014. METHODS: Using data from the Alaska Trauma Registry and the Alaska Occupational Injury Surveillance System, we described fatal and nonfatal injuries by factors including worker sex and age, timing and geographic location of injuries, and four injury characteristics. Annual injury rates and associated 5 year simple moving averages were calculated. RESULTS: We identified an increase in the 5-year simple moving averages of fatal injury rates beginning around 2005. While injury characteristics were largely consistent between the first 14 and most recent 10 years of the investigation, the size of logging companies declined significantly between these periods. CONCLUSIONS: Factors associated with declines in the size of Alaska logging companies might have contributed to the observed increase in fatal injury rates. PMID- 29159877 TI - Crystalline structure of pulverized dental calculus induces cell death in oral epithelial cells. AB - BACKGROUND AND OBJECTIVE: Dental calculus is a mineralized deposit attached to the tooth surface. We have shown that cellular uptake of dental calculus triggers nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, leading to the processing of the interleukin-1beta precursor into its mature form in mouse and human phagocytes. The activation of the NLRP3 inflammasome also induced a lytic form of programmed cell death, pyroptosis, in these cells. However, the effects of dental calculus on other cell types in periodontal tissue have not been investigated. The aim of this study was to determine whether dental calculus can induce cell death in oral epithelial cells. MATERIAL AND METHODS: HSC-2 human oral squamous carcinoma cells, HOMK107 human primary oral epithelial cells and immortalized mouse macrophages were exposed to dental calculus or 1 of its components, hydroxyapatite crystals. For inhibition assays, the cells were exposed to dental calculus in the presence or absence of cytochalasin D (endocytosis inhibitor), z YVAD-fmk (caspase-1 inhibitor) or glyburide (NLRP3 inflammasome inhibitor). Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release and staining with propidium iodide. Tumor necrosis factor-alpha production was quantified by enzyme-linked immunosorbent assay. Oral epithelial barrier function was examined by permeability assay. RESULTS: Dental calculus induced cell death in HSC-2 cells, as judged by LDH release and propidium iodide staining. Dental calculus also induced LDH release from HOMK107 cells. Following heat treatment, dental calculus lost its capacity to induce tumor necrosis factor-alpha in mouse macrophages, but could induce LDH release in HSC-2 cells, indicating a major role of inorganic components in cell death. Hydroxyapatite crystals also induced cell death in both HSC-2 and HOMK107 cells, as judged by LDH release, indicating the capacity of crystal particles to induce cell death. Cell death induced by dental calculus was significantly inhibited by cytochalasin D, z-YVAD-fmk and glyburide, indicating NLRP3 inflammasome involvement. In permeability assays, dental calculus attenuated the barrier function of HSC-2 cell monolayers. CONCLUSION: Dental calculus induces pyroptotic cell death in human oral epithelial cells and the crystalline structure plays a major role in this process. Oral epithelial cell death induced by dental calculus might be important for the etiology of periodontitis. PMID- 29159878 TI - Arsenobetaine: an ecophysiologically important organoarsenical confers cytoprotection against osmotic stress and growth temperature extremes. AB - Arsenic, a highly cytotoxic and cancerogenic metalloid, is brought into the biosphere through geochemical sources and anthropogenic activities. A global biogeochemical arsenic biotransformation cycle exists in which inorganic arsenic species are transformed into organoarsenicals, which are subsequently mineralized again into inorganic arsenic compounds. Microorganisms contribute to this biotransformation process greatly and one of the organoarsenicals synthesized and degraded in this cycle is arsenobetaine. Its nitrogen-containing homologue glycine betaine is probably the most frequently used compatible solute on Earth. Arsenobetaine is found in marine and terrestrial habitats and even in deep-sea hydrothermal vent ecosystems. Despite its ubiquitous occurrence, the biological function of arsenobetaine has not been comprehensively addressed. Using Bacillus subtilis as a well-understood platform for the study of microbial osmostress adjustment systems, we ascribe here to arsenobetaine both a protective function against high osmolarity and a cytoprotective role against extremes in low and high growth temperatures. We define a biosynthetic route for arsenobetaine from the precursor arsenocholine that relies on enzymes and genetic regulatory circuits for glycine betaine formation from choline, identify the uptake systems for arsenobetaine and arsenocholine, and describe crystal structures of ligand binding proteins from the OpuA and OpuB ABC transporters complexed with either arsenobetaine or arsenocholine. PMID- 29159879 TI - New insights into pemphigoid diseases. PMID- 29159880 TI - Swim bladder mycosis in pretty tetra (Hemigrammus pulcher) caused by Exophiala pisciphila and Phaeophleospora hymenocallidicola, and experimental verification of pathogenicity. AB - Spontaneous invasive and chronic disseminated mycosis affected Hemigrammus pulcher kept in a public aquarium, and infection was manifested by inappetence, exophthalmia, erratic swimming, eroded scales, anaemia of the gills and abdominal distension. Internally, there was a grossly swollen swim bladder with a thickened wall filled with a dark mass. The body cavities contained a clear, light amber fluid and a swollen intestine which was full of a watery fluid containing small gas bubbles. Histopathology revealed a granulomatous inflammatory response with fungal hyphae in the lumen and wall of the swim bladder, hepatopancreas, spleen and kidneys with signs of nephrohydrosis. Exophiala pisciphila and Phaeophleospora hymenocallidicola were isolated from the swim bladder, abdominal cavity and gastrointestinal tract. The exogenous source of infection was probably the ample wooden decoration and plants inside the aquarium. Koch's postulates were fulfilled by re-isolation of both fungal species from fish artificially infected under laboratory conditions. As P. hymenocallidicola is less capable of defence against phagocytosis, E. pisciphila probably played a major role. Severe clinical manifestations with 100% mortality developed in two fish species infected by E. pisciphila. A significant increase in the plasma levels of amino acids was observed as a result of the activation of proteolysis. PMID- 29159881 TI - Characterization of photon-counting multislit breast tomosynthesis. AB - PURPOSE: It has been shown that breast tomosynthesis may improve sensitivity and specificity compared to two-dimensional mammography, resulting in increased detection-rate of cancers or lowered call-back rates. The purpose of this study is to characterize a spectral photon-counting multislit breast tomosynthesis system that is able to do single-scan spectral imaging with multiple collimated x ray beams. The system differs in many aspects compared to conventional tomosynthesis using energy-integrating flat-panel detectors. METHODS: The investigated system was a prototype consisting of a dual-threshold photon counting detector with 21 collimated line detectors scanning across the compressed breast. A review of the system is done in terms of detector, acquisition geometry, and reconstruction methods. Three reconstruction methods were used, simple back-projection, filtered back-projection and an iterative algebraic reconstruction technique. The image quality was evaluated by measuring the modulation transfer-function (MTF), normalized noise-power spectrum, detective quantum-efficiency (DQE), and artifact spread-function (ASF) on reconstructed spectral tomosynthesis images for a total-energy bin (defined by a low-energy threshold calibrated to remove electronic noise) and for a high-energy bin (with a threshold calibrated to split the spectrum in roughly equal parts). Acquisition was performed using a 29 kVp W/Al x-ray spectrum at a 0.24 mGy exposure. RESULTS: The difference in MTF between the two energy bins was negligible, that is, there was no energy dependence on resolution. The MTF dropped to 50% at 1.5 lp/mm to 2.3 lp/mm in the scan direction and 2.4 lp/mm to 3.3 lp/mm in the slit direction, depending on the reconstruction method. The full width at half maximum of the ASF was found to range from 13.8 mm to 18.0 mm for the different reconstruction methods. The zero-frequency DQE of the system was found to be 0.72. The fraction of counts in the high-energy bin was measured to be 59% of the total detected spectrum. Scantimes ranged from 4 s to 16.5 s depending on voltage and current settings. CONCLUSIONS: The characterized system generates spectral tomosynthesis images with a dual-energy photon-counting detector. Measurements show a high DQE, enabling high image quality at a low dose, which is beneficial for low-dose applications such as screening. The single scan spectral images open up for applications such as quantitative material decomposition and contrast-enhanced tomosynthesis. PMID- 29159882 TI - Cardiotocography versus intermittent auscultation of foetal heart on admission to labour ward for assessment of foetal wellbeing. PMID- 29159883 TI - Phase-sensitive B1 mapping: Effects of relaxation and RF spoiling. AB - PURPOSE: To develop a phase-based B1 mapping technique accounting for the effects of imperfect RF spoiling and magnetization relaxation. THEORY AND METHODS: The technique is based on a multi-gradient-echo sequence with 2 successive orthogonal radiofrequency (RF) excitation pulses followed by the train of gradient echoes measurements. We have derived a theoretical expression relating the MR signal phase produced by the 2 successive RF pulses to the B1 field and B0 -related frequency shift. The expression takes into account effects of imperfections of RF spoiling and T1 and T2* relaxations. RESULTS: Our computer simulations and experiments revealed that imperfections of RF spoiling cause significant errors in B1 mapping if not accounted for. By accounting for these effects along with effects of magnetization relaxation and frequency shift, we demonstrated the high accuracy of our approach. The technique has been tested on spherical phantoms and a healthy volunteer. CONCLUSION: In this paper, we have proposed, implemented, and demonstrated the accuracy of a new phase-based technique for fast and robust B1 mapping based on the measured MR signal phase, frequency, and relaxation. Because imperfect RF spoiling effects are accounted for, this technique can be applied with short TRs and therefore substantially reduces the scan time. Magn Reson Med 80:101-111, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29159884 TI - Serum homocysteine levels in acne patients. AB - OBJECTIVE: This study was designed to investigate serum homocysteine (HCY) levels in acne patients. METHODS: Acne patients (n = 124) and healthy volunteers (n = 70), matched in terms of both age and sex, were enrolled. Serum HCY levels for all subjects were measured by a clinical laboratory. RESULTS: Serum HCY levels in male and female patients with severe and moderate acne were significantly higher than in the healthy control group (P < .05). The constituent ratio of male and female acne patients with HCY above the normal range (10 mmol/L) was significantly higher than the healthy control group. The severity of acne patients was positively correlated with serum homocysteine concentration, (P < .01). CONCLUSION: Hyperhomocysteinemia may be an independent risk factor for acne vulgaris. Detection of serum HCY is important for acne patients. PMID- 29159885 TI - Two-stage ionoacoustic range verification leveraging Monte Carlo and acoustic simulations to stably account for tissue inhomogeneity and accelerator-specific time structure - A simulation study. AB - PURPOSE: Range errors constrain treatment planning by limiting choice of ion beam angles and requiring large margins. Ionoacoustic range verification requires recovering the location of an acoustic source from low frequency signals. A priori information is applied to stably overcome resolution limits of inverse acoustic source imaging in this simulation study. In particular, the accuracy and robustness of ionoacoustic range verification for lateral and oblique delivery of high-energy protons to the prostate is examined. METHODS: Dose maps were computed using GEANT4 Monte Carlo simulations via the TOPAS user interface. Thermoacoustic pulses were propagated using k-Wave software, with initial pressures corresponding to instantaneous dose deposition and piecewise constant maps of tissue properties derived from the planning CT. A database of dose maps with corresponding thermoacoustic emissions and Bragg peak locations, referred to as "control points," were precomputed. Corresponding thermoacoustic emissions were also precomputed. Pulses were recorded at four coplanar locations corresponding to the outer surface of a virtual transrectal array. To model experimental beam delivery, k-Wave results were convolved in time with a Gaussian envelope to account for noninstantaneous proton delivery by a synchrocyclotron. Thermoacoustic pulses were bandlimited below 150 kHz, and amplitudes were directly proportional to charge delivered. To test robustness of our method, white noise was added. Range was estimated in a two-step process. The first step obtained a preliminary range estimate by one-way beamforming. The second step was taken using data corresponding to the "control point" nearest to the preliminary range estimate. For each receiver, the time of flight difference, ?t, between the measured and control thermoacoustic signals were accurately estimated by applying the Fourier shift theorem. Receiver-Bragg peak distance was then estimated by adding vs ?t to the known distance of the control point, where vs is soundspeed. A linear system of equations based upon all receiver locations and distances was solved to recover the Bragg peak location. All simulations were performed relative to the planning CT. Because ultrasound (US) images were not available, results were overlaid onto the planning CT. RESULTS: Beamformed estimates from noise-free data tracked all beam locations within 1 cm. Final estimates for oblique and lateral beams were accurate to within 1.0 and 1.6 mm respectively. Average errors of final range estimates for oblique beams from data with SNR = 0 dB were no greater than 2.0 mm. CONCLUSIONS: Ionoacoustic range verification may improve current practice. Ionoacoustic range estimates can be inherently co registered to ultrasound images of underlying anatomy. To ensure estimates are robust in clinical practice, dose maps based upon the planning CT should be overlaid onto ultrasound volumes acquired at time of treatment and acoustic simulations re-computed to provide a database of control points and corresponding thermoacoustic emissions. Computation times for beamformed estimates are already fast enough for online range verification, but are not accurate enough for a measurement aperture limited to the surface of a transrectal ultrasound probe. Accelerated acoustic simulations will be required to enable online two-stage correction, but offline calculation is already suitable for adaptive planning. PMID- 29159886 TI - Radiomics in lung cancer: Its time is here. PMID- 29159887 TI - Bioderived Muconates by Cross-Metathesis and Their Conversion into Terephthalates. AB - Polyethylene terephthalate that is 100 % bioderived is in high demand in the market guided by the ever-more exigent sustainability regulations with the challenge of producing renewable terephthalic acid remaining. Renewable terephthalic acid or its precursors can be obtained by Diels-Alder cycloaddition and further dehydrogenation of biomass-derived muconic acid. The cis,cis isomer of the dicarboxylic acid is typically synthesized by fermentation with genetically modified microorganisms, a process that requires complex separations to obtain a high yield of the pure product. Furthermore, the cis isomer has to be transformed into the trans,trans form and has to be esterified before it is suitable for terephthalate synthesis. To overcome these challenges, we investigated the synthesis of dialkyl muconates by cross-metathesis. The Ru catalyzed cross-coupling of sorbates with acrylates, which can be bioderived, proceeded selectively to yield diester muconates in up to 41 % yield by using very low catalyst amounts (0.5-3.0 mol %) and no solvent. In the optimized procedure, the muconate precipitated as a solid and was easily recovered from the reaction medium. Analysis by GC-MS and NMR spectroscopy showed that this method delivered exclusively the trans,trans isomer of dimethyl muconate. The Diels Alder reaction of dimethyl muconate with ethylene was studied in various solvents to obtain 1,4-bis(carbomethoxy)cyclohexene. The cycloaddition proceeded with very high conversions (77-100 %) and yields (70-98 %) in all of the solvents investigated, and methanol and tetrahydrofuran were the best choices. Next, the aromatization of 1,4-bis(carbomethoxy)cyclohexene to dimethyl terephthalate over a Pd/C catalyst resulted in up to 70 % yield in tetrahydrofuran under an air atmosphere. Owing to the high yield of the reaction of dimethyl muconate to 1,4 bis(carbomethoxy)cyclohexene, no separation step was needed before the aromatization. This is the first time that cross-metathesis is used to produce bioderived trans,trans-muconates as precursors to renewable terephthalates, important building blocks in the polymer industry. PMID- 29159888 TI - Salivary alpha-amylase as a marker of stress reduction in individuals with intellectual disability and autism in response to occupational and music therapy. AB - BACKGROUND: Although the benefits of a range of disability-centric therapies have been well studied, little remains known about how they work, let alone how to monitor these benefits in a precise and reliable way. METHODS: Here, in two independent studies, we examine how sessions consisting of occupational or music therapy, both widely recognised for their effectiveness, modulate levels of salivary alpha-amylase (sAA), a now time- and cost-efficient marker of stress, in individuals with intellectual disability and autism spectrum disorder. Pre session and post-session levels of sAA were compared in both groups in response to therapy and control sessions. RESULTS: In comparison to control sessions, occupational therapy significantly dampened rises in sAA levels while music therapy significantly decreased baseline sAA levels, highlighting the ability of both types of therapy to reduce stress and by proxy contribute to enhancing overall well-being. CONCLUSIONS: Not only do these results confirm the stress reducing nature of two types of multisensory therapy, but they support the use of sAA as a potential tool for evaluating stress levels in individuals with intellectual disability and autism spectrum disorder, providing an important physiological lens that may guide strategies in clinical and non-clinical care for individuals with disabilities. PMID- 29159889 TI - A systematic surveillance programme for infectious salmon anaemia virus supports its absence in the Pacific Northwest of the United States. AB - In response to reported findings of infectious salmon anaemia virus (ISAV) in British Columbia (BC), Canada, in 2011, U.S. national, state and tribal fisheries managers and fish health specialists developed and implemented a collaborative ISAV surveillance plan for the Pacific Northwest region of the United States. Accordingly, over a 3-1/2-year period, 4,962 salmonids were sampled and successfully tested by real-time reverse-transcription PCR. The sample set included multiple tissues from free-ranging Pacific salmonids from coastal regions of Alaska and Washington and farmed Atlantic salmon (Salmo salar L.) from Washington, all representing fish exposed to marine environments. The survey design targeted physiologically compromised or moribund animals more vulnerable to infection as well as species considered susceptible to ISAV. Samples were handled with a documented chain of custody and testing protocols, and criteria for interpretation of test results were defined in advance. All 4,962 completed tests were negative for ISAV RNA. Results of this surveillance effort provide sound evidence to support the absence of ISAV in represented populations of free ranging and marine-farmed salmonids on the northwest coast of the United States. PMID- 29159890 TI - Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental retardation, ptosis, and polydactyly. AB - Intellectual disability (ID) refers to deficits in mental abilities, social behavior, and motor skills to perform activities of daily living as compared to peers. Numerous genetic and environmental factors may be responsible for ID. We report on elucidation of molecular basis for syndromic ID associated with ptosis, polydactyly, and MRI features suggestive of Joubert syndrome using homozygosity mapping followed by exome sequencing. The analysis revealed a novel synonymous variation p.T293T (c.879G>A) which leads to a splicing defect in ARMC9 gene. The variant is present in conserved region of ARM domain of ARMC9 protein, which is predicted to form a platform for protein interaction. This domain is likely to be altered in patient due to splicing defect caused by this synonymous variation. Our report of variant in ARMC9 Leading to Joubert syndrome phenotype (JS30), elucidates the genetic heterogeneity of Joubert syndrome, and expands the gene list for ciliopathies. PMID- 29159891 TI - The experience of sexuality in adults with intellectual disability. AB - BACKGROUND: People with intellectual disability have the same sexual needs as those without any disability, yet their sexuality is often restricted by reluctant attitudes and/or fears based on irrational beliefs. The aim of this study is to describe and analyse different areas of sexuality in adults with mild or moderate intellectual disability. METHOD: The sample consisted of 180 men and 180 women attending occupational centres. All the participants were administered a questionnaire about sexuality adapted to their characteristics. RESULTS: Results show that 84.2% have had sexual relationships with another person, this percentage being higher in females and in people aged between 38 and 55 years old. Condoms are used by 41.4%. The most frequently used contraceptive methods are the pill (39.6%), transdermal patch (30.2%) and intrauterine device (6.7%). 9.4% of the women and 2.8% of the men has experienced sexual abuse. CONCLUSION: In conclusion, there is a need to draw up educational programmes, differentiated according to gender and adapted to their reality, which include contents related with sexual health, sexual abuse and condom use. PMID- 29159892 TI - Reliability of body-weight scalars on the assessment of propofol induction dose in obese patients. AB - BACKGROUND: Obese patients require specific perioperative care when compared with non-obese patients. The present study aimed to analyse the ability of size descriptors to estimate propofol induction dose in class II and III obese patients. METHODS: A cross-sectional study on adult patients with body mass index (BMI) equal to or greater than 35 kg/m2 and on adult patients with BMI lower than 35 kg/m2 was carried out. General anaesthesia was induced with remifentanil, propofol and rocuronium. Propofol infusion was started at 2000 mg/h until loss of consciousness. Bioelectrical impedance analysis and Brice modified interview was completed during pre- and post-operative evaluation, respectively. Measurements of propofol plasma concentration were performed using gas chromatography/ion trap mass spectrometry. RESULTS: Forty patients were enrolled in the study. The median values of fat free mass (FFM) in BMI < 35 kg/m2 and BMI >= 35 kg/m2 groups were 70% and 55% of total body weight, respectively. Our results did not demonstrate a strong correlation level between the studied size descriptors and propofol induction dose in both groups. Nevertheless, when propofol doses were normalized by FFM, an apparent convergence of the empirical cumulative distribution functions was observed. CONCLUSION: None of the size descriptors was seen to be an effective predictor of the propofol induction dose in class II and III obese patients when a fixed infusion rate was used. Due to the observed variability between patients, guiding propofol induction dose against a clinical endpoint of unconsciousness appears more appropriate in order to avoid side effects related both with under or overdosing of propofol. PMID- 29159893 TI - Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease. AB - BACKGROUND: Therapeutic drug monitoring may optimize therapy for Crohn's disease (CD). AIM: To use a population pharmacokinetic model that accounts for the time varying nature of covariates to simulate certolizumab pegol (CZP) concentrations to evaluate the exposure-response relationship for CZP in Crohn's disease. METHODS: Adults (N = 2157) with Crohn's disease were treated with CZP in nine clinical trials. Simulated CZP concentrations were compared to outcomes at weeks 6 and 26, including Crohn's disease activity index (CDAI) response (decrease from baseline >= 100 points), remission (CDAI <= 150), C-reactive protein (CRP) <= 5 mg/L, faecal calprotectin (FC) <= 250 MUg/g, and a composite endpoint of CDAI <= 150 and FC <= 250 MUg/g. Multivariable analyses identified covariates associated with outcomes and receiver operating characteristic analyses determined optimal CZP concentrations. RESULTS: CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical response, remission, CRP <= 5 mg/L or FC <= 250 MUg/g at week 6 than without. In multivariable analyses, higher CZP concentrations at week 6 were associated with the composite outcome at weeks 6 and 26 (P < .001). Although the exposure-response relationship varied among patients, approximate CZP concentrations of at least 36.1 MUg/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 MUg/mL (PPV 28.0% and NPV 90.4%) at weeks 6 and 12 were associated with weeks 6 and 26 outcomes. CONCLUSIONS: An exposure-response relationship was apparent for CZP in Crohn's disease and achieving higher CZP concentrations may increase the likelihood of attaining efficacy outcomes, but this remains to be evaluated prospectively. PMID- 29159895 TI - Proliferation and differentiation of mesenchymal stem cells on scaffolds containing chitosan, calcium polyphosphate and pigeonite for bone tissue engineering. AB - OBJECTIVES: Treatment of critical-sized bone defects with cells and biomaterials offers an efficient alternative to traditional bone grafts. Chitosan (CS) is a natural biopolymer that acts as a scaffold in bone tissue engineering (BTE). Polyphosphate (PolyP), recently identified as an inorganic polymer, acts as a potential bone morphogenetic material, whereas pigeonite (Pg) is a novel iron containing ceramic. In this study, we prepared and characterized scaffolds containing CS, calcium polyphosphate (CaPP) and Pg particles for bone formation in vitro and in vivo. MATERIALS AND METHODS: Chitosan/CaPP scaffolds and CS/CaPP scaffolds containing varied concentrations of Pg particles (0.25%, 0.5%, 0.75% and 1%) were prepared and characterized by SEM, XRD, EDAX, FT-IR, degradation, protein adsorption, mechanical strength and biomineralization studies. The cytocompatibility of these scaffolds with mouse mesenchymal stem cells (mMSCs, C3H10T1/2) was determined by MTT assay and fluorescence staining. Cell proliferation on scaffolds was assessed using MUSETM (Merck-Millipore, Germany) cell analyser. The effect of scaffolds on osteoblast differentiation at the cellular level was evaluated by Alizarin red (AR) and alkaline phosphatase (ALP) staining. At the molecular level, the expression of osteoblast differentiation marker genes such as Runt-related transcription factor-2 (Runx2), ALP, type I collagen-1 (Col-I) and osteocalcin (OC) was determined by real-time reverse transcriptase (RT-PCR) analysis. Bone regeneration was assessed by X-ray radiographs, SEM and EDAX analyses, and histological staining such as haematoxylin and eosin staining and Masson's trichrome staining (MTS) in a rat critical-sized tibial defect model system. RESULTS: The inclusion of iron containing Pg particles at 0.25% concentration in CS/CaPP scaffolds showed enhanced bioactivity by protein adsorption and biomineralization, compared with that shown by CS/CaPP scaffolds alone. Increased proliferation of mMSCs was observed with CS/CaPP/Pg scaffolds compared with control and CS/CaPP scaffolds. Increase in cell proliferation was accompanied by G0/G1 to G2/M phase transition with increased levels of cyclin(s) A, B and C. Pg particles in CS/CaPP scaffolds enhanced osteoblast differentiation at the cellular and molecular levels, as evidenced by increased calcium deposits, ALP activity and expression of osteoblast marker genes. In vivo implantation of scaffolds in rat critical-sized tibial defects displayed accelerated bone formation after 8 weeks. CONCLUSION: The current findings indicate that CS/CaPP scaffolds containing iron-containing Pg particles serve as an appropriate template to support proliferation and differentiation of MSCs to osteoblasts in vitro and bone formation in vivo and thus support their candidature for BTE applications. PMID- 29159896 TI - Comparisons of glyphosate adsorption properties of different functional Cr-based metal-organic frameworks. AB - A Cr-based metal-organic framework, namely, MIL-101(Cr), was modified with amino (NH2 -) and urea (UR2 -) groups, and the materials were evaluated as adsorbents for glyphosate, and a comparison with commercial activated carbon was also discussed. The effects of the adsorption factors, such as adsorbent concentration, adsorption time, pH and ionic strength were mainly investigated. The results showed that a pseudo-second-order rate equation described the adsorption kinetics mechanisms well, while the Langmuir model and the Freundlich model fitted different adsorption isotherms, respectively. Among the adsorbents we studied, NH2 -MIL-101(Cr) showed the maximum adsorbing capacity, which is 64.25 mg/g when pH = 3.0, while UR2 -MIL-101(Cr) did not reach the best adsorption performance due to the steric hindrance. The work opens up a new way for the modification of metal-organic frameworks for adsorption process. PMID- 29159897 TI - Identification and characterization of two variants of the Hfq-sRNA-chaperone in the fish pathogen Piscirickettsia salmonis. AB - Small RNA and chaperone proteins form synergistic duos that play pivotal roles in controlling gene expression in bacteria. This is the case for Hfq, a highly pleiotropic pretranslational modulator of general protein expression, which responds to harsh environmental conditions and influences fitness and virulence in a wide range of pathogenic Enterobacteria. Given this relevancy, we evaluated the presence and potential role of Hfq in the fish pathogen Piscirickettsia salmonis, a Gram-negative bacterium that threatens the sustainability of Chilean salmon production. Using bioinformatics tools were identified and characterized two variants of Hfq, which share the consensus RNA-binding domains and the active sites described functional Hfq other bacteria. Additionally, we demonstrated that hfq-1 and hfq-2 were transcriptionally active when growing in cell-free media and in infected susceptible fish cell line. Expression of both genes differed under different growth conditions and under stress, suggesting that their roles might be independent and different, depending on the bacterial physiological status. In conclusion, we demonstrate the existence of two different and functional ORF coding for the hfq marker in marine bacteria and a preliminary analysis indicating that these two novel proteins might have relevant roles in the biology and pathogenic potential of P. salmonis. PMID- 29159898 TI - Optimal number of multiple rapid swallows needed during high-resolution esophageal manometry for accurate prediction of contraction reserve. AB - BACKGROUND: Multiple rapid swallows (MRS) is a provocative test for assessment of contraction reserve, however reproducibility on repetitive MRS is incompletely understood. Our aim was to determine the optimal number of MRS sequences for consistent assessment of contraction reserve. METHODS: One hundred and fifty-nine consecutive patients (79 IEM and 80 normal motility) who underwent high resolution manometers were enrolled. Ten single swallows (SS) and 10 MRS were performed. Gold standard for evaluation of the contraction reserve was the ratio between the mean DCI of 10 MRS and the mean DCI of 10 SS (MRS/SS DCI ratio). Rates of false negatives and false positives were calculated for increasing numbers of MRS sequences, using either mean DCI or the MRS with the highest DCI. KEY RESULTS: According to the gold standard, 50 IEM and 50 normal motility patients had contraction reserve. With progressively increasing numbers of MRS sequences, contraction reserve was detected using mean MRS DCI within three and four MRS sequences in IEM and normal motility respectively, whereas two and three MRS sequences were needed using the MRS sequence with the highest DCI. False positives were much higher with highest DCI method compared with mean DCI, (22% vs 9% respectively in IEM; 24% vs 9% in normal motility) when three MRS sequences were considered. CONCLUSIONS & INFERENCES: At least three MRS are needed to reliably assess contraction reserve. The mean DCI of the three MRS sequences is the best variable to utilize as evidence of contraction reserve. PMID- 29159899 TI - Extremely Painful Multifocal Acquired Predominant Axonal Sensorimotor Neuropathy of the Upper Limb. AB - The differential diagnosis of upper extremity mononeuritis multiplex includes neuralgic amyotrophy, vasculitic neuropathy, and Lewis-Sumner syndrome. We describe 3 patients initially suspected of neuralgic amyotrophy, who had an extremely painful, protracted, progressive disease course, not fitting one of these established diagnoses. Nerve ultrasonography showed focal caliber changes of the roots, plexus, and limb nerves. Electromyography showed predominant multifocal axonopathy. Ongoing autoimmune neuropathy was suspected. Steroid treatment provided temporary relief, and intravenous immunoglobulin A sustained pain decrease and functional improvement. These patients appear to have extremely painful axonal inflammatory neuropathy, with a good response to immune-modulating treatment. PMID- 29159900 TI - p100 functions as a metastasis activator and is targeted by tumor suppressing microRNA-320a in lung cancer. AB - BACKGROUND: Lung cancer is among the most frequently diagnosed types of cancer worldwide, with high morbidity and mortality. Metastasis accounts for the deadliest and most poorly understood feature of lung cancer. Herein, we demonstrate that SND1 (also known as p100) acts as a candidate metastasis activator and is targeted by microRNA-320a (miR-320a) in lung cancer cells. METHODS: p100 expression in lung cancer cell lines and tissues was determined by quantitative real time-PCR and Western blot. RNA interference was applied to investigate the functions of p100 in lung cancer cell migration, reflected by wound healing and transwell assays. Luciferase reporter assay, quantitative real time-PCR, and Western blot were finally used to examine miR-320a targeting of p100 in lung cancer cells. RESULTS: p100 expression was significantly higher in lung cancer cell lines and tissues compared to normal human bronchial epithelial cells and matched normal lung tissues. Downregulation of p100 by RNA interference obviously inhibited lung cancer cell migration in vitro. Moreover, we validated p100 as a direct target of miR-320a, a tumor suppressing microRNA repressing lung cancer cell migration. Finally, we showed an inversely expressed correlation between p100 and miR-320a in tested lung cancer tissues and cell lines, both of which acted as important prognostic factors in lung cancer. CONCLUSION: Our findings identify that p100, targeted by tumor suppressing miR-320a, is a key metastasis activator in lung cancer, and both p100 and miR-320a could be considered as biomarkers for prognosis of lung cancer patients. PMID- 29159901 TI - Severe Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome beyond skin involvement. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but serious dermatologic diseases with many potential multisystem complications. We describe the case of an 8-year-old girl who developed severe SJS/TEN overlap syndrome (25% of her body surface area was affected) complicated by pancreatitis and bronchiolitis obliterans. These rare complications emphasize the need for careful, intensive monitoring of possible complications and an interdisciplinary team approach to provide optimal treatment and follow-up. PMID- 29159902 TI - Histamine-enhanced contractile responses of gastric smooth muscle via interstitial cells of Cajal in the Syrian hamster. AB - BACKGROUND: Gastric motility is controlled by the autonomic and enteric nervous systems and by interstitial cells of Cajal (ICCs). Although histamine is known to be released from enterochromaffin-like cells in the gastric mucosa, its regulatory roles in gastric motility are still controversial. Therefore, we investigated the functional roles of histamine in gastric motility. METHODS: Stomach preparations from hamsters were used because the stomach of hamsters can be easily separated into the forestomach and the glandular stomach. A whole preparation of the stomach was mounted in a Magnus tube, and mechanical responses were recorded using a force transducer. KEY RESULTS: Exogenous application of histamine had little effect on contractile activity of the glandular stomach. In contrast, the monoamine evoked regular, periodic contractions in the forestomach. An H1 receptor agonist reproduced the contractile responses and an H1 receptor antagonist blocked histamine-evoked contractions. Atropine and tetrodotoxin did not affect the histamine-evoked contractions. Pretreatment with drugs that inhibit the activity of ICCs abolished the effects of histamine. CONCLUSION & INFERENCES: The findings suggest that histamine regulates gastric motility by acting on ICCs via H1 receptors in the hamster. The remarkable ability of histamine to induce rhythmic contractions would be useful for treatment of gastric dysmotility. PMID- 29159904 TI - Growing into teen fatherhood: a grounded theory study. AB - BACKGROUND: Becoming an adolescent father is a significant and critical life event. Expectant fathers are faced with a concurrent dual developmental crisis: being an adolescent and becoming a father. This transition has a tremendous impact on these adolescents, their families and society. The impact on these individuals and society does not, at this point, seem to be clearly understood. PURPOSE: To explore the process of Thai adolescents becoming first-time fathers with an unplanned pregnancy during their girlfriend's pregnancy. METHODS: A grounded theory approach was used, drawing upon semi-structured interviews with 16 expectant fathers in Chiang Mai, Thailand. FINDINGS: 'Growing into teen fatherhood' was the basic social process that emerged as the core category. These fathers used this process for developing themselves to fatherhood. This process was further divided into three phases: enduring the conflict of future role, accepting impending fatherhood and developing a sense of being teen expectant father. Throughout this process, the participants encountered many conflicts and challenges. They employed various strategies to manage the emotional, financial and interpersonal challenges they faced during the transition to fatherhood. CONCLUSION: This study provides data as well as anecdotal evidence for healthcare professionals to better understand adolescent fathers and their unique challenges during their girlfriend's pregnancy. A better understanding of these rich findings will enable healthcare professionals to assist young men and boys in their struggle to transition to fatherhood. IMPLICATIONS FOR NURSING POLICY: Our data may guide policymakers in developing support groups, effective mentoring programs and national follow-up services as standard services in hospitals' care for first-time adolescent fathers in Thailand. PMID- 29159903 TI - Soluble major histocompatibility complex molecules in immune regulation: highlighting class II antigens. AB - The involvement of major histocompatibility complex (MHC) antigens in the development and regulation of immune response has been well defined over the years, starting from maturation, antigenic peptide loading, migration to the cell membrane for recognition by the T-cell receptor and recycling for immune response cessation. During this intracellular trafficking, MHC antigens find a way to be excreted by the cells, because they can be found as soluble MHC class I (sMHC-I) and class II (sMHC-II) molecules in all body fluids. Although secretion mechanisms have not been sufficiently studied, sMHC molecules have been shown to display important immunoregulatory properties. Their levels in the serum have been shown to be altered in a variety of diseases, including viral infections, inflammation, autoimmunities and cancer, etc. while they seem to be involved in a number of physiological reactions, including maintenance of tolerance, reproduction, as well as mate choice vis-a-vis species evolution. The present review aims to present the thus far existing literature on sMHC molecules and point out the importance of these molecules in the maintenance of immune homeostasis. PMID- 29159906 TI - Sexual Orientation in Autism Spectrum Disorder. AB - : Clinical impressions suggest a different sexual profile between individuals with and without Autism Spectrum Disorder (ASD). Little is presently known about the demographics of sexual orientation in ASD. Sexual Orientation was surveyed using the Sell Scale of Sexual Orientation in an international online sample of individuals with ASD (N = 309, M = 90, F= 219), aged (M = 32.30 years, SD = 11.93) and this was compared to sexual orientation of typically-developing individuals (N = 310, M = 84, F= 226), aged (M = 29.82 years, SD = 11.85). Findings suggested that sexual orientation was contingent on diagnosis (N = 570, chi2(9) =104.05, P < 0.001, phi = 0.43). In the group with ASD, 69.7% of the sample reported being non-heterosexual, while in the TD group, 30.3% reported being non-heterosexual. The group with ASD reported higher rates of homosexuality, bisexuality and asexuality, but lower rates of heterosexuality. The results support the impression that non-heterosexuality is more prevalent in the autistic population. Increased non-heterosexuality in ASD has important clinical implications to target unique concerns of this population, and suggests a need for specialized sex education programs for autistic populations for increased support and awareness. Autism Res 2018, 11: 133-141. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Research suggests that individuals with Autism Spectrum Disorder (ASD) report increased homosexuality, bisexuality, and asexuality, but decreased heterosexuality. It is important to increase awareness about increased non heterosexuality in ASD among autistic populations, medical professionals and care takers, so as to provide specialized care, if needed and increase support and inclusion for non-heterosexual autistic individuals. PMID- 29159905 TI - Autologous Mesenchymal Stem Cell and Islet Cotransplantation: Safety and Efficacy. AB - Islet engraftment after transplantation is impaired by high rates of islet/beta cell death caused by cellular stressors and poor graft vascularization. We studied whether cotransplantation of ex vivo expanded autologous bone marrow derived mesenchymal stem cells (MSCs) with islets is safe and beneficial in chronic pancreatitis patients undergoing total pancreatectomy with islet autotransplantation. MSCs were harvested from the bone marrow of three islet autotransplantation patients and expanded at our current Good Manufacturing Practices (cGMP) facility. On the day of islet transplantation, an average dose of 20.0 +/- 2.6 *106 MSCs was infused with islets via the portal vein. Adverse events and glycemic control at baseline, 6, and 12 months after transplantation were compared with data from 101 historical control patients. No adverse events directly related to the MSC infusions were observed. MSC patients required lower amounts of insulin during the peritransplantation period (p = .02 vs. controls) and had lower 12-month fasting blood glucose levels (p = .02 vs. controls), smaller C-peptide declines over 6 months (p = .01 vs. controls), and better quality of life compared with controls. In conclusion, our pilot study demonstrates that autologous MSC and islet cotransplantation may be a safe and potential strategy to improve islet engraftment after transplantation. (Clinicaltrials.gov registration number: NCT02384018). Stem Cells Translational Medicine 2018;7:11-19. PMID- 29159907 TI - The ability to self-monitor cognitive performance during 60 h total sleep deprivation and following 2 nights recovery sleep. AB - We aimed to investigate whether self-monitoring of performance is altered during 60 h of total sleep deprivation, following 2 nights of recovery sleep, and by task difficulty and/or subjective sleepiness. Forty adults (22 females, aged 19 39 years) underwent a 5-day protocol, with a well-rested day, 66 h total sleep deprivation (last test session at 60 h), and 2 nights of 8 h recovery sleep. An arithmetic task (MATH) with three difficulty levels assessed working memory. The Psychomotor Vigilance Task assessed sustained attention. Arithmetic accuracy and Psychomotor Vigilance Task median reaction time measured objective performance. Subjective performance was measured with self-reported accuracy and speed. Objective-subjective differences assessed self-monitoring ability. The performance on both tasks declined during total sleep deprivation and improved following recovery. During total sleep deprivation, participants accurately self monitored performance on the Psychomotor Vigilance Task; however, they overestimated cognitive deficits on MATH, self-reporting performance as worse than actually observed. Following recovery, participants overestimated the extent of performance improvement on the Psychomotor Vigilance Task. Task difficulty influenced self-monitoring ability, with greater overestimation of performance deficits during total sleep deprivation as difficulty increased. Subjective sleepiness predicted subjective performance ratings at several time points, only for the Psychomotor Vigilance Task. The ability to self-monitor performance was impaired during total sleep deprivation for working memory and after recovery sleep for the Psychomotor Vigilance Task, but was otherwise accurate. The development of self-monitoring strategies, assessing both subjective perceptions of performance and subjective sleepiness, within operational contexts may help reduce the consequences of sleep-related impairments. PMID- 29159908 TI - Twenty years later, the cognitive portrait of openness to reconciliation in Rwanda. AB - With this work, we intended to draw a cognitive portrait of openness to reconciliation. No study had yet examined the potential contribution of high level cognitive functioning, in addition to psychological health, to explaining attitudes towards reconciliation in societies exposed to major trauma such as post-genocide Rwanda. We measured the contribution of general cognitive capacity, analytical thinking, and subjective judgements. Our results show that higher cognitive capacity is not associated with greater openness to reconciliation. On the other hand, proneness to think analytically about the genocide predicts more favorable attitudes towards reconciliation. The latter effect is associated with more tempered judgements about retrospective facts (e.g., number of genocide perpetrators) and prospective events (e.g., risk of genocide reoccurrence). This work establishes the importance of cognitive functioning in the aftermath of political violence: A better understanding of the influence of information processing on openness to reconciliation may help improve reconciliation policies and contribute to reducing risks of conflict reoccurrence. PMID- 29159909 TI - Essential role of brain-derived neurotrophic factor (bdnf) in diabetic erectile dysfunction. AB - Erectile dysfunction (ED) is a worldwide problem threatens men's health. The incidence of ED in diabetic patients is higher than that in the healthy population. The incidence of peripheral and autonomic neuropathy is significantly higher in diabetic patients than in normal men. Vasomotor nerves play an important role in the regulation of erectile function. Degeneration of autonomic and sensory nerves is a common type of diabetic neuropathy (DNP) and is closely related to erectile function. Brain-derived neurotrophic factor (BDNF) has been demonstrated to improve diabetic erectile dysfunction in rat models and in humans. However, this process has not yet been fully elucidated yet. In this article, we summarise the mechanisms by which BDNF improves diabetic erectile dysfunction. PMID- 29159911 TI - Early mechanical stimulation only permits timely bone healing in sheep. AB - Bone fracture healing is sensitive to the fixation stability. However, it is unclear which phases of healing are mechano-sensitive and if mechanical stimulation is required throughout repair. In this study, a novel bone defect model, which isolates an experimental fracture from functional loading, was applied in sheep to investigate if stimulation limited to the early proliferative phase is sufficient for bone healing. An active fixator controlled motion in the fracture. Animals of the control group were unstimulated. In the physiological like group, 1 mm axial compressive movements were applied between day 5 and 21, thereafter the movements were decreased in weekly increments and stopped after 6 weeks. In the early stimulatory group, the movements were stopped after 3 weeks. The experimental fractures were evaluated with mechanical and micro-computed tomography methods after 9 weeks healing. The callus strength of the stimulated fractures (physiological-like and early stimulatory) was greater than the unstimulated control group. The control group was characterized by minimal external callus formation and a lack of bone bridging at 9 weeks. In contrast, the stimulated groups exhibited advanced healing with solid bone formation across the defect. This was confirmed quantitatively by a lower bone volume in the control group compared to the stimulated groups.The novel experimental model permits the application of a well-defined load history to an experimental bone fracture. The poor healing observed in the control group is consistent with under stimulation. This study has shown early mechanical stimulation only is sufficient for a timely healing outcome. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1790-1796, 2018. PMID- 29159910 TI - Patients with advanced hepatocellular carcinoma need a personalized management: A lesson from clinical practice. AB - : The Barcelona Clinic Liver Cancer (BCLC) advanced stage (BCLC C) of hepatocellular carcinoma (HCC) includes a heterogeneous population, where sorafenib alone is the recommended treatment. In this study, our aim was to assess treatment and overall survival (OS) of BCLC C patients subclassified according to clinical features (performance status [PS], macrovascular invasion [MVI], extrahepatic spread [EHS] or MVI + EHS) determining their allocation to this stage. From the Italian Liver Cancer database, we analyzed 835 consecutive BCLC C patients diagnosed between 2008 and 2014. Patients were subclassified as: PS1 alone (n = 385; 46.1%), PS2 alone (n = 146; 17.5%), MVI (n = 224; 26.8%), EHS (n = 51; 6.1%), and MVI + EHS (n = 29; 3.5%). MVI, EHS, and MVI + EHS patients had larger and multifocal/massive HCCs and higher alpha-fetoprotein (AFP) levels than PS1 and PS2 patients. Median OS significantly declined from PS1 (38.6 months) to PS2 (22.3 months), EHS (11.2 months), MVI (8.2 months), and MVI + EHS (3.1 months; P < 0.001). Among MVI patients, OS was longer in those with peripheral than with central (portal trunk) MVI (11.2 vs. 7.1 months; P = 0.005). The most frequent treatments were: curative approaches in PS1 (39.7%), supportive therapy in PS2 (41.8%), sorafenib in MVI (39.3%) and EHS (37.3%), and best supportive care in MVI + EHS patients (51.7%). Independent prognostic factors were: Model for End-stage Liver Disease score, Child-Pugh class, ascites, platelet count, albumin, tumor size, MVI, EHS, AFP levels, and treatment type. CONCLUSION: BCLC C stage does not identify patients homogeneous enough to be allocated to a single stage. PS1 alone is not sufficient to include a patient into this stage. The remaining patients should be subclassified according to PS and tumor features, and new patient-tailored therapeutic indications are needed. (Hepatology 2018;67:1784-1796). PMID- 29159912 TI - Nickel(0)-Catalyzed Hydroarylation of Styrenes and 1,3-Dienes with Organoboron Compounds. AB - A Ni-catalyzed hydroarylation of styrenes and 1,3-dienes with organoboron compounds has been developed. The reaction offers a highly selective approach to diarylalkanes and allylarenes under redox-neutral conditions. In this hydroarylation reaction, a new strategy that uses the proton of methanol to generate the active catalyst species Ni-H was developed. The Ni-catalyzed hydroarylation, combined with a Ir-catalyzed C-H borylation, affords a very efficient and straightforward access to a retinoic acid receptor agonist. PMID- 29159913 TI - A Small Organic Molecule Blocks EGFR Transport into the Nucleus by the Nonclassical Pathway Resulting in Repression of Cancer Invasion. AB - In addition to the traditional epidermal growth factor receptor (EGFR) signaling pathways, nuclear EGFR has been shown to control multiple cellular functions, including cell proliferation and invasion. It has been reported that EGFR is transported into the nucleus after forming a complex with KPNA/KPNB1 or KPNB1. Herein, it is shown that EGFR can interact with both KP and KPNA, but EGF activated EGFR mostly binds with KPNB1 through the pull-down assay. Also, a small organic molecule (1), an effective binder of KPNB1, inhibits the interaction between EGFR and KPNB1 in the nonclassical transport pathway, but not KPNA. Furthermore, treatment of cancer cells with 1 noticeably blocks the nuclear entry of EGFR, which results in significant suppression of invasion by lung cancer H1299 cells. These findings show that 1 is an effective inhibitor of EGFR/KPNB1 interactions in vitro, it may be used in cellular studies as a tool to determine the role of nuclear EGFR, and it is a drug candidate. PMID- 29159914 TI - GABA concentration in sensorimotor cortex following high-intensity exercise and relationship to lactate levels. AB - KEY POINTS: Magnetic resonance spectroscopy was conducted before and after high intensity interval exercise. Sensorimotor cortex GABA concentration increased by 20%. The increase was positively correlated with the increase in blood lactate. There was no change in dorsolateral prefrontal cortex. There were no changes in the glutamate-glutamine-glutathione peak. ABSTRACT: High-intensity exercise increases the concentration of circulating lactate. Cortical uptake of blood borne lactate increases during and after exercise; however, the potential relationship with changes in the concentration of neurometabolites remains unclear. Although changes in neurometabolite concentration have previously been demonstrated in primary visual cortex after exercise, it remains unknown whether these changes extend to regions such as the sensorimotor cortex (SM) or executive regions such as the dorsolateral prefrontal cortex (DLPFC). In the present study, we explored the acute after-effects of high-intensity interval training (HIIT) on the concentration of gamma-Aminobutyric acid (GABA) and the combined glutamate glutamine-glutathione (Glx) spectral peak in the SM and DLPFC, as well as the relationship with blood lactate levels. Following HIIT, there was a robust increase in GABA concentration in the SM, as evident across the majority of participants. This change was not observed in the DLPFC. Furthermore, the increase in SM GABA was positively correlated with an increase in blood lactate. There were no changes in Glx concentration in either region. The observed increase in SM GABA concentration implies functional relevance, whereas the correlation with lactate levels may relate to the metabolic fate of exercise derived lactate that crosses the blood-brain barrier. PMID- 29159915 TI - Performance of a hybrid Monte Carlo-Pencil Beam dose algorithm for proton therapy inverse planning. AB - PURPOSE: Analytical algorithms have a limited accuracy when modeling very heterogeneous tumor sites. This work addresses the performance of a hybrid dose optimizer that combines both Monte Carlo (MC) and pencil beam (PB) dose engines to get the best trade-off between speed and accuracy for proton therapy plans. METHODS: The hybrid algorithm calculates the optimal spot weights (w) by means of an iterative optimization process where the dose at each iteration is computed by using a precomputed dose influence matrix based on the conventional PB plus a correction term c obtained from a MC simulation. Updates of c can be triggered as often as necessary by calling the MC dose engine with the last corrected values of w as input. In order to analyze the performance of the hybrid algorithm against dose calculation errors, it was applied to a simplistic water phantom for which several test cases with different errors were simulated, including proton range uncertainties. Afterwards, the algorithm was used in three clinical cases (prostate, lung, and brain) and benchmarked against full MC-based optimization. The influence of different stopping criteria in the final results was also investigated. RESULTS: The hybrid algorithm achieved excellent results provided that the estimated range in a homogeneous material is the same for the two dose engines involved, i.e., PB and MC. For the three patient cases, the hybrid plans were clinically equivalent to those obtained with full MC-based optimization. Only a single update of c was needed in the hybrid algorithm to fulfill the clinical dose constraints, which represents an extra computation time to obtain c that ranged from 1 (brain) to 4 min (lung) with respect to the conventional PB based optimization, and an estimated average gain factor of 14 with respect to full MC-based optimization. CONCLUSION: The hybrid algorithm provides an improved trade-off between accuracy and speed. This algorithm can be immediately considered as an option for improving dose calculation accuracy of commercial analytical treatment planning systems, without a significant increase in the computation time (?5 min) with respect to current PB-based optimization. PMID- 29159916 TI - Purification and characterization of ribosomal proteins L27 and L30 having antimicrobial activity produced by the Lactobacillus salivarius SGL 03. AB - AIMS: The aim of this study was to investigate the antimicrobial potential of proteins secreted by a new strain of Lactobacillus salivarius. METHODS AND RESULTS: The secretome of L. salivarius SGL 03 strain was analysed by gel assisted fractionation and MS/MS to identify low-molecular-mass proteins. This strategy allowed us to identify 10 secreted proteins. Then, a combination of heterologous expression and agar well diffusion was used to characterize them as to their antimicrobial activity, mechanisms of action and stability. Our findings indicate that L27 and L30 proteins of the 50S ribosomal subunit have antimicrobial activity against Streptococcus pyogenes, Streptococcus uberis and Enterococcus faecium. In addition, both proteins are bactericidal against S. pyogenes and maintain their antimicrobial activity after different protease treatments, at acidic pH, after heat treatment, and if stored in a refrigerated ambient at least at 4 degrees C. CONCLUSIONS: The overall results demonstrated that the L27 and L30 ribosomal proteins are of interest as new antimicrobial molecules to prevent the growth of S. pyogenes, S. uberis and E. faecium. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results provide the first insight into the extra-ribosomal activity of L27 and L30 secreted proteins of L. salivarius. This study demonstrated the capacity of L. salivarius SGL 03 to produce antimicrobial molecules and suggested this strain as a promising probiotic candidate. PMID- 29159918 TI - Juvenile mycosis fungoides with large-cell transformation: Successful treatment with psoralen with ultraviolet A light, interferon-alfa, and localized radiation. AB - Mycosis fungoides with large-cell transformation is historically associated with a poor prognosis. Pediatric cases of mycosis fungoides with large-cell transformation are rare, with only three other cases reported in the literature. We present the first case of a child with almost complete remission of his mycosis fungoides with large-cell transformation shortly after administration of psoralen plus ultraviolet A, interferon-alfa, and localized radiation. PMID- 29159919 TI - Smart phone accessibility and mHealth use in a limited resource setting. AB - AIM: To determine smartphone access and use including future opportunities for mHealth and potential ethical implications among health care professionals practicing at a health care facility in Bengaluru, India. BACKGROUND: The evolution of smart phones can provide convenient, portable, and rapid access to resources for health care professionals. While mobile phone accessibility has improved in recent years in many low and middle-income countries, the use of smart phones to address health priorities remains limited in some limited resource settings. DESIGN: A quantitative descriptive design was used. METHODS: A survey was administered in November of 2016 to nurses and physicians at a tertiary care hospital in India. RESULTS/FINDINGS: All respondents had a mobile phone, and the majority owned a smart phone that was used for text messaging, email, accessing internet, and downloading apps. Participants recommended smart phone use to improve health care provider access to continuing education and to improve patient knowledge about health. Physicians had better access to mHealth resources compared with nurses. CONCLUSION: Credible, evidence-based, affordable mobile applications are needed to provide a platform for continuing health education to health professionals and patients in India and limited resource settings. Nurses need equitable access to mHealth resources to build successful mHealth initiatives. PMID- 29159920 TI - Quality assurance for a six degrees-of-freedom table using a 3D printed phantom. AB - PURPOSE: To establish a streamlined end-to-end test of a 6 degrees-of-freedom (6DoF) robotic table using a 3D printed phantom for periodic quality assurance. METHODS: A 3D printed phantom was fabricated with translational and rotational offsets and an imbedded central ball-bearing (BB). The phantom underwent each step of the radiation therapy process: CT simulation in a straight orientation, plan generation using the treatment planning software, setup to offset marks at the linac, registration and corrected 6DoF table adjustments via hidden target test, delivery of a Winston-Lutz test to the BB, and verification of table positioning via field and laser lights. The registration values, maximum total displacement of the combined Winston-Lutz fields, and a pass or fail criterion of the laser and field lights were recorded. The quality assurance process for each of the three linacs were performed for the first 30 days. RESULTS: Within a 95% confidence interval, the overall uncertainty values for both translation and rotation were below 1.0 mm and 0.5 degrees for each linac respectively. When combining the registration values and other uncertainties for all three linacs, the average deviations were within 2.0 mm and 1.0 degrees of the designed translation and rotation offsets of the 3D print respectively. For all three linacs, the maximum total deviation for the Winston-Lutz test did not exceed 1.0 mm. Laser and light field verification was within tolerance every day for all three linacs given the latest guidance documentation for table repositioning. CONCLUSION: The 3D printer is capable of accurately fabricating a quality assurance phantom for 6DoF positioning verification. The end-to-end workflow allows for a more efficient test of the 6DoF mechanics while including other important tests needed for routine quality assurance. PMID- 29159921 TI - Pharmacokinetic profile of Ceftiofur Hydrochloride Injection in lactating Holstein dairy cows. AB - Ceftiofur (CEF), a broad-spectrum third-generation cephalosporin, exhibits a good activity against a broad range of gram-negative and gram-positive bacteria, including many that produce beta-lactamase. To design a rational dosage regimen for the drug in lactating Holstein dairy cows, the pharmacokinetic properties of ceftiofur hydrochloride injection were investigated in six cows after intravenous, intramuscular, and subcutaneous administration of single dose of 2.2 mg/kg BW (body weight). Plasma concentration-time curves and relevant parameters were best described by noncompartmental analysis through WinNonlin 6.3 software. After subcutaneous administration, the absolute bioavailability was 61.12% and the T1/2lambdaz (elimination half-life) was 8.67 +/- 0.72 hr. The Cmax (maximum plasma concentration) was 0.88 +/- 0.21 MUg/ml and Tmax (the time after initial injection to when Cmax occurs) was 1.50 +/- 0.55 hr. The MRT (mean residence time) was 11.00 +/- 0.30 hr. Following intramuscular administration, the Cmax (1.09 +/- 0.21 MUg/ml) was achieved at Tmax (1.20 +/- 0.26 hr) with an absolute availability of 70.52%. In this study, the detailed pharmacokinetic profiles of free and total CEF showed that this drug is widely distributed and rapidly eliminated and may contribute to a better understanding of the usage of ceftiofur hydrochloride injection in Holstein dairy cows. PMID- 29159922 TI - Design considerations in clinical trials with cure rate survival data: A case study in oncology. AB - For clinical trials with time-to-event as the primary endpoint, the clinical cutoff is often event-driven and the log-rank test is the most commonly used statistical method for evaluating treatment effect. However, this method relies on the proportional hazards assumption in that it has the maximal power in this circumstance. In certain disease areas or populations, some patients can be curable and never experience the events despite a long follow-up. The event accumulation may dry out after a certain period of follow-up and the treatment effect could be reflected as the combination of improvement of cure rate and the delay of events for those uncurable patients. Study power depends on both cure rate improvement and hazard reduction. In this paper, we illustrate these practical issues using simulation studies and explore sample size recommendations, alternative ways for clinical cutoffs, and efficient testing methods with the highest study power possible. PMID- 29159924 TI - Using the Icelandic genealogical database to define the familial risk of primary biliary cholangitis. AB - : Hereditary factors in primary biliary cholangitis (PBC) have been well defined in genome-wide association studies, but there are few direct data available that define the relative risk (RR) for family members with an affected proband. An increased risk in first-degree relatives has been demonstrated in a variety of studies, but data have been lacking on further detailed associations for subsequent generations. The objective of this study was to use the unique Icelandic genealogical database to study the familiality of PBC. All patients with positive antimitochondrial antibody measurements in Iceland during the period 1991-2015 who fulfilled diagnostic criteria for PBC were included. The Icelandic genealogical database was used to assess familial relations. For each case of PBC, 10,000 control subjects matched for age, sex, and number of known relatives were randomly chosen from this database to calculate the familial RR of PBC. The average kinship coefficient (KC) of the patients was calculated and compared with the average KC of controls. Overall, 222 PBC patients were identified (182 females, 40 males; median age, 62 years). First-, second- and third-degree relatives of the PBC patients had a high RR of the disease: 9.13 (P < 0.0001), 3.61 (P = 0.014) and 2.59 (P = 0.008), respectively. In fourth- and fifth-degree relatives, the RR was also increased to 1.66 (P = 0.08) and 1.42 (P = 0.08), respectively. The average KC of the patients was also higher than that of the control subjects, with 21.34 * 10-5 versus 9.56 * 10-5 (P < 0.0001). CONCLUSION: Relatives of PBC patients had markedly higher risk for development of the disease compared with controls and importantly our data demonstrate that the risk was significantly increased even in second- and third-degree relatives. (Hepatology 2018;68:166-171). PMID- 29159923 TI - Sea trout adapt their migratory behaviour in response to high salmon lice concentrations. AB - Sea trout face growth-mortality trade-offs when entering the sea to feed. Salmon lice epizootics resulting from aquaculture have shifted these trade-offs, as salmon lice might both increase mortality and reduce growth of sea trout. We studied mortality and behavioural adaptations of wild sea trout in a large-scale experiment with acoustic telemetry in an aquaculture intensive area that was fallowed (emptied of fish) synchronically biannually, creating large variations in salmon lice concentrations. We tagged 310 wild sea trout during 3 years, and gave half of the individuals a prophylaxis against further salmon lice infestation. There was no difference in survival among years or between treatments. In years of high infestation pressure, however, sea trout remained closer to the river outlet, used freshwater (FW) habitats for longer periods and returned earlier to the river than in the low infestation year. This indicates that sea trout adapt their migratory behaviour by actively choosing FW refuges from salmon lice to escape from immediate mortality risk. Nevertheless, simulations show that these adaptations can lead to lost growth opportunities. Reduced growth can increase long-term mortality of sea trout due to prolonged exposure to size-dependent predation risk, lead to lower fecundity and, ultimately, reduce the likelihood of sea migration. PMID- 29159925 TI - The use of micro-CT imaging to examine and illustrate fetal skeletal abnormalities in Dutch Belted rabbits and to prove concordance with Alizarin Red stained skeletal examination. AB - OBJECTIVES: In our laboratory we evaluated the use of micro-computed tomography (micro-CT) using a high resolution acquisition protocol and fetuses obtained on Gestation Day (GD) 29 (mating = GD 0). METHODS: To show concordance between traditional Alizarin Red S stain and micro-CT skeletal examination methods, 103 fetuses from 19 untreated Dutch belted rabbits were obtained by cesarean section and stored frozen. The fetuses were thawed, imaged and examined digitally by micro-CT, then stained and re-examined using traditional methods. RESULTS: A total of 12 individual malformations and 35 unique variations were detected by both methods. Differences in the extent of ossification were found in only 51 of 26,196 bones while 99.8% of the observations were identical. Of the 51 differences, 31 were an unossified fifth medial phalanx of the forepaw indicating that very low-density skeletal bones may be visible by Alizarin Red stain but not by micro-CT scan. To establish this methodology under pharmaceutical testing conditions, we obtained and imaged by micro-CT Alizarin Red S stained abnormal fetal rabbit skeletons previously exposed to a drug candidate associated with craniofacial malformations in humans. All of the types of skeletal abnormalities first identified by staining were also detected by micro-CT examination. Representative images of these 66 different fetal skeletal abnormalities were characterized, and compiled to illustrate visual concordance between micro-CT scanned and traditional Alizarin Red S stained skeletons. CONCLUSION: Micro-CT imaging is an accurate, reliable and robust method that can be used as an alternative to stain when examining fetal rabbit skeletons in developmental toxicity studies. PMID- 29159926 TI - Deep ocean prokaryotic communities are remarkably malleable when facing long-term starvation. AB - The bathypelagic ocean is one of the largest ecosystems on Earth and sustains half of the ocean's microbial activity. This microbial activity strongly relies on surface-derived particles, but there is growing evidence that the carbon released through solubilization of these particles may not be sufficient to meet the energy demands of deep ocean prokaryotes. To explore how bathypelagic prokaryotes respond to the absence of external inputs of carbon, we followed the long-term (1 year) dynamics of an enclosed community. Despite the lack of external energy supply, we observed a continuous succession of active prokaryotic phylotypes, which was driven by recruitment of taxa from the seed bank (i.e., initially rare operational taxonomic units [OTUs]). A single OTU belonging to Marine Group I of Thaumarchaeota, which was originally rare, dominated the microbial community for ~ 4 months and played a fundamental role in this succession likely by introducing new organic carbon through chemolithoautotrophy. This carbon presumably produced a priming effect, because after the decline of Thaumarchaeota, the diversity and metabolic potential of the community increased back to the levels present at the start of the experiment. Our study demonstrates the profound versatility of deep microbial communities when facing organic carbon deprivation. PMID- 29159927 TI - Hormonal contraceptive use and vitamin A deficiency among women in Tanzania. AB - OBJECTIVE: To examine the association between hormonal contraceptive use and vitamin A deficiency among women in Tanzania. METHODS: Secondary analysis of data from 8231 women who participated in the 2010 Tanzania Demographic and Health Survey. Both descriptive and inferential statistical analyses were performed. RESULTS: Overall, 1291 (weight percentage 17.8%) women reported a history of hormonal contraceptive use. The weighted prevalence of vitamin A deficiency was 36.9% (n=3027). After adjustment for potential confounders, women with hormonal contraceptive use had lower odds of vitamin A deficiency (adjusted odds ratio [aOR], 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.009). There was a negative dose-response relationship between duration of hormonal contraceptive use and vitamin A deficiency. As compared with non-users, the odds of vitamin A deficiency decreased significantly among women who used hormonal contraceptives for 1-12 months (aOR, 0.58; 95% CI, 0.40-0.84; P=0.004) and more than 12 months (aOR, 0.26; 95% CI, 0.15-0.46; P<0.001). Women with a history of using oral contraceptive pills had a lower odds of vitamin A deficiency versus non-users (aOR, 0.49; 95% CI, 0.37-0.65; P<0.001). CONCLUSION: In addition to contraceptive effectiveness, hormonal contraception use might have nutritional benefit in preventing vitamin A deficiency. PMID- 29159929 TI - S100beta in newborns after C-section with general vs. epidural anesthesia: a prospective observational study. AB - BACKGROUND: Preclinical evidence suggests that general anesthetics can dose dependently induce neurodegeneration in the developing brains of animals which can be reliably determined by measurement of blood S100beta, but this correlation remains unclear in humans. We hypothesized that S100beta would not be increased in cord arterial blood of fetuses exposed briefly to general anesthetics during a C-section, compared with epidural anesthesia. METHODS: A prospective observational clinical study comparatively measured changes of brain damage biomarker S100beta ratio of umbilical artery over vein (changes after fetus circulation) immediately after delivery under C-section with either epidural or general anesthesia. Newborn blood gas measurements, APGAR scores, and maternal well-being were also compared. RESULTS: Compared with epidural anesthesia, general anesthesia resulted in the lower S100beta ratio of umbilical artery over the vein (medium 2.64 [quartiles 1.39, 3.45] vs. medium 1.59 [quartiles 0.88, 2.01], P = 0.031), without changing the S100beta level in the vein of the mother. There was no significant difference between general and epidural anesthesia when comparing other maternal and newborn parameters. CONCLUSION: S100beta levels in newborn after C-section is lower with general anesthesia than epidural anesthesia, with unclear mechanisms. PMID- 29159930 TI - Molecular testing of adult Pacific salmon and trout (Oncorhynchus spp.) for several RNA viruses demonstrates widespread distribution of piscine orthoreovirus in Alaska and Washington. AB - This research was initiated in conjunction with a systematic, multiagency surveillance effort in the United States (U.S.) in response to reported findings of infectious salmon anaemia virus (ISAV) RNA in British Columbia, Canada. In the systematic surveillance study reported in a companion paper, tissues from various salmonids taken from Washington and Alaska were surveyed for ISAV RNA using the U.S.-approved diagnostic method, and samples were released for use in this present study only after testing negative. Here, we tested a subset of these samples for ISAV RNA with three additional published molecular assays, as well as for RNA from salmonid alphavirus (SAV), piscine myocarditis virus (PMCV) and piscine orthoreovirus (PRV). All samples (n = 2,252; 121 stock cohorts) tested negative for RNA from ISAV, PMCV, and SAV. In contrast, there were 25 stock cohorts from Washington and Alaska that had one or more individuals test positive for PRV RNA; prevalence within stocks varied and ranged from 2% to 73%. The overall prevalence of PRV RNA-positive individuals across the study was 3.4% (77 of 2,252 fish tested). Findings of PRV RNA were most common in coho (Oncorhynchus kisutch Walbaum) and Chinook (O. tshawytscha Walbaum) salmon. PMID- 29159931 TI - Targets and teamwork: Understanding differences in pediatric diabetes centers treatment outcomes. AB - OBJECTIVE: The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes. RESEARCH DESIGN AND METHODS: Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated. Clinical, medical, and demographic data were obtained, along with blood sample for centralized assay. Parents and all members of the diabetes care team completed questionnaires on treatment targets for hemoglobin A1c (HbA1c) and recommended frequency of blood glucose monitoring. RESULTS: Totally 1113 (53% male) children (mean age 8.0 +/- 2.1 years) from 18 centers in 17 countries, along with parents and 113 health-care professionals, participated. There were substantial differences in mean HbA1c between centers ranging from 7.3 +/- 0.8% (53 mmol/mol +/- 8.7) to 8.9 +/- 1.1% (74 mmol/mol +/- 12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams with less disagreement about recommended targets. Multiple regression analysis indicated that teams reporting higher HbA1c targets and more target disagreement had parents reporting higher treatment targets. This seemed to partially account for center differences in Hb1Ac. CONCLUSIONS: The diabetes care teams' cohesiveness and perspectives on treatment targets, expectations, and recommendations have an influence on parental targets, contributing to the differences in pediatric diabetes center outcomes. PMID- 29159932 TI - Barriers to adopting a Mediterranean diet in Northern European adults at high risk of developing cardiovascular disease. AB - BACKGROUND: Strong evidence links the consumption of a Mediterranean diet (MD) with a reduced cardiovascular disease (CVD) risk; however, there is uncertainty as to whether non-Mediterranean regions will adopt this diet. The present qualitative research aimed to investigate attitudes towards a MD in individuals at high CVD risk in a Northern European population. This information is needed to inform development of MD interventions in non-Mediterranean high-risk populations. METHODS: Focus groups (n = 12) were held with individuals at high CVD risk from Northern Europe (>=2 CVD risk factors, aged >=50 years, no established CVD/type 2 diabetes). Attitudes to dietary change towards a MD were explored. Data were analysed using inductive thematic analysis. RESULTS: Sixty seven adults participated (60% female, mean age 64 years). There was some awareness of the term MD but limited knowledge of its composition. Barriers to general dietary change were evident, including perception of expense, concern over availability, expectation of time commitment, limited knowledge, lack of cooking skills, amount and conflicting nature of media information on diets, changing established eating habits and resistance to dietary change. Barriers specific to MD adoption were also identified, including perceived difficulty living in a colder climate, perceived impact on body weight, acceptability of a MD and cultural differences. CONCLUSIONS: Knowledge of a MD was limited in this Northern European sample at high CVD risk. In addition to general barriers to dietary change, barriers specific to a MD were identified. These findings have implications for the development of interventions aiming to promote MD adoption in non-Mediterranean populations. PMID- 29159928 TI - The immunogenetics of neurological disease. AB - Genes encoding antigen-presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. Myriad genetic, immunological and environmental factors may contribute to an individual's susceptibility to neurological disease. Here, we review and discuss the decades long research on the influence of genetic variation at the MHC locus and the role of immunogenetic killer cell immunoglobulin-like receptor (KIR) loci in neurological diseases, including multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. The findings of immunogenetic association studies are consistent with a polygenic model of inheritance in the heterogeneous and multifactorial nature of complex traits in various neurological diseases. Future investigation is highly recommended to evaluate both coding and non-coding variation in immunogenetic loci using high-throughput high-resolution next-generation sequencing technologies in diverse ethnic groups to fully appreciate their role in neurological diseases. PMID- 29159933 TI - Dyspraxia in clinical education: a review. AB - BACKGROUND: The stereotype of the student with dyspraxia as 'clumsy and disorganised' may cause clinical teachers to be concerned about the student's performance in a clinical environment; however, if it is understood that dyspraxic students possess many strengths, as well as weaknesses, it may be that some stereotypical myths will be dispelled and more effective support offered to them. This review considers research surrounding the experiences of students and health professionals with dyspraxia within higher education (HE), alongside the personal experiences of EW, in order to inform the development of clinical teachers with respect to their support for learners with dyspraxia. FINDINGS: A literature review found five relevant articles. Four studies focused on HE students and one on doctors. A significant theme was that dyspraxia impaired learning new skills. Doctors with dyspraxia tended not to disclose their condition, for fear of stigmatisation and negative effects on their career. Positive attributes of dyspraxia included resilience and determination to succeed. Two main adaptations to dyspraxia were highlighted; a 'difference' view focusing on individuals' strengths, and a 'medical/deficit' view, focusing on their weaknesses and the negative perceptions of others. Doctors with dyspraxia tended not to disclose their condition, for fear of stigmatisation DISCUSSION AND RECOMMENDATIONS: It is important for clinical educators to understand and support students with dyspraxia, as clinical environments can be particularly difficult for them. Dyspraxia has both positive and negative effects. Here we discuss the findings of previous studies in the context of EW's personal experiences. We also present a series of practical recommendations, whilst recognising that more research is required to document their impact in clinical education. PMID- 29159935 TI - Bayesian estimation of multicomponent relaxation parameters in magnetic resonance fingerprinting. AB - PURPOSE: To estimate multiple components within a single voxel in magnetic resonance fingerprinting when the number and types of tissues comprising the voxel are not known a priori. THEORY: Multiple tissue components within a single voxel are potentially separable with magnetic resonance fingerprinting as a result of differences in signal evolutions of each component. The Bayesian framework for inverse problems provides a natural and flexible setting for solving this problem when the tissue composition per voxel is unknown. Assuming that only a few entries from the dictionary contribute to a mixed signal, sparsity-promoting priors can be placed upon the solution. METHODS: An iterative algorithm is applied to compute the maximum a posteriori estimator of the posterior probability density to determine the magnetic resonance fingerprinting dictionary entries that contribute most significantly to mixed or pure voxels. RESULTS: Simulation results show that the algorithm is robust in finding the component tissues of mixed voxels. Preliminary in vivo data confirm this result, and show good agreement in voxels containing pure tissue. CONCLUSIONS: The Bayesian framework and algorithm shown provide accurate solutions for the partial volume problem in magnetic resonance fingerprinting. The flexibility of the method will allow further study into different priors and hyperpriors that can be applied in the model. Magn Reson Med 80:159-170, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29159936 TI - Influence of socioeconomic factors and distance to radiotherapy on breast conserving surgery rates for early breast cancer in regional Australia; implications of change. AB - AIMS: Breast conserving surgery rates are affected by many factors including distance to radiotherapy and tumor-related features. Numerous studies have found women who must travel further for radiotherapy are more likely to choose mastectomy and avoid radiotherapy. We examined relationships between socioeconomic group, distance to radiotherapy services and mastectomy rates across a range of rural and metropolitan settings. METHODS: We used a dataset extracted from the Evaluation of Cancer Outcomes Barwon South Western Registry, which captured data on new breast cancer diagnoses in the southwest region of Victoria, Australia. Using logistic regression, we modeled treatment choice of women with early breast cancer (mastectomy vs breast conserving surgery) using explanatory variables that included distance to radiotherapy, and area-level socioeconomic data from the Australian Bureau of Statistics, while controlling for clinical factors. RESULTS: Mastectomy was associated with tumor size, nodal burden and younger age at surgery. Distance to a radiotherapy center was also strongly associated with increased rates of mastectomy for women who traveled 100 200 km for radiotherapy (odds ratio = 1.663; P = 0.03) compared to the reference group who were within 100 km of radiotherapy. No socioeconomic differences were seen between the two groups. CONCLUSION: A strong association between distance to radiotherapy and the type of surgery for early breast cancer was found. Improving access to radiotherapy therefore has the potential to improve breast cancer outcomes for women in regional Australia. PMID- 29159934 TI - Ovarian cancer early detection by circulating CA125 in the context of anti-CA125 autoantibody levels: Results from the EPIC cohort. AB - CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to four matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated toward the absolute risk estimates from a pre existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76-0.92]; lowest tertile: 0.76 [0.67-0.86]; phet = 0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection. PMID- 29159937 TI - Diffusion-weighted MRI and intravoxel incoherent motion model for diagnosis of pediatric solid abdominal tumors. AB - BACKGROUND: Pediatric retroperitoneal tumors in the renal bed are often large and heterogeneous, and their diagnosis based on conventional imaging alone is not possible. More advanced imaging methods, such as diffusion-weighted (DW) MRI and the use of intravoxel incoherent motion (IVIM), have the potential to provide additional biomarkers that could facilitate their noninvasive diagnosis. PURPOSE: To assess the use of an IVIM model for diagnosis of childhood malignant abdominal tumors and discrimination of benign from malignant lesions. STUDY TYPE: Retrospective. POPULATION: Forty-two pediatric patients with abdominal lesions (n = 32 malignant, n = 10 benign), verified by histopathology. FIELD STRENGTH/SEQUENCE: 1.5T MRI system and a DW-MRI sequence with six b-values (0, 50, 100, 150, 600, 1000 s/mm2 ). ASSESSMENT: Parameter maps of apparent diffusion coefficient (ADC), and IVIM maps of slow diffusion coefficient (D), fast diffusion coefficient (D*), and perfusion fraction (f) were computed using a segmented fitting model. Histograms were constructed for whole-tumor regions of each parameter. STATISTICAL TESTS: Comparison of histogram parameters of and their diagnostic performance was determined using Kruskal-Wallis, Mann-Whitney U, and receiver-operating characteristic (ROC) analysis. RESULTS: IVIM parameters D* and f were significantly higher in neuroblastoma compared to Wilms' tumors (P < 0.05). The ROC analysis showed that the best diagnostic performance was achieved with D* 90th percentile (area under the curve [AUC] = 0.935; P = 0.002; cutoff value = 32,376 * 10-6 mm2 /s) and f mean values (AUC = 1.00; P < 0.001; cutoff value = 14.7) in discriminating between neuroblastoma (n = 11) and Wilms' tumors (n = 8). Discrimination between tumor types was not possible with IVIM D or ADC parameters. Malignant tumors revealed significantly lower ADC, D, and higher D* values than in benign lesions (all P < 0.05). DATA CONCLUSION: IVIM perfusion parameters could distinguish between malignant childhood tumor types, providing potential imaging biomarkers for their diagnosis. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1475-1486. PMID- 29159938 TI - Proximate cause, anatomical correlates, and obstetrical implication of a supernumerary lumbar vertebra in humans. AB - OBJECTIVES: Three issues are considered on variation in number of presacral vertebrae (PSV) in humans: (1) sexual difference in number of PSV, (2) inactivation of Hoxd-11 gene as etiology for a supernumerary lumbar vertebra, and (3) anatomical correlates of a supernumerary lumbar vertebra, including lumbar sacral nearthrosis, and pelvic size. MATERIALS AND METHODS: Sample was 407 skeletonized females and 1,318 males from United States; ages at death were 20 to 49 years. Two subsamples of males were used: (1) 98 with modal numbers of cervical, thoracic, lumbar, and sacral vertebrae (PSV = 24) and (2) 45 with a supernumerary lumbar vertebra but modal numbers for other vertebral segments (PSV = 25). Measurements were taken of ulna, second metacarpal, vertebrae, femur, and pelvis; presence of lumbar-sacral nearthrosis was observed. RESULTS: Although 90% of females and males have 24 PSV, females have higher frequency of 23 PSV and males have higher frequency of 25 PSV. Compared to males with 24 PSV, males with 25 PSV and supernumerary lumbar vertebra show (1) no difference in anatomies associated with inactivation of Hoxd-11, and (2) higher frequency of lumbar sacral nearthrosis and smaller pelvic inlet circumference. DISCUSSION: Sexual difference in number of PSV may be due to tempo of somite formation and Hox gene activation. Hypothesis is not supported that a supernumerary lumbar vertebra is due to inactivation of Hoxd-11. The presence of a supernumerary lumbar vertebra is associated with small pelvic inlet circumference, which can be obstetrically disadvantageous. PMID- 29159940 TI - Nop5 interacts with the archaeal RNA exosome. AB - The archaeal exosome, a protein complex responsible for phosphorolytic degradation and tailing of RNA, has an RNA-binding platform containing Rrp4, Csl4, and DnaG. Aiming to detect novel interaction partners of the exosome, we copurified Nop5, which is a part of an rRNA methylating ribonucleoprotein complex, with the exosome of Sulfolobus solfataricus grown to a late stationary phase. We demonstrated the capability of Nop5 to bind to the exosome with a homotrimeric Rrp4-cap and to increase the proportion of polyadenylated RNAin vitro, suggesting that Nop5 is a dual-function protein. Since tailing of RNA probably serves to enhance RNA degradation, association of Nop5 with the archaeal exosome in the stationary phase may enhance tailing and degradation of RNA as survival strategy. PMID- 29159939 TI - Marked yield of re-evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities. AB - The diagnosis of intellectual disability/developmental delay (ID/DD) benefits from the clinical application of target/exome sequencing. The yield in Mendelian diseases varies from 25% to 68%. The aim of the present study was to identify the genetic causes of 33 ID/DD patients using target/exome sequencing. Recent studies have demonstrated that reanalyzing undiagnosed exomes could yield additional diagnosis. Therefore, in addition to the normal data analysis, in this study, re evaluation was performed prior to manuscript preparation after updating OMIM annotations, calling copy number variations (CNVs) and reviewing the current literature. Molecular diagnosis was obtained for 19/33 patients in the first round of analysis. Notably, five patients were diagnosed during the re-evaluation of the geno/phenotypic data. This study confirmed the utility of exome sequencing in the diagnosis of ID/DD. Furthermore, re-evaluation leads to a 15% improvement in diagnostic yield. Thus, to maximize the diagnostic yield of next-generation sequencing (NGS), periodical re-evaluation of the geno/phenotypic data of undiagnosed individuals is recommended by updating the OMIM annotation, applying new algorithms, reviewing the literature, sharing pheno/genotypic data, and re contacting patients. PMID- 29159941 TI - The role of off-focus radiation in scatter correction for dedicated cone beam breast CT. AB - PURPOSE: Dedicated cone beam breast CT (CBBCT) suffers from x-ray scatter contamination. We aim to identify the source of the significant difference between the scatter distributions estimated by two recent methods proposed by our group and to investigate its effect on CBBCT image quality. METHOD: We recently proposed two novel methods of scatter correction for CBBCT, using a library based (LB) technique and a forward projection (FP) model. Despite similar enhancement on CBBCT image qualities, these two methods obtain very different scatter distributions. We hypothesize that the off-focus radiation (OFR) is the contributor and results in nontrivial signals in x-ray projections, which is ignored in the scatter estimation via the LB method. Experiments using a thin wire test tool are designed to study the effect of OFR on CBBCT spatial resolution by measuring the point spread function (PSF) and the modulation transfer function (MTF). A narrow collimator setting is used to suppress the OFR induced signals. In addition, "PSFs" and "MTFs" are measured on clinical CBBCT images obtained by the LB and FP methods using small calcifications as point sources. The improvement of spatial resolution achieved by suppressing OFR in the wire experiment as well as in the clinical study is quantified by the improvement ratios of PSFs and spatial frequencies at different MTF values. Our hypothesis that OFR causes the imaging difference between the FP and LB methods is verified if these ratios obtained from experimental and clinical data are consistent. RESULTS: In the wire experiment, the results show that suppression of OFR increases the maximum signal of the PSF by about 14% and reduces the full-width at-half-maximum (FWHM) by about 12.0%. Similar improvement on spatial resolution is achieved by the FP method compared with the LB method in the patient study. The improvement ratios of spatial frequencies at different MTF values without OFR match very well in both studies at a level of around 16%, with an average root mean-square difference of 0.47%. CONCLUSION: The results of the wire experiment and the clinical study indicate that the main difference between the LB and FP methods is whether the OFR-induced signals are included after scatter correction. Our study further shows that OFR significantly affects the image spatial resolution of CBBCT, indicating that the visualization of micro-calcifications is susceptible to OFR contamination. Our finding is therefore important in further improvement of diagnostic performance of CBBCT. PMID- 29159942 TI - Horizontal transmission of Metarhizium anisopliae (Hypocreales: Clavicipitacea) and the effects of infection on oviposition rate in laboratory populations of Musca domestica (Diptera: Muscidae). AB - BACKGROUND: Effective control of house fly, Musca domestica (L.), populations currently relies on the use of chemical insecticides in most situations. Entomopathogenic fungi such as Metarhizium anisopliae (Metschn.) Sorokin may provide an alternative to chemicals and their efficacy may be enhanced by autodissemination amongst flies. This study assessed the capacity of M. anisopliae for transmission between adult M. domestica flies and the effects of infection on the fecundity of females. RESULTS: Metarhizium anisopliae was transmitted between adult M. domestica with 91.67-100% mortality resulting across the three ratios of infected: non-infected flies tested (1:2, 1:5 and 1:10). The mean lethal time (LT50 ) for female recipients mixed with infected male donor flies at the three ratios was 3.95, 4.79 and 5.65 days, respectively, whereas for male recipients mixed with infected female donors at the same ratios the LT50 was 4.98, 5.98 and 7.44 days, respectively. Infection with M. anisopliae significantly reduced the reproductive capacity of female flies during the first 4 days of infection, with 25% fewer eggs oviposited by infected flies than by those that were uninfected. CONCLUSION: Autodissemination among house flies and reduction in oviposition in the early stages of infection could contribute significantly to the effectiveness of M. anisopliae used in biocontrol programmes. (c) 2017 Society of Chemical Industry. PMID- 29159943 TI - Retrospective multicenter study of leaving the placenta in situ for patients with placenta previa on a cesarean scar. AB - OBJECTIVE: To investigate maternal outcomes after leaving the placenta in situ for placenta accreta spectrum (PAS) disorders in patients with placenta previa on a cesarean delivery scar. METHODS: The present retrospective study reviewed medical records from women with placenta previa on a cesarean scar underwent perinatal care at secondary- or tertiary-level perinatal centers in Japan between January 1, 2010, and December 31, 2014. Perinatal management was conducted based on each leading obstetrician's discretion. The primary outcome was success of the leaving the placenta in situ approach for PAS disorders (defined as preserving the uterus without hysterectomy). RESULTS: Of 178 eligible centers, 126 (71%) participated in this study; data from 613 patients were included. Of these, 41 had the placenta left in situ owing to PAS disorders and follow-up data were available for 36 women. Leaving the placenta in situ was successful in 25 (69%) patients, with placental resorption occurring postpartum (median 89 days; range 6 510). Hysterectomy was performed for 11 patients, primarily owing to hemorrhage and/or infection (median 30 days; range 0-95 days, postpartum). CONCLUSION: Leaving the placenta in situ, with close postpartum follow-up for at least several months, could be a uterus-preserving option for patient with PAS disorders. PMID- 29159944 TI - Effect of iron on the growth of Phaeodactylum tricornutum via photosynthesis. AB - Iron is a limiting factor that controls the phytoplankton biomass in the modern ocean, and iron fertilization of the ocean could lead to blooms dominated by diatoms. Thus, iron plays an important role in controlling the distribution of diatoms. In this study, we measured the growth rate and photosynthetic activity of the model diatom Phaeodactylum tricornutum cultured under different iron concentrations and found that it grew more rapidly and had a much higher photosynthetic efficiency under higher iron concentrations. In order to explore the unique mechanism of the response of diatoms to iron, a proteomic analysis was carried out, and the results indicated that iron promotes the Calvin cycle of P. tricornutum. Diatoms can tolerate the pressure of iron limitation by replacing iron-rich proteins with flavodoxin, and so on. Moreover, we found that the photosystem I (PSI) activity of iron-limited algae that were treated by N',N',N',N'-tetramethyl-p-phenylenediamine (TMPD) was increased significantly. As TMPD plays the role of a cytochrome b6 /f complex that transfers electrons from photosystem II to PSI, the cytochrome b6 /f complex is the key to photosynthesis regulation. Iron could influence the growth of P. tricornutum by regulating its biosynthesis. All of the results suggest that iron might affect the growth of diatoms through the Calvin cycle and the cytochrome b6 /f complex. PMID- 29159945 TI - Cantharidic acid induces apoptosis through the p38 MAPK signaling pathway in human hepatocellular carcinoma. AB - Cantharidin analogs exhibit anticancer activities, including apoptosis. However, the molecular mechanisms underlying the effects of cantharidic acid (CA), a cantharidin analog, on apoptosis in hepatocellular carcinoma (HCC) cells are unclear. Thus, in this study, we evaluated the anticancer activities of CA by investigating its ability to trigger apoptosis in SK-Hep-1 cells. Our data demonstrated that CA effectively inhibited the proliferation of SK-Hep-1 cells in a dose-dependent manner. Furthermore, CA effectively triggered cell cycle arrest and induced apoptosis, as determined by flow cytometric analysis. Western blotting revealed that CA significantly activated proapoptotic signaling including caspase-3, -8, and -9 in SK-Hep-1 cells. Moreover, treatment of SK-Hep 1 cells with CA induced the activation of ERK, p38, and c-Jun N-terminal kinase. Moreover, the inhibition of p38 by specific inhibitors abolished CA-induced cell apoptosis. In conclusion, our results indicated that CA induces apoptosis in SK Hep-1 cells through a p38-mediated apoptotic pathway and could be a new HCC therapeutic agent. PMID- 29159946 TI - Extracellular volume with bolus-only technique in amyloidosis patients: Diagnostic accuracy, correlation with other clinical cardiac measures, and ability to track changes in amyloid load over time. AB - BACKGROUND: Extracellular volume (ECV) by T1 mapping requires the contrast agent distribution to be at equilibrium. This can be achieved either definitively with a primed contrast infusion (infusion ECV), or sufficiently with a delay postbolus (bolus-only ECV). For large ECV, the bolus-only approach measures higher than the infusion ECV, causing some uncertainty in diseases such as amyloidosis. PURPOSE: To characterize the relationship between the bolus-only and current gold-standard infusion ECV in patients with amyloidosis. STUDY TYPE: Bolus-only and infusion ECV were prospectively measured. POPULATION: In all, 186 subjects with systemic amyloidosis attending our clinic and 23 subjects with systemic amyloidosis who were participating in an open-label, two-part, dose-escalation, phase 1 trial. FIELD STRENGTH: Avanto 1.5T, Siemens Medical Solutions, Erlangen, Germany. ASSESSMENT: Bolus-only and infusion ECV were measured in all subjects using shortened modified Look-Locker inversion recovery (ShMOLLI) T1 mapping sequence. STATISTICAL TESTS: Pearson correlation coefficient (r); Bland-Altman; receiver operating characteristic (ROC) curve analysis. Linear regression model with a fractional polynomial transformation. RESULTS: The difference between the bolus only and infusion myocardial ECV increased as the average of the two measures increased, with the bolus-ECV measuring higher. For an average ECV of 0.4, the difference was 0.013. The 95% limits of agreement for the two methods, after adjustment for the bias, were +/-0.056. However, cardiac diagnostic accuracy was comparable (bolus-only vs. infusion ECV area under the curve [AUC] = 0.839 vs. 0.836), as were correlations with other clinical cardiac measures, and, in the trial patients, the ability to track changes in the liver/spleen with therapy. DATA CONCLUSION: In amyloidosis, with large ECVs, the bolus-only technique reads higher than the infusion technique, but clinical performance by any measure is the same. Given the work-flow advantages, these data suggest that the bolus-only approach might be acceptable for amyloidosis, and might support its use as a surrogate endpoint in future clinical trials. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1677-1684. PMID- 29159947 TI - Flexible water excitation for fat-free MRI at 3T using lipid insensitive binomial off-resonant RF excitation (LIBRE) pulses. AB - PURPOSE: To develop a robust and flexible low power water excitation pulse that enables effective fat suppression at high magnetic field strength. METHODS: A water excitation method that uses spatially non-selective pulses was optimized in numerical simulations, and implemented and tested in phantoms and healthy volunteers at 3T. The lipid insensitive binomial off-resonant excitation (LIBRE) pulse comprises two low power rectangular subpulses that have a variable frequency offset, phase offset and duration. The capability and extent of LIBRE fat suppression was quantitatively compared with conventional fat saturation (FS) and water excitation (WE) techniques. RESULTS: LIBRE enables simultaneous water excitation and near complete fat suppression in large volumes at 3T as demonstrated by numerical simulations, and experiments. In phantoms and in human subjects, the frequency responses matched well with those from the numerical simulation. Comparing FS and WE, LIBRE demonstrated an improved robustness to magnetic field inhomogeneities, and a much more effectively suppressed fat signal. This applied for a range of pulse durations and pulses as short as 1.4 ms. CONCLUSION: A flexible water excitation method was developed that shows robust, near complete fat suppression at 3T. Magn Reson Med 79:3007-3017, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29159948 TI - Gastrointestinal risk factors and prescribing pattern of antiulcer agents in patients taking low-dose aspirin in Japan. AB - OBJECTIVES: To identify prescribing patterns of antiulcer agents in patients on low-dose aspirin (LDA) and to evaluate the number of gastrointestinal (GI) risk factors of the patients. METHODS: A retrospective chart review of patients taking LDA was conducted at the National Cerebral and Cardiovascular Center in Japan. The rate of concomitant use of antiulcer agents and the risk of each patient to develop GI complications were evaluated. RESULTS: Of the 314 patients, 64 were not on antiulcer agents and 55 of them had >1 risk factor. More patients not on antiulcer agents had started LDA before hospitalization. CONCLUSION: The rate of coprescribing antiulcer agents with LDA was high. However, the timing of initiating LDA therapy affected the prescribing pattern of antiulcer agents. PMID- 29159949 TI - Cognitive Function After Transcatheter Aortic Valve Replacement: Reassuring Findings For Now. PMID- 29159950 TI - Evaluation of the template-based modeling in CASP12. AB - The article describes results of numerical evaluation of CASP12 models submitted on targets for which structural templates could be identified and for which servers produced models of relatively high accuracy. The emphasis is on analysis of details of models, and how well the models compete with experimental structures. Performance of contributing research groups is measured in terms of backbone accuracy, all-atom local geometry, and the ability to estimate local errors in models. Separate analyses for all participating groups and automatic servers were carried out. Compared with the last CASP, two years ago, there have been significant improvements in a number of areas, particularly the accuracy of protein backbone atoms, accuracy of sequence alignment between models and available structures, increased accuracy over that which can be obtained from simple copying of a closest template, and accuracy of modeling of sub-structures not present in the closest template. These advancements are likely associated with more effective strategies to build non-template regions of the targets ab initio, better algorithms to combine information from multiple templates, enhanced refinement methods, and better methods for estimating model accuracy. PMID- 29159951 TI - Prevalence of sun protection behaviors in Hispanic youth residing in a high ultraviolet light environment. AB - Although rates of late-stage melanoma are rising in Hispanics, particularly those living in high ultraviolet light environments, little is known about the prevalence of sun protective behaviors in Hispanic children. We analyzed baseline data including frequency of sunburn, sun protective behaviors, level of U.S. acculturation, and skin phototype from a cross-sectional survey of 2003 Hispanic elementary school children in Los Angeles, California, who participated in a skin cancer prevention intervention. Although the Hispanic children reported frequently engaging in some sun protective behaviors, they also had a high rate of sunburn (59%) that exceeded previous national estimates for non-Hispanic white children (43%). Fewer U.S.-acculturated children reported more frequent shade seeking at home (P = .02), along with less shade-seeking at school (P = .001) and more sunscreen use at school (P = .02). The surprisingly high rate of sunburn in Hispanic children suggests that the way in which they are practicing sun protection is not preventing sunburns. Sun safety interventions should be targeted toward Hispanic youth to provide them with practical methods of effective sun protection, in addition to education on the risks of high sun exposure. PMID- 29159952 TI - Single axonal morphology and termination to cerebellar aldolase C stripes characterize distinct spinocerebellar projection systems originating from the thoracic spinal cord in the mouse. AB - The spinocerebellar projection has an essential role in sensorimotor coordination of limbs and the trunk. Multiple groups of spinocerebellar projections have been identified in retrograde labeling studies. In this study, we aimed at characterizing projection patterns of these groups using a combination of anterograde labeling of the thoracic spinal cord and aldolase C immunostaining of longitudinal stripes of the cerebellar cortex in the mouse. We reconstructed 22 single spinocerebellar axons, wholly in the cerebellum and brain stem and partly, in the spinal cord. They were classified into three groups, (a) non-crossed axons of Clarke's column neurons (NCC, 8 axons), (b) non-crossed axons of marginal Clarke's column neurons (NMCC, 7 axons), and (c) crossed axons of neurons in the medial ventral horn (CMVH, 7 axons), based on previous retrograde labeling studies. While NCC axons projected mainly to multiple bilateral stripes in vermal lobules II-IV and VIII-IX, and the ipsilateral medial cerebellar nucleus, NMCC axons projected mainly to ipsilateral stripes in paravermal lobules II-V and copula pyramidis, and the anterior interposed nucleus. CMVH axons projected bilaterally to multiple stripes in lobules II-V with a small number of terminals but had abundant collaterals in the spinal cord and medullary reticular nuclei as well as in the vestibular and cerebellar nuclei. The results indicate that, while CMVH axons overlap with propriospinal and spinoreticular projections, NCC and NMCC axons are primarily spinocerebellar axons, which seem to be involved in relatively more proximal and distal sensorimotor controls, respectively. PMID- 29159953 TI - Relationship between heart failure, concurrent chronic obstructive pulmonary disease and beta-blocker use: a Danish nationwide cohort study. AB - AIMS: To compare the hazard of all-cause, chronic obstructive pulmonary disease (COPD) and heart failure (HF) hospitalization in carvedilol vs. metoprolol/bisoprolol/nebivolol users with COPD and concurrent HF from 2009 to 2012, and to evaluate the use and persistence in treatment of these beta blockers, their impact on the risk of COPD-related hospitalization, and the factors important for their selection. METHODS AND RESULTS: Cox and logistic regression were used for both unadjusted and adjusted analyses. Carvedilol users had a higher hazard of being hospitalized for HF compared with metoprolol/bisoprolol/nebivolol users in both the unadjusted [hazard ratio (HR) 1.74; 95% confidence interval (CI) 1.65-1.83] and adjusted (HR 1.61; 95% CI 1.52 1.70) analyses. No significant differences were found for all-cause and COPD hospitalization between the two groups. Carvedilol users had a significant lower restricted mean persistence time than metoprolol/bisoprolol/nebivolol users. Patients exposed to carvedilol had an odds ratio (OR) of 1.38 (95% CI 1.23-1.56) for being hospitalized due to COPD within 60 days after redeeming the first carvedilol prescription, which was similar to that observed in metoprolol/bisoprolol/nebivolol users (OR 1.37; 95% CI 1.27-1.48). Patients with concurrent chronic kidney disease had a higher probability of receiving carvedilol (OR 1.16; 95% CI 1.04-1.29). CONCLUSION: Carvedilol prescription carried an increased hazard of HF hospitalization and lower restricted mean persistence time among patients with COPD and concurrent HF. Additionally, we found a widespread phenomenon of carvedilol prescription at variance with the European Society of Cardiology guidelines and potential for improving the proportion of patients treated with beta-blockers. PMID- 29159954 TI - Unraveling the Mechanistic Complexity of the Glomerulocystic Phenotype in Dicer Conditional KO Mice by 2D Gel Electrophoresis Coupled Mass Spectrometry. AB - PURPOSE: Dicer, an RNase III type endonuclease, is a key enzyme involved in miRNA biogenesis. It has been shown that this enzyme is essential for several aspects of postnatal kidney functions and homeostasis. In this study, we have examined conditional knockout (cKO) mice for Dicer in Pax8 (Paired-box gene 8) expressing cells to investigate the kidney protein profile. This specific model develops a glomerulocystic phenotype coupled with urinary concentration impairment, proteinuria, and severe renal failure. EXPERIMENTAL DESIGN: Proteomic analysis was performed on kidney tissue extracts from cKO and control (Ctr) mice by 2D Gel Electrophoresis coupled with mass spectrometry. RESULTS: The analysis highlighted 120 protein spots differentially expressed in Dicer cKO tissue compared with control; some of these proteins were validated by Western blotting. Ingenuity Pathway Analysis led to the identification of some interesting networks; among them, the one having ERK as a central hub may explain, through the modulation of the expression of a number of identified protein targets, the metabolic and structural alterations occurring during kidney cyst development in Dicer cKO mouse model. CONCLUSIONS AND CLINICAL RELEVANCE: Our results contribute to gain new insights into molecular mechanisms through which Dicer endonuclease controls kidney development and physiological functions. PMID- 29159955 TI - Reply. PMID- 29159956 TI - Vulvar swelling as the first presentation of Crohn's disease in children-A report of three cases. AB - Vulvar swelling is a rare manifestation of metastatic Crohn's disease in children. It often predates gastrointestinal symptoms and can be the first presentation of pediatric Crohn's disease. We report three cases of pediatric Crohn's disease presenting with vulvar swelling. We discuss this rare presentation and its treatment and highlight the importance of recognizing it so that prompt investigation and appropriate management can be initiated. PMID- 29159957 TI - Evaluating performance of a user-trained MR lung tumor autocontouring algorithm in the context of intra- and interobserver variations. AB - PURPOSE: Real-time tracking of lung tumors using magnetic resonance imaging (MRI) has been proposed as a potential strategy to mitigate the ill-effects of breathing motion in radiation therapy. Several autocontouring methods have been evaluated against a "gold standard" of a single human expert user. However, contours drawn by experts have inherent intra- and interobserver variations. In this study, we aim to evaluate our user-trained autocontouring algorithm with manually drawn contours from multiple expert users, and to contextualize the accuracy of these autocontours within intra- and interobserver variations. METHODS: Six nonsmall cell lung cancer patients were recruited, with institutional ethics approval. Patients were imaged with a clinical 3 T Philips MR scanner using a dynamic 2D balanced SSFP sequence under free breathing. Three radiation oncology experts, each in two separate sessions, contoured 130 dynamic images for each patient. For autocontouring, the first 30 images were used for algorithm training, and the remaining 100 images were autocontoured and evaluated. Autocontours were compared against manual contours in terms of Dice's coefficient (DC) and Hausdorff distances (dH ). Intra- and interobserver variations of the manual contours were also evaluated. RESULTS: When compared with the manual contours of the expert user who trained it, the algorithm generates autocontours whose evaluation metrics (same session: DC = 0.90(0.03), dH = 3.8(1.6) mm; different session DC = 0.88(0.04), dH = 4.3(1.5) mm) are similar to or better than intraobserver variations (DC = 0.88(0.04), and dH = 4.3(1.7) mm) between two sessions. The algorithm's autocontours are also compared to the manual contours from different expert users with evaluation metrics (DC = 0.87(0.04), dH = 4.8(1.7) mm) similar to interobserver variations (DC = 0.87(0.04), dH = 4.7(1.6) mm). CONCLUSIONS: Our autocontouring algorithm delineates tumor contours (<20 ms per contour), in dynamic MRI of lung, that are comparable to multiple human experts (several seconds per contour), but at a much faster speed. At the same time, the agreement between autocontours and manual contours is comparable to the intra- and interobserver variations. This algorithm may be a key component of the real time tumor tracking workflow for our hybrid Linac-MR device in the future. PMID- 29159958 TI - Evaluation of a Low-risk Mild Traumatic Brain Injury and Intracranial Hemorrhage Emergency Department Observation Protocol. AB - OBJECTIVES: Among emergency physicians, there is wide variation in admitting practices for patients who suffered a mild traumatic brain injury (TBI) with an intracranial hemorrhage (ICH). The purpose of this study was to evaluate the effects of implementing a protocol in the emergency department (ED) observation unit for patients with mild TBI and ICH. METHODS: This retrospective cohort study was approved by the institutional review board. Study subjects were patients >= 18 years of age with an International Classification of Diseases code corresponding to a traumatic ICH and admitted to an ED observation unit (EDOU) of an urban, academic Level I trauma center between February 1, 2015, and January 31, 2017. Patient data and discharge disposition were abstracted from the electronic health record, and imaging data, from the final neuroradiologist report. To measure kappa, two abstractors independently collected data for presence of neuro deficit from a 10% random sample of the medical charts. Using a multivariable logistic regression model with a propensity score of the probability of placement in the EDOU before and after protocol implementation as a covariate, we sought to determine the pre-post effects of implementing a protocol on the composite outcome of admission to the floor, intensive care unit, or operating room from the EDOU and the proportion of patients with worsening findings on repeat computed tomography (CT) head scan in the EDOU. RESULTS: A total of 379 patients were identified during the study period; 83 were excluded as they were found to have no ICH on chart review. Inter-rater reliability kappa statistic was 0.63 for 30 charts. Among the 296 patients who remained eligible and comprised the study population, 143 were in the preprotocol period and 153 after protocol implementation. The EDOU protocol was associated with an independently statistically significant decreased odds ratio (OR) for admission or worsening ICH on repeat CT scan (OR = 0.45, 95% confidence interval [CI] = 0.25-0.82, p = 0.009) in the observation unit. After a stay in the EDOU, 26% (37/143) of patients required an inpatient admission before implementation of the protocol and 13% (20/153) of patients required an inpatient admission after protocol implementation. There was no statistically significant difference in log transformed EDOU length of stay (LOS) between the groups after adjusting for propensity score (p = 0.34). CONCLUSIONS: While there was no difference in EDOU LOS, implementing a low-risk mild TBI and ICH protocol in the EDOU may decrease the rate of inpatient admissions from the EDOU. A protocol-driven observation unit may help physicians by standardizing eligibility criteria and by providing guidance on management. As the propensity score method limits our ability to create a straightforward predictive model, a future larger study should validate the results. PMID- 29159959 TI - Influence of body condition on the population dynamics of Atlantic salmon with consideration of the potential impact of sea lice. AB - Atlantic salmon Salmo salar is an iconic species of high conservation and economic importance. At sea, individuals typically are subject to sea lice infestation, which can have detrimental effects on their host. Over recent decades, the body condition and marine survival in NE Atlantic stocks have generally decreased, reflected in fewer adults returning to rivers, which is partly attributable to sea lice. We developed a deterministic stage-structured population model to assess condition-mediated population dynamics resulting in changing fecundity, age at sexual maturation and marine survival rate. The model is parameterized using data from the North Esk system, north-east Scotland. Both constant and density-dependent juvenile survival rates are considered. We show that even small sea lice-mediated changes in mean body condition of MSW can cause substantial population declines, whereas 1SW condition is less influential. Density dependence alleviates the condition-mediated population effect. The resilience of the population to demographic perturbations declines as adult condition is reduced. Indirect demographic changes in salmonid life-history traits (e.g., body condition) are often considered unimportant for population trajectory. The model shows that Atlantic salmon population dynamics can be highly responsive to sea lice-mediated effects on adult body condition, thus highlighting the importance of non-lethal parasitic long-term effects. PMID- 29159961 TI - Primary pleural squamous cell carcinoma: A diagnostic challenge. PMID- 29159962 TI - Expression profile of N-cadherin and protocadherin-19 in postnatal mouse limbic structures. AB - Cadherins are a superfamily of calcium-dependent cell adhesion molecules that are involved in brain development and organization. Previous genetic studies revealed that mutations in protocadherin-19 (Pcdh19) lead to an epilepsy syndrome with a variable degree of cognitive disability. Seizure origins are located in the frontotemporal and limbic structures. Expression studies of Pcdh19 in mouse confirmed a widespread presence during brain development while the function and the pathogenesis of Pcdh19 are still unknown in mammals. The neuronal cadherin (N cadherin; Ncdh) is known for its important role in neurulation, brain development and regulation of synaptic function. Studies in zebrafish revealed that both cadherins can interact with each other in cell adhesion. We investigated the expression pattern of Pcdh19 and Ncdh in limbic structures at four postnatal stages of C57BL/6J mice by using double-label in situ hybridization. Results confirm a strong expression of both, Ncdh and Pcdh19, in structures of the limbic system with overlapping expression patterns particularly within regions of the amygdala, the hippocampus and the ventral hypothalamus. A detailed analysis of the limbic system highlight clear expression boundaries between several nuclei and reveal the fine regulation of Pcdh19 and Ncdh expression during the first postnatal week. Most expression patterns of both cadherins remain constant with a few exceptions particularly between P2 and P5. PMID- 29159963 TI - Nevi and lasers: Practical considerations. AB - Lasers are increasingly used for elective ablation of melanocytic nevi (MN). However, the associated risks of treating MN with lasers are debated and not well studied. Theoretical risks include inadvertently treating a melanoma mistaken for a nevus, the inability to remove all nevus cells and the possibility for residual cells to undergo malignant transformation, and the difficulty in clinically monitoring the remnant nevus for melanoma progression. Additional concerns include the morphological suitability of a lesion for laser removal and managing patients' expectations about the variable cosmetic outcomes. These potential issues have prompted us to outline some practical suggestions for clinicians and patients to consider when determining the suitability of a nevus for laser ablation. The choice to perform laser removal of a nevus is personal, both from the perspective of the treating physician and that of the person being treated. While acknowledging some uncertainty, we believe that these suggestions can help mitigate risk and improve patient outcomes. Lasers Surg. Med. 50:7-9, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29159960 TI - Mapping the structural and functional network architecture of the medial temporal lobe using 7T MRI. AB - Medial temporal lobe (MTL) subregions play integral roles in memory function and are differentially affected in various neurological and psychiatric disorders. The ability to structurally and functionally characterize these subregions may be important to understanding MTL physiology and diagnosing diseases involving the MTL. In this study, we characterized network architecture of the MTL in healthy subjects (n = 31) using both resting state functional MRI and MTL-focused T2 weighted structural MRI at 7 tesla. Ten MTL subregions per hemisphere, including hippocampal subfields and cortical regions of the parahippocampal gyrus, were segmented for each subject using a multi-atlas algorithm. Both structural covariance matrices from correlations of subregion volumes across subjects, and functional connectivity matrices from correlations between subregion BOLD time series were generated. We found a moderate structural and strong functional inter hemispheric symmetry. Several bilateral hippocampal subregions (CA1, dentate gyrus, and subiculum) emerged as functional network hubs. We also observed that the structural and functional networks naturally separated into two modules closely corresponding to (a) bilateral hippocampal formations, and (b) bilateral extra-hippocampal structures. Finally, we found a significant correlation in structural and functional connectivity (r = 0.25). Our findings represent a comprehensive analysis of network topology of the MTL at the subregion level. We share our data, methods, and findings as a reference for imaging methods and disease-based research. PMID- 29159964 TI - Blocking antibodies induced by allergen-specific immunotherapy ameliorate allergic airway disease in a human/mouse chimeric model. AB - BACKGROUND: Allergen-specific immunotherapy (AIT) induces specific blocking antibodies (Ab), which are claimed to prevent IgE-mediated reactions to allergens. Additionally, AIT modulates cellular responses to allergens, for example, by desensitizing effector cells, inducing regulatory T and B lymphocytes and immune deviation. It is still enigmatic which of these mechanisms mediate(s) clinical tolerance. We sought to address the role of AIT-induced blocking Ab separately from cellular responses in a chimeric human/mouse model of respiratory allergy. METHODS: Nonobese diabetic severe combined immunodeficient gammac-/- (NSG) mice received intraperitoneally allergen-reactive PBMC from birch pollen allergic patients together with birch pollen extract and human IL-4. Engraftment was assessed by flow cytometry. Airway hyperresponsiveness (AHR) and bronchial inflammation were analyzed after intranasal challenges with allergen or PBS. Sera collected from patients before and during AIT with birch pollen were added to the allergen prior to intranasal challenge. The IgE-blocking activity of post-AIT sera was assessed in vitro. RESULTS: Human cells were detected in cell suspensions of murine lungs and spleens indicating successful humanization. Humanized mice displayed a more pronounced AHR and bronchial inflammation when challenged with allergen compared to negative controls. Post-AIT sera exerted IgE blocking activity. In contrast to pre-AIT sera, the presence of heterologous and autologous post-AIT sera significantly reduced the allergic airway inflammation and matched their IgE-blocking activity determined in vitro. CONCLUSION: Our data demonstrate that post-AIT sera with IgE-blocking activity ameliorate allergic airway inflammation in a human/mouse chimeric model of respiratory allergy independently of AIT-induced cellular changes. PMID- 29159966 TI - Interrogating marine virus-host interactions and elemental transfer with BONCAT and nanoSIMS-based methods. AB - While the collective impact of marine viruses has become more apparent over the last decade, a deeper understanding of virus-host dynamics and the role of viruses in nutrient cycling would benefit from direct observations at the single virus level. We describe two new complementary approaches - stable isotope probing coupled with nanoscale secondary ion mass spectrometry (nanoSIMS) and fluorescence-based biorthogonal non-canonical amino acid tagging (BONCAT) - for studying the activity and biogeochemical influence of marine viruses. These tools were developed and tested using several ecologically relevant model systems (Emiliania huxleyi/EhV207, Synechococcus sp. WH8101/Syn1 and Escherichia coli/T7). By resolving carbon and nitrogen enrichment in viral particles, we demonstrate the power of nanoSIMS tracer experiments in obtaining quantitative estimates for the total number of viruses produced directly from a particular production pathway (by isotopically labelling host substrates). Additionally, we show through laboratory experiments and a pilot field study that BONCAT can be used to directly quantify viral production (via epifluorescence microscopy) with minor sample manipulation and no dependency on conversion factors. This technique can also be used to detect newly synthesized viral proteins. Together these tools will help fill critical gaps in our understanding of the biogeochemical impact of viruses in the ocean. PMID- 29159967 TI - Exploiting lambda-Orthogonal Photoligation for Layered Surface Patterning. AB - We exploit lambda-orthogonal photoligation of nitrile imine-mediated tetrazole ene cycloaddition (NITEC) chemistry to generate complex, interconnected surface modifications via a simple layered surface patterning approach. By judicious choice of activating chromophores, we introduce a one pot reaction where nitrile imine formation can be triggered independently of other tetrazoles present. When irradiated with visible light, a tetrazole bearing a pyrene chromophore undergoes quantitative elimination of nitrogen to release nitrile imine (which subsequently undergoes trapping with a dipolarophile in a 1,3 dipolar cycloaddition) whereas a tetrazole bearing a phenyl moiety remains unreacted. Subsequent irradiation of the solution with UV light yields the N-phenyl containing nitrile imine quantitatively, while the pyrene pyrazoline adduct remains unchanged. This lambda orthogonal photoligation was subsequently exploited for the generation of layered patterned surfaces. Specifically, the visible light active tetrazole was grafted to a silicon wafer and subsequently photolithographically patterned with a dipolarophile modified with a UV-active tetrazole. Various electron deficient olefins were then patterned in a spatially resolved manner relying on different light activation. The desired functionality was successfully imaged on the silicon wafers using time-of-flight-secondary ion mass spectrometry (ToF-SIMS), demonstrating that a powerful mask-less lithographic platform technology has been established. PMID- 29159965 TI - Improvement in lipids after switch to boosted atazanavir or darunavir in children/adolescents with perinatally acquired HIV on older protease inhibitors: results from the Pediatric HIV/AIDS Cohort Study. AB - OBJECTIVES: Dyslipidaemia is common in perinatally HIV-infected (PHIV) youth receiving protease inhibitors (PIs). Few studies have evaluated longitudinal lipid changes in PHIV youth after switch to newer PIs. METHODS: We compared longitudinal changes in fasting lipids [total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and TC:HDL-C ratio] in PHIV youth enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol (AMP) study who switched to atazanavir/ritonavir (ATV/r)- or darunavir/ritonavir (DRV/r)-based antiretroviral therapy (ART) from an older PI-based ART and those remaining on an older PI. Generalized estimating equation models were fitted to assess the association of a switch to ATV/r- or DRV/r-based ART with the rate of change in lipids, adjusted for potential confounders. RESULTS: From 2007 to 2014, 47 PHIV children/adolescents switched to ATV/r or DRV/r, while 120 remained on an older PI [primarily lopinavir/r (72%) and nelfinavir (24%)]. Baseline age ranged from 7 to 21 years. After adjustment for age, Tanner stage, race/ethnicity, and HIV RNA level, a switch to ATV/r or DRV/r was associated with a more rapid annual rate of decline in the ratio of TC:HDL-C. (beta = -0.12; P = 0.039) than remaining on an older PI. On average, TC declined by 4.57 mg/dL/year (P = 0.057) more in the switch group. A switch to ATV/r or DRV/r was not associated with the rate of HDL C, LDL-C, or TG change. CONCLUSIONS: A switch to ATV/r or DRV/r may result in more rapid reduction in TC and the TC:HDL-C ratio in PHIV youth, potentially impacting long-term cardiovascular disease risk. PMID- 29159968 TI - Histochemical and immunohistochemical characterization of rodlet cells in the intestine of two teleosts, Anguilla anguilla and Cyprinus carpio. AB - Rodlet cells (RC) are characterized by a distinctive cell cortex and conspicuous inclusions named "rodlets." These cells are particularly abundant and large in size in intestine of eels. Histochemical, immunohistochemical and ultrastructural investigations were carried out on European eel Anguilla anguilla and Common carp Cyprinus carpio from Northern Italy. Eight biotinylated lectins were used to probe for specific carbohydrate residues in deparaffinized, hydrated intestinal sections of eel and carp. Five antibodies were tested on intestinal sections of both fish species: inducible nitric oxide synthase (i-NOS), leu-enkephalin, lysozyme, serotonin and tumour necrosis factor-alpha. Lectin histochemistry revealed rodlet cells (RCs) of the eel intestine to react with two of the eight lectins tested, specifically Concanavalin A (ConA) and Sambucus Nigra Agglutinin (SNA). This contrasted to lectin staining of RCs in the intestine of common carp, where four of the eight lectins showed a positive reaction; Dolichos Biflorus Agglutinin (DBA), Wheat Germ Agglutinin (WGA), SNA and ConA. RCs in eel and carp intestine were immunoreactive with antibodies to lysozyme and i-NOS. The occurrence of the inflammatory peptides lysozyme and i-NOS in RCs of the eel and common carp poses in favour that these cells are involved in the mechanism of defence against pathogens. PMID- 29159969 TI - Reply. PMID- 29159970 TI - Parental education accounts for variability in the IQs of probands with Down syndrome: A longitudinal study. AB - Recent work has demonstrated that variability in probands' phenotypes, including physical features, cognitive abilities, social functioning, and other developmental domains, is influenced by parental traits. Here we examine the role of parental education as a factor contributing to the variability of intelligence quotient (IQ) of offspring with trisomy 21. Participants were 43 probands with trisomy 21, aged 4-21 years of age, and their parents. Data were collected on parental education, and a bi-parental mean education score (BMES) was calculated. Probands' cognitive abilities were assessed by the Stanford-Binet 4th edition at baseline (T1), and again 24 months later (T2). Probands were placed into one of two age groups: 4-12 years and 13-21 years. Results indicated higher parent proband correlations in Age Group 2 (mean r = .47) relative to Age Group 1 (mean r = .33) and increasing parent-proband correlations across time, with mean correlations of Age Group 1, T1: r = .26, T2: 39; Age Group 2 T1: r = .49, T2: r = 46. Despite the expected IQ deficits observed in trisomy 21 probands, parental education may still contribute to the variability of probands' cognitive abilities. These findings are consistent with the literature noting increasing heritability of IQ with development. PMID- 29159971 TI - Vocabulary intervention for adolescents with language disorder: a systematic review. AB - BACKGROUND: Language disorder and associated vocabulary difficulties can persist into adolescence, and can impact on long-term life outcomes. Previous reviews have shown that a variety of intervention techniques can successfully enhance students' vocabulary skills; however, none has investigated vocabulary intervention specifically for adolescents with language disorder. AIMS: To carry out a systematic review of the literature on vocabulary interventions for adolescents with language disorder. METHODS & PROCEDURES: A systematic search of 14 databases and other sources yielded 1320 studies, of which 13 met inclusion criteria. Inclusion criteria were: intervention effectiveness studies with a focus on enhancing oral receptive and/or expressive vocabulary skills in the study's aims; participants in the age range 11;0-16;11 with receptive and/or expressive language difficulties of any aetiology. MAIN CONTRIBUTION: There was a high degree of diversity between studies. Types of intervention included: semantic intervention (four studies); comparison of phonological versus semantic intervention (two); and combined phonological-semantic intervention (seven). The strongest evidence for effectiveness was found with a combined phonological semantic approach. The evidence suggested a potential for all models of delivery to be helpful (individual, small group and whole class). CONCLUSIONS & IMPLICATIONS: Tentative evidence is emerging for the effectiveness of a phonological-semantic approach in enhancing the vocabulary skills of adolescents who have language disorder. Future research needs to refine and develop the methodologies used in this diverse group of studies in order to replicate their findings and to build consensus. PMID- 29159973 TI - Diverse effect of phosphatidylcholine biosynthetic genes on phospholipid homeostasis, cell autophagy and fungal developments in Metarhizium robertsii. AB - Phosphatidylcholine (PC) plays an important role in maintaining membrane integrity and functionality. In this study, two key genes (Mrpct and Mrpem) putatively involved in the cytidine diphosphate (CDP)-choline and phosphatidylethanolamine N-methyltransferase (PEMT) pathways for PC biosynthesis were characterized in the insect pathogenic fungus Metarhizium robertsii. The results indicated that disruption of Mrpct did not lead to any reduction of total PC content but impaired fungal virulence and increased cellular accumulation of triacylglycerol. Deletion of Mrpem reduced PC content and impaired fungal conidiation and infection structure differentiation but did not result in virulence defects. Lipidomic analysis revealed that deletion of Mrpct and Mrpem resulted in dissimilar effects on increase and decrease of PC moieties and other phospholipid species accumulations. Interestingly, we found that these two genes played opposite roles in activation of cell autophagy when the fungi were grown in a nutrient-rich medium. The connection between PC metabolism and autophagy was confirmed because PC content was drastically reduced in Mratg8Delta and that the addition of PC could rescue null mutant sporulation defect. The results of this study facilitate the understanding of PC metabolism on fungal physiology. PMID- 29159972 TI - Vitamin B12 deficiency and impaired expression of amnionless during aging. AB - BACKGROUND: Physical frailty and loss of mobility in elderly individuals lead to reduced independence, quality of life, and increased mortality. Vitamin B12 deficiency has been linked to several age-related chronic diseases, including in the musculo-skeletal system, where vitamin B12 deficiency is generally believed to be linked to poor nutritional intake. In the present study, we asked whether aging and frailty associate with altered vitamin B12 homeostasis in humans and investigated the underlying molecular mechanisms using preclinical models. METHODS: We analysed a subset of the Singapore Longitudinal Aging Study and stratified 238 participants based on age and Fried frailty criteria. Levels of methyl-malonic acid (MMA), a marker for vitamin B12 deficiency, and amnionless, the vitamin B12 co-receptor that anchors the vitamin B12 transport complex to the membrane of epithelial cells, were measured in plasma. In addition, vitamin B12 levels and the molecular mechanisms of vitamin B12 uptake and excretion were analysed in ileum, kidney, liver, and blood using a rat model of natural aging where nutritional intake is fully controlled. RESULTS: We demonstrate that aging and frailty are associated with a higher prevalence of functional vitamin B12 deficiency that can be detected by increased levels of MMA in blood (rho = 0.25; P = 0.00013). The decline in circulating vitamin B12 levels is recapitulated in a rat model of natural aging where food composition and intake are stable. At the molecular level, these perturbations involve altered expression of amnionless in the ileum and kidney. Interestingly, we demonstrate that amnionless can be detected in serum where its levels increase during aging in both rodents and human (P = 3.3e-07 and 9.2e-07, respectively). Blood amnionless levels negatively correlate with vitamin B12 in rats (r2 = 0.305; P = 0.0042) and positively correlate with the vitamin B12 deficiency marker MMA in humans (rho = 0.22; P = 0.00068). CONCLUSIONS: Our results demonstrate that aging and frailty cause intrinsic vitamin B12 deficiencies, which can occur independently of nutritional intake. Mechanistically, vitamin B12 deficiency involves the physio-pathological decline of both the intestinal uptake and the renal reabsorption system for vitamin B12. Finally, amnionless is a novel biomarker which can detect perturbed vitamin B12 bioavailability during aging and physical frailty. PMID- 29159974 TI - Ultrasonographic anatomy of the atlanto-occipital region and ultrasound-guided cerebrospinal fluid collection in rabbits (Oryctolagus cuniculus). AB - Cerebrospinal fluid analyses are important for diagnosis of neurologic problems in rabbits and for translational research projects using rabbits as models. Blind puncture of the cisterna magna is the current standard technique for sampling cerebrospinal fluid in this species. However, the complexity and small size of the cisterna magna and surrounding structures are limitations of this technique. Aims of this prospective, anatomic, pilot study were to (1) describe the normal anatomy of the atlanto-occipital region, (2) describe ultrasonographic anatomic landmarks, and (3) develop and evaluate a technique for ultrasound-guided puncture of the cisterna magna for cerebrospinal fluid sampling in rabbits. Thirty healthy rabbits were included and the study was conducted in three stages. Three rabbit cadavers were used for the first stage of the study. Then, the second stage was completed using 13 rabbit cadavers. Finally, the third stage was completed in 14 live rabbits. The ultrasound-guided puncture performed in 13 cadavers was successful at the first attempt in 10 cases, and at the second attempt in the remaining three cases. In the in vivo study, the ultrasound-guided puncture was successful in all 14 cases, without signs of complications. Findings supported the use of ultrasound-guided puncture of the cisterna magna as a safe technique that may be used routinely or when the sample of cerebrospinal fluid cannot be obtained with the blind technique in rabbits. PMID- 29159975 TI - RCAT reflects symptom control and quality of life in allergic rhinoconjunctivitis patients. AB - BACKGROUND: The Global Allergy and Asthma European Network (GA2 LEN) Taskforce has requested more data on correlations between various patient-reported outcomes (PROs) in clinical trials on allergy. We compared three tools-the Rhinitis Control Assessment Test (RCAT), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Rhinitis Total Symptom Score (RTSS)-to determine whether the RCAT alone is a sufficient primary outcome parameter in clinical trials on allergic rhinoconjunctivitis. METHODS: In two double-blind, placebo-controlled immunotherapy studies, 33 patients allergic to grass pollen and 94 to birch pollen completed two questionnaires (RCAT and RQLQ) and kept their own symptom diary from which the RTSS was calculated. RESULTS: Upon comparing RCAT and RQLQ results, we found strong correlations of r = -0.871 for grass pollen-allergic patients and r = -0.795 for birch pollen-allergic patients. The comparison between RCAT and RTSS results showed a strong correlation of r = -0.811 (grass pollen-allergic patients) and a moderate correlation of r = -0.539 (birch pollen allergic patients). In the RCAT, 69.7% of grass pollen-allergic patients and 45.7% of birch pollen-allergic patients receiving guideline-concordant therapy were regarded as having insufficiently controlled symptoms. CONCLUSION: The strong correlations suggest that the RCAT alone is equivalent to the RQLQ with respect to patients' symptom control and quality of life. Patients with uncontrolled symptoms can be identified using the RCAT. Hence, the physician can decide whether symptomatic therapy can be intensified or allergy immunotherapy should be administered. PMID- 29159976 TI - Design and study of lipopeptide inhibitors on preventing aggregation of human islet amyloid polypeptide residues 11-20. AB - Type 2 diabetes mellitus, a kind of conformational disease, has become an epidemic disease, which seriously endangers the quality of life and health of human beings. The deposition of human islet amyloid polypeptide (hIAPP) has been considered as one of the major pathological features of type 2 diabetes mellitus. As lipopeptides have some hydrophobic groups, which are similar to the reported aggregation inhibitors, and some lipopeptides could prevent cells from depositing of amyloid fibrils, several potential lipopeptide inhibitors have been engineered and synthesized, which have been assessed for their inhibitory effect in preventing amyloid fibrils formation of hIAPP11-20 by using the conventional thioflavin-T fluorescence assay and new technique microscale thermophoresis (MST). The final amyloid fibrils of hIAPP11-20 were characterized by transmission electron microscopy. Results suggested that with the increasing length of alkyl chain, the antiaggregation efficiency of lipopeptide inhibitors towards hIAPP11 20 increased gradually. Meanwhile, the amount of arginines, which represent the head groups of lipopeptides, may also have some influence. The binding events also showed that the inhibitory efficiency of these lipopeptide inhibitors was enhanced with the increase of affinities between lipopeptides and hIAPP11-20 , which were obtained from MST. This study demonstrated the efficiency of lipopeptides in inhibiting the aggregation of hIAPP11-20 and proved that MST could be regarded as an appropriate and rapid method to screen potential inhibitors of hIAPP11-20 or other amyloid proteins. This study also broadens the types of inhibitors on inhibiting amyloid formation of hIAPP. PMID- 29159977 TI - Migrant children's health problems, care needs, and inequalities: European primary care paediatricians' perspective. AB - BACKGROUND: Primary care paediatricians' perception of migrant children's health in Europe has not been explored before. Our aim was to examine European paediatricians' knowledge on migrant children's health problems, needs, inequalities, and barriers to access health care. METHODS: European primary care paediatricians were invited by the European Academy of Paediatrics Research in Ambulatory Setting Network country coordinators to complete a web-based survey concerning health care of migrant children. A descriptive analysis of all variables was performed. RESULTS: The survey was completed by 492 paediatricians. Sixty-three per cent of the respondents reported that the general health of migrant children is worse than that of nonmigrants, chronic diseases cited by 66% of the respondents as the most frequent health problem. Sixty-six per cent of the paediatricians reported that migrant children have different health needs compared to nonmigrant children, proper oral health care mentioned by 86% of the respondents. Cultural/linguistic factors have been reported as the most frequent barrier (90%).to access health care. However, only 37% of providers have access to professional interpreters and cultural mediators. Fifty-two per cent and 32% do not know whether one or more of the family members are undocumented and whether they are refugees/asylum seekers, respectively. Updated guidelines for care of migrant children are available for only 35% of respondents, and 80% of them have not received specific training on migrant children's care. CONCLUSIONS: European primary care paediatricians recognize migrant children as a population at risk with more frequent and specific health problems and needs, but they are often unaware of their legal state. Lack of interpreters augments the existing language barriers to access proper care and should be solved. Widespread lack of guidelines and specific providers' training should be addressed to optimize health care delivery to migrant children. PMID- 29159978 TI - AHNS Series: Do you know your guidelines? Guideline recommendations for head and neck cancer of unknown primary site. AB - This article reviews the clinical practice guidelines for head and neck oncology focusing on the management of head and neck cancers of unknown primary (CUP). The primary purpose of this series is to raise awareness of the current guidelines in head and neck oncology by reviewing the recommendations and the evidence supporting such recommendations, particularly those published by the National Comprehensive Cancer Network (NCCN). We review the importance of a thorough history and physical examination, the impact of the American Joint Committee on Cancer (AJCC) eighth edition changes and the importance of immunohistochemistry, the timing and type of imaging, the role of panendoscopy and tonsillectomy (palatine and lingual), and the role of surgery, radiation, and chemotherapy in the primary management of these tumors. PMID- 29159979 TI - Ultrasound Microbubbles Enhance the Activity of Vancomycin Against Staphylococcus epidermidis Biofilms In Vivo. AB - OBJECTIVES: Staphylococcus epidermidis is the predominant pathogen of device associated infections. By forming biofilms on the device surface, S epidermidis has substantial resistance to antibiotics and is difficult to eradicate. This study aimed to explore the synergistic effect of ultrasound (US)-mediated microbubbles combined with vancomycin on S epidermidis biofilms in a rabbit model. METHODS: Two polytetrafluoroethene catheters with preformed S epidermidis biofilms were implanted subcutaneously in a rabbit, one on either side of the spine. Animals were randomized into different treatment groups, with each rabbit acting as its own control and treatment. Ultrasound was applied from 24 to 72 hours after surgery 2 times a day. The parameters were 300 kHz and 0.5 W/cm2 in a 50% duty cycle, with or without microbubbles injected subcutaneously into the implantation site. After treatments, animals were euthanized, and implants were removed for a scanning electron microscopic examination and bacterial counting. The hearts, kidneys, livers, and subcutaneous tissues were sent for histopathologic examinations. RESULTS: Ultrasound + microbubbles increased the bactericidal action of vancomycin by decreasing biofilm viability from a mean +/- SD of 6.44 +/- 0.03 log10 colony-forming units per catheter in the control group to 3.49 +/- 0.02 log10 colony-forming units per catheter in US + microbubble + vancomycin group (P < .001). The antibacterial effect of US + microbubbles + vancomycin was more pronounced than that of US + vancomycin (P < .001). Under scanning electron microscopy, biofilms exposed to US + microbubbles + vancomycin showed a greater reduction in thickness and bacterial density than other treatments. Histopathologic examinations showed no abnormalities in organs and skins. CONCLUSIONS: Ultrasound microbubbles enhanced the antibacterial effect of vancomycin against S epidermidis biofilms in vivo without exerting obvious harms to the animals. PMID- 29159980 TI - Role of PI3K in myocardial ischaemic preconditioning: mapping pro-survival cascades at the trigger phase and at reperfusion. AB - The Reperfusion Injury Salvage Kinase (RISK) pathway is considered the main pro survival kinase cascade mediating the ischaemic preconditioning (IPC) cardioprotective effect. To assess the role of PI3K-Akt, its negative regulator PTEN and other pro-survival proteins such as ERK and STAT3 in the context of IPC, C57BL/6 mouse hearts were retrogradely perfused in a Langendorff system and subjected to 4 cycles of 5 min. ischaemia and 5 min. reperfusion prior to 35 min. of global ischaemia and 120 min. of reperfusion. Wortmannin, a PI3K inhibitor, was administered either at the stabilization period or during reperfusion. Infarct size was assessed using triphenyl tetrazolium staining, and phosphorylation levels of Akt, PTEN, ERK, GSK3beta and STAT3 were evaluated using Western blot analyses. IPC reduced infarct size in hearts subjected to lethal ischaemia and reperfusion, but this effect was lost in the presence of Wortmannin, whether it was present only during preconditioning or only during early reperfusion. IPC increased the levels of Akt phosphorylation during both phases and this effect was fully abrogated by PI3K, whilst its downstream GSK3beta was phosphorylated only during the trigger phase after IPC. Both PTEN and STAT3 were phosphorylated during both phases after IPC, but this was PI3K independent. IPC increases ERK phosphorylation during both phases, being only PI3K-dependent during the IPC phase. In conclusion, PI3K-Akt plays a major role in IPC-induced cardioprotection. However, PTEN, ERK and STAT3 are also phosphorylated by IPC through a PI3K-independent pathway, suggesting that cardioprotection is mediated through more than one cell signalling cascade. PMID- 29159981 TI - Understanding the metabolic burden of recombinant antibody production in Saccharomyces cerevisiae using a quantitative metabolomics approach. AB - The cellular changes induced by heterologous protein expression in the yeast Saccharomyces cerevisiae have been analysed on many levels and found to be significant. However, even though high-level protein production poses a metabolic burden, evaluation of the expression host at the level of the metabolome has often been neglected. We present a comparison of metabolite profiles of a wild type strain with those of three strains producing recombinant antibody variants of increasing size and complexity: an scFv fragment, an scFv-Fc fusion protein and a full-length IgG molecule. Under producing conditions, all three recombinant strains showed a clear decrease in growth rate compared with the wild-type strain and the severity of the growth phenotype increased with size of the protein. The levels of 76 intracellular metabolites were determined using a targeted (semi) quantitative mass spectrometry based approach. Based on unsupervised and supervised multivariate analysis of metabolite profiles, together with pathway activity profiling, the recombinant strains were found to be significantly different from each other and from the wild-type strain. We observed the most prominent changes in metabolite levels for metabolites involved in amino acid and redox metabolism. Induction of the unfolded protein response was detected in all producing strains and is considered to be a contributing factor to the overall metabolic burden on the cells. PMID- 29159982 TI - Temple syndrome as a differential diagnosis to Prader-Willi syndrome: Identifying three new patients. AB - The two imprinting syndromes Temple syndrome (TS14) and Prader-Willi syndrome (PWS) share many features in infancy and childhood. TS14 is an important, yet often neglected, differential diagnosis to PWS. We wanted to assess the frequency of TS14 among patients tested for PWS. In all samples submitted to our lab for genetic PWS testing during 2014 and 2015, we consecutively conducted additional analyses for TS14. A total of 143 samples were included. The most frequent indications for testing were developmental delay, overweight, and hypotonia. For TS14 testing, we performed a methylation-sensitive MLPA-kit detecting deletions and methylation aberrations in chromosomal region 14q32. TS14 was confirmed in 3 out of 143 patients (2.1%). In comparison, PWS was also confirmed in three patients. Brief clinical descriptions of the TS14 patients are presented. Temple syndrome is presumably underdiagnosed, and should be considered when testing children for PWS. PMID- 29159983 TI - Frequency of folate-related polymorphisms varies by skin pigmentation. AB - OBJECTIVES: Folate-mediated 1-carbon transfer processes are vital in human health but are susceptible to independent and interactive influences of genetic variance and environmental exposures. Evidence suggests folate levels may be impacted by genetic variance and environmental UVR, with the effect of UVR levels influenced in part by degree of skin pigmentation. Folate-related genes are also influenced by UVR levels; however, the potential relationship between key folate-related genes and skin pigmentation has not yet been explored. The purpose of this study was to examine potential associations between frequencies of key folate variants and degree of skin pigmentation. METHODS: Association between population prevalence of 17 variants in 9 folate-related genes (MTRR, MTR, MTHFR, CBS, SHMT1, MTHFD1, RFC1, BHMT, TYMS) and the Fitzpatrick skin phototype of populations was assessed via collation of genotypic data from ALFRED (Allele Frequency Database) and 1000 Genomes databases. RESULTS: A significant association between variant frequency and Fitzpatrick phototype was observed for 16 of 17 examined variants (P < .0029 Bonferroni corrected significance threshold in all cases). CONCLUSIONS: These findings demonstrate novel relationships between skin color and folate-related genes, with trends suggesting folate genotypes are selected to maintain homeostasis in the folate system under differing UVR conditions. PMID- 29159984 TI - Laryngeal candidiasis: Our experience from sixty biopsy specimens. PMID- 29159985 TI - Synthesized tissue-equivalent dielectric phantoms using salt and polyvinylpyrrolidone solutions. AB - PURPOSE: To explore the use of polyvinylpyrrolidone (PVP) for simulated materials with tissue-equivalent dielectric properties. METHODS: PVP and salt were used to control, respectively, relative permittivity and electrical conductivity in a collection of 63 samples with a range of solute concentrations. Their dielectric properties were measured with a commercial probe and fitted to a 3D polynomial in order to establish an empirical recipe. The material's thermal properties and MR spectra were measured. RESULTS: The empirical polynomial recipe (available at https://www.amri.ninds.nih.gov/cgi-bin/phantomrecipe) provides the PVP and salt concentrations required for dielectric materials with permittivity and electrical conductivity values between approximately 45 and 78, and 0.1 to 2 siemens per meter, respectively, from 50 MHz to 4.5 GHz. The second- (solute concentrations) and seventh- (frequency) order polynomial recipe provided less than 2.5% relative error between the measured and target properties. PVP side peaks in the spectra were minor and unaffected by temperature changes. CONCLUSION: PVP-based phantoms are easy to prepare and nontoxic, and their semitransparency makes air bubbles easy to identify. The polymer can be used to create simulated material with a range of dielectric properties, negligible spectral side peaks, and long T2 relaxation time, which are favorable in many MR applications. Magn Reson Med 80:413-419, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29159986 TI - L-asparaginase isolated from Streptomyces ansochromogenes promotes Th1 profile and activates CD8+ T cells in human PBMC: an in vitro investigation. AB - AIMS: A new L-asparaginase produced by Streptomyces ansochromogenes UFPEDA 3420 actinobacteria was used in this study against human lymphocyte cultures to evaluate the immunological profile induced by this enzyme. METHODS AND RESULTS: Cultures of lymphocytes were stimulated with S. ansochromogenes L-asparaginase, and cytotoxicity, cell viability, cell stimulation and cytokine production were analysed. This new S. ansochromogenes L-asparaginase induced activation and proliferation of the TCD8+ lymphocyte subset and produced higher TNF-alpha, IFN gamma, IL-2 and IL-10 levels in a 24-h assay. CONCLUSION: Streptomyces ansochromogenes L-asparaginase is a promising molecule to be used in in vivo models and to deepen preclinical tests against acute lymphoblast leukaemia. SIGNIFICANCE AND IMPACT OF STUDY: L-asparaginase is an indispensable component of the chemotherapeutic treatment of acute lymphoblast leukaemia (ALL) and acute myeloid leukaemia (AML). Currently, drugs such as Asparaginase(r) , Kidrolase(r) , and Elspar(r) and Erwinase(r) are efficient against leukemic disease, but promote immunosuppression and other side effects in human organisms. Our purified S. ansochromogenes L-asparaginase showed promissory results inducing, in vitro, higher immunostimulation in human PBMC, especially in T CD8+ lymphocyte subsets. PMID- 29159987 TI - MED13L loss-of-function variants in two patients with syndromic Pierre Robin sequence. AB - We report two unrelated patients with Pierre Robin sequence (PRS) and a strikingly similar combination of associated features. Whole exome sequencing was performed for both patients. No single gene containing likely pathogenic point mutations in both patients could be identified, but the finding of an essential splice site mutation in mediator complex subunit 13 like (MED13L) in one patient prompted the investigation of copy number variants in MED13L in the other, leading to the identification of an intragenic deletion. Disruption of MED13L, encoding a component of the Mediator complex, is increasingly recognized as the cause of an intellectual disability syndrome with associated facial dysmorphism. Our findings suggest that MED13L-related disorders are a possible differential diagnosis for syndromic PRS. PMID- 29159988 TI - Bleomycin-induced flagellate erythema after venous malformation sclerosis-Case report and brief review. AB - Bleomycin-induced flagellate erythema is a rare but typical skin toxicity of bleomycin. We report the case of a boy with a left foot venous malformation who developed this skin rash after two sessions of bleomycin intralesional injection. We discuss the mechanism and characteristics of this reaction to bleomycin, which is usually benign and self-limited. We conclude that, although rare, flagellate pigmentation can occur when bleomycin is used as a sclerosant in children. PMID- 29159990 TI - Context Effects and Spoken Word Recognition of Chinese: An Eye-Tracking Study. AB - This study examined the time-course of context effects on spoken word recognition during Chinese sentence processing. We recruited 60 native Mandarin listeners to participate in an eye-tracking experiment. In this eye-tracking experiment, listeners were told to listen to a sentence carefully, which ended with a Chinese homophone, and look at different visual probes (Chinese characters or different line-drawing pictures) presented concurrently on the computer screen naturally. Different types of context and probe types were manipulated in the experiment. The results showed that (1) preceding sentence context had an early effect on spoken word recognition processes and (2) phonological information of the distracters had only a negligible effect on the spoken word recognition processes. Finally, the patterns of eye-tracking results seemed to favor an interactive approach in spoken word recognition. PMID- 29159989 TI - General phase regularized reconstruction using phase cycling. AB - PURPOSE: To develop a general phase regularized image reconstruction method, with applications to partial Fourier imaging, water-fat imaging and flow imaging. THEORY AND METHODS: The problem of enforcing phase constraints in reconstruction was studied under a regularized inverse problem framework. A general phase regularized reconstruction algorithm was proposed to enable various joint reconstruction of partial Fourier imaging, water-fat imaging and flow imaging, along with parallel imaging (PI) and compressed sensing (CS). Since phase regularized reconstruction is inherently non-convex and sensitive to phase wraps in the initial solution, a reconstruction technique, named phase cycling, was proposed to render the overall algorithm invariant to phase wraps. The proposed method was applied to retrospectively under-sampled in vivo datasets and compared with state of the art reconstruction methods. RESULTS: Phase cycling reconstructions showed reduction of artifacts compared to reconstructions without phase cycling and achieved similar performances as state of the art results in partial Fourier, water-fat and divergence-free regularized flow reconstruction. Joint reconstruction of partial Fourier + water-fat imaging + PI + CS, and partial Fourier + divergence-free regularized flow imaging + PI + CS were demonstrated. CONCLUSION: The proposed phase cycling reconstruction provides an alternative way to perform phase regularized reconstruction, without the need to perform phase unwrapping. It is robust to the choice of initial solutions and encourages the joint reconstruction of phase imaging applications. Magn Reson Med 80:112-125, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29159991 TI - Journey to the centre of the cell: Virtual reality immersion into scientific data. AB - Visualization of scientific data is crucial not only for scientific discovery but also to communicate science and medicine to both experts and a general audience. Until recently, we have been limited to visualizing the three-dimensional (3D) world of biology in 2 dimensions. Renderings of 3D cells are still traditionally displayed using two-dimensional (2D) media, such as on a computer screen or paper. However, the advent of consumer grade virtual reality (VR) headsets such as Oculus Rift and HTC Vive means it is now possible to visualize and interact with scientific data in a 3D virtual world. In addition, new microscopic methods provide an unprecedented opportunity to obtain new 3D data sets. In this perspective article, we highlight how we have used cutting edge imaging techniques to build a 3D virtual model of a cell from serial block-face scanning electron microscope (SBEM) imaging data. This model allows scientists, students and members of the public to explore and interact with a "real" cell. Early testing of this immersive environment indicates a significant improvement in students' understanding of cellular processes and points to a new future of learning and public engagement. In addition, we speculate that VR can become a new tool for researchers studying cellular architecture and processes by populating VR models with molecular data. PMID- 29159992 TI - Clinical and histopathologic features of antibody-mediated rejection among pediatric renal transplant recipients with preformed vs de novo donor-specific antibodies. AB - Preformed and de novo donor specific antibodies (pDSA and dnDSA) are risk factors for ABMR. This study compares the effects of pDSA vs dnDSA in pediatric kidney transplant recipients. Sixteen pediatric patients with biopsy-proven ABMR were evaluated. Strong DSA (MFI >10 000) was recorded at transplant, rejection, and follow-up. DSAs with the highest MFI were termed iDSAs. Allograft biopsies were scored according to Banff 2013 criteria. Seven of 16 (44%) patients had pDSA at transplant; 9 (56%) developed dnDSA. Patients with pDSA developed ABMR earlier (median = 63 vs 1344 days, P = .017), while patients with dnDSA were more likely to have strong Class II iDSA (100% vs 28%, P = .009). Viral infection or non adherence was more common in patients developing dnDSA (88.8% vs 28.6%, P < .01). Pathology in those with pDSAs demonstrated worse transplant glomerulitis (g score 1.57 +/- 0.98 vs 0.56 +/- 0.73, P = .031); however, those with dnDSAs exhibited higher C4d+ ABMR (P = .013). Patients developing dnDSAs showed ABMR later post transplant with predominance of HLA-Class II iDSAs. Inadequate immunosuppression likely contributes to dnDSA formation. Patients with no DSA who have unprotocolized decreases in immunosuppression should be screened for dnDSA as it could lead to early intervention and potentially better outcomes. PMID- 29159993 TI - Low fermentable oligo-di-mono-saccharides and polyols diet versus general dietary advice in patients with diarrhea-predominant irritable bowel syndrome: A randomized controlled trial. AB - BACKGROUND AND AIM: Recent evidence indicates that new approach of the diet with low fermentable oligo-di-mono-saccharides and polyols (FODMAPs) may have an effective role in management of the patients with irritable bowel syndrome (IBS). We compared the results of low FODMAP diet with current dietary treatment, general dietary advices (GDA), on the clinical response in patients with diarrhea subtype of IBS (IBS-D). METHODS: In this randomized, controlled, single-blind trial, we included 110 patients with IBS-D in two intervention groups. Participants were randomly assigned to the low FODMAP diet (n = 55) and GDA (n = 55) for 6 weeks after a 10-day screening period. Gastrointestinal symptoms and bowel habit status were evaluated using a symptom severity scoring system and Bristol stool form scale pre-intervention and post-intervention. Patients completed 3-day food diary before and after the intervention. RESULTS: Of 110 patients, 101 completed the dietary interventions. At the baseline, the nutrient intake, severity of symptoms, and demographic data were similar between two groups. After 6 weeks, the low FODMAP diet improves significantly overall gastrointestinal symptoms scores, stool frequency, and consistency versus GDA group (P < 0.001, P < 0.001, and P = 0.003, respectively). Compared with the baseline, both intervention groups expressed a significant reduction in overall scores of symptom severity scoring system, abdominal pain, distension, consistency, and frequency, but this reduction is greater in low FODMAP diet group. CONCLUSIONS: Both low FODMAP diet and GDA in patients with IBS-D led to adequate improvement of gastrointestinal symptoms for 6 weeks. However, the low FODMAP diet has greater benefits in IBS improvement. PMID- 29159994 TI - Solitary soft tissue Langerhans cell histiocytosis of the neck. Cytohistological correlation and review of the literature. PMID- 29159995 TI - Multiple ABC glucoside transporters mediate sugar-stimulated growth in the heterocyst-forming cyanobacterium Anabaena sp. strain PCC 7120. AB - Cyanobacteria are generally capable of photoautotrophic growth and are widely distributed on Earth. The model filamentous, heterocyst-forming strain Anabaena sp. PCC 7120 has long been considered as a strict photoautotroph but is now known to be able to assimilate fructose. We have previously described two components of ABC glucoside uptake transporters from Anabaena that are involved in uptake of the sucrose analog esculin: GlsC [a nucleotide-binding domain subunit (NBD)] and GlsP [a transmembrane component (TMD)]. Here, we created Anabaena mutants of genes encoding three further ABC transporter components needed for esculin uptake: GlsD (NBD), GlsQ (TMD) and GlsR (periplasmic substrate-binding protein). Phototrophic growth of Anabaena was significantly stimulated by sucrose, fructose and glucose. Whereas the glsC and glsD mutants were drastically hampered in sucrose-stimulated growth, the different gls mutants were generally impaired in sugar-dependent growth. Our results suggest the participation of Gls and other ABC transporters encoded in the Anabaena genome in sugar-stimulated growth. Additionally, Gls transporter components influence the function of septal junctions in the Anabaena filament. We suggest that mixotrophic growth is important in cyanobacterial physiology and may be relevant for the wide success of these organisms in diverse environments. PMID- 29159996 TI - Demographic characteristics of teenage boys with horizontal striae distensae of the lower back. AB - BACKGROUND: This study examines the clinical characteristics and demographics of teenage boys with horizontal striae distensae of the lower back in an outpatient setting. METHODS: Retrospective medical chart reviews and telephone survey studies were completed on an outpatient cohort of 12 boys 11 to 17 years of age with a clinical diagnosis of transverse striae distensae of the lower back at a single-center, university-based, pediatric dermatology practice. We evaluated the clinical features of the striae, participant demographic characteristics, and past medical history. A review of the literature concerning risk factors was conducted using PubMed and Google Scholar. RESULTS: Of the 14 patients we contacted, 12 agreed to participate. The average age of onset for the striae was 14.3 years. All boys were above the 50th percentile in height at the time of onset. Eight (66.7%) reported a significant growth spurt before the appearance of the stretch marks. Most were asymptomatic. None of the boys had a history of unmonitored exogenous steroid use or prior infection with Bartonella henselae or Borrelia burgdorferi. Only one (8.3%) had a chronic medical condition. Eleven (91.7%) had at least one first-degree relative with striae distensae. CONCLUSION: Our results indicate that horizontal striae distensae of the lower back in adolescent boys is associated with a rapid growth spurt, tall stature, and family history of striae distensae. There is no association between this type of striae distensae and any chronic medical condition, bacterial infection, or exogenous steroid use. Thus a careful review of systems and counseling without further medical testing is reasonable management. PMID- 29159997 TI - Sporulation capability and amylosome conservation among diverse human colonic and rumen isolates of the keystone starch-degrader Ruminococcus bromii. AB - Ruminococcus bromii is a dominant member of the human colonic microbiota that plays a 'keystone' role in degrading dietary resistant starch. Recent evidence from one strain has uncovered a unique cell surface 'amylosome' complex that organizes starch-degrading enzymes. New genome analysis presented here reveals further features of this complex and shows remarkable conservation of amylosome components between human colonic strains from three different continents and a R. bromii strain from the rumen of Australian cattle. These R. bromii strains encode a narrow spectrum of carbohydrate active enzymes (CAZymes) that reflect extreme specialization in starch utilization. Starch hydrolysis products are taken up mainly as oligosaccharides, with only one strain able to grow on glucose. The human strains, but not the rumen strain, also possess transporters that allow growth on galactose and fructose. R. bromii strains possess a full complement of sporulation and spore germination genes and we demonstrate the ability to form spores that survive exposure to air. Spore formation is likely to be a critical factor in the ecology of this nutritionally highly specialized bacterium, which was previously regarded as 'non-sporing', helping to explain its widespread occurrence in the gut microbiota through the ability to transmit between hosts. PMID- 29159998 TI - Summary of the first inaugural joint meeting of the International Consortium for scoliosis genetics and the International Consortium for vertebral anomalies and scoliosis, March 16-18, 2017, Dallas, Texas. AB - Scoliosis represents the most common musculoskeletal disorder in children and affects approximately 3% of the world population. Scoliosis is separated into two major phenotypic classifications: congenital and idiopathic. Idiopathic scoliosis is defined as a curvature of the spine of 10 degrees or greater visualized on plane radiograph and does not have associated vertebral malformations (VM). "Congenital" scoliosis (CS) due to malformations in vertebrae is frequently associated with other birth defects. Recently, significant advances have been made in understanding the genetic basis of both conditions. There is evidence that both conditions are etiologically related. A 2-day conference entitled "Genomic Approaches to Understanding and Treating Scoliosis" was held at Scottish Rite Hospital for Children in Dallas, Texas, to synergize research in this field. This first combined, multidisciplinary conference featured international scoliosis researchers in basic and clinical sciences. A major outcome of the conference advancing scoliosis research was the proposal and subsequent vote in favor of merging the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) and International Consortium for Scoliosis Genetics (ICSG) into a single entity called International Consortium for Spinal Genetics, Development, and Disease (ICSGDD). The ICSGDD is proposed to meet annually as a forum to synergize multidisciplinary spine deformity research. PMID- 29159999 TI - "Economies of Experience"-Disambiguation of Degraded Stimuli Leads to a Decreased Dispersion of Eye-Movement Patterns. AB - We demonstrate "economies of experience" in eye-movement patterns-that is, optimization of eye-movement patterns aimed at more efficient and less costly visual processing, similar to the priming-induced formation of sparser cortical representations or reduced reaction times. Participants looked at Mooney-type, degraded stimuli that were difficult to recognize without prior experience, but easily recognizable after exposure to their undegraded versions. As predicted, eye-movement dispersion, velocity, and the number of fixations decreased with each stimulus presentation. Further analyses showed that this effect was contingent on recognition, and the selection of information from the stimulus could be informed by the identity of the presented object. Finally, our study demonstrates that after exposure to the undegraded version of the stimulus, eye movement patterns associated with its degraded and undegraded versions become more similar. This suggests that eye-movement patterns can evolve to facilitate the optimal processing of a given stimulus via experience-driven perceptual learning. PMID- 29160000 TI - New soft tissue filler derived from autologous keratin and fibroblast for neck wrinkles. AB - OBJECTIVE: To assess the effectiveness of injection of autologous keratin gel and fibroblast for neck aging as soft tissue filler. MATERIALS AND METHODS: Totally 30 volunteers received treatment of autologous keratin and fibroblast for neck wrinkles and 5 of them received hyaluronic acid (HA) treatment as control. Clinical features of the volunteers were collected at 1st, 3rd, 6th, 12th, and 24th months after treatment. The volunteers were independently assessed using Lemperle's methods at different time points. RESULTS: The neck wrinkles ameliorated observably and no severe complications were reported after treatment. The effect and maintain time of autologous keratin and fibroblast were better than HA control. CONCLUSION: Autologous keratin and fibroblast as soft tissue filler is an effective treatment option for neck rejuvenation with long-term efficacy for reversing of skin aging. PMID- 29160001 TI - Low level laser therapy induces increased viability and proliferation in isolated cancer cells. AB - OBJECTIVES: Low level laser therapy (LLLT), which stimulates natural biological processes in the application region, is frequently used in dental treatments. The aim of our study was to evaluate the effects of LLLT which could activate precancerous cells or increase existing cancerous tissue in case of clinically undetectable situations. MATERIALS AND METHODS: Saos-2 osteoblast-like osteosarcoma cells and A549 human lung carcinoma cells were used. Twenty-four hours after preparation of cell culture plates, laser irradiation was performed 1, 2 and 3 times according to the test groups using Nd:YAG laser with the power output 0.5, 1, 2 and 3 W. Cell proliferation analysis was performed by MTT assay at the 24th hour following the last laser applications. RESULTS: Generally, it was observed that the proliferation rates increased as the number of applications increased, when compared to the controls, especially in those cases in which the irradiation was performed 2 or 3 times more. CONCLUSION: The findings of this study have led to the conclusion that LLLT increases cancer cell proliferation, depending on the power output level of the laser and the number of applications. In addition to the proliferation and mitotic activity of the cancer tissue cells, we concluded that LLLT, which is frequently used in dental practice, could activate precancerous cells or increase existing cancerous tissue. PMID- 29160002 TI - A Randomized Double Blind Trial of Needle-free Injected Lidocaine Versus Topical Anesthesia for Infant Lumbar Puncture. AB - OBJECTIVES: Lumbar punctures (LPs) are commonly performed in febrile infants to evaluate for meningitis, and local anesthesia increases the likelihood of LP success. Traditional methods of local anesthesia require injection that may be painful or topical application that is not effective immediately. Recent advances in needle-free jet injection may offer a rapid alternative to these modalities. We compared a needle-free jet-injection system (J-Tip) with 1% buffered lidocaine to topical anesthetic (TA) cream for local anesthesia in infant LPs. METHODS: This was a single-center randomized double-blind trial of J-Tip versus TA for infant LPs in an urban tertiary care children's hospital emergency department. A computer randomization model was used to allocate patients to either intervention. Patients aged 0 to 4 months were randomized to J-Tip syringe containing 1% lidocaine and a placebo TA cream or J-Tip syringe containing saline and TA. The primary outcome was the difference between the Neonatal Faces Coding Scale (NFCS) before the procedure and during LP needle insertion. Secondary outcomes included changes in heart rate (HR) and NFCS throughout the procedure, difficulty with LP, number of LP attempts, provider impression of pain control, additional use of lidocaine, skin changes at LP site, and LP success. RESULTS: We enrolled 66 subjects; 32 were randomized to J-Tip with lidocaine and 34 to EMLA. Six participants were excluded from the final analysis due to age greater than 4 months, and the remaining 58 were analyzed in their respective groups (32 J-Tip, 34 TA). There was no difference detected in NFCS between the two treatment groups before the procedure and during needle insertion for the LP (p = 0.58, p = 0.37). Neither HR nor NCFS differed among the groups throughout the procedure. Median perception of pain control by the provider and the need for additional lidocaine were comparable across groups. LPs performed with a J-Tip were twice as likely to be successful compared to those performed using TA (relative risk = 2.0; 95% confidence interval = 1.01-3.93; p = 0.04) with no difference in level of training or number of prior LPs performed by providers. CONCLUSIONS: In a randomized controlled trial of two modalities for local anesthesia in infant LPs, J-Tip was not superior to TA cream as measured by pain control or physiologic changes. Infant LPs performed with J-Tip were twice as likely to be successful. PMID- 29160003 TI - Two viruses, MCV1 and MCV2, which infect Marinitoga bacteria isolated from deep sea hydrothermal vents: functional and genomic analysis. AB - Viruses represent a driving force in the evolution of microorganisms including those thriving in extreme environments. However, our knowledge of the viral diversity associated to microorganisms inhabiting the deep-sea hydrothermal vents remains limited. The phylum of Thermotogae, including thermophilic bacteria, is well represented in this environment. Only one virus was described in this phylum, MPV1 carried by Marinitoga piezophila. In this study, we report on the functional and genomic characterization of two new bacterioviruses that infect bacteria from the Marinitoga genus. Marinitoga camini virus 1 and 2 (MCV1 and MCV2) are temperate siphoviruses with a linear dsDNA genome of 53.4 kb and 50.5 kb respectively. Here, we present a comparative genomic analysis of the MCV1 and MCV2 viral genomes with that of MPV1. The results indicate that even if the host strains come from geographically distant sites, their genomes share numerous similarities. Interestingly, heavy metals did not induce viral production, instead the host of MCV1 produced membrane vesicles. This study highlights interaction of mobile genetic elements (MGE) with their hosts and the importance of including hosts-MGEs' relationships in ecological studies. PMID- 29160004 TI - Urological dysfunction in young women: an inheritance of childhood? AB - OBJECTIVE: To investigate the correlation of a history of lower urinary tract symptomatology during childhood with lower urinary tract dysfunction in young adult women. SUBJECTS AND METHODS: This was a multicentre, prospective, case control study conducted between April 2013 and November 2015. A total of 300 women, aged 18-40 years, participated. The case group comprised women attending urogynaecology clinics for various lower urinary tract complaints and the control group was recruited from a healthy population. Exclusion criteria were designed to avoid common causes of lower urinary tract dysfunction and symptoms and included diabetes mellitus, neurological disease and pelvic inflammatory disease. All women completed a self-administered 77-item questionnaire, exploring childhood urological and bowel history, as well as current urological, bowel and sexual symptoms. Statistical analysis was performed using chi-squared and Fisher's exact tests to compare categorical variables. Multivariate logistic regression models were fit for the prediction of the adult outcomes, incorporating as explanatory variables all those that showed a significant P value in bivariate analysis. P values < 0.05 were considered statistically significant. RESULTS: Women with childhood urinary voiding and storage symptoms had a higher prevalence of these symptoms in adult life compared with women without such history. Women with urinary tract infections (UTIs) during childhood had a higher incidence of adult UTIs compared with women without this problem in childhood. CONCLUSIONS: Lower urinary tract dysfunction in childhood seems to 'persist' in young adult life but the implications of this finding in clinical practice need to be defined in future studies. PMID- 29160005 TI - Investigation of parameters predicting the need for diagnostic imaging beyond computed tomography in the evaluation of dogs with thoracolumbar myelopathy: Retrospective evaluation of 555 dogs. AB - Thoracolumbar myelopathy encompasses a number of disease processes such as intervertebral disc disease, discospondylitis, trauma, congenital malformations, neoplasia, and intramedullary spinal cord disease. Compressive disc herniations are most common in dogs and require imaging procedures such as myelography, computed tomography (CT), and/or magnetic resonance imaging (MRI) to determine the need and location for decompressive surgery. The purposes of this retrospective, cross-sectional study were to evaluate all dogs undergoing thoracolumbar CT imaging as the initial diagnostic step between 2010 and 2015 and determine whether any of the imaging characteristics could be used to predict the need for additional imaging in the form of myelography, CT myelography, and/or MRI. A total of 555 dogs were identified in this time frame which underwent CT imaging for myelopathy of the thoracolumbar region. Various parameters including age, gender, sexual status, breed, chronicity, site of lesion, time of study, and contrast administration were evaluated. Findings indicated that 7.6% of dogs needed additional imaging after CT. Dachshunds were less likely to need additional imaging (P = 0.0111) as were patients scanned during normal business hours (P = 0.0075). Increasing age of the patient increased the likelihood of additional imaging (P = 0.0107). Dogs which did not have additional imaging performed were 21.89 times more likely to require surgery than those which did have additional imaging (P < 0.0001). Findings supported the use of CT as a first line imaging modality for dogs presenting with thoracolumbar myelopathy. PMID- 29160007 TI - Identification of factors contributing to successful self-directed weight loss: a qualitative study. AB - BACKGROUND: Despite the number of weight management programmes and their wide promotion, most overweight and obese individuals tend to lose weight on their own. The present study aimed to understand the characteristics and strategies of those who successfully engage in self-directed weight loss, which could empower other overweight and obese individuals with information and strategies to manage their weight on their own. METHODS: Men and women who had lost at least 5% of their body weight without direct interaction with professionals or weight management programmes were recruited. Demographic data were collected by questionnaire and participants' weight-loss experiences were explored using semi- structured interviews to elicit in-depth individual experiences and perspectives. Iterative thematic method data analysis was used to generate themes describing contributing factors to the success of self-directed weight loss identified by participants. RESULTS: Most characteristics of those who successfully self managed their weight loss were in line with those reported by successful weight losers participating in professional-led projects. However, strategies such as early embedding of new lifestyle behaviours into daily routine, the ability to learn from previous weight-loss experiences, and not requiring social support were identified as distinctive factors that contributed to the success of self directed weight loss by participants of the present study. CONCLUSIONS: Overweight or obese individuals with strong internal motivation, problem-solving skills and self-reliance are more likely to be successful at achieving self directed weight loss. The patients identified with these characteristics could be encouraged to self-manage their weight-loss process, leaving the places available in more resource-intensive professional-led programmes to those individuals unlikely to succeed on their own. PMID- 29160006 TI - Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients. AB - The "blepharophimosis-mental retardation" syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge. and anteverted nares. Here we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies. PMID- 29160008 TI - Clinical diagnosis and treatment outcomes for parapharyngeal space schwannomas: A single-institution review of 21 cases. AB - BACKGROUND: Because the incidence of schwannoma arising from the parapharyngeal space (PPS) is very low, no studies have analyzed extirpation methods and postoperative neurological complications exclusively in PPS schwannomas. METHODS: The preoperative diagnosis and clinical outcomes of surgical treatment in 21 patients with PPS schwannoma who underwent surgery were investigated. RESULTS: Neurological deficit of the involved nerve developed in all patients regardless of the extirpation method used. However, the incidence of first bite syndrome in sympathetic chain schwannoma was significantly lower after intracapsular enucleation (40%) than after total resection (100%; P = .045). Furthermore, the incidence of postoperative complications unrelated to the involved nerve was lower after intracapsular enucleation (0%) than after total resection (42.9%; P = .055). CONCLUSION: Although postoperative neurological deficit of the involved nerve was unavoidable in PPS schwannoma, intracapsular enucleation could be beneficial by reducing its severity and the incidence of complications unrelated to the involved nerve. PMID- 29160010 TI - Effects of a short midday nap on habitual nappers' alertness, mood and mental performance across cognitive domains. AB - This study examines whether the benefits of a short midday nap on habitual nappers' mental performance depend on the cognitive domain and the task difficulty. Eighteen healthy college students with the long-term habit of a midday nap (13:00-14:00 hours) participated in a nap-deprivation study. On two separate days with at least 3 days in between, participants either took a nap or remained awake, and were subsequently tested on a simple sustained attention task (Psychomotor Vigilance Test), two more complex attention tasks (Go/No-Go and Flanker task) and one working memory task (2-back). For each task, an easy and a difficult version were administered. The time course of subjective sleepiness and mood were also measured in both napping conditions. The results revealed that short midday nap deprivation significantly impaired participants' performance on both the easy and difficult versions of the Psychomotor Vigilance Test task, as well as accuracy but not reaction speed in the Go/No-Go task. Accuracy in the difficult version of the Flanker task and the 2-back task was also lower in the no-nap condition, while reaction speed in the 2-back task but not the Flanker task was reduced without a nap in both the easy and difficult versions. Moreover, subjective sleepiness was significantly increased after nap deprivation, but moods remained unaffected in the no-nap condition. These findings contribute to current research suggesting that effects of a midday nap on task performance depend on the cognitive domain as well as task difficulty. Our study highlights the importance of considering task characteristics to evaluate the benefits of a regular midday nap in practical working life. PMID- 29160009 TI - miRNA in spinal muscular atrophy pathogenesis and therapy. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by the selective death of lower motor neurons in the brain stem and spinal cord. SMA is caused by mutations in the survival motor neuron 1 gene (SMN1), leading to the reduced expression of the full-length SMN protein. microRNAs (miRNAs) are small RNAs that regulate post-transcriptional gene expression. Recent findings have suggested an important role for miRNAs in the pathogenesis of motor neuron diseases, including SMA. Motor neuron-specific miRNA dysregulation in SMA might be implicated in their selective vulnerability. In this study, we discuss recent findings regarding the consequences of SMN defects on miRNAs and their target mRNAs in motor neurons. Taken together, these data suggest that cell-specific changes in miRNAs are not only involved in the SMA motor neuron phenotype but can also be used as biomarkers and therapeutic targets. PMID- 29160011 TI - Microscopic investigations of palynological features of convolvulaceous species from arid zone of Pakistan. AB - The pollen morphology of some species of glamorous family Convolvulaceae from arid zones of Pakistan has been evaluated. The pollen grains were acetolyzed, measured, described qualitatively, and illustrated using Light microscopy and scanning electron microscopy (SEM). The examined species have differences in shape, size, polarity and exine ornamentation, confirming the eurypalynous character. The pollen types varies from psilate to echinate and colpi to tricolporate, tetracolporate and pantocolporate. Exine ornamentation was exposed as perforate, reticulate and echinate. Spine morphology and exine sculpture are vital for the distinction of species. Pollen fertility shows that selected plants species are well-known in the Arid Zone. A taxonomic key is prepared to use these variations in the identification of species. Statistical analysis by using the Software XLSTAT exhibited that some morphological features is the main characters in identification of the taxa. These studied taxa were separated from each other using cluster Analysis. Our results constructed on MVSP ver. 3.22 software analyses that show morphological explanation; thus, the results highlight the importance of pollen morphology in the identification and characterization of species of the family convolvulacae in arid zone. PMID- 29160012 TI - Near-infrared spectroscopy might be a useful tool for predicting the risk of vascular complications after pediatric liver transplants: Two case reports. AB - In patients that have undergone liver transplants, a postoperative reduction in the blood flow of the liver graft represents a critical complication. We recently encountered an interesting phenomenon; that is, we found that the rSO2 level of the liver graft, as measured by NIRS, drops in patients that subsequently require an emergency liver biopsy. An 8-month-old female and an 8-month-old male underwent living donor liver transplants for biliary atresia. In both cases, a reduction in rSO2 was detected before an emergency liver biopsy was required. As a result of biopsy examinations, both patients were diagnosed with acute graft rejection. NIRS might be useful for graft management during the postoperative period in pediatric patients that undergo liver transplantation. After a liver transplant, a reduction in the rSO2 of the graft might be indicative of the onset of vascular complications. PMID- 29160013 TI - Less common underlying genetic diagnoses found in a cohort of 139 individuals surgically corrected for craniosynostosis. PMID- 29160014 TI - Loss of tenascin X gene function impairs injury-induced stromal angiogenesis in mouse corneas. AB - To determine the contribution by tenascin X (Tnx) gene expression to corneal stromal angiogenesis, the effects were determined of its loss on this response in TNX knockout (KO) mice. In parallel, the effects of such a loss were evaluated on vascular endothelial growth factor (VEGF) and transforming growth factor beta1 (TGFbeta1) gene and protein expression in fibroblasts and macrophages in cell culture. Histological, immunohistochemical and quantitative RT-PCR changes determined if Tnx gene ablation on angiogenic gene expression, inflammatory cell infiltration and neovascularization induced by central corneal stromal cauterization. The role was determined of Tnx function in controlling VEGF-A or TGFbeta1 gene expression by comparing their expression levels in ocular fibroblasts and macrophages obtained from wild-type (WT) and body-wide Tnx KO mice. Tnx was up-regulated in cauterized cornea. In Tnx KO, macrophage invasion was attenuated, VEGF-A and its cognate receptor mRNA expression along with neovascularization were lessened in Tnx KOs relative to the changes occurring in their WT counterpart. Loss of Tnx instead up-regulated in vivo mRNA expression of anti-angiogenic VEGF-B but not VEGF-A. On the other hand, TGFbeta1 mRNA expression declined in Tnx KO cultured ocular fibroblasts. Loss of Tnx gene expression caused VEGF-A expression to decline in macrophages. Tnx gene expression contributes to promoting TGFbeta1 mRNA expression in ocular fibroblasts and VEGF-A in macrophages, macrophage invasion, up-regulation of VEGF A expression and neovascularization in an injured corneal stroma. On the other hand, it suppresses anti-angiogenic VEGF-B mRNA expression in vivo. PMID- 29160015 TI - Response to: "In reply to: 'Mast Cell Disorders in Ehlers-Danlos Syndrome' (Jaime Vengoechea, Department of Human Genetics, Emory University)". PMID- 29160016 TI - Synthetic Oligosaccharide Libraries and Microarray Technology: A Powerful Combination for the Success of Current Glycosaminoglycan Interactomics. AB - Glycosaminoglycans (GAGs) are extracellular matrix and/or cell-surface sulfated glycans crucial to the regulation of various signaling proteins, the functions of which are essential in many pathophysiological systems. Because structural heterogeneity is high in GAG chains and purification is difficult, the use of structurally defined GAG oligosaccharides from natural sources as molecular models in both biophysical and pharmacological assays is limited. To overcome this obstacle, GAG-like oligosaccharides of well-defined structures are currently being synthesized by chemical and/or enzymatic means in many research groups around the world. These synthetic GAG oligosaccharides serve as useful molecular tools in studies of GAG-protein interactions. In this review, besides discussing the commonest routes used for the synthesis of GAG oligosaccharides, we also survey some libraries of these synthetic models currently available for research and discuss their activities in interaction studies with functional proteins, especially through the microarray approach. PMID- 29160018 TI - Multifragment melting analysis of yeast species isolated from spoiled fruits. AB - AIMS: In this study, we developed a novel approach, multifragment melting analysis (MFMA), based on the simultaneous analysis of the melting characteristics of multiple DNA fragments for the differentiation and identification of yeast species isolated from spoiled fruits. METHODS AND RESULTS: In total, 183 yeast isolates recovered from spoiled fruit samples were differentiated and grouped using MFMA. Six different DNA fragments of the 26S rRNA gene showing a high interspecific heterogeneity were amplified, and the PCR products were individually subjected to MFMA. An excellent discrimination and classification were obtained when the melting characteristics of all target DNA fragments for each species were simultaneously assessed. Species-level identification was performed by sequence analysis of representative isolates from each group. In the fruit samples, Hanseniaspora uvarum (Kloeckera apiculata) was found to be the most frequently isolated species followed by members of the Pichia genus, namely P. kluyveri, P. fermentans and P. kudriavzevii (Issatchenkia orientalis). CONCLUSIONS: Multifragment melting analysis provided a rapid and reliable approach for discrimination and grouping of a large number of yeast isolates recovered from fruit samples prior to sequence analysis-based identification. SIGNIFICANCE AND IMPACT OF THE STUDY: The MFMA has great potential for fast and accurate investigation of yeast communities associated with food spoilage to determine their sources and routes and to prevent contamination. PMID- 29160017 TI - Do Disordered Eating Behaviours Have Long-term Health-related Consequences? AB - OBJECTIVE: Long-term health-related consequences of disordered eating behaviours of young adults remain poorly understood. We examined whether disordered eating behaviours in mid-20s are associated with physical and mental health 10 years later. METHODS: Women (n = 2631) and men (n = 2394) from a population-based FinnTwin16 cohort were assessed using three subscales of the Eating Disorder Inventory-2 at age 24. Self-rated health, body mass index (BMI), waist circumference and psychological distress were assessed at age 24 and reassessed 10 years later. RESULTS: In crude models, disordered eating behaviours at age 24 were associated cross-sectionally and prospectively with poor self-rated health, higher BMI, larger waist circumference and psychological distress in both sexes. In models adjusted for baseline BMI and potential confounders, disordered eating behaviours predicted increased psychological distress in both sexes and poor self rated health in men. CONCLUSIONS: Among young adults, disordered eating behaviours are associated with long-term health-related consequences, particularly psychological distress. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 29160019 TI - Comparison of animal, action and phonemic fluency in aphasia. AB - BACKGROUND: The ability to generate words that follow certain constraints, or verbal fluency, is a sensitive indicator of neurocognitive impairment, and is impacted by a variety of variables. AIMS: To investigate the effect of post stroke aphasia, elicitation category and linguistic variables on verbal fluency performance. METHODS & PROCEDURES: Twenty-eight persons with aphasia (PWA) with a single left-hemisphere lesion and 40 age-matched neurotypical community-dwelling adults were administered three verbal fluency tasks: two semantic (animals and actions) and one phonemic (the letters F, A and S). Data analysis included comparison of total scores, clusters and perseverations. Individual responses were coded for frequency of occurrence, age of acquisition and syllable length to investigate qualitative differences in word generation. OUTCOMES & RESULTS: PWA performed worse than neurotypical participants across all verbal fluency tasks, and animal fluency scores were farthest from neurotypical performance. PWAs' animal and action fluency were correlated with other language measures, while phonemic fluency was uncorrelated with language measures. While some PWAs showed dissociations between verbal fluency tasks, the dissociations did not pattern along with aphasia fluency. PWAs produced fewer clusters and responses with higher word frequency across all three verbal fluency tasks. Responses had earlier age of acquisition and shorter word length for animal and phonemic fluency, but not action fluency. CONCLUSIONS & IMPLICATIONS: Verbal fluency, particularly animal fluency, is sensitive to even mild aphasia. PWA produced lexically simpler responses than their neurotypical peers. This study identifies the relevance of qualitative analysis of verbal fluency responses. PMID- 29160020 TI - Comparison of quantitative regional ventilation-weighted fourier decomposition MRI with dynamic fluorinated gas washout MRI and lung function testing in COPD patients. AB - BACKGROUND: Ventilation-weighted Fourier decomposition-MRI (FD-MRI) has matured as a reliable technique for quantitative measures of regional lung ventilation in recent years, but has yet not been validated in COPD patients. PURPOSE/HYPOTHESIS: To compare regional fractional lung ventilation obtained by ventilation-weighted FD-MRI with dynamic fluorinated gas washout MRI (19 F-MRI) and lung function test parameters. STUDY TYPE: Prospective study. POPULATION: Twenty-seven patients with chronic obstructive pulmonary disease (COPD, median age 61 [54-67] years) were included. FIELD STRENGTH/SEQUENCE: For FD-MRI and for 19 F-MRI a spoiled gradient echo sequence was used at 1.5T. ASSESSMENT: FD-MRI coronal slices were acquired in free breathing. Dynamic 19 F-MRI was performed after inhalation of 25-30 L of a mixture of 79% fluorinated gas (C3 F8 ) and 21% oxygen via a closed face mask tubing using a dedicated coil tuned to 59.9 MHz. 19 F washout times in numbers of breaths (19 F-nbreaths ) as well as fractional ventilation maps for both methods (FD-FV, 19 F-FV) were calculated. Slices were matched using a landmark driven algorithm, and only corresponding slices with an overlap of >90% were coregistered for evaluation. STATISTICAL TESTS: The obtained parameters were correlated with each other using Spearman's correlation coefficient (r). RESULTS: FD-FV strongly correlated with 19 F-nbreaths on a global (r = -0.72, P < 0.0001) as well as on a lobar level and with lung function test parameters (FD-FV vs. FEV1, r = 0.76, P < 0.0001). There was a small systematic overestimation of FD-FV compared to 19 F-FV (mean difference -0.03 (95% confidence interval [CI]: -0.097; -0.045). DATA CONCLUSION: Regional ventilation-weighted Fourier decomposition-MRI is a promising noninvasive, radiation-free tool for quantification of regional ventilation in COPD patients. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1534-1541. PMID- 29160021 TI - Sleep timing is associated with diet and physical activity levels in 9-11-year old children from Dunedin, New Zealand: the PEDALS study. AB - It is well documented that short sleep duration is associated with excess body weight and poor food intake in children. It has been suggested that sleep timing behaviour may also be an important predictor of weight and other related behaviours, independent of sleep duration; however, there is a lack of research investigating these relationships. The present study investigated sleep timing in association with diet and physical activity levels in 439 children aged 9-11 years old from New Zealand. Sleep and physical activity data were collected using accelerometry, and food choice using a short food-frequency questionnaire. Participants were classified into one of four sleep timing behaviour categories using the median split for sleep-onset and -offset times. Differences between sleep timing groups for weekly consumption frequency of selected food groups, dietary pattern scores and minutes of moderate-to-vigorous physical activity were examined. Children in the late sleep/late wake category had a lower 'Fruit & Vegetables' pattern score [mean difference (95% CI): -0.3 (-0.5, -0.1)], a lower consumption frequency of fruit and vegetables [mean weekly difference (95% CI): 2.9 (-4.9, -0.9)] and a higher consumption frequency of sweetened beverages [mean weekly difference (95% CI): 1.8 (0.2, 3.3)] compared with those in the early sleep/early wake category. Additionally, children in the late sleep/late wake category accumulated fewer minutes of moderate-to-vigorous physical activity per day compared with those in the early sleep/early wake category [mean difference (95% CI): -9.4 (-15.3, -3.5)]. These findings indicate that sleep timing, even after controlling for sleep duration, was associated with both food consumption and physical activity. PMID- 29160022 TI - First prenatal diagnosis of a 'pure' 9q34.3 deletion (Kleefstra syndrome): A case report and literature review. AB - Kleefstra syndrome (KS) is characterized by developmental delay, intellectual disability, hypotonia and distinct facial features. Additional clinical features include congenital heart defects, cerebral abnormalities, urogenital defects and weight gain. The syndrome is caused by a microdeletion in chromosomal region 9q34.3 (in 85% of cases) or by a mutation in the EHMT1 gene coding for euchromatin histone methyltransferase 1. The prenatal phenotype has not yet been characterized. Herein, we sought to define this phenotype on the basis of a new case report and literature review. PMID- 29160024 TI - A conceptual framework for understanding the perspectives on the causes of the science-practice gap in ecology and conservation. AB - Applying scientific knowledge to confront societal challenges is a difficult task, an issue known as the science-practice gap. In Ecology and Conservation, scientific evidence has been seldom used directly to support decision-making, despite calls for an increasing role of ecological science in developing solutions for a sustainable future. To date, multiple causes of the science practice gap and diverse approaches to link science and practice in Ecology and Conservation have been proposed. To foster a transparent debate and broaden our understanding of the difficulties of using scientific knowledge, we reviewed the perceived causes of the science-practice gap, aiming to: (i) identify the perspectives of ecologists and conservation scientists on this problem, (ii) evaluate the predominance of these perspectives over time and across journals, and (iii) assess them in light of disciplines studying the role of science in decision-making. We based our review on 1563 sentences describing causes of the science-practice gap extracted from 122 articles and on discussions with eight scientists on how to classify these sentences. The resulting process-based framework describes three distinct perspectives on the relevant processes, knowledge and actors in the science-practice interface. The most common perspective assumes only scientific knowledge should support practice, perceiving a one-way knowledge flow from science to practice and recognizing flaws in knowledge generation, communication, and/or use. The second assumes that both scientists and decision-makers should contribute to support practice, perceiving a two-way knowledge flow between science and practice through joint knowledge production/integration processes, which, for several reasons, are perceived to occur infrequently. The last perspective was very rare, and assumes scientists should put their results into practice, but they rarely do. Some causes (e.g. cultural differences between scientists and decision-makers) are shared with other disciplines, while others seem specific to Ecology and Conservation (e.g. inadequate research scales). All identified causes require one of three general types of solutions, depending on whether the causal factor can (e.g. inadequate research questions) or cannot (e.g. scientific uncertainty) be changed, or if misconceptions (e.g. undervaluing abstract knowledge) should be solved. The unchanged predominance of the one-way perspective over time may be associated with the prestige of evidence-based conservation and suggests that debates in Ecology and Conservation lag behind trends in other disciplines towards bidirectional views ascribing larger roles to decision-makers. In turn, the two way perspective seems primarily restricted to research traditions historically isolated from mainstream conservation biology. All perspectives represented superficial views of decision-making by not accounting for limits to human rationality, complexity of decision-making contexts, fuzzy science-practice boundaries, ambiguity brought about by science, and different types of knowledge use. However, joint knowledge-production processes from the two-way perspective can potentially allow for democratic decision-making processes, explicit discussions of values and multiple types of science use. To broaden our understanding of the interface and foster productive science-practice linkages, we argue for dialogue among different research traditions within Ecology and Conservation, joint knowledge-production processes between scientists and decision-makers and interdisciplinarity across Ecology, Conservation and Political Science in both research and education. PMID- 29160023 TI - The Self-Reference Effect on Perception: Undiminished in Adults with Autism and No Relation to Autism Traits. AB - : Memory for (and perception of) information about the self is superior to memory for (and perception of) other kinds of information. This self-reference effect (SRE) in memory appears diminished in ASD and related to the number of ASD traits manifested by neurotypical individuals (fewer traits = larger SRE). Here, we report the first experiments exploring the relation between ASD and the SRE in perception. Using a "Shapes" Task (Sui et al., Journal of Experimental Psychology: Human Perception and Performance, 38, 1105, 2012), participants learned to associate three different shapes (triangle, circle, square) with three different labels representing self, a familiar other, or an unfamiliar other (e.g., "you", "mother", "stranger"). Participants then completed trials during which they were presented with one shape and one label for 100 ms, and made judgments about whether the shape and label was a match. In Experiment 1, neurotypical participants (n = 124) showed the expected SRE, detecting self related matches more reliably and quickly than matches involving familiar or unfamiliar other. Most important, number of ASD traits was unrelated to the size of the SRE for either accuracy or RT. Bayesian association analyses strongly supported the null hypothesis. In Experiment 2, there were no differences between 22 adults with ASD and 21 matched comparison adults in performance on the Shapes Task. Despite showing large and significant theory of mind impairments, participants with ASD showed the typical SRE and there were no associations with ASD traits in either group. In every case, Bayesian analyses favored the null hypothesis. These findings challenge theories about self-representation in ASD, as discussed in the article. Autism Res 2018, 11: 331-341. (c) 2017 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: Neurotypical people tend to find it easier to perceive and remember information that relates to themselves than information that relates to others. Research suggests that people with ASD show a diminished (or absent) self-bias in memory and that severity of ASD predicts the extent of this diminution (more severe ASD = smaller self-bias in memory). However, the current research suggests strongly that people with ASD do show a self-bias in their perception. This research informs our understanding of psychological functioning in ASD and challenges theories regarding self-awareness in this disorder. PMID- 29160025 TI - Development of a specific fluorescent phage endolysin for in situ detection of Clostridium species associated with cheese spoilage. AB - Late blowing defect (LBD) is a major cause of spoilage in cheeses, caused by the growth of Clostridium spp. in the cheese matrix. We investigated the application of CTP1L, a bacteriophage endolysin active against Clostridium tyrobutyricum, and its enzymatically active and cell wall-binding domains (EAD and CBD) attached to green fluorescent protein (GFP) to detect dairy-related Clostridium species by fluorescence microscopy. GFP-CTP1L and GFP-CBD demonstrated specificity for Clostridium spp. by labelling 15 and 17 of 20 Clostridium strains, respectively, but neither bound to other members of the cheese microbiota. However, GFP-EAD did not label any Clostridium strain tested. Unexpectedly, GFP-CTP1L and GFP-CBD were also able to bind to clostridial spores. In addition, GFP-CBD allowed us to visualize the vegetative cells of C. tyrobutyricum directly in the matrix of a LBD cheese. Site-directed mutants of GFP-CTP1L and GFP-CBD were made to examine the amino acids involved in binding and oligomer formation. Oligomerization was not essential for binding, but specific mutations in the CBD which affected oligomer formation also affected binding and lytic activity. We conclude that GFP CTP1L and GFP-CBD could be good biomarkers for rapid detection of Clostridium spores in milk, so measures can be taken for the prevention of LBD in cheese, and also provide effective tools to study the development of Clostridium populations during cheese ripening. PMID- 29160027 TI - Identification of Syntrophobacteraceae as major acetate-degrading sulfate reducing bacteria in Italian paddy soil. AB - Methane is an important greenhouse gas and acetate is the most important intermediate (average 70%) of the carbon flow to CH4 in paddy fields. Sulfate (e.g., gypsum) application can reduce CH4 emissions up to 70%. However, the effect of gypsum application on acetate degradation and the microbial communities involved are unclear. Therefore, we studied acetate-dependent sulfate reduction in anoxic microcosms of Italian rice paddy soil, combining profiling of 16S rRNA and dissimilatory sulfite reductase (dsrB) genes and transcripts and rRNA based stable isotope probing (SIP) analysis. Methane production was completely inhibited by gypsum in the absence of exogenous acetate. Amended acetate (either 13 C labelled or non-labelled) was stoichiometrically coupled to sulfate reduction or CH4 production. With methyl fluoride in the presence of sulfate, added propionate and butyrate were incompletely oxidized to acetate, which transiently accumulated. After the depletion of propionate and butyrate the accumulated acetate was rapidly consumed. The relative abundance of dsrB and 16S rRNA genes and transcripts from Syntrophobacteraceae (Desulfovirga spp., Syntrophobacter spp. and unclassified Syntrophobacteraceae) increased upon addition of gypsum and acetate. Simultaneously, Syntrophobacteraceae affiliated species were significantly labelled with 13 C. In addition, minor groups like Desulforhabdus spp., Desulfobacca spp. and Desulfotomaculum spp. substantially incorporated 13 C into their nucleic acids. The relative abundance of Desulfovibrio spp. slightly increased upon gypsum amendments. However, 13 C labelling of Desulfovibrio spp. was only moderate. In summary, Syntrophobacteraceae affiliated species were identified as the major acetotrophic sulfate reducers (SRB) in Italian paddy soil. The identification of these SRB as dominant acetate degraders well explained the scenarios of competition between SRB and acetoclastic methanogens as observed in rice paddy soil. PMID- 29160026 TI - Enrichment of syngas-converting communities from a multi-orifice baffled bioreactor. AB - The substitution of natural gas by renewable biomethane is an interesting option to reduce global carbon footprint. Syngas fermentation has potential in this context, as a diverse range of low-biodegradable materials that can be used. In this study, anaerobic sludge acclimatized to syngas in a multi-orifice baffled bioreactor (MOBB) was used to start enrichments with CO. The main goals were to identify the key players in CO conversion and evaluate potential interspecies metabolic interactions conferring robustness to the process. Anaerobic sludge incubated with 0.7 * 105 Pa CO produced methane and acetate. When the antibiotics vancomycin and/or erythromycin were added, no methane was produced, indicating that direct methanogenesis from CO did not occur. Acetobacterium and Sporomusa were the predominant bacterial species in CO-converting enrichments, together with methanogens from the genera Methanobacterium and Methanospirillum. Subsequently, a highly enriched culture mainly composed of a Sporomusa sp. was obtained that could convert up to 1.7 * 105 Pa CO to hydrogen and acetate. These results attest the role of Sporomusa species in the enrichment as primary CO utilizers and show their importance for methane production as conveyers of hydrogen to methanogens present in the culture. PMID- 29160028 TI - Predictive markers and prenatal management of isolated fetal complete atrioventricular block: A retrospective review at a single institution. AB - AIM: The study was conducted to determine an effective method for identifying patients at high risk of developing isolated complete atrioventricular block (CAVB) and to review the efficacy of prenatal anti-inflammatory treatment. METHODS: Fourteen CAVB cases and 76 anti-Ro-positive cases without CAVB were included in the study. Anti-Ro/La titers by double immunodiffusion and the prevalence of anti-52 kDa/60 kDa-Ro/48 kDa-La by Western blotting were compared between anti-Ro-positive women with and without CAVB. Outcomes of anti-Ro positive CAVB cases were compared based on active prenatal anti-inflammatory treatment (plasma exchange or transplacental betamethasone). We evaluated the outcomes of five pregnancies from three women who had an affected child and underwent prophylactic plasma exchange (PEX) during subsequent pregnancy. RESULTS: Ten out of 14 patients with CAVB were positive for anti-Ro. Anti-Ro titers were significantly higher in patients with CAVB (CAVB median 64; without CAVB median 16; P < 0.01). All cases with CAVB showed high titers of anti-Ro (>= 32*), whereas only 42% of cases without CAVB showed high titers (>= 32*) (P < 0.001). The survival rate at one year was 80% in anti-Ro-positive CAVB cases with active prenatal anti-inflammatory treatment, but only 40% in cases that did not receive treatment. Recurrence was not observed in cases treated with prophylactic PEX. CONCLUSIONS: An anti-Ro level of 32* could be the threshold value for CAVB development. Prenatal anti-inflammatory treatment in patients with CAVB and prophylactic PEX in patients who had an affected child may have the potential to improve pregnancy outcomes. PMID- 29160029 TI - Dose Dependencies and Biocompatibility of Renal Clearable Gold Nanoparticles: From Mice to Non-human Primates. AB - While dose dependencies in pharmacokinetics and clearance are often observed in clinically used small molecules, very few studies have been dedicated to the understandings of potential dose-dependent in vivo transport of nanomedicines. Here we report that the pharmacokinetics and clearance of renal clearable gold nanoparticles (GS-AuNPs) are strongly dose-dependent once injection doses are above 15 mg kg-1 : high dose expedited the renal excretion and shortened the blood retention. As a result, the no-observed-adverse-effect-level (NOAEL) of GS AuNPs was >1000 mg kg-1 in CD-1 mice. The efficient renal clearance and high compatibility can be translated to the non-human primates: no adverse effects were observed within 90 days after intravenous injection of 250 mg kg-1 GS-AuNPs. These fundamental understandings of dose effect on the in vivo transport of ultrasmall AuNPs open up a pathway to maximize their biomedical potentials and minimize their toxicity in the future clinical translation. PMID- 29160030 TI - Dihydromyricetin enhances glucose uptake by inhibition of MEK/ERK pathway and consequent down-regulation of phosphorylation of PPARgamma in 3T3-L1 cells. AB - Accumulating evidence suggests that inhibition of mitogen-activated protein kinase signalling can reduce phosphorylation of peroxisome proliferator-activated receptor gamma (PPARgamma) at serine 273, which mitigates obesity-associated insulin resistance and might be a promising treatment for type 2 diabetes. Dihydromyricetin (DHM) is a flavonoid that has many beneficial pharmacological properties. In this study, mouse fibroblast 3T3-L1 cells were used to investigate whether DHM alleviates insulin resistance by inhibiting PPARgamma phosphorylation at serine 273 via the MEK/ERK pathway. 3T3-L1 pre-adipocytes were differentiated, and the effects of DHM on adipogenesis and glucose uptake in the resulting adipocytes were examined. DHM was found to dose dependently increase glucose uptake and decrease adipogenesis. Insulin resistance was then induced in adipocytes using dexamethasone, and DHM was shown to dose and time dependently promote glucose uptake in the dexamethasone-treated adipocytes. DHM also inhibited phosphorylation of PPARgamma and ERK. Inhibition of PPARgamma activity with GW9662 potently blocked DHM-induced glucose uptake and adiponectin secretion. Interestingly, DHM showed similar effects to PD98059, an inhibitor of the MEK/ERK pathway. DHM acted synergistically with PD98059 to improve glucose uptake and adiponectin secretion in dexamethasone-treated adipocytes. In conclusion, our findings indicate that DHM improves glucose uptake in adipocytes by inhibiting ERK-induced phosphorylation of PPARgamma at serine 273. PMID- 29160031 TI - Maternal inheritance of BDNF deletion, with phenotype of obesity and developmental delay in mother and child. AB - Childhood obesity is a significant world health problem. Understanding the genetic and environmental factors contributing to the development of obesity in childhood is important for the rational design of strategies for obesity prevention and treatment. Brain-derived neurotrophic factor (BDNF) plays an important role in the growth and development of the central nervous system, there is also an evidence that BDNF plays a role in regulation of appetite. Disruption of the expression of this gene in a child has been previously reported to result in a phenotype of severe obesity, hyperphagia, impaired cognitive function, and hyperactivity. We report a mother and child, both with micro-deletions encompassing the BDNF gene locus, who both have obesity and developmental delay, although without hyperactivity. This report highlights the maternal inheritance of a rare genetic cause of childhood obesity. PMID- 29160032 TI - Coverage and capacity: addressing the 'night & weekend effect' in obstetrics. PMID- 29160033 TI - Discordant fetal phenotype of hypophosphatasia in two siblings. AB - Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks' gestation. Post mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks' gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates. PMID- 29160034 TI - Free-living chemoautotrophic and particle-attached heterotrophic prokaryotes dominate microbial assemblages along a pelagic redox gradient. AB - Using the anoxic Cariaco Basin as a natural laboratory, particle association of bacterial and archaeal taxa was assessed by iTag sequencing and qPCR gene assays of samples spanning an oxic-anoxic-euxinic gradient. A total of 10%-12% of all bacterial and archaeal cells were found in the particle-associated (PA) fraction, operationally defined as prokaryotes captured on 2.7 um membranes. Both redox condition and size fraction segregated bacterial taxa. Archaeal taxa varied according to redox conditions, but were similar between size fractions. Taxa putatively associated with chemoautotrophic sulfur oxidation and nitrification dominated the free-living (FL) fraction throughout the oxycline (< 1-120 uM O2 ) and upper anoxic layer. Bacteria in the oxycline's PA fraction included taxa known to be aerobic and anaerobic chemoorganotrophs. At shallow anoxic depths, PA taxa were primarily affiliated with anaerobic sulfate ( SO42-)-reducing lineages. PA fractions in the most sulfidic samples were dominated by taxa affiliated with CH4 oxidizing, fermenting and SO42- reducing lineages. Prevalence of particle associated SO42--reducing taxa and abundant sulfur-oxidizing taxa in both size fractions across the oxic-anoxic interface is consistent with the cryptic sulfur cycling concept. Bacterial assemblage diversity in the PA fraction always exceeded the FL fraction except in the most oxic samples, whereas Archaeal diversity was not consistently different between size fractions. Our results suggest that these particle-associated and free-living bacterial assemblages are functionally different and that the interplay between particle microhabitats and surrounding geochemical regimes is a strong selective force shaping microbial communities throughout the water column. PMID- 29160036 TI - Alternative control of Aedes aegypti resistant to pyrethroids: lethal and sublethal effects of monoterpene bioinsecticides. AB - BACKGROUND: The mosquito Aedes aegypti is intensively controlled because it is a vector of viruses that cause numerous diseases, especially in tropical regions. As a consequence of the indiscriminate use of insecticides, populations from different regions have become resistant to pyrethroids. Here, we analyzed the lethal and sublethal effects of essential oil of Aristolochia trilobata and its major compounds on A. aegypti from susceptible and pyrethroid-resistant populations. RESULTS: Our results showed that the toxicity of the different compounds and behavioral changes in response to them are dependent on the stage of the insect life cycle. The monoterpene rho-cymene caused high mortality in both larvae and adult females of A. aegypti, including those from the pyrethroid resistant population. The monoterpenes limonene and linalool caused a sublethal effect in the larvae, triggering changes in the swimming pattern. CONCLUSION: This study highlights the potential of the essential oil of A. trilobata and its major compounds rho-cymene and limonene for the control of A. aegypti and reveals the importance of analyzing sublethal effects on the population dynamics of the A. aegypti mosquito. (c) 2017 Society of Chemical Industry. PMID- 29160035 TI - Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay. AB - Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next-generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in beta galactosidase deficiency. A 10-year-old girl had progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however beta-galactosidase assay was normal. Trio WES identified a paternally-inherited pathogenic splice-site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis; however, enzymatic testing in blood was normal, presumably compensated for by non-UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells. PMID- 29160037 TI - Interactions of effects of host plant resistance and seed treatments on soybean aphid (Aphis glycines Matsumura) and soybean cyst nematode (Heterodera glycines Ichinohe). AB - BACKGROUND: The soybean cyst nematode, Heterodera glycines, and soybean aphid, Aphis glycines, are invasive, widespread and economically important pests of soybean, Glycine max, in North America. Management of these pests relies primarily on use of pesticides and soybean germplasm with genetic resistance. A 3 year field study and complementary greenhouse experiment were conducted to determine the benefits of host plant resistance (HPR) and pesticidal seed treatments for managing pest populations and preserving soybean yield. RESULTS: Host plant resistance significantly decreased the abundance of A. glycines and, in most study sites, suppressed H. glycines. Neonicotinoid seed treatment reduced A. glycines abundance on the cultivar that was susceptible to both aphids and nematodes, but abamectin nematicide seed treatment had no effect on H. glycines populations in the field or greenhouse. CONCLUSION: These results suggest that the seed treatments included in our experiments may suppress pests, but not consistently for all soybean cultivars or study sites. Ultimately, HPR more consistently reduced pest numbers compared with the use of pesticidal seed treatments. The planting of HPR cultivars should be a primary tool for integrated pest management of both soybean pests. (c) 2017 Society of Chemical Industry. PMID- 29160038 TI - Endoplasmic reticulum in health and disease: the 12th International Calreticulin Workshop, Delphi, Greece. AB - Starting from 1994, every 2 years, an international workshop is organized focused on calreticulin and other endoplasmic reticulum chaperones. In 2017, the workshop took place at Delphi Greece. Participants from North and South America, Europe, Asia and Australia presented their recent data and discussed them extensively with their colleagues. Presentations dealt with structural aspects of calreticulin and calnexin, the role of Ca2+ in cellular signalling and in autophagy, the endoplasmic reticulum stress and the unfolded protein response, the role of calreticulin in immune responses. Several presentations focused on the role of calreticulin and other ER chaperones in a variety of disease states, including haemophilia, obesity, diabetes, Sjogren's syndrome, Chagas diseases, multiple sclerosis, amyotrophic lateral sclerosis, neurological malignancies (especially glioblastoma), haematological malignancies (especially essential thrombocythemia and myelofibrosis), lung adenocarcinoma, renal pathology with emphasis in fibrosis and drug toxicity. In addition, the role of calreticulin and calnexin in growth and wound healing was discussed, as well as the possible use of extracellular calreticulin as a marker for certain diseases. It was agreed that the 13th International Calreticulin Workshop will be organized in 2019 in Montreal, Quebec, Canada. PMID- 29160040 TI - FGFR1 disruption identified by whole genome sequencing in a male with a complex chromosomal rearrangement and hypogonadotropic hypogonadism. PMID- 29160039 TI - Fine-tuning the P. pastoris iMT1026 genome-scale metabolic model for improved prediction of growth on methanol or glycerol as sole carbon sources. AB - The methylotrophic yeast Pichia pastoris (Komagataella spp.) is widely used as cell factory for recombinant protein production. In the past recent years, important breakthroughs in the systems-level quantitative analysis of its physiology have been achieved. This wealth of information has allowed the development of genome-scale metabolic models, which make new approaches possible for host cell and bioprocess engineering. Nevertheless, the predictive accuracy of the previous consensus model required to be upgraded and validated with new experimental data sets for P. pastoris growing on glycerol or methanol as sole carbon sources, two of the most relevant substrates for this cell factory. In this study, we have characterized P. pastoris growing in chemostat cultures using glycerol or methanol as sole carbon sources over a wide range of growth rates, thereby providing physiological data on the effect of growth rate and culture conditions on biomass macromolecular and elemental composition. In addition, these data sets were used to improve the performance of the P. pastoris consensus genomic-scale metabolic model iMT1026. Thereupon, new experimentally determined bounds, including the representation of biomass composition for these growth conditions, have been incorporated. As a result, here, we present version 3 (v3.0) of the consensus P. pastoris genome-scale metabolic model as an update of the iMT1026 model. The v3.0 model was validated for growth on glycerol and methanol as sole carbon sources, demonstrating improved prediction capabilities over an extended substrate range including two biotechnologically relevant carbon sources. PMID- 29160041 TI - Associations between observed temperament in preschoolers and parent psychopathology. AB - Parent history of psychopathology is an established marker of children's own risk for later disorder and can therefore be used as a means of validating other risks, such as child temperament. While associations between children's temperament and parent psychopathology have been reported, few studies have used observational measures of child temperament or examined trait interactions, particularly between children's affective and regulatory traits such as effortful control (EC). In this bottom-up family study of 968 three-year-olds and their parents, we examined interactions between preschoolers' observed positive and negative affectivity (NA) and EC as predictors of a known marker of psychopathology risk: parent history of disorder. Children with lower positive affectivity had an increased probability of paternal depression history in the context of higher child NA. In addition, children with lower EC and higher NA had an increased probability of maternal anxiety. Findings shed new light on the main effects and interactions that account for associations between child temperament and parent history of disorder, one of the best-established markers of an individual's own risk for future disorder, implicating reactive and regulatory traits that merit special consideration in future longitudinal work. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29160042 TI - Hypoxia challenge test and retinal circulation changes - a study using ocular coherence tomography angiography. AB - PURPOSE: Previous studies report that the response of retinal vessels to a decrease in oxygen (hypoxia) is vasodilation, thus increasing blood flow. We aimed to characterize the changes in retinal microvasculature induced by a mild hypoxia stress test in a healthy population, using ocular coherence tomography angiography (OCT-A) technology. METHODS: Interventional repeated-measures study. The standardized hypoxia challenge test (HCT) was performed to all volunteers, according to the British Thoracic Society protocol. Ocular coherence tomography angiography (OCT-A) was performed at three time-points (baseline, during HCT and 30' posthypoxia). Macular and peripapillary vessel densities were assessed using the built-in software. To minimize bias, analysis was performed separately in right (OD) and left (OS) eyes. Repeated-measures anova and mean comparison analysis were used as statistical tests (stata v13). RESULTS: Studied population included 30 healthy subjects (14 women), with a mean age of 28.8 +/- 4.2 [range 22-37] years. Baseline vessel density increased in hypoxic conditions and subsequently decreased to near-baseline values in posthypoxia conditions. This pattern was observed for both eyes in both parafovea (OD: 55.3 +/- 2.3 to 56.7 +/ 1.9 to 55.8 +/- 1.9, p < 0.05; OS: 56.9 +/- 2.1 to 57.9 +/- 1.9 to 57.3 +/- 1.7, p < 0.05) and peripapillary (OD: 60.5 +/- 0.5 to 62.6 +/- 0.5 to 60.1 +/- 0.4, p < 0.05; OS: 60.4 +/- 0.4 to 62.3 +/- 0.5 to 60.7 +/- 0.4, p < 0.05) areas. CONCLUSION: To our knowledge, there are no published data specifically addressing mild hypoxia conditions and retinal microvasculature changes, using OCT-A. This pilot study may pave way to better understand vascular responses in disease setting. PMID- 29160043 TI - Influence of probe pressure on diffuse reflectance spectra of human skin measured in vivo. AB - Mechanical pressure superficially applied on the human skin surface by a fiber optic probe influences the spatial distribution of blood within the cutaneous tissues. Upon gradual load of weight on the probe, a stepwise increase in the skin reflectance spectra is observed. The decrease in the load follows the similar inverse staircase-like tendency. The observed stepwise reflectance spectra changes are due to, respectively, sequential extrusion of blood from the topical cutaneous vascular beds and their filling afterward. The obtained results are confirmed by Monte Carlo modeling. This implies that pressure-induced influence during the human skin diffuse reflectance spectra measurements in vivo should be taken into consideration, in particular, in the rapidly developing area of wearable gadgets for real-time monitoring of various human body parameters. PMID- 29160044 TI - Aortic valve surgery of the 21st century: sutureless AVR versus TAVI. AB - Surgical aortic valve replacement (sAVR) has been a safe, effective and time proven technique and is still the standard of care all over the world for aortic valve treatment. The vast majority of centers perform this procedure by doing a median sternotomy with several disadvantages. While many others specialties went minimally invasive decades ago, in cardiovascular field transcatheter valve implantation was the first minimally invasive valvular procedure that gained rapid worldwide acceptance. Transcatheter valve replacement (TAVR) is now marketed as a procedure that should be performed under local anesthesia, by an interventional cardiologist via trans femoral route with no other healthcare professional invited to the patient selection or case planning. An increasing number of surgeons are promoting minimally invasive aortic valve replacement, which is gaining grounds, especially with the help of the new sutureless valve technology. With these two new technologies emerging, legitimate questions arise and need to be answered - which has the longest durability, lower complication rate and lower overall mortality. PMID- 29160046 TI - Sutureless aortic valve and TAVI: pros and cons. AB - Aortic valve replacement (AVR) with biological heart valves remains the gold standard for treating operable older patients with symptomatic aortic stenosis. Over the last few years, transcatheter aortic valve implantation (TAVI) has been shown to be superior to medical treatment in high-risk patients with severe aortic stenosis. The transfemoral TAVI route has been also found in randomized controlled trials to be as good as, if not superior to, standard AVR at 5 years in high-risk patients. In intermediate-risk patients, TAVI was found in randomized controlled trials as a non-inferior alternative to surgery, with a different pattern of adverse events associated with each procedure. In retrospective propensity matched analysis, the use of TAVI in patients with an intermediate to high risk profile was associated with a significantly higher incidence of perioperative complications and decreased survival at short and mid term when compared with conventional surgery and sutureless valve implantation. More data is needed to draw a firm conclusion comparing the two treatments in intermediate-risk patients. Sutureless bioprostheses may represent a viable alternative to standard bioprostheses for intermediate and high-risk patients when having conventional surgery. PMID- 29160045 TI - Stentless sutureless and transcatheter valves: a comparison of the hemodynamic performance of different prostheses concept. AB - BACKGROUND: Stentless aortic valves have been developed to overcome obstructive limitations associated with stented bioprostheses. A new concept of surgical sutureless (SU) bioprosthesis has been developed in the last decade. In this multi-institutional study we sought to compare hemodynamics of different bioprosthesis concept as transcatheter (TAVR), Livanova Perceval S sutureless valve and Freedom Solo Stentless (FS) valve in patients undergoing aortic valve replacement (sAVR). METHODS: From 2010 to 2016, 478 patients underwent sAVR with FS, 518 Perceval S and 367 patients underwent TAVR. After a propensity matched analysis 185 patients in each group were selected. Thirty-day postoperative clinical and echocardiographic parameters were evaluated. Echocardiographic hemodynamic data were also collected at 12 and 24 months. RESULTS: Mean prosthesis diameter was 23.8+/-1.3 mm for FS, 23.2+/-2.1 mm for Perceval S and 25.1+/-2.6 mm for TAVR. In-hospital mortality was 2.0% for FS, 1.9% for Perceval, 5.8% for TAVR (P=0.02). Postoperative FS peak gradients were 15.6+/-9.1 mmHg (mean 7.6+/-5.4 mmHg); SU gradients were 18.7+/-9.1 mmHg (mean 10.9+/-5.4 mmHg), TAVR peak gradients were 14.7+/-9.1 mmHg (mean 6.1+/-5.4 mmHg) P=0.018 (P<0.001). Postoperative effective orifice area (EOA) was 1.94+/-0.7 cm2 for FS, 1.6+/-0.7 cm2 for SU and 1.97+/-0.7cm2 for TAVR (P<0.001). There was no prostheses-patient mismatch (PPM) in FS group, while 4 cases and 2 cases are reported in SU and TAVR respectively. Postoperative grade 2-3 paravalvular leak (PVL) was present in 4.3% for TAVR and 0.5% in SU valves and no cases in FS. Postoperative permanent pacemaker implant rate was 11.9% for TAVR (1.0%) in FS group and 5.4% in SU valves (P<0.001). CONCLUSIONS: SU patients demonstrated post-operative excellent hemodynamic performance with smaller EROA and higher gradients compared to FS and TAVR. TAVR demonstrated higher mortality and pacemaker rates. Further studies are warrented to validate TAVR indications in this subset of patients. PMID- 29160047 TI - Neoatherosclerosis: from basic principles to intravascular imaging. AB - Development of new atherosclerotic lesions within the neointima of stented vessels has been recognized as a novel disease manifestation of atherosclerosis (neoatherosclerosis), often manifesting as in-stent restenosis (ISR) or in-stent thrombosis (ST). The pathobiology of this entity is still not fully understood and definite diagnosis is challenging owing to limitations in resolution of contemporary intravascular imaging modalities and lack of consequent histopathology correlation studies. Yet, intravascular imaging has emerged as the gold standard for the diagnosis of in-stent pathologies, the most routinely used modalities being intravascular ultrasound (IVUS) and optical coherence tomography (OCT). In this review, we will give a concise summary about the basic understanding and histological findings of neoatherosclerosis. We will focus on the description of in-vivo findings using IVUS and OCT, discussing advantages and pitfalls. Furthermore, recent developments regarding innovative molecular imaging techniques for a more precise and advanced examination of neoatherosclerotic plaques will be discussed. PMID- 29160048 TI - From biodegradable polymers to bioresorbable vascular scaffolds: available evidence in the era of new-generation drug-eluting stents. AB - New-generation drug-eluting stents (DES) encompass a large variety of coronary devices, featuring thin struts, biocompatible durable or biodegradable polymer coatings, and limus-eluting drugs. Due to improved early and long-term outcomes among patients undergoing percutaneous coronary intervention, new-generation metallic DES are recommended in almost all patient and lesion subsets. Available evidence from randomized trials indicates a similar safety and efficacy profile between biodegradable and durable polymers new-generation DES. Recently, polymer free DES provided promising results particularly as alternative to bare-metal stents. Ultimately, although remaining conceptually solid, bioresorbable vascular scaffolds represent an immature technology owing to increased risk of thrombosis. In this review, we summarized current evidence about contemporary coronary devices. PMID- 29160049 TI - Lower irisin levels in coronary artery disease: a meta-analysis. AB - INTRODUCTION: Irisin is a newly discovered myokine, which is involved in energy metabolism and associated with "browning" of the white adipose tissue, obesity, diabetes mellitus and metabolic syndrome. It's still uncertain that whether irisin level is associated with coronary artery disease. The purpose of this study is to explore the relationship between irisin levels and coronary artery disease. EVIDENCE ACQUISITION: A search of PubMed, MEDLINE, Elsevier Science Direct, Springer, Web of Science and China National Knowledge Infrastructure (CNKI) for studies published from 2000 to 2017 was undertaken to identify relevant studies. Case-control studies that reported the association between irisin levels and coronary artery disease were included. Methodological quality of the studies was assessed according to the Newcastle-Ottawa Scale. Random efforts models were used to analyze the weighted mean difference (WMD) and its 95% confidence interval (CI). Subgroup analysis was performed to explore potential sources of heterogeneity. EVIDENCE SYNTHESIS: From 741 studies, 7 case control studies involving 867 patients and 700 controls were selected for meta analysis based on our inclusion and exclusion criteria. In these case-control studies, irisin concentrations were lower in coronary artery disease patients compared with healthy controls. In the meta-analysis, the pooled data indicated that irisin levels were -18.10ng/ml ([95%CI, -35.53 to -0.68ng/ml]; P<0.05) lower in patients with cardiovascular disease or atherosclerosis than healthy controls. CONCLUSIONS: This study confirmed that irisin levels were significantly lower in patients with coronary artery disease. PMID- 29160050 TI - Study on clinical indicators of diabetic retinopathy. PMID- 29160051 TI - Irisin as a regulator of bone and glucose metabolism. AB - In humans, irisin is produced mainly by skeletal muscle in response to physical activity. It has been demonstrated that irisin plays a pivotal role in inducing fat browning and regulating energy expenditure. New findings from various studies conducted in both animals and humans suggest that irisin can affect bone and glucose metabolism. In particular, irisin is able to increase bone cortical mass by stimulating the osteoblast pathways, and irisin levels are inversely correlated with the incidence of fragility fractures among postmenopausal women affected by osteoporosis. Most available evidence shows that irisin significantly influences glucose and energy homeostasis. Indeed, higher irisin concentrations are inversely correlated with type 2 diabetes. Unfortunately, contradictory findings exist concerning the role of irisin in humans, and most of the human studies that have analyzed interactions between bone health, glucose metabolism, and irisin have several limitations; therefore, their results must be interpreted with caution. The purpose of this narrative review is mainly to describe the effects of irisin on glucose and bone metabolism. PMID- 29160052 TI - Disorders of calcium, phosphate and bone: an overview. PMID- 29160053 TI - Cervical plexus innervation of mandibular molars. PMID- 29160054 TI - Dear editor. PMID- 29160055 TI - Clinical Challenges Q&A 26. Mouth and Skin Ulcerations. PMID- 29160057 TI - Effective and Durable Co Single Atomic Cocatalysts for Photocatalytic Hydrogen Production. AB - This research reports for the first time that single cobalt atoms anchored in nitrogen-doped graphene (Co-NG) can serve as a highly effective and durable cocatalyst for visible light photocatalytic hydrogen production from water. Results show that, under identical conditions, the hydrogen production rate (1382 MUmol/h) for 0.25 wt % Co-NG-loaded CdS photocatalyst (0.25 wt % Co-NG/CdS) is 3.42 times greater than that of nitrogen-doped graphene (NG) loaded CdS photocatalyst (NG/CdS) and about 1.3 times greater than the greatest hydrogen production rate (1077 MUmol/h) for 1.5 wt % Pt nanoparticle loaded CdS photocatalyst (1.5 wt % Pt-NPs/CdS). At 420 nm irradiation, the quantum efficiency of the 0.25 wt % Co-NG/CdS photocatalyst is 50.5%, the highest efficiency among those literature-reported non-noble metal cocatalysts. The Co NG/CdS nanocomposite-based photocatalyst also has an extended durability. No activity decline was detected during three cyclic photocatalytic life span tests. The very low cocatalyst loading, along with the facile preparation technology for this non-noble metal cocatalyst, will significantly reduce the hydrogen production costs and finally lead to the commercialization of the solar catalytic hydrogen production process. Based on experimental results, we conclude that Co NG can successfully replace noble metal cocatalysts as a highly effective and durable cocatalyst for renewable solar hydrogen production. This finding will point to a new way for the development of highly effective, long life span, non noble metal-based cocatalysts for renewable and cost-effective hydrogen production. PMID- 29160056 TI - Technique Tips - Repairing Fractured Metal-Ceramic Restorations using Tribochemical Impregnation. PMID- 29160058 TI - Unraveled Face-Dependent Effects of Multilayered Graphene Embedded in Transparent Organic Light-Emitting Diodes. AB - With increasing demand for transparent conducting electrodes, graphene has attracted considerable attention, owing to its high electrical conductivity, high transmittance, low reflectance, flexibility, and tunable work function. Two faces of single-layer graphene are indistinguishable in its nature, and this idea has not been doubted even in multilayered graphene (MLG) because it is difficult to separately characterize the front (first-born) and the rear face (last-born) of MLG by using conventional analysis tools, such as Raman and ultraviolet spectroscopy, scanning probe microscopy, and sheet resistance. In this paper, we report the striking difference of the emission pattern and performance of transparent organic light-emitting diodes (OLEDs) depending on the adopted face of MLG and show the resolved chemical and physical states of both faces by using depth-selected absorption spectroscopy. Our results strongly support that the interface property between two different materials rules over the bulk property in the driving performance of OLEDs. PMID- 29160059 TI - Deuterated Drug Molecules: Focus on FDA-Approved DeutetrabenazinePublished as part of the Biochemistry series "Biochemistry to Bedside". PMID- 29160060 TI - Phase Transition Nanoparticles as Multimodality Contrast Agents for the Detection of Thrombi and for Targeting Thrombolysis: in Vitro and in Vivo Experiments. AB - Thrombotic disease is extremely harmful to human health, and early detection and treatment can improve the prognosis and reduce mortality. Multimodal molecular imaging can provide abundant information about thrombi, but to date, few studies have used multimodal and multifunctional nanoparticles (NPs) for thrombus detection and for targeting thrombolysis. In this study, phase transition multimodal and multifunctional NPs (EWVDV-Fe-Ink-PFH NPs) were constructed for the first time using a three-step emulsification and carbodiimide method, and the physical and chemical properties of the NPs were investigated. The targeting abilities of the NPs and multimodal imaging, that is, photoacoustic, magnetic resonance, and ultrasound imaging, were successfully achieved in vitro and in vivo. The ability of the EWVDV peptide on the NPs to effectively target the P selectin of thrombi was confirmed by multimodal imaging and pathology, and the penetration depths of the NPs into the thrombi were far deeper than the previously reported depths. Moreover, a perfluorohexane (PFH) phase transition induced by low-intensity focused ultrasound irradiation enabled the EWVDV-Fe-Ink PFH NPs to cause thrombolysis in vitro. In summary, EWVDV-Fe-Ink-PFH NPs are a theranostic contrast agent that will provide a simple, effective, and noninvasive approach for the diagnosis and treatment of thrombosis. PMID- 29160061 TI - A Dual Macrophage Targeting Nanovector for Delivery of Oligodeoxynucleotides To Overcome Cancer-Associated Immunosuppression. AB - To overcome cancer-associated immunosuppression, we prepared a dual-targeting vector to deliver CpG oligodeoxynucleotides (ODN) to macrophages. The dual targeting system composed of mannosylated carboxymethyl chitosan (MCMC)/hyaluronan (HA) for macrophage targeting and protamine sulfate for ODN complexation was prepared by self-assembly. The effects of ODN delivery on immune cells was studied in J774A.1 cells. Due to the enhanced delivery efficiency, the dual-targeting delivery system exhibits a higher immune stimulatory activity compared with the monotargeting delivery system containing either MCMC or HA, resulting in a dramatically enhanced secretion of proinflammatory cytokines and a successful shift to activated macrophages (M1). Besides macrophages, the influence of the delivery system on tumor cells (MCF-7) was also investigated. In MCF-7 cells, the increased expressions of nuclear transcription factor-kappaB (NF kappaB), PIK3R3, and phosphorylated protein kinase B (p-Akt) caused by activated NF-kappaB and phosphoinositide 3-kinase/Akt signalings were observed. Nevertheless, upregulated Fas as well as Fas ligand (FasL) may induce Fas/FasL mediated apoptosis, which results in the increased expressions of caspases in tumor cells. PMID- 29160062 TI - Arsenene-Based Heterostructures: Highly Efficient Bifunctional Materials for Photovoltaics and Photocatalytics. AB - Constructing suitable type II heterostructures is a reliable solution for high efficient photovoltaic and photocatalytic materials. Arsenene, as a rising member of monoelemental two-dimensional materials, shows great potential as a building block of heterostructures because of its suitable band gap, high carrier mobility, and good optical properties. On the basis of accurate band structure calculations by combining the many-body perturbation GW method with an extrapolation technique, we demonstrate that arsenene-based heterostructures paired with molybdenum disulfide, tetracyano-quinodimethane, or tetracyanonaphtho quinodimethane can form type II band alignments. These arsenene-based heterostructures cannot only satisfy all the requirements as photocatalysts for photocatalytic water splitting but can also show an excellent power conversion efficiency of ~20% as potential photovoltaics. PMID- 29160063 TI - Effect on Electrode Work Function by Changing Molecular Geometry of Conjugated Polymer Electrolytes and Application for Hole-Transporting Layer of Organic Optoelectronic Devices. AB - In this study, we synthesized three conjugated polymer electrolytes (CPEs) with different conjugation lengths to control their dipole moments by varying spacers. P-type CPEs (PFT-D, PFtT-D, and PFbT-D) were generated by the facile oxidation of n-type CPEs (PFT, PFtT, and PFbT) and introduced as the hole-transporting layers (HTLs) of organic solar cells (OSCs) and polymer light-emitting diodes (PLEDs). To identify the effect on electrode work function tunability by changing the molecular conformation and arrangement, we simulated density functional theory calculations of these molecules and performed ultraviolet photoelectron spectroscopy analysis for films of indium tin oxide/CPEs. Additionally, we fabricated OSCs and PLEDs using the CPEs as the HTLs. The stability and performance were enhanced in the optimized devices with PFtT-D CPE HTLs compared to those of PEDOT:PSS HTL-based devices. PMID- 29160064 TI - Effect of Polarization Reversal in Ferroelectric TiN/Hf0.5Zr0.5O2/TiN Devices on Electronic Conditions at Interfaces Studied in Operando by Hard X-ray Photoemission Spectroscopy. AB - Because of their compatibility with modern Si-based technology, HfO2-based ferroelectric films have recently attracted attention as strong candidates for applications in memory devices, in particular, ferroelectric field-effect transistors or ferroelectric tunnel junctions. A key property defining the functionality of these devices is the polarization dependent change of the electronic band alignment at the metal/ferroelectric interface. Here, we report on the effect of polarization reversal in functional ferroelectric TiN/Hf0.5Zr0.5O2/TiN capacitors on the potential distribution across the stack and the electronic band line-up at the interfaces studied in operando by hard X ray photoemission spectroscopy. By tracking changes in the position of Hf0.5Zr0.5O2 core-level lines with respect to those of the TiN electrode in both short- and open-circuit configurations following in situ polarization reversal, we derive the conduction band offset to be 0.7 (1.0) eV at the top and 1.7 (1.0) eV at the bottom interfaces for polarization, pointing up (down), respectively. Energy dispersive X-ray spectroscopy profiling of the sample cross-section in combination with the laboratory X-ray photoelectron spectroscopy reveal the presence of a TiOx/TiON layer at both interfaces. The observed asymmetry in the band line-up changes in the TiN/Hf0.5Zr0.5O2/TiN memory stack is explained by different origin of these oxidized layers and effective pinning of polarization at the top interface. The described methodology and first experimental results are useful for the optimization of HfO2-based ferroelectric memory devices under development. PMID- 29160065 TI - Transformation of the Anticancer Drug Doxorubicin in the Human Gut Microbiome. AB - Bacteria living in the human gut are implicated in the etiology of several diseases. Moreover, dozens of drugs are metabolized by elements of the gut microbiome, which may have further implications for human health. Here, we screened a collection of gut isolates for their ability to inactivate the widely used antineoplastic drug doxorubicin and identified a strain of Raoultella planticola as a potent inactivator under anaerobic conditions. We demonstrate that R. planticola deglycosylates doxorubicin to metabolites 7-deoxydoxorubicinol and 7-deoxydoxorubicinolone via a reductive deglycosylation mechanism. We further show that doxorubicin is degraded anaerobically by Klebsiella pneumoniae and Escherichia coli BW25113 and present evidence that this phenotype is dependent on molybdopterin-dependent enzyme(s). Deglycosylation of doxorubicin by R. planticola under anaerobic conditions is found to reduce toxicity to the model species Caenorhabditis elegans, providing a model to begin understanding the role of doxorubicin metabolism by microbes in the human gut. Understanding the in vivo metabolism of important therapeutics like doxorubicin by the gut microbiome has the potential to guide clinical dosing to maximize therapeutic benefit while limiting undesirable side effects. PMID- 29160066 TI - BN Nanosheet/Polymer Films with Highly Anisotropic Thermal Conductivity for Thermal Management Applications. AB - The development of advanced thermal transport materials is a global challenge. Two-dimensional nanomaterials have been demonstrated as promising candidates for thermal management applications. Here, we report a boron nitride (BN) nanosheet/polymer composite film with excellent flexibility and toughness prepared by vacuum-assisted filtration. The mechanical performance of the composite film is highly flexible and robust. It is noteworthy that the film exhibits highly anisotropic properties, with superior in-plane thermal conductivity of around 200 W m-1 K-1 and extremely low through-plane thermal conductivity of 1.0 W m-1 K-1, making this material an excellent candidate for thermal management in electronics. Importantly, the composite film shows fire resistant properties. The newly developed unconventional flexible, tough, and refractory BN films are also promising for heat dissipation in a variety of applications. PMID- 29160067 TI - Molecular Tension Probes for Imaging Forces at the Cell Surface. AB - Mechanical forces are essential for a variety of biological processes ranging from transcription and translation to cell adhesion, migration, and differentiation. Through the activation of mechanosensitive signaling pathways, cells sense and respond to physical stimuli from the surrounding environment, a process widely known as mechanotransduction. At the cell membrane, many signaling receptors, such as integrins, cadherins and T- or B-cell receptors, bind to their ligands on the surface of adjacent cells or the extracellular matrix (ECM) to mediate mechanotransduction. Upon ligation, these receptor-ligand bonds transmit piconewton (pN) mechanical forces that are generated, in part, by the cytoskeleton. Importantly, these forces expose cryptic sites within mechanosensitive proteins and modulate the binding kinetics (on/off rate) of receptor-ligand complexes to further fine-tune mechanotransduction and the corresponding cell behavior. Over the past three decades, two categories of methods have been developed to measure cell receptor forces. The first class is traction force microscopy (TFM) and micropost array detectors (mPADs). In these methods, cells are cultured on elastic polymers or microstructures that deform under mechanical forces. The second category of techniques is single molecule force spectroscopy (SMFS) including atomic force microscopy (AFM), optical or magnetic tweezers, and biomembrane force probe (BFP). In SMFS, the experimenter applies external forces to probe the mechanics of individual cells or single receptor-ligand complexes, serially, one bond at a time. Although these techniques are powerful, the limited throughput of SMFS and the nN force sensitivity of TFM have hindered further elucidation of the molecular mechanisms of mechanotransduction. In this Account, we introduce the recent advent of molecular tension fluorescence microscopy (MTFM) as an emerging tool for molecular imaging of receptor mechanics in living cells. MTFM probes are composed of an extendable linker, such as polymer, oligonucleotide, or protein, and flanked by a fluorophore and quencher. By measuring the fluorescence emission of immobilized MTFM probes, one can infer the extension of the linker and the externally applied force. Thus, MTFM combines aspects of TFM and SMFS to optically report receptor forces across the entire cell surface with pN sensitivity. Specifically, we provide an in-depth review of MTFM probe design, which includes the extendable "spring", spectroscopic ruler, surface immobilization chemistry, and ligand design strategies. We also demonstrate the strengths and weaknesses of different versions of MTFM probes by discussing case studies involving the pN forces involved in epidermal growth factor receptor, integrin, and T-cell receptor signaling pathways. Lastly, we present a brief future outlook, primarily from a chemists' perspective, on the challenges and opportunities for the design of next generation MTFM probes. PMID- 29160068 TI - Regioregular Bis-Pyridal[2,1,3]thiadiazole-Based Semiconducting Polymer for High Performance Ambipolar Transistors. AB - We report a regioregular bis-pyridal[2,1,3]-thiadiazole (BPT) acceptor strategy to construct the first ambipolar pyridal[2,1,3]thiadiazole-based semiconducting polymer (PBPTV). The use of BPT unit enables PBPTV to achieve high electron affinity, low LUMO level, and extended pi-conjugation. All these factors provide PBPTV with encouraging hole and electron mobilities up to 6.87 and 8.49 cm2 V-1 s 1, respectively. Our work demonstrates that the BPT unit is a promising building block for designing high-performance electron-transporting semiconductors in organic electronics. PMID- 29160069 TI - Correction to Analysis of the Geometrical Evolution in On-the-Fly Surface-Hopping Nonadiabatic Dynamics with Machine Learning Dimensionality Reduction Approaches: Classical Multidimensional Scaling and Isometric Feature Mapping. PMID- 29160070 TI - Cation Hydration in Supercritical NaOH and HCl Aqueous Solutions. AB - We present a study of the local atomic environment of the oxygen atoms in the aqueous solutions of NaOH and HCl under simultaneous high-temperature and high pressure conditions. Experimental nonresonant X-ray Raman scattering core-level spectra at the oxygen K-edge show systematic changes as a function of temperature and pressure. These systematic changes are distinct for the two different solutes and are described well by calculations within the Bethe-Salpeter formalism for snapshots from ab initio molecular dynamics simulations. The agreement between experimental and simulation results allows us to use the computations for a detailed fingerprinting analysis in an effort to elucidate the local atomic structure and hydrogen-bonding topology in these relevant solutions. We observe that both electrolytes, especially NaOH, enhance hydrogen bonding and tetrahedrality in the water structure at supercritical conditions, in particular in the vicinity of the hydration shells. This effect is accompanied with the association of the HCl and NaOH molecules at elevated temperatures. PMID- 29160071 TI - Real-Time Investigation of the H/D Exchange Kinetics of Porphyrins and Oligopeptides by Means of Neutral Cluster-Induced Desorption/Ionization Mass Spectrometry. AB - The kinetics of the H/D exchange reaction in angiotensin II, hexaglycine (Gly6), Co(II)tetra(3-carboxyphenyl)porphyrin, and tetra(4-carboxyphenyl)porphyrin were followed in real time by mass spectrometry employing desorption/ionization induced by neutral SO2 clusters. The change of the isotope patterns with increasing degree of deuteration was recorded as a function of D2O exposure and the underlying H/D exchange kinetics, i.e., the dependence of the different degrees of deuteration on time, were deduced. The results were modeled by means of Monte Carlo simulations taking into account different reaction constants for the H/D exchange reaction at different functional groups. In the case of the investigated porphyrins, the rate constants were directly assigned to the functional groups involved; in the case of the peptides, reaction at the explicit functional groups and the backbone chain of the molecules could be discriminated. PMID- 29160072 TI - Solvent-Controlled Branching of Localized versus Delocalized Singlet Exciton States and Equilibration with Charge Transfer in a Structurally Well-Defined Tetracene Dimer. AB - A detailed photophysical picture is elaborated for a structurally well-defined and symmetrical bis-tetracene dimer in solution. The molecule was designed for interrogation of the initial photophysical steps (S1 -> 1TT) in intramolecular singlet fission (SF). (Triisopropylsilyl)acetylene substituents on the dimer TIPS BT1 as well as a monomer model TIPS-Tc enable a comparison of photophysical properties, including transient absorption dynamics, as solvent polarity is varied. In nonpolar toluene solutions, TIPS-BT1 decays via radiative and nonradiative pathways to the ground state with no evidence for dynamics related to the initial stages of SF. This contrasts with the behavior of the previously reported unsubstituted dimer BT1 and is likely a consequence of energetic perturbations to the singlet excited-state manifold of TIPS-BT1 by the (trialkylsilyl)acetylene substituents. In polar benzonitrile, two key findings emerge. First, photoexcited TIPS-BT1 shows a bifurcation into both arm-localized (S1-loc) and dimer-delocalized (S1-dim) singlet exciton states. The S1-loc decays to the ground state, and weak temperature dependence of its emissive signatures suggests that once it is formed, it is isolated from S1-dim. Emissive signatures of the S1-dim state, on the other hand, are strongly temperature-dependent, and transient absorption dynamics show that S1-dim equilibrates with an intramolecular charge-transfer state in 50 ps at room temperature. This equilibrium decays to the ground state with little evidence for formation of long lived triplets nor 1TT. These detailed studies spectrally characterize many of the key states in intramolecular SF in this class of dimers but highlight the need to tune electronic coupling and energetics for the S1 -> 1TT photoreaction. PMID- 29160073 TI - Synthesis of beta-Amino Ketones by Addition of Aryl Methyl Ketones to Sulfinimines: Application to the Total Synthesis of HPA-12, Norsedamine, and Sedamine. AB - Synthesis of beta-sulfinamido ketones was accomplished by the addition of silyl enol ethers derived from arylmethyl ketones to chiral sulfinimines in excellent yield and selectivity. Application of the formed beta-amino substituted ketones is exemplified in the total synthesis of sphingolipid HPA-12 and the sedamine alkaloids. PMID- 29160074 TI - Stereoselective and Catalytic Synthesis of anti-beta-Alkoxy-alpha-azido Carboxylic Derivatives. AB - Direct addition of a chiral N-azidoacetyl thiazolidinethione to a variety of dialkyl acetals catalyzed by a commercially available and structurally simple nickel(II) complex gives access in good yields and a highly stereocontrolled manner to anti-beta-alkoxy-alpha-azido carboxylic derivatives which, in turn, can be easily converted into a wide array of enantiomerically pure compounds. PMID- 29160075 TI - Electron and Hole g-Factors and Spin Dynamics of Negatively Charged Excitons in CdSe/CdS Colloidal Nanoplatelets with Thick Shells. AB - We address spin properties and spin dynamics of carriers and charged excitons in CdSe/CdS colloidal nanoplatelets with thick shells. Magneto-optical studies are performed by time-resolved and polarization-resolved photoluminescence, spin-flip Raman scattering and picosecond pump-probe Faraday rotation in magnetic fields up to 30 T. We show that at low temperatures the nanoplatelets are negatively charged so that their photoluminescence is dominated by radiative recombination of negatively charged excitons (trions). Electron g-factor of 1.68 is measured, and heavy-hole g-factor varying with increasing magnetic field from -0.4 to -0.7 is evaluated. Hole g-factors for two-dimensional structures are calculated for various hole confining potentials for cubic- and wurtzite lattice in CdSe core. These calculations are extended for various quantum dots and nanoplatelets based on II-VI semiconductors. We developed a magneto-optical technique for the quantitative evaluation of the nanoplatelets orientation in ensemble. PMID- 29160076 TI - Segregation of Native Defects to the Grain Boundaries in Methylammonium Lead Iodide Perovskite. AB - Native point and grain boundary (GB) defects are ubiquitous in methylammonium lead iodide (MAPbI3) sensitizers employed in solar cells that are polycrystalline in nature. Here we use density functional theory (DFT) in conjunction with a thermodynamic approach to determine the stability and electronic properties of all native point defects and their interplays with Sigma5-(210) GB in MAPbI3. The transition levels of charged defects are investigated with inclusion of electrostatic charge corrections and spin-orbit coupling. We find that the GB region is a sink for most of the native point defects under different synthesis conditions. For the crystalline and bicrystalline MAPbI3 with Sigma5-(210) GB, we find respectively that the p-type antisite defects MAI and PbI, where I substitutes for MA or Pb, introduce deep levels, and both are relatively stable under I-rich conditions. Hence, I-poor conditions are more preferable for synthesis of MAPbI3 to have defects with electronically benign character. PMID- 29160077 TI - Enhanced yet Inverted Effects of pi-Extension in Self-Assembly of Curved pi Systems with Helicity. AB - A sextuple helix molecule possessing four cove regions of helicene and two axes of biaryls was synthesized. The entropy-driven self-assembly in solution was determined by concentration- and temperature-dependent NMR spectra, which also revealed unique dynamics of isomerization involving structural changes at the cove regions. Unexpectedly, the assembly retarded the isomerization in solution, and the sextuple helix structure was rigidified. PMID- 29160078 TI - Formation of Lipid-Bilayer Nanodiscs by Diisobutylene/Maleic Acid (DIBMA) Copolymer. AB - Membrane proteins usually need to be extracted from their native environment and separated from other membrane components for in-depth in vitro characterization. The use of styrene/maleic acid (SMA) copolymers to solubilize membrane proteins and their surrounding lipids into bilayer nanodiscs is an attractive approach toward this goal. We have recently shown that a diisobutylene/maleic acid (DIBMA) copolymer similarly solubilizes model and cellular membranes but, unlike SMA(3:1), has a mild impact on lipid acyl-chain order and thermotropic phase behavior. Here, we used fluorescence spectroscopy, small-angle X-ray scattering, size-exclusion chromatography, dynamic light scattering, and 31P nuclear magnetic resonance spectroscopy to examine the self-association of DIBMA and its membrane solubilization properties against lipids differing in acyl-chain length and saturation. Although DIBMA is less hydrophobic than commonly used SMA(3:1) and SMA(2:1) copolymers, it efficiently formed lipid-bilayer nanodiscs that decreased in size with increasing polymer/lipid ratio while maintaining the overall thickness of the membrane. DIBMA fractions of different molar masses were similarly efficient in solubilizing a saturated lipid. Coulomb screening at elevated ionic strength or reduced charge density on the polymer at low pH enhanced the solubilization efficiency of DIBMA. The free-energy penalty for transferring phospholipids from vesicular bilayers into nanodiscs became more unfavorable with increasing acyl-chain length and unsaturation. Altogether, these findings provide a rational framework for using DIBMA in membrane-protein research by shedding light on the effects of polymer and lipid properties as well as experimental conditions on membrane solubilization. PMID- 29160079 TI - Comprehensive Mass Spectrometric Survey of Streptococcus pyogenes Subcellular Proteomes. AB - Streptococcus pyogenes is a major global health burden causing a wide variety of diseases. Because a vaccine against this bacterium is still lacking, vaccine candidates or antimicrobial therapies are urgently needed. Here we use an invasive and clinically relevant streptococcal M1 serotype to characterize the bacterial proteome in-depth. An elaborate fractionation technique is employed to separate the different cell fractions, followed by shotgun mass-spectrometry analysis, allowing us to confirm the expression of nearly two-thirds (1022) of the 1690 open reading frames predicted for the streptococcal M1 reference proteome. In contrast with other studies, we present the entire isolated membrane proteome, which opens up a whole new source for drug targets. We show both the unique and most prevalent proteins for each cellular fraction and analyze the presence of predicted cell-wall-anchored proteins and lipoproteins. With our approach, we also identify a variety of novel proteins whose presence has not been reported in previous proteome studies. Proteins of interest, potential virulence factors, and drug or vaccine targets are discussed for each cellular fraction. Overall, the results of this work represent the so-far widest proteomic approach to characterize the protein composition and localization in S. pyogenes. PMID- 29160080 TI - Adjuvant Activity of Poly-epsilon-caprolactone/Chitosan Nanoparticles Characterized by Mast Cell Activation and IFN-gamma and IL-17 Production. AB - Polymeric nanoparticles (NPs) are extremely attractive vaccine adjuvants, able to promote antigen delivery and in some instances, exert intrinsic immunostimulatory properties that enhance antigen specific humoral and cellular immune responses. The poly-epsilon-caprolactone (PCL)/chitosan NPs were designed with the aim of being able to combine the properties of the 2 polymers in the preparation of an adjuvant for the hepatitis B surface antigen (HBsAg). This article reports important results of an in vitro mechanistic study and immunization studies with HBsAg associated with different concentrations of the nanoparticles. The results revealed that PCL/chitosan NPs promoted mast cell (MC) activation (beta hexosaminidase release) and that its adjuvant effect is not mediated by the TNF alpha secretion. Moreover, we demonstrated that HBsAg loaded PCL/chitosan NPs, administered through the subcutaneous (SC) route, were able to induce higher specific antibody titers without increasing IgE when compared to a commercial vaccine, and that the IgG titers are nanoparticle-dose dependent. The results also revealed the NPs' capability to promote a cellular immune response against HBsAg, characterized by the production of IFN-gamma and IL-17. These results demonstrated that PCL/chitosan NPs are a good hepatitis B antigen adjuvant, with direct influence on the intensity and type of the immune response generated. PMID- 29160081 TI - Iridium-Catalyzed Enantioselective Synthesis of Dihydroimidazoquinazolinones by Elaborate Tuning of Chiral Cyclic Ligands. AB - A highly efficient, enantioselective intramolecular allylation of (E)-4-(alkyl(4 oxo-3,4-dihydroquinazolin-2-yl)amino)but-2-en-1-yl methyl carbonates was developed, and the corresponding dihydroimidazoquinazolinones were prepared in high yields and enantiomeric excess. The allylation was performed under catalysis of iridium-chiral cyclic phosphoramidite complexes, in which the reactivity and enantioselectivity of the substrates were elaborately tuned by our developed chiral cyclic phosphoramidite ligands with adjustable sizes of rings. PMID- 29160083 TI - Mechanisms and Applications of Redox-Sensitive Green Fluorescent Protein-Based Hydrogen Peroxide Probes. AB - SIGNIFICANCE: Genetically encoded hydrogen peroxide (H2O2) sensors, based on fusions between thiol peroxidases and redox-sensitive green fluorescent protein 2 (roGFP2), have dramatically broadened the available "toolbox" for monitoring cellular H2O2 changes. Recent Advances: Recently developed peroxiredoxin-based probes such as roGFP2-Tsa2DeltaCR offer considerably improved H2O2 sensitivity compared with previously available genetically encoded sensors and now permit dynamic, real-time, monitoring of changes in endogenous H2O2 levels. CRITICAL ISSUES: The correct understanding and interpretation of probe read-outs is crucial for their meaningful use. We discuss probe mechanisms, potential pitfalls, and best practices for application and interpretation of probe responses and highlight where gaps in our knowledge remain. FUTURE DIRECTIONS: The full potential of the newly available sensors remains far from being fully realized and exploited. We discuss how the ability to monitor basal H2O2 levels in real time now allows us to re-visit long-held ideas in redox biology such as the response to ischemia-reperfusion and hypoxia-induced reactive oxygen species production. Further, recently proposed circadian cycles of peroxiredoxin hyperoxidation might now be rigorously tested. Beyond their application as H2O2 probes, roGFP2-based H2O2 sensors hold exciting potential for studying thiol peroxidase mechanisms, inactivation properties, and the impact of post translational modifications, in vivo. Antioxid. Redox Signal. 29, 552-568. PMID- 29160082 TI - Cyclic versus Noncyclic Chelating Scaffold for 89Zr-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression. AB - : Zirconium-89 is an emerging radionuclide for positron emission tomography (PET) especially for biomolecules with slow pharmacokinetics as due to its longer half life, in comparison to fluorine-18 and gallium-68, imaging at late time points is feasible. Desferrioxamine B (DFO), a linear bifunctional chelator (BFC) is mostly used for this radionuclide so far but shows limitations regarding stability. Our group recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study was designed to compare FSC and DFO head-to-head as bifunctional chelators for 89Zr-radiolabeled EGFR-targeting ZEGFR:2377 affibody bioconjugates. FSC-ZEGFR: 2377 and DFO-ZEGFR:2377 were evaluated regarding radiolabeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution, and microPET-CT imaging. Both conjugates were efficiently labeled with zirconium-89 at room temperature but radiochemical yields increased substantially at elevated temperature, 85 degrees C. Both 89Zr-FSC-ZEGFR:2377 and 89Zr-DFO-ZEGFR:2377 revealed remarkable specificity, affinity and slow cell line dependent internalization. Radiolabeling at 85 degrees C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake. In comparison 89Zr-DFO-ZEGFR:2377, radiolabeled at room temperature, showed a significant difference regarding tumor to-organ ratios. MicroPET-CT imaging studies of 89Zr-FSC-ZEGFR:2377 as well as 89Zr-DFO-ZEGFR:2377 confirmed these findings. In summary we were able to show that FSC is a suitable alternative to DFO for radiolabeling of biomolecules with zirconium-89. Furthermore, our findings indicate that 89Zr-radiolabeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast. PMID- 29160084 TI - Serial testing of the ICHD-3 beta diagnostic criteria for probable reversible cerebral vasoconstriction syndrome: A prospective validation study. AB - Objectives To serially test the International Classification of Headache Disorders (ICHD) 3rd edition beta version criteria for 6.7.3.1 probable reversible cerebral vasoconstriction syndrome (probable RCVS) in patients with thunderclap headache. Methods We prospectively screened consecutive patients with thunderclap headache who visited the Samsung Medical Center between October 2015 and March 2017. Patients were included in the analysis if they a) visited our hospital within 1 month after onset, b) completed a diagnostic work-up, and c) had no secondary causes other than RCVS. The ICHD-3 beta 6.7.3.1 criteria were evaluated serially during the first visit (visit 1), 2 weeks after the first visit (visit 2), and 1-3 months after onset (visit 3). Results A total of 99 patients completed this study. Based on the first clinical and radiological evaluation, 63 (63.6%) were diagnosed with angiogram-proven RCVS, whilst 36 (36.4%) showed normal neuroimaging. The ICHD-3 beta 6.7.3.1 criteria were fulfilled in 76.2% of patients with angiogram-proven RCVS. In patients with normal angiograms, the ICHD diagnosis of probable RCVS changed over time: 25.0%, 47.2%, and 38.9% at visits 1, 2, and 3, respectively. The sensitivity and specificity of the criteria at visit 1 were 72.4% and 95.5%, respectively, for the prediction of a final diagnosis of overall (angiogram-proven + probable) RCVS. Conclusions The ICHD-3 beta criteria for probable RCVS are applicable for patients with thunderclap headaches at the acute stage, with the exception of criterion C3. Criteria C1 and C2 are less reliable when applied at the first visit. Repeated evaluation is necessary to enhance diagnostic sensitivity. PMID- 29160085 TI - Some like it hot: Cardiovascular health benefits of Finnish sauna. PMID- 29160086 TI - Anatomic and Radiologic Study of Renal Avascular Plane (Brodel's Line) and Its Potential Relevance on Percutaneous and Surgical Approaches to the Kidney. AB - OBJECTIVE: The aim of the present anatomic and radiologic study was to evaluate the location, extension, and characteristics of the Brodel's plane and eventually define its different patterns. MATERIALS AND METHODS: We evaluated 15 human normal kidneys sampled from unembalmed cadavers without clinical history or anatomical evidence of renal diseases. Kidneys with the surrounding perirenal fat tissue were removed en bloc with the abdominal segment of the aorta. The renal artery was injected with acrylic and radiopaque resins. A CT examination of the injected kidneys was performed. After the imaging acquisition, the specimens were treated with sodium hydroxide for removal of the parenchyma to obtain the vascular casts. All the CT images were elaborated using dedicated three dimensional (3D) software with the aim to improve the possibility to identify the Brodel's plane. The avascular plane was identified directly on the vascular casts and confirmed on the corresponding 3D images. RESULTS: The avascular plane was located in all cases medially to the lateral convex border of the kidneys. The recorded mean distance was 2.04 cm (range 1.8-2.4 cm). Three patterns of distribution of the Brodel's line were identified. In five (33.3%) cases the avascular plane was extended from the apical to the inferior segment of the kidneys (type 1); in six (40%) from the superior to the inferior segment (type 2); and in four (26.7%) from the apical to the middle segment (type 3). Fourth and fifth order vessels crossing the Brodel's line were detected in all the analyzed cases. CONCLUSIONS: The renal avascular plane showed a different extension allowing us to cluster three different patterns. Preoperative identification of the Brodel's line patterns could help surgeons to minimize hemorrhagic complications during percutaneous and surgical procedures requiring an incision of the renal parenchyma such as traditional or robot-assisted nephrolithotomy or partial nephrectomy for endophytic renal tumors. Radiologic studies validated that the described patterns in the clinical practice are strongly needed. PMID- 29160087 TI - Glyoxalase 1 Modulation in Obesity and Diabetes. AB - SIGNIFICANCE: Obesity and type 2 diabetes mellitus are increasing globally. There is also increasing associated complications, such as non-alcoholic fatty liver disease (NAFLD) and vascular complications of diabetes. There is currently no licensed treatment for NAFLD and no recent treatments for diabetic complications. New approaches are required, particularly those addressing mechanism-based risk factors for health decline and disease progression. Recent Advances: Dicarbonyl stress is the abnormal accumulation of reactive dicarbonyl metabolites such as methylglyoxal (MG) leading to cell and tissue dysfunction. It is a potential driver of obesity, diabetes, and related complications that are unaddressed by current treatments. Increased formation of MG is linked to increased glyceroneogenesis and hyperglycemia in obesity and diabetes and also down regulation of glyoxalase 1 (Glo1)-which provides the main enzymatic detoxification of MG. Glo1 functional genomics studies suggest that increasing Glo1 expression and activity alleviates dicarbonyl stress; slows development of obesity, related insulin resistance; and prevents development of diabetic nephropathy and other microvascular complications of diabetes. A new therapeutic approach constitutes small-molecule inducers of Glo1 expression-Glo1 inducers exploiting a regulatory antioxidant response element in the GLO1 gene. A prototype Glo1 inducer, trans-resveratrol (tRES)-hesperetin (HESP) combination, in corrected insulin resistance, improved glycemic control and vascular inflammation in healthy overweight and obese subjects in clinical trial. CRITICAL ISSUES: tRES and HESP synergize pharmacologically, and HESP likely overcomes the low bioavailability of tRES by inhibition of intestinal glucuronosyltransferases. FUTURE DIRECTIONS: Glo1 inducers may now be evaluated in Phase 2 clinical trials for treatment of NAFLD and vascular complications of diabetes. Antioxid. Redox Signal. 00, 000-000. PMID- 29160088 TI - Resting-State Functional Connectivity of the Subthalamic Nucleus to Limbic, Associative, and Motor Networks. AB - The subthalamic nucleus (STN) is a small structure situated deep in the midbrain that exhibits wide-ranging functionality. In addition to its role in motor control, the STN is considered a hub for synchronizing aspects of emotion and cognition including attention, inhibitory control, motivation, and working memory. Evidence from neuroanatomical tracer studies suggests that the medial, ventromedial, and dorsolateral parts of the STN correspond to limbic, associative, and motor subdivisions, respectively. Although the extent of STN functional anatomical overlap remains unclear, blood oxygenation level dependent imaging of the STN may provide complementary information about the diverse functions of this structure. Methodological limitations in spatial and temporal resolutions, however, have prevented a comprehensive exploration of temporal correlations from the STN to the whole brain. In this study, we optimize spatial (2 mm isotropic) and temporal (TR = 1 s) resolutions to take full advantage of the time series signal-to-noise ratio capabilities of multichannel array coils and simultaneous multislice imaging. We interrogated STN seed-to-voxel resting state functional MRI connectivity in a group of 30 healthy participants that included the whole brain at high-temporal and spatial resolutions. This analysis revealed STN functional connectivity to limbic, associative, and motor networks. Our findings contribute to the understanding of STN functional neuroanatomy in humans and are clinically relevant for ongoing research in deep brain stimulation. PMID- 29160089 TI - A comparison of multi-component systems approaches to suicide prevention. AB - OBJECTIVE: To describe the new Australian approach to suicide prevention, LifeSpan, and compare it to other multi-component intervention models. METHOD: The components, implementation strategies and effectiveness of three multi component intervention models are described and compared in a narrative review. RESULTS: The LifeSpan, European Alliance Against Depression (EAAD), and Zero Suicide models emphasise the provision of evidence-based interventions and continuity of care. Only LifeSpan and EAAD include community-based interventions at the population level, and LifeSpan is the only model to include school-based interventions. Zero Suicide focuses on healthcare settings. Implementation of LifeSpan and EAAD involves the convening of multi-stakeholder teams at the local level. To date, there is some, albeit mixed, evidence in support of EAAD, while LifeSpan and Zero Suicide await further evaluation. CONCLUSIONS: Although multi component approaches to suicide prevention share similar components, there are some important differences. Multiple interventions implemented at the same time and tailored to the local community context are likely to be the most effective way of reducing the rate of suicide. There is growing evidence for the effectiveness of multi-component systems approaches to suicide prevention; however, further evaluation is required. PMID- 29160090 TI - Two Consecutive Cases of Persistent Stapedial Artery Managed With a Carbon Dioxide Laser. AB - OBJECTIVE: (1) Discuss the presentation and management of persistent stapedial artery (PSA) discovered incidentally during cholesteatoma surgery. (2) Review use of carbon dioxide (CO2) laser for treatment of PSA in the setting of chronic ear disease. PATIENTS: Two consecutive patients with PSA and primary acquired cholesteatoma. INTERVENTION(S): Tympanomastoidectomy using a canal wall reconstruction technique. MAIN OUTCOME MEASURE(S): Surgical healing, collateral damage to surrounding anatomy, and postoperative hearing. RESULTS: Persistent stapedial artery was detected incidentally in 2 patients, manifesting with heavy pulsatile bleeding arising during dissection of mesotympanic cholesteatoma. Preoperative computed tomography scans demonstrated absent foramen spinosum but no other aberrant vascular anatomy. Using CO2 laser, the PSAs were ablated and controlled, allowing complete resection of cholesteatoma and successful completion of the procedure. In both patients, surrounding anatomical structures suffered no iatrogenic injury. Postoperatively, no significant complications occurred. To date, neither patient has demonstrated evidence of recidivistic cholesteatoma. CONCLUSIONS: A CO2 laser can be useful for managing a PSA in the setting of chronic ear disease. PMID- 29160091 TI - Probabilistic description of infant head kinematics in abusive head trauma. AB - Abusive head trauma (AHT) is a potentially fatal result of child abuse, but the mechanisms by which injury occur are often unclear. To investigate the contention that shaking alone can elicit the injuries observed, effective computational models are necessary. The aim of this study was to develop a probabilistic model describing infant head kinematics in AHT. A deterministic model incorporating an infant's mechanical properties, subjected to different shaking motions, was developed in OpenSim. A Monte Carlo analysis was used to simulate the range of infant kinematics produced as a result of varying both the mechanical properties and the type of shaking motions. By excluding physically unrealistic shaking motions, worst-case shaking scenarios were simulated and compared to existing injury criteria for a newborn, a 4.5 month-old, and a 12 month-old infant. In none of the three cases were head kinematics observed to exceed previously estimated subdural haemorrhage injury thresholds. The results of this study provide no biomechanical evidence to demonstrate how shaking by a human alone can cause the injuries observed in AHT, suggesting either that additional factors, such as impact, are required, or that the current estimates of injury thresholds are incorrect. PMID- 29160092 TI - Prevention of Urethral Retraction with Stay Sutures (PURS) During Robot-Assisted Radical Prostatectomy Improves Early Urinary Control: A Prospective Cohort Study. AB - OBJECTIVE: To evaluate early continence rates with a novel modified vesicourethral anastomosis technique based on prevention of urethral retraction using anastomosis sutures as stay sutures (PURS) during robot-assisted radical prostatectomy. MATERIALS AND METHODS: Sixty patients operated by a single surgeon were enrolled and data collected prospectively. This cohort was compared with another consecutive 60 patients operated with standard anastomosis. The new technique is based on preventing urethral retraction of the posterior urethra with two anastomosis sutures being used as stay sutures. The outcomes were prospectively followed and groups compared regarding early continence. International Consultation on Incontinence Questionnaire Short Form was used to assess incontinence and its impact on the quality of life. Pad use (yes or no pads) was evaluated as a more stringent criterion. RESULTS: Preoperative patient characteristics were similar between the two groups. Anastomosis was completed faster in PURS group (15.1 vs 18.5 min, p = 0.05). At postoperative week 1 and month 1, the severity and bother of incontinence were significantly less in the PURS group (12.7 vs 4.1 and 10.1 vs 2.6, p < 0.001). PURS cohort reported significantly superior pad-free rates at both postoperative month 1 (73% vs 35%, p < 0.0001) and month 3 (83% vs 53%, p = 0.0004). On multivariable analysis, younger age and the new anastomosis technique were two independent predictors to improve early continence. Four patients in modified anastomosis group (4/60) and 1 in standard anastomosis group (1/60) necessitated temporary urethral recatheterization because of urinary retention. CONCLUSION: We describe a simple and time-efficient modified urethrovesical anastomosis technique by using anastomosis sutures as stay sutures to prevent perineal retraction of the urethral stump. Our results demonstrated that the technique is an independent factor impacting early recovery of urinary continence. Future randomized controlled studies would be required to further test the reproducibility of this technique. PMID- 29160093 TI - Comparison of fall prediction by the Hessisch Oldendorf Fall Risk Scale and the Fall Risk Scale by Huhn in neurological rehabilitation: an observational study. AB - OBJECTIVE: To calculate scale performance of the newly developed Hessisch Oldendorf Fall Risk Scale (HOSS) for classifying fallers and non-fallers in comparison with the Risk of Falling Scale by Huhn (FSH), a frequently used assessment tool. DESIGN: A prospective observational trail was conducted. SETTING: The study was performed in a large specialized neurological rehabilitation facility. SUBJECTS: The study population ( n = 690) included neurological and neurosurgery patients during neurological rehabilitation with varying levels of disability. Around the half of the study patients were independent and dependent in the activities of daily living (ADL), respectively. INTERVENTIONS: Fall risk of each patient was assessed by HOSS and FSH within the first seven days after admission. MAIN MEASURES: Event of fall during rehabilitation was compared with HOSS and FSH scores as well as the according fall risk. Scale performance including sensitivity and specificity was calculated for both scales. RESULTS: A total of 107 (15.5%) patients experienced at least one fall. In general, fallers were characterized by an older age, a prolonged length of stay, and a lower Barthel Index (higher dependence in the ADL) on admission than non-fallers. The verification of fall prediction for both scales showed a sensitivity of 83% and a specificity of 64% for the HOSS scale, and a sensitivity of 98% with a specificity of 12% for the FSH scale, respectively. CONCLUSION: The HOSS shows an adequate sensitivity, a higher specificity and therefore a better scale performance than the FSH. Thus, the HOSS might be superior to existing assessments. PMID- 29160094 TI - Novel approach to constructing laser ionization elemental time-of-flight mass spectrometer. AB - The main advantages of laser sampling are associated with following features: sample preparations as well as consumables are not needed, low risk of sample contamination, good spatial resolution. In mass spectrometry, high laser irradiance can be used for both ablation and ionization processes. The method is especially profitable in time-of-flight mass spectrometry. A new principle of constructing laser ionization time-of-flight mass spectrometer based on wedge shaped ion mirrors and the absence of electrostatic ion acceleration before mass analysis is discussed. Among advantages of the analyzer there are ability to provide temporal focusing of ions in a wide energy range (+/-20%), compactness of the analyzer, and minimization of the requirements for power supplies. The approach is expected to be profitable for standardless elemental analysis of solid samples, which should be possible at laser irradiation power density more than 3 * 109 W/cm2 that ensures complete ionization of all elements in a laser plasma. The analytical signal of each element is formed as the sum of the signals for all charge states and the energy scan of the mass spectra is provided. PMID- 29160095 TI - Teaching reading comprehension to learners with autism spectrum disorder: Discrepancies between teacher and research-recommended practices. AB - Students with autism spectrum disorder have been found to experience difficulty with reading comprehension despite intact decoding and word recognition. This identified need for targeted reading comprehension remediation results in a need for teachers to utilize research-based practices and to individualize instruction for students with autism spectrum disorder; however, teachers report a lack of access to such practices. This study utilized survey methodology to gather perceptions and experiences of teachers and to compare teacher preparedness to use effective instructional practices emerging from the extant research to teacher-reported effective practices in the classroom. Study findings, based on 112 participants, reveal a discrepancy between teacher-reported effective practices, and the practices identified as effective through research, indicating a research to practice gap. Implications for practice include professional development recommendations, and the need for increased communication between researchers and teachers. PMID- 29160096 TI - Initial Fibular Displacement as a Predictor of Medial Clear Space Widening in Weber B Ankle Fractures. AB - BACKGROUND: The diagnosis of medial ankle instability in Weber B ankle fractures remains controversial. Manual stress and gravity stress radiographs as well as magnetic resonance imaging (MRI) are used, but there is no consensus gold standard. The purpose of this study was to determine the relationship between initial fibular displacement and medial clear space widening on a gravity stress radiograph as a predictor of instability. METHODS: A retrospective review was conducted of all patients with isolated Weber B ankle fractures with both initial injury radiographs and gravity stress view from August 1, 2014, through April 1, 2016. A total of 17 patients were identified. On the mortise view of initial injury radiographs, medial clear space (MCS), superior clear space, lateral fibular displacement (LFDP), and fibular shortening (FS) were measured, and on the lateral view, anterior to posterior fibular gap (A to P FG) was measured. MCS was again measured on the gravity stress view (MCS-W). Statistical analyses identified the correlations of each displacement variable relative to MCS-W as well as the sensitivity and specificity of each parameter. RESULTS: A cutoff point for MCS-W was set as less than 5.0 mm (n = 8) and 5.0 mm or more (n = 9). Strong significant correlations with MCS-W were found for A to P FG (0.84, P < .001), with a trend for LFDP (0.62, P = .008), but no significance with FS (0.38, P = .84). Linear regression analysis revealed significant ability to predict MCS W for both LFDP ( P = .002) and A to P FG ( P = .001) but not FS. Receiver operating characteristic analysis for A to P FG using a threshold value of 1.0 mm yielded sensitivity and specificity of 100% in predicting an MCS-W of 5.0 mm or more. CONCLUSION: The initial fibular displacement was a strong predictor of MCS W in Weber B ankle fractures. On lateral radiographs, an A to P FG greater than 1.0 mm showed a sensitivity and specificity of 100% in predicting an MCS-W of 5.0 mm or more on gravity stress view. LEVEL OF EVIDENCE: Level III case series, prognostic. PMID- 29160098 TI - Editorial Comment on: Three-Layer Two-Step Posterior Reconstruction Using Peritoneum During Robot-Assisted Radical Prostatectomy to Improve Recovery of Urinary Continence: A Prospective Comparative Study by Ogawa et al. PMID- 29160100 TI - Establishing a laboratory model of dental unit waterlines bacterial biofilms using a CDC biofilm reactor. AB - In this study, a laboratory model to reproduce dental unit waterline (DUWL) biofilms was developed using a CDC biofilm reactor (CBR). Bacteria obtained from DUWLs were filtered and cultured in Reasoner's 2A (R2A) for 10 days, and were subsequently stored at -70 degrees C. This stock was cultivated on R2A in batch mode. After culturing for five days, the bacteria were inoculated into the CBR. Biofilms were grown on polyurethane tubing for four days. Biofilm accumulation and thickness was 1.3 * 105 CFU cm-2 and 10-14 MUm respectively, after four days. Bacteria in the biofilms included cocci and rods of short and medium lengths. In addition, 38 bacterial genera were detected in biofilms. In this study, the suitability and reproducibility of the CBR model for DUWL biofilm formation were demonstrated. The model provides a foundation for the development of bacterial control methods for DUWLs. PMID- 29160099 TI - Safety of Intradiaphragmatic Delivery of Adeno-Associated Virus-Mediated Alpha Glucosidase (rAAV1-CMV-hGAA) Gene Therapy in Children Affected by Pompe Disease. AB - A first-in-human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory and neural dysfunction in early-onset Pompe disease was conducted. The primary objective of this study was to assess the safety of rAAV1-CMV-hGAA vector delivered to the diaphragm muscle of Pompe disease subjects with ventilatory insufficiency. Safety was assessed by measurement of change in serum chemistries and hematology, urinalysis, and immune response to GAA and AAV, as well as change in level of health. The data demonstrate that the AAV treatment was safe and there were no adverse events related to the study agent. Adverse events related to the study procedure were observed in subjects with lower baseline neuromuscular function. All adverse events were resolved before the end of the study, except for one severe adverse event determined not to be related to either the study agent or the study procedure. In addition, an anti-capsid and anti-transgene antibody response was observed in all subjects who received rAAV1 CMV-hGAA, except for subjects who received concomitant immunomodulation to manage reaction to enzyme replacement therapy, as per their standard of care. This observation is significant for future gene therapy studies and serves to establish a clinically relevant approach to blocking immune responses to both the AAV capsid protein and transgene product. PMID- 29160101 TI - Postoperative Analgesia Using Peripheral Anesthetic Block of the Foot and Ankle. AB - BACKGROUND: Anesthetic block of the peripheral nerves in the foot and ankle is generally used as anesthesia. The increased use of anesthetic blocks has made this technique an increasingly safe method, and its use has been expanded to postoperative analgesia in foot and ankle surgeries. The objective of this study was to evaluate the analgesia time and pain intensity, using objective scores, after peripheral nerve block in foot and ankle surgeries. METHODS: Patients who underwent surgery by the foot and ankle group of our institution from March 2016 to January 2017 were invited to participate in this prospective, randomized, and blinded study after signing an informed consent form. The study was approved by the local ethics committee. In total, 57 patients and 59 feet (2 bilateral surgeries) were subjected to spinal anesthesia and were randomized into the group receiving peripheral nerve block in the foot and ankle (7.5 mg/mL ropivacaine) and the control group. The patients answered a questionnaire, administered by phone during the postoperative period, regarding measurement of pain intensity, using the visual analog scale (VAS), and the time of onset of pain. RESULTS: Improved pain was noted in patients who received a supplemental peripheral nerve block in relation to the duration of postoperative analgesia and the intensity of pain during the immediate postoperative period. No significant difference was found between the 2 groups in terms of pain intensity on the first or second postoperative day. CONCLUSION: Peripheral nerve block in the foot and ankle region can be used effectively as postoperative analgesia to reduce pain intensity during the immediate postoperative period and prolong analgesia. LEVEL OF EVIDENCE: Level I, high-quality prospective randomized clinical trial. PMID- 29160103 TI - Integration Site Analysis in Gene Therapy Patients: Expectations and Reality. AB - Integration site (IS) analysis is one of the major tools for addressing the safety of gene therapy clinical protocols based on the use of integrating vectors. Over the past years, the study of viral insertions in gene therapy treated patients has allowed identifying insertional mutagenesis events, evaluating the safety of new viral vector platforms and tracking the in vivo clonal dynamics of genetically engineered cell products. While gene therapy is progressively expanding its impact on a broader area of clinical applications, increasingly more accessible, faster, and more reliable safety readouts are required from IS analysis. Several actors, from researchers to clinicians, from regulatory agencies to private companies, have to interface to different degrees with the results of IS analysis while developing and evaluating gene therapy products based on retroviral vectors. This review is aimed at providing a brief overview of what the current state and the future is of these studies with a particular focus on what are the main analytical constraints that should be considered upon conducting IS analysis in clinical gene therapy. PMID- 29160104 TI - Corrigendum. PMID- 29160102 TI - Improving the Transduction of Bone Marrow-Derived Cells with an Integrase Defective Lentiviral Vector. AB - In lentiviral vector (LV) applications where transient transgene expression is sufficient, integrase-defective lentiviral vectors (IDLVs) are beneficial for reducing the potential for off-target effects associated with insertional mutagenesis. It was previously demonstrated that human RPE65 mRNA expression from an integrating lentiviral vector (ILV) induces endogenous Rpe65 and Cralbp mRNA expression in murine bone marrow-derived cells (BMDCs), initiating programming of the cells to retinal pigment epithelium (RPE)-like cells. These cells regenerate RPE in retinal degeneration models when injected systemically. As transient expression of RPE65 is sufficient to activate endogenous RPE-associated genes for programming BMDCs, use of an ILV is an unnecessary risk. In this study, an IDLV expressing RPE65 (IDLV3-RPE65) was generated. Transduction with IDLV3-RPE65 is less efficient than the integrating vector (ILV3-RPE65). Therefore, IDLV3-RPE65 transduction was enhanced with a combination of preloading 20 * -concentrated viral supernatant on RetroNectin at a multiplicity of infection of 50 and transduction of BMDCs by low-speed centrifugation. RPE65 mRNA levels increased from ~12-fold to ~25-fold (p < 0.05) after modification of the IDLV3-RPE65 transduction protocol, achieving expression similar to the ~27-fold (p < 0.05) increase observed with ILV3-RPE65. Additionally, the study shows that the same preparation of RetroNectin can be used to coat up to three wells with no reduction in transduction. Critically, IDLV3-RPE65 transduction initiates endogenous Rpe65 mRNA expression in murine BMDCs and Cralbp/CRALBP mRNA in both murine and human BMDCs, similar to expression observed in ILV3-RPE65-transduced cells. Systemic administration of ILV3-RPE65 or IDLV3-RPE65 programmed BMDCs in a mouse model of retinal degeneration is sufficient to retain visual function and reduce retinal degeneration compared to mice receiving no treatment or naive BMDC. It is concluded that IDLV3-RPE65 is appropriate for programming BMDCs to RPE-like cells. PMID- 29160105 TI - Identity work and illness careers of patients with medically unexplained symptoms. AB - This article reports a case study of the illness career and identity work of patients who have had medically unexplained symptoms for many years with a particular emphasis on their interactions with a specialized and standardized health care system. Patients with medically unexplained symptoms often experience being met with mistrust and feel their identity threatened as a consequence of being illegitimately ill. There is a strong tendency in health care towards assessment thorough standardized so-called assessment packages. The study used a case study approach. Ethnographic fieldwork was carried out and several types of data were sampled through theoretical sampling, resulting in data from and about a sample of 13 patients, from which two patients were selected as cases. The study showed that a standardized health care system characterized by a tendency towards narrow diagnostic assessment with limited time can lead to a diagnostic limbo and that patients and health care professionals keep on searching for legitimate explanations for the patients' still unexplained symptoms. Consequently the patients were left in a constant identity negotiation. PMID- 29160107 TI - Editorial Comment on: An Innovative Technique of Transurethral Seminal Vesiculoscopy with Ultrasonic Lithotripter for Severe Persistent Hematospermia by Zhang et al. PMID- 29160106 TI - Display of the Albumin-Binding Domain in the Envelope Improves Lentiviral Vector Bioavailability. AB - Vesicular stomatitis virus G glycoprotein (VSVg) is extensively used for retroviral and lentiviral vector (LV) pseudotyping. However, VSVg pseudotyped vectors are serum inactivated, blocking the in vivo gene delivery. Several strategies have been employed to prevent complement inactivation, including chemical and genetic envelope modifications. This study employed the streptococcal albumin-binding domain (ABD) to generate a construct to express ABD as a glycosylphosphatidylinositol-anchored protein. LV particles bearing ABD are able to bind bovine and human serum albumin in vitro. Neither the lentiviral vector production titer nor the in vitro transduction was affected by the ABD display. The study demonstrated that ABD-bearing LVs are protected from human complement inactivation. More importantly, intravenous administration demonstrated that the presence of ABD significantly reduces lentivector sequestration in liver and bone-marrow cells. Therefore, the use of ABD represents an improvement for in vivo gene therapy applications. The results strongly point to ABD display as a universal strategy to increase the in vivo efficacy of different viral vectors. PMID- 29160108 TI - Effects of hepato-preferential basal insulin peglispro on nuclear magnetic resonance biomarkers lipoprotein insulin resistance index and GlycA in patients with diabetes. AB - AIM: To characterize the effects of hepato-preferential basal insulin peglispro (BIL) and insulin glargine on insulin resistance (lipoprotein insulin resistance index [LP-IR]) and inflammation (GlycA), and to explore the biological implications. METHODS: This substudy included 847 patients with Type 1 diabetes (T1D) or Type 2 diabetes (T2D) in four cohorts of the BIL development program. LP IR and GlycA were measured before and after insulin treatment. Correlations between LP-IR, GlycA, clinical parameters and liver biomarkers were assessed. RESULTS: LP-IR and GlycA were higher in T2D than T1D. LP-IR increased in patients switched from basal insulins to BIL but not in insulin-naive patients. GlycA decreased in T2D patients treated with BIL and T1D patients treated with glargine. CONCLUSION: These exploratory analyses help to characterize differences in biological effects between BIL and glargine treatment. PMID- 29160109 TI - Editorial Comment on: Complications, Re-Intervention Rates, and Natural History of Residual Stone Fragments After Percutaneous Nephrolithotomy by Emmott et al. PMID- 29160110 TI - Peroxiredoxin6, a Multitask Antioxidant Enzyme Involved in the Pathophysiology of Chronic Noncommunicable Diseases. AB - SIGNIFICANCE: Chronic noncommunicable diseases (NCDs) are the leading causes of disability and death worldwide. NCDs mainly comprise diabetes mellitus, cardiovascular diseases, chronic obstructive pulmonary disease, cancer, and neurological degenerative diseases, which kill more than 80% of population, especially the elderly, worldwide. Recent Advances: Several recent theories established NCDs as multifactorial diseases, where a combination of genetic, epigenetic, and environmental factors contributes to their pathogenesis. Nevertheless, recent findings suggest that the common factor linking all these pathologies is an increase in oxidative stress and the age-related loss of the antioxidant mechanisms of defense against it. Impairment in mitochondrial homeostasis with consequent deregulation in oxidative stress balance has also been suggested. CRITICAL ISSUES: Therefore, antioxidant proteins deserve particular attention for their potential role against NCDs. In particular, peroxiredoxin(Prdx)6 is a unique antioxidant enzyme, belonging to the Prdx family, with double properties, peroxidase and phospholipase activities. Through these activities, Prdx6 has been shown to be a powerful antioxidant enzyme, implicated in the pathogenesis of different NCDs. Recently, we described a phenotype of diabetes mellitus in Prdx6 knockout mice, suggesting a pivotal role of Prdx6 in the pathogenesis of cardiometabolic diseases. FUTURE DIRECTIONS: Increasing awareness on the role of antioxidant defenses in the pathogenesis of NCDs may open novel therapeutic approaches to reduce the burden of this pandemic phenomenon. However, knowledge of the role of Prdx6 in NCD prevention and pathogenesis is still not clarified. Antioxid. Redox Signal. 00, 000-000. PMID- 29160111 TI - New cytotoxic sesquiterpene lactones from Achillea cretica L. growing in Tunisia. AB - The phytochemical study of Achillea cretica growing in Tunisia led to the isolation of two novel sesquiterpene lactones, which have been designated achicretin 1 and achicretin 2. Their chemical structures were further confirmed by mass spectroscopy (ESI-MS) and by extensive application of one- and two dimensional NMR spectroscopy. The isolated compounds were tested for their cytotoxic activity against four human cancer cell lines, IGROV-1, OVCAR-3, MCF-7, and HCT-116 using the MTT assay. It has been found that achicretin 2 exhibited more potent inhibitory activity with IC50 = values of 14.0 +/- 1.0 and 16.0 +/- 2.0 MUM against OVCAR-3 and HCT-116 cells, respectively. PMID- 29160112 TI - The human right to communicate and our need to listen: Learning from people with a history of childhood communication disorder. AB - PURPOSE: In 2013, the Australian Government Senate formed a committee for inquiry and report into the prevalence of speech, language, and communication disorders and speech pathology services in Australia. Submissions were sought from individuals and organisations. In this paper, submissions made by individuals with a history of childhood communication disorder were examined to explore their life experiences and the impact on their lives when the right to communicate could not be enacted. METHOD: There were 305 submissions to the Australian Government Senate Committee Inquiry, of which 288 were publically accessible. In this study, the submissions (n = 17) from children or adults with a history of communication disorder (including speech, language and stuttering), who provided personal accounts of their experiences, were analysed using an interpretative phenomenological approach. RESULT: Four themes emerged relating to: personal identity, life with communication disorder, the importance of help, and how life would be different without a communication disorder. CONCLUSIONS: This paper gives voice to children and adults with communication disorder. In listening to these voices, the impact of communication disorder on the right to communicate and on other human rights can be heard, and the need for a response is clear. However, the challenge is to determine how the voices of these individuals, and others like them, can be enabled to exert real influence on practice and policy so communication disorder will no longer be a barrier to attainment of their human rights. PMID- 29160113 TI - Superficial siderosis of central nervous system with unknown cause: report of 2 cases and review of the literature. AB - OBJECTIVE: To report 2 cases of superficial siderosis of central nervous system (SS-CNS) and a review of the literature. METHODS: We have analyzed the clinical data and relevant features of two patients with SS-CNS who were presented with ataxia and slurred speech. Both patients undertook blood tests, lumbar puncture, head CT (computer tomography) scans, and brain and spinal cord magnetic resonance (MR) scans. In addition, the first patient also undewent enhanced susceptibility weighted angiography (ESWAN) and the second patient undertook susceptibility weighted imaging (SWI) scan. We searched PubMed with the keywords superficial siderosis and superficial siderosis of central nervous system, and selected publications that seemed appropriate. RESULTS: A neurological examination revealed bilateral sensorineural hearing impairment in both the patients. Their past history was not significant to identify hemorrhage. Brain MR scans demonstrated typical hypointensity rimming at the brain surface on T2 weighted images. The patients were diagnosed with SS-CNS. CONCLUSION: SS-CNS should be highly suspected in patients with progressive sensorineural hearing loss, ataxia, and signs of pyramidal tracts, and MR scans of brain and whole spinal cord should be undertaken to confirm the diagnosis. Advanced MRI techniques such as SWI and ESWAN are helpful in making the diagnosis of SS-CNS. The cause of hemorrhage is not identified in most cases. PMID- 29160114 TI - Complex spinal fixation of a cervical vertebra Brown tumour: report of an unusual case. AB - Brown tumours affecting the cervical spine are a rare but recognised complication of renal failure-related secondary hyperparathyroidism. We present a case of a 26 year-old female with radiculopathy who was managed successfully with 360 degrees cervical spine fixation and parathyroidectomy. PMID- 29160115 TI - Linking Participatory Action Research on Health Systems to Justice in Global Health: A Case Study of the Maternal and Neonatal Implementation for Equitable Health Systems Project in Rural Uganda. AB - An ethical framework called "research for health justice" provides initial guidance on how to link health systems research in low- and middle-income countries to health equity. To further develop the largely conceptual framework, we tested its guidance against the experience of the Maternal and Neonatal Implementation for Equitable Health Systems (Manifest) project, which was performed in rural Uganda by researchers from Makerere University. We conducted 21 in-depth interviews with investigators and research implementers, directly observed study sites, and reviewed study-related documents. Our analysis identifies where alignment exists between the framework's guidance and the Manifest project, providing initial lessons on how that was achieved. It also identifies where nonalignment occurred and gaps in the framework's guidance. Suggestions are then made for revising and expanding "research for health justice." PMID- 29160116 TI - Assessment of Adeno-Associated Virus Serotype Tropism in Human Retinal Explants. AB - Advances in the discovery of the causes of monogenic retinal disorders, combined with technologies for the delivery of DNA to the retina, offer enormous opportunities for the treatment of previously untreatable blinding diseases. However, for gene augmentation to be most effective, vectors that have the correct cell-type specificity are needed. While animal models are very useful, they often exhibit differences in retinal cell surface receptors compared to the human retina. This study evaluated the use of an ex vivo organotypic explant system to test the transduction efficiency and tropism of seven different adeno associated virus type 2 (AAV2) serotypes in the human retina and retinal pigment epithelium-choroid-AAV2/1, AAV2/2, AAV2/4, AAV2/5, AAV2/6, AAV2/8, and AAV2/9-all driving expression of GFP under control of the cytomegalovirus promoter. After 7 days in culture, it was found that AAV2/4 and AAV2/5 were particularly efficient at transducing photoreceptor cells and that AAV2/5 was highly specific to the outer nuclear layer, whereas AAV2/8 displayed consistently low transduction of photoreceptors. To validate the authenticity of the organotypic culture system, the transduction of the same set of AAVs was also compared in a pig model, in which sub-retinal injections in vivo were compared to cultured and transduced organotypic cultures ex vivo. This study shows how different AAV serotypes behave in the human retina and provides insight for further investigation of each of these serotypes for gene augmentation-based treatment of inherited retinal degeneration. PMID- 29160117 TI - Determination and identification of antibiotic-resistant oral streptococci isolated from active dental infections in adults. AB - OBJECTIVE: To determine and identify antibiotic-resistant bacteria (ARB) of oral streptococci from active dental infections in adults and its association with age and gender. MATERIAL AND METHODS: This cross-sectional study included 59 subjects from 18 to 62 years old. Ninety-eighth samples obtained from the subjects were cultivated in agar plates containing antibiotics amoxicillin/clavulanic acid (A CA), clindamycin, and moxifloxacin (concentrations of 16, 32 or 64 ug/ml). PCR assay was performed to identify bacterial species. RESULTS: The bacterial species that showed more antibiotic-resistance (AR) was S. mutans (45.9%), followed by S. gordonii (21.6%), S. oralis (17.6%), S. sanguinis (9.5%), S. salivarius (5.4%) and S. sobrinus (0%). Moreover, clindamycin (59.4%) showed the highest frequency of AR. Moxifloxacin and A-CA showed an susceptibility >99.1%, while clindamycin showed the lowest efficacy (93.3%); there was a significant statistically difference (p < .01). The age group between 26 and 50 years old (32.2%) and females (28.8%) showed more multiresistance. Clindamycin showed a statistical difference (p < .05) when comparing groups by gender. CONCLUSIONS: Clindamycin was the antibiotic with the highest frequency of ARB and lower bactericidal effect. Moxifloxacin and A-CA showed the highest efficacy and the lowest ARB frequency. Streptococcus mutans was the bacterial specie that showed an increased frequency of AR. PMID- 29160118 TI - The effectiveness of a classroom-based phonological awareness program for 4-5 year-olds. AB - PURPOSE: Numerous studies have reported a robust relationship between early phonological awareness (PA) and subsequent reading achievement, in addition to the critical role of the alphabetic principle in predicting and supporting later reading and spelling development. Given this association, there has been an increasing push to teach these skills to young children prior to word level reading and spelling instruction. This study evaluated the effectiveness of the Cracking the Code (CtC) program with students aged 3;8-5;4. CtC is a teacher implemented program, designed to explicitly target PA skills and alphabet knowledge. METHOD: A pre-test post-test group design was used to evaluate the effectiveness of the program. Four schools in metropolitan Western Australia were randomly assigned to either the control or experimental condition within a parallel groups design. The control group participated in an alternative program matched for duration and frequency, targeting semantics and grammar. RESULT: The children in the experimental condition improved significantly more in PA, alphabet knowledge and non-word reading, and spelling after intervention than the control group. CONCLUSION: These findings demonstrate that classroom-based, teacher-delivered PA and alphabet knowledge instruction can be effective for 3;8 5;4 year-olds. PMID- 29160119 TI - A review of the infection pathogenesis and prophylaxis recommendations in patients with chronic lymphocytic leukemia. AB - INTRODUCTION: The majority of patients with CLL will suffer from infections during their disease, accounting for approximately 60% of deaths in CLL. Patients are predisposed to infection due to immune defects related to the primary disease, and as a result of therapy. The range of infectious complications has evolved alongside therapeutic advances in the treatment of CLL. More recently several novel therapeutic compounds have been introduced in CLL, whose unique safety profiles will probably have an impact on the prophylaxis and management of infections in these patients. Areas covered: This review describes the pathogenesis of infections due to intrinsic CLL or therapy-related immunosuppression, and elightens the importance of proactive and reactive infection management as a key focus of patient care. Infections related to conventional chemotherapy, immunochemotherapy with monoclonal antibodies, target therapies with B-cell receptor pathway inhibitors and Bcl-2 antagonists are reviewed. Expert commentary: Despite the importance of infection management and prevention in high-risk patients, there are only limited infection risk assessment guidelines that can be easily used in clinical practice to guide more appropriate infection prophylaxis and its management. Here we provide an overview of suggested prophylaxis management of infection, and include key prophylactic interventions that we feel should be performed in CLL patients routinely. PMID- 29160120 TI - Oral administration of a novel lipophilic PPARdelta agonist is not neuroprotective after rodent cerebral ischemia. AB - Peroxisome proliferator-activated receptors are regulators of inflammatory signaling. This has fostered hope that PPAR agonists might have neuroprotective potential. We hypothesized that PPARdelta activation by the novel orally administered lipophilic PPARdelta agonist SAR145 may improve short- and long-term outcome after focal brain ischemia. We induced ischemia by transient filamentous middle cerebral artery occlusion (MCAo) in 227 C57BL/6 mice and administered SAR145 in varying doses and time windows post-injury. Outcome was assessed by three functional tests and histologically determining ischemic lesion sizes. In a second experiment, we tested SAR145 treatment in 40 PPARdelta-knockout mice using the same procedures. Three independent groups treated with 10 mg/kg bodyweight SAR145 directly after filament removal showed a mean reduction in lesion sizes of 18 +/- 10% compared to vehicle-treated groups. We did not observe a consistent improvement in the long-term functional outcome by SAR145-treatment. PPARdelta knockout mice showed a significantly higher mortality after MCAo. As expected, we did not find a reduction of lesion size by SAR145-treatment in PPARdelta-knockout mice. In summary, we found no evidence of a long-term neuroprotective effect of post-injury SAR145 treatment in cerebral ischemia. However, PPARdelta appears to play a pathophysiologic role in acute infarct development and overall mortality after brain ischemia. PMID- 29160121 TI - Near-infrared light-responsive nanoparticles for improved anticancer efficacy through synergistic chemo-photothermal therapy. AB - Combined treatment is more effective than single treatment against most forms of cancer. The synergistic chemo-thermotherapy mediated by nanoparticles has superior advantages of lesser adverse effects as a promising cancer therapy modality. In this study, we report a theranostic carrier system co-encapsulating Doxorubicin (DOX) and Indocyanine green (ICG) into the D-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS). Full physicochemical characterization studies of the DOX/ICG-loaded TPGS nanoparticles (TNPs) are performed. TNPs have a mean size around 60 nm with superior photostability, and entrapment efficiency of drugs in TNPs was 75.0% for ICG and 68.3% for DOX. TNPs also exhibit a longer sustained release with around 63% of the entrapped drug in 24 h. In vitro studies, TNPs could effectively enhance cellular uptake of DOX and ICG, which permitted high therapeutic efficacy against cancer cells. Further, we investigate antitumor efficacy of TNPs along with its impact on major organs in vivo, TNPs also exhibit a complete inhibition of tumor growth and minimal side effects after irradiation. Collectively, these results suggest that near-infrared light responsive TNPs can further enhance antitumor effects by synergistic chemo photothermal therapy. PMID- 29160122 TI - Reduced soluble Toll-like receptors 2 in type 2 diabetes. AB - BACKGROUND: Soluble forms of Toll-like receptors (sTLR) 2 and 4 exert negative regulatory control on membrane-bound receptor activation. The study estimates the sTLR2 and sTLR4's serum levels in type 2 diabetes (T2D) and evaluates their relationship with metabolic and inflammatory parameters. SUBJECTS AND METHODS: Sixty three patients with T2D and 25 controls were enrolled. sTLR were assayed through ELISA. Inflammatory markers included Interleukin 6 (IL-6), high sensitivity C-reactive protein (hs-CRP) and tumour necrosis factor alpha. RESULTS: Analysis demonstrated lower sTLR2 level in T2D than in control subjects (1.15 +/- 0.65 versus 1.44 +/- 0.60 ng/ml, p = .019) while sTLR4 level remained similar (0.09 +/- 0.16 versus 0.07 +/- 0.12 ng/ml, p > .05) despite higher IL-6 (2.65 +/- 2.46 versus 1.44 +/- 0.22 pg/ml, p = .005) and hs-CRP (2.79 +/- 2.89 versus 0.70 +/- 0.89 mg/l, p < .001) concentrations. Neither sTLR correlated with BMI, HbA1c, plasma glucose and analysed cytokines (p > .05). CONCLUSION: The sTLR2 serum level in T2D patients was reduced despite elevated inflammatory parameters. PMID- 29160123 TI - Fast-tracking for total knee replacement reduces use of institutional care without compromising quality. AB - Background and purpose - Fast-tracking shortens the length of the primary treatment period (length of stay, LOS) after total knee replacement (TKR). We evaluated the influence of the fast-track concept on the length of uninterrupted institutional care (LUIC) and other outcomes after TKR. Patients and methods - 4,256 TKRs performed in 4 hospitals between 2009-2010 and 2012-2013 were identified from the Finnish Hospital Discharge Register and the Finnish Arthroplasty Register. Hospitals were classified as fast track (Hospital A) and non-fast track (Hospitals B, C and D). We analyzed length of uninterrupted institutional care (LUIC), LOS, discharge destination, readmission, revision, manipulation under anesthesia (MUA) and mortality rate in each hospital. We compared these outcomes for TKRs performed in Hospital A before and after fast track implementation and we also compared Hospital A outcomes with the corresponding outcomes for the other 3 hospitals. Results - After fast-track implementation, median LOS in Hospital A fell from 5 to 3 days (p < 0.001) and (median) LUIC from 7 to 3 (p < 0.001) days. These reductions in LOS and LUIC were accompanied by an increase in the discharge rate to home (p = 0.01). Fast tracking in Hospital A led to no increase in 14- and 42-day readmissions, MUA, revision or mortality compared with the rates before fast-tracking, or with those in the other hospitals. Of the 4 hospitals, LOS and LUIC were most reduced in Hospital A. Interpretation - A fast-track protocol reduces LUIC and LOS after TKR without increasing readmission, complication or revision rates. PMID- 29160124 TI - An Evaluation of Talent 4 . . . : A Programme to Identify Talent and Skills for Prisoners, Disadvantaged, Unemployed, and Vulnerable Groups. AB - Previous research suggests that the relationship between employment and recidivism is complex, with more support needed to facilitate employability motivation for sustained change. An arts-based programme designed to facilitate vocational self-determinism among prisoners with evidence of impact across three prisons in the United Kingdom was replicated and delivered to 234 prisoners and long-term unemployed participants from six European countries, to explore whether the findings from the previous evaluation would be replicated on a much larger scale. The research presented in this article found that supporting prisoners and the long-term unemployed to articulate employability goals had a positive effect on personal growth as well as understanding of individual strengths and weaknesses with respect to work, employment, problem solving, and thinking styles. Future research might explore the longer term impact on employment and recidivism. PMID- 29160125 TI - Effects of paeoniflorin on the activities and mRNA expression of rat CYP1A2, CYP2C11 and CYP3A1 enzymes in vivo. AB - 1. Paeoniflorin is the major constituent in extracts of the peony root, the purpose of the present study was to assess the effects of paeoniflorin on the activities and mRNA expression of the rat hepatic drug-metabolizing enzymes cytochrome P450 (CYP1A2), CYP2C11 and CYP3A1 in vivo. 2. Sprague-Dawley (SD) male rats were treated with paeoniflorin at the dosage of 25, 50 and 100 mg/kg or 0.9% sodium chloride solution by intragastric administration for 7 days, then were given probe drugs phenacetin (CYP1A2), tolbutamide (CYP2C11), or midazolam (CYP3A1) orally on the eighth day. Blood samples were collected at various times, and the plasma concentrations of the probe drugs were estimated with ultra-high performance liquid chromatography. The mRNA expression levels of rat hepatic CYP1A2, CYP2C11 and CYP3A1 were analyzed with real-time PCR. 3. The pharmacokinetic results indicated that paeoniflorin inhibits the activities of CYP1A2, CYP2C11 and CYP3A1 in vivo. The effect was most pronounced on CYP3A1, according to the United States Food and Drug Administration classification of inhibitors of CYP3A, it reached the category of moderate inhibition. The mRNA expression levels of 3 CYP enzymes were also tended to be inhibited. 4. We conclude that paeoniflorin can inhibit the activities of CYP1A2, CYP2C11 and CYP3A1 in vivo, which may affect the metabolism of drugs that are primarily dependent on these pathways. PMID- 29160126 TI - Leishmanicidal candidate LASSBio-1736, a cysteine protease inhibitor with favorable pharmacokinetics: low clearance and good distribution. AB - 1. LASSBio-1736 ((E)-1-4(trifluoromethyl) benzylidene)-5-(2-4-dichlorozoyl) carbonylhydrazine) is proposed to be an oral cysteine protease leishmanicidal inhibitor. 2. This work aimed to investigate plasma pharmacokinetics, protein binding and tissue distribution of LASSBio-1736 in male Wistar rats. 3. LASSBio 1736 was administered to male Wistar rats at doses of 3.2 mg/kg intravenously and 12.6 mg/kg oral and intraperitoneal. The individual plasma-concentration profiles were determined by HPLC-UV and evaluated by non-compartmental and population pharmacokinetic analysis (Monolix 2016R1, Lixoft). Tissue distribution was evaluated after iv injection of 3.2 mg/kg drug by non-compartmental approach. 4. After intravenous administration, Vdss (1.79 L/kg), t 1/2 (23.1 h) and CLtot (56.1 mL/h/kg) were determined, and they were statistically similar (alpha =0.05) to oral and intraperitoneal pharmacokinetic parameters. The plasma profiles obtained after intravenous, oral and intraperitoneal administration of the compound were best fitted to a three-compartment and one-compartment open model with first-order absorption. 5. The intraperitoneal and oral bioavailability were around 40 and 15%, respectively. 6. Liver, spleen and skin tissues showed penetration of 340, 130 and 40%, respectively, with t 1/2 like plasma values. 7. LASSBio-1736 protein binding was 95 +/- 2%. 8. The t 1/2, CLtot and tissue distribution of the compound agreed with the desired drug characteristics for leishmanicidal activity. PMID- 29160127 TI - The fetal programming effect of prenatal smoking on Igf1r and Igf1 methylation is organ- and sex-specific. AB - The impact of prenatal smoke exposure (PSE) on DNA methylation has been demonstrated in blood samples from children of smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. As the identified differentially methylated genes can be associated with developmental processes, and insulin-like growth factors (IGFs) play a critical role in prenatal tissue growth, we hypothesized that PSE induces fetal programming of Igf1r and Igf1. Using a mouse model of smoking during pregnancy, we show that PSE alters promoter methylation of Igf1r and Igf1 and deregulates their gene expression in lung and liver of fetal (E17.5) and neonatal (D3) mouse offspring. By further comparing female versus male, lung versus liver, or fetal versus neonatal time point, our results demonstrate that CpG site-specific aberrant methylation patterns sex-dependently vary per organ and time point. Moreover, PSE reduces gene expression of Igf1r and Igf1, dependent on organ, sex, and offspring's age. Our results indicate that PSE may be a source of organ-specific rather than general systemic fetal programming. This is exemplified here by gene promoter methylation and mRNA levels of Igf1r and Igf1, together with a sex- and organ-specific naturally established correlation of both parameters that is affected by prenatal smoke exposure. Moreover, the comparison of fetuses with neonates suggests a CpG site-dependent reversibility/persistence of PSE-induced differential methylation patterns. PMID- 29160128 TI - Hospital utilization for patients with amyotrophic lateral sclerosis in saskatoon, Canada. AB - OBJECTIVE: This retrospective study reviewed hospital and intensive care unit (ICU) admissions for patients with amyotrophic lateral sclerosis (ALS) in Saskatoon, Canada, between 2005 and 2017. The purpose was to understand hospital utilization and admission patterns for patients with ALS in the absence of coordinated multidisciplinary care. METHODS: Hospital/ICU admissions were detected at two hospitals in Saskatoon using the International Classification of Diseases (ICD-10) coding for ALS. Patient demographic data, hospitalization and pre-hospitalization information were recorded, and descriptive statistics were generated. RESULTS: Of the 83 patients identified, 52% were male with a mean age of 66.8 years. Fifty-two percent were undiagnosed prior to hospitalization, with significantly longer ICU stays compared to those diagnosed prior to admission (49.4 +/- 46.6 vs. 21.9 +/- 32.0 days; p = 0.0003). Eighty-nine percent of all admissions (n = 118) were non-elective. Although respiratory dysfunction was the most common reason for admission (n = 41, 49%), and all ICU admissions were for respiratory dysfunction, only 2% were on non-invasive ventilation prior to ICU admission. All tracheostomies (n =10, 12%) were placed non-electively, and 50% were in previously undiagnosed patients. Thirty-four percent (n = 28) of patients died in hospital in an ICU (n = 8, 29%) and hospital wards (n = 20, 71%). CONCLUSION: ALS patients in Saskatoon had high non-elective admission rates, with over half undiagnosed prior to hospitalization, and high rates of emergent tracheostomy. This study highlights the need for early diagnosis and coordinated multidisciplinary care for improved outpatient management of ALS to reduce lengthy and complicated hospitalizations. PMID- 29160129 TI - Injectable nanosilica-chitosan microparticles for bone regeneration applications. AB - This study was aimed at assessing the effects of silica nanopowder incorporation into chitosan-tripolyphosphate microparticles with the ultimate goal of improving their osteogenic properties. The microparticles were prepared by simple coacervation technique and silica nanopowder was added at 0% (C), 2.5% (S1), 5% (S2) and 10% (S3) (w/w) to chitosan. We observed that this simple incorporation of silica nanopowder improved the growth and proliferation of osteoblasts along the surface of the microparticles. In addition, the composite microparticles also showed the increased expression of alkaline phosphatase and osteoblast specific genes. We observed a significant increase ( p < 0.05) in the expression of alkaline phosphatase by the cells growing on all sample groups compared to the control (C) groups at day 14. The morphological characterization of these microparticles through scanning electron microscopy showed that these microparticles were well suited to be used as the injectable scaffolds with perfectly spherical shape and size. The incorporation of silica nanopowder altered the nano-roughness of the microparticles as observed through atomic force microscopy scans with roughness values going down from C to S3. The results in this study, taken together, show the potential of chitosan-tripolyphosphate silica nanopowder microparticles for improved bone regeneration applications. PMID- 29160130 TI - The effect of bearing type on the outcome of total hip arthroplasty. AB - Background and purpose - Alternative bearing surfaces such as ceramics and highly crosslinked polyethylene (HXLPE) were developed in order to further improve implant performance of total hip arthroplasties (THAs). Whether these alternative bearing surfaces result in increased longevity is subject to debate. Patients and methods - Using the Dutch Arthroplasty Register (LROI), we identified all patients with a primary, non-metal-on-metal THA implanted in the Netherlands in the period 2007-2016 (n = 209,912). Cumulative incidence of revision was calculated to determine differences in survivorship of THAs according to bearing type: metal-on-polyethylene (MoPE), metal-on-HXLPE (MoHXLPE), ceramic-on polyethylene (CoPE), ceramic-on-HXLPE (CoHXLPE), ceramic-on-ceramic (CoC), and oxidized-zirconium-on-(HXL)polyethylene (Ox(HXL)PE). Multivariable Cox proportional hazard regression ratios (HRs) were used for comparisons. Results - After adjustment for confounders, CoHXLPE, CoC, and Ox(HXL)PE resulted in a statistically significantly lower risk of revision compared with MoPE after 9 years follow-up (HR =0.8-0.9 respectively, compared with HR =1.0). For small (22 28 mm) femoral head THAs, lower revision rates were found for CoPE and CoHXLPE (HR =0.9). In the 36 mm femoral head subgroup, CoC-bearing THAs had a lower HR compared with MoHXLPE (HR =0.7 versus 1.0). Crude revision rates in young patients (< 60 years) for CoHXLPE, CoC, and Ox(HXL)PE (HR =0.7) were lower than MoPE (HR =1.0). However, after adjustment for case mix and confounders these differences were not statistically significant. Interpretation - We found a mid term lower risk of revision for CoHXLPE, CoC, and Ox(HXL)PE bearings compared with traditional MoPE-bearing surfaces. PMID- 29160131 TI - The views of early intervention service staff on the treatment of first episode bipolar disorder. AB - OBJECTIVE: Little is known about how first episode bipolar disorder (BD) is managed in early intervention for psychosis services (EIS). We aimed to investigate the knowledge and views of EIS staff on the assessment and treatment of BD. METHODS: A 27-item anonymised online questionnaire was distributed to EIS mental health professionals in England. Descriptive data analysis was undertaken. RESULTS: Responses were received from 117 EIS staff. Most were 'fairly confident' in their knowledge about causes, presentations and relapse indicators of BD, but less confident on pharmacological and psychological treatments. Eighty five percent expressed the view that more BD training was necessary in this area with 78% reporting no clear care packages within the service. Seventy two percent believe early BD should be treated within EIS only if patients have psychosis. CONCLUSIONS: Clearer care packages and staff training are needed for EIS staff to optimise care for BD. PMID- 29160132 TI - Active H3K27me3 demethylation by KDM6B is required for normal development of bovine preimplantation embryos. AB - The substantial epigenetic remodeling that occurs during early stages of mammalian embryonic development likely contributes to reprogramming the parental genomes from a differentiated to a totipotent state and activation of the embryonic genome. Trimethylation of lysine 27 of histone 3 (H3K27me3) is a repressive mark that undergoes global dynamic changes during preimplantation development of several species. To ascertain the role of H3K27me3 in bovine preimplantation development we perturbed the activity of KDM6B, which demethylates H3K27me3. Knockdown of maternal KDM6B mRNA inhibited the reduction in global levels of H3K27me3 from 2-cell to 8-cell embryo stages and compromised development to the blastocyst stage; embryos that developed to the blastocyst stage had fewer inner cell mass (ICM) and trophectoderm (TE) cells. In addition, the transcriptome of KDM6B knockdown embryos was altered at the 8-cell stage and characterized by downregulation of transcripts related to transcriptional regulation, chromatin remodeling, and protein catabolism. Inhibiting the catalytic activity of KDM6B with a specific small molecule inhibitor also prevented the global decrease in H3K27me3 and compromised development to the blastocyst stage. These results indicate that histone demethylation activity, mediated by KDM6B, is required for the global decrease in H3K27me3, correct activation of the embryonic genome, and development to the blastocyst stage in bovine embryos. PMID- 29160133 TI - Inhibition of metastasis and angiogenesis in Hep-2 cells by wheatgrass extract - an in vitro and in silico approach. AB - Metastasis is the major hindrance in the treatment of all cancers, including laryngeal squamous cell carcinoma. Intensive researches are under way to identify the effective natural polyphenols with anti-metastatic ability for cancer treatment. Wheatgrass, an herbal plant has been reported to show anticancer effects. Hence, in this study, we aimed to analyze the anti-metastatic effect of methanol extract of wheatgrass (MEWG). The levels of metastatic marker proteins were determined by western blot. PI3K and AKT levels were determined by real time (RT)-PCR analysis. In silico molecular docking was done to check the interaction of the 14 components (identified by HPLC/GCMS) of MEWG with PI3K and AKT. MEWG effectively decreased the metastatic protein expressions, namely VEGF, MMP-9 and COX-2 and increased TIMP-2. RT-PCR results showed reduced m-RNA levels of both PI3K and AKT when compared to control. Molecular docking studies revealed interaction of most of the identified compounds of the extract with the important residues of PI3K and AKT. These findings indicate that MEWG inhibits metastasis and angiogenesis in Hep-2 cells possibly via PI3K/AKT due to the cumulative effect of polyphenols and other constituent present in extract. The compounds of the extract were also found to be directly involved in inhibition of AKT/PI3K, thus could help to restrain metastasis. PMID- 29160134 TI - Surfactant protein-A nanobody-conjugated liposomes loaded with methylprednisolone increase lung-targeting specificity and therapeutic effect for acute lung injury. AB - The advent of nanomedicine requires novel delivery vehicles to actively target their site of action. Here, we demonstrate the development of lung-targeting drug loaded liposomes and their efficacy, specificity and safety. Our study focuses on glucocorticoids methylprednisolone (MPS), a commonly used drug to treat lung injuries. The steroidal molecule was loaded into functionalized nano-sterically stabilized unilamellar liposomes (NSSLs). Targeting functionality was performed through conjugation of surfactant protein A (SPANb) nanobodies to form MPS-NSSLs SPANb. MPS-NSSLs-SPANb exhibited good size distribution, morphology, and encapsulation efficiency. Animal experiments demonstrated the high specificity of MPS-NSSLs-SPANb to the lung. Treatment with MPS-NSSLs-SPANb reduced the levels of TNF-alpha, IL-8, and TGF-beta1 in rat bronchoalveolar lavage fluid and the expression of NK-kappaB in the lung tissues, thereby alleviating lung injuries and increasing rat survival. The nanobody functionalized nanoparticles demonstrate superior performance to treat lung injury when compared to that of antibody functionalized systems. PMID- 29160135 TI - Short-term histopathological effects of dienogest therapy on ovarian endometriomas: in vivo, nonrandomized, controlled trial. AB - Ovarian endometriosis is a common gynecological disorder. To date, progestins are recommended as the first-line medical treatment for symptomatic ovarian endometriosis. The aim of this study was to evaluate the main histopathological effects of short-term dienogest therapy in patients with ovarian endometriomas scheduled for surgery. A prospective, nonrandomized controlled trial, including 70 symptomatic women with single ovarian endometriotic cyst (diameter between 30 50 mm) was conducted. Women scheduled for surgery were divided into two groups, depending on the treatment established at enrollment: 36 women received progestin therapy with dienogest (P group) and 34 women received no therapy (C group). At histopathological examination necrosis, inflammation, decidualization, glandular atrophy and angiogenesis were blindly evaluated. At tissue level, decidualization was significantly more frequent in P group compared to C group (p = .001). A nonsignificant tendency (p = .29) towards a slight decreased inflammation in P group was found. No significant differences were observed between the two groups in terms of necrosis, glandular atrophy and angiogenesis. The study suggests that high decidualization rate and the tendency to reduced inflammatory reaction in the short-term administration of dienogest might contribute to its therapeutic efficacy. PMID- 29160136 TI - Utility of bulging technique for endovascular treatment of small and wide-necked aneurysms with a Low-profile Visualized Intraluminal Support (LVIS Jr.) device: A case report and review of the literature. AB - Small and broad-necked aneurysms are generally very difficult to treat using endovascular therapy. The arrival of the low-profile stent (e.g., Low-profile Visualized Intraluminal Support; LVIS) has enabled reconstructive treatment for these aneurysms. In addition, the bulging technique using LVIS is an effective and attractive technique for performing stent-assisted coiling to preserve parent arteries and achieve neck coverage. We report here a patient with a small and wide-necked ruptured basilar artery (BA) top aneurysm, in whom successful treatment was achieved by stent-assisted coiling with LVIS Jr. using the bulging technique. A 74-year-old woman with moderate hypertension consulted for treatment of subarachnoid hemorrhage with a ruptured BA top aneurysm measuring 2.7 mm in height with a 4.3 mm neck. We initially tried emergency balloon-assisted coiling, but coiling proved difficult. We therefore performed stent-assisted coiling with LVIS Jr. using the bulging technique. The postoperative course was uneventful, with no aggravation of neurological symptoms, and the patient was discharged 14 days postoperatively. This treatment strategy with LVIS Jr. using the bulging technique may be very useful for patients with a ruptured aneurysm with a small and broad neck that would otherwise require treatment with intravascular devices or open surgery. PMID- 29160137 TI - Symptomatic communicating hydrocephalus in a contemporary cohort of high grade glioma patients. AB - INTRODUCTION: High grade glioma (HGG) treatment has seen a paradigm shift with intensified regimes, but hospitalisation burden is partially attributed to side effects of therapy. Symptomatic communicating hydrocephalus (HC) is a potential complication. Aim of this study was to investigate its incidence, risk factors and treatment in a contemporary cohort. METHODS: We performed a retrospective review of HGG patients. Patients with symptomatic communicating HC were identified and demographic, tumour and treatment variables extracted from hospital notes. Descriptive statistics were performed and odds ratios (OR) with 95% confidence intervals (CI) calculated. RESULTS: From a cohort of 278 eligible HGG patients, 8 (3%) were diagnosed with symptomatic communicating HC. In the subgroup of patients with intraoperative opening of the ventricular system during previous surgery (N = 66), hydrocephalus developed in 10.6% of cases (N = 7). Symptoms were lethargy (N = 5), headache (N = 3), confusion (N = 3), gait disturbance (N = 3) and urinary incontinence (N = 1); three patients presented resembling normal pressure hydrocephalus. A higher rate of intraoperative opening of the ventricles was found in the HC group (p = .0002); all other variables were equally distributed. The increased odds for developing HC for patients with intraoperative opening of the ventricles reached statistical significance (OR = 25.0339, 95% CI = 3.0196-207.5449, p = .0028), whereas previous radiotherapy only increased odds by tendency. Hydrocephalic patients were treated with ventriculoperitoneal shunts and all but one patient improved. One patient had a complication attributed to the shunt procedure The median overall survival after shunting was 4 months. CONCLUSIONS: Symptomatic communicating hydrocephalus occurred in 3% of HGG patients and in 10.6% in the subgroup with previous intraoperative opening of the ventricles. Treatment with a ventriculoperitoneal shunt is effective and has a low complication rate. PMID- 29160138 TI - A case of dedifferentiated chondrosarcoma arising in the cricoid cartilage that mimicked an aneurysmal bone cyst. AB - Dedifferentiated chondrosarcoma of the larynx is a rare and highly malignant tumor. We present the report of a 59-year-old man with dedifferentiated laryngeal chondrosarcoma, which was difficult to diagnose even under microscopic examination. The original diagnosis was an aneurysmal bone cyst, and the final diagnosis was established only after careful consideration of the imaging, surgical, and microscopic findings. In clinical practice, there are many similarities between dedifferentiated chondrosarcoma and aneurysmal bone cysts. Furthermore, it is difficult to identify dedifferentiated laryngeal chondrosarcoma with a giant-cell malignant mesenchymal component. This report describes our experience and discusses this phenomenon. PMID- 29160139 TI - High and rising burden of hip and knee osteoarthritis in the Nordic region, 1990 2015. AB - Background and purpose - Osteoarthritis (OA) imposes a substantial burden on individuals and societies. We report on the burden of knee and hip OA in the Nordic region. Patients and methods - We used the findings from the 2015 Global Burden of Diseases Study to explore prevalence, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) of OA in the 6 Nordic countries during 1990-2015 (population of about 27 million in 2015). Results - During 1990-2015, the number of prevalent OA cases increased by 43% to 1,507,587 (95% uncertainty interval [UI] 1,454,338-1,564,778) in the region. OA accounted for 1.3% (UI 1.0-1.7) of YLDs in 1990, increasing to 1.6% (UI 1.2-2.0) in 2015. Of 315 causes studied, OA was the 15th leading cause of YLDs, causing 52,661 (UI 34,056-77,499) YLDs in 2015; of these 23% were attributable to high body mass index. The highest relative importance of OA was reported for women aged 65-74 years (8th leading cause of YLDs in 2015). Among the top 30 leading causes of YLDs in the region, OA had the 5th greatest relative increase in total YLDs during 1990-2015. From 1990 to 2015, increase in age-standardized YLDs from OA in the region was slightly lower than increase at the global level (7.5% vs. 10.5%). OA was, however, responsible for a higher proportional burden of DALYs in the region compared with the global level. Interpretation - The OA burden is high and rising in the Nordic region. With population growth, aging, and the obesity epidemic, a substantial rise in the burden of OA is expected and should be addressed in health policies. PMID- 29160140 TI - The effects of weighted skates on ice-skating kinematics, kinetics and muscular activity. AB - Sport-specific resistance training, through limb loading, can be a complimentary training method to traditional resistance training by loading the working muscles during all phases of a specific movement. The purpose of this study was to examine the acute effects of skating with an additional load on the skate, using a skate weight prototype, on kinematics, kinetics, and muscle activation during the acceleration phase while skating on a synthetic ice surface. 10 male hockey skaters accelerated from rest (standing erect with knees slightly bent) under four non-randomized load conditions: baseline 1 (no weight), light (0.9 kg per skate), heavy (1.8 kg per skate), and baseline 2 (no weight). Skating with additional weight caused athletes to skate slower (p < 0.001; eta2 = 0.551), and led to few changes in kinematics: hip sagittal range of motion (ROM) decreased (2.2 degrees ; p = 0.032; eta2 = 0.274), hip transverse ROM decreased (3.4 degrees ; p < 0.001; eta2 = 0.494), ankle sagittal ROM decreased (2.3 degrees ; p = 0.022; eta2 = 0.295), and knee sagittal ROM increased (7.8 degrees ; p < 0.001, eta2 = 0.761). Overall, weighted skates decreased skating velocity, but athletes maintained similar muscle activation profiles (magnitude and trends) with minor changes to their skating kinematics. PMID- 29160142 TI - Structural Fat Grafting to Improve Outcomes of Vocal Folds' Fat Augmentation: Long-term Results. AB - Objective Evaluating the long-term outcomes of vocal fold structural fat grafting. Study Design Case series with chart review. Setting University hospital. Subjects and Methods Seventy-nine dysphonic patients (16-82 years; 55 with unilateral laryngeal paralysis and 24 with vocal fold scarring) underwent vocal fold fat injection. Fat was harvested by low-pressure liposuction and then processed by centrifugation. Refined fat aliquots were placed in the vocal fold and paraglottic space in multiple tunnels to enhance graft neovascularization. All patients were followed for 12 months, 15 for 3 years, and 5 for 10 years with videolaryngostroboscopy, maximal phonation time (MPT) measurement, Voice Handicap Index (VHI) questionnaire, and GRBAS (grade, roughness, breathiness, asthenia, strain) perceptual evaluation. Laryngeal computed tomography (CT) and/or magnetic resonance imaging (MRI) studies were performed in 16 patients 3 to 28 months postoperatively; MRI was repeated in 5 cases 12 to 18 months after the first radiological study. Results The voice quality of all patients improved after surgery, and long-term stability was confirmed by MPT, GRBAS, and VHI ( P ranging between .004 and <.001). The results achieved 1 year postoperatively remained stable at 3 and 10 years. Videolaryn-gostroboscopy showed improved glottic closure in all patients despite a limited amount of fat resorption. CT and MRI demonstrated survival of the fat grafts in all of the 16 examined cases. Serial MRI scans showed no change in graft size over time. Conclusions The reported clinical and radiological data demonstrate that fat is an effective filler for permanent vocal fold augmentation if the refined micro-aliquots are placed in multiple tunnels. PMID- 29160143 TI - Some Autonomic Deficits of Acute or Chronic Cervical Spinal Contusion Reversed by Interim Brainstem Stimulation. AB - Prolonged electrical stimulation of the hindbrain's nucleus raphe magnus (NRM) or of its major midbrain input region, the periaqueductal gray (PAG), was previously found in rats to promote recovery from sensory-motor and histological deficits of acute thoracic spinal cord injury (SCI). Here, some visceral deficits of acute and chronic midline cervical (C5) contusion are similarly examined. Cranially implanted wireless stimulators delivered intermittent 8 Hz, 30-70 MUA cathodal pulse trains to a brainstem microelectrode. Injured controls were given inactive stimulators; rats without injuries or implants were also compared. Rectal distension or squeezing of the forepaws caused an exaggerated rise in mean arterial pressure in injured, untreated rats under anesthesia on post-injury week 6, probably reflecting autonomic dysreflexia (AD). These pressor responses became normal when 7 days of unilateral PAG stimulation was started on the injury day. Older untreated injuries (weeks 18-19) showed normal pressor responses, but unexpectedly had significant resting and nociceptive bradycardia, which was reversed by 3 weeks of PAG stimulation started on weeks 7 or 12. Subsequent chronic studies examined gastric emptying (GE), as indicated by intestinal transit of gavaged dye, and serum chemistry. GE and fasting serum insulin were reduced on injury weeks 14-15, and were both normalized by ~5 weeks of PAG stimulation begun in weeks 7-8. Increases in calcitonin gene-related peptide, a prominent visceral afferent neurotransmitter, measured near untreated injuries (first thoracic segment) in superficial dorsal laminae were reversed by acutely or chronically initiated PAG stimulation. The NRM, given 2-3 weeks of stimulation beginning 2 days after SCI, prevented abnormalities in both pressor responses and GE on post-injury week 9, consistent with its relaying of repair commands from the PAG. The descending PAG-NRM axis thus exhibits broadly restorative influences on visceral as well as sensory-motor deficits, improving chronic as well as acute signs of injury. PMID- 29160141 TI - Effects of Mild Blast Traumatic Brain Injury on Cerebral Vascular, Histopathological, and Behavioral Outcomes in Rats. AB - To determine the effects of mild blast-induced traumatic brain injury (bTBI), several groups of rats were subjected to blast injury or sham injury in a compressed air-driven shock tube. The effects of bTBI on relative cerebral perfusion (laser Doppler flowmetry [LDF]), and mean arterial blood pressure (MAP) cerebral vascular resistance were measured for 2 h post-bTBI. Dilator responses to reduced intravascular pressure were measured in isolated middle cerebral arterial (MCA) segments, ex vivo, 30 and 60 min post-bTBI. Neuronal injury was assessed (Fluoro-Jade C [FJC]) 24 and 48 h post-bTBI. Neurological outcomes (beam balance and walking tests) and working memory (Morris water maze [MWM]) were assessed 2 weeks post-bTBI. Because impact TBI (i.e., non-blast TBI) is often associated with reduced cerebral perfusion and impaired cerebrovascular function in part because of the generation of reactive oxygen and nitrogen species such as peroxynitrite (ONOO-), the effects of the administration of the ONOO- scavenger, penicillamine methyl ester (PenME), on cerebral perfusion and cerebral vascular resistance were measured for 2 h post-bTBI. Mild bTBI resulted in reduced relative cerebral perfusion and MCA dilator responses to reduced intravascular pressure, increases in cerebral vascular resistance and in the numbers of FJC positive cells in the brain, and significantly impaired working memory. PenME administration resulted in significant reductions in cerebral vascular resistance and a trend toward increased cerebral perfusion, suggesting that ONOO- may contribute to blast-induced cerebral vascular dysfunction. PMID- 29160144 TI - Parkinson's disease psychosis: presentation, diagnosis and management. AB - Parkinson's disease is a neurodegenerative disorder characterized by motor and nonmotor symptoms. Psychosis is a common feature of Parkinson's disease. Parkinson's disease psychosis (PDP) encompasses minor phenomena (illusions, passage hallucinations and presence hallucinations), visual and nonvisual hallucinations and delusions. PDP is associated with reduced function and quality of life. The initial management approach should focus on identification and treatment of any contributory medical factors, reduction or discontinuation of medications with potential to induce or worsen psychosis, nonpharmacological strategies and consideration of acetylcholinesterase inhibitor treatment in the setting of dementia. Pimavanserin, quetiapine and clozapine may all be considered for use in PDP. In this review, we discuss the presentation, diagnosis and management of PDP. PMID- 29160145 TI - The Graded and Redefined Assessment of Strength, Sensibility, and Prehension Version 2 Provides Interval Measure Properties. AB - The Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) is a valid, reliable, and responsive outcome measure to evaluate upper limb function in individuals with tetraplegia. GRASSP generates ordinal total scores; therefore, applicability as an interval level measurement requires testing of its measurement properties. This study examined the metric characteristics with Rasch Analysis to derive interval level scales of the respective GRASSP subtests. The GRASSP was recorded within 10 days, and at 1, 3, 6, and 12 months after cervical spinal cord injury (SCI). Rasch analysis was performed for each GRASSP subscale to assess the following metric assumptions: absence of local item dependency (LID), unidimensionality, monotonicity, item and model fit, reliability, and absence of differential item functioning (DIF) for side (left and right) and examination stage. If these assumptions could not be met, adjustments were undertaken to achieve a good fit to the Rasch model. Seventy-seven individuals with cervical SCI were included (n = 154 arms). Stacking the data for the side (left and right) resulted in a total of 614 observations, which were based on the repeated measurements. With minor adjustments, the GRASSP subscales showed good reliability, item fit, and ordered response options. Local item dependencies were found in the strength and sensibility subscales. Redundancies among some measurement items allowed shortening of the subscales without reasonable loss of reliability. Absence of DIF for the examination stage supported robustness of the subscales over time. The modified GRASSP, now Version 2, subtest scores can be applied as interval level measurements, and the reduction of items within subscales allows for shorter assessment times in clinical studies without degrading metric properties. PMID- 29160146 TI - Dementia risk assessment tools: an update. PMID- 29160147 TI - Impact of Complete Spinal Cord Injury on Healing of Skin Ulcers in Mouse Models. AB - Pressure ulcers (PUs) are common debilitating complications of traumatic spinal cord injury (SCI) and tend to occur in soft tissues around bony prominences. There is, however, little known about the impact of SCI on skin wound healing because of the lack of suitable animal models for studies in controlled experimental settings. Herein, we describe a reproducible and clinically relevant mouse model of PUs in the context of complete SCI. Adult male mice (BALB/c) were subjected to thoracic (T9-T10) complete SCI. Immediately after, a skin fold on the back of mice was lifted and sandwiched between two magnetic discs held in place for 12 h, thus creating an ischemic area that developed into a PU over the following days. The wounded areas demonstrated tissue edema and epidermis disappearance by day 3 post-magnet removal. PUs spontaneously healed, although slower in SCI mice compared to control non-SCI mice (5 vs. 3 weeks; p < 0.001). A similar delay in healing was observed for full-thickness excisional wounds. Histology data showed that there was a slower migration of epidermal cells over the granulation tissue in the SCI group compared to the control group. The SCI group also showed the smaller thickness of epidermis and dermis, lower blood vessel density, decreased numbers of proliferating cells, and decreased expression of alpha-smooth muscle actin compared to the control group at the time of wound closure. Taken together, these data suggest that SCI significantly slows down the dynamics of skin wound healing in experimental pressure and excisional wounds in mice. PMID- 29160148 TI - Are pupils' 'Programme for International Student Assessment (PISA)' scores associated with a nation's fish consumption? AB - AIMS: Omega-3 fatty acids are essential for neurodevelopment. Fish is a major source of these essential nutrients. We asked whether a nation's fish consumption is associated with its pupils' PISA scores as measures of school achievement, independent of economic status and breastfeeding. Method (Design and Setting): This was a regression analytic study based on published data. RESULTS: Data on fish consumption and PISA scores were available for 64 countries. A significant regression model explained 72% of the variance in PISA scores. Breastfeeding does not enter the model. After controlling for technical and/or economic development, a nation's fish consumption remains a significant predictor, explaining an additional 4% of the variance. DISCUSSION: This effect is likely due to the fact that fish, as the major source of omega-3 polyunsaturated fatty acids for a population, is important for the omega-3 supply to mothers and the early neurodevelopment of their children. CONCLUSIONS: Fish consumption, as a proxy for a population's omega-3 supply, is an independent predictor of pupils' school achievement, in addition to a nation's economic development. PMID- 29160149 TI - In vitro and in vivo evaluation of silk fibroin functionalized with GABA and allopregnanolone for Schwann cell and neuron survival. AB - AIM: This in vitro and in vivo study reports on silk fibroin (SF) scaffold, functionalized for in situ delivery of GABA and/or allopregnanolone (ALLO), as biomaterial for potential application in tissue engineering and nerve regeneration. MATERIALS & METHODS: We evaluated the feasibility to design 2D scaffolds (films) made of regenerated Bombyx mori SF, functionalized with GABA and/or ALLO to enhance in vitro biological functions, health, survival and growth of Schwann cells and sensitive neurons of the dorsal root ganglia. RESULTS & CONCLUSION: Our 2D-SF film showed an efficient loading and controllable release of drugs promoting nerve regeneration. SF functionalized film may be helpful for the development of bioengineered conduits and, in principle, have great potential for long-gap nerve injury repair. PMID- 29160150 TI - Electrocardiogram Screening in Children with Congenital Sensorineural Hearing Loss: Prevalence and Follow-up of Abnormalities. AB - Objective The purpose is to determine the prevalence of electrocardiogram (ECG) abnormalities, including borderline and prolonged QT, among screened children with sensorineural hearing loss (SNHL) and to analyze their subsequent medical workup. Study Design Institutional Review Board-approved case series with chart review. Setting Tertiary academic center. Subjects and Methods Cases from 1996 to 2014 involving pediatric patients (N = 1994) with SNHL were analyzed. Abnormal ECGs were categorized as borderline/prolonged QT or other. A board-certified pediatric cardiologist retrospectively determined the clinical significance of ECG changes. For follow-up analysis, children with heart disease, known syndromes, or inaccessible records were excluded. Results Among 772 children who had ECGs, 215 (27.8%) had abnormal results: 35 (4.5%) with QT abnormalities and 180 (23.3%) with other abnormalities. For children with QT abnormalities meeting inclusion criteria (n = 30), follow-up measures included cardiology referral (46.6%), repeat ECG by ear, nose, and throat (ENT) specialist (20%), clearance by ENT specialist with clinical correlation and/or comparison with old ECGs (20%), and pediatrician follow-up (6.7%). Documentation of further workup by ENT or referral was absent for 6.7%. For children with other ECG changes meeting inclusion criteria (n = 136), abnormalities were documented for 57 (41.9%); normal QT without other abnormality was documented for 18 (13.2%). The most common follow-up referrals were to pediatricians (16.9%) and cardiologists (10.3%). Among patients with clinically significant non-QT abnormalities mandating further evaluation (n = 122), 38 (31.1%) had documented follow-up in medical records. Conclusion There is a high prevalence of ECG abnormalities among children with congenital SNHL. If findings are confirmed by future studies, screening should be considered for congenital unilateral or bilateral SNHL, regardless of severity. We describe a standardized protocol for ECG screening/follow-up. PMID- 29160151 TI - Extracellular Matrix from Periodontal Ligament Cells Could Induce the Differentiation of Induced Pluripotent Stem Cells to Periodontal Ligament Stem Cell-Like Cells. AB - The periodontal ligament (PDL) plays an important role in anchoring teeth in the bone socket. Damage to the PDL, such as after severe inflammation, can be treated with a therapeutic strategy that uses stem cells derived from PDL tissue (PDLSCs), a strategy that has received intense scrutiny over the past decade. However, there is an insufficient number of PDLSCs within the PDL for treating such damage. Therefore, we sought to induce the differentiation of induced pluripotent stem (iPS) cells into PDLSCs as an initial step toward PDL therapy. To this end, we first induced iPS cells into neural crest (NC)-like cells. We then captured the p75 neurotrophic receptor-positive cells (iPS-NC cells) and cultured them on an extracellular matrix (ECM) produced by human PDL cells (iPS NC-PDL cells). These iPS-NC-PDL cells showed reduced expression of embryonic stem cell and NC cell markers as compared with iPS and iPS-NC cells, and enrichment of mesenchymal stem cell markers. The cells also had a higher proliferative capacity, multipotency, and elevated expression of PDL-related markers than iPS NC cells cultured on fibronectin and laminin (iPS-NC-FL cells) or ECM produced by human skin fibroblast cells (iPS-NC-SF cells). Overall, we present a culture method to produce high number of PDLSC-like cells from iPS cells as a first step toward a strategy for PDL regeneration. PMID- 29160152 TI - Effect of wetted surface area on friction, pressure, wave and total drag of a kayak. AB - Using theoretical principles, the components of drag (friction D F, pressure D PR and wave D W) of a single-seat kayak were analysed. The purpose was to examine the effect of changes in wetted surface area due to changes in kayaker's weight and the relative contribution of D F, D PR and D W to the total passive drag as function of velocity. The total passive drag values were based on experimental data collected in a single-seat kayak. Three different kayaker simulated weights were tested - 65, 75 and 85 kg. D F was the drag component that contributed the greatest percentage (between 60 and 68% at 5.56 m/s the top velocity tested) to the total passive drag for all the velocities tested and simulated weights. D W was the most affected by the increase in kayaker's simulated weight, mainly when comparing 65/75 to 85 kg. Results support the importance of a kayak design selection that minimises the kayak's drag for the individual weight of the kayaker. Also, the results suggest that the path for better hydrodynamic kayak performance should seek changes that can reduce D F, D PR and D W with D F offering the most potential to reduce passive drag. PMID- 29160153 TI - Voice and Swallowing Dysfunction in Neurofibromatosis 2. AB - Objective Neurofibromatosis 2 (NF2) is a neuro-oncologic condition that presents with bilateral vestibular schwannomas of the cerebellopontine angle (CPA). Voice and swallowing impairment can occur from direct involvement or compression of the vagus nerve or as the result of surgical excision of CPA tumors. The objectives in this study are to (1) assess the prevalence of voice and swallowing impairments and (2) analyze the effects of vagal dysfunction in patients with NF2. Study Design Cross-sectional. Setting Academic tertiary care center. Subjects and Methods Patients at a neurofibromatosis center were mailed Voice Handicap Index and Sydney Swallow Questionnaire surveys. Stroboscopic, voice, and swallowing evaluations were performed for patients who elected to participate in screening exams. Results There were high rates of self-assessed and objective voice and swallowing handicaps in this population. Fourteen of 40 (35%) patients had a self-assessed voice handicap, and 20 of 40 (50%) patients had a self assessed swallow handicap. Vocal fold motion impairment (VFMI) was observed in 22 of 31 (71%) patients examined, with 27 of 62 (44%) possible vocal cords affected. Velopharyngeal insufficiency (45%) and piriform sinus pooling or residue (39%) were seen in a significant percentage of patients. There was a significant relationship between vocal cord motion impairment and CPA surgical intervention ipsilateral to the impairment ( P = .002). The presence of VFMI was strongly associated with voice ( P = .002) and swallowing ( P = .01) impact on quality of life. Conclusion Speech and swallowing impairments are highly prevalent in patients with NF2, cause significant impact on quality of life, and are most commonly related to surgical interventions in the CPA region. PMID- 29160154 TI - Staging Neck Dissection and Transoral Robotic Surgery Treatment Algorithm in Palatine Tonsil Cancer. AB - Objective This study introduces a treatment algorithm based on staging neck dissection to identify patients with palatine tonsil squamous cell carcinoma who can be effectively treated with single-modality transoral robotic surgery while maintaining quality of life. Study Design Retrospective case series. Setting Kaiser Permanente Southern California Medical Group from 2012 to 2017. Subjects and Methods Patients with early-stage (T1/2) palatine tonsil squamous cell carcinoma with clinically and radiographically N0 necks underwent staging neck dissection. Those with pN2/3 disease or extracapsular extension on final pathology were triaged to definitive chemoradiation treatment. Patients with confirmed pN0/1 necks without extracapsular extension were treated definitively with transoral robotic surgery. Results Nineteen patients with cN0 disease underwent selective neck dissection. All were p16 positive. Of these, 14 had pathologically confirmed N0/1 necks without extracapsular extension and were treated with primary surgical resection via transoral robotic surgery. Clear margins were obtained on all patients. There were no significant intra- or postoperative complications. No patients required gastrostomy tube or tracheostomy placement. Mean and median follow-up was 28 months with no recurrences to date. Conclusion Up-front staging neck dissection accurately triages low-risk patients, determining candidates for single-modality definitive treatment with transoral robotic surgery. This approach provides excellent survival outcomes and minimal morbidity and maintains quality of life among appropriately selected patients with palatine tonsil cancer. PMID- 29160155 TI - Design and manufacturing of patient-specific orthodontic appliances by computer aided engineering techniques. AB - Orthodontic treatments are usually performed using fixed brackets or removable oral appliances, which are traditionally made from alginate impressions and wax registrations. Among removable devices, eruption guidance appliances are used for early orthodontic treatments in order to intercept and prevent malocclusion problems. Commercially available eruption guidance appliances, however, are symmetric devices produced using a few standard sizes. For this reason, they are not able to meet all the specific patient's needs since the actual dental anatomies present various geometries and asymmetric conditions. In this article, a computer-aided design-based methodology for the design and manufacturing of a patient-specific eruption guidance appliances is presented. The proposed approach is based on the digitalization of several steps of the overall process: from the digital reconstruction of patients' anatomies to the manufacturing of customized appliances. A finite element model has been developed to evaluate the temporomandibular joint disks stress level caused by using symmetric eruption guidance appliances with different teeth misalignment conditions. The developed model can then be used to guide the design of a patient-specific appliance with the aim at reducing the patient discomfort. At this purpose, two different customization levels are proposed in order to face both arches and single tooth misalignment issues. A low-cost manufacturing process, based on an additive manufacturing technique, is finally presented and discussed. PMID- 29160156 TI - Prestin as an Otologic Biomarker of Cisplatin Ototoxicity in a Guinea Pig Model. AB - Objective To evaluate (1) whether changes in serum prestin aid in early detection of cisplatin ototoxicity, (2) the role of diltiazem as an otoprotectant, and (3) whether prestin levels are sensitive to effects of diltiazem. Study Design Experimental animal study. Setting Translational research laboratory. Subjects Twenty female guinea pigs. Methods Two groups of 10 guinea pigs were used. The relationship between serum prestin levels and auditory brainstem response (ABR) thresholds was compared between the groups. All animals had baseline blood draws and ABR thresholds recorded prior to cisplatin administration. Intraperitoneal cisplatin bolus (8 mg/kg) was administered followed by 5 consecutive days of intratympanic (IT) diltiazem (2 mg/kg) or sham IT-saline injection. Serum prestin levels and ABR thresholds were measured at days 1, 2, 3, 7, and 14 postcisplatin. Results In sham, IT-saline-treated animals, mean prestin levels were elevated above baseline on days 1 to 7. The prestin levels were significantly elevated from baseline on day 1 ( P < .001), while significant ABR threshold elevations did not occur until day 2 ( P = .028) for click-evoked ABRs and day 3 ( P = .041) for tones. In diltiazem-treated animals, prestin levels were not elevated above baseline but ABR thresholds were elevated on days 1 to 3. However, the thresholds returned toward baseline on days 7 and 14. Conclusion Changes in serum prestin levels were detectable prior to shifts in ABR thresholds in a guinea pig cisplatin ototoxicity model. These changes did not occur in diltiazem-treated animals. Prestin may serve as a biomarker of cochlear injury that is sensitive to therapeutic interventions in cisplatin ototoxicity. PMID- 29160157 TI - Social support, self-rated health and low mood in people on sick leave due to heart failure: a cross-sectional study. AB - AIMS: The aim of this study was to investigate social support in relation to self rated health and the prevalence of low mood in people on sick leave due to heart failure. METHODS: A cross-sectional design was used, and 590 individuals on sick leave due to heart failure in Sweden responded to the postal questionnaire. The questions therein concerned received and needed functional and structural support from managers, work colleagues, families and friends. Multivariate analyses were conducted. RESULTS: The variables of income and needed support from family contributed significantly and negatively to self-rated health. Those who perceived that they needed more support from their manager reported experiencing low mood more frequently. CONCLUSIONS: The results showed a negative relation between manager support and low mood. Thus, support from managers and perceptions of low mood during sick leave are negatively associated, however, we do not know anything about the causality of this association. The results also indicated that needed support from family was negatively associated with self-rated health. The results also highlighted a multidimensional frailty in people with heart failure that needs to be recognized in future research as well as in clinical practice. PMID- 29160158 TI - "I Think He Will Have It Throughout His Whole Life": Parent and Youth Perspectives About Childhood Mental Health Problems. AB - Children's mental health (CMH) problems can be long-lasting. Even among children and youth who receive specialized CMH treatment, recurrence of problems is common. It is unknown whether youth and their parents view the possibility of future mental health problems. This has important implications for how CMH services should be delivered. This grounded theory study gained perspectives from youth (aged 12-15 years) who received CMH treatment ( n = 10) and their parents ( n = 10) about the expected course of CMH problems. Three disorder trajectories emerged: (a) not chronic, (b) chronic and persistent, and (c) chronic and remitting, with the majority of youth falling in the third trajectory. A gap in available services between CMH and adult care was perceived by parents, leaving them either help hopeful or help hungry about their child's future care. Improving care for youth with ongoing mental health problems is needed to minimize costs to families and the system. PMID- 29160159 TI - Reported habitual intake of breakfast and selected foods in relation to overweight status among seven- to nine-year-old Swedish children. AB - AIM: The aim of this study was to examine the reported frequency of breakfast intake and selected food and beverages in the investigated group of Swedish children in comparison with recommended intakes. Furthermore, the study analyses these food habits and some demographic and lifestyle factors in relation to overweight and obesity. METHODS: This cross-sectional study builds on data collected in 2008 and 2010. Measured anthropometric data and parent questionnaire data were collected. A total of 2620 Swedish children (52.1% boys) aged seven to nine years were included. RESULTS: The majority of parents reported that their children (95.4%) had breakfast every day. The majority of children had fresh fruit (84.7%) and vegetables (83.9%) most days a week. Only 1.6% of the children were reported to have fast food and 6.0% to have sugar containing soft drinks, four days a week or more. The prevalence of overweight including obesity (OW/OB) was 17.8% for boys, 18.6% for girls. The odds of being OW/OB was higher among those not having breakfast every day (odds ratio (OR) 1.9, 95% confidence interval (CI) 1.20-2.96), drinking diet soft drink (OR 2.6, 95% CI 1.52-4.42) and skimmed/semi-skimmed milk (OR 1.8, 95% CI 1.37-2.36) four days a week or more. Parents being overweight and having low education levels were also related to a higher risk of their children being overweight. CONCLUSIONS: The parental reports of children's food habits pointed at favourable eating patterns for most investigated children. Breakfast skipping, diet soft drinks and low-fat milk consumption were more frequent among OW/OB children. Longitudinal studies are needed to determine the causal relationships. PMID- 29160160 TI - Ideal Particle Sizes for Inhaled Steroids Targeting Vocal Granulomas: Preliminary Study Using Computational Fluid Dynamics. AB - Objectives Vocal fold granulomas are benign lesions of the larynx commonly caused by gastroesophageal reflux, intubation, and phonotrauma. Current medical therapy includes inhaled corticosteroids to target inflammation that leads to granuloma formation. Particle sizes of commonly prescribed inhalers range over 1 to 4 um. The study objective was to use computational fluid dynamics to investigate deposition patterns over a range of particle sizes of inhaled corticosteroids targeting the larynx and vocal fold granulomas. Study Design Retrospective, case specific computational study. Setting Tertiary academic center. Subjects/Methods A 3-dimensional anatomically realistic computational model of a normal adult airway from mouth to trachea was constructed from 3 computed tomography scans. Virtual granulomas of varying sizes and positions along the vocal fold were incorporated into the base model. Assuming steady-state, inspiratory, turbulent airflow at 30 L/min, computational fluid dynamics was used to simulate respiratory transport and deposition of inhaled corticosteroid particles ranging over 1 to 20 um. Results Laryngeal deposition in the base model peaked for particle sizes 8 to 10 um (2.8%-3.5%). Ideal sizes ranged over 6 to 10, 7 to 13, and 7 to 14 um for small, medium, and large granuloma sizes, respectively. Glottic deposition was maximal at 10.8% for 9-um-sized particles for the large posterior granuloma, 3 times the normal model (3.5%). Conclusion As the virtual granuloma size increased and the location became more posterior, glottic deposition and ideal particle size generally increased. This preliminary study suggests that inhalers with larger particle sizes, such as fluticasone propionate dry-powder inhaler, may improve laryngeal drug deposition. Most commercially available inhalers have smaller particles than suggested here. PMID- 29160162 TI - Is college education an equalizer for social disparities in health literacy? A case study in Shanghai, China. AB - OBJECTIVES: The aim of the study was to illustrate the immediate effect of the college education process (across college grades) on the strength of association between parental education and college attendees' health literacy. METHODS: Cross sectional analysis was conducted based on data from a random sample of students in one university in Shanghai, China ( N = 574). Exploratory factor analysis was used to generate factors of different dimensions of health literacy. Ordinary least square regression models were estimated to investigate how college education process alters the family-based disparity in health literacy. RESULTS: The link between parental education and health-related skills did not vary significantly across grades of participants, but participants in their third ( p < 0.05) and fourth year ( p < 0.001) revealed a significantly weaker association between health-promoting proactivity and parental education, relative to the first-year counterparts. Also, the impact of parental education on health-related attitudes significantly declined among the fourth-year seniors, compared with first-year students ( p < 0.05). CONCLUSIONS: Higher education experience is an important mechanism to alleviate the socioeconomic gap in health literacy. Such an equalizer effect, nevertheless, is contingent on the particular dimensions of health literacy. PMID- 29160161 TI - Serum from differently exercised subjects induces myogenic differentiation in LHCN-M2 human myoblasts. AB - Myogenesis is the formation of muscle tissue from muscle precursor cells. Physical exercise induces satellite cell activation in muscle. Currently, C2C12 murine myoblast cells are used to study myogenic differentiation. Herein, we evaluated whether human LHCN-M2 myoblasts can differentiate into mature myotubes and express early (myotube formation, creatine kinase activity and myogenin) and late (MyHC-beta) muscle-specific markers when cultured in differentiation medium (DM) for 2, 4 and 7 days. We demonstrate that treatment of LHCN-M2 cells with DM supplemented with 0.5% serum from long-term (3 years) differently exercised subjects for 4 days induced myotube formation and significantly increased the early (creatine kinase activity and myogenin) and late (MyHC-beta expression) differentiation markers versus cells treated with serum from untrained subjects. Interestingly, serum from aerobic exercised subjects (swimming) had a greater positive effect on late-differentiation marker (MyHC-beta) expression than serum from anaerobic (body building) or from mixed exercised (soccer and volleyball) subjects. Moreover, p62and anti-apoptotic Bcl-2 protein expression was lower in LHCN-M2 cells cultured with human sera from differently exercised subjectst han in cells cultured with DM. In conclusion, LHCN-M2 human myoblasts represent a species-specific system with which to study human myogenic differentiation induced by serum from differently exercised subjects. PMID- 29160163 TI - Cancer Risk Associated with Nuclear Atypia in Cytologically Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Indeterminate categories of thyroid cytopathology (categories B-III and B-IV of the Bethesda system) are integrated by a heterogeneous spectrum of cytological scenarios that are generally clustered for analysis and management recommendations. It has been suggested that aspirates exhibiting nuclear atypia have a higher risk of malignancy. This study aimed to assess whether cytologically indeterminate thyroid nodules with nuclear atypia have a significantly higher cancer risk than those without nuclear atypia. METHODS: On June 30, 2016, PubMed and EMBASE were searched for articles in English or Spanish using a search strategy developed by an endocrinologist and a librarian. Case reports were excluded, and no date limits were used. The references of all included studies were also screened for relevant missing studies. Studies were included if the prevalences of malignancy of cytologically indeterminate thyroid nodules with histological confirmation with and without nuclear atypia were reported. Studies were excluded if they had: (i) nodules suspicious for malignancy; (ii) nodules with non-indeterminate (B-III or B-IV) cytology on repeated biopsy, if performed; (iii) nodules not consecutively evaluated; or (iv) cohorts overlapping with another larger series. Two investigators independently assessed the eligibility and risk of bias of the studies. PRISMA and MOOSE guidelines were followed. Summary data were extracted from published reports by one investigator and independently reviewed by another. Data were pooled using a random-effects model. Heterogeneity was explored using subgroup analysis and mixed-effect model meta-regression. The odds ratio for malignancy of cytologically indeterminate thyroid nodules with nuclear atypia over cytologically indeterminate thyroid nodules without nuclear atypia was calculated. RESULTS: Of 2571 retrieved studies, 20 were eligible. The meta analysis was conducted on summary data of 3532 cytologically indeterminate thyroid nodules: 1162 with and 2370 without nuclear atypia. The odds ratio for malignancy in cytologically indeterminate thyroid nodules with nuclear atypia was 3.63 [confidence interval 3.06-4.35]. There was no evidence of publication bias, and heterogeneity was insignificant (I2 < 0.01%, p = 0.40). CONCLUSIONS: Nuclear atypia is a significant indicator of malignancy in cytologically indeterminate thyroid nodules and needs to be standardized and implemented into clinical practice. PMID- 29160164 TI - Rutin Scavenges Reactive Oxygen Species, Inactivates 5'-Adenosine Monophosphate Activated Protein Kinase, and Increases Sodium-Iodide Symporter Expression in Thyroid PCCL3 Cells. AB - BACKGROUND: Thyroid iodide uptake, mediated by the sodium-iodide symporter (NIS), is essential for thyroid hormone synthesis and also for treatment of thyroid diseases, such as thyroid cancer, through radioiodine therapy. Therefore, compounds able to increase thyroid iodide uptake could be clinically useful, and it is of great importance to unravel the mechanisms underlying such an effect. It has been shown previously that the flavonoid rutin increases thyroid radioiodide uptake in vivo in rats. This study aimed to investigate the mechanisms involved in the stimulatory effect of rutin on iodide uptake. METHODS: This study evaluated iodide uptake, NIS expression and its subcellular distribution, iodide efflux, reactive oxygen species levels, and the intracellular pathways involved in NIS regulation in a rat thyroid PCCL3 cell line treated with rutin. RESULTS: Similar to previous results found in vivo, rutin increased radioiodide uptake in PCCL3 cells, which was accompanied by increased NIS expression (at both the mRNA and protein levels) and a reduction of radioiodide efflux. Moreover, the results suggest that rutin could regulate NIS subcellular distribution, leading to higher levels of NIS at the cell membrane. In addition, rutin decreased the levels of intracellular reactive oxygen species and phospho-5'-adenosine monophosphate activated protein kinase. CONCLUSIONS: The flavonoid rutin seems to be an important stimulator of radioiodide uptake, acting at multiple levels, an effect that can be due to decreased oxidative stress, reduced 5'-adenosine monophosphate activated protein kinase activation, or both. Since thyroid iodide uptake is crucial for effective radioiodine therapy, the results suggest that rutin could be useful as an adjuvant in radioiodine therapy. PMID- 29160165 TI - Machine learning, social learning and the governance of self-driving cars. AB - Self-driving cars, a quintessentially 'smart' technology, are not born smart. The algorithms that control their movements are learning as the technology emerges. Self-driving cars represent a high-stakes test of the powers of machine learning, as well as a test case for social learning in technology governance. Society is learning about the technology while the technology learns about society. Understanding and governing the politics of this technology means asking 'Who is learning, what are they learning and how are they learning?' Focusing on the successes and failures of social learning around the much-publicized crash of a Tesla Model S in 2016, I argue that trajectories and rhetorics of machine learning in transport pose a substantial governance challenge. 'Self-driving' or 'autonomous' cars are misnamed. As with other technologies, they are shaped by assumptions about social needs, solvable problems, and economic opportunities. Governing these technologies in the public interest means improving social learning by constructively engaging with the contingencies of machine learning. PMID- 29160166 TI - Scope of practice and supervision of orthodontic therapists in the United Kingdom: Part 1: a national cross-sectional survey of orthodontists. AB - OBJECTIVE: Since the introduction of orthodontic therapists (OTs), there has been little research on the scope of practice and the level of supervision they receive. This study investigates how OTs are being utilised and supervised, and how this compares with current recommendations. METHODS AND PARTICIPANTS: A postal cross-sectional survey was mailed to all UK General Dental Council (GDC) registered specialist orthodontists. RESULTS: A 59.7% response rate (747) was achieved. 52% of the respondents reported they worked with/employed an OT. The majority of orthodontists worked with an OT in primary care (67%) seeing predominantly NHS (56%) patients and performed a wide range of duties. Orthodontists reported a perceived increase in clinical output (74%) and time available for treatment planning (61%). The majority (85%) of orthodontists indicated they provide a written prescription for the OT. Forty-two per cent reported the prescription did not contain the required information as stipulated by the GDC. CONCLUSIONS: OTs are valued members of the orthodontic team, improving productivity and allowing orthodontists more time for treatment planning. The majority of orthodontists appeared to be working to the BOS and GDC recommendations, with greater awareness needed regarding the provision of a written treatment prescription. PMID- 29160167 TI - An innovative long final year assistantship in general practice: description and evaluation. AB - We describe and evaluate an innovative immersive 15 week final year assistantship in general practice. Evaluation data was taken from five years of routinely collected School data and available national comparative data. The assistantship aims to enable students to consolidate knowledge and hone their skills through central participation in the care of large numbers of patients with acute and long term conditions. We estimate that most students consulted with over 450 patients during the assistantship. Students report that they became useful to their practice teams, had multiple episodes of feedback on their performance which they found useful and, in the school exit survey, reported that they were highly prepared for practice. 9.4 per cent of students reported that the assistantship was 'too long' and, especially those who completed the assistantship in the second semester, they were out of hospital for too long before F1. Some described a learning 'plateau' after the 10th week which was addressed by modifications to the assistantship. Nevertheless, in national surveys, our graduates' self-reported preparedness for practice is high, a perception shared by their F1 supervisors. General practice can make a valuable contribution to the education of senior medical students and contribute to their preparedness for practice. PMID- 29160168 TI - Cerebral blood volume lesion extent predicts functional outcome in patients with vertebral and basilar artery occlusion. AB - Background CT perfusion may improve diagnostic accuracy in posterior circulation stroke. The posterior circulation Acute Stroke Prognosis Early CT score (pc ASPECTS) on Computed Tomography Angiography source images (CTA-SI) predicts functional outcome in patients with basilar artery occlusion. Aims We assessed the prognostic value of pc-ASPECTS on CT perfusion in patients with vertebral and basilar artery occlusion (VBAO) in comparison with CTA-SI. Methods Whole-brain CT perfusion from consecutive stroke patients with VBAO at four stroke centers was retrospectively analyzed. pc-ASPECTS - a 10-point score assessing hypoattenuation on CTA-SI - was calculated from CT perfusion parameters as focally reduced cerebral blood flow or cerebral blood volume, focally increased time to peak of the deconvolved tissue residue function (Tmax) or mean transit time. Two investigators independently reviewed the images. Reliability was assessed with intraclass correlation coefficient. Good outcome was defined as modified Rankin scale <=3 at three months. Results We included 60 patients with VBAO. After assessment of four CT perfusion maps simultaneously, area-under-ROC curve (AROC) was 0.83 (95%CI 0.72-0.93) for cerebral blood volume, 0.76 (95%CI 0.64-0.89) for cerebral blood flow, 0.77 (95%CI 0.64-0.89) for Tmax, 0.70 (95%CI 0.56-0.84) for mean transit time versus area-under-ROC curve 0.64 (95%CI 0.50-0.79) for CTA-SI. Cerebral blood volume had greater accuracy compared with CTA-SI for poor outcome (p = 0.04). In logistic regression analysis, cerebral blood volume pc-ASPECTS<=8 was independently associated with poor outcome (OR 9.3 95%CI 2.2-41; p = 0.003, adjusted for age and clinical severity). Inter-rater agreement was substantial for cerebral blood volume pc-ASPECTS (intraclass correlation coefficient 0.82 95%CI 0.71-0.90 versus 0.67 for CTA-SI 95%CI 0.43-0.81). Conclusions Cerebral blood volume pc-ASPECTS may identify VBAO patients at higher risk of disability. PMID- 29160169 TI - Effect of Ramadan fasting in incidence of cerebral venous sinus thrombosis. PMID- 29160170 TI - Diagnostic X-Ray Exposure and Thyroid Cancer Risk: Systematic Review and Meta Analysis. AB - BACKGROUND: Radiation exposure is a well-known risk factor for thyroid cancer. However, the specific effects of diagnostic radiation exposure on thyroid cancer risk are controversial. The purpose of this study was to perform a systematic review and meta-analysis to assess the effects of diagnostic radiation exposure on thyroid cancer risk. METHODS: The PubMed and EMBASE databases were searched to identify eligible studies. Summary odds ratio (OR) estimates and confidence intervals (CIs) were used to compute the risk of thyroid cancer using fixed- and random-effects models. Subgroup and sensitivity analyses were performed to evaluate the potential heterogeneity. RESULTS: Nine studies from 12 publications were included in the meta-analysis. Overall exposure to diagnostic radiation exposure was associated with a significantly increased thyroid cancer risk (OR = 1.52 [CI 1.13-2.04]). The subgroup and sensitivity analyses revealed similar results. By type of exposure, exposure to computed tomography scans (OR = 1.46 [CI 1.27-1.68]) or dental x-rays (OR = 1.69 [CI 1.17-2.44]) were associated with an increased thyroid cancer risk. Head and neck (OR = 1.31 [CI 1.02-1.69]) and chest (OR = 1.71 [CI 1.09-2.69]) exposure to diagnostic radiation was associated with an increased thyroid cancer risk. CONCLUSIONS: The results of this meta analysis indicate that diagnostic radiation exposure is associated with an increased thyroid cancer risk. Therefore, to the extent that it will not compromise the information being sought, radiation exposure to the thyroid should be minimized during diagnostic examinations. PMID- 29160171 TI - Recent Pregnancy Is Not Associated with High-Risk Pathological Features of Well Differentiated Thyroid Cancer. AB - BACKGROUND: Thyroid cancer is commonly diagnosed in the first postpartum year, supporting the theory that high levels of estrogen may stimulate progression of hormone-mediated thyroid cancer. The aim of this study was to assess the effect of recent pregnancy on histopathologic disease characteristics of well differentiated thyroid cancer (WDTC). METHODS: Cases of WDTC (1999-2012) were identified from the California Cancer Registry and linked to data from the Office of Statewide Health Planning and Development. Using a matched control design, recently pregnant women (pregnancy up to five years before and nine months after a thyroid cancer diagnosis) were compared with non-pregnant controls matched by age and race/ethnicity. The main outcome measures were histopathologic tumor characteristics (tumor size, extrathyroidal extension, and nodal metastases), disease status at last follow-up, and five-year disease-specific survival. RESULTS: The study sample of 1204 women (Mage +/- standard deviation = 30.9 +/- 5.5 years; 46.5% Caucasian and 40.0% Hispanic) included 301 recently pregnant women matched against 903 non-pregnant controls. Comparing recently pregnant versus non-pregnant women, no significant differences were observed with respect to tumor size (M = 2.2 +/- 1.6 vs. 2.3 +/- 3.9 cm; p = 0.39), extrathyroidal extension (12.0% vs. 14.1%; p = 0.46), stage at diagnosis (localized disease: 67.4% vs. 62.8%; regional metastases: 30.6% vs. 33.4%; distant metastases: 2.0% vs. 3.8%; p = 0.17), disease status at last follow-up (free of tumor vs. not free of tumor; p = 0.48), and five-year disease-specific survival (99.5% vs. 99.5%). In multivariate analyses, after controlling for patient age and ethnicity, recent pregnancy was not a significant predictor of tumor size, extrathyroidal extension, nodal metastases, or distant metastases. CONCLUSIONS: In this cohort, recent pregnancy was not associated with high-risk pathological features of differentiated thyroid cancer. These findings provide reassurance with regards to the concern that pregnancy may act as a potential stimulus for thyroid cancer growth. PMID- 29160174 TI - Round Table on Reproducibility of Animal Studies at the 2017 LAVA-ESLAV-ECLAM Conference. PMID- 29160172 TI - Neural Differentiation of Spheroids Derived from Human Induced Pluripotent Stem Cells-Mesenchymal Stem Cells Coculture. AB - Organoids, the condensed three-dimensional (3D) tissues emerged at the early stage of organogenesis, are a promising approach to regenerate functional and vascularized organ mimics. While incorporation of heterotypic cell types, such as human mesenchymal stem cells (hMSCs) and human induced pluripotent stem cells (hiPSCs)-derived neural progenitors aid neural organ development, the interactions of secreted factors during neurogenesis have not been well understood. The objective of this study is to investigate the impact of the composition and structure of 3D hybrid spheroids of hiPSCs and hMSCs on dorsal cortical differentiation and the secretion of extracellular matrices and trophic factors in vitro. The hybrid spheroids were formed at different hiPSC:hMSC ratios (100:0, 75:25, 50:50, 25:75, 0:100) using direct mixing or pre-hiPSC aggregation method, which generated dynamic spheroid structure. The cellular organization, proliferation, neural marker expression, and the secretion of extracellular matrix proteins and the cytokines were characterized. The incorporation of MSCs upregulated Nestin and beta-tubulin III expression (the dorsal cortical identity was shown by Pax6 and TBR1 expression), matrix remodeling proteins, and the secretion of transforming growth factor-beta1 and prostaglandin E2. This study indicates that the appropriate composition and structure of hiPSC-MSC spheroids promote neural differentiation and trophic factor and matrix secretion due to the heterotypic cell-cell interactions. PMID- 29160175 TI - How can we assess their suffering? German research consortium aims at defining a severity assessment framework for laboratory animals. PMID- 29160173 TI - Gene Delivery to Joints by Intra-Articular Injection. AB - Most forms of arthritis are incurable, difficult to treat, and a major cause of disability in Western countries. Better local treatment of arthritis is impaired by the pharmacokinetics of the joint that make it very difficult to deliver drugs to joints at sustained, therapeutic concentrations. This is especially true of biologic drugs, such as proteins and RNA, many of which show great promise in preclinical studies. Gene transfer provides a strategy for overcoming this limitation. The basic concept is to deliver cDNAs encoding therapeutic products by direct intra-articular injection, leading to sustained, endogenous synthesis of the gene products within the joint. Proof of concept has been achieved for both in vivo and ex vivo gene delivery using a variety of vectors, genes, and cells in several different animal models. There have been a small number of clinical trials for rheumatoid arthritis (RA) and osteoarthritis (OA) using retrovirus vectors for ex vivo gene delivery and adeno-associated virus (AAV) for in vivo delivery. AAV is of particular interest because, unlike other viral vectors, it is able to penetrate deep within articular cartilage and transduce chondrocytes in situ. This property is of particular importance in OA, where changes in chondrocyte metabolism are thought to be fundamental to the pathophysiology of the disease. Authorities in Korea have recently approved the world's first arthritis gene therapy. This targets OA by the injection of allogeneic chondrocytes that have been transduced with a retrovirus carrying transforming growth factor-beta1 cDNA. Phase III studies are scheduled to start in the United States soon. Meanwhile, two additional Phase I trials are listed on Clinicaltrials.gov , both using AAV. One targets RA by transferring interferon beta, and the other targets OA by transferring interleukin-1 receptor antagonist. The field is thus gaining momentum and promises to improve the treatment of these common and debilitating diseases. PMID- 29160176 TI - Impact of bedding volume on physiological and behavioural parameters in laboratory mice. AB - The standard housing temperature in animal facilities is substantially below the lower critical temperature of mice. This does not only endanger animal welfare, it can also jeopardize scientific research as cold stress has a major impact on mouse physiology. There is some evidence that deep bedding, comparable to nesting material, can help mice to reduce heat loss. Whenever changes are applied to the cage environment, the potential impact on experimental results, including variation, needs to be assessed. An increased variation can result in a conflict between reduction and refinement, when more animals are needed for significance due to the housing design. The aim of this study was to assess the impact of different bedding volumes (0.5 L, 1.5 L and 6 L per type III cage) on mean values and coefficient of variation (CV) of physiological (pentobarbital sleeping time, blood and anatomical parameters) and behavioural parameters (open-field and novel object recognition tests) of group-housed female and male BALB/c and C57BL/6 mice. A larger bedding volume did not interfere with the CVs, but influenced mean values of organ weights and tail lengths. Mice housed on deeper bedding showed a significant reduction in adrenal, liver, kidney and heart weights as well as an increase in tail lengths; these anatomical changes are akin to warm adaptation, and were previously observed for mice housed under warmer environments. A larger bedding volume appears to be a sensible way to reduce cold stress for laboratory mice without increasing variation in experimental results. PMID- 29160177 TI - Neurological examination in healthy chinchillas ( Chinchilla lanigera). AB - Chinchillas are popular as laboratory models and companion animals, and they can be affected by a variety of infectious and non-infectious neurological diseases. Little information is available on making a neurological diagnosis in this species, in part because the neurological examination has not been standardized in chinchillas and the expected physiological findings in healthy chinchillas have not been reported. In this study, a standardized neurological examination was performed on 30 clinically normal chinchillas. The perineal reflex and the menace response were absent in all chinchillas evaluated and so should not be used as functional tests. Several tests were consistently positive, such as the oculocephalic reflex, maxillary, mandibular and auricular sensations, withdrawal reflexes, thoracic limb paw replacement, and the wheelbarrow test. Other tests, such as the cutaneous trunci reflex and pelvic limb paw replacement, had variable responses. Based on these findings, it is advised that clinicians prioritize tests that can be easily performed without undue stress to the animal, and give consistent results in a healthy patient. PMID- 29160179 TI - The MiAge Calculator: a DNA methylation-based mitotic age calculator of human tissue types. AB - Cell division is important in human aging and cancer. The estimation of the number of cell divisions (mitotic age) of a given tissue type in individuals is of great interest as it allows not only the study of biological aging (using a new molecular aging target) but also the stratification of prospective cancer risk. Here, we introduce the MiAge Calculator, a mitotic age calculator based on a novel statistical framework, the MiAge model. MiAge is designed to quantitatively estimate mitotic age (total number of lifetime cell divisions) of a tissue using the stochastic replication errors accumulated in the epigenetic inheritance process during cell divisions. With the MiAge model, the MiAge Calculator was built using the training data of DNA methylation measures of 4,020 tumor and adjacent normal tissue samples from eight TCGA cancer types and was tested using the testing data of DNA methylation measures of 2,221 tumor and adjacent normal tissue samples of five other TCGA cancer types. We showed that within each of the thirteen cancer types studied, the estimated mitotic age is universally accelerated in tumor tissues compared to adjacent normal tissues. Across the thirteen cancer types, we showed that worse cancer survivals are associated with more accelerated mitotic age in tumor tissues. Importantly, we demonstrated the utility of mitotic age by showing that the integration of mitotic age and clinical information leads to improved survival prediction in six out of the thirteen cancer types studied. The MiAge Calculator is available at http://www.columbia.edu/~sw2206/softwares.htm . PMID- 29160180 TI - Incidental Findings on FDG PET/CT in Head and Neck Cancer. AB - Objective 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG PET/CT) imaging is common in head and neck cancer and often identifies incidental findings that necessitate additional patient evaluations. Our goal was to assess the frequency and nature of these incidental imaging findings on FDG-PET/CT. Study Design Retrospective cohort study. Setting Tertiary medical center. Subjects and Methods All patients with head and neck cancer who had undergone FDG-PET/CT imaging between January 2014 and June 2015 at our institution were evaluated for incidental findings. Results A total of 293 patients met criteria; more than one-third (n = 103) had at least 1 finding unrelated to their head and neck cancer, for a total of 134 incidental findings. Incidental findings within the head and neck (33.5% of all) excluding the thyroid were most common: 35% incidental findings were concerning for malignancy; of these, 25.5% were malignant with further workup. Recommendations were given by the head and neck radiologist on 72 (53.7%) findings: 74.5% of potentially malignant findings and 42.5% of benign findings had recommendations for follow up. Significantly more patients with findings described as malignant were given recommendations for follow-up ( P = .0004). Conclusion Incidental findings on FDG PET/CT are present in more than one-third of patients with head and neck cancer. More than one-third of incidental findings were concerning for malignancy. This study illustrates how the incidental findings discovered on FDG PET/CT frequently necessitate additional evaluations unrelated to the index head and neck cancer. The impact of these additional assessments on the cost and quality of health care warrants future evaluation. PMID- 29160181 TI - Chick Embryo Model for Homing and Host Interactions of Tissue Engineering Purposed Human Dental Stem Cells. AB - Human dental stem cells (hDSC) have a potential for regenerative therapies and could differentiate in vitro into many tissues, such as dentin, nerve, and vascular endothelium. Gallus gallus domesticus developing fertilized egg or chick embryo is an experimental model absent of xenografts rejection, largely employed in replacement of mammal species in scientific research and preclinical studies to evaluate angiogenesis and vasculogenesis, tissue differentiation, and embryonic development. This multiscale research deals with the homing and cell signaling effects of a standardized hDSC toward the receptor tissues of G. gallus domesticus in ovo. The hDSC were obtained from the explantation from third molars, characterized by cell cytometry, and employed without any further purification procedure. Four experimental groups were studied, according to the kind of cell tracing strategy, named: Control, mCherry-labeled hDSC, QTracker labeled hDSC, and QTracker-exposed controls. The eggs were kept in an incubator temperature of 37.6 degrees C and humidity 86%, and the embryos were euthanized after 10 days of incubation. In vivo fluorescence and histological analysis were conducted. The fluorescence of the embryos inoculated with mCherry hDSC or the QTracker hDSC was associated with the bones and the beak tooth, and labeled cell islands could be localized in part of the samples. The inoculation of the QTracker probe resulted in proliferating bone tissue labeling. The hDSC inoculated groups presented cartilage plate hypertrophy and atypical morphology, meanwhile Control eggs were negative. The results demonstrated that hDSC can migrate to the cartilaginous tissues of the chick embryos, survive in this environment, implant, and interfere with the growth of developing bone. PMID- 29160182 TI - Enhanced Bone Regeneration by Diabetic Cell-Based Adenoviral BMP-2 Gene Therapy in Diabetic Animals. AB - The application of bone morphogenetic protein 2 (BMP-2) has been extensively investigated to improve diabetes-impaired bone healing; however, the delivery of BMP-2 by gene therapy for bone regeneration has rarely been investigated in diabetic animals. In this study, we aimed to evaluate which cells induce more new bone formation in diabetic animals when cell-based BMP2 gene therapy is applied. For this purpose, we harvested bone marrow stromal cells (BMSCs) twice in the same animal before (non-diabetic BMSCs; nBMSCs) and after diabetes induction (diabetic BMSCs; dBMSCs) using modified bone marrow ablation methods. And then, cells were transduced by adenoviral vectors carrying the BMP2 gene (AdBMP2). In in vitro, AdBMP2-transfected dBMSCs (B2/dBMSCs) produced higher BMP-2 mRNA levels over 48 h, whereas AdBMP2-transfected nBMSCs (B2/nBMSCs) exhibited a transient increase in BMP-2 mRNA followed by a decrease to the baseline level within 48 h. Both B2/dBMSCs and B2/nBMSCs induced secretion of BMP-2 for 3 weeks. However, B2/dBMSC BMP-2 secretion peaked from day 3 to 10, whereas B2/nBMSC BMP-2 secretion peaked from day 1 to 7. The analysis of osteogenic activity revealed that mineralization nodule formation and the expression levels of osteogenic genes were significantly higher in B2/dBMSCs than B2/nBMSCs and were accompanied by upregulation of canonical Wnt/beta-catenin and Smad signaling. AdBMP2 transfected autologous cells were implanted into critical-sized calvarial defects in diabetic animals and induced significantly more bone regeneration than non AdBMP2-transfected cells. In addition, B2/dBMSCs led to significantly more new bone formation than B2/nBMSCs. Thus, BMP2 gene therapy using diabetic cells effectively supported diabetic bone healing and it was related to the enhanced responses to AdBMP2 of dBMSCs. PMID- 29160183 TI - Social violence: Time to Innovate. PMID- 29160184 TI - Awareness, use and information sources of folic acid supplementation to prevent neural tube defects in pregnant Japanese women. AB - OBJECTIVE: Folic acid supplementation and folate-rich diets are recommended for women of childbearing age worldwide to prevent congenital anomalies. We aimed to determine the current status of folic acid supplementation among pregnant Japanese women and identify means to increase the intake of these supplements. DESIGN: Cross-sectional study. SUBJECTS: A total of 1862 pregnant women who consulted the perinatal centre from September 2014 to December 2015 completed a questionnaire concerning knowledge about folic acid, sources of information and the use of folic acid supplements. SETTING: Osaka Medical Center and Research Institute for Maternal and Child Health (Japan). RESULTS: In our study population, only 20.5 % of pregnant women took folic acid supplements periconceptionally even though 70.4 % knew about the protective effect of folic acid. A multivariate analysis demonstrated that age >=35 years (OR=2.80; 95 % CI 1.24, 6.29) and knowledge of the benefits of folic acid (OR=2.64; 95 % CI 1.92, 3.62) were associated with periconceptional folic acid use, and multiparity was negatively associated with such use. Compared with those who took folic acid supplements periconceptionally, women who did not take supplements received information through passive and less interactive media. CONCLUSIONS: Although folic acid awareness was relatively high among pregnant Japanese women, folic acid supplementation before conception was insufficient. To increase the intake of folic acid supplements in countries in which foods are not fortified with folic acid, an effective public health approach promoting behavioural change is necessary for women of reproductive age. PMID- 29160185 TI - Temperature modulates the interaction between fungicide pollution and disease: evidence from a Daphnia-microparasitic yeast model. AB - Temperature is expected to modulate the responses of organisms to stress. Here, we aimed to assess the influence of temperature on the interaction between parasitism and fungicide contamination. Specifically, using the cladoceran Daphnia as a model system, we explored the isolated and interactive effects of parasite challenge (yeast Metschnikowia bicuspidata) and exposure to fungicides (copper sulphate and tebuconazole) at two temperatures (17 and 20 degrees C), in a fully factorial design. Confirming a previous study, M. bicuspidata infection and copper exposure caused independent effects on Daphnia life history, whereas infection was permanently suppressed with tebuconazole exposure. Here, we show that higher temperature generally increased the virulence of the parasite, with the hosts developing signs of infection earlier, reproducing less and dying at an earlier age. These effects were consistent across copper concentrations, whereas the joint effects of temperature (which enhanced the difference between non infected and infected hosts) and the anti-parasitic action of tebuconazole resulted in a more pronounced parasite * tebuconazole interaction at the higher temperature. Thus, besides independently influencing parasite and contaminant effects, the temperature can act as a modulator of interactions between pollution and disease. PMID- 29160186 TI - The impact of urban gardens on adequate and healthy food: a systematic review. AB - OBJECTIVE: To examine the impacts on food and nutrition-related outcomes resulting from participation in urban gardens, especially on healthy food practices, healthy food access, and healthy food beliefs, knowledge and attitudes. DESIGN: The systematic review identified studies by searching the PubMed, ERIC, LILACS, Web of Science and Embase databases. An assessment of quality and bias risk of the studies was carried out and a narrative summary was produced. SETTING: Studies published as original articles in peer-reviewed scientific journals in English, Spanish or Portuguese between 2005 and 2015 were included. SUBJECTS: The studies included were based on data from adult participants in urban gardens. RESULTS: Twenty-four studies were initially selected based on the eligibility criteria, twelve of which were included. There was important heterogeneity of settings, population and assessment methods. Assessment of quality and bias risk of the studies revealed the need for greater methodological rigour. Most studies investigated community gardens and employed a qualitative approach. The following were reported: greater fruit and vegetable consumption, better access to healthy foods, greater valuing of cooking, harvest sharing with family and friends, enhanced importance of organic production, and valuing of adequate and healthy food. CONCLUSIONS: Thematic patterns related to adequate and healthy food associated with participation in urban gardens were identified, revealing a positive impact on practices of adequate and healthy food and mainly on food perceptions. PMID- 29160187 TI - THE ROLE OF COMMUNITY STRUCTURE IN SHAPING AFRICAN FERTILITY PATTERN: EVIDENCE FROM DEMOGRAPHIC AND HEALTH SURVEYS. AB - Anthropological explanations of demographic outcomes have emphasized the need to understand how community structures contribute to those outcomes. However, studies on fertility dynamics in Africa have largely focused on micro-level factors, thus ignoring the influence of community contexts. Using the most recent Demographic and Health Survey data from Egypt (Northern Africa), Cameroon (Middle Africa), Kenya (Eastern Africa), Nigeria (Western Africa) and Zimbabwe (Southern Africa), the study employed multilevel Poisson regression models to examine the influence of community factors on African fertility levels and patterns. The number of sampled women (aged 15-44) ranged from 7774 in Kenya (2008-09) to 30,480 in Nigeria (2008). The findings demonstrate some significant community effects on African fertility patterns, even after controlling for a number of individual-level factors. For instance, residence in socioeconomically disadvantaged regions, rural settings, poor neighbourhood and communities with high family size norm were found to be associated with higher fertility levels in the selected countries. The emerging African fertility patterns require the need to go beyond addressing individual-level characteristics in the efforts to reduce fertility levels in Africa. PMID- 29160188 TI - POST-TRANSITIONAL FERTILITY: THE ROLE OF CHILDBEARING POSTPONEMENT IN FUELLING THE SHIFT TO LOW AND UNSTABLE FERTILITY LEVELS. AB - This study discusses fertility trends and variation in countries that completed the transition from high to around-replacement fertility in the 1950s to 1980s, especially in Europe, East Asia and North America, and summarizes the key relevant findings for those countries with a more recent experience of fertility decline towards replacement level. A central finding is that there is no obvious theoretical or empirical threshold around which period fertility tends to stabilize. Period fertility rates usually continue falling once the threshold of replacement fertility is crossed, often to very low levels. While cohort fertility rates frequently stabilize or change gradually, period fertility typically remains unstable. This instability also includes marked upturns and reversals in Total Fertility Rates (TFRs), as experienced in many countries in Europe in the early 2000s. The long-lasting trend towards delayed parenthood is central for understanding diverse, low and unstable post-transitional fertility patterns. In many countries in Europe this shift to a late childbearing pattern has negatively affected the TFR for more than four decades. Many emerging post transitional countries and regions are likely to experience a similar shift over the next two to three decades, with a depression of their TFRs to very low levels. PMID- 29160189 TI - AFTER FERTILITY'S NADIR? ETHNIC DIFFERENTIALS IN PARITY-SPECIFIC BEHAVIOURS IN KYRGYZSTAN. AB - After a swift decline in the 1990s, the countries of Central Asia have experienced significant fertility increases over the last 15 years. These fertility upturns have remained off the radar of demographers. This study examines the recent fertility increase in Kyrgyzstan, focusing on fertility development by parity and among the main ethnic groups, in order to go beyond classic fertility indicators and national averages. Using a sample from the 2009 Census micro-dataset, sibling progression ratios were computed using information on the relationships and dates of birth of children under the age of 15. The results allow an analysis of the fertility increase by identifying the contribution of parity and ethnic group. It was found that the fertility increase in Kyrgyzstan has been experienced across the main ethnic groups, but their respective share in the population of the country has resulted in distinct contributions to the increase. Between 2001 and 2009, 82.4% of the fertility increase was due to an increase in the fertility of Kyrgyz women. In comparison, Uzbek and Russian women contributed 10.2% and 7.4%, respectively. By accounting for the parity component and ethnic factor, this study adds important disaggregated information, not only on family-building behaviours, but also on the social dimension, which is of prime importance for a better understanding of the demography of Central Asia. The study highlights important information on family-building behaviours, which are essential for the formulation of appropriate and more effective social policies aimed at sustaining and/or increasing fertility. PMID- 29160190 TI - FAR BELOW REPLACEMENT FERTILITY IN URBAN CHINA. AB - China's urban population has experienced rapid fertility decline over the past six decades. This drastic change will have a significant impact on China's demographic, social and economic future. However, the patterns and characteristics of urban China's fertility decline have not been systematically examined. This study analyses the trends and age patterns of fertility in urban China since the 1950s, and summarizes the major characteristics of reproductive behaviours into four 'lows': extremely 'low' level of fertility; 'low' proportion of two and higher parity births; 'low' mean age at birth; and 'low' level of childlessness. The paper argues that the highly homogenous reproductive behaviours found in China's now near 800 million urban population have been in part shaped by the country's unprecedented government intervention in family planning. The 'later, longer, fewer' campaign in the 1970s and the 'one-child' policy, in particular, have left clear imprints on China's reproductive norms and fertility patterns. The government-led family planning programme, however, has not been the only driving force of fertility decline. A wide range of social, economic, political and cultural changes have also affected the transition in family formation, reproductive behaviour and fertility patterns, and this has become increasingly prominent in the past two decades. PMID- 29160191 TI - SMALL FAMILY NORMS AND FAMILY WELL-BEING IN INDONESIA, 2006-2014. AB - This study examines the consequences of the universalization of small family norms in Indonesia for family well-being over the past decade (2006-2014) using contrasting views of Malthusian theory. Data came from Indonesia's 2006-2014 Socio-Economic Survey (Susenas) conducted by Indonesia's Bureau of Statistics and from official statistics. The survey covered 2.3 million households in 483 districts of the country. The findings show a steady small family ratio and an increase in family well-being over this period. A small family was found to be positively associated with high family well-being. The benefits of a small family for family well-being were found to vary between different sub-groups and sub national levels. The data reveal that improving human capital and increasing access to formal jobs may be among the channels by which small family norms have increased family well-being in Indonesia. PMID- 29160192 TI - SIBSHIP SIZE AND YOUNG WOMEN'S TRANSITIONS TO ADULTHOOD IN INDIA. AB - In India, a substantial proportion of young people are growing up in smaller families with fewer siblings than earlier generations of young people. Studies exploring the associations between declines in sibship size and young people's life experiences are limited. Drawing on data from a sub-nationally representative study conducted in 2006-08 of over 50,000 youths in India, this paper examines the associations between surviving sibship size and young women's (age 20-24) transitions to adulthood. Young women who reported no or a single surviving sibling were categorized as those with a small surviving sibship size, and those who reported two or more surviving siblings as those with a large surviving sibship size. Bivariate and multivariate regression analyses were conducted to ascertain the relationship between sibship size and outcome indicators. Analysis was also done separately for low- and high-fertility settings. Small sibship size tended to have a positive influence in many ways on young women's chances of making successful transitions to adulthood. Young women with fewer siblings were more likely than others to report secondary school completion, participation in vocational skills training programmes, experience of gender egalitarian socialization practices, adherence to gender egalitarian norms, exercise of pre-marital agency and small family size preferences. These associations were more apparent in low- than high-fertility settings. PMID- 29160193 TI - FERTILITY TRANSITION IN SRI LANKA: IS IT A TEMPORARY PHENOMENON? AB - This paper examines the fertility transition and its recent dynamics in Sri Lanka using data from Demographic and Health Surveys and Population Censuses. Fertility trends and patterns were analysed for two periods: 1953-2000 and 2000-2012. The findings revealed that Sri Lanka's fertility transition has been relatively rapid and has taken place over a period of about four decades to reach replacement level. Social and health-related factors, including decline in maternal and infant mortality, increase in women's education, changes in institutions, reproductive values and behaviour, and increased contraceptive use all contributed to bringing down the fertility level by 2000. However, in the 2006/07 Sri Lankan DHS and 2012 Population Census, a slight increase in Total Fertility Rate (TFR) to 2.3 and 2.4, respectively, was observed. Binary logistic regression estimates based on 2006/2007 DHS data were used to identify the significant predictors of fertility preferences of ever-married women. The analysis of factors affecting the likelihood of having a larger family (more than 2 children) revealed that lower educated women were more likely to have a higher number of children than their counterparts with a higher level of education. Women who lived in rural and estate (commercial area of 20 acres or more employing 10 or more labourers) sectors were 1.4 and 1.2 times, respectively, more likely to prefer more children compared with urban women. In terms of ethnic groups, Moor and Tamil women were 4.5 and 1.4 times, respectively, more likely to prefer more children than Sinhalese women. When the economic status of women was considered, the poorer women were 1.4 times more likely to desire a higher number of children compared with rich women, while women in the middle wealth quintile were 1.2 times more likely to desire more children. The findings suggest that the Sri Lankan government should re-visit population and reproductive health policy and family planning programmes to see how it can better manage fertility among the different population groups in Sri Lanka. PMID- 29160194 TI - SOCIAL DETERMINANTS OF LOW FERTILITY IN BRAZIL. AB - An increasing number of developing countries are experiencing below replacement fertility rates. Although the factors associated with low fertility in developed countries have been widely explored in the literature, studies of low fertility in middle- and low-income countries continue to be rare. To help fill this gap, Brazil was used as a case study to assess whether human development, gender equality and the ability of mothers with young children to work are associated with the likelihood of married or cohabiting women to have a child. For this purpose, multilevel logistic regressions were estimated using the 1991, 2000 and 2010 Brazilian Demographic Censuses. It was found that human development was negatively associated with fertility in the three periods analysed. Gender equality and the ability of mothers with young children to work were positively associated with the odds of having higher order births in Brazil in 2000 and 2010. In 1991, these variables were not associated with higher order births, and gender equality was negatively associated with first births. The positive association found in 2000 and 2010 may constitute a reversal of the relationship that in all likelihood prevailed earlier in the demographic transition when gender equality was most likely negatively correlated with fertility levels. PMID- 29160195 TI - POLITICAL BOUNDARY VERSUS SOCIAL CONTEXT: DYNAMICS OF SOCIOECONOMIC DIFFERENTIALS IN FERTILITY IN INDIAN STATES. AB - Using data from India's first (1992-93) and third (2005-06) National Family Health Surveys (NFHS-I and NFHS-III) this study examined the fertility differentials between major social groups and the extent to which these varied between states and over time. The analysis was based on a sample of 54,030 and 55,369 currently married women aged 15-34 in the NFHS-I and NFHS-III respectively. Reported parity and desired family size were used to assess variations in fertility behaviour. The results show that interstate variation in childbearing patterns within social groups was at least as high as, if not higher than, variation between states (net of other influences) in both periods, 1992-93 and 2005-06. The variations among Hindus, the poor and Muslims were more noticeable than for other groups. These variations did not decline between 1992 93 and 2005-06 and may have even increased slightly for some groups. Further, there was no consistent north-south divide in either fertility behaviour or desired family size. Together, these results may point to the gradual disappearance of the influences that were once unique to southern or northern India, and the simultaneous emergence of social, political, economic and cultural forces that are pan-Indian in their reach. PMID- 29160196 TI - Rheinheimera marina sp. nov., isolated from a deep-sea seamount. AB - A bacterial strain designated TP462T, isolated from a seamount near the Yap Trench in the tropical western Pacific, was characterized using a polyphasic taxonomic approach. Strain TP462T was found to be Gram-stain-negative, aerobic, rod-shaped and motile by means of a single polar flagellum. Growth occurred at 4 37 degrees C (optimum, 25-30 degrees C) and with 0-4.0 % NaCl (optimum, 2-3 %). Phylogenetic analysis based on 16S rRNA gene sequence showed that strain TP462T was related to the genus Rheinheimera and had the highest 16S rRNA gene sequence similarity with the type strain Rheinheimera tangshanensis JA3-B52T (96.8 %). The predominant cellular fatty acids were C17 : 1omega8c, summed feature 3 (composed of iso-C15 : 0 2-OH and/or C16 : 1omega7c) and C16 : 0. The polar lipid profile contained phosphatidylglycerol, phosphatidylethanolamine and two unidentified lipids. The genomic DNA G+C content of strain TP462T was 48.7 mol%. On the basis of the evidence presented in this study, strain TP462T represents a novel species of the genus Rheinheimera, for which we propose the name Rheinheimera marina sp. nov. (type strain TP462T=KACC 18560T=CGMCC 1.15399T). PMID- 29160197 TI - Isolation and molecular characterization of group B Streptococcus from laboratory Long-Evans rats (Rattus norvegicus) with and without invasive group B streptococcal disease. AB - PURPOSE: Group B Streptococcus (S. agalactiae, GBS) is a Gram-positive opportunistic pathogen that inhabits the respiratory, urogenital and gastrointestinal tracts of humans and animals. Maternal colonization of GBS is a risk factor for a spectrum of clinical diseases in humans and a principle cause of neonatal meningitis and septicaemia. METHODOLOGY: We describe polymicrobial sepsis including GBS in two gravid adult female Long-Evans rats experiencing acute mortality from a colony of long-term breeding pairs. Fluorescent in situ hybridization confirmed GBS association with pathological changes in affected tissues, including the heart and uterus. RESULTS: Characterization of seven GBS strains obtained from clinically affected and non-affected animals indicated similar antibiotic resistance and susceptibility patterns to that of human strains of GBS. The rat strains have virulence factors known to contribute to pathogenicity, and shared serotypes with human invasive isolates. Phylogenetic analyses revealed that one rat-derived GBS strain was more closely related to human-derived strains than other rat-derived strains, strengthening the notion that interspecies transmission is possible. CONCLUSIONS: To our knowledge, this is the first investigation of genotypic and phenotypic features of rat-derived GBS strains and their comparison to human- and other animal-derived GBS strains. Since GBS commonly colonizes commercially available rats, its exclusion as a potential pathogen for immunocompromised or stressed animals is recommended. PMID- 29160198 TI - Herbidospora soli sp. nov., isolated from soil. AB - A novel actinomycete strain PS42-9T, which formed short chains of spores borne on the tip of long sporophores arising from the substrate mycelium, was isolated from soil in Phu-Sang National Park, Phayao province, Thailand. The isolate contained meso-diaminopimelic acid in the cell-wall peptidoglycan. The whole-cell sugars of strain PS42-9T were glucose, madurose, mannose, rhamnose and ribose. The characteristic phospholipids were phosphatidylethanolamine, phosphatidylmethylethanolamine, hydroxyphosphatidylethanolamine and ninhydrin positive glycophospholipids. The major menaquinone was MK-10(H4). The main cellular fatty acids were C17 : 1omega8c and C17 : 0. The G+C content of the genomic DNA was 71.5 mol%. Phylogenetic analysis using 16S rRNA gene sequences revealed that strain PS42-9T should be classified in the genus Herbidospora and was closely related to Herbidospora sakaeratensis DMKUA 205T (99.10 %) and Herbidospora yilanensis NBRC 106371T (98.61 %). The result of DNA-DNA hybridization and some physiological and biochemical properties indicated that strain PS42-9T could be readily distinguished from its closest phylogenetic relatives. On the basis of these phenotypic and genotypic data, this strain represents a novel species, for which the name Herbidospora soli sp. nov. is proposed. The type strain is PS42-9T (=BCC 46909T=NBRC 108780T). PMID- 29160199 TI - Marmosets (Callithrix jacchus) as a non-human primate model for evaluation of candidate dengue vaccines: induction and maintenance of specific protective immunity against challenges with clinical isolates. AB - Dengue virus (DENV) is one of the major infectious diseases in tropical regions and approximately half of the world population is at risk of infection. Vaccines would offer an effective control measure against this disease. We previously reported on the utility of marmosets as an animal model for studying primary and secondary dengue infections. Infected marmosets consistently develop viraemia and antibody kinetics that reflect those of patients with dengue. Thus, it is important to determine the utility of marmosets as an animal model for demonstrating vaccine efficacy. In this study, marmosets were inoculated with candidate vaccine and parent strains and challenged with a clinical DENV strain. The viraemia and antibody kinetics in these marmosets were determined. Marmosets consistently develop lower viraemia with an attenuated vaccine strain. During secondary challenge, the IgM response was delayed, whereas the IgG levels rose rapidly, indicating a secondary antibody response. The neutralizing activities against the homotypic serotype were high; all marmosets were protected against viraemia following secondary inoculation. The viraemia markers and antibody responses were consistent with those of human DENV infection and vaccinees. These results demonstrate the utility of marmosets as an animal model for the study of vaccine efficacy. PMID- 29160200 TI - Methylobacterium frigidaeris sp. nov., isolated from an air conditioning system. AB - A reddish pink-pigmented, Gram-stain-negative, aerobic and methylotrophic bacterial strain, designated strain IER25-16T, was isolated from a laboratory air conditioning system in the Republic of Korea. Cells were motile rods showing catalase- and oxidase-positive reactions. Strain IER25-16T grew at 10-40 degrees C (optimum, 30 degrees C), at pH 4.0-7.0 (optimum, pH 5.0-7.0) and in the presence of 0-1.0 % (w/v) NaCl (optimum, 0 %). The major respiratory quinone was ubiquinone-10 and ubiquinone-9 was also detected as the minor respiratory quinone. Summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c) was detected as the predominant fatty acids. The genomic DNA G+C content of strain IER25-16T was 70.0 mol%. Phylogenetic analysis based on 16S rRNA gene sequence comparison revealed that strain IER25-16T belonged to the genus Methylobacterium of the class Alphaproteobacteria. Strain IER25-16T was most closely related to Methylobacterium platani PMB02T (97.9 %), Methylobacterium aquaticum GR16T (97.9 %) and Methylobacterium tarhaniae N4211T (97.5 %). The average nucleotide identity and in silico DNA-DNA hybridization values between strain IER25-16T and M. platani, M. aquaticum and M. tarhaniae were 88.3, 88.8 and 89.6 % and 36.2, 37.3 and 39.3 %, respectively. The phenotypic and chemotaxonomic features and the phylogenetic inference clearly suggested that strain IER25-16T represents a novel species of the genus Methylobacterium, for which the name Methylobacteriumfrigidaeris sp. nov. is proposed. The type strain is strain IER25 16T (=KACC 19280T=JCM 32048T). PMID- 29160201 TI - Aquicoccus porphyridii gen. nov., sp. nov., isolated from a small marine red alga, Porphyridium marinum. AB - A Gram-stain-negative, non-motile and aerobic bacterial strain, designated L1 8 17T, was isolated from a marine alga, Porphyridium marinum, in South Korea. Cells of strain L1 8-17T were found to be oxidase- and catalase-positive cocci without flagella. Growth of strain L1 8-17T was observed at 20-40 degrees C (optimum, 37 degrees C), pH 6.0-10.0 (optimum, pH 7.0-8.0) and in the presence of 0-7 % (w/v) NaCl (optimum, 2-3 %). The isoprenoid quinone detected was only ubiquinone-10. Summed feature 8 (comprising C18 : 1omega7c/C18 : 1omega6c) and C16 : 0 were detected as major cellular fatty acids. The major polar lipids of strain L1 8-17T consisted of phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, an unidentified aminolipid, an unidentified phospholipid and an unidentified lipid. The G+C content of the genomic DNA was 59.3 mol%. Strain L1 8-17T was most closely related to Marimonas arenosa CAU 1311T, Tropicibacter naphthalenivorans C02T and Donghicola eburneus SW-277T with 96.68, 96.68 and 96.60 % 16S rRNA gene sequence similarities, respectively, but the strain formed a phylogenetic lineage clearly distinct from them within the family Rhodobacteraceae. On the basis of phenotypic, chemotaxonomic and molecular properties, strain L1 8-17T represents a novel genus of the family Rhodobacteraceae, for which the name Aquicoccus porphyridii gen. nov., sp. nov. is proposed. The type strain of the type species is L1 8-17T (KACC 18806T=JCM 31543T). PMID- 29160202 TI - Re-classification of Clavibacter michiganensis subspecies on the basis of whole genome and multi-locus sequence analyses. AB - Although the genus Clavibacter was originally proposed to accommodate all phytopathogenic coryneform bacteria containing B2gamma diaminobutyrate in the peptidoglycan, reclassification of all but one species into other genera has resulted in the current monospecific status of the genus. The single species in the genus, Clavibacter michiganensis, has multiple subspecies, which are all highly host-specific plant pathogens. Whole genome analysis based on average nucleotide identity and digital DNA-DNA hybridization as well as multi-locus sequence analysis (MLSA) of seven housekeeping genes support raising each of the C. michiganensis subspecies to species status. On the basis of whole genome and MLSA data, we propose the establishment of two new species and three new combinations: Clavibacter capsici sp. nov., comb. nov. and Clavibacter tessellarius sp. nov., comb. nov., and Clavibacter insidiosus comb. nov., Clavibacter nebraskensis comb. nov. and Clavibacter sepedonicus comb. nov. PMID- 29160203 TI - Molecular epidemiology and antimicrobial susceptibility of Clostridium difficile isolated from hospitals during a 4-year period in China. AB - OBJECTIVE: The aim of this study was to perform molecular characterization for and determine the antimicrobial susceptibility profiles of Clostridium difficile collected from hospitals during a 4-year period (2009-2013) in China. METHODS: Strains of toxigenic C. difficile were isolated from patients with diarrhoea, and this was followed by typing using multilocus sequence typing (MLST) and testing for susceptibility to 10 antimicrobials by using the E-test. The mechanisms of resistance to moxifloxacin, erythromycin, clindamycin and tetracycline were investigated by PCR. RESULTS: A total of 405 non-duplicate toxigenic C. difficile isolates were identified, while 31 sequence types (STs) were identified. A predominant type, ST-54, accounted for 20.2 % of the STs, followed by ST-35 (16.3 %) and ST-37 (13.6 %). We found that 6.2 % of the isolates were binary toxin genes-positive, and 83.7 % of these belonged to ST-5. All of the isolates demonstrated 100 % susceptibility to first-line Clostridium difficile infection (CDI) therapies (i.e. metronidazole and vancomycin), while the resistance rates varied for the other antibiotics tested. Two hundred and ninety three (72.3 %) isolates were susceptible to moxifloxacin. All 112 moxifloxacin-resistant isolates had mutations resulting in an amino acid substitution in gryA and/or gyrB. The ermB gene was detected in 86.7 % (241/278) of the erythromycin- and clindamycin-resistant isolates, while the tetM gene was present in 97.1 % (85/87) of the tetracycline-resistant isolates. CONCLUSION: MLST typing revealed a wide variety of STs causing CDI, while ST-54 was the most common ST. All of the isolates were susceptible to metronidazole and vancomycin, while the resistance rates varied for the other antibiotics tested. There were no changes in the trends for the STs and antibiotic susceptibility profiles over 4 years. PMID- 29160204 TI - Proteins acting out of (dis)order. AB - A disordered region at the N-terminus of the glucocorticoid receptor can fine tune how cells respond to a hormone via an allosteric mechanism. PMID- 29160207 TI - Serial EEG findings in anti-NMDA receptor encephalitis: correlation between clinical course and EEG. AB - Anti-NMDA receptor encephalitis is a paraneoplastic encephalitis characterised by psychiatric features, involuntary movement, and autonomic instability. Various EEG findings in patients with anti-NMDA receptor encephalitis have been reported, however, the correlation between the EEG findings and clinical course of anti NMDA receptor encephalitis remains unclear. We describe a patient with anti-NMDA receptor encephalitis with a focus on EEG findings, which included: status epilepticus, generalised rhythmic delta activity, excess beta activity, extreme delta brush, and paroxysmal alpha activity upon arousal from sleep, which we term"arousal alpha pattern". Initially, status epilepticus was observed on the EEG when the patient was comatose with conjugate deviation. The EEG then indicated excess beta activity, followed by the emergence of continuous slow activity, including generalised rhythmic delta activity and extreme delta brush, in the most severe phase. Slow activity gradually faded in parallel with clinical amelioration. Excess beta activity persisted, even after the patient became almost independent in daily activities, and finally disappeared with full recovery. In summary, our patient with anti-NMDA receptor encephalitis demonstrated slow activity on the EEG, including extreme delta brush during the most severe phase, which gradually faded in parallel with clinical amelioration, with excess beta activity persisting into the recovery phase. PMID- 29160205 TI - Clarinet (CLA-1), a novel active zone protein required for synaptic vesicle clustering and release. AB - Active zone proteins cluster synaptic vesicles at presynaptic terminals and coordinate their release. In forward genetic screens, we isolated a novel Caenorhabditis elegans active zone gene, clarinet (cla-1). cla-1 mutants exhibit defects in synaptic vesicle clustering, active zone structure and synapse number. As a result, they have reduced spontaneous vesicle release and increased synaptic depression. cla-1 mutants show defects in vesicle distribution near the presynaptic dense projection, with fewer undocked vesicles contacting the dense projection and more docked vesicles at the plasma membrane. cla-1 encodes three isoforms containing common C-terminal PDZ and C2 domains with homology to vertebrate active zone proteins Piccolo and RIM. The C-termini of all isoforms localize to the active zone. Specific loss of the ~9000 amino acid long isoform results in vesicle clustering defects and increased synaptic depression. Our data indicate that specific isoforms of clarinet serve distinct functions, regulating synapse development, vesicle clustering and release. PMID- 29160208 TI - A case of post-leptospirosis autoimmune epilepsy presenting with sleep-related hypermotor seizures. AB - This video-illustrated case report concerns a 49-year-old woman who presented with sleep-related hypermotor seizures. The antecedent history of leptospirosis, high frequency of new-onset seizures, presence of an unclassified anti-neuronal antibody, and dramatic response to steroids strongly supported post-infectious immune-mediated pathogenesis in our patient. To the best of our knowledge, post leptospirosis autoimmune epilepsy presenting as sleep-related hypermotor seizures has not hitherto been reported. [Published with video sequence on www.epilepticdisorders.com]. PMID- 29160206 TI - An orphan cbb3-type cytochrome oxidase subunit supports Pseudomonas aeruginosa biofilm growth and virulence. AB - Hypoxia is a common challenge faced by bacteria during associations with hosts due in part to the formation of densely packed communities (biofilms). cbb3-type cytochrome c oxidases, which catalyze the terminal step in respiration and have a high affinity for oxygen, have been linked to bacterial pathogenesis. The pseudomonads are unusual in that they often contain multiple full and partial (i.e. 'orphan') operons for cbb3-type oxidases and oxidase subunits. Here, we describe a unique role for the orphan catalytic subunit CcoN4 in colony biofilm development and respiration in the opportunistic pathogen Pseudomonas aeruginosa PA14. We also show that CcoN4 contributes to the reduction of phenazines, antibiotics that support redox balancing for cells in biofilms, and to virulence in a Caenorhabditis elegans model of infection. These results highlight the relevance of the colony biofilm model to pathogenicity and underscore the potential of cbb3-type oxidases as therapeutic targets. PMID- 29160209 TI - De novo absence status epilepticus of late onset (DNASLO) precipitated by oral treatment with cefuroxime: description of an ambulatory case. AB - We describe the case of an elderly woman with an episode of ambulatory de novo absence status epilepticus of late onset (DNASLO) after oral treatment with cefuroxime. A high level of suspicion of DNASLO in cases of unexplained confusion in adults or elderly subjects taking cephalosporins is essential to prompt an emergency EEG and, in turn, rapidly achieve an appropriate diagnosis and enable optimal treatment. PMID- 29160211 TI - Patients with axillary Paget's disease should be carefully screened for other sites affected by the disease. PMID- 29160210 TI - Exceptional response to brivaracetam in a patient with refractory idiopathic generalized epilepsy and absence seizures. AB - Brivaracetam is currently indicated as adjunctive therapy for patients with focal onset seizures with or without secondary generalization. However, it has been suggested that it could provide broad-spectrum efficacy given its similarity to levetiracetam and based on the results from preclinical studies and others of patients with generalized epilepsy. We present the case of a woman with refractory idiopathic generalized epilepsy and absence seizures with dramatic response to brivaracetam. Our report supports a consideration of treatment with this new antiepileptic drug on a case-by-case basis in patients with refractory generalized epilepsy, while we await further studies on this topic. PMID- 29160212 TI - Stellate erosion: the dermoscopic Nikolsky sign? PMID- 29160213 TI - Cutaneous metastases of internal malignancies: an experience from a single institution. AB - BACKGROUND: Cutaneous metastases represent 2% of all skin tumours. Their recognition can be challenging, as they may present with different clinical features, with consequent frequent delay and failure in diagnosis. OBJECTIVES: To review our series of cutaneous metastatic lesions, analyse their frequency according to patient gender, histotype, localization of the primary tumour, and site of cutaneous metastasis, and correlate this data with clinicopathological parameters. MATERIALS & METHODS: We conducted a retrospective review of all cases of cutaneous metastases from visceral neoplasms diagnosed in our dermatopathology department from July 2003 to February 2017. We registered clinical, histological, and immunohistochemical data. Additional immunohistochemical staining panels were elaborated to confirm or identify the origin of the primary tumour, or at least to specify the histological subtype. RESULTS: We identified 45 histological diagnoses of cutaneous and mucocutaneous metastases. The primary tumour that was most likely to metastasize to the skin was breast cancer. Most cases of breast (89%) and lung cancer (86%) metastasized to the trunk. Of the lesions, 57.5% were nodules and 32.5% were plaques, more frequently multiple (64.4%). In 58% of cases, a metastasis was clinically suspected. Histological examination most frequently revealed an adenocarcinoma, sometimes suggestive of the site of origin. CONCLUSIONS: Cutaneous metastases should be primarily considered when discrete firm painless nodules emerge rapidly. Clinicians should carefully consider infiltrated lesions of the chest in women since scleroderma and erysipelas-like presentation can be a clue for undiagnosed breast cancer. PMID- 29160214 TI - Auer rod-like inclusions in non blast cells. AB - We report a 69-year-old adult case with a monoclonal gammopathy incidentally discovered, associated with a moderate thrombocytopenia of 90 G/L. Study of blood smear revealed the presence of tumor cells presenting Auer rod-like inclusions, although there were not blast cells. Blood cytology as well as immunophenotyping allowed us to make the diagnosis of malignant hemopathy. PMID- 29160215 TI - A case of lichen planus pemphigoides with palmoplantar keratoderma. PMID- 29160216 TI - Serological survey of Australian native reptiles for exposure to ranavirus. AB - Ranaviruses have been isolated from many ectothermic vertebrates, and serological surveys of both amphibians and reptiles have shown the presence of ranaviral antibodies in a proportion of these populations. An enzyme-linked immunosorbent assay (ELISA) was developed to measure serum antibodies against ranavirus in Australian reptiles. The ELISA was validated with serum from challenge trials with Bohle iridovirus (BIV) in 6 reptilian species. A preliminary sero-survey of northern Queensland riparian reptile fauna (saw-shelled turtles Myuchelys latisternum, Krefft's river turtles Emydura macquarii krefftii, freshwater crocodiles Crocodylus johnstoni, as well as the snakes Boiga irregularis, Dendrelaphis punctulatus, Tropidonophis mairii, Morelia spilota, Liasis childreni and L. fuscus) revealed evidence of past exposure to Bohle iridoviral antigens in part of the population at several locations sampled. Furthermore, in Krefft's river turtles and freshwater crocodiles, a statistically significant trend was apparent for larger reptiles to be more likely to have BIV-reactive sera than smaller individuals. The use of adult tortoise populations as sentinels can assist in monitoring the presence of BIV in northern Australian freshwater streams, and thereby the potential dangers to native fauna from this agent. PMID- 29160217 TI - Morphological and molecular confirmation of Myxobolus cerebralis myxospores infecting wild-caught and cultured trout in North Carolina (SE USA). AB - We used microscopy and molecular biology to provide the first documentation of infections of Myxobolus cerebralis (Myxozoa: Myxobolidae), the etiological agent of whirling disease, in trout (Salmonidae) from North Carolina (USA) river basins. A total of 1085 rainbow trout Oncorhynchus mykiss, 696 brown trout Salmo trutta, and 319 brook trout Salvelinus fontinalis from 43 localities across 9 river basins were screened. Myxospores were observed microscopically in pepsin trypsin digested heads of rainbow and brown trout from the Watauga River Basin. Those infections were confirmed using the prescribed nested polymerase chain reaction (PCR; 18S rDNA), which also detected infections in rainbow, brown, and brook trout from the French Broad River Basin and the Yadkin Pee-Dee River Basin. Myxospores were 9.0-10.0 um (mean +/- SD = 9.6 +/- 0.4; N = 119) long, 8.0-10.0 um (8.8 +/- 0.6; 104) wide, and 6.0-7.5 um (6.9 +/- 0.5; 15) thick and had polar capsules 4.0-6.0 um (5.0 +/- 0.5; 104) long, 2.5-3.5 um (3.1 +/- 0.3; 104) wide, and with 5 or 6 polar filament coils. Myxospores from these hosts and rivers were morphologically indistinguishable and molecularly identical, indicating conspecificity, and the resulting 18S rDNA and ITS-1 sequences derived from these myxospores were 99.5-100% and 99.3-99.8% similar, respectively, to published GenBank sequences ascribed to M. cerebralis. This report comprises the first taxonomic circumscription and molecular confirmation of M. cerebralis in the southeastern USA south of Virginia. PMID- 29160218 TI - Antimicrobial resistance, heavy metal resistance and integron content in bacteria isolated from a South African tilapia aquaculture system. AB - Antibacterial compounds and metals co-select for antimicrobial resistance when bacteria harbour resistance genes towards both types of compounds, facilitating the proliferation and evolution of antimicrobial and heavy metal resistance. Antimicrobial and heavy metal resistance indices of 42 Gram-negative bacteria from a tilapia aquaculture system were determined to identify possible correlations between these phenotypes. Agar dilution assays were carried out to determine susceptibility to cadmium, copper, lead, mercury, chromate and zinc, while susceptibility to 21 antimicrobial agents was investigated by disk diffusion assays. Presence of merA, the mercury resistance gene, was determined by dot-blot hybridizations and PCR. Association of mercury resistance with integrons and transposon Tn21 was also investigated by PCR. Isolates displayed a high frequency of antimicrobial (erythromycin: 100%; ampicillin: 85%; trimethoprim: 78%) and heavy metal (Zn2+: 95%; Cd2+: 91%) resistance. No correlation was established between heavy metal and multiple antibiotic resistance indices. Significant positive correlations were observed between heavy metal resistance profiles, indices, Cu2+ and Cr3+ resistance with erythromycin resistance. Significant positive correlations were observed between merA (24%)/Tn21 (24%) presence and heavy metal resistance profiles and indices; however, significant negative correlations were obtained between integron associated qacE?1 (43%) and sulI (26%) gene presence and heavy metal resistance indices. Heavy metal and antimicrobial agents co-select for resistance, with fish associated, resistant bacteria demonstrating simultaneous heavy metal resistance. Thus, care should be taken when using anti-fouling heavy metals as feed additives in aquaculture facilities. PMID- 29160219 TI - Complete sequences of 4 viral hemorrhagic septicemia virus IVb isolates and their virulence in northern pike fry. AB - Four viral hemorrhagic septicemia virus (VHSV) genotype IVb isolates were sequenced, their genetic variation explored, and comparative virulence assayed with experimental infections of northern pike Esox lucius fry. In addition to the type strain MI03, the complete 11183 bp genome of the first round goby Neogobius melanostomus isolate from the St. Lawrence River, and the 2013 and 2014 isolates from gizzard shad Dorosoma cepedianum die-offs in Irondequoit Bay, Lake Ontario and Dunkirk Harbor, Lake Erie were all deep sequenced on an Illumina platform. Mutations documented in the 11 yr since the MI03 index case from Lake St. Clair muskellunge Esox masquinongy showed 87 polymorphisms among the 4 isolates. Twenty six mutations were non-synonymous and located at 18 different positions within the matrix protein, glycoprotein, non-virion protein, and RNA polymerase genes. The same 4 isolates were used to infect northern pike fry by a single 1 h bath exposure. Cumulative percent mortality varied from 42.5 to 62.5%. VHSV was detected in 57% (41/72) of the survivors at the end of the 21-d trial, suggesting that the virus was not rapidly cleared. Lesions were observed in many of the moribund and dead northern pike, such as hemorrhaging in the skin and fins, as well as hydrocephalus. Mean viral load measured from the trunk and visceral tissues of MI03-infected pike was significantly higher than the quantities detected in fish infected with the most recent isolates of genotype IVb, but there were no differences in cumulative mortality observed. PMID- 29160220 TI - Immune status of the spiny lobster Jasus edwardsii with tail fan necrosis. AB - Tail fan necrosis (TFN), a disorder commonly found in some populations of commercially fished and cultured lobsters, is thought to be initiated by injuries caused by handling and containment. The unsightly appearance of affected lobster tails significantly lowers their commercial value. Knowledge about TFN is limited. In this study we describe the morphological features of TFN and apply 6 common methods for evaluating the immune status of wild-caught Australasian red spiny lobsters Jasus edwardsii with and without TFN. The disease was more frequent in uropods than in telsons of the tail fan, and more extensive on the ventral versus the dorsal surfaces of the tail fan. Missing appendages (i.e. antenna, pereiopod or pleopod) were significantly more common and greater in number for individual lobsters affected with TFN versus those without, possibly as a result of handling in the fishery or as an indirect effect of the disease. Two immune parameters, total haemocyte count and phenoloxidase activity in the haemocyte lysate supernatant (HLS), were significantly compromised in lobsters with TFN. No differences were found in the other immune parameters, i.e. haemocyte viability, haemolymph bacterial count and the protein content of haemolymph plasma and HLS. The results are consistent with injury sustained during prior capture and handling that initiates TFN in these natural caught lobsters. These results raise some potential concerns about the fitness of lobsters in natural populations that are affected by TFN, and some potential solutions are proposed. PMID- 29160221 TI - Evaluation of blue mussel Mytilus edulis as vector for viral hemorrhagic septicemia virus (VHSV). AB - When viral diseases occur in aquaculture farms, the virus released into the seawater from infected animals can re-infect other susceptible species or accumulate in filter-feeding organisms. We conducted a viral hemorrhagic septicemia virus (VHSV) survivability analysis of blue mussel Mytilus edulis digestive enzymes, viral depuration, and infectivity tests via in vitro and in vivo inoculation to evaluate the infectious state. VHSV particles were not completely digested within 24 h in vitro and were maintained for 7 d in the mussel digestive gland. Mussels cohabitating with naturally VHSV-infected olive flounder Paralichthys olivaceus could accumulate the viral particles. Although the viral particles in the gill as the entrance of filter-feeding organisms are infectious, the presence of these particles in the digestive gland were not able to induce cytopathic effects in vitro. Viral particles detected by RT-PCR from bivalve mollusks (Pacific oyster Crassostrea gigas and mussel) from the field did not produce cytopathic effects in cell culture and did not replicate after intraperitoneal injection into olive flounder. Therefore, VHSV particles in blue mussel might be in a non-infectious stage and the possibilities of VHSV transmission to fish under field conditions are scarce. PMID- 29160222 TI - Database documentation of marine mammal stranding and mortality: current status review and future prospects. AB - Databases are systematic tools to archive and manage information related to marine mammal stranding and mortality events. Stranding response networks, governmental authorities and non-governmental organizations have established regional or national stranding networks and have developed unique standard stranding response and necropsy protocols to document and track stranded marine mammal demographics, signalment and health data. The objectives of this study were to (1) describe and review the current status of marine mammal stranding and mortality databases worldwide, including the year established, types of database and their goals; and (2) summarize the geographic range included in the database, the number of cases recorded, accessibility, filter and display methods. Peer reviewed literature was searched, focussing on published databases of live and dead marine mammal strandings and mortality and information released from stranding response organizations (i.e. online updates, journal articles and annual stranding reports). Databases that were not published in the primary literature or recognized by government agencies were excluded. Based on these criteria, 10 marine mammal stranding and mortality databases were identified, and strandings and necropsy data found in these databases were evaluated. We discuss the results, limitations and future prospects of database development. Future prospects include the development and application of virtopsy, a new necropsy investigation tool. A centralized web-accessed database of all available postmortem multimedia from stranded marine mammals may eventually support marine conservation and policy decisions, which will allow the use of marine animals as sentinels of ecosystem health, working towards a 'One Ocean-One Health' ideal. PMID- 29160223 TI - Hematology and condition factor of tui chub and fathead minnow parasitized by nematode from Upper Klamath Lake, Oregon, USA. AB - This study evaluated the hematological profile and condition factor (Kn) of tui chub Siphateles bicolor and fathead minnow Pimephales promelas and their associations with larvae of Contracaecum sp. infection of the heart. A total of 30 tui chub and 17 fathead minnow were collected from Upper Klamath Lake, Oregon, USA, measured, and weighed and blood was drawn for hematological analysis. Nematode larvae parasitized tui chub with a prevalence of 50% and mean intensity of 1.40, while 11.8% of fathead minnow were parasitized at a mean intensity of 1.0. Non-parasitized tui chub were significantly larger than the parasitized fish, indicating that small fish could be easily predated by the definitive host, a piscivorous bird. Although the relatively large worm occupied a large portion of the atrium, the presence of the larvae did not affect tui chub Kn, possibly associated with low parasite intensity and a harmonic co-evolution. Only parasitized fathead minnow showed significant differences in red blood cell measurements (greater cell width and larger nuclei) compared to non-parasitized fish. Lymphocytes were the most common white blood cells found in tui chub, followed by neutrophils, monocytes, and periodic acid-Schiff positive granular leukocytes; in fathead minnow lymphocytes were followed by heterophils, monocytes, neutrophils and eosinophils. This study is the first report of Kn and description of blood cells and hematological parameters in these fish species. PMID- 29160224 TI - Colloidal paradigm in supercapattery electrode systems. AB - Among decades of development, electrochemical energy storage systems are now sorely in need of a new design paradigm at the nano size and ion level to satisfy the higher energy and power demands. In this review paper, we introduce a new colloidal electrode paradigm for supercapattery that integrates multiple-scale forms of matter, i.e. ion clusters, colloidal ions, and nanosized materials, into one colloid system, coupled with multiple interactions, i.e. electrostatic, van der Waals forces, and chemical bonding, thus leading to the formation of many redox reactive centers. This colloidal electrode not only keeps the original ionic nature in colloidal materials, but also creates a new attribute of high electroactivity. Colloidal supercapattery is a perfect application example of the novel colloidal electrode, leading to higher specific capacitance than traditional electrode materials. The high electroactivity of the colloidal electrode mainly comes from the contribution of exposed reactive centers, owing to the confinement effect of carbon and a binder matrix. Systematic and thorough research on the colloidal system will significantly promote the development of fundamental science and the progress of advanced energy storage technology. PMID- 29160225 TI - Phosphatidylserine targeted single-walled carbon nanotubes for photothermal ablation of bladder cancer. AB - Bladder cancer has a 60%-70% recurrence rate most likely due to any residual tumour left behind after a transurethral resection (TUR). Failure to completely resect the cancer can lead to recurrence and progression into higher grade tumours with metastatic potential. We present here a novel therapy to treat superficial tumours with the potential to decrease recurrence. The therapy is a heat-based approach in which bladder tumour specific single-walled carbon nanotubes (SWCNTs) are delivered intravesically at a very low dose (0.1 mg SWCNT per kg body weight) followed 24 h later by a short 30 s treatment with a 360 degrees near-infrared light that heats only the bound nanotubes. The energy density of the treatment was 50 J cm-2, and the power density that this treatment corresponds to is 1.7 W cm-2, which is relatively low. Nanotubes are specifically targeted to the tumour via the interaction of annexin V (AV) and phosphatidylserine, which is normally internalised on healthy tissue but externalised on tumours and the tumour vasculature. SWCNTs are conjugated to AV, which binds specifically to bladder cancer cells as confirmed in vitro and in vivo. Due to this specific localisation, NIR light can be used to heat the tumour while conserving the healthy bladder wall. In a short-term efficacy study in mice with orthotopic MB49 murine bladder tumours treated with the SWCNT-AV conjugate and NIR light, no tumours were visible on the bladder wall 24 h after NIR light treatment, and there was no damage to the bladder. In a separate survival study in mice with the same type of orthotopic tumours, there was a 50% cure rate at 116 days when the study was ended. At 116 days, no treatment toxicity was observed, and no nanotubes were detected in the clearance organs or bladder. PMID- 29160226 TI - Annealing cycles and the self-organization of functionalized colloids. AB - The self-assembly of functionalized (patchy) particles with directional interactions into target structures is still a challenge, despite the significant experimental advances in their synthesis. Self-assembly pathways are typically characterized by high energy barriers that hinder access to stable (equilibrium) structures. A possible strategy to tackle this challenge is to perform annealing cycles. By periodically switching on and off the inter-particle bonds, one expects to smooth-out the kinetic pathways and favor the assembly of targeted structures. Preliminary results have shown that the efficiency of annealing cycles depends strongly on their frequency. Here, we study numerically how this frequency-dependence scales with the strength of the directional interactions (size of the patch sigma). We use analytical arguments to show that the scaling results from the statistics of a random walk in configurational space. PMID- 29160227 TI - Enhanced green upconversion luminescence in ZnO:Er3+, Yb3+ on Mo6+ co-doping for temperature sensor application. AB - Erbium (Er) doped zinc oxide (ZnO) powder was prepared using co-precipitation method. Effect of ytterbium (Yb) and molybdenum (Mo) co-doping on upconversion emission was studied. The emission intensity has been enhanced on Yb co-doping due to energy transfer from Yb to Er. Co-doping Mo in ZnO:Er, Yb has brought a significant enhancement in green upconversion emission, when excited with 980 nm laser. The enhancement in green emission on Mo doping is because of the formation of [Formula: see text] dimer. Since ZnO is a material having high thermal stability, the enhanced green emission in Mo, Er, Yb doped ZnO can be used for temperature sensor applications. The variation in relative intensity ratio of 2H11/2 -> 4I15/2,4S3/2 -> 4I15/2 transition can be used to sense the sample temperature. PMID- 29160228 TI - Controlled Synthesis of Quantum Confined CsPbBr3 perovskite Nanocrystals under Ambient Condition. AB - Room temperature recrystallization is a simple and convenient method for synthesis of all-inorganic perovskite nanomaterials with excellent luminescent properties. However, the fast crystallization usually brings the colloidal stability and uncontrollable synthesis issues in the formation of all-inorganic perovskite. In the present study, we present a new strategy to prepare the quantum confined CsPbBr3 nanocrystals with controlled morphology under ambient condition. With the assist of fatty acid-capped precursor, the crystallization and the following growth rate can be retarded. Thanks to the retarded reaction, the morphology can be varied from nanowires to nanoplates and the thickness can be controlled from 5 to 7 monolayers by simply adjusting the amount of octylammonium cations and oleic acid. The nanoplates exhibit a higher photoluminescence quantum yield than the nanowires possibly due to fewer defects in the nanoplates. PMID- 29160229 TI - Improved localized surface plasmon resonance index sensitivity based on chemically-synthesized gold nanoparticles on indium tin oxide surfaces. AB - The results of this reported work indicated that gold nanoparticle arrays self assembled on indium tin oxide (ITO) glasses can obtain broader localized surface plasmon resonance (LSPR) wavelength range and higher sensitivity than the bare quartz. The results of surface electric field calculated using finite difference time domain showed that the electric field of nanoparticles on ITO glasses is enhanced and the repulsive forces within each particle is weakened. According to the dipolar interaction mechanism, a weakened repulsive forces within each particle lead to a lower resonance frequency and a strong redshift of the LSPR spectra. PMID- 29160230 TI - Paediatric interventional cardiology in Costa Rica: diagnostic reference levels and estimation of population dose. AB - The goal of the present study was to propose a set of national diagnostic reference levels (DRLs) in Costa Rica for paediatric interventional cardiology (IC) procedures classified by age and weight and to estimate the collective dose of the paediatric population from these intervention practices. The data collection period was May 2016 to May 2017. The third quartile of patient dose data distributions for kerma-area product (KAP) values was set as the national DRLs. A sample of 154 paediatric IC procedures (collected in the national paediatric hospital with a single x-ray system) was used and divided into four age ranges and five weight ranges. The national DRLs obtained for KAPs by age range were 1.79 Gy cm2 (<1 year) to 23.0 Gy cm2 (10-15 years). The national DRLs obtained for KAPs by weight range were 1.0 Gy cm2 (<10 kg) to 49.6 Gy cm2 (50-79 kg). The contribution to the collective dose of the population of Costa Rica amounted to 0.78 person Sv. PMID- 29160231 TI - Hydrothermal synthesis of stable metallic 1T phase WS2 nanosheets for thermoelectric application. AB - Two-dimensional materials have gained great attention as a promising thermoelectric (TE) material due to their unique density of state with confined electrons and holes. Here, we synthesized 1T phase tungsten disulfide (WS2) nanosheets with high TE performance via the hydrothermal method. Flexible WS2 nanosheets restacked thin films were fabricated by employing the vacuum filtration technique. The measured electrical conductivity was 45 S cm-1 with a Seebeck coefficient of +30 MUV K-1 at room temperature, indicating a p-type characteristic. Furthermore, the TE performance could be further improved by thermal annealing treatment. It was found the electrical conductivity could be enhanced 2.7 times without sacrificing the Seebeck coefficient, resulting in the power factor of 9.40 MUW m-1 K-2. Moreover, such 1T phase WS2 nanosheets possess high phase stability since the TE properties maintained constant at least half one year in the air atmosphere. Notably, other kinds of 1T phase transitional metal dichalcogenides (TMDCs) with excellent TE performance also could be imitated by using the procedure in this work. Finally, we believe a variety of materials based on 1T phase TMDCs nanosheets have great potential as candidate for future TE applications. PMID- 29160233 TI - COMET strongly supported the development and implementation of medium-term topical research roadmaps consistent with the ALLIANCE Strategic Research Agenda. AB - The ALLIANCE6 Strategic Research Agenda (SRA) initiated by the STAR7 Network of Excellence and integrated in the research strategy implemented by the COMET consortium, defines a long-term vision of the needs for, and implementation of, research in radioecology. This reference document, reflecting views from many stakeholders groups and researchers, serves as an input to those responsible for defining EU research call topics through the ALLIANCE SRA statement delivered each year to the EJP-CONCERT8 (2015-2020). This statement highlights a focused number of priorities for funding. Research in radioecology and related sciences is justified by various drivers, such as policy changes, scientific advances and knowledge gaps, radiological risk perception by the public, and a growing awareness of interconnections between human and ecosystem health. The SRA is being complemented by topical roadmaps that have been initiated by the COMET9 EC funded project, with the help and endorsement of the ALLIANCE. The strategy underlying roadmap development is driven by the need for improved mechanistic understanding across radioecology. By meeting this need, we can provide fit-for purpose human and environmental impact/risk assessments in support of the protection of man and the environment in interaction with society and for the three exposure situations defined by the ICRP (i.e., planned, existing and emergency). Within the framework of the EJP-CONCERT the development of a joint roadmap is under discussion among all the European research platforms and will highlight the major research needs for the whole radiation protection field and how these are likely to be addressed by 2030. PMID- 29160232 TI - Direct electrical stimulation of human cortex evokes high gamma activity that predicts conscious somatosensory perception. AB - OBJECTIVE: Direct electrical stimulation (DES) is a clinical gold standard for human brain mapping and readily evokes conscious percepts, yet the neurophysiological changes underlying these percepts are not well understood. APPROACH: To determine the neural correlates of DES, we stimulated the somatosensory cortex of ten human participants at frequency-amplitude combinations that both elicited and failed to elicit conscious percepts, meanwhile recording neural activity directly surrounding the stimulation site. We then compared the neural activity of perceived trials to that of non-perceived trials. MAIN RESULTS: We found that stimulation evokes distributed high gamma activity, which correlates with conscious perception better than stimulation parameters themselves. SIGNIFICANCE: Our findings suggest that high gamma activity is a reliable biomarker for perception evoked by both natural and electrical stimuli. PMID- 29160234 TI - Sustainability and integration of radioecology-position paper. AB - This position paper gives an overview of how the COMET project (COordination and iMplementation of a pan-European instrumenT for radioecology, a combined Collaborative Project and Coordination and Support Action under the EC/Euratom 7th Framework Programme) contributed to the integration and sustainability of radioecology in Europe via its support to and interaction with the European Radioecology ALLIANCE. COMET built upon the foundations laid by the FP7 project STAR (Strategic Network for Integrating Radioecology) Network of Excellence in radioecology. In close association with the ALLIANCE, and based on the Strategic Research Agenda (SRA), COMET developed innovative mechanisms for joint programming and implementation of radioecological research. To facilitate and foster future integration under a common federating structure, research activities developed within COMET were targeted at radioecological research needs identified in the SRA. Furthermore, COMET maintained and developed strong mechanisms for knowledge exchange, dissemination and training to enhance and maintain European capacity, competence and skills in radioecology. In the short term the work to promote radioecology will continue under the H2020 project EJP CONCERT (European Joint Programme for the Integration of Radiation Protection Research). The EJP-CONCERT project (2015-2020) aims to develop a sustainable structure for promoting and administering joint programming and open research calls in the field of radiation protection research for Europe. In the longer term, radioecological research will be facilitated by the ALLIANCE. External funding is, however, required in order to be able to answer emerging research needs. PMID- 29160235 TI - Possibile half-metallicity and variable range hopping transport in Sb-substituted Fe2TiSn Heusler alloys. AB - Investigation of magnetotransport properties on Fe2TiSn1 xSbx with 0 <= x <= 0.6 are presented in this paper. The substitution of Sb in place of Sn decreases the antisite disorder as evident from X ray diffraction patterns as well as from transport properties measurement. The much-disputed upturn in low temperature electrical resistivity of Fe2TiSn has been demonstrated to be a result of weak localization induced by antisite disorder. With increased Sb substitution (>= 25%) the metallic transport behaviour of Fe2TiSn changes to semiconductor-like. At low temperature the carrier transport in such compositions occur via variable range hopping mechanism. Moreover, a systematic increase in the anomalous Hall voltage is observed with increasing Sb content, attributable to a side jump or Berry phase curvature effect. Electrical resistivity in the high temperature regime hints towards half metallicity of the system. Our Ab-initio electronic structure calculations using the GGA formalism further supports the results of our magnetotransport study. PMID- 29160236 TI - Radioecology in Europe. PMID- 29160237 TI - Chemical vapor deposition growth of boron-carbon-nitrogen layers from methylamine borane thermolysis products. AB - This work investigates the growth of B-C-N layers by chemical vapor deposition using methylamine borane (MeAB) as the single-source precursor. MeAB has been synthesized and characterized, paying particular attention to the analysis of its thermolysis products, which are the gaseous precursors for B-C-N growth. Samples have been grown on Cu foils and transferred onto different substrates for their morphological, structural, chemical, electronic and optical characterizations. The results of these characterizations indicate a segregation of h-BN and graphene-like (Gr) domains. However, there is an important presence of B and N interactions with C at the Gr borders, and of C interacting at the h-BN-edges, respectively, in the obtained nano-layers. In particular, there is a significant presence of C-N bonds, at Gr/h-BN borders and in the form of N doping of Gr domains. The overall B:C:N contents in the layers is close to 1:3:1.5. A careful analysis of the optical bandgap determination of the obtained B-C-N layers is presented, discussed and compared with previous seminal works with samples of similar composition. PMID- 29160238 TI - Thermal transport in epitaxial Si1-x Ge x alloy nanowires with varying composition and morphology. AB - We report on structural, compositional, and thermal characterization of self assembled in-plane epitaxial Si1-x Ge x alloy nanowires grown by molecular beam epitaxy on Si (001) substrates. The thermal properties were studied by means of scanning thermal microscopy (SThM), while the microstructural characteristics, the spatial distribution of the elemental composition of the alloy nanowires and the sample surface were investigated by transmission electron microscopy and energy dispersive x-ray microanalysis. We provide new insights regarding the morphology of the in-plane nanostructures, their size-dependent gradient chemical composition, and the formation of a 5 nm thick wetting layer on the Si substrate surface. In addition, we directly probe heat transfer between a heated scanning probe sensor and Si1-x Ge x alloy nanowires of different morphological characteristics and we quantify their thermal resistance variations. We correlate the variations of the thermal signal to the dependence of the heat spreading with the cross-sectional geometry of the nanowires using finite element method simulations. With this method we determine the thermal conductivity of the nanowires with values in the range of 2-3 W m-1 K-1. These results provide valuable information in growth processes and show the great capability of the SThM technique in ambient environment for nanoscale thermal studies, otherwise not possible using conventional techniques. PMID- 29160239 TI - Education and training in radioecology during the EU-COMET project-successes and suggestions for the future. AB - The 2014 Strategic Research Agenda (SRA) for Radioecology identified the key challenge in education and training (E&T) as being 'to maintain and develop a skilled workforce in Europe and world-wide, through university candidates and professionals trained within radioecology' since 'scientific research in radioecology and application of that knowledge ... requires scientists and workers with adequate competence and appropriate skills.' Radioecology is a multidisciplinary science and E&T is needed by both students and professionals within research, industry and radiation protection. In order to address these needs, the EU COMET project has developed an E&T web platform and arranged a number of field courses, training courses, PhD and MSc courses, refresher courses and workshops, drawing on the COMET consortium to assemble relevant experts. In addition, COMET has been engaged in discussions with stakeholders for more long term solutions to maintain the sustainability of radioecology E&T after the end of the project. Despite much progress in some areas, many of the challenges outlined in the 2014 SRA remain, mainly due to the lack of sustainable dedicated funding. Future plans within the ALLIANCE radioecology platform and the CONCERT European Joint Programme for the Integration of Radiation Protection Research must urgently address this lack of sustainability if radioecological competence is to be maintained in Europe. PMID- 29160241 TI - Evidence for confinement induced phase separation in ethanol-water mixture: a positron annihilation study. AB - We report an experimental evidence for the phase separation of ethanol-water mixture confined in mesoporous silica with different pore size using positron annihilation lifetime spectroscopy (PALS). A bulk-like liquid in the core of the pore and a distinct interfacial region near the pore surface have been identified based on ortho-positronium lifetime components. The lifetime corresponding to the core liquid shows similar behavior to the bulk liquid mixture while the interfacial lifetime shows an abrupt rise within a particular range of ethanol concentration depending on the pore size. This abrupt increase is attributed to the appearance of excess free-volume near the interfacial region. The excess free volume is originated due to microphase separation of confined ethanol-water primarily at the vicinity of the pore wall. We envisage that probing free-volume changes at the interface using PALS is a sensitive way to investigate microphase separation under nanoconfinement. PMID- 29160242 TI - Angular-dependent magnetoresistance study in Ca0.73La0.27FeAs2: a "parent" compound of 112-type iron pnictide superconductors. AB - We report a study of angular-dependent magnetoresistance (AMR) with the magnetic field rotated in the plane perpendicular to the current on a Ca0.73La0.27FeAs2 single crystal, which is regarded as a "parent" compound of 112-type iron pnictide superconductors. A pronounced AMR with twofold symmetry is observed, signifying the highly anisotropic Fermi surface. By further analyzing the AMR data, we find that the Fermi surface above the structural/antiferromagnetic (AFM) transition (Ts/TN) is quasi-two-dimensional (2D), as revealed by the 2D scaling behavior of the AMR, Deltarho/rho(0) (H, theta)=Deltarho/rho(0) (MU0Hcostheta), theta being the magnetic field angle with respect to the c axis. While such a 2D scaling becomes invalid at temperatures below Ts/TN, the three-dimensional (3D) scaling approach by inclusion of the anisotropy of Fermi surface is efficient, indicating that the appearance of 3D Fermi surface contributed to the anisotropic electronic transport. Compared with other experimental observations, we suspect that the additional 3D hole pocket (generated by the Ca d orbital and As1 pz orbital) around the Gamma point in CaFeAs2 will disappear in the heavily electron doped regime, and moreover, the Fermi surface should be reconstructed across the structural/AFM transition. Besides, a quasi-linear in-plane magnetoresistance is observed at low temperatures and its possible origins are also discussed. Our results provide more information to further understand the electronic structure of 112-type IBSs. PMID- 29160240 TI - Remapping cortical modulation for electrocorticographic brain-computer interfaces: a somatotopy-based approach in individuals with upper-limb paralysis. AB - OBJECTIVE: Brain-computer interface (BCI) technology aims to provide individuals with paralysis a means to restore function. Electrocorticography (ECoG) uses disc electrodes placed on either the surface of the dura or the cortex to record field potential activity. ECoG has been proposed as a viable neural recording modality for BCI systems, potentially providing stable, long-term recordings of cortical activity with high spatial and temporal resolution. Previously we have demonstrated that a subject with spinal cord injury (SCI) could control an ECoG based BCI system with up to three degrees of freedom (Wang et al 2013 PLoS One). Here, we expand upon these findings by including brain-control results from two additional subjects with upper-limb paralysis due to amyotrophic lateral sclerosis and brachial plexus injury, and investigate the potential of motor and somatosensory cortical areas to enable BCI control. APPROACH: Individuals were implanted with high-density ECoG electrode grids over sensorimotor cortical areas for less than 30 d. Subjects were trained to control a BCI by employing a somatotopic control strategy where high-gamma activity from attempted arm and hand movements drove the velocity of a cursor. MAIN RESULTS: Participants were capable of generating robust cortical modulation that was differentiable across attempted arm and hand movements of their paralyzed limb. Furthermore, all subjects were capable of voluntarily modulating this activity to control movement of a computer cursor with up to three degrees of freedom using the somatotopic control strategy. Additionally, for those subjects with electrode coverage of somatosensory cortex, we found that somatosensory cortex was capable of supporting ECoG-based BCI control. SIGNIFICANCE: These results demonstrate the feasibility of ECoG-based BCI systems for individuals with paralysis as well as highlight some of the key challenges that must be overcome before such systems are translated to the clinical realm. ClinicalTrials.gov Identifier: NCT01393444. PMID- 29160243 TI - Formation and magnetic properties of InFeP:Ag nanorods fabricated with noble metal Ag using an ion milling method. AB - The formation, including the density and height of the InFeP:Ag nanorods doped with noble metal Ag using an ion milling method, was preponderantly determined from transmission electron microscopy and x-ray diffraction analyses. We investigate, in particular, the enhanced ferromagnetism of the well-aligned InFeP:Ag nanorods. Auger electron spectroscopy and x-ray photoelectron spectroscopy measurements were carried out in order to investigate the incorporation of Ag and to verify the local chemical bonding of the InFeP:Ag nanorods. The variation of FWHM for the double-crystal x-ray rocking curve and triple-axis diffraction peaks demonstrates that noble metal Ag is incorporated into the InFeP:Ag nanorods. The noticeable ferromagnetic signature (M-H curve) of the InFeP:Ag nanorods is observed and T c persists up to almost 350 K (3.9 * 10-4 emu g-1), as determined by temperature-dependence magnetization (M-T curve) measurements. This study suggests that the InFeP:Ag nanorods should be a potential candidate for the application of spintronic devices. PMID- 29160245 TI - Evaluation of Serologic Tests For Syphilis Using Drops of Blood From Puncture of the Finger. PMID- 29160246 TI - Vegetable Oils and Acneform Lesions. PMID- 29160247 TI - Reaction of Patients Towards V. D. Infection. PMID- 29160248 TI - Betamethasone 17-valerate and Hydrocortisone Under Occulsive Dressing. PMID- 29160249 TI - "Angiosarcoma". PMID- 29160250 TI - Multiple Hair Defects. PMID- 29160251 TI - A Study of 100 Cases of Pemphigus-Clinical Features. PMID- 29160252 TI - Serum Copper Levels in Vitiligo. PMID- 29160253 TI - Venereal Diseases in Animals. PMID- 29160254 TI - Association Oration. PMID- 29160255 TI - A New Year Greeting. PMID- 29160256 TI - Presidental Address. PMID- 29160257 TI - Editorial. PMID- 29160259 TI - Steatocystoma Multiplex. PMID- 29160258 TI - Familial Benign Chronic Pemphigus (hailey & Hailey). PMID- 29160260 TI - Incontinentia Pigmenti. PMID- 29160261 TI - Ichthyosis Hystrix. AB - Three cases of ichthyosis hystrix have been reported in the same family, a very rare occurrence. PMID- 29160262 TI - Harlequin Baby. PMID- 29160263 TI - Sex Problems Treated With Indigenous Drugs. PMID- 29160264 TI - Trial With Lepsulmin Ointment In Ulcers of Leprosy. PMID- 29160265 TI - Association Activities. PMID- 29160266 TI - Annual Report For The Year 1969. PMID- 29160267 TI - Sampling of Blood From Finger Puncture in Blotting Paper Discs (Rondelles) For Fluorescent Treponemal Antibody (F. T. A.) Tests For Treponematoses. PMID- 29160268 TI - Incidence of Dermatophytosis in Chandigarh and Surrounding Areas. PMID- 29160269 TI - History of Exposure To Infection in Venereal Disease Patients. PMID- 29160270 TI - Mucopolysaccharide Changes in Lichen Pianus. PMID- 29160271 TI - White Piedra in India. PMID- 29160272 TI - Naevus Pigmentosus et Pilosus. PMID- 29160273 TI - Development of Psoriasis in Areas of Vitiligo. PMID- 29160274 TI - Cluiton's Joints - A Case Report. PMID- 29160275 TI - A Review of Cysticercosis Cel- Lulosae with Two Case Reports. PMID- 29160276 TI - Dracontiasis. PMID- 29160277 TI - Histopathological Changes of Reticular Fibers in Different Types of Lichen Planus. PMID- 29160279 TI - Clinical and Mycological Study of Superficial Fungal Infections at Government General Hospital, Guntur and their Response to Treatment with Hamycin, Dermostatin and Dermamycin. PMID- 29160278 TI - Leprosy. PMID- 29160280 TI - A Study on the Ecology and Treatment of Dermatophytosis in Delhi. PMID- 29160281 TI - Association of Psoriasis and Lupus Erythematosus. PMID- 29160282 TI - Rimactane in Acute Gonococcal Urethritis. PMID- 29160283 TI - Letters to the Editor (Correspondence). PMID- 29160285 TI - A Study of 100 Patients of Pemphigus-experiences of the Treatment. PMID- 29160284 TI - Impotency in Male Diabetics. PMID- 29160286 TI - Lichen Planus: Histopathological Study of 57 Cases. PMID- 29160287 TI - Socio-physical Factors and Incidence of V. D. PMID- 29160288 TI - Vallergan an Adjuvant in the Management of Itching Dermatoses. PMID- 29160289 TI - A Study on the Trichophyton Simii Infections in Man at Delhi. PMID- 29160290 TI - A Study of Dermatomycoses. PMID- 29160291 TI - Chromoblastomycosis in India. PMID- 29160292 TI - Melanosis Caused by Hair Oils. PMID- 29160293 TI - Corticosteroids in Medicine. PMID- 29160294 TI - Urticaria Pigmentosa. PMID- 29160295 TI - Condylomata Lata Involving Face. PMID- 29160296 TI - Structure of the fission yeast S. pombe telomeric Tpz1-Poz1-Rap1 complex. AB - Telomeric shelterin complex caps chromosome ends and plays a crucial role in telomere maintenance and protection. In the fission yeast Schizosaccharomyces pombe, shelterin is composed of telomeric single- and double-stranded DNA-binding protein subcomplexes Pot1-Tpz1 and Taz1-Rap1, which are bridged by their interacting protein Poz1. However, the structure of Poz1 and how Poz1 functions as an interaction hub in the shelterin complex remain unclear. Here we report the crystal structure of Poz1 in complex with Poz1-binding motifs of Tpz1 and Rap1. The crystal structure shows that Poz1 employs two different binding surfaces to interact with Tpz1 and Rap1. Unexpectedly, the structure also reveals that Poz1 adopts a dimeric conformation. Mutational analyses suggest that proper interactions between Tpz1, Poz1, and Rap1 in the shelterin core complex are required for telomere length homeostasis and heterochromatin structure maintenance at telomeres. Structural resemblance between Poz1 and the TRFH domains of other shelterin proteins in fission yeast and humans suggests a model for the evolution of shelterin proteins. PMID- 29160298 TI - TDP2, TOP2, and SUMO: what is ZATT about? AB - Recently, ZATT (also known as ZNF451 or Zpf451) was reported by Schellenberg et al. to aid the removal of Topoisomerase II cleavage complexes by stimulating the phosphodiesterase activity of Tyrosyl DNA Phosphodiesterase 2. Although the full implication of this discovery is unknown, it will help us understand how cells respond to topoisomerase-induced genome damage and chemotherapeutic topoisomerase 'poisons'. PMID- 29160299 TI - Understanding the Legal and Regulatory Framework Governing Physician Collective Bargaining. PMID- 29160297 TI - Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex. AB - Telomeres are nucleoprotein complexes that play essential roles in protecting chromosome ends. Mammalian telomeres consist of repetitive DNA sequences bound by the shelterin complex. In this complex, the POT1-TPP1 heterodimer binds to single stranded telomeric DNAs, while TRF1 and TRF2-RAP1 interact with double-stranded telomeric DNAs. TIN2, the linchpin of this complex, simultaneously interacts with TRF1, TRF2, and TPP1 to mediate the stable assembly of the shelterin complex. However, the molecular mechanism by which TIN2 interacts with these proteins to orchestrate telomere protection remains poorly understood. Here, we report the crystal structure of the N-terminal domain of TIN2 in complex with TIN2-binding motifs from TPP1 and TRF2, revealing how TIN2 interacts cooperatively with TPP1 and TRF2. Unexpectedly, TIN2 contains a telomeric repeat factor homology (TRFH) like domain that functions as a protein-protein interaction platform. Structure based mutagenesis analyses suggest that TIN2 plays an important role in maintaining the stable shelterin complex required for proper telomere end protection. PMID- 29160300 TI - Genome-wide association study identifies the common variants in CYP3A4 and CYP3A5 responsible for variation in tacrolimus trough concentration in Caucasian kidney transplant recipients. AB - The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study. Only CYP3A4*22 was identified and no additional variants were genome-wide significant. Additional high allele frequency genetic variants with strong genetic effects associated with TAC trough variability are unlikely to be associated with TAC variation in the EA population. These data suggest that low allele frequency variants, identified by DNA sequencing, should be evaluated and may identify additional variants that contribute to TAC pharmacokinetic variability. PMID- 29160301 TI - New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation. AB - Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin alpha9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role. PMID- 29160302 TI - Role of CYP24A1, VDR and GC gene polymorphisms on deferasirox pharmacokinetics and clinical outcomes. AB - beta-Thalassemia patients develop deficiency in vitamin D absorption and liver hydroxylation, resulting in extremely low calcitriol levels. We explored the role of single-nucleotide polymorphisms (SNPs) involved in vitamin D metabolism, transport and activity on deferasirox pharmacokinetics and outcomes (effectiveness trough levels (Ctrough) and the area under the curve (AUC) cutoffs of 20 MUg ml-1 and 360 MUg ml-1 h-1, respectively; nonresponse AUC limit of 250 MUg ml-1 h-1). Ninety-nine beta-thalassemic patients were enrolled. Drug plasma Ctrough and AUC were measured by the high-performance liquid chromatography system coupled with an ultraviolet determination method. Allelic discrimination for VDR, CYP24A1, CYP27B1 and GC gene SNPs was performed by real-time PCR. CYP24A1 22776 TT significantly influenced Cmin and negatively predicted it in regression analysis. CYP24A1 3999 CC was associated with Ctrough and Cmin and was a negative predictor of Tmax, whereas CYP24A1 8620 GG seemed to have a role in Ctrough, AUC, t1/2 and Cmin, and was an AUC negative predictor factor. Considering treatment outcome, Cdx2 and GC 1296 were retained in regression analysis as AUC efficacy cutoff negative predictors. PMID- 29160303 TI - The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro. AB - Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials. Magnetic resonance imaging assessments of LFC were conducted in a subset of patients (n=296). Analyses showed alpha-corrected significant increases in change from baseline in AST (P=0.0004) and nominal increases in ALT (P=0.019), and LFC (P=0.035) for PNPLA3 (148M/M) genotypes in the BIL arm at 26 weeks but no significant associations in GL. PNPLA3 (148M/M) was also associated with increases in total cholesterol (P=0.014) and low-density lipoprotein cholesterol (P=0.005) but not with hemoglobin A1c or TG. T2D patients with the PNPLA3 (148M/M) genotype treated with BIL may be more susceptible to increased liver fat deposition. The current data provide further insights into the biological role of PNPLA3 in lipid metabolism. PMID- 29160305 TI - A brief visit from a red and extremely elongated interstellar asteroid. AB - None of the approximately 750,000 known asteroids and comets in the Solar System is thought to have originated outside it, despite models of the formation of planetary systems suggesting that orbital migration of giant planets ejects a large fraction of the original planetesimals into interstellar space. The high predicted number density of icy interstellar objects (2.4 * 10-4 per cubic astronomical unit) suggests that some should have been detected, yet hitherto none has been seen. Many decades of asteroid and comet characterization have yielded formation models that explain the mass distribution, chemical abundances and planetary configuration of the Solar System today, but there has been no way of telling whether the Solar System is typical of planetary systems. Here we report observations and analysis of the object 1I/2017 U1 ('Oumuamua) that demonstrate its extrasolar trajectory, and that thus enable comparisons to be made between material from another planetary system and from our own. Our observations during the brief visit by the object to the inner Solar System reveal it to be asteroidal, with no hint of cometary activity despite an approach within 0.25 astronomical units of the Sun. Spectroscopic measurements show that the surface of the object is spectrally red, consistent with comets or organic rich asteroids that reside within the Solar System. Light-curve observations indicate that the object has an extremely oblong shape, with a length about ten times its width, and a mean radius of about 102 metres assuming an albedo of 0.04. No known objects in the Solar System have such extreme dimensions. The presence of 'Oumuamua in the Solar System suggests that previous estimates of the number density of interstellar objects, based on the assumption that all such objects were cometary, were pessimistically low. Planned upgrades to contemporary asteroid survey instruments and improved data processing techniques are likely to result in the detection of more interstellar objects in the coming years. PMID- 29160304 TI - IL-11 is a crucial determinant of cardiovascular fibrosis. AB - Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor beta1 (TGFbeta1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFbeta1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFbeta1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases. PMID- 29160306 TI - Discovery of a big void in Khufu's Pyramid by observation of cosmic-ray muons. AB - The Great Pyramid, or Khufu's Pyramid, was built on the Giza plateau in Egypt during the fourth dynasty by the pharaoh Khufu (Cheops), who reigned from 2509 bc to 2483 bc. Despite being one of the oldest and largest monuments on Earth, there is no consensus about how it was built. To understand its internal structure better, we imaged the pyramid using muons, which are by-products of cosmic rays that are only partially absorbed by stone. The resulting cosmic-ray muon radiography allows us to visualize the known and any unknown voids in the pyramid in a non-invasive way. Here we report the discovery of a large void (with a cross section similar to that of the Grand Gallery and a minimum length of 30 metres) situated above the Grand Gallery. This constitutes the first major inner structure found in the Great Pyramid since the nineteenth century. The void, named ScanPyramids' Big Void, was first observed with nuclear emulsion films installed in the Queen's chamber, then confirmed with scintillator hodoscopes set up in the same chamber and finally re-confirmed with gas detectors outside the pyramid. This large void has therefore been detected with high confidence by three different muon detection technologies and three independent analyses. These results constitute a breakthrough for the understanding of the internal structure of Khufu's Pyramid. Although there is currently no information about the intended purpose of this void, these findings show how modern particle physics can shed new light on the world's archaeological heritage. PMID- 29160307 TI - A non-canonical Notch complex regulates adherens junctions and vascular barrier function. AB - The vascular barrier that separates blood from tissues is actively regulated by the endothelium and is essential for transport, inflammation, and haemostasis. Haemodynamic shear stress plays a critical role in maintaining endothelial barrier function, but how this occurs remains unknown. Here we use an engineered organotypic model of perfused microvessels to show that activation of the transmembrane receptor NOTCH1 directly regulates vascular barrier function through a non-canonical, transcription-independent signalling mechanism that drives assembly of adherens junctions, and confirm these findings in mouse models. Shear stress triggers DLL4-dependent proteolytic activation of NOTCH1 to expose the transmembrane domain of NOTCH1. This domain mediates establishment of the endothelial barrier; expression of the transmembrane domain of NOTCH1 is sufficient to rescue defects in barrier function induced by knockout of NOTCH1. The transmembrane domain restores barrier function by catalysing the formation of a receptor complex in the plasma membrane consisting of vascular endothelial cadherin, the transmembrane protein tyrosine phosphatase LAR, and the RAC1 guanidine-exchange factor TRIO. This complex activates RAC1 to drive assembly of adherens junctions and establish barrier function. Canonical transcriptional signalling via Notch is highly conserved in metazoans and is required for many processes in vascular development, including arterial-venous differentiation, angiogenesis and remodelling. We establish the existence of a non-canonical cortical NOTCH1 signalling pathway that regulates vascular barrier function, and thus provide a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodelling. PMID- 29160311 TI - Microstructure variations induced by excess PbX2 or AX within perovskite thin films. AB - We systematically investigated the impact of stoichiometric ratio variation between PbX2 and AX on hybrid perovskite films from the perspective of microstructure, especially on the plane stacking directions, using the two dimensional synchrotron radiation grazing incidence wide-angle X-ray scattering (GIWAXS) technique. The tuned crystal plane stacking in perovskite films can consequently enlighten further explorations about the relationship between microstructure and solar cell performance. PMID- 29160312 TI - pH-Dependent spin state population and 19F NMR chemical shift via remote ligand protonation in an iron(ii) complex. AB - An FeII complex that features a pH-dependent spin state population, by virtue of a variable ligand protonation state, is described. This behavior leads to a highly pH-dependent 19F NMR chemical shift with a sensitivity of 13.9(5) ppm per pH unit at 37 degrees C, thereby demonstrating the potential utility of the complex as a 19F chemical shift-based pH sensor. PMID- 29160308 TI - Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. AB - The spontaneous deamination of cytosine is a major source of transitions from C*G to T*A base pairs, which account for half of known pathogenic point mutations in humans. The ability to efficiently convert targeted A*T base pairs to G*C could therefore advance the study and treatment of genetic diseases. The deamination of adenine yields inosine, which is treated as guanine by polymerases, but no enzymes are known to deaminate adenine in DNA. Here we describe adenine base editors (ABEs) that mediate the conversion of A*T to G*C in genomic DNA. We evolved a transfer RNA adenosine deaminase to operate on DNA when fused to a catalytically impaired CRISPR-Cas9 mutant. Extensive directed evolution and protein engineering resulted in seventh-generation ABEs that convert targeted A*T base pairs efficiently to G*C (approximately 50% efficiency in human cells) with high product purity (typically at least 99.9%) and low rates of indels (typically no more than 0.1%). ABEs introduce point mutations more efficiently and cleanly, and with less off-target genome modification, than a current Cas9 nuclease-based method, and can install disease-correcting or disease-suppressing mutations in human cells. Together with previous base editors, ABEs enable the direct, programmable introduction of all four transition mutations without double stranded DNA cleavage. PMID- 29160313 TI - Matrix-isolation and comparative far-IR investigation of free linear [Cl3]- and a series of alkali trichlorides. AB - Here we discuss the reaction products of laser ablated alkali chlorides and elemental chlorine. Salt ablation using this technique combined with matrix isolation spectroscopy allows for the formation and characterization of novel anionic species. The laser ablation of solid MCl with M = Cs, Rb, and K in the presence of Cl2 produced free [Cl3]- ions which were isolated in solid noble-gas matrices. For M = Cs, Rb, K, and Na, the ion pairs M+[Cl3]- are the main reaction products. Trends in the formation and bonding of these trichloride anions will be discussed. In contrast to the trifluoride analogues, the isolated ion pairs M+[Cl3]- feature a systematic distortion due to metal coordination. PMID- 29160309 TI - Structure of PINK1 in complex with its substrate ubiquitin. AB - Autosomal-recessive juvenile Parkinsonism (AR-JP) is caused by mutations in a number of PARK genes, in particular the genes encoding the E3 ubiquitin ligase Parkin (PARK2, also known as PRKN) and its upstream protein kinase PINK1 (also known as PARK6). PINK1 phosphorylates both ubiquitin and the ubiquitin-like domain of Parkin on structurally protected Ser65 residues, triggering mitophagy. Here we report a crystal structure of a nanobody-stabilized complex containing Pediculus humanus corporis (Ph)PINK1 bound to ubiquitin in the 'C-terminally retracted' (Ub-CR) conformation. The structure reveals many peculiarities of PINK1, including the architecture of the C-terminal region, and reveals how the N lobe of PINK1 binds ubiquitin via a unique insertion. The flexible Ser65 loop in the Ub-CR conformation contacts the activation segment, facilitating placement of Ser65 in a phosphate-accepting position. The structure also explains how autophosphorylation in the N lobe stabilizes structurally and functionally important insertions, and reveals the molecular basis of AR-JP-causing mutations, some of which disrupt ubiquitin binding. PMID- 29160314 TI - A bimetallic carbide derived from a MOF precursor for increasing electrocatalytic oxygen evolution activity. AB - We have successfully obtained heterometallic oxides and/or carbides that are calcined from a new bimetallic metal-organic framework (InOF-16, [(Me2NH2)2][In3(BTC)5Co2(DMF)6].solvent). Through different thermal treatments, the change in the resultant composition has been observed, thus leading to the product of InOF-16-Ar/O2-T (T = 550, 700 and 1000 degrees C) for efficient oxygen evolving reactions. PMID- 29160310 TI - Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. AB - Treatments that target immune checkpoints, such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1, have been approved for treating human cancers with durable clinical benefit. However, many patients with cancer fail to respond to compounds that target the PD-1 and PD-L1 interaction, and the underlying mechanism(s) is not well understood. Recent studies revealed that response to PD-1-PD-L1 blockade might correlate with PD-L1 expression levels in tumour cells. Hence, it is important to understand the mechanistic pathways that control PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1-PD-L1 blockade in patients with cancer. Here we show that PD-L1 protein abundance is regulated by cyclin D-CDK4 and the cullin 3-SPOP E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 (hereafter CDK4/6) in vivo increases PD L1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of speckle type POZ protein (SPOP) and thereby promoting SPOP degradation by the anaphase promoting complex activator FZR1. Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumour-infiltrating lymphocytes in mouse tumours and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhances tumour regression and markedly improves overall survival rates in mouse tumour models. Our study uncovers a novel molecular mechanism for regulating PD-L1 protein stability by a cell cycle kinase and reveals the potential for using combination treatment with CDK4/6 inhibitors and PD-1-PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers. PMID- 29160321 TI - UV photodissociation dynamics of CHI2Cl and its role as a photolytic precursor for a chlorinated Criegee intermediate. AB - Photolysis of geminal diiodoalkanes in the presence of molecular oxygen has become an established route to the laboratory production of several Criegee intermediates, and such compounds also have marine sources. Here, we explore the role that the trihaloalkane, chlorodiiodomethane (CHI2Cl), may play as a photolytic precursor for the chlorinated Criegee intermediate ClCHOO. CHI2Cl has been synthesized and its UV absorption spectrum measured; relative to that of CH2I2 the spectrum is shifted to longer wavelength and the photolysis lifetime is calculated to be less than two minutes. The photodissociation dynamics have been investigated using DC slice imaging, probing ground state I and spin-orbit excited I* atoms with 2 + 1 REMPI and single-photon VUV ionization. Total translational energy distributions are bimodal for I atoms and unimodal for I*, with around 72% of the available energy partitioned in to the internal degrees of freedom of the CHICl radical product, independent of photolysis wavelength. A bond dissociation energy of D0 = 1.73 +/- 0.11 eV is inferred from the wavelength dependence of the translational energy release, which is slightly weaker than typical C-I bonds. Analysis of the photofragment angular distributions indicate dissociation is prompt and occurs primarily via transitions to states of A'' symmetry. Complementary high-level MRCI calculations, including spin-orbit coupling, have been performed to characterize the excited states and confirm that states of A'' symmetry with highly mixed singlet and triplet character are predominantly responsible for the absorption spectrum. Transient absorption spectroscopy has been used to measure the absorption spectrum of ClCHOO produced from the reaction of CHICl with O2 over the range 345-440 nm. The absorption spectrum, tentatively assigned to the syn conformer, is at shorter wavelengths relative to that of CH2OO and shows far weaker vibrational structure. PMID- 29160324 TI - Atomic layer MoS2-graphene van der Waals heterostructure nanomechanical resonators. AB - Heterostructures play significant roles in modern semiconductor devices and micro/nanosystems in a plethora of applications in electronics, optoelectronics, and transducers. While state-of-the-art heterostructures often involve stacks of crystalline epi-layers each down to a few nanometers thick, the intriguing limit would be hetero-atomic-layer structures. Here we report the first experimental demonstration of freestanding van der Waals heterostructures and their functional nanomechanical devices. By stacking single-layer (1L) MoS2 on top of suspended single-, bi-, tri- and four-layer (1L to 4L) graphene sheets, we realize an array of MoS2-graphene heterostructures with varying thickness and size. These heterostructures all exhibit robust nanomechanical resonances in the very high frequency (VHF) band (up to ~100 MHz). We observe that fundamental-mode resonance frequencies of the heterostructure devices fall between the values of graphene and MoS2 devices. Quality (Q) factors of heterostructure resonators are lower than those of graphene but comparable to those of MoS2 devices, suggesting interface damping related to interlayer interactions in the van der Waals heterostructures. This study validates suspended atomic layer heterostructures as an effective device platform and provides opportunities for exploiting mechanically coupled effects and interlayer interactions in such devices. PMID- 29160325 TI - Copper-catalyzed highly selective synthesis of 2-benzyl- and 2-benzylidene substituted benzo[b]thiazinones from 2-iodophenylcinnamamides and potassium sulfide. AB - An efficient and practical procedure for the synthesis of 2-benzyl- and 2 benzylidene-substituted benzo[b]thiazinones from easily available 2 iodophenylcinnamamides and potassium sulfide has been developed. In the presence of DBU, the reaction proceeds via electrophilic addition, followed by dehydrogenation and reduction to give 2-benzyl benzo[b]thiazinones. Furthermore, 2-benzylidenebenzo[b]thiazinones were obtained in moderate to good yields without the addition of DBU. PMID- 29160326 TI - Controlling graphene plasmons with a zero-index metasurface. AB - Graphene plasmons, owing to their diverse applications including electro-optical modulation, optical sensing, spectral photometry and tunable lighting at the nanoscale, have recently attracted much attention. One key challenge in advancing this field is to precisely control the propagation of graphene plasmons. Here, we propose an on-chip integrated platform to engineer the wave front of the graphene plasmons through a metasurface with a refractive index of zero. We demonstrate that a well-designed graphene/photonic-crystal metasurface can possess conical plasmonic dispersion at the Brillouin zone center with a triply degenerate state at the Dirac frequency, giving rise to the zero-effective-index of graphene plasmons. Plane-wave-emission and focusing effects of the graphene plasmons are achieved by tailoring such a zero-index metasurface. In addition to the tunable Dirac point frequency enabled by the electrical tuning of the graphene Fermi level, our highly integrated system also provides stable performance even when defects exist. This actively controllable on-chip platform can potentially be useful for integrated photonic circuits and devices. PMID- 29160327 TI - Imbalance in amino acid and purine metabolisms at the hypothalamus in inflammation-associated depression by GC-MS. AB - Hypothalamic dysfunction is a key factor in depression; increasing evidence highlights neuroinflammation abnormalities as well as imbalances in neurotransmitters and the purinergic system in the pathophysiology of depression. However, little is known about the metabolomic changes in the hypothalamus of depressed patients with neuroinflammation. Herein, taking advantage of the well established lipopolysaccharide (LPS)-induced depression mouse model, we measured metabolic changes in the hypothalamus using gas chromatography-mass spectrometry (GC-MS). Sucrose preference test (SPT), open field test (OFT), forced swimming test (FST), and tail suspension test (TST) were conducted to assess our depressive model. To better understand the metabolic disturbances occurring in the hypothalamus of depressed mice, multivariate statistics were applied to analyse the clinical significance of differentially expressed metabolites in the hypothalamus of mice with LPS-induced depression. Bioinformatic analysis was conducted to detect potential relationships among the changed metabolites. The data confirmed that mice with LPS-induced depression were good mimics of depression patients in some characteristic symptoms such as decreased sucrose intake and increased immobility. In our study, 27 differentially expressed metabolites were identified in the hypothalamus of mice with LPS-induced depression. Herein, seventeen of these metabolites decreased, whereas 10 metabolites increased. These molecular changes were closely related to perturbations in the amino acid and purine metabolisms. Our data indicate that dysfunction of amino acid and purine metabolisms is one of main characteristics of inflammation-mediated depression. These results provide new insights into the mechanisms underlying depression, which may shed some light on the role of the hypothalamus in the pathogenesis of inflammation-mediated depression. PMID- 29160328 TI - Unravelling the energy transfer of Er3+-self-sensitized upconversion in Er3+-Yb3+ Er3+ clustered core@shell nanoparticles. AB - Unravelling upconversion (UC) energy transfer mechanisms is significant for designing novel efficient anti-Stokes phosphors. We have studied the correlation of different lanthanide dopants within Er3+-self-sensitized core@shell upconversion nanoparticles (UCNPs). Here, our focus will be on high-concentration dopants that are able to sufficiently produce the clustering effect, especially within the interplay between Er3+ and Yb3+. We demonstrate that whatever the amount of the self-sensitizer (e.g., Er3+), abnormal absorption enhancement will occur as long as Yb3+ clusters are present. This effect originates from the substantial energy transfer between Yb3+-Yb3+ clusters despite the increased energy transfer from Yb3+ to Er3+. Therefore, the energy transfer efficiency is still constrained. However, we conversely used one of the aforementioned quench paths of UC energy transfer to easily transfer the energy from the in-shell shell layer to the in-core area with the assistance of the energy potential reservoir, which was given by the homogeneous core@shell band offset at the interface region. Indirectly, we actualize the Er3+ UC luminescence with self-sensitization through an extended energy transfer path. This work provides a solid support and analytic theory for unraveling the energy transfer mechanism from recent works on Er3+ self-sensitized UC luminescence. PMID- 29160329 TI - Effects of length and hydrophilicity/hydrophobicity of diamines on self-assembly of diamine/SDS gemini-like surfactants. AB - This work studied gemini-like surfactants formed from anionic surfactant sodium dodecyl sulfate (SDS) and cationic charged bola-type diamines with hydrophilic or hydrophobic spacers of different lengths using surface tension, small angle neutron scattering, isothermal titration microcalorimetry and cryogenic transmission electron microscopy. The critical micelle concentrations (CMC) and the surface tension at CMC (gammaCMC) for all the diamine/SDS mixtures are markedly lower than that of SDS. The shorter diamines reduce gammaCMC to a greater extent regardless of the hydrophilicity/hydrophobicity of the diamines. Meanwhile, either the hydrophobic diamine with a longer spacer or the hydrophilic diamine with a shorter spacer is more beneficial to decrease CMC and leads to the transition from spherical micelles into rodlike or wormlike micelles. This is principally because of the formation of gemini-like surfactants by the electrostatic binding between SDS and the diamines, where the electrostatic repulsion between the adjacent headgroups of SDS becomes much weaker due to the electrostatic binding of oppositely charged diamine with SDS, and the longer hydrophobic spacer may also bend into the hydrophobic domain of micelles to promote micellar growth. However, the hydrophilic spacers are more compatible with the headgroup region, leading to micelles with a larger curvature. This work contributes to the understanding of the relationship between the properties of constructed gemini-like surfactants and the natures of connecting molecules, and provides guidance to efficiently improve the performance of surfactants. PMID- 29160330 TI - Anxiety and depression symptoms in Brazilian sexual minority ecstasy and LSD users. AB - BACKGROUND: This study examined drug use patterns and psychiatric symptoms of anxiety and depression among young Brazilian sexual minority ecstasy and LSD users and compared findings with those reported for their heterosexual peers. METHOD: This cross-sectional study employed targeted sampling and ethnographic mapping approaches via face-to-face interviews conducted at bars and electronic music festivals using an adapted, semi-structured version of the Global Appraisal of Individual Needs questionnaire. The sample comprised 240 male and female young adults who had used ecstasy and/or LSD in the 90 days prior to the interview and who were not on treatment for alcohol and drug abuse. RESULTS: Of the 240 subjects enrolled (mean age: 22.9+/-4.5 years), 28.7% were gay or bisexuals. Multivariate regression analysis showed that the prevalence of depression symptoms in the past 12 months in the sexual minority group was 37% higher than among heterosexuals (prevalence ratio [PR]=1.79; 95% confidence interval [95%CI] 1.03-3.11; p=0.037). CONCLUSION: Strategies should be developed to assess and address individual needs and treatment approaches should be tailored to address depressive symptoms in young, sexual minority club drug users. PMID- 29160331 TI - Primum non nocere or primum facere meliorem? Hacking the brain in the 21st century. AB - Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that modulates cortical excitability. It is devoid of serious adverse events and exerts variable effects on cognition, with several research findings suggesting that it can improve memory, verbal and mathematical skills. Because tDCS devices are low-cost, portable and relatively easy to assemble, they have become available outside of the medical setting and used for non-medical ("cosmetic") purposes by laypersons. In this sense, tDCS has become a popular technique aiming to improve cognition and the achievement of a better performance not only at work, but also in other fields such as sports, leisure activities (video games) and even the military. In spite of these unforeseen developments, there has been a general paralysis of the medical and regulatory agencies to develop guidelines for the use of tDCS for cosmetic purposes. Several challenges are present, most importantly, how to restrict tDCS use outside of the medical setting in face of variable and sometimes conflicting results from scientific research. This article aims to describe the popular use of tDCS, in light of the pillars of neuroethics, a branch of bioethics relative to brain research. Between two possible but extreme solutions - total release or total restriction of tDCS - it is paramount to develop a spectrum of alternatives, which may vary over time and in different cultural backgrounds. PMID- 29160332 TI - The contribution of human sciences to the challenges of contemporary psychiatry. PMID- 29160333 TI - Effect of education on listening comprehension of sentences on healthy elderly: analysis of number of correct responses and task execution time. AB - PURPOSE: To analyze the effect of education on sentence listening comprehension on cognitively healthy elderly. METHODS: A total of 111 healthy elderly, aged 60 80 years of both genders were divided into two groups according to educational level: low education (0-8 years of formal education) and high education (>=9 years of formal education). The participants were assessed using the Revised Token Test, an instrument that supports the evaluation of auditory comprehension of orders with different working memory and syntactic complexity demands. The indicators used for performance analysis were the number of correct responses (accuracy analysis) and task execution time (temporal analysis) in the different blocks. RESULTS: The low educated group had a lower number of correct responses than the high educated group on all blocks of the test. In the temporal analysis, participants with low education had longer execution time for commands on the first four blocks related to working memory. However, the two groups had similar execution time for blocks more related to syntactic comprehension. CONCLUSION: Education influenced sentence listening comprehension on elderly. Temporal analysis allowed to infer over the relationship between comprehension and other cognitive abilities, and to observe that the low educated elderly did not use effective compensation strategies to improve their performances on the task. Therefore, low educational level, associated with aging, may potentialize the risks for language decline. PMID- 29160334 TI - Prevalence of speech and language disorders in children in the western region of Sao Paulo. AB - PURPOSE: To establish the speech-language disorders in children living in the western region of Sao Paulo; to assess associations between diagnosis hypotheses (DH) and the age, gender and origin of referral; and to investigate the degree of agreement between the complaint and the DH at the moment of speech-language screening. METHODS: Observational epidemiological study conducted at a laboratory of Primary Health Care. A survey of 525 medical records of children between 2002 and 2011 was conducted. The following variables were analyzed: gender and age of the child; origin of referral, complaint reported by parents, diagnosis hypothesis and referrals. RESULTS: There was a predominance of male children (68.3%) and of the age group between 3 and 5 years and 11 months (48.7%), referred by a health professional (51.9%) and with more than one complaint reported by parents (26.1%). The most frequent DH were Phonological Disorder (22.9%) and more than one Diagnosis Hypothesis (19.4%). Most children were referred to a clinic-school where screening was performed (77.9%). There was an association between DH and the variables age (p <0.001*), gender (p = 0.008*) and origin of referrals (p <0.001). The degree of agreement between complaints and DHs was moderate. CONCLUSION: It has been proven that there are different DHs according to age, gender and origin of referrals. The use of speech-language screening with the information provided by parents for tracking of speech pathology is recommended. PMID- 29160335 TI - Study on the application of the time-compressed speech in children. AB - PURPOSE: To analyze the performance of children without alteration of central auditory processing in the Time-compressed Speech Test. METHODS: This is a descriptive, observational, cross-sectional study. Study participants were 22 children aged 7-11 years without central auditory processing disorders. The following instruments were used to assess whether these children presented central auditory processing disorders: Scale of Auditory Behaviors, simplified evaluation of central auditory processing, and Dichotic Test of Digits (binaural integration stage). The Time-compressed Speech Test was applied to the children without auditory changes. RESULTS: The participants presented better performance in the list of monosyllabic words than in the list of disyllabic words, but with no statistically significant difference. No influence on test performance was observed with respect to order of presentation of the lists and the variables gender and ear. Regarding age, difference in performance was observed only in the list of disyllabic words. CONCLUSION: The mean score of children in the Time compressed Speech Test was lower than that of adults reported in the national literature. Difference in test performance was observed only with respect to the age variable for the list of disyllabic words. No difference was observed in the order of presentation of the lists or in the type of stimulus. PMID- 29160336 TI - Relationship between the caregiver's report on the patient's spontaneous-speech and the Brief Aphasia Evaluation. AB - PURPOSE: To study the relationship between the caregiver's perception about the patient's impairment in spontaneous speech, according to an item of four questions administered by semi-structured interview, and the patient's performance in the Brief Aphasia Evaluation (BAE). METHODS: 102 right-handed patients with focal brain lesions of different types and location were examined. BAE is a valid and reliable instrument to assess aphasia. The caregiver's perception was correlated with the item of spontaneous speech, the total score and the three main factors of the BAE: Expression, Comprehension and Complementary factors. The precision (sensitivity/ specificity) about the caregiver's perception of the patient's spontaneous speech was analyzed with reference to the presence or absence of disorder, according to the professional, on the BAE item of spontaneous speech. RESULTS: The studied correlation was satisfactory, being greater (higher than 80%) for the following indicators: the item of spontaneous speech, the Expression factor and the total score of the scale; the correlation was a little smaller (higher than 70%) for the Comprehension and Complementary factors. Comparing two cut-off points that evaluated the precision of the caregiver's perception, satisfactory results were observed in terms of sensitivity and specificity (>70%) with likelihood ratios higher than three. By using the median as the cut-off point, more satisfactory diagnostic discriminations were obtained. CONCLUSION: Interviewing the caregiver specifically on the patient's spontaneous speech, in an abbreviated form, provides relevant information for the aphasia diagnosis. PMID- 29160337 TI - Can parenting practices predict externalizing behavior problems among children with hearing impairment? AB - OBJECTIVE: To identify possible differences in the level of externalizing behavior problems among children with and without hearing impairment and determine whether any relationship exists between this type of problem and parenting practices. METHODS: The Behavior Assessment System for Children was used to evaluate externalizing variables in a sample of 118 boys and girls divided into two matched groups: 59 with hearing disorders and 59 normal-hearing controls. RESULTS: Significant between-group differences were found in hyperactivity, behavioral problems, and externalizing problems, but not in aggression. Significant differences were also found in various aspects of parenting styles. A model for predicting externalizing behavior problems was constructed, achieving a predicted explained variance of 50%. CONCLUSION: Significant differences do exist between adaptation levels in children with and without hearing impairment. Parenting style also plays an important role. PMID- 29160338 TI - Changes in energy and motor activity: core symptoms of bipolar mania and depression? AB - OBJECTIVE: To evaluate how well symptom rating scales differentiate bipolar disorder (BD) episode types. METHODS: One hundred and six patients with BD were followed for 13 years. At each visit, the following clinical scales were administered: Young Mania Rating Scale (YMRS), Hamilton Depression Scale (HAM-D) and Clinical Global Impressions scale for use in bipolar illness (CGI-BP). To perform a comparison between the affective states of BP, three time points in each patient's follow-up period were chosen for evaluation: the most severe manic episode, the most severe depressive episode, and the euthymic period with least symptoms. Canonical discriminant analyses (CDA) were performed to identify which symptoms best discriminated episodes. RESULTS: CDA revealed HAM-D was worse than YMRS and CGI-BP to discriminate mood states. The items evaluating increased motor activity in YMRS (2, increased motor activity/energy) and HAM-D (9, agitation) were the best to distinguish mania, depression, and euthymia. In contrast, HAM-D item 8 (retardation) and the HAM-D and YMRS items related to mood symptoms were less important and precise. CONCLUSION: Higher levels of energy or activity should be considered a core symptom of mania. However, our results do not confirm the association between a decrease in energy or activity and depression. HAM-D probably does not assess motor activity adequately. PMID- 29160339 TI - Congresses: what do you crave? PMID- 29160340 TI - An interview with Kevin O'Brien. PMID- 29160341 TI - Dehiscences and fenestrations: methodological care necessary to avoid errors in diagnosis and measurement. AB - The low prevalence of gingival recessions observed in orthodontic clinical practice may be assigned to the fact that in studies in which dehiscences and bone fenestrations are described as frequent, they were diagnosed based on: 1) dry skull studies; 2) areas with periosteal reflection together with flap; and 3) imaging techniques with low sensitivity to detect these defects, which have a delicate structure and function. In areas of pseudo-dehiscences and fenestrations, the periosteum and the alveolar cortical bone are very thin; also, they either have been removed during preparation of the dry specimens in the areas for analysis, or, alternatively, have not been investigated using an ideal imaging method. PMID- 29160342 TI - Cephalometric evaluation of adult anterior open bite non-extraction treatment with Invisalign. AB - OBJECTIVE: The purpose of this study was to evaluate, by means of cephalometric appraisal, the vertical effects of non-extraction treatment of adult anterior open bite with clear aligners (Invisalign system, Align Technology, Santa Clara, CA, USA). METHODS: Lateral cephalograms of 30 adult patients with anterior open bite treated using Invisalign (22 females, 8 males; mean age at start of treatment: 28 years and 10 months; mean anterior open bite at start of treatment: 1.8 mm) were analyzed. Pre- and post-treatment cephalograms were traced to compare the following vertical measurements: SN to maxillary occlusal plane (SN MxOP), SN to mandibular occlusal plane (SN-MnOP), mandibular plane to mandibular occlusal plane (MP-MnOP), SN to mandibular plane (SN-MP), SN to palatal plane (SN PP), SN to gonion-gnathion plane (SN-GoGn), upper 1 tip to palatal plane (U1-PP), lower 1 tip to mandibular plane (L1-MP), mesiobuccal cusp of upper 6 to palatal plane (U6-PP), mesiobuccal cusp of lower 6 to mandibular plane (L6-MP), lower anterior facial height (LAFH), and overbite (OB). Paired t-tests and descriptive statistics were utilized to analyze the data and assess any significant changes resulting from treatment. RESULTS: Statistically significant differences were found in overall treatment changes for SN-MxOP, SN-MnOP, MP-MnOP, SN-MP, SN-GoGn, L1-MP, L6-MP, LAFH, and OB. CONCLUSIONS: The Invisalign system is a viable therapeutic modality for non-extraction treatment of adult anterior mild open bites. Bite closure was mainly achieved by a combination of counterclockwise rotation of the mandibular plane, lower molar intrusion and lower incisor extrusion. PMID- 29160343 TI - The effect of hard tissue surgical changes on soft tissue displacement: a pilot CBCT study. AB - INTRODUCTION: This pilot study had as main objective to test the reliability of a new method to evaluate orthognathic surgery outcomes and also, to understand the effect of hard tissue changes on soft tissue displacement. METHODS: The sample consisted of eight patients that underwent bimaxillary advancement and had CBCT at two time points (before surgery and 6-8 months follow-up). Voxel-based cranial base superimposition was used to register the scans. A different technique of iterative closest point (ICP) was used to measure and correlate the changes. The average displacement of 15 areas (4 hard tissue and 11 soft tissue) were measured twice. RESULTS: ICC was > 0.99 for all areas. Changes in the tip of the nose did not correlate with changes in any maxillary area, whereas soft tissue A point, A point and upper lips had correlation with several areas. The highest correlation for the maxilla was between the upper lip and the left/right supra cheilion (p< 0.001, r= 0.91 and p< 0.001, r= 0.93, respectively). In the mandible, the majority of the correlations involved soft tissue pogonion, pogonion and lower incisors, with the strongest one between pogonion and lower incisors (p< 0.001, r= 0.98). CONCLUSION: With the proper case selection, ICP is a reliable method that can be used to assess three-dimensional changes. PMID- 29160344 TI - Quantification of intrusive/retraction force and moment generated during en-masse retraction of maxillary anterior teeth using mini-implants: A conceptual approach. AB - OBJECTIVE: The aim of the present study was to clarify the biomechanics of en masse retraction of the upper anterior teeth and attempt to quantify the different forces and moments generated using mini-implants and to calculate the amount of applied force optimal for en-masse intrusion and retraction using mini implants. METHODS: The optimum force required for en-masse intrusion and retraction can be calculated by using simple mathematical formulae. Depending on the position of the mini-implant and the relationship of the attachment to the center of resistance of the anterior segment, different clinical outcomes are encountered. Using certain mathematical formulae, accurate measurements of the magnitude of force and moment generated on the teeth can be calculated for each clinical outcome. RESULTS: Optimum force for en-masse intrusion and retraction of maxillary anterior teeth is 212 grams per side. Force applied at an angle of 5o to 16o from the occlusal plane produce intrusive and retraction force components that are within the physiologic limit. CONCLUSION: Different clinical outcomes are encountered depending on the position of the mini-implant and the length of the attachment. It is possible to calculate the forces and moments generated for any given magnitude of applied force. The orthodontist can apply the basic biomechanical principles mentioned in this study to calculate the forces and moments for different hypothetical clinical scenarios. PMID- 29160345 TI - Influence of the cranial base flexion on Class I, II and III malocclusions: a systematic review. AB - OBJECTIVE: The aim of this study was to perform a systematic review on the morphological characteristics of the skull base (flexion, anterior length and posterior length) and the concomitant development of malocclusions, by comparing differences in dimorphism, ethnicity and age. METHODS: The articles were selected by means of electronic search on BBO, MEDLINE and LILACS databases from 1966 to 2016. A qualitative evaluation of the methodologies used on the articles was also performed. RESULTS: Although the literature on this topic is abundant, only 16 articles were selected for the present systematic review. The cranial base angle itself does not seem to play a significant role in the development of malocclusions. In fact, the cranial base angle is relatively stable at the ages of 5 to 15 years. CONCLUSIONS: A more obtuse angle at the skull base, in association or not with a greater anterior length of the cranial base, can contribute to the development of Class II division 1 malocclusions. On the other hand, a more acute angle at the skull base can contribute to a more anterior positioning of the mandible and to the development of Class III malocclusions. PMID- 29160346 TI - Effect of TiO2 nanoparticles incorporation on antibacterial properties and shear bond strength of dental composite used in Orthodontics. AB - INTRODUCTION: Plaque accumulation and bond failure are drawbacks of orthodontic treatment, which requires composite for bonding of brackets. As the antimicrobial properties of TiO2 nanoparticles (NPs) have been proven, the aim of this study was to evaluate the antimicrobial and mechanical properties of composite resins modified by the addition of TiO2 NPs. METHODS: Orthodontics composite containing 0%, 1%, 5% and 10% NPs were prepared. 180 composite disks were prepared for elution test, disk agar diffusion test and biofilm inhibition test to collect the counts of microorganisms on three days, measure the inhibition diameter and quantify the viable counts of colonies consequently. For shear bond strength (SBS) test, 48 intact bovine incisors were divided into four groups. Composites containing 0%, 1%, 5% and 10% NPs were used for bonding of bracket. The bracket/tooth SBS was measured by using an universal testing machine. RESULTS: All concentration of TiO2 NPs had a significant effect on creation and extension of inhibition zone. For S. mutans and S. sanguinis, all concentration of TiO2 NPs caused reduction of the colony counts. Composite containing 10% TiO2 NPs had significant effect on reduction of colony counts for S. mutans and S. sanguinis in all three days. The highest mean shear bond strength belonged to the control group, while the lowest value was seen in 10% NPs composite. CONCLUSIONS: Incorporating TiO2 nanoparticles into composite resins confer antibacterial properties to adhesives, while the mean shear bond of composite containing 1% and 5% NPs still in an acceptable range. PMID- 29160347 TI - Stability comparison of two different dentoalveolar expansion treatment protocols. AB - OBJECTIVE: The aim of this study was to compare the longitudinal stability of the conventional straight-wire system after the use of a quad-helix appliance with Damon self-ligating system in patients with Class I malocclusion. METHODS: 27 adolescent patients were evaluated at three different periods: pre-treatment (T1), post-treatment (T2) and three years post-treatment (T3). Group 1 included 12 patients (with a mean age of 14.65 year) treated with Damon 3MX bracket system; and Group 2 included 15 patients (with a mean age of 14.8 year) who underwent orthodontic treatment with Roth prescribed brackets after expansion with Quad-Helix appliance. Relapse was evaluated with dental cast examination and cephalometric radiograph tracings. Statistical analysis was performed with IBM SPSS for Windows software, version 21 (SPSS Inc., Chicago, IL). A p-value smaller than 0.05 was considered statistically significant. RESULTS: There were significant increases in all transverse dental and postero-anterior measurements (except for UL6-ML mm in Group 1) with active treatment. There was some significant relapse in the long-term in inter-canine width in both groups and in the inter-first premolar width in Group 2 (p< 0.05). Significant decrease in all frontal measurements from T2 to T3 was seen for both groups. Upper and lower incisors significantly proclined in T1-T2 (p< 0.05), however no relapse was found for both groups. When two systems were compared, there was no significant difference for the long-term follow-up period. CONCLUSION: Conventional (quad helix appliance with conventional brackets) and Damon systems were found similar with regard to the long-term incisor positions and transverse dimension changes of maxillary arch. PMID- 29160348 TI - Distribution of stress on TMJ disc induced by use of chincup therapy: assessment by the finite element method. AB - OBJECTIVE: To assess the distribution of stress produced on TMJ disc by chincup therapy, by means of the finite element method. METHODS: a simplified three dimensional TMJ disc model was developed by using Rhinoceros 3D software, and exported to ANSYS software. A 4.9N load was applied on the inferior surface of the model at inclinations of 30, 40, and 50 degrees to the mandibular plane (GoMe). ANSYS was used to analyze stress distribution on the TMJ disc for the different angulations, by means of finite element method. RESULTS: The results showed that the tensile and compressive stresses concentrations were higher on the inferior surface of the model. More presence of tensile stress was found in the middle-anterior region of the model and its location was not altered in the three directions of load application. There was more presence of compressive stress in the middle and mid-posterior regions, but when a 50o inclined load was applied, concentration in the middle region was prevalent. Tensile and compressive stresses intensities progressively diminished as the load was more vertically applied. CONCLUSIONS: stress induced by the chincup therapy is mainly located on the inferior surface of the model. Loads at greater angles to the mandibular plane produced distribution of stresses with lower intensity and a concentration of compressive stresses in the middle region. The simplified three dimensional model proved useful for assessing the distribution of stresses on the TMJ disc induced by the chincup therapy. PMID- 29160349 TI - Average interradicular sites for miniscrew insertion: should dental crowding be considered? AB - OBJECTIVE: To define a map of interradicular spaces where miniscrew can be likely placed at a level covered by attached gingiva, and to assess if a correlation between crowding and availability of space exists. METHODS: Panoramic radiographs and digital models of 40 patients were selected according to the inclusion criteria. Interradicular spaces were measured on panoramic radiographs, while tooth size-arch length discrepancy was assessed on digital models. Statistical analysis was performed to evaluate if interradicular spaces are influenced by the presence of crowding. RESULTS: In the mandible, the most convenient sites for miniscrew insertion were in the spaces comprised between second molars and first premolars; in the maxilla, between first molars and second premolars as well as between canines and lateral incisors and between the two central incisors. The interradicular spaces between the maxillary canines and lateral incisors, and between mandibular first and second premolars revealed to be influenced by the presence of dental crowding. CONCLUSIONS: The average interradicular sites map hereby proposed can be used as a general guide for miniscrew insertion at the very beginning of orthodontic treatment planning. Then, the clinician should consider the amount of crowding: if this is large, the actual interradicular space in some areas might be significantly different from what reported on average. Individualized radiographs for every patient are still recommended. PMID- 29160350 TI - Angle's Class II division 1 associated to mandibular retrusion and skeletal open bite: a 5-year post-orthodontic/orthopedic treatment follow-up. AB - Obtaining long term stability allied to functional and aesthetic balance is the main goal of any orthodontic-orthopedic therapy. This case report describes the orthodontic therapy applied to a 7-year-9-month old child, who presented a Class II, division 1 malocclusion associated to skeletal open bite. Functional and skeletal corrections (sagittally and vertically) were obtained by means of mandible advancement achieved with a closed Balter's bionator appliance followed by a fixed appliance. This approach showed to be efficient in accomplishing both functional and aesthetic goals, that were kept stable five years after the treatment was finished. This case report was presented to the Board of Directors of the Brazilian Board of Orthodontics and Facial Orthopedics (BBO), as partial requirement to becoming a Diplomate of the BBO. PMID- 29160351 TI - Writing scientific manuscripts: most common mistakes. AB - I have had the privilege of serving as editor-in-chief for 11 years of two scientific journals: The Dental Press Journal of Orthodontics and the Journal of the World Federation of Orthodontists. I had the opportunity to read and correct thousands of manuscripts. This experience was greatly enriching, because reading a text professionally completely differs from the perspective of readers in general. The routine practice of correcting manuscripts has made me realize that some errors recur frequently. To help authors to improve their manuscripts before submission, these problems are discussed here in the order that they appear in conventional manuscript sections. PMID- 29160352 TI - Genital myiasis associated with genital piercing. Case report. AB - CONTEXT: Myiasis is caused by larval infestation that usually occurs in exposed wounds. Dermatobia hominis is the most common fly species responsible for this parasitic infection. Genital piercing is an ornamental practice used in certain social circles. At placement, it transverses the skin surface and, as such, may be related to complications. CASE REPORT: We report a case of a 31-year-old man with a history of wound infection secondary to genital piercing who was exposed to an environment with flies, leading to myiasis. Mechanical removal and systemic antiparasitic drugs are possible treatments for myiasis. However, prevention that includes wound cleaning and dressing is the best way to avoid this disease. CONCLUSIONS: Genital piercing can lead to potential complications and myiasis may occur when skin lesions are not properly treated. PMID- 29160353 TI - In vitro evaluation of ivermectin, moxidectin, albendazole and pyrantel against cyathostomins of horses. AB - Cyathostomins are the most prevalent nematodes of horses, and multidrug resistance has been reported worldwide. There is a need to implement alternative drug monitoring analytical tests. The objective of this study was to determine the consistency (5 repetitions) of the larval migration on agar test (LMAT) using ivermectin, moxidectin, pyrantel or albendazole against cyathostomin infective stage larvae in eight different concentrations. LMAT showed a strong coefficient of determination (R2 > 0.91), between the test repetitions (n=5). The average 50% effective concentration (EC50) for ivermectin, moxidectin, pyrantel and albendazole were 0.0404, 0.0558, 0.0864 and 0.0988 nMol, respectively. The results of the EC50 for albendazole showed the greatest range of concentration. Ivermectin and moxidectin had the lowest in between-test variation. In the future, internationally certified susceptible isolates could be used for screening new drug candidates, or to follow up the pattern of drug efficacy from field populations. PMID- 29160354 TI - Dynamics of haemocytes from Pseudosuccinea columella circulating infected by Fasciola hepatica. AB - The lymnaeids are important in the epidemiology of Fasciola hepatica, a neglected and endemic zoonosis. The interaction between the internal defense system of Pseudosuccinea columella and F. hepatica has been little studied. In the present study the effect of infection by F. hepatica on P. columella circulating haemocytes was investigated. Changes in the average number of total circulating haemocytes have been observed at 30 minutes post-infection and 1, 7, 10, 14, 21, 28 and 50 days post-infection (dpi). Miracidia were observed head-foot and mantle at 30 minutes post-infection. Miracidia/Sporocysts in the mantle skirt 1 dpi, and fully formed sporocysts were observed in the head-foot at 7 dpi. Rediae became evident at 10 dpi and were located between the haemocoel and the muscles from 14 dpi; 50 dpi, the rediae in the digestive gland contained cercariae. The statistical analysis of the total haemocytes of P. columella infected by F. hepatica showed significant differences on the 30 minutes post-infection and 1, 14, 21, and 28 dpi in comparison to uninfected molluscs (0 dpi). Therefore, the interference observed on the internal defence system of P. columella may have direct association with the development of F. hepatica. PMID- 29160355 TI - Growth, mortality and susceptibility of oyster Crassostrea spp. to Perkinsus spp. infection during on growing in northeast Brazil. AB - Crassostrea rhizophorae and C. gasar oysters are cultivated in the northeast region. Perkinsus parasites infect bivalves, and their effects on oysters from tropical regions are poorly understood. This study evaluated the impact of Perkinsus infection on the productive traits of native oysters. Oysters were sampled bimonthly during 7 months, from July 2010 to February 2011, to evaluate growth rate, mortality and shell color patterns (white and dark-gray) (n = 500), and to determine the prevalence and intensity of Perkinsus (n = 152). Perkinsus and Crassostrea species were determined using molecular tools. Results showed that most dark-gray (90%, n = 20) and white (67%, n = 18) oysters were C. gasar and C. rhizophorae, respectively. Oysters showed a high growth rate and moderate cumulative mortality (44%). C. gasar oysters grew better and showed lower mortality and lower incidence of Perkinsus compared to C. rhizophorae. The mean prevalence of Perkinsus was moderate (48%), but the infection intensity was light (2.2). Perkinsosis affected very small oysters (19.4 mm). In conclusion, native oysters, especially C. gasar, have a great potential for culture, mortality is not associated with perkinsosis, and the shell color of oysters can be used to improve selection for spats with better performance. PMID- 29160356 TI - Seasonality of parasitic helminths of Leporinus macrocephalus and their parasitism rates in farming systems in the Amazon. AB - The objective of the present study was to analyze the seasonality of parasitic helminths of Leporinus macrocephalus from fish farms in the municipality of Cruzeiro do Sul, Acre, Brazil, and their parasitism rates. Between June 2014 and March 2015, 200 specimens were sampled from two fish farms: one with a semi intensive system and the other with an extensive system (100 fish from each farm: 50 during the dry season and 50 during the rainy season). Fifteen species of parasites were found, with seasonal variations of some according to the farming system. In the semi-intensive fish farm, there was greater prevalence of infection during the dry season. Also, Urocleidoides paradoxus, Procamallanus (Spirocamallanus) inopinatus, Goezia leporini and Rhabdochona (Rhabdochona) acuminata presented differences in their parasitism rates between the seasons. In the extensive fish farm, no variation in the prevalence of infection was observed between the seasons and two species Tereancistrum parvus and G. leporini demonstrated differences only regarding the mean intensity of infection. The data presented here may help fish farmers to understand the parasite dynamics of L. macrocephalus in farming systems during the dry and rainy seasons in the state of Acre. PMID- 29160357 TI - Co-infection with arthropod-borne pathogens in domestic cats. AB - The role of several feline vector-borne pathogens (FVBP) as a cause of disease in cats has not been clearly determined. In fact, with the exception of Bartonella spp. and hemoplasmas, FVBP in cats has not been clearly determined in Brazil yet. The present study aimed at identifying, by using molecular methods, the presence of FVBP in three cats showing non-specific clinical signs and inclusions suggestive of hemoparasites in blood smears. Cytauxzoon felis, 'Candidatus Mycoplasma haemominutum', Ehrlichia sp. closely related to Ehrlichia canis, and Anaplasma sp. closely related to Anaplasma phagocytophilum were detected in blood samples from two out of three sampled cats. Both cats positive for multiple FVBP did not show hematological and biochemical abnormalities. The present work emphasizes the need for molecular confirmation of co-infection by multiple FVBP in cats presenting non-specific clinical signs and inclusions resembling hemoparasites in blood smears. PMID- 29160358 TI - Potential of entomopathogenic nematodes of the genus Heterorhabditis for the control of Stomoxys calcitrans (Diptera: Muscidae). AB - The present study verified the pathogenic potential of entomopathogenic nematodes (EPNs) of the genus Heterorhabditis (Heterorhabditis bacteriophora, isolate HP88 and Heterorhabditis baujardi isolate LPP7) to immature stages of Stomoxys calcitrans in the laboratory. All EPN concentrations of the H. bacteriophora HP88 strain caused mean larval mortality greater than 90% after four days. Higher concentrations of the H. baujardi LPP7 isolate (>=50 EPNs/larva) eliminated more than 70% of larvae after six days with the concentration 200 EPNs/larva reaching mortality levels of 93.3%. The larval mortality at all concentrations of EPNs (25, 50, 100, 150, and 200 EPNs/larva) for both strains was significant (p<0.05) when compared to the respective control groups. Concentrations of H. bacteriophora HP88 yielded an LC50 of 0.36 EPN/larva and LC90 of 29.1; while H. baujardi LPP7 yielded an LC50 of 39.85 and LC90 of 239.18. H. bacteriophora HP88 provided greater inhibition of the emergence of adults when compared to the response obtained with H. baujardi LPP7. EPNs did not cause considerable mortality when applied directly to pupae. The set of observed results suggests that the EPNs of the genus Heterorhabditis, isolates HP88 and LPP7, are a promising alternative in the control of the stable fly. PMID- 29160359 TI - Gastrointestinal parasites in feral cats and rodents from the Fernando de Noronha Archipelago, Brazil. AB - Gastrointestinal parasites are important pathogens affecting animals, some of them are of medical and veterinary concern. Although the dynamic of parasitic infections is a complex phenomenon that has been studied under experimental conditions, it shows several gaps in knowledge, especially in insular regions where a confined population of animals and parasites co-exists. In this study was assessed the parasitism by endoparasite gastrointestinal in feral cats (n = 37) and rodents (n = 30) from the Fernando de Noronha Archipelago; in addition, the risk of human infection and ecological implications of these findings were discussed. Out of all samples analysed, 100% scored positive for the presence of gastrointestinal parasites in both feral cats and rodents. A total 17 genera and/or species of endoparasite gastrointestinal were identified, Ancylostoma sp., Strongyloides sp., Trichuris campanula and Toxocara cati were the parasites more frequently in feral cats. In rodents Eimeria sp., Strongyloides sp. and Trichuris muris were parasites more frequently herein detected. Human population living in this area are at risk of parasite infections due to the population of rodents and feral cats in the archipelago. PMID- 29160360 TI - Gill metazoan parasites of the spotted goatfish Pseudupeneus maculatus (Ostheichthyes: Mullidae) from the Coast of Pernambuco, northeastern Brazil. AB - This study evaluated the parasite fauna on the gills of spotted goatfish Pseudupeneus maculatus captured in the dry and rainy seasons in the coast of the State of Pernambuco, Brazil. Eight parasite species were identified belonging to the following taxa: Monogenea (Haliotrema caraibensis, Haliotrema caballeroi and Haliotrema golvani); Crustacea (Rocinela signata, Hamaticolax scutigerulus and Caligidae gen. sp.) and Cestoda (Nybelinia indica and Pseudolacistorhynchus noodti). The most prevalent parasites were: Monogenea (100%), H. scutigerulus (35%), N. indica (11.7%), R. signata (8.3%), Caligidae gen. sp. (3.33%) and P. noodti (0.83%). Values of infestation are compared to other studies, and the uncommon occurrence of Trypanorhyncha on the gills suggests that the spotted goatfish could be an intermediate host for the parasite. PMID- 29160361 TI - Phylogeny of the Trichogramma endosymbiont Wolbachia, an alpha-proteobacteria (Rickettsiae). AB - Wolbachia (Hertig) endosymbionts are extensively studied in a wide range of organisms and are known to be transmitted through the egg cytoplasm to the offsping. Wolbachia may cause several types of reproductive modifications in arthropods. In Trichogramma species, parthenogenesis-inducing Wolbachia bacteria allow females wasps to produce daughters from unfertilized eggs and these bacteria are present in at least 9% of all Trichogramma species. Phylogenetic studies have led to the subdivision of the Wolbachia clade in five supergroups (A, B, C, D and E) and Wolbachia from Trichogramma belong to supergroup B. Here, using the wsp gene, four groups of Wolbachia that infect Trichogramma species were distinguished and the addition of a new group "Ato" was suggested due to the addition of Wolbachia from Trichogramma atopovirilia (Oatman and Platner). Specific primers were designed and tested for the "Ato" group. Seventy-five percent of all evaluated Wolbachia strains from Trichogramma fell within "Sib" group. PMID- 29160362 TI - Potential of endophytic fungi as biocontrol agents of Duponchelia fovealis (Zeller) (Lepidoptera:Crambidae). AB - This study reports the first assessment of endophytic fungi isolated from strawberry leaves and selection of isolates for the control of Duponchelia fovealis, a new pest of strawberries. A total of 400 strawberry leaves of the cultivar 'Albion' were collected in four commercial farms. Leaves were disinfected, cut in fragments, and placed on Petri dishes containing potato dextrose agar media with tetracycline and incubated for 30 days. Following this time, 517 fungal colonies were isolated, and thirteen genera were identified: Cladosporium, Aspergillus, Nigrospora, Fusarium, Trichoderma, Chaetomium, Alternaria, Paecilomyces, Penicillium, Ulocladium, Bipolaris, Diaporthe, and Phoma. Eight isolates belonging to the genera Aspergillus, Diaporthe, Paecilomyces, and Cladosporium were selected for pathogenicity bioassays against third instar larvae of D. fovealis. Isolates of Paecilomyces induced the highest mortality rates. PMID- 29160364 TI - New reports of host plants of Euchistus nicaraguensis Rolston, 1972 (Heteroptera: Pentatomidae) and natural parasitism of Telenomus podisi Ashmead, 1893 (Hymenoptera: Platygastridae) in the rice agricultural ecosystem in Panama. PMID- 29160363 TI - Documented records of two migratory bird species in the State of Pernambuco, North-East Brazil. PMID- 29160365 TI - Foraging behavior and at-sea distribution of White-Tailed Tropicbirds in tropical ocean. AB - We used miniaturized GPS loggers and site observations to access foraging patterns and nest behaviour of the White-tailed Tropicbird Phaethon lepturus (WTTB), an endangered species at its South Atlantic breeding colony. Dual foraging pattern was observed with alternation between long and short foraging trips. Birds responsible for nest attendance engaged in short foraging trips with mean distance from colony of 25 +/- 17 km, total distance covered of 79 +/- 65 km and mean duration of 4.02 +/- 5.28 hours. Birds flew by dawn and returned before dusk while partners were at sea for long foraging trips that ranged from four to 11 days, with mean maximum distance from colony of 105 +/- 47.48 km. Chicks were usually left alone for hours and chick predation by Land Crab Johngartia lagostroma, egg consumption by Goniopsis cruentata and intra-specific competition are suspected to be responsible for high chick mortality rates. PMID- 29160366 TI - Erdosteine ameliorates the harmful effects of ischemia-reperfusion injury on the liver of rats. AB - PURPOSE: To investigate the potential protective effects of erdosteine against the harmful effects of ischemia-reperfusion injury on the liver in an experimental rat model. METHODS: Forty rats were divided into 4 groups. In the sham group, only the hepatic pedicle was mobilized. No other manipulation or treatment was performed. In the other groups, ischemia was achieved by clamping the hepatic pedicle for 60 min. After that, 90 min reperfusion was provided. In the control group, no treatment was given. In the perioperative treatment group, 100 mg/kg erdosteine was administered 2 hours before ischemia induction. In the preoperative treatment group, 100 mg/kg/day erdosteine was administered daily for ten days before the operation. At the end of the procedures, blood and liver samples were obtained for biochemical and histopathological assessment. RESULTS: Treatment with erdosteine ameliorated the histopathological abnormalities when compared with the control group. Furthermore, this treatment significantly decreased the serum liver function test values. It was also found that erdosteine ameliorated the oxidative stress parameters in both the perioperative and preoperative treatment groups. CONCLUSION: The current study is the first to have shown the favorable effects of erdosteine on the harmful effects of experimental hepatic ischemia-reperfusion injury. PMID- 29160367 TI - Numeric and volumetric changes in Leydig cells during aging of rats. AB - PURPOSE: To analyze the effects of aging in rats on the nuclear volume, cytoplasmic volume, and total volume of Leydig cells, as well as their number. METHODS: Seventy-two Wistar rats were divided into six subgroups of 12 rats, which underwent right orchiectomy at 3, 6, 9, 12, 18, and 24 months of age. The weight and volume of the resected testicles were assessed. A stereological study of Leydig cells was conducted, which included measurements of cell number and nuclear, cytoplasmic, and total cell volumes. RESULTS: The weight and volume of the resected testicles showed reductions with age. Only the subgroup composed of 24-month old rats showed a decrease in the nuclear volume of Leydig cells. Significant reductions in the cytoplasmic volume and total volume of Leydig cells were observed in 18- and 24-month old rats. The number of Leydig cells did not vary significantly with age. CONCLUSIONS: Aging in rats resulted in reduction of the nuclear, cytoplasmic, and total cell volumes of Leydig cells. There was no change in the total number of these cells during aging. PMID- 29160368 TI - The effects of local ischemic preconditioning and topical hypothermia in renal ischemia/reperfusion injury in rats. AB - PURPOSE: Topical hypothermia and local ischemic preconditioning have been shown to reduce renal ischemia-reperfusion (I/R) injury individually. We examined whether combination of both strategies lessens renal I/R injury. METHODS: Post right nephrectomy, 40 male Wistar rats were randomly assigned to five experimental protocols performed in the left kidney: topical hypothermia without ischemia (TH), warm ischemia (IR), ischemic preconditioning followed by warm ischemia (IPC+IR), cold ischemia (TH+IR), and ischemic preconditioning followed by cold ischemia (IPC+TH+IR). Eight randomly assigned right kidneys constituted the control group. After 240 min of reperfusion, the left kidney was retrieved to evaluate histological changes, lipid peroxidation and antioxidant enzymes activity. Serum was collected to evaluate urea and creatinine. RESULTS: IPC+TH+IR group revealed no difference to any other group subjected to ischemia in relation to histological changes, lipid peroxidation and antioxidant enzymes activity. Creatinine was lower in IPC+TH+IR group compared with IPC+IR, but showed no difference compared to TH+IR group. CONCLUSIONS: Combination of local ischemic preconditioning (IPC) and topical hypothermia conferred no protection in renal I/R injury. Moreover, local IPC solely followed by warm ischemia impaired renal function more than warm ischemia alone. PMID- 29160369 TI - Biomechanical study of the effect of platelet rich plasma on the treatment of medial collateral ligament lesion in rabbits. AB - PURPOSE: To evaluate the use of platelet-rich plasma in the early stages of healing of traumatic injury of the medial collateral ligament in the knee of rabbits. METHODS: Thirty rabbits were subjected to surgical lesion of the medial collateral ligament. Of these, 16 were treated with platelet-rich plasma and 14 with saline (control). After 3 and 6 weeks of treatment, 50% of the animals from each group were sacrificed, and biomechanical tests were performed on the injured ligament to compare the tensile strength between the two groups. RESULTS: Platelet-rich plasma significantly increased the tensile strength of the ligament in the groups treated after3 and 6 weeks. In the group treated with platelet-rich plasma vs. saline, the tensile strength values were 3192.5 +/- 189.7 g/f vs. 2851.1 +/- 193.1 g/f at3 weeks (p = 0.005) and 5915.6 +/- 832.0 g/f vs. 4187.6 +/ 512.9 g/f at 6 weeks (p = 0.0001). CONCLUSION: The use of platelet-rich plasma at the injury site accelerated ligament healing in an animal model, demonstrated by an increase in the tensile strength of the medial collateral ligament. PMID- 29160370 TI - Alternative animal model for studies of total skin thickness burns. AB - PURPOSE: To present an alternative experimental model of third degree burn of easy reproducibility. METHODS: Eighteen male Wister rats were randomly divided into three groups, 6 of which were allocated to each group. A soldering iron coupled to an aluminum plate was used to produce burn, at a temperature of 150oC, with different exposure times per group. Group 5 (G5) animals were burned at 150 degrees C with exposure time of 5 seconds; Group 10 (G10) the animals were burned at 150 degrees C with exposure time of 10 seconds and group 15 (G15) the animals were burned at 150 degrees C with exposure time of 15 seconds. RESULTS: Histopathological analyzes showed that all three groups had similar morphological characteristics, with total thickness involvement. CONCLUSION: The technique is effective to reproduce a third degree burn and suggests the temperature of 150oC with 5 seconds of exposure in order to minimize the risks to the animals. PMID- 29160371 TI - Effect of ovariectomy in bone structure of mandibular condyle. AB - PURPOSE: To evaluate the bone structure of the mandibular condyle through an animal model, after ovariectomy. METHODS: Thirty-six female Wistar rats were divided into 2 groups. The OVX group was submitted to bilateral ovariectomy, the SHAM group underwent the same surgical treatment, but without removal of the ovaries. After 90, 105 and 135 days after surgery, six animals from each group were submitted to euthanasia and the part containing the condyle was removed. RESULTS: The microscopic analysis shows an increase in marrow spaces over time in the OVX group. The morphometric study shows reduction in the amount of bone tissue in the OVX group 135 days period in comparison with for the initial period (90 days) (p <0.05, ANOVA, Tukey). CONCLUSION: The estrogen deficiency also affects the bone structure of the condyle. PMID- 29160372 TI - An experimental study of ascorbic acid effects in acute renal failure under general anesthesia. AB - PURPOSE: To evaluate the preventive effect of ascorbic acid on sevoflurane induced acute renal failure in an experimental rat model. METHODS: Twenty-four adult male Wistar rats were randomly distributed into three groups. Subjects were allocated into 3 groups: Group I received sevoflurane only, whereas Groups II and III had moderate (150 mg/kg) and high (300 mg/kg) doses of AA in addition to sevoflurane, respectively. Rhabdomyolysis and myohemoglobinuric ARF was formed by intramuscular administration of glycerol on the upper hind limb on the 15th minute of inhalation anesthesia. Biochemical parameters consisted of serum levels of blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), total antioxidant capacity (TAC), and protein carbonyl content. Histopathological variables were tubular necrosis, fibrin, and cast formation. RESULTS: NGAL levels were significantly lower in Group III than Group II and Group I. On the other hand, TAC, PCO, urea and creatinine levels were notably higher in Group I compared with Groups II and III. There was a significant difference between 3 groups on frequencies of acute tubular necrosis (p=0.003), fibrin (p<0.001) and cast (p<0.001). Acute tubular necrosis and fibrin formation were more prominent in Group I. Casts were more common in Groups II and III. CONCLUSIONS: The ascorbic acid serve as a prophylactic agent against renal damage in patients receiving sevoflurane anesthesia and higher doses were associated with more apparent protective effects. PMID- 29160373 TI - The role of histone deacetylase inhibitors in regulation of Akt/GSK-3beta signaling pathway in mice following transient focal cerebral ischemia. AB - PURPOSE: To investigate whether the neuroprotective effect of TSA on cerebral ischemia reperfusion injury is mediated by the activation of Akt/GSK-3beta signaling pathway. METHODS: Mice were randomly divided into four groups (n=15): sham group (S); ischemia reperfusion group (IR); ischemia reperfusion and pretreated with TSA group (IR+T); ischemia reperfusion and pretreated with TSA and LY294002 group (IR+T+L). The model of cerebral ischemia reperfusion was established by 1h of MCAO following 24h of reperfusion. TSA (5mg/kg) was intraperitoneally given for 3 days before MCAO, Akt inhibitor, LY294002 (15 nmol/kg) was injected by tail vein 30 min before the MCAO. RESULTS: TSA significantly increased the expression of p-Akt, p-GSK-3beta proteins and the levels of SOD, Bcl-2, reduced the infarct volume and the levels of MDA, ROS, TNF alpha, IL-1beta, Bax, Caspase-3, TUNEL and attenuated neurological deficit in mice with transient MCAO, LY294002 weakened such effect of TSA dramatically. CONCLUSIONS: TSA could significantly decrease the neurological deficit and reduce the cerebral infarct volume, oxidative stress, inflammation, as well as apoptosis during cerebral ischemia reperfusion injury, which was achieved by activation of the Akt/GSK-3beta signaling pathway. PMID- 29160374 TI - Study of the protective effect of dexamethasone on cisplatin-induced ototoxicity in rats. AB - PURPOSE: To evaluate the ability of dexamethasone to protect against cisplatin (CDDP)-induced ototoxicity. METHODS: Male Wistar rats were divided into the following three groups: 1) Control (C): 6 animals received intraperitoneal (IP) saline solution, 8 ml/kg/day for four days; 2) C + CDDP: 11 animals received 8 ml/kg/day of IP saline and, 90 min after saline administration, 8 mg/kg/day of IP CDDP for four days; and 3) DEXA15 + CDDP: 11 animals received IP dexamethasone 15 mg/kg/day and, 90 min after dexamethasone administration, received 8 mg/kg/day of IP CDDP for four days. RESULTS: It was found that dexamethasone did not protect against weight loss in CDDP-exposed animals. The mortality rate was comparable with that previously reported in the literature. The auditory threshold of animals in the DEXA15 + CDDP group was not significantly altered after exposure to CDDP. The stria vascularis of animals in the DEXA15 + CDDP group was partially preserved after CDDP exposure. CONCLUSIONS: Dexamethasone at the dose of 15 mg/kg/day partially protected against CDDP-induced ototoxicity, based on functional evaluation by brainstem evoked response audiontry (BERA) and morphological evaluation by optical microscopy. However, dexamethasone did not protect against systemic toxicity. PMID- 29160375 TI - Comparative study of respiratory muscle strength in women undergoing conventional and single-port laparoscopic cholecystectomy. AB - PURPOSE: To evaluate respiratory muscle strength (PImax and PEmax) before and 24 and 48 h after conventional and single-port laparoscopic cholecystectomy. METHODS: Forty women with symptomatic cholelithiasis (18 to 70 years) participated in the study. The patients were divided into two groups: 21 patients undergoing conventional laparoscopic cholecystectomy and 19 patients undergoing single-port laparoscopic cholecystectomy. Differences were considered to be significant when p<0.05. RESULTS: The results showed a greater decline in PImax after 24 h in the group submitted to conventional laparoscopic cholecystectomy, with a significant difference between groups (p=0.0308). CONCLUSION: Recovery of the parameters studied was more satisfactory and respiratory muscle strength was less compromised in the group submitted to single-port laparoscopic cholecystectomy. PMID- 29160376 TI - Eosinophilic esophagitis and proton pump inhibitors: is there a new link? PMID- 29160377 TI - Momentum. PMID- 29160378 TI - Honeycombing. PMID- 29160379 TI - Understanding diagnostic tests. Part 1. PMID- 29160380 TI - Frequency of COPD in health care workers who smoke. AB - OBJECTIVE: COPD is one of the major causes of morbidity and mortality worldwide. Health care providers should counsel their smoking patients with COPD to quit smoking as the first treatment step. However, in countries with high prevalences of smoking, health care workers may also be smokers. The aim of this study was to determine the frequency and severity of COPD in health care workers who smoke. METHODS: This was a cross-sectional study. All health care workers who smoke, from nine health care centers in Serbia, were invited to participate in the study and perform spirometry. The diagnosis of COPD was based on a post-bronchodilator FEV1/FVC ratio of < 0.70. All patients completed the COPD Assessment Test and the Fagerstrom Test for Nicotine Dependence. RESULTS: The study involved 305 subjects, and 47 (15.4%) were male. The mean age of the participants was 49.0 +/- 6.5 years. Spirometry revealed obstructive ventilatory defect in 33 subjects (10.8%); restrictive ventilatory defect, in 5 (1.6%); and small airway disease, in 96 (31.5%). A diagnosis of COPD was made in 29 patients (9.5%), 25 (86.2%) of whom were newly diagnosed. On the basis of the Global Initiative for COPD guidelines, most COPD patients belonged to groups A or B (n = 14; 48.2%, for both); 1 belonged to group D (3.6%); and none, to group C. Very high nicotine dependence was more common in those with COPD than in those without it (20.7% vs. 5.4%, p = 0.01). CONCLUSIONS: In this sample of health care workers, the frequency of COPD was comparable with that in the general population. The presence of COPD in health care workers who smoke was associated with higher nicotine dependence. PMID- 29160381 TI - Quality of Communication Questionnaire for COPD patients receiving palliative care: translation and cross-cultural adaptation for use in Brazil. AB - OBJECTIVE: To translate the Quality of Communication Questionnaire (QOC) to Portuguese and adapt it for use in Brazil in COPD patients receiving palliative care. METHODS: After approval from the first author of the original QOC and the local research ethics committee, the original, 13-item version of the questionnaire was independently translated to Brazilian Portuguese by two Brazilian translators fluent in English. The two translations were analyzed by a bilingual physician and the two Brazilian translators, who reached a consensus and produced another Portuguese version of the QOC. That version was back translated to English by two translators originally from English-speaking countries and fluent in Portuguese. In order to resolve any discrepancies, an expert panel compared the original version of the QOC with all five versions produced up to that point, the "prefinal" version of the QOC for use in Brazil being thus arrived at. A total of 32 patients admitted to any of three public hospital ICUs in the greater metropolitan area of Florianopolis, in southern Brazil, participated in the pretesting phase of the study, which was aimed at assessing the clarity and cultural acceptability of the prefinal version of the QOC for use in Brazil. RESULTS: Mean patient age was 48.5 +/- 18.8 years. Most of the items were well understood and accepted, being rated 8 or higher. One item, regarding death, was considered difficult to understand by the participants in the pretesting phase. After analyzing the back-translated version of the QOC, the first author of the original questionnaire requested that the items "Caring about you as a human being" and "Talking about what death might be like" be changed to "Caring about you as a person" and "Talking about how dying might be", respectively. The final version of the QOC for use in Brazil was thus arrived at. CONCLUSIONS: The QOC was successfully translated to Portuguese and adapted for use in Brazil. PMID- 29160382 TI - Lung cancer: changes in histology, gender, and age over the last 30 years in Brazil. AB - OBJECTIVE: To describe the trends in tumor histology, gender and age among patients with non-small cell lung cancer (NSCLC) treated with lung resection. The histology of lung cancer has changed in developed countries, and there is still little information available on the topic for developing countries. METHODS: This was a retrospective study of 1,030 patients with NSCLC treated with lung resection between 1986 and 2015 at a university hospital in southern Brazil. Differences in histology, stage, and type of surgery were analyzed by gender and for three periods (1986-1995, 1996-2005, and 2006-2015). RESULTS: Most (64.5%) of the patients were males, and the main histological types were squamous cell carcinoma (in 40.6%) and adenocarcinoma (in 44.5%). The mean age at surgery during the first period was 56.4 years for women and 58.9 years for men, compared with 62.2 for women and 64.6 for men in the third period (p < 0.001). The proportion of females increased from 26.6% in the first period to 44.1% in the third. From the first to the third period, the proportion of patients with squamous cell carcinoma decreased from 49.6% to 34.8% overall (p < 0.001), decreasing to an even greater degree (from 38.9% to 23.2%) among men. Among the NSCLC patients in our sample, females with adenocarcinoma accounted for 11.9% in the first period and 24.0% in the third period (p < 0.001). CONCLUSIONS: As has been seen in developed countries, the rates of lung cancer in females in southern Brazil have been rising over the last three decades, although they have yet to surpass those observed for males in the region. The incidence of squamous cell carcinoma has decreased in males, approaching adenocarcinoma rates, whereas adenocarcinoma has significantly increased among women. PMID- 29160383 TI - Epidemiological trends of allergic diseases in adolescents. AB - OBJECTIVE: To assess the prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis in adolescents in the city of Belo Horizonte, Brazil, in 2012 by administering the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, as well as to compare the observed prevalences with those found in studies performed 10 years earlier and employing the same methodology used here. METHODS: This was a cross-sectional study conducted between May and December of 2012 and involving adolescents in the 13- to 14-year age bracket. Participants were randomly selected from among adolescents studying at public schools in Belo Horizonte and completed the ISAAC questionnaire. Proportions were calculated in order to assess the prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis in the sample as a whole, and the chi-square goodness-of-fit test was used in order to compare the prevalences observed in 2012 with those found in 2002. RESULTS: The prevalences of symptoms of asthma, allergic rhinitis, and allergic rhinoconjunctivitis in 2012 were 19.8%, 35.3%, and 16.3%, respectively, being significantly higher than those found in 2002 (asthma, p = 0.006; allergic rhinitis, p < 0.01; and allergic rhinoconjunctivitis, p = 0.002). CONCLUSIONS: The prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis among adolescents in 2012 were found to be high, having increased in comparison with those found 10 years earlier, despite efforts in prevention, diagnosis, and treatment. PMID- 29160384 TI - Current use and acceptability of novel diagnostic tests for active tuberculosis: a worldwide survey. AB - OBJECTIVE: To determine the current use and potential acceptance (by tuberculosis experts worldwide) of novel rapid tests for the diagnosis of tuberculosis that are in line with World Health Organization target product profiles. METHODS: A multilingual survey was disseminated online between July and November of 2016. RESULTS: A total of 723 individuals from 114 countries responded to the survey. Smear microscopy was the most commonly used rapid tuberculosis test (available to 90.9% of the respondents), followed by molecular assays (available to 70.7%). Only a small proportion of the respondents in middle- and low-income countries had access to interferon-gamma-release assays. Serological and lateral flow immunoassays were used by more than a quarter (25.4%) of the respondents. Among the respondents who had access to molecular tests, 46.7% were using the Xpert assay overall, that proportion being higher in lower middle-income countries (55.6%) and low-income countries (76.6%). The data also suggest that there was some alignment of pricing for molecular assays. Respondents stated they would accept novel rapid tuberculosis tests if available, including molecular assays (acceptable to 86.0%) or biomarker-based serological assays (acceptable to 81.7%). Simple biomarker-based assays were more commonly deemed acceptable in middle- and low-income countries. CONCLUSIONS: Second-generation molecular assays have become more widely available in high- and low-resource settings. However, the development of novel rapid tuberculosis tests continues to be considered important by tuberculosis experts. Our data also underscore the need for additional training and education of end users. PMID- 29160385 TI - Usual interstitial pneumonia: typical, possible, and "inconsistent" patterns. AB - Idiopathic pulmonary fibrosis is a severe and progressive chronic fibrosing interstitial lung disease, a definitive diagnosis being established by specific combinations of clinical, radiological, and pathological findings. According to current international guidelines, HRCT plays a key role in establishing a diagnosis of usual interstitial pneumonia (UIP). Current guidelines describe three UIP patterns based on HRCT findings: a typical UIP pattern; a pattern designated "possible UIP"; and a pattern designated "inconsistent with UIP", each pattern having important diagnostic implications. A typical UIP pattern on HRCT is highly accurate for the presence of histopathological UIP, being currently considered to be diagnostic of UIP. The remaining patterns require further diagnostic investigation. Other known causes of a UIP pattern include drug induced interstitial lung disease, chronic hypersensitivity pneumonitis, occupational diseases (e.g., asbestosis), and connective tissue diseases, all of which should be included in the clinical differential diagnosis. Given the importance of CT studies in establishing a diagnosis and the possibility of interobserver variability, the objective of this pictorial essay was to illustrate all three UIP patterns on HRCT. PMID- 29160386 TI - Liquid silicone injection in the chest wall simulating cysticercosis. PMID- 29160387 TI - When is the use of contrast media in chest CT indicated? PMID- 29160388 TI - Incremental Prognostic Value of the Incorporation of Clinical Data Into Coronary Anatomy Data in Acute Coronary Syndromes: SYNTAX-GRACE Score. AB - BACKGROUND: When performing coronary angiography in patients with acute coronary syndrome (ACS), the anatomical extent of coronary disease usually prevails in the prognostic reasoning. It has not yet been proven if clinical data should be accounted for in risk stratification together with anatomical data. OBJECTIVE: To test the hypothesis that clinical data increment the prognostic value of anatomical data in patients with ACS. METHODS: Patients admitted with objective criteria for ACS and who underwent angiography during hospitalization were included. Primary outcome was defined as in-hospital cardiovascular death, and the prognostic value of the SYNTAX Score (anatomical data) was compared to that of the SYNTAX-GRACE Score, which resulted from the incorporation of the GRACE Score into the SYNTAX score. The Integrated Discrimination Improvement (IDI) was calculated to evaluate the SYNTAX-GRACE Score ability to correctly reclassify information from the traditional SYNTAX model. RESULTS: This study assessed 365 patients (mean age, 64 +/- 14 years; 58% male). In-hospital cardiovascular mortality was 4.4%, and the SYNTAX Score was a predictor of that outcome with a C statistic of 0.81 (95% CI: 0.70 - 0.92; p < 0.001). The GRACE Score was a predictor of in-hospital cardiac death independently of the SYNTAX Score (p < 0.001, logistic regression). After incorporation into the predictive model, the GRACE Score increased the discrimination capacity of the SYNTAX Score from 0.81 to 0.92 (95% CI: 0.87 - 0.96; p = 0.04). CONCLUSION: In patients with ACS, clinical data complement the prognostic value of coronary anatomy. Risk stratification should be based on the clinical-anatomical paradigm, rather than on angiographic data only. PMID- 29160389 TI - Protective Effect of Ischemic Preconditioning on Myocardium Against Remote Tissue Injury Following Transient Focal Cerebral Ischemia in Diabetic Rats. AB - BACKGROUND: Remote ischemic preconditioning (IPreC) could provide tissue protective effect at a remote site by anti-inflammatory, neuronal, and humoral signaling pathways. OBJECTIVES: The aim of the study was to investigate the possible protective effects of remote IPreC on myocardium after transient middle cerebral artery occlusion (MCAo) in streptozotocin- induced diabetic (STZ) and non-diabetic rats. METHODS: 48 male Spraque Dawley rats were divided into eight groups: Sham, STZ, IPreC, MCAo, IPreC+MCAo, STZ+IPreC, STZ+MCAo and STZ+IPreC+MCAo groups. We induced transient MCAo seven days after STZ-induced diabetes, and performed IPreC 72 hours before transient MCAo. Remote myocardial injury was investigated histopathologically. Bax, Bcl2 and caspase-3 protein levels were measured by Western blot analysis. Total antioxidant status (TAS), total oxidant status (TOS) of myocardial tissue were measured by colorimetric assay. Oxidative stress index(OSI) was calculated as TOS-to-TAS ratio. For all statistical analysis, p values < 0.05 were considered significant. RESULTS: We observed serious damage including necrosis, congestion and mononuclear cell infiltration in myocardial tissue of the diabetic and ischemic groups. In these groups TOS and OSI levels were significantly higher; TAS levels were lower than those of IPreC related groups (p < 0.05). IPreC had markedly improved histopathological alterations and increased TAS levels in IPreC+MCAo and STZ+IPreC+MCAo compared to MCAo and STZ+MCAo groups (p < 0.05). In non-diabetic rats, MCAo activated apoptotic cell death via increasing Bax/Bcl2 ratio and caspase-3 levels. IPreC reduced apoptotic cell death by suppressing pro-apoptotic proteins. Diabetes markedly increased apoptotic protein levels and the effect did not reversed by IPreC. CONCLUSIONS: We could suggest that IPreC attenuates myocardial injury via ameliorating histological findings, activating antioxidant mechanisms, and inducing antiapoptotic activity in diabetic rats. PMID- 29160390 TI - Left Atrial Appendage Closure with Amplatzer Cardiac Plug in Nonvalvular Atrial Fibrillation: Safety and Long-Term Outcome. AB - BACKGROUND: Atrial fibrillation (AF) is a cardiac arrhythmia with high risk for thromboembolic events, specially stroke. OBJECTIVE: To assess the safety of left atrial appendage closure (LAAC) with the Amplatzer Cardiac Plug for the prevention of thromboembolic events in patients with nonvalvular AF. METHODS: This study included 15 patients with nonvalvular AF referred for LAAC, 6 older than 75 years (mean age, 69.4 +/- 9.3 years; 60% of the male sex). RESULTS: The mean CHADS2 score was 3.4 +/- 0.1, and mean CHA2DS2VASc , 4.8 +/- 1.8, evidencing a high risk for thromboembolic events. All patients had a HAS-BLED score > 3 (mean, 4.5 +/- 1.2) with a high risk for major bleeding within 1 year. The device was successfully implanted in all patients, with correct positioning in the first attempt in most of them (n = 11; 73.3%). CONCLUSION: There was no periprocedural complication, such as device migration, pericardial tamponade, vascular complications and major bleeding. All patients had an uneventful in-hospital course, being discharged in 2 days. The echocardiographic assessments at 6 and 12 months showed neither device migration, nor thrombus formation, nor peridevice leak. On clinical assessment at 12 months, no patient had thromboembolic events or bleeding related to the device or risk factors. In this small series, LAAC with Amplatzer Cardiac Plug proved to be safe, with high procedural success rate and favorable outcome at the 12-month follow-up. (Arq Bras Cardiol. 2017; [online].ahead print, PP.0-0). PMID- 29160391 TI - AgNPs: The New Allies Against S. Mutans Biofilm - A Pilot Clinical Trial and Microbiological Assay. AB - The purpose of this study was to evaluate the antimicrobial properties of a new formulation containing silver nanoparticles, named Nano Silver Fluoride (NSF), to inhibit Streptococcus mutans biofilm formation on children's dental enamel. The variations in dental biofilm pH and in the Simplified-Oral-Hygiene-Index (OHI-S) also were evaluated after the treatment with NSF. This was a randomized, double blind, crossover and prospective pilot clinical trial study in which 12 schoolchildren, aged between 7-8 years, had their dental enamel treated with two solutions: S1 - Nano Silver Fluoride and S2 - negative control (saline solution), in different experimental moments. The dental biofilm adhered to enamel treated with NSF had lower values of S. mutans viability (absorbance) and colony forming units (CFU) than the S0 (baseline) and S2. There was a statistically significant difference between the OHI-S mean values of S0 and S1. There were no differences between the biofilm pH (both before and after the use of the test substances) and among the different groups. These properties suggest that NSF has bactericidal effect against S. mutans biofilm and it may be used for clinical control and prevention of dental biofilm formation. PMID- 29160392 TI - Prevalence and Sensitivity of Bacilli and Pseudomonas in the Newborn's Oral Cavity. AB - The aim of this study was to isolate Enterobacteria and Pseudomonas from the oral cavity of hospitalized newborns (NB) and determine their prevalence and the sensitivity profile to most commonly used antibiotics for this age group. Samples from the oral cavity of NB from 24 to 48 h age were collected using swabs. The samples were inoculated on MacConkey agar, incubated and the colonies counted and identified. For each strain, the minimum inhibitory concentration (MIC) was determined using agar dilution test. Tests for enterobacteria producing extended spectrumbeta-lactamases (ESBL) were performed using agar diffusion. Descriptive statistics was used for data analysis. Two of the isolated strains were submitted to the susceptibility test in biofilm. Of the collected samples, 8% presented Enterobacteria (mean of 6,141 CFU/mL) and no Pseudomona species was isolated. Positive samples were from NB in accommodation set or in the NB nursery. Enterobacter was the most prevalent genus and some strains were resistant to ampicillin, gentamicin and cephalothin. No ESBL strain was detected. Microorganisms in biofilms were resistant to all antibiotics, with concentrations four times higher than MIC. The presence of enterobacteria in the oral cavity of newborns, especially some strains resistant to normally used antibiotics, warns to the need for care to avoid the early colonization of this niche and the occurrence of a possible hospital infection in this age group. PMID- 29160393 TI - Pro-inflammatory Analysis of Macrophages in Contact with Titanium Particles and Porphyromonas gingivalis. AB - During insertion of titanium dental implants, particles may shear from the implant to the periimplant region causing osteolysis, and their association with bacteria can exacerbate the inflammatory reaction. However, the association of a high invasive bacterium from the oral cavity, Porphyromonas gingivalis (Pg), and titanium particles remains unknown. This study evaluated pro-inflammatory reaction of human macrophages in contact with micro and nanoparticles of titanium associated with Porphyromonas gingivalis lipopolysaccharide (PgLPS). THP-1 cell were used and treated for 12, 24 and 48 h following 6 groups: Control(C), PgLPS (L); Microparticles (M); Nanoparticles (N); PgLPS and microparticles (LM); PgLPS and nanoparticles (LN). The following assays were carried out: i) cell viability using MTS, ii) cell morphology by SEM and iii) expression of tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6) by qRT-PCR and ELISA. For statistics two-way ANOVA followed by Tukey's test was used (p<0.05). After treatment, cells presented similar viability and morphology demonstrating that the treatments were not able to induce cell death. Gene expression was significantly higher for TNF-alpha and IL1-beta after 12 h, and for IL-6 after 24 h in the N and LN groups. Cytokine production over time was an ascending curve for TNF-alpha with the peak at 48 h and IL1-beta and IL-6 had a straight line among the time points, although cells from N group presented a significant production of IL-6 at 48 h. In conclusion, these results suggest that titanium nanoparticles stimulate stronger pro-inflammatory response in macrophages, independent of their association with LPS from P.gingivalis. PMID- 29160394 TI - Effect of Milk Renewal on Cell Viability In Vitro at Different Time Frames. AB - The purpose of this study was to evaluate if the renewal of milk as a storage medium, every 12, 24 and 48 h, is able to increase its ability to maintain human periodontal ligament fibroblasts (PDLF) viability over time. PDLF were soaked in Minimum Essential Medium at 37 degrees C (MEM-37) (positive control), tap water (Water) (negative control) and in skimmed milk (44 wells) at 5 degrees C and 20 degrees C. The skimmed milk was renewed every 12 h (Milk-12), 24 h (Milk-24) and 48 h (Milk-48) in 11 wells of each plate, and the milk in the remaining 11 wells of each plate was maintained in situ (not renewed milk) (NRM). After 24, 48, 72, 96 and 120 h, cell viability was determined by the tetrazolium salt-based colorimetric (MTT) assay. Data were statistically analyzed by Kruskal-Wallis, Scheffe and Mann-Whitney tests (a=5%). At 5 degrees C, only Milk-48 was significantly better than NRM. At 20 degrees C, NRM was more effective than Milk 12 and Milk-24 in all time periods. In relation to the temperature (5 degrees C or 20 degrees C), renewal of milk at 5 degrees C was better in maintaining cell viability than the renewal at 20 degrees C. In conclusion, the renewal of milk was able to increase its ability to maintain cell viability only when performed every 48 h in milk maintained at 5 degrees C. PMID- 29160395 TI - Tooth Loss in Patients under Periodontal Maintenance in a Private Practice: A Retrospective Study. AB - The aim of the present study was to evaluate the incidence and causes of tooth loss in periodontal subjects from a private practice in Brazil. Two trained examiners extracted data from the records of subjects who sought periodontal treatment from 1980 to 2013. Only records of patients who completed the non surgical periodontal treatment and had at least one visit for maintenance were included. Data were analyzed by chi-square test, Student's t-test, Kaplan-Meier survival curve and Cox regression. A total of 3,319 records were reviewed and 737 records included (58.6% women, mean age of 46.6+/-13.0 years at the beginning of the treatment). Maintenance period ranged from 1 to 33 years (7.4+/-6 years). During this period, 202 individuals (27.4%) lost 360 teeth, 47.5% of losses within the first five years (n=171). Non-compliers lost more teeth than compliers (p<0.001), respectively 211 and 149 teeth. Regarding reasons of tooth loss, 84 individuals lost 38% of the teeth from periodontal disease progression (n=137). Survival analysis showed that most patients lost only one tooth from periodontal disease, and differences in the survival rates between compliers and non compliers were observed following the second tooth loss. Approximately one-third of tooth losses was related to periodontal disease progression, and there was stability in time of the proportion of losses from disease progression and other reasons. Therefore, it is possible to conclude that compliant patients in a private practice lose fewer teeth than do non-compliers. Among compliers, periodontal disease progression was not the main cause of tooth loss. PMID- 29160396 TI - Effect of Intermediate Flush Using Different Devices to Prevent Chemical Smear Layer Formation. AB - This study compared the effect of intermediate flush with distilled water delivered by conventional irrigation, EndoVac microcannula or Self-Adjusting File (SAF) system in the prevention of chemical smear layer (CSL) formation. Thirty human premolars were used. Canals were prepared with Reciproc system and 5.25% NaOCl. After chemomechanical preparation, samples were divided in 3 groups (n=10) according to the intermediate irrigation protocol with distilled water using: conventional irrigation, EndoVac microcannula or SAF. A final flush with 2% chlorhexidine solution was used and scanning electron microscopy was performed to assess protocol effectiveness. Two calibrated evaluators attributed scores according the presence or absence of CSL on the surface of the root canal walls at the coronal, middle and apical thirds, as follows: (1) no CSL; (2) small amounts of CSL; (3) moderate CSL; and (4) heavy CSL. Differences between protocols were analyzed with Kruskal-Wallis and Mann-Whitney U tests. Friedman and Wilcoxon signed rank tests were used for comparison between each root canal third. SAF resulted in less formation of CSL when compared with the conventional irrigation and EndoVac microcannula (p<0.05). When root canal thirds were analyzed, conventional irrigation and EndoVac groups showed less CSL formation at coronal and middle thirds in comparison to the apical third (p<0.05). In SAF group, there was no difference among the thirds (p>0.05). It may be concluded that an intermediate flush of distilled water, delivered by the SAF system resulted in a better reduction of CSL formation during chemomechanical preparation. PMID- 29160397 TI - Mechanical Preparation Showed Superior Shaping Ability than Manual Technique in Primary Molars - A Micro-Computed Tomography Study. AB - : The aim of the study was to evaluate canal preparation in primary molars with hand files, ProTaper Next and Self-Adjusting File (SAF) by 2D and 3D micro computed tomography (micro-CT) analysis. Canals of 24 primary molars were prepared with hand files (HF), ProTaper Next (PTN) and SAF (n=8/group). The teeth were scanned before and after root canal preparation and the pre- and postoperative micro-CT images were reconstructed. Changes in 2D (area, perimeter, roundness, minor and major diameter) and 3D [volume, surface area, structure model index (SMI)] morphological parameters, as well as canal transportation and lateral perforations were evaluated (Kruskal-Wallis and ANOVA; a=0.05). SAF presented smaller changes in minor diameter, volume and surface area compared with HF and PTN (p<0.05). PTN presented more circular canals after preparation. 3D analysis revealed greater transportation in HF. PTN and SAF presented more centered canal preparation, especially in curved areas. SAF and HF presented, respectively, the lowest (0.05+/-0.02 and 0.07+/-0.04) and highest (0.14+/-0.11 and 0.29+/-0.17) apical transportation. There were fewer lateral perforations in SAF (4.2%) and PTN (7.7%) than in HF (47.8%) (p<0.05). In primary molars, mechanical preparation showed better shaping ability than hand files, promoting more centered preparations and lower occurrence of lateral perforations and canal transportation. CLINICAL RELEVANCE: Manual instrumentation is still reported as the main choice in the primary teeth preparation; however, studies have shown limitations in its use. The morphological characteristics of primary teeth and the limited knowledge of shaping procedures in these teeth using mechanical preparation become a challenge for clinical practice and might impair the predictability of endodontic treatment. PMID- 29160398 TI - Topographic and Chemical Analysis of Reciprocating and Rotary Instruments Surface after Continuous Use. AB - This study aimed at evaluating the changes in surface characteristics and NiTi content of reciprocating and rotary instruments after continuous use. Thirty brand-new instruments were assigned to 3 groups (n=10): PNX1 Group - ProTaper Next system - instrument X1; PNX2 Group - ProTaper Next system - instrument X2 and WO Group - WaveOne system - Primary instrument 25.08. The instruments were used to prepare 60 simulated root canals. Analysis of surface characteristics by scanning electron microscopy (SEM) and chemical analysis of Ni and Ti content by energy-dispersive spectroscopy (EDS) were performed before and after the first and third use of the instruments. Only WO Group had significant increase in the quantity of defects and deformations after the third use (p<0.05). PNX1 Group had significant decrease in Ni content after the third use, in comparison with the unused instruments (p<0.05). PNX1 Group had no decrease in Ti content throughout the time of use (p>0.05), however, in PNX2 Group, there was significant decrease in the different time interval of analysis (p<0.05). Continuous use promoted increase in defects and deformations only for WaveOne instruments. Chemical composition presented significant changes according to the time of instruments use. PMID- 29160399 TI - Marginal and Internal Adaptation of Zirconia Crowns: A Comparative Study of Assessment Methods. AB - Marginal and internal adaptation is critical for the success of indirect restorations. New imaging systems make it possible to evaluate these parameters with precision and non-destructively. This study evaluated the marginal and internal adaptation of zirconia copings fabricated with two different systems using both silicone replica and microcomputed tomography (micro-CT) assessment methods. A metal master model, representing a preparation for an all-ceramic full crown, was digitally scanned and polycrystalline zirconia copings were fabricated with either Ceramill Zi (Amann-Girrbach) or inCoris Zi (Dentslpy-Sirona), n=10. For each coping, marginal and internal gaps were evaluated by silicone replica and micro-CT assessment methods. Four assessment points of each replica cross section and micro-CT image were evaluated using imaging software: marginal gap (MG), axial wall (AW), axio-occlusal angle (AO) and mid-occlusal wall (MO). Data were statistically analyzed by factorial ANOVA and Tukey test (a=0.05). There was no statistically significant difference between the methods for MG and AW. For AO, there were significant differences between methods for Amann copings, while for Dentsply-Sirona copings similar values were observed. For MO, both methods presented statistically significant differences. A positive correlation was observed determined by the two assessment methods for MG values. In conclusion, the assessment method influenced the evaluation of marginal and internal adaptation of zirconia copings. Micro-CT showed lower marginal and internal gap values when compared to the silicone replica technique, although the difference was not always statistically significant. Marginal gap and axial wall assessment points showed the lower gap values, regardless of ceramic system and assessment method used. PMID- 29160400 TI - Microtensile Bond Strength of Adhesive Systems in Different Dentin Regions on a Class II Cavity Configuration. AB - The aim of this study was to evaluate microtensile bond strength (uTBS) of self etch and etch-and-rinse adhesives systems compared in different dentin regions (central-CD or proximal-PD) in a class II cavity configuration. A class II (mesial-oclusal-distal) cavity configuration was simulated on 20 extracted human third-molars (4 mm wide/3 mm deep). Etch-and-rinse adhesive (Scotchbond Multi Purpose, n=5, SBMP and Optibond FL, n=5, OPFL) and self-etch adhesives (Clearfil SE Bond, n=5, CSE and Optibond XTR, n=5, OPXTR) were applied. Class II restorations were performed by incremental technique and photo-activated (Bluephase/G2). Samples were sectioned to beam shape (1 mm2 cross-section), placed on Geraldeli's device for uTBS test (0.5 mm/min cross-head speed). Fracture patterns were analyzed on stereomicroscope and classified as cohesive resin, adhesive, mixed/resin or mixed/dentin. Samples (n=4) were prepared for scanning electron microscope observation. Data were submitted to one-way ANOVA with Split-Plot arrangement and Tukey's test (alpha=0.05). There were no statistically significant differences among SBMP, OPFL, CSE and OPXTR on CD (p>0.05). However, on PD for SBMP and OPFL, uTBS values were significantly lower compared to CSE and OPXTR (p<0.05). In all groups, mixed failure pattern was more frequently observed, except for SBMP/CD (adhesive). In class II type cavity configuration, PD location negatively influenced bond strength of etch-and-rinse adhesive systems. Opposite to self-etching adhesives, which presented higher bond strength values compared to etch-and-rinse adhesives in PD. PMID- 29160401 TI - Fluoride Varnishes against Dental Erosion Caused by Soft Drink Combined with Pediatric Liquid Medicine. AB - The present study evaluated the effect of NaF and CPP-ACP/NaF varnishes to reduce erosion produced by soft drink (SD) combined or not with pediatric liquid medicine. Enamel specimens were pre-treated with fluoride varnish, according to the following groups: NaF varnish (Duraphat(r)) or CPP-ACP/NaF varnish (MI varnishTM). Two types of erosive cycles were made: by soft drink erosion (SDE) or by pediatric liquid medicine plus soft drink erosion (PLM/SDE). Bovine enamel specimens were randomly assigned in six groups (n=10): G1=NaF + SDE; G2=CPP ACP/NaF + SDE; G3=Distilled and deionized (DD) water + SDE; G4=NaF + PLM/SDE; G5=CPP-ACP/NaF + PLM/SDE and G6=DD water + PLM/SDE. Before treatments, the sample surface was divided in two areas (unexposed area-UA and exposed area-EA). The specimens were evaluated by 3D non-contact profilometry technique to determinate tooth structure loss (TSL) and surface roughness (Sa). Scanning electron microscopy (SEM) analysis was also performed. After SDE, G2 presented the lowest TSL values compared to G3 (p=0.008). G1 and G2 did not differ between them (p=0.203) and no groups differed among them despite Sa. Regarding TSL and Sa, G4 and G5 differed from G6 (p=0.0001), but not between them (p=1.00). Examining 3D and SEM images, the greatest differences between UA and EA were observed for G3 and G6. CPP-ACP/NaF varnish seems to be a promising treatment to reduce enamel loss from the erosion produced by a soft drink. Both varnishes also showed capacity to reduce TSL and Sa after erosion by soft drink combined to pediatric liquid medicine. PMID- 29160403 TI - Quantification of Streptococcus mutans in Different Types of Ligature Wires and Elastomeric Chains. AB - This study aimed to test the hypothesis that Streptococcus mutans contamination levels differ according to the type of the orthodontic ligature. Thirteen patients were selected. Each quadrant was randomly subjected to one of the following ligature-use protocols: I) elastomeric chain, II) steel ligature crossed over the archwire, III) steel ligature crossed under the archwire, and IV) steel ligature in a figure-eight pattern under the archwire. After seven days, the devices were removed and the Streptococcus mutans colony-forming unit count per mg of biofilm weight was determined. Twelve specimens (n=3) were also processed for scanning electron microscopy analysis. ANOVA and Tukey-Kramer test were used for comparisons to assess S. mutans differences between groups at a 5% significance level. There was no statistical difference in detectable levels of S. mutans among the groups (p=0.294). Scanning electron microscopy results showed abundant biofilms and microbial contamination in all groups. In conclusion, S. mutans contamination levels are similar in the different orthodontic ligatures. PMID- 29160402 TI - Effect of a Bioactive Glass Ceramic on the Control of Enamel and Dentin Erosion Lesions. AB - This study evaluated the effect of a bioactive glass ceramic for the control of erosion and caries lesions. Fragments (n=10) of bovine enamel and root dentin received daily application of different treatments (Biosilicate; Acidulated Phosphate Fluoride- APF; Untreated - control) during the performance of erosive cycles. Surfaces were analyzed with 3D optical profilometry to quantify the superficial loss in four periods (1, 7, 14 and 21 days), as well as the lesion depth with confocal laser scanning microscopy. For caries progression assessment, initial Knoop microhardness was measured on enamel bovine fragments. Initial carious lesions were developed and specimens were divided into three groups (n=10), according to the daily topical application (Biosilicate; APF; no application - control), during the de-remineralization cycles for 14 days. Final microhardness was obtained to calculate the change of surface microhardness. Subsurface demineralization was analyzed using cross-sectional microhardness (depths 10, 30, 50, 70, 90, 110 and 220 um). Data were tested using ANOVA and Tukey's test (a=5%). Results of erosive evaluation showed that Biosilicate promoted the lowest (p<0.05) values of surface loss, regardless of time, for both enamel and dentin; APF promoted lower (p<0.05) surface loss than control; analyzing different periods of time, APF did not show difference (p>0.05) between 14 and 21 days of demineralization. Results of enamel caries assessment showed that Biosilicate resulted in higher (p<0.05) surface and subsurface microhardness than both APF and control-applications. It may be concluded that Biosilicate application showed a higher potential to reduce surface loss and development of erosion and caries lesions. PMID- 29160404 TI - Interaction of Anabolic Androgenic Steroids and Induced Tooth Movement in Rats. AB - This study evaluated the interaction between tooth movement and two anabolic androgenic steroids (AAS), Deposteron(r) and Nebido(r). One hundred Wistar rats were divided into 3 groups: control (C) n=30, Nebido experimental (N) n=35 and Deposteron experimental (D) n=35. The control group was subdivided into 6 subgroups: 1, 2, 3, 5, 7 and 14. The experimental groups were subdivided into 7 subgroups: 0, 1, 2, 3, 5, 7 and 14, which corresponded to the day of animal's euthanasia after applying orthodontic force. Orthodontic devices were used to induce tooth movement using 50 cN of reciprocal force between the maxillary right first molar and the maxillary incisors. After euthanasia, the tissues were processed and stained with hematoxylin and eosin (HE) and tartrate-resistant acid phosphatase (TRAP). Osteoclasts, Howship's lacunae and blood vessels were quantified. Groups N and D showed acceleration in the reorganization of the periodontal ligament compared to group C. The peak of the histological events occurred in group C on day 5 and in groups N and D on day 3 after installation of the orthodontic device. There was a statistically significant difference in the number of osteoclasts (p<0.05) between groups N3 and C3, and between groups N3 and D3. Supra-physiological doses of the AAS Nebido(r) and Deposteron(r) altered the number of osteoclasts, Howship's lacunae and blood vessels, accelerating the reorganization of the periodontal ligament, resulting in accelerated biological effects from the induced tooth movement in rats. PMID- 29160405 TI - Dosimetry in CBCT with Different Protocols: Emphasis on Small FOVs Including Exams for TMJ. AB - This study aimed to estimate the absorbed dose in cone beam computed tomography (CBCT) exams according to different exposure parameters and size and position of the field of view (FOV). In addition was compared the absorbed dose of two smaller FOV scans with that of a larger FOV scan for evaluation of temporomandibular joint (TMJ), as it is a bilateral structure. CBCT scans were obtained on OP300 Maxio unit varying scanning mode (standard, high and endo) as well as size (5x5, 6x8 and 8x15 cm) and positioning of FOV. With a small FOV, different areas were scanned (maxilla or mandible, anterior or posterior and TMJ). Absorbed doses were determined using thermoluminescent dosimeters on the skin surface of sensitive organs of an anthropomorphic phantom. Endo mode showed the highest dose, followed by the high and standard modes in all FOV positions. With small FOV, doses were higher in the posterior region, especially in the mandible. Dose reduction occurred when small FOVs were used, but it was not proportional to FOV size reduction. For TMJ, the dose in a single acquisition with large FOV was greater than two acquisitions with small FOV, but lower than two acquisitions with medium FOV (6x8 cm). In conclusion, scanning mode, size and FOV position have great influence on the absorbed dose. Small FOV decreases the dose, but there is no linear relation between FOV size and dose. For bilateral exams of TMJ, double acquisition with small FOVs produces decrease in absorbed dose relative to a large FOV. PMID- 29160406 TI - Cheiloscopic Study among Monozygotic Twins, Non-Twin Brothers and Non-Relative Individuals. AB - This study aimed to investigate cheiloscopic patterns among monozygotic twins (MT), non-twin siblings (NTS) and unrelated individuals (UI). The sample consisted of 20 pairs of monozygotic twins (G1), 20 pairs of non-twin siblings (G2) and 20 pairs of unrelated individuals (G3). Lip thickness, commissures and grooves were evaluated and the latter were classified as: I - clear-cut vertical grooves; I' - incomplete vertical grooves; II - branched grooves; III - intersecting; IV - reticular grooves and V - undetermined, in 8 labial regions (sub-quadrants). The data were analyzed using descriptive and inferential statistics, with a 5% significance level. Concordance Correlation Coefficient (CCC) and Kappa coefficient, with a 95% confidence interval, were employed to check for agreement rates between G1, G2 and G3 pairs. There was a weak correlation for lip thickness (<0.90) in the total group, with higher values in G1 (CCC from 0.25 to 0.83 and from 0.34 to 0.86, upper and lower lips, respectively), followed by G2 (CCC from -0.03 to 0.70 and from -0.21 to 0.62, upper and lower lips, respectively) and G3 (CCC from -0.25 to 0.56 and from -0.38 to 0.34, upper and lower lips, respectively). With regard to labial commissures, Kappa statistic values were found to be 1.00 for G1, 0.45 for G2 and -0.24 for G3. As for the main groove pattern by sub-quadrant, Kappa values ranged from 0.48 to 0.87 for G1, from 0.17 to 0.59 for G2, and from -0.18 to 0.19 for G3. Monozygotic twins presented a relevant percentage of cheiloscopic agreements. Similarities were also found among NTS, while UI showed greater differences compared to their pairs, highlighting the influence of hereditary relationships on inherited cheiloscopic features. PMID- 29160407 TI - Oral Problems and Self-Confidence in Preschool Children. AB - The aim of the present study was to evaluate the impact of clinical oral factors, socioeconomic factors and parental sense of coherence on affected self-confidence in preschool children due to oral problems. A cross-sectional study with probabilistic sampling was conducted at public and private preschools with 769 five-year-old children and their parents/caretakers. A questionnaire addressing socio-demographic characteristics as well as the Scale of Oral Health Outcomes for Five-Year-Old Children (SOHO-5) and the Sense of Coherence Scale (SOC-13) were administered. The dependent variable was self-confidence and was determined using the SOHO-5 tool. Dental caries (ICDAS II), malocclusion and traumatic dental injury (TDI) were recorded during the clinical exam. Clinical examinations were performed by examiners who had undergone training and calibration exercises (intra-examiner agreement: 0.82-1.00 and inter-examiner agreement: 0.80-1.00). Descriptive statistics and Poisson regression analysis were performed (a=5%). Among the children, 91.3% had dental caries, 57.7% had malocclusion, 52.8% had signs of traumatic dental injury and 26.9% had bruxism. The following variables exerted a greater negative impact on the self-confidence of the preschool children due to oral problems: attending public school (PR=2.26; 95% CI: 1.09 4.68), a history of toothache (PR=4.45; 95% CI: 2.00-9.91) and weak parental sense of coherence (PR=2.27; 95% CI: 1.03-5.01). Based on the present findings, clinical variables (dental pain), socio-demographic characteristics and parental sense of coherence can exert a negative impact on self-confidence in preschool children due to oral problems. PMID- 29160408 TI - COGNITIVE PERFORMANCE OF STUNTED PRE-SCHOOL CHILDREN UNDERGOING NUTRITIONAL RECOVERY TREATMENT. AB - OBJECTIVE: To determine if the treatment of stunted children offered at a specialized center influences their cognitive performance. METHODS: Two groups of children from vulnerable families were selected, one consisting of stunted children being treated at the Nutrition Education and Recovery Center (CREN), and the other group of eutrophic children from a local, public day care center. At CREN, children are treated in a day-hospital system (9 hours/day, 5 days/week), receiving medical, nutritional and psycho-pedagogical support. All children were submitted to the Denver-II Development Screening Test and had their development and the height-for-age index assessed at 3 moments: at the beginning of the follow-up, and after 6 and 12 months. The socioeconomic status, according to the Brazilian Economic Classification Criteria, was assessed at the beginning of the follow-up. Data were treated by prevalence ratios for cross-sectional baseline analysis, using the Poisson regression, and by pooled prevalence ratios for longitudinal analysis, using a generalized equation estimation model, both adjusted by age, sex and economic status. RESULTS: Seventy-four children were included, 37 for each group. There were no differences in age, sex and socioeconomic status between groups. In the longitudinal analysis, the CREN group showed better performance in the personal-social domain (pooled prevalence ratio: 0.89; 95% confidence interval - 95%IC 0.82-0.95), with no differences in the other domains. CONCLUSIONS: The treatment offered at CREN satisfactorily improved the social skills of the treated children, without changing other domains. PMID- 29160409 TI - ASSOCIATION BETWEEN POSTURAL BALANCE AND ANTHROPOMETRIC INDEXES IN ELEMENTARY SCHOOLCHILDREN. AB - OBJECTIVE: To analyze the association between postural balance and anthropometric indicators in elementary school students. METHODS: This cross-sectional, descriptive and quantitative study included children enrolled in the first year of elementary school, of both sexes, in the age group of 6 to 7 years. Children with any physical or cognitive impairment, children who did not participate in all stages of the study evaluation, or those who failed to perform postural balance assessments were excluded. The children underwent a balance evaluation through a computerized dynamic posturograph, with sensory organization tests (TOSs) in six different sensory conditions. In order to verify the anthropometric indicators, the body weight and height measurements were evaluated for later calculation of the body mass index (BMI), which was categorized into four groups: low weight, normal, overweight and obesity. RESULTS: Eighty children with a mean age of 6.2+/-0.8 years were included, being 47 girls (58.8%). The analysis of the anthropometric indicators identified that 26.3% of students were overweight and 15% were obese. The children had averages below the reference values considered for their age range in conditions III and VI. There was a negative association between condition V and BMI and a positive association between values below normal in condition VI with overweight and obesity. CONCLUSIONS: There were associations between excess body weight and values below normal in some balance conditions, indicating that the anthropometric indicators interfered in the children's postural balance. PMID- 29160410 TI - FUZZY COMPUTATIONAL MODELS TO EVALUATE THE EFFECTS OF AIR POLLUTION ON CHILDREN. AB - OBJECTIVE: To build a fuzzy computational model to estimate the number of hospitalizations of children aged up to 10 years due to respiratory conditions based on pollutants and climatic factors in the city of Sao Jose do Rio Preto, Brazil. METHODS: A computational model was constructed using the fuzzy logic. The model has 4 inputs, each with 2 membership functions generating 16 rules, and the output with 5 pertinence functions, based on the Mamdani's method, to estimate the association between the pollutants and the number of hospitalizations. Data from hospitalizations, from 2011-2013, were obtained in DATASUS - and the pollutants Particulate Matter (PM10) and Nitrogen Dioxide (NO2), wind speed and temperature were obtained by the Environmental Company of Sao Paulo State (Cetesb). RESULTS: A total of 1,161 children were hospitalized in the period and the mean of pollutants was 36 and 51 ug/m3 - PM10 and NO2, respectively. The best values of the Pearson correlation (0.34) and accuracy measured by the Receiver Operating Characteristic (ROC) curve (NO2 - 96.7% and PM10 - 90.4%) were for hospitalizations on the same day of exposure. CONCLUSIONS: The model was effective in predicting the number of hospitalizations of children and could be used as a tool in the hospital management of the studied region. PMID- 29160411 TI - SPIROMETRY IN SCHOOLCHILDREN FOR FIELD STUDIES: DOES TESTING ON DIFFERENT DAYS CHANGE THE RESULT OF THE EXAM? AB - OBJECTIVE: To analyze if there is variation in the results of spirometry performed by healthy schoolchildren on different days. METHODS: Cross-sectional study with healthy schoolchildren aged 7 to 12 years old, in Florianopolis, Santa Catarina, Southern Brazil. Prepubescent children, non-athletes, born at full term, without cardiorespiratory, rheumatic, musculoskeletal, neurological and visual or hearing deficit were included. The child's health was assessed by a health questionnaire and by the survey International Study of Asthma and Allergies in Childhood. The spirometric test was performed on 3 different days, not exceeding the interval of 15 days between the first and last exams, following the guidelines of the American Thoracic Society. The absolute values and percentages of predicted values of forced vital capacity, forced volume in the first second and peak expiratory flow were analyzed. Statistical analysis was performed using the Shapiro-Wilk normality test followed by one-way analysis of variance or Friedman test and by Bonferroni's post-hoc test for multiple parametric comparisons. Also, the intraclass correlation coefficient was applied to compare results on the same patients on the different tested days. RESULTS: Twenty-two children were analyzed, with a mean age of 9.3+/-1.1 years. All the spirometric parameters showed a reduction in absolute value after the first exam, but without significant difference. Regarding reproducibility of spirometry results, the tests presented intraclass correlation coefficient >0.70. CONCLUSIONS: There was no change in the results of spirometry performed by healthy schoolchildren on three different days. PMID- 29160412 TI - Exosomes promote cetuximab resistance via the PTEN/Akt pathway in colon cancer cells. AB - Cetuximab is widely used in patients with metastatic colon cancer expressing wildtype KRAS. However, acquired drug resistance limits its clinical efficacy. Exosomes are nanosized vesicles secreted by various cell types. Tumor cell derived exosomes participate in many biological processes, including tumor invasion, metastasis, and drug resistance. In this study, exosomes derived from cetuximab-resistant RKO colon cancer cells induced cetuximab resistance in cetuximab-sensitive Caco-2 cells. Meanwhile, exosomes from RKO and Caco-2 cells showed different levels of phosphatase and tensin homolog (PTEN) and phosphor Akt. Furthermore, reduced PTEN and increased phosphorylated Akt levels were found in Caco-2 cells after exposure to RKO cell-derived exosomes. Moreover, an Akt inhibitor prevented RKO cell-derived exosome-induced drug resistance in Caco-2 cells. These findings provide novel evidence that exosomes derived from cetuximab resistant cells could induce cetuximab resistance in cetuximab-sensitive cells, by downregulating PTEN and increasing phosphorylated Akt levels. PMID- 29160413 TI - Long non-coding RNA CHCHD4P4 promotes epithelial-mesenchymal transition and inhibits cell proliferation in calcium oxalate-induced kidney damage. AB - Kidney stone disease is a major cause of chronic renal insufficiency. The role of long non-coding RNAs (lncRNAs) in calcium oxalate-induced kidney damage is unclear. Therefore, we aimed to explore the roles of lncRNAs in glyoxylate exposed and healthy mouse kidneys using microarray technology and bioinformatics analyses. A total 376 mouse lncRNAs were differentially expressed between the two groups. Using BLAST, 15 lncRNA homologs, including AU015836 and CHCHD4P4, were identified in mice and humans. The AU015836 expression in mice exposed to glyoxylate and the CHCHD4P4 expression in human proximal tubular epithelial (HK 2) cells exposed to calcium oxalate monohydrate were analyzed, and both lncRNAs were found to be upregulated in response to calcium oxalate. To further evaluate the effects of CHCHD4P4 on the cell behavior, we constructed stable CHCHD4P4 overexpressing and CHCHD4P4-knockdown HK-2 cells. The results showed that CHCHD4P4 inhibited cell proliferation and promoted the epithelial-mesenchymal transition in kidney damage and fibrosis caused by calcium oxalate crystallization and deposition. The silencing of CHCHD4P4 reduced the kidney damage and fibrosis and may thus be a potential molecular target for the treatment of kidney stones. PMID- 29160414 TI - Predicting pathway cross-talks in ankylosing spondylitis through investigating the interactions among pathways. AB - Given that the pathogenesis of ankylosing spondylitis (AS) remains unclear, the aim of this study was to detect the potentially functional pathway cross-talk in AS to further reveal the pathogenesis of this disease. Using microarray profile of AS and biological pathways as study objects, Monte Carlo cross-validation method was used to identify the significant pathway cross-talks. In the process of Monte Carlo cross-validation, all steps were iterated 50 times. For each run, detection of differentially expressed genes (DEGs) between two groups was conducted. The extraction of the potential disrupted pathways enriched by DEGs was then implemented. Subsequently, we established a discriminating score (DS) for each pathway pair according to the distribution of gene expression levels. After that, we utilized random forest (RF) classification model to screen out the top 10 paired pathways with the highest area under the curve (AUCs), which was computed using 10-fold cross-validation approach. After 50 bootstrap, the best pairs of pathways were identified. According to their AUC values, the pair of pathways, antigen presentation pathway and fMLP signaling in neutrophils, achieved the best AUC value of 1.000, which indicated that this pathway cross talk could distinguish AS patients from normal subjects. Moreover, the paired pathways of SAPK/JNK signaling and mitochondrial dysfunction were involved in 5 bootstraps. Two paired pathways (antigen presentation pathway and fMLP signaling in neutrophil, as well as SAPK/JNK signaling and mitochondrial dysfunction) can accurately distinguish AS and control samples. These paired pathways may be helpful to identify patients with AS for early intervention. PMID- 29160415 TI - Interregional correlations of glucose metabolism between the basal ganglia and different cortical areas: an ultra-high resolution PET/MRI fusion study using 18F FDG. AB - Basal ganglia have complex functional connections with the cerebral cortex and are involved in motor control, executive functions of the forebrain, such as the planning of movement, and cognitive behaviors based on their connections. The aim of this study was to provide detailed functional correlation patterns between the basal ganglia and cerebral cortex by conducting an interregional correlation analysis of the 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) data based on precise structural information. Fifteen participants were scanned with 7-Tesla magnetic resonance imaging (MRI) and high resolution research tomography (HRRT)-PET fusion system using 18F-FDG. For detailed interregional correlation analysis, 24 subregions of the basal ganglia including pre-commissural dorsal caudate, post-commissural caudate, pre-commissural dorsal putamen, post-commissural putamen, internal globus pallidus, and external globus pallidus and 80 cerebral regions were selected as regions of interest on the MRI image and their glucose metabolism were calculated from the PET images. Pearson's product-moment correlation analysis was conducted for the interregional correlation analysis of the basal ganglia. Functional correlation patterns between the basal ganglia and cerebral cortex were not only consistent with the findings of previous studies, but also showed new functional correlation between the dorsal striatum (i.e., caudate nucleus and putamen) and insula. In this study, we established the detailed basal ganglia subregional functional correlation patterns using 18F-FDG PET/MRI fusion imaging. Our methods and results could potentially be an important resource for investigating basal ganglia dysfunction as well as for conducting functional studies in the context of movement and psychiatric disorders. PMID- 29160416 TI - Agonistic activity of tamoxifen, a selective estrogen-receptor modulator (SERM), on arthritic ovariectomized mice. AB - Arthritis is positively associated with the decline of sex hormones, especially estrogen. Tamoxifen (TMX) is a selective estrogen receptor modulator, possessing agonist or antagonistic activity in different tissues. Thus, the objective of this study was to investigate the effect of TMX on the zymosan-induced arthritis model. Female Swiss normal and ovariectomized (OVX) mice were divided into groups and treated for five days with TMX (0.3, 0.9 or 2.7 mg/kg) or 17-beta-estradiol (E2, 50 ug/kg). On the fifth day, arthritis was induced and 4 h later, leukocyte migration into joint cavities was evaluated. The neutrophil migration in OVX animals, but not in normal mice, treated with TMX (all tested doses) was significantly decreased compared with mice that received the vehicle (P<=0.05). Similarly, this effect was also demonstrated in the E2-treated group. Therefore, the present study demonstrates that TMX presented agonist effects in inhibiting neutrophil migration and preventing arthritis progression in OVX mice. PMID- 29160417 TI - Radiotherapy modulates expression of EGFR, ERCC1 and p53 in cervical cancer. AB - Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism. PMID- 29160418 TI - Vitamin D3 levels and NLRP3 expression in murine models of obese asthma: association with asthma outcomes. AB - Vitamin D (25(OH)D3) is an essential nutrient that plays a role in the immune system. Serum 25(OH)D3 is found to be associated with asthma. However, the role of vitamin D in obese asthma remains unclear. Therefore, we investigated the association between vitamin D levels and asthma outcomes in a murine model of obese asthma. We also evaluated NLRP3 inflammasome activity in the pathogenesis of obese asthma. We divided 20 male Balb/c mice (3-4 weeks old) into 4 groups: normal control, asthma, obese, and obese asthma and developed an obese asthma mouse model. Airway hyperreactivity, cytokine concentrations, 25(OH)D3 levels, NLRP3 mRNA and IL-1beta mRNA expressions were measured. Lung histology and bronchoalveolar lavage fluid (BALF) cell count were also determined. Obese asthma mice showed a significant increase in airway hyper-responsiveness, airway inflammation, pro-inflammatory cytokine levels and NLRP3 mRNA, IL-1beta mRNA expression. Both asthma and obese groups had lower 25(OH)D3 levels. Vitamin D levels in obese asthma were the lowest among all groups. Vitamin D levels correlated negatively with body weight, lung resistance levels at 25 mg/mL of methacholine, total inflammatory cells, and IL-1beta and IL-17 concentrations in BALF. These data demonstrated an association between serum vitamin D levels and outcomes of obese asthma, and indicated that NLRP3 inflammasome may play a role in this disorder. PMID- 29160419 TI - Synthesis, crystal structure, and anti-breast cancer activity of a novel metal porphyrinic complex [YK(TCPP)(OH)2.(solvents)x]. AB - A novel heterometallic metal-porphyrinic framework (MPFs) built from Y and K ions as nods and meso-tetra(4-carboxyphenyl)porphyrin as linkers has been successfully synthesized and characterized. The single crystal X-ray diffraction indicated that this complex 1 exhibited a bilayered architecture of the porphyrins, which is seldom seen in MPFs. In addition, in vitro anticancer activity of complex 1 on three human breast cancer cells (BT474, SKBr-3 and ZR-75-30) was further determined. PMID- 29160420 TI - Next-generation Sequencing-based genomic profiling: Fostering innovation in cancer care? AB - OBJECTIVES: With the development of next-generation sequencing (NGS) technologies, DNA sequencing has been increasingly utilized in clinical practice. Our goal was to investigate the impact of genomic evaluation on treatment decisions for heavily pretreated patients with metastatic cancer. METHODS: We analyzed metastatic cancer patients from a single institution whose cancers had progressed after all available standard-of-care therapies and whose tumors underwent next-generation sequencing analysis. We determined the percentage of patients who received any therapy directed by the test, and its efficacy. RESULTS: From July 2013 to December 2015, 185 consecutive patients were tested using a commercially available next-generation sequencing-based test, and 157 patients were eligible. Sixty-six patients (42.0%) were female, and 91 (58.0%) were male. The mean age at diagnosis was 52.2 years, and the mean number of pre test lines of systemic treatment was 2.7. One hundred and seventy-seven patients (95.6%) had at least one identified gene alteration. Twenty-four patients (15.2%) underwent systemic treatment directed by the test result. Of these, one patient had a complete response, four (16.7%) had partial responses, two (8.3%) had stable disease, and 17 (70.8%) had disease progression as the best result. The median progression-free survival time with matched therapy was 1.6 months, and the median overall survival was 10 months. CONCLUSION: We identified a high prevalence of gene alterations using an next-generation sequencing test. Although some benefit was associated with the matched therapy, most of the patients had disease progression as the best response, indicating the limited biological potential and unclear clinical relevance of this practice. PMID- 29160421 TI - Longitudinal study of lung function in pregnant women: Influence of parity and smoking. AB - OBJECTIVES: To evaluate pulmonary function in the first and third trimesters of pregnancy and analyze the influence of parity and smoking on spirometry parameters. METHODS: This longitudinal prospective study included a cohort of 120 pregnant women. The inclusion criteria were as follows: singleton pregnancy, gestational age less than 13.86 weeks, and no preexisting maternal diseases. The exclusion criteria were as follows: change of address, abortion, and inadequate spirometry testing. ClinicalTrials.gov: NCT02807038. RESULTS: A decrease in values of forced vital capacity and forced expiratory volume were noted in the first second from the first to third trimester. In the first and third trimesters, multiparous women demonstrated lower absolute forced vital capacity and forced expiratory volume values in the first second compared with nulliparous women (p<0.0001 and p=0.001, respectively). Multiparous women demonstrated reduced forced expiratory flow in 25% to 75% of the maneuver compared with nulliparous women in the first (p=0.005) and third (p=0.031) trimesters. The absolute values of forced expiratory flow in 25% to 75%, forced expiratory volume in the first second and predicted peak expiratory flow values in the third trimester were higher in smokers compared with nonsmokers (p=0.042, p=0.039, p=0.024, and p=0.021, respectively). CONCLUSION: There was a significant reduction in forced vital capacity and forced expiratory volume values in the first second during pregnancy. Parity and smoking significantly influence spirometric variables. PMID- 29160422 TI - Identification of the difference in the pathogenesis in heart failure arising from different etiologies using a microarray dataset. AB - OBJECTIVES: Clinically, patients with chronic heart failure arising from different etiologies receive the same treatment. However, the prognoses of these patients differ. The purpose of this study was to elucidate whether the pathogenesis of heart failure arising from different etiologies differs. METHODS: Heart failure-related dataset GSE1145 was obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using R. A protein-protein interaction network of the differentially expressed genes was constructed using Search Tool for the Retrieval of Interacting Genes. The modules in each network were analyzed by Molecular Complex Detection of Cytoscape. The Database for Annotation, Visualization and Integrated Discovery was used to obtain the functions of the modules. RESULTS: Samples contained in GSE1145 were myocardial tissues from patients with dilated cardiomyopathy, familial cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, and post partum cardiomyopathy. The differentially expressed genes, modules, and functions of the modules associated with different etiologies varied. Abnormal formation of extracellular matrix was overlapping among five etiologies. The change in cytoskeleton organization was specifically detected in dilated cardiomyopathy. The activation of the Wnt receptor signaling pathway was limited to hypertrophic cardiomyopathy. The change in nucleosome and chromatin assembly was associated with only familial cardiomyopathy. Germ cell migration and disrupted cellular calcium ion homeostasis were solely detected in ischemic cardiomyopathy. The change in the metabolic process of glucose and triglyceride was detected in only post-partum cardiomyopathy. CONCLUSION: These results indicate that the pathogenesis of heart failure arising from different etiologies varies, which may provide molecular evidence supporting etiology-based treatment for heart failure patients. PMID- 29160423 TI - Comparison of short-segment monoaxial and polyaxial pedicle screw fixation combined with intermediate screws in traumatic thoracolumbar fractures: a finite element study and clinical radiographic review. AB - OBJECTIVES: No studies have compared monoaxial and polyaxial pedicle screws with regard to the von Mises stress of the instrumentation, intradiscal pressures of the adjacent segment and adjacent segment degeneration. METHODS: Short-segment monoaxial/polyaxial pedicle screw fixation techniques were compared using finite element methods, and the redistributed T11-L1 segment range of motion, largest maximal von Mises stress of the instrumentation, and intradiscal pressures of the adjacent segment under displacement loading were evaluated. Radiographic results of 230 patients with traumatic thoracolumbar fractures treated with these fixations were reviewed, and the sagittal Cobb's angle, vertebral body angle, anterior vertebral body height of the fractured vertebrae and adjacent segment degeneration were calculated and evaluated. RESULTS: The largest maximal values of the von Mises stress were 376.8 MPa for the pedicle screws in the short segment monoaxial pedicle screw fixation model and 439.9 MPa for the rods in the intermediate monoaxial pedicle screw fixation model. The maximal intradiscal pressures of the upper adjacent segments were all greater than those of the lower adjacent segments. The maximal intradiscal pressures of the monoaxial pedicle screw fixation model were larger than those in the corresponding segments of the normal model. The radiographic results at the final follow-up evaluation showed that the mean loss of correction of the sagittal Cobb's angle, vertebral body angle and anterior vertebral body height were smallest in the intermediate monoaxial pedicle screw fixation group. Adjacent segment degeneration was less likely to be observed in the intermediate polyaxial pedicle screw fixation group but more likely to be observed in the intermediate monoaxial pedicle screw fixation group. CONCLUSION: Smaller von Mises stress in the pedicle screws and lower intradiscal pressure in the adjacent segment were observed in the polyaxial screw model than in the monoaxial pedicle screw fixation spine models. Fracture level fixation could significantly correct kyphosis and reduce correction loss, and adjacent segment degeneration was less likely to be observed in the intermediate polyaxial pedicle screw fixation group. PMID- 29160424 TI - Effect of prophylactic non-invasive mechanical ventilation on functional capacity after heart valve replacement: a clinical trial. AB - OBJECTIVE: During cardiac surgery, several factors contribute to the development of postoperative pulmonary complications. Non-invasive ventilation is a promising therapeutic tool for improving the functionality of this type of patient. The aim of this study is to evaluate the functional capacity and length of stay of patients in a nosocomial intensive care unit who underwent prophylactic non invasive ventilation after heart valve replacement. METHOD: The study was a controlled clinical trial, comprising 50 individuals of both sexes who were allocated by randomization into two groups with 25 patients in each group: the control group and experimental group. After surgery, the patients were transferred to the intensive care unit and then participated in standard physical therapy, which was provided to the experimental group after 3 applications of non invasive ventilation within the first 26 hours after extubation. For non-invasive ventilation, the positive pressure was 10 cm H2O, with a duration of 1 hour. The evaluation was performed on the 7th postoperative day/discharge and included a 6 minute walk test. The intensive care unit and hospitalization times were monitored in both groups. Brazilian Registry of Clinical Trials (REBeC): RBR number 8bxdd3. RESULTS: Analysis of the 6-minute walk test showed that the control group walked an average distance of 264.34+/-76 meters and the experimental group walked an average distance of 334.07+/-71 meters (p=0.002). The intensive care unit and hospitalization times did not differ between the groups. CONCLUSION: Non-invasive ventilation as a therapeutic resource was effective toward improving functionality; however, non-invasive ventilation did not influence the intensive care unit or hospitalization times of the studied cardiac patients. PMID- 29160425 TI - Local and systemic effects of fibrin and cyanoacrylate adhesives on lung lesions in rabbits. AB - OBJECTIVES: Tissue adhesives can be used to prevent pulmonary air leaks, which frequently occur after lung interventions. The objective of this study is to evaluate local and systemic effects of fibrin and cyanoacrylate tissue adhesives on lung lesions in rabbits. METHODS: Eighteen rabbits were submitted to videothoracoscopy + lung incision alone (control) or videothoracoscopy + lung incision + local application of fibrin or cyanoacrylate adhesive. Blood samples were collected and assessed for leukocyte, neutrophil and lymphocyte counts and interleukin-8 levels preoperatively and at 48 hours and 28 days post-operatively. After 28 days, the animals were euthanized for gross examination of the lung surface, and lung fragments were excised for histopathological analysis. RESULTS: Fibrin and cyanoacrylate produced similar adhesion scores of the lung to the parietal pleura. Microscopic analysis revealed uniform low-cellular tissue infiltration in the fibrin group and an intense tissue reaction characterized by dense inflammatory infiltration of granulocytes, giant cells and necrosis in the cyanoacrylate group. No changes were detected in the leukocyte, neutrophil or lymphocyte count at any time-point, while the interleukin-8 levels were increased in the fibrin and cyanoacrylate groups after 48 hours compared with the pre operative control levels (p<0.01). CONCLUSION: Both adhesive agents promoted normal tissue healing, with a more pronounced local inflammatory reaction observed for cyanoacrylate. Among the serum markers of inflammation, only the interleukin-8 levels changed post-operatively, increasing after 48 hours and decreasing after 28 days to levels similar to those of the control group in both the fibrin and cyanoacrylate groups. PMID- 29160426 TI - Impact assessment of an automated drug-dispensing system in a tertiary hospital. AB - OBJECTIVE: To evaluate the costs and patient safety of a pilot implementation of an automated dispensing cabinet in a critical care unit of a private tertiary hospital in Sao Paulo/Brazil. METHODS: This study considered pre- (January-August 2013) and post- (October 2013-October 2014) intervention periods. We considered the time and cost of personnel, number of adverse events, audit adjustments to patient bills, and urgent requests and returns of medications to the central pharmacy. Costs were evaluated based on a 5-year analytical horizon and are reported in Brazilian Reals (R$) and US dollars (USD). RESULTS: The observed decrease in the mean number of events reported with regard to the automated drug dispensing system between pre- and post-implementation periods was not significant. Importantly, the numbers are small, which limits the power of the mean comparative analysis between the two periods. A reduction in work time was observed among the nurses and administrative assistants, whereas pharmacist assistants showed an increased work load that resulted in an overall 6.5 hours of work saved/day and a reduction of R$ 33,598 (USD 14,444) during the first year. The initial investment (R$ 206,065; USD 88,592) would have been paid off in 5 years considering only personnel savings. Other findings included significant reductions of audit adjustments to patient hospital bills and urgent requests and returns of medications to the central pharmacy. CONCLUSIONS: Evidence of the positive impact of this technology on personnel time and costs and on other outcomes of interest is important for decision making by health managers. PMID- 29160427 TI - Review of magnetic resonance-guided focused ultrasound in the treatment of uterine fibroids. AB - Uterine leiomyoma is the most frequently occurring solid pelvic tumor in women during the reproductive period. Magnetic resonance-guided high-intensity focused ultrasound is a promising technique for decreasing menorrhagia and dysmenorrhea in symptomatic women. The aim of this study is to review the role of Magnetic resonance-guided high-intensity focused ultrasound in the treatment of uterine fibroids in symptomatic patients. We performed a review of the MEDLINE and Cochrane databases up to April 2016. The analysis and data collection were performed using the following keywords: Leiomyoma, High-Intensity Focused Ultrasound Ablation, Ultrasonography, Magnetic Resonance Imaging, Menorrhagia. Two reviewers independently performed a quality assessment; when there was a disagreement, a third reviewer was consulted. Nineteen studies of Magnetic resonance-guided high-intensity focused ultrasound-treated fibroid patients were selected. The data indicated that tumor size was reduced and that symptoms were improved after treatment. There were few adverse effects, and they were not severe. Some studies have reported that in some cases, additional sessions of Magnetic resonance-guided high-intensity focused ultrasound or other interventions, such as myomectomy, uterine artery embolization or even hysterectomy, were necessary. This review suggests that Magnetic resonance-guided high-intensity focused ultrasound is a safe and effective technique. However, additional evidence from future studies will be required before the technique can be recommended as an alternative treatment for fibroids. PMID- 29160428 TI - Plasmid-mediated mcr-1 in carbapenem-susceptible Escherichia coli ST156 causing a blood infection: an unnoticeable spread of colistin resistance in Brazil? AB - OBJECTIVE: We describe an IncX4 pHC891/16mcr plasmid carrying mcr-1 in a colistin resistant and carbapenem-susceptible E. coli isolate (HC891/16), ST156, which caused a blood infection in a Brazilian patient with gallbladder adenocarcinoma. METHODS: Strain HC891/16 was subjected to whole genome sequencing using the MiSeq Platform (Illumina, Inc., USA). Assembly was performed using Mira and ABACAS. RESULTS: The isolates showed resistance only to ciprofloxacin, ampicillin and cefoxitin, and whole-genome sequencing revealed the presence of aac(6')Ib-cr and blaTEM1. CONCLUSION: Our findings warn of the possible silent dissemination of colistin resistance by carbapenem-susceptible mcr-1 producers, as colistin susceptibility is commonly tested only among carbapenem-resistant isolates. PMID- 29160430 TI - [10th Brazilian Congress of Epidemiology]. PMID- 29160429 TI - Reduction of venous pressure during the resection of liver metastases compromises enteric blood flow: IGFBP-1 as a novel biomarker of intestinal barrier injury. AB - OBJECTIVES: Disruption of the intestinal barrier and bacterial translocation commonly occur when intestinal blood flow is compromised. The aim of this study was to determine whether liver resection induces intestinal damage. METHODS: We investigated intestinal fatty-acid binding protein and insulin-like growth factor binding protein levels in the plasma of patients who underwent liver resection. RESULTS: We show that liver resection is associated with significant intestinal barrier injury, even if the Pringle maneuver is not performed. CONCLUSION: We propose the use of insulin-like growth factor binding protein-1 as a novel biomarker of intestinal damage in such situations. PMID- 29160431 TI - Classification of deaths in women with human immunodeficiency virus/acquired immunodeficiency syndrome in pregnancy and childbirth. AB - OBJECTIVE: To reclassify deaths of women infected with the human immunodeficiency virus/acquired immunodeficiency syndrome in pregnancy and childbirth in the State of Pernambuco, Brazil, from 2000 to 2010. METHODS: A descriptive exploratory study, developed from the following steps: translation to Portuguese of the item "HIV and aids" of the United Nations document "The WHO application of ICD-10 to deaths during pregnancy, childbirth and the puerperium: DCI MM 2012"; development of a classification algorithm of deaths of women living with the human immunodeficiency virus/acquired immunodeficiency syndrome in pregnancy and childbirth; and reclassification of deaths by a group of experts. RESULTS: Among the 25 reclassified deaths, 12 were due to human immunodeficiency virus/acquired immunodeficiency syndrome, and pregnancy condition was coexisting; 9 were reclassified as indirect maternal death, with O98.7 code, proposed by the World Health Organization; 2 as direct/indirect maternal death; and 2 were considered indeterminate. CONCLUSION: The reclassification showed a possible pattern of change in maternal mortality, since most of the deaths were attributed to the virus and may lead to a reduction in deaths from maternal causes. The algorithm will subsidize the use of the new classification of maternal death and human immunodeficiency virus/acquired immunodeficiency syndrome. PMID- 29160432 TI - Hypertriglyceridemic waist phenotype and nutritional factors: a study with participants of ELSA-Brasil. AB - OBJECTIVE: To investigate the association between fat and fiber intakes and the hypertriglyceridemic waist phenotype (HWP). METHODS: Cross-sectional survey conducted from the baseline of Brazilian Longitudinal Study of Health Adult (ELSA Brasil). Anthropometric measurements were conducted and the body mass index was calculated (BMI). Participants were classified according to the presence of HWP when waist circumference >= 102 and >= 88 cm, respectively, in men and women, and triglycerides >= 150 mg/dL. Fat and fiber intakes were assessed using a validated food frequency questionnaire, and socioeconomic, demographic and behavioral variables were collected through a questionnaire. The chi2 test, Mann-Whitney and Poisson regression were performed with significance level of 5%. RESULTS: There was no association between fiber and fat intakes with HWP. A lower prevalence of HWP among men was observed (IRR = 0.959; 95%CI 0.948 - 0.969). A higher prevalence of HWP was observed in participants with low physical activity (OR = 1.039, 95%CI 1.021 - 1.057), smoking history (OR = 1.044, 95%CI 1.031 - 1.057), lower per capita income (IRR = 1.035; 95%CI 1.022 - 1.049) and obesity (OR = 1.32, 95%CI 1.305 - 1.341). Fat and fiber intakes were not associated with HWP. CONCLUSION: A higher prevalence of HWP was found in obese, but no association was found between intake of fat and fiber and phenotype. PMID- 29160433 TI - Individual- and contextual-level factors associated with client-initiated HIV testing. AB - BACKGROUND: Knowing the reasons for seeking HIV testing is central for HIV prevention. Despite the availability of free HIV counseling and testing in Brazil, coverage remains lacking. METHODS: Survey of 4,760 respondents from urban areas was analyzed. Individual-level variables included sociodemographic characteristics; sexual and reproductive health; HIV/AIDS treatment knowledge and beliefs; being personally acquainted with a person with HIV/AIDS; and holding discriminatory ideas about people living with HIV. Contextual-level variables included the Human Development Index (HDI) of the municipality; prevalence of HIV/AIDS; and availability of local HIV counseling and testing (CT) services. The dependent variable was client-initiated testing. Multilevel Poisson regression models with random intercepts were used to assess associated factors. RESULTS: Common individual-level variables among men and women included being personally acquainted with a person with HIV/AIDS and age; whereas discordant variables included those related to sexual and reproductive health and experiencing sexual violence. Among contextual-level factors, availability of CT services was variable associated with client-initiated testing among women only. The contextual-level variable "HDI of the municipality" was associated with client initiated testing among women. CONCLUSION: Thus, marked gender differences in HIV testing were found, with a lack of HIV testing among married women and heterosexual men, groups that do not spontaneously seek testing. PMID- 29160434 TI - Brazilian Health Survey (2013): relation between alcohol use and sociodemographic characteristics by sex in Brazil. AB - OBJECTIVE: To analyze sociodemographic factors associated with alcohol use according to gender in Brazil. METHODS: Cross-sectional study using data from 2013 Brazilian Health Survey about 60,202 adults. We analyzed recent alcohol use and heavy episodic drinking in the 30 days prior to the research stratified by gender. The covariates were: age, educational level, skin color, marital status, and place of residence. RESULTS: The prevalence of recent alcohol use was 26.5%. In women, the prevalence was 14.4%; in men, 38.1%. In women, recent alcohol use was associated with younger age, higher educational level, being single or separated/divorced, and living in urban areas. In men, there was association with white skin color in addition to these factors. Among adults who used alcohol, 51.5% reported heavy episodic drinking - in women, this proportion was 43.4%; in men, 55.0%. In women, heavy episodic drinking was associated with younger age, being single or separated/divorced and living in urban areas; white skin color and higher educational level had negative association with this pattern. In men, heavy episodic drinking was directly associated with younger age and being single or divorced and inversely to white skin color; there was no significant relation with education and place of residence. CONCLUSION: We observed that men consume more alcohol than women. There is a convergence of alcohol consumption, including heavy episodic drinking, between men and women who are younger, single and divorced, and residents of urban areas. Skin color, educational level, and place of residence showed variations in the models by sex. PMID- 29160435 TI - Risk factors in cardiovascular disease mortality associated with high exposure to vehicular traffic. AB - OBJECTIVE: To identify areas and risk factors in cardiovascular disease (CD) mortality associated with air pollution from high exposure to vehicular traffic. METHODS: Cross-sectional study of CD mortality in 2,617 individuals aged 45-85 years living in the urban area of Cuiaba and Varzea Grande, Mato Grosso State, Brazil, between 2009 and 2011. We used the residential proximity of up to 150 meters to a roadway of great vehicle flow as a proxy of high exposure to air pollution from vehicular traffic. The association between age, gender, income, and traffic intensity with vehicular traffic exposure was assessed through the multiple logistic regression. We conducted stratified analyses to observe the influence of seasons and groups of causes. We used Bernoulli's spatial model of probability to identify high-risk clusters. RESULTS: Risk factors for CD mortality associated with high exposure to vehicular traffic were: living in census tracts with very unequal income (OR = 1.78; 95%CI 1.36 - 2.33), heavy traffic (OR = 1.20; 95%CI 1.01 - 1.43), and female gender (OR = 1.18; 95%CI 1.01 1.38). The CD mortality risk increases about 10% during the dry season period. We identified nine areas of risk. CONCLUSION: High exposure to traffic is associated with CD mortality in Cuiaba and Varzea Grande. Income inequality, traffic intensity, and female gender presented as the main determiners for this exposure. The dry season period enhances the effects of traffic exposure. PMID- 29160436 TI - Use of injected heroin and risk of hepatitis C in three cities in Colombia. AB - INTRODUCTION: Hepatitis C is one of the most neglected diseases by governments internationally. OBJECTIVE: Identify the prevalence of hepatitis C and associated injection drug users in three cities of factors Colombia. METHODS: Cross sectional study of 668 injecting drug users recruited through respondent-driven sampling, inquired about demographic characteristics and risk behaviors. Laboratory testing was used on filter paper and cases of hepatitis C viral load tests with RNA were confirmed. Hepatitis C prevalence and associated factors was estimated with Chi-square test statistics and reasons for crude and adjusted prevalence were calculated using logistic regression. RESULTS: The prevalence of hepatitis C was 17.5% and were found as factors that increase the prevalence of hepatitis: having HIV, injecting another person carrying the virus dose used was sharing a syringe, injected with a syringe and consume marijuana. As a factor that reduces the prevalence, purchase syringes in drug stores or other stores. CONCLUSION: This research evidence established consumption of drugs by injection , and the presence of hepatitis C in social networks of IDUs and highlights the importance of developing interventions for harm reduction and prevention of hepatitis C in this population these three cities. PMID- 29160437 TI - Access and adherence to medication among people with diabetes in Brazil: evidences from PNAUM. AB - OBJECTIVE: To describe people with diabetes in Brazil and to compare their sociodemographic characteristics, access and self-reported adherence to diabetes prescribed drugs. METHODS: Data analysis from the National Survey on Access, Use and Promotion of the Rational Use of Medicines, a household survey, with sampling by clusters, according to sex and age domains and national and macro-regional representativeness. Adults (>= 20 years old) who reported having diabetes constituted the sample. The weighted frequencies of the variables in the sample were analyzed and the Pearson chi2 test was applied to evaluate the statistical significance of the differences between the strata for the data of access, form of financing and adherence to the drugs, considering the level of significance of 5%. RESULTS: We found a higher proportion of women, people over 60 years and economy class C. Most participants reported having two or more comorbidities, in addition to diabetes, and taking five or more drugs. Regarding access, 97.8% say they have access to prescription drugs for diabetes and 70.7% say they get them totally free of charge. There was low adherence to anti-diabetic treatment, with significant macro-regional differences (p = 0,001), and greater vulnerability in the South and Northeast regions. CONCLUSION: Better access to diabetes medicines in the country has been demonstrated. However, to improve the efficiency of health public spending, it is necessary to achieve higher rates of adherence to treatment. PMID- 29160438 TI - Psychiatric admission and readmission in a general hospital of Porto Alegre: sociodemographic, clinic, and use of Network for Psychosocial Care characteristics. AB - INTRODUCTION: The revolving door phenomenon is characterized by repeated and frequent psychiatric readmissions. OBJECTIVE: We aim to investigate sociodemographic, clinic, and follow-up characteristics in health services associated to psychiatric admissions and readmissions of inpatients in a general hospital of Porto Alegre. METHODS: It is a cross-sectional study with a sample of 96 participants. RESULTS: More than half of the sample (53.1%) were female, 51% were single, and the average age was 44.3 years old. From clinic data, 36% (n = 35) of the users were in their first admission, and 36% (n = 35) met the criteria for frequent readmission. The results show that users with frequent readmissions significantly mentioned fewer people on whom they could rely. Alternatively, users in first admission lived with a significant larger number of people than the rest of the sample and had, with less frequency, bond with health services other than hospitals, using hospitals as an entrance door to mental health care. Regarding follow-up in the network, 34.4% of the sample did not visit often NPC services before admission, and only 4.1% used psychosocial rehabilitation services. CONCLUSION: We highlight the importance of hospitals as an articulation point in the network, and as strategic to connect with NPC services. In spite of international literature investigation and registration of the frequent psychiatric readmission phenomenon, we notice it is a field that needs greater investigation in Brazil. PMID- 29160439 TI - Causality in Pharmacoepidemiology and Pharmacovigilance: a theoretical excursion. AB - The article presents some considerations about causality in Pharmacoepidemiology and Pharmacovigilance. To begin, we provide a brief introduction about the importance of the issue, noting that the understanding of causal relationships is considered one of science's greatest achievements and has been, over time, a continuous and central concern of philosophers and epidemiologists. Next, we describe definitions and types of causes, demonstrating their influences on pharmacoepidemiological thought. After that, we present Rothman's multi-causal model as one of the founding explanations of multiple causality and the issue of causality assessment. We conclude with some comments and reflections on causality from the perspective of health surveillance, particularly with regard to regulations on pharmacovigilance. PMID- 29160440 TI - Comparing definitions of spatial relations for the analysis of geographic disparities in mortality within a Bayesian mixed-effects framework. AB - OBJECTIVE: To analyze the conceptual and technical differences between three definitions of spatial relations within a Bayesian mixed-effects framework: classical multilevel definition, spatial multiple membership definition and conditional autoregressive definition with an illustration of the estimate of geographic disparities in early neonatal mortality in Colombia, 2011-2014. METHODS: A registry based cross-sectional study was conducted. Births and early neonatal deaths were obtained from the Colombian vital statistics registry for 2011-2014. Crude and adjusted Bayesian mixed effects regressions were performed for each definition of spatial relation. Model fit statistics, spatial autocorrelation of residuals and estimated mortality rates, geographic disparity measures, relative ratios and relative differences were compared. RESULTS: The definition of spatial relations between municipalities based on the conditional autoregressive prior showed the best performance according to both fit statistics and residual spatial pattern analyses. Spatial multiple membership definition had a poor performance. CONCLUSION: Bayesian mixed effects regression with conditional autoregressive prior as an analytical framework may be an important contribution to epidemiological design as an improved alternative to ecological methods in the analyses of geographic disparities of mortality, considering potential ecological bias and spatial model misspecification. PMID- 29160441 TI - Psychosocial hearing disadvantage and associated factors among construction workers in Mato Grosso, Brazil. AB - OBJECTIVE: To estimate the prevalence and to analyze the factors associated with self-reported hearing handicap by construction workers in the state of Mato Grosso, Brazil. METHODS: A cross-sectional study was conducted with 866 construction and heavy construction workers. Participants responded to an epidemiological survey subdivided in: identification data, sociodemographic data; lifestyle; work environment characteristics; occupational exposure factors; hearing protection measures; and hearing handicap inventory to quantify the psychosocial consequences of work-related hearing loss. RESULTS: The prevalence of hearing impairment among workers in the construction sector was 14.43% (n = 125). There were 311 emotional and social complaints related to hearing problems. Hearing handicap was associated with: 60 or over age group (PR = 1.94, 95%CI 1.01 - 3.71); alcohol consumption (PR = 1.94, 95%CI 1.38 - 2.73); direct exposure to noise (PR = 1.75; 95%CI 1.03 - 2.97); exposure to dust (PR = 1.59, 95%CI 1.13 - 2.24); non-use of earplugs (PR = 1.39, 95%CI 1.00 - 1.93); and non-use of neck flap cap (PR = 1.52, 95%CI 1.09 - 2.13). CONCLUSION: We observed a high prevalence of hearing impairment among workers in the construction sector associated with: individuals aged 60 years or older; alcoholism; exposure to noise and dust; non-use of earplugs; and non-use of neck flap cap. Therefore, it is necessary to implement policies aimed at preserving the hearing health of construction and heavy construction workers. PMID- 29160442 TI - Effects of socioeconomic position and social mobility on linear growth from early childhood until adolescence. AB - OBJECTIVE: To assess the effect of socioeconomic position (SEP) in childhood and social mobility on linear growth through adolescence in a population-based cohort. METHODS: Children born in Cuiaba-MT, central-western Brazil, were evaluated during 1994 - 1999. They were first assessed during 1999 - 2000 (0 - 5 years) and again during 2009 - 2011 (10 - 17 years), and their height-for-age was evaluated during these two periods.Awealth index was used to classify the SEP of each child's family as low, medium, or high. Social mobility was categorized as upward mobility or no upward mobility. Linear mixed models were used. RESULTS: We evaluated 1,716 children (71.4% of baseline) after 10 years, and 60.6% of the families showed upward mobility, with a higher percentage among the lowest economic classes. A higher height-for-age was also observed among those from families with a high SEP both in childhood (low SEP= -0.35 z-score; high SEP= 0.15 z-score, p < 0.01) and adolescence (low SEP= -0.01 z-score; high SEP= 0.45 z score, p < 0.01), whereas upward mobility did not affect their linear growth. CONCLUSION: Expressive social mobility was observed, but SEP in childhood and social mobility did not greatly influence linear growth through childhood in this central-western Brazilian cohort. PMID- 29160443 TI - Body fat redistribution and changes in lipid and glucose metabolism in people living with HIV/AIDS. AB - INTRODUCTION: The HIV lipodystrophy syndrome is characterized by changes in metabolism, and body composition that increase cardiovascular risk of people living with HIV/AIDS (PLWHA) using highly active antiretroviral therapy (HAART). OBJECTIVE: To assess the prevalence of lipodystrophy and changes in lipid and glucose metabolism in PLWHA in use of HAART. METHODS: For the anthropometric evaluation we measured weight, height and abdominal circumference (AC). For the lipodystrophy evaluation we conducted physical examination (subjective) and the (objective) examination of absorptiometry with X-ray dual energy (DEXA) by fat mass ratio (FMR). We also conducted lipid profile tests and fasting glucose and used the criteria suggested by The National Cholesterol Education Program III for metabolic disorders classification. RESULTS: The final sample consisted of 262 patients with a mean age of 44.3 +/- 10.2 years. Lipodystrophy, according to the physical examination, was present in 47.7% (95%CI 41.7 - 53.8) of patients, while the prevalence using FMR (DEXA) was 40.8% (95%CI 33.1 - 48.5). Most (53.0%; 95%CI 47.0 - 59.1) of the patients showed increased abdominal adiposity according to AC. The most prevalent metabolic alterations were reduced HDL (67.6%; 95%CI 61.9 73.2) and hypertriglyceridemia (55.7%; 95%CI 49.7 - 61.7). CONCLUSION: The high prevalence of lipodystrophy and changes in lipid and glucose metabolism show the importance of early intervention in this group of patients to prevent cardiovascular complications. PMID- 29160444 TI - Family context and the physical activity of adolescents: comparing differences. AB - INTRODUCTION: Family context plays an important role with regard to the physical activity (PA) of adolescents. Intense changes in family composition, including an increase of single-parent structures can affect behavior. OBJECTIVE: To estimate the prevalence of PA, between boys and girls of 11-17 years old, and investigate its association with family context variables. METHODS: A cross-sectional population-based study "The BH Health Study" was conducted in two health districts of Belo Horizonte. The outcome was PA (>= 300 minutes/week), which was created from a score that combined time and frequency of cycling and walking to school and leisure time. The independent variables were family context, sociodemographic characteristics and nutritional status. Poisson regression was used with a robust variance and was stratified by gender. RESULTS: 1,015 adolescents participated, 52.8% of whom were male, with a mean age of 14 (+/- 1.9) years old. The prevalence of PA was 38.8% for girls and 54.5% for boys. Among girls, the family context variables were not significantly associated with PA. Boys were more active when there was an adult in the household reported who did PA (PR = 1.26; 95%CI 1.02 - 1.55) and when living with a single mother (PR = 1.63; 95%CI 1.01 - 2.63). It was also observed that boys that live with their mother and father (PR=1.90; 95%CI 1.06 - 3.41) or only with their mother (PR = 1.82; 95%CI 1.01 - 3.27) reported did PA more frequently in their free time. CONCLUSION: The presence of an active adult in the household, mainly the mother, appears to be an important factor associated with boys' PA. PMID- 29160445 TI - Epidemiological profile of tuberculosis in Sao Paulo municipality from 2006 to 2013. AB - BACKGROUND: Tuberculosis is a serious public health problem that still persists in the world and in Brazil. The municipality of Sao Paulo, Brazil, is among the prioritized ones in the country for disease control. OBJECTIVE: To describe the epidemiological profile of all new tuberculosis cases in Sao Paulo municipality reported between the years 2006 and 2013. METHODS: The variables selected for the study were: socioeconomic, demographic and clinical-epidemiologic obtained through the online information system TB-WEB. A descriptive analysis of the data was performed to undertake the comparison among the years. To study the historical series, linear trend analysis was held. RESULTS AND DISCUSSION: There was an increase in the tuberculosis incidence rate in children under 15 years and in homeless people. The cure rate has improved as the proportion of completion of supervised treatment and the proportion of cases diagnosed by primary care clinics. The disease is unevenly distributed within the municipality of Sao Paulo and there are districts that were not able to improve the tuberculosis control. CONCLUSION: The municipal tuberculosis program control needs to target the vulnerable groups and the regions of the city where the incidence rates are higher. PMID- 29160446 TI - National Survey on Access, Use and Promotion of Rational Use of Medicines: methods. AB - The Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos -Servicos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services) aimed to characterize the organization of pharmaceutical services in the Primary Health Care of the Brazilian Unified Health System (SUS). PNAUM - Services is a cross-sectional and evaluative study, with planned sample of 600 cities, held between 2014 and 2015, composed of a remote phase, with telephone interviews with health managers. Of these 600 cities, 300 were selected for a survey on health services. We selected the 27 capitals, the 0.5% largest cities of each region, and the remaining cities were drawn. The estimate of the representative national sample size considered three levels: cities, medicine dispensing services, and patients. The interviews were carried out with a structured questionnaire specific for: municipal secretaries of health, professionals responsible for pharmaceutical services in the city, professionals responsible for the dispensing of medicines, physicians, and patients. The secondary data were obtained in official databases, in the latest update date. PNAUM - Services was the first nationwide research aimed at the assessment and acquisition of national and regional indicators on access to medicines, as well as use and rational use, from the perspective of various social subjects. PMID- 29160447 TI - Financing of Pharmaceutical Services in the municipal management of the Brazilian Unified Health System. AB - OBJECTIVE: To discuss factors related to the financing of the Basic Component of Pharmaceutical Services within the municipal management of the Brazilian Unified Health System. METHODS: The Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos no Brasil - Servicos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services) is a cross sectional, exploratory, and evaluative study that performed an information survey in a representative sample, stratified by Brazilian regions It considered different study populations in the sampling plan, which represent primary health care services in the cities. Data were collected in 2015 by two methods: in person, by applying direct observation scripts and interviews with users, physicians, and professionals responsible for the dispensing of medicines in primary care services; by telephone interviews with municipal health managers and municipal professionals responsible for Pharmaceutical Services. The results were extracted from the questionnaires applied by telephone. RESULTS: Of the sample of 600 eligible cities, we collected 369 interviews (61.5%) with secretaries and 507 (84.5%) with pharmaceutical services managers. 70.8% of the cities have a computerized management system; and 11.9% have qualification/training of professionals. More than half (51.3%) of the cities received funds for the structuring of pharmaceutical services, and almost 60% of these cities performed this type of spending. In 35.4% of cases, municipal secretaries of health said that they use resources of medicines from the Componente Basico da Assistencia Farmaceutica (CBAF - Basic Component of Pharmaceutical Services) to cover demands of other medicines, but only 9.7% believed that these funds were sufficient to cover the demands. The existence of a permanent bidding committee exclusively for acquiring medicines was reported in 40.0% of the cities. CONCLUSIONS: We found serious deficiencies in the public financing of medicines, as well as little concern about the formality in the use of public resources, expenses that meet individual demands to the detriment of the community, insufficient resources allocated to the Basic Component of Pharmaceutical Services, and exhaustion of the financing model. PMID- 29160448 TI - Availability of essential medicines in primary health care of the Brazilian Unified Health System. AB - OBJECTIVE: To characterize the availability of tracer medicines in pharmaceutical services in primary health care of the Brazilian Unified Health System (SUS). METHODS: This is a cross-sectional and evaluative study, part of the Pesquisa Nacional Sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015). To analyze the availability of medicines, we verified 50 items selected from the Relacao Nacional de Medicamentos Essenciais (Rename - National List of Essential Medicines) of 2012. Observation scripts were applied to medicine dispensing services in the primary health care. Interviews were carried out with patients, health care professionals, and public managers, using semi-structured questionnaires. The availability index was presented as the percentage of health units where the medicines were available. For statistical analysis, absolute, relative, and mean frequencies were presented (with 95% confidence intervals). The comparison of groups was carried out by Pearson Chi square tests or variance analysis, when needed. RESULTS: One thousand, one hundred, and seventy-five observation scripts were filled in a national representative sample composed by 273 cities. Statistically significant differences were observed regarding the type of unit, infrastructure, and presence of a pharmacist between regions of Brazil. The average availability of tracer medicines in primary health care was 52.9%, with differences between regions and sampling strata. This index increased to 62.5% when phytotherapic medicines were excluded. We found limited availability of medicines for treatment of chronic and epidemiological diseases, such as tuberculosis and congenital syphilis. CONCLUSIONS: The low availability of essential medicines purchased centrally by the Brazilian Ministry of Health indicates deficiencies in supply chain management. The different views on the availability of tracer medicines in SUS confirm the general availability verified in this study. Among patients, about 60% said they obtain medicines in SUS units, data consistent with the lack of medicines reported by medicine dispensers and in line with physicians' evaluations. PMID- 29160449 TI - Management of pharmaceutical services in the Brazilian primary health care. AB - OBJECTIVE: To identify limiting factors in the management of pharmaceutical services in the primary health care provided by the Brazilian Unified Health System (SUS). METHODS: This study was based on the data from the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos no Brasil (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines), and it was conducted by interviews with professionals responsible for pharmaceutical services in Brazilian cities, in 2015. To identify the management limiting factors, we considered the organizational, operational, and sustainability indicators of the management. For the analyses, we included the weights and structure of analysis plan for complex samples. The results were expressed by frequencies and measures of central tendency with 95% confidence interval, considering the Brazilian geographic regions. RESULTS: We identified the following limiting factors: lack of pharmaceutical services in the Municipal Health Secretariat organization chart (24%) and in the health plan (18%); lack of participation of managers in the Health Board and the absence of reference to this topic in the agenda of meetings (58.4%); lack of financial autonomy (61.5%) and lack of knowledge on the available values (81.7%); lack of adoption of operational procedures (about 50%) for selection, scheduling, and acquisition; and the fact that most professionals evaluate the organization of pharmaceutical services as good and great (58.8%), despite the worrisome indicators. CONCLUSIONS: Pharmaceutical services management is currently supported by a legal and political framework that should guide and contribute to improve the pharmaceutical services in the Brazilian Unified Health System primary health care. However, there is a mismatch between the goals established by these guidelines and what is actually happening. PMID- 29160450 TI - Characterization of the selection of medicines for the Brazilian primary health care. AB - OBJECTIVE: To characterize the process of selection of medicines for primary health care in the Brazilian regions. METHODS: This article is part of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015), a cross-sectional study that consisted of an information gathering in a sample of cities in the five regions of Brazil. The data used were collected by interviews with those responsible for pharmaceutical services (PS) (n = 506), professionals responsible for the dispensing of medicines (n = 1,139), and physicians (n = 1,558). To evaluate the difference between ratios, we adopted the Chi-square test for complex samples. The differences between the averages were analyzed in generalized linear models with F-test with Bonferroni correction for multiple comparisons. The analyses considered significant had p<=0.05. RESULTS: The professionals responsible for pharmaceutical services reported non-existence of a formally constituted Pharmacy and Therapeutics Committee (PTC) (12.5%). They claimed to have an updated (80.4%) list of Essential Medicines (85.3%) and being active participants of this process (88.2%). However, in the perception of respondents, the list only partially (70.1%) meets the health demands. Of the interviewed professionals responsible for the dispensing of medicines, only 16.6% were pharmacists; even so, 47.8% reported to know the procedures to change the list. From the perspective of most of these professionals (70.9%), the list meets the health demands of the city. Among physicians, only 27.2% reported to know the procedures to change the list, but 76.5% would have some claim to change it. Most of them reported to base their claims in clinical experiences (80.0%). For 13.0% of them, the list meets the health demands. CONCLUSIONS: As this is the first national survey of characterization of the process of selection of medicines within primary health care, it brings unpublished data for the assessment of policies related to medicines in Brazil. PMID- 29160451 TI - Main characteristics of patients of primary health care services in Brazil. AB - OBJECTIVE: To characterize patients of primary health care services according to demographic and socioeconomic aspects, habits and lifestyle, health condition, and demand for health services and medicines. METHODS: This study is part of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services), a cross-sectional study carried out between 2014 and 2015. Interviews were conducted with patients over the age of 17 years, with a standardized questionnaire, in primary health care services of a representative sample of cities, stratified by regions of Brazil. The analysis was performed for complex samples and weighted according to the population size of each region. RESULTS: A total of 8,676 patients were interviewed, being 75.8% women, most of them aged from 18 to 39 years; 24.2% men, most of them aged from 40 to 59 years; 53.7% with elementary school; 50.5% reported to be of mixed race ethnicity, 39.7%, white, and 7.8%, black. Half of patients were classified as class C and 24.8% received the Bolsa Familia benefit. Only 9.8% had health insurance, with higher proportion in the South and lower in the North and Midwest. The proportion of men who consumed alcohol was higher than among women, as well as smokers. The self-assessment of health showed that 57% believed it to be very good or good, with lower proportion in the Northeast. The prevalence of chronic diseases/conditions, such as hypertension (38.6%), dyslipidemia (22.7%), arthritis/rheumatism (19.4%), depression (18.5%), diabetes (13.6%), and others are higher in these patients them among the general population. Medicines were predominantly sought in the health care service or in pharmacies of the Brazilian Unified Health System. CONCLUSIONS: It was possible to characterize the profile of patients of Primary Health Care, but the originality of the research and its national scope hinders the comparison of results with official data or other articles. PMID- 29160452 TI - Technical issues and conservation conditions of medicines in the primary health care of the Brazilian Unified Health System. AB - OBJECTIVE: To characterize the technical issues and conditions of medicines conservation in Primary Health Care of Brazilian regions, responsible for pharmacy/dispensing unit profile; environmental, storage, and dose fractioning conditions; inventory control and waste management; fire and electrical failure safety items; transportation problems; advertising regulation; and pharmacovigilance. METHODS: This article is part of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos (National Survey on Access, Use and Promotion of Rational Use of Medicines - Services)-, a cross-sectional and exploratory study, of evaluative nature, consisting of an information survey within a representative sample of municipalities, stratified by Brazilian regions, which constitute the study domains, and a sample of Primary Health Care services. Pharmaceutical services (PS) were directly observed with photographic record and face-to-face interviews with those responsible for the dispensing of medicines and over the telephone with those responsible for pharmaceutical services. Data were processed with the SPSS(r) software version 21. RESULTS: The investigated dimensions showed relevant deficiencies and inequalities between the regions, generally more favorable in the Southeast and Midwest regions and weaker in the Northeast and North regions. We verified non-compliance with technical requirements and conditions essential to the conservation of medicines, which may interfere with the maintenance of stability and, thus, on their quality, efficacy, and safety. The regulation of advertising/promotion of medicines is still incipient and there is some progress in the structuring of mechanisms regarding pharmacovigilance. CONCLUSIONS: The sanitary situation of medicines in Brazilian Primary Health Care is alarming due to the violation of the specific sanitary legislation for dispensing establishments and due to a wide range of requirements essential to the conservation of medicines. We observed a disconnection between the efforts made in the Brazilian Unified Health System to promote access to medicines for all population and the organization and qualification of pharmaceutical services. PMID- 29160453 TI - Conceptions on pharmaceutical services in Brazilian primary health care. AB - OBJECTIVE: To identify and discuss the conceptions of pharmaceutical services in Brazilian Primary Health Care, according to different subjects. METHODS: This study is part of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015), which is composed of an information survey in a representative sample of cities, stratified according to Brazilian regions, and a subsample of primary health care services. Municipal secretaries of health, those responsible for pharmaceutical services, and those responsible for medicine delivery in pharmacies/dispensing units of the selected services were interviewed. The questionnaires included one question about the understanding of the interviewee regarding pharmaceutical services. The content analysis technique was used to apprehend, in the statements, the meanings attributed to pharmaceutical services, which were subsequently classified into categories according to their main conceptions. RESULTS: Among the wide diversity of conceptions on pharmaceutical services (PS), we highlight the ones focused on 1) logistic control of medicines with activities concerning guidance or information on their use and 2) guidance or information to users on the use of medicine. The findings reveal a shifting tendency from a medicine-focused conception to one that considers the users and their needs as the final recipient of these actions. However, the lack of references to conceptions regarding care management and integrality point out the slowness of this change; after all, this is a social and historical process that comprises the production of meanings that transcend legal, logistic, and technical arrangements in pharmaceutical services. CONCLUSIONS: The diversity of conceptions expresses the several meanings attributed to pharmaceutical services; we also identified, in their reorientation process, a movement that reflects a gradual shift in the technical paradigm, from the focus on medicine logistics to a user-oriented approach of health services. PMID- 29160454 TI - Pharmaceutical care in Brazil's primary health care. AB - OBJECTIVE: To characterize the activities of clinical nature developed by pharmacists in basic health units and their participation in educational activities aiming at health promotion. METHODS: This article is part of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015), a cross-sectional and exploratory study, of evaluative nature, consisting of a survey of information in a representative sample of cities, stratified by the Brazilian regions that constitute domains of study, and a subsample of primary health care services. The interviewed pharmacists (n=285) were responsible for the delivery of medicines and were interviewed in person with the use of a script. The characterization of the activities of clinical nature was based on information from pharmacists who declared to perform them, and on participation in educational activities aiming at health promotion, according to information from all pharmacists. The results are presented in frequency and their 95% confidence intervals. RESULTS: From the interviewed subjects, 21.3% said they perform activities of clinical nature. Of these, more than 80% considered them very important; the majority does not dispose of specific places to perform them, which hinders privacy and confidentiality in these activities. The main denominations were "pharmaceutical guidance" and "pharmaceutical care." The registration of activities is mainly made in the users' medical records, computerized system, and in a specific document filed at the pharmacy, impairing the circulation of information among professionals. Most pharmacists performed these activities mainly along with physicians and nurses; 24.7% rarely participated in meetings with the health team, and 19.7% have never participated. CONCLUSIONS: Activities of clinical nature performed by pharmacists in Brazil are still incipient. The difficulties found point out to the professionals' improvisation and effort. The small participation in educational activities of health promotion indicates little integration of pharmacists with the health team and of pharmaceutical services with other health actions. PMID- 29160455 TI - Workforce in the pharmaceutical services of the primary health care of SUS, Brazil. AB - OBJECTIVE: To characterize the workforce in the pharmaceutical services in the primary care of the Brazilian Unified Health System (SUS). METHODS This is a cross-sectional and quantitative study, with data from the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015). For the analysis, we considered the data stratification into geographical regions. We analyzed the data on workers in the municipal pharmaceutical services management and in the medicine dispensing units, according to the country's regions. For the statistical association analysis, we carried out a Pearson correlation test for the categorical variables. RESULTS: We analyzed 1,175 pharmacies/dispensing units, 507 phone interviews (495 pharmaceutical services coordinators), and 1,139 professionals responsible for medicine delivery. The workforce in pharmaceutical services was mostly constituted by women, aged from 18 to 39 years, with higher education (90.7% in coordination and 45.5% in dispensing units), having permanent employment bonds (public tender), being for more than one year in the position or duty, and with weekly work hours above 30h, working both in municipal management and in medicine dispensing units. We observed regional differences in the workforce composition in dispensing units, with higher percentage of pharmacists in the Southeast and Midwest regions. CONCLUSIONS: The professionalization of municipal management posts in primary health care is an achievement in the organization of the workforce in pharmaceutical services. However, significant deficiencies exist in the workforce composition in medicine dispensing units, which may compromise the medicine use quality and its results in population health. PMID- 29160456 TI - Infrastructure of pharmacies of the primary health care in the Brazilian Unified Health System: Analysis of PNAUM - Services data. AB - OBJECTIVE: To characterize the infrastructure of the primary health care pharmacies of the Brazilian Unified Health System, aiming at humanizing the offered services. METHODS: This is a cross-sectional study, of quantitative approach, from data obtained in the Pesquisa Nacional de Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015). Information on 1,175 pharmacies/dispensing units were gathered from direct observation and assessment of dispensing units installations conducted by trained researchers who used a standardized form. The analyzed variables refer to the physical structure of pharmacies or medicine dispensing units of the health units under research. RESULTS: The pharmacy area was greater than 14 m2 in 40.3% of the sampled units, highlighting those from Midwest (56.9%) and Southeast (56.2%) regions and those of Northeast, with only 23.3%. About 80.2% units had waiting rooms with chairs for patients, 31.8% of them had dispensing areas inferior to 5m2, while in 46.2% these areas were superior to 10m2. Bars were found in service counters in 23.8% of health units, thus separating the patient from the professional; 44.1% had internet access. In most units, the area of medicine storage had no refrigerator or freezer for their exclusive storage and 13.7% had a specific room for pharmaceutical consultation. CONCLUSION: Aiming at achieving care humanization and improving working conditions for professionals, the structuring of the environment of pharmacy services is necessary. This would contribute to the better qualification of pharmacy services, comprising more than medicine delivery. Data on the Northeast region indicated less favorable conditions to the development of adequate dispensing services. Based on the panorama pointed out, we suggest the expansion of stimulus concerning the physical structure of pharmaceutical services, considering regional specificities. PMID- 29160457 TI - Medicine dispensing service in primary health care of SUS. AB - OBJECTIVE: To characterize the medicine dispensing services in the primary health care network in Brazil and in its different regions, aiming to promote the access and rational use of medicines. METHODS: This is a cross-sectional, quantitative study with data obtained from the Pesquisa Nacional sobre Acesso, Utilizacao e Uso Racional de Medicamentos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines), 2015. Observation visits were carried out in 1,175 dispensing units, and interviews were held with 1,139 professionals responsible for the dispensation of medicines in the dispensing units and 495 municipal coordinators of pharmaceutical services. RESULTS: More than half (53%) of the units presented a space smaller than 10 m2 for dispensing of medicines; 23.8% had bars or barriers between users and dispenser; 41.7% had computerized system; and 23.7% had counters for individual care. Among those responsible for dispensation, 87.4% said they always or repeatedly inform users how to use the medicines, and 18.1% reported developing some type of clinical activity. Isolated pharmacies presented a more developed physical and personal structure than those belonging to health units, but we found no significant differences regarding the information provided and the development of clinical activities. CONCLUSIONS: There are major differences in the organization models of dispensation between cities, with regional differences regarding the physical structure and professionals involved. The centralization of medicine dispensing in pharmacies separated from the health services is associated with better structural and professional conditions, as in the dispensing units of the South, Southeast, and Midwest regions. However, the development of dispensation as health service does not prevail in any pharmacy or region of the Country yet. PMID- 29160458 TI - Health-related quality of life of patients of Brazilian primary health care. AB - OBJECTIVE: To analyze the Health-Related Quality of Life (HRQoL) of patients of the primary health care of the Brazilian Unified Health System (SUS) and its associated factors. METHODS: This is a cross-sectional study with data from the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015). Data were collected with a questionnaire that included the EuroQol 5 Dimensions (EQ-5D) instrument. Patients from the five regions of Brazil were interviewed. Multiple linear regression was used to analyze their Health-Related Quality of Life and its associated factors. RESULTS: Of the total of 8,590 patients, the most frequent dimensions were pain/discomfort (50.7%) and anxiety/depression (38.8%). About 10% of the patients reported extreme problems in these dimensions. The following factors were significantly associated with a worse quality of life: being female; having arthritis, osteoarthritis, or rheumatism; cerebrovascular accident; heart disease; depression; health self-assessment as poor or very poor; drinking alcoholic beverages once or more per month; dieting to lose weight, avoiding salt consumption, and reducing fat intake. Significant association was observed between a better quality of life and: living in the North and Southeast regions of Brazil; practicing physical activities; and having a higher educational level. No association was observed with factors related to the health services. CONCLUSIONS: The Health-Related Quality of Life of patients was influenced by demographic and socioeconomic factors that were related to health conditions and lifestyle, being useful to guide specific actions for promoting health and the integral care to patients of the Brazilian Unified Health System. PMID- 29160459 TI - Characterization of the institutionalization of pharmaceutical services in Brazilian primary health care. AB - OBJECTIVE: To characterize the current stage of the institutionalization of pharmaceutical services in Brazilian cities. METHODS: This study is part of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines), a cross-sectional, exploratory, and evaluative study composed by an information survey in a representative sample of cities, stratified by Brazilian regions. We interviewed municipal secretaries of health, responsible for pharmaceutical services, and pharmacists responsible for the dispensing of medicines. The variables selected from the interviews were grouped into five dimensions that defined three stages of pharmaceutical services institutionalization: incipient (0%-34.0%), partial (35.0%-69.0%), and advanced (70.0%-100%), estimated based on the interviewees' answers. Frequencies were estimated with 95% confidence intervals. For the statistical association analysis, the Chi-square test was applied, with significance level of p<0.05. RESULTS: Our results show a partial and heterogeneous process of institutionalization of pharmaceutical services in Brazil, and an advanced stage in formal structures, such as the municipal health plans and the existence of a standardized list of medicines. The analysed variables in the "organization, structure, and financing" dimension configured stages that range from partial to advanced. The management presented partial institutionalization, positively showing the existence of computerized system, but also disparate results regarding the autonomy in the management of financial resources. Indispensable items related to the structure expressed disparities between the regions, with statistically significant differences. CONCLUSION: The study showed a partial and heterogeneous process of institutionalization of pharmaceutical services in Brazilian cities, showing regional disparities. Variables related to the normative aspects of institutionalization were positively highlighted in all dimensions; however, it is necessary to conduct new studies to evaluate the institutionalization of pharmaceutical services' finalistic activities. PMID- 29160460 TI - Polypharmacy: a challenge for the primary health care of the Brazilian Unified Health System. AB - OBJECTIVE: To characterize the polypharmacy in primary health care patients and to identify its associated factors. METHODS: This is a cross-sectional, exploratory, and evaluative study, part of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015). The variable of interest was polypharmacy, defined as the use of five or more medicines. We sought to identify the association of sociodemographic variables and indicators of health conditions to polypharmacy. For group comparison, the Pearson's Chi-square test was used. The association between polypharmacy and explanatory variables was evaluated by logistic regression model (p < 0.05). The quality of the adjustment was verified by Hosmer-Lemeshow test. RESULTS: The prevalence of polypharmacy among medicine users was 9.4% (95%CI 7.8 12.0) in the general population and 18.1% (95%CI 13.6-22.8) in older adults above 65 years old. We found statistically significant association between polypharmacy and age above 45 years, lower self-perception of health, presence of chronic diseases, having health insurance, care in emergency services, and region of the Country. South users presented the highest chances to polypharmacy. The most used medicines were those of the cardiovascular system, being compatible with the national epidemiological profile. CONCLUSIONS: Polypharmacy is a reality in the population met within the primary care of Brazilian Unified Health System and may be related to excessive or inappropriate use of medicines. The main challenge to qualify health care is to ensure that prescription of multiple medicines be appropriate and safe. PMID- 29160461 TI - Indicators related to the rational use of medicines and its associated factors. AB - OBJECTIVE: To evaluate indicators related to the rational use of medicines and its associated factors in Basic Health Units. METHOD: This is a cross-sectional study carried out in a representative sample of Brazilian cities included in the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015). The data were collected by interviews with users, medicine dispensing professionals, and prescribers; and described by prescription, dispensing, and health services indicators. We analyzed the association between human resources characteristics of pharmaceutical services and dispensing indicators. RESULTS: At national level, the average number of medicines prescribed was 2.4. Among the users, 5.8% had antibiotic prescription, 74.8% received guidance on how to use the medicines at the pharmacy and, for 45.1% of users, all prescribed medicines were from the national list of essential medicines. All the indicators presented statistically significant differences between the regions of Brazil. The dispensing professionals that reported the presence of a pharmacist in the unit with a working load of 40 hours or more per week presented 1.82 more chance of transmitting information on the way of using the medicines in the dispensing process. CONCLUSION: The analysis of prescription, dispensing, and health services indicators in the basic health units showed an unsatisfactory proportion of essential medicines prescription and limitations in the correct identification of the medicine, orientation to the patients on medicines, and availability of therapeutic protocols in the health services. PMID- 29160462 TI - Access to medicines: relations with the institutionalization of pharmaceutical services. AB - OBJETIVE: To analyze the relationship between access to medicines by the population and the institutionalization of pharmaceutical services in Brazilian primary health care. METHODS: This study is part of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services 2015), a cross-sectional, exploratory, and evaluative study composed of an information survey in a representative sample of cities, stratified by Brazilian regions. Access was defined based on the acquisition of medicines reported by the patient, ranging between: total, partial, or null. The institutionalization of pharmaceutical services was analyzed based on information provided by pharmaceutical services providers and by those responsible for medicines delivery. Chi-square test and multinomial logistic regression were used in the statistical analysis. RESULTS: Full access to medicines was greater when professionals affirmed there were the following aspects of the dimensions: "management tools," "participation and social control," "financing," and "personnel structure," with significant associations in the bivariate analysis. The "pharmaceutical care" dimension did not achieve such an association. After multinomial logistic regression, full access was more prevalent when those in charge of pharmaceutical services stated that: they always or repeatedly attend meetings of the Municipal Health Council, OR = 3.3 (95%CI 1.5-7.3); there are protocols for medicines delivery, OR = 2.7 (95%CI 1.2-6.1); there is computerized system for managing pharmaceutical services, OR = 3.9 (95%CI 1.9-8.0); those responsible for medicines delivery reported having participated in a course or training for professionals in the past two years, OR = 2.0 (95%CI 1.1-3.5); there is computerized system for pharmaceutical services management, OR = 4.3 (95%CI 2.4-7.5). CONCLUSIONS: Aspects related to the institutionalization of pharmaceutical services have been strongly related to access to medicines. Our results indicate the need to prioritize its implementation, contributing to its consolidation in Brazil and to the effectiveness of health services regarding the purposes of pharmaceutical services policies. PMID- 29160463 TI - Access to medicines by patients of the primary health care in the Brazilian Unified Health System. AB - OBJECTIVE: To evaluate the access to medicines in primary health care of the Brazilian Unified Health System (SUS), from the patients' perspective. METHODS: This is a cross-sectional study that used data from the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Services, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines), conducted by interviews with 8,591 patients in cities of the five regions of Brazil. Evaluation of access to medicines used concepts proposed by Penshansky and Thomas (1981), according to the dimensions: availability, accessibility, accommodation, acceptability, and affordability. Each dimension was evaluated by its own indicators. RESULTS: For the "availability" dimension, 59.8% of patients reported having full access to medicines, without significant difference between regions. For "accessibility," 60% of patients declared that the basic health unit (UBS) was not far from their house, 83% said it was very easy/easy to get to the UBS, and most patients reported that they go walking (64.5%). For "accommodation," UBS was evaluated as very good/good for the items "comfort" (74.2%) and "cleanliness" (90.9%), and 70.8% of patients reported that they do not wait to receive their medicines, although the average waiting time was 32.9 minutes. For "acceptability," 93.1% of patients reported to be served with respect and courtesy by the staff of the dispensing units and 90.5% declared that the units' service was very good/good. For "affordability," 13% of patients reported not being able to buy something important to cover expenses with health problems, and 41.8% of participants pointed out the expense with medicines. CONCLUSIONS: Results show 70%-90% compliance, which is compatible with developed countries. However, access to medicines remains a challenge, because it is still heavily compromised by the low availability of essential medicines in public health units, showing that it does not occur universally, equally, and decisively to the population. PMID- 29160464 TI - Use of medicines by patients of the primary health care of the Brazilian Unified Health System. AB - OBJECTIVE: To characterize the use of medicines by patients of the primary health care of the Brazilian Unified Health System (SUS). METHODS: This is a cross sectional, exploratory, and descriptive study, part of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015). Interviews were carried out with patients present in the services by semi-structured questionnaires. Sociodemographic, clinical, and use of medicines variables were assessed and the use of medicines in the 30 days prior to the interview was also verified. The population was stratified into three age groups: 18 to 44, 45 to 64, and 65 years or more. The differences between the age groups were verified using the Student's t-test for continuous variables and chi-square test for the categorical ones. The complex samples analysis plan was employed. The medicines were classified according to the Anatomical Therapeutic Chemical Classification System. RESULTS: Of the 8,803 patients interviewed, 6,511 (76.2%) reported to have used medicines in the 30 days prior to the interview. On average, each patient used 2.32 medicines, without difference between the sexes. Among medicine users, 18.2% were aged 65 years or more. Compared to the other age groups, older adults presented more comorbidities, used more medicines, and self-reported worse health conditions. They were also less educated, reported worse economic situation, and lived alone. The medicines that were mostly used were "other analgesics and antipyretics" (3rd ATC level) and Losartan (5th ATC level). CONCLUSIONS: Most medicine users had lower education level and presented comorbidities. The most used medicines were the antihypertensive ones. Self-medication was higher among young people. Most patients reported to use generic medicines. The average number of medicines and the prevalence of use increased with age. Due to the characteristics observed and the difficulties in the use of medicines, older adults are in a situation of greater vulnerability. PMID- 29160465 TI - Patient satisfaction with pharmaceutical services in Brazilian primary health care. AB - OBJECTIVE: To evaluate patient satisfaction with pharmaceutical services in Brazilian primary health care. METHODS: This is a cross-sectional, exploratory, and evaluative study on a representative sample from the five Brazilian geopolitical regions resulting from the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos - Servicos, 2015 (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines - Services, 2015). The outcome was the patient's satisfaction, obtained using the item response theory. Associations were tested using Pearson's Chi-square test with sociodemographic and health variables, and multiple logistic regression analyses were carried out. The Hosmer-Lemeshow test was used to verify the adequacy of the final model. Logistic regression results were presented as odds ratio. RESULTS: The overall percentage of patients satisfied with these services was 58.4% (95%CI 54.4-62.3). The "opportunity/convenience" aspect had the lowest satisfaction percentage (49.5%; 95%CI 46.4-52.6) and "interpersonal aspects," the highest percentage (90.5%; 95%CI 88.9-91.8), significantly higher than other aspects. Sex, age group, limitations due to disease, and self-perception of health remained associated in the final multiple logistic model regarding general satisfaction. CONCLUSIONS: Most of the interviewed users were satisfied with pharmaceutical services in Brazilian cities, and the satisfaction with the customer's service was determinant in the patient's overall satisfaction. PMID- 29160466 TI - Pharmaceutical services in the primary health care of the Brazilian Unified Health System: advances and challenges. AB - This study is a synthesis of the main results of the Pesquisa Nacional sobre Acesso, Utilizacao e Promocao do Uso Racional de Medicamentos (PNAUM - National Survey on Access, Use and Promotion of Rational Use of Medicines), Evaluation Component of the Basic Pharmaceutical Services. Based on the critical narrative of the elements of Brazil's pharmaceutical policies, we discuss aspects related to the structure of the pharmaceutical services, the medicines' sanitary state, human resources, access to medicines, rational use and management. Despite the advances that reflect the commitment of the group of actors involved, the results of the Survey indicate challenges, such as equitable access to medicines, the structuring of pharmaceutical services, the improvement of logistics and administration, and the implementation of actions directed to pharmaceutical care in the health units. PMID- 29160467 TI - Pharmaceutical services in primary health care: interfederative agreement in the development of pharmaceutical policies in the Brazilian Unified Health System (SUS). PMID- 29160468 TI - National Survey on Access, Use and Promotion of Rational Use of Medicines (PNAUM): evaluation of pharmaceutical services in the primary health care. PMID- 29160470 TI - Actions of nurses in early detection of breast cancer. AB - OBJECTIVE: Identify the actions for early detection of breast cancer performed by nurses from basic health units; compare the compliance of these actions with the recommendations from the Ministry of Health; analyze the availability of documents to check these recommendations and analyze the association of variables "training," "lato sensu training," and "years of activity" of these professionals with the actions performed. METHOD: A cross-sectional study conducted with 133 nurses from 38 basic health units in the Southeast region of the municipality of Sao Paulo, interviewed with a validated questionnaire. RESULT: Most nurses reported actions to detect this neoplasm. Guidance on the first mammogram age was significantly associated with training, years of activity and availability of Basic Attention Book no 13. CONCLUSION: This study observed a positive influence of training and years of activity on the actions for early detection of breast cancer and the need for adjustments in national guidelines. PMID- 29160471 TI - Family interview guide: strategy to develop skills in novice nurses. AB - OBJECTIVE: describe the skills of nurses to conduct family interviews based on the Family Care Guide for Nursing Clinical Practice. METHOD: exploratory case study that analyzed the content of 16 guides applied to a child emergency service by a novice nurse from the family nursing area. RESULTS: the records indicated the presence of perceptual, conceptual, and executive skills required to conduct family interviews, in particular skills for the development of genograms, therapeutic relationships, and actions to fulfill family needs. FINAL CONSIDERATIONS: the Family Care Guide for Nursing Clinical Practice is a useful tool to guide the training processes, promote the development of family interview skills in novice nurses, and allow the cognitive consolidation of essential elements of patient- and family-centered care. PMID- 29160472 TI - Technical nursing students interacting with family members of hospitalized children. AB - OBJECTIVE: To understand technical nursing students' meaning of interacting with family members of hospitalized children. METHOD: Symbolic Interactionism was used as the theoretical framework and Qualitative Content Analysis was the methodological procedure. A total of eight graduates from an institution situated in the city of Osasco, Sao Paulo state, participated in this study. Data were collected through semi-structured interviews. RESULTS: A total of five representative themes were revealed: Dealing with difficult situations with family members; Perceiving oneself to be unprepared to interact with family members; Family members being a helpful tool; Developing strategies to obtain a good interaction with family members; and Teachers being facilitators of the interaction with family members. FINAL CONSIDERATIONS: To be acquainted with this experience has led to the understanding of the need to include the theme of family care in the curriculum of the Technical Nursing Course. Additionally, the present study contributed to reflections on the importance of such knowledge for this population and to the development of future studies, as this theme has been scarcely explored in the literature. PMID- 29160473 TI - Tracheal cuff pressure change before and after the performance of nursing care. AB - OBJECTIVE: Verify the changes of endotracheal cuff pressure before and after oral hygiene, head-of-bed elevation at 0o, 30o, and 60o, change in body position, aspiration of the endotracheal tube, and in-bed bathing. METHOD: The study sample was composed of 88 patients. We performed 3,696 checks from July to September 2014. RESULTS: Pressure values were analyzed in seven nursing care in the morning. Six of them were significantly altered before and after nursing procedure. In the afternoon, five of the health care provided were altered, and in the evening, only two. Most of pressure values were below recommended. CONCLUSION: There were differences before and after health care provided, showing changes in cuff pressure. In-bed bathing and head-of-bed elevation at 30o were the ones that most altered pressure values in the three working shifts. Therefore, it is necessary to measure cuff pressure at least twice per working shift, preferably after bathing. PMID- 29160474 TI - Validation of Family Management Measure for the Brazilian culture. AB - ETJECTIVE: To validate the Family Management Measure (FaMM) for Brazilian culture. METHOD: Quantitative research excerpt, following the recommendations for validation studies. The data presented refer to the last stage of the process. RESULTS: The internal consistency of the items was analyzed through Cronbach's alpha of the six domains: Child's Daily Life (0.78); Condition Management Effort (0.51); Condition Management Ability (0.55); Family Life Difficulty (0.86); View of Condition Impact (0.56); and Parental Mutuality (0.80). Exploratory factorial analysis of the instrument was carried out, obtaining an acceptable adjustment, according to validation standards. CONCLUSION: The FaMM presents evidence of validation and can be used in the Brazilian culture under the name of Instrumento de Medida de Manejo Familiar, which was adjusted in eight domains, providing varied aspects of family management and a good evaluation of the fundamental aspects of family life in the context of childhood chronic conditions. PMID- 29160475 TI - Revalidation of game for teaching blood pressure auscultatory measurement: a pilot study. AB - OBJECTIVE: To adapt a pre-existing educational game, making it specific to the teaching of blood pressure auscultatory measurement, and to apply this game in a pilot study. METHOD: The original game cards were altered by the authors and submitted to content validation by six experts in the field. After redesigns, the game was applied to 30 subjects, who answered a questionnaire (pre-test and post test) on auscultatory measurement. Data were analyzed descriptively and by the paired Student's t-test and paired Wilcoxon test. RESULTS: Throughout the content validation process, 17 of the 28 original cards were modified. Of these 17 cards, 13 obtained 80% agreement, and the rest were modified according to the judges' suggestions. The obtained grades significantly increased between pre- and the post-test. CONCLUSION: It was concluded that the reformulated game presented satisfactory evidence of content validity. Its use as a teaching-learning method was effective for this sample. PMID- 29160476 TI - Cultural adaptation of The End-Stage Renal Disease Adherence Questionnaire for hemodialysis patients. AB - OBJECTIVE: To describe the stages in the cultural adaptation of "The End-Stage Renal Disease Adherence Questionnaire" for use in Brazil. METHOD: A descriptive, transversal study with a quantitative approach. The cultural adaptation followed the steps of translation, professional committee, back translation, panel of patients and pretest. RESULTS: the translation stage created a version in Portuguese that was analyzed by specialists, who suggested alterations in the title, seven sentences in the questions and three sets of answers. In the panel of patients phase, two questions were altered. The back translation considered the original characteristics of the instrument were maintained, likewise there were no modifications in the pretest phase. The third version written in Portuguese was considered to be the final version of the questionnaire. CONCLUSION: this instrument should facilitate nursing care management in hemodialysis, enabling the monitoring of adherence among these patients and also contribute to improving the indicators of morbidity and mortality. PMID- 29160477 TI - Efficiency of cleaning and disinfection of surfaces: correlation between assessment methods. AB - OBJECTIVE: to assess the correlation among the ATP-bioluminescence assay, visual inspection and microbiological culture in monitoring the efficiency of cleaning and disinfection (C&D) of high-touch clinical surfaces (HTCS) in a walk-in emergency care unit. METHOD: a prospective and comparative study was carried out from March to June 2015, in which five HTCS were sampled before and after C&D by means of the three methods. The HTCS were considered dirty when dust, waste, humidity and stains were detected in visual inspection; when >=2.5 colony forming units per cm2 were found in culture; when >=5 relative light units per cm2 were found at the ATP-bioluminescence assay. RESULTS: 720 analyses were performed, 240 per method. The overall rates of clean surfaces per visual inspection, culture and ATP-bioluminescence assay were 8.3%, 20.8% and 44.2% before C&D, and 92.5%, 50% and 84.2% after C&D, respectively (p<0.001). There were only occasional statistically significant relationships between methods. CONCLUSION: the methods did not present a good correlation, neither quantitative nor qualitatively. PMID- 29160478 TI - Family resilience and chemical dependency: perception of mental health professionals. AB - OBJECTIVE: To learn the perception of health professionals from the Psychosocial Attention Center for Alcohol and Other Drugs regarding the resilience attributes that are critical to family members of psychoactive substance dependents. METHOD: A qualitative descriptive study conducted from February to May 2016, using a focus group technique for data collection. In total, 15 professionals participated in the study: 13 health professionals and two administrative professionals. The statements were recorded and transcribed, and these data were analyzed using the technique of thematic content analysis. RESULTS: Health professionals recognize the family resilience attributes needed for efficient and assertive communication, as well as organizational patterns and facilitating family strengths, factors that contribute to improved family relationship and family functionality. FINAL CONSIDERATIONS: This study contributed to a perspective of clinical intervention with family members that is not limited to the negative aspects of family relationship and life, such as fragility and family dysfunction. PMID- 29160479 TI - Interactive Theory of Breastfeeding: creation and application of a middle-range theory. AB - OBJECTIVE: To describe a breastfeeding theory based on King's Conceptual System. METHOD: Theoretical study that used analysis of concept, assertion synthesis, and derivation of theory for the creation of a new theory. RESULTS: King's system components were associated with elements of the breastfeeding process and a middle-range theory was created, which describes, explains, predicts, and prescribes breastfeeding by analyzing factors that precede and affect it, as well as their consequences on the breastfeeding process. CONCLUSION: The Breastfeeding Interactive Model is abstract enough to be applied in different social, cultural, political, and economic contexts, because it conceptualizes breastfeeding in systemic, dynamic, and procedural aspects. Based on a conceptual model of nursing, it contributes to the scientific construction of the subject; however it can also potentially be applied by other professionals involved in breastfeeding assistance. PMID- 29160480 TI - Possibilities of care for serodiscordant couples for HIV who got pregnant. AB - OBJECTIVE: Understanding the meaning of pregnancy for heterosexual couples facing serodiscordant situation for HIV, aiming at construction of care possibilities based on subjectivity. METHOD: Phenomenological research, theoretical philosophical-methodological framework by Martin Heidegger. Research was conducted in a University Hospital in the countryside of Southern Brazil, from September 2013 to May 2014 through a phenomenological interview, with participation of eleven couples. RESULTS: For the couples, pregnancy is part of life when they wish to have a child, even when one or both of them already have children from previous relationships. In addition, it is part of life when they consider the risks and do not want to have children in such circumstances anymore, but it happened unexpectedly. CONCLUSION: Understanding reproductive needs and demands of these couples is an aid for qualification and improvement of care as a contribution to nursing care planning towards reproductive health of these couples. PMID- 29160481 TI - Stimulus-response time to alarms of the intra-aortic balloon pump: safe care practices. AB - OBJECTIVE: To characterize the sound alarms of the Intra-Aortic Balloon Pump (IABP) during aortic counterpulsation therapy; to measure the stimulus-response time of the team to these; and to discuss the implications of increasing this time for patient safety from the alarm fatigue perspective. METHOD: This is an observational and descriptive study with quantitative and qualitative approach, case study type, carried out in a Cardiac Surgical Intensive Care Unit. RESULTS: The most audible IABP alarm was the one of high priority increased-reduced diastolic blood pressure. The stimulus-response time was 33.9 seconds on average. CONCLUSION: Managing the alarms of these equipment is essential to minimize the occurrence of the alarm fatigue phenomenon and to offer a safer assistance to patients who rely on this technology. PMID- 29160482 TI - Challenges in the end-of-course paper for nursing technical training. AB - OBJECTIVE: To verify the opinion of Nursing Technical Training students on the stages of construction of the End-of-Course Paper. METHOD: A cross-sectional study with a qualitative and quantitative approach. A total of 94 students participated from a Nursing Technical course of an institution in the State of Sao Paulo. A questionnaire was used with assertions, followed by a "Likert Scale" and open field for additional comments. RESULTS: The students gave a positive evaluation of the stages involved in completing the paper, but negative responses regarding the time available and obligatory nature (38%). Nevertheless, they understood the essence of the task, in order to foster personal and professional growth; with perspectives to advance in other modalities of the course. CONCLUSION: It is important that course administrators and professors are prepared to support their students, aiming at an effective transformation for the way of thinking and practice in health care. PMID- 29160483 TI - Nurses in the labor market: professional insertion, competencies and skills. AB - OBJECTIVE: to characterize nurses graduated from the School of Nursing of the University of Sao Paulo, from 2006 to 2012; verify their entry, facilitating factors and difficulties of these graduates in the labor market and to consider their skills and competences in the world of work. METHOD: an exploratory, descriptive study with a qualitative approach. RESULTS: out of 505 graduates, 172 (34.1%) participated in the research. Entry into the labor market was mainly via public hospital institutions, in the SE of Brazil, in the caregiving sectors. The greater part remained from one to two years in their first job. Most agreed that they were prepared to meet the health needs of the population. Furthermore, they had been encouraged to seek systematic and continuous improvement in a critical, reflexive and creative way, while combining technical-scientific knowledge and personal skills. CONCLUSION: the results show that the University of Sao Paulo has been preparing nurses for work in the labor market, in accordance with the provisions of the National Curricular Guidelines. PMID- 29160484 TI - Critical points for the control of Tuberculosis on Primary Health Care. AB - OBJECTIVE: To analyze the discourses of professionals that work on the reference service about the critical points that affects the essential attributes of the Primary Health Care (PHC) related to the control of tuberculosis in the city of Joao Pessoa. METHOD: The empirical material collected from August to October in 2014, through the interview technique was analyzed through the methodological theoretical framework of French Discourse Analysis. RESULTS: The discourses demonstrated the critical points on the control of the disease on PHC as being the lack of bond and welcoming from the professionals in relation to patients with tuberculosis. It was realized that the professionals have prejudice about the disease, that they have difficulties on the access to conducting exams, appointments and treatments, as well as there are fails on the reference and counter-referencing system. FINAL CONSIDERATIONS: Managers should be aware about the results that were found, so that facing actions can be planned and executed in order to minimize the existent of critical points. PMID- 29160485 TI - Social representations of sex and gender among trans people. AB - OBJECTIVE: To analyze the social representations of sex and gender among transsexual people, through their life histories. METHOD: Qualitative, multicenter and descriptive research. The participants were 70 transsexuals from Brazil and Costa Rica. Data were analyzed according to the technique of Content Analysis. RESULTS: Two complementary representations related to sex were identified: "Sex as a natural categorical imposition sealed and acquired (irremediably) at birth" and "Sex as an element that labels, condemns and differentiates people." Regarding gender, a single representation was associated with "synthetic-social constructions associated with (necro/bio) power, cisnormativity and culture." FINAL CONSIDERATIONS: The former absolute division of gender as social construction and of sex as considered as natural must be questioned in order to analyze both concepts as an interconnected dyad. In addition, it should be recognized that this dyad presents itself as an organizational and cognitive construct, mediated by the still prevalent cispatriarchal (necro/bio) power. PMID- 29160486 TI - Influence of Therapeutic Play on the anxiety of hospitalized school-age children: Clinical trial. AB - OBJECTIVE: To evaluate the effects of Dramatic Therapeutic Play (DTP) technique on the degree of anxiety in hospitalized school-age children. METHOD: Randomized clinical trial performed in two hospitals ofSao Paulo, between May and October 2015. The intervention consisted of the application of DTP and the outcome was evaluated through the Child Drawing: Hospital (CD: H) instrument. The Wilcoxon Mann Whitney, Corrected t, Fisher's exact and Chi-square tests were used in the analysis. Statistical significance was set at 5%. RESULTS: In all, 28 children participated in the study. The majority of children (75%) had a low anxiety score, with a mean CD: H score of 73.9 and 69.4 in the intervention and control groups respectively, and with no significant difference. CONCLUSION: Children submitted to DTP had the same degree of anxiety as those in the control group. However, it is suggested that new studies be performed with a larger number of children in different hospitalization scenarios. PMID- 29160487 TI - Educational practices of nursing in the puerperium: social representations of puerperal mothers. AB - OBJECTIVE: To understand the social representations of puerperal women regarding the contents of the educational practices carried out by nursing in the puerperium. METHOD: Descriptive and qualitative study, carried out from June to September 2014, in Fortaleza, Ceara State, Brazil. Nineteen puerperal women were administered a semi-structured interview. The Theory of Social Representations was used as a theoretical reference. Lexical analysis was performed with ALCESTE (version 2012) software. RESULTS: The contents of the representations on educational practice were associated to the nursing team's orientations, with emphasis on breastfeeding and nursing. A lack of educational action regarding self-care of the puerperal woman was also revealed. FINAL CONSIDERATIONS: It is necessary to redirect educational practices in the puerperium, in order to cover the biopsychosocial needs of women in this period of life. The educational actions should be based on the problematizing model, with a stimulus for the autonomy of puerperal mothers and valorization of their social knowledge. PMID- 29160488 TI - Profile of intimate partner violence in Family Health Units. AB - OBJECTIVE: To estimate the profile of intimate partner violence involving women in a scenario of Family Health Strategy in the municipality of Nova Iguacu (Rio de Janeiro). METHOD: A transversal study was conducted in four units with a sample of 640 women between the ages of 25 to 64. The phenomena of violence was determined using the tool Revised Conflict Tactics Scales, validated for Brazil. Statistical analysis took into consideration an estimation of prevalence in the calculation of the p values. RESULTS: The situations of violence and the sociodemographic profiles demonstrated a statistically significant relationship with the variables of educational level and housing conditions. Age, ethnicity and economic class demonstrated an association with certain types of violence, varying in type and severity. CONCLUSION: The study investigated the profile of these situations of violence and enabled reflection regarding the approaches adopted by the Family Health Strategy teams. PMID- 29160489 TI - Cross-cultural adaptation of the Filial Responsibility protocol for use in Brazil. AB - OBJECTIVE: To carry out a cross-cultural adaptation of the Filial Responsibility protocol for use in Brazil with adult child caregivers for elderly parents. METHOD: A methodological study that included the steps of initial translation, synthesis of translations, back-translation, committee of experts, pre-test, evaluation of psychometric measures and submission to authors. The protocol comprises a qualitative step, closed questions and seven scales: Filial Expectation, Subsidiary Compassion, Caregiver burden, Life Satisfaction, Personal Well-being and Quality of Relationships. RESULTS: The final version in Portuguese was applied, through a pre-test, to a sample of 30 caregivers for elderly parents. In order to verify internal consistency, we used Cronbach's alpha coefficient: Filial Expectation (alpha = 0.64), Filial Duty (alpha = 0.65), Satisfaction with Life (alpha = 0.75), Personal Wellbeing (alpha = 0.87). FINAL CONSIDERATIONS: The Brazilian version presented good conceptual and face equivalence. The results demonstrate that the concepts used in the Canadian protocol are applicable in the Brazilian context. PMID- 29160490 TI - Care management and nursing governance in a maternity ward: grounded theory. AB - ETJECTIVE: To understand the care management strategies used by nurses in the governance of nursing practice in a maternity ward. METHOD: Qualitative study based on grounded theory conducted with 27 participants, partitioned into four sample groups. The data were collected through semi-structured interviews and analyzed through open, axial, and selective coding. RESULT: The care management strategies used by the nurses were: planning professional practice, leading the nursing team, search for scientific knowledge, and training inthe best practices in obstetric care. CONCLUSION: Associating care management with nursing governance can foster better care outcomes and strengthen nursing autonomy when coordinating nursing work in maternity wards. PMID- 29160491 TI - Perception of nursing professionals on patient safety culture. AB - OBJECTIVE: To evaluate nursing professionals' perception on safety climate, to check if this perception differs between categories and if there is correlation between the Safety Attitude Questionaire (SAQ) domains and personal and professional variables. METHOD: Quantitative and transversal study held in a teaching hospital in the countryside of Sao Paulo, in Brazil. Data collection occurred in the period from April to July 2014, with the application of the SAQ. RESULTS: 259 professionals participated in the study. The domain job satisfaction obtained scores above 75 for both categories. The perception of safety climate differed between the categories for most areas, except for the recognition of stress, and there is correlation between five SAQ domains and the variables time of experience and intention to leave the profession. CONCLUSION: Knowing the professionals' perception on safety climate will contribute to a secure assistance. PMID- 29160492 TI - Use of virtual reality for treating burned children: case reports. AB - OBJECTIVE: To report the use of virtual reality (VR) in pain intensity during dressing change of two burned children hospitalized in a Burn Treatment Center (BTC) in Southern Brazil. METHOD: Case report on the use of VR during dressing change of two burned children hospitalized in a BTC, from May to July 2016. For assessing pain, a facial pain rating scale was applied at four times: just before the dressing, during the dressing without the use of VR, during the dressing with the VR, and after the use of VR. RESULTS: The use of goggles was easy to apply and well-accepted by the children, and also had a relevant effect reducing pain. CONCLUSION: VR can become an important nonpharmacological method for treating pain in burned children. PMID- 29160493 TI - Neonatal appendicitis: a survival case study. AB - OBJECTIVE: To report a case of neonatal appendicitis in a children's hospital in southern Brazil, demonstrating the impact on neonatal survival. METHOD: Case study with data collection from medical records, approved by the Institution and Ethics Committee for Research with Human Beings. RESULTS: The clinical picture is initially characterized by food intolerance, evolving to hypoactivity, alteration of vital signs and septicemia due to intestinal perforation. Management is exclusively surgical, since no case described in the literature was diagnosed preoperatively and the findings usually point to acute abdomen. CONCLUSION: A focused clinical surveillance should be established when the infant presents peritoneal irritation. Follow-up of the evolution and the worsening of the symptoms by nurses, as part of the care team in partnership with the medical team, enables an early surgical intervention, thereby avoiding complications such as septicemia and death. PMID- 29160494 TI - Managing febrile neutropenia in adult cancer patients: an integrative review of the literature. AB - OBJECTIVE: To analyze the interventions performed by health professionals with a view to managing chemotherapy-induced febrile neutropenia. METHOD: Integrative literature review, the sample of 12 primary articles was selected from the following databases: LILACS, SciELO, BVS, PubMed, CINAHL and Web of Science. RESULTS: There was a prevalence of studies, realized by doctors, focused on pharmacological treatment and on the association of methods for greater diagnostic accuracy of febrile neutropenia. A study was found on pharmaceutical management regarding antibiotic dosing efficacy and a study indicating that nurses could contribute to the identification of elderly patients who would benefit from prophylactic use of growth factor. CONCLUSION: There was a shortage of studies involving the participation of other health professionals, besides the doctors, and a knowledge gap regarding interprofessional practice in the management of interventions specific to their area of specialism, joint interventions and non-pharmacological interventions. PMID- 29160495 TI - Systemic Arterial Hypertension in people living with HIV/AIDS: integrative review. AB - OBJECTIVE: To analyze scientific productions about the relationship between HIV and Systemic Arterial Hypertension (SAH) in people living with HIV/AIDS (PLWHA). METHOD: Integrative literature review in six databases, held in March 2016. "AIDS" and "hypertension" were the keywords used in Portuguese, English and Spanish languages. We found 248 articles and selected 17. The categories formulated were "prevalence of SAH in PLWHA," "risk factors for SAH in PLWHA" and "adverse events of antiretroviral therapy (ART) that contribute to HAS." RESULTS: There is no consensus whether HIV and ART influence the SAH development, but there are several risk factors for SAH among PLWHA. It was observed that protease inhibitors medicines influence SAH the most. CONCLUSION: Guidelines for SAH prevention must be performed in all individuals, however, in PLWHA, they must focus on characteristic risk factors of this population. PMID- 29160496 TI - Supported self-care for children and adolescents with chronic disease and their families. AB - OBJECTIVE: analyze the scientific production between 2006 and 2015 on strategies for supported self-care by children and adolescents with chronic disease and their families. METHOD: integrative review of the literature conducted July and August 2016 in the databases: BDENF, LILACS, IBECS, ADOLEC, MEDLINE/PubMed and SCIELO. The 27 selected studies were analyzed and categorized into the five pillars of supported self-care: evaluation, counseling, agreement, care and accompaniment. RESULTS: only two studies covered all five pillars, evaluation was considered most, but accompaniment was essential for adherence to the therapeutics of the goal plan. There was a prevalence of actions to evaluate the emotional state of the child/adolescent/family and technological interventions to empower the individual in self-care. FINAL CONSIDERATIONS: these actions are concentrated in countries with health systems directed to the health needs of people with chronic disease. In Brazil, this is still incipient, since the actions are focused on exacerbation. PMID- 29160497 TI - Clinical indicators for nursing diagnosis Ineffective protection in adolescents with cancer. AB - OBJECTIVE: To investigate scientific evidence related to the term protection and clinical indicators and etiologic factors for nursing diagnosis Ineffective protection in adolescents with cancer. METHOD: Integrative literature review in the databases of Scopus, Web of Science, National Library of Medicine and National Institutes of Health (PubMed) and Cochrane; by intersection of the descriptors protection and childhood cancer, which resulted in seven articles. These were insufficient for a comprehension of the term protection and aspects related to its impairment, therefore it was necessary to include a further three reference books. RESULTS: Five clinical indicators and three etiologic factors associated to Ineffective protection were identified some of which were not cited in NANDA-International. CONCLUSIONS: There are clinical and etiologic factors important for the identification of ineffective protection in adolescents with cancer. PMID- 29160498 TI - Bath for dependent patients: theorizing aspects of nursing care in rehabilitation. AB - OBJECTIVE: to produce a reflective essay on what has been produced in relation to bath as a procedure related to nursing care and diagnosis for dependent patients undergoing mediate and immediate rehabilitation processes after a traumatic event. METHOD: discursive, reflective study supported by classical content analysis consisting of the following stages: a) reading of the texts in their most comprehensive form; b) emphasizing the relevant elements produced about bathing; c) reflection on texts and what is produced about bathing. RESULTS: the texts point out to three categories for nursing practice and reflection: Meaning to patients on the purposes of bathing; Representation for nurses in the work process; Representation for nurses in the management of care and nursing care planning. CONCLUSION: the reflection points out understandings on bathing as a care focused on the autonomy of nursing rehabilitation patients, requiring further investigations. PMID- 29160500 TI - ERRATUM. AB - [This corrects the article doi: 10.1590/0034-7167.2015680606i]. PMID- 29160499 TI - Theory of communicative action: a basis for the development of critical thinking. AB - Reflections on some assumptions of the theory of Communicative Action and the development of Critical Thinking in the context of training students in undergraduate nursing courses. The perspective is based on concepts of Jurgen Habermas, as a possibility for the development of critical thinking among the students of these courses. Communication is therefore understood as inherent in the training of nurses in a continuous, dynamic, dialogical process, with interventions that are related to the context of the students and that have meaning for them, in order to contribute to the promotion of Critical Thinking. PMID- 29160501 TI - ERRATUM. AB - [This corrects the article doi: 10.1590/0034-7167-2016-0352]. PMID- 29160502 TI - Large outbreaks of Chikungunya virus in Brazil reveal uncommon clinical features and fatalities. PMID- 29160503 TI - Alert: Severe cases and deaths associated with Chikungunya in Brazil. AB - Since the detection of the Chikungunya virus in America in 2013, two million cases of the disease have been notified worldwide. Severe cases and deaths related to Chikungunya have been reported in India and Reunion Island, estimated at 1 death per 1,000 inhabitants. Joint involvement in the acute and chronic phase is the main clinical manifestation associated with Chikungunya. The severity of the infection may be directly attributable to viral action or indirectly, owing to decompensation of preexisting comorbidities. In Brazil, the virus was identified in 2014, and recently, there has been a significant increase in the number of deaths caused by the Chikungunya virus infection, especially in Pernambuco. However, the numbers of fatalities are probably underreported, since for many cases, the diagnosis of Chikungunya infection may not be considered, for deaths by indirect causes. An increase in the mortality rate within months of epidemic occurrence, compared to previous years has also been reported and may be associated with Chikungunya virus infection. An in-depth investigation of reported mortality in Brazil is necessary, to measure the actual impact of the deaths, thereby, allowing the identification of possible causes. This will alert professionals about the risks, and hence, enable creation of protocols that target reducing mortality. PMID- 29160504 TI - Nasal carriage rate of methicillin resistant Staphylococcus aureus among Iranian healthcare workers: a systematic review and meta-analysis. AB - Globally, methicillin-resistant Staphylococcus aureus (MRSA) remains a major cause of healthcare-associated infections. Healthcare workers (HCWs), patients and the environment may act as reservoirs for the spread of MRSA to patients and other HCWs. Screening and eradication of MRSA colonization is an effective method of reducing the MRSA infection rate. There are limited data on the prevalence of MRSA among Iranian HCWs. We performed a systematic search by using different electronic databases including Medline (via PubMed), Embase, Web of Science, and Iranian Databases (from January 2000 to July 2016). Meta-analysis was performed using the Comprehensive Meta-Analysis (Biostat V2.2) software. The meta-analyses showed that the prevalence of S. aureus and MRSA among HCWs were 22.7% [95% confidence interval (CI): 19.3-26.6] and 32.8% (95% CI: 26.0-40.4) respectively. The high rate of nasal MRSA carriage among Iranian HCWs has been attributed to poor compliance to hand hygiene, injudicious use of antibiotics, and ineffective infection control and prevention measures. The rational use of antibiotics plus strict infection control are the main pillars for controlling multidrug resistant microorganisms such as MRSA in the hospital setting. These measurements should be applied nationally. PMID- 29160505 TI - Metabolic disorders and cardiovascular risk in people living with HIV/AIDS without the use of antiretroviral therapy. AB - INTRODUCTION: Metabolic disorders in people living with HIV/AIDS (PLH) have been described even before the introduction of antiretroviral (ARV) drugs in the treatment of HIV infection and are risk factors for cardiovascular diseases. Based on this, the purpose of this study was to assess metabolic disorders and cardiovascular risk in PLH before the initiation of antiretroviral treatment (ART). METHODS: This was a cross-sectional descriptive study of 87 PLH without the use of ART, which was carried out between January and September 2012 at a specialized infectious diseases center in Minas Gerais, Brazil. RESULTS: The main metabolic disorders in the population were low serum levels of HDL-cholesterol, hypertriglyceridemia and abdominal obesity. Dyslipidemia was prevalent in 62.6% of the study population, whereas metabolic syndrome (MS) was prevalent in 11.5% of patients assessed by the International Diabetes Federation (IDF) criteria and 10.8% assessed by the National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATPIII) criteria. Regarding cardiovascular risk, 89.7% of the population presented a low coronary risk according to the Framingham Risk Score. A greater proportion of patients diagnosed with MS presented low cardiovascular risk (80% assessed by IDF criteria and 77.8% assessed by NCEP-ATPIII criteria). CONCLUSIONS: Metabolic disorders in this population may be due to HIV infection or lifestyle (smoking, sedentary lifestyle and inadequate diet). The introduction of ART can enhance dyslipidemia, increasing cardiovascular risk, especially among those who have classic risks of cardiovascular disease. PMID- 29160506 TI - Treatment adherence in patients living with HIV/AIDS assisted at a specialized facility in Brazil. AB - INTRODUCTION: In the 1990s, Brazil adopted a public policy that allowed for universal, free access to antiretroviral therapy (ART). Since then, treatment adherence has become a new challenge for administrators of sexually transmitted disease/acquired immunodeficiency syndrome (STD/AIDS) policies. This study quantified adherence to ART and verified whether there is an association between sociodemographic variables and clinical/laboratory data in human immunodeficiency virus (HIV)-infected patients. METHODS: This was a cross-sectional, exploratory study with a quantitative approach that was conducted over 8 months. The target population contained patients who were assisted at the ambulatory care facility specialized in STD/AIDS of a medium-size city located in Northwest Sao Paulo. In order to verify the level of adherence to ART, a validated CEAT-VIH (Assessment of Adherence to Antiretroviral Therapy Questionnaire) questionnaire was used. Sociodemographic aspects and clinical/laboratory data were obtained from the medical records. The results were analyzed using the Student's t-test and Pearson's coefficient. RESULTS: Herein, 109 patients were interviewed, 56% of whom were male. The age of the population ranged 18-74 years (mean 45.67 years). Adherence to ART was classified as insufficient in 80.7% of cases. There was an association between ART adherence and presence of symptoms and/or opportunistic infection (p=0.008) and economic status (p<0.001). CONCLUSIONS: Adherence to ART among HIV carriers cared for by the public health system is low. Patients who reported a favorable economic status and those without symptoms and/or opportunistic infection demonstrated greater treatment adherence than those who needed to take more than 3 pills a day. PMID- 29160507 TI - Epidemiological profile of patients co-infected with visceral leishmaniasis and HIV/AIDS in Northeast, Brazil. AB - INTRODUCTION: Visceral leishmaniasis (VL) and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) co-infection has been a research topic of interest worldwide. In Brazil, it has been observed that there is a relative underreporting and failure in the understanding and management of this important association. The aim of this study was to analyze epidemiological and clinical aspects of patients with VL with and without HIV/AIDS. METHODS: We conducted an observational and analytical study of patients with VL followed in a Reference Service in the State of Maranhao, Brazil from 2007-2013. RESULTS: In total 126 patients were enrolled, of which 61 (48.4%) were co-infected with HIV/AIDS. There were more males among those with HIV/AIDS (85.2%, P>0.05) or with VL only (81.5%, P>0.05). These findings significantly differed based on age group (P<0.003); the majority of patients were aged 31-40 years (41.0%) and 21-30 years (32.3%) among those with and without HIV/AIDS co-infection, respectively. The incidence of diarrhea and splenomegaly significantly differed between the two groups (P=0.0014 and P=0.019, respectively). The myelogram parasitic examination was used most frequently among those with HIV/AIDS (91.8%), followed by those with VL only (69.2%). VL recurrences and mortality were significantly higher in the HIV/AIDS co-infected patients (P<0.0001 and P=0.012, respectively). CONCLUSIONS: Patients with VL with or without HIV/AIDS co-infection were mostly adult men. Diarrhea was more frequent in HIV/AIDS co-infected patients, whereas splenomegaly was more common in patients with VL only. In the group of HIV/AIDS co-infected patients, there was a higher rate of VL recurrence and mortality. PMID- 29160508 TI - Detection and genotyping of human adenovirus and sapovirus in children with acute gastroenteritis in Belem, Para, between 1990 and 1992: first detection of GI.7 and GV.2 sapoviruses in Brazil. AB - INTRODUCTION: Acute gastroenteritis (AGE) is one of the most common causes of morbidity and mortality, especially among children from developing countries. Human adenovirus (HAdV) and sapovirus (SaV) are among the agents that cause AGE. The present study aimed to detect and genotype HAdV and SaV in 172 fecal samples from children with AGE, collected during a surveillance study carried out in a low-income community in Belem, Para, between 1990 and 1992. METHODS: HAdV was detected by nested PCR, using primers Hex1deg/Hex2deg and NeHex3deg/NeHex4deg. SaV was assayed by reverse transcription PCR (RT-PCR), nested PCR, and quantitative PCR. The nucleotide sequence was determined by direct cycle sequencing. RESULTS: Overall, 43% (74/172) of samples were positive for HAdV, of which 70.3% (52/74) were sequenced and classified as belonging to five different species, mostly A and F. For SaV, positivity was 5.2% (9/172) and genotypes GI.1, GI.7, GII.1, and GV.2 were detected. CONCLUSIONS: The present results reinforce the need for further studies to obtain epidemiological data about the circulation of these viruses in Brazil, especially in the Amazon Region, where data from the early 1990's are scarce. Furthermore, the study describes for the first time the detection of SaV genotypes GI.7 and GV.2 in Brazil, showing that these types circulated in the region more than 25 years ago. PMID- 29160509 TI - Sympatry influence in the interaction of Trypanosoma cruzi with triatomine. AB - INTRODUCTION: Trypanosoma cruzi, the etiologic agent of Chagas disease, is widely distributed in nature, circulating between triatomine bugs and sylvatic mammals, and has large genetic diversity. Both the vector species and the genetic lineages of T. cruzi present a varied geographical distribution. This study aimed to verify the influence of sympatry in the interaction of T. cruzi with triatomines. Methods: The behavior of the strains PR2256 (T. cruzi II) and AM14 (T. cruzi IV) was studied in Triatoma sordida (TS) and Rhodnius robustus (RR). Eleven fifth stage nymphs were fed by artificial xenodiagnosis with 5.6 * 103 blood trypomastigotes/0.1mL of each T. cruzi strain. Every 20 days, their excreta were examined for up to 100 days, and every 30 days, the intestinal content was examined for up to 120 days, by parasitological (fresh examination and differential count with Giemsa-stained smears) and molecular (PCR) methods. Rates of infectivity, metacyclogenesis and mortality, and mean number of parasites per insect and of excreted parasites were determined. RESULTS: Sympatric groups RR+AM14 and TS+PR2256 showed higher values of the four parameters, except for mortality rate, which was higher (27.3%) in the TS+AM14 group. General infectivity was 72.7%, which was mainly proven by PCR, showing the following decreasing order: RR+AM14 (100%), TS+PR2256 (81.8%), RR+PR2256 (72.7%) and TS+AM14 (36.4%). CONCLUSIONS: Our working hypothesis was confirmed once higher infectivity and vector capacity (flagellate production and elimination of infective metacyclic forms) were recorded in the groups that contained sympatric T. cruzi lineages and triatomine species. PMID- 29160510 TI - Changes in the epidemiology of visceral leishmaniasis in Brazil from 2001 to 2014. AB - INTRODUCTION: Visceral leishmaniasis (VL) is a neglected disease, with territorial expansion and regional differences in Brazil that require explanation. This study aimed to describe changes in the epidemiology of VL in Brazil from 2001 to 2014. METHODS: The incidence rates, sociodemographic and clinical data, and case evolution were subgrouped from 2001 to 2006 and from 2007 to 2014 and presented descriptively. Spatial distribution of disease incidence rates and changes in the spatial and temporal pattern were examined. RESULTS: In total, 47,859 VL cases were reported in Brazil between 2001 and 2014, with predominance in the Northeast macroregion (55%), though the incidence rate in this region declined between the two study periods. The State of Tocantins had the highest crude rate (26.2/100,000 inhabitants), which was responsible for VL increasing in the North macroregion. VL predominated in the urban zone (70%), in children under 4 years (34%); however, an increase in the incidence of VL in adults older than 40 years was identified, with 12.3% and 31% in the first and second period, respectively. The mapping of crude rates and autochthonous canine cases showed territorial expansion. The temporal distribution of VL was consistent in Brazil in general, with no pattern observed, but regional differences were found. CONCLUSIONS: The incidence of VL is increasing in Brazil. In addition to the State of Tocantins, which had the highest rate, new outbreaks of VL have occurred in the South macroregion of Brazil with small decreases identified in the incidence rate in the Northeast. PMID- 29160511 TI - The importance of audiometric monitoring in patients with multidrug-resistant tuberculosis. AB - INTRODUCTION: A total of 771 cases of multidrug-resistant tuberculosis (MDR-TB) were reported in Brazil in 2014. Treatment of MDR-TB with aminoglycosides can produce serious side effects such as permanent and irreversible hearing loss, which occurs in 5-64% of cases, and severely compromise patient quality of life. The goal of this research was to evaluate auditory and vestibular side effects in patients treated for MDR-TB and to identify associations between these complaints and the type of aminoglycoside used. METHODS: We performed a retrospective review of 599 medical records from patients with MDR-TB who were treated at the Helio Fraga/Fiocruz Reference Center between 2006 and 2010. Cases without auditory or vestibular complaints and patients who were not treated with aminoglycoside drugs were excluded from the study. RESULTS: Of 164 eligible cases, 55 (33.5%) reported an auditory or vestibular complaint and medication was subsequently suspended, although hearing damage was not confirmed in all cases. Audiometric testing confirmed hearing loss in 11 (21.7%) of 12 cases submitted for evaluation. Hearing loss related to ototoxicity was confirmed in 15 (62.5%) cases. Tinnitus was significantly associated with the use of amikacin and streptomycin. CONCLUSIONS: Evaluations of ototoxicity symptoms were not usually reported in the routine care of patients with MDR-TB. Complaints of tinnitus were associated with amikacin and streptomycin use. These results require confirmation in future studies. PMID- 29160512 TI - Evaluation of the immunogenicity of Schistosoma mansoni egg surface. AB - INTRODUCTION: Immunogenicity of Schistosoma mansoni egg surface was examined to determine whether intact eggshells have lower antigenicity than ruptured eggs. METHODS: Swiss Webster mice were inoculated with intact or ultrasonicated S. mansoni eggs isolated from infected human feces. Mice were separated into four groups of six animals each and immunizations were performed approximately every 20 days during a 60-day period. Groups 1-4 were administered with saline solution, sonicated eggs with Freund's adjuvant, sonicated eggs without Freund's adjuvant, and intact eggs, respectively. IgG humoral immune response was assessed by ELISA using Soluble Egg Antigen produced from eggs isolated from the livers of infected mice. RESULTS: Sonicated eggs co-administered with adjuvant induced the highest humoral response at 58 days, which was 11.9-fold (95% CI 6.2-17.5) greater than the response induced by saline solution. Sonicated eggs without adjuvant induced a 4.3-fold stronger response (95% CI 2.4-6.2) than normal saline. Intact eggs induced humoral response that was nominally twice stronger (95% CI 0.8-3.2) than that induced by normal saline but the effect did not reach statistical significance. CONCLUSIONS: Soluble antigens are not abundant on the surface of S. mansoni eggs and/or are not secreted in sufficient quantities to induce a significant immune response to intact eggs. Assuming that isolation procedures had not damaged the eggs used for inoculation, our observations suggest that intact eggs either do not induce a significant immune response or, if they do, the mechanism involves insoluble antigens from the egg surface. PMID- 29160513 TI - Detection of schistosomiasis in an area directly affected by the Sao Francisco River large-scale water transposition project in the Northeast of Brazil. AB - INTRODUCTION: The development of the Sao Francisco River Integration Project [Projeto de Integracao do Rio Sao Francisco (PISF)] in the State of Ceara, Brazil, has resulted in environmental and socioeconomic changes with potential risks to public health. We aimed to determine the presence of Schistosoma mansoni infections in schoolchildren (aged 7-14 years) and workers from the construction site in an area under the direct influence of the PISF in the municipality of Brejo Santo-CE, to aid in the prevention and control of schistosomiasis. METHODS: We conducted a cross-sectional study using two S. mansoni-detection methods: detection of S. mansoni eggs by the Kato-Katz parasitological method in stool samples (assessed in triplicate for each sample) and S. mansoni circulating cathodic antigen by the point-of-care immunochromatographic rapid test (POC-CCA) in urine. RESULTS: In general, the positivity rates for S. mansoni detection were 1.9% (2/106) among schoolchildren and 2.9% (4/138) among workers. No child had evidence of S. mansoni eggs in their stools; 1.9% tested positive by the POC-CCA method. Among workers, two (1.4%) tested positive by the Kato-Katz test and three (2.2%) by the POC-CCA test. If the POC-CCA test results that were scored as traces were considered negative, then the positivity rates dropped to 0.9% and 0.7% for schoolchildren and workers, respectively. CONCLUSIONS: The active transmission of schistosomiasis in a region covered by the PISF was recognized, reinforcing the necessity to consolidate surveillance and control actions, as well as structural sanitation measures to reverse the social determinants of the disease. PMID- 29160514 TI - Influence of comorbidities on CD4+/CD8+ proportion in HIV-positive patients in Blumenau, State of Santa Catarina: a retrospective study. AB - INTRODUCTION: The objective was to identify comorbidities related to HIV-positive patients in Blumenau, State of Santa Catarina. METHODS: A retrospective, descriptive observational design study which analyzed data from 424 patients assisted by the sexually transmitted disease/acquired immunodeficiency syndrome (STD/AIDS) Specialized Care Service (SCS). RESULTS: Of 424 medical records analyzed, 388 patients presented CD4+/CD8+ ratios lower than 1. The most prevalent comorbidities were smoking, depression, alcoholism, and herpes zoster infection, in males and females. CONCLUSIONS: The most relevant comorbidity in both genders was herpes zoster, an important marker of immunity in patients. The lowest mean was observed among patients with neurotoxoplasmosis. PMID- 29160515 TI - Visceral leishmaniasis and leishmaniasis-HIV coinfection: comparative study. AB - INTRODUCTION: This study aimed to draw clinical and epidemiological comparisons between visceral leishmaniasis (VL) and VL associated with human immunodeficiency virus (HIV) infection. METHOD: Retrospective study. RESULTS: Of 473 cases of VL, 5.5% were coinfected with HIV. The highest proportion of cases of both VL and VL/HIV were found among men. A higher proportion of VL cases was seen in children aged 0-10 years, whereas coinfection was more common in those aged 18-50 years. CONCLUSIONS: VL/HIV coinfected patients presented slightly differently to and had a higher mortality rate than those with VL only. PMID- 29160516 TI - Hepatitis E seroprevalence and associated factors in rural settlers in Central Brazil. AB - INTRODUCTION: Prevalence of hepatitis E virus (HEV) infection and associated factors were investigated in rural settlements in Central Brazil. METHODS: A total of 464 settlers were interviewed, and serum samples were tested for anti HEV IgG/IgM. Positive samples were tested for HEV RNA. RESULTS: Sixteen participants (3.4%; 95% CI 2.0-5.7) were positive for anti-HEV IgG. None was positive for anti-HEV IgM. HEV RNA was not detected. Dwelling in a rural settlement for >5 years was associated with HEV seropositivity. CONCLUSIONS: The results revealed the absence of acute infection and a low prevalence of previous exposure to HEV. PMID- 29160518 TI - Evaluation of carbapenem-resistant Enterobacteriaceae in a tertiary-level reference hospital in Rio Grande do Sul, Brazil. AB - INTRODUCTION: The rapid global spread of carbapenem-resistant Enterobacteriaceae (CRE) is a threat to the health system. METHODS: We evaluated the antimicrobial susceptibility profiles of 70 CRE isolated in a tertiary hospital in Brazil between August and December 2015, and determined their resistance mechanisms. RESULTS: The most prevalent microorganism was Klebsiella pneumoniae (95.7%); it showed high-level resistance to carbapenems (>98%), with sensitivity to colistin (91.4%) and amikacin (98.6%). The bla KPC gene was detected in 80% of the CRE isolates. CONCLUSIONS: Evaluation of bacterial resistance contributes to an appropriate treatment, and the reduction of morbimortality and dissemination of resistance. PMID- 29160517 TI - Prevalence and antibiogram of methicillin resistant Staphylococcus aureus isolated from medical device-related infections; a retrospective study in Lahore, Pakistan. AB - INTRODUCTION: With the advancement of medicine and surgery, various types of medical devices have become part of treatment strategies. METHODS: Identification and antimicrobial sensitivity testing were done according to CLSI guidelines following standard microbiological practices. RESULTS: Urinary catheter infections (31%) were most frequent followed by central venous catheter (18%) and orthopedic implants (15%). Methicillin resistant Staphylococcus aureus (MRSA) was a major cause of device-related infection after Escherichia coli (21%); other pathogens were Klebsiella pneumoniae (14%), Pseudomonas spp. (10%), Acinetobacter spp. (8%) and Candida species (7%). None of MRSA was resistant to vancomycin (MIC >=16ug/mL). Resistance rates were 98% and 97% for ofloxacin and ciprofloxacin, respectively. CONCLUSIONS: Escherichia coli and MRSA are major pathogens of medical device-related infections. PMID- 29160519 TI - Ex vivo T-lymphocyte chemokine receptor phenotypes in patients with chronic Chagas disease. AB - INTRODUCTION: Elucidating the molecules involved in the inflammatory process of chronic Chagas disease may allow identification of treatment targets. METHODS: The ex vivo phenotypic expression of chemokine receptors CCR1, CCR3, CCR4, CCR5, CXCR2, CXCR3, CXCR4, and CXCR5 on the CD4+ and CD8+ T-cells of patients with chronic Chagas cardiomyopathy of varying severity was evaluated using flow cytometry. RESULTS: Differential expression of CD4+CCR3+ and CD8+CCR4+ T-cells was observed in patients with mild cardiac involvement compared, respectively, with patients with severe cardiac and asymptomatic forms of Chagas disease. CONCLUSIONS: These receptors are possibly involved in the pathogenesis of chronic Chagas cardiomyopathy. PMID- 29160520 TI - Spatial risk of tuberculosis mortality and social vulnerability in Northeast Brazil. AB - INTRODUCTION: Tuberculosis (TB) is the most common infectious disease in the world. We aimed to analyze the spatial risk of tuberculosis mortality and to verify associations in high-risk areas with social vulnerability. METHODS: This was an ecological study. The scan statistic was used to detect areas at risk, and the Bivariate Moran Index was used to verify relationships between variables. RESULTS: High-risk areas of tuberculosis mortality were statistically significantly associated with domain 2 of the Social Vulnerability Index (I=0.010; p=0.001). CONCLUSIONS: This study provides evidence regarding areas with high risk and that vulnerability is a determinant of TB mortality. PMID- 29160521 TI - Migration pattern of Toxocara canis larvae in experimentally infected male and female Rattus norvegicus. PMID- 29160522 TI - Cardiac tamponade in a patient with severe dengue fever. AB - A 26-year-old postpartum female presented with symptoms characteristic of dengue fever on the 16th day of puerperium. On the third day of the illness, the patient presented a clinical picture consistent with shock. Tests determined primary infection with dengue virus serotype 2. Cardiac tamponade was confirmed by echocardiography. This rare manifestation is described in a patient without any associated comorbidity. PMID- 29160523 TI - Infective endocarditis due to Bartonella bacilliformis associated with systemic vasculitis: a case report. AB - Infective endocarditis due to Bartonella bacilliformis is rare. A 64-year-old woman, without previous heart disease, presented with 6 weeks of fever, myalgias, and arthralgias. A systolic murmur was heard on the tricuspid area upon examination, and an echocardiogram showed endocardial lesions in the right atrium. Bartonella bacilliformis was isolated in blood cultures, defining the diagnosis of infective endocarditis using Duke's criteria. Subsequently, the patient developed clinical and laboratory features compatible with antineutrophil cytoplasmic antibody-associated vasculitis. This case presents an uncommon complication of B. bacilliformis infection associated with the development of systemic vasculitis. PMID- 29160524 TI - A fatal case of tuberculous meningitis in a child with juvenile idiopathic arthritis: a diagnostic challenge. AB - The prognosis of tuberculous meningitis, a rare form of extrapulmonary tuberculosis, depends on the stage of treatment initiation. We report a fatal case of tuberculous meningitis. The patient had received successive tumor necrosis factor (TNF) antagonists and abatacept to treat juvenile idiopathic arthritis, with negative results for polymerase chain reaction and acid-fast bacilli on smear, had normal cerebrospinal fluid (CSF) adenosine deaminase and glucose levels. Six weeks post-admission, the CSF culture demonstrated Mycobacterium tuberculosis. The altered immunological responses caused by anti TNF treatment made the diagnosis challenging. Clinicians should bear this in mind and, if suspected, treatment should be initiated immediately. PMID- 29160526 TI - Dengue fever with thrombocytopenia and gingival bleeding. PMID- 29160525 TI - Colonic basidiobolomycosis with liver involvement masquerading as gastrointestinal lymphoma: a case report and literature review. AB - Basidiobolomycosis is an unusual fungal skin infection that rarely involves the gastrointestinal tract. This study reported a 5-year-old boy with gastrointestinal basidiobolomycosis that had been misdiagnosed as gastrointestinal lymphoma. He was treated by surgical resection and a combination of posaconazole and amphotericin B deoxycholate with an acceptable response and no recurrence. PMID- 29160527 TI - Infiltration in a child's face due to borderline lepromatous leprosy. PMID- 29160528 TI - Confirmatory factor analysis of the general activities of daily living scale: further evidences of internal validity. PMID- 29160529 TI - Trajectory of brain maturation and sex-specific cognitive abnormalities in early onset psychosis. PMID- 29160530 TI - Zika virus infection followed by a first episode of psychosis: another flavivirus leading to pure psychiatric symptomatology. PMID- 29160531 TI - Lack of protocols for handling missing sessions of transcranial direct current stimulation (tDCS) in depression trials: what are the risks of neglecting missing sessions? PMID- 29160532 TI - Brazil: world leader in anxiety and depression rates. PMID- 29160533 TI - Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version (K-SADS-PL), DSM-5 update: translation into Brazilian Portuguese. PMID- 29160534 TI - Contribution of medical science in Turkey to the scientific world and the field of ophthalmology. PMID- 29160535 TI - An investigation of human beta-defensins and cathelicidin expression in patients with pterygium. AB - PURPOSE: To investigate human beta-defensins (HBDs) and cathelicidin LL-37 (LL 37) expressions in patients with pterygium. METHODS: In this retrospective consecutive case series, 26 pterygium specimens and 15 normal conjunctival specimens of 15 control subjects were in vestigated. Expressions of HBD-1, HBD-2, HBD-3, and LL-37 were assessed using immuno histochemical staining. A brown color in the cytoplasm and/or nuclei of epithelial cells indicated positive staining for HBDs and LL-37. For each antibody, the intensity of the reaction (negative [ ], weak [1+], moderate [2+], or strong [3+]) was determined to describe the immunoreactions. RESULTS: The median age was 52 years in both groups. There were no significant differences in age and sex between the groups (p=0.583, p=0.355, respectively). Of the 26 pterygium specimens, 15 (57.7%) (14 weak, 1 moderate staining) showed HBD-2 expression, which was not observed in any of the control specimens. One (3.8%) pterygium and one (6.7%) control specimen demonstrated weak staining for HBD-3. HBD-2 expression was significantly higher in the pterygium specimens than in the controls (p=0.002). None of the tissue specimens had positive staining for HBD-1 or LL-37 in either group (both; p=1.00). CONCLUSIONS: HBD-2 expression was higher in pterygium specimens than in the controls. HBD-2 expression that might be stimulated by inflammatory cytokines may be related to inflammation and fibrovascular proliferation and may play a role in pterygium pathogenesis. PMID- 29160536 TI - Use of the Ishikawa diagram in a case-control analysis to assess the causes of a diffuse lamellar keratitis outbreak. AB - PURPOSE: To identify the causes of a diffuse lamellar keratitis (DLK) outbreak using a systematic search tool in a case-control analysis. METHODS: An Ishikawa diagram was used to guide physicians to determine the potential risk factors involved in this outbreak. Coherence between the occurrences and each possible cause listed in the diagram was verified, and the total number of eyes at risk was used to calculate the proportion of affected eyes. Multivariate analysis was performed using logistic regression to determine the independent effect of the risk factors, after controlling for confounders and test interactions. RESULTS: All DLK cases were reported in 2007 between June 13 and December 21; during this period, 3,698 procedures were performed. Of the 1,682 flap-related procedures, 204 eyes of 141 individuals presented with DLK. No direct relationship was observed between the occurrence of DLK and the presence of any specific factors; however, flap-lifting enhancements, procedures performed during the morning shift, and non-use of therapeutic contact lenses after the surgery were significantly related to higher occurrence percentages of this condition. CONCLUSIONS: The Ishikawa diagram, like most quality tools, is a visualization and knowledge organization tool. This systematization allowed the investigators to thoroughly assess all the possible causes of DLK outbreak. A clear view of the entire surgical logistics permitted even more rigid management of the main factors involved in the process and, as a result, highlighted factors that deserved attention. The case-control analysis on every factor raised by the Ishikawa diagram indicated that the commonly suspected factors such as biofilm contamination of the water reservoir in autoclaves, the air-conditioning filter system, glove powder, microkeratome motor oil, and gentian violet markers were not related to the outbreak. PMID- 29160537 TI - Relationship between anterior segment and optic nerve head parameters in healthy subjects. AB - PURPOSE: To determine the relationship between anterior segment and optic nerve head (ONH) parameters. METHODS: Two hundred healthy subjects were enrolled in this study. The par-ticipants underwent measurement of anterior segment parameters with a Pentacam Scheimpflug system and imaging of the optic disc with confocal scanning laser ophthalmoscopy. Pearson's correlation coefficient was calculated to assess the associations between ONH and anterior segment parameters. Multivariate regression analyses controlling for age and disc area as confounding factors were also conducted. RESULTS: There were significant negative relationships between optic disc area and corneal thickness (p=0.03, r=-0.217) and volume (p=0.017, r=-0.239). Corneal refractive power was significantly correlated with cup area, rim area, rim volume, and cup/disc ratio (p<0.05 for all). An increase of 1 diopter in anterior corneal refractive power corresponded to a decrease of 0.022 in cup/disc ratio. Rim volume was negatively correlated with anterior chamber depth and anterior chamber volume (p<0.05 for both). A 1 mm3 increase in anterior chamber depth corresponded to a 0.154-mm3 decrease in rim volume. Mean and maximum cup depth measurements were not associated with any of the anterior segment parameters. CONCLUSIONS: In nonglaucomatous eyes, the dimensions and shape of the ONH may be related to anterior segment morphology. Therefore, it may be helpful to take anterior segment parameters into consideration in evaluating the OHN. PMID- 29160538 TI - Are the effects of hemodialysis on ocular parameters similar during and after a hemodialysis session? AB - PURPOSE: To evaluate the changes in several ocular parameters, including choroidal thickness, during and after hemodialysis. METHODS: Twenty-seven eyes of 27 patients with chronic renal failure undergoing hemodialysis were included. The patients underwent an ophthalmic examination, including intraocular pressure, central corneal thickness, iridocorneal angle, subfoveal choroidal thickness, and blood pressure, just before a hemodialysis session, during the second hour of the session, and half an hour after the end of the session. Body weight was measured before and after the session, and ultrafiltration volume was noted after the session. Central corneal thickness, intraocular pressure, and subfoveal choroidal thickness were measured by optical coherence tomography. RESULTS: In comparison with baseline levels, mean intraocular pressure and central corneal thickness increased significantly during the second hour of hemodialysis (p=0.001 and p=0.011, respectively) and showed no significant changes after hemodialysis (p=0.844 and p=0.246, respectively). Mean iridocorneal angle did not significantly change during the second hour of hemodialysis (p=0.101) and after hemodialysis (p=0.589). Mean subfoveal choroidal thickness was significantly lower during the second hour of hemodialysis (p<0.001) and after hemodialysis (p<0.001). CONCLUSIONS: Mean intraocular pressure and central corneal thickness increased and subfoveal choroidal thickness decreased during the second half of the hemodialysis session. During the second half of the session, intraocular pressure and central corneal thickness had a trend toward reduction, while subfoveal choroidal thickness had a relatively steady course. Because of possible fluctuations in the values, it would be reasonable to evaluate the changes not only from before to after hemodialysis but also during hemodialysis when analyzing the ocular effects of dialysis. PMID- 29160539 TI - Prevalence and associated factors of external punctal stenosis among elderly patients in Turkey. AB - PURPOSE: To estimate the prevalence of external punctal stenosis (EPS) in the elderly population and investigate associated factors. METHODS: A total of 278 patients >=65 years of age were evaluated for evidence of EPS from January to July 2016. Associated systemic, ocular, demographic, and lifestyle factors were investigated. Multiple logistic regression analyses were applied to evaluate the factors related to having EPS. P values <0.05 were considered statistically significant. RESULTS: The prevalence of EPS in this study population was 63.3%, with a mean age of 70.67 +/- 7.85 (65-92 years). The ocular factor that was most commonly related to EPS was chronic blepharitis (48.9%). EPS was also associated with taking glaucoma medications (95% CI, 0.08-0.96, p=0.043), smoking history (95% CI, 0.13-0.84, p=0.021), ectropion (95% CI, 0.004-0.26, p=0.001), complaints of tearing (95% CI, 1.11-3.52, p=0.02), and outdoor occupational activity (95% CI, 3.42-9.97, p<0.05). CONCLUSIONS: EPS is more common in elderly patients than in the general population. Outdoor occupational activity, taking antiglaucomatous medications, ectropion, and smoking are significantly associated with EPS. In addition, surgical treatment decisions should be made after complete evaluation and interviewing the patients. PMID- 29160540 TI - Aqueous humor concentrations of topical fluoroquinolones alone or in combination with a steroid. AB - PURPOSE: To compare the aqueous humor (AH) concentrations of moxifloxacin 0.5% and gatifloxacin 0.3% solutions alone or when treatment was combined with steroids, and to correlate these concentrations with the minimum inhibitory concentrations (MIC) for the most common endophthalmitis-causing organisms. METHODS: Patients undergoing phacoemulsification were enrolled to receive one drop of one of the following solutions: moxifloxacin (G1), moxifloxacin + dexamethasone (G2), gatifloxacin (G3), or gatifloxacin + c (G4), every 15 min, 1h before surgery. AH samples were collected before surgery and analyzed using HPLC tandem mass spectrometry. RESULTS: The mean antibiotic concentrations in the AH were: G1= 1280.8 ng/mL; G2= 1644.3 ng/mL; G3= 433.7 ng/mL; and G4= 308.1 ng/mL. The mean concentrations statistically differed between G1 and G2 (p=0.01), and G3 and G4 (p=0.008). All samples achieved the MIC for Staphylococcus epidermidis; 100% of the samples from G1 and G2, and 97% from G3 and G4 reached the MIC for fluoroquinolone-sensitive Staphylococcus aureus; 100% of the samples from G1 and G2, 88% from G3, and 72% from G4 reached the MIC for enterococci (p<0.001); and 100% of samples from G1 and G2, 59% from G3, and 36% from G4 reached the MIC for Streptococcus pneumoniae (p<0.001). For fluoroquinolone-resistant S. aureus, 23% from G1, 44% from G2, and no samples from G3 or G4 achieved the MIC (p<0.001). CONCLUSIONS: Moxifloxacin + dexamethasone demonstrated a higher concen-tration in the AH than the moxifloxacin alone. Gatifloxacin + steroids demonstrated less penetration into the anterior chamber than gatifloxacin alone. Moxifloxacin was superior to gatifloxacin considering the MIC for enterococci, S. pneumoniae, and fluoroquinolone-resistant S. aureus. PMID- 29160541 TI - Eyelid fissure dimensions in Japanese and in Brazilians of European descent over 50 years of age. AB - PURPOSE: To investigate differences in the palpebral fissure eyelid position in Japanese subjects and in Brazilian subjects of European descent over 50 years of age. METHODS: A cross-sectional study evaluating 50 Japanese subjects and 50 Bra- -zilian subjects of European descent over 50 years of age was performed to evaluate the effect of aging on eyelid position. Digital photographs were taken with the eyes in the primary position and transferred to a computer to be processed by Scion imaging software for evaluation of palpebral fissure width, height, and margin reflex distance (MRD). The data were statistically analyzed according to sex, age, and race. RESULTS: The width of the eyelid fissure in Japanese subjects was higher than that in Brazilian subjects, whereas the height of the eyelid fissure and the MRD1 was higher in Brazilians than in Japanese (p<0.01). Width, height, and MRD1 were linearly associated with age only in the Japanese group (p<0.05); this association was observed only with width in the Brazilian group (p<0.05). There were no differences according to laterality in either group (p>0.05). CONCLUSION: There are racial differences in age-related changes in the eyelids, which are more marked in Japanese subjects. PMID- 29160542 TI - Corneal biomechanical features in patients with ankylosing spondylitis. AB - PURPOSE: To evaluate the corneal biomechanical features and central corneal thickness in ankylosing spondylitis patients and to evaluate correlations of these parameters with disease activity. METHODS: The study included 51 patients diagnosed with ankylosing spondylitis (mean age, 40.80 +/- 13.15 years; range, 18 72 years) and 34 age- and sex-matched healthy controls (mean age, 42.00 +/- 12.32 years; range, 18-60 years). All underwent a complete ophthalmological and physical examination, including visual acuity testing and biomicroscopic anterior and posterior segment examinations. Corneal hysteresis, corneal resistance factor, Goldmann-correlated intraocular pressure, and corneal compensated intraocular pressure were evaluated with an ocular response analyzer, and the central corneal thickness was measured with Sirius(r) corneal tomography. The Bath Ankylosing Spondylitis Disease Activity Index, Functional Index, and Metrology Index scores were recorded. RESULTS: In the ankylosing spondylitis patients, the mean disease duration was 7.73 +/- 6.05 (range, 1-30) years. There was no statistically significant difference between the patients and controls in the corneal biomechanical features. The Goldmann-correlated intraocular pressure and corneal compensated intraocular pressure both showed positive correlations with age (p=0.003 and p=0.001, res-pectively). There was a negative correlation between corneal hysteresis and disease duration (p=0.002), and between central corneal thickness and the Bath Ankylosing Spondylitis Metrology Index score (p=0.003). CONCLUSION: This study demonstrated a significant negative correlation between corneal hysteresis and disease duration in ankylosing spondylitis patients. Furthermore, the central corneal thickness value decreased with an increase in Bath Ankylosing Spondylitis Metrology Index score, which may result in an underestimate of intraocular pressure readings and thus an inaccurate risk assessment of glaucoma. PMID- 29160543 TI - Intraocular pressure and central corneal thickness in full-term newborns. AB - OBJECTIVE: The aim of this study was to determine the central corneal thickness (CCT) and intraocular pressure (IOP) in full-term newborns and to correlate these values with the following variables: weight, sex, and post-conception age (PCA). METHODS: IOP and CCT were determined in 52 full-term newborns with a mean gestational age of 39.43 +/- 1.03 weeks and a mean birth weight of 3,273 +/- 558 g. The mean age of the neonates at the time of taking the measurements was 1.15 +/- 1.38 days after birth. IOP was determined with a Tono-Pen, and CCT was determined using a handheld ultrasound pachymeter. RESULTS: The mean overall IOP was 14.0 +/- 2.91 mmHg, and the mean IOP in male and female newborns was 13.77 +/ 2.88 mmHg and 14.32 +/- 3.05 mmHg, respectively. The mean overall CCT was 605.87 +/- 62.98 um, and the mean CCT in male and female newborns was 626.70 +/- 67.46 um and 577.45 +/- 45.50 um, respectively; the mean CCT was higher in male newborns than in female newborns. PCA was negatively associated with CCT, IOP, and weight; however, only the correlation with CCT was statistically significant. Comparisons between the sexes showed significant differences for two variables: weight and CCT. CONCLUSIONS: No relationship was found between CCT and IOP; however, we found a positive association between weight and CCT. PMID- 29160544 TI - Corneal endothelial cell density and pterygium: a cross-sectional study. AB - PURPOSE: To investigate the effects of pterygium on corneal endothelial cell density in patients with unilateral pterygium. METHODS: We performed a cross sectional analysis of data from patients with unilateral pterygium who were selected from September 1, 2015 to July 31, 2016 at Hospital de Base do Distrito Federal to assess the corneal endothelial cell density, coefficient of variation in the cell area, hexagonality, and corneal pa-chymetric results. In all patients, noncontact specular microscopy was performed in both eyes and a minimum endothelial cell count of 75 cells/mm2 was required for inclusion in the study. The contralateral eye served as the control. RESULTS: Sixty-one patients were included in the study. Twenty-nine (47.5%) patients were men and 32 (52.5%) were women (mean age, 50.84 +/- 13.8). The percentage of pterygium that invaded the cornea ranged from 4.87% to 24.59% (median, 9.70% +/- 4.99%). The mean corneal endothelial cell density (cells/mm) was lower in the pterygium eyes than in the controls (2451.83 +/- 284.96 vs. 2549.95 +/- 268.94, respectively; p=0.04). No differences in the mean coefficients of variation of cell size, hexagonality, and corneal pachymetric results were observed between the patients and controls. The Pearson correlation test showed a significant negative linear relationship between pterygium invasion and endothelial cell density [p<0.001, n=61, r=-0.553 (95% CI, -0.34 to -0.73)]. CONCLUSION: Compared with the contralateral eyes, those of patients with unilateral pterygium were associated with a decrease in corneal endothelial cell density. PMID- 29160545 TI - Benign familial fleck retina: multimodal imaging including optical coherence tomography angiography. AB - This report presents multimodal imaging of a 27-year-old woman diagnosed with benign familial fleck retina (OMIM 228980), an uncommon disorder. Fundus photographs revealed retinal flecks that affected her post-equatorial retina but spared the macular area. Fundus autofluorescence and infrared imaging demonstrated a symmetrical pattern of yellow-white fleck lesions that affected both eyes. Her full-field electroretinogram and electrooculogram were normal. An optical coherence tomography B-scan was performed for both eyes, revealing increased thickness of the retinal pigmented epithelium leading to multiple small pigmented epithelium detachments. The outer retina remained intact in both eyes. Spectral-domain optical coherence tomography angiography with split-spectrum amplitude decorrelation algorithm and 3 * 3 mm structural en face optical coherence tomography did not show macular lesions. Benign familial fleck retina belongs to a heterogenous group of so-called flecked retina syndromes, and should be considered in patients with yellowish-white retinal lesions without involvement of the macula. PMID- 29160546 TI - Cortical blindness secondary to posterior reversible encephalopathy syndrome, recovered by successful blood pressure management. AB - We report a case of cortical blindness secondary to posterior leukoencephalopathy syndrome, which was successfully treated by blood pressure management. A 66-year old white man presented at the emergency room complaining of severe frontal headache, disorientation, and progressive blurred vision. The initial physical examination disclosed a blood pressure of 200/176 mmHg. One hour later the patient exhibited mental confusion and bilateral blindness. Computed tomography and magnetic resonance imaging were performed, and a systemic workup was conducted, resulting in a diagnosis of posterior leukoencephalopathy syndrome. This syndrome is a rare manifestation of systemic hypertension that requires proper diagnosis and management to avoid irreversible brain damage. Early recognition of this condition and prompt control of the patient's blood pressure are essential because they may bring about a reversal of the syndrome, which may otherwise result in permanent brain damage. PMID- 29160547 TI - Ultrasound biomicroscopy in acetazolamide-induced myopic shift with appositional angle closure. AB - We report a case of a 49-year-old female who presented to the emergency department with blurred vision and vomiting, hours after taking two tablets of 250 mg of acetazolamide. The anterior chamber was bilaterally flat, with normal intraocular pressure in both eyes. An ultrasound biomicroscopic (UBM) examination showed bilateral ciliary effusion and complete appositional angle closure in all quadrants. Acetazolamide-induced bilateral angle closure was diagnosed. Steroid and cycloplegic therapy were initiated, and acetazolamide was discontinued. The following day, the anterior chamber had regained its volume without substantial change in the effusion size. Three weeks later, complete resolution of the ciliary effusion was verified by means of a third UBM scan. PMID- 29160548 TI - Botulinum toxin for treating unilateral apraxia of eyelid opening in a patient with congenital myotonia. AB - A 37-year-old female presented with severe apraxia of lid opening (ALO) affecting the right upper lid associated with Becker congenital myotonia (MC). The patient had a history of right upper lid ptosis for 25 years that was exacerbated over the previous month with severe incapacity to open her right eye. No other associated neurological or ophthalmic symptoms were observed. The patient was treated with botulinum toxin (BoNT-A) injection into the pretarsal and lateral canthus region of the orbicularis oculi of the affected eyelid. Treatment with BoNT-A is an effective method of managing ALO in Becker MC. This is the first case of unilateral ALO in the course of Becker MC that was successfully treated with injections of botulinum toxin. PMID- 29160549 TI - A need for standardization in visual acuity measurement. AB - Standardization of terminologies and methods is increasingly important in all fields including ophthalmology, especially currently when research and new technology are rapidly driving improvements in medicine. This review highlights the range of notations used by vision care professionals around the world for vision measurement, and the challenges resulting from this practice. The global community is urged to move toward a uniform standard. PMID- 29160550 TI - Iris metastases from systemic cancer: a report of three cases. PMID- 29160551 TI - Effects of Pilates and yoga in patients with chronic neck pain: A sonographic study. AB - BACKGROUND: Various studies have shown the efficacy of conventional isometric, Pilates and yoga exercises. However, data on the effects and comparison of these specific exercises on the cervical muscle morphology are insufficient or lacking. OBJECTIVE: To investigate the effects of different exercise treatments on neck muscles in patients with chronic neck pain. DESIGN: A randomized study. METHODS: Fifty-six patients with chronic neck pain were randomized into 3 groups as follows: Pilates group (n = 20), yoga group (n = 18) and isometric group (n = 18). Demographics and background information were recorded. The thickness and cross-sectional area of neck muscles were evaluated by ultrasound imaging. Cervical motions were measured with a goniometer. Pain severity was evaluated with the McGill Pain Scale, disability with the Neck Disability Index, quality of life with the Nottingham Health Profile, and emotional status with the Beck Depression Inventory. In addition to a conventional physio-therapy programme, 15 sessions of physical therapy, including hot pack, ultrasound, and transcutaneous electrical nerve stimulation (TENS), were provided to all patients. All groups performed the exercises for 6 weeks. The aforementioned assessments were performed before and 6 weeks after the treatment. RESULTS: Although pain, disability, depression and quality of life improved similarly within all groups (all p < 0.05), muscle thickness values as regards the semispinalis capitis were increased only in the Pilates group (p = 0.022). STUDY LIMITATIONS: The lack of complex (progressive resistive) exercise treatment protocols, short treatment duration and partial supervision. CONCLUSION: All 3 types of exercise had favourable effects on pain and functional scores, but no differences were found among the groups, except for the Pilates group, in which the semispinalis capitis muscle increased in thickness. PMID- 29160552 TI - Cotton rats (Sigmodon hispidus) possess pharyngeal pouch remnants originating from different primordia. AB - Pharyngeal pouches in mammals develop into specific derivatives. If the differentiation of the pharyngeal pouches is anomalous, their remnants can result in cysts, sinuses, and fistulae in the differentiated organs or around the neck. In the present study, we found several pharyngeal pouch remnants, such as cystic structures in thymus and parathyroid gland and fossulae extended from the piriform fossa, in the inbred cotton rats maintained at Hokkaido Institute of Public Health (HIS/Hiph) and University of Miyazaki (HIS/Mz). In HIS/Hiph, the fossulae extended from the apex of the piriform fossa into the thyroid glands and were lined with stratified squamous and cuboidal epithelium. Calcitonin-positive C-cells were present within their epithelium in HIS/Hiph. In contrast, the fossulae of HIS/Mz ran outside the thyroid glands toward the parathyroid glands; they were lined with columnar ciliated epithelium and a few goblet cells, but had no C-cells, which was consistent with the cystic structures in the thymus and the parathyroid gland. These results indicated that the fossulae were a remnant of the ultimobranchial body in HIS/Hiph and of the thymopharyngeal duct in HIS/Mz. Thus, the fossulae of the piriform fossa resembled the piriform sinus fistula in human. In conclusion, cotton rats frequently possessed pharyngeal pouch remnants, including the piriform sinus fistula, and therefore, might serve as a novel model to elucidate the mechanisms of pharyngeal pouch development. PMID- 29160553 TI - The evolutionary dynamics of adaptive virginity, sex-allocation, and altruistic helping in haplodiploid animals. AB - In haplodiploids, females can produce sons from unfertilized eggs without mating. However, virgin reproduction is usually considered to be a result of a failure to mate, rather than an adaptation. Here, we build an analytical model for evolution of virgin reproduction, sex-allocation, and altruistic female helping in haplodiploid taxa. We show that when mating is costly (e.g., when mating increases predation risk), virginity can evolve as an adaptive female reproductive strategy. Furthermore, adaptive virginity results in strongly divergent sex-ratios in mated and virgin queen nests ("split sex ratios"), which promotes the evolution of altruistic helping by daughters in mated queen nests. However, when helpers evolve to be efficient and increase nest production significantly, virgin reproduction is selected against. Our results suggest that adaptive virginity could have been an important stepping stone on the pathway to eusociality in haplodiploids. We further show that virginity can be an adaptive reproductive strategy also in primitively social haplodiploids if workers bias the sex ratio toward females. By remaining virgin, queens are free to produce sons, the more valuable sex in a female-biased population. Our work brings a new dimension to the studies linking reproductive strategies with social evolution. PMID- 29160554 TI - Digest: Evolution of sperm size and number in external fertilizers. PMID- 29160556 TI - Digest: Room for geckos of all shapes and sizes. PMID- 29160555 TI - The Effect of Sleep Disorders, Sedating Medications, and Depression on Cognitive Processing Therapy Outcomes: A Fuzzy Set Qualitative Comparative Analysis. AB - Cognitive processing therapy (CPT) for posttraumatic stress disorder (PTSD) is an effortful process requiring engagement in cognitive restructuring. Sleep disorders may lead to avoidance of effortful tasks and cognitive performance deficits. We explored whether sleep disorders, as assessed by polysomnography, were consistently associated with treatment response in combination with other factors. This study included 32 U.S. veterans who were examined both before and after CPT for combat-related PTSD. We employed a novel, case-comparative technique, fuzzy set qualitative comparative analysis (fsQCA), to identify combinations of fuzzy and crisp factors (recipes) that achieve a clinically significant outcome. Approximately one-quarter of cases experiencing clinically significant change were either (a) Vietnam era veterans without sedating medications, moderate sleep disordered breathing, and severe depression; or (b) non-Vietnam era veterans with sedating medications and without severe periodic limb movements (or significant periodic limb movement arousals). Recipes involving the absence of the relevant sleep disorder were associated with the highest coverage values. These results using fsQCA (a) provide valuable information about the heterogeneity of CPT response and (b) suggest that sleep disorders are important factors to consider in theoretical discussions of who responds to CPT for PTSD. PMID- 29160557 TI - The Complex Trauma Inventory: A Self-Report Measure of Posttraumatic Stress Disorder and Complex Posttraumatic Stress Disorder. AB - The work group revising the criteria for trauma-related disorders in the International Classification of Diseases (ICD-11) made several changes. Specifically, they simplified the criteria for posttraumatic stress disorder (PTSD) and added a new trauma disorder called complex PTSD (CPTSD). These proposed changes to taxonomy require new instruments to assess these novel constructs. We developed a measure of PTSD and CPTSD (the Complex Trauma Inventory; CTI) according to the proposed domains, creating several items to assess each domain. We examined the factor structure of the CTI in two separate samples of diverse college students (n1 = 391; n2 = 391) who reported exposure to at least one traumatic event and at least occasional functional impairment. After reducing the original 50 items in the item pool to 20 items, confirmatory factor analyses supported two highly correlated second-order factors-PTSD and disturbances in self-organization (DSO)-with PTSD (i.e., reexperiencing, avoidance, sense of threat) and DSO (i.e., affect dysregulation, negative self concept, and disturbances in relationships), each loading on three of the six ICD 11-consistent first-order factors, root mean square error of approximation (RMSEA) = .056, 95% confidence interval (CI) [.048, .064], comparative fit index (CFI) = .956, Tucker-Lewis index (TLI) = .948, standardized root mean square residual (SRMR) = .043, Bayesian information criterion (BIC) = 641.55, chi2 (163) = 361.02, p < .001. Internal consistencies for PTSD and DSO were good to excellent (Cronbach's alphas = .89 to .92). Supplementary analyses supported the gender invariance of the CFA model, as well as convergent and discriminant validity of the CTI. The validity of the CTI supports the distinction between CPTSD and PTSD. Moreover, the CTI will assist clinicians with diagnosis, symptom tracking, treatment planning, and assessing outcomes. PMID- 29160559 TI - Removable prosthesis hygiene in elders with Parkinson's disease. AB - AIM: To evaluate changes in prosthesis hygiene in elders with Parkinson's disease (PD) in response to verbal instruction and positive reinforcement. METHODS AND RESULTS: Elders with removable prostheses were divided into PD (n = 17) and control (n = 20) groups. Biofilm on prostheses was measured at baseline, and verbal instructions on prosthesis hygiene were given. After 7, 14, and 30 days, biofilm presence was re-evaluated and the results were shown to participants, with repeated cleaning instruction. At baseline, participants with PD had more biofilm on maxillary prostheses than did controls (p = 0.009). At 30 days, biofilm presence on maxillary and mandibular prostheses did not differ between groups. Both groups showed reductions in biofilm accumulation on prostheses over time, but this effect took longer to appear on mandibular prostheses in the PD group (p < 0.05). CONCLUSION: Verbal instruction and positive reinforcement can improve prosthesis hygiene in elders with and without PD. PMID- 29160558 TI - Simpson's paradox in the integrated discrimination improvement. AB - The integrated discrimination improvement (IDI) is commonly used to compare two risk prediction models; it summarizes the extent a new model increases risk in events and decreases risk in non-events. The IDI averages risks across events and non-events and is therefore susceptible to Simpson's paradox. In some settings, adding a predictive covariate to a well calibrated model results in an overall negative (positive) IDI. However, if stratified by that same covariate, the strata-specific IDIs are positive (negative). Meanwhile, the calibration (observed to expected ratio and Hosmer-Lemeshow Goodness of Fit Test), area under the receiver operating characteristic curve, and Brier score improve overall and by stratum. We ran extensive simulations to investigate the impact of an imbalanced covariate upon metrics (IDI, area under the receiver operating characteristic curve, Brier score, and R2), provide an analytic explanation for the paradox in the IDI, and use an investigative metric, a Weighted IDI, to better understand the paradox. In simulations, all instances of the paradox occurred under stratum-specific mis-calibration, yet there were mis-calibrated settings in which the paradox did not occur. The paradox is illustrated on Cancer Genomics Network data by calculating predictions based on two versions of BRCAPRO, a Mendelian risk prediction model for breast and ovarian cancer. In both simulations and the Cancer Genomics Network data, overall model calibration did not guarantee stratum-level calibration. We conclude that the IDI should only assess model performance among a clinically relevant subset when stratum-level calibration is strictly met and recommend calculating additional metrics to confirm the direction and conclusions of the IDI. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 29160560 TI - A Functional Near-Infrared Spectroscopy Study of Trauma-Related Auditory and Olfactory Cues: Posttraumatic Stress Disorder or Combat Experience? AB - The prevalence of posttraumatic stress disorder (PTSD) among U.S. veterans deployed to Iraq or Afghanistan necessitates the need for comprehensive assessment and treatment strategies. This study investigated the utility of a combat-related PTSD symptom provocation paradigm to elicit unique neurological responses across three groups: combat veterans with PTSD, combat veterans without PTSD, and nonmilitary participants without PTSD. Using functional near-infrared spectroscopy (fNIRS) the results indicated that combat veterans with PTSD demonstrated significant activation to a trauma-related sound compared with nonmilitary personnel, channel 14: d = 1.03, 95% confidence interval (CI) [0.28, 1.76]; channel 15: d = 1.30, 95% CI [0.53, 2.06]; and combat veterans without PTSD, channel 14: d = 0.87, 95% CI [0.14, 1.59]. Specifically, this increased neural activation was approximately located in the right medial superior prefrontal cortex (Brodmann areas 9/10), an area associated with experiencing negative or threatening stimuli and emotional detachment. There were no differences across the groups for nontrauma-related sounds. Results were less clear with respect to a combat-related odor. These results suggest a specific neurophysiological response to trauma-related cues and, if replicated, may offer a biomarker for combat-related PTSD. Such a response could provide incremental validity over diagnostic assessments alone and assist in planning and monitoring of treatment outcome. PMID- 29160561 TI - Can overnight stenting be safely eliminated following a pharyngeal flap? A matched comparison study. AB - OBJECTIVE: Determine if overnight stenting is warranted after pharyngeal flap for management of velopharyngeal insufficiency (VPI) in pediatric patients METHODS: This is a retrospective age-matched cohort study from a single tertiary pediatric facility. Patients who underwent a posterior pharyngeal flap for VPI from January 1, 2013, to December 31, 2016, were included. Two equal groups were constructed based on when their nasal stents were removed, that is, postoperative day (POD) 0 or POD 1. Primary outcome measure was oxygen desaturation after surgery. Secondary outcome measures were total length of stay, need for narcotics, and oral intake based on POD. Additional information was gathered and evaluated as possible prognostic variables. RESULTS: There were 27 matched pairs included in the study. One patient from each group required supplemental oxygen during the night of surgery. No escalation of care was needed in either case. The group whose stents were removed on POD 0 were discharged earlier than the group whose stents were removed on POD 1, P < 0.0001. The POD 0 group took significantly more oral intake on POD 0 than the POD 1 group, P = 0.03. The POD 0 group had significantly more genetic syndromes than the POD 1 group, P = 0.02. CONCLUSION: There was no benefit with overnight stenting. Earlier discharge from the hospital was achieved in the POD 0 group. No patient experienced need for reintubation, escalation of clinical care, postoperative hemorrhage, or death. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:750-755, 2018. PMID- 29160562 TI - Aqueous extract of yellow maca (Lepidium meyenii) improves sperm count in experimental animals but response depends on hypocotyl size, pH and routes of administration. AB - Lepidium meyenii, a Peruvian plant growing over 4000 m.a.s.l., has effects on nutrition and fertility. The purpose of this study was to evaluate the sperm count in 105 male mice receiving boiled aqueous extract of yellow maca hypocotyls from different sizes, under different pH conditions and using two different routes of administration. Five mice per group were treated daily for 3 days with vehicle (oral and intraperitoneal) or maca aqueous extracts (5 mg/0.5 ml/day) belonging to the first, second, third and fourth categories, according to their hypocotyl size. On day four, sperm count was evaluated at testis, epididymis and vas deferens. Sperm count was higher in mice receiving maca from the larger sizes (first and second categories). Reduction in maca extract pH increased sperm count, whereas an increase in the pH resulted in a reduction in sperm count. The effect of pH reduction is observed only in maca from the first and second categories. Aqueous extract of maca was effective only after oral administration. In conclusion, the larger size of hypocotyls presented the best biological effect, and the low pH in the extract and the transformation after gastrointestinal passage are both important for its biological action. PMID- 29160564 TI - Functional differences in transport properties of natural HKT1;1 variants influence shoot Na+ exclusion in grapevine rootstocks. AB - Under salinity, Vitis spp. rootstocks can mediate salt (NaCl) exclusion from grafted V. vinifera scions enabling higher grapevine yields and production of superior wines with lower salt content. Until now, the genetic and mechanistic elements controlling sodium (Na+ ) exclusion in grapevine were unknown. Using a cross between two Vitis interspecific hybrid rootstocks, we mapped a dominant quantitative trait locus (QTL) associated with leaf Na+ exclusion (NaE) under salinity stress. The NaE locus encodes six high-affinity potassium transporters (HKT). Transcript profiling and functional characterization in heterologous systems identified VisHKT1;1 as the best candidate gene for controlling leaf Na+ exclusion. We characterized four proteins encoded by unique VisHKT1;1 alleles from the parents, and revealed that the dominant HKT variants exhibit greater Na+ conductance with less rectification than the recessive variants. Mutagenesis of VisHKT1;1 and TaHKT1.5-D from bread wheat, demonstrated that charged amino acid residues in the eighth predicted transmembrane domain of HKT proteins reduces inward Na+ conductance, and causes inward rectification of Na+ transport. The origin of the recessive VisHKT1;1 alleles was traced to V. champinii and V. rupestris. We propose that the genetic and functional data presented here will assist with breeding Na+ -tolerant grapevine rootstocks. PMID- 29160563 TI - CIN and Aneuploidy: Different Concepts, Different Consequences. AB - Chromosomal instability (CIN) and aneuploidy are similar concepts but not synonymous. CIN is the process that leads to chromosome copy number alterations, and aneuploidy is the result. While CIN and resulting aneuploidy often cause growth defects, they are also selected for in cancer cells. Although such contradicting fates may seem paradoxical at first, they can be better understood when CIN and aneuploidy are assessed separately, taking into account the in vitro or in vivo context, the rate of CIN, and severity of the aneuploid karyotype. As CIN can only be measured in living cells, which proves to be technically challenging in vivo, aneuploidy is more frequently quantified. However, CIN rates might be more predictive for tumor outcome than assessing aneuploidy rates alone. In reviewing the literature, we therefore conclude that there is an urgent need for new models in which we can monitor chromosome mis-segregation and its consequences in vivo. Also see the video abstract here: https://youtu.be/fL3LxZduchg. PMID- 29160566 TI - It started from scratch: The first 50 years of the Australasian College of Dermatologists. PMID- 29160568 TI - Nerve detection using optical spectroscopy, an evaluation in four different models: In human and swine, in-vivo, and post mortem. AB - OBJECTIVE: Identification of peripheral nerve tissue is crucial in both surgery and regional anesthesia. Recently, optical tissue identification methods are presented to facilitate nerve identification in transcutaneous procedures and surgery. Optimization and validation of such techniques require large datasets. The use of alternative models to human in vivo, like human post mortem, or swine may be suitable to test, optimize and validate new optical techniques. However, differences in tissue characteristics and thus optical properties, like oxygen saturation and tissue perfusion are to be expected. This requires a structured comparison between the models. STUDY DESIGN: Comparative observational study. METHODS: Nerve and surrounding tissues in human (in vivo and post mortem) and swine (in vivo and post mortem) were structurally compared macroscopically, histologically, and spectroscopically. Diffuse reflective spectra were acquired (400-1,600 nm) after illumination with a broad band halogen light. An analytical model was used to quantify optical parameters including concentrations of optical absorbers. RESULTS: Several differences were found histologically and in the optical parameters. Histologically nerve and adipose tissue (subcutaneous fat and sliding fat) showed clear similarities between human and swine while human muscle enclosed more adipocytes and endomysial collagen. Optical parameters revealed model dependent differences in concentrations of beta-carotene, water, fat, and oxygen saturation. The similarity between optical parameters is, however, sufficient to yield a strong positive correlation after cross model classification. CONCLUSION: This study shows and discusses similarities and differences in nerve and surrounding tissues between human in vivo and post mortem, and swine in vivo and post mortem; this could support the discussion to use an alternative model to optimize and validate optical techniques for clinical nerve identification. Lasers Surg. Med. 50:253-261, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29160569 TI - Reconstruction of bladder function and prevention of renal deterioration by means of end-to-side neurorrhaphy in rats with neurogenic bladder. AB - AIMS: To investigate the feasibility of restoring bladder function and prevention of renal deterioration by neurorrhaphy in rats with neurogenic bladder (NB). METHODS: Forty-two rats were assigned to the end-to-side nerve coaptation group (ECG, n = 16), no nerve coaptation group (NCG, n = 16), and control group (CG, n = 10). In the ECG, the left ventral root (VR) and dorsal root (DR) of L6 and S1 were transected, and the distal stump of L6VR was sutured to the lateral face of L4VR. In the NCG, the left VR and DR of L6 and S1 were transected, but coaptation was not performed. In the CG, no operation was performed. Nerve regeneration, bladder function, and renal function were evaluated by FluoroGold (FG) retrograde tract tracing, cystometry, electrical stimulation, MRI, histology and biochemical assays. RESULTS: In the ECG, FG-labeled neurons were observed in the left ventral horn of L4 spinal cord. There was a significant increase in intravesical pressure upon stimulation of the left L4VR proximal to the coaptation. Maximum cystometric capacity, post-void residual urine, bladder compliance and weight, serum creatinine, blood urea nitrogen, and fibrotic area of bladder and kidney were lower in the ECG than in the NCG, but higher than the CG. Hydronephrosis was noticed in ECG and NCG rats. Maximum detrusor voiding pressure was higher in the ECG and CG than in the NCG. CONCLUSIONS: End-to-side neurorrhaphy is a useful method for restoring bladder function and preventing renal injury in rats with NB. PMID- 29160570 TI - Bayesian Occam's Razor Is a Razor of the People. AB - Occam's razor-the idea that all else being equal, we should pick the simpler hypothesis-plays a prominent role in ordinary and scientific inference. But why are simpler hypotheses better? One attractive hypothesis known as Bayesian Occam's razor (BOR) is that more complex hypotheses tend to be more flexible-they can accommodate a wider range of possible data-and that flexibility is automatically penalized by Bayesian inference. In two experiments, we provide evidence that people's intuitive probabilistic and explanatory judgments follow the prescriptions of BOR. In particular, people's judgments are consistent with the two most distinctive characteristics of BOR: They penalize hypotheses as a function not only of their numbers of free parameters but also as a function of the size of the parameter space, and they penalize those hypotheses even when their parameters can be "tuned" to fit the data better than comparatively simpler hypotheses. PMID- 29160571 TI - Sacral neuromodulation and pregnancy: Results of a national survey carried out for the neuro-urology committee of the French Association of Urology (AFU). AB - AIMS: To assess the impact of sacral neuromodulation (SNM) on pregnancy and vice versa, by identifying women who had received SNM for lower-urinary tract symptoms (LUTS) and had become pregnant. METHODS: A cross-sectional descriptive study was carried out based on responses to an on-line questionnaire sent to practitioners listed on the InterStim enCaptureTM National Registry. Questions were related to pre-pregnancy health and SNM efficacy, deactivation of the device, its impact on LUTS, childbirth, the infant, its reactivation and postpartum effectiveness. RESULTS: Twenty-seven pregnancies were recorded among 21 women. Six women had had a pregnancy prior to implantation, two of whom had had a c-section. A total of 18.5% of women had the device disabled prior to conception. The others had their device disabled during the first trimester and did not reactivate it before delivery. Complications were reported in 25.9% of pregnancies: six women had urinary infections, including three of the four treated for chronic retention of urine (CRU), and 1 woman had pain at the stimulation site. There were 24 live births (including one premature birth and four c-sections), one spontaneous miscarriage and two voluntary interruptions of pregnancy. No neonatal disorders have been reported. Effectiveness of sacral neuromodulation decreased in 20% in postpartum. CONCLUSIONS: In 27 pregnancies established during SNM for LUTS, 18.5% of patients deactivated their case before pregnancy and the others switched it off during the first trimester. Three-quarters of women with CRU had urinary infection. No adverse effects on fetuses were found. SNM effectiveness deteriorated in 20% cases after childbirth. PMID- 29160572 TI - Rapid on-site evaluation of routine biochemical parameters to predict right ventricular dysfunction in and the prognosis of patients with acute pulmonary embolism upon admission to the emergency room. AB - INTRODUCTION: Patients with acute pulmonary embolism(APE)who present with right ventricular dysfunction (RVD) have a worse prognosis. This study aimed to evaluate the value of routine biochemical parameters in predicting RVD and 30-day mortality in patients with APE. METHODS: We retrospectively collected the clinical data for 154 enrolled patients, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), D-dimer, cardiac troponin I (cTnI), and N-terminal pro-brain natriuretic peptide (NT-proBNP). We analyzed the correlation between RVD and the parameters and conducted a receiver operating characteristic (ROC) curve to confirm the cut-off values for predicting RVD and 30-day mortality. Formulas were built with relevant parameters to predict RVD and 30-day mortality. RESULTS: Age, NLR, PLR, D-dimer, the ratio of cTnI (+), and NT proBNP (+) were significantly higher in RVD (+) patients. The ratio of cTnI (+) and NT-proBNP (+) in 30-day mortality (+) patients was significantly higher than that in 30-day mortality (-) patients. According to the logistic regression analysis, NLR, cTnI (+), and NT-proBNP (+) correlated with RVD. The formula for the RVD risk score is 0.072 * NLR+1.460 * NT-proBNP (+)+2.113 * cTnI (+), and the area under the curve (AUC) = 0.890 (95% CI: 0.839-0.941, P = .001). The formula for the 30-day mortality risk score is 0.115 * NLR + 2.046 * NT-proBNP (+) + 1.946 * cTnI (+) -0.016 * PLR, and the AUC = 0.903 (95% CI: 0.829-0.976, P = .001). CONCLUSIONS: The rapid on-site evaluation of routine biochemical parameters, including NLR, cTnI, and NT-proBNP levels, and the formula developed using these parameters are valuable for predicting RVD and 30-day mortality in patients with APE. PMID- 29160574 TI - Spatially constrained minimization of macromolecules. AB - A structural minimization procedure which converges rapidly and restricts the atomic shifts is outlined. It is implemented by adding a harmonic penalty term for the displacements of atomic positions and resetting the reference coordinates with respect to which the constraints are computed during the minimization. The resetting serves to reduce the constraint energy of the minimized structure to negligible levels. PMID- 29160573 TI - Activation of voltage-dependent K+ channels strongly limits hypoxia-induced elevation of [Ca2+ ]i in rat carotid body glomus cells. AB - KEY POINTS: We studied the role of the large-conductance Ca2+ -activated K+ channel (BK) and voltage-dependent K+ channels (Kv) on [Ca2+ ]i responses to a wide range of hypoxia at different resting cell membrane potential (Em ). BK/Kv were mostly closed at rest in normoxia. BK/Kv became basally active when cells were depolarized by elevated [KCl]o (>12 mm). Regardless of whether BK/Kv were closed or basally open, hypoxia-induced elevation of [Ca2+ ]i was enhanced 2- to 3-fold by inhibitors of BK/Kv. Hypoxia-induced elevation of [Ca2+ ]i was enhanced ~2-fold by an inhibitor of Kv2, a major Kv in rat glomus cells. Hypoxia did not inhibit BK in inside-out patches. Our study supports a scheme in which activation of BK/Kv strongly limits the magnitude of hypoxia-induced [Ca2+ ]i rise, with Kv having a much greater effect than BK. ABSTRACT: Large-conductance KCa (BK) and other voltage-dependent K+ channels (Kv) are highly expressed in carotid body (CB) glomus cells, but their role in hypoxia-induced excitation is still not well defined and remains controversial. We addressed this issue by studying the effects of inhibitors of BK (IBTX) and BK/Kv (TEA/4-AP) on [Ca2+ ]i responses to a wide range of hypoxia at different levels of resting cell membrane potential (Em ). IBTX and TEA/4-AP did not affect the basal [Ca2+ ]i in isolated glomus cells bathed in 5 mm KClo , but elicited transient increases in [Ca2+ ]i in cells that were moderately depolarized (11-20 mV) by elevation of [KCl]o (12-20 mm). Thus, BK and Kv were mostly closed at rest and activated by depolarization. Four different levels of hypoxia (mild, moderate, severe, anoxia) were used to produce a wide range of [Ca2+ ]i elevation (0-700 nm). IBTX did not affect the rise in [Ca2+ ]i , but TEA/4-AP strongly (~3-fold) enhanced [Ca2+ ]i rise by moderate and severe levels of hypoxia. Guangxitoxin, a Kv2 blocker, inhibited the whole-cell current by ~50%, and enhanced 2-fold the [Ca2+ ]i rise elicited by moderate and severe levels of hypoxia. Anoxia did not directly affect BK, but activated BK via depolarization. Our findings do not support the view that hypoxia inhibits BK/Kv to initiate or maintain the hypoxic response. Rather, our results show that BK/Kv are activated as glomus cells depolarize in response to hypoxia, which then limits the rise in [Ca2+ ]i . Inhibition of Kv may provide a mechanism to enhance the chemosensory activity of the CB and ventilation. PMID- 29160575 TI - A force-field study of the conformational characteristics of the iduronate ring. AB - Methods of molecular mechanics were applied to investigate the conformation of the (methyl 2-O-sulfate-4-methyl-alpha-L-idopyranose) uronic acid (DMIS), in order to correlate the peculiar vicinal proton coupling constants observed in polysaccharides containing the iduronate ring to the conformational characteristics of this sugar ring. We found three conformers with comparable energies, namely the two chair forms 1 C4 and 4 C1 and the skew-boat form 2 S0 (L); the latter is separated from each chair form by a barrier of about 9 kcal/mol. Along the pseudorotational path three additional minima (3 S1 , 1 S3 , and 1 S5 ) were found, yet at least 4 kcal/mol higher than 2 S0 . The results obtained for the relative energies of the three conformers and the conformation of the side groups were affected by the inclusion of the electrostatic term and, in particular, by the charge assigned to the ionic groups of DMIS. However, the conformational properties of the idopyranosidic ring in DMIS (and in related compounds) should still be interpreted in terms of equilibrium among these three conformers only. PMID- 29160576 TI - Matrix elements for anharmonic potentials: Application to I2 morse oscillator. AB - Many authors have contributed expressions for obtaining analytical matrix elements for Morse oscillators. In this work, we discuss the advantages of using these expressions. At the same time, we propose a full numerical method to calculate these matrix elements and we compare, for the I2 system, the different results given by Gallas, Vasan, and Cross, and the variational method. PMID- 29160577 TI - Molecular mechanics and molecular shape. III. Surface area and cross-sectional areas of organic molecules. AB - A nonanalytical procedure is proposed to calculate the surface area and cross sectional areas of molecules. Results are reviewed for about 70 species comprising alkanes, acyclic and cyclic, alkyl halides, and alcohols. By regression analysis, relationships are detected between surface areas or segment areas and physical properties. Computed cross-sectional areas are confronted with adsorption values. Four ways are proposed to define quantitatively the intuitive notion of "molecular globularity". PMID- 29160578 TI - Reference Energies in Semiempirical Parametrizations. AB - The MNDO scheme has been reparametrized for hydrocarbons using both molecular binding energies and heats of formation at 0 K as experimental reference data. Compared with MNDO, there are only minor changes in the optimized parameters, and the results are essentially of the same accuracy. These tests justify the use of heats of formation at 298 K as reference data in the original MNDO parametrization. PMID- 29160579 TI - Mindo/3 and mndo calculations of closed- and open-shell cations containing C, H, N, and O. AB - Heats of formation of 119 closed- and open-shell carbocations calculated by the semiempirical quantum chemical methods MINDO/3 and MNDO are reported and compared with experimental data. With proper consideration of failures in specific areas, both methods can be used for the thermodynamics of carbocations containing C, H, N, and O. MINDO/3 predicts unrealistic values for nitrogen containing cations with nitrogen multiple bonds and is not suited for closed-shell cations containing oxygen. Saturated acyclic hydrocarbon radical cations often are computed with abnormally long CC bonds by MNDO. Otherwise, the standard deviation of the two methods is not very different, being in the range of +/-13 kcal/mol. MINDO/3 tends to overestimate the cation stabilities, whereas MNDO calculates cations usually too high in energy. Some of the errors which were found in the calculations of the ions are related to the computed values for the parent neutral structures, but others are not. PMID- 29160580 TI - A minimal multiconfigurational technique. AB - A direct minimization method previously presented by the authors is applied here to biconfigurational wave functions. A very moderate increasing in the time by iteration with respect to the one-determinant calculation and good convergence properties have been found. So qualitatively correct studies on singlet systems with strong biradical character can be performed with a cost similar to that required by Hartree-Fock calculations. PMID- 29160581 TI - An improved set of mndo parameters for sulfur. AB - The MNDO parameters for sulfur have been reoptimized. Calculations for a number of sulfur compounds indicate a very significant improvement. Inclusion of d AOs failed to correct the errors for compounds of sulfur in its higher valence states. Since d AOs are not included, the calculations are still confined to compounds of divalent sulfur. PMID- 29160582 TI - Conformational study of the trinucleotide CpGpCp-pentapeptide Gly5 complex: The important role of bridging water in the complex formation. AB - Conformational changes in the RNA-protein interaction were studied by calculating the intramolecular interaction energy of a model complex with the use of potential functions. The model complex has hydrogen-bonded water molecules bridging polypeptide NH groups to 2'-hydroxyl groups and sugar ring oxygen atoms. Since the sugar ring is constrained by the bridging water, preliminary calculations with the model compounds, the sugar ring, mononucleoside diphosphates, pCp and pGp, were carried out, and the flexibility and energetics of the sugar ring were compared with the previous results of DNA. The shift of the phase angle of the sugar ring occurred in the complex formation because of the hydrogen bond through the bridging water and the flexibility of the sugar ring. The free energy difference at 298 K is about -74.0 kcal/mol which was obtained from the intramolecular interaction energy difference of -67.5 kcal/mol by adding the conformational entropy change of 21.9 e.u., which in turn was calculated from the evaluation of the determinant of the matrix containing variances and covariances of the internal coordinates. PMID- 29160583 TI - A method for the machine detection of near equivalence of major substructures in a molecule. AB - The use of the concept of near equivalence of substructures in a computer program concerned with organic synthesis requires a concrete definition of "nearness" and an efficient method for implementing the concept. Such a method has been devised and its use is described and examples are given. PMID- 29160584 TI - An all atom force field for simulations of proteins and nucleic acids. PMID- 29160585 TI - The computed force constants and vibrational spectra of toluene. AB - The complete harmonic force field and dipole moment derivatives have been computed for toluene at the Hartree-Fock level using a 4-21G basis set. The six scale factors optimized for benzene were used to scale the computed harmonic force constants of toluene. The vibrational frequencies of toluene computed from this scaled quantum mechanical force field are quite good. After a correction was made to two previously proposed spectral assignments, the mean deviation from the experimental frequencies is only 7.8 cm-1 except for the frequencies related to the methyl group. Five more scale factors for the vibrational modes of the methyl group were reoptimized. The final comparison showed an overall mean deviation of 7.5 cm-1 between the theoretical spectrum and the experimental spectrum. Computed intensities are qualitatively in agreement with experiments. They are highly useful in the investigation of questionable assignments. PMID- 29160586 TI - Comparison of sequences as a method for evaluation of the molecular similarity. AB - String comparison techniques were developed and applied for measuring the molecular similarity of chemical structures. The molecular structures were encoded as a sequence of numbers representing counts of paths of different lengths. The similarity index between two compounds was calculated as the difference between the gains of information derived through comparison of the corresponding molecular path sequences. Ranks between the structures of the studied data base obtained according to this similarity were used as basic data for deriving correspondences between the elements of the set of compounds. The method was applied on a group of 41 barbiturates. Correlation equations were calculated for different groups of compounds grouped according to the displayed similarity. The correlation equations and the corresponding statistics were obtained using standard computer programs. Special algorithm for computing the similarity index and the correlation matrix (outlined very briefly) was developed and implemented on VAX 11/750. PMID- 29160587 TI - A fast algorithm for the interactive docking maneuver with flexible macromolecules and probes. AB - A new algorithm for the interactive docking maneuver is presented. Full attention is given to the flexibility of both substrate and macromolecule, i.e., all the fragments are allowed to move. It is assumed that any numerical quantity which depends only on the isolated macromolecule at energy minimum is disposable when approximate expressions are derived. The central idea is the concept of relevant docking coordinates which reflect the essential features of the macromolecular deformations during the docking maneuver and which substantially diminish the number of considered degrees of freedom (DF). The conformational energy is divided into two parts. The first part, represented by condensed potential functions, needs no approximations. For the second part, termed Erest , a quadratic approximation in the subspace spanned by the relevant docking coordinates is used. All the pairwise interactions between the atoms of the macromolecule are eliminated. A simple computational example using the ECEPP force field is given. Atomic coordinate computations are simplified by the introduction of virtual rotation axes for the backbone. In connection with drug design the concept of pressure pattern is defined and related to quantities appearing in the energy gradient. Extensions to substrate induced allosteric transitions are discussed. PMID- 29160588 TI - Vectorization of a classical trajectory code on a floating point systems, Inc. Model 164 attached processor. AB - A triatomic classical trajectory code has been modified by extensive vectorization of the algorithms to achieve much improved performance on an FPS 164 attached processor. Extensive timings on both the FPS 164 and a VAX 11/780 with floating point accelerator are presented as a function of the number of trajectories simultaneously run. The timing tests involve a potential energy surface of the LEPS variety and trajectories with 1000 time steps. The results indicate that vectorization results in timing improvements on both the VAX and the FPS. For larger numbers of trajectories run simultaneously, up to a factor of 25 improvement in speed occurs between VAX and FPS vectorized code. PMID- 29160589 TI - The effect of including polarization functions on the geometrical parameters calculated for pyridine. AB - Geometrical parameters for pyridine have been calculated using the 6-31G, 6-31G* (5D), 6-31G** (6D), and 6-31G(2 * 6D) basis sets. Comparisons are made with a microwave substitution structure and with results of other ab initio calculations reported in the literature. Particular attention is paid to the influence of polarization functions on the magnitude of the ring angle, 14 drinks/week or >5 drinks on one occasion for men, and >7 drinks/week or >4 drinks on one occasion for women. We used Generalized Estimating Equations (GEE) analyses to examine factors independently associated with hazardous alcohol use. RESULTS: Between 2005 and 2014, 1,149 drug-using youth were recruited and 423 (36.8%) reported hazardous alcohol use in the previous 6 months at study baseline. In multivariable GEE analyses, intimate partner violence (Adjusted Odds Ratio [AOR] = 1.53, 95% Confidence Interval [95%CI] = 1.12-2.10), and non-partner physical assault (AOR = 1.39, 95%CI = 1.21-1.59) were independently associated with hazardous alcohol use after adjusting for multiple potential confounders. DISCUSSION AND CONCLUSIONS: A considerable proportion of youth in this setting reported hazardous alcohol use, which was independently associated with experiencing recent intimate and non-partner violence. SCIENTIFIC SIGNIFICANCE: Combined interventions for violence and hazardous alcohol use should be integrated into service provision programs for street-involved youth. (Am J Addict 2017;26:852-858). PMID- 29160609 TI - Plant-arthropod interactions: who is the winner? AB - Herbivorous arthropods have interacted with plants for millions of years. During feeding they release chemical cues that allow plants to detect the attack and mount an efficient defense response. A signaling cascade triggers the expression of hundreds of genes, which encode defensive proteins and enzymes for synthesis of toxic metabolites. This direct defense is often complemented by emission of volatiles that attract beneficial parasitoids. In return, arthropods have evolved strategies to interfere with plant defenses, either by producing effectors to inhibit detection and downstream signaling steps, or by adapting to their detrimental effect. In this review, we address the current knowledge on the molecular and chemical dialog between plants and herbivores, with an emphasis on co-evolutionary aspects. PMID- 29160608 TI - Apple fruit superficial scald resistance mediated by ethylene inhibition is associated with diverse metabolic processes. AB - Fruits stored at low temperature can exhibit different types of chilling injury. In apple, one of the most serious physiological disorders is superficial scald, which is characterized by discoloration and brown necrotic patches on the fruit exocarp. Although this phenomenon is widely ascribed to the oxidation of alpha farnesene, its physiology is not yet fully understood. To elucidate the mechanism of superficial scald development and possible means of prevention, we performed an integrated metabolite screen, including an analysis of volatiles, phenols and lipids, together with a large-scale transcriptome study. We also determined that prevention of superficial scald, through the use of an ethylene action inhibitor, is associated with the triggering of cold acclimation-related processes. Specifically, the inhibition of ethylene perception stimulated the production of antioxidant compounds to scavenge reactive oxygen species, the synthesis of fatty acids to stabilize plastid and vacuole membranes against cold temperature, and the accumulation of the sorbitol, which can act as a cryoprotectant. The pattern of sorbitol accumulation was consistent with the expression profile of a sorbitol 6-phosphate dehydrogenase, MdS6PDH, the overexpression of which in transgenic Arabidopsis thaliana plants confirmed its involvement in the cold acclimation and freezing tolerance. PMID- 29160610 TI - Do pregnancy characteristics contribute to rising childhood cancer incidence rates in the United States? AB - BACKGROUND: Since 1975, childhood cancer incidence rates have gradually increased in the United States; however, few studies have conducted analyses across time to unpack this temporal rise. The aim of this study was to test the hypothesis that increasing cancer incidence rates are due to secular trends in pregnancy characteristics that are established risk factors for childhood cancer incidence including older maternal age, higher birthweight, and lower birth order. We also considered temporal trends in sociodemographic characteristics including race/ethnicity and poverty. PROCEDURE: We conducted a time series county-level ecologic analysis using linked population-based data from Surveillance, Epidemiology, and End Results cancer registries (1975-2013), birth data from the National Center for Health Statistics (1970-2013), and sociodemographic data from the US Census (1970-2010). We estimated unadjusted and adjusted average annual percent changes (AAPCs) in incidence of combined (all diagnoses) and individual types of cancer among children, ages 0-4 years, from Poisson mixed models. RESULTS: There was a statistically significant unadjusted temporal rise in incidence of combined childhood cancers (AAPC = 0.71%; 95% CI = 0.55-0.86), acute lymphoblastic leukemia (0.78%; 0.49-1.07), acute myeloid leukemia (1.86%; 1.13 2.59), central nervous system tumors (1.31%; 0.94-1.67), and hepatoblastoma (2.70%; 1.68-3.72). Adjustment for county-level maternal age reduced estimated AAPCs between 8% (hepatoblastoma) and 55% (combined). However, adjustment for other county characteristics did not attenuate AAPCs, and AAPCs remained significantly above 0% in models fully adjusted for county-level characteristics. CONCLUSION: Although rising maternal age may account for some of the increase in childhood cancer incidence over time, other factors, not considered in this analysis, may also contribute to temporal trends. PMID- 29160611 TI - Pathogenesis and surgical resolution of acute hydrops in primary congenital glaucoma. PMID- 29160613 TI - Posttraumatic Stress Disorder and Its Effects on Pregnancy and Mothering. PMID- 29160612 TI - Central sensitization: Nice to know? PMID- 29160614 TI - Attention-Deficit Hyperactivity Disorder: Clinical Considerations for Women. AB - Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention. Women with ADHD represent a particularly vulnerable group, given their increased risk for psychosocial and parenting difficulties. Women's health care clinicians should expect to encounter women with diagnosed and undiagnosed ADHD that may or may not be treated. Pharmacologic intervention, namely, prescription stimulants, is an important consideration for pregnant and breastfeeding women with ADHD, especially because the US Food and Drug Administration has determined that there is not enough information to confirm either harm or lack of harm to the developing fetus following exposure to these drugs. Due to the increase in use of prescription stimulants without a prescription, clinicians are also likely to encounter women misusing stimulants for a variety of reasons. This article provides an overview of ADHD diagnosis, outlines effective treatment options, and offers insight into the importance for clinicians to consider prescription stimulant misuse. Guidance concerning treatment of ADHD during pregnancy and lactation is reviewed. PMID- 29160615 TI - Defining the Field of Sequence-Controlled Polymers. AB - Over the last ten years, the development of synthetic polymers containing controlled monomer sequences has become a prominent topic in fundamental and applied polymer science. This emerging area is particularly broad and combines classical polymer chemistry tools with techniques imported from other domains such as biology, biochemistry, organic synthesis, engineering, and bioanalytics. Consequently, it also generates new structures, terminologies, and applications that are not within the traditional scope of polymer science. The term "sequence controlled polymers" (SCPs) was recently proposed as a generic name to describe all these recent trends. However, since the field of SCPs has been growing very rapidly in recent literature, it is urgent to accurately define its scientific frontiers. In this important context, this review is an attempt to define, rationalize, and classify the field of SCPs. In particular, all synthetic approaches that have been reported for the synthesis of SCPs are discussed and categorized. In addition, the characterization tools, properties, and potential applications of these new polymers are described herein. Overall, this review serves as a reference guide for understanding the burgeoning field of SCPs. PMID- 29160616 TI - Evaluation of microtitre plate-based Haemoglobin estimation. AB - INTRODUCTION: Haemoglobin estimation is one of the most important clinical investigations. Many techniques are available to measure haemoglobin; still there is a need for a haemoglobin assay technique which is cheap, robust and simple and can be used in field conditions very quickly using figure prick sample. We evaluated a cyanmethaemoglobin-based haemoglobin estimation using a microtitre plates for the purpose. METHODS: Microtitre plate-based haemoglobin estimation was developed using cyanmethaemoglobin-based assay and was compared with standard haematology analyser-based haemoglobin estimation in a large number of samples from a population of voluntary blood donors. Various tests were performed to evaluate the stability of colour, variation of the results during duplicate assay on the same days and on different days as well as linearity of the test was performed against broad range of haemoglobin values for the new microtitre plate based technique. Standard statistical test of significance was applied to validate the assay. RESULTS: Total 200 samples from in-house and field conditions were evaluated. 10 MUL blood sample in 300 MUL Drabkin's solution provided optimum and comparable results after 10 minutes of incubation. The colour was stable up to 6 hours, the coefficient of variation was less than 3%, and the cost per test including everything was less than 3 cent/2P. Turnaround time for 90 samples was only 30 minutes. CONCLUSION: Cyanmethaemoglobin-based assay in microtitre plate is feasible, robust, rapid, cheap and cost-effective method for haemoglobin estimation in field conditions. PMID- 29160617 TI - Exploring the enantiorecognition mechanism of Cinchona alkaloid-based zwitterionic chiral stationary phases and the basic trans-paroxetine enantiomers. AB - The enantiomers of trans-paroxetine (the selectand) were separated on four chiral stationary phases incorporating either quinine [ZWIX(+), ZWIX(+A)] or quinidine [ZWIX(-), ZWIX(-A)] and (R,R)-aminocyclohexanesulfonic acid [in ZWIX(-), and ZWIX(+A)] or (S,S)-aminocyclohexanesulfonic acid [in ZWIX(+), and ZWIX(-A)] chiral selectors. The zwitterion nature of the phases is due to the presence of either (R,R)- or (S,S)-aminocyclohexanesulfonic acid in the selector structure bearing the quinuclidine moiety. ZWIX(+) and ZWIX(-) phases are available on the market with the commercial names CHIRALPAK ZWIX(+) and CHIRALPAK ZWIX(-), respectively. With the aim of rationalizing the enantiomer elution order with the above chiral stationary phases, a molecular dynamic protocol was applied and two energetic parameters were initially measured: selectand conformational energy and selectand interaction energy. In the search for other descriptors allowing a better fitting with the experimental evidences, in the present work we consider an energetic parameter, defined as the selector conformational energy, which resulted to be relevant in the explanation of the experimental elution order in most of the cases. Very importantly, the computational data produced by the present study strongly support the outstanding role of the conformational energy of the chiral selector as it interacts with the analytes. PMID- 29160619 TI - Tendinopathy diagnosis and treatment monitoring using attenuated total reflectance-Fourier transform infrared spectroscopy. AB - Tendinopathy, an important sports injury afflicting athletes and general public, is associated with huge economic losses. The currently used diagnostic tests are subjective, show moderate sensitivity and specificity; while treatment failures persist despite advances in therapy. This highlights the need for tendinopathy diagnostic and treatment monitoring tools. This study investigates tendon injury, natural healing and effect of treatment using ATR-FTIR complemented with histopathology. Control (C), injured (I) and treated (T) rat tendons were extracted 3, 7, 14 and 28 days post-injury/treatment, representing phases of healing; and subjected to hematoxylin & eosin staining as well as spectroscopy. While C showed no change, I- and T-related histological changes could be clearly observed in stained sections. ATR-FTIR spectra highlighted the biochemical changes within groups. Multivariate analysis could classify C, I and T with 75%; different days between groups with 84%; and different days within group with 65% efficiency. Results suggest that such analysis can not only identify C, I or T but also different phases of healing. Difference between I and T at different time points also suggest change in rate of healing. Further studies may help develop this technique for clinical diagnosis and treatment monitoring in future. PMID- 29160618 TI - Deciphering the fine nucleotide diversity of full HLA class I and class II genes in a well-documented population from sub-Saharan Africa. AB - With the aim to understand how next-generation sequencing (NGS) improves both our assessment of genetic variation within populations and our knowledge on HLA molecular evolution, we sequenced and analysed 8 HLA loci in a well-documented population from sub-Saharan Africa (Mandenka). The results of full-gene NGS-MiSeq sequencing compared with those obtained by traditional typing techniques or limited sequencing strategies showed that segregating sites located outside exon 2 are crucial to describe not only class I but also class II population diversity. A comprehensive analysis of exons 2, 3, 4 and 5 nucleotide diversity at the 8 HLA loci revealed remarkable differences among these gene regions, notably a greater variation concentrated in the antigen recognition sites of class I exons 3 and some class II exons 2, likely associated with their peptide presentation function, a lower diversity of HLA-C exon 3, possibly related to its role as a KIR ligand, and a peculiar molecular diversity of HLA-A exon 2, revealing demographic signals. Based on full-length HLA sequences, we also propose that the most frequent DRB1 allele in the studied population, DRB1*13:04, emerged from an allelic conversion involving 3 potential alleles as donors and DRB1*11:02:01 as recipient. Finally, our analysis revealed a high occurrence of the DRB1*13:04-DQA1*05:05:01-DQB1*03:19 haplotype, possibly resulting from a selective sweep due to protection to Onchorcerca volvulus, a prevalent pathogen in West Africa. This study unveils highly relevant information on the molecular evolution of HLA genes in relation to their immune function, calling for similar analyses in other populations living in contrasting environments. PMID- 29160620 TI - DNA methylation of membrane-bound catechol-O-methyltransferase in Malaysian schizophrenia patients. AB - AIM: This study examined catechol-O-methyltransferase (COMT) DNA methylation in the peripheral blood of schizophrenia patients and also in healthy controls to investigate its potential use as a peripheral biomarker of schizophrenia and its relations with the clinical variables of schizophrenia patients. METHODS: We examined the DNA methylation levels of COMT using genomic DNA from the peripheral blood of schizophrenia patients (n = 138) and healthy control participants (n = 132); all were Malaysian Malays. The extracted DNA was bisulfite converted, and the percentage methylation ratio value was calculated based on the results following a MethyLight protocol analysis. RESULTS: The percentage methylation ratio of COMT was lower in schizophrenia than it was in the healthy controls (P < 0.001) and was different between the body mass index (P = 0.003) and antipsychotic (P = 0.004) groups. The COMT DNA methylation rate was lower in patients receiving atypical antipsychotics (P = 0.004) and risperidone (P = 0.049) as compared to typical antipsychotics. The Excitement and Depressed subdomains of the Positive and Negative Syndrome Scale were inversely related (P < 0.001) and therefore predictors (Excitement: b = -11.396, t = -4.760, P < 0.001; Depressed: b = -7.789, t = -3.487, P = 0.001) of COMT DNA methylation. CONCLUSION: Our results suggested that the methylation level was affected by the severity of the clinical symptoms of schizophrenia and might also be influenced by pharmacological treatment. The epigenetic alteration of COMT in the peripheral blood could be a potential peripheral biomarker of schizophrenia. PMID- 29160621 TI - Magnetic resonance imaging in heart failure, including coronary imaging: numbers, facts, and challenges. AB - Coronary artery disease (CAD) is a major risk factor for the incidence and progression of heart failure (HF). HF is characterized by a substantial morbidity and mortality and its lifetime risk is estimated at approximately 20% for men and women. As patients are in most cases identified only after developing overt clinical symptoms, detecting early stages of CAD and HF is of paramount importance. Due to its non-invasiveness, excellent soft-tissue contrast, high spatial resolution, and multiparametric nature, cardiovascular magnetic resonance (CMR) imaging has emerged as a promising radiation-free technique to assess a wide range of cardiovascular diseases such as CAD or HF, enabling a comprehensive evaluation of myocardial anatomy, regional and global function, and viability with the additional benefit of in vivo tissue characterization. CMR has the potential to enhance our understanding of coronary atherosclerosis and the aetiology of HF on functional and biological levels, to identify patients at risk for CAD or HF, and to enable individualized patient management and improved outcomes. Even though larger-scale studies on the different applications of CMR for the assessment of heart failure are scarce, recent research highlighted new possible clinical applications for CMR in the evaluation of CAD and HF. PMID- 29160622 TI - Mechanical colon cleansing for screening colonoscopy: A randomized controlled trial. AB - OBJECTIVE: Effective screening colonoscopy depends on the quality of colon preparation. This study aimed to compare pulsed irrigation evacuation (PIE), polyethylene glycol (PEG) and sodium phosphate colon preparations. METHODS: Outpatients at a VA hospital were randomized using sealed envelopes. Preparations consisted of polyethylene glycol 4L, Fleet sodium phosphate 90 mL with four to six glasses water twice daily and 296 mL of magnesium citrate in the evening with PIE prior to colonoscopy. Colon cleansing was assessed blindly using a five-point scale: 0 (very poor) to 4 (excellent). RESULTS: Altogether 391 patients participated in the study (129 in the PEG group, 127 in the sodium phosphate and 135 in the PIE group), with a mean age of 62 years, of whom 75% were men. PIE and sodium phosphate were superior to PEG: median cleansing scored 4 (excellent) versus 3 with PEG (P < 0.01). Inadequate preparations were more common with PEG than PIE (18% vs 5%) (P < 0.01). Side-effects included vomiting: 37% in the sodium phosphate group versus 5% in the PEG and 2% in the PIE groups (P < 0.01). The three preparations were judged intolerable in <= 5%. CONCLUSIONS: PIE and sodium phosphate are superior to PEG for colon preparations. PIE is the preferred preparation for those at high risk of unsatisfactory preparations or with unsatisfactory traditional preparations. PMID- 29160623 TI - Saddlebags: A software interface for submitting full-length HLA allele sequences to the EMBL-ENA nucleotide database. AB - Submission of full-length HLA allele sequences presents a unique challenge, both for high-throughput sequencing laboratories and smaller diagnostic laboratories. HLA's extensive polymorphism means that accurate representation and annotation of allele sequence is of critical importance, and curators of nucleotide databases must establish submission formats to ensure high-quality data and prevent ambiguities. The IPD-IMGT/HLA database is established as the standard repository for HLA sequences, and it is a major goal of the 17th International HLA and Immunogenetics Workshop to fill the IPD-IMGT/HLA database with full-length HLA sequences. The process of preparing sequence annotation and metadata is cumbersome and error prone, and it is desirable to create a straightforward and concise method of preparing sequence submissions. We introduce Saddlebags, a software tool for rapid generation of HLA (novel) full-length allele sequence submissions. HLA allele sequences are submitted first to EMBL European Nucleotide Archive (EMBL-ENA), and metadata is gathered for subsequent preparation of an IPD IMGT/HLA formatted submission. Combining these steps into a pipeline reduces effort and minimizes errors for submitting laboratories. This software has been used by Maastricht University Medical Center Transplantation Immunology Laboratory to submit 79 novel alleles to EMBL-ENA, and the tool is freely available for the HLA community. PMID- 29160625 TI - Evaluation of two novel plant gums for bioadhesive microsphere and sustained release formulations of metformin hydrochloride. AB - BACKGROUND: The biological half life of metformin requires multiple doses which are associated with poor patient compliance. This justifies the need for a dosage form with reduced dosing frequency. OBJECTIVES: Gums from Enterolobium cyclocarpum and Cedrela odorata trees were evaluated in formulating bioadhesive microspheres containing metformin hydrochloride, for sustained drug release. Hydroxylpropylmethyl cellulose (HPMC) was the standard. MATERIAL AND METHODS: Microspheres were produced from formulations of API and either cedrela gum (FC), enterolobium gum (FE) or HPMC (FH), using a W/O solvent extraction technique. The microspheres were characterized using a particle size analyzer, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffractometer (PXRD), drug entrapment, in vitro release and mucoadhesion studies. The data was analyzed using ANOVA and t-test at p = 0.05. RESULTS: FT-IR spectroscopy indicated no alteration in the functional groups of metformin. A yield of 92-98% microspheres was obtained from all the formulations which had a particle size range of 72-84 MUm. SEM revealed cylindrical to near-spherical particles with rough surfaces. The drug release profile showed a burst over the first 30 min followed by a steady release for about 5 h and a slow release for 5 days. Formulations containing the gums sustained the release of API for almost the same time as HPMC formulations; the ranking order was FE > FH > FC (p > 0.05). All the formulations exhibited good concentration-dependent mucoadhesive properties. CONCLUSIONS: The gums were suitable for formulation of mucoadhesive microspheres for sustained release of metformin. The formulations showed good release properties in an alkaline pH. PMID- 29160624 TI - Buccal patches of atenolol formulated using fenugreek (Trigonella foenum-graecum L.) seed mucilage. AB - BACKGROUND: The use of mucoadhesive natural polymers in designing mucoadhesive patch systems has received much attention. OBJECTIVES: The study involved the development and evaluation of buccal patches of atenolol using fenugreek (Trigonella foenum-graecum L.) seed mucilage with hydroxylpropyl methyl cellulose (HPMC K4M) and a backing membrane (ethyl cellulose 5% w/v). MATERIAL AND METHODS: These atenolol-releasing buccal patches were prepared using a solvent casting technique. The buccal patches prepared were evaluated for average weight, thickness, drug content, folding endurance and moisture content. Ex vivo mucoadhesive strength, force of adhesion and bonding strength were determined using porcine buccal mucosa. The mucosal permeation of atenolol through the porcine buccal mucosa was carried out using a Franz diffusion cell in phosphate buffer saline, pH 6.8. These buccal patches were also characterized by SEM and FTIR spectroscopy. RESULTS: The average weight, thickness, drug content, folding endurance and moisture content of these atenolol-releasing buccal patches were found satisfactory for all the patches. Amongst all, the F-4 buccal patch showed maximum mucoadhesive strength (31.12 +/-1.86 g), force of adhesion (30.53 * 10-2 N) and bond strength (1748.89 N/m2). Ex vivo atenolol permeation from the buccal patches showed drug permeation across the excised porcine buccal mucosa over 12 h. The F-4 buccal patch showed maximum permeation flux (29.12 MUg/cm2/h). CONCLUSIONS: The developed atenolol-releasing buccal patches can be beneficial over the conventional drug delivery systems to decrease the dosing frequency and enhance patient compliance. PMID- 29160626 TI - Film forming properties of Cissus pulpunea (Guill and Perr) and Irvingia gabonensis (O'Rorke) gums. AB - BACKGROUND: Natural polymers such as gums have gained attention in drug delivery systems due to their availability, compatibility and degradation under natural and physiological conditions. OBJECTIVES: The aim of the present study was to investigate the film forming properties of gums obtained from the stem of Cissus polpunea (Guill and Perr) and the seed of Irvingia gabonensis (O'Rorke). MATERIAL AND METHODS: Gums were extracted from the relevant plant parts and characterized using functional, proximate and elemental properties. Films were prepared by the casting method using gum concentrations of 1-4% w/v and varied with propylene glycol (PG). The films were assessed through physical observation, thickness, swelling power and moisture sorption effects using the relative humidity of 0, 27, 43, 57, 75 and 90%. The gum yielding optimal film properties was used as coating material in ibuprofen tablet formulations. The mechanical and release properties of the tablets were determined. RESULTS: The functional and proximate properties of gums showed a similarity in the majority of the parameters, but significant (p < 0.05) variation existed in their solubility, while elemental assessment revealed the absence of toxic metals. Generally, the films were homogenous, opaque and demonstrated high swelling power in phosphate buffer, which was pH-dependent. Moisture sorption properties of the gums increased with the increase in relative humidity in the order HPMC < Cissus < Irvingia. Film coated ibuprofen tablets showed higher mechanical properties and disintegration and dissolution times compared with uncoated tablets. CONCLUSIONS: Cissus and irvingia gums have demonstrated acceptable functional, proximate and elemental properties. Film-coated ibuprofen tablets showed higher mechanical and release properties than was the case in uncoated tablets. PMID- 29160627 TI - Native and microwave-modified Terminalia mantaly gums as sustained-release and bioadhesive excipients in naproxen matrix tablet formulations. AB - BACKGROUND: Hydrophilic polymers provide a means of sustaining drug delivery. Native gums may be limited in function, but modification may improve their activity. OBJECTIVES: The aim of the study was to evaluate native and modified forms of Terminalia mantaly gum for their sustained-release and bioadhesive properties. MATERIAL AND METHODS: The native gum (NTM) was modified by microwave irradiation for 20 seconds (MTM20) and 60 seconds (MTM60) and characterized using microscopy, Fourier transform infrared spectroscopy (FTIR) and packing properties. The effects of the thermally induced molecular reorientation were determined. Tablet formulations of naproxen were produced by direct compression. The mechanical, bioadhesive and release properties of the formulations were determined. RESULTS: Irradiation of NTM improved the gum's flow properties, resulting in Carr's Index and Hausner's ratios lower than 16% and 1.25, respectively. Swelling studies showed that MTM20 and MTM60 had lower water absorption capacity and swelling index values, while packing properties improved upon irradiation, as depicted by lower tapped density values. FTIR spectra of samples showed that the irradiated gums were distinct from the native gums and did not interact with naproxen sodium. The gum's mechanical properties improved with MTM20 and MTM60 and sustained-release action of up 12 h was obtained. CONCLUSIONS: Inclusion of hydroxypropyl methylcellulose (HPMC) in the tablet formulations proved critical for bioadhesion. Microwave irradiation of native Terminalia mantaly gum improved the flow, mechanical and sustained-release properties of Naproxen tablets, and the addition of HPMC increased bioadhesion properties. The tablet properties of the native gum were significantly improved after 20 s of microwave irradiation. PMID- 29160628 TI - The role of chitin and chitosan in peripheral nerve reconstruction. AB - Chitin is a natural polysaccharide commonly found in nature and chitosan is its partially deacetylated derivative. The properties of both biopolymers allow their wide use in medicine and various industries. This paper presents the possibilities offered by chitin and chitosan for the creation of neurotubes utilized in peripheral nerve repair procedures. In the initial part of this manuscript, experimental studies on both polysaccharides carried out by numerous authors have been presented and their results have been discussed. Further, basic information on Reaxon(r) Nerve Guide, being the first chitosan tube approved for clinical use, is provided. Finally, existing limitations in the optimal use of chitosan tubes in peripheral nerve reconstruction have been pointed out. It is expected that modification of the properties of chitosan itself as well as enriching neurotubes with components of extracellular matrix, cells, growth factors and filaments will further improve the results of nerve regeneration obtained with chitosan-based nerve conduits. PMID- 29160629 TI - Chitosan and its composites: Properties for use in bone substitution. AB - For many years, research has been carried out on finding an ideal bone substitute. Chitosan (CTS) is a naturally occurring polysaccharide, obtained mainly from, inter alia, the shells of crustaceans. It is characterized by its high level of biocompatibility, biodegradability and antimicrobial properties as well as its support in the healing of wounds. Chitosan, due to its ability to form porous structures, can be used in the production of scaffolds used in the treatment of bone defects. There are numerous studies on the use of CTS in combination with other substances which aim to improve its biological and mechanical properties. The combination of chitosan with the calcium phosphate hydroxyapatite (HAp) has been extensively tested. The objective of the current studies is to verify the properties of scaffolds consisting of chitosan and other substances like polybutylene succinate, human bone marrow mesenchymal stem cells (hBMSCs), collagen, alginate, transforming growth factor - beta (TGF-beta), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) or bone morphogenetic proteins (BMP). The aim of the current research is to develop a scaffold with sufficiently good mechanical properties. Trials are underway with many of the biological and synthetic components affecting the biological properties of chitosan. This will allow for the creation of a substitute that fully meets the conditions for an ideal artificial bone. PMID- 29160630 TI - Synthetic grafts in the treatment of ruptured anterior cruciate ligament of the knee joint. AB - The anterior cruciate ligament (ACL) is cited as the most frequently injured ligament in the knee. The standard treatment of ACL injury remains ligament reconstruction followed by a postoperative physiotherapeutic procedure. During the reconstruction, the torn ligament can be replaced with an autograft or an allograft. A synthetic ligament is also one of the available graft options. Synthetic grafts in ruptured ACL treatment have been used as scaffolds, stents, or prostheses. The story of using synthetic materials in ACL deficient knee treatment started in the beginning of the 20th century with the usage of silk and silver fibers. The second half of the 20th century abounded in new synthetic materials being proposed as torn ACL replacements, such as Supramid(r), Teflon(r) or Dacron(r), Proplast(r), carbon fiber graft, ABC graft, Kennedy-LAD(r), Trevia, Leeds-Keio, Gore-Tex(r), PDS(r), EULIT(r), and Polyflex(r) or LARS(r). Artificial ligaments have intrigued surgeons for all these years as they represent the hope for grafts that are easily available and stronger than soft tissue "off-the shelf" grafts, simplifying the surgery, and avoiding graft harvesting and donor site morbidity. However, most of the artificial grafts have been characterized by high rates of failure. One of the very few synthetic grafts gaining more widespread popularity has been LARS(r). However, it is suggested that the ligament not be considered as a potential graft for primary reconstruction of the ACL, and it should be rather treated as an alternative graft in special cases, so the optimal synthetic graft material remains controversial. PMID- 29160631 TI - Catatonia. AB - Catatonia is associated with psychomotor symptoms and severe disturbances of executive functioning. While the prognosis is good in most cases, malignant catatonia still continues to occur. The first-line choice for drug therapy is lorazepam, which usually results in a good response. In catatonic stupor, i.e. immobility and stupor, the first-line therapy is electrotherapy, preferably at an earliest possible stage. In mania, catatonia may become manifest also as psychomotor excitement. Electrotherapy can be used primarily in malignant catatonia, with dantrolene and bromocriptin also finding use in a critical situation. PMID- 29160632 TI - LGL leukemia and autoimmunity - the borderline between autoimmune disease and cancer is becoming blurred. AB - Large granular lymphocyte (LGL) leukemia is a chronic hematological disease, in which the diseased cells consist of clonal large, mature T or NK cells. Major symptoms and findings of the disease include anemia, neutropenia and rheumatoid arthritis. Immunosuppressive treatments, such as methotrexate, usually relieve the symptoms in patients. In LGL leukemia, next-generation sequencing has recently revealed mutations in the STAT3 and STAT5B genes that lead to the activation of these proteins. Similar mutations have been detected in hereditary autoimmune diseases, disorders of bone marrow and malignancies of lymphocyte origin. PMID- 29160633 TI - Monitoring the condition of the fetus during delivery. AB - Uterine contractions during delivery increase the resistance to flow in the blood vessels of the placenta and decreases placental blood circulation, possibly subjecting the fetus to hypoxia. Several methods have been developed for monitoring the condition of the fetus during delivery. Cardiotocography is used to monitor the fetus's heart rate and variability in relation to the mother's contractions. A change in cardiotocography recording due to stimulation of the presenting part is an indication of a healthy fetus. ST analysis of fetal ECG depicts the oxygenation of fetal cardiac muscle during delivery. In addition to cardiotocography and ST analysis, analysis of blood gases and lactate determination are used in assessing the condition of the fetus. PMID- 29160634 TI - How does early stress affect brain development? AB - Early stress would seem to be associated with alterations in certain structures of the brain, such as the amygdala and hippocampus, cerebral cortex and white matter, in structures of pathways essential to emotional control. Furthermore, a tendency to have higher levels of stress hormone, i.e. cortisol, as well as hormonal responses to stress has been shown in individuals exposed to early stress. Early stress, already experienced in utero, may in fact program the central nervous system to become more susceptible to later-onset disturbances of regulation of stress and emotions. Prevention and treatment of stress during pregnancy and its consequences would thus require more investments than at present. PMID- 29160635 TI - Cyclist injuries. AB - A cyclist is relatively susceptible to accidents, most of which occur without the involvement of another party. The most common parts of the body receiving injuries include the head, the clavicular and the chest region as well as the upper limbs. It is common for a cyclist upon falling to suffer injuries of several parts of the body. While the use of a cyclist's helmet has clearly increased in the course of the years, it is still being used by less than half of the cyclists. During the past decade, 20 to 30 cyclists have died in bicycle accidents in Finland. The most common cause leading to a cyclist's death is brain injury. PMID- 29160636 TI - Conservative treatment of finger fractures. AB - Most fractures of the hand and fingers can be treated conservatively. When evaluating the fracture, special attention should be paid on sufficient quality of the radiographs and that the fracture will not cause a rotational malposition or functionally significant shortening of the finger. A finger fracture can be immobilized as soon as the fracture is stable in motion. This is often possible immediately. A broken finger should not be immobilized for more than a month. Open fractures and properly immobilized fractures still remaining in malposition shall be operated. PMID- 29160637 TI - Fetal surgery for lower urinary tract obstruction: the importance of staging prior to intervention. AB - Fetal lower urinary tract obstruction (LUTO) is a heterogeneous pathology associated with a high morbidity and mortality due to pulmonary hypoplasia. Previously, when a fetus was diagnosed on ultrasound with LUTO, expectant care or termination was the only option; this has changed because of fetal surgical intervention. Vesicoamniotic shunts and cystoscopy are the current methods utilized to treat LUTO; however, it remains difficult to determine whether fetal prognosis favors intervention and long-term outcome follow-up has been limited. This review covers the history and current challenges of fetal intervention for obstructive uropathies. We also present the Ruano's LUTO staging system which integrates information from fetal urine analysis with ultrasound findings to assess whether a specific fetal intervention is recommended. Utilizing a standard staging system that is readily adopted by providers carrying out fetal surgery is crucial for determining the true impact on outcomes intervention has on fetuses diagnosed with LUTO. PMID- 29160638 TI - Tissue repair in neonatal and pediatric surgery: analysis on infections in surgically implanted natural biomaterials. AB - INTRODUCTION: Over the past 4 decades commercially available natural and synthetic biomaterials have been employed for various reconstructive procedures in the pediatric population. The aim of this study was to identify the types of commercially available natural biomaterials and their areas of application in the pediatric age group. Furthermore, to perform an analysis to identify areas of application and types of biomaterials those have increased susceptibility to infections in the pediatric population. EVIDENCE ACQUISITION: The literature was reviewed from 1970-2015 using a Medline search and data concerning application of different natural biomaterials was collected. Specific search was performed regarding to infections associated with these biomaterials. EVIDENCE SYNTHESIS: The rate of major infection after implantation of the biomaterial in the group of 298 reviewed cases was 5%. Patients with acute burn wounds which were treated with biomaterials presented the group with higher infection rates of 5-33%. CONCLUSIONS: The demand for these biomaterials has exponentially increased due to the worldwide rise in interest in tissue engineering research. Even using the appropriate techniques of implantation and professional postoperative care biomaterial associated infections cannot be eliminated. However, the current rate of infections is not a limiting factor for using the biomaterials in pediatric surgery. PMID- 29160639 TI - Predictors of mortality in neonates with giant omphaloceles. AB - INTRODUCTION: This analysis performed a review of giant-omphaloceles to determine the predictors of mortality. EVIDENCE ACQUISITION: PubMed and KoBson databases were searched for terms "giant," "omphalocele," and "mortality." Primary end points included mortality correlation with gestational age (GA), birth weight (BW), eviscerated organs, associated anomalies and management. To calculate mean and median values IBM SPSS v. 23.0 was used. EVIDENCE SYNTHESIS: After de duplication and review search revealed 42 articles of which 23 met the inclusion criteria with 396 giant-omphaloceles for this analysis. Median gestational age (GA) was 36 weeks for all neonates (range 21-41); 21 neonates were reported as premature with median GA 33.5 (range 21-36). Overall median birth weight (BW) was 3100 g (range 1100-4100 g). The diameter of abdominal wall defect was 4-15 cm with the average size of 7.6 cm except for non-giant giant omphaloceles (N.=7) where the defect was measuring between 2.7 and 4 cm. Amniotic sac contents beside intestines included liver (N.=154), stomach (N.=11), spleen (N.=2), pancreas (N.=1), gallbladder (N.=5), and 5 giant omphaloceles were reported to contain only liver; sac was ruptured in 22. Giant omphaloceles were associated with a variety of other anomalies, most often with cardiac anomalies (N.=93; 23.4%) and pulmonary hypoplasia and/or pulmonary hypertension (N.=39; 9.8%). Management included conservative treatment N.=264 (66.6%), primary closure (N.=17; 4.3%), staged closures (N.=98; 24.7%) primary or staged closure (N.=17; 4.3%). The most frequent complication was sepsis (N.=52). There were 90 (22.7%) lethal outcomes, 6 lethal outcomes in neonates even before final closure could be achieved and 12 in prematures. Leading cause of mortality was sepsis (N.=51; 56.6%), the cause of lethal outcome was not reported in 8 cases. CONCLUSIONS: Giant-omphaloceles have a lethal outcome in one-fifth of neonates. Predictors of mortality included pulmonary hypoplasia and respiratory failure with prematurity and ruptured sacs implicated within this group. Sepsis was the independent iatrogenic factor in mortality. PMID- 29160640 TI - Thoracoscopic repair of congenital diaphragmatic hernia: review of the results. AB - Congenital diaphragmatic hernia (CDH) remains one of the major challenges in neonatal surgery. Survival rate has increased in the last decades mainly due to perinatal care and surgical technique improvements. Classically, a laparotomy has been performed after cardiovascular and respiratory stabilization. Introduction of thoracoscopy in the repair of CDH brought the known advantages of reduced postoperative pain and better cosmesis. However, its safety and effectiveness have been questioned in the last few years. Although there is lack of high evidence data, it seems consensual that thoracoscopy is associated with: 1) longer operative time on account of the learning curve; 2) increased acidosis during surgery whose effects have not been clarified but there is evidence suggesting that neurodevelopment is not affected; 3) reduced morbidity, namely postoperative ileum and adhesions, pain and scar formation; 4) similar mortality rate; 5) higher number of recurrences. While the majority of outcomes are comparable between open and thoracoscopic repair, reduced postoperative morbidity and better cosmesis are advantages to be considered. Technique improvements are still required to reduce recurrence rate. Division of the pleura from the peritoneum is a major step of the procedure; suture type and quality must simulate those in the open repair. The authors believe that careful and meticulous execution of the principles of open surgery will improve outcomes regarding recurrence. PMID- 29160641 TI - Pediatric epilepsy and psychiatric comorbidity: could celiac disease diagnosis improve the outcome? PMID- 29160642 TI - Neonatal bacterial meningitis: a systematic review of European available data. AB - BACKGROUND: Despite advances in neonatal intensive care and the improvements in surveillance, prevention and vaccination programs, neonatal meningitis still represents an important cause of morbidity and mortality in infants, with the highest mortality in the newborn population. AIM: To summarize current knowledge about this topic with particular attention to management of neonatal meningitis in order to provide a useful tool for clinicians. METHODS: We reviewed the existent literature from five European Countries (France, German, Italy, Spain and United Kingdom) on the effectiveness of treatments for bacterial meningitis in newborns taking into consideration the antibiotic resistance phenomenon. RESULTS: There are few data available on this topic; bacterial neonatal meningitis treatment and management is currently based more on experience than on high quality evidences. CONCLUSIONS: Identification of the knowledge gaps may stimulate researchers to design new studies aiming to better define management strategies of bacterial meningitis in newborns. PMID- 29160643 TI - Antithrombotic treatment in neonates and children. AB - Despite the increasing incidence of venous thromboembolic disease in pediatric patients, it remains a rare complication in childhood. Particularly neonates and adolescents are at risk for development of venous thrombosis. Spontaneous thrombotic events are sporadic, the majority of children have multiple coexisting risk factors, including central venous catheter, asphyxia, congenital heart disease, infection, malignancy, surgery and hypovolemia. Most thrombi are diagnosed by ultrasonography. Recommendations for management of pediatric thrombosis are typically extrapolated from adult studies, despite many differences between adults and children, including developmental hemostasis. This review will focus on the management of venous thrombosis in neonates and children, and discuss the use of the available antithrombotic agents in both age categories with reference to those differences. PMID- 29160644 TI - Joint pain management in children and adolescents. AB - In children, joint pain is common complaint and it proves challenging for primary care physicians. The possible differential diagnoses include a wide range of disorders, from the common and benign ones to serious and even life-threating conditions. An accurate work-up of these patients is needed, with thorough patient history and a systematic physical examination as essential tools. Clarifying the nature, the site, and the duration of the pain is fundamental as well as identifying systemic symptoms such as fever, weight loss, and night sweating. We will provide a description of the different clinical presentations of such disorders, and suggest how to approach a targeted patient history and a complete physical examination, which may lead to the appropriate investigation and consequently to the correct diagnosis. PMID- 29160645 TI - Quality of prior warfarin therapy in ischemic stroke patients with a pre-stroke diagnosis of atrial fibrillation. AB - In atrial fibrillation (AF), warfarin prevents ischemic strokes (IS), but its implementation varies. We conducted a retrospective registry study on clinical features and prior warfarin therapy in AF patients with IS. Of our 540 patients, 143 had a prior diagnosis of AF, of which 51% used warfarin. Warfarin use was more common in those having permanent than paroxysmal AF (76% versus 36%, p<0.001). On admission, 42% had INR within the therapeutic range. Average TTR was 64%. Advanced age (p=0.009) and permanent AF (p<0.001) were associated with higher TTR. Better warfarin therapy quality was associated with advanced age and permanent AF. PMID- 29160646 TI - Update on current care guideline: status epileptics. AB - Status epileptics is a medical emergency. Most epileptic seizures last for 1-4 minutes, Seizures lasting over five minutes should be treated a status epileptics. EEG essential for diagnostics. The treatment can be divided into first-aid medications, such as buccal/intranasal midazolam or rectal diazepam, first-line medications such as intravenous diazepam or lorazepam and second-line medications such as fosphenytoin, levetiracetam, valproate and lacosamide, and in addition phenobarbital for children. Third-line treatment is suppressive general anesthesia, monitored by continuous EEG. Antiepileptic medication of patients with epilepsy should be carefully re-evaluated after status epilepticus. PMID- 29160647 TI - Designing cost-efficient surveillance for early detection and control of multiple biological invaders. AB - Wood borers and bark beetles are among the most serious forest pestsworldwide. Many such species have become successful invaders, often causing substantial,costly damages to forests. Here we design and evaluate the cost efficiency of a trap-basedsurveillance program for early detection of wood borers and bark beetles at risk of establishingin New Zealand. Although costly, a surveillance program could lead to earlier detection ofnewly established forest pests, thereby increasing the likelihood of successful eradication andreducing control costs and damages from future invasions. We develop a mechanisticbioeconomic model that relates surveillance intensity (i.e., trap density) and invasion size toprobabilities of detection and control. It captures the dynamics of invasive speciesestablishment, spread, and damages to urban and plantation forests. We employ the modelto design surveillance programs that provide the greatest net present benefits. Our findingssuggest that implementing a surveillance trapping program for invasive wood borers and barkbeetles would provide positive net benefits under all scenarios considered. The economicallyoptimal trapping strategy calls for a very high investment in surveillance: about 10 000 traps ineach year of the 30-year surveillance program, at a present value cost of US$54 million. Thisstrategy provides a 39% reduction in costs compared with no surveillance, corresponding to anexpected net present benefit of approximately US$300 million. Although surveillance mayprovide the greatest net benefits when implemented at relatively high levels, our findings alsoshow that even low levels of surveillance are worthwhile: the economic benefits fromsurveillance more than offset the rising costs associated with increasing trapping density. Ourresults also show that the cost-efficiency of surveillance varies across target regions because ofdifferences in pest introduction and damage accumulation rates across locales, with greatersurveillance warranted in areas closer to at-risk, high-value resources and in areas that receivemore imported goods that serve as an invasion pathway. PMID- 29160648 TI - [Infection by the Epstein-Barr virus between the years 2006-2015 in the health area of Santiago de Compostela. Relationship with age and sex]. AB - OBJECTIVE: In Spain, the age and sex to which the primary infection by EBV is produced is poorly studied. The objective of this work is to know its relation with the presence of the primary infection by EBV between the years 2006 and 2015 in our health area. METHODS: From the Santiago de Compostela health area between 2006 and 2015, 578 patients with serological patterns of EBV primoinfection were selected. This patients presented serological results of IgM-VCA positive, IgG VCA positive and EBNA negative. RESULTS: We found 260/578 (45%) adolescents (11- 19 years). In the number of cases by age the maximum was observed, at 2 and 16 years. Between 14-19 years, 62% (79/127) of women between 14-16 years of age, median age 15.8 years (IQ: 14.8-16.4) compared to 48% (49/102) of men, median age 16 years (IQ: 15.7-16.6) (p = 0.032, p = 0.02, respectively). CONCLUSIONS: As in our study, in the developed countries the majority of primary infections by EBV occur in adolescence and a bimodal distribution is observed in relation to age. During adolescence women acquire before men the first infection by EBV. PMID- 29160649 TI - [Performance of the KAtex test in screening and diagnosis for visceral leishmaniasis in a reference hospital]. AB - OBJECTIVE: Performing of diagnostic test simple using samples not invasive in the diagnosis of visceral leishmaniasis (VL) may be very beneficial, being necessary comparing to traditional methods. The objective of this study was to know the reliability of test KAtex in the urine of patients with suspicion of VL. METHODS: Retrospectively were reviewed the medical histories of patients with suspected of VL to which are performed the test between 2009 and 2015. For its analysis were selected the patients to which is them had made study of the parasite in bone marrow. RESULTS: A total of 110 patients were studied, and bone marrow biopsy for research of Leishmania was performed in 44 (40%). In these patients the sensitivity of the test was 50%, the specificity of 96.7%, positive predictive value of 87.5% and negative predictive value of 80.5%. CONCLUSIONS: KAtex antigenuria sensitivity is too low recommending it as a unique method in the detection of VL in our medium. PMID- 29160650 TI - Assessing predictions of population viability analysis: Peregrine Falcon populations in California. AB - Population viability analysis (PVA) has been an important tool for evaluating species extinction risk and alternative management strategies, but there is little information on how well PVA predicts population trajectories following changes in management actions. We tested previously published predictions from a stage-structured PVA of Peregrine Falcons (Falco peregrinus) in California, USA (Wootton and Bell 1992), against population trajectories following the 1992 termination of statewide, active management (population supplementation of captive-reared young). In the absence of extensive post-management monitoring, we developed surrogate estimates of breeding population size by calibrating several citizen science data sets (Christmas Bird Count, CBC; and North American Breeding Bird Survey, BBS) to intensive population surveys taken primarily during the active management period. CBC abundance data standardized by observer effort exhibited a strong relationship to intensive survey data (r2 = 0.971), indicated significantly reduced annual population growth rates after management was terminated (lambda = 0.023 +/- 0.013 SE) than when supplementation occurred (lambda = 0.089 +/- 0.023 SE), and demonstrated an increasing population as predicted by the PVA. The population trajectory fell within the 95% CI of stochastic simulations of the model either with or without density dependence and assuming either measurement error or process error, but models with process error were most strongly supported by the data. These results indicate that PVA can quantitatively anticipate population trajectories following changes in management, highlight the importance of post-management monitoring of species of concern, and illustrate the benefits of using management changes as large-scale experiments to more rigorously test PVA. PMID- 29160651 TI - Cross-sectional and temporal relationships between bird occupancy and vegetation cover at multiple spatial scales. AB - Scale is a key concept in ecology, but the statistically based quantification of scale effects has often proved difficult. This is exemplified by the challenges of quantifying relationships between biodiversity and vegetation cover at different spatial scales to guide restoration and conservation efforts in agricultural environments. We used data from 2002 to 2010 on 184 sites (viz., site scale) nested within 46 farms (the farm scale), nested within 23 landscapes (the landscape scale). We found cross-sectional relationships with the amount of vegetation cover that were typically positive for woodland birds and negative for open-country birds. However, for some species, relationships differed between spatial scales, suggesting differences in nesting and foraging requirements. There was a 3.5% increase in the amount of native vegetation cover in our study region between 2002 and 2010, and our analyses revealed that some open country species responded negatively to these temporal changes, typically at the farm and/or site scale, but not the landscape scale. Species generally exhibited stronger cross-sectional relationships with the amount of vegetation cover than relationships between changes in occupancy and temporal changes in vegetation cover. This unexpected result can be attributed to differences in habitat use by birds of existing vegetation cover (typically old-growth woodland) vs. plantings and natural regeneration, which are the main contributors to temporal increases in vegetation cover. By taking a multi-scaled empirical approach, we have identified species-specific, scale-dependent responses to vegetation cover. These findings are of considerable practical importance for understanding which species will respond to different scales of protection of existing areas of native vegetation, efforts to increase the amount of native vegetation over time, and both approaches together. PMID- 29160652 TI - Mapping tropical forest canopy diversity using high-fidelity imaging spectroscopy. AB - There is a growing need for operational biodiversity mapping methods to quantify and to assess the impact of climate change, habitat alteration, and human activity on ecosystem composition and function. Here, we present an original method for the estimation of alpha- and beta-diversity of tropical forests based on high-fidelity imaging spectroscopy. We acquired imagery over high-diversity Amazonian tropical forest landscapes in Peru with the Carnegie Airborne Observatory and developed an unsupervised method to estimate the Shannon index (H') and variations in species composition using Bray-Curtis dissimilarity (BC) and nonmetric multidimensional scaling (NMDS). An extensive field plot network was used for the validation of remotely sensed alpha- and beta-diversity. Airborne maps of H' were highly correlated with field alpha-diversity estimates (r = 0.86), and BC was estimated with demonstrable accuracy (r = 0.61-0.76). Our findings are the first direct and spatially explicit remotely sensed estimates of alpha- and beta-diversity of humid tropical forests, paving the way for new applications using airborne and space-based imaging spectroscopy. PMID- 29160653 TI - Microtopographic controls on lowland Amazonian canopy diversity from imaging spectroscopy. AB - Microtopographic variation is ubiquitous throughout lowland Amazonia, and it may impart patterns of species richness and abundance, and perhaps community compositional changes. To date, no studies have determined the degree to which lowland microtopography influences forest canopy diversity. We developed the first high-resolution maps of forest canopy diversity in Amazonia, focusing on four landscapes on two river systems in Peru. Spectroscopic images were acquired using the Carnegie Airborne Observatory combined with a new method based on spectral species to map alpha- and beta-diversity. We analyzed spatial patterns in diversity with respect to floodplain and terrace (terra firme) surfaces and in upriver and downriver locations with contrasting landscape morphologies. We found slightly lower average alpha-diversity in floodplains, but with greater variance than in terrace communities caused by the floodplain mix of swamp forests, anoxic low-diversity ecosystems, and high-diversity areas. beta-diversity estimated with the Bray-Curtis dissimilarity (BC) was strongly related to microtopography, with floodplains showing higher internal compositional dissimilarity than terraces. Throughout all landscapes, remotely mapped BC within terrace environments ranged from 0.25 to 0.43, but these values increased 30-77% on floodplains. Upriver landscapes characterized by higher terraces showed more distinct community turnover than did their downstream counterparts. We conclude that microtopography strongly influences beta-diversity throughout the study landscapes, but terrain is weakly associated with variation in alpha-diversity. We uncover the importance of microtopography in determining species composition in lowland Amazonia and highlight the value of imaging spectroscopy for biodiversity research and conservation. PMID- 29160654 TI - Underwater endoscopic mucosal resection: who, how and when. PMID- 29160655 TI - Quality of life and adherence in liver transplant recipients. AB - The assessment of quality of life (QoL) after transplantation represents an ancillary tool to evaluate the efficacy of solid organ transplantation, in addition to graft and patient survival rates and complication. The global assessment of QoL after transplantation usually confirms the improvement when compared to pre-transplant setting. However, whereas significant improvement in physical activity has been widely reported, several studies have demonstrated that social domain and cognitive function do not reach the level of general population after surgery. Post-transplant adherence depends on several factors, including patient personality, level of education, understanding of disease, complexity of medical prescriptions, family support. The evaluation of post transplant adherence includes adherence to medical prescriptions, in particular to immunosuppressive regimens. QoL and adherence represent crucial issues in the long-term management of liver transplant recipients. Therefore, the transplant professionals should be able to identify risk factors of poor adherence and limited quality of life, in adult and pediatric liver transplant recipients. PMID- 29160656 TI - Linking removal targets to the ecological effects of invaders: a predictive model and field test. AB - Species invasions have a range of negative effects on recipient ecosystems, and many occur at a scale and magnitude that preclude complete eradication. When complete extirpation is unlikely with available management resources, an effective strategy may be to suppress invasive populations below levels predicted to cause undesirable ecological change. We illustrated this approach by developing and testing targets for the control of invasive Indo-Pacific lionfish (Pterois volitans and P. miles) on Western Atlantic coral reefs. We first developed a size-structured simulation model of predation by lionfish on native fish communities, which we used to predict threshold densities of lionfish beyond which native fish biomass should decline. We then tested our predictions by experimentally manipulating lionfish densities above or below reef-specific thresholds, and monitoring the consequences for native fish populations on 24 Bahamian patch reefs over 18 months. We found that reducing lionfish below predicted threshold densities effectively protected native fish community biomass from predation-induced declines. Reductions in density of 25-92%, depending on the reef, were required to suppress lionfish below levels predicted to overconsume prey. On reefs where lionfish were kept below threshold densities, native prey fish biomass increased by 50-70%. Gains in small (<6 cm) size classes of native fishes translated into lagged increases in larger size classes over time. The biomass of larger individuals (>15 cm total length), including ecologically important grazers and economically important fisheries species, had increased by 10-65% by the end of the experiment. Crucially, similar gains in prey fish biomass were realized on reefs subjected to partial and full removal of lionfish, but partial removals took 30% less time to implement. By contrast, the biomass of small native fishes declined by >50% on all reefs with lionfish densities exceeding reef-specific thresholds. Large inter-reef variation in the biomass of prey fishes at the outset of the study, which influences the threshold density of lionfish, means that we could not identify a single rule of thumb for guiding control efforts. However, our model provides a method for setting reef specific targets for population control using local monitoring data. Our work is the first to demonstrate that for ongoing invasions, suppressing invaders below densities that cause environmental harm can have a similar effect, in terms of protecting the native ecosystem on a local scale, to achieving complete eradication. PMID- 29160657 TI - Land cover change interacts with drought severity to change fire regimes in Western Amazonia. AB - Fire is becoming a pervasive driver of environmental change in Amazonia and is expected to intensify, given projected reductions in precipitation and forest cover. Understanding of the influence of post-deforestation land cover change on fires in Amazonia is limited, even though fires in cleared lands constitute a threat for ecosystems, agriculture, and human health. We used MODIS satellite data to map burned areas annually between 2001 and 2010. We then combined these maps with land cover and climate information to understand the influence of land cover change in cleared lands and dry-season severity on fire occurrence and spread in a focus area in the Peruvian Amazon. Fire occurrence, quantified as the probability of burning of individual 232-m spatial resolution MODIS pixels, was modeled as a function of the area of land cover types within each pixel, drought severity, and distance to roads. Fire spread, quantified as the number of pixels burned in 3 * 3 pixel windows around each focal burned pixel, was modeled as a function of land cover configuration and area, dry-season severity, and distance to roads. We found that vegetation regrowth and oil palm expansion are significantly correlated with fire occurrence, but that the magnitude and sign of the correlation depend on drought severity, successional stage of regrowing vegetation, and oil palm age. Burning probability increased with the area of nondegraded pastures, fallow, and young oil palm and decreased with larger extents of degraded pastures, secondary forests, and adult oil palm plantations. Drought severity had the strongest influence on fire occurrence, overriding the effectiveness of secondary forests, but not of adult plantations, to reduce fire occurrence in severely dry years. Overall, irregular and scattered land cover patches reduced fire spread but irregular and dispersed fallows and secondary forests increased fire spread during dry years. Results underscore the importance of land cover management for reducing fire proliferation in this landscape. Incentives for promoting natural regeneration and perennial crops in cleared lands might help to reduce fire risk if those areas are protected against burning in early stages of development and during severely dry years. PMID- 29160658 TI - An analysis of controls on fire activity in boreal Canada: comparing models built with different temporal resolutions. AB - Fire regimes of the Canadian boreal forest are driven by certain environmental factors that are highly variable from year to year (e.g., temperature, precipitation) and others that are relatively stable (e.g., land cover, topography). Studies examining the relative influence of these environmental drivers on fire activity suggest that models making explicit use of interannual variability appear to better capture years of climate extremes, whereas those using a temporal average of all available years highlight the importance of land cover variables. It has been suggested that fire models built at different temporal resolutions may provide a complementary understanding of controls on fire regimes, but this claim has not been tested explicitly with parallel data and modeling approaches. We addressed this issue by building two models of area burned for the period 1980-2010 using 14 explanatory variables to describe ignitions, vegetation, climate, and topography. We built one model at an annual resolution, with climate and some land-cover variables being updated annually, and the other model using 31-year fire "climatology" based on averaged variables. Despite substantial differences in the variables' contributions to the two models, their predictions were broadly similar, which suggests coherence between the spatial patterns of annually varying climate extremes and long-term climate normals. Where the models' predictions diverged, discrepancies between the annual and averaged models could be attributed to specific explanatory variables. For instance, annually updating land cover allowed us to identify a possible negative feedback between flammable biomass and fire activity. These results show that building models at more than one temporal resolution affords a deeper understanding of controls on fire activity in boreal Canada than can be achieved by examining a single model. However, in terms of spatial predictions, the additional effort required to build annual models of fire activity may not always be warranted in this study area. From a management and policy standpoint, this key finding should boost confidence in models that incorporate climatic normals, thereby providing a stronger foundation on which to make decisions on adaptation and mitigation strategies for future fire activity. PMID- 29160659 TI - Informed actions: where to cost effectively manage multiple threats to species to maximize return on investment. AB - Conservation practitioners, faced with managing multiple threats to biodiversity and limited funding, must prioritize investment in different management actions. From an economic perspective, it is routine practice to invest where the highest rate of return is expected. This return-on-investment (ROI) thinking can also benefit species conservation, and researchers are developing sophisticated approaches to support decision-making for cost-effective conservation. However, applied use of these approaches is limited. Managers may be wary of "black-box" algorithms or complex methods that are difficult to explain to funding agencies. As an alternative, we demonstrate the use of a basic ROI analysis for determining where to invest in cost-effective management to address threats to species. This method can be applied using basic geographic information system and spreadsheet calculations. We illustrate the approach in a management action prioritization for a biodiverse region of eastern Australia. We use ROI to prioritize management actions for two threats to a suite of threatened species: habitat degradation by cattle grazing, and predation by invasive red foxes (Vulpes vulpes). We show how decisions based on cost-effective threat management depend upon how expected benefits to species are defined and how benefits and costs co-vary. By considering a combination of species richness, restricted habitats, species vulnerability, and costs of management actions, small investments can result in greater expected benefit compared with management decisions that consider only species richness. Furthermore, a landscape management strategy that implements multiple actions is more efficient than managing only for one threat, or more traditional approaches that don't consider ROI. Our approach provides transparent and logical decision support for prioritizing different actions intended to abate threats associated with multiple species; it is of use when managers need a justifiable and repeatable approach to investment. PMID- 29160660 TI - Sugammadex: hunting for new side effects? PMID- 29160661 TI - Multimodel simulations of forest harvesting effects on long-term productivity and CN cycling in aspen forests. AB - The effects of forest management on soil carbon (C) and nitrogen (N) dynamics vary by harvest type and species. We simulated long-term effects of bole-only harvesting of aspen (Populus tremuloides) on stand productivity and interaction of CN cycles with a multiple model approach. Five models, Biome-BGC, CENTURY, FORECAST, LANDIS-II with Century-based soil dynamics, and PnET-CN, were run for 350 yr with seven harvesting events on nutrient-poor, sandy soils representing northwestern Wisconsin, United States. Twenty CN state and flux variables were summarized from the models' outputs and statistically analyzed using ordination and variance analysis methods. The multiple models' averages suggest that bole only harvest would not significantly affect long-term site productivity of aspen, though declines in soil organic matter and soil N were significant. Along with direct N removal by harvesting, extensive leaching after harvesting before canopy closure was another major cause of N depletion. These five models were notably different in output values of the 20 variables examined, although there were some similarities for certain variables. PnET-CN produced unique results for every variable, and CENTURY showed fewer outliers and similar temporal patterns to the mean of all models. In general, we demonstrated that when there are no site specific data for fine-scale calibration and evaluation of a single model, the multiple model approach may be a more robust approach for long-term simulations. In addition, multimodeling may also improve the calibration and evaluation of an individual model. PMID- 29160662 TI - Altered water and nitrogen input shifts succession in a southern California coastal sage community. AB - Vegetation-type conversions between grasslands and shrublands have occurred worldwide in semiarid regions over the last 150 years. Areas once covered by drought-deciduous shrubs in Southern California (coastal sage scrub) are converting to grasslands dominated by nonnative species. Increasing fire frequency, drought, and nitrogen deposition have all been hypothesized as causes of this conversion, though there is little direct evidence. We constructed rain out shelters in a coastal sage scrub community following a wildfire, manipulated water and nitrogen input in a split-plot design, and collected annual data on community composition for four years. While shrub cover increased through time in all plots during the postfire succession, both drought and nitrogen significantly slowed recovery. Four years after the fire, average native shrub cover ranged from over 80% in water addition, ambient-nitrogen plots to 20% in water reduction, nitrogen addition plots. Nonnative grass cover was high following the fire and remained high in the water reduction plots through the third spring after the fire, before decreasing in the fourth year of the study. Adding nitrogen decreased the cover of native plants and increased the cover of nonnative grasses, but also increased the growth of one crown-sprouting shrub species. Our results suggest that extreme drought during postfire succession may slow or alter succession, possibly facilitating vegetation-type conversion of coastal sage scrub to grassland. Nitrogen addition slowed succession and, when combined with drought, significantly decreased native cover and increased grass cover. Fire, drought, and atmospheric N deposition are widespread aspects of environmental change that occur simultaneously in this system. Our results imply these drivers of change may reinforce each other, leading to a continued decline of native shrubs and conversion to annual grassland. PMID- 29160663 TI - Ecological site-based assessments of wind and water erosion: informing accelerated soil erosion management in rangelands. AB - Accelerated soil erosion occurs when anthropogenic processes modify soil, vegetation, or climatic conditions causing erosion rates at a location to exceed their natural variability. Identifying where and when accelerated erosion occurs is a critical first step toward its effective management. Here we explored how erosion assessments structured in the context of ecological sites (a land classification based on soils, landscape setting, and ecological potential) and their vegetation states (plant assemblages that may change due to management) can inform systems for reducing accelerated soil erosion in rangelands. We evaluated aeolian horizontal sediment flux and fluvial sediment erosion rates for five ecological sites in southern New Mexico, USA, using monitoring data and rangeland specific wind and water erosion models. Across the ecological sites, plots in shrub-encroached and shrub-dominated vegetation states were consistently susceptible to aeolian sediment flux and fluvial sediment erosion. Both processes were found to be highly variable for grassland and grass-succulent states across the ecological sites at the plot scale (0.25 ha). We identified vegetation thresholds that define cover levels below which rapid (exponential) increases in aeolian sediment flux and fluvial sediment erosion occur across the ecological sites and vegetation states. Aeolian sediment flux and fluvial erosion in the study area could be effectively controlled when bare ground cover was <20% of a site or the cover of canopy interspaces >100 cm in length was less than ~35%. Land use and management activities that alter cover levels such that they cross thresholds, and/or drive vegetation state changes, may increase the susceptibility of areas to erosion. Land use impacts that are constrained within the range of natural variability should not result in accelerated soil erosion. Evaluating land condition against the erosion thresholds identified here will enable identification of areas susceptible to accelerated soil erosion and the development of practical management solutions. PMID- 29160664 TI - Spatial patterns of grassland-shrubland state transitions: a 74-year record on grazed and protected areas. AB - Tree and shrub abundance has increased in many grasslands causing changes in ecosystem carbon and nitrogen pools that are related to patterns of woody plant distribution. However, with regard to spatial patterns of shrub proliferation, little is known about how they are influenced by grazing or the extent to which they are influenced by intraspecific interactions. We addressed these questions by quantifying changes in the spatial distribution of Prosopis velutina (mesquite) shrubs over 74 years on grazed and protected grasslands. Livestock are effective agents of mesquite dispersal and mesquite plants have lateral roots extending well beyond the canopy. We therefore hypothesized that mesquite distributions would be random on grazed areas mainly due to cattle dispersion and clustered on protected areas due to decreased dispersal and interspecific interference with grasses; and that clustered or random distributions at early stages of encroachment would give way to regular distributions as stands matured and density-dependent interactions intensified. Assessments in 1932, 1948, and 2006 supported the first hypothesis, but we found no support for the second. In fact, clustering intensified with time on the protected area and the pattern remained random on the grazed site. Although shrub density increased on both areas between 1932 and 2006, we saw no progression toward a regular distribution indicative of density-dependent interactions. We propose that processes related to seed dispersal, grass-shrub seedling interactions, and hydrological constraints on shrub size interact to determine vegetation structure in grassland to-shrubland state changes with implications for ecosystem function and management. PMID- 29160665 TI - Spatiotemporal variation in resource selection: insights from the American marten (Martes americana). AB - Behavioral and genetic adaptations to spatiotemporal variation in habitat conditions allow species to maximize their biogeographic range and persist over time in dynamic environments. An understanding of these local adaptations can be used to guide management and conservation of populations over broad extents encompassing diverse habitats. This understanding is often achieved by identifying covariates related to species' occurrence in multiple independent studies conducted in relevant habitats and seasons. However, synthesis across studies is made difficult by differences in the model covariates evaluated and analytical frameworks employed. Furthermore, inferences may be confounded by spatiotemporal variation in which habitat attributes are limiting to the species' ecological requirements. In this study, we sought to quantify spatiotemporal variation in resource selection by the American marten (Martes americana) in forest ecosystems of the Pacific Northwest, USA. We developed resource selection functions for both summer and winter based on occurrence data collected in mesic and xeric forest habitats. Use of a consistent analytical framework facilitated comparisons. Habitat attributes predicting marten occurrence differed strongly between the two study areas, but not between seasons. Moreover, the spatial scale over which covariates were calculated greatly influenced their predictive power. In the mesic environment, marten resource selection was strongly tied to riparian habitats, whereas in the xeric environment, marten responded primarily to canopy cover and forest fragmentation. These differences in covariates associated with marten occurrence reflect differences in which factors were limiting to marten ecology in each study area, as well as local adaptations to habitat variability. Our results highlight the benefit of controlled meta-replication studies in which analyses of multiple study areas and seasons at varying spatial scales are integrated into a single framework. PMID- 29160666 TI - Housing development erodes avian community structure in U.S. protected areas. AB - Protected areas are a cornerstone for biodiversity conservation, but they also provide amenities that attract housing development on inholdings and adjacent private lands. We explored how this development affects biodiversity within and near protected areas among six ecological regions throughout the United States. We quantified the effect of housing density within, at the boundary, and outside protected areas, and natural land cover within protected areas, on the proportional abundance and proportional richness of three avian guilds within protected areas. We developed three guilds from the North American Breeding Bird Survey, which included Species of Greatest Conservation Need, land cover affiliates (e.g., forest breeders), and synanthropic species associated with urban environments. We gathered housing density data for the year 2000 from the U.S. Census Bureau, and centered the bird data on this year. We obtained land cover data from the 2001 National Land Cover Database, and we used single- and multiple-variable analyses to address our research question. In all regions, housing density within protected areas was positively associated with the proportional abundance or proportional richness of synanthropes, and negatively associated with the proportional abundance or proportional richness of Species of Greatest Conservation Need. These relationships were strongest in the eastern forested regions and the central grasslands, where more than 70% and 45%, respectively, of the variation in the proportional abundance of synanthropes and Species of Greatest Conservation Need were explained by housing within protected areas. Furthermore, in most regions, housing density outside protected areas was positively associated with the proportional abundance or proportional richness of synanthropes and negatively associated with the proportional abundance of land cover affiliates and Species of Greatest Conservation Need within protected areas. However, these effects were weaker than housing within protected areas. Natural land cover was high with little variability within protected areas, and consequently, was less influential than housing density within or outside protected areas explaining the proportional abundance or proportional richness of the avian guilds. Our results indicate that housing development within, at the boundary, and outside protected areas impacts avian community structure within protected areas throughout the United States. PMID- 29160667 TI - Synergistic effects of climate change and harvest on extinction risk of American ginseng. AB - Over the next century, the conservation of biodiversity will depend not only on our ability to understand the effect of climate change, but also on our capacity to predict how other factors interact with climate change to influence species viability. We used American ginseng (Panax quinquefolius L.), the United States' premier wild-harvested medicinal, as a model system to ask whether the effect of harvest on extinction risk depends on changing climatic conditions. We performed stochastic projections of viability response to an increase in maximum growing season temperature of 1 degrees C over the next 70 years by sampling matrices from long-term demographic studies of 12 populations (representing 75 population years of data). In simulations that included harvest and climate change, extinction risk at the median population size (N = 140) was 65%, far exceeding the additive effects of the two factors (extinction risk = 8% and 6% for harvest and climate change, respectively; quasi-extinction threshold = 20). We performed a life table response experiment (LTRE) to determine underlying causes of the effect of warming and harvest on deterministic lambda (lambdad). Together, these factors decreased lambdad values primarily by reducing growth of juvenile and small adult plants to the large-adult stage, as well as decreasing stasis of the juveniles and large adults. The interaction observed in stochastic model results followed from a nonlinear increase in extinction risk as the combined impact of harvest and warming consistently reduced lambda values below the demographic tipping point of lambda = 1. While further research is needed to create specific recommendations, these findings indicate that ginseng harvest regulations should be revised to account for changing climate. Given the possibility of nonlinear response like that reported here, pre-emptive adaptation of management strategies may increase efficacy of biodiversity conservation by allowing behavior modification prior to precipitous population decline. PMID- 29160668 TI - Tracking forest phenology and seasonal physiology using digital repeat photography: a critical assessment. AB - Digital repeat photography is becoming widely used for near-surface remote sensing of vegetation. Canopy greenness, which has been used extensively for phenological applications, can be readily quantified from camera images. Important questions remain, however, as to whether the observed changes in canopy greenness are directly related to changes in leaf-level traits, changes in canopy structure, or some combination thereof.We investigated relationships between canopy greenness and various metrics of canopy structure and function, using five years (2008-2012) of automated digital imagery, ground observations of phenological transitions, leaf area index (LAI) measurements, and eddy covariance estimates of gross ecosystem photosynthesis from the Harvard Forest, a temperate deciduous forest in the northeastern United States. Additionally, we sampled canopy sunlit leaves on a weekly basis throughout the growing season of 2011. We measured physiological and morphological traits including leaf size, mass (wet/dry), nitrogen content, chlorophyll fluorescence, and spectral reflectance and characterized individual leaf color with flatbed scanner imagery.Our results show that observed spring and autumn phenological transition dates are well captured by information extracted from digital repeat photography. However, spring development of both LAI and the measured physiological and morphological traits are shown to lag behind spring increases in canopy greenness, which rises very quickly to its maximum value before leaves are even half their final size. Based on the hypothesis that changes in canopy greenness represent the aggregate effect of changes in both leaf-level properties (specifically, leaf color) and changes in canopy structure (specifically, LAI), we developed a two end-member mixing model. With just a single free parameter, the model was able to reproduce the observed seasonal trajectory of canopy greenness. This analysis shows that canopy greenness is relatively insensitive to changes in LAI at high LAI levels, which we further demonstrate by assessing the impact of an ice storm on both LAI and canopy greenness. Our study provides new insights into the mechanisms driving seasonal changes in canopy greenness retrieved from digital camera imagery. The nonlinear relationship between canopy greenness and canopy LAI has important implications both for phenological research applications and for assessing responses of vegetation to disturbances. PMID- 29160669 TI - Fishery management priorities vary with self-recruitment in sedentary marine populations. AB - Fisheries science often uses population models that assume no external recruitment, but nearshore marine populations harvested on small scales of <200 km often exhibit an unknown mix of self-recruitment and recruitment from external sources. Since empirical determination of self-recruitment vs. external recruitment is difficult, we used a modeling approach to examine the sensitivity of fishery management priorities to recruitment assumptions (self [closed], external [open]) in a local population of harvested giant clams (Tridacna maxima) on Mo'orea, French Polynesia. From 2006 to 2010, we measured growth, fecundity, recruitment, and survival (resulting from natural and fishing mortality). We used these data to parameterize both a closed (complete self-recruitment) and an open (no self-recruitment) integral projection model (IPM), and then calculated elasticities of demographic rates (growth, survival, recruitment) to future population abundance in 20 years. The models' lowest projected abundance was 93.4% (95% CI, [86.5%, 101.8%]) of present abundance, if the local population is entirely open and the present level of fishing mortality persists. The population will exhibit self-sustaining dynamics (1 <= lambda <= 1.07) as for a closed population if the ratio of self-recruits per gram of dry gonad is >0.775 (equivalent to 52.85% self-recruitment under present conditions). Elasticity analysis of demographic parameters indicated that future abundance can most effectively be influenced by increasing survival of mid-sized clams (~80-120 mm) if the population is self-sustaining, and by increasing survival of juvenile clams (~40-70 mm) if the population is non-self-sustaining (as for an open population). Our results illustrate that management priorities can vary depending on the amount of self-recruitment in a local population. PMID- 29160670 TI - Combining demographic and genetic factors to assess population vulnerability in stream species. AB - Accelerating climate change and other cumulative stressors create an urgent need to understand the influence of environmental variation and landscape features on the connectivity and vulnerability of freshwater species. Here, we introduce a novel modeling framework for aquatic systems that integrates spatially explicit, individual-based, demographic and genetic (demogenetic) assessments with environmental variables. To show its potential utility, we simulated a hypothetical network of 19 migratory riverine populations (e.g., salmonids) using a riverscape connectivity and demogenetic model (CDFISH). We assessed how stream resistance to movement (a function of water temperature, fluvial distance, and physical barriers) might influence demogenetic connectivity, and hence, population vulnerability. We present demographic metrics (abundance, immigration, and change in abundance) and genetic metrics (diversity, differentiation, and change in differentiation), and combine them into a single vulnerability index for identifying populations at risk of extirpation. We considered four realistic scenarios that illustrate the relative sensitivity of these metrics for early detection of reduced connectivity: (1) maximum resistance due to high water temperatures throughout the network, (2) minimum resistance due to low water temperatures throughout the network, (3) increased resistance at a tributary junction caused by a partial barrier, and (4) complete isolation of a tributary, leaving resident individuals only. We then applied this demogenetic framework using empirical data for a bull trout (Salvelinus confluentus) metapopulation in the upper Flathead River system, Canada and USA, to assess how current and predicted future stream warming may influence population vulnerability. Results suggest that warmer water temperatures and associated barriers to movement (e.g., low flows, dewatering) are predicted to fragment suitable habitat for migratory salmonids, resulting in the loss of genetic diversity and reduced numbers in certain vulnerable populations. This demogenetic simulation framework, which is illustrated in a web-based interactive mapping prototype, should be useful for evaluating population vulnerability in a wide variety of dendritic and fragmented riverscapes, helping to guide conservation and management efforts for freshwater species. PMID- 29160671 TI - Deposit-feeder diets in the Bering Sea: potential effects of climatic loss of sea ice-related microalgal blooms. AB - Climate warming in seasonally ice-covered seas is expected to reduce the extent and duration of annual sea ice. Resulting changes in sea ice related blooms of ice algae or phytoplankton may in turn alter the timing, magnitude, or quality of organic matter inputs to the sea floor. If benthic taxa rely differently on direct consumption of settling fresh microalgae for growth and reproduction, altered blooms may lead to reorganization of deposit-feeding assemblages. To assess the potential for such changes, we examined the diets of five abundant deposit-feeders (three infaunal bivalves, a polychaete, and a brittle star) with different feeding modes over the course of the spring bloom in May-June 2007 in the north-central Bering Sea (30-90 m depth). Short-term data from gut contents reflected feeding modes, with the bivalves Macoma calcarea, Ennucula tenuis, and Nuculana radiata, and the brittle star Ophiura sarsi, responding more quickly to deposition of fresh algae than did the head-down polychaete Pectinaria hyperborea. Fatty acid biomarkers also indicated rapid ingestion of settling algae by the bivalves (especially Macoma) and the brittle star, while Pectinaria continued to ingest mainly bacteria. Fatty acid biomarkers did not indicate any unique dietary importance of ice algae released from melting ice. Longer-term inference from stable isotopes suggested that fresh microalgae contributed little to overall carbon assimilated by any of these species. Instead, deposit-feeders appeared to select a consistent fraction from the pool of sediment organic matter, probably heterotrophic microbes, microbial products, and reworked phytodetritus that form a longer-term sediment "food bank." Redistribution of settled organic matter via scouring and accumulation by currents, as well as the multi-year life spans of macroinvertebrates, may further overwhelm effects of short-term variations in the timing, magnitude, and dispersion of blooms in the water column. More diet data are needed from midsummer to account for any lag in assimilation of fresh microalgae at these cold temperatures. Nevertheless, our results suggest that if annual sea ice cover is reduced, increased production of phytoplankton during longer ice-free periods could replace inputs of ice associated microalgae to the sediment food bank used by deposit-feeders. PMID- 29160672 TI - Trade-offs between supportive and provisioning ecosystem services of forage species in marine food webs. AB - Ecosystem-based management of natural resources involves an explicit consideration of trade-offs among ecosystem services. In marine fisheries, there is the potential for a trade-off between the supporting role of small pelagic fish and cephalopods in food webs, and the provisioning service they play as a major target of fisheries. Because these species play central roles in food webs by providing a conduit of energy from small prey to upper trophic level predators, we hypothesized that trade-offs between these two ecosystem services could be predicted based on energetic properties of predator-prey linkages and food-web structure. We compiled information from 27 marine food-web models (all within the Ecopath framework) that included either small pelagic fish or cephalopods, described predator-prey linkages involving these species, and developed a novel analytical framework to estimate how changes in yields of forage species would propagate through food webs and other fisheries. Consistent with expectations, diet overlap between predators and prey was generally low, and predator-prey linkages tended to be asymmetric; contribution of these species to predator diets was, on average, larger than the contribution of individual predator stocks to prey mortality. The estimated trade-offs between yields of forage fish and predator species were highly variable when we assumed joint bottom-up and top-down control on predation. Roughly one-third of this variance was related to an interactive effect of fishing and predation intensity; strong trade-offs were predicted when fishing intensity on forage species is high and when predators account for a high proportion of total forage mortality. When trophic connections were presumed to be driven by bottom-up processes, trade-offs were more predictable, but generally very small. Contrary to our expectations, trade-offs were not easily predicted from energetic properties, largely because predators of forage species exhibited a high degree of intra-guild predation, and also consumed many of the same prey as forage species. Given the limited ability to a priori predict the food-web implications of forage fisheries, we suggest that a precautionary risk-based approach be applied to decisions about acceptable biological removals of forage fish and biological targets used for their management. PMID- 29160673 TI - You Can and Should Be a Leader - Even If You Aren't a Natural. PMID- 29160674 TI - How to Lead Up in Your Organization. PMID- 29160675 TI - Change Is Hard: What Really Happens When You Try to Implement a New Care Model. PMID- 29160676 TI - Getting Paid for Screening and Assessment Services. PMID- 29160677 TI - How to Make Friends With Urgent Care. PMID- 29160678 TI - Opting Out of Medicare: How to Get Out and Stay Out. PMID- 29160679 TI - Back to Basics: Five Steps to Better Influenza Vaccination Rates. PMID- 29160684 TI - Improving the Stability of High-Performance Multilayer MoS2 Field-Effect Transistors. AB - In this study, we propose a method for improving the stability of multilayer MoS2 field-effect transistors (FETs) by O2 plasma treatment and Al2O3 passivation while sustaining the high performance of bulk MoS2 FET. The MoS2 FETs were exposed to O2 plasma for 30 s before Al2O3 encapsulation to achieve a relatively small hysteresis and high electrical performance. A MoOx layer formed during the plasma treatment was found between MoS2 and the top passivation layer. The MoOx interlayer prevents the generation of excess electron carriers in the channel, owing to Al2O3 passivation, thereby minimizing the shift in the threshold voltage (Vth) and increase of the off-current leakage. However, prolonged exposure of the MoS2 surface to O2 plasma (90 and 120 s) was found to introduce excess oxygen into the MoOx interlayer, leading to more pronounced hysteresis and a high off current. The stable MoS2 FETs were also subjected to gate-bias stress tests under different conditions. The MoS2 transistors exhibited negligible decline in performance under positive bias stress, positive bias illumination stress, and negative bias stress, but large negative shifts in Vth were observed under negative bias illumination stress, which is attributed to the presence of sulfur vacancies. This simple approach can be applied to other transition metal dichalcogenide materials to understand their FET properties and reliability, and the resulting high-performance hysteresis-free MoS2 transistors are expected to open up new opportunities for the development of sophisticated electronic applications. PMID- 29160685 TI - Graphene Oxide: A New Carrier for Slow Release of Plant Micronutrients. AB - The environmental problems and low efficiency associated with conventional fertilizers provides an impetus to develop advanced fertilizers with slower release and better performances. Here, we report of development of a new carrier platform based on graphene oxide (GO) sheets that can provide a high loading of plant micronutrients with controllable slow release. To prove this concept, two micronutrients, zinc (Zn) and copper (Cu), were used to load on GO sheets and hence formulate GO-based micronutrients fertilizer. The chemical composition and successful loading of both nutrients on GO sheets were confirmed by X-ray photoelectron spectroscopy, thermogravimetric analysis, and X-ray diffraction (XRD). The prepared Zn-graphene oxide (Zn-GO) and Cu-graphene oxide (Cu-GO) fertilizers showed a biphasic dissolution behavior compared to that of commercial zinc sulfate and copper sulfate fertilizer granules, displaying desirable fast and slow micronutrient release. A visualization method and chemical analysis were used to assess the release and diffusion of Cu and Zn in soil from GO-based fertilizers compared with commercial soluble fertilizers to demonstrate the advantages of GO carriers and show their capability to be used as a generic platform for macro- and micronutrients delivery. A pot trial demonstrated that Zn and Cu uptake by wheat was higher when using GO-based fertilizers compared to that when using standard zinc or copper salts. This is the first report on the agronomic performance of GO-based slow-release fertilizer. PMID- 29160686 TI - Human Hair Keratin for Biocompatible Flexible and Transient Electronic Devices. AB - Biomaterials have been attracting attention as a useful building block for biocompatible and bioresorbable electronics due to their nontoxic property and solution processability. In this work, we report the integration of biocompatible keratin from human hair as dielectric layer for organic thin-film transistors (TFTs), with high performance, flexibility, and transient property. The keratin dielectric layer exhibited a high capacitance value of above 1.27 MUF/cm2 at 20 Hz due to the formation of electrical double layer. Fully solution-processable TFTs based on p-channel poly[4-(4,4-dihexadecyl-4H-cyclopenta[1,2-b:5,4 b]dithiophen-2-yl)-alt[1,2,5]thiadiazolo[3,4-c]-pyridine] (PCDTPT) and keratin dielectric exhibited high electrical property with a saturation field-effect mobility of 0.35 cm2/(Vs) at a low gate bias of -2 V. We also successfully demonstrate flexible TFTs, which exhibited good mechanical flexibility and electrical stability under bending strain. An artificial electronic synaptic PCDTPT/keratin transistor was also realized and exhibited high-performance synaptic memory effects via simple operation of proton conduction in keratin. An added functionality of using keratin as a substrate was also presented, where similar PCDTPT TFTs with keratin dielectric were built on top of keratin substrate. Finally, we observed that our prepared devices can be degraded in ammonium hydroxide solution, establishing the feasibility of keratin layer as various components of transient electrical devices, including as a substrate and dielectric layer. PMID- 29160687 TI - Janus Reactors with Highly Efficient Enzymatic CO2 Nanocascade at Air-Liquid Interface. AB - Though enzymatic cascade reactors have been the subject of intense research over the past few years, their application is still limited by the complicated fabrication protocols, unsatisfactory stability and lack of effective reactor designs. In addition, the spatial positioning of the cascade reactor has so far not been investigated, which is of significant importance for biphase catalytic reaction systems. Inspired by the Janus properties of the lipid cellular membrane, here we show a highly efficient Janus gas-liquid reactor for CO2 hydration and conversion. Within the Janus reactor, nanocascades containing the nanoscale compartmentalized carbonic anhydrase and formic dehydrogenase were positioned at a well-defined gas-liquid interface, with a high substrate concentration gradient. The Janus reactor exhibited 2.5 times higher CO2 hydration efficiency compared with the conventional gas-liquid contactor with pristine membranes, and the formic acid conversion rate can reach approximately 90%. Through this work, we provide evidence that the spatial arrangement of the nanocascade is also crucial to efficient reactions, and the Janus reactor can be a promising candidate for the biphase catalytic reactions in environmental, biological and energy aspects. PMID- 29160688 TI - Novel Real-Time Proximity Assay for Characterizing Multiple Receptor Interactions on Living Cells. AB - Cellular receptor activity is often controlled through complex mechanisms involving interactions with multiple molecules, which can be soluble ligands and/or other cell surface molecules. In this study, we combine a fluorescence based technology for real-time interaction analysis with fluorescence quenching to create a novel time-resolved proximity assay to study protein-receptor interactions on living cells. This assay extracts the binding kinetics and affinity for two proteins if they bind in proximity on the cell surface. One application of real-time proximity interaction analysis is to study relative levels of receptor dimerization. The method was primarily evaluated using the HER2 binding antibodies Trastuzumab and Pertuzumab and two EGFR binding antibodies including Cetuximab. Using Cetuximab and Trastuzumab, proximity of EGFR and HER2 was investigated before and after treatment of cells with the tyrosine-kinase inhibitor Gefitinib. Treated cells displayed 50% increased proximity signal, whereas the binding characteristics of the two antibodies were not significantly affected, implying an increase in the EGFR-HER2 dimer level. These results demonstrate that real-time proximity interaction analysis enables determination of the interaction rate constants and affinity of two ligands while simultaneously quantifying their relative colocalization on living cells. PMID- 29160689 TI - Fast and Selective Two-Stage Ratiometric Fluorescent Probes for Imaging of Glutathione in Living Cells. AB - Two fluorescent, m-nitrophenol-substituted difluoroboron dipyrromethene dyes have been designed by nucleophilic substitution reaction of 3,5-dichloro-4,4-difluoro 4-bora-3a,4a-diaza-s-indacene (BODIPY). Nonsymmetric and symmetric probes, that is. BODIPY 1 (with one nitrophenol group at the position 3) and BODIPY 2 (with two nitrophenol groups at the positions 3 and 5) were applied to ratiometric fluorescent glutathione detection. The detection is based on the two-step nucleophilic aromatic substitution of the nitrophenol groups of the probes by glutathione in buffer solution containing CTAB. In the first stage, probe 1 showed ratiometric fluorescent color change from green (lambdaem = 530 nm) to yellow (lambdaem = 561 nm) because of monosubstitution with glutathione (I561nm/I530nm). Addition of excess glutathione caused the second stage of ratiometric fluorescent color change from yellow to reddish orange (lambdaem = 596 nm, I596nm/I561nm) due to disubstitution with glutathione. Therefore, different concentration ranges of glutathione (from less to excess) could be rapidly detected by the two-stage ratiometric fluorescent probe 1 in 5 min. While, probe 2 shows single-stage ratiometric fluorescent detection to GSH (from green to reddish orange, I596nm/I535nm). Probes 1 and 2 exhibit excellent properties with sensitive, specific colorimetric response and ratiometric fluorescent response to glutathione over other sulfur nucleophiles. Application to cellular ratiometric fluorescence imaging indicated that the probes were highly responsive to intracellular glutathione. PMID- 29160690 TI - Correction to Imprinted NanoVelcro Microchips for Isolation and Characterization of Circulating Fetal Trophoblasts: Toward Noninvasive Prenatal Diagnostics. PMID- 29160691 TI - Bioinspired Tribotronic Resistive Switching Memory for Self-Powered Memorizing Mechanical Stimuli. AB - Haptic memory, from the interaction of skin and brain, can not only perceive external stimuli but also memorize it after removing the external stimuli. For the mimicry of human sensory memory, a self-powered artificial tactile memorizing system was developed by coupling bionic electronic skin and nonvolatile resistive random access memory (RRAM). The tribotronic nanogenerator is utilized as electronic skin to transform the touching signal into electric pulse, which will be programmed into the artificial brain: RRAM. Because of the advanced structural designs and accurate parameter matching, including the output voltages and the resistances in different resistive states, the artificial brain can be operated in self-powered mode to memorize the touch stimuli with the responsivity up to 20 times. For demonstrating the application potential of this system, it was fabricated as an independently addressed matrix to realize the memorizing of motion trace in two-dimensional space. The newly designed self-powered nonvolatile system has broad applications in next-generation high-performance sensors, artificial intelligence, and bionics. PMID- 29160692 TI - S100A9 Protein Aggregates Boost Hippocampal Glutamate Modifying Monoaminergic Neurochemistry: A Glutamate Antibody Sensitive Outcome on Alzheimer-like Memory Decline. AB - Alzheimer's disease (AD) involves dementia conceivably arising from integrated inflammatory processes, amyloidogenesis, and neuronal apoptosis. Glutamate can also cause neuronal death via excitotoxicity, and this is similarly implicated in some neurological diseases. The aim was to examine treatment with in vitro generated proinflammatory protein S100A9 aggregate species alone or with glutamate antibodies (Glu-Abs) on Morris water maze (MWM) spatial learning and memory performance in 12 month old mice. Amino acid and monoamine cerebral neurotransmitter metabolic changes were concurrently monitored. Initially, S100A9 fibrils were morphologically verified by atomic force microscopy and Thioflavin T assay. They were then administered intranasally alone or with Glu-Abs for 14 days followed by a 5 day MWM protocol before hippocampal and prefrontal cortical neurochemical analysis. S100A9 aggregates evoked spatial amnesia which correlated with disrupted glutamate and dopaminergic neurochemistry. Hippocampal glutamate release, elevation of DOPAC and HVA, as well as DOPAC/DA and HVA/DA ratios were subsequently reduced by Glu-Abs which simultaneously prevented the spatial memory deficit. The present outcomes emphasized the pathogenic nature of S100A9 fibrillar aggregates in causing spatial memory amnesia associated with enhanced hippocampal glutamate release and DA-ergic disruption in the aging brain. This finding might be exploited during dementia management through a neuroprotective strategy. PMID- 29160694 TI - Quick and Selective Dual Mode Detection of H2S Gas by Mobile App Employing Silver Nanorods Array. AB - Hydrogen sulfide (H2S) is a hazardous gas, which not only harms living beings but also poses a significant risk to damage materials placed in culture and art museums, due to its corrosive nature. We demonstrate a novel approach for selective rapid detection of H2S gas using silver nanorods (AgNRs) arrays on glass substrates at ambient conditions. The arrays were prepared by glancing angle deposition method. The colorimetric and water wetting properties of as fabricated arrays were found to be highly sensitive toward the sulfurization, in the presence of H2S gas with a minimal concentration in ppm range. The performance of AgNRs as H2S gas sensor is investigated by its sensing ability of 5 ppm of gas with an exposure time of only 30 s. We have developed an android based mobile app to monitor real-time colorimetric detection of H2S. The wettability detection has been carried out by a mobile camera. A comparative analysis for different gases reveals the highest sensitivity and selectivity of the array AgNRs toward H2S. The rapid detection has also been demonstrated for H2S emission from aged wool fabric. Thus, high sensing ability of AgNRs toward H2S gas may have potential applications in health monitoring and art conservation. PMID- 29160695 TI - Fabrication of New Uranyl Phosphonates by Varying Quaternary Ammonium Cation: Synthesis, Structure, Luminescent Properties, and Single-Crystal to Single Crystal Transformation. AB - Four new uranyl triphosphonates, namely, [N(CH4)4][UO2(H3L)][H2O] (1), [(UO2)1.5(H3L)(H2O)1.5][H2O] (2), [NBu4][(UO2)3.5(H2L)2][(H2O)4.5] (3), and [(UO2)1.5(H3L)(H2O)2.5][(H2O)2.5] (4), where H6L = benzene-1,3,5 triyltris(methylene)triphosphonic acid, were obtained from a triphosphonate ligand in the presence of different quaternary ammonium cations. The structural characterization revealed that the introduction of quaternary ammonium cation had a major impact on the structure formation of uranyl phosphonates. Compound 1 possesses a three-dimensional anionic framework structure. Tetramethylammonium cations are accommodated in the channels, serving as counterions and structure directing agents. Compound 2 also displays a three-dimensional framework structure but is neutral, because the tetrapropylammonium cations are not involved in the crystal structure. Compound 3 has an intercalation structure; between the layers are the tetrabutylammonium cations, balancing the charge and strengthening the supramolecular structure with C-H...O interactions. No obvious uptake of N2 and CO2 could be observed for compound 2 due to the shrinkage of the framework and structural transformation. Compound 2 undergoes single-crystal to single-crystal transformation under vacuum, leading to the formation of compound 4, which possesses a two-dimensional layer structure. The photophysical properties of these compounds were also investigated. PMID- 29160696 TI - Opening the Cages of Faujasite-Type Zeolite. AB - Zeolites are widely used in industrial processes, mostly as catalysts or adsorbents. Increasing their micropore volume could further improve their already exceptional catalytic and separation performances. We report a tunable extraction of zeolite framework cations (Si, Al) on a faujasite-type zeolite, the archetype of molecular sieves with cages and the most widely used as a catalyst and sorbent; this results in ca. 10% higher micropore volume with limited impact on its thermal stability. This increased micropore volume results from the opening of some of the small (sodalite) cages, otherwise inaccessible to most molecules. As more active sites become accessible, the catalytic performances for these modified zeolites are substantially improved. The method, based on etching with NH4F, is also applicable to other cage-containing microporous molecular sieves, where some of the most industrially relevant zeolites are found. PMID- 29160697 TI - Cascade Synthesis of 3-Functionalized Indoles from Nitrones and Their Conversion to Cycloheptanone-Fused Indoles. AB - A cascade reaction of N-aryl-alpha,beta-unsaturated nitrones and electron deficient allenes has been discovered that allows single-step access to 3 functionalized indoles that usually require preformation and alkylation of an indole precursor. The heterocycles prepared through the hydrogen bond donor catalyzed cascade reaction are poised to undergo a McMurry coupling to form previously synthetically elusive cycloheptanone-fused indoles. The scope of these transformations is discussed as well as mechanistic experiments describing proposed intermediates of the cascade reaction and an initial catalytic asymmetric example that generates a carbon stereocenter during the cascade process. PMID- 29160693 TI - Cross-Linking Mass Spectrometry: An Emerging Technology for Interactomics and Structural Biology. PMID- 29160699 TI - Diversity and Abundance of High-Molecular-Weight Azaarenes in PAH-Contaminated Environmental Samples. AB - Azaarenes are N-heterocyclic polyaromatic pollutants that co-occur with polycyclic aromatic hydrocarbons (PAHs) in contaminated soils. Despite the known toxicity of some high-molecular-weight azaarenes, their diversity, abundance, and fate in contaminated soils remain to be elucidated. We applied high-resolution mass spectrometry and mass-defect filtering to four PAH-contaminated samples from geographically distant sites and detected 232 azaarene congeners distributed in eight homologous series, including alkylated derivatives and two hitherto unknown series. Four- and five-ring azaarenes were detected among these series, and the most abundant nonalkylated congeners groups (C13H9N, C15H9N, C17H11N, C19H11N, and C21H13N) were quantified. The profiles of congener groups varied among different sites. Three-ring azaarenes presented higher concentrations in unweathered sites, while four- and five-ring azaarenes predominated in weathered sites. Known toxic and carcinogenic azaarenes, such as benzo[c]acridine and dibenzo[a,h]acridine, were detected along with their multiple isomers. Our results highlight a previously unrecognized diversity and abundance of azaarenes in PAH-contaminated sites, with corresponding implications for environmental monitoring and risk assessment. PMID- 29160698 TI - Functional Characterization of Salicylic Acid Carboxyl Methyltransferase from Camellia sinensis, Providing the Aroma Compound of Methyl Salicylate during the Withering Process of White Tea. AB - Methyl salicylate (MeSA) is one of the volatile organic compounds (VOCs) that releases floral scent and plays an important role in the sweet flowery aroma of tea. During the withering process for white tea producing, MeSA was generated by salicylic acid carboxyl methyltransferase (SAMT) with salicylic acid (SA), and the specific floral scent was formed. In this study, we first cloned a CsSAMT from tea leaves (GenBank accession no. MG459470) and used Escherichia coli and Saccharomyces cerevisiae to express the recombinant CsSAMT. The enzyme activity in prokaryotic and eukaryotic expression systems was identified, and the protein purification, substrate specificity, pH, and temperature optima were investigated. It was shown that CsSAMT located in the chloroplast, and the gene expression profiles were quite different in tea organs. The obtained results might give a new understanding for tea aroma formation, optimization, and regulation and have great significance for improving the specific quality of white tea. PMID- 29160700 TI - Tailoring Panchromatic Absorption and Excited-State Dynamics of Tetrapyrrole Chromophore (Bodipy, Rylene) Arrays-Interplay of Orbital Mixing and Configuration Interaction. AB - Three sets of tetrapyrrole-chromophore arrays have been examined that exhibit panchromatic absorption across large portions of the near-ultraviolet (NUV) to near-infrared (NIR) spectrum along with favorable excited-state properties for use in solar-energy conversion. The arrays vary the tetrapyrrole (porphyrin, chlorin, bacteriochlorin), chromophore (boron-dipyrrin, perylene, terrylene), and attachment sites (meso-position, beta-pyrrole position). In all, seven dyads, one triad, and nine benchmarks in toluene and benzonitrile were studied using steady state and time-resolved absorption and fluorescence spectroscopy. The results were analyzed with the aid of density functional theory (DFT) and time-dependent DFT calculations. Natural transition orbitals (NTOs) were constructed to assess the net change in electron density associated with each NUV-NIR absorption transition. The porphyrin-perylene dyad P-PMI displays the most even spectral coverage from 400 to 700 nm, with an average epsilon ~ 43 000 M-1 cm-1. A significant contributor is a chromophore-induced reduction in the configuration interaction involving the four frontier molecular orbitals of benchmark porphyrins and associated constructive/destructive transition-dipole interference that results in intense (epsilon ~ 400 000 M-1 cm-1) NUV and weak (<20 000 M-1 cm 1) visible features. P-PMI has an S1 lifetime (tauS) of 4.7 ns in toluene and 1.3 ns in benzonitrile. Bacteriochlorin analogue BC-PMI has more extended spectral coverage (350-750 nm) and tauS = 2.8 ns in toluene and 30 ps in benzonitrile. Terrylene analogue P-TMI has intermediate optical characteristics with tauS = 310 ps in toluene and 150 ps in benzonitrile. The NTOs for most arrays show that S0 > S1 primarily involves the tetrapyrrole, but for P-TMI the NTOs have electron density delocalized over the two units as a result of extensive orbital mixing. Collectively, the insights obtained should aid the design of tetrapyrrole-based architectures for panchromatic light-harvesting systems for solar-energy conversion. PMID- 29160701 TI - Flux Crystal Growth of the RE2Ru3Ge5 (RE = La, Ce, Nd, Gd, Tb) Series and Their Magnetic and Metamagnetic Transitions. AB - Previously synthesized only as powders, single crystals of the RE2Ru3Ge5 (RE = La, Ce, Nd, Gd, Tb) series of compounds have now been obtained from molten In. These materials crystallize with the U2Co3Si5-type structure in orthorhombic space group Ibam with lattice parameters a ~ 10.00-9.77 A (La-Tb), b ~ 12.51 12.35 A, and c ~ 5.92-5.72 A. The structure is a three-dimensional framework consisting of RuGe5 and RuGe6 units, as well as Ge-Ge zigzag chains. This structure type and those of the other five (Sc2Fe3Si5, Lu2Co3Si5, Y2Rh3Sn5, Yb2Ir3Ge5, and Yb2Pt3Sn5) to compose the RE2T3X5 phase space are discussed in depth. For the three compounds with RE = Nd, Gd, Tb, multiple magnetic transitions and metamagnetic behavior are observed. Electronic band structure calculations performed on La2Ru3Ge5 indicate that these materials have a negative band gap and are semimetallic in nature. PMID- 29160702 TI - Heterometallic Heptanuclear [Cu5Ln2] (Ln = Tb, Dy, and Ho) Single-Molecule Magnets Organized in One-Dimensional Coordination Polymeric Network. AB - The reaction of a multisite coordination ligand, LH3, with Cu(II) salts and Ln(NO3)3.nH2O in a 1:2:1 stoichiometric ratio in the presence of triethylamine was found to afford a series of one-dimensional heterometallic [{Cu5Ln2(L)2(MU3 OH)4(ClO4)(NO3)3(OH2)5}(ClO4)2(H2O)x]infinity [Ln = Tb(1), Dy(2) and Ho(3), x = 4.25, 5.5, and 5 for 1-3, respectively] coordination polymers. Complexes 1-3 have been characterized by single crystal X-ray crystallography. The detailed study of the magnetic properties has also been performed and compared with the parent [Cu5Ln2] molecular analogues. The ac susceptibility measurements for complexes 1 3 confirm their SMM behavior with the following characteristics: Deltaeff/kB = 23.4 K, tau0 = 1.1 * 10-6 s and Deltaeff/kB = 27.9 K, tau0 = 6.6 * 10-7 s under 0 and 1200 Oe dc fields, respectively for 1; Deltaeff/kB = 8.3 K, tau0 = 3.1 * 10-6 s for 2 under 0 dc field. For 3, the fast QTM below 4 K prevents the estimation of the SMM energy barrier. Remarkably, the magnetic and SMM properties of the previously reported molecular [Cu5Ln2] analogues are preserved after their assembly in these coordination networks. PMID- 29160703 TI - Ruthenium Carbon-Rich Group as a Redox-Switchable Metal Coupling Unit in Linear Trinuclear Complexes. AB - The preparation and properties of novel ruthenium carbon-rich complexes [(Ph-C=C )2-nRu(dppe)2(-C=C-bipyM(hfac)2)n] (n = 1, 2; M = CuII, MnII; bipy = 2,2' bipyridin-5-yl) characterized by single-crystal X-ray diffraction and designed for molecular magnetism are reported. With the help of EPR spectroscopy, we show that the neutral ruthenium system sets up a magnetic coupling between two remote paramagnetic CuII units. More specifically, these copper compounds are unique examples of bimetallic and linear heterotrimetallic compounds for which a complete rationalization of the magnetic interactions could be made for exceptionally long distances between the spin carriers (8.3 A between adjacent Cu and Ru centers, 16.6 A between external Cu centers) and compared at two different redox states. Surprisingly, oxidation of the ruthenium redox-active metal coupling unit (MCU), which introduces an additional spin unit on the carbon-rich part, leads to weaker magnetic interactions. In contrast, in the simpler parent complexes bearing only one paramagnetic metal unit [Ph-C=C-Ru(dppe)2-C=C bipyCu(hfac)2], one-electron oxidation of the ruthenium bis(acetylide) unit generates an interaction between the Cu and Ru spin carriers of magnitude comparable to that observed between the two far apart Cu ions in the above corresponding neutral trimetallic system. Evaluation and rationalization of this coupling with theoretical tools are in rational agreement with experiments for such complex systems. PMID- 29160704 TI - Nanobiotechnology for the Environment: Innovative Solutions for the Management of Harmful Algal Blooms. AB - Nanobiotechnology has played important roles in solving contemporary health problems, including cancer and diabetes, but has not yet been widely exploited for problems in food security and environmental protection. Water scarcity is an emerging worldwide problem as a result of climate change and population increase. Current methods of managing water resources are not efficient or sustainable. In this perspective, we focus on harmful algal blooms to demonstrate how nanobiotechnology can be explored to understand microbe-environment interactions and allow for toxin/pollutant detection with significantly improved sensitivity. These capabilities hold potential for future development of sustainable solutions for drinking water management. PMID- 29160705 TI - H-X (X = H, CH3, CH2F, CHF2, CF3, and SiH3) Bond Activation by Criegee Intermediates: A Theoretical Perspective. AB - Using theoretical calculations and Born-Oppenheimer molecular dynamics simulations, it is shown here that Criegee intermediate, which is principally produced in the olefin ozonolysis, can activate H-X (X = H, CH3, CH2F, CHF2, CF3, and SiH3) under mild conditions, a reaction that has long been known for transition metals. The zwitterionic electronic structure of Criegee intermediate makes it an interesting metal-free system for activating enthalpically strong small molecules such as H2, methane, silanes, and boranes. The calculated barriers for the H2 or SiH4 reactions of CH2OO are significantly lower than those for the CH4 or its fluorinated analogue reactions. The distortion-interaction energy model is found to be successful in explaining the differential reactivity of the Criegee intermediate toward activating the various H-X bonds. The canonical transition state theory calculations suggest that the CH2OO-H2 reaction is 9-11 orders of magnitude faster than the CH2OO-CH4 reaction over the 200-300 K temperature range. Considering that the laboratory synthesis of Criegee intermediate is now feasible, these findings may open up new vistas in the metal free activation of small molecules. PMID- 29160706 TI - Synthesis and Characterization of Ultralow Fouling Poly(N-acryloyl-glycinamide) Brushes. AB - The rational design of biomaterials with antifouling properties still remains a challenge, although this is important for many bench-to-bedside applications for biomedical implants, drug delivery carriers, and marine coatings. Herein, we synthesized and characterized poly(N-acryloylglycinamide) (polyNAGA) and then grafted poly(NAGA) onto Au substrate to form polymer brushes with well-controlled film stability, wettability, and thickness using surface-initiated atom transfer radical polymerization (SI-ATRP). The NAGA monomer integrates two hydrophilic amides on the side chain to enhance surface hydration, which is thought as a critical contributor to its antifouling property. The antifouling performances of poly(NAGA) brushes of different film thicknesses were then rigorously assessed and compared using protein adsorption assay from undiluted blood serum and plasma, cell-adhesive assay, and bacterial assay. The resulting poly(NAGA) brushes with a film thickness of 25-35 nm exhibited excellent in vitro antifouling ability to prevent unwanted protein adsorption (<0.3 ng/cm2) and bacterial and cell attachments up to 3 days. Molecular dynamics (MD) simulations further showed that two hydrophilic amide groups can interact with water molecules strongly to form a strong hydration layer via coordinated hydrogen bonds. This confirms a positive correlation between antifouling property and surface hydration. In line with a series of polyacrylamides and polyacrylates as antifouling materials synthesized in our lab, we propose that small structural changes in the pendent groups of polymers could largely improve the antifouling capacity, which may be used as a general design rule for developing next generation antifouling materials. PMID- 29160707 TI - Molecular Structure Inhibiting Synergism in Charged Surfactant Mixtures: An Atomistic Molecular Dynamics Simulation Study. AB - Synergistic and nonsynergistic surfactant-water mixtures of sodium dodecyl sulfate (SDS), lauryl betaine (C12B), and cocoamidopropyl betaine (CAPB) systems are studied using molecular simulation to understand the role of interactions among headgroups, tailgroups, and water on structural and thermodynamic properties at the air-water interface. SDS is an anionic surfactant, while C12B and CAPB are zwitterionic; CAPB differs from C12B by an amide group in the tail. While the lowest surface tensions at high surface concentrations in the SDS-C12B synergistic system could not be reproduced by simulation, estimated partitioning between surface and bulk shows trends consistent with synergism. Structural analysis shows the influence of the SDS headgroup pulling C12B to the surface, resulting in closely packed structures compared to their respective homomolecular surfactant systems. The SDS-CAPB system, on the other hand, is nonsynergistic when the surfactants are mixed on account of the tilted structure of the CAPB tail. The translational excess entropy due to the tailgroup interactions discriminates between the synergistic and nonsynergistic systems. The implications of such interactions on surfactant effects in complex, multicomponent atmospheric aerosols are discussed. PMID- 29160708 TI - Photophysics of Zinc Porphyrin Aggregates in Dilute Water-Ethanol Solutions. AB - Dimeric and multimeric aggregates of a model metalloporphyrin, zinc tetraphenylporphyrin (ZnTPP), have been produced in a controlled manner by incrementally increasing the water content of dilute aqueous ethanol solutions. Steady state absorption, fluorescence emission, and fluorescence excitation spectra have been measured to identify the aggregates present as a function of solvent composition. The dynamics of the excited states of the aggregates produced initially by excitation in the Soret region have been measured by ultrafast fluorescence upconversion techniques. Only the monomer produces measurable emission from S2 with a picosecond lifetime; all Soret-excited aggregates, including the dimer, decay radiationlessly on a femtosecond time scale. The S1 state is the only significant product of the radiationless decay of the S2 state of the excited monomer, and the aggregates also produce substantial quantum yields of S1 fluorescence when initially excited in the Soret region. The resulting fluorescent aggregates all decay on a subnanosecond time scale, likely by a mechanism that involves dissociation of the excited monomer from the excitonic multimer. The ZnTPP dimers excited at their ground state geometries in the Soret region exhibit a dynamic behavior that is quite different from those produced following noncoherent triplet-triplet annihilation under the same conditions. The important implications of these observations in determining the aggregation conditions promoting efficient photon upconversion by excitonic annihilation in a variety of media are thoroughly discussed. PMID- 29160709 TI - 2D-IR Spectroscopy of an AHA Labeled Photoswitchable PDZ2 Domain. AB - We explore the capability of the non-natural amino acid azidohomoalanine (AHA) as an IR label to sense relatively small structural changes in proteins with the help of 2D IR difference spectroscopy. To that end, we AHA-labeled an allosteric protein (the PDZ2 domain from human tyrosine-phosphatase 1E) and furthermore covalently linked it to an azobenzene-derived photoswitch as to mimic its conformational transition upon ligand binding. To determine the strengths and limitations of the AHA label, in total six mutants have been investigated with the label at sites with varying properties. Only one mutant revealed a measurable 2D IR difference signal. In contrast to the commonly observed frequency shifts that report on the degree of solvation, in this case we observe an intensity change. To understand this spectral response, we performed classical MD simulations, evaluating local contacts of the AHA labels to water molecules and protein side chains and calculating the vibrational frequency on the basis of an electrostatic model. Although these simulations revealed in part significant and complex changes of the number of intraprotein and water contacts upon trans-cis photoisomerization, they could not provide a clear explanation of why this one label would stick out. Subsequent quantum-chemistry calculations suggest that the response is the result of an electronic interaction involving charge transfer of the azido group with sulfonate groups from the photoswitch. To the best of our knowledge, such an effect has not been described before. PMID- 29160710 TI - Evaporation Dynamics of Mixed-Nanocolloidal Sessile Droplets. AB - Evaporation dynamics of a particle-laden droplet has been a topic of interest in recent times owing to its widespread applications, ranging from surface patterning to drug delivery systems. The interplay of evaporation-induced internal flow dynamics, contact line dynamics, and nanoparticle self-assembly govern the morphologies of the residual structures. Fine-tuning of these residual structures is thus possible by controlling the governing parameters. A nanoparticle-laden sessile droplet placed on a hydrophobic substrate undergoes buckling phenomenon that results in a domelike structure with cavity on the surface. In the present work, it is shown that the addition of sodium dodecyl sulfate (SDS) surfactant in minute concentrations (0.005-0.02 wt %) can affect the contact line dynamics and subsequent buckling dynamics of a nanoparticle laden droplet evaporating on a hydrophobic substrate. With increase in the initial SDS concentration, the morphologies of the residual structures show transition from a buckled dome structure to a flat flowerlike shape. Moreover, a critical SDS concentration (>0.0075 wt % in 20 wt % silica) is identified for the complete suppression of buckling instabilities. Last, the effects of droplet spreading on the surface crack dynamics are discussed. PMID- 29160711 TI - Catalytic Asymmetric Mukaiyama-Mannich Reaction of Cyclic C-Acylimines with Difluoroenoxysilanes: Access to Difluoroalkylated Indolin-3-ones. AB - A catalytic enantioselective Mukaiyama-Mannich reaction of cyclic C-acylimines with difluoroenoxysilanes is reported. (S)-TRIP enables the enantioselective synthesis of a series of novel difluoroalkylated indolin-3-ones bearing a quaternary stereocenter in up to 97% yield and 98% ee. The synthetic utility of this protocol is highlighted by efficient conversion of the products to the corresponding indolin-3-one derivatives without any erosion of the enantiopurity. PMID- 29160712 TI - Phosphine-Catalyzed [4 + 2] Annulation of Allenoate with Sulfamate-Derived Cyclic Imines: A Reaction Mode Involving gamma'-Carbon of alpha-Substituted Allenoate. AB - A phosphine-catalyzed [4 + 2] cycloaddition of cyclic alpha-substituted allenoates with sulfamate-derived cyclic imines has been reported. Using dibenzylphenylphosphine as the nucleophilic catalyst, the reaction worked efficiently to yield various fused multicyclic heterocyclic compounds in high yields with excellent diastereoselectivities. It undergoes a new reaction mode involving gamma'-carbon of alpha-substituted allenoate. PMID- 29160713 TI - Synthesis of 3-(Arylsulfonyl)benzothiophenes and Benzoselenophenes via TBHP Initiated Radical Cyclization of 2-Alkynylthioanisoles or -selenoanisoles with Sulfinic Acids. AB - tert-Butyl hydroperoxide-initiated radical cyclization of 2-alkynylthioanisoles or -selenoanisoles with sulfinic acids has been developed. This reaction is applicable to a wide substrate scope via one C(sp3)-S(Se) bond cleavage and two C(sp2)-S(Se) bond formation, leading to the synthesis of 3 (arylsulfonyl)benzothiophenes or -benzoselenophenes under mild conditions. PMID- 29160714 TI - Understanding the Aqueous Stability and Filtration Capability of MoS2 Membranes. AB - Membranes made of layer-stacked two-dimensional molybdenum disulfide (MoS2) nanosheets have recently shown great promise for water filtration. At present, the reported water fluxes vary significantly, while the accountable structure and properties of MoS2 nanochannels are largely unknown. This paper aims to mechanistically relate the performance of MoS2 membranes to the size of their nanochannels in different hydration states. We discovered that fully hydrated MoS2 membranes retained a 1.2 nm interlayer spacing (or 0.9 nm free spacing), leading to high water permeability and moderate-to-high ionic and molecular rejection. In comparison, completely dry MoS2 membranes had a 0.62 nm interlayer spacing (or 0.3 nm free spacing) due to irreversible nanosheet restacking and were almost impermeable to water. Furthermore, we revealed that the interlayer spacing of MoS2 membranes in aqueous solution is maintained by comparable van der Waals and hydration forces, thereby ensuring the aqueous stability of MoS2 membranes without the need of cross-linking. In addition, we attributed the high water flux (30-250 L m-2 h-1 bar-1) of MoS2 membranes to the low hydraulic resistance of smooth, rigid MoS2 nanochannels. We also concluded that compaction of MoS2 membranes with a high pressure helps create a more neatly stacked nanostructure with minimum voids or looseness, leading to stable water flux and separation performance. Besides, this paper systematically compares MoS2 membranes with the widely studied graphene oxide membranes to highlight the uniqueness and advantages of MoS2 membranes for water-filtration applications. PMID- 29160715 TI - Deciphering Charging Status, Absolute Quantum Efficiency, and Absorption Cross Section of Multicarrier States in Single Colloidal Quantum Dots. AB - Upon photo- or electrical-excitation, colloidal quantum dots (QDs) are often found in multicarrier states due to multiphoton absorption, photocharging, or imbalanced carrier injection of the QDs. While many of these multicarrier states are observed in single-dot spectroscopy, their properties are not well studied due to random charging/discharging, emission intensity intermittency, and uncontrolled surface defects of single QDs. Here we report in situ deciphering of the charging status, precisely assessing the absorption cross section, and determining the absolute emission quantum yield of monoexciton and biexciton states for neutral, positively charged, and negatively charged single core/shell CdSe/CdS QDs. We uncover very different photon statistics of the three charge states in single QDs and unambiguously identify their charge signs together with the information on their photoluminescence decay dynamics. We then show their distinct photoluminescence saturation behaviors and evaluate the absolute values of absorption cross sections and quantum efficiencies of monoexcitons and biexcitons. We demonstrate that the addition of an extra hole or electron in a QD not only changes its emission properties but also varies its absorption cross section. PMID- 29160716 TI - (+)- and (-)-Ecarlottones, Uncommon Chalconoids from Fissistigma latifolium with Pro-Apoptotic Activity. AB - Four new compounds, (+)- and (-)-ecarlottone (1), (+/-)-fislatifolione (5), (+/-) isofislatifolione (6), and (+/-)-fislatifolic acid (7), and the known desmethoxyyangonin (2), didymocarpin-A (3), and dehydrodidymocarpin-A (4) were isolated from the stem bark of Fissistigma latifolium, by means of bioassay guided purification using an in vitro affinity displacement assay based on the modulation of Bcl-xL/Bak and Mcl-1/Bid interactions. The structures of the new compounds were elucidated by NMR spectroscopic data analysis, and the absolute configurations of compounds (+)-1 and (-)-1 were assigned by comparison of experimental and computed ECD spectra. (-)-Ecarlottone 1 exhibited a potent antagonistic activity on both protein-protein associations with Ki values of 4.8 MUM for Bcl-xL/Bak and 2.4 MUM for Mcl-1/Bid. PMID- 29160717 TI - Reprogramming Tumor-Associated Macrophages To Reverse EGFRT790M Resistance by Dual-Targeting Codelivery of Gefitinib/Vorinostat. AB - Gefitinib is a first-line therapy in the EGFR-mutated nonsmall cell lung cancer (NSCLC). However, the development of drug resistance is almost unavoidable, thus leading to an unsustainable regimen. EGFRT790M mutation is the major cause responsible for the molecular-targeting therapy failure in NSCLC. Although the recently approved osimertinib is effective for the EGFRT790M-positive NSCLC, the osimertinib-resistant EGFR mutation is rapidly developed, too. In this study, we proposed a tumor-associated macrophage (TAM) reprogramming strategy for overcoming the EGFRT790M-associated drug resistance via a dual-targeting codelivery system of gefitinib/vorinostat that acted on both TAM with overexpression of mannose receptors and the HER-2 positive NSCLC cells. The trastuzumab-modified, mannosylated liposomal system was able to repolarize the protumor M2 phenotype to the antitumor M1 and cause the elevating ROS in the cancer cells, consequently modulating the intracellular redox balance via ROS/NOX3/MsrA axis. The suppressed MsrA facilitated the EGFRT790M degradation through 790M oxidation by ROS, thus resensitizing the EGFRT790M-positive cells to gefitinib. The dual-targeting codelivery and TAM-reprogramming strategies provided a potential method for rescuing the EGFRT790M-caused resistance to tyrosine kinase inhibitor treatment. PMID- 29160718 TI - Social and leisure activity profiles and well-being among the older adults: a longitudinal study. AB - OBJECTIVES: Studies highlight the beneficial effects of social and leisure activities on the well-being of aging people. Our aims were: to investigate activity profiles among older adults living in their own homes, to highlight potential changes in profiles over a period of five years and to examine effects of differences between these profiles on well-being variables. METHODS: Three waves were considered in this longitudinal study, with 550, 410 and 374 people (76, 79, 82 years on average), respectively. We used cluster analysis to obtain activity profiles of social and leisure activities, ANOVAs with age and external variables (satisfaction with life, time occupation satisfaction, self-esteem and depression) to explore differences between cluster groups, and chi-square tests of association to explore whether the same individual belonged to the same activity profile over time. RESULTS: The number of clusters decreased strongly from the first wave to the other two waves (n = 7 to n = 2 and 3). Two main types of activity differentiated the profiles: social activities (voluntary work and associations) and recreational activities outside the home/at home. The activities showed no systematic or strong effects on external variables, nevertheless for the oldest subjects when comparing the less active to the more active (recreational profile and social profile) the latter expressed a greater satisfaction of time occupation and self-esteem, and lower scores of depressive symptoms. CONCLUSIONS: Such activities could be an indicator of a certain independence (physical and mental availability) which plays a strong role in the well-being of older adults. PMID- 29160719 TI - Geographical proximity and depressive symptoms among adult child caregivers: social support as a moderator. AB - OBJECTIVES: This study examined whether geographical proximity is a predictor of depressive symptoms, and whether family and friend support can moderate the relationship between geographical proximity and depressive symptoms. METHOD: A survey of 557 adult child primary caregivers was conducted in Shanghai, China in 2013. Geographical proximity was measured as a categorical variable: coresidence, short distance (less than 30 minutes' travel time), and long distance (more than 30 minutes' travel time). Family and friend support were assessed using the Multidimensional Scale of Perceived Social Support. Depressive symptoms were evaluated using the Center on Epidemiologic Studies Depression Scale. Multiple regression analyses and interaction terms were used to test the moderating roles of family and friend support. RESULTS: Adult child caregivers who live more than 30 minutes away from care recipients experienced higher depressive symptoms than coresiding caregivers (beta = .114, p < .01). Family support (beta = -.408, p < .05) and friend support (beta = -.235, p < .05) were protective factors that lessened depressive symptoms for long-distance adult child caregivers. CONCLUSION: This study adds spatial dimension to caregiving literature and extends stress process theory. These findings have important implications for service planning and social support for adult child caregivers. PMID- 29160720 TI - Effects of a dry-ice process on surface and carcase decontamination in the poultry industry. AB - 1. The objective of this study was to evaluate the effects of dry-ice decontamination on equipment and carcase surfaces in a poultry slaughterhouse and to present an effective alternative method to the conventional decontamination processes. 2. Appreciable reductions occurred in total aerobic mesophilic bacterial counts of surface swab samples treated with dry ice (maximum difference 3.92 log cfu/100 cm2). 3. After dry-ice treatment, Listeria spp. were detected on surfaces of pluckers and chiller cylinders, whereas Salmonella spp. were totally inhibited. 4. A dry-ice spraying application was more effective than a dry-ice immersing application on total aerobic mesophilic bacteria and yeast and mould counts on poultry carcases. 5. Dry-ice treatment has advantages over conventional processes. Unlike other decontamination techniques, there are no residues, so no need to wash off chemical residues from surfaces as it removes contaminants effortlessly and is environmentally friendly. 6. Dry-ice blasting of production equipment can reduce the microbial load and has potential for use in the poultry industry. PMID- 29160721 TI - Isolated Atypical Lobular Hyperplasia Diagnosed on Breast Biopsy: Low Upgrade Rate on Subsequent Excision With Long-Term Follow-up. AB - CONTEXT: - The upgrade rate to carcinoma on excision for atypical lobular hyperplasia diagnosed on breast biopsy is controversial. OBJECTIVE: - To review cases with isolated atypical lobular hyperplasia on biopsy to establish the rate of upgrade on excision and correlate with long-term follow-up. DESIGN: - A database search was performed for 191 months to identify breast core biopsies with isolated atypical lobular hyperplasia. Cases with other atypical lesions in the biopsy or discordant radiologic-pathologic findings were excluded. Invasive carcinoma and ductal carcinoma in situ were considered upgraded pathology on excision. Patients without and with a history of, or concurrent diagnosis of, breast carcinoma were compared. RESULTS: - Eighty-seven cases of isolated atypical lobular hyperplasia on biopsy underwent subsequent excision, which resulted in 3 upgraded cases (3.4%). All 3 cases with immediate upgrades revealed ductal carcinoma in situ. Upgrade was higher in patients with a concurrent diagnosis of breast carcinoma (2 of 26 and 1 of 61; 7.7% versus 1.6%, respectively). Follow-up information was available for 63 patients (57.8 +/- 43.9 months; range, 6-183 months). Overall, 13% of patients without a history of breast carcinoma had a future breast cancer event, with the majority (83%) presenting in the contralateral breast. CONCLUSIONS: - With careful radiologic pathologic correlation, the upgrade rate for isolated atypical lobular hyperplasia on biopsy is low, and a more conservative approach may be appropriate. PMID- 29160722 TI - Do Infection Patterns of Human Papillomavirus Affect the Cytologic Detection of High-Grade Cervical Lesions on Papanicolaou Tests? AB - CONTEXT: - Persistent infection with high-risk human papillomavirus (hrHPV) is the major cause of cervical cancer. The effect of HPV infection patterns on cytologic detection of cervical lesions is unknown. OBJECTIVE: - To determine the effect of HPV infection patterns on the sensitivity of cytologic detection of high-grade cervical lesions. DESIGN: - Papanicolaou tests from 257 women with biopsy-confirmed, high-grade squamous intraepithelial lesions were analyzed with respect to HPV infection patterns. RESULTS: - Among 257 biopsy-confirmed, high grade squamous intraepithelial lesion cases, the preceding cytology showed 20 cases (8%) were benign; 166 cases (65%) were low-grade cervical lesions, including atypical squamous cell of undetermined significance and low-grade squamous intraepithelial lesions; and 71 cases (28%) were high-grade cervical lesions, including atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion (atypical squamous cell-high), atypical glandular cells, and high-grade squamous intraepithelial lesions. In 236 cases tested for HPV, those exhibiting low-grade cervical lesions on cytology were often associated with coinfections of mixed hrHPV genotypes (31 of 40; 78%) or non-16/18 hrHPV (75/103; 73%), compared with single-genotype infections of HPV-16 (33 of 62; 53%) or HPV-18 (2 of 6; 33%) ( P = .001). In contrast, high-grade cervical lesion cytomorphology tended to associate with the single-genotype infection of HPV-16 (20 of 62; 32%) or HPV-18 (3 of 6; 50%), compared with non-16/18 hrHPV (25 of 103; 24%) or multigenotype infection (8 of 40; 20%) ( P = .01). CONCLUSIONS: - Our findings suggest that multigenotypic or non-16/18 hrHPV infections often produce deceptive lower-grade cytomorphology, which could result in underdiagnosis and delay of treatment. The HPV infection patterns may offer unrecognized benefit beyond HPV genotyping and should be considered during clinical risk evaluation of women with lower-grade cytology. PMID- 29160723 TI - Automation of a dosing-disc capsule filler from the perspective of reliability and safety. AB - The aim of this paper is to explore the possibility to develop an automatically adjustable, reliable, and safe capsule filling operation. Process parameters that are critical for the tamping pin process were reviewed based on the literature and via experiment. Dosing disc height, powder bed height, machine speed, pressure on the tamping pin, and immersion depth were reviewed. Two investigations were performed on a GKF 702. In the first one, the powder feed rate onto the dosing disc was examined and modified. A distance sensor with a PID controller enabled a constant powder bed level with an online changeable set point. For a bad flowing product an improvement of the fill weight variation could be achieved by automatically adjusting the feed rate to the correct speed and matching the actual process conditions of the capsule filler. The second part of the study concerned the safety of the filler operation. Introducing a force transducer on the transfer station is a promising option for running the capsule filler safely within its process specifications. The tamping pin pressure was used to provoke different transfer forces. A deviation from a defined process specification led to a safe stop of the machine. In summary, the automated adjustment of several critical process parameters appears to be feasible and supports the rational development of efficient production processes using a dosing disc capsule filler. This is especially relevant for continuous production of pharmaceuticals. PMID- 29160724 TI - Exosome Treatment of Bronchopulmonary Dysplasia: How Pure Should Your Exosome Preparation Be? PMID- 29160725 TI - Management of Neurologic Deformity of the Ankle and Foot With Concurrent Osteomyelitis With the Ilizarov Method. AB - BACKGROUND: The combination of neurologic deformity of the ankle and foot with osteomyelitis is a therapeutic challenge. We investigated the role of Ilizarov with regard to eradication of infection, correction of deformities and improvement of patient function. METHODS: We retrospectively reviewed 77 patients (77 feet) with neurologic deformity of the ankle and foot with osteomyelitis treated sequentially in 3 stages by Ilizarov method. The 3 stages were (1) active debridement and Ilizarov stabilization, (2) further strengthening of Ilizarov fixator and active osteosynthesis consisting of strategies like arthrodesis, osteotomy distraction, bone transport, or combination thereof, (3) consolidation of fusion/regeneration achieved in second stage. Patients with Charcot arthropathy were not included in the study. There were 43 males and 34 females with mean age of 34.4 (range, 18 to 70) years. All patients had a minimum of 1 year follow-up and 49 patients had 5 years follow-up. RESULTS: Mean duration of external fixation was 179.9 (range, 128 to 413) days. The success of infection eradication was 90.9% and 91.9% at the end of 1 and 5 years, respectively. We achieved plantigrade feet in all cases with no recurrence of deformity. The American Orthopaedic Foot & Ankle Score (AOFAS) improved from a median preoperative value of 74 (interquartile range, 65 to 75.25) to 81 (interquartile range, 77 to 88) ( P < .0001). The improvement of the score was by 7 points only considering the painless nature of the pathology, and the fact that pain contributed to 40% of total score. A total of 39 complications occurred in 30 patients which were managed successfully by alteration of rehabilitation and carefully chosen interventions. CONCLUSION: Ilizarov external fixation was an effective technique to address problems associated with neurologic foot and ankle deformity with infection. It allowed eradication of infection and achievement of a stable plantigrade foot. It had some disadvantages like lengthy duration of treatment, pin-tract infections, need for operative expertise, and supervised rehabilitation, but we feel these were definitely outweighed by its benefits. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29160726 TI - Gene-Environment Interactions Associated with the Severity of Acute Asthma Exacerbation in Children. PMID- 29160727 TI - A Review of Perioperative Complications of Outpatient Total Ankle Arthroplasty. AB - BACKGROUND: Total ankle arthroplasty (TAA) is commonly pursued for patients with painful arthritis. Outpatient TAA are increasingly common and have been shown to decrease costs compared to inpatient surgery. However, there are very few studies examining the safety of outpatient TAA. In this study, we retrospectively reviewed 65 consecutive patients who received outpatient TAA to identify complication rates. METHODS: The medical records of 65 consecutive outpatient TAA from October 2012 to May 2016 with a minimum 6-month follow-up were reviewed. All patients received popliteal and saphenous blocks prior to surgery and were managed with oral pain medication postoperatively. All received a STAR total ankle. Demographics, comorbidities, American Society of Anesthesiologists (ASA) class, and perioperative complications including wound breakdown, infection, revision, and nonrevision surgeries were observed. Mean follow-up was 16.6 +/- 9.1 months (range, 6-42 months). RESULTS: There were no readmissions for pain control and 1 patient had a wound infection. The overall complication rate was 15.4%. One ankle (1.5%) had a wound breakdown requiring debridement and flap coverage. This patient thrombosed a popliteal artery stent 1 month postop. The 1 ankle (1.5%) with a wound infection occurred in a patient with diabetes, obesity, hypertension, and rheumatoid arthritis. CONCLUSION: This study demonstrates the safety of outpatient TAA. The combination of regional anesthesia and oral narcotics provided a satisfactory experience with no readmissions for pain control and 1 wound infection. The 1 wound breakdown complication (1.5%) was attributed to arterial occlusion and not outpatient management. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29160729 TI - Editorial. PMID- 29160728 TI - Selection of Amino Acid Chirality via Neutrino Interactions with 14N in Crossed Electric and Magnetic Fields. AB - Previous work has suggested that the chirality of the amino acids could be established in the magnetic field of a nascent neutron star from a core-collapse supernova or massive collapsar. The magnetic field would orient the 14N nuclei, and the alignment of its nuclear spin with respect to those of the electron antineutrinos emitted from the collapsing star would determine the probability of destruction of the 14N nuclei by interactions with the antineutrinos. Subsequent work estimated the bulk polarization of the 14N nuclei in large rotating meteoroids in such an environment. The present work adds a crucial piece of this model by describing the details by which the selective 14N nuclear destruction would produce molecular chiral selectivity. The effects of the neutrino-induced interactions on the 14N nuclei bound in amino acids polarized in strong magnetic fields are studied. It is shown that electric fields in the reference frame of the nuclei modify the magnetic field at the nucleus, creating nuclear magnetizations that are asymmetric in chirality. The antineutrino cross sections depend on this magnetization, creating a selective destructive effect. The environmental conditions and sites in which such a selection mechanism could occur are discussed. Selective destruction of D-enantiomers results in enantiomeric excesses which may be sufficient to drive subsequent autocatalysis necessary to produce the few-percent enantiomeric excesses found in meteorites and subsequent homochirality. Molecular quantum chemical calculations were performed for alanine, and the chirality-dependent effects studied were included. A preference for left-handed molecules was found, and enantiomeric excesses as high as 0.02% were estimated for molecules in the electromagnetic conditions expected from a core-collapse supernova. Key Words: Amino acids-Supernovae Antineutrinos-Enantiomeric excess-Chirality. Astrobiology 18, 190-206. PMID- 29160730 TI - Reply to Muraca et al.: Exosome Treatment of Bronchopulmonary Dysplasia: How Pure Should Your Exosome Preparation Be? PMID- 29160732 TI - Optimization and characterization of sertaconazole nitrate flexisomes embedded in hydrogel for improved antifungal activity. AB - The aim of the present research work was to develop, characterize and optimize sertaconazole nitrate (STZN) embedded flexisomes (STZN-FS) to improve the cutaneous anti-fungal activity of STZN. Flexisomes are self-aggregating, flexible, deformable lipidic vesicles possessing an aqueous core. A 32 factorial design was implemented to optimize the effects of the critical material attributes of concentration of phospholipid (X1) and edge activator (X2) on the critical quality attributes of particle size (Y1), entrapment efficiency (Y2), and deformability index (Y3). Statistical analysis was performed to be identify the best fit model and determine its significance. The sizes of the optimized STZN-FS were found to be 246.2 +/- 2.49 nm with entrapment efficiencies of 86.16 +/- 0.56% and deformability indices of 30.46 +/- 0.41. Zeta potential analysis showed negatively charged surface with a zeta potential value of -30.9 mV. TEM analysis showed spherical shapes, confirming the vesicular characteristics. The optimized STZN-FS were further formulated into hydrogels. The % drug diffusion of STZN-FS hydrogels was found to be 13.24% and drug deposition in the skin layers was found to be 83.54%, showing that a high concentration of the drug was available at the site of action. The zone of inhibition STZN-FS hydrogel (30 mm) was higher than the marketed formulation (22 mm) and the plain STZN hydrogel (14 mm) against Candida albicans. From the above studies, it was concluded that STZN loaded STZN-FS shows high flexibility and enhanced antifungal activity. STZN-FS are thus found to be potential carriers for drug deposition in skin layers without disturbing their integrity. PMID- 29160731 TI - Combination antiretroviral therapy accelerates immune recovery in patients with HIV-related lymphoma treated with EPOCH: a comparison within one prospective trial AMC034. AB - Drug-drug interactions between cART and chemotherapy may impact HIV and lymphoma control or lead to increased toxicities. No prospective comparative data informs potential harms and benefits. In AMC034, HIV-associated high-grade B-cell NHL patients received DA-EPOCH with rituximab. cART was given with EPOCH or delayed until chemotherapy completion per investigator choice. Pharmacokinetic, immunological, and treatment effects of concurrent cART were evaluated. CD4 counts dropped during EPOCH in both groups but recovered to higher than baseline 6 months post-EPOCH only in the cART group. HIV viral load decreased during chemotherapy in the cART group but increased in the non-cART group. Incidence of grade >=3 infectious, hematologic, or neurological toxicities was similar. Concurrent cART was not associated with 1-year EFS or OS. cART with EPOCH was well-tolerated and allowed for faster immune recovery. While we did not observe differences in outcome, the preponderance of evidence is in favor of combining cART with chemotherapy. PMID- 29160733 TI - Potential impact of inorganic nanoparticles on macronutrient digestion: titanium dioxide nanoparticles slightly reduce lipid digestion under simulated gastrointestinal conditions. AB - Titanium dioxide (TiO2) particles are used in some food products to alter their optical properties, such as whiteness or brightness. These additives typically contain a population of TiO2 nanoparticles (d < 100 nm), which has led to concern about their potential toxicity. The objective of this study was to examine the impact of TiO2 particles on the gastrointestinal fate of oil-in-water emulsions using a simulated gastrointestinal tract (GIT) that includes mouth, stomach, and small intestine phases. Theoretical predictions suggested that TiO2 nanoparticles might inhibit lipid digestion through two physicochemical mechanisms: (i) a fraction of the lipase adsorbs to TiO2 particle surfaces, thereby reducing the amount available to hydrolyze lipid droplets; (ii) some TiO2 particles adsorb to the surfaces of lipid droplets, thereby reducing the lipid surface area exposed to lipase. The importance of these mechanisms was tested by passing protein coated lipid droplets (2%, w/w) through the simulated GIT in the absence and presence of TiO2 (0.5%, w/w) nanoparticles (18 nm) and fine particles (167 nm). Changes in particle characteristics (size, organization, and charge) and lipid digestion were then measured. Both TiO2 nanoparticles and fine particles had little impact on the aggregation state and charge of the lipid droplets in the different GIT regions, as well as on the rate and extent of lipid digestion. This suggests that the theoretically predicted impact of particle size on lipid digestion was not seen in practice. PMID- 29160734 TI - Immunoparesis and polyclonal immunoglobulin recovery after auto-SCT for patients with multiple myeloma treated at a single institution. AB - Immunoparesis and polyclonal immunoglobulin recovery have been recently described as common indicators of immune dysfunction in patients with multiple myeloma. In the present study, we aimed to assess the impact of immunoparesis and polyclonal immunoglobulin recovery at day-100 post autologous stem cell transplant (auto SCT) on clinical outcomes. A total of 302 patients were included for the analysis of immunoparesis, and 197 were evaluable for polyclonal immunoglobulin recovery evaluation. Immunoparesis was observed in 93.5% of cases, with 47% of cases having polyclonal immunoglobulin recovery at 12 months post auto-SCT. Median overall and progression-free survival were longer in the group of patients with complete or partial normalization of polyclonal immunoglobulins. Patients receiving consolidation had a lower level of polyclonal reconstitution. In conclusion, polyclonal immunoglobulin recovery by 12 months post-auto-SCT is associated with superior overall and progression free survival in patients with MM. Efforts to better enhance polyclonal recovery deserve further investigation. PMID- 29160736 TI - GAT3 selective substrate l-isoserine upregulates GAT3 expression and increases functional recovery after a focal ischemic stroke in mice. AB - Ischemic stroke triggers an elevation in tonic GABA inhibition that impairs the ability of the brain to form new structural and functional cortical circuits required for recovery. This stroke-induced increase in tonic inhibition is caused by impaired GABA uptake via the glial GABA transporter GAT3, highlighting GAT3 as a novel target in stroke recovery. Using a photothrombotic stroke mouse model, we show that GAT3 protein levels are decreased in peri-infarct tissue from 6 h to 42 days post-stroke. Prior studies have shown that GAT substrates can increase GAT surface expression. Therefore, we aimed to assess whether the GAT3 substrate, L isoserine, could increase post-stroke functional recovery. L-Isoserine (38 uM or 380 uM) administered directly into the infarct from day 5 to 32 post-stroke, significantly increased motor performance in the grid-walking and cylinder tasks in a concentration-dependent manner, without affecting infarct volumes. Additionally, L-isoserine induced a lasting increase in GAT3 expression in peri infarct regions accompanied by a small decrease in GFAP expression. This study is the first to show that a GAT3 substrate can increase GAT3 expression and functional recovery after focal ischemic stroke following a delayed long-term treatment. We propose that enhancing GAT3-mediated uptake dampens tonic inhibition and promotes functional recovery after stroke. PMID- 29160735 TI - Up-regulation of Wnt/beta-catenin expression is accompanied with vascular repair after traumatic brain injury. AB - Recent data suggest that repairing the cerebral vasculature after traumatic brain injury (TBI) may help to improve functional recovery. The Wnt/beta-catenin signaling pathway promotes blood vessel formation during vascular development, but its role in vascular repair after TBI remains elusive. In this study, we examined how the cerebral vasculature responds to TBI and the role of Wnt/beta catenin signaling in vascular repair. We induced a moderate controlled cortical impact in adult mice and performed vessel painting to visualize the vascular alterations in the brain. Brain tissue around the injury site was assessed for beta-catenin and vascular markers. A Wnt transgenic mouse line was utilized to evaluate Wnt gene expression. We report that TBI results in vascular loss followed by increases in vascular structure at seven days post injury (dpi). Immature, non-perfusing vessels were evident in the tissue around the injury site. beta-catenin protein expression was significantly reduced in the injury site at 7 dpi. However, there was an increase in beta-catenin expression in perilesional vessels at 1 and 7 dpi. Similarly, we found increased number of Wnt GFP-positive vessels after TBI. Our findings suggest that Wnt/beta-catenin expression contributes to the vascular repair process after TBI. PMID- 29160737 TI - Community singing groups for people with chronic obstructive pulmonary disease: participant perspectives. AB - AIM: Chronic obstructive pulmonary disease (COPD) is a major public health issue which is irreversible and progressive, but previous research suggests that singing may have beneficial effects. The aim of this study was to establish the views of participants with COPD taking part in a singing for better breathing programme. METHODS: This was a descriptive qualitative study nested within a single-cohort feasibility study which included measures of lung function and wellbeing. Participants ( n = 37) were interviewed following a community singing programme that ran over 10 months in South East England. RESULTS: Findings support those from previous studies regarding the impact of singing on respiratory wellbeing. These included the teaching on breath control, relaxation and the breathing exercises, singing as a means to deflect attention away from breathing problems, leading to increased activity levels and the mutual support for respiratory problems. Beyond the impact on breathing, the singing was also seen as fun, and provided friendship and a 'feel-good' factor which led to motivation to participate in further activities. For some, it was the highlight of the week, and singing together in a group was felt to be central to the benefits experienced. Findings are compared with the quantitative measures within the same study. CONCLUSION: The majority of participants reported improvements in respiratory symptoms as well as mental and social wellbeing following the programme. The study contributes to the evidence base in supporting and highlighting the consistently positive experiences of a large sample of participants, despite variable outcomes in clinical measures. PMID- 29160739 TI - Neural correlates of effort-dependent and effort-independent cognitive fatigue components in patients with multiple sclerosis. AB - BACKGROUND: Among patients with multiple sclerosis (MS), fatigue is the most commonly reported symptom. It can be subdivided into an effort-dependent (fatigability) and an effort-independent component (trait-fatigue). OBJECTIVE: The objective was to disentangle activity changes associated with effort independent "trait-fatigue" from those associated with effort-dependent fatigability in MS patients. METHODS: This study employed behavioral measures and functional magnetic imaging to investigate neural changes in MS patients associated with fatigue. A total of 40 MS patients and 22 age-matched healthy controls performed in a fatigue-inducing N-back task. Effort-independent fatigue was assessed using the Fatigue Scale of Motor and Cognition (FSMC) questionnaire. RESULTS: Effort-independent fatigue was observed to be reflected by activity increases in fronto-striatal-subcortical networks primarily involved in the maintenance of homeostatic processes and in motor and cognitive control. Effort dependent fatigue (fatigability) leads to activity decreases in attention-related cortical and subcortical networks. CONCLUSION: These results indicate that effort independent (fatigue) and effort-dependent fatigue (fatigability) in MS patients have functionally related but fundamentally different neural correlates. Fatigue in MS as a general phenomenon is reflected by complex interactions of activity increases in control networks (effort-independent component) and activity reductions in executive networks (effort-dependent component) of brain areas. PMID- 29160738 TI - H4K20me2 distinguishes pre-replicative from post-replicative chromatin to appropriately direct DNA repair pathway choice by 53BP1-RIF1-MAD2L2. AB - The main pathways for the repair of DNA double strand breaks (DSBs) are non homologous end-joining (NHEJ) and homologous recombination directed repair (HDR). These operate mutually exclusive and are activated by 53BP1 and BRCA1, respectively. As HDR can only succeed in the presence of an intact copy of replicated DNA, cells employ several mechanisms to inactivate HDR in the G1 phase of cell cycle. As cells enter S-phase, these inhibitory mechanisms are released and HDR becomes active. However, during DNA replication, NHEJ and HDR pathways are both functional and non-replicated and replicated DNA regions co-exist, with the risk of aberrant HDR activity at DSBs in non-replicated DNA. It has become clear that DNA repair pathway choice depends on inhibition of DNA end-resection by 53BP1 and its downstream factors RIF1 and MAD2L2. However, it is unknown how MAD2L2 accumulates at DSBs to participate in DNA repair pathway control and how the NHEJ and HDR repair pathways are appropriately activated at DSBs with respect to the replication status of the DNA, such that NHEJ acts at DSBs in pre replicative DNA and HDR acts on DSBs in post-replicative DNA. Here we show that MAD2L2 is recruited to DSBs in H4K20 dimethylated chromatin by forming a protein complex with 53BP1 and RIF1 and that MAD2L2, similar to 53BP1 and RIF1, suppresses DSB accumulation of BRCA1. Furthermore, we show that the replication status of the DNA locally ensures the engagement of the correct DNA repair pathway, through epigenetics. In non-replicated DNA, saturating levels of the 53BP1 binding site, di-methylated lysine 20 of histone 4 (H4K20me2), lead to robust 53BP1-RIF1-MAD2L2 recruitment at DSBs, with consequent exclusion of BRCA1. Conversely, replication-associated 2-fold dilution of H4K20me2 promotes the release of the 53BP1-RIF1-MAD2L2 complex and favours the access of BRCA1. Thus, the differential H4K20 methylation status between pre-replicative and post replicative DNA represents an intrinsic mechanism that locally ensures appropriate recruitment of the 53BP1-RIF1-MAD2L2 complex at DNA DSBs, to engage the correct DNA repair pathway. PMID- 29160740 TI - Effects of Regular Physical Activity on the Cognitive Performance of Type 2 Diabetic Patients: A Systematic Review. AB - BACKGROUND: Cognitive decline has been shown to be associated with long-term type 2 diabetes mellitus (T2DM). This review analyzes the present literature to ascertain the role of regular physical activity (PA) for the functioning of the diabetic brain. METHODS: PubMed was systematically searched for relevant publications up to July 2017. RESULTS: Four cross-sectional, one longitudinal observational, and nine interventional studies with a total of ~7000 T2DM subjects are included in this review. Some significant positive relationships between the PA level of T2DM patients and their performance in several cognitive tests are reported in the cross-sectional studies. The longitudinal observational study implies a higher risk for developing dementia/mild cognitive impairment in T2DM patients with low PA behavior. Some significantly improved cognitive test results are reported for T2DM patients following physical training (PT) in six interventional studies. The quality of most of the training studies is low due to small sample sizes and/or missing control groups. DISCUSSION: PT may potentially contribute to improving the cognitive performance in T2DM patients. Additional high-quality studies with standardized cognitive assessments are needed to further determine the dose-effect relationships between PA and cognitive performance in T2DM patients. PMID- 29160741 TI - The Best of Both Worlds: Adaptation During Natural Tasks Produces Long-Lasting Plasticity in Perceptual Ocular Dominance. AB - In human vision, one eye is usually stronger than the other. This is called ocular dominance. Extremely imbalanced ocular dominance can be found among certain patient groups, for example, in patients with amblyopia. Here, we introduce a novel method to rebalance ocular dominance. We developed an altered reality system that subjects used to interact with the natural world, the appearance of which was changed through a real-time image process. Several daily adaptation sessions lasting 3 hr each reduced sensory ocular dominance in adults who were not diagnosed with amblyopia and improved vision in patients with amblyopia. Surprising additional strengthening was found over the subsequent 2 months, when subjects experienced natural vision only. Our method effectively trains subjects to use both eyes in the wide variety of everyday tasks. The transfer of this training to everyday vision likely produced the continuing growth in effects during the months after the training. These findings are promising for the application of this method in future clinical research on amblyopia. PMID- 29160742 TI - University-Affiliated Alcohol Marketing Enhances the Incentive Salience of Alcohol Cues. AB - We tested whether affiliating beer brands with universities enhances the incentive salience of those brands for underage drinkers. In Study 1, 128 undergraduates viewed beer cues while event-related potentials (ERPs) were recorded. Results showed that beer cues paired with in-group backgrounds (logos for students' universities) evoked an enhanced P3 ERP component, a neural index of incentive salience. This effect varied according to students' levels of identification with their university, and the amplitude of the P3 response prospectively predicted alcohol use over 1 month. In Study 2 ( N = 104), we used a naturalistic advertisement exposure to experimentally create in-group brand associations and found that this manipulation caused an increase in the incentive salience of the beer brand. These data provide the first evidence that marketing beer via affiliating it with students' universities enhances the incentive salience of the brand for underage students and that this effect has implications for their alcohol involvement. PMID- 29160744 TI - Modulation of Neural Oscillatory Activity during Dynamic Face Processing. AB - Various neuroimaging and neurophysiological methods have been used to examine neural activation patterns in response to faces. However, much of previous research has relied on static images of faces, which do not allow a complete description of the temporal structure of face-specific neural activities to be made. More recently, insights are emerging from fMRI studies about the neural substrates that underpin our perception of naturalistic dynamic face stimuli, but the temporal and spectral oscillatory activity associated with processing dynamic faces has yet to be fully characterized. Here, we used MEG and beamformer source localization to examine the spatiotemporal profile of neurophysiological oscillatory activity in response to dynamic faces. Source analysis revealed a number of regions showing enhanced activation in response to dynamic relative to static faces in the distributed face network, which were spatially coincident with regions that were previously identified with fMRI. Furthermore, our results demonstrate that perception of realistic dynamic facial stimuli activates a distributed neural network at varying time points facilitated by modulations in low-frequency power within alpha and beta frequency ranges (8-30 Hz). Naturalistic dynamic face stimuli may provide a better means of representing the complex nature of perceiving facial expressions in the real world, and neural oscillatory activity can provide additional insights into the associated neural processes. PMID- 29160743 TI - Left Inferior Frontal Gyrus Sensitivity to Phonetic Competition in Receptive Language Processing: A Comparison of Clear and Conversational Speech. AB - The speech signal is rife with variations in phonetic ambiguity. For instance, when talkers speak in a conversational register, they demonstrate less articulatory precision, leading to greater potential for confusability at the phonetic level compared with a clear speech register. Current psycholinguistic models assume that ambiguous speech sounds activate more than one phonological category and that competition at prelexical levels cascades to lexical levels of processing. Imaging studies have shown that the left inferior frontal gyrus (LIFG) is modulated by phonetic competition between simultaneously activated categories, with increases in activation for more ambiguous tokens. Yet, these studies have often used artificially manipulated speech and/or metalinguistic tasks, which arguably may recruit neural regions that are not critical for natural speech recognition. Indeed, a prominent model of speech processing, the dual-stream model, posits that the LIFG is not involved in prelexical processing in receptive language processing. In the current study, we exploited natural variation in phonetic competition in the speech signal to investigate the neural systems sensitive to phonetic competition as listeners engage in a receptive language task. Participants heard nonsense sentences spoken in either a clear or conversational register as neural activity was monitored using fMRI. Conversational sentences contained greater phonetic competition, as estimated by measures of vowel confusability, and these sentences also elicited greater activation in a region in the LIFG. Sentence-level phonetic competition metrics uniquely correlated with LIFG activity as well. This finding is consistent with the hypothesis that the LIFG responds to competition at multiple levels of language processing and that recruitment of this region does not require an explicit phonological judgment. PMID- 29160746 TI - Nucleic Acid Therapies for Cystic Fibrosis. AB - Nucleic acid therapeutics are an established class of drugs that enable specific targeting of a gene of interest. This diverse family of drugs includes antisense oligonucleotides, siRNAs, and mRNA replacement therapies, which can elicit both gene repression and activation, primarily at the RNA level. Recent advances in medicinal chemistry have increased drug potency and enhanced delivery and distribution to a broad array of tissue and cell types. A key advantage of nucleic acid therapeutics is in their application to monogenic diseases. Cystic fibrosis (CF) is one such disease that affects ~70,000 people globally. This severe disease is an excellent candidate for nucleic acid therapies, as it is due to a genetic defect in a single epithelial chloride channel. Although CF affects many tissues, the primary cause of patient mortality is lung disease. Here we review the various nucleic acid therapeutic modalities and their mechanisms of action, the opportunities and challenges associated with application of nucleic acid drugs to the lung pathology of CF, and the current state and prospects for nucleic acid drugs for the treatment of CF. PMID- 29160745 TI - The unveiling of the Warburg effect and the inscribed innovative approach to a radical non toxic anticancer therapy. AB - The purpose of this research has been deciphering the Warburg paradox, the biochemical enigma unsolved since 1923. We solved it by demonstrating that its specific character, i.e. the forced aerobic lactate exportation, represents a crucial metabolic device to counteract the cytotoxic effect produced by an excess of pyruvate at the connection of glycolysis with the Krebs cycle. This solution was verified by exposing cancer cells of different histogenesis to pyruvate concentrations higher than the physiological ones, after showing that these concentrations are totally innocuous when injected into mice. The mechanism of the pyruvate cytotoxicity relies on the saturation of the respiratory chain, leading to a negative shift of the cytosolic NADP/NADPH ratio and the consequent restriction of the purine synthesis and the related cell apoptosis. The reducing equivalents generated by glycolysis and by cytosolic metabolism compete each other for their disposal trough the respiratory chain; this makes it that the cytotoxicity of pyruvate is inversely related to the mitochondrial number and efficiency of various cell types. Thus, the cytotoxicity is high in anaplastic cancer stem cells, whose mitochondria are extremely few and immature (cristae poor); on the contrary, no inhibition is brought about in adult differentiated cells, physiologically rich of mature mitochondria. All this generates the pyruvate anticancer selectivity, together with the lack of a general toxicity, making pyruvate represent an ideal candidate for a radical non toxical anticancer treatment. PMID- 29160747 TI - Lipopolysaccharide mediates hepatic stellate cell activation by regulating autophagy and retinoic acid signaling. AB - Bacterial translocation and lipopolysaccharide (LPS) leakage occur at a very early stage of liver fibrosis in animal models. We studied the role of LPS in hepatic stellate cell (HSC) activation and the underlying mechanisms in vitro and in vivo. Herein, we demonstrated that LPS treatment led to a dramatic increase in autophagosome formation and autophagic flux in LX-2 cells and HSCs, which was mediated through the AKT-MTOR and AMPK-ULK1 pathway. LPS significantly decreased the lipid content, including the lipid droplet (LD) number and lipid staining area in HSCs; pretreatment with macroautophagy/autophagy inhibitors or silencing ATG5 attenuated this decrease. Furthermore, lipophagy was induced by LPS through the autophagy-lysosomal pathway in LX-2 cells and HSCs. Additionally, LPS-induced autophagy further reduced retinoic acid (RA) signaling, as demonstrated by a decrease in the intracellular RA level and Rar target genes, resulting in the downregulation of Bambi and promoting the sensitization of the HSC's fibrosis response to TGFB. Compared with CCl4 injection alone, CCl4 plus LPS injection exaggerated liver fibrosis in mice, as demonstrated by increased Col1a1 (collagen, type I, alpha 1), Acta2, Tgfb and Timp1 mRNA expression, ACTA2/alpha SMA and COL1A1 protein expression, and Sirius Red staining area, which could be attenuated by injection of an autophagy inhibitor. LPS also reduced lipid content in HSCs in vivo, with this change being attenuated by chloroquine (CQ) administration. In conclusion, LPS-induced autophagy resulted in LD loss, RA signaling dysfunction, and downregulation of the TGFB pseudoreceptor Bambi, thus sensitizing HSCs to TGFB signaling. PMID- 29160748 TI - ? PMID- 29160749 TI - ? PMID- 29160750 TI - ? PMID- 29160751 TI - ? PMID- 29160752 TI - ? PMID- 29160753 TI - ? PMID- 29160754 TI - ? PMID- 29160755 TI - Comparison of Visual Analog Pain Score Reported to Physician vs Nurse. AB - BACKGROUND: The visual analog scale (VAS) is considered a reliable and validated measure of patient-reported acute pain. Patient-reported outcome measures are becoming the standard of care throughout the orthopedic community, but interpretation and clinical applications are still under investigation. The aim of the current study was to compare preoperative patient-reported VAS scores reported at the same visit to nursing staff and the treating surgeon. Our hypothesis was that there would be no difference in the scores reported. METHODS: This study is a retrospective cohort of 201 consecutive foot and ankle patients treated by a single surgeon. The patients were asked to rate their pain intensity by the nursing staff and then by the surgeon using a standard horizontal VAS 0 to 10, from "no pain" to the "worst pain." Differences in reported pain values were analyzed. RESULTS: The results demonstrate that patients reported higher pain scores to the surgeon in 81% of the encounters, nursing staff 8%, and equal 11%. On average, the VAS score reported to the surgeon was significantly ( P < .05) higher than that reported to the nursing staff. CONCLUSION: The current study found a statistically significant higher patient-reported pain score to the treating surgeon compared to the nursing staff. While the exact cause is unclear, the discrepant pain scores call into question the validity of the VAS, considered a fifth vital sign and standard outcome measure in an outpatient clinic setting. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 29160757 TI - Comment on the Article "Dietary Supplements for Improving Body Composition and Reducing Body Weight: Where Is the Evidence?" and Reply from the Author. PMID- 29160756 TI - Recent developments on treatment strategies and the prognosis of dermatomyositis: a review. AB - Dermatomyositis is an autoimmune disease affecting both skin and muscle. Steroids are the first line treatment. However, no consensus regarding dosing, length of treatment, tapering speed, or when to add which immunosuppressant in case of steroid resistance, has been reached, as randomized-controlled trials are scarce. Especially data on long-term treatment is lacking in order to decide on the most effective treatment for long-term remission. Empiric evidence suggests that with an initially aggressive treatment with oral steroids followed by a slow taper, during which disease activity is adequately controlled, patients can be off therapy within typically 24-48 months, and remain disease-free without medication for over 20 years. Biologics such as rituximab have shown good results in the treatment of refractory DM. New, targeted therapies have been reported to improve DM in single cases or case series, but have to be evaluated for efficacy in randomized controlled trials. PMID- 29160760 TI - Identification of organic compounds in landfill leachate treated by advanced oxidation processes. AB - Landfill leachates are considered to be complex effluents of a variable composition containing many biorecalcitrant and highly toxic compounds. Considering the shortage of studies concerning the treatment of landfill leachates using ozone, as well as its combination with catalysts, the aim of this paper was to identify the organic compounds in this effluent treated with advanced oxidation processes (AOPs) of ozonation (O3), and heterogeneous catalytic ozonation with TiO2 (O3/TiO2) and with ZnO (O3/ZnO). In addition, this study sought to assess the efficiency of the removal of the organic matter present in the leachate. For the pre- and post-AOPs, the leachate was characterized through physicochemical parameters and identification of organic compounds using gas chromatography coupled to the mass spectrometry (GC-MS). The three processes studied (O3, O3/TiO2, and O3/ZnO) presented color removal, turbidity, BOD above 95%, and lower COD removals (19%, 24%, and 33%, respectively). All AOPs studied promoted a similar reduction of organic compounds from leachate, some of which with toxic and carcinogenic potential, such as p cresol, bisphenol A, atrazine, and hexazinone. In addition, upon the removal of organic matter and organic compounds, the heterogeneous catalytic ozonation processes proved more efficient than the process carried out only with ozone. PMID- 29160759 TI - Sensitivity enhancement of aminoglycosides in hydrophilic interaction liquid chromatography with tandem mass spectrometry by post-column addition of trace sodium acetate in methanol. AB - The development of a sensitive and accurate analytical method for monitoring aminoglycosides in food, environmental, and clinical samples is needed for many purposes. This study found that the responses of sodiated and protonated aminoglycosides in hydrophilic interaction chromatography with tandem mass spectrometry were enhanced upon addition of sodium acetate in methanol (5 mg L-1 at a flow rate of 0.2 mL min-1) as a post-column reagent. The sensitivities of sodiated spectinomycin, kanamycin, gentamicins, neomycin, and amikacin were significantly higher than those of the protonated molecules. Streptomycin and dihydrostreptomycin only formed protonated molecules, suggesting the preferential ionisation of the guanidine moieties in these aminoglycosides. The limits of quantification of these aminoglycosides were 0.19-2.5 ng mL-1. Notably, this is the first quantification of aminoglycosides that uses the sodiated molecules. The enhancement technique enables us to eliminate a concentration step from the clean up process from food samples. We also proposed a rapid analytical method for residual aminoglycosides in milk and meat samples; validation showed good accuracy and precision of this method at the Japanese maximum residual limits of aminoglycosides (40-500 ug kg-1). The application of this method to contaminated bovine tissues revealed remarkably high residual levels of kanamycin. This technique will be useful for the sensitive detection of aminoglycosides not only in food, but also in environmental samples and human plasma. PMID- 29160761 TI - Fronto-parietal coherence response to tDCS modulation in patients with disorders of consciousness. AB - AIM OF THE STUDY: A transcranial direct current stimulation (tDCS) protocol (20 min, 2 mA, anodal electrode at the left dorsolateral prefrontal cortex and cathodal electrode at the right supraorbital area) was applied in patients with different degrees of disorders of consciousness (DoC). Although previous research indicates that it could improve patients' coma recovery scale-revised (CRS-R) scores, the brain's electrophysiological responses to tDCS are still unclear. Therefore, the present study was performed to explore the underlying brain responses of patients in a minimally conscious state (MCS) and an unresponsive wakefulness syndrome (UWS) to tDCS modulation. MATERIALS AND METHODS: Seventeen patients with DoC were recruited in a sham controlled crossover study receiving real and sham tDCS. EEG coherence was used to measure functional connectivity changes induced by the tDCS modulation. RESULTS: After real tDCS modulation, the fronto-parietal coherence significantly increased in the theta band and decreased in the gamma band in the MCS group. No significant changes were found in the UWS group. The coherence responses significantly correlated with the patients' baseline CRS-R scores. No distinct alteration occurred in the sham session for either the MCS or UWS patients. CONCLUSIONS: The coherence responses to the present tDCS protocol may be a tool for diagnosing MCS versus UWS, as they may be a crucial cause of the different clinical effects in the two states. PMID- 29160762 TI - Commentary on the Article "Improving the Prediction of Maturity From Anthropometric Variables Using a Maturity Ratio". PMID- 29160763 TI - Efficient brain uptake of piperine and its pharmacokinetics characterization after oral administration. AB - 1. Piperine, the major biological active component in black pepper has been associated with miscellaneous pharmacological effects, especially on central nervous system. To correlate with its neurological activity, a comprehensive pharmacokinetic profile of piperine in brain, plasma and cerebrospinal fluid after oral administration in rats was investigated in this study. 2. It was noted that piperine could efficiently penetrate and homogeneously distribute into brain with similar pharmacokinetics profiles in each region. In addition, piperine concentrations in brain and plasma were found to be comparable with brain to plasma area under curve extrapolated to infinity (AUC0->infinity) ratios of 0.95 and 1.10 for total concentration and unbound concentrations, respectively. Piperine also demonstrated high affinity toward brain tissue (98.4-98.5%) and plasma protein (96.2-97.8%) leading to a brain distribution volume of 36.32 +/- 1.40 ml/g brain. Moreover, its efficient membrane permeability (P app values of 5.41 +/- 0.40 * 10- 5 cm/s and 4.78 +/- 0.16 * 10- 5 cm/s for basolateral to apical and apical to basolateral transport in Caco-2 monolayer model) and limited hepatic metabolism (Clint of 8.15 MUl/min/mg) could also contribute to its quick and high extent brain exposure. 3. In summary, this study for the first time demonstrated high brain penetration potency of piperine could be resulted from its high brain tissue affinity and membrane permeability together with its limited liver metabolism. PMID- 29160764 TI - DNA methylation profile in chronic myelomonocytic leukemia associates with distinct clinical, biological and genetic features. AB - Chromosomal abnormalities are detected in 20-30% of patients with chronic myelomonocytic leukemia (CMML) and correlate with prognosis. On the mutation level, disruptive alterations are particularly frequent in chromatin regulatory genes. However, little is known about the consequential alterations in the epigenetic marking of the genome. Here, we report the analysis of genomic DNA methylation patterns of 64 CMML patients and 10 healthy controls, using a DNA methylation microarray focused on promoter regions. Differential methylation analysis between patients and controls allowed us to identify abnormalities in DNA methylation, including hypermethylation of specific genes and large genome regions with aberrant DNA methylation. Unsupervised hierarchical cluster analysis identified two main clusters that associated with the clinical, biological, and genetic features of patients. Group 1 was enriched in patients with adverse clinical and biological characteristics and poorer overall and progression-free survival. In addition, significant differences in DNA methylation were observed between patients with low risk and intermediate/high risk karyotypes and between TET2 mutant and wild type patients. Taken together, our results demonstrate that altered DNA methylation patterns reflect the CMML disease state and allow to identify patient groups with distinct clinical features. PMID- 29160765 TI - Antithrombotic treatment in peripheral artery disease. AB - This review treats antithrombotic use for peripheral arterial disease (PAD). In asymptomatic patients, there are no scientific data to support single antiplatelet therapy (SAPT) for primary prophylaxis. In symptomatic PAD, SAPT with aspirin or clopidogrel is indicated. The efficacy of aspirin is controversial. Clopidogrel may be preferred over aspirin. Ticagrelor is not superior to clopidogrel in reducing major adverse cardiovascular events and major adverse limb events, but lowers the risk of ischaemic stroke. In symptomatic PAD, dual antiplatelet therapy (DAPT) with clopidogrel and aspirin does not provide benefit over SAPT with aspirin alone and is associated with increased risk of major bleeding. DAPT with ticagrelor 60 mg b. i. d. and aspirin provides a significant major adverse cardiovascular events reduction in symptomatic PAD patients and may be considered in PAD patients with prior myocardial infarction. The use of a new thrombin receptor antagonist, vorapaxar, on top of SAPT or DAPT with aspirin and/or clopidogrel, reduces the risk of acute limb ischaemia and peripheral artery revascularization in patients with symptomatic PAD, at the cost of an increased risk for bleeding. Rivaroxaban (2.5 mg b. i. d.) plus aspirin (100 mg daily) is the first antithrombotic association that proved significant benefit for PAD patients, in terms of strong endpoints - total mortality and cardiovascular mortality. Therefore, this association shows the strongest evidence for secondary prevention of symptomatic PAD patients. In PAD patients undergoing percutaneous peripheral interventions, at least four weeks of DAPT with aspirin and clopidogrel is recommended after infrainguinal stent implantation. Stenting below-the-knee arteries is often followed by a longer period of DAPT, but no specific evidence is available. Anticoagulation is mandatory to prevent arterial occlusion during radial or brachial invasive procedures. The strategy includes use of unfractioned heparin, bivalirudin or enoxaparin. Vitamin K antagonists may be considered after autologous vein infrainguinal bypass. PMID- 29160766 TI - Sugar-sweetened beverage taxation: an update on the year that was 2017. PMID- 29160767 TI - Sugar-sweetened beverage tax: the inconvenient truths. PMID- 29160769 TI - Correction. PMID- 29160770 TI - Cascaded longitudinal stimulated Raman scattering and the frequency doubling process of potassium dihydrogen phosphate crystals. AB - Cascaded longitudinal stimulated Raman scattering (LSRS) and the frequency doubling process are reported for the first time. When potassium dihydrogen phosphate (KDP) crystals are used as the type I and type II frequency doublers of picosecond, focused 1064 nm laser pulses, strong LSRS effects are observed. Three new laser spectrum lines appeared successively, i.e. at 558.9, 588.9 and 622.1 nm, and were excited by the frequency doubling laser at 532 nm. Second- and third order nonlinear optical frequency conversions were achieved in a single KDP crystal. The near-infrared light was thus converted into a new spectra laser spanning the green-to-red spectral range. PMID- 29160768 TI - Diverse modes of synaptic signaling, regulation, and plasticity distinguish two classes of C. elegans glutamatergic neurons. AB - Synaptic vesicle release properties vary between neuronal cell types, but in most cases the molecular basis of this heterogeneity is unknown. Here, we compare in vivo synaptic properties of two neuronal classes in the C. elegans central nervous system, using VGLUT-pHluorin to monitor synaptic vesicle exocytosis and retrieval in intact animals. We show that the glutamatergic sensory neurons AWCON and ASH have distinct synaptic dynamics associated with tonic and phasic synaptic properties, respectively. Exocytosis in ASH and AWCON is differentially affected by SNARE-complex regulators that are present in both neurons: phasic ASH release is strongly dependent on UNC-13, whereas tonic AWCON release relies upon UNC-18 and on the protein kinase C homolog PKC-1. Strong stimuli that elicit high calcium levels increase exocytosis and retrieval rates in AWCON, generating distinct tonic and evoked synaptic modes. These results highlight the differential deployment of shared presynaptic proteins in neuronal cell type specific functions. PMID- 29160771 TI - Synthesis of oxide-free aluminum nanoparticles for application to conductive film. AB - Aluminum nanoparticles are considered promising as alternatives to conventional ink materials, replacing silver and copper nanoparticles, due to their extremely low cost and low melting temperature. However, a serious obstacle to realizing their use as conductive ink materials is the oxidation of aluminum. In this research, we synthesized the oxide-free aluminum nanoparticles using catalytic decomposition and an oleic acid coating method, and these materials were applied to conductive ink for the first time. The injection time of oleic acid determines the size of the aluminum nanoparticles by forming a self-assembled monolayer on the nanoparticles instead of allowing the formation of an oxide phase. Fabricated nanoparticles were analyzed by transmission electron microscopy and x-ray photoelectron spectroscopy to verify their structural and chemical composition. In addition, conductive inks made of these nanoparticles exhibit electrical properties when they are sintered at over 300 degrees C in a reducing atmosphere. This result shows that aluminum nanoparticles can be used as an alternative conductive material in printed electronics and can solve the cost issues associated with noble metals. PMID- 29160772 TI - Crystal identification for a dual-layer-offset LYSO based PET system via Lu-176 background radiation and mean shift algorithm. AB - Modern positron emission tomography (PET) detectors are made from pixelated scintillation crystal arrays and readout by Anger logic. The interaction position of the gamma-ray should be assigned to a crystal using a crystal position map or look-up table. Crystal identification is a critical procedure for pixelated PET systems. In this paper, we propose a novel crystal identification method for a dual-layer-offset LYSO based animal PET system via Lu-176 background radiation and mean shift algorithm. Single photon event data of the Lu-176 background radiation are acquired in list-mode for 3 h to generate a single photon flood map (SPFM). Coincidence events are obtained from the same data using time information to generate a coincidence flood map (CFM). The CFM is used to identify the peaks of the inner layer using the mean shift algorithm. The response of the inner layer is deducted from the SPFM by subtracting CFM. Then, the peaks of the outer layer are also identified using the mean shift algorithm. The automatically identified peaks are manually inspected by a graphical user interface program. Finally, a crystal position map is generated using a distance criterion based on these peaks. The proposed method is verified on the animal PET system with 48 detector blocks on a laptop with an Intel i7-5500U processor. The total runtime for whole system peak identification is 67.9 s. Results show that the automatic crystal identification has 99.98% and 99.09% accuracy for the peaks of the inner and outer layers of the whole system respectively. In conclusion, the proposed method is suitable for the dual-layer-offset lutetium based PET system to perform crystal identification instead of external radiation sources. PMID- 29160773 TI - Rationalizing substituent effects in 1-azathioxanthone photophysics. AB - The influence of an electron donating substituent on the photophysical properties of 1-azathioxanthone dyes has been investigated using optical spectroscopy and theoretical models. The motivation behind the study is based on the fact that thioxanthones are efficient triplet sensitizers, and thus promising sensitizers for lanthanide centered emission. By adding an aza group to one of the phenyl ring systems, direct coordination to a lanthanide center becomes possible, which makes azathoixanthones great candidates as antenna chromophores in lanthanide(III) based dyes. Here, three 1-azathioxanthone derivatives have been synthesized targeting efficient triplet formation following absorption in the visible range of the spectrum. This is achieved by adding methoxy groups to the 1 azathioxanthone core. The derivatives were characterized using absorption, emission, and time-gated emission spectroscopy, where fluorescent quantum yields, singlet and triplet excited states lifetimes were determined. The experimentally determined photophysical properties of the three 1-azathioxanthone compounds are contrasted to those of the parent thioxanthone and is rationalized using the Strickler-Berg equation, Huckel MO theory, and Dewar's rules in combination with computational chemistry. We find that the transition energies follow predictions, but that the overall photophysical properties are determined by the relative energies as well as the nature of the involved states in both the singlet and the triplet excited state manifolds. PMID- 29160774 TI - Etchant-free transfer of 2D nanostructures. AB - The effective use of the van der Waals 2D materials relies on their successful transfer from the growth substrate onto other target substrates in the form of large films or flakes. In particular, it is important to transfer such atomically thin samples to various substrates with minimal sample damage and exposure to etchants and chemicals to realize their applications. Here we develop a universal transfer method that not only is free of reactive etchants, but also can maintain the film morphology intact with no tears and cracks. We show a variety of different 2D crystals and thin films with various sizes and thicknesses transferred from different substrates, i.e. metal-organic chemical vapor deposition-grown WSe2 coalesced thin films on sapphire and mechanically exfoliated 2D crystalline flakes on titanium nitride. Further examination by transmission electron microscopy indicates successful transfer of all the samples. This study presents a universal and etchant-free transfer method that can be used to transfer a variety of 2D crystals and other nanostructures from/to various substrates. PMID- 29160775 TI - Anatomical robust optimization to account for nasal cavity filling variation during intensity-modulated proton therapy: a comparison with conventional and adaptive planning strategies. AB - The aim of this study is to develop an anatomical robust optimization method for intensity-modulated proton therapy (IMPT) that accounts for interfraction variations in nasal cavity filling, and to compare it with conventional single field uniform dose (SFUD) optimization and online plan adaptation. We included CT data of five patients with tumors in the sinonasal region. Using the planning CT, we generated for each patient 25 'synthetic' CTs with varying nasal cavity filling. The robust optimization method available in our treatment planning system 'Erasmus-iCycle' was extended to also account for anatomical uncertainties by including (synthetic) CTs with varying patient anatomy as error scenarios in the inverse optimization. For each patient, we generated treatment plans using anatomical robust optimization and, for benchmarking, using SFUD optimization and online plan adaptation. Clinical target volume (CTV) and organ-at-risk (OAR) doses were assessed by recalculating the treatment plans on the synthetic CTs, evaluating dose distributions individually and accumulated over an entire fractionated 50 GyRBE treatment, assuming each synthetic CT to correspond to a 2 GyRBE fraction. Treatment plans were also evaluated using actual repeat CTs. Anatomical robust optimization resulted in adequate CTV doses (V95% ? 98% and V107% ? 2%) if at least three synthetic CTs were included in addition to the planning CT. These CTV requirements were also fulfilled for online plan adaptation, but not for the SFUD approach, even when applying a margin of 5 mm. Compared with anatomical robust optimization, OAR dose parameters for the accumulated dose distributions were on average 5.9 GyRBE (20%) higher when using SFUD optimization and on average 3.6 GyRBE (18%) lower for online plan adaptation. In conclusion, anatomical robust optimization effectively accounted for changes in nasal cavity filling during IMPT, providing substantially improved CTV and OAR doses compared with conventional SFUD optimization. OAR doses can be further reduced by using online plan adaptation. PMID- 29160776 TI - Proton range verification in homogeneous materials through acoustic measurements. AB - Clinical proton beam quality assurance (QA) requires a simple and accurate method to measure the proton beam Bragg peak (BP) depth. Protoacoustics, the measurement of the pressure waves emitted by thermal expansion resulting from proton dose deposition, may be used to obtain the depth of the BP in a phantom by measuring the time-of-flight of the pressure wave. Rectangular and cylindrical phantoms of different materials (aluminum, lead, and polyethylene) were used for protoacoustic studies. Four different methods for analyzing the protoacoustic signals are compared. Data analysis shows that, for Methods 1 and 2, plastic phantoms have better accuracy than metallic ones because of the lower speed of sound. Method 3 does not require characterizing the speed of sound in the material, but it results in the largest error. Method 4 exhibits minimal error, less than 3 mm (with an uncertainty ?1.5 mm) for all the materials and geometries. Psuedospectral wave-equation simulations (k-Wave MATLAB toolbox) are used to understand the origin of acoustic reflections within the phantom. The presented simulations and experiments show that protoacoustic measurements may provide a low cost and simple QA procedure for proton beam range verification as long as the proper phantoms and calculation methods are used. PMID- 29160777 TI - Motion compensation with skin contact control for high intensity focused ultrasound surgery in moving organs. AB - High intensity focused ultrasound (HIFU) is an emerging therapeutic solution that enables non-invasive treatment of several pathologies, mainly in oncology. On the other hand, accurate targeting of moving abdominal organs (e.g. liver, kidney, pancreas) is still an open challenge. This paper proposes a novel method to compensate the physiological respiratory motion of organs during HIFU procedures, by exploiting a robotic platform for ultrasound-guided HIFU surgery provided with a therapeutic annular phased array transducer. The proposed method enables us to keep the same contact point between the transducer and the patient's skin during the whole procedure, thus minimizing the modification of the acoustic window during the breathing phases. The motion of the target point is compensated through the rotation of the transducer around a virtual pivot point, while the focal depth is continuously adjusted thanks to the axial electronically steering capabilities of the HIFU transducer. The feasibility of the angular motion compensation strategy has been demonstrated in a simulated respiratory-induced organ motion environment. Based on the experimental results, the proposed method appears to be significantly accurate (i.e. the maximum compensation error is always under 1 mm), thus paving the way for the potential use of this technique for in vivo treatment of moving organs, and therefore enabling a wide use of HIFU in clinics. PMID- 29160778 TI - OPTICAL COHERENCE TOMOGRAPHY 2: DIAGNOSTIC TOOL TO STUDY PERIPHERAL VITREORETINAL PATHOLOGIES. AB - PURPOSE: To investigate the utility of new wide-field optical coherence tomography (OCT) device in the evaluation of mid and far retinal periphery and to show its feasibility and advantages in clinical practice. METHODS: Consecutive patients underwent a complete ophthalmologic examination including standard OCT and new prototype OCT2 derived from Heidelberg Spectralis. RESULTS: Thirty-one eyes of 31 patients were studied with a total of 44 lesions, including 18 retinal detachments, 15 retinal holes and tears, 9 retinoschisis, and 2 retinal tufts. Fourteen (32%) lesions were found in mid and 30 (68%) in far periphery with 9 (20%) lesions in the superior region, 10 (23%) in the superior temporal, 8 (18%) in the temporal, 4 (9%) in the inferior temporal, 7 (16%) in the inferior, 4 (9%) in the nasal, and 2 (5%) in the superior nasal. Among the lesions evaluated by OCT2, 10 (71%) in mid periphery and 11 (37%) in far periphery could be imaged by standard OCT. CONCLUSION: The introduction of OCT2 into clinical practice may provide significant benefits for imaging peripheral retinal disorders. The application of OCT2 technology with 55 degrees lens and scan length and angle modulation could improve our understanding of peripheral vitreoretinal disorders and facilitate their management. PMID- 29160779 TI - OUTCOME OF INTRAVITREAL AFLIBERCEPT FOR REFRACTORY PIGMENT EPITHELIAL DETACHMENT WITH OR WITHOUT SUBRETINAL FLUID AND SECONDARY TO AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To investigate the outcomes of intravitreal aflibercept in refractory pigment epithelial detachment (PED) with or without subretinal fluid (SRF) in patients with neovascular age-related macular degeneration. METHODS: A prospective, nonrandomized, interventional case series involved 40 patients with persistent vascularized PED previously treated with at least 3 injections of intravitreal bevacizumab or ranibizumab. Intravitreal aflibercept was administered as 3 initial loading doses every 4 weeks, followed by pro re nata retreatment every 8 weeks over 48 weeks. Pigment epithelial detachment was classified into solid-, hollow-, or mixed-type according to the reflective properties visualized using optical coherence tomography. The mean changes in best-corrected visual acuity, central subfield thickness, and the volumes of SRF and PED were analyzed. RESULTS: The PED volume (baseline: 0.43 +/- 0.55 mm) significantly reduced to 0.23 +/- 0.32 mm at Week 8 (P = 0.003) and increased to 0.36 +/- 0.41 mm at Week 48 (P = 0.345). The SRF volume (baseline: 0.52 +/- 0.64 mm) significantly reduced to 0.24 +/- 0.43 mm at Week 48 (P = 0.021). The mean baseline best-corrected visual acuity was 20/75 (47.5 letters); it showed no significant difference at Week 48 (+4.4 letters; P = 0.125). The baseline central subfield thickness was 323.2 +/- 92.3 MUm; it significantly reduced to 281.2 +/- 90.7 MUm at Week 48 (P = 0.001). In solid-type PEDs, there were poorer improvements in central subfield thickness, best-corrected visual acuity, and the volumes of the SRF and PED, with newly developed intraretinal cysts. CONCLUSION: Intravitreal aflibercept in treatment-resistant neovascular age-related macular degeneration led to significant reduction in PED and SRF volume, central subfield thickness, and best-corrected visual acuity preserved, over 12 months. However, solid-type PED showed less improvement than hollow- or mixed-type PED. PMID- 29160780 TI - Multiple Sub-Internal Limiting Membrane Hemorrhages With Double Ring Sign in Eyes With Valsalva Retinopathy. PMID- 29160781 TI - CHOROIDAL THICKNESS CHANGES IN ACUTE ZONAL OCCULT OUTER RETINOPATHY. AB - PURPOSE: To investigate the longitudinal morphologic choroidal changes in eyes with acute zonal occult outer retinopathy. METHODS: In this retrospective observational case series, we studied 10 patients (11 eyes) with unilateral acute zonal occult outer retinopathy at the first visit who were followed more than 12 months by enhanced depth optical coherence tomography. The retinal and choroidal thicknesses (CTs) were measured at six sites in the macula. RESULTS: The integrity of the ellipsoid zone was lost 1,500 MUm and 3,000 MUm nasally in all 11 eyes at the first visit. Compared with the unaffected fellow eyes, the mean total retinal thickness at the first visit was significantly (P = 0.03) thinner 3,000 MUm nasal to the fovea in the affected eyes. The mean CTs in the affected eyes did not differ from that in the unaffected eyes at any evaluation; the mean subfoveal CT in the affected eyes gradually decreased during the follow-up period. Compared with the first visit, the mean subfoveal CT decreased significantly (P = 0.011) at the foveal center and nasal, superior, and temporal to the fovea 12 months after disease onset. CONCLUSION: The subfoveal CT in eyes with acute zonal occult outer retinopathy can decrease during follow-up. PMID- 29160782 TI - Three Port Sutureless Posterior Chamber Intraocular Lens Intrascleral Fixation: A Novel Approach. PMID- 29160783 TI - LONG-TERM INTRAOCULAR PRESSURE AFTER UNCOMPLICATED PARS PLANA VITRECTOMY FOR IDIOPATHIC EPIRETINAL MEMBRANE. AB - PURPOSE: To investigate long-term intraocular pressure trends after uncomplicated pars plana vitrectomy for idiopathic epiretinal membrane. METHODS: Three hundred and sixty-eight eyes of 368 consecutive patients were enrolled. Changes in intraocular pressure 1, 3, 6, and 12 months after surgery and during the final follow-up visit were evaluated in vitrectomized eyes and nonvitrectomized fellow eyes. RESULTS: The median follow-up period was 36 months (range 12-92 months). Longitudinal data analysis evidenced a 2.5-mmHg (2.2 mmHg; 2.7 mmHg, 95% confidence interval) statistically significant difference in intraocular pressure 30 days after surgery between treated and fellow untreated eyes, gradually recovering to a not significant 0.2-mmHg (-0.1 mmHg; 0.4 mmHg, 95% confidence interval) difference within 26 months. The incidence of late-onset ocular hypertension was 5.7% (21 over 347, 2%; 12%, 95% confidence interval) without difference between the treated eyes and the group control. No significant difference in the incidence of late-onset ocular hypertension and sex, lens status, or gauge of vitrectomy instruments was detected. Only patient's age was significantly higher (mean difference 4.2 years; 0.1-8.0 years, Monte Carlo, 95% confidence interval) in those who developed late-onset ocular hypertension in the vitrectomized eye. CONCLUSION: Uncomplicated pars plana vitrectomy for idiopathic epiretinal membrane seems not to increase the risk of late-onset ocular hypertension or open-angle glaucoma development. PMID- 29160784 TI - RETINAL PIGMENT EPITHELIUM-CHOROID GRAFT WITH A PERIPHERAL RETINOTOMY FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION: Long-Term Outcome. AB - PURPOSE: To investigate the long-term outcome of autologous retinal pigment epithelium -choroid transplantation with a peripheral retinotomy for exudative age-related macular degeneration. METHODS: In a retrospective study, we selected all patients who underwent a retinal pigment epithelium-choroid transplantation from 2007 through 2013. Exclusion criteria were age <60 years, <12 months of follow-up, and retinal pigment epithelium-choroid graft for other diseases than age-related macular degeneration. The main outcome measure was best-corrected visual acuity converted into logarithm of the minimum angle of resolution. RESULTS: In this study, 81 patients were included with a mean follow-up of 38 months (SD = 19). Median best-corrected visual acuity improved from 1.30 logarithm of the minimum angle of resolution (20/400 Snellen) to 0.90 logarithm of the minimum angle of resolution (20/160 Snellen) 1 year after surgery (P < 0.001). A >=3-line gain was achieved in 43 patients (53%) 1 year postoperatively and 37 patients (46%) preserved their visual gain until last visit. Of 4 patients with an 8-year follow-up, 3 patients had a >=6-line gain at last visit. Severe complications were submacular hemorrhage (n = 8, 10%), macular hole (n = 6, 7%), and proliferative vitreoretinopathy (n = 3, 4%). CONCLUSION: Best-corrected visual acuity improved significantly after retinal pigment epithelium-choroid transplantation in patients with age-related macular degeneration and preservation of visual gain was possible in the long term. PMID- 29160786 TI - Outer Retinal Protrusion Toward the Retinal Pigment Epithelium During Retinal Reattachment After Scleral Buckling. PMID- 29160785 TI - SCLERAL PITS IN CHOROIDEREMIA: Implications for Retinal Gene Therapy. AB - PURPOSE: We report a novel finding on spectral domain optical coherence tomography in patients with choroideremia, which we describe as scleral pits (SCPs). METHODS: Cross-sectional observational case series of 36 patients with choroideremia, who underwent ophthalmic examination and multimodal imaging, including optical coherence tomography of the macula. Optical coherence tomography images were reviewed for SCP, which were defined as discrete tracts of hyporeflectivity that traverse the sclera with or without the involvement of Bruch membrane, retinal pigment epithelium, and retina. Unpaired two-tailed t test with Welch correction was used for statistical analysis. RESULTS: Of the 36 patients, 19 had SCP in at least one eye. Scleral pits were confined to areas of advanced chorioretinal degeneration and never involved the foveola. Type 1 SCP affected only the sclera, whereas Type 2 SCP also involved the Bruch membrane and the retinal pigment epithelium. Type 3 SCP additionally had a full-thickness retinal defect. Patients with SCP were significantly older (51 +/- 2 vs. 33 +/- 4 years; P < 0.05) and had lower best-corrected visual acuity (20/160 vs. 20/30 or 0.9 +/- 0.2 vs. 0.2 +/- 0.07 logarithm of the minimum angle of resolution; P < 0.05) than patients without SCP. Patients with SCP had a greater myopic refractive error compared with patients without SCP (-2.6 +/- 0.5 vs. -0.3 +/- 0.5D; P < 0.05), but there was no significant correlation between the number of SCPs with refraction. Short posterior ciliary arteries were observed to enter the eye through one Type 3 SCP. CONCLUSION: Scleral pits are, to the best of our knowledge, a novel optical coherence tomography finding in advanced choroideremia that likely represents the abnormal juxtaposition of penetrating short posterior ciliary arteries with the retina. PMID- 29160787 TI - FUNCTIONAL AND ANATOMICAL SIGNIFICANCE OF THE ECTOPIC INNER FOVEAL LAYERS IN EYES WITH IDIOPATHIC EPIRETINAL MEMBRANES: Surgical Results at 12 Months. AB - PURPOSE: To describe the functional and anatomical outcomes of pars plana vitrectomy with epiretinal membrane and internal limiting membrane peel in eyes with and without ectopic inner foveal layers (EIFLs). METHODS: In this retrospective multicenter study, patients diagnosed with idiopathic epiretinal membranes who underwent pars plana vitrectomy with epiretinal membrane and internal limiting membrane peel were enrolled, with a minimum follow-up of 12 months. Preoperative and postoperative spectral domain optical coherence tomography scans were qualitatively and quantitatively evaluated. The association of the EIFL and other spectral domain optical coherence tomography parameters with preoperative and postoperative best-corrected visual acuity (BCVA) was analyzed. RESULTS: One hundred eleven eyes of 107 patients were included. Preoperatively, the EIFLs were present in 56 of 111 eyes (50.4%). The presence of EIFL was significantly associated with lower preoperative and postoperative BCVA (P < 0.001). Ectopic inner foveal layer thickness was negatively correlated with preoperative BCVA (r = 0.58, P < 0.001). Postoperatively, the EIFL persisted in 51 of 56 eyes (91%) with Stage 3 and 4 epiretinal membranes. Ectopic inner foveal layer thickness decreased significantly after surgery (P < 0.001), but postoperative EIFL thinning had no direct effect on postoperative change in BCVA. At 12 months from surgery, EIFL thickness maintained a significant negative correlation with BCVA (r = 0.55, P < 0.001). CONCLUSION: The presence of EIFL should be considered a negative prognostic factor for postoperative anatomical and functional recovery. PMID- 29160788 TI - RELIABILITY OF CONFOCAL WHITE-LIGHT FUNDUS IMAGING FOR MEASUREMENT OF RETINA PIGMENT EPITHELIAL ATROPHY IN AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To assess the reproducibility of confocal white-light color fundus photography (C-CFP) for the measurement of retinal pigment epithelial atrophy in comparison with confocal blue-light fundus autofluorescence (FAF) imaging and flash color fundus photography (F-CFP). METHODS: In this prospective study, eyes with age-related macular degeneration associated with evidence of retinal pigment epithelial atrophy were imaged by C-CFP, F-CFP, and FAF. Intergrader reproducibility of each modality was assessed by comparison of manual measurements by two expert graders. RESULTS: The mean areas of atrophy measured by the 2 graders were 6.67 +/- 6.39, 6.35 +/- 6.13, and 6.07 +/- 5.48 mm for FAF, C-CFP, and F-CFP, respectively. The mean differences between the 2 graders in measuring the atrophic areas were 0.52, 0.69, and 1.62 mm for the three modalities. The intraclass correlation coefficient between the 2 graders for each modality was 0.998, 0.990, and 0.961, respectively. CONCLUSION: Measurements of atrophy from C-CFP were similar to those obtained by FAF and F-CFP. The grading reproducibility for C-CFP, however, was better than that for F-CFP and approached the level of FAF imaging. The use of C-CFP as a tool for quantitatively monitoring atrophic age-related macular degeneration lesions warrants further study, particularly in the context of clinical trials. PMID- 29160789 TI - Surgical Technique for Sutureless Intrascleral Fixation of a 3-Piece Intraocular Lens Using a 30-Gauge Needle. PMID- 29160790 TI - Communication or Toxicity: What Is the Effect of Cycloheximide on Leaf-Cutting Ant Workers? AB - Leaf-cutting ants are insects that use plant material to grow fungus from which they feed. These fungus-growing ants perform various behavioral activities to establish an environment conducive to the fungus. Among these behaviors are activities that can serve to detect materials harmful to the colony, such as licking, scraping, chopping, etc. However, there are substances that may not be detected as harmful to the fungus on first contact. Cycloheximide (CHX) is one such substance, described as a fungicide that inhibits the synthesis of proteins in eukaryotes, although its mechanism of action remains unclear. The present study aimed at evaluating the behavioral changes of worker ants, time carrying orange pellets, waste deposition and mortality, when subjected to seven days of CHX-incorporated pellets and another seven days of CHX-free pellets. The fungicide adversely and structurally affected the leaf-cutter ant colonies. Their behavior went through changes, such as an increase in pellet-licking frequencies and cleaning among the ants from the third day onward. Moreover, there was an increase in time carrying orange pellets, as well as in the mortality of workers during CHX incorporation. PMID- 29160791 TI - Antimalarial Activity of Acetylenic Thiophenes from Echinops hoehnelii Schweinf. AB - Malaria is one of the world's most severe endemic diseases and due to the emergence of resistance to the currently available medicines, the need for new targets and relevant antimalarial drugs remains acute. The crude extract, four solvent fractions and two isolated compounds from the roots of Echinops hoehnelii were tested for their antimalarial activity using the standard four-day suppressive method in Plasmodium berghei-infected mice. The 80% methanol extract exhibited suppression of 4.6%, 27.8%, 68.5% and 78.7% at dose of 50, 100, 200 and 400 mg/kg respectively. The dichloromethane fraction displayed chemosuppression of 24.9, 33.5 and 43.0% dose of 100, 200 and 400 mg/kg of body weight. Five acetylenicthiophenes were isolated from the dichloromethane fraction of which 5 (penta-1,3-diynyl)-2-(3,4-dihydroxybut-1-ynyl)-thiophene decreased the level of parasitaemia by 43.2% and 50.2% while 5-(penta-1,3-diynyl)-2-(3-chloro-4-acetoxy but-1-yn)-thiophene suppressed by 18.8% and 32.7% at 50 and 100 mg/kg, respectively. The study confirmed the traditional claim of the plant to treat malaria and could be used as a new lead for the development of antimalarial drugs. PMID- 29160792 TI - Cross-Sectional Serological Survey for Leptospira spp. in Beef and Dairy Cattle in Two Districts in Uganda. AB - Seroprevalence of Leptospira spp. in cattle is unknown in Uganda. The aim of this study was to estimate the seroprevalence of L. interrogans Icterohaemorrhagiae, Pomona, L. kirschneri Butembo, Grippotyphosa, L. borgpetersenii Nigeria, Hardjo, Wolfii, and Kenya and an overall seroprevalence in cattle from Kole and Mbale districts. Two hundred-seventy five bovine sera from 130 small holder farms from Kole (n = 159) and Mbale (n = 116), collected between January and July 2015, were tested for antibodies against eight Leptospira strains by Microscopic Agglutination Test. A titer of >=100 was considered seropositive, indicating past exposure. Overall, the seroprevalence was 19.27% (95% CI 14.9-24.5%). Pomona seroprevalence was highest with 9.45% (6.4-13.7%), followed by Kenya 5.09% (2.9 8.6%), Nigeria 4.00% (2.1-7.2%), Wolfii 3.27% (1.6-6.3%), Butembo 1.86% (0.7 4.4%), Hardjo 1.45% (0.5-3.9%), and Icterohaemorragiae and Grippotyphosa with less than 1% positive. Seroprevalence did not differ between districts and gender (p >= 0.05). Seven animals had titers >=400. Cross-reactions or exposure to >=1 serovar was measured in 43% of serum samples. Seroprevalence of 19% implies exposure of cattle to leptospires. PMID- 29160793 TI - A Gal-MuS Device to Evaluate Cell Migratory Response to Combined Galvano Chemotactic Fields. AB - Electric fields have been studied extensively in biomedical engineering (BME) for numerous regenerative therapies. Recent studies have begun to examine the biological effects of electric fields in combination with other environmental cues, such as tissue-engineered extracellular matrices (ECM), chemical gradient profiles, and time-dependent temperature gradients. In the nervous system, cell migration driven by electrical fields, or galvanotaxis, has been most recently studied in transcranial direct stimulation (TCDS), spinal cord repair and tumor treating fields (TTF). The cell migratory response to galvano-combinatory fields, such as magnetic fields, chemical gradients, or heat shock, has only recently been explored. In the visual system, restoration of vision via cellular replacement therapies has been limited by low numbers of motile cells post transplantation. Here, the combinatory application of electrical fields with other stimuli to direct cells within transplantable biomaterials and/or host tissues has been understudied. In this work, we developed the Gal-MuS device, a novel microfluidics device capable of examining cell migratory behavior in response to single and combinatory stimuli of electrical and chemical fields. The formation of steady-state, chemical concentration gradients and electrical fields within the Gal-MuS were modeled computationally and verified experimentally within devices fabricated via soft lithography. Further, we utilized real-time imaging within the device to capture cell trajectories in response to electric fields and chemical gradients, individually, as well as in combinatory fields of both. Our data demonstrated that neural cells migrated longer distances and with higher velocities in response to combined galvanic and chemical stimuli than to either field individually, implicating cooperative behavior. These results reveal a biological response to galvano-chemotactic fields that is only partially understood, as well as point towards novel migration-targeted treatments to improve cell-based regenerative therapies. PMID- 29160794 TI - GhMAP3K65, a Cotton Raf-Like MAP3K Gene, Enhances Susceptibility to Pathogen Infection and Heat Stress by Negatively Modulating Growth and Development in Transgenic Nicotiana benthamiana. AB - Mitogen-activated protein kinase kinase kinases (MAP3Ks), the top components of MAPK cascades, modulate many biological processes, such as growth, development and various environmental stresses. Nevertheless, the roles of MAP3Ks remain poorly understood in cotton. In this study, GhMAP3K65 was identified in cotton, and its transcription was inducible by pathogen infection, heat stress, and multiple signalling molecules. Silencing of GhMAP3K65 enhanced resistance to pathogen infection and heat stress in cotton. In contrast, overexpression of GhMAP3K65 enhanced susceptibility to pathogen infection and heat stress in transgenic Nicotiana benthamiana. The expression of defence-associated genes was activated in transgenic N. benthamiana plants after pathogen infection and heat stress, indicating that GhMAP3K65 positively regulates plant defence responses. Nevertheless, transgenic N. benthamiana plants impaired lignin biosynthesis and stomatal immunity in their leaves and repressed vitality of their root systems. In addition, the expression of lignin biosynthesis genes and lignin content were inhibited after pathogen infection and heat stress. Collectively, these results demonstrate that GhMAP3K65 enhances susceptibility to pathogen infection and heat stress by negatively modulating growth and development in transgenic N. benthamiana plants. PMID- 29160795 TI - Differential Expression Patterns of Pleurotus ostreatus Catalase Genes during Developmental Stages and under Heat Stress. AB - Catalases are ubiquitous hydrogen peroxide-detoxifying enzymes. They participate in fungal growth and development, such as mycelial growth and cellular differentiation, and in protecting fungi from oxidative damage under stressful conditions. To investigate the potential functions of catalases in Pleurotus ostreatus, we obtained two catalase genes from a draft genome sequence of P. ostreatus, and cloned and characterized them (Po-cat1 and Po-cat2). Po-cat1 (group II) and Po-cat2 (group III) encoded putative peptides of 745 and 528 amino acids, respectively. Furthermore, the gene structures were variant between Po cat1 and Po-cat2. Further research revealed that these two catalase genes have divergent expression patterns during different developmental stages. Po-cat1/Po cat1 was at a barely detectable level in mycelia, accumulated gradually during reproductive growth, and was maximal in separated spores. But no catalase activity of Po-cat1 was detected by native-PAGE during any part of the developmental stages. In contrast, high Po-cat2/Po-cat2 expression and Po-cat2 activity found in mycelia were gradually lost during reproductive growth, and at a minimal level in separated spores. In addition, these two genes responded differentially under 32 degrees C and 40 degrees C heat stresses. Po-cat1 was up-regulated under both temperature conditions, while Po-cat2 was up-regulated at 32 degrees C but down-regulated at 40 degrees C. The accumulation of catalase proteins correlated with gene expression. These results indicate that the two divergent catalases in P. ostreatus may play different roles during development and under heat stress. PMID- 29160797 TI - Target Tracking with Sensor Navigation Using Coupled RSS and AoA Measurements. AB - This work addresses the problem of tracking a signal-emitting mobile target in wireless sensor networks (WSNs) with navigated mobile sensors. The sensors are properly equipped to acquire received signal strength (RSS) and angle of arrival (AoA) measurements from the received signal, while the target transmit power is assumed not known. We start by showing how to linearize the highly non-linear measurement model. Then, by employing a Bayesian approach, we combine the linearized observation model with prior knowledge extracted from the state transition model. Based on the maximum a posteriori (MAP) principle and the Kalman filtering (KF) framework, we propose new MAP and KF algorithms, respectively. We also propose a simple and efficient mobile sensor navigation procedure, which allows us to further enhance the estimation accuracy of our algorithms with a reduced number of sensors. Model flaws, which result in imperfect knowledge about the path loss exponent (PLE) and the true mobile sensors' locations, are taken into consideration. We have carried out an extensive simulation study, and our results confirm the superiority of the proposed algorithms, as well as the effectiveness of the proposed navigation routine. PMID- 29160796 TI - Role of Galectin-3 in Bone Cell Differentiation, Bone Pathophysiology and Vascular Osteogenesis. AB - Galectin-3 is expressed in various tissues, including the bone, where it is considered a marker of chondrogenic and osteogenic cell lineages. Galectin-3 protein was found to be increased in the differentiated chondrocytes of the metaphyseal plate cartilage, where it favors chondrocyte survival and cartilage matrix mineralization. It was also shown to be highly expressed in differentiating osteoblasts and osteoclasts, in concomitance with expression of osteogenic markers and Runt-related transcription factor 2 and with the appearance of a mature phenotype. Galectin-3 is expressed also by osteocytes, though its function in these cells has not been fully elucidated. The effects of galectin-3 on bone cells were also investigated in galectin-3 null mice, further supporting its role in all stages of bone biology, from development to remodeling. Galectin-3 was also shown to act as a receptor for advanced glycation endproducts, which have been implicated in age-dependent and diabetes-associated bone fragility. Moreover, its regulatory role in inflammatory bone and joint disorders entitles galectin-3 as a possible therapeutic target. Finally, galectin 3 capacity to commit mesenchymal stem cells to the osteoblastic lineage and to favor transdifferentiation of vascular smooth muscle cells into an osteoblast like phenotype open a new area of interest in bone and vascular pathologies. PMID- 29160799 TI - [-25]A Similarity Analysis of Audio Signal to Develop a Human Activity Recognition Using Similarity Networks. AB - Human Activity Recognition (HAR) is one of the main subjects of study in the areas of computer vision and machine learning due to the great benefits that can be achieved. Examples of the study areas are: health prevention, security and surveillance, automotive research, and many others. The proposed approaches are carried out using machine learning techniques and present good results. However, it is difficult to observe how the descriptors of human activities are grouped. In order to obtain a better understanding of the the behavior of descriptors, it is important to improve the abilities to recognize the human activities. This paper proposes a novel approach for the HAR based on acoustic data and similarity networks. In this approach, we were able to characterize the sound of the activities and identify those activities looking for similarity in the sound pattern. We evaluated the similarity of the sounds considering mainly two features: the sound location and the materials that were used. As a result, the materials are a good reference classifying the human activities compared with the location. PMID- 29160800 TI - Study and Validation of Eavesdropping Scenarios over a Visible Light Communication Channel. AB - The security and privacy provided by Visible Light Communication (VLC) technologies is an area that has been slightly addressed due to the misconception that, since light does not go through solid objects like walls, VLC-based communications cannot be eavesdropped on by outside observers. As an upcoming technology, VLC is expected to be used in multiple environments were, due to radio frequency RF overuse or limitations, RF solutions cannot or should not be employed. In this work, we study the eavesdropping characteristics of a VLC-based communication. To evaluate these concerns, a two-step process was followed. First, several simulations of a standardly used scenario were run. Later on, experimental tests were performed. Following those tests, the results of the simulations and the experimental tests were analyzed. The results of these simulations and tests seemed to indicate that VLC channels can be eavesdropped on without considerable difficulties. Furthermore, the results showed that sniffing attacks could be performed from areas outside the expected coverage of the VLC infrastructure. Finally, the use of the simulation such as the one implemented in this work to recognize places from which sniffing is possible helps determine the risk for eavesdropping that our VLC-based network has. PMID- 29160798 TI - Selectivity/Specificity Improvement Strategies in Surface-Enhanced Raman Spectroscopy Analysis. AB - Surface-enhanced Raman spectroscopy (SERS) is a powerful technique for the discrimination, identification, and potential quantification of certain compounds/organisms. However, its real application is challenging due to the multiple interference from the complicated detection matrix. Therefore, selective/specific detection is crucial for the real application of SERS technique. We summarize in this review five selective/specific detection techniques (chemical reaction, antibody, aptamer, molecularly imprinted polymers and microfluidics), which can be applied for the rapid and reliable selective/specific detection when coupled with SERS technique. PMID- 29160801 TI - The Protective Effects of Astaxanthin on the OVA-Induced Asthma Mice Model. AB - Although astaxanthin has a variety of biological activities such as anti-oxidant effects, inhibitory effects on skin deterioration and anti-inflammatory effects, its effect on asthma has not been studied. In this paper, the inhibitory effect of astaxanthin on airway inflammation in a mouse model of ovalbumin (OVA)-induced asthma was investigated. We evaluated the number of total cells, Th1/2 mediated inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and airway hyperresponsiveness as well as histological structure. The level of total IgE, IgG1, IgG2a, OVA-specific IgG1, and OVA-specific IgG2a were also examined. The oral administration of 50 mg/mL astaxanthin inhibited the respiratory system resistance, elastance, newtonian resistance, tissue damping, and tissue elastance. Also, astaxanthin suppressed the total cell number, IL-4, and IL-5, and increased the IFN-gamma in the BALF. In the sera, total IgE, IgG1, and OVA specific IgG1 were reduced by astaxanthin exposure and IgG2a and OVA-specific IgG2a were enhanced via oral administration of astaxanthin. Infiltration of inflammatory cells in the lung, production of mucus, lung fibrosis, and expression of caspase-1 or caspase-3 were suppressed in OVA-induced asthmatic animal treated with astaxanthin. These results suggest that astaxanthin may have therapeutic potential for treating asthma via inhibiting Th2-mediated cytokine and enhancing Th1-mediated cytokine. PMID- 29160802 TI - Modification of the Selectivity Properties of Tubular Ceramic Membranes after Alkaline Treatment. AB - This work focuses on the selectivity modification of ceramic membranes after a mild alkaline treatment. Filtration of pure salt-water solutions was carried out with commercial titania membranes before and after the treatment. After treatment, the rejection of NaF significantly decreased, while the rejection of NaCl and NaBr increased. Additionally, NaI and Na2SO4 remained close to zero. Pore size and electrical charge being almost unchanged, only significant modifications in the dielectric effects can explain this modification of selectivity. Therefore, the surface chemistry and the interaction (nature and magnitude) with the solvent and with the species present in the solution appear to be modified by the alkaline treatment. This trend is also illustrated by discussing the electric and the dielectric properties that were numerically identified before and after treatment. The alkaline treatment significantly decreased the apparent dielectric constant of NaCl-water solution in the pore, highlighting the rejection of sodium chloride. Contrariwise, the modification of the surface chemistry increased the apparent dielectric constant of NaF-water solution by promoting fluoride transmission. PMID- 29160803 TI - Solution Growth of Two-Dimensional Bi2Se3 Nanosheets for Two-Color All-Optical Switching. AB - Two-dimensional Bi2Se3 nanosheets with hexagonal shape are synthesized by a solution synthetic route. The Bi2Se3 nanosheets are 120 nm in edge width and 7 nm in thickness. The size of the Bi2Se3 nanosheets can be controlled by choosing different kinds of reducing agents including hydroxylamine and ethylenediamine. Subsequently, we demonstrate a configuration of two-color all-optical switching based on plasma channels effect using the as-synthesized Bi2Se3 nanosheets as an optical media. The signal light can be modulated as two states including dot and ring shape by changing the intensity of control light. The modulated signal light exhibits excellent spatial propagation properties. As a type of interesting optical material, ultrathin two-dimensional Bi2Se3 nanosheets might provide an effective option for photoelectric applications. PMID- 29160804 TI - Residual Endodontic Filling Material after Post Space Preparation: A Confocal Microscopic Study. AB - This laboratory study assessed removability of endodontic alkaline cements and resin sealers using coronal cross-sectional slices of roots with single canals. Materials were labelled with 0.1% (w/w) sodium fluorescein prior to mixing so that confocal microscopy could be used to quantify material remaining on the walls of post spaces, to assess cleanliness. Roots of extracted teeth were prepared using rotary NiTi instruments then obturated using lateral condensation with gutta percha and epoxy resin sealers (AH-PlusTM or ZirmixTM), or were filled by injecting mineral trioxide aggregate (MTA) cement (GC NexTM MTA or MTAmixTM) or a hard-setting calcium hydroxide cement (SupercalTM). Brown (#3) ParaPostTM drills were used at 600 rpm with a torque setting of 3 N cm-1 for 2 min to remove 5 mm of the root filling. Roots were embedded and coronal slices examined by confocal microscopy, with the perimeter of the drill channel divided into clean, unclean and non-accessible regions. The choice of material affects cleanliness, with MTA being the most difficult and calcium hydroxide cement the easiest to remove. With epoxy resin-based sealers, almost half of the accessible canal walls remained coated with remnants of sealer after post space preparation. PMID- 29160805 TI - Indole-3-Butyric Acid Induces Ectopic Formation of Metaxylem in the Hypocotyl of Arabidopsis thaliana without Conversion into Indole-3-Acetic Acid and with a Positive Interaction with Ethylene. AB - The role of the auxins indole-3-acetic acid (IAA) and indole-3-butyric acid (IBA) and of the auxin-interacting phytohormone ethylene, on the ectopic formation of primary xylem (xylogenesis in planta) is still little known. In particular, auxin/ethylene-target tissue(s), modality of the xylary process (trans differentiation vs. de novo formation), and the kind of ectopic elements formed (metaxylem vs. protoxylem) are currently unknown. It is also unclear whether IBA may act on the process independently of conversion into IAA. To investigate these topics, histological analyses were carried out in the hypocotyls of Arabidopsis wild type seedlings and ech2ibr10 and ein3eil1 mutants, which are blocked in IBA to-IAA conversion and ethylene signalling, respectively. The seedlings were grown under darkness with either IAA or IBA, combined or not with the ethylene precursor 1-aminocyclopropane-1-carboxylic acid. Adventitious root formation was also investigated because this process may compete with xylogenesis. Our results show that ectopic formation of protoxylem and metaxylem occurred as an indirect process starting from the pericycle periclinal derivatives of the hypocotyl basal part. IAA favoured protoxylem formation, whereas IBA induced ectopic metaxylem with ethylene cooperation through the EIN3EIL1 network. Ectopic metaxylem differentiation occurred independently of IBA-to-IAA conversion as mediated by ECH2 and IBR10, and in the place of IBA-induced adventitious root formation. PMID- 29160806 TI - Synthesis of Nitrogen Heterocycles Using Samarium(II) Iodide. AB - Nitrogen heterocycles represent vital structural motifs in biologically-active natural products and pharmaceuticals. As a result, the development of new, convenient and more efficient processes to N-heterocycles is of great interest to synthetic chemists. Samarium(II) iodide (SmI2, Kagan's reagent) has been widely used to forge challenging C-C bonds through reductive coupling reactions. Historically, the use of SmI2 in organic synthesis has been focused on the construction of carbocycles and oxygen-containing motifs. Recently, significant advances have taken place in the use of SmI2 for the synthesis of nitrogen heterocycles, enabled in large part by the unique combination of high reducing power of this reagent (E1/2 of up to -2.8 V) with excellent chemoselectivity of the reductive umpolung cyclizations mediated by SmI2. In particular, radical cross-coupling reactions exploiting SmI2-induced selective generation of aminoketyl radicals have emerged as concise and efficient methods for constructing 2-azabicycles, pyrrolidines and complex polycyclic barbiturates. Moreover, a broad range of novel processes involving SmI2-promoted formation of aminyl radicals have been leveraged for the synthesis of complex nitrogen containing molecular architectures by direct and tethered pathways. Applications to the synthesis of natural products have highlighted the generality of processes and the intermediates accessible with SmI2. In this review, recent advances involving the synthesis of nitrogen heterocycles using SmI2 are summarized, with a major focus on reductive coupling reactions that enable one-step construction of nitrogen-containing motifs in a highly efficient manner, while taking advantage of the spectacular selectivity of the venerable Kagan's reagent. PMID- 29160807 TI - Entamoeba histolytica under Oxidative Stress: What Countermeasure Mechanisms Are in Place? AB - Entamoeba histolytica is the causative agent of human amoebiasis; it affects 50 million people worldwide and causes approximately 100,000 deaths per year. Entamoeba histolytica is an anaerobic parasite that is primarily found in the colon; however, for unknown reasons, it can become invasive, breaching the gut barrier and migrating toward the liver causing amoebic liver abscesses. During the invasive process, it must maintain intracellular hypoxia within the oxygenated human tissues and cellular homeostasis during the host immune defense attack when it is confronted with nitric oxide and reactive oxygen species. But how? This review will address the described and potential mechanisms available to counter the oxidative stress generated during invasion and the possible role that E. histolytica's continuous endoplasmic reticulum (Eh-ER) plays during these events. PMID- 29160808 TI - Interplay between Colistin Resistance, Virulence and Fitness in Acinetobacter baumannii. AB - Acinetobacter baumannii is an important opportunistic nosocomial pathogen often resistant to multiple antibiotics classes. Colistin, an "old" antibiotic, is now considered a last-line treatment option for extremely resistant isolates. In the meantime, resistance to colistin has been reported in clinical A. baumannii strains. Colistin is a cationic peptide that disrupts the outer membrane (OM) of Gram-negative bacteria. Colistin resistance is primarily due to post translational modification or loss of the lipopolysaccharide (LPS) molecules inserted into the outer leaflet of the OM. LPS modification prevents the binding of polymyxin to the bacterial surface and may lead to alterations in bacterial virulence. Antimicrobial pressure drives the evolution of antimicrobial resistance and resistance is often associated with a reduced bacterial fitness. Therefore, the alterations in LPS may induce changes in the fitness of A. baumannii. However, compensatory mutations in clinical A. baumannii may ameliorate the cost of resistance and may play an important role in the dissemination of colistin-resistant A. baumannii isolates. The focus of this review is to summarize the colistin resistance mechanisms, and understand their impact on the fitness and virulence of bacteria and on the dissemination of colistin-resistant A. baumannii strains. PMID- 29160809 TI - Evaluation of Dietary Intakes and Supplement Use in Paralympic Athletes. AB - Dietary intakes and supplement use in Paralympic athletes remains largely unexplored, and specialized recommendations are lacking. The aim of this study was to evaluate nutrient intakes and supplement use in high-performance athletes with physical disabilities using three-day food records and a validated dietary supplement use questionnaire. A secondary aim examined gender differences in nutrient and supplement intakes. Male (n = 18) and female (n = 22) athletes were recruited from nine Paralympic sports through sporting organizations, coaches, and social media. Athletes generally met able-bodied recommendations for macronutrients. Male and female athletes often failed to meet the Recommended Dietary Allowance (RDA) or Adequate Intake (AI) for vitamin D, vitamin E, pantothenic acid, magnesium, and potassium. On average, females did not meet the RDA for iron and calcium, whereas males did not meet the RDA for vitamin A and folate. Commonly consumed supplements were vitamin D, protein powder, sport bars, and sport drinks. Analysis of diet and supplement use within this population shows several micronutrient deficiencies and irregular use of specific supplements. Athlete support and education is required to optimize nutrition in Paralympic athletes. PMID- 29160810 TI - Towards More Nuanced Classification of NGOs and Their Services to Improve Integrated Planning across Disaster Phases. AB - Nongovernmental organizations (NGOs) are being integrated into U.S. strategies to expand the services that are available during health security threats like disasters. Identifying better ways to classify NGOs and their services could optimize disaster planning. We surveyed NGOs about the types of services they provided during different disaster phases. Survey responses were used to categorize NGO services as core-critical to fulfilling their organizational mission-or adaptive-services implemented during a disaster based on community need. We also classified NGOs as being core or adaptive types of organizations by calculating the percentage of each NGO's services classified as core. Service types classified as core were mainly social services, while adaptive service types were those typically relied upon during disasters (e.g., warehousing, food services, etc.). In total, 120 NGOs were classified as core organizations, meaning they mainly provided the same services across disaster phases, while 100 NGOs were adaptive organizations, meaning their services changed. Adaptive NGOs were eight times more likely to report routinely participating in disaster planning as compared to core NGOs. One reason for this association may be that adaptive NGOs are more aware of the changing needs in their communities across disaster phases because of their involvement in disaster planning. PMID- 29160811 TI - Relationships between Vacant Homes and Food Swamps: A Longitudinal Study of an Urban Food Environment. AB - Research indicates that living in neighborhoods with high concentrations of boarded-up vacant homes is associated with premature mortality due to cancer and diabetes, but the mechanism for this relationship is unclear. Boarded-up housing may indirectly impact residents' health by affecting their food environment. We evaluated the association between changes in vacancy rates and changes in the density of unhealthy food outlets as a proportion of all food outlets, termed the food swamp index, in Baltimore, MD (USA) from 2001 to 2012, using neighborhood fixed-effects linear regression models. Over the study period, the average food swamp index increased from 93.5 to 95.3 percentage points across all neighborhoods. Among non-African American neighborhoods, increases in the vacancy rate were associated with statistically significant decreases in the food swamp index (b = -0.38; 90% CI, -0.64 to -0.12; p-value: 0.015), after accounting for changes in neighborhood SES, racial diversity, and population size. A positive association was found among low-SES neighborhoods (b = 0.15; 90% CI, 0.037 to 0.27; p-value: 0.031). Vacant homes may influence the composition of food outlets in urban neighborhoods. Future research should further elucidate the mechanisms by which more distal, contextual factors, such as boarded-up vacant homes, may affect food choices and diet-related health outcomes. PMID- 29160812 TI - Micro-Droplet Detection Method for Measuring the Concentration of Alkaline Phosphatase-Labeled Nanoparticles in Fluorescence Microscopy. AB - This paper developed and evaluated a quantitative image analysis method to measure the concentration of the nanoparticles on which alkaline phosphatase (AP) was immobilized. These AP-labeled nanoparticles are widely used as signal markers for tagging biomolecules at nanometer and sub-nanometer scales. The AP-labeled nanoparticle concentration measurement can then be directly used to quantitatively analyze the biomolecular concentration. Micro-droplets are mono dispersed micro-reactors that can be used to encapsulate and detect AP-labeled nanoparticles. Micro-droplets include both empty micro-droplets and fluorescent micro-droplets, while fluorescent micro-droplets are generated from the fluorescence reaction between the APs adhering to a single nanoparticle and corresponding fluorogenic substrates within droplets. By detecting micro-droplets and calculating the proportion of fluorescent micro-droplets to the overall micro droplets, we can calculate the AP-labeled nanoparticle concentration. The proposed micro-droplet detection method includes the following steps: (1) Gaussian filtering to remove the noise of overall fluorescent targets, (2) a contrast-limited, adaptive histogram equalization processing to enhance the contrast of weakly luminescent micro-droplets, (3) an red maximizing inter-class variance thresholding method (OTSU) to segment the enhanced image for getting the binary map of the overall micro-droplets, (4) a circular Hough transform (CHT) method to detect overall micro-droplets and (5) an intensity-mean-based thresholding segmentation method to extract the fluorescent micro-droplets. The experimental results of fluorescent micro-droplet images show that the average accuracy of our micro-droplet detection method is 0.9586; the average true positive rate is 0.9502; and the average false positive rate is 0.0073. The detection method can be successfully applied to measure AP-labeled nanoparticle concentration in fluorescence microscopy. PMID- 29160813 TI - Homoeologous Recombination of the V1r1-V1r2 Gene Cluster of Pheromone Receptors in an Allotetraploid Lineage of Teleosts. AB - In contrast to other olfactory receptor families that exhibit frequent lineage specific expansions, the vomeronasal type 1 receptor (V1R) family exhibits a canonical six-member repertoire in teleosts. V1r1 and V1r2 are present in no more than one copy in all examined teleosts, including salmons, which are ancient polyploids, implying strict evolutionary constraints. However, recent polyploids have not been examined. Here, we identified a young allotetraploid lineage of weatherfishes and investigated their V1r1-V1r2 cluster. We found a novel pattern that the parental V1r1-V1r2 clusters had recombined in the tetraploid genome and that the recombinant was nearly fixed in the tetraploid population. Subsequent analyses suggested strong selective pressure, for both a new combination of paralogs and homogeneity among gene duplicates, acting on the V1r1-V1r2 pair. PMID- 29160814 TI - Using Twitter to Explore (un)Healthy Housing: Learning from the #Characterbuildings Campaign in New Zealand. AB - While increasingly used for research, Twitter remains largely untapped as a source of data about housing. We explore the growth of social media and use of Twitter in health and social research, and question why housing researchers have avoided using Twitter to explore housing issues to date. We use the #characterbuildings campaign, initiated by an online media platform in New Zealand in 2014 to illustrate that Twitter can provide insights into housing as a public health and social problem. We find that Twitter users share details of problems with past and present homes on this public platform, and that this readily available data can contribute to the case for improving building quality as a means of promoting public health. Moreover, the way people responded to the request to share details about their housing experiences provides insight into how New Zealanders conceive of housing problems. PMID- 29160815 TI - Assessment of Bifidobacterium Species Using groEL Gene on the Basis of Illumina MiSeq High-Throughput Sequencing. AB - The next-generation high-throughput sequencing techniques have introduced a new way to assess the gut's microbial diversity on the basis of 16S rRNA gene-based microbiota analysis. However, the precise appraisal of the biodiversity of Bifidobacterium species within the gut remains a challenging task because of the limited resolving power of the 16S rRNA gene in different species. The groEL gene, a protein-coding gene, evolves quickly and thus is useful for differentiating bifidobacteria. Here, we designed a Bifidobacterium-specific primer pair which targets a hypervariable sequence region within the groEL gene that is suitable for precise taxonomic identification and detection of all recognized species of the genus Bifidobacterium so far. The results showed that the novel designed primer set can specifically differentiate Bifidobacterium species from non-bifidobacteria, and as low as 104 cells of Bifidobacterium species can be detected using the novel designed primer set on the basis of Illumina Miseq high-throughput sequencing. We also developed a novel protocol to assess the diversity of Bifidobacterium species in both human and rat feces through high-throughput sequencing technologies using groEL gene as a discriminative marker. PMID- 29160816 TI - Optimization of Goat Milk with ACE Inhibitory Peptides Fermented by Lactobacillus bulgaricus LB6 Using Response Surface Methodology. AB - In the present study, the incubation conditions of goat milk fermented by Lactobacillus bulgaricus LB6 were optimized to increase the angiotensin converting enzyme (ACE, EC 3.4.15.1) inhibitory activity by Box-Behnken design of response surface methodology. Incubation temperature, whey powder, and calcium lactate had significant effects on ACE inhibition rate and viable counts of LB6 during incubation. The results showed that optimal conditions of fermentation were found to be 37.05 degrees C, 0.8% (w/w) whey powder and 0.50% (w/w) calcium lactate. ACE inhibition rate increased significantly from 71.04 +/- 0.37% to 83.31 +/- 0.45% and the viable counts of Lactobacillus bulgaricus LB6 reached to 8.03 * 107 cfu.mL-1 under the optimal conditions, which approached the predicted values 83.25% and 8.04 * 107 cfu.mL-1. The optimal fermentation conditions can be a good reference for preparing ACE inhibitory peptides from goat milk. PMID- 29160817 TI - Impact of High-Dose Multi-Strain Probiotic Supplementation on Neurocognitive Performance and Central Nervous System Immune Activation of HIV-1 Infected Individuals. AB - BACKGROUND: Gut microbiota has metabolic activity which influences mucosal homeostasis, local and systemic immune responses, and other anatomical systems (i.e., brain). The effects of dysbiosis are still poorly studied in Human Immunodeficiency Virus-1 (HIV-1) positive subjects and insufficient data are available on the impairment of the gut-brain axis, despite neurocognitive disorders being commonly diagnosed in these patients. This study evaluated the impact of a probiotic supplementation strategy on intrathecal immune activation and cognitive performance in combined antiretroviral therapy (cART) treated HIV-1 infected subjects. METHODS: Thirty-five HIV-1 infected individuals were included in this study. At baseline (T0) a battery of tests was administered, to evaluate neurocognitive function and a lumbar puncture was performed to determine neopterin concentration in cerebrospinal fluid (CSF), as a marker of Central Nervous System (CNS) immune activation. Subsequently, a subgroup of participants underwent a 6-month course of multi-strain probiotics supplementation; this intervention group was evaluated, after probiotic treatment, with a second lumbar puncture and with repeated neurocognitive tests. RESULTS: At T0, all participants showed impaired results in at least one neurocognitive test and elevated neopterin concentrations in CSF. After supplementation with probiotics (T6), the interventional group presented a significant decrease in neopterin concentration and a significant improvement in several neurocognitive tests. In contrast, no significant modifications were observed in the neurocognitive performance of controls between T0 and T6. The CNS Penetration Effectiveness Score of antiretroviral therapy did not show an influence from any of the investigated variables. CONCLUSIONS: Multi-strain probiotic supplementation seems to exert a positive effect on neuroinflammation and neurocognitive impairment in HIV-1 infected subjects, but large trials are needed to support the concept that modulation of the gut microbiota can provide specific neurological benefits in these patients. PMID- 29160818 TI - Effect of Different Skin Penetration Promoters in Halobetasol Propionate Permeation and Retention in Human Skin. AB - Halobetasol propionate (HB) is a potent synthetic corticosteroid used against inflammatory skin diseases, such as dermatitis, eczema, and psoriasis, among others. The aim of this study is to define how the presence of different skin penetration enhancers (nonane, menthone, limonene, azone, carene, decanol, linoleic acid and cetiol) affects the penetration and retention in skin of HB. To determine drug penetration through skin, 5% of each promoter was used in an ex vivo system with human skin on Franz cells. The results showed that the highest permeation occurs in the presence of menthone, followed by nonane. Permeation parameters were determined. The in vivo test was assessed, and the formulation containing HB-menthone presented better anti-inflammatory efficacy. These results are useful to generate a specific treatment according to each patient's needs, and the inflammatory characteristics of the disease. PMID- 29160819 TI - Physical Fighting and Associated Factors among Adolescents Aged 13-15 Years in Six Western Pacific Countries. AB - Youth violence is an important public health challenge around the world, yet the literature on this problem in low- and middle-income countries (LMICs) has been limited. The present study aims to examine the prevalence of adolescent physical fighting (defined as having been involved in at least one physical fight during the past 12 months) in selected LMICs, and its relations with potential risk factors. We included 6377 school-going adolescents aged 13-15 years from six Western Pacific (WP) countries that had recently conducted a Global School-based Student Health Survey. Information was gathered through a self-administered anonymous closed-ended questionnaire. The prevalence of adolescent physical fighting varied across countries, ranging from 34.5% in Kiribati to 63.3% in Samoa. The prevalence was higher in boys than in girls, and lower at age 15 than 13-14 years. Physical fighting was significantly associated (pooled odds ratios (ORs), 95% confidence intervals (CIs)) with smoking (1.78, 1.53-2.06), drinking (1.57, 1.33-1.85), drug use (1.72, 1.33-2.23), and missing school (1.72, 1.51 1.95). The association with physical fighting increased with increasing number of joint adverse behaviors (increased from 1.99 (1.73-2.29) for one risk behavior to 4.95 (4.03-6.07) for at least 3 risk behaviors, versus having none of the 4 risk behaviors). The high prevalence of physical fighting and the associations with risk behaviors emphasize the need for comprehensive prevention programs to reduce youth violence and associated risk behaviors. PMID- 29160820 TI - Ergostane-Type Sterols from King Trumpet Mushroom (Pleurotus eryngii) and Their Inhibitory Effects on Aromatase. AB - Two new ergostane-type sterols; (22E)-5alpha,6alpha-epoxyergosta-8,14,22-triene 3beta,7beta-diol (1) and 5alpha,6alpha-epoxyergost-8(14)-ene-3beta,7alpha-diol (2) were isolated from the fruiting bodies of king trumpet mushroom (Pleurotus eryngii), along with eight known compounds (3-10). All isolated compounds were evaluated for their inhibitory effects on aromatase. Among them, 4 and 6 exhibited comparable aromatase inhibitory activities to aminoglutethimide. PMID- 29160821 TI - A Portable Stiffness Measurement System. AB - A new stiffness measurement method is proposed that utilizes the lateral deformation profile of an object under indentation. The system consists of a force measurement module between a pair of equidistant touch sensing modules. Unique feature of the method is that by adjusting the touch module separation, indenter protrusion, and spring constant of the force sensing module, one can choose a desired sensing range for the force module. This feature helps to enhance the stiffness differentiation between objects of similar hardness and avoids measurement saturation. We devised a portable measurement system based on the method, and tested its performance with several materials including polymer foams and human skin. PMID- 29160822 TI - How Secondary and Tertiary Amide Moieties are Molecular Stations for Dibenzo-24 crown-8 in [2]Rotaxane Molecular Shuttles? AB - Interlocked molecular machines like [2]rotaxanes are intriguing aesthetic molecules. The control of the localization of the macrocycle, which surrounds a molecular axle, along the thread leads to translational isomers of very different properties. Although many moieties have been used as sites of interactions for crown ethers, the very straightforwardly obtained amide motif has more rarely been envisaged as molecular station. In this article, we report the use of secondary and tertiary amide moieties as efficient secondary molecular station in pH-sensitive molecular shuttles. Depending on the N-substitution of the amide station, and on deprotonation or deprotonation-carbamoylation, the actuation of the molecular machinery differs accordingly to very distinct interactions between the axle and the DB24C8. PMID- 29160823 TI - In-Doped ZnO Hexagonal Stepped Nanorods and Nanodisks as Potential Scaffold for Highly-Sensitive Phenyl Hydrazine Chemical Sensors. AB - Herein, we report the growth of In-doped ZnO (IZO) nanomaterials, i.e., stepped hexagonal nanorods and nanodisks by the thermal evaporation process using metallic zinc and indium powders in the presence of oxygen. The as-grown IZO nanomaterials were investigated by several techniques in order to examine their morphological, structural, compositional and optical properties. The detailed investigations confirmed that the grown nanomaterials, i.e., nanorods and nanodisks possess well-crystallinity with wurtzite hexagonal phase and grown in high density. The room-temperature PL spectra exhibited a suppressed UV emissions with strong green emissions for both In-doped ZnO nanomaterials, i.e., nanorods and nanodisks. From an application point of view, the grown IZO nanomaterials were used as a potential scaffold to fabricate sensitive phenyl hydrazine chemical sensors based on the I-V technique. The observed sensitivities of the fabricated sensors based on IZO nanorods and nanodisks were 70.43 MUA.mM-1 cm-2 and 130.18 MUA.mM-1 cm-2, respectively. For both the fabricated sensors, the experimental detection limit was 0.5 MUM, while the linear range was 0.5 MUM-5.0 mM. The observed results revealed that the simply grown IZO nanomaterials could efficiently be used to fabricate highly sensitive chemical sensors. PMID- 29160824 TI - Microneedle-Assisted Percutaneous Delivery of a Tetramethylpyrazine-Loaded Microemulsion. AB - This study examined the efficacy of the percutaneous delivery of a tetramethylpyrazine-loaded microemulsion (TMP-ME) on skin pretreated with microneedles (MN). The TMP-ME formulation was optimized in vitro with skin permeation experiments, using a uniform experimental design, guided by a pseudo ternary phase diagram, in which the TMP skin permeation level and mean particle size were indices. The effects of MN pretreatment on skin permeation by TMP-ME were assessed using in vitro skin permeation, in vivo skin microdialysis, and pharmacokinetic studies in rats. The influence of MN pretreatment on the skin barrier function was evaluated by measuring the electrical resistance of rat skin before and after MN insertion. In the optimal formulation of TMP-ME, the weight percentages of Maisine(r) 35-1 (oil phase), Labrasol(r) (surfactant), and Transcutol(r) P (co-surfactant) were 7%, 30% and 10%, respectively, with 1.5% TMP loading. In the in vitro skin permeation study, MN-assisted TMP-ME exhibited a two-fold increase in a 24-h cumulative TMP permeation compared with TMP-ME alone (p < 0.05). In the skin microdialysis study, TMP in MN-assisted TMP-ME exhibited a 1.25-fold increase in Cmax, a 0.93-fold decrease in Tmax, and a 0.88-fold increase in AUC0-t (p < 0.05). Similarly, in the pharmacokinetic study, TMP in MN assisted TMP-ME exhibited a 2.11-fold increase in Cmax, a 0.67-fold decrease in Tmax, and a 1.07-fold increase in AUC0-t (p < 0.05). The percutaneous electrical resistance of rat skin before and after MN insertion was 850 +/- 50 Omega/cm2 and 283 +/- 104 Omega/cm2 respectively, indicating that MN dramatically compromises the skin barrier. These results suggest that MN assistance increases the skin permeation rate and the extent of percutaneous absorption of TMP-ME, and that the mechanism may involve the reversible barrier perturbation effect. The rate and extent of percutaneous absorption of TMP-ME can be significantly enhanced by MN assistance, possibly because MN causes a reversible barrier perturbation effect on skin. PMID- 29160825 TI - Theoretical Investigation of the Enantioselective Complexations between pfDHFR and Cycloguanil Derivatives. AB - Point mutations in Plasmodium falciparum dihydrofolate reductase (pfDHFR), especially the double mutant variant (A16V + S108T), led to ineffective inhibiting by cycloguanil (Cyc). Cycloguanil derivatives showed good inhibiting properties against wild-type and mutant pfDHFR with an inhibition constant as low as the nanomolar level. However, there have been no reports on the stereochemistry of the compounds, and this is important because the pure enantiomeric form of a chiral drug can exert desirable, as well as non-desirable responses on the body or both. In this work, three-dimensional structures of Cyc derivatives in R and S configuration were constructed and optimized using Hartree Fock/6-31G (d,p). Their structures were docked into the binding pocket of wild type and double mutant (A16V + S108T) pfDHFR, complexed with nicotinamide adenine dinucleotide phosphate (NADPH). Results indicate that both wild-type and mutant pfDHFR are enantioselective towards enantiomeric Cyc derivatives (R and S configuration). PMID- 29160826 TI - The Communication, Awareness, Relationships and Empowerment (C.A.R.E.) Model: An Effective Tool for Engaging Urban Communities in Community-Based Participatory Research. AB - Little is known about recruitment methods for racial/ethnic minority populations from resource-limited areas for community-based health and needs assessments, particularly assessments that incorporate mobile health (mHealth) technology for characterizing physical activity and dietary intake. We examined whether the Communication, Awareness, Relationships and Empowerment (C.A.R.E.) model could reduce challenges recruiting and retaining participants from faith-based organizations in predominantly African American Washington, D.C. communities for a community-based assessment. Employing C.A.R.E. model elements, our diverse research team developed partnerships with churches, health organizations, academic institutions and governmental agencies. Through these partnerships, we cultivated a visible presence at community events, provided cardiovascular health education and remained accessible throughout the research process. Additionally, these relationships led to the creation of a community advisory board (CAB), which influenced the study's design, implementation, and dissemination. Over thirteen months, 159 individuals were recruited for the study, 99 completed the initial assessment, and 81 used mHealth technology to self-monitor physical activity over 30 days. The culturally and historically sensitive C.A.R.E. model strategically engaged CAB members and study participants. It was essential for success in recruitment and retention of an at-risk, African American population and may be an effective model for researchers hoping to engage racial/ethnic minority populations living in urban communities. PMID- 29160827 TI - Organocatalytic Access to Enantioenriched Spirooxindole-Based 4 Methyleneazetidines. AB - This work describes the synthesis of enantioenriched spiro compounds, incorporating the azetidine and the oxindole motifs. The preparation relies on a formal [2 + 2] annulation reaction of isatin-derived N-tert-butylsulfonyl ketimines with allenoates. The asymmetric induction is secured by an organocatalytic strategy, exploiting a bifunctional cinchona-type beta isocupridine-based catalyst. Some post-transformation products, including unexpected spiropyrroline and 3,3-disubstituted oxindole derivatives, are also presented. PMID- 29160828 TI - Parent Cardiac Response in the Context of Their Child's Completion of the Cold Pressor Task: A Pilot Study. AB - Parents' ability to regulate their emotions is essential to providing supportive caregiving behaviours when their child is in pain. Extant research focuses on parent self-reported experience or observable behavioural responses. Physiological responding, such as heart rate (HR) and heart rate variability (HRV), is critical to the experience and regulation of emotions and provides a complementary perspective on parent experience; yet, it is scarcely assessed. This pilot study examined parent (n = 25) cardiac response (HR, HRV) at rest (neutral film clip), immediately before the cold pressor task (pre-CPT), and following the CPT (post-CPT). Further, variables that may influence changes in HR and HRV in the context of pediatric pain were investigated, including (1) initial HRV, and (2) parent perception of their child's typical response to needle procedures. Time-domain (root mean square of successive differences; RMSSD) and frequency-domain (high-frequency heart rate variability; HF-HRV) parameters of HRV were computed. HR and HF-HRV varied as a function of time block. Typical negative responses to needle pain related to higher parental HR and lower HRV at rest. Parents with higher HRV at baseline experienced the greatest decreases in HRV after the CPT. Consequently, considering previous experience with pain and resting HRV levels are relevant to understanding parent physiological responses before and after child pain. PMID- 29160829 TI - Spatiotemporal Distribution of U5MR and Their Relationship with Geographic and Socioeconomic Factors in China. AB - Epidemiological studies conducted around the world have reported that the under five mortality rate (U5MR) is closely associated with income and educational attainment. However, geographic elements should also remain a major concern in further improving child health issues, since they often play an important role in the survival environment. This study was undertaken to investigate the relationship between the U5MR, geographic, and socioeconomic factors, and to explore the associated spatial variance of the relationship in China using the geographically weighted regression (GWR) model. The results indicate that the space pattern of a high U5MR had been narrowed notably during the period from 2001 to 2010. Nighttime lights (NL) and the digital elevation model (DEM) both have obvious influences on the U5MR, with the NL having a negative impact and DEM having a positive impact. Additionally, the relationship between the NL and DEM varied over space in China. Moreover, the relevance between U5MR and DEM was narrowed in 2010 compared to 2001, which indicates that the development of economic and medical standards can overcome geographical limits. PMID- 29160830 TI - Warm Pre-Strain: Strengthening the Metastable 304L Austenitic Stainless Steel without Compromising Its Hydrogen Embrittlement Resistance. AB - Plastic pre-strains were applied to the metastable 304L austenitic stainless steel at both room temperature (20 degrees C) and higher temperatures (i.e., 50, 80 and 100 degrees C), and then the hydrogen embrittlement (HE) susceptibility of the steel was evaluated by cathodically hydrogen-charging and tensile testing. The 20 degrees C pre-strain greatly strengthened the steel, but simultaneously significantly increased the HE susceptibility of the steel, since alpha' martensite was induced by the pre-strain, causing the pre-existence of alpha' martensite, which provided "highways" for hydrogen to transport deep into the steel during the hydrogen-charging. Although the warm pre-strains did not strengthen the steel as significantly as the 20 degrees C pre-strain, they retained the HE resistance of the steel. This is because the higher temperatures, particularly 80 and 100 degrees C, suppressed the alpha' martensite transformation during the pre-straining. Pre-strain at a temperature slightly higher than room temperature has a potential to strengthen the metastable 304L austenitic stainless steel without compromising its initial HE resistance. PMID- 29160831 TI - A Novel Detection Method of Human Serum Albumin Based on the Poly(Thymine) Templated Copper Nanoparticles. AB - In this work, we developed a facile fluorescence method for quantitative detection of human serum albumin (HSA) based on the inhibition of poly(thymine) (poly T)-templated copper nanoparticles (CuNPs) in the presence of HSA. Under normal circumstances, poly T-templated CuNPs can display strong fluorescence with excitation/emission peaks at 340/610 nm. However, in the presence of HSA, it will absorb cupric ion, which will prevent the formation of CuNPs. As a result, the fluorescence intensity will become obviously lower in the presence of HSA. The analyte HSA concentration had a proportional linear relationship with the fluorescence intensity of CuNPs. The detection limit for HSA was 8.2 * 10-8 mol.L 1. Furthermore, it was also successfully employed to determine HSA in biological samples. Thus, this method has potential applications in point-of-care medical diagnosis and biomedical research. PMID- 29160832 TI - First Spaceborne SAR-GMTI Experimental Results for the Chinese Gaofen-3 Dual Channel SAR Sensor. AB - In spaceborne synthetic aperture radar (SAR) sensors, it is a challenging task to detect ground slow-moving targets against strong clutter background with limited spatial channels and restricted pulse repetition frequency (PRF). In this paper, we evaluate the image-based dual-channel SAR-ground moving target indication (SAR GMTI) workflow for the Gaofen-3 SAR sensor and analyze the impact of strong azimuth ambiguities on GMTI when the displaced phase center antenna (DPCA) condition is not fully satisfied, which has not been demonstrated yet. An effective sliding window design technique based on system parameters analysis is proposed to deal with azimuth ambiguities and reduce false alarm. In the SAR-GMTI experiments, co-registration, clutter suppression, constant false alarm rate (CFAR) detector, vector velocity estimation and moving target relocation are analyzed and discussed thoroughly. With the real measured data of the Gaofen-3 dual-channel SAR sensor, the GMTI capability of this sensor is demonstrated and the effectiveness of the proposed method is verified. PMID- 29160834 TI - Underlying Physics of Conductive Polymer Composites and Force Sensing Resistors (FSRs). A Study on Creep Response and Dynamic Loading. AB - Force Sensing Resistors (FSRs) are manufactured by sandwiching a Conductive Polymer Composite (CPC) between metal electrodes. The piezoresistive property of FSRs has been exploited to perform stress and strain measurements, but the rheological property of polymers has undermined the repeatability of measurements causing creep in the electrical resistance of FSRs. With the aim of understanding the creep phenomenon, the drift response of thirty two specimens of FSRs was studied using a statistical approach. Similarly, a theoretical model for the creep response was developed by combining the Burger's rheological model with the equations for the quantum tunneling conduction through thin insulating films. The proposed model and the experimental observations showed that the sourcing voltage has a strong influence on the creep response; this observation-and the corresponding model-is an important contribution that has not been previously accounted. The phenomenon of sensitivity degradation was also studied. It was found that sensitivity degradation is a voltage-related phenomenon that can be avoided by choosing an appropriate sourcing voltage in the driving circuit. The models and experimental observations from this study are key aspects to enhance the repeatability of measurements and the accuracy of FSRs. PMID- 29160833 TI - Taxon- and Site-Specific Melatonin Catabolism. AB - Melatonin is catabolized both enzymatically and nonenzymatically. Nonenzymatic processes mediated by free radicals, singlet oxygen, other reactive intermediates such as HOCl and peroxynitrite, or pseudoenzymatic mechanisms are not species- or tissue-specific, but vary considerably in their extent. Higher rates of nonenzymatic melatonin metabolism can be expected upon UV exposure, e.g., in plants and in the human skin. Additionally, melatonin is more strongly nonenzymatically degraded at sites of inflammation. Typical products are several hydroxylated derivatives of melatonin and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK). Most of these products are also formed by enzymatic catalysis. Considerable taxon- and site-specific differences are observed in the main enzymatic routes of catabolism. Formation of 6-hydroxymelatonin by cytochrome P450 subforms are prevailing in vertebrates, predominantly in the liver, but also in the brain. In pineal gland and non-mammalian retina, deacetylation to 5 methoxytryptamine (5-MT) plays a certain role. This pathway is quantitatively prevalent in dinoflagellates, in which 5-MT induces cyst formation and is further converted to 5-methoxyindole-3-acetic acid, an end product released to the water. In plants, the major route is catalyzed by melatonin 2-hydroxylase, whose product is tautomerized to 3-acetamidoethyl-3-hydroxy-5-methoxyindolin-2-one (AMIO), which exceeds the levels of melatonin. Formation and properties of various secondary products are discussed. PMID- 29160836 TI - An In Vitro Study of the Photodynamic Effectiveness of GO-Ag Nanocomposites against Human Breast Cancer Cells. AB - Graphene-based materials have garnered significant attention because of their versatile bioapplications and extraordinary properties. Graphene oxide (GO) is an extremely oxidized form of graphene accompanied by the functional groups of oxygen on its surface. GO is an outstanding platform on which to pacify silver nanoparticles (Ag NPs), which gives rise to the graphene oxide-silver nanoparticle (GO-Ag) nanocomposite. In this experimental study, the toxicity of graphene oxide-silver (GO-Ag) nanocomposites was assessed in an in vitro human breast cancer model to optimize the parameters of photodynamic therapy. GO-Ag was prepared using the hydrothermal method, and characterization was done by X-ray diffraction, field-emission scanning electron microscope (FE-SEM), transmission Electron Microscopy (TEM), energy dispersive X-rays Analysis (EDAX), atomic force microscopy and ultraviolet-visible spectroscopy. The experiments were done both with laser exposure, as well as in darkness, to examine the phototoxicity and cytotoxicity of the nanocomposites. The cytotoxicity of the GO-Ag was confirmed via a methyl-thiazole-tetrazolium (MTT) assay and intracellular reactive oxygen species production analysis. The phototoxic effect explored the dose-dependent decrease in the cell viability, as well as provoked cell death via apoptosis. An enormously significant escalation of 1O2 in the samples when exposed to daylight was perceived. Statistical analysis was performed on the experimental results to confirm the worth and clarity of the results, with p-values < 0.05 selected as significant. These outcomes suggest that GO-Ag nanocomposites could serve as potential candidates for targeted breast cancer therapy. PMID- 29160837 TI - Application of an Ultrafine Shearing Method for the Extraction of C-Phycocyanin from Spirulina platensis. AB - Cell disruption is an important step during the extraction of C-phycocyanin from Spirulina platensis. An ultrafine shearing method is introduced and combined with soaking and ultrasonication to disrupt the cell walls of S. platensis efficiently and economically. Five kinds of cell disruption method, including soaking, ultrasonication, freezing-thawing, soaking-ultrafine shearing and soaking ultrafine shearing-ultrasonication were applied to break the cell walls of S. platensis. The effectiveness of cell breaking was evaluated based on the yield of the C-phycocyanin. The results show that the maximum C-phycocyanin yield was 9.02%, achieved by the soaking-ultrafine shearing-ultrasonication method, followed by soaking (8.43%), soaking-ultrafine shearing (8.89%), freezing and thawing (8.34%), and soaking-ultrasonication (8.62%). The soaking-ultrafine shearing-ultrasonication method is a novel technique for breaking the cell walls of S. platensis for the extraction of C-phycocyanin. PMID- 29160838 TI - Symposium on Vitamin C, 15th September 2017; Part of the Linus Pauling Institute's 9th International Conference on Diet and Optimum Health. AB - The Linus Pauling Institute's 9th International Conference on Diet and Optimum Health took place on 13-15 September 2017 in Corvallis, OR, USA, on the beautiful Oregon State University campus [...]. PMID- 29160839 TI - Inkjet Printing of Drug-Loaded Mesoporous Silica Nanoparticles-A Platform for Drug Development. AB - Mesoporous silica nanoparticles (MSNs) have shown great potential in improving drug delivery of poorly water soluble (BCS class II, IV) and poorly permeable (BCS class III, IV) drugs, as well as facilitating successful delivery of unstable compounds. The nanoparticle technology would allow improved treatment by reducing adverse reactions of currently approved drugs and possibly reintroducing previously discarded compounds from the drug development pipeline. This study aims to highlight important aspects in mesoporous silica nanoparticle (MSN) ink formulation development for digital inkjet printing technology and to advice on choosing a method (2D/3D) for nanoparticle print deposit characterization. The results show that both unfunctionalized and polyethyeleneimine (PEI) surface functionalized MSNs, as well as drug-free and drug-loaded MSN-PEI suspensions, can be successfully inkjet-printed. Furthermore, the model BCS class IV drug remained incorporated in the MSNs and the suspension remained physically stable during the processing time and steps. This proof-of-concept study suggests that inkjet printing technology would be a flexible deposition method of pharmaceutical MSN suspensions to generate patterns according to predefined designs. The concept could be utilized as a versatile drug screening platform in the future due to the possibility of accurately depositing controlled volumes of MSN suspensions on various materials. PMID- 29160835 TI - Vitamin D and Neurological Diseases: An Endocrine View. AB - Vitamin D system comprises hormone precursors, active metabolites, carriers, enzymes, and receptors involved in genomic and non-genomic effects. In addition to classical bone-related effects, this system has also been shown to activate multiple molecular mediators and elicit many physiological functions. In vitro and in vivo studies have, in fact, increasingly focused on the "non-calcemic" actions of vitamin D, which are associated with the maintenance of glucose homeostasis, cardiovascular morbidity, autoimmunity, inflammation, and cancer. In parallel, growing evidence has recognized that a multimodal association links vitamin D system to brain development, functions and diseases. With vitamin D deficiency reaching epidemic proportions worldwide, there is now concern that optimal levels of vitamin D in the bloodstream are also necessary to preserve the neurological development and protect the adult brain. The aim of this review is to highlight the relationship between vitamin D and neurological diseases. PMID- 29160840 TI - Cloning and Molecular Characterization of an Alpha-Glucosidase (MalH) from the Halophilic Archaeon Haloquadratum walsbyi. AB - We report the heterologous expression and molecular characterization of the first extremely halophilic alpha-glucosidase (EC 3.2.1.20) from the archaeon Haloquadratum walsbyi. A 2349 bp region (Hqrw_2071) from the Hqr. walsbyi C23 annotated genome was PCR-amplified and the resulting amplicon ligated into plasmid pET28b(+), expressed in E. coli Rosetta cells, and the resulting protein purified by Ni-NTA affinity chromatography. The recombinant protein showed an estimated molecular mass of 87 kDa, consistent with the expected value of the annotated protein, and an optimal activity for the hydrolysis of alpha-PNPG was detected at 40 degrees C, and at pH 6.0. Enzyme activity values were the highest in the presence of 3 M NaCl or 3-4 M KCl. However, specific activity values were two-fold higher in the presence of 3-4 M KCl when compared to NaCl suggesting a cytoplasmic localization. Phylogenetic analyses, with respect to other alpha glucosidases from members of the class Halobacteria, showed that the Hqr. walsbyi MalH was most similar (up to 41%) to alpha-glucosidases and alpha-xylosidases of Halorubrum. Moreover, computational analyses for the detection of functional domains, active and catalytic sites, as well as 3D structural predictions revealed a close relationship with an E. coli YicI-like alpha-xylosidase of the GH31 family. However, the purified enzyme did not show alpha-xylosidase activity. This narrower substrate range indicates a discrepancy with annotations from different databases and the possibility of specific substrate adaptations of halophilic glucosidases due to high salinity. To our knowledge, this is the first report on the characterization of an alpha-glucosidase from the halophilic Archaea, which could serve as a new model to gain insights into carbon metabolism in this understudied microbial group. PMID- 29160842 TI - Environmental Exposure to Dioxins, Dibenzofurans, Bisphenol A, and Phthalates in Children with and without Autism Spectrum Disorder Living near the Gulf of Mexico. AB - Environmental exposure to organic endocrine disrupting chemicals, including dioxins, dibenzofurans, bisphenol A (BPA), and phthalates has been associated with neurodevelopmental disorders, including autism spectrum disorder (ASD). We conducted a pilot monitoring study of 30 ASD cases and 10 typically developing (TD) controls ages 2-8 years from communities along the Gulf of Mexico near Alabama, which houses 14 Superfund sites, to assess the concentrations of dioxins and dibenzofurans in serum, and BPA and phthalate ester metabolites in urine. Based on General Linear Models, the lipid- or creatinine-adjusted geometric mean concentrations of the aforementioned chemicals did not differ between the ASD case and TD control groups (all p >= 0.27). We compared our findings to the adjusted means as reported by the National Health and Nutrition Examination Survey, survey years 2011-2012, and found that TD controls in our study had lower BPA (59%) and MEHHP (26%) concentrations, higher MBP (50%) concentration, and comparable (<20% difference) MEP, MBZP, MEOHP, and MCPP concentrations. We also conducted a preliminary investigation of dietary exposures and found that the consumption of certain types of fish may be associated with higher OCDD concentrations, and the consumption of soft drinks and juices may be associated with lower BPA and MEOHP concentrations, respectively. PMID- 29160841 TI - The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update. AB - Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion. PMID- 29160843 TI - Public and Healthcare Professionals' Knowledge and Attitudes toward Binge Eating Disorder: A Narrative Review. AB - Binge eating disorder (BED) is characterized by recurrent binge eating and marked distress in the absence of inappropriate compensatory behaviors for weight control. BED is prevalent in men and women, is associated with elevated psychosocial and functional impairment, and is associated strongly with obesity and related medical comorbidities. The aim is to provide a brief, state-of-the art review of the major and recent findings to inform educational and awareness campaigns, stigma reduction interventions, as well as current clinical practice and future research. A narrative approach was used to synthesize emerging literature on the public and healthcare professionals' knowledge and attitudes toward individuals with BED in comparison to other eating disorders (EDs) or mental illness. A total of 13 articles were reviewed. Nine studies investigated community samples and four studies investigated healthcare professionals. The reviewed literature suggested that BED is perceived by the public as less impairing, less severe, and "easier-to-treat" than other EDs. Attitudes and beliefs reflecting perceived blameworthiness and lack of self-discipline were ascribed to vignettes with BED. Community studies indicated a low level of public awareness that BED constitutes a discreet eating disorder. The literature on healthcare professionals' knowledge and attitudes toward BED remains very limited. The few existing studies suggest encouraging trends in recognition and diagnostic accuracy, yet there remains a need for increased clinical awareness of BED-associated medical complications and knowledge of full BED diagnostic criteria. PMID- 29160844 TI - Altered Aconitase 2 Activity in Huntington's Disease Peripheral Blood Cells and Mouse Model Striatum. AB - Huntington's disease (HD) is caused by an unstable cytosine adenine guanine (CAG) trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin protein. Previously, we identified several up- and down-regulated protein molecules in the striatum of the Hdh(CAG)150 knock-in mice at 16 months of age, a mouse model which is modeling the early human HD stage. Among those molecules, aconitase 2 (Aco2) located in the mitochondrial matrix is involved in the energy generation and susceptible to increased oxidative stress that would lead to inactivation of Aco2 activity. In this study, we demonstrate decreased Aco2 protein level and activity in the brain of both Hdh(CAG)150 and R6/2 mice. Aco2 activity was decreased in striatum of Hdh(CAG)150 mice at 16 months of age as well as R6/2 mice at 7 to 13 weeks of age. Aco2 activity in the striatum of R6/2 mice could be restored by the anti-oxidant, N-acetyl-l-cysteine, supporting that decreased Aco2 activity in HD is probably caused by increased oxidative damage. Decreased Aco2 activity was further found in the peripheral blood mononuclear cells (PBMC) of both HD patients and pre-symptomatic HD mutation (PreHD) carriers, while the decreased Aco2 protein level of PBMC was only present in HD patients. Aco2 activity correlated significantly with motor score, independence scale, and functional capacity of the Unified Huntington's Disease Rating Scale as well as disease duration. Our study provides a potential biomarker to assess the disease status of HD patients and PreHD carriers. PMID- 29160845 TI - Vascular Endothelial Growth Factor Sequestration Enhances In Vivo Cartilage Formation. AB - Autologous chondrocyte transplantation for cartilage repair still has unsatisfactory clinical outcomes because of inter-donor variability and poor cartilage quality formation. Re-differentiation of monolayer-expanded human chondrocytes is not easy in the absence of potent morphogens. The Vascular Endothelial Growth Factor (VEGF) plays a master role in angiogenesis and in negatively regulating cartilage growth by stimulating vascular invasion and ossification. Therefore, we hypothesized that its sole microenvironmental blockade by either VEGF sequestration by soluble VEGF receptor-2 (Flk-1) or by antiangiogenic hyperbranched peptides could improve chondrogenesis of expanded human nasal chondrocytes (NC) freshly seeded on collagen scaffolds. Chondrogenesis of several NC donors was assessed either in vitro or ectopically in nude mice. VEGF blockade appeared not to affect NC in vitro differentiation, whereas it efficiently inhibited blood vessel ingrowth in vivo. After 8 weeks, in vivo glycosaminoglycan deposition was approximately two-fold higher when antiangiogenic approaches were used, as compared to the control group. Our data indicates that the inhibition of VEGF signaling, independently of the specific implementation mode, has profound effects on in vivo NC chondrogenesis, even in the absence of chondroinductive signals during prior culture or at the implantation site. PMID- 29160847 TI - Multifunctional Carbon Aerogels Derived by Sol-Gel Process of Natural Polysaccharides of Different Botanical Origin. AB - In this manuscript, we describe the results of our recent studies on carbon aerogels derived from natural starches. A facile method for the fabrication of carbon aerogels is presented. Moreover, the complete analysis of the carbonization process of different starch aerogels (potato, maize, and rice) was performed using thermogravimetric studies combined with a detailed analysis of evolved decomposition products. The prepared carbon aerogels were studied in terms of their morphology and electrical properties to relate the origin of starch precursor with final properties of carbon materials. The obtained results confirmed the differences in carbon aerogels' morphology, especially in materials' specific surface areas, depending on the botanical origin of precursors. The electrical conductivity measurements suggest that carbon aerogels with the best electrical properties can be obtained from potato starch. PMID- 29160846 TI - A Triphenylphosphonium-Functionalized Mitochondriotropic Nanocarrier for Efficient Co-Delivery of Doxorubicin and Chloroquine and Enhanced Antineoplastic Activity. AB - Drug delivery systems that target subcellular organelles and, in particular, mitochondria are considered to have great potential in treating disorders that are associated with mitochondrial dysfunction, including cancer or neurodegenerative diseases. To this end, a novel hyperbranched mitochondriotropic nanocarrier was developed for the efficient co-delivery of two different (both in chemical and pharmacological terms) bioactive compounds. The carrier is based on hyperbranched poly(ethyleneimine) functionalized with triphenylphosphonium groups that forms ~100 nm diameter nanoparticles in aqueous media and can encapsulate doxorubicin (DOX), a well-known anti-cancer drug, and chloroquine (CQ), a known chemosensitizer with arising potential in anticancer medication. The anticancer activity of this system against two aggressive DOX-resistant human prostate adenocarcinoma cell lines and in in vivo animal studies was assessed. The co administration of encapsulated DOX and CQ leads to improved cell proliferation inhibition at extremely low DOX concentrations (0.25 MUMU). In vivo experiments against DU145 human prostate cancer cells grafted on immunodeficient mice resulted in tumor growth arrest during the three-week administration period and no pervasive side effects. The findings put forward the potential of such targeted low dose combination treatments as a therapeutic scheme with minimal adverse effects. PMID- 29160848 TI - Application of Enzymatic Extracts from a CALB Standard Strain as Biocatalyst within the Context of Conventional Biodiesel Production Optimization. AB - The application of biocatalysts in the transesterification process of triglycerides (TG) allows integrating the glycerol in the form of monoglyceride (MG), sharply increasing the yield and the environmental sustainability of the conventional biodiesel production process. This is known as Ecodiesel. To overcome the inconvenient of the high cost of the currently employed highly purified commercial enzymes, the use of scarcely purified extracts obtained from standard strains of the same species of commercial lipases currently applied in this process is being investigated. Thus, Candidaantarctica type B (CALB) was chosen to determine the optimal conditions of culture of this yeast. The standard strain was obtained from the Spanish Type Microbial Cultures Collection (CECT) and has been used to carry out several studies to elucidate its optimum growth conditions. Through a process of lyophilization with prior dialysis of the liquid cultures, the enzymatic extracts were obtained. The different obtained cultures have been applied as biocatalysts in the 1,3-selective transesterification reaction of sunflower oil with ethanol to obtain Ecodiesel (FAEE + MG). Selectivity and reaction yields were obtained by gas chromatography. Acceptable yields are obtained during the reaction time as well as in successive reactions, demonstrating the feasibility of using these CALB enzymatic extracts as biocatalysts. PMID- 29160849 TI - Associations of Shift Work and Its Duration with Work-Related Injury among Electronics Factory Workers in South Korea. AB - This study aimed to explore the association between shift work and work-related injuries. We collected data on workers from an electronics factory. This cross sectional study included 13,610 subjects, who were assessed based on a self reported questionnaire about their shift work experiences, work-related injuries, and other covariates. Multiple logistic regression models were used to evaluate the associations between shift work and work-related injuries and were estimated using the odds ratio. We found that the current and past shift workers, compared to non-shift workers, were associated with a 2.7- and 1.7-fold higher risk of work-related injury. There was a dose-response relationship between shift work duration and work-related injury among current female shift workers. Shift work increased the risk of work-related injuries, and the impact could be different depending on gender. PMID- 29160850 TI - Analgesic Mechanisms of Antidepressants for Neuropathic Pain. AB - Tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors are used to treat chronic pain, such as neuropathic pain. Why antidepressants are effective for treatment of neuropathic pain and the precise mechanisms underlying their effects, however, remain unclear. The inhibitory effects of these antidepressants for neuropathic pain manifest more quickly than their antidepressive effects, suggesting different modes of action. Recent studies of animal models of neuropathic pain revealed that noradrenaline is extremely important for the inhibition of neuropathic pain. First, increasing noradrenaline in the spinal cord by reuptake inhibition directly inhibits neuropathic pain through alpha2-adrenergic receptors. Second, increasing noradrenaline acts on the locus coeruleus and improves the function of an impaired descending noradrenergic inhibitory system. Serotonin and dopamine may reinforce the noradrenergic effects to inhibit neuropathic pain. The mechanisms of neuropathic pain inhibition by antidepressants based mainly on experimental findings from animal models of neuropathic pain are discussed in this review. PMID- 29160851 TI - Development of An Impedimetric Aptasensor for the Detection of Staphylococcus aureus. AB - In combination with electrochemical impedance spectroscopy, aptamer-based biosensors are a powerful tool for fast analytical devices. Herein, we present an impedimetric aptasensor for the detection of the human pathogen Staphylococcus aureus. The used aptamer targets protein A, a surface bound virulence factor of S. aureus. The thiol-modified protein A-binding aptamer was co-immobilized with 6 mercapto-1-hexanol onto gold electrodes by self-assembly. Optimization of the ratio of aptamer to 6-mercapto-1-hexanol resulted in an average density of 1.01 +/- 0.44 * 1013 aptamer molecules per cm2. As shown with quartz crystal microbalance experiments, the immobilized aptamer retained its functionality to bind recombinant protein A. Our impedimetric biosensor is based on the principle that binding of target molecules to the immobilized aptamer decreases the electron transfer between electrode and ferri-/ferrocyanide in solution, which is measured as an increase of impedance. Microscale thermophoresis measurements showed that addition of the redox probe ferri-/ferrocyanide has no influence on the binding of aptamer and its target. We demonstrated that upon incubation with various concentrations of S. aureus, the charge-transfer resistance increased proportionally. The developed biosensor showed a limit of detection of 10 CFU.mL 1 and results were available within 10 minutes. The biosensor is highly selective, distinguishing non-target bacteria such as Escherichia coli and Staphylococcus epidermidis. This work highlights the immense potential of impedimetric aptasensors for future biosensing applications. PMID- 29160852 TI - The Complete Chloroplast Genome Sequences of Aconitum pseudolaeve and Aconitum longecassidatum, and Development of Molecular Markers for Distinguishing Species in the Aconitum Subgenus Lycoctonum. AB - Aconitum pseudolaeve Nakai and Aconitum longecassidatum Nakai, which belong to the Aconitum subgenus Lycoctonum, are distributed in East Asia and Korea. Aconitum species are used in herbal medicine and contain highly toxic components, including aconitine. A. pseudolaeve, an endemic species of Korea, is a commercially valuable material that has been used in the manufacture of cosmetics and perfumes. Although Aconitum species are important plant resources, they have not been extensively studied, and genomic information is limited. Within the subgenus Lycoctonum, which includes A. pseudolaeve and A. longecassidatum, a complete chloroplast (CP) genome is available for only one species, Aconitum barbatum Patrin ex Pers. Therefore, we sequenced the complete CP genomes of two Aconitum species, A. pseudolaeve and A. longecassidatum, which are 155,628 and 155,524 bp in length, respectively. Both genomes have a quadripartite structure consisting of a pair of inverted repeated regions (51,854 and 52,108 bp, respectively) separated by large single-copy (86,683 and 86,466 bp) and small single-copy (17,091 and 16,950 bp) regions similar to those in other Aconitum CP genomes. Both CP genomes consist of 112 unique genes, 78 protein-coding genes, 4 ribosomal RNA (rRNA) genes, and 30 transfer RNA (tRNA) genes. We identified 268 and 277 simple sequence repeats (SSRs) in A. pseudolaeve and A. longecassidatum, respectively. We also identified potential 36 species-specific SSRs, 53 indels, and 62 single-nucleotide polymorphisms (SNPs) between the two CP genomes. Furthermore, a comparison of the three Aconitum CP genomes from the subgenus Lycoctonum revealed highly divergent regions, including trnK-trnQ, ycf1-ndhF, and ycf4-cemA. Based on this finding, we developed indel markers using indel sequences in trnK-trnQ and ycf1-ndhF. A. pseudolaeve, A. longecassidatum, and A. barbatum could be clearly distinguished using the novel indel markers AcoTT (Aconitum trnK-trnQ) and AcoYN (Aconitum ycf1-ndhF). These two new complete CP genomes provide useful genomic information for species identification and evolutionary studies of the Aconitum subgenus Lycoctonum. PMID- 29160854 TI - Biomass-Derived Oxygen and Nitrogen Co-Doped Porous Carbon with Hierarchical Architecture as Sulfur Hosts for High-Performance Lithium/Sulfur Batteries. AB - In this work, a facile strategy to synthesize oxygen and nitrogen co-doped porous carbon (ONPC) is reported by one-step pyrolysis of waste coffee grounds. As prepared ONPC possesses highly rich micro/mesopores as well as abundant oxygen and nitrogen co-doping, which is applied to sulfur hosts as lithium/sulfur batteries' appropriate cathodes. In battery testing, the sulfur/oxygen and nitrogen co-doped porous carbon (S/ONPC) composite materials reveal a high initial capacity of 1150 mAh.g-1 as well as a reversible capacity of 613 mAh.g-1 after the 100th cycle at 0.2 C. Furthermore, when current density increases to 1 C, a discharge capacity of 331 mAh.g-1 is still attainable. Due to the hierarchical porous framework and oxygen/nitrogen co-doping, the S/ONPC composite exhibits a high utilization of sulfur and good electrochemical performance via the immobilization of the polysulfides through strong chemical binding. PMID- 29160853 TI - Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors. AB - Epstein-Barr virus (EBV) is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma) and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma). To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral lytic reactivation, modify cell cycle checkpoints, prevent apoptosis and evade immune surveillance. In this review, we aim to provide an overview of the mechanisms by which the virus manipulates the ubiquitin-proteasome system in EBV-associated lymphoid and epithelial malignancies, to evaluate the efficacy of proteasome inhibitors on the treatment of these cancers and discuss potential novel viral-targeted treatment strategies against the EBV-associated cancers. PMID- 29160855 TI - Effects of Red Palm Oil on Myocardial Antioxidant Enzymes, Nitric Oxide Synthase and Heart Function in Spontaneously Hypertensive Rats. AB - The purpose of this study was to investigate the effect of antioxidants rich red palm oil (RPO) supplementation on cardiac oxidative stress known as crucial factor deteriorating heart function in hypertension. 3-month-old, male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) were fed standard rat chow without or with RPO (0.2 mL/day/5 weeks). General characteristic of rats were registered. Left ventricular tissue (LV) was used to determine expression of superoxide dismutases (SOD1, SOD2) and glutathione peroxidases (Gpx) as well as activity of nitric oxide synthase (NOS). Functional parameters of the heart were examined during basal conditions and at the early phase of post-ischemic reperfusion using Langendorff-perfused system. RPO intake significantly reduced elevated blood pressure and total NOS activity as well as increased lowered expression of mitochondrial SOD2 in SHR hearts during basal condition. Moreover, RPO supplementation resulted in suppression of elevated heart rate, increase of reduced coronary flow and enhancement of systolic and diastolic heart function at the early-phase of post-ischemic reperfusion. It is concluded that SHR benefit from RPO intake due to decrease of blood pressure, amelioration of oxidative stress and protection of heart function that was deteriorated by post-ischemic reperfusion. PMID- 29160856 TI - Correction: S. Vogelgsang et al. Fusarium Mycotoxins in Swiss Wheat: A Survey of Growers' Samples between 2007 and 2014 Shows Strong Year and Minor Geographic Effects. Toxins 2017, 9, 246. PMID- 29160857 TI - Synergistic Effects of Danshen (Salvia Miltiorrhizae Radix et Rhizoma) and Sanqi (Notoginseng Radix et Rhizoma) Combination in Angiogenesis Behavior in EAhy 926 Cells. AB - Background: This study investigated the combination effects of the Danshen and Sanqi herb pair on angiogenesis in vitro. Methods: Nine combination ratios of Danshen-Sanqi extracts (DS-SQ) were screened for their angiogenic effects in the human vascular endothelial EAhy 926 cell line via cell proliferation, cell migration and tube formation activities against the damage to the cells exerted by DL-homocysteine (Hcy) and adenosine (Ado). The type of interaction (synergistic, antagonistic, additive) between Danshen and Sanqi was analyzed using combination index (CI) and isobologram models. The angiogenic activities of key bioactive compounds from Danshen and Sanqi were tested in the same models. Results: DS-SQ ratios of 2:8 and 3:7 (50-300 ug/mL) potentiated angiogenic synergistic effects (CI < 1) in all three assays. The observed wound healing effects of DS-SQ 2:8 was significantly attenuated by phosphatidylinositol-3 kinases (PI3K), mitogen-activated protein kinase (MEK) and extracellular signal regulated kinases (ERK) inhibitors which inferred the potential mechanistic pathways. Out of all the tested compounds, Notoginsenoside R1 from Sanqi exhibited the most potent bioactivity in cell proliferation assay. Conclusions: This study provides scientific evidence to support the traditional use of the Danshen-Sanqi combination for vascular disease, in particular through their synergistic interactions on previously unexamined angiogenic pathways. PMID- 29160858 TI - Hyperplanar Morphological Clustering of a Hippocampus by Using Volumetric Computerized Tomography in Early Alzheimer's Disease. AB - Background: On diagnosing Alzheimer's disease (AD), most existing imaging-based schemes have relied on analyzing the hippocampus and its peripheral structures. Recent studies have confirmed that volumetric variations are one of the primary indicators in differentiating symptomatic AD from healthy aging. In this study, we focused on deriving discriminative shape-based parameters that could effectively identify early AD from volumetric computerized tomography (VCT) delineation, which was previously almost intangible. Methods: Participants were 63 volunteers of Thai nationality, whose ages were between 40 and 90 years old. Thirty subjects (age 68.51 +/- 5.5) were diagnosed with early AD, by using Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria and the National Institute of Neurological and Communicative Disorders and the Stroke and the Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) criteria, while the remaining 33 were in the healthy control group (age 67.93 +/- 5.5). The structural imaging study was conducted by using VCT. Three uninformed readers were asked to draw left and right hippocampal outlines on a coronal section. The resultant shapes were aligned and then analyzed with statistical shape analysis to obtain the first few dominant variational parameters, residing in hyperplanes. A supervised machine learning, i.e., support vector machine (SVM) was then employed to elucidate the proposed scheme. Results: Provided trivial delineations, relatively as low as 5 to 7 implicit model parameters could be extracted and used as discriminants. Clinical verification showed that the model could differentiate early AD from aging, with high sensitivity, specificity, accuracy and F-measure of 0.970, 0.968, 0.983 and 0.983, respectively, with no apparent effect of left-right asymmetry. Thanks to a less laborious task required, yet high discriminating capability, the proposed scheme is expected to be applicable in a typical clinical setting, equipped with only a moderate-specs VCT. PMID- 29160859 TI - The Role of RNF213 4810G>A and 4950G>A Variants in Patients with Moyamoya Disease in Korea. AB - Although a founder variant of RNF213 4810G>A is a major genetic risk factor for moyamoya disease (MMD) in East Asians, the frequency and disease susceptibility of RNF213 variants remain largely unknown. This study investigated the mutation analysis of RNF213 (4448, 4810, 4863, and 4950) between Korean MMD and healthy controls. We performed a polymerase chain reaction-restriction fragment length polymorphism analysis. To identify the association between RNF213 gene polymorphisms and MMD disease, we performed statistical analyses such as multivariable logistic regression and Fisher's exact test. Genetic data from 117 MMD patients were analyzed and compared with 253 healthy controls. We assessed and compared single nucleotide polymorphisms of RNF213 (4448, 4810, 4863, and 4950) between MMD and control groups. We performed genome-wide association studies to investigate the genetic pathophysiology of MMD. Among the RNF213 variants (4448G>A, 4810G>A, 4863G>A, and 4950G>A), RNF213 4810G>A and 4950G>A variants were more frequent in MMD patients. In a subgroup analysis, the RNF213 4810G>A was more frequent in moyamoya disease, and the comparison with GG+AA genotype was also significantly different in moyamoya patients. These results confirm that RNF213 4810G>A and RNF213 4950G>A were more frequent in MMD patients. We have confirmed that RNF213 4810G>A and 4950G>A are strongly associated with Korean MMD in children and adults as well as for the ischemic and hemorrhagic types. PMID- 29160861 TI - A Lightweight Anonymous Authentication Protocol with Perfect Forward Secrecy for Wireless Sensor Networks. AB - Due to their frequent use in unattended and hostile deployment environments, the security in wireless sensor networks (WSNs) has attracted much interest in the past two decades. However, it remains a challenge to design a lightweight authentication protocol for WSNs because the designers are confronted with a series of desirable security requirements, e.g., user anonymity, perfect forward secrecy, resistance to de-synchronization attack. Recently, the authors presented two authentication schemes that attempt to provide user anonymity and to resist various known attacks. Unfortunately, in this work we shall show that user anonymity of the two schemes is achieved at the price of an impractical search operation-the gateway node may search for every possible value. Besides this defect, they are also prone to smart card loss attacks and have no provision for perfect forward secrecy. As our main contribution, a lightweight anonymous authentication scheme with perfect forward secrecy is designed, and what we believe the most interesting feature is that user anonymity, perfect forward secrecy, and resistance to de-synchronization attack can be achieved at the same time. As far as we know, it is extremely difficult to meet these security features simultaneously only using the lightweight operations, such as symmetric encryption/decryption and hash functions. PMID- 29160860 TI - Self-Assembled InAs Nanowires as Optical Reflectors. AB - Subwavelength nanostructured surfaces are realized with self-assembled vertically aligned InAs nanowires, and their functionalities as optical reflectors are investigated. In our system, polarization-resolved specular reflectance displays strong modulations as a function of incident photon energy and angle. An effective-medium model allows one to rationalize the experimental findings in the long wavelength regime, whereas numerical simulations fully reproduce the experimental outcomes in the entire frequency range. The impact of the refractive index of the medium surrounding the nanostructure assembly on the reflectance was estimated. In view of the present results, sensing schemes compatible with microfluidic technologies and routes to innovative nanowire-based optical elements are discussed. PMID- 29160862 TI - Time-Resolved Photoluminescence Microscopy for the Analysis of Semiconductor Based Paint Layers. AB - In conservation, science semiconductors occur as the constituent matter of the so called semiconductor pigments, produced following the Industrial Revolution and extensively used by modern painters. With recent research highlighting the occurrence of various degradation phenomena in semiconductor paints, it is clear that their detection by conventional optical fluorescence imaging and microscopy is limited by the complexity of historical painting materials. Here, we illustrate and prove the capabilities of time-resolved photoluminescence (TRPL) microscopy, equipped with both spectral and lifetime sensitivity at timescales ranging from nanoseconds to hundreds of microseconds, for the analysis of cross sections of paint layers made of luminescent semiconductor pigments. The method is sensitive to heterogeneities within micro-samples and provides valuable information for the interpretation of the nature of the emissions in samples. A case study is presented on micro samples from a painting by Henri Matisse and serves to demonstrate how TRPL can be used to identify the semiconductor pigments zinc white and cadmium yellow, and to inform future investigations of the degradation of a cadmium yellow paint. PMID- 29160863 TI - Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups. AB - This corrects the article DOI: 10.1038/leu.2017.177. PMID- 29160865 TI - Pain: Long-term outcomes of TRMDSC for chronic orchialgia. PMID- 29160864 TI - Clonal expansion behind a marine diatom bloom. AB - Genetic diversity is what selection acts on, thus shaping the adaptive potential of populations. We studied micro-evolutionary patterns of the key planktonic diatom Pseudo-nitzschia multistriata at a long-term sampling site over 2 consecutive years by genotyping isolates with 22 microsatellite markers. We show that both sex and vegetative growth interplay in shaping intraspecific diversity. We document a brief but massive demographic and clonal expansion driven by strains of the same mating type. The analysis of an extended data set (6 years) indicates that the genetic fingerprint of P. multistriata changed over time with a nonlinear pattern, with intermittent periods of weak and strong diversification related to the temporary predominance of clonal expansions over sexual recombination. These dynamics, rarely documented for phytoplankton, contribute to the understanding of bloom formation and of the mechanisms that drive microevolution in diatoms. PMID- 29160866 TI - Prostate cancer: A nervous disposition: the angiometabolic switch. PMID- 29160868 TI - Anchoring beta-cyclodextrin modified lysine to polymer monolith with biotin: specific capture of plasminogen. AB - Plasminogen (Plg) is a kind of glycoprotein which plays an important role in cell migration. The determination of Plg content can directly reflect the abnormal manifestation of fibrinolytic system dysfunctions. In the present work, lysine (Lys)-based adsorbents were prepared for the specific capture of Plg through the covalent binding of Lys with a polymer monolithic substrate. Lys was modified with beta-cyclodextrin (beta-CD) via a click reaction and anchored to the substrate with biotin by host-guest interaction. The biotin-Lys-CD based monolithic material was employed for the specific capture of Plg. Combining with mass spectrometry (MS) determinations, the method exhibited a low detection limit of 1.0 fmol with relative standard deviations below 10.0% for Plg. Considering the advantages of simplicity, sensitivity, and high specificity, the developed approach was successfully applied to the determination of Plg in human plasma samples and opened a gallery for testing Plg as a biomarker for the diagnosis of fibrinolytic system dysfunctions. PMID- 29160867 TI - Protocols and characterization data for 2D, 3D, and slice-based tumor models from the PREDECT project. AB - Two-dimensional (2D) culture of cancer cells in vitro does not recapitulate the three-dimensional (3D) architecture, heterogeneity and complexity of human tumors. More representative models are required that better reflect key aspects of tumor biology. These are essential studies of cancer biology and immunology as well as for target validation and drug discovery. The Innovative Medicines Initiative (IMI) consortium PREDECT (www.predect.eu) characterized in vitro models of three solid tumor types with the goal to capture elements of tumor complexity and heterogeneity. 2D culture and 3D mono- and stromal co-cultures of increasing complexity, and precision-cut tumor slice models were established. Robust protocols for the generation of these platforms are described. Tissue microarrays were prepared from all the models, permitting immunohistochemical analysis of individual cells, capturing heterogeneity. 3D cultures were also characterized using image analysis. Detailed step-by-step protocols, exemplary datasets from the 2D, 3D, and slice models, and refined analytical methods were established and are presented. PMID- 29160869 TI - An electrochemical microRNA sensing platform based on tungsten diselenide nanosheets and competitive RNA-RNA hybridization. AB - In this work, we report an ultrasensitive electrochemical biosensor for microRNA 21 (miRNA-21) detection by using a competitive RNA-RNA hybridization configuration. A biotinylated miRNA of the self-same sequence with the target miRNA is mixed with the samples, and allowed competition with the target miRNA for a thiolated RNA probe immobilized onto a tungsten diselenide (WSe2) nanosheet modified electrode. Thereafter the current response is obtained by forming the hybridized biotinylated miRNA with streptavidin-horseradish peroxidase (HRP) conjugates to catalyze the H2O2 + hydroquinone (HQ) system. Benefiting from the high specific surface area of WSe2 nanosheets, the competitive hybridization configuration and the signal amplification of the H2O2 + HQ detection system, the proposed assay exhibits a wide linear range of 0.0001-100 pM towards target miRNA with a detection limit of 0.06 fM (S/N = 3), and shows excellent discrimination ability for base-mismatched miRNA sequences. Therefore, the designed platform has promising prospects for the detection of miRNA in biomedical research and early clinical diagnosis. PMID- 29160870 TI - Engineering high-performance hairpin stacking circuits for logic gate operation and highly sensitive biosensing assay of microRNA. AB - Recently, hairpin stacking circuits (HSC) based on toehold-mediated strand displacement have been engineered to detect nucleic acids and proteins. However, the three metastable hairpins in a HSC system can potentially react non specifically in the absence of a catalyst, limiting its practical application. Here, we developed a unique hairpin design guideline to eliminate circuit leakage of HSC, and the high-performance HSC was successfully implemented on logic gate building and biosensing. We began by analyzing the sources of circuit leakage and optimizing the toehold lengths of hairpins in the HSC system based on the surface plasmon resonance (SPR) technique. Next, a novel strategy of substituting two nucleotides in a specific domain, termed 'loop-domain substitution', was introduced to eliminate leakages. We also systematically altered the positions and numbers of the introduced substitutions to probe their potential contribution to circuit leakage suppression. Through these efforts, the circuit leakage of HSC was significantly reduced. Finally, by designing different DNA input strands, the logic gates could be activated to achieve the output signal. Using miRNA as a model analyte, this strategy could detect miRNA down to pM levels with minimized circuit leakage. We believe these work indicate significant progress in the DNA circuitry. PMID- 29160871 TI - Molecular mechanism of activation of Burkholderia cepacia lipase at aqueous organic interfaces. AB - Lipases are water-soluble enzymes that catalyze the hydrolysis of lipids. Since lipids are mostly hydrophobic, lipase activity occurs preferentially at interfaces of aqueous and organic phases. In this work, we study the molecular mechanisms by which the Burkholderia cepacia lipase (BCL) is activated at interfaces of water with octane and with methyl caprylate (CAME). We show that BCL assumes very rapidly a preferential orientation at the interfaces, in which the active site is exposed to the organic phase. With BCL oriented to the interface, we compute the free energy of the aperture of the catalytic pocket using Adaptive Biasing Force MD simulations. The exposure to the organic phase promotes a clear stabilization of the open form of the catalytic pocket relative to the enzyme in water. This stabilization stems from the hydrophobicity of domains U1 and U2, which allows the penetration of organic solvents into the catalytic cleft impeding the closure of the pocket. Our results suggest that the structure and hydrophobicity of BCL are optimized for its activation in biphasic systems through the regulation of the accessibility of the catalytic pocket by, and for, hydrophobic substrates. The understanding of this mechanism may be useful for the design of proteins with targeted activation. PMID- 29160872 TI - Zinc(ii), cobalt(ii) and manganese(ii) networks with phosphoserine ligand: synthesis, crystal structures and magnetic and proton conductivity properties. AB - A series of zinc(ii), cobalt(ii) and manganese(ii) coordination networks with phosphoserine ligand (H3PSer) are synthesized and characterized. Whereas in compounds 1 and 2 with the general formula [M(HPser)]n [M = Zn (1) and Co (2)], the metal(ii) ion presents a tetrahedral geometry, in [Co(HPSer)(H2O)2]n (3) and [Mn(HPSer)(H2O)]n (4), the metal(ii) ions are in a distorted octahedral geometry. The 3D frameworks are formed by inorganic layers built up from MO4 or MO6 polyhedra and phosphate groups. These layers are linked by the carboxylate groups of the phosphoserine ligand. The presence of extended hydrogen bonding stabilizes the 3D network and favours the proton transfer leading to moderate proton conductors. The highest proton conductivity, 2.70 * 10-5 S cm-1 (at 80 degrees C and 95% RH), is obtained for compound 3. Temperature-dependent magnetic susceptibility measurements for 2-4 reveal predominant antiferromagnetic interactions between the paramagnetic metal(ii) ions. PMID- 29160873 TI - Low oxidation state silicon clusters - synthesis and structure of [NHCDippCu(eta4 Si9)]3. AB - The reaction of NHCDippCuCl with the silicide phases A12Si17 (A: K, K/Rb, Rb) in NH3(l) yields [NHCDippCu(eta4-Si9)]3- (1) as only the third example of a substituted [Si9] cluster. The corresponding salts A3[A(2.2.2 crypt)]3[NHCDippCu(eta4-Si9)]2.26NH3 (A: K (1a), K/Rb (1b), Rb (1c)) crystallize isostructurally in the space group P1[combining macron] and have been characterized by single crystal structure determination. ESI-MS and NMR experiments reveal that the anion [NHCDippCu(eta4-Si9)]3- can also be transferred to pyridine or acetonitrile solutions at low temperature. However, at room temperature dissociation under the release of the NHC ligand occurs. Variation of the NHC ligand in the [Cu-NHC]+-substituted silicide clusters is possible, whereas the reactions of K12Si17 with the corresponding NHCDippMCl (M: Ag, Au) complexes result in a partial oxidation of the silicide clusters, without attachment of [M-NHC]+, yielding [Si9]3- species. PMID- 29160874 TI - Biofilm dispersal using nitric oxide loaded nanoparticles fabricated by photo PISA: influence of morphology. AB - Polymeric nanoparticles (NPs) of different morphologies (spheres and worms) were synthesized using a visible light mediated polymerization-induced self-assembly (PISA) approach. Spherical and worm-like NPs were subsequently modified to generate diazeniumdiolate functionalized NPs. Interestingly, the NO release rate and the dispersal of biofilms were found to strongly depend on the NP morphology. NPs with a higher aspect ratio (worms) exhibited a slower NO release rate and greater biofilm dispersal after 1 h of incubation. PMID- 29160876 TI - Synthesis and antioxidant evaluation of lipophilic oleuropein aglycone derivatives. AB - Oleuropein is the most important phenolic compound present in olive cultivars, but it is scarcely present in extra virgin olive oil (EVOO) due to its high hydrophilicity and degradability. Thus, a set of oleuropein aglycone derivatives were synthesized by transacetylation under mild conditions with the aim of circumventing these drawbacks and making the active moiety in oleuropein suitable to be added to food fats. The oleuropein aglycone (closed ring form) is obtained by hydrolyzing oleuropein using Lewis acid catalysis. Then, the permeation profiles as well as the antioxidant capacity of the oleuropein aglycone derivatives were evaluated by ORAC, DPPH assays and by ROS formation using the SH SY5Y cell line. The biological activities of the obtained compounds exhibited a dependence on their level of lipophilicity. PMID- 29160877 TI - Efficient light hydrocarbon separation and CO2 capture and conversion in a stable MOF with oxalamide-decorated polar tubes. AB - The first strontium-based MOF possessing polar tubular channels embedded with a high density of open Lewis acidic metal sites and basic oxalamide groups was constructed, which shows not only a high CO2 and C2H6 adsorption capability and significant selectivity for CO2 over both CH4 and CO, and for C2H6 over CH4, but also size-selective chemical conversion of CO2 with epoxides producing cyclic carbonates under ambient conditions. PMID- 29160879 TI - Molten BaCN2 for the sintering and crystal growth of dielectric oxynitride perovskites Sr1-xBaxTaO2N (x = 0.04-0.23). AB - Solid phase sintering of dielectric oxynitride perovskites above 1000 degrees C is accompanied by their decomposition. Post-ammonolysis is required to recover their stoichiometric nitrogen content and dielectric properties. In the present work, the oxynitride perovskite SrTaO2N was sintered with a BaCN2 flux at approximately 900 degrees C avoiding its thermal decomposition. The resulting solid product with a relative density of 68.9% showed relative dielectric constants in the range from 68 to 90 with loss values less than 0.11, without the post-ammonolysis. The interior of the solids contained rectangular Sr1-xBaxTaO2N crystals for which 0.04 <= x <= 0.23 reflecting their euhedral form. These crystals were grown in molten BaCN2 from 20 to 100 times larger than the original SrTaO2N particles and had a maximum grain size of 3.7 MUm. The Sr1-xBaxTaO2N precipitated on the surfaces of the residual SrTaO2N crystals that had partially dissolved in the BaCN2 flux. A compositional gradient from barium-rich to strontium-rich was observed in a single crystal of the product on going from the exterior to the interior. This is the first-ever report of the preliminary liquid phase sintering and crystal growth of a dielectric oxynitride perovskite using a molten metal cyanamide. PMID- 29160880 TI - Low temperature growth of gallium oxide thin films via plasma enhanced atomic layer deposition. AB - Herein we describe an efficient low temperature (60-160 degrees C) plasma enhanced atomic layer deposition (PEALD) process for gallium oxide (Ga2O3) thin films using hexakis(dimethylamido)digallium [Ga(NMe2)3]2 with oxygen (O2) plasma on Si(100). The use of O2 plasma was found to have a significant improvement on the growth rate and deposition temperature when compared to former Ga2O3 processes. The process yielded the second highest growth rates (1.5 A per cycle) in terms of Ga2O3 ALD and the lowest temperature to date for the ALD growth of Ga2O3 and typical ALD characteristics were determined. From in situ quartz crystal microbalance (QCM) studies and ex situ ellipsometry measurements, it was deduced that the process is initially substrate-inhibited. Complementary analytical techniques were employed to investigate the crystallinity (grazing incidence X-ray diffraction), composition (Rutherford backscattering analysis/nuclear reaction analysis/X-ray photoelectron spectroscopy), morphology (X-ray reflectivity/atomic force microscopy) which revealed the formation of amorphous, homogeneous and nearly stoichiometric Ga2O3 thin films of high purity (carbon and nitrogen <2 at.%) under optimised process conditions. Tauc plots obtained via UV-Vis spectroscopy yielded a band gap of 4.9 eV and the transmittance values were more than 80%. Upon annealing at 1000 degrees C, the transformation to oxygen rich polycrystalline beta-gallium oxide took place, which also resulted in the densification and roughening of the layer, accompanied by a slight reduction in the band gap. This work outlines a fast and efficient method for the low temperature ALD growth of Ga2O3 thin films and provides the means to deposit Ga2O3 upon thermally sensitive polymers like polyethylene terephthalate. PMID- 29160881 TI - Effect of nobiletin on the MAPK/NF-kappaB signaling pathway in the synovial membrane of rats with arthritis induced by collagen. AB - Nobiletin (5,6,7,8,3',4'-hexamethoxyflavone) is a natural compound in the fruit peel of citrus fruit in the Rutaceae family. It is active in inhibiting inflammation, reducing plasma lipids and has anti-oxidative properties. In studying the effect of nobiletin on rheumatoid arthritis (RA), the collagen induced arthritis (CIA) model on Sprague-Dawley (SD) rats was established by bovine type II collagen (BIIC), and the effect of nobiletin on RA was investigated using hematoxylin-eosin (H&E) staining, serum enzyme linked immunosorbent assay (ELISA) detection and western blotting. The experimental results in animals revealed that the angiogenesis and inflammatory infiltration in synovial tissue, the serum pro-inflammatory cytokines of interleukin-1beta (IL 1beta), monocyte chemotactic protein-1 (MCP-1), IL-6 and tumor necrosis factor alpha (TNF-alpha) levels in BIIC immunized rats were significantly decreased after treatment with nobiletin. The protein expression levels of phosphorylated p38, p-p65 and the nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha (IkappaBalpha) in the synovial membrane of CIA rats were down-regulated by nobiletin. These results demonstrated that nobiletin inhibited the development of RA by inhibiting the degree of angiogenesis and inflammatory infiltration by down-regulating the protein expression level of the p38/nuclear factor kappa B (NF-kappaB) signaling pathway in the synovium of rats with CIA. PMID- 29160883 TI - Correction: Synthesis and X-ray structural characterization of the (chlorochalcogeno)phosphonium cations R2R'PSCl+ and R2R'PSeCl+ as their AuCl4- salts. AB - Correction for 'Synthesis and X-ray structural characterization of the (chlorochalcogeno)phosphonium cations R2R'PSCl+ and R2R'PSeCl+ as their AuCl4- salts' by Daniel Upmann and Peter G. Jones, Dalton Trans., 2013, 42, 7526-7528. PMID- 29160885 TI - Drying kinetics of water droplets stabilized by surfactant molecules or solid particles in a thin non-volatile oil layer. AB - We have investigated drying of water droplets stabilized by solid particles or surfactant molecules in a thin oil layer. The surfactant-stabilized droplets isotropically shrink, whereas the droplets stabilized by spherical particles severely deform during drying because of buckling of the particulate shells. However, buckling of the shells hardly affects droplet drying. The drying times for complete evaporation are almost the same for water droplets with the same initial diameter and the drying time is independent of the type of surface stabilizer (particles or surfactant). The drying kinetics of the water droplets is well described by mathematical models, in which diffusion of water molecules in the oil phase to the oil-air interface is proposed as the rate-determining process. Droplets with a diameter comparable with the thickness of the oil layer shrink faster than small droplets because of the short diffusion length from the water droplets to the oil-air interface. We also investigated drying of water droplets stabilized by plate-like mica particles. The droplets also buckled but larger shells of mica particles remained compared with those of spherical particles. In addition, a longer drying time is necessary for some droplets stabilized by mica particles. These results indicate the possible effect of the particle morphology on the buckling and drying kinetics of particle-stabilized water droplets. PMID- 29160888 TI - Iron(iii) complexes of 2-methyl-6-(pyrimidin-2-yl-hydrazonomethyl)-phenol as spin crossover molecular materials. AB - Four new mononuclear Fe(iii) complexes 1-4 of 2-methyl-6-(pyrimidin-2-yl hydrazonomethyl)-phenol (H2L) have been synthesized and characterized by magnetic susceptibility measurements and single-crystal X-ray diffraction analysis. Complexes 1-3 are ionic compounds with the formula [Fe(HL)2]X.nsolvent (X = ClO4- (1), BF4- (2) and Cl- (3)), while complex 4 ([Fe(HL)(L)]) is neutral. The central Fe(iii) ion in complexes 1-4 is coordinated by four nitrogen and two oxygen atoms of two Schiff base ligands HL- or L2-, and the coordination geometries of FeIII are all distorted octahedral. Magnetic measurements indicate that complex 1 shows an abrupt spin transition with a thermal hysteresis of 32 K (T1/2? = 158 K and T1/2? = 190 K), and complex 4 exhibits a gradual incomplete spin transition. Complexes 2 and 3 are high spin with a room-temperature chimT value of 4.32 cm3 K mol-1 and 4.39 cm3 K mol-1, respectively. PMID- 29160892 TI - Growth of a sea urchin-like rutile TiO2 hierarchical microsphere film on Ti foil for a quasi-solid-state dye-sensitized solar cell. AB - A sea urchin-like rutile TiO2 microsphere (RMS) film was fabricated on Ti foil via a hydrothermal process. The resulting rutile TiO2 hierarchical microspheres with a diameter of 5-6 MUm are composed of nanorods with a diameter of ~200 nm and a length of 1-2 MUm. The sea urchin-like hierarchical structure leads to the Ti foil-based RMS film possessing much better light-scattering capability in the visible region than the bare Ti foil. By using it as an underlayer of a nanosized anatase TiO2 film (bTPP3) derived from a commercially available paste (TPP3), the corresponding bilayer Ti foil-based quasi-solid-state dye-sensitized solar cell (DSSC) only gives a conversion efficiency of 4.05%, much lower than the single bTPP3 film-based one on Ti foil (5.97%). By spin-coating a diluted TPP3 paste (sTPP3) on the RMS film prior to scraping the bTPP3 film, the resulting RMS/sTPP3/bTPP3 film-based DSSC achieves a significantly enhanced efficiency (7.27%). The electrochemical impedance spectra (EIS) show that the RMS/sTPP3/bTPP3 film possesses better electron transport capability and longer electron lifetime than the bTPP3 film. This work not only provides the first example of directly growing rutile TiO2 hierarchically structured microsphere film on Ti foil suitable for replacing the rigid, heavy and expensive transparent conductive oxide (TCO) glass substrate to serve as a light-scattering underlayer of Ti foil-based quasi-solid-state DSSCs, but also paves a new route to develop Ti foil-based flexible DSSCs with high efficiency, low cost and a wide application field through optimizing the composition and structure of the photoanode. PMID- 29160893 TI - SERS in biology/biomedical SERS: general discussion. PMID- 29160894 TI - Chlorogenic acids and the acyl-quinic acids: discovery, biosynthesis, bioavailability and bioactivity. AB - Covering: 2000 up to late 2017This review is focussed upon the acyl-quinic acids, the most studied group within the ca. 400 chlorogenic acids so far reported. The acyl-quinic acids, the first of which was characterised in 1846, are a diverse group of plant-derived compounds produced principally through esterification of an hydroxycinnamic acid and 1l-(-)-quinic acid. Topics addressed in this review include the confusing nomenclature, quantification and characterisation by NMR and MS, biosynthesis and role in planta, and the occurrence of acyl-quinic acids in coffee, their transformation during roasting and delivery to the beverage. Coffee is the major human dietary source world-wide of acyl-quinic acids and consideration is given to their absorption and metabolism in the upper gastrointestinal tract, and the colon where the microbiota play a key role in the formation of catabolites. Evidence on the potential of the in vivo metabolites and catabolites of acyl-quinic acids to promote the consumer's health is evaluated. PMID- 29160895 TI - Differential expression of microRNAs contributed to the health efficacy of EGCG in in vitro subarachnoid hemorrhage model. AB - (-)-Epigallocatechin-3-gallate (EGCG) exhibits a broader spectrum health efficacy in subarachnoid hemorrhage (SAH) therapy; the mechanisms, however, are largely unknown. Given that miRNAs play important roles in regulation of thousands of gene expressions, the effect of EGCG on the expression of miRNAs was investigated to explore the multi-targeting actions of EGCG by using an in vitro SAH model. MTT and western blot assays were used to assess the health effects of EGCG in SAH progression; the results showed that oxyhemoglobin (OxyHb)-induced cell proliferation and excessive autophagic activation were significantly inhibited by 50 MUM EGCG, but not by 1 MUM EGCG. By high throughput sequencing analysis, the miRNA profiles of normal, SAH and EGCG (1 and 50 MUM) groups were compared and a total of 953 miRNAs were identified. Of 192 differentially expressed miRNAs, 43 miRNAs were significantly differentially expressed in SAH (p < 0.01). However, EGCG significantly increased the number of differential expressions of miRNAs, which showed 144 and 138 miRNAs (112 and 115 upregulated, 32 and 23 downregulated, p < 0.01) in 1 MUM and 50 MUM EGCG groups, respectively. Among all the differentially expressed miRNAs, 13 miRNAs were shared by the three groups. 5 miRNAs (miR-218-5p, miR-218b, miR-143-3p, miR-101a-3p, miR-30a-3p) were detected in both SAH and EGCG 1 MUM groups, and 104 miRNAs were shared by the EGCG 1 MUM and EGCG 50 MUM groups. Only 1 miRNA (miR-532-5p) was discovered in both SAH and EGCG 50 MUM groups. Moreover, 24, 22 and 20 specific differentially expressed miRNAs were discovered in SAH, 1 MUM and 50 MUM EGCG groups, respectively. The predicted target genes of differentially expressed miRNAs showed that the most impacted MAPK signaling pathway, particularly the upregulated p38 expression in the SAH group, was restored to the normal level in both EGCG groups, but the calcium signaling pathway was enriched only in the EGCG 50 MUM group. These results revealed that differential expression of miRNAs is fundamental to understand the multiple targets actions of EGCG in SAH therapy, and simultaneously targeting more robust signaling pathways could determine the therapeutic effects of EGCG. PMID- 29160896 TI - Influence of fracture stability on Staphylococcus epidermidis and Staphylococcus aureus infection in a murine femoral fracture model. AB - Fracture-related infection (FRI) is a major complication in surgically fixed fractures. Instability of the fracture after fixation is considered a risk factor for infection; however, few experimental data are available confirming this belief. To study whether stable fractures led to higher infection clearance, mouse femoral osteotomies were fixed with either stable or unstable fixation and the surgical site was contaminated with either Staphylococcus epidermidis (S. epidermidis)or Staphylococcus aureus (S. aureus)clinical isolates. Infection progression was assessed at different time points by quantitative bacteriology, total cell counts in spleen and lymph node and histological analysis. Operated, non-inoculated mice were used as controls. Two inbred mouse strains (C57BL/6 and BALB/c) were included in the study to determine the influence of different host background in the outcome. Stable fixation allowed a higher proportion of C57BL/6 mice to clear S. epidermidis inoculation in comparison to unstable fixation. No difference associated with fixation type was observed for BALB/c mice. Inoculation with S. aureus resulted in a more severe infection for both stable and unstable fractures in both mouse strains; however, significant osteolysis around the screws rendered the stable group functionally unstable. Our results suggested that fracture stability could have an influence on S. epidermidis infection, although host factors also played a role. No differences were observed when using S. aureus, due to a more severe infection, leading to osteolysis and loss of stability in both groups. Further studies are required in order to address the biological features underlying the differences observed. PMID- 29160898 TI - Variation in range size and dispersal capabilities of microbial taxa. AB - Geographic range size can span orders of magnitude for plant and animal species, with the study of why range sizes vary having preoccupied biogeographers for decades. In contrast, there have been few comparable studies of how range size varies across microbial taxa and what traits may be associated with this variation. We determined the range sizes of 74,134 bacterial and archaeal taxa found in settled dust collected from 1,065 locations across the United States. We found that most microorganisms have small ranges and few have large ranges, a pattern similar to the range size distributions commonly observed for macrobes. However, contrary to expectations, those microbial taxa that were locally abundant did not necessarily have larger range sizes. The observed differences in microbial range sizes were generally predictable from taxonomic identity, phenotypic traits, genomic attributes, and habitat preferences, findings that provide insight into the factors shaping patterns of microbial biogeography. PMID- 29160897 TI - Social integration and survival after diagnosis of colorectal cancer. AB - BACKGROUND: Although larger social networks have been associated with lower all cause mortality, few studies have examined whether social integration predicts survival outcomes among patients with colorectal cancer (CRC). The authors examined the association between social ties and survival after CRC diagnosis in a prospective cohort study. METHODS: Participants included 896 women in the Nurses' Health Study who were diagnosed with stage I, II, or III CRC between 1992 and 2012. Stage was assigned using the American Joint Committee on Cancer criteria. Social integration was assessed every 4 years since 1992 using the Berkman-Syme Social Network Index, which included marital status, social network size, contact frequency, religious participation, and other social group participation. RESULTS: During follow-up, there were 380 total deaths, 167 of which were due to CRC. In multivariable analyses, women who were socially integrated before diagnosis had a subsequent reduced risk of all-cause mortality (hazard ratio [HR], 0.65; 95% confidence interval [95% CI], 0.46-0.92) and CRC mortality (HR, 0.63; 95% CI, 0.38-1.06) compared with women who were socially isolated. In particular, women with more intimate ties (family and friends) had lower all-cause mortality (HR, 0.61; 95% CI, 0.42-0.88) and CRC mortality (HR, 0.59; 95% CI, 0.34-1.03) compared with those with few intimate ties. Participation in religious or community activities was not found to be related to outcomes. The analysis of postdiagnosis social integration yielded similar results. CONCLUSIONS: Socially integrated women were found to have better survival after a diagnosis of CRC, possibly due to beneficial caregiving from their family and friends. Interventions aimed at strengthening social network structures to ensure access to care may be valuable programmatic tools in the management of patients with CRC. Cancer 2018;124:833-40. (c) 2017 American Cancer Society. PMID- 29160899 TI - Persistent sample circulation microextraction combined with graphite furnace atomic absorption spectroscopy for trace determination of heavy metals in fish species marketed in Kermanshah, Iran, and human health risk assessment. AB - BACKGROUND: Persistent sample circulation microextraction (PSCME) combined with graphite furnace atomic absorption spectrometry (GFAAS) was developed as a high pre-concentration technique for the determination of heavy metals in fish species. In this method, a few microliters of organic solvent (40.0 uL carbon tetrachloride) was transferred to the bottom of a conical sample cup. Then 10.0 mL of aqueous solution was transformed to fine droplets while passing through the organic solvent. At this stage, metal-ligand hydrophobic complex was extracted into the organic solvent. After extraction, 20 uL of extraction solvent was injected into the graphite tube using an auto-sampler. RESULTS: Under optimal conditions, enrichment factors and enhancement factor were in the range of 180 240 and 155-214, respectively. The calibration curves were linear in the range of 0.03-200 ug kg-1 and the limits of detection (LODs) were in the range of 0.01 0.05 ug kg-1 . Repeatability (intra-day) and reproducibility (inter-day) for 0.50 ug L-1 Hg and 0.10 ug L-1 Cd and Pb were in the range of 3.1-4.2% (n = 7) and 4.3 6.1% (n = 7), respectively. CONCLUSION: Potential human health risk assessment was conducted by calculating estimated weekly intake (EWI) of the metals from eating fish and comparison of these values with provisional tolerable weekly intake (PTWI) values. EWI data for the studied metals through fish consumption were lower than the PTWI values. (c) 2017 Society of Chemical Industry. PMID- 29160900 TI - Fusarium graminearum: pathogen or endophyte of North American grasses? AB - Mycotoxin-producing Fusarium graminearum and related species cause Fusarium head blight on cultivated grasses, such as wheat and barley. However, these Fusarium species may have had a longer evolutionary history with North American grasses than with cultivated crops and may interact with the ancestral hosts in ways which are biochemically distinct. We assayed 25 species of asymptomatic native grasses for the presence of Fusarium species and confirmed infected grasses as hosts using re-inoculation tests. We examined seed from native grasses for the presence of mycotoxin-producing Fusarium species and evaluated the ability of these fungi to produce mycotoxins in both native grass and wheat hosts using biochemical analysis. Mycotoxin-producing Fusarium species were shown to be prevalent in phylogenetically diverse native grasses, colonizing multiple tissue types, including seeds, leaves and inflorescence structures. Artificially inoculated grasses accumulated trichothecenes to a much lesser extent than wheat, and naturally infected grasses showed little to no accumulation. Native North American grasses are commonly inhabited by Fusarium species, but appear to accommodate these toxigenic fungi differently from cultivated crops. This finding highlights how host identity and evolutionary history may influence the outcome of plant-fungal interactions and may inform future efforts in crop improvement. PMID- 29160902 TI - Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. AB - Contemporary information on the fraction of cancers that potentially could be prevented is useful for priority setting in cancer prevention and control. Herein, the authors estimate the proportion and number of invasive cancer cases and deaths, overall (excluding nonmelanoma skin cancers) and for 26 cancer types, in adults aged 30 years and older in the United States in 2014, that were attributable to major, potentially modifiable exposures (cigarette smoking; secondhand smoke; excess body weight; alcohol intake; consumption of red and processed meat; low consumption of fruits/vegetables, dietary fiber, and dietary calcium; physical inactivity; ultraviolet radiation; and 6 cancer-associated infections). The numbers of cancer cases were obtained from the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute; the numbers of deaths were obtained from the CDC; risk factor prevalence estimates were obtained from nationally representative surveys; and associated relative risks of cancer were obtained from published, large-scale pooled analyses or meta analyses. In the United States in 2014, an estimated 42.0% of all incident cancers (659,640 of 1570,975 cancers, excluding nonmelanoma skin cancers) and 45.1% of cancer deaths (265,150 of 587,521 deaths) were attributable to evaluated risk factors. Cigarette smoking accounted for the highest proportion of cancer cases (19.0%; 298,970 cases) and deaths (28.8%; 169,180 deaths), followed by excess body weight (7.8% and 6.5%, respectively) and alcohol intake (5.6% and 4.0%, respectively). Lung cancer had the highest number of cancers (184,970 cases) and deaths (132,960 deaths) attributable to evaluated risk factors, followed by colorectal cancer (76,910 cases and 28,290 deaths). These results, however, may underestimate the overall proportion of cancers attributable to modifiable factors, because the impact of all established risk factors could not be quantified, and many likely modifiable risk factors are not yet firmly established as causal. Nevertheless, these findings underscore the vast potential for reducing cancer morbidity and mortality through broad and equitable implementation of known preventive measures. CA Cancer J Clin 2018;68:31-54. (c) 2017 American Cancer Society. PMID- 29160901 TI - Dietary Advanced Glycation End Products Have Sex- and Age-Dependent Effects on Vertebral Bone Microstructure and Mechanical Function in Mice. AB - Back pain is a leading cause of global disability that can arise from vertebral fracture and osteoporosis. Although poor general health and obesity are among the strongest risk factors for back pain, there is remarkably little known about how diet influences spinal diseases. Advanced glycation end-products (AGEs) are implicated in increased fracture risk, yet no studies investigated how dietary AGEs affect spinal health. We tested the hypothesis that high dietary AGE ingestion will diminish vertebral structure and function in a sex- and age dependent manner. Female and male mice were fed low-AGE (L-AGE) or high-AGE (H AGE) isocaloric diets for 6 and 18 months and multiple measurements of bone structure and function were taken. AGE levels in serum and cortical vertebrae were increased only for 6-month-old H-AGE female mice while blood glucose and body weight remained normal for all animals. When fed an H-AGE diet, 6-month-old female mice had inferior vertebral trabecular structure with decreased bone mineral density (BMD) and bone volume fraction. Biomechanical testing and analytical modeling further showed functional deterioration in 6-month-old H-AGE females with reduced shear and compression moduli, and maximum load to failure. At 18 months, H-AGE mice of both sexes had significant but small decreases in cortical BMD and thickness, yet functional biomechanical behaviors were not distinguishable from other aging changes. We conclude that an H-AGE diet, without diabetic or overweight conditions, diminished vertebral microstructure, mechanical behaviors, and fracture resistance in young female mice in a manner suggesting accelerated bone aging. (c) 2017 American Society for Bone and Mineral Research. PMID- 29160903 TI - Smoking cessation leads to changes in survivin expression in oral mucosa. AB - BACKGROUND: Survivin is an inhibitor protein of apoptosis and plays a role in oral carcinogenesis mechanism. METHODS: The aim of this study was to evaluate the effect of smoking in survivin expression of oral mucosa of chronic smokers with and without oral squamous cell carcinoma (OSCC). The study was composed of three groups: Group 1-26 patients smoking more than 20 cigarettes/day/10 years without either history of oral malignant neoplasia or visible clinical signs in the examined site; Group 2-26 patients with OSCC; Group 3-22 patients surgically treated for OSCC for at least 1 month. The immunohistochemistry was performed with 1 smear for each group and analyzed by microscopy regarding extension, intensity of positive cells for survivin, and intracellular location. RESULTS: The survivin expression was observed in 100% of the cases in Group 1, 88.5% in Group 2, and 100% in Group 3. Concerning to Groups 1 and 3, the survivin expression with cytoplasmic location occurred in 100%, while in Group 2 occurred in 87.5%. The cytoplasmic and nuclear expression was observed only in Group 2, with 7.69%. The results were correlated with clinical-pathological data by Fischer's exact test with significant relation between smoking cessation and intensity (P = .015) for Group 2. CONCLUSIONS: The extension and intensity of survivin expression in the cytological smears were related to the smoking cessation in the group with OSCC. However, the smoking history (packs/years) did not influence the survivin expression. PMID- 29160904 TI - Three-Dimensional Accuracy of Digital Static Interocclusal Registration by Three Intraoral Scanner Systems. AB - PURPOSE: Prior studies have defined the accuracy of intraoral scanner (IOS) systems but the accuracy of the digital static interocclusal registration function of these systems has not been reported. This study compared the three dimensional (3D) accuracy of the digital static interocclusal registration of 3 IOS systems using the buccal bite scan function. MATERIALS AND METHODS: Three IOS systems compared were 3MTM True Definition Scanner (TDS), TRIOS Color (TRC), and CEREC AC with CEREC Omnicam (CER). Using each scanner, 7 scans (n = 7) of the mounted and articulated SLA master models were obtained. The measurement targets (SiN reference spheres and implant abutment analogs) were in the opposing models at the right (R), central (C), and left (L) regions; abutments #26 and #36, respectively. A coordinate measuring machine with metrology software compared the physical and virtual targets to derive the global 3D linear distortion between the centroids of the respective target reference spheres and abutment analogs (dRR , dRC , dRL , and dRM ) and 2D distances between the pierce points of the abutment analogs (dXM , dYM , dZM ), with 3 measurement repetitions for each scan. RESULTS: Mean 3D distortion ranged from -471.9 to 31.7 MUm for dRR , -579.0 to -87.0 MUm for dRC , -381.5 to 69.4 MUm for dRL , and -184.9 to -23.1 MUm for dRM . Mean 2D distortion ranged from -225.9 to 0.8 MUm for dXM , -130.6 to -126.1 MUm for dYM , and -34.3 to 26.3 MUm for dZM . Significant differences were found for interarch distortions across the three systems. For dRR and dRL , all three test groups were significantly different, whereas for dRC , the TDS was significantly different from the TRC and CER. For 2D distortion, significant differences were found for dXM only. CONCLUSIONS: Interarch and global interocclusal distortions for the three IOS systems were significantly different. TRC performed overall the best and TDS was the worst. The interarch (dRR , dRC , dRL ) and interocclusal (dXM ) distortions observed will affect the magnitude of occlusal contacts of restorations clinically. The final restoration may be either hyperoccluded or infraoccluded, requiring compensations during the CAD design stage or clinical adjustments at issue. PMID- 29160905 TI - Regulated recruitment of SRGAP1 modulates RhoA signaling for contractility during epithelial junction maturation. AB - Adherens junctions in epithelia are contractile structures, where coupling of adhesion to the actomyosin cytoskeleton generates mechanical tension for morphogenesis and homeostasis. In established monolayers, junctional contractility is supported by the interplay between cell signals and scaffolding proteins. However, less is known about how contractile junctions develop, especially during the establishment of epithelial monolayers. Here, we show that junctional tension increases concomitant with accumulation of actomyosin networks as Caco-2 epithelia become confluent. This is associated with development of a zone of RhoA signaling at junctions. Further, we find that the low levels of RhoA signaling and contractility found in subconfluent cultures reflect a mechanism for their active suppression. Specifically, the RhoA antagonist, SRGAP1, is present at subconfluent junctions to a greater extent than in confluent cultures and SRGAP1 RNAi restores RhoA signaling and contractility in subconfluent cultures to levels seen in confluent cells. Overall, these observations suggest that regulated changes in junctional contractility mediated by modulation of RhoA signaling occur as epithelial monolayers mature. PMID- 29160906 TI - 100-Fold Enhancement of Charge Transport in Uniaxially Oriented Mesoporous Anatase TiO2 Films. AB - Mesoporous semiconductor films are of considerable interest for applications in photoelectrochemical devices, however, despite intensive research till now, their charge transport properties remain significantly lower than their single-crystal counterparts. Herein, we report a novel low-temperature template-free technique for growing high surface area mesoporous anatase TiO2 films with a preferred [001] crystalline-orientation on FTO-coated glass substrate. Compared to mesoporous films that comprised of randomly oriented crystallites, the uniaxial orientation enables a 100-fold increase in the rate of electron transport. The uniaxially oriented mesoporous anatase TiO2 films exhibit should greatly facilitate the development and application of photoelectrochemical and electrochemical devices. PMID- 29160907 TI - Inhibition effects of flavonoids on 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline formation and alkoxy radical scavenging capabilities of flavonoids in a model system. AB - BACKGROUND: Heterocyclic aromatic amines (HAAs) have been considered as carcinogenic and mutagenic chemicals generated during thermal processing of protein-rich foods that can be inhibited by some flavonoids. Free radical scavenging is a major characteristic of flavonoids. RESULTS: The half-maximal inhibitory concentration (IC50 ) values of nine flavonoids were determined by evaluating their capacity to inhibit 2-amino-3,8-dimethylimidazo[4,5 f]quinoxaline (MeIQx) and 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (7,8 DiMeIQx) formation in a model system. The results of the 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO) test validated that MeIQx and 7,8-DiMeIQx formed via a free radical pathway. Electron spin resonance (ESR) spectroscopic analysis with spin trapping (alpha-(4-pyridyl N-oxide)-N-tert-butylnitrone (POBN) spin adduct, aN = 15.2 G and aH = 2.7 G) revealed that an alkoxy radical was the generated intermediate. The scavenging capacities of the nine flavonoids on alkoxy radicals were then evaluated based on the ESR spectra of the POBN spin adducts. CONCLUSION: The weak correlation between the alkoxy radical scavenging capacities and IC50 of the flavonoids suggested that their inhibitory activity against MeIQx and 7,8-DiMeIQx formation operates by a more complex mechanism than simply scavenging alkoxy radicals. (c) 2017 Society of Chemical Industry. PMID- 29160908 TI - Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation. AB - Connective tissue growth factor (CCN2/CTGF) is a matricellular protein that is overexpressed in progressive human renal diseases, mainly in fibrotic areas. In vitro studies have demonstrated that CCN2 regulates the production of extracellular matrix (ECM) proteins and epithelial-mesenchymal transition (EMT), and could therefore contribute to renal fibrosis. CCN2 blockade ameliorates experimental renal damage, including diminution of ECM accumulation. We have reported that CCN2 and its C-terminal degradation product CCN2(IV) bind to epidermal growth factor receptor (EGFR) to modulate renal inflammation. However, the receptor involved in CCN2 profibrotic actions has not been described so far. Using a murine model of systemic administration of CCN2(IV), we have unveiled a fibrotic response in the kidney that was diminished by EGFR blockade. Additionally, in conditional CCN2 knockout mice, renal fibrosis elicited by folic acid-induced renal damage was prevented, and this was linked to inhibition of EGFR pathway activation. Our in vitro studies demonstrated a direct effect of CCN2 via the EGFR pathway on ECM production by fibroblasts and the induction of EMT in tubular epithelial cells. Our studies clearly show that the EGFR regulates CCN2 fibrotic signalling in the kidney, and suggest that EGFR pathway blockade could be a potential therapeutic option to block CCN2-mediated profibrotic effects in renal diseases. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29160909 TI - Revisiting chronic rejection following living donor liver transplantation in the tacrolimus era: A single center experience. AB - BACKGROUND AND AIMS: Chronic rejection (CR) is an uncommon but important cause of graft dysfunction, leading to graft loss and often requires retransplantation. This study evaluates the incidence and outcome of the patients with CR at a large living donor liver transplant (LDLT) center. METHODS: Data of patients with CR were retrospectively analyzed in 1232 adult (age >18 years) LDLT on tacrolimus (mainly)-based immunosuppression. Sirolimus/everolimus (mammalian target of rapamycin [mTOR] inhibitors) was added to baseline immunosuppression as rescue therapy in patients with CR. Data are shown as median (interquartile range [IQR]). RESULTS: Twenty-three patients (22 males), aged 42 (IQR 45-56) years, had biopsy-proven chronic rejection at 21 (8-44) months after liver transplantation. The incidence of chronic rejection was 1.9% in this cohort. The patients with CR (n = 23) had a significantly higher incidence of cytomegalovirus (CMV) viremia, acute cellular rejection, and history of anastomotic biliary strictures as compared to patients without CR. Five patients were noncompliant with immunosuppression before the diagnosis of CR. Twelve patients (52%) responded to addition of mTOR inhibitors, whereas 11 did not respond and had poor outcome. CONCLUSION: The incidence of chronic rejection is low in LDLT. Treatment with mTOR inhibitors can reverse graft dysfunction in approximately half of the patients. PMID- 29160910 TI - Epithelial disruptions, but not immune cell invasion, induced secretory dysfunction following innate immune activation in a novel model of acute salivary gland injury. AB - BACKGROUND: Salivary gland (SG) injurious agents are all translated into loss of salivation (xerostomia). An association has been established between activation of innate immunity and SG injury and dysfunction. However, it remains unclear how the secretory epithelia respond by halting saliva production. METHODS: C57BL/6 submandibular glands (SMGs) were acutely challenged using a single dose of the innate immune stimulant: polyinosinic-polycytidylic acid (poly (I:C)). Secretory capacity of the infected SMGs was substantiated by assessing the flow rate in response to pilocarpine stimulation. Depletion of the acute inflammatory cells was achieved by pre-treating mice with RB6-8C5 depletion antibody. Flow cytometry, histology and immunohistochemistry were conducted to verify the immune cell depletion. Epithelial expression of saliva-driving molecules: muscarinic 3 receptor (M3R), aquaporin 5 water channel (AQP5), Na-K-CL-Cotransporter 1 (NKCC1) and transmembrane member 16A (TMEM16A), was characterized using RT-qPCR and immunohistochemistry. Tight junction (TJ) protein; zonula occludens (ZO-1) and basement membrane (BM) protein; and laminin were assessed by immunohistochemistry. RESULTS: Innate immune challenge prompted dysfunction in the exocrine SGs. Dysregulated gene and protein expression of molecules that drive saliva secretion was substantiated. Aberrant expression of TJ and BM proteins followed innate immune activation. Hyposalivation in the current model was independent of myeloperoxidase (MPO)-positive, acute inflammatory cells. CONCLUSIONS: In this study, we developed a novel injury model of the SGs, featuring acute secretory dysfunction and immediate structural disruptions. Our results ruled out the injurious role of aggressively infiltrating inflammatory cells. PMID- 29160911 TI - Simultaneous use of erythropoietin and LFM-A13 as a new therapeutic approach for colorectal cancer. AB - BACKGROUND AND PURPOSE: Bruton's tyrosine kinase (Btk) is a non-receptor tyrosine kinase involved in the activation of signalling pathways responsible for cell maturation and viability. Btk has previously been reported to be overexpressed in colon cancers. This kind of cancer is often accompanied by anaemia, which is treated with an erythropoietin supplement. The goal of the present study was to assess the effects of combination therapy with erythropoietin beta (Epo) and LFM A13 (Btk inhibitor) on colon cancer in in vitro and in vivo models. EXPERIMENTAL APPROACH: DLD-1 and HT-29 human colon adenocarcinoma cells were cultured with Epo and LFM-A13. Cell number and viability, and mRNA and protein levels of Epo receptors, Btk and Akt were assessed. Nude mice were inoculated with adenocarcinoma cells and treated with Epo and LFM-A13. KEY RESULTS: The combination of Epo and LFM-A13 mostly exerted a synergistic inhibitory effect on colon cancer cell growth. The therapeutic scheme used effectively killed the cancer cells and attenuated the Btk signalling pathways. Epo + LFM-A13 also prevented the normal process of microtubule assembly during mitosis by down regulating the expression of Polo-like kinase 1. The combination of Epo and LFM A13 significantly reduced the growth rate of tumour cells, while it showed high safety profile, inducing no nephrotoxicity, hepatotoxicity or changes in the haematological parameters. CONCLUSION AND IMPLICATIONS: Epo significantly enhances the antitumour activity of LFM-A13, indicating that a combination of Epo and LFM-A13 has potential as an effective therapeutic approach for patients with colorectal cancer. PMID- 29160913 TI - Bigger testes increase paternity in a simultaneous hermaphrodite, independently of the sperm competition level. AB - Hermaphroditic animals face the fundamental evolutionary optimization problem of allocating their resources to their male vs. female reproductive function (e.g. testes and sperm vs. ovaries and eggs), and this optimal sex allocation can be affected by both pre- and post-copulatory sexual selection. For example, local sperm competition (LSC) - the competition between related sperm for the fertilization of a partner's ova - occurs in small mating groups and can favour a female-biased sex allocation, because, under LSC, investment into sperm production is predicted to show diminishing fitness returns. Here, we test whether higher testis investment increases an individual's paternity success under sperm competition, and whether the strength of this effect diminishes when LSC is stronger, as predicted by sex allocation theory. We created two subsets of individuals of the simultaneously hermaphroditic flatworm Macrostomum lignano - by sampling worms from either the highest or lowest quartile of the testis investment distribution - and estimated their paternity success in group sizes of either three (strong LSC) or eight individuals (weak LSC). Specifically, using transgenic focal individuals expressing a dominant green-fluorescent protein marker, we showed that worms with high testis investment sired 22% more offspring relative to those with low investment, corroborating previous findings in M. lignano and other species. However, the strength of this effect was not significantly modulated by the experienced group size, contrasting theoretical expectations of more strongly diminishing fitness returns under strong LSC. We discuss the possible implications for the evolutionary maintenance of hermaphroditism in M. lignano. PMID- 29160914 TI - Hospital variation in costs - a challenge to the value proposition. PMID- 29160912 TI - Low sensitivity and frequent cross-reactions in commercially available antibody detection ELISA assays for Taenia solium cysticercosis. AB - OBJECTIVE: To evaluate the diagnostic performance of two commercially available ELISA kits, Novalisa(r) and Ridascreen(r) , for the detection of antibodies to Taenia solium, compared to serological diagnosis of neurocysticercosis (NCC) by LLGP-EITB (electro-immunotransfer blot assay using lentil-lectin purified glycoprotein antigens). METHODS: Archive serum samples from patients with viable NCC (n = 45) or resolved, calcified NCC (n = 45), as well as sera from patients with other cestode parasites (hymenolepiasis, n = 45 and cystic hydatid disease, n = 45), were evaluated for cysticercosis antibody detection using two ELISA kits, Novalisa(r) and Ridascreen(r) . All NCC samples had previously tested positive, and all samples from heterologous infections were negative on LLGP-EITB for cysticercosis. Positive rates were calculated by kit and sample group and compared between the two kits. RESULTS: Compared to LLGP-EITB, the sensitivity of both ELISA assays to detect specific antibodies in patients with viable NCC was low (44.4% and 22.2%), and for calcified NCC, it was only 6.7% and 4.5%. Sera from patients with cystic hydatid disease were highly cross-reactive in both ELISA assays (38/45, 84.4%; and 25/45, 55.6%). Sera from patients with hymenolepiasis cross-reacted in five cases in one of the assays (11.1%) and in only one sample with the second assay (2.2%). CONCLUSIONS: The performance of Novalisa(r) and Ridascreen(r) was poor. Antibody ELISA detection cannot be recommended for the diagnosis of neurocysticercosis. PMID- 29160916 TI - Changing of the Guard. PMID- 29160915 TI - Spray Drying of Spinach Juice: Characterization, Chemical Composition, and Storage. AB - The 1st aim of this study is to determine the influence of inlet and outlet air temperatures on the physical and chemical properties of obtained powders from spinach juice (SJ) with 3.2 +/- 0.2 degrees Brix ( degrees Bx). Second, the effect of 3 different drying agents (maltodextrin, whey powder, and gum Arabic) on the same properties was investigated for the selected inlet/outlet temperatures (160/100 degrees C) which gives the minimum moisture content and water activity values. For this purpose, the total soluble solid content of SJ was adjusted to 5.0 +/- 0.2 degrees Bx with different drying agents. Finally, the effects of different storage conditions (4, 20, and 30 degrees C) on the physical and chemical properties of spinach powders (SPs) produced at selected conditions were examined. A pilot scale spray dryer was used at 3 different inlet/outlet air temperatures (160 to 200 degrees C/80 to 100 degrees C) where the outlet air temperature was controlled by regulating the feed flow rate. Results showed that the moisture content, water activity, browning index, total chlorophyll, and total phenolic contents of the SP significantly decreased and pH and total color change of the SP significantly increased by the addition of different drying agents (P < 0.05). In addition, the changes in the above mentioned properties were determined during the storage period, at 3 different temperatures. It was also observed that the vitamin C, beta-carotene, chlorophyll, and phenolic compounds retention showed first-order degradation kinetic with activation energy of 32.6840, 10.2736, 27.7031, and 28.2634 kJ/K.mol, respectively. PMID- 29160917 TI - Visualization of calcium phosphate cement in teeth by zero echo time 1 H MRI at high field. AB - 1 H magnetic resonance imaging (MRI) by a zero echo time (ZTE) sequence is an excellent method to image teeth. Calcium phosphate cement (CPC) materials are applied in the restoration of tooth lesions, but it has not yet been investigated whether they can be detected by computed tomography (CT) or MRI. The aim of this study was to optimize high-field ZTE imaging to enable the visualization of a new CPC formulation implanted in teeth and to apply this in the assessment of its decomposition in vivo. CPC was implanted in three human and three goat teeth ex vivo and in three goat teeth in vivo. An ultrashort echo time (UTE) sequence with multiple flip angles and echo times was applied at 11.7 T to measure T1 and T2 * values of CPC, enamel and dentin. Teeth with CPC were imaged with an optimized ZTE sequence. Goat teeth implanted with CPC in vivo were imaged after 7 weeks ex vivo. T2 * relaxation of implanted CPC, dentin and enamel was better fitted by a model assuming a Gaussian rather than a Lorentzian distribution. For CPC and human enamel and dentin, the average T2 * values were 273 +/- 19, 562 +/- 221 and 476 +/- 147 MUs, respectively, the average T2 values were 1234 +/- 27, 963 +/- 151 and 577 +/- 41 MUs, respectively, and the average T1 values were 1065 +/- 45, 972 +/- 40 and 903 +/- 7 ms, respectively. In ZTE images, CPC had a higher signal to-noise-ratio than dentin and enamel because of the higher water content. Seven weeks after in vivo implantation, the CPC-filled lesions showed less homogeneous structures, a lower T1 value and T2 * separated into two components. MRI by ZTE provides excellent contrast for CPC in teeth and allows its decomposition to be followed. PMID- 29160918 TI - Impact of weight loss and eating difficulties on health-related quality of life up to 10 years after oesophagectomy for cancer. AB - BACKGROUND: Severe weight loss is experienced by patients with eating difficulties after surgery for oesophageal cancer. The aim of this prospective cohort study was to asssess the influence of eating difficulties and severe weight loss on health-related quality of life (HRQoL) up to 10 years after oesophagectomy. METHODS: Data on bodyweight and HRQoL were collected at 6 months, 3, 5 and 10 years in patients who underwent surgery for oesophageal cancer in Sweden between 2001 and 2005. Exposures were percentage weight loss, and eating difficulties defined by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-OES18 questionnaire. Outcomes were HRQoL scores from the EORTC QLQ-C30 questionnaire. Repeated-measures ANOVA, adjusting for potential confounders, was used to assess the association between eating difficulties and weight loss (4 exposure groups) and HRQoL scores at each time point. Mean score differences (MDs) between time points or exposure groups were defined as clinically relevant in accordance with evidence-based interpretation guidelines. RESULTS: In total, 92 of 104 10-year survivors (88.5 per cent) responded to the questionnaires. Weight loss was greatest within 6 months of surgery. Patients with eating difficulties with or without weight loss reported clinically and statistically significantly worsened HRQoL in almost all aspects. The largest MD was seen between 5 and 10 years after surgery for global quality of life, physical, role and social function (MD -22 to -30), as well for fatigue, nausea, dyspnoea, insomnia, appetite loss and diarrhoea (MD 24-36). CONCLUSION: Eating difficulties are associated with deterioration in several aspects of HRQoL up to 10 years after surgery for oesophageal cancer. PMID- 29160919 TI - Appropriate use criteria for transthoracic echocardiography: Are they relevant to European centers? AB - BACKGROUND: There is a growing interest in appropriate use criteria (AUC) for cardiovascular imaging referrals in Europe. These criteria, developed by American subspecialty societies, have been in use since 2007 and show a temporal reduction in inappropriate transthoracic echocardiogram (TTE) requests. When applied to European centers, inappropriate referral rates as high as 15% have been observed. METHODS: A retrospective analysis of TTE referrals for appropriateness and major abnormality detection was conducted over a two-month period at Cork University Hospital (CUH). RESULTS: Overall, 1277 requests were assessed, of which 97.7% were classifiable. Of the 1235 classifiable studies, 1049 (84.9%) were appropriate, 135 (10.9%) were inappropriate, and 51 (4.1%) were uncertain. Main indications were the evaluation of cardiac structure and function (496, 40.2%), hypertension, heart failure or cardiomyopathy (349, 28.3%), and valvular function (228, 18.5%). Inappropriate referral rates were significantly higher for outpatients compared to inpatients (13.8% vs 7.1%, P < .05) and cardiologist referrals compared to noncardiologists (13.1 vs 8.0%, P < .05), while one in three requests for the evaluation of valvular function (32.5%) were inappropriate. Compared to inappropriate studies, appropriate and uncertain scans had a greater prevalence of >=1 major abnormalities (33.6% vs 19.3%, P < .001) and greater detection rates of new abnormalities (27.6% vs 13.3%, P < .001). CONCLUSION: Application of the 2011 AUC yields similar results to those reported from the US. The application of said criteria to our center could avoid one of every ten scans currently ordered. PMID- 29160920 TI - Cobalt-Catalyzed Electrophilic Amination of Aryl- and Heteroarylzinc Pivalates with N-Hydroxylamine Benzoates. AB - Aryl- and heteroarylzinc pivalates can be aminated with O-benzoylhydroxylamines at 25 degrees C within 2-4 h in the presence of 2.5-5.0 % CoCl2 ?2 LiCl to furnish the corresponding tertiary arylated or heteroarylated amines in good yields. This electrophilic amination also provides access to diarylamines and aryl(heteroaryl)amines. A new tuberculosis drug candidate (Q203) was prepared in six steps and 56 % overall yield by using this cobalt-catalyzed amination as the key step. PMID- 29160921 TI - Sustained adoption of water, sanitation and hygiene interventions: systematic review. AB - OBJECTIVE: To understand factors that influence sustained adoption of water, sanitation and hygiene (WASH) technologies or behaviours. METHODS: Systematic review of the current literature. Articles were gathered from databases of peer reviewed articles and grey literature, and screened for relevance. After exclusion, we created a descriptive map of 148 articles and analysed in-depth 44 articles that had an explicit focus on promoting or evaluating sustained adoption or programme sustainability. Twenty-two of these articles met our definition of measuring sustained adoption. RESULTS: Definitions of sustained adoption varied widely and were often inadequate, making comparison of sustained adoption across studies difficult. The time frame for measurements of sustained adoption is frequently inadequate for examination of longer-term behaviour change. CONCLUSIONS: Ideally, an evaluation should specify the project period and describe the context surrounding adoption, make measurements at multiple time points, diversify measurement methods and describe and measure a range of factors affecting sustained adoption. Additional consideration needs to be given to developing behaviour change models that emphasise factors related to sustained adoption, and how they differ from those related to initial adoption. PMID- 29160922 TI - IGF1R signalling in testicular germ cell tumour cells impacts on cell survival and acquired cisplatin resistance. AB - Testicular germ cell tumours (TGCTs) are the most frequent malignancy and cause of death from solid tumours in the 20- to 40-year age group. Although most cases show sensitivity to cis-platinum-based chemotherapy, this is associated with long term toxicities and chemo-resistance. Roles for receptor tyrosine kinases other than KIT are largely unknown in TGCT. We therefore conducted a phosphoproteomic screen and identified the insulin growth factor receptor-1 (IGF1R) as both highly expressed and activated in TGCT cell lines representing the nonseminomatous subtype. IGF1R was also frequently expressed in tumour samples from patients with nonseminomas. Functional analysis of cell line models showed that long-term shRNA mediated IGF1R silencing leads to apoptosis and complete ablation of nonseminoma cells with active IGF1R signalling. Cell lines with high levels of IGF1R activity also showed reduced AKT signalling in response to decreased IGF1R expression as well as sensitivity to the small-molecule IGF1R inhibitor NVP-AEW541. These results were in contrast to those in the seminoma cell line TCAM2 that lacked IGF1R signalling via AKT and was one of the two cell lines least sensitive to the IGF1R inhibitor. The dependence on IGF1R activity in the majority of nonseminomas parallels the known role of IGF signalling in the proliferation, migration, and survival of primordial germ cells, the putative cell of origin for TGCT. Upregulation of IGF1R expression and signalling was also found to contribute to acquired cisplatin resistance in an in vitro nonseminoma model, providing a rationale for targeting IGF1R in cisplatin-resistant disease. (c) 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29160923 TI - Pregnancy weight gain by gestational age and stillbirth: a population-based cohort study. AB - OBJECTIVE: To study the association between total and early pregnancy (<22 completed weeks) weight gain and risk of stillbirth, stratified by early pregnancy body mass index (BMI). DESIGN: Population-based cohort study. SETTING: Stockholm-Gotland Region, Sweden. POPULATION: Pregnant women with singleton births (n = 160 560). METHODS: Pregnancy weight gain was standardised into gestational age-specific z-scores. For analyses of total pregnancy weight gain, a matched design with an incidence density sampling approach was used. Findings were also contrasted with current Institute of Medicine (IOM) weight gain recommendations. MAIN OUTCOME MEASURES: Stillbirth defined as fetal death at >=22 completed weeks of gestation. RESULTS: For all BMI categories, there was no statistical association between total or early pregnancy weight gain and stillbirth within the range of a weight gain z-score of -2.0 SD to +2.0 SD. Among normal-weight women, the adjusted odds ratio of stillbirth for lower (-2.0 to 1.0 SD) and higher (+1.0 to +1.9 SD) total weight gain was 0.85 (95% CI; 0.48 1.49) and 1.03 (0.60-1.77), respectively, as compared with the reference category. Further, there were no associations between total or early pregnancy weight gain and stillbirth within the range of weight gain currently recommended by the IOM. For the majority of the BMI categories, the point estimates at the extremes of weight gain values (<-2.0SD and >=2.0 SD) suggested protective effects of low weight gain and increased risks of high weight gain, but estimates were imprecise and not statistically significant. CONCLUSION: We found no associations between total or early pregnancy weight gain and stillbirth across the range of weight gain experienced by most women. TWEETABLE ABSTRACT: There was no association between weight gain during pregnancy and stillbirth among most women. PMID- 29160924 TI - Accelerated, untargeted metabolomics analysis of cutaneous T-cell lymphoma reveals metabolic shifts in plasma and tumor adjacent skins of xenograft mice. AB - Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms. Clinical management is stage based but diagnosis and prognosis could be extremely challenging. The presented study aims to explore the metabolic profiling of CTCL by an accelerated untargeted metabolomics data analysis tool "Mummichog" to facilitate the discoveries of potential biomarkers for clinical early stage diagnosis, prognosis, and treatments in CTCL. Ultra high-performance liquid chromatography-quadrupole time-of-flight-based untargeted metabolomics were conducted on the skin and plasma of CTCL mice. It showed that the metabolism of skin changed greatly versus control samples in the development of CTCL. Increased l-glutamate and decreased adenosine monophosphate were the most essential metabolic features of CTCL tumor and tumor adjacent skins. Unique metabolism changes in tumor adjacent non-involved skin tissues (ANIT) occurred in the progress of carcinogenesis, including upregulated cytidine-5'-triphosphate, aberrant biosynthesis of prostaglandins, pyrimidine, mevalonate pathway, and tryptophan degradation. Sharply elevated 5-phospho-alpha-d-ribose 1-diphosphate (PRPP) marked the final state of tumor in CTCL. In the plasma, systematic shifts in corticosterone, sphingolipid, and ceramide metabolism were found. These uncovered aberrant metabolites and metabolic pathways suggested that the metabolic reprogramming of PRPP in tumor tissues may cause the disturbance of cytidine and uridine metabolic homeostasis in ANIT. Accumulative cytidine-5' triphosphate in ANIT may exert positive feedback on the PRPP level and leads to CTCL further development. In addition, the accelerated data analysis tool "Mummichog" showed good practicability and can be widely used in high-resolution liquid chromatography mass spectrometry-based untargeted metabolomics. PMID- 29160925 TI - Effects of swaddled and traditional tub bathing methods on crying and physiological responses of newborns. AB - PURPOSE: The purpose of this study was to examine the effects of two bathing methods on crying duration and physiological measurements of newborns. DESIGN AND METHODS: A randomized trial design was used in this study. The sample consisted of newborns (n = 80) who were admitted to neonatal intensive care unit of a university hospital located in a large city. The groups were determined as swaddled bathing (SB) (n = 40) and traditional tub bathing (TTB) (n = 40) by using random number table. All newborns were bathed 24 hours after the birth. Environmental variables were organised identically in both experimental and control groups. Duration of bathing was determined as maximum 5 min in both groups. Body temperature, heart rate (HR), and O2 saturation values were evaluated before bath, just after the bath and at 10 min after the bath. The groups were compared in terms of all vital symptoms and duration of crying during bath. Pre-bath and post-bath stress levels between newborns in both groups were compared by using the Newborn Infant Pain Scale (NIPS). RESULTS: When the newborns were compared based on groups, it was observed that there was no statistically significant difference between SB and TTB groups in terms of the gestational week, APGAR score, postnatal age, and body weight. Body temperatures of the newborns in SB group just after the bath and 10 minutes after the bath were significantly higher than those in TTB group. HR was higher in TTB group in the post-bath period. NIPS scores of the newborns in SB group after bath decreased at a statistically significant level, but the scores of the newborns in TTB group increased. The results of the study indicated that SB was effective in maintaining body temperature, SpO2 level, and HR of newborns within normal limits and may decrease stress experienced during the bath. PRACTICE IMPLICATIONS: Swaddled bathing decreases behavioural stress symptoms such as crying, agitation, and pulling arms and legs back unintentionally and thus the infants feel relaxed. Swaddled bathing can be recommended because swaddled bathing method decreases behavioural stress symptoms in infants. PMID- 29160926 TI - Electro-mechanical response of a 3D nerve bundle model to mechanical loads leading to axonal injury. AB - Traumatic brain injuries and damage are major causes of death and disability. We propose a 3D fully coupled electro-mechanical model of a nerve bundle to investigate the electrophysiological impairments due to trauma at the cellular level. The coupling is based on a thermal analogy of the neural electrical activity by using the finite element software Abaqus CAE 6.13-3. The model includes a real-time coupling, modulated threshold for spiking activation, and independent alteration of the electrical properties for each 3-layer fibre within a nerve bundle as a function of strain. Results of the coupled electro-mechanical model are validated with previously published experimental results of damaged axons. Here, the cases of compression and tension are simulated to induce (mild, moderate, and severe) damage at the nerve membrane of a nerve bundle, made of 4 fibres. Changes in strain, stress distribution, and neural activity are investigated for myelinated and unmyelinated nerve fibres, by considering the cases of an intact and of a traumatised nerve membrane. A fully coupled electro mechanical modelling approach is established to provide insights into crucial aspects of neural activity at the cellular level due to traumatic brain injury. One of the key findings is the 3D distribution of residual stresses and strains at the membrane of each fibre due to mechanically induced electrophysiological impairments, and its impact on signal transmission. PMID- 29160927 TI - Climate change impacts on selected global rangeland ecosystem services. AB - Rangelands are Earth's dominant land cover and are important providers of ecosystem services. Reliance on rangelands is projected to grow, thus understanding the sensitivity of rangelands to future climates is essential. We used a new ecosystem model of moderate complexity that allows, for the first time, to quantify global changes expected in rangelands under future climates. The mean global annual net primary production (NPP) may decline by 10 g C m-2 year-1 in 2050 under Representative Concentration Pathway (RCP) 8.5, but herbaceous NPP is projected to increase slightly (i.e., average of 3 g C m-2 year-1 ). Responses vary substantially from place-to-place, with large increases in annual productivity projected in northern regions (e.g., a 21% increase in productivity in the US and Canada) and large declines in western Africa (-46% in sub-Saharan western Africa) and Australia (-17%). Soil organic carbon is projected to increase in Australia (9%), the Middle East (14%), and central Asia (16%) and decline in many African savannas (e.g., -18% in sub-Saharan western Africa). Livestock are projected to decline 7.5 to 9.6%, an economic loss of from $9.7 to $12.6 billion. Our results suggest that forage production in Africa is sensitive to changes in climate, which will have substantial impacts on the livelihoods of the more than 180 million people who raise livestock on those rangelands. Our approach and the simulation tool presented here offer considerable potential for forecasting future conditions, highlight regions of concern, and support analyses where costs and benefits of adaptations and policies may be quantified. Otherwise, the technical options and policy and enabling environment that are needed to facilitate widespread adaptation may be very difficult to elucidate. PMID- 29160928 TI - Genotyping-by-sequencing for estimating relatedness in nonmodel organisms: Avoiding the trap of precise bias. AB - There has been remarkably little attention to using the high resolution provided by genotyping-by-sequencing (i.e., RADseq and similar methods) for assessing relatedness in wildlife populations. A major hurdle is the genotyping error, especially allelic dropout, often found in this type of data that could lead to downward-biased, yet precise, estimates of relatedness. Here, we assess the applicability of genotyping-by-sequencing for relatedness inferences given its relatively high genotyping error rate. Individuals of known relatedness were simulated under genotyping error, allelic dropout and missing data scenarios based on an empirical ddRAD data set, and their true relatedness was compared to that estimated by seven relatedness estimators. We found that an estimator chosen through such analyses can circumvent the influence of genotyping error, with the estimator of Ritland (Genetics Research, 67, 175) shown to be unaffected by allelic dropout and to be the most accurate when there is genotyping error. We also found that the choice of estimator should not rely solely on the strength of correlation between estimated and true relatedness as a strong correlation does not necessarily mean estimates are close to true relatedness. We also demonstrated how even a large SNP data set with genotyping error (allelic dropout or otherwise) or missing data still performs better than a perfectly genotyped microsatellite data set of tens of markers. The simulation-based approach used here can be easily implemented by others on their own genotyping-by-sequencing data sets to confirm the most appropriate and powerful estimator for their data. PMID- 29160929 TI - Anatomical Variations of the Human Cochlea Determined from Micro-CT and High Resolution CT Imaging and Reconstruction. AB - Understanding the anatomical variations in the human cochlea is important for cochlear implants. This study examined these variations using a reconstructed fusion model of the skull and temporal bone. The three-dimensional (3D) digital model of the temporal bone was reconstructed from multiple axial micro-computed tomography (CT) scans of temporal bone and high resolution CT of the skull from 15 cadavers. A skull model was reconstructed and merged with the reconstructed temporal bone. The 3D relationship between the cochlea and the skull's mid sagittal plane was analyzed. The alpha and beta angles of the cochlear autogenous rotation and bottom position, respectively, further subdivided the cochlear spatial orientation. The relationship between the base of the cochlea and the round window was evaluated with the Phi angle. Cochlear size was measured and the relationship was statistically analyzed. Cochlear implant electrode arrays were observed in five cases of right-temporal bone specimens. The alpha, beta, and Phi angles were 46.01 +/- 9.65, 56.79 +/- 3.58, and 44.41 +/- 7.23, respectively. The alpha angle varied greatly and was negatively correlated to the Phi angle (correlation coefficient = -0.211, P < 0.05). Among the five specimens, the alpha and Phi angle of the 2R and 4R cochlear specimens was lower and higher than the mean value, respectively. These measurements revealed variations in the size and position of the cochlea. Some of these variations may require surgical adjustments for insertion of electrodes with cochlear implants and present a greater challenge for implantation of cochlear electrode implantation. These data also provide a better understanding of variations in human cochlear anatomy. Anat Rec, 301:1086-1095, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29160931 TI - Hepatitis C viremic donors for hepatitis C nonviremic liver transplant recipients: Ready for prime time? PMID- 29160930 TI - Brain responses to social norms: Meta-analyses of fMRI studies. AB - Social norms have a critical role in everyday decision-making, as frequent interaction with others regulates our behavior. Neuroimaging studies show that social-based and fairness-related decision-making activates an inconsistent set of areas, which sometimes includes the anterior insula, anterior cingulate cortex, and others lateral prefrontal cortices. Social-based decision-making is complex and variability in findings may be driven by socio-cognitive activities related to social norms. To distinguish among social-cognitive activities related to social norms, we identified 36 eligible articles in the functional magnetic resonance imaging (fMRI) literature, which we separate into two categories (a) social norm representation and (b) norm violations. The majority of original articles (>60%) used tasks associated with fairness norms and decision-making, such as ultimatum game, dictator game, or prisoner's dilemma; the rest used tasks associated to violation of moral norms, such as scenarios and sentences of moral depravity ratings. Using quantitative meta-analyses, we report common and distinct brain areas that show concordance as a function of category. Specifically, concordance in ventromedial prefrontal regions is distinct to social norm representation processing, whereas concordance in right insula, dorsolateral prefrontal, and dorsal cingulate cortices is distinct to norm violation processing. We propose a neurocognitive model of social norms for healthy adults, which could help guide future research in social norm compliance and mechanisms of its enforcement. PMID- 29160932 TI - On the Use of Polyelectrolytes and Polymediators in Organic Electrosynthesis. AB - Although organic electrosynthesis is generally considered to be a green method, the necessity for excess amounts of supporting electrolyte constitutes a severe drawback. Furthermore, the employment of redox mediators results in an additional separation problem. In this context, we have explored the applicability of soluble polyelectrolytes and polymediators with the TEMPO-mediated transformation of alcohols into carbonyl compounds as a test reaction. Catalyst benchmarking based on cyclic voltammetry studies indicated that the redox-active polymer can compete with molecularly defined TEMPO species. Alcohol oxidation was also highly efficient on a preparative scale, and our polymer-based approach allowed for the separation of both mediator and supporting electrolyte in a single membrane filtration step. Moreover, we have shown that both components can be reused multiple times. PMID- 29160933 TI - Xyloglucan in the primary cell wall: assessment by FESEM, selective enzyme digestions and nanogold affinity tags. AB - Xyloglucan has been hypothesized to bind extensively to cellulose microfibril surfaces and to tether microfibrils into a load-bearing network, thereby playing a central role in wall mechanics and growth, but this view is challenged by newer results. Here we combined high-resolution imaging by field emission scanning electron microscopy (FESEM) with nanogold affinity tags and selective endoglucanase treatments to assess the spatial location and conformation of xyloglucan in onion cell walls. FESEM imaging of xyloglucanase-digested cell walls revealed an altered microfibril organization but did not yield clear evidence of xyloglucan conformations. Backscattered electron detection provided excellent detection of nanogold affinity tags in the context of wall fibrillar organization. Labelling with xyloglucan-specific CBM76 conjugated with nanogold showed that xyloglucans were associated with fibril surfaces in both extended and coiled conformations, but tethered configurations were not observed. Labelling with nanogold-conjugated CBM3, which binds the hydrophobic surface of crystalline cellulose, was infrequent until the wall was predigested with xyloglucanase, whereupon microfibril labelling was extensive. When tamarind xyloglucan was allowed to bind to xyloglucan-depleted onion walls, CBM76 labelling gave positive evidence for xyloglucans in both extended and coiled conformations, yet xyloglucan chains were not directly visible by FESEM. These results indicate that an appreciable, but still small, surface of cellulose microfibrils in the onion wall is tightly bound with extended xyloglucan chains and that some of the xyloglucan has a coiled conformation. PMID- 29160934 TI - Highly Efficient Perovskite Solar Cells Based on Zn2 Ti3 O8 Nanoparticles as Electron Transport Material. AB - Developing ternary metal oxides as electron transport layers (ETLs) for perovskite solar cells is a great challenge in the field of third-generation photovoltaics. In this study, a highly mesoporous Zn2 Ti3 O8 (m-ZTO) scaffold is synthesized by ion-exchange method and used as ETL for the fabrication of methyl ammonium lead halide (CH3 NH3 PbI3 ) perovskite solar cells. The optimized devices exhibit 17.21 % power conversion efficiency (PCE) with an open circuit voltage (Voc ) of 1.02 V, short-circuit current density (Jsc ) of 21.97 mA cm-2 and fill factor (FF) of 0.77 under AM 1.5G sunlight (100 mW cm-2 ). The PCE is significantly higher than that based on mesoporous ST01 (m-ST01; 10 nm TiO2 powder) layer (eta=14.93 %), which is ascribed to the deeper conductive band of ZTO nanoparticles, better light absorption and smaller charge recombination. The devices stored for 100 days at ambient temperature with humidity of 10 % showed excellent stability with only 12 % reduction of the PCE. The charge transmission kinetic and long-term stability parameters of the ZTO-based perovskite film growth are discussed as well. PMID- 29160935 TI - Oh, the places they'll go! A survey of phytopathogen effectors and their host targets. AB - Phytopathogens translocate effector proteins into plant cells where they sabotage the host cellular machinery to promote infection. An individual pathogen can translocate numerous distinct effectors during the infection process to target an array of host macromolecules (proteins, metabolites, DNA, etc.) and manipulate them using a variety of enzymatic activities. In this review, we have surveyed the literature for effector targets and curated them to convey the range of functions carried out by phytopathogenic proteins inside host cells. In particular, we have curated the locations of effector targets, as well as their biological and molecular functions and compared these properties across diverse phytopathogens. This analysis validates previous observations about effector functions (e.g. immunosuppression), and also highlights some interesting features regarding effector specificity as well as functional diversification of phytopathogen virulence strategies. PMID- 29160936 TI - Liquid Photonic Crystals for Mesopore Detection. AB - Nitrogen adsorption-desorption for mesopore characterization requires the using of expensive instrumentation, time-consuming processes, and the consumption of liquid nitrogen. Herein, a new method is developed to measure the pore parameters through mixing a mesoporous substance with a supersaturated SiO2 colloidal solution at different temperatures, and subsequent rapid measurement of reflection changes of the precipitated liquid photonic crystals. The pore volumes and diameters of mesoporous silica were measured according to the positive correlation between unit mass reflection change (Deltalambda/m) and pore volume (V), and the negative correlation between average absorption temperature (T) and pore diameter (D). This new approach may provide an alternative method for fast, convenient and economical characterization of mesoporous materials. PMID- 29160938 TI - 'Knitting-through-the-mesh': Novel single-channel troubleshooter technique for dilation-assisted transstricture retrieval of a migrated gastroduodenal stent. PMID- 29160937 TI - MicroRNA 26b promotes colorectal cancer metastasis by downregulating phosphatase and tensin homolog and wingless-type MMTV integration site family member 5A. AB - Invasion and metastasis are crucially important factors in the survival of malignant tumors. Epithelial-mesenchymal transition (EMT) is an early step in metastatic progression and the presence of cancer stem cells is closely related to tumor survival, proliferation, metastasis, and recurrence. Herein we report that ectopic overexpression of microRNA 26b (miR-26b) in colorectal cancer (CRC) cell lines promoted EMT and stem cell-like phenotypes in vitro. Furthermore, miR 26b directly targeted and suppressed multiple tumor suppressors, including phosphatase and tensin homolog (PTEN) and wingless-type MMTV integration site family member 5A (WNT5A). Notably, miR-26b is markedly upregulated in tumor samples from patients with lymphatic metastases. These results indicate that miR 26b promotes CRC metastasis by downregulating PTEN and WNT5A, and may represent a therapeutic target for metastatic CRC. PMID- 29160939 TI - Ir-Catalyzed Asymmetric and Regioselective Hydrogenation of Cyclic Allylsilanes and Generation of Quaternary Stereocenters via the Hosomi-Sakurai Allylation. AB - A number of cyclic dienes containing the allylsilane moiety were prepared by a Birch reduction and subjected to iridium-catalyzed regioselective and asymmetric hydrogenation, which provided chiral allylsilanes in high conversion and enantiomeric excess (up to 99 % ee). The compounds were successively used in the Hosomi-Sakurai allylation with various aldehydes employing TiCl4 as Lewis acid, providing adducts with two additional stereogenic centers in excellent diastereoselectivity. PMID- 29160940 TI - Morphological transformation of hBMSC from 2D monolayer to 3D microtissue on low crystallinity SF-PCL patch with promotion of cardiomyogenesis. AB - The effects of the stiffness of substrates on the cell behaviours of human bone marrow-derived mesenchymal stem cells (hBMSC) have been investigated, but the effects of the secondary structures of proteins in the substrates on the morphological transformation and differentiation of hBMSC have yet been elucidated. To investigate these issues, silk fibroin-poly(epsilon-caprolactone) SP cardiac patches of poly(epsilon-caprolactone; P), on which is grafted by silk fibroin (SF) with various beta-sheet contents (or crystallinity) to provide various degrees of stiffness, were produced to examine the in vitro behaviours of hBMSC during proliferation, and cardiomyogenesis on the SP patches. beta-sheet contents of SF from 20% to 44% (SP20 to SP44, respectively) were induced on patches, which were examined by attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy, and analysed using the Fourier self deconvolution method. The stiffness of the SP patches, quantified by their Young's moduli and elasticities, increased with the crystallinity of the SF. During 3 days of proliferation, hBMSC migrated and morphologically transformed into 3D microtissues with diameters of approximately 150-200 MUm on low-stiffness SP20 and SP30 patches, whereas 2D monolayers were observed on the SP37 and SP44 patches. The 3D microtissues/patch yielded more extensive in vitro cardiomyogenesis of hBMSC than the 2D cell monolayer with significantly higher expressions of all examined cardiac-specific proteins after induction by 5-aza. Notably, in vivo subcutaneously growing 3D microtissues on SP20 patches and a 2D monolayer on SP44 patches were preliminarily demonstrated in a rat model. Morphological transformations of hBMSC from a 2D monolayer to a 3D microtissue by low-stiffness SP cardiac patches, promoting cardiomyogenesis, provide a new opportunity for cardiac tissue engineering. PMID- 29160941 TI - Age of Alcohol Initiation and Progression to Binge Drinking in Adolescence: A Prospective Cohort Study. AB - BACKGROUND: Early alcohol initiation is common and has been associated with the development of alcohol problems. Yet, past research on the association of age of initiation with later problem drinking has produced inconsistent findings. Using prospective data from the Australian Parental Supply of Alcohol Longitudinal Study cohort, this study examined age of alcohol initiation, and of first drunkenness, and associations with subsequent drinking in adolescence. METHODS: A total of 1,673 parent-child dyads recruited through Australian secondary schools completed annual surveys for 5 years (grades 7 to 11). Limiting the sample to those adolescents who had initiated alcohol use by age 17 (n = 839), multinomial logistic regression models were used to examine associations between (i) age of initiation to alcohol use (consuming at least 1 full serve) and (ii) age of first drunkenness, and 2 outcomes: (i) binge drinking (consuming >4 standard drinks on a single occasion), and (ii) the total number of alcoholic drinks consumed in the past year, adjusted for a range of potential child, parent, family, and peer covariates. RESULTS: Fifty percent of adolescents reported alcohol use and 36% reported bingeing at wave 5 (mean age 16.9 years), and the mean age of initiation to alcohol use for drinkers was 15.1 years. Age of initiation was significantly associated with binge drinking and total quantity of alcohol consumed in unadjusted and adjusted models. Age of first drunkenness was associated with total quantity of alcohol consumed in unadjusted models but not adjusted models and was not associated with subsequent bingeing. CONCLUSIONS: Initiating alcohol use earlier in adolescence is associated with an increased risk of binge drinking and higher quantity of consumption in late secondary school, supporting an argument for delaying alcohol initiation for as long as possible to reduce the risk for problematic use in later adolescence and the alcohol-related harms that may accompany this use. PMID- 29160943 TI - A meta-analysis of the differential relations of traditional and cyber victimization with internalizing problems. AB - This meta-analysis examined the associations between cyber-victimization and internalizing problems controlling for the occurrence of traditional victimization. Twenty independent samples with a total of 90,877 participants were included. Results confirmed the significant intercorrelation between traditional and cyber-victimization (r = .43). They both have medium-to-large bivariate correlations with internalizing problems. Traditional victimization (sr = .22) and cyber-victimization (sr = .12) were also uniquely related to internalizing problems. The difference in the relations between each type of victimization and internalizing problems was small (differential d = .06) and not statistically significant (p = .053). Moderation of these effect sizes by sample characteristics (e.g., age and proportion of girls) and study features (e.g., whether a definition of bullying was provided to participants and the time frame used as reference) was investigated. Results are discussed within the extant literature on cyber-aggression and cyber-victimization and future directions are proposed. PMID- 29160942 TI - Bioinspired Mesoporous Chiral Nematic Graphitic Carbon Nitride Photocatalysts modulated by Polarized Light. AB - Endowing materials with chirality and exploring the responses of the material under circularly polarized light (CPL) can enable further insight into the physical and chemical properties of the semiconductors to be gained, thus expanding on optoelectronic applications. Herein a bioinspired mesoporous chiral nematic graphitic carbon nitride (g-C3 N4 ) for efficient hydrogen evolution with polarized light modulation based on chiral nematic cellulose nanocrystal films prepared through silica templating is described. The mesoporous nematic chiral g C3 N4 exhibits an ultrahigh hydrogen evolution rate of 219.9 MUmol h-1 (for 20 mg catalyst), corresponding to a high enhancement factor of 55 when compared to the bulk g-C3 N4 under lambda>420 nm irradiation. Furthermore, the chiral g-C3 N4 material exhibits unique photocatalytic activity modulated by CPL within the absorption region. This CPL-assisted photocatalytic regulation strategy holds great promise for a wide range of applications including optical devices, asymmetric photocatalysis, and chiral recognition/separation. PMID- 29160944 TI - Ketogenic Diet Suppresses Alcohol Withdrawal Syndrome in Rats. AB - BACKGROUND: Alcohol use disorder is underdiagnosed and undertreated, and up to 50% of alcohol-abstinent patients diagnosed with alcohol dependence relapse within the first year of treatment. Current treatments for the maintenance of alcohol abstinence in patients with alcohol use disorder have limited efficacy, and there is an urgent need for novel treatment strategies. Decreased cerebral glucose metabolism and increased brain uptake of acetate were recently reported in heavy drinkers, relative to controls. Given the switch of metabolic fuel from glucose to acetate in the alcohol-dependent brain, we investigated the potential therapeutic benefit of a ketogenic diet in managing alcohol withdrawal symptoms during detoxification. METHODS: Male Sprague Dawley rats fed either ketogenic or regular diet were administered ethanol or water orally, twice daily for 6 days while the diet conditions were maintained. Abstinence symptoms were rated 6, 24, 48, and 72 hours after the last alcohol administration. RESULTS: Maintenance on a ketogenic diet caused a significant decrease in the alcohol withdrawal symptoms' "rigidity" and "irritability." CONCLUSIONS: Our preclinical pilot study suggests that a ketogenic diet may be a novel approach for treating alcohol withdrawal symptoms in humans. PMID- 29160945 TI - Lacosamide Pharmacokinetics in a Critically Ill Patient Receiving Continuous Venovenous Hemofiltration. AB - Lacosamide is a new-generation antiepileptic drug (AED) that is eliminated by both hepatic and renal mechanisms. Lacosamide elimination by continuous renal replacement therapy (CRRT) has never been studied. The objective of this case report was to describe lacosamide pharmacokinetics in the setting of CRRT. We describe a single patient admitted to the study center with status epilepticus and multiorgan failure. The patient required both continuous venovenous hemofiltration (CVVH) and several AEDs. He was receiving intravenous lacosamide 200 mg twice/day at steady state prior to sampling. Plasma lacosamide concentrations were derived using a validated high-performance liquid chromatography method. Parameters were calculated using Phoenix WinNonlin 7.1 software. The peak concentration at steady state was 7.7 mg/L, the trough concentration was 5.9 mg/L (goal 5-12 mg/L). The volume of distribution was 0.7 L/kg, the elimination half-life was 21 hours, and the sieving coefficient was 0.8 (+/- 0.06). Lacosamide was cleared by CVVH as demonstrated by the sieving coefficient, but plasma concentrations remained within goal range throughout the dosing interval. These results may suggest that lacosamide 200 mg twice/day is a useful dosing strategy for critically ill patients who require CVVH. PMID- 29160946 TI - Panel proposal for the immunophenotypic diagnosis of hematological malignancies. A collaborative consensus from the groupe d'Etude Immunologique des Leucemies (GEIL). AB - After a cycle of meetings and discussions, members of the French Groupe d'Etude Immunologique des Leucemies obtained consensus on a series of immunophenotyping panels for hematological malignancies. The rationale of the markers chosen is depicted for each of them. This proposal comes for instruments with 8 or 10 colors. Care was taken to minimize the fluorochromes attached to any given specificity and to leave, whenever possible, some free slots for the cytometrist's choice. PMID- 29160947 TI - Thymic function is a major determinant of onset of antibody-mediated rejection in heart transplantation. AB - Thymic function decreases progressively with age but may be boosted in certain circumstances. We questioned whether heart transplantation was such a situation and whether thymic function was related to the onset of rejection. Twenty-eight antithymocyte globulin-treated heart transplant recipients were included. Patients diagnosed for an antibody-mediated rejection on endomyocardial biopsy had a higher proportion of circulating recent thymic emigrant CD4+ T cells and T cell receptor excision circle levels than other transplanted subjects. Thymus volume and density, assessed by computed tomography in a subset of patients, was also higher in patients experiencing antibody-mediated rejection. We demonstrate that thymic function is a major determinant of onset of antibody-mediated rejection and question whether thymectomy could be a prophylactic strategy to prevent alloimmune humoral responses. PMID- 29160950 TI - Superconductivity in a Copper(II)-Based Coordination Polymer with Perfect Kagome Structure. AB - A highly crystalline copper(II) benzenehexathiolate coordination polymer (Cu-BHT) has been prepared. The two-dimensional kagome structure has been confirmed by powder X-ray diffraction, high-resolution transmission electron microscopy, and high-resolution scanning transmission electron microscopy. The as-prepared sample exhibits bulk superconductivity at about 0.25 K, which is confirmed by the zero resistivity, AC magnetic susceptibility, and specific heat measurements. Another diamagnetic transition at about 3 K suggests that there is a second superconducting phase that may be associated with a single layer or few layers of Cu-BHT. It is the first time that superconductivity has been observed in a coordination polymer. PMID- 29160951 TI - Exploiting the Strong Hydrogen Bond Donor Properties of a Borinic Acid Functionality for Fluoride Anion Recognition. AB - Borinic acids have typically not been considered as hydrogen bond donor groups in molecular recognition. Described herein is a bifunctional borane/borinic acid derivative (2) in which the two functionalities are connected by a 1,8 biphenylenediyl backbone. Anion binding studies reveal that 2 readily binds a fluoride anion by formation of a unique B-F???H-O-B hydrogen bond. This hydrogen bond is characterized by a short H-F distance of 1.79(3) A and a large coupling constant (1 JHF ) of 57.2 Hz. The magnitude of this interaction, which has also been investigated computationally, augments the fluoride anion binding properties of 2, thus making it compatible with aqueous environments. PMID- 29160948 TI - Disability, social functioning and school inclusion among older children and adolescents living with HIV in Zimbabwe. AB - OBJECTIVE: Increasing numbers of children with HIV are surviving to adolescence and encountering multiple clinical and social consequences of long-standing HIV infection. We aimed to investigate the association between HIV and disability, social functioning and school inclusion among 6- to 16-year-olds in Zimbabwe. METHODS: HIV-infected children receiving antiretroviral therapy from a public sector HIV clinic and HIV-uninfected children attending primary care clinics in the same catchment area were recruited. Standardised questionnaires were used to collect socio-demographic, social functioning and disability data. Multivariable logistic regression was used to assess the relationship between HIV status and disability and functioning. RESULTS: We recruited 202 HIV-infected and 285 HIV uninfected children. There was no difference in age and gender between the two groups, but a higher proportion of HIV-infected children were orphaned. The prevalence of any disability was higher in HIV-infected than uninfected children (37.6% vs. 18.5%, P < 0.001). HIV-infected children were more likely to report anxiety (adjusted odds ratio (aOR) 4.4; 95% CI 2.4, 8.1), low mood (aOR 4.2; 2.1, 8.4) and difficulty forming friendships (aOR 14.8; 1.9, 116.6) than uninfected children. Children with HIV also reported more missed school days, repeating a school year and social exclusion in class. These associations remained apparent when comparing children with HIV and disability to those with HIV but no disabilities. CONCLUSIONS: Children with HIV commonly experience disabilities, and this is associated with social and educational exclusion. Rehabilitation and support services are needed to facilitate educational attainment and social participation in this group. PMID- 29160949 TI - Failure to initiate HIV treatment in patients with high CD4 counts: evidence from demographic surveillance in rural South Africa. AB - OBJECTIVES: To assess the relationship between CD4 count at presentation and ART uptake and assess predictors of timely treatment initiation in rural KwaZulu Natal, South Africa. METHODS: We used Kaplan-Meier and Cox proportional hazards models to assess the association between first CD4 count and time from first CD4 to ART initiation among all adults presenting to the Hlabisa HIV Treatment and Care Programme between August 2011 and December 2012 with treatment-eligible CD4 counts (<= 350 cells/mm3 ). For a subset of healthier patients (200 < CD4 <= 350 cells) residing within the population surveillance of the Africa Health Research Institute, we assessed sociodemographic, economic and geographic predictors hypothesised to influence ART uptake. RESULTS: A total of 4739 patients presented for care with eligible CD4 counts. The proportion initiating ART within six months of diagnosis was 67% (95% CI 63, 71) in patients with CD4 <= 50, 59% (0.55, 0.63) in patients with CD4 151-200 and 48% (95% CI 44, 51) in patients with CD4 301-350. The hazard of starting ART fell by 17% (95% CI 14, 20) for every 100-cell increase in baseline CD4 count. Among healthier patients under demographic surveillance (n = 193), observable sociodemographic, economic and geographic predictors did not add discriminatory power beyond CD4 count, age and sex to identify patients at high risk of non-initiation. CONCLUSIONS: Individuals presenting for HIV care at higher CD4 counts were less likely to initiate ART than patients presenting at low CD4 counts. Overall, ART uptake was low. Under new guidelines that establish ART eligibility regardless of CD4 count, patients with high CD4 counts may require additional interventions to encourage treatment initiation. PMID- 29160952 TI - Transit time mapping in the mouse brain using time-encoded pCASL. AB - The cerebral blood flow (CBF) is a potential biomarker for neurological disease. However, the arterial transit time (ATT) of the labeled blood is known to potentially affect CBF quantification. Furthermore, ATT could be an interesting biomarker in itself, as it may reflect underlying macro- and microvascular pathologies. Currently, no optimized magnetic resonance imaging (MRI) sequence exists to measure ATT in mice. Recently, time-encoded labeling schemes have been implemented in rats and humans, enabling ATT mapping with higher signal-to-noise ratio (SNR) and shorter scan time than multi-delay arterial spin labeling (ASL). In this study, we show that time-encoded pseudo-continuous arterial spin labeling (te-pCASL) also enables transit time measurements in mice. As an optimal design that takes the fast blood flow in mice into account, time encoding with 11 sub boli of 50 ms is proposed to accurately probe the inflow of labeled blood. For perfusion imaging, a separate, traditional pCASL scan was employed. From the six studied brain regions, the hippocampus showed the shortest ATT (169 +/- 11 ms) and the auditory/visual cortex showed the longest (284 +/- 16 ms). Furthermore, ATT was found to be preserved in old wild-type mice. In a mouse with an induced carotid artery occlusion, prolongation of ATT was shown. In conclusion, this study shows the successful implementation of te-pCASL in mice, making it possible, for the first time, to measure ATT in mice in a time-efficient manner. PMID- 29160953 TI - Assessing Hypervalency in Iodanes. AB - The so-called hypervalent iodane compounds are very useful and versatile reactants and oxidizing agents in modern organic chemistry. The hypercoordinated central iodine in these compounds hints at a hypervalent state, which is often stressed to justify their reactivity. In this study a theoretical analysis of the electronic structure of a large, representative set of hypercoordinated iodane compounds has been carried out. We observed that the iodonium is not hypervalent in these compounds. In contrast, the analysis reveals a variation of the iodine valence state from a normal octet state to hypovalent depending on the ligands, but irrespective of the coordination number. On the basis of the calculations the reactivity of these compounds can be ascribed to the strong unquenched charge separation present in these molecules which represents a compromise between Coulomb interaction and the resistance of iodonium toward hypervalency. In extreme cases this leads to hypovalency and enhanced reactivity. PMID- 29160954 TI - Islet alloautotransplantation: Allogeneic pancreas transplantation followed by transplant pancreatectomy and islet transplantation. AB - Simultaneous pancreas-kidney (SPK) transplantation is an important treatment option for patients with type 1 diabetes (T1D) and end-stage renal disease (ESRD). Due to complications, in up to 10% of patients, allograft pancreatectomy is necessary shortly after transplantation. Usually the donor pancreas is discarded. Here, we report on a novel procedure to rescue endocrine tissue after allograft pancreatectomy. A 39-year-old woman with T1D and ESRD who had undergone SPK transplantation required emergency allograft pancreatectomy due to bleeding at the vascular anastomosis. Islets were isolated from the removed pancreas allograft, and almost 480 000 islet equivalents were infused into the portal vein. The patient recovered fully. After 3 months, near-normal mixed meal test (fasting glucose 7.0 mmol/L, 2-hour glucose 7.5 mmol/L, maximal stimulated C peptide 3.25 nmol/L, without insulin use in the preceding 36 hours) was achieved. Glycated hemoglobin while taking a low dose of long-acting insulin was 32.7 mmol/mol hemoglobin (5.3%). When a donor pancreas is lost after transplantation, rescue beta cell therapy by islet alloautotransplantation enables optimal use of scarce donor pancreata to optimize glycemic control without additional HLA alloantigen exposure. PMID- 29160955 TI - Synthesis and Biological Evaluation of Pyrrolo[2,1-f][1,2,4]triazine C Nucleosides with a Ribose, 2'-Deoxyribose, and 2',3'-Dideoxyribose Sugar Moiety. AB - The synthesis of hitherto unknown pyrrolo[2,1-f][1,2,4]triazine C-nucleosides is described. Structural variations (chlorine, bromine, iodine, and cyano groups) were introduced at position 7 of 4-aza-7,9-dideazaadenine. In addition, pyrrolo[2,1-f][1,2,4]triazine C-nucleosides bearing a 2'-deoxy-, 2',3'-dideoxy-, and 2',3'-dehydrodideoxyribose moiety were also prepared. Among these analogues, the pyrrolo[2,1-f][1,2,4]triazine C-ribonucleosides with either a hydrogen atom or cyano group at position 7 of the nucleobase displayed potent cytotoxic activity in a panel of various cancer cell lines. PMID- 29160956 TI - Photosensitization of Molecular Oxygen on Graphene Oxide for Ultrasensitive Signal Amplification. AB - H2 O2 and horseradish peroxidase (HRP) are commonly used together in bioassays. HRP is required to accelerate the reaction between a chromogenic substrate (e.g., 3,3',5,5'-tetramethylbenzidine, TMB) and H2 O2 , and thus amplifies the signal. Herein, molecular oxygen for enzyme-free and H2 O2 -free oxidation is explored, still using the same colorimetric reaction. Restricted by spin selection rules, the ground-state triplet oxygen needs to be converted to the singlet state to oxidize TMB. Phloxine B (PB) is used as the photosensitizer because of its excellent performance and safety. Under green light irradiation, each PB has a turnover of approximately 51 TMB molecules in 20 min, making PB a "molecular enzyme mimic" for signal amplification. With its small size, multiple PB molecules are loaded on a graphene oxide nanosheet to design a modified enzyme linked immunosorbance (ELISA) assay (termed photosensitization immunosorbent assay, PISA), improving the 1:1 enzyme/target ratio to n:1. PISA is more sensitive for carcinoembryonic antigen than a commercial ELISA kit, and successfully measures the antigen in the serum of multiple cancer patients. This simple and green method of oxidation coupled with the small size of the photosensitizer and graphene oxide may enable many other applications in biosensor development, smart materials, and energy harvesting. PMID- 29160957 TI - Insect cuticular melanins are distinctly different from those of mammalian epidermal melanins. AB - Melanin from several insect samples was isolated and subjected to chemical degradation and HPLC analysis for melanin markers. Quantification of different melanin markers reveals that insect melanins are significantly different from that of the mammalian epidermal melanins. The eumelanin produced in mammals is derived from the oxidative polymerization of both 5,6-dihydroxyindole and 5,6 dihydroxyindole-2-carboxylic acids. The pheomelanin is formed by the oxidative polymerization of cysteinyldopa. Thus, dopa is the major precursor for both eumelanin and pheomelanin in mammals. But insect eumelanin appears to be mostly made from 5,6-dihydroxyindole and originates from dopamine. More importantly, our study points out the wide spread occurrence of pheomelanin in many insect species. In addition, cysteinyldopamine and not cysteinyldopa is the major precursor for insect pheomelanin. Thus, both eumelanin and pheomelanin in insects differ from higher animals using dopamine and not dopa as the major precursor. PMID- 29160959 TI - Invited response to recurrence of oxalate nephropathy after isolated kidney transplantation for primary hyperoxaluria type 2. PMID- 29160958 TI - Prognostic value of an immunohistochemical signature in patients with esophageal squamous cell carcinoma undergoing radical esophagectomy. AB - Here, we aimed to identify an immunohistochemical (IHC)-based classifier as a prognostic factor in patients with esophageal squamous cell carcinoma (ESCC). A cohort of 235 patients with ESCC undergoing radical esophagectomy (with complete clinical and pathological information) were enrolled in the study. Using the least absolute shrinkage and selection operator (LASSO) regression model, we extracted six IHC features associated with progression-free survival (PFS) and then built a classifier in the discovery cohort (n = 141). The prognostic value of this classifier was further confirmed in the validation cohort (n = 94). Additionally, we developed a nomogram integrating the IHC-based classifier to predict the PFS. We used the IHC-based classifier to stratify patients into high- and low-risk groups. In the discovery cohort, 5-year PFS was 22.4% (95% CI: 0.14 0.36) for the high-risk group and 43.3% (95% CI: 0.32-0.58) for the low-risk group (P = 0.00064), and in the validation cohort, 5-year PFS was 20.58% (95% CI: 0.12-0.36) for the high-risk group and 36.43% (95% CI: 0.22-0.60) for the low risk group (P = 0.0082). Multivariable analysis demonstrated that the IHC-based classifier was an independent prognostic factor for predicting PFS of patients with ESCC. We further developed a nomogram integrating the IHC-based classifier and clinicopathological risk factors (gender, American Joint Committee on Cancer staging, and vascular invasion status) to predict the 3- and 5-year PFS. The performance of the nomogram was evaluated and proved to be clinically useful. Our 6-IHC marker-based classifier is a reliable prognostic tool to facilitate the individual management of patients with ESCC after radical esophagectomy. PMID- 29160960 TI - Risk of Past Year Injury Related to Hours of Exposure to an Elevated Blood Alcohol Concentration and Average Monthly Alcohol Volume: Data from 4 National Alcohol Surveys (2000 to 2015). AB - BACKGROUND: While a strong association exists between alcohol and injury in emergency department (ED) studies, these studies are not representative of the general population. METHODS: The association of injury with the number of hours of exposure to a blood alcohol concentration (BAC) >= 0.05 and average monthly volume in drinks, both based on self-report of quantity and frequency of drinking in the last year, in a merged sample of respondents (n = 29,571) from 4 U.S. National Alcohol Surveys (2000 to 2015) are analyzed. Risk curves based on categorical step function and fractional polynomial modeling were analyzed separately by gender, and by age and race/ethnicity for males. RESULTS: Risk of injury increased at 1 hour of a BAC exposure of >= 0.05 and at an average monthly volume of 1 drink. Risk of injury for spirits increased to an average daily volume of 1 drink, but no association was found for injury risk and average volume for either wine or beer. Risk of injury increased with both exposure hours and monthly volume among males, but little association was found for either consumption measure with risk of injury for females. Among males, increased risk of injury was greater for whites than for blacks or Hispanics for BAC exposure; Hispanics showed a continued elevated risk up to 8 hours of exposure. After peaking at a monthly volume of 1 drink, injury risk decreased substantially for blacks, but was more gradual for whites, while risk increased very slightly for Hispanics to about 4 drinks per day. Males aged 18 to 29 showed the largest increase in risk associated with the number of hours of exposure to a BAC of >=0.05, with risk doubling at 1 hour of exposure, but subsequently falling. CONCLUSIONS: While findings here are weaker than those from ED studies and likely due to the context of drinking, risk of injury appears to increase at relatively low levels of consumption, suggesting the importance of preventive efforts to reduce injury not only for heavier drinkers but also for more moderate drinkers. PMID- 29160961 TI - A Metal-Organic Framework with Exceptional Activity for C-H Bond Amination. AB - The development of catalysts capable of fast, robust C-H bond amination under mild conditions is an unrealized goal despite substantial progress in the field of C-H activation in recent years. A Mn-based metal-organic framework (CPF-5) is described that promotes the direct amination of C-H bonds with exceptional activity. CPF-5 is capable of functionalizing C-H bonds in an intermolecular fashion with unrivaled catalytic stability producing >105 turnovers. PMID- 29160962 TI - Recognizing and Dealing with Moral Distress. PMID- 29160963 TI - Nephrology Nurses Week - 2017. PMID- 29160964 TI - Examining Depression in Patients on Dialysis. AB - This study measured the prevalence of depression in 39 patients on hemodialysis and peritoneal dialysis in two urban outpatient facilities in the southeastern United States. Additionally, it evaluated the number of patients who sought and scheduled a mental health evaluation after screening and education. The prevalence of mild to severely depressed individuals among participants in this study was 36%, affirming previous findings of depressive symptoms in the ESRD population. Results suggest that patients with ESRD are at a higher risk for depression than the general population. The effects of depression may exacerbate ESRD symptoms, affect treatment adherence, and increase hospitalizations and morbidity. It is likely that screening, diagnosing, and treating depression will be associated with improvement in quality and quantity of life. The practicality of using the screening procedure may improve the detection of depression in this population. However, only a fraction of identified patients in this study pursued further mental health evaluation within the 45-day period. Continued research is needed to identify barriers to seeking mental health consultation and treatment in this community. PMID- 29160965 TI - Current State-of-Practice: Transportation for Patients with End Stage Renal Disease. AB - Patients receiving care for the management of end stage renal disease require transport to nephrology practice settings and treatment centers for hemodialysis and peritoneal dialysis. This type of transportation, defined as non-emergency medical transportation, has long presented a challenge for patients, families, and healthcare providers. This article explores the current and projected statistics and trends for chronic kidney disease,transportation challenges faced by patients and nephrology healthcare providers, and examples of successful transportation services and programs. Implications for practice with a focus placed on the importance of an interprofessional approach are described. PMID- 29160966 TI - Emphasizing the Value of Nephrology Nursing Through Nursing-Sensitive Indicators: A Call for Action. AB - Nursing is the largest healthcare profession in the United States (U.S.). As principal frontline caregivers in the U.S. healthcare system, nurses have tremendous influence over a patient's healthcare experience. A growing body of evidence states that the nursing workforce has a direct impact on healthcare quality. A standardized approach to measuring nursing's contribution to patient care and safety using nursing-sensitive quality indicators assists in examining the extent to which nurses and nursing affect the quality and safety of health care. This article focuses on nursing-sensitive quality indicators and discusses healthcare quality indicators and nursing-sensitive indicators used in the U.S. A summary of the work of the American Nephrology Nurses' Association Task Force on Nephrology Nursing-Sensitive Quality Indicators (NNSQI) and an NNSQI exemplar are provided. PMID- 29160967 TI - Holistic Care of Hemodialysis Access in Patients with Kidney Failure. AB - Kidney failure requiring hemodialysis is a chronic illness that has physical, psychosocial, and financial consequences. Patients with kidney failure receiving hemodialysis need a renewed focus on self-care, prevention, and community-based health management to reduce healthcare costs and complications, and improve outcomes and quality of life, while living with an altered lifestyle. A holistic chronic care model was applied as a guideline for healthcare professionals involved with this population to more effectively engage people with kidney failure in their management of their hemodialysis access. PMID- 29160968 TI - Fatigue in Patients with Chronic Kidney Disease: Evidence and Measures. AB - As many as 70% to 97% of individuals with chronic kidney disease (CKD) report fatigue. Fatigue is one of the common, troubling symptoms that affects one's quality of life. This narrative review summarizes the evidence and gaps about the epidemiology, causative factors, and assessment of fatigue in individuals with CKD. Most studies are focused on the hemodialysis population, with very few focused on the peritoneal dialysis and transplant populations in which fatigue is also prevalent. Understanding fatigue and its correlates can help in assessing fatigue and in implementing interventions to alleviate fatigue. PMID- 29160969 TI - Nursing Care for Patients with Biological Arteriovenous Grafts. AB - Patients receiving hemodialysis are challenged with maintaining adequate vascular access. Nephrology nurses are on the forefront of daily care, assessment, and monitoring of patients' vascular accesses for hemodialysis. This article discusses the literature and manufacturer information to support best nursing practices. PMID- 29160970 TI - Audits: Is Audit a Four-Letter Word? PMID- 29160972 TI - The Entry Way to Excellent Care Begins with the Access. PMID- 29160971 TI - Dialysis Access - A Lifeline for Patients and a Challenge. PMID- 29160973 TI - Outcomes for Successful Cannulation of the Arteriovenous Fistula: Perspectives from Patients on Hemodialysis. AB - There is a lack of consensus in the literature on what constitutes successful arteriovenous fistula (AVF) cannulation outcomes from the patient perspective. The purpose of this study was to describe what successful cannulation means to patients on hemodialysis. A qualitative descriptive approach was used. A purposeful sample of 17 patients dialyzing with an AVF participated in one face to-face interview. Using content analysis, four themes were identified that impact the patient experience in defining successful cannulation: 1) an emotional response - pain and anxiety, 2) a 'friendly' nurse-patient relationship, 3) nursing interventions/technical skills during cannulation, and 4) the impact of the environment. Results provide valuable insight into what patients define as successful cannulation, recognizing that it goes beyond the actual needle insertion procedure. PMID- 29160974 TI - Nursing Care for Patients with Synthetic Arteriovenous Grafts. AB - Dealing with a growing older adult patient population, keeping pace with current guidelines, and adhering to new recommendations is a perpetual endeavor for healthcare professionals. Because determining the best access for individual patients is not always obvious, vascular access is a challenging aspect of patient care. This article presents information on the ever-evolving and improving world of vascular access, specifically synthetic grafts. PMID- 29160975 TI - Peritoneal Dialysis Access Management: More Than Skin Deep. AB - Providing care and education for a patient on peritoneal dialysis (PD) requires that the nephrology nurse have knowledge and expertise in the PD access. This article provides information on types and placement of PD catheters, pre placement and post-placement education and care, how to assess PD catheter exit site healing, and initial use of the PD catheter for access. PMID- 29160976 TI - Cannulation Outcomes of the Arteriovenous Fistula for Hemodialysis: A Scoping Review. AB - The arteriovenous fistula (AVF) is the recommended access for most people requiring hemodialysis. Success or failure of cannulation of the AVF greatly impacts the patient's experience. Research suggests that skill development in this area is needed. This scoping review was conducted to review current research on cannulation of the AVF to find strategies to improve successful cannulation. Results of this scoping review (n = 36)demonstrated that most studies can be categorized under the technique of cannulation, and concerns and preferences with the AVF as a consequence of cannulation. There are large gaps in the literature, with interventions to improve cannulation and a need to understand more about cannulation from both patient and nurse perspectives. PMID- 29160977 TI - Using Evidence-Based Practice and an Educational Intervention to Improve Vascular Access Management: A Pilot Project. AB - Abstract. PMID- 29160978 TI - Cannulation Technique and Arteriovenous Fistula Survival in Older Adult Patients on Hemodialysis. AB - Cannulation technique has the potential to impact arteriovenous fistula (AVF) function. The aim of this research was to determine the impact of cannulation technique on the length of the functioning AVFs in older adult patients on hemodialysis. The study included 110 participants with fistula thrombosis who had used area technique or rope ladder technique. Biochemical parameters, gender, demographic, and clinical variables were determined. Patients who used the area cannulation technique differed significantly from patients using the rope ladder technique with regard to duration of hemodialysis (p < 0.001), outcome of the AVF revision (p = 0.045), and positioning of the anastomosis (p = 0.013). The group that used the area cannulation technique had a longer duration of hemodialysis, proximal anastomoses, and more successful revisions of AVFs. PMID- 29160979 TI - Patient Care Technicians Managing Hemodialysis Central Venous Catheter Care: Pro and Con. AB - In the United States, the responsibilities and scope of practice of nephrology nurses and patient care technicians working in hemodialysis units vary from state to state. This occurs in relation to the care and management of central venous catheters (CVCs) used for hemodialysis. The aim of this article is to review the pros and cons of non-nursing staff performing the management and care of CVCs. The pros include decreasing nursing task time, allowing nurses to devote their time to other higher functioning roles, while the cons include lack of technician skill, education, and experience to perform CVC management and care. PMID- 29160980 TI - Antegrade vs. Retrograde Cannulation: Does the Evidence Support a Practice Change? PMID- 29160981 TI - Effect of Fluid Status on Access Blood Flow Measurements as Observed in a Hospital-Based Hemodialysis Unit Servicing Inpatients and Outpatients. PMID- 29160982 TI - Gold Can Tarnish. It's hard to stay on the EMS leadership highway. PMID- 29160983 TI - EDs Report Strong Surges in Flu-related Volume, Straining Capacity in Some Regions. AB - With influenza season intensifying, many EDs report strong surges in flu related volume. Although illness severity does not appear to be atypical, hospitals that see high numbers of older patients and the chronically ill face extra challenges meeting the needs of patients who have added susceptibility to flu-related complications. Experts note that all flu strains circulating this year appear to be sensitive to antiviral medications. In mid-February, the CDC reported the number of flu cases was still on the increase in most regions of the country, with 28 states reporting a high incidence of influenza-like illness. Hospitals in Portland, OR, have instituted "zone management" multiple times -- a process whereby ambulances are supervised closely and redirected so that individual hospitals do not become overwhelmed. EDs in both Pennsylvania and Missouri report that flu-related volume is much higher this year than in 2016. The vast majority of flu cases this year involve influenza A (H3N2), although the CDC notes that influenza B viruses also are circulating. PMID- 29160984 TI - In Search of Effective Solutions to Curb Workplace Violence. AB - Investigators have applied epidemiological principles to the study of workplace violence, producing results that offer intriguing information to hospitals struggling for a way forward on this issue. In a randomized, to hospitals struggling for a wary forward on this issue. In a randomized, controlled trial, the researchers found that a one-time, unit-based intervention can reduce the incidence of violent events, and that the approach offers some lasting effect over time. The intervention consisted of a 45-minute discussion with unit supervisors in which unit-specific data regarding violent incidents in their workplace were shared along with an array of improvement strategies. Unit supervisors then were directed to work with their teams to develop action plans to address violence, although they were free to adopt whatever solutions they deemed best. At six moths post-intervention, there was a clear reduction in the incident rate ratios of violent events on the intervention units as compared with control units that did not conduct an intervention. Experts note that the study demonstrates that an effective workplace violence intervention or program must be data-driven and based on principles of continuous quality improvement. PMID- 29160985 TI - Emergency Medicine Stakeholders Voice Priorities for Healthcare Reform, Urge Individual Clinicians to Get Involved. AB - With President Trump and congressional Republicans promising to repeal or replace parts of the entirety of the Affordable Care Act (ACA), emergency medicine stakeholders are making sure lawmakers know what provisions in the law must remain intact, and what new reforms are needed. They also are urging emergency medicine clinicians to stay informed on the issues, and to advocate for their interests. The American College of Emergency Physicians (ACEP) wants to ensure that emergency services remain essential covered benefits, and that freestanding EDs and other emerging healthcare delivery models are supported.Although ACEP calls on lawmakers to preserve Medicaid, Medicare, and the Children's Health Insurance Program, the organization is less than satisfied with the insurance products offered on the ACA exchanges. The organization wants lawmakers to address both the affordability and transparency of coverage options. The Emergency Nurses Association calls for an expanded role for advanced practice registered nurses in both primary and emergency care, and it wants more action to improve access to mental healthcare services. PMID- 29160986 TI - Defining Innovation. Supervising EMS officer competencies. PMID- 29160987 TI - Simulate to Educate. Training is more than classrooms and textbooks. PMID- 29160988 TI - Against the Grain. Reacting to today's most fashionable allergen. PMID- 29160989 TI - Backboard Blues. Study says long spine boards may not be worth the trouble. PMID- 29160990 TI - Physiological Pediatrics. An all-encompassing refresher on pediatrics. PMID- 29160991 TI - Just Culture. How accountability in EMS creates a culture of trust. PMID- 29160992 TI - Culture of Safety. Are we really practicing what we preach? PMID- 29160993 TI - Clinical Competitions. Patient care competitions offer providers a unique EMS learning experience. PMID- 29160994 TI - Learning to Save a Life. Using simulation to refine skills and take your system to the next level. PMID- 29160995 TI - Jam packed. How and when to escalate hemorrhage control to more invasive means. PMID- 29160996 TI - Fighting Futility. Traumatic cardiac arrest survivability is possible. PMID- 29160997 TI - Last Word. The Ups and Downs of EMS. PMID- 29161005 TI - ESI MS for Microsized Bioparticles. AB - An ESI ion trap mass spectrometer was designed for high-throughput and rapid mass analysis of large bioparticles. Mass calibration of the instrument was performed using commercially available polystyrene (PS) microparticles with a size comparable to cancer cells. Different sizes of MCF-7 breast cancer cells (8 to 15 MUm) were used in this study. The masses of different cancer cells were measured. This system allows for the analysis of all types of particles. PMID- 29161007 TI - Polymer-Based Technologies for Sensing Applications. PMID- 29161008 TI - Mapping the Functional Tortuosity and Spatiotemporal Heterogeneity of Porous Polymer Membranes with Super-Resolution Nanoparticle Tracking. AB - As particles flow through porous media, they follow complex pathways and experience heterogeneous environments that are challenging to characterize. Tortuosity is often used as a parameter to characterize the complexity of pathways in porous materials and is useful in understanding hindered mass transport in industrial filtration and mass separation processes. However, conventional calculations of tortuosity provide only average values under static conditions; they are insensitive to the intrinsic heterogeneity of porous media and do not account for potential effects of operating conditions. Here, we employ a high-throughput nanoparticle tracking method which enables the observation of actual particle trajectories in polymer membranes under relevant operating conditions. Our results indicate that tortuosity is not simply a structural material property but is instead a functional property that depends on flow rate and particle size. We also resolved the spatiotemporal heterogeneity of flowing particles in these porous media. The distributions of tortuosity and of local residence/retention times were surprisingly broad, exhibiting heavy tails representing a population of highly tortuous trajectories and local regions with anomalously long residence times. Interestingly, local tortuosity and residence times were directly correlated, suggesting the presence of highly confining regions that cause more meandering trajectories and longer retention times. The comprehensive information about tortuosity and spatiotemporal heterogeneity provided by these methods will advance the understanding of complex mass transport and assist rational design and synthesis of porous materials. PMID- 29161006 TI - ToP-DNJ, a Selective Inhibitor of Endoplasmic Reticulum alpha-Glucosidase II Exhibiting Antiflaviviral Activity. AB - Iminosugars have therapeutic potential against a range of diseases, due to their efficacy as glycosidase inhibitors. A major challenge in the development of iminosugar drugs lies in making a compound that is selective for the glycosidase associated with a given disease. We report the synthesis of ToP-DNJ, an antiviral iminosugar-tocopherol conjugate. Tocopherol was incorporated into the design of the iminosugar in order to direct the drug to the liver and immune cells, specific tissues of interest for antiviral therapy. ToP-DNJ inhibits ER alpha glucosidase II at low micromolar concentrations and selectively accumulates in the liver in vivo. In cellular assays, the drug showed efficacy exclusively in immune cells of the myeloid lineage. Taken together, these data demonstrate that inclusion of a native metabolite into an iminosugar provides selectivity with respect to target enzyme, target cell, and target tissue. PMID- 29161009 TI - A Sensitive Microbead-Based Organic Media-Assisted Method for Proteomics Sample Preparation from Dilute and Denaturing Solutions. AB - We developed a robust and sensitive sample preparation method for proteomics termed microbead-based and organic-media-assisted proteolysis strategy (BOPs). BOPs combines two advantages of current techniques, (1) unbiased binding of reversed-phase polymeric microbeads to any type of protein and (2) enhanced trypsin digestion efficiency in CH3CN-aqueous solvent systems, into a single-tube workflow. Compared with conventional techniques, this method effectively concentrates proteins and improves proteolytic digestion, and can be used with submicromolar protein samples in dilute or denaturing solutions, such as 70% formic acid, 8 M urea, or 7 M guanidine hydrochloride without any sample pretreatment. Proteome analysis of single Caenorhabditis elegans organisms demonstrates that BOPs has the sensitivity, reproducibility, and unbiasedness required to characterize worm proteins at a single organism level. We also show that, by simply incorporating an acetone washing step for detergent removal, BOPs is applicable to low concentration samples contaminated with a variety of detergents, including sodium dodecyl sulfate, with negligible protein loss. Moreover, the utility of this modification has also been demonstrated through proteomic characterization of 2000 human (HEK293T) cells lysed using 1% Triton X 100. The simplicity and availability of the present BOPs make it especially attractive for next-stage proteomics of rare and sample-limited systems. PMID- 29161010 TI - Emerging Approaches for Spatiotemporal Control of Targeted Genome with Inducible CRISPR-Cas9. PMID- 29161011 TI - Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics. AB - Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2 hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Ki values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 A resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC50 of 11.7 +/- 3.2 MUM against Pf lines grown in culture and a CC50 in human A549 cell lines of 102 +/- 11 MUM, thus giving it a ~10-fold selectivity index. PMID- 29161013 TI - Intelligent "Peptide-Gathering Mechanical Arm" Tames Wild "Trojan-Horse" Peptides for the Controlled Delivery of Cancer Nanotherapeutics. AB - Cell-penetrating peptides (CPPs), also called "Trojan-Horse" peptides, have been used for facilitating intracellular delivery of numerous diverse cargoes and even nanocarriers. However, the lack of targeting specificity ("wildness" or nonselectivity) of CPP-nanocarriers remains an intractable challenge for many in vivo applications. In this work, we used an intelligent "peptide-gathering mechanical arm" (Int PMA) to curb CPPs' wildness and enhance the selectivity of R9-liposome-based cargo delivery for tumor targeting. The peptide NGR, serving as a cell-targeting peptide for anchoring, and peptide PLGLAG, serving as a substrate peptide for deanchoring, were embedded in the Int PMA motif. The Int PMA construct was designed to be sensitive to tumor microenvironmental stimuli, including aminopeptidase N (CD13) and matrix metalloproteinases (MMP-2/9). Moreover, Int PMA could be specifically recognized by tumor tissues via CD13 mediated anchoring and released for cell entry by MMP-2/9-mediated deanchoring. To test the Int PMA design, a series of experiments were conducted in vitro and in vivo. Functional conjugates Int PMA-R9-poly(ethylene glycol) (PEG)2000 distearoylphosphatidyl-ethanolamine (DSPE) and R9-PEG2000-DSPE were synthesized by Michael addition reaction and were characterized by thin-layer chromatography and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. The Int PMA-R9-modified doxorubicin-loaded liposomes (Int PMA-R9-Lip-DOX) exhibited a proper particle diameter (approximately 155 nm) with in vitro sustained release characteristics. Cleavage assay showed that Int PMA-R9 peptide molecules could be cleaved by MMP-2/9 for completion of deanchoring. Flow cytometry and confocal microscopy studies indicated that Int PMA-R9-Lip-DOX can respond to both endogenous and exogenous stimuli in the presence/absence of excess MMP-2/9 and MMP-2/9 inhibitor (GM6001) and effectively function under competitive receptor-binding conditions. Moreover, Int PMA-R9-Lip-DOX generated more significant subcellular dispersions that were especially evident within endoplasmic reticulum (ER) and Golgi apparatus. Notably, Int PMA-R9-Lip-DOX could induce enhanced apoptosis, during which caspase 3/7 might be activated. In addition, Int PMA-R9-Lip-DOX displayed enhanced in vitro and in vivo antitumor efficacy versus "wild" R9-Lip-DOX. On the basis of investigations at the molecular level, cellular level, and animals' level, the control of Int PMA was effective and promoted selective delivery of R9-liposome cargo to the target site and reduced nonspecific uptake. This Int PMA-controlled strategy based on aminopeptidase-guided anchoring and protease-triggered deanchoring effectively curbed the wildness of CPPs and bolstered their effectiveness for in vivo delivery of nanotherapeutics. The specific nanocarrier delivery system used here could be adapted using a variety of intelligent designs based on combinations of multifunctional peptides that would specifically and preferentially bind to tumors versus nontumor tissues for tumor-localized accumulation in vivo. Thus, CPPs have a strong advantage for the development of intelligent nanomedicines for targeted tumor therapy. PMID- 29161014 TI - Toward an Axial Nanoscale Ruler for Fluorescence Microscopy. AB - In the discussion of resolution in optical microscopy, axial precision has often come second to its lateral counterpart. However, biological systems make no special arrangements for our preferred direction of imaging. The ability to measure axial distances, that is, the heights of fluorophores relative to a plane of reference, is thus of paramount importance and has been the subject of several recent advances. A novel method is to modify the fluorescence emission based on the height of the individual fluorophore, such that its z-position is encoded somehow in the detected signal. One such approach is metal-enhanced energy transfer, recently extended to multicolor distance measurements and applied to study the topography of the nuclear membrane. Here, the fluorescence lifetime is shortened due to the proximity of the fluorophores to a thin metallic surface. Fluorescence lifetime imaging can therefore be used as an axial ruler with nanometer precision. PMID- 29161015 TI - Exploring the Potential of Biocompatible Osmoprotectants as Highly Efficient Cryoprotectants. AB - Cryoprotectants (CPAs) are critical to successful cryopreservation because they can protect cells from cryoinjuries. Because of the limitations of current CPAs, especially the toxicity, the search for new effective CPAs is attracting increasing attention. In this work, we reported that natural biocompatible osmoprotectants, which could protect cells from osmotic injury in various biological systems, might also be ideal candidates for CPAs. Three representative biocompatible osmoprotectants (proline, glycine, and taurine) were tested and compared. It was found that, aside from presenting a different ability to prevent osmotic injury, these biocompatible osmoprotectants also possessed a different ability to inhibit ice formation and thus mitigate intra-/extracellular ice injury. Because of the strongest ability to prevent the two types of injuries, we found that proline performed the best in cryopreserving five different types of cells. Moreover, the natural osmoprotectants are intrinsically biocompatible with the cells, superior to the current state-of-the-art CPA, dimethyl sulfoxide (DMSO), which is a toxic organic solvent. This work opens a new window of opportunity for DMSO-free cryopreservation, and sheds light on the applications of osmoprotectants in cryoprotection, which may revolutionize the current cryopreservation technologies. PMID- 29161017 TI - Detecting Interactions between Nanomaterials and Cell Membranes by Synthetic Nanopores. AB - Engineered nanomaterials have been increasingly utilized in industry for various consumer products, environmental treatments, energy storage, and biomedical applications. Meanwhile, it has been established that certain nanomaterials can be toxic to biological cells from extensive experimental and theoretical studies. Despite that the exact molecular mechanisms of this nanomaterial toxicity are still not well understood, it is ubiquitous that their interactions with cell membranes, through either endocytosis or penetration (and thus potential lysis), act as the first step toward the inflammation or even the death of a cell. To facilitate the study of nanomaterial-membrane interactions, here we demonstrate a nanopore-based single-molecule approach that can be applied to monitor a specific nanomaterial-membrane interaction in real time. Combined with molecular dynamics and experimental approaches, we show how an ionic current can be used to detect membrane damage by a graphene nanosheet and illustrate the underlying molecular mechanism. More generally, we expect that measured transmembrane ionic currents (both DC and AC) can signify many particle-induced membrane modifications, such as hole formation, particle adsorption, and protein insertion. PMID- 29161016 TI - Selective Voltage-Gated Sodium Channel Peptide Toxins from Animal Venom: Pharmacological Probes and Analgesic Drug Development. AB - Voltage-gated sodium channels (Navs) play critical roles in action potential generation and propagation. Nav channelopathy as well as pathological sensitization contribute to allodynia and hyperalgesia. Recent evidence has demonstrated the significant roles of Nav subtypes (Nav1.3, 1.7, 1.8, and 1.9) in nociceptive transduction, and therefore these Navs may represent attractive targets for analgesic drug discovery. Animal toxins are structurally diverse peptides that are highly potent yet selective on ion channel subtypes and therefore represent valuable probes to elucidate the structures, gating properties, and cellular functions of ion channels. In this review, we summarize recent advances on peptide toxins from animal venom that selectively target Nav1.3, 1.7, 1.8, and 1.9, along with their potential in analgesic drug discovery. PMID- 29161018 TI - Self-Powered Biosensors. AB - Self-powered electrochemical biosensors utilize biofuel cells as a simultaneous power source and biosensor, which simplifies the biosensor system, because it no longer requires a potentiostat, power for the potentiostat, and/or power for the signaling device. This review article is focused on detailing the advances in the field of self-powered biosensors and discussing their advantages and limitations compared to other types of electrochemical biosensors. The review will discuss self-powered biosensors formed from enzymatic biofuel cells, organelle-based biofuel cells, and microbial fuel cells. It also discusses the different mechanisms of sensing, including utilizing the analyte being the substrate/fuel for the biocatalyst, the analyte binding the biocatalyst to the electrode surface, the analyte being an inhibitor of the biocatalyst, the analyte resulting in the blocking of the bioelectrocatalytic response, the analyte reactivating the biocatalyst, Boolean logic gates, and combining affinity-based biorecognition elements with bioelectrocatalytic power generation. The final section of this review details areas of future investigation that are needed in the field, as well as problems that still need to be addressed by the field. PMID- 29161012 TI - Top-Down Proteomics: Ready for Prime Time? PMID- 29161019 TI - Local Enhancement of Lipid Membrane Permeability Induced by Irradiated Gold Nanoparticles. AB - Photothermal therapies are based on the optical excitation of plasmonic nanoparticles in the biological environment. The effects of the irradiation on the biological medium depend critically on the heat transfer process at the nanoparticle interface, on the temperature reached by the tissues, as well as on the spatial extent of temperature gradients. Unfortunately, both the temperature and its biological effects are difficult to be probed experimentally at the molecular scale. Here, we approach this problem using nonequilibrium molecular dynamics simulations. We focus on photoporation, a photothermal application based on the irradiation of gold nanoparticles by single, short-duration laser pulses. The nanoparticles, stably bound to cell membranes, convert the radiation into heat, inducing transient changes of membrane permeability. We make a quantitative prediction of the temperature gradient around the nanoparticle upon irradiation by typical experimental laser fluences. Water permeability is locally enhanced around the nanoparticle, in an annular region that extends only a few nanometers from the nanoparticle interface. We correlate the local enhancement of permeability at the nanoparticle-lipid interface to the temperature inhomogeneities of the membrane and to the consequent availability of free volume pockets within the membrane core. PMID- 29161020 TI - Deformation Drives Alignment of Nanofibers in Framework for Inducing Anisotropic Cellulose Hydrogels with High Toughness. AB - Deformation-driven alignment of macromolecules or nanofibers leading to anisotropy is a challenge in functional soft materials. Here, tough cellulose hydrogels that exhibited deformation-induced anisotropy are fabricated by reacting cellulose with a small amount of epichlorohydrin (EPI) in LiOH/urea solution and subsequent treating with dilute acid. The loosely cross-linked network that was obtained via chemical cross-linking of cellulose with EPI as a large framework maintained the elasticity of hydrogels, whereas nanofibers produced by the acid treatment formed physical cross-linked networks through hydrogen bonds which could efficiently dissipated mechanical energy. Meanwhile, the nanofibers could further aggregate to form submicrobundles and participate in the formation of frameworks during the acid treatment. Under deformation, the nanofibers and submicrobundles in the physical networks synchronize easily to align with the large framework, generating the rapidly responsive birefringence behaviors with highly stable colors. Thus, the cellulose hydrogels possessing sensitively mechano-responsive behavior could be utilized as a dynamic light switch and a soft sensor to accurately detect small external force, respectively. This work opens a novel pathway to construct tough and mechanoresponsive hydrogels via a green conversion of natural polysaccharide. PMID- 29161021 TI - Recent Advances in Solid Nanopore/Channel Analysis. PMID- 29161022 TI - Structural and Functional Studies of the Daunorubicin Priming Ketosynthase DpsC. AB - Daunorubicin is a type II polyketide, one of a large class of polyaromatic natural products with anticancer, antibiotic, and antiviral activity. Type II polyketides are formed by the assembly of malonyl-CoA building blocks, though in rare cases, biosynthesis is initiated by the incorporation of a nonmalonyl derived starter unit, which adds molecular diversity to the poly-beta-ketone backbone. Priming mechanisms for the transfer of novel starter units onto polyketide synthases (PKS) are still poorly understood. Daunorubicin biosynthesis incorporates a unique propionyl starter unit thought to be selected for by a subclass ("DpsC type") of priming ketosynthases (KS III). To date, however, no structural information exists for this subclass of KS III enzymes. Although selectivity for self-acylation with propionyl-CoA has previously been implied, we demonstrate that DpsC shows no discrimination for self-acylation or acyl-transfer to the cognate acyl carrier protein, DpsG with short acyl-CoAs. We present five crystal structures of DpsC, including apo-DpsC, acetyl-DpsC, propionyl-DpsC, butyryl-DpsC, and a cocrystal of DpsC with a nonhydrolyzable phosphopantetheine (PPant) analogue. The DpsC crystal structures reveal the architecture of the active site, the molecular determinants for catalytic activity and homology to O malonyl transferases, but also indicate distinct differences. These results provide a structural basis for rational engineering of starter unit selection in type II polyketide synthases. PMID- 29161024 TI - Performance and Stability Enhancement of In-Sn-Zn-O TFTs Using SiO2 Gate Dielectrics Grown by Low Temperature Atomic Layer Deposition. AB - Silicon dioxide (SiO2) films were synthesized by plasma-enhanced atomic layer deposition (PEALD) using BTBAS [bis(tertiarybutylamino) silane] as the precursor and O2 plasma as the reactant, at a temperature range from 50 to 200 degrees C. While dielectric constant values larger than 3.7 are obtained at all deposition temperatures, the leakage current levels are drastically reduced to below 10-12 A at temperatures above 150 degrees C, which are similar to those obtained in thermally oxidized and PECVD grown SiO2. Thin film transistors (TFTs) based on In Sn-Zn-O (ITZO) semiconductors were fabricated using thermal SiO2, PECVD SiO2, and PEALD SiO2 grown at 150 degrees C as the gate dielectrics, and superior device performance and stability are observed in the last case. A linear field effect mobility of 68.5 cm2/(V s) and a net threshold voltage shift (DeltaVth) of approximately 1.2 V under positive bias stress (PBS) are obtained using the PEALD SiO2 as the gate insulator. The relatively high concentration of hydrogen in the PEALD SiO2 is suggested to induce a high carrier density in the ITZO layer deposited onto it, which results in enhanced charge transport properties. Also, it is most likely that the hydrogen atoms have passivated the electron traps related to interstitial oxygen defects, thus resulting in improved stability under PBS. Although the PECVD SiO2 contains a hydrogen concentration similar to that of PEALD SiO2, its relatively large surface roughness appears to induce scattering effects and the generation of electron traps, which result in inferior device performance and stability. PMID- 29161023 TI - The in Vivo Neurochemical Profile of Selectively Bred High-Responder and Low Responder Rats Reveals Baseline, Cocaine-Evoked, and Novelty-Evoked Differences in Monoaminergic Systems. AB - Relative to bred low-responder (bLR) rats, bred high-responder (bHR) rats have an exaggerated locomotor response to a novel environment, take more risks, are more impulsive, and more likely to exhibit compulsive drug-seeking behaviors. These phenotypic differences in addiction-related behaviors and temperament have previously been associated with differences in neurotransmitter signaling, including the mesolimbic dopamine system. In this study, we applied advanced in vivo microdialysis sampling in the nucleus accumbens of bHRs and bLRs to assess differences in basal and stimulated neurochemical efflux more broadly. We used liquid chromatography-mass spectrometry measurements of dialysate samples to quantify a panel of 17 neurochemicals, including dopamine, norepinephrine, serotonin, histamine, glutamate, GABA, acetylcholine, adenosine, DOPAC, 3-MT, HVA, 5-HIAA, normetanephrine, taurine, serine, aspartate, and glycine. We also applied a stable isotope labeling technique to assess absolute baseline concentrations of dopamine and norepinephrine in the nucleus accumbens. Finally, we investigated the role of norepinephrine tone in the nucleus accumbens on the bHR phenotype. Our findings show that bHRs have elevated basal and cocaine-evoked dopamine and norepinephrine levels in the nucleus accumbens compared to those of bLRs. Furthermore, norepinephrine signaling in the nucleus accumbens appeared to be an important contributor to the bHR phenotype because bilateral perfusion of the alpha1 adrenergic receptor antagonist terazosin (10 MUM) into the nucleus accumbens abolished the response of bHRs to novelty. These findings are the first to demonstrate a role for norepinephrine in the bHR phenotype. They reveal a positive relationship between dopamine and norepinephrine signaling in the nucleus accumbens in mediating the exaggerated response to novelty and point to norepinephrine signaling as a potential target in the treatment of impulse control disorders. PMID- 29161025 TI - E-H (E = B, Si, C) Bond Activation by Tuning Structural and Electronic Properties of Phosphenium Cations. AB - In this work, strategic enhancement of electrophilicity of phosphenium cations for the purpose of small-molecule activation was described. Our synthetic methodology for generation of novel two-coordinate phosphorus(III)-based compounds [{C6H4(MeN)2C}2C.PR]2+ ([2a]2+, R = NiPr2; [2b]2+, R = Ph) was based on the exceptional electron-donating properties of the carbodicarbene ligand (CDC). The effects of P-centered substituent exchange and increase in the overall positive charge on small substrate activation were comparatively determined by incorporating the bis(amino)phosphenium ion [(iPr2N)2P]+ ([1]+) in this study. Implemented structural and electronic modifications of phosphenium salts were computationally verified and subsequently confirmed by isolation and characterization of the corresponding E-H (E = B, Si, C) bond activation products. While both phosphenium mono- and dications oxidatively inserted/cleaved the B-H bond of Lewis base stabilized boranes, the increased electrophilicity of doubly charged species also afforded the activation of significantly less hydridic Si-H and C-H bonds. The preference of [2a]2+ and [2b]2+ to abstract the hydride rather than to insert into the corresponding bond of silanes, as well as the formation of the carbodicarbene-stabilized parent phosphenium ion [{C6H4(MeN)2C}2C.PH2]+ ([2.PH2]+) were experimentally validated. PMID- 29161026 TI - Conditional Reversible Work Coarse-Grained Models of Molecular Liquids with Coulomb Electrostatics - A Proof of Concept Study on Weakly Polar Organic Molecules. AB - Scale bridging simulations of soft matter rely on the availability of transferable coarse-grained models. In systematic coarse-graining approaches, core principles of statistical mechanics are used to relate the coarse-grained models to the underlying molecular interactions. The conditional reversible work (CRW) method provides effective, nonbonded pair potentials by means of computing coupling free energies between mapped chemical groups. This method has so far been used almost exclusively for systems composed of apolar organic molecules, but additional challenges arise when developing coarse-grained models for polar molecules in which (long-range) electrostatic interactions are important. Herein, we present a modified formulation of the CRW method where we divide the effective interaction potential into van der Waals and electrostatic components. The shape of the effective electrostatic interaction justifies modeling the electrostatics using a Coulomb potential with point charges on each site that are equal to the net charge of the underlying group of atoms. We perform CRW calculations using two polar molecules as test cases (an ether (1,2-dimethoxyethane) and an ester (ethyl propionate)). The results of subsequent liquid state simulations indicate that the coarse-grained models obtained by the new method are of similar quality with respect to representability and thermodynamic transferability as formerly developed models for apolar systems. PMID- 29161027 TI - Virus Transfer at the Skin-Liquid Interface. AB - Understanding virus transfer between liquid and skin is necessary to estimate transmission during water-related activities. Here, we modeled virus transfer from liquid-to-skin and skin-to-liquid. We performed human subject studies using three bacteriophages as pathogenic virus surrogates: nonenveloped MS2 and Qbeta and enveloped Phi6. Our study shows that transfer from liquid-to-skin is describable by a single model based on (1) virus concentration and (2) volume of liquid remaining on skin. Contact times (0.1-30 min), and virus species had little-to-no influence on virus transfer. Likewise, liquid conditions (pH 6-9, ionic strength 10-550 mM) had no influence on transfer as shown for MS2. The model accounts for both, virus adsorbed onto the skin, and virus in the liquid retained on skin. In comparison, virus transfer from skin-to-liquid was influenced by the wetness of the skin and by liquid type (water, saliva). 90 +/- 19% of the virus inoculated on the skin are transferred to the water when the skin remains wet compared to 30 +/- 17% when the skin is dry. The transfer from skin-to-liquid was 41% higher when the recipient liquid was water as compared with saliva. This study quantifies virus transfer between liquid and skin and guides risk assessments of water-related activities. PMID- 29161028 TI - Exploring the Active Center of the LSD1/CoREST Complex by Molecular Dynamics Simulation Utilizing Its Co-crystallized Co-factor Tetrahydrofolate as a Probe. AB - Epigenetic targeting of cancer is a recent effort to manipulate the gene without destroying the genetic material. Lysine-specific demethylase 1 (LSD1) is one of the enzymes associated with the chromatin for post-translational modifications, where it demethylates lysine amino acid in the chromatin H3 tail. Many studies showed that inhibiting LSD1 could potentially be used to treat cancer epigenetically. LSD1 is associated with its corepressor protein CoREST, and it uses tetrahydrofolate as a co-factor to accept CH2 from the demethylation process. In this study, the co-crystallized co-factor tetrahydrofolate was utilized to determine possible binding regions in the active center of the LSD1/CoREST complex. Also, the flexibility of the complex has been investigated by molecular dynamics simulation and subsequent analysis by clustering and principal component analysis. This research supported other studies and showed that LSD1/CoREST complex exists in two main conformational structures: open and closed. Furthermore, this study showed that tetrahydrofolate stably binds to the LSD1/CoREST complex, in its open conformation, at its entrance. It then binds to the core of the complex, inducing the closed conformation. Furthermore, the interactions of tetrahydrofolate to these two binding regions and the corresponding binding mode of tetrahydrofolate were investigated to be used in structure-based drug design. PMID- 29161029 TI - Harmonic Force Constants for Molecular Mechanics Force Fields via Hessian Matrix Projection. AB - A modification to the Seminario method [ Int. J. Quantum Chem. 1996 , 60 , 1271 - 1277 ] is proposed, which derives accurate harmonic bond and angle molecular mechanics force field parameters directly from the quantum mechanical Hessian matrix. The new method reduces the average error in the reproduction of quantum mechanical normal-mode frequencies of a benchmark set of 70 molecules from 12.3% using the original method, to 6.3%. The modified Seminario method is fully automated, and all parameters are computed directly from quantum mechanical data, thereby avoiding interdependency between bond and angle parameters and other components of the force field. A complete set of bond and angle force field parameters for the 20 naturally occurring amino acids is also provided for use in the future development of protein force fields. PMID- 29161030 TI - Nanoplastic in the North Atlantic Subtropical Gyre. AB - Plastics can be found in all ecosystems across the globe. This type of environmental pollution is important, even if its impact is not fully understood. The presence of small plastic particles at the micro- and nanoscales is of growing concern, but nanoplastic has not yet been observed in natural samples. In this study, we examined four size fractions (meso-, large micro-, small micro-, and nanoplastics) of debris collected in the North Atlantic subtropical gyre. To obtain the nanoplastic portion, we isolated the colloidal fraction of seawater. After ultrafiltration, the occurrence of nanoscale particles was demonstrated using dynamic light scattering experiments. The chemical fingerprint of the colloids was obtained by pyrolysis coupled with gas chromatography-mass spectrometry. We demonstrated that the signal was anthropogenic and attributed to a combination of plastics. The polymer composition varied among the size classes. At the micro- and nanoscales, polyvinyl chloride, polyethylene terephthalate, polystyrene and polyethylene were observed. We also observed changes in the pyrolytic signals of polyethylene with decreasing debris size, which could be related to the structural modification of this plastic as a consequence of weathering. PMID- 29161031 TI - Computational Exploration of Concerted and Zwitterionic Mechanisms of Diels-Alder Reactions between 1,2,3-Triazines and Enamines and Acceleration by Hydrogen Bonding Solvents. AB - The mechanisms of Diels-Alder reactions between 1,2,3-triazines and enamines have been explored with density functional theory computations. The focus of this work is on the origins of the different reactivities and mechanisms induced by substituents and by hexafluoroisopropanol (HFIP) solvent. These inverse electron demand Diels-Alder reactions of triazines have wide applications in bioorthogonal chemistry and natural product synthesis. Both concerted and stepwise cycloadditions are predicted, depending on the nature of substituents and solvents. The nature of zwitterionic intermediates and the mechanism by which HFIP accelerates cycloadditions with enamines are characterized. Our results show the delicate nature of the concerted versus stepwise mechanism of inverse electron-demand Diels-Alder reactions of 1,2,3-triazines, and that these mechanisms can be altered by electron-withdrawing substituents and hydrogen bonding solvents. PMID- 29161032 TI - Transfer and Dynamic Inversion of Coassembled Supramolecular Chirality through 2D Sheet to Rolled-Up Tubular Structure. AB - Transfer and inversion of supramolecular chirality from chiral calix[4]arene analogs (3D and 3L) with an alanine moiety to an achiral bipyridine derivative (1) with glycine moieties in a coassembled hydrogel are demonstrated. Molecular chirality of 3D and 3L could transfer supramolecular chirality to an achiral bipyridine derivative 1. Moreover, addition of 0.6 equiv of 3D or 3L to 1 induced supramolecular chirality inversion of 1. More interestingly, the 2D-sheet structure of the coassembled hydrogels formed with 0.2 equiv of 3D or 3L changed to a rolled-up tubular structure in the presence of 0.6 equiv of 3D or 3L. The chirality inversion and morphology change are mainly mediated by intermolecular hydrogen-bonding interactions between the achiral and chiral molecules, which might be induced by reorientations of the assembled molecules, confirmed by density functional theory calculations. PMID- 29161033 TI - Carbon Quantum Dots Grafted Antifouling Membranes for Osmotic Power Generation via Pressure-Retarded Osmosis Process. AB - Osmotic power generated by pressure-retarded osmosis (PRO) has attracted global attention as a clean, abundant and renewable energy resource. However, the substrates of PRO membranes are particularly prone to fouling because of their direct contact with various foulants in raw water. This leads to a significant decline in power density and impedes the commercialization of PRO technology. In this work, a facile surface modification method has been developed to obtain a new type of nanoparticle functionalized antifouling PRO membranes. Carbon quantum dots (CQDs), with an average size around 3.2 nm, are fabricated from citric acid via a simple method. Subsequently, they are immobilized onto the polydopamine (PDA) layer grafted on the substrate surface of poly(ether sulfone) (PES) membranes via covalent bonding. The bacteria diffusion tests show that the CQD modified PRO membranes possess much enhanced antibacterial activity and antibiofouling propensity. The continuous PRO operations at 15 bar also confirm that the CQD modified membranes exhibit a much higher power density (11.0 vs 8.8 W/m2) and water recovery after backwash (94 vs 89%) than the unmodified ones. This study may open up a new avenue in the fabrication of nanostructure functionalized polymeric membranes for wastewater treatment and osmotic power generation. PMID- 29161035 TI - Synthesis of Photoswitchable Delta9-Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling. AB - The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nervous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Delta9-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly rectifying potassium channels, as well as adenylyl cyclase. PMID- 29161036 TI - Visible-Light-Activated Asymmetric beta-C-H Functionalization of Acceptor Substituted Ketones with 1,2-Dicarbonyl Compounds. AB - We report a visible-light-activated asymmetric beta-C(sp3)-H functionalization of 2-acyl imidazoles and 2-acylpyridines with 1,2-dicarbonyl compounds (typically alpha-ketoesters) catalyzed by a tailored stereogenic-at-rhodium Lewis acid catalyst. The C-C bond formation products are obtained in high yields (up to 99%) and with excellent stereoselectivities (up to >20:1 dr and up to >99% ee). Experimental and computational studies support a mechanism in which a photoactivated Rh-enolate transfers a single electron to the 1,2-dicarbonyl compound followed by proton transfer and a subsequent stereocontrolled radical radical recombination. PMID- 29161037 TI - Biodegradation of Carbon Nanotube/Polymer Nanocomposites using a Monoculture. AB - The biodegradation rates of carbon nanotube (CNT)/ polymer nanocomposites (PNCs) containing poly-epsilon-caprolactone (PCL) were investigated using Pseudomonas aeruginosa, a microorganism commonly found in the environment. CNT/PCL nanocomposite mass loss profiles revealed that the rate of PCL matrix biodegradation decreased systematically as the CNT loading increased from 0.1 to 10% w/w. Addition of even a low CNT loading (<1% w/w) caused the CNT/PCL biodegradation rate constant to decrease by more than 50%. Similar trends in biodegradation rate were observed for both pristine and oxidized multiwall CNTs embedded in PCL. During PCL matrix biodegradation, CNT accumulation was observed at the surface of CNT/PCL nanocomposites and single particle inductively coupled mass spectrometry experiments revealed no measurable CNT release to the culture fluid. Experimental data indicated that biodegradation proceeded as a result of biofilm formation on the CNT/PCL nanocomposites and decreased as a function of CNT loading due to the cytotoxicity of CNTs toward P. aeruginosa and the physical barrier presented by the surface-accumulated CNTs to the underlying PCL substrate. As the CNT loading in the CNT/PCL nanocomposites increased, the microbial proliferation of planktonic cells in the surrounding media also decreased as did the biodegradation rate of PCL samples present in the same reactors. Results from this study demonstrate that the inclusion of CNTs into polymer matrices could increase the environmental persistence of polymers in lakes, landfills, and surface waters. PMID- 29161034 TI - Dynamic Glycosylation Governs the Vertebrate COPII Protein Trafficking Pathway. AB - The COPII coat complex, which mediates secretory cargo trafficking from the endoplasmic reticulum, is a key control point for subcellular protein targeting. Because misdirected proteins cannot function, protein sorting by COPII is critical for establishing and maintaining normal cell and tissue homeostasis. Indeed, mutations in COPII genes cause a range of human pathologies, including cranio-lenticulo-sutural dysplasia (CLSD), which is characterized by collagen trafficking defects, craniofacial abnormalities, and skeletal dysmorphology. Detailed knowledge of the COPII pathway is required to understand its role in normal cell physiology and to devise new treatments for disorders in which it is disrupted. However, little is known about how vertebrates dynamically regulate COPII activity in response to developmental, metabolic, or pathological cues. Several COPII proteins are modified by O-linked beta-N-acetylglucosamine (O GlcNAc), a dynamic form of intracellular protein glycosylation, but the biochemical and functional effects of these modifications remain unclear. Here, we use a combination of chemical, biochemical, cellular, and genetic approaches to demonstrate that site-specific O-GlcNAcylation of COPII proteins mediates their protein-protein interactions and modulates cargo secretion. In particular, we show that individual O-GlcNAcylation sites of SEC23A, an essential COPII component, are required for its function in human cells and vertebrate development, because mutation of these sites impairs SEC23A-dependent in vivo collagen trafficking and skeletogenesis in a zebrafish model of CLSD. Our results indicate that O-GlcNAc is a conserved and critical regulatory modification in the vertebrate COPII-dependent trafficking pathway. PMID- 29161038 TI - Ag-Catalyzed Tandem Three-Component Reaction toward the Synthesis of Multisubstituted Imidazoles. AB - A facile one-pot, Ag-catalyzed tandem three-component reaction of amidines, ynals, and carboxylic acids or amines to form imidazole skeletons has been developed. This multicomponent reaction has been applied to various substituted amidines and carboxylic acids substrates, affording the products in good yields. The strategy could provide an efficient and green molecular fragment assembly to access imidazoles. PMID- 29161039 TI - X-ray Emission Spectrum of Liquid Ethanol: Origin of Split Peaks. AB - The X-ray emission spectrum of liquid ethanol was calculated using density functional theory and a semiclassical approximation to the Kramers-Heisenberg formula including core-hole-induced dynamics. Our spectrum agrees well with the experimental spectrum. We found that the intensity ratio between the two peaks at 526 and 527 eV assigned as 10a' and 3a" depends not only on the hydrogen bonding network around the target molecule but also on the intramolecular conformation. This effect is absent in liquid methanol and demonstrates the high sensitivity of X-ray emission to molecular structure. The dependence of spectral features on hydrogen-bonding as well as on dynamical effects following core excitation are also discussed. PMID- 29161040 TI - Does the Cl + CH4 -> H + CH3Cl Reaction Proceed via Walden Inversion? AB - We report a chemically accurate global ab initio full-dimensional potential energy surface (PES) for the Cl(2P3/2) + CH4 reaction improving the high-energy region of our previous PES [Czako, G.; Bowman, J. M. Science 2011, 334, 343-346]. Besides the abstraction (HCl + CH3) and the Walden-inversion substitution (H + CH3Cl) channels, the new PES accurately describes novel substitution pathways via retention of configuration. Quasiclassical trajectory simulation on this PES reveals that the substitution channel opens around 40 kcal/mol collision energy via Walden inversion and the retention cross sections raise from ~50 kcal/mol. At collision energy of 80 kcal/mol, the retention pathways provide nearly 40% of the substitution cross section, and retention substitution may become the dominant mechanism of the Cl + CH4 reaction at superhigh collision energies. The substitution probability can be as high as ~70% at zero impact parameter (b) and decreases rapidly with increasing b, whereas the abstraction opacity function is broad having 5-10% probability over a larger b-range. The high-energy angular distributions show scattering into forward and backward directions for the abstraction (direct stripping) and face-attack Walden-inversion substitution (direct rebound) channels, respectively. Retention can proceed via edge- and vertex-attack pathways producing dominant sideways scattering because the breaking C-H or Cl-H bond is usually at a side position of the forming Cl-C bond. PMID- 29161041 TI - Base-Mediated Three-Component Tandem Reactions for the Synthesis of Multisubstituted Pyrimidines. AB - A base-mediated three-component tandem reaction for the synthesis of multisubstituted pyrimidines from amidines, aryl alkynes, and aldehydes in a one pot manner has been developed. Advantages of this transformation include being transition-metal-free, high efficiency, available starting materials, and being environmentally friendly. PMID- 29161042 TI - Conformational Dynamics of Matrix Metalloproteinase-1.Triple-Helical Peptide Complexes. AB - Matrix metalloproteinase-1 (MMP-1) is a zinc-dependent protease that catalyzes hydrolysis of interstitial collagens. A previously reported X-ray crystallographic structure revealed specific interactions between a triple helical peptide (THP) model of interstitial collagen and the hemopexin-like (HPX) and catalytic (CAT) domains of MMP-1. An NMR-based structure of MMP-1 in a complex with a different THP was also solved, where docking was used to model the MMP-1.THP interactions and develop a mechanism for the early stages of collagenolysis. To provide greater insight into and reveal specific details of the collagenolytic mechanism, molecular dynamics (MD) studies of the MMP-1.THP NMR-derived and X-ray crystallographic complexes were performed and compared. The "open/extended" conformation of the NMR-derived MMP-1.THP complex was found to lead to a catalytically productive complex. The X-ray crystallographic MMP-1.THP complex was initially in a "closed/collapsed" conformation, and did not yield a productive complex. The NMR-derived structure of the MMP-1.THP complex possessed many more atomistic interactions between MMP-1 and the THP compared with the X ray crystallographic structure of the MMP-1.THP complex, and also had greater participation of MMP-1 in the local unwinding/destabilization of the THP. The atomistic interactions support the favorable energetics of the initial step of collagenolysis originating from the NMR-derived MMP-1.THP complex structure. PMID- 29161043 TI - Gold(I)-Catalyzed Cyclization/Carbonylation Cascade Reaction of 1,6-Diynes: An Access to beta,gamma-Unsaturated Ketones. AB - A gold-catalyzed cyclization/carbonylation cascade reaction of 1,6-diynes is reported. The reaction goes through 6-exo-dig and 6-endo-dig cyclizations in sequence, followed by hydration to provide the beta,gamma-unsaturated ketones with moderate to high yields under mild reaction conditions. This is the first example of intercepting the postulated 1,3-oxazine vinylgold intermediate with another pendant alkyne, which not only verifies the proposed mechanism but also provides the ketone products with cyclized 1,2,3,6-tetrahydropyridine or 3,6 dihydro-2H-pyran frameworks from corresponding diynes. PMID- 29161044 TI - Scalable Synthesis of Trifluoromethylated Imidazo-Fused N-Heterocycles Using TFAA and Trifluoroacetamide as CF3-Reagents. AB - A scalable synthesis of trifluoromethylated imidazo-fused N-heterocyles from heterocyclic benzylamines using TFAA as trifluoromethylating reagent is presented. The reaction proceeds via intermediate benzylic N-trifluoroacetamides followed by dehydrative cyclization to the products. To further broaden the scope and practicality, a new method for the preparation of benzylic N trifluoroacetamides via alkylation of trifluoroacetamide with benzyl (pseudo)halides was developed. Both methods proceed under mild conditions, and their symbiosis provides access to a wide range of novel CF3-heterocycles. PMID- 29161045 TI - Principles around Accurate Blood Volume Collection Using Capillary Action. AB - Capillary action is one mechanism microfluidics uses to draw liquid autonomously in a substrate without the need of external energy. This behavior can be exploited to collect accurate volumes of liquids such as blood in narrow columns known as capillary tubes and help the development of inexpensive, user-friendly personalized biomedical tools. Precision bore glass capillaries demonstrate the "state of the art" for volume accuracy and precision, but height and radius must be carefully chosen in order to exploit the capillary action behavior efficiently. This Article investigates the influence of surface glass aging, due to prolonged exposure to humid air, and hematocrit level on the blood capillary rise. It provides also the tools to correctly define the optimum capillary dimensions to collect an accurate volume of blood in a glass capillary tube. PMID- 29161046 TI - Heavy Metal-Free Tannin from Bark for Sustainable Energy Storage. AB - A novel renewable cathode made from earth abundant, low-cost materials can contribute to the intermittent storage needs of renewable energy-based society. In this work, we report for the first-time tannin from Nature as a cathode material. Our approach exploits the charge storage mechanism of the redox active quinone moiety. Tannins extracted from tree bark using environmental friendly aqueous solvents have the highest phenol content (5.56 mol g-1) among all the natural phenolic biopolymers, 5000 times higher than lignin. Tannins coupled with a conductive polymer polypyrrole acquire high specific capacitance values of 370 F g-1 at 0.5 A g-1 as well as excellent rate performance of 196 F g-1 at 25 A g 1. Additionally, we employed carbonized wood as an electrode substrate to produce a sustainable electrochemical device with dramatically improved performance compared to conventional devices. The high surface area provided by the well aligned, cellular porosity of wood-derived substrate combined with the high mobility of ions and electrons in the carbonized cell walls and deposited tannin can achieve an areal capacitance of 4.6 F cm-2 at 1 mA cm-2, which is 1.5 times higher than activated wood carbon. PMID- 29161047 TI - Mapping Extracellular Matrix Proteins in Formalin-Fixed, Paraffin-Embedded Tissues by MALDI Imaging Mass Spectrometry. AB - Collagens and elastin form the fundamental framework of all tissues and organs, and their expression and post-translational processing are tightly regulated in disease and health. Because of their unique structural composition and properties, it is a recognized challenge to access these protein structures within the complex tissue microenvironment to understand how localized changes modulate tissue health. We describe a new workflow using a combination of matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) with matrix metalloproteinase (MMP) enzymes to access and report on spatial localization of collagen and elastin sequences in formalin-fixed, paraffin embedded (FFPE) tissues. The developed technology provides new access to collagens and elastin sequences localized to tissue features that were previously unattainable. This high-throughput technological advance should be applicable to any tissue regardless of disease type, tissue origin, or disease status and is thus relevant to all research: basic, translational, or clinical. PMID- 29161048 TI - Local Chemical Ordering and Negative Thermal Expansion in PtNi Alloy Nanoparticles. AB - An atomic insight into the local chemical ordering and lattice strain is particular interesting to recent emerging bimetallic nanocatalysts such as PtNi alloys. Here, we reported the atomic distribution, chemical environment, and lattice thermal evolution in full-scale structural description of PtNi alloy nanoparticles (NPs). The different segregation of elements in the well-faceted PtNi nanoparticles is convinced by extended X-ray absorption fine structure (EXAFS). Atomic pair distribution function (PDF) study evidences the coexistence of the face-centered cubic and tetragonal ordering parts in the local environment of PtNi nanoparticles. Further reverse Monte Carlo (RMC) simulation with PDF data obviously exposed the segregation as Ni and Pt in the centers of {111} and {001} facets, respectively. Layer-by-layer statistical analysis up to 6 nm for the local atomic pairs revealed the distribution of local tetragonal ordering on the surface. This local coordination environment facilitates the distribution of heteroatomic Pt-Ni pairs, which plays an important role in the negative thermal expansion of Pt41Ni59 NPs. The present study on PtNi alloy NPs from local short range coordination to long-range average lattice provides a new perspective on tailoring physical properties in nanomaterials. PMID- 29161049 TI - Empirical Analysis of Optical Kerr Effect Spectra: A Case for Constraint. AB - Ultrafast optical Kerr effect (OKE) spectroscopy is a widely used method for studying the depolarized, Raman-active intermolecular dynamics of liquids. Through appropriate manipulation of OKE data, it is possible to determine the reduced spectral density (RSD), which is the Bose-Einstein-corrected, low frequency Raman spectrum with the contribution of diffusive reorientation removed. OKE RSDs for van der Waals liquids can often be fit well to an empirical function that is the sum of a Bucaro-Litovitz function and an antisymmetrized Gaussian (AG). Although these functions are not directly representative of specific intermolecular dynamics, the AG fit parameters can provide useful insights into the microscopic properties of liquids. Here we show that fits using the AG function are typically not well-determined, and that equally good results can be obtained with a wide range of fitting parameters. We propose the use of a physically motivated constraint on the amplitude of the AG function, and demonstrate that this constraint leads to more intuitive trends in the fit parameters for temperature-dependent RSDs in 1,3,5-trifluorobenzene and hexafluorobenzene. PMID- 29161050 TI - FeCl3-Mediated Domino Reaction of Benzoxazinones with Aroylmethylidene Malonates: Synthesis to Functionalized Pyrrolobenzoxazines. AB - An efficient domino approach for the synthesis of pyrrolobenzoxazine derivatives is described. The FeCl3-promoted domino reaction between aroylmethylidene malonates and benzoxazinones has been successfully established to afford the title compounds in good to excellent yield under mild reaction conditions. The domino protocol provides a concise and straightforward access to highly substituted pyrrolobenzoxazines with high efficiency and excellent functional group tolerance. PMID- 29161051 TI - New Avenue for Limiting Degradation in NanoLi4Ti5O12 for Ultrafast-Charge Lithium Ion Batteries: Hybrid Polymer-Inorganic Particles. AB - Lithium titanium oxide (Li4Ti5O12)-based cells are a very promising battery technology for ultrafast-charge-discharge and long-cycle-life batteries. However, the surface reactivity of lithium titanium oxide in the presence of organic electrolytes continues to be a problem that may cause expansion of pouch cells. In this study, we report on the development of a simple and economical grafting method for forming hybrid polymer-Li4Ti15O12 nanoparticles, which can be successfully applied in lithium-ion batteries. This method utilizes a low-cost and scalable hydrophobic polymer that is applicable in industrial processes. The hybrid materials demonstrated exceptional capability for preventing the degradation of cells in accelerated aging and operating over 150 cycles at 1C and 45 degrees C. PMID- 29161052 TI - Recurrent anaphylaxis in patient allergic to eggplant - a Lipid transfer protein (LTP) syndrome. AB - Eggplant allergy is rare and most of the previously described reactions were mild. In this case report, we present an interesting case of a 27-year-old male who experienced symptoms of anaphylaxis (shortness of breath, and swelling of the face, lips and tongue, which was followed by hypotension, tachycardia of 140/min and a sudden loss of consciousness) several minutes after eating a dish containing backed eggplant. Previously, the patient had experienced symptoms of allergy after eating different types of food, such as salad and chicken in spices. The symptoms were enhanced by co-factors. They were heterogeneous, ranging from oral symptoms to anaphylactic shock. During the diagnostic pathway, skin prick tests (SPTs) were positive to grass and cat. Prick by prick skin tests were positive for eggplant, both cooked and fresh. In ImmunoCap ISAC, IgE specific to rPhl p 1 (1.7 ISU-E), rCan f 5 (1,2 ISU-E), Fel d 1 (9.6 ISU-E ) and LTPs - nJug r 3 (0.5 ISU-E), rPru p 3 (0.6 ISU-E), rPla a 3 (1.3 ISU-E) were found. Based on the clinical pattern of the disease and the results of component resolved diagnosis, we suspect that this complex case of anaphylaxis may be gathered with LTP syndrome. PMID- 29161053 TI - Long-term effectiveness of omalizumab treatment in Thai severe asthmatic patients: a real-life experience. AB - BACKGROUND: To evaluate long-term effectiveness of omalizumab in 'real-life' setting of Thai asthmatic patients. METHODS: We conducted multi-center, observational study in severe asthma patients who received omalizumab in Thailand. Outcomes were asthma exacerbation (hospitalization and ER visit), asthma control test (ACT), and daily ICS dose. Data were evaluated at baseline, 16 Week, and 52 Week. RESULTS: A total of 78 patients received omalizumab treatment (average duration 16.9 months with range 16 weeks-2 years). The mean annualized rate of exacerbations was reduced from baseline (3.79) at Week 16 (3.54) and Week 52 (1.16), (p<0.05), respectively. The mean hospitalization rate was reduced from 0.49 in previous year to 0.15 at Week 16 and 0.19 at Week 52. A reduction in ER visit rates was observed at Week 16 (0.15) and Week 52 (0.97) respectively from baseline (1.44) (p<0.05). The ACT score increased from 15.4 at baseline to 20.6 at Week 16 (p<0.001) and increased to 21.5 at Week 52 (p<0.001). The number of patients with controlled asthma (ACT>=20) increased from 16 of 51 at baseline to 32 of 45 at Week 16 and 25 of 32 at week 52, respectively. The median daily dose of ICS equivalent to fluticasone was reduced from baseline 680 mcg to 500 mcg at Week 52. In all, 22 patients discontinued omalizumab after 1 year. Six patients who discontinued omalizumab were restarted due to relapse of symptoms. CONCLUSIONS: These data confirms the effectiveness of one-year duration of omalizumab treatment in Thai severe asthmatic patients. Furthermore, 27% of patients who discontinued treatment required restarting due to relapse of symptoms. PMID- 29161054 TI - Great flood and aeroallergen sensitization in children with asthma and/or allergic rhinitis. AB - BACKGROUND: Flooding may affect aeroallergen sensitization. OBJECTIVE: To evaluate aeroallergen sensitization in children with asthma and/or allergic rhinitis (AR) by skin prick test (SPT) before and after the great flood of 2011 in Bangkok, Thailand. METHODS: The study was performed retrospectively in asthma and/or AR children (aged 0-18 years) in Siriraj Hospital, Bangkok, Thailand from 2009 to 2013. All of the cases received SPT with common aeroallergens. RESULTS: SPTs were performed from 2009-2013 in a total of 2,010 asthma and/or AR children and 58.2% and 60.5% showed positive results, respectively. Poly-sensitization to aeroallergens was found in 67.5% of asthma and 67.0% of AR SPT-positive patients. In the study period, Dermatophagoides pteronyssinus (Dp) and Dermatophagoides ferinae (Df) were the most common causes of aeroallergen sensitization (82.4% and 76.5%, respectively), followed by American cockroach (43.5%). After the severe flood in Bangkok in 2011, the trend of sensitization to American cockroach, Bermuda grass, Johnson grass, and Cladosporium spp. significantly decreased. However, the trend of sensitization to dog and Alterneria allergens in 2010 studied cases, significantly increased. During the study period, mean wheal diameter (MWD) of dog SPT was significantly associated with asthma severity, while the MWD of Dp SPT was significantly associated with AR severity. CONCLUSIONS: The aeroallergen sensitizations patterns had changed from previous years compared to the year during or after the flood. Thus, the great flood may have had a major impact on types of sensitization and the clinical patterns of airway allergy. Further confirmed by a prospective study is warranted. PMID- 29161055 TI - Expression of cysteinyl leukotriene receptor GPR17 in eosinophilic and non eosinophilic chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: The cysteinyl leukotrienes (cysLTs) are proinflammatory lipid mediators that act on the type 1 cysLT receptor (CysLT1R) in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). GPR17, a G protein-coupled orphan receptor with homology to the cysLT receptors, has been proposed as a damage sensor during inflammation. However, the expression and correlation of GPR17 and CysLT1R in eosinophilic CRSwNP (ECRS) and non-eosinophilic CRSwNP (non ECRS) have not been well investigated. OBJECTIVE: To evaluate the expression of GPR17 and its correlation with CysLT1R in the 2 CRSwNP subsets. METHODS: Polyp tissues were collected from CRSwNP subjects (15 ECRS and 14 non-ECRS), and uncinate processes were collected from 12 CRSsNP subjects and 13 control subjects. The mRNA and protein levels of GPR17 and CysLT1R were examined using qRT-PCR, immunohistochemistry, and western blotting. Additionally, the correlation between GPR17 and CysLT1R at the mRNA and protein levels was evaluated. All assays were performed in a blinded manner. RESULTS: Polyp tissues exhibited significantly increased GPR17 expression relative to uncinate process tissues from CRSsNP patients, or healthy controls (P=0.0012 and P<0.0001, respectively). Compared with the non-ECRS subset, the ECRS subset showed significantly increased GPR17 expression. Moreover, the GPR17 expression was positively correlated with CysLT1R in nasal polyps. CONCLUSIONS: The increased expression of GPR17 in nasal polyps and the differential expression between eosinophilic and non-eosinophilic CRSwNP subsets suggest that these subsets may have distinct pathogenic mechanisms. The positive correlation between GPR17 and CysLT1R in polyp tissues might imply substantial regulatory mechanisms that must be elucidated. PMID- 29161056 TI - De novo food allergy in pediatric liver transplantation recipients. AB - BACKGROUND: Food allergy (FA) prevalence is increasing in pediatric liver transplantation (LT). However, the clinical course is still limited. OBJECTIVE: This retrospective cohort study aimed to identify the prevalence, risk factors, and the natural history of de novo FA in children post LT. METHODS: Medical records of pediatric LT recipients from Jan 2001 - Dec 2014 were reviewed. De novo FA was diagnosed by symptoms after exposure to culprit food occurring after LT, and improvement after diet elimination. FA was confirmed if reproduced symptoms after re-challenge or documented sensitization or indicated gastrointestinal eosinophilia. RESULTS: Among 46 post LT children, 54.3% developed de novo FA at a median time of 12.2 months [Interquartile range (IQR) 6.2, 21.3 months] post LT. The confirmed FA was 39.1%. Gastrointestinal symptom was the most common manifestation followed by skin, anaphylaxis, and others. Culprit foods were cow's milk, shellfish, egg, wheat, soybean, peanut, coconut, fish and monosodium glutamate. The risk factors of FA were transplantation during age below 2 years [hazard ratio (HR), 2.62; 95% confidence interval (CI), 1.04 - 6.59; p = 0.03), atopic history in family (HR, 5.67; 95% CI, 1.33 - 24.12; p = 0.01), and Epstein-Barr (EBV) viremia (HR, 2.39; 95% CI, 1.02 - 5.63; p = 0.04). CONCLUSIONS: de novo FA in pediatric LT is not uncommon. Age at LT younger than 2 years, family history of atopy, and EBV viremia are associated with developing FA. Development of tolerance after elimination culprit diets for 3 years is similar to general population. PMID- 29161057 TI - E-Cigarettes: Mucus Measurements Make Marks. PMID- 29161058 TI - Trends in Daily Cannabis Use Among Cigarette Smokers: United States, 2002-2014. AB - OBJECTIVES: To estimate changes in the prevalence of daily cannabis use among current, former, and never cigarette smokers from 2002 to 2014 in the United States. METHODS: The National Survey on Drug Use and Health is a nationally representative cross-sectional study conducted annually among persons aged 12 years and older in the United States. RESULTS: Daily cannabis use occurs nearly exclusively among nondaily and daily cigarette smokers compared with former and never smokers (8.03%, 9.01%, 2.79%, 1.05%, respectively). Daily cannabis use increased over the past decade among both nondaily (8.03% [2014] vs 2.85% [2002]; linear trend P < .001) and daily smokers (9.01% [2014]; 4.92% [2002]; linear trend P < .001). Daily cannabis use increased most rapidly among former cigarette smokers (2.79% [2014] vs 0.98% [2002]; linear trend P < .001). CONCLUSIONS: Daily cannabis use occurs predominantly among cigarette smokers in the United States. Daily cannabis use increased among current, former, and never smokers over the past decade, with particularly rapid increases among youth and female cigarette smokers. Future research is needed to monitor the observed increase in daily cannabis use, especially among youths and adults who smoke cigarettes. PMID- 29161059 TI - American Doctors at the Nuremberg Medical Trial. AB - Three Hippocratic physicians played critical roles in the prosecution of 23 Nazi doctors charged with murder and torture for conducting lethal medical experiments on concentration camp prisoners. Two of the physicians, Leopold Alexander and Andrew C. Ivy, were Americans, and the other, Werner Leibbrandt, was German. At the 70th anniversary of the Doctors' Trial it is fitting to recall the three's influences and contributions to the formulation of strict research ethics rules, known as the Nuremberg Code. Their contributions help us better understand why they insisted on strict research rules and yet ultimately were unable to apply these rules to their own research. Exploring their contributions at Nuremberg may help us appreciate the continuing difficulty physician-researchers have with accepting public regulation of research. PMID- 29161060 TI - Beyond Nazi War Crimes Experiments: The Voluntary Consent Requirement of the Nuremberg Code at 70. AB - The year 2017 marks both the 70th anniversary of the Nuremberg Code and the first major revisions of federal research regulations in almost 3 decades. I suggest that the informed consent provisions of the federal research regulations continue to follow the requirements of the Nuremberg Code. However, modifications are needed to the informed consent (and institutional review board) provisions to make the revised federal regulations more effective in promoting a genuine conversation between the researcher and the research subject. This conversation must take seriously both the therapeutic illusion and the desire of both the researcher and the research subject not to engage in sharing uncertainty. PMID- 29161061 TI - Evaluation of the Environmental Scoring System in Multiple Child Asthma Intervention Programs in Boston, Massachusetts. AB - OBJECTIVES: To test the applicability of the Environmental Scoring System, a quick and simple approach for quantitatively measuring environmental triggers collected during home visits, and to evaluate its contribution to improving asthma outcomes among various child asthma programs. METHODS: We pooled and analyzed data from multiple child asthma programs in the Greater Boston Area, Massachusetts, collected in 2011 to 2016, to examine the association of environmental scores (ES) with measures of asthma outcomes and compare the results across programs. RESULTS: Our analysis showed that demographics were important contributors to variability in asthma outcomes and total ES, and largely explained the differences among programs at baseline. Among all programs in general, we found that asthma outcomes were significantly improved and total ES significantly reduced over visits, with the total Asthma Control Test score negatively associated with total ES. CONCLUSIONS: Our study demonstrated that the Environmental Scoring System is a useful tool for measuring home asthma triggers and can be applied regardless of program and survey designs, and that demographics of the target population may influence the improvement in asthma outcomes. PMID- 29161062 TI - Exposure to Marijuana Marketing After Legalization of Retail Sales: Oregonians' Experiences, 2015-2016. AB - OBJECTIVES: To assess exposure to marijuana advertising in Oregon after the start of retail marijuana sales in October 2015. METHODS: We conducted a repeated cross sectional online survey of 4001 Oregon adults aged 18 years and older in November 2015 and April-May 2016. We assessed subgroup differences by using the Pearson chi2 test. RESULTS: More than half of adults (54.8%) statewide reported seeing marijuana advertising in the past month. These adults reported that they most frequently saw storefront (74.5%), streetside (66.5%), and billboard (55.8%) advertising. Exposure did not significantly differ by participant's age or marijuana use but was higher among those living in counties with retail sales (56.5%) than in counties without (32.5%). CONCLUSIONS: Most adults reported exposure to marijuana advertising following the start of retail marijuana sales in Oregon. People who do not use marijuana and those aged 18 to 24 years were as exposed to advertising as other groups. Public Health Implications. Advertising restrictions may be needed to protect youths and young adults from pro-use messages. Commercial free speech afforded by the First Amendment makes advertising restrictions challenging, but public policy experts note that restrictions aimed at protecting youths may be allowed. PMID- 29161063 TI - Impact of the 2010 US Healthy, Hunger-Free Kids Act on School Breakfast and Lunch Participation Rates Between 2008 and 2015. AB - OBJECTIVES: To evaluate National School Lunch Program (NSLP) and School Breakfast Program (SBP) participation over a 7-year period before and after the implementation of the 2010 Healthy, Hunger-Free Kids Act (HHFKA), which required healthier school lunch options beginning in school year (SY) 2012-2013 and healthier school breakfast options beginning in SY2013-2014. METHODS: Data were gathered from low-income, high-minority public schools in 4 New Jersey cities. We conducted longitudinal analyses of annual average daily participation (ADP) in school meals among enrolled students overall and among those eligible for free or reduced-price meals. We used linear mixed models to compare NSLP and SBP participation rates from SY2008-2009 to SY2014-2015. RESULTS: NSLP participation rates among students overall differed little across years (from 70% to 72%). SBP rates among enrolled students were stable from the beginning of the study period to SY2013-2014 and then increased from 52% to 59%. Among students eligible for free or reduced-price meals, the ADP was lowest in SY2012-2013 (when the HHFKA was implemented) before rebounding. CONCLUSIONS: The HHFKA did not have a negative impact on school meal participation over time. Public Health Implications. The HHFKA-strengthened nutrition standards have not affected school meal participation rates. With time, students are likely to accept healthier options. PMID- 29161064 TI - Meeting the Institute of Medicine's 2030 US Life Expectancy Target. AB - OBJECTIVES: To quantify the improvement in US life expectancy required to reach parity with high-resource nations by 2030, to document historical precedent of this rate, and to discuss the plausibility of achieving this rate in the United States. METHODS: We performed a demographic analysis of secondary data in 5-year periods from 1985 to 2015. RESULTS: To achieve the United Nations projected mortality estimates for Western Europe in 2030, the US life expectancy must grow at 0.32% a year between 2016 and 2030. This rate has precedent, even in low mortality populations. Over 204 country-periods examined, nearly half exhibited life-expectancy growth greater than 0.32%. Of the 51 US states observed, 8.2% of state-periods demonstrated life-expectancy growth that exceeded the 0.32% target. CONCLUSIONS: Achieving necessary growth in life expectancy over the next 15 years despite historical precedent will be challenging. Much all-cause mortality is structured decades earlier and, at present, older-age mortality reductions in the United States are decelerating. Addressing mortality decline at all ages will require enhanced political will and a strong commitment to equity improvement in the US population. PMID- 29161065 TI - From Nuremberg to Guantanamo Bay: Uses of Physicians in the War on Terror. AB - Seventy years after the Nuremberg Doctors' Trial, health professionals and lawyers working together after 9/11 played a critical role in designing, justifying, and carrying out the US state-sponsored torture program in the CIA "Black Sites" and US military detention centers, including Abu Ghraib, Bagram, and Guantanamo Bay, Cuba. We analyze the similarities between the Nazi doctors and health professionals in the War on Terror and address the question of how it happened that health professionals, including doctors, psychologists, physician assistants, and nurses, acted as agents of the state to utilize their medical and healing skills to cause harm and sanitize barbarous acts, similar to (though not on the scale of) how Nazi doctors were used by the Third Reich. PMID- 29161066 TI - Increasing Prescription Opioid and Heroin Overdose Mortality in the United States, 1999-2014: An Age-Period-Cohort Analysis. AB - OBJECTIVES: To assess cohort effects in prescription opioid and heroin overdose mortality in the United States. METHODS: Using the National Center for Health Statistics' multiple-cause-of-death file for 1999 to 2014, we performed an age period-cohort analysis of drug overdose mortality in the United States. RESULTS: Compared with those born in 1977 and 1978, individuals born between 1947 and 1964 experienced excess risks of prescription opioid overdose death (e.g., for the 1955-1956 birth cohort, rate ratio [RR] = 1.27; 95% confidence interval [CI] = 1.09, 1.48) and of heroin overdose death (e.g., for the 1953-1954 birth cohort, RR = 1.32; 95% CI = 1.11, 1.57). Those born between 1979 and 1992 also experienced an increased risk of heroin overdose death (e.g., for the 1989-1990 birth cohort, RR = 1.23; 95% CI = 1.01, 1.50). The cohort effects were consistent between sexes. CONCLUSIONS: Individuals born between 1947 and 1964 and between 1979 and 1992 are particularly afflicted by the opioid epidemic. Intervention programs are needed to reduce the excess overdose mortality in these specific demographic groups. PMID- 29161067 TI - Long-Term Health Consequences of Movement Restrictions for Palestinians, 1987 2011. AB - OBJECTIVES: To estimate the long-term association between Israeli-imposed restrictions on travel for medical care in the occupied Palestinian territory and health status in adulthood. METHODS: Using event history calendar methods, we collected annual data from 1987 to 2011 from a representative sample of 1778 Palestinians aged 32 to 43 years and analyzed the subsample of whomever had a serious medical condition and needed to travel for medical care (n = 246; contributing 1163 person-years). We used ordered logistic regression with person year data to test the association between movement restrictions from 1987 to 2011 and health status in 2011. RESULTS: Two thirds (65%; n = 161) of participants reported travel restrictions, and 38% (n = 92) reported ever being barred from travel for medical care. Compared with study participants who experienced no travel restrictions in a year (n = 559 person-years), those who were barred from travel in that same year (n = 122 person-years) reported worse self-rated health (57% vs 22% reported bad or very bad self-rated health; P < .05) and greater limits on daily functioning caused by physical health (41% vs 16% reported regular limits; P < .05). CONCLUSIONS: Being barred from travel for medical care was associated with poor health as long as 25 years later. PMID- 29161068 TI - The Nazi Physicians as Leaders in Eugenics and "Euthanasia": Lessons for Today. AB - This article, in commemoration of the 70th anniversary of the Doctors' Trial at Nuremberg, reflects on the Nazi eugenics and "euthanasia" programs and their relevance for today. The Nazi doctors used eugenic ideals to justify sterilizations, child and adult "euthanasia," and, ultimately, genocide. Contemporary euthanasia has experienced a progression from voluntary to nonvoluntary and from passive to active killing. Modern eugenics has included both positive and negative selective activities. The 70th anniversary of the Doctors' Trial at Nuremberg provides an important opportunity to reflect on the implications of the Nazi eugenics and "euthanasia" programs for contemporary health law, bioethics, and human rights. In this article, we will examine the role that health practitioners played in the promotion and implementation of State-sponsored eugenics and "euthanasia" in Nazi Germany, followed by an exploration of contemporary parallels and debates in modern bioethics. 1. PMID- 29161070 TI - Declines in Anogenital Warts Among Age Groups Most Likely to Be Impacted by Human Papillomavirus Vaccination, United States, 2006-2014. AB - OBJECTIVES: To detect decreases in anogenital warts (AGW) among sex and age groups likely to be affected by human papillomavirus vaccination. METHODS: We estimated annual AGW prevalence during 2006 to 2014 using health care claims among US private health insurance enrollees aged 15 to 39 years. We derived AGW diagnoses using 1 of the following: (1) condylomata acuminata diagnosis, (2) viral wart diagnosis combined with a benign anogenital neoplasm diagnosis or destruction or excision of an anogenital lesion, or (3) AGW medication combined with a benign anogenital neoplasm diagnosis or destruction or excision of an anogenital lesion. RESULTS: Prevalence decreased during 2008 to 2014 among females aged 15 to 19 years (annual percentage change [APC] = -14.1%; P < .001) and during 2009 to 2014 among women aged 20 to 24 years (APC = -12.9%; P < .001) and among women aged 25 to 29 years (APC = -6.0%; P = .001). We observed significant declines among men aged 20 to 24 years (APC = -6.5%; P = .005). Prevalence increased or was stable in all other sex and age groups. CONCLUSIONS: We observed AGW decreases among females in the age groups most likely to be affected by human papillomavirus vaccination and decreases in men aged 20 to 24 years. Decreased prevalence in young men is likely attributable to herd protection from vaccination among females. PMID- 29161069 TI - Characteristics of HIV-Positive Transgender Men Receiving Medical Care: United States, 2009-2014. AB - OBJECTIVES: To present the first national estimate of the sociodemographic, clinical, and behavioral characteristics of HIV-positive transgender men receiving medical care in the United States. METHODS: This analysis included pooled interview and medical record data from the 2009 to 2014 cycles of the Medical Monitoring Project, which used a 3-stage, probability-proportional-to size sampling methodology. RESULTS: Transgender men accounted for 0.16% of all adults and 11% of all transgender adults receiving HIV medical care in the United States from 2009 to 2014. Of these HIV-positive transgender men receiving medical care, approximately 47% lived in poverty, 69% had at least 1 unmet ancillary service need, 23% met criteria for depression, 69% were virally suppressed at their last test, and 60% had sustained viral suppression over the previous 12 months. CONCLUSIONS: Although they constitute a small proportion of all HIV positive patients, more than 1 in 10 transgender HIV-positive patients were transgender men. Many experienced socioeconomic challenges, unmet needs for ancillary services, and suboptimal health outcomes. Attention to the challenges facing HIV-positive transgender men may be necessary to achieve the National HIV/AIDS Strategy goals of decreasing disparities and improving health outcomes among transgender persons. PMID- 29161071 TI - Risk of Concussion During Sports Versus Physical Education Among New Mexico Middle and High School Students. AB - OBJECTIVES: To measure the risk of concussion among New Mexico middle and high school students during both sports and physical education. METHODS: Athletic directors or athletic trainers in 147 schools were asked to report the number of concussions occurring during sports and physical education in the 2013 to 2014 school year. We calculated 1-year cumulative incidence rates. RESULTS: Of the 147 schools, 99 responded (67%). During the school year, 598 students were removed from athletics because of a concussion, a 1-year cumulative incidence of 3.5 per 100. The concussion rate during sports was 3.0: 3.5 for boys and 2.4 for girls (relative risk [RR] = 1.5; 95% confidence interval [CI] = 1.2, 1.7). An additional 335 students experienced concussions during physical education. Concussion rates during physical education were 60% higher than during sports (RR = 1.6; 95% CI = 1.4, 1.8). CONCLUSIONS: In our data, the risk of concussion was higher in physical education than in sports. This suggests that concussions should be tracked for a wide range of youth athletic activities, not just for sports. Monitoring cumulative incidence, in addition to other measures, may allow comparisons across schools and regions. More prevention efforts are needed. PMID- 29161073 TI - Evaluating Public Health Interventions: 7. Let the Subject Matter Choose the Effect Measure: Ratio, Difference, or Something Else Entirely. AB - We define measures of effect used in public health evaluations, which include the risk difference and the risk ratio, the population-attributable risk, years of life lost or gained, disability-adjusted life years, quality-adjusted life years, and the incremental cost-effectiveness ratio. Except for the risk ratio, all of these are absolute effect measures. For constructing externally generalizable absolute measures of effect when there is superior fit of the multiplicative model, we suggest using the multiplicative model to estimate relative risks, which will often be obtained in simple linear form with no interactions, and then converting these to the desired absolute measure. The externally generalizable absolute measure of effect can be obtained by suitably standardizing to the risk factor distribution of the population to which the results are to be generalized. External generalizability will often be compromised when absolute measures are computed from study populations with risk factor distributions different from those of the population to whom the results are to be generalized, even when these risk factors are not confounders of the intervention effect. PMID- 29161074 TI - Challenging and Preventing Policies That Prohibit Local Civil Rights Protections for Lesbian, Gay, Bisexual, Transgender, and Queer People. AB - Discrimination causes health inequities for stigmatized groups. Lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals, in particular, are at significantly increased risk for disparate health outcomes when they reside in states that fail to extend equal protections to them or that actively deprive equal rights to them. Several states and the federal government have proposed or enacted laws that permit residents to discriminate against LGBTQ individuals. One such law, Arkansas's Intrastate Commerce Improvement Act of 2015, preempts or prohibits local governments from enacting civil rights protections for LGBTQ individuals that are also lacking at the state level. State laws such as Arkansas's undermine local control, damage the economy, and create injustices that harm LGBTQ people. I set forth 2 constitutional arguments to challenge such laws, and I provide information to help advocates support evidence-based policymaking and prevent the passage of similar laws in their states. PMID- 29161072 TI - Sexual Assertiveness Skills and Sexual Decision-Making in Adolescent Girls: Randomized Controlled Trial of an Online Program. AB - OBJECTIVES: To evaluate the efficacy of an interactive, Web-based sexual health program (Health Education and Relationship Training [HEART]) for developing sexual assertiveness skills and enhancing sexual decision-making in adolescent girls. METHODS: Participants were 222 tenth-grade girls (mean age = 15.2; 38% White, 29% Hispanic, 25% Black) in the Southeastern United States who were randomized in fall 2015 to the HEART intervention or an attention-matched control. We assessed participants at pretest, immediate posttest, and 4-month follow-up. RESULTS: Both groups had similar demographic and sexual behavior characteristics at pretest. At immediate posttest, girls who completed the HEART program demonstrated better sexual assertiveness skills measured with a behavioral task, higher self-reported assertiveness, intentions to communicate about sexual health, knowledge regarding HIV and other sexually transmitted diseases (STDs), safer sex norms and attitudes, and condom self-efficacy compared with the control condition. At 4-month follow-up, group differences remained in knowledge regarding HIV and other STDs, condom attitudes, and condom self efficacy. CONCLUSIONS: This brief online sexual health program can improve short term outcomes among adolescent girls and offers an exciting new option in the growing array of digital health interventions available to youths. TRIAL REGISTRATION NUMBER: NCT02579135. PMID- 29161075 TI - Metabolic Dysregulation, Systemic Inflammation, and Pediatric Obesity-related Asthma. AB - Obesity-related asthma is a distinct pediatric asthma phenotype. It is associated with higher disease burden, lower pulmonary function, and suboptimal response to current asthma medications. Recent studies have made inroads into elucidating its pathophysiology. Systemic immune responses in obese children with asthma are skewed to a nonatopic T-helper cell type 1 (Th1) pattern that correlates with pulmonary function deficits. The prevalence of metabolic dysregulation is also higher among obese children with asthma than among normal-weight children with asthma. Insulin resistance and dyslipidemia, particularly low levels of high density lipoprotein (HDL), are associated with lower airway obstruction and low expiratory reserve volume. These associations are independent of truncal and general adiposity and thereby suggest a direct association between metabolic abnormalities and pulmonary function. Furthermore, insulin resistance is associated with Th1 polarization, whereas low HDL is associated with monocyte activation. Although insulin resistance mediates the association of Th1 polarization with pulmonary function, HDL does not have a similar influence on the association of monocyte activation with pulmonary function. Together, these recent studies have paved the way to the understanding of obesity-related asthma as a distinct asthma phenotype and have begun to identify the complex relationships between metabolic dysregulation, systemic inflammation, and pulmonary function deficits in obese children with asthma. Studies are now needed to elucidate the mechanisms that link metabolic dysregulation and systemic immune responses to pulmonary function. PMID- 29161076 TI - Obesity and Metabolic Abnormalities in Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) and obesity are major causes of morbidity and mortality worldwide, and a relationship between COPD and obesity is increasingly recognized. The nature and underlying mechanisms of the link between obesity and COPD are still largely unknown. Obesity, and abdominal adiposity in particular, is linked to metabolic syndrome. Hypertension, hyperglycemia, and abdominal adiposity seem to be the most prevalent components of metabolic syndrome in COPD. Adipose tissues function as a source of a variety of signaling molecules in the pathobiology of respiratory diseases. Computed tomography allows measurement of various fat depots and allows better understanding of the impact of abdominal visceral fat in the pathophysiology of COPD. Innovative statistical methodology has identified obesity as a relevant and distinguishing characteristic in patients with COPD. Integrated research combining COPD and its multimorbidity network may unravel underlying endotypes to direct future interventions in this specific COPD cluster. PMID- 29161077 TI - Mitochondrial Dysfunction in Pulmonary Fibrosis. AB - The aging of the human population has resulted in an unprecedented increase in the incidence and prevalence of age-related diseases, including those of the lung. Idiopathic pulmonary fibrosis is a disease of aging, and is characterized by a progressive decline in lung function and high mortality. Recent studies suggest that mitochondrial dysfunction, which can accompany aging phenotypes, may contribute to the pathogenesis of idiopathic pulmonary fibrosis. In this review, we explore current evidence for mitochondrial dysfunction in alveolar epithelial cells, fibroblasts, and immune cells that participate in the fibrotic process. Further, the fates of these cell populations and the potential to target mitochondrial dysfunction as a therapeutic strategy are discussed. PMID- 29161078 TI - Obesity Impairs the Adaptive Immune Response to Influenza Virus. AB - Influenza, a highly contagious respiratory tract infection, affects millions of adults and children each year. Several high-risk populations include children, the elderly, the immunocompromised, and recently the obese. Given the dramatic rise in obesity over the past few decades, this increased risk for influenza infection poses a serious public health threat because nearly 500 million adults and children worldwide are classified as obese. Obesity impairs the immune response to influenza and influenza vaccination through alterations of the cellular immune system. Compared with vaccinated healthy-weight adults, vaccinated obese adults have twice the risk of influenza or influenza-like illness despite equal serological response to vaccination. This challenges the current standard of protection for influenza and suggests that further vaccination methods or therapeutics are required to combat this virulent respiratory virus. PMID- 29161080 TI - Microbial Insights into Asthmatic Immunopathology. A Forward-Looking Synthesis and Commentary. AB - Asthma is an aberrant inflammatory condition of the airways affecting approximately 1 in 10 children in affluent countries. An increasing body of evidence suggests that microbial exposures during a "critical window" of development in early life play a central role in determining future asthma susceptibility. However, like the disease itself, considerable heterogeneity exists among studies in which researchers have investigated the associations between particular microbial taxa and asthma immunology. As our understanding of asthmatic pathology evolves to enable clearer definition of asthma endotypes, it will be important to consider the impact of various environmental factors on each endotype. Given the strong evidence in support of the hypothesis that early-life microbial exposures predict later disease states such as asthma, consideration of these endotypes when establishing experimental outcomes in epidemiological studies could allow for increased precision when determining exposure-outcome associations and engaging in more focused follow-up mechanistic investigations. PMID- 29161079 TI - A New Frontier in Immunometabolism. Cholesterol in Lung Health and Disease. AB - The lung has a unique relationship to cholesterol that is shaped by its singular physiology. On the one hand, the lungs receive the full cardiac output and have a predominant dependence on plasma lipoprotein uptake for their cholesterol supply. On the other hand, surfactant lipids, including cholesterol, are continually susceptible to oxidation owing to direct environmental exposure and must be cleared or recycled because of the very narrow biophysical mandates placed upon surfactant lipid composition. Interestingly, increased lipid-laden macrophage "foam cells" have been noted in a wide range of human lung pathologies. This suggests that lipid dysregulation may be a unifying and perhaps contributory event in chronic lung disease pathogenesis. Recent studies have shown that perturbations in intracellular cholesterol trafficking critically modify the immune response of macrophages and other cells. This minireview discusses literature that has begun to demonstrate the importance of regulated cholesterol traffic through the lung to pulmonary immunity, inflammation, and fibrosis. This emerging recognition of coupling between immunity and lipid homeostasis in the lung presents potentially transformative concepts for understanding lung disease and may also offer novel and exciting avenues for therapeutic development. PMID- 29161081 TI - Diet, Obesity, and Asthma. AB - Obesity has reached epidemic proportions in many developed countries as Western dietary patterns have been widely adopted. These diets are characterized by excess energy intake as well as regular consumption of processed or "fast" foods and limited consumption of fruit, vegetables, and whole grains. The result is a high intake of saturated fat, refined carbohydrates, and sodium; and a low intake of fiber, vitamins, and other phytochemicals. This type of poor-quality diet has been associated with increased risk of chronic inflammatory diseases, including asthma. Of particular note, high intake of saturated fat stimulates proinflammatory pathways via activation of pattern recognition receptors, endoplasmic reticulum stress, and fatty acid-binding protein activity. Conversely, with a low intake of soluble fiber, beneficial antiinflammatory mechanisms, such as free fatty acid receptor activation and histone deacetylase inhibition, are suppressed. Similarly, with a low intake of antioxidants such as vitamin C, vitamin E, and carotenoids, nuclear factor kappa-light-chain-enhancer of activated B cells activity is enhanced, creating a proinflammatory environment. There is evidence derived from human and experimental models of asthma suggesting that these mechanisms contribute to the development of airway inflammation, loss of asthma control, and/or worse lung function. Obese individuals have increased asthma morbidity and reduced quality of life, so strategies for better management of these patients are urgently needed. Evidence suggests that, in addition to reducing the quantity of food consumed, interventions should also target the quality of food consumed to improve both asthma management and the overall health and well being of these patients. PMID- 29161083 TI - Chair's Summary: Obesity and Associated Changes in Metabolism, Implications for Lung Diseases. PMID- 29161082 TI - Gut Microbiome and Obesity. How to Prove Causality? AB - In recent years, the gut microbiota (the microorganisms that live in our digestive tract) has become an area of great interest. Indeed, this intestinal microbial community performs essential functions in maintaining our health, and has been proven to influence host physiology and metabolism. Thereby, dysregulation of this gut microbiota may be implicated in the development of various diseases, including obesity. However, studies rarely assess causality, which requires the use of germ-free animals and microbiota transplant. Using these strategies, some gut microbiota were shown to confer obesity and associated metabolic disorders to mice, suggesting a causative link between gut bacteria and metabolic diseases. PMID- 29161084 TI - Mitochondrial Dysfunction Linking Obesity and Asthma. AB - The bidirectional epidemiological association between asthma and obesity is well known. Recent evidence suggests that there is an intersection of the pathophysiological molecular pathways leading to either obesity or asthma, at the level of mitochondria. This is not surprising, because mitochondria, beyond their roles as the metabolic powerhouses of the cell, serve as sensors of threats, regulators of stress signaling, and effectors of cytotoxicity. Reduced mitochondrial function and low metabolic activity are well-recognized features of obesity. Three distinct lines of experimental evidences connect mitochondrial dysfunction with asthma. First, asthma is associated with aberrant mitochondrial metabolism. Second, mitochondrial dysfunction may either induce asthma-like features or increase asthma severity. Third, mitochondria-targeted therapies appear effective in preventing or reversing asthma features. Importantly, mitochondrial dysfunction in airway epithelial cells appears to be a powerful trigger for airway remodeling that is independent of cellular inflammation. This is clinically relevant to the obese-asthma phenotype, with exaggerated symptoms despite apparently low levels of inflammation, and poor response to antiinflammatory treatment. In summary, mitochondrial dysfunction is a common thread tying together the twin epidemics of obesity and asthma. Environmental and lifestyle factors leading to primary mitochondrial dysfunction may be increasing the risk for either disease. Further, secondary mitochondrial dysfunction emerging from the pathogenesis of either obesity or asthma may increase the risk of the other. Mitochondrial health-centric strategies may be relevant to prevention and treatment of both obesity and asthma, and should be actively considered. PMID- 29161085 TI - Purpose of the Conference: The 2017 Transatlantic Conference on Lung Diseases. PMID- 29161086 TI - Potential Role of the Lung Microbiome in Shaping Asthma Phenotypes. AB - The introduction of 16s ribosomal RNA sequencing as a nonculture technique has led to the discovery of the presence of microbiota in the lower airways of healthy individuals. These bacterial communities may originate from the mouth and nasopharynx or from the environment by inhalation. The microbial composition of the lower airways may be modulated by dietary factors, antibiotic therapy, and microbial infections, particularly in early life. In addition, circulatory products from gut microbiota may influence the lung microbiota to maintain mucosal immunity. Recent studies have revealed that, in asthma, the lower airway microbiota show reduced diversity and community composition that is linked to severity and inflammatory phenotype. There is also a greater prevalence of proteobacteria, including Haemophilus, in symptomatic asthma. Microbial dysbiosis may contribute to both the inception and progression of asthma in infants and children, and to corticosteroid resistance in asthma. A better understanding of the regulation of the lung and gut microbiota in asthma may pave the way for targeting microbiota to prevent and treat asthma. PMID- 29161087 TI - The Hygiene Hypothesis in the Age of the Microbiome. AB - The original version of the hygiene hypothesis suggested that infections transmitted early in life by "unhygienic contact" prevented allergies. Examples were endemic fecal-oral infections by viral, bacterial, or protozoic pathogens, such as hepatitis A virus, Helicobacter pylori, or Toxoplasma gondii. Later, this concept also included microorganisms beyond pathogens, such as commensals and symbionts, and the hygiene hypothesis was extended to inflammatory diseases in general. An impressive illustration of the hygiene hypothesis was found in the consistent farm effect on asthma and allergies, which has partly been attributed to immunomodulatory properties of endotoxin as emitted by livestock. Assessment of environmental microorganisms by molecular techniques suggested an additional protective effect of microbial diversity on asthma beyond atopy. Whether microbial diversity stands for a higher probability to encounter protective clusters of microorganisms or whether it is a proxy of a balanced environmental exposure remains elusive. Diversity of the mucosal microbiome of the upper airways probably reflects an undisturbed balance of beneficial microorganisms and pathogens, such as Moraxella catarrhalis, which has been associated with subsequent development of asthma and pneumonia. In addition, specific fermenters of plant fibers, such as the genera Ruminococcus and Bacteroides, have been implied in asthma protection through production of short-chain fatty acids, volatile substances with the capability to reduce T-helper cell type 2-mediated allergic airway inflammation. Evolutionary thinking may offer a key to understanding noncommunicable inflammatory diseases as delayed adaptation to a world of fast and profound environmental changes. Better adaptation may be fostered by growing insight into the interplay between man and microbiome and an adequate choice of the environmental exposure. PMID- 29161088 TI - Mechanistic Basis for Obesity-related Increases in Ozone-induced Airway Hyperresponsiveness in Mice. AB - Obesity is a risk factor for asthma, especially nonallergic asthma. Ozone, a common air pollutant, is a nonallergic asthma trigger. Importantly, ozone-induced decrements in lung function are greater in obese and overweight human subjects than in lean individuals. Obese mice also exhibit exaggerated pulmonary responses to ozone. Ozone causes greater increases in pulmonary resistance, in bronchoalveolar lavage neutrophils, and in airway hyperresponsiveness in obese than in lean mice. Our data indicate that IL-33 plays a role in mediating these events. Ozone causes greater release of IL-33 into bronchoalveolar lavage fluid in obese than in lean mice. Furthermore, an antibody blocking the IL-33 receptor, ST2, attenuates ozone-induced airway hyperresponsiveness in obese but not in lean mice. Our data also indicate a complex role for tumor necrosis factor (TNF)-alpha in obesity-related effects on the response to ozone. In obese mice, genetic deficiency in either TNF-alpha or TNF-alpha receptor 2 augments ozone-induced airway hyperresponsiveness, whereas TNF-alpha receptor 2 deficiency virtually abolishes ozone-induced airway hyperresponsiveness in lean mice. Finally, obesity is known to alter the gut microbiome. In female mice, antibiotics attenuate obesity-related increases in the effect of ozone on airway hyperresponsiveness, possibly by altering microbial production of short-chain fatty acids. Asthma control is often difficult to achieve in obese patients with asthma. Our data suggest that therapeutics directed against IL-33 may ultimately prove effective in these patients. The data also suggest that dietary manipulations and other strategies (prebiotics, probiotics) that alter the microbiome and/or its metabolic products may represent a new frontier for treating asthma in obese individuals. PMID- 29161089 TI - Protein Folding and the Challenges of Maintaining Endoplasmic Reticulum Proteostasis in Idiopathic Pulmonary Fibrosis. AB - Alveolar epithelial type II (AEII) cells are "professional" secretory cells that synthesize and secrete massive quantities of proteins to produce pulmonary surfactant and maintain airway immune defenses. To facilitate this high level of protein synthesis, AEII cells are equipped with an elaborate endoplasmic reticulum (ER) structure and possess an abundance of the machinery needed to fold, assemble, and secrete proteins. However, conditions that suddenly increase the quantity of new proteins entering the ER or that impede the capacity of the ER to fold proteins can cause misfolded or unfolded proteins to accumulate in the ER lumen, also called ER stress. To minimize this stress, AEII cells adapt by (1) reducing the quantity of proteins entering the ER, (2) increasing the amount of protein-folding machinery, and (3) removing misfolded proteins when they accumulate. Although these adaptive responses, aptly named the unfolded protein response, are usually effective in reducing ER stress, chronic aggregation of misfolded proteins is recognized as a hallmark feature of AEII cells in patients with idiopathic pulmonary fibrosis (IPF). Although mutations in surfactant proteins are linked to the development of ER stress in some rare IPF cases, the mechanisms causing protein misfolding in most cases are unknown. In this article, we review the mechanisms regulating ER proteostasis and highlight specific aspects of protein folding and the unfolded protein response that are most vulnerable to failure. Then, we postulate mechanisms other than genetic mutations that might contribute to protein aggregation in the alveolar epithelium of IPF lung. PMID- 29161090 TI - Pathophysiology to Phenotype in the Asthma of Obesity. AB - Obesity affects numerous diseases, including asthma, for reasons that remain incompletely understood. Recent research suggests that the asthma of obesity is not a single disease, and that it breaks out into at least two distinct phenotypes. One phenotype is conventional allergic asthma modulated by obesity, whereas another arises solely due to the presence of obesity. The latter is postulated to be a consequence of the chronic lung compression caused by the obese chest wall in individuals with particularly collapsible lungs. Allergic obese asthma, on the other hand, appears to result from the way that obesity affects the immune system, which we hypothesize can be understood in terms of effects on the dynamic regulation of the inflammatory response. PMID- 29161092 TI - The Impact of Diet on Immunity and Respiratory Diseases. AB - The Western world has witnessed a tremendous increase in the occurrence of allergy and autoimmunity in the second half of the 20th century. Extensive efforts have been made to explain this phenomenon and various hypotheses have been formulated. Among them, two concepts have attracted the most attention: the "hygiene hypothesis," identifying the reduced exposure to environmental microorganisms as a driving force behind the observed epidemiological trends; and the "diet hypotheses," pointing to the importance of changes in our dietary habits. In this review, we discuss the interplay between the Western diet, microbiota, and inflammatory conditions, with particular emphasis on respiratory diseases. This is followed by an in-depth overview of the immunomodulatory potential of different dietary fatty acids. We conclude by identifying the outstanding questions, which, if answered, could shed further light on the impact of dietary habits on immunity and interconnect it with postulates proposed by the hygiene hypothesis. Linking these two concepts will be an important step towards understanding how Western lifestyle shapes disease susceptibility. PMID- 29161091 TI - Dealing with Stress: Defective Metabolic Adaptation in Chronic Obstructive Pulmonary Disease Pathogenesis. AB - The mitochondrion is the main site of energy production and a hub of key signaling pathways. It is also central in stress-adaptive response due to its dynamic morphology and ability to interact with other organelles. In response to stress, mitochondria fuse into networks to increase bioenergetic efficiency and protect against oxidative damage. Mitochondrial damage triggers segregation of damaged mitochondria from the mitochondrial network through fission and their proteolytic degradation by mitophagy. Post-translational modifications of the mitochondrial proteome and nuclear cross-talk lead to reprogramming of metabolic gene expression to maintain energy production and redox balance. Chronic obstructive pulmonary disease (COPD) is caused by chronic exposure to oxidative stress arising from inhaled irritants, such as cigarette smoke. Impaired mitochondrial structure and function, due to oxidative stress-induced damage, may play a key role in causing COPD. Deregulated metabolic adaptation may contribute to the development and persistence of mitochondrial dysfunction in COPD. We discuss the evidence for deregulated metabolic adaptation and highlight important areas for investigation that will allow the identification of molecular targets for protecting the COPD lung from the effects of dysfunctional mitochondria. PMID- 29161094 TI - The Effect of Resistance Training in a Hypoxic Chamber on Physical Performance in Elite Rugby Athletes. AB - Mayo, Brad, Cory Miles, Stacy Sims, and Matthew Driller. The effect of resistance training in a hypoxic chamber on physical performance in elite rugby athletes. High Alt Med Biol 19:28-34, 2018.-Limited research suggests that muscle adaptations may be enhanced through resistance training in a hypoxic environment. Seventeen professional rugby union athletes (age [mean +/- SD], 24 +/- 3 years; body mass, 98.7 +/- 12.8 kg; and height, 188.9 +/- 7.9 cm), performed 12 resistance training sessions over a 3-week period. Participants were randomly divided into two groups: HYP (n = 8), where resistance training sessions were performed in an environmental chamber with O2 concentration maintained at ~14.4% (~3000 m simulated altitude), or CON (n = 9), where identical resistance training sessions were performed without the simulated altitude (O2 = 20.9%, at sea level). Before and after the training intervention, tests included measures of strength, power, endurance, speed, and body composition. Two-way interactions between treatment and time for any of the measured variables were not significant (p > 0.05). Small positive effect sizes for HYP were found for bench press (d = 0.24), weighted chin-up (d = 0.23), and bronco endurance tests (d = -0.21). Resistance training in a hypoxic environmental chamber may lead to small improvements in upper body strength and endurance compared to the same training performed at sea level. These findings are somewhat novel, given the short timeframe of the study and the elite population sampled. PMID- 29161095 TI - Resection-Induced Leveling of Elevated Plug Cartilage in Osteochondral Autologous Transplantation of the Knee Achieves Acceptable Clinical Results. AB - BACKGROUND: Plug protuberance occasionally occurs in osteochondral autologous transplantation (OAT). The incongruity of plugs results in poor clinical outcomes, especially in cases of protuberance. However, a surgical procedure to deal with this problem has not been reported. Purpose/Hypothesis: The purpose was to evaluate the efficacy and safety of cartilage resection of elevated plugs, with the hypothesis that patients whose elevated plugs were resected and leveled would achieve clinical outcomes equivalent to those of patients with flush plugs. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Cases (group P) included 22 patients who underwent OAT of the knee and whose plugs showed protuberance greater than 1 mm that was resected with a scalpel to obtain smooth congruity, while controls (group C) included 22 background-matched patients who did not require plug resection. The International Knee Documentation Committee (IKDC) subjective score, IKDC objective grade, and Japanese Orthopaedic Association score for knee osteoarthritis (JOA knee score) were used preoperatively and at the final follow-up (mean +/- SD, 49.3 +/- 18.1 months). International Cartilage Repair Society (ICRS) Cartilage Repair Assessment was used to evaluate lesion healing during the second-look arthroscopy. RESULTS: IKDC subjective scores of group C (82.5 +/- 11.8) and group P (82.1+/- 15.1) showed no difference at the final follow-up. On postoperative IKDC objective grading, 86% of group C and 82% of group P patients were graded as "nearly normal" or better ( P = .639). The mean JOA knee scores of group C (90.9 +/- 8.9) and group P (90.1 +/- 9.5) did not differ significantly ( P = .647). Nine second-look arthroscopies were performed in group C versus 8 in group P, and all patients had plugs that were graded as "nearly normal" or better by the ICRS Cartilage Repair Assessment. Larger plugs tended to be used in those patients who required resection. CONCLUSION: Resection of the elevated plug surface did not negatively affect patient outcomes in the midterm follow-up period. PMID- 29161096 TI - The Role of Healthcare Technology Management in Facilitating Medical Device Cybersecurity. AB - This article discusses the role of healthcare technology management (HTM) in medical device cybersecurity and outlines concepts that are applicable to HTM professionals at a healthcare delivery organization or at an integrated delivery network, regardless of size. It provides direction for HTM professionals who are unfamiliar with the security aspects of managing healthcare technologies but are familiar with standards from The Joint Commission (TJC). It provides a useful set of recommendations, including relevant references for incorporating good security practices into HTM practice. Recommendations for policies, procedures, and processes referencing TJC standards are easily applicable to HTM departments with limited resources and to those with no resource concerns. The authors outline processes from their organization as well as best practices learned through information sharing at AAMI, National Health Information Sharing and Analysis Center (NH-ISAC), and Medical Device Innovation, Safety, and Security Consortium (MDISS) conferences and workshops. PMID- 29161097 TI - Feeling the Pain of Cyberattacks. PMID- 29161093 TI - B Cells Producing Type I IFN Modulate Macrophage Polarization in Tuberculosis. AB - RATIONALE: In addition to their well-known function as antibody-producing cells, B lymphocytes can markedly influence the course of infectious or noninfectious diseases via antibody-independent mechanisms. In tuberculosis (TB), B cells accumulate in lungs, yet their functional contribution to the host response remains poorly understood. OBJECTIVES: To document the role of B cells in TB in an unbiased manner. METHODS: We generated the transcriptome of B cells isolated from Mycobacterium tuberculosis (Mtb)-infected mice and validated the identified key pathways using in vitro and in vivo assays. The obtained data were substantiated using B cells from pleural effusion of patients with TB. MEASUREMENTS AND MAIN RESULTS: B cells isolated from Mtb-infected mice displayed a STAT1 (signal transducer and activator of transcription 1)-centered signature, suggesting a role for IFNs in B-cell response to infection. B cells stimulated in vitro with Mtb produced type I IFN, via a mechanism involving the innate sensor STING (stimulator of interferon genes), and antagonized by MyD88 (myeloid differentiation primary response 88) signaling. In vivo, B cells expressed type I IFN in the lungs of Mtb-infected mice and, of clinical relevance, in pleural fluid from patients with TB. Type I IFN expression by B cells induced an altered polarization of macrophages toward a regulatory/antiinflammatory profile in vitro. In vivo, increased provision of type I IFN by B cells in a murine model of B cell-restricted Myd88 deficiency correlated with an enhanced accumulation of regulatory/antiinflammatory macrophages in Mtb-infected lungs. CONCLUSIONS: Type I IFN produced by Mtb-stimulated B cells favors macrophage polarization toward a regulatory/antiinflammatory phenotype during Mtb infection. PMID- 29161098 TI - Cybersecurity Standards Are Standing Up to the Bad Actors. PMID- 29161099 TI - Using Standards to Establish Foundational Security Requirements for Medical Devices. PMID- 29161100 TI - Hardening Infusion Pump Communication Software for Medical Device Cybersecurity. PMID- 29161101 TI - Designing Robust Medical Devices that Are Ready for Enterprise Security Scanning. PMID- 29161103 TI - Top 10 Ways to Mitigate the Risk and Effect of Cyberattacks on Medical Devices. PMID- 29161104 TI - Time to Get a Taste of Our Own Medicine. PMID- 29161102 TI - Ensuring Secure and Safe Infusion Delivery in a Connected World. PMID- 29161105 TI - The Economics of Cybersecurity. PMID- 29161106 TI - Holding the Line: Events that Shaped Healthcare Cybersecurity. PMID- 29161107 TI - Doing What Is Right with Coordinated Vulnerability Disclosure. PMID- 29161108 TI - A Roundtable Discussion: Thawing Out Healthcare Technology's 'Special Snowflake' Cybersecurity Challenges. PMID- 29161110 TI - Biotechnological Applications of an Insect-Specific Alphavirus. AB - The coupling of viral and arthropod host diversity, with evolving methods of virus discovery, has resulted in the identification and classification of a growing number of novel insect-specific viruses (ISVs) that appear to be evolutionarily related to many human pathogens but have either lost or have yet to gain the ability to replicate in vertebrates. The discovery of ISVs has raised many questions as to the origin and evolution of many human pathogenic viruses and points to the role that arthropods may play in this evolutionary process. Furthermore, the use of ISVs to control the transmission of arthropod-borne viruses has been proposed and demonstrated experimentally. Previously, our laboratory reported on the discovery and characterization of Eilat virus (EILV), an insect-specific alphavirus that phylogenetically groups within the mosquito borne clade of medically relevant alphaviruses, including eastern equine encephalitis virus (EEEV) and Venezuelan equine encephalitis virus (VEEV), as well as chikungunya virus (CHIKV). Despite its evolutionary relationship to these human pathogens, EILV is unable to replicate in vertebrate cells due to blocks at attachment/entry and RNA replication. We recently demonstrated that, using a chimeric virus approach, EILV could be utilized as a platform for vaccine and diagnostic development, serving as a proof-of-concept for other ISVs. Due to the vast abundance of ISVs, there is an untapped resource for the development of vaccines and diagnostics for a variety of human pathogens and further work in this area is warranted. PMID- 29161111 TI - Discussion of "Can measures of critical power precisely estimate the maximal metabolic steady-state?" - Is it still necessary to compare critical power to maximal lactate steady state? PMID- 29161112 TI - Reply to "Discussion of 'Can measures of critical power precisely estimate the maximal metabolic steady-state?' - Is it still necessary to compare critical power to maximal lactate steady state?" - When is it appropriate to compare critical power to maximal lactate steady-state? PMID- 29161113 TI - Disseminability of computerized cognitive training: Performance across coaches. AB - Cogmed is a computerized cognitive intervention utilizing coaches who receive standardized instruction in analyzing training indices and tailoring feedback to remotely monitor participant's performance. The goal of this study was to examine adherence, satisfaction, and efficacy of Cogmed across coaches. Survivors of pediatric brain tumors and acute lymphoblastic leukemia (N = 68) were randomized to intervention (Cogmed) or waitlist control. The intervention group was matched with one of two coaches. Cognitive assessments were completed before and after intervention, and participants and caregivers in the intervention group completed satisfaction surveys. T-tests showed no differences in adherence across coaches (number of sessions completed p = .38; d = .32). Noninferiority statistics were not consistently equivalent for satisfaction, but equivalence was supported for caregiver perceptions of pragmatic utility and participant perceptions of logistical ease of Cogmed. Equivalence was not consistently suggested for cognitive outcomes, but was supported on measures tapping relevant cognitive domains (attention, working memory, processing speed, academic fluency). This study suggests adherence can be maintained across coaches. While aspects of satisfaction and cognitive outcomes were equivalent, the possible influence of coach-based variables cannot be ruled out. Findings highlight challenges in standardizing the coaching component of multicomponent computerized interventions and the need for ongoing research to establish dessiminability. PMID- 29161114 TI - Suicide and High Altitude: An Integrative Review. AB - : Reno, Elaine, Talia L. Brown, Marian E. Betz, Michael H. Allen, Lilian Hoffecker, Jeremy Reitinger, Robert Roach, and Benjamin Honigman. Suicide and high altitude: an integrative review. High Alt Med Biol 19:99-108, 2018. INTRODUCTION: Suicide rates are greater at high altitudes, and multiple mechanisms have been suggested for this relationship, including hypoxia, differences in population density, characteristics of suicide victims, and firearms ownership and access. To better understand these potential mechanisms, studies evaluating the associations between high altitude and suicide were examined. METHODS: A literature review of published studies on high altitude and suicide was conducted in Medline, Embase, Web of Science, the Cochrane Database of Systematic Reviews, and the Cochrane CENTRAL database. We extracted and analyzed all studies that met the inclusion criteria, excluding foreign language studies and letters. Most of the measurements and results were synthesized using modified Letts' criteria. RESULTS: Searches using an extensive list of keywords returned 470 articles, but only 6 met the inclusion criteria. The studies' samples ranged in size from 8871 to 596,704, while studies which did not document sample size reported suicide rates. In five of the studies selected, individuals living at high altitudes were at greater risk of suicide. Four studies used aggregated data at a county or state level to analyze variables, such as age, gender, race, socioeconomic factors, and firearms access. All the studies found that high altitude was independently associated with suicide. One study found that many individual characteristics of those who committed suicide were different at high altitudes than low altitude, including a lack of access or barriers to mental healthcare. Depression exacerbated by hypoxia was hypothesized as a possible biologic mechanism in three studies. CONCLUSION: These research studies published since 2009 support an association between high altitude and suicide rates at the state or county level, but do not provide sufficient data to estimate the effect of high altitude on an individuals' suicide risk. Although the impact of hypoxia on mood and depression has been hypothesized to be a contributing cause, many other individual factors likely play more important roles. PMID- 29161115 TI - Hip Arthroscopic Surgery for Femoroacetabular Impingement With Capsular Management: Factors Associated With Achieving Clinically Significant Outcomes. AB - BACKGROUND: There has been increasing interest in defining clinically meaningful outcomes in patient reported outcomes following orthopaedic surgery. Little is known about the factors associated with clinically meaningful outcomes after hip arthroscopy for femoroacetabular impingement. STUDY DESIGN: Case-control study; Level of evidence, 3. PURPOSE: To report on a large, prospectively collected consecutive series of patients who underwent comprehensive arthroscopic treatment of femoroacetabular impingement (FAI) and capsular management with greater than 2 year follow-up. The objectives were to determine (1) what percentage of patients achieve clinically significant outcomes after hip arthroscopic surgery for FAI as determined by the minimal clinically important difference (MCID) and patient acceptable symptom state (PASS) and (2) what factors are associated with achieving the MCID and PASS. METHODS: Data from an institutional repository of consecutive patients undergoing primary hip arthroscopic surgery with routine capsular closure for FAI that had failed nonsurgical management between January 2012 and January 2014 were prospectively collected and analyzed. Of 474 patients during the enrollment period, 386 (81.4%) patients were available for a minimum 2 year follow-up. Demographics, radiographic measurements, intraoperative characteristics, and patient-reported outcome scores were collected. The primary outcome measure was achieving published thresholds for the MCID and PASS for the Hip Outcome Score (HOS)-Activities of Daily Living (ADL) in patients with FAI. The HOS-Sport-Specific Subscale (SSS), complications, and reoperations were secondary outcome measures. Multivariate regression analyses were conducted to identify factors associated with achieving the MCID and PASS. RESULTS: At a minimum of 2-year follow-up, the patients had statistically significant improvements in all patient-reported outcomes (HOS-ADL, HOS-SSS, and modified Harris Hip Score [mHHS]; P < .001 for all), with a 1.2% rate of revision hip arthroscopic surgery and 1.7% rate of conversion to total hip arthroplasty. The MCID was achieved by 78.8% of patients for the HOS-ADL, and the PASS was achieved by 62.5% for the HOS-ADL. Younger age ( P = .008), Tonnis grade 0 ( P = .022), and lower preoperative HOS-ADL score ( P < .001) were associated with successfully achieving the MCID for the HOS-ADL. Younger age ( P < .001), larger medial joint space width ( P = .028), and higher preoperative HOS-ADL score ( P < .001) were associated with achieving the PASS for the HOS-ADL. Younger age ( P < .001), lower body mass index ( P = .006), non-workers' compensation status ( P = .020), and lower preoperative HOS-SSS score ( P < .001) were associated with achieving the MCID for the HOS-SSS. Younger age ( P = .001), Tonnis grade 0 ( P = .014), running ( P = .008), and higher preoperative HOS-SSS score ( P < .001) were associated with achieving the PASS for the HOS-SSS. Overall, 49.4% of patients achieved all 4 clinically significant outcomes: both the MCID and PASS for the HOS-ADL and HOS-SSS. CONCLUSION: The majority of patients undergoing hip arthroscopic surgery with routine capsular closure for FAI experienced clinically significant outcomes that met the MCID or PASS criteria, with low rates of revision and conversion to total hip arthroplasty. Factors associated with these successful outcomes on multivariate analyses included younger age with a normal joint space. Patients with lower preoperative HOS scores were more likely to achieve the MCID, whereas patients with higher preoperative HOS scores were more likely to achieve the PASS. PMID- 29161116 TI - Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. AB - RATIONALE: Corticosteroid therapy is commonly used among critically ill patients with Middle East Respiratory Syndrome (MERS), but its impact on outcomes is uncertain. Analyses of observational studies often do not account for patients' clinical condition at the time of corticosteroid therapy initiation. OBJECTIVES: To investigate the association of corticosteroid therapy on mortality and on MERS coronavirus RNA clearance in critically ill patients with MERS. METHODS: ICU patients with MERs were included from 14 Saudi Arabian centers between September 2012 and October 2015. We performed marginal structural modeling to account for baseline and time-varying confounders. MEASUREMENTS AND MAIN RESULTS: Of 309 patients, 151 received corticosteroids. Corticosteroids were initiated at a median of 3.0 days (quartile 1 [Q1]-Q3, 1.0-7.0) from ICU admission. Patients who received corticosteroids were more likely to receive invasive ventilation (141 of 151 [93.4%] vs. 121 of 158 [76.6%]; P < 0.0001) and had higher 90-day crude mortality (112 of 151 [74.2%] vs. 91 of 158 [57.6%]; P = 0.002). Using marginal structural modeling, corticosteroid therapy was not significantly associated with 90-day mortality (adjusted odds ratio, 0.75; 95% confidence interval, 0.52-1.07; P = 0.12) but was associated with delay in MERS coronavirus RNA clearance (adjusted hazard ratio, 0.35; 95% CI, 0.17-0.72; P = 0.005). CONCLUSIONS: Corticosteroid therapy in patients with MERS was not associated with a difference in mortality after adjustment for time-varying confounders but was associated with delayed MERS coronavirus RNA clearance. These findings highlight the challenges and importance of adjusting for baseline and time-varying confounders when estimating clinical effects of treatments using observational studies. PMID- 29161117 TI - Safety Innovations: Vital Signs Monitoring Leads to Increased Patient Safety and Workflow Efficiency. PMID- 29161120 TI - Ten Questions With .... PMID- 29161119 TI - Cultivating Leaders: To Lead or to Manage? Exploring the Subtle Nuances between Two Key Roles. PMID- 29161121 TI - Research: Design and Analysis of a Low-Stiffness Porous Hip Stem. AB - Two major problems are associated with total hip replacement: 1) stress shielding and 2) the adverse tissue reaction to certain elements of the implant material. In this regard, a porous implant provides lower stiffness and vacancies for bone ingrowth, making it more suitable for the human bone compared with a solid stem. Moreover, second-generation titanium biomedical alloys, such as TNZT (Ti35Nb7Zr5Ta) and TMZF (Ti12Mo6Zr2Fe), have been introduced to prevent the adverse tissue reactions related to aluminum and vanadium elements of the popular Ti6Al4V alloy. In the current work, an analysis was performed based on uniaxial compression testing of cubic Ti6Al4V structures of different porosities to predict the governing equations that relate the relative density of the structure to the mechanical properties of the structure according to the Gibson-Ashby model. A numerical study was conducted to evaluate the change in stress distribution obtained by incorporating the new titanium alloys in porous hip stem implants. Implants modeled with the mechanical properties of TNZT and TMZF showed a minimum safety factor of 1.69 and 3.02, respectively, with respect to the yield strength. The results demonstrated an increase in the equivalent von Mises stresses and maximum principal elastic strain up to 7% and 15%, respectively, compared with the porous Ti6Al4V implant and up to 108% and 156%, respectively, compared with the solid Ti6Al4V implant. PMID- 29161122 TI - Cochlear Implant Standard Seeks to Enhance Reliability, Clinical Decision Making. PMID- 29161123 TI - The Best of Both Worlds: Implementing a Hybrid In-House Central Support Program. PMID- 29161125 TI - Frontlines: Curbing Medical Device Misuse. PMID- 29161128 TI - The Roundup. PMID- 29161127 TI - A Roundtable Discussion: Leveraging Data to Benefit Healthcare Technology Management. PMID- 29161129 TI - Research: Validity of Measurements when Reusing Icare Probes. AB - BACKGROUND: It has been reported that reusing Icare tonometer probes may not pose a considerable risk of transmission of infection, thereby supporting this practice under extraordinary circumstances, such as mass glaucoma screenings in developing countries. The present study sought to determine whether reusing the probes reduced the validity of pressure readings. METHODS: Thousands of measurements were made with the same Icare probe on a purpose-built calibration device. A second set of measurements was made during which the Icare probe head was wiped with an alcohol pad between each reading. RESULTS: Statistically different readings were observed between the no-wipe and wipe groups for most of the settings evaluated. In addition, statistically significant readings were noted for a few of the settings as the number of readings increased for either group. However, these differences would not be considered clinically significant. CONCLUSION: This study suggests that reusing Icare tonometer probes, even for hundreds of measurements, would not reduce the clinical utility of the pressure readings. For mass screenings in developing countries where cost savings is crucial, considering the reuse of Icare tonometer probes seems reasonable. PMID- 29161130 TI - Considerations Surrounding TENS Units and Patient-Used CPAP and BPAP Machines. PMID- 29161131 TI - Reflections on HTM, Compliance, and Patient Safety. PMID- 29161132 TI - The Doctor Is In. PMID- 29161133 TI - How to Get What You Need (or Want). PMID- 29161134 TI - Handled with Care? Protecting Medical Devices from Harm. PMID- 29161135 TI - 'Crunch Berries' Analogy Helps Underscore Importance of Bioburden Monitoring. PMID- 29161136 TI - Securing Data Across the Continuum of Care Is a Key Priority at Children's Health. PMID- 29161137 TI - Pragmatic competence of children with autism spectrum disorder. Impact of theory of mind, verbal working memory, ADHD symptoms, and structural language. AB - The primary aim of this study is to increase the existing knowledge about the pragmatic skills of children with autism spectrum disorders (ASD). Specifically, the study has two objectives. The first is to provide a profile of characteristics based on The Children's Communication Checklist (CCC-2) pragmatics scales (inappropriate initiation, stereotyped language, use of context, nonverbal communication, and general pragmatics) and narrative task indicators. To this end, children with ASD will be compared to children with typical development (TD), controlling the effects of sex and structural language (speech, syntax, semantics, coherence). The second objective is to analyze whether theory of mind (ToM), verbal working memory, ADHD symptoms, and structural language can predict pragmatic competence in children with ASD without intellectual disability (ID). The results showed worse performance in the group with ASD on the majority of the pragmatic aspects evaluated. In addition, the application of ToM skills and structural language were significant predictors of the pragmatic skills of the children with ASD. These findings reinforce the importance of focusing intervention programs on mentalist abilities through experiences in real social scenarios, along with strengthening structural language components. PMID- 29161138 TI - Autologous Matrix-Induced Chondrogenesis: A Systematic Review of the Clinical Evidence. AB - BACKGROUND: The addition of a type I/III collagen membrane in cartilage defects treated with microfracture has been advocated for cartilage repair, termed "autologous matrix-induced chondrogenesis" (AMIC). PURPOSE: To examine the current clinical evidence regarding AMIC for focal chondral defects. STUDY DESIGN: Systematic review. METHODS: A systematic review was performed by searching PubMed, ScienceDirect, and Cochrane Library databases. Inclusion criteria were clinical studies of AMIC for articular cartilage repair, written in English. Relative data were extracted and critically analyzed. PRISMA guidelines were applied, the methodological quality of the included studies was assessed by the modified Coleman Methodology Score (CMS), and aggregate data were generated. RESULTS: Twenty-eight clinical articles were included: 12 studies (245 patients) of knee cartilage defects, 12 studies (214 patients) of ankle cartilage defects, and 4 studies (308 patients) of hip cartilage defects. The CMS demonstrated a suboptimal study design in the majority of published studies (knee, 57.8; ankle, 55.3; hip, 57.7). For the knee, 1 study reported significant clinical improvements for AMIC compared with microfracture for medium-sized cartilage defects (mean defect size 3.6 cm2) after 5 years (level of evidence, 1). No study compared AMIC with matrix-assisted autologous chondrocyte implantation (ACI) in the knee. For the ankle, no clinical trial was available comparing AMIC versus microfracture or ACI. In the hip, only one analysis (level of evidence, 3) compared AMIC with microfracture for acetabular lesions. For medium-sized acetabular defects, one study (level of evidence, 3) found no significant differences between AMIC and ACI at 5 years. Specific aspects not appropriately discussed in the currently available literature include patient-related factors, membrane fixation, and defect properties. No treatment-related adverse events were reported. CONCLUSION: This systematic review reveals a paucity of high quality, randomized controlled studies testing the AMIC technique versus established procedures such as microfracture or ACI. Evidence is insufficient to recommend joint-specific indications for AMIC. Additional nonbiased, high powered, randomized controlled clinical trials will provide better clinical and structural long-term evidence, thus helping to define possible indications for this technique. PMID- 29161139 TI - Occupational Radiation Exposure in Interventional Radiology and the Risks of Acquiring a Brain Tumor. PMID- 29161140 TI - Medicolegal-Malpractice and Ethical Issues in RadiologyBreast Density Laws. PMID- 29161141 TI - Work in Progress: Subdividing MRI BI-RADS Category 4 Assessment. PMID- 29161142 TI - Reply to "Prevention of Air Embolism During Transthoracic Biopsy of the Lung". PMID- 29161143 TI - Controversies in Colonoscopy Screening. PMID- 29161144 TI - Comment on "Extracolonic Findings at Screening CT Colonography: Prevalence, Benefits, Challenges, and Opportunities". PMID- 29161145 TI - Reply to "Occupational Radiation Exposure in Interventional Radiology and the Risks of Acquiring a Brain Tumor". PMID- 29161146 TI - Guest Editorial: Discovery and Artificial Intelligence. PMID- 29161147 TI - Propofol in Screening Colonoscopy: Point of Strength or Weakness? PMID- 29161148 TI - Prevention of Air Embolism During Transthoracic Biopsy of the Lung. PMID- 29161150 TI - Cognitive impairment in schizophrenia and depression: A comparison of stability and course. AB - Cognitive deficits are clinically relevant features in schizophrenia and depression, yet little comparative data on changes in both disorders is available. This study compares cognitive performance of inpatients with schizophrenia (N = 52) and unipolar major depression (N = 67) during psychiatric treatment, assessing performance twice: after admission to hospital (acute) and prior to discharge (postacute) on average seven weeks later. A group of healthy controls was tested at comparable intervals. Data was analyzed using a multivariate linear model. Patients with schizophrenia and depression showed significantly impaired performance compared to healthy controls. On follow-up both patient groups showed improved performance. Contrary to expectation, patients with schizophrenia showed greater improvement in verbal memory, visual memory, and psychomotor speed than depressive patients. Verbal fluency presented as a possible candidate to differentiate between both disorders. Similar profiles of generalized cognitive deficits were observed in both patient-groups on acute and postacute assessment, which might indicate trait-like deficits with persistent functional implications in both disorders. Findings do not support assumptions of greater cognitive impairment in schizophrenia compared to depression. A distinction of the disorders on the grounds of cognitive functioning seems to be less specific than presumed. PMID- 29161151 TI - An index of decline or recovery following nonimpact and impact mTBI. AB - This study investigated the degree to which litigants/insurance claimants sustaining Nonimpact mild traumatic brain injury (mTBI) in motor vehicle accidents differed from compensation-seeking motor vehicle accident victims that suffered Impact mTBI in terms of neuropsychological decline/recovery, using as a control litigants/insurance claimants that did not experience mTBI in motor vehicle accidents. A clinical index (C-Voc) was employed as the dependent measure for decline/recovery, consisting of T-score algebraic differences between a highly sensitive neurocognitive measure (Category Test) and a relatively insensitive "hold" measure (Wechsler Adult Intelligence Scale Vocabulary subtest). Nonimpact mTBI subjects showed significantly greater neurocognitive decline than Impact mTBI participants and, interestingly, Impact mTBI individuals did not differ significantly from individuals with no diagnosis of mTBI. These findings suggest that Nonimpact subjects may experience significantly greater persistent neurocognitive residua of mTBI than Impact participants. PMID- 29161152 TI - Proliferative Cells Isolated from the Adult Human Peripheral Retina only Transiently Upregulate Key Retinal Markers upon Induced Differentiation. AB - : Purpose/Aim: The adult human retina has limited regenerative potential, and severe injury will result in permanent damage. Lower vertebrates handle retinal injury by activating neural stem cells (NSCs) in the ciliary marginal zone (CMZ). Muller glia-like cells expressing markers of NSCs are also present in the peripheral retina (PR) of the adult human eye, leading to the hypothesis that a CMZ-like zone might exists also in humans. In order to shed further light on this hypothesis we investigated the in vitro differentiation potential of proliferative cells isolated from the adult human PR towards a retinal phenotype. MATERIALS AND METHODS: Proliferative cells were isolated from the peripheral retina of human eyes (n = 6) within 24 to 48 hours post mortem and further expanded for 2 or 3 passages before being differentiated for 1-3 weeks. Gene expression was analyzed by microarray and qRT-PCR analysis, while protein expression was identified by immunocytochemistry. RESULTS: A high density of cells co-staining with markers for progenitor cells and Muller glia was found in situ in the PR. Cells isolated from this region and cultured adherently showed fibrillary processes and were positive for the immature marker Nestin and the glial marker GFAP, while a few co-expressed PAX6. After 7 days of differentiation, there was a transient upregulation of early and mature photoreceptor markers, including NRL, CRX, RHO and RCVRN, as well as the Muller cell and retinal pigmented epithelium (RPE) marker CRALBP, and the early RPE marker MITF. However, the expression of all these markers dropped from Day 14 and onwards. CONCLUSIONS: Upon exposure of proliferating cells from the adult human PR to differentiating conditions in culture, there is a widespread change in morphology and gene expression, including the upregulation of key retinal markers. However, this upregulation is only transient and decreases after 14 days of differentiation. PMID- 29161153 TI - Protective effects of agomelatine on testicular damage caused by bortezomib. AB - Bortezomib is a chemotherapeutic agent used to treat several cancers; however, it exhibits severe side effects in testicular tissue. We investigated the use of agomelatine to prevent testicular tissue damage caused by bortezomib. We used 36 male Sprague-Dawley rats divided randomly into six equal groups: group 1, no treatment control; group 2, agomelatine treatment only; group 3, bortezomib treatment only for 48 h; group 4, bortezomib + agomelatine treatment for 48 h; group 5, bortezomib treatment only for 72 h; and group 6, bortezomib + agomelatine treatment for 72 h. After treatments, the rats were sacrificed and testicular tissue was harvested. Lipid oxidation (LPO) and superoxide dismutase (SOD) levels in the tissues were determined using biochemical methods. Tissue samples also were examined using histopathological and immunohistochemical techniques. The LPO level was increased, while the SOD level was decreased in the bortezomib treated groups. We found that agomelatine treatment normalized LPO and SOD activities in the bortezomib treated groups. In the spermatogonia and Sertoli cells, the staining density of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and caspase 3 were decreased in the bortezomib + agomelatine groups at both 48 and 72 h compared to bortezomib only treated groups. We observed maturation arrest, basal membrane thickening, increase in inflammatory cells and connective tissue, and edema between germ cells in the bortezomib only treated groups. By contrast, normal basal membrane, less edema and more normal maturation were observed in the bortezomib + agomelatine groups at 48 and 72 h. We found that agomelatine reduced the damaging effects of bortezomib. The use of agomelatine to prevent bortezomib induced testicular tissue damage in human patients should be investigated further. PMID- 29161155 TI - The use of virtual communities of practice to improve interprofessional collaboration and education: findings from an integrated review. AB - The recent growth in online technology has led to a rapid increase in the sharing of health related information globally. Health and social care professionals are now using a wide range of virtual communities of practice (VCoPs) for learning, support, continuing professional education, knowledge management and information sharing. In this article, we report the findings from a review of the literature that explored the use of VCoPs by health and social care professionals to determine their potential for interprofessional education and collaboration. We employed integrated review methods to search and identify relevant VCoP articles. We undertook searches of PubMed and Google Scholar from 2000, which after screening, resulted in the inclusion of 19 articles. A thematic analysis generated the following key issues related to the use of VCoPs: 'definitions and approaches', 'technological infrastructure', 'reported benefits', 'participation issues', 'trust and privacy and 'technical ability'. Based on the findings from this review, there is some evidence that VCoPs can offer an informal method of professional and interprofessional development for clinicians, and can decrease social and professional isolation. However, for VCoPs to be successful, issues of privacy, trust, encouragement and technology need to be addressed. PMID- 29161154 TI - Effects of Gloves and Pulling Task on Achievable Downward Pull Forces on a Rung. AB - Objective We examined the impacts of pulling task (breakaway and pull-down tasks at different postures), glove use, and their interaction on achievable downward pull forces from a ladder rung. Background Posture, glove use, and the type of pulling task are known to affect the achievable forces. However, a gap in the literature exists regarding how these factors affect achievable downward pulling forces, which are relevant to recovery from a perturbation during ladder climbing. Methods Forty subjects completed four downward pulling tasks (breakaway force; pull force at maximum height, shoulder height, and a middle height), using three glove conditions with varying coefficient of friction (COF) levels (cotton glove, low COF; bare hand, moderate COF; and latex-coated glove, high COF) with their dominant and nondominant hand. The outcome variable was the maximum force normalized to body weight. Results The highest forces were observed for the highest hand postures (breakaway and maximum height). Increased COF led to higher forces and had a larger effect on breakaway force than the other tasks. The dominant hand was associated with higher forces than the nondominant hand. Male subjects generated greater forces than female subjects, particularly for higher hand positions. Conclusion This study suggests that a higher hand position on the ladder, while avoiding low-friction gloves, may be effective for improving recovery from ladder perturbations. Application This study may guide preferred climbing strategies (particularly those that lead to a higher hand position) for improving recovery from a perturbation during ladder climbing. PMID- 29161156 TI - Sense of Community among Female Residents of a Trauma-Informed Sober Living Home. AB - BACKGROUND: Substance use disorders (SUDs) and domestic and/or sexual violence (DSV) co-occur at high rates. Although some studies have examined sober living homes (SLHs), no research to date has evaluated SLHs specifically designed for women with histories of SUDS and DSV. OBJECTIVE: The purpose of this article is to present data from an exploratory analysis of the association between sense of community (SOC) and mental health symptoms within a unique trauma-informed and gender-responsive SLH (i.e., Support, Education, Empowerment, and Directions [SEEDs]). METHOD: Participants included current or former residents of SEEDs (N = 28) who completed surveys assessing SOC and mental health symptoms. The sample was predominantly White (85.7%), heterosexual (64.3%), low income (71.4% < $20,000 per year), had children (67.9%), and reported a history of incarceration (71.4%). RESULTS: On average women reported high levels of SOC. Higher SOC was related to lower posttraumatic stress and depression symptoms and higher coping self-efficacy and sexual assault resistance self-efficacy, with large effect sizes. CONCLUSIONS: Trauma-informed SLHs may promote positive mental health symptoms for women with histories of DSV and SUDs via SOC. Additional research is needed to more rigorously evaluate these preliminary findings. Further, longitudinal, prospective research is needed to better understand the process by which SOC develops and mechanisms by which SOC promotes (and/or is impacted by) positive mental health symptoms. PMID- 29161157 TI - Event-Specific Cannabis Use and Cannabis Use Motives. AB - BACKGROUND: Specific events such as Mardi Gras (MG) and St. Patrick's Day (SPD) have been identified as high-risk events for cannabis use. Further, some campuses may have traditions that are associated with more event-specific cannabis use. OBJECTIVES: Campus A has specific traditions regarding MG whereas Campus B has specific traditions regarding SPD and these campuses are differentially related to event-specific cannabis use (Buckner, Henslee, & Jeffries, 2015 ). Yet, little work has identified individual difference variables related to high-risk cannabis use events. METHODS: Current cannabis using undergraduates (N = 154) at two campuses completed an online survey of event-specific cannabis use motives, cannabis use, and cannabis-related problems. RESULTS: Campus A endorsed more MG specific social and enhancement motives than Campus B. Campus A reported more socially, enhancement, coping, conformity, and expansion motivated cannabis use on MG than on SPD, whereas Campus B reported more socially and enhancement motivated cannabis use on SPD than on MG. Campus A was indirectly related to more MG-specific cannabis use through MG-specific social and enhancement motives. Conclusions/Importance: Event-specific cannabis motives are differentially related to specific high-risk cannabis use events and may be important therapeutic targets. PMID- 29161159 TI - Unilateral Coats'-like disease and an intragenic deletion in the TERC gene: A case report. AB - We report a case of a 25-year-old woman with unilateral Coats'-like disease. Her brother was previously diagnosed with an autosomal dominant form of dyskeratosis congenita. Genetic testing was performed by screening the TERC gene for mutations and identified heterozygosity for the n.68_124del mutation. Our case demonstrates that the exudative retinopathy seen in Coats'-like disease can be caused by mutations in a telomere-capping gene TERC as a part of the dyskeratosis congenita spectrum without other systemic involvement. This is an interesting case that illustrates that retinal Coats'-like involvement can be the first manifestation of dyskeratosis congenita. PMID- 29161158 TI - Drug Use and Incarceration among Rural Appalachian Women: Findings From a Jail Sample. AB - BACKGROUND/OBJECTIVE: The purpose of this paper is to examine drug use and incarceration history among rural Appalachian women. METHODS: This study involved random selection, screening, and interviews with rural women from local jails in Appalachia. RESULTS: Of the women randomly selected and screened, 97% met criteria for substance use intervention. Significant factors associated with incarceration history included age, education, custody status, and mental health. A significant interaction was observed between male sex partners and drug use on incarceration history. CONCLUSIONS: Study findings suggest that the drug/crime relationship among rural Appalachian women is associated with their high-risk home environment, partner relationships, and mental health. Specifically, in addition to drug use, factors such as family and child relationships, anxiety, victimization, and relationships with partners should also be considered in the trajectory of criminal careers among rural Appalachian women. PMID- 29161160 TI - Upholding Ethical Decision Making in Children With Life Limiting Illnesses. AB - Emeritus Professor Edward Alan Glasper from the University of Southampton discusses the complexities of care delivery to children in hospital who have life limiting medical conditions. PMID- 29161161 TI - The Association between Heavy Episodic Drinking and Gender Orientation among U.S. College Students: The Significance of Masculinity. AB - BACKGROUND: Heavy episodic drinking (HED) remains a public health concern among college students. Sex differences are routinely reported in the literature although some evidence of convergence in drinking patterns has been observed. The association between sex and gender-orientation in HED remains unclear because sex and gender are often conflated. OBJECTIVE: We examine the intersection of sex, gender-orientation and HED to determine if gender-orientation alone and/or in conjunction with sex play a role in HED among college students. METHODS: Data were collected using a web-based self-administered survey made available to students enrolled in courses at a mid-sized Midwestern public university during the Fall of 2013 and the Spring of 2014 (N = 793). Multiple logistic regression was used to determine the relationship between HED, sex, and gender orientation (measured using the short-form Bem Sex Role Inventory). RESULTS: Our findings indicate that, regardless of sex, a masculine gender-orientation was positively associated with HED. Those who were found to have a feminine gender-orientation appeared to be at decreased risk for HED. CONCLUSIONS: Our findings indicate that sex and gender-orientation should be taken into account in prevention and intervention protocols at colleges and universities. Future work should examine the role of gender orientation among LGBTQ and ethno-racial minority populations. PMID- 29161162 TI - Patient-Perceived and Laboratory-Measured Halos Associated with Diffractive Bifocal and Trifocal Intraocular Lenses. AB - PURPOSE: To examine and assess the halos generated in distance vision by multifocal intraocular lenses (IOLs) using both in vitro objective and in vivo subjective methods. SETTING: The objective method was carried out in the optics laboratory of the Applied Optics and Image Processing Group (Universitat Politecnica de Catalunya -Barcelona). The psychophysical and subjective methods were carried out in the Instituto de Oftalmologia Avanzada Madrid Innova Ocular. DESIGN: Optical bench results and prospective evaluation of consecutive cases. METHODS: The IOLs examined were TECNIS(r)one-piece bifocals with addition powers of +4.00 D, +3.25 D, and +2.75 D and the trifocals AT-LISA-tri(r) and FineVision(r). In the objective assessment, we examined halos around the far focus images of a pinhole formed by each IOL in an optical bench. For the in vivo study, we recruited 100 patients who had been bilaterally implanted one month earlier with the IOLs under study. Participants were subjected to psychophysical halometry (Halo v1.0) on the eye with better, distance-corrected, visual acuity and were required to subjectively grade halos by responding to the question "How much do halos bother you?" RESULTS: The objective method revealed that the halo size increased with addition power and that the two trifocals gave rise to a double-halo pattern. Scores in the halometry also indicated a direct relationship between the halo size and addition power. The subjective results indicated fewer complaints about halos associated with the trifocal than bifocal IOLs. CONCLUSIONS: The addition power of the tested IOLs affected both laboratory measured and patient-perceived halos. Trifocal lenses generated fewer complaints about halos. Precise: Multifocal intraocular lenses (MIOLs) give rise to halos observed by patients under conditions of dim lighting. This study compares laboratory characterized halos generated by five MIOLs with patient-perceived halos. PMID- 29161163 TI - Classification of Chronic Obstructive Pulmonary Disease (COPD) according to the new Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017: Comparison with GOLD 2011. AB - Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality worldwide. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) project has been working to improve awareness, prevention and management of this disease. The aim of this study is to evaluate how COPD patients are reclassified by the 2017 GOLD system (versus GOLD 2011), to calculate the level of agreement between these two classifications in allocation to categories and to compare the performance of each classification to predict future exacerbations. Two-hundred COPD patients (>40 years, post bronchodilator forced expiratory volume in one second/forced vital capacity<0.7) followed in pulmonology consultation were recruited into this prospective multicentric study. Approximately half of the patients classified as GOLD D [2011] changed to GOLD B [2017]. The extent of agreement between GOLD 2011 and GOLD 2017 was moderate (Cohen's Kappa = 0.511; p < 0.001) and the ability to predict exacerbations was similar (69.7% and 67.6%, respectively). GOLD B [2017] exacerbated 17% more than GOLD B [2011] and had a lower percent predicted post bronchodilator forced expiratory volume in one second (FEV1). GOLD B [2017] turned to be the predominant category, more heterogeneous and with a higher risk of exacerbation versus GOLD B [2011]. Physicians should be cautious in assessing the GOLD B [2017] patients. The assessment of patients should always be personalized. More studies are needed to evaluate the impact of the 2017 reclassification in predicting outcomes such as future exacerbations and mortality. PMID- 29161164 TI - Health science students' attitudes towards healthcare teams: A comparison between two universities. AB - There have been few studies comparing the attitudes towards healthcare teams between different universities. This study analysed the differences in attitudes towards healthcare teams between health science students at Gunma University, Japan, which implements a comprehensive interprofessional education (IPE) programme, and Kanazawa University, a similar national university. Study populations were first- and third-year students at the Gunma University School of Health Sciences and the Kanazawa University School of Health Sciences. The present study was performed just after the IPE and multi-professional education subjects at Gunma University in the first term of the 2012 academic year. The first-year students were different cohort from the third-year students. The modified Attitudes Toward Health Care Teams Scale (ATHCTS) was used to measure attitudes towards healthcare teams. The overall mean score on the modified ATHCTS of students at Gunma University was significantly higher than that of those at Kanazawa University. In both first- and third-year students, the regression factor score of "patient-centred care" was significantly higher at Gunma University than at Kanazawa University. Based on the present study, it can be stated that IPE may foster the value of collaborative practice (CP) among health science students. PMID- 29161165 TI - Alcohol Misuse in Reserve Soldiers and their Partners: Cross-Spouse Effects of Deployment and Combat Exposure. AB - BACKGROUND: Military deployment and combat are associated with worse outcomes, including alcohol misuse. Less is known about how these experiences affect soldiers' spouses. OBJECTIVE: The study objective was to explore relationships between deployment, combat exposure, and alcohol misuse; especially cross-spouse effects (effect of one partner's experiences/behavior on the other partner), which has been under-examined in military samples. METHODS: U.S. Army Reserve/National Guard soldiers and their partners completed a questionnaire covering physical and mental health, military service and substance use. Negative binomial regression models examined number of deployments and combat exposure individually for alcohol misuse and frequent heavy drinking (FHD). In additional models, we examined combat exposure's role on alcohol outcomes, controlling for the soldiers' number of deployments, PTSD symptoms, age, and in cross-spouse models, alcohol use and FHD. We considered individuals' deployment experiences related to their alcohol outcomes and to their spouses' alcohol outcomes. RESULTS: The study sample included male soldiers with current/lifetime military service (n = 248) and their female partners. Combat exposure was related to FHD (RR: 1.01, p < .05, 95% CI: 1.01, 1.01) among male soldiers while controlling for PTSD symptoms, number of deployments, and age. Female partners of male soldiers were more likely to engage in FHD (RR: 1.01, p < .05, 95% CI: 1.01, 1.01) if their spouse experienced combat. CONCLUSIONS: Our results demonstrate that male soldiers and their spouses are at increased risk of FHD if the soldier experienced combat. This points to the need for better screening, particularly of spouses of soldiers, whose alcohol misuse may be overlooked. PMID- 29161167 TI - Depression and Marijuana Use among a Sample of Urban Females: Is Stage of Development Important? AB - BACKGROUND: Increasing rates of marijuana use and high rates of depression among females are major public health concerns and ambiguous study results suggest a complex association between the two. Inconsistent findings may be due to differences in sample characteristics (e.g., females vs. males) and result from differences in the relationship over time (i.e., across developmental stages). OBJECTIVES: Presently, the extent to which the relationship between depression and marijuana use differed for females in emerging adulthood, compared to young adult females, was examined. METHODS: Two hundred forty females (mean age = 23.9 +/- 3.4 years) from low-income urban neighborhoods completed a semi-structured HIV-risk interview, Beck's Depression Inventory II, and provided a urine sample that was tested for the presence of psychoactive drugs. RESULTS: Approximately 35% tested positive for marijuana and 21% were experiencing depression. Results from unadjusted logistic regression analyses indicated a relationship between depression and marijuana use (OR = 2.1; 95% CI = 1.08-3.93). African Americans had higher odds of testing positive for marijuana, compared to Whites (OR = 4.6; 95% CI = 2.52-8.68). In the full model, the relationship between depression and marijuana use did not differ by developmental stage. CONCLUSIONS: Interventions aimed at reducing depression may prove beneficial for decreasing marijuana use among females between 18 and 29 years of age residing in disadvantaged communities. However, more research is needed to identify risk factors for marijuana use and to explicate the relationship between marijuana use and depression. Special consideration should be given to African American females. PMID- 29161166 TI - Helping Smokers with Severe Mental Illness Who Do Not Want to Quit. AB - BACKGROUND: People with a severe and persistent mental illness are far more likely to smoke than others. While a large portion would like to quit, they are less likely to make quit attempts and succeed. OBJECTIVE: This study used an Randomized Controlled Trial (RCT) to test an intervention designed to increase engagement in cessation treatment, quit attempts, and quitting in smokers who did not want to quit in the next 30 days. It also compared these smokers with those who were motivated to quit in the next 30 days. METHODS: Participants (N = 222), were smokers with significant mental illness receiving intensive outpatient care from Wisconsin Community Support Programs who were not interested in quitting in the next 30 days. They were randomly assigned to either an intervention group or an attention control group. The intervention, administered during four weekly sessions, included a motivational element, components designed to prepare the smoker for a quit attempt, and pre-quit nicotine patch. Additionally, 48 smokers motivated to quit in the next 30 days served as a comparison group. RESULTS: Compared to control participants, smokers receiving the intervention were more likely to be abstinent at the three month follow-up (biochemically verified, intent to treat, 8.5% vs. 1.0%, respectively, p = .01). They were also more likely to accept four more quitting preparation sessions (intent to treat, 50.8% vs 29.2%, respectively, p < .001) but were not more likely to call a telephone tobacco quit line. Conclusion/Importance: Brief motivational interventions increased engagement in cessation treatment and abstinence among smokers with signification mental illness. PMID- 29161169 TI - Investigation of apoptosis in cultured cells infected with equine herpesvirus 1. AB - Many viruses alter different stages of apoptosis of infected cells as a strategy for successful infection. Few studies have addressed mechanisms of equine herpesvirus 1 (EHV-1) strain-induced cell death. We investigated the effect of an abortigenic strain (AR8 strain) on heterologous Madin-Darby bovine kidney cells and homologous equine dermis (ED) cells cell lines. We compared morphologic and biochemical features of early and late apoptosis at different postinfection times. We investigated translocation of phosphatidylserine to the cell surface, nuclear fragmentation and changes in the cytoskeleton using flow cytometry and annexin V/propidium iodide staining, DNA laddering, terminal deoxynucleotidyl transferase UTP nick-end labeling assay and immunofluorescence staining of cytokeratin 18 cleavage. AR8 EVH-1 strain interfered with apoptosis in both cell lines, particularly during the middle stage of the replication cycle; this was more evident in ED cells. Although this antiapoptotic effect has been reported for other alpha herpesviruses, our findings may help elucidate how EHV-1 improves its infectivity during its cycle. PMID- 29161170 TI - Examining the implementation of collaborative competencies in a critical care setting: Key challenges for enacting competency-based education. AB - Interprofessional collaboration is recognised as an important factor in improving patient care in intensive care units (ICUs). Competency frameworks, and more specifically interprofessional competency frameworks, are a key strategy being used to support the development of attitudes, knowledge, skills, and behaviours needed for an interprofessional approach to care. However, evidence for the application of competencies is limited. This study aimed to extend our empirically based understanding of the significance of interprofessional competencies to actual clinical practice in an ICU. An ethnographic approach was employed to obtain an in-depth insight into healthcare providers' perspectives, behaviours, and interactions of interprofessional collaboration in a medical surgical ICU in a community teaching hospital in Canada. Approximately 160 hours of observations were undertaken and 24 semi-structured interviews with healthcare workers were conducted over a period of 6 months. Data were analysed using a directed content approach where two national competency frameworks were used to help generate an understanding of the practice of interprofessional collaboration. Healthcare professionals demonstrated numerous instances of interprofessional communication, role understandings, and teamwork in the ICU setting, which supported a number of key collaborative competencies. However, organisational factors such as pressures for discharge and patient flow, staffing, and lack of prioritisation for interprofessional learning undermined competencies designed to improve collaboration and teamwork. The findings demonstrate that interprofessional competencies can play an important role in promoting knowledge, attitudes, skills, and behaviours needed. However, competencies that promote interprofessional collaboration are dependent on a range of contextual factors that enable (or impede) individuals to actually enact these competencies. PMID- 29161171 TI - At the Expense of a Life: Race, Class, and the Meaning of Buprenorphine in Pharmaceuticalized "Care". AB - BACKGROUND/OBJECTIVE: Office-based buprenorphine maintenance has been legalized and promoted as a treatment approach that not only expands access to care, but also reduces the stigma of addiction treatment by placing it in a mainstream clinical setting. At the same time, there are differences in buprenorphine treatment utilization by race, ethnicity, and socioeconomic status. METHODS: This article draws on qualitative data from interviews with 77 diverse patients receiving buprenorphine in a primary care clinic and two outpatient substance dependence clinics to examine differences in patients' experiences of stigma in relation their need for psychosocial supports and services. RESULTS: Management of stigma and perception of social needs varied significantly by ethnicity, race and SES, with white educated patients best able to capitalize on the medical focus and confidentiality of office-based buprenorphine, given that they have other sources of support outside of the clinic, and Black or Latino/a low income patients experiencing office-based buprenorphine treatment as isolating. CONCLUSION: Drawing on Agamben's theory of "bare life," and on the theory of intersectionality, the article argues that without attention to the multiple oppressions and survival needs of addiction patients who are further stigmatized by race and class, buprenorphine treatment can become a form of clinical abandonment. PMID- 29161172 TI - Development of an Attachable Endoscopic Nerve Stimulator for Intraoperative Neuromonitoring during Endoscopic or Robotic Thyroidectomy. AB - We developed a simple attachable endoscopic nerve stimulator that can be connected to monopolar cauterization surgical instruments. This study on porcine models aimed to investigate the feasibility and efficacy of an attachable endoscopic nerve stimulator for intraoperative neuromonitoring (IONM) before application in humans. We evaluated the electromyography (EMG) amplitudes of 8 recurrent laryngeal nerves in 4 pigs with a conventional nerve probe and the attachable endoscopic nerve stimulator. The attachable endoscopic nerve stimulator was feasible and safe in all cases. There was no significant difference in the EMG amplitude of the recurrent laryngeal nerve among instruments ( P = .429). The application of stimulating dissection with an attachable endoscopic nerve stimulator during endoscopic or robotic thyroidectomy with IONM is simple, convenient, and effective. It provides surgeons with real time feedback of the EMG response during intermittent IONM. We believe that this novel device could be an essential guide and functional navigator for most surgeons, especially for less experienced ones. PMID- 29161173 TI - A Relational Ethics Framework for Advancing Practice with Children with Complex Health Care Needs and Their Parents. AB - Children with complex health care needs are an emerging population that commonly requires long-term supportive services. A growing body of evidence has highlighted that these children and their families experience significant challenges. Many of these challenges involve ethical concerns that have been under-recognized. In this article, we (a) outline ethical concerns that arise in clinical practice with children with complex health care needs and their families (e.g.: exclusion of children's voices in discussions and decisions that affect them; difficulties in defining their best interests; clashes across the array of social roles that parents manage; limited recognition of the ethical significance of parents' and other family members' interests) and (b) propose a relational ethics framework for addressing these concerns. Our framework draws on hermeneutical interpretation and moral experience as foundational orientations, recognizing children with complex health care needs as relationally embedded agents, who while dependent and entitled to protection, are simultaneously agential. Children's and parents' interests are relationally intertwined and interdependent. Families are recognized as significant social microcosms for the cultivation and transmission of intergenerational cultural heritage, narratives, and outlooks. We describe strategies for (a) conducting a relational ethics inquiry and (b) reconciliation of identified ethical concerns through a process of rapprochement. A relational ethics framework can promote clinical practices that are ethically attuned to the complexity of this population's needs. PMID- 29161175 TI - Performance discrepancies on the Boston Naming Test in African-American and non Hispanic White American young adults. AB - The Boston Naming Test (BNT) is one of the most commonly used naming measures in neuropsychology. Although research in the older adult population has shown that African-American (AA) adults perform more poorly on the BNT than non-Hispanic White American (WA) adults, these findings have yet to be replicated in younger adults. The BNT and measures of word reading (WJ-Letter Word ID) and vocabulary (Wechsler Abbreviated Scale of Intelligence Vocabulary) were administered to 50 WA and 33 AA young adults. Performance was age-normed based on published norms and transformed into z-scores. Despite being matched on age, gender, SES, and level of education, the AA group performed more poorly on the BNT (z = - 1.01(1.09)) than the WA group (z = - .28(.92)), t(104) = 3.44, p < .01, d = 0.73. AAs (18%) were more likely to perform in the impaired range than WAs (4%) when impairment cutoff was z-score<= - 2. Healthy AA young adults are more likely to perform poorly on the BNT despite vocabulary and word reading being well within normal limits. Average BNT performance in both groups were at least one z-score lower than average vocabulary z-scores. Clinicians should interpret poor scores on the BNT with caution, and within the context of individual vocabulary or word reading performance. PMID- 29161174 TI - The Telescoping Phenomenon: Origins in Gender Bias and Implications for Contemporary Scientific Inquiry. AB - BACKGROUND: In an article published in International Journal of the Addictions in 1989, Nick Piazza and his coauthors described "telescoping," an accelerated progression through "landmark symptoms" of alcoholism, among a sample of recovering women. OBJECTIVES: The aim of this critical analysis is to apply a feminist philosophy of science to examine the origins of the framework of telescoping research and its implications for contemporary scientific inquiry. METHODS: A feminist philosophy of science framework is outlined and applied to key source publications of telescoping literature drawn from international and United States-based peer-reviewed journals published beginning in 1952. RESULTS: A feminist philosophy of science framework identifies gender bias in telescoping research in three ways. First, gender bias was present in the early conventions that laid the groundwork for telescoping research. Second, a "masculine" framework was present in the methodology guiding telescoping research. Third, gender bias was present in the interpretation of results as evidenced by biased comparative language. CONCLUSIONS: Telescoping research contributed to early evidence of critical sex and gender differences helping to usher in women's substance abuse research more broadly. However, it also utilized a "masculine" framework that perpetuated gender bias and limited generative, novel research that can arise from women-focused research and practice. A feminist philosophy of science identifies gender bias in telescoping research and provides an alternative, more productive approach for substance abuse researchers and clinicians. PMID- 29161176 TI - Translation and cultural adaptation of the Japanese version of the interprofessional facilitation scale. AB - Effective interaction in interprofessional collaboration requires skills in interprofessional facilitation. The need for interprofessional learning and practice in Japan is highlighted by Japan's status as one of the most rapidly aging societies because good care for elderly people with complex needs requires effective collaboration between different professional groups. The development of interprofessional facilitation skills (including management of the additional complexities) among learners or professionals enhances interprofessional learning and consensus building and empowers them to make appropriate commitments when faced with difficult challenges. The 18-item interprofessional facilitation scale (IPFS) can be used to enhance interprofessional facilitation skills. Here, we aimed to develop a Japanese adapted version of the IPFS and to validate it for use with Japanese healthcare professionals. Consistent with guidelines for cross cultural adaptation, three translators translated the original IPFS from English into Japanese, and an expert and all authors confirmed its face and content validity. The translated items were amended during backtranslation and expert reviews. Exploratory factor analysis was performed with 167 healthcare professionals to explore the underlying structure of the items. This analysis revealed two factors with good internal consistency (Cronbach's alpha > 0.8), which were labelled as: (1) encouraging interprofessional interaction and (2) respect for each professional. The original factor 'Encouraging interprofessional interaction' was divided into two factors in the study. One reason for this division might be related to the behaviour of Japanese health professionals, that is, most Japanese might understand that 'facilitation' encourages relationships as contextual belonging that are distinct from relationships based on respect for others. This mindset is likely based on the notion of 'relationalism', which is fundamental in Japanese culture. Further investigation of this Japanese version of the IPFS will strengthen factor construction and improve scrutiny of the relationships between factors. PMID- 29161177 TI - Interactions Among Sexual Activity, Menstrual Cycle Phase, and Immune Function in Healthy Women. AB - Past research has found menstrual-cycle-related changes in functional immune response; we examined if sexual activity also changed markers of immune defense. We followed 32 naturally cycling women (15 sexually active with a partner >= 1 time/week, 17 sexually abstinent for the last four months) over one menstrual cycle. Participants provided serum and saliva samples at menses and ovulation, and additional saliva samples at midfollicular and midluteal phases. At each phase, participants also self-reported symptoms associated with colds, flu, pain, menstrual discomfort, and premenstrual syndrome. We tested saliva and serum for ability to kill Escherichia coli or Candida albicans, and serum for complement protein activity. For serum-mediated pathogen killing, among sexually active women only, there was a significant midcycle decrease in killing of E. coli. For saliva-mediated pathogen killing, among abstinent women only, there was a significant midcycle decrease in killing of E. coli, and midcycle increase in killing of C. albicans. Sexually active women had significantly lower complement activity than abstinent women overall. Finally, both groups reported lower physical symptoms at midcycle and higher symptoms at menses. There may be important differences in immune function between healthy women who are sexually active versus abstinent. Further replication is warranted. PMID- 29161178 TI - Association Between Gross-Motor and Executive Function Depends on Age and Motor Task Complexity. AB - The objective was to examine associations between motor and executive function across the adult lifespan and to investigate the role of motor complexity in these associations. Young, middle-aged and older adults (n = 82; 19-83y) performed two gross-motor tasks with different levels of complexity and a Stroop like computer task. Performance was decreased in older adults. The association between motor and cognitive performance was significant for older adults in the complex motor task (p = 0.03, rs = -0.41), whereas no significant associations were found for young or middle-aged groups, suggesting that the link between gross-motor and executive function emerges with age and depends on motor complexity. PMID- 29161179 TI - Synergistic Induction of Apoptosis by Quercetin and Curcumin in Chronic Myeloid Leukemia (K562) Cells. AB - Chronic myeloid leukemia is a major hematopoietic malignancy characterized by expansion of myeloid cells. In this study, we have investigated whether quercetin, curcumin and their combination induce apoptosis and inhibit growth of K562 cells. We have observed that quercetin and curcumin combination induced apoptosis accompanied by increased ROS and decreased GSH levels as well as loss of mitochondrial membrane potential. Our mRNA and protein expression results suggested that cytochrome c was released from mitochondria causing PARP and caspase-9 cleavages, the hallmarks of mitochondrial apoptotic pathway. We believe that triggering of apoptosis is mostly via mitochondrial pathway and ROS generation may induce impairment of mitochondrial membrane potential. The use of quercetin and curcumin combination potentiates individual apoptotic effects of the polyphenols and reduces their effective dose thereby preventing potential toxic effects on normal cells. Additional preclinical studies and clinical trials are certainly required to further validate their usefulness as potent anticancer agents. PMID- 29161180 TI - Comparison of verdeluz orange G and modified Gallego stains. AB - Tumors of the oral cavity include combinations of hard and soft tissues that may be difficult to identify using routine hematoxylin and eosin (H & E) staining. Although combination stains can demonstrate hard and soft tissues, trichrome stains, such as VanGieson and Masson, cannot differentiate dental hard tissues, such as dentin, cementum and osteoid. Modified Gallegos (MGS) and verdeluz orange G-acid fuchsin (VOF) stains can differentiate components of teeth. We used 10 tissue sections of decalcified bone and 10 pathologic tissue sections that contained different calcified tissues including peripheral ossifying fibroma, odontoma, central ossifying fibroma and cemento-ossifying fibroma. Sections were stained with H & E, VOF or MGS. H and E stained both hard tissues pink. VOF stained bone purple-red, cementum red and collagen blue. MGS stained bone green blue, cementum red and collagen blue. VOF staining intensity and differentiation was better than MGS staining. VOF staining demonstrated hard tissue components distinctly and exhibited good contrast with the surrounding connective tissue. VOF also is a simple, single step, rapid staining procedure. PMID- 29161182 TI - Alcohol Biomarkers Associated with Obstructive Sleep Apnea. AB - The views expressed in this presentation are those of the author and do not reflect the official policy of the Department of the Army/Navy/Air Force or the Department of Defense The identification of specific products or scientific instrumentation does not constitute an endorsement or implied endorsement on the part of the authors, DoD, or any component agency. While we generally excise references to products, companies, manufacturers, organizations, etc. in government produced works, the abstracts produced and other similarly situated researchers presents a special circumstance when such product inclusions become an integral part of the scientific endeavor. PMID- 29161181 TI - Public Perception of Telemedicine and Surgical Telementoring in the Pediatric Population: Results of a Parental Survey. AB - INTRODUCTION: Telemedicine and surgical telementoring strive to provide equal access to specialized healthcare, regardless of patient location. It also aims to provide providers in remote locations real-time, second opinions from more experienced physicians who are otherwise not readily available. The goal of this study is to gauge the public perception of this technology in the pediatric population. METHODS: Patient families in our pediatric surgery and gastroenterology clinics were asked to complete a seven-question survey after being shown a 1-minute video describing telemedicine and surgical telementoring. RESULTS: A total of 129 people were surveyed. Among respondents, 89% were amenable to telemedicine for routine physician visit, 70% said "yes" for a postoperative visit, and 67% agreed to telemedicine and telementoring as a way to be evaluated by a specialist. Regarding surgical telementoring, 49% would consider it for their child, 58% would consider it for themselves, and 10% said "yes" for themselves, but "no" for their child. In addition, 24% and 19% were unsure about surgical telementoring for their child and themselves, respectively. Those with history of surgery without complications were more likely to say "yes" than "no" to telemedicine for a postoperative visit and surgical telementoring. Although a higher proportion of those with an annual income of >$100K said "no" to surgical telementoring for their child and themselves, this was not statistically significant (P = .23 and .25, respectively). Desire to see a physician in person was cited by 63% as a reason against telemedicine, although 35% reported concern about a physician's competence as a reason against surgical telementoring. CONCLUSION: Overall, surgical telementoring was only supported by about half of the respondents. We predict that with increased education about surgical telementoring, this technology will have increased public support in the pediatric population. PMID- 29161183 TI - Epitope Mapping of Monoclonal Antibody PMab-38 Against Dog Podoplanin. AB - Podoplanin (PDPN), a type I transmembrane sialoglycoprotein, is extensively expressed by normal lymphatic endothelial cells, renal podocytes, and pulmonary type I alveolar cells. Nevertheless, increased expression of PDPN in malignant tumors not only associates with poor prognosis but also facilitates hematogenous metastasis through interaction with C-type lectin-like receptor-2 presented on platelets, followed by PDPN-mediated platelet activation. We previously reported a novel PMab-38 antibody, an anti-dog PDPN (dPDPN) monoclonal antibody, which specifically recognizes PDPN in squamous cell carcinomas melanomas and cancer associated fibroblasts in canine cancer tissues. However, the specific binding with the epitope of PMab-38 remains undefined. In this study, flow cytometry was utilized to investigate the epitope of PMab-38, which was determined using a series of deletion or point mutants of dPDPN. The results revealed that the critical epitope of PMab-38 is Tyr67 and Glu68 of dPDPN. PMID- 29161184 TI - Comparison of mental health treatment status and use of antidepressants in men and women with eating disorders. AB - Mental health treatment status and antidepressant use were investigated among men and women with an eating disorder (ED) who were interviewed in a general population survey of 3005 adults (aged >=15 years). Compared to women, men with an ED were significantly less likely to receive treatment for a mental health problem or to be currently using an antidepressant. On multivariate analyses, female gender, lower mental health-related quality of life, and lower weight/shape overvaluation were significant predictors of receiving treatment and antidepressant use. Treatment was less likely in men and in people with higher ED cognitions. PMID- 29161185 TI - Medications for Sleep Schedule Adjustments in Athletes. AB - CONTEXT: Sleep schedule adjustments are common requirements of modern-day athletes. Many nonpharmacologic and pharmacologic strategies exist to facilitate circadian rhythm shifts to maximize alertness and performance during competition. This review summarizes the evidence for commonly used pharmacologic agents and presents recommendations for the sports medicine provider. EVIDENCE ACQUISITION: MEDLINE searches were performed using the following keywords: sleep aids, circadian rhythm adjustment, athletes and sleep, caffeine and sports, melatonin and athletes, and sleep aids and sports. Pertinent articles were extracted and discussed. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 2. RESULTS: There are very few available studies investigating pharmacologic sleep aids in athletes. Data from studies involving shift workers and airline personnel are more abundant and were used to formulate recommendations and conclusions. CONCLUSION: Melatonin, caffeine, and nonbenzodiazepine sleep aids have a role in facilitating sleep schedule changes in athletes and maximizing sports performance through sleep enhancement. PMID- 29161189 TI - Outlying Observation Diagnostics in Growth Curve Modeling. AB - Growth curve models are widely used for investigating growth and change phenomena. Many studies in social and behavioral sciences have demonstrated that data without any outlying observation are rather an exception, especially for data collected longitudinally. Ignoring the existence of outlying observations may lead to inaccurate or even incorrect statistical inferences. Therefore, it is crucial to identify outlying observations in growth curve modeling. This study comparatively evaluates six methods in outlying observation diagnostics through a Monte Carlo simulation study on a linear growth curve model, by varying factors of sample size, number of measurement occasions, as well as proportion, geometry, and type of outlying observations. It is suggested that the greatest chance of success in detecting outlying observations comes from use of multiple methods, comparing their results and making a decision based on research purposes. A real data analysis example is also provided to illustrate the application of the six outlying observation diagnostic methods. PMID- 29161187 TI - Network Mapping with GIMME. AB - Network science is booming! While the insights and images afforded by network mapping techniques are compelling, implementing the techniques is often daunting to researchers. Thus, the aim of this tutorial is to facilitate implementation in the context of GIMME, or group iterative multiple model estimation. GIMME is an automated network analysis approach for intensive longitudinal data. It creates person-specific networks that explain how variables are related in a system. The relations can signify current or future prediction that is common across people or applicable only to an individual. The tutorial begins with conceptual and mathematical descriptions of GIMME. It proceeds with a practical discussion of analysis steps, including data acquisition, preprocessing, program operation, a posteriori testing of model assumptions, and interpretation of results; throughout, a small empirical data set is analyzed to showcase the GIMME analysis pipeline. The tutorial closes with a brief overview of extensions to GIMME that may interest researchers whose questions and data sets have certain features. By the end of the tutorial, researchers will be equipped to begin analyzing the temporal dynamics of their heterogeneous time series data with GIMME. PMID- 29161190 TI - Using Video Stimuli to Examine Judgments of Nonoffending and Offending Pedophiles: A Brief Communication. AB - In this experimental study, 89 participants were allocated to an offending pedophile, nonoffending pedophile, or control video condition. They then watched two short help-seeking video clips of an older male and a younger male (counterbalanced). Judgments about each male were assessed, as were general attitudes toward pedophiles and sexual offenders. Offending pedophiles were judged as more deserving of punishment than the nonoffending pedophiles and controls. Age of the male was found to have an effect on judgments of dangerousness. Existing attitudes toward pedophiles and sexual offenders did not statistically differ. Limitations and future research ideas are discussed. PMID- 29161191 TI - Progress on maternal health care in Vietnam: Findings from Vietnam Multiple Indicator Cluster Survey 2000, 2006, 2011, and 2014. AB - This paper aims to describe a trend in coverage of maternal care services, and provides a detailed analysis of socio-economic correlations to the existing inequities. The paper uses data from the Vietnam Multiple Indicator Cluster Survey 2000, 2006, 2011, and 2014. In the MICS, there were 9,117 women in 2000, 9,473 women in 2006, 11,614 women in 2011, and 9,827 women in 2014 participated in. We found the coverage of antenatal care increase from 68.6% in 2000 to 95.9% in 2014. Similarly, the percentages of women who gave birth with the assistance of skilled staff increased during the studied period ( from 69.9% in 2000, 87.7% to 94.5% in 2014). However, improvements in antenatal care and skilled birth attendance in Vietnam have been uneven across different segments of the population. In all the four surveys, the proportions of women who received ANC by a skilled staff and percentages of women who gave birth with the assistance of a skilled health personnel were much higher among those with higher education, belonged to Kinh majority tribe, had better economic status, and lived in an urban area. The degrees of inequity in both antenatal and delivery care in Vietnam are likely to increase over time. PMID- 29161192 TI - Patient Preferences in Subglottic Stenosis Treatment: A Discrete Choice Experiment. AB - Objectives Subglottic stenosis can be addressed with several different surgical techniques, but patient preferences for these treatment modalities are poorly understood. Economic methods are increasingly being used to understand how patients make decisions. The objective of this pilot study was to assess preferences in subglottic stenosis treatment using patient-centric stated preference techniques. Study Design Discrete choice experiment (DCE). Setting Academic research facility. Subjects and Methods A computer-based DCE was administered in a monitored setting to volunteers from the general population. Signs and symptoms of subglottic stenosis were described, and participants were asked to imagine they had subglottic stenosis. Hypothetical treatments were offered, with 5 systematically varied attributes: need for external incision, length of hospital stay, postoperative voice quality, likelihood of repeat procedures, and risk of complication. A conditional logistic model was used to assess the relative attribute importance. Results In total, 162 participants were included. Attributes with the greatest impact on decision making included potential need for repeat procedures (importance 30.2%; P < .001), amount of operative risk (importance 28.1%; P < .001), and postoperative voice quality (importance 27.7%; P < .001), whereas presence of incision (importance 5.0%; P = .001) was less important, and hospital stay was not (importance 9.0%; P = .089). Based on aggregate responses for these attributes, the model demonstrated that most participants (80.4%) would prefer endoscopic surgery for subglottic stenosis as opposed to open tracheal resection (19.6%). Conclusion In this pilot population, most participants preferred voice-sparing, low-risk procedures as treatment for subglottic stenosis, consistent with an endoscopic approach, even if multiple procedures were required. PMID- 29161193 TI - Infectious Disease and Imperfections of Self-Image. AB - Infectious disease is an ever-present threat in daily life. Recent literature indicates that people manage this threat with a suite of antipathogenic psychological and behavioral defense mechanisms, which motivate the avoidance of people and objects bearing cues to pathogen risk. Here, we demonstrate that self image is also impacted by these mechanisms. In seven studies, pathogen cues led individuals chronically averse to germs to express greater concern about their own physical appearance. Correspondingly, these people exhibited behavioral intentions and decisions intended to conceal or improve their appearance, such as purchasing facial products, taking pharmaceuticals, and undergoing cosmetic surgery. This work opens a new area of investigation for infectious-disease psychology research and highlights the central role played by physical appearance in pathogen-related cognition. PMID- 29161194 TI - Intraoperative Ultrasound in Oral Tongue Cancer Resection: Feasibility Study and Early Outcomes. AB - The current standard of care in oral tongue cancer surgery is complete resection with a target of 5-mm microscopic clearance at all margins on final pathologic review. While current methods of resection are often successful at determining the mucosal margins of the lesion, they may be limited when attempting to achieve an adequate deep margin. A number of previous studies suggested that ultrasound is superior to manual palpation and other imaging modalities (computed tomography, magnetic resonance imaging) at demarcating the margins of tongue lesions. Recent clinical reports of the intraoperative use of this modality have used an invasive method to mark the proposed deep resection margin. In this communication, we report our initial experience with the use of intraoperative ultrasound as an adjunct to oral tongue cancer surgery without the use of an invasive method to mark the deep resection margin. PMID- 29161195 TI - Successful aging: The role of cognitive gerontology. AB - This commentary explores the relationships between the construct of successful aging and the experimental psychology of human aging-cognitive gerontology. What can or should cognitive gerontology contribute to understanding, defining, and assessing successful aging? Standards for successful aging reflect value judgments that are culturally and historically situated. Fundamentally, they address social policy; they are prescriptive. If individuals or groups are deemed to be aging successfully, then their characteristics or situations can be emulated. If an individual or a group is deemed to be aging unsuccessfully, then intervention should be considered. Although science is never culture-free or ahistorical, cognitive gerontology is primarily descriptive of age-related change. It is not prescriptive. It is argue that cognitive gerontology has little to contribute to setting standards for successful aging. If, however, better cognitive function is taken as a marker of more successful aging-something not universally accepted-then cognitive gerontology can play an important assessment role. It has a great deal to contribute in determining whether an individual or a group evidences better cognitive function than another. More importantly, cognitive gerontology can provide tools to evaluate the effects of interventions. It can provide targeted measures of perception, attention, memory, executive function, and other facets of cognition that are more sensitive to change than most clinical measures. From a deep understanding of factors affecting cognitive function, cognitive gerontology can also suggest possible interventions. A brief narrative review of interventions that have and have not led to improved cognitive function in older adults. Finally, the enormous range is addressed in the estimates of the proportion of the population that meets a standard for aging successfully, from less than 10% to more than 90%. For research purposes, it would be better to replace absolute cutoffs with correlational approaches (e.g., Freund & Baltes, 1998, Psychology and Aging, 13, 531-543). For policy purposes, cutoffs are necessary, but we propose that assessments of successful aging be based not on absolute cutoffs but on population proportions. An example of one possible standard is this: Those more than 1 standard deviation above the mean are aging successfully; those more than 1 standard deviation below the mean are aging unsuccessfully; those in between are aging usually. Adoption of such a standard may reduce the wide discrepancies in the incidence of successful aging reported in the literature. PMID- 29161196 TI - Emergence of Mixed-Oil Fat Emulsions for Use in Parenteral Nutrition. AB - Since early work by Wretlind and Schuberth led to the development of a stable and safe intravenous fat emulsion (IFE) using soybean oil (SO) and egg phospholipid emulsifier, IFEs have become a crucial source of essential fatty acids and nonprotein energy in parenteral nutrition. However, largely due to their high omega-6 polyunsaturated fatty acid (PUFA) and phytosterol content, SO IFEs have been associated with complications, including a proinflammatory profile and hypertriglyceridemia, as well as intestinal failure-associated liver disease. Subsequent generations of IFEs have used other sources of triglycerides, including medium-chain triglycerides (MCTs), olive oil (OO), and fish oil (FO), to reduce the SO component. Although these IFEs showed some improvement in complications compared with SO IFE, the quest to develop an IFE with a better side effect profile and beneficial physiologic effects led to the development of a mixed-oil (MO) IFE (Smoflipid; 30% SO, 30% MCTs, 25% OO, and 15% FO) that was recently approved by the Food and Drug Administration. The use of a MO approach is theoretically and intuitively more physiologically similar to normal dietary human consumption. Although the data are from small, short-term trials, MO IFE results thus far have been promising, with some studies showing improved liver function tests, improvement in triglycerides, higher omega-3/omega-6 PUFA ratio, and higher alpha-tocopherol. Larger long-term studies are needed to ensure these theoretical benefits lead to significant improvement in clinical outcomes. PMID- 29161198 TI - A systematic review of factors influencing human papillomavirus vaccination among immigrant parents in the United States. AB - To critically appraise factors influencing human papillomavirus (HPV) vaccination among immigrant parents in the United States, a comprehensive search of electronic databases and reference lists was conducted. The findings from 22 articles were ordered based on a socioecological model. About 30% of children initiated and 14% completed a three-dose series. Correlates of HPV vaccine initiation rates included lack of information, concerns about vaccine safety and promiscuity, providers' recommendations, school mandates, financial issues, immigration laws, and living in disadvantaged neighborhoods. Upstream initiatives embracing cultural descriptors could facilitate HPV vaccination, reducing HPV related disparities in cancer among immigrants in the US. PMID- 29161197 TI - Acceptance and psychological change at the higher levels of care: A naturalistic outcome study. AB - This naturalistic outcome study reports on psychological change among a large (N = 617), transdiagnostic sample of eating disordered adults treated at higher levels of care at a private facility. Patients were assessed at admission and discharge for eating disorder psychopathology, depression, personality, and acceptance. Effect sizes ranged from d = .29 to d = 1.29, and the majority of participants (58.2%) were treatment responders, with BN patients showing a higher response rate than AN-R patients. Increased acceptance over the course of treatment was strongly associated with decreased eating disorder risk and may be an important factor in recovery. PMID- 29161199 TI - Intranasal Budesonide and Quality of Life in Pediatric Sleep-Disordered Breathing: A Randomized Controlled Trial. AB - Objective To study the efficacy of budesonide nasal spray on the health-related quality of life and symptoms among children with sleep-disordered breathing. Study Design Randomized, parallel, double-blind, placebo-controlled trial. Setting Tertiary referral center. Subjects and Methods Sixty children (ages, 4-10 years) who were referred because of snoring and/or apneas for >3 months were included between January 2015 and June 2016 and randomized in a double-blind design to treatment with 64 MUg/mL of budesonide nasal spray (n = 30) or placebo nasal spray (n = 30) twice daily for 6 weeks. The primary outcome measurement was the change in the mean OSA-18 total score from baseline. Other variables examined were individual OSA-18 domains, a visual analog scale for quality of life, symptoms (snoring, apneas, and nasal obstruction), and adenoid and tonsil size. The trial was investigator initiated and not sponsored by the pharmaceutical industry. Results Fifty-five children completed the trial. An intention-to-treat analysis revealed a significantly greater improvement in the mean OSA-18 total score after treatment with budesonide than placebo (19.5 vs 7.5, P = .0014). Intranasal budesonide also improved 2 OSA-18 domains (sleep disturbance, caregivers' concerns), the visual analog scale score for quality of life, as well as snoring, apneas, and nasal obstruction. No serious adverse events were reported that could be linked to the treatment. Conclusion Among children with sleep-disordered breathing, 6 weeks' treatment with intranasal budesonide significantly improved quality of life and symptoms as compared with placebo nasal spray. PMID- 29161200 TI - Early Placement of Ventilation Tubes in Infants with Cleft Lip and Palate: A Systematic Review. AB - Objective Studies have shown that the majority of cleft lip and palate (CLP) children have middle ear fluid present at the time of lip repair (3-4 months). Despite hearing loss, the majority of children do not undergo ventilation tube treatment if required until the time of palate repair (9-12 months). We aimed to examine the effectiveness and potential complications of early ventilation tube placement prior to palatoplasty in infants with cleft lip and palate. Data Sources Medline (1946-2015), Embase (1980-2015), and EBM Reviews (Cochrane Central Register of Controlled). Review Methods Data sources were searched for publications that described the results of early ventilation tube placement in children with CLP prior to cleft palate repair. Two independent reviewers appraised the selected studies. Results Of 226 studies identified, 6 studies met the inclusion criteria. Early ventilation tube insertion in CLP gave similar speech and audiology outcomes to non-CLP children undergoing ventilation tube insertion and better outcomes than those children with CLP having later ventilation tube insertion at or after the time of palate closure. The main reported side effect was otorrhea, being higher for children with CLP having early ventilation tube insertion (67% vs 33%), with a reduction in otorrhea with increasing age. Larger studies with longer-term outcome reporting are required to fully address the study objectives. Conclusion Published data are limited but appear to support early insertion of ventilation tubes in children with CLP to restore middle ear function and maximize audiologic and speech outcomes. PMID- 29161201 TI - Reply to M. Mo et al. PMID- 29161203 TI - A Pathologic Fascination With Humanity. PMID- 29161202 TI - The HELOISE Study: Concerns About Trial Design. PMID- 29161205 TI - Imbalance Between Clinical and Pathologic Staging in the Updated American Joint Commission on Cancer Staging System for Human Papillomavirus-Positive Oropharyngeal Cancer. PMID- 29161204 TI - Effect of Neoadjuvant Chemoradiotherapy on Health-Related Quality of Life in Esophageal or Junctional Cancer: Results From the Randomized CROSS Trial. AB - Purpose To compare pre-agreed health-related quality of life (HRQOL) domains in patients with esophageal or junctional cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery or surgery alone. Secondary aims were to examine the effect of nCRT on HRQOL before surgery and the effect of surgery on HRQOL. Patients and Methods Patients were randomly assigned to nCRT (carboplatin plus paclitaxel with concurrent 41.4-Gy radiotherapy) followed by surgery or surgery alone. HRQOL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and -Oesophageal Cancer Module (QLQ-OES24) questionnaires pretreatment and at 3, 6, 9, and 12 months postoperatively. The nCRT group also received preoperative questionnaires. Physical functioning (PF; QLQ-C30) and eating problems (EA; QLQ OES24) were chosen as predefined primary end points. Predefined secondary end points were global QOL (GQOL; QLQ-C30), fatigue (FA; QLQ-C30), and emotional problems (EM; QLQ-OES24). Results A total of 363 patients were analyzed. No statistically significant differences in postoperative HRQOL were found between treatment groups. In the nCRT group, PF, EA, GQOL, FA, and EM scores deteriorated 1 week after nCRT (Cohen's d: -0.93, P < .001; 0.47, P < .001; -0.84, P < .001; 1.45, P < .001; and 0.32, P = .001, respectively). In both treatment groups, all end points declined 3 months postoperatively compared with baseline (Cohen's d: 1.00, 0.33, -0.47, -0.34, and 0.33, respectively; all P < .001), followed by a continuous gradual improvement. EA, GQOL, and EM were restored to baseline levels during follow-up, whereas PF and FA remained impaired 1 year postoperatively (Cohen's d: 0.52 and -0.53, respectively; both P < .001). Conclusion Although HRQOL declined during nCRT, no effect of nCRT was apparent on postoperative HRQOL compared with surgery alone. In addition to the improvement in survival, these findings support the view that nCRT according to the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study-regimen can be regarded as a standard of care. PMID- 29161206 TI - A Hypersensitivity-Like Response to Meloidogyne graminicola in Rice (Oryza sativa). AB - Meloidogyne graminicola is a major plant-parasitic nematode affecting rice cultivation in Asia. Resistance to this nematode was found in the African rice genotypes Oryza glaberrima and O. longistaminata; however, due to interspecific hybrid sterility, the introgression of resistance genes in the widely consumed O. sativa varieties remains challenging. Recently, resistance was found in O. sativa and, here, we report for the first time the histological and genetic characterization of the resistance to M. graminicola in Zhonghua 11, an O. sativa variety. Bright-light microscopy and fluorescence observations of the root tissue of this variety revealed that the root cells surrounding the nematode displayed a hypersensitivity-like reaction with necrotic cells at early stages of infection when nematodes are migrating in the root's mesoderm. An accumulation of presumably phenolic compounds in the nematodes' neighboring root cells was also observed. In addition, at a later stage of infection, not only were few feeding sites observed but also the giant cells were underdeveloped, underlining an incompatible interaction. Furthermore, we generated a hybrid O. sativa population by crossing Zhonghua 11 with the susceptible O. sativa variety IR64 in order to describe the genetic background of this resistance. Our data suggested that the resistance to M. graminicola infection was qualitative rather than quantitative and, therefore, major resistance genes must be involved in this infection process. The full characterization of the defense mechanism and the preliminary study of the genetic inheritance of novel sources of resistance to Meloidogyne spp. in rice constitute a major step toward their use in crop breeding. PMID- 29161207 TI - Composite Intravenous Fat Emulsion in a Postsurgical Critically Ill Patient: A Case Report. AB - Parenteral nutrition (PN), including lipids, in high-risk or poorly nourished critically ill patients is indicated when enteral nutrition is contraindicated; however, soybean oil-based PN can stimulate proinflammatory processes. Fish oil (FO) is generally less inflammatory and has recently been shown to be active in the resolution of inflammatory processes. In this study, we look at whether the use of a blended intravenous fat emulsion that includes soybean, medium-chain triglycerides, olive oil, and FO confers clinical benefits in critically ill patients. PMID- 29161208 TI - Power that Builds Others and Power that Breaks: Effects of Power and Humility on Altruism and Incivility in Female Employees. AB - Building on the approach/inhibition theory of power and the situated focus theory of power, we examine the roles of positional and personal power on altruism and incivility in workplace dyads. Results from a field study in daycare centers showed that legitimate power (a dimension of positional power) was positively associated with incivility. In contrast, personal power-referent power and expert power-was positively associated altruism and was negatively associated with incivility. Referent power was a stronger predictor of both altruism and incivility for individuals with low humility than those with high humility. Coercive power was a stronger predictor of incivility for individuals with high humility than those with low humility. PMID- 29161210 TI - Index Use of Smoflipid in a Tertiary Intestinal Rehabilitation and Transplantation Program. AB - Long-term parenteral nutrition (PN) may be complicated by PN-associated liver disease (PNALD), and some studies suggest an association between the use of soy based fat emulsions and PNALD development. Patients' liver function typically improves and PNALD resolves after reducing or stopping a soy-based fat emulsion, and thus lipid minimization has been the primary strategy for managing PNALD in many intestinal rehabilitation programs. However, fat emulsions often cannot be stopped entirely, leading some patients to develop PNALD even after lipid reduction strategies have been implemented. Smoflipid emulsion (Kabi-Fresenius, Bad Homburg, Germany), a balanced mixture of soybean oil, medium-chain triglycerides (MCTs), olive oil, and fish oil, was recently approved by the Food and Drug Administration for use in the United States as an equivalent alternative to Intralipid (Baxter Healthcare Corporation, Deerfield, IL). In several pediatric studies, patients who received Smoflipid had significantly lower serum bilirubin levels than those who received Intralipid. In this case report, we present a patient who developed severe PNALD with subsequent resolution after 20 weeks on Smoflipid. PMID- 29161211 TI - Sexual Cognitions, Trait Anxiety, Sexual Anxiety, and Distress in Men With Different Subtypes of Premature Ejaculation and in Their Partners. AB - This study examined trait anxiety and sexual cognitions in 610 men with premature ejaculation (PE) (DSM-IV-TR criteria) and in 107 partners of these men, and compared their scores to normative data. Sexual anxiety, intravaginal ejaculatory latency time, feeling of control over ejaculation, and PE-related distress were also assessed. The scores of 343 participants (56.23%) with clearly identifiable subtypes of PE according to Waldinger's classification system (lifelong, acquired, variable, and subjective subtypes) were compared in these domains. Finally, the predictive value of these factors in determining PE-related distress was explored. The following conclusions can be summarized from the results: (1) Men affected by PE are more distressed by the problem than their partners; (2) there is no evidence that levels of trait anxiety in individuals with PE are dissimilar to those found in the general population; (3) "dysfunctional" sexual cognitions likely play a role in PE, especially with regard to PE-related distress; (4) different subtypes of PE have similar profiles on measures of trait anxiety, sexual anxiety, and sexual cognitions; (5) differences between subtypes are only apparent with regard to feeling of control over ejaculation, with men with lifelong or acquired PE scoring significantly lower than those with a subjective form of the problem. PMID- 29161212 TI - Positive Affect as a Predictor of Smoking Cessation and Relapse: Does It Offer Unique Predictive Value among Depressive Symptom Domains? AB - BACKGROUND: Prior studies have suggested that, among the domains of depressive symptoms, low positive affect (PA) may have a distinct relationship with smoking cessation and relapse. However, the empirical basis for PA-focused interventions cessation is limited, with some mixed findings. OBJECTIVES: Using a large, diverse sample of treatment-seeking smokers, this study tested the hypothesis that PA adds unique predictive value beyond the effects of the other symptom domains in models of cessation and relapse. METHODS: Adult smokers participating in a smoking cessation trial (n = 450) were included in this post hoc analysis. Cessation outcomes included smoking abstinence at end of treatment and at 6-month follow-up. Relapse was defined as recurrence of smoking at 6-month follow-up among the end-of-treatment abstainers. Depressive symptoms were assessed at baseline using the Center for Epidemiologic Studies-Depression (CES-D) scale. RESULTS: With the exception of PA, all of the CES-D domains predicted reduced likelihood of smoking abstinence at end of treatment and cotinine-confirmed (but not self-reported) abstinence at 6 months, as did total CES-D score (all p-values < .05). None of the symptom domains predicted relapse. Conclusions/Importance: Our results provide further evidence that current depressive symptoms predict worse cessation outcomes, but they fail to support recent work suggesting that low PA has incremental predictive value for cessation or relapse beyond the other depressive symptom domains. To improve quit rates for smokers with depressive symptoms, evidence-based mood management interventions should be included in treatment planning. PMID- 29161213 TI - Laparoscopic Management of Penetrating Thoracoabdominal Trauma. AB - BACKGROUND: Traumatic thoracoabdominal injuries can involve multiple organs and multiple cavities, which increases the complexity of surgical management. Traditionally, these injuries required laparotomy and thoracotomy. However, minimally invasive intervention may be reasonable for stable patients. MATERIALS AND METHODS: We present a case of a thoracoabdominal gunshot wound resulting in multiorgan, multicavity injury to the lung, diaphragm, and liver. We performed hepatorrhaphy and diaphragm repair, and addressed a retained hemothorax through a transabdominal laparoscopic approach. RESULTS: The patient tolerated the procedure well. He required no further procedures, and had no evidence of retained hemothorax or bile leak from the liver injury. After a short stay in the hospital, the patient recovered uneventfully. CONCLUSIONS: In hemodynamically stable patients, the transabdominal laparoscopic approach is a feasible and effective approach to penetrating thoracoabdominal trauma. PMID- 29161214 TI - A Randomized Trial of an Advanced Sun Safety Intervention for Vacationers at 41 North American Resorts. AB - Taking vacations in sunny locations is associated with the development of skin cancer. This study tested a multi-component sun protection intervention based on diffusion of innovations theory and transportation theory designed to increase vacationers' comprehensive sun protection, i.e., use of clothing, hats, and shade, and use, pre-application, and reapplication of sunscreen. The trial enrolled 41 warm weather resorts in North America in a pair-matched group randomized pretest-posttest design and assessed samples of adult vacationers at resort outdoor recreation venues regarding sun protection at pretest (n = 3,531) and posttest (n = 3,226). While results showed no overall effect of the intervention on comprehensive sun protection across venues, the intervention produced statistically significant improvements in sun protection at waterside venues (pools and beaches). The intervention's overall effects may have been impeded by a lack of uniformly robust implementation, low interest in skin cancer prevention by guests, or shortcomings of the theories used to create prevention messages. The intervention may have worked best with guests in the highest-risk recreation venue, i.e., waterside recreation where they exposed the most skin. Alternative approaches that alter resort organizations, such as through changes in policy, environmental features, or occupational efforts might be more effective than targeting vacationers with behavior-change messages. PMID- 29161215 TI - Recent advances in nanomedicine and survivin targeting in brain cancers. AB - Brain cancer is a highly lethal disease, especially devastating toward both the elderly and children. This cancer has no therapeutics available to combat it, predominately due to the blood-brain barrier (BBB) preventing treatments from maintaining therapeutic levels within the brain. Recently, nanoparticle technology has entered the forefront of cancer therapy due to its ability to deliver therapeutic effects while potentially passing physiological barriers. Key nanoparticles for brain cancer treatment include glutathione targeted PEGylated liposomes, gold nanoparticles, superparamagnetic iron oxide nanoparticles and nanoparticle-albumin bound drugs, with these being discussed throughout this review. Recently, the survivin protein has gained attention as it is over expressed in a majority of tumors. This review will briefly discuss the properties of survivin, while focusing on how both nanoparticles and survivin targeting treatments hold potential as brain cancer therapies. This review may provide useful insight into new brain cancer treatment options, particularly survivin inhibition and nanomedicine. PMID- 29161216 TI - Focus on Effector-Triggered Susceptibility. AB - Effector biology exhibits diversity at every level. Effector proteins play key roles in the molecular interplay between plants and plant-associated organisms, and effector biology remains one of the most active areas in the research field of molecular plant-microbe interactions. Using effectors as probes, much has been learned about pathogen virulence and host immunity, which has broad implications in developing disease-resistant crops that are essential for global food security. Thus, the MPMI Editorial Board is publishing this Focus Issue to showcase recent progress in this area. PMID- 29161217 TI - Use of vascular closure devices for endovascular interventions requiring a direct puncture of PETE grafts. AB - BACKGROUND: Effectiveness of vascular closure devices during endovascular procedures requiring a direct puncture of a vascular prosthesis placed in the inguinal region is unknown. PATIENTS AND METHODS: The retrospective analysis included 134 patients with a history of polyethylene terephthalate (PETE) graft implantation in the inguinal region. In 20 (15 %) patients, haemostasis was achieved with manual compression, in 21 (16 %) with the StarCloseTM, and in 93 (69 %) with the AngioSealTM device. RESULTS: The incidence of vascular complications in the manual compression group was higher (at a threshold of statistical significance) than in the device closure group (45.0 vs. 24.5 %, p = 0.059). The difference was considered statistically significant when manual compression was compared with the AngioSealTM closure group (45.0 vs. 13.9 %, p < 0.01). The vascular complication rate in the StarCloseTM group was significantly higher than in the AngioSealTM group (71.4 vs. 13.9 %, p < 0.000001). While haematomas were the only vascular complications observed after application of AngioSealTM, both haematomas and pseudoaneurysms were found in the StarCloseTM group. CONCLUSIONS: The AngioSealTM vascular closure device provides better local haemostasis than the StarCloseTM device or manual compression during endovascular interventions requiring a direct puncture of PETE grafts. PMID- 29161218 TI - The Impact of Dementia on Relationships, Intimacy, and Sexuality in Later Life Couples: An Integrative Qualitative Analysis of Existing Literature. AB - OBJECTIVES: The onset and progression of dementia can have a profound effect on the couple dyad. The aim of this systematic review was to analyze the literature investigating the impact of dementia on the relationships, intimacy, and sexuality in older couples. METHODS: A systematic literature search was conducted in May 2016 for relevant research articles. Five databases were searched: Web of Science, PsycINFO, MedLine, Scopus and CINAHL. The reference lists of articles included in the review were screened along with the reference list of other relevant reviews. RESULTS: Thirteen studies were identified that investigated relationships, intimacy, and sexuality from the perspective of the partner, the person with dementia or from the perspective of the couple jointly. The analysis revealed several themes including changes in responsibilities and roles, identity and self-esteem, affection, commitment, reciprocity, and sexual activity and satisfaction. CONCLUSION: The results strongly suggest dementia has a significant impact on the couple relationship. There is a dearth of research involving the perspective of the person with dementia or the couple jointly. Future research should investigate the impact of dementia on relationships, intimacy, and sexuality from the perspective of partners, the person with dementia, and the couple jointly to ensure the development of appropriate information and services that meet the needs of both people in the couple relationship. CLINICAL IMPLICATIONS: Clinicians should work closely with couples to develop tailored information and supports to assist couples in managing the multiple changes that occur in their relationship, intimacy, and sexuality due to dementia. PMID- 29161219 TI - A Case Study Perspective: The Experiences of Young Persons Testifying to Child Sexual Exploitation in British Criminal Court. AB - Three young persons who gave evidence about child sexual exploitation in criminal court using various testimonial supports were interviewed about their testimony experiences. The witnesses reported that they felt extreme pressure to remember events accurately and cared greatly about being believed. None reported their own coping strategies to alleviate stress and took comfort breaks only after they cried on the stand. Defense attorney questions were reportedly repetitive, rapid, confusing, and focused on secondary content rather than the central criminal acts. The witnesses mentioned dissatisfaction in having supportive social workers whom they trusted leave the case and be replaced. PMID- 29161220 TI - Speaking With and Without Words-An Analysis of Foster Children's Expressions and Behaviors That Are Suggestive of Prior Sexual Abuse. AB - This exploratory study reports on foster children's informal self-disclosures of previously unknown histories of sexual abuse. Data were collected from 40 children's files, and an inductive thematic analysis of verbal and behavioral expressions was conducted. Findings suggest that foster children's self disclosures can be fragmented, spontaneous, narrative, or triggered and often occur during everyday activities in the foster family. The children disclose their past by referring to the perpetrator or the severity of the abuse or by acting out, mostly by reenacting sexual abuse experiences. In addition, some children use childish vocabulary focusing on genitals or sexual acts they were involved in or want to be involved in. Last, some foster children seem to be linguistically challenged to disclose that a female person abused them or that they were forced to reciprocate sexually. This study adds to the understanding of the complex process of child sexual abuse disclosure in the context of foster care. PMID- 29161222 TI - Perspectives of Mothers of Transgender and Gender-Nonconforming Children With Autism Spectrum Disorder. AB - This study represents findings from interviews at two time points with three mothers of transgender and gender-nonconforming (TGNC) children (ages 8 to 12 years at T1) with autism spectrum disorder (ASD). Of interest was the mothers' experiences of raising a TGNC child with ASD, and whether/how the children's autism played a role in their understandings of their children's gender identities and expressions. The mothers' fear of a transphobic/cisnormative society and wondering about whether their children's ASD influenced or caused their children's gender variance were barriers to fully embracing their children's gender nonconformity. Unclear causes of children's social/emotional difficulties and lack of adequate resources and support were identified challenges. Positive interventions and resources were also discussed. Recommendations for clinicians and other professionals who serve TGNC youth with autism and their families are presented. PMID- 29161221 TI - From Freud to Feminism: Gendered Constructions of Blame Across Theories of Child Sexual Abuse. AB - Most theories of child sexual abuse are, to some degree, gendered, with nonoffending mothers bearing the burden of blame, ideologically and legally, for the transgressions of predominantly male offenders. This article explores the social construction of blame for child sexual abuse via critical analyses of evolving theoretical perspectives on maternal culpability for the inception and maintenance of abuse dynamics. Drawing on selected conceptual and research knowledge that supports and refutes anecdotal claims, this synthesis of the literature culminates in the proposal of an evidence-informed, feminist-grounded, multitheoretical child sexual abuse framework that disrupts dominant mother blaming discourse and guides socially just and ethically responsive policy, practice, and research. PMID- 29161223 TI - The Impact of Marriage Equality on Sexual Minority Women's Relationships With Their Families of Origin. AB - Support from family of origin is important to the health and wellbeing of sexual minority women (SMW) and structural stigma may impact that support. The recent extension of marriage rights to same-sex couples in all U.S. states provided an opportunity to examine whether this change in law would impact the relationship of SMW with their families of origin regarding their same-sex relationships, including marriage. Interviews with 20 SMW were conducted to learn about their perceptions of how support from families of origin had been impacted by or changed since the U.S. Supreme Court decision (Obergefell v. Hodges, 135 S. Ct. 2584, 2015). Thematic analysis of the narrative responses revealed stories of continued family support; increases in acceptance or support; mixed support/rejection or unclear messages; "don't ask, don't tell" or silence; and continued or increased family rejection. Most participant narratives included more than one theme. Implications for SMW's health and relationships are discussed. PMID- 29161224 TI - Viewing Sexual Desire as Stable Versus Fluid: The Impact of Implicit Beliefs on Women's Coping With Sexual Desire Problems. AB - Our goal was to examine how implicit theories can be applied to understanding women's coping responses to sexual problems. The belief that sexual desire changes over time is a type of incremental theory, while the belief that sexual desire is stable is a type of entity theory (Dweck, 2012 ). We examined how different implicit theories of sexual desire influence how women cope with sexual desire challenges. Also, we sought to determine whether women's perceptions of experiencing a sexual desire challenge moderate the relationship between their implicit beliefs and their coping responses. We randomly assigned women to read an article designed to induce either an entity or incremental theory about sexual desire. We further asked them to indicate how true it is that they have experienced, or are likely to experience, a sexual desire problem (1 = not at all true to 4 = very true). They then completed a measure of coping with desire problems, the Modified Cope Inventory. Results from both studies showed that women primed with entity theories who expected to experience a sexual desire issue reported significantly more negative coping than women primed with incremental theories. Implications of this research and future directions are discussed. PMID- 29161225 TI - From Sexual Desire Discrepancies to Desirable Sex: Creating the Optimal Connection. AB - Beginning in 2005, our team conducted a series of studies on optimal sexual experiences. We have applied our findings to develop a group therapy intervention for couples presenting with low sexual desire/frequency and sexual desire discrepancy. The goal was to improve the quality of erotic intimacy by focusing on such elements as being fully embodied during sex, increasing authenticity, trustworthiness, and vulnerability. Twenty-eight heterosexual individuals (14 couples) were seen in 16 hours of couples group therapy. Each completed the New Sexual Satisfaction Scale in pretests, posttests and six-month follow-ups. Significant differences in satisfaction (p <.001) were found in overall sample means from pretests to posttests and follow-ups. Significant differences were also found in 10 of 20 items, plus in two of three added items, including satisfaction with intensity of sexual arousal, variety, frequency, partner's initiation, and emotional opening up. Although this is a small sample, the results indicate that this intervention is effective. We interpret these findings in terms of creating just enough safety to enable couples to take erotic risks and thereby create desirable sexual intimacy. PMID- 29161227 TI - Motor Skill Learning and the Development of Visual Perception Processes Supporting Action Identification. AB - This study examined physical training and observational training influences on motor learning and the development of visual discrimination processes. Participants were trained on a bimanual task (relative phase of +90 degrees ) defined by a visual training stimulus. There were 2 observational contexts: 1) model-only, watch a learning model, and 2) stimulus-only, watch the visual training stimulus. After 2 d of training, the learning models performed the +90 degrees pattern with reduced error in 2 retention tests. Each observer group showed improvement in performance of the +90 degrees pattern, with the stimulus only group characterized by a more significant improvement. The learning models and observer groups were characterized by an improvement in visually discriminating 2 features of the trained pattern, relative phase and hand-lead. Overall, physical practice (learning models) established a stronger link between the action and visual discrimination processes compared with the observational contexts. The results show that the processes supporting action production and the visual discrimination of actions are modified in ways specific to the trained action following both physical and observational training. PMID- 29161226 TI - Development of Competitive Enzyme-Linked Immunosorbent Assays for Antibody Detection Based on Bluetongue Virus Monoclonal Antibodies. AB - Bluetongue is a ruminant infectious disease that is characterized by hyperpyrexia, leukocyte decrease and mucosal ulcerative inflammation changes. In this study, three segments of Bluetongue virus (BTV)-8 VP2 protein (BTV-8A, 8B, and 8C) were cloned into pET-28a (+) and pMAl-c5X vectors and expressed in Escherichia coli BL21 (DE3) as histidine (His)-tagged (His-8A/8B/8C) and maltose binding protein (MBP)-tagged (MBP-8A/8B/8C) fusion proteins. After purification, His-8A/8B/8C were used to immunize BALB/mice and MBP-8A/8B/8C were used to screen for monoclonal antibody (mAb)-secreting hybridomas. Two mAbs (8B-5D4 and 8B-3G11) that could recognize BTV-8 were obtained. Two competitive enzyme-linked immunosorbent assays with good specificity and sensitivity using mAbs 8B-5D4 or 8B-3G11 as competitive antibody were established. With the joint reaction of these methods, serum samples containing anti-BTV-7 or anti-BTV-8 antibody could be screened out, suggesting that these methods would be useful for the diagnosis and epidemiological studies of BTV-8. PMID- 29161228 TI - Homelessness predicts attrition but not alcohol abstinence in outpatients experiencing co-occurring alcohol dependence and serious mental illness. AB - BACKGROUND: Adults experiencing homelessness and serious mental illnesses (SMI) are at an increased risk of poor mental health and treatment outcomes compared with stably housed adults with SMI. The additional issue of alcohol misuse further complicates the difficulties of those living with homelessness and SMI. In this secondary data analysis, the authors investigated the impact of homelessness on attrition and alcohol use in a contingency management (CM) intervention that rewarded alcohol abstinence in outpatients with SMI. METHODS: The associations between housing status and attrition and alcohol abstinence during treatment, as assessed by ethyl glucuronide (EtG) urine tests, were evaluated in 79 adults diagnosed with alcohol dependence and SMI. RESULTS: Thirty nine percent (n = 31) of participants reported being homeless at baseline. Individuals who were homeless were more likely to drop out of CM (n = 10, 62.5%) than those who were housed (n = 4, 16.7%), chi2(1) = 8.86, P < .05. Homelessness was not associated with attrition in the noncontingent control group. Accounting for treatment group and prerandomization EtG levels, neither the effect of housing status nor the interaction of housing status and group were associated with EtG-assessed alcohol abstinence during treatment. CONCLUSIONS: Individuals experiencing homelessness and co-occurring alcohol dependence and SMI receiving CM had higher rates of attrition, relative to those who were housed. Homelessness was not associated with differences in biologically assessed alcohol abstinence. PMID- 29161231 TI - Epigenetic regulation mechanisms of microRNA expression. AB - MicroRNAs (miRNAs) are single-stranded RNAs of 18-25 nucleotides that regulate gene expression at the post-transcriptional level. They are involved in many physiological and pathological processes, including cell proliferation, apoptosis, development and carcinogenesis. Because of the central role of miRNAs in the regulation of gene expression, their expression needs to be tightly controlled. Here, we summarize the different mechanisms of epigenetic regulation of miRNAs, with a particular focus on DNA methylation and histone modification. PMID- 29161230 TI - Long-Term Exposure to Transportation Noise in Relation to Development of Obesity a Cohort Study. AB - BACKGROUND: Exposure to transportation noise is widespread and has been associated with obesity in some studies. However, the evidence from longitudinal studies is limited and little is known about effects of combined exposure to different noise sources. OBJECTIVES: The aim of this longitudinal study was to estimate the association between exposure to noise from road traffic, railways, or aircraft and the development of obesity markers. METHODS: We assessed individual long-term exposure to road traffic, railway, and aircraft noise based on residential histories in a cohort of 5,184 men and women from Stockholm County. Noise levels were estimated at the most exposed facade of each dwelling. Waist circumference, weight, and height were measured at recruitment and after an average of 8.9 y of follow-up. Extensive information on potential confounders was available from repeated questionnaires and registers. RESULTS: Waist circumference increased 0.04 cm/y (95% CI: 0.02, 0.06) and 0.16 cm/y (95% CI: 0.14, 0.17) per 10 dB Lden in relation to road traffic and aircraft noise, respectively. No corresponding association was seen for railway noise. Weight gain was only related to aircraft noise exposure. A similar pattern occurred for incidence rate ratios (IRRs) of central obesity and overweight. The IRR of central obesity increased from 1.22 (95% CI: 1.08, 1.39) in those exposed to only one source of transportation noise to 2.26 (95% CI: 1.55, 3.29) among those exposed to all three sources. CONCLUSION: Our results link transportation noise exposure to development of obesity and suggest that combined exposure from different sources may be particularly harmful. https://doi.org/10.1289/EHP1910. PMID- 29161232 TI - Development concepts of a Smart Cyber Operating Theater (SCOT) using ORiN technology. AB - Currently, networking has not progressed in the treatment room. Almost every medical device in the treatment room operates as a stand-alone device. In this project, we aim to develop a networked operating room called "Smart Cyber Operating Theater (SCOT)". Medical devices are connected using Open Resource interface for the Network (ORiN) technology. In this paper, we describe the concept of the SCOT project. SCOT is integrated using the communication interface ORiN, which was originally developed for industry. One feature of ORiN is that the system can be constructed flexibly. ORiN creates abstracts of the same type of devices and increases the robustness of the system for device exchange. By using ORiN technology, we are developing new applications, such as decision making navigation or a precision guided treatment system. PMID- 29161229 TI - Sex- and Dose-Specific Effects of Maternal Bisphenol A Exposure on Pancreatic Islets of First- and Second-Generation Adult Mice Offspring. AB - BACKGROUND: Exposure to the environmental endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with the increased risk of diabetes and obesity. However, the underlying mechanisms remain unknown. We recently demonstrated that perinatal BPA exposure is associated with higher body fat, impaired glucose tolerance, and reduced insulin secretion in first- (F1) and second-generation (F2) C57BL/6J male mice offspring. OBJECTIVE: We sought to determine the multigenerational effects of maternal bisphenol A exposure on mouse pancreatic islets. METHODS: Cellular and molecular mechanisms underlying these persistent changes were determined in F1 and F2 adult offspring of F0 mothers exposed to two relevant human exposure levels of BPA (10MUg/kg/d-LowerB and 10mg/kg/d-UpperB). RESULTS: Both doses of BPA significantly impaired insulin secretion in male but not female F1 and F2 offspring. Surprisingly, LowerB and UpperB induced islet inflammation in male F1 offspring that persisted into the next generation. We also observed dose-specific effects of BPA on islets in males. UpperB exposure impaired mitochondrial function, whereas LowerB exposure significantly reduced beta-cell mass and increased beta-cell death that persisted in the F2 generation. Transcriptome analyses supported these physiologic findings and there were significant dose-specific changes in the expression of genes regulating inflammation and mitochondrial function. Previously we observed increased expression of the critically important beta-cell gene, Igf2 in whole F1 embryos. Surprisingly, increased Igf2 expression persisted in the islets of male F1 and F2 offspring and was associated with altered DNA methylation. CONCLUSION: These findings demonstrate that maternal BPA exposure has dose- and sex-specific effects on pancreatic islets of adult F1 and F2 mice offspring. The transmission of these changes across multiple generations may involve either mitochondrial dysfunction and/or epigenetic modifications. https://doi.org/10.1289/EHP1674. PMID- 29161233 TI - Swimming, but not vitamin E, ameliorates prothrombotic state and hypofibrinolysis in a rat model of nonalcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is associated with a systemic procoagulant hypofibrinolysis state that is considered as a risk factor for microangiopathy and peripheral vascular diseases. Swimming exercise ameliorates the metabolic dysfunction in type 2 diabetes. Vitamin E is a natural antioxidant that reduces the risk of endothelial dysfunction in metabolic syndrome. The aim of the present study is to investigate the effect of combined swimming exercise with vitamin E on coagulation as well as blood fibrinolysis markers in rats with NAFLD. METHODS: Eighty male rats were divided into control, control+vitamin E, control+exercise, high-fat diet (HFD), HFD+vitamin E, HFD+exercise, and HFD+vitamin E+exercise groups. Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglycerides, cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL), alanine transaminase (ALT) and aspartate transaminase (AST), intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), endothelin-1, von Willebrand factor (vWF), fibrinogen, plasminogen activator inhibitor (PAI-1), fibrin degradation products (FDP), platelet count and aggregation, bleeding and clotting times, activated partial thromboplastin time (aPTT), and prothrombin time (PT) were determined. RESULTS: HFD increased lipid profile, insulin, glucose, HOMA-IR, liver enzymes, adhesion molecules, endothelin-1, vWF, platelet aggregation, fibrinogen, FDP, and PAI-1, and decreased clotting and bleeding times and HDL. Although exercise reduced lipid profile, glucose, insulin, HOMA IR, vWF, platelet aggregation, fibrinogen, FDP, and PAI-1 and increased PT, aPTT, bleeding and clotting times, and HDL, vitamin E had no effect. CONCLUSIONS: Exercise, but not vitamin E, ameliorated the HFD-induced prothrombotic state and enhanced fibrinolytic activity. PMID- 29161234 TI - Synthesis of methyl 4-dihydrotrisporate B and methyl trisporate B, morphogenetic factors of Zygomycetes fungi. AB - (9Z)-Methyl 4-dihydrotrisporate B and (9Z)-methyl trisporate B, pheromones of Zygomycetes fungi, have been synthesized using Stille cross-coupling from previously described cyclohexenone precursors. Conducting the coupling without protection groups allowed for a short and stereospecific synthesis route of the late trisporoids. Stability studies for both the compounds revealed (9Z)-methyl trisporate B to be very unstable against UV irradiation. PMID- 29161235 TI - Influence of ductus arteriosus on peripheral muscle oxygenation and perfusion in neonates. AB - OBJECTIVE: In neonates, a patent ductus arteriosus (DA) may be associated with severe complications. We used near-infrared spectroscopy (NIRS) with venous occlusion to investigate the influence of an open DA on peripheral muscle oxygenation/perfusion in preterm neonates. APPROACH: We analyzed secondary outcome parameters collected as part of prospective observational studies. NIRS measurements were performed between the first and third day of life. Arterial oxygen saturation (SaO2) and heart rate (HR) were monitored by pulse oximetry on the ipsilateral foot. Venous occlusion was performed with a blood pressure cuff on the thigh. Tissue oxygenation index (TOI), hemoglobin flow (Hbflow), oxygen delivery (DO2), oxygen consumption (VO2), mixed venous oxygenation (SvO2), and fractional oxygen extraction (FOE) were assessed. Echocardiography was performed within plus/minus 6 h from NIRS measurements. MAIN RESULTS: Twenty-eight neonates were included. In neonates with open DA (n = 15), the FOE was significantly higher (p = 0.046). DA diameter correlated negatively with SvO2 (r = -0.413, p = 0.032) and positively with FOE (r = 0.417, p = 0.030). In neonates with open DA, SaO2 was significantly lower (p = 0.041). DA diameter correlated negatively with SaO2 (r = -0.377, p = 0.048) and positively with HR (r = 0.489, p = 0.010). SIGNIFICANCE: Our results showed that an open DA influences peripheral muscle oxygenation in preterm neonates. PMID- 29161236 TI - Quantitative investigation of the edge enhancement in in-line phase contrast projections and tomosynthesis provided by distributing microbubbles on the interface between two tissues: a phantom study. AB - The objective of this study was to quantitatively investigate the ability to distribute microbubbles along the interface between two tissues, in an effort to improve the edge and/or boundary features in phase contrast imaging. The experiments were conducted by employing a custom designed tissue simulating phantom, which also simulated a clinical condition where the ligand-targeted microbubbles are self-aggregated on the endothelium of blood vessels surrounding malignant cells. Four different concentrations of microbubble suspensions were injected into the phantom: 0%, 0.1%, 0.2%, and 0.4%. A time delay of 5 min was implemented before image acquisition to allow the microbubbles to become distributed at the interface between the acrylic and the cavity simulating a blood vessel segment. For comparison purposes, images were acquired using three system configurations for both projection and tomosynthesis imaging with a fixed radiation dose delivery: conventional low-energy contact mode, low-energy in-line phase contrast and high-energy in-line phase contrast. The resultant images illustrate the edge feature enhancements in the in-line phase contrast imaging mode when the microbubble concentration is extremely low. The quantitative edge enhancement-to-noise ratio calculations not only agree with the direct image observations, but also indicate that the edge feature enhancement can be improved by increasing the microbubble concentration. In addition, high-energy in-line phase contrast imaging provided better performance in detecting low-concentration microbubble distributions. PMID- 29161237 TI - BILATERAL VISUAL FIELD DEFECTS IN A PATIENT TREATED WITH THE MEK AND BRAF INHIBITORS TRAMETINIB AND DABRAFENIB FOR MELANOMA OF UNKNOWN ORIGIN. AB - INTRODUCTION: Although the introduction of BRAF and MEK inhibitors has greatly enhanced treatment possibilities in advanced BRAFV600-mutated melanoma, class related toxicities are rather frequent and often involve the eye. Ophthalmologic side effects most commonly include central/diffuse serous retinopathy and retinal vein occlusion. Affection of the optic nerve head however has not been described clinically. CASE REPORT: A 29-year-old man presented in our eye clinic with bilateral blurred vision. Seventeen days earlier, he had been started on trametinib and dabrafenib combination therapy for metastasized melanoma of unknown origin. Visual field testing revealed diffuse bilateral defects, which regressed spontaneously on pause of MEK and BRAF inhibitor treatment. DISCUSSION: In addition to the widely known class-related retinal toxicity, MEK and BRAF inhibitor-associated adverse events may also involve the optic nerve head, causing visual field defects probably regressing spontaneously after discontinuation of targeted oncologic therapy. In such cases, repeat brain imaging and exclusion of melanoma-associated retinopathy is recommended. Reinitiation of treatment and subsequent dose escalation seem to be feasible, but should be monitored by an ophthalmologist. PMID- 29161238 TI - Downregulation of Inhibition of Apoptosis-Stimulating Protein of p53 (iASPP) Suppresses Cisplatin-Resistant Gastric Carcinoma In Vitro. AB - BACKGROUND Gastric cancer (GC) with cisplatin resistance is one of the leading causes of limitations to therapy. Inhibition of apoptosis-stimulating protein of p53 (iASPP) plays a key role in GC. However, the role of iASPP in GC with cisplatin resistance remains unclear. The aim of this study was to investigate iASPP expression in GC, and the functions of iASPP in cisplatin-resistant cell lines. MATERIAL AND METHODS In this study, the expression of iASPP was investigated in normal GC patients and patients with cisplatin resistance, along with GC cell lines and cell lines with cisplatin resistance. Furthermore, knockdown of iASPP was conducted in cell lines; and cell proliferation, apoptosis rate, cell cycle distribution, and cell migration and invasion were determined through CCK8, flow cytometry, Scratch test and Transwell assay, respectively. RESULTS The expression of iASPP in GC patients with cisplatin resistance was significant higher than in the health control group. Higher expression of iASPP was detected in cisplatin-resistant cancer cell lines. Cell proliferation of SGC 7901 and MGC-803 was inhibited by transfection with siRNA, along with evaluated apoptosis rate and G1 phase retardant. Furthermore, cells viability, including migration and invasion, was suppressed post-transfection with siRNA. CONCLUSIONS iASPP induced cisplatin resistance in GC patients. Thus, knockdown of iASPP might be a novel therapeutic strategy for the treatment of GC cisplatin-resistant patients. PMID- 29161239 TI - The impact of folate intake on the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort. AB - BACKGROUND: Although low levels of folate leads to disturbances in DNA replication, DNA methylation and DNA repair, the association between dietary folate intake and head and neck cancer (HNC) risk remains unclear. METHODS: We evaluated the association between folate intake and HNC risk using prospective cohort data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. This study included 101 700 participants and 186 cases with confirmed incident HNC. The median follow-up was 12.5 years. We estimated hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) using Cox proportional hazard model including age, sex, body mass index, education, race, tobacco smoking, alcohol drinking and total fruit and vegetable intake. RESULTS: Higher intake of food folate and fortified folic acid in foods was associated with a decreasing HNC risk in a dose-response manner. The HRs of highest vs the lowest quartile of intake were 0.35 (95%CI: 0.18-0.67) for food folate, and 0.49 (95%CI: 0.30-0.82) for fortified folic acid. Intakes of total folate, natural folate and supplemental folic acid were not associated with the risk of HNC and its subsites. We did not detect any interaction between smoking, drinking and food folate intake on HNC risk. CONCLUSIONS: These findings provide evidence of the protective role of dietary folate intake on HNC risk. PMID- 29161240 TI - Rapid nodal staging of head and neck cancer surgical specimens with flow cytometric analysis. AB - BACKGROUND: Detection of metastatic spread of head and neck cancer to cervical lymph nodes is essential for optimal design of therapy. Undetected metastases lead to mortality, which can be prevented by better detection methods. METHODS: We analysed 41 lymph nodes from 19 patients with oral squamous cell carcinoma (OSCC). Each lymph node was divided in two, one half processed for histopathology and the other half dissociated into single-cell suspension, stained for the carcinoma cell markers cytokeratin 5/8 (CK5/8), epithelial cell adhesion molecule (EpCAM) and epithelial mucin (MUC-1), and analysed with flow cytometry. Flow cytometry data were compared with histopathology performed on serial sections and immunohistochemistry. Six cervical lymph nodes from cancer-free patients were used to establish baseline levels in flow cytometry. RESULTS: Flow cytometry analysis (fluorescence-activated cell sorting; FACS) detected all six metastases confirmed by histopathology as well as the histologically negative nodes. Importantly, among nine sentinel lymph nodes, FACS analysis detected <1% malignant cells in four cases, not found in histopathology. Results from flow cytometry analysis can be obtained within 3 h of the time of biopsy. CONCLUSIONS: We show that flow cytometric analysis of nodal tissue is sensitive and reliable in identifying metastases of OSCC. Flow cytometry is inexpensive and fast, providing a possibility of perioperative diagnostics and immediate treatment planning. PMID- 29161241 TI - Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response. AB - BACKGROUND: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ?30% size decrease from baseline) are infrequent. METHODS: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. RESULTS: Data for 237 patients (85 placebo; 152 sunitinib (n=66.50 mg '4-weeks on/2-weeks off' schedule; n=86 '37.5 mg continuous daily dosing (CDD)')) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6 12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P<0.001). A PR was seen in 19 patients (13%) on sunitinib; the median change in the sum of the lesions (vs baseline) was -12.8% (range -100 to +36.4). Month 7 was the most informative time-point (AUC 0.78 (95% CI 0.66-0.9); odds ratio 1.05 (95% CI 1.01-1.08), P=0.002). Reduction of 10% (vs baseline) achieved the highest sensitivity (50%) and specificity (82%), amongst cut-offs tested. A 10% reduction in marker lesions was associated with improved PFS in the whole sunitinib population (HR 0.55 (95 CI 0.3-0.9); P=0.04); mostly in patients on sunitinib CDD (HR 0.33 (95% CI 0.2-0.7); P=0.005). A 10% reduction in marker lesions (P=0.034) and sunitinib treatment (P=0.012) independently impacted on PFS (multivariable analysis). CONCLUSIONS: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design. PMID- 29161242 TI - Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an extensive tissue invasion and an early formation of metastasis. Alterations in the expression of cadherins have been reported in PDAC. Yet, how these changes contribute to tumour progression is poorly understood. Here, we investigated the relationship between cadherins expression and PDAC development. METHODS: Cadherins expression was assessed by immunostaining in both human and murine tissue specimens. We have generated pancreatic cancer cell lines expressing both cadherin-1 and cadherin-3 or only one of these cadherins. Functional implications of such genetic alterations were analysed both in vitro and in vivo. RESULTS: Cadherin-3 is detected early at the plasma membrane during progression of pancreatic intraepithelial neoplasia 1 (PanIN-1) to PDAC. Despite tumoural cells turn on cadherin-3, a significant amount of cadherin-1 remains expressed at the cell surface during tumourigenesis. We found that cadherin-3 regulates tumour growth, while cadherin-1 drives type I collagen organisation in the tumour. In vitro assays showed that cadherins differentially participate to PDAC aggressiveness. Cadherin-3 regulates cell migration, whereas cadherin-1 takes part in the invadopodia activity. CONCLUSIONS: Our results show differential, but complementary, roles for cadherins during PDAC carcinogenesis and illustrate how their expression conditions the PDAC aggressiveness. PMID- 29161244 TI - Errata: Functional annotation of chemical libraries across diverse biological processes. AB - This corrects the article DOI: 10.1038/nchembio.2436. PMID- 29161245 TI - Cancer systems biology: Harnessing off-target effects. PMID- 29161243 TI - The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells. AB - BACKGROUND: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K+ channel modulators on colorectal cancer (CRC) cells. METHODS: The functional expression of Ca2+-activated (KCa3.1, also known as KCNN4) and voltage-dependent (Kv11.1, also known as KCNH2 or hERG1) K+ channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K+ channel modulators were tested in vitro for their action on K+ currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance. RESULTS: Cisplatin-resistant CRC cells expressed higher levels of KCa3.1 and Kv11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, KCa3.1 activators (SKA-31) and Kv11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when KCa3.1 activation and Kv11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate KCa3.1 and inhibit Kv11.1. Cisplatin uptake into resistant cells depended on KCa3.1 channel activity, as it was potentiated by KCa3.1 activators. Kv11.1 blockade led to increased KCa3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a KCa3.1 activator and a Kv11.1 inhibitor also overcame Cisplatin resistance in vivo. CONCLUSIONS: As Riluzole, an activator of KCa3.1 and inhibitor of Kv11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC. PMID- 29161246 TI - Peptide design: Hacking hemagglutinin. PMID- 29161248 TI - Nucleic acids: mRNAs get a TREAT. PMID- 29161247 TI - Errata: Functional annotation of chemical libraries across diverse biological processes. AB - This corrects the article DOI: 10.1038/nchembio.2436. PMID- 29161249 TI - Genetic code expansion: Synthetases pick up the PACE. PMID- 29161250 TI - Host-pathogen interactions: A ubiquitin defense. PMID- 29161251 TI - Enzymology: I want my cluster back. PMID- 29161252 TI - Choose, rate or squeeze: Comparison of economic value functions elicited by different behavioral tasks. AB - A standard view in neuroeconomics is that to make a choice, an agent first assigns subjective values to available options, and then compares them to select the best. In choice tasks, these cardinal values are typically inferred from the preference expressed by subjects between options presented in pairs. Alternatively, cardinal values can be directly elicited by asking subjects to place a cursor on an analog scale (rating task) or to exert a force on a power grip (effort task). These tasks can vary in many respects: they can notably be more or less costly and consequential. Here, we compared the value functions elicited by choice, rating and effort tasks on options composed of two monetary amounts: one for the subject (gain) and one for a charity (donation). Bayesian model selection showed that despite important differences between the three tasks, they all elicited a same value function, with similar weighting of gain and donation, but variable concavity. Moreover, value functions elicited by the different tasks could predict choices with equivalent accuracy. Our finding therefore suggests that comparable value functions can account for various motivated behaviors, beyond economic choice. Nevertheless, we report slight differences in the computational efficiency of parameter estimation that may guide the design of future studies. PMID- 29161253 TI - Mutualism in museums: A model for engaging undergraduates in biodiversity science. AB - Museums have an untapped potential to engage students in hands-on learning. Here, we describe the development of a tiered museum-based program at the University of California, Berkeley as a model for engaging undergraduates in biodiversity science. This decade-long effort to increase student participation in collections demonstrates the mutual benefits of undergraduate involvement. Museums benefit from critical help in collections care and an increased intellectual vitality, while students simultaneously gain essential research skills and an unparalleled exposure to biodiversity. Five first steps to creating a program are: dedicate a coordinator, offer credit, diversify participation, create a tiered structure, and build community. PMID- 29161254 TI - Lansoprazole use and tuberculosis incidence in the United Kingdom Clinical Practice Research Datalink: A population based cohort. AB - BACKGROUND: Recent in vitro and animal studies have found the proton pump inhibitor (PPI) lansoprazole to be highly active against Mycobacterium tuberculosis. Omeprazole and pantoprazole have no activity. There is no evidence that, in clinical practice, lansoprazole can treat or prevent incident tuberculosis (TB) disease. METHODS AND FINDINGS: We studied a cohort of new users of lansoprazole, omeprazole, or pantoprazole from the United Kingdom Clinical Practice Research Datalink to determine whether lansoprazole users have a lower incidence of TB disease than omeprazole or pantoprazole users. Negative control outcomes of myocardial infarction (MI) and herpes zoster were also studied. Multivariable Cox proportional hazards regression was used to adjust for potential confounding by a wide range of factors. We identified 527,364 lansoprazole initiators and 923,500 omeprazole or pantoprazole initiators. Lansoprazole users had a lower rate of TB disease (n = 86; 10.0 cases per 100,000 person years; 95% confidence interval 8.1-12.4) than omeprazole or pantoprazole users (n = 193; 15.3 cases per 100,000 person years; 95% confidence interval 13.3 17.7), with an adjusted hazard ratio (HR) of 0.68 (0.52-0.89). No association was found with MI (adjusted HR 1.04; 95% confidence interval 1.00-1.08) or herpes zoster (adjusted HR 1.03; 95% confidence interval 1.00-1.06). Limitations of this study are that we could not determine whether TB disease was due to reactivation of latent infection or a result of recent transmission, nor could we determine whether lansoprazole would have a beneficial effect if given to people presenting with TB disease. CONCLUSIONS: In this study, use of the commonly prescribed and cheaply available PPI lansoprazole was associated with reduced incidence of TB disease. Given the serious problem of drug resistance and the adverse side effect profiles of many TB drugs, further investigation of lansoprazole as a potential antituberculosis agent is warranted. PMID- 29161255 TI - Neurogenic mediators contribute to local edema induced by Micrurus lemniscatus venom. AB - BACKGROUND/AIMS: Micrurus is one of the four snake genera of medical importance in Brazil. Coral snakes have a broad geographic distribution from the southern United States to Argentina. Micrurine envenomation is characterized by neurotoxic symptoms leading to dyspnea and death. Moreover, various local manifestations, including edema formation, have been described in patients bitten by different species of Micrurus. Thus, we investigated the ability of Micrurus lemniscatus venom (MLV) to induce local edema. We also explored mechanisms underlying this effect, focusing on participation of neuropeptides and mast cells. METHODOLOGY/PRINCIPAL FINDINGS: Intraplantar injection of MLV (1-10 MUg/paw) in rats caused dose- and time-dependent edema with a peak between 15 min and 1 h after injection. MLV also induced degranulation of peritoneal mast cells (MCs). MC depletion by compound 48/80 markedly reduced MLV-induced edema. Pre-treatment (30 min) of rats with either promethazine a histamine H1 receptor antagonist or methysergide, a nonselective 5-HT receptor antagonist, reduced MLV-induced edema. However, neither thioperamide, a histamine H3/H4 receptor antagonist, nor co injection of MLV with HOE-140, a BK2 receptor antagonist, altered the response. Depletion of neuropeptides by capsaicin or treatment of animals with NK1- and NK2 receptor antagonists (SR 140333 and SR 48968, respectively) markedly reduced MLV induced edema. CONCLUSIONS/SIGNIFICANCE: In conclusion, MLV induces paw edema in rats by mechanisms involving activation of mast cells and substance P-releasing sensory C-fibers. Tachykinins NKA and NKB, histamine, and serotonin are major mediators of the MLV-induced edematogenic response. Targeting mast cell- and sensory C-fiber-derived mediators should be considered as potential therapeutic approaches to interrupt development of local edema induced by Micrurus venoms. PMID- 29161256 TI - HIV pre-exposure prophylaxis and early antiretroviral treatment among female sex workers in South Africa: Results from a prospective observational demonstration project. AB - BACKGROUND: Operational research is required to design delivery of pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART). This paper presents the primary analysis of programmatic data, as well as demographic, behavioural, and clinical data, from the TAPS Demonstration Project, which offered both interventions to female sex workers (FSWs) at 2 urban clinic sites in South Africa. METHODS AND FINDINGS: The TAPS study was conducted between 30 March 2015 and 30 June 2017, with the enrolment period ending on 31 July 2016. TAPS was a prospective observational cohort study with 2 groups receiving interventions delivered in existing service settings: (1) PrEP as part of combination prevention for HIV-negative FSWs and (2) early ART for HIV-positive FSWs. The main outcome was programme retention at 12 months of follow-up. Of the 947 FSWs initially seen in clinic, 692 were HIV tested. HIV prevalence was 49%. Among those returning to clinic after HIV testing and clinical screening, 93% of the women who were HIV-negative were confirmed as clinically eligible for PrEP (n = 224/241), and 41% (n = 110/270) of the women who were HIV-positive had CD4 counts within National Department of Health ART initiation guidelines at assessment. Of the remaining women who were HIV-positive, 93% were eligible for early ART (n = 148/160). From those eligible, 98% (n = 219/224) and 94% (n = 139/148) took up PrEP and early ART, respectively. At baseline, a substantial fraction of women had a steady partner, worked in brothels, and were born in Zimbabwe. Of those enrolled, 22% on PrEP (n = 49/219) and 60% on early ART (n = 83/139) were seen at 12 months; we observed high rates of loss to follow-up: 71% (n = 156/219) and 30% (n = 42/139) in the PrEP and early ART groups, respectively. Little change over time was reported in consistent condom use or the number of sexual partners in the last 7 days, with high levels of consistent condom use with clients and low use with steady partners in both study groups. There were no seroconversions on PrEP and 7 virological failures on early ART among women remaining in the study. Reported adherence to PrEP varied over time between 70% and 85%, whereas over 90% of participants reported taking pills daily while on early ART. Data on provider side costs were also collected and analysed. The total cost of service delivery was approximately US$126 for PrEP and US$406 for early ART per person-year. The main limitations of this study include the lack of a control group, which was not included due to ethical considerations; clinical study requirements imposed when PrEP was not approved through the regulatory system, which could have affected uptake; and the timing of the implementation of a national sex worker HIV programme, which could have also affected uptake and retention. CONCLUSIONS: PrEP and early ART services can be implemented within FSW routine services in high prevalence, urban settings. We observed good uptake for both PrEP and early ART; however, retention rates for PrEP were low. Retention rates for early ART were similar to retention rates for the current standard of care. While the cost of the interventions was higher than previously published, there is potential for cost reduction at scale. The TAPS Demonstration Project results provided the basis for the first government PrEP and early ART guidelines and the rollout of the national sex worker HIV programme in South Africa. PMID- 29161257 TI - Regulation of cAMP and GSK3 signaling pathways contributes to the neuronal conversion of glioma. AB - Glioma is the most malignant type of primary central nervous system tumors, and has an extremely poor prognosis. One potential therapeutic approach is to induce the terminal differentiation of glioma through the forced expression of pro neural factors. Our goal is to show the proof of concept of the neuronal conversion of C6 glioma through the combined action of small molecules. We investigated the various changes in gene expression, cell-specific marker expression, signaling pathways, physiological characteristics, and morphology in glioma after combination treatment with two small molecules (CHIR99021, a glycogen synthase kinase 3 [GSK3] inhibitor and forskolin, a cyclic adenosine monophosphate [cAMP] activator). Here, we show that the combined action of CHIR99021 and forskolin converted malignant glioma into fully differentiated neurons with no malignant characteristics; inhibited the proliferation of malignant glioma; and significantly down-regulated gene ontology and gene expression profiles related to cell division, gliogenesis, and angiogenesis in small molecule-induced neurons. In vivo, the combined action of CHIR99021 and forskolin markedly delayed neurological deficits and significantly reduced the tumor volume. We suggest that reprogramming technology may be a potential treatment strategy replacing the therapeutic paradigm of traditional treatment of malignant glioma, and a combination molecule comprising a GSK3 inhibitor and a cAMP inducer could be the next generation of anticancer drugs. PMID- 29161258 TI - Insulin resistance and hyperandrogenism drive steatosis and fibrosis risk in young females with PCOS. AB - BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) recognize obesity and insulin resistance (IR) as common pathogenic background. We assessed 1) whether PCOS is a risk factor for steatosis, and 2) the impact, in PCOS patients, of IR and hyperandrogenism on steatosis and fibrosis. METHODS: We considered 202 consecutive Italian PCOS nondiabetic patients and 101 age-matched controls. PCOS was diagnosed applying the Rotterdam diagnostic criteria. Steatosis was diagnosed if hepatic steatosis index (HSI) >36, while fibrosis by using the FIB-4 score. As surrogate estimate of insulin sensitivity we considered the insulin sensitivity index (ISI). Free androgen index (FAI) was calculated as estimate of biochemical hyperandrogenism. RESULTS: In the entire population, steatosis was observed in 68.8% of patients with PCOS, compared to 33.3 of controls (p<0.001), this association being maintained after adjusting for metabolic confounders (OR 3.73, 95% CI 1.74-8.02; P = 0.001). In PCOS patients, steatosis was independently linked to WC (OR 1.04, 95% CI 1.01-1.08; P = 0.006) and ISI Matsuda (OR 0.69, 95% CI 0.53-0.88; P = 0.004), not to free androgen index (OR 1.10, 95% CI 0.96-1.26; P = 0.14). Notably, ISI Matsuda was confirmed as independently associated with steatosis in both obese (OR 0.42, 95% CI 0.23-0.77, P = 0.005) and nonobese (OR 0.69, 95% CI 0.53-0.91, P = 0.009), patients, while FAI (OR 1.45, 95% CI 1.12-1.87; P = 0.004) emerged as an independent risk factor only in nonobese PCOS. Similarly, higher FIB-4 was independently associated with higher FAI (p = 0.02) in nonobese and with lower ISI Matsuda (p = 0.04) in obese patients. CONCLUSIONS: We found that PCOS is an independent risk factor for steatosis, and that, IR and hyperandrogenism, this last especially in nonobese patients, are the key players of liver damage in PCOS. PMID- 29161259 TI - The US President's Malaria Initiative, Plasmodium falciparum transmission and mortality: A modelling study. AB - BACKGROUND: Although significant progress has been made in reducing malaria transmission globally in recent years, a large number of people remain at risk and hence the gains made are fragile. Funding lags well behind amounts needed to protect all those at risk and ongoing contributions from major donors, such as the President's Malaria Initiative (PMI), are vital to maintain progress and pursue further reductions in burden. We use a mathematical modelling approach to estimate the impact of PMI investments to date in reducing malaria burden and to explore the potential negative impact on malaria burden should a proposed 44% reduction in PMI funding occur. METHODS AND FINDINGS: We combined an established mathematical model of Plasmodium falciparum transmission dynamics with epidemiological, intervention, and PMI-financing data to estimate the contribution PMI has made to malaria control via funding for long-lasting insecticide treated nets (LLINs), indoor residual spraying (IRS), and artemisinin combination therapies (ACTs). We estimate that PMI has prevented 185 million (95% CrI: 138 million, 230 million) malaria cases and saved 940,049 (95% CrI: 545,228, 1.4 million) lives since 2005. If funding is maintained, PMI-funded interventions are estimated to avert a further 162 million (95% CrI: 116 million, 194 million) cases, saving a further 692,589 (95% CrI: 392,694, 955,653) lives between 2017 and 2020. With an estimate of US$94 (95% CrI: US$51, US$166) per Disability Adjusted Life Year (DALY) averted, PMI-funded interventions are highly cost effective. We also demonstrate the further impact of this investment by reducing caseloads on health systems. If a 44% reduction in PMI funding were to occur, we predict that this loss of direct aid could result in an additional 67 million (95% CrI: 49 million, 82 million) cases and 290,649 (95% CrI: 167,208, 395,263) deaths between 2017 and 2020. We have not modelled indirect impacts of PMI funding (such as health systems strengthening) in this analysis. CONCLUSIONS: Our model estimates that PMI has played a significant role in reducing malaria cases and deaths since its inception. Reductions in funding to PMI could lead to large increases in the number of malaria cases and deaths, damaging global goals of malaria control and elimination. PMID- 29161260 TI - HIV self-testing among female sex workers in Zambia: A cluster randomized controlled trial. AB - BACKGROUND: HIV self-testing (HIVST) may play a role in addressing gaps in HIV testing coverage and as an entry point for HIV prevention services. We conducted a cluster randomized trial of 2 HIVST distribution mechanisms compared to the standard of care among female sex workers (FSWs) in Zambia. METHODS AND FINDINGS: Trained peer educators in Kapiri Mposhi, Chirundu, and Livingstone, Zambia, each recruited 6 FSW participants. Peer educator-FSW groups were randomized to 1 of 3 arms: (1) delivery (direct distribution of an oral HIVST from the peer educator), (2) coupon (a coupon for collection of an oral HIVST from a health clinic/pharmacy), or (3) standard-of-care HIV testing. Participants in the 2 HIVST arms received 2 kits: 1 at baseline and 1 at 10 weeks. The primary outcome was any self-reported HIV testing in the past month at the 1- and 4-month visits, as HIVST can replace other types of HIV testing. Secondary outcomes included linkage to care, HIVST use in the HIVST arms, and adverse events. Participants completed questionnaires at 1 and 4 months following peer educator interventions. In all, 965 participants were enrolled between September 16 and October 12, 2016 (delivery, N = 316; coupon, N = 329; standard of care, N = 320); 20% had never tested for HIV. Overall HIV testing at 1 month was 94.9% in the delivery arm, 84.4% in the coupon arm, and 88.5% in the standard-of-care arm (delivery versus standard of care risk ratio [RR] = 1.07, 95% CI 0.99-1.15, P = 0.10; coupon versus standard of care RR = 0.95, 95% CI 0.86-1.05, P = 0.29; delivery versus coupon RR = 1.13, 95% CI 1.04-1.22, P = 0.005). Four-month rates were 84.1% for the delivery arm, 79.8% for the coupon arm, and 75.1% for the standard-of-care arm (delivery versus standard of care RR = 1.11, 95% CI 0.98-1.27, P = 0.11; coupon versus standard of care RR = 1.06, 95% CI 0.92-1.22, P = 0.42; delivery versus coupon RR = 1.05, 95% CI 0.94-1.18, P = 0.40). At 1 month, the majority of HIV tests were self-tests (88.4%). HIV self-test use was higher in the delivery arm compared to the coupon arm (RR = 1.14, 95% CI 1.05-1.23, P = 0.001) at 1 month, but there was no difference at 4 months. Among participants reporting a positive HIV test at 1 (N = 144) and 4 months (N = 235), linkage to care was non significantly lower in the 2 HIVST arms compared to the standard-of-care arm. There were 4 instances of intimate partner violence related to study participation, 3 of which were related to HIV self-test use. Limitations include the self-reported nature of study outcomes and overall high uptake of HIV testing. CONCLUSIONS: In this study among FSWs in Zambia, we found that HIVST was acceptable and accessible. However, HIVST may not substantially increase HIV cascade progression in contexts where overall testing and linkage are already high. TRIAL REGISTRATION: ClinicalTrials.gov NCT02827240. PMID- 29161261 TI - mRNA processing in mutant zebrafish lines generated by chemical and CRISPR mediated mutagenesis produces unexpected transcripts that escape nonsense mediated decay. AB - As model organism-based research shifts from forward to reverse genetics approaches, largely due to the ease of genome editing technology, a low frequency of abnormal phenotypes is being observed in lines with mutations predicted to lead to deleterious effects on the encoded protein. In zebrafish, this low frequency is in part explained by compensation by genes of redundant or similar function, often resulting from the additional round of teleost-specific whole genome duplication within vertebrates. Here we offer additional explanations for the low frequency of mutant phenotypes. We analyzed mRNA processing in seven zebrafish lines with mutations expected to disrupt gene function, generated by CRISPR/Cas9 or ENU mutagenesis methods. Five of the seven lines showed evidence of altered mRNA processing: one through a skipped exon that did not lead to a frame shift, one through nonsense-associated splicing that did not lead to a frame shift, and three through the use of cryptic splice sites. These results highlight the need for a methodical analysis of the mRNA produced in mutant lines before making conclusions or embarking on studies that assume loss of function as a result of a given genomic change. Furthermore, recognition of the types of adaptations that can occur may inform the strategies of mutant generation. PMID- 29161262 TI - The value of confirmatory testing in early infant HIV diagnosis programmes in South Africa: A cost-effectiveness analysis. AB - BACKGROUND: The specificity of nucleic acid amplification tests (NAATs) used for early infant diagnosis (EID) of HIV infection is <100%, leading some HIV uninfected infants to be incorrectly identified as HIV-infected. The World Health Organization recommends that infants undergo a second NAAT to confirm any positive test result, but implementation is limited. Our objective was to determine the impact and cost-effectiveness of confirmatory HIV testing for EID programmes in South Africa. METHOD AND FINDINGS: Using the Cost-effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, we simulated EID testing at age 6 weeks for HIV-exposed infants without and with confirmatory testing. We assumed a NAAT cost of US$25, NAAT specificity of 99.6%, NAAT sensitivity of 100% for infants infected in pregnancy or at least 4 weeks prior to testing, and a mother-to-child transmission (MTCT) rate at 12 months of 4.9%; we simulated guideline-concordant rates of testing uptake, result return, and antiretroviral therapy (ART) initiation (100%). After diagnosis, infants were linked to and retained in care for 10 years (false-positive) or lifelong (true-positive). All parameters were varied widely in sensitivity analyses. Outcomes included number of infants with false-positive diagnoses linked to ART per 1,000 ART initiations, life expectancy (LE, in years) and per-person lifetime HIV-related healthcare costs. Both without and with confirmatory testing, LE was 26.2 years for HIV infected infants and 61.4 years for all HIV-exposed infants; clinical outcomes for truly infected infants did not differ by strategy. Without confirmatory testing, 128/1,000 ART initiations were false-positive diagnoses; with confirmatory testing, 1/1,000 ART initiations were false-positive diagnoses. Because confirmatory testing averted costly HIV care and ART in truly HIV uninfected infants, it was cost-saving: total cost US$1,790/infant tested, compared to US$1,830/infant tested without confirmatory testing. Confirmatory testing remained cost-saving unless NAAT cost exceeded US$400 or the HIV uninfected status of infants incorrectly identified as infected was ascertained and ART stopped within 3 months of starting. Limitations include uncertainty in the data used in the model, which we examined with sensitivity and uncertainty analyses. We also excluded clinical harms to HIV-uninfected infants incorrectly treated with ART after false-positive diagnosis (e.g., medication toxicities); including these outcomes would further increase the value of confirmatory testing. CONCLUSIONS: Without confirmatory testing, in settings with MTCT rates similar to that of South Africa, more than 10% of infants who initiate ART may reflect false-positive diagnoses. Confirmatory testing prevents inappropriate HIV diagnosis, is cost-saving, and should be adopted in all EID programmes. PMID- 29161263 TI - The nucleoid as a scaffold for the assembly of bacterial signaling complexes. AB - The FrzCD chemoreceptor from the gliding bacterium Myxococcus xanthus forms cytoplasmic clusters that occupy a large central region of the cell body also occupied by the nucleoid. In this work, we show that FrzCD directly binds to the nucleoid with its N-terminal positively charged tail and recruits active signaling complexes at this location. The FrzCD binding to the nucleoid occur in a DNA-sequence independent manner and leads to the formation of multiple distributed clusters that explore constrained areas. This organization might be required for cooperative interactions between clustered receptors as observed in membrane-bound chemosensory arrays. PMID- 29161265 TI - Closing the gaps in the HIV care continuum. AB - In a Perspective, Ruanne Barnabas and Connie Celum discuss the implications of the accompanying Link4Health and Engage4Health studies for HIV care in sub Saharan Africa. PMID- 29161264 TI - Proprioceptive assessment in clinical settings: Evaluation of joint position sense in upper limb post-stroke using a robotic manipulator. AB - Proprioception is a critical component for motor functions and directly affects motor learning after neurological injuries. Conventional methods for its assessment are generally ordinal in nature and hence lack sensitivity. Robotic devices designed to promote sensorimotor learning can potentially provide quantitative precise, accurate, and reliable assessments of sensory impairments. In this paper, we investigate the clinical applicability and validity of using a planar 2 degrees of freedom robot to quantitatively assess proprioceptive deficits in post-stroke participants. Nine stroke survivors and nine healthy subjects participated in the study. Participants' hand was passively moved to the target position guided by the H-Man robot (Criterion movement) and were asked to indicate during a second passive movement towards the same target (Matching movement) when they felt that they matched the target position. The assessment was carried out on a planar surface for movements in the forward and oblique directions in the contralateral and ipsilateral sides of the tested arm. The matching performance was evaluated in terms of error magnitude (absolute and signed) and its variability. Stroke patients showed higher variability in the estimation of the target position compared to the healthy participants. Further, an effect of target was found, with lower absolute errors in the contralateral side. Pairwise comparison between individual stroke participant and control participants showed significant proprioceptive deficits in two patients. The proposed assessment of passive joint position sense was inherently simple and all participants, regardless of motor impairment level, could complete it in less than 10 minutes. Therefore, the method can potentially be carried out to detect changes in proprioceptive deficits in clinical settings. PMID- 29161266 TI - Knowledge-based prediction of protein backbone conformation using a structural alphabet. AB - Libraries of structural prototypes that abstract protein local structures are known as structural alphabets and have proven to be very useful in various aspects of protein structure analyses and predictions. One such library, Protein Blocks, is composed of 16 standard 5-residues long structural prototypes. This form of analyzing proteins involves drafting its structure as a string of Protein Blocks. Predicting the local structure of a protein in terms of protein blocks is the general objective of this work. A new approach, PB-kPRED is proposed towards this aim. It involves (i) organizing the structural knowledge in the form of a database of pentapeptide fragments extracted from all protein structures in the PDB and (ii) applying a knowledge-based algorithm that does not rely on any secondary structure predictions and/or sequence alignment profiles, to scan this database and predict most probable backbone conformations for the protein local structures. Though PB-kPRED uses the structural information from homologues in preference, if available. The predictions were evaluated rigorously on 15,544 query proteins representing a non-redundant subset of the PDB filtered at 30% sequence identity cut-off. We have shown that the kPRED method was able to achieve mean accuracies ranging from 40.8% to 66.3% depending on the availability of homologues. The impact of the different strategies for scanning the database on the prediction was evaluated and is discussed. Our results highlight the usefulness of the method in the context of proteins without any known structural homologues. A scoring function that gives a good estimate of the accuracy of prediction was further developed. This score estimates very well the accuracy of the algorithm (R2 of 0.82). An online version of the tool is provided freely for non-commercial usage at http://www.bo-protscience.fr/kpred/. PMID- 29161267 TI - Sugar industry sponsorship of germ-free rodent studies linking sucrose to hyperlipidemia and cancer: An historical analysis of internal documents. AB - In 1965, the Sugar Research Foundation (SRF) secretly funded a review in the New England Journal of Medicine that discounted evidence linking sucrose consumption to blood lipid levels and hence coronary heart disease (CHD). SRF subsequently funded animal research to evaluate sucrose's CHD risks. The objective of this study was to examine the planning, funding, and internal evaluation of an SRF funded research project titled "Project 259: Dietary Carbohydrate and Blood Lipids in Germ-Free Rats," led by Dr. W.F.R. Pover at the University of Birmingham, Birmingham, United Kingdom, between 1967 and 1971. A narrative case study method was used to assess SRF Project 259 from 1967 to 1971 based on sugar industry internal documents. Project 259 found a statistically significant decrease in serum triglycerides in germ-free rats fed a high sugar diet compared to conventional rats fed a basic PRM diet (a pelleted diet containing cereal meals, soybean meals, whitefish meal, and dried yeast, fortified with a balanced vitamin supplement and trace element mixture). The results suggested to SRF that gut microbiota have a causal role in carbohydrate-induced hypertriglyceridemia. A study comparing conventional rats fed a high-sugar diet to those fed a high starch diet suggested that sucrose consumption might be associated with elevated levels of beta-glucuronidase, an enzyme previously associated with bladder cancer in humans. SRF terminated Project 259 without publishing the results. The sugar industry did not disclose evidence of harm from animal studies that would have (1) strengthened the case that the CHD risk of sucrose is greater than starch and (2) caused sucrose to be scrutinized as a potential carcinogen. The influence of the gut microbiota in the differential effects of sucrose and starch on blood lipids, as well as the influence of carbohydrate quality on beta-glucuronidase and cancer activity, deserve further scrutiny. PMID- 29161268 TI - Nucleic acid purification from plants, animals and microbes in under 30 seconds. AB - Nucleic acid amplification is a powerful molecular biology tool, although its use outside the modern laboratory environment is limited due to the relatively cumbersome methods required to extract nucleic acids from biological samples. To address this issue, we investigated a variety of materials for their suitability for nucleic acid capture and purification. We report here that untreated cellulose-based paper can rapidly capture nucleic acids within seconds and retain them during a single washing step, while contaminants present in complex biological samples are quickly removed. Building on this knowledge, we have successfully created an equipment-free nucleic acid extraction dipstick methodology that can obtain amplification-ready DNA and RNA from plants, animals, and microbes from difficult biological samples such as blood and leaves from adult trees in less than 30 seconds. The simplicity and speed of this method as well as the low cost and availability of suitable materials (e.g., common paper towelling), means that nucleic acid extraction is now more accessible and affordable for researchers and the broader community. Furthermore, when combined with recent advancements in isothermal amplification and naked eye DNA visualization techniques, the dipstick extraction technology makes performing molecular diagnostic assays achievable in limited resource settings including university and high school classrooms, field-based environments, and developing countries. PMID- 29161270 TI - Tracking urban human activity from mobile phone calling patterns. AB - Timings of human activities are marked by circadian clocks which in turn are entrained to different environmental signals. In an urban environment the presence of artificial lighting and various social cues tend to disrupt the natural entrainment with the sunlight. However, it is not completely understood to what extent this is the case. Here we exploit the large-scale data analysis techniques to study the mobile phone calling activity of people in large cities to infer the dynamics of urban daily rhythms. From the calling patterns of about 1,000,000 users spread over different cities but lying inside the same time-zone, we show that the onset and termination of the calling activity synchronizes with the east-west progression of the sun. We also find that the onset and termination of the calling activity of users follows a yearly dynamics, varying across seasons, and that its timings are entrained to solar midnight. Furthermore, we show that the average mid-sleep time of people living in urban areas depends on the age and gender of each cohort as a result of biological and social factors. PMID- 29161269 TI - Identifying influential neighbors in animal flocking. AB - Schools of fish and flocks of birds can move together in synchrony and decide on new directions of movement in a seamless way. This is possible because group members constantly share directional information with their neighbors. Although detecting the directionality of other group members is known to be important to maintain cohesion, it is not clear how many neighbors each individual can simultaneously track and pay attention to, and what the spatial distribution of these influential neighbors is. Here, we address these questions on shoals of Hemigrammus rhodostomus, a species of fish exhibiting strong schooling behavior. We adopt a data-driven analysis technique based on the study of short-term directional correlations to identify which neighbors have the strongest influence over the participation of an individual in a collective U-turn event. We find that fish mainly react to one or two neighbors at a time. Moreover, we find no correlation between the distance rank of a neighbor and its likelihood to be influential. We interpret our results in terms of fish allocating sequential and selective attention to their neighbors. PMID- 29161271 TI - A mathematical function for the description of nutrient-response curve. AB - Several mathematical equations have been proposed to modeling nutrient-response curve for animal and human justified on the goodness of fit and/or on the biological mechanism. In this paper, a functional form of a generalized quantitative model based on Rayleigh distribution principle for description of nutrient-response phenomena is derived. The three parameters governing the curve a) has biological interpretation, b) may be used to calculate reliable estimates of nutrient response relationships, and c) provide the basis for deriving relationships between nutrient and physiological responses. The new function was successfully applied to fit the nutritional data obtained from 6 experiments including a wide range of nutrients and responses. An evaluation and comparison were also done based simulated data sets to check the suitability of new model and four-parameter logistic model for describing nutrient responses. This study indicates the usefulness and wide applicability of the new introduced, simple and flexible model when applied as a quantitative approach to characterizing nutrient response curve. This new mathematical way to describe nutritional-response data, with some useful biological interpretations, has potential to be used as an alternative approach in modeling nutritional responses curve to estimate nutrient efficiency and requirements. PMID- 29161272 TI - Global transcriptome profile reveals abundance of DNA damage response and repair genes in individuals from high level natural radiation areas of Kerala coast. AB - The high level natural radiation areas (HLNRA) of Kerala coast in south west India is unique for its wide variation in the background radiation dose (<1.0mGy to 45mGy/year) and vast population size. Several biological studies conducted in this area did not reveal any adverse effects of chronic low dose and low dose rate radiation on human population. In the present study, global transcriptome analysis was carried out in peripheral blood mono-nuclear cells of 36 individuals belonging to different background dose groups [NLNRA, (Group I, <=1.50 mGy/year) and three groups of HLNRA; Group II, 1.51-5.0 mGy/year), Group III, 5.01 15mGy/year and Group IV, >15.0 mGy/year] to find out differentially expressed genes and their biological significance in response to chronic low dose radiation exposure. Our results revealed a dose dependent increase in the number of differentially expressed genes with respect to different background dose levels. Gene ontology analysis revealed majority of these differentially expressed genes are involved in DNA damage response (DDR) signaling, DNA repair, cell cycle arrest, apoptosis, histone/chromatin modification and immune response. In the present study, 64 background dose responsive genes have been identified as possible chronic low dose radiation signatures. Validation of 30 differentially expressed genes was carried out using fluorescent based universal probe library. Abundance of DDR and DNA repair genes along with pathways such as MAPK, p53 and JNK in higher background dose groups (> 5.0mGy/year) indicated a possible threshold dose for DDR signaling and are plausible reason of observing in vivo radio-adaptive response and non-carcinogenesis in HLNRA population. To our knowledge, this is the first study on molecular effect of chronic low dose radiation exposure on human population from high background radiation areas at transcriptome level using high throughput approach. These findings have tremendous implications in understanding low dose radiation biology especially, the effect of low dose radiation exposure in humans. PMID- 29161273 TI - Enrichment of colorectal cancer associations in functional regions: Insight for using epigenomics data in the analysis of whole genome sequence-imputed GWAS data. AB - BACKGROUND: The evaluation of less frequent genetic variants and their effect on complex disease pose new challenges for genomic research. To investigate whether epigenetic data can be used to inform aggregate rare-variant association methods (RVAM), we assessed whether variants more significantly associated with colorectal cancer (CRC) were preferentially located in non-coding regulatory regions, and whether enrichment was specific to colorectal tissues. METHODS: Active regulatory elements (ARE) were mapped using data from 127 tissues and cell types from NIH Roadmap Epigenomics and Encyclopedia of DNA Elements (ENCODE) projects. We investigated whether CRC association p-values were more significant for common variants inside versus outside AREs, or 2) inside colorectal (CR) AREs versus AREs of other tissues and cell-types. We employed an integrative epigenomic RVAM for variants with allele frequency <1%. Gene sets were defined as ARE variants within 200 kilobases of a transcription start site (TSS) using either CR ARE or ARE from non-digestive tissues. CRC-set association p-values were used to evaluate enrichment of less frequent variant associations in CR ARE versus non-digestive ARE. RESULTS: ARE from 126/127 tissues and cell-types were significantly enriched for stronger CRC-variant associations. Strongest enrichment was observed for digestive tissues and immune cell types. CR-specific ARE were also enriched for stronger CRC-variant associations compared to ARE combined across non-digestive tissues (p-value = 9.6 * 10-4). Additionally, we found enrichment of stronger CRC association p-values for rare variant sets of CR ARE compared to non-digestive ARE (p-value = 0.029). CONCLUSIONS: Integrative epigenomic RVAM may enable discovery of less frequent variants associated with CRC, and ARE of digestive and immune tissues are most informative. Although distance-based aggregation of less frequent variants in CR ARE surrounding TSS showed modest enrichment, future association studies would likely benefit from joint analysis of transcriptomes and epigenomes to better link regulatory variation with target genes. PMID- 29161274 TI - Bacillus spp., a bio-control agent enhances the activity of antioxidant defense enzymes in rice against Pyricularia oryzae. AB - Plant growth promoting rhizobacteria (PGPR) are found to control the plant diseases by adopting various mechanisms. Induced systemic resistance (ISR) is an important defensive strategy manifested by plants against numerous pathogens especially infecting at aerial parts. Rhizobacteria elicit ISR by inducing different pathways in plants through production of various metabolites. In the present study, potential of Bacillus spp. KFP-5, KFP-7, KFP-17 was assessed to induce antioxidant enzymes against Pyricularia oryzae infection in rice. The antagonistic Bacillus spp. significantly induced antioxidant defense enzymes i-e superoxide dismutase (1.7-1.9-fold), peroxidase (3.5-4.1-fold), polyphenol oxidase (3.0-3.8-fold), phenylalanine ammonia-lyase (3.9-4.4-fold), in rice leaves and roots under hydroponic and soil conditions respectively. Furthermore, the antagonistic Bacillus spp significantly colonized the rice plants (2.0E+00 9.1E+08) and secreted multiple biocontrol determinants like protease (1.1-5.5 U/mg of soil or U/mL of hydroponic solution), glucanase, (1.0-1.3 U/mg of soil or U/mL of hydroponic solution), siderophores (6.5-42.8 MUg/mL or mg) in the rhizosphere of different rice varieties. The results showed that treatment with Bacillus spp. enhanced the antioxidant defense activities in infected rice, thus alleviating P. oryzae induced oxidative damage and suppressing blast disease incidence. PMID- 29161275 TI - HIV prevalence and behavioral risk factors in the Sudan People's Liberation Army: Data from South Sudan. AB - OVERVIEW: After two decades of civil war, South Sudan has limited published data on HIV prevalence and behavioral determinants of HIV infection risk. A surge in HIV/AIDS prevalence is a real concern for this new country with limited access to medical or HIV preventive services, and low education and literacy levels. We present findings from the first bio-behavioral surveillance survey conducted within the Sudan People's Liberation Army (SPLA). METHODS: A cross-sectional survey of 1,149 randomly selected soldiers from thirteen SPLA bases was conducted in two phases: July to August 2010 and April to May 2012. Consenting participants received HIV rapid tests, pre- and post-test counseling, and a personal interview. Demographics, knowledge, attitudes, and behaviors, including sexual behavior, alcohol use, and mental health were assessed using computer-assisted interviews. FINDINGS: The final sample included 1,063 survey participants (96.7% male). Education levels within the SPLA are low; only 16.4% attended school beyond the primary level. The overall HIV prevalence in the sample was 5.0% (95% confidence interval [CI]: 3.6-6.9). High-risk behaviors (e.g., multiple or concurrent sexual partners, heavy alcohol use, low condom use) were noted among SPLA members. High levels of HIV stigma were identified: 90.6% (n = 916) responded with one or more negative beliefs towards PLHIV, and 60.3% thought a healthy-looking person with HIV should not be allowed to remain in the SPLA. CONCLUSION: Results from this first evaluation of risk behaviors and HIV prevalence among the SPLA highlight high-risk behaviors that may contribute to the spread of HIV. Understanding potential comorbid conditions will be critical to designing strategies to reduce HIV risk. This survey represents the first steps in understanding the HIV epidemic within the SPLA context. PMID- 29161276 TI - Association between diabetes mellitus and active tuberculosis: A systematic review and meta-analysis. AB - The burgeoning epidemic of diabetes mellitus (DM) is one of the major global health challenges. We systematically reviewed the published literature to provide a summary estimate of the association between DM and active tuberculosis (TB). We searched Medline and EMBASE databases for studies reporting adjusted estimates on the TB-DM association published before December 22, 2015, with no restrictions on region and language. In the meta-analysis, adjusted estimates were pooled using a DerSimonian-Laird random-effects model, according to study design. Risk of bias assessment and sensitivity analyses were conducted. 44 eligible studies were included, which consisted of 58,468,404 subjects from 16 countries. Compared with non-DM patients, DM patients had 3.59-fold (95% confidence interval (CI) 2.25 5.73), 1.55-fold (95% CI 1.39-1.72), and 2.09-fold (95% CI 1.71-2.55) increased risk of active TB in four prospective, 16 retrospective, and 17 case-control studies, respectively. Country income level (3.16-fold in low/middle-vs. 1.73 fold in high-income countries), background TB incidence (2.05-fold in countries with >50 vs. 1.89-fold in countries with <=50 TB cases per 100,000 person-year), and geographical region (2.44-fold in Asia vs. 1.71-fold in Europe and 1.73-fold in USA/Canada) affected appreciably the estimated association, but potential risk of bias, type of population (general versus clinical), and potential for duplicate data, did not. Microbiological ascertainment for TB (3.03-fold) and/or blood testing for DM (3.10-fold), as well as uncontrolled DM (3.30-fold), resulted in stronger estimated association. DM is associated with a two- to four fold increased risk of active TB. The association was stronger when ascertainment was based on biological testing rather than medical records or self-report. The burgeoning DM epidemic could impact upon the achievements of the WHO "End TB Strategy" for reducing TB incidence. PMID- 29161277 TI - Women's opinion on the justification of physical spousal violence: A quantitative approach to model the most vulnerable households in Bangladesh. AB - Bangladesh is a culturally conservative nation with limited freedom for women. A number of studies have evaluated intimate partner violence (IPV) and spousal physical violence in Bangladesh; however, the views of women have been rarely discussed in a quantitative manner. Three nationwide surveys in Bangladesh (2007, 2011, and 2014) were analyzed in this study to characterize the most vulnerable households, where women themselves accepted spousal physical violence as a general norm. 31.3%, 31.9% and 28.7% women in the surveys found justification for physical violence in household in 2007, 2011 and 2014 respectively. The binary logistic model showed wealth index, education of both women and their partner, religion, geographical division, decision making freedom and marital age as significant household contributors for women's perspective in all the three years. Women in rich households and the highly educated were found to be 40% and 50% less likely to accept domestic physical violence compared to the poorest and illiterate women. Similarly, women who got married before 18 years were 20% more likely accept physical violence in the family as a norm. Apart from these particular groups (richest, highly educated and married after 18 years), other groups had around 30% acceptance rate of household violence. For any successful attempt to reduce spousal physical violence in the traditional patriarchal society of Bangladesh, interventions must target the most vulnerable households and the geographical areas where women experience spousal violence. Although this paper focuses on women's attitudes, it is important that any intervention scheme should be devised to target both men and women. PMID- 29161278 TI - Resilience of honeybee colonies via common stomach: A model of self-regulation of foraging. AB - We propose a new regulation mechanism based on the idea of the "common stomach" to explain several aspects of the resilience and homeostatic regulation of honeybee colonies. This mechanism exploits shared pools of substances (pollen, nectar, workers, brood) that modulate recruitment, abandonment and allocation patterns at the colony-level and enable bees to perform several survival strategies to cope with difficult circumstances: Lack of proteins leads to reduced feeding of young brood, to early capping of old brood and to regaining of already spent proteins through brood cannibalism. We modeled this system by linear interaction terms and mass-action law. To test the predictive power of the model of this regulatory mechanism we compared our model predictions to experimental data of several studies. These comparisons show that the proposed regulation mechanism can explain a variety of colony level behaviors. Detailed analysis of the model revealed that these mechanisms could explain the resilience, stability and self-regulation observed in honeybee colonies. We found that manipulation of material flow and applying sudden perturbations to colony stocks are quickly compensated by a resulting counter-acting shift in task selection. Selective analysis of feedback loops allowed us to discriminate the importance of different feedback loops in self-regulation of honeybee colonies. We stress that a network of simple proximate mechanisms can explain significant colony-level abilities that can also be seen as ultimate reasoning of the evolutionary trajectory of honeybees. PMID- 29161279 TI - Whole exome sequencing for determination of tumor mutation load in liquid biopsy from advanced cancer patients. AB - Tumor mutation load (TML) has been proposed as a biomarker of patient response to immunotherapy in several studies. TML is usually determined by tumor biopsy DNA (tDNA) whole exome sequencing (WES), therefore TML evaluation is limited by informative biopsy availability. Circulating cell free DNA (cfDNA) provided by liquid biopsy is a surrogate specimen to biopsy for molecular profiling. Nevertheless performing WES on DNA from plasma is technically challenging and the ability to determine tumor mutation load from liquid biopsies remains to be demonstrated. In the current study, WES was performed on cfDNA from 32 metastatic patients of various cancer types included into MOSCATO 01 (NCT01566019) and/or MATCHR (NCT02517892) molecular triage trials. Results from targeted gene sequencing (TGS) and WES performed on cfDNA were compared to results from tumor tissue biopsy. In cfDNA samples, WES mutation detection sensitivity was 92% compared to targeted sequencing (TGS). When comparing cfDNA-WES to tDNA-WES, mutation detection sensitivity was 53%, consistent with previously published prospective study comparing cfDNA-TGS to tDNA-TGS. For samples in which presence of tumor DNA was confirmed in cfDNA, tumor mutation load from liquid biopsy was correlated with tumor biopsy. Taken together, this study demonstrated that liquid biopsy may be applied to determine tumor mutation load. Qualification of liquid biopsy for interpretation is a crucial point to use cfDNA for mutational load estimation. PMID- 29161280 TI - Microbial-caddisfly bioherm association from the Lower Cretaceous Shinekhudag Formation, Mongolia: Earliest record of plant armoring in fossil caddisfly cases. AB - Caddisfly larvae construct underwater protective cases using surrounding materials, thus providing information on environmental conditions in both modern and ancient systems. Microbial bioherms associated with caddisfly cases are found in the Berriassian-Hauterivian (~140-130 Ma) Shinekhudag Formation of Mongolia, and yield new insights into aspects of lacustrine paleoecosystems and paleoenvironments. This formation contains the earliest record of plant-armored caddisfly cases and a rare occurrence of microbial-caddisfly association from the Mesozoic. The bioherms are investigated within the context of stratigraphic correlations, depositional environment interpretations, and basin-evolution models of the sedimentary fill. The bioherms form 0.5-2.0 m diameter mound-shaped bodies and are concentrated within a single, oil shale-bound stratigraphic interval. Each bioherm is composed of up to 40% caddisfly cases along with stromatolites of millimeter-scale, micritic laminations. Petrographic analyses reveal these bioherms are composed of non-systematic associations of columnar and oncoidal microbialites, constructed around colonies of caddisfly cases. The cases are straight to curved, slightly tapered, and tube-shaped, with a progressively increasing length and width trend (7-21 mm by 1.5-2.5 mm). Despite these variations, the case architectures reveal similar construction materials; the particles used for cases are dominated by plant fragments, ostracod valves, carbonate rocks, and rare mica and feldspar grains. Allochems within the bioherms include ooids, ostracods, plant fragments, rare gastropods, feldspar grains bound in micritic matrices, and are consolidated by carbonate dominated cements. The combination of microbial-caddisfly association, plant fragment case particles, and ooids/oncoids are indicative of a shallow, littoral lake setting. Stratigraphic juxtaposition of nearshore bioherms and the bounding distal oil shale facies suggests that the bioherms developed in an underfilled lake basin, resulting from an abrupt and short-lived lake desiccation event. Lake chemistry is believed to have been relatively alkaline, saline to hypersaline, and rich in Ca, Mg, and HCO3 ions. Through analyzing bioherm characteristics, caddisfly case architecture, carbonate microfacies, and stratigraphic variability, we infer larger-scale processes that controlled basin development during their formation. PMID- 29161281 TI - The administration of hydrogen sulphide prior to ischemic reperfusion has neuroprotective effects in an acute stroke model. AB - Emerging evidence has suggested that hydrogen sulfide (H2S) may alleviate the cellular damage associated with cerebral ischemia/reperfusion (I/R) injury. In this study, we assessed using 1H-magnetic resonance imaging/magnetic resonance spectroscopy (1H-MRI/MRS) and histologic analysis whether H2S administration prior to reperfusion has neuroprotective effects. We also evaluated for differences in the effects of H2S treatment at 2 time points. 1H-MRI/MRS data were obtained at baseline, and at 3, 9, and 24 h after ischemia from 4 groups: sham, control (I/R injury), sodium hydrosulfide (NaHS)-30 and NaHS-1 (NaHS delivery at 30 and 1 min before reperfusion, respectively). The total infarct volume and the midline shift at 24 h post-ischemia were lowest in the NaHS-1, followed by the NaHS-30 and control groups. Peri-infarct volume was significantly lower in the NaHS-1 compared to NaHS-30 and control animals. The relative apparent diffusion coefficient (ADC) in the peri-infarct region showed that the NaHS-1 group had significantly lower values compared to the NaHS-30 and control animals and that NaHS-1 rats showed significantly higher relative T2 values in the peri-infarct region compared to the controls. The relative ADC value, relative T2 value, levels of N-acetyl-L-aspartate (NAA), and the NAA, glutamate, and taurine combination score (NGT) in the ischemic core region at 24 h post ischemia did not differ significantly between the 2 NaHS groups and the control except that the NAA and NGT values were higher in the peri-infarct region of the NaHS-1 animals at 9 h post-ischemia. In the ischemic core and peri-infarct regions, the apoptosis rate was lowest in the NaHS-1 group, followed by the NaHS 30 and control groups. Our results suggest that H2S treatment has neuroprotective effects on the peri-infarct region during the evolution of I/R injury. Furthermore, our findings indicate that the administration of H2S immediately prior to reperfusion produces the highest neuroprotective effects. PMID- 29161282 TI - Altruistic behavior in cohesive social groups: The role of target identifiability. AB - People's tendency to be more generous toward identifiable victims than toward unidentifiable or statistical victims is known as the Identifiable Victim Effect. Recent research has called the generality of this effect into question, showing that in cross-national contexts, identifiability mostly affects willingness to help victims of one's own "in-group." Furthermore, in inter-group conflict situations, identifiability increased generosity toward a member of the adversary group, but decreased generosity toward a member of one's own group. In the present research we examine the role of group-cohesiveness as an underlying factor accounting for these divergent findings. In particular, we examined novel groups generated in the lab, using the minimal group paradigm, as well as natural groups of students in regular exercise sections. Allocation decisions in dictator games revealed that a group's cohesiveness affects generosity toward in-group and out-group recipients differently, depending on their identifiability. In particular, in cohesive groups the identification of an in-group recipient decreased, rather than increased generosity. PMID- 29161283 TI - Prognostic significance of promoter DNA hypermethylation of the cysteine dioxygenase 1 (CDO1) gene in primary gallbladder cancer and gallbladder disease. AB - BACKGROUND: Aberrant promoter DNA methylation of the cysteine dioxygenase 1 (CDO1) gene is found in various human cancers and is associated with clinical outcome. In this study, we assessed for the first time the clinicopathological significance of CDO1 methylation in primary gallbladder cancer (GBC) in comparison with non-malignant gallbladder disease. METHODS: CDO1 DNA methylation was quantified using quantitative TaqMan methylation specific PCR (Q-MSP) in 99 primary GBC patients together with the 78 corresponding non-tumor tissues and 26 benign gallbladder disease (including 7 patients with xanthogranulomatous cholecystitis) who underwent surgical resection between 1986 and 2014. RESULTS: The average CDO1 TaqMeth value of primary GBCs was 23.5+/-26. These values were significantly higher than those of corresponding non-tumor tissues (average 8+/ 13, p < .0001) and diseased gallbladder tissues from patients with benign gallbladder diseases (average 0.98+/-1.6, p < .0001). CDO1 hypermethylation is also found in xanthogranulomatous cholecystitis. Using a cut-off value of 17.7, GBC cases with CDO1 hypermethylation (n = 47) showed significantly poorer prognosis than those with CDO1 hypomethylation (n = 52) (p = 0.0023). Multivariate Cox proportional hazards analysis identified that CDO1 hypermethylation was an independent prognostic factor. Notably, CDO1 hypermethylation showed prognostic relevance, especially in stage II GBC, in which it is highly anticipated to work as a predictive marker for candidates of adjuvant therapy. CONCLUSIONS: Promoter NA methylation of CDO1 was demonstrated for the first time to be a cancer-associated methylation in primary GBC, and it has the potential to be a prognostic biomarker of GBC for high-risk patients with stage II GBC. PMID- 29161284 TI - Lung and heart-lung transplantation in pulmonary arterial hypertension. AB - BACKGROUND: Real use of lung (LT) and heart-lung (HLT) transplantation in pulmonary arterial hypertension (PAH) is unknown. The objectives were to describe the indication of these procedures on PAH treatment in a national cohort of PAH patients, and to analyze the potential improvement of its indication in severe patients. METHODS: Eligibility for LT/HLT was assessed for each deceased patient. Incident patients from REHAP diagnosed between January 2007 and March 2015 and considered eligible for LT/HLT were grouped as follows: those who finally underwent transplantation (LTP) and those who died (D-Non-LT). FINDINGS: Of 1391 patients included in REHAP, 36 (3%) were LTP and 375 (27%) died. Among those who died, 36 (3%) were D-Non-LT. LTP and D-Non-LT were equal in terms of age, gender, and clinical status. Ten percent of those who died were functional class I-II. Patients functional class IV were less likely to undergo LT (8.3% LTP vs. 30.6% D Non-LT, p = 0.017). Patients with idiopathic and drug/toxin-associated PAH were more likely to undergo LT (44.4% LTP vs. 16.7% D-Non-LT, p = 0.011). CONCLUSIONS: The present results show that the use of LT/HLT could double for this indication. Relevant mortality in early functional class reflects the difficulties in establishing the risk of death in PAH. PMID- 29161285 TI - HPV genotypes co-infections associated with cervical carcinoma: Special focus on phylogenetically related and non-vaccine targeted genotypes. AB - HPV is the major causative agent for cervical cancer. Study on the risk of cervical cancer associated with different hr-HPV genotypes would be useful for disease management and new vaccine strategy. With limited reports available, the present study aimed to investigate the pattern of HPV genotypes coinfections and risk of cervical carcinoma associated with them in Indian population. 15 HPV genotypes were detected by E6/E7 multiplex nested type-specific PCR in the HPV positive cervical samples of 172 cervical cancer cases and 174 subjects with normal cytology. Association between the genotypes and cervical cancer was estimated by calculating the Odds ratio and 95% confidence interval. Risk of cervical carcinoma was associated with multiple genotypes excluding HPV16 (OR:5.87; 95% CI-1.28-26-29; p = .02), multiple genotypes excluding HPV18 (OR = 2.5; 95% CI = 1.09-6.05; p = .03), multiple genotypes of alpha9 species(OR = 5.3 95% CI = 1.14-24.03; p = .007), and multiple genotypes of alpha7 species (OR = 2.5; 95% CI = .49-13.45; p = .2). Genotypes not targeted by quadrivalent vaccine types (OR = 2.94 95% CI = 1.48-5.80; p = .001) conferred 2.94 fold higher risk of cervical carcinoma. Cases those coinfected with phylogenetically related genotypes (OR = 2.29; 95% CI(.69-7.59) p = .17) were at 2.9 fold higher risk of invasive cervical carcinoma than those infected with other genotypes although it is not statistically significant. Whereas phylogenetically unrelated genotypes coinfection is negatively associated with cervical carcinoma (OR = .44 95% CI (.244-.8) p = .007) and it is statistically significant.Genotypes not targeted by 9-valent vaccines (OR = .40; 95% CI = .19-.85; p = .017) associated with lesser risk of cervical carcinoma as compared to other genotypes. Subjects infected with any HPV genotype/genotypes excluding HPV16 in association with HPV 18 (OR = 4.1; 95% CI = 1.81-9.25 P = < .001) were at 4.1 fold higher risk of developing invasive cervical carcinoma.In conclusion, the risk of development of cervical cancer is genotype specific and might be associated with type-specific interactions between the genotypes in multiple infections. PMID- 29161287 TI - TGF-beta contamination of purified recombinant GDF15. AB - Purified recombinant proteins for use in biomedical research are invaluable to investigate protein function. However, purity varies in protein batches made in mammalian expression systems, such as CHO-cells or HEK293-cells. This study points to caution while investigating effects of proteins related to the transforming growth factor (TGF)-beta superfamily. TGF-beta itself is a very potent cytokine and has effects on cells in the femtomolar range. Thus, even very small amounts of contaminating TGF-beta in purified protein batches may influence the experimental results given that receptors for TGF-beta are present. When we attempted to characterize possible receptors for the TGF-beta superfamily ligand GDF15, striking similarities between GDF15-induced activities and known TGF-beta activities were found. However, differences between batches of GDF15 were a concern and finally led us to the conclusion that the measured effects were caused by TGF-beta and not by GDF15. Our results emphasize that purified recombinant proteins must be used with caution and warrant proper controls. Notably, some conclusions made about GDF15 in already published papers may not be supported by the results shown. Awareness about this issue in the scientific community may prevent spreading of false positive results. PMID- 29161286 TI - Cluster-randomized controlled trial of the effects of free glasses on purchase of children's glasses in China: The PRICE (Potentiating Rural Investment in Children's Eyecare) study. AB - BACKGROUND: Offering free glasses can be important to increase children's wear. We sought to assess whether "Upgrade glasses" could avoid reduced glasses sales when offering free glasses to children in China. METHODS: In this cluster randomized, controlled trial, children with uncorrected visual acuity (VA)< = 6/12 in either eye correctable to >6/12 in both eyes at 138 randomly-selected primary schools in 9 counties in Guangdong and Yunnan provinces, China, were randomized by school to one of four groups: glasses prescription only (Control); Free Glasses; Free Glasses + offer of $15 Upgrade Glasses; Free Glasses + offer of $30 Upgrade Glasses. Spectacle purchase (main outcome) was assessed 6 months after randomization. RESULTS: Among 10,234 children screened, 882 (8.62%, mean age 10.6 years, 45.5% boys) were eligible and randomized: 257 (29.1%) at 37 schools to Control; 253 (28.7%) at 32 schools to Free Glasses; 187 (21.2%) at 31 schools to Free Glasses + $15 Upgrade; and 185 (21.0%) at 27 schools to Free Glasses +$30 Upgrade. Baseline ownership among these children needing glasses was 11.8% (104/882), and 867 (98.3%) children completed follow-up. Glasses purchase was significantly less likely when free glasses were given: Control: 59/250 = 23.6%; Free glasses: 32/252 = 12.7%, P = 0.010. Offering Upgrade Glasses eliminated this difference: Free + $15 Upgrade: 39/183 = 21.3%, multiple regression relative risk (RR) 0.90 (0.56-1.43), P = 0.65; Free + $30 Upgrade: 38/182 = 20.9%, RR 0.91 (0.59, 1.42), P = 0.69. CONCLUSIONS: Upgrade glasses can prevent reductions in glasses purchase when free spectacles are provided, providing important program income. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02231606. Registered on 31 August 2014. PMID- 29161288 TI - Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-week results of a randomized trial. AB - OBJECTIVES: Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. METHODS: Patients on 3-drug ART with stable HIV-1 RNA <50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm). RESULTS: In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. CONCLUSION: Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therapy. PMID- 29161289 TI - Mitochondrial DNA sequence context in the penetrance of mitochondrial t-RNA mutations: A study across multiple lineages with diagnostic implications. AB - Mitochondrial DNA (mtDNA) mutations are well recognized as an important cause of inherited disease. Diseases caused by mtDNA mutations exhibit a high degree of clinical heterogeneity with a complex genotype-phenotype relationship, with many such mutations exhibiting incomplete penetrance. There is evidence that the spectrum of mutations causing mitochondrial disease might differ between different mitochondrial lineages (haplogroups) seen in different global populations. This would point to the importance of sequence context in the expression of mutations. To explore this possibility, we looked for mutations which are known to cause disease in humans, in animals of other species unaffected by mtDNA disease. The mt-tRNA genes are the location of many pathogenic mutations, with the m.3243A>G mutation on the mt-tRNA-Leu(UUR) being the most frequently seen mutation in humans. This study looked for the presence of m.3243A>G in 2784 sequences from 33 species, as well as any of the other mutations reported in association with disease located on mt-tRNA-Leu(UUR). We report a number of disease associated variations found on mt-tRNA-Leu(UUR) in other chordates, as the major population variant, with m.3243A>G being seen in 6 species. In these, we also found a number of mutations which appear compensatory and which could prevent the pathogenicity associated with this change in humans. This work has important implications for the discovery and diagnosis of mtDNA mutations in non-European populations. In addition, it might provide a partial explanation for the conflicting results in the literature that examines the role of mtDNA variants in complex traits. PMID- 29161290 TI - Comparative analysis of weighted gene co-expression networks in human and mouse. AB - The application of complex network modeling to analyze large co-expression data sets has gained traction during the last decade. In particular, the use of the weighted gene co-expression network analysis framework has allowed an unbiased and systems-level investigation of genotype-phenotype relationships in a wide range of systems. Since mouse is an important model organism for biomedical research on human disease, it is of great interest to identify similarities and differences in the functional roles of human and mouse orthologous genes. Here, we develop a novel network comparison approach which we demonstrate by comparing two gene-expression data sets from a large number of human and mouse tissues. The method uses weighted topological overlap alongside the recently developed network decomposition method of s-core analysis, which is suitable for making gene centrality rankings for weighted networks. The aim is to identify globally central genes separately in the human and mouse networks. By comparing the ranked gene lists, we identify genes that display conserved or diverged centrality characteristics across the networks. This framework only assumes a single threshold value that is chosen from a statistical analysis, and it may be applied to arbitrary network structures and edge-weight distributions, also outside the context of biology. When conducting the comparative network analysis, both within and across the two species, we find a clear pattern of enrichment of transcription factors, for the homeobox domain in particular, among the globally central genes. We also perform gene-ontology term enrichment analysis and look at disease-related genes for the separate networks as well as the network comparisons. We find that gene ontology terms related to regulation and development are generally enriched across the networks. In particular, the genes FOXE3, RHO, RUNX2, ALX3 and RARA, which are disease genes in either human or mouse, are on the top-10 list of globally central genes in the human and mouse networks. PMID- 29161291 TI - DEclust: A statistical approach for obtaining differential expression profiles of multiple conditions. AB - High-throughput RNA sequencing technology is widely used to comprehensively detect and quantify cellular gene expression. Thus, numerous analytical methods have been proposed for identifying differentially expressed genes (DEGs) between paired samples such as tumor and control specimens, but few studies have reported methods for analyzing differential expression under multiple conditions. We propose a novel method, DEclust, for differential expression analysis among more than two matched samples from distinct tissues or conditions. As compared to conventional clustering methods, DEclust more accurately extracts statistically significant gene clusters from multi-conditional transcriptome data, particularly when replicates of quantitative experiments are available. DEclust can be used for any multi-conditional transcriptome data, as well as for extending any DEG detection tool for paired samples to multiple samples. Accordingly, DEclust can be used for a wide range of applications for transcriptome data analysis. DEclust is freely available at http://www.dna.bio.keio.ac.jp/software/DEclust. PMID- 29161292 TI - Individual marking of soft-bodied subtidal invertebrates in situ - A novel staining technique applied to the giant plumose anemone Metridium farcimen (Tilesius, 1809). AB - The ability to recognize individuals and track growth over time is crucial to population dynamics research as well as studies of animal behavior. Invertebrates are particularly difficult to track as they often molt, have regenerative capabilities, or lack hard parts to attach markers. We tested, in laboratory and field studies, a new way of marking sea anemones (order Actiniaria) by injection of three vital stains (i.e., neutral red, methylene blue, and fluorescein). Neutral red and methylene blue did not affect growth or survival, but fluorescein was lethal at high concentrations. Marked individuals could be identified up to seven months after injection with neutral red, six weeks with methylene blue, and three days with low concentrations of fluorescein. Neutral red could be used for long-term monitoring of growth and survival in the field, and in combination with methylene blue could be used to mark individuals in distinguishable patterns for short-term studies such as examining predator-prey interactions, movement of individuals, and recruitment survival. PMID- 29161293 TI - High-intensity focused ultrasound ablation around the tubing. AB - High-intensity focused ultrasound (HIFU) has been emerging as an effective and noninvasive modality in cancer treatment with very promising clinical results. However, a small vessel in the focal region could be ruptured, which is an important concern for the safety of HIFU ablation. In this study, lesion formation in the polyacrylamide gel phantom embedded with different tubing (inner diameters of 0.76 mm and 3 mm) at varied flow speeds (17-339 cm/s) by HIFU ablation was photographically recorded. Produced lesions have decreased length (~30%) but slightly increased width (~6%) in comparison to that without the embedded tubing. Meanwhile, bubble activities during the exposures were measured by passive cavitation detection (PCD) at the varied pulse repetition frequency (PRF, 10-30 Hz) and duty cycle (DC, 10%-20%) of the HIFU bursts. High DC and low flow speed were found to produce stronger bubble cavitation whereas no significant influence of the PRF. In addition, high-speed photography illustrated that the rupture of tubing was produced consistently after the first HIFU burst within 20 ms and then multiple bubbles would penetrate into the intraluminal space of tubing through the rupture site by the acoustic radiation force. Alignment of HIFU focus to the anterior surface, middle, and posterior surface of tubing led to different characteristics of vessel rupture and bubble introduction. In summary, HIFU-induced vessel rupture is possible as shown in this phantom study; produced lesion sizes and shapes are dependent on the focus alignment to the tubing, flow speed, and tubing properties; and bubble cavitation and the formation liquid jet may be one of the major mechanisms of tubing rupture as shown in the high-speed photography. PMID- 29161294 TI - Embryonic cholesterol esterification is regulated by a cyclic AMP-dependent pathway in yolk sac membrane-derived endodermal epithelial cells. AB - During avian embryonic development, endodermal epithelial cells (EECs) absorb yolk through the yolk sac membrane. Sterol O-acyltransferase (SOAT) is important for esterification and yolk lipid utilization during development. Because the major enzyme for yolk sac membrane cholesteryl ester synthesis is SOAT1, we cloned the avian SOAT1 promoter and elucidated the cellular functions of SOAT1. Treatments with either glucagon, isobutylmethylxanthine (IBMX), an adenylate cyclase activator (forskolin), a cAMP analog (dibutyryl-cAMP), or a low glucose concentration all increased SOAT1 mRNA accumulation in EECs from Japanese quail, suggesting that SOAT1 is regulated by nutrients and hormones through a cAMP dependent pathway. Activity of protein kinase A (PKA) was increased by IBMX, whereas co-treatment with the PKA inhibitor, H89 negated the increase in PKA activity. Cyclic AMP-induced EECs had greater cholesterol esterification than untreated EECs. By promoter deletion and point-mutation, the cAMP-response element (-349 to -341 bp) was identified as critical in mediating transcription of SOAT1. In conclusion, expression of SOAT1 was regulated by a cAMP-dependent pathway and factors that increase PKA will increase SOAT1 to improve the utilization of lipids in the EECs and potentially modify embryonic growth. PMID- 29161295 TI - Cardiac and renal dysfunction is associated with progressive hearing loss in patients with Fabry disease. AB - BACKGROUND: Fabry disease (FD) is an X-linked recessive hereditary lysosomal storage disorder which results in the accumulation of globotriaosylceramid (Gb3) in tissues of kidney and heart as well as central and peripheral nervous system. Besides prominent renal and cardiac organ involvement, cochlear symptoms like high-frequency hearing loss and tinnitus are frequently found with yet no comprehensive data available in the literature. OBJECTIVE: To examine hearing loss in patients with FD depending on cardiac and renal function. MATERIAL AND METHODS: Single-center study with 68 FD patients enrolled between 2012 and 2016 at the Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery of the University of Wurzburg. Every subject underwent an oto-rhino-laryngological examination as well as behavioral, electrophysiological and electroacoustical audiological testing. High-frequency thresholds were evaluated by using a modified PTA6 (0.5, 1, 2, 4, 6, 8) and HF-PTA (6, 8 kHz). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. RESULTS: Sensorineural hearing loss was detected in 58.8% of the cohort, which occurred typically in sudden episodes and affected especially high frequencies. Hearing loss is asymmetric, beginning unilaterally and affecting the contralateral ear later. Tinnitus was reported by 41.2%. Renal and cardiac impairment influenced the severity of hearing loss (p < 0.05). CONCLUSIONS: High frequency hearing loss is a common problem in patients with FD. Although not life threatening, it can seriously reduce quality of life and should be taken into account in diagnosis and therapy. Optimized extensive hearing assessment including higher frequency thresholds should be used. PMID- 29161296 TI - Epithelial periostin expression is correlated with poor survival in patients with invasive breast carcinoma. AB - Invasion and metastasis are direct causes of mortality in patients with breast cancer and require reciprocal interactions between cancer cells and the extracellular matrix (ECM). Periostin, a fasciclin-containing adhesive ECM glycoprotein, is frequently overexpressed in various types of human cancer, and its overexpression in cancer-associated stroma and/or cancer cells is usually associated with poor clinical outcomes. However, the expression of periostin in the successive steps of breast tumorigenesis and its association with outcome variables have not been well established in breast carcinoma. The present study aimed to assess the role of periostin alteration in breast tumorigenesis and evaluate the putative prognostic value of periostin as a function of its compartmentalization. Immunohistochemical staining with anti-periostin antibody was performed in a total of 300 patients (26 patients with normal breast tissues, 76 patients with ductal carcinoma in situ [DCIS], and 198 patients with invasive breast carcinoma [IBC]) using tissue microarray. Periostin immunoreactivity was assessed in both epithelial tissue and the surrounding stromal compartment. The mRNA and protein expression of periostin were analyzed in 10 paired normal/invasive cancer frozen specimens by quantitative real time-polymerase chain reaction and western blot analysis, respectively. In cancer tissues, periostin mRNA and protein expression were increased compared with adjacent normal tissues. Both epithelial and stromal periostin staining scores significantly increased in a stepwise manner with disease progression from normal breast tissue to DCIS and IBC (P = 0.000 and 0.000, respectively). High epithelial and stromal periostin expression was observed in 109/189 (57.7%) and 158/189 (83.6%) cases of IBC, respectively. High epithelial periostin expression was more frequently observed in the distant metastatic relapse-positive group than in the distant metastatic relapse-negative group (41/51 [80.4%] vs. 68/138 [49.3%] cases [P = 0.000]). Furthermore, high epithelial periostin expression was associated with reduced disease-free survival and overall survival in univariate and multivariate analysis. Periostin may play an important role in the progression of breast tumor, and epithelial periostin expression may serve as a new parameter for prediction of prognosis in patients with IBC. Further studies examining periostin expression and its potential as a target of IBC therapy are warranted. PMID- 29161297 TI - Prognostic performance of MR-pro-adrenomedullin in patients with community acquired pneumonia in the Emergency Department compared to clinical severity scores PSI and CURB. AB - AIM: (i) evaluate the performance of MR-pro-ADM in reflecting the outcome and risk for CAP patients in the emergency department, and (ii) compare the prognostic performance of MR-pro-ADM with that of clinical scores PSI and CURB65. METHODS: Observational prospective, single-center study in patients with suspected community acquired pneumonia (CAP). Eighty one patients underwent full clinical and laboratory assessment as by protocol, and were followed up a 28 days. Primary endpoints measured were: death, death at 14 days, non-invasive mechanical ventilation (NIMV), endotracheal intubation (EI), ICU admission, overall hospital stay >10 days, emergency department stay >4 days. The discriminative performance of MR-pro-ADM and clinical scores was assessed by AUROC analysis. RESULTS: The distribution for MR-pro-ADM followed an upward trend, increasing with the increase of both PSI (p<0.001) and CURB65 (p<0.001) classes. However, the difference between MRproADM values and score classes was significant only in the case of CURB65 classes 0 and 1 (p = 0.046), 2 (p = 0.013), and 3 (p = 0.011); and with PSI classes 5, 3 (p = 0.044), and 1 (p = 0.020). As to the differences among variables for the six end-points, MR-pro-ADM values in the two groups selected for each considered end-point differed in a statistically significant manner for all endpoints. Both PSI and CURB65 differed significantly for all end-points, except for stay in the ED longer than 4 days and the hospital stay longer than 10 days and endotracheal intubation (only PSI classes differed with statistical significance). ROC analyses evidenced that MR pro-ADM values gave the greatest AUC for the prediction of death, endotracheal intubation, hospital stay >10 days and DE stay >4 days, compared to the PSI and CURB (though difference not statistically significant). For each endpoint measured, the best thresholds values for Mr-pro-ADM were: 1.6 (specificity 76.5%; sensitivity 77.8%) for death; 2.5 (specificity 88.9%; sensitivity 80.0%) for death at 14 days; 1.5 (specificity 77.0%; sensitivity 87.5%) for NIMV; 2.4 (specificity 88.7%; sensitivity 83.3%) for endotracheal intubation; 0.9 (specificity 53.5%; sensitivity 70.6%) for DE stay greater than 4 days; 1.9 (specificity 82.1%; sensitivity 55.3%) for hospital stay greater than 10 days. The AUC for the combination of MR-pro-ADM and PSI was 81.29% [63.41%-99.17%], but not in a statistically significant manner compared to the AUCs of the single predictors. Conversely, the AUC for the combination of MR-pro-ADM and CURB65 was 87.58% [75.54%-99.62%], which was significantly greater than the AUC of CURB65 (p = 0.047) or PSI (p = 0.017) alone. CONCLUSIONS: The present study confirms that assessment of MR-pro-ADM levels in CAP patients in addition to CURB scores increases the prognostic accuracy of CURB alone and may help rule out discrepancies arising from flawed clinical severity classification. With particular reference to patients scoring in the upper classes of CURB and PSI, MR pro-ADM values provided additional information towards a better risk stratification of those patients. In particular, our results pointed towards two MR-pro-ADM threshold values that appear to predict with a good degree of accuracy the patient's need for non-invasive mechanical ventilation, endotracheal intubation, or intensive care. This aspect, however, deserves further investigation. PMID- 29161298 TI - Controlled placement of multiple CNS cell populations to create complex neuronal cultures. AB - In vitro brain-on-a-chip platforms hold promise in many areas including: drug discovery, evaluating effects of toxicants and pathogens, and disease modelling. A more accurate recapitulation of the intricate organization of the brain in vivo may require a complex in vitro system including organization of multiple neuronal cell types in an anatomically-relevant manner. Most approaches for compartmentalizing or segregating multiple cell types on microfabricated substrates use either permanent physical surface features or chemical surface functionalization. This study describes a removable insert that successfully deposits neurons from different brain areas onto discrete regions of a microelectrode array (MEA) surface, achieving a separation distance of 100 MUm. The regional seeding area on the substrate is significantly smaller than current platforms using comparable placement methods. The non-permanent barrier between cell populations allows the cells to remain localized and attach to the substrate while the insert is in place and interact with neighboring regions after removal. The insert was used to simultaneously seed primary rodent hippocampal and cortical neurons onto MEAs. These cells retained their morphology, viability, and function after seeding through the cell insert through 28 days in vitro (DIV). Co cultures of the two neuron types developed processes and formed integrated networks between the different MEA regions. Electrophysiological data demonstrated characteristic bursting features and waveform shapes that were consistent for each neuron type in both mono- and co-culture. Additionally, hippocampal cells co-cultured with cortical neurons showed an increase in within burst firing rate (p = 0.013) and percent spikes in bursts (p = 0.002), changes that imply communication exists between the two cell types in co-culture. The cell seeding insert described in this work is a simple but effective method of separating distinct neuronal populations on microfabricated devices, and offers a unique approach to developing the types of complex in vitro cellular environments required for anatomically-relevant brain-on-a-chip devices. PMID- 29161299 TI - Relationship between lower eyelid epiblepharon and epicanthus in Korean children. AB - PURPOSE: This study aimed to determine the relationship between lower eyelid epiblepharon and epicanthus in Korean children. METHODS: We performed a retrospective review of the medical records and preoperative photographs of 119 patients. These patients were aged 18 years or younger who underwent lower lid epiblepharon repair from January 2010 to December 2012. We also included 119 age- and sex-matched controls. RESULTS: The mean age of the patients was 5.7 years (range: 2-16 years) in both groups. The presence of an epicanthal fold was common in each group (98.3%). The inner intercanthal distance/interpupillary distance (IICD/IPD) ratio was significantly greater in the epiblepharon group than in the control group (mean: 0.70 vs 0.67, p<0.001), especially in those aged 5 years or older. The IICD/outer intercanthal distance ratio was also greater in the epiblepharon group than in the control group (mean: 0.48 vs 0.46, p<0.001). The IICD/IPD ratio decreased with growth in the control group, but it did not decrease with growth in the epiblepharon group. The configuration of the epicanthus, in which the upper skin fold formed a confluent fold with the lower eyelid, had a higher prevalence in the epiblepharon group than in the control group (p = 0.001), especially in those aged 5 years or older. CONCLUSION: In early childhood (<5 years), the relationship between epicanthus and epiblepharon cannot be established because of the high prevalence of epicanthus in children with or without epiblepharon. In children aged >=5 years, persistent epicanthus was related to severe epiblepharon formation requiring corrective surgery. PMID- 29161300 TI - BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population? AB - BACKGROUND: Germline pathogenic variants in BRCA1 and BRCA2 (BRCA) are the main cause of Hereditary Breast and Ovarian Cancer syndrome (HBOC). METHODS: In this study we evaluated the mutational profile and prevalence of BRCA pathogenic/likely pathogenic variants among probands fulfilling the NCCN HBOC testing criteria. We characterized the clinical profile of these individuals and explored the performance of international testing criteria. RESULTS: A pathogenic/likely pathogenic variant was detected in 19.1% of 418 probands, including seven novel frameshift variants. Variants of uncertain significance were found in 5.7% of individuals. We evaluated 50 testing criteria and mutation probability algorithms. There was a significant odds-ratio (OR) for mutation prediction (p <= 0.05) for 25 criteria; 14 of these had p <= 0.001. Using a cutoff point of four criteria, the sensitivity is 83.8%, and the specificity is 53.5% for being a carrier. The prevalence of pathogenic/likely pathogenic variants for each criterion ranged from 22.1% to 55.6%, and criteria with the highest ORs were those related to triple-negative breast cancer or ovarian cancer. CONCLUSIONS: This is the largest study of comprehensive BRCA testing among Brazilians to date, and the first to analyze clinical criteria for genetic testing. Several criteria that are not included in the NCCN achieved a higher predictive value. Identification of the most informative criteria for each population will assist in the development of a rational approach to genetic testing, and will enable the prioritization of high-risk individuals as a first step towards offering testing in low-income countries. PMID- 29161301 TI - Detection and quantification of dengue virus using a novel biosensor system based on dengue NS3 protease activity. AB - BACKGROUND: The traditional methods, plaque assays and immuno-focus assays, used to titrate infectious dengue virus (DENV) particles are time consuming and labor intensive. Here, we developed a DENV protease activity detection system (DENPADS) to visualize DENV infection in cells based on dengue protease activity. METHODOLOGY/PRINCIPAL FINDINGS: Dengue NS3 protease cleaves NS4B-NS5. BHK-21 cells stably expressing the sensor module comprising DENV-2 NS4 and the 10 amino terminal amino acids of NS5 (N10NS5) fused with the SV40 nuclear localization signal (NLS) and Cre recombinase (Cre), were generated. Cre is constrained outside the nucleus in the absence of NS3 activity but translocates into the nucleus through NS4B-NS5 cleavage when cells are infected with DENV. Nuclear translocation of Cre can trigger the reporter system, which contains a cis-loxP flanked mCherry with three continuous stop codons following an SV40 polyA tail cDNA upstream of EGFP or mHRP cDNA. Our results show that DENPADS is an efficient and accurate method to titrate 4 DENV serotypes in 24 hours. Compared with current virus titration methods, the entire process is easy to perform, and the data are easily acquired. CONCLUSIONS/SIGNIFICANCE: In this study, we demonstrate that DENPADS can be used to detect dengue viral infection through a fluorescence switch or HRP activity in the infected cells. This approach is sensitive with less incubation time and labor input. In addition, DENPADS can simultaneously evaluate the efficacy and cytotoxicity of potential anti-DENV candidates. Overall, DENPADS is a useful tool for dengue research. PMID- 29161303 TI - Nonlinear dynamics of early atherosclerotic plaque formation may determine the efficacy of high density lipoproteins (HDL) in plaque regression. AB - We use a computational model to explore the effect of foam cell accumulation on plaque regression following an increase in high density lipoprotein (HDL) influx into the plaque. Atherosclerotic plaque formation is the outcome of cellular and cytokine responses to low density lipoproteins (LDL) that penetrate the artery wall following an injury to the endothelium and become modified. We modelled the cells and cytokines that are most important in plaque formation using partial differential equations. The model includes monocytes and macrophages, foam cells, macrophage chemoattractants, endothelium-stimulating cytokines, modified low density lipoproteins (mod LDL) and HDL. We included interactions both at the endothelium surface and inside the artery wall. The model predicts that when HDL influx into a well-established plaque with large numbers of foam cells is increased, the plaque may not regress but may continue to grow at a slower rate. If HDL influx is increased when a model plaque is recently established and has fewer foam cells, then the plaque does regress. If modLDL influx into the plaque is lowered at the same time that HDL influx increased or the capacity of the HDL to remove cholesterol from foam cells is increased, then the plaque is more likely to regress. The predictions of the model are in qualitative agreement with experimental studies in mice and rabbits. The results suggest that the intrinsic dynamics of reverse cholesterol transport by HDL are important in determining the success of HDL raising in promoting plaque regression. PMID- 29161302 TI - Characteristics of somatic tinnitus patients with and without hyperacusis. AB - OBJECTIVE: Determine if somatic tinnitus patients with hyperacusis have different characteristics from those without hyperacusis. PATIENTS AND METHODS: 172 somatic tinnitus patients with (n = 82) and without (n = 90) hyperacusis referred to the Tinnitus Unit of Sapienza University of Rome between June 2012 and June 2016 were compared for demographic characteristics, tinnitus features, self-administered questionnaire scores, nature of somatic modulation and history. RESULTS: Compared to those without hyperacusis, patients with somatic tinnitus and hyperacusis: (a) were older (43.38 vs 39.12 years, p = 0.05), (b) were more likely to have bilateral tinnitus (67.08% vs 55.56%, p = 0.04), (c) had a higher prevalence of somatic modulation of tinnitus (53.65% vs 36.66%, p = 0.02) and (d) scored significantly worse on tinnitus annoyance (39.34 vs 22.81, p<0.001) and subjective hearing level (8.04 vs 1.83, p<0.001). CONCLUSION: Our study shows significantly higher tinnitus modulation and worse self-rating of tinnitus and hearing ability in somatic tinnitus patients with hyperacusis versus somatic tinnitus patients without hyperacusis. These differences could prove useful in developing a better understanding of the pathophysiology and establishing a course of treatment for these two groups of patients. PMID- 29161305 TI - Impact of Austropuccinia psidii (myrtle rust) on Myrtaceae-rich wet sclerophyll forests in south east Queensland. AB - In April 2010, Austropuccinia psidii (formerly Puccinia psidii) was detected for the first time in Australia on the central coast of New South Wales. The fungus spread rapidly along the east coast and can now be found infecting vegetation in a range of native forest ecosystems with disease impacts ranging from minor leaf spots to severe shoot and stem blight and tree dieback. Localised extinction of some plant species has been recorded. In 2014, the impact of A. psidii was observed for the first time in a wet sclerophyll site with a rainforest understory, dominated by species of Myrtaceae, in Tallebudgera Valley, south east Queensland, Australia. This study aimed to determine the impact of A. psidii on individual species and species composition. Here we provide quantitative and qualitative evidence on the significant impact A. psidii has in native ecosystems, on a broader range of species than previously reported. Archirhodomyrtus beckleri, Decaspermum humile, Gossia hillii and Rhodamnia maideniana are in serious decline, with significant increases in tree mortality over the period of our study. This research further highlights the potential of this invasive pathogen to negatively impact native ecosystems and biodiversity. PMID- 29161304 TI - Proposal for a common nomenclature for fragment ions in mass spectra of lipids. AB - Advances in mass spectrometry-based lipidomics have in recent years prompted efforts to standardize the annotation of the vast number of lipid molecules that can be detected in biological systems. These efforts have focused on cataloguing, naming and drawing chemical structures of intact lipid molecules, but have provided no guidelines for annotation of lipid fragment ions detected using tandem and multi-stage mass spectrometry, albeit these fragment ions are mandatory for structural elucidation and high confidence lipid identification, especially in high throughput lipidomics workflows. Here we propose a nomenclature for the annotation of lipid fragment ions, describe its implementation and present a freely available web application, termed ALEX123 lipid calculator, that can be used to query a comprehensive database featuring curated lipid fragmentation information for more than 430,000 potential lipid molecules from 47 lipid classes covering five lipid categories. We note that the nomenclature is generic, extendable to stable isotope-labeled lipid molecules and applicable to automated annotation of fragment ions detected by most contemporary lipidomics platforms, including LC-MS/MS-based routines. PMID- 29161306 TI - Comparison of methods for determining the effectiveness of antibacterial functionalized textiles. AB - Antimicrobial functionalization of textiles is important for various applications, such as protection of textile materials from decomposition, generation of more effective wound dressings, and the prevention of infections or malodors resulting from bacterial growth. In order to test the efficacy of new products, their antibacterial activity needs to be evaluated. At present, several different procedures are being used for this purpose, hindering comparisons among different studies. The present paper compares five of these assays using a sample panel of different textiles functionalized with copper (Cu) and silver (Ag) as antibacterial agents, and discusses the suitability of these methods for different analytical requirements. Bacterial viability was determined by measuring the optical density at 600 nm, a colorimetric assay based on MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyl tetrazolium bromide) conversion, an agar diffusion assay, and colony formation, either after culturing in media containing textile samples, or after recovery from textiles soaked with bacterial suspension. All experiments were performed with a Gram-negative (Escherichia coli) and a Gram-positive (Staphylococcus warneri) model organism. In general, the results yielded by the different methods were of good comparability. To identify the most suitable test system for the particular type of antibacterial coating, several factors need to be taken into account, such as choosing appropriate endpoints for analyzing passive or active antibacterial effects, selection of relevant microorganisms, correcting for potential interference by leaching of colored textile coatings, required hands on time, and the necessary sensitivity. PMID- 29161308 TI - Effects of tones associated with drilling activities on bowhead whale calling rates. AB - During summer 2012 Shell performed exploratory drilling at Sivulliq, a lease holding located in the autumn migration corridor of bowhead whales (Balaena mysticetus), northwest of Camden Bay in the Beaufort Sea. The drilling operation involved a number of vessels performing various activities, such as towing the drill rig, anchor handling, and drilling. Acoustic data were collected with six arrays of directional recorders (DASARs) deployed on the seafloor over ~7 weeks in Aug-Oct. Whale calls produced within 2 km of each DASAR were identified and localized using triangulation. A "tone index" was defined to quantify the presence and amplitude of tonal sounds from industrial machinery. The presence of airgun pulses originating from distant seismic operations was also quantified. For each 10-min period at each of the 40 recorders, the number of whale calls localized was matched with the "dose" of industrial sound received, and the relationship between calling rates and industrial sound was modeled using negative binomial regression. The analysis showed that with increasing tone levels, bowhead whale calling rates initially increased, peaked, and then decreased. This dual behavioral response is similar to that described for bowhead whales and airgun pulses in earlier work. Increasing call repetition rates can be a viable strategy for combating decreased detectability of signals arising from moderate increases in background noise. Meanwhile, as noise increases, the benefits of calling may decrease because information transfer becomes increasingly error-prone, and at some point calling may no longer be worth the effort. PMID- 29161307 TI - Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis. AB - BACKGROUND: Idiopathic and diabetic gastroparesis in Homo sapiens cause significant morbidity. Etiology or risk factors have not been clearly identified. Failure to sustain elevated heme oxygenase-1 (HO1) expression is associated with delayed gastric emptying in diabetic mice and polymorphisms in the HO1 gene (HMOX1, NCBI Gene ID:3162) are associated with worse outcomes in other diseases. AIM: Our hypothesis was that longer polyGT alleles are more common in the HMOX1 genes of individuals with gastroparesis than in controls without upper gastrointestinal motility disorders. METHODS: Repeat length was determined in genomic DNA. Controls with diabetes (84 type 1, 84 type 2) and without diabetes (n = 170) were compared to diabetic gastroparetics (99 type 1, 72 type 2) and idiopathic gastroparetics (n = 234). Correlations of repeat lengths with clinical symptom sub-scores on the gastroparesis cardinal symptom index (GCSI) were done. Statistical analyses of short (<29), medium and long (>32) repeat alleles and differences in allele length were used to test for associations with gastroparesis. RESULTS: The distribution of allele lengths was different between groups (P = 0.016). Allele lengths were longest in type 2 diabetics with gastroparesis (29.18+/-0.35, mean +/- SEM) and longer in gastroparetics compared to non-diabetic controls (28.50+/-0.14 vs 27.64+/-0.20 GT repeats/allele, P = 0.0008). Type 2 diabetic controls had longer alleles than non-diabetic controls. In all gastroparetic groups, allele lengths were longer in African Americans compared to other racial groups, differences in the proportion of African Americans in the groups accounted for the differences between gastroparetics and controls. Diabetic gastroparetics with 1 or 2 long alleles had worse GCSI nausea sub-scores (3.30+/-0.23) as compared to those with 0 long alleles (2.66+/-0.12), P = 0.022. CONCLUSIONS: Longer poly-GT repeats in the HMOX1 gene are more common in African Americans with gastroparesis. Nausea symptoms are worse in subjects with longer alleles. PMID- 29161309 TI - Dronedarone produces early regression of myocardial remodelling in structural heart disease. AB - BACKGROUND AND AIMS: Left ventricular hypertrophy (LVH) in hypertension is associated with a greater risk of sustained supraventricular/atrial arrhythmias. Dronedarone is an antiarrhythmic agent that was recently approved for the treatment of atrial fibrillation. However, its effect on early regression of LVH has not been reported. We tested the hypothesis that short-term administration of dronedarone induces early regression of LVH in spontaneously hypertensive rats (SHRs). METHODS: Ten-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where animals received dronedarone treatment (100 mg/kg) for a period of 14 days, or to a control group (SHR) where rats were given vehicle. A third group with normotensive control rats (WKY) was also added. At the end of the treatment with dronedarone we studied the cardiac anatomy and function in all the rats using transthoracic echocardiogram, cardiac metabolism using the PET/CT study (2-deoxy-2[18F]fluoro-D-glucose) and cardiac structure by histological analysis of myocyte size and collagen content. RESULTS: The hypertensive vehicle treated SHR rats developed the classic cardiac pattern of hypertensive cardiomyopathy as expected for the experimental model, with increases in left ventricular wall thickness, a metabolic shift towards an increase in glucose use and increases in myocyte and collagen content. However, the SHR-D rats showed statistically significant lower values in comparison to SHR group for septal wall thickness, posterior wall thickness, ventricular mass, glucose myocardial uptake, size of left ventricular cardiomyocytes and collagen content. All these values obtained in SHR-D rats were similar to the values measured in the normotensive WKY control group. CONCLUSION: The results suggest by three alternative and complementary ways (analysis of anatomy and cardiac function, metabolism and histological structure) that dronedarone has the potential to reverse the LVH induced by arterial hypertension in the SHR model of compensated ventricular hypertrophy. PMID- 29161310 TI - Vision in high-level football officials. AB - Officiating in football depends, at least to some extent, upon adequate visual function. However, there is no vision standard for football officiating and the nature of the relationship between officiating performance and level of vision is unknown. As a first step in characterising this relationship, we report on the clinically-measured vision and on the perceived level of vision in elite-level, Portuguese football officials. Seventy-one referees (R) and assistant referees (AR) participated in the study, representing 92% of the total population of elite level football officials in Portugal in the 2013/2014 season. Nine of the 22 Rs (40.9%) and ten of the 49 ARs (20.4%) were international-level. Information about visual history was also gathered. Perceived vision was assessed using the preference-values-assigned-to-global-visual-status (PVVS) and the Quality-of Vision (QoV) questionnaire. Standard clinical vision measures (including visual acuity, contrast sensitivity and stereopsis) were gathered in a subset (n = 44, 62%) of the participants. Data were analysed according to the type (R/AR) and level (international/national) of official, and Bonferroni corrections were applied to reduce the risk of type I errors. Adopting criterion for statistical significance of p<0.01, PVVS scores did not differ between R and AR (p = 0.88), or between national- and international-level officials (p = 0.66). Similarly, QoV scores did not differ between R and AR in frequency (p = 0.50), severity (p = 0.71) or bothersomeness (p = 0.81) of symptoms, or between international-level vs national-level officials for frequency (p = 0.03) or bothersomeness (p = 0.07) of symptoms. However, international-level officials reported less severe symptoms than their national-level counterparts (p<0.01). Overall, 18.3% of officials had either never had an eye examination or if they had, it was more than 3 years previously. Regarding refractive correction, 4.2% had undergone refractive surgery and 23.9% wear contact lenses when officiating. Clinical vision measures in the football officials were similar to published normative values for young, adult populations and similar between R and AR. Clinically-measured vision did not differ according to officiating level. Visual acuity measured with and without a pinhole disc indicated that around one quarter of participants may be capable of better vision when officiating, as evidenced by better acuity (>=1 line of letters) using the pinhole. Amongst the clinical visual tests we used, we did not find evidence for above-average performance in elite-level football officials. Although the impact of uncorrected mild to moderate refractive error upon officiating performance is unknown, with a greater uptake of eye examinations, visual acuity may be improved in around a quarter of officials. PMID- 29161312 TI - Correction: Induction of Connective Tissue Growth Factor Expression by Hypoxia in Human Lung Fibroblasts via the MEKK1/MEK1/ERK1/GLI-1/GLI-2 and AP-1 Pathways. AB - [This corrects the article DOI: 10.1371/journal.pone.0160593.]. PMID- 29161311 TI - Expression and regulation of ATL9, an E3 ubiquitin ligase involved in plant defense. AB - Plants are continually exposed to a variety of pathogenic organisms, including bacteria, fungi and viruses. In response to these assaults, plants have developed various defense pathways to protect themselves from pathogen invasion. An understanding of the expression and regulation of genes involved in defense signaling is essential to controlling plant disease. ATL9, an Arabidopsis RING zinc finger protein, is an E3 ubiquitin ligase that is induced by chitin and involved in basal resistance to the biotrophic fungal pathogen, Golovinomyces cichoracearum (G. cichoracearum). To better understand the expression and regulation of ATL9, we studied its expression pattern and the functions of its different protein domains. Using pATL9:GUS transgenic Arabidopsis lines we found that ATL9 is expressed in numerous tissues at various developmental stages and that GUS activity was induced rapidly upon wounding. Using a GFP control protein, we showed that ATL9 is a short-lived protein within plant cells and it is degraded via the ubiquitin-proteasome pathway. ATL9 contains two transmembrane domains (TM), a RING zinc-finger domain, and a PEST domain. Using a series of deletion mutants, we found that the PEST domain and the RING domain have effects on ATL9 degradation. Further infection assays with G. cichoracearum showed that both the RING domain and the TM domains are important for ATL9's resistance phenotype. Interestingly, the PEST domain was also shown to be significant for resistance to fungal pathogens. This study demonstrates that the PEST domain is directly coupled to plant defense regulation and the importance of protein degradation in plant immunity. PMID- 29161313 TI - Biomarkers and echocardiography for evaluating the improvement of the ventricular diastolic function after surgical relief of hydronephrosis. AB - The pathophysiology of cardio-renal syndrome (CRS) is complex. Hydronephrosis caused by urolithiasis may cause cytokine release and lead to cardiac dysfunction. The aim of this study was to evaluate cardiac function changes observed in patients who received double J placement using feasible biomarkers and echocardiography. This was a prospective, single-center study. Eighty-seven patients who presented with acute unilateral hydronephrosis and received ureteroscope stone manipulation were enrolled. Echocardiography and cytokines were measured on the day of the operation and 24 hours after the procedure. Changes before and after surgery were assessed by the paired t-test and Wilcoxon test. Correlation analyses between echocardiographic diastolic indices and cytokine levels were performed using Pearson's correlation coefficients. Patients with hydronephrosis showed a higher left atrium volume index (LAVI), decreased E', and increased E/ E' ratio, which indicated diastolic dysfunction. Patients with hydronephrosis also exhibited decreased global strain rates during isovolumetric relaxation (SRIVR) and E/ SRIVR, which confirmed the diastolic dysfunction. Significant reductions in LAVI, increases in SRIVR and decreases in E/ SRIVR were observed after the operation. Biomarkers, such as TGF-beta and serum NT-proBNP, were significantly decreased after surgery. In addition, a significant correlation was observed between the post-surgical decrease in TGF beta1 and increase in SRIVR. Unilateral hydronephrosis causes cardiac diastolic dysfunction, and relieving hydronephrosis could improve diastolic function. Improvements in cardiac dysfunction can be evaluated by echocardiography and measuring cytokine levels. The results of this study will inform efforts to improve the early diagnosis of CRS and prevent further deterioration of cardiac function when treating patients with hydronephrosis. PMID- 29161314 TI - Conventional and technical diving surveys reveal elevated biomass and differing fish community composition from shallow and upper mesophotic zones of a remote United States coral reef. AB - The world's coral reefs appear to be in a global decline, yet most previous research on coral reefs has taken place at depths shallower than 30 m. Mesophotic coral ecosystem (depths deeper than ~30 m) studies have revealed extensive, productive habitats and rich communities. Despite recent advances, mesophotic coral ecosystems remain understudied due to challenges with sampling at deeper depths. The few previous studies of mesophotic coral ecosystems have shown variation across locations in depth-specific species composition and assemblage shifts, potentially a response to differences in habitat or light availability/water clarity. This study utilized scuba to examine fish and benthic communities from shallow and upper mesophotic (to 45 m) zones of Flower Garden Banks National Marine Sanctuary (FGBNMS, 28 degrees 0'N; 93 degrees 50'W) from 2010-2012. Dominant planktivores were ubiquitous in shallow and upper mesophotic habitats, and comparisons with previous shallow research suggest this community distribution has persisted for over 30 years. Planktivores were abundant in shallow low-relief habitats on the periphery of the coral reef, and some of these sites that contained habitat transitioning from high to low relief supported high biomass of benthic predators. These peripheral sites at FGBNMS may be important for the trophic transfer of oceanic energy to the benthic coral reef. Distinct differences between upper mesophotic and shallow communities were also observed. These included greater overall fish (as well as apex predator) biomass in the upper mesophotic, differences in apex predator community composition between depth zones, and greater percent cover of algae, rubble, sand, and sponges in the upper mesophotic. Greater fish biomass in the upper mesophotic and similar fish community composition between depth zones provide preliminary support that upper mesophotic habitats at FGBNMS have the capacity to serve as refugia for the shallow-water reefs. Diving surveys of the upper mesophotic and shallow-water coral reef have revealed valuable information concerning the reef fish community in the northern Gulf of Mexico, with implications for the conservation of apex predators, oceanic coral reefs, and the future management of FGBNMS. PMID- 29161315 TI - Transcriptome analysis of plasmid-induced genes sheds light on the role of type I IFN as adjuvant in DNA vaccine against infectious salmon anemia virus. AB - A previous study showed that a plasmid expressing IFNa (pIFNa) strongly enhanced protection and antibody production of a DNA vaccine against infectious salmon anemia virus (ISAV) in Atlantic salmon. The vaccine consisted of a plasmid (pHE) expressing the virus hemagglutinin-esterase as an antigen. To increase the understanding of the adjuvant effect of pIFNa, we here compared transcriptome responses in salmon muscle at the injection site at week 1 and 2 after injection of pIFNa, pHE, plasmid control (pcDNA3.3) and PBS, respectively. The results showed that the IFNa plasmid mediates an increase in gene transcripts of at least three major types in the muscle; typical IFN-I induced genes (ISGs), certain chemokines and markers of B- cells, T-cells and antigen-presenting cells. The latter suggests recruitment of cells to the plasmid injection site. Attraction of lymphocytes was likely caused by the induction of chemokines homologous to mammalian CCL5, CCL8, CCL19 and CXCL10. IFN may possibly also co-stimulate activation of lymphocytes as suggested by studies in mammals. A major finding was that both pcDNA3.3 and pHE caused responses similar to pIFNa, but at lower magnitude. Plasmid DNA may thus by itself have adjuvant activity as observed in mammalian models. Notably, pHE had a lower effect on many immune genes including ISGs and chemokines than pcDNA3.3, which suggests an inhibitory effect of HE expression on the immune genes. This hypothesis was supported by an Mx-reporter assay. The present study thus suggests that a main role for pIFNa as adjuvant in the DNA vaccine against ISAV may be to overcome the inhibitory effect of HE- expression on plasmid-induced ISGs and chemokines. PMID- 29161317 TI - Evaluating architecture impact on system energy efficiency. AB - As the energy consumption has been surging in an unsustainable way, it is important to understand the impact of existing architecture designs from energy efficiency perspective, which is especially valuable for High Performance Computing (HPC) and datacenter environment hosting tens of thousands of servers. One obstacle hindering the advance of comprehensive evaluation on energy efficiency is the deficient power measuring approach. Most of the energy study relies on either external power meters or power models, both of these two methods contain intrinsic drawbacks in their practical adoption and measuring accuracy. Fortunately, the advent of Intel Running Average Power Limit (RAPL) interfaces has promoted the power measurement ability into next level, with higher accuracy and finer time resolution. Therefore, we argue it is the exact time to conduct an in-depth evaluation of the existing architecture designs to understand their impact on system energy efficiency. In this paper, we leverage representative benchmark suites including serial and parallel workloads from diverse domains to evaluate the architecture features such as Non Uniform Memory Access (NUMA), Simultaneous Multithreading (SMT) and Turbo Boost. The energy is tracked at subcomponent level such as Central Processing Unit (CPU) cores, uncore components and Dynamic Random-Access Memory (DRAM) through exploiting the power measurement ability exposed by RAPL. The experiments reveal non-intuitive results: 1) the mismatch between local compute and remote memory node caused by NUMA effect not only generates dramatic power and energy surge but also deteriorates the energy efficiency significantly; 2) for multithreaded application such as the Princeton Application Repository for Shared-Memory Computers (PARSEC), most of the workloads benefit a notable increase of energy efficiency using SMT, with more than 40% decline in average power consumption; 3) Turbo Boost is effective to accelerate the workload execution and further preserve the energy, however it may not be applicable on system with tight power budget. PMID- 29161316 TI - Acute exercise alters skeletal muscle mitochondrial respiration and H2O2 emission in response to hyperinsulinemic-euglycemic clamp in middle-aged obese men. AB - Obesity, sedentary lifestyle and aging are associated with mitochondrial dysfunction and impaired insulin sensitivity. Acute exercise increases insulin sensitivity in skeletal muscle; however, whether mitochondria are involved in these processes remains unclear. The aim of this study was to investigate the effects of insulin stimulation at rest and after acute exercise on skeletal muscle mitochondrial respiratory function (JO2) and hydrogen peroxide emission (JH2O2), and the associations with insulin sensitivity in obese, sedentary men. Nine men (means +/- SD: 57 +/- 6 years; BMI 33 +/- 5 kg.m2) underwent hyperinsulinemic-euglycemic clamps in two separate trials 1-3 weeks apart: one under resting conditions, and another 1 hour after high-intensity exercise (4x4 min cycling at 95% HRpeak). Muscle biopsies were obtained at baseline, and pre/post clamp to measure JO2 with high-resolution respirometry and JH2O2 via Amplex UltraRed from permeabilized fibers. Post-exercise, both JO2 and JH2O2 during ADP stimulated state-3/OXPHOS respiration were lower compared to baseline (P<0.05), but not after subsequent insulin stimulation. JH2O2 was lower post exercise and after subsequent insulin stimulation compared to insulin stimulation in the rest trial during succinate supported state-4/leak respiration (P<0.05). In contrast, JH2O2 increased during complex-I supported leak respiration with insulin after exercise compared with resting conditions (P<0.05). Resting insulin sensitivity and JH2O2 during complex-I leak respiration were positively correlated (r = 0.77, P<0.05). We conclude that in obese, older and sedentary men, acute exercise modifies skeletal muscle mitochondrial respiration and H2O2 emission responses to hyperinsulinemia in a respiratory state-specific manner, which may have implications for metabolic diseases involving insulin resistance. PMID- 29161318 TI - Loss of mTORC2 signaling in oligodendrocyte precursor cells delays myelination. AB - Myelin abnormalities are increasingly being recognized as an important component of a number of neurologic developmental disorders. The integration of many signaling pathways and cell types are critical for correct myelinogenesis. The PI3-K and mechanistic target of rapamycin (mTOR) pathways have been found to play key roles. mTOR is found within two distinct complexes, mTORC1 and mTORC2. mTORC1 activity has been shown to play a major role during myelination, while the role of mTORC2 is not yet well understood. To determine the role of mTORC2 signaling in myelinogenesis, we generated a mouse lacking the critical mTORC2 component Rictor in oligodendrocyte precursors (OPCs). Targeted deletion of Rictor in these cells decreases and delays the expression of myelin related proteins and reduces the size of cerebral white matter tracts. This is developmentally manifest as a transient reduction in myelinated axon density and g-ratio. OPC cell number is reduced at birth without detectable change in proliferation with proportional reductions in mature oligodendrocyte number at P15. The total number of oligodendrocytes as well as extent of myelination, does improve over time. Adult conditional knock-out (CKO) animals do not demonstrate a behavioral phenotype likely due in part to preserved axonal conduction velocities. These data support and extend prior studies demonstrating an important but transient contribution of mTORC2 signaling to myelin development. PMID- 29161319 TI - The association of Social Anxiety Disorder, Alcohol Use Disorder and reproduction: Results from four nationally representative samples of adults in the USA. AB - Social Anxiety Disorder (SAD) and Alcohol Use Disorder (AUD) are highly prevalent and frequently co-occur. The results of population studies suggest that SAD tends to precede AUD, and the results of laboratory studies suggest that alcohol use facilitates social behaviors in socially anxious individuals. Therefore, we posited that, in a modern context, a tendency to consume alcohol may be positively selected for among socially anxious individuals by its effect on the likelihood of finding a partner and reproducing. We tested the hypothesis that a higher proportion of individuals with a lifetime diagnosis of SAD and AUD reproduce (i.e., have at least one child) relative to individuals with SAD absent AUD in an individual participant meta-analysis based on over 65,000 adults derived from four nationally representative cross-sectional samples. We then cross-validated these findings against the results of a 10-year follow up of one of these surveys. Lifetime history of SAD was not associated with reproduction whereas lifetime history of AUD was positively associated with reproduction. There was no statistically detectable difference in the proportion of individuals with a lifetime history of SAD with or without AUD who reproduced. There was considerable heterogeneity in all of the analyses involving SAD, suggesting that there are likely to be other pertinent variables relating to SAD and reproduction that should be delineated. PMID- 29161320 TI - In-vivo effects of intraocular and intracranial pressures on the lamina cribrosa microstructure. AB - There is increasing clinical evidence that the eye is not only affected by intraocular pressure (IOP), but also by intracranial pressure (ICP). Both pressures meet at the optic nerve head of the eye, specifically the lamina cribrosa (LC). The LC is a collagenous meshwork through which all retinal ganglion cell axons pass on their way to the brain. Distortion of the LC causes a biological cascade leading to neuropathy and impaired vision in situations such as glaucoma and idiopathic intracranial hypertension. While the effect of IOP on the LC has been studied extensively, the coupled effects of IOP and ICP on the LC remain poorly understood. We investigated in-vivo the effects of IOP and ICP, controlled via cannulation of the eye and lateral ventricle in the brain, on the LC microstructure of anesthetized rhesus monkeys eyes using the Bioptigen spectral-domain optical coherence tomography (OCT) device (Research Triangle, NC). The animals were imaged with their head upright and the rest of their body lying prone on a surgical table. The LC was imaged at a variety of IOP/ICP combinations, and microstructural parameters, such as the thickness of the LC collagenous beams and diameter of the pores were analyzed. LC microstructure was confirmed by histology. We determined that LC microstructure deformed in response to both IOP and ICP changes, with significant interaction between the two. These findings emphasize the importance of considering both IOP and ICP when assessing optic nerve health. PMID- 29161322 TI - Altered juvenile fish communities associated with invasive Halophila stipulacea seagrass habitats in the U.S. Virgin Islands. AB - Caribbean seagrass habitats provide food and protection for reef-associated juvenile fish. The invasive seagrass Halophila stipulacea is rapidly altering these seascapes. Since its arrival in the Caribbean in 2002, H. stipulacea has colonized and displaced native seagrasses, but the function of this invasive seagrass as a juvenile fish habitat remains unknown. To compare diversity, community structure, and abundance of juvenile fish between H. stipulacea and native seagrass beds, fish traps were deployed in four nearshore bays around St. Thomas, U.S. Virgin Islands. Traps were deployed in Frenchman, Lindbergh, and Sprat Bays for 24 h intervals in patches of bare sand, patches of H. stipulacea and patches of the native Caribbean seagrasses Thalassia testudinum and Syringodium filiforme. Traps were then deployed in Brewers Bay for 12 h intervals in stands of H. stipulacea and S. filiforme. Relative and total abundances of juvenile fish, identified at least to family, were compared across treatment habitats for each trap deployment period. The catch from H. stipulacea, compared to native seagrasses, comprised a greater abundance of nocturnal carnivores Lutjanus synagris (family Lutjanidae) and Haemulon flavolineatum (family Haemulidae). Additionally, the herbivore species Sparisoma aurofrenatum (family Labridae) and Acanthurus bahianus (family Acanthuridae) and the diurnal carnivore species Pseudopeneus maculatus (family Mullidae) were relatively scarce in H. stipulacea. The catch from sand was much smaller, compared to vegetated habitats, and comprised only L. synagris, H. flavolineatum, and H. aurolineatum. These results provide evidence of reduced family diversity and altered juvenile fish assemblages in H. stipulacea, driven by an abundance of some nocturnal carnivores and scarcity of herbivores and diurnal carnivores. The findings from the present work underpin the need for further investigation and mitigation of this invasion, particularly where H. stipulacea is driving seascape-alterations of key juvenile fish habitats. PMID- 29161323 TI - Correction: Conjugated Linoleic Acid Administration Induces Amnesia in Male Sprague Dawley Rats and Exacerbates Recovery from Functional Deficits Induced by a Controlled Cortical Impact Injury. AB - [This corrects the article DOI: 10.1371/journal.pone.0169494.]. PMID- 29161324 TI - Patterns and determinants of plant biodiversity in non-commercial forests of eastern China. AB - Non-commercial forests represent important habitats for the maintenance of biodiversity and ecosystem function in China, yet no studies have explored the patterns and determinants of plant biodiversity in these human dominated landscapes. Here we test the influence of (1) forest type (pine, mixed, and broad leaved), (2) disturbance history, and (3) environmental factors, on tree species richness and composition in 600 study plots in eastern China. In total, we found 143 species in 53 families of woody plants, with a number of species rare and endemic in the study region. Species richness in mixed forest and broad-leaved forest was higher than that in pine forest, and was higher in forests with less disturbance. Species composition was influenced by environment factors in different ways in different forest types, with important variables including elevation, soil depth and aspect. Surprisingly, we found little effect of forest age after disturbance on species composition. Most non-commercial forests in this region are dominated by species poor pine forests and mixed young forests. As such, our results highlight the importance of broad-leaved forests for regional plant biodiversity conservation. To increase the representation of broad-leaved non-commercial forests, specific management practices such as thinning of pine trees could be undertaken. PMID- 29161321 TI - Association mapping unveils favorable alleles for grain iron and zinc concentrations in lentil (Lens culinaris subsp. culinaris). AB - Lentil is a major cool-season grain legume grown in South Asia, West Asia, and North Africa. Populations in developing countries of these regions have micronutrient deficiencies; therefore, breeding programs should focus more on improving the micronutrient content of food. In the present study, a set of 96 diverse germplasm lines were evaluated at three different locations in India to examine the variation in iron (Fe) and zinc (Zn) concentration and identify simple sequence repeat (SSR) markers that associate with the genetic variation. The genetic variation among genotypes of the association mapping (AM) panel was characterized using a genetic distance-based and a general model-based clustering method. The model-based analysis identified six subpopulations, which satisfactorily explained the genetic structure of the AM panel. AM analysis identified three SSRs (PBALC 13, PBALC 206, and GLLC 563) associated with grain Fe concentration explaining 9% to 11% of phenotypic variation and four SSRs (PBALC 353, SSR 317-1, PLC 62, and PBALC 217) were associated with grain Zn concentration explaining 14%, to 21% of phenotypic variation. These identified SSRs exhibited consistent performance across locations. These candidate SSRs can be used in marker-assisted genetic improvement for developing Fe and Zn fortified lentil varieties. Favorable alleles and promising genotypes identified in this study can be utilized for lentil biofortification. PMID- 29161325 TI - The mechanisms of humic substances self-assembly with biological molecules: The case study of the prion protein. AB - Humic substances (HS) are the largest constituent of soil organic matter and are considered as a key component of the terrestrial ecosystem. HS may facilitate the transport of organic and inorganic molecules, as well as the sorption interactions with environmentally relevant proteins such as prions. Prions enter the environment through shedding from live hosts, facilitating a sustained incidence of animal prion diseases such as Chronic Wasting Disease and scrapie in cervid and ovine populations, respectively. Changes in prion structure upon environmental exposure may be significant as they can affect prion infectivity and disease pathology. Despite its relevance, the mechanisms of prion interaction with HS are still not completely understood. The goal of this work is to advance a structural-level picture of the encapsulation of recombinant, non-infectious, prion protein (PrP) into different natural HS. We observed that PrP precipitation upon addition of HS is mainly driven by a mechanism of "salting-out" whereby PrP molecules are rapidly removed from the solution and aggregate in insoluble adducts with humic molecules. Importantly, this process does not alter the protein folding since insoluble PrP retains its alpha-helical content when in complex with HS. The observed ability of HS to promote PrP insolubilization without altering its secondary structure may have potential relevance in the context of "prion ecology". These results suggest that soil organic matter interacts with prions possibly without altering the protein structures. This may facilitate prions preservation from biotic and abiotic degradation leading to their accumulation in the environment. PMID- 29161326 TI - Fasting glucose and risk of colorectal cancer in the Korean Multi-center Cancer Cohort. AB - Previous cohort studies have demonstrated a positive association between diabetes mellitus (DM) and colorectal cancer (CRC). However, there are few comparisons between DM groups categorized by fasting glucose level. This study examined associations between diabetes as defined by fasting glucose level and self reported history of DM and CRC risk among Korean adults. Data from the Korean Multi-center Cancer Cohort between 1993 and 2005 were analyzed. The study population comprised 14,570 participants aged 20 years or older. Participants were followed until December 31, 2012 (median follow-up: 11.9 years). Among participants with high fasting glucose (>=126mg/dL), the risk of developing CRC was significantly higher (HR: 1.51 [1.02-2.25]) than among participants with low fasting glucose (<126mg/dL). Risk was not significantly higher among participants with self-reported history of DM (HR: 1.34 [0.78-2.31]). When both fasting glucose and history of DM were considered together, the risk of CRC among participants with both high fasting glucose and history of DM was 54% (HR: 1.54 [0.97-2.43]), and the risk of CRC among participants with high fasting glucose and no history of DM was 50% (HR: 1.50 [0.73-3.05]). When the first 5 years of follow-up were excluded, among participants with high fasting glucose, the risk of developing CRC was significantly higher (HR: 1.61 [1.02-2.56]) than among participants with low fasting glucose. Risk of CRC was also significantly higher among participants with high fasting glucose and no history of DM (HR: 1.69 [1.01 2.84]). High fasting glucose and self-reported history of DM were associated with increased risk of CRC in this Korean population. PMID- 29161327 TI - Thallium stimulates ethanol production in immortalized hippocampal neurons. AB - Lactate and ethanol (EtOH) were determined in cell culture medium (CCM) of immortalized hippocampal neurons (HN9.10e cell line) before and after incubation with Thallium (Tl). This cell line is a reliable, in vitro model of one of the most vulnerable regions of central nervous system. Cells were incubated for 48 h with three different single Tl doses: 1, 10, 100 MUg/L (corresponding to 4.9, 49 and 490 nM, respectively). After 48 h, neurons were "reperfused" with fresh CCM every 24/48 h until 7 days after the treatment and the removed CCM was collected and analysed. Confocal microscopy was employed to observe morphological changes. EtOH was determined by head space-solid phase microextraction -gas chromatography -mass spectrometry (HS-SPME-GCMS), lactate by RP-HPLC with UV detection. Tl exposure had significant effects on neuronal growth rate and morphology. The damage degree was dose-dependent. In not exposed cells, EtOH concentration was 0.18 +/- 0.013 mM, which represents about 5% of lactate concentration (3.4 +/- 0.10 mM). After Tl exposure lactate and EtOH increased. In CCM of 100 and 10 MUg/L Tl-treated cells, lactate increased 24 h after reperfusion up to 2 and 3.3 times the control value, respectively. In CCM of 10 and 100 MUg/L Tl-treated cells 24 h after reperfusion, EtOH increased up to 0.3 and 0.58 mmol/L. respectively. These results are consistent with significant alterations in energy metabolism, despite the low doses of Tl employed and the relatively short incubation time. PMID- 29161328 TI - Use of QuantiFERON(r)-TB Gold in-tube culture supernatants for measurement of antibody responses. AB - QuantiFERON(r)-TB Gold in-tube (QFT-GIT) supernatants may be important samples for use in assessment of anti-tuberculosis (TB) antibodies when only limited volumes of blood can be collected and when a combination of antibody and cytokine measurements are required. These analytes, when used together, may also have the potential to differentiate active pulmonary TB (APTB) from latent TB infection (LTBI). However, few studies have explored the use of QFT-GIT supernatants for investigations of antibody responses. This study determined the correlation and agreement between anti-CFP-10 and anti-ESAT-6 antibody concentrations in QFT-GIT nil supernatant and serum pairs from 68 TB household contacts. We also explored the ability of Mycobacterium tuberculosis (M.tb) specific antibodies, or ratios of antibody to interferon gamma (IFN-gamma) in QFT-GIT supernatants, to differentiate 97 APTB cases from 58 individuals with LTBI. Sputum smear microscopy was used to define APTB, whereas the QFT-GIT and tuberculin skin test were used to define LTBI. There were strong and statistically significant correlations between anti-CFP-10 and anti-ESAT-6 antibodies in unstimulated QFT GIT supernatants and sera (r = 0.89; p<0.0001 for both), and no significant differences in antibody concentration between them. Anti-CFP-10 & anti-ESAT-6 antibodies differentiated APTB from LTBI with sensitivities of 88.7% & 71.1% and specificities of 41.4% & 51.7% respectively. Anti-CFP-10 antibody/M.tb specific IFN-gamma and anti-ESAT-6 antibody/M.tb specific IFN-gamma ratios had sensitivities of 48.5% & 54.6% and specificities of 89.7% and 75.9% respectively. We conclude that QFT-GIT nil supernatants may be used in the place of sera when measuring antibody responses, reducing blood volumes needed for such investigations. Antibodies in QFT-GIT nil supernatants on their own discriminate APTB from LTBI with high sensitivity but have poor specificity, whereas the reverse is true when antibodies are used in combination with M.tb specific cytokines. Further antibody and antibody/cytokine combinations need to be explored to achieve better diagnostic accuracy. PMID- 29161329 TI - Comparative metabolomics profiling of engineered Saccharomyces cerevisiae lead to a strategy that improving beta-carotene production by acetate supplementation. AB - A comparative metabolomic analysis was conducted on recombinant Saccharomyces cerevisiae strain producing beta-carotene and the parent strain cultivated with glucose as carbon source using gas chromatography-mass spectrometry (GC-MS), high performance liquid chromatography-mass spectrometry (HPLC-MS) and ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) based approach. The results showed that most of the central intermediates associated with amino acids, carbohydrates, glycolysis and TCA cycle intermediates (acetic acid, glycerol, citric acid, pyruvic acid and succinic acid), fatty acids, ergosterol and energy metabolites were produced in a lower amount in recombinant strain, as compared to the parent strain. To increase beta-carotene production in recombinant strain, a strategy that exogenous addition of acetate (10 g/l) in exponential phase was developed, which could enhance most intracellular metabolites levels and result in 39.3% and 14.2% improvement of beta-carotene concentration and production, respectively, which was accompanied by the enhancement of acetyl-CoA, fatty acids, ergosterol and ATP contents in cells. These results indicated that the amounts of intracellular metabolites in engineered strain are largely consumed by carotenoid formation. Therefore, maintaining intracellular metabolites pool at normal levels is essential for carotenoid biosynthesis. To relieve this limitation, rational supplementation of acetate could be a potential way because it can partially restore the levels of intracellular metabolites and improve the production of carotenoid compounds in recombinant S. cerevisiae. PMID- 29161330 TI - Fasciola spp: Mapping of the MF6 epitope and antigenic analysis of the MF6p/HDM family of heme-binding proteins. AB - MF6p/FhHDM-1 is a small cationic heme-binding protein which is recognized by the monoclonal antibody (mAb) MF6, and abundantly present in parenchymal cells and secreted antigens of Fasciola hepatica. Orthologs of this protein (MF6p/HDMs) also exist in other causal agents of important foodborne trematodiasis, such as Clonorchis sinensis, Opisthorchis viverrini and Paragonimus westermani. Considering that MF6p/FhHDM-1 is relevant for heme homeostasis in Fasciola and was reported to have immunomodulatory properties, this protein is expected to be a useful target for vaccination. Thus, in this study we mapped the epitope recognized by mAb MF6 and evaluated its antigenicity in sheep. The sequence of the MF6p/FhHDM-1 ortholog from F. gigantica (MF6p/FgHDM-1) was also reported. By means of ELISA inhibitions with overlapping synthetic peptides, we determined that the epitope recognized by mAb MF6 is located within the C-terminal moiety of MF6p/FhHDM-1, which is the most conserved region of MF6p/HDMs. By immunoblotting analysis of parasite extracts and ELISA inhibitions with synthetic peptides we also determined that mAb MF6 reacted with the same intensity with F. hepatica and F. gigantica, and in decreasing order of intensity with C. sinensis, O.viverrini and P. westermani orthologs. On the contrary, mAb MF6 showed no reactivity against Dicrocoelium dendriticum and Schistosoma mansoni. The study of the recognition of peptides covering different regions of MF6p/FhHDM-1 by sera from immunized sheep revealed that the C-terminal moiety is the most antigenic, thus being of potential interest for vaccination. We also demonstrated that the production of antibodies to MF6p/FhHDM-1 in sheep infected by F. hepatica occurs relatively early and follows the same pattern as those produced against L cathepsins. PMID- 29161331 TI - Combined effects of fruit and vegetables intake and physical activity on the risk of metabolic syndrome among Chinese adults. AB - BACKGROUND: Unbalanced dietary intake and insufficient physical activity (PA) have been recognized as risk factors for metabolic syndrome (MetS). We aimed to examine the independent and combined effects of fruit and vegetables (FV) intake and PA on MetS. METHODS AND FINDINGS: A cross-sectional survey was conducted among residents of China in 2009, with fasting blood samples collected. Participants were divided into sufficient/insufficient FV intake and adequate/ inadequate PA groups according to self-reported questionnaires. MetS was defined using the NCEP-ATPIII criteria. The difference of individual MetS components was compared across different PA or FV groups. Multivariable logistic regression was used to assess association between FV/PA and the risk of MetS. A total of 7424 adults were included in the current study. MetS was prevalent in 28.7% of participants, with 24.7% and 32.9% in male and female, respectively. Compared with those with inadequate PA and insufficient FV intake, participants with the combination of adequate PA and sufficient FV intake had the lowest risk of MetS (OR = 0.69,95%CI: 0.59-0.82), following by the group with adequate PA time but insufficient FV intake (OR = 0.74, 95%CI:0.65-0.83). CONCLUSION: Findings of the current study show that the combination of sufficient FV intake and adequate PA was significantly associated with reduced MetS risk among adult residents of China. PMID- 29161332 TI - Osteoglycin inhibition by microRNA miR-155 impairs myogenesis. AB - Skeletal myogenesis is a regulated process in which mononucleated cells, the myoblasts, undergo proliferation and differentiation. Upon differentiation, the cells align with each other, and subsequently fuse to form terminally differentiated multinucleated myotubes. Previous reports have identified the protein osteoglycin (Ogn) as an important component of the skeletal muscle secretome, which is expressed differentially during muscle development. However, the posttranscriptional regulation of Ogn by microRNAs during myogenesis is unknown. Bioinformatic analysis showed that miR-155 potentially targeted the Ogn transcript at the 3'-untranslated region (3' UTR). In this study, we tested the hypothesis that miR-155 inhibits the expression of the Ogn to regulate skeletal myogenesis. C2C12 myoblast cells were cultured and miR-155 overexpression or Ogn knockdown was induced by transfection with miR-155 mimic, siRNA-Ogn, and negative controls with lipofectamine for 15 hours. Near confluence (80-90%), myoblasts were induced to differentiate myotubes in a differentiation medium. Luciferase assay was used to confirm the interaction between miR-155 and Ogn 3'UTR. RT-qPCR and Western blot analyses were used to confirm that the differential expression of miR-155 correlates with the differential expression of myogenic molecular markers (Myh2, MyoD, and MyoG) and inhibits Ogn protein and gene expression in myoblasts and myotubes. Myoblast migration and proliferation were assessed using Wound Healing and MTT assays. Our results show that miR-155 interacts with the 3'UTR Ogn region and decrease the levels of Ogn in myotubes. The overexpression of miR-155 increased MyoG expression, decreased myoblasts wound closure rate, and decreased Myh2 expression in myotubes. Moreover, Ogn knockdown reduced the expression levels of MyoD, MyoG, and Myh2 in myotubes. These results reveal a novel pathway in which miR-155 inhibits Ogn expression to regulate proliferation and differentiation of C2C12 myoblast cells. PMID- 29161333 TI - Precise mass determination of single cell with cantilever-based microbiosensor system. AB - Having determined the mass of a single cell of brewer yeast Saccharomyces cerevisiae by means of a microcantilever-based biosensor Cantisens CSR-801 (Concentris, Basel, Switzerland), it was found that its dry mass is 47,65 +/- 1,05 pg. Found to be crucial in this mass determination was the cell position along the length of the cantilever. Moreover, calculations including cells positions on the cantilever provide a threefold better degree of accuracy than those which assume uniform mass distribution. We have also examined the influence of storage time on the single cell mass. Our results show that after 6 months there is an increase in the average mass of a single yeast cell. PMID- 29161334 TI - Correction: CFD study on NACA 4415 airfoil implementing spherical and sinusoidal Tubercle Leading Edge. AB - [This corrects the article DOI: 10.1371/journal.pone.0183456.]. PMID- 29161336 TI - Efficacy of Electrical Stimulation of the Occipital Nerve in Intractable Primary Headache Disorders: A Systematic Review with Meta-Analyses. AB - AIMS: To determine the efficacy of occipital nerve stimulation (ONS) in reducing the intensity, duration, and frequency of medically intractable primary headaches. METHODS: A systematic review was carried out by searching three electronic databases: the Cochrane Library, MEDLINE via PubMed, and Web of Science. Randomized controlled trials (RCTs) and case series were eligible for inclusion. RCTs were assessed for quality of evidence by using the Cochrane Risk of Bias and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tools. Descriptive statistics of reported outcomes in eligible studies are presented in tabular form. Meta-analyses of RCTs comparing ONS therapy to sham therapy in chronic migraine patients were conducted for the outcomes responder rate, headache frequency, and headache intensity. RESULTS: Four RCTs, 1 follow-up study, and 19 case series met the inclusion criteria. The quality of the evidence was low, with all four RCTs assessed as having a high risk of bias and small sample size. Meta-analyses of three RCTs showed patients receiving ONS therapy had a significant reduction of 3 headache days per month (difference in means = -3.061; 95% confidence interval [CI] = -5.162 to -0.961; P = .004) and a significant reduction in Migraine Disability Assessment score (standardized difference in means [SDM] = -0.634; 95% CI = -0.933 to -0.335; P < .001) compared to sham (subthreshold) therapy. There were no statistically significant differences in reduction in pain intensity (SDM = -1.220; 95% CI = 2.489 to -0.049; P = .060) or in the number of responders (risk ratio [RR] = 1.581; 95% CI = 0.749 to 3.355; P = .229). CONCLUSION: ONS may be effective when compared to sham therapy, but the small number of RCTs and the heterogeneity of outcomes suggest further research in this field is needed. PMID- 29161337 TI - Age at diagnosis and prostate cancer treatment and prognosis: a population-based cohort study. AB - Background: Old age at prostate cancer diagnosis has been associated with poor prognosis in several studies. We aimed to investigate the association between age at diagnosis and prognosis, and if it is independent of tumor characteristics, primary treatment, year of diagnosis, mode of detection and comorbidity. Patients and methods: We conducted a nation-wide cohort study including 121 392 Swedish men aged 55-95 years in Prostate Cancer data Base Sweden 3.0 diagnosed with prostate cancer in 1998-2012 and followed for prostate cancer death through 2014. Data were available on age, stage, grade, prostate-specific antigen (PSA)-level, mode of detection, comorbidity, educational level and primary treatment. We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: With increasing age at diagnosis, men had more comorbidity, fewer PSA-detected cancers, more advanced cancers and were less often treated with curative intent. Among men with high-risk or regionally metastatic disease, the proportion of men with unknown M stage was higher among old men versus young men. During a follow-up of 751 000 person-years, 23 649 men died of prostate cancer. In multivariable Cox-regression analyses stratified by treatment, old age at diagnosis was associated with poorer prognosis among men treated with deferred treatment (HRage 85+ versus 60-64: 7.19; 95% CI: 5.61-9.20), androgen deprivation therapy (HRage 85+ versus 60-64: 1.72; 95% CI: 1.61-1.84) or radical prostatectomy (HRage 75+ versus 60-64: 2.20; 95% CI: 1.01-4.77), but not radiotherapy (HRage 75+ versus 60-64: 1.08; 95% CI: 0.76-1.53). Conclusion: Our findings argue against a strong inherent effect of age on risk of prostate cancer death, but indicate that in current clinical practice, old men with prostate cancer receive insufficient diagnostic workup and subsequent curative treatment. PMID- 29161335 TI - Shoulder complaints in wheelchair athletes: A systematic review. AB - BACKGROUND: In recent years the popularity of disabled sports and competition among disabled athletes has grown considerably. With this rise in exposure of, and participation in wheelchair sports comes an increase in related stressors, including musculoskeletal load. External mechanical loading may increase the risk of shoulder complaints. The objective of this literature review was to 1) identify and describe the prevalence and/or incidence of shoulder complaints in wheelchair athletes in the literature, to 2) examine the factors and underlying mechanisms that could be potentially involved, and 3) provide some insights into the development of preventative measures. METHODS: A literature search was conducted using PubMed, Scopus and Embase databases, to identify relevant published articles. All articles in the English language that contained any type of shoulder complaint in relation with a wheelchair sports player, at any level of status (recreational to elite), of any sport, were included. Articles were excluded if they did not include any statistical analysis. Articles that included studies with wheelchair athletes in combination with athletes of other disability sports were excluded in order to be able to differentiate between the two. Narrative, exploratory and case studies were also excluded. Two reviewers independently assessed articles for inclusion. Thirteen articles matched the selection criteria. These were judged on their quality by use of an adapted version of the Webster checklist. RESULTS: Of the included studies the overall quality was low. A relatively high prevalence of complaints was found, ranging from 16% to 76%. Pain was found to be a common complaint in wheelchair athletes. Based on the current literature the cause of shoulder problems is difficult to identify and is likely multifactorial, nevertheless characteristics of the user (i.e. increased years of disability, age and BMI) were shown to increase risk. Preventative measures were indistinct. There may be a role for balanced strength training regimens to decrease risk. CONCLUSION: Shoulder complaints in wheelchair athletes are a common problem that must be addressed further. Future studies on shoulder overuse injuries of wheelchair athletes should be directed towards biomechanical modeling to develop knowledge of load and its effects. PMID- 29161338 TI - CLIPPERS, a possible symptomatic lymphohistiocytic immune reaction. PMID- 29161339 TI - Astrocyte-Specific Deletion of Sox2 Promotes Functional Recovery After Traumatic Brain Injury. AB - Injury to the adult brain induces activation of local astrocytes, which serves as a compensatory response that modulates tissue damage and recovery. However, the mechanism governing astrocyte activation during brain injury remains largely unknown. Here we provide in vivo evidence that SOX2, a transcription factor critical for stem cells and brain development, is also required for injury induced activation of adult cortical astrocytes. Genome-wide chromatin immunoprecipitation-seq analysis of mouse cortical tissues reveals that SOX2 binds to regulatory regions of genes associated with signaling pathways that control glial cell activation, such as Nr2e1, Mmd2, Wnt7a, and Akt2. Astrocyte specific deletion of Sox2 in adult mice greatly diminishes glial response to controlled cortical impact injury and, most unexpectedly, dampens injury-induced cortical loss and benefits behavioral recovery of mice after injury. Together, these results uncover an essential role of SOX2 in somatic cells under pathological conditions and indicate that SOX2-dependent astrocyte activation could be targeted for functional recovery after traumatic brain injury. PMID- 29161340 TI - Prefrontal Executive Control Rescues Risk for Anxiety Associated with High Threat and Low Reward Brain Function. AB - Compared with neural biomarkers of risk for mental illness, little is known about biomarkers of resilience. We explore if greater executive control-related prefrontal activity may function as a resilience biomarker by "rescuing" risk associated with higher threat-related amygdala and lower reward-related ventral striatum activity. Functional MRI was used to assay baseline threat-related amygdala, reward-related ventral striatum, and executive control-related prefrontal activity in 120 young adult volunteers. Participants provided self reported mood and anxiety ratings at baseline and follow-up. A moderation model revealed a significant three-way interaction wherein higher amygdala and lower ventral striatum activity predicted increases in anxiety in those with average or low but not high prefrontal activity. This effect was specific to anxiety, with the neural biomarkers explaining ~10% of the variance in change over time, above and beyond baseline symptoms, sex, age, IQ, presence or absence of DMS-IV diagnosis, and both early and recent stress. Our findings are consistent with the importance of top-down executive control in adaptive regulation of negative emotions, and highlight a unique combination of neural biomarkers that may identify at-risk individuals for whom the adoption of strategies to improve executive control of negative emotions may prove particularly beneficial. PMID- 29161342 TI - Oral Frailty as a Risk Factor for Physical Frailty and Mortality in Community Dwelling Elderly. AB - Background: Oral health is important for maintaining general health among the elderly. However, a longitudinal association between poor oral health and general health has not been reported. We investigated whether poor oral status can predict physical weakening (physical frailty, sarcopenia, and subsequent disability) and identified the longitudinal impact of the accumulated poor oral health (i.e. oral frailty) on adverse health outcomes, including mortality. Methods: A total of 2,011 elderly individuals (aged >= 65 years) participated in the baseline survey of the Kashiwa study in 2012. At baseline, 16 oral status measures and covariates such as demographic characteristics were assessed. As outcomes, physical frailty and sarcopenia were assessed at baseline and at follow up in 2013 and 2014. Physical independence and survival were assessed from 2012 to 2016 at the time of long-term care certification and time of death. Results: Poor oral status as determined by the number of natural teeth, chewing ability, articulatory oral motor skill, tongue pressure, and subjective difficulties in eating and swallowing significantly predicted future physical weakening (new onsets of physical frailty, sarcopenia, and disability). Oral frailty was defined as co-existing poor status in >=3 of the six measures. Sixteen per cent of participants had oral frailty at baseline, which was significantly associated with 2.4-, 2.2-, 2.3-, and 2.2-fold increased risk of physical frailty, sarcopenia, disability, and mortality, respectively. Conclusion: Accumulated poor oral status strongly predicted the onset of adverse health outcomes, including mortality among the community-dwelling elderly. Prevention of oral frailty at an earlier stage is essential for healthy aging. PMID- 29161341 TI - Distinct spatiotemporal accumulation of N-truncated and full-length amyloid beta42 in Alzheimer's disease. AB - Accumulation of amyloid-beta peptides is a dominant feature in the pathogenesis of Alzheimer's disease; however, it is not clear how individual amyloid-beta species accumulate and affect other neuropathological and clinical features in the disease. Thus, we compared the accumulation of N-terminally truncated amyloid beta and full-length amyloid-beta, depending on disease stage as well as brain area, and determined how these amyloid-beta species respectively correlate with clinicopathological features of Alzheimer's disease. To this end, the amounts of amyloid-beta species and other proteins related to amyloid-beta metabolism or Alzheimer's disease were quantified by enzyme-linked immunosorbent assays (ELISA) or theoretically calculated in 12 brain regions, including neocortical, limbic and subcortical areas from Alzheimer's disease cases (n = 19), neurologically normal elderly without amyloid-beta accumulation (normal ageing, n = 13), and neurologically normal elderly with cortical amyloid-beta accumulation (pathological ageing, n = 15). We observed that N-terminally truncated amyloid beta42 and full-length amyloid-beta42 accumulations distributed differently across disease stages and brain areas, while N-terminally truncated amyloid beta40 and full-length amyloid-beta40 accumulation showed an almost identical distribution pattern. Cortical N-terminally truncated amyloid-beta42 accumulation was increased in Alzheimer's disease compared to pathological ageing, whereas cortical full-length amyloid-beta42 accumulation was comparable between Alzheimer's disease and pathological ageing. Moreover, N-terminally truncated amyloid-beta42 were more likely to accumulate more in specific brain areas, especially some limbic areas, while full-length amyloid-beta42 tended to accumulate more in several neocortical areas, including frontal cortices. Immunoprecipitation followed by mass spectrometry analysis showed that several N terminally truncated amyloid-beta42 species, represented by pyroglutamylated amyloid-beta11-42, were enriched in these areas, consistent with ELISA results. N terminally truncated amyloid-beta42 accumulation showed significant regional association with BACE1 and neprilysin, but not PSD95 that regionally associated with full-length amyloid-beta42 accumulation. Interestingly, accumulations of tau and to a greater extent apolipoprotein E (apoE, encoded by APOE) were more strongly correlated with N-terminally truncated amyloid-beta42 accumulation than those of other amyloid-beta species across brain areas and disease stages. Consistently, immunohistochemical staining and in vitro binding assays showed that apoE co-localized and bound more strongly with pyroglutamylated amyloid beta11-x fibrils than full-length amyloid-beta fibrils. Retrospective review of clinical records showed that accumulation of N-terminally truncated amyloid beta42 in cortical areas was associated with disease onset, duration and cognitive scores. Collectively, N-terminally truncated amyloid-beta42 species have spatiotemporal accumulation patterns distinct from full-length amyloid beta42, likely due to different mechanisms governing their accumulations in the brain. These truncated amyloid-beta species could play critical roles in the disease by linking other clinicopathological features of Alzheimer's disease. PMID- 29161343 TI - Distinct reorganization of collagen architecture in lipopolysaccharide-mediated premature cervical remodeling. AB - Previous work has identified divergent mechanisms by which cervical remodeling is achieved in preterm birth (PTB) induced by hormone withdrawal (mifepristone) or lipopolysaccharide (LPS). Our current study aims to document how collagen architecture is modified to achieve premature cervical remodeling in mice treated with LPS as a model of infection-induced inflammation. Cervices were collected on gestation day (d) 15 from mice with premature cervical ripening induced by LPS and compared to d15 and d18 controls as well as a hormone withdrawal PTB model. Second harmonic generation (SHG) and electron microscopy were utilized for visualization of collagen morphology and ultrastructure. LPS-mediated premature cervical ripening is characterized by unique structural changes in collagen fiber morphology. LPS treatment increased the interfibrillar spacing of collagen fibrils. A preferential disruption of collagen fiber architecture in the subepithelial region compared to midstroma region was evidenced by increased pores lacking collagen signal in SHG images in the LPS-treated mice. Coinciding with this alteration, the infiltration of neutrophils was concentrated in the subepithelial stromal region as compared to midstromal region implicating the potential role of immune cells to extracellular matrix reorganization in inflammation-induced preterm cervical ripening. The current study demonstrates a preferential disorganization of collagen interfibrillar spacing and collagen fiber structure in LPS-mediated ripening. PMID- 29161345 TI - An interview with Dr Sudhansu K. Dey. PMID- 29161346 TI - Co-Transplantation of Nanofat Enhances Neovascularization and Fat Graft Survival in Nude Mice. AB - Background: Autologous fat grafting is commonly used for soft-tissue augmentation and reconstruction. However, this technique is limited by a high rate of graft absorption. Thus, approaches to improve fat graft survival that promote neovascularization are of great interest. Nanofat has several beneficial features that may render it more suitable for clinical applications than other stem-cell based approaches. Objectives: We aimed to determine whether nanofat could enhance new vessel formation and improve the long-term retention of fat grafts. Methods: Nanofat was processed via mechanical emulsification and filtration. Fat grafts were transplanted subcutaneously under the scalps of nude mice with different nanofat volumes or without nanofat. The grafted fat was dissected 12 weeks after transplantation. Graft weight and volume were measured, and histological evaluations, including capillary density measurement, were performed. Results: The co-transplantation of fat with nanofat showed higher graft weight and volume retention, better histological structure, and higher capillary density compared to that in controls. However, there were no significant differences between the two nanofat volumes utilized. Conclusions: Nanofat can enhance neovascularization and improve fat graft survival, providing a potential clinically viable approach to fat graft supplementation in plastic and reconstructive surgery. PMID- 29161344 TI - Nuclear localization of EIF4G3 suggests a role for the XY body in translational regulation during spermatogenesis in mice. AB - Eukaryotic translation initiation factor 4G (EIF4G) is an important scaffold protein in the translation initiation complex. In mice, mutation of the Eif4g3 gene causes male infertility, with arrest of meiosis at the end of meiotic prophase. This study documents features of the developmental expression and subcellular localization of EIF4G3 that might contribute to its highly specific role in meiosis and spermatogenesis. Quite unexpectedly, EIF4G3 is located in the nucleus of spermatocytes, where it is highly enriched in the XY body, the chromatin domain formed by the transcriptionally inactive sex chromosomes. Moreover, many other, but not all, translation-related proteins are also localized in the XY body. These unanticipated observations implicate roles for the XY body in controlling mRNA metabolism and/or "poising" protein translation complexes before the meiotic division phase in spermatocytes. PMID- 29161348 TI - Multi-institutional competing risks analysis of distant brain failure and salvage patterns after upfront radiosurgery without whole brain radiotherapy for brain metastasis. AB - Background: In this study, we use a competing risks analysis to assess factors predictive of early-salvage whole brain radiotherapy (WBRT) and early death after upfront stereotactic radiosurgery (SRS) alone for brain metastases in an attempt to identify populations that benefit less from upfront SRS. Patients and methods: Patients from eight academic centers were treated with SRS for brain metastasis. Competing risks analysis was carried out for distant brain failure (DBF) versus death prior to DBF as well as for salvage SRS versus salvage WBRT versus death prior to salvage. Linear regression was used to determine predictors of the number of brain metastases at initial DBF (nDBF). Results: A total of 2657 patients were treated with upfront SRS alone. Multivariate analysis (MVA) identified an increased hazard of DBF associated with increasing number of brain metastases (P < 0.001), lowest SRS dose received (P < 0.001), and melanoma histology (P < 0.001), while there was a decreased hazard of DBF associated with increasing age (P < 0.001), KPS < 70 (P < 0.001), and progressive systemic disease (P = 0.004). MVA for first salvage SRS versus WBRT versus death prior to salvage revealed an increased hazard of first salvage WBRT seen with increasing number of brain metastases (P < 0.001) and a decreased hazard with widespread systemic disease (P = 0.002) and increasing age (P < 0.001). Variables associated with nDBF included age (P = 0.02), systemic disease status (P = 0.03), melanoma histology (P = 0.05), and initial number of brain metastases (P < 0.001). Conclusions: Patients with a higher initial number of brain metastases were more likely to experience DBF, have a higher nDBF, and receive early-salvage WBRT, while patients who were older, had lower KPS, or had more systemic disease were more likely to experience death prior to DBF or salvage WBRT. PMID- 29161347 TI - Pharmacological blockage of the CXCR4-CXCL12 axis in endometriosis leads to contrasting effects in proliferation, migration, and invasion. AB - High levels of inflammatory factors including chemokines have been reported in peritoneal fluid and blood of women with endometriosis. CXCL12 mediates its action by interaction with its specific receptor, CXCR4, reported to be elevated in human endometriosis lesions and in the rat model of endometriosis. Activation of the CXCR4-CXCL12 axis increases cell proliferation, migration, and invasion of cancer cells. To obtain insights into the CXCR4 expression profile in lesions and endometrium, as well as functionality of the CXCR4-CXCL12 axis in endometriosis, we analyzed the expression of CXCR4 in tissues on a human tissue array and studied CXCL12-mediated activation of proliferation, invasion, and migration in vitro. We observed differences in levels of nuclear CXCR4 expression among lesion types, being higher in ovarian lesions. Endometriotic cell lines (12Z) showed higher levels of CXCR4, proliferative and migratory potential, and AKT phosphorylation/kinase activity compared to untreated control cells (endometrial epithelial cells). CXCL12 and endometriotic stromal cell-enriched media increased proliferation of non-endometriotic epithelial cells. CXCL12 caused a significant increase in 12Z cell invasion but had no effect on migration; AMD3100, a CXCR4 specific inhibitor, significantly increased invasion of 12Z cells but decreased their migration. However, treatment with CXCL12 plus AMD3100 significantly decreased invasion and migration of 12Z cells. In conclusion, the CXCR4-CXCL12 axis is functional in endometriosis cells, but the expression of CXCR4 varies among lesions. CXCL12 promoted proliferation, migration, and invasion of endometriotic cells, while inducing AKT phosphorylation and activity, but pharmacologically blocking this axis in the absence of the ligand induced their invasiveness. PMID- 29161349 TI - Relation of Retinal and Serum Lutein and Zeaxanthin to White Matter Integrity in Older Adults: A Diffusion Tensor Imaging Study. AB - Objective: Lutein (L) and zeaxanthin (Z) are phytonutrients that accumulate in human brain tissue and positively impact cognition. Given their antioxidant and anti-inflammatory properties and their role in stabilizing cell membranes, L&Z may relate to measures of white matter integrity (WMI). Method: The current study tested the relation of retinal (macular pigment optical density/MPOD) and blood serum concentrations of L&Z to WMI in community-dwelling older adults (n = 54) using diffusion tensor imaging (DTI). Younger adults (n = 38) were recruited as a control group to confirm age-related changes in WMI. A priori analyses focused on four regions of interest (ROIs-genu of the corpus callosum, cingulum, fornix, and uncinate fasciculus). Exploratory whole-brain analyses were also conducted. Results: Consistent with previous literature, age group (young vs. old) negatively predicted WMI globally, in the genu, cingulum, and fornix (p < .001). ROI analysis in the older adult sample showed relations of MPOD and serum L&Z to better WMI in the uncinate fasciculus and cingulum (p < .05, FWE-corrected). Whole-brain analysis suggested associations between L&Z and WMI in both anterior white matter tracts vulnerable to age-related decline and posterior tracts (p < .01, uncorrected). Conclusions: The current study is among the first to use neuroimaging to measure the relation of L&Z to brain structure in vivo. Results confirm previous findings that L&Z influence white matter integrity, particularly in regions vulnerable to age-related decline. The current study contributes to a growing literature investigating the relationship between diet and neural integrity by identifying white matter tracts that may be associated with modifiable dietary factors in older adults. PMID- 29161350 TI - Embedded Performance Validity Tests in the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised: A Replication Study. AB - Objective: Embedded performance validity tests (PVTs) within the Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT R) were recently identified. This study aimed to further validate/replicate these embedded PVTs. Method: Eighty clinically referred veterans who underwent neuropsychological evaluation were included. Validity groups were established by passing/failing 2-3 well-validated PVTs, with 75% (n = 60) classified as valid and 25% (n = 20) noncredible. Fifty-two percent of valid participants were cognitively impaired. Results: HVLT-R Recognition Discrimination (RD) of <=5 yielded 67% sensitivity/80% specificity for identifying noncredible performance. Removal of seven valid participants with an amnestic profile who produced a false positive, improved specificity to 92%, which replicated the original findings. Replication efforts failed for BVMT-R Percent Retained; however, significant findings for RD were elucidated. Conclusion: Replication efforts were positive for the HVLT-R embedded PVT, corroborating its ability to identify invalid performance in this heterogeneous clinical veteran sample with and without cognitive impairment. PMID- 29161351 TI - Echoes of Affective Stimulation in Brain connectivity Networks. AB - Affective experience has effects on subjective feelings, physiological indices, entails immediate activity changes in the brain, and even influences brain networks in a protracted manner. However, it is still unclear, how the functional connectivity (FC) interplay between major intrinsic connectivity networks upon affective stimulation depends on affective valence, and whether this is specific for affective experience, i.e., can be distinguished from cognitive task execution. Our study included fMRI scans during and after affective stimulation with sad and neutral movies and a working memory task complemented with measures of cardiovascular activity and mood. Via parcellation of the brain into default mode network (DMN), central executive network (CEN), and dorsal attention network, and application of network-based statistics, we identified subnetworks associated with changing psychological contexts. Specific effects for affective stimulation with negative valence were both reduced heart rate variability and mood, and upregulated FC of inter-CEN-DMN connections while intra-DMN connections were downregulated. Furthermore, results demonstrated a valence-specific dynamic carry-over effect in nodes of the CEN, which temporarily increased their FC strength after affective stimulation with negative valence and exhibited distinct temporal profiles. The reported effects were clearly distinguishable from those of a cognitive task and further elucidate the trajectory of affective experience. PMID- 29161352 TI - Delta Rhythm Orchestrates the Neural Activity Underlying the Resting State BOLD Signal via Phase-amplitude Coupling. AB - Spontaneous ongoing neuronal activity is a prominent feature of the mammalian brain. Temporal and spatial patterns of such ongoing activity have been exploited to examine large-scale brain network organization and function. However, the neurophysiological basis of this spontaneous brain activity as detected by resting-state functional Magnetic Resonance Imaging (fMRI) remains poorly understood. To this end, multi-site local field potentials (LFP) and blood oxygenation level-dependent (BOLD) fMRI were simultaneously recorded in the rat striatum along with local pharmacological manipulation of striatal activity. Results demonstrate that delta (delta) band LFP power negatively, while beta (beta) and gamma (gamma) band LFPs positively correlated with BOLD fluctuation. Furthermore, there was strong cross-frequency phase-amplitude coupling (PAC), with the phase of delta LFPs significantly modulating the amplitude of the high frequency signal. Enhancing dopaminergic neuronal activity significantly reduced ventral striatal functional connectivity, delta LFP-BOLD correlation, and the PAC effect. These data suggest that different frequency bands of the LFP contribute distinctively to BOLD spontaneous fluctuation and that PAC is the organizing mechanism through which low frequency LFPs orchestrate neural activity that underlies resting state functional connectivity. PMID- 29161353 TI - Novel treatment options for refractory Germ Cell Tumours: back to the bench! PMID- 29161354 TI - p140Cap Regulates GABAergic Synaptogenesis and Development of Hippocampal Inhibitory Circuits. AB - The neuronal scaffold protein p140Cap was investigated during hippocampal network formation. p140Cap is present in presynaptic GABAergic terminals and its genetic depletion results in a marked alteration of inhibitory synaptic activity. p140Cap /- cultured neurons display higher frequency of miniature inhibitory postsynaptic currents (mIPSCs) with no changes of their mean amplitude. Consistent with a potential presynaptic alteration of basal GABA release, p140Cap-/- neurons exhibit a larger synaptic vesicle readily releasable pool, without any variation of single GABAA receptor unitary currents and number of postsynaptic channels. Furthermore, p140Cap-/- neurons show a premature and enhanced network synchronization and appear more susceptible to 4-aminopyridine-induced seizures in vitro and to kainate-induced seizures in vivo. The hippocampus of p140Cap-/- mice showed a significant increase in the number of both inhibitory synapses and of parvalbumin- and somatostatin-expressing interneurons. Specific deletion of p140Cap in forebrain interneurons resulted in increased susceptibility to in vitro epileptic events and increased inhibitory synaptogenesis, comparable to those observed in p140Cap-/- mice. Altogether, our data demonstrate that p140Cap finely tunes inhibitory synaptogenesis and GABAergic neurotransmission, thus regulating the establishment and maintenance of the proper hippocampal excitatory/inhibitory balance. PMID- 29161355 TI - Reply to Weinbren and Collins. PMID- 29161356 TI - Medial Orbitofrontal Cortex Mediates Effort-related Responding in Rats. AB - The medial orbitofrontal cortex (mOFC) is known to support flexible control of goal-directed behavior. However, limited evidence suggests that the mOFC also mediates the ability of organisms to work with vigor towards a selected goal, a hypothesis that received little consideration to date. Here we show that excitotoxic mOFC lesion increased responding under a progressive ratio (PR) schedule of reinforcement, that is, the highest ratio achieved, and increased the preference for the high effort-high reward option in an effort-related decision making task, but left intact outcome-selective Pavlovian-instrumental transfer and outcome-specific devaluation. Moreover, pharmacological inhibition of the mOFC increased, while pharmacological stimulation reduced PR responding. In addition, pharmacological mOFC stimulation attenuated methylphenidate-induced increase of PR responding. Intact rats tested for PR responding displayed higher numbers of c-Fos positive mOFC neurons than appropriate controls; however, mOFC neurons projecting to the nucleus accumbens did not show a selective increase in neuronal activation implying that they may not play a major role in regulating PR responding. Collectively, these results suggest that the mOFC plays a major role in mediating effort-related motivational functions. Moreover, our data demonstrate for the first time that the mOFC modulates effort-related effects of psychostimulant drugs. PMID- 29161357 TI - Nivolumab in non-small-cell lung cancer with EGFR mutation. PMID- 29161358 TI - Neural Mechanisms of Episodic Retrieval Support Divergent Creative Thinking. AB - Prior research has indicated that brain regions and networks that support semantic memory, top-down and bottom-up attention, and cognitive control are all involved in divergent creative thinking. Kernels of evidence suggest that neural processes supporting episodic memory-the retrieval of particular elements of prior experiences-may also be involved in divergent thinking, but such processes have typically been characterized as not very relevant for, or even a hindrance to, creative output. In the present study, we combine functional magnetic resonance imaging with an experimental manipulation to test formally, for the first time, episodic memory's involvement in divergent thinking. Following a manipulation that facilitates detailed episodic retrieval, we observed greater neural activity in the hippocampus and stronger connectivity between a core brain network linked to episodic processing and a frontoparietal brain network linked to cognitive control during divergent thinking relative to an object association control task that requires little divergent thinking. Stronger coupling following the retrieval manipulation extended to a subsequent resting-state scan. Neural effects of the episodic manipulation were consistent with behavioral effects of enhanced idea production on divergent thinking but not object association. The results indicate that conceptual frameworks should accommodate the idea that episodic retrieval can function as a component process of creative idea generation, and highlight how the brain flexibly utilizes the retrieval of episodic details for tasks beyond simple remembering. PMID- 29161359 TI - Recurrent Processing of Contour Integration in the Human Visual Cortex as Revealed By fMRI-Guided TMS. AB - Contour integration is a critical step in visual perception because it groups discretely local elements into perceptually global contours. Previous investigations have suggested that striate and extrastriate visual areas are involved in this mid-level processing of visual perception. However, the temporal dynamics of these areas in the human brain during contour integration is less understood. The present study used functional magnetic resonance imaging-guided transcranial magnetic stimulation (TMS) to briefly disrupt 1 of 2 visual areas (V1/V2 and V3B) and examined the causal contributions of these areas to contour detection. The results demonstrated that the earliest critical time window at which behavioral detection performance was impaired by TMS pluses differed between V1/V2 and V3B. The first critical window of V3B (90-110 ms after stimulus onset) was earlier than that of V1/V2 (120-140 ms after stimulus onset), thus indicating that feedback connection from higher to lower area was necessary for complete contour integration. These results suggested that the fine processing of contour-related information in V1/V2 follows the generation of a coarse template in the higher visual areas, such as V3B. Our findings provide direct causal evidence that a recurrent mechanism is necessary for the integration of contours from cluttered background in the human brain. PMID- 29161360 TI - Reply: CLIPPERS, a possible symptomatic lymphohistiocytic immune reaction. PMID- 29161361 TI - Trajectories of frailty among Chinese older people in Hong Kong between 2001 and 2012: an age-period-cohort analysis. AB - Background: there is little evidence to suggest that older people today are living in better health than their predecessors did at the same age. Only a few studies have evaluated whether there are birth cohort effects on frailty, an indicator of health in older people, encompassing physical, functional and mental health dimensions. Objectives: this study examined longitudinal trajectories of frailty among Chinese older people in Hong Kong. Methods: this study utilised data from the 18 Elderly Health Centres of the Department of Health comprising a total of 417,949 observations from 94,550 community-dwelling Chinese people aged >=65 years in one early birth cohort (1901-23) and four later birth cohorts (1924 29, 1930-35, 1936-41, 1942-47) collected between 2001 and 2012, to examine trajectories of the frailty index and how birth cohorts may have contributed to the trends using an age-period-cohort analysis. Results: more recent cohorts had higher levels of frailty than did earlier cohorts at the same age, controlling for period, gender, marital status, educational levels, socioeconomic status, lifestyle and social factors. Older age, being female, widowhood, lower education and smoking were associated with higher levels of frailty. Conclusion: more recent cohorts had higher levels of frailty than did earlier cohorts. Frailty interventions, coupled with early detection, should be developed to combat the increasing rates of frailty in Hong Kong Chinese. PMID- 29161363 TI - Improved survival in metastatic germ-cell cancer. AB - Background: The prognostic score of the International Germ-Cell Cancer Collaborative Group (IGCCCG) in metastatic germ-cell cancers (mGCC) relies on treatments delivered before 1990. It is unclear, if this score is still relevant to contemporary cohorts of patients who receive modern-type chemotherapy and supportive care. Patients and methods: All patients who underwent cisplatin/etoposide-based first-line chemotherapy for mGCC at the University Hospital Zurich (USZ) between 1991 and 2016 were identified retrospectively. Clinical characteristics were extracted from medical charts and patients classified according to the IGCCCG score. International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15: 594-603.). Progression-free survival (PFS) and overall survival (OS) probabilities at 5 years served as outcome parameters. Results: The study cohort consisted of 204 patients at a median age of 32 years and a median follow-up of 4.2 years. According to the IGCCCG score, PFS in the contemporary USZ cohort was 71% overall: 83% for good-risk, 69% for intermediate risk and 30% for poor-risk patients, P < 0.001. OS for the entire cohort was 88%. In respect to OS, we observed no difference between good- and intermediate-risk patients (94% versus 91%, P = 0.62), but a statistically significant difference between those two risk groups and poor-risk patients, who had an OS of only 65%, P < 0.001. Conclusions: Within the contemporary USZ cohort of mGCC patients no improvements in PFS probabilities were observed compared with the ones predicted by the IGCCCG score for any prognostic category, but marked improvements in OS probabilities for intermediate- and poor-risk patients, possibly due to better salvage treatments. PMID- 29161364 TI - Reply to the letter to the editor 'Re-aligning the ASCO and ESMO clinical benefit frameworks or modern cancer therapies'. PMID- 29161362 TI - The Hierarchical Organization of the Default, Dorsal Attention and Salience Networks in Adolescents and Young Adults. AB - An important characteristic of spontaneous brain activity is the anticorrelation between the core default network (cDN) and the dorsal attention network (DAN) and the salience network (SN). This anticorrelation may constitute a key aspect of functional anatomy and is implicated in several brain disorders. We used dynamic causal modeling to assess the hypothesis that a causal hierarchy underlies this anticorrelation structure, using resting-state fMRI of healthy adolescent and young adults (N = 404). Our analysis revealed an asymmetric effective connectivity, such that the regions in the SN and DAN exerted an inhibitory influence on the cDN regions; whereas the cDN exerted an excitatory influence on the SN and DAN regions. The relative strength of efferent versus afferent connections places the SN at the apex of the hierarchy, suggesting that the SN modulates anticorrelated networks with descending hierarchical connections. In short, this study of directed neuronal coupling reveals a causal hierarchical architecture that generates or orchestrates anticorrelation of brain activity. These new findings shed light on functional integration of intrinsic brain networks at rest and speak to future dynamic causal modeling studies of large scale networks. PMID- 29161366 TI - A Request for Standardization of Publishing of Blood Culture Processing Interventions. PMID- 29161365 TI - Genome scale analysis of Escherichia coli with a comprehensive prokaryotic sequence-based biophysical model of translation initiation and elongation. AB - Translation initiation in prokaryotes is affected by the mRNA folding and interaction of the ribosome binding site with the ribosomal RNA. The elongation rate is affected, among other factors, by the local biophysical properties of the coding regions, the decoding rates of different codons, and the interactions among ribosomes. Currently, there is no comprehensive biophysical model of translation that enables the prediction of mRNA translation dynamics based only on the transcript sequence and while considering all of these fundamental aspects of translation. In this study, we provide, for the first time, a computational simulative biophysical model of both translation initiation and elongation with all aspects mentioned above. We demonstrate our model performance and advantages focusing on Escherichia coli genes. We further show that the model enables prediction of translation rate, protein levels, and ribosome densities. In addition, our model enables quantifying the effect of silent mutations on translation rate in different parts of the transcript, the relative effect of mutations on translation initiation and elongation, and the effect of mutations on ribosome traffic jams. Thus, unlike previous models, the proposed one provides comprehensive information, facilitating future research in disciplines such as molecular evolution, synthetic biology, and functional genomics. A toolkit to estimate translation dynamics of transcripts is available at: https://www.cs.tau.ac.il/~tamirtul/transim. PMID- 29161367 TI - Left atrial low-voltage area as a novel indicator of cerebrovascular events in atrial fibrillation. PMID- 29161368 TI - Management of cardiac tamponade in catheter ablation of atrial fibrillation: single-centre 15 year experience on 5222 procedures. AB - Aims: Cardiac tamponade during atrial fibrillation (AF) ablation is infrequent but potentially fatal. This study aimed to retrospectively investigate the incidence, management, and outcomes of tamponade in large patient series. Methods and results: The study analysed 5222 AF ablation procedures in 3483 patients between 2002 and 2016 under a heparin-bridge anticoagulation protocol. Cardiac tamponade occurred in 51 procedures/patients, and the incidence was 0.98% per procedure and 1.46% per patient and was noted during the procedure in 42 patients and in the ward in the remaining 9 patients. No clinical factors were associated with the occurrence, but it was lower during cryoballoon than radiofrequency ablation (P = 0.025). Pericardiocentesis was required in 44 (86.3%) patients, and the haemodynamic state stabilized after a total of 377 (260-530) mL of pericardial blood drainage except for in 2 (3.9%) patients requiring subsequent emergent surgical repairs. The pericardial drain was successfully removed after a median of 1.0 (1.0-2.0) days. In 44 patients, anticoagulation therapy was restarted a median of 3.0 (1.0-7.0) days after the procedure. Thirty (58.8%) patients experienced early recurrent AF with low-grade fevers (37.4 +/- 0.5 degrees C) and an elevated C-reactive protein [2.4 (1.1-8.5) mg/dL]. After successful management of tamponade, 2 (3.9%) patients exhibited cerebral infarctions despite restarting anticoagulation therapy. One patient died, and the other completely recovered without any neurological deficit. Recurrent post cardiac injury syndrome (PCIS) occurred on post-procedural Day 13 in another patient, requiring oral prednisone administration for 10 months. During a median follow-up of 23 (5.4-46.1) months, 34 (66.7%) patients were arrhythmia free. Conclusions: Despite an infrequent incidence, surgical backup is essential for performing AF ablation. Even after successful management of tamponade, care should be taken for subsequent complications. PMID- 29161370 TI - Association of left atrial low-voltage area and thrombo-embolic risk in patients with atrial fibrillation: Authors' reply. PMID- 29161369 TI - Pace-capture-guided ablation after contact-force-guided pulmonary vein isolation: results of the randomized controlled DRAGON trial. AB - Aims: Before the discovery of contact-force guidance, eliminating pacing capture along the pulmonary vein (PV) isolation line had been reported to improve PV isolation durability and rhythm outcomes. DRAGON (UMIN-CTR, UMIN000015332) aimed to elucidate the efficacy of pace-capture-guided ablation following contact-force guided PV isolation ablation in paroxysmal atrial fibrillation (AF) patients. Methods and results: A total of 156 paroxysmal AF patients with AF-trigger ectopies from any of the four PVs induced by isoproterenol were randomly assigned to undergo pace-capture-guided ablation along a contact-force-guided isolation line around AF-trigger PVs (PC group, n = 76) or contact-force-guided PV isolation ablation alone (control group, n = 80). Follow-up of at least 1 year commenced with serial 24 h Holter and symptom-triggered ambulatory monitoring. There was no significant difference in acute PV reconnection rates during a 20 min waiting period after the last ablation or adenosine infusion testing between the PC and the control groups (per patient, 21% vs. 27%, P = 0.27; per AF-trigger PV, 5.9% vs. 7.3%, P = 0.70; and per non-AF-trigger PV, 7.1% vs. 7.4%, P = 0.92). Atrial tachyarrhythmia-free survival rates off antiarrhythmic drugs after the initial session were comparable at 19.3 +/- 6.2 months between the two groups (82% vs. 80%, P = 0.80). Among 22 patients who required a second ablation procedure, there was no difference between the PC and the control groups in the PV reconnection rates at both previously AF-trigger (29% vs. 43%, P = 0.70) and non-AF-trigger PVs (18% vs. 19%, P = 0.88). Conclusions: Pace-capture-guided ablation performed after contact-force-guided PV isolation demonstrated no improvement in PV isolation durability or rhythm outcome. PMID- 29161371 TI - Long-term remineralizing effect of MI Paste Plus on regression of early caries after orthodontic fixed appliance treatment: a 12-month follow-up randomized controlled trial. AB - Background: Casein-phosphopeptide-amorphous-calcium-fluoride-phosphate (CPP-ACFP) can remineralize subsurface lesions. It is the active ingredient of MI-Paste Plus(r) (MPP). The long-term remineralization efficacy is unknown. Objective: To evaluate the long-term effect of MPP versus a placebo paste on remineralization of enamel after fixed orthodontic treatment over a 12-month period. Design: This trial was designed as a prospective, double-blinded, placebo-controlled RCT. Methods: Patients with subsurface lesions scheduled for removal of the appliance were included. They applied either MPP or control paste once a day at bedtime for 12 months, complementary to normal oral hygiene. Main outcome measures: Changes in enamel lesions (primary outcome) were fluorescence loss and lesion area determined by quantitative light-induced fluorescence (QLF). Secondary outcomes were Microbial composition, by conventional plating, and acidogenicity of plaque, by capillary ion analysis (CIA), and lesion changes scored visually on clinical photographs. Randomization: Participants [age = 15.5 years (SD = 1.6)] were randomly assigned to either the MPP or the control group, as determined by a computer-randomization scheme, created and locked before the start of the study. Participants received neutral-coloured concealed toothpaste tubes marked A or B. Blinding: The patients and the observers were blinded with respect to the content of tube A or B. Results: A total of 51 patients were analysed; MPP (n = 25) versus control group (n = 26); data loss (n = 14). There was no significant difference between the groups over time for all the used outcome measures. There was a significant improvement in enamel lesions (fluorescence loss) over time in both groups (P < 0.001 and P < 0.001), with no differences between groups. Limitations: Being an in vivo study, non-compliance of the subjects could have influenced the result. Conclusion: The additional use of MPP in patients with subsurface enamel lesions after orthodontic fixed appliance treatment did not improve these lesions during the 1 year following debonding. Registration: This trial is registered at the medical ethical committee of the VU Medical Centre in Amsterdam (NL.199226.029.07). PMID- 29161372 TI - PLAAF score as a novel predictor of long-term outcome after second-generation cryoballoon pulmonary vein isolation. AB - Aims: Predictors of atrial arrhythmia recurrence have not been described in a long-term follow-up study of patients undergoing pulmonary vein isolation (PVI) using the cryoballoon technique. We aimed to evaluate the efficacy of a second generation cryoballoon and identify pre-procedural predictors of 3-year outcome after PVI. Methods and results: For this observational cohort study, we enrolled 440 patients ablated at our institution with a second-generation cryoballoon. The endpoint was the first documented recurrence (>30 s) of atrial fibrillation (AF), atrial flutter, or atrial tachycardia after a 3-month blanking period. The impact of several pre-existing variables on clinical outcome was evaluated by univariate and multivariate analyses using the Cox proportional hazards regression model. The PLAAF (persistent AF, left atrial area, abnormal PV anatomy, AF history, female gender) score was defined to predict outcome. After a median follow-up of 36 months (interquartile range 25/75-27/42), the endpoint was achieved in 95 of 440 (21.6%) patients. Cox regression analysis showed that persistent AF, left atrial (LA) area, abnormal PV anatomy, AF history, and female gender independently predicted recurrence. The calculated optimal cut-offs for LA area and AF history were 21 cm2 and 3 years, respectively. Patients with a PLAAF score of 0 showed the best outcome, with an arrhythmia-free survival of 86.7%. Conclusion: PVI using the cryoballoon technique shows acceptable long-term results depending on predictors described by the new PLAAF score, which may facilitate patient selection for PVI. PMID- 29161374 TI - The challenges of antithrombotic therapy in patients with left ventricular thrombosis. PMID- 29161373 TI - Studying the degeneration of bioprostheses requires specific statistical analysis. PMID- 29161375 TI - Health system factors affecting implementation of integrated management of childhood illness (IMCI): qualitative insights from a South African province. AB - The Integrated Management of Childhood Illness (IMCI) strategy has been adopted by 102 countries including South Africa, as the preferred primary health care (PHC) delivery strategy for sick children under 5 years. Despite substantial investment to support IMCI in South Africa, its delivery remains sub-optimal, with varied implementation in different settings. There is scarce research globally, and in the local context, examining the effects of health system characteristics on IMCI implementation. This study explored key determinants of IMCI delivery in a South African province, with a specific focus on health system building blocks using a health system dynamics framework. In-depth interviews were conducted with 38 districts, provincial and national respondents involved with IMCI co-ordination and delivery, exploring their involvement in, and perceptions of, IMCI strategy implementation. Identified barriers included poor definition of elements of a service package for children and how IMCI aligned with this, incompetence of trained nurses exacerbated by inappropriate rotation practices, use of inappropriate indicators to track progress, multiple cadres coordinating similar activities with poor role delineation, and fragmented, vertical governance of programmes included within IMCI, such as immunization. Enabling practices in one district included the use of standardized child health records incorporating IMCI activities and stringent practice monitoring through record audits. Using IMCI as a case study, our work highlights critical health system deficiencies affecting service delivery for young children which need to be resolved to reposition IMCI within the broader child 'survive, thrive and transform' agenda. Recommendations for appropriate health system strengthening include the need for redefining IMCI within a broader PHC service package for children, prioritizing post-training supervision and mentoring of practitioners through appropriate duty allocation and rotation policies, strengthening IMCI monitoring with a specific focus on quality of care and building stronger clinical governance through workforce allocation, role delineation and improved accountability. PMID- 29161376 TI - Incisor root resorption in class II division 2 patients in relation to orthodontic treatment. AB - Background/Objectives: The aims were 1. to analyse differences in the occurrence of orthodontic induced inflammatory root resorption (OIIRR) of the upper and lower incisors in Angle Class II division 2 patients, between patients treated with fixed appliance only (one-phase treatment group) and patients treated with removable appliance before treatment with fixed appliance (two-phase treatment group) and 2. to analyse differences in OIIRR between treatment time, age, gender, craniofacial morphology and deviations in the dentition for the two groups together. Materials/Methods: Seventy-four subjects treated for Class II division 2 malocclusion were divided into two groups: 46 patients in the one phase treatment group (28 girls, 18 boys, mean age 14.4) and 28 patients in the two-phase treatment group (18 girls, 10 boys, mean age 12.4) where 336 and 201 incisors were analysed respectively. OIIRR was assessed on intra oral radiographs, deviations of the dentition were assessed on orthopantomograms and the craniofacial morphology was assessed on lateral cephalograms. Differences were tested by Fisher Exact test, McNemar, and multiple regression analysis. Results: The one-phase treatment group showed significantly more OIIRR for lower central incisors (P = 0.002) compared to the two-phase treatment group. For the both groups combined, boys showed more OIIRR than girls (P = 0.002) and patients with agenesis showed more OIIRR than patients without agenesis (P = 0.019) for the lower central incisors. Conclusion: The results indicate that two-phase treatment modalities may be considered as an option for Angle Class II division 2 patients with enhanced risk for OIIRR. PMID- 29161377 TI - Transmission and persistence of IncF conjugative plasmids in the gut microbiota of full-term infants. AB - Conjugative plasmids represent major reservoirs for horizontal transmission of antibiotic resistance and virulence genes. Our knowledge about the ecology and persistence of these plasmids in the gut microbiota remains limited. The IncF plasmids are the most widespread in clinical samples and in healthy humans and the main aim of this work was to study their ecology and association with the developing gut microbiota. Using a longitudinal (2, 10, 30 and 90 days) cohort of full-term infants, we investigated the transmission and persistence of IncFIA and IncFIB plasmids. The prevalence of IncFIB plasmids was higher than IncFIA in the cohort, while IncFIA always co-occurred with IncFIB. However, the relative gene abundance of IncFIA was significantly higher than IncFIB for all time points, indicating that IncFIA may be a higher copy-number plasmid. Through linear discriminant analysis effect size and operational taxonomic unit-level associations, we observed major differences in the abundance of Enterobacteriaceae in samples positive and negative for IncFIB. This association was significant at 2, 10 and 30 days and showed an association with vaginal delivery. From shot-gun analyses, we assembled de novo multi-replicon shared (IncFIA/IncFIB) and integrated (IncFIA/IB) plasmids that were persistent through the dataset. Overall, the study demonstrates the nature of IncF plasmids in complex microbial communities. PMID- 29161378 TI - Health behaviours as a predictor of quitting hazardous alcohol use in the Stockholm Public Health Cohort. AB - Background: Adopting healthy behaviours may facilitate the transition from hazardous to non-hazardous use of alcohol, yet, longitudinal studies of health behaviours in relation to the cessation of hazardous alcohol use are rare. We addressed this question using data from a large population-based cohort of adults in Sweden (Stockholm Public Health Cohort). Methods: Participants from two sub cohorts (inception in 2002 and 2010), with follow-up until the year 2014 were included. Health behaviours (tobacco use, diet and physical activity) and alcohol use were self-reported in questionnaire-based surveys. Hazardous alcohol use was defined as either usual weekly consumption (2002 sub-cohort) or heavy occasional alcohol consumption (2010 sub-cohort). Baseline hazardous drinkers with complete data constituted the analytical sample (n = 8946). Logistic regression was used to calculate the Odds Ratios and their 95% confidence intervals of quitting hazardous alcohol use, with tobacco use, diet and physical activity as predictors of change. Results: In the 2002 sub-cohort, 28% reported non-hazardous use sustained through two consecutive follow-up points. In the 2010 sub-cohort, 36% of the participants reported non-hazardous use of alcohol at follow-up. Favourable health behaviours at baseline (e.g. no tobacco use, sufficient fruit intake and physical activity) were associated with a 19% to 75% higher of odds quitting hazardous alcohol use. Further, favourable changes in diet and tobacco cessation were associated with non-hazardous alcohol use at follow-up. Conclusions: As many as one-third of hazardous alcohol users may quit this drinking pattern in a medium-long term. Holding or achieving a healthy lifestyle may facilitate this transition. PMID- 29161379 TI - Strong, vertical TB programme embedded in a developing primary healthcare system: impact on patient and community experiences in Cambodia. PMID- 29161380 TI - Anaemia and associated factors in homeless children in the Paris region: the ENFAMS survey. AB - Background: Food insecurity is a major concern in homeless population, however nutritional consequences remain poorly documented, especially for children. The objective of this study was to assess the prevalence of anaemia and to investigate the relation between both food insecurity and dietary intake to moderate-to-severe anaemia (MSA) in homeless sheltered children. Methods: In 2013, a cross-sectional survey was conducted on a random sample of 801 sheltered homeless families in the Paris region. Haemoglobin concentration was measured in 630 mother/child dyads and questionnaires administrated to mothers collected socio-demographic, socioeconomic, health and dietary data. Factors associated with MSA were analysed in two stratified child age groups; 0.5-5 and 6-12 years old. Results: Anaemia was detected in 39.9% of the children and 50.6% of the mothers, and MSA in 22.3% and 25.6%, respectively. In both age groups, MSA was positively associated with maternal MSA. In the 0.5-5 years group, it was also positively associated with child food insecurity, no cooking facilities and household monthly income. In the 6-12 years group, it was positively associated with household food insecurity and children's age. Conclusion: A higher food insecurity score was associated with greater prevalence of moderate-to-severe anaemia in children. Considering the high prevalence of anaemia among homeless mothers and their children, these findings highlight the need for reducing food insecurity in shelters so as to prevent anaemia in this vulnerable population. PMID- 29161381 TI - Dynamic change in left ventricular apical back rotation: a marker of diastolic suction with exercise. AB - Aims: We hypothesized that the absence of a decrease in minimal left ventricular (LV) pressure during exercise would be associated with impaired LV apical back rotation during exercise. Methods and results: A total of 21 patients (59 +/- 10 years) underwent invasive LV pressure measurements and simultaneous echocardiography at rest and during submaximal supine bicycle exercise. Patients were classified according to the changes in minimal LV pressure from rest to maximal exercise (Deltaminimal LVP); Group 1 (n = 8) had a decrease in minimal LV pressure with exercise, whereas Group 2 (n = 13) had an increase in minimal LV pressure. LV apical back-rotation parameters by speckle-tracking echocardiography at rest and during 50 W of exercise were compared. At rest, there were no differences in LV pressure and echocardiographic parameters between groups. However, at 50 W of exercise, Group 2 had higher LV early and end-diastolic pressures and a prolonged time constant of LV relaxation. In Group 2, e' velocity was lower and E/e' was higher. Apical back rotation at the mitral valve opening (MVO) was reduced and minimal apical back-rotation velocity was lower in Group 2. Deltaminimal LVP significantly correlated with apical back rotation at MVO (r = 0.77, P = 0.009) and minimal apical back-rotation velocity at 50 W (r = 0.69, P = 0.028). Conclusion: The lack of decrease in minimal LV pressure during exercise, a manifestation of impaired LV suction in early diastole, is linked closely with impaired LV apical back rotation during exercise. Dynamic changes in LV apical back rotation during exercise can be used as a non-invasive parameter of diastolic suction during exercise. PMID- 29161382 TI - Need for better diastolic stress test: twistin' time is here? PMID- 29161383 TI - Basal Forebrain Gating by Somatostatin Neurons Drives Prefrontal Cortical Activity. AB - The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing neurons constitute a heterogeneous GABAergic population known to functionally inhibit basal forebrain cortically projecting cells thus favoring sleep and cortical synchronization. However, it remains unclear if somatostatin cells can regulate population activity patterns in the basal forebrain and modulate cortical dynamics. Here, we demonstrate that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo rapidly modified neural activity in the basal forebrain, with the consequent enhancement and desynchronization of activity in the prefrontal cortex, reflected in both neuronal spiking and network oscillations. Cortical activation was partially dependent on cholinergic transmission, suppressing slow waves and potentiating gamma oscillations. In addition, recruitment dynamics was cell type-specific, with interneurons showing similar temporal profiles, but stronger responses than pyramidal cells. Finally, optogenetic stimulation of quiescent animals during resting periods prompted locomotor activity, suggesting generalized cortical activation and increased arousal. Altogether, we provide physiological and behavioral evidence indicating that somatostatin neurons are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms. PMID- 29161384 TI - Growing the next generation of anaesthesia research leaders. PMID- 29161385 TI - Are we close to the ideal intravenous fluid? AB - The approach to i.v. fluid therapy for hypovolaemia may significantly influence outcomes for patients who experience a systemic inflammatory response after sepsis, trauma, or major surgery. Currently, there is no single i.v. fluid agent that meets all the criteria for the ideal treatment for hypovolaemia. The physician must choose the best available agent(s) for each patient, and then decide when and how much to administer. Findings from large randomized trials suggest that some colloid-based fluids, particularly starch-based colloids, may be harmful in some situations, but it is unclear whether they should be withdrawn from use completely. Meanwhile, crystalloid fluids, such as saline 0.9% and Ringer's lactate, are more frequently used, but debate continues over which preparation is preferable. Perhaps most importantly, it remains unclear how to select the optimal dose of fluid in different patients and different clinical scenarios. There is good reason to believe that both inadequate and excessive i.v. fluid administration may lead to poor outcomes, including increased risk of infection and organ dysfunction, for hypovolaemic patients. In this review, we summarize the current knowledge on this topic and identify some key pitfalls and some areas of agreed best practice. PMID- 29161386 TI - To err is human: use of simulation to enhance training and patient safety in anaesthesia. AB - Human beings who work in complex, dynamic, and stressful situations make mistakes. This is as true for anaesthetists as for any other health-care professional, but we face unique challenges in the many roles and responsibilities we have in diverse clinical contexts. As a profession, we are well versed in the development and utilization of improvement techniques and technologies that prioritize high-quality, safe care for patients. This article focuses on one particular domain of patient safety in which anaesthetists have been pre-eminent, the use of simulation in training to improve both professional capabilities and patient safety in anaesthetic practice. This review considers the impact of error in health care; the role of anaesthetists in promoting simulation-based education for the development of clinical skills and improved teamwork; and their role in disseminating human factors and quality improvement science to enhance safety in the clinical workplace. Finally, we consider our position at the vanguard of developments in patient safety and how the profession should continue to pursue a leadership role in the application of simulation based interventions to training and systems design across health care. PMID- 29161387 TI - Reversal of residual neuromuscular block: complications associated with perioperative management of muscle relaxation. AB - The use of anticholinesterases to reverse residual neuromuscular block at the end of surgery became routine practice in the 1950s. These drugs could only be used when recovery from block was established [two twitches of the train-of-four (TOF) count detectable] and concern was expressed about their cholinergic side-effects. By the 1990s, it was recognized that failure to reverse residual block adequately to a TOF ratio (TOFR) >0.7 was associated with increased risk of postoperative pulmonary complications (POPCs) following the long-acting non-depolarizing neuromuscular blocking drug (NDNMBD) pancuronium. By 2003, and the introduction of acceleromyography, a TOFR >=0.9 was considered necessary to protect the airway from aspiration before tracheal extubation. It was also considered that four, not two, twitches of the TOF should be detectable before neostigmine was given. Use of any NDNMBD was subsequently shown to be associated with increased risk of POPCs, but it was thought that neostigmine reduced that risk. Recently, there has been conflicting evidence that use of neostigmine might increase the incidence of POPCs. Although sugammadex has been shown to rapidly reverse profound neuromuscular block from aminosteroidal agents, there is currently no evidence that sugammadex is superior to neostigmine in its effect on POPCs. Other new antagonists, including cysteine to degrade CW002 and calabadion 1 and 2 to antagonize aminosteroidal and benzylisoquinolium NDNMBDs, are being studied in preclinical and clinical trials. Quantitative neuromuscular monitoring is essential whenever a NDNMBD is used to ensure full recovery from neuromuscular block. PMID- 29161388 TI - Critical care at the end of life: balancing technology with compassion and agreeing when to stop. AB - Modern intensive care saves lives. However, the substantial related financial costs are, for many, married to substantial costs in terms of suffering. In the most sick, the experience of intensive care is commonly associated with the development of profound physical debility, which may last years after discharge. Likewise, the negative psychological impact commonly experienced by such patients during their care is now widely recognized, as is the persistence of psychological morbidity. Such issues become increasingly important as the population of the frail elderly increases, and the health and social care services face budgetary restriction. Efforts must be made to humanize intensive care as much as possible. Meanwhile, an open conversation must be held between those within the medical professions, and between such healthcare workers and the public in general, regarding the balancing of the positive and negative impacts of intensive care. Such conversations should extend to individual patients and their families when considering what care is genuinely in their best interests. PMID- 29161389 TI - Innovations in management of cardiac disease: drugs, treatment strategies and technology. AB - Within the last generation, the management of patients with heart disease has been transformed by advances in drug treatments, interventions and diagnostic technologies. The management of arterial hypertension saw beta-blockers demoted from first- to third-line treatment. Recent studies suggest that the goal of treatment may have to change to lower systolic blood pressures to prevent long term organ damage. Today less than 15% of coronary revascularizations are surgical and more than 85% are done by interventional cardiologists inserting coronary stents. Thus, managing patients on dual antiplatelet therapy has become an important issue. With new generations of coronary stents, recommendations are changing fast. In the past, decisions concerning non-cardiac surgery after acute myocardial infarction were based on the delay between infarction and non-cardiac surgery. Today, the main concern is the patient's status in respect of dual antiplatelet therapy after primary percutaneous intervention. There have been advances in the management of heart failure but new drugs (ivabradine, sacubitril/valsartan) and cardiac resynchronization are recommended only in patients with an ejection fraction below 35% on optimal medication. Heart failure remains a major perioperative risk factor. Prospective studies have shown that troponin elevations represent myocardial injury (not necessarily myocardial infarction), are mostly silent and are associated with increased 30-day mortality. Monitoring (troponin assays) for myocardial injury in non-cardiac surgery (MINS) seems increasingly justified. The treatment of MINS needs further research. Technological advances, such as intelligent, portable monitors benefit not only patients with cardiac disease but all patients who have undergone major surgery and are on the wards postoperatively. PMID- 29161390 TI - Thiopental to desflurane - an anaesthetic journey. Where are we going next? AB - Development targets in anaesthetic pharmacology have evolved from minimizing harm caused by unwanted effects through an era in which rapid onset and offset of drug effect were prioritised. Today's anaesthetists have access to a library of effective drugs whose characteristics offer controllable hypnosis, analgesia and paralysis with manageable off-target effects. The availability of these agents at generic prices inhibits commercial interest and this is reflected in the limited number of current anaesthetic drug development projects. Recently, questions around neonatal neurotoxicity, delirium and postoperative cognitive dysfunction have stimulated research to characterise these phenomena and explain them in mechanistic terms. Emergent basic science from these enquiries together with exploration of possible effects of anaesthetic drug choice on patient outcomes from cancer surgery may yield new targets for drug discovery. PMID- 29161391 TI - An overview of space medicine. AB - Space medicine is fundamental to the human exploration of space. It supports survival, function and performance in this challenging and potentially lethal environment. It is international, intercultural and interdisciplinary, operating at the boundaries of exploration, science, technology and medicine. Space medicine is also the latest UK specialty to be recognized by the Royal College of Physicians in the UK and the General Medical Council. This review introduces the field of space medicine and describes the different types of spaceflight, environmental challenges, associated medical and physiological effects, and operational medical considerations. It will describe the varied roles of the space medicine doctor, including the conduct of surgery and anaesthesia, and concludes with a vision of the future for space medicine in the UK.Space medicine doctors have a responsibility to space workers and spaceflight participants. These 'flight surgeons' are key in developing mitigation strategies to ensure the safety, health and performance of space travellers in what is an extreme and hazardous environment. This includes all phases from selection, training and spaceflight itself to post-flight rehabilitation and long-term health. The recent recognition of the speciality provides a pathway to train in this fascinating field of medicine and is a key enabler for the UK Government's commercial spaceflight ambition. PMID- 29161392 TI - The future United Kingdom anaesthetic workforce: training, education, and role boundaries for anaesthetists and others. AB - Anaesthesia is the largest hospital-based specialty in the UK, and the activities of the anaesthesia workforce underpin the care of all patients in the hospital sector. Changes in the way care will be delivered in the future will impact on the workforce as a consequence of patient requirements and funding issues. This article considers these and other factors in the context of the current and future workforce. PMID- 29161393 TI - Quality, safety, and outcomes in anaesthesia: what's to be done? An international perspective. AB - This article reviews of some of the key topics and challenges in quality, safety, and the measurement and improvement of outcomes in anaesthesia. The topics were selected based on the perspective of an individual with quality and safety expertise and recent experience of the specialty in both the UK and USA. The review does not seek to be exhaustive or systematic, but to highlight current areas of concern and potential solutions. The topic is subdivided into sections where the system of health care is viewed from different levels. These levels are as follows: the microsystem or patient and individual clinician perspective; the meso or hospital perspective; and the macro or government and policy perspective. Topics covered include medication safety, changes in approaches to patient safety, payment reform, longer term measurement of outcomes, large-scale improvement programmes, the ageing population, and burnout. The article begins with a section on the success of the specialty of anaesthesia in improving the quality, safety, and outcomes for our patients, and ends with a look to future developments, including greater use of technology and patient engagement. PMID- 29161394 TI - Managing anaesthetic provision for global disasters. AB - The numbers of people affected by large-scale disasters has increased in recent decades. Disasters produce a huge burden of surgical morbidity at a time when the affected country is least able to respond. For this reason an international disaster response is often required. For many years this disaster response was not coordinated. The response consisted of what was available not what was needed and standards of care varied widely producing a healthcare lottery for the affected population. In recent years the World Health organisation has initiated the Emergency Medical Team programme to coordinate the response to disasters and set minimum standards for responding teams. Anaesthetists have a key role to play in Level 2 Surgical Field Hospitals. The disaster context produces a number of logistical challenges that directly impact on the anaesthetist requiring adaptation of anaesthetic techniques from their everyday practice. The context in which they will be working and the wider scope of practice that will be expected from them in the field mandates that deploying anaesthetists should be trained for disaster response. There have been significant improvements in recent years in the speed of response, equipment availability, coordination and training for disasters. Future challenges include increasing local disaster response capacity, agreeing international standards for training and improving data collection to allow for future research and improvement in disaster response. The goal of this review article is to provide an understanding of the disaster context and what logistical challenges it provides. There has been a move during the last decade from a globally uncoordinated, unregulated response, with no consensus on standards, to a globally coordinated response through the World Health Organisation (WHO). A classification system for responding Emergency Medical Teams (EMTs) and a set of agreed minimum standards has been defined. This review outlines the scope of the role of the anaesthetist in a Level 2 field hospital and some of the challenges that this scope and context present. It focuses mainly on natural disasters, but also outline some of the differences encountered in responding to other global disasters such as conflict and infectious outbreaks, and concludes with some of the challenges for the future. PMID- 29161395 TI - Postoperative cognitive dysfunction and dementia: what we need to know and do. AB - Approximately 12% of apparently previously cognitively well patients undergoing anaesthesia and noncardiac surgery will develop symptoms of cognitive dysfunction after their procedure. Recent articles in this Journal have highlighted the difficulties of confirming any clear links between anaesthesia and cognitive dysfunction, in part because of the lack of consistency regarding definition and diagnosis. Postoperative cognitive dysfunction (POCD) is usually self-limiting and rarely persists in the longer term, although plausible biological mechanisms for an impact on brain protein deposition do exist. Clinical research studies are frequently confounded by a lack of agreed definitions and consistency of testing. Preoperative assessment of neurocognitive function and risk factor identification is imperative in order to ascertain the true extent of POCD and any causative link to anaesthesia and surgery. At present a multidisciplinary care bundle approach to risk factor stratification and reduction is the most attractive management plan based on evidence of slight benefit from individual interventions. As yet no individual anaesthetic technique, drug or mode of monitoring has been proved to reduce the incidence of POCD. Providing patients with appropriate and accurate information can be difficult because of conflicting evidence. The Royal College of Anaesthetists' patient liaison group has produced a useful patient information leaflet that is designed to provide guidance in discussions of individual risks whilst considerable uncertainties remain. PMID- 29161396 TI - Demands and requests for 'inappropriate' or 'inadvisable' treatments at the end of life: what do you do at 2 o'clock in the morning when ...? AB - In an era when healthcare has become increasingly complex and patient expectations are higher than ever before, we can find the decision-making process for patients, potentially at the end of their lives, increasingly difficult. In the shift from paternalism to patient choice, we can struggle to know what to do when faced with a patient, their family, or both requesting or demanding inadvisable, inappropriate, or futile treatments. It can feel as if we are being asked to subject patients to intrusions and interventions that 'just feel wrong'. In this article, we aim to look at how ethical frameworks, legal statute, case law, and professional guidance, as they apply in the UK, interact when we make these decisions, and we discuss some of the conflicts and challenges that such guidance pose. PMID- 29161397 TI - Abdominal aortic aneurysm repair in the United Kingdom: an exemplar for the role of anaesthetists in perioperative medicine. AB - The past two decades have seen an increasing recognition that the delivery of safe surgery with low complication rates and good long-term outcomes is a team endeavour embracing the whole patient care pathway. The key role of the anaesthetist in managing the patient through the surgical process is widely understood and has driven the emergence of perioperative medicine. In parallel with these developments there has been a sea change in the organisation of the care of patients presenting for elective abdominal aortic aneurysm (AAA) repair. Data from the 2008 report of the VASCUNET vascular registry suggested that the UK had the highest mortality for elective open AAA repair in Europe (7.9%). In response, a national quality improvement programme (AAAQIP) spanning the disciplines of surgery, anaesthesia, radiology and nursing was put in place. This led to significant changes in all aspects of AAA repair including the role of the anaesthetist. Preoperative assessment by an anaesthetist with a vascular practice was mandated and the role of the anaesthetist in the vascular multidisciplinary team meeting (MDT) established. Anaesthetic data were included in the national data collection system for vascular surgery, the National Vascular Registry. These changes paralleled and in some cases led the wider evolution of the role of the anaesthetist in perioperative medicine. The mortality from infrarenal AAA repair in the UK decreased to 2.4% by 2012. This improvement reflects changes in perioperative care supported and in some cases led by anaesthetists. PMID- 29161398 TI - Role of GABAA receptor subtypes in the behavioural effects of intravenous general anaesthetics. AB - Since the introduction of general anaesthetics into clinical practice, researchers have been mystified as to how these chemically disparate drugs act to produce their dramatic effects on central nervous system function and behaviour. Scientific advances, particularly during the last 25 years, have now begun to reveal the molecular mechanisms underpinning their behavioural effects. For certain i.v. general anaesthetics, such as etomidate and propofol, a persuasive case can now be made that the GABAA receptor, a major inhibitory receptor in the mammalian central nervous system, is an important target. Advances in molecular pharmacology and in genetic manipulation of rodent genes reveal that different subtypes of the GABAA receptor are responsible for mediating particular aspects of the anaesthetic behavioural repertoire. Such studies provide a better understanding of the neuronal circuitry involved in the various anaesthetic induced behaviours and, in the future, may result in the development of novel therapeutics with a reduced propensity for side-effects. PMID- 29161399 TI - Global lessons: developing military trauma care and lessons for civilian practice. AB - The wars in Iraq and Afghanistan have helped to shape the modern Defence Medical Services. Many lessons were learnt including the need for rapid haemorrhage control, senior decision-making and the evolution of deployed transfusion support. These changes were implemented simultaneously with a coherent, end-to end medical plan from point of wounding through to rehabilitation. Implementation of the medical plan is harmonious with the NHS trauma pathway, and is key to ensuring effective delivery. Military anaesthetists have a long pre-deployment training pathway starting with a Certificate of Completion of Training (CCT) in anaesthesia and/or critical care, and with an emphasis on military skills related to their specific role. Pre-deployment training includes additional skill training, team training and finally whole hospital collective training. This pathway ensures ongoing and continuing competence on an individual basis, and assurance that hospital management systems and clinical staff can function effectively as a deploying unit. PMID- 29161400 TI - The evolution of robotic surgery: surgical and anaesthetic aspects. AB - Robotic surgery pushes the frontiers of innovation in healthcare technology towards improved clinical outcomes. We discuss the evolution to five generations of robotic surgical platforms including stereotactic, endoscopic, bioinspired, microbots on the millimetre scale, and the future development of autonomous systems. We examine the challenges, obstacles and limitations of robotic surgery and its future potential including integrated real-time anatomical and immune histological imaging and data assimilation with improved visualisation, haptic feedback and robot-surgeon interactivity. We consider current evidence, cost effectiveness and the learning curve in relation to the surgical and anaesthetic journey, and what is required to continue to realise improvements in surgical operative care. The innovative impact of this technology holds the potential to achieve transformative clinical improvements. However, despite over 30 yr of incremental advances it remains formative in its innovative disruption. PMID- 29161401 TI - The evolution of airway management - new concepts and conflicts with traditional practice. AB - In the last 25 yr, there have been several advances in the safe management of the airway. Videolaryngoscopes and supraglottic airways, now in routine use by new trainees in anaesthesia, have had their genesis in the recent past. The 4th National Audit Project of the Royal College of Anaesthetists and the Difficult Airway Society published in 2011 a seminal report that has influenced airway management worldwide . Understanding how the report's recommendations were constructed and how clinical guidelines compliment rather than contradict them is important in understanding the tenets of safe airway management. Over the last 25 yr there has been an increasing understanding of the effects of human factors in anaesthesiology: we may not perform in a predictable or optimal manner when faced with unusual and threatening challenges. The place of cricoid pressure in anaesthetic practice has also evolved. Current recommendations are that it be applied, but it should be released rapidly should airway difficulty be encountered. The need to prevent hypoxaemia by preoxygenation has long been recognized, but the role of high-flow nasal oxygen in anaesthesia is now being realized and developed. Clinicians must decide how novel therapies and long standing practices are adapted to best meet the needs of our patients and prevent harm during airway management. PMID- 29161402 TI - Fit for surgery? Perspectives on preoperative exercise testing and training. AB - There is a consistent relationship between physical activity, physical fitness, and health across almost all clinical contexts, including the perioperative setting. Physiological measurements obtained during physical exercise may be used to infer the risk of adverse outcome after major surgery. In particular, data obtained from perioperative cardiopulmonary exercise testing have an expanding role in perioperative care. Such information may be used to inform a variety of changes in clinical practice, including interventions that may reduce the risk of perioperative adverse events. Specifically, for patients undergoing major cancer surgery there is a complex interplay between different cancer treatments, including neoadjuvant therapies (chemo- and chemo- plus radiotherapy), surgery, and physical fitness, and the modulation of these relationships by perioperative exercise interventions. Preoperative cardiopulmonary exercise testing provides an objective evaluation of physical fitness and has been used to provide an individualized risk profile in order to guide collaborative decision-making, inform the consent process, characterize and optimize co-morbidities, and to triage patients to perioperative care. Furthermore, studies evaluating exercise interventions aimed at increasing preoperative exercise capacity have established that training improves physical fitness. However, to date, this literature is largely composed of feasibility and pilot studies with small sample sizes, which are in general underpowered to assess clinical outcomes. Adequately powered prospective multicentre studies are needed to characterize the most effective means of improving patient fitness before surgery and to evaluate the impact of such improvements on surgical and disease-specific (e.g. cancer) outcomes. PMID- 29161403 TI - School practices important for students' sexual health: analysis of the school health research network survey in Wales. AB - Background: This study investigates how the sexual health outcomes of a representative sample of students aged 15-16 in Wales vary according to the person delivering Sex and Relationships Education (SRE) in schools, students' access to on-site sexual health services and access to free condoms. Methods: Cross-sectional, self-report survey data were collected from students who participated in the 2015/16 School Health Research Network questionnaire in Wales. Data were analyzed from 59 schools, totalling 3781 students aged 15-16 (M = 15.7; SD = 0.3) who responded to questions about ever having had sex; age of sexual initiation and condom use at last intercourse. School level data were also collected, examining who delivers school SRE, provision of on-site, school 'drop in' sexual health services and provision of free condoms for students. Binary and linear multi-level analyses explored the relationship between school level predictors and sexual health outcomes. Results: Compared to teachers, other modes of SRE delivery were associated with better sexual health outcomes, including remaining sexually inactive, later age of first intercourse and condom use. Providing on-site sexual health services did not significantly reduce the odds of having ever had sex or delaying first intercourse; but was associated with increased condom use. On-site condom provision was associated with lower condom use. Conclusions: SRE delivery by educators other than teachers is optimum to young people's sexual health outcomes. Further funding and coordination of on site sexual health advice services are required. Longitudinal research is needed to identify the temporal sequence of sexual health practices and outcomes. PMID- 29161405 TI - Quantifying infective endocarditis risk in patients with predisposing cardiac conditions. AB - Aims: There are scant comparative data quantifying the risk of infective endocarditis (IE) and associated mortality in individuals with predisposing cardiac conditions. Methods and results: English hospital admissions for conditions associated with increased IE risk were followed for 5 years to quantify subsequent IE admissions. The 5-year risk of IE or dying during an IE admission was calculated for each condition and compared with the entire English population as a control. Infective endocarditis incidence in the English population was 36.2/million/year. In comparison, patients with a previous history of IE had the highest risk of recurrence or dying during an IE admission [odds ratio (OR) 266 and 215, respectively]. These risks were also high in patients with prosthetic valves (OR 70 and 62) and previous valve repair (OR 77 and 60). Patients with congenital valve anomalies (currently considered 'moderate risk') had similar levels of risk (OR 66 and 57) and risks in other 'moderate-risk' conditions were not much lower. Congenital heart conditions (CHCs) repaired with prosthetic material (currently considered 'high risk' for 6 months following surgery) had lower risk than all 'moderate-risk' conditions-even in the first 6 months. Infective endocarditis risk was also significant in patients with cardiovascular implantable electronic devices. Conclusion: These data confirm the high IE risk of patients with a history of previous IE, valve replacement, or repair. However, IE risk in some 'moderate-risk' patients was similar to that of several 'high-risk' conditions and higher than repaired CHC. Guidelines for the risk stratification of conditions predisposing to IE may require re-evaluation. PMID- 29161404 TI - Mutation-dependent aggregation and toxicity in a Drosophila model for UBQLN2 associated ALS. AB - Members of the conserved ubiquilin (UBQLN) family of ubiquitin (Ub) chaperones harbor an antipodal UBL (Ub-like)-UBA (Ub-associated) domain arrangement and participate in proteasome and autophagosome-mediated protein degradation. Mutations in a proline-rich-repeat region (PRR) of UBQLN2 cause amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD); however, neither the normal functions of the PRR nor impacts of ALS-associated mutations within it are well understood. In this study, we show that ALS mutations perturb UBQLN2 solubility and folding in a mutation-specific manner. Biochemical impacts of ALS mutations were additive, transferable to UBQLN1, and resulted in enhanced Ub association. A Drosophila melanogaster model for UBQLN2-associated ALS revealed that both wild-type and ALS-mutant UBQLN2 alleles disrupted Ub homeostasis; however, UBQLN2ALS mutants exhibited age-dependent aggregation and caused toxicity phenotypes beyond those seen for wild-type UBQLN2. Although UBQLN2 toxicity was not correlated with aggregation in the compound eye, aggregation prone UBQLN2 mutants elicited climbing defects and neuromuscular junctions (NMJ) abnormalities when expressed in neurons. An UBA domain mutation that abolished Ub binding also diminished UBQLN2 toxicity, implicating Ub binding in the underlying pathomechanism. We propose that ALS-associated mutations in UBQLN2 disrupt folding and that both aggregated species and soluble oligomers instigate neuron autonomous toxicity through interference with Ub homeostasis. PMID- 29161406 TI - Evaluation of the BacterioScan 216Dx for Standalone Preculture Screen of Preserved Urine Specimens in a Clinical Setting. AB - Background: The BacterioScan 216Dx laser microbial growth monitoring system was evaluated as an option for preurine culture screening of preserved urine specimens at an acute care medical center. Methods: The BacterioScan 216Dx system performance characteristics and the economic impact (cost effectiveness) for the laboratory were assessed. Urinalysis performance compared to urine culture was assessed if urinalysis was ordered as part of the patient care set. Results: When compared to urine culture, the BacterioScan had an overall performance with corresponding 95% confidence intervals of 76% (68-83) sensitivity, 84% (80-87) specificity, 55% (48-63) positive predictive value, and 93% (90-95) negative predictive value for 610 randomly selected preserved urine specimens. Urinalysis compared to urine culture overall performance was 59% (48-69) sensitivity, 87% (83-90) specificity, 53% (43-63) positive predictive value, 89% (86-92) negative predictive value for 414 urine specimens. Conclusions: While the system did improve the turnaround time to a negative report, adoption of the BacterioScan system would increase the reagent budget for laboratory urine culture by 2.34 times the current cost, potentially making BacterioScan prohibitive in a budget restricted environment. Additionally, performance when compared to traditional urine culture was less than acceptable for a diagnostic laboratory to use as a stand-alone urinary tract infection screen. PMID- 29161408 TI - Landscape of DNA Methylation on the Marsupial X. AB - DNA methylation plays a key role in maintaining transcriptional silence on the inactive X chromosome of eutherian mammals. Beyond eutherians, there are limited genome wide data on DNA methylation from other vertebrates. Previous studies of X borne genes in various marsupial models revealed no differential DNA methylation of promoters between the sexes, leading to the conclusion that CpG methylation plays no role in marsupial X-inactivation. Using reduced representation bisulfite sequencing, we generated male and female CpG methylation profiles in four representative vertebrates (mouse, gray short-tailed opossum, platypus, and chicken). A variety of DNA methylation patterns were observed. Platypus and chicken displayed no large-scale differential DNA methylation between the sexes on the autosomes or the sex chromosomes. As expected, a metagene analysis revealed hypermethylation at transcription start sites (TSS) of genes subject to X-inactivation in female mice. This contrasted with the opossum, in which metagene analysis did not detect differential DNA methylation between the sexes at TSSs of genes subject to X-inactivation. However, regions flanking TSSs of these genes were hypomethylated. Our data are the first to demonstrate that, for genes subject to X-inactivation in both eutherian and marsupial mammals, there is a consistent difference between DNA methylation levels at TSSs and immediate flanking regions, which we propose has a silencing effect in both groups. PMID- 29161407 TI - Myonectin Predicts the Development of Type 2 Diabetes. AB - Context: Myonectin has been identified as a myokine, expressed predominantly in skeletal muscle. However, its clinical implications are largely unknown. Objective: The aim of this study is to investigate the relationship between myonectin (C1q tumor necrosis factor-alpha-related protein isoform 15) and type 2 diabetes mellitus (T2DM) in cross-sectional and interventional studies. Design: In a separate study, oral glucose tolerance tests, a 45-minute bout of exercise, lipid infusions, and euglycemic-hyperinsulinemic clamps (EHCs) were performed to investigate the association of myonectin with homeostasis model assessment of insulin resistance (HOMA-IR) and T2DM. Circulating myonectin was measured by enzyme-linked immunosorbent assay. Patients: One hundred four newly diagnosed T2DM (nT2DM), 109 impaired glucose tolerance (IGT), and 128 healthy individuals were recruited for this study. Results: nT2DM and IGT subjects had higher circulating myonectin concentrations than normal subjects (82.3 +/- 47.6 and 68.9 +/- 46.6 vs. 45.2 +/- 23.5 ug/L, P < 0.05 or P < 0.01). It was also found that in nT2DM individuals, circulating myonectin was higher than in IGT subjects. Plasma myonectin correlated positively with waist/hip ratio, percentage of body fat, triglyceride, fasting blood glucose, 2-hour blood glucose after glucose overload, fasting insulin, hemoglobin A1c, and HOMA-IR and negatively with the insulin sensitivity index in all of the study population. Multivariate logistic regression analysis revealed that circulating myonectin levels were significantly correlated with IGT and T2DM. A 45-minute bout of exercise did not change circulating myonectin levels in healthy, young individuals. Circulating myonectin levels were not significantly altered in response to an oral glucose challenge or EHC. In addition, acute elevated free fatty acid levels induced by lipid infusion had no effects on circulating myonectin. Conclusions: These data suggest that myonectin may be a useful marker in predicting the development of prediabetes and diabetes. PMID- 29161410 TI - Autonomy, Affinity, and the Assessment of Damages: ACB v Thomson Medical Pte Ltd [2017] SGCA 20 and Shaw v Kovak [2017] EWCA Civ 1028. AB - In ACB v Thomson Medical Pte Ltd [2017] SGCA 20 and Shaw v Kovak [2017] EWCA Civ 1028, the idea that 'lost autonomy' should be recognised as a new form of actionable damage in the tort of negligence was rejected in Singapore and England, respectively. This, it will be argued, was the correct outcome. Protecting an interest in autonomy via the tort of negligence would undermine the coherence of that tort. In ACB, however, a new, different, form of damage was recognised: loss of 'genetic affinity'. This commentary will discuss some problems that protecting an interest in 'genetic affinity' raises before critiquing the approach to assessing damages in ACB. PMID- 29161409 TI - Transfer and Metabolism of Cortisol by the Isolated Perfused Human Placenta. AB - Context: Fetal overexposure to glucocorticoids in utero is associated with fetal growth restriction and is postulated to be a key mechanism linking suboptimal fetal growth with cardiovascular disease in later life. Objective: To develop a model to predict maternal-fetal glucocorticoid transfer. We hypothesized placental 11-beta-hydroxysteroid dehydrogenase-type 2 (11beta-HSD2) would be the major rate-limiting step in maternal cortisol transfer to the fetus. Design: We used a deuterated cortisol tracer in the ex vivo placental perfusion model, in combination with computational modeling, to investigate the role of interconversion of cortisol and its inactive metabolite cortisone on transfer of cortisol from mother to fetus. Participants: Term placentas were collected from five women with uncomplicated pregnancies, at elective caesarean delivery. Intervention: Maternal artery of the isolated perfused placenta was perfused with D4-cortisol. Main Outcome Measures: D4-cortisol, D3-cortisone, and D3-cortisol were measured in maternal and fetal venous outflows. Results: D4-cortisol, D3 cortisone, and D3-cortisol were detected and increased in maternal and fetal veins as the concentration of D4-cortisol perfusion increased. D3-cortisone synthesis was inhibited when 11-beta-hydroxysteroid dehydrogenase (11beta-HSD) activity was inhibited. At the highest inlet concentration, only 3.0% of the maternal cortisol was transferred to the fetal circulation, whereas 26.5% was metabolized and 70.5% exited via the maternal vein. Inhibiting 11beta-HSD activity increased the transfer to the fetus to 7.3% of the maternal input, whereas 92.7% exited via the maternal vein. Conclusions: Our findings challenge the concept that maternal cortisol diffuses freely across the placenta and confirm that 11beta-HSD2 acts as a major "barrier" to cortisol transfer to the fetus. PMID- 29161411 TI - Reply to Hernandez-Vaquero et al. PMID- 29161412 TI - Fluid dynamics in heart development: effects of hematocrit and trabeculation. AB - Recent in vivo experiments have illustrated the importance of understanding the haemodynamics of heart morphogenesis. In particular, ventricular trabeculation is governed by a delicate interaction between haemodynamic forces, myocardial activity, and morphogen gradients, all of which are coupled to genetic regulatory networks. The underlying haemodynamics at the stage of development in which the trabeculae form is particularly complex, given the balance between inertial and viscous forces. Small perturbations in the geometry, scale, and steadiness of the flow can lead to changes in the overall flow structures and chemical morphogen gradients, including the local direction of flow, the transport of morphogens, and the formation of vortices. The immersed boundary method was used to solve the two-dimensional fluid-structure interaction problem of fluid flow moving through a two chambered heart of a zebrafish (Danio rerio), with a trabeculated ventricle, at 96 hours post fertilization (hpf). Trabeculae heights and hematocrit were varied, and simulations were conducted for two orders of magnitude of Womersley number, extending beyond the biologically relevant range (0.2-12.0). Both intracardial and intertrabecular vortices formed in the ventricle for biologically relevant parameter values. The bifurcation from smooth streaming flow to vortical flow depends upon the trabeculae geometry, hematocrit, and Womersley number, $Wo$. This work shows the importance of hematocrit and geometry in determining the bulk flow patterns in the heart at this stage of development. PMID- 29161414 TI - Structural diversity of the nucleosome. AB - In eukaryotes, genomic DNA is compacted in chromatin, which generally suppresses transcription, replication, repair, and recombination. The fundamental unit of chromatin is the nucleosome, whose structure was first determined at atomic resolution in 1997. However, recent findings have revealed that the nucleosome is not a structurally homogenous entity. Nucleosomes containing histone variants often have subtle but clear differences in their structural and functional characteristics, as compared to the canonical nucleosome. In addition to the conventional nucleosome structure, the structure of the overlapping dinucleosome, a new structural unit of chromatin, has been determined. Although archaeal chromatin adopts a unique polymer architecture, its structural unit is very similar to that of the eukaryotic nucleosome, suggesting that the archaeal histone-like protein is orthologous to the eukaryotic histones. In this article, we review the diversity of the nucleosome structures, which plays key roles in their specific functions in the epigenetic regulation of chromatin. PMID- 29161413 TI - NRF2 regulates endothelial glycolysis and proliferation with miR-93 and mediates the effects of oxidized phospholipids on endothelial activation. AB - Phospholipids, such as 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC), are the major components of cell membranes. Their exposure to reactive oxygen species creates oxidized phospholipids, which predispose to the development of chronic inflammatory diseases and metabolic disorders through endothelial activation and dysfunction. Although the effects of oxidized PAPC (oxPAPC) on endothelial cells have been previously studied, the underlying molecular mechanisms evoking biological responses remain largely unknown. Here, we investigated the molecular mechanisms of oxPAPC function with a special emphasis on NRF2-regulated microRNAs (miRNAs) in human umbilical vein endothelial cells (HUVECs) utilizing miRNA profiling, global run-on sequencing (GRO-seq), genome-wide NRF2 binding model, and RNA sequencing (RNA-seq) with miRNA overexpression and silencing. We report that the central regulators of endothelial activity, KLF2 for quiescence, PFKFB3 for glycolysis, and VEGFA, FOXO1 and MYC for growth and proliferation, are regulated by transcription factor NRF2 and the NRF2-regulated miR-106b~25 cluster member, miR-93, in HUVECs. Mechanistically, oxPAPC was found to induce glycolysis and proliferation NRF2 dependently, and oxPAPC-dependent induction of the miR-106b~25 cluster was mediated by NRF2. Additionally, several regulatory loops were established between NRF2, miR-93 and the essential regulators of healthy endothelium, collectively implying that NRF2 controls the switch between the quiescent and the proliferative endothelial states together with miR-93. PMID- 29161415 TI - Letter to the Editor: "Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe". PMID- 29161416 TI - Combined Ovarian and Adrenal Venous Sampling in the Localization of Adrenocorticotropic Hormone-Independent Ectopic Cushing Syndrome. AB - Context: Cushing syndrome is rarely caused by the secretion of cortisol from ovarian tumors. In clinical decision-making, it is important to determine whether the ovarian tumor is capable of secreting cortisol. Selective ovarian and adrenal venous sampling is scarcely reported in the localization of ACTH-independent ectopic Cushing syndrome. Case Description: We present a case of 40-year-old Chinese woman who had weight gain, hirsutism, hypertension, and menstrual disorder over 6 months. Her physical examination and biochemical assessment revealed adrenocorticotropic hormone-independent Cushing syndrome. Adrenal computed tomography scan indicated no abnormality. A mass of 5.7 cm * 4.2 cm * 3.4 cm was discovered by pelvic ultrasonography. Somatostatin receptor scintigraphy revealed no abnormal radioactivity intake. Combined ovarian and adrenal venous sampling together with a cortisol assay were conducted. Results revealed cortisol concentration of the right-side ovarian vein, left-side ovarian vein, and peripheral vein of 268.60, 29.00, and 35.18 MUg/dL, respectively, suggesting a right-side ovarian origin. A right-side salpingo-oophorectomy was performed and the pathological diagnosis revealed ovarian steroid cell tumor, not otherwise specified. The cortisol level was substantially lower after the patient underwent surgery and symptoms of Cushing syndrome disappeared. At 3-year follow up, the patient remained disease free, and no tumor was observed on pelvic ultrasonogram. Conclusion: Combined ovarian and adrenal venous sampling is valuable in the localization of adrenocorticotropic hormone-independent ectopic Cushing syndrome. PMID- 29161418 TI - No Improvement in Hemoglobin A1c Following Hepatitis C Viral Clearance in Patients With and Without HIV. AB - Hepatitis C clearance with directly acting antivirals (DAAs) may be associated with acute decreases in hemoglobin A1c (HbA1c). We prospectively evaluated 251 chronic hepatitis C virus (HCV)-infected subjects (31% human immunodeficiency virus [HIV] positive) pre- and post-DAA therapy (median follow-up 28 months). Changes in HbA1c and glucose were minimal and did not differ by sustained virologic response (SVR), HIV, diabetes, or fibrosis. Following SVR, mean change in HbA1c was -0.022 +/- 0.53%; however, total and low-density lipoprotein cholesterol increased significantly. Subjects with HIV had smaller transaminase reductions after SVR. Sustained benefits in glycemia were not identified following HCV clearance irrespective of HIV, diabetes, or fibrosis stage, whereas lipid alterations may warrant further investigation. PMID- 29161419 TI - Incidence of postoperative atrial fibrillation recurrence in patients discharged in sinus rhythm after cardiac surgery: a systematic review and meta-analysis. AB - Postoperative atrial fibrillation (POAF) is associated with increased stroke risk and mortality post-discharge. POAF is often considered transient; however, recurrence is likely under-recognized as symptoms are an unreliable guide. Surveillance post-discharge may identify asymptomatic POAF recurrences in patients discharged in sinus rhythm. Therefore, we performed a systematic review and meta-analysis of studies investigating POAF recurrence post-discharge, in patients with new-onset POAF following cardiac surgery who reverted to sinus rhythm prior to discharge. Two independent reviewers searched medical databases, clinical trial registries, reference lists and the Internet. After screening from 6525 studies, 8 studies were identified (n = 1157 participants, mean age 66 +/- 10 years and 73% men). Monitoring methods included the following: telemetry during twice-daily exercise sessions (n = 2), continuous telemetry for 3 weeks (n = 1), daily 20-s electrocardiography (ECG) using wearable event recorder (n = 1), 30-s single-lead ECG, 4 times/day (n = 1) and implanted continuous monitoring (n = 2). The incidence rate of POAF recurrence identified through non-invasive monitoring in the first 4 weeks post-discharge was 28.3% [confidence interval (CI) 23.0-33.6%]; recurring 12 +/- 5 days (mean +/- SD) post-surgery. The incidence rate identified through implanted continuous monitoring was 61-100% within 2 years. Between 40% and 93% of episodes were asymptomatic. In one small study reporting stroke risk, 8 of 10 patients with recurrence were guideline indicated (CHA2DS2-VASc score >=2) for oral anticoagulation for stroke prevention. Monitoring for POAF recurrence post-hospital discharge identifies significant numbers of early asymptomatic recurrences in patients at high risk of stroke who may benefit from anticoagulation for stroke prevention. More intense monitoring is more likely to identify POAF recurrence. Future research is required to investigate the prognostic significance of POAF recurrence, especially stroke and mortality risk. PMID- 29161417 TI - Bolus Weekly Vitamin D3 Supplementation Impacts Gut and Airway Microbiota in Adults With Cystic Fibrosis: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial. AB - Context: Disruption of gut microbiota may exacerbate severity of cystic fibrosis (CF). Vitamin D deficiency is a common comorbidity in patients with CF that may influence composition of the gut microbiota. Objectives: Compare microbiota of vitamin D-sufficient and -insufficient CF patients and assess impact of a weekly high-dose vitamin D3 bolus regimen on gut and airway microbiome in adults with CF and vitamin D insufficiency (25-hydroxyvitamin D < 30 ng/mL). Design: Forty-one subjects with CF were classified into two groups: vitamin D insufficient (n = 23) and vitamin D sufficient (n = 18). Subjects with vitamin D insufficiency were randomized to receive 50,000 IU of oral vitamin D3 or placebo weekly for 12 weeks. Sputum and stool samples were obtained pre- and postintervention and 16S ribosomal RNA genes sequenced using Illumina MiSeq technology. Results: Gut microbiota differed significantly based on vitamin D status with Gammaproteobacteria, which contain numerous, potentially pathogenic species enriched in the vitamin D-insufficient group. Principal coordinates analysis showed differential gut microbiota composition within the vitamin D-insufficient patients following 12 weeks treatment with placebo or vitamin D3 (permutation multivariate analysis of variance = 0.024), with Lactococcus significantly enriched in subjects treated with vitamin D3, whereas Veillonella and Erysipelotrichaceae were significantly enriched in patients treated with placebo. Conclusion: This exploratory study suggests that vitamin D insufficiency is associated with alterations in microbiota composition that may promote inflammation and that supplementation with vitamin D has the potential to impact microbiota composition. Additional studies to determine the impact of vitamin D on microbiota benefit clinical outcomes in CF are warranted. PMID- 29161420 TI - Interview with Christina Smolke. PMID- 29161421 TI - Europe PMC in 2017. AB - Europe PMC (https://europepmc.org) is a comprehensive resource of biomedical research publications that offers advanced tools for search, retrieval, and interaction with the scientific literature. This article outlines new developments since 2014. In addition to delivering the core database and services, Europe PMC focuses on three areas of development: individual user services, data integration, and infrastructure to support text and data mining. Europe PMC now provides user accounts to save search queries and claim publications to ORCIDs, as well as open access profiles for authors based on public ORCID records. We continue to foster connections between scientific data and literature in a number of ways. All the data behind the paper - whether in structured archives, generic archives or as supplemental files - are now available via links to the BioStudies database. Text-mined biological concepts, including database accession numbers and data DOIs, are highlighted in the text and linked to the appropriate data resources. The SciLite community annotation platform accepts text-mining results from various contributors and overlays them on research articles as licence allows. In addition, text miners and developers can access all open content via APIs or via the FTP site. PMID- 29161422 TI - Prevalence and Genetic Variability of Human Polyomaviruses 6 and 7 in Healthy Skin Among Asymptomatic Individuals. AB - Background: Despite the pathogenetic potential of human polyomavirus 6 (HPyV6) and human polyomavirus 7 (HPyV7), they have been found in the normal skin of healthy individuals. However, little is known about the prevalence, infection levels, and geographical variations of these polyomaviruses in the skin. Methods: Using skin swabs from 470 participants aged 2-98 years, we estimated the prevalence of copy numbers of HPyV6 and HPyV7 with respect to age and ethnicity. Phylogenetic analyses were conducted based on viral sequences obtained from Asian and white populations. Results: This study provides the first analyses of the age specific prevalence and levels of HPyV6 and HPyV7 infections in normal skin. Comparisons of age groups revealed that the prevalence and viral loads were significantly higher in elderly persons. Phylogenetic analyses demonstrated the existence of Asian/Japanese-specific strains genetically distinct from strains prevalent in the skin of the white population studied. Conclusions: This large study suggests that HPyV6 and HPyV7 infections in the skin are highly prevalent in elderly adults. Further research is warranted to understand whether persistent infection with high viral loads in the skin could be a risk factor for the development of HPyV6- and HPyV7-associated skin disorders. PMID- 29161423 TI - Partial bisulfite conversion for unique template sequencing. AB - We introduce a new protocol, mutational sequencing or muSeq, which uses sodium bisulfite to randomly deaminate unmethylated cytosines at a fixed and tunable rate. The muSeq protocol marks each initial template molecule with a unique mutation signature that is present in every copy of the template, and in every fragmented copy of a copy. In the sequenced read data, this signature is observed as a unique pattern of C-to-T or G-to-A nucleotide conversions. Clustering reads with the same conversion pattern enables accurate count and long-range assembly of initial template molecules from short-read sequence data. We explore count and low-error sequencing by profiling 135 000 restriction fragments in a PstI representation, demonstrating that muSeq improves copy number inference and significantly reduces sporadic sequencer error. We explore long-range assembly in the context of cDNA, generating contiguous transcript clusters greater than 3,000 bp in length. The muSeq assemblies reveal transcriptional diversity not observable from short-read data alone. PMID- 29161424 TI - Clinical impact of implantable cardioverter-defibrillator in primary prevention of total mortality in non-ischaemic cardiomyopathy: results from a meta-analysis of prospective randomized clinical trials. AB - Aim: Primary prophylactic implantable cardioverter defibrillators (ICDs) have demonstrated a clear all-cause mortality benefit in patients with ischaemic cardiomyopathy, with less compelling evidence supporting its use in patients with non-ischaemic cardiomyopathy (NICM). We performed a meta-analysis of randomized controlled trials (RCTs) evaluating the role of ICD for reduction in total mortality in NICM patients. Methods and results: An electronic search on PubMed, the Cochrane Library, and EMBASE databases was performed to identify the RCTs evaluating the role of prophylactic ICD placement in NICM patients. Mantel Haenszel risk ratio (RR) fixed-effects model was used to summarize data across treatment arms. Random-effects model was used if heterogeneity (I2) >= 25. Patients with cardiac resynchronization therapy pacemaker (CRT-P) were included in the control group. Six RCTs, with a total of 3128 patients and a mean follow up period of 48 +/- 22 months comparing ICD with medical therapy in NICM were included in this analysis. There was a significant reduction in all-cause mortality in the ICD group compared with the medical therapy group [RR 0.79, 95% confidence interval (95% CI) 0.68-0.92; P = 0.002]. No publication bias was noted. Conclusion: Currently available evidence demonstrates that the use of ICD provides a clear and significant reduction in all-cause mortality among patients with NICM. PMID- 29161425 TI - Linnorm: improved statistical analysis for single cell RNA-seq expression data. PMID- 29161426 TI - Family history of gastric mucosal abnormality and the risk of gastric cancer: a population-based observational study. AB - Background: An increased prevalence of gastric premalignant abnormalities was reported among relatives of gastric cancer (GC) patients, with rather unexplored clinical significance. Methods: In Swedish computerized pathology registers, we identified, as 'index' persons, 232 681 patients who were born after 1931 and underwent endoscopic examination with stomach biopsy between 1979 and 2014. Through linkage with the Multi-Generation Register, we compiled a cohort consisting of 903 337 first-degree relatives of these biopsied patients. The relatives were grouped according to their 'family histories', defined as the first gastric mucosal diagnosis of the index person or GC family history known before that. Standardized incidence ratios (SIRs) provided comparisons with the matched general population. For internal comparisons with relatives with 'normal/minor changes' mucosal family history, hazard ratios (HRs) were derived from adjusted Cox regression modelling. Results: During follow-up, 1302 relatives developed GC. Crude incidence rates of non-cardia GC were 7.7 * 10-5 year-1 for the 'normal/minor changes' family history group (SIR = 1.0), 11.2 to 12.6 * 10-5 year-1 for precancerous changes groups (atrophic gastritis/intestinal metaplasia/dysplasia, SIR = 1.5 to 1.6), and 18.4 * 10-5 year-1 for those with a family history of GC (SIR = 2.3). HRs derived from Cox models corroborated the family history-related risk pattern, with the most conspicuous trend observed among siblings-a family history of any precancerous changes and GC was associated with, respectively, a 2.5-fold and a 3.8-fold increment in non-cardia GC hazard, compared with siblings of index persons with 'normal/minor mucosal changes'. Conclusions: The precancerous mucosal abnormalities recorded in a person's first degree relatives may improve GC risk stratification for this person. PMID- 29161427 TI - Natural genetic variation and hybridization in plants. PMID- 29161428 TI - Arabidopsis inositol polyphosphate multikinase delays flowering time through mediating transcriptional activation of FLOWERING LOCUS C. AB - Timely flowering is critical for successful reproduction and seed yield in plants. A diverse range of regulators have been found to control flowering time in response to environmental and endogenous signals. Among these regulators, FLOWERING LOCUS C (FLC) acts as a central repressor of floral transition by blocking the expression of flowering integrator genes. Here, we report that Arabidopsis inositol polyphosphate multikinase (AtIPK2beta) functions in flowering time control by mediating transcriptional regulation of FLC at the chromatin level. The atipk2beta mutant flowers earlier, and AtIPK2beta overexpressing plants exhibit late-flowering phenotypes. Quantitative reverse transcription-PCR (qRT-PCR) revealed that AtIPK2beta promotes FLC expression. We performed chromatin immunoprecipitation-qPCR (ChIP-qPCR) assays and found that AtIPK2beta binds to FLC chromatin. Further analysis showed that AtIPK2beta interacts with FVE, a key repressor required for epigenetic silencing of FLC. qRT PCR, ChIP-qPCR, and genetic analysis demonstrated that AtIPK2beta is involved in FVE-mediated transcriptional regulation of FLC by repressing the accumulation of FVE on FLC. Moreover, we found that AtIPK2beta associates with HDA6, an interaction partner of FVE mediating FLC chromatin silencing, and attenuates HDA6 accumulation at the FLC locus. Taken together, these findings suggest that AtIPK2beta negatively regulates flowering time by blocking chromatin silencing of FLC. PMID- 29161429 TI - Crosstalk between the microbiome and epigenome: messages from bugs. AB - Mammals exist in a complicated symbiotic relationship with their gut microbiome, which is postulated to have broad impacts on host health and disease. As omics based technologies have matured, the potential mechanisms by which the microbiome affects host physiology are being addressed. The gut microbiome, which provides environmental cues, can modify host cell responses to stimuli through alterations in the host epigenome and, ultimately, gene expression. Increasing evidence highlights microbial generation of bioactive compounds that impact the transcriptional machinery in host cells. Here, we review current understanding of the crosstalk between gut microbiota and the host epigenome, including DNA methylation, histone modification and non-coding RNAs. These studies are providing insights into how the host responds to microbial signalling and are predicted to provide information for the application of precision medicine. PMID- 29161431 TI - Volunteering in the Community: Potential Benefits for Cognitive Aging. AB - Objectives: This review aims to advance understanding of the potential benefits of volunteering in the community for older adults' cognitive functioning by taking an in-depth look at the relevant evidence to date. Method: This review describes the main pathways through which volunteering could plausibly benefit cognitive functioning and critically examines research that has specifically investigated links between volunteering and cognition. Fifteen articles that assessed in adults aged >= 55 years the relationship between volunteering (predictor) and cognitive functioning (outcome) were identified via literature database searches. Results: On balance, evidence from the small number of relevant studies to date supports the idea that volunteering can protect against cognitive aging with respect to global functioning and at least some specific cognitive domains. Studies that used robust designs and assessed domain-specific cognitive functioning produced the largest effect sizes. Discussion: To help advance the field, this review puts forward recommendations for future research, with an emphasis on the need for robust study designs and specific investigations into the nature and extent of the cognitive benefits of volunteering. Through that work, researchers can determine how a simple and accessible activity like volunteering can best be used to help reduce the burden of age-related cognitive decline. PMID- 29161430 TI - MethBank 3.0: a database of DNA methylomes across a variety of species. AB - MethBank (http://bigd.big.ac.cn/methbank) is a database that integrates high quality DNA methylomes across a variety of species and provides an interactive browser for visualization of methylation data. Here, we present an updated implementation of MethBank (version 3.0) by incorporating more DNA methylomes from multiple species and equipping with more enhanced functionalities for data annotation and more friendly web interfaces for data presentation, search and visualization. MethBank 3.0 features large-scale integration of high-quality methylomes, involving 34 consensus reference methylomes derived from a large number of human samples, 336 single-base resolution methylomes from different developmental stages and/or tissues of five plants, and 18 single-base resolution methylomes from gametes and early embryos at multiple stages of two animals. Additionally, it is enhanced by improving the functionalities for data annotation, which accordingly enables systematic identification of methylation sites closely associated with age, sites with constant methylation levels across different ages, differentially methylated promoters, age-specific differentially methylated cytosines/regions, and methylated CpG islands. Moreover, MethBank provides tools to estimate human methylation age online and to identify differentially methylated promoters, respectively. Taken together, MethBank is upgraded with significant improvements and advances over the previous version, which is of great help for deciphering DNA methylation regulatory mechanisms for epigenetic studies. PMID- 29161433 TI - JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework. PMID- 29161432 TI - Modeling mutant/wild-type interactions to ascertain pathogenicity of PROKR2 missense variants in patients with isolated GnRH deficiency. AB - A major challenge in human genetics is the validation of pathogenicity of heterozygous missense variants. This problem is well-illustrated by PROKR2 variants associated with Isolated GnRH Deficiency (IGD). Homozygous, loss of function variants in PROKR2 was initially implicated in autosomal recessive IGD; however, most IGD-associated PROKR2 variants are heterozygous. Moreover, while IGD patient cohorts are enriched for PROKR2 missense variants similar rare variants are also found in normal individuals. To elucidate the pathogenic mechanisms distinguishing IGD-associated PROKR2 variants from rare variants in controls, we assessed 59 variants using three approaches: (i) in silico prediction, (ii) traditional in vitro functional assays across three signaling pathways with mutant-alone transfections, and (iii) modified in vitro assays with mutant and wild-type expression constructs co-transfected to model in vivo heterozygosity. We found that neither in silico analyses nor traditional in vitro assessments of mutants transfected alone could distinguish IGD variants from control variants. However, in vitro co-transfections revealed that 15/34 IGD variants caused loss-of-function (LoF), including 3 novel dominant-negatives, while only 4/25 control variants caused LoF. Surprisingly, 19 IGD-associated variants were benign or exhibited LoF that could be rescued by WT co transfection. Overall, variants that were LoF in >= 2 signaling assays under co transfection conditions were more likely to be disease-associated than benign or 'rescuable' variants. Our findings suggest that in vitro modeling of WT/Mutant interactions increases the resolution for identifying causal variants, uncovers novel dominant negative mutations, and provides new insights into the pathogenic mechanisms underlying heterozygous PROKR2 variants. PMID- 29161434 TI - Designing a mutant Candida uricase with improved polymerization state and enzymatic activity. AB - As human uricase has been silenced during evolution, counterparts from other species become an alternative for the treatment of hyperuricemia. Candida uricase is a promising option among them, but its aggregation propensity remains a major obstacle to clinical use. In this study, we designed two mutations according to homology-modeled 3D structure of Candida uricase: Cys249Ser substitution and C terminal Leu deletion. The wild-type uricase and three mutants containing either or both of the mutations were expressed in Escherichia coli BL21 and validated by mass spectrometry. Size-exclusion chromatography and electrophoresis analysis demonstrated that aggregation was induced by interchain disulfide bonds and could be significantly avoided by Cys249Ser substitution. In combination with Cys249Ser substitution, deletion of Leu increased the enzymatic activity by 8%. Taken together, mutant containing both mutations is chosen as our target protein which is comparatively more suitable for therapeutic use. In addition, homology-modeled 3D structure was proved to be an efficient approach for protein engineering. PMID- 29161435 TI - Erratum to Douglas et al., Evacuating People and Their Pets: Older Floridians' Need for and Proximity to Pet-Friendly Shelters. PMID- 29161436 TI - Right ventricular failure after surgical ventricular restoration: operation or myocardial protection problem? PMID- 29161437 TI - Spotlight on recently published ICVTS articles. PMID- 29161438 TI - Response to letter to editor from Dr O.M.P. Jolobe. PMID- 29161439 TI - Paget-Schroetter syndrome. PMID- 29161440 TI - Novel arch fenestrated stent graft for acute Stanford Type A aortic dissection with open antegrade implantation. AB - OBJECTIVES: The best surgical strategy for acute Stanford Type A aortic dissection (aTAAD) involving the arch remains controversial. Here, we report on the satisfactory results following aTAAD repair using a novel arch fenestrated stent graft. METHODS: From December 2014 to December 2015, 42 aTAAD patients (27 male and 15 female) underwent ascending aorta replacement and fenestrated stent graft implantation. The fenestrated stent graft was implanted into the true lumen of the aortic arch and proximal descending aorta, with the fenestration opening located at the ostia of 3 head vessels in the arch. The proximal end of the stent graft was anastomosed to the distal end of the Dacron tube graft that replaced the proximal ascending aorta. All patients underwent contrast-enhanced computed tomography angiography prior to discharge and during follow-up. RESULTS: The average cardiopulmonary bypass duration was 213 +/- 49 min, aortic cross-clamp duration was 133 +/- 39 min and unilateral cerebral perfusion and lower body arrest duration was 27 +/- 8 min. There were 2 in-hospital deaths due to circulation failure (mortality 4.8%). During a mean follow-up period of 7.4 +/- 3.2 months, 1 patient with Behcet's disease died of aortic root pseudoaneurysm. The 39 surviving patients underwent contrast-enhanced computed tomography scans at 3, 6 and 12 months, which indicated increasing false-lumen thrombosis. CONCLUSIONS: In aTAAD patients, the use of the novel arch fenestrated stent graft achieved excellent aortic remodelling of the aortic arch and descending aorta without any increase in the morbidity and mortality. PMID- 29161442 TI - Origin and Evolution of the Bartonella Gene Transfer Agent. AB - Gene transfer agents (GTAs) are domesticated bacteriophages that have evolved into molecular machines for the transfer of bacterial DNA. Despite their widespread nature and their biological implications, the mechanisms and selective forces that drive the emergence of GTAs are still poorly understood. Two GTAs have been identified in the Alphaproteobacteria: the RcGTA, which is widely distributed in a broad range of species; and the BaGTA, which has a restricted host range that includes vector-borne intracellular bacteria of the genus Bartonella. The RcGTA packages chromosomal DNA randomly, whereas the BaGTA particles contain a relatively higher fraction of genes for host interaction factors that are amplified from a nearby phage-derived origin of replication. In this study, we compare the BaGTA genes with homologous bacteriophage genes identified in the genomes of Bartonella species and close relatives. Unlike the BaGTA, the prophage genes are neither present in all species, nor inserted into homologous genomic sites. Phylogenetic inferences and substitution frequency analyses confirm codivergence of the BaGTA with the host genome, as opposed to multiple integration and recombination events in the prophages. Furthermore, the organization of segments flanking the BaGTA differs from that of the prophages by a few rearrangement events, which have abolished the normal coordination between phage genome replication and phage gene expression. Based on the results of our comparative analysis, we propose a model for how a prophage may be transformed into a GTA that transfers amplified bacterial DNA segments. PMID- 29161443 TI - Fragile X Syndrome with Congenital Diaphragmatic Hernia. AB - The authors present a case of Fragile X syndrome (FXS) in siblings from an Indian family with no developmental delay in previous generations. The boy presented with developmental delay, autistic features and defiant behaviours that raised clinical suspicion. He also had congenital diaphragmatic hernia (CDH). Social anxiety and difficulty in making friends were the subtle features in his sister with dull normal intelligence. FXS was confirmed by clinical features and DNA testing. Intervention was initiated for both the siblings. Screening siblings in FXS is important. CDH can be associated with FXS. PMID- 29161441 TI - Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty. AB - Context: Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures: We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients: We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity-associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/- mice. Results: We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/- mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Conclusions: Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self limited DP. PMID- 29161445 TI - Practicing Medicine in the "Age of Accelerations". PMID- 29161446 TI - Microglia Activation and Gene Expression Alteration of Neurotrophins in the Hippocampus Following Early-Life Exposure to E-Cigarette Aerosols in a Murine Model. AB - Recent epidemiological data indicate that the popularity of electronic cigarettes (e-cigarettes), and consequently nicotine use, is rising in both adolescent and adult populations. As nicotine is a known developmental neurotoxin, these products present a potential threat for those exposed during early life stages. Despite this, few studies have evaluated the toxicity of e-cigarettes on the developing central nervous system. The goal of this study was to assess neurotoxicity resulting from early-life exposure to electronic cigarette aerosols in an in vivo model. Specifically, studies here focused on neuro-parameters related to neuroinflammation and neurotrophins. To accomplish this, pregnant and neonatal C57BL/6 mice were exposed to aerosols produced from classic tobacco flavor e-cigarette cartridges (with [13 mg/ml] and without nicotine) during gestation (~3 weeks) and lactation (~3 weeks) via whole-body inhalation. Exposure to e-cigarette aerosols with and without nicotine caused significant reductions in hippocampal gene expression of Ngfr and Bdnf, as well as in serum levels of cytokines IL-1beta, IL-2, and IL-6. Exposure to e-cigarette aerosols without nicotine enhanced expression of Iba-1, a specific marker of microglia, in the cornus ammonis 1 region of the hippocampus. Overall, our novel results indicate that exposure to e-cigarette aerosols, with and without nicotine, poses a considerable risk to the developing central nervous system. Consequently, e cigarettes should be considered a potential public health threat, especially early in life, requiring further research and policy considerations. PMID- 29161444 TI - Risk perceptions of public health and food safety hazards in poultry husbandry by citizens, poultry farmers and poultry veterinarians. AB - Differences in risk perceptions of public health and food safety hazards in various poultry husbandry systems by various stakeholder groups, may affect the acceptability of those husbandry systems. Therefore, the objective was to gain insight into risk perceptions of citizens, poultry farmers, and poultry veterinarians regarding food safety and public health hazards in poultry husbandry systems, and into factors explaining these risk perceptions. We surveyed risk perceptions of Campylobacter contamination of broiler meat, avian influenza introduction in laying hens, and altered dioxin levels in eggs for the most commonly used broiler and laying hen husbandry systems in Dutch citizens (n = 2,259), poultry farmers (n = 100), and poultry veterinarians (n = 41). Citizens perceived the risks of the three hazards in the indoor systems higher and in the outdoor systems lower than did the professionals. Citizens reported higher concerns regarding aspects reflecting underlying psychological factors of risk perception compared to professionals. Professionals indicated a relatively low level of personal control, which might imply risk denial. Of the socio demographic characteristics, gender and childhood residence were associated with risk perceptions. The influence of other factors of risks perception are discussed. It is suggested that risk perceptions of all stakeholder groups are influenced by affect, stigma, and underlying values. To adapt current or new husbandry systems that can count on societal support, views of key stakeholders and multiple aspects such as animal welfare, public health, food safety, and underlying values should be considered integrally. When trade-offs, such as between animal welfare and public health have to be made, insight into underlying values might help to find consensus among stakeholders. PMID- 29161447 TI - DNA polymerase beta participates in DNA End-joining. AB - DNA double strand breaks (DSBs) are one of the most deleterious lesions and if left unrepaired, they lead to cell death, genomic instability and carcinogenesis. Cells combat DSBs by two pathways: homologous recombination (HR) and non homologous end-joining (NHEJ), wherein the two DNA ends are re-joined. Recently a back-up NHEJ pathway has been reported and is referred to as alternative NHEJ (aNHEJ), which joins ends but results in deletions and insertions. NHEJ requires processing enzymes including nucleases and polymerases, although the roles of these enzymes are poorly understood. Emerging evidence indicates that X family DNA polymerases lambda (Pol lambda) and mu (Pol MU) promote DNA end-joining. Here, we show that DNA polymerase beta (Pol beta), another member of the X family of DNA polymerases, plays a role in aNHEJ. In the absence of DNA Pol beta, fewer small deletions are observed. In addition, depletion of Pol beta results in cellular sensitivity to bleomycin and DNA protein kinase catalytic subunit inhibitors due to defective repair of DSBs. In summary, our results indicate that Pol beta in functions in aNHEJ and provide mechanistic insight into its role in this process. PMID- 29161449 TI - Endovascular repair for three-channelled aortic dissection. AB - Surgical repair of extensive thoracic aortic disease induced by repeated aortic dissection is challenging due to its invasive nature in some cases. We report a rare case of successful endovascular repair of a dissected 3-channelled thoracic aortic aneurysm using the PETTICOAT (provisional extension to induce complete attachment) technique and false-lumen embolization (the candy-plug technique). The PETTICOAT technique improved visceral flow, and the false lumen of the aneurysm was completely thrombosed by the candy-plug technique. This minimally invasive combination technique might be a good option for the treatment of complex dissected thoracic aorta. PMID- 29161448 TI - Prenatal famine exposure, adulthood obesity patterns and risk of type 2 diabetes. AB - Background: Prenatal exposure to famine and adulthood obesity have been independently related to the risk of type 2 diabetes; however, little is known about the joint effects of these risk factors at different stages of life on adulthood diabetes risk. Methods: The analysis included 88 830 participants of the China Kadoorie Biobank, who were born around the time of the Chinese Great Famine and without diabetes, cardiovascular diseases, or cancer at baseline. We defined famine exposure subgroups as nonexposed (born between 1 October 1962 and 30 September 964), fetal-exposed (born between 1 October 1959 and 30 September 1961) and early-childhood exposed (born between 1 October 1956 and 30 September 1958). General obesity was assessed by body mass index (BMI: overweight >= 24.0, obesity >= 28.0) and abdominal obesity assessed by waist-to-hip ratio (WHR, men/women: moderate >= 0.90/0.85, high >= 0.95/0.90). Results: During a median 7.3 years (642 552 person-years) of follow-up, we identified 1372 incident cases of type 2 diabetes. Compared with nonexposed and early-childhood exposed participants combined as a single comparison group, fetal-exposed participants showed an increased risk of diabetes in adulthood [hazard ratio (HR) = 1.25; 95% confidence interval (CI): 1.07-1.45]. The association between general obesity and diabetes was consistent across subgroups according to famine exposure (P for interaction > 0.05). A stronger association between abdominal obesity and diabetes was observed in the fetal-exposed subgroup than in other subgroups (P for interaction = 0.025 in the whole population). This interaction was more obvious in women (P = 0.013) but not in men (P = 0.699). Compared with normal-BMI and -WHR participants, those with both general (BMI >= 24.0) and abdominal (WHR >= 0.90/0.85) obesity in adulthood had 5.32 (95% CI: 3.81-7.43)-, 3.13 (2.48 3.94)- and 4.43 (3.45-5.68)-fold higher risks if these were carried during, before and after times of famine, respectively. Conclusions: Coexistence of prenatal experience of undernutrition and abdominal obesity in adulthood was associated with a higher risk of type 2 diabetes. PMID- 29161450 TI - Response to Letter by Dr. Champion. PMID- 29161451 TI - Combat, Posttraumatic Stress Disorder, and Smoking Trajectory in a Cohort of Male Australian Army Vietnam Veterans. AB - Background: Whether trauma exposure itself or consequent posttraumatic stress disorder (PTSD) is primarily responsible for smoking and failure to quit remains unclear. Methods: A cohort of male Australian Vietnam veterans (N = 388) was interviewed twice, 22 and 36 years after their return to Australia using standardized psychiatric diagnostic and health interviews and assessment of combat exposure. The smoking trajectory over time revealed a spectrum of outcomes (never smoked, early quitters, late quitters, and continuing smokers). Analysis used multivariate statistics to assess the relative contributions of combat trauma exposure and PTSD while controlling for potential confounders. Results: The trajectory of smoking over time revealed that 21.9% of veterans had never smoked, 45.1% had quit smoking by the time of wave 1, 16.2% were current smokers at wave 1 who had quit by the time of wave 2, 2.8% were late adopters who were current smokers, and 13.9% were continuing smokers. Smoking was associated in single-predictor models with demographics, intelligence, combat exposure, PTSD symptom clusters and diagnosis, and alcohol disorders. Multivariate analysis revealed that PTSD, combat, and intelligence were related to the smoking spectrum but, after adding demographics and other Axis I psychiatric diagnoses, only combat remained significant. No PTSD symptom cluster uniquely predicted smoking status. Conclusions: The results suggest that trauma exposure in the form of military combat may be a more robust predictor of smoking status over time than PTSD. It may be stress itself, rather than poststress disorder, that is more germane to smoking and failure to quit. Implications: Exposure to traumatic stress and development of PTSD have been implicated separately in the maintenance of smoking. This longitudinal cohort study of smoking in war veterans up to three decades postwar enabled evaluation of traumatic stress exposure in combat and the course of PTSD in smoking and quitting while controlling for intelligence, background disadvantage, and other psychiatric conditions. Combat rather than PTSD emerged as more significant to smoking status, suggesting that it may be the traumatic stress itself rather than the development of a poststress disorder that is more germane to smoking in war veterans. PMID- 29161452 TI - Psychometric examination of the Center for Epidemiologic Studies Depression scale with older American Indians: The Native Elder Care Study. AB - Measuring mental health accurately is an important endeavor for screening purposes. Depression scales, such as the Center for Epidemiologic Studies Depression (CES-D) scale, have been well-established among different populations. Yet, little work has been done to examine the reliability and validity of the CES D among older American Indians and Alaska Natives. The purpose of our study was to examine the factor structure, reliability, and concurrent validity of the full 20-item and abbreviated 12-item CES-D scale with a sample of older American Indians. Our findings demonstrate excellent internal reliability and concurrent validity of the full and abbreviated CES-D scales in our study sample. PMID- 29161453 TI - Comparison of American Indian and Non-Native BASC-2 Self-Report-Adolescent Scores. AB - BASC-2 SRP-A scores of 162 American Indian (AI) youth were compared with those of an ethnically diverse sample (N = 200) to explore group equivalence. A MANOVA indicated group differences among the five composites. AIs outscored non-Natives in Inattention/Hyperactivity. We examined AIs' ADHD scores in relation to their acculturation strategies, measured using the Bicultural Ethnic Identity Scale. Culturally marginalized AIs (low White and low Indian acculturation) reported stronger ADHD symptoms than bicultural, assimilated, or separated youth. The potential impact of culture on clinical measures is discussed. PMID- 29161454 TI - Religious and Spiritual Practices Among Home-less Urban American Indians and Alaska Natives with Severe Alcohol Problems. AB - Engagement in religious and spiritual practices may be protective for homeless individuals with alcohol-related problems. However, little is known in this regard for urban-dwelling American Indians and Alaska Natives (AI/ANs) who have disproportionately high rates of homelessness and co-occurring alcohol use problems. Using secondary data from a nonrandomized controlled study testing a Housing First intervention, AI/AN participants (n = 52) and non-AI/AN participants (n = 82) were compared on demographic variables, alcohol use problems, religious affiliations, and religious/spiritual practices (importance, frequency, and type). AI/ANs who engaged in Native-specific independent spiritual practices had significantly lower alcohol use frequency in comparison to AI/ANs who did not. PMID- 29161455 TI - Responding to concerning posts on social media: Insights and solutions from American Indian and Alaska Native youth. AB - PURPOSE: This study aimed to understand American Indian and Alaska Native (AI/AN) adolescents' perspectives on concerning social media posts, including those expressing suicidal intent. METHODS: A purposive sample of AI/AN youth were recruited; trained facilitators conducted focus groups. Participants discussed experiences viewing concerning posts on social media. Qualitative analysis used the constant comparative method. RESULTS: A total of 32 AI/AN youth ages 14-22 participated. Three salient themes emerged: 1) youth typically respond alone; 2) barriers to action; 3) recommended training and support - trusted adults, anonymity, and privacy. CONCLUSION: Study findings will guide the development of resources trusted by AI/AN youth. PMID- 29161456 TI - Integrated Care with Indigenous Populations: A Systematic Review of the Literature. AB - INTRODUCTION: The integration of behavioral health into medical care is related to positive results including improved patient health outcomes, provider satisfaction, and cost-offset. Indigenous people suffer from the highest health disparities in the nation and disproportionately experience barriers to health care; yet it is unknown if integrated care is effective for this population. METHODS: A systematic literature review was completed on the state of integrated care at Indigenous-serving health care sites in 2014 and was updated in 2016. Three databases were selected (Eric, Medline, and PsycInfo) and keywords pertaining to an Indigenous population and integrated care services (e.g., Native American, American Indian, or First Nations with integrated care, primary care, or family medicine) were used. After inclusion and exclusion criteria were applied, nine articles were selected out of the 2,889 articles found. Five additional articles were added in the 2016-update search. The selected articles were then evaluated using standards of integrated care. RESULTS: The selected articles demonstrated wide-ranging and positive results including improved physical and mental health symptoms, reduced substance use, improvements in education and employment status, as well as a decreased involvement with the criminal justice system. It appears that interventions that additionally integrated culturally relevant health beliefs and practices experienced the largest gains in health outcomes. DISCUSSION: Integrated care appears to be an intervention that can ameliorate these disparities by reducing stigma for those seeking care and providing coordinated care to prevent or reduce health care disparities in this population. While integrated care appears to be an effective system of care for Indigenous people, it must be noted that integration of local Indigenous health beliefs and practices is equally necessary. PMID- 29161457 TI - The soluble guanylate cyclase CYG12 is required for the acclimation to hypoxia and trophic regimes in Chlamydomonas reinhardtii. AB - Oxygenic phototrophs frequently encounter environmental conditions that result in intracellular energy crises. Growth of the unicellular green alga Chlamydomonas reinhardtii in hypoxia in the light depends on acclimatory responses of which the induction of photosynthetic cyclic electron flow is essential. The microalga cannot grow in the absence of molecular oxygen (O2 ) in the dark, although it possesses an elaborate fermentation metabolism. Not much is known about how the microalga senses and signals the lack of O2 or about its survival strategies during energy crises. Recently, nitric oxide (NO) has emerged to be required for the acclimation of C. reinhardtii to hypoxia. In this study, we show that the soluble guanylate cyclase (sGC) CYG12, a homologue of animal NO sensors, is also involved in this response. CYG12 is an active sGC, and post-transcriptional down regulation of the CYG12 gene impairs hypoxic growth and gene expression in C. reinhardtii. However, it also results in a disturbed photosynthetic apparatus under standard growth conditions and the inability to grow heterotrophically. Transcriptome profiles indicate that the mis-expression of CYG12 results in a perturbation of responses that, in the wild-type, maintain the cellular energy budget. We suggest that CYG12 is required for the proper operation of the photosynthetic apparatus which, in turn, is essential for survival in hypoxia and darkness. PMID- 29161458 TI - Proton pump inhibitors for functional dyspepsia. AB - BACKGROUND: Functional dyspepsia (FD or non-ulcer dyspepsia) is defined as continuous or frequently recurring epigastric pain or discomfort for which no organic cause can be found. Acid suppressive therapy, including proton pump inhibitors (PPIs), has been proposed as a therapeutic option in FD, but its efficacy remains controversial. While PPIs are generally considered safe and well tolerated, they have been associated with adverse events, especially in the long term. For this reason, decisions on whether to initiate or continue PPI therapy should be made based on an appropriate clinical indication. Therefore, we conducted a systematic review to evaluate whether PPI therapy provides symptomatic relief in FD. OBJECTIVES: To determine the efficacy of proton pump inhibitors in the improvement of global symptoms of dyspepsia and quality of life compared to placebo, H2 receptor antagonists or prokinetics, in people with functional dyspepsia. SEARCH METHODS: We searched in the following electronic databases: the Cochrane Library (to May 2017), MEDLINE (OvidSP; to May 2017), Embase (OvidSP; to May 2017), and SIGLE grey literature (up to May 2017) and clinical trial registries; we handsearched abstracts from conferences up to May 2017. We screened non-systematic reviews, systematic reviews and guidelines to identify any additional trials. We contacted trialists to obtain missing information. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing any PPI with placebo, H2 receptor antagonists (H2RAs) or prokinetics for the treatment of FD of at least two weeks' duration. Participants were adults (aged 16 years or greater) with an adequate diagnosis of FD (any validated criteria such as Rome I, II, III or Lancet Working Group). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and trial quality, and extracted data. We collected data on dyspeptic symptoms, quality of life and number of overall adverse events. Specific adverse events were beyond the scope of this review. MAIN RESULTS: We identified 25 RCTs from 27 papers (with 8453 participants) studying the effect of PPIs versus placebo, H2RAs or prokinetics for improvement of global symptoms of dyspepsia and quality of life in people with FD. Low-dose PPIs had similar efficacy as standard-dose PPIs, therefore we combined these subgroups for the analysis. PPI was more effective than placebo at relieving overall dyspepsia symptoms in people with FD (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.82 to 0.94; participants = 6172; studies = 18; number needed to treat for an additional beneficial outcome (NNTB) 11; moderate quality evidence). PPIs may have little or no effect compared with H2RAs (RR 0.88, 95% CI 0.74 to 1.04; participants = 740; studies = 2; low quality evidence), and may be slightly more effective than prokinetics (RR 0.89, 95% CI 0.81 to 0.99; participants = 1033; studies = 5; NNTB 16; low quality evidence) at relieving overall dyspepsia symptoms in people with FD. PPIs plus prokinetics have probably little or no effect compared with PPIs alone at relieving overall dyspepsia symptoms (RR 0.85, 95% CI 0.68 to 1.08; participants = 407; studies = 2; moderate quality evidence).There was no difference when subgrouped by Helicobacter pylori status, country of origin, or presence of reflux or Rome III subtypes. There were no differences in the number of adverse events observed between PPIs and any of the other treatments. There were fewer adverse events in the combination of PPI plus prokinetics compared to prokinetics alone (RR 0.60, 95% CI 0.39 to 0.93; participants = 407; studies = 2; moderate quality evidence). AUTHORS' CONCLUSIONS: There is evidence that PPIs are effective for the treatment of FD, independent of the dose and duration of treatment compared with placebo. PPIs may be slightly more effective than prokinetics for the treatment of FD; however, the evidence is scarce. The trials evaluating PPIs versus prokinetics are difficult to interpret as they are at risk of bias. Although the effect of these drugs seems to be small, the drugs are well tolerated. PMID- 29161459 TI - Ageing impairs parasite-specific antibody responses in cystic echinococcosis. AB - Humoral immunity wanes during healthy ageing, increasing susceptibility to infections in the elderly. In this sense, information about parasite infections and human immunosenescence is scarce. Cystic echinococcosis (CE) is an infectious disease caused by the larval stage of the cestode parasite Echinococcus granulosus, whose prevalence in humans shows an increase with host age. Susceptibility to human CE has been associated with humoral immunity to some extent, and, therefore, we have here analysed the influence of host age on the serological profile of young, middle-aged and aged patients. Our results highlighted the detrimental influence of ageing on the intensity and quality of the antiparasite antibody response. Remarkable differences in serological profiles between young and aged individuals were observed. In this sense, through Principal Components Analysis, we identified aged patients as those exhibiting overall less intense antibody responses, mainly in isotypes/subclasses supposed to exert efficient antiparasite activities (eg IgE and IgG1). Thus, these humoral defects could at least partially explain the reported increase in CE prevalence among older individuals, as a weaker immune response in the elderly might facilitate the establishment and maintenance of the parasite infection. Finally, a possible association between age-dependent susceptibility to CE and host immunosenescence is discussed. PMID- 29161460 TI - Editorial: Wnt Signaling Related to Subchondral Bone Density and Cartilage Degradation in Osteoarthritis. PMID- 29161461 TI - Ruthenium-Crosslinked Hydrogels with Rapid, Visible-Light Degradation. AB - Incorporation of photoresponsive molecules within soft materials can provide spatiotemporal control over bulk properties and address challenges in targeted delivery and mechanical variability. However, the kinetics of in situ photochemical reactions are often slow and typically employ ultraviolet wavelengths. Here, we present a novel photoactive crosslinker Ru(bipyridine)2 (3 pyridinaldehyde)2 (RuAldehyde), which was reacted with hydrazide-functionalized hyaluronic acid to form hydrogels capable of encapsulating protein cargo. Visible light irradiation (400-500 nm) initiated rapid ligand exchange on the ruthenium center, which degraded the hydrogel within seconds to minutes, depending on gel thickness. An exemplar enzyme cargo, TEM1 beta-lactamase, was loaded into and photoreleased from the Ru-hydrogel. To expand their applications, Ru-hydrogels were also processed into microgels using a microfluidic platform. PMID- 29161462 TI - The influence of coping strategies on subsequent well-being in older patients with cancer: A comparison with 2 control groups. AB - OBJECTIVE: To evaluate dispositional coping strategies as predictors for changes in well-being after 1 year in older patients with cancer (OCP) and 2 control groups. METHODS: OCP were compared with 2 control groups: middle-aged patients with cancer (MCP) (aging effect) and older patients without cancer (ONC) (cancer effect). Patients were interviewed shortly after a cancer diagnosis and 1 year later. Dispositional coping was measured with the Short Utrecht Coping List. For well-being, we considered psychological well-being (depression, loneliness, distress) and physical health (fatigue, ADL, IADL). Logistic regression analyses were performed to study baseline coping as predictor for subsequent well-being while controlling for important baseline covariates. RESULTS: A total of 1245 patients were included in the analysis at baseline: 263 OCP, 590 ONC, and 392 MCP. Overall, active tackling was employed most often. With the exception of palliative reacting, OCP utilized each coping strategy less frequently than MCP. At 1-year follow-up, 833 patients (66.9%) were interviewed. Active coping strategies (active tackling and seeking social support) predicted subsequent well being only in MCP. Avoidance coping strategies did not predict well-being in any of the patient groups. Palliative reacting predicted distress in OCP; depression and dependency for ADL in MCP. CONCLUSIONS: Coping strategies influence subsequent well-being in patients with cancer, but the impact is different in the age groups. Palliative reacting was the only coping strategy that predicted well being (ie, distress) in OCP and is therefore, especially in this population, a target for coping skill interventions. PMID- 29161463 TI - Blockade of Treg Cell Differentiation and Function by the Interleukin-21 Mechanistic Target of Rapamycin Axis Via Suppression of Autophagy in Patients With Systemic Lupus Erythematosus. AB - OBJECTIVE: The mechanistic target of rapamycin (mTOR) has become a therapeutic target in systemic lupus erythematosus (SLE). In T cells, mTOR plays a central role in lineage specification, including development of regulatory cells (Treg cells). This study sought to investigate whether mTOR is activated within Treg cells and whether this contributes to the depletion and dysfunction of Treg cells in patients with SLE. METHODS: Activities of mTOR complexes 1 (mTORC1) and 2 (mTORC2) were examined by quantifying phosphorylation of translation initiation factor 4E-binding protein 1, S6 kinase, and Akt in SLE patients relative to age- and sex-matched female healthy control subjects. Polarization of Treg cells from naive CD4+ T cells was assessed in the presence of interleukin-6 (IL-6), IL-17, and IL-21. The suppressor function of sorted CD4+CD25+ Treg cells was measured by determining their impact on the proliferation of autologous CD4+CD25- responder T cells. Treg cell expression of FoxP3, GATA-3, and CTLA-4 was monitored by flow cytometry. Autophagy was assessed using immunoblotting of light chain 3 lipidation. The effect of mTOR blockade was evaluated by testing the impact of rapamycin treatment on Treg cell function. RESULTS: SLE Treg cells exhibited increased activities of mTORC1 and mTORC2, whereas autophagy, the expression of GATA-3 and CTLA-4, and the suppressor function of Treg cells were diminished. IL 21, but not IL-6 or IL-17, blocked the development of Treg cells. IL-21 stimulated mTORC1 and mTORC2, and it abrogated the autophagy, differentiation, and function of Treg cells. Moreover, IL-21 constrained the expression of GATA-3 and CTLA-4 selectively in Treg cells. In turn, blockade of mTORC1 by 3-day rapamycin treatment enhanced transforming growth factor beta production, while dual blockade of mTORC1 and mTORC2 by 4-week rapamycin treatment induced autophagy, restored the expression of GATA-3 and CTLA-4, and corrected Treg cell function. CONCLUSION: IL-21-driven mTOR activation is a pharmacologically targetable checkpoint of the deficient autophagy that underlies Treg cell dysfunction in SLE. PMID- 29161464 TI - Increased efficiency of targeted mutagenesis by CRISPR/Cas9 in plants using heat stress. AB - The CRISPR/Cas9 system has greatly improved our ability to engineer targeted mutations in eukaryotic genomes. While CRISPR/Cas9 appears to work universally, the efficiency of targeted mutagenesis and the adverse generation of off-target mutations vary greatly between different organisms. In this study, we report that Arabidopsis plants subjected to heat stress at 37 degrees C show much higher frequencies of CRISPR-induced mutations compared to plants grown continuously at the standard temperature (22 degrees C). Using quantitative assays relying on green fluorescent protein (GFP) reporter genes, we found that targeted mutagenesis by CRISPR/Cas9 in Arabidopsis is increased by approximately 5-fold in somatic tissues and up to 100-fold in the germline upon heat treatment. This effect of temperature on the mutation rate is not limited to Arabidopsis, as we observed a similar increase in targeted mutations by CRISPR/Cas9 in Citrus plants exposed to heat stress at 37 degrees C. In vitro assays demonstrate that Cas9 from Streptococcus pyogenes (SpCas9) is more active in creating double-stranded DNA breaks at 37 degrees C than at 22 degrees C, thus indicating a potential contributing mechanism for the in vivo effect of temperature on CRISPR/Cas9. This study reveals the importance of temperature in modulating SpCas9 activity in eukaryotes, and provides a simple method to increase on-target mutagenesis in plants using CRISPR/Cas9. PMID- 29161465 TI - Neuromuscular electrical stimulation for the prevention of venous thromboembolism. AB - BACKGROUND: Venous thromboembolism (VTE) is a serious but preventable cause of morbidity and mortality. Neuromuscular electrical stimulation systems (NMES) for the prevention of VTE may be beneficial for patients in whom pharmacological or standard mechanical prophylaxis methods are contraindicated or are regarded as unsafe or impractical. Although findings of experimental studies suggest that NMES reduce venous stasis, the clinical utility and effectiveness of NMES in VTE prevention remain controversial. OBJECTIVES: To assess the effectiveness of neuromuscular electrical stimulation in the prevention of venous thromboembolism. SEARCH METHODS: The Cochrane Vascular Group Information Specialist (CIS) searched the Specialised Register (22 March 2017) and the Cochrane Central Register of Controlled Studies (CENTRAL (2017, Issue 2)). The CIS also searched trial registries for details of ongoing and unpublished studies. The review authors searched the bibliographic lists of relevant articles and reviews to look further for potentially eligible trials. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and quasi-randomised trials that compared any form of neuromuscular electrical stimulation as an intervention for VTE prophylaxis (alone or combined with pharmacological or other mechanical methods) versus no prophylaxis and other mechanical or pharmacological methods of VTE prophylaxis. DATA COLLECTION AND ANALYSIS: At least two independent review authors were involved in study selection, data extraction, methodological quality assessment of included studies, and data analysis. We resolved disagreements by discussion between the two review authors. If no agreement could be reached, a third review author acted as an adjudicator. The main outcomes of the review were total deep vein thrombosis (DVT), symptomatic and asymptomatic DVT, pulmonary embolism (PE), total VTE and bleeding (major and minor). The quality of evidence was assessed using the GRADE approach and is indicated in italics. MAIN RESULTS: We included in the review five randomised controlled trials and three quasi randomised trials, enrolling a total of 904 participants. Among these, four studies included patients undergoing major surgical procedures; one study included patients undergoing surgery for hip fracture under spinal anaesthesia; one study included trauma patients with a contraindication for prophylactic heparin; one study included neurosurgical patients who were operated on under general anaesthesia; and one study included patients with non-functional spinal cord injuries. Overall, eight studies investigated 22 treatment arms. Four studies compared the NMES arm with a no prophylaxis arm, and five studies compared the NMES arm with alternative methods of prophylaxis arms. Alternative methods of prophylaxis included low-dose heparin (5000 IU subcutaneously) - two studies, Dextran 40 - one study, graduated compression stockings (GCS) and intermittent pneumatic compression devices (IPCD) - one study. One study compared combined NMES and low-dose heparin versus no prophylaxis or low-dose heparin alone.We found no clear difference in risks of total DVT (odds ratio (OR) 1.01, 95% confidence interval (CI) 0.60 to 1.70, P = 0.98; 6 studies, 415 participants; low-quality evidence), asymptomatic DVT (OR 1.61, 95% CI 0.40 to 6.43, P = 0.50; 1 study, 89 participants; low-quality evidence), symptomatic DVT (OR 0.40, 95% CI 0.02 to 10.07, P = 0.58; 1 study, 89 participants; low-quality evidence), PE (OR 1.31, 95% CI 0.38 to 4.48, P = 0.67; 2 studies, 126 participants;low-quality evidence), and total VTE (OR 0.92, 95% CI 0.34 to 2.52, P = 0.88; 1 study, 72 participants; low-quality evidence) between prophylaxis with NMES and alternative methods of prophylaxis. None of the studies in this comparison reported bleeding.Compared with no prophylaxis, NMES showed lower risks of total DVT (OR 0.40, 95% CI 0.23 to 0.70, P = 0.02; 4 studies, 576 participants; moderate quality evidence) and total VTE (OR 0.23, 95% CI 0.09 to 0.59, P = 0.002; 1 study, 77 participants; low-quality evidence). Data show no clear differences in risk of asymptomatic DVT (OR 0.32, 95% CI 0.06 to 1.62, P = 0.17; 1 study, 200 participants; low-quality evidence), symptomatic DVT (OR 0.06, 95% CI 0.00 to 1.36, P = 0.08; 1 study, 160 participants;low-quality evidence), or PE (OR 0.36, 95% CI 0.12 to 1.07, P = 0.07; 1 study, 77 participants; low-quality evidence) between prophylaxis with NMES and no prophylaxis. None of the studies in this comparison reported bleeding.In comparison with low-dose heparin, NMES was associated with higher risk of total DVT (OR 2.78, 95% CI 1.19 to 6.48, P = 0.02; 2 studies, 194 participants; low-quality evidence), but data were inadequate for other comparisons (NMES vs Dextran 40, NMES vs GCS, or NMES vs IPCD) and for other clinical outcomes such as symptomatic or asymptomatic DVT, PE, total VTE, and bleeding in individual comparisons.Overall, we judged the quality of available evidence to be low owing to high or unclear risk of bias and imprecise effect estimates due to small numbers of studies and events. AUTHORS' CONCLUSIONS: Low-quality evidence shows no clear difference in the risk of DVT between NMES and alternative methods of prophylaxis but suggest that NMES may be associated with lower risk of DVT compared with no prophylaxis (moderate-quality evidence) and higher risk of DVT compared with low-dose heparin (low-quality evidence). The best available evidence about the effectiveness of NMES in the prevention of VTE is not adequately robust to allow definitive conclusions. Adequately powered high-quality randomised controlled trials are required to provide adequately robust evidence. PMID- 29161466 TI - Treating Early Undifferentiated Arthritis: A Systematic Review and Meta-Analysis of Direct and Indirect Trial Evidence. AB - OBJECTIVE: We undertook a systematic review and meta-analysis of direct and indirect trial evidence to evaluate the efficacy of treatments for patients with undifferentiated arthritis (UA). METHODS: We searched 4 electronic databases from inception to January 2016, clinicaltrials.gov, and bibliographies of relevant articles. Two reviewers independently screened and evaluated the studies. The primary outcome was development of rheumatoid arthritis (RA). RESULTS: Nine studies were included. Interventions included methotrexate, abatacept, infliximab, intraarticular or intramuscular glucocorticoids, and radiation synovectomy. Treating patients resulted in lower rates of RA at 12 months compared to placebo or no treatment (odds ratio [OR] 0.49 [95% confidence interval (95% CI) 0.26, 0.90]). From direct meta-analysis, patients treated with methotrexate were less likely to develop RA at 12 months compared to patients treated without methotrexate (OR 0.13 [95% CI 0.03, 0.48]). This difference was no longer significant at 30 or 60 months. From indirect comparisons, most interventions showed decreased risk of developing RA compared to placebo at 12 months, reaching statistical significance for methotrexate (OR 0.16 [95% CI 0.08, 0.33]) and intramuscular methylprednisolone (OR 0.72 [95% CI 0.53, 0.99]). Most individual interventions included a limited number of studies. CONCLUSION: Treating patients with UA resulted in a statistically significant delay in the development of RA, with the largest effect observed for methotrexate. These findings suggest that there is a window of opportunity to treat patients with UA early, to delay subsequent progression to RA. PMID- 29161467 TI - Continuous-Flow Synthesis of Supported Magnetic Iron Oxide Nanoparticles for Efficient Isoeugenol Conversion into Vanillin. AB - This work presents the synthesis of iron oxide nanocatalysts supported on mesoporous Al-SBA-15 by using a continuous-flow setup. The magnetic nanomaterials were tested as catalysts in the oxidative disruption of isoeugenol by using hydrogen peroxide as a green oxidant, featuring high activities (63-88 % conversion) and good selectivities to vanillin (44-68 %). The catalytic systems exhibited good magnetic properties when synthesized under continuous-flow conditions at temperatures not exceeding 190 degrees C. The use of microwave irradiation significantly reduced times of reaction drastically but exerted negative effects on catalyst reusability. PMID- 29161468 TI - The Relationship Between Endogenous beta-Glucuronidase Activity and Biologically Active Flavones-Aglycone Contents in Hairy Roots of Baikal Skullcap. AB - Here, we examine the relationship between contents of principal flavones in hairy roots of Scutellaria baicalensis with the activity of the beta-glucuronidase (sGUS) enzyme during a culturing cycle. Using RP-HPLC, we show that the highest contents of aglycones, baicalin and wogonin is observed at the growth days 8, 14, and 71 and reach 45, 41, and 62% (based on the total weight of hairy roots of the Baikal skullcap), correspondingly. Their accumulation is accompanied by increase of the sGUS activity, which we determined fluorometrically. Moreover, the enzyme activity is characterized by significant and reasonable correlation only with the wogonin contents. Our results confirm a significant role of sGUS at the final steps of the metabolism in root-specific flavones of Baikal skullcap and suggest how one can optimize the conditions of culturing the hairy roots for biotechnological production of individual flavonoids. For example, at the culturing day 71 wogonin constituted over 80% of all flavones extracted from cells. PMID- 29161469 TI - Brief Report: Validation of a Definition of Flare in Patients With Established Gout. AB - OBJECTIVE: To perform external validation of a provisional definition of disease flare in patients with gout. METHODS: Five hundred nine patients with gout were enrolled in a cross-sectional study during a routine clinical care visit at 17 international sites. Data were collected to classify patients as experiencing or not experiencing a gout flare, according to a provisional definition. A local expert rheumatologist performed the final independent adjudication of gout flare status. Sensitivity, specificity, predictive values, and receiver operating characteristic (ROC) curves were used to determine the diagnostic performance of gout flare definitions. RESULTS: The mean +/- SD age of the patients was 57.5 +/- 13.9 years, and 89% were male. The definition requiring fulfillment of at least 3 of 4 criteria (patient-defined gout flare, pain at rest score of >3 on a 0-10 point numerical rating scale, presence of at least 1 swollen joint, and presence of at least 1 warm joint) was 85% sensitive and 95% specific in confirming the presence of a gout flare, with an accuracy of 92%. The ROC area under the curve was 0.97. The definition based on a classification and regression tree algorithm (entry point, pain at rest score >3, followed by patient-defined flare "yes") was 73% sensitive and 96% specific. CONCLUSION: The definition of gout flare that requires fulfillment of at least 3 of 4 patient-reported criteria is now validated to be sensitive, specific, and accurate for gout flares, as demonstrated using an independent large international patient sample. The availability of a validated gout flare definition will improve the ascertainment of an important clinical outcome in studies of gout. PMID- 29161470 TI - Resequencing of a mutant bearing an iron starvation recovery phenotype defines Slr1658 as a new player in the regulatory network of a model cyanobacterium. AB - Photosynthetic microorganisms encounter an erratic nutrient environment characterized by periods of iron limitation and sufficiency. Surviving in such an environment requires mechanisms for handling these transitions. Our study identified a regulatory system involved in the process of recovery from iron limitation in cyanobacteria. We set out to study the role of bacterioferritin co migratory proteins during transitions in iron bioavailability in the cyanobacterium Synechocystis sp. PCC 6803 using knockout strains coupled with physiological and biochemical measurements. One of the mutants displayed slow recovery from iron limitation. However, we discovered that the cause of the phenotype was not the intended knockout but rather the serendipitous selection of a mutation in an unrelated locus, slr1658. Bioinformatics analysis suggested similarities to two-component systems and a possible regulatory role. Transcriptomic analysis of the recovery from iron limitation showed that the slr1658 mutation had an extensive effect on the expression of genes encoding regulatory proteins, proteins involved in the remodeling and degradation of the photosynthetic apparatus and proteins modulating electron transport. Most significantly, expression of the cyanobacterial homologue of the cyclic electron transport protein PGR5 was upregulated 1000-fold in slr1658 disruption mutants. pgr5 transcripts in the Deltaslr1658 mutant retained these high levels under a range of stress and recovery conditions. The results suggest that slr1658 is part of a regulatory operon that, among other aspects, affects the regulation of alternative electron flow. Disruption of its function has deleterious results under oxidative stress promoting conditions. PMID- 29161472 TI - A Young Child With Fever, Alopecia, and Skin Nodules. PMID- 29161473 TI - ? PMID- 29161471 TI - Peer-to-Peer Mentoring for African American Women With Lupus: A Feasibility Pilot. AB - OBJECTIVE: To examine the feasibility and potential benefits of peer mentoring to improve the disease self-management and quality of life of individuals with systemic lupus erythematosus (SLE). METHODS: Peer mentors were trained and paired with up to 3 mentees to receive self-management education and support by telephone over 12 weeks. This study took place at an academic teaching hospital in Charleston, South Carolina. Seven quads consisting of 1 peer mentor and 3 mentees were matched, based on factors such as age, area of residence, and marital and work status. Mentee outcomes of self-management, health-related quality of life, and disease activity were measured using validated tools at baseline, mid-intervention, and post-intervention. Descriptive statistics and effect sizes were calculated to determine clinically important (>0.3) changes from baseline. RESULTS: Mentees showed trends toward lower disease activity (P = 0.004) and improved health-related quality of life, in the form of decreased anxiety (P = 0.018) and decreased depression (P = 0.057). Other improvements in health-related quality of life were observed with effect sizes >0.3, but did not reach statistical significance. In addition, both mentees and mentors gave very high scores for perceived treatment credibility and service delivery. CONCLUSION: The intervention was well received. Training, the peer-mentoring program, and outcome measures were demonstrated to be feasible with modifications. This result provides preliminary support for the efficacy, acceptability, and perceived credibility of a peer-mentoring approach to improve disease self-management and health-related quality of life in African American women with SLE. Peer mentoring may augment current rheumatologic care. PMID- 29161474 TI - ? PMID- 29161475 TI - ? PMID- 29161476 TI - [Spatial distribution of Aedes aegypti (Diptera: Culicidae) in the rural area of two municipalities of Cundinamarca, Colombia]. AB - INTRODUCTION: It is difficult to adapt or create new strategies for dengue control in rural areas due to the dispersion of homes and the lack of knowledge about the presence and behavior of the vector in these areas. Spatial data analysis could help understand time and space dynamics related to the transmission of vector-borne diseases in rural areas and, thus, contribute to the prevention and control of dengue. OBJECTIVE: To determine the probability of the presence of the dengue vector Aedes aegypti in the rural area of the municipalities of Anapoima and La Mesa, in the central area of Colombia. MATERIALS AND METHODS: The probability of the presence or absence of the vector in the study area was determined by means of the kriging spatial interpolation method. RESULTS: The region with the highest probability of the presence of the vector was located in the central part, close to the urban centers of both municipalities. CONCLUSION: This study shows the importance of geostatistics for the surveillance of vector-borne diseases and the analysis of time and space dynamics of vector insects and of diseases transmitted by them. PMID- 29161477 TI - [Insecticidal action of synthetic girgensohnine analogues and essential oils on Rhodnius prolixus (Hemiptera: Reduviidae)]. AB - INTRODUCTION: The alkaloid girgensohnine has been used as a natural model in the synthesis of new alkaloid-like alpha-aminonitriles with insecticidal effect against disease vectors. OBJECTIVE: To evaluate the biocide activity of girgensohnine analogues and essential oils of Cymbopogon flexuosus, Citrus sinensis and Eucalyptus citriodora in stage I and stage V Rhodnius prolixus nymphs. MATERIALS AND METHODS: We used a topical application model in tergites and sternites, as well as exposure to treated surfaces with different exploratory doses of each of the molecules and essential oils to determine the lethal doses (LD50 and LD95). RESULTS: Analogue 3 showed the highest insecticidal activity with 83.3+/-16.7% of mortality when applied on tergites, 38.9+/-4.8% on sternites and 16.7+/-0% on treated surfaces in stage I nymphs at 72 hours (h) and 500 mg.L 1. In stage V nymphs, the compounds induced mortality only in sternums (11.1+/ 9.6% for analogue 6 and 5.5+/-4.7% for analogues 3 and 7 at 72 h and 1500 mg.L 1). The lethal doses for molecule 3 on tergites in stage I nymphs were LD50 225.60 mg.L-1 and LD95 955.90 mg.L-1. The insecticidal effect of essential oils was observed only in stage I nymphs, with 11.1+/-4.8% for C. flexuosus when applied in sternites, while using exposure to surfaces treated it was 5.6+/-4.8% for C. sinensis applied on tergites and 8.3+/-0% on sternites at 72 h and 1000 mg.L-1. CONCLUSION: Synthetic girgensohnine analogues, and C. flexuosus and C. sinensis essential oils showed insecticidal activity in R. prolixus. Analogue 3 showed the greatest insecticidal activity among all molecules and oils evaluated under our laboratory conditions. PMID- 29161478 TI - [Spatial distribution of potential and positive Aedes aegypti breeding sites]. AB - INTRODUCTION: The spatial distribution of Aedes aegypti is heterogeneous, and the interaction between positive and potential breeding sites located both inside and outside homes is one of the most difficult aspects to characterize in vector control programs. OBJECTIVE: To describe the spatial relationship between potential and positive breeding sites of A. aegypti inside and outside homes in Cali, Colombia. MATERIALS AND METHODS: We conducted an entomological survey to collect data from both indoor and outdoor breeding sites. The exploratory analysis of spatial data included location, spatial trends, local spatial autocorrelation, spatial continuity and spatial correlation of positive and potential breeding sites according to habitat. RESULTS: Spatial trends were identified, as well as clusters of potential and positive breeding sites outdoors using local spatial autocorrelation analysis. A positive correlation was found between potential and positive breeding sites, and a negative correlation existed between indoor and outdoor sites. CONCLUSIONS: The spatial relationship between positive and potential A. aegypti breeding sites both indoors and outdoors is dynamic and highly sensitive to the characteristics of each territory. Knowing how positive and potential breeding sites are distributed contributes to the prioritization of resources and actions in vector control programs. PMID- 29161479 TI - [Laboratory susceptibility tests of Aedes aegypti and Culex quinquefasciatus larvae to the entomopathogenic nematode Heterorhabditis bacteriophora]. AB - INTRODUCTION: Aedes aegypti is the vector of dengue, yellow fever, Zika and Chikungunya viruses, and Culex quinquefasciatus is the vector of St. Louis and West Nile encephalitis viruses. OBJECTIVE: To evaluate infectivity of Heterorhabditis bacteriophora N4 in C. quinquefasciatus and A. aegypti larvae under laboratory conditions. MATERIALS AND METHODS: Thirty second-instar larvae of the two mosquito species were exposed each to different doses (0:1, 1:1, 5:1, 15:1, 100:1, 500:1, 750:1 and 1,500:1) of nematode infective juveniles. Four replications per dose were performed. RESULTS: Parasitism varied between 2.5 and 80 % in C. quinquefasciatus, and between 4.2 and 92.5 % in A. aegypti, with significant differences between doses (p<0.0001). DL50 were: 160.8 infective juveniles per larva for C. quinquefasciatus and 113.6 infective juveniles per larva for A. aegypti. In C. quinquefasciatus, 4 to 6 % of the infective juveniles developed to adults and in A. aegypti, 12- 61 %. In A. aegypti the emergence of new infective juveniles occurred with 100:1, 500:1, 750:1 and 1,500:1 infective juveniles per larva, and in C. quinquefasciatus, with 1,500:1 infective juveniles per larva. Melanization of infective juveniles was observed in both mosquito species. CONCLUSION: The susceptibility of these mosquito species to parasitism of an indigenous isolate of H. bacteriophora in the laboratory was demonstrated. Heterorhabditis bacteriophora N4 could be an efficient biological control agent. PMID- 29161480 TI - [Biological parameters of Meccus phyllosomus phyllosomus (Burmeister), 1835, Triatoma recurva (Stal), 1868 (Hemiptera, Reduviidae) and their laboratory hybrids]. AB - INTRODUCTION: Hybrids from species and subspecies of Mexican triatomines have shown outstanding biological and behavioral characteristics as compared with their parental groups. This could lead to an increasing risk of transmission of Trypanosoma cruzi to human and animal reservoir hosts. OBJECTIVE: To describe and compare biological parameters related to the life cycle of Triatoma recurva, Meccus phyllosomus phyllosomus and their laboratory hybrids and estimate their risk as transmitters of T. cruzi to humans. MATERIALS AND METHODS: We kept a cohort of each one of the three groups (T. recurva, M. p. phyllosomus and their hybrids) under similar laboratory conditions and then compared them to record the data related to their life cycles, number of blood meals to molt, mortality rates, egg eclosion rates and female fecundity. RESULTS: The hybrid cohort showed the lowest mean time from first-instar nymph to adult (136.6 +/- 17.5 days). The number of blood meals from molt to next instar (13.4 +/- 1.7; 15.6 +/- 5.2) was higher in the hybrid and T. recurva cohorts. The hybrid cohort showed the lowest mortality rate (29.5%) and the highest rate (70%) of adult females at the end of the biological cycle. Fecundity per day per female (range: 1.1 +/- 0.6- 1.6 +/- 0.7 eggs) was similar in the three cohorts. Egg hatching rate was higher than 70% in both hybrid and M. p. phyllosomus cohorts. CONCLUSION: The hybrid cohort showed some outstanding biological characteristics, which would entail a higher risk of transmission of T. cruzi to hosts than their parentals. PMID- 29161481 TI - [Eco-epidemiological aspects, natural detection and molecular identification of Leishmania spp. in Lutzomyia reburra, Lutzomyia barrettoi majuscula and Lutzomyia trapidoi]. AB - INTRODUCTION: The province of Pichincha in Ecuador is an endemic area of cutaneous leishmaniasis, where anthropophilic sand flies with natural infection by Leishmania, have been reported as vectors. However, the role in transmission of zoophilic species has not been evaluated. OBJECTIVE: To evaluate natural infection by Leishmania in two zoophilic phlebotomine sand fly species, Lutzomyia reburra and Lu. barrettoi majuscula, and one anthropophilic species, Lu. trapidoi, as well as the endophagy and synanthropism of these species in the northwest of Pichincha. MATERIALS AND METHODS: Phlebotomines were collected using CDC light traps in different habitats and altitudes with presence of cutaneous leishmaniasis. Leishmania infection was detected using genomic DNA from females of the collected sand flies. We amplified the internal transcribed spacer gene of ribosomal RNA I (ITS1), the mitochondrial topoisomerase II gene (mtTOPOII), and the nuclear topoisomerase II gene (TopoII). Percentages of positivity for Leishmania, at spatio-temporal scale, proportion of endophagy and synanthropism index were calculated. RESULTS: Natural infection was determined for Le. amazonensis in Lu. reburra (9.5%) and Lu. b. majuscula (23.8%), while in Lu. trapidoi we detected Le. amazonensis, Le. brazilienis and Le. naiffi-lainsoni. Phlebotomines were asynanthropic and with low endophagy. CONCLUSION: Natural infection with Le. amazonensis was recorded for the first time in Lu. reburra and Lu. b. majuscula, demonstrating the importance of zoophilic phlebotomines in the maintenance of the Leishmania transmission cycle in endemic foci. PMID- 29161482 TI - [Abundance, composition and natural infection of Anopheles mosquitoes from two malaria-endemic regions of Colombia]. AB - INTRODUCTION: In Colombia there are three Anopheles species implicated in malaria transmission as primary vectors; however, the local role of some Anopheles species must still be defined. OBJECTIVE: To determine the abundance, composition and natural infection rates for Anopheles mosquitoes with Plasmodium spp. in two malaria-endemic regions of Colombia. MATERIALS AND METHODS: Anopheles mosquitoes were collected using the human-landing catches and while resting in livestock corrals in nine localities of two malaria-endemic regions of Colombia. Mosquitoes were morphologically identified and confirmed by PCR-RFLP-ITS2. Identified mosquitoes were processed and tested for Plasmodium parasite infection by ELISA and ssrRNA-based nested PCR. RESULTS: We collected 1,963 Anopheles mosquitoes corresponding to nine species. The most abundant species were Anopheles nuneztovari (53.5%) and A. darlingi (34.5%), followed by A. triannulatus s.l. (6%), and other species (~5.9%). Three species were naturally infected with Plasmodium spp.: A. darlingi, A. nuneztovari and A. triannulatus s.l. CONCLUSIONS: Natural infection of A. darlingi and A. nuneztovari indicate that these malaria vectors continue to be effective carriers of Plasmodium in the localities under study in Valle del Cauca and Choco. Additionally, the infected A. triannulatus s.l. collected in livestock corrals in the locality of the department of Cordoba suggests the need for further studies to define the epidemiological importance of this species given its abundance and opportunistic anthropophilic behavior. PMID- 29161483 TI - [Spatio-temporal analysis of the biophysical and ecological conditions of Triatoma dimidiata (Hemiptera: Reduviidae: Triatominae) in the northeast region of Colombia]. AB - INTRODUCTION: Due to the lack of information regarding biophysical and spatio temporal conditions (hydrometheorologic and vegetal coverage density) in areas with Triatoma dimidiata in the Colombian departments of Santander and Boyaca, there is a need to elucidate the association patterns of these variables to determine the distribution and control of this species. OBJECTIVE: To make a spatio-temporal analysis of biophysical variables related to the distribution of T. dimidiate observed in the northeast region of Colombia. MATERIALS AND METHODS: We used the Intergovernmental Panel on Climate Change Special Report on Emissions Scenarios (IPCC SRES) data bases registering vector presence and hydrometheorologic data. We studied the variables of environmental temperature, relative humidity, rainfall and vegetal coverage density at regional and local levels, and we conducted spatial geostatistic, descriptive statistical and Fourier temporal series analyses. RESULTS: Temperatures two meters above the ground and on covered surface ranged from 14,5 degrees C to 18,8 degrees C in the areas with the higher density of T. dimidiata. The environmental temperature fluctuated between 30 and 32 degrees C. Vegetal coverage density and rainfall showed patterns of annual and biannual peaks. Relative humidity values fluctuated from 66,8 to 85,1%. CONCLUSIONS: Surface temperature and soil coverage were the variables that better explained the life cycle of T. dimidiata in the area. High relative humidity promoted the seek of shelters and an increase of the geographic distribution in the annual and biannual peaks of regional rainfall. The ecologic and anthropic conditions suggest that T. dimidiata is a highly resilient species. PMID- 29161484 TI - [Anopheles darlingi (Diptera: Culicidae) Rood 1926: Morphometric variations in wings and legs of populations from Colombia]. AB - INTRODUCTION: Natural populations of Anopheles darlingi, the main malaria vector in Colombia, have shown phenotypic variations in some of their diagnostic characters. OBJECTIVE: To characterize morphometric variations in wing spot patterns and diagnostic characters of the hind leg of adult females of An. darlingi collected in areas where malaria is endemic. MATERIALS AND METHODS: Patterns of the costal vein spots of wild females of An. darling populations collected in the departments of Choco, Guaviare, Meta and Vichada were analyzed using linear and morphometric approaches. The second tarsomere of the hind leg of females was characterized by linear morphometric analysis. RESULTS: We found 19 patterns of spots in the costal vein; patterns I (n=118/240, 49%) and VI (n=66, 28%) were the most frequent. The proportion of the basal dark area of hind tarsomere II and the length of hind tarsomere II (DSIII2/Ta-III2) constituted a robust diagnostic character as it represented 89% (n=213/240) of the total specimens studied. Significant differences were found in the wing shape (F=1.65, df =50, p<0.001) and the wing size (F=3.37, df=5, p=0.005) among populations from different locations. The smallest centroid size (2.64 mm) was found in populations from Choco. CONCLUSIONS: We registered 11 new wing spot patterns in the costal vein and the dominance of the patterns I and VI for populations of An. darlingi from Colombia. We confirmed DSIII2/TaIII2 ratio as a robust diagnostic character for the taxonomy of this species. We found differences between the size and shape of the wings of An. darlingi populations in accordance to their geographical distribution, which constitute important bionomic aspects for this malaria vector. PMID- 29161485 TI - Aedes albopictus (Skuse, 1894) infected with the American-Asian genotype of dengue type 2 virus in Medellin suggests its possible role as vector of dengue fever in Colombia. AB - INTRODUCTION: Aedes aegypti and Ae. albopictus are recognized vectors of dengue, yellow fever, chikungunya and Zika arboviruses in several countries worldwide. In Colombia, Ae. albopictus geographical distribution has increased to include highly populated cities such as Cali and Medellin. Although this species has been frequently found in urban and semi-urban zones in the country, its role as vector of the dengue fever is poorly known. OBJECTIVE: To identify the presence of Ae. albopictus specimens naturally infected with dengue virus collected in Medellin. MATERIALS AND METHODS: Insects were collected in the Universidad Nacional de Colombia campus in Medellin. Individuals were classified as Ae. albopictus and confirmed by DNA barcode region analysis. Mosquitoes were processed for dengue virus identification, and a fragment of the NS3 gen was sequenced and compared with DENV-2 genotypes reported in the literature. RESULTS: Sequence analysis of COI indicated Ae. albopictus individuals were similar to those recently reported in Colombia, and genetically close to those from other regions worldwide. Among the pools tested one was positive for DENV-2, and the NS3 analysis indicated it belonged to the Asian-American clade. CONCLUSION: We report the presence Ae. albopictus naturally infected with the Asian-American genotype of DENV-2 in Colombia. The presence of Ae. albopictus specimens carrying the most common genotype infecting humans in a highly populated city such as Medellin indicates its potential role as dengue vector in Colombia and highlights the relevance of including it in current vector surveillance strategies. PMID- 29161486 TI - [Phylogenetic signal at the Cytb-SertRNA-IG1-ND1 mitochondrial region in Anopheles (Kerteszia) neivai Howard, Dyar & Knab, 1913]. AB - INTRODUCTION: Mitochondrial DNA has proven its utility for the study of insect evolution. Genes such as cytochrome b (Cytb) and the transfer gene for serine (SertRNA) can be used to compare closely related organisms. OBJECTIVE: The phylogenetic utility of Cytb-SertRNA-IG1-ND1 was tested for polymorphisms, and secondary structure modeling in SertRNA was done to detect possible cryptic species in Anopheles neivai. MATERIALS AND METHODS: Specimens from Colombia, Guatemala, and the type locality in Panama were collected and sequenced for specimen comparison based on DNA polymorphisms, and secondary structure modeling for the SertRNA gene. RESULTS: Thirty-six sequences for A. neivai and A. pholidotus were obtained. CONCLUSIONS: Polymorphic variants were detected in A. neivai for Cytb-SertRNA-IG1- ND1. Despite this variation in A. neivai, cryptic species could not be detected. PMID- 29161487 TI - Virological surveillance of Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus as support for decision making for dengue control in Medellin. AB - INTRODUCTION: Dengue represents an important public health problem in Colombia. No treatment is available and the vaccine has not been approved in all countries, hence, actions should be strengthened to mitigate its impact through the control of Aedes aegypti, the vector mosquito. In Colombia, surveillance is done using entomological indexes and case notification, which is usually informed late, leading to untimely interventions. Viral detection in urban mosquitoes using molecular techniques provides more accurate entomological information for decision-making. OBJECTIVE: To report results of virological surveillance in Aedes specimens collected during routine entomological activities of the Secretaria de Salud de Medellin. MATERIALS AND METHODS: Specimens were collected during two periods in each of which we selected 18 dwellings around each one of the 250 larva traps arranged for mosquitoe surveillance, as well as 70 educational institutions and 30 health centers. Specimens were identified morphologically, and divided in pools for viral detection using reverse transcription polymerase chain reaction (RT-PCR). We calculated the minimum infection rate and the adult infestation index for each group. RESULTS: We collected 1,507 adult mosquitoes, 10 of which were identified as A. albopictus. Out of the 407 pools, 132 (one of them Ae. albopictus) were positive, and 14.39% were A. aegypti males. The minimum infection rates for Ae. aegypti were 120.07 and 69,50 for the first and second periods, respectively, and the adult infestation index was higher in educational institutions (23.57%). CONCLUSIONS: Using RT-PCR we identified natural infectivity and vertical transmission of dengue virus in A. aegypti and A. albopictus. We suggest the use of molecular techniques in arbovirosis surveillance and control programs in Colombia. PMID- 29161488 TI - Identifying Trypanosoma cruzi discreet typing units in triatomines collected in different natural regions of Peru. AB - INTRODUCTION: Trypanosoma cruzi has been divided by international consensus into six discrete typing units (DTU): TcI, TcII, TcIII, TcIV, TcV y TcVI. The factors determining the dynamics of T. cruzi genotypes vector transmission of Chagas' disease in the different geographical regions of Peru are still unknown. OBJECTIVE: To detect and type T. cruzi DTUs from the faeces of seven species of triatomines (Panstrongylus chinai, P. geniculatus, P. herreri, Rhodnius robustus, R. pictipes, Triatoma carrioni and T. infestans) captured in eight departments from different natural regions of Peru. MATERIALS AND METHODS: We examined 197 insects for detecting trypanosomes. DNA was extracted from each insect intestinal contents and PCR amplification of kDNA, SL-IR, 24Salpha rRNA and 18Salpha RNA was performed for detecting T. cruzi DTUs. RESULTS: Five T. rangeli and 113 T. cruzi infections were detected; 95 of the latter were identified as TcI (two in P. chinai, one in P. geniculatus, 68 in P. herreri, four in R. pictipes, seven in R. robustus, one in T. carrioni, 12 in T. infestans), five as TcII (four in P. herreri, one in T. infestans), four as TcIII (three in P. herreri, one in R. robustus) and four TcIV infections in P. herreri. CONCLUSIONS: This is the first study which has attempted a large-scale characterization of T. cruzi found in the intestine of epidemiologically important vectors in Peru, thus providing basic information that will facilitate a better understanding of the dynamics of T. cruzi vector transmission in Peru. PMID- 29161489 TI - Effect of the type and number of washes in the efficacy of long lasting insecticidal nets for Aedes aegypti control in Girardot, Colombia. AB - INTRODUCTION: The use of long lasting insecticidal materials has shown promising results in the control of Aedes aegypti. OBJECTIVE: To evaluate the efficacy of long-lasting insecticidal nets (PermaNet(r)) for Aedes aegypti control after three washing treatments in the city of Girardot, Colombia. MATERIALS AND METHODS: Standard bioassays were conducted with the nets following the World Health Organization protocols using wild A. aegypti after three washing treatments: (1) Detergent powder, (2) detergent powder and bleach, and (3) bar soap, until completing 20 washes. RESULTS: The type and number of wash treatments had a significant effect on net efficacy. Greater effects in the insecticide bioavailability were seen for the bar soap treatment. After six washes, mortality decreased by 50% (25/50), vs 66% (33/50) for the detergent powder and 84% (42/50) for the detergent powder and bleach treatments. Regarding the number of washes, the bar soap treatment reduced the efficacy to 68% after only three washes. CONCLUSION: The effectiveness of long-lasting insecticidal nets (PermaNet 2.0) for A. aegypti control varied in relation to the treatment and number of washes. The bar soap treatment resulted in the greatest reduction of mortality. Further studies on insecticidal reductions are needed under local conditions. PMID- 29161490 TI - [Estimation of time detection limit for human cytochrome b in females of Lutzomyia evansi]. AB - INTRODUCTION: Molecular biology techniques have allowed a better knowledge of sources of blood meals in vector insects. However, the usefulness of these techniques depends on both the quantity of ingested blood and the digestion process in the insect. OBJECTIVE: To identify the time limit for detection of the human cytochrome b (Cyt b) gene in experimentally fed females of Lutzomyia evansi. MATERIALS AND METHODS: Eight groups of L. evansi females were fed on human blood and sacrificed at intervals of 24 hours post-ingestion. Total DNA was extracted from each female and a segment of 358 bp of Cyt b was amplified. In order to eliminate false positives, amplification products were subjected to a restriction fragment length polymorphism (RFLP) analysis. RESULTS: The human Cyt b gene segment was detected in 86% (49/57) of the females of L. evansi, from 0 to 168 hours after blood ingestion. In 7% (4/57) of the individuals we amplified insect DNA, while in the remaining 7%, the band of interest was not amplified. We did not find any statistical differences between groups of females sacrificed at different times post-blood meal regarding the amplification of the human Cyt b gene segment or the number of samples amplified. CONCLUSION: The human Cyt b gene segment was detectable in L. evansi females up to 168 hours after blood ingestion. PMID- 29161491 TI - Dengue virus detection in Aedes aegypti larvae and pupae collected in rural areas of Anapoima, Cundinamarca, Colombia. AB - INTRODUCTION: There is a high incidence and prevalence of dengue in the department of Cundinamarca, and recently Aedes aegypti, the main vector of dengue virus (DENV), was detected in some of its rural areas. OBJECTIVE: To evaluate viral transovarial transmission in larvae and pupae collected in rural areas of the municipality of Anapoima, Cundinamarca. MATERIALS AND METHODS: Live larvae and pupae were collected from 53 homes and later they were taken to the laboratory in Anapoima, where they were classified, pooled and frozen. In Bogota, they were homogenized, RNA was extracted with TrizolTM, and RT-PCR and conventional PCR were performed. The amplified products were analyzed on 2% agarose gels. RESULTS: In 54.7% of the houses we found A. aegypti in immature stages, and DENV-1 was the most frequent serotype. However, the simultaneous presence of DENV 1 and 2, DENV 1 and 3, DENV 1 and 4, and DENV 1, 2 and 3 serotypes was detected in some pools. CONCLUSION: The results confirmed the natural vertical transmission of the virus in the rural area under study. These findings confirmed the vector capacity of A. aegypti, and partly explains the persistence of the virus in the region and the possibility of transmission by the vector during adulthood without having ingested infected blood. This situation increases the risk of DENV infection in Colombia and the need for prevention and control programs in all areas where the mosquito is present. PMID- 29161492 TI - Bionomics of Anopheles (Nyssorhynchus) albimanus (Diptera: Culicidae) in two villages of the Wayuu people, Riohacha, La Guajira, Colombia. AB - INTRODUCTION: Riohacha, capital of the department of La Guajira, reports the highest rates for malaria in the department, and the most vulnerable people are those of the Wayuu indigenous group. OBJECTIVE: To describe some aspects of the bionomics of the Anopheles species in two Wayuu settlements. MATERIALS AND METHODS: Two sampling events were carried out during dry and rainy seasons in Marbacella and El Horno (Riohacha, La Guajira). Immature stages of Anopheles spp. were collected, and breeding sites were described. Adult mosquitoes were collected with human landing catches, Shannon traps and CDC traps. RESULTS: All collected specimens were Anopheles albimanus. Biting activity occurred outdoors during all the night (n=7), while indoors, only two mosquitoes were captured between 18:00 and 20:00 hours. The positive breeding sites corresponded to jagueyes (n=7, 38.8%), pools (n=2, 10.5%), and fishponds (n=2, 10.5%). The highest abundance of immature forms was found in the jagueyes (n=25, 78%), which had pH values between 7.20 and 7.81 and a temperature of 25 degrees C, and were located 150 m away from Wayuu homes. CONCLUSION: Anopheles albimanus was the only collected species found in water supply deposits in the villages Marbacella and El Horno. Given that the species is the main vector for malaria in the area, we suggest the implementation of a community-based entomological surveillance system which should respect Wayuu cosmology and routine activities such as fishing. PMID- 29161493 TI - Detection of Leishmania (V) guyanensis in Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) collected from Pecari tajacu. AB - INTRODUCTION: Previous studies identified the presence of Leishmania infantum in Rhipicephalus sanguineus and indicated the possibility that it could transmit leishmaniasis to a variety of hosts. OBJECTIVE: To identify parasites of Leishmania (Viannia) spp. in ticks collected from wild animals in an endemic area for leishmaniasis. MATERIALS AND METHODS: We performed 81 individual DNA extractions from ticks collected from three Tapirus terrestris and three Pecari tajacu in Madre de Dios, Peru. Ticks were taxonomically identified and they were subsequently prepared to identify Leishmania (Viannia) spp. kDNA by PCR and the species of Leishmania by HRM-PCR. RESULTS: Leishmania (Viannia) kDNA was detected in three wild ticks of the species R. microplus, collected from a collard peccary (P. tajacu) hunted in the forests of Madre de Dios. The HRM-PCR showed that one of the positive samples had a kDNA curve compatible with L. (V) guyanensis. CONCLUSION: The results showed the presence of L. (V) guyanensis DNA in R. microplus possibly acquired after biting a collarde peccary. Therefore, it is important to design future studies to clarify R. microplus involvement in the transmission of leishmaniasis. PMID- 29161494 TI - Species of sand flies (Diptera: Psychodidae) collected from natural reserves in the Pacific and Darien regions of Colombia. AB - INTRODUCTION: The departments of Choco and Antioquia in Colombia show climatic and vegetation conditions favoring the establishment of vector species of the genus Lutzomyia and the transmission of Leishmania spp. to human populations entering conserved forest environments. OBJECTIVE: To report the species of Phlebotomine sandflies present in three natural reserves in the Darien and Pacific regions of Colombia. MATERIALS AND METHODS: Sand flies were collected specifically in the natural reserves El Aguacate (Acandi, Choco), Nabuga (Bahia Solano, Choco) and Tulenapa (Carepa, Antioquia). Sand flies were collected with CDC light traps, active search in resting places and Shannon traps. The taxonomic determination of species was based on taxonomic keys. For some species of taxonomic interest, we evaluated the partial sequences of the 5' region of COI gene. RESULTS: A total of 611 adult sand flies were collected: 531 in Acandi, 45 in Carepa and 35 in Bahia Solano. Seventeen species of the genus Lutzomyia, three of the genus Brumptomyia and one of the genus Warileya were identified. The genetic distances (K2P) and grouping supported (>99%) in the neighbor joining dendrogram were consistent for most established molecular operational taxonomic units (MOTU) of the Aragaoi group and clearly confirmed the identity of Lu. coutinhoi. CONCLUSION: Species that have importance in the transmission of leishmaniasis in Acandi, Bahia Solano and Carepa were identified. The presence of Lu. coutinhoi was confirmed and consolidated in Colombia. PMID- 29161495 TI - Essential oils and their components as an alternative in the control of mosquito vectors of disease. AB - More than half of the human population is exposed to mosquito-borne infections. Climate change and the emergence of strains resistant to traditionally used insecticides have motivated the search of new agents for mosquito population control. Essential oils have been effective repellents and larvicidal agents.The aim of this work was to review research studies conducted in recent years on the larvicidal activity of essential oils and their components against Aedes, Anopheles and Culex mosquitoes, as well as the latest reports about their possible mechanism of action. PMID- 29161497 TI - Three-Dimensional Microstructured Poly(vinyl alcohol) Hydrogel Platform for the Controlled Formation of Multicellular Cell Spheroids. AB - Three-dimensional (3D) multicellular cell spheroids (MCSs) are excellent in vitro cell models, in which, e.g., the in vivo cell-cell interaction processes are much better mimicked than in conventional two-dimensional (2D) cell layers. However, the difficulties in the generation of well-defined MCSs with controlled size severely limit their application. Herein, low-adhesive poly(vinyl alcohol) (PVA) hydrogels structured with inverted pyramid-shaped microwells were used to guide the aggregation of cells into MCSs. The cells settling down into the microwells by gravity accumulated at the central tip of the wells and then gradually grew into spheroids. The size of cell spheroids can be straightforwardly controlled by the culture time and initially seeded cell number. The MCSs generated in a parallel microarray format were further used for drug testing. Our results suggest in agreement with complementary literature data that the cell culture format plays a critical role in the cellular response to drugs, and also confirms that spheroids possess a much higher drug resistance than cells in 2D layers. This novel microstructured PVA hydrogel is expected to offer a potential platform for the facile preparation of spheroids for various applications in the biomedical field. PMID- 29161496 TI - Ion Transport across Biological Membranes by Carborane-Capped Gold Nanoparticles. AB - Carborane-capped gold nanoparticles (Au/carborane NPs, 2-3 nm) can act as artificial ion transporters across biological membranes. The particles themselves are large hydrophobic anions that have the ability to disperse in aqueous media and to partition over both sides of a phospholipid bilayer membrane. Their presence therefore causes a membrane potential that is determined by the relative concentrations of particles on each side of the membrane according to the Nernst equation. The particles tend to adsorb to both sides of the membrane and can flip across if changes in membrane potential require their repartitioning. Such changes can be made either with a potentiostat in an electrochemical cell or by competition with another partitioning ion, for example, potassium in the presence of its specific transporter valinomycin. Carborane-capped gold nanoparticles have a ligand shell full of voids, which stem from the packing of near spherical ligands on a near spherical metal core. These voids are normally filled with sodium or potassium ions, and the charge is overcompensated by excess electrons in the metal core. The anionic particles are therefore able to take up and release a certain payload of cations and to adjust their net charge accordingly. It is demonstrated by potential-dependent fluorescence spectroscopy that polarized phospholipid membranes of vesicles can be depolarized by ion transport mediated by the particles. It is also shown that the particles act as alkali-ion specific transporters across free-standing membranes under potentiostatic control. Magnesium ions are not transported. PMID- 29161498 TI - Selective Isolation of Myosin Subfragment-1 with a DNA-Polyoxovanadate Bioconjugate. AB - The bioconjugation of a polyoxometalate (POMs), i.e., dodecavanadate (V12O32), to DNA strands produces a functional labeled DNA primer, V12O32-DNA. The grafting of DNA primer onto streptavidin-coated magnetic nanoparticles (SVM) produces a novel composite, V12O32-DNA@SVM. The high binding-affinity of V12O32 with the ATP binding site in myosin subfragment-1 (S1) facilitates favorable adsorption of myosin, with an efficiency of 99.4% when processing 0.1 mL myosin solution (100 MUg mL-1) using 0.1 mg composite. Myosin adsorption fits the Langmuir model, corresponding to a theoretical adsorption capacity of 613.5 mg g-1. The retained myosin is readily recovered by 1% SDS (m/m), giving rise to a recovery of 58.7%. No conformational change is observed for myosin after eliminating SDS by ultrafiltration. For practical use, high-purity myosin S1 is obtained by separation of myosin from the rough protein extract from porcine left ventricle, followed by digestion with alpha-chymotryptic and further isolation of S1 subfragment. The purified myosin S1 is identified with matrix-assisted laser desorption/ionization time-of-flight/mass spectrometry, giving rise to a sequence coverage of 38%. PMID- 29161499 TI - Polymerization of Well-Aligned Organic Nanowires on a Ferromagnetic Rare-Earth Surface Alloy. AB - The high reactivity of magnetic substrates toward molecular overlayers has so far inhibited the realization of more sophisticated on-surface reactions, thereby depriving these interfaces of a significant class of chemically tailored organics such as graphene nanoribbons, oligonuclear spin-chains, and metal-organic networks. Here, we present a multitechnique characterization of the polymerization of 4,4"-dibromo-p-terphenyl precursors into ordered poly(p phenylene) arrays on top of the bimetallic GdAu2 surface alloy. The activation temperatures for bromine scission and subsequent homocoupling of molecular precursors were followed by temperature-dependent X-ray photoelectron spectroscopy. The structural characterizations of supramolecular and polymeric phases, performed by low-energy electron diffraction and scanning tunneling microscopy, establish an extraordinary degree of order extending into the mesoscale. Taking advantage of the high homogeneity, the electronic structure of the valence band was determined with angle-resolved photoemission spectroscopy. Importantly, the transition of localized molecular orbitals into a highly dispersive pi-band, the fingerprint of successful polymerization, was observed while leaving all surface-related bands intact. Moreover, ferromagnetic ordering in the GdAu2 alloy was demonstrated for all phases by X-ray absorption spectroscopy. The transfer of well-established in situ methods for growing covalently bonded macromolecules with atomic precision onto magnetic rare-earth alloys is an important step toward toward studying and controlling intrinsic carbon- and rare-earth-based magnetism. PMID- 29161500 TI - A Small Molecule Mimetic of the Humanin Peptide as a Candidate for Modulating NMDA-Induced Neurotoxicity. AB - Humanin (HN), a 24-amino acid bioactive peptide, has been shown to increase cell survival of neurons after exposure to Abeta and NMDA-induced toxicity and thus could be beneficial in the treatment of Alzheimer's disease (AD). The neuroprotection by HN is reported to be primarily through its agonist binding properties to the gp130 receptor. However, the peptidic nature of HN presents challenges in its development as a therapeutic for AD. We report here for the first time the elucidation of the binding site of Humanin (HN) peptide to the gp130 receptor extracellular domain through modeling and the synthesis of small molecule mimetics that interact with the HN binding site on the gp130 receptor and provide protection against NMDA-induced neurotoxicity in primary hippocampal neurons. A brain permeable small molecule mimetic was identified through exploratory medicinal chemistry using microfluidic flow chemistry to facilitate the synthesis of new analogues for screening and SAR optimization. PMID- 29161501 TI - Phenanthrene-Induced Apoptosis and Its Underlying Mechanism. AB - Phenanthrene (Phe) is one of the most abundant low-molecular-weight polycyclic aromatic hydrocarbons (PAHs). Widespread human and aquatic organism exposure to Phe has been reported, but the toxic effects of Phe and potential mechanisms are unclear. We focused on the chronic hepatotoxicity of Phe in adult Chinese rare minnows (Gobiocypris rarus) and the underlying mechanisms. The chronic effects of exposing Chinese rare minnows to 8.9, 82.3, or 510.0 MUg/L Phe for 30 days were examined by histopathological observation, TUNEL assays, caspase activity assays, and gene expression profiles. The liver lesion frequency and hepatocyte apoptosis were increased in Phe-exposed groups. Caspase 9 and caspase 3 enzyme activity in liver tissues was markedly increased. The expression of miR-17/92 cluster members was significantly increased in the 82.3 and 510.0 MUg/L groups. Moreover, the response of primary hepatocytes indicated a significant decrease in the mitochondrial membrane potential (MMP) after a 48 h exposure to Phe. Interestingly, miR-18a was significantly decreased in primary hepatocytes in all treatments. Moreover, molecular docking indicated that Phe might have the same binding domain as pri-miR-18a, forming pi-pi and pi-sigma interactions with heterogeneous nuclear ribonucleoprotein (hnRNP) A1. Given the above, Phe caused liver lesions and induced hepatocyte apoptosis through the intrinsic apoptosis pathway, and the interaction of Phe with hnRNP A1 contributes to the suppression of miR-18a expression and hepatocyte apoptosis. PMID- 29161502 TI - Polarization Multiplexing of Fluorescent Emission Using Multiresonant Plasmonic Antennas. AB - Combining the ability to localize electromagnetic fields at the nanoscale with a directional response, plasmonic antennas offer an effective strategy to shape the far-field pattern of coupled emitters. Here, we introduce a family of directional multiresonant antennas that allows for polarization-resolved spectral identification of fluorescent emission. The geometry consists of a central aperture surrounded by concentric polygonal corrugations. By varying the periodicity of each axis of the polygon individually, this structure can support multiple resonances that provide independent control over emission directionality for multiple wavelengths. Moreover, since each resonant wavelength is directly mapped to a specific polarization orientation, spectral information can be encoded in the polarization state of the out-scattered beam. To demonstrate the potential of such structures in enabling simplified detection schemes and additional functionalities in sensing and imaging applications, we use the central subwavelength aperture as a built-in nanocuvette and manipulate the fluorescent response of colloidal-quantum-dot emitters coupled to the multiresonant antenna. PMID- 29161503 TI - Hierarchical Mesoporous NiO/MnO2@PANI Core-Shell Microspheres, Highly Efficient and Stable Bifunctional Electrocatalysts for Oxygen Evolution and Reduction Reactions. AB - We report on the new facile synthesis of mesoporous NiO/MnO2 in one step by modifying inverse micelle templated UCT (University of Connecticut) methods. The catalyst shows excellent electrocatalytic activity and stability for both the oxygen evolution reaction (OER) and the oxygen reduction reaction (ORR) in alkaline media after further coating with polyaniline (PANI). For electrochemical performance, the optimized catalyst exhibits a potential gap, DeltaE, of 0.75 V to achieve a current of 10 mA cm-2 for the OER and -3 mA cm-2 for the ORR in 0.1 M KOH solution. Extensive characterization methods were applied to investigate the structure-property of the catalyst for correlations with activity (e.g., XRD, BET, SEM, HRTEM, FIB-TEM, XPS, TGA, and Raman). The high electrocatalytic activity of the catalyst closely relates to the good electrical conductivity of PANI, accessible mesoporous structure, high surface area, as well as the synergistic effect of the specific core-shell structure. This work opens a new avenue for the rational design of core-shell structure catalysts for energy conversion and storage applications. PMID- 29161504 TI - Effects of Solvent and Temperature on Free Radical Formation in Electronic Cigarette Aerosols. AB - The ever-evolving market of electronic cigarettes (e-cigarettes) presents a challenge for analyzing and characterizing the harmful products they can produce. Earlier we reported that e-cigarette aerosols can deliver high levels of reactive free radicals; however, there are few data characterizing the production of these potentially harmful oxidants. Thus, we have performed a detailed analysis of the different parameters affecting the production of free radical by e-cigarettes. Using a temperature-controlled e-cigarette device and a novel mechanism for reliably simulating e-cigarette usage conditions, including coil activation and puff flow, we analyzed the effects of temperature, wattage, and e-liquid solvent composition of propylene glycol (PG) and glycerol (GLY) on radical production. Free radicals in e-cigarette aerosols were spin-trapped and analyzed using electron paramagnetic resonance. Free radical production increased in a temperature-dependent manner, showing a nearly 2-fold increase between 100 and 300 degrees C under constant-temperature conditions. Free radical production under constant wattage showed an even greater increase when going from 10 to 50 W due, in part, to higher coil temperatures compared to constant-temperature conditions. The e-liquid PG content also heavily influenced free radical production, showing a nearly 3-fold increase upon comparison of ratios of 0:100 (PG:GLY) and 100:0 (PG:GLY). Increases in PG content were also associated with increases in aerosol-induced oxidation of biologically relevant lipids. These results demonstrate that the production of reactive free radicals in e-cigarette aerosols is highly solvent dependent and increases with an increase in temperature. Radical production was somewhat dependent on aerosol production at higher temperatures; however, disproportionately high levels of free radicals were observed at >=100 degrees C despite limited aerosol production. Overall, these findings suggest that e-cigarettes can be designed to minimize exposure to these potentially harmful products. PMID- 29161505 TI - Characterization of the Distribution of Pyrene Molecules in Confined Geometries with the Model Free Analysis. AB - Evidence is provided showing that global Model Free Analysis (MFA) of monomer and excimer fluorescence decays of pyrene dissolved in aqueous solutions of sodium dodecyl sulfate (SDS) provides the same structural and dynamic information on SDS micelles as the well-established Micelle Model (MM) does. Both MFA and MM were employed to characterize the quenching kinetics between dyes and quenchers located in surfactant micelles and the aggregation number of surfactant micelles. However, contrary to the MM, which assumes that dyes and quenchers distribute themselves among SDS micelles according to a Poisson distribution and react with a rate constant that is proportional to the number of reactants in a micelle, the MFA accomplishes this task without making any assumption about the process of pyrene excimer formation in SDS micelles. The ability of the MFA to retrieve accurately the molar fraction of pyrene molecules that are isolated in SDS micelles and do not form excimers was taken advantage of to establish that it equaled the Poisson probability of exciting micelles that contained a single pyrene. The molar fraction of isolated pyrenes could then be utilized to determine the aggregation number of the SDS micelles, and the rate constant of excimer formation between one excited- and one ground-state pyrene located inside a same micelle. Within experimental error, both the MFA and MM yielded the same micelle aggregation number and rate constant of excimer formation, with the MFA making no prior assumptions about the physical principles underlying the process of excimer formation contrary to the MM. The ability of the MFA to retrieve quantitative parameters providing structural and dynamic information about macromolecular systems with no prior knowledge about their architecture or labeling scheme implies that it can be applied to characterize a wide range of macromolecular architectures in solution. PMID- 29161506 TI - Multiplexed CRISPR/Cas9 Genome Editing and Gene Regulation Using Csy4 in Saccharomyces cerevisiae. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) technology has greatly accelerated the field of strain engineering. However, insufficient efforts have been made toward developing robust multiplexing tools in Saccharomyces cerevisiae. Here, we exploit the RNA processing capacity of the bacterial endoribonuclease Csy4 from Pseudomonas aeruginosa, to generate multiple gRNAs from a single transcript for genome editing and gene interference applications in S. cerevisiae. In regards to genome editing, we performed a quadruple deletion of FAA1, FAA4, POX1 and TES1 reaching 96% efficiency out of 24 colonies tested. Then, we used this system to efficiently transcriptionally regulate the three genes, OLE1, HMG1 and ACS1. Thus, we demonstrate that multiplexed genome editing and gene regulation can be performed in a fast and effective manner using Csy4. PMID- 29161507 TI - Development of Spiroligomer-Peptoid Hybrids. AB - Creating functional macromolecules that possess the diversity and functionality of proteins poses an enormous challenge, as this requires large, preorganized macromolecules to facilitate interactions. Peptoids have been shown to interact with proteins, and combinatorial libraries of peptoids have been useful in discovering new ligands for protein binding. We have created spiroligomer-peptoid hybrids that have a spirocyclic core that preorganizes functional groups in three dimensional space. By utilizing spiroligomers, we can reduce the number of rotatable bonds between functional groups while increasing the stereochemical diversity of the molecules. We have synthesized 15 new spiroligomer monomer amines that contain two stereocenters and three functional groups (67-84% yields from a common hydantoin starting material) as well as a spiroligomer trimer 25 with six stereocenters and five functional groups. These 16 amines were used to synthesize five first-generation spiroligomer-peptoids hybrids. PMID- 29161508 TI - Design and Fabrication of Wettability Gradients with Tunable Profiles through Degrafting Organosilane Layers from Silica Surfaces by Tetrabutylammonium Fluoride. AB - Surface-bound wettability gradients allow for a high-throughput approach to evaluate surface interactions for many biological and chemical processes. Here we describe the fabrication of surface wettability gradients on flat surfaces by a simple, two-step procedure that permits precise tuning of the gradient profile. This process involves the deposition of homogeneous silane SAMs followed by the formation of a surface coverage gradient through the selective removal of silanes from the substrate. Removal of silanes from the surface is achieved by using tetrabutylammonium fluoride which selectively cleaves the Si-O bonds at the headgroup of the silane. The kinetics of degrafting has been modeled by using a series of first order rate equations, based on the number of attachment points broken to remove a silane from the surface. Degrafting of monofunctional silanes exhibits a single exponential decay in surface coverage; however, there is a delay in degrafting of trifunctional silanes due to the presence of multiple attachment points. The effects of degrafting temperature and time are examined in detail and demonstrate the ability to reliably and precisely control the gradient profile on the surface. We observe a relatively homogeneous coverage of silane (i.e., without the presence of islands or holes) throughout the degrafting process, providing a much more uniform surface when compared to additive approaches of gradient formation. Linear gradients were formed on the substrates to demonstrate the reproducibility and tuneability of this subtractive approach. PMID- 29161509 TI - Variation in Supersaturation and Phase Behavior of Ezetimibe Amorphous Solid Dispersions upon Dissolution in Different Biorelevant Media. AB - The delivery of poorly water-soluble drugs using amorphous solid dispersions (ASDs) has been widely acknowledged as a promising strategy for enhancing oral bioavailability. Upon dissolution, ASDs have accelerated dissolution rates and yield supersaturated solutions leading to higher apparent solubilities. Understanding the complex phase behavior of ASDs during dissolution is crucial for developing an effective formulation. Since the absorption of a lipophilic, high permeability drug is determined primarily by the intraluminal dissolution process and the final concentration achieved, there is a need for evaluation in biorelevant dissolution media that simulate both fasting and fed gastrointestinal states. In this study, using ezetimibe as a model drug, three different ASDs were prepared using poly(acrylic acid) (PAA), polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose acetyl succinate (HPMC-AS). Dissolution of ASDs was carried out in sodium phosphate buffer, fed-state simulated intestinal fluid (FeSSIF), and Ensure Plus to evaluate the impact of different dissolution media on release profile, supersaturation, and phase behavior. The supersaturation level and crystallization kinetics varied among the dispersions and were found to be highly dependent on the medium employed. The presence of solubilizing additives in biorelevant media greatly affected the generation and stabilization of supersaturated solutions. Second harmonic generation microscopy was found to enable the detection of crystals in all media including the highly turbid Ensure Plus system. In conclusion, it is important to evaluate the impact of complex biorelevant media on the dissolution performance of ASDs to better design supersaturating formulations for oral delivery. PMID- 29161510 TI - Solvation Structure and Thermodynamic Mapping (SSTMap): An Open-Source, Flexible Package for the Analysis of Water in Molecular Dynamics Trajectories. AB - We have developed SSTMap, a software package for mapping structural and thermodynamic water properties in molecular dynamics trajectories. The package introduces automated analysis and mapping of local measures of frustration and enhancement of water structure. The thermodynamic calculations are based on Inhomogeneous Fluid Solvation Theory (IST), which is implemented using both site based and grid-based approaches. The package also extends the applicability of solvation analysis calculations to multiple molecular dynamics (MD) simulation programs by using existing cross-platform tools for parsing MD parameter and trajectory files. SSTMap is implemented in Python and contains both command-line tools and a Python module to facilitate flexibility in setting up calculations and for automated generation of large data sets involving analysis of multiple solutes. Output is generated in formats compatible with popular Python data science packages. This tool will be used by the molecular modeling community for computational analysis of water in problems of biophysical interest such as ligand binding and protein function. PMID- 29161511 TI - A Customizable Flow Injection System for Automated, High Throughput, and Time Sensitive Ion Mobility Spectrometry and Mass Spectrometry Measurements. AB - To better understand disease conditions and environmental perturbations, multiomic studies combining proteomic, lipidomic, and metabolomic analyses are vastly increasing in popularity. In a multiomic study, a single sample is typically extracted in multiple ways, and various analyses are performed using different instruments, most often based upon mass spectrometry (MS). Thus, one sample becomes many measurements, making high throughput and reproducible evaluations a necessity. One way to address the numerous samples and varying instrumental conditions is to utilize a flow injection analysis (FIA) system for rapid sample injections. While some FIA systems have been created to address these challenges, many have limitations such as costly consumables, low pressure capabilities, limited pressure monitoring, and fixed flow rates. To address these limitations, we created an automated, customizable FIA system capable of operating at a range of flow rates (~50 nL/min to 500 MUL/min) to accommodate both low- and high-flow MS ionization sources. This system also functions at varying analytical throughputs from 24 to 1200 samples per day to enable different MS analysis approaches. Applications ranging from native protein analyses to molecular library construction were performed using the FIA system, and results showed a highly robust and reproducible platform capable of providing consistent performance over many days without carryover, as long as washing buffers specific to each molecular analysis were utilized. PMID- 29161512 TI - Trophodynamics of Organic Pollutants in Pelagic and Benthic Food Webs of Lake Dianchi: Importance of Ingested Sediment As Uptake Route. AB - Habitat is of great importance in determining the trophic transfer of pollutants in freshwater ecosystems; however, the major factors influencing chemical trophodynamics in pelagic and benthic food webs remain unclear. This study investigated the levels of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), polycyclic aromatic hydrocarbons (PAHs), and substituted PAHs (s-PAHs) in 2 plankton species, 6 invertebrate species, and 10 fish species collected from Lake Dianchi in southern China. Relatively high concentrations of PAHs and s-PAHs were detected with total concentrations of 11.4-1400 ng/g wet weight (ww) and 5.3-115 ng/g ww, respectively. Stable isotope analysis and stomach content analysis were applied to quantitatively determine the trophic level of individual organisms and discriminate between pelagic and benthic pathways, and the trophodynamics of the detected compounds in the two food webs were assessed. P,p'-DDE was found to exhibit relatively higher trophic magnification rate in the pelagic food web than in the benthic food web. In contrast, PAHs and s-PAHs exhibited greater dilution rates along the trophic levels in the pelagic food web. The lower species differences of pollutants accumulated in benthic organisms compared to pelagic organisms is attributable to extra uptake via ingested sediment in benthos. The average uptake proportions of PAHs and s-PAHs via ingested sediment in benthic biotas were estimated to be 31-77%, and that of p,p'-DDE was 46%. The uptake routes are of importance for assessing the trophic magnification potentials of organic pollutants, especially in eutrophic freshwater ecosystems. PMID- 29161513 TI - Insights into the Molecular Basis of the Acute Contact Toxicity of Diverse Organic Chemicals in the Honey Bee. AB - Use of chemical pollutants, including pesticides and other industrial chemicals, has resulted in significant risks to the whole ecosystem. Therefore, ecological risk assessment of chemicals is vital and necessary. Since the honey bee (Apis mellifera) is probably among the most exposed species to the polluting chemicals, we focused on the in silico estimation of honey bee toxicity (HBT) of chemicals and the analysis of the relevance of chemical HBT and several key physical chemical properties and structural characteristics. A total of 40 classification models were developed by combination of five machine learning methods along with seven kinds of fingerprints and a set of molecular descriptors. After 5-fold cross validation and external validation, several models showed good predictive power. The relevance of 12 key physical-chemical properties and chemical HBT was also investigated. Five properties, including AlogP, logD, molecular weight (MW), molecular surface area (MSA), and the number of rotatable bonds (nRTB), indicated positive correlation coefficients with HBT, while molecular solubility (logS) and the number of hydrogen bond donors (nHBD) indicated negative correlation coefficients. Finally, seven privileged substructures responsible for chemical HBT were identified from KRFP and SubFP fingerprints. The results of this study should provide critical information and useful tools for chemical HBT estimation in environmental risk assessment. PMID- 29161514 TI - Discovery of an Orally Bioavailable Benzofuran Analogue That Serves as a beta Amyloid Aggregation Inhibitor for the Potential Treatment of Alzheimer's Disease. AB - We developed an orally active and blood-brain-barrier-permeable benzofuran analogue (8, MDR-1339) with potent antiaggregation activity. Compound 8 restored cellular viability from Abeta-induced cytotoxicity but also improved the learning and memory function of AD model mice by reducing the Abeta aggregates in the brains. Given the high bioavailability and brain permeability demonstrated in our pharmacokinetic studies, 8 will provide a novel scaffold for an Abeta-aggregation inhibitor that may offer an alternative treatment for AD. PMID- 29161515 TI - Potential Profile of Stabilized Field-Induced Lateral p-n Junction in Transition Metal Dichalcogenides. AB - Electric field-induced p-n junctions are often used to realize peculiar functionalities in various materials. This method can be applied not only to conventional semiconductors but also to carbon nanotubes, graphene, and organic semiconductors to which the conventional chemical doping method is difficult to apply. Transition-metal dichalcogenides (TMDs) are one of such materials where the field-induced p-n junctions play crucial roles in realizing solar cell and light-emitting diode operations as well as circularly polarized electroluminescence. Although the field-induced p-n junction is a well established technique, many of its physical properties are left to be understood because their doping mechanism is distinct from that of conventional p-n junctions. Here we report a direct electrical measurement of the potential variation along the field-induced p-n junction using multiple pairs of voltage probes. We detected the position of the junction, estimated the built-in potential, and monitored the effect of the bias voltage. We found that the built in potential becomes negative under a forward bias voltage range where field induced TMD p-n junctions have been operated as light-emitting diodes. This feature well reproduced the circularly polarized electroluminescence from the WSe2 p-n junction, indicating that the present observation provides a useful background for understanding and functionalizing field-induced p-n junctions. PMID- 29161516 TI - Influence of Grafted Block Copolymer Structure on Thermoresponsiveness of Superparamagnetic Core-Shell Nanoparticles. AB - The morphology and topology of thermoresponsive polymers have a strong impact on their responsive properties. Grafting onto spherical particles has been shown to reduce responsiveness and transition temperatures; grafting of block copolymers has shown that switchable or retained wettability of a surface or particle during desolvation of one block can take place. Here, doubly thermoresponsive block copolymers were grafted onto spherical, monodisperse, and superparamagnetic iron oxide nanoparticles to investigate the effect of thermal desolvation on spherical brushes of block copolymers. By inverting the block order, the influence of core proximity on the responsive properties of the individual blocks could be studied as well as their relative influence on the nanoparticle colloidal stability. The inner block was shown to experience a stronger reduction in transition temperature and transition enthalpy compared to the outer block. Still, the outer block also experiences a significant reduction in responsiveness due to the restricted environment in the nanoparticle shell compared to that of the free polymer state. The demonstrated pronounced distance dependence importantly implies the possibility, but also the necessity, to radially tailor polymer hydration transitions for applications such as drug delivery, hyperthermia, and biotechnological separation for which thermally responsive nanoparticles are being developed. PMID- 29161517 TI - Global Biobank Week: Toward Harmonization in Biobanking. PMID- 29161518 TI - Sexual Functioning in Experienced Meditators. AB - Given evidence of the benefits of mindfulness for women's sexual difficulties, we investigated the relationship between meditation experience and women's sexual function. Women (N = 450) answered online survey questions about meditation experience, sexual function and desire, interoceptive awareness, health and mood. Women who meditated scored higher than nonmeditators on measures of sexual function and desire, however there was no significant correlation between frequency/length of meditation experience and either of these domains. Global mental health was a significant predictor of both increased sexual function and desire in women who meditate. These findings suggest that, compared to women with no meditation experience, women who meditate to any extent have, on average, improved sexual function associated with better overall mental health. PMID- 29161519 TI - Bioinformatics Advances to Accelerate Omics Innovations and Applications in the Postgenomic Era. PMID- 29161520 TI - EZH2 Histone Methyltransferase and JMJD3 Histone Demethylase Implications in Prostate Cancer. PMID- 29161521 TI - Lessons from the Camden Coalition of Healthcare Providers' First Medicaid Shared Savings Performance Evaluation. AB - Accountable Care Organizations (ACOs) aim to reduce health care costs while improving patient outcomes. Camden Coalition of Healthcare Providers' (Camden Coalition) work already aligned with this aim before receiving state approval to operate a certified Medicaid ACO in New Jersey. Upon its formation, the Camden Coalition ACO partnered with UnitedHealthcare and, through state legislation, Rutgers Center for State Health Policy (CSHP) was established as its external evaluator. In evaluating the Camden Coalition ACO, Rutgers CSHP built on the Medicare Shared Savings model, but modified it based on the understanding that the Medicaid population differs from the Medicare population. Annual savings rate (ASR) was used to measure shared savings, and was calculated at the Medicaid product level and aggregated up to reflect a single ASR for the first performance year. The calculated performance yielded a range of shared savings from an ASR of 0.4% to 5.3%, depending on which dollar amount was used to create the outlier ceiling (limit at which a subset of members with expensive utilization patterns are excluded) and how the appropriate statewide trend factor (the expected percentage increase in Medicaid costs across the state) was chosen. In all scenarios, the ASR resulted in less cost savings than predicted. The unfavorable results may be caused by the fact that the evaluation was not calibrated to capture areas where Camden Coalition's ACO was likely to make its impact. Future ACO evaluations should be designed to better correlate with the patient populations and practice areas of the ACO. PMID- 29161522 TI - Development of a Measure to Assess Parent Perceptions of Barriers to Child Weight Management. AB - BACKGROUND: Families face many barriers related to creating or maintaining a healthy lifestyle, which likely contributes to the prevalence of childhood obesity in the United States; however, no measure currently exists to examine these barriers. This study developed a quantitative measure of parents' perceptions of barriers to family healthy lifestyle. METHODS: Parents of children between the ages of 7-17 were recruited using Amazon Mturk (n = 812). Exploratory and confirmatory factor analyses and preliminary convergent validity analyses were conducted. RESULTS: Four factors emerged in the final measure: Parent Disengagement, Cost and Built Environment, Lack of Family Support, and Family Time Constraints, with the final 19-item measure having good initial psychometric properties, including reliability and validity. CONCLUSIONS: Future research is needed to examine whether this measure may be used in clinical practice to identify barriers to a healthy family lifestyle, to tailor interventions for families. PMID- 29161523 TI - Does Acute Propranolol Treatment Prevent Posttraumatic Stress Disorder, Anxiety, and Depression in Children with Burns? AB - OBJECTIVE: This study examined whether acute propranolol treatment prevented posttraumatic stress disorder (PTSD), anxiety, and depression in children hospitalized in the pediatric intensive care unit for large burns. We hypothesized that the prevalence of PTSD, anxiety, and depression would be significantly less in the propranolol than nonpropranolol groups. METHODS: Children who had previously participated in a randomized controlled clinical trial of acute propranolol and nonpropranolol controls were invited to participate in long-term follow-up interviews. Eligible participants from 1997 to 2008 were identified from the electronic medical records, and data were collected in 2010-2011. Measures included the Missouri Assessment of Genetics Interview for Children to assess lifetime PTSD, Revised Children's Manifest Anxiety Scale to assess anxiety, and two depression inventories Children's Depression Inventory and Beck Depression Inventory-II. RESULTS: Of 202 participants, 89 were in the propranolol group and 113 were nonpropranolol controls. Children were an average of 7 years postburn. The average total body surface area burned was 56.4 + 15.1% (range = 24%-99%). The mean dose of propranolol was 3.64 +/- 3.19 mg/kg per day (range = 0.36-12.12). The duration of propranolol inpatient treatment days varied, mean days 26.5 +/- 19.8. The prevalence of lifetime PTSD in the propranolol group was 3.5% and controls 7.2%, but this difference was not statistically significant. We controlled for administration of pain medications, anxiolytics, and antidepressants overall and no significant differences were detected in the rates of PTSD, anxiety, or depression. CONCLUSIONS: The prevalence of PTSD, anxiety, and depression was similar in children who received propranolol acutely and those who did not. This may be influenced by the standard of care that all children received timely pharmacotherapy for pain and anxiety management and psychotherapy beginning in their acute phase of treatment. PMID- 29161524 TI - Words Matter! PMID- 29161525 TI - Sea Cucumber Lipid-Soluble Extra Fraction Prevents Ovalbumin-Induced Allergic Airway Inflammation. AB - In a previous study, our research group demonstrated that sea cucumber (Apostichopus japonicus) extracts ameliorated allergic airway inflammation through CD4+CD25+Foxp3+ T (regulatory T; Treg) cell activation and recruitment to the lung. In this study, we aimed to determine which components of sea cucumber contribute to the amelioration of airway inflammation. We used n-hexane fractionation to separate sea cucumber into three phases (n-hexane, alcohol, and solid) and evaluated the ability of each phase to elevate Il10 expression in splenocytes and ameliorate symptoms in mice with ovalbumin (OVA)/alum-induced asthma. Splenocytes treated with the n-hexane phase showed a significant increase in Il10 expression. In the n-hexane phase, 47 fatty acids were identified. Individual fatty acids that comprised at least 5% of the total fatty acids were 16:0, 16:1n-7, 18:0, 18:1n-7, 20:4n-6, and 20:5n-3 (eicosapentaenoic acid). After administering the n-hexane phase to mice with OVA/alum-induced asthma, their asthma symptoms were ameliorated. Several immunomodulatory effects were observed in the n-hexane phase-pretreated group, compared with a vehicle control group. First, eosinophil infiltration and goblet cell hyperplasia were significantly reduced around the airways. Second, the concentrations of Th2-related cytokines (IL-4, IL-5, and IL-13) and Th17-related cytokines (IL-17) were significantly decreased in the spleen and bronchoalveolar lavage fluid (BALF). Finally, the concentrations of TGF-beta and IL-10, which are associated with Treg cells, were significantly increased in the BALF and splenocyte culture medium. In conclusion, a fatty acid-rich fraction (n-hexane phase) of sea cucumber extract ameliorated allergic airway inflammation in a mouse model. PMID- 29161527 TI - Applications of Microcosting Economic Analysis in Breastfeeding. PMID- 29161526 TI - Individualism-Collectivism, Social Self-Control and Adolescent Substance Use and Risky Sexual Behavior. AB - Individualism and collectivism are cultural syndromes that have been associated with adolescent problem behavior in studies conducted in the U.S. and Southeast Asia. However, research investigating the mechanisms of how cultural orientation impacts health risk behaviors has been limited. This study tested a new model explaining the relationship between cultural orientation (i.e., individualism, collectivism) and adolescent problem behavior (i.e., substance use and risky sex) in terms of interpersonal self-regulation (i.e., social self-control). As such, the study is rooted in theories of the role of culture in developing self regulation. Participants were high school students (N = 716) from the Bashkirtostan Republic of the Russian Federation. Adolescents from the Russian Federation tend to show high prevalence of cigarette smoking and binge drinking. People of the Russian Federation in general are traditionally collectivist in orientation, although increased globalization and post-Soviet capitalism may indicate high individualist values in younger generation Russians. Using path analysis we found that in addition to having direct effects, higher individualism indirectly affected substance use and risky sexual behavior through social self control and negative life events. Higher collectivism was found to have a direct protective effect on risky sexual behavior and a direct effect on social self control. However, collectivism was not found to have indirect effects on substance use or risky sexual behavior. Higher individualism appears to function as a risk factor for adolescent problem behavior and this relationship may be mediated by lower social self-control. Culturally-tailored prevention programs utilizing the individualism-collectivism framework may benefit from addressing social self-control. PMID- 29161528 TI - Changes in Speech-Language Pathology Students' Attitudes Toward Breastfeeding During a Pediatric Dysphagia Course. AB - BACKGROUND: Speech-language pathologists provide infant feeding assessment and intervention; their training in breastfeeding management is highly variable. Research aim: The purpose of this study was to evaluate student attitudes toward breastfeeding and self-identified factors in attitude change. METHODS: Before and after their course in pediatric dysphagia, two cohorts of graduate students in speech-language pathology ( N = 36) completed an assignment designed to capture qualitative and quantitative data on changes in their attitudes toward breastfeeding. Students rated their reactions to two hypothetical breastfeeding scenarios before and after the class, which included multiple sources of information on the importance of human milk and on breastfeeding management. Additionally, they completed a postclass reflection describing the nature of any changes in their attitudes toward breastfeeding and their ideas about the factors that were responsible for these changes. Nonparametric statistical tests were used to assess quantitative results; the qualitative data were evaluated via content analysis to identify themes. RESULTS: Significant positive changes in student attitudes were measured at the completion of the course. Students identified parents' stories as a particularly compelling component of their increased openness to breastfeeding. CONCLUSION: Attitudes toward breastfeeding may improve significantly over a relatively short period of time following a targeted intervention. Implications for lactation consultants and continuing education providers are discussed. PMID- 29161530 TI - Family-Centered Breastfeeding Education to Promote Primiparas' Exclusive Breastfeeding in China. AB - BACKGROUND: Few breastfeeding education programs focus on primiparas and the importance of family members on exclusive breastfeeding in China. Research aim: This study aimed to explore the influence of a family-centered breastfeeding education program in promoting exclusive breastfeeding up to 6 months postpartum and to improve women's attitude and knowledge, family members' knowledge, and family support. METHODS: This was a two-group quasi-experimental design with multiple comparisons. Participants ( N = 59) were randomized to either the intervention ( n = 29) or the control ( n = 30) group. The intervention group received two prenatal breastfeeding education lectures that included important family members, three home visits, eight telephone calls, text or video/audio support, and quality online resources during lactation. The control group received in-hospital care and follow-up by community nurses after discharge. RESULTS: Compared with the control group, the intervention group was more likely to exclusively breastfeed in the first 6 months, odds ratio = 0.44, 95% confidence interval [0.20, 0.98]. The mean knowledge level of the intervention group improved more across time ( p < .05) and was higher than the control group ( p < .05). Perceived family support within the intervention group was significantly higher than the control group from 1 to 6 months ( p < .05). CONCLUSION: The breastfeeding education program is an effective strategy to promote exclusive breastfeeding in China. PMID- 29161529 TI - Developing a Serious Videogame for Preteens to Motivate HPV Vaccination Decision Making: Land of Secret Gardens. AB - INTRODUCTION: Vaccination against human papillomavirus (HPV) is routinely recommended for ages 11-12, yet in 2016 only 49.5% of women and 37.5% of men had completed the three-dose series in the United States. Offering information and cues to action through a serious videogame for preteens may foster HPV vaccination awareness, information seeking, and communication. MATERIALS AND METHODS: An iterative process was used to develop an interactive videogame, Land of Secret Gardens. Three focus groups were conducted with 16 boys and girls, ages 11-12, for input on game design, acceptability, and functioning. Two parallel focus groups explored parents' (n = 9) perspectives on the game concept. Three researchers identified key themes. RESULTS: Preteens wanted a game that is both entertaining and instructional. Some parents were skeptical that games could be motivational. A back-story about a secret garden was developed as a metaphor for a preteen's body and keeping it healthy. The goal is to plant a lush secret garden and protect the seedlings by treating them with a potion when they sprout to keep them healthy as they mature. Points to buy seeds and create the potion are earned by playing mini-games. Throughout play, players are exposed to messaging about HPV and the benefits of the vaccine. Both boys and girls liked the garden concept and getting facts about HPV. Parents were encouraged to discuss the game with their preteens. CONCLUSION: Within a larger communication strategy, serious games could be useful for engaging preteens in health decision making about HPV vaccination. PMID- 29161531 TI - Pulmonary Safety and Tolerability of Inhaled Levodopa (CVT-301) Administered to Patients with Parkinson's Disease. AB - BACKGROUND: CVT-301, an inhaled levodopa (LD) formulation, is under development for relief of OFF periods in Parkinson's disease (PD). Previously, we reported that CVT-301 improved OFF symptoms relative to placebo. In this study, we evaluate pulmonary function in patients treated with a single dose of CVT-301 or placebo for 3 hours, or received multiple doses/day for 4 weeks. METHODS: As part of two phase 2 studies, pulmonary safety and tolerability of CVT-301 were evaluated in PD patients experiencing motor fluctuations (>=2 hours OFF/day), Hoehn and Yahr stage 1-3, and forced expiratory volume in 1 second/forced vital capacity ratio >=75% of predicted (in ON state). In study A, patients received single doses of oral carbidopa/LD and each of the following via the inhaled route: placebo and 25 and 50 mg LD fine particle dose (FPD) CVT-301. In study B, patients received up to 3 inhaled doses/day of 35 mg (weeks 1-2) and 50 mg LD FPD CVT-301 (weeks 3-4) versus placebo. Assessments included spirometry and treatment emergent adverse events (TEAEs). RESULTS: In study A, (n = 24) mean age +/- standard deviation was 61.3 +/- 7.4 years, mean time since diagnosis was 10.5 +/- 4.6 years, and mean duration of LD treatment 8.4 +/- 3.7 years. Assessment of pulmonary function (predose to 3 hours postdose) showed that spirometry findings were within normal ranges, regardless of treatment groups, or motor status at screening. In study B, (n = 86) mean age was 62.4 +/- 8.7 years, time since PD diagnosis was 9.4 +/- 3.9 years, and duration of LD treatment 7.8 +/- 3.9 years. Longitudinal assessment of pulmonary function over 4 weeks showed no significant difference in spirometry between CVT-301 versus placebo groups. In both studies, the most common CVT-301 TEAE was mild-to-moderate cough (study A: 21%; study B: 7% vs. 2% in placebo). Other common TEAEs in study B were dizziness and nausea. CONCLUSION: Acute and longitudinal assessment of pulmonary function showed that CVT-301 treatment was not associated with acute airflow obstruction in this population. CVT-301 was generally safe and well tolerated. PMID- 29161532 TI - The Role of Paternity Acknowledgment in Breastfeeding Noninitiation. AB - BACKGROUND: In the United States, less than a quarter of mothers breastfeed in accordance with national recommendations. To date, researchers have demonstrated that paternal support directly influences breastfeeding outcomes; however, healthcare practitioners may not be able to quantify a lack of support in the immediate postpartum period. Research aim: The aim is to investigate the relationship between breastfeeding noninitiation and paternity acknowledgment, a factor that can be easily identified in the immediate postpartum period. METHODS: Data from the 2014 Vital Statistics Natality Birth database were analyzed. Analysis included primiparous singleton births with no health complications ( N = 1,127,861). Based on the birth certificate data, paternity acknowledgment was categorized as married with paternity acknowledged, unmarried with paternity acknowledged, and unmarried without paternity acknowledged. Breastfeeding initiation was dichotomized (yes or no). Multiple logistic regression analyses were conducted to obtain crude and adjusted odds ratios and 99% confidence intervals (alpha = .01). RESULTS: Approximately one in seven births had no paternity acknowledgment on their birth certificate. After adjusting for confounders, mothers who were not married but the paternity of the infant was acknowledged had 50% higher odds of breastfeeding noninitiation compared with mothers who were married and their infants' paternity was acknowledged (adjusted odds ratio = 1.50, 99% confidence interval [1.47, 1.53]). Furthermore, women who were unmarried and without paternity acknowledgment had 135% higher odds of breastfeeding noninitiation compared with married women with paternity acknowledgment (adjusted odds ratio = 2.35, 99% confidence interval [2.30, 2.41]). CONCLUSION: Women whose births were not acknowledged by the fathers may need additional breastfeeding support from healthcare practitioners. PMID- 29161533 TI - The Nuts and Bolts of Implementing a Pasteurized Donor Human Milk Program on a Mother Baby Unit. PMID- 29161534 TI - Omics and Bioinformatics: Time for New Data Analysis Approaches? PMID- 29161535 TI - Effect of Dedicated Lactation Support Services on Breastfeeding Outcomes in Extremely-Low-Birth-Weight Neonates. AB - BACKGROUND: Breastfeeding is associated with major benefits for high-risk infants born prematurely, yet this population faces significant challenges to breastfeeding. Lactation services provide successful interventions, yet the impact of lactation services on breastfeeding outcomes in preterm infants is understudied. Research aim: The provision of full-time lactation support in the neonatal intensive care unit (NICU) will improve quantitative breastfeeding measures in premature infants. METHODS: A longitudinal retrospective nonexperimental design was used. Data were collected from medical records of breastfeeding outcomes in patients 30 weeks' gestational age and under admitted to a level IV regional NICU over three epochs of varying levels of lactation services, from none to full time. Demographic, medical, and breastfeeding data were collected. Data analysis was performed using standard statistical tests and hierarchical regression analysis. RESULTS: A significant increase in the number of lactation consults was observed across epochs, and the number of infants who received human milk via feeding at the breast, as the first oral feeding, increased across epochs. After controlling for covariates, the odds of infants receiving any human milk compared with exclusive formula feeding increased across epochs. CONCLUSION: The provision of full-time dedicated NICU lactation support is associated with an increase in breastfeeding outcome measures for high-risk preterm infants. PMID- 29161536 TI - Multiple health conditions and barriers to healthcare among older Australians: prevalence, reasons and types of barriers. AB - Accompanying population ageing is an increase in the number of older Australians living with multiple health conditions and disabilities (Australian Institute of Health and Welfare 2014). This study sought to examine the barriers to accessing healthcare faced by older Australians. Utilising the 2014 Australian Bureau of Statistics General Social Survey, it was found that 6% of respondents aged 50 years and over reported experiencing a barrier to accessing healthcare within the previous 12 months. Those with multiple health conditions are at a considerably higher risk of experiencing a barrier to healthcare (21% with four or more disabilities) compared with people with no or fewer health conditions, and this risk persists once wide-ranging control variables are included. Long waiting times or unavailability of appointments (43%) were the main type of barriers to accessing healthcare, followed by cost (23%). Points-of-care barriers experienced included accessing GPs, specialists and hospital sector care. Respondents who experienced a barrier were more likely to have low levels of trust in the healthcare system compared with people who had no experience of barriers to healthcare, and were more likely to have a perception of experiencing discrimination or unfair treatment in a healthcare setting. PMID- 29161537 TI - Association of H3K79 monomethylation (an epigenetic signature) with arsenic induced skin lesions. AB - Arsenic, a non mutagenic carcinogen, poses a profound health risk upon prolonged exposure. The objective of the study was to analyze the post-translational modifications of the major histone H3 and the associated molecular crosstalk to identify the epigenetic signature of arsenic susceptibility. Herein, we identified significant upregulation of H3K79me1, in individuals with arsenic induced skin lesion (WSL), and H3K79me1 was found to be regulated by the upstream methyltransferase DOT1L. Moreover, the downstream target molecule 53BP1, a tumor suppressor protein that has a docking preference for H3K79me1 at a site of a double-strand break (DSB), was downregulated, indicating greater DNA damage in the WSL group. Western blot data confirmed higher levels of gammaH2AX, a known marker of DSBs, in group WSL. In vitro dose-response analysis also confirmed the association of the H3K79me1 signature with arsenic toxicity. Taken together, our findings revealed that H3K79me1 and DOT1L could be a novel epigenetic signature of the arsenic-exposed WSL group. PMID- 29161538 TI - Analysis of crash proportion by vehicle type at traffic analysis zone level: A mixed fractional split multinomial logit modeling approach with spatial effects. AB - In traffic safety literature, crash frequency variables are analyzed using univariate count models or multivariate count models. In this study, we propose an alternative approach to modeling multiple crash frequency dependent variables. Instead of modeling the frequency of crashes we propose to analyze the proportion of crashes by vehicle type. A flexible mixed multinomial logit fractional split model is employed for analyzing the proportions of crashes by vehicle type at the macro-level. In this model, the proportion allocated to an alternative is probabilistically determined based on the alternative propensity as well as the propensity of all other alternatives. Thus, exogenous variables directly affect all alternatives. The approach is well suited to accommodate for large number of alternatives without a sizable increase in computational burden. The model was estimated using crash data at Traffic Analysis Zone (TAZ) level from Florida. The modeling results clearly illustrate the applicability of the proposed framework for crash proportion analysis. Further, the Excess Predicted Proportion (EPP)-a screening performance measure analogous to Highway Safety Manual (HSM), Excess Predicted Average Crash Frequency is proposed for hot zone identification. Using EPP, a statewide screening exercise by the various vehicle types considered in our analysis was undertaken. The screening results revealed that the spatial pattern of hot zones is substantially different across the various vehicle types considered. PMID- 29161540 TI - Delirium symptoms are associated with decline in cognitive function between ages 53 and 69 years: Findings from a British birth cohort study. AB - INTRODUCTION: Few population studies have investigated whether longitudinal decline after delirium in mid-to-late life might affect specific cognitive domains. METHODS: Participants from a birth cohort completing assessments of search speed, verbal memory, and the Addenbrooke's Cognitive Examination at age 69 were asked about delirium symptoms between ages 60 and 69 years. Linear regression models estimated associations between delirium symptoms and cognitive outcomes. RESULTS: Period prevalence of delirium between 60 and 69 years was 4% (95% confidence interval 3.2%-4.9%). Self-reported symptoms of delirium over the seventh decade were associated with worse scores in the Addenbrooke's Cognitive Examination (-1.7 points; 95% confidence interval -3.2, -0.1; P = .04). In association with delirium symptoms, verbal memory scores were initially lower, with subsequent decline in search speed by the age of 69 years. These effects were independent of other Alzheimer's risk factors. DISCUSSION: Delirium symptoms may be common even at relatively younger ages, and their presence may herald cognitive decline, particularly in search speed, over this time period. PMID- 29161541 TI - Retroclavicular approach to infraclavicular brachial plexus block for distal radius fracture in a patient with implanted pacemaker. PMID- 29161539 TI - Home is where the future is: The BrightFocus Foundation consensus panel on dementia care. AB - INTRODUCTION: A national consensus panel was convened to develop recommendations on future directions for home-based dementia care (HBDC). METHODS: The panel summarized advantages and challenges of shifting to HBDC as the nexus of care and developed consensus-based recommendations. RESULTS: The panel developed five core recommendations: (1) HBDC should be considered the nexus of new dementia models, from diagnosis to end of life in dementia; (2) new payment models are needed to support HBDC and reward integration of care; (3) a diverse new workforce that spans the care continuum should be prepared urgently; (4) new technologies to promote communication, monitoring/safety, and symptoms management must be tested, integrated, and deployed; and (5) targeted dissemination efforts for HBDC must be employed. DISCUSSION: HBDC represents a promising paradigm shift to improve care for those living with dementia and their family caregivers: these recommendations provide a framework to chart a course forward for HBDC. PMID- 29161542 TI - Takotsubo cardiomyopathy complicating thoracoabdominal aortic aneurysm repair. AB - We describe the management of a patient with symptomatic spinal cord hypoperfusion after thoracoabdominal aortic aneurysm repair, where the neurological insult and associated emotional stress precipitated Takotsubo cardiomyopathy. Transthoracic Echocardiography showed akinetic mid and apical left ventricular segments, while basal segments were spared. Emergent coronary angiography ruled out acute coronary syndrome. Excess catecholamines have been postulated as a contributing mechanism to the disease, therefore, catecholamines were avoided to prevent further myocardial injury. Takotsubo cardiomyopathy is associated with serious morbidity and mortality, which highlights the importance of early recognition and proper management for complete recovery of both cardiac and neurologic functions. PMID- 29161543 TI - A patient with femoral triangle anatomy transposition challenges NAVY rule. PMID- 29161544 TI - Nuances of the cervical interfascial plane and multifidus cervicis plane blocks: Balancing efficacy and risk as a function of technique. PMID- 29161545 TI - A simple method for preventing the fog in the videolaryngoscope monitor during awake intubation. PMID- 29161546 TI - Ketorolac dose-response for acute pain is well known and the safety rules for adequate prescribing are clear. PMID- 29161547 TI - Agenesis of the left internal jugular vein: An unusual finding during an ultra sound guided central venous catheterization. PMID- 29161548 TI - Anesthetic management for laparoscopic sleeve gastrectomy to a child. PMID- 29161549 TI - Ultrasound-guided versus conventional injection for caudal block in children: A prospective randomized clinical study. AB - STUDY OBJECTIVE: The aim of this study was to compare the efficacies of ultrasound guided sacral hiatus injection and conventional sacral canal injection performed for caudal block in children. DESIGN: Randomized controlled clinical trial. SETTING: Operating rooms of university hospital of Erzurum, Turkey. PATIENTS: One hundred-thirty four children, American Society of Anesthesiologists I-II, between the ages of 5 and 12, scheduled for elective phimosis and circumcision surgery. INTERVENTIONS: Patients assigned to two groups for ultrasound guided caudal block (Group U, n=68) or conventional caudal block (Group C, n=66). Caudal solution was prepared as 0.125% levobupivacaine plus 10mcg/kg morphine (total volume: 0.5ml/kg), and was administered to both groups. MEASUREMENTS: The block performing time, the block success rate, the number of needle puncture, the success at first puncture and the complications were recorded. MAIN RESULTS: The block performing time and the success rate of block were similar between Group U and Group C (109.96+/-49.73s vs 103.17+/-45.12s, and 97% vs 93%, respectively p>0.05). The first puncture success rate was higher in Group U than in Group C (80% vs 63%, respectively p=0.026). No significant difference was observed between the groups with regard to the number of needle punctures (p=0.060). The rates of vascular puncture and subcutaneus bulging were higher in Group C than in Group U (8/66 vs 1/68, and 8/66 vs 0/68, respectively p<0.05). CONCLUSIONS: Despite the limitations in central neuroaxial anesthesia we recommend the use of ultrasound since it reduces the complications and increases the success rate of first puncture in pediatric caudal injection. PMID- 29161550 TI - Profound reversible seasonal changes of individual skull size in a mammal. PMID- 29161551 TI - Morphometric, Behavioral, and Genomic Evidence for a New Orangutan Species. PMID- 29161552 TI - Cerebrospinal-fluid-contacting neurons. PMID- 29161553 TI - Habits. AB - What is a habit? One problem with the concept of habit has been that virtually everyone has their own ideas of what is meant by such a term. Whilst not eschewing folk psychology, it is useful to re-examine dictionary definitions of 'habit'. The Oxford Dictionary of English defines habit as "a settled or regular tendency or practice, especially one that is hard to give up" and also "an automatic reaction to a specific situation". The latter, reassuringly, is not too far from what has come to be known as stimulus-response theory. PMID- 29161554 TI - Context-dependent lateralized feeding strategies in blue whales. AB - Lateralized behaviors benefit individuals by increasing task efficiency in foraging and anti-predator behaviors [1-4]. The conventional lateralization paradigm suggests individuals are left or right lateralized, although the direction of this laterality can vary for different tasks (e.g. foraging or predator inspection/avoidance). By fitting tri-axial movement sensors to blue whales (Balaenoptera musculus), and by recording the direction and size of their rolls during lunge feeding events, we show how these animals differ from such a paradigm. The strength and direction of individuals' lateralization were related to where and how the whales were feeding in the water column. Smaller rolls (<=180 degrees ) predominantly occurred at depth (>70 m), with whales being more likely to rotate clockwise around their longest axis (right lateralized). Larger rolls (>180 degrees ), conversely, occurred more often at shallower depths (<70 m) and were more likely to be performed anti-clockwise (left lateralized). More acrobatic rolls are typically used to target small, less dense krill patches near the water's surface [5,6], and we posit that the specialization of lateralized feeding strategies may enhance foraging efficiency in environments with heterogeneous prey distributions. PMID- 29161555 TI - Emergent acoustic order in arrays of mosquitoes. AB - The yellow fever mosquito Aedes aegypti forms aerial swarms that serve as mating aggregations [1]. Despite lacking the remarkable collective order of other animal ensembles, such as fish and birds [2], the kinematic properties of these swarms bear the hallmarks of local interaction and global cohesion [3,4]. However, the mechanisms responsible for collective behaviour in mosquitoes are not well understood. Mosquitoes use their antennae as hearing organs to locate and interact with one another via the frequencies of sounds generated by their beating wings [5]. Acoustic detection and recognition are known to mediate copula formation in opposite-sex pairs [6], but have not been investigated in larger groups. By recording the flight tones of multiple, tethered, male Ae. aegypti, we test the hypothesis that acoustic signalling is a determinant of swarm morphology and present the first compelling evidence that flight tone interactions between males drive observed group coherence in the frequency domain. We find that group size critically affects collective and individual acoustic traits: cohesive acoustic behaviours emerge in groups of more than six male mosquitoes, occurring to a greater degree than predicted in the absence of interaction. Importantly, acoustic interactions between multiple males differ from those reported previously for same-sex pairs [7,8]. Our findings enable future research targeting key behavioural and reproductive aspects of the biology of mosquitoes of epidemiological importance. PMID- 29161556 TI - Adaptation can explain evidence for encoding of probabilistic information in macaque inferior temporal cortex. AB - In predictive coding theory, the brain is conceptualized as a prediction machine that constantly constructs and updates expectations of the sensory environment [1]. In the context of this theory, Bell et al.[2] recently studied the effect of the probability of task-relevant stimuli on the activity of macaque inferior temporal (IT) neurons and observed a reduced population response to expected faces in face-selective neurons. They concluded that "IT neurons encode long term, latent probabilistic information about stimulus occurrence", supporting predictive coding. They manipulated expectation by the frequency of face versus fruit stimuli in blocks of trials. With such a design, stimulus repetition is confounded with expectation. As previous studies showed that IT neurons decrease their response with repetition [3], such adaptation (or repetition suppression), instead of expectation suppression as assumed by the authors, could explain their effects. The authors attempted to control for this alternative interpretation with a multiple regression approach. Here we show by using simulation that adaptation can still masquerade as expectation effects reported in [2]. Further, the results from the regression model used for most analyses cannot be trusted, because the model is not uniquely defined. PMID- 29161557 TI - Reply to Vinken and Vogels. AB - In their comment, Vinken and Vogels [1] take issue with our claim [2] that "IT neurons encode long-term, latent probabilistic information about stimulus occurrence". They offer a biologically plausible model of our findings, which they argue is based on neuronal fatigue. However, like our account, their model includes latent variables that are modulated slowly with stimulus probability; models without such latent processes, such as those based on temporally local fatigue effects, cannot explain our findings. Although we share their desire for more clarity about the mechanisms underlying visual expectation, and appreciate their thoughtful critique, we argue here that their comment mostly restates our findings with a more complex model and alternative terminology. PMID- 29161558 TI - Electrical Synapses: New Rules for Assembling an Old Structure Asymmetrically. AB - Electrical synapses are emerging as complex structures, consisting of gap junction-forming connexin proteins and also multiple scaffolding and regulatory protein components, which were assumed to be symmetrically organized across these synapses; however, new findings reveal their synaptic asymmetry. PMID- 29161559 TI - Bacterial Size: Tuning In to a Clearer Connection. AB - An innovative approach to harness cellular dimensions reveals fundamental links between cell size and other cellular processes in the bacterium Escherichia coli. PMID- 29161560 TI - Immunity: Insect Immune Memory Goes Viral. AB - Adaptive memory in insect immunity has been controversial. In this issue, Andino and co-workers propose that acquisition of viral sequences in the host genome gives rise to anti-sense, anti-viral piRNAs. Such sequences can be regarded as both a genomic archive of past infections and as an armour of potential heritable memory. PMID- 29161561 TI - Nucleolar Condensation: A New Mechanism to Control Mitotic Exit. AB - The nucleolus in Saccharomyces cerevisiae is one of the last genomic regions to be condensed in mitosis. A new study shows that this extended nucleolar relaxation state is fundamental for the timely execution of mitotic exit. PMID- 29161562 TI - Membrane Traffic: Trans-Golgi Tethers Leave a Surprisingly Small GAP. AB - Activation and inactivation of Rab GTPases by GEFs and GAPs promotes or terminates vesicle tethering to organelles, respectively. This simple model is challenged by new evidence revealing that a catalytically inactive Rab GAP promotes rather than terminates vesicle tethering at the trans-Golgi. PMID- 29161563 TI - Memory Retrieval: Taking the Route via Subiculum. AB - An episodic memory goes through three different stages: acquisition, consolidation and recall. A new study suggests that distinct microcircuits in the hippocampus underlie the process of memory acquisition and recall. PMID- 29161565 TI - Shape Control: Cell Growth Hits the Mechanical Buffers. AB - Organs are made from cells whose individual growth rates differ, yet the final shape of organs is highly robust. A new mechanics-based system is proposed to physically restrain cells that grow more than their neighbours, buffering their influence on organ size and shape. PMID- 29161564 TI - Cell Biology: When Your Own Chromosomes Act like Foreign DNA. AB - Two recent papers report the activation of a pro-inflammatory response by cytoplasmic DNA from aberrant nuclear structures called micronuclei. The findings have implications for tumor immunity, immunotherapy biomarker discovery, and possibly the many-sided effects of senescence-associated secretory phenotype. PMID- 29161566 TI - Endosomal Trafficking: Retromer and Retriever Are Relatives in Recycling. AB - Transmembrane proteins are sorted from endosomes to avoid lysosomal degradation. A recent study has identified a new multimeric complex called retriever that is essential for recycling numerous cell-surface cargoes from endosomes and is structurally and functionally related to the well-characterised retromer complex. PMID- 29161567 TI - The Biology of REM Sleep. AB - Considerable advances in our understanding of the mechanisms and functions of rapid-eye-movement (REM) sleep have occurred over the past decade. Much of this progress can be attributed to the development of new neuroscience tools that have enabled high-precision interrogation of brain circuitry linked with REM sleep control, in turn revealing how REM sleep mechanisms themselves impact processes such as sensorimotor function. This review is intended to update the general scientific community about the recent mechanistic, functional and conceptual developments in our current understanding of REM sleep biology and pathobiology. Specifically, this review outlines the historical origins of the discovery of REM sleep, the diversity of REM sleep expression across and within species, the potential functions of REM sleep (e.g., memory consolidation), the neural circuits that control REM sleep, and how dysfunction of REM sleep mechanisms underlie debilitating sleep disorders such as REM sleep behaviour disorder and narcolepsy. PMID- 29161568 TI - Feasibility of high-concentration cellulosic bioethanol production from undetoxified whole Monterey pine slurry. AB - The economic feasibility of high-concentration cellulosic bioethanol production remains challenging because it requires easily available feedstock and low energy consumption process. Simultaneous saccharification and fermentation (SSF) of sulfite pretreated Momentary pine slurry at 20% (w/w) loadings increased ethanol concentration from 59.3 g/L to 68.5 g/L by washing strategy. Effects of inhibitors in pretreatment liquor were further investigated. Besides HMF, furfural and acetic acid, other inhibitors and/or their synergistic effects proved to be responsible for a lower fermentability. To bypass the inhibition and achieve high-efficient bioethanol concentration, a fermentation temperature of 28 degrees C was optimized for both cell growth and ethanol production. Under the optimal conditions with prehydrolyzed 25% (w/w) whole undetoxified slurry, a high ethanol concentration (up to 82.1 g/L) were produced with a yield of 205 kg/ton Monterey pine in the SSF. Thus, this high cellulosic bioethanol production from Monterey pine makes it a potential strategy for biofuel production. PMID- 29161569 TI - Denitrification of landfill leachate under different hydraulic retention time in a two-stage anoxic/oxic combined membrane bioreactor process: Performances and bacterial community. AB - Two-stage anoxic/oxic combined membrane bioreactor (A/O-A/O-MBR) process was used to treat leachate generated from Shenyang Laohuchong landfill, and the effect of hydraulic retention time (HRT) was studied. A long HRT of 9 d and a short HRT of 5 d showed negative effect on the stability of process, resulting in a higher organic concentration of effluent than that with a HRT of 7 d, while the highest removal of chemical oxygen demand (COD), ammonia (NH4+-N) and total nitrogen (TN) were achieved with a HRT of 7 d, which was 82.4%, 99.1% and 75.3% respectively. The analysis of microbial communities by high-throughput sequencing showed that phyla Proteobacteria and Bacteroidetes were the dominant bacteria, which accounted for 36.63-42.39%, 29.21-38.66%, respectively. For genus classification, the most representative of Ferruginibacter, unclassified-Saprospiraceae and Nitrosomonas accounted for 20.76-35.11% totally. The other communities, including Nitrobacter, Planctomyces, Rhodobacteraceae and Nitrospirae, were also developed for organic degradation and denitrification. PMID- 29161570 TI - Acclimation of acid-tolerant methanogenic propionate-utilizing culture and microbial community dissecting. AB - The acid-tolerant methanogenic propionate degradation culture was acclimated in a propionate-fed semi-continuous bioreactor by daily adjusting the digestate pH. The performance of propionate fermentation, the respond of microbial community structure to the acidic environment, and the microbial network for propionate degradation in the acid-tolerant culture was investigated. The results demonstrated that after long term of acclimation to low pH, the digester could produce methane from propionate at pH 4.8-5.5 with 0.3-0.4 L g-1 propionic acid (HPr) d-1 of the volatile solids (VS) methane production. The predominant methanogens shifted from acetoclastic methanogens (~87%) to hydrogenotrophic methanogens (~67%) in the bioreactor with the dropping pH, indicating that hydrogenotrophic methanogens were more acid-tolerant than acetoclastic methanogens. Smithella (~11%), Syntrophobacter (~7%) and Pelotomaculum (~3%) were the main propionate oxidizers in the acid-tolerant propionate-utilizing culture. Methanothrix dominant acetoclastic methanogens, while Methanolinea and Methanospirillum were the major H2 scavengers to support Syntrophobacter and Pelotomaculum syntrophic propionate degradation. PMID- 29161571 TI - Effects of inorganic carbon on the nitrous oxide emissions and microbial diversity of an anaerobic ammonia oxidation reactor. AB - Inorganic carbon (IC) is important for anaerobic ammonium oxidation (anammox). In this study, the effects of the IC concentration on N2O emissions and microbial diversity in an anammox reactor were investigated. N2O emissions were positively correlated with IC concentrations, and IC concentrations in the range of 55-130 mg/L were optimal, considering the nitrogen removal rate and N2O emissions. High IC concentrations resulted in the formation of CaCO3 on the surface of anammox granules, which impacted the diffusion conditions of the substrate. Microbial community analysis indicated that high IC concentrations decreased the populations of specific bacteria, such as Achromobacter spanius strain YJART-7, Achromobacter xylosoxidans strain IHB B 6801, and Denitratisoma oestradiolicum clone 20b_15. D. oestradiolicum clone 20b_15 appeared to be the key contributor to N2O emissions. High N2O emissions may result from changes in organic carbon sources, which lead to denitrification by D. oestradiolicum clone 20b_15. PMID- 29161572 TI - New beta-galactosidase producers with potential for prebiotic synthesis. AB - beta-Galactosidases (EC 3.2.1.23) are interesting enzymes with potential application in the pharmaceutical and food industry. In this work, a screening study was carried out to identify new fungal sources of beta-galactosidase. A total of 50 fungi were evaluated using a chromogenic test performed in agar plates. The most promising microorganisms were validated as effective beta galactosidase producers under submerged fermentation conditions. The crude beta galactosidases were characterized regarding their optimal pH (3.0-5.5) and temperature (45-65 degrees C). All enzymes showed ability to synthesize lactose based prebiotics, namely lactulose (maximal yield 3.3%) and a galacto oligosaccharide (GOS) (maximal yield 20%). Additionally, some enzymatic extracts with fructosyltransferase activity allowed to produce other type of prebiotics, namely fructo-oligosaccharides (FOS). This work, reports for the first time the simultaneous synthesis of different mixtures of GOS (2-15% yield and 0.07-0.5 g/L.h-1 productivity) and FOS (4-30% yield and 0.1-1 g/L.h-1 productivity) by crude extracts exhibiting dual enzymatic activity. PMID- 29161573 TI - Decentralized biorefinery for lignocellulosic biomass: Integrating anaerobic digestion with thermochemical conversion. AB - Anaerobic digestion (AD) of lignocellulosic biomass i.e. Napier grass (Pennisetum purpureum), was investigated via a series of batch and bench-scale experiments. Two semi-continuous bench-scale horizontal bioreactors were operated in parallel for nearly 300 days, and the reactors were able to handle the organic loading rate (OLR) up to 6 kg volatile solids (VS)/m3-d, which was among the highest OLR reported in the literature for lignocellulosic biomass. Hemicellulose was the main structural carbohydrate of lignocellulosic biomass per unit respective mass (dry weight) basis contributing to methane production. The cellulose- and lignin rich digestate was further examined for its bioenergy potential via torrefaction and hydrothermal carbonization, and was found to have higher mass and energy yield compared with those of raw Napier grass. The produced solid char has energy content similar to bituminous coal with low ash content. Thus, this study provided a successful integration of anaerobic digestion with thermochemical conversion representing a biorefinery concept for lignocellulosic feedstocks. PMID- 29161574 TI - Fast spectroscopic monitoring of inhibitors in the 2G ethanol process. AB - One of the main challenges of second generation (2G) ethanol production is the high quantities of phenolic compounds and furan derivatives generated in the pretreatment of the lignocellulosic biomass, which inhibit the enzymatic hydrolysis and fermentation steps. Fast monitoring of these inhibitory compounds could provide better control of the pretreatment, hydrolysis, and fermentation processes by enabling the implementation of strategic process control actions. We investigated the feasibility of monitoring these inhibitory compounds by ultraviolet-visible (UV-Vis) spectroscopy associated with partial least squares (PLS) regression. Hydroxymethylfurfural, furfural, vanillin, and ferulic and p coumaric acids generated during different severities of liquid hot water pretreatment of sugarcane bagasse were quantified with highly accuracy. In cross validation (leave-one-out), the PLS-UV-Vis method presented root mean square error of prediction (RMSECV) of around only 5.0%. The results demonstrated that the monitoring performance achieved with PLS-UV-Vis could support future studies of optimization and control protocols for application in industrial processes. PMID- 29161576 TI - Unraveling physiological, biochemical and molecular mechanisms involved in olive (Olea europaea L. cv. Chetoui) tolerance to drought and salt stresses. AB - Olive (Olea europaea L.) is an economically important crop for the Mediterranean basin, where prolonged drought and soil salinization may occur. This plant has developed a series of mechanisms to tolerate and grow under these adverse conditions. By using an integrated approach, we described in Chetoui olive cultivar the changes in plant growth, oxidative damage and osmolyte accumulation in leaves, in combination with corresponding changes in physiological parameters and proteome. Our results showed, under both stress conditions, a greater growth reduction of the aboveground plant organs than of the underground counterparts. This was associated with a reduction of all photosynthetic parameters, the integrity of photosystem II and leaf nitrogen content, and corresponding representation of photosynthetic apparatus proteins, Calvin-Benson cycle and nitrogen metabolism. The most significant changes were observed under the salinity stress condition. Oxidative stress was also observed, in particular, lipid peroxidation, which could be tentatively balanced by a concomitant photoprotective/antioxidative increase of carotenoid levels. At the same time, various compensative mechanisms to cope with nitrogen source demands and to control plant cell osmolarity were also shown by olive plants under these stresses. Taken together, these findings suggest that the Chetoui variety is moderately sensitive to both drought and salt stress, although it has greater ability to tolerate water depletion. PMID- 29161575 TI - Sulfadiazine/ciprofloxacin promote opportunistic pathogens occurrence in bulk water of drinking water distribution systems. AB - Effects of sulfadiazine and ciprofloxacin on the occurrence of free-living and particle-associated opportunistic pathogens in bulk water of simulated drinking water distribution systems (DWDSs) were investigated. It was found that sulfadiazine and ciprofloxacin greatly promoted the occurrence of opportunistic pathogens including Pseudomonas aeruginosa, Legionella pneumophila, Mycobacterium avium and its broader genus Mycobacterium spp., as well as the amoebae Acanthamoeba spp. and Hartmanella vermiformis, in bulk water of DWDSs. Moreover, sulfadiazine and ciprofloxacin exhibited much stronger combined effects on the increase of these opportunistic pathogens. Based on the analysis of the antibiotic resistance genes (ARGs) and extracellular polymeric substances (EPS), it was verified that EPS production was increased by the antibiotic resistant bacteria arising from the effects of sulfadiazine/ciprofloxacin. The combined effects of sulfadiazine and ciprofloxacin induced the greatest increase of EPS production in DWDSs. Furthermore, the increased EPS with higher contents of proteins and secondary structure beta-sheet led to greater bacterial aggregation and adsorption. Meanwhile, large numbers of suspended particles were formed, increasing the chlorine-resistance capability, which was responsible for the enhancement of the particle-associated opportunistic pathogens in bulk water of DWDSs with sulfadiazine/ciprofloxacin. Therefore, sulfadiazine and ciprofloxacin promoted the occurrence of particle-associated opportunistic pathogens in bulk water of DWDSs due to the role of EPS produced by the bacteria with ARGs. PMID- 29161577 TI - Histological characteristics of the gonads of pig fetuses and their relationship with fetal anatomical measurements. AB - The objective was to evaluate the histomorphometric characteristics of the testis and ovaries of pig fetuses at different gestational ages, as well as their correlation with some fetus measurements. Forty-four fetuses were separated for gender (male and female) and gestational age (50, 80 and 106days of gestation). After slaughter, fetuses had their body length, head and thoracic perimeters measured and their gonads submitted to histomorphometric analyses. The gonadal characteristics at different gestational ages were statistically compared, correlations with the fetal measurements were performed and equations to predict the gonadal characteristics from the fetal measurements were obtained. The testis weight logarithmically increased along pregnancy, whereas ovary weight increased in a linear manner. The cordonal length and number of Sertoli cells were positively correlated with the fetal measurements, being higher at 106days gestation, while the nuclear volume of these cells were negatively correlated. The total number of follicles was higher at day 80 and 106 of pregnancy. The number of oogonia decreased along the pregnancy, however, their nucleus size was increased. The number of follicles and volume of oogonia were positively correlated with the fetal measurements, while the number of oogonia was negatively correlated. Equations were obtained for the prediction of gonadal characteristics of fetuses. We concluded that in pigs testis cell proliferation, ovary development and histological organization was more pronounced during the final third of pregnancy. Fetal weight and size were strongly related to gonadal development, and can be used to estimate the histological characteristics of gonads. PMID- 29161578 TI - Probabilistic pharmacokinetic models of decompression sickness in humans: Part 2, coupled perfusion-diffusion models. AB - Decompression sickness (DCS) can be experienced following a reduction in ambient pressure; such as that associated with diving or ascent to high altitudes. DCS is believed to result when supersaturated inert gas dissolved in biological tissues exits solution and forms bubbles. Models to predict the probability of DCS are typically based on nitrogen and/or helium gas uptake and washout in several theoretical tissues, each represented by a single perfusion-limited compartment. It has been previously shown that coupled perfusion-diffusion compartments are better descriptors than solely perfusion-based models of nitrogen and helium uptake and elimination kinetics observed in the brain and skeletal muscle of sheep. In this work, we examine the application of these coupled pharmacokinetic structures with at least one diffusion compartment to the prediction of the incidence of decompression sickness in humans. We compare these models to LEM NMRI98, a well-described U.S. Navy gas content model, consisting of three uncoupled perfusion-limited compartments incorporating oxygen and linear exponential kinetics. Pharmacokinetic gas content models with a diffusion component describe the probability of DCS in human bounce dives made with air, single non-air bounce dives, and oxygen decompression dives better than LEM NMRI98. However, for the full data set, LEM-NMRI98 remains the best descriptor of the data. PMID- 29161579 TI - Correlation between lung perfusion blood volume and SPECT images in patients with chronic thromboembolic pulmonary hypertension by balloon pulmonary angioplasty. AB - OBJECTIVES: We evaluated the reperfusion by balloon pulmonary angioplasty (BPA) in lung PBV and SPECT images. METHODS: In total, 17 patients and 57 sessions were evaluated. Pre-BPA and post-BPA lung PBV and SPECT/CT images, based on both anatomical segments and physiologic regions (upper/middle/lower) were compared. RESULTS: BPA had a positive effect on most hypoperfused/unperfused segments/regions. There was generally a high rate of agreement between PBV measurements and SPECT/CT. CONCLUSIONS: BPA shows promise as a treatment modality for CTEPH patients. SPECT/CT, and, to a lesser extent, PBV, were useful in indicating areas in need of balloon angioplasty. PMID- 29161580 TI - Artificial intelligence and deep learning - Radiology's next frontier? AB - Tracing the use of computers in the radiology department from administrative functions through image acquisition, storage, and reporting, to early attempts at improved diagnosis, we begin to imagine possible new frontiers for their use in exam interpretation. Given their initially slow but ultimately substantial progress in the noninterpretive areas, we are left desiring and even expecting more in the interpretation realm. New technological advances may provide the next wave of progress and radiologists should be early adopters. Several potential applications are discussed and hopefully will serve to inspire future progress. PMID- 29161581 TI - DNA/RNA hybrid substrates modulate the catalytic activity of purified AID. AB - Activation-induced cytidine deaminase (AID) converts cytidine to uridine at Immunoglobulin (Ig) loci, initiating somatic hypermutation and class switching of antibodies. In vitro, AID acts on single stranded DNA (ssDNA), but neither double stranded DNA (dsDNA) oligonucleotides nor RNA, and it is believed that transcription is the in vivo generator of ssDNA targeted by AID. It is also known that the Ig loci, particularly the switch (S) regions targeted by AID are rich in transcription-generated DNA/RNA hybrids. Here, we examined the binding and catalytic behavior of purified AID on DNA/RNA hybrid substrates bearing either random sequences or GC-rich sequences simulating Ig S regions. If substrates were made up of a random sequence, AID preferred substrates composed entirely of DNA over DNA/RNA hybrids. In contrast, if substrates were composed of S region sequences, AID preferred to mutate DNA/RNA hybrids over substrates composed entirely of DNA. Accordingly, AID exhibited a significantly higher affinity for binding DNA/RNA hybrid substrates composed specifically of S region sequences, than any other substrates composed of DNA. Thus, in the absence of any other cellular processes or factors, AID itself favors binding and mutating DNA/RNA hybrids composed of S region sequences. AID:DNA/RNA complex formation and supporting mutational analyses suggest that recognition of DNA/RNA hybrids is an inherent structural property of AID. PMID- 29161582 TI - The role of emotional clarity and distress tolerance in deliberate self-harm in a sample of trauma-exposed inpatient adolescents at risk for suicide. AB - OBJECTIVE: The purpose of this study was to examine distress tolerance as a moderator of the relationship between emotional clarity and deliberate self-harm (DSH) in a diverse sample of trauma-exposed adolescents in acute psychiatric care at high risk of suicidal behavior. It was hypothesized that distress tolerance would emerge as a significant moderator, such that the association between emotional clarity and DSH would be significant among youth with high, but not low, distress tolerance. METHOD: Participants (N=50; 52.0% female; M=15.1years, SD=0.51; 44% White) completed measures of emotion dysregulation, DSH, history of suicide attempts, as well as a behavioral measure of distress tolerance. RESULTS: Controlling for history of suicide attempts, results revealed a significant interaction between distress tolerance and emotional clarity in relation to DSH. Specifically, emotional clarity difficulties were related to DSH at high, but not low, levels of distress tolerance. CONCLUSIONS: Findings suggest that DSH among trauma-exposed youth with high rates of past suicide attempts is most likely when low emotion clarity is coupled with a high tolerance for emotional distress. Given that DSH significantly increases risk for suicide among youth with psychiatric needs, assessment of emotional clarity and distress tolerance deficits is apt to be warranted to facilitate identification of these youth for targeted intervention. PMID- 29161583 TI - Chrysin: Sources, beneficial pharmacological activities, and molecular mechanism of action. AB - In recent years, public and scientific interest in plant flavonoids has tremendously increased because of their postulated health benefits. This review was mainly focuses on the flavone chrysin (5,7-dihydroxyflavone), which occurs naturally in many plants, honey, and propolis. A number of in vitro and in vivo studies have revealed the therapeutic effects of chrysin against various diseases. In general, chrysin exhibits many biological activities and pharmacological effects, including antioxidant, anti-inflammatory, anticancer, and antiviral activities. Moreover, many studies have reported on the bioavailability of chrysin. Because of its compromised bioavailability and enhanced protein stability, chrysin solid lipid nanoparticle (SLN) synthesis avoids proteolytic degradation and sustained release of drug delivery. To clarify the mechanism of action of chrysin, researchers have investigated the structural binding relationship of chrysin through the docking computation method. PMID- 29161584 TI - Investigating Regeneration. PMID- 29161585 TI - Localized Lysosome Exocytosis Helps Breach Tissue Barriers. AB - Cell invasion across basement membrane barriers is important in both normal development and cancer metastasis. In this issue of Developmental Cell, Naegeli et al. (2017) identify a mechanism for breaching basement membranes. Localized lysosome exocytosis fuels generation of large, invasive cellular protrusions that expand tiny basement membrane openings. PMID- 29161586 TI - Re-cyclin' Cell-Cycle Components to Make NETs. AB - Neutrophil extracellular traps (NETs) are critical for the clearance of large pathogens and are also implicated in thrombosis, autoimmunity, and cancer. In this issue of Developmental Cell, Amulic et al. (2017) show that the terminally differentiated, non-cycling neutrophils repurpose cell-cycle proteins and pathways to form NETs. PMID- 29161587 TI - Versatile Scaffold: Extrajunctional Roles for alpha-Catenin. AB - alpha-catenin is a scaffolding molecule that can bind F-actin and other cytoskeletal proteins. It is best known for its contribution to cell-cell adhesion. In this issue of Developmental Cell, Vassilev et al. (2017) identify an extrajunctional pool of alpha-catenin that regulates RhoA signaling and controls directional migration of single cells. PMID- 29161588 TI - Intestinal Flossing Keeps Pathogens at Bay. AB - Intraepithelial lymphocytes (IELs) are tissue-resident immune cells that surveil the intestine and provide the first line of defense against pathogens. Reporting in Cell, van Konijnenburg et al. (2017) combine high-resolution microscopy and intersectional genetic tools to provide a detailed characterization of IEL dynamics in response to both commensal and pathogenic microorganisms. PMID- 29161589 TI - Mitosis sans Mitosis: The Mitotic Oscillator in Differentiation. AB - Differentiation and proliferation are usually considered to be antagonistic partners in development. However, in a recent issue of Science, Al Jord et al. (2017) show that key regulators of the mitotic cycle are redeployed in differentiating multiciliated cells to promote ciliogenesis without mitotic progression. PMID- 29161590 TI - Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche. AB - Tissues have a natural capacity to replace dying cells and to heal wounds. This ability resides in resident stem cells, which self-renew, preserve, and repair their tissue during homeostasis and following injury. The skin epidermis and its appendages are subjected to daily assaults from the external environment. A high demand is placed on renewal and regeneration of the skin's barrier in order to protect the body from infection and dehydration and to heal wounds. This review focuses on the epithelial stem cells of skin, where they come from, where they reside, and how they function in normal homeostasis and wound repair. PMID- 29161593 TI - Mitotic Cortical Waves Predict Future Division Sites by Encoding Positional and Size Information. AB - Dynamic spatial patterns such as traveling waves could theoretically encode spatial information, but little is known about whether or how they are employed by biological systems, especially higher eukaryotes. Here, we show that concentric target or spiral waves of active Cdc42 and the F-BAR protein FBP17 are invoked in adherent cells at the onset of mitosis. These waves predict the future sites of cell divisions and represent the earliest known spatial cues for furrow assembly. Unlike interphase waves, the frequencies and wavelengths of the mitotic waves display size-dependent scaling properties. While the positioning role of the metaphase waves requires microtubule dynamics, spindle and microtubule independent inhibitory signals are propagated by the mitotic waves to ensure the singularity of furrow formation. Taken together, we propose that metaphase cortical waves integrate positional and cell size information for division-plane specification in adhesion-dependent cytokinesis. PMID- 29161591 TI - Cell Invasion In Vivo via Rapid Exocytosis of a Transient Lysosome-Derived Membrane Domain. AB - Invasive cells use small invadopodia to breach basement membrane (BM), a dense matrix that encases tissues. Following the breach, a large protrusion forms to clear a path for tissue entry by poorly understood mechanisms. Using RNAi screening for defects in Caenorhabditis elegans anchor cell (AC) invasion, we found that UNC-6(netrin)/UNC-40(DCC) signaling at the BM breach site directs exocytosis of lysosomes using the exocyst and SNARE SNAP-29 to form a large protrusion that invades vulval tissue. Live-cell imaging revealed that the protrusion is enriched in the matrix metalloprotease ZMP-1 and transiently expands AC volume by more than 20%, displacing surrounding BM and vulval epithelium. Photobleaching and genetic perturbations showed that the BM receptor dystroglycan forms a membrane diffusion barrier at the neck of the protrusion, which enables protrusion growth. Together these studies define a netrin-dependent pathway that builds an invasive protrusion, an isolated lysosome-derived membrane structure specialized to breach tissue barriers. PMID- 29161594 TI - Clathrin Assembly Defines the Onset and Geometry of Cortical Patterning. AB - Assembly of the endocytic machinery is a constitutively active process that is important for the organization of the plasma membrane, signal transduction, and membrane trafficking. Existing research has focused on the stochastic nature of endocytosis. Here, we report the emergence of the collective dynamics of endocytic proteins as periodic traveling waves on the cell surface. Coordinated clathrin assembly provides the earliest spatial cue for cortical waves and sets the direction of propagation. Surprisingly, the onset of clathrin waves, but not individual endocytic events, requires feedback from downstream factors, including FBP17, Cdc42, and N-WASP. In addition to the localized endocytic assembly at the plasma membrane, intracellular clathrin and phosphatidylinositol-3,4-bisphosphate predict the excitability of the plasma membrane and modulate the geometry of traveling waves. Collectively, our data demonstrate the multiplicity of clathrin functions in cortical pattern formation and provide important insights regarding the nucleation and propagation of single-cell patterns. PMID- 29161595 TI - A Coincidence Detection Mechanism Controls PX-BAR Domain-Mediated Endocytic Membrane Remodeling via an Allosteric Structural Switch. AB - Clathrin-mediated endocytosis occurs by bending and remodeling of the membrane underneath the coat. Bin-amphiphysin-rvs (BAR) domain proteins are crucial for endocytic membrane remodeling, but how their activity is spatiotemporally controlled is largely unknown. We demonstrate that the membrane remodeling activity of sorting nexin 9 (SNX9), a late-acting endocytic PX-BAR domain protein required for constriction of U-shaped endocytic intermediates, is controlled by an allosteric structural switch involving coincident detection of the clathrin adaptor AP2 and phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) at endocytic sites. Structural, biochemical, and cell biological data show that SNX9 is autoinhibited in solution. Binding to PI(3,4)P2 via its PX-BAR domain, and concomitant association with AP2 via sequences in the linker region, releases SNX9 autoinhibitory contacts to enable membrane constriction. Our results reveal a mechanism for restricting the latent membrane remodeling activity of BAR domain proteins to allow spatiotemporal coupling of membrane constriction to the progression of the endocytic pathway. PMID- 29161596 TI - An In Toto Approach to Dissecting Cellular Interactions in Complex Tissues. AB - Single-cell measurements have broadened our understanding of heterogeneity in biology, yet have been limited to mostly observational studies of normal or globally perturbed systems. Typically, perturbations are utilized in an open ended approach wherein an endpoint is assayed during or after the biological event of interest. Here we describe ShootingStar, a platform for perturbation analysis in vivo, which combines live imaging, real-time image analysis, and automated optical perturbations. ShootingStar builds a quantitative record of the state of the sample being analyzed, which is used to automate the identification of target cells for perturbation, as well as to validate the impacts of the perturbation. We used ShootingStar to dissect the cellular basis of development, morphogenesis, and polarity in the lateral line of Danio rerio and the embryo of Caenorhabditis elegans. ShootingStar can be extended to diverse optical manipulations and enables more robust and informative single-cell perturbations in complex tissues. PMID- 29161597 TI - Sustainability of mega water diversion projects: Experience and lessons from China. AB - Water availability and water demand are not evenly distributed in time and space. Many mega water diversion projects have been launched to alleviate water shortages in China. This paper analyzes the temporal and spatial features of 59 mega water diversion projects in China using statistical analysis. The relationship between nine major basins is measured using a network analysis method, and the associated economic, environmental and social impacts are explored using an impact analysis method. The study finds the development of water diversion has experienced four stages in China, from a starting period through to a period of high-speed development. Both the length of water diversion channels and the amount of transferred water have increased significantly in the past 50years. As of 2015, over 100billionm3 of water was transferred in China through 16,000km in channels. These projects reached over half of China's provinces. The Yangtze River Basin is now the largest source of transferred water. Through inter-basin water diversion, China gains the opportunity to increase Gross Domestic Product by 4%. However, the construction costs exceed 150 billion US dollars, larger than in any other country. The average cost per unit of transferred water has increased with time and scale but decreased from western to eastern China. Furthermore, annual total energy consumption for pumping exceeded 50billionkilowatt-hours and the related greenhouse gas emissions are estimated to be 48milliontons. It is worth noting that ecological problems caused by water diversion affect the Han River and Yellow River Basins. Over 500 thousand people have been relocated away from their homes due to water diversion. To improve the sustainability of water diversion, four kinds of innovative measures have been provided for decision makers: national diversion guidelines, integrated water basin management, economic incentives and ex-post evaluation. PMID- 29161592 TI - Tumor-Suppressor Inactivation of GDF11 Occurs by Precursor Sequestration in Triple-Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous carcinoma in which various tumor-suppressor genes are lost by mutation, deletion, or silencing. Here we report a tumor-suppressive mode of action for growth differentiation factor 11 (GDF11) and an unusual mechanism of its inactivation in TNBC. GDF11 promotes an epithelial, anti-invasive phenotype in 3D triple-negative cultures and intraductal xenografts by sustaining expression of E-cadherin and inhibitor of differentiation 2 (ID2). Surprisingly, clinical TNBCs retain the GDF11 locus and expression of the protein itself. GDF11 bioactivity is instead lost because of deficiencies in its convertase, proprotein convertase subtilisin/kexin type 5 (PCSK5), causing inactive GDF11 precursor to accumulate intracellularly. PCSK5 reconstitution mobilizes the latent TNBC reservoir of GDF11 in vitro and suppresses triple-negative mammary cancer metastasis to the lung of syngeneic hosts. Intracellular GDF11 retention adds to the concept of tumor-suppressor inactivation and reveals a cell-biological vulnerability for TNBCs lacking therapeutically actionable mutations. PMID- 29161598 TI - Roles and potential mechanisms of selenium in countering thyrotoxicity of DEHP. AB - Di-(2-ethylhexyl) phthalate (DEHP) as a ubiquitous environmental contaminant could disturb thyroid hormone (TH) homeostasis. Selenium as an essential trace element has protective effects on thyroids. To verify roles of selenium in countering thyrotoxicity of DEHP and elucidate potential mechanisms, Sprague Dawley rats and Nthy-ori 3-1 cells were treated with DEHP or/and selenomethionine (SeMet). Results showed that selenium supplementation elevated plasma free thyroxine (FT4) that was decreased by DEHP, and free triiodothyronine (FT3) and thyroid stimulating hormone (TSH) levels were also partially recovered. DEHP caused histopathologic changes were ameliorated after selenium supplementation, as indicated by recovered thyroid follicular epithelial cell numbers and cavity diameters. DEHP disrupted the redox equilibrium, causing depletions of SOD, GPx1, GPx3, and TxnRd, and accumulations of MDA. Nevertheless, selenium supplementation effectively improved the redox status. DEHP affected biosynthesis, biotransformation, biotransport, and metabolism of THs, as well as thyrotropin releasing hormone receptor (TRHr) levels. Plasma selenium, thyroid peroxidase (TPO), deiodinase 1 (Dio1), and transthyretin (TTR) were downregulated, while Dio3, Ugt1a1, Sult1e1, CYP2b1, CYP3a1, and TRHr were upregulated by DEHP. However, selenium supplementation led to elevations of selenium, Dio1 and TTR, and reductions of Ugt1a1, Sult1e1, CYP2b1, and TRHr. TPO, Dio3, and CYP3a1 were not significantly affected by selenium supplementation. Taken together, selenium could ameliorate DEHP-caused TH dyshomeostasis via modulations of the redox status, Dio1, TTR, TRHr, and hepatic enzymes. PMID- 29161599 TI - Perfluorinated alkyl acids and fecundity assessment in striped mullet (Mugil cephalus) at Merritt Island national wildlife refuge. AB - This study investigated wild caught striped mullet (Mugil cephalus) at Merritt Island National Wildlife Refuge (MINWR) for levels of 15 perfluoroalkyl acids (PFAA) in tandem with individual fecundity measurements (Oocyte sub-stage 2 late, n=42) and oocyte reproductive stages (Stages 1-5, n=128). PFAA measurements were quantified in striped mullet liver (n=128), muscle (n=49), and gonad (n=10). No significant negative impacts of liver PFAA burden on wild-caught, mullet fecundity endpoints were observed in this study; however, changes in PFAA were observed in the liver as mullet progressed through different sub-stages of oocyte development. Of the PFAA with significant changes by sub-stage of oocyte development, the carboxylic acids (perfluorooctanoic acid, perfluorononanoic acid, and perfluorotridecanoic acid) increased in the liver with increasing sub stage while the sulfonic acid and its precursor (perfluorooctanesulfonic acid (PFOS) and perfluorooctanesulfonamide, respectively) decreased in the liver with increasing sub-stage of oocyte development. This is a unique find and suggests PFAA change location of compartmentalization as mullet progress towards spawning. Investigations also revealed higher than expected median muscle and gonad levels of PFOS in striped mullet collected at MINWR (9.01ng/g and 80.2ng/g, respectively). PMID- 29161601 TI - Characterizing emission rates of regulated pollutants from model year 2012+ heavy duty diesel vehicles equipped with DPF and SCR systems. AB - The regulated emissions of five 2012 and newer, low-mileage, heavy-duty Class 8 diesel trucks equipped with diesel particulate filters (DPFs) and selective catalytic reduction (SCR) systems were evaluated over test cycles representing urban, highway, and stop-and-go driving on a chassis dynamometer. NOx emissions over the Urban Dynamometer Driving Schedule (UDDS) ranged from 0.495 to 1.363g/mi (0.136 to 0.387g/bhp-hr) for four of the normal emitting trucks. For those trucks, NOx emissions were lowest over the cruise (0.068 to 0.471g/mi) and high speed cruise (0.067 to 0.249g/mi) cycles, and highest for the creep cycle (2.131 to 9.468g/mi). A fifth truck showed an anomaly in that it had never regenerated throughout its relatively short operating lifetime due to its unusual, unladed service history. This truck exhibited NOx emissions of 3.519g/mi initially over the UDDS, with UDDS NOx emissions decreasing to 0.39g/mi after a series of parked regenerations. PM, THC, and CO emissions were found to be very low for most of the testing conditions, due to the presence of the DPF/SCR aftertreatment system, and were comparable to background levels in some cases. PMID- 29161602 TI - Gravel beaches nourishment: Modelling the equilibrium beach profile. AB - The erosion of the world's coasts and the shortage of sand to mitigate beach erosion are leading to the increasingly common use of gravel for coastal protection and beach nourishment. Therefore, in order to determine the amount of gravel required for such actions, it is important to know perfectly the equilibrium profile of gravel beaches. However, at present, this profile is obtained from formulas obtained mainly after channel tests, and therefore most of them do not adapt to the real profiles formed by gravel beaches in nature. In this article, 31 variables related to sedimentology, waves, morphology and marine vegetation present on the beaches are studied to determine which are the most influential in the profile. From the study carried out, it is obtained that these variables are the steepness and probability of occurrence of the wave perpendicular to the coast, the profile starting slope (between MWL and -2m), the energy reduction coefficient due to Posidonia oceanica as well as the width of the meadow. Using these variables, different numerical models were generated to predict accurately the gravel beach profile, which will lead to a saving in the volume of material used in the order of 1300m3/ml of beach with respect to current formulations, and a greater certainty that the beach nourishment carried out will have the desired effect. PMID- 29161603 TI - 37Cl-compound specific isotope analysis and assessment of functional genes for monitoring monochlorobenzene (MCB) biodegradation under aerobic conditions. AB - A laboratory approach was adopted in this study to explore the potential of 37Cl CSIA in combination with 13C-CSIA and Biological Molecular Tools (BMTs) to estimate the occurrence of monochloroenzene (MCB) aerobic biodegradation. A new analytical method for 37Cl-CSIA of MCB was developed in this study. This methodology using a GC-IRMS allowed to determine delta37Cl values within an internal error of +/-0.30/00. Samples from a heavily MCB contaminated site were collected and MCB aerobic biodegradation microcosms with indigenous cultures in natural and enhanced conditions were set up. The microcosms data show a negligible fractionation for 13C associated to MCB mass decrease of >95% over the incubation time. Conversely, an enrichment factor of -0.6+/-0.10/00 was estimated for 37Cl, which is a reflection of a secondary isotope effect. Moreover, the dual isotope approach showed a pattern for aerobic degradation which differ from the theoretical trend for reductive dehalogenation. Quantitative Polymerase Chain Reaction (qPCR) results showed a significant increase in todC gene copy number with respect to its initial levels for both natural attenuation and biostimulated microcosms, suggesting its involvement in the MCB aerobic degradation, whereas phe gene copy number increased only in the biostimulated ones. Indeed, 37Cl fractionation in combination with the dual carbon-chlorine isotope approach and the todC gene copy number represent valuable indicators for a qualitative assessment of MCB aerobic biodegradation in the field. PMID- 29161600 TI - Monitoring wastewater for assessing community health: Sewage Chemical-Information Mining (SCIM). AB - Timely assessment of the aggregate health of small-area human populations is essential for guiding the optimal investment of resources needed for preventing, avoiding, controlling, or mitigating human exposure risks, as well as for maintaining or promoting health. Seeking those interventions yielding the greatest benefit with respect to the allocation of resources is critical for making progress toward community sustainability, reducing health disparities, promoting social justice, and maintaining or improving collective health and well being. More informative, faster, and less-costly approaches are needed for guiding investigation of cause-effect linkages involving communities and stressors originating from both the built and natural environments. One such emerging approach involves the continuous monitoring of sewage for chemicals that serve as indicators of the collective status of human health (or stress/disease) or any other facet relevant to gauging time-trends in community-wide health. This nascent approach can be referred to as Sewage Chemical-Information Mining (SCIM) and involves the monitoring of sewage for the information that resides in the form of natural and anthropogenic chemicals that enter sewers as a result of the everyday actions, activities, and behaviors of humans. Of particular interest is a specific embodiment of SCIM that would entail the targeted monitoring of a broad suite of endogenous biomarkers of key physiologic processes (as opposed to xenobiotics or their metabolites). This application is termed BioSCIM-an approach roughly analogous to a hypothetical community-wide collective clinical urinalysis, or to a hypothetical en masse human biomonitoring program. BioSCIM would be used for gauging the status or time-trends in community-wide health on a continuous basis. This paper presents an update on the progress made with the development of the BioSCIM concept in the period of time since its original publication in 2012, as well as the next steps required for its continued development. PMID- 29161604 TI - Ecological effects and potential risks of the water diversion project in the Heihe River Basin. AB - To curb the severe ecological deterioration in the lower Heihe River Basin (HRB) in northwest China, a water diversion project was initiated in 2000. A comprehensive analysis of the ecological effects and potential risks associated with the project is needed. We assessed the hydrological and ecological achievements, and also analyzed the potential problems after the project was completed. We found that since the project began the hydrological regime has changed, with more than 57.82% of the upstream water being discharged to the lower reaches on average. As a result, the groundwater level in the lower reaches has risen; the terminal lake has gradually expanded to a maximum area in excess of 50km2 since 2010, and there has been a significant recovery of vegetation in the riparian zone and the Ejin core oases, which represents the initial rehabilitation of the degraded downstream environment. Additionally, the economy of Ejin has developed spectacularly, with an annual growth rate of 28.06%. However, in the middle reaches, the average groundwater level has continuously declined by a total of 5.8m and significant degradation of the vegetation has occurred along the river course. The discrepancy in the water allocation between the middle and lower reaches has intensified. This highlights the inability of the current water diversion scheme to realize further ecological restoration and achieve sustainable development throughout the whole basin. In future water management programs, we recommend that water allocation is coordinated by considering the basin as an integrated entity and to scientifically determine the size of the midstream farmland and downstream oasis; restrict non-ecological water use in the lower reaches, and jointly dispatch the surface water and groundwater. PMID- 29161605 TI - Sustainability of UK shale gas in comparison with other electricity options: Current situation and future scenarios. AB - Many countries are considering exploitation of shale gas but its overall sustainability is currently unclear. Previous studies focused mainly on environmental aspects of shale gas, largely in the US, with scant information on socio-economic aspects. To address this knowledge gap, this paper integrates for the first time environmental, economic and social aspects of shale gas to evaluate its overall sustainability. The focus is on the UK which is on the cusp of developing a shale gas industry. Shale gas is compared to other electricity options for the current situation and future scenarios up to the year 2030 to investigate whether it can contribute towards a more sustainable electricity mix in the UK. The results obtained through multi-criteria decision analysis suggest that, when equal importance is assumed for each of the three sustainability aspects shale gas ranks seventh out of nine electricity options, with wind and solar PV being the best and coal the worst options. However, it outranks biomass and hydropower. Changing the importance of the sustainability aspects widely, the ranking of shale gas ranges between fourth and eighth. For shale gas to become the most sustainable option of those assessed, large improvements would be needed, including a 329-fold reduction in environmental impacts and 16 times higher employment, along with simultaneous large changes (up to 10,000 times) in the importance assigned to each criterion. Similar changes would be needed if it were to be comparable to conventional or liquefied natural gas, biomass, nuclear or hydropower. The results also suggest that a future electricity mix (2030) would be more sustainable with a lower rather than a higher share of shale gas. These results serve to inform UK policy makers, industry and non-governmental organisations. They will also be of interest to other countries considering exploitation of shale gas. PMID- 29161606 TI - Maternal depressive symptoms and adolescent academic attainment: Testing pathways via parenting and self-control. AB - Maternal depression is associated with reduced academic attainment in children, however, it is not clear how this association comes about. Depressive symptoms are associated with impairment in social roles including parenting. Children's self-control is an important contributor to academic attainment and is influenced by parenting. We therefore hypothesised that impaired parenting and children's self-control may mediate links between maternal depression and children's academic attainment. Data were from a brief longitudinal study (3 waves) of UK children aged 11-12 years and their mothers. Higher maternal depressive symptoms at baseline were associated with lower academic attainment in children assessed one year later. There was evidence to support an indirect effect of maternal depressive symptoms on children's academic attainment through the mother-child and the father-child relationship which, in turn, reduced children's self control. These influences were independent of socio-economic deprivation. A direct effect of maternal depression on children's academic attainment was also observed. PMID- 29161607 TI - How discrimination and perspective-taking influence adolescents' attitudes about justice. AB - Little is known about factors influencing adolescents' justice attitudes. This online study investigates perspective-taking and experiences with discrimination for their associations with adolescents' beliefs about how justice is best served. Participants included 179 ethnically/racially diverse high school students (Mage = 16.67 years; SD = 1.02). Higher perspective-taking was associated with less punitive and more restorative attitudes. Youth reporting more personal and ethnic/racial discrimination experiences endorsed more restorative justice attitudes. Perspective-taking also moderated the associations between reports of family, personal, and religious discrimination and punitive justice attitudes: adolescents reporting higher discrimination showed a stronger inverse relationship between perspective-taking and punitive attitudes. Findings have implications for school and community programs aiming to implement restorative policies, and for adolescents' civic participation. PMID- 29161608 TI - The underlying mechanism of deficits of speech comprehension and hallucinations in Chinese patients with schizophrenia. AB - Sentence context and fundamental frequency (F0) contours are important factors to speech perception and comprehension. In Chinese-Mandarin, lexical tones can be distinguished by the F0 contours. Previous studies found healthy people could use the cue of context to recover the phonological representations of lexical tones from the altered tonal patterns to comprehend the sentences in quiet condition, but can not in noise environment. Lots of research showed that patients with schizophrenia have deficits of speech perception and comprehension. However, it is unclear how context and F0 contours influence speech perception and comprehension in patients with schizophrenia. This study detected the contribution of context and lexical tone to sentence comprehension in four types of sentences by manipulating the context and F0 contours in 32 patients with schizophrenia and 33 healthy controls. The results showed that (1) in patients with schizophrenia, the interaction between context and F0 contour was not significant, which was significant in healthy controls; (2) the scores of sentences with two types of sentences with flattened F0 contours were negatively correlated with hallucination trait scores; (3) the patients with schizophrenia showed significantly lower scores on the intelligibility of sentences in all conditions, which were negatively correlated with PANSS-P. The patients with schizophrenia couldn't use the cue of context to recover the phonological representations of lexical tones from the altered tonal patterns when they comprehend the sentences, inner noise may be the underlying mechanism for the deficits of speech perception and comprehension. PMID- 29161609 TI - Cancers in France in 2015 attributable to high body mass index. AB - BACKGROUND: Overweight, as defined by high body mass index (BMI), is an established risk factor for various morbidities including cancer. Globally, its prevalence has increased markedly over the past decades. The aim of this study was to estimate the proportion and number of cancers that were attributable to high BMI in France in 2015. METHODS: Population attributable fractions (PAFs) and numbers of cancer cases attributable to high BMI (a population mean BMI above the optimum of 22kg/m2) were estimated by age and sex, for cancer sites with convincing or probable evidence of an established causal link. Assuming a 10-year lag-period, PAFs were calculated using mean BMI estimates from a cross-sectional French population survey, and relative risk estimates from published meta analyses. RESULTS: An estimated 18,639 cancer cases diagnosed in France in 2015 were attributable to high BMI, corresponding to 5.3% of all cancer cases (6.7% in women and 4.1% in men). This included 4507 cases of postmenopausal breast and 3380 cases of colon cancer. The highest estimated PAFs were for oesophageal adenocarcinoma and corpus uteri cancer (37% and 34%, respectively). CONCLUSION: High BMI is associated with a substantial number of cancer cases in France, a country with a low but increasing prevalence of overweight and obesity when compared to other European countries. Assuming that the association between high BMI and cancer is causal, these results highlight the need to prioritise the prevention of this risk factor as part of cancer control planning in France and elsewhere in Europe. PMID- 29161610 TI - Experimental modification of dysfunctional interpretations in individuals with contamination concerns. AB - BACKGROUND AND OBJECTIVES: Dysfunctional interpretations of intrusive thoughts are implicated in the etiology and maintenance of Obsessive-Compulsive Disorder (OCD). Cognitive Bias Modification training for interpretations (CBM-I) has successfully modified dysfunctional interpretations in the context of several disorders, including OCD. However, research regarding CBM-I's impact on symptom reduction and behavior is mixed, which limits its clinical application. Further, support for the specific efficacy of CBM-I in individuals with contamination concerns is limited. The current study aimed to modify dysfunctional interpretations in individuals with contamination concerns, and examine the effect of the modification on both interpretation bias and performance on a behavioral approach task (BAT). METHODS: Participants (N = 74) completed a word sentence association task by indicating whether a threatening or benign word was related to an ambiguous scenario. The active condition received feedback designed to reduce maladaptive interpretations; the control condition received random feedback. RESULTS: Findings revealed that the active-but not the control condition showed a significant decrease in interpretation bias for threat cues. Analyses of behavioral effects indicated that when ceiling effects were accounted for, the active condition completed more BAT steps than the control condition (p = 0.06; d = 0.45). LIMITATIONS: The current study is preliminary and requires replication with a clinical sample. CONCLUSIONS: Completion of the CBM-I was beneficial for reducing dysfunctional interpretations relevant to naturally occurring contamination concerns and, importantly, this reduction may help those individuals approach feared situations. PMID- 29161611 TI - The application of ion mobility mass spectrometry to metabolomics. AB - Mass spectrometry-based metabolomics is being increasingly utilized in various research fields including investigating human diseases, nutrition, industrial applications, and plant/natural products studies. Although new analytical approaches have enhanced the performance of metabolomic analyses, significant challenges associated with throughput, metabolome coverage, and compound identification still exist. Ion mobility mass spectrometry offers great potential for improving throughput and depth of coverage in metabolomics experiments. For example, multi-dimensional, structural resolution offered by ion mobility enables improved identification of metabolites and chemical classes. This mini-review discusses the advantages, recent developments and limitations of using ion mobility mass spectrometry as part of a metabolomics workflow. PMID- 29161612 TI - Microfluidic reactor for lipase-catalyzed regioselective synthesis of neohesperidin ester derivatives and their antimicrobial activity research. AB - Lipase-catalyzed regioselective synthesis of neohesperidin ester derivatives was performed by Lipase TL IM from Thermomyces lanuginosus in a continuous-flow microreactor and then their antimicrobial activity was studied. It appears that neohesperidin, neohesperidin dihydrochalcone with primary OH on the sugar part is the most reactive substrate. Various reaction parameters were investigated including substrate molar ratio, reaction time and temperature. Maximum conversion (92%) was obtained under the optimal condition of substrate molar ratio of 8:1 (vinyl esters: neohesperidin) at 52 degrees C for about 35 min. Then, the antibacterial activity of modified neohesperidin ester derivatives was examined and showed great improvement against gram negative and gram positive bacteria. PMID- 29161613 TI - Molecular Characterization of Urothelial Carcinoma of the Bladder and Upper Urinary Tract. AB - PURPOSE: A better understanding of the molecular basis of urothelial carcinoma (UC) is needed to refine the clinical decision-making process. METHODS AND MATERIALS: We performed next-generation sequencing to investigate the mutational and transcriptional profiles of commonly mutated genes in UC using Ampliseq v2. Copy number variations (CNVs) were detected with nCounter assay. Genetic alterations between upper tract UC (UTUC) and urinary bladder UC (UBUC) were compared. RESULTS: Tumor samples from 31 UTUC and 61 UBUC patients were included in analysis. The two groups showed similar clinicopathologic features including tumor grade and stage. Median survival was longer in UTUC than UBUC patients, though this was statistically nonsignificant (59 vs 41 months, P=.137). In total, we found 982 genetic alterations from 92 samples: single nucleotide variants were the most common type of somatic mutation (479/508, 94.3%). Frequently detected somatic mutations included TP53 (68.5%), KDR (41.3%), and PIK3CA (17.4%). Notably, RB1 mutations were the only mutations significantly different between the UBUC and UTUC groups (19.7% vs. 0%, P=.020). The most common types of CNVs included amplifications (56/62, 90.3%): 17.7% of patients identified amplifications in NOTCH1. We also identified five translocations in the entire study population, including one case with FGFR3-TACC3 (Chr4) fusion. CONCLUSION: Within a small study population, we identified similar genetic alterations in both UTUC and UBUC patients, indicating a basis for similar management strategies. PMID- 29161615 TI - More than a Tad: spatiotemporal control of Caulobacter pili. AB - The Type IV pilus (T4P) is a powerful and sophisticated bacterial nanomachine involved in numerous cellular processes, including adhesion, DNA uptake and motility. Aside from the well-described subtype T4aP of the Gram-negative genera, including Myxococcus, Pseudomonas and Neisseria, the Tad (tight adherence) pilus secretion system re-shuffles homologous parts from other secretion systems along with uncharacterized components into a new type of protein translocation apparatus. A representative of the Tad apparatus, the Caulobacter crescentus pilus assembly (Cpa) machine is built exclusively at the newborn cell pole once per cell cycle. Recent comprehensive genetic analyses unearthed a myriad of spatiotemporal determinants acting on the Tad/Cpa system, many of which are conserved in other alpha-proteobacteria, including obligate intracellular pathogens and symbionts. PMID- 29161614 TI - Changes of lumbar posture and tissue loading during static trunk bending. AB - Static trunk bending is an occupational risk factor for lower back pain (LBP). When assessing relative short duration trunk bending tasks, existing studies mostly assumed unchanged spine biomechanical responses during task performance. The purpose of the current study was to assess the biomechanical changes of lumbar spine during the performance of relatively short duration, sustained trunk bending tasks. Fifteen participants performed 40-s static trunk bending tasks in two different trunk angles (30 degrees or 60 degrees ) with two different hand load levels (0 or 6.8 kg). Results of the current study revealed significantly increased lumbar flexion and lumbar passive moment during the 40 s of trunk bending. Significantly reduced lumbar and abdominal muscle activities were also observed in most conditions. These findings suggest that, during the performance of short duration, static trunk bending tasks, a shift of loading from lumbar active tissues to passive tissues occurs naturally. This mechanism is beneficial in reducing the accumulation of lumbar muscle fatigue; however, lumbar passive tissue creep could be introduced due to prolonged or repetitive exposure. PMID- 29161616 TI - The deceleration of a spherical projectile passing through porcine organs at laboratory temperature (16 degrees C) and core body temperature (37 degrees C). PMID- 29161617 TI - Early pregnancy immune biomarkers in peripheral blood may predict preeclampsia. AB - We performed a prospective cohort study in 197 pregnant women. Peripheral blood was collected between 5 and 16 weeks of gestation. Intracellular cytokine analysis and immunophenotype were performed by flow-cytometry. Serum levels of cytokines and chemokines were analyzed by multiplex assay. 86 patients were eligible for the analysis and 10.5% (n=9) developed preeclampsia. Patients with preeclampsia had significantly higher percentage of CD3+CD4+TNFalpha+ T helper (Th) 1 cells (45.4+/-10.3 vs 37.1+/-8.5, P=0.032) and CD3+CD4+IL17+ Th 17 cells (2.4+/-1.3 vs 1.6+/-1.1, P=0.029) when compared to those of patients without preeclampsia. CD3+CD4+CD25+CD127dim/- T regulatory cells (Treg) cells (5.7+/-1.2% vs 7.0+/-1.6%, P=0.015) were significantly lower in patients with preeclampsia when compared to those without preeclampsia. Patients with preeclampsia had significantly higher TNFalpha/IL-10 cell ratio (43.8+/-10.3 vs 34.3+/-7.9, P=0.005) and Th17/Treg cell ratio (0.5+/-0.3 vs 0.2+/-0.2, P=0.011) when compared to those of patients without preeclampsia. IL-8 and Macrophage inflammatory protein (MIP)-1alpha serum levels were significantly higher in patients with preeclampsia when compared with patients without preeclampsia (Median=341.0 vs 87.6, U=152, P=0.020 and Median=35.7 vs 17.7, U=120, P=0.029 respectively). Serum MCP-1 levels were significantly lower in patients with preeclampsia when compared with patients without preeclampsia (Median=233.8 vs 390.9, U=183, P=0.021). The logistic regression predictive model combining TNFalpha/IL-10 ratios, IL-8 and MCP-1 serum levels had the best performance (AUC=0.886, 95%CI 0.8-0.9). We concluded that elevated Th1 and Th17 cell percentages, elevated TNFalpha/IL-10 and Th17/Treg cell ratios and decreased Treg cell percentages in early pregnancy are associated with preeclampsia. PMID- 29161618 TI - Bayesian synthesis for simulation-based generation of probability of detection (PoD) curves. AB - This paper examines the feasibility of using Bayesian synthesis to reduce the number of experimental cases and trials required for generation of probability of detection (PoD) curves. A Bayesian framework is developed for the data-level combination of experimental and simulated datasets, in the context of the inspection of back-wall breaking notches in metallic samples by bulk ultrasonic shear waves. PoD curves generated using the proposed approach, where results from a reduced number of experimental defect cases and trials are used in combination with simulated datasets, are shown to compare well with those from the conventional approach using a large number of experiments. Finally, the framework is also shown to be versatile for generating PoD curves for complex defects (illustrated through the example of an inclined notch) using simulations for canonical defects (vertical notches). PMID- 29161619 TI - The application of ultrasound and enzymes in textile processing of greige cotton. AB - A review is reported herein of the research progress made at the USDA's Southern Regional Research Center to provide an ultrasound and enzymatic alternative to the current textile processing method of scouring greige cotton textile with caustic chemicals. The review covers early efforts to measure pectin and wax removal from greige cotton textiles using standard wicking methodology and further describes an investigation of newly discovered polygalacturonase enzymes as bioscouring agents. Additional research is reviewed involving efforts to characterize and optimize the ultrasound-enhanced enzymatic scouring process through a statistical examination of the operating parameters of power, enzyme concentration, ultrasonic frequency and time. PMID- 29161620 TI - In-situ elastic strain mapping during micromechanical testing using EBSD. AB - Compared to more commonly used strain measurement techniques, electron backscatter diffraction (EBSD) offers improved spatial resolution and measurement sensitivity. Additionally, EBSD can provide the full deformation tensor, whereas other techniques, such as digital image correlation (DIC), are limited to only in plane strains and rotations. In this work, EBSD was used to measure strains and rotations in-situ during testing of a single-crystal silicon micromechanical test specimen. The theta-like specimen geometry was chosen due to the complex and spatially-varying strain states that exist in the circular frame of the sample during testing, as well as the nominally uniform strains in the central web. Full field strain maps were generated for each strain and rotation component and compared to those from finite element analyses (FEA), showing strong agreement in all cases. Additionally, potential sources of error and their impact on both measurement accuracy and uncertainty are discussed. PMID- 29161621 TI - Human subthalamic oscillatory dynamics following somatosensory stimulation. AB - OBJECTIVE: Electrical median nerve somatosensory stimulation leads to a distinct modulation of cortical oscillations. Initial high frequency and gamma augmentation, as well as modulation of beta and alpha oscillations have been reported. We aimed at investigating the involvement of the subthalamic nucleus in somatosensory processing by means of local field potential recordings, since recordings during passive movements and peripheral somatosensory stimulation have suggested a prominent role. METHODS: Recordings of subthalamic neuronal activity following median nerve stimulation in 11 Parkinson's disease patients were performed. Time-frequency analysis from 1 to 500 Hz was averaged and analyzed. RESULTS: Several oscillatory components in response to somatosensory stimulation were revealed in the time-frequency analysis: (I) prolonged increase in alpha band power, followed by attenuation; (II) initial suppression of power followed by a subsequent rebound in the beta band; (III) early broad-frequency increase in gamma band power; (IV) and sustained increase of 160 Hz frequency oscillations throughout the trial. CONCLUSIONS: These results further corroborate the involvement of the subthalamic nucleus in somatosensory processing. SIGNIFICANCE: The present results not only support the notion of somatosensory processing in the subthalamic nucleus. Moreover, an improvement of somatosensory processing during subthalamic deep brain stimulation in Parkinson's disease might be accounted for by enhancement of prevailing high frequency oscillations. PMID- 29161622 TI - On Denny-Brown's 'spastic dystonia' - What is it and what causes it? AB - In this review, we will work around two simple definitions of two different entities, which most often co-exist in patients with lesions to central motor pathways: Spasticity is "Enhanced excitability of velocity-dependent responses to phasic stretch at rest", which will not be the subject of this review, while Spastic dystonia is tonic, chronic, involuntary muscle contraction in the absence of any stretch or any voluntary command (Gracies, 2005). Spastic dystonia is a much less well understood entity that will be the subject this review. Denny Brown (1966) observed involuntary sustained muscle activity in monkeys with lesions restricted to the motor cortices . He further observed that such involuntary muscle activity persisted following abolition of sensory input to the spinal cord and concluded that a central mechanism rather than exaggerated stretch reflex activity had to be involved. He coined the term spastic dystonia to describe this involuntary tonic activity in the context of otherwise exaggerated stretch reflexes. Sustained involuntary muscle activity in the absence of any stretch or any voluntary command contributes to burdensome and disabling body deformities in patients with spastic paresis. Yet, little has been done since Denny-Brown's studies to determine the pathophysiology of this non- stretch or effort related sustained involuntary muscle activity following motor lesions and there is a clear need for research studies in order to improve current therapy. The purpose of the present review is to discuss some of the possible mechanisms that may be involved in the hope that this may guide future research. We discuss the existence of persistent inward currents in spinal motoneurones and present the evidence that the channels involved may be upregulated following central motor lesions. We also discuss a possible contribution from alterations in synaptic inputs from surviving or abnormally branched sensory and descending fibres leading to over-activity and lack of motor coordination. We finally discuss evidence of alterations in motor cortical representational maps and basal ganglia lesions. PMID- 29161623 TI - Functions of myosin motors tailored for parasitism. AB - Myosin motors are one of the largest protein families in eukaryotes that exhibit divergent cellular functions. Their roles in protozoans, a diverse group of anciently diverged, single celled organisms with many prominent members known to be parasitic and to cause diseases in human and livestock, are largely unknown. In the recent years many different approaches, among them whole genome sequencing, phylogenetic analyses and functional studies have increased our understanding on the distribution, protein architecture and function of unconventional myosin motors in protozoan parasites. In Apicomplexa, myosins turn out to be highly specialized and to exhibit unique functions tailored to accommodate the lifestyle of these parasites. PMID- 29161624 TI - Are there associations with age and sex in walking stability in healthy older adults? AB - The variability of the centre of pressure (COP) during walking can provide information in relation to stability when walking. The aim of this study was to investigate if age and sex were associated with COP variability, COP excursions, and COP velocities during walking. One-hundred and fourteen older adults (age 65.1+/-5.5 yrs.) participated in the study. A Kistler force platform (1000Hz) recorded the ground reaction forces and COPs during walking at a self-selected walking speed. The stance phase was divided, using the vertical GRF, into four sub-phases: loading response (LR), mid-stance (MSt), terminal stance (TSt), and pre-swing (PSw). The standard deviations of the COP displacement (variability), the COP velocity, and COP excursion in the medial-lateral and anterior-posterior directions, as well as the resultant magnitude were assessed. When controlling for walking speed, a greater age was associated with a higher variability and excursion of the COP during LR only suggesting that stability is maintained during the majority of the stance phase. During LR lower COP velocity was significantly associated for females for anterior-posterior and total COP, which may be a strategy to facilitate stability before, and moving into, MSt and TSt. PMID- 29161625 TI - Prediction of walk-to-run transition using stride frequency: A test-retest reliability study. AB - The transition from walking to running has previously been predicted to occur at a point where the stride frequency starts getting closer to the running attractor than to the walking attractor. The two behavioural attractors were considered to be represented by the freely chosen stride frequencies during unrestricted treadmill walking and running. The aim of the present study was to determine the relative and absolute test-retest reliability of the predicted walk-to-run transition stride frequency. Healthy individuals (n=25) performed walking and running on a treadmill in a day-to-day test-retest design. The two behavioral attractors were determined during walking and running at freely chosen velocities and stride frequencies. Subsequently, the walk-to-run transition stride frequency was predicted using camera recordings and a previously reported equation for prediction. The walk-to-run transition occurred at a velocity of 7.7+/-0.5kmh-1 at day 1 as well as at day 2. Besides, the predicted walk-to-run transition stride frequencies were 69.7+/-3.3 strides min-1 and 70.5+/-3.4 strides min-1 on day 1 and day 2, respectively (p=0.08). A further comparison between the predicted walk-to-run transition stride frequencies at day 1 and day 2 showed an ICC3,1 of 0.89, which indicated almost perfect relative reliability. The absolute reliability was reflected by a%-value of the standard error of the measurement (SEM%) of 1.6% and a%-value of the smallest real difference (SRD%) of 4.4%. In conclusion, the predicted walk-to-run transition stride frequency can be considered reliable across days. PMID- 29161626 TI - The effect of augmented somatosensory feedback on standing postural sway. AB - Impaired balance resulting from reduced postural control occurs with aging and various medical conditions. Sensory input for balance control is provided by the visual, vestibular and somatosensory systems. Previous research suggests that increased proprioceptive feedback from various lower extremity devices improves balance. Mixed results have been reported with the use of orthoses such as ankle foot orthoses (AFOs). In this study, 20 healthy subjects wore footplates in their shoes or straps around their lower legs in order to imitate the somatosensory feedback produced by wearing AFOs, but without providing ankle restriction. Subjects' standing balance was assessed using force plates and computerized dynamic posturography (the sensory organization test-SOT) to determine if either the footplates or the lower-leg straps would affect standing balance. The results revealed no significant difference with the use of the footplates, however, wearing the straps resulted in reduced postural sway for conditions when visual cue deprivation was combined with manipulation of somatosensory or vestibular feedback. This effect was more pronounced in participants with the poorest baseline measures of balance. These findings suggest that lower extremity devices, such as AFOs, may augment somatosensory feedback that could improve balance during challenging sensory deprivation conditions, independent of orthotic support at the ankle. PMID- 29161627 TI - Nanoscaled red blood cells facilitate breast cancer treatment by combining photothermal/photodynamic therapy and chemotherapy. AB - Red blood cells (RBCs)-based vesicles have been widely used for drug delivery due to their unique advantages. Intact RBCs contain a large amount of oxyhemoglobin (oxyHb), which can assist with photodynamic therapy (PDT). Indocyanine green (ICG), a photosensitizer both for photothermal therapy (PTT) and PDT, shows potent anticancer efficacy when combined with chemotherapeutic drug doxorubicin (DOX). In this study, we prepared nanoscaled RBCs (RAs) containing oxyHb and gas generating agent ammonium bicarbonate (ABC) for co-loading and controlled release of ICG and DOX, thus hoping to achieve synergistic effects of PTT/PDT and chemotherapy against breast cancer. Compared to free ICG, ICG and DOX co-loaded RAs (DIRAs) exhibited nearly identical PTT efficiency both in vitro and in vivo, but meanwhile their PDT efficiency was enhanced significantly. In mouse breast cancer cells, DIRAs significantly inhibited cell growth and induced cell apoptosis after laser irradiation. In breast tumor-bearing mice, intratumoral injection of DIRAs and followed by local laser irradiation almost completely ablated breast tumor and further suppressed tumor recurrence and metastasis. In conclusion, this biomimetic multifunctional nanosystem can facilitate breast cancer treatment by combining PTT/PDT and chemotherapy. PMID- 29161628 TI - Stigma accounts for depression in patients with epilepsy. AB - OBJECTIVE: Epilepsy is a chronic disease with an increased risk of stigmatization due to psychosocial consequences of the seizures. Intuitively, one may well conclude that stigmatization would lead to depression in patients with epilepsy as well as in other patient groups with increased risk of stigmatization. Indeed, there are a few studies in support of this intuition. In this study, we aimed to investigate the relationship between level of stigmatization and the severity of the depressive symptoms in our patients with epilepsy. METHODS: This is a substudy of our main study, which aimed to develop a scale for the quantification of the stigma level in patients with epilepsy. The study included a total of 302 patients with epilepsy, who had at least a literacy level education and one-week seizure-freedom. Beck Depression Inventory (BDI) was used to quantify depressive symptoms. The correlation between BDI scores and the Stigma Scale for Epilepsy Self Report (SSE-SR) scores was evaluated. A regression analysis was done in order to parse out significant sociodemographic and clinical factors contributing to depressive symptoms. Statistical analyses were done using the Statistics Package for the Social Sciences software 24.0 package program. RESULTS: We saw that 46.9% (n=139) of this population rated themselves as having at least mildly depressive symptoms with BDI (BDI>9). There was a moderate positive correlation between stigma scores and BDI scores (p=0.000, r=0.504), and 96.3% of highly stigmatized patients had at least mildly depressive scores, 73.9% of the nonstigmatized group had none or minimal depressive scores. Stigma scores (beta=.51), gender, educational level, seizure frequency, and income level were the variables significantly affecting the BDI scores. Stigma score accounted for 26.2% of the variance in the BDI score. CONCLUSION: This study shows that stigmatization of the patients with epilepsy leads to depression in those patients. Therefore, protection of the patients with epilepsy against stigmatization may also help to protect them from a concomitant disabling condition. On the other hand, detection for depressive symptoms in already stigmatized patients with epilepsy may unearth a treatable condition. PMID- 29161629 TI - The effects of felbamate on appetitive and aversive instrumental learning in adult rats. AB - Antiepileptic medications are the frontline treatment for seizure conditions but are not without cognitive side effects. Previously, our laboratory reported learning deficits in phenytoin-, carbamazepine-, and valproate-treated rats. In the present experiment, the effects of felbamate (FBM) have been compared to water-treated controls (controls) using the same instrumental training tasks employed here. Rats treated with FBM displayed a deficit in acquiring a tone signaled avoidance response, relative to controls, but this was true only if they had no prior appetitive experience. Terminal avoidance behavior was equivalent to healthy controls. In contrast, the FBM-treated rats showed enhanced acquisition of the avoidance response relative to controls when given the benefit of prior experience in the appetitive condition. Relative to animals treated with phenytoin, carbamazepine, or valproate, FBM-treated rats showed the lowest overall pattern of deficits using these instrumental learning tasks. While FBM treatment has been severely restricted because of rather low risks of serious medical side effects, we suggest that the risks are not substantially higher than those shown to exist for phenytoin, carbamazepine, or valproate. As psychologists, we further suggest that negative cognitive deficits associated with these various drugs, along with their quality-of-life costs, are of relevance in the design of treatment strategies for individuals with seizure disorders. PMID- 29161630 TI - Active epilepsy prevalence, the treatment gap, and treatment gap risk profile in eastern China: A population-based study. AB - We measured the prevalence of active epilepsy and investigated the treatment gap and treatment gap risk profile in eastern China. This was a cross-sectional population-based survey conducted in Zhejiang, China, from October 2013 to March 2014. A total 54,976 people were selected using multi-stage cluster sampling. A two-stage questionnaire-based process was used to identify patients with active epilepsy and to record their demographic, socioeconomic, and epilepsy-related features. Logistic regression analysis was used to analyze risk factors of the treatment gap in eastern China, as adjusted for age and sex. We interviewed 50,035 people; 118 had active epilepsy (2.40/00), among which the treatment gap was 58.5%. In multivariate analysis, failure to receive appropriate antiepileptic treatment was associated with higher seizure frequency of 12-23 times per year (adjusted odds ratio=6.874; 95% confidence interval [CI]=2.372-19.918), >24 times per year (adjusted odds ratio=19.623; 95% CI=4.999-77.024), and a lack of health insurance (adjusted odds ratio=7.284; 95% CI=1.321-40.154). Eastern China has relatively lower prevalence of active epilepsy and smaller treatment gap. Interventions aimed at reducing seizure frequency, improving the health insurance system should be investigated as potential targets to further bridge the treatment gap. PMID- 29161631 TI - Perceived epilepsy stigma mediates relationships between personality and social well-being in a diverse epilepsy population. AB - INTRODUCTION: Perceived epilepsy stigma and reduced social well-being are prevalent sources of distress in people with epilepsy (PWE). Yet, research on patient-level correlates of these difficulties is lacking, especially among underserved groups. MATERIALS AND METHODS: Racially/ethnically diverse adults with intractable seizures (N=60, 62% female; 79% Black, 20% Hispanic/Latino, 8% White) completed validated measures of personality (NEO Five Factor Inventory, NEO-FFI-3), perceived epilepsy stigma (Epilepsy Stigma Scale, ESS), and quality of life (Quality of Life Inventory in Epilepsy, QOLIE-89). Controlling for covariates, ordinary least-squares (OLS) regression evaluated the total, direct, and indirect effects of NEO-FFI-3 neuroticism and extraversion scores on epilepsy related social well-being (i.e., combination of QOLIE-89 social isolation and work/driving/social function subscales, alpha=0.87), mediated through perceived stigma. RESULTS: In separate models, higher levels of neuroticism (N) and lower levels of extraversion (E) were significantly and independently associated with greater perceived stigma (N path a=0.71, p=0.005; E path a=-1.10, p<0.005). Stigma, in turn, was significantly and independently associated with poorer social well-being (N path b=0.23, p<0.001; E path b=-0.23, p<0.001). Bias corrected bootstrap confidence intervals (CIs) showed that neuroticism and extraversion were indirectly associated with social well-being through their respective associations with perceived stigma (N path ab=-0.16, 95% CIs [-0.347, 0.044]; E path ab=0.25, 95% CIs [0.076, 0.493]). CONCLUSION: Higher neuroticism and lower extraversion covaried with stigma beliefs, and these may be markers of poor social outcomes in PWE. Mediation models suggest that targeting epilepsy stigma beliefs may be a particularly useful component to incorporate when developing interventions aimed at promoting social well-being in diverse PWE. PMID- 29161634 TI - Shielding effect in protein folding. AB - One of the most important interactions responsible for protein folding and stability are hydrogen bonds between peptide groups. There is a constant competition between the water molecules and peptide groups in a hydrogen bond formation. Also side-chains take part in this process by reducing hydration of peptide group (shielding effect) that promotes the protein folding. In this paper, a new approach to take into account a shielding effect is presented. A modification of the energy function is derived and incorporated into the UNited RESidue (UNRES) force field. Canonical Molecular Dynamics and Replica Exchange Molecular Dynamics with UNRES force field is applied to study the influence of this effect on protein structure, folding kinetics and free energy landscapes. The results of test calculations suggest that even small contribution of this effect into energy function changes force field behavior as well as speeds up the folding process significantly. PMID- 29161633 TI - Urinary concentrations of biomarkers of phthalates and phthalate alternatives and IVF outcomes. AB - Phthalates are a class of chemicals found in a large variety of consumer products. Available experimental and limited human data show adverse effects of some phthalates on ovarian function, which has raised concerns regarding potential effects on fertility. The aim of the current study was to determine whether urinary concentrations of metabolites of phthalates and phthalate alternatives are associated with intermediate and clinical in vitro fertilization (IVF) outcomes. We enrolled 136 women undergoing IVF in a Tertiary University Affiliated Hospital. Participants provided one to two urine samples per cycle during ovarian stimulation and before oocyte retrieval. IVF outcomes were abstracted from medical records. Concentrations of 17 phthalate metabolites and two metabolites of the phthalate alternative di(isononyl) cyclohexane-1,2 dicarboxylate (DINCH) were measured. Multivariable Poisson regression models with log link were used to analyze associations between tertiles of specific gravity adjusted phthalate or DINCH metabolites and number of total oocytes, mature oocytes, fertilized oocytes, and top quality embryos. Multivariable logistic regression models were applied to evaluate the association between tertiles of specific gravity adjusted phthalate or DINCH metabolites and probability of live birth. Urinary concentrations of the sum of di-2-ethylhexyl phthalate metabolites (?DEHP) and the individual metabolites mono-2-ethyl-5-hydroxyhexyl phthalate, mono-2-ethyl-5-oxohexyl phthalate, and mono-2-ethyl-5-carboxypentyl phthalate were negatively associated with the number of total oocytes, mature oocytes, fertilized oocytes, and top quality embryos. Of the low molecular weight phthalates, higher monoethyl phthalate and mono-n-butyl phthalate concentrations were associated with significantly fewer total, mature, and fertilized oocytes. None of the urinary phthalate metabolite concentrations were associated with a reduced probability implantation, clinical pregnancy or live birth. Metabolites of DINCH were not associated with intermediate or clinical IVF outcomes. Our results suggest that DEHP may impair early IVF outcomes, specifically oocyte parameters. Additional research is needed to elucidate the potential effect of DEHP on female fertility in the general population. PMID- 29161632 TI - Ambient air pollution, adipokines, and glucose homeostasis: The Framingham Heart Study. AB - OBJECTIVE: To examine associations of proximity to major roadways, sustained exposure to fine particulate matter (PM2.5), and acute exposure to ambient air pollutants with adipokines and measures of glucose homeostasis among participants living in the northeastern United States. METHODS: We included 5958 participants from the Framingham Offspring cohort examination cycle 7 (1998-2001) and 8 (2005 2008) and Third Generation cohort examination cycle 1 (2002-2005) and 2 (2008 2011), who did not have type 2 diabetes at the time of examination visit. We calculated 2003 annual average PM2.5 at participants' home address, residential distance to the nearest major roadway, and daily PM2.5, black carbon (BC), sulfate, nitrogen oxides (NOx), and ozone concentrations. We used linear mixed effects models for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) which were measured up to twice, and used linear regression models for adiponectin, resistin, leptin, and hemoglobin A1c (HbA1c) which were measured only once, adjusting for demographics, socioeconomic position, lifestyle, time, and seasonality. RESULTS: The mean age was 51years and 55% were women. Participants who lived 64m (25th percentile) from a major roadway had 0.28% (95% CI: 0.05%, 0.51%) higher fasting plasma glucose than participants who lived 413m (75th percentile) away, and the association appeared to be driven by participants who lived within 50m from a major roadway. Higher exposures to 3- to 7-day moving averages of BC and NOx were associated with higher glucose whereas the associations for ozone were negative. The associations otherwise were generally null and did not differ by median age, sex, educational attainment, obesity status, or prediabetes status. CONCLUSIONS: Living closer to a major roadway or acute exposure to traffic-related air pollutants were associated with dysregulated glucose homeostasis but not with adipokines among participants from the Framingham Offspring and Third Generation cohorts. PMID- 29161635 TI - Temperature-dependent conformational dynamics of cytochrome c: Implications in apoptosis. AB - Heat, electric shock, and burn injuries induce apoptosis by releasing cytochrome c (cyt-c) from mitochondria and by subsequently activating the death protease, caspases-3. During apoptosis, cyt-c undergoes changes in the secondary structure that have been suggested to increase its peroxidase activity. Information about these structural changes will provide better understanding of the apoptotic mechanism. Hence, temperature-dependent conformational dynamics of cyt-c has been investigated through molecular dynamics (MD) simulations to explain the structural changes and to correlate them with its apoptotic behavior. We observe that, at lower temperatures (223, 248, and 300K), the secondary structure of cyt c, remains stable, while at higher temperatures (323, 373, 423, and 473K), the secondary structural regions change significantly. Further, our MD results indicate that these structural changes are mainly localized on alpha-helices, turns, beta-sheets, and important loops that were involved in the stabilization of the heme conformation. This conformational transition between specific regions of secondary structure of cyt-c directly affects the electron tunneling properties of the proteins as observed experimentally. We quantify and compare these changes and explain that the temperature plays a vital role in assuring the structural stability of cyt-c and thus its functions. Our findings from this MD study reproduce experimental results at high temperatures and provide evidence for the alteration of the heme through the disruption of the H-bonding interactions between specific regions of cyt-c, thereby enhancing its peroxidase activity which plays a crucial role in the apoptotic process. PMID- 29161636 TI - Infant HPA axis as a potential mechanism linking maternal mental health and infant telomere length. AB - Maternal depression has been suggested to be an independent risk factor for both dysregulated hypothalamic-pituitary-adrenal axis (HPA) functioning and shorter telomere length in offspring. In contrast, research suggests that individual differences in mindfulness may act as a protective factor against one's own telomere degradation. Currently, research has yet to investigate the association between longitudinal changes in maternal mental health (depressive symptoms and mindfulness) and salivary infant telomere length, and whether such changes might be mediated by alterations in infant cortisol response. In 48 mother-infant dyads, we investigated whether the changes in maternal mental health, when infants were 6-12 months of age, predicted change in infant cortisol reactivity and recovery over this period. We also investigated whether these changes in infant HPA functioning predicted subsequent infant salivary telomere length at 18 months of age. Furthermore, we investigated whether change in infant HPA functioning provided a potential pathway between changes in maternal mental health factors and infant salivary telomere length. Analyses revealed that increases in maternal depressive symptoms over that six-month period indirectly related to subsequent shorter infant telomere length through increased infant cortisol reactivity. Implications for the ways in which maternal mental health can impact offspring stress mechanisms related to aging and disease trajectories are discussed. PMID- 29161637 TI - La donna e mobile? Lack of cyclical shifts in facial symmetry, and facial and body masculinity preferences-A hormone based study. AB - Although under investigation for more than two decades, a common agreement on the occurrence of cyclical shifts in women's masculinity and symmetry preferences is still missing. Such shifts are considered to be an important feature of sexual selection as they supposedly direct women's attention towards cues for "good genes" (e.g. masculinity and symmetry) during times when probability of conception is the highest. Multiple studies have, however, failed to find these shifts. We attempt to address this lack of agreement analysing a sample of 110 healthy women, using intra-participant design and repeated measurements of oestradiol and LH during the cycle. To ensure the reliable detection of increased conception probability, both LH- based ovulation tests and multiple oestradiol measurements were used. We found no significant differences between women's preferences during different cycle phases for either body or facial masculinity, or for facial symmetry. Differences remained non-significant after controlling for participants' sexual openness, relationship status, and self-judged attractiveness. We suggest that putative cyclical shifts in preferences for cues for good genes are either very small (impossible to be tracked even with a relatively large sample) or they are far more complex than previously assumed, and further studies accounting for more confounding variables should be undertaken. PMID- 29161639 TI - Specification, plasticity and evolutionary origin of peripheral glial cells. AB - Peripheral glia includes predominantly myelinating and non-myelinating Schwann cells in addition to satellite, terminal and enteric glia as well as other unresolved subtypes with localized functions. Of these subtypes, all of them originate from neural crest-derived embryonic Schwann cell precursors (SCPs). Specific gene regulatory networks control neural crest specification and downstream events, including SCP differentiation and myelination. Embryonic SCPs are multipotent and generate neuroendocrine cells, parasympathetic and enteric neurons, melanocytes and other cell types. The evolutionary origin of peripheral Schwann cell lineage is not widely discussed in the literature, despite numerous similarities between central and peripheral glia. Here, we review the major features of the Schwann cell lineage and proceed to an evolutionary discussion around possible relations between central and peripheral glial cells. PMID- 29161638 TI - To what extent do structural changes in catalytic metal sites affect enzyme function? AB - : About half of known enzymatic reactions involve metals. Enzymes belonging to the same superfamily often evolve to catalyze different reactions on the same structural scaffold. The work presented here investigates how functional differentiation, within superfamilies that contain metalloenzymes, relates to structural changes at the catalytic metal site. In general, when the catalytic metal site is unchanged across the enzymes of a superfamily, the functional differentiation within the superfamily tends to be low and the mechanism conserved. Conversely, all types of structural changes in the metal binding site are observed for superfamilies with high functional differentiation. Overall, the catalytic role of the metal ions appears to be one of the most conserved features of the enzyme mechanism within metalloenzyme superfamilies. In particular, when the catalytic role of the metal ion does not involve a redox reaction (i.e. there is no exchange of electrons with the substrate), this role is almost always maintained even when the site undergoes significant structural changes. In these enzymes, functional diversification is most often associated with modifications in the surrounding protein matrix, which has changed so much that the enzyme chemistry is significantly altered. On the other hand, in more than 50% of the examples where the metal has a redox role in catalysis, changes at the metal site modify its catalytic role. Further, we find that there are no examples in our dataset where metal sites with a redox role are lost during evolution. SYNOPSIS: In this paper we investigate how functional diversity within superfamilies of metalloenzymes relates to structural changes at the catalytic metal site. Evolution tends to strictly conserve the metal site. When changes occur, they do not modify the catalytic role of non-redox metals whereas they affect the role of redox-active metals. PMID- 29161640 TI - Aging Schwann cells: mechanisms, implications, future directions. AB - The aging peripheral nervous system (PNS) is prone to a number of disorders, including the development of neuropathies and increased regenerative failure. Although the basic mechanisms of the aging PNS are still rather murky, recent work has revealed that 'old' Schwann cells acquire a number of dysfunctions in mammals. This review will assess our current knowledge about aging Schwann cells while emphasizing where gaps exist. Indeed, as our understanding of how these peripheral glia contribute to the development, maintenance and regeneration of the PNS becomes increasingly refined, we should also turn our attention to questions of escalating importance in our rapidly greying society: how do Schwann cells change with aging, how might these changes contribute to dysfunction and disease, and what, if anything, might this tell us about the aging central nervous system? PMID- 29161641 TI - Health care at birth and infant mortality: Evidence from nighttime deliveries in Nigeria. AB - High rates of home births in developing countries are often linked to high rates of newborn deaths, but there is considerable debate about how much of this is causal. This paper weighs in on this question by analyzing data on the timing of birth, health care utilization, and mortality for a sample of births between 2009 2014 in 7021 rural Nigerian households. First, we show that timing of birth is strongly linked to use of institutional care: women with a nighttime birth are significantly less likely to use a health facility because of the difficulties associated with accessing care at night. In turn, this is associated with a sharp increase in the rate of newborn mortality at night. Leveraging variation in household proximity to a health care facility that offers 24-h coverage, we show that this increase in mortality is plausibly due to lack of formal health care at the time of birth: infants born at night to households without a nearby health care facility that offers 24-h coverage, experience an increase in mortality equivalent to about 10 additional newborn deaths per 1000 live births. In contrast, when households have a nearby health facility that provides care at night, there is no detectable increase in mortality. These results suggest that well-designed policies to increase access to (and quality of) formal care at birth may lead to significant reductions in newborn deaths. PMID- 29161642 TI - Microbial diversity of consumption milk during processing and storage. AB - Bovine milk contains a complex microbial community that affects the quality and safety of the product. Detailed knowledge of this microbiota is, therefore, of importance for the dairy industry. In this study, the bacterial composition of consumption milk was assessed during different stages in the production line and throughout the storage in cartons by using culturing techniques and 16S rRNA marker gene sequencing. Monthly samples from two dairies were analyzed to capture the seasonal variations in the milk microbiota. Although there was a core microbiota present in milk samples from both dairies, the composition of the bacterial communities were significantly influenced by sampling month, processing stage and storage temperature. Overall, a higher abundance of operational taxonomic units (OTUs) within the order Bacillales was detected in samples of raw and pasteurized milk from the spring and summer months, while Pseudomonadales and Lactobacillales OTUs were predominant in the winter months. OTUs belonging to the order Lactobacillales, Pseudomonadales, Clostridiales and Bacillales were significantly more abundant in milk samples taken immediately after pasteurization compared to raw milk samples. During storage of milk in cartons at 4 degrees C, the bacterial composition remained stable throughout the product shelf life, while storage at 8 degrees C significantly increased the abundance of OTUs belonging to the genus Bacillus and the plate count levels of presumptive Bacillus cereus. The knowledge obtained in this work will be useful to the dairy industry during their quality assurance work and risk assessment practices. PMID- 29161643 TI - Effect of vacuum and modified atmosphere packaging on the microbiological, chemical and sensory properties of tropical red drum (Sciaenops ocellatus) fillets stored at 4 degrees C. AB - AIMS: The effect of vacuum (VP - 4 degrees C) and CO2/N2-atmosphere (MAP - 4 degrees C) packaging on the quality of red drum fillets compared with whole gutted iced fish was investigated. METHODS AND RESULTS: A metagenomic approach, bacterial enumeration and isolation, biochemical and sensory analyses were carried out. The organoleptic rejection of whole fish was observed at day 15 whereas VP and MAP fillets appeared unacceptable only after 29days. At these dates, total mesophilic counts reached 107-108CFU g-1. According to Illumina MiSeq sequencing, Arthrobacter, Chryseobacterium, Brevibacterium, Staphylococcus and Kocuria were the main genera of the fresh red drum fillets. At the sensory rejection time, lactic acid bacteria (LAB), particularly Carnobacterium sp., dominated the microbiota of both types of packaging. The pH value of fresh samples was between 5.96 and 6.37 and did not vary greatly in all trials. Total volatile basic nitrogen (TVBN) and trimethylamine (TMA) concentrations were low and not represent reliable indicators of the spoilage, contrary to some biogenic amines (cadaverine, putrescine and tyramine). CONCLUSION: Chilled packed fillets of red drum have an extended shelf-life compared to whole gutted iced fish. Overall, few differences in sensory and microbial quality were observed between the VP and MAP samples. SIGNIFICANCE AND IMPACT OF THE STUDY: Next-Generation Sequencing (NGS) provided data on the microbiota of a tropical fish. PMID- 29161645 TI - The impact of domestic violence exposure on South Asian children in the United States: Perspectives of domestic violence agency staff. AB - The South Asian community is the fastest growing ethnic group in the United States, and past research suggests that South Asian domestic violence (DV) survivors may require culturally-specific resources. Similarly, South Asian children in the US exposed to DV may have unique responses and needs, but this has not been explored to date. The objective of this study was to examine the specific needs of South Asian children exposed to DV from the vantage point of staff from South Asian DV agencies across the United States. Thirty interviews were conducted, with data coded and consolidated into larger themes using thematic analysis. Participants described several factors important to understanding the impact of DV on South Asian children including the role of the extended family, identifying with two cultures, fear about what the South Asian community will think, gender differences, and the importance of projecting an image of perfection. Participants also discussed development of culturally tailored resources. This study suggests the importance of framing South Asian children's experiences within the context of interweaving South Asian and American cultural values, with careful attention paid to how potential culture clashes between parents and children may impact the way children process trauma. Further work should triangulate these themes with children, parents, and extended family, as well as collaborate with South Asian DV agencies to design child focused programs. PMID- 29161644 TI - Treatment of industrial estate wastewater by the application of electrocoagulation process using iron electrodes. AB - In this study electrocoagulation (EC) of industrial estate wastewater taken from the inlet of wastewater treatment plant was investigated using sacrificial iron electrodes. Employing a pole changer to homogenous consumption of electrodes, studies on the parameters such as current density, supporting electrolyte concentration and initial pH, which have significant effects on COD removal and hence the energy consumption, were performed. Hydrogen peroxide was used in different concentrations to observe its effects on COD removal efficiency and the energy consumption. Sludge productions were also calculated for all experiments. COD removal efficiency of ~92% was obtained at the best experimental conditions (i = 30 mA/cm2, SE = 3 mM Na2SO4, pH = original pH (~6) of the wastewater, 1500 mg/L H2O2) with an energy cost of ?3.41/m3 wastewater treated and the sludge production of 5.45 g per g COD removed. PMID- 29161646 TI - Antimicrobial colloidal hydrogels assembled by graphene oxide and thermo sensitive nanogels for cell encapsulation. AB - Hydrogels are promising 3D materials that have demonstrated increasing applications in the encapsulation and delivery of drugs and cells. Herein we report an injectable colloidal hydrogel that directly assembled by graphene oxide (GO) and thermo-sensitive nanogels (tNG). The pH dependent hydrogen bonding interactions between the carboxyl and oxethyl groups induce the reversible assembly of GO and nanogels. The hydrogel is mouldable and can be shaped into different macroscopic objects, and the mechanical strengths are tunable with pH and temperature adjustment. The hybrid hydrogel by its own possesses high antibacterial activity, and demonstrates responsive drug release behaviour and high viability of 3D encapsulated cells. We expect this hybrid colloidal hydrogel can serve as an interesting scaffold for active cargo delivery and cell culture. PMID- 29161647 TI - Simple synthesis of self-supported hierarchical AuPd alloyed nanowire networks for boosting electrocatalytic activity toward formic acid oxidation. AB - Herein, self-supported hierarchical AuPd alloyed interconnected nanowire networks (AuPd NCNs) were fabricated by a one-pot co-reduction method. Theophylline was acted as the capping and structure-directing agents. The product was mainly characterized by a series of techniques such as transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The hierarchical nanostructures had the enlarged electrochemically active surface area (EASA), and the enhanced catalytic activity toward formic acid oxidation reaction (FAOR) and strengthened poisoning tolerance for poisoning CO-like intermediates by cyclic voltammetry and chronoamperometry, which outperformed commercial Pd black catalyst. This strategy supplies a simple and general method for mass preparation of AuPd NCNs with potential applications in fuel cells. PMID- 29161648 TI - Derivation and characterization of the NYSCFe003-A human embryonic stem cell line. AB - The human embryonic stem cell line NYSCFe003-A was derived from a day 5 to day 6 blastocyst in feeder-free and antibiotic free conditions. The blastocyst was voluntarily donated for research as surplus after in vitro fertilization treatment following informed consent. The NYSCFe003-A line expresses all the pluripotency markers and has the potential to differentiate into all three germ layers in vitro. The line presents normal karyotype and is mycoplasma free. PMID- 29161649 TI - Magic angle spinning NMR below 6 K with a computational fluid dynamics analysis of fluid flow and temperature gradients. AB - We report magic angle spinning (MAS) up to 8.5 kHz with a sample temperature below 6 K using liquid helium as a variable temperature fluid. Cross polarization 13C NMR spectra exhibit exquisite sensitivity with a single transient. Remarkably, 1H saturation recovery experiments show a 1H T1 of 21 s with MAS below 6 K in the presence of trityl radicals in a glassy matrix. Leveraging the thermal spin polarization available at 4.2 K versus 298 K should result in 71 times higher signal intensity. Taking the 1H longitudinal relaxation into account, signal averaging times are therefore predicted to be expedited by a factor of >500. Computer assisted design (CAD) and finite element analysis were employed in both the design and diagnostic stages of this cryogenic MAS technology development. Computational fluid dynamics (CFD) models describing temperature gradients and fluid flow are presented. The CFD models bearing and drive gas maintained at 100 K, while a colder helium variable temperature fluid stream cools the center of a zirconia rotor. Results from the CFD were used to optimize the helium exhaust path and determine the sample temperature. This novel cryogenic experimental platform will be integrated with pulsed dynamic nuclear polarization and electron decoupling to interrogate biomolecular structure within intact human cells. PMID- 29161650 TI - How the morphological properties of Mentha longifolia.(L.) Huds. may be affected by geographical differences. AB - With respect to the benefits of medicinal plants for human health and their use as food, they are extensively being researched and planted in different parts of the world including Iran. Among the most important parameters, which may affect the growth and the yield of medicinal plants is their geographical (ecotype) properties. Accordingly, a research work was proposed to investigate the effects of 10 different regions or ecotypes on the morphological properties of pennyroyal [Mentha longifolia. (L.) Huds.] from the Lamiaceae family in one of the Iranian provinces, namely Ilam. According to the geographical characteristics of the experimental province, the longitudes were in the range of 60-65 degrees , the latitudes varied from 36-37 degrees and the heights above the sea level were in the range of 860-1410m. The experiment was a completely randomized block design in three replicates and for each plant ecotype, 20 plant samples in three replicates were collected. Different plant morphological properties related to plant stem, leaf, inflorescence, rhizome, and dry weight were determined. Data were subjected to analysis of variance and different plant statistical properties were determined. Using the Ward's method, the cluster analysis of data was also conducted and similar ecotypes were grouped. Data indicated the significant effects of regional (ecotype) differences on plant morphological properties and dry weight. The highest stem length was related to the Alamdar region (90cm), stem diameter and leaf number to Kolm region at 0.76cm and 128, respectively, leaf length to Chenarbashi at 4.07cm, leaf width to Helaesm at 2.83cm, inflorescence number and length to Sarab at 22.10 and 11.63cm, respectively, inflorescence width to Kolm at 1.04cm, rhizome length to Mishkhas at 11.00cm, and rhizome width to Kolm at 1.03cm. The highest dry weights were resulted by Siahkal (260g), Kolm (205g) and Chemarbashi (220g). Interestingly, stem length (22.17), inflorescence width (12.12) and rhizome length (27.11) indicated the least rate of coefficient of variation and had the highest effects on plant growth and yield production. Data indicated how geographical and soil properties (such as organic matter) may affect pennyroyal growth and yield. Such analyses can be used for the selection and the subsequent domestication of wild populations of pennyroyal with the highest efficiency. PMID- 29161651 TI - Enhanced anticancer effect of fabricated gallic acid/CdS on the rGO nanosheets on human glomerular mesangial (IP15) and epithelial proximal (HK2) kidney cell lines - Cytotoxicity investigations. AB - In spite of the technological innovation in the biomedical science, cancer remains a critical disease. In this study, we designed a gallic acid/cadmium sulfide (GA/CdS) nanocomposite fabricated on the reduced graphene oxide (GA/CdS rGO) nanosheets for the treatment system of human kidney cancer cells. The GA/CdS rGO nanosheets have been prepared using gallic acid as a reducing agent. The characterization of nanocomposites was studied using UV-Vis spectroscope, FT-IR, XRD, SEM and TEM. The microscopic images showed the spherical shape and nano scaled CdS nanoparticles on the sheet like rGO nanomaterials. These structural and morphology investigations show that excellent properties of as-prepared GA/CdS-rGO has ability to treat the human glomerular mesangial (IP15) cancer cells at 50MUg/ml as an IC50 value, without affecting the epithelial proximal (HK 2) normal cells. In vitro cytotoxicity results showed that the variability of toxic effects after CdS exposure was strongly associated to the cellular Cd content. Release of Cd2+ from nanocomposites depended to solubility and particle degradation of CdS nanoparticles were considered to be the main cause of these cytotoxicity. The in vitro analysis results indicated that heterogeneity of Cd and gallic acid toxicity that was highly dependent on the physico-chemical properties of the nanocomposites. The cytotoxicity results suggested that the prepared nanomaterials were toxic and inhibitory efficiency to human kidney cancer cells. PMID- 29161652 TI - Impact of body mass index on the clinical outcomes of patients with HER2-positive metastatic breast cancer. AB - BACKGROUND: Overweight and obesity are associated with an increased risk of developing many types of cancer, including breast cancer. Moreover, increased body mass index (BMI) seems to be associated with a worse prognosis in patients with HER2-positive early breast cancer. However, little is known about the impact of BMI on the clinical outcomes of HER2-positive metastatic breast cancer (MBC). METHODS: This was a multicenter retrospective cohort study including 329 consecutive patients with HER2-positive MBC treated with first-line trastuzumab based regimens. BMI at the time of MBC diagnosis was collected. World Health Organization BMI categories were used: underweight <18.5, normal 18.5-24.9 Kg/m2, overweight 25-29.9 Kg/m2, and obese >=30 Kg/m2. The analyses were conducted using two categories: BMI < 25.0 (normal/underweight) and BMI >= 25 (overweight/obese). Progression-free survival (PFS) and overall survival (OS) rates were estimated using Kaplan-Meier method. Univariate and multivariate survival analyses were performed using the Cox's proportional hazards model. Disease response to therapy was analyzed using univariate and multivariate logistic regression. RESULTS: Overall, 176 (53.5%) patients were normal/underweight and 153 (46.5%) overweight/obese. Median PFS was 14.8 months in BMI < 25 group and 15.7 months in BMI >= 25 group (adjusted-HR 0.88; 95% CI 0.66-1.17; p = 0.387). Median OS was 58.6 months in BMI < 25 group and 52.6 in BMI >= 25 group (adjusted-HR 0.88; 95% CI 0.59-1.31; p = 0.525). Overall response rate was 71.7% and 65.9% (p = 0.296) and clinical benefit rate was 82.1% and 83.3% (p = 0.781) in BMI < 25 and BMI >= 25 groups, respectively. CONCLUSIONS: BMI does not seem to be associated with clinical outcomes in HER2-positive MBC patients. PMID- 29161653 TI - Psychosocial issues of a population approach to high genetic risk identification: Behavioural, emotional and informed choice issues. AB - To allow women at high genetic risk of breast cancer to benefit from prevention or early prevention strategies, a screening programme is required to identify them. The present review considers the likelihood of key outcomes that would arise from such a programme, in relation to behavioural, emotional and informed choice outcomes. The likelihood of outcomes in each category is considered in relation to the limited direct evidence and relevant indirect evidence, given the dearth of studies that have directly studied the effects of communication of personal genetic risk of breast cancer. Overall, there is promise that such a programme would have several behavioural benefits, such as good uptake of increased screening in women at high risk but little effect on screening in women at low risk. The available evidence suggests that major adverse effects on emotional outcomes are unlikely. There is very limited evidence in this developing area on the extent to which decisions of women offered breast cancer risk estimation will be fully informed choices. Recommendations are made for increasing benefits and reducing harms of population-wide breast cancer risk estimation in light of current evidence. Key research gaps are identified. PMID- 29161654 TI - Prevalence of various environmental intolerances in a Swedish and Finnish general population. AB - OBJECTIVE: To determine the prevalence of various environmental intolerances (EIs), using several criteria in a Swedish and a Finnish general population. Ill health attributed to low-level environmental exposures is a commonly encountered challenge in occupational and environmental medicine. METHODS: In population based questionnaire surveys, the Vasterbotten Environmental Health Study (Sweden) and the Osterbotten Environmental Health Study (Finland), EI was inquired by one item questions on symptom attribution to chemicals, certain buildings, or electromagnetic fields (EMFs), and difficulties tolerating sounds. The respondents were asked whether they react with central nervous system (CNS) symptoms or have a physician-diagnosed EI attributed to the corresponding exposures. Prevalence rates were determined for different age and sex groups and the Swedish and Finnish samples in general. RESULTS: In the Swedish sample (n = 3406), 12.2% had self-reported intolerance to chemicals, 4.8% to certain buildings, 2.7% to EMFs, and 9.2% to sounds. The prevalence rates for the Finnish sample (n = 1535) were 15.2%, 7.2%, 1.6%, and 5.4%, respectively, differing statistically significantly from the Swedish. EI to chemicals and certain buildings was more prevalent in Finland, while EI to EMFs and sounds more prevalent in Sweden. The prevalence rates for EI with CNS-symptoms were lower and physician-diagnosed EIs considerably lower than self-reported EIs. Women reported EI more often than men and the young (18-39 years) to a lesser degree than middle aged and elderly. CONCLUSIONS: The findings reflect the heterogeneous nature of EI. The differences in EI prevalence between the countries might reflect disparities concerning which exposures people perceive harmful and focus their attention to. PMID- 29161655 TI - The association between ambient temperature and mortality in South Africa: A time series analysis. AB - BACKGROUND: There is an extensive literature describing temperature-mortality associations in developed regions, but research from developing countries, and Africa in particular, is limited. METHODS: We conducted a time-series analysis using daily temperature data and a national dataset of all 8.8 million recorded deaths in South Africa between 1997 and 2013. Mortality and temperature data were linked at the district municipality level and relationships were estimated with a distributed lag non-linear model with 21 days of lag, and pooled in a multivariate meta-analysis. RESULTS: We found an association between daily maximum temperature and mortality. The relative risk for all-age all-cause mortality on very cold and hot days (1st and 99th percentile of the temperature distribution) was 1.14 (1.10,1.17) and 1.06 (1.03,1.09), respectively, when compared to the minimum mortality temperature. This "U" shaped relationship was evident for every age and cause group investigated, except among 25-44 year olds. The strongest associations were in the youngest (< 5) and oldest (> 64) age groups and for cardiorespiratory causes. Heat effects occurred immediately after exposure but diminished quickly whereas cold effects were delayed but persistent. Overall, 3.4% of deaths (~ 290,000) in South Africa were attributable to non optimum temperatures over the study period. We also present results for the 52 district municipalities individually. CONCLUSIONS: An assessment of the largest ever dataset for analyzing temperature-mortality associations in (South) Africa indicates mortality burdens associated with cold and heat, and identifies the young and elderly as particularly vulnerable. PMID- 29161656 TI - Comparing objective measures of the built environment in their associations with youth physical activity and sedentary behavior across heterogeneous geographies. AB - We compared two strategies for measuring built environment features in their associations with youth physical activity and sedentary behavior across heterogeneous geographies of Pennsylvania. Physical activity environments of communities representing a rural-to-urban gradient were characterized through direct observation and spatially referenced archival data subjected to confirmatory factor analysis. Stratified regression analyses assessed associations between environmental measures and behavioral outcomes by community type. Neither strategy was consistently associated with behavior across communities. Findings highlight the importance of differentiating community type in evaluating associations of the built environment, and the challenge of measuring meaningful differences that influence youth behavior across heterogeneous geographies. PMID- 29161657 TI - Effects of local lipopolysaccharide administration on the expression of Toll-like receptor 4 and pro-inflammatory cytokines in uterus and oviduct of rabbit does. AB - Inflammation of the uterus and oviduct is associated with reduced reproductive performance in humans and domestic animals. Toll-like receptors are expressed in various immune and non-immune cells and play a crucial role in innate immunity. Toll-like receptor - 4 (TLR4) can detect lipopolysaccharide (LPS) from Gram negative bacteria leading to the secretion of pro-inflammatory cytokines, chemokines, antimicrobial peptides and other inflammatory mediators. To investigate the effects of a local inflammation on the expression levels of TLR4 and pro-inflammatory cytokines, 12 female rabbits received an intracervical infusion with either saline solution endotoxin-free (carrier, 2 mL; n = 6) or LPS (500 MUg diluted in 2 mL of saline solution; n = 6). Blood samples were performed at 0, 30, 60 and 90 min and 2,4,6 and 24 h after treatment to evaluate interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) plasma concentrations. Animals were sacrificed 24 h post-treatment. The uterus and oviducts were immediately collected. The gene expression and protein levels of TLR4 and pro-inflammatory cytokines were detected by quantitative real-time PCR (qRT-PCR) and immuno-histochemical assay, respectively. Our study showed that the intracervical administration of LPS induced local inflammation given that the animals showed no clinical signs, the histological samples revealed signs of inflammation and plasma levels of pro-inflammatory cytokines were unchanged compared to the control. LPS produced an increase in the TLR4 mRNA expression levels in the uterus with respect to the control (P < 0.05). In LPS-treated rabbits the gene expression of IL-1beta was higher in the uterus and oviducts and TNF-alpha only in the oviduct (P < 0.05) as compared to the control. The immuno histochemical assay showed that TLR4, IL-1beta and TNF-alpha were expressed in the reproductive tissues of the rabbit. Moreover, after the LPS stimulation the stromal cells of the uterus exhibited a higher staining for TLR4 (P < 0.05) and the epithelial cells of the oviduct for TNF-alpha and IL-1beta (P < 0.05) with respect to the control. These results suggest that (1) TRL4, IL-1beta and TNF alpha are expressed in uterus and oviducts of the doe, and (2) LPS up-regulates the gene and protein expression of TLR4 and pro-inflammatory cytokines in uterus and oviducts. Therefore, the rabbit could be a useful animal model for studying the local mechanisms involved in reproductive dysfunctions caused by subclinical infections. PMID- 29161658 TI - Reproductive performance of lactating dairy cows after inducing ovulation using hCG in a five-day progesterone-based fixed-time AI protocol. AB - This study compares the effects of inducing ovulation using human chorionic gonadotropin (hCG) or gonadotropin releasing hormone (GnRH) at the end of a 5-day progesterone(P4)-based protocol for fixed-time artificial insemination (FTAI) in lactating dairy cows on ovarian dynamics and fertility. A P4 intravaginal device (PRID) was fitted for five days and GnRH administered upon PRID insertion and a double dose (24 h apart) of prostaglandin F2alpha upon PRID removal. Cows received either GnRH (GnRH group; n = 98), 1000 IU hCG (hCG-1 group; n = 97), or 3000 IU hCG (hCG-2 group; n = 104) 36 h after PRID removal and were inseminated 50-56 h after PRID removal. Based on Tukey-Kramer tests, cows in hCG-1 and hCG-2 showed a larger follicle diameter at AI than cows in GnRH (P < 0.05). HCG-2 treatment increased corpus luteum (CL) size on Day 7 post-AI compared with the GnRH and hCG-1 treatments (P < 0.05). Based on odds ratios, the likelihood of ovulation failure decreased with increasing follicle diameter at AI (P = 0.002). Cows in hCG-1 or hCG-2 that did not become pregnant were more likely to return to estrus than cows in GnRH (P < 0.01). A larger CL size post-AI was related to an increased conception rate at FTAI (P = 0.003). Cows given hCG-2 treatment showed a 1.9-fold cumulative pregnancy rate after two rounds of AI compared to cows receiving GnRH. Our results indicate that hCG treatment hCG treatment used to induce ovulation at the end of a short protocol for FTAI improves follicular/luteal dynamics compared to GnRH treatment. Of the two hCG treatments tested, better results were obtained with the 3000 IU dose. PMID- 29161659 TI - Lipopolysaccharide (LPS)-mediated priming of toll-like receptor 4 enhances oxidant-induced prostaglandin E2 biosynthesis in primary murine macrophages. AB - Agonists and pseudo-agonists for toll-like receptor 4 (TLR4) are common in our environment. Thus, human exposure to these agents may result in "priming or sensitization" of TLR4. A body of evidence suggests that LPS-mediated sensitization of TLR4 can increase the magnitude of responses to exogenous agents in multiple tissues. We have previously shown that reactive oxygen and nitrogen species (RONS) stimulate TLR4. There is no evidence that LPS-primed TLR4 can influence the magnitude of responses to oxidants from either endogenous or exogenous sources. In the present study, we directly tested the hypothesis that LPS-primed TLR4 will sensitize primary murine peritoneal macrophages (pM) to oxidant-mediated prostaglandin E2 (PGE2) production. We used potassium peroxychromate (PPC) and potassium peroxynitrite (PPN) as direct in vitro sources of exogenous RONS. Our results showed that a direct treatment with PPC or PPN alone as sources of exogenous oxidants had a limited effect on PGE2 biosynthesis. In contrast, pM sensitized by prior incubation with LPS-EK, a TLR4-specific agonist, followed by oxidant stimulation exhibited increased transcriptional and translational expression of cyclooxygenase-2 (COX-2) with enhanced PGE2 biosynthesis/production only in pM derived from TLR4-WT mice but not in TLR4-KO mice. Thus, we have shown a critical role for LPS-primed TLR4 in oxidant-induced inflammatory phenotypes that have the potential to initiate, propagate and maintain many human diseases. PMID- 29161660 TI - Molecular mechanisms of anti-inflammatory effect of chrysophanol, an active component of AST2017-01 on atopic dermatitis in vitro models. AB - AST2017-01 mainly consists of Rumex crispus and -Cordyceps militaris and has been widely consumed as an herbal medicine or functional food in Korea. Here we investigated the influences of AST2017-01 and its active component, chrysophanol on human mast cell (HMC-1 cell) and human keratinocyte (HaCaT cell)-mediated inflammatory reactions. Pretreatment with AST2017-01 or chrysophanol suppressed intracellular calcium levels and histamine release in phorbol 12-myristate 13 acetate and calcium ionophore A23187 (PMACI)-treated HMC-1 cells. Levels of phosphorylated-mitogen-activated protein kinase increased by PMACI stimulation were reduced by AST2017-01 or chrysophanol pretreatment. Protein levels of IkappaB kinasebeta and receptor-interacting protein 2 in PMACI-treated HMC-1 cells were decreased by AST2017-01 or chrysophanol pretreatment. Pretreatment with AST2017-01 or chrysophanol significantly blocked PMACI-induced activation of caspase-1 and nuclear factor-kappaB. In addition, pretreatment with AST2017-01 or chrysophanol significantly decreased the PMACI-induced levels of interleukin (IL) 1beta, IL-6, tumor necrosis factor-alpha, and thymic stromal lymphopoietin (TSLP) on HMC-1 cells. In activated HaCaT cells, pretreatment with AST2017-01 or chrysophanol significantly reduced production of TSLP and activation of caspase 1. In conclusion, these findings indicate that chrysophanol is an active component of AST2017-01 and AST2017-01 acts as a novel potent anti-inflammatory herbal medicine or functional food. PMID- 29161661 TI - Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NF-KB pathways. AB - Oxidative and inflammatory damage have been suggested to play important roles in the pathogenesis of diabetic nephropathy (DN). Chlorogenic acid (CGA) is one of the most abundant polyphenols and has known immunoprotective, antioxidant and anti-inflammatory properties. In the present study, animal experiments were designed to examine the protective effects of CGA in DN, and cellular experiments were designed to explore the underlying mechanisms. CGA significantly attenuated diabetic renal damage based on histological pathology and molecular biological methods. Pre-treatment with CGA increased the nuclear translocation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) and reduced the phosphorylation of IKB and subsequent nuclear translocation of nuclear factor kappa beta (NF-KB). Nrf2 small interfering RNA (siRNA) and the HO-1 inhibitor zinc protoporphyrin (ZnPPIX) significantly increased the nuclear translocation of NF-KB and the production of pro inflammatory cytokines in HBZY-1 cells. The NF-KB inhibitor pyrrolidine dithiocarbamate (PDTC) increased Nrf2 nuclear translocation and HO-1 expression and antioxidant levels. Thus, these results suggest that CGA is a potential therapeutic agent in the treatment of DN due to its antioxidant and anti inflammatory effects which are mediated via the modulation of the Nrf2/HO-1 and NF-KB pathways. Moreover, CGA-induced the activation of Nrf2/HO-1,which interacts with the inhibition of NF-KB, as each begets and amplifies the other. PMID- 29161662 TI - Deiodination of iopamidol by zero valent iron (ZVI) enhances formation of iodinated disinfection by-products during chloramination. AB - Iodinated X-ray contrast media (ICM) is considered as one of iodine sources for formation of toxic iodinated disinfection byproducts (I-DBPs) during disinfection. This study investigated transformation of a typical ICM, iopamidol (IPM) by zero valent iron (ZVI) and the effect of transformation on the formation of I-DBPs during chloramination. It was found that the presence of ZVI could deiodinate IPM into I- and the transformation of IPM exhibited a pseudo-first order kinetics. Acidic circumstance, SO42-, Cl- and monochloramine could promote the transformation of IPM by ZVI, while SiO32- inhibited the transformation of IPM. Moreover, the transformation of IPM by ZVI changed both the formed species and amounts of I-DBPs during chloramination. During the chloramination of IPM containing water, CHCl2I and iodoacetic acid were the predominant iodinated trihalomethanes (I-THMs) and iodinated haloacetic acids (I-HAAs), respectively in the absence of ZVI, while CHI3 and triiodoacetic acid became the predominant ones with 1.0 g L-1 ZVI. The addition of 5.0 g L-1 ZVI increased I-DBPs formation amounts by 6.0 folds after 72 h and maximum formation of I-DBPs occurred at pH 5.0. Enhanced I-DBPs formation was also observed with various real water sources. Given that ZVI ubiquitously exists in the unlined cast iron distribution pipes, the deiodination of IPM by ZVI during distribution may increase the formation of I-DBPs, which needs receive enough attention. PMID- 29161663 TI - Quantifying the flow efficiency in constant-current capacitive deionization. AB - Here we detail a previously unappreciated loss mechanism inherent to capacitive deionization (CDI) cycling operation that has a substantial role determining performance. This mechanism reflects the fact that desalinated water inside a cell is partially lost to re-salination if desorption is carried out immediately after adsorption. We describe such effects by a parameter called the flow efficiency, and show that this efficiency is distinct from and yet multiplicative with other highly-studied adsorption efficiencies. Flow losses can be minimized by flowing more feed solution through the cell during desalination; however, this also results in less effluent concentration reduction. While the rationale outlined here is applicable to all CDI cell architectures that rely on cycling, we validate our model with a flow-through electrode CDI device operated in constant-current mode. We find excellent agreement between flow efficiency model predictions and experimental results, thus giving researchers simple equations by which they can estimate this distinct loss process for their operation. PMID- 29161664 TI - Sandwich-type biosensor for the detection of alpha2,3-sialylated glycans based on fullerene-palladium-platinum alloy and 4-mercaptophenylboronic acid nanoparticle hybrids coupled with Au-methylene blue-MAL signal amplification. AB - alpha2,3-sialylated glycans (alpha2,3-sial-Gs) are one of the significant tumour biomarkers for the early diagnosis of cancer. In this work, a neoteric sandwich type biosensor was developed for detecting alpha2,3-sial-Gs using 4 mercaptophenylboronic acid (4-MPBA) to construct a novel molecular recognition system by the coordination of a boron atom of 4-MPBA to the amide group of Neu5Ac in the alpha2,3-sial-Gs structure. Amino-functionalized fullerene coupled with palladium-platinum bimetallic alloy nanocrystals (n-C60-PdPt) was synthesized to modify the surface of a glassy carbon electrode (GCE) because the n-C60 nanomaterial affords a large surface area for the on-site reduction of bimetallic alloy nanoparticles and an excellent capacity for electron transfer. Abundant 4 MPBA were immobilized on the n-C60-PdPt, since the 4-MPBA has the mercapto group can combine with PdPt alloy through strong adsorption. Maackia amurensis lectin (MAL) was covalently immobilized on Au-poly (methylene blue) (Au-PMB) acting as the signal amplification components, which was used to recognize the alpha2, 3 sial-Gs specifically like a second antibody linked on Au-PMB. The differential pulse voltammetry (DPV) current response of the biosensor in 5mL of PBS (0.1M, pH = 7.4) was recorded, and the proposed sandwich-type biosensor showed a wide linear range of 10 fg mL-1 -100ngmL-1 as well as, a low detection limit of 3fgmL 1 (S/N = 3). Furthermore, the proposed method exhibited good recovery and stability, indicating its potential for use in clinical studies. PMID- 29161665 TI - Switchable electrochemiluminescence aptasensor coupled with resonance energy transfer for selective attomolar detection of Hg2+ via CdTe@CdS/dendrimer probe and Au nanoparticle quencher. AB - In the present study, an ultrasensitive electrochemiluminescence (ECL) aptasensing assay for selective detection of Hg2+ was designed. In this electrochemiluminescence resonance energy transfer (ECL-RET) approach, Fe3O4@SiO2/dendrimers/QDs exhibited amplified ECL emissions (switch "on" state) and with the hybridization between T-rich ssDNA(S1) immobilized on the Fe3O4@SiO2/dendrimers/QDs and AuNPs modified with complementary aptamer (AuNPs S2), the ECL of QDs nanocomposites was efficiently quenched (switch "off" state). In the presence of Hg2+ ions, formation of strong and stable T-Hg2+-T complex led to the release of the AuNPs-S2 from double-stranded DNA(dsDNA) and the recovery of the ECL signal of QDs (second signal switch "on" state). Under optimal conditions, Hg2+ can be detected in a wide linear range from 20aM to 2uM with a very low detection limit of 2aM. The proposed ECL aptasensor showed high selectivity for Hg2+ determination compared to other environmentally relevant metal ions at concentration ratio more than 1000 times. The aptasensor was used for detection Hg2+ ions from samples of tap waters, carp and saltwater fishes with satisfactory results. The aptasensor exhibited high sensitivity, wide linear response (11 orders of magnitude), excellent reproducibility and stability. The proposed aptasensor will be a promising candidate for facile and rapid determination of Hg2+in environmental and fishery samples. PMID- 29161666 TI - Genetic variants and acute kidney injury: A review of the literature. AB - PURPOSE: Limited data exists on potential genetic contributors to acute kidney injury. This review examines current knowledge of AKI genomics. MATERIALS AND METHODS: 32 studies were selected from PubMed and GWAS Catalog queries for original data studies of human AKI genetics. Hand search of references identified 3 additional manuscripts. RESULTS: 33 of 35 studies were hypothesis-driven investigations of candidate polymorphisms that either did not consistently replicate statistically significant findings, or obtained significant results only in few small-scale studies. Vote-counting meta-analysis of 9 variants examined in >1 candidate gene study showed >=50% non-significant studies, with larger studies generally finding non-significant results. The remaining 2 studies were large-scale unbiased investigations: One examining 2,100 genes linked with cardiovascular, metabolic, and inflammatory syndromes identified BCL2, SERPINA4, and SIK3 variants, while a genome-wide association study (GWAS) identified variants in BBS9 and the GRM7|LMCD1-AS1 intergenic region. All studies had relatively small sample sizes (<2300 subjects). Study heterogeneity precluded candidate gene and GWA meta-analysis. CONCLUSIONS: Most studies of AKI genetics involve hypothesis-driven (rather than hypothesis-generating) candidate gene investigations that have failed to identify contributory variants consistently. A limited number of unbiased, larger-scale studies have been carried out, but there remains a pressing need for additional GWA studies. PMID- 29161667 TI - Pre-hospital frailty and hospital outcomes in adults with acute respiratory failure requiring mechanical ventilation. AB - PURPOSE: We aimed to estimate the independent effect of pre-hospital frailty (PHF) on hospital mortality and prolonged hospital length of stay (pLOS) while adjusting for other patient level factors. METHODS: This is a cohort study of hospitalized adults with acute respiratory failure (ARF) who required invasive mechanical ventilation for >=24h in 2013. We used inpatient/outpatient claims from a list of diagnoses from the year before index hospital admission to define PHF. Differences in characteristics/outcomes by PHF were explored using descriptive statistics; multivariable logistic regression was used to estimate association between PHF and hospital outcomes. RESULTS: Among 1157 patients (mean age (standard deviation) 67.1 [16.4]), 53.2% had PHF. PHF was independently associated with higher hospital mortality (44.2% in PHF patients vs. 34.6% in those without, adjusted Odds Ratio (aOR) (95% Confidence Interval [CI] 1.56 (1.19 2.05), p<0.001). PHF was also significantly associated with pLOS in hospital survivors (55.5% PHF patients had pLOS versus 34.2% in those without, aOR (95% CI) 2.61 (1.87-3.65), p<0.001). CONCLUSIONS: PHF, identified by frailty diagnoses from before index hospitalization, may be a useful approach for identifying adults with ARF at increased risk of hospital mortality and pLOS. PMID- 29161668 TI - Patterns of C-reactive protein ratio response to antibiotics in pediatric sepsis: A prospective cohort study. AB - PURPOSE: Evaluate sequential C-reactive protein (CRP) measurements and patterns of CRP-ratio response to antibiotic therapy during first 7days in Pediatric Intensive Care Unit (PICU) of septic children. METHODS: Prospective, cohort study of children (1month-12years) admitted at 3 PICUs, with diagnosis of sepsis with <72h course. CRP-ratio was calculated in relation to D0_CRP value. Children were classified according to an individual pattern of CRP-ratio response: fast - CRP_D4 of therapy was <0.4 of D0_CRP; slow - continuous but slow decrease of CRP; non - CRP remained >=0.8 of D0_CRP; biphasic - initial CRP decrease to levels <0.8 of D0_CRP followed by secondary rise >=0.8. RESULTS: 103 septic children (age-median: 2yrs; 54% male) were prospectively included (infection focus: 65% respiratory, 12.5% central nervous system). Overall PICU mortality was 11.7%. 102 children could be classified according to a predefined CRP-ratio response pattern. Time-dependent analysis of CRP-ratio and CRP course of the different patterns were significantly different. Besides, PICU mortality rate was significantly different according CRP-ratio response patterns: fast response 4.5%; slow response 5.8%; non-response 29.4%; biphasic response 42.8%. CONCLUSIONS: In pediatric sepsis, CRP-ratio serial evaluation was useful in early identification of patients with poor outcome. PMID- 29161669 TI - The coastal environment affects lead and sodium uptake by the moss Hypnum cupressiforme used as an air pollution biomonitor. AB - Several studies suggest that potential competition exists between marine cations and heavy metals for binding sites on the cell wall of mosses. This competition would impact the heavy metal concentration measured in mosses by biomonitoring programs, which may underestimate air pollution by heavy metals in a coastal environment. In the present study, we aim to identify possible mechanisms affecting lead uptake by mosses in a coastal environment, specifically, the competition between lead (Pb2+) and sodium (Na+) for binding sites in Hypnum cupressiforme (Hc). We also compared the response of continental and coastal Hc populations to Pb2+ exposure by immersing the moss samples in artificial solutions that comprised six experimental treatments and subsequently locating and quantifying Pb2+ and Na+ using the sequential elution technique and X-ray microanalyses with a scanning electron microscope. We demonstrated that high concentrations of Pb2+ prevented Na+ from binding to the cell wall. We also examined the effect of the salt acclimation of Hc on Pb2+ and Na+ accumulation. Coastal Hc populations accumulated more Na and less Pb than continental Hc populations in all treatments. Moreover, our results showed treatment effects on the intra/extracellular distribution of Na+, as well as site. This feedback on the influence of salt stress tolerance on Pb2+ uptake by mosses requires further study and can be investigated for other heavy metals, leading to a better use of mosses as biomonitoring tools. PMID- 29161670 TI - Construction of plasmonic Ag modified phosphorous-doped ultrathin g-C3N4 nanosheets/BiVO4 photocatalyst with enhanced visible-near-infrared response ability for ciprofloxacin degradation. AB - To realize the full utilization of solar energy, the design of highly efficient photocatalyst with improved visible-near-infrared photocatalysis performance has attracted great attentions for environment pollutant removal. In this work, we rationally employed the surface plasmon resonance effect of metallic Ag in the phosphorus doped ultrathin g-C3N4 nanosheets (PCNS) and BiVO4 composites to construct a ternary Ag@PCNS/BiVO4 photocatalyst. It was applied for the photodegradation of ciprofloxacin (CIP), exhibiting 92.6% removal efficiency under visible light irradiation (lambda>420nm) for 10mg/L CIP, and presenting enhanced photocatalytic ability than that of single component or binary nanocomposites under near-infrared light irradiation (lambda>760nm). The improved photocatalytic activity of the prepared Ag@PCNS/BiVO4 nanocomposite can be attributed to the synergistic effect among the PCNS, BiVO4 and Ag, which not only improves the visible light response ability and hinders the recombination efficiency of the photogenerated electrons and holes, but also retains the strong the redox ability of the photogenerated charges. According to the trapping experiment and ESR measurements results, OH, h+ and O2- all participated in the photocatalytic degradation process. Considering the SPR effect of metallic Ag and the established local electric field around the interfaces, a dual Z-scheme electrons transfer mechanism was proposed. PMID- 29161671 TI - Effective removal of hazardous trace metals from recovery boiler fly ashes. AB - The objective of this study is to introduce a treatment sequence enabling straightforward and effective recovery of hazardous trace elements from recovery boiler fly ash (RBFA) by a novel method, and to demonstrate the subsequent removal of Cl and K with the existing crystallization technology. The treatment sequence comprises two stages: dissolution of most other RBFA components than the hazardous trace elements in water in Step 1 of the treatment, and crystallization of the process chemicals in Step 2. Solid-liquid separation has an important role in the treatment, due to the need to separate first the small solid residue containing the trace elements, and to separate the valuable crystals, containing Na and S, from the liquid rich in Cl and K. According to the results, nearly complete recovery of cadmium, lead and zinc can be reached even without pH adjustment. Some other metals, such as Mg and Mn, are removed together with the hazardous metals. Regarding the removal of Cl and K from the process, in this non optimized case the removal efficiency was satisfactory: 60-70% for K when 80% of sodium was recovered, and close to 70% for Cl when 80% of sulfate was recovered. PMID- 29161672 TI - Interpersonal trauma and hoarding: The mediating role of aggression. AB - BACKGROUND: A growing body of literature indicates that exposure to interpersonal trauma contributes to the onset or exacerbation of hoarding symptoms. However, little research has explored psychosocial factors that may help to explain the relationship between interpersonal trauma and hoarding symptoms. One outcome of trauma exposure that may be associated with hoarding symptoms is aggression, defined as the tendency to experience and express hostility and anger, and to engage in aggressive behavior. Therefore, the current study examined the relationship between hoarding and aggression, as well as the mediating role of aggression in the relationship between exposure to interpersonal trauma and hoarding symptoms. METHODS: Community participants (n = 258) completed a battery of questionnaires assessing trauma exposure, hoarding symptoms, aggression, and negative affect. RESULTS: Results revealed that when accounting for negative affect, hoarding symptoms were associated with greater aggression, and the relationship between exposure to interpersonal trauma and hoarding symptoms was mediated by aggression. Specificity analyses indicated that depression symptoms and emotion dysregulation did not mediate the relationship between interpersonal trauma exposure and hoarding, providing further support for the importance of aggression. LIMITATIONS: Findings should be interpreted in light of limitations, including the use of cross-sectional and self-report data, and a general community sample. CONCLUSIONS: Taken together, our findings suggest that interpersonal processes, such as aggression toward others, may be associated with increased hoarding symptoms. PMID- 29161673 TI - Reduced resting-state thalamostriatal functional connectivity is associated with excessive daytime sleepiness in persons with and without depressive disorders. AB - BACKGROUND: Excessive daytime sleepiness (EDS) is a common and significant problem encountered in affective illness, however, the biological underpinnings of EDS in persons with psychiatric disorders are not clear. This study evaluated the associations between thalamic connectivity with cortical and subcortical brain regions with EDS in persons with and without depressive disorders (DD). METHODS: Resting-state functional connectivity magnetic resonance imaging scans from 67 unmedicated young to middle-aged women with current DD (n = 30), remitted DD (n = 13), and healthy controls (n = 24) were utilized to examine the associations between thalamic connectivity with cortical/subcortical structures and EDS. RESULTS: After correction for multiple comparisons and adjustment for age, habitual sleep duration, and depressive symptomatology, reduced resting state connectivity between the bilateral thalamus and left rostral striatum (caudate/putamen) was significantly associated with EDS. LIMITATIONS: Causal inferences between thalamostriatal connectivity and EDS could not be determined. CONCLUSIONS: These results further implicate the role of the striatum and thalamus as central components of the experience of EDS. Further research is indicated to clarify the specific role these structures play in EDS in psychiatric disorders. PMID- 29161674 TI - Deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: A double-blinded randomized controlled study and long-term follow-up in eight patients. AB - BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) is an experimental approach in treatment-resistant depression (TRD). Short-term results of efficacy in DBS are incongruent and studies investigating long-term effects are warranted. METHODS: We assessed efficacy of SCG-DBS in eight patients randomized into a delayed-onset group (sham-DBS four weeks) and a non-delayed onset group. The primary outcome measure was improvement on the Hamilton Depression Rating-Scale (HAMD-24-item-version). Response was defined as HAMD-24 reduction of at least 50% compared to baseline. Assessment was double-blind for a period of eight weeks and after 6,- 12,- 24,- and 28,- months open-label. RESULTS: The average improvement in HAMD-24 scores after 6,- 12,- and 24-months were 34%, 25%, and 37%. After 6 months, HAMD-24 revealed a significant difference (P = .022) and 37.5% of the patients were responders. After 12 months, HAMD-24 scores dropped, but no significant difference was observed. After 24 months, a significant improvement was found (P = .041). After the four weeks lasting sham vs. DBS-ON period, there was no group difference (P = .376) in HAMD-24 and patients did not improve during sham stimulation. Patients were followed until 28 months and two up to 4 years under SCG-DBS and average response rate was 51%, whereas two patients were remitters (33,3%). LIMITATIONS: The small sample size limited the statistical power and external validity. CONCLUSIONS: Long-term improvement after SCG-DBS revealed a stable effect. There was no significant difference in response rates between the delayed and non-delayed-onset group. DBS for TRD remains experimental and longitudinal investigations of large samples are needed. PMID- 29161675 TI - A comparison of two digestion methods for assessing heavy metals level in urban soils influenced by mining and industrial activities. AB - A comparison between two digestion methods of hot plate Hossner (total-total) and USEPA method 3051 (total-recoverable) was carried out to suggest a proper method for determining nine heavy metals (Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb and Zn) content of three urban soils affected by mining (Mahd AD'Dahab) or industrial activities (Riyadh and Jubail) at Saudi Arabia. The results showed no significant differences between two digestion methods for Cd, Cu, Pb and Zn in soils affected by mining and for Cr, Cu, Pb and Zn in soils affected by industrial activities. Additionally, lower biases were obtained between two methods for metals Cd, Cu, Zn and Pb in the urban soil samples from mining area with the percent biases of 16.5%, +6.24%, -12.4% and +24.1%, respectively. The results also revealed that only Cu and Zn in the soil samples from Riyadh were extracted satisfactorily using USEPA 3051 with low biases of +5.69% and -9.61%, respectively. Meanwhile, only Pb in soil samples from Jubail showed lower baise between two methods with satisfactory biase of -8.07%. The correlation coefficients were significant between total-recoverable and total-total concentrations for Cu (r = 0.66), Pb (r = 0.72) and Cd (r = 0.65) in soil samples from mining area. Overall, concentrations of Co, Cr, Fe, Mn, and Ni that may show soil background concentrations were found higher by Hossner method than by USEPA 3051; thus, this suggests the addition of hydrofluoric acid (HF) is necessary for the determination of lithogenic metal concentrations. It could be concluded that the USEPA 3051 may be recommended and applied for total Cd, Cu, Pb and Zn originated from anthropogenic source in mining and industrial areas. PMID- 29161676 TI - Hydrophilic and positively charged polyethylenimine-functionalized mesoporous magnetic clusters for highly efficient removal of Pb(II) and Cr(VI) from wastewater. AB - We develop mesoporous magnetic clusters (MMCs) functionalized with hydrophilic branched polyethylenimine (b-PEI), later called b-MG, and MMCs functionalized with positively charged b-PEI (p-MG). These materials efficiently remove Pb(II) and Cr(VI) from wastewater. Fourier-transform infrared spectroscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis, and nitrogen adsorption desorption analysis results clearly indicate that hydrophilic b-PEI and positively charged b-PEI are successfully attached to the MMC surfaces. Wide angle X-ray diffraction, high-resolution transmission electron microscopy, and field-emission scanning electron microscopy analyses confirm that the crystal structures and morphologies of the MMCs are maintained well even when wet chemical modification processes are used to introduce hydrophilic b-PEI and positively charged b-PEI to the MMC surfaces. Langmuir and Sips isotherm models are applied to describe Pb(II) adsorption behavior of the b-MG and Cr(VI) adsorption behavior of the p-MG. The isotherm models indicate that the maximum adsorption capacities of b-MG and p-MG, respectively, are 216.3 and 334.1 mg g-1, respectively. These are higher than have previously been found for other adsorbents. In reusability tests, using magnetic separation and controlling the pH, the Pb(II) recovery efficiency of the b-MG is 95.6% and the Cr(VI) recovery efficiency of the p-MG is 68.0% even after the third cycle. PMID- 29161677 TI - Nanotechnology-based recent approaches for sensing and remediation of pesticides. AB - Pesticides are meant to control and destroy the pests and weeds. They are classified into different categories on the basis their origin and type of pest they target. Chemical pesticides such as insecticides, herbicides and fungicides are commonly used in agricultural fields. However, the excessive use of these agrochemicals have adverse effects on environment such as reduced population of insect pollinators, threat to endangered species and habitat of birds. Upon consumption; chemical pesticides also cause various health issues such as skin, eye and nervous system related problems and cancer upon prolonged exposure. Various techniques in the past have been developed on the basis of surface adsorption, membrane filtration and biological degradation to reduce the content of pesticides. However, slow response, less specificity and sensitivity are some of the drawbacks of such techniques. In recent times, Nanotechnology has emerged as a helping tool for the sensing and remediation of pesticides. This review focuses on the use of this technology for the detection, degradation and removal of pesticides. Nanomaterials have been classified into nanoparticles, nanotubes and nanocomposites that are commonly used for detection, degradation and removal of pesticides. The review also focuses on the chemistry behind the sensing and remediation of pesticides using nanomaterials. Different types of nanoparticles, viz. metal nanoparticles, bimetallic nanoparticles and metal oxide nanoparticles; nanotubes such as carbon nanotubes and halloysite nanotubes have been used for the detection, degradation and removal of pesticides. Further, various enzyme based biosensors for detection of pesticides have also been summarized. PMID- 29161678 TI - Preliminary evaluation of pathogenic bacteria loading on organic Municipal Solid Waste compost and vermicompost. AB - The use of composts or vermicomposts derived from organic fraction of Municipal Solid Waste (OFMSW) brought about certain disagreement in terms of high level of bacterial pathogens, thereby surpassing the legal restrictions. This preliminary study was undertaken to compare the evolution of pathogenic bacteria on OFMSW compost against vermicompost (generated by Eudrilus eugeniae) with promises of achieving sanitation goals. Analysis to quality data showed that OFMSW vermicomposting caused a moderately higher reduction in total coliforms in contrast to composting. E. coli in OFMSW composts was found to be in the range of 4.72-4.96 log10 CFU g-1 whilst on a clear contrary, E. coli was undetectable in the final vermicomposts (6.01-6.14 logs of reduction) which might be explained by the involvement of the digestive processes in worms' guts. Both OFMSW composts and vermicomposts generated Salmonella-free products which were acceptable for agricultural usage and soil improvement. In comparison to compost, the analysis of this research indicated that earthworm activity can effectively destroy bacterial pathogenic load in OFMSW vermicomposts. But still, this study necessitates extra research in order to comprehend the factors that direct pathogenic bacteria in vermicomposting and earthworm-free decomposition systems. PMID- 29161679 TI - The changes of nutrient composition of piled laying hen manure and anaerobic fermentation for recycling as a dietary ingredient for ruminants. AB - This study investigated the changes of nutrient compositions of piled laying hen manure, detected the physical and chemical components of laying hen manure fermented by mixed strains, and analysed its application effects on feeding ruminants. The results showed that with increasing of piling time, the contents of crude protein (CP) and ether extract (EE) in laying hen manure were reduced, while the contents of crude ash (CA), calcium (Ca) and phosphorus (P) were increased. Fermentation could effectively decrease pH value, reduce Ca/P ratio, lessen the total bacterial counts, and maintain the organisms contents in laying hen manure. The results of ruminants feeding test indicated that replacing 20% diet with laying hen manure fermentation products (MFP), the weight gain and reproductive rate were respectively decreased by 9.99% and 2% compared with the control group, and the differences were not statistically significant. This technology could recycle laying hen manures as ruminant feeds, for the purpose of reducing environmental pollution and improving economic efficiency. PMID- 29161680 TI - Prediction of violent crime on discharge from secure psychiatric hospitals: A clinical prediction rule (FoVOx). AB - BACKGROUND: Current approaches to assess violence risk in secure hospitals are resource intensive, limited by accuracy and authorship bias and may have reached a performance ceiling. This study seeks to develop scalable predictive models for violent offending following discharge from secure psychiatric hospitals. METHODS: We identified all patients discharged from secure hospitals in Sweden between January 1, 1992 and December 31, 2013. Using multiple Cox regression, pre specified criminal, sociodemographic, and clinical risk factors were included in a model that was tested for discrimination and calibration in the prediction of violent crime at 12 and 24 months post-discharge. Risk cut-offs were pre specified at 5% (low vs. medium) and 20% (medium vs. high). RESULTS: We identified 2248 patients with 2933 discharges into community settings. We developed a 12-item model with good measures of calibration and discrimination (area under the curve=0.77 at 12 and 24 months). At 24 months post-discharge, using the 5% cut-off, sensitivity was 96% and specificity was 21%. Positive and negative predictive values were 19% and 97%, respectively. Using the 20% cut-off, sensitivity was 55%, specificity 83% and the positive and negative predictive values were 37% and 91%, respectively. The model was used to develop a free online tool (FoVOx). INTERPRETATION: We have developed a prediction score in a Swedish cohort of patients discharged from secure hospitals that can assist in clinical decision-making. Scalable predictive models for violence risk are possible in specific patient groups and can free up clinical time for treatment and management. Further evaluation in other countries is needed. FUNDING: Wellcome Trust (202836/Z/16/Z) and the Swedish Research Council. The funding sources had no involvement in writing of the manuscript or decision to submit or in data collection, analysis or interpretation or any aspect pertinent to the study. PMID- 29161681 TI - Revisiting task orientated care: Oral histories of former student nurses in Ireland (1960-2001). AB - The apprenticeship model of nurse training was in place in Ireland up to the end of the twentieth century. Task orientated care was a feature of this model. It is important to examine task allocation from the student's perspective, in light of current and on-going debates regarding student nurses' supernumerary status. Both approaches influence the status of the student; as a worker with task allocation and as a learner with supernumerary status. Oral history interviews were undertaken with twelve former student nurses (1960-2001) to explore their experiences of clinical learning and task allocation. Task allocation consisted of household tasks and tasks involving patient care. Students' experiences were influenced more by issues surrounding the task, particularly the 'task-person', than the task itself. Therefore, a learning environment that is inclusive, supportive and understanding of students' learning is recommended, regardless of the model of nurse training or education that might be in place. These findings can inform current debate on supernumerary status and task allocation for the student nurse within their clinical learning environment, but also on the history of nurse education in Ireland in the twentieth century. PMID- 29161682 TI - Socioeconomic status disparities in late-life disability based on age, period, and cohort in Japan. AB - INTRODUCTION: Effects of disparities in socioeconomic status (SES) on late-life disabilities have been reported around the world. However, there are only a few studies that have examined age, period, and cohort dependent influences of SES disparities on late-life disabilities. We investigated associations between SES disparities and late-life disability based on the Age-Period-Cohort. We also investigated how macro-economic conditions unique to a period, or a cohort might explain the period or the cohort trends. METHODS: Data were obtained from people aged 65 and over that responded to the Comprehensive Survey of Living Conditions, which had been conducted every three years from 1989 to 2013. SES was assessed via household income. Disability was assessed as disabilities in performing Basic Activities of Daily Living (BADL). Income disparities were evaluated by the slope index of inequality (SII) and the relative index of inequality (RII). Each Age Period-Cohort dimension was simultaneously controlled using a model for cross classification of random effects. RESULTS: Differences in BADL disabilities due to income disparities decreased with age and reversed after approximately 80 years of age. Income disparities in BADL disability changed across periods, by increasing in periods with a high unemployment rate, which started two to four years before the period. Moreover, results of using SII and RII were nearly identical. CONCLUSIONS: Higher mortality in elderly with lower income might be related to a reduction of income disparities in BADL disability in Japan. Furthermore, exposure to harsh economic conditions might contribute to increased disparities in BADL disability a few years later. PMID- 29161683 TI - Out of the blue finger ischaemia and occult colorectal cancer. AB - A woman aged 66 years with a history of unprovoked deep venous thrombosis (DVT) presented with persistent digital ischaemic changes of 2 of her right hand fingers. Physical examination was otherwise normal and extensive laboratory and imaging studies were unremarkable. A history of unprovoked DVT and the current episode of digital ischaemia prompted concern for underlying occult malignancy. Repeated history-taking revealed a strongly positive family history suggesting an occult colorectal cancer. Colonoscopy with biopsy revealed adenocarcinoma. Adenocarcinoma of the colon has rarely been associated with paraneoplastic acral vascular syndrome. This report suggests that occult malignancy needs to be considered in patients with focal digital ischaemia as this association is poorly unrecognised. PMID- 29161684 TI - Higher versus Lower Continuous Renal Replacement Therapy Intensity in Critically ill Patients with Liver Dysfunction. AB - AIMS: To study the association between higher versus lower continuous renal replacement therapy (CRRT) intensity and mortality in critically ill patients with combined acute kidney injury and liver dysfunction. METHODS: Post-hoc analysis of patients with liver dysfunction (Sequential Organ Failure Assessment liver score >=2 or diagnosis of liver failure/transplant) included in the Randomized Evaluation of Normal versus Augmented Level renal replacement therapy (RENAL) trial. RESULTS: Of 444 patients, 210 (47.3%) were randomized to higher intensity (effluent flow 40 mL/kg/h) and 234 (52.7%) to lower intensity (effluent flow 25 mL/kg/h) therapy. Overall, 79 and 86% of prescribed effluent flow was delivered in the higher-intensity and lower-intensity groups, respectively (p < 0.001). In total, 113 (54.1%) and 120 (51.3%) patients died in each group. On multivariable Cox regression analysis, we found no independent association between higher CRRT intensity and mortality (HR 0.93, 95% CI 0.70-1.24; p = 0.642). CONCLUSIONS: In RENAL patients with liver dysfunction, higher CRRT intensity was not associated with reduced mortality. PMID- 29161685 TI - Intergenotype Recombination among New Norovirus GII.4 Variants in the Complete Genome. AB - GII.4 noroviruses (NoVs) are a major cause of acute gastroenteritis in humans. A new variant of GII.4, the Sydney variant, has recently become more prevalent on a global scale. Intragenotype recombinations are widespread within the pandemic NoV GII.4 lineage, and are likely to be important forces driving the evolution and emergence of novel GII.4 viruses. In this study, we sought to examine the role that intergenotype recombination has played in the emergence of GII.4 Sydney 2012 variants. The results show that the GII.4 Sydney 2012 variants, Kawasaki194 and CA3477, were intergenotype recombination NoV strains with a GII.4 capsid and a GII.P16 polymerase gene. It has been reported for the first time that GII.4 new variant recombinants come from intergenotype recombination of GII.P16 and GII.4 strains in the complete genome. PMID- 29161686 TI - Impact of an in-Hospital Patient Education Program on Choice of Renal Replacement Modality in Unplanned Dialysis Initiation. AB - BACKGROUND/AIMS: Up to 50% patients requiring dialysis receive an urgent, unplanned start (UPS) to renal replacement therapy (RRT). Most of these are initiated with an intravenous catheter and commenced and maintained on hemodialysis (HD). Although peritoneal dialysis (PD) could be an equipotent initial modality for RRT, it is used less frequently as long-term RRT in UPS patients. This multicenter-study aimed to evaluate the impact of a structured, in hospital education program and factors influencing PD rates, especially in UPS patients. METHODS: Three German nephrology departments collaborated to implement an in-hospital education program. Retrospective analysis included 336 subjects and compared the rates of HD and PD in consecutive patients who started RRT 12 months prior (two centers) and for 12 months after (three centers) implementing the education program. RESULTS: PD rates increased significantly (p < 0.05) by 66% in all planned and unplanned dialysis starts after implementation of a structured, patient-centered education program. A highly significant (p < 0.0001) rise in utilization of PD was found, especially in UPS patients. In logistic regression analysis, PD modality choice was significantly influenced by age (p < 0.0001) and gender (p = 0.006). CONCLUSIONS: A structured, patient-centered in hospital education program increases the frequency of PD in patients needing unplanned RRT. PD modality choice is significantly higher in young (p < 0.0001) and male (p = 0.006) patients. PMID- 29161687 TI - Obesity Knowledge among Final-Year Medical Students in Norway. AB - OBJECTIVES: To assess the level of obesity knowledge in final-year medical students in Norway and to compare it to an expert group and first-year medical students. METHODS: A 20-item questionnaire was specifically designed for this purpose (18 knowledge-based questions and 2 subjective questions looking at attitudes and self-perceived proficiency). All medical schools in Norway were included (n = 226). For comparison purposes, an expert group (n = 13) and first year medical students (n = 96) were included. RESULTS: Experts (81%; 15 out of 18 (13.5-16.0)) scored significantly higher than both final-year (60%; 11 out of 18 (9.0-12.0)) and first-year (48%; 9 out of 18 (7.0-10.0)) students. Final-year students scored significantly higher than first-year students, but showed inadequate obesity knowledge, especially with regard to etiology, diagnosis, and treatment aspects. Subjective questions revealed that medical students trust their acquired knowledge, but feel pressured by time constraints and the complexity of lifestyle issues and experience barriers to long-term follow-up. CONCLUSION: Final-year medical students in Norway show an inadequate knowledge level within the obesity field, although a significant improvement is seen during the course of medical education. They also show a high self-perceived proficiency in dealing with obesity, despite several constraints/barriers. PMID- 29161688 TI - Plasma Beta-Trace Protein as a Marker of Residual Renal Function: The Effect of Different Hemodialysis Modalities and Intra-Individual Variability over Time. AB - BACKGROUND/AIMS: Beta-trace protein (BTP) is a low-molecular-weight molecule, which may be used to assess residual renal function (RRF) in dialysis patients. Here we evaluated the influence of hemodialysis (HD) and hemodiafiltration (HDF) on plasma BTP, and analyzed the inter- and intra-individual variability of plasma BTP over time in HD and peritoneal dialysis (PD) patients. METHODS: In 12 prevalent HD patients, the effect of a single session of low-flux HD, high-flux HD and HDF on plasma BTP was studied. Blood samples were taken at baseline, after 120 and 240 minutes, and at the start of the next dialysis session. In 13 HD patients and 10 PD patients, inter- and intra-individual variability over three months was studied (monthly and weekly, respectively). Plasma BTP was measured using a nephelometric method. RESULTS: No significant decrease in plasma BTP was seen following a session of low-flux HD. Both high-flux HD and HDF resulted in a significant decrease immediately after dialysis (22% and 61% median decrease, respectively). A significant reduction of the molecule persisted only in HDF and a significant decrease (-15%) was still found immediately before the start of the next dialysis session. In both HD and PD patients, the reproducibility over time was excellent with intra-class correlation coefficient of 0.96 (0.93-0.99) and 0.92 (0.86-0.99) respectively. In a small cohort of PD patients, fair agreement existed between mGFR (average of renal urea and creatinine clearance from a 24 hours urine collection) and the BTP-based GFR estimation. CONCLUSION: BTP is a stable marker and a promising tool for RRF estimations in PD and HD patients. In patients receiving HDF, plasma levels of BTP should be interpreted with caution. PMID- 29161689 TI - Interactive Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers or Their Combination on Survival of Hemodialysis Patients. AB - BACKGROUND: Does the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers individually or as a combination confer a survival benefit in hemodialysis patients? The answer to this question is yet unclear. METHODS: We performed a case-cohort study using data from the Mineral and Bone Disorder Outcomes Study for Japanese CKD stage 5D patients (MBD-5D), a 3-year multicenter prospective case-cohort study, including 8,229 hemodialysis patients registered from 86 facilities in Japan. All patients had secondary hyperparathyroidism, a condition defined as a parathyroid hormone level >=180 pg/mL and/or receiving vitamin D receptor activators. We compared all-cause mortality rates between those receiving ACEI, ARB, and their combination and non users with interaction testing. We used marginal structural Poisson regression (causal model) to estimate the causal effect and interaction adjusted for possible time-dependent confounding. Cardiovascular mortality was also evaluated. RESULTS: Among 3,762 randomly sampled subcohort patients, those taking ACEI, ARB, and their combination at baseline accounted for 4.0, 31.6, and 3.8%, respectively. Over 3 years, 1,226 all-cause and 462 cardiovascular deaths occurred. Compared to non-users, ARB-alone users had a lower all-cause mortality rate (adjusted incident rate ratio [aIRR] 0.62, 95% CI 0.50-0.76), whereas ACEI alone users showed a statistically similar rate (aIRR 1.01, 95% CI 0.57-1.77). On the contrary, combination users had a greater mortality rate (aIRR 2.56, 95% CI 1.22-5.37), showing significant interaction (p = 0.03). Analysis for cardiovascular mortality showed similar results. CONCLUSION: Among hemodialysis patients with secondary hyperparathyroidism, unlike ACEI use, ARB use was associated with greater survival than non-use. Conversely, combination use was associated with greater mortality. Controlled trials are warranted to verify the causality factors of these associations. PMID- 29161690 TI - Catechins Blunt the Effects of oxLDL and its Primary Metabolite Phosphatidylcholine Hydroperoxide on Endothelial Dysfunction Through Inhibition of Oxidative Stress and Restoration of eNOS in Rats. AB - BACKGROUND/AIMS: We explored the effects of catechins (decaffeinated green tea extracts containing (-)-epicatechin, (-)-epigallocatechin, (-)-epicatechin gallate and (-)-epigallocatechin gallate) on atherosclerosis risk factors, oxidized low-density lipoprotein (oxLDL) and its primary metabolite, phosphatidylcholine hydroperoxide (PCOOH) induced oxidative injury in cultured endothelial cell line and rats. METHODS: We used endothelial cell line and male Wistar rats to determine the effect of catechins on oxLDL or PCOOH induced oxidative injury including apoptosis, H2O2 level, vascular responses and urinary 8-isoprostane and nitrite/nitrate concentration. Plasma catechins concentration was determined by a CoulArray HPLC. Responses of aortic and renal vasoconstriction were evaluated by a transonic meter and a full-field laser perfusion imager. RESULTS: PCOOH administration significantly increased H2O2 amounts and cell apoptosis and decreased endothelial nitric oxide synthase (eNOS) expression in the cultured endothelial cells. Catechins pretreatment significantly reduced PCOOH-elevated H2O2 amounts, endothelial cell apoptosis and partly recovered eNOS expression. Intravenous administration of oxLDL, PCOOH or H2O2, not native LDL, significantly decreased renal and aortic blood flow associated with enhanced ICAM-1 expression and 4-hydroxynoneal (4-HNE) accumulation, and decreased eNOS expression in the male Wistrar rats. One hour after oral intake of green tea extracts, 4 peaks of catechins were found in the rat plasma. The increased plasma catechins significantly inhibited oxLDL-, PCOOH- or H2O2-induced renal and aortic vasoconstriction, decreased urinary 8 isoprostane levels, renal ICAM-1 expression and 4-HNE accumulation, and restored nitrite/nitrate amounts and eNOS activity. CONCLUSIONS: Our data suggests that catechins pretreatment decrease PCOOH-induced endothelial apoptosis and arterial vasoconstriction through the action of H2O2 inhibition and eNOS restoration. PMID- 29161691 TI - Failure to Thrive in the Context of Carney Complex. AB - BACKGROUND/AIMS: Carney complex (CNC) is a rare syndrome associated with multiple tumors and several other unique manifestations. We describe the clinical, genetic, and laboratory findings in a cohort of patients with CNC and failure to thrive (FTT). METHODS: A retrospective case series of pediatric patients with CNC presenting with FTT. RESULTS: We describe a patient with infantile Cushing syndrome (CS) who presented with severe FTT and liver disease; the patient was subsequently diagnosed with CNC. This led to the realization that at least 10 other patients with CNC and FTT have been investigated in the last 22 years at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Four of those had primary pigmented nodular adrenocortical disease (PPNAD), 2 had cardiac myxomas, and 3 had liver disease. CONCLUSION: Pediatric patients with CNC may present with FTT whose primary cause is variable and includes CS due to PPNAD, hepatic involvement, and other manifestations of CNC. FTT due to liver disease and/or other causes is a unique new presentation of this rare syndrome with which clinicians need to be familiar. PMID- 29161692 TI - Association between Extreme Values of Markers of Chronic Kidney Disease: Mineral and Bone Disorder and 5-Year Mortality among Prevalent Hemodialysis Patients. AB - BACKGROUND/AIMS: We examined the association between markers of chronic kidney disease - mineral and bone disorder (CKD-MBD) and mortality in hemodialysis (HD) patients. METHODS: We retrospectively reviewed the association between markers of CKD-MBD and mortality in 1,126 HD patients from 2009 to 2013 with baseline (B), time-average (TA), and time-dependent (TD) Cox regression models. RESULTS: Hypercalcemia (10.9-11.9 mg/dL) indicated an increased risk of all-cause mortality (TA: hazard ratio [HR] 3.49; p = 0.01). Hypophosphatemia (2.0-2.5 mg/dL) was significantly associated with an increased risk of all-cause mortality (TA: HR 5.18; p = 0.01). Hypophosphatemia (<2.0 mg/dL) was significantly associated with an increased risk of cardiovascular mortality in all models. Intact parathyroid hormone levels <60 and >1,500 pg/mL indicated an increased risk of all-cause mortality (TA: HR 1.64; p = 0.02; TD: HR 2.26; p = 0.02). CONCLUSION: Extreme values of CKD-MBD markers are associated with mortality risk in HD patients. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=478972. PMID- 29161693 TI - Long-Term Outcomes of Ischemic Stroke of Undetermined Mechanism: A Population Based Prospective Cohort. AB - BACKGROUND AND PURPOSE: Little is known about the short- and long-term outcomes of ischemic stroke of undetermined mechanism (ISUM). METHODS: Subjects were recruited from the Mashhad Stroke Incidence Study. Ischemic stroke (IS) was classified on the basis of the TOAST criteria. We further categorized patients with ISUM into ISUMneg (negative clinical/test results for large artery, small artery) and ISUMinc (incomplete investigations). Cox proportional hazard models and the competing-risk regression model were used to compare 1 and 5 years mortality (all-causes) and recurrent rate among IS subtypes. RESULTS: Overall, 1 year mortality was higher in those with ISUMinc than in ISUMneg (adjusted hazard ratio [aHR] 1.6, 95% CI 1.01-2.8; p = 0.04) and in other stroke subtypes. Cardioembolic stroke was associated with the greatest risk of stroke recurrence at one year (aHR 4.9, 95% CI 1.8-12.9; p = 0.001) and 5 years (HR 2.1, 95% CI 1.1 3.7; p = 0.01) as compared to ISUMneg. CONCLUSIONS: The classification of ISUM as a single group may lead to over- or underestimation of mortality and recurrence in this major category of IS. A better definition of ISUM is necessary to predict death and recurrence accurately. PMID- 29161695 TI - A Randomized Controlled Trial of Comparing Ultrasound-Guided Transversus Abdominis Plane Block with Local Anesthetic Infiltration in Peritoneal Dialysis Catheter Implantation. AB - BACKGROUND: The ultrasound-guided transversus abdominis plane (TAP) block has been demonstrated as a useful analgesia technique in lower-abdomen surgeries. We hypothesized that it could be the principal anesthesia technique for end-stage renal disease (ESRD) patients undergoing peritoneal dialysis (PD) catheter (PDC) implantation using the open dissection method. METHODS: This was a single-center, prospective, randomized, and double-blinded study. All eligible patients were randomized into 2 groups: the TAP block group (n = 20) and the local anesthetic infiltration (LAI) group (n = 20). RESULTS: Compared with the LAI group, the TAP block group revealed a remarkably lower visual analogue score, lower switching rate into general anesthesia, higher satisfaction rate, and less rescuing analgesic consumption during operation (p < 0.05). Both PD- and anesthesia related complications were rare in the 4-week follow-up. CONCLUSIONS: The ultrasound-guided TAP block had better analgesic effect than LAI and can be used as a principal anesthesia technique for PDC implantation in ESRD patients without previous abdominal surgery. PMID- 29161694 TI - Immunohistochemical Localization of DARPP-32 in the Brain of Two Lungfishes: Further Assessment of Its Relationship with the Dopaminergic System. AB - The distribution of DARPP-32 (a phosphoprotein related to the dopamine D1 receptor) has been widely used as a means to clarify the brain regions with dopaminoceptive cells, primarily in representative species of tetrapods. The relationship between dopaminergic and dopaminoceptive elements is frequently analyzed using the catecholamine marker tyrosine hydroxylase (TH). In the present study, by means of combined immunohistochemistry, we have analyzed these relationships in lungfishes, the only group of sarcopterygian fishes represented by 6 extant species that are the phylogenetically closest living relatives of tetrapods. We used the Australian lungfish Neoceratodus forsteri and the African lungfish Protopterus dolloi. The DARPP-32 antibody yields a distinct and consistent pattern of neuronal staining in brain areas that, in general, coincide with areas that are densely innervated by TH-immunoreactive fibers. The striatum, thalamus, optic tectum, and torus semicircularis contain intensely DARPP-32 immunoreactive cell bodies and fibers. Cells are also located in the olfactory bulbs, amygdaloid complex, lateral septum, pallidum, preoptic area, suprachiasmatic nucleus, tuberal hypothalamic region, rostral rhombencephalic reticular formation, superior raphe nucleus, octavolateral area, solitary tract nucleus, and spinal cord. Remarkably, DARPP-32-immunoreactive fibers originating in the striatum reach the region of the dopaminergic cells in the mesencephalic tegmentum and represent a well-established striatonigral pathway in lungfishes. Double immunolabeling reveals that DARPP-32 is present in neurons that most likely receive TH input, but it is absent from the catecholaminergic neurons themselves, with the only exception of a few cells in the suprachiasmatic nucleus of Neoceratodus and the solitary tract nucleus of Protopterus. In addition, some species differences exist in the localization of DARPP-32 cells in the pallium, lateral amygdala, thalamus, prethalamus, and octavolateral area. In general, the present study demonstrates that the distribution pattern of DARPP-32, and its relationship with TH, is largely comparable to those reported for tetrapods, highlighting a shared situation among all sarcopterygians. PMID- 29161696 TI - The Protein Expression Level of a Heterogeneous Gene Inserted in LIPI-1 of the Listeria ivanovii Genome Relies on Its Insertion Orientation. AB - Due to its capability to multiply in either phagocytic or nonphagocytic cells, and to subsequently elicit a robust cellular immune response, Listeria ivanovii (LI) is thought to be feasible for developing bacteria-based live attenuated vaccines. We previously generated several recombinant LI strains expressing Mycobacterium tuberculosis antigens. Since the expression level of heterogeneous protein was sometimes very low, we attempted to elucidate the principle of heterogeneous protein expression in such recombinant LI strains. In this study, we inserted the M. tuberculosis antigen gene Rv0129c into LI strains at the same site as the genome but with a different insertion orientation. RT-qPCR and Western blot showed that when the insertion orientation of the heterogeneous gene was opposite to the LIorfXYZ gene in the Listeria pathogenicity island 1 in the bacterial genome, the heterogeneous gene could be transcribed well but the protein expression level seemed limited, both in vitro and in vivo. When inserted at an orientation consistent with LIorfXYZ at the same site in the genome, the expected 43-kD protein was observed in vitro as well as in a mouse model. Bacterial virulence was found to have decreased after recombination. This work confirms that the protein expression level of the heterogenous gene in such genome-recombinant LI-based vaccines is related to its inserted orientation in the bacterial genome, and a foreign gene inserted at this position of LIPI-1 will abolish Listeria virulence without affecting its growth. PMID- 29161697 TI - Age-Period-Cohort Modeling of Multiple Sclerosis Incidence Rates in Kuwait: 1980 2014. AB - BACKGROUND: Multiple sclerosis (MS) is a complex immune-mediated disorder of the central nervous system with undefined etiology. Genetic predisposition and environmental factors play an imperative role in MS causation and its sustained increasing burden worldwide. This study examined the age, period, and cohort effects on MS incidence rates in Kuwait. METHODS: In this retrospective cohort study, data on MS cases diagnosed between January 1, 1980 and December 31, 2014 and registered in National MS Registry and reference population were obtained. Age-period-cohort (APC) analysis was conducted using a loglinear Poisson regression model to supplement the descriptive and graphical presentation. Descriptive statistics were complemented with APC parameters' estimates including net drift, local drift, age at onset curve, and longitudinal age trend. Age effect was presented as incidence rates (per 105 person-years), whereas period and cohort effects were presented as adjusted relative rates. RESULTS: A total of 1,131 cases were diagnosed in 1,385,923 person-years. Overall age-standardized MS incidence rate was 64.5 (95% CI 52.4-79.8). An estimated annual percentage change revealed 7.4% annual increase in MS incidence rate during the study period (Net drift = 7.4%; 95% CI 4.1-10.8%). APC "fitted" age-at-onset curve showed a bimodal pattern with peaked incidence rates at 20-24 years and 45-49 years of age. Compared with the referent period (1980-1984) and cohort (1970-1974), MS incidence rates progressively and significantly (p < 0.001) increased during subsequent time periods and in successive cohorts. Results of APC analysis are descriptive in nature and specific etiological hypotheses were not evaluated. However, the findings of this study substantiated the notion of multiplicity of genetic and/or environmental risk factors' contributions. CONCLUSION: A substantial increase in MS incidence rates was recorded, which significantly varied in all 3 temporal dimensions during the study period. Future studies may contemplate biological basis for recorded temporal increase in MS risk. PMID- 29161699 TI - Patterns of Detection of Fetal Posterior Fossa Anomalies: Analysis of 81 Cases in the Second Half of Gestation. AB - OBJECTIVE: To establish which characteristics of fetal ultrasound screening lead to the diagnosis of posterior fossa (PF) anomalies. METHODS: A total of 81 fetuses with PF anomalies diagnosed after dedicated neuroimaging between July 1, 2007, and January 1, 2013, were included. The ultrasound characteristics of the fetal cerebellum categorized according to an anatomical approach to the PF, associated fetal anomalies, gestational age at diagnosis, and the potential benefits from systematic measurement of the transverse cerebellar diameter (TCD) were analyzed. RESULTS: Fifty fetuses (61.7%) presented with a PF malformation responsible for an increased "fluid-filled" space of the PF, 24 fetuses (29.6%) had a malformation associated with a decreased cerebellar biometry, 23 fetuses (28.4%) had an abnormal cerebellar anatomy and/or echogenicity, and 2 fetuses (2.4%) showed an isolated malformation of the brainstem. Forty-seven cases (58%) showed additional cerebral or extracerebral anomalies, which led to the diagnosis of PF anomaly in 55.3% of the cases. Isolated PF anomalies were associated with an increased "fluid-filled" space of the PF in 91.2% of the cases. Twenty-eight fetuses had a TCD measurement considered as pathological. DISCUSSION: Examination of the transcerebellar plane during 2nd- and 3rd-trimester ultrasound screening combined with systematic measurement of the TCD would allow improving the detection of PF anomalies. PMID- 29161698 TI - A Comparison of Three Methods for the Detection of Circulating Tumor Cells in Patients with Early and Metastatic Breast Cancer. AB - BACKGROUND: We directly compared CTC detection rates and prognostic significance, using three different methods in patients with breast cancer (BC). METHODS: Early (n=200) and metastatic (n=164) patients were evaluated before initiating adjuvant or first-line chemotherapy, using the CellSearchTM System, an RT-qPCR for CK-19 mRNA detection and by double immunofluorescence (IF) microscopy using A45-B/B3 and CD45 antibodies. RESULTS: Using the CellSearchTM System, 37% and 16.5% of early BC patients were CTC-positive (at >=1 and >=2 CTCs/23 ml of blood), 18.0% by RT-qPCR and 16.9% by IF; no agreement was observed between methods. By the CellSearchTM 34.8% and 53.7% (at>= 5 and >= 2 CTCs/7.5 ml) of metastatic patients were CTC-positive, 37.8% by RT-qPCR and 28.5% by IF. A significant agreement existed only between the CellSearchTM and RT-qPCR. In 60.8% of cases, differential EpCAM and CK-19 expression on CTCs by IF could explain the discrepancies between the CellSearchTM and RT-qPCR. CTC-positivity by either method was associated with decreased overall survival in metastatic patients. CONCLUSION: A significant concordance was observed between the CellSearchTM and RT-qPCR in metastatic but not in early BC. Discordant results could be explained in part by CTC heterogeneity. CTC detection by all methods evaluated had prognostic relevance in metastatic patients. PMID- 29161700 TI - Association Between Environmental Particulate Matter and Carpal Tunnel Syndrome in Patients Undergoing Hemodialysis. AB - BACKGROUND/AIMS: The deposition of beta2-microglobulin induced by reactive inflammation causing carpal tunnel syndrome (CTS) is one of the complications of dialysis-related amyloidosis in maintenance hemodialysis (MHD) patients. Air pollution levels, especially particulate matter with an aerodynamic diameter of <2.5 mm (PM2.5), have significantly been associated with the elevation of systemic inflammatory markers. There is no previous research on possible associations between CTS and PM2.5. METHODS: This study enrolled 866 MHD patients treated at the outpatient HD centers. Senior neurologists diagnosed the presence of CTS. Air pollution levels were recorded by a network of 27 monitoring stations near or in the patients' living areas throughout Taiwan. The 12- and 24-month average concentrations of PM with an aerodynamic diameter of <10 and <2.5 mm (PM10 and PM2.5, respectively), sulfur dioxide, nitrogen dioxide, carbon monoxide, and ozone were included. RESULTS: Multivariate logistic regression analyses showed that HD duration, the normalized protein catabolic rate (nPCR), hypoalbuminemia (albumin < 4 g/dl), and the mean previous 12-month environmental PM2.5 were positively associated with CTS; HD duration, nPCR, hypoalbuminemia (albumin < 4 g/dl), and the mean previous 24-month environmental PM2.5 were positively associated with CTS; HD duration, hypoalbuminemia (albumin < 4 g/dl), and previous 12-month PM2.5 excess days were positively associated with CTS; and HD duration, nPCR, hypoalbuminemia (albumin < 4 g/dl), and previous 24-month PM2.5 excess days were positively associated with CTS. CONCLUSION: PM2.5 levels and PM2.5 excessing days were positively correlated with CTS. PMID- 29161702 TI - Favorable Effects of Endoscopic Ligation Combined with Drugs on Rebleeding and Mortality in Cirrhotic Patients: A Network Meta-Analysis. AB - BACKGROUND: To assess the effects of combination therapies (endoscopic plus drug[s], drug combinations) on variceal/any-cause rebleeding and mortality among cirrhotic patients with one previous episode of variceal hemorrhage. SUMMARY: We searched PubMed, Embase, Cochrane Library, and Web of Science for eligible studies. We included 26 randomized controlled trials involving 2,536 adults using OR to measure the effects. Endoscopic variceal ligation (EVL) plus nadolol ranked first for reducing recurrent bleeds. Both EVL + nadolol and EVL + drugs (nadolol, sucralfate) decreased the risk of any-cause rebleeding than EVL alone (OR 0.34, 95% CI 0.12-0.97; OR 0.40, 95% CI 0.18-0.88, respectively). Meanwhile, EVL + drugs ranked first lowering mortality rates (P-score >0.85) with a marginal superiority over EVL alone (OR 0.52, 95% CI 0.26-1.01). Beta-blockers with isosorbide mononitrate (ISMN) also reached a marginal superiority (OR 0.78, 95% CI 0.56-1.09) for improving mortality. Key Messages: Our findings indicated that EVL + nadolol might be the preferred choice to cirrhotic patients with one previous episode of variceal hemorrhage for preventing rebleeding. EVL + nadolol + sucralfate and beta-blockers + ISMN may be potential alternatives to improve mortality. Further, well-controlled studies are warranted to compare the promising combination therapies. PMID- 29161701 TI - Yin Yang 1 Dynamically Regulates Antiviral Innate Immune Responses During Viral Infection. AB - BACKGROUND/AIMS: Type I interferon (IFN-1) production and IFN-1 signaling play critical roles in the host antiviral innate immune responses. Although transcription factor Yin Yang 1 (YY1) has been reported to have a dual activator/repressor role during the regulation of interferon beta (IFN-beta) promoter activity, the roles of YY1 in the regulation of upstream signaling pathways leading to IFN-1 induction and IFN-1 signaling during viral infection remain to be elucidated. METHODS: The roles of YY1 in IFN-1 production and IFN-1 signaling were investigated using immunoblotting, real-time PCR, small interfering RNA (siRNA)-mediated YY1 knockdown, YY1 overexpression by transient transfection, and co-immunoprecipitation, using mouse cells. RESULTS: YY1 was shown to interact with STAT1 in the absence of viral infection. Following viral infection, YY1 protein expression levels were decreased. YY1 knockdown led to a considerable downregulation of phosphorylated (p) TBK1 and pIRF3 expressions, while YY1 overexpression significantly upregulated pTBK1 and pIRF3 expression levels and promoted virus-induced IFN-beta production. Additionally, YY1 knockdown led to a significant upregulation of pSTAT1, pSTAT2 and antiviral interferon-stimulated genes, and inhibited viral replication. CONCLUSION: We demonstrated here that YY1 interacts with STAT1 and dynamically regulates the induction of IFN-1 production and activation of IFN-1 signaling in different stages during viral infection. PMID- 29161703 TI - Expression Profile of NOTCH3 in Mouse Spermatogonia. AB - Stable and sustainable spermatogenesis is supported by the strict regulation of self-renewal and differentiation of spermatogonial stem cells (SSC), which are a rare population of undifferentiated spermatogonia. It has been revealed that some signaling factors regulate the self-renewal of SSC; however, the molecular mechanism of SSC maintenance is still not completely understood. Notch signaling is an evolutionarily conserved juxtacrine signaling that plays important roles in the cell fate determination of various tissue stem cells. Recently, analyses of loss- and gain-of-function suggested that Notch signaling was necessary for normal spermatogenesis. However, the expression of Notch signal components in spermatogonia is still unclear. Here, we analyzed the distribution of NOTCH3 expressing spermatogonia and the target genes. Double immunostaining with differentiation markers revealed that NOTCH3 was expressed in some undifferentiated and differentiated spermatogonia in mouse testes. To define the target gene of Notch3 signaling in spermatogonia, we analyzed the mRNA expression pattern of Hes and Hey family genes during testis development. Hes1 abundance was decreased during testis development, suggesting that spermatogonia may express Hes1. Immunohistochemical analysis showed that HES1 was expressed in prepubertal spermatogonia, whereas it was expressed predominantly in adult Sertoli cells and weakly in adult spermatogonia. Furthermore, NOTCH3-HES1 double-positive spermatogonia were in pup and adult testes. These results suggest that Notch3 signaling in spermatogonia could promote Hes1 expression. PMID- 29161705 TI - Maintained Folic Acid Supplementation Reduces the Risk of Mortality in Continuous Ambulatory Peritoneal Dialysis Patients. AB - BACKGROUND: The association between folic acid (FA) supplementation and mortality in continuous ambulatory peritoneal dialysis (CAPD) patients is unclear. METHODS: FA exposure was calculated as a percentage of cumulative duration of drug usage to total follow-up duration (FA%). A total of 1,358 patients were classified by a cutoff value of FA%. The association of FA with mortality was evaluated using Cox proportional hazards models. RESULTS: The cutoff value of FA% for predicting mortality was <34% at a median follow-up of 40.7 months. FA >=34% was associated with decreased risk for all-cause (adjusted hazard ratios [HRs] 95% CI 0.64 [0.48 0.85] and cardiovascular mortality 0.67 (95% CI 0.47-0.97). Moreover, the adjusted HRs per 10% higher FA for all-cause and cardiovascular mortality were 0.925 (95% CI 0.879-0.973) and 0.926 (95% CI 0.869-0.988), respectively. CONCLUSIONS: Longer period of FA supplementation led to a reduction in risk of both all-cause and cardiovascular mortality in CAPD patients. PMID- 29161704 TI - Long-Term Renal and Cardiac Outcomes after Stenting in Patients with Resistant Hypertension and Atherosclerotic Renal Artery Stenosis. AB - BACKGROUND/AIMS: Atherosclerotic renal artery stenosis (ARAS) is frequently detected in patients with resistant hypertension (RHTN), but the evidence supporting the utility of renal revascularization in these patients is limited. This prospective, observational study investigates the outcomes of renal stenting in patients with RHTN and hemodynamically significant ARAS. METHODS: Fifty-four patients with RHTN were selected because of angiographic evidence of ARAS >70% and were followed for 4 years after renal stenting. Renal function and echocardiographic variables were assessed at baseline and during follow-up. RESULTS: Blood pressure decreased rapidly after renal stenting and was normalized in 67% of patients at six months, with significant reduction in the number of antihypertensive drugs. Creatinine clearance increased in 39% of patients, decreased in 52%, and remained stable in the remaining 9%, with an average value that had a nonsignificant decrease during follow-up. Urinary albumin excretion did not change throughout the study. After 4 years, left ventricular (LV) wall thickness and concentric geometry decreased significantly and variables of LV diastolic function improved. CONCLUSION: In patients with RHTN, stenting of hemodynamically significant ARAS decreases blood pressure, preserves renal function in a substantial proportion of patients, and improves LV structure and function, suggesting the opportunity for timely identification of ARAS in these patients. PMID- 29161706 TI - Endotoxin Effects on Cardiac and Renal Functions and Cardiorenal Syndromes. AB - Gram-negative sepsis is a major cause of morbidity and mortality in critical ill patients. Recent findings in molecular biology and in signaling pathways have enhanced our understanding of its pathogenesis and opened up opportunities of innovative therapeutic approaches. Endotoxin plays a pivotal role in the pathogenesis of multi-organ dysfunction in the setting of gram-negative sepsis. Indeed, heart and kidney impairments seem to be induced by the release of circulating pro-inflammatory and pro-apoptotic mediators triggered by endotoxin interaction with immune cells. These molecules are responsible for cellular apoptosis, autophagy, cell cycle arrest, and microRNAs activation. Therefore, the early identification of sepsis-associated acute kidney injury and heart dysfunction may improve the patient clinical outcome. In this report, we will consider the role of endotoxin in the pathogenesis of sepsis, its effects on both cardiac and renal functions, and the interactions between these 2 systems in the setting of cardiorenal syndromes (CRS), particularly in CRS type 5. Finally, we will discuss the possible role of extracorporeal therapies in reducing endotoxin levels. PMID- 29161707 TI - A Novel Animal Model Simulating the Beginning of Combat Exposure. AB - OBJECTIVE: Predator stress, social defeat stress, and fear conditioning animal models have been applied to investigate combat-related posttraumatic stress disorder (PTSD). However, no animal model psychopharmacological studies have investigated prevention of somatization of increased mental stress and fatigue at the beginning of combat exposure. This study utilized a novel animal model simulating the beginning of combat exposure that aided specification of a set of biomarkers. METHODS: Psychological stress was induced by both inescapable electric foot shock and noise stimuli. Physical fatigue was induced by sleep deprivation and forced exercise in a rotating cage. A new device reflecting simultaneous psychological stress and physical fatigue was constructed. The protocol simulating combat exposure was set as 3 rounds of 24-h exposure in a 2 week period, which was specified as intermittent unpredictable stress (IUS). RESULTS: Mice exposed to IUS (IUS mice) had significantly higher serum corticosterone levels (p < 0.05), excessive locomotive activity (p < 0.001), and anxiety-like behavior (p < 0.02) compared to control mice. IUS mice also had significantly higher IFN-gamma (p < 0.001) and TNF-alpha (p < 0.05) levels in the supernatant of splenic T-cell culture compared to control mice. Brain-derived neurotropic factor levels were significantly decreased (p < 0.04) after IUS exposure. CONCLUSION: The proposed animal model of combat exposure reflected cognitive function impairment, behavior disturbance, and altered neuroimmune interactions without any apparent histopathological changes, and this animal model may be more applicable to protective research on war syndrome than combat related PTSD after war because the hypothalamic-pituitary-adrenal axis has not been blunted. PMID- 29161708 TI - Association between Childhood Obesity and Neighbourhood Accessibility to Fast Food Outlets: A Nationwide 6-Year Follow-Up Study of 944,487 Children. AB - OBJECTIVES: The aim of this 6-year follow-up study was to examine whether neighbourhood accessibility to fast-food outlets was associated with diagnosed childhood obesity, after adjustment for neighbourhood- and individual-level socio demographic factors. METHODS: This 6-year follow-up study comprised 484,677 boys and 459,810 girls aged 0-14 years in Sweden. The follow-up period ran from January 1, 2005, until hospitalisation/out-patient treatment for obesity, death, emigration or the end of the study period on December 31, 2010. Multilevel logistic regression models (individual-level factors at the first level and neighbourhood-level factors at the second level) were used to calculate odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: We identified 6,968 obesity cases (3,878 boys and 3,090 girls) during the follow-up period. Higher odds of childhood obesity for those living in neighbourhoods with accessibility to fast-food outlets was observed (OR = 1.14, 95% CI = 1.07-1.22) that remained significant after adjustments (OR = 1.06, 95% CI = 1.00-1.13). CONCLUSIONS: This prospective nationwide study showed that the neighbourhood accessibility to fast-food outlets was independently associated with increased odds of diagnosed childhood obesity. This finding implicates that residential environments should be considered when developing health promotion programmes. PMID- 29161709 TI - Impact of Local and Systemic Factors on Kidney Dysfunction in Bardet-Biedl Syndrome. AB - Bardet Biedl syndrome (BBS) is a rare inherited syndromic condition characterized by renal and extra-renal disorders. Renal defect, at either structural or functional level, is one of the cardinal clinical features, and is a major cause of morbidity. However, the pathogenic mechanism underlying its dysfunction remains largely unknown, and to date only symptomatic treatment with no specific therapy is available for these patients. Elucidating aberrant cellular and/or systemic processes that impact kidney function is therefore a prerequisite to develop targeted innovative therapeutic strategies for the BBS patients. Given the proven role of BBS proteins in the function of the primary cilium (PC) and considering the clinical overlapping of BBS with other ciliopathies, BBS is considered the result of disruption of ciliary activities. The present review aims at giving an updated overview of the spectrum of renal abnormalities in BBS patients according to the existing scientific literature, and discusses the possible role of intrinsic PC dysfunction into the pathogenesis of renal defects based on the most recent findings demonstrating a possible role of systemic factors in favoring the progression of renal disease. PMID- 29161710 TI - Distribution of Hepatitis C Virus Genotypes and Subtypes in the Metropolitan Area of Naples, Italy, in the Era of Interferon-Free Regimens. AB - AIMS: The objective of this work was to study the distribution of hepatitis C virus (HCV) genotypes and subtypes from 2010 to 2015 in 1,221 anti-HCV/HCV-RNA positive specimens from patients living in the metropolitan area of Naples, since HCV genotypes and subtypes remain cornerstones in the management of chronic HCV infection even in the directly acting antivirals era. METHODS: The study was carried out on 1,221 anti-HCV/HCV-RNA-positive plasma samples collected between April 2010 and December 2015. RESULTS: Of the 1,221 patients enrolled, 633 (51.9%) were males and 588 (48.1%) were females, with a mean age of 60 +/- 13 (SD) years. The most frequent HCV genotype observed was genotype 1 (68.1%; 1b in 55.3% and 1a in 9.5%); HCV genotype 2 was found in 289 samples (23.67%), genotype 3 in 6.47%, genotype 4 in only 19 samples, and only 2 samples were classified as genotype 5. The mean age of the patients with genotype 1a or 3 was lower (51 +/- 12 and 49 +/- 12 years, respectively) than those with genotype 1b (62 +/- 11, p < 0.0001 for both) or 2 (62 +/- 14, p < 0.0001 for both). CONCLUSIONS: The data from the present study suggest that HCV genotype 1b remains the most prevalent in this area, followed by genotype 2, 1a, and 3a. PMID- 29161711 TI - Hemofiltration Prescription in Children, or How to Get an Espresso from a Cappuccino. PMID- 29161712 TI - Clostridium Difficile Infection in the Nephrology Ward. AB - Clostridium difficile is currently the most frequently identified pathogen causing antibiotic-associated diarrhea and the main cause of nosocomial diarrhea. In recent years, increases incidence of infection, severe infection, recurrent infection and mortality from Clostridium difficile infection (CDI) have been observed. This may be a consequence of excessive antibiotic use and spread of the hypervirulent epidemic BI/NAP1/027 strain of Clostridium difficile. The main risk factors for CDI are: antibiotic therapy, previous hospitalizations and number of comorbid conditions. Prevention of CDI mainly is focused in two directions: reducing the exposure of patients to the disease pathogen by intensifying hygiene measures, and reducing the impact of risk factors. A meta-analyses of clinical studies (observational, cohort and case control) showed significantly higher risk of CDI and CDI recurrence in patients with chronic kidney disease and increased mortality risk in chronic kidney disease patients with CDI comparing those without CDI. Increased risk of CDI in patients with chronic kidney disease can be caused by: frequent antibiotic therapy associated with numerous infections resulting in intestinal microflora dysfunction, frequent hospitalizations, older age of the patients and an impaired immune system. Among preventative measures against CDI, the use of probiotics were also studied. In patients hospitalized in nephrology ward highly significant reduction of the CDI incidence was observed after the introduction of Lactobacillus plantarum 299v as CDI prophylaxis. Therefore, the use of Lactobacillus plantarum 299v seems to be a promising method of CDI prevention in chronic kidney disease patients hospitalized in nephrology ward. PMID- 29161714 TI - A Rare Cause of Male Infertility: 45,X/46,XY Mosaicism. AB - OBJECTIVE: To present the clinical, chromosomal, and endocrinological features of 8 infertile male cases with the 45,X/46,XY karyotype who were admitted to our infertility clinic. MATERIALS AND METHODS: The records of cases who were admitted to our infertility clinic between 1999 and 2015 were investigated. Eight cases with 45,X/46,XY were detected. The clinical, endocrinological, and chromosomal assessments were analyzed. Each patient's height, weight, body mass index, testicular volume, endocrine hormone levels, follow-up period semen analysis, testicular biopsy reports, and karyotype analysis were evaluated retrospectively. RESULTS: Some cases had a short stature, but often their phenotypes were normal. Seven of the cases had normal testosterone levels and all cases, except one, had elevated gonadotropin levels. All cases were azoospermic and testicular biopsy showed Sertoli cell-only syndrome. Peripheral blood karyotype revealed 45,X/46,XY mosaicism in all cases. Metaphase counts and percentages were different. CONCLUSIONS: Individuals with 45,X/46,XY mosaicism that have a normal male phenotype form make up a rare subgroup of the 45,X/46,XY karyotype. These individuals usually present with infertility and were diagnosed based on the results of the karyotype analysis during azoo or severe oligospermia evaluation. PMID- 29161713 TI - Clinical Benefits of High-Volume Hemofiltration in Critically Ill Pediatric Patients with Severe Sepsis: A Retrospective Cohort Study. AB - AIMS: The study aimed to assess the clinical benefits of high-volume hemofiltration (HVHF) in pediatric patients with severe sepsis compared with standard-volume continuous veno-venous hemofiltration (CVVH). METHODS: We retrospectively analyzed the medical records of 155 pediatric patients with severe sepsis admitted to the pediatric intensive care unit of Shanghai Children's Hospital from January 2010 to June 2016. A total of 93 patients were treated with HVHF and 62 patients were treated with CVVH. RESULTS: HVHF treatment did not significantly reduce 28-day mortality. Moreover, there was no significant difference in reducing the plasma level of inflammatory mediators and improving hemodynamic variables between HVHF and CVVH group. However, the incidence of hyperglycemia was significantly higher in HVHF group than in CVVH group. CONCLUSIONS: There is no evidence to indicate that HVHF is superior to CVVH in reducing 28-day mortality as an adjunct to the treatment of severe sepsis in pediatric patients. PMID- 29161715 TI - Management of Biochemical Recurrence after Primary Curative Treatment for Prostate Cancer: A Review. AB - How to manage patients with prostate cancer (PCa) with biochemical recurrence (BCR) following primary curative treatment is a controversial issue. Importantly, this prostate-specific antigen (PSA)-only recurrence is a surrogate neither of PCa-specific survival nor of overall survival. Physicians are therefore challenged with preventing or delaying the onset of clinical progression in those deemed at risk, while avoiding over-treating patients whose disease may never progress beyond PSA-only recurrence. Adjuvant therapy for radical prostatectomy (RP) or local radiotherapy (RT) has a role in certain at-risk patients, although it is not recommended in low-risk PCa owing to the significant side-effects associated with RT and androgen deprivation therapy (ADT). The recommendations for salvage therapy differ depending on whether BCR occurs after RP or primary RT, and in either case, definitive evidence regarding the best strategy is lacking. Options for treatment of BCR after RP are RT at least to the prostatic bed, complete or intermittent ADT, or observation; for BCR after RT, salvage RP, cryotherapy, complete or intermittent ADT, brachytherapy, high-intensity focused ultrasound (HIFU), or observation can be considered. Many patient- and cancer specific factors need to be taken into account when deciding on the best strategy, and optimal management depends on the involvement of a multidisciplinary team, consultation with the patient themselves, and the adoption of an individualised approach. Improvements in imaging techniques may enable earlier detection of metastases, which will hopefully refine future management decisions. PMID- 29161716 TI - A Seven Year-Using Single Hemodialysis Catheter without Complication. PMID- 29161717 TI - Subconjunctival PRGF Fibrin Membrane as an Adjuvant to Nonpenetrating Deep Sclerectomy: A 2-Year Pilot Study. AB - PURPOSE: To evaluate the potential role of the autologous PRGF (plasma rich in growth factors) fibrin membrane in tissue regeneration after glaucoma filtering surgery. MATERIALS AND METHODS: Ten patients with medically uncontrolled primary open-angle glaucoma underwent nonpenetrating deep sclerectomy and were treated with PRGF fibrin membrane as adjuvant. Intraocular pressure reduction was the primary outcome. This variable was measured preoperatively and also at each follow-up visit. Secondary outcomes included the number of antiglaucoma medications, anterior segment optical coherence tomography bleb examination, photographic bleb evaluation, and subjective clinical symptomatology evaluation. RESULTS: The surgical technique showed a significant reduction (p < 0.05) in intraocular pressure in relation to preoperative values at each time of the study, decreasing from 23.3 +/- 6.4 to 15.2 +/- 4.6 mm Hg at 2 years. Furthermore, the number of antiglaucoma medications consumed showed a significant reduction at the end point of the study compared with the preoperative situation. Optical coherence tomography and photographic filtering bleb variables experienced a progressive reduction during the follow-up. Subjective symptoms showed a reduction from 8.3 +/- 4.5 to 4.2 +/- 5.3 at 2 years. CONCLUSIONS: PRGF Endoret treatment could promote ocular surface regeneration after glaucoma surgery, enhancing the surgery success rates and reducing the need for postoperative medications. It is important to highlight that this is a preliminary study and some large clinical studies are necessary to verify these results. PMID- 29161718 TI - Transport Characteristics of Asymmetric Cellulose Triacetate Hemodialysis Membranes. AB - AIMS: The objective of this study was to compare the transport characteristics of highly asymmetric cellulose triacetate (ATATM) membranes with that of both symmetric cellulose triacetate and asymmetric polysulfone membranes. METHODS: Data were obtained for solute clearance and sieving coefficients of vitamin B12 and a range of polydisperse dextrans using ATATM SOLACEA-25H and Optiflux F250NR polysulfone dialyzers. Results for these, and the CT190 symmetric cellulose triacetate dialyzer, were analyzed using available membrane transport models. RESULTS: The ATATM had the largest solute clearance, although the homogeneous CT190 dialyzer had the highest sieving coefficients. These differences were a direct result of the differences in the underlying membrane morphology, with the asymmetric ATATM membrane providing much higher diffusive transport rates (and thus higher solute clearance). CONCLUSIONS: These results demonstrate the importance of membrane morphology on dialyzer transport and provide important insights into the effective clinical performance observed with the highly asymmetric ATATM dialyzers. PMID- 29161719 TI - Palmitic Acid Curcumin Ester Facilitates Protection of Neuroblastoma against Oligomeric Abeta40 Insult. AB - BACKGROUND/AIMS: The generation of reactive oxygen species (ROS) caused by amyloid-beta (Abeta) is considered to be one of mechanisms underlying the development of Alzheimer's disease. Curcumin can attenuate Abeta-induced neurotoxicity through ROS scavenging, but the protective effect of intracellular curcumin on neurocyte membranes against extracellular Abeta may be compromised. To address this issue, we synthesized a palmitic acid curcumin ester (P-curcumin) which can be cultivated on the cell membrane and investigated the neuroprotective effect of P-curcumin and its interaction with Abeta. METHODS: P-curcumin was prepared through chemical synthesis. Its structure was determined via nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). An MTT assay was used to assess Abeta cytotoxicity and the protective effect of P curcumin on SH-SY5Y cells. The effect of P-curcumin on Abeta-induced ROS production in vitro and in vivo were assessed based on changes in dichlorofluorescein (DCF) fluorescence. A spectrophotometric method was employed to detect lipid peroxidation. To mimic the interaction of P-curcumin on cell membranes with Abeta, liposomes were prepared by thin film method. Finally, the interactions between free P-curcumin and P-curcumin cultivated on liposomes and Abeta were determined via spectrophotometry. RESULTS: A novel derivative, palmitic acid curcumin ester was prepared and characterized. This curcumin, cultivated on the membranes of neurocytes, may prevent Abeta-mediated ROS production and may inhibit the direct interaction between Abeta and the cellular membrane. Furthermore, P-curcumin could scavenge Abeta-mediated ROS as curcumin in vitro and in vivo, and had the potential to prevent lipid peroxidation. Morphological analyses showed that P-curcumin was better than curcumin at protecting cell shape. To examine P-curcumin's ability to attenuate direct interaction between Abeta and cell membranes, the binding affinity of Abeta to curcumin and P-curcumin was determined. The association constants for free P curcumin and curcumin were 7.66 * 104 M-1 and 7.61 * 105 M-1, respectively. In the liposome-trapped state, the association constants were 3.71 * 105 M-1 for P curcumin and 1.44* 106 M-1 for curcumin. With this data, the thermodynamic constants of P-curcumin association with soluble Abeta (DeltaH, DeltaS, and DeltaG) were also determined. CONCLUSION: Cultivated curcumin weakened the direct interaction between Abeta and cell membranes and showed greater neuroprotective effects against Abeta insult than free curcumin. PMID- 29161720 TI - Development of OSTQOL: A Measure of Quality of Life for Patients in Opioid Substitution Treatment. AB - BACKGROUND: Quality of life (QOL) of patients in opioid substitution treatment (OST) is increasingly being addressed in research. However, no disease- or treatment-specific instrument is available to assess the QOL of this target population. The purpose of this project was to develop the first QOL instrument for OST patients. METHODS: Focus groups with 60 OST patients were analyzed using thematic analysis to elicit key QOL themes as perceived by patients. Identified themes were developed into items and refined through pilot testing and cognitive debriefing. The resulting 82 items were tested in a large sample of OST patients (n = 577). Principal component analysis with varimax rotation was performed to explore a possible factor structure and reduce the number of items. Psychometric properties were assessed. RESULTS: Factor analysis revealed 6 subscales accounting for 46.1% of the variance: Personal Development, Mental Distress, Social Contacts, Material Well-being, Opioid Substitution Treatment, and Discrimination. The 38-item instrument demonstrated good to acceptable internal consistency reliability for all subscales (Cronbach's alpha = 0.75-0.88), and good convergent and discriminant validity. CONCLUSION: The Opioid Substitution Treatment Quality of Life scale (OSTQOL) is a multidimensional instrument with low respondent and administrator burden. A thorough validation is needed to assess its validity. PMID- 29161721 TI - Impact of Nocturnal Noninvasive Ventilation on Pulmonary Rehabilitation in Patients with End-Stage Lung Disease Awaiting Lung Transplantation. AB - BACKGROUND: Pulmonary rehabilitation (PR) in patients awaiting lung transplantation is crucial to ensure a transplant benefit. However, PR in patients with end-stage lung disease treated with noninvasive ventilation (NIV) remains an area of uncertainty. OBJECTIVES: The aim of the study was to assess the potential benefit of PR in patients awaiting lung transplantation treated with NIV. METHODS: Patients awaiting lung transplantation who underwent comprehensive inpatient PR from 1998 to 2015 were retrospectively analyzed. Success of PR was assessed by comparing admission and discharge. Multivariate regression models were applied to assess the impact of long-term nocturnal NIV on PR success. RESULTS: In total, 1,044 patients were included in the analysis. Thereof, 296 patients (28%) were treated with NIV. PR in patients treated with NIV resulted in a significant increase in 6-min walk distance (6MWD; from 250 +/- 117 to 309 +/- 116 m; p < 0.0001) and in various items of the Short Form Health Survey (SF)-36 questionnaire. The increase in 6MWD was higher in patients treated with NIV than in patients without NIV (59 +/- 63 vs. 48 +/- 55 m; p = 0.003). Furthermore, improvements of various lung function variables were higher in patients with NIV. Finally, multivariate generalized regression analysis revealed that NIV therapy was associated with improvement of 6MWD (p = 0.023) while controlling for various baseline characteristics. CONCLUSIONS: PR in patients with end-stage lung disease awaiting lung transplantation on nocturnal NIV is feasible and is associated with improvements of exercise capacity and quality of life. Furthermore, despite more advanced lung disease, patients treated with NIV have an increased benefit of PR compared to patients without NIV while awaiting lung transplantation. PMID- 29161722 TI - The Impact of Tumor Necrosis Factor-alpha and Interleukin-1beta Levels and Polymorphisms on Long-Term Stroke Outcomes. AB - BACKGROUND: The accuracy of predictions regarding disability that sets in after stroke could be improved by using blood biomarker measurements. This study aimed to investigate the roles of serum tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta concentrations and polymorphisms in stroke outcomes. METHODS: In total, 286 patients were evaluated at the time of admission and at 2 weeks after stroke, and 222 of these patients (78%) were followed up for 1 year to evaluate the consequences of stroke during both the acute and chronic stages. Stroke outcomes were dichotomized into good and poor using the modified Rankin Scale. RESULTS: The association of TNF-alpha and IL-1beta concentrations and their corresponding genotypes with stroke outcomes was investigated using multivariate logistic regression. Higher TNF-alpha levels were associated with poor outcomes 1 year after stroke in the presence of the -850T and -308A alleles, and IL-1beta levels were associated with poor 1-year stroke outcomes in the presence of the -511T and +3953T alleles. No such associations were found at 2 weeks after stroke. CONCLUSIONS: These data provide evidence that serum TNF-alpha and IL-1beta concentrations are related to poor long-term outcomes after stroke in the presence of particular alleles. PMID- 29161723 TI - Correction: Molecular Phylogeny of a RING E3 Ubiquitin Ligase, Conserved in Eukaryotic Cells and Dominated by Homologous Components, the Muskelin/RanBPM/CTLH Complex. AB - [This corrects the article DOI: 10.1371/journal.pone.0075217.]. PMID- 29161725 TI - Correction: Correcting for Population Structure and Kinship Using the Linear Mixed Model: Theory and Extensions. AB - [This corrects the article DOI: 10.1371/journal.pone.0075707.]. PMID- 29161724 TI - Correction: Molecular Vibration-Sensing Component in Human Olfaction. AB - [This corrects the article DOI: 10.1371/journal.pone.0055780.]. PMID- 29161726 TI - Correction: Young Children Consider Merit when Sharing Resources with Others. AB - [This corrects the article DOI: 10.1371/journal.pone.0043979.]. PMID- 29161727 TI - Correction: Synaptic Metaplasticity Underlies Tetanic Potentiation in Lymnaea: A Novel Paradigm. AB - [This corrects the article DOI: 10.1371/journal.pone.0078056.]. PMID- 29161728 TI - Correction: Transcription Fluctuation Effects on Biochemical Oscillations. AB - [This corrects the article DOI: 10.1371/journal.pone.0060938.]. PMID- 29161729 TI - Correction: FoxO3a Modulates Hypoxia Stress Induced Oxidative Stress and Apoptosis in Cardiac Microvascular Endothelial Cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0080342.]. PMID- 29161730 TI - Correction: Incidence and Predictors of Pregnancy among a Cohort of HIV-Positive Women Initiating Antiretroviral Therapy in Mbarara, Uganda. AB - [This corrects the article DOI: 10.1371/journal.pone.0063411.]. PMID- 29161731 TI - Correction: Evaluating Caveolin Interactions: Do Proteins Interact with the Caveolin Scaffolding Domain through a Widespread Aromatic Residue-Rich Motif? AB - [This corrects the article DOI: 10.1371/journal.pone.0044879.]. PMID- 29161732 TI - Correction: The Relationship between Endogenous Androgens and Body Fat Distribution in Early and Late Postmenopausal Women. AB - [This corrects the article DOI: 10.1371/journal.pone.0058448.]. PMID- 29161733 TI - Correction: Knockdown of the Sodium-Dependent Phosphate Co-Transporter 2b (NPT2b) Suppresses Lung Tumorigenesis. AB - [This corrects the article DOI: 10.1371/journal.pone.0077121.]. PMID- 29161734 TI - Correction: Effects of Late-Cenozoic Glaciation on Habitat Availability in Antarctic Benthic Shrimps (Crustacea: Decapoda: Caridea). AB - [This corrects the article DOI: 10.1371/journal.pone.0046283.]. PMID- 29161735 TI - Correction: Electrical Pulse Stimulation of Cultured Human Skeletal Muscle Cells as an In Vitro Model of Exercise. AB - [This corrects the article DOI: 10.1371/journal.pone.0033203.]. PMID- 29161736 TI - Correction: Classification of Lung Cancer Tumors Based on Structural and Physicochemical Properties of Proteins by Bioinformatics Models. AB - [This corrects the article DOI: 10.1371/journal.pone.0040017.]. PMID- 29161737 TI - Correction: Synergic Activation of Toll-Like Receptor (TLR) 2/6 and 9 in Response to Ureaplasma parvum & urealyticum in Human Amniotic Epithelial Cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0061199.]. PMID- 29161738 TI - Correction: A Replication Study Confirms the Association of Dendritic Cell Immunoreceptor (DCIR) Polymorphisms with ACPA - Negative RA in a Large Asian Cohort. AB - [This corrects the article DOI: 10.1371/journal.pone.0041228.]. PMID- 29161739 TI - Correction: Wogonin Improves Histological and Functional Outcomes, and Reduces Activation of TLR4/NF-kappaB Signaling after Experimental Traumatic Brain Injury. AB - [This corrects the article DOI: 10.1371/journal.pone.0030294.]. PMID- 29161740 TI - Correction: Platelets Recognize Brain-Specific Glycolipid Structures, Respond to Neurovascular Damage and Promote Neuroinflammation. AB - [This corrects the article DOI: 10.1371/journal.pone.0058979.]. PMID- 29161741 TI - Correction: Selection of Diethylstilbestrol-Specific Single-Chain Antibodies from a Non-Immunized Mouse Ribosome Display Library. AB - [This corrects the article DOI: 10.1371/journal.pone.0033186.]. PMID- 29161742 TI - Correction: KATP Channel Opener Diazoxide Prevents Neurodegeneration: A New Mechanism of Action via Antioxidative Pathway Activation. AB - [This corrects the article DOI: 10.1371/journal.pone.0075189.]. PMID- 29161743 TI - Pharmacological Foundations of Cannabis Chemovars. AB - An advanced Mendelian Cannabis breeding program has been developed utilizing chemical markers to maximize the yield of phytocannabinoids and terpenoids with the aim to improve therapeutic efficacy and safety. Cannabis is often divided into several categories based on cannabinoid content. Type I, Delta9 tetrahydrocannabinol-predominant, is the prevalent offering in both medical and recreational marketplaces. In recent years, the therapeutic benefits of cannabidiol have been better recognized, leading to the promotion of additional chemovars: Type II, Cannabis that contains both Delta9-tetrahydrocannabinol and cannabidiol, and cannabidiol-predominant Type III Cannabis. While high-Delta9 tetrahydrocannabinol and high-myrcene chemovars dominate markets, these may not be optimal for patients who require distinct chemical profiles to achieve symptomatic relief. Type II Cannabis chemovars that display cannabidiol- and terpenoid-rich profiles have the potential to improve both efficacy and minimize adverse events associated with Delta9-tetrahydrocannabinol exposure. Cannabis samples were analyzed for cannabinoid and terpenoid content, and analytical results are presented via PhytoFacts, a patent-pending method of graphically displaying phytocannabinoid and terpenoid content, as well as scent, taste, and subjective therapeutic effect data. Examples from the breeding program are highlighted and include Type I, II, and III Cannabis chemovars, those highly potent in terpenoids in general, or single components, for example, limonene, pinene, terpinolene, and linalool. Additionally, it is demonstrated how Type I - III chemovars have been developed with conserved terpenoid proportions. Specific chemovars may produce enhanced analgesia, anti-inflammatory, anticonvulsant, antidepressant, and anti-anxiety effects, while simultaneously reducing sequelae of Delta9-tetrahydrocannabinol such as panic, toxic psychosis, and short-term memory impairment. PMID- 29161744 TI - Thyroid Dysfunction States and Incident Cardiovascular Events: The Tehran Thyroid Study. PMID- 29161745 TI - Resting Autonomic Function in Active and Insufficiently Active People Living with HIV. AB - Autonomic dysfunction appears to be prevalent in people living with HIV/AIDS (PLWHA). However, there are limited data on the resting autonomic responses to exercise in active and insufficiently active PLWHA. We aimed to determine whether active PLWHA have better autonomic responses compared with insufficiently active PLWHA. Active PLWHA receiving anti-retroviral therapy (n=13) and insufficiently active PLWHA (n=10) were recruited. A 10-min recording of the supine electrocardiogram was taken. Resting heart rate variability was analyzed from this electrocardiogram. Parasympathetic modulation, as measured by high frequency power in normalized units, was greater in active PLWHA when compared to insufficiently active PLWHA (41.0+/-15.6 vs. 25.2+/-9.7; p<0.05). Sympathetic modulation as measured by low frequency power in normalized units was greater in insufficiently active PLWHA when compared to active PLWHA (55.6+/-15.8 vs 79.3+/ 17.5; p<0.05). Sympathovagal balance as measured by low frequency/high frequency ratio was greater in insufficiently active PLWHA when compared to active PLWHA (3.4+/-1.8 vs 1.6+/-0.9; p<0.05), indicating greater parasympathetic dominance in the active group. In conclusion, PLWHA who regularly exercised demonstrated enhanced autonomic function compared with insufficiently active PLWHA. These results suggest that exercise is associated with enhanced autonomic function, and may improve cardiovascular risk. PMID- 29161746 TI - Exercise Performed Concomitantly with Particulate Matter Exposure Inhibits Lung Injury. AB - Air pollution is a growing problem worldwide, inducing and exacerbating several diseases. Among the several components of air pollutants, particulate matter (PM), especially thick (10-2.5 um; PM 10) and thin (<=2.5 um; PM 2.5), are breathable particles that easily can be deposited within the lungs, resulting in pulmonary and systemic inflammation. Although physical activity is strongly recommended, its effects when practiced in polluted environments are questionable. Therefore, the present study evaluated the pulmonary and systemic response of concomitant treadmill training with PM 2.5 and PM 10 exposure. Treadmill training inhibited PM 2.5- and PM 10-induced accumulation of total leukocytes (p<0.001), neutrophils (p<0.001), macrophages (p<0.001) and lymphocytes (p<0.001) in bronchoalveolar lavage (BAL), as well as the BAL levels of IL-1beta (p<0.001), CXCL1/KC (p<0.001) and TNF-alpha (p<0.001), whereas it increased IL-10 levels (p<0.05). Similar effects were observed on accumulation of polymorphonuclear (p<0.01) and mononuclear (p<0.01) cells in the lung parenchyma and in the peribronchial space. Treadmill training also inhibited PM 2.5- and PM 10-induced systemic inflammation, as observed in the number of total leukocytes (p<0.001) and in the plasma levels of IL-1beta (p<0.001), CXCL1/KC (p<0.001) and TNF-alpha (p<0.001), whereas it increased IL-10 levels (p<0.001). Treadmill training inhibits lung and systemic inflammation induced by particulate matter. PMID- 29161747 TI - A functional MRI Exploration of Hamstring Activation During the Supine Bridge Exercise. AB - The single leg supine bridge (SLB) is a commonly employed strengthening exercise and is used as a clinical test for hamstring function in sports, however, little is known about the patterns of muscle activation in this task. To explore these activation patterns, nine healthy, recreationally active males underwent functional magnetic resonance imaging (fMRI) of their thighs at rest and immediately after 5 sets of 10 repetitions of the SLB exercise. Exercise-induced increases in the transverse (T2) relaxation time of the biceps femoris long and short heads, semitendinosus and semimembranosus, were determined via signal intensity changes in pre- and post-exercise images and used as an index of muscle activation. The Bonferroni adjusted alpha was set at p<0.008. The semitendinosus exhibited a greater T2 increase than the biceps femoris short head (p<0.001, d=2.0) and semimembranosus (p=0.001, d=1.2), but not biceps femoris long head (p=0.029, d=0.9). Furthermore, the percentage change in T2 for biceps femoris long head was greater than its short head (p=0.003, d=1.4). During the SLB exercise, the semitendinosus is most selectively targeted and the biceps femoris long head is preferentially activated over its short head. These findings may have implications for the use of the SLB in hamstring injury prevention and rehabilitation programs. PMID- 29161748 TI - Whole-body Cryotherapy as a Recovery Technique after Exercise: A Review of the Literature. AB - This review aims to evaluate the current body of literature investigating the effect of whole body cryotherapy on recovery after exercise. A systematic search was conducted to investigate the effect of whole body cryotherapy (WBC, exposure to temperatures between -110 to -190 degrees C) on markers of recovery after damaging exercise in healthy, physically active subjects. Of the 16 eligible articles extracted, ten induced muscle damage using controlled exercise in a laboratory setting, while six induced damage during sport-specific training. Results indicated that muscle pain was reduced in 80% of studies following WBC. Two applied studies found recovery of athletic capacity and performance with WBC improved, variables of this nature were also improved in 71% of studies using controlled exercise. Further benefits of WBC treatment included reduction of systemic inflammation and lower concentrations of markers for muscle cell damage. These results suggest that WBC may improve recovery from muscle damage, with multiple exposures more consistently exhibiting improvements in recovery from pain, loss of muscle function, and markers of inflammation and damage. The diversity in muscle damage protocols, exposure timing with regards to exercise, as well as temperatures, duration and frequencies of exposure, make specific recommendations preliminary at present. PMID- 29161750 TI - False-Negative NIPT Result for Trisomy 21. PMID- 29161749 TI - Role of Drug Anesthesia and Cancer. AB - Mortality and morbidity rate among cancer patients is at an alarming rate and its ratio of incidence is increasing as a result of its effects of metastasis and recurrence in its patients. Anesthetists are faced with the challenges daily of handling and treating cancer patients, for surgical resection to removal of the primary tumor. Retrospective analyses and studies have proposed a link between anesthetic technique and cancer outcomes. In this mini-review, we will give a summary of some of the available effects of anesthetic and analgesic techniques on cancer metastasis as derived from experimental cell culture and live animal data and also from clinical studies. PMID- 29161751 TI - The Jellyfish Sign: A New Sonographic Cervical Marker to Predict Maternal Morbidity in Abnormally Invasive Placenta Previa. AB - Purpose To investigate the value of a new cervical sonographic sign, called the jellyfish sign (JS), for predicting the risk of maternal morbidity in cases of abnormally invasive placenta (AIP) previa totalis. Materials and Methods Retrospective evaluation of transvaginal (TV) and transabdominal (TA) scans performed in all singleton pregnancies with placenta previa totalis. JS, i. e. the absence of the normal linear demarcation between the placenta previa and the cervix, was evaluated by TV scans. The presence/severity of AIP and outcomes of maternal morbidity were related to this sign. Results JS was noted in 8/39 (20.5 %) patients. The two analyzed groups, i. e. with and without JS, were similar. The specificity of JS in AIP diagnosis, histological findings of accreta/increta/percreta, need for caesarean hysterectomy or blood loss > 2000 ml ranges between 92 % and 96.2 %, with the PPV and NPV ranging between 71.4 % and 85.7 % and 61.3 % and 80.6 %, respectively. The JS group had a significant increase in blood loss (ml) (p = 0.003), transfusions (%) (p = 0.016), red blood cells (p = 0.002) and plasma (p = 0.002), admission to an postoperative intensive care unit (ICU) (%) (p = 0.002), hospitalization length (p < 0.001) and the need of cesarean hysterectomy (%) (p < 0.001). JS was independently correlated to cesarean hysterectomy (OR 25.6; 95 % CI 2.0:322.3, p = 0.012) and blood loss > 2000 ml (OR 16.6; 95 % CI 1.5:180.1, p = 0.021) also in a logistic regression model. Conclusion JS is useful in predicting the increase in maternal morbidity: massive transfusion, admission to the ICU and cesarean hysterectomy related to intraoperative bleeding in patients with a previa AIP. PMID- 29161752 TI - Prenatal Megacystis - Is Prediction of Outcome and Renal Function Possible? AB - OBJECTIVE: To assess prenatal prognostic criteria for fetuses with megacystis in order to counsel parents. METHODS: In a retrospective observational study at a single tertiary referral center, we assessed the clinical course of 53 fetuses with megacystis cared for at the Department of Obstetrics of the University Hospital Zurich between 1995 and 2008 and followed them up for 2 to 12 years. We determined fetal karyotype, amniotic fluid volume and fetal urinary biochemistry as prenatal prognostic factors. The renal function of survivors was grouped according to age-related creatinine values. Using logistic regression analysis, gestational age-dependent discrimination curves and corresponding ROC curves for fetal urine, beta-2 microglobulin, osmolarity and chloride were calculated. RESULTS: 43 out of 53 fetuses underwent vesicocentesis, and spontaneous remission occurred in 3 fetuses. 15 fetuses survived, termination of pregnancy was requested in 23 cases, and 12 neonatal and 3 intrauterine deaths were observed. Reduced amniotic fluid volume showed a significant (p = 0.0027) increase of impaired renal function or perinatal death. Discrimination between survivors and non-survivors was complete for fetal urine beta-2 microglobulin with an area under the curve (AUC) of 1.0. For fetal urine osmolarity and fetal urinary chloride, the AUC was 0.81 and 0.76, respectively. CONCLUSION: The assessment of prognosis for fetal megacystis should include fetal k aryotyping, determination of amniotic fluid and assessment of fetal urine biochemistry. Gestational age-dependent regression lines disclose clinically relevant discrimination and can be used as selection criteria for fetal interventions and parental counselling. PMID- 29161753 TI - Improving the efficacy of proteasome inhibitors in the treatment of renal cell carcinoma by combination with the human immunodeficiency virus (HIV)-protease inhibitors lopinavir or nelfinavir. AB - OBJECTIVES: To assess the potential of second-generation proteasome inhibition by carfilzomib and its combination with the human immunodeficiency virus (HIV) protease inhibitors (HIV-PIs) lopinavir and nelfinavir in vitro for improved treatment of clear cell renal cell cancer (ccRCC). MATERIALS AND METHODS: Cytotoxicity, reactive oxygen species (ROS) production, and unfolded protein response (UPR) activation of proteasome inhibitors, HIV-PIs, and their combination were assessed in three cell lines and primary cells derived from three ccRCC tumours by MTS assay, flow cytometry, quantitative reverse transcriptase-polymerase chain reaction and western blot, respectively. Proteasome activity was determined by activity based probes. Flow cytometry was used to assess apoptosis by annexin V/propidium iodide assay and ATP-binding cassette sub-family B member 1 (ABCB1) activity by MitoTrackerTM Green FM efflux assay (Thermo Fisher Scientific, MA, USA). RESULTS: Lopinavir and nelfinavir significantly increased the cytotoxic effect of carfilzomib in all cell lines and primary cells. ABCB1 efflux pump inhibition, induction of ROS production, and UPR pre-activation by lopinavir were identified as underlying mechanisms of this strong synergistic effect. Combined treatment led to unresolved protein stress, increased activation of pro-apoptotic UPR pathway, and a significant increase in apoptosis. CONCLUSION: The combination of the proteasome inhibitor carfilzomib and the HIV-PIs lopinavir and nelfinavir has a strong synergistic cytotoxic activity against ccRCCin vitro at therapeutically relevant drug concentrations. This effect is most likely explained by synergistic UPR triggering and ABCB1 modulation caused by HIV-PIs. Our findings suggest that combined treatment of second-generation proteasome inhibitors and HIV-PIs should be investigated in patients with metastatic RCC within a clinical trial. PMID- 29161754 TI - The Sorghum bicolor reference genome: improved assembly, gene annotations, a transcriptome atlas, and signatures of genome organization. AB - Sorghum bicolor is a drought tolerant C4 grass used for the production of grain, forage, sugar, and lignocellulosic biomass and a genetic model for C4 grasses due to its relatively small genome (approximately 800 Mbp), diploid genetics, diverse germplasm, and colinearity with other C4 grass genomes. In this study, deep sequencing, genetic linkage analysis, and transcriptome data were used to produce and annotate a high-quality reference genome sequence. Reference genome sequence order was improved, 29.6 Mbp of additional sequence was incorporated, the number of genes annotated increased 24% to 34 211, average gene length and N50 increased, and error frequency was reduced 10-fold to 1 per 100 kbp. Subtelomeric repeats with characteristics of Tandem Repeats in Miniature (TRIM) elements were identified at the termini of most chromosomes. Nucleosome occupancy predictions identified nucleosomes positioned immediately downstream of transcription start sites and at different densities across chromosomes. Alignment of more than 50 resequenced genomes from diverse sorghum genotypes to the reference genome identified approximately 7.4 M single nucleotide polymorphisms (SNPs) and 1.9 M indels. Large-scale variant features in euchromatin were identified with periodicities of approximately 25 kbp. A transcriptome atlas of gene expression was constructed from 47 RNA-seq profiles of growing and developed tissues of the major plant organs (roots, leaves, stems, panicles, and seed) collected during the juvenile, vegetative and reproductive phases. Analysis of the transcriptome data indicated that tissue type and protein kinase expression had large influences on transcriptional profile clustering. The updated assembly, annotation, and transcriptome data represent a resource for C4 grass research and crop improvement. PMID- 29161756 TI - Factors to improve the interobserver agreement for gastric atrophy and intestinal metaplasia: consensus of definition and criteria. AB - AIMS: Intestinal metaplasia and atrophy of the gastric mucosa are associated with Helicobacter pylori infection and are considered premalignant lesions. The updated Sydney system is used for these parameters, but experienced pathologists and consensus processes are required for interobserver agreement. We sought to determine the influence of the consensus process on the assessment of intestinal metaplasia and atrophy. METHODS AND RESULTS: Two study sets were used: consensus and validation. The consensus set was circulated and five gastrointestinal pathologists evaluated them independently using the updated Sydney system. The consensus of the definitions was then determined at the first consensus meeting. The same set was recirculated to determine the effect of the consensus. The second consensus meeting was held to standardise the grading criteria and the validation set was circulated to determine the influence. Two additional circulations were performed to assess the maintainance of consensus and intraobserver variability. Interobserver agreement of intestinal metaplasia and atrophy was improved through the consensus process (intestinal metaplasia: baseline kappa = 0.52 versus final kappa = 0.68, P = 0.006; atrophy: baseline kappa = 0.19 versus final kappa = 0.43, P < 0.001). Higher interobserver agreement in atrophy was observed after consensus regarding the definition (pre consensus: kappa = 0.19 versus post-consensus: kappa = 0.34, P = 0.001). There was improved interobserver agreement in intestinal metaplasia after standardisation of the grading criteria (pre-standardisation: kappa = 0.56 versus post-standardisation: kappa = 0.71, P = 0.010). CONCLUSIONS: This study suggests that interobserver variability regarding intestinal metaplasia and atrophy may result from lack of a precise definition and fine criteria, and can be reduced by consensus of definition and standardisation of grading criteria. PMID- 29161755 TI - Shaker-related voltage-gated K+ channel expression and vasomotor function in human coronary resistance arteries. AB - OBJECTIVES: KV channels are important regulators of vascular tone, but the identity of specific KV channels involved and their regulation in disease remain less well understood. We determined the expression of KV 1 channel subunits and their role in cAMP-mediated dilation in coronary resistance arteries from subjects with and without CAD. METHODS: HCAs from patients with and without CAD were assessed for mRNA and protein expression of KV 1 channel subunits with molecular techniques and for vasodilator response with isolated arterial myography. RESULTS: Assays of mRNA transcripts, membrane protein expression, and vascular cell-specific localization revealed abundant expression of KV 1.5 in vascular smooth muscle cells of non-CAD HCAs. Isoproterenol and forskolin, two distinct cAMP-mediated vasodilators, induced potent dilation of non-CAD arterioles, which was inhibited by both the general KV blocker 4-AP and the selective KV 1.5 blocker DPO-1. The cAMP-mediated dilation was reduced in CAD and was accompanied by a loss of or reduced contribution of 4-AP-sensitive KV channels. CONCLUSIONS: KV 1.5, as a major 4-AP-sensitive KV 1 channel expressed in coronary VSMCs, mediates cAMP-mediated dilation in non-CAD arterioles. The cAMP-mediated dilation is reduced in CAD coronary arterioles, which is associated with impaired 4-AP-sensitive KV channel function. PMID- 29161757 TI - Impact of CYP3A5 genomic variances on clinical outcomes among African American kidney transplant recipients. AB - Little is known about the impact of CYP3A5 polymorphisms on transplantation outcomes among African American (AA) kidney transplant recipients (KTRs). To assess this issue, clinical outcomes were compared between AA CYP3A5*1 expressers and nonexpressers. This retrospective cohort study analyzed AA KTRs. Biopsy proven acute rejection (BPAR), delayed graft function (DGF), glomerular filtration rate (GFR), infections, and tacrolimus dosing requirements were examined in 106 immunologically high-risk AA kidney transplant patients over a 2 year follow-up period. In CYP3A5*1 expressers compared to nonexpressers, the incidence of BPAR was significantly higher in the first 6 months (13% vs 0%; P = .016) compared to 24 months (13% vs 7%; P = .521). Tacrolimus total daily dose at first therapeutic level was significantly higher in CYP3A5*1 expressers (12 mg/day) compared to nonexpressers (8 mg/day; P < .001). Compared to CYP3A5*1 nonexpressers, DGF incidence was significantly higher among CYP3A5*1 expressers (27.6% vs 6.7%; P = .006). By contrast, median GFR was significantly higher in CYP3A5*1 expressers compared to nonexpressers (54.5 mL/min vs 50.0 mL/min; P = .003) at 24 months. The findings from this retrospective study suggest that AAs with CYP3A5*1 expression require 50% more tacrolimus and have an increased incidence of DGF and acute rejection. PMID- 29161758 TI - Young athletes' health knowledge system: Qualitative analysis of health learning processes in adolescent sportspersons. AB - Recognized side effects on health associated with sports participation in youth include overtraining, doping, and exposure to harassment and violence. Many of these effects originate in contexts where young athletes are beginning to make decisions about their sports practices on their own. This study sets out to explore knowledge and reasoning about health among adolescent athletes and to describe how health knowledge management structures are associated with different social systems. Qualitative data were collected from focus groups involving 65 young Swedish athletes aged 16-17 years. The participants' knowledge and reasoning about health were examined using a deductive thematic analysis, categories from Bloom's taxonomy of educational objectives, and Luhmann's social systems theory. The meaning of health was found to have a dynamic character for the young athletes, associated with constantly striving to satisfy immediate needs and fulfill short-time life goals. The athletes' thinking about health was associated with a pragmatic "health-as-a-resource" perspective, characterized by group self-comparisons, rapid cognitive processing, and opportunistic substitutions. They expressed a particular interest in experiential learning and personally relevant procedural knowledge, and they perceived that their factual knowledge about health was saturated. The results of this study add emphasis to the importance of involving adolescent sportspersons in the development of health education programs and contextualizing the programs to the athletes' specific age and social environment. PMID- 29161759 TI - Asymmetry during Functional Movement Screening and injury risk in junior football players: A replication study. AB - An indicator of movement quality and potential injury risk during Functional Movement Screen (FMS) testing is the presence of asymmetry when comparing the left and right sides of the body. The aim of the study was to investigate the reproducibility of the injury risk model proposed in our previous research (Chalmers et al. 2017; derivation study) that showed an increased injury risk for elite junior Australian football players demonstrating >=2 asymmetrical FMS subtests. We used a direct replication design. Players underwent pre-season FMS testing, and an injury surveillance system monitored 277 male participants during the subsequent regular season competition. Designated club officials monitored the weekly competition participation of players. The definition of an injury was "a trauma or medical condition which caused a player to miss a competitive game". Cox proportional hazards regression models were used to investigate the relationship between asymmetry and number of games played before first injury (ie, survival time). The level of reproducibility was determined according to statistical significance, effect size, and subjective assessment. Demonstrating asymmetry during FMS testing was not associated with a significant increase in prospective injury risk in the replication study (P > .05). Moreover, effect sizes (hazard ratios) from the derivation dataset were not within the 95% confidence intervals of the respective asymmetry predictor in the replication dataset. Subjectively, researchers were in agreement that the findings from the derivation data were not successfully reproduced. Clinicians and researchers should be cautious about using FMS asymmetry findings to derive injury risk for junior football players. PMID- 29161760 TI - Ecological selection of siderophore-producing microbial taxa in response to heavy metal contamination. AB - Some microbial public goods can provide both individual and community-wide benefits, and are open to exploitation by non-producing species. One such example is the production of metal-detoxifying siderophores. Here, we investigate whether conflicting selection pressures on siderophore production by heavy metals - a detoxifying effect of siderophores, and exploitation of this detoxifying effect - result in a net increase or decrease. We show that the proportion of siderophore producing taxa increases along a natural heavy metal gradient. A causal link between metal contamination and siderophore production was subsequently demonstrated in a microcosm experiment in compost, in which we observed changes in community composition towards taxa that produce relatively more siderophores following copper contamination. We confirmed the selective benefit of siderophores by showing that taxa producing large amounts of siderophore suffered less growth inhibition in toxic copper. Our results suggest that ecological selection will favour siderophore-mediated decontamination, with important consequences for potential remediation strategies. PMID- 29161761 TI - Pelvic local recurrence from colorectal cancer: surgical challenge with changing preconditions. AB - AIM: Although the rate of local recurrence (LR) after colorectal cancer surgery has decreased, it still poses major surgical and oncological challenges. The aims of this study, based on an audit from a tertiary referral centre, was to evaluate determinants associated with outcomes after surgery for pelvic LR and how these have changed over time. METHOD: Retrospective analysis of all resections for pelvic LR of colorectal cancer performed at the Karolinska University Hospital from January 2003 until August 2009 (period 1) and from September 2009 until November 2013 (period 2) . RESULTS: Ninety-five patients with pelvic LR were operated on with a curative intent. An R0 resection was achieved in 77% and an R1 resection in 23%. Lateral compartments were invaded in 48% and this proportion increased in resections performed in period 2 (37% vs 60%, P = 0.05). R1 resections were associated with a higher risk of local re-recurrence than R0 resections (64% vs 16%; OR = 8.90, 95% CI: 2.71-29.78). Lateral recurrences were associated with a lower R0-resection rate than nonlateral recurrences (63% vs 90%; OR = 0.20, 95% CI: 0.05-0.64) and a higher risk of treatment failure in terms of local re-recurrence or distant metastases, or death, as first event (hazard ratio [HR] = 1.75, 95% CI: 1.06-2.75). However, in a multivariate analysis only R1 resections remained a significant prognostic factor for treatment failure (HR = 2.37, 95% CI: 1.32-4.27). CONCLUSION: The proportion of lateral pelvic recurrences has increased over time. In comparison with non lateral LRs, lateral LRs are more difficult to resect radically and are associated with worse overall and disease-free survival. However, with radical surgery many patients with pelvic locally recurrent colorectal cancer may be offered curative treatment. PMID- 29161762 TI - Temperature-dependent body size effects determine population responses to climate warming. AB - Current understanding of animal population responses to rising temperatures is based on the assumption that biological rates such as metabolism, which governs fundamental ecological processes, scale independently with body size and temperature, despite empirical evidence for interactive effects. Here, we investigate the consequences of interactive temperature- and size scaling of vital rates for the dynamics of populations experiencing warming using a stage structured consumer-resource model. We show that interactive scaling alters population and stage-specific responses to rising temperatures, such that warming can induce shifts in population regulation and stage-structure, influence community structure and govern population responses to mortality. Analysing experimental data for 20 fish species, we found size-temperature interactions in intraspecific scaling of metabolic rate to be common. Given the evidence for size temperature interactions and the ubiquity of size structure in animal populations, we argue that accounting for size-specific temperature effects is pivotal for understanding how warming affects animal populations and communities. PMID- 29161763 TI - Quantifying the relationship between inhibition of VEGF receptor 2, drug-induced blood pressure elevation and hypertension. AB - BACKGROUND AND PURPOSE: Several anti-angiogenic cancer drugs that inhibit VEGF receptor (VEGFR) signalling for efficacy are associated with a 15-60% incidence of hypertension. Tyrosine kinase inhibitors (TKIs) that have off-target activity at VEGFR-2 may also cause blood pressure elevation as an undesirable side effect. Therefore, the ability to translate VEGFR-2 off-target potency into blood pressure elevation would be useful in development of novel TKIs. Here, we have sought to quantify the relationship between VEGFR-2 inhibition and blood pressure elevation for a range of kinase inhibitors. EXPERIMENTAL APPROACH: Porcine aortic endothelial cells overexpressing VEGFR-2 (PAE) were used to determine IC50 for VEGFR-2 phosphorylation. These IC50 values were compared with published reports of exposure attained during clinical use and the corresponding incidence of all grade hypertension. Unbound average plasma concentration (Cav,u ) was selected to be the most appropriate pharmacokinetic parameter. The pharmacokinetic pharmacodynamic (PKPD) relationship for blood pressure elevation was investigated for selected kinase inhibitors, using data derived either from clinical papers or from rat telemetry experiments. KEY RESULTS: All-grade hypertension was predominantly observed when the Cav,u was >0.1-fold of the VEGFR-2 (PAE) IC50 . Furthermore, based on the PKPD analysis, an exposure-dependent blood pressure elevation >1 mmHg was observed only when the Cav,u was >0.1-fold of the VEGFR-2 (PAE) IC50 . CONCLUSIONS AND IMPLICATIONS: Taken together, these data show that the risk of blood pressure elevation is proportional to the amount of VEGFR-2 inhibition, and a margin of >10-fold between VEGFR-2 IC50 and Cav,u appears to confer a minimal risk of hypertension. PMID- 29161764 TI - Mechanism of doxorubicin cardiotoxicity evaluated by integrating multiple molecular effects into a biophysical model. AB - BACKGROUND AND PURPOSE: Doxorubicin (DOX) is an effective cancer therapeutic agent but causes therapy-limiting cardiotoxicity. The effects of DOX and its metabolite doxorubicinol (DOXL) on individual channels have been well characterized in isolation. However, it is unknown how the action and interaction of affected channels combine to generate the phenotypic cardiotoxic outcome. We sought to develop an in silico model that links drug effects on channels to action potential duration (APD) and intracellular Ca2+ concentration in order to address this gap in knowledge. EXPERIMENTAL APPROACH: We first propose two methods to obtain, from published values, consensus drug effects on the currents of individual channels, transporters and pumps. Separately, we obtained equivalent values for APD and Ca2+ concentration (the readouts used as surrogates for cardiotoxicity). Once derived, the consensus effects on the currents were incorporated into established biophysical models of the cardiac myocyte and were refined adjusting the sarcoplasmic reticulum Ca2+ leak current (ILeak ) until the consensus effects on APD and Ca2+ dynamics were replicated. Using factorial analysis, we then quantified the relative contribution of each channel to DOX and DOXL cardiotoxicity. KEY RESULTS: The factorial analysis identified the rapid delayed rectifying K+ current, the L-type Ca2+ current and the sarcoplasmic reticulum ILeak as the targets primarily responsible for the cardiotoxic effects on APD and Ca2+ dynamics. CONCLUSIONS AND IMPLICATIONS: This study provides insight into the mechanisms of DOX-induced cardiotoxicity and a framework for the development of future diagnostic and therapeutic strategies. PMID- 29161765 TI - miR-335 inhibited cell proliferation of lung cancer cells by target Tra2beta. AB - Accumulating evidence has suggested that the dysregulation of miRNA is an important factor in the pathogenesis of lung cancer. Here, we demonstrate that miR-335 expression is reduced in non-small cell lung cancer (NSCLC) tumors relative to non-cancerous adjacent tissues, while the expression of Tra2beta is increased. In addition, clinical data revealed that the increased Tra2beta and decreased miR-335 expression observed in NSCLC cells was associated with poor patient survival rates. In vitro experimentation showed that the overexpression of miR-335 inhibited the growth, invasion and migration capabilities of A459 lung cancer cells, by targeting Tra2beta. In contrast, inhibition of miR-335 or overexpression of the Tra2beta target gene stimulated the growth, invasion and migratory capabilities of A459 lung cancer cells in vitro. Furthermore, overexpression of miR-335 or inhibition of Tra2beta decreased the phosphorylation of Rb-S780 and Rb-AKT. Overall, these findings suggest that the downregulation of miR-335 in A459 lung cancer cells promoted cell proliferation through upregulation of Tra2beta, mediated via activation of the AKT/mTOR signaling pathway, and suggest that miR-335 may have potential as a novel therapeutic target for NSCLC. PMID- 29161766 TI - Identification of alpha-gal sensitivity in patients with a diagnosis of idiopathic anaphylaxis. AB - IgE antibodies (Ab) specific to galactose-alpha-1,3-galactose (alpha-gal) are responsible for a delayed form of anaphylaxis that occurs 3-6 hours after red meat ingestion. In a unique prospective study of seventy participants referred with a diagnosis of idiopathic anaphylaxis (IA), six (9%) were found to have IgE to alpha-gal. Upon institution of a diet free of red meat, all patients had no further episodes of anaphylaxis. Two of these individuals had indolent systemic mastocytosis (ISM). Those with ISM had more severe clinical reactions but lower specific IgE to alpha-gal and higher serum tryptase levels, reflective of the mast cell burden. The identification of alpha-gal syndrome in patients with IA supports the need for routine screening for this sensitivity as a cause of anaphylaxis, where reactions to alpha-gal are delayed and thus may be overlooked. PMID- 29161767 TI - Effects of different endurance exercise modalities on migraine days and cerebrovascular health in episodic migraineurs: A randomized controlled trial. AB - Aerobic exercise training is a promising complementary treatment option in migraine and can reduce migraine days and improve retinal microvascular function. Our aim was to elucidate whether different aerobic exercise programs at high vs moderate intensities distinctly affect migraine days as primary outcome and retinal vessel parameters as a secondary. In this randomized controlled trial, migraine days were recorded by a validated migraine diary in 45 migraineurs of which 36 (female: 28; age: 36 (SD:10)/BMI: 23.1 (5.3) completed the training period (dropout: 20%). Participants were assigned (Strata: age, gender, fitness and migraine symptomatology) to either high intensity interval training (HIT), moderate continuous training (MCT), or a control group (CON). Intervention groups trained twice a week over a 12-week intervention period. Static retinal vessel analysis, central retinal arteriolar (CRAE) and venular (CRVE) diameters, as well as the arteriolar-to-venular diameter ratio (AVR) were obtained for cerebrovascular health assessment. Incremental treadmill testing yielded maximal and submaximal fitness parameters. Overall, moderate migraine day reductions were observed (etaP2 = .12): HIT revealed 89% likely beneficial effects (SMD = 1.05) compared to MCT (SMD = 0.50) and CON (SMD = 0.59). Very large intervention effects on AVR improvement (etaP2 = 0.27), slightly favoring HIT (SMD=-0.43) over CON (SMD=0), were observed. HIT seems more effective for migraine day reduction and improvement of cerebrovascular health compared to MCT. Intermittent exercise programs of higher intensities may need to be considered as an additional treatment option in migraine patients. PMID- 29161768 TI - The safety of complete mesocolic excision once again confirmed. PMID- 29161769 TI - Influence of biceps brachii tendon mechanical properties on elbow flexor force steadiness in young and old males. AB - Elbow flexor force steadiness (FS) depends on strength and decreases with age. Achilles tendon mechanics effect standing balance and isometric plantarflexion FS. This study investigated the influence of distal biceps brachii (BB) tendon mechanics and elbow flexor strength on age-related decline in FS. Nine young (23 +/- 2 years) and nine old (77 +/- 5 years) males performed submaximal isometric elbow flexion tasks at low (2.5%, 5%, 10% maximal voluntary contraction (MVC)) and high (20%, 40%, 60%, 80%MVC) forces in a neutral forearm position. Distal BB tendon elongation and cross-sectional area (CSA) were recorded on ultrasound to calculate mechanics of strain, stress, and stiffness. Coefficient of variation (CV) of force was used to assess relationship of FS to tendon mechanics and strength. Young were 22% stronger and 41% steadier than old (P < .05). Tendon stiffness (170.1 +/- 132.9 N/mm; 113.0 +/- 55.1 N/mm) did not differ with age (P > .05). Young had 40% less strain compared to old at 5% MVC, but 42% greater strain at 60% and 80% MVC (P <= .05). Stress was ~18% greater in young at 10%, 20%, and 80% MVC (P <= .05). At low forces, CV of force was predicted by stress (r2 = 0.56) in young, and stress and MVC (r2 = 0.641) in old. At high forces for both age groups, CV of force was predicted by MVC and stress (r2 = 0.39 0.43). Stress and strain is greater in young compared with old males. Because strength influences tendon mechanics and is also associated with FS, absolute strength is a large and modifiable contributor to age-related decline in FS. PMID- 29161770 TI - Twin models of environmental and genetic influences on pubertal development, salivary testosterone, and estradiol in adolescence. AB - OBJECTIVE: Research on sources of variation in adolescent's gonadal hormone levels is limited. We sought to decompose individual differences in adolescent testosterone, estradiol, and pubertal status, into genetic and environmental components. DESIGN: A sample of male and female adolescent twins from the greater Austin and Houston areas provided salivary samples, with a subset of participants providing longitudinal data at 2 waves. PARTICIPANTS: The sample included 902 adolescent twins, 49% female, aged 13-20 years (M = 15.91) from the Texas Twin Project. Thirty-seven per cent of twin pairs were monozygotic; 30% were same-sex dizygotic (DZ) pairs; and 33% were opposite-sex DZ pairs. MEASUREMENTS: Saliva samples were assayed for testosterone and estradiol using chemiluminescence immunoassays. Pubertal status was assessed using self-report. Biometric decompositions were performed using multivariate quantitative genetic models. RESULTS: Genetic factors contributed substantially to variation in testosterone in males and females in the follicular phase of their menstrual cycle (h2 = 60% and 51%, respectively). Estradiol was also genetically influenced in both sexes, but was predominately influenced by nonshared environmental factors. The correlation between testosterone and estradiol was mediated by a combination of genetic and environmental influences for males and females. Genetic and environmental influences on hormonal concentrations were only weakly correlated with self-reported pubertal status, particularly for females. CONCLUSIONS: Between-person variability in adolescent gonadal hormones and their interrelationship reflects both genetic and environmental processes, with both testosterone and estradiol containing sizeable heritable components. PMID- 29161772 TI - Microarray analysis of gene expression in the cyclooxygenase knockout mice - a connection to autism spectrum disorder. AB - The cellular and molecular events that take place during brain development play an important role in governing function of the mature brain. Lipid-signalling molecules such as prostaglandin E2 (PGE2 ) play an important role in healthy brain development. Abnormalities along the COX-PGE2 signalling pathway due to genetic or environmental causes have been linked to autism spectrum disorder (ASD). This study aims to evaluate the effect of altered COX-PGE2 signalling on development and function of the prenatal brain using male mice lacking cyclooxygenase-1 and cyclooxygenase-2 (COX-1-/- and COX-2-/- ) as potential model systems of ASD. Microarray analysis was used to determine global changes in gene expression during embryonic days 16 (E16) and 19 (E19). Gene Ontology: Biological Process (GO:BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were implemented to identify affected developmental genes and cellular processes. We found that in both knockouts the brain at E16 had nearly twice as many differentially expressed genes, and affected biological pathways containing various ASD-associated genes important in neuronal function. Interestingly, using GeneMANIA and Cytoscape we also show that the ASD-risk genes identified in both COX-1-/- and COX-2-/- models belong to protein-interaction networks important for brain development despite of different cellular localization of these enzymes. Lastly, we identified eight genes that belong to the Wnt signalling pathways exclusively in the COX-2-/- mice at E16. The level of PKA-phosphorylated beta catenin (S552), a major activator of the Wnt pathway, was increased in this model, suggesting crosstalk between the COX-2-PGE2 and Wnt pathways during early brain development. Overall, these results provide further molecular insight into the contribution of the COX-PGE2 pathways to ASD and demonstrate that COX-1-/- and COX-2-/- animals might be suitable new model systems for studying the disorders. PMID- 29161771 TI - Tetramethylpyrazine nitrone activates the BDNF/Akt/CREB pathway to promote post ischaemic neuroregeneration and recovery of neurological functions in rats. AB - BACKGROUND AND PURPOSE: Neuronal regeneration from endogenous precursors is an attractive strategy for the treatment of ischaemic stroke. However, most stroke generated newborn neurons die over time. Therefore, a drug that is both neuroprotective and pro-neurogenic may be beneficial after stroke. Here, we assessed the neurogenic and oligodendrogenic effects of tetramethylpyrazine nitrone (TBN), a neuroprotective drug candidate for stroke, in a rat model of ischaemic stroke. EXPERIMENTAL APPROACH: We used Sprague Dawley rats with middle cerebral artery occlusion (MCAO). TBN was administered by tail vein injection beginning at 3 h post ischaemia. Therapeutic effect of TBN was evaluated by neurological behaviour and cerebral infarction. Promotion of neurogenesis and oligodendrogenesis was determined by double immunofluorescent staining and Western blotting analyses. Primary cultures of cortical neurons were used to assess the effect of TBN on neuronal differentiation in vitro. KEY RESULTS: TBN reduced cerebral infarction, preserved and/or restored neurological function and promoted neurogenesis and oligodendrogenesis in rats after MCAO. In addition, TBN stimulated neuronal differentiation on primary culture of cortical neurons in vitro. Pro-neurogenic effects of TBN were attributed to its activation of the AKT/cAMP responsive element-binding protein through increasing brain-derived neurotrophic factor (BDNF) expression, as shown by the abolition of the effects of TBN by a specific inhibitor of BDNF receptor ANA-12 and by the PI3K inhibitor LY294002. CONCLUSION AND IMPLICATIONS: As TBN can simultaneously provide neuroprotection and pro-neurogenic effects, it may be a promising treatment for both acute phase neuroprotection and long-term functional recovery after ischaemic stroke. PMID- 29161773 TI - Silodosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia. AB - BACKGROUND: A variety of alpha-blockers are used for treating lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). Silodosin is a novel, more selective alpha-blocker, which is specific to the lower urinary tract and may have fewer side effects than other alpha-blockers. OBJECTIVES: To assess the effects of silodosin for the treatment of LUTS in men with BPH. SEARCH METHODS: We performed a comprehensive search using multiple databases (Cochrane Library, MEDLINE, EMBASE, Scopus, Google Scholar, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up until 13 June 2017. SELECTION CRITERIA: We included all parallel, randomized controlled trials. We also included cross-over designs. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies and abstracted data from the included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of evidence according to the GRADE approach. MAIN RESULTS: We included 19 unique studies with 4295 randomized participants across four comparisons for short-term follow-up. The mean age, prostate volume, and International Prostate Symptom Score were 66.5 years, 38.2 mL, and 19.1, respectively. Silodosin versus placeboBased on four studies with a total of 1968 randomized participants, silodosin may reduce urologic symptom scores in an appreciable number of men (mean difference (MD) -2.65, 95% confidence interval (CI) -3.23 to -2.08; low-quality evidence). Silodosin likely does not result in a clinically important reduction in quality of life (MD -0.42, 95% CI -0.71 to 0.13; moderate-quality evidence). It may not increase rates of treatment withdrawal for any reason (relative risk (RR) 1.08, 95% CI 0.70 to 1.66; low quality evidence). We are uncertain about the effect of silodosin on cardiovascular adverse events (RR 1.28, 95% CI 0.67 to 2.45; very low-quality evidence). Silodosin likely increases sexual adverse events (RR 26.07, 95% CI 12.36 to 54.97; moderate-quality evidence); this would result in 180 more sexual adverse events per 1000 men (95% CI 82 more to 388 more). Silodosin versus tamsulosinBased on 13 studies with a total of 2129 randomized participants, silodosin may result in little to no difference in urologic symptom scores (MD 0.04, 95% CI -1.31 to 1.24; low-quality evidence) and quality of life (MD -0.15, 95% CI -0.53 to 0.22; low-quality evidence). We are uncertain about treatment withdrawals for any reason (RR 1.02, 95% CI 0.62 to 1.69; very low-quality evidence). Silodosin may result in little to no difference in cardiovascular adverse events (RR 0.77, 95% CI 0.53 to 1.12; low-quality evidence). Silodosin likely increases sexual adverse events (RR 6.05, 95% CI 3.55 to 10.31; moderate quality evidence); this would result in 141 more sexual adverse events per 1000 men (95% CI 71 more to 261 more). Silodosin versus naftopidilBased on five studies with a total of 763 randomized participants, silodosin may result in little to no differences in urologic symptom scores (MD -0.85, 95% CI -2.57 to 0.87; low-quality evidence), quality of life (MD -0.17, 95% CI -0.60 to 0.27; low quality evidence), treatment withdrawal for any reason (RR 1.25, 95% CI 0.81 to 1.93; low-quality evidence), and cardiovascular adverse events (RR 1.02, 95% CI 0.41 to 2.56; low-quality evidence). Silodosin likely increases sexual adverse events (RR 5.93, 95% CI 2.16 to 16.29; moderate-quality evidence); this would result in 74 more sexual adverse events per 1000 men (95% CI 17 more to 231 more). Silodosin versus alfuzosinBased on two studies with a total of 155 randomized participants, silodosin may or may not result in a clinically important increase in urologic symptom scores (MD 3.83, 95% CI 0.12 to 7.54; low quality evidence). Silodosin likely results in little to no difference in quality of life (MD 0.14, 95% CI -0.46 to 0.74; moderate-quality evidence). We found no event of treatment withdrawal for any reason. Silodosin may not reduce cardiovascular adverse events (RR 0.67, 95% CI 0.36 to 1.24; low-quality evidence) but likely increases sexual adverse events (RR 37.21, 95% CI 5.32 to 260.07; moderate-quality evidence); this would result in 217 more sexual adverse events per 1000 men (95% CI 26 more to 1000 more). AUTHORS' CONCLUSIONS: Silodosin may reduce urologic symptom scores in an appreciable number of men compared to placebo. Quality of life and treatment withdrawals for any reason appears similar. Its efficacy appears similar to that of other alpha blockers (tamsulosin, naftopidil and alfuzosin) but the rate of sexual side effects is likely higher. Our certainty in the estimates of effect was lowered due to study limitations, inconsistency and imprecision. PMID- 29161774 TI - Building trophic specializations that result in substantial niche partitioning within a young adaptive radiation. AB - Dietary partitioning often accompanies the increased morphological diversity seen during adaptive radiations within aquatic systems. While such niche partitioning would be expected in older radiations, it is unclear how significant morphological divergence occurs within a shorter time period. Here we show how differential growth in key elements of the feeding mechanism can bring about pronounced functional differences among closely related species. An incredibly young adaptive radiation of three Cyprinodon species residing within hypersaline lakes in San Salvador Island, Bahamas, has recently been described. Characterized by distinct head shapes, gut content analyses revealed three discrete feeding modes in these species: basal detritivory as well as derived durophagy and lepidophagy (scale-feeding). We dissected, cleared and stained, and micro-CT scanned species to assess functionally relevant differences in craniofacial musculoskeletal elements. The widespread feeding mode previously described for cyprinodontiforms, in which the force of the bite may be secondary to the requisite dexterity needed to pick at food items, is modified within both the scale specialist and the durophagous species. While the scale specialist has greatly emphasized maxillary retraction, using it to overcome the poor mechanical advantage associated with scale-eating, the durophage has instead stabilized the maxilla. In all species the bulk of the adductor musculature is composed of AM A1. However, the combined masses of both adductor mandibulae (AM) A1 and A3 in the scale specialist were five times that of the other species, showing the importance of growth in functional divergence. The scale specialist combines plesiomorphic jaw mechanisms with both a hypertrophied AM A1 and a slightly modified maxillary anatomy (with substantial functional implications) to generate a bite that is both strong and allows a wide range of motion in the upper jaw, two attributes that normally tradeoff mechanically. Thus, a significant feeding innovation (scale-eating, rarely seen in fishes) may evolve based largely on allometric changes in ancestral structures. Alternatively, the durophage shows reduced growth with foreshortened jaws that are stabilized by an immobile maxilla. Overall, scale specialists showed the most divergent morphology, suggesting that selection for scale-biting might be stronger or act on a greater number of traits than selection for either detritivory or durophagy. The scale specialist has colonized an adaptive peak that few lineages have climbed. Thus, heterochronic changes in growth can quickly produce functionally relevant change among closely related species. PMID- 29161775 TI - The influence of different peptide combinations to increase the immunogenicity of the Gonadotrophin Releasing Hormone Vaccine for prostate cancer treatment. AB - Purpose: Therapeutic vaccines, specifically the Gonadotrophin Releasing Hormone (GnRH) vaccine, are considered an additional therapeutic option for advanced stage prostate cancer. Our work showed amplification of the immune response when combining two peptides with and without the Very Small Size Proteoliposomes (VSSP). VSSP is a potent adjuvant for dendritic cells activation and Th1 differentiation. as enhanced immune response. Methods: The test was carried out in Copenhagen rats as animal model. Resultst: The use of both peptides and their combination with VSSP generated a potentiation of the immune response statistically superior, in term of generating anti GnRH antibody and effects on target organs, when it was compared with the effects which occurs with independent peptides and with and without the VSSP. These results can find application in the development of GnRH vaccine candidates and in peptide based vaccine strategies. Conclusions: Immunization with the peptide combination enhances the immune response when mixed with the VSSPs. PMID- 29161776 TI - Awareness on cytology procedure in oral cancer detection among undergraduates: An institutional study. AB - Background: The screening and the early detection of the premalignant and malignant lesions are the only means for controlling the oral cancer which is known to be one of the leading causes for mortality worldwide. Oral exfoliative cytology though not a substitute for biopsy can be a powerful tool for its early detection. Dental Surgeons can play a great role in this direction. Aims and Objectives: The present study was undertaken to assess the self-reported knowledge and attitude regarding the early detection of oral cancer and exfoliative cytology among the undergraduates of Rama Dental College, Kanpur. Material and Methods: A pretested questionnaire based cross sectional study consisting of twenty four questions was conducted among hundred randomly selected students from third year, final year and intern's batch. Results: According to 73% of students biopsy was the special test done in oral cancer detection and only 59% had heard regarding oral cytology technique. Formalin was the fixative known for cytology smears among 61%. Significance of toluidine blue staining was not known by 62%. Seventy seven percent of students were not aware about classes of cytology reporting. Eighty six percent of students felt that the adequacy of training in cytology was lagging. Conclusion: This survey identified an existing gap in the knowledge among the dental students regarding cytology as a diagnostic aid in oral cancer detection. This emphasizes the need to provide training for undergraduates at clinical level on regular basis and also through CDE and oral can-cer detection workshops. PMID- 29161777 TI - Structure-based design and evaluation of synthetic porphyrin derivatives as G quadruplex stabilizing anticancer agents. AB - OBJECTIVE: G-quadruplex structures formed in telomeres and proto-oncogene represent a potentially useful target for anticancer drugs. Stabilization of this arrangement may inhibit the further action of different enzymes involved in cancer cell immortalization. In present work structure based drug design and synthesis was carried out on series of meso-substituted porphyrin analogues. The interaction of porphyrin derivatives with G-quadruplex DNA has been explored by virtual screening procedure. Some of the potential binding agents were then synthesized and evaluated in-vitro by MTT and PCR stop assay. The study indicates that these compounds had strong G-Quadruplex binding affinity with very good inhibitory activity in MCF-7 and A549 cell lines. PMID- 29161778 TI - Highly efficient destruction of squamous carcinoma cells of the head and neck by photochemical internalization of Ranpirnase. AB - Introduction: Photochemical Internalization is a novel drug delivery technology for cancer treatment based on the principle of Photodynamic Treatment. Using a photosensitizer that locates in endocytic vesicles membranes of tumor cells, Photochemical internalization enables cytosolic release of endocytosed antitumor agents in a site-specific manner. The purpose of the present in-vitro study was to explore whether Photochemical Internalization is able to enhance the efficacy of Ranpirnase, a cytotoxic amphibian ribonuclease, for eradication of squamous cell carcinoma of the head and neck. Methods: Cell viability was measured in 8 primary human cell lines of squamous cell carcinoma of the head and neck after treatment with Ranpirnase and Photochemical Internalization. For Photochemical Internalization the photosensitizer disulfonated tetraphenyl porphine was incubated with tumor cells followed by exposure to blue light (435 nm). Results: Our study demonstrates significant enhancement of antitumor activity of Ranpirnase by Photochemical Internalization. Treatment responses were heterogeneous between the primary cancer cell lines. Combining Photochemical Internalization with Ranpirnase resulted in 4.6 to 1,940-fold increased cytotoxicity when compared with the ribonuclease alone (P < 0.05). Conclusion: Cytotoxicity of Ranpirnase can be markedly enhanced by Photochemical Internalization in squamous cell carcinoma of the head and neck. PMID- 29161779 TI - Micronuclei assay in exfoliated buccal cells of radiation treated oral cancer patients. AB - BACKGROUND: Micronuclei are suitable internal dosimeters for revealing tissue specific genotoxic damage in individuals exposed to carcinogenic mixtures. Evaluation of radiation-induced cellular changes to predict radiosensitivity has invested many investigators since such changes were first found in biopsy material. AIM: The aim of the present study was to assess the relationship of with histopathological grade and number of radiation therapy sittings with the frequency of micronuclei and nuclear anomalies among oral cancer patients. MATERIAL & METHOD: Thirty male patients with histologically proven cases of oral cancer undergoing radiation therapy and age and sex matched 20 healthy controls were included in the study. Scrape cytology smears of exfoliated buccal cells were prepared and stained using Feulgen stain and frequency of micronuclei and other nuclear anomalies counts were evaluated with the help of light microscope expressed as per 1000 buccal cells. RESULTS: The mean values of the micronuclei and nuclear anomalies were 14.03 and 21.30 respectively. There was a significant association and strong positive correlation of Radiation exposure and grades of squamous cell carcinoma with micronuclei and nuclear anomalies. There was no statistically significant association and correlation between nuclear anomalies in well differentiated and moderately differentiated carcinomas. CONCLUSION: With increase number of radiation therapy sittings, there was increase in number of micronuclei and nuclear anomalies. Hence the result of this study highlights that increased number of micronuclei and nuclear anomalies provides information regarding radiosensitivity of epithelial cells. PMID- 29161780 TI - Assessment of relationship of ABO blood groups among tobacco induced oral cancer patients of Kanpur Population, Uttar Pradesh. AB - Background: The possibility of association between ABO blood groups and malignancy was first discussed by Anderson DE & Haas C. The association between blood group and oral cancer is least explored and hence this study was undertaken to evaluate relationship of ABO blood groups with an increased risk for oral cancer. Materials and method: The present study was conducted at various cancer hospitals in Kanpur. The study samples comprised 100 oral cancer patients and 50 controls with tobacco chewing habit. The information regarding the socio demographic profile, history on tobacco habits, type of oral cancer and ABO blood group profile was obtained from the case sheets of the patients. Results: The frequency of squamous cell carcinoma was significantly higher in men (78%) than women (22%) and mostly found in the age range of 45-65 years and also consuming chewing type of tobacco. It was found that out of 100 patients, 53 were of blood group B+ve, 28 of O +ve, 16 of A+ve and 3 had the blood group AB+ve. The high potential risk of developing OSCC was more in B+ve blood group (1.96 times), and relative frequency (%) in blood group O+ve (1.64 times) than in the control group Among locations of oral cancers, squamous cell carcinoma of tongue (25%) and buccal mucosa (15%) was more common in B+ve and Carcinoma of floor of mouth (11%) was more common in O+ve blood group cases. It was found that people with blood group B+ve, followed by O+ve had increased risk of developing OSCC with most prevalent being Well Differentiated OSCC as compared to people of other blood groups. Conclusion: The present study reveals that there is an inherited element in the susceptibility against different types of oral cancers. The people with blood group B+ve and O+ve having tobacco chewing habits can be appraised that they are more at risk to develop oral cancer than people with other blood groups. PMID- 29161781 TI - In silico docking studies of Lupeol with MAPK pathway proteins- Raf-1, MEK & ERK. AB - OBJECTIVE: Lupeol, A triterpenoid found in variety of plants is reported to have beneficial medicinal effects on several ailments. Lupeol is also found to show inhibitory effect on proliferation of breast cancer cells. Metastasis is considered to be a major cause for worldwide deaths related to cancer. Ras related MAPK Signaling Pathway is one of the crucial pathways leading to metastasis. Lupeols binding possibility with Ras is already reported. In present study, Interaction between with downstream proteins of Ras- MAPK pathway, Raf ,MEK ,ERK1/2 and their corresponding domains are studied using STRING Database and their structures are retrieved in PDB Format. Lupeols binding affinity with downstream proteins of these signaling proteins at their interacting domains are analyzed. Here in silico docking approach to identify binding sites of each of these proteins with Lupeol is used. FDA approved standard drug molecule CH5126766 was used as reference ligand. Lupeol shows potent binding at significant sites with extremely high affinity. Since it binds with all the proteins involved in the pathway with high efficiency it is an important compound which can be developed as a therapeutic molecule. PMID- 29161782 TI - Cancer Cell Controller. AB - OBJECTIVE: Cancer is the disease which exists when the cell is uncontrolled. This paper presents a controller for the same. The cancer cell is reviewed via algebraic structures. PMID- 29161783 TI - Cancer treatment and management for elderly patients 80 years of age or older with malignant solid tumors. AB - OBJECTIVE: We retrospectively analyzed the backgrounds, treatment and nursing care for 96 patients aged 80 years or more with malignant tumors. Twenty of them were hospitalized on an emergency basis. Sixty patients were male and 36 were female, with a median age of 83 years (range: 80-94 years). Twenty-seven had a PS of 3 or 4, and 41 were rated as not independent based on analysis of autonomy at hospitalization. Forty-seven patients had clinical stage III or IV malignancies. The proportions of patients with disease complications were 33.3% for neurological disease, 21.9% for respiratory disease, 70.8% for cardiovascular disease including hypertension, and 36.5% for metabolic disease. Thirty-nine patients underwent surgical or endoscopic resection of their tumors. Twenty-three patients received chemotherapy: hormonal treatment in 14, local injection of cytotoxic agent(s) in 6 and systemic anti-cancer therapy in 3. Thirty-nine patients received supportive care only. Forty-three patients newly required nursing care or an increased level of care at discharge. The median survival time was 10.9 and 15.3 months for stage III/IV and 0/I/II patients, respectively. In conclusion, most elderly patients with malignant tumors require full supportive care, including social nursing care, from the time of cancer diagnosis. PMID- 29161784 TI - Calcifying epithelial odontogenic cyst. AB - OBJECTIVE: The Calcifying Odontogenic Cyst was first described as a distinct clinicopathologic entity by Gorlin and his colleagues in 1962. Gold (1963) chose a similar, but not identical term for the lesion, namely 'keratinizing and calcifying odontogenic cyst'. The calcifying cystic odontogenic tumor (CCOT) is a new designation of calcifying odontogenic cyst (COC) recommended by the 2005 classification of the World Health Organization (WHO). The calcifying odontogenic cyst is not a common lesion; the dentinogenic ghost cell tumor is even less common and should be considered rare. The lesions have in common the peculiar abnormal keratinization of odontogenic and metrical (hair) epithelial cells that is termed 'ghost cell' or 'shadow cell' keratinization. A rare, well circumscribed, solid or cystic lesion derived from odontogenic epithelium that resembles follicular ameloblastoma but contains 'ghost cells' and spherical calcifications. The so-called calcifying odontogenic cyst (COC) represents a heterogeneous group of lesions that exhibit a variety of clinicopathologic and behavioural features. Because of this diversity, there has been confusion and disagreement on the terminology and classification of these lesions. Here we present a classic case of Calcifying Odontogenic Cyst (COC) or Calcifying Cystic Odontogenic Tumor in a 37 years old male patient. which is provisionally diagnosed by means of clinical & radiographical findings and later on confirmed by histological examination. PMID- 29161785 TI - Intraoperative MRI for resection of intracranial meningiomas. AB - Objective: To examine whether intraoperative MRI can enhance safety and extent of resection of complex intracranial meningiomas, given its positive role in the resection of malignant brain tumors and pituitary tumors. Methods: Over a ten year period, 70 operations were performed on 66 patients with intracranial meningiomas using the compact, mobile PoleStar N20 iMRI navigation system. A retrospective review was conducted examining patient demographics, surgical characteristics, and outcomes. Results: 36 meningiomas were above the skull base and 30 were of the skull base. Four (5.7%) operations were done for recurrent meningiomas. 63 patients (95.5%) had WHO grade I and 3 patients (4.5%) had WHO grade III meningiomas. 9 (12.8%) patients required additional tumor resection based on iMRI findings, and in 4 patients (6%) iMRI imaging allowed for avoidance of additional dissection near critical neurovascular structures. Conclusions: Up to 15.7% of patients had surgery positively affected by intraoperative imaging either improving the resection or avoiding unnecessary additional dissection which could potentially harm critical neurologic structures. As iMRI becomes more widely available it may be valuable to use in an appropriate subset of patients with intracranial meningiomas. PMID- 29161786 TI - Oral submucous fibrosis: an etiological dilemma. AB - OBJECTIVE: Oral Submucous Fibrosis (OSF), is a well-recognized, oral potentially malignant disorder predominantly affecting the South- Asian countries. OSF causes unique generalized fibrosis of the submucosal oral soft tissues, resulting in marked rigidity of the oral mucosa leading to progressive inability to open the mouth, rigidity of lips and difficulty in protruding the tongue. In this review we have discussed the multifactorial etiology of this potentially malignant disorder, including Chillies, Nutritional Deficiencies, Inducible nitric oxide synthsis (iNOS), genetic and immunological predisposition; and most importantly the role of areca nut and the effect of copper content in it. PMID- 29161787 TI - Cancer Control Algorithm. AB - OBJECTIVE: Curing cancer by controlling the growth of the cancer cell is the objective of this paper. The growth of the cancer cell is analysed by the optimization programming. The algorithm is proposed for minimizing the rate of growth of the cancer cell. Hence the chaotic cancer became structured for the further research. This is an extended work of Warburg [1], where he defined the centre of the cancer cell, known by Warburg effect, but here we control the increasing radius of the cancer circle by the proposed Cancer Control Algorithm. PMID- 29161788 TI - Aggressive Supratentorial Ependymoma, RELA Fusion-Positive with Extracranial Metastasis: A Case Report. AB - Ependymoma is the third most common pediatric primary brain tumor. Ependymomas are categorized according to their locations and genetic abnormalities, and these two parameters are important prognostic factors for patient outcome. For supratentorial (ST) ependymomas, RELA fusion-positive ependymomas show a more aggressive behavior than YAP1 fusion-positive ependymomas. Extracranial metastases of intra-axial neuroepithelial tumors are extremely rare. In this paper, we report a case of aggressive anaplastic ependymoma arising in the right frontoparietal lobe, which had genetically 1q25 gain, CDKN2A homozygous deletion, and L1CAM overexpression. The patient was a 10-year-old boy who underwent four times of tumor removal and seven times of gamma knife surgery. Metastatic loci were scalp and temporalis muscle overlying primary operation site, lung, liver, buttock, bone, and mediastinal lymph nodes. He had the malignancy for 10 years and died. This tumor is a representative case of RELA fusion-positive ST ependymoma, showing aggressive behavior. PMID- 29161789 TI - Current Status of Thyroid Fine-Needle Aspiration Practice in Thailand. AB - Thyroid carcinoma is one of the leading malignancies in Thailand increasingly prevalent in the female population. Fine-needle aspiration (FNA) cytology is a widely used diagnostic tool for evaluation of thyroid nodules and thyroid cancer. Thyroid FNA is a routine procedure universally performed in Thai hospitals by a variety of clinical specialists. Manual guidance is the first-line choice complemented by ultrasound assistance in selected cases. Despite national guidelines recommendations, the diagnostic criteria and terminology of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) was slowly adopted in the local settings. Currently, the Bethesda system is actively promoted by the local professional societies as a uniform reporting system. Experience with thyroid FNA has been rarely reported to date-only a handful of publications are available in local journals. Our review, in addition to presenting various aspects of thyroid FNA in Thailand, established for the first time national references for a certain statistical outputs of TBSRTC based on the original multi-institutional cohort. The risk of malignancy in 2,017 operated thyroid nodules collected from three tertiary thyroid cancer centers was 21.7%, 14.7%, 35.9%, 44.4%, 76.7%, and 92.6% for categories I to VI, respectively. The malignancy risk in several diagnostic categories (II to IV) was higher than the risk estimated by TBSRTC and recent meta-analysis studies. We endorse the use of uniform terminology of the Bethesda system in Thailand, which will help facilitate communication among diverse medical professionals involved in the management of patients with thyroid nodules, to share local experience with the international audience. PMID- 29161790 TI - [Anticoagulation in Patients with Liver Cirrhosis]. AB - Cirrhotic patients have bleeding tendencies due to the lack of coagulation factors and thrombocytopenia. However, decreased levels of procoagulants are also accompanied by decreased levels of natural anticoagulants. However, there have been contrasting reports. It has been reported that patients with cirrhosis are at risk for thrombotic complications, including portal vein thrombosis and venous thromboembolism. Physicians consider active anticoagulation for prophylaxis and treatment of portal vein thrombosis and/or venous thromboembolism in cirrhotic patients with high risk of thrombosis. Concurrently, there are safety concerns regarding the risk of bleeding from anticoagulants in people with advanced liver disease. Further prospective studies are required to determine not only if cirrhotic patients benefit from receiving anticoagulation therapy for preventing thrombotic complications, but also to determine which prophylactic regimen is most appropriate. PMID- 29161791 TI - Development of Metachronous Tumors after Endoscopic Resection for Gastric Neoplasm according to the Baseline Tumor Grade at a Health Checkup Center. AB - Background/Aims: Endoscopic resection (ER) procedure has been performed widely to treat gastric neoplasms. Here, we compared the long-term prognosis based on the clinical features of three types of recurred gastric neoplasms after ER, including low-grade dysplasia (LGD), high-grade dysplasia (HGD), and early gastric carcinoma (EGC). Methods: Between 2003 and 2014, subjects who were diagnosed with gastric neoplasm during screening endoscopy were included. The baseline clinicopathologic and tumor recurrence were analyzed. Results: Of the 316 patients enrolled, 170 patients (53.8%) were categorized into the LGD group, 34 patients (10.8%) into the HGD group, and 112 patients (35.4%) into the EGC group. The median follow-up duration was 4.2 years. Among the total, 14 patients experienced a development of metachronous gastric cancer; 4 patients (2.3%) in the LGD group, 3 patients (8.3%) in the HGD group, and 7 patients (6.1%) in the EGC group. Metachronous gastric neoplasm had developed in 17 LGD patients (10.0%), 5 HGD patients (14.7%), and 14 EGC patients (12.5%). There was no significant difference in the incidence of metachronous gastric cancer and neoplasm among the three groups (p=0.15 and p=0.72, respectively). Conclusions: We identified that the incidence rates of gastric neoplasm and cancer after endoscopic treatment were not significantly different between the LGD, HGD, and EGC groups. PMID- 29161792 TI - [Trend in the Eradication Rates of Helicobacter pylori Infection Over the Last 10 Years in West Gyeonggi-do, Korea: A Single Center Experience]. AB - Background/Aims: The eradication rate of Helicobacter pylori (H. pylori) has been decreasing recently in Korea due to antibiotics resistance. The aim of this study was to investigate the trend of eradication rate and clinical factors affecting the eradication rate of H. pylori in the last 10 years in west Gyeonggi-do, Korea. Methods: The trends of eradication rate of H. pylori, gender, age, concomitant mediations, and clinical factors were retrospectively evaluated in patients with H. pylori infection between 2006 and 2015 (n=2,485). Results: The overall H. pylori eradication rate for the standard triple therapy was 82.5%. The annual eradication rates from 2006 to 2015 were 90%, 77.9%, 75.8%, 83.2%, 85.6%, 90.1%, 81.3%, 81.1%, 78.7%, and 78.8%, respectively, showing a significant decrement during the last five years (p<0.001). Higher eradication rate was observed in males than in females (p<0.001). Esomeprazole showed a higher eradication rate compared with pantoprazole between 2006 and 2010 (p<0.022). Age and the use of probiotics and mucosal protective agents played no significant role in the H. pylori eradication rate. The overall eradication rate for bismuth based quadruple therapy was 94.4%. Conclusions: The eradication rate of H. pylori over the last 10 years for first-line therapy ranged from 75.8 to 90.1%; the eradication rate for triple therapy has declined. However, the eradication rate for quadruple therapy has remained unchanged over the last 10 years. PMID- 29161793 TI - Effect of Rifaximin on Hepatic Fibrosis in Bile Duct-ligated Rat Model. AB - Background/Aims: The translocation of bacteria and their lipopolysaccharides from the gut can promote fibrosis in cirrhotic patients. The aim of this study was to investigate the effects of rifaximin on hepatic fibrosis in a bile duct-ligated rat model. Methods: The bile duct ligation (BDL) was carried out for eight days (acute injury model: sham-operated rats [G1], BDL rats [G2], and BDL rats treated with rifaximin [G3]) or 22 days (chronic injury model: sham-operated rats [G4], BDL rats [G5], and BDL rats treated with rifaximin [G6]). Rifaximin (50 mg/kg/day) was administered daily via gavage after BDL. Liver function, serum tumor necrosis factor-alpha (TNF-alpha), and hepatic hydroxyproline levels were measured. Moreover, a histological analysis of fibrosis contents was performed using sirius red stain. Results: In the acute injury model, the liver function and TNF-alpha level were not improved after the rifaximin treatment. The hydroxyproline levels (ug/g liver tissue) in G1, G2, and G3 were 236.4+/-103.1, 444.8+/-114.4, and 312.5+/-131.6, respectively; and fibrosis contents (%) were 0.22+/-0.04, 1.64+/-0.53, and 1.66+/-0.44, respectively. The rifaximin treatment did not ameliorate acute BDL-induced fibrosis. In the chronic injury model, the hydroxyproline levels in G4, G5, and G6 were 311.5+/-72.9, 1,110.3+/-357.9, and 944.3+/-209.3, respectively; and fibrosis contents (%) were 0.19+/-0.03, 5.04+/ 0.18, and 4.42+/-0.68, respectively (G5 vs. G6, p=0.059). The rifaximin treatment marginally ameliorated chronic BDL-induced fibrosis. Conclusions: Rifaximin did not reduce inflammation and fibrosis in bile duct-ligated rat model. PMID- 29161794 TI - Feasibility of Temporary Pancreatic Stenting after Early Endoscopic Retrograde Cholangiopancreatography in Patients with Acute Biliary Pancreatitis. AB - Background/Aims: To assess the safety and effectiveness of temporary pancreatic stenting after early endoscopic retrograde cholangiopancreatography (ERCP) in patients with acute biliary pancreatitis regardless of the severity or concomitant cholangitis. Methods: Temporary pancreatic stenting was performed in 79 patients with visualized pancreatic duct during ERCP. The outcomes of 64 patients with adequate pancreatic stenting (PS) and 15 patients with inadequate pancreatic stenting (no PS) were compared in this prospective, observational trial. Results: The baseline characteristics were similar. Development of systemic inflammatory response syndrome (7.8% for PS vs. 13.3% for no PS; p=0.50) and mortality (none for both groups; p=0.99) did not differ. However, fewer local complications occurred in PS than in no PS (4.7% for PS vs. 20.0% for no PS; p=0.04) and the difference was most outstanding in necrosis (1.6% for PS vs. 13.3% for no PS; p=0.03). Conclusions: Temporary pancreatic stenting after early ERCP should be considered safe, as complications did not increase even in cases of inadequate stenting. However, if successful, there appears to be a reduction in local complications. PMID- 29161795 TI - Superior Mesenteric Artery Syndrome Combined with Renal Nutcracker Syndrome in a Young Male: A Case Report. AB - Superior mesenteric artery (SMA) syndrome is one of the rare causes of small bowel obstruction. It develops following a marked decrease in the angle between SMA and the abdominal aorta due to weight loss, anatomical anomalies, or following surgeries. Nutcracker syndrome in the left renal vein may also occur following a decrease in the aortomesenteric angle. Though SMA syndrome and renal nutcracker syndrome share the same pathogenesis, concurrent development has rarely been reported. Herein, we report a 23-year-old healthy male diagnosed with SMA syndrome and renal nutcracker syndrome due to severe weight reduction. The patient visited our outpatient clinic presenting bilious vomiting and indigested vomitus for 3 consecutive days. He had lost 20 kg during military service. We suspected SMA syndrome based on abnormal air-shadow in the stomach and small bowel on abdominal X-ray; we confirmed compression of the third portion of the duodenum with upper gastrointestinal series and abdominal computed tomography (CT). Concurrently, renal nutcracker syndrome was also detected via abdominal CT and Doppler ultrasound. Considering bilious vomiting and no urinary symptoms, SMA syndrome was corrected by laparoscopic duodenojejunostomy, and close observation for the renal nutcracker syndrome was recommended. PMID- 29161796 TI - [Small Bowel Perforation Caused by Press-through Package]. AB - With an increased use of the press-through package (PTP) tablet, there has also been an increase in mis-swallowing cases, especially in elderly patients. We report a rare case of PTP-induced small bowel perforation and fistula formation with adjacent small bowel in a healthy elderly patient, who experienced persistent abdominal pain of unknown cause. A 62-year-old healthy man was admitted to our hospital with left abdominal pain that started one month ago. Neither abdominal tenderness nor rebound tenderness was present on physical examination. His vital signs and all other test results were within normal limits. However, a 2.5 cm curved radiopaque material within his thickened small intestine was incidentally detected on an abdominal computed tomography. He underwent laparoscopic small bowel resection, which revealed foreign body in the distal small intestine. Edema, perforation, and adhesions with the surrounding tissues were also noticed in the distal small intestine. Foreign body was turned out to be PTP, and this was considered to be responsible for the small bowel perforation and fistula formation. Precautions regarding PTP usage are necessary to prevent inadvertent PTP ingestion and its related complications, such as perforation, especially in the elderly population. PMID- 29161797 TI - Electromechanical morcellators' black-box warning: tribulations, expectations and solutions. AB - Laparoscopic minimally invasive gynecologic surgery (MIGS) for benign conditions results in decreased morbidity, and faster recovery, compared with laparotomy. Tissue fragmentation by electromechanical morcellation permits the removal of large specimens through small laparoscopic incisions. Since the US Food and Drug Administration (FDA) published its safety warning about the risk of power morcellators spreading cancer during fibroid surgery in 2014, power morcellation has become rare. MIGS for fibroids and other large tissue specimens has declined. Current alternatives to preserve MIGS for large specimens include intact specimen retrieval through periumbilical mini-laparotomy incisions, vaginal removal, or in bag manual morcellation, have limitations. Innovative intracorporeal containment tissue extraction system (ICTES) prototypes capable of enclosing, manipulating, morcellating, and removing tissue, while avoiding intraperitoneal leakage and maintaining pneumoperitoneum, are being evaluated. There is ample opportunity to optimize efficacy of ICTES by scientific study in clinical trials. PMID- 29161798 TI - Intrapartum care quality indicators: a literature review. AB - INTRODUCTION: Quality of care is increasingly recognized as a critical aspect of the maternal and newborn health, mainly with respect to care around labor and delivery and in the immediate postnatal period. The aim of this review was to identify the recommended intrapartum care indicators in order to measure the quality of midwifery care. EVIDENCE ACQUISITION: A structured literature search was conducted in August 2017 incorporating English and Italian language studies from 1993 and onwards to identify published articles on quality standards of intrapartum care. Research was performed into the area of enquiry in electronic database (Medline, Cochrane Library, CINAHL, Trip) and in relevant midwifery websites. EVIDENCE SYNTHESIS: We identified 369 quality indicators to measure the intrapartum care. Following a systematic process that allows to classify all indicators in domains and categories, we analyzed 268 outcome and process indicators specifically designated to monitor the intrapartum care in a low risk population. Through the identification of further exclusion criteria and semantic analogies we obtained 80 final quality indicators (39 outcome indicators and 41 process indicators). CONCLUSIONS: We identified 80 indicators that should be used to measure the quality of low risk intrapartum care. Although the majority of indicators we could monitor through hospital databases and the Italian Birth Register-CeDAP are outcome indicators, it is important to give attention also to process indicators that measure the activities performed and whether or not they are evidence-based. For a low risk population they could measure adherence with guidelines that promote and support the normality of the process. PMID- 29161799 TI - Risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review of the literature. AB - INTRODUCTION: The aim of this paper was to estimate the risk of miscarriage after amniocentesis or chorionic villus sampling (CVS) based on a systematic review of the literature. EVIDENCE ACQUISITION: A search of Medline, Embase, and The Cochrane Library (2000-2017) was carried out to identify studies reporting complications following CVS or amniocentesis. The inclusion criteria for the systematic review were studies reporting results from large controlled studies (N.>=1000 invasive procedures) and those reporting data for pregnancy loss prior to 24 weeks' gestation. Data for cases that had invasive procedure and controls were inputted in contingency tables and risk of miscarriage was estimated for each study. Summary statistics were calculated after taking into account the weighting for each study included in the systematic review. Procedure-related risk of miscarriage was estimated as a weighted risk difference from the summary statistics for cases and controls. EVIDENCE SNTHESIS: The electronic search from the databases yielded 2465 potential citations of which 2431 were excluded, leaving 34 studies for full-text review. The final review included 10 studies for amniocentesis and 6 studies for CVS, which were used to estimate risk of miscarriage in pregnancies that had an invasive procedure and the control pregnancies that did not. The procedure-related risk of miscarriage following amniocentesis was 0.35% (95% confidence interval [CI]: 0.07 to 0.63) and that following CVS was 0.35% (95% CI: -0.31 to 1.00). CONCLUSIONS: The procedure related risks of miscarriage following amniocentesis and CVS are lower than currently quoted to women. PMID- 29161801 TI - Impact of sarcopenia on long-term mortality and cardiovascular events in patients undergoing hemodialysis. AB - Background/Aims: A high body mass index (BMI) is known to correlate with better survival in patients on hemodialysis (HD). However, the impacts of body composition and sarcopenia on survival have not been well studied in this population. Methods: One hundred and forty-two prevalent HD patients were recruited and followed prospectively for up to 4.5 years. Low muscle mass (measured using a portable, whole-body, bioimpedance spectroscopic device) was defined as a lean tissue index (LTI) two standard deviations (SD) or more below the normal gender-specific mean for young people. Low muscle strength was a handgrip strength (HGS) of less than 30 kg in males and less than 20 kg in females. Sarcopenia was considered present when both LTI and HGS were reduced. Results: The mean age was 59.8 +/- 13.1 years; 57.0% were male and 47.2% had diabetes. Forty-seven patients (33.1%) had sarcopenia. During follow-up, 28 patients (19.7%) died, and low LTI (adjusted hazard ratio [HR], 2.77; 95% confidence interval [CI], 1.10 to 6.97) and low HGS (HR 5.65; 95% CI, 1.99 to 16.04) were independently associated with mortality. Sarcopenia was a significant predictor for death (HR, 6.99; 95% CI, 1.84 to 26.58; p = 0.004) and cardiovascular events (HR, 4.33; 95% CI, 1.51 to 12.43; p = 0.006). Conclusions: Sarcopenia was strongly associated with long-term mortality and cardiovascular events in HD patients. Assessment of muscle strength and muscle mass may provide additional prognostic information to survival in patients with end-stage renal disease. PMID- 29161802 TI - The Impact of Surgical Timing on Pathologic Tumor Response after Short Course and Long Course Preoperative Chemoradiation for Locally Advanced Rectal Adenocarcinoma. AB - Purpose: A pooled analysis of multi-institutional trials was performed to analyze the effect of surgical timing on tumor response by comparing short course concurrent chemoradiotherapy (CCRT) with long course CCRT followed by delayed surgery in locally advanced rectal cancer. Materials and Methods: Three hundred patients with cT3-4N0-2 rectal adenocarcinoma were included. Long course patients from KROG 14-12 (n=150) were matched 1:1 to 150 short course patients from KROG 10-01 (NCT01129700) and KROG 11-02 (NCT01431599) according to stage, age, and other risk factors. The primary endpoint was to determine the interval between surgery and the last day of neoadjuvant CCRT which yields the best tumor response after the short course and long course CCRT. Downstaging was defined as ypT0 2N0M0 and pathologic complete response (ypCR) was defined as ypT0N0M0, respectively. Results: Both the long and short course groups achieved lowest downstaging rates at < 6 weeks (long 20% vs. short 8%) and highest downstaging rates at 6-7 weeks (long 44% vs. short 40%). The ypCR rates were lowest at < 6 weeks (both long and short 0%) and highest at 6-7 weeks (long 21% vs. short 11%) in both the short and long course arms. The downstaging and ypCR rates of long course group gradually declined after the peak at 6-7 weeks and those of the short course group trend to constantly increase afterwards. Conclusion: It is optimal to perform surgery at least 6 weeks after both the short course and long course CCRT to obtain maximal tumor regression in locally advanced rectal adenocarcinoma. PMID- 29161803 TI - Modeling the effects of pollutant emissions from large industrial complexes on benzene, toluene, and xylene concentrations in urban areas. AB - This study utilized the Community Multiscale Air Quality model to simulate the spatial distribution of benzene, toluene, and xylene (BTX) concentrations from large national industrial complexes (IC) located in the Ulsan metropolitan region (UMR). Through controlling pollutant emissions from major IC, this study performed a quantitative analysis of the influence of pollutant emissions on BTX concentrations in surrounding urban areas. The results showed that approximately 40% of the annual average BTX concentrations in nearby urban grids were directly influenced by pollutant emissions from the IC. Seasonal modeling results indicated that average BTX concentrations were high around petrochemical complexes, with higher concentrations in the surrounding urban areas during the summer (July). All three of the BTX pollutants showed similar seasonal differences. Daily contributions differed significantly throughout the modeling period, with some values reaching a maximum of 80% during July. Overall, when urban areas were located downwind of the IC, contributions rose. Moreover, this study compared the differences in BTX contributions at each measurement point within the IC and urban areas, which showed that the influence of the IC emissions decreased significantly with distance. The spatial distribution and direct influence of the IC on BTX concentrations in the UMR identified through this study could be used to provide input data in environmental epidemiological studies. PMID- 29161804 TI - Importance of indoor dust biological ultrafine particles in the pathogenesis of chronic inflammatory lung diseases. AB - The role of infectious agents in the etiology of inflammatory diseases once believed to be non-infectious is increasingly being recognized. Many bacterial components in the indoor dust can evoke inflammatory lung diseases. Bacteria secrete nanometer-sized vesicles into the extracellular milieu, so-called extracellular vesicles (EV). which are pathophysiologically related to inflammatory diseases. Microbiota compositions in the indoor dust revealed the presence of both Gram-negative and Gram-positive bacteria. Escherichia coli is a model organism of Gram-negative Enterobacteriaceae. The repeated inhalation of E. coli-derived EVs caused neutrophilic inflammation and emphysema in a dose dependent manner. The emphysema induced by E. coli-derived EVs was partially eliminated by the absence of Interferon-gamma or interleukin-17, suggesting that Th1 and/or Th17 cell responses are important in the emphysema development. Meanwhile, the repeated inhalation of Staphylococcus aureus-derived EVs did not induce emphysema, although they induced neutrophilic inflammation in the lung. In terms of microbial EV compositions in the indoor dust, genera Pseudomonas, Acinetobacter, Enterobacter, and Staphylococcus were dominant. As for the clinical significance of sensitization to EVs in the indoor dust, EV sensitization was closely associated with asthma, chronic obstructive pulmonary disorder (COPD), and lung cancer. These data indicate that biological ultrafine particles in the indoor dust, which are mainly composed of microbial EVs, are important in the pathogenesis of chronic lung diseases associated with neutrophilic inflammation. Taken together, microbial EVs in the indoor dust are an important diagnostic and therapeutic target for the control of chronic lung diseases, such as asthma, COPD, and lung cancer. PMID- 29161800 TI - Present status and perspectives of endosonography 2017 in gastroenterology. AB - Endoscopic ultrasound has become an essential tool in modern gastroenterology and abdominal surgery. Compared with all other endoscopic methods, it has the most potential for innovation and its future looks bright. Thus, we compiled this summary of established and novel applications of endoscopic ultrasound methods to inform the reader about what is already possible and where future developments will lead in improving patient care further. This review is structured in four parts. The first section reports on developments in diagnostic endoscopic ultrasound, the second looks at semi-invasive endoscopic ultrasound, and the third discusses advances in therapeutic endoscopic ultrasound. An overview on the future prospects of endoscopic ultrasound methods concludes this article. PMID- 29161806 TI - Young Academic Urologists' benign prostatic obstruction nomogram predicts clinical outcome in patients treated with transurethral resection of prostate: an Italian cohort study. AB - BACKGROUND: The aim of this study was to test the Young Academic Urologist nomogram for the prediction of transurethral resection of prostate outcome in patients with lower urinary tract symptoms and benign prostatic enlargement. METHODS: Between April 2014 and March 2016, a consecutive series of patients with lower urinary tract symptoms undergoing trans-urethral resection of prostate in one center were enrolled. At baseline patients were assessed with international prostate symptom score, prostate specific antigen, prostate volume, transitional zone volume, maximal urinary flow rate and post void residual urine. At 3 months after trans-urethral resection of prostate patients were evaluated with uroflowmetry and international prostate symptom score questionnaire. Maximum urinary flow and transitional zone volume were plotted on the Young Academic Urologist nomogram to predict trans-urethral resection of prostate outcome. Receiver-operator characteristics curve analysis was used to evaluate predictive properties of the nomogram for the outcome of transurethral resection of the prostate. RESULTS: A total of 232 patients were consecutively enrolled. Out of them, 149 patients (65%) presented a positive outcome. The novel Young Academic Urologist nomogram presented an area under the curve of 0.77 (95% CI: 0.70-0.83) for trans-urethral resection of prostate outcome prediction. At the best cut-off value of 75% (nomogram probability) the sensitivity was 62% and specificity was 73%, the positive predictive value was 81% and the negative predictive value was 52%. CONCLUSIONS: The Young Academic Urologist nomogram was, in our experience, an excellent tool to predict a positive outcome after transurethral resection of prostate, although further studies are needed to confirm our results. PMID- 29161805 TI - Robot assisted radical cystectomy with totally intracorporeal urinary diversion: initial, single-surgeon's experience after a modified modular training. AB - BACKGROUND: To report the perioperative and early functional outcomes of patients undergoing Robot-assisted radical cystectomy (RARC) with totally intracorporeal urinary diversion performed by a single surgeon after a modified modular training. METHODS: The surgeon (A.P.) attained a 30-days modified modular training at a referring Center mentored by a worldwide-recognized robotic surgeon (P.W.). The training program consisted of: 1) e-learning based on 10 hours of theoretical lessons made by the mentor; 2) video-session concerning the different steps of the procedure, 3) step-by-step in vivo modular training. Demographics, intraoperative data and post-operative complications were recorded for each patient. RESULTS: Twenty-four consecutive patients were prospectively evaluated. Median age was 68.5 years (IQR 59-75). Thirteen (54.2%) and 11 (45.8%) patients received RARC with orthotopic neobladder (ONB) and ileal conduit (IC), respectively. Overall mean (+/-SD) operative time was 392 (+/- 34.8) minutes. The median number of lymph node retrieved was 30 (IQR 24-42), the mean intraoperative estimated blood loss (EBL) was 403 mL (+/-60) with average hospitalization of 7.8 days (+/-2.2). All procedures were completed successfully without open conversion. A statistically significant difference in terms of overall operative time (OT) and urinary diversion operative time (UDOT) was found in favor of IC group compared to ONB group (P=0.002). Overall complication rate was 33%, 7 out of 9 (88%) were graded as minor (Clavien 1-2). Two (22%) major complications (Clavien 3-5) occurred solely on ONB group. CONCLUSIONS: Robot-assisted radical cystectomy with totally intracorporeal urinary diversion is a challenging procedure with a steep learning curve. An adequate modular training with an experienced mentor and a skilled robotic team could be essential to reach these optimal results. Further studies investigating the impact of modular learning curve and a dedicated menthorship on operative and functional outcomes after RARC are needed. PMID- 29161807 TI - Intravenous dextran 70 infusion has protective effects on ischemia reperfusion injury of kidney: an experimental study. AB - BACKGROUND: Renal ischemia-reperfusion (IR) leads to alterations of tubular epithelial cells, interstitial microvasculopathy and endothelial cell dysfunction in peritubular capillaries. Although dextrans have deteriorative effects on healthy kidney, their favorable effects on postischemic microvascular disturbances have been demonstrated. Therefore, we aimed to investigate in vivo effects of systemic dextran 70 administration in kidney tissue with ischemia reperfusion injury. METHODS: Twenty-one rats were allocated as sham, IR and IR+ dextran 70 treatment groups. Perirenal dissection without ischemia-reperfusion injury was performed with 0.9 NaCl solution infusions in the sham group. The left renal ischemia-reperfusion injury model was induced with % 0.9 NaCl and dextran 70 solutions infusion in the IR and IR+ dextran 70 treatment groups, respectively. At the end of the experimental procedures, histopathologic findings, serum creatinine and blood urea nitrogen levels, 24 hour urinary volumes, urinary albumin, KIM-1and IL-18 levels, and tissue MDA and SOD levels were compared between the groups. RESULTS: We determined slightly reduction of the histopathologic structural changes and significant reduced levels of the albuminuria and KIM-1 in the IR +dextran 70 treatment group (P=0.03 and P=0.02, respectively). Higher 24 hour urine out put and free radical scavenger SOD levels were also detected with Dextran 70 treatment (P=0.0 and P=0.03, respectively). CONCLUSIONS: Intravenous Dextran 70 infusion has some substantial protective effects against the ischemic injury of kidney. PMID- 29161808 TI - Renal outcome of congenital anomalies of the kidney and urinary tract system: a single-center retrospective study. AB - BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) have been defined in 20% to 50% of all fetal anomalies. The aim of this study was to determine the demographic and clinical characteristics of such patients, as well as to describe the outcome and risk factors that affect the prognosis. METHODS: The analysis investigated retrospective data from 303 patients diagnosed with CAKUT between January 2015 and April 2017. Demographic data, clinical history, diagnosis, investigations, disease outcomes, and treatment procedures were evaluated. RESULTS: A total of 303 children were included (126 females, 177 males). The median age was 3.0 years (range 0.01-17), and the median follow-up time was 1.65 years (range 0.02-12). The most commonly diagnosed anomalies of CAKUT were hydronephrosis (N.=139; isolated HN, N.=58), followed by renal parenchymal malformations (N.=109), collecting system anomalies (N.=56), migration and fusion anomalies (N.=53), and abnormalities of the bladder and urethra (N.=27). In 56 cases with isolated hydronephrosis, ultrasound normalized at a median age of 0.9 years (range 0.02-6). Surgery was performed on 44 children, and anomalies persisted in 201 children without any need for intervention. Poor outcome was defined in patients with renal parenchymal malformations and patients with abnormalities of the bladder and urethra. For 28 children (9.3%) who developed chronic kidney disease, the most common diagnoses were vesicoureteral reflux and neurogenic bladder. CONCLUSIONS: Children with isolated hydronephrosis had a good prognosis. The risk factors for poor outcome were postnatal bilateral anomalies, a need for surgery, and persisting anomalies with impaired renal function. PMID- 29161809 TI - Retrograde intrarenal surgery versus percutaneous surgery: do we have a winner? PMID- 29161810 TI - Chemical Cosubstitution-Oriented Design of Rare-Earth Borates as Potential Ultraviolet Nonlinear Optical Materials. AB - A chemical cosubstitution strategy was implemented to design potential ultraviolet (UV) and deep-UV nonlinear optical (NLO) materials. Taking the classic beta-BaB2O4 as a maternal structure, by simultaneously replacing the Ba2+ and [B3O6]3- units with monovalant (K+), divalent (alkaline earth metal), trivalent (rare-earth metal, Bi3+) ions, and the [B5O10]5- clusters through two different practical routes, 12 new mixed-metal noncentrosymmetric borates K7MIIRE2(B5O10)3 (MII = Ca, Sr, Ba, K/RE0.5; RE = Y, Lu, Gd) as well as K7MIIBi2(B5O10)3 (MII = Pb, Sr) were successfully designed and synthesized as high-quality single crystals. The selected K7CaY2(B5O10)3, K7SrY2(B5O10)3, and K7BaY2(B5O10)3 compounds were subjected to experimental and theoretical characterizations. They all exhibit suitable second-harmonic generation (SHG) responses, as large as that of commercial KH2PO4 (KDP), and also exhibit short UV cutoff edges. These results confirm the feasibility of this chemical cosubstitution strategy to design NLO materials and that the three selected crystals may have potential application as UV NLO materials. PMID- 29161811 TI - Coordination Structure and Fragmentation Chemistry of the Tripositive Lanthanide Thio-Diglycolamide Complexes. AB - Tripositive Ln(TMTDA)33+ complexes (Ln = La-Lu except Pm, TMTDA = tetramethyl 3 thio-diglycolamide) were observed in the gas phase by electrospray ionization of LnCl3 and TMTDA mixtures. Collision-induced dissociation (CID) was employed to investigate their fragmentation chemistry, which revealed the influence of metal center as well as ligand on the ligated complexes. Ln(TMTDA)2(TMTDA-45)3+ resulting from Ccarbonyl-N bond cleavage of TMTDA and hydrogen transfer was the major CID product for all Ln(TMTDA)33+ except Eu(TMTDA)33+, which predominantly formed charge-reducing product EuII(TMTDA)22+ via electron transfer from TMTDA to Eu3+. Density functional theory calculations on the structure of La(TMTDA)33+ and Lu(TMTDA)33+ revealed that Ln3+ was coordinated by six Ocarbonyl atoms from three neutral TMTDA ligands, and both complexes possessed C3h symmetry. The Sether atom deviating from the ligand plane was not coordinated to the metal center. On the basis of the CID results of Ln(TMTDA)33+, Ln(TMGA)33+, and Ln(TMOGA)33+, the fragmentation chemistry associated with the ligand depends on the coordination mode, while the redox chemistry of these tripositive ions is related to the nature of both metal centers and diamide ligands. PMID- 29161812 TI - Acute Amino Acid d-Serine Administration, Similar to Ketamine, Produces Antidepressant-like Effects through Identical Mechanisms. AB - d-Serine is an amino acid and can work as an agonist at the glycine sites of N methyl-d-aspartate receptor (NMDAR). Interestingly, both types of glutamatergic modulators, NMDAR enhancers and blockers, can improve depression through common targets, namely alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionaic acid receptors (AMPARs) and mammalian target of rapamycin (mTOR). To elucidate the cellular signaling pathway underlying this counterintuitive observation, we activated NMDARs in rats by using d-serine. Saline, ketamine (NMDAR antagonist), and desipramine (tricyclic antidepressant) were used as controls. The antidepressant-like effects of all agents were evaluated using the forced swim test. The activation of the AMPAR-mTOR signaling pathway, release of brain derived neurotrophic factor (BDNF), and alteration of AMPAR and NMDAR trafficking in the hippocampus of rats were examined. A single high dose of d-serine exerted an antidepressant-like effect that was mediated by rapid AMPAR-induced mTOR signaling pathway and increased BDNF proteins, identical to that of ketamine. Furthermore, in addition to the increased protein kinase A phosphorylation of the AMPAR subunit GluR1 (an indicator of AMPAR insertion in neurons), treatment with individual optimal doses of d-serine and ketamine also increased adaptin beta2 NMDAR association (an indicator of the intracellular endocytic machinery and subsequent internalization of NMDARs). Desipramine did not influence these processes. Our study is the first to demonstrate an association between d-serine and ketamine; following adaptative regulation of AMPAR and NMDAR may lead to common changes of them. These findings provide novel targets for safer antidepressant agents with mechanisms similar to those of ketamine. PMID- 29161813 TI - Functional Analysis of an Uridine Diphosphate Glycosyltransferase Involved in the Biosynthesis of Polyphenolic Glucoside in Tea Plants (Camellia sinensis). AB - Polyphenols are one of the largest groups of compounds that confer benefits to the health of plants and humans. Flavonol glycosides are a major ingredient of polyphenols in Camellia sinensis. Flavonol-3-O-glycosides are characteristic astringent taste compounds in tea infusion. A polyphenolic glycosyltransferase (CsUGT72AM1) belonging to cluster IIIb was isolated from the tea plant. The full length cDNA of CsUGT72AM1 is 1416 bp. It encodes 472 amino acids with a calculated molecular mass of 50.92 kDa and an isoelectric point of 5.21. The recombinant CsUGT72AM1 protein was expressed in Escherichia coli and exhibited catalytic activity toward multiple flavonoids and coniferyl aldehyde. The enzyme assay indicated that rCsUGT72AM1 could perform glycosidation of flavonols or coniferyl aldehyde in vitro to form 3-O-glucoside or 4-O-glucoside, respectively. Interestingly, this enzyme also had activities and performed multisite glycosidation toward flavanones. The consistent products were confirmed to be naringenin-7-O-glucoside and -4'-O-glucoside by the nuclear magnetism assay. In addition, in the enzyme assay with cyanidin as the substrate, the results suggested that the glycosylated activity of CsUGT72AM1 was remarkably inhibited by a high concentration of anthocyanins. The above results indicate that CsUGT72AM1 may be involved in the metabolism of flavonol, flavanone, anthocyanin, and lignin. PMID- 29161814 TI - Changes in the Aromatic Profile, Sugars, and Bioactive Compounds When Purple Garlic Is Transformed into Black Garlic. AB - Black garlic is an elaborated product obtained from fresh garlic (Allium sativum L.) at a controlled high humidity and temperature, which leads to modifications in color, taste, and texture. To clarify the physicochemical changes that occur during the thermal process, this work aimed to evaluate and contrast the antioxidant capacity and that of other compounds between purple garlic ecotype "Purple from Las Pedroneras" and its black garlic derivative. Our results showed numerous differences between both, because black garlic presented a significant divergence in its volatile profile, a decreased amount of ascorbic acid, an increment in sugar and polyphenol contents, a greater antioxidant capacity, and a different composition of phenolic acids and flavonoids. PMID- 29161815 TI - Bioactive Compounds of Edible Purple Laver Porphyra sp. (Nori). AB - Porphyra sp. (nori) is widely cultivated as an important marine crop. Dried nori contains numerous nutrients, including vitamin B12, which is the only vitamin absent from plant-derived food sources. Vegetarian diets are low in iron and vitamin B12; depletion of both causes severe anemia. Nori also contains large amounts of iron compared with other plant-derived foods and eicosapentaenoic acid, which is an important fatty acid found in fish oils. In nori, there are also many bioactive compounds that exhibit various pharmacological activities, such as immunomodulation, anticancer, antihyperlipidemic, and antioxidative activities, indicating that consumption of nori is beneficial to human health. However, Porphyra sp. contains toxic metals (arsenic and cadmiun) and/or amphipod allergens, the levels of which vary significantly among nori products. Further evidence from human studies of such beneficial or adverse effects of nori consumption is required. PMID- 29161817 TI - Correction to "Kinetically Determined Hygroscopicity and Efflorescence of Sucrose Ammonium Sulfate Aerosol Droplets under Lower Relative Humidity". PMID- 29161816 TI - Rapid and Efficient Desulfonation Method for the Analysis of Glucosinolates by High-Resolution Liquid Chromatography Coupled with Quadrupole Time-of-Flight Mass Spectrometry. AB - The goal of our present research was to develop a simple and rapid method for the quantitation of desulfoglucosinolates (desulfoGLS) without using column chromatography. The proposed method involves extraction, concentration, incubation of glucosinolates with a sulfatase enzyme, and HPLC analysis. Identification of desulfoGLS in green kohlrabi was performed by LC-HR-ESI-QTOF-MS in positive-ionization mode. A total of 11 desulfoGLS were identified with neoglucobrassicin (3.32 +/- 0.05 MUmol/g DW) as the predominant indolyl, whereas progoitrin and sinigrin were the major aliphatic desulfoGLS. The levels of the aliphatic desulfoGLS glucoiberin, progoitrin, and glucoerucin at 7 h were found to be 3.6-, 1.9-, and 1.6-fold higher, respectively, than those produced through the conventional method. This technique was successfully applied in the identification of desulfoGLS from cabbage. The developed method has fewer unit operations, has maximum recovery, and is reproducible in the determination of desulfoGLS in a large number of Brassicaceae samples in a short time. PMID- 29161818 TI - Avoiding the Reject after Editorial Review for X and Characterization [Where X = Synthesis, Preparation, or Fabrication]. PMID- 29161819 TI - Avoiding the Reject after Editorial Review for X and Characterization [Where X = Synthesis, Preparation, or Fabrication]. PMID- 29161820 TI - How Do I Get My Paper to Stand Out and Be Noticed? PMID- 29161822 TI - Peer Review at the Journal of the American Chemical Society. PMID- 29161824 TI - Special issue on Erice 'MathCompEpi 2015' Proceedings. AB - The mathematical and computational modelling of the spread of infectious diseases is a research field in applied mathematics that in the same time was both able to give an impetum to various areas of the dynamical systems theory and mathematical analysis, and to give an important contribution to the biological and epidemiological understanding of the spread of these diseases. National as well as Inter-National health authorities adopt routinely in the practice methodologies and concept that were born in the field of Mathematical and Computational Epidemiology (MCE) for assisting public Health decisions and policies. A major example is provided by the huge advancement in modelling and prediction on pandemic threats, and related preparedness plans for disease containment/mitigation. This operative influence in biomedicine is unparalleled in any other fields of mathematical and computational biology, with the possible exception of intra-host virus dynamics, whose models partly derive from those of MCE. PMID- 29161825 TI - The interplay between models and public health policies: Regional control for a class of spatially structured epidemics (think globally, act locally). AB - A review is presented here of the research carried out, by a group including the authors, on the mathematical analysis of epidemic systems. Particular attention is paid to recent analysis of optimal control problems related to spatially structured epidemics driven by environmental pollution. A relevant problem, related to the possible eradication of the epidemic, is the so called zero stabilization. In a series of papers, necessary conditions, and sufficient conditions of stabilizability have been obtained. It has been proved that it is possible to diminish exponentially the epidemic process, in the whole habitat, just by reducing the concentration of the pollutant in a nonempty and sufficiently large subset of the spatial domain. The stabilizability with a feedback control of harvesting type is related to the magnitude of the principal eigenvalue of a certain operator. The problem of finding the optimal position (by translation) of the support of the feedback stabilizing control is faced, in order to minimize both the infected population and the pollutant at a certain finite time. PMID- 29161826 TI - Modeling ebola virus disease transmissions with reservoir in a complex virus life ecology. AB - We propose a new deterministic mathematical model for the transmission dynamics of Ebola Virus Disease (EVD) in a complex Ebola virus life ecology. Our model captures as much as possible the features and patterns of the disease evolution as a three cycle transmission process in the two ways below. Firstly it involves the synergy between the epizootic phase (during which the disease circulates periodically amongst non-human primates populations and decimates them), the enzootic phase (during which the disease always remains in fruit bats population) and the epidemic phase (during which the EVD threatens and decimates human populations). Secondly it takes into account the well-known, the probable/suspected and the hypothetical transmission mechanisms (including direct and indirect routes of contamination) between and within the three different types of populations consisting of humans, animals and fruit bats. The reproduction number R0 for the full model with the environmental contamination is derived and the global asymptotic stability of the disease free equilibrium is established when R0andlt;1. It is conjectured that there exists a unique globally asymptotically stable endemic equilibrium for the full model when R0andgt;1. The role of a contaminated environment is assessed by comparing the human infected component for the sub-model without the environment with that of the full model. Similarly, the sub-model without animals on the one hand and the sub-model without bats on the other hand are studied. It is shown that bats influence more the dynamics of EVD than the animals. Global sensitivity analysis shows that the effective contact rate between humans and fruit bats and the mortality rate for bats are the most influential parameters on the latent and infected human individuals. Numerical simulations, apart from supporting the theoretical results and the existence of a unique globally asymptotically stable endemic equilibrium for the full model, suggest further that: (1) fruit bats are more important in the transmission processes and the endemicity level of EVD than animals. This is in line with biological findings which identified bats as reservoir of Ebola viruses; (2) the indirect environmental contamination is detrimental to human beings, while it is almost insignificant for the transmission in bats. PMID- 29161827 TI - Mathematical analysis of a weather-driven model for the population ecology of mosquitoes. AB - A new deterministic model for the population biology of immature and mature mosquitoes is designed and used to assess the impact of temperature and rainfall on the abundance of mosquitoes in a community. The trivial equilibrium of the model is globally-asymptotically stable when the associated vectorial reproduction number (R0) is less than unity. In the absence of density-dependence mortality in the larval stage, the autonomous version of the model has a unique and globally-asymptotically stable non-trivial equilibrium whenever 1 andlt;R0 andlt;RC0 (this equilibrium bifurcates into a limit cycle, via a Hopf bifurcation at R0=RC0). Numerical simulations of the weather-driven model, using temperature and rainfall data from three cities in Sub-Saharan Africa (Kwazulu Natal, South Africa; Lagos, Nigeria; and Nairobi, Kenya), show peak mosquito abundance occurring in the cities when the mean monthly temperature and rainfall values lie in the ranges [22-25]0C, [98-121] mm; [24-27]0C, [113-255] mm and [20.5-21.5]0C, [70-120] mm, respectively (thus, mosquito control efforts should be intensified in these cities during the periods when the respective suitable weather ranges are recorded). PMID- 29161828 TI - Numerical solution of a spatio-temporal gender-structured model for hantavirus infection in rodents. AB - In this article we describe the transmission dynamics of hantavirus in rodents using a spatio-temporal susceptible-exposed-infective-recovered (SEIR) compartmental model that distinguishes between male and female subpopulations [L.J.S. Allen, R.K. McCormack and C.B. Jonsson, Bull. Math. Biol. 68 (2006), 511- 524]. Both subpopulations are assumed to differ in their movement with respect to local variations in the densities of their own and the opposite gender group. Three alternative models for the movement of the male individuals are examined. In some cases the movement is not only directed by the gradient of a density (as in the standard diffusive case), but also by a non-local convolution of density values as proposed, in another context, in [R.M. Colombo and E. Rossi, Commun. Math. Sci., 13 (2015), 369--400]. An efficient numerical method for the resulting convection-diffusion-reaction system of partial differential equations is proposed. This method involves techniques of weighted essentially non-oscillatory (WENO) reconstructions in combination with implicit-explicit Runge-Kutta (IMEX RK) methods for time stepping. The numerical results demonstrate significant differences in the spatio-temporal behavior predicted by the different models, which suggest future research directions. PMID- 29161829 TI - Sex-biased prevalence in infections with heterosexual, direct, and vector mediated transmission: A theoretical analysis. AB - Three deterministic Kermack-McKendrick-type models for studying the transmission dynamics of an infection in a two-sex closed population are analyzed here. In each model it is assumed that infection can be transmitted through heterosexual contacts, and that there is a higher probability of transmission from one sex to the other than vice versa. The study is focused on understanding whether and how this bias in transmission reflects in sex differences in final attack ratios (i.e. the fraction of individuals of each sex that eventually gets infected). In the first model, where the other two transmission modes are not considered, the attack ratios (fractions of the population of each sex that will eventually be infected) can be obtained as solutions of a system of two nonlinear equations, that has a unique solution if the net reproduction number exceeds unity. It is also shown that the ratio of attack ratios depends solely on the ratio of gender specific susceptibilities and on the basic reproductive number of the epidemic Ro, and that the gender-specific final attack-ratio is biased in the same direction as the gender-specific susceptibilities. The second model allows also for infection transmission through direct, non-sexual, contacts. In this case too, an analytical expression is derived from which the attack ratios can be obtained. The qualitative results are similar to those obtained for the previous model, but another important parameter for determining the value of the ratio between the attack ratios in the two sexes is obtained, the relative weight of direct vs. heterosexual transmission (namely, rho). Quantitatively, the ratio of final attack ratios generally will not exceed 1.5, if non-sexual transmission accounts for most transmission events (rho>=0.6) and the ratio of gender-specific susceptibilities is not too large (say, 5 at most). The third model considers vector-borne, instead of direct transmission. In this case, we were not able to find an analytical expression for the final attack ratios, but used instead numerical simulations. The results on final attack ratios are actually quite similar to those obtained with the second model. It is interesting to note that transient patterns can differ from final attack ratios, as new cases will tend to occur more often in the more susceptible sex, while later depletion of susceptibles may bias the ratio in the opposite direction. The analysis of these simple models, despite their lack of realism, can help in providing insight into, and assessment of, the potential role of gender-specific transmission in infections with multiple modes of transmission, such as Zika virus (ZIKV), by gauging what can be expected to be seen from epidemiological reports of new cases, disease incidence and seroprevalence surveys. PMID- 29161830 TI - On the usefulness of set-membership estimation in the epidemiology of infectious diseases. AB - We present a method, known in control theory, to give set-membership estimates for the states of a population in which an infectious disease is spreading. An estimation is reasonable due to the fact that the parameters of the equations describing the dynamics of the disease are not known with certainty. We discuss the properties of the resulting estimations. These include the possibility to determine best- or worst-case-scenarios and identify under which circumstances they occur, as well as a method to calculate confidence intervals for disease trajectories under sparse data. We give numerical examples of the technique using data from the 2014 outbreak of the Ebola virus in Africa. We conclude that the method presented here can be used to extract additional information from epidemiological data. PMID- 29161831 TI - An exact approach to calibrating infectious disease models to surveillance data: The case of HIV and HSV-2. AB - When mathematical models of infectious diseases are used to inform health policy, an important first step is often to calibrate a model to disease surveillance data for a specific setting (or multiple settings). It is increasingly common to also perform sensitivity analyses to demonstrate the robustness, or lack thereof, of the modeling results. Doing so requires the modeler to find multiple parameter sets for which the model produces behavior that is consistent with the surveillance data. While frequently overlooked, the calibration process is nontrivial at best and can be inefficient, poorly communicated and a major hurdle to the overall reproducibility of modeling results. In this work, we describe a general approach to calibrating infectious disease models to surveillance data. The technique is able to match surveillance data to high accuracy in a very efficient manner as it is based on the Newton-Raphson method for solving nonlinear systems. To demonstrate its robustness, we use the calibration technique on multiple models for the interacting dynamics of HIV and HSV-2. PMID- 29161832 TI - A simple model of HIV epidemic in Italy: The role of the antiretroviral treatment. AB - In the present paper we propose a simple time-varying ODE model to describe the evolution of HIV epidemic in Italy. The model considers a single population of susceptibles, without distinction of high-risk groups within the general population, and accounts for the presence of immigration and emigration, modelling their effects on both the general demography and the dynamics of the infected subpopulations. To represent the intra-host disease progression, the untreated infected population is distributed over four compartments in cascade according to the CD4 counts. A further compartment is added to represent infected people under antiretroviral therapy. The per capita exit rate from treatment, due to voluntary interruption or failure of therapy, is assumed variable with time. The values of the model parameters not reported in the literature are assessed by fitting available epidemiological data over the decade 2003/2012. Predictions until year 2025 are computed, enlightening the impact on the public health of the early initiation of the antiretroviral therapy. The benefits of this change in the treatment eligibility consist in reducing the HIV incidence rate, the rate of new AIDS cases, and the rate of death from AIDS. Analytical results about properties of the model in its time-invariant form are provided, in particular the global stability of the equilibrium points is established either in the absence and in the presence of infected among immigrants. PMID- 29161833 TI - Prediction of influenza peaks in Russian cities: Comparing the accuracy of two SEIR models. AB - This paper is dedicated to the application of two types of SEIR models to the influenza outbreak peak prediction in Russian cities. The first one is a continuous SEIR model described by a system of ordinary differential equations. The second one is a discrete model formulated as a set of difference equations, which was used in the Baroyan-Rvachev modeling framework for the influenza outbreak prediction in the Soviet Union. The outbreak peak day and height predictions were performed by calibrating both models to varied-size samples of long-term data on ARI incidence in Moscow, Saint Petersburg, and Novosibirsk. The accuracy of the modeling predictions on incomplete data was compared with a number of other peak forecasting methods tested on the same dataset. The drawbacks of the described prediction approach and possible ways to overcome them are discussed. PMID- 29161834 TI - A TB model: Is disease eradication possible in India? AB - Tuberculosis (TB) is returning to be a worldwide global public health threat. It is estimated that 9.6 million cases occurred in 2014, of which just two-thirds notified to public health authorities. The "missing cases" constitute a severe challenge for TB transmission control. TB is a severe disease in India, while, worldwide, the WHO estimates that one third of the entire world population is infected. Nowadays, incidence estimation relies increasingly more on notifications of new cases from routine surveillance. There is an urgent need for better estimates of the load of TB, in high-burden settings. We developed a simple model of TB transmission dynamics, using a dynamical system model, consisting of six classes of individuals. It contains the current medical epidemiologists' understanding of the spread of the Mycobacterium tuberculosis in humans, which is substantiated by field observations at the district level in India. The model incorporates the treatment options provided by the public and private sectors in India. Mathematically, an interesting feature of the system is that it exhibits a backward, or subcritical, bifurcation. One of the results of the investigation shows that the discrepancy between the diagnosis rates of the public and private sector does not seem to be the cause of the endemicity of the disease, and, unfortunately, even if they reached 100% of correct diagnosis, this would not be enough to achieve disease eradication. Several other approaches have been attempted on the basis of this model to indicate possible strategies that may lead to disease eradication, but the rather sad conclusion is that they unfortunately do not appear viable in practice. PMID- 29161835 TI - Three-level global resource allocation model for hiv control: A hierarchical decision system approach. AB - Funds from various global organizations, such as, The Global Fund, The World Bank, etc. are not directly distributed to the targeted risk groups. Especially in the so-called third-world-countries, the major part of the fund in HIV prevention programs comes from these global funding organizations. The allocations of these funds usually pass through several levels of decision making bodies that have their own specific parameters to control and specific objectives to achieve. However, these decisions are made mostly in a heuristic manner and this may lead to a non-optimal allocation of the scarce resources. In this paper, a hierarchical mathematical optimization model is proposed to solve such a problem. Combining existing epidemiological models with the kind of interventions being on practice, a 3-level hierarchical decision making model in optimally allocating such resources has been developed and analyzed. When the impact of antiretroviral therapy (ART) is included in the model, it has been shown that the objective function of the lower level decision making structure is a non-convex minimization problem in the allocation variables even if all the production functions for the intervention programs are assumed to be linear. PMID- 29161836 TI - A frailty model for intervention effectiveness against disease transmission when implemented with unobservable heterogeneity. AB - For an intervention against the spread of communicable diseases, the idealized situation is when individuals fully comply with the intervention and the exposure to the infectious agent is comparable across all individuals. Some level of non compliance is likely where the intervention is widely implemented. The focus is on a more accurate view of its effects population-wide. A frailty model is applied. Qualitative analysis, in mathematical terms, reveals how large variability in compliance renders the intervention less effective. This finding sharpens our vague, intuitive and empirical notions. An effective reproduction number in the presence of frailty is defined and is shown to be invariant with respect to the time-scale of disease progression. This makes the results in this paper valid for a wide spectrum of acute and chronic infectious diseases. Quantitative analysis by comparing numerical results shows that they are also robust with respect to assumptions on disease progression structure and distributions, such as with or without the latent period and the assumed distributions of latent and infectious periods. PMID- 29161837 TI - Effect of seasonality on the dynamics of an imitation--based vaccination model with public health intervention. AB - We extend here the game-theoretic investigation made by d'Onofrio et al (2012) on the interplay between private vaccination choices and actions of the public health system (PHS) to favor vaccine propensity in SIR-type diseases. We focus here on three important features. First, we consider a SEIR--type disease. Second, we focus on the role of seasonal fluctuations of the transmission rate. Third, by a simple population--biology approach we derive - with a didactic aim - the game theoretic equation ruling the dynamics of vaccine propensity, without employing 'economy--related' concepts such as the payoff. By means of analytical and analytical--approximate methods, we investigate the global stability of the of disease--free equilibria. We show that in the general case the stability critically depends on the 'shape' of the periodically varying transmission rate. In other words, the knowledge of the average transmission rate (ATR) is not enough to make inferences on the stability of the elimination equilibria, due to the presence of the class of latent subjects. In particular, we obtain that the amplitude of the oscillations favors the possible elimination of the disease by the action of the PHS, through a threshold condition. Indeed, for a given average value of the transmission rate, in absence of oscillations as well as for moderate oscillations, there is no disease elimination. On the contrary, if the amplitude exceeds a threshold value, the elimination of the disease is induced. We heuristically explain this apparently paradoxical phenomenon as a beneficial effect of the phase when the transmission rate is under its average value: the reduction of transmission rate (for example during holidays) under its annual average over--compensates its increase during periods of intense contacts. We also investigate the conditions for the persistence of the disease. Numerical simulations support the theoretical predictions. Finally, we briefly investigate the qualitative behavior of the non--autonomous system for SIR--type disease, by showing that the stability of the elimination equilibria are, in such a case, determined by the ATR. PMID- 29161838 TI - Optimal time to intervene: The case of measles child immunization. AB - The recent measles outbreaks in US and Germany emphasize the importance of sustaining and increasing vaccination rates. In Slovakia, despite mandatory vaccination scheme, decrease in the vaccination rates against measles has been observed in recent years. Different kinds of intervention at the state level, like a law making vaccination a requirement for school entry or education and advertising seem to be the only strategies to improve vaccination coverage. This study aims to analyze the economic effectiveness of intervention in Slovakia. Using real options techniques we determine the level of vaccination rate at which it is optimal to perform intervention. We represent immunization rate of newborns as a stochastic process and intervention as a one-period jump of this process. Sensitivity analysis shows the importance of early intervention in the population with high initial average vaccination coverage. Furthermore, our numerical results demonstrate that the less certain we are about the future development of the immunization rate of newborns, the more valuable is the option to intervene. PMID- 29161839 TI - The potential impact of a prophylactic vaccine for Ebola in Sierra Leone. AB - The 2014 outbreak of Ebola virus disease (EVD) in West Africa was multinational and of an unprecedented scale primarily affecting the countries of Guinea, Liberia, and Sierra Leone. One of the qualities that makes EVD of high public concern is its potential for extremely high mortality rates (up to 90%). A prophylactic vaccine for ebolavirus (rVSV-ZEBOV) has been developed, and clinical trials show near-perfect efficacy. We have developed an ordinary differential equations model that simulates an EVD epidemic and takes into account (1) transmission through contact with infectious EVD individuals and deceased EVD bodies, (2) the heterogeneity of the risk of becoming infected with EVD, and (3) the increased survival rate of infected EVD patients due to greater access to trained healthcare providers. Using fitted parameter values that closely simulate the dynamics of the 2014 outbreak in Sierra Leone, we utilize our model to predict the potential impact of a prophylactic vaccine for the ebolavirus using various vaccination strategies including ring vaccination. Our results show that an rVSV-ZEBOV vaccination coverage as low as 40% in the general population and 95% in healthcare workers will prevent another catastrophic outbreak like the 2014 outbreak from occurring. PMID- 29161840 TI - A multiscale model for heterogeneous tumor spheroid in vitro. AB - In this paper, a novel multiscale method is proposed for the study of heterogeneous tumor spheroid growth in vitro. The entire tumor spheroid is described by an ellipsoid-based model while nutrient and other environmental factors are treated as continua. The ellipsoid-based discrete component is capable of incorporating mechanical effects and deformability, while keeping a minimum set of free variables to describe complex shape variations. Moreover, our purely cell-based description of tumor avoids the complex mutual conversion between a cell-based model and continuum model within a tumor, such as force and mass transformation. This advantage makes it highly suitable for the study of tumor spheroids in vitro whose size are normally less than 800 MUm in diameter. In addition, our numerical scheme provides two computational options depending on tumor size. For a small or medium tumor spheroid, a three-dimensional (3D) numerical model can be directly applied. For a large spheroid, we suggest the use of a 3D-adapted 2D cross section configuration, which has not yet been explored in the literature, as an alternative for the theoretical investigation to bridge the gap between the 2D and 3D models. Our model and its implementations have been validated and applied to various studies given in the paper. The simulation results fit corresponding in vitro experimental observations very well. PMID- 29161841 TI - Effect of rotational grazing on plant and animal production. AB - It is a common understanding that rotational cattle grazing provides better yields than continuous grazing, but a quantitative analysis is lacking in agricultural literature. In rotational grazing, cattle periodically move among paddocks in contrast to continuous grazing, in which the cattle graze on a single plot for the entire grazing season. We construct a differential equation model of vegetation grazing on a fixed area to show that production yields and stockpiled forage are greater for rotational grazing than continuous grazing. Our results show that both the number of cattle per acre and stockpiled forage increase for many rotational configurations. PMID- 29161842 TI - Mathematical model for the growth of Mycobacterium tuberculosis in the granuloma. AB - In this work we formulate a model for the population dynamics of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Our main interest is to assess the impact of the competition among bacteria on the infection prevalence. For this end, we assume that Mtb population has two types of growth. The first one is due to bacteria produced in the interior of each infected macrophage, and it is assumed that is proportional to the number of infected macrophages. The second one is of logistic type due to the competition among free bacteria released by the same infected macrophages. The qualitative analysis and numerical results suggests the existence of forward, backward and S-shaped bifurcations when the associated reproduction number R0 of the Mtb is less unity. In addition, qualitative analysis of the model shows that there may be up to three bacteria-present equilibria, two locally asymptotically stable, and one unstable. PMID- 29161843 TI - Mathematical analysis and modeling of DNA segregation mechanisms. AB - The precise regulation of cell life division is indispensable to the reliable inheritance of genetic material, i.e. DNA, in successive generations of cells. This is governed by dedicated biochemical networks which ensure that all requirements are met before transition from one phase to the next. The Spindle Assembly Checkpoint (SAC) is an evolutionarily mechanism that delays mitotic progression until all chromosomes are properly linked to the mitotic spindle. During some asymmetric cell divisions, such as those observed in budding yeast, an additional mechanism, the Spindle Position Checkpoint (SPOC), is required to delay exit from mitosis until the mitotic spindle is correctly aligned. These checkpoints are complex and their elaborate spatiotemporal dynamics are challenging to understand intuitively. In this study, bistable mathematical models for both activation and silencing of mitotic checkpoints were constructed and analyzed. A one-parameter bifurcation was computed to show the realistic biochemical switches considering all signals. Numerical simulations involving systems of ODEs and PDEs were performed over various parameters, to investigate the effect of the diffusion coefficient. The results provide systems-level insights into mitotic transition and demonstrate that mathematical analysis constitutes a powerful tool for investigation of the dynamic properties of complex biomedical systems. PMID- 29161844 TI - A network model for control of dengue epidemic using sterile insect technique. AB - In this paper, a network model has been proposed to control dengue disease transmission considering host-vector dynamics in n patches. The control of mosquitoes is performed by SIT. In SIT, the male insects are sterilized in the laboratory and released into the environment to control the number of offsprings. The basic reproduction number has been computed. The existence and stability of various states have been discussed. The bifurcation diagram has been plotted to show the existence and stability regions of disease-free and endemic states for an isolated patch. The critical level of sterile male mosquitoes has been obtained for the control of disease. The basic reproduction number for n patch network model has been computed. It is evident from numerical simulations that SIT control in one patch may control the disease in the network having two/three patches with suitable coupling among them. PMID- 29161845 TI - Spatially-implicit modelling of disease-behaviour interactions in the context of non-pharmaceutical interventions. AB - Pair approximation models have been used to study the spread of infectious diseases in spatially distributed host populations, and to explore disease control strategies such as vaccination and case isolation. Here we introduce a pair approximation model of individual uptake of non-pharmaceutical interventions (NPIs) for an acute self-limiting infection, where susceptible individuals can learn the NPIs either from other susceptible individuals who are already practicing NPIs ("social learning"), or their uptake of NPIs can be stimulated by being neighbours of an infectious person ("exposure learning"). NPIs include individual measures such as hand-washing and respiratory etiquette. Individuals can also drop the habit of using NPIs at a certain rate. We derive a spatially defined expression of the basic reproduction number R0 and we also numerically simulate the model equations. We find that exposure learning is generally more efficient than social learning, since exposure learning generates NPI uptake in the individuals at immediate risk of infection. However, if social learning is pre-emptive, beginning a sufficient amount of time before the epidemic, then it can be more effective than exposure learning. Interestingly, varying the initial number of individuals practicing NPIs does not significantly impact the epidemic final size. Also, if initial source infections are surrounded by protective individuals, there are parameter regimes where increasing the initial number of source infections actually decreases the infection peak (instead of increasing it) and makes it occur sooner. The peak prevalence increases with the rate at which individuals drop the habit of using NPIs, but the response of peak prevalence to changes in the forgetting rate are qualitatively different for the two forms of learning. The pair approximation methodology developed here illustrates how analytical approaches for studying interactions between social processes and disease dynamics in a spatially structured population should be further pursued. PMID- 29161846 TI - Optimal vaccination strategies for an SEIR model of infectious diseases with logistic growth. AB - In this paper an improved SEIR model for an infectious disease is presented which includes logistic growth for the total population. The aim is to develop optimal vaccination strategies against the spread of a generic disease. These vaccination strategies arise from the study of optimal control problems with various kinds of constraints including mixed control-state and state constraints. After presenting the new model and implementing the optimal control problems by means of a first discretize-then-optimize method, numerical results for six scenarios are discussed and compared to an analytical optimal control law based on Pontrygin's minimum principle that allows to verify these results as approximations of candidate optimal solutions. PMID- 29161847 TI - Formulation of the protein synthesis rate with sequence information. AB - Translation is a central biological process by which proteins are synthesized from genetic information contained within mRNAs. Here, we investigate the kinetics of translation at the molecular level by a stochastic simulation model. The model explicitly includes RNA sequences, ribosome dynamics, the tRNA pool and biochemical reactions involved in the translation elongation. The results show that the translation efficiency is mainly limited by the available ribosome number, translation initiation and the translation elongation time. The elongation time is a log-normal distribution, with the mean and variance determined by the codon saturation and the process of aa-tRNA selection at each codon binding site. Moreover, our simulations show that the translation accuracy exponentially decreases with the sequence length. These results suggest that aa tRNA competition is crucial for both translation elongation, translation efficiency and the accuracy, which in turn determined the effective protein production rate of correct proteins. Our results improve the dynamical equation of protein production with a delay differential equation that is dependent on sequence information through both the effective production rate and the distribution of elongation time. PMID- 29161848 TI - Complex wolbachia infection dynamics in mosquitoes with imperfect maternal transmission. AB - Dengue, malaria, and Zika are dangerous diseases primarily transmitted by Aedes aegypti, Aedes albopictus, and Anopheles stephensi. In the last few years, a new disease control method, besides pesticide spraying to kill mosquitoes, has been developed by releasing mosquitoes carrying bacterium Wolbachia into the natural areas to infect the wild population of mosquitoes and block disease transmission. The bacterium is transmitted by infected mothers and the maternal transmission was assumed to be perfect in virtually all previous models. However, recent experiments on Aedes aegypti and Anopheles stephensi showed that the transmission can be imperfect. In this work, we develop a model to describe how the imperfect maternal transmission affects the dynamics of Wolbachia spread. We establish two useful identities and employ them to find sufficient and necessary conditions under which the system exhibits monomorphic, bistable, and polymorphic dynamics. These analytical results may help find a plausible explanation for the recent observation that the Wolbachia strain omegaMelPop failed to establish in the natural populations in Australia and Vietnam. PMID- 29161849 TI - Transmission dynamics and optimal control of brucellosis in Inner Mongolia of China. AB - A multigroup model is developed to characterize brucellosis transmission, to explore potential effects of key factors, and to prioritize control measures. The global threshold dynamics are completely characterized by theory of asymptotic autonomous systems and Lyapunov direct method. We then formulate a multi objective optimization problem and, by the weighted sum method, transform it into a scalar optimization problem on minimizing the total cost for control. The existence of optimal control and its characterization are well established by Pontryagin's Maximum Principle. We further parameterize the model and compute optimal control strategy for Inner Mongolia in China. In particular, we expound the effects of sheep recruitment, vaccination of sheep, culling of infected sheep, and health education of human on the dynamics and control of brucellosis. This study indicates that current control measures in Inner Mongolia are not working well and Brucellosis will continue to increase. The main finding here supports opposing unregulated sheep breeding and suggests vaccination and health education as the preferred necessary emergency intervention control. The policymakers must take a new look at the current control strategy, and, in order to control brucellosis better in Inner Mongolia, the governments have to preemptively press ahead with more effective measures. PMID- 29161850 TI - Preface. AB - In the new century, with rapid population growth, large-scale urbanization, global warming and many other factors, we are facing unprecedented ecological, health, social, and other challenges and issues. These include biological invasion, environmental degradation, sharp increase in cancer morbidity, high frequency of emerging and re-emerging infectious diseases, which pose a grave threat to biological diversity, public health, economic development and so on. Based on the solid research in population dynamics and disease dynamics, mathematical modeling, analysis and simulation have been widely used over the past decades to study various problems in life sciences and medicine, from the expression of gene sequence to the pathogenesis of cancer, from the control of molecular organisms to the resistance of bacteria and viruses, from immune response to diseases to the design and evaluation of treatments, and so on. To provide a platform for researchers in mathematical biology and related fields to present latest findings and research trends, to exchange ideas and approaches, and to enhance communication and cooperation, we organized a workshop entitled "Current Topics in Mathematical Biology (CTMB)" at Shanghai Normal University, December 18-20, 2015. We acknowledge the support from the Mathematics and Science College at Shanghai Normal University and Shanghai Gaofeng Project for University Academic Development Program. PMID- 29161851 TI - Global stability of the steady states of an epidemic model incorporating intervention strategies. AB - In this paper, we investigate the global stability of the steady states of a general reaction-diffusion epidemiological model with infection force under intervention strategies in a spatially heterogeneous environment. We prove that the reproductoin number R0 can be played an essential role in determining whether the disease will extinct or persist: if R0< 1, there is a unique disease-free equilibrium which is globally asymptotically stable; and if R0 >1, there exists a unique endemic equilibrium which is globally asymptotically stable. Furthermore, we study the relation between R0 with the diffusion and spatial heterogeneity and find that, it seems very necessary to create a low-risk habitat for the population to effectively control the spread of the epidemic disease. This may provide some potential applications in disease control. PMID- 29161852 TI - Effect of seasonal changing temperature on the growth of phytoplankton. AB - An non-autonomous nutrient-phytoplankton interacting model incorporating the effect of time-varying temperature is established. The impacts of temperature on metabolism of phytoplankton such as nutrient uptake, death rate, and nutrient releasing from particulate nutrient are investigated. The ecological reproductive index is formulated to present a threshold criteria and to characterize the dynamics of phytoplankton. The positive invariance, dissipativity, and the existence and stability of boundary and positive periodic solution are established. The analyses rely on the comparison principle, the coincidence degree theory and Lyapunov direct method. The effect of seasonal temperature and daily temperature on phytoplankton biomass are simulated numerically. Numerical simulation shows that the phytoplankton biomass is very robust to the variation of water temperature. The dynamics of the model and model predictions agree with the experimental data. Our model and analysis provide a possible explanation of triggering mechanism of phytoplankton blooms. PMID- 29161853 TI - Effects of isolation and slaughter strategies in different species on emerging zoonoses. AB - Zoonosis is the kind of infectious disease transmitting among different species by zoonotic pathogens. Different species play different roles in zoonoses. In this paper, we established a basic model to describe the zoonotic pathogen transmission from wildlife, to domestic animals, to humans. Then we put three strategies into the basic model to control the emerging zoonoses. Three strategies are corresponding to control measures of isolation, slaughter or similar in wildlife, domestic animals and humans respectively. We analyzed the effects of these three strategies on control reproductive numbers and equilibriums and we took avian influenza epidemic in China as an example to show the impacts of the strategies on emerging zoonoses in different areas at beginning. PMID- 29161854 TI - An SIR epidemic model with vaccination in a patchy environment. AB - In this paper, an SIR patch model with vaccination is formulated to investigate the effect of vaccination coverage and the impact of human mobility on the spread of diseases among patches. The control reproduction number Rv is derived. It shows that the disease-free equilibrium is unique and is globally asymptotically stable if Rv< 1, and unstable if Rv>1. The sufficient condition for the local stability of boundary equilibria and the existence of equilibria are obtained for the case n=2. Numerical simulations indicate that vaccines can control and prevent the outbreak of infectious in all patches while migration may magnify the outbreak size in one patch and shrink the outbreak size in other patch. PMID- 29161855 TI - Global dynamics of a vector-host epidemic model with age of infection. AB - In this paper, a partial differential equation (PDE) model is proposed to explore the transmission dynamics of vector-borne diseases. The model includes both incubation age of the exposed hosts and infection age of the infectious hosts which describe incubation-age dependent removal rates in the latent period and the variable infectiousness in the infectious period, respectively. The reproductive number R0 is derived. By using the method of Lyapunov function, the global dynamics of the PDE model is further established, and the results show that the basic reproduction number R0 determines the transmission dynamics of vector-borne diseases: the disease-free equilibrium is globally asymptotically stable if R0 <= 1, and the endemic equilibrium is globally asymptotically stable if R0 > 1. The results suggest that an effective strategy to contain vector-borne diseases is decreasing the basic reproduction number R0 below one. PMID- 29161856 TI - Invasion entire solutions in a time periodic Lotka-Volterra competition system with diffusion. AB - This paper is concerned with invasion entire solutions of a monostable time periodic Lotka-Volterra competition-diffusion system. We first give the asymptotic behaviors of time periodic traveling wave solutions at infinity by a dynamical approach coupled with the two-sided Laplace transform. According to these asymptotic behaviors, we then obtain some key estimates which are crucial for the construction of an appropriate pair of sub-super solutions. Finally, using the sub-super solutions method and comparison principle, we establish the existence of invasion entire solutions which behave as two periodic traveling fronts with different speeds propagating from both sides of x-axis. In other words, we formulate a new invasion way of the superior species to the inferior one in a time periodic environment. PMID- 29161857 TI - Structural calculations and propagation modeling of growing networks based on continuous degree. AB - When a network reaches a certain size, its node degree can be considered as a continuous variable, which we will call continuous degree. Using continuous degree method (CDM), we analytically calculate certain structure of the network and study the spread of epidemics on a growing network. Firstly, using CDM we calculate the degree distributions of three different growing models, which are the BA growing model, the preferential attachment accelerating growing model and the random attachment growing model. We obtain the evolution equation for the cumulative distribution function F(k,t), and then obtain analytical results about F(k,t) and the degree distribution p(k,t). Secondly, we calculate the joint degree distribution p(k1,k2,t) of the BA model by using the same method, thereby obtain the conditional degree distribution p(k1|k2). We find that the BA model has no degree correlations. Finally, we consider the different states, susceptible and infected, according to the node health status. We establish the continuous degree SIS model on a static network and a growing network, respectively. We find that, in the case of growth, the new added health nodes can slightly reduce the ratio of infected nodes, but the final infected ratio will gradually tend to the final infected ratio of SIS model on static networks. PMID- 29161858 TI - Global dynamics of a delay virus model with recruitment and saturation effects of immune responses. AB - In this paper, we formulate a virus dynamics model with the recruitment of immune responses, saturation effects and an intracellular time delay. With the help of uniform persistence theory and Lyapunov method, we show that the global stability of the model is totally determined by the basic reproductive number R0. Furthermore, we analyze the effects of the recruitment of immune responses on virus infection by numerical simulation. The results show ignoring the recruitment of immune responses will result in overestimation of the basic reproductive number and the severity of viral infection. PMID- 29161859 TI - Theoretical investigation on models of circadian rhythms based on dimerization and proteolysis of PER and TIM. AB - Circadian rhythms of physiology and behavior are widespread?break mechanisms in many organisms. The internal biological rhythms are driven by molecular clocks, which oscillate with a period nearly but not exactly 24 hours. Many classic models of circadian rhythms are based on a time-delayed negative feedback, suggested by the protein products inhibiting transcription of their own genes. In 1999, based on stabilization of PER upon dimerization, Tyson et al. [J. J. Tyson, C. I. Hong, C. D. Thron, B. Novak, Biophys. J. 77 (1999) 2411--2417] proposed a crucial positive feedback to the circadian oscillator. This idea was mathematically expressed in a three-dimensional model. By imposing assumptions that the dimerization reactions were fast and dimeric proteins were in rapid equilibrium, they reduced the model to a pair of nonlinear ordinary differential equations of mRNA and total protein concentrations. Then they used phase plane analysis tools to investigate circadian rhythms. In this paper, the original three-dimensional model is studied. We explore the existence of oscillations and their periods. Much attention is paid to investigate how the periods depend on model parameters. The numerical simulations are in good agreement with their reduced work. PMID- 29161860 TI - Modulation of first-passage time for bursty gene expression via random signals. AB - The stochastic nature of cell-specific signal molecules (such as transcription factor, ribosome, etc.) and the intrinsic stochastic nature of gene expression process result in cell-to-cell variations at protein levels. Increasing experimental evidences suggest that cell phenotypic variations often depend on the accumulation of some special proteins. Hence, a natural and fundamental question is: How does input signal affect the timing of protein count up to a given threshold? To this end, we study effects of input signal on the first passage time (FPT), the time at which the number of proteins crosses a given threshold. Input signal is distinguished into two types: constant input signal and random input signal, regulating only burst frequency (or burst size) of gene expression. Firstly, we derive analytical formulae for FPT moments in each case of constant signal regulation and random signal regulation. Then, we find that random input signal tends to increases the mean and noise of FPT compared with constant input signal. Finally, we observe that different regulation ways of random signal have different effects on FPT, that is, burst size modulation tends to decrease the mean of FPT and increase the noise of FPT compared with burst frequency modulation. Our findings imply a fundamental mechanism that random fluctuating environment may prolong FPT. This can provide theoretical guidance for studies of some cellular key events such as latency of HIV and lysis time of bacteriophage lambda. In conclusion, our results reveal impacts of external signal on FPT and aid understanding the regulation mechanism of gene expression. PMID- 29161861 TI - A mathematical model for the seasonal transmission of schistosomiasis in the lake and marshland regions of China. AB - Schistosomiasis, a parasitic disease caused by ?textit{ Schistosoma Japonicum}, is still one of the most serious parasitic diseases in China and remains endemic in seven provinces, including Hubei, Anhui, Hunan, Jiangsu, Jiangxi, Sichuan, and Yunnan. The monthly data of human schistosomiasis cases in Hubei, Hunan, and Anhui provinces (lake and marshland regions) released by the Chinese Center for Disease Control and Prevention (China CDC) display a periodic pattern with more cases in late summer and early autumn. Based on this observation, we construct a deterministic model with periodic transmission rates to study the seasonal transmission dynamics of schistosomiasis in these lake and marshland regions in China. We calculate the basic reproduction number R0, discuss the dynamical behavior of solutions to the model, and use the model to fit the monthly data of human schistosomiasis cases in Hubei. We also perform some sensitivity analysis of the basic reproduction number R0 in terms of model parameters. Our results indicate that treatment of at-risk population groups, improving sanitation, hygiene education, and snail control are effective measures in controlling human schistosomiasis in these lakes and marshland regions. PMID- 29161862 TI - Modeling co-infection of Ixodes tick-borne pathogens. AB - Ticks, including the Ixodes ricinus and Ixodes scapularis hard tick species, are regarded as the most common arthropod vectors of both human and animal diseases in Europe and the United States capable of transmitting a large number of bacteria, viruses and parasites. Since ticks in larval and nymphal stages share the same host community which can harbor multiple pathogens, they may be co infected with two or more pathogens, with a subsequent high likelihood of co transmission to humans or animals. This paper is devoted to the modeling of co infection of tick-borne pathogens, with special focus on the co-infection of Borrelia burgdorferi (agent of Lyme disease) and Babesia microti (agent of human babesiosis). Considering the effect of co-infection, we illustrate that co infection with B. burgdorferi increases the likelihood of B. microti transmission, by increasing the basic reproduction number of B. microti below the threshold smaller than one to be possibly above the threshold for persistence. The study confirms a mechanism of the ecological fitness paradox, the establishment of B. microti which has weak fitness (basic reproduction number less than one). Furthermore, co-infection could facilitate range expansion of both pathogens. PMID- 29161863 TI - An SEI infection model incorporating media impact. AB - To study the impact of media coverage on spread and control of infectious diseases, we use a susceptible-exposed-infective (SEI) model, including individuals' behavior changes in their contacts due to the influences of media coverage, and fully investigate the model dynamics. We define the basic reproductive number ?0 for the model, and show that the modeled disease dies out regardless of initial infections when ?0< 1, and becomes uniformly persistently endemic if ?0>1. When the disease is endemic and the influence of the media coverage is less than or equal to a critical number, there exists a unique endemic equilibrium which is asymptotical stable provided ?0 is greater than and near one. However, if ?0 is larger than a critical number, the model can undergo Hopf bifurcation such that multiple endemic equilibria are bifurcated from the unique endemic equilibrium as the influence of the media coverage is increased to a threshold value. Using numerical simulations we obtain results on the effects of media coverage on the endemic that the media coverage may decrease the peak value of the infectives or the average number of the infectives in different cases. We show, however, that given larger ?0, the influence of the media coverage may as well result in increasing the average number of the infectives, which brings challenges to the control and prevention of infectious diseases. PMID- 29161864 TI - Global stability in a tuberculosis model of imperfect treatment with age dependent latency and relapse. AB - In this paper, an SEIR epidemic model for an imperfect treatment disease with age dependent latency and relapse is proposed. The model is well-suited to model tuberculosis. The basic reproduction number R0 is calculated. We obtain the global behavior of the model in terms of R0. If R0< 1, the disease-free equilibrium is globally asymptotically stable, whereas if R0>1, a Lyapunov functional is used to show that the endemic equilibrium is globally stable amongst solutions for which the disease is present. PMID- 29161865 TI - A bacteriophage model based on CRISPR/Cas immune system in a chemostat. AB - Clustered regularly interspaced short palindromic repeats(CRISPRs) along with Cas proteins are a widespread immune system across bacteria and archaea. In this paper, a mathematical model in a chemostat is proposed to investigate the effect of CRISPR/Cas on the bacteriophage dynamics. It is shown that the introduction of CRISPR/Cas can induce a backward bifurcation and transcritical bifurcation. Numerical simulations reveal the coexistence of a stable infection-free equilibrium with an infection equilibrium, or a stable infection-free equilibrium with a stable periodic solution. PMID- 29161866 TI - A mathematical model of stem cell regeneration with epigenetic state transitions. AB - In this paper, we study a mathematical model of stem cell regeneration with epigenetic state transitions. In the model, the heterogeneity of stem cells is considered through the epigenetic state of each cell, and each epigenetic state defines a subpopulation of stem cells. The dynamics of the subpopulations are modeled by a set of ordinary differential equations in which epigenetic state transition in cell division is given by the transition probability. We present analysis for the existence and linear stability of the equilibrium state. As an example, we apply the model to study the dynamics of state transition in breast cancer stem cells. PMID- 29161867 TI - On the continuity of the function describing the times of meeting impulsive set and its application. AB - The properties of the limit sets of orbits of planar impulsive semi-dynamic system strictly depend on the continuity of the function, which describes the times of meeting impulsive sets. In this note, we will show a more realistic counter example on the continuity of this function which has been proven and widely used in impulsive dynamical system and applied in life sciences including population dynamics and disease control. Further, what extra condition should be added to guarantee the continuity of the function has been addressed generally, and then the applications and shortcomings have been discussed when using the properties of this function. PMID- 29161868 TI - Dynamics of epidemic models with asymptomatic infection and seasonal succession. AB - In this paper, we consider a compartmental SIRS epidemic model with asymptomatic infection and seasonal succession, which is a periodic discontinuous differential system. The basic reproduction number R0 is defined and evaluated directly for this model, and uniform persistence of the disease and threshold dynamics are obtained. Specially, global dynamics of the model without seasonal force are studied. It is shown that the model has only a disease-free equilibrium which is globally stable if R0 <= 1, and as R0 > 1 the disease-free equilibrium is unstable and there is an endemic equilibrium, which is globally stable if the recovering rates of asymptomatic infectives and symptomatic infectives are close. These theoretical results provide an intuitive basis for understanding that the asymptomatically infective individuals and the seasonal disease transmission promote the evolution of the epidemic, which allow us to predict the outcomes of control strategies during the course of the epidemic. PMID- 29161869 TI - Dynamical behaviors of an Echinococcosis epidemic model with distributed delays. AB - In this paper, a novel spreading dynamical model for Echinococcosis with distributed time delays is proposed. For the model, we firstly give the basic reproduction number R0 and the existence of a unique endemic equilibrium when R0>1. Furthermore, we analyze the dynamical behaviors of the model. The results show that the dynamical properties of the model is completely determined by R0. That is, if R0< 1, the disease-free equilibrium is globally asymptotically stable, and if R0>1, the model is permanent and the endemic equilibrium is globally asymptotically stable. According to human Echinococcosis cases from January 2004 to December 2011 in Xinjiang, China, we estimate the parameters of the model and study the transmission trend of the disease in Xinjiang, China. The model provides an approximate estimate of the basic reproduction number R0=1.23 in Xinjiang, China. From theoretic results, we further find that Echinococcosis is endemic in Xinjiang, China. Finally, we perform some sensitivity analysis of several model parameters and give some useful measures on controlling the transmission of Echinococcosis. PMID- 29161870 TI - Modeling transcriptional co-regulation of mammalian circadian clock. AB - The circadian clock is a self-sustaining oscillator that has a period of about 24 hours at the molecular level. The oscillator is a transcription-translation feedback loop system composed of several genes. In this paper, a scalar nonlinear differential equation with two delays, modeling the transcriptional co-regulation in mammalian circadian clock, is proposed and analyzed. Sufficient conditions are established for the asymptotic stability of the unique nontrivial positive equilibrium point of the model by studying an exponential polynomial characteristic equation with delay-dependent coefficients. The existence of the Hopf bifurcations can be also obtained. Numerical simulations of the model with proper parameter values coincide with the theoretical result. PMID- 29161871 TI - Transition of interaction outcomes in a facilitation-competition system of two species. AB - A facilitation-competition system of two species is considered, where one species has a facilitation effect on the other but there is spatial competition between them. Our aim is to show mechanism by which the facilitation promotes coexistence of the species. A lattice gas model describing the facilitation-competition system is analyzed, in which nonexistence of periodic solution is shown and previous results are extended. Global dynamics of the model demonstrate essential features of the facilitation-competition system. When a species cannot survive alone, a strong facilitation from the other would lead to its survival. However, if the facilitation is extremely strong, both species go extinct. When a species can survive alone and its mortality rate is not larger than that of the other species, it would drive the other one into extinction. When a species can survive alone and its mortality rate is larger than that of the other species, it would be driven into extinction if the facilitation from the other is weak, while it would coexist with the other if the facilitation is strong. Moreover, an extremely strong facilitation from the other would lead to extinction of species. Bifurcation diagram of the system exhibits that interaction outcome between the species can transition between competition, amensalism, neutralism and parasitism in a smooth fashion. A novel result of this paper is the rigorous and thorough analysis, which displays transparency of dynamics in the system. Numerical simulations validate the results. PMID- 29161872 TI - Asymptotic behavior of a delayed stochastic logistic model with impulsive perturbations. AB - In this paper, we investigate the dynamics of a delayed logistic model with both impulsive and stochastic perturbations. The impulse is introduced at fixed moments and the stochastic perturbation is of white noise type which is assumed to be proportional to the population density. We start with the existence and uniqueness of the positive solution of the model, then establish sufficient conditions ensuring its global attractivity. By using the theory of integral Markov semigroups, we further derive sufficient conditions for the existence of the stationary distribution of the system. Finally, we perform the extinction analysis of the model. Numerical simulations illustrate the obtained theoretical results. PMID- 29161873 TI - Bogdanov-Takens bifurcations in the enzyme-catalyzed reaction comprising a branched network. AB - There have been some results on bifurcations of codimension one (such as saddle node, transcritical, pitchfork) and degenerate Hopf bifurcations for an enzyme catalyzed reaction system comprising a branched network but no further discussion for bifurcations at its cusp. In this paper we give conditions for the existence of a cusp and compute the parameter curves for the Bogdanov-Takens bifurcation, which induces the appearance of homoclinic orbits and periodic orbits, indicating the tendency to steady-states or a rise of periodic oscillations for the concentrations of the substrate and the product. PMID- 29161875 TI - Threshold dynamics of a time periodic and two--group epidemic model with distributed delay. AB - In this paper, a time periodic and two--group reaction--diffusion epidemic model with distributed delay is proposed and investigated. We firstly introduce the basic reproduction number R0 for the model via the next generation operator method. We then establish the threshold dynamics of the model in terms of R0, that is, the disease is uniformly persistent if R0>1, while the disease goes to extinction if R0< 1. Finally, we study the global dynamics for the model in a special case when all the coefficients are independent of spatio--temporal variables. PMID- 29161874 TI - Onset and termination of oscillation of disease spread through contaminated environment. AB - We consider a reaction diffusion equation with a delayed nonlocal nonlinearity and subject to Dirichlet boundary condition. The model equation is motivated by infection dynamics of disease spread (avian influenza, for example) through environment contamination, and the nonlinearity takes into account of distribution of limited resources for rapid and slow interventions to clean contaminated environment. We determine conditions under which an equilibrium with positive value in the interior of the domain (disease equilibrium) emerges and determine conditions under which Hope bifurcation occurs. For a fixed pair of rapid and slow response delay, we show that nonlinear oscillations can be avoided by distributing resources for both fast or slow interventions. PMID- 29161876 TI - The risk index for an SIR epidemic model and spatial spreading of the infectious disease. AB - In this paper, a reaction-diffusion-advection SIR model for the transmission of the infectious disease is proposed and analyzed. The free boundaries are introduced to describe the spreading fronts of the disease. By exhibiting the basic reproduction number RDA0 for an associated model with Dirichlet boundary condition, we introduce the risk index RF0(t) for the free boundary problem, which depends on the advection coefficient and time. Sufficient conditions for the disease to prevail or not are obtained. Our results suggest that the disease must spread if RF0(t0) <= 1 for some t0 and the disease is vanishing if RF0(infinity) < 1, while if RF0 (0) < 1, the spreading or vanishing of the disease depends on the initial state of infected individuals as well as the expanding capability of the free boundary. We also illustrate the impacts of the expanding capability on the spreading fronts via the numerical simulations. PMID- 29161877 TI - Modeling and analyzing the transmission dynamics of visceral leishmaniasis. AB - In this paper, we develop a mathematical model to study the transmission dynamics of visceral leishmaniasis. Three populations: dogs, sandflies and humans, are considered in the model. Based on recent studies, we include vertical transmission of dogs in the spread of the disease. We also investigate the impact of asymptomatic humans and dogs as secondary reservoirs of the parasites. The basic reproduction number and sensitivity analysis show that the control of dog sandfly transmission is more important for the elimination of the disease. Vaccination of susceptible dogs, treatment of infective dogs, as well as control of vertical transmission in dogs are effective prevention and control measures for visceral leishmaniasis. PMID- 29161878 TI - In vitro model of potential metal cation exchanges in biological apatite. AB - Biological apatite is ion-doped and provides an active pool for the exchange with foreign impurity ions. In this work, an in vitro model of hydrated metastable octacalcium phosphate (OCP) crystals was established to mimetically investigate the distinct exchange of trivalent and divalent cations (Fe3+ and Sr2+) with biological apatite. Fe3+ significantly promoted the collapses of OCP crystals and the formation of amorphous sol-like ferric phosphates, while Sr2+ facilitated the epitaxial growth and stability of OCP crystals. The involvement of Ca2+ maintained the crystalline integrity and inhibited the ion exchange within OCP crystals. This in vitro model would lay the foundation for the further investigation of the metabolism of biological apatite. PMID- 29161879 TI - Managing Expectations of an HIV Cure: What Should We Expect? PMID- 29161880 TI - HIV, Hepatitis B Virus, and Hepatitis C Virus Prevalence Among High-Risk Populations in South India. PMID- 29161881 TI - Accuracy of the raw-data-based effective atomic numbers and monochromatic CT numbers for contrast medium with a dual-energy CT technique. AB - OBJECTIVE: To evaluate the accuracy of raw-data-based effective atomic number (Zeff) values and monochromatic CT numbers for contrast material of varying iodine concentrations, obtained using dual-energy CT. METHODS: We used a tissue characterization phantom and varying concentrations of iodinated contrast medium. A comparison between the theoretical values of Zeff and that provided by the manufacturer was performed. The measured and theoretical monochromatic CT numbers at 40-130 keV were compared. RESULTS: The average difference between the Zeff values of lung (inhale) inserts in the tissue characterization phantom was 81.3% and the average Zeff difference was within 8.4%. The average difference between the Zeff values of the varying concentrations of iodinated contrast medium was within 11.2%. For the varying concentrations of iodinated contrast medium, the differences between the measured and theoretical monochromatic CT values increased with decreasing monochromatic energy. The Zeff and monochromatic CT numbers in the tissue characterization phantom were reasonably accurate. CONCLUSION: The accuracy of the raw-data-based Zeff values was higher than that of image-based Zeff values in the tissue-equivalent phantom. The accuracy of Zeff values in the contrast medium was in good agreement within the maximum SD found in the iodine concentration range of clinical dynamic CT imaging. Moreover, the optimum monochromatic energy for human tissue and iodinated contrast medium was found to be 70 keV. Advances in knowledge: The accuracy of the Zeff values and monochromatic CT numbers of the contrast medium created by raw-data-based, dual energy CT could be sufficient in clinical conditions. PMID- 29161882 TI - Redox-Active Quinone Chelators: Properties, Mechanisms of Action, Cell Delivery, and Cell Toxicity. AB - SIGNIFICANCE: Chemotherapy is currently the principal method for treating many malignancies. Thus, the development of improved antitumor drugs with enhanced efficacy and selectivity remains a high priority. Recent Advances: Anthracycline antibiotics (AAs), for example, doxorubicin, daunomycin, and mitomycin C, belong to an important family of antitumor agents widely used in chemotherapy. These compounds are all quinones. They are, thus, capable of being reduced by appropriate chemicals or reductases. One of their important properties is that under aerobic conditions their reduced forms undergo oxidation, with concomitant generation of reactive oxygen species (ROS), namely, superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals. The presence of metal ions is essential for the generation of ROS by AAs in biological systems. CRITICAL ISSUES: A fundamental shortcoming of the AAs is their high cardiotoxicity. We have proposed, and experimentally realized, a new type of quinones that is capable of coordinating metal ions. We have demonstrated in vitro that they can be reduced by electron transfer chains and glutathione with concomitant generation of ROS. They can also produce ROS under photo-excitation. The mechanisms of these reactions have been characterized by using nuclear magnetic resonance and electron paramagnetic resonance. FUTURE DIRECTIONS: To enhance their therapeutic effectiveness, and decrease cardiotoxicity and other side effects, we intend to conjugate the quinone chelators with monoclonal antibodies and peptide hormones that are specifically targeted to receptors on the cancer cell surface. Some such candidates have already been synthesized. An alternative approach for delivery of our compounds involves the use of specific peptide-based nanoparticles. In addition, our novel approach for treating malignancies is also suitable for photodynamic therapy. Antioxid. Redox Signal. 28, 1394-1403. PMID- 29161883 TI - Targeting Oncogenic Nuclear Factor Kappa B Signaling with Redox-Active Agents for Cancer Treatment. AB - SIGNIFICANCE: Nuclear factor kappa B (NF-kappaB) signaling is essential under physiologically relevant conditions. However, aberrant activation of this pathway plays a pertinent role in tumorigenesis and contributes to resistance. Recent Advances: The importance of the NF-kappaB pathway means that its targeting must be specific to avoid side effects. For many currently used therapeutics and those under development, the ability to generate reactive oxygen species (ROS) is a promising strategy. CRITICAL ISSUES: As cancer cells exhibit greater ROS levels than their normal counterparts, they are more sensitive to additional ROS, which may be a potential therapeutic niche. It is known that ROS are involved in (i) the activation of NF-kappaB signaling, when in sublethal amounts; and (ii) high levels induce cytotoxicity resulting in apoptosis. Indeed, ROS-induced cytotoxicity is valuable for its capabilities in killing cancer cells, but establishing the potency of ROS for effective inhibition of NF-kappaB signaling is necessary. Indeed, some cancer treatments, currently used, activate NF-kappaB and may stimulate oncogenesis and confer resistance. FUTURE DIRECTIONS: Thus, combinatorial approaches using ROS-generating agents alongside conventional therapeutics may prove an effective tactic to reduce NF-kappaB activity to kill cancer cells. One strategy is the use of thiosemicarbazones, which form redox active metal complexes that generate high ROS levels to deliver potent antitumor activity. These agents also upregulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which functions as an NF-kappaB signaling inhibitor. It is proposed that targeting NF-kappaB signaling may proffer a new therapeutic niche to improve the efficacy of anticancer regimens. Antioxid. Redox Signal. 00, 000-000. PMID- 29161884 TI - Accounting for Non-Gaussian Sources of Spatial Correlation in Parametric Functional Magnetic Resonance Imaging Paradigms II: A Method to Obtain First Level Analysis Residuals with Uniform and Gaussian Spatial Autocorrelation Function and Independent and Identically Distributed Time-Series. AB - In a recent study Eklund et al. have shown that cluster-wise family-wise error (FWE) rate-corrected inferences made in parametric statistical method-based functional magnetic resonance imaging (fMRI) studies over the past couple of decades may have been invalid, particularly for cluster defining thresholds less stringent than p < 0.001; principally because the spatial autocorrelation functions (sACFs) of fMRI data had been modeled incorrectly to follow a Gaussian form, whereas empirical data suggest otherwise. Hence, the residuals from general linear model (GLM)-based fMRI activation estimates in these studies may not have possessed a homogenously Gaussian sACF. Here we propose a method based on the assumption that heterogeneity and non-Gaussianity of the sACF of the first-level GLM analysis residuals, as well as temporal autocorrelations in the first-level voxel residual time-series, are caused by unmodeled MRI signal from neuronal and physiological processes as well as motion and other artifacts, which can be approximated by appropriate decompositions of the first-level residuals with principal component analysis (PCA), and removed. We show that application of this method yields GLM residuals with significantly reduced spatial correlation, nearly Gaussian sACF and uniform spatial smoothness across the brain, thereby allowing valid cluster-based FWE-corrected inferences based on assumption of Gaussian spatial noise. We further show that application of this method renders the voxel time-series of first-level GLM residuals independent, and identically distributed across time (which is a necessary condition for appropriate voxel level GLM inference), without having to fit ad hoc stochastic colored noise models. Furthermore, the detection power of individual subject brain activation analysis is enhanced. This method will be especially useful for case studies, which rely on first-level GLM analysis inferences. PMID- 29161885 TI - Critical Limb Ischemia: A Practical Up-To-Date Review. AB - Critical limb ischemia (CLI) is the most advanced form of peripheral artery disease. It is associated with significant morbidity and mortality and high management costs. It carries a high risk of amputation and local infection. Moreover, cardiovascular complications remain a major concern. Although it is a well-known entity and new technological and therapeutic advances have been made, this condition remains poorly addressed, with significantly heterogeneous management, especially in nonexperienced centers. This review, from a third-level dedicated inpatient and outpatient cardioangiology structure, aims to provide an updated summary on the topic of CLI of its complexity, encompassing epidemiological, social, economical and, in particular, diagnostic/imaging issues, together with potential therapeutic strategies (medical, endovascular, and surgical), including the evaluation of cardiovascular risk factors, the diagnosis, and treatment together with prognostic stratification. PMID- 29161886 TI - Perceived Barriers and Enablers of Help-Seeking for Substance Use Problems During Adolescence. AB - AIM: Receiving professional help early can reduce long-term harms associated with substance use. However, little is known about the factors that influence help seeking for substance use problems during early-mid adolescence, prior to the emergence of disorder. Given that beliefs regarding help-seeking are likely to develop early, understanding adolescent views of help-seeking during this period is likely to provide important information for prevention and intervention efforts. The current study identifies perceptions that would facilitate or prevent adolescents from seeking support for substance use problems from formal and informal help sources. METHOD: Thirty-four 12- to 16-year-olds from two schools in Melbourne, Victoria, Australia, were recruited. A qualitative interpretative design was used, incorporating semistructured, audio-recorded interviews. RESULTS: Three overlapping themes that reflected barriers or enablers to help-seeking were identified: approachability, confidentiality and trustworthiness, and expertise. Help-seeking was facilitated when adolescents believed that the help source would be supportive and understanding, would keep information confidential, and had expertise in the alcohol and drug field. Conversely, adolescents were reluctant to seek help from sources they believed would be judgmental, lacked expertise, or would inform their parents. CONCLUSIONS: These findings highlight perceptions that may influence help-seeking for alcohol and drug problems during adolescence. Further research is needed to determine if help-seeking can be facilitated by improving parents' and peers' knowledge and promoting health professionals' expertise in working with young people's alcohol and drug issues. PMID- 29161887 TI - New chemical constituents from the fruits of Zanthoxylum armatum and its in vitro anti-inflammatory profile. AB - Chemical investigations on the fruits of Zanthoxylum armatum Roxb. (Rutaceae) led to the isolation of two new constituents characterised as 2alpha-methyl-2beta ethylene-3beta-isopropyl-cyclohexan-1beta, 3alpha-diol (1) and phenol-O-beta-D arabinopyranosyl-4'-(3", 7", 11", 15"-tetramethyl)-hexadecan-1"-oate (2) along with known compounds m-methoxy palmityloxy benzene (3), acetyl phenyl acetate (4), linoleiyl-O-alpha-D-xylopyranoside (5), m-hydroxyphenoxy benzene (6) and palmitic acid (7). The chemical structures were established with the help of physical, chemical and spectroscopic methods. The anti-inflammatory potential of isolated compounds 1 and 2 was evaluated using in vitro target-based anti inflammatory activity in LPS-stimulated primary peritoneal macrophages isolated from mice. Production of pro-inflammatory cytokines (TNF-alpha and IL-6) was significantly inhibited by the treatment of isolated compounds 1 and 2 in a dose dependent manner. PMID- 29161888 TI - Multiple-physiological benefits of bird's nest fern (Asplenium australasicum) frond extract for dermatological applications. AB - p-coumaric acid and fucose-rich polysaccharide have been studied for many bio functions in skin including cutaneous protection from oxidative damage and antiageing, respectively, as well as wound healing. The physiological activities of various bird's nest fern extracts (BNFE), containing considerable fucose-rich mucilage and p-coumaric acid, on fibroblast and human skin were first investigated. BNFE with higher polysaccharide content generally contributed to a better moisture holding capability. Furthermore, BNFE showed pronouncedly enhancing effect on collagen production and growth of fibroblast (NIH-3T3), clinical trial results revealed that the emulsions with 1% BNFE showed good moisturising effect and improved the elasticity of human skins effectively. The potential of BNFE for cosmetics and medical applications such as natural moisturiser, antiageing and wound repairing was possibly related to the fucose rich mucilage and various phenolic compounds including p-coumaric acid in BNFE. PMID- 29161889 TI - Intersections of Physician Autonomy, Religion, and Health Care When Working With LGBT+ Patients. AB - The purpose of this study is to explore the ways that some health care providers perceive the intersectionality of their autonomy, religious faith, and their medical practice, specifically when it comes to providing care for the LGBT+ (lesbian, gay, bisexual, transgender, queer, intersex, and asexual) community. Physicians (n = 25) and medical residents (n = 17) located in the southeast completed a qualitative survey regarding their views of working with LGBT+ patients. Five main themes resulted from the analysis: adequate education, communication, discrimination, duty versus physician autonomy, and religious exemption. In this analysis, we focus specifically on duty versus physician autonomy and religious exemption since the other themes have been addressed in literature. The physicians and medical residents in this sample were divided among groups on the right to refuse treatment. Although there was not a question specific to religion, participants discussed religion in their responses to whether they believe in the right to refuse treatment. This division supports the need to decrease the current gap in knowledge regarding how religious views can affect physician treatment of LGBT+ patients and research effective ways to bridge the gap between physician autonomy and the duty to provide treatment. PMID- 29161890 TI - Impact of physical activity on the risk of cardiovascular disease in middle-aged and older adults: EPIC Norfolk prospective population study. AB - Background There is broad consensus that regular physical activity yields major health benefits. However, current guidelines on physical activity are mainly aimed at middle-aged adults. It is unclear whether physical activity also translates into cardiovascular health benefits in older adults. Therefore, we aimed to compare the association between different levels of physical activity and the risk of cardiovascular disease (CVD) in elderly to middle-aged individuals. Methods We analysed data from the EPIC Norfolk prospective population study. Cox proportional hazards models were used to analyse the association between physical activity levels and time to CVD events in three age categories (<55, 55-65 and >65 years). Interaction between age categories and physical activity levels was assessed. Results Analyses were based on 24,502 study participants aged 39-79 years. A total of 5240 CVD events occurred during 412,954 person-years follow-up (median follow-up was 18.0 years). Among individuals aged over 65 years, hazard ratios for CVD were 0.86 (95% confidence interval (CI) 0.78-0.96), 0.87 (95% CI 0.77-0.99) and 0.88 (95% CI 0.77-1.02) in moderately inactive, moderately active and active people, respectively, compared to inactive people. Among people aged 55-65 and less than 55 years, the associations were directionally similar, but not statistically significant. The interaction term between physical activity levels and age categories was not significant ( P = 0.38). Conclusion The inverse association between physical activity and the risk of CVD was significant in elderly and comparable with middle-aged individuals. In addition, we observed that modest levels of physical activity confer benefits in terms of CVD risk, compared to being completely inactive. PMID- 29161891 TI - The Significance of Impulsive Error in Children With ADHD. AB - A deficit of inhibition ability is a neuropsychological problem in children with attention deficit hyperactivity disorder (ADHD). We investigated whether in children who made impulsive error (IE), less error-related negativity (ERN) would correlate with poorer executive attention functions (EAFs). Ninety children (49 with ADHD and 41 without ADHD) were investigated by a 4-minute simple reaction time task and simultaneous electroencephalogram. When they made IE, the ERN in response-locked event-related potential (ERP) was defined as error awareness. The average area under curve of ERN in the control group with IEs was used as the proper criterion for regrouping the children with ADHD into 2 groups: ADHD children with enough ERN (ADHD-enough ERN) and those with less ERN (ADHD-less ERN). EAFs from Comprehensive Nonverbal Attention Test were used as objective indices, and behavioral questionnaires were used as subjective indices and statistically analyzed within ADHD groups. Forty-eight percent of the children made IEs. ADHD(n = 31, 63%) was significantly more than in the control group (n = 12, 29%; P < .001). The ADHD group had significantly less ERN than did the control group while making IE, especially at frontal and central electrodes ( P < .01). Both ADHD-less ERN and ADHD-enough ERN groups had poorer subjective EAFs on questionnaires. Only the ADHD-less ERN group had significant poorer objective EAFs on the Comprehensive Nonverbal Attention Test than did the ADHD without IE. We conclude that investigating the IE and ERN of IE in children with ADHD might help to differentiate subtypes of ADHD with different neuropsychological abilities, and the possibility that ADHD-less ERN children might be confirmed a meaningful subgroup that needs close follow-up, treatments different from standard, or both. PMID- 29161892 TI - The Speak UP! Salon Project: Using Hair Stylists as Lay Health Educators About Unintended Pregnancy. AB - The Speak UP! Salon Project trained 126 hair stylists from 60 salons as lay health educators to increase knowledge about contraceptives and inform clients about financial support for long-acting reversible contraceptives at local family planning clinics. Stylists' informal social support system, combined with the rapport built with clients over time, make them excellent candidates for lay health educator projects. This 3-year salon-based intervention was implemented in nine counties in a Midwestern state. Results from a subsample of participants who completed an online questionnaire (n = 177) indicate that hair stylists are a feasible method to link target populations to health information and to the health care system. The benefits and challenges of collecting data in a salon environment are also discussed. PMID- 29161893 TI - Using Text Message Surveys to Evaluate a Mobile Sexual Health Question-and-Answer Service. AB - Text message programs for sexual health are becoming increasingly popular as practitioners aim to meet youth on media they use frequently. Two-way mobile health (mHealth) interventions allow for feedback solicitation from participants. This study explores the use of a text message survey to assess demographics and program feedback from users of an adolescent sexual health text message question and-answer service. Development and feasibility of the short-message service survey are discussed. The text message survey achieved a 43.9% response rate, which is comparable to response rates of surveys conducted via other methods. When compared to respondents who used the service and completed an online in school questionnaire, text survey respondents were more likely to be female and older. They also reported higher service satisfaction. Results have implications for text message service providers and researchers. This article examines a community application of a new intervention strategy and research methodology. PMID- 29161894 TI - New advanced bench model for flexible ureteroscopic training: the Smart Simulator. AB - Smart Simulator is a new advanced bench training model for achieving proficiency in flexible ureteroscopy (fURS). Its important features are portability and the ability to simulate breathing-induced kidney movements, model pyelocalices similar to those in humans, create a situation closely resembling a fURS field, and create papillae of a size equivalent to that of the access sheath. Smart Simulator thus creates a situation more closely resembling that in a clinical setting than the other bench training models for fURS. Sixteen urologists experienced in fURS assessed Smart Simulator for face validity and content validity. The model was acceptable in terms of realism, acceptability and feasibility. Trainees can use it to practice laser manipulation for kidney stone fragmentation and retrieval in accord with breathing-induced movements and various other created fields sometimes confronted during fURS. Training in situations in nearly real fURS surgical fields may improve trainees' technical skills. PMID- 29161895 TI - Editorial Comment on: Randomized Controlled Trial Comparing Three Different Modalities of Lithotrites for Intracorporeal Lithotripsy in Percutaneous Nephrolithotomy by York et al. (From: York NE, Borofsky MS, Chew BH, et al. J Endourol 2017;31:1145-1151). PMID- 29161896 TI - Qualitative Analysis of Infant Safe Sleep Public Campaign Messaging. AB - The 1994 Back to Sleep public education campaign resulted in dramatic reductions in sleep-related infant deaths, but comparable progress in recent years has been elusive. We conducted qualitative analyses of recent safe sleep campaigns from 13 U.S. cities. Goals were to (a) determine whether the campaigns reflect the full range of American Academy of Pediatrics (AAP) 2011 safe sleep recommendations, (b) describe tone and framing of the messages (e.g., use of fear appeals), (c) describe targeting/tailoring of messages to priority populations, and (d) ascertain whether the campaigns have been evaluated for reach and/or effectiveness. Methods included computer-assisted analyses of campaign materials and key informant interviews. All campaigns included "ABC" (Alone, Back, Crib) messaging; many ignored other AAP recommendations such as breastfeeding, room sharing, immunizations, and avoiding smoke exposure. Campaigns frequently targeted priority populations such as African Americans. Fear appeals were used in three quarters of the campaigns, and 60% of the fear-based campaigns used guilt/blame messaging. We did not find published evaluation data for any of the campaigns. More attention is needed in public education campaigns to the full range of AAP recommendations, and evaluations are needed to determine the impact of these interventions on knowledge, behavior, and health outcomes. PMID- 29161897 TI - Status Epilepticus and Multiple Sclerosis: A Case Presentation and Literature Review. AB - PURPOSE: To search the literature for the frequency, pathogenesis, prognosis, and treatment of seizures and status epilepticus (SE) in patients with multiple sclerosis (MS). METHODS: We report 2 patients with MS who presented with SE and review the literature. RESULTS: Seizures and SE episodes worsened during MS relapses in the first patient. SE episodes and MS relapses significantly decreased after initiation of natalizumab treatment but she still had seizures and was taking 4 antiepileptic drugs (AEDs). The second patient had super refractory SE and was treated with AEDs and coma induction; SE was controlled in 1 week. Antibodies against glycine receptors were reported in her serum after her death. CONCLUSION: SE has been reported to remain refractory to conventional AEDs, and improve with treatment of MS relapse. Seizures often occur during MS relapses, and might be the presenting symptom of MS or the only symptom of a relapse. Patients with MS and epilepsy have been reported to have more severe MS disease courses. Seizures are refractory to treatment in patients with MS with chronic epilepsy; however, prognosis is quite good in patients experiencing provoked seizures during an MS relapse. Since some EEG findings may have prognostic value, their evaluation is invaluable for the determination of outcome. No treatment guidelines have been specified for patients with MS and SE. However, treatment with AEDs, ideally new-generation AEDs, and an MS treatment review with a new protocol will ensure a fast response to the improvement of SE. PMID- 29161898 TI - Delta Brush Pattern Is Not Unique to NMDAR Encephalitis: Evaluation of Two Independent Long-Term EEG Cohorts. AB - PURPOSE: Although its specificity has not previously been investigated in other cohorts, delta brush pattern (DBP) is increasingly reported in the EEGs of patients with anti- N-methyl-d-aspartate receptor (NMDAR) encephalitis. METHODS: We aimed to investigate the DBP in the EEGs of 2 cohorts; patients with change in consciousness for various causes monitored in the intensive care unit (ICU) (n = 106) and patients with mesial temporal lobe epilepsy (MTLE) with or without antineuronal antibodies (n = 76). RESULTS: These patients were investigated for the presence of DBP, defined as an EEG pattern characterized by delta activity at 1 to 3 Hz with superimposed bursts of rhythmic 12- to 30-Hz activity. Two investigators blindfolded for the clinical and immunological data independently analyzed the EEGs for recognition of this pattern. An EEG picture compatible with DBP was observed in 4 patients; only 1 of them (1.3%) belonged to the MTLE group. She did not bear any of the investigated autoantibodies and was seizure-free after epilepsy surgery. In the ICU group, there were 3 additional patients showing DBP with various diagnoses such as hypoxic encephalopathy, brain tumor, stroke, and metabolic derangements. All of them had died in 1-month period. CONCLUSIONS: Our results underlined that DBP is not unique to NMDAR encephalitis; it may very rarely occur in MTLE with good prognosis after surgery and second, in ICU patients who have high mortality rate. Therefore, the presence of this pattern should alert the clinician for NMDAR encephalitis but other possible etiologies should not be ignored. PMID- 29161899 TI - How Long Should Routine EEG Be Recorded to Get Relevant Information? AB - OBJECTIVE: The optimal duration of routine EEG (rEEG) has not been determined on a clinical basis. This study aims to determine the time required to obtain relevant information during rEEG with respect to the clinical request. METHOD: All rEEGs performed over 3 months in unselected patients older than 14 years in an academic hospital were analyzed retrospectively. The latency required to obtain relevant information was determined for each rEEG by 2 independent readers blinded to the clinical data. EEG final diagnoses and latencies were analyzed with respect to the main clinical requests: subacute cognitive impairment, spells, transient focal neurologic manifestation or patients referred by epileptologists. RESULTS: From 430 rEEGs performed in the targeted period, 364 were analyzed: 92% of the pathological rEEGs were provided within the first 10 minutes of recording. Slowing background activity was diagnosed from the beginning, whereas interictal epileptiform discharges were recorded over time. Moreover, the time elapsed to demonstrate a pattern differed significantly in the clinical groups: in patients with subacute cognitive impairment, EEG abnormalities appeared within the first 10 minutes, whereas in the other groups, data could be provided over time. CONCLUSION: Patients with subacute cognitive impairment differed from those in the other groups significantly in the elapsed time required to obtain relevant information during rEEG, suggesting that 10 minute EEG recordings could be sufficient, arguing in favor of individualized rEEG. However, this conclusion does not apply to intensive care unit patients. PMID- 29161900 TI - Asthma Disparity Photovoice: The Discourses of Black Adolescent and Public Health Policymakers. AB - BACKGROUND: Policies in U.S. public schools that address asthma management for Black adolescents may not sufficiently transform sociocultural determinants of disparities. A critical analysis of public health policy maker and adolescent discourses on asthma management using an ecological framework could inform policy development. This study describes the discourses of asthma management disparities of school and other public health policymakers and Black adolescents with asthma during a statewide asthma planning activity. METHOD: I conducted a qualitative critical discourse analysis on transcripts and phototexts from a photovoice project with Black adolescents with asthma (n = 19), an asthma-planning meeting with school and public health policymakers (n = 12), and an observation of a photovoice dissemination event that included the same adolescents and policymakers. RESULTS: Policymakers did not discuss sociocultural discourses concerning asthma management disparities such as racism and discrimination, but the adolescents did. The only shared discourses between adolescents and policymakers were on the management of indoor environments, health care quality, inadequate housing, and outdoor air pollution. CONCLUSIONS: Including Black adolescents in policymaking activities concerning asthma management disparities furthers the identification of differing and shared discourses. School policies should include multilevel strategies that address structural inequities. Photovoice presents an opportunity for including the voice of marginalized youth in policy-planning processes. PMID- 29161901 TI - Long-term outcomes of the randomized controlled trial comparing 5-aminolaevulinic acid and Photofrin photodynamic therapy for Barrett's oesophagus related neoplasia. AB - OBJECTIVE: Photodynamic therapy (PDT) was used as therapy for early neoplasia associated with Barrett's oesophagus (BE). This is 5-year follow-up of patients enrolled into randomised controlled trial of 5-aminolaevulinic acid (ALA) vs. Photofrin PDT. METHODS: Biopsies were taken from original Barrett's segment during endoscopic follow up using Seattle protocol. Endoscopic mucosal resection (EMR) +/- radiofrequency ablation (RFA) was preferred therapy in patients who failed PDT and/or had recurrent neoplasia. RESULTS: Fifty eight of 64 patients enrolled in the original trial were followed up including 31 patients treated with ALA PDT (17 patients with <=6 cm, 14 patients with >6 cm segment of BE) and 27 treated with Photofrin PDT (14 patients with <=6 cm, 13 patients with >6 cm BE). Initial success was achieved in 65% (20/31) ALA and 48% (13/27) Photofrin patients (p = .289). Thirty five percent patients (7/20) relapsed in ALA group and 54% (7/13) relapsed in Photofrin group (p = .472). At a median follow-up of 67 months, no significant difference was found in long-term complete reversal of intestinal metaplasia (CR-IM) and complete reversal of dysplasia (CR-D) between ALA and Photofrin groups (78% vs. 63%; p = .18; 90% vs. 76%; p = .26). Original length of BE did not alter long-term outcome. Four patients from each group progressed to invasive oesophageal adenocarcinoma. Initial success of ALA PDT was associated with significantly better likelihood of long-term remission (p = .03). CONCLUSIONS: Initial response to PDT plays key role in long term outcome. RFA +/- EMR have, however, become preferred minimally invasive ablative therapy for BE related neoplasia due to poor efficacy of PDT. PMID- 29161902 TI - Organizational-Level Recruitment of Barbershops as Health Promotion Intervention Study Sites: Addressing Health Disparities Among Black Men. AB - This article describes the process and results associated with the organizational level recruitment of Black barbershops into Fitness in the Shop (FITShop), a 6 month barbershop-based intervention study designed to promote physical activity among Black men. Organizational-level recruitment activities included (1) a telephone call to prospective barbershop owners to assess their interest and eligibility for participation, (2) an organizational eligibility letter sent to all interested and eligible barbershops, (3) a visit to interested and eligible barbershops, where a culturally sensitive informational video was shown to barbershop owners to describe the study activities and share testimonies from trusted community stakeholders, and (4) a signed agreement with barbershop owners and barbers, which formalized the organizational partnership. Structured interviews were conducted with owners of a total of 14 enrolled barbershops, representing 30% of those determined to be eligible and interested. Most enrolled shops were located in urban settings and strip malls. Barbershop owners were motivated to enroll in the study based on commitment to their community, perceived client benefits, personal interest in physical activity, and a perception that the study had potential to make a positive impact on the barbershop and on reducing health disparities. Results offer important insights about recruiting barbershops into intervention trials. PMID- 29161903 TI - Spatial resolution measurements by Radia diagnostic software with SEDENTEXCT image quality phantom in cone beam CT for dental use. AB - OBJECTIVES: We aimed to employ the Radia diagnostic software with the safety and efficacy of a new emerging dental X-ray modality (SEDENTEXCT) image quality (IQ) phantom in CT, and to evaluate its validity. METHODS: The SEDENTEXCT IQ phantom and Radia diagnostic software were employed. The phantom was scanned using one medical full-body CT and two dentomaxillofacial cone beam CTs. The obtained images were imported to the Radia software, and the spatial resolution outputs were evaluated. The oversampling method was employed using our original wire phantom as a reference. The resultant modulation transfer function (MTF) curves were compared. The null hypothesis was that MTF curves generated using both methods would be in agreement. One-way analysis of variance tests were applied to the f50 and f10 values from the MTF curves. The f10 values were subjectively confirmed by observing the line pair modules. RESULTS: The Radia software reported the MTF curves on the xy-plane of the CT scans, but could not return f50 and f10 values on the z-axis. The null hypothesis concerning the reported MTF curves on the xy-plane was rejected. There were significant differences between the results of the Radia software and our reference method, except for f10 values in CS9300. These findings were consistent with our line pair observations. CONCLUSIONS: We evaluated the validity of the Radia software with the SEDENTEXCT IQ phantom. The data provided were semi-automatic, albeit with problems and statistically different from our reference. We hope the manufacturer will overcome these limitations. PMID- 29161904 TI - Consequences of testing for mismatch repair deficiency of colorectal cancer in clinical practice. AB - INTRODUCTION: Mismatch repair deficiency (dMMR) can be found in Lynch syndrome (LS)-associated colorectal carcinoma and in 15% of sporadic colorectal cancer (CRC). Outcome of MMR-deficiency testing is important for surgical decisions as extended colectomy is recommended in young LS-patients with CRC. Moreover, the finding of a dMMR tumour has consequences for the choices of adjuvant chemotherapy as MMR-deficient CRC is resistant to 5-fluorouracil (5-FU) monotherapy. Aims of our study are to evaluate whether MMR-deficiency testing leads to (1) identification of LS, (2) change in surgical treatment and (3) adjustment of systemic therapy in patients with dMMR CRC. METHODS: We performed a multicentre, retrospective study, in a community hospital and a University Medical Centre. We included all CRC-patients between 2012 and 2016 who were tested for microsatellite instability. We collected clinical data such as gender, age, referral to clinical geneticist, surgical procedure and choice of chemotherapy. RESULTS: We analysed 225 CRCs. Twenty-four (10.7%) of 225 CRC were MMR-deficient. Of the 24 patients with dMMR CRC, 18 (75%) were referred to the clinical geneticist and in nine (37%) patients a MMR mutation was identified. In one (4%) of the 24 patients, a subtotal colectomy was performed. In seven (35%) out of 20 MMR deficient patients, the chemotherapy regimen was adjusted. CONCLUSIONS: The finding of a dMMR CRC had consequences for decisions on chemotherapy in a relative high proportion of patients. We recommend testing in all patients with CRC independent of age at diagnosis, as proper treatment decisions and genetic counselling are very important. PMID- 29161905 TI - A Focused Review on the Effects of Preoperative 5alpha-Reductase Inhibitors Treatment in Patients Undergoing Holmium Laser Enucleation of the Prostate: What Do We Know So Far? AB - INTRODUCTION: The effects of medical therapy with finasteride or dutasteride during transurethral enucleation of prostate and tissue morcellation are not well defined. In theory, the risk of prostatic fibrosis versus the potential benefit of reduced intraoperative bleeding has been addressed as potential competing factors. The aim of this review was to provide evidence whether 5alpha-reductase inhibitors (5-ARIs) put the surgeon at a disadvantage or impact on patient outcomes. MATERIALS AND METHODS: We performed a literature search of PubMed, Scopus, and Web of Science databases. All articles in English language related to the topic were reviewed to provide data on the influence of preoperative 5-ARIs in holmium laser enucleation of prostate (HoLEP). RESULTS: Parameters of surgical efficiency such as enucleation time and efficiency, morcellation time, operating time, prostate tissue volume resected, energy, and saline usage were evaluated in the included studies. The review failed to show any definite impact of preoperative 5-ARI use on the mentioned parameters. One study, assessing the surgical difficulty using retrospective video recording analysis, showed that use of dutasteride increases the difficulty of enucleation step, which did not translate in statistical difference of surgical efficiency in an experienced level of surgeons. CONCLUSIONS: Overall, 5-ARIs do not seem to affect HoLEP. However, the quality of evidence is still quite poor in comparison with other surgical techniques. Further well-designed studies are required before making any definite recommendations on the use of 5-ARIs in patients undergoing HoLEP. PMID- 29161906 TI - Association Between Pathology and Electroencephalographic Activity in Parkinson's Disease. AB - INTRODUCTION: The key mechanisms that connect Parkinson's disease pathology with dementia are unclear. We tested the hypothesis that the quantitative spectral electroencephalographic measure, delta bandpower, correlates with Lewy type synucleinopathy on pathological examination in Parkinson's disease. As a corollary hypothesis, we analyzed whether there would be delta bandpower electroencephalographic differences between Parkinson's disease dementia cases with and without pathological criteria for Alzheimer's disease. METHODS: We used pathological examination results from 44 Parkinson's disease subjects from our brain bank with various degrees of cognitive decline, who had undergone electroencephalography. Pathological grading for Lewy type synucleinopathy, plaques, tangles, and indications of vascular pathology in subcortical and cortical areas were correlated with the most associated electroencephalographic biomarker with Parkinson's disease dementia in our laboratory, delta bandpower. Group differences for all spectral electroencephalographic measures were also analyzed between cases with and without pathological criteria for Alzheimer's disease. RESULTS: Findings revealed significant correlations between delta bandpower with Lewy type synucleinopathy, whereas indications of Alzheimer's disease or vascular pathology had nonsignificant correlation. The strongest association was with delta bandpower and Lewy type synucleinopathy in the anterior cingulate region. Mean delta bandpower was higher in the group for Parkinson's disease dementia with Alzheimer's disease pathology criteria than without. CONCLUSIONS: Lewy type synucleinopathy severity appears to be more associated with increased delta bandpower than with Alzheimer's disease pathology or indications of vascular pathology over all cases. However, the presence of Alzheimer's pathology may associate with more cortex physiological disruption in a subset of cases. PMID- 29161907 TI - Heightened Background Cortical Synchrony in Patients With Epilepsy: EEG Phase Synchrony Analysis During Awake and Sleep Stages Using Novel Ensemble Measure. AB - INTRODUCTION: Excessive cortical synchrony within neural ensembles has been implicated as an important mechanism driving epileptiform activity. The current study measures and compares background electroencephalographic (EEG) phase synchronization in patients having various types of epilepsies and healthy controls during awake and sleep stages. METHODS: A total of 120 patients with epilepsy (PWE) subdivided into 3 groups (juvenile myoclonic epilepsy [JME], temporal lobe epilepsy [TLE], and extra-temporal lobe epilepsy [Ex-TLE]; n = 40 in each group) and 40 healthy controls were subjected to overnight polysomnography. EEG phase synchronization (SI) between the 8 EEG channels was assessed for delta, theta, alpha, sigma, and high beta frequency bands using ensemble measure on 10-second representative time windows and compared between patients and controls and also between awake and sleep stages. Mean +/- SD of SI was compared using 2-way analysis of variance followed by pairwise comparison ( P <= .05). RESULTS: In both delta and theta bands, the SI was significantly higher in patients with JME, TLE, and Ex-TLE compared with controls, whereas in alpha, sigma, and high beta bands, SI was comparable between the groups. On comparison of SI between sleep stages, delta band: progressive increase in SI from wake => N1 => N2 => N3, whereas REM (rapid eye movement) was comparable to wake; theta band: decreased SI during N2 and increase during N3; alpha band: SI was highest in wake and lower in N1, N2, N3, and REM; and sigma and high beta bands: progressive increase in SI from wake => N1 => N2 => N3; however, sigma band showed lower SI during REM. CONCLUSION: This study found an increased background cortical synchronization in PWE compared with healthy controls in delta and theta bands during wake and sleep. This background hypersynchrony may be an important property of epileptogenic brain circuitry in PWE, which enables them to effortlessly generate a paroxysmal EEG depolarization shift. PMID- 29161908 TI - An Exploration of the Determinants of Gestational Weight Gain in African American Women: Genetic Factors and Energy Expenditure. AB - BACKGROUND: Excessive gestational weight gain (GWG) has a long-term impact on women's body weight and contributes to the development of obesity in the mother and her child. Many risk factors for GWG have been identified, but to date, only 6-33.8% of the variance in GWG has been explained. The purpose of this study was to evaluate the overall variance of GWG that can be explained by including weight adjusted resting metabolic rate (aRMR) and a genetic risk score constructed on obesity-related genes in addition to sociodemographic and lifestyle factors. METHODS: In this observational study involving 55 African American women, data collected/measured during pregnancy included sociodemographic factors, medical information, lifestyle factors, aRMR, and seven obesity-related genes. Multivariable linear regression was performed to evaluate the variance in GWG explained by the potential risk factors listed above. RESULTS: The mean GWG was 15 kg (+/-7.5 kg), and 63.6% of women gained more than the Institute of Medicine's GWG recommendations. The final regression model explained 53.3% of the variance in GWG. Higher genetic risk score, lower aRMR, and higher dietary intake of total energy and percentage of fat were significantly associated with increased GWG ( p < .05). These factors explained 18% additional variance in GWG over that explained by significant sociodemographic and lifestyle factors in the analysis (i.e., maternal age, prepregnancy body mass index, parity, illegal drug use, and education). CONCLUSION: Overall, our results indicate that the genetic risk score, aRMR, and dietary intake have a substantial impact on GWG in African American women. PMID- 29161909 TI - DIMITRA paediatric skull phantoms: development of age-specific paediatric models for dentomaxillofacial radiology research. AB - OBJECTIVES: This report aims to describe the development of age-specific phantoms for use in paediatric dentomaxillofacial radiology research. These phantoms are denoted DIMITRA paediatric skull phantoms as these have been primarily developed and validated for the DIMITRA European research project (Dentomaxillofacial paediatric imaging: an investigation towards low-dose radiation induced risks). METHODS: To create the DIMITRA paediatric phantoms, six human paediatric skulls with estimated ages ranging between 4 and 10 years- old were selected, protected with non-radiopaque tape and immersed in melted Mix-D soft tissue equivalent material, by means of a careful procedure (layer-by-layer). Mandibles were immersed separately and a Mix-D tongue model was also created. For validation purposes, the resulting paediatric phantoms were scanned using a cone-beam CT unit with different exposure parameter settings. RESULTS: Preliminary images deriving from all scans were evaluated by two dentomaxillofacial radiologists, to check for air bubbles, artefacts and inhomogeneities of the Mix-D and a potential effect on the visualization of the jaw bone. Only skulls presenting perfect alignment of Mix-D surrounding the bone surfaces with adequate and realistic soft tissue thickness density were accepted. CONCLUSIONS: The DIMITRA anthropomorphic phantoms can yield clinically equivalent images for optimization studies in dentomaxillofacial research. In addition, the layer-by-layer technique proved to be practical and reproducible, as long as recommendations are carefully followed. PMID- 29161910 TI - Characterization of a Large Novel alpha-Globin Gene Cluster Deletion Causing alpha0-Thalassemia in a Chinese Family. AB - We report a large novel alpha-globin cluster deletion that we named - -PG (NG_000006.1: g.93628_542759del450131), in a Chinese family. This large deletion is approximately 450 kb long, spanning from upstream of the PolR3k gene at the 5' end to the RAB11FIP3 gene at the 3' end of chromosome 16p13.3. This deletion removes all the globin distal regulatory elements as well as the whole alpha globin gene cluster. Patients with heterozygous - -PG/alphaalpha had red blood cell (RBC) indices consistent with alpha-thalassemia (alpha-thal) trait, but no apparent increase in a cancer tendency or mental disability, microcephaly, relative hypertelorism, unusual facies or genital anomalies. PMID- 29161911 TI - The Efficacy of Naikan Therapy on Male Offenders: Changes in Perceived Social Support and Externalized Blame. AB - Naikan is a contemplative self-observation practice that originated from Japanese Shin Buddhism and is utilized for rehabilitating prison inmates in many countries. Although some investigations have provided initial evidence for its efficiency in decreasing recidivism, there is still a need for further investigation of the effectiveness of Naikan on other outcomes through more controlled studies. The present study aimed to investigate the efficacy of Naikan therapy on male offenders' perceived social support and externalized blame. Ninety-two male offenders were randomly assigned to either the experimental group or to the waiting group. All participants were evaluated by the Multidimensional Scale of Perceived Social Support and the Externalization subscale of the Test of Self-Conscious Affect before and after Naikan therapy. The results suggested that participants who received Naikan therapy showed higher levels of perceived social support and lower levels of externalized blame after Naikan therapy than before. PMID- 29161912 TI - Developing an Integrative Treatment Program for Cancer-Related Fatigue Using Stakeholder Engagement - A Qualitative Study. AB - BACKGROUND: Although cancer-related fatigue (CRF) has gained increased attention in the past decade, it remains difficult to treat. An integrative approach combining conventional and complementary medicine interventions seems highly promising. Treatment programs are more likely to be effective if the needs and interests of the people involved are well represented. This can be achieved through stakeholder engagement. OBJECTIVES: The aim of the study was to develop an integrative CRF treatment program using stakeholder engagement and to compare it to an expert version. METHOD: In a qualitative study, a total of 22 stakeholders (4 oncologists, 1 radiation-oncologist, 1 psycho-oncologist, 5 nurses/nurse experts, 9 patients, 1 patient family member, 1 representative of a local Swiss Cancer League) were interviewed either face-to-face or in a focus group setting. For data analysis, qualitative content analysis was used. RESULTS: With stakeholder engagement, the integrative CRF treatment program was adapted to usual care using a prioritizing approach and allowing more patient choice. Unlike the expert version, in which all intervention options were on the same level, the stakeholder engagement process resulted in a program with 3 different levels. The first level includes mandatory nonpharmacological interventions, the second includes nonpharmacological choice-based interventions, and the third includes pharmacological interventions for severe CRF. The resulting stakeholder based integrative CRF treatment program was implemented as clinical practice guideline at our clinic (Institute for Complementary and Integrative Medicine, University Hospital Zurich). CONCLUSION: Through the stakeholder engagement approach, we integrated the needs and preferences of people who are directly affected by CRF. This resulted in an integrative CRF treatment program with graded recommendations for interventions and therefore potentially greater sustainability in a usual care setting. PMID- 29161913 TI - Development and optimization of locust bean gum and sodium alginate interpenetrating polymeric network of capecitabine. AB - OBJECTIVE: The objective of the study was to develop interpenetrating polymeric network (IPN) of capecitabine (CAP) using natural polymers locust bean gum (LBG) and sodium alginate (NaAlg). SIGNIFICANCE: The IPN microbeads were optimized by Box-Behnken Design (BBD) to provide anticipated particle size with good drug entrapment efficiency. The comparative dissolution profile of IPN microbeads of CAP with the marketed preparation proved an excellent sustained drug delivery vehicle. METHODS: Ionotropic gelation method utilizing metal ion calcium (Ca2+) as a cross-linker was used to prepare IPN microbeads. The optimization study was done by response surface methodology based Box-Behnken Design. The effect of the factors on the responses of optimized batch was exhibited through response surface and contour plots. The optimized batch was analyzed for particle size, % drug entrapment, pharmacokinetic study, in vitro drug release study and further characterized by FTIR, XRD, and SEM. To study the water uptake capacity and hydrodynamic activity of the polymers, swelling studies and viscosity measurement were performed, respectively. RESULTS: The particle size and % drug entrapment of the optimized batch was 494.37 +/- 1.4 um and 81.39 +/- 2.9%, respectively, closer to the value predicted by Minitab 17 software. The in vitro drug release study showed sustained release of 92% for 12 h and followed anomalous drug release pattern. The derived pharmacokinetic parameters of optimized batch showed improved results than pure CAP. CONCLUSION: Thus, the formed IPN microbeads of CAP proved to be an effective extended drug delivery vehicle for the water soluble antineoplastic drug. PMID- 29161914 TI - A good practice guide for translating and adapting hearing-related questionnaires for different languages and cultures. AB - OBJECTIVES: To raise awareness and propose a good practice guide for translating and adapting any hearing-related questionnaire to be used for comparisons across populations divided by language or culture, and to encourage investigators to publish detailed steps. DESIGN: From a synthesis of existing guidelines, we propose important considerations for getting started, followed by six early steps: (1) Preparation, (2, 3) Translation steps, (4) Committee Review, (5) Field testing and (6) Reviewing and finalising the translation. STUDY SAMPLE: Not applicable. RESULTS: Across these six steps, 22 different items are specified for creating a questionnaire that promotes equivalence to the original by accounting for any cultural differences. Published examples illustrate how these steps have been implemented and reported, with shared experiences from the authors, members of the International Collegium of Rehabilitative Audiology and TINnitus research NETwork. CONCLUSIONS: A checklist of the preferred reporting items is included to help researchers and clinicians make informed choices about conducting or omitting any items. We also recommend using the checklist to document these decisions in any resulting report or publication. Following this step-by-step guide would promote quality assurance in multinational trials and outcome evaluations but, to confirm functional equivalence, large-scale evaluation of psychometric properties should follow. PMID- 29161915 TI - Capillaroscopy in pregnancy. AB - INTRODUCTION: In pregnancy, the circulatory system undergoes profound adaptation to meet the requirements in blood supply for the mother and the foetus. With the development of new techniques, research of the microcirculatory changes becomes available. This expert review gives an overview of the current evidence in the field of capillaroscopy. The aim of this review is to summarize the available techniques in the assessment of the microcirculation during pregnancy. Areas covered: A literature search was done, using the strategy: (microcirculation OR capillary OR capillaries OR capillaroscopy) AND pregnancy AND (density OR diameter OR count OR number). All articles were screened and all English articles were considered, when containing information regarding imaging of capillaries. Only structural parameters were considered, functional parameters (e.g. flow velocity) were not considered. Reference search was undertaken after reading full text articles. Articles from reference search underwent same selection criteria as in the primary search. Expert commentary: With growing insight in microcirculatory changes in hypertensive pregnancy conditions, the field of capillaroscopy will become more important in future. The technique is feasible and easy to use in clinical practice as well as in research setting. The first step, necessary to perform further research in this field in future, is to get consensus in technique to perform capillaroscopy and in methods to quantitatively and qualitatively describe the observed changes in microvasculature. PMID- 29161916 TI - Smartphone accelerometers for the detection of heart rate. AB - INTRODUCTION: Micro-electro-mechanical systems technology, now embedded into smartphones, potentially allows measuring heart mechanical activity by positioning the phone on the body and acquiring vibrational signals, without the need for additional peripherals or interfaces. However, lack of standardization in experimental protocol, processing methodology and validation procedures, together with the wide range of available smartphones on the market, impact on the comparability of results and their general validity. The aim of this review is to provide information on the state-of-the art of research in this field, with current limitations and potentials, thus potentially serving as a basis for the creation of a standard based on current experiences. Areas covered: The review focused on studies relevant to the extraction of the heart rate using accelerometric technology, searching for relevant literature (papers or conference proceedings) both in Pubmed and IEEE eXplore engines. Expert commentary: From the results of this review, the smartphone can be considered a powerful device able to accurately measure the resting heart rate, thanks to embedded accelerometer technology. However, lack of a shared standard in the acquisition protocol and analysis procedure, thus affecting user-collected data reliability, could limit clinical acceptability and prevent recommending this approach as a self-tracking tool in patients. PMID- 29161917 TI - Baker's Yeast Sensitizes Metastatic Breast Cancer Cells to Paclitaxel In Vitro. AB - Our earlier studies have demonstrated that phagocytosis of baker's yeast ( Saccharomyces cerevisiae) induces apoptosis in different cancer cell lines in vitro and in vivo. This study aimed to examine how baker's yeast sensitizes murine and human breast cancer cells (BCC) to paclitaxel in vitro. This sensitizing effect makes lower concentrations of chemotherapy more effective at killing cancer cells, thereby enhancing the capacity of treatment. Three BCC lines were used: the metastatic murine 4T1 line, the murine Ehrlich ascites carcinoma (EAC) line, and the human breast cancer MCF-7 line. Cells were cultured with different concentrations of paclitaxel in the presence or absence of baker's yeast. Cell survival and the IC50 values were determined by MTT assay and trypan blue exclusion method. Percent of DNA damage, apoptosis, and cell proliferation were examined by flow cytometry. Yeast alone and paclitaxel alone significantly decreased 4T1 cell viability postculture (24 and 48 hours), caused DNA damage, increased apoptosis, and suppressed cell proliferation. Baker's yeast in the presence of paclitaxel increased the sensitivity of 4T1 cells to chemotherapy and caused effects that were greater than either treatment alone. The chemosensitizing effect of yeast was also observed with murine EAC cells and human MCF-7 cells, but to a lesser extent. These data suggest that dietary baker's yeast is an effective chemosensitizer and can enhance the apoptotic capacity of paclitaxel against breast cancer cells in vitro. Baker's yeast may represent a novel adjuvant for chemotherapy treatment. PMID- 29161918 TI - In-process rheometry as a PAT tool for hot melt extrusion. AB - Real time measurement of melt rheology has been investigated as a Process Analytical Technology (PAT) to monitor hot melt extrusion of an Active Pharmaceutical Ingredient (API) in a polymer matrix. A developmental API was melt mixed with a commercial copolymer using a heated twin screw extruder at different API loadings and set temperatures. The extruder was equipped with an instrumented rheological slit die which incorporated three pressure transducers flush mounted to the die surface. Pressure drop measurements within the die at a range of extrusion throughputs were used to calculate rheological parameters, such as shear viscosity and exit pressure, related to shear and elastic melt flow properties, respectively. Results showed that the melt exhibited shear thinning behavior whereby viscosity decreased with increasing flow rate. Increase in drug loading and set extrusion temperature resulted in a reduction in melt viscosity. Shear viscosity and exit pressure measurements were found to be sensitive to API loading. These findings suggest that this technique could be used as a simple tool to measure material attributes in-line, to build better overall process understanding for hot melt extrusion. PMID- 29161919 TI - The effects of ADHD on cognitive performance. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a common and impairing neurodevelopmental disorder. The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computerized test battery with standardized procedures and solid psychometric properties targeting multiple neuropsychological functions. AIMS: The aim of this study was to look at the effects of ADHD on cognitive performance using CANTAB expressed as a statistical interaction term in regression modeling. METHODS: We assessed 112 drug-naive subjects (age: 7-18 years) with ADHD based on DSM IV criteria and compared them to 95 control subjects (age: 7-18 years). All participants were administered five CANTAB tasks designed to capture different aspects of executive functioning: Stockings of Cambridge (SOC), Intra/Extra dimensional shift (IED), Spatial Working Memory (SWM), Simple Reaction Time (SRT) and Stop Signal Task (SST). RESULTS: T-tests showed a difference between ADHD and control subjects in all cognitive measures except SOC. The majority of measures showed a non-linear effect of age. SWM strategy and SST direction errors showed a linear effect of age. ADHD diagnosis had a statistically significant effect on performance. For all tests except SOC, ADHD produced the main effect without interaction with age. DISCUSSION: For all CANTAB measures, ADHD diagnosis had a significant effect on performance and produced this effect without interaction with age in all tests except SOC, indicating that the developmental trajectories were parallel in both groups. The results indicate that cognitive performance is impaired in youth with ADHD and that CANTAB can be a valuable tool in the diagnostic assessment of ADHD. PMID- 29161920 TI - Development, optimization, and in vitro characterization of dasatinib-loaded PEG functionalized chitosan capped gold nanoparticles using Box-Behnken experimental design. AB - OBJECTIVE: The purpose of this research study was to develop, optimize, and characterize dasatinib loaded polyethylene glycol (PEG) stabilized chitosan capped gold nanoparticles (DSB-PEG-Ch-GNPs). METHODS: Gold (III) chloride hydrate was reduced with chitosan and the resulting nanoparticles were coated with thiol terminated PEG and loaded with dasatinib (DSB). Plackett-Burman design (PBD) followed by Box-Behnken experimental design (BBD) were employed to optimize the process parameters. Polynomial equations, contour, and 3D response surface plots were generated to relate the factors and responses. The optimized DSB-PEG-Ch-GNPs were characterized by FTIR, XRD, HR-SEM, EDX, TEM, SAED, AFM, DLS, and ZP. RESULTS: The results of the optimized DSB-PEG-Ch-GNPs showed particle size (PS) of 24.39 +/- 1.82 nm, apparent drug content (ADC) of 72.06 +/- 0.86%, and zeta potential (ZP) of -13.91 +/- 1.21 mV. The responses observed and the predicted values of the optimized process were found to be close. The shape and surface morphology studies showed that the resulting DSB-PEG-Ch-GNPs were spherical and smooth. The stability and in vitro drug release studies confirmed that the optimized formulation was stable at different conditions of storage and exhibited a sustained drug release of the drug of up to 76% in 48 h and followed Korsmeyer Peppas release kinetic model. CONCLUSIONS: A process for preparing gold nanoparticles using chitosan, anchoring PEG to the particle surface, and entrapping dasatinib in the chitosan-PEG surface corona was optimized. PMID- 29161921 TI - Foam pad of appropriate thickness can improve diagnostic value of foam posturography in detecting postural instability. AB - OBJECTIVE: The present study investigated the effect of foam thickness on postural stability in patients with unilateral vestibular hypofunction (UVH) during foam posturography. METHODS: Static and foam posturography were performed in 33 patients (UVH group) and 30 healthy subjects (control group) with eyes open (EO) and closed (EC) on firm surface and on 1-5 foam pad(s). Sway velocity (SV) of center of pressure, standing time before falling (STBF) and falls reaction were recorded and analyzed. RESULTS: (1) SVs had an increasing tendency in both groups as the foam pads were added under EO and EC conditions. (2) STBFs, only in UVH group with EC, decreased with foam thickness increasing. (3) Significant differences in SV were found between the control and UVH group with EO (except for standing on firm surface, on 1 and 2 foam pad(s)) and with EC (all surface conditions). (4) Receiver operating characteristic curve analysis showed that the SV could better reflect the difference in postural stability between the two groups while standing on the 4 foam pads with EC. CONCLUSION: Our study showed that diagnostic value of foam posturography in detecting postural instability might be enhanced by using foam pad of right thickness. PMID- 29161922 TI - Existing issues and valid concerns in continuous-flow ventricular assist devices. AB - INTRODUCTION: Through concerted endeavours in the fields of surgery, medicine, and biomedical engineering, patronized by government and industry, ventricular assist devices have become an established surgical treatment to support the failing heart, which could easily and simply surpass the frequency of heart transplantation. Be it as it may, complications and adverse events have unfolded, and these facilitated the way to newer biomedically-engineered pump designs in search of the perfect support for a failing heart. Areas covered: This review focuses on the evolution of the continous-flow ventricular assist device as an accepted mode of treatment in advanced heart failure, as a bridge to myocardial recovery, as a bridge to heart transplantation and as a permanent therapy, with its attendant complications and long-term outcome. Expert commentary: Continuous flow devices offer improved durability, less surgical trauma due to their smaller size, high-energy efficiency, and lower thrombogenicity, regardless of administration of single or dual anti-thrombotic therapy. These benefits translate into better survival, lower frequency of adverse events, improved quality of life and higher functional capacity of patients. Through ceaseless innovations and technology, newer pumps have been developed; however, none has been proven to be superior over the others. PMID- 29161923 TI - Recognizing and reacting to complications of trans-septal puncture. AB - INTRODUCTION: The transseptal puncture (TSP) enables access to the left heart, through the fossa ovalis (FO), both in electrophysiology and in cardiac interventional procedures. TSP is usually safe in experienced hands. Sometimes TSP can be technically demanding and carries the risk of severe complications in approximately 1%. While performing a TSP, every effort should be taken in order to avoid complications. In the event of complications, prompt recognition and reaction are essential and a combined 'heart-team' management may be the most effective approach. Areas covered: Main TSP-related complications are cardiac tamponade, aortic root puncture, embolic stroke, transient ST elevation of inferior leads and iatrogenic atrial septal defect. A challenging TSP may be expected in presence of difficult IAS-FO anatomies, previous TSP, IAS occluder device and previous IAS surgical repair. Use of echo imaging and special needles (ie., radiofrequency needle and J-shaped guidewire) may avoid TSP-related complications in difficult settings. Expert commentary: Some tools are available to help minimize the risks of TSP. However, their availability might be limited. To increase safety of TSP, an adequate training of physicians, identification of patients in whom it might be difficult and a prompt recognition of complications seem to be the most important background. PMID- 29161924 TI - Ultrasound-guided percutaneous microwave ablation vs. surgical resection for thoracoabdominal wall implants from hepatocellular carcinoma: intermediate-term results. AB - OBJECTIVE: The aims of this study were to compare the clinical outcomes between ultrasound (US)-guided percutaneous microwave ablation (MWA) and surgical resection (SR) in patients with thoracoabdominal wall implants from hepatocellular carcinom (HCC) and to identify the prognostic factors associated with the two treatment methods. MATERIALS AND METHODS: A total of 47 patients (mean age, 56.7 +/- 15.9 years, range, 18-78 years; 34 men and 13 women) with 61 thoracoabdominal wall HCC seeding were included from April 2007 to May 2017. Twenty-five patients underwent US-guided MWA and 22 patients underwent SR. Survival, recurrence and liver function were compared between the two groups. Effect of changes in key parameters (i.e. overall survival (OS), disease-free survival (DFS) and local tumour reoccurrence-free (LTRF)) was statistically analysed with the log-rank test. Univariate and multivariate analyses were performed on several clinicopathological variables to identify factors affecting long-term outcome and recurrence. RESULTS: The OS, DFS and LTRF after MWA were comparable to those of SR (p =0.493, p = 0.578 and p =0.270, respectively). Estimated 5-year overall survival rates were 63% after MWA and 48.1% after SR; for disease-free survival, estimated 5-year rates were 67.5% after MWA and 48.8% after SR; estimated 24-month LTRF rates were 71.3% after MWA and 87.8% after SR. The MWA group had less surgical time (p = <0.001), estimated blood loss (p = <0.001) and post-operative hospitalisation (p = 0.032) and cost (p = 0.015). Multivariate analysis showed remnant intrahepatic tumour (p =0.007), Child Pugh grade (p = 0.009) and metastasis (p= <0.001), were predictors for survival rate. CONCLUSIONS: Ultrasound-guided percutaneous MWA is a safe and effective treatment method for metastatic HCC on the thoracoabdominal wall with similar outcomes to SR. Residual intrahepatic HCC, Child Pugh grade and distant metastasis are predictors for survival. PMID- 29161925 TI - Male Perpetrators of Intimate Partner Violence: A Comparison Between Incarcerated and Community Offenders. AB - The literature considers intimate partner violence (IPV) perpetrators to be a heterogeneous group. In Portugal, IPV perpetrators may be sentenced to either of two types of sentences: deprivation of freedom or alternatives to prison (in the community). In the present study, we performed a comparative analysis between 76 male individuals sentenced to prison and 76 male individuals sentenced to community measures for crimes against their current or former partners, using a set of psychological measures. The results indicate that although incarcerated and nonincarcerated IPV perpetrators demonstrate considerable differences, some similarities may also be observed. Incarcerated IPV perpetrators present the lowest socioeconomic status and education, perpetrate more severe IPV, and have more criminal convictions. A hierarchical regression analysis revealed that the use of weapons and objects increased the probability of IPV perpetrators belonging to the prison group above and beyond sociodemographic variables. Based on these results, implications for IPV perpetrators' treatment are discussed. PMID- 29161926 TI - Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, neutrophil-platelet score and prognostic nutritional index: do they have prognostic significance in metastatic pancreas cancer? AB - INTRODUCTION: We aimed to evaluate the prognostic significance of neutrophil lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), neutrophil-platelet score (NPS) and prognostic nutritional index (PNI) as proinflammatory markers in metastatic pancreas cancer (MPC). MATERIAL AND METHODS: A total of 146 MPC patients followed up at our center were evaluated retrospectively for clinicopathological characteristics and hematological ratios (NLR, PLR, NPS and PNI). PNI was calculated as (10 * serum albumin [g/dL]) + (0.005 * peripheral lymphocyte count [per mm3]). Log rank and Cox regression analysis were used. RESULTS: Median age was 53 years (range: 22-78) with male predominance (73.3%). Liver (94.7%) was the most common site for metastasis. Half (53.4%) of the patients had ECOG-PS <2; 18% had cholestasis. Palliative chemotherapy predominantly gemcitabine was given to 86.3% of the patients. Clinical benefit rate was 58.2% and objective response rate (ORR) was 23%. Median overall survival (OS) and progression-free survival (PFS) were 6.3 months (95% CI: 5.2-7.8) and 4.9 months (95% CI: 3.6-6.1). Age (p = .003), ECOG-PS (p = .0001), palliative chemotherapy (p = .002), cholestasis (p = .001) and NLR (p = .001) were statistically significant but PLR (p = .062), NPS (p = .86) and PNI (p = .51) were not significant in univariate analysis. Age (HR 1.026, 95% CI: 1.007-1.045, p = .007), ECOG-PS (HR 0.299, 95% CI: 0.202-0.443, p = .0001), cholestasis (HR 0.541, 95% CI: 0.325-0.901, p = .01) and NLR (HR 1.076, 95% CI: 1.025-1.130, p = .003) were significant prognostic factors in multivariate analysis. CONCLUSIONS: Basal high NLR (>3), advanced age (>60 years), poor ECOG-PS (>2) and cholestasis were independent poor prognostic factors in MPC. However, PNI, NPS and PLR had no prognostic significance (p = .51, p = .86 and p = .062, respectively). PMID- 29161927 TI - Preventing Violence: A Public Health Participatory Approach to Homicide Reviews. AB - Death review teams are a common method for assessing preventable deaths, yet they rarely review adult homicides and do not typically include community members. Academic-community partnerships can enhance public health research by encouraging translation of research into practice and support a data-driven approach to improve community health and well-being. We describe the Pittsburgh Homicide Review Group, a community-partnered initiative to prevent future homicides through data review and community dialogue. Group members reviewed all 42 Pittsburgh 2012 homicides informed by three primary data sources: publicly available data, local service databases, and community outreach resources. Thirty two individuals representing relevant county agencies and community groups participated in eight reviews. Data sharing among partners resulted in a comprehensive understanding of the context of homicides. Review meetings supported a collective discussion around potential contributing factors to homicides, intervention implications, and recommendations. Academic-community homicide review partnerships are a productive approach to inform homicide prevention and interventions that are relevant to communities and should be implemented widely. PMID- 29161928 TI - Synthesis of new pyridothienopyrimidinone and pyridothienotriazolopyrimidine derivatives as pim-1 inhibitors. AB - Three series of 2-arylpyridothieno[3,2-d]pyrimidin-4-ones 3a-j, pyridothienotriazolopyrimidines 6-8 and 4-imino-pyridothieno[3,2-d]pyrimidines 9a,b were prepared to improve the pim-1 inhibitory activity of the previously reported 2-arylpyridothieno[3,2-d]pyrimidin-4-ones. All the test compounds showed highly potent pim-1 inhibition with IC50 in the range of 0.06-1.76 uM. No significant difference was detected between the pim-1 inhibitory activity of the 4-pyrimidinone and the 4-imino (=NH) or the cyclised triazolopyrimidine derivatives. The most active compounds were tested for their cytotoxic activity on MCF7 and HCT116 and showed potent activity on both the cell lines. PMID- 29161929 TI - Changes in Anthropometry and Selected Metabolic Parameters in Young Men During Their First Year of Study at a University of Physical Education. AB - This study aims to determine main health-related anthropometric and metabolic parameters in young physically active male students in their first year of study. Sixty one male students from a Polish university of physical education were studied twice-at the beginning of their first and second academic years. Body weight, height, waist circumference, and body composition were measured. Plasma levels of thyroid-stimulating hormone (TSH), leptin, cortisol, and insulin, as well as insulin resistance (IR) using the homeostatic model assessment (HOMA) were determined. In 64% of the participants body weight and body mass index (BMI) significantly increased during the study. An average students' weight gain amounted to 1.2 kg. In most of the subjects it resulted from the increase of fat free mass ( r = .886, p < .001). TSH and leptin levels did not change, but a significant increase of cortisol levels and a tendency toward decreased insulin levels and also HOMA-IR values were observed. However, there were no significant correlations identified between the changes in anthropometric and biochemical parameters. The study revealed that body weight gain seen in male students during their first year at the university of physical education was mainly due to the increase in fat-free mass. Apart from anthropometrics, changes in their insulin and cortisol levels were also detected, but further studies are required to evaluate these findings. The documented insufficient energy and carbohydrates consumption in physically active male students proves the need for nutritional education among them. PMID- 29161930 TI - No radiological and clinical advantages with patient-specific positioning guides in total knee replacement. AB - Background and purpose - Although the use of patient-specific positioning guides (PSPGs) in total knee replacement (TKR) in theory is promising, the technique has not yet proven its superior- ity compared with the conventional method. We compared radio- logical alignment and clinical outcome between TKR performed with the use of PSPGs and the conventional operation method. Patients and methods - 3 hospitals participated in a prospec- tive trial. 109 patients were randomized to either the conventional method or to the use of PSPGs. Postoperatively a full length standing anteroposterior radiograph and a postoperative CT scan were taken. On the CT scan the alignments were measured for both the femoral and tibial components in the frontal, sagit- tal, and axial plane. The Knee injury and Osteoarthritis Outcome Score (KOOS), the Eurocol-5D-3L (Eq5D) descriptive system and visual analogue scale (VAS), a pain score (NRS), and range of motion (ROM) were recorded preoperatively, and at 3 months, 1, and 2 years. The operation time and length of hospital stay were recorded. Results - 90 patients were available for postoperative CT mea- surements. A statistically significant difference was found between the conventional TKR instrumentation and the use of PSPGs for the frontal femoral (mean (SD) 0.6 degrees (1.7) vs. -0.3 degrees (2.2), CI 0.08 to 1.69) and tibial (-0.3 degrees (1.5) vs. 0.9 degrees (2.1), CI -1.98 to -0.44) compo- nent angles and for the tibial alignment in the sagittal plane (-3.8 degrees (3.0) vs. -2.2 degrees (2.5), CI -2.72; -0.42). The proportions of outliers were similar between the groups as well as the hip knee-ankle angle, the KOOS sub scores, the Eq5D, pain (NRS), ROM, opera- tion time, and length of hospital stay. Interpretation - The use of PSPGs requires a preoperative CT scan or MRI and the guides have an additional cost. As this study was not able to prove any extra benefit of the use of PSPGs we recommend the conventional operation method for TKR. PMID- 29161931 TI - What are the trends and demographics in sports-related pediatric spinal cord injuries? AB - OBJECTIVES: Pediatric spinal cord injury (PSCI) is a devastating injury that can cause significant long-term consequences. The purpose of this study is to calculate and report the prevalence of PSCI, identify risk factors for sports related PSCI, and evaluate associated factors. METHODS: The data sets of the Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID) from 2000-2012 were analyzed using ICD-9-CM external cause of injury codes to identify the mechanism of injury contributing to PSCI hospitalization. We then extracted demographic data on each admission including age, gender, race, and year of admission. We further stratified the data by sports-related cases of injury. Multivariate logistic regression analyses were used to identify independent risk factors. RESULTS: Of our study population, 0.8% had a documented diagnosis of spinal cord injury (SCI). The most common documented external cause of injury code was motor vehicle accidents, representing roughly half of all cases in patients 0-9 years-old (p = 0.001). PSCI due to sports as an external cause of injury was more prevalent in patients 10-17 years old, and was especially prevalent in the 10-13 year-old age category in which sports-related PSCI reached a high of 25.6%. Risk factors for traumatic PSCI after a sports related external cause included being of older age, male, and white. CONCLUSIONS: The prevalence of SCI increased with age. Given the popularity of youth sports in the United States, parents and sports officials should be aware of the increased risk of sports-related PSCI among patients 10-17 years old. LEVEL OF EVIDENCE: Level III, retrospective cohort study. PMID- 29161932 TI - Current trends in in silico, in vitro toxicology, and safety biomarkers in early drug development. AB - The development of new medicines is a long and expensive process. Despite growing efforts in R&D over the last decades, attrition rate due to safety issues (especially cardiac and hepatic toxicity) remains a major challenge for the pharmaceutical industry. This may lead to market withdrawal or late stage halting of a drug development program. Consequently, early detection of toxicity issues is critical to avoid late-stage failures. To this end, development of predictive toxicology assays and models have become a strategic matter for drug makers. An integrated approach confronting knowledge-based data sources with in vitro and in vivo experimental data should be performed. A well-defined balance between in vivo and in vitro assays should guide the safety assessment process and include a rationale taking into account ethical considerations as well as associated resourcing involved with animal use. Innovation in de-risking strategies may support refinement of regulatory testing and contribute to (i) improve drug safety evaluation alleviating assessment of the risk-benefit ratio and (ii) promote the access to safe drugs for patients. In this review, promising innovative approaches aiming at facilitating early detection of toxicity during drug development are described. PMID- 29161933 TI - Safety of Zilver PTX Drug-Eluting Stent Implantation Following Drug-Coated Balloon Dilation in a Healthy Swine Model. AB - PURPOSE: To compare the safety of Zilver PTX drug-eluting stents (DES) following drug-coated balloon (DCB) angioplasty or conventional balloon angioplasty (BA) in a healthy porcine iliofemoral artery model. METHODS: DES implantation following DCB (DCB+DES) or BA (BA+DES) was assessed by angiography and histology in the nondiseased iliofemoral arteries of 20 animals, with sacrifice at 1, 3, and 6 months. Safety assessment compared quantitative measures of vessel integrity (eg, preservation of artery geometry, structure, and lumen dimensions; absence of aneurysm; malapposition) and histological parameters (eg, excessive inflammation). The percentage of uncovered struts could not be >30% per section and the endothelial cell loss had to be <50%. The vascular and skeletal muscle changes in the downstream regions were also assessed histologically for evidence of emboli. RESULTS: No significant differences in safety parameters, including inflammation and endothelial cell loss, were observed between the 2 groups at all time points. Percentage of fibrin was significantly higher in DCB+DES at 3 months [20.0% (IQR 11.6, 28.4) vs BA+DES 4.2% (IQR 1.4, 9.6), respectively; p=0.04], with consistent trends between groups at all time points. Medial smooth muscle cell loss peaked at 1 month and was not statistically different between groups at any time point, although the loss was greater in the DCB+DES group. Sections with arterioles exhibiting paclitaxel-associated fibrinoid necrosis in downstream tissues were observed exclusively in the DCB group at 1 month (14.3% of sections) and 3 months (11.5%). CONCLUSION: This preclinical study suggests that Zilver PTX stent implantation is a safe strategy after DCB angioplasty and might be considered for patients who require stenting after DCB treatment. PMID- 29161934 TI - Barriers to and Facilitators of Help-Seeking Behavior Among Men Who Experience Sexual Violence. AB - Research on sexual violence and related support services access has mainly focused on female victims; there is still a remarkable lack of research on men who experience sexual violence. Research demonstrates that people who both self identify as men and are members of sexual-orientation minority populations are at higher risk of sexual violence. They are also less likely to either report or seek support services related to such experiences. The present study is an exploratory one aimed at filling the gap in the literature and better understanding how men, both straight and gay as well as cisgender and transgender, conceptualize, understand, and seek help related to sexual violence. A sample of 32 men was recruited on-line and participated in either a one-on-one in-depth interview ( N = 19) or one of two focus group discussions ( N = 13). All interviews and groups were audiotaped, professionally transcribed and coded using NVivo 9 qualitative software. The present analysis focused on barriers to and facilitators of support service access. Emergent and cross-cutting themes were identified and presented, with an emphasis on understanding what factors may prevent disclosure of a sexual violence experience and facilitate seeking support services and/or professional help. Through this analysis, the research team aims to add knowledge to inform the development of tools to increase service access and receipt, for use by both researchers and service professionals. Although this study contributes to the understanding of the issue of men's experiences of sexual violence, more research with diverse populations is needed. PMID- 29161935 TI - Extended Versus Short-Course Corticosteroid Taper Regimens in the Management of Chronic Obstructive Pulmonary Disease Exacerbations in Critically Ill Patients. AB - BACKGROUND: Previous literature has suggested that a short course of corticosteroids is similarly effective as an extended course for managing an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, there are limited data regarding the optimal corticosteroid regimen in critically ill patients and the dosing strategies remain highly variable in this population. METHODS: This retrospective cohort study evaluated patients with AECOPD admitted to the intensive care unit within a 2-year period. Patients were divided into short-course (<=5 days) or extended-course (>5 days) corticosteroid taper groups. The primary end point was treatment failure, defined as the need for intubation, reintubation, or noninvasive mechanical ventilation. Secondary end points included the duration of mechanical ventilation, hospital and intensive care unit length of stay, and adverse events. RESULTS: Of the 151 patients who met the inclusion criteria, 94 received an extended taper and 57 received a short taper. Treatment failure occurred in 3 patients, who were all in the extended taper group ( P = .17). In a propensity score-matched cohort, the hospital length of stay was 7 days in the short taper group compared to 11 days in the extended taper group ( P < .0001). No differences in adverse events were observed. CONCLUSION: A short-course corticosteroid taper in critically ill patients with AECOPD is associated with reduced hospital length of stay and decreased corticosteroid exposure without increased risk of treatment failure. A prospective randomized trial is warranted. PMID- 29161936 TI - A Morphological and Quantitative Analysis of Lung CT Scan in Patients With Acute Respiratory Distress Syndrome and in Cardiogenic Pulmonary Edema. AB - BACKGROUND: The acute respiratory distress syndrome (ARDS) and cardiogenic pulmonary edema (CPE) are both characterized by an increase in lung edema that can be measured by computed tomography (CT). The aim of this study was to compare possible differences between patients with ARDS and CPE in the morphologic pattern, the aeration, and the amount and distribution of edema within the lung. METHODS: Lung CT was performed at a mean positive end-expiratory pressure level of 5 cm H2O in both groups. The morphological evaluation was performed by two radiologists, while the quantitative evaluation was performed by a dedicated software. RESULTS: A total of 60 patients with ARDS (20 mild, 20 moderate, 20 severe) and 20 patients with CPE were enrolled. The ground-glass attenuation regions were similarly present among the groups, 8 (40%), 8 (40%), 14 (70%), and 10 (50%), while the airspace consolidations were significantly more present in ARDS. The lung gas volume was significantly lower in severe ARDS compared to CPE (830 [462] vs 1120 [832] mL). Moving from the nondependent to the dependent lung regions, the not inflated lung tissue significantly increased, while the well inflated tissue decreased (rho = 0.96-1.00, P < .0001). Significant differences were found between ARDS and CPE mostly in dependent regions. In severe ARDS, the estimated edema was significantly higher, compared to CPE (757 [740] vs 532 [637] g). CONCLUSIONS: Both ARDS and CPE are characterized by a similar presence of ground-glass attenuation and different airspace consolidation regions. Acute respiratory distress syndrome has a higher amount of not inflated tissue and lower amount of well inflated tissue. However, the overall regional distribution is similar within the lung. PMID- 29161937 TI - The interplay between TGF-beta/SMAD and BMP/SMAD signaling pathways in the epithelial mesenchymal transition of A549 cells induced by silica. AB - The epithelial-mesenchymal transition (EMT) is a phenotype transdifferentiation of epithelial into mesenchymal cells and contributes to pulmonary fibrotic disease. SMAD-dependent pathway has been reported to play a key role in the multiple fibrotic diseases. We hypothesized that TGF-beta/SMAD signaling could cross-interact with BMP/SMAD signaling pathways in silica-induced EMT in A549 cells. We investigated that the ability of silica-induced EMT in A549 cells, and this process was significantly inhibited by SB431542 through up-regulation of Vimentin, alpha-SMA and collagen type I expression and down-regulation of E cadherin expression. Whereas BMP/SMAD inhibition using LDN193189 enhanced EMT. In addition, we also demonstrated that SB431542 could enhance BMP/SMAD signaling pathways in silica-induced EMT and vice versa. Therefore, our study provides evidence that the TGF-beta/SMAD pathway was a crucial regulator in silica-induced EMT and that SB431542 could prevent the EMT. More importantly, we have identified that the interplay of TGF-beta/SMAD and BMP/SMAD pathways in silica-induced EMT in A549 cells. PMID- 29161938 TI - Oral mucosal lesions in electronic cigarettes consumers versus former smokers. AB - OBJECTIVES: Electronic cigarettes (ECs) have become very popular in recent years. However, many uncertainties remain about their side effects. This study aims to evaluate the prevalence and characteristics of oral mucosal lesions (OMLs) in former smokers compared to ECs consumers. METHODS: A prospective case-control study was carried out. Outpatients for dental consultation were consecutively enrolled into two groups based on their habits, i.e. former smokers and ECs consumers. Each patient was examined to detect possible oral lesions and, if needed, a swab or biopsy of the lesion was taken for diagnosis. Data was entered into a spreadsheet and analyzed. RESULTS: A total of 90 patients were examined, 45 were former smokers (group A) and 45 were ECs consumers (group B). OMLs were detected in 55 cases, of which 19/55 (34.6%) belonged to group A and 36/55 (65.4%) to group B. Nicotine stomatitis, a hairy tongue and angular cheilitis resulted to be significantly more common among EC consumers. CONCLUSIONS: We found no statistically significant differences in terms of total prevalence of OMLs between former smokers and ECs consumers. An increased prevalence of three specific types of OMLs was detected among ECs consumers. PMID- 29161940 TI - Helping Others by First Affirming the Self: When Self-Affirmation Reduces Ego Defensive Downplaying of Others' Misfortunes. AB - We show that self-affirmation increases helping behavior toward others in need. We argue that as awareness of others' pain causes discomfort, individuals are often motivated to ignore information about such pain. However, ignoring others' suffering implies that one is not a good and caring person, which presents a threat to self-integrity. To resolve this conflict, people might downplay others' pain. Studies show that self-affirmation intervenes in this process, thereby increasing willingness to help (Studies 1-4). Findings further show that self affirmation leads people to attend more closely to information about others' difficulties (Study 2) and to construe others' pain as a pressing need instead of an ordinary hardship (Study 3). Study 4 provides evidence supporting the ego defensive account and rules out an alternative account based on other-directed emotions. Studies 1 to 4 also reveal that the effect of self-affirmation is more pronounced among people who are less likely to identify with victims. PMID- 29161939 TI - Oil encapsulation techniques using alginate as encapsulating agent: applications and drawbacks. AB - Oils are used in agriculture, nutrition, food and cosmetics; however, these substances are oxidisable and may readily lose their properties. To reduce their degradation or to mask certain undesirable aspects, one strategy consists in encapsulating the oil in inert structures (capsules). The capsules are classified according to the morphology, the number of cores and size, can be produced by several techniques: jet-cutting, vibrating jet, spray-drying, dispersion and milli-microfluidic. Among the polymers used as a membrane in the capsules, alginates are used in oil encapsulation because of their high gelling capacity, biocompatibility and low toxicity. In the presence of calcium ions, the alginate macromolecules crosslink to form a three-dimensional network called hydrogel. The oil encapsulation using alginate as encapsulating material can be carried out using technologies based on the external, internal or inverse gelation mechanisms. These capsules can found applications in areas as cosmetics, textile, foods and veterinary, for example. PMID- 29161941 TI - Are we missing the Staphylococcus aureus bacteraemia forest for the MRSA trees? AB - In this edition of the journal, Jokinen et al. report on a population based study of Staphylococcus aureus bacteraemia (SAB) in Finland. They observe increasing incidence of cases over time that are associated with an increase in blood culture sampling. As compared to methicillin-sensitive SAB that increases during the study period, the incidence of methicillin-resistant SAB increases and then decreases. The proportion of cases with penicillin-sensitive SAB markedly increases in the study representing 43% of isolates in the most recent year of surveillance. While much attention and focus is typically placed on methicillin resistant SAB, the major part of the burden of illness associated with SAB is from methicillin-sensitive and penicillin-sensitive strains. A narrow focus on prevention of methicillin-resistant Staphylococcus aureus will only have a limited impact on the overall burden of disease due to SAB. PMID- 29161942 TI - Trends in incidence and resistance patterns of Staphylococcus aureus bacteremia. AB - BACKGROUND: Staphylococcus aureus bacteremia (SAB) causes a significant burden on the population. Several infection control measures have been implemented in Pirkanmaa county to combat a local epidemic with methicillin-resistant Staphylococcus aureus (MRSA). We aimed to study the epidemiology of SAB and antibiotic resistance of S. aureus and the possible influence of improved infection control. METHODS: Register data from 2005 to 2015 were retrospectively analysed to study the antimicrobial susceptibility, the incidence and mortality in SAB in a population-based setting. RESULTS: The incidence of SAB increased during the study period from 21.6 to 35.8/100,000 population. The number of both health care-associated (HA) and community-associated (CA) cases has increased. The incidence of MSSA bacteremia increased from 19.9 to 35.2/100,000 population in Pirkanmaa in parallel to other parts of Finland. The incidence of MRSA bacteremia was 10-fold (4.5/100,000 population) higher in 2011 than in other parts of the country, but sank to the national level (0.59/100,000 population) in 2015. The fatality rate decreased from 22% to 17%. The proportion of penicillin susceptible Staphylococcus aureus (PSSA) increased from 23.9% in 2008 to 43.1% in 2015. CONCLUSION: The incidence of both HA and CA SAB has increased since 2005. Conversely, the proportion of MRSA and PRSA bacteremia has decreased. Promotion of infection control measures may have reduced the incidence of MRSA bacteremia but not the overall incidence of SAB. The rising proportion of PSSA enables the use of targeted, narrow spectrum antimicrobials. PMID- 29161943 TI - Analysis of sequence divergence in redfin (Cypriniformes, Cyprinidae, Tribolodon) based on mtDNA and nDNA markers with inferences in systematics and genetics of speciation. AB - To clarify relationship of species of the genus Tribolodon in the Russian part of their distribution ranges, two mitochondrial markers (Co-1 and Cyt-b), a nuclear marker (Rho), and a gene marker of rDNA internal transcribed spacer (ITS-1,2) were used. Depending on the marker, different numbers of species groups were detected by the ABGD method, but in combination with the analysis of phylograms, these data generally support the known species clusters and regional intraspecies groups. A complex analysis of sequences from three redfin species within the area of the study, based on four marker genes and using the methods of molecular phylogenetics, ordination of genetic distances, recombinant analysis, and population genetic approaches, has revealed clusters of three commonly recognized species, regional intraspecific groups or individuals of local populations, and few hybrid individuals. DNA barcoding technique proved to be efficient with the use of two mtDNA markers: Co-1 and Cyt-b. It has been found that analysis of insertions and substitutions within the ITS-1,2 gene marker is also suitable for identification of Tribolodon species. Results of the studies of local groups do not confirm a sufficient level of differences for defining any new taxa of a species rank in the genus Tribolodon. PMID- 29161944 TI - A Structured Process Description of a Pragmatic Implementation Project: Improving Integrated Care for Older Persons in Residential Care Homes. AB - Evaluation of the implementation of integrated care can differ from trial-based research due to complexity. Therefore, we examined whether a theory-based method for process description of implementation can contribute to improvement of evidence-based care. MOVIT, a Dutch project aimed at implementing integrated care for older vulnerable persons in residential care homes, was used as a case study. The project activities were defined according to implementation taxonomy and mapped in a matrix of theoretical levels and domains. Project activities mainly targeted professionals (both individual and group). A few activities targeted the organizational level, whereas none targeted the policy level, or the patient, or the "social, political, and legal" domains. However, the resulting changes in care delivery arrangement had consequences for professionals, patients, organizations, and the social, political, and legal domains. A structured process description of a pragmatic implementation project can help assess the fidelity and quality of the implementation, and identify relevant contextual factors for immediate adaptation and future research. The description showed that, in the MOVIT project, there was a discrepancy between the levels and domains targeted by the implementation activities and those influenced by the resulting changes in delivery arrangement. This could have influenced, in particular, the adoption and sustainability of the project. PMID- 29161945 TI - Identification of an NDM-1-producing Klebsiella pneumoniae from diabetic foot ulcer in China. PMID- 29161946 TI - The Uptake of Human Papillomavirus Vaccination and Its Associated Factors Among Adolescents: A Systematic Review. AB - BACKGROUND: The purpose of this review was to explore the uptake of the human papillomavirus (HPV) vaccination, its associated factors, and the facilitators of and barriers to HPV vaccination among adolescents. METHODS: A comprehensive literature search was conducted through 5 electronic databases, including PubMed, CINAHL, Cochrane Library, Medline, and PsycInfo from January 2006 to March 2015 for studies examining the uptake, awareness, knowledge, acceptability, and intention of adolescents with regard to HPV vaccination. RESULTS: Twenty-eight studies were identified and included. The HPV vaccination uptake rate (at least 1 dose) varied significantly among countries, ranging from 2.4% to 94.4%. Scotland achieved the highest uptake of all the studies included in this review, while Hong Kong had the lowest, at 2.4% to 9.1%. This review also showed that adolescents had limited awareness and knowledge of HPV infections and vaccines, even 10 years after the vaccine had become available. CONCLUSIONS: It is recommended that barriers to the uptake of the vaccine should be addressed, and that school-based sexual health education of HPV infection and vaccine promotion should be reinforced. PMID- 29161947 TI - Associations Between Waiting Times, Service Times, and Patient Satisfaction in an Endocrinology Outpatient Department: A Time Study and Questionnaire Survey. AB - The issue of long patient waits has attracted increasing public attention due to the negative effects of waiting on patients' satisfaction with health care. The present study examined the associations between actual waiting time, perceived acceptability of waiting time, actual service time, perceived acceptability of service time, actual visit duration, and the level of patient satisfaction with care. We conducted a cross-sectional time study and questionnaire survey of endocrinology outpatients visiting a major teaching hospital in China. Our results show that actual waiting time was negatively associated with patient satisfaction regarding several aspects of the care they received. Also, patients who were less satisfied with the sociocultural atmosphere and the identity oriented approach to their care tended to perceive the amounts of time they spent waiting and receiving care as less acceptable. It is not always possible to prevent dissatisfaction with waiting, or to actually reduce waiting times by increasing resources such as increased staffing. However, several improvements in care services can be considered. Our suggestions include providing clearer, more transparent information to keep patients informed about the health care services that they may receive, and the health care professionals who are responsible for those services. We also suggest that care providers are encouraged to continue to show empathy and respect for patients, that patients are provided with private areas where they can talk with health professionals and no one can overhear, and that hospital staff treat the family members or friends who accompany patients in a courteous and friendly way. PMID- 29161948 TI - What Happens to a Nursing Home Chain When Private Equity Takes Over? A Longitudinal Case Study. AB - We analyzed what happens to a nursing home chain when private equity takes over, with regard to strategy, financial performance, and resident well-being. We conducted a longitudinal (2000-2012) case study of a large nursing home chain that triangulated qualitative and quantitative data from 5 different data sources. Results show that private equity owners continued and reinforced several strategies that were already put in place before the takeover, including a focus on keeping staffing levels low; the new owners added restructuring, rebranding, and investment strategies such as establishing new companies, where the nursing home chain served as an essential "launch customer." PMID- 29161949 TI - Learning Letters With the Whole Body: Visuomotor Versus Visual Teaching in Kindergarten. AB - What constitutes effective teaching of letter learning in early school years is still uncertain. We assessed the impact of a teacher-implemented visuomotor intervention program to teach 5-year-olds' cursive letter knowledge. We compared a program in which letters were explored with the arm and whole body, with a typical visual training program. Children were tested before and after the intervention with different measures of letter knowledge. We showed a greater improvement in letter recognition following the visuomotor intervention, compared with the visual intervention. Results were mixed for letter handwriting for which we found higher scores on stroke direction and overall quality, but lower scores on fluency following whole body visuomotor teaching. We discuss our results in terms of the link between action and perception, the interaction between the different components of letter knowledge, and the link between fine and gross motor development and handwriting. PMID- 29161950 TI - X-ray microtomography assessment of Carisolv and Papacarie effect on dentin mineral density and amount of removed tissue. AB - OBJECTIVE: The aim of the present study was to directly compare Carisolv and Papacarie regarding the volume of removed tissue (RT) and dentin mineral density (DMD) after excavation. MATERIALS AND METHODS: Twenty permanent molars were randomized into two groups where caries was excavated using Carisolv or Papacarie followed by removal of softened tissue by a blunt instrument. X-ray microtomography was used to scan teeth before and after excavation generating two and three-dimensional images that were used to calculate the percentage of RT relative to baseline tooth tissue volume and DMD that was categorized into sound dentin (>1.11 g/cm3) and residual caries (<=1.11 g/cm3). The two groups were compared using t-test Fisher exact test. RESULTS: DMD was higher after Papacarie than Carisolv (mean = 1.70 and 1.14, p = .14) with higher percentage of cases with sound dentin (70 and 60%, p = 1.00). The percentage of RT was lower after Papacarie than Carisolv (7.40 and 8.95%, p = .31) with 22.95% less RT in cases that ended with sound dentin after excavation. CONCLUSIONS: There was higher DMD, more sound dentin and less RT when Papacarie was used compared to Carisolv. PMID- 29161951 TI - An open-treatment six-week study of the clinical effectiveness of Paliperidone Palmitate in schizophrenia: data from acute units in Spain (SHADOW study). AB - OBJECTIVES: To evaluate clinical evolution of patients with schizophrenia admitted in acute units because of a relapse and treated with once-monthly Paliperidone Palmitate (PP1M). METHODS: This multicentre, open-label, prospective observational study followed patients with schizophrenia treated with PP1M in acute psychiatric units for up to 6 weeks. RESULTS: Out of the 280 enrolled patients, 61 received PP1M as antipsychotic monotherapy, and 219 in combination with other antipsychotics. The average Clinical Global Impression-Schizophrenia (CGI-SCH) score decreased from 4.7 at baseline to 3.3 at final visit (p < .0001); the change was clinically and statistically significant both in patients treated with PP1M in monotherapy and in combination with other antipsychotics. Clear improvements in functioning and high patient satisfaction with the treatment were observed. Time from admission to PP1M therapy initiation correlated with the length of hospital stay (p < .0001); earlier start of PP1M treatment was associated with shorter hospital stay. Adverse events were reported in 7.1% of patients (all non-serious). CONCLUSIONS: PP1M was effective and well tolerated in treatment of acute episodes of schizophrenia both in monotherapy and in combination with other antipsychotics in clinical setting. Early start of PP1M therapy in acute schizophrenia episodes might help to shorten hospital stay. PMID- 29161952 TI - Reduced antibiotic prescription rates following physician-targeted interventions in a dental practice. AB - BACKGROUND: The prescription rate for antibiotics in dental clinics is not declining despite the increase in the antibiotic resistance problem. In this study, we observed the change in antibiotic prescription rates by dentists in a Korean dental hospital for various treatments after conducting interventions targeting dentists. METHODS: The first intervention was to distribute guidelines. The second intervention was to remove the bundled prescription button containing antibiotics from the Electronic Medical Record system. A total of 22,098 treatment records were divided into 12 main treatment categories, and Chi-square tests and logistic regression analyses were performed. RESULTS: After the interventions were applied, the overall prescription rate for antibiotics dropped. The antibiotic prescription rate decreased by an odds ratio of 0.774 (95% CI: 0.686-0.873) after intervention 1 and by an odds ratio of 0.574 (95% CI: 0.501-0.658) after intervention 2. The treatments with significantly reduced antibiotic prescription rates were extraction for orthodontic treatment, dental implant surgery, extraction of an impacted tooth and general extraction. These treatments are typically performed in patients without an active infection. The prescription rate did not change for periodontal treatments or endodontic treatments, which are usually performed in patients with an infection. The prescription rate also remained constant for minor operations and other basic treatments. CONCLUSION: The interventions induced behavioural changes in the dentists and were effective in lowering the antibiotic prescription rates in a dental hospital. In particular, there was a significant reduction in the prescription rates for implant surgery and tooth extraction in the absence of infection. PMID- 29161953 TI - Mental Simulation of Visceral States Affects Preferences and Behavior. AB - Preferences and behavior are heavily influenced by one's current visceral experience, yet people often fail to anticipate such effects. Although research suggests that this gap is difficult to overcome-to act as if in another visceral state-research on mental simulation has demonstrated that simulations can substitute for experiences, albeit to a weaker extent. We examine whether mentally simulating visceral states can impact preferences and behavior. We show that simulating a specific visceral state (e.g., being cold or hungry) shifts people's preferences for relevant activities (Studies 1a-2) and choices of food portion sizes (Study 3). Like actual visceral experiences, mental simulation only affects people's current preferences but not their general preferences (Study 4). Finally, people project simulated states onto similar others, as is the case for actual visceral experiences (Study 5). Thus, mental simulation may help people anticipate their own and others' future preferences, thereby improving their decision making. PMID- 29161954 TI - "We hide...": Perceptions of HIV Risk Among Black and Latino MSM in New York City. AB - Black and Latino men who have sex with men (BLMSM) are disproportionately infected with HIV; they comprised 66% of HIV diagnoses among men who have sex with men (MSM) in the United States in 2015. Risk factors for HIV infection among BLMSM include a high community prevalence of diagnosed and undiagnosed HIV/STDs, and dense sex partner networks. Perceptions of HIV risk among BLMSM were explored to inform HIV prevention efforts. During 2011-2012, semistructured interviews were conducted with BLMSM in New York City. Using computer-assisted thematic analyses (NVivo), transcribed interview responses to questions regarding HIV risk for main themes were examined. Interview data were available for 108 BLMSM: 86% Black, 13% Latino, 26% aged 18-24 years, 59% self-identified as "gay," and 33% self-identified as "bisexual." The main emergent theme was stigma. Subthemes related to stigma included: (a) homophobia in the Black and Latino community, (b) fear of losing support from family and friends, and (c) lack of support leading to low self-esteem. Addressing the stigma felt by BLMSM may be an important strategy to facilitate improved HIV prevention efforts, HIV care and treatment, and to decrease HIV-related disparities. PMID- 29161955 TI - Mixed Type A Thymoma and Micronodular Thymoma With Lymphoid Stroma. PMID- 29161956 TI - Percutaneous repair of mitral valve regurgitation in patients with severe heart failure: comparison with optimal medical treatment. AB - BACKGROUND: Occurrence of severe mitral valve (MV) regurgitation (MR) is an independent negative predictor of mortality in patients with severe systolic heart failure (HF). This study examines clinical effects and cardiac reverse remodelling in patients with severe systolic HF receiving percutaneous mitral valve repair (PMVR) using MitraClip in comparison to patients receiving optimal medical therapy only. METHODS: Between 2010 and 2014, 86 patients (Society of Thoracic Surgeons score: 10.5% +/- 1.2%) with severe HF (left ventricular [LV] ejection fraction; LVEF: 25% +/- 2%; LV endsystolic diameter [LVESD]: 55 +/- 3 mm) and severe MR received PMVR using MitraClip. Cardiac reverse remodelling and clinical parameters were compared to HF patients with severe MR (from our HF outpatient clinic; n = 69; LVEF: 26% +/- 1.4%; LVESD: 53 +/- 2 mm) receiving optimal medical therapy (OMT) only. All patients received stable OMT and were characterised by echocardiography, 6-minwalk-distance test and cardiac biomarkers within a 24 months observation period. RESULTS: PMVR in patients with end-stage HF and severe MR resulted in reduction of MR and significant additional cardiac reverse remodelling (LVEF: 26 +/- 1.4 vs. 33% +/- 2%, p < .05; LVESD: 53 +/- 2 vs. 47 +/- 2 mm, p < .05) over the 24 months observation period as compared to pharmacologically-only managed comparators. CONCLUSIONS: Both OMT and PMVR cause cardiac reverse remodelling and relief of symptoms in patients with HF and severe MR. PMVR results in significant additional cardiac reverse remodelling compared to pharmacologically-only managed patients. PMID- 29161957 TI - Induced Pluripotent Stem Cells from a Marsupial, the Tasmanian Devil (Sarcophilus harrisii): Insight into the Evolution of Mammalian Pluripotency. AB - We demonstrate the generation of Tasmanian devil (Sarcophilus harrisii) induced pluripotent stem cells (DeviPSCs) from dermal fibroblasts by lentiviral delivery of human transcription factors. DeviPSCs display characteristic pluripotent stem cell colony morphology, with individual cells having a high nuclear-to cytoplasmic ratio and alkaline phosphatase activity. DeviPSCs are leukemia inhibitory factor dependent and have reactivated endogenous octamer-binding transcription factor 4 [OCT4, POU domain, class 5, transcription factor 1 (POU5F1)], POU2 [POU domain, class 5, transcription factor 3 (POU5F3)], sex determining region Y-box 2 (SOX2), Nanog homeobox (NANOG) and dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1) genes, retained a normal karyotype, and concurrently silenced exogenous human transgenes. Notably, co-expression of both OCT4 and POU2 suggests that they are representative of cells of the epiblast, the marsupial equivalent of the inner cell mass. DeviPSCs readily form embryoid bodies and in vitro teratomas containing derivatives of all three embryonic germ layers. To date, DeviPSCs have been stably maintained for more than 45 passages. Our DeviPSCs provide an invaluable resource for studies into marsupial pluripotency and development, and they may also serve as an important tool in efforts to combat the threat of devil facial tumor disease. PMID- 29161959 TI - Right Ventricular Function is Important for Pulmonary Artery Banding in Left Ventricular Dysfunction. AB - Small infants with severe left ventricular dysfunction (LVD) carry a poor prognosis with limited therapeutic options. Although mechanical support and heart transplantation are definitive therapies, improvement of left ventricular function with reversible pulmonary artery banding (rPAB) has been described. We report two cases of LVD treated with rPAB. One was successfully temporized, and one progressed to requiring transplantation, indicating that appropriate patient selection is critical to this technique's success. PMID- 29161958 TI - Leukemia Inhibitory Factor Is Essential for the Self-Renewal of Embryonic Stem Cells from Nile Tilapia (Oreochromis niloticus) Through Stat3 Signaling. AB - To date, little is known about the mechanisms underlying the self-renewal of embryonic stem (ES) cells from fish species. In this study, we report that the leukemia inhibitory factor (LIF; named as OnLif) from a teleost fish, Nile tilapia (Oreochromis niloticus), is essential for the proliferation, survival, and pluripotency maintenance of Nile tilapia ES cells (TES1) by activating the signal transducer and activator of transcription 3 (Stat3). This protein has 221 amino acid residues with similar sequence features to mammalian LIF. By fusing to a small ubiquitin-related modifier and inducing expression at 16 degrees C, the soluble tag-free protein had been successfully obtained. Further investigation indicates that OnLif could significantly enhance the proliferation and survival of TES1. Moreover, it contributed to the pluripotency maintenance of TES1 characteristic of high expression of pluripotency genes, no or low expression of differentiation genes, and strong alkaline phosphatase activity. Notably, it mediated Stat3 phosphorylation, whose inhibitor treatment could lead to apoptosis. In addition, OnLif significantly enhanced the proliferation of ES cells from medaka (Oryzias latipes), suggesting its potential role in other fish ES cells. These data first suggest that Lif/Stat3 signaling has an essential role in the self-renewal of ES cells from fish, just like that in the ground state pluripotency maintenance of mouse and human ES cells. Our study would not only be helpful for the understanding of molecular mechanisms underlying self-renewal of ES cells from the perspective of evolution but also facilitate ES-based biotechnology application in fishery. PMID- 29161960 TI - Efficacy and Safety of Long-Term Use of Dienogest in Women With Ovarian Endometrioma. AB - Dienogest (DNG) is a progestin with highly selective progesterone activity and minimal androgenic activity and is helpful in reducing endometriosis-related pain. This study assessed the long-term efficacy and safety and recurrence rate of endometrioma with DNG use beyond 12 months of treatment. A retrospective cohort study was conducted with data collected from 7 university-affiliated hospitals and included a total of 514 women with ovarian endometrioma. All patients received 2 mg of oral DNG daily for at least 48 weeks postoperatively. During continuation of DNG, the recurrence rate of ovarian endometrioma on ultrasound, adverse events, changes in menstrual pattern, and pain score (visual analogue scale) were analyzed. The average period of DNG administration in this study was 72.2 +/- 5.2 weeks (range: 48-164). The recurrence rate of endometrioma was 1.8% (9 of 514), and the median duration to recurrence was 58 weeks (range: 24-76). Pain was described as overall improved by 82.2% of patients; 61.6% stated the pain was "improved" and 20.6% reported "much improved." The mean VAS score was 4.9 at baseline and significantly decreased to 2.68, 2.2, 1.6, and 2.6 at 12, 24, 48, and 96 weeks. Amenorrhea rate was 58.3% in the first 12 weeks and increased to 86.4% at 72 weeks. Prolonged daily administration of 2 mg DNG followed by surgery was associated with a lower recurrence rate of ovarian endometrioma and a reduced pain score and symptoms. PMID- 29161961 TI - Corrigendum. PMID- 29161962 TI - Purification and structural analysis of volatile sesquiterpenes produced by Escherichia coli carrying unidentified terpene synthase genes from edible plants of the family Araliaceae. AB - A simple method to purify volatile sesquiterpenes from recombinant Escherichia coli was developed using the cells that carried known sesquiterpene synthase (Tps) genes ZzZss2 (ZSS2) and ZoTps1. This method was applied for the purification and structural analyses of volatile sesquiterpenes produced by E. coli cells that carried unidentified Tps genes, which were isolated from the Aralia-genus edible plants belonging to the family Araliaceae. Recombinant cells carrying each Tps gene were cultured in the two-layer medium (n-octane/TB medium), and volatile sesquiterpenes trapped in n-octane were purified through two-phase partition, silica gel column chromatography, and reversed-phase preparative high-performance liquid chromatography, if necessary. Further, their structures were confirmed by nuclear magnetic resonance, [alpha]D, and gas chromatography-mass spectrometry analyses. Herein, the products of E. coli cells that carried two Tps gene (named AcTps1 and AcTps2) in Araria cordata "Udo" and a Tps gene (named AeTps1) in Aralia elata "Taranoki" were studied resulting in identifying functionalities of these cryptic Tps genes. PMID- 29161963 TI - Age-differences in cognitive flexibility when overcoming a preexisting bias through feedback. AB - INTRODUCTION: Older adults are often worse than younger adults at adapting to changing situational demands, and this difference is commonly attributed to an age-related decline in acquiring and updating information. Previous research on aging and cognitive flexibility has used measures that require adapting to novel associations learned during a laboratory task (e.g., choice X led to positive outcomes but now leads to negative outcomes). However, in everyday life people must frequently overcome associations based on preexisting beliefs and biases (e.g., you like to eat cake, but your doctor said to limit your sugar intake). The goal of the present study was to examine possible age-differences in overcoming a preexisting bias and determine whether age-related changes in the acquisition and updating of information influence this form of flexibility. METHOD: Older (n = 20) and younger (n = 20) adults completed a novel task in which repeated choices were made between a sure option (gain or loss) and one of two risky options that were initially ambiguous. Optimal performance required overcoming a framing bias toward being risk seeking to avoid a sure loss and risk averse when offered a sure gain. Probe questions assessed knowledge of choice outcomes, while skin conductance assessed physiological reactions to choices and choice outcomes. RESULTS: Both older and younger adults demonstrated flexibility by reducing the impact of bias over trials, but younger adults had better performance overall. Age-differences were associated with distinct aspects of processing. Young adults had more precise knowledge of choice outcomes and developed skin conductance responses in anticipation of bad choices that were not apparent in older adults. CONCLUSIONS: Older adults showed significant improvement over trials in their ability to decrease bias-driven choices, but younger showed greater flexibility. Age-differences in task performance were based on differences in learning and corresponding representations of task relevant information. PMID- 29161964 TI - Suicidal ideation in systemic lupus erythematosus: NR2A gene polymorphism, clinical and psychosocial factors. AB - Background Systemic lupus erythematosus (SLE) patients are a high-risk population for suicide. Glutamatergic neurosystem genes have been implicated in the neurobiology of depression in SLE and suicidal behaviour in general. However, the role of glutamate receptor gene polymorphisms in suicidal behaviour among SLE patients remains unclear in the context of established clinical and psychosocial factors. We aimed to investigate the association of NR2A gene polymorphism with suicidal ideation in SLE while accounting for the interaction between clinical and psychosocial factors. Methods A total of 130 SLE patients were assessed for mood disorders (MINI International Neuropsychiatric Interview), severity of depression (Patient Health Questionnaire-9), suicidal behaviour (Columbia-Suicide Severity Rating Scale), socio-occupational functioning (Work and Social Adjustment Scale), recent life events (Social Readjustment Rating Scale) and lupus disease activity (SELENA-SLE Disease Activity Index). Eighty-six out of the 130 study participants consented for NR2A genotyping. Results Multivariable logistic regression showed nominal significance for the interaction effect between the NR2A rs2072450 AC genotype and higher severity of socio-occupational impairment with lifetime suicidal ideation in SLE patients ( p = 0.038, odds ratio = 1.364, 95% confidence interval = 1.018-1.827). However, only the association between lifetime mood disorder and lifetime suicidal ideation remained significant after Bonferroni correction ( p < 0.001, odds ratio = 33.834, 95% confidence interval = 7.624-150.138). Conclusions Lifetime mood disorder emerged as a more significant factor for suicidal ideation in SLE compared with NR2A gene polymorphism main and interaction effects. Clinical implications include identification and treatment of mood disorders as an early intervention for suicidal behaviour in SLE. More adequately-powered gene environment interaction studies are required in the future to clarify the role of glutamate receptor gene polymorphisms in the risk stratification of suicidal behaviour among SLE patients. PMID- 29161965 TI - I Am There ... but Not Quite: An Unfaithful Mirror That Reduces Feelings of Ownership and Agency. AB - The experience of seeing one's own face in a mirror is a common experience in daily life. Visual feedback from a mirror is linked to a sense of identity. We developed a procedure that allowed individuals to watch their own face, as in a normal mirror, or with specific distortions (lag) for active movement or passive touch. By distorting visual feedback while the face is being observed on a screen, we document an illusion of reduced embodiment. Participants made mouth movements, while their forehead was touched with a pen. Visual feedback was either synchronous (simultaneous) with reality, as in a mirror, or asynchronous (delayed). Asynchronous feedback was exclusive to touch or movement in different conditions and incorporated both in a third condition. Following stimulation, participants rated their perception of the face in the mirror, and perception of their own face, on questions that tapped into agency and ownership. Results showed that perceptions of both agency and ownership were affected by asynchrony. Effects related to agency, in particular, were moderated by individual differences in depersonalisation and auditory hallucination-proneness, variables with theoretical links to embodiment. The illusion presents a new way of investigating the extent to which body representations are malleable. PMID- 29161966 TI - Altered downstream target gene expression of the placental Vitamin D receptor in human idiopathic fetal growth restriction. AB - Fetal growth restriction (FGR) affects up to 5% of pregnancies and is associated with significant perinatal complications. Maternal deficiency of vitamin D, a secosteroid hormone, is common in FGR-affected pregnancies. We recently demonstrated that decreased expression of the vitamin D receptor (VDR) in idiopathic FGR placentae could impair trophoblast growth. As strict regulation of cell-cycle genes in trophoblast cells is critical for optimal feto-placental growth, we hypothesised that pathologically decreased placental VDR contributes to aberrant regulation of cell-cycle genes. The study aims were to (i) identify the downstream cell-cycle regulatory genes of VDR in trophoblast cells, and (ii) determine if expression was changed in cases of FGR. Targeted cell-cycle gene cDNA arrays were used to screen for downstream targets of VDR in VDR siRNA transfected BeWo and HTR-8/SVneo trophoblast-derived cell lines, and in third trimester placentae from FGR and gestation-matched control pregnancies (n = 25 each). The six candidate genes identified were CDKN2A, CDKN2D, HDAC4, HDAC6, TGFB2 and TGFB3. TGFB3 was prioritised for further validation, as its expression is largely unknown in FGR. Significantly reduced mRNA and protein expression of TGFB3 was verified in FGR placentae and the BeWo and HTR-8/SVneo trophoblast cell lines, using real-time PCR and immunoblotting respectively. In summary, decreased placental VDR expression alters the expression of regulatory cell-cycle genes in FGR placentae. Aberrant regulation of cell-cycle genes in the placental trophoblast cells may constitute a mechanistic pathway by which decreased placental VDR reduces feto-placental growth. PMID- 29161967 TI - Whole-transcriptome analysis of oxidative stress response genes in carotenoid producing Enterococcus gilvus. AB - Whole-transcriptome analysis of aerobic stress response gene in Enterococcus gilvus was performed using RNA-sequencing to identify carotenoid-based stress response genes in lactic acid bacteria. The expression of gene responsible for pyruvate dehydrogenase complex synthesis was highly upregulated after aerobic treatment. In addition, the expression of transcriptional regulator spx and genes encoding UvrABC system protein was also upregulated. PMID- 29161968 TI - Assessment of depression in epilepsy: the utility of common and disease-specific self-report depression measures. AB - OBJECTIVES: Depression is common in epilepsy, with rates ranging from 20 to 55% in most samples and reports as high as 70% in patients with intractable epilepsy. However, some contend that depression may be over- and/or under-reported and treated in this population. This may be due to the use of common self-report depression measures that fail to take into account the overlap of disease and depressive symptoms and also the host of side effects associated with antiepileptic medication, which may also be construed as depression. METHODS: The present study examined the utility of common self-report depression measures and those designed specifically for the medically ill, including a proposed new measure, to determine which may be more appropriate for use among people with epilepsy. RESULTS: We found that common self-report depression measures are useful for screening depression in epilepsy, particularly with a raised cutoff for one, with sensitivities ranging from .91 to .96. A measure designed for the medically ill obtained the greatest specificity of .91, suggesting its use as a diagnostic tool with a slightly raised cutoff. The positive likelihood ratio of this latter measure was 8.76 with an overall classification accuracy of 88%. CONCLUSIONS: Assessment of depression in epilepsy can be improved when utilizing self-report measures that better differentiate disease symptoms from neurovegetative symptoms of depression (e.g. fatigue, sleep disturbance). This was demonstrated in the present study. Clinical implications are discussed. PMID- 29161969 TI - Schizophrenia and prospective memory impairments: a review. AB - OBJECTIVE: Prospective memory (PM) is the ability to remember to carry out intended actions in the future. Prospective forgetting has been shown to be one of the key cognitive impairments that contribute to medication non-adherence, reduced independence, and social dysfunction in individuals with schizophrenia. This review aimed to provide an up to date appraisal of the nature and extent of PM impairments in individuals with schizophrenia and those who are at risk and to discuss clinical applications in this area. METHOD: We searched and reviewed relevant studies in this area between 2013 and August 2017. RESULTS: Findings of studies conducted so far indicate that PM is severely impaired in schizophrenia. The most frequent type of PM errors in individuals with schizophrenia is no response, or failure to carry out the intended action. PM impairments in schizophrenia have been found to be related to everyday functioning. For individuals with schizophrenia, a number of assessment techniques have been developed to assess PM. These include: self-report questionnaires, computerized tasks, psychometric test batteries, and virtual reality tasks. So far, a few studies have used the compensatory approach to improve PM performance in individuals with schizophrenia and those who are at risk, and the results reported are promising. Based on findings of these studies, suggestions for the development of interventions for PM impairments in individuals with schizophrenia are provided. CONCLUSIONS: PM dysfunction is an important impairment in individuals with schizophrenia, and more rehabilitation studies to improve PM performance in these individuals are needed. PMID- 29161970 TI - The mediating effect of ethical climate on religious orientation and ethical behavior. AB - BACKGROUND: Nurses' behavior in Educational-Medical centers is very important for improving the condition of patients. Ethical climate represents the ethical values and behavioral expectations. Attitude of people toward religion is both intrinsic and extrinsic. Different ethical climates and attitude toward religion could be associated with nurses' behavior. AIM: To study the mediating effect of ethical climate on religious orientation and ethical behaviors of nurses. RESEARCH DESIGN: In an exploratory analysis study, the path analysis method was used to identify the effective variables on ethical behavior. Participants/context: The participants consisted of 259 Iranian nurses from Hamadan University of Medical Sciences. Ethical considerations: This project with an ethical code and a unique ID IR.UMSHA.REC.1395.67 was approved in the Research Council of Hamadan University of Medical Sciences. FINDINGS: The beta coefficients obtained by regression analysis of perception of ethical climate of individual egoism (B = -0.202, p < 0.001), individual ethical principles (B = 0.184, p = 0.001), local egoism (B = -0.136, p = 0.003), and extrinsic religious orientation (B = -0.266, p = 0.007) were significant that they could act as predictors of ethical behavior. The summary of regression model indicated that 0.27% of ethical behaviors of nurses are justified by two variables: ethical climate and religious orientation. DISCUSSION AND CONCLUSION: Intrinsic religious orientation has the most direct impact and then, respectively, the variables of ethical climate of perceptions in the dimensions of individual egoism, individual ethical principles, local egoism, global ethical principle, and ethical behavior and extrinsic religious orientation follow. All the above, except global ethical principles and intrinsic orientation of religion have a negative effect on ethical behavior and can be predictors of ethical behavior. Therefore, applying strategies to promote theories of intrinsic religious orientation and global ethical principles in different situations of nursing is recommended. PMID- 29161971 TI - Lying to patients with dementia: Attitudes versus behaviours in nurses. AB - BACKGROUND: Using lies, in dementia care, reveals a common practice far beyond the diagnosis and prognosis, extending to the entire care process. OBJECTIVES: In this article, we report results about the attitude and the behaviour of nurses towards the use of lies to patients with dementia. RESEARCH DESIGN: An epidemiological cross-sectional study was conducted between September 2016 and February 2017 in 12 elderly residential facilities and in the geriatric, psychiatric and neurological wards of six specialised hospitals of Italy's Campania Region. PARTICIPANTS: In all, 106 nurses compiled an attitude questionnaire (A) where the main question was 'Do you think it is ethically acceptable to use lies to patients with dementia?', instead 106 nurses compiled a behaviour questionnaire (B), where the main question was 'Have you ever used lies to patients with dementia?' Ethical considerations: Using lies in dementia care, although topic ethically still controversial, reveals a common practice far beyond the diagnosis and prognosis, extending to the entire care process. FINDINGS: Only a small percentage of the interviewed nurses stated that they never used lies/that it is never acceptable to use lies (behaviour 10.4% and attitude 12.3%; p = 0.66). The situation in which nurses were more oriented to use lies was 'to prevent or reduce aggressive behaviors'. Indeed, only the 6.7% in the attitude group and 3.8% in the behaviour group were against using lies. On the contrary, the case in which the nurses were less oriented to use lies was 'to avoid wasting time giving explanations', in this situation were against using lies the 51.0% of the behaviour group and the 44.6% of the attitude group. CONCLUSION: Our results, according to other studies, support the hypothesis of a low propensity of nurses to ethical reflection about use of lies. In our country, the implementation of guidelines about a correct use of lie in the relationship between health operators and patients would be desirable. PMID- 29161973 TI - A meta-analysis and systematic review of reactivity to judgements of learning. AB - Judgements of learning (JoL) are often used in memory research as a means for assessing an individual's metacognitive beliefs about their learning. JoL have been shown to reliably predict performance as well as learning behaviours and decisions . Participants may, however, modify their behaviour in response to performing JoL. There has, however, been little consensus as to the reliability and direction of the effect. We report on a meta-analyses that assesses the evidence that memory performance is reactive to JoL. The results indicate that overall providing JoL does not have a significant effect on memory performance (g = 0.054, 95% CI -0.027 to 0.135). However, sub-groups analysis showed that this effect depends on the nature of the stimuli to be recalled, with moderate positive reactivity observed for related word pairs (g = 0.323, 95% CI 0.083 to 0.563) and word lists (g = 0.384, 95% CI 0.146 to 0.622) but no reactivity when pairs were unrelated or a mixture of related and unrelated pairs. These results indicate that researchers should be aware that eliciting JoL may well influence participants' underlying encoding processes, especially when using related word pairs or word lists. PMID- 29161972 TI - Impacts of Initial Transformation to a Patient-Centered Medical Home on Diabetes Outcomes in Federally Qualified Health Centers in Florida. AB - OBJECTIVE: Federally qualified health centers (FQHCs) in Florida see large numbers of vulnerable patients with diabetes. Patient-centered medical home (PCMH) models can lead to improvements in health for patients with chronic conditions and cost savings for providers. Therefore, FQHCs are increasingly moving to PCMH models of care. The study objective was to examine the effects of initial transformation to a level 3 National Committee for Quality Assurance (NCQA) certified PCMH in 2011, on clinical diabetes outcomes among 27 clinic sites from a network of FQHCs in Florida. METHODS: We used de-identified, longitudinal electronic health record (EHR) data from 2010-2012 and multivariate logistic regression to analyze the effects of initial transformation on the odds of having well-controlled HbA1c, body mass index (BMI), and blood pressure (BP) among vulnerable patients with diabetes. Models controlled for clustering by year, patient, and organizational characteristics. RESULTS: Overall, transformation to a PCMH was associated with 19% greater odds of having well controlled HbA1c values with no statistically significant impact on BMI or BP. Subanalyses showed transformation had less of an effect on BP for African American patients and HbA1c control for Medicare enrollees but a greater effect on weight control for patients older than 35 years. CONCLUSION: Transformation to a PCMH in FQHCs appears to improve the health of vulnerable patients with diabetes, with less improvement for subsets of patients. Future research should seek to understand the heterogeneous effects of patient-centered transformation on various subgroups. PMID- 29161974 TI - The Oncology Family App: Providing Information and Support for Families Caring for Their Child With Cancer. AB - The Oncology Family App supports families across the vast state of Queensland, Australia, with easy access to vital information, including management plans for a deteriorating child, patient specific information and other resources. This article describes the development and evaluation of this mobile app. The app was developed and tested in collaboration with parents, caregivers, and clinicians and released in November 2015. This first version featured "Statewide Hospital Contacts," including phone numbers, links to Google maps, and 24-hour emergency contacts with click to call functionality; "When to Call" describing symptoms to look out for in a deteriorating child; "Blood Results Table"; and "Information" listing recommended websites, health care team contacts, appointments, and notes. The app was evaluated through interviews with parents, caregivers and patients and download metrics. Six months after the app release, 68% of the 38 parents and caregivers surveyed had downloaded the app. The most used modules were "Blood Results Table," "When to Call," and "Statewide Hospital Contacts," but families reported using all features available. Families were enthusiastic about the support the app provided and gave useful feedback to direct future development. Using mobile health technology to support families is a novel, but rapidly growing concept. Family and caregiver feedback showed that the Oncology Family App was an efficient and convenient way to provide much needed information. A new version of the app is under development and evaluation of outcomes will be ongoing. PMID- 29161975 TI - A Gene selection approach based on the fisher linear discriminant and the neighborhood rough set. AB - In recent years, tumor classification based on gene expression profiles has drawn great attention, and related research results have been widely applied to the clinical diagnosis of major gene diseases. These studies are of tremendous importance for accurate cancer diagnosis and subtype recognition. However, the microarray data of gene expression profiles have small samples, high dimensionality, large noise and data redundancy. To further improve the classification performance of microarray data, a gene selection approach based on the Fisher linear discriminant (FLD) and the neighborhood rough set (NRS) is proposed. First, the FLD method is employed to reduce the preliminarily genetic data to obtain features with a strong classification ability, which can form a candidate gene subset. Then, neighborhood precision and neighborhood roughness are defined in a neighborhood decision system, and the calculation approaches for neighborhood dependency and the significance of an attribute are given. A reduction model of neighborhood decision systems is presented. Thus, a gene selection algorithm based on FLD and NRS is proposed. Finally, four public gene datasets are used in the simulation experiments. Experimental results under the SVM classifier demonstrate that the proposed algorithm is effective, and it can select a smaller and more well-classified gene subset, as well as obtain better classification performance. PMID- 29161976 TI - A new approach for the determination of ECAP thresholds. AB - BACKGROUND: Electrically evoked compound action potentials (ECAPs) of the auditory nerve are routinely recorded for testing the cochlear implant integrity and its functional connection to the auditory system. The response thresholds derived from ECAP recordings are widely used as a helpful guide in the fitting of the dynamic range of electric stimulation, although they may not always predict the behavioral thresholds of individuals well. Conventionally, this threshold is based on the identification of a minimum N peak and maximum P peak and linear extrapolation of the resulting amplitude growth function (AGF). As an alternative, a new procedure involving numeric signal processing and requiring less user intervention is presented here. Data acquisition: In 12 adults implanted with MED-EL FLEX28 electrodes, two series of ECAPs were recorded immediately after implantation: (i) a full profile involving all 12 channels across the whole stimulus range in steps of 200 current units and (ii) a high resolution section (20 records in the immediate neighborhood of the threshold) of the AGF in one selected channel. Data treatment: It was observed that N and P wave latencies do not depend on stimulus intensity. Fixed time windows were hence defined for stimulus plus noise and noise alone regions. In these windows, the variance of the compound signal representing response and noise is extracted, whereas the noise variance is extracted from the tail of the curve following this time window. The base line is corrected by fitting an exponential function to reduce stimulus or amplifier artifacts. The response threshold is then derived from the response to noise ratio which should exceed the limit of 6 dB. RESULTS: The ECAP thresholds obtained from the new procedure coincide well with those determined by the conventional linear extrapolation of the AGF and they correlate to a greater degree with psychometric thresholds than the existing approach. CONCLUSIONS: The new ECAP algorithm looks promising and may reduce the need for user intervention in determining thresholds. PMID- 29161977 TI - Coordinated Care Organizations: Neonatal and Infant Outcomes in Oregon. AB - In 2012, Oregon's Medicaid program implemented a comprehensive accountable care model delivered through coordinated care organizations (CCOs). Because CCOs are expected to improve utilization of services and health outcomes, neonatal and infant outcomes may be important indicators of their impact. Estimating difference-in-differences models, we compared prepost CCO changes in outcomes (e.g., low birth weight, abnormal conditions, 5-minute Apgar score, congenital anomalies, and infant mortality) between Medicaid and non-Medicaid births among 99,924 infants born in Oregon during 2011 and 2013. We further examined differences in the impact of CCOs by ethnicity and rurality. Following CCO implementation the likelihood of low birth weight and abnormal conditions decreased by 0.95% and 1.08%, a reduction of 13.4% and 10.4% compared with the pre-CCO level for Medicaid enrollees, respectively. These reductions could be predictive of lifelong health benefits for infants and lower costs for acute care and are, therefore, important markers of success for the CCO model. PMID- 29161978 TI - School Nurse Perceptions of Nurse-Family Relationships in the Care of Elementary Students With Chronic Conditions. AB - The purpose of this study was to explore school nurse perceptions of the nurse family relationship in the care of elementary students with asthma and attention deficit hyperactivity disorder (ADHD). A cross-sectional survey design was used to collect data from 97 school nurses in Minnesota. The Family Nursing Practice Scale measured nurses' perceptions of their family nursing practice. Bivariate analyses were conducted to compare scores by factors at the community, school, nurse, and child levels. Results suggest that school nurses have positive appraisals of their family nursing practice, though scores were generally lower in the context of ADHD compared to asthma. Participants with a graduate degree reported greater skill in working with families, whereas novice nurses reported less confidence working with families and less comfort initiating family involvement in care. Results suggest that interventions at the nurse and school levels may support enhanced family nursing practice by nurses caring for students with chronic conditions. PMID- 29161979 TI - Clinical Characteristics of Intravenous PEG-Asparaginase Hypersensitivity Reactions in Patients Undergoing Treatment for Acute Lymphoblastic Leukemia [Formula: see text]. AB - BACKGROUND: Asparaginase poses a substantial risk for hypersensitivity reactions during and after administration; however, these reactions vary by asparaginase formulation and administration route. It is imperative that nurses be knowledgeable of clinical symptoms associated with intravenous (IV) monomethoxypolyethylene glycol (PEG)-asparaginase reactions, as well as potential reaction timing. PURPOSE: This single institution retrospective study describes the clinical factors among patients with IV PEG-asparaginase hypersensitivity reactions. METHODS: Reaction frequency and severity, dose, phase of treatment, and time between infusion initiation and reaction were collected on patients identified as having an IV PEG-asparaginase hypersensitivity reaction while undergoing acute lymphoblastic leukemia treatment. RESULTS: Sixty-three patients (12.8%) developed a hypersensitivity reaction to IV PEG-asparaginase, with the reaction occurring during a median of 3 doses in both risk arms. Reactions were noted <=60 minutes after infusion initiation in 98% of patients, and no reactions were fatal. CONCLUSION: Nurses should carefully observe patients throughout the infusion and anticipate adverse reactions, particularly during the first 3 doses and first 10 minutes of each infusion. Patient and family education should include the rare risk of delayed reactions. PMID- 29161980 TI - Prognostic impact of CD200 and CD56 expression in adult acute lymphoblastic leukemia patients. AB - BACKGROUND: The aim of the study is to determine the prognostic relevance of CD200/ CD56 expression in adult acute lymphoblastic leukemia patients. METHODS: The expression of CD200 and CD56 by blast cells was assessed by flow cytometry before the start of chemotherapy in 70 B-ALL patients. RESULTS: Positive expression of CD200 was detected in forty-six patients (66%) and CD56 was detected in 7 patients (10%) out of 70 patients, respectively. Only three patients (4.3%) had co-expression for CD200+ and CD56+. Splenomegaly and thrombocytopenia were frequently observed more in CD200+ patients. Increased frequency of CD34+ was associated with CD200+and CD56+ patients. The CD200+ and CD56+ subgroups of B-ALL patients had inferior OS and disease free survival compared to CD 200- and CD 56- patients. CONCLUSIONS: CD200+ and/or CD56+ positive expression in B-ALL patients at diagnosis is a poor prognostic biomarker. Identification of CD200+ and CD56+ expression at diagnosis is recommended for a better stratification of adult B-ALL patients. PMID- 29161981 TI - Presenting symptoms and clinical findings in HPV-positive and HPV-negative oropharyngeal cancer patients. AB - OBJECTIVES: Oropharyngeal squamous cell carcinoma (OPSCC) is divided in two different disease entities depending on HPV involvement. We investigated differences in presenting symptoms and clinical findings in patients with HPV positive and -negative OPSCC tumors. METHODS: Altogether 118 consecutive patients diagnosed with primary OPSCC between 2012 and 2014 at the Helsinki University Hospital were included. HPV-status of the tumors was assessed by PCR detection of HPV DNA and immunostaining with p16-INK4a antibody. RESULTS: Fifty-one (47.7%) of the patients had HPV-positive and 56 (52.3%) HPV-negative tumors. Forty-nine (49/51, 96.1%) of the HPV+ tumors were also p16+ showing high concordance. The most common presenting symptom among HPV+/p16+ patients was a neck mass (53.1%), whereas any sort of pain in the head and neck area was more frequently related to the HPV-/p16- (60.0%) group. HPV+/p16+ tumors had a tendency to locate in the tonsillar complex and more likely had already spread into regional lymph nodes compared with HPV-/p16- tumors. Smoking and heavy alcohol consumption were significantly more common among HPV-/p16- patients but also rather common among HPV+/p16+ patients [corrected]. CONCLUSIONS: This analysis of symptoms and signs confirm that OPSCC can be dichotomized in two distinct disease entities as defined by HPV status. PMID- 29161983 TI - Ammonium removal from aqueous solutions by fixed-bed column using corncob-based modified biochar. AB - This study investigated the potential of removing ammonium ([Formula: see text]) from aqueous solutions using corncob based on modified biochar (MBCC) in the fixed-bed column. Corncob biochar was soaked in a mixture of HNO3 6.0 M and NaOH 0.3 M to prepare active binding sites for ammonium removal. The effect of initial ammonium concentrations (10-40 mg/L), flow rates (1-9 mL/min) and MBCC fixed-bed heights (8-24 cm) on the breakthrough characteristics of the adsorption system were studied. The results showed that the highest adsorption capacity of fix-bed column, the breakthrough time and value of Ct/Co were 12.83 mg/g, 480 min and 0.862 +/- 0.025 at 10 mg/L of initial ammonium concentration, 8 cm of MBCC fixed bed height and 3 mL/min of flow rate, respectively. The breakthrough curve model in this study also indicated that all Yoon-Nelson, Thomas and Adam-Bohart models well fit with the experimental data with a high R2. The results also proved that MBCC can be used as a potential adsorbent for eliminating [Formula: see text] in the fixed-bed column. The saturated MBCC was also regenerated and reused consecutively for four cycles. The usage of mixture of NaOH and NaCl in recovering MBCC was better than NaCl only. PMID- 29161982 TI - The Effects of Musical Training on Speech Detection in the Presence of Informational and Energetic Masking. AB - Recent research has suggested that musicians have an advantage in some speech-in noise paradigms, but not all. Whether musicians outperform nonmusicians on a given speech-in-noise task may well depend on the type of noise involved. To date, few groups have specifically studied the role that informational masking plays in the observation of a musician advantage. The current study investigated the effect of musicianship on listeners' ability to overcome informational versus energetic masking of speech. Monosyllabic words were presented in four conditions that created similar energetic masking but either high or low informational masking. Two of these conditions used noise-vocoded target and masking stimuli to determine whether the absence of natural fine structure and spectral variations influenced any musician advantage. Forty young normal-hearing listeners (20 musicians and 20 nonmusicians) completed the study. There was a significant overall effect of participant group collapsing across the four conditions; however, planned comparisons showed musicians' thresholds were only significantly better in the high informational masking natural speech condition, where the musician advantage was approximately 3 dB. These results add to the mounting evidence that informational masking plays a role in the presence and amount of musician benefit. PMID- 29161984 TI - The prognostic value of physiological and physical characteristics in youth soccer: A systematic review. AB - Talent identification and selection in soccer is typically based on subjective evaluations of experienced coaches. Recently, there has been a trend to complement these subjective assessments with objective tests. However, there is currently no comprehensive overview of the prognostic relevance of objective measurements in youth soccer. Therefore, the primary purpose of the current study was to systematically review published empirical studies related to the prognostic relevance of physiological (e.g. endurance and speed) and physical characteristics (i.e. height and weight). Of 6876 initially identified studies, nine articles were included. In those studies, endurance (nine studies), change of direction (seven), height (seven), and weight (seven) received the most meaningful consideration within the literature. In regard to physiological predictors, between 16 and 29 effect sizes were tested for endurance, sprint, and change of direction, and about half of them were found to be significant with small to moderate effects (0.37 <= Mdn(d) <= 0.57). In addition, while only investigated in two studies all tested effect sizes for repeated sprint ability were found to be significant. Despite their frequent consideration in the literature, low numbers of significant effect sizes (<= 26%) and magnitude (0.23 <= Mdn(d) <= 0.29) were found for the physical predictors height and weight. Overall, results appear to be dependent on the respective study design and, in particular, moderator variables (i.e. soccer development stage, performance level T1/T2, prognostic period, and sample size). Consequently, additional research seems warranted to more comprehensively investigate the predictive relevance of the individual characteristics using more homogeneous study designs. PMID- 29161985 TI - Fatty acid profile from immobilised Chlorella vulgaris cells in different matrices. AB - The immobilisation of Chlorella vulgaris 211/11B entrapped in combinations of natural matrices to simplify the harvesting process was demonstrated in this study. Three combinations of matrices composed of calcium alginate (CA) and sodium alginate (SA), sodium carboxymethyl cellulose (CMC) and SA, and mixed matrices (SA, CA, and CMC) were investigated. The number of cells grown for each immobilised matrix to microalgae volume ratios (0.2:1-1:1) were explored and compared with using SA solely as a control. The optimum volume ratios obtained were 1:1 for SA, 0.3:1 for CA and SA, 1:1 for CMC and SA, and 0.3:1 for mixed matrices. The immobilised microalgae of mixed matrices exhibited the highest number of cells with 1.72 * 109 cells/mL at day 10 and 30.43% of oil extraction yield followed by CA and SA (24.29%), CMC and SA (13.00%), and SA (6.71%). Combining SA, CA, and CMC had formed a suitable structure which improved the growth of C. vulgaris and increased the lipid production compared to the immobilisation using single matrix. Besides, the fatty acids profile of the oil extracted indicates a high potential for biodiesel production. PMID- 29161986 TI - Real-World Experience with Targeted Therapy for the Treatment of Anaplastic Thyroid Carcinoma. AB - BACKGROUND: Patients with anaplastic thyroid cancer (ATC) have a dismal prognosis, despite systemic cytotoxic chemotherapy. The objective of this study was to investigate the efficacy and safety of targeted therapy in ATC patients when used outside of a clinical trial. METHODS: This is a retrospective review from April 2015 to May 2016 at a single academic institution where 16 ATC patients receiving targeted therapy outside of a clinical trial were studied. Ten patients (eight BRAF wild type and two BRAFV600E mutant tumors) were started on lenvatinib, and six with BRAFV600E-mutated tumors received a combination of dabrafenib plus trametinib. Best response evaluated by RECIST v1.1, progression free survival, and overall survival were determined. Adverse events were evaluated for safety. RESULTS: The majority of patients (63%) were men, and all had distant metastases or radiation-resistant primary disease at the time of treatment. In the entire cohort, 6/16 (38%) had a partial response, 6/16 (38%) had stable disease, and 2/16 (12%) had progressive disease. Two (12%) patients died before restaging. Median follow-up time was 11.8 months. Median progression free survival was 3.7 months [confidence interval 1.8-7.6] in the entire cohort, 2.7 months for lenvatinib, and 5.2 months for dabrafenib plus trametinib. Median OS was 6.3 months [confidence interval 1.8-7.6] for the entire cohort, 3.9 months for lenvatinib, and 9.3 months for dabrafenib plus trametinib. Adverse events were as expected and manageable. CONCLUSIONS: Targeted therapies, lenvatinib, and dabrafenib plus trametinib (for BRAFV600E mutants) may provide clinical benefit in ATC patients who are unable to participate in clinical trials, and toxicities are manageable. PMID- 29161987 TI - Encoding a Melody Using Only Temporal Information for Cochlear-Implant and Normal Hearing Listeners. AB - One way to provide pitch information to cochlear implant users is through amplitude-modulation rate. It is currently unknown whether amplitude-modulation rate can provide cochlear implant users with pitch information adequate for perceiving melodic information. In the present study, the notes of a song were encoded via amplitude-modulation rate of pulse trains on single electrodes at the apex or middle of long electrode arrays. The melody of the song was either physically correct or modified by compression or expansion. Nine cochlear implant users rated the extent to which the song was out of tune in the different conditions. Cochlear implant users on average did not show sensitivity to melody compression or expansion regardless of place of stimulation. These results were found despite the fact that three of the cochlear implant users showed the expected sensitivity to melody compression and expansion with the same task using acoustic pure tones in a contralateral acoustic ear. Normal-hearing listeners showed an inconsistent and weak effect of melody compression and expansion when the notes of the song were encoded with acoustic pulse rate. The results suggest that amplitude-modulation rate provides insufficient access to melodic information for cochlear-implant and normal-hearing listeners. PMID- 29161988 TI - Improved cognitive performance in preadolescent Danish children after the school based physical activity programme "FIFA 11 for Health" for Europe - A cluster randomised controlled trial. AB - OBJECTIVE: Recent studies have shown promising effects of physical activity on cognitive function, but there is a need to investigate this link in real-life settings such as schools. Hence, the objective of the present pilot study was to investigate whether the school-based physical activity programme "FIFA 11 for Health" for Europe could improve cognitive performance in preadolescent Danish children. METHODS: The pilot study used an 11-week cluster-randomised intervention study design. School classes were randomly assigned to either a control group (CG) (n = 93 children, age = 11.8, s = 0.2 years), which performed the obligatory daily school-based physical activity (5 * 45 minutes per week); or an intervention group (IG) (n = 838 children, age = 11.9, s = 0.4 years), which substituted 2 * 45 minutes per week of the daily school physical activity with the "FIFA 11 for Health" for Europe programme. The programme combines small-sided football games, drills and health education. Cognitive performance was evaluated at baseline and follow-up. RESULTS: The IG improved their cognitive performance compared to the CG for psychomotor function (56, sx- = 22 ms, p < .001), attention (39, sx- = 17 ms, p = .012) and working memory (79, sx- = 35 ms, p = .020). CONCLUSION: This pilot study provides evidence that the school-based physical activity programme "FIFA 11 for Health" for Europe can improve cognitive performance in preadolescent Danish schoolchildren. Future studies should attempt to disentangle the effects of "FIFA 11 for Health" for Europe on cognitive performance by investigating the characteristics of the programme's physical activity. PMID- 29161990 TI - Efficient phenol removal from petrochemical wastewater using biochar La/ultrasonic/persulphate system: characteristics, reusability, and kinetic study. AB - This research has analysed the physiochemical properties of a catalyst that has been developed - biochar-La, including BJH, BET, EDX, SEM, FTIR, pHpzc, and iodine number. The catalyst consisted of effective functional groups, including C=S, C-O, C=C, -COOH and O-H, with a specific surface area of 31.2 m2/g. The catalyst was used in the biochar-La/ultrasonic/persulphate system to remove phenol from wastewater. The kinetics, mechanism, and reusability of the catalyst for the phenol removal from synthetic wastewater were determined. The results suggested that phenol removal kinetics follows pseudo-first-order model (k = 0.0386 1/min), and the catalyst can be reused three times. The potential of operation of the biochar-La/ultrasonic/persulphate system - with the effective removal of phenol and other organic compounds from real petrochemical wastewater was tested. The results indicated that the removal of phenol from the petrochemical wastewater with a relatively high total dissolved solid is >99%. The gas chromatography-mass spectrometry (GC-mass) test revealed that the complete decomposition of some contaminants in the petrochemical wastewater had occurred, as H2O and CO2 were detected. The contribution of a heterogeneous mechanism for phenol oxidation by biochar-La/ultrasonic/persulphate was calculated to be 60%. Overall, the results showed that the biochar La/ultrasonic/persulphate system is very effective and promising for the removal of phenol from the petrochemical wastewater. PMID- 29161989 TI - Comparison of Toxicity and Recovery in the Duodenum of B6C3F1 Mice Following Treatment with Intestinal Carcinogens Captan, Folpet, and Hexavalent Chromium. AB - High concentrations of hexavalent chromium (Cr(VI)), captan, and folpet induce duodenal tumors in mice. Using standardized tissue collection procedures and diagnostic criteria, we compared the duodenal histopathology in B6C3F1 mice following exposure to these 3 carcinogens to determine whether they share similar histopathological characteristics. B6C3F1 mice ( n = 20 per group) were exposed to 180 ppm Cr(VI) in drinking water, 12,000 ppm captan in feed, or 16,000 ppm folpet in feed for 28 days. After 28 days of exposure, villous enterocyte hypertrophy and mild crypt epithelial hyperplasia were observed in all exposed mice. In a subset of mice allowed to recover for 28 days, duodenal samples were generally indistinguishable from those of unexposed mice. Changes in the villi and lack of observable damage to the crypt compartment suggest that toxicity was mediated in the villi, which is consistent with earlier studies on each chemical. These findings indicate that structurally diverse agents can induce similar (and reversible) phenotypic changes in the duodenum. These intestinal carcinogens likely converge on common pathways involving irritation and wounding of the villi leading to crypt regenerative hyperplasia that, under protracted high-dose exposure scenarios, increases the risk of spontaneous mutation and tumorigenesis. PMID- 29161991 TI - Simple and innovative method of removal of unfavourable root: technical note. AB - Extraction of teeth is one of the most commonly performed minor oral surgical procedures. However, some clinical situations render routine extractions challenging. Here we report such a situation and a simple and innovative technique that involves the use of braided stainless steel wire to remove an unfavorable palatally inclined left upper lateral incisor with least damage to adjacent structures. PMID- 29161992 TI - Stenotrophomonas maltophilia causing blood stream infection in neonates and infants: a cause for concern. AB - Stenotrophomonas maltophilia ( S. maltophilia) is an important Gram-negative, non fermentative, multidrug resistant (MDR) nosocomial organism. We evaluated the isolation of S. maltophilia from the seven blood culture specimens received from the Paediatric Emergency Department (PED) of BP Koirala Institute of Health Sciences (BPKIHS) over the duration of two weeks. The suspicion of a possible outbreak was raised and the hospital infection control team investigated the source and found the hand of one healthcare provider harbouring a similar organism. All six steps of hand hygiene were subsequently strictly enforced after which the same bacteria were no longer isolated. Infection control measures should be rigorously adopted for the control of such nosocomial bacteria. PMID- 29161994 TI - Synthesis, characterization and application of biodegradable polymer grafted novel bioprosthetic tissue. AB - Animal tissue has an extended history of clinical use in applications like heart valve bioprosthesis devices, cardiovascular surgical applications etc. but often does not last long after implantation in the body due to rapid unwanted degradation. The goal of this work is to develop novel composite biomaterials by grafting biological tissue with synthetic, biodegradable polymers. In the current research phase, porcine submucosa, ureter and bovine pericardial tissue are grafted with poly DL-lactide (PLA), poly glycolide (PGA) and poly DL-lactide glycolide (PLGA) copolymers. The grafted and control tissues are characterized by FTIR and SEM. The biodegradability of the tissue-graft composite materials is determined by pepsin and collagenase digestion assays, showing it can be tailored by varying the grafted polymer type and amount. The grafted tissues can be tuned for a particular clinical or tissue engineering applications including drug delivery with little or no burst release and sustained/controlled delivery. PMID- 29161993 TI - Burden of asymptomatic malaria, anemia and relationship with cotrimoxazole use and CD4 cell count among HIV1-infected adults living in Gabon, Central Africa. AB - : Objective : This study determined the prevalence of asymptomatic Plasmodium (P.) falciparum infection and anemia in adults living with HIV/AIDS (PLHIV) and compared malaria prevalence between 858 HIV-infected (PLHIV) and 272 uninfected individuals in Gabon where such information are lacking. Factors influencing malaria and anemia were also investigated. PATIENTS AND METHODS: Participants were screened for malaria. Available hemoglobin level, socio-demographic and use of prevention or treatment data were compared between both groups. RESULTS: The prevalence of asymptomatic parasitemia was 13.5%, lower in PLHIV (7.1%) than uninfected individuals (33.8%) (p<0.01). Among the PLHIV, females (p<0.01), those aged below 25 years old (p=0.03), those with primary education (p=0.03) and those with a CD4 cell count below 200/mm3 (p=0.03) had a higher median parasitemia. Cotrimoxazole use was associated with a lower prevalence of malaria (p<0.01). Age below 25 years was independently associated with malaria in PLHIV (p<0.01). Anemia prevalence was 42.1% among the PLHIV, higher in the youngest and those with low CD4 cell count (p<0.01). P.falciparum-infected PLHIV aged below 25 years old, not under ART, with low CD4 cell count and under cotrimoxazole had the lowest median hemoglobin level. CONCLUSION: The prevalence of asymptomatic malaria is low among the PLHIV while the burden of anemia is considerable. Age below 25 years and CD4 cell count are associated factors. The cotrimoxazole use reduces the frequency of malaria. PMID- 29161995 TI - Carbon capture from natural gas using multi-walled CNTs based mixed matrix membranes. AB - Most of the polymers and their blends, utilized in carbon capture membranes, are costly, but cellulose acetate (CA) being inexpensive is a lucrative choice. In this research, pure and mixed matrix membranes (MMMs) have been fabricated to capture carbon from natural gas. Polyethylene glycol (PEG) has been utilized in the fabrication of membranes to modify the chain flexibility of polymers. Multi walled carbon nanotubes (MWCNTs) provide mechanical strength, thermal stability, an extra free path for CO2 molecules and augment CO2/CH4 selectivity. Membranes of pure CA, CA/PEG blend of different PEG concentrations (5%, 10%, 15%) and CA/PEG/MWCNTs blend of 10% PEG with different MWCNTs concentrations (5%, 10%, 15%) were prepared in acetone using solution casting techniques. Fabricated membranes were characterized using SEM, TGA and tensile testing. Permeation results revealed remarkable improvement in CO2/CH4 selectivity. In single gas experiments, CO2/CH4 selectivity is enhanced 8 times for pure membranes containing 10% PEG and 14 times for MMMs containing 10% MWCNTs. In mix gas experiments, the CO2/CH4 selectivity is increased 13 times for 10% PEG and 18 times for MMMs with 10% MWCNTs. Fabricated MMMs have a tensile strength of 13 MPa and are more thermally stable than CA membranes. PMID- 29161996 TI - Computational screening of fatty acid synthase inhibitors against thioesterase domain. AB - Thioesterase (TE) domain of fatty acid synthase (FAS) is an attractive therapeutic target for design and development of anticancer drugs. In this present work, we search for the potential FAS inhibitors of TE domain from the ZINC database based on similarity search using three natural compounds as templates, including flavonoids, terpenoids, and phenylpropanoids. Molecular docking was used to predict the interaction energy of each screened ligand compared to the reference compound, which is methyl gamma linolenylfluorophosphonate (MGLFP). Based on this computational technique, rosmarinic acid and its eight analogs were observed as a new series of potential FAS inhibitors, which showed a stronger binding affinity than MGLFP. Afterward, nine docked complexes were studied by molecular dynamics simulations for investigating protein-ligand interactions and binding free energies using MM PB(GB)SA, MM-3DRISM-KH, and QM/MM-GBSA methods. The binding free energy calculation indicated that the ZINC85948835 (R34) displayed the strongest binding efficiency against the TE domain of FAS. There are eight residues (S2308, I2250, E2251, Y2347, Y2351, F2370, L2427, and E2431) mainly contributed for the R34 binding. Moreover, R34 could directly form hydrogen bonds with S2308, which is one of the catalytic triad of TE domain. Therefore, our finding suggested that R34 could be a potential candidate as a novel FAS-TE inhibitor for further drug design. PMID- 29161997 TI - Controlling the extrudate swell in melt extrusion additive manufacturing of 3D scaffolds: a designed experiment. AB - Tissue engineering using three-dimensional porous scaffolds has shown promise for the restoration of normal function in injured and diseased tissues and organs. Rigorous control over scaffold architecture in melt extrusion additive manufacturing is highly restricted mainly due to pronounced variations in the deposited strand diameter upon any variations in process conditions and polymer viscoelasticity. We have designed an I-optimal, split-plot experiment to study the extrudate swell in melt extrusion additive manufacturing and to control the scaffold architecture. The designed experiment was used to generate data to relate three responses (swell, density, and modulus) to a set of controllable factors (plotting needle diameter, temperature, pressure, and the dispensing speed). The fitted regression relationships were used to optimize the three responses simultaneously. The swell response was constrained to be close to 1 while maximizing the modulus and minimizing the density. Constraining the extrudate swell to 1 generates design-driven scaffolds, with strand diameters equal to the plotting needle diameter, and allows a greater control over scaffold pore size. Hence, the modulus of the scaffolds can be fully controlled by adjusting the in-plane distance between the deposited strands. To the extent of the model's validity, we can eliminate the effect of extrudate swell in designing these scaffolds, while targeting a range of porosity and modulus appropriate for bone tissue engineering. The result of this optimization was a predicted modulus of 14 MPa and a predicted density of 0.29 g/cm3 (porosity ~ 75%) using polycaprolactone as scaffold material. These predicted responses corresponded to factor levels of 0.6 MUm for the plotting needle diameter, plotting pressure of 2.5 bar, melt temperature of 113.5 degrees C, and dispensing speed of 2 mm/s. The validation scaffold enabled us to quantify the percentage difference for the predictions, which was 9.5% for the extrudate swell, 19% for the density, and 29% for the modulus. PMID- 29161999 TI - Zero waste bio-refineries: The example of Brazilian pulp and paper sector. PMID- 29161998 TI - Cognitive rehabilitation for individuals with opioid use disorder: A randomized controlled trial. AB - AIM: To examine the efficacy of cognitive rehabilitation treatment (CRT) for people with opioid use disorder who were recruited into a methadone maintenance treatment (MMT) programme. METHOD: 120 male subjects were randomly assigned to (1) MMT plus CRT in two months or (2) MMT plus a control intervention. Subjects were assessed at the beginning, mid-point and post-intervention as well as at 1-, 3- and 6-month follow-up time points. RESULTS: Analysis with repeated measure ANOVA showed that the CRT group performed significantly better in tests of learning, switching, processing speed, working memory and memory span. Moreover, the CRT group had significantly lower opiate use over the control group during 3 months follow-up. Analysis including only those with a history of methamphetamine use showed that the CRT group had significantly lower amphetamine use. No group differences were observed for treatment retention. CONCLUSIONS: Our findings provide evidence that adding CRT as an adjunct intervention to MMT can improve cognitive performance as well as abstinence from both opiates and stimulants. PMID- 29162000 TI - Recycling possibilities for reducing waste from cutters on combined cutter loaders and road builders. AB - The objective of this study was to find opportunities for metal waste recycling in the process of rock breaking in mines. A built-up cutter design for a combined cutter-loader and a recycling technique for a considerable portion of the deteriorated tool are suggested. Industrial tests have proven the possibility of a ten-fold increase in the use of cutters on mining machines for coal rock mass destruction. The proposed technique allows a four times reduction in metal consumption in the production and use of cutters and a reduction of the ultimate resulting waste by 80%. This advanced technique could be transferred extensively into such industries as open-cast mining, repair of motor-roads, construction and agriculture. PMID- 29162001 TI - A Single, Continuously Applied Control Policy for Modeling Reaching Movements with and without Perturbation. AB - It has been debated whether kinematic features, such as the number of peaks or decomposed submovements in a velocity profile, indicate the number of discrete motor impulses or result from a continuous control process. The debate is particularly relevant for tasks involving target perturbation, which can alter movement kinematics. To simulate such tasks, finite-horizon models require two preset movement durations to compute two control policies before and after the perturbation. Another model employs infinite- and finite-horizon formulations to determine, respectively, movement durations and control policies, which are updated every time step. We adopted an infinite-horizon optimal feedback control model that, unlike previous approaches, does not preset movement durations or use multiple control policies. It contains both control-dependent and independent noises in system dynamics, state-dependent and independent noises in sensory feedbacks, and different delays and noise levels for visual and proprioceptive feedbacks. We analytically derived an optimal solution that can be applied continuously to move an effector toward a target regardless of whether, when, or where the target jumps. This single policy produces different numbers of peaks and "submovements" in velocity profiles for different conditions and trials. Movements that are slower or perturbed later appear to have more submovements. The model is also consistent with the observation that subjects can perform the perturbation task even without detecting the target jump or seeing their hands during reaching. Finally, because the model incorporates Weber's law via a state representation relative to the target, it explains why initial and terminal visual feedback are, respectively, less and more effective in improving end-point accuracy. Our work suggests that the number of peaks or submovements in a velocity profile does not necessarily reflect the number of motor impulses and that the difference between initial and terminal feedback does not necessarily imply a transition between open- and closed-loop strategies. PMID- 29162003 TI - Feedforward Approximations to Dynamic Recurrent Network Architectures. AB - Recurrent neural network architectures can have useful computational properties, with complex temporal dynamics and input-sensitive attractor states. However, evaluation of recurrent dynamic architectures requires solving systems of differential equations, and the number of evaluations required to determine their response to a given input can vary with the input or can be indeterminate altogether in the case of oscillations or instability. In feedforward networks, by contrast, only a single pass through the network is needed to determine the response to a given input. Modern machine learning systems are designed to operate efficiently on feedforward architectures. We hypothesized that two-layer feedforward architectures with simple, deterministic dynamics could approximate the responses of single-layer recurrent network architectures. By identifying the fixed-point responses of a given recurrent network, we trained two-layer networks to directly approximate the fixed-point response to a given input. These feedforward networks then embodied useful computations, including competitive interactions, information transformations, and noise rejection. Our approach was able to find useful approximations to recurrent networks, which can then be evaluated in linear and deterministic time complexity. PMID- 29162002 TI - Encoding Time in Feedforward Trajectories of a Recurrent Neural Network Model. AB - Brain activity evolves through time, creating trajectories of activity that underlie sensorimotor processing, behavior, and learning and memory. Therefore, understanding the temporal nature of neural dynamics is essential to understanding brain function and behavior. In vivo studies have demonstrated that sequential transient activation of neurons can encode time. However, it remains unclear whether these patterns emerge from feedforward network architectures or from recurrent networks and, furthermore, what role network structure plays in timing. We address these issues using a recurrent neural network (RNN) model with distinct populations of excitatory and inhibitory units. Consistent with experimental data, a single RNN could autonomously produce multiple functionally feedforward trajectories, thus potentially encoding multiple timed motor patterns lasting up to several seconds. Importantly, the model accounted for Weber's law, a hallmark of timing behavior. Analysis of network connectivity revealed that efficiency-a measure of network interconnectedness-decreased as the number of stored trajectories increased. Additionally, the balance of excitation (E) and inhibition (I) shifted toward excitation during each unit's activation time, generating the prediction that observed sequential activity relies on dynamic control of the E/I balance. Our results establish for the first time that the same RNN can generate multiple functionally feedforward patterns of activity as a result of dynamic shifts in the E/I balance imposed by the connectome of the RNN. We conclude that recurrent network architectures account for sequential neural activity, as well as for a fundamental signature of timing behavior: Weber's law. PMID- 29162004 TI - Sequence Classification Using Third-Order Moments. AB - Model-based classification of sequence data using a set of hidden Markov models is a well-known technique. The involved score function, which is often based on the class-conditional likelihood, can, however, be computationally demanding, especially for long data sequences. Inspired by recent theoretical advances in spectral learning of hidden Markov models, we propose a score function based on third-order moments. In particular, we propose to use the Kullback-Leibler divergence between theoretical and empirical third-order moments for classification of sequence data with discrete observations. The proposed method provides lower computational complexity at classification time than the usual likelihood-based methods. In order to demonstrate the properties of the proposed method, we perform classification of both simulated data and empirical data from a human activity recognition study. PMID- 29162005 TI - On Rhythms in Neuronal Networks with Recurrent Excitation. AB - We investigate rhythms in networks of neurons with recurrent excitation, that is, with excitatory cells exciting each other. Recurrent excitation can sustain activity even when the cells in the network are driven below threshold, too weak to fire on their own. This sort of "reverberating" activity is often thought to be the basis of working memory. Recurrent excitation can also lead to "runaway" transitions, sudden transitions to high-frequency firing; this may be related to epileptic seizures. Not all fundamental questions about these phenomena have been answered with clarity in the literature. We focus on three questions here: (1) How much recurrent excitation is needed to sustain reverberating activity? How does the answer depend on parameters? (2) Is there a positive minimum frequency of reverberating activity, a positive "onset frequency"? How does it depend on parameters? (3) When do runaway transitions occur? For reduced models, we give mathematical answers to these questions. We also examine computationally to which extent our findings are reflected in the behavior of biophysically more realistic model networks. Our main results can be summarized as follows. (1) Reverberating activity can be fueled by extremely weak slow recurrent excitation, but only by sufficiently strong fast recurrent excitation. (2) The onset of reverberating activity, as recurrent excitation is strengthened or external drive is raised, occurs at a positive frequency. It is faster when the external drive is weaker (and the recurrent excitation stronger). It is slower when the recurrent excitation has a longer decay time constant. (3) Runaway transitions occur only with fast, not with slow, recurrent excitation. We also demonstrate that the relation between reverberating activity fueled by recurrent excitation and runaway transitions can be visualized in an instructive way by a (generalized) cusp catastrophe surface. PMID- 29162006 TI - Sufficient Dimension Reduction via Direct Estimation of the Gradients of Logarithmic Conditional Densities. AB - Sufficient dimension reduction (SDR) is aimed at obtaining the low-rank projection matrix in the input space such that information about output data is maximally preserved. Among various approaches to SDR, a promising method is based on the eigendecomposition of the outer product of the gradient of the conditional density of output given input. In this letter, we propose a novel estimator of the gradient of the logarithmic conditional density that directly fits a linear in-parameter model to the true gradient under the squared loss. Thanks to this simple least-squares formulation, its solution can be computed efficiently in a closed form. Then we develop a new SDR method based on the proposed gradient estimator. We theoretically prove that the proposed gradient estimator, as well as the SDR solution obtained from it, achieves the optimal parametric convergence rate. Finally, we experimentally demonstrate that our SDR method compares favorably with existing approaches in both accuracy and computational efficiency on a variety of artificial and benchmark data sets. PMID- 29162007 TI - Joint Concept Correlation and Feature-Concept Relevance Learning for Multilabel Classification. AB - In recent years, multilabel classification has attracted significant attention in multimedia annotation. However, most of the multilabel classification methods focus only on the inherent correlations existing among multiple labels and concepts and ignore the relevance between features and the target concepts. To obtain more robust multilabel classification results, we propose a new multilabel classification method aiming to capture the correlations among multiple concepts by leveraging hypergraph that is proved to be beneficial for relational learning. Moreover, we consider mining feature-concept relevance, which is often overlooked by many multilabel learning algorithms. To better show the feature-concept relevance, we impose a sparsity constraint on the proposed method. We compare the proposed method with several other multilabel classification methods and evaluate the classification performance by mean average precision on several data sets. The experimental results show that the proposed method outperforms the state-of the-art methods. PMID- 29162008 TI - A Perceptual-Like Population-Coding Mechanism of Approximate Numerical Averaging. AB - Humans possess a remarkable ability to rapidly form coarse estimations of numerical averages. This ability is important for making decisions that are based on streams of numerical or value-based information, as well as for preference formation. Nonetheless, the mechanism underlying rapid approximate numerical averaging remains unknown, and several competing mechanism may account for it. Here, we tested the hypothesis that approximate numerical averaging relies on perceptual-like processes, instantiated by population coding. Participants were presented with rapid sequences of numerical values (four items per second) and were asked to convey the sequence average. We manipulated the sequences' length, variance, and mean magnitude and found that similar to perceptual averaging, the precision of the estimations improves with the length and deteriorates with (higher) variance or (higher) magnitude. To account for the results, we developed a biologically plausible population-coding model and showed that it is mathematically equivalent to a population vector. Using both quantitative and qualitative model comparison methods, we compared the population-coding model to several competing models, such as a step-by-step running average (based on leaky integration) and a midrange model. We found that the data support the population coding model. We conclude that humans' ability to rapidly form estimations of numerical averages has many properties of the perceptual (intuitive) system rather than the arithmetic, linguistic-based (analytic) system and that population coding is likely to be its underlying mechanism. PMID- 29162009 TI - Rank-Optimized Logistic Matrix Regression toward Improved Matrix Data Classification. AB - While existing logistic regression suffers from overfitting and often fails in considering structural information, we propose a novel matrix-based logistic regression to overcome the weakness. In the proposed method, 2D matrices are directly used to learn two groups of parameter vectors along each dimension without vectorization, which allows the proposed method to fully exploit the underlying structural information embedded inside the 2D matrices. Further, we add a joint [Formula: see text]-norm on two parameter matrices, which are organized by aligning each group of parameter vectors in columns. This added co regularization term has two roles-enhancing the effect of regularization and optimizing the rank during the learning process. With our proposed fast iterative solution, we carried out extensive experiments. The results show that in comparison to both the traditional tensor-based methods and the vector-based regression methods, our proposed solution achieves better performance for matrix data classifications. PMID- 29162010 TI - Statistics of Visual Responses to Image Object Stimuli from Primate AIT Neurons to DNN Neurons. AB - Under the goal-driven paradigm, Yamins et al. ( 2014 ; Yamins & DiCarlo, 2016 ) have shown that by optimizing only the final eight-way categorization performance of a four-layer hierarchical network, not only can its top output layer quantitatively predict IT neuron responses but its penultimate layer can also automatically predict V4 neuron responses. Currently, deep neural networks (DNNs) in the field of computer vision have reached image object categorization performance comparable to that of human beings on ImageNet, a data set that contains 1.3 million training images of 1000 categories. We explore whether the DNN neurons (units in DNNs) possess image object representational statistics similar to monkey IT neurons, particularly when the network becomes deeper and the number of image categories becomes larger, using VGG19, a typical and widely used deep network of 19 layers in the computer vision field. Following Lehky, Kiani, Esteky, and Tanaka ( 2011 , 2014 ), where the response statistics of 674 IT neurons to 806 image stimuli are analyzed using three measures (kurtosis, Pareto tail index, and intrinsic dimensionality), we investigate the three issues in this letter using the same three measures: (1) the similarities and differences of the neural response statistics between VGG19 and primate IT cortex, (2) the variation trends of the response statistics of VGG19 neurons at different layers from low to high, and (3) the variation trends of the response statistics of VGG19 neurons when the numbers of stimuli and neurons increase. We find that the response statistics on both single-neuron selectivity and population sparseness of VGG19 neurons are fundamentally different from those of IT neurons in most cases; by increasing the number of neurons in different layers and the number of stimuli, the response statistics of neurons at different layers from low to high do not substantially change; and the estimated intrinsic dimensionality values at the low convolutional layers of VGG19 are considerably larger than the value of approximately 100 reported for IT neurons in Lehky et al. ( 2014 ), whereas those at the high fully connected layers are close to or lower than 100. To the best of our knowledge, this work is the first attempt to analyze the response statistics of DNN neurons with respect to primate IT neurons in image object representation. PMID- 29162011 TI - Skeletal Muscle Injury Biomarkers: Assay Qualification Efforts and Translation to the Clinic. AB - Skeletal muscle (SKM) injury or myopathy results in structural or functional defects in SKMs that can be caused by variety of factors such as (1) genetic, (2) drug-induced, (3) disease progression (cachexia), or (4) aging (sarcopenia). Creatine kinase (CK) and aspartate transaminase (AST) activity assays have been routinely used as SKM injury biomarkers, but they lack sensitivity and tissue specificity. In collaboration with the Predictive Safety Testing Consortium, we evaluated the diagnostic performance of a muscle injury biomarker panel (MIP) compared to CK and AST and their correlation with the histology scores across 34 different rat studies. The MIP panel included the analytes skeletal troponin I, myosin light chain 3, fatty acid binding protein 3, and a CK mass (versus activity) assay. The area under the receiver operator characteristic curve for MIP panel ranged from 0.82 to 0.91 as compared to 0.71 and 0.82 for CK and AST activity assays, respectively. Because the MIP biomarkers outperformed the routine biomarkers, the European Medicines Agency and U.S. Food and Drug Administration posted Letters of Support encouraging further study of these analytes and acknowledged the utility of the MIP panel. Ongoing efforts are directed toward the application of the MIP panel biomarkers in clinical studies and regulatory qualification. PMID- 29162012 TI - Meeting Report: Tissue-based Image Analysis. AB - Quantitative image analysis (IA) is a rapidly evolving area of digital pathology. Although not a new concept, the quantification of histological features on photomicrographs used to be cumbersome, resource-intensive, and limited to specialists and specialized laboratories. Recent technological advances like highly efficient automated whole slide digitizer (scanner) systems, innovative IA platforms, and the emergence of pathologist-friendly image annotation and analysis systems mean that quantification of features on histological digital images will become increasingly prominent in pathologists' daily professional lives. The added value of quantitative IA in pathology includes confirmation of equivocal findings noted by a pathologist, increasing the sensitivity of feature detection, quantification of signal intensity, and improving efficiency. There is no denying that quantitative IA is part of the future of pathology; however, there are also several potential pitfalls when trying to estimate volumetric features from limited 2-dimensional sections. This continuing education session on quantitative IA offered a broad overview of the field; a hands-on toxicologic pathologist experience with IA principles, tools, and workflows; a discussion on how to apply basic stereology principles in order to minimize bias in IA; and finally, a reflection on the future of IA in the toxicologic pathology field. PMID- 29162013 TI - Closing the health gap. AB - One way of characterising the good society is one that has achieved a high degree of health equity. For a low-income country, one route to this achievement is to increase national income. But other features of society come to the fore, for low, middle and high-income societies alike. In England, my review of health inequalities highlighted: good early child development, education and life long learning, employment and working conditions, having enough income to lead a healthy life, healthy and sustainable places to live and work, taking a social determinants approach to prevention. Taking action on these requires commitment and cross-government action. PMID- 29162015 TI - Introducing Sir Michael Marmot as Dr Honoris Causas at the Norwegian University of Science and Technology (NTNU). PMID- 29162014 TI - Technological innovations and the rise of social inequalities in health. AB - Social inequalities in health have been categorised as a human-rights issue that requires action. Unfortunately, these inequalities are on the rise in many countries, including welfare states. Various theories have been offered to explain the persistence (and rise) of these inequalities over time, including the social determinants of health and fundamental cause theory. Interestingly, the rise of modern social inequalities in health has come at a time of great technological innovation. This article addresses whether these technological innovations are significantly influencing the persistence of modern social inequalities in health. A theoretical argument is offered for this potential connection and is discussed alongside the typical social determinants of health perspective and the increasingly popular fundamental cause perspective. This is followed by a proposed research agenda for further investigation of the potential role that technological innovations may play in influencing social inequalities in health. PMID- 29162016 TI - Can social epidemiology contribute to a better world? PMID- 29162017 TI - Public health educational comprehensiveness: The strategic rationale in establishing networks among schools of public health. AB - The establishment and continuing development of a sufficient and competent public health workforce is fundamental for the planning, implementation, evaluation, effect and ethical validity of public health strategies and policies and, thus, for the development of the population's health and the cost-effectiveness of health and public health systems and interventions. Professional public health strategy-making demands a background of a comprehensive multi-disciplinary curriculum including mutually, dynamically coherent competences - not least, competences in sociology and other behavioural sciences and their interaction with, for example, epidemiology, biostatistics, qualitative methods and health promotion and disease prevention. The size of schools and university departments of public health varies, and smaller entities may run into problems if seeking to meet the comprehensive curriculum challenge entirely by use of in-house resources. This commentary discusses the relevance and strength of establishing comprehensive curriculum development networks between schools and university departments of public health, as one means to meet the comprehensiveness challenge. This commentary attempts to consider a two-stage strategy to develop complete curricula at the bachelor and master's as well as PhD levels. PMID- 29162019 TI - The health gap: Doctors and the social determinants of health. AB - The social gradient in health has the clear implication that action to improve health and reduce inequalities has to take place at social level, not simply depending on individual changes. Individuals' ability to change is constrained by social circumstances. The evidence that the magnitude of the gradient varies between countries, and can change within a country over time, suggests that conscious strategies to change it can be successful. In my review of evidence in Britain, the Marmot Review, we made recommendations in six domains: give every child the best start in life; education and life-long learning; employment and working conditions; ensure that everyone has at least the minimum income necessary to lead a health life; healthy and sustainable places; taking a social determinants approach to prevention. A big question is the role of health professionals in action on social determinants of health. We have identified five actions in implementing recommendations: education and training; seeing the patient in broader perspective; the health service as employer; working in partnership; advocacy. The evidence is encouraging that health professionals can make a big difference in advancing the cause of health equity. PMID- 29162020 TI - Meeting Sir Michael Marmot - another 'Marmot Review'. PMID- 29162021 TI - Time-Motion Analysis of Nurses Utilizing Insulin Pen Devices Compared to Vial and Syringe in an Inpatient Setting. AB - OBJECTIVE: To compare the time taken and steps completed by nurses in the process of insulin preparation and administration using the pen device compared to the vial and syringe method. METHODS: Observational and exploratory study utilizing a time-motion analysis of nurses' administration of insulin using the pen versus vial and syringe delivery methods. Nurses were observed, video-recorded, and timed during insulin preparation and administration using each delivery method. The steps performed by nurses were observed against recommended processes for preparing and administering insulin, and the percentage of nurses completing each step was noted. RESULTS: A total of 137 (94%) nurses participated. Nurses took less time preparing and administering insulin with the pen device compared with the vial and syringe method (79 +/- 18 seconds vs 88 +/- 20 seconds, respectively, P < .001). The overall average completion rate of steps with the pen device was 90% +/- 7% compared to 88% +/- 7% with the vial and syringe method. CONCLUSION: The time taken by nurses to prepare and administer insulin was lower with the pen device compared with vial and syringe. Furthermore, areas were identified for potential nursing education to enhance safe and appropriate use of insulin with both delivery methods. PMID- 29162022 TI - Confronting the Challenge of Beta-Lactam Allergies: A Quasi-Experimental Study Assessing Impact of Pharmacy-Led Interventions. AB - OBJECTIVE: To improve allergy history documentation and increase the use of beta lactams when appropriate in patients with a reported beta-lactam allergy. METHODS: This pre-post study was conducted at a 167-bed tertiary care community hospital and evaluated multidisciplinary interventions on allergy documentation and antibiotic selection. Interventions included education, creation of local practice guidelines, and modified practices for pharmacists and pharmacy technicians. Inpatients with a reported beta-lactam allergy receiving at least 1 antibiotic for >24 hours were included; first admissions were assessed. Primary outcomes were documentation of reaction type and percentage of patients receiving non-beta-lactam therapy. Secondary outcomes included documentation of previously tolerated beta-lactams, modification of non-beta-lactam therapy, discharge antibiotics, and adverse reactions. RESULTS: A total of 179 patients were included, 91 preintervention and 88 postintervention. No significant differences were observed between the before versus after groups in the percentage of patients with documentation of reaction type (90.1% vs 89.8%, P = .940) or the overall percentage of patients receiving non-beta-lactams (86.8% vs 84.1%, P = .605). However, significantly more patients in the after phase had documentation of previously tolerated beta-lactams (8.8% vs 28.4%, P = .001), and among patients receiving a non-beta-lactam, a greater percentage was subsequently switched to a beta-lactam (11.4% vs 25.7%, P = .022). One allergic reaction was documented during the study, which occurred in the before phase. CONCLUSION: Multidisciplinary education and local guideline implementation led by pharmacists may improve allergy documentation and antibiotic selection in patients with reported beta-lactam allergies. PMID- 29162023 TI - Pentobarbital Removal During Continuous Venovenous Hemofiltration: Case Report and Review of the Literature. AB - BACKGROUND: Renal replacement therapy may enhance the elimination of barbiturates. Pentobarbital clearance during continuous venovenous hemofiltration (CVVH) has not been described previously. We report a patient case involving the measurement of serial pentobarbital levels during CVVH and review relevant literature characterizing extracorporeal pentobarbital elimination. METHODS: The following is a retrospective report of a previously healthy 26-year-old woman who sustained a severe traumatic brain injury (TBI) and required administration of pentobarbital on hospital day 0 for intracranial pressure (ICP) control. Given concern for interference with the patient's ongoing neurologic assessments, pentobarbital was discontinued on hospital day 4. The patient's hospital course was complicated by acute kidney injury (AKI), requiring initiation of CVVH on hospital day 5. Daily serum pentobarbital levels were obtained during CVVH. RESULTS: While on CVVH, the patient's estimated pentobarbital clearance ranged from 6 to 44 mL/min and the elimination half-life ranged from 17.7 to 65.9 hours. Based on reductions in pentobarbital clearance during CVVH interruption, the elimination of drug was dependent upon extracorporeal removal in this patient. CVVH facilitated pentobarbital elimination in a manner approaching endogenous clearance in healthy individuals. CONCLUSION: We report clinically significant pentobarbital removal by CVVH in a patient with severe TBI. Application of CVVH may expedite reliable neurologic assessments and facilitate the application of clinical brain death examination following pentobarbital exposure. PMID- 29162024 TI - Modern Fixed Imaging Systems Reduce Radiation Exposure to Patients and Providers. AB - High-definition fluoroscopic imaging is required to perform endovascular procedures safely and precisely, especially in complex cases, resulting in longer procedures and increased radiation exposure. This is of importance for training institutions as trainees, even with sound instruction in as low as reasonably achievable (ALARA) principles, tend to have high radiation exposures. Recently, there was an upgrade in the imaging system allowing for comparison of radiation exposure to patients and providers. We performed an analysis of consecutive endovascular aneurysm repair (EVAR) and superficial femoral artery (SFA) interventions in the years 2013 to 2014. We recorded body mass index (BMI) and fluoroscopy time (FT) and subsequently matched 1:1 based on BMI, FT, or both. We determined radiation dose using air kerma (AK) and also recorded individual surgeons' badge readings. Allura Xper FD20 was upgraded to AlluraClarity with ClarityIQ. We identified a total of 77 EVARs (52 pre and 25 post) and 134 SFA interventions (99 pre and 35 post). Unmatched results for EVAR were BMI pre 26.2 versus post 25.8 (kg/m2, P = .325), FT 28.1 versus 21.2 (minutes, P = .051), and AK 1178.5 versus 581 (mGy, P < .001), respectively. After matching, there was a 53.2% reduction in AK (846.1 vs 395.9 mGy; P = .004) for EVAR. Unmatched results for SFA interventions were BMI pre 28.1 versus post 26.6 ( P = .327), FT 18.7 versus 16.2 ( P = .282), and AK 285.6 versus 106.0 ( P < .001), respectively. After matching, there was a 57.0% reduction in AK (305.0 vs 131.3, P < .001). The total deep dose equivalent from surgeons' badge readings decreased from 39.5 to 17 mrem ( P = .029). Aortic and peripheral endovascular interventions can be performed with reduced radiation exposure to patients and providers, employing modern fixed imaging systems with advanced dose reduction technology. This is of particular importance in the light of the increasing volume and complexity of endovascular and hybrid procedures as well as the prospect of decades of radiation exposure during training and practice. PMID- 29162025 TI - Atypical Endoleak Associated With Inadvertent Cannulation of the Ipsilateral Gate in an Ovation Trimodular Stent-Graft. AB - We report on a 54-year-old man who presented with an atypical, proximal, intraoperative endoleak after endovascular aortic repair with an Ovation endograft for a 65-mm-diameter abdominal aortic aneurysm. The endografting was complicated by inadvertent bilateral iliac limb insertion into the right gate without cannulation of the left gate. The endoleak was treated by brachial approach: Through the open left gate, the outflow inferior mesenteric artery was coil embolized and the inflow left gate was closed with an Amplatzer plug. Follow up computed tomography over 3 years showed absence of any endoleak and a stable diameter of the excluded abdominal aortic aneurysm. PMID- 29162026 TI - Spontaneous Rupture of Multiple Occipital Artery Aneurysms in a Patient With Neurofibromatosis Type 1. AB - Neurofibromatosis type 1 (NF-1) is an autosomal dominant genetic disorder, mainly characterized by skin and peripheral nervous system abnormalities. Uncommonly, NF 1 may be associated with peripheral or supra-aortic trunks artery aneurysms. We report a case of symptomatic multiple occipital artery aneurysms detected in a 53 year-old woman affected by sporadic NF-1. An endovascular approach was performed to exclude aneurysms and to stop laterocervical spontaneous hematoma. PMID- 29162027 TI - Nonenhanced MRI Planning for Endovascular Repair of Abdominal Aortic Aneurysms: Comparison With Contrast-Enhanced CT Angiography. AB - BACKGROUND: To assess whether noncontrast-enhanced magnetic resonance imaging (NC MRI) is an alternative to contrast-enhanced computed tomography angiography (CTA) for aortoiliac measurements before endovascular abdominal aortic aneurysm repair (EVAR). METHODS: This study encompasses 30 patients admitted for elective EVAR (27 men and 3 women). Two expert readers (vascular radiologist and vascular surgeon) reviewed CTA images in consensus and chose the proper endograft for each patient. Subsequently, a vascular radiologist and a resident radiologist (observer 1 and 2) reviewed CTA and NC-MRI examinations in a double-blind way and completed standard measurements. The interobserver and intermodality agreement was calculated by intraclass correlation coefficients (ICCs). Furthermore, the correlation between the endograft size chosen by the first pair and the second pair of observers was evaluated. RESULTS: Concerning all measurements, no significant difference was found. Both CTA and NC-MRI angiographic measurements showed strong correlation. Interobserver ICCs for CTA and NC-MRI showed ranges of 0.62 to 0.99 (mean: 0.92) and 0.56 to 0.99 (mean: 0.91); intermodality ICCs for observer 1 and 2 showed ranges of 0.64 to 0.99 (mean: 0.92) and 0.56 to 0.99 (mean: 0.92). The CTA and NC-MRI vascular measurements correlated strongly, except for both external iliac artery diameters. The choice of stent size was always the same between the 2 observers; furthermore, graft size was always in agreement with that selected prospectively. CONCLUSION: Computed tomography angiography remains the standard of reference for EVAR planning; NC-MRI can be an option for patients with contraindications for CTA, in particular those with renal impairment. PMID- 29162028 TI - Endovascular Renal Artery Stent Retriever Embolectomy in a Young Patient With Cardiac Myxoma: Case Report and Review of the Literature. AB - PURPOSE: Cardiac myxomas are common tumors of the heart with disproportionate impact on young patients, occasionally with dramatic systemic dissemination of tumor emboli with catastrophic multiorgan system ischemia. The coincident comorbidities can increase the risk of traditional treatments for tumor embolus in each region. CASE REPORT: A young patient with previously unknown cardiac myxoma presented with seizure and was found to have stress cardiomyopathy, multiple cerebral large vessel occlusions with acute ischemic stroke, bilateral lower extremity tumor emboli and rhabdomyolysis, and renal tumor embolus with acute tubular necrosis. We describe a multidisciplinary approach applying cerebrovascular stent retriever devices in tumor embolectomy of the renal artery of a young patient with systemic morbidity, preventing safe laparotomy for open surgical tumor embolectomy. CONCLUSION: We describe 2-month renal function outcomes and the considerations in applying a neuroendovascular mechanical thrombectomy device within the renal artery. This was a radiographically successful technique and her renal function appears to be improving at the 2 month follow-up, although this is complicated by other renal insults and support. PMID- 29162029 TI - Longwing (Heliconius) butterflies combine a restricted set of pigmentary and structural coloration mechanisms. AB - BACKGROUND: Longwing butterflies, Heliconius sp., also called heliconians, are striking examples of diversity and mimicry in butterflies. Heliconians feature strongly colored patterns on their wings, arising from wing scales colored by pigments and/or nanostructures, which serve as an aposematic signal. RESULTS: Here, we investigate the coloration mechanisms among several species of Heliconius by applying scanning electron microscopy, (micro)spectrophotometry, and imaging scatterometry. We identify seven kinds of colored scales within Heliconius whose coloration is derived from pigments, nanostructures or both. In yellow-, orange- and red-colored wing patches, both cover and ground scales contain wavelength-selective absorbing pigments, 3-OH-kynurenine, xanthommatin and/or dihydroxanthommatin. In blue wing patches, the cover scales are blue either due to interference of light in the thin-film lower lamina (e.g., H. doris) or in the multilayered lamellae in the scale ridges (so-called ridge reflectors, e.g., H. sara and H. erato); the underlying ground scales are black. In the white wing patches, both cover and ground scales are blue due to their thin-film lower lamina, but because they are stacked upon each other and at the wing substrate, a faint bluish to white color results. Lastly, green wing patches (H. doris) have cover scales with blue-reflecting thin films and short-wavelength absorbing 3-OH-kynurenine, together causing a green color. CONCLUSIONS: The pigmentary and structural traits are discussed in relation to their phylogenetic distribution and the evolution of vision in this highly interesting clade of butterflies. PMID- 29162030 TI - Fast batch searching for protein homology based on compression and clustering. AB - BACKGROUND: In bioinformatics community, many tasks associate with matching a set of protein query sequences in large sequence datasets. To conduct multiple queries in the database, a common used method is to run BLAST on each original querey or on the concatenated queries. It is inefficient since it doesn't exploit the common subsequences shared by queries. RESULTS: We propose a compression and cluster based BLASTP (C2-BLASTP) algorithm to further exploit the joint information among the query sequences and the database. Firstly, the queries and database are compressed in turn by procedures of redundancy analysis, redundancy removal and distinction record. Secondly, the database is clustered according to Hamming distance among the subsequences. To improve the sensitivity and selectivity of sequence alignments, ten groups of reduced amino acid alphabets are used. Following this, the hits finding operator is implemented on the clustered database. Furthermore, an execution database is constructed based on the found potential hits, with the objective of mitigating the effect of increasing scale of the sequence database. Finally, the homology search is performed in the execution database. Experiments on NCBI NR database demonstrate the effectiveness of the proposed C2-BLASTP for batch searching of homology in sequence database. The results are evaluated in terms of homology accuracy, search speed and memory usage. CONCLUSIONS: It can be seen that the C2-BLASTP achieves competitive results as compared with some state-of-the-art methods. PMID- 29162031 TI - Norgal: extraction and de novo assembly of mitochondrial DNA from whole-genome sequencing data. AB - BACKGROUND: Whole-genome sequencing (WGS) projects provide short read nucleotide sequences from nuclear and possibly organelle DNA depending on the source of origin. Mitochondrial DNA is present in animals and fungi, while plants contain DNA from both mitochondria and chloroplasts. Current techniques for separating organelle reads from nuclear reads in WGS data require full reference or partial seed sequences for assembling. RESULTS: Norgal (de Novo ORGAneLle extractor) avoids this requirement by identifying a high frequency subset of k-mers that are predominantly of mitochondrial origin and performing a de novo assembly on a subset of reads that contains these k-mers. The method was applied to WGS data from a panda, brown algae seaweed, butterfly and filamentous fungus. We were able to extract full circular mitochondrial genomes and obtained sequence identities to the reference sequences in the range from 98.5 to 99.5%. We also assembled the chloroplasts of grape vines and cucumbers using Norgal together with seed-based de novo assemblers. CONCLUSION: Norgal is a pipeline that can extract and assemble full or partial mitochondrial and chloroplast genomes from WGS short reads without prior knowledge. The program is available at: https://bitbucket.org/kosaidtu/norgal . PMID- 29162032 TI - The metabolic side effects of 12 antipsychotic drugs used for the treatment of schizophrenia on glucose: a network meta-analysis. AB - BACKGROUND: Antipsychotics have serious metabolic side effects on blood glucose. However, the comparative influence of these drugs on blood glucose levels has not been comprehensively evaluated. We conducted a network meta-analysis to create a hierarchy of the side effects of 12 antipsychotic drugs on changes in blood glucose levels. METHODS: A systematic search of the PubMed, EMBASE and Cochrane databases (last search June 2016) was conducted to identify studies that reported randomized controlled trials (RCTs) comparing changes in blood glucose levels between patients receiving one of 12 antipsychotic drugs or a placebo for the treatment of schizophrenia or related disorders. The studies we searched were limited to those published in English. Two reviewers independently extracted data. The primary outcome of interest was changes in fasting glucose levels. RESULTS: We included 47 studies with 114 relevant arms. Of the antipsychotic drugs, only olanzapine was associated with significantly increased glucose levels compared to a placebo (mean difference (MD) = 3.95, 95% confidence interval (CI) = 0.14 to 7.76). Moreover, olanzapine was associated with a significantly greater change in the glucose levels than ziprasidone (MD = 5.51, 95% CI = 1.62 to 9.39), lurasidone (MD = 5.58, 95% CI = 0.53 to 10.64) or risperidone (MD = 3.05, 95% CI = 0.87 to 5.22). Ziprasidone and lurasidone were associated with minimal glucose changes compared to the other antipsychotics. CONCLUSIONS: Olanzapine was associated with a significantly greater change in blood glucose levels than ziprasidone, lurasidone, risperidone or placebo treatment. The application of a hierarchy of glucose metabolism-related side effects may help clinicians tailor the choice of antipsychotic drug to meet the needs of individual patients. PMID- 29162033 TI - Identification of genome-wide SNP-SNP interactions associated with important traits in chicken. AB - BACKGROUND: In addition to additive genetic effects, epistatic interactions can play key roles in the control of phenotypic variation of traits of interest. In the current study, 475 male birds from lean and fat chicken lines were utilized as a resource population to detect significant epistatic effects associated with growth and carcass traits. RESULTS: A total of 421 significant epistatic effects were associated with testis weight (TeW), from which 11 sub-networks (Sub network1 to Sub-network11) were constructed. In Sub-network1, which was the biggest network, there was an interaction between GGA21 and GGAZ. Three genes on GGA21 (SDHB, PARK7 and VAMP3) and nine genes (AGTPBP1, CAMK4, CDC14B, FANCC, FBP1, GNAQ, PTCH1, ROR2 and STARD4) on GGAZ that might be potentially important candidate genes for testis growth and development were detected based on the annotated gene function. In Sub-network2, there was a SNP on GGA19 that interacted with 8 SNPs located on GGA10. The SNP (Gga_rs15834332) on GGA19 was located between C-C motif chemokine ligand 5 (CCL5) and MIR142. There were 32 Refgenes on GGA10, including TCF12 which is predicted to be a target gene of miR 142-5p. We hypothesize that miR-142-5p and TCF12 may interact with one another to regulate testis growth and development. Two genes (CDH12 and WNT8A) in the same cadherin signaling pathway were implicated as potentially important genes in the control of metatarsus circumference (MeC). There were no significant epistatic effects identified for the other carcass and growth traits, e.g. heart weight (HW), liver weight (LW), spleen weight (SW), muscular and glandular stomach weight (MGSW), carcass weight (CW), body weight (BW1, BW3, BW5, BW7), chest width (ChWi), metatarsus length (MeL). CONCLUSIONS: The results of the current study are helpful to better understand the genetic basis of carcass and growth traits, especially for testis growth and development in broilers. PMID- 29162034 TI - Genetic diversity and structure of Iberian Peninsula cowpeas compared to world wide cowpea accessions using high density SNP markers. AB - BACKGROUND: Cowpea (Vigna unguiculata L. Walp) is an important legume crop due to its high protein content, adaptation to heat and drought and capacity to fix nitrogen. Europe has a deficit of cowpea production. Knowledge of genetic diversity among cowpea landraces is important for the preservation of local varieties and is the basis to obtain improved varieties. The aims of this study were to explore diversity and the genetic structure of a set of Iberian Peninsula cowpea accessions in comparison to a worldwide collection and to infer possible dispersion routes of cultivated cowpea. RESULTS: The Illumina Cowpea iSelect Consortium Array containing 51,128 SNPs was used to genotype 96 cowpea accessions including 43 landraces and cultivars from the Iberian Peninsula, and 53 landraces collected worldwide. Four subpopulations were identified. Most Iberian Peninsula accessions clustered together with those from other southern European and northern African countries. Only one accession belonged to another subpopulation, while two accessions were 'admixed'. A lower genetic diversity level was found in the Iberian Peninsula accessions compared to worldwide cowpeas. CONCLUSIONS: The genetic analyses performed in this study brought some insights into worldwide genetic diversity and structure and possible dispersion routes of cultivated cowpea. Also, it provided an in-depth analysis of genetic diversity in Iberian Peninsula cowpeas that will help guide crossing strategies in breeding programs. PMID- 29162036 TI - Sorafenib treatment for papillary thyroid carcinoma with diffuse lung metastases in a child with autism spectrum disorder: a case report. AB - BACKGROUND: Pediatric papillary thyroid carcinoma frequently presents with lymph node involvement and distant metastases. Sorafenib, an oral multikinase inhibitor, has been used to treat radioactive iodine (RAI) therapy-refractory thyroid carcinoma in adults; however, pediatric experience is limited. Medical procedures and hospitalization for children with autism spectrum disorder may be challenging. CASE PRESENTATION: An 11-year-old boy with autism spectrum disorder and moderate intellectual impairment presented with dyspnea on exertion with thyroid carcinoma and diffuses lung metastases. Total thyroidectomy and adjuvant RAI therapy is the standard treatment; however, the latter therapy was impractical because of his respiratory status and challenging behaviors. He was therefore started on sorafenib 200 mg/day (150 mg/m2/day) and this dosage was increased to 400 mg/day (300 mg/m2/day). The adverse effects were mild and tolerable. After administration of medication, his dyspnea improved and surgery was performed. We attempted to administer RAI therapy after surgery; however, we abandoned it because he had difficulty taking care of himself according to isolation room rules. Thyrotropin suppression therapy was therefore started and sorafenib treatment (400 mg/day) resumed. Follow-up imaging showed regression of pulmonary metastases. The metastases have remained stable for over 24 months on continuous sorafenib treatment without serious adverse events. CONCLUSION: We inevitably used sorafenib as an alternative to standard therapy because of the patient's specific circumstances. Individualized strategies for pediatric cancer patients with autism spectrum disorder are needed. PMID- 29162035 TI - Reliability and validity of the international dementia alliance schedule for the assessment and staging of care in China. AB - BACKGROUND: Clinical and social services both are important for dementia care. The International Dementia Alliance (IDEAL) Schedule for the Assessment and Staging of Care was developed to guide clinical and social care for dementia. Our study aimed to assess the validity and reliability of the IDEAL schedule in China. METHODS: Two hundred eighty-two dementia patients and their caregivers were recruited from 15 hospitals in China. Each patient-caregiver dyad was assessed with the IDEAL schedule by a rater and an observer simultaneously. The Clinical Dementia Rating (CDR), Mini-Mental Status Examination (MMSE), and Caregiver Burden Inventory (CBI) were assessed for criterion validity. IDEAL repeated assessment was conducted 7-10 days after the initial interview for 62 dyads. RESULTS: Two hundred seventy-seven patient-caregiver dyads completed the IDEAL assessment. Inter-rater reliability for the total score of the IDEAL schedule was 0.93 (95%CI = 0.92-0.95). The inter-class coefficient for the total score of IDEAL was 0.95 for the interviewers and 0.93 for the silent raters. The IDEAL total score correlated with the global CDR score (rho = 0.72, p < 0.001), the CDR-sum of box (CDR-SOB, rho = 0.74, p < 0.001), the total score of MMSE (rho = -0.65, p < 0.001) and CBI (rho = 0.70, p < 0.001). All item scores of the IDEAL schedule were associated with the CDR-SOB (rho = 0.17 ~ 0.79, all p < 0.05). CONCLUSION: The IDEAL schedule is a valid and reliable tool for the staging of care for dementia in the Chinese population. PMID- 29162037 TI - ICU-treated influenza A(H1N1) pdm09 infections more severe post pandemic than during 2009 pandemic: a retrospective analysis. AB - BACKGROUND: We compared in a single mixed intensive care unit (ICU) patients with influenza A(H1N1) pdm09 between pandemic and postpandemic periods. METHODS: Retrospective analysis of prospectively collected data in 2009-2016. Data are expressed as median (25th-75th percentile) or number (percentile). RESULTS: Seventy-six influenza A(H1N1) pdm09 patients were admitted to the ICU: 16 during the pandemic period and 60 during the postpandemic period. Postpandemic patients were significantly older (60 years vs. 43 years, p < 0.001) and less likely to have epilepsy or other neurological diseases compared with pandemic patients (5 [8.3%] vs. 6 [38%], respectively; p = 0.009). Postpandemic patients were more likely than pandemic patients to have cardiovascular disease (24 [40%] vs. 1 [6%], respectively; p = 0.015), and they had higher scores on APACHE II (17 [13 22] vs. 14 [10-17], p = 0.002) and SAPS II (40 [31-51] vs. 31 [25-35], p = 0.002) upon admission to the ICU. Postpandemic patients had higher maximal SOFA score (9 [5-12] vs. 5 [4-9], respectively; p = 0.03) during their ICU stay. Postpandemic patients had more often septic shock (40 [66.7%] vs. 8 [50.0%], p = 0.042), and longer median hospital stays (15.0 vs. 8.0 days, respectively; p = 0.006). During 2015-2016, only 18% of the ICU- treated patients had received seasonal influenza vaccination. CONCLUSIONS: Postpandemic ICU-treated A(H1N1) pdm09 influenza patients were older and developed more often septic shock and had longer hospital stays than influenza patients during the 2009 pandemic. PMID- 29162038 TI - A qualitative study on Singaporean women's views towards breast cancer screening and Single Nucleotide Polymorphisms (SNPs) gene testing to guide personalised screening strategies. AB - BACKGROUND: Breast cancer is the top cancer by incidence and mortality in Singaporean women. Mammography is by far its best screening tool, but current recommended age and interval may not yield the most benefit. Recent studies have demonstrated the potential of single nucleotide polymorphisms (SNPs) to improve discriminatory accuracy of breast cancer risk assessment models. This study was conducted to understand Singaporean women's views towards breast cancer screening and SNPs gene testing to guide personalised screening strategies. METHODS: Focus group discussions were conducted among English-speaking women (n = 27) between 40 to 65 years old, both current and lapsed mammogram users. Women were divided into four groups based on age and mammogram usage. Discussions about breast cancer and screening experience, as well as perception and attitude towards SNPs gene testing were conducted by an experienced moderator. Women were also asked for factors that will influence their uptake of the test. Transcripts were analysed using thematic analysis to captured similarities and differences in views expressed. RESULTS: Barriers to repeat mammogram attendance include laziness to make appointment and painful and uncomfortable screening process. However, the underlying reason may be low perceived susceptibility to breast cancer. Facilitators to repeat mammogram attendance include ease of making appointment and timely reminders. Women were generally receptive towards SNPs gene testing, but required information on accuracy, cost, invasiveness, and side effects before they decide whether to go for it. Other factors include waiting time for results and frequency interval. On average, women gave a rating of 7.5 (range 5 to 10) when asked how likely they will go for the test. CONCLUSION: Addressing concerns such as pain and discomfort during mammogram, providing timely reminders and debunking breast cancer myths can help to improve screening uptake. Women demonstrated a spectrum of responses towards a novel test like SNPs gene testing, but need more information to make an informed decision. Future public health education on predictive genetic testing should adequately address both benefits and risks. Findings from this study is used to inform a discrete choice experiment to empirically quantify women preferences and willingness-to-pay for SNPs gene testing. PMID- 29162039 TI - Experiences and wishes of women regarding systemic aspects of midwifery care in Germany: a qualitative study with focus groups. AB - BACKGROUND: Knowledge of pregnant women's and mothers' viewpoints on midwifery care is crucial for its appropriate delivery and research. In Germany, comprehensive research to more fully understand women's needs in pregnancy, labour, birth and the postpartum period until weaning is lacking. International studies provide some knowledge of women's expectations, their choices, and subjective criteria indicating good midwifery care. METHODS: This study explores pregnant women's and mothers' experiences, needs and wishes regarding systemic aspects of midwifery care (access, availability, choices, model of midwifery care; maternity care in the healthcare system). 50 women participated in 10 focus groups in 5 states of Germany. The groups were heterogeneous with regard to age, parity, model of maternity care used, and rating of satisfaction. Women with limited educational years (n = 9) were personally contacted by midwives and reached by social media. Also, mothers living in a mother-child home (n = 6) or attending a peer group for grieving parents (n = 5) were included. The digitally documented focus groups were systematically analysed in an itinerary hermeneutic manner. RESULTS: Three themes were identified: (a) Knowledge or lack of awareness of midwifery care, (b) availability of and access to midwives, and (c) midwifery care in the healthcare system. Theme (a) entails the scope of midwifery care and the midwife's competence, but also a lack of information, inconsistent counselling, and difficulty identifying midwives. Theme (b) encompasses aspects such as the availability, accessibility and selection of a midwife, the effort involved in looking for a midwife, the challenge of transition points, and family midwives. Theme (c) relates interprofessional cooperation, gaps/inadequacies of care during latency phase, alternative models of care, and the importance of family and peer groups for women. CONCLUSIONS: Midwifery care and research in Germany must address the issue of imparting relevant information about midwifery services. Interprofessional cooperation and management of transition points ought to be improved in the interests of the women concerned. Moreover, the quality of antenatal classes, support during latency phase, and intrapartum care in hospitals need to be addressed. Lastly, the special needs of vulnerable women in midwifery care must become a major focus in Germany. PMID- 29162040 TI - Cloning and expression of BpMYC4 and BpbHLH9 genes and the role of BpbHLH9 in triterpenoid synthesis in birch. AB - BACKGROUND: Birch (Betula platyphylla Suk.) contains triterpenoids with anti-HIV and anti-tumor pharmacological activities. However, the natural abundance of these triterpenoids is low, and their chemical synthesis is costly. Transcription factors have the ability to regulate the metabolite pathways of triterpenoids via multi-gene control, thereby improving metabolite yield. Thus, transcription factors have the potential to facilitate the production of birch triterpenoids. Plant bHLH (basic helix-loop-helix) transcription factors play important roles in stress response and secondary metabolism. RESULTS: In this study, we cloned two genes, BpMYC4 and BpbHLH9, that encode bHLH transcription factors in Betula platyphylla Suk. The open reading frame (ORF) of BpMYC4 was 1452 bp and encoded 483 amino acids, while the ORF of BpbHLH9 was 1140 bp and encoded 379 amino acids. The proteins of BpMYC4 and BpbHLH9 were localized in the cell membrane and nucleus. The tissue-specific expression patterns revealed that BpMYC4 expression in leaves was similar to that in the stem and higher than in the roots. The expression of BpbHLH9 was higher in the leaves than in the root and stem. The expressions of BpMYC4 and BpbHLH9 increased after treatment with abscisic acid, methyl jasmonate, and gibberellin and decreased after treatment with ethephon. The promoters of BpMYC4 and BpbHLH9 were isolated using a genome walking approach, and 900-bp and 1064-bp promoter sequences were obtained for BpMYC4 and BpbHLH9, respectively. The ORF of BpbHLH9 was ligated into yeast expression plasmid pYES3 and introduced into INVScl and INVScl1-pYES2-SS yeast strains. The squalene and total triterpenoid contents in the different INVScl1 transformants decreased in the following order INVScl1-pYES-SS-bHLH9 > INVScl1-pYES3-bHLH9 > INVScl1-pYES2- BpSS > INVScl-pYES2. In BpbHLH9 transgenic birch, the relative expression of the genes that encodes for enzymes critical for triterpenoid synthesis showed a different level of up-regulation compair with wild birch(control), and the contents of betulinic acid, oleanolic acid and betulin in bHLH9-8 transgenic birch were increased by 11.35%, 88.34% and 23.02% compared to in wild birch, respectively. CONCLUSIONS: Our results showed that the modulation of BpbHLH9 by different hormones affected triterpenoid synthesis and triterpenoid contents. This is the first report of the cloning of BpbHLH9, and the findings are important for understanding the regulatory role of BpbHLH9 in the synthesis of birch triterpenoids. PMID- 29162041 TI - Does anthracycline-based chemotherapy in pregnant women with cancer offer safe cardiac and neurodevelopmental outcomes for the developing fetus? AB - BACKGROUND: Cancer treatment during pregnancy is a growing problem especially now that women delay childbearing. Systemic treatment of these malignancies during pregnancy centers mainly on the anticancer drugs anthracyclines, widely used in treating hematological and breast cancer during pregnancy and sometimes associated with early and late toxicity for the fetus. Owing to concern about their cardiac and neurodevelopmental toxicity more information is needed on which anthracycline to prefer and whether they can safely guarantee a cardiotoxicity free outcome in the fetus. DISCUSSION: The major research findings underline anthracycline-induced dose-dependent effects, including cardiotoxicity, many avoidable. Partly because the placenta acts mainly as a barrier, research findings indicate low transplacental anthracycline transfer. Anthracycline induced teratogenicity depends closely on when patients receive chemotherapy. Anthracycline cardiac toxicity may depend on the association with drugs that inhibit or induce placental P-glycoprotein (P-gp). P-gp-induced drug interactions may alter placental P-gp barrier function and subsequently change fetal exposure. Though many anthracyclines have acceptable safety profiles clinical studies suggest giving idarubicin with special caution. Patients and doctors who care for pregnant women should whenever possible avoid prematurity and hence reduce prematurity-induced medical complications at birth and in the long-term. Information is lacking on long-term anthracycline-induced effects. CONCLUSION: Pregnant women receiving anthracycline-based chemotherapy should undergo regular, state-of-the-art diagnostic imaging to detect fetal drug-induced cardiac damage early, and allow alternative therapeutic options. Recognizing drug-induced interactions and understanding the most vulnerable fetuses will help in choosing tailored therapy. Future research on placental transport, blood-brain barrier drug passage and pharmacokinetics will improve the way we manage these difficult to-treat patients and their fetuses. PMID- 29162042 TI - Novel intragenic deletions within the UBE3A gene in two unrelated patients with Angelman syndrome: case report and review of the literature. AB - BACKGROUND: Patients with Angelman syndrome (AS) are affected by severe intellectual disability with absence of speech, distinctive dysmorphic craniofacial features, ataxia and a characteristic behavioral phenotype. AS is caused by the lack of expression in neurons of the UBE3A gene, which is located in the 15q11.2-q13 imprinted region. Functional loss of UBE3A is due to 15q11.2 q13 deletion, mutations in the UBE3A gene, paternal uniparental disomy and genomic imprinting defects. CASE PRESENTATION: We report here two patients with clinical features of AS referred to our hospital for clinical follow-up and genetic diagnosis. Methylation Specific-Multiplex Ligation-Dependent Probe Amplification (MS-MLPA) of the 15q11.2-q13 region was carried out in our laboratory as the first diagnostic tool detecting two novel UBE3A intragenic deletions. Subsequently, the MLPA P336-A2 kit was used to confirm and determine the size of the UBE3A deletion in the two patients. A review of the clinical features of previously reported patients with whole UBE3A gene or partial intragenic deletions is presented here together with these two new patients. CONCLUSION: Although rare, UBE3A intragenic deletions may represent a small fraction of AS patients without a genetic diagnosis. Testing for UBE3A intragenic exonic deletions should be performed in those AS patients with a normal methylation pattern and no mutations in the UBE3A gene. PMID- 29162043 TI - Exploring consensus on how to measure smoking cessation. A Delphi study. AB - BACKGROUND: Different criteria regarding outcome measures in smoking research are used, which can lead to confusion about study results. Consensus in outcome criteria may enhance the comparability of future studies. This study aims (1) to provide an overview of tobacco researchers' considered preferences regarding outcome criteria in randomized controlled smoking cessation trials, and (2) to identify the extent to which researchers can reach consensus on the importance of these outcome criteria. METHODS: A three-round online Delphi study was conducted among smoking cessation experts. In the first round, the most important smoking cessation outcome measures were collected by means of open-ended questions, which were categorized around self-reported and biochemical validation measures. Experts (n = 17) were asked to name the outcome measures (as well as their assessment method and ideal follow-up period) that they thought were important when assessing smoking-related outcomes. In the second (n = 48) and third rounds (n = 37), a list of outcome measures-identified in the first round-was presented to experts. Asking them to rate the importance of each measure on a seven-point scale. RESULTS: Experts reached consensus on several items. For self-reports, experts agreed that prolonged abstinence (6 or/and 12 months), point prevalence abstinence (7 days), continuous abstinence (6 months), and the number of cigarettes smoked (7 days) are important outcome measures. Experts reached consensus that biochemical validation methods should not always be used. The preferred biochemical validation methods were carbon monoxide (expired air) and cotinine (saliva). Preferred follow-ups included 6 and/or 12 months, with or without intermediate measurements. CONCLUSIONS: Findings suggest only partial compliance with the Russell standard and that more outcome measures may be important (including seven-day point-prevalence abstinence, number of cigarettes smoked, and cotinine when using biochemical validation). This study showed where there is and is not consensus, reflecting the need to develop a more comprehensive standard. For these purposes we provided suggestions for the Russell 2.0 standard. PMID- 29162044 TI - Migrants' motives and expectations for contacting out-of-hours primary care: a survey study. AB - BACKGROUND: Migrants are more likely to use out-of-hours primary care, especially for nonurgent problems. Their motives and expectations for help-seeking are as yet unknown. The objective of this study is to examine the motives and expectations of migrants for contacting out-of-hours primary care. METHODS: We used data from a survey study of 11,483 patients who contacted a General Practitioner (GP) cooperative in the Netherlands between 2009 and 2014 (response rate 45.6%). Logistic regression analysis was used to test differences in motives and expectations between non-western and western migrants and native Dutch patients. RESULTS: The main motives for contacting a GP cooperative for non western and western migrants were an urgent need for contact with a GP (54.9% 52.4%), worry (49.3%-43.0%), and a need for medical information (21.3%-26.2%). These were also the most important motives for native Dutch patients. Compared to native Dutch patients, non-western migrants more often perceived an urgent need for a GP (OR 1.65; 99% CI 1.27-2.16), less often needed information (OR 0.59; 99% CI 0.43-0.81), and more often experienced problems contacting their own GP during office hours (OR 1.71; 99% CI 1.21-2.43). Western migrants also reported experiencing problems more often in contacting their own GP (OR 1.38; 99% CI 1.04 1.84). As well as for natives, most non-western and western migrants expected to see a doctor (46.2%-46.6%) or get advice (39.6%-41.5%). Non-western migrants expected more often to get physical examination (OR 1.53; 99% CI 1.14-2.04), and prescription (OR 1.37; 99% CI 1.00-1.88). We found no differences in expectations between western migrants and native Dutch patients. CONCLUSION: The main motives and expectations of migrants are similar to native Dutch patients, yet non western migrants more often wanted action from the GP, e.g. examination or prescription, and less often passive forms of assistance such as giving information. At the same time they experience problems accessing their own GP. We recommend stimulation of self-care, education about the purpose of a GP cooperative, and examination and improvement of accessibility of daytime primary care. PMID- 29162045 TI - Serial pseudoprogression of metastatic malignant melanoma in a patient treated with nivolumab: a case report. AB - BACKGROUND: Pseudoprogression refers to a specific pattern of response sometimes observed in malignant melanoma patients receiving treatment with immune checkpoint inhibitors. Although cases with pseudoprogression documented once have been reported previously, there have been no case reports yet of pseudoprogression events documented twice during treatment. CASE PRESENTATION: A 55-year-old man underwent surgery for locally advanced esophageal malignant melanoma and received postoperative adjuvant interferon therapy. However, he presented with multiple liver and bone metastases at 6 months after the surgery, and was initiated on treatment with nivolumab 2 mg/kg every 3 weeks as the first line treatment for recurrent disease. Follow-up computed tomography revealed that the liver metastases initially increased transiently in size, but eventually regressed. However, while the liver metastases continued to shrink, a new peritoneal nodule emerged, that also subsequently shrinked during the course of treatment with nivolumab. With only grade 1 pruritus, the patient continues to be on nivolumab treatment at 15 months after the induction therapy, with no progression observed after the second episode of pseudoprogression in the liver and peritoneal nodule. CONCLUSIONS: We present the case of a patient with metastatic malignant melanoma who showed the unique response pattern of serial pseudoprogression during treatment with nivolumab. This case serves to highlight the fact that development of a new lesion may not always signify failure of disease control during treatment with nivolumab. PMID- 29162046 TI - Association of common genetic variants related to atrial fibrillation and the risk of ventricular fibrillation in the setting of first ST-elevation myocardial infarction. AB - BACKGROUND: Cohort studies have revealed an increased risk for ventricular fibrillation (VF) and sudden cardiac death (SCD) in patients with atrial fibrillation (AF). In this study, we hypothesized that single nucleotide polymorphisms (SNP) previously associated with AF may be associated with the risk of VF caused by first ST-segment elevation myocardial infarction (STEMI). METHODS: We investigated association of 24 AF-associated SNPs with VF in the prospectively assembled case-control study among first STEMI-patients of Danish ancestry. RESULTS: We included 257 cases (STEMI with VF) and 537 controls (STEMI without VF). The median age at index infarction was 60 years for the cases and 61 years for the controls (p = 0.100). Compared to the control group, the case group was more likely to be male (86% vs. 75%, p = 0.001), have a history of AF (7% vs. 2%, p = 0.006) or hypercholesterolemia (39% vs. 31%, p = 0.023), and a family history of sudden death (40% vs. 25%, p < 0.001). All 24 selected SNPs have previously been associated with AF. None of the 24 SNPs were associated with the risk of VF after adjustment for age and sex under additive genetic model of inheritance in the logistic regression model. CONCLUSION: In this study, we found that the 24 AF-associated SNPs may not be involved in increasing the risk of VF. Larger VF cohorts and use of new next generation sequencing and epigenetic may in future identify additional AF and VF risk loci and improve our understanding of genetic pathways behind the two arrhythmias. PMID- 29162047 TI - Treatment recommendations within the leeway of clinical guidelines: A qualitative interview study on oncologists' clinical deliberation. AB - BACKGROUND: Recommending the optimal treatment for an individual patient requires a well-balanced consideration of various medical, social and ethical factors. The interplay of these factors, interpretation of the patient's situation and understanding of the existing clinical guidelines can lead to divergent therapy recommendations, depending on the attending physician. Gaining a better understanding of the individual process of medical decision-making and the differences occurring will support the delivery of optimal individualized care within the clinical setting. METHODS: A case vignette of a 64-year-old patient with locally advanced pancreatic adenocarcinoma was discussed with oncologists in 14 qualitative, semi-structured interviews at two academic institutions. Relevant factors that emerged were ranked by the participants using the Q card sorting method. Qualitative data analysis and descriptive statistics were performed. RESULTS: Oncologists recommend different therapeutic approaches within the leeway of the relevant clinical guidelines. One group of participants endorses a rather aggressive and potentially curative approach with a combination chemotherapy following the FOLFIRINOX protocol to provide the patient with the best chances of resectability. The second group suggests a milder chemotherapy approach with gemcitabine, highlighting the palliative approach and the patient's quality of life. Clinical guidelines are generally seen as an important point of reference, but are complicated to apply in highly individual cases. CONCLUSION: The physician's individual assessment of factors, such as biological age, general condition or prognosis, plays a decisive role in treatment recommendations, particularly in those cases which are not fully covered by guidelines. Judgment and discretion remain crucial in clinical decision-making and cannot and should not be fully ruled out by evidence-based guidelines. Therefore, a more comprehensive reflection on the interaction between evidence-based medicine and the physician's estimation of each individual case is desirable. Knowledge of existing barriers can enhance the implementation of guidelines, for example, through medical education. PMID- 29162048 TI - Dietary patterns, gender, and weight status among middle-aged and older adults in Taiwan: a cross-sectional study. AB - BACKGROUND: Diet has been associated with differences in weight and nutritional status of an individual. The prevalence of overweight and obesity increased among adults in Taiwan. Hence, we examined the relationship between dietary patterns and weight status by gender among middle-aged and older adults in Taiwan. METHODS: The cross-sectional data of 62,965 participants aged >=40 years were retrieved from the Mei Jau health screening institutions' database collected from 2001 and 2010. Diet information was evaluated using a food frequency questionnaire, while the dietary patterns were derived using principal component analysis before summing up and dividing into quintiles of consumption. The association between dietary patterns and weight status among adult men and women was explored using multinomial logistic regression models. Three models were analyzed before stratifying data by gender. RESULTS: Two dietary patterns were derived with one reflecting a high consumption of vegetables and fruits (vegetable-fruit dietary pattern) and the other a high consumption of meat and processed foods (meat-processed dietary pattern). After adjustment, highest consumption of vegetables and fruits (Q5) reduced the likelihood of being overweight (OR = 0.91; 95% CI, 0.85-0.97) or obese (OR = 0.85; 95% CI, 0.78 0.92), while highest consumption of meat and processed foods increased the likelihood of being overweight (OR = 1.50; 95% CI, 1.40-1.59) or obese (OR = 1.94; 95% CI, 1.79-2.10). Women were less likely to be overweight or obese with the highest intake of fruits and vegetables (Q5) while both genders were more likely to be overweight or obese with high consumption of meat and processed foods. CONCLUSIONS: High intake of vegetables and fruits is associated with lower odds of being overweight or obese, especially among women. But, high intake of meat and processed foods is associated with higher odds of overweight and obesity in both genders. PMID- 29162049 TI - RNA-seq and Tn-seq reveal fitness determinants of vancomycin-resistant Enterococcus faecium during growth in human serum. AB - BACKGROUND: The Gram-positive bacterium Enterococcus faecium is a commensal of the human gastrointestinal tract and a frequent cause of bloodstream infections in hospitalized patients. The mechanisms by which E. faecium can survive and grow in blood during an infection have not yet been characterized. Here, we identify genes that contribute to growth of E. faecium in human serum through transcriptome profiling (RNA-seq) and a high-throughput transposon mutant library sequencing approach (Tn-seq). RESULTS: We first sequenced the genome of E. faecium E745, a vancomycin-resistant clinical isolate, using a combination of short- and long read sequencing, revealing a 2,765,010 nt chromosome and 6 plasmids, with sizes ranging between 9.3 kbp and 223.7 kbp. We then compared the transcriptome of E. faecium E745 during exponential growth in rich medium and in human serum by RNA-seq. This analysis revealed that 27.8% of genes on the E. faecium E745 genome were differentially expressed in these two conditions. A gene cluster with a role in purine biosynthesis was among the most upregulated genes in E. faecium E745 upon growth in serum. The E. faecium E745 transposon mutant library was then used to identify genes that were specifically required for growth of E. faecium in serum. Genes involved in de novo nucleotide biosynthesis (including pyrK_2, pyrF, purD, purH) and a gene encoding a phosphotransferase system subunit (manY_2) were thus identified to be contributing to E. faecium growth in human serum. Transposon mutants in pyrK_2, pyrF, purD, purH and manY_2 were isolated from the library and their impaired growth in human serum was confirmed. In addition, the pyrK_2 and manY_2 mutants were tested for their virulence in an intravenous zebrafish infection model and exhibited significantly attenuated virulence compared to E. faecium E745. CONCLUSIONS: Genes involved in carbohydrate metabolism and nucleotide biosynthesis of E. faecium are essential for growth in human serum and contribute to the pathogenesis of this organism. These genes may serve as targets for the development of novel anti-infectives for the treatment of E. faecium bloodstream infections. PMID- 29162051 TI - In vitro characterization of CD133lo cancer stem cells in Retinoblastoma Y79 cell line. AB - BACKGROUND: Retinoblastoma (Rb), the most common childhood intraocular malignant tumor, is reported to have cancer stem cells (CSCs) similar to other tumors. Our previous investigation in primary tumors identified the small sized cells with low CD133 (Prominin-1) and high CD44 (Hyaluronic acid receptor) expression to be putative Rb CSCs using flow cytometry (FSClo/SSClo/CD133lo/CD44hi). With this preliminary data, we have now utilized a comprehensive approach of in vitro characterization of Y79 Rb cell line following CSC enrichment using CD133 surface marker and subsequent validation to confirm the functional properties of CSCs. METHODS: The cultured Rb Y79 cells were evaluated for surface markers by flow cytometry and CD133 sorted cells (CD133lo/CD133hi) were compared for CSC characteristics by size/percentage, cell cycle assay, colony formation assay, differentiation, Matrigel transwell invasion assay, cytotoxicity assay, gene expression using microarray and validation by semi-quantitative PCR. RESULTS: Rb Y79 cell line shared the profile (CD133, CD90, CXCR4 and ABCB1) of primary tumors except for CD44 expression. The CD133lo cells (16.1 +/- 0.2%) were FSClo/SSClo, predominantly within the G0/G1 phase, formed larger and higher number of colonies with ability to differentiate to CD133hi cells, exhibited increased invasive potential in a matrigel transwell assay (p < 0.05) and were resistant to Carboplatin treatment (p < 0.001) as compared to CD133hi cells. The CD133lo cells showed higher expression of several embryonic stem cell genes (HOXB2, HOXA9, SALL1, NANOG, OCT4, LEFTY), stem cells/progenitor genes (MSI2, BMI1, PROX1, ABCB1, ABCB5, ABCG2), and metastasis related gene- MACC1, when compared to the CD133hi cells. CONCLUSIONS: This study validates the observation from our earlier primary tumor study that CSC properties in Rb Y79 cell line are endowed within the CD133lo population, evident by their characteristics- i.e. small sized, dormant in nature, increased colony forming ability, differentiation to CD133hi cells, higher invasiveness potential, drug resistance and primitive gene expression pattern. These findings provide a proof of concept for methodological characterization of the retinoblastoma CSCs with future implications for improved diagnostic and treatment strategies. PMID- 29162052 TI - Chloroplast PetD protein: evidence for SRP/Alb3-dependent insertion into the thylakoid membrane. AB - BACKGROUND: In thylakoid membrane, each monomer of the dimeric complex of cytochrome b 6 f is comprised of eight subunits that are both nucleus- and plastid-encoded. Proper cytochrome b 6 f complex integration into the thylakoid membrane requires numerous regulatory factors for coordinated transport, insertion and assembly of the subunits. Although, the chloroplast-encoded cytochrome b 6 f subunit IV (PetD) consists of three transmembrane helices, the signal and the mechanism of protein integration into the thylakoid membrane have not been identified. RESULTS: Here, we demonstrate that the native PetD subunit cannot incorporate into the thylakoid membranes spontaneously, but that proper integration occurs through the post-translational signal recognition particle (SRP) pathway. Furthermore, we show that PetD insertion into thylakoid membrane involves the coordinated action of cpFTSY, cpSRP54 and ALB3 insertase. CONCLUSIONS: PetD subunit integration into the thylakoid membrane is a post translational and an SRP-dependent process that requires the formation of the cpSRP-cpFtsY-ALB3-PetD complex. This data provides a new insight into the molecular mechanisms by which membrane proteins integration into the thylakoid membrane is accomplished and is not limited to PetD. PMID- 29162050 TI - Transcriptome profiling of aging Drosophila photoreceptors reveals gene expression trends that correlate with visual senescence. AB - BACKGROUND: Aging is associated with functional decline of neurons and increased incidence of both neurodegenerative and ocular disease. Photoreceptor neurons in Drosophila melanogaster provide a powerful model for studying the molecular changes involved in functional senescence of neurons since decreased visual behavior precedes retinal degeneration. Here, we sought to identify gene expression changes and the genomic features of differentially regulated genes in photoreceptors that contribute to visual senescence. RESULTS: To identify gene expression changes that could lead to visual senescence, we characterized the aging transcriptome of Drosophila sensory neurons highly enriched for photoreceptors. We profiled the nuclear transcriptome of genetically-labeled photoreceptors over a 40 day time course and identified increased expression of genes involved in stress and DNA damage response, and decreased expression of genes required for neuronal function. We further show that combinations of promoter motifs robustly identify age-regulated genes, suggesting that transcription factors are important in driving expression changes in aging photoreceptors. However, long, highly expressed and heavily spliced genes are also more likely to be downregulated with age, indicating that other mechanisms could contribute to expression changes at these genes. Lastly, we identify that circular RNAs (circRNAs) strongly increase during aging in photoreceptors. CONCLUSIONS: Overall, we identified changes in gene expression in aging Drosophila photoreceptors that could account for visual senescence. Further, we show that genomic features predict these age-related changes, suggesting potential mechanisms that could be targeted to slow the rate of age-associated visual decline. PMID- 29162053 TI - Duloxetine-induced rapid eye movement sleep behavior disorder: a case report. AB - BACKGROUND: Tricyclic antidepressants and selective serotonin reuptake inhibitors have been reported to induce the symptoms of rapid eye movement (REM) sleep behavior disorder (RBD) or to exacerbate REM sleep without atonia. With this case report, we found an association between typical RBD and duloxetine, a serotonin noradrenaline reuptake inhibitor. CASE PRESENTATION: We present a case of a 62 year-old woman who experienced enactment behaviors with violent dreams that were associated with increased tonic or phasic chin electromyography activity during REM sleep after treated with duloxetine. RBD symptoms were gradually reduced and completely ceased after discontinuation of duloxetine for 37 days. CONCLUSION: The current case appears to be the first observation of duloxetine-induced RBD. We describe features of RBD induced by duloxetine that are similar and different from that induced by tricyclic antidepressants and selective serotonin reuptake inhibitors. PMID- 29162054 TI - "Lay epidemiology": an important factor in Danish parents' decision of whether to allow their child to receive a BCG vaccination. A qualitative exploration of parental perspective. AB - BACKGROUND: Vaccination is used worldwide to prevent infectious diseases. However, vaccination programmes in western countries face challenges in sustaining high coverage rates. The aim of this study was to explore how parents in Denmark make a decision about whether to allow their child to receive a Bacille Calmette Guerin vaccine at birth for the purpose of achieving non specific effects on the immune system. METHODS: A total of five focus groups were conducted with expectant mothers and fathers. Written information about the vaccine and information about the hypothesis of non-specific effects of the vaccine were delivered in order to discuss considerations and determinants of parents' decisions. RESULTS: Heritable factors and the possibility of stimulating the immune system of the child to achieve less atopic diseases and fewer infections were identified as arguments in favour of receiving the BCG vaccine. Arguments against receiving BCG mainly focused on concerns about its described and non-described side effects. Both arguments for and arguments against the vaccine were seen as parents attempt to make an individual risk evaluation for their child. Attitudes and beliefs in the local network were identified as important for parents' decisions. DISCUSSION: It is discussed how "lay epidemiology" characterizes parents' risk evaluation as an individual addition to the population-based risk declaration. It is furthermore discussed how health professionals should engage with both the empirical element and the value element of "Lay epidemiology". CONCLUSION: "Lay epidemiology" forms the basis for the parental decision of whether to allow their child to receive a BCG vaccination. Attitudes and beliefs about the causes and distribution of illnesses in the family or local network influence parents' risk evaluations. It would be ideal for parents if health professionals focused their communication about the BCG vaccine on individual risk evaluations. PMID- 29162056 TI - Synima: a Synteny imaging tool for annotated genome assemblies. AB - BACKGROUND: Ortholog prediction and synteny visualization across whole genomes are valuable methods for detecting and representing a range of evolutionary processes such as genome expansion, chromosomal rearrangement, and chromosomal translocation. Few standalone methods are currently available to visualize synteny across any number of annotated genomes. RESULTS: Here, I present a Synteny Imaging tool (Synima) written in Perl, which uses the graphical features of R. Synima takes orthologues computed from reciprocal best BLAST hits or OrthoMCL, and DAGchainer, and outputs an overview of genome-wide synteny in PDF. Each of these programs are included with the Synima package, and a pipeline for their use. Synima has a range of graphical parameters including size, colours, order, and labels, which are specified in a config file generated by the first run of Synima - and can be subsequently edited. Synima runs quickly on a command line to generate informative and publication quality figures. Synima is open source and freely available from https://github.com/rhysf/Synima under the MIT License. CONCLUSIONS: Synima should be a valuable tool for visualizing synteny between two or more annotated genome assemblies. PMID- 29162055 TI - Stereotactic body radiotherapy (SBRT) for locally advanced intrahepatic and extrahepatic cholangiocarcinoma. AB - BACKGROUND: To evaluate the role of ablative radiotherapy doses in the treatment of hilar or intrahepatic cholangiocarcinoma (CCC) using stereotactic body radiotherapy (SBRT). METHODS: Consecutive patients treated from 2007 to 2016 with CCC were evaluated. Local control and toxicities were assessed every 3 months according to the Response Evaluation Criteria In Solid Tumors (RECIST) and the Common Terminology Criteria for Adverse Events v4.0, respectively. Overall survival (OS), local control (LC) and progression free survival were calculated from SBRT. RESULTS: Thirty seven patients with 43 lesions were retrospectively evaluated. The median dose delivered was 45 Gy (range 25-66 Gy) in 3-12 fractions, corresponding to a median equivalent dose in 2 Gy fractions (EQD210) of 56 (range 25-85) Gy. The median follow up was 24 months. The OS at 1 year was 56% with a median OS of 14 (95% CI: 7.8-20.2) months from start of SBRT and 22 (95% CI: 17.5-26.5) months from diagnosis. Eight lesions progressed locally. The local control rate (LC) at 1 year was 78%. The median progression free survival was 9 months (95% CI 2.8-15.2) 21 patients progressed in the liver but out of field and 15 progressed distantly. SBRT was well tolerated. Three patients (9%) developed a Grade III bleeding. Seven patients developed a cholangitis, one due to progression and the other because of a stent dysfunction 2-21(median 8) months from SBRT. CONCLUSION: In patients with locally advanced cholangiocarcinoma, SBRT is a local treatment option with an acceptable toxicity profile which warrants further investigation in prospective trials. PMID- 29162057 TI - Translating a child care based intervention for online delivery: development and randomized pilot study of Go NAPSACC. AB - BACKGROUND: As part of childhood obesity prevention initiatives, Early Care and Education (ECE) programs are being asked to implement evidence-based strategies that promote healthier eating and physical activity habits in children. Translation of evidence-based interventions into real world ECE settings often encounter barriers, including time constraints, lack of easy-to-use tools, and inflexible intervention content. This study describes translation of an evidence based program (NAPSACC) into an online format (Go NAPSACC) and a randomized pilot study evaluating its impact on centers' nutrition environments. METHODS: Go NAPSACC retained core elements and implementation strategies from the original program, but translated tools into an online, self-directed format using extensive input from the ECE community. For the pilot, local technical assistance (TA) agencies facilitated recruitment of 33 centers, which were randomized to immediate (intervention, n = 18) or delayed (control, n = 15) access groups. Center directors were oriented on Go NAPSACC tools by their local TA providers (after being trained by researchers), after which they implemented Go NAPSACC independently with minimal TA support. The Environment and Policy Assessment and Observation instrument (self-report), collected prior to and following the 4 month intervention period, was used to assess impact on centers' nutrition environments. Process data were also collected from a sample of directors and all TA providers to evaluate program usability and implementation. RESULTS: Demographic characteristics of intervention and control centers were similar. Two centers did not complete follow-up measures, leaving 17 intervention and 14 control centers in the analytic sample. Between baseline and follow-up, intervention centers improved overall nutrition scores (Cohen's d effect size = 0.73, p = 0.15), as well as scores for foods (effect size = 0.74, p = 0.16), beverages (effect size = 0.54, p = 0.06), and menus (effect size = 0.73, p = 0.08), but changes were not statistically significant. CONCLUSIONS: Core elements of NAPSACC were effectively translated into online tools and successfully implemented by center directors. Results suggest that the online program may have retained its ability to drive change in centers' nutrition environments using a streamlined, self-directed, and flexible implementation approach. Results need to be confirmed in a larger more definitive trial. TRIAL REGISTRATION: NCT02889198 (retrospectively registered). PMID- 29162058 TI - Cognitive rehabilitation and mindfulness in multiple sclerosis (REMIND-MS): a study protocol for a randomised controlled trial. AB - BACKGROUND: Cognitive problems frequently occur in patients with multiple sclerosis (MS) and profoundly affect their quality of life. So far, the best cognitive treatment options for MS patients are a matter of debate. Therefore, this study aims to investigate the effectiveness of two promising non pharmacological treatments: cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT). Furthermore, this study aims to gain additional knowledge about the aetiology of cognitive problems among MS patients, since this may help to develop and guide effective cognitive treatments. METHODS/DESIGN: In a dual-centre, single-blind randomised controlled trial (RCT), 120 MS patients will be randomised into one of three parallel groups: CRT, MBCT or enhanced treatment as usual (ETAU). Both CRT and MBCT consist of a structured 9-week program. ETAU consists of one appointment with an MS specialist nurse. Measurements will be performed at baseline, post-intervention and 6 months after the interventions. The primary outcome measure is the level of subjective cognitive complaints. Secondary outcome measures are objective cognitive function, functional brain network measures (using magnetoencephalography), psychological symptoms, well-being, quality of life and daily life functioning. DISCUSSION: To our knowledge, this will be the first RCT that investigates the effect of MBCT on cognitive function among MS patients. In addition, studying the effect of CRT on cognitive function may provide direction to the contradictory evidence that is currently available. This study will also provide information on changes in functional brain networks in relation to cognitive function. To conclude, this study may help to understand and treat cognitive problems among MS patients. TRIAL REGISTRATION: This trial was prospectively registered at the Dutch Trial Registration (number NTR6459 , registered on 31 May 2017). PMID- 29162059 TI - Suppression of microRNA159 impacts multiple agronomic traits in rice (Oryza sativa L.). AB - BACKGROUND: microRNAs (miRNAs) are important regulators in plant growth and development. miR159 is a conserved miRNA among different plant species and has various functions in plants. Studies on miR159 are mostly done on model plant, Arabidopsis thaliana. In rice, studies on miR159 were either based upon genome wide expression analyses focused upon responses to different nitrogen forms and abiotic stress or upon phenotypic studies of transgenic plants overexpressing its precursor. STTM (Short Tandem Target Mimic) is an effective tool to block the activity of endogenous mature miRNA activity in plant. Therefore, specific roles of miR159 in rice could be explored by down regulating miR159 through STTM. RESULTS: In this study, expression of mature miR159 was successfully suppressed by STTM which resulted in the increased expressions of its two targets genes, OsGAMYB and OsGAMYBL1 (GAMYB-LIKE 1). Overall, STTM159 plants exhibited short stature along with smaller organ size and reduction in stem diameter, length of flag leaf, main panicle, spikelet hulls and grain size. Histological analysis of stem, leaf and mature spikelet hull showed the reduced number of small vascular bundles (SVB), less number of small veins (SV) between two big veins (LV) and less cell number in outer parenchyma. Gene Ontology (GO) enrichment analysis of differentially expressed genes between wild type plants and STTM159 transgenic plants showed that genes involved in cell division, auxin, cytokinin (CK) and brassinosteroids (BRs) biosynthesis and signaling are significantly down regulated in STTM159 plants. CONCLUSION: Our data suggests that in rice, miR159 positively regulates organ size, including stem, leaf, and grain size due to the promotion of cell division. Further analysis from the RNA-seq data showed that the decreased cell divisions in STTM159 transgenic plants may result, at least partly from the lower expression of the genes involved in cell cycle and hormone homeostasis, which provides new insights of rice miR159-specific functions. PMID- 29162060 TI - Long-term prognosis of chronic cough: a prospective, observational cohort study. AB - BACKGROUND: The long-term prognosis of chronic cough and its determinants need to be clarified. METHODS: This is a prospective, observational cohort study. Eighty nine unselected subjects with chronic (> 8 weeks' duration) cough were carefully investigated: Clinical examination, symptom questionnaire, Leicester Cough Questionnaire (LCQ), skin prick tests, ambulatory peak expiratory flow monitoring, spirometry before and after 0.4 mgs of salbutamol, exhaled nitric oxide concentration measurement, hypertonic saline cough provocation test, and histamine bronchial provocation test. After five years, a letter was sent to the subjects containing questions about continuation of cough, smoking, indoor exposures, presence of co-morbidities, and current medication. It also contained LCQ and Cough Clinic diagnostic questionnaire. Sixty-eight subjects (76%) responded. RESULTS: At five years, continuing regular cough was present in 31 (46%) of the subjects and continuing impairment in cough-related quality of life (less than 1.3 points' improvement in LCQ) in 32 (47%). Continuing regular cough was associated with presence of chronic rhinitis or esophageal reflux disease, baseline mild airway responsiveness to histamine, and baseline strong cough responsiveness to hypertonic saline. Continuing impairment in cough-related quality of life was associated with high body mass index, absence of atopy, absence of pets, and high number of background disorders (esophageal reflux disease, asthma, or chronic rhinitis). CONCLUSIONS: Almost half of subjects with chronic cough suffered of the disorder at five years from initial assessment. Several possible determinants of poor prognosis could be identified. PMID- 29162061 TI - Medical student attitudes and educational interventions to prevent neurophobia: a longitudinal study. AB - BACKGROUND: With an aging American population, the burden of neurologic disease is intensifying and the decline in neurology residents and practicing neurologists is leaving these patients helpless and unable to find care. 'Neurophobia', a chronic illness that begins early in medical school, has been identified as a cause for the low number of neurology residents. METHODS: A longitudinal study surveyed medical students at the beginning of their first year (M1) and then again at the beginning of their second year (M2). Three neuroscience educational interventions were studied: team based learning (TBL), case based teaching (CBT), and problem based learning (PBL). Participants provided self-reported neurophobia levels, attitudes about neuroscience, and the effectiveness of educational interventions. RESULTS: A total of 446 students during M1 and 206 students during M2 participated in the survey. A significant change in self-reported neurophobia (p = 0.035) was observed from 19% in M1 to 26% in M2. Neuroscience knowledge and confidence managing a neurologic condition also significantly increased (p < 0.001 and p = 0.038 respectively). Perceived interest, difficulty, and desire to pursue a career in neuroscience did not a change significantly. Majority of students perceived CBT (76%), TBL (56%), and PBL (66%) beneficial. Only CBT demonstrated a statistical difference (p = 0.026) when stratified by self-reported change in neurophobia. CONCLUSION: An increase in neurophobia after completing a neuroscience was observed but the prevalence rate of 26% was lower than previous studies. Knowledge about neuroscience increased significantly and educational interventions were considered beneficial by students. Thus, interventions that increase knowledge and decrease neurophobia can lead to an increase in students pursuing neurology residencies. PMID- 29162062 TI - Rural households at risk of malaria did not own sufficient insecticide treated nets at Dabat HDSS site: evidence from a cross sectional re-census. AB - BACKGROUND: Malaria is the leading cause of disease burden across the world, especially in African countries. Ethiopia has designed a five year (2011-2015) plan to cover 100% of the households in malarious areas with one insecticide treated net (ITN) for every two persons, and to raise consistent ITN utilization to at least 80%. However, evidence on ownership of ITN among malarious rural households in northwest Ethiopia is quite limited. Hence, the present study aimed at assessing ownership of ITN and associated factors among rural households at risk of malaria at Dabat Health and Demographic Surveillance System site, northwest Ethiopia. METHODS: A cross sectional re-census was carried out in Dabat Health and Demographic Surveillance System site during peak malaria seasons from October to December, 2014. Data for 15,088 households at Dabat Health and Demographic Surveillance System site were used for the analysis. Descriptive measures and binary logistic regression were carried out. RESULTS: Among those who owned at least one ITN, 53.4% were living at an altitude >2500 m above sea level. However, out of households living at an altitude <2000 m above sea level, 15.8% (95% CI 14.4%, 17.3%) owned ITN at an average of 4.3 +/- 2.1 persons per ITN. Of these, 69.5% (95% CI 64.7%, 74.1%) used the ITN. Among utilizing households at malarious areas, 23.7% prioritized pregnant women and 31.4% children to use ITN. The availability of radio receiver/mobile (AOR 1.60, 95%CI 1.08, 2.35) and secondary/above educational status of household member (AOR 1.54, 95%CI 1.19, 2.04) were predictors of ownership of ITN. CONCLUSION: Rural households at risk of malaria did not own a sufficient number of ITN though the utilization is promising. Moreover, prioritizing children and pregnant women to sleep under ITN remains public health problems. Programmers, partners and implementers should consider tailored intervention strategy stratified by altitude in distributing ITN. ITN distribution should also be accompanied by using exhaustive promotion strategies that consider people without access to any source of information, and educating households to prioritize pregnant and under five children to sleep under ITN. PMID- 29162063 TI - Elevated Aspergillus-specific antibody levels among HIV infected Ugandans with pulmonary tuberculosis. AB - BACKGROUND: The incidence of tuberculosis (TB) is high among human immunodeficiency virus (HIV) infected Ugandans. Recent evidence suggests that Chronic Pulmonary Aspergillosis and Aspergillus sensitisation might be responsible for significant mortality in patients treated for tuberculosis in Uganda. METHODS: We retrieved and tested paired serum aliquots for 101 HIV-TB co infected patients at the beginning and week 24 of TB treatment. We tested samples for Aspergillus-specific immunoglobulin G (IgG) and immunoglobulin E (IgE) using ImmunoCAP(r); and Aspergillus-specific IgG and total serum IgE using Immulite(r) immunoassays. We compared antibody levels between baseline and week 24, relating them to selected baseline characteristics. RESULTS: 10% of the patients had elevated Aspergillus-specific IgE (Aspergillus sensitization) and Aspergillus specific IgG antibodies were elevated in 9% of the patients at the end of TB treatment. There was a significant fall in the Aspergillus-specific IgG antibody levels between baseline and week 24 (P = 0.02). Patients with cluster of differentiation 4 (CD4) T-cell count <100 cells/MUl and those who were not on anti-retroviral therapy at baseline had more elevated Aspergillus-specific IgG antibodies (P = 0.01, P = 0.03). The ImmunoCAP(r) Aspergillus-specific IgG antibody titres were higher at week 24 than baseline with more positives at week 24; even though the difference in means was small. However, this difference was statistically significant (P = 0.02). Pulmonary infiltrates were the commonest x ray abnormality and only 5% of the patients had pulmonary cavities on chest x-ray at week 24. CONCLUSION: These results suggest that Aspergillus infection may complicate active pulmonary TB and further studies including fungal culture and thoracic imaging may now be indicated to measure the prevalence of pulmonary aspergillosis complicating tuberculosis. TRIAL REGISTRATION: The SOUTH trial was registered prospectively. ClinicalTrials.gov Identifier: NCT01782950 ; Registration date: 4th February 2013; Last verified: 13th April 2015. PMID- 29162064 TI - Effect of exclusive breastfeeding on selected adverse health and nutritional outcomes: a nationally representative study. AB - BACKGROUND: Despite growing evidence in support of exclusive breastfeeding (EBF) among infants in the first 6 months of birth, the debate over the optimal duration of EBF continues. This study examines the effect of termination of EBF during the first 2, 4 and 6 months of birth on a set of adverse health and nutritional outcomes of infants. METHODS: Three waves of Bangladesh Demographic and Health Survey data were analysed using multivariate regression. The adverse health outcomes were: an episode of diarrhea, fever or acute respiratory infection (ARI) during the 2 weeks prior to the survey. Nutritional outcomes were assessed by stunting (height-for-age), wasting (weight-for-height) and underweight (weight-for-age). Population attributable fraction was calculated to estimate percentages of these six outcomes that could have been prevented by supplying EBF. RESULTS: Fifty-six percent of infants were exclusively breastfed during the first 6 months. Lack of EBF increased the odds of diarrhea, fever and ARI. Among the babies aged 6 months or less 27.37% of diarrhea, 13.24% of fever and 8.94% of ARI could have been prevented if EBF was not discontinued. If EBF was terminated during 0-2 months, 2-4 months the odds of becoming underweight were 2.16 and 2.01 times higher, respectively, than babies for whom EBF was not terminated. CONCLUSION: Children who are not offered EBF up to 6 months of their birth may suffer from a range of infectious diseases and under-nutrition. Health promotion and other public health interventions should be enhanced to encourage EBF at least up to six-month of birth. TRAIL REGISTRATION: Data of this study were collected following the guidelines of ICF International and Bangladesh Medical Research Council. The registration number of data collection is 132,989.0.000 and the data-request was registered on September 11, 2016. PMID- 29162065 TI - From policy to practice: exploring the implementation of antiretroviral therapy access and retention policies between 2013 and 2016 in six sub-Saharan African countries. AB - BACKGROUND: Understanding the implementation of 2013 World Health Organization (WHO) consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection at the facility level provides important lessons for the roll-out of future HIV policies. METHODS: A national policy review was conducted in six sub-Saharan African countries to map the inclusion of the 2013 WHO HIV treatment recommendations. Twenty indicators of policy adoption were selected to measure ART access (n = 12) and retention (n = 8). Two sequential cross-sectional surveys were conducted in facilities between 2013/2015 (round 1) and 2015/2016 (round 2) from ten health and demographic surveillance sites in Kenya, Malawi, South Africa, Tanzania, Uganda and Zimbabwe. Using standardised questionnaires, facility managers were interviewed. Descriptive analyses were used to assess the change in the proportion of facilities that implemented these policy indicators between rounds. RESULTS: Although, expansion of ART access was explicitly stated in all countries' policies, most lacked policies that enhanced retention. Overall, 145 facilities were included in both rounds. The proportion of facilities that initiated ART at CD4 counts of 500 or less cells/MUL increased between round 1 and 2 from 12 to 68%, and facilities initiating patients on 2013 WHO recommended ART regimen increased from 42 to 87%. There were no changes in the proportion of facilities reporting stock-outs of first-line ART in the past year (18 to 11%) nor in the provision of three-month supply of ART (43 to 38%). None of the facilities provided community-based ART delivery. CONCLUSION: The increase in ART initiation CD4 threshold in most countries, and substantial improvements made in the provision of WHO recommended first-line ART regimens demonstrates that rapid adoption of WHO recommendations is possible. However, improved logistics and resources and/or changes in policy are required to further minimise ART stock-outs and allow lay cadres to dispense ART in the community. Increased efforts are needed to offer longer durations between clinic visits, a strategy purported to improve retention. These changes will be important as countries move to implement the revised 2015 WHO guidelines to initiate all HIV positive people onto ART regardless of their immune status. PMID- 29162067 TI - Necrotizing fasciitis after high-dose rate brachytherapy and external beam radiation for prostate cancer: a case report. AB - BACKGROUND: In recent years, the delayed side effects associated with radiotherapy for prostate cancer have drawn the interest of urologists. Although urosymphyseal fistula is one of these delayed side effects, this serious complication is rarely described in literature and is poorly recognized. CASE PRESENTATION: We report our experience in treating a 77-year-old male patient with necrotizing fasciitis after high-dose rate brachytherapy plus external beam radiation for prostate cancer. The patient was referred to our hospital with complaints of inguinal swelling and fever. He had a past history of radiotherapy for prostate cancer and subsequent transurethral operation for a stricture of the urethra. Computed tomography showed extensive gas within the femoral and retroperitoneal tissues and pubic bone fracture. Surgical exploration suggested that necrotizing fasciitis was caused by urosymphyseal fistula. CONCLUSION: To the best of our knowledge, this is the first case report of necrotizing fasciitis caused by urosymphyseal fistula after radiotherapy for prostate cancer. There is a strong association between urosymphyseal fistula and prostate radiotherapy with subsequent surgical intervention for bladder neck contracture or urethral stricture. Therefore, surgical treatment for bladder neck contracture or urethral stricture after radiotherapy for prostate cancer should be performed with care. The present case emphasizes the importance of early diagnosis of urosymphyseal fistula. Immediate removal of necrotic tissues and subsequent urinary diversion in the present case may have led to good patient outcome. PMID- 29162066 TI - Effect of sivelestat sodium in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Sivelestat is widely used in treating acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), although the clinical efficacy of sivelestat remains controversial. This study aimed to evaluate the impact of sivelestat in patients with ALI/ARDS. METHODS: Electronic databases, PubMed, Embase, and the Cochrane Library, were searched to identify trials through April 2017. Randomized controlled trials (RCTs) were included irrespective of blinding or language that compared patients with and without sivelestat therapy in ALI/ARDS. A random-effects model was used to process the data, and the relative risk (RR) and standard mean difference (SMD) with corresponding 95% confidence intervals (CIs) were used to evaluate the effect of sivelestat. RESULTS: Six RCTs reporting data on 804 patients with ALI/ARDS were included. Overall, no significant difference was found between sivelestat and control for the risk of 28-30 days mortality (RR: 0.94; 95% CI: 0.71-1.23; P = 0.718). Sivelestat therapy had no significant effect on ventilation days (SMD: 0.05; 95% CI: -0.27 to 0.38; P = 0.748), arterial oxygen partial pressure (PaO2)/fractional inspired oxygen (FiO2) level (SMD: 0.48; 95% CI: -0.45 to 1.41; P = 0.315), and intensive care unit (ICU) stays (SMD: -9.87; 95% CI: -24.30 to 4.56; P = 0.180). The results of sensitivity analysis indicated that sivelestat therapy might affect the PaO2/FiO2 level in patients with ALI/ARDS (SMD: 0.87; 95% CI: 0.39 to 1.35; P < 0.001). CONCLUSIONS: Sivelestat therapy might increase the PaO2/FiO2 level, while it had little or no effect on 28-30 days mortality, ventilation days, and ICU stays. These findings need to be verified in large-scale trials. PMID- 29162068 TI - New steps of robot-assisted radical prostatectomy using the extraperitoneal approach: a propensity-score matched comparison between extraperitoneal and transperitoneal approach in Japanese patients. AB - BACKGROUND: Robot-assisted radical prostatectomy (RARP) is commonly performed using the transperitoneal (TP) approach with six trocars over an 8-cm distance in the steep Trendelenburg position. In this study, we investigated the feasibility and the benefit of using the extraperitoneal (EP) approach with six trocars over a 4-cm distance in a flat or 5 degrees Trendelenburg position. We also introduced four new steps to the surgical procedure and compared the surgical results and complications between the EP and TP approach using propensity score matching. METHODS: Between August 2012 and August 2016, 200 consecutive patients without any physical restrictions underwent RARP with the EP approach in a less than 5 degrees Trendelenburg position, and 428 consecutive patients underwent RARP with the TP approach in a steep Trendelenburg position. Four new steps to RARP using the EP approach were developed: 1) arranging six trocars; 2) creating the EP space using laparoscopic forceps; 3) holding the separated prostate in the EP space outside the robotic view; and 4) preventing a postoperative inguinal hernia. Clinicopathological results and complications were compared between the EP and TP approaches using propensity score matching. Propensity scores were calculated for each patient using multivariate logistic regression based on the preoperative covariates. RESULTS: All 200 patients safely underwent RARP using the EP approach. The mean volume of estimated blood loss and duration of indwelling urethral catheter use were significantly lower with the EP approach than the TP approach (139.9 vs 184.9 mL, p = 0.03 and 5.6 vs 7.7 days, p < 0.01, respectively). No significant differences in the positive surgical margin were observed. None of the patients developed an inguinal hernia postoperatively after we introduced this technique. CONCLUSIONS: The EP approach to RARP was safely performed regardless of patient physique or contraindications to a steep Trendelenburg position. Our method, which involved using the EP approach to perform RARP, can decrease the amount of perioperative blood loss, the duration of indwelling urethral catheter use, and the incidence of postoperative inguinal hernia development. PMID- 29162069 TI - Martius' flap for recurrent perineal and rectovaginal fistulae in a patient with Crohn's disease, endometriosis and a mullerian anomaly. AB - BACKGROUND: Rectovaginal fistulas represent 5% of all anorectal fistulae and are a disastrous manifestation of Crohn's disease that negatively affects patients' social and sexual quality of life. Treatment remains challenging for colorectal surgeons, and the recurrence rate remains high despite the numerous available options. CASE PRESENTATION: We describe a 31-year-old female patient with a Crohn's disease-related recurrent perineo-vaginal and recto-vaginal fistulae and a concomitant mullerian anomaly. She complained of severe dyspareunia associated with penetration difficulties. The patient's medical history was also significant for a previous abdominal laparoscopic surgery for endometriosis for the removal of macroscopic nodules and a septate uterus with cervical duplication and a longitudinal vaginal septum. The patient was successfully treated using a Martius' flap. The postoperative outcome was uneventful, and no recurrence of the fistula occurred at the last follow-up, eight months from the closure of the ileostomy. CONCLUSION: Martius' flap was first described in 1928, and it is considered a good option in cases of rectovaginal fistulas in patients with Crohn's disease. The patient should be referred to a colorectal centre with expertise in this disease to increase the surgical success rate. PMID- 29162070 TI - The R.I.R.S. scoring system: An innovative scoring system for predicting stone free rate following retrograde intrarenal surgery. AB - BACKGROUND: To establish and internally validate an innovative R.I.R.S. scoring system that allows urologists to preoperatively estimate the stone-free rate (SFR) after retrograde intrarenal surgery (RIRS). METHODS: This study included 382 eligible samples from a total 573 patients who underwent RIRS from January 2014 to December 2016. Four reproducible factors in the R.I.R.S. scoring system, including renal stone density, inferior pole stone, renal infundibular length and stone burden, were measured based on preoperative computed tomography of urography to evaluate the possibility of stone clearance after RIRS. RESULTS: The median cumulative diameter of the stones was 14 mm, and the interquartile range was 10 to 21. The SFR on postoperative day 1 in the present cohort was 61.5% (235 of 382), and the final SFR after 1 month was 73.6% (281 of 382). We established an innovative scoring system to evaluate SFR after RIRS using four preoperative characteristics. The range of the R.I.R.S. scoring system was 4 to 10. The overall score showed a great significance of stone-free status (p < 0.001). The area under the receiver operating characteristic curve of the R.I.R.S. scoring system was 0.904. CONCLUSIONS: The R.I.R.S. scoring system is associated with SFR after RIRS. This innovative scoring system can preoperatively assess treatment success after intrarenal surgery and can be used for preoperative surgical arrangement and comparisons of outcomes among different centers and within a center over time. PMID- 29162071 TI - Acceptability of a digital health intervention alongside physiotherapy to support patients following anterior cruciate ligament reconstruction. AB - BACKGROUND: Physiotherapy rehabilitation following surgical reconstruction to the Anterior Cruciate Ligament (ACL) can take up to 12 months to complete. Given the lengthy rehabilitation process, a blended intervention can be used to compliment face-to-face physiotherapy with a digital exercise intervention. In this study, we used TRAK, a web-based tool that has been developed to support knee rehabilitation, which provides individually tailored exercise programs with videos, instructions and progress logs for each exercise, relevant health information and a contact option that allows a patient to email a physiotherapist for additional support. The aim of this study was to evaluate the acceptability of TRAK-based blended intervention in post ACL reconstruction rehabilitation. METHODS: A qualitative research design using semi-structured interviews was used on a convenience sample of participants following an ACL reconstruction, and their treating physiotherapists, in a London NHS hospital. Participants were asked to use TRAK alongside face-to-face physiotherapy for 16 weeks. Interviews were carried out, audio recorded, transcribed verbatim and coded by two researchers independently. Data were analyzed using thematic analysis. RESULTS: Of the 25 individuals that were approached to be part of the study, 24 consented, comprising 8 females and 16 males, mean age 30 years. 17 individuals used TRAK for 16 weeks and were available for interview. Four physiotherapists were also interviewed. The six main themes identified from patients were: the experience of TRAK rehabilitation, personal characteristics for engagement, strengths and weaknesses of the intervention, TRAK in the future and attitudes to digital healthcare. The main themes from the physiotherapist interviews were: potential benefits, availability of resources and service organization to support use of TRAK. CONCLUSIONS: TRAK was found to be an acceptable method of delivering ACL rehabilitation alongside face-to-face physiotherapy. Patients reported that TRAK, specifically the videos, increased their confidence and motivation with their rehabilitation. They identified ways in which TRAK could be developed in the future to meet technological expectations and further support rehabilitation. For Physiotherapists time and availability of computers affected acceptability. Organization of care to support integration of digital exercise interventions such as TRAK into a blended approach to rehabilitation is required. PMID- 29162072 TI - Functional midterm follow-up comparison of stemless total shoulder prostheses versus conventional stemmed anatomic shoulder prostheses using a 3D-motion analysis. AB - BACKGROUND: The aim of this study is to compare the functional midterm outcome of stemless shoulder prostheses with standard anatomical stemmed shoulder prostheses and to show that the STEMLESS results are comparable to the STEMMED with respect to active maximum range of shoulder motion (ROM) and Constant score (CS). METHODS: Seventeen patients underwent total shoulder arthroplasty (TSA) in 25 shoulder joints. Stemless TSA was performed in 12 shoulder joints (group STEMLESS), third-generation stemmed TSA in 13 shoulder joints (group STEMMED). Functional results were documented using the CS. 3D-motion-analysis using the Heidelberg upper extremity model (HUX) was conducted to measure active maximum (ROM). RESULTS: The group STEMLESS achieved a CS of 67.9 (SD 12.0) points and the group STEMMED of 70.2 (SD 5.8 points) without significant difference between the groups (p = 0.925). The maximum ROM of the group STEMLESS, ascertained by 3-D motion-analysis, was in forward flexion 125.5 degrees (SD 17.2 degrees ), in extension 49.4 degrees (SD 13.8 degrees ), in abduction 126.2 degrees (SD 28.5 degrees ) and in external rotation 40.3 degrees (SD 13.9 degrees ). The maximum ROM of the group STEMMED, also ascertained by 3-D-motion analysis, was in forward flexion 135.0 degrees (SD 16.8 degrees ), in extension 47.2 degrees (SD 11.5 degrees ), in abduction 136.3 degrees (SD 24.2 degrees ) and in external rotation 40.1 degrees (SD 12.2 degrees ). The maximum ROM of the STEMLESS group was lower in forward flexion and abduction, higher in extension and almost identical in external rotation. But there was no significant difference (forward flexion p = 0.174, extension p = 0.470, abduction p = 0.345, external rotation p = 0.978). CONCLUSION: Both types of shoulder prostheses achieve a similar and good active ROM and similar results in CS. TRIAL REGISTRATION: DRKS00013166 , retrospectively registered, 11.10.2017. PMID- 29162073 TI - Patient navigation to improve diabetes outpatient care at a safety-net hospital: a retrospective cohort study. AB - BACKGROUND: Recent emphasis on value based care and population management, such as Accountable Care Organizations in the United States, promote patient navigation to improve the quality of care and reduce costs. Evidence supporting the efficacy of patient navigation for chronic disease care is limited. The objective of this study was to evaluate the effect of a patient navigation program on medical and administrative outcomes among patients with diabetes in an urban, safety-net hospital clinic setting. METHODS: A retrospective cohort study with pre- and post-intervention periods was conducted. Eligible patients were those with A1C >= 8.5% and at least one appointment no-show in the previous 12 months. The intervention and reference groups were balanced on observed characteristics and baseline outcome levels using propensity score matching. The effect of patient navigation was isolated using the difference-in-differences approach. Primary outcomes were A1C, low-density lipoprotein cholesterol, triglycerides, random urine microalbumin, the number of scheduled appointments, clinic visits, emergency visits, and inpatient stays, and the percentage of arrivals, cancellations, and no-shows to scheduled appointments. RESULTS: Of 797 eligible patients, 328 entered the navigation program. Matching reduced the sample size to 392 individuals (196 in each group). Patient navigation resulted in improved A1C (-1.1 percentage points; p < .001), more scheduled appointments (+ 5.3 per year; p < .001), more clinic visits (+6.4 per year; p < .001), more arrivals to scheduled appointments (+7.4 percentage points; p = .009) and fewer no-shows (-9.8 percentage points; p < .001). CONCLUSIONS: Navigation was associated with improved glycemic control and better clinic engagement among patients with diabetes. Further research is important to identify what features of navigation in diabetes care are critical to achieving success and to understand navigators' role in other settings. PMID- 29162074 TI - The role of cage height on the flexibility and load sharing of lumbar spine after lumbar interbody fusion with unilateral and bilateral instrumentation: a biomechanical study. AB - BACKGROUND: One- and two-level lumbar interbody fusion with unilateral instrumentation is as effective as that with bilateral instrumentation. The height of the interbody cage influences the operated segment stability and the fusion technique success. The purpose of this research was to determine the effect of the fusion cage height (i.e. long and short) on both the stability (based on flexibility measures) and load sharing of the unilateral and bilateral instrumented transforaminal lumbar interbody fusion (TLIF) technique. METHODS: The flexibility and load sharing tests were performed on seven human lumbar spines. Different configurations combining a long or short cage with a unilateral, bilateral, or no posterior fixation were used to stabilize the operated segment. Two sets of modular cages were designed for each type of test to simulate the long and short cages. During the flexibility test, a pure-moment load of 7.5 Nm was applied. The range of motion (ROM) was recorded for flexion extension, lateral bending, and axial rotation. During the load sharing test, an axial-compression load of 400 N was applied. The load bearing of the cages was recorded using a cage-embedded load cell. RESULTS: When the fusion cage height decreased 2 mm, the segment flexibility with unilateral fixation showed a significant increase in the ROM for flexion-extension, lateral bending, and axial rotation of 74.9, 83.8, and 175.2% (P < 0.01), respectively. In contrast, for bilateral fixation, the height decrease resulted in no significant change in ROM for flexion-extension (P = 0.686), lateral bending (P = 0.698), and axial rotation (P = 0.133). Using a short fusion cage, the load bearing decreased in 17.1, 21.5, and 54.1% (P < 0.05) for the cage alone, unilateral, and bilateral fixation, respectively. CONCLUSIONS: A cage longer than the intervertebral space should be chosen to increase the stability and intervertebral graft load borne when performing TLIF with unilateral instrumentation. PMID- 29162075 TI - The Antibiofilm efficacy of nitric oxide on soft contact lenses. AB - BACKGROUND: To investigate the antibiofilm efficacy of nitric oxide (NO) on soft contact lenses. METHODS: Nitrite (NO precursor) release from various concentrations (0-1000 MUM) of sodium nitrite (NaNO2, NO donor) was measured by Griess Assay. Cell viability assay was performed using human corneal epithelial cell under various concentration (0-1000 MUM) of NaNO2. Biofilm formation on soft contact lenses was achieved by adding Staphylococcus aureus or Pseudomonas aeruginosa to the culture media. Various concentrations of NaNO2 (0-1000 MUM) were added to the culture media, each containing soft contact lens. After incubation in NaNO2 containing culture media for 1, 3, or 7 days, each contact lens was transferred to a fresh, bacteria-free media without NaNO2. The bacteria in the biofilm were dispersed in the culture media for planktonic growth. After reculturing the lenses in the fresh media for 24 h, optical density (OD) of media was measured at 600 nm and colony forming unit (CFU) was counted by spreading media on tryptic soy agar plate for additional 18 h. RESULTS: Nitrite release from NaNO2 showed dose-dependent suppressive effect on biofilm formation. Most nitrite release from NaNO2 tended to occur within 30 min. The viability of human corneal epithelial cells was well maintained at tested NaNO2 concentrations. The bacterial CFU and OD showed dose-dependent decrease in the NaNO2 treated samples on days 1, 3 and 7 for both Staphylococcus aureus and Pseudomonas aeruginosa. CONCLUSIONS: NO successfully inhibited the biofilm formation by Staphylococcus aureus or Pseudomonas aeruginosa on soft contact lenses in dose-dependent manner. PMID- 29162076 TI - Preoperative prone position exercises: a simple and novel method to improve tolerance to kyphoplasty for treatment of single level osteoporotic vertebral compression fractures. AB - BACKGROUND: The proper choice of anesthesia for kyphoplasty remains controversy. There are only a few clinical studies specially focusing on and giving detailed information about this treatment under local anesthesia with or without conscious sedation. To evaluate the effect of preoperative prone position exercises on patient tolerance to percutaneous kyphoplasty under local anesthesia. METHODS: Eighty-three patients with single level osteoporotic vertebral compression fractures were nonrandomly assigned to undergo percutaneous kyphoplasty under local anesthesia with preoperative prone position exercises or without. The number of procedure with or without a pause, need for intravenous sedation, and patient satisfactory were recorded and analyzed. Clinical outcomes were assessed using the visual analog scale and the Oswestry Disability Index. The follow-up time was 6 months. RESULTS: The baseline characteristics of both groups were comparable. The number of procedure without a pause in the exercises group was more than the control group (30/42 patients and 10/41 patients, respectively, P < 0.001), and fewer patients required intravenous sedation in the exercises group (7/42 and 28/41, respectively, P < 0.001). Patients in the exercises group were more satisfied compared to the control group (41/42 and 32/41, respectively, P < 0.01). There were no significant differences between the two groups with regard to improvement in pain and functional scores at all postoperative intervals. CONCLUSIONS: Prone position exercises may improve patient tolerance and satisfaction and reduce the need for intravenous sedation for those with single level vertebral compression fracture undergoing kyphoplasty under local anesthesia. We expect large sample size and multi-center randomized controlled trial studies to be conducted. PMID- 29162077 TI - Subtalar instability: imaging features of subtalar ligaments on 3D isotropic ankle MRI. AB - BACKGROUND: MRI analysis of subtalar ligaments in the tarsal sinus has not been well performed. We retrospectively investigated the appearance of subtalar ligaments using 3D isotropic MRI and compared imaging findings of subtalar ligaments between patients with subtalar instability (STI) and controls. METHODS: Preoperative MRIs of 23 STI patients treated with arthroscopic subtalar reconstruction were compared to MRIs of 23 age- and sex-matched control subjects without STI. Thickness and width of anterior capsular ligament (ACL) and interosseous talocalcaneal ligament (ITCL) as well as thickness of calcaneofibular ligament (CFL) and anterior talofibular ligament (ATFL) were measured. Abnormalities in ACL, ITCL, CFL, ATFL, cervical ligament, and inferior extensor retinaculum were analyzed. RESULTS: STI patients had significantly smaller ACL thickness and ACL width than controls (ACL thickness: 1.73 mm vs. 2.22 mm, p = 0.007; ACL width: 7.21 mm vs. 8.80 mm, p = 0.004). ACL thickness of <=2.1 mm had a sensitivity of 66.7% and a specificity of 66.7% for diagnosis of STI. ACL width of <=7.9 mm had a sensitivity of 80.0% and a specificity of 76.2% for the diagnosis of STI. However, thickness and width of ITCL, thickness of CFL, or thickness of ATFL was not significantly different between the two groups. Absence or complete tear of ACL was significantly more frequent in STI patients than that in controls (34.8% vs. 8.7%, p = 0.035). Complete tear of CFL and ATFL was more common in STI patients than that in controls, although the difference between the two groups was not statistically significant. Abnormalities of ITCL, cervical ligament, or inferior extensor retinaculum were not significantly different between the two groups. CONCLUSIONS: MRI features of thin or narrow ACLs may suggest STI. Absence or complete tear of ACL was significantly more common in STI patients than that in controls. PMID- 29162078 TI - A tailored counseling and home-based rehabilitation program to increase physical activity and improve mobility among community-dwelling older people after hospitalization: protocol of a randomized controlled trial. AB - BACKGROUND: Physical activity (PA) decreases during hospitalization. In particular, the amount of PA engaged in by older people who are hospitalized following musculoskeletal injury is likely to be limited for months after discharge home. Given the importance of an active lifestyle for their recovery and the prevention of future adverse outcomes, there is clearly a need for interventions to increase PA. This article describes the protocol of a randomized controlled trial set up to investigate the effects of a physical activity oriented home rehabilitation program (ProPA) on PA and the restoration of mobility in community-dwelling older people. METHODS: Men and women aged 60 years or older hospitalized due to a musculoskeletal injury or disorder in the back or lower limbs are recruited. After discharge from hospital to home, participants are randomized into a six-month ProPA program or a standard care (control) group. The ProPA program consists of a motivational interview, goal attainment process, guidance for safe walking, a progressive home exercise program and physical activity counseling. In addition, frail participants who are not able to go outdoors alone receive support from volunteers. Primary outcomes are PA measured using a 3-dimentional accelerometer, and mobility assessed by the Short Physical Performance Battery and self-reports. Secondary outcomes are life space mobility, participation restriction, fear of falling, pain, mood, and grip strength. Information on barriers to and enablers of PA participation are also collected. Data on mortality and use of health services are collected from the national register. In this 6-month intervention, all participants are assessed in their homes at baseline and after three and six months, and at 12 months after randomization they will receive a follow-up questionnaire. DISCUSSION: This study investigates the effects of a rehabilitation program on PA and mobility among older people at risk for increased sedentary time and mobility problems. If positive effects are observed, the program can be considered for incorporation into the health care system and thereby contribute to the rehabilitation of older people who have recently been discharged from hospital. TRIAL REGISTRATION: ISRCTN13461584 . Registered 27 January 2016. PMID- 29162079 TI - Examination of concomitant glenohumeral pathologies in patients treated arthroscopically for calcific tendinitis of the shoulder and implications for routine diagnostic joint exploration. AB - BACKGROUND: Glenohumeral exploration is routinely performed during arthroscopic removal of rotator cuff calcifications in patients with calcific tendinitis of the shoulder (CTS). However, evidence on the prevalence of intraarticular co pathologies is lacking and the benefit of glenohumeral exploration remains elusive. The aim of the present study was to assess and quantify intraoperative pathologies during arthroscopic removal of rotator cuff calcifications in order to determine whether standardized diagnostic glenohumeral exploration appears justified in CTS patients. METHODS: One hundred forty five patients undergoing arthroscopic removal of calcific depots (CD) that failed conservative treatment were included in a retrospective cohort study. Radiographic parameters including number/localization of calcifications and acromial types, intraoperative arthroscopic findings such as configuration of glenohumeral ligaments, articular cartilage injuries, and characteristics of calcifications and sonographic parameters (characteristics/localization of calcification) were recorded. RESULTS: One hundred forty five patients were analyzed. All CDs were removed by elimination with a blunt hook probe via "squeeze-and-stir-technique" assessed postoperatively via conventional X-rays. Neither subacromial decompression nor refixation of the rotator cuff were performed in any patient. Prevalence of glenohumeral co-pathologies, such as partial tears of the proximal biceps tendon (2.1%), superior labral tears from anterior to posterior (SLAP) lesions (1.4%), and/or partial rotator cuff tears (0.7%) was low. Most frequently, glenohumeral articular cartilage was either entirely intact (ICRS grade 0 (humeral head/glenoid): 46%/48%) or showed very mild degenerative changes (ICRS grade 1: 30%/26%). Two patients (1.3%) required intraarticular surgical treatment due to a SLAP lesion type III (n = 1) and an intraarticular rupture of CD (n = 1). CONCLUSIONS: Routine diagnostic glenohumeral exploration does not appear beneficial in arthroscopic treatment of CTS due to the low prevalence of intraarticular pathologies which most frequently do not require surgical treatment. Exploration of the glenohumeral joint in arthroscopic removal of CD should only be performed in case of founded suspicion of relevant concomitant intraarticular pathologies. PMID- 29162080 TI - Modifications to advanced Core decompression for treatment of Avascular necrosis of the femoral head. AB - BACKGROUND: "Advanced Core Decompression" (ACD) is a new technique for treatment of osteonecrosis of the femoral head (ONFH) that includes removal of the necrotic tissue using a percutaneous expandable reamer followed by refilling of the drill hole and the defect with an injectable, hard-setting, composite calcium sulphate (CaSO4)-calcium phosphate (CaPO4) bone graft substitute. As autologous bone has been shown to be superior to all other types of bone grafts, the aim of the study is to present and evaluate a modified technique of ACD with impaction of autologous bone derived from the femoral neck into the necrotic defect. METHODS: A cohort of patients with an average follow-up of 30.06 months (minimum 12 months) was evaluated for potential collapse of the femoral head and any reasons that led to replacement of the operated hip. Only patients in stages 2a to 2c according to the Steinberg classification were included in the study. RESULTS: In 75.9% the treatment was successful with no collapse of the femoral head or conversion to a total hip replacement. Analysis of the results of the different subgroups showed that the success rate was 100% for stage 2a lesions and 84.6% respectively 61.5% for stages 2b and 2c lesions. CONCLUSIONS: Previous studies with a comparable follow-up reported less favourable results for ACD without autologous bone. Especially in stages 2b and 2c the additional use of autologous bone has a positive effect. In comparison to other hip-preserving techniques, the modified ACD technique is a very promising and minimally invasive method for treatment of ONFH. TRIAL REGISTRATION: German clinical trials register ( DRKS00011269 , retrospectively registered). PMID- 29162081 TI - Self-management support and eHealth for patients and informal caregivers confronted with advanced cancer: an online focus group study among nurses. AB - BACKGROUND: Self-management by patients and informal caregivers confronted with advanced cancer is not self-evident. Therefore they might need self-management support from nurses. This article reports on nurses' perspectives on self management support for people confronted with advanced cancer, and nurses' experiences with eHealth in this context. METHODS: Six online focus groups were organized, with a total of 45 Dutch nurses with different educational levels and working in different care settings. Nurses were asked how they support patients and informal caregivers facing advanced cancer in managing physical and psychosocial problems in their daily life. Questions were also asked regarding the nurses' experiences with eHealth. Transcripts of the online focus group discussions were analyzed qualitatively following the principles of thematic analysis. The main themes derived from the analyses were ordered according to the elements in the 5 A's Behavior Change Model. RESULTS: Within the scope of self management support, nurses reported that they discuss the background, personal situation, wishes, and needs of advanced cancer patients ('Assess' in the 5 A's model), and they provide information about cancer and specifically the advanced type ('Advise'). However, nurses hardly give any advice on how patients can manage physical and psychological problems themselves and/or pay any attention to collaborative goal-setting ('Agree'). Neither do they explain how follow-up can be arranged ('Arrange'). In addition, they do not appear to pay much attention to self-management support for informal caregivers. Nurses' attitudes towards eHealth within the scope of self-management support are positive. They see many advantages, such as allowing advanced cancer patients to stay in charge of their own care and lives. However, nurses also explicitly stressed that eHealth can never be a substitute for personal contact between nurses and patients. CONCLUSIONS: Nurses value self-management support and eHealth for advanced cancer patients and their informal caregivers. However, they seem to disregard important elements in the support of self-management, such as providing practical advice, collaborative goal-setting, and arrangement of follow-up. We recommend further promoting and clarifying the essence and importance of self-management support, including self-management support for informal caregivers. PMID- 29162082 TI - Spatial geometric and magnetic resonance signal intensity changes with advancing stages of nucleus pulposus degeneration. AB - BACKGROUND: With advancing stages of degeneration, denaturation and degradation of proteoglycans in the nucleus pulposus (NP) lead to tissue dehydration and signal intensity loss on T2-weighted MR images. Pfirrmann grading is widely used for grading degeneration of intervertebral discs (IVDs). The criterion to differentiate IVDs of Pfirrmann Grade I from the other grades is NP homogeneity. Pfirrmann grading is qualitative and its assessment may be subjective. Therefore, assessment of quantitative objective measures correlating with early disc degeneration may complement the grading. This study aimed to evaluate the applicability of the distance between the center weighted by signal intensity (weighted center) and the geometric center as a parameter of NP homogeneity. Other phenomena related to advancing stages of degeneration were also investigated. METHODS: MR images of 65 asymptomatic volunteers with a total of 288 lumbar IVDs with clearly identifiable nucleus pulposus boundary (Pfirrmann Grade I, II and III) were included in this study. A custom-written program was developed to determine the IVD longitudinal axis, define the NP boundary, and to locate the coordinates of geometric and weighted NP centers on the mid-sagittal image of each studied IVD. The distances between the weighted and geometric centers on the longitudinal axis and the perpendicular axis of each IVD were calculated. RESULTS: The weighted center located posterior to the geometric center, which indicated the signal intensity was lower at the anterior portion of the NP, in 85.8% of studied IVDs. The distance between the weighted and geometric center on the longitudinal axis was significantly shorter in homogeneous (Pfirrmann Grade I) than in inhomogeneous (Grade II) IVDs. The distance on the perpendicular axis in Grade III IVDs was significantly larger than that in Grade I and Grade II IVDs. CONCLUSION: The relationship between the weighted and geometric centers can serve as an indicator for NP homogeneity. The distance between both centers through advancing stages of degeneration demonstrated decrease of signal intensity progressing along the longitudinal axis initially and then along the cranio-caudal direction at later stages. These findings could provide insights of initiation and subsequent progression of degenerative changes in IVDs. PMID- 29162083 TI - Clinical significance of cigarette smoking and dust exposure in pulmonary alveolar proteinosis: a Korean national survey. AB - BACKGROUND: This study aimed to investigate clinical characteristics of Korean PAP patients and to examine the potential risk factors of PAP. METHODS: We retrospectively reviewed medical records of 78 Korean PAP patients diagnosed between 1993 and 2014. Patients were classified into two groups according to the presence/absence of treatment (lavage). Clinical and laboratory features were compared between the two groups. RESULTS: Of the total 78 PAP patients, 60% were male and median age at diagnosis was 47.5 years. Fifty three percent were ever smokers (median 22 pack-years) and 48% had a history of dust exposure (metal 26.5%, stone or sand 20.6%, chemical or paint 17.7%, farming dust 14.7%, diesel 14.7%, textile 2.9%, and wood 2.9%). A history of cigarette smoking or dust exposure was present in 70.5% of the total PAP patients, with 23% having both of them. Patients who underwent lavage (n = 38) presented symptoms more frequently (38/38 [100%] vs. 24/40 [60%], P < 0.001) and had significantly lower PaO2 and DLCO with higher D(A-a)O2 at the onset of disease than those without lavage (n = 40) (P = 0.006, P < 0.001, and P = 0.036, respectively). Correspondingly, the distribution of disease severity score (DSS) differed significantly between the two groups (P = 0.001). Based on these, when the total patients were categorized according to DSS (low DSS [DSS 1-2] vs. high DSS [DSS 3-5]), smoking status differed significantly between the two groups with the proportion of current smokers significantly higher in the high DSS group (11/22 [50%] vs. 7/39 [17.9%], P = 0.008). Furthermore, current smokers had meaningfully higher DSS and serum CEA levels than non-current smokers (P = 0.011 and P = 0.031), whereas no difference was found between smokers and non-smokers. Regarding type of exposed dust, farming dust was significantly associated with more severe form of PAP (P = 0.004). CONCLUSION: A considerable proportion of PAP patients had a history of cigarette smoking and/or dust exposure, suggestive of their possible roles in the development of PAP. Active cigarette smoking at the onset of PAP is associated with the severity of PAP. PMID- 29162084 TI - Infection following fractures of the proximal tibia - a systematic review of incidence and outcome. AB - BACKGROUND: To systematically review all available studies of operatively treated proximal tibia fractures and to report the incidence of superficial or deep infection and subsequent outcomes. METHODS: A systematic review of the literature in Medline, Cochrane, Embase and GoogleScholar was conducted to identify studies with cohorts of patients with infection after surgical treatment of proximal tibia fractures. Studies were included according to predefined inclusion and exclusion criteria. The studies were analysed for methodological deficiencies and quality of outcome reporting based on the Level of Evidence (LOE) and Coleman Methodology Scoring (CMS.) RESULTS: In total 32 studies were included. There was heterogeneity between the studies, in terms of subject of the studies, outcome criteria, fracture type and classification, surgical techniques and length of follow-up. Therefore, no meta-analysis could be performed. The average CMS was 54.2 (range 36-75). The included studies were 25 case series (LOE IV), 6 were prospective cohort studies (LOE III) and one was a prospective randomized trial (LOE I). 203 (12.3%, range: 2.6-45.0%) infections occurred in the overall population (n = 2063). Those were divided into 129 deep infections and 74 superficial infections. Revision due to infection was reported in 29 studies, microbiological results in 6, respectively. 72 (55,8%) of 129 cases reporting outcome after deep infection had an unsatisfactory outcome with substantial limitations of the affected joint and leg. CONCLUSIONS: Postoperative infections are a challenge, sometimes requiring several revisions and often with a worse outcome. Further studies with structured study protocols should be performed for a better understanding of risk factors to improve treatment outcomes. PMID- 29162085 TI - Association of lower urinary tract symptoms and OAB severity with quality of life and mental health in China, Taiwan and South Korea: results from a cross sectional, population-based study. AB - BACKGROUND: Lower urinary tract symptoms (LUTS) and overactive bladder (OAB) symptoms have a substantial effect on quality of life (QoL). We report QoL and mental health results from a LUTS prevalence study in three Asian countries. METHODS: A cross-sectional, population-representative, internet-based study among individuals aged >=40 years in China, Taiwan and South Korea. Instruments included: Overactive Bladder Symptom Score (OABSS); International Prostate Symptom Score (IPSS); other International Continence Society (ICS) symptom questions; health-related QoL 12-item short-form (HRQoL-SF12v2); Work Limitations Questionnaire (WLQ); Hospital Anxiety and Depression Scale (HADS). Presence of LUTS was determined according to ICS criteria, with three symptom groups (storage, voiding and post-micturition). Post-stratification weighting matched the age and sex population distribution per country. Initial data analyses were based on descriptive statistics. Significance testing undertaken post hoc included: independent-samples t-test (differences in HRQoL between sexes and between individuals with/without LUTS; relationship between HRQoL score and OABSS; differences in HADS anxiety and depression scores between individuals with/without LUTS; association between HADS anxiety/depression scores and OABSS), chi-square test (association between LUTS prevalence and workplace productivity) and analysis of variance (differences in HRQoL score and in HADS anxiety/depression scores between individuals with different symptom groups, association between HADS anxiety/depression scores and IPSS). RESULTS: In total, 8284 participants were included. HRQoL scores were significantly worse (p < 0.001) among individuals with versus without LUTS (ICS criteria): mean physical health domain scores were 61.1 (standard deviation [SD], 20.1) and 76.7 (17.0), respectively; corresponding mental health domain scores were 34.8 (12.7) and 43.7 (10.7). Workplace productivity was best among individuals without LUTS (difficulties reported by 2-3% of individuals), and worst in those with all three ICS symptom groups (difficulties reported by 29-38% of individuals; p = 0.001). Mean HADS scores showed significantly worse (p < 0.001) levels of anxiety and depression among individuals with versus without LUTS: anxiety, 6.5 (SD, 3.7) and 4.0 (3.3); corresponding mean depression scores were 6.8 (4.3) and 4.2 (3.6). Increasing OAB severity was also associated with decreasing HRQoL physical and mental health scores. CONCLUSION: LUTS and increasing OAB severity are both associated with impaired QoL, reduced workplace productivity, and increased tendency towards anxiety and depression. These results highlight the need to ensure that individuals with LUTS receive appropriate, effective treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02618421 , registered 26 November 2015 (retrospectively registered). PMID- 29162086 TI - Tribes and tribulations: interdisciplinary eHealth in providing services for people with a traumatic brain injury (TBI). AB - BACKGROUND: eHealth has potential for supporting interdisciplinary care in contemporary traumatic brain injury (TBI) rehabilitation practice, yet little is known about whether this potential is being realised, or what needs to be done to further support its implementation. The purpose of this study was to explore health professionals' experiences of, and attitudes towards eHealth technologies to support interdisciplinary practice within rehabilitation for people after TBI. METHODS: A qualitative study using narrative analysis was conducted. One individual interview and three focus groups were conducted with health professionals (n = 17) working in TBI rehabilitation in public and private healthcare settings across regional and metropolitan New South Wales, Australia. RESULTS: Narrative analysis revealed that participants held largely favourable views about eHealth and its potential to support interdisciplinary practice in TBI rehabilitation. However, participants encountered various issues related to (a) the design of, and access to electronic medical records, (b) technology, (c) eHealth implementation, and (d) information and communication technology processes that disconnected them from the work they needed to accomplish. In response, health professionals attempted to make the most of unsatisfactory eHealth systems and processes, but were still mostly unsuccessful in optimising the quality, efficiency, and client-centredness of their work. CONCLUSIONS: Attention to sources of disconnection experienced by health professionals, specifically design of, and access to electronic health records, eHealth resourcing, and policies and procedures related to eHealth and interdisciplinary practice are required if the potential of eHealth for supporting interdisciplinary practice is to be realised. PMID- 29162087 TI - Investigation of the association between quality of life and depressive symptoms during postpartum period: a correlational study. AB - BACKGROUND: The onset of a major depressive episode is experienced by a large number of women in the weeks or months following delivery. Postpartum depression may deem those women experiencing it incapable of taking care for themselves, their family and their infants, while at the same time it could negatively affect their quality of life. The present study assessed the quality of life of a sample of mothers in Greece, in order to investigate the association between postpartum depression and quality of life (QoL). METHODS: 145 women in a Private-General Obstetrics and Pediatric Clinic in Greece completed the Edinburgh Postnatal Depression scale (EPDS) and SF-36 questionnaire on the third and fourth day after delivery (caesarean or normal childbirth). The data were analyzed using SPSS version 17.0. Linear and logistic regression analysis was performed in order to find the independent factors related to the quality of life and postpartum depression symptoms. RESULTS: 9.9% of the participants experienced postpartum depression symptoms. Significant associations were found between the place of residence and symptoms of postpartum depression, and more specifically, women outside of Attica indicated higher levels of postpartum depression symptoms (p = 0.008) than women living in Attica. The level of education was also found to be significantly associated with postpartum depression symptoms, since women with Primary and Secondary education experienced higher levels of postpartum depression symptoms (p = 0.005) than those with a tertiary education. Concerning quality of life, women with postpartum depression symptoms scored 24.27 lower in "Role-Physical", 15.60 lower in "Bodily pain", 11.45 lower in "General Health", 14.18 lower in dimension of "Vitality", 38.25 lower in Role - Emotional and 16.82 lower in dimension of mental health, compared to those without depression symptoms. CONCLUSION: Postpartum depression symptoms are associated with the quality of life of women after pregnancy, and therefore constitute a powerful predictor of the quality of life. Health care professionals should provide individualized care for the prevention and treatment of Postpartum Depression symptoms in order to help women improve their quality of life. PMID- 29162088 TI - Prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model. AB - BACKGROUND: Glucocorticoid-associated osteonecrosis is an intractable condition, making the establishment of preventative strategies of particular importance. Recently various studies using mesenchymal stem cells (MSC) have been conducted. Using a rabbit glucocorticoid-associated osteonecrosis model we administered green fluorescent protein (GFP)-labeled MSC intravenously to investigate their effect on osteonecrosis. METHODS: A rabbit osteonecrosis model in which methylprednisolone (MP) 20 mg/kg was injected into the gluteus of a Japanese white rabbit was used. Simultaneously with MP, MSC labeled with GFP (GFP-labeled MSC) were injected intravenously. Fourteen days later the animals were killed (MSC(+)/MP(+)/14d), femurs were extracted, and the prevalence of osteonecrosis was determined histopathologically. Also, animals were killed 3 days after simultaneous administration of GFP-labeled MSC and MP (MSC(+)/MP(+)/3d), and western blotting (WB) for GFP was performed of the femur, liver, kidney, lung, blood vessel, and vertebra, in addition to immunohistochemical study of femur. As a control for the histopathological study, animals were killed 14 days after MP administration and intravenous vehicle injection (MSC(-)/MP(+)/14d). For WB, animals were killed 3 days after intravenous GFP-labeled MSC administration and vehicle injection into the gluteus (MSC(+)/MP(-)/3d). RESULTS: In MSC( )/MP(+)/14d osteonecrosis was found in 7 of 10 rabbits (70%), while in MSC(+)/MP(+)/14d, partial bone marrow necrosis was found in only 1 rabbit (12.5%); osteonecrosis was not found in 7 of 8 rabbits (p < 0.05). WB showed expression of GFP in the femur, not in the liver, kidney, lung, blood vessel, or vertebra, of MSC(+)/MP(+)/3d; expression of GFP-labeled MSC was absent in the femur of MSC(+)/MP(-)/3d. In the immunohistochemical study of MSC(+)/MP(+)/3d, homing of GFP-labeled MSC was noted perivascularly in the femur, but not in MSC(+)/MP(-)/3d. CONCLUSIONS: With transvenous MSC administration a significant prophylactic effect against glucocorticoid-associated osteonecrosis was found. Direct administration of MSC to the site of tissue injury requires highly invasive surgery. In contrast, as shown here the simple and hardly invasive intravenous administration of MSC may succeed in preventing osteonecrosis. PMID- 29162089 TI - Patient perspectives on continuity of care: adaption and preliminary psychometric assessment of a Norwegian version of the Nijmegen Continuity Questionnaire (NCQ N). AB - BACKGROUND: Continuity of care is regarded as a core quality element in healthcare. Continuity can be related to one or more specific caregivers but also applies to collaboration within a team or across boundaries of healthcare. Measuring continuity is important to identify problems and evaluate quality improvement of interventions. This study aimed to assess the feasibility and psychometric properties of a Norwegian version of the Nijmegen Continuity Questionnaire (NCQ). METHODS: The NCQ was developed in The Netherlands. It measures patients' experienced continuity of care across multiple care settings and as a multidimensional concept regardless of morbidity. The NCQ comprises 28 items categorised into three subscales; two personal continuity scales, "care giver knows me" and "shows commitment", asked regarding the patient's general practitioner (GP) and the most important specialist; and one "team/cross boundary continuity" scale, asked regarding primary care, specialised care and cooperation between GP and specialist, with a total of seven factors. The NCQ was translated and adapted to Norwegian (NCQ-N) and distributed among patients referred to somatic rehabilitation (N = 984, response rate 34.5%). Confirmatory factor analyses (CFA), Cronbach's alpha, intra-class correlation (ICC) and Bland-Altman plots were used to assess psychometric properties. RESULTS: All patients (N = 375) who had responded to all parts of the NCQ-N were included in CFA. The CFA fit indices (CFI 0.941, RMSEA 0.064 (95% CI 0.059-0.070), SRMR 0.041) support a seven-factor structure in the NCQ-N based on the three subscales of the original NCQ. Cronbach's alpha showed internal consistency (0.84-0.97), and was highest for the team/cross-boundary subscales. The NCQ-N showed overall high reliability with ICC 0.84-91 for personal continuity factors and 0.67-0.91 for team factors, with the lowest score for team continuity within primary care. CONCLUSIONS: Psychometric assessment of the NCQ-N supports that this instrument, based on the three subscales of the original Dutch NCQ, captures the concept of "continuity of care" among adult patients with a variety of longstanding medical conditions who use healthcare on a regular basis. However, its usefulness among varied patient groups, including younger people, patients with acute disorders and individuals with mental health problems, should be further evaluated. PMID- 29162090 TI - Assessment of motivational interviewing: a qualitative study of response process validity, content validity and feasibility of the motivational interviewing target scheme (MITS) in general practice. AB - BACKGROUND: The Motivational Interviewing target Scheme (MITS) is an instrument to assess competency in Motivational Interviewing (MI) and can be used to assess MI in long and brief consultations. In this qualitative study we examined two sources of the Unified Model of Validity, the current standard of assessment validation, in the context of General Practice. We collected evidence concerning response process validity and content validity of the MITS in general practice. Furthermore, we investigated its feasibility. METHODS: Assessing consultations of General Practitioners and GP-trainees (GPs), the assessors systematically noted down their considerations concerning the scoring process and the content of the MITS in a semi-structured questionnaire. Sampling of the GPs was based on maximum variation and data saturation was used as a stopping criterion. An inductive approach was used to analyse the data. In response to scoring problems the score options were adjusted and all consultations were assessed using the original and the adjusted score options. RESULTS: Twenty seven assessments were needed to reach data saturation. In most consultations, the health behaviour was not the reason for encounter but was discussed on top of discussing physical problems. The topic that was most discussed in the consultations was smoking cigarettes. The adjusted score options increased the response process validity; they were more in agreement with theoretical constructs and the observed quality of MI in the consultations. Concerning content validity, we found that the MITS represents the broad spectrum and the current understanding of MI. Furthermore, the MITS proved to be feasible to assess MI in brief consultations in general practice. CONCLUSIONS: Based on the collected evidence the MITS seems a promising instrument to measure MI interviewing in brief consultations. The evidence gathered in this study lays the foundation for research into other aspects of validation. PMID- 29162092 TI - Applying systems biology to biomedical research and health care: a precising definition of systems medicine. AB - BACKGROUND: Systems medicine has become a key word in biomedical research. Although it is often referred to as P4-(predictive, preventive, personalized and participatory)-medicine, it still lacks a clear definition and is open to interpretation. This conceptual lack of clarity complicates the scientific and public discourse on chances, risks and limits of Systems Medicine and may lead to unfounded hopes. Against this background, our goal was to develop a sufficiently precise and widely acceptable definition of Systems Medicine. METHODS: In a first step, PubMed was searched using the keyword "systems medicine". A data extraction tabloid was developed putting forward a means/ends-division. Full-texts of articles containing Systems Medicine in title or abstract were screened for definitions. Definitions were extracted; their semantic elements were assigned as either means or ends. To reduce complexity of the resulting list, summary categories were developed inductively. In a second step, we applied six criteria for adequate definitions (necessity, non-circularity, non-redundancy, consistency, non-vagueness, and coherence) to these categories to derive a so called precising definition of Systems Medicine. RESULTS: We identified 185 articles containing the term Systems Medicine in title or abstract. 67 contained at least one definition of Systems Medicine. In 98 definitions, we found 114 means and 132 ends. From these we derived the precising definition: Systems Medicine is an approach seeking to improve medical research (i.e. the understanding of complex processes occurring in diseases, pathologies and health states as well as innovative approaches to drug discovery) and health care (i.e. prevention, prediction, diagnosis and treatment) through stratification by means of Systems Biology (i.e. data integration, modeling, experimentation and bioinformatics). Our study also revealed the visionary character of Systems Medicine. CONCLUSIONS: Our insights, on the one hand, allow for a realistic identification of actual ethical as well as legal issues arising in the context of Systems Medicine and, in consequence, for a realistic debate of questions concerning its matter and (future) handling. On the other hand, they help avoiding unfounded hopes and unrealistic expectations. This especially holds for goals like improving patient participation which are intensely debated in the context of Systems Medicine, however not implied in the concept. PMID- 29162091 TI - Role of microRNAs in embryo implantation. AB - Failure of embryo implantation is a major limiting factor in early pregnancy and assisted reproduction. Determinants of implantation include the embryo viability, the endometrial receptivity, and embryo-maternal interactions. Multiple molecules are involved in the regulation of implantation, but their specific regulatory mechanisms remain unclear. MicroRNA (miRNA), functioning as the transcriptional regulator of gene expression, has been widely reported to be involved in embryo implantation. Recent studies reveal that miRNAs not only act inside the cells, but also can be released by cells into the extracellular environment through multiple packaging forms, facilitating intercellular communication and providing indicative information associated with physiological and pathological conditions. The discovery of extracellular miRNAs shed new light on implantation studies. MiRNAs provide new mechanisms for embryo-maternal communication. Moreover, they may serve as non-invasive biomarkers for embryo selection and assessment of endometrial receptivity in assisted reproduction, which improves the accuracy of evaluation while reducing the mechanical damage to the tissue. In this review, we discuss the involvement of miRNAs in embryo implantation from several aspects, focusing on the role of extracellular miRNAs and their potential applications in assisted reproductive technologies (ART) to promote fertility efficiency. PMID- 29162093 TI - Receptivity to malaria in the China-Myanmar border in Yingjiang County, Yunnan Province, China. AB - BACKGROUND: The re-establishment of malaria has become an important public health issue in and out of China, and receptivity to this disease is key to its re emergence. Yingjiang is one of the few counties with locally acquired malaria cases in the China-Myanmar border in China. This study aimed to understand receptivity to malaria in Yingjiang County, China, from June to October 2016. METHODS: Light-traps were employed to capture the mosquitoes in 17 villages in eight towns which were categorized into four elevation levels: level 1, 0-599 m; level 2, 600-1199 m; level 3, 1200-1799 m; and level 4, > 1800 m. Species richness, diversity, dominance and evenness were used to picture the community structure. Similarity in species composition was compared between different elevation levels. Data of seasonal abundance of mosquitoes, human biting rate, density of light-trap-captured adult mosquitoes and larvae, parous rate, and height distribution (density) of Anopheles minimus and Anopheles sinensis were collected in two towns (Na Bang and Ping Yuan) each month from June to October, 2016. RESULTS: Over the study period, 10,053 Anopheles mosquitoes were collected from the eight towns, and 15 Anopheles species were identified, the most-common of which were An. sinensis (75.4%), Anopheles kunmingensis (15.6%), and An. minimus (3.5%). Anopheles minimus was the major malaria vector in low-elevation areas (< 600 m, i.e., Na Bang town), and An. sinensis in medium-elevation areas (600-1200 m, i.e., Ping Yuan town). In Na Bang, the peak human-biting rate of An. minimus at the inner and outer sites of the village occurred in June and August 2016, with 5/bait/night and 15/bait/night, respectively. In Ping Yuan, the peak human-biting rate of An. sinensis was in August, with 9/bait/night at the inner site and 21/bait/night at the outer site. The two towns exhibited seasonal abundance with high density of the two adult vectors: The peak density of An. minimus was in June and that of An. sinensis was in August. Meanwhile, the peak larval density of An. minimus was in July, but that of An. sinensis decreased during the investigation season; the slightly acidic water suited the growth of these vectors. The parous rates of An. sinensis and An. minimus were 90.46 and 93.33%, respectively. CONCLUSIONS: The Anopheles community was spread across different elevation levels. Its structure was complex and stable during the entire epidemic season in low-elevation areas at the border. The high human biting rates, adult and larval densities, and parous rates of the two Anopheles vectors reveal an exceedingly high receptivity to malaria in the China-Myanmar border in Yingjiang County. PMID- 29162094 TI - Threats to patient safety in primary care reported by older people with multimorbidity: baseline findings from a longitudinal qualitative study and implications for intervention. AB - BACKGROUND: In primary care, older patients with multimorbidity (two or more long term conditions) are especially likely to experience patient safety incidents. Risks to safety in this setting arise as a result of patient, staff and system factors; particularly where these interact or fail to do so. Recent research and policy highlight the important contribution patients can make to improving safety. Older patients with multimorbidity may have the most to gain from increasing their involvement but before interventions can be developed to support them to improve their patient safety, more needs to be known about how this is threatened and how patients respond to perceived threats. We sought to identify and describe threats to patient safety in primary care among older people with multimorbidity, to provide a better understanding of how these are experienced and to inform the development of interventions to reduce risks to patient safety. METHODS: Twenty-six older people, aged 65 or over, with multimorbidity were recruited to a longitudinal qualitative study. At baseline, data on their health and healthcare were collected through semi-structured interviews. Data were analysed thematically, using a framework developed from a previous synthesis of qualitative studies of patient safety in primary care. RESULTS: Threats to patient safety were organised into six themes, across three domains of health and care. These encompassed all aspects of the patient journey, from access to everyday management. Across the journey, many issues arose due to poor communication, and uncoordinated care created extra burdens for patients and healthcare staff. Patients' sense of safety and trust in their care providers were especially threatened when they felt their needs were ignored, or when they perceived responses from staff as inappropriate or insensitive. CONCLUSIONS: For older patients with multimorbidity, patient safety is intrinsically linked to the challenges people face when managing health conditions, navigating the healthcare system, and negotiating care. We consider the implications of this for the development of interventions to reduce threats to patient safety. Potential patient-centred mechanisms include providing patients with more realistic expectations for primary care, and supporting them to communicate their needs and concerns more effectively. PMID- 29162095 TI - How are compassion fatigue, burnout, and compassion satisfaction affected by quality of working life? Findings from a survey of mental health staff in Italy. AB - BACKGROUND: Quality of working life includes elements such as autonomy, trust, ergonomics, participation, job complexity, and work-life balance. The overarching aim of this study was to investigate if and how quality of working life affects Compassion Fatigue, Burnout, and Compassion Satisfaction among mental health practitioners. METHODS: Staff working in three Italian Mental Health Departments completed the Professional Quality of Life Scale, measuring Compassion Fatigue, Burnout, and Compassion Satisfaction, and the Quality of Working Life Questionnaire. The latter was used to collect socio-demographics, occupational characteristics and 13 indicators of quality of working life. Multiple regressions controlling for other variables were undertaken to predict Compassion Fatigue, Burnout, and Compassion Satisfaction. RESULTS: Four hundred questionnaires were completed. In bivariate analyses, experiencing more ergonomic problems, perceiving risks for the future, a higher impact of work on life, and lower levels of trust and of perceived quality of meetings were associated with poorer outcomes. Multivariate analysis showed that (a) ergonomic problems and impact of work on life predicted higher levels of both Compassion Fatigue and Burnout; (b) impact of life on work was associated with Compassion Fatigue and lower levels of trust and perceiving more risks for the future with Burnout only; (c) perceived quality of meetings, need of training, and perceiving no risks for the future predicted higher levels of Compassion Satisfaction. CONCLUSIONS: In order to provide adequate mental health services, service providers need to give their employees adequate ergonomic conditions, giving special attention to time pressures. Building trustful relationships with management and within the teams is also crucial. Training and meetings are other important targets for potential improvement. Additionally, insecurity about the future should be addressed as it can affect both Burnout and Compassion Satisfaction. Finally, strategies to reduce possible work-life conflicts need to be considered. PMID- 29162096 TI - Carer involvement in compulsory out-patient psychiatric care in England. AB - BACKGROUND: There is an expectation in current heath care policy that family carers are involved in service delivery. This is also the case with compulsory outpatient mental health care, Community Treatment Orders (CTOs) that were introduced in England in 2008. No study has systematically investigated family involvement through the CTO process. METHOD: We conducted qualitative interviews with 24 family carers to ascertain their views and experiences of involvement in CTOs. The transcripts were subjected to thematic analysis that incorporated both deductive and inductive elements. RESULTS: We found significant variation in both the type and extent of family carer involvement throughout the CTO process (initiation, recall to hospital, renewal, tribunal hearings, discharge). Some were satisfied with their level of involvement while others felt (at least partly) excluded or that they wanted to be more involved. Some wanted less involvement than what they had. From the interviews we identified key factors shaping carers' involvement. These included: perceptions of patient preference; concern over the relationship to the patient; carers' knowledge of the CTO and of the potential for carer involvement; access to and relationships with health professionals; issues of patient confidentiality; opportunities for private discussions, and; health professionals limiting involvement. These factors show that health professionals have many opportunities to facilitate, or hinder, carer involvement. The various roles attributed to carers, such 'proxy' for patient decision, 'gatekeeper' to services, 'mother' or 'expert carer', however, conflict with one another and make the overall role unclear. CONCLUSIONS: There is a need for clarification of the expectations of carers in individual care situations, for carers to be equipped with the information they need to in order to be involved, and for services to find flexible and innovative ways of ensuring continuous, open communication. The introduction of CTOs in England has not been successful in its ambition for carer involvement. PMID- 29162097 TI - Correlation between lymphatic endothelial markers and lymph node status or N staging of colorectal cancer. AB - BACKGROUND: The purpose of this study is to examine the expression levels of lymphatic endothelial markers in colorectal cancer and to explore the correlation between the expression levels of markers and lymph node status. METHODS: Forty seven paired fresh tumor tissues and para-cancerous tissues were collected from colorectal cancer patients who received surgical treatment between August 2015 and March 2016 in Cancer Hospital, Chinese Academy of Medical Sciences. Real-time quantitative PCR (RTQ-PCR) was used to check the expression levels of LYVE-1, VEGFR-3, Podoplanin, and Prox-1 in tumor and para-cancerous tissues. RESULTS: The positive expression rates of LYVE-1, VEGFR-3, Podoplanin, and Prox-1 in tumor tissues were 100, 93.6, 100, and 91.4%, but 100, 100, 100, and 87.2% in para cancerous tissues. Comparing with para-cancerous tissues, tumor tissues had significantly lower expression levels of LYVE-1 (P < 0.001) and VEGFR-3 (P = 0.013) and higher levels of Podoplanin (P = 0.016) and Prox-1 (P = 0.078). There was no correlation between lymph node status and the expression level of LYVE-1 in tumor tissues (P = 0.354) or par-cancerous tissues (P = 0.617); similar results were found for VEGFR-3 (P = 0.631, 0.738), Podoplanin (P = 0.490, 0.625), and Prox-1 (P = 0.503, 0.174). Meanwhile, there was no correlation between N staging and the expression level of LYVE-1 in tumor tissues (P = 0.914) or para cancerous tissues (P = 0.784); similar results were found for VEGFR-3 (P = 0.493, 0.955), Podoplanin (P = 0.199, 0.370), and Prox-1 (P = 0.780, 0.234). CONCLUSIONS: There was no correlation between expression levels of lymphatic endothelial markers and lymph node status; LYVE-1, VEGFR-3, Podoplanin, and Prox 1 could not be used for predicting the lymph node status or N-staging of colorectal cancer. PMID- 29162098 TI - Malaria early warning tool: linking inter-annual climate and malaria variability in northern Guadalcanal, Solomon Islands. AB - BACKGROUND: Malaria control remains a significant challenge in the Solomon Islands. Despite progress made by local malaria control agencies over the past decade, case rates remain high in some areas of the country. Studies from around the world have confirmed important links between climate and malaria transmission. This study focuses on understanding the links between malaria and climate in Guadalcanal, Solomon Islands, with a view towards developing a climate based monitoring and early warning for periods of enhanced malaria transmission. METHODS: Climate records were sourced from the Solomon Islands meteorological service (SIMS) and historical malaria case records were sourced from the National Vector-Borne Disease Control Programme (NVBDCP). A declining trend in malaria cases over the last decade associated with improved malaria control was adjusted for. A stepwise regression was performed between climate variables and climate associated malaria transmission (CMT) at different lag intervals to determine where significant relationships existed. The suitability of these results for use in a three-tiered categorical warning system was then assessed using a Mann Whitney U test. RESULTS: Of the climate variables considered, only rainfall had a consistently significant relationship with malaria in North Guadalcanal. Optimal lag intervals were determined for prediction using R2 skill scores. A highly significant negative correlation (R = - 0.86, R2 = 0.74, p < 0.05, n = 14) was found between October and December rainfall at Honiara and CMT in northern Guadalcanal for the subsequent January-June. This indicates that drier October December periods are followed by higher malaria transmission periods in January June. Cross-validation emphasized the suitability of this relationship for forecasting purposes [Formula: see text] as did Mann-Whitney U test results showing that rainfall below or above specific thresholds was significantly associated with above or below normal malaria transmission, respectively. CONCLUSION: This study demonstrated that rainfall provides the best predictor of malaria transmission in North Guadalcanal. This relationship is thought to be underpinned by the unique hydrological conditions in northern Guadalcanal which allow sandbars to form across the mouths of estuaries which act to develop or increase stagnant brackish marshes in low rainfall periods. These are ideal habitats for the main mosquito vector, Anopheles farauti. High rainfall accumulations result in the flushing of these habitats, reducing their viability. The results of this study are now being used as the basis of a malaria early warning system which has been jointly implemented by the SIMS, NVBDCP and the Australian Bureau of Meteorology. PMID- 29162099 TI - Malaria prevalence metrics in low- and middle-income countries: an assessment of precision in nationally-representative surveys. AB - BACKGROUND: One pillar to monitoring progress towards the Sustainable Development Goals is the investment in high quality data to strengthen the scientific basis for decision-making. At present, nationally-representative surveys are the main source of data for establishing a scientific evidence base, monitoring, and evaluation of health metrics. However, little is known about the optimal precisions of various population-level health and development indicators that remains unquantified in nationally-representative household surveys. Here, a retrospective analysis of the precision of prevalence from these surveys was conducted. METHODS: Using malaria indicators, data were assembled in nine sub Saharan African countries with at least two nationally-representative surveys. A Bayesian statistical model was used to estimate between- and within-cluster variability for fever and malaria prevalence, and insecticide-treated bed nets (ITNs) use in children under the age of 5 years. The intra-class correlation coefficient was estimated along with the optimal sample size for each indicator with associated uncertainty. FINDINGS: Results suggest that the estimated sample sizes for the current nationally-representative surveys increases with declining malaria prevalence. Comparison between the actual sample size and the modelled estimate showed a requirement to increase the sample size for parasite prevalence by up to 77.7% (95% Bayesian credible intervals 74.7-79.4) for the 2015 Kenya MIS (estimated sample size of children 0-4 years 7218 [7099-7288]), and 54.1% [50.1 56.5] for the 2014-2015 Rwanda DHS (12,220 [11,950-12,410]). CONCLUSION: This study highlights the importance of defining indicator-relevant sample sizes to achieve the required precision in the current national surveys. While expanding the current surveys would need additional investment, the study highlights the need for improved approaches to cost effective sampling. PMID- 29162100 TI - Host age and Plasmodium falciparum multiclonality are associated with gametocyte prevalence: a 1-year prospective cohort study. AB - BACKGROUND: Since Plasmodium falciparum transmission relies exclusively on sexual stage parasites, several malaria control strategies aim to disrupt this step of the life cycle. Thus, a better understanding of which individuals constitute the primary gametocyte reservoir within an endemic population, and the temporal dynamics of gametocyte carriage, especially in seasonal transmission settings, will not only support the effective implementation of current transmission control programmes, but also inform the design of more targeted strategies. METHODS: A 1-year prospective cohort study was initiated in June 2013 with the goal of assessing the longitudinal dynamics of P. falciparum gametocyte carriage in a village in Mali with intense seasonal malaria transmission. A cohort of 500 individuals aged 1-65 years was recruited for this study. Gametocyte prevalence was measured monthly using Pfs25-specific RT-PCR, and analysed for the effects of host age and gender, seasonality, and multiclonality of P. falciparum infection over 1 year. RESULTS: Most P. falciparum infections (51-89%) in this population were accompanied by gametocytaemia throughout the 1-year period. Gametocyte prevalence among P. falciparum-positive individuals (proportion of gametocyte positive infections) was associated with age (p = 0.003) but not with seasonality (wet vs. dry) or gender. The proportion of gametocyte positive infections were similarly high in children aged 1-17 years (74-82% on median among 5 age groups), while older individuals had relatively lower proportion, and those aged > 35 years (median of 43%) had significantly lower than those aged 1-17 years (p < 0.05). Plasmodium falciparum-positive individuals with gametocytaemia were found to have significantly higher P. falciparum multiclonality than those without gametocytaemia (p < 0.033 in two different analyses). CONCLUSIONS: Taken together, these results suggest that a substantial proportion of Pf-positive individuals carries gametocytes throughout the year, and that age is a significant determinant of gametocyte prevalence among these P. falciparum positive individuals. Furthermore, the presence of multiple P. falciparum genotypes in an infection, a common feature of P. falciparum infections in high transmission areas, is associated with gametocyte prevalence. PMID- 29162101 TI - Ivermectin susceptibility, sporontocidal effect, and inhibition of time to re feed in the Amazonian malaria vector Anopheles darlingi. AB - BACKGROUND: Outdoor malaria transmission hinders malaria elimination efforts in the Amazon region and novel vector control tools are needed. Ivermectin mass drug administration (MDA) to humans kills wild Anopheles, targets outdoor-feeding vectors, and can suppress malaria parasite transmission. Laboratory investigations were performed to determine ivermectin susceptibility, sporontocidal effect and inhibition of time to re-feed for the primary Amazonian malaria vector, Anopheles darlingi. METHODS: To assess ivermectin susceptibility, various concentrations of ivermectin were mixed in human blood and fed to An. darlingi. Mosquito survival was monitored daily for 7 days and a non-linear mixed effects model with Probit analysis was used to calculate lethal concentrations of ivermectin that killed 50% (LC50), 25% (LC25) and 5% (LC5) of mosquitoes. To examine ivermectin sporonticidal effect, Plasmodium vivax blood samples were collected from malaria patients and offered to mosquitoes without or with ivermectin at the LC50, LC25 or LC5. To assess ivermectin inhibition of mosquito time to re-feed, concentrations of ivermectin predicted to occur after a single oral dose of 200 MUg/kg ivermectin were fed to An. darlingi. Every day for 12 days thereafter, individual mosquitoes were given the opportunity to re-feed on a volunteer. Any mosquitoes that re-blood fed or died were removed from the study. RESULTS: Ivermectin significantly reduced An. darlingi survivorship: 7-day-LC50 = 43.2 ng/ml [37.5, 48.6], -LC25 = 27.8 ng/ml [20.4, 32.9] and -LC5 = 14.8 ng/ml [7.9, 20.2]. Ivermectin compound was sporontocidal to P. vivax in An. darlingi at the LC50 and LC25 concentrations reducing prevalence by 22.6 and 17.1%, respectively, but not at the LC5. Oocyst intensity was not altered at any concentration. Ivermectin significantly delayed time to re-feed at the 4-h (48.7 ng/ml) and 12-h (26.9 ng/ml) concentrations but not 36-h (10.6 ng/ml) or 60-h (6.3 ng/ml). CONCLUSIONS: Ivermectin is lethal to An. darlingi, modestly inhibits sporogony of P. vivax, and delays time to re-feed at concentrations found in humans up to 12 h post drug ingestion. The LC50 value suggests that a higher than standard dose (400-MUg/kg) is necessary to target An. darlingi. These results suggest that ivermectin MDA has potential in the Amazon region to aid malaria elimination efforts. PMID- 29162102 TI - Micro-spatial distribution of malaria cases and control strategies at ward level in Gwanda district, Matabeleland South, Zimbabwe. AB - BACKGROUND: Although there has been a decline in the number of malaria cases in Zimbabwe since 2010, the disease remains the biggest public health threat in the country. Gwanda district, located in Matabeleland South Province of Zimbabwe has progressed to the malaria pre-elimination phase. The aim of this study was to determine the spatial distribution of malaria incidence at ward level for improving the planning and implementation of malaria elimination in the district. METHODS: The Poisson purely spatial model was used to detect malaria clusters and their properties, including relative risk and significance levels at ward level. The geographically weighted Poisson regression (GWPR) model was used to explore the potential role and significance of environmental variables [rainfall, minimum and maximum temperature, altitude, Enhanced Vegetation Index (EVI), Normalized Difference Vegetation Index (NDVI), Normalized Difference Water Index (NDWI), rural/urban] and malaria control strategies [indoor residual spraying (IRS) and long-lasting insecticide-treated nets (LLINs)] on the spatial patterns of malaria incidence at ward level. RESULTS: Two significant clusters (p < 0.05) of malaria cases were identified: (1) ward 24 south of Gwanda district and (2) ward 9 in the urban municipality, with relative risks of 5.583 and 4.316, respectively. The semiparametric-GWPR model with both local and global variables had higher performance based on AICc (70.882) compared to global regression (74.390) and GWPR which assumed that all variables varied locally (73.364). The semiparametric GWPR captured the spatially non-stationary relationship between malaria cases and minimum temperature, NDVI, NDWI, and altitude at the ward level. The influence of LLINs, IRS and rural or urban did not vary and remained in the model as global terms. NDWI (positive coefficients) and NDVI (range from negative to positive coefficients) showed significant association with malaria cases in some of the wards. The IRS had a protection effect on malaria incidence as expected. CONCLUSIONS: Malaria incidence is heterogeneous even in low-transmission zones including those in pre-elimination phase. The relationship between malaria cases and NDWI, NDVI, altitude, and minimum temperature may vary at local level. The results of this study can be used in planning and implementation of malaria control strategies at district and ward levels. PMID- 29162103 TI - Phenolic compounds apigenin, hesperidin and kaempferol reduce in vitro lipid accumulation in human adipocytes. AB - BACKGROUND: Adipocytes derived from human mesenchymal stem cells (MSCs) are widely used to investigate adipogenesis. Taking into account both the novelty of these MSCs and the scarcity of studies focused on the effects of phenolic compounds, the aim of the present study was to analyze the effect of apigenin, hesperidin and kaempferol on pre-adipocyte and mature adipocytes derived from this type of cells. In addition, the expression of genes involved in TG accumulation was also measured. METHODS: Pre-adipocytes were cultured from day 0 to day 8 and mature adipocytes for 48 h with the polyphenols at doses of 1, 10 and 25 uM. RESULTS: Apigenin did not show an anti-adipogenic action. Pre adipocytes treated with hesperidin and kaempferol showed reduced TG content at the three experimental doses. Apigenin did not modify the expression of the main adipogenic genes (c/ebpbeta, c/ebpalpha, ppargamma and srebp1c), hesperidin inhibited genes involved in the three phases of adipogenesis (c/ebpbeta, srebp1c and perilipin) and kaempferol reduced c/ebpbeta. In mature adipocytes, the three polyphenols reduced TG accumulation at the dose of 25 uM, but not at lower doses. All compounds increased mRNA levels of atgl. Apigenin and hesperidin decreased fasn expression. The present study shows the anti-adipogenic effect and delipidating effects of apigenin, hesperidin and kaempferol in human adipocytes derived from hMSCs. While hesperidin blocks all the stages of adipogenesis, kaempferol only inhibits the early stage. Regarding mature adipocytes, the three compounds reduce TG accumulation by activating, at least in part, lipolysis, and in the case of hesperidin and apigenin, also by reducing lipogenesis. CONCLUSIONS: The present study shows for the first time the anti-adipogenic effect and delipidating effect of apigenin, hesperidin and kaempferol in human adipocytes derived from MSCs for the first time. PMID- 29162104 TI - Elimination kinetics of eugenol in grass carp in a simulated transportation setting. AB - BACKGROUND: Fish are vulnerable to stress from over-crowding during transportation and eugenol is the most common sedative used to minimize fish injury. The ADI value of 2.5 mg/kg is recommended by the Joint FAO/WHO Expert Committee on Food Additives. The aim of this work was to study the elimination kinetics of eugenol following exposure of grass carp to a eugenol bath in a simulated transportation setting. RESULTS: Grass carp, Ctenopharyngodon idella (120 fish) were exposed for 24 h to a 10 mg/L eugenol bath. Sampling was performed during a 96 h period after the 24 h bath. Eight fish were sampled at each time point and muscle, plasma and liver concentrations of the drug were determined by ultra-performance liquid chromatography-tandem mass spectrometry. The concentration-time data of eugenol in each tissue were analyzed using non compartmental methods. The peak concentrations (Cmax) in plasma, muscle and liver were 7.68, 5.30 and 24.63 mg/kg and the elimination half-lives (t1/2beta) were 19.79, 10.27 and 55.28 h, respectively. The clearance (CL) values were 0.10, 0.44 and 0.04 L/h/kg and the areas under the concentration-time curve (AUC0-96h) were 91.54, 22.44, and 214.12 mg.h/L in plasma, muscle and liver, respectively. After a eugenol exposure bath, drug concentrations in muscle tissue of grass carp were below 1 mg/kg at 8 h and 0.1 mg/kg at 24 h. CONCLUSIONS: The drug concentrations in muscle tissue at 8 h were lower than the recommended ADI value. PMID- 29162105 TI - Changing oxidoreduction potential to improve water-soluble yellow pigment production with Monascus ruber CGMCC 10910. AB - BACKGROUND: Monascus pigments are widely used in the food and pharmaceutical industries due to their safety to human health. Our previous study found that glucose concentration induced extracellular oxidoreduction potential (ORP) changes could influence extracellular water-soluble yellow pigment production by Monascus ruber CGMCC 10910 in submerged fermentation. In this study, H2O2 and dithiothreitol (DTT) were used to change the oxidoreduction potential for investigating the effects of oxidative or reductive substances on Monascus yellow pigment production by Monascus ruber CGMCC 10910. RESULTS: The extracellular ORP could be controlled by H2O2 and DTT. Both cell growth and extracellular water soluble yellow pigment production were enhanced under H2O2-induced oxidative (HIO) conditions and were inhibited under dithiothreitol-induced reductive conditions. By optimizing the amount of H2O2 added and the timing of the addition, the yield of extracellular water-soluble yellow pigments significantly increased and reached a maximum of 209 AU, when 10 mM H2O2 was added on the 3rd day of fermentation with M. ruber CGMCC 10910. Under HIO conditions, the ratio of NADH/NAD+ was much lower than that in the control group, and the expression levels of relative pigment biosynthesis genes were up-regulated; moreover, the activity of glucose-6-phosphate dehydrogenase (G6PDH) was increased while 6 phosphofructokinase (PFK) activity was inhibited. CONCLUSIONS: Oxidative conditions induced by H2O2 increased water-soluble yellow pigment accumulation via up-regulation of the expression levels of relative genes and by increasing the precursors of pigment biosynthesis through redirection of metabolic flux. In contrast, reductive conditions induced by dithiothreitol inhibited yellow pigment accumulation. This experiment provides a potential strategy for improving the production of Monascus yellow pigments. PMID- 29162106 TI - Extent, regional variation and impact of gynecologist payment models in routine pelvic examinations: a nationwide cross-sectional study. AB - BACKGROUND: Based on moderate quality evidence, routine pelvic examination is strongly recommended against in asymptomatic women. The aims of this study was to quantify the extent of routine pelvic examinations within specialized health care in Norway, to assess if the use of these services differs across hospital referral regions and to assess if the use of colposcopy and ultrasound differs with gynecologists' payment models. METHODS: Nationwide cross-sectional study including all women aged 18 years and older in Norway in the years 2014-16 (2,038,747). Data was extracted from the Norwegian Patient Registry and Statistics Norway. The main outcome measures were 1. The number of appointments per 1000 women with a primary diagnosis of "Encounter for gynecological examination without complaint, suspected or reported diagnosis." 2. The age standardized number of these appointments per 1000 women in the 21 different hospital referral regions of Norway. 3. The use of colposcopy and ultrasound in routine pelvic examinations, provided by gynecologists with fixed salaries and gynecologists paid by a fee-for-service model. RESULTS: Annually 22.2 out of every 1000 women in Norway had a routine pelvic examination, with variation across regions from 6.6 to 43.9 per 1000. Gynecologists with fixed salaries performed colposcopy in 1.6% and ultrasound in 74.5% of appointments. Corresponding numbers for fee-for-service gynecologists were 49.2% and 96.2%, respectively. CONCLUSIONS: Routine pelvic examinations are widely performed in Norway. The variation across regions is extensive. Our results strongly indicate that fee-for-service payments for gynecologists skyrocket the use of colposcopy and increase the use of ultrasound in pelvic examinations of asymptomatic women. PMID- 29162107 TI - Production of highly efficient cellulase mixtures by genetically exploiting the potentials of Trichoderma reesei endogenous cellulases for hydrolysis of corncob residues. AB - BACKGROUND: Trichoderma reesei is one of the most important fungi utilized for cellulase production. However, its cellulase system has been proven to be present in suboptimal ratio for deconstruction of lignocellulosic substrates. Although previous enzymatic optimization studies have acquired different types of in vitro synthetic mixtures for efficient lignocellulose hydrolysis, production of in vivo optimized cellulase mixtures by industrial strains remains one of the obstacles to reduce enzyme cost in the biofuels production from lignocellulosic biomass. RESULTS: In this study, we used a systematic genetic strategy based on the pyrG marker to overexpress the major cellulase components in a hypercellulolytic T. reesei strain and produce the highly efficient cellulase mixture for saccharification of corncob residues. We found that overexpression of CBH2 exhibited a 32-fold increase in the transcription level and a comparable protein level to CBH1, the most abundant secreted protein in T. reesei, but did not contribute much to the cellulolytic ability. However, when EG2 was overexpressed with a 46-fold increase in the transcription level and a comparable protein level to CBH2, the engineered strain QPE36 showed a 1.5-fold enhancement in the total cellulase activity (up to 5.8 U/mL FPA) and a significant promotion of saccharification efficiency towards differently pretreated corncob residues. To assist the following genetic manipulations, the marker pyrG was successfully excised by homologous recombination based on resistance to 5-FOA. Furthermore, BGL1 was overexpressed in the EG2 overexpression strain QE51 (pyrG-excised) and a 11.6-fold increase in BGL activity was obtained. The EG2-BGL1 double overexpression strain QEB4 displayed a remarkable enhancement of cellulolytic ability on pretreated corncob residues. Especially, a nearly complete cellulose conversion (94.2%) was found for the delignified corncob residues after 48 h enzymatic saccharification. CONCLUSIONS: These results demonstrate that genetically exploiting the potentials of T. reesei endogenous cellulases to produce highly efficient cellulase mixtures is a powerful strategy to promote the saccharification efficiency, which will eventually facilitate cost reduction for lignocellulose-based biofuels. PMID- 29162108 TI - Reduced suppressive effect of beta2-adrenoceptor agonist on fibrocyte function in severe asthma. AB - BACKGROUND: Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting beta2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of beta2-AR agonists, alone or in combination with corticosteroids, on fibrocyte function. METHODS: Non-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the beta2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I+/CD45+ cells) and differentiating fibrocytes (alpha-smooth muscle actin+ cells), and the expression of CC chemokine receptor 7 and of beta2-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8 bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram. RESULTS: Salmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface beta2-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased beta2-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation. CONCLUSIONS: Fibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids. PMID- 29162109 TI - Road traffic noise and children's inattention. AB - BACKGROUND: An increasing number of children are exposed to road traffic noise levels that may lead to adverse effects on health and daily functioning. Childhood is a period of intense growth and brain maturation, and children may therefore be especially vulnerable to road traffic noise. The objective of the present study was to examine whether road traffic noise was associated with reported inattention symptoms in children, and whether this association was mediated by sleep duration. METHODS: This study was based on the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. Parental reports of children's inattention at age 8 were linked to modelled levels of residential road traffic noise. We investigated the association between inattention and noise exposure during pregnancy (n = 1934), noise exposure averaged over 5 years (age 3 to 8 years; n = 1384) and noise exposure at age 8 years (n = 1384), using fractional logit response models. The participants were children from Oslo, Norway. RESULTS: An association with inattention at age 8 years was found for road traffic noise exposure at age 8 years (coef = .0083, CI = [.0012, .0154]; 1.2% point increase in inattention score per 10 dB increase in noise level), road traffic noise exposure average for the last 5 years (coef = .0090, CI = [.0016, .0164]; 1.3% point increase/10 dB), and for pregnancy road traffic noise exposure for boys (coef = .0091, CI = [.0010, .0171]), but not girls (coef = -.0021, CI = [-.0094, .0053]). Criteria for doing mediation analyses were not fulfilled. CONCLUSION: Results indicate that road traffic noise has a negative impact on children's inattention. We found no mediation by sleep duration. PMID- 29162110 TI - Production of D-lactate from glucose using Klebsiella pneumoniae mutants. AB - BACKGROUND: D-Lactate is a valued chemical which can be produced by some bacteria including Klebsiella pneumoniae. However, only a few studies have focused on K. pneumoniae for D-lactate production with a significant amount of by-products, which complicated the purification process and decreased the yield of D-lactate. RESULTS: Based on the redirection of carbon towards by-product formation, the effects of single-gene and multiple-gene deletions in K. pneumoniae on D-lactate production from glucose via acetolactate synthase (budB), acetate kinase (ackA), and alcohol dehydrogenase (adhE) were tested. Klebsiella pneumoniae mutants had different production behaviours. The accumulation of the main by-products was decreased in the mutants. The triple mutant strain had the most powerful ability to produce optically pure D-lactate from glucose, and was tested with xylose and arabinose as carbon sources. Fed-batch fermentation was also carried out under various aeration rates, and the strain accumulated 125.1 g/L D-lactate with a yield of 0.91 g/g glucose at 2.5 vvm. CONCLUSIONS: Knocking out by-product synthesis genes had a remarkable influence on the production and yield of D lactate. This study demonstrated, for the first time, that K. pneumoniae has great potential to convert monosaccharides into D-lactate. The results provide new insights for industrial production of D-lactate by K. pneumoniae. PMID- 29162111 TI - The role of primary care in adult weight management: qualitative interviews with key stakeholders in weight management services. AB - BACKGROUND: Primary care has a key role to play in the prevention and management of obesity, but there remain barriers to engagement in weight management by primary care practitioners. The aim of this study was to explore the views of key stakeholders in adult weight management services on the role of primary care in adult weight management. METHODS: Qualitative study involving semi-structured interviews with nine senior dietitians involved in NHS weight management from seven Scottish health boards. Transcripts were analysed using an inductive thematic approach. RESULTS: A range of tensions were apparent within three key themes: weight management service issues, the role of primary care, and communication with primary care. For weight management services, these tensions were around funding, the management model of obesity, and how to configure access to services. For primary care, they were around what primary care should be doing, who should be doing it, and where this activity should fit within wider weight management policy. With regard to communication between weight management services and primary care, there were tensions related to the approach taken (locally adapted versus centralised), the message being communicated (weight loss versus wellbeing), and the response from practitioners (engagement versus resistance). CONCLUSIONS: Primary care can do more to support adult weight management, but this requires better engagement and communication with weight management services, to overcome the tensions highlighted in this study. This, in turn, requires more secure, sustained funding. The example of smoking cessation in the UK, where there is a network of well-resourced NHS Stop Smoking Services, accessible via different means, could be a model to follow. PMID- 29162112 TI - Continuity of care as experienced by mental health service users - a qualitative study. AB - BACKGROUND: People who struggle with mental health problems can provide valuable insight into understanding and improving the coordination of mental health and welfare services. The aims of the study were to explore service users' experiences and perceptions of continuity of care within and across services relevant to personal recovery, to elicit which dimensions of continuity of care are most essential to service users, and to generate ideas for improving service users' experiences of continuity of care. METHODS: In the context of a hermeneutic-phenomenological approach, ten service users at a community mental health centre were interviewed about their experiences of continuity of care in and across services. Eight of these were re-interviewed two years later. A collaborative research approach was adopted. Data were analysed by means of a data-driven stepwise approach in line with thematic analysis. RESULTS: Following the analysis five themes representing experiences of continuity of care were developed. Each theme ranged from poor to good experiences of continuity of care: Relationship - from experiencing frequent setbacks and anxiety due to breaks in relationships, to feeling safe in an ongoing personal relationship; Timeliness - from experiencing frustrating waiting times with worsening of problems, to getting help when needed; Mutuality - from having a one-sided struggle, to a situation in which both professionals and service users take initiatives; Choice from not having the opportunity to make practical arrangements within the context of one's everyday life, to having an array of support options to choose from; Knowledge - from feeling confused and insecure because one does not know what is happening, to feeling safe because one is informed about what is going to happen. Participants provided a range of suggestions for improving experiences of continuity of care. CONCLUSIONS: A discrepancy between aspects of continuity that are essential for service users and their experiences of actual practice was revealed. The valid evidence generated in the present collaborative study therefore offers knowledge to policy makers, professionals and service users that may be of help in their future efforts in orienting primary care, mental health, addiction and welfare services towards recovery. PMID- 29162113 TI - Determination of the residual efficacy of carbamate and organophosphate insecticides used for indoor residual spraying for malaria control in Ethiopia. AB - BACKGROUND: Indoor residual spraying is one of the key vector control interventions for malaria control in Ethiopia. As malaria transmission is seasonal in most parts of Ethiopia, a single round of spraying can usually provide effective protection against malaria, provided the insecticide remains effective over the entire malaria transmission season. This experiment was designed to evaluate the residual efficacy of bendiocarb, pirimiphos-methyl, and two doses of propoxur on four different wall surfaces (rough mud, smooth mud, dung, and paint). Filter papers affixed to wall surfaces prior to spraying were analyzed to determine the actual concentration applied. Cone bioassays using a susceptible Anopheles arabiensis strain were done monthly to determine the time for which insecticides were effective in killing mosquitoes. RESULTS: The mean insecticide dosage of bendiocarb applied to walls was 486 mg/m2 (target 400/mg). This treatment lasted 1 month or less on rough mud, smooth mud, and dung, but 4 months on painted surfaces. Pirimiphos-methyl was applied at 1854 mg/m2 (target 1000 mg/m2), and lasted between 4 and 6 months on all wall surfaces. Propoxur with a target dose of 1000 mg/m2 was applied at 320 mg/m2, and lasted 2 months or less on all surfaces, except painted surfaces (4 months). Propoxur with a target dose of 2000 mg/m2, was applied at 638 mg/m2, and lasted 3 months on rough mud, but considerably longer (5-7 months) on the other substrates. CONCLUSIONS: It would appear that the higher dose of propoxur and pirimiphos-methyl correspond best to the Ethiopian transmission season, although interactions between insecticide and the substrate should be taken into account as well. However, the insecticide quantification revealed that the dosages actually applied differed considerably from the target dosages, even though care was taken in the mixing of insecticide formulations and spraying of the walls. It is unclear whether this variability is due to initial concentrations of insecticides, poor application, or other factors. Further work is needed to ensure that target doses are correctly applied, both operationally and in insecticide evaluations. PMID- 29162114 TI - A computational study of the inhibition mechanisms of P-glycoprotein mediated paclitaxel efflux by kinase inhibitors. AB - BACKGROUND: Drug resistance mediated by P-glycoprotein (P-gp) renders many cancer therapies ineffective. One P-gp substrate is the widely used chemotherapy drug paclitaxel. Co-administration of paclitaxel and another drug that inhibits P-gp may enhance the therapeutic effectiveness of paclitaxel by preventing its efflux from tumor cells. RESULTS: Here we present a computational approach that combines docking studies with mass action kinetic modeling to investigate how kinase inhibitors may inhibit P-gp mediated paclitaxel efflux. The results show that the inhibition can be attributed to competition between paclitaxel and a tyrosine kinase inhibitor (TKI) for the substrate binding domain (SBD) as well as competition between the kinase inhibitor and ATP for the nuclear (ATP) binding domain (NBD). The relative scales of these two competitions are TKI dependent and determined by the relative affinities of paclitaxel and TKIs to the SBD and NBD of P-gp, and their membrane partition coefficients. Additional simulations suggested that there is no single strategy to further improve the ability of TKIs to inhibit paclitaxel efflux and the most efficient way likely depends on the properties of the TKIs. CONCLUSIONS: The developed model fits existing experimental results well and thus detailed analyses of isolated parameters provide insight into the mechanisms of rather important drug efflux. It can be used to guide how to design better TKIs or develop feasible drug combination strategies for targeting P-gp induced drug resistance. PMID- 29162115 TI - Opportunities for topical antimicrobial therapy: permeation of canine skin by fusidic acid. AB - BACKGROUND: Staphylococcal infection of the canine epidermis and hair follicle is amongst the commonest reasons for antimicrobial prescribing in small animal veterinary practice. Topical therapy with fusidic acid (FA) is an attractive alternative to systemic therapy based on low minimum inhibitory concentrations (MICs, commonly <0.03 mg/l) documented in canine pathogenic staphylococci, including strains of MRSA and MRSP (methicillin-resistant Staphylococcus aureus and S. pseudintermedius). However, permeation of canine skin by FA has not been evaluated in detail. This study aimed to define the degree and extent of FA permeation in canine skin in vitro from two sites with different hair follicle density following application of a licensed ophthalmic formulation that shares the same vehicle as an FA-betamethasone combination product approved for dermal application in dogs. Topical FA application was modelled using skin held in Franz type diffusion cells. Concentrations of FA in surface swabs, receptor fluid, and transverse skin sections of defined anatomical depth were determined using high performance liquid chromatography and ultraviolet (HPLC-UV) analysis. RESULTS: The majority of FA was recovered by surface swabs after 24 h, as expected (mean +/- SEM: 76.0 +/- 17.0%). FA was detected within 424/470 (90%) groups of serial sections of transversely cryotomed skin containing follicular infundibula, but never in 48/48 (100%) groups of sections containing only deeper follicular structures, nor in receptor fluid, suggesting that FA does not permeate beyond the infundibulum. The FA concentration (mean +/- SEM) in the most superficial 240 MUm of skin was 2000 +/- 815 MUg/g. CONCLUSIONS: Topically applied FA can greatly exceed MICs for canine pathogenic staphylococci at the most common sites of infection. Topical FA therapy should now be evaluated using available formulations in vivo as an alternative to systemic therapy for canine superficial bacterial folliculitis. PMID- 29162116 TI - Health-related quality of life, handgrip strength and falls during detraining in elderly habitual exercisers. AB - BACKGROUND: The effects of regular exercise on physical functioning and health related quality of life (HRQOL) have been thoroughly studied. In contrast, little is known about the changes which occur following cessation of activity (detraining). Here, we have investigated the effect of a 3 month detraining period on HRQOL and on handgrip strength in elderly people who had regularly exercised, and examined the association of these variables with falls. METHODS: Thirty-eight women and 11 men (mean age, 75.5+/-5.7 years) took part in a supervised physical exercise program for 9 months, followed by a 3 month detraining period. Participants completed the SF-36 HRQOL questionnaire at the beginning of detraining (baseline) and 3 months later. Handgrip strength and number of falls were also recorded. RESULTS: Participants had been exercising for 12.1+/-8.7 years. After the detraining period, we found a significant (p < 0.001- 0.05) decline in all SF-36 dimensions, with the exception of handgrip strength. Women presented a larger decline (p < 0.05) in more items than men. During the detraining period, 18.4% participants had a fall incident. HRQOL declined in both fallers and non-fallers during detraining. Interestingly, fallers already had at baseline significantly lower values in physical functioning (p < 0.05), emotional role (p < 0.05) and mental health (p < 0.01), than non-fallers. CONCLUSIONS: An important decline was found in most items of the SF-36 following a 3 month detraining period, particularly in women. In contrast, strength of the upper limb was not affected by the detraining. The prior lower HRQOL values of those who will subsequently fall suggest that this criterion should be studied as a candidate risk factor for falls. Efforts should be made to encourage the elderly to continue with exercise activities and/or to shorten holiday break periods, in order to maintain their quality of life. TRIAL REGISTRATION: The protocol was registered as a clinical trial in the ANZCTR (trial ID: ACTRN12617000716369 ). PMID- 29162117 TI - Community based intervention to prevent domestic violence against women in the reproductive age in Northwestern Ethiopia: a protocol for quasi-experimental study. AB - BACKGROUND: Violence against women is a well understood devastating global pandemic, and human right violation. One in three women experienced intimate partner violence worldwide. In Ethiopia, the level of domestic violence against women is one of the highest in the world. However, Ethiopia is signatory for various conventions and incorporated in legal frameworks. Nevertheless, effective implementation of the existing policy documents, and engaging different stakeholders is very limited. Therefore, we aimed to pilot feasibility of implementing available research evidence and policy documents at community level to prevent domestic violence against women in Awi zone, northwestern Ethiopia. METHODS: A community-based quasi-experimental study design will be employed using mixed method. Multistage stratified systematic sampling and purposive sampling will be used to recruit quantitative and qualitative study participants, respectively. A total of 1,269 women will be participated in the intervention, active comparator and control groups. Pre and post-test quantitative data will be collected using face-to-face interview. Qualitative data will be collected through in-depth, key informant interview and focus group discussions. INTERVENTION: advocacy meeting will be held to persuade local politicians and sustain the implementation of community based intervention to prevent domestic violence against women. Community representatives will be trained to enhance peer education to promote community awareness and engage stakeholders to transform the traditional gender norm within local context. Awareness creation and husband involvement will be made through integrating the intervention with community health extension program. Only husband involvement will not be promoted in the active comparator to test the role of husband involvement on the domestic violence prevention activities. Intervention progress will be monitored regularly. Gathered data will be entered in Epidata and exported to SPSS (23.0) software for analysis. Descriptive statistics, logistic regressions, intention to treat analysis and difference in differences will be computed. Qualitative data will be transcribed, color coded, thematically analyzed and arranged using Nvivo. DISCUSSION: This interventional study is aimed to design, pilot and translate proven research evidence, agreed conventions and country policy document to real setting implementation. We are expecting to initiate implementation of culturally acceptable intervention through engaging stakeholders. Policy makers, planners and any concerned bodies will be benefited. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03265626. PMID- 29162118 TI - Multilevel lumbar spine infection due to poor dentition in an immunocompetent adult: a case report. AB - BACKGROUND: Although spinal infections have been reported following dental procedures, development of a spinal infection attributed to poor dentition without a history of a dental procedure in an immunocompetent adult has not been previously reported. Here we provide a case report of a multilevel lumbar spine infection that developed in an immunocompetent adult with poor dentition. CASE PRESENTATION: A 63-year-old white male man with past medical history of hypertension presented to a hospital emergency department with a 4-month history of progressively worsening low back pain. A musculoskeletal examination demonstrated diffuse tenderness in his lumbar spine area and the results of a neurological examination were within normal limits. Computed tomography and magnetic resonance imaging of his lumbar spine demonstrated a prevertebral and presacral fluid collection ventral to the L4 to L5 and L5 to S1 interspaces. Blood cultures grew pan-sensitive Streptococcus intermedius in four of four bottles within 45 hours. Using computed tomography guidance, three core biopsies of the L4 to L5 interspace were taken and subsequent cultures were positive for Streptococcus intermedius. He reported that his last episode of dental care occurred more than 20 years ago and a dental panoramic radiograph demonstrated significant necrotic dentition. Ten teeth were extracted and the necrotic dentition was assumed to be the most likely source of infection. On hospital dismissal, he received a 12-week course of intravenously administered ceftriaxone followed by an 8-week course of orally administered cefadroxil pending repeat imaging. CONCLUSIONS: This case report demonstrates the importance of determining the source of infection in a patient with a spontaneous spinal infection. Even in the absence of a recent dental procedure, dentition should be considered a possible source of infection in an immunocompetent patient who presents with a spontaneous spinal infection. PMID- 29162119 TI - Improving health worker performance of abortion services: an assessment of post training support to providers in India, Nepal and Nigeria. AB - BACKGROUND: Health worker performance has been the focus of numerous interventions and evaluation studies in low- and middle-income countries. Few have examined changes in individual provider performance with an intervention encompassing post-training support contacts to improve their clinical practice and resolve programmatic problems. This paper reports the results of an intervention with 3471 abortion providers in India, Nepal and Nigeria. METHODS: Following abortion care training, providers received in-person visits and virtual contacts by a clinical and programmatic support team for a 12-month period, designed to address their individual practice issues. The intervention also included technical assistance to and upgrades in facilities where the providers worked. Quantitative measures to assess provider performance were established, including: 1) Increase in service provision; 2) Consistent service provision; 3) Provision of high quality of care through use of World Health Organization recommended uterine evacuation technologies, management of pain and provision of post-abortion contraception; and 4) Post-abortion contraception method mix. Descriptive univariate analysis was conducted, followed by examination of the bivariate relationships between all independent variables and the four dependent performance outcome variables by calculating unadjusted odds ratios, by country and overall. Finally, multivariate logistic regression was performed for each outcome. RESULTS: Providers received an average of 5.7 contacts. Sixty-two percent and 46% of providers met measures for consistent service provision and quality of care, respectively. Fewer providers achieved an increased number of services (24%). Forty-six percent provided an appropriate postabortion contraceptive mix to clients. Most providers met the quality components for use of WHO-recommended abortion methods and provision of pain management. Factors significantly associated with achievement of all measures were providers working in sites offering community outreach and those trained in intervention year two. The number of in-person contacts was significantly associated with achievement of three of four measures. CONCLUSION: Post-training support holds promise for strengthening health worker performance. Further research is needed to compare this intervention with other approaches and assess how post-training contacts could be incorporated into current health system supervision. PMID- 29162120 TI - A village level cluster-randomized entomological evaluation of combination long lasting insecticidal nets containing pyrethroid plus PBO synergist in Southern Mali. AB - BACKGROUND: There is growing concern that malaria vector resistance to pyrethroid insecticides may reduce the effectiveness of long-lasting insecticidal nets (LLINs). Combination LLINs are designed to control susceptible and pyrethroid resistant mosquito populations through a mixture of pyrethroid with piperonyl butoxide (PBO) synergist. A cluster randomized trial with entomology outcome measures was conducted in Mali to determine the added benefit over mono-treated pyrethroid predecessors. Four LLIN treatments; permethrin + PBO, permethrin, deltamethrin + PBO, and deltamethrin, were randomly allocated to four villages each (16 villages total) and distributed to cover every sleeping place. Entomological monitoring of indoor Anopheles resting densities, host preference, vector longevity, and sporozoite rates were monitored every 2 months over 2 years in 2014 and 2015. RESULTS: Bottle bioassays confirmed permethrin and deltamethrin resistance in Anopheles gambiae sensu lato (s.l.), (the predominant species throughout the study) with pre-exposure to PBO indicating partial involvement of oxidases. Between 2014 and 2015 the mean indoor resting density was greater in the deltamethrin + PBO LLIN arm than the deltamethrin LLIN arm at 3.05 (95% CI 3.00-3.10) An. gambiae s.l. per room per day compared with 1.9 (95% CI 1.87 1.97). There was no significant difference in sporozoite rate at 3.97% (95% CI 2.91-5.02) for the deltamethrin LLIN arm and 3.04% (95% CI 2.21-3.87) for deltamethrin + PBO LLIN arm (P = 0.17). However, when analysed by season there was some evidence that the sporozoite rate was lower in the deltamethrin + PBO LLIN arm than deltamethrin LLIN arm during the rainy/high malaria transmission seasons at 1.95% (95% CI 1.18-2.72) and 3.70% (95% CI 2.56-4.84) respectively (P = 0.01). CONCLUSIONS: While there was some evidence that An. gambiae s.l. sporozoite rates were lower in villages with deltamethrin + PBO LLINs during the high malaria transmission seasons of 2014-2015, there was no reduction in parity rates or indoor resting densities. There was also no evidence that permethrin + PBO LLINs provided any improved control when compared with permethrin LLINs. Combination nets may have a greater impact in areas where mixed function oxidases play a more important role in pyrethroid resistance. PMID- 29162121 TI - The involvement of musculoskeletal system and its influence on postural stability in children and young adults with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) affects the musculoskeletal system via a multifactorial pathway that includes vitamin D deficiency and involvement of respiratory muscles such as intercostals due to recurrent upper and lower respiratory tract infections. Eventual result is the deterioration of musculoskeletal health and posture in CF patients. Postural stability is directly affected by posture and can be compromised in every musculoskeletal problem. The aim of this study is to evaluate musculoskeletal system and postural stability in patients with CF. METHODS: Patients with CF over six years of age and age and sex matched control groups were included in the study. Cobb angle and thoracic kyphosis angles were measured on the spine radiographs. Both patients and control group were examined with pediatric gait, arms, legs and spine scale (pGALS). They also were evaluated with a NeuroCom Balance Master for their postural stability. RESULTS: Fifty-one patients with CF and 94 healthy controls participated in the study. In results of the pGALS examination, CF group had significantly more pathological findings than the control group in lower extremity appearance and movement (p = 0.006 and p = 0.01) and spine appearance and movement (p = 0.001 and p = 0.022) domains. The tandem walking speed was significantly higher in controls with a mean of 24.45 +/- 7.79 while it was 20.47 +/- 6.95 in the CF group (p = 0.03). Various limits of stability parameters also showed significant differences. Medium correlations were found between musculoskeletal examination and postural stability parameters. CONCLUSION: In patients with CF, a systematic but simple musculoskeletal examination can detect pathologies, which are more frequent than the normal population. These pathologies show a medium correlation with the involvement of postural stability. PMID- 29162122 TI - Overdose prevention training with naloxone distribution in a prison in Oslo, Norway: a preliminary study. AB - BACKGROUND: Prison inmates face a ten times increased risk of experiencing a fatal drug overdose during their first 2 weeks upon release than their non incarcerated counterparts. Naloxone, the antidote to an opioid overdose, has been shown to be feasible and effective when administered by bystanders. Given the particular risk that newly released inmates face, it is vital to assess their knowledge about opioid overdoses, as well as the impact of brief overdose prevention training conducted inside prisons. METHODS: Prison inmates nearing release (within 6 months) in Oslo, Norway, voluntarily underwent a brief naloxone training. Using a questionnaire, inmates were assessed immediately prior to and following a naloxone training. Descriptive statistics were performed for main outcome variables, and the Wilcoxon signed-rank test was used to compare the participants' two questionnaire scores from pre-and post-training. RESULTS: Participating inmates (n = 31) were found to have a high baseline knowledge of risk factors, symptoms, and care regarding opioid overdoses. Nonetheless, a brief naloxone training session prior to release significantly improved knowledge scores in all areas assessed (p < 0.001). The training appears to be most beneficial in improving knowledge regarding the naloxone, including its use, effect, administration, and aftercare procedures. CONCLUSIONS: Given the high risk of overdosing that prison inmates face upon release, the need for prevention programs is critical. Naloxone training in the prison setting may be an effective means of improving opioid overdose response knowledge for this particularly vulnerable group. Naloxone training provided in the prison setting may improve the ability of inmates to recognize and manage opioid overdoses after their release; however, further studies on a larger scale are needed. PMID- 29162123 TI - Prospective comparison of novel dark blood late gadolinium enhancement with conventional bright blood imaging for the detection of scar. AB - BACKGROUND: Conventional bright blood late gadolinium enhancement (bright blood LGE) imaging is a routine cardiovascular magnetic resonance (CMR) technique offering excellent contrast between areas of LGE and normal myocardium. However, contrast between LGE and blood is frequently poor. Dark blood LGE (DB LGE) employs an inversion recovery T2 preparation to suppress the blood pool, thereby increasing the contrast between the endocardium and blood. The objective of this study is to compare the diagnostic utility of a novel DB phase sensitive inversion recovery (PSIR) LGE CMR sequence to standard bright blood PSIR LGE. METHODS: One hundred seventy-two patients referred for clinical CMR were scanned. A full left ventricle short axis stack was performed using both techniques, varying which was performed first in a 1:1 ratio. Two experienced observers analyzed all bright blood LGE and DB LGE stacks, which were randomized and anonymized. A scoring system was devised to quantify the presence and extent of gadolinium enhancement and the confidence with which the diagnosis could be made. RESULTS: A total of 2752 LV segments were analyzed. There was very good inter observer correlation for quantifying LGE. DB LGE analysis found 41.5% more segments that exhibited hyperenhancement in comparison to bright blood LGE (248/2752 segments (9.0%) positive for LGE with bright blood; 351/2752 segments (12.8%) positive for LGE with DB; p < 0.05). DB LGE also allowed observers to be more confident when diagnosing LGE (bright blood LGE high confidence in 154/248 regions (62.1%); DB LGE in 275/324 (84.9%) regions (p < 0.05)). Eighteen patients with no bright blood LGE were found to have had DB LGE, 15 of whom had no known history of myocardial infarction. CONCLUSIONS: DB LGE significantly increases LGE detection compared to standard bright blood LGE. It also increases observer confidence, particularly for subendocardial LGE, which may have important clinical implications. PMID- 29162124 TI - Geraniin extracted from the rind of Nephelium lappaceum binds to dengue virus type-2 envelope protein and inhibits early stage of virus replication. AB - BACKGROUND: The rapid rise and spread in dengue cases, together with the unavailability of safe vaccines and effective antiviral drugs, warrant the need to discover and develop novel anti-dengue treatments. In this study the antiviral activity of geraniin, extracted from the rind of Nephelium lappaceum, against dengue virus type-2 (DENV-2) was investigated. METHODS: Geraniin was prepared from Nephelium lappaceum rind by reverse phase C-18 column chromatography. Cytotoxicity of geraniin towards Vero cells was evaluated using MTT assay while IC50 value was determined by plaque reduction assay. The mode-of-action of geraniin was characterized using the virucidal, attachment, penetration and the time-of-addition assays'. Docking experiments with geraniin molecule and the DENV envelope (E) protein was also performed. Finally, recombinant E Domain III (rE DIII) protein was produced to physiologically test the binding of geraniin to DENV-2 E-DIII protein, through ELISA competitive binding assay. RESULTS: Cytotoxicity assay confirmed that geraniin was not toxic to Vero cells, even at the highest concentration tested. The compound exhibited DENV-2 plaque formation inhibition, with an IC50 of 1.75 MUM. We further revealed that geraniin reduced viral infectivity and inhibited DENV-2 from attaching to the cells but had little effect on its penetration. Geraniin was observed to be most effective when added at the early stage of DENV-2 infection. Docking experiments showed that geraniin binds to DENV E protein, specifically at the DIII region, while the ELISA competitive binding assay confirmed geraniin's interaction with rE-DIII with high affinity. CONCLUSIONS: Geraniin from the rind of Nephelium lappaceum has antiviral activity against DENV-2. It is postulated that the compound inhibits viral attachment by binding to the E-DIII protein and interferes with the initial cell-virus interaction. Our results demonstrate that geraniin has the potential to be developed into an effective antiviral treatment, particularly for early phase dengue viral infection. PMID- 29162125 TI - How to get a nation walking: reach, retention, participant characteristics and program implications of Heart Foundation Walking, a nationwide Australian community-based walking program. AB - BACKGROUND: Community-based walking programs represent a low-cost, accessible approach to increasing physical activity among inactive adults. However, recruiting participants from vulnerable and hard-to-reach groups remains a challenge. This study examined the reach, retention, sociodemographic and health characteristics, physical activity levels and motivators of participants in Heart Foundation Walking, a nationwide Australian community-based walking program. METHODS: Descriptive cross-sectional analyses were undertaken with data from 22,416 participants aged 15+ years in the Heart Foundation Walking registration database in December 2015, and from four surveys of participants in 2010 (n = 2400), 2011 (n = 3274), 2012 (n = 4158) and 2015 (n = 1890). RESULTS: Heart Foundation Walking reached participants in every geographic region of Australia, including remote and sparsely populated regions, and engaged sizeable proportions of the following at-risk participants: older than 60 years (>70%); with very low incomes (17-25%); who were overweight or obese (around 60%); and with one or more chronic disease or disease risk factors (57-81%). For all demographic groups, one year retention rates were at least 75%. Seventy percent of participants met physical activity recommendations. Over 75% reported joining the program for health and fitness reasons while the most cited motivator for continuing was the social aspect (57-73%). CONCLUSIONS: Volunteer-run, group-based walking programs can have substantial reach and retention, in particular among those at risk for physical inactivity. The provision of opportunities for social interaction appears to be a key program element in promoting long-term participation, including among high-risk groups. PMID- 29162126 TI - Targeting the master regulator mTOR: a new approach to prevent the neurological of consequences of parasitic infections? AB - A systematic analysis of 240 causes of death in 2013 revealed that parasitic diseases were responsible for more than one million deaths. The vast majority of these fatalities resulted from protozoan infections presenting with neurological sequelae. In the absence of a vaccine, development of effective therapies is essential to improving global public health. In 2015, an intriguing strategy to prevent cerebral malaria was proposed by Gordon et al. 2015 mBio, 6:e00625. Their study suggested that inhibition of the mammalian target of rapamycin prevented experimental cerebral malaria by blocking the damage to the blood brain barrier and stopping the accumulation of parasitized red blood cells and T cells in the brain. Here, we hypothesize that the same therapeutic strategy could be adopted for other protozoan infections with a brain tropism, to prevent cerebral parasitosis by limiting pathogen replication and preventing immune mediated destruction of brain tissue. PMID- 29162127 TI - Association of the S2 allele of the SstI polymorphism in the apoC3 gene with plasma apoCIII interacts with unfavorable lipid profiles to contribute to atherosclerosis in the Li ethnic group in China. AB - BACKGROUND: The SstI polymorphism in the apolipoprotein 3 gene (apoC3) has been identified in many ethnic groups. In addition, the S2 allele of the SstI polymorphism is shown to be associated with increased plasma triglyceride (TG) levels. Plasma apoCIII is an important atherogenic factor, which interrupts lipid metabolism and is positively associated with plasma TG levels. However, the existence of the SstI polymorphism in the Li ethnic group in China remains to be confirmed. The relationship between the S2 allele of the SstI polymorphism and plasma apoCIII or TG and their roles in atherosclerosis are also unknown. METHODS: A cohort of 628 participants was recruited (316 atherosclerotic patients and 312 healthy controls) from both the Li and Han ethnic groups. Blood samples were obtained to evaluate the SstI polymorphism in the apoC3 and lipid profiles. Chi-squared and t-tests and multiple unconditional logistic regression were employed to analyze the genotypic and allelic frequencies and lipid profiles using SPSS version 20.0 software. RESULTS: The SstI polymorphism in the apoC3 was identified in the Li ethnic group. The S2 allele and plasma apoCIII and TG levels were associated with the development of atherosclerosis (P < 0.01, S2 allele and apoCIII; P < 0.05, TG) in the Li ethnic group. The S2 allele was associated with increased plasma apoCIII levels in the atherosclerotic group (P < 0.01), but with increased plasma apoCIII and TG levels in control group (both P < 0.01). In addition to the increases in the S2 allele frequency and plasma TG and apoCIII levels, atherosclerotic patients in the Li ethnic group also exhibited increased apoB, decreased HDL-C and apoAI and a lower apoAI:apoB ratio (all P < 0.01). CONCLUSIONS: Our results indicate that the S2 allele of the SstI polymorphism in the apoC3 gene is associated with plasma apoCIII levels in the Li population. In combination with unfavorable lipid profiles, this might contribute to susceptibility to atherosclerosis. PMID- 29162128 TI - Glycosylation at 11Asn on hemagglutinin of H5N1 influenza virus contributes to its biological characteristics. AB - A stem glycosylation site of hemagglutinin (HA) is important to the stability of the HA trimmer. A previous study shows that the stem 10/11 overlap glycosylation site of the H5 subtype avian influenza virus may influence the cleavage of HA, whereas the exact site and its effect on virulence remain unclear. In this study, site-directed mutagenesis was used to generate single or double mutant rSY Delta10(10NNAT), rSY-Delta11(10NNSA), and rSY-Delta10/11(10NNAA) of the overlapping glycosylation site (10NNST) on the HA of A/Mallard/Huadong/S/2005(SY). By using Western blot analysis, we show that both rSY-Delta11 and rSY-Delta10/11 mutant viruses had significant delay on HA cleavage and a reduced HA molecular mass compared to the wild-type virus rSY, while the rSY-Delta10 mutant virus exhibited a similar HA molecular mass to that of the wild-type virus rSY. Interestingly, both rSY-Delta11 and rSY-Delta10/11 mutant viruses reverted their glycosylation sites at 11N after passage, indicating that 11N is a true and critical glycosylation site. Compared to the wild-type virus rSY, rSY-Delta11 and rSY-Delta10/11 mutant viruses had decreased growth rates, reduced thermo- and pH-stability, decreased pathogenicity, and limited systemic spread. Therefore, our study suggests that the 11N glycosylation site plays a key role in HA cleavage, structural stability and pathogenicity in H5 subtype avian influenza virus. PMID- 29162129 TI - Integrating molecular and structural findings: Wnt as a possible actor in shaping cognitive impairment in Cornelia de Lange syndrome. AB - Cornelia de Lange Syndrome (CdLS) is a choesinopathy: a severe genetic disorder caused by mutations in the cohesin complex genes. The phenotype is characterized by typical facial dysmorphism, growth impairment and multiorgan abnormalities including brain alterations. Wnt pathway is known to play a fundamental role in central nervous system development and it has been shown that Wnt pathway is disrupted in CdLS animal models and patients cells. In this review we investigate the possible link between Wnt pathway disruption and brain abnormalities in Cornelia de Lange Syndrome as such molecular impairment could lead to an abnormal embryonic development resulting in brain abnormalities (i.e. microcephaly, cerebellar hypoplasia, abnormal cortical development) in patients with Cornelia de Lange Syndrome. PMID- 29162130 TI - Toward a comprehensive evidence map of overview of systematic review methods: paper 1-purpose, eligibility, search and data extraction. AB - BACKGROUND: Overviews of systematic reviews attempt to systematically retrieve and summarise the results of multiple systematic reviews. Methods for conducting, interpreting and reporting overviews are in their infancy. To date, there has been no evidence map of the methods used in overviews, thus making it difficult to determine the gaps and priorities for methods research. Our objectives were to develop and populate a comprehensive framework of methods for conducting, interpreting and reporting overviews (stage I) and to create an evidence map by mapping studies that have evaluated overview methods to the framework (stage II). METHODS: We searched methods collections (e.g. Cochrane Methodology Register, Meth4ReSyn library, AHRQ Effective Health Care Program) to identify eligible studies for both stages of this research. In stage I, cross-sectional studies, guidance documents and commentaries that described methods proposed for, or used in, overviews were used to develop and populate the framework of methods. Drafts and multiple iterations of the framework were discussed and refined by all authors. In stage II, we identified and described studies evaluating overview methods and mapped these evaluations to the framework. RESULTS: In this paper, we present results for the four initial steps of conducting an overview: (a) specification of the purpose, objectives and scope, (b) specification of the eligibility criteria, (c) search methods and (d) data extraction. Twenty-nine studies mentioned or described methods relevant to one or more of these steps. In the developed framework, identified methods and approaches were grouped according to the steps an overview author would need to undertake. Fifteen studies evaluated identified methods, all of which mapped to the search methods step. These studies either reported the development and evaluation of a new search filter to retrieve systematic reviews or compared the performance of multiple filters. CONCLUSION: Gaps in the evaluation of methods were found for the majority of steps in the framework. More empirical studies are needed to evaluate the methods outlined and provide a comprehensive evidence map. The framework is useful for planning these evaluations and for planning methods required to deal with challenges that arise when conducting an overview. PMID- 29162131 TI - Absence of nuclease activity in commonly used oxygen-scavenging systems. AB - OBJECTIVE: Oxygen scavenging systems are routinely used during single-molecule imaging experiments to improve fluorescent dye stability. Previous work has shown nuclease contamination in the commonly used oxygen scavenging systems. This study evaluates the potential for nuclease contamination in these oxygen scavenging systems. RESULTS: Linear and plasmid DNA was incubated with two different oxygen scavenging systems (1) protocatechuic acid (PCA)-protocatechuate-3,4-dioxygenase (PCD) and (2) glucose-coupled glucose oxidase/catalase (GODCAT). No nucleic acid degradation was observed on single and double-stranded linear DNA and plasmid DNA, indicating the absence of nuclease contamination in these oxygen scavenging systems. PMID- 29162132 TI - Comparison of the effect of high versus low mean arterial pressure levels on clinical outcomes and complications in elderly patients during non-cardiothoracic surgery under general anesthesia: study protocol for a randomized controlled trial. AB - BACKGROUND: Intraoperative blood pressure (BP) is a concern in daily clinic anesthesia and contributes to the differences in clinical outcome. We conducted a randomized controlled trial (RCT) to compare the effect of high vs. low mean arterial pressure (MAP) levels on clinical outcomes and complications in elderly patients under general anesthesia (GA). METHODS: In this multicenter, randomized, parallel-controlled, open-label, assessor-blinded clinical trial, 322 patients aged more than 65 years will be randomized for a low-level MAP (60-70 mmHg) or high-level MAP (90-100 mmHg) during non-cardiothoracic surgery under GA. The primary outcome will be the incidence of postoperative delirium. The secondary outcomes will include the delirium duration days, intraoperative urine volume, intraoperative blood loss, specific postoperative complications, and all-cause 28 day mortality. DISCUSSION: Results of this trial will help clarify whether BP management is beneficial for elderly patients under GA and will make clear whether the effect of high-level MAP can reduce the postoperative complication compared to low-level MAP. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02857153 . Registered on 15 July 2016. PMID- 29162133 TI - Humoral response in experimental autoimmune encephalomyelitis targets neural precursor cells in the central nervous system of naive rodents. AB - BACKGROUND: Neural precursor cells (NPCs) located in the subventricular zone (SVZ), a well-defined NPC niche, play a crucial role in central nervous system (CNS) homeostasis. Moreover, NPCs are involved in the endogenous reparative process both in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, the possibility that NPCs may be vulnerable to immune-related components may not be ruled out. Therefore, we investigated the potential affinity of myelin oligodendrocyte glycoprotein (MOG)-induced humoral response(s) to NPCs. METHODS: MOG35-55-EAE was induced in C57BL/6 mice; blood sampling was performed on days 17-21 (acute phase) along with a naive group and corresponding antisera (AS) were collected (EAE-AS, NAIVE-AS). The presence of anti-CNS autoantibodies was examined with western blotting. Furthermore, using the collected antisera and anti-MOG antibody (as positive control), immunohistochemistry and double immunofluorescence were implemented on normal neonatal, postnatal, and adult mouse brain sections. Targeted NPCs were identified with confocal microscopy. In vitro immunoreactivity assessment on NPCs challenged with autoantibodies was evaluated for apoptotic/autophagic activity. RESULTS: Western blotting verified the existence of autoantibodies in EAE mice and demonstrated bands corresponding to yet unidentified NPC surface epitopes. A dominant selective binding of EAE-AS in the subventricular zone in all age groups compared to NAIVE-AS (p < 0.001) was observed. Additionally, anti-BrdU+/EAE-AS+ colocalization was significantly higher than anti-BrdU+/anti-MOG+, a finding suggesting that the EAE humoral response colocalized with NPCs(BrdU+), cells that do not express MOG. Well-established NPC markers (Nestin, m-Musashi-1, Sox2, DCX, GFAP, NG2) were used to identify the distinct cell types which exhibited selective binding with EAE-AS. The findings verified that EAE-AS exerts cross reactivity with NPCs which varies throughout the neonatal to adult stage, with a preference to cells of early developmental stages. Finally, increased expressions of Caspase 3 and Beclin 1 on NPCs were detected. CONCLUSION: We provide evidence for the first time that MOG35-55 EAE induces production of antibodies with affinity to SVZ of naive mice in three different age groups. These autoantibodies target lineage-specific NPCs as brain develops and have the potential to trigger apoptotic pathways. Thus, our findings provide indication that cross-talk between immunity and NPCs may lead to functional alteration of NPCs regarding their viability and potentially oligodendrogenesis and effective remyelination. PMID- 29162134 TI - Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. AB - BACKGROUND: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774). METHODS: Patients with clinical stage II/III estrogen receptor positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4 weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was > 10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3-5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA) levels. RESULTS: Despite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2 weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per liter Du/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2% - 96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% - 100%) and 84% (95% CI 69.6% -98.4%), respectively. The kappa-statistic was 0.76 (p < 0.001) between TK1 and Ki-67, indicating substantial agreement. CONCLUSIONS: Serum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01723774. Registered on 6 November 2012. PMID- 29162136 TI - No long-term effect of a 2-days intervention on how to prepare homemade food, on toddlers' skepticism for new food and intake of fruits and vegetables and sweet beverages: a randomized, controlled trial. AB - OBJECTIVE: Optimal nutrition from early age reduces the risk of developing non communicable diseases later in life. The aim of this study was to examine the long-term effect on toddlers' fruit and vegetable intake and sweet beverages, and skepticism for new food, of a 2-days' intervention on how to prepare homemade food for toddlers. RESULTS: The effect of the cooking intervention was evaluated by a randomized, controlled trial where 110 parents of 4-6 months old infants were included. Child diet and food skepticism were measured at 6, 15 and 24 months of age. There were no differences between the control and intervention group in the consumption of fruits and vegetables and intake of water or sweet beverages at 15 and 24 months. There were no differences between the control and intervention group, respectively, in percentage reporting having children who were skeptical regarding new food at baseline (29% vs 20%, p = .372), nor at 3 and 9 months after the intervention (20 vs 18%, p = .804 and 43% vs 32%, p = .383). The intervention did not influence intake of fruits and vegetables, nor did it reduce food skepticism among toddlers. Trial registration first food for infants ISRCTN45864056, 20.05.2016. Retrospectively registered. PMID- 29162135 TI - The effect of midazolam on pain control after knee arthroscopy: a systematic review and meta-analysis. AB - BACKGROUND: Midazolam has some potential in pain control of patients undergoing knee arthroscopy. However, the results remain controversial. We conduct a systematic review and meta-analysis to explore the effect of midazolam on pain control after knee arthroscopy. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases are systematically searched. Randomized controlled trials (RCTs) assessing the effect of midazolam on pain management after knee arthroscopy are included. Two investigators have independently searched articles, extracted the data, and assessed the quality of the included studies. This meta analysis is performed using the random-effect model. RESULTS: Six RCTs are included in this meta-analysis. Compared with control intervention after knee arthroscopy, midazolam intervention can significantly reduce the pain scores (standard mean difference (Std. MD) = - 3.70; 95% confidence interval (CI) = - 6.81 to - 0.60; P = 0.02), the number of patients requiring analgesics (risk ratio (RR) = 0.66; 95% CI = 0.49 to 0.88; P = 0.005), and analgesic consumption (Std. MD = -1.62; 95% CI = - 3.04 to - 0.19; P = 0.03), as well as increase the time to first analgesic requirement (Std. MD = 1.58; 95% CI = 0.17 to 2.99; P = 0.03). In addition, midazolam intervention results in no increase in adverse events following knee arthroscopy (RR = 0.74; 95% CI = 0.18 to 2.98; P = 0.67). CONCLUSIONS: Midazolam intervention is revealed to substantially reduce the pain scores, the number of patients requiring analgesics, and analgesic consumption, as well as improve the time to first analgesic requirement after knee arthroscopy. PMID- 29162137 TI - Potentiating angiogenesis arrest in vivo via laser irradiation of peptide functionalised gold nanoparticles. AB - BACKGROUND: Anti-angiogenic therapy has great potential for cancer therapy with several FDA approved formulations but there are considerable side effects upon the normal blood vessels that decrease the potential application of such therapeutics. Chicken chorioallantoic membrane (CAM) has been used as a model to study angiogenesis in vivo. Using a CAM model, it had been previously shown that spherical gold nanoparticles functionalised with an anti-angiogenic peptide can humper neo-angiogenesis. RESULTS: Our results show that gold nanoparticles conjugated with an anti-angiogenic peptide can be combined with visible laser irradiation to enhance angiogenesis arrest in vivo. We show that a green laser coupled to gold nanoparticles can achieve high localized temperatures able to precisely cauterize blood vessels. This combined therapy acts via VEGFR pathway inhibition, leading to a fourfold reduction in FLT-1 expression. CONCLUSIONS: The proposed phototherapy extends the use of visible lasers in clinics, combining it with chemotherapy to potentiate cancer treatment. This approach allows the reduction of dose of anti-angiogenic peptide, thus reducing possible side effects, while destroying blood vessels supply critical for tumour progression. PMID- 29162139 TI - Effect of aging and curing mode on the compressive and indirect tensile strength of resin composite cements. AB - BACKGROUND: Resin composite cements are used in dentistry to bond ceramic restorations to the tooth structure. In the oral cavity these cements are subjected to aging induced by masticatory and thermal stresses. Thermal cycling between 5 and 55 degrees C simulates the effect of varying temperatures in vitro. Purpose of this study was to compare indirect tensile to compressive strength of different cements before and after thermal cycling. The effect of the curing mode was additionally assessed. METHODS: Indirect tensile strength and compressive strength of 7 dual-curing resin composite cements (Multilink Automix, Multilink SpeedCem, RelyX Ultimate, RelyX Unicem 2 Automix, Panavia V5, Panavia SA Plus, Harvard Implant semi-permanent) was measured. The specimens were either autopolymerized or light-cured (n = 10). The mechanical properties were assessed after 24 h water storage at 37 degrees C and after aging (20,000 thermo cycles) with previous 24 h water storage at 37 degrees C. RESULTS: Indirect tensile strength ranged from 5.2 +/- 0.8 to 55.3 +/- 4.2 MPa, compressive strength from 35.8 +/- 1.8 MPa to 343.8 +/- 19.6 MPa. CONCLUSIONS: Thermocyclic aging of 20,000 cycles can be considered a suitable method to simulate the degradation of indirect tensile strength but not compressive strength of resin composite cements. The effect of thermocycling and the curing mode on the resin composite cements is material dependent and cannot be generalized. PMID- 29162138 TI - Predictability of the effects of facet joint infiltration in the degenerate lumbar spine when assessing MRI scans. AB - BACKGROUND: Imaging results are frequently considered as hallmarks of disease by spine surgeons to plan their future treatment strategy. Numerous classification systems have been proposed to quantify or grade lumbar magnetic resonance imaging (MRI) scans and thus objectify imaging findings. The clinical impact of the measured parameters remains, however, unclear. To evaluate the pathological significance of imaging findings in patients with multisegmental degenerative findings, clinicians can perform image-guided local infiltrations to target defined areas such as the facet joints. The aim of the present retrospective study was to evaluate the correlation of MRI facet joint degeneration and spinal stenosis measurements with improvement obtained by image-guided intraarticular facet joint infiltration. METHODS: Fifty MRI scans of patients with chronic lumbar back pain were graded radiologically using a wide range of classification and measurement systems. The reported effect of facet joint injections at the site was recorded, and a comparative analysis performed. RESULTS: When we allocated patients according to their reported pain relief, 27 showed no improvement (0-30%), 16 reported good improvement (31-75%) and 7 reported excellent improvement (> 75%). MRI features assessed in this study did, however, not show any relevant correlation with reported pain after facet joint infiltration: Values for Kendall's tau ranged from tau = - 0.190 for neuroforaminal stenosis grading as suggested by Lee, to tau = 0.133 for posterior disc height as proposed by Hasegawa. CONCLUSION: Despite the trend in evidence based medicine to provide medical algorithms, our findings underline the continuing need for individualised spine care that, along with imaging techniques or targeted infiltrations, includes diagnostic dimensions such as good patient history and clinical examination to formulate a diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03308149 , retrospectively registered October 2017. PMID- 29162140 TI - Using a multi-state Learning Community as an implementation strategy for immediate postpartum long-acting reversible contraception. AB - BACKGROUND: Implementation strategies are imperative for the successful adoption and sustainability of complex evidence-based public health practices. Creating a learning collaborative is one strategy that was part of a recently published compilation of implementation strategy terms and definitions. In partnership with the Centers for Disease Control and Prevention and other partner agencies, the Association of State and Territorial Health Officials recently convened a multi state Learning Community to support cross-state collaboration and provide technical assistance for improving state capacity to increase access to long acting reversible contraception (LARC) in the immediate postpartum period, an evidence-based practice with the potential for reducing unintended pregnancy and improving maternal and child health outcomes. During 2015-2016, the Learning Community included multi-disciplinary, multi-agency teams of state health officials, payers, clinicians, and health department staff from 13 states. This qualitative study was conducted to better understand the successes, challenges, and strategies that the 13 US states in the Learning Community used for increasing access to immediate postpartum LARC. METHODS: We conducted telephone interviews with each team in the Learning Community. Interviews were semi structured and organized by the eight domains of the Learning Community. We coded transcribed interviews for facilitators, barriers, and implementation strategies, using a recent compilation of expert-defined implementation strategies as a foundation for coding the latter. RESULTS: Data analysis showed three ways that the activities of the Learning Community helped in policy implementation work: structure and accountability, validity, and preparing for potential challenges and opportunities. Further, the qualitative data demonstrated that the Learning Community integrated six other implementation strategies from the literature: organize clinician implementation team meetings, conduct educational meetings, facilitation, promote network weaving, provide ongoing consultation, and distribute educational materials. CONCLUSIONS: Convening a multi-state learning collaborative is a promising approach for facilitating the implementation of new reimbursement policies for evidence-based practices complicated by systems challenges. By integrating several implementation strategies, the Learning Community serves as a meta-strategy for supporting implementation. PMID- 29162141 TI - More than meets the I: the diverse antiviral and cellular functions of interferon induced transmembrane proteins. AB - The first responders of human antiviral immunity are components of the intrinsic immune response that reside within each and every one of our cells. This cell autonomous arsenal consists of nucleic acid sensors and antiviral effectors strategically placed by evolution to detect and restrict invading viruses. While some factors are present at baseline to allow for constant surveillance of the cell interior, others are upregulated by cytokines (such as interferons) that signal a viral infection underway in neighboring cells. In this review, we highlight the multiple roles played by the interferon-induced transmembrane (IFITM) proteins during viral infection, with focuses on IFITM3 and HIV-1. Moreover, we discuss the cellular pathways in which IFITM proteins are intertwined and the various functions they have been ascribed outside the context of infection. While appreciated as broadly-acting, potent restriction factors that prevent virus infection and pathogenesis in cell culture and in vivo, questions remain regarding their precise mode of action and importance in certain viral contexts. Continued efforts to study IFITM protein function will further cement their status as critical host determinants of virus susceptibility and prioritize them in the development of new antiviral therapies. PMID- 29162143 TI - Prevalence and risk of hepatitis E virus infection in the HIV population of Nepal. AB - BACKGROUND: Infection with the hepatitis E virus (HEV) can cause acute hepatitis in endemic areas in immune-competent hosts, as well as chronic infection in immune-compromised subjects in non-endemic areas. Most studies assessing HEV infection in HIV-infected populations have been performed in developed countries that are usually affected by HEV genotype 3. The objective of this study is to measure the prevalence and risk of acquiring HEV among HIV-infected individuals in Nepal. METHODS: We prospectively evaluated 459 Human Immunodeficiency Virus (HIV)-positive individuals from Nepal, an endemic country for HEV, for seroprevalence of HEV and assessed risk factors associated with HEV infection. All individuals were on antiretroviral therapy and healthy blood donors were used as controls. RESULTS: We found a high prevalence of HEV IgG (39.4%) and HEV IgM (15.3%) in HIV-positive subjects when compared to healthy HIV-negative controls: 9.5% and 4.4%, respectively (OR: 6.17, 95% CI 4.42-8.61, p < 0.001 and OR: 3.7, 95% CI 2.35-5.92, p < 0.001, respectively). Individuals residing in the Kathmandu area showed a significantly higher HEV IgG seroprevalance compared to individuals residing outside of Kathmandu (76.8% vs 11.1%, OR: 30.33, 95% CI 18.02-51.04, p = 0.001). Mean CD4 counts, HIV viral load and presence of hepatitis B surface antigen correlated with higher HEV IgM rate, while presence of hepatitis C antibody correlated with higher rate of HEV IgG in serum. Overall, individuals with HEV IgM positivity had higher levels of alanine aminotransferase (ALT) than IgM negative subjects, suggesting active acute infection. However, no specific symptoms for hepatitis were identified. CONCLUSIONS: HIV-positive subjects living in Kathmandu are at higher risk of acquiring HEV infection as compared to the general population and to HIV-positive subjects living outside Kathmandu. PMID- 29162142 TI - "HEATPAC" - a phase II randomized study of concurrent thermochemoradiotherapy versus chemoradiotherapy alone in locally advanced pancreatic cancer. AB - BACKGROUND: Pancreatic cancer has a dismal prognosis with 5-year overall survival rate of around 5%. Although surgery is still the best option in operable cases, majority of the patients who present in locally advanced stages are deemed inoperable. Novel approaches are therefore needed for the management of around 80% of these inoperable locally advanced pancreatic cancers (LAPC). Hyperthermia (39-43 degrees C) is a potent radiosensitizer and further enhances the action of gemcitabine, also a known radiosensitizer. Thus through triple sensitization, a combination of hyperthermia, radiotherapy and gemcitabine could be expected to improve the therapeutic outcomes in LAPC. METHODS: This phase II randomized trial, HEATPAC in unresectable LAPC, explores the feasibility and efficacy of concurrent thermochemoradiotherapy (HTCTRT) over chemoradiotherapy (CTRT) alone with pre- and post-intervention FOLFIRINOX at standard dosage and schedule. Following 4 cycles of neoadjuvant FOLFIRINOX, patients with no metastasis and absence of gross peritoneal carcinomatosis would be randomized to either (a) control arm: concurrent CTRT with gemcitabine (400 mg/m2, weekly *6) or (b) study arm: locoregional hyperthermia (weekly *6 during radiotherapy) with concurrent CTRT (same as in control arm). All patients would receive simultaneous-integrated boost intensity-modulated radiation therapy to doses of 56Gy and 50.4Gy to the gross and clinical target volumes respectively delivered in 28 fractions over 5.5 weeks. Deep locoregional hyperthermia would be administered weekly and monitored with real-time intraduodenal multisensor thermometry probe. A temperature of 40 43 degrees C for 60 min would be aimed for each hyperthermia session. On completion of CTRT/HTCTRT, patients of both groups would receive an additional 8 cycles of FOLFIRINOX. DISCUSSION: The expected 1-year baseline overall survival with CTRT alone is considered as 40%. With HTCTRT, a survival advantage of +20% is expected. Considering alpha = 0.05 and beta = 0.80 for sample size computation, a total of 86 patients would be equally randomized into the two treatment groups. This phase II study if found to be safe and effective, would form the basis of a future phase III randomized study. TRIAL REGISTRATION: The trial has been registered with the ClinicalTrials.gov ( NCT02439593 ). The study has been approved by the Ethical Commissions of Basel and Zurich and is open for patient recruitment. PMID- 29162144 TI - Schistosoma mansoni and other helminthes infections at Haike primary school children, North-East, Ethiopia: a cross-sectional study. AB - OBJECTIVES: Schistosomiasis and soil-transmitted helminthes infections are among the widely distributed infections worldwide. In Ethiopia, parasitic helminthic infections and schistosomiasis are among the most predominant causes of outpatient morbidity. Hence there is still lack of epidemiological information in North-Eastern Ethiopia, this study aimed to determine the prevalence and associated factors of Schistosoma mansoni and other helminthes infections at Haike primary school children, Haike, North-East Ethiopia. RESULTS: The overall prevalence of S. mansoni and other helminthes infections using formol-ether concentration technique was 85/279 (30.5%). Schistosoma mansoni was the dominant parasites as detected by both direct wet mount and formol-ether concentration technique with 44/52 (84.6%) and 65/85 (76.5%) respectively. Chi square test showed significant association between parasitic infections and age of the school children (p = 0.003). The binary logistic regression analysis was showed strong statistical association (p = 0.00) between swimming habit and parasitic infections (AOR = 6.61, 95% CI 3.31-13.12). Family used lake as source of water showed statistically significant association (AOR = 5.35, 95% CI 2.97-12.32). Furthermore, those who get water from river (AOR = 1.24, 95% CI 0.33-4.66) were more likely to be infected with S. mansoni and geo-helminthes than those who used tap water. PMID- 29162145 TI - Reducing hospital admissions in remote Australia through the establishment of a palliative and chronic disease respite facility. AB - BACKGROUND: There are limited respite services for palliative care patients and their families in the Northern Territory (NT). The high prevalence of complex chronic diseases, limited access to primary care services, and the poor living situations of many Aboriginal and Torres Strait Islander Australians result in high hospitalisation rates and pressure on tertiary health services. Palliative Care NT identified a need for a flexible, community based, culturally appropriate respite service in Alice Springs. It was of particular interest to assess the impact of the respite service on the extent to which hospital resources were accessed by this population of patients. METHODS: Respite service use and hospital use data were collected over two time periods: the 12 months prior to the establishment of the service; and the first 10 months of the operation of the service. The financial implications of the facility were assessed in terms of the National Weighted Activity Unit (NWAU). Of primary interest in this study was the impact of the respite service on admissions to the Emergency Department (ED), to the Wards, and to the Intensive Care Unit (ICU). The amount of ventilator hours consumed was also of interest. RESULTS: Overall, there was a mean cost saving of $1882.50 per episode for hospital admissions with a reduction in: hospital admissions; mean length of stay; Intensive Care Unit (ICU) hours; and ventilator hours. CONCLUSIONS: The establishment of the respite service has met an important and unmet need in Alice Springs: provision of respite where none has existed before. The service did assist with savings to the health department which could contribute to the cost of the facility over time. Two features of the respite facility that may have contributed to the savings generated were the enhanced coordination of care for patients with complex chronic diseases, as well as improved medication compliance and symptom management. PMID- 29162146 TI - Smoking and risk of breast cancer in the Generations Study cohort. AB - BACKGROUND: Plausible biological reasons exist regarding why smoking could affect breast cancer risk, but epidemiological evidence is inconsistent. METHODS: We used serial questionnaire information from the Generations Study cohort (United Kingdom) to estimate HRs for breast cancer in relation to smoking adjusted for potentially confounding factors, including alcohol intake. RESULTS: Among 102,927 women recruited 2003-2013, with an average of 7.7 years of follow-up, 1815 developed invasive breast cancer. The HR (reference group was never smokers) was 1.14 (95% CI 1.03-1.25; P = 0.010) for ever smokers, 1.24 (95% CI 1.08-1.43; P = 0.002) for starting smoking at ages < 17 years, and 1.23 (1.07-1.41; P = 0.004) for starting smoking 1-4 years after menarche. Breast cancer risk was not statistically associated with interval from initiation of smoking to first birth (P-trend = 0.97). Women with a family history of breast cancer (ever smoker vs never smoker HR 1.35; 95% CI 1.12-1.62; P = 0.002) had a significantly larger HR in relation to ever smokers (P for interaction = 0.039) than women without (ever smoker vs never smoker HR 1.07; 95% CI 0.96-1.20; P = 0.22). The interaction was prominent for age at starting smoking (P = 0.003) and starting smoking relative to age at menarche (P = 0.0001). CONCLUSIONS: Smoking was associated with a modest but significantly increased risk of breast cancer, particularly among women who started smoking at adolescent or peri-menarcheal ages. The relative risk of breast cancer associated with smoking was greater for women with a family history of the disease. PMID- 29162147 TI - A systematic review describing incidence rate and prevalence of dysvascular partial foot amputation; how both have changed over time and compare to transtibial amputation. AB - BACKGROUND: Partial foot amputation (PFA) is a common consequence of advanced peripheral vascular disease. Given the different ways incidence rate and prevalence data have been measured and reported, it is difficult to synthesize data and reconcile variation between studies. As such, there is uncertainty in whether the incidence rates and prevalence of PFA have increased over time compared to the decline in transtibial amputation (TTA). The aims of this systematic review were to describe the incidence rate and prevalence of dysvascular PFA over time, and how these compare to TTA. METHOD: Databases (i.e., MEDLINE, EMBASE, psychINFO, AMED, CINAHL, ProQuest Nursing and Allied Health) were searched using MeSH terms and keywords related to amputation level and incidence rate or prevalence. Original research published in English from 1 January 2000 to 31 December 2015 were independently appraised, and data extracted, by two reviewers. The McMaster Critical Review Forms were used to assess methodological quality and bias. Results were reported as narrative summaries given heterogeneity of the literature and included the weighted mean annual incidence rate and 95% confidence interval. RESULTS: Twenty two cohort studies met the inclusion criteria. Twenty one reported incidence rate data for some level of PFA; four also included a TTA cohort. One study reported prevalence data for a cohort with toe(s) amputation. Samples were typically older, male and included people with diabetes among other comorbidities. Incidence rates were reported using a myriad of denominators and strata such as diabetes type or initial/recurrent amputation. CONCLUSION: When appropriately grouped by denominator and strata, incidence rates were more homogenous than might be expected. Variation between studies did not necessarily reduce confidence in the conclusion; for example, incidence rate of PFA were many times larger in cohorts with diabetes (94.24 per 100,000 people with diabetes; 95% CI 55.50 to 133.00) compared to those without (3.80 per 100,000 people without diabetes; 95% CI 1.43 to 6.16). It is unclear whether the incidence rates of PFA have changed over time or how they have changed relative to TTA. Further research requires datasets that include a large number of amputations each year and lengthy time periods to determine whether small annual changes in incidence rates have a cumulative and statistically significant effect over time. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015029186 . PMID- 29162148 TI - Text messages to increase attendance to follow-up cervical cancer screening appointments among HPV-positive Tanzanian women (Connected2Care): study protocol for a randomised controlled trial. AB - BACKGROUND: Cervical cancer is a major health concern in Tanzania, caused by poor attendance for cervical cancer screening and follow-up of women at risk. Mobile telephone health interventions are proven effective tools to improve health behaviour in African countries. So far, no knowledge exists on how such interventions may perform in relation to cervical cancer screening in low-income settings. This study aims to assess the degree to which a Short Message Service (SMS) intervention can increase attendance at appointments among women who have tested positive for high-risk (HR) Human Papillomavirus (HPV) during cervical cancer screening. METHODS/DESIGN: Connected2Care is a non-blinded, multicentre, parallel-group, randomised controlled trial. Tanzanian women testing positive to HR HPV at inclusion are randomly assigned in an allocation ratio of 1:1 to the SMS intervention or the control group (standard care). In a period of 10 months, the intervention group will receive 15 one-directional health educative text messages and SMS reminders for their appointment. The total sample size will be 700 with 350 women in each study arm. Primary outcome is attendance rate for follow-up. Secondary objectives are cost-effectiveness, measured through incremental ratios, and knowledge of cervical cancer by a 16-item true/false scale questionnaire at baseline and follow-up. Barriers against implementing the intervention will be assessed in a mixed-methods sub-population study. DISCUSSION: This study may provide information on the potential effects, costs, and barriers in implementing an SMS intervention targeting a group of women who are followed up after testing positive for HR HPV and are, therefore, at increased risk of developing cervical cancer. This can guide decision-makers on the effective use of mobile technology in a low-income setting. Trial status: recruiting. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02509702 . Registered on 15 June 2015. PMID- 29162149 TI - High-throughput SuperSAGE for gene expression analysis of Nicotiana tabacum Rhizoctonia solani interaction. AB - OBJECTIVE: The ubiquitous soil pathogen Rhizoctonia solani causes serious diseases in different plant species. Despite the importance of this disease, little is known regarding the molecular basis of susceptibility. SuperSAGE technology and next-generation sequencing were used to generate transcript libraries during the compatible Nicotiana tabacum-R. solani interaction. Also, we used the post-transcriptional silencing to evaluate the function of a group of important genes. RESULTS: A total of 8960 and 8221 unique Tag sequences identified as differentially up- and down-regulated were obtained. Based on gene ontology classification, several annotated UniTags corresponded to defense response, metabolism and signal transduction. Analysis of the N. tabacum transcriptome during infection identified regulatory genes implicated in a number of hormone pathways. Silencing of an mRNA induced by salicylic acid reduced the susceptibility of N. tabacum to R. solani. We provide evidence that the salicylic acid pathway was involved in disease development. This is important for further development of disease management strategies caused by this pathogen. PMID- 29162150 TI - A content analysis of dissemination and implementation science resource initiatives: what types of resources do they offer to advance the field? AB - BACKGROUND: The recent growth in organized efforts to advance dissemination and implementation (D & I) science suggests a rapidly expanding community focused on the adoption and sustainment of evidence-based practices (EBPs). Although promising for the D & I of EBPs, the proliferation of initiatives is difficult for any one individual to navigate and summarize. Such proliferation may also result in redundant efforts or missed opportunities for participation and advancement. A review of existing D & I science resource initiatives and their unique merits would be a significant step for the field. The present study aimed to describe the global landscape of these organized efforts to advance D & I science. METHODS: We conducted a content analysis between October 2015 and March 2016 to examine resources and characteristics of D & I science resource initiatives using public, web-based information. Included resource initiatives must have engaged in multiple efforts to advance D & I science beyond conferences, offered D & I science resources, and provided content in English. The sampling method included an Internet search using D & I terms and inquiry among internationally representative D & I science experts. Using a coding scheme based on a priori and grounded approaches, two authors consensus coded website information including interactive and non-interactive resources and information regarding accessibility (membership, cost, competitive application, and location). RESULTS: The vast majority (83%) of resource initiatives offered at least one of seven interactive resources (consultation/technical assistance, mentorship, workshops, workgroups, networking, conferences, and social media) and one of six non-interactive resources (resource library, news and updates from the field, archived talks or slides, links pages, grant writing resources, and funding opportunities). Non-interactive resources were most common, with some appearing frequently across resource initiatives (e.g., news and updates from the field). CONCLUSION: Findings generated by this study offer insight into what types of D & I science resources exist and what new resources may have the greatest potential to make a unique and needed contribution to the field. Additional interactive resources may benefit the field, particularly mentorship opportunities and resources that can be accessed virtually. Moving forward, it may be useful to consider strategic attention to the core tenets of D & I science put forth by Glasgow and colleagues to most efficiently and effectively advance the field. PMID- 29162151 TI - Are identities oral? Understanding ethnobotanical knowledge after Irish independence (1937-1939). AB - BACKGROUND: The Schools' Folklore Scheme (1937-1939) was implemented at a pivotal time in Irelands' political history. It resulted in a body of ethnological information that is unique in terms of when, why and how it was collected. This material consists of over 700,000 pages of information, including ethnomedicinal and ethnobotanical traditions, reflecting an oral identity that spans generations and that in many cases was not documented in writing until the 1930s. The intention of this study is to highlight the importance of the Schools' Folklore Scheme and to demonstrate an ethnographic approach based on recollections of original participants of the scheme, to further understand the material in the collection and the impact it had on the participants. METHODS: This study involves an analysis of both oral and archival data. Eleven semi-structured interviews with original participants of the scheme were carried out between April and September 2016. Their corresponding schools' archival contributions to the scheme were located, and ethnomedicinal information was analysed and compared with the participants' recollections. RESULTS: The majority of participants' stated the scheme had a positive impact on them. Five participants' recalled collecting ethnomedicinal information, and there was a direct correlation between three of the participants' ethnomedicinal recollections and their entries in the archives. One third of all the ethnomedicinal entries analysed included the use of a plant. There were 191 plant mentions and 64 plant species named. CONCLUSIONS: Contacting the original participants offers a novel approach of analysing this archival material. It provides a unique first-hand account of this historical initiative, an insight into how the scheme was implemented and how it impacted upon the children. The ethnomedicinal and ethnobotanical information provides an understanding of the medicinal practices in Ireland during the 1930s. The plant species that were both orally recalled by participants and documented in the archives are in keeping with key ethnomedicinal systems throughout the world. PMID- 29162152 TI - The peptidylglycine-alpha-amidating monooxygenase (PAM) gene rs13175330 A>G polymorphism is associated with hypertension in a Korean population. AB - BACKGROUND: Peptidylglycine-alpha-amidating monooxygenase (PAM) may play a role in the secretion of atrial natriuretic peptide (ANP), which is a hormone involved in the maintenance of blood pressure (BP). The objective of the present study was to determine whether PAM is a novel candidate gene for hypertension (HTN). RESULTS: A total of 2153 Korean participants with normotension and HTN were included. Genotype data were obtained using the Korean Chip. The rs13175330 polymorphism of the PAM gene was selected from the ten single nucleotide polymorphisms (SNPs) most strongly associated with BP. The presence of the G allele of the PAM rs13175330 A>G SNP was associated with a higher risk of HTN after adjustments for age, sex, BMI, smoking, and drinking [OR 1.607 (95% CI 1.220-2.116), p = 0.001]. The rs13175330 G allele carriers in the HTN group treated without antihypertensive therapy (HTN w/o therapy) had significantly higher systolic and diastolic BP than the AA carriers, whereas the G allele carriers in the HTN group treated with antihypertensive therapy (HTN w/ therapy) showed significantly higher diastolic BP. Furthermore, rs13175330 G allele carriers in the HTN w/o therapy group had significantly increased levels of insulin, insulin resistance, and oxidized low-density lipoprotein (LDL) and significantly decreased LDL-cholesterol levels and LDL particle sizes compared to the AA carriers. CONCLUSION: These results suggest that the PAM rs13175330 A>G SNP is a novel candidate gene for HTN in the Korean population. Additionally, the PAM rs13175330 G allele might be associated with insulin resistance and LDL atherogenicity in patients with HTN. PMID- 29162154 TI - Pigeon paramyxovirus type 1 from a fatal human case induces pneumonia in experimentally infected cynomolgus macaques (Macaca fascicularis). AB - Although avian paramyxovirus type 1 is known to cause mild transient conjunctivitis in human beings, there are two recent reports of fatal respiratory disease in immunocompromised human patients infected with the pigeon lineage of the virus (PPMV-1). In order to evaluate the potential of PPMV-1 to cause respiratory tract disease, we inoculated a PPMV-1 isolate (hPPMV 1/Netherlands/579/2003) from an immunocompromised human patient into three healthy cynomolgus macaques (Macaca fascicularis) and examined them by clinical, virological, and pathological assays. In all three macaques, PPMV-1 replication was restricted to the respiratory tract and caused pulmonary consolidation affecting up to 30% of the lung surface. Both alveolar and bronchiolar epithelial cells expressed viral antigen, which co-localized with areas of diffuse alveolar damage. The results of this study demonstrate that PPMV-1 is a primary respiratory pathogen in cynomolgus macaques, and support the conclusion that PPMV 1 may cause fatal respiratory disease in immunocompromised human patients. PMID- 29162155 TI - Timing of first focused antenatal care booking and associated factors among pregnant mothers who attend antenatal care in Central Zone, Tigray, Ethiopia. AB - OBJECTIVE: Focused antenatal care became the recommended type of antenatal care following the publication of a World Health Organization trial on antenatal care where it was discovered that the traditional antenatal care approach do not necessarily improve pregnancy out-come. This study was aimed to assess timing of first focused antenatal care booking and associated factors among pregnant mothers. Facility based cross sectional study was used in the randomly selected health facilities. Total 239 pregnant women who visited antenatal clinic were selected using simple random sampling technique and data were entered and analyzed using SPSS version 20.0 software. RESULTS: The study shows that only 41% of pregnant mothers booked timely antenatal care and the median duration of pregnancy at the first visit was 5 months. Multivariate logistic regression analysis showed that gravidity and information received on correct time of antenatal care booking from health care provider were significantly associated with timely initiation of antenatal care. Late antenatal care booking remains high in the study area and this indicated that provide information, education and communication to create community awareness is remarkable and implementing community based discussion up to the local level will be crucial. PMID- 29162153 TI - Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. AB - Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy. PMID- 29162156 TI - The use of 5-fluorouracil-loaded nanobubbles combined with low-frequency ultrasound to treat hepatocellular carcinoma in nude mice. AB - OBJECTIVE: This study aimed to investigate the therapeutic effects of 5 fluorouracil (5-FU)-loaded nanobubbles irradiated with low-intensity, low frequency ultrasound in nude mice with hepatocellular carcinoma (HCC). METHODS: A transplanted tumor model of HCC in nude mice was established in 40 mice, which were then randomly divided equally into four groups: group A (saline), group B (5 FU-loaded nanobubbles), group C (5-FU-loaded nanobubbles with non-low-frequency ultrasound), and group D (5-FU-loaded nanobubbles with low-frequency ultrasound). The tumor size in each mouse was observed via ultrasound before and after the treatments. Inhibition of the tumor growth in each group was compared, and survival curves were generated. Tumor tissues were removed to determine the apoptotic index using the TUNEL method and quantitative analysis. Tumor tissues with CD34-positive microvessels were observed by immunohistochemistry, and the tumor microvessel densities were calculated. RESULTS: The growth rate of the tumor volumes in group D was significantly slower than that in the other groups, while the tumor inhibition rates and apoptotic index in group D were significantly higher than those of the other groups. The number of microvessels staining positive for CD34 was decreased in group D. Therefore, group D presented the most significant inhibitory effects. CONCLUSIONS: Therefore, 5-FU-loaded nanobubbles subjected to irradiation with low-frequency ultrasound could further improve drug targeting and effectively inhibit the growth of transplanted tumors, which is expected to become an ideal drug carrier and targeted drug delivery system for the treatment of HCC in the future. PMID- 29162157 TI - Role of regenerating gene IA expression on local invasion and survival in nasopharyngeal carcinoma. AB - BACKGROUND: Regenerating gene IA (REGIA) plays an important role in tissue regeneration and tumors prognosis of epithelium origin. However, the role of REGIA in nasopharyngeal carcinoma (NPC) is unclear. This study aims to investigate the expression and function of REG1A in NPC. RESULTS: We have found that there was 63 patients with REGIA positive expression of 155 patients in this study (40.65%). The positive expression rate of REGIA was 30.50, 44.44 and 47.83% in stage T2, T3 and T4 patients, respectively. The REGIA expression was significantly difference in T2 and T4 stage tumors or T2 and T3-T4 stage. The positive expression rate of REGIA was found to be higher in patients with cervical lymph node persistence than those with cervical lymph node complete regression. Patients with negative REGIA expression had a better overall survival and free survival than those with REGIA positive expression. In addition, according to the univariate and multivariate analysis, the REGIA expression was an independent adverse prognostic factor for NPC patients. CONCLUSION: REGIA expression was a useful biomarker in NPC patients for assessing T stage and survival. PMID- 29162158 TI - Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR 23b-3p sequestration in gastric cancer. AB - BACKGROUND: Chemoresistance has long been recognized as a major obstacle in cancer therapy. Clarifying the underlying mechanism of chemoresistance would result in novel strategies to improve patient's response to chemotherapeutics. METHODS: lncRNA expression levels in gastric cancer (GC) cells was detected by quantitative real-time PCR (qPCR). MALAT1 shRNAs and overexpression vector were transfected into GC cells to down-regulate or up-regulate MALAT1 expression. In vitro and in vivo assays were performed to investigate the functional role of MALAT1 in autophagy associated chemoresistance. RESULTS: We showed that chemoresistant GC cells had higher levels of MALAT1 and increased autophagy compared with parental cells. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 promoted autophagy in gastric cancer cells. Knockdown of MALAT1 sensitized GC cells to chemotherapeutics. MALAT1 acts as a competing endogenous RNA for miR-23b-3p and attenuates the inhibitory effect of miR-23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells. CONCLUSIONS: Taken together, our study revealed a novel mechanism of lncRNA regulated autophagy-related chemoresistance in GC, casting new lights on the understanding of chemoresistance. PMID- 29162159 TI - Pulsed electron avalanche knife (PEAK) PlasmaBladeTM in pacemaker and defibrillator procedures. AB - BACKGROUND: The pulsed electron avalanche knife (PEAK) PlasmaBladeTM is an innovative electrosurgical device that uses a novel technology to cut tissues. It has been proven to be safe and feasible in ear, nose, and throat surgery, but there are only limited data concerning the use of PlasmaBladeTM instead of conventional electrocautery in cardiac implantable electronic device (CIED) procedures except for generator replacements. METHODS: We conducted a retrospective, single-center study with patients undergoing CIED surgery at our center between December 2015 and March 2017 and evaluate the feasibility and the clinical outcome of the PlasmaBladeTM. RESULTS: 282 patients (mean age 70.7 +/- 12.9 years; 65.6% male) were included, of which 119 (42.2%) underwent pacemaker implantation, 95 (33.7%) implantable cardioverter defibrillator implantation, and 68 (24.1%) received a generator replacement. At the time of the procedure, 55 patients (19.5%) were on dual antiplatelet therapy, and 109 (38.7%) patients were on oral anticoagulation (30.5% vitamin K antagonists, 8.2% novel oral anticoagulants). The overall perioperative complication rate was 3.9%. Device pocket hematoma occurred in 9 patients (3.2%) requiring further surgery. No lead damage was seen within a follow-up of 6 months. One patient presented with device pocket infection 2.9 months after implantation of a cardiac resynchronization therapy defibrillator requiring CIED system extraction. CONCLUSIONS: Replacing conventional electrocautery by PlasmaBladeTM for CIED procedures is feasible with a moderate rate of perioperative complications compared to the literature. Studies comparing the PlasmaBladeTM with conventional electrocautery are necessary to investigate whether PlasmaBladeTM offers an additional benefit over conventional electrocautery. PMID- 29162160 TI - High urinary interleukin-2 in late post-transplant period portends a risk of decline in kidney allograft function: a preliminary study. AB - BACKGROUND: Predictive factors for the rate of decline in kidney allograft function beyond the first post-transplant year have not been thoroughly studied. We aimed to determine whether a single measurement of serum and urinary interleukin 2, interleukin 8 and interleukin 10 at 1-15 years after kidney transplantation could predict a decline in estimated glomerular filtration rate (eGFR) over a 2-year period. RESULTS: Greater serum concentrations of interleukin 8 and interleukin 10 in 30 recipients of kidney allograft at enrollment were associated with lower eGFR after 1 year (beta = - 0.616, p = 0.002 and beta = - 0.393, p = 0.035, respectively), whereas serum concentrations of interleukin 8 also demonstrated significant association with eGFR after 2 years of follow-up (beta = - 0.594, p = 0.003). Higher urinary interleukin 2 concentrations were associated with lower eGFR at baseline (rho = - 0.368, p = 0.049) and after the first (beta = - 0.481, p = 0.008) and the second year (beta = - 0.502, p = 0.006) of follow-up. Higher urinary interleukin 2 concentrations predicted certain decline in eGFR of >= 25% from baseline after 1 year of follow-up in logistic regression: odds ratio = 2.94, confidence interval 1.06-8.18, p = 0.038. When combined with time after transplantation, urinary interleukin 2 demonstrated good accuracy in predicting rapid decline in eGFR by > -5 mL/min/1.73 m2/year (area under the receiver-operator characteristic curve: 0.855, confidence interval 0.687-1.000, and p = 0.008). CONCLUSIONS: Our findings suggest that urinary interleukin 2 in the late period after kidney transplantation has promise in identifying patients who are at risk for progressive loss of graft function in a short-time perspective and need closer monitoring. PMID- 29162161 TI - International Szent-Gyorgyi Prize for Progress in Cancer Research: basic and translational research recognition : Mary-Claire King received the 2016 Prize for her pioneering research that demonstrated the first evidence of genetic predisposition to breast cancer. AB - The Szent-Gyorgyi Prize for Progress in Cancer Research is a prestigious scientific award sponsored by the National Foundation for Cancer Research (NFCR) a leading cancer research charitable organization in the United States that supports innovative cancer research globally with the ultimate goal to cure cancer. The coveted Szent-Gyorgyi Prize annually honors a scientist whose seminal discovery or body of work has resulted in, or led toward, notable contributions to cancer prevention, diagnosis, or treatment; and the discovery has had a high direct impact of saving people's lives. In addition, the prize promotes public awareness of the importance of basic cancer research and encourages the sustained investment needed to accelerate the translation of these research discoveries into new cancer treatments. In 2016, NFCR's Szent-Gyorgyi Prize Selection Committee was unanimous in its decision to recognize an icon in human disease genetics, Dr. Mary-Claire King, for her pioneering research that demonstrated the first evidence of genetic predisposition to breast cancer. Her proof of existence of BRCA1 gene and its location has made genetic screening for breast and ovarian cancers possible, saving lives of many people who are at high risk with inherited BRCA1 mutations. PMID- 29162162 TI - A preliminary study of cross-amplified microsatellite loci using molted feathers from a near-threatened Painted Stork (Mycteria leucocephala) population of north India as a DNA source. AB - OBJECTIVE: In continuation of an earlier study in which we reported the cross amplification of Wood stork microsatellites on the DNA obtained from molted feathers of Painted stork (Mycteria leucocephala), here we investigated the nature of cross-amplified microsatellites and the effect of non-invasive samples on cross-amplification success. In a limited manner, we also addressed the genetic diversity and differentiation in a north Indian population of the Painted Stork examined over three nesting seasons. RESULTS: Among the nine cross amplified loci, only 5 were polymorphic. Three and 6 loci exhibited low (< 50%) and high amplification success rates (> 80), respectively. For 36 of 145 samples most of the loci failed to amplify. For genetic diversity, only 3 loci could be used since others exhibited low amplification and linkage disequilibrium. Probability of identity (0.034) was not low enough to develop a confidence that the similar genotypes originate from the same individual. Forty-two unique genotypes were identified. In 3 loci, a low to moderate level of genetic diversity (mean He = 0.435) was reported. Non-significant Fst (0.003, P = 0.230), G'stH (0.005, P = 0.247) and Dest (0.003, P = 0.250) values indicate a lack of structuring in temporally distributed populations of Delhi Zoo. The limitations and uniqueness of this study are discussed. PMID- 29162164 TI - Vitamin D status is associated with underweight and stunting in children aged 6 36 months residing in the Ecuadorian Andes. AB - OBJECTIVE: There is limited knowledge on vitamin D status of children residing in the Andes and its association with undernutrition. We evaluated the vitamin D status of children residing in a low socio-economic status (SES) setting in the Ecuadorian Andes and assessed the association between vitamin D status, stunting and underweight. We hypothesized that children who were underweight would have lower serum 25-hydroxyvitamin D (25(OH)D) levels and lower 25(OH)D levels would be associated with a higher risk of stunting. DESIGN: We conducted a cross sectional secondary analysis of a randomized controlled trial, the Vitamin A, Zinc and Pneumonia study. Children had serum 25(OH)D concentrations measured. A sensitivity analysis was undertaken to determine a vitamin D cut-off specific for our endpoints. Associations between serum 25(OH)D and underweight (defined as weight-for-age Z-score<=-1) and stunting (defined as height-for-age Z-score<=-2) were assessed using multivariate logistic regression. SETTING: Children residing in five low-SES peri-urban neighbourhoods near Quito, Ecuador. SUBJECTS: Children (n 516) aged 6-36 months. RESULTS: Mean serum 25(OH)D concentration was 58.0 (sd 17.7) nmol/l. Sensitivity analysis revealed an undernutrition-specific 25(OH)D cut-off of <42.5 nmol/l; 18.6 % of children had serum 25(OH)D<42.5 nmol/l. Children who were underweight were more likely to have serum 25(OH)D<42.5 nmol/l (adjusted OR (aOR)=2.0; 95 % CI 1.2, 3.3). Children with low serum 25(OH)D levels were more likely to be stunted (aOR=2.8; 95 % CI 1.6, 4.7). CONCLUSIONS: Low serum 25(OH)D levels were more common in underweight and stunted Ecuadorian children. PMID- 29162163 TI - alpha-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration. AB - Genetic variation in a major histocompatibility complex II (MHCII)-encoding gene (HLA-DR) increases risk for Parkinson disease (PD), and the accumulation of MHCII expressing immune cells in the brain correlates with alpha-synuclein inclusions. However, the timing of MHCII-cell recruitment with respect to ongoing neurodegeneration, and the types of cells that express MHCII in the PD brain, has been difficult to understand. Recent studies show that the injection of short alpha-synuclein fibrils into the rat substantia nigra pars compacta (SNpc) induces progressive inclusion formation in SNpc neurons that eventually spread to spiny projection neurons in the striatum. Herein, we find that alpha-synuclein fibrils rapidly provoke a persistent MHCII response in the brain. In contrast, equivalent amounts of monomeric alpha-synuclein fail to induce MHCII or persistent microglial activation, consistent with our results in primary microglia. Flow cytometry and immunohistochemical analyses reveal that MHCII expressing cells are composed of both resident microglia as well as cells from the periphery that include monocytes, macrophages, and lymphocytes. Over time, alpha-Synuclein fibril exposures in the SNpc causes both axon loss as well as monocyte recruitment in the striatum. While these monocytes in the striatum initially lack MHCII expression, alpha-synuclein inclusions later form in nearby spiny projection neurons and MHCII expression becomes robust. In summary, in the rat alpha-synuclein fibril model, peripheral immune cell recruitment occurs prior to neurodegeneration and microglia, monocytes and macrophages all contribute to MHCII expression. PMID- 29162165 TI - Epigenetic correlates of neonatal contact in humans. AB - Animal models of early postnatal mother-infant interactions have highlighted the importance of tactile contact for biobehavioral outcomes via the modification of DNA methylation (DNAm). The role of normative variation in contact in early human development has yet to be explored. In an effort to translate the animal work on tactile contact to humans, we applied a naturalistic daily diary strategy to assess the link between maternal contact with infants and epigenetic signatures in children 4-5 years later, with respect to multiple levels of child-level factors, including genetic variation and infant distress. We first investigated DNAm at four candidate genes: the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), MU-opioid receptor M1 (OPRM1) and oxytocin receptor (OXTR; related to the neurobiology of social bonds), and brain derived neurotrophic factor (BDNF; involved in postnatal plasticity). Although no candidate gene DNAm sites significantly associated with early postnatal contact, when we next examined DNAm across the genome, differentially methylated regions were identified between high and low contact groups. Using a different application of epigenomic information, we also quantified epigenetic age, and report that for infants who received low contact from caregivers, greater infant distress was associated with younger epigenetic age. These results suggested that early postnatal contact has lasting associations with child biology. PMID- 29162166 TI - Shaping long-term primate development: Telomere length trajectory as an indicator of early maternal maltreatment and predictor of future physiologic regulation. AB - The molecular, neurobiological, and physical health impacts of child maltreatment are well established, yet mechanistic pathways remain inadequately defined. Telomere length (TL) decline is an emerging molecular indicator of stress exposure with definitive links to negative health outcomes in maltreated individuals. The multiple confounders endemic to human maltreatment research impede the identification of causal pathways. This study leverages a unique randomized, cross-foster, study design in a naturalistic translational nonhuman primate model of infant maltreatment. At birth, newborn macaques were randomly assigned to either a maltreating or a competent control mother, balancing for sex, biological mother parenting history, and social rank. Offspring TL was measured longitudinally across the first 6 months of life (infancy) from peripheral blood. Hair cortisol accumulation was also determined at 6, 12, and 18 months of age. TL decline was greater in animals randomized to maltreatment, but also interacted with biological mother group. Shorter TL at 6 months was associated with higher mean cortisol levels through 18 months (juvenile period) when controlling for relevant covariates. These results suggest that even under the equivalent social, nutritional, and environmental conditions feasible in naturalistic translational nonhuman primate models, early adverse caregiving results in lasting molecular scars that foreshadow elevated health risk and physiologic dysregulation. PMID- 29162167 TI - Effects of pre- and postnatal maternal stress on infant temperament and autonomic nervous system reactivity and regulation in a diverse, low-income population. AB - We examined the prospective associations of objective and subjective measures of stress during pregnancy with infant stress reactivity and regulation, an early life predictor of psychopathology. In a racially and ethnically diverse low income sample of 151 mother-infant dyads, maternal reports of stressful life events (SLE) and perceived stress (PS) were collected serially over gestation and the early postpartum period. Infant reactivity and regulation at 6 months of age was assessed via maternal report of temperament (negativity, surgency, and regulation) and infant parasympathetic nervous system physiology (respiratory sinus arrhythmia [RSA]) during the Still Face Paradigm. Regression models predicting infant temperament showed higher maternal prenatal PS predicted lower surgency and self-regulation but not negativity. Regression models predicting infant physiology showed higher numbers of SLE during gestation predicted greater RSA reactivity and weaker recovery. Tests of interactions revealed SLE predicted RSA reactivity only at moderate to high levels of PS. Thus, findings suggest objective and subjective measures of maternal prenatal stress uniquely predict infant behavior and physiology, adjusting for key pre- and postnatal covariates, and advance the limited evidence for such prenatal programming within high-risk populations. Assessing multiple levels of maternal stress and offspring stress reactivity and regulation provides a richer picture of intergenerational transmission of adversity. PMID- 29162168 TI - Immune and neuroendocrine correlates of temperament in infancy. AB - There is now a clear focus on incorporating, and integrating, multiple levels of analysis in developmental science. The current study adds to research in this area by including markers of the immune and neuroendocrine systems in a longitudinal study of temperament in infants. Observational and parent-reported ratings of infant temperament, serum markers of the innate immune system, and cortisol reactivity from repeated salivary collections were examined in a sample of 123 infants who were assessed at 6 months and again when they were, on average, 17 months old. Blood from venipuncture was collected for analyses of nine select innate immune cytokines; salivary cortisol collected prior to and 15 min and 30 min following a physical exam including blood draw was used as an index of neuroendocrine functioning. Analyses indicated fairly minimal significant associations between biological markers and temperament at 6 months. However, by 17 months of age, we found reliable and nonoverlapping associations between observed fearful temperament and biological markers of the immune and neuroendocrine systems. The findings provide some of the earliest evidence of robust biological correlates of fear behavior with the immune system, and identify possible immune and neuroendocrine mechanisms for understanding the origins of behavioral development. PMID- 29162169 TI - Stress exposure and psychopathology alter methylation of the serotonin receptor 2A (HTR2A) gene in preschoolers. AB - Serotonin signaling pathways play a key role in brain development, stress reactivity, and mental health. Epigenetic alterations in the serotonin system may underlie the effect of early life stress on psychopathology. The current study examined methylation of the serotonin receptor 2A (HTR2A) gene in a sample of 228 children including 119 with child welfare documentation of moderate to severe maltreatment within the last 6 months. Child protection records, semistructured interviews in the home, and parent reports were used to assess child stress exposure, psychiatric symptoms, and behavior. The HTR2A genotype and methylation of HTR2A were measured at two CpG sites (-1420 and -1224) from saliva DNA. HTR2A genotype was associated with HTR2A methylation at both CpG sites. HTR2A genotype also moderated associations of contextual stress exposure and HTR2A methylation at site -1420. Contextual stress was positively associated with -1420 methylation among A homozygotes, but negatively associated with -1420 methylation among G homozygotes. Posttraumatic stress disorder and major depressive disorder symptoms were negatively associated with methylation at -1420, but positively associated with methylation at -1224. Results support the view that the serotonin system is sensitive to stress exposure and psychopathology, and HTR2A methylation may be a mechanism by which early adversity is biologically encoded. PMID- 29162170 TI - Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: The role of child maltreatment. AB - Epigenetics processes may play a vital role in the biological embedding of early environmental adversity and the development of psychopathology. Accumulating evidence suggests that maltreatment is linked to methylation of the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), which is a key regulator of the hypothalamus-pituitary-adrenal axis. However, prior work has been exclusively cross-sectional, greatly constraining our understanding of stress-related epigenetic processes over time. In the current study, we examined the effect of maltreatment and other adversity on change in NR3C1 methylation among at-risk preschoolers to begin to characterize within-child epigenetic changes during this sensitive developmental period. Participants were 260 preschoolers (3-5 years old, 53.8% female), including 51.5% with moderate to severe maltreatment in the past 6 months. Child protection records, semistructured interviews, and parent reports were used to assess child stress exposure. Methylation of exons 1D and 1F of NR3C1 via saliva DNA were measured at two time points approximately 6 months apart. Results indicate that maltreated children evidence higher baseline levels of NR3C1 methylation, significant decreases in methylation over time, and then at follow-up, lower levels of methylation, relative to nonmaltreated preschoolers. Findings from the current study highlight the complex nature of stress-related epigenetic processes during early development. PMID- 29162171 TI - Positive maternal mental health during pregnancy associated with specific forms of adaptive development in early childhood: Evidence from a longitudinal study. AB - The quality of prenatal maternal mental health, from psychological stress and depressive symptoms to anxiety and other nonpsychotic mental disorders, profoundly affects fetal neurodevelopment. Despite the evidence for the influence of positive mental well-being on health, there is, to our knowledge, no research examining the possible effects of positive antenatal mental health on the development of the offspring. Using exploratory bifactor analysis, this prospective study (n = 1,066) demonstrated the feasibility of using common psychiatric screening tools to examine the effect of positive maternal mental health. Antenatal mental health was assessed during 26th week of pregnancy. The effects on offspring were assessed when the child was 12, 18, and 24 months old. Results showed that positive antenatal mental health was uniquely associated with the offspring's cognitive, language and parentally rated competences. This study shows that the effects of positive maternal mental health are likely to be specific and distinct from the sheer absence of symptoms of depression or anxiety. PMID- 29162172 TI - Cumulative prenatal exposure to adversity reveals associations with a broad range of neurodevelopmental outcomes that are moderated by a novel, biologically informed polygenetic score based on the serotonin transporter solute carrier family C6, member 4 (SLC6A4) gene expression. AB - While many studies focus on the association between early life adversity and the later risk for psychopathology, few simultaneously explore diverse forms of environmental adversity. Moreover, those studies that examined the cumulative impact of early life adversity focus uniquely on postnatal influences. The objective of this study was to focus on the fetal period of development to construct and validate a cumulative prenatal adversity score in relation to a wide range of neurodevelopmental outcomes. We also examined the interaction of this adversity score with a biologically informed genetic score based on the serotonin transporter gene. Prenatal adversities were computed in two community birth cohorts using information on health during pregnancy, birth weight, gestational age, income, domestic violence/sexual abuse, marital strain, as well as maternal smoking, anxiety, and depression. A genetic score based on genes coexpressed with the serotonin transporter in the amygdala, hippocampus, and prefrontal cortex during prenatal life was constructed with an emphasis on functionally relevant single nucleotide polymorphisms, that is, expression quantitative trait loci. Prenatal adversities predicted a wide range of developmental and behavioral alterations in children as young as 2 years of age in both cohorts. There were interactions between the genetic score and adversities for several domains of the Child Behavior Checklist (CBCL), with pervasive developmental problems remaining significant adjustment for multiple comparisons. Scores combining different prenatal adverse exposures predict childhood behavior and interact with the genetic background to influence the risk for psychopathology. PMID- 29162173 TI - Change in FK506 binding protein 5 (FKBP5) methylation over time among preschoolers with adversity. AB - FK506 binding protein 5 (FKBP5) alters stress response system functioning, and childhood maltreatment is associated with methylation of the FKBP5 gene. Yet it is unknown if maltreatment contributes to change in FKBP5 methylation over time. The current study draws upon a sample of 231 preschoolers, including 123 with child welfare documentation of moderate to severe maltreatment in the past 6 months, to understand if maltreatment contributes to change in FKBP5 methylation over a 6-month period. Review of child protection records and semistructured interviews in the home were used to assess maltreatment and exposure to other contextual stressors, as well as service utilization. Methylation of FKBP5 at two CpG sites in intron 7 was measured from saliva DNA at the time of initial study enrollment, and 6 months following enrollment. Child maltreatment was associated with change in FKBP5 methylation over time, but only when children were exposed to high levels of other contextual stressors. Service utilization was associated with increases in methylation over time, but only among children with the FKPB5 rs1360780 protective CC genotype. Methylation of FKBP5 is sensitive to stress exposure and may be a mechanism linking early adversity to long-term health and developmental outcomes. PMID- 29162174 TI - Exploring longitudinal associations between neighborhood disadvantage and cortisol levels in early childhood. AB - Children who grow up in poverty are more likely to experience chronic stressors that generate "wear" on stress regulatory systems including the hypothalamus pituitary-adrenal (HPA) axis. This can have long-term consequences for health and well-being. Prior research has examined the role of proximal family and home contributions to HPA axis functioning. However, there is evidence to suggest that more distal levels of context, including neighborhoods, also matter. Prior evidence has primarily focused on adolescents and adults, with little evidence linking the neighborhood context with HPA activity in infancy and toddlerhood. We tested whether neighborhood disadvantage (indexed by US Census data) was associated with basal salivary cortisol levels at 7, 15, and 24 months of child age in a large sample of families (N = 1,292) residing in predominately low income and rural communities in the United States. Multilevel models indicated that neighborhood disadvantage was positively associated with salivary cortisol levels and that this effect emerged across time. This effect was moderated by the race/ethnicity of children such that the association was only observed in White children in our sample. Findings provide preliminary evidence that the neighborhood context is associated with stress regulation during toddlerhood, elucidating a need for future work to address possible mechanisms. PMID- 29162176 TI - A neurocomputational investigation of reinforcement-based decision making as a candidate latent vulnerability mechanism in maltreated children. AB - Alterations in reinforcement-based decision making may be associated with increased psychiatric vulnerability in children who have experienced maltreatment. A probabilistic passive avoidance task and a model-based functional magnetic resonance imaging analytic approach were implemented to assess the neurocomputational components underlying decision making: (a) reinforcement expectancies (the representation of the outcomes associated with a stimulus) and (b) prediction error signaling (the ability to detect the differences between expected and actual outcomes). There were three main findings. First, the maltreated group (n = 18; mean age = 13), relative to nonmaltreated peers (n = 19; mean age = 13), showed decreased activity during expected value processing in a widespread network commonly associated with reinforcement expectancies representation, including the striatum (especially the caudate), the orbitofrontal cortex, and medial temporal structures including the hippocampus and insula. Second, consistent with previously reported hyperresponsiveness to negative cues in the context of childhood abuse, the maltreated group showed increased prediction error signaling in the middle cingulate gyrus, somatosensory cortex, superior temporal gyrus, and thalamus. Third, the maltreated group showed increased activity in frontodorsal regions and in the putamen during expected value representation. These findings suggest that early adverse environments disrupt the development of decision-making processes, which in turn may compromise psychosocial functioning in ways that increase latent vulnerability to psychiatric disorder. PMID- 29162175 TI - Reward sensitivity, impulse control, and social cognition as mediators of the link between childhood family adversity and externalizing behavior in eight countries. AB - Using data from 1,177 families in eight countries (Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand, and the United States), we tested a conceptual model of direct effects of childhood family adversity on subsequent externalizing behaviors as well as indirect effects through psychological mediators. When children were 9 years old, mothers and fathers reported on financial difficulties and their use of corporal punishment, and children reported perceptions of their parents' rejection. When children were 10 years old, they completed a computerized battery of tasks assessing reward sensitivity and impulse control and responded to questions about hypothetical social provocations to assess their hostile attributions and proclivity for aggressive responding. When children were 12 years old, they reported on their externalizing behavior. Multigroup structural equation models revealed that across all eight countries, childhood family adversity had direct effects on externalizing behaviors 3 years later, and childhood family adversity had indirect effects on externalizing behavior through psychological mediators. The findings suggest ways in which family-level adversity poses risk for children's subsequent development of problems at psychological and behavioral levels, situated within diverse cultural contexts. PMID- 29162177 TI - Using an adoption-biological family design to examine associations between maternal trauma, maternal depressive symptoms, and child internalizing and externalizing behaviors. AB - Maternal trauma is a complex risk factor that has been linked to adverse child outcomes, yet the mechanisms underlying this association are not well understood. This study, which included adoptive and biological families, examined the heritable and environmental mechanisms by which maternal trauma and associated depressive symptoms are linked to child internalizing and externalizing behaviors. Path analyses were used to analyze data from 541 adoptive mother adopted child (AM-AC) dyads and 126 biological mother-biological child (BM-BC) dyads; the two family types were linked through the same biological mother. Rearing mother's trauma was associated with child internalizing and externalizing behaviors in AM-AC and BM-BC dyads, and this association was mediated by rearing mothers' depressive symptoms, with the exception of biological child externalizing behavior, for which biological mother trauma had a direct influence only. Significant associations between maternal trauma and child behavior in dyads that share only environment (i.e., AM-AC dyads) suggest an environmental mechanism of influence for maternal trauma. Significant associations were also observed between maternal depressive symptoms and child internalizing and externalizing behavior in dyads that were only genetically related, with no shared environment (i.e., BM-AC dyads), suggesting a heritable pathway of influence via maternal depressive symptoms. PMID- 29162179 TI - Variation in DNA methylation of the oxytocin receptor gene predicts children's resilience to prenatal stress. AB - Emerging research in epigenetics has shown that there is variability in how environmental exposures "get under the skin" through mechanisms like DNA methylation to influence gene expression that may lead to differential adaptations to stress. This is the first study to examine prospectively the relationship between DNA methylation at birth and resilience to prenatal environmental stressors in several domains (conduct, hyperactivity, emotional problems, and global symptomatology) in middle childhood. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously associated with impairments in social-cognitive processes that may underlie a wide range of childhood psychopathology. Participants were 91 youth exposed to pre- and postnatal adversity with established conduct problem trajectories drawn from the Avon Longitudinal Study of Parents and Children. Consistent with our hypothesis, OXTR DNA methylation was predictive of resilience in the conduct problems domain in middle childhood. DNA methylation profiles did not predict resilience in domains of emotional, hyperactivity, and global symptomatology, suggesting a potential role for OXTR in the development of conduct problems in particular. However, individuals who were resilient to conduct problems were also broadly resilient across multiple domains. Therefore, future research should elucidate the biological pathways between OXTR DNA methylation and gene expression and its relation to impairments in social behavior. PMID- 29162178 TI - Childhood maltreatment moderates the effect of combat exposure on cingulum structural integrity. AB - Limbic white matter pathways link emotion, cognition, and behavior and are potentially malleable to the influences of traumatic events throughout development. However, the impact of interactions between childhood and later life trauma on limbic white matter pathways has yet to be examined. Here, we examined whether childhood maltreatment moderated the effect of combat exposure on diffusion tensor imaging measures within a sample of military veterans (N = 28). We examined five limbic tracts of interest: two components of the cingulum (cingulum, cingulate gyrus, and cingulum hippocampus [CGH]), the uncinate fasciculus, the fornix/stria terminalis, and the anterior limb of the internal capsule. Using effect sizes, clinically meaningful moderator effects were found only within the CGH. Greater combat exposure was associated with decreased CGH fractional anisotropy (overall structural integrity) and increased CGH radial diffusivity (perpendicular water diffusivity) among individuals with more severe childhood maltreatment. Our findings provide preliminary evidence of the moderating effect of childhood maltreatment on the relationship between combat exposure and CGH structural integrity. These differences in CGH structural integrity could have maladaptive implications for emotion and memory, as well as provide a potential mechanism by which childhood maltreatment induces vulnerability to later life trauma exposure. PMID- 29162180 TI - Threat vigilance and socioeconomic disparities in metabolic health. AB - A quarter of the global population meets diagnostic criteria for metabolic syndrome (MetS). MetS prevalence stratifies by socioeconomic status (SES), such that low SES is associated with higher MetS risk starting in childhood. Despite this trend, some low-SES children maintain good metabolic health across the life span, but the factors responsible for their resilience are not well understood. This study examined the role of threat vigilance as either a moderator or a mediator of the effects of low early life SES on adult metabolic risk. Three hundred twenty-five Canadians aged 15-55 participated (M = 36.4 years, SD = 10.7; 55.4% female). We coded parental occupational status between the ages of 0 and 5 to index early life SES. We used the International Diabetes Federation case definition for MetS based on waist circumference, blood pressure, triglyceride levels, HDL cholesterol, and glycosylated hemoglobin measures. Threat vigilance was assessed using the Weapons Identification Procedure, a visual discrimination paradigm that captures implicit perceptions of threat. Analyses supported the moderator hypothesis: low early life SES was associated with MetS diagnosis exclusively among those with high levels of threat vigilance. This suggests that low early life SES environments that heighten vigilance to threat might be particularly detrimental for metabolic health. Conversely, low threat vigilance may buffer against the metabolic risks associated with socioeconomic disadvantage. PMID- 29162181 TI - Effects of early institutionalization on emotion processing in 12-year-old youth. AB - We examined facial emotion recognition in 12-year-olds in a longitudinally followed sample of children with and without exposure to early life psychosocial deprivation (institutional care). Half of the institutionally reared children were randomized into foster care homes during the first years of life. Facial emotion recognition was examined in a behavioral task using morphed images. This same task had been administered when children were 8 years old. Neutral facial expressions were morphed with happy, sad, angry, and fearful emotional facial expressions, and children were asked to identify the emotion of each face, which varied in intensity. Consistent with our previous report, we show that some areas of emotion processing, involving the recognition of happy and fearful faces, are affected by early deprivation, whereas other areas, involving the recognition of sad and angry faces, appear to be unaffected. We also show that early intervention can have a lasting positive impact, normalizing developmental trajectories of processing negative emotions (fear) into the late childhood/preadolescent period. PMID- 29162182 TI - Child temperament and teacher relationship interactively predict cortisol expression: The prism of classroom climate. AB - Entry into kindergarten is a developmental milestone that children may differentially experience as stressful, with implications for variability in neurobiological functioning. Guided by the goodness-of-fit framework, this study tested the hypothesis that kindergarten children's (N = 338) daily cortisol would be affected by the "match" or "mismatch" between children's temperament and qualities of the classroom relational context. The robustness of these associations was also explored among a separate sample of children in third grade (N = 165). Results among kindergarten children showed negative affectivity and overcontrolled temperament were positively related to cortisol expression within classrooms characterized by lower levels of teacher motivational support, but there was no relation between temperament and cortisol when motivational support was higher. Among third-grade children, negative affectivity was marginally positively related to cortisol at lower levels of teacher-child closeness and unrelated at higher levels of teacher-child closeness. Findings suggest children's cortisol expression depends on the extent to which specific temperamental characteristics "fit" within the relational and contextual qualities of the classroom environment, particularly as children navigate the new roles and relationships that emerge during the transition to formal schooling. Developmentally informed neurobiological research in classrooms may contribute to tailored programmatic efforts to support children's school adjustment. PMID- 29162183 TI - Dimensions of childhood adversity have distinct associations with neural systems underlying executive functioning. AB - Childhood adversity is associated with increased risk for psychopathology. Neurodevelopmental pathways underlying this risk remain poorly understood. A recent conceptual model posits that childhood adversity can be deconstructed into at least two underlying dimensions, deprivation and threat, that are associated with distinct neurocognitive consequences. This model argues that deprivation (i.e., a lack of cognitive stimulation and learning opportunities) is associated with poor executive function (EF), whereas threat is not. We examine this hypothesis in two studies measuring EF at multiple levels: performance on EF tasks, neural recruitment during EF, and problems with EF in daily life. In Study 1, deprivation (low parental education and child neglect) was associated with greater parent-reported problems with EF in adolescents (N = 169; 13-17 years) after adjustment for levels of threat (community violence and abuse), which were unrelated to EF. In Study 2, low parental education was associated with poor working memory (WM) performance and inefficient neural recruitment in the parietal and prefrontal cortex during high WM load among adolescents (N = 51, 13 20 years) after adjusting for abuse, which was unrelated to WM task performance and neural recruitment during WM. These findings constitute strong preliminary evidence for a novel model of the neurodevelopmental consequences of childhood adversity. PMID- 29162184 TI - In the eye of the beholder: Perceptions of neighborhood adversity and psychotic experiences in adolescence. AB - Adolescent psychotic experiences increase risk for schizophrenia and other severe psychopathology in adulthood. Converging evidence implicates urban and adverse neighborhood conditions in the etiology of adolescent psychotic experiences, but the role of young people's personal perceptions of disorder (i.e., physical and social signs of threat) in their neighborhood is unknown. This was examined using data from the Environmental Risk Longitudinal Twin Study, a nationally representative birth cohort of 2,232 British twins. Participants were interviewed at age 18 about psychotic phenomena and perceptions of disorder in the neighborhood. Multilevel, longitudinal, and genetically sensitive analyses investigated the association between perceptions of neighborhood disorder and adolescent psychotic experiences. Adolescents who perceived higher levels of neighborhood disorder were significantly more likely to have psychotic experiences, even after accounting for objectively/independently measured levels of crime and disorder, neighborhood- and family-level socioeconomic status, family psychiatric history, adolescent substance and mood problems, and childhood psychotic symptoms: odds ratio = 1.62, 95% confidence interval [1.27, 2.05], p < .001. The phenotypic overlap between adolescent psychotic experiences and perceptions of neighborhood disorder was explained by overlapping common environmental influences, rC = .88, 95% confidence interval [0.26, 1.00]. Findings suggest that early psychological interventions to prevent adolescent psychotic experiences should explore the role of young people's (potentially modifiable) perceptions of threatening neighborhood conditions. PMID- 29162185 TI - External-environmental and internal-health early life predictors of adolescent development. AB - A wealth of evidence documents associations between various aspects of the rearing environment and later development. Two evolutionary-inspired models advance explanations for why and how such early experiences shape later functioning: (a) the external-prediction model, which highlights the role of the early environment (e.g., parenting) in regulating children's development, and (b) the internal-prediction model, which emphasizes internal state (i.e., health) as the critical regulator. Thus, by using data from the NICHD Study of Early Child Care and Youth Development, the current project draws from both models by investigating whether the effect of the early environment on later adolescent functioning is subject to an indirect effect by internal-health variables. Results showed a significant indirect effect of internal health on the relation between the early environment and adolescent behavior. Specifically, early environmental adversity during the first 5 years of life predicted lower quality health during childhood, which then led to problematic adolescent functioning and earlier age of menarche for girls. In addition, for girls, early adversity predicted lower quality health that forecasted earlier age of menarche leading to increased adolescent risk taking. The discussion highlights the importance of integrating both internal and external models to further understand the developmental processes that effect adolescent behavior. PMID- 29162186 TI - The association between early life stress and prefrontal cortex activation during implicit emotion regulation is moderated by sex in early adolescence. AB - Early life stress (ELS) is a significant risk factor for the emergence of internalizing problems in adolescence. Beginning in adolescence, females are twice as likely as males to experience internalizing disorders. The present study was designed to examine sex differences in the association between ELS and internalizing problems in early pubertal adolescents, and whether and how corticolimbic function and connectivity may underlie these associations. Fifty nine early pubertal males and 78 early pubertal females, ages 9-13 years (all Tanner Stage 3 or below) underwent functional magnetic resonance imaging as they performed an emotion label task that robustly interrogates corticolimbic function. Participants were also interviewed about their experience of ELS. Females exhibited a positive association between ELS and internalizing problems, whereas males exhibited no such association. Whole-brain and amygdala region of interest analyses indicated that whereas females exhibited a positive association between ELS and the ventrolateral prefrontal cortex during implicit emotion regulation, males showed no such association. Activation in these regions was positively associated with internalizing problems in females but not males; however, activation in these regions did not mediate the association between ELS and internalizing problems. Finally, both boys and girls exhibited an association between ELS and increased negative connectivity between the right ventrolateral prefrontal cortex and bilateral amygdala. Using a carefully characterized sample of early pubertal adolescents, the current study highlights important sex differences in the development of corticolimbic circuitry during a critical period of brain development. These sex differences may play a significant role in subsequent risk for internalizing problems. PMID- 29162187 TI - Methylation of the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), in maltreated and nonmaltreated children: Associations with behavioral undercontrol, emotional lability/negativity, and externalizing and internalizing symptoms. AB - The present study examined the effect of various dimensions of child maltreatment (i.e., developmental timing of maltreatment, number of maltreatment subtypes, and chronicity of maltreatment) on methylation of the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), and investigated the associations between NR3C1 methylation and child outcomes. Participants included 534 children who attended a research summer camp program for school-aged maltreated (53.4%) and nonmaltreated (46.6%) children from low socioeconomic backgrounds. Results show that children with early onset maltreatment evidence significant hypermethylation compared to nonmaltreated children. Moreover, more maltreatment subtypes experienced and more chronic maltreatment are both related to greater NR3C1 hypermethylation. Findings also indicate that hypermethylation of NR3C1 is linked with a number of negative child outcomes including greater emotional lability-negativity, higher levels of ego undercontrol, more externalizing behavior, and greater depressive symptoms. Together, results highlight the role of methylation of NR3C1 in the effects of child maltreatment on the development of emotion dysregulation and psychopathology. PMID- 29162188 TI - From child maltreatment to emerging adult problem drinking: Identification of a multilevel internalizing pathway among African American youth. AB - The present study tested the role of FKBP5 binding protein 5 (FKBP5) genetic variation in an internalizing pathway from child maltreatment to emerging adult problem drinking among a sample of African American youth (N = 280) followed prospectively from ages 11 to 20. Specifically, whether childhood internalizing symptoms and emerging adult tension reduction alcohol expectancies sequentially mediate the effect of child maltreatment on emerging adult problem drinking and whether FKBP5 moderates these associations were investigated. The results indicate that individuals with at least one copy of the FKBP5 CATT haplotype (minor alleles) are more vulnerable to traversing the hypothesized internalizing pathway of risk than individuals without this genotypic profile. Taken together our findings highlight the importance of FKBP5 genetic variation in the context of early adversity; support the role of two prospective sequential mediators of an internalizing pathway to problematic drinking, namely, childhood internalizing symptoms and emerging adult tension reduction alcohol expectancies; and identify a subgroup of maltreated children most susceptible to progressing along this less common pathway of risk. PMID- 29162190 TI - Early life stress, FK506 binding protein 5 gene (FKBP5) methylation, and inhibition-related prefrontal function: A prospective longitudinal study. AB - Individuals who have experienced high levels of childhood stress are at increased risk for a wide range of behavioral problems that persist into adulthood, yet the neurobiological and molecular mechanisms underlying these associations remain poorly understood. Many of the difficulties observed in stress-exposed children involve problems with learning and inhibitory control. This experiment was designed to test individuals' ability to learn to inhibit responding during a laboratory task. To do so, we measured stress exposure among a community sample of school-aged children, and then followed these children for a decade. Those from the highest and lowest quintiles of childhood stress exposure were invited to return to our laboratory as young adults. At that time, we reassessed their life stress exposure, acquired functional magnetic resonance imaging data during an inhibitory control task, and assayed these individuals' levels of methylation in the FK506 binding protein 5 (FKBP5) gene. We found that individuals who experienced high levels of stress in childhood showed less differentiation in the dorsolateral prefrontal cortex between error and correct trials during inhibition. This effect was associated only with childhood stress exposure and not by current levels of stress in adulthood. In addition, FKBP5 methylation mediated the association between early life stress and inhibition-related prefrontal activity. These findings are discussed in terms of using multiple levels of analyses to understand the ways in which adversity in early development may affect adult behavioral adaptation. PMID- 29162189 TI - Altered ventral striatal-medial prefrontal cortex resting-state connectivity mediates adolescent social problems after early institutional care. AB - Early caregiving adversity is associated with increased risk for social difficulties. The ventral striatum and associated corticostriatal circuitry, which have demonstrated vulnerability to early exposures to adversity, are implicated in many aspects of social behavior, including social play, aggression, and valuation of social stimuli across development. Here, we used resting-state functional magnetic resonance imaging to assess the degree to which early caregiving adversity was associated with altered coritocostriatal resting connectivity in previously institutionalized youth (n = 41) relative to youth who were raised with their biological families from birth (n = 47), and the degree to which this connectivity was associated with parent-reported social problems. Using a seed-based approach, we observed increased positive coupling between the ventral striatum and anterior regions of medial prefrontal cortex (mPFC) in previously institutionalized youth. Stronger ventral striatum-mPFC coupling was associated with parent reports of social problems. A moderated-mediation analysis showed that ventral striatal-mPFC connectivity mediated group differences in social problems, and more so with increasing age. These findings show that early institutional care is associated with differences in resting-state connectivity between the ventral striatum and the mPFC, and this connectivity seems to play an increasingly important role in social behaviors as youth enter adolescence. PMID- 29162191 TI - Childhood adversity moderates the influence of proximal episodic stress on the cortisol awakening response and depressive symptoms in adolescents. AB - Childhood adversity (CA) is known to predict sensitization to proximal stressors. Researchers have suggested that disruptions in hypothalamus-pituitary-adrenal axis functioning may be a biological mechanism. If so, CA may predict altered associations between proximal life stress and markers of cortisol secretion. We examined whether CA moderates associations between recent episodic stress and (a) the cortisol awakening response (CAR), and (b) depressive symptoms, in 241 adolescents aged 14-17 years (cortisol n = 196). Salivary cortisol was sampled at 0, 30, and 60 min postawakening for 2 days. The CAR was calculated as the area under the curve with respect to increase and waking cortisol. CA and episodic stress were assessed using contextual-threat-method-coded objective interviews. CA significantly interacted with episodic stress to predict both the CAR and depression. Among those with low CA, episodic stress predicted increased CAR but did not predict depression. For adolescents with high CA, episodic stress predicted lower CAR and higher depression. These interactions were found only for independent (uncontrollable, fateful) events, and not for dependent (self generated) stress. Increased allostatic load resulting from CA exposure may interfere with adolescents' ability to optimally regulate their CAR in relation to recent stress, contributing to increased depression risk. PMID- 29162193 TI - Childhood quality influences genetic sensitivity to environmental influences across adulthood: A life-course Gene * Environment interaction study. AB - While environmental adversity has been shown to increase risk for psychopathology, individuals differ in their sensitivity to these effects. Both genes and childhood experiences are thought to influence sensitivity to the environment, and these factors may operate synergistically such that the effects of childhood experiences on later sensitivity are greater in individuals who are more genetically sensitive. In line with this hypothesis, several recent studies have reported a significant three-way interaction (Gene * Environment * Environment) between two candidate genes and childhood and adult environment on adult psychopathology. We aimed to replicate and extend these findings in a large, prospective multiwave longitudinal study using a polygenic score of environmental sensitivity and objectively measured childhood and adult material environmental quality. We found evidence for both Environment * Environment and Gene * Environment * Environment effects on psychological distress. Children with a poor-quality material environment were more sensitive to the negative effects of a poor environment as adults, reporting significantly higher psychological distress scores. These effects were further moderated by a polygenic score of environmental sensitivity. Genetically sensitive children were more vulnerable to adversity as adults, if they had experienced a poor childhood environment but were significantly less vulnerable if their childhood environment was positive. These findings are in line with the differential susceptibility hypothesis and suggest that a life course approach is necessary to elucidate the role of Gene * Environment in the development of mental illnesses. PMID- 29162192 TI - Does striving to succeed come at a physiological or psychosocial cost for adults who experienced child maltreatment? AB - While striving to succeed in the face of adversity may provide individuals with outward benefits, it may come at a cost to individuals' physical health. The current study examines whether striving predicts greater physiological or psychosocial costs among those who experienced child maltreatment, a stressor that disrupts the caregiving environment and threatens relationship security. Using data from the National Longitudinal Study of Adolescent to Adult Health, we tested whether greater striving after childhood maltreatment would come at a cost, increasing underlying cardiovascular disease (CVD) risk and depressive symptoms despite showing outward success via income and college degree attainment. The study included 13,341 Black, Hispanic, and White adolescents who self-reported striving and their experiences of childhood neglect, physical abuse, and sexual abuse. As young adults, participants reported depressive symptoms, income, and college degree attainment and completed a health assessment from which a 30-year Framingham-based CVD risk score was calculated. Higher striving was associated with lower CVD risk and depressive symptoms, and higher income and college degree attainment, regardless of maltreatment history. These findings highlight the potential for striving as a target for interventions and support the need to examine multiple biological and behavioral outcomes to understand the multifaceted nature of resilience. PMID- 29162194 TI - Childhood abuse and neglect and physical health at midlife: Prospective, longitudinal evidence. AB - Previous research suggests that the experience of abuse and neglect in childhood has negative implications for physical health in adulthood. Using data from the Minnesota Longitudinal Study of Risk and Adaptation (N = 115), the present research examined the predictive significance of childhood physical abuse, sexual abuse, and physical/cognitive neglect for multilevel assessments of physical health at midlife (age 37-39 years), including biomarkers of cardiometabolic risk, self-reports of quality of health, and a number of health problems. Analyses revealed that childhood physical/cognitive neglect, but not physical or sexual abuse, predicted all three health outcomes in middle adulthood, even when controlling for demographic risk factors and adult health maintenance behaviors. We discuss possible explanations for the unique significance of neglect in this study and suggest future research that could clarify previous findings regarding the differential impact of different types of abuse and neglect on adult health. PMID- 29162195 TI - Assessing the interplay between multigenic and environmental influences on adolescent to adult pathways of antisocial behaviors. AB - The current investigation utilized a developmental psychopathology approach to test the hypothesis that multigenic (i.e., dopaminergic and serotonergic genes) and multienvironmental factors interactively contribute to developmental pathways of antisocial behavior (ASB). A sample of 8,834 Caucasian individuals from the National Longitudinal Study of Adolescent to Adult Health (Add Health) were used to (a) examine the developmental pathways of ASB from age 13 to 32 using growth mixture modeling, (b) compute weighted multigenic risk scores (Add Health MRS) for ASB from six well-characterized polymorphisms in dopamine and serotonin genes, and (c) test the interaction between the Add Health MRS and a measures of support (incorporating indicators of both positive and negative support from parents and schools). Four pathways of adolescent to adult ASB emerged from the growth mixture models: low, adolescence-peaked, high decline, and persistent. Add Health MRS predicted the persistent ASB pathway, but not other ASB pathways. Males with high Add Health MRS, but not low MRS, had significantly greater odds of being in the adolescence-peaked pathway relative to the low pathway at low levels of school connectedness. Nonfamilial environmental influences during adolescence may have a cumulative impact on the development of ASB, particularly among males with greater underlying genetic risks. PMID- 29162197 TI - Surveillance of anti-tuberculosis drug resistance in Europe, 1999. AB - With the exception of Israel, representative data from Western and Central Europe indicate consistently low levels of resistance to isoniazid (0-9,3%) or rifampicin (0-2,1%) and of multidrug resistance (0-2,1%) among new tuberculosis (TB) cases. Resistance is more frequent among previously treated cases, but comparisons of data should be done cautiously, as criteria for inclusion in TB notifications may vary across countries. In Western Europe, drug resistance is more frequent among cases of foreign origin, a group with high TB incidence. In 1999, cases of foreign origin accounted for over 90% of the MDR cases in the West, and for all MDR cases notified in Israel. The majority of foreign born cases notified originated from Africa or Asia. In the East, representative data from the Baltic States show that overall, 15% of TB cases notified in 1999 were MDR, among the highest proportion worldwide and indicating inadequacies in previous treatment programmes. In the other countries of the former Soviet Union, non-representative data show high levels of resistance which, along with data from the Baltic states and results of surveys, are very alarming. PMID- 29162196 TI - When inflammation and depression go together: The longitudinal effects of parent child relationships. AB - Parent-child relationships have long-term effects on health, particularly later inflammation and depression. We hypothesized that these effects would be mediated by later romantic partner relationships and elevated stressors in young adulthood, helping promote chronic, low grade, inflammation as well as depressive symptoms, and driving their covariation. It has been proposed recently that youth experiencing harsher parenting may also develop a stronger association between inflammation and depressive symptoms in adulthood and altered effects of stressors on outcomes. In the current investigation, we test these ideas using an 18-year longitudinal study of N = 413 African American youth that provides assessment of the parent-child relationship (at age 10), pro-inflammatory cytokine profile and depressive symptoms (at age 28), and potential mediators in early young adulthood (assessed at ages 21 and 24). As predicted, the effect of harsher parent-child relationships (age 10) on pro-inflammatory state and increased depressive symptoms at age 28 were fully mediated through young adult stress and romantic partner relationships. In addition, beyond these mediated effects, parent-child relationships at age 10 moderated the concurrent association between inflammation and depressive symptoms, as well as the prospective association between romantic partner relationships and inflammation, and resulted in substantially different patterns of indirect effects from young adult mediators to outcomes. The results support theorizing that the association of depression and inflammation in young adulthood is conditional on earlier parenting, and suggest incorporating this perspective into models predicting long term health outcomes. PMID- 29162198 TI - Antimicrobial resistance in Italy: preliminary results from the AR-ISS project. AB - Antimicrobial resistance represents a critical problem in human medicine today, from both clinical and economic points of view. In 1999, the Council of the European Union included antibiotic resistance among the public health priorities in the Community, and a resolution entitled 'A strategy against the microbial threat' was issued (1). According to this document, the establishment or strengthening of a surveillance system for the collection of reliable and comparable data on a national and international scale is one of the main interventions needed to control and prevent antibiotic resistance. Surveillance systems should also integrate data about the use and prescription of antibiotics (2). PMID- 29162199 TI - Salmonella - "old" organism, continued challenges ! AB - Following the events of 11 September 2001, the ensuing spectre of bioterrorism and considerable efforts planning for the unthinkable (1), this Eurosurveillance issue reminds us of the continuing threat to public health from well-recognised pathogens, sometimes mistakenly judged to be controlled. Recently the incidence of salmonellosis has decreased substantially across the European Union, the number of cases reported to Enternet (2) declining from 100 267 in the peak year of 1997 to 73 006 in 2001 (I.S.T. Fisher - personal communication). However, recent events and the following articles illustrate continued challenges in salmonella control. PMID- 29162200 TI - European Surveillance of Travel Associated Legionnaires' Disease. AB - Disease acquired in one country but diagnosed and reported in another, necessitates international cooperation if it is to be controlled, investigated and further cases prevented. The European surveillance scheme for travel associated legionnaires' disease (EWGLINET) was established in 1987 to operate in this type of context and has been highly active in sharing information and coordinating its actions since then. In July 2002 European guidelines were introduced by EWGLINET that have standardised the response to clusters across most countries in Europe. Three papers presented in this special issue show how the guidelines have been successfully adopted in France (1), Italy (1) and Spain (2), despite the additional workload associated with their implementation. The paper from the coordinating centre in London provides an overview of EWGLINET results in 2002. PMID- 29162201 TI - Flavobacterium lacunae sp. nov., isolated from a freshwater pond. AB - A novel bacterial strain AHQ-46T was isolated from a freshwater lake in Taiwan. The strain was Gram-stain-negative, strictly aerobic, motile by gliding, rod shaped and formed translucent yellow colonies. Optimal growth occurred at 20-25 degrees C, pH 7.0, and in the absence of NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain AHQ-46T belonged to the genus Flavobacterium and was most closely related to Flavobacterium verecundum TTM-46T with a sequence similarity of 95.8 %. Strain AHQ-46T contained iso-C15 : 1 G, iso C15 : 0, summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c) and iso-C17 : 0 3-OH as the predominant fatty acids. The polar lipid profile consisted of phosphatidylethanolamine and several uncharacterized aminophospholipids and phospholipids. The major polyamine was homospermidine. The major isoprenoid quinone was MK-6. The DNA G+C content of the genomic DNA was 32.1 mol%. Differential phenotypic properties, together with the phylogenetic inference, demonstrate that strain AHQ-46T should be classified as a representative of a novel species of the genus Flavobacterium, for which the name Flavobacterium lacunae sp. nov. is proposed. The type strain is AHQ-46T (=BCRC 80889T=LMG 28710T). PMID- 29162203 TI - Author's correction for Euro Surveill. 2017;22(43). PMID- 29162202 TI - Epidemiological information is key when interpreting whole genome sequence data - lessons learned from a large Legionella pneumophila outbreak in Warstein, Germany, 2013. AB - IntroductionWhole genome sequencing (WGS) is increasingly used in Legionnaires' disease (LD) outbreak investigations, owing to its higher resolution than sequence-based typing, the gold standard typing method for Legionella pneumophila, in the analysis of endemic strains. Recently, a gene-by-gene typing approach based on 1,521 core genes called core genome multilocus sequence typing (cgMLST) was described that enables a robust and standardised typing of L. pneumophila. Methods: We applied this cgMLST scheme to isolates obtained during the largest outbreak of LD reported so far in Germany. In this outbreak, the epidemic clone ST345 had been isolated from patients and four different environmental sources. In total 42 clinical and environmental isolates were retrospectively typed. Results: Epidemiologically unrelated ST345 isolates were clearly distinguishable from the epidemic clone. Remarkably, epidemic isolates split up into two distinct clusters, ST345-A and ST345-B, each respectively containing a mix of clinical and epidemiologically-related environmental samples. Discussion/conclusion: The outbreak was therefore likely caused by both variants of the single sequence type, which pre-existed in the environmental reservoirs. The two clusters differed by 40 alleles located in two neighbouring genomic regions of ca 42 and 26 kb. Additional analysis supported horizontal gene transfer of the two regions as responsible for the difference between the variants. Both regions comprise virulence genes and have previously been reported to be involved in recombination events. This corroborates the notion that genomic outbreak investigations should always take epidemiological information into consideration when making inferences. Overall, cgMLST proved helpful in disentangling the complex genomic epidemiology of the outbreak. PMID- 29162204 TI - Surveillance and laboratory detection for non-polio enteroviruses in the European Union/European Economic Area, 2016. AB - Enteroviruses (EVs) cause severe outbreaks of respiratory and neurological disease as illustrated by EV-D68 and EV-A71 outbreaks, respectively. We have mapped European laboratory capacity for identification and characterisation of non-polio EVs to improve preparedness to respond to (re)-emerging EVs linked to severe disease. An online questionnaire on non-polio EV surveillance and laboratory detection was submitted to all 30 European Union (EU)/European Economic Area (EEA) countries. Twenty-nine countries responded; 26 conducted laboratory-based non-polio EV surveillance, and 24 included neurological infections in their surveillance. Eleven countries have established specific surveillance for EV-D68 via sentinel influenza surveillance (n = 7), typing EV positive respiratory samples (n = 10) and/or acute flaccid paralysis surveillance (n = 5). Of 26 countries performing non-polio EV characterisation/typing, 10 further characterised culture-positive EV isolates, whereas the remainder typed PCR-positive but culture-negative samples. Although 19 countries have introduced sequence-based EV typing, seven still rely entirely on virus isolation. Based on 2015 data, six countries typed over 300 specimens mostly by sequencing, whereas 11 countries characterised under 50 EV-positive samples. EV surveillance activity varied between EU/EEA countries, and did not always specifically target patients with neurological and/or respiratory infections. Introduction of sequence-based typing methods is needed throughout the EU/EEA to enhance laboratory capacity for the detection of EVs. PMID- 29162206 TI - Authors' correction for Euro Surveill. 2017;22(27). PMID- 29162205 TI - Gastroenteritis outbreaks on cruise ships: contributing factors and thresholds for early outbreak detection. AB - When an increased number of acute gastroenteritis (AG) cases is detected among tourists staying at the same accommodation, outbreak management plans must be activated in a timely manner to prevent large outbreaks. Syndromic surveillance data collected between 1 January 2010 and 31 December 2013 by five seagoing cruise ships were analysed to identify attack rate thresholds for early outbreak detection. The overall incidence rate of AG was 2.81 cases per 10,000 traveller days (95% confidence interval (CI): 0.00-17.60), while the attack rate was 19.37 cases per 10,000 travellers (95% CI: 0.00-127.69). The probability of an outbreak occurring was 11% if 4 per 1,000 passengers reported symptoms within the first 2 days of the voyage, and this increased to 23 % if 5 per 1,000 passengers reported such within the first 3 days. The risk ratio (RR) for outbreak occurrence was 2.35, 5.66 and 8.63 for 1, 2 and 3 days' delay of symptoms reporting respectively, suggesting a dose-response relationship. Shipping companies' policies and health authorities' efforts may consider these thresholds for initiating outbreak response measures based on the number of cases according to day of cruise. Efforts should focus on ensuring travellers report symptoms immediately and comply with isolation measures. PMID- 29162207 TI - Note from the editors: 10th European Antibiotic Awareness Day (EAAD) - raising awareness about prudent use of antimicrobials to help curb antimicrobial resistance. PMID- 29162210 TI - Letter to the editor: Livestock-associated meticillin-resistant Staphylococcus aureus (LA-MRSA), Austria, 2013. PMID- 29162209 TI - An outbreak of chickenpox in an asylum seeker centre in Italy: outbreak investigation and validity of reported chickenpox history, December 2015-May 2016. AB - An outbreak of chickenpox occurred between December 2015 and May 2016 among asylum seekers in a reception centre in Latium, Italy. We describe the epidemiological and laboratory investigations, control measures and validity of reported history of chickenpox infection. Serological screening of all residents and incoming asylum seekers was performed, followed by vaccine offer to all susceptible individuals without contraindication. Forty-six cases were found and 41 were associated with the outbreak. No complications, hospitalisations or deaths occurred. Serological testing was performed in 1,278 individuals and 169 were found to be susceptible, with a seroprevalence of 86.8%. A questionnaire was administered to 336 individuals consecutively attending the CARA health post to collect their serological result. The sensitivity, specificity and the positive and negative predictive value (PPV and NPV) of the reported history of chickenpox were 45.0%, 76.1%, 88.3% and 25.6%, respectively. We observed an increasing trend for the PPV and decreasing trend for the NPV with increasing age. Our report confirms that, in the asylum seeker population, chickenpox history is not the optimal method to identify susceptible individuals. Our experience supports the need for additional prevention and control measures and highlights the importance of national and local surveillance systems for reception centres. PMID- 29162211 TI - Dynamics of the pneumonic plague epidemic in Madagascar, August to October 2017. AB - Transmission potential and severity of pneumonic plague in Madagascar were assessed. Accounting for reporting delay, the reproduction number was estimated at 1.73. The case fatality risk was estimated as 5.5%. Expected numbers of exported cases from Madagascar were estimated across the world and all estimates were below 1 person from August to October, 2017. PMID- 29162208 TI - National laboratory-based surveillance system for antimicrobial resistance: a successful tool to support the control of antimicrobial resistance in the Netherlands. AB - An important cornerstone in the control of antimicrobial resistance (AMR) is a well-designed quantitative system for the surveillance of spread and temporal trends in AMR. Since 2008, the Dutch national AMR surveillance system, based on routine data from medical microbiological laboratories (MMLs), has developed into a successful tool to support the control of AMR in the Netherlands. It provides background information for policy making in public health and healthcare services, supports development of empirical antibiotic therapy guidelines and facilitates in-depth research. In addition, participation of the MMLs in the national AMR surveillance network has contributed to sharing of knowledge and quality improvement. A future improvement will be the implementation of a new semantic standard together with standardised data transfer, which will reduce errors in data handling and enable a more real-time surveillance. Furthermore, the scientific impact and the possibility of detecting outbreaks may be amplified by merging the AMR surveillance database with databases from selected pathogen based surveillance programmes containing patient data and genotypic typing data. PMID- 29162212 TI - Comparing antibiotic consumption between two European countries: are packages an adequate surrogate for prescriptions? AB - Defined daily doses (DDD) are the gold standard indicator for quantifying prescriptions. Since 2014, the European Centre for Disease Prevention and Control (ECDC) has also been using the number of packages per 1,000 inhabitants per day (ipd), as a surrogate for prescriptions, to report antibiotic consumption in the community and to perform comparisons between European Union (EU) countries participating in the European Surveillance of Antimicrobial Consumption Network (ESAC-Net). In 2015, consumption was reported to range across Europe from 1.0 to 4.7 packages per 1,000 ipd. Our analysis showed that consumption of antibiotics for systemic use per 1,000 ipd was on average 1.3 times greater in France than in Belgium when considering prescriptions in the numerator, 2.5 times greater when considering packages and 1.2 times greater when considering DDD. As long as the same metrics are used over time, antibiotic consumption data aggregated and disseminated by ECDC are useful for assessing temporal trends at the European level and within individual countries; these data may also be used for benchmarking across EU countries. While DDD - although imperfect - are the most widely accepted metric for this purpose, antibiotic packages do not appear suitable for comparisons between countries and may be misleading. PMID- 29162213 TI - Composition of marsupial zona pellucida: a molecular and phylogenetic approach. AB - The zona pellucida (ZP) is an extracellular matrix that surrounds mammalian oocytes. In eutherians it is formed from three or four proteins (ZP1, ZP2, ZP3, ZP4). In the few marsupials that have been studied, however, only three of these have been characterised (ZP2, ZP3, ZP4). Nevertheless, the composition in marsupials may be more complex, since a duplication of the ZP3 gene was recently described in one species. The aim of this work was to elucidate the ZP composition in marsupials and relate it to the evolution of the ZP gene family. For that, an in silico and molecular analysis was undertaken, focusing on two South American species (gray short-tailed opossum and common opossum) and five Australian species (brushtail possum, koala, Bennett's wallaby, Tammar wallaby and Tasmanian devil). This analysis identified the presence of ZP1 mRNA and mRNA from two or three paralogues of ZP3 in marsupials. Furthermore, evidence for ZP1 and ZP4 pseudogenes in the South American subfamily Didelphinae and for ZP3 pseudogenes in two marsupials is provided. In conclusion, two different composition models are proposed for marsupials: a model with four proteins (ZP1, ZP2 and ZP3 (two copies)) for the South American species and a model with six proteins (ZP1, ZP2, ZP3 (three copies) and ZP4) for the Australasian species. PMID- 29162214 TI - Pharmacokinetics and bioequivalence of a rosuvastatin/ezetimibe fixed-dose combination tablet versus single agents in healthy male subjects?. AB - OBJECTIVE: The pharmacokinetic profiles and bioequivalence of a new rosuvastatin/ezetimibe fixed-dose combination (FDC; NVP-1205) vs. rosuvastatin and ezetimibe concomitantly administered as single agents were evaluated. MATERIALS AND METHODS: In this open-label, single-dose, crossover study (NCT02029625), eligible subjects were randomly assigned in a 1 : 1 ratio to receive a single dose of rosuvastatin (10 mg) with ezetimibe (10 mg) as either a FDC or as single agents concomitantly administered under fasted conditions, followed by a 2-week washout period and administration of the alternate formulation. Serial blood samples were collected predose and up to 96 hours postdose in each period for determination of plasma rosuvastatin and ezetimibe concentrations by liquid-chromatography tandem mass spectroscopy and calculation of pharmacokinetic parameters. RESULTS: The mean Cmax and AUC0 t values of rosuvastatin were 12.5 ng/mL and 115.6 ng*h/mL for the FDC, and 12.2 ng/mL and 115.1 ng*h/mL for the single agents concomitantly administered, respectively. The mean Cmax and AUC0-t values of ezetimibe were 4.7 ng/mL and 67.3 ng*h/mL for the FDC, and 4.5 ng/mL and 68.2 ng*h/mL for the single agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the rosuvastatin Cmax and AUC0-t were 106.20 (96.62 - 116.74) and 102.88 (96.32 - 109.90), respectively. The GMR and 90% CI for the ezetimibe Cmax and AUC0 t were 108.96 (98.56 - 120.51) and 98.13 (92.01 - 104.66), respectively. All treatments were well tolerated during this study, with no serious adverse events reported. CONCLUSION: The rosuvastatin/ezetimibe (10/10 mg) FDC was bioequivalent to single agents concomitantly administered. A single dose of rosuvastatin/ezetimibe as the FDC or as single agents was well tolerated.?. PMID- 29162215 TI - Time course of the drug-drug interaction of acenocoumarol-miconazole. PMID- 29162216 TI - Treatment regimens by pediatric nephrologists in children with congenital nephrogenic diabetes insipidus: A MWPNC study?. AB - BACKGROUND: Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder affecting urinary concentration. Clinicians have varied medication regimens as well as nutritional plan approaches for these children. MATERIALS AND METHODS: An electronic survey was distributed to member pediatric nephrologists of the Midwest Pediatric Nephrology Consortium via email (n = 179). Questions included types of drugs prescribed, factors contributing to drug choice, common drug combinations given, and dietary/failure to thrive interventions used. RESULTS: We analyzed results from 72 respondents (42% overall response rate). 72% treated only 1 - 3 patients with NDI per year, 12% treated 4 or more, and 17% had no NDI patients. Of providers treating NDI patients, almost all prescribed thiazides (93%), 62% prescribed amiloride, and 55% reported prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) as part of their drug regimen. gastrointestinal (GI) and renal side effects (43%) were given as reasons for not prescribing indomethacin. For 70%, drug choice was determined by severity of failure to thrive (FTT). Physicians were asked to define the most common drug combinations they prescribed. 48% reported prescribing indomethacin with hydrochlorothiazide. 84% of respondents have a renal dietitian on staff, and half included appointments with a dietitian as part of FTT therapy. The most common intervention for FFT was gastrostomy tube placement (78%). CONCLUSION: Our results suggest consensus on the use of thiazides, while the use of indomethacin is limited by GI and renal side effect profile. Our results revealed that multiple drug combinations are frequently used without one specific preferred regimen.?. PMID- 29162217 TI - Atypical case of classical polyarteritis nodosa: alveolar hemorrhage and positive antineutrophil cytoplasmic antibody?. AB - Classical polyarteritis nodosa (PAN) is a necrotizing arteritis affecting medium sized vessels. A 73-year-old gentleman who presented with progressive anemia and scant hemoptysis developed acute kidney injury over the course of hospital admission. Kidney biopsy was initially interpreted as consistent with cephalosporin-associated acute interstitial nephritis (AIN) and acute tubular injury (ATI). After oral prednisone (5 days), the patient was discharged with improving serum creatinine. Two days later, he presented with diffuse alveolar hemorrhage. C-ANCA, ANA, anti-GBM, C4, cryoglobulin, HIV, HBV, and HCV studies were negative. P-ANCA was positive. Biopsy tissue was revisited, in addition to AIN, ATI, and non-caseating interstitial granulomas, lymphocytic infiltration of medium-sized vessels with endothelitis consistent with a diagnosis of PAN was noted. This case is notable for its atypical clinical presentation - alveolar hemorrhage - and atypical laboratory presentation - P-ANCA positivity for classical PAN. We describe an atypical presentation of PAN as a means of reviewing the range of clinical presentations, criteria for diagnosis, and treatment approaches for PAN and drug-induced vasculitis, which may present similar to PAN.?. PMID- 29162218 TI - Renal histology and MRI in a 25-year-old Japanese man with nephronophthisis 4?. AB - We investigated a 25-year-old Japanese man who had polycystic kidneys and end stage renal failure without a positive family history. Ultrasonography revealed enlarged kidneys with increased echogenicity and multiple cystic lesions. MRI showed replacement of both kidneys by cystic lesions without definite walls. Renal biopsy demonstrated interstitial fibrosis, especially at the corticomedullary junction. The residual tubular system showed starfish-like disruption. Tubules with cystic dilation were mainly the distal loop of Henle and the distal tubules since immunohistochemical staining was positive for cytokeratin 7 (the distal loop of Henle and the distal tubule) and Tamm-Horsfall protein (the distal loop of Henle), while being negative for aquaporin 3 (the collecting duct) and CD10 (proximal tubule). Comprehensive genetic analysis identified compound heterozygous missense mutations of NPHP4 with autosomal recessive inheritance since his asymptomatic parents each had a single heterozygous missense mutation of NPHP4. In conclusion, MRI and immunohistochemical analysis of renal biopsy specimens may be useful for evaluation of this disease.?. PMID- 29162219 TI - Outcomes of rectal resection following neoadjuvant therapy in the elderly: Can rectal cancer patients be too old for a neoadjuvant approach? AB - BACKGROUND: Neoadjuvant therapy has improved outcomes of resection for rectal carcinoma, however, there is limited data regarding its impact on elderly patients. METHODS: A retrospective review of 109 patients, 74 patients <70 years (Group 1) vs 35 elderly patients >= 70 years (Group 2), who underwent neoadjuvant therapy followed by open resection from 1999 to 2010. RESULTS: Neoadjuvant therapy was completed by 73/74 patients in Group 1 (99%) vs 30/35 patients in Group 2 (86%) (p = 0.013). R0 resection was accomplished in 94% (Group 1-96%, Group 2-91%). The overall recurrence rate was 12% for Group 1 vs 9% for Group 2. Kaplan-Meier analysis revealed a statistically significant difference in overall survival favoring Group 1 (p = 0.002). CONCLUSIONS: Neoadjuvant therapy was safely administered to completion in 86% of elderly patients with similar rates of R0 resection and recurrence versus a younger patient population and should not be denied on the basis of advanced age alone. PMID- 29162221 TI - PRESIDENT'S WELCOME (iv). PMID- 29162220 TI - Clinicopathologic Predictive Factors of Cervical Lymph Node Metastasis in Differentiated Thyroid Cancer. AB - BACKGROUND: Cervical lymph node metastasis (LNM) has been proven to be a predictor for locoregional recurrence in differentiated thyroid carcinoma (DTC). Clinicopathological features could be effective predictive factors for central and lateral LNM of DTC, and provide references to surgeons for cervical neck dissection. METHODS: Retrospective analysis of clinicopathological data was performed on 420 patients who underwent initial surgery from 2010 to 2015. RESULTS: The incidence of central and lateral LNM was calculated. Of 420 patients, 247 (58.8%) exhibited central LNM, and 185 (44.1%) exhibited lateral LNM. There were 29 (6.9%) cases confirmed to have skip metastasis. Univariate and multivariate analysis revealed that tumour location, tumour size, multifocality, capsular invasion, affected lobes, and age were independent predictors of central LNM. Tumour location, capsular invasion, affected lobes, and tumour size were independent predictors of lateral LNM. CONCLUSIONS: Our findings suggest that tumour location, affected lobes, capsular invasion, age, tumour size and multifocality may be taken as predictive factors for cervical LNM of DTC. Meticulous perioperative evaluation of cervical LNM and prophylactic cervical lymph node dissection that aims to remove the occult lymph nodes may be an option for DTC with risk factors. PMID- 29162222 TI - Impact of Solid Minor Histologic Subtype in Postsurgical Prognosis of Stage I Lung Adenocarcinoma. AB - BACKGROUND: Few studies focus on the outcome and effect of a postsurgical treatment strategy for early stage patients with minor solid components pattern. This study investigated the prognosis and the adjuvant chemotherapy benefit among stage I invasive lung adenocarcinoma patients with minor solid components pattern according to the eighth TNM staging classification. METHODS: A total of 3,308 lung adenocarcinoma patients with mixed histologic components was divided into three groups: solid predominant, solid minor, and solid absent pattern. Disease free survival and overall survival were analyzed to evaluate survival difference among patients in the different groups using the Kaplan-Meier approach and multivariable Cox models. RESULTS: Both solid predominant and solid minor groups showed significantly worse disease-free survival (p < 0.001) and overall survival (p < 0.001) compared with the solid absent group. There were no significant disease-free survival (hazard ratio [HR] 1.41, 95% confidence interval [CI]: 0.87 to 2.30, p = 0.161) or overall survival (HR 1.60, 95% CI: 0.83 to 3.09, p = 0.159) difference between the former two groups. For patients in stage IB, adjuvant chemotherapy improves disease-free survival (HR 0.33, 95% CI: 0.11 to 1.02, p = 0.044) but not overall survival (HR 0.61, 95% CI: 0.21 to 1.77, p = 0.360) in the solid predominant group. No adjuvant chemotherapy benefits for disease-free survival (HR 1.04, 95% CI: 0.49 to 2.22; p = 0.922) and overall survival (HR 0.49, 95% CI: 0.13 to 1.90; p = 0.291) were seen for the solid minor group. CONCLUSIONS: Solid minor components predict a significantly worse prognosis compared with the solid absent pattern. However, adjuvant chemotherapy may be unhelpful to improve outcomes for stage IB patients with solid minor components after surgery. PMID- 29162223 TI - Effects of Pectus Excavatum Repair on Right and Left Ventricular Strain. AB - BACKGROUND: The cardiopulmonary benefits of pectus excavatum repair have been debated. Echocardiographic speckle-tracking strain and strain rate have been used to evaluate and detect subclinical myocardial dysfunction in patients receiving cardiotoxic chemotherapy, and patients with valvular heart disease. This technology was applied to evaluate the effects of pectus excavatum surgery on left ventricular (LV) and right ventricular (RV) function. METHODS: Speckle tracing strain evaluation was performed on intraoperative transesophageal echocardiographic images acquired immediately before and after Nuss repair in adult patients (aged 18 years or more) from 2011 to 2014. Standard severity and compression indices were measured on chest imaging performed before pectus excavatum repair. RESULTS: In total, 165 patients with transesophageal echocardiographic images during repair were reviewed (71.5% male; mean age 33.0 years; range, 18 to 71; Haller index 5.7; range, 2.3 to 24.3). Significant improvement after repair was seen in global RV longitudinal strain (-13.5% +/- 4.1% to -16.7% +/- 4.4%, p < 0.0001) and strain rate (-1.3 +/- 0.4 s-1 to -1.4 +/ 0.4 s-1, p = 0.0102); LV global circumferential strain (-18.7% +/- 5.7% to 23.5% +/- 5.8%, p < 0.0001) and strain rate (-1.5 +/- 0.5 s-1 to -1.9 +/- 0.8 s 1, p = 0.0003); and LV radial strain (24.1% +/- 13.5% to 31.1% +/- 16.4%, p = 0.0050). There was a strong correlation between preoperative right atrial compression on transesophageal echocardiogram and improvement in RV global longitudinal strain rate immediately after pectus repair. CONCLUSIONS: Mechanical compression and impaired RV and LV strain is improved by Nuss surgical repair of pectus deformity. PMID- 29162224 TI - [Cancer stem cells and chemotherapy]. PMID- 29162225 TI - The Burden of Atopic Dermatitis in Adults. PMID- 29162226 TI - Management of Corticosteroid-Induced Osteoporosis: A Practical Approach for the Dermatologist. PMID- 29162227 TI - Anti-MDA5-Positive Dermatomyositis: A Description of the Cutaneous and Systemic Manifestations in 2 Cases. PMID- 29162228 TI - Palatal implant surgery effectiveness in treatment of obstructive sleep apnea: A numerical method with 3D patient-specific geometries. AB - Obstructive sleep apnea (OSA) affects a large percentage of the population and is increasingly recognized as a major global health problem. One surgical procedure for OSA is to implant polyethylene (PET) material into the soft palate, but its efficacy remains to be discussed. In this study, we provide input to this topic based on numerical simulations. Three 3 dimensional (3D) soft palate finite element models including mouth-close and mouth-open cases were created based on three patient-specific computed tomography (CT) images. A simplified material modeling approach with the Neo-Hookean material model was applied, and nonlinear geometry was accounted for. Young's modulus for the implant material was obtained from uniaxial tests, and the PET implant pillars were inserted to the 3D soft palate model. With the finite element model, we designed different surgical schemes and investigated their efficacy with respect to avoiding the soft palate collapse. Several pillar schemes were tested, including different placement directions, different placement positions, different settings for the radius and the array parameters of the implant pillars, and different Young's moduli for the pillars. Based on our simulation results, the longitudinal-direction implant surgery improved the stiffness of the soft palate to a small degree, and implanting in the transverse direction was evaluated to be a good choice for improving the existing surgical scheme. In addition, the Young's modulus of the polyethylene material implants has an influence on the reinforcement efficacy of the soft palate. PMID- 29162229 TI - Design of experiments confirms optimization of lithium administration parameters for enhanced fracture healing. AB - Fracture healing is a lengthy process which fails in 5-10% of cases. Lithium, a low-cost therapeutic used in psychiatric medicine, up-regulates the canonical Wingless pathway crucial for osteoblastic mineralization in fracture healing. A design-of-experiments (DOE) methodology was used to optimize lithium administration parameters (dose, onset time and treatment duration) to enhance healing in a rat femoral fracture model. In the previously completed first stage (screening), onset time was found to significantly impact healing, with later (day 7 vs. day 3 post-fracture) treatment yielding improved maximum yield torque. The greatest strength was found in healing femurs treated at day 7 post fracture, with a low lithium dose (20 mg/kg) for 2 weeks duration. This paper describes the findings of the second (optimization) and third (verification) stages of the DOE investigation. Closed traumatic diaphyseal femur fractures were induced in 3 month old rats. Healing was evaluated on day 28 post fracture by CT-based morphometry and torsional loading. In optimization, later onset times of day 10 and 14 did not perform as well as day 7 onset. As such, efficacy of the best regimen (20 mg/kg dose given at day 7 onset for 2 weeks duration) was reassessed in a distinct cohort of animals to complete the DOE verification. A significant 44% higher maximum yield torque (primary outcome) was seen with optimized lithium treatment vs. controls, which paralleled the 46% improvement seen in the screening stage. Successful completion of this robustly designed preclinical DOE study delineates the optimal lithium regimen for enhancing preclinical long-bone fracture healing. PMID- 29162230 TI - Preface Drug discovery in neurodegenerative disorders: a defeat for pharmacology? PMID- 29162231 TI - [Food mycology: ?An emerging discipline?] PMID- 29162232 TI - Chemomics-based marker compounds mining and mimetic processing for exploring chemical mechanisms in traditional processing of herbal medicines, a continuous study on Rehmanniae Radix. AB - Exploring processing chemistry, in particular the chemical transformation mechanisms involved, is a key step to elucidate the scientific basis in traditional processing of herbal medicines. Previously, taking Rehmanniae Radix (RR) as a case study, the holistic chemome (secondary metabolome and glycome) difference between raw and processed RR was revealed by integrating hyphenated chromatographic techniques-based targeted glycomics and untargeted metabolomics. Nevertheless, the complex chemical transformation mechanisms underpinning the holistic chemome variation in RR processing remain to be extensively clarified. As a continuous study, here a novel strategy by combining chemomics-based marker compounds mining and mimetic processing is proposed for further exploring the chemical mechanisms involved in herbal processing. First, the differential marker compounds between raw and processed herbs were rapidly discovered by untargeted chemomics-based mining approach through multivariate statistical analysis of the chemome data obtained by integrated metabolomics and glycomics analysis. Second, the marker compounds were mimetically processed under the simulated physicochemical conditions as in the herb processing, and the final reaction products were chemically characterized by targeted chemomics-based mining approach. Third, the main chemical transformation mechanisms involved were clarified by linking up the original marker compounds and their mimetic processing products. Using this strategy, a set of differential marker compounds including saccharides, glycosides and furfurals in raw and processed RR was rapidly found, and the major chemical mechanisms involved in RR processing were elucidated as stepwise transformations of saccharides (polysaccharides, oligosaccharides and monosaccharides) and glycosides (iridoid glycosides and phenethylalcohol glycosides) into furfurals (glycosylated/non-glycosylated hydroxymethylfurfurals) by deglycosylation and/or dehydration. The research deliverables indicated that the proposed strategy could advance the understanding of RR processing chemistry, and therefore may be considered a promising approach for delving into the scientific basis in traditional processing of herbal medicines. PMID- 29162233 TI - Mechanical characterisation of agarose-based chromatography resins for biopharmaceutical manufacture. AB - Mechanical characterisation of agarose-based resins is an important factor in ensuring robust chromatographic performance in the manufacture of biopharmaceuticals. Pressure-flow profiles are most commonly used to characterise these properties. There are a number of drawbacks with this method, including the potential need for several re-packs to achieve the desired packing quality, the impact of wall effects on experimental set up and the quantities of chromatography media and buffers required. To address these issues, we have developed a dynamic mechanical analysis (DMA) technique that characterises the mechanical properties of resins based on the viscoelasticity of a 1ml sample of slurry. This technique was conducted on seven resins with varying degrees of mechanical robustness and the results were compared to pressure-flow test results on the same resins. Results show a strong correlation between the two techniques. The most mechanically robust resin (Capto Q) had a critical velocity 3.3 times higher than the weakest (Sepharose CL-4B), whilst the DMA technique showed Capto Q to have a slurry deformation rate 8.3 times lower than Sepharose CL-4B. To ascertain whether polymer structure is indicative of mechanical strength, scanning electron microscopy images were also used to study the structural properties of each resin. Results indicate that DMA can be used as a small volume, complementary technique for the mechanical characterisation of chromatography media. PMID- 29162234 TI - Impact of CO2-solvent separators on the degradation of benzyl-2,3 dihydroxypiperidine-1-carboxylate during preparative supercritical fluid chromatographic (SFC) purification. AB - During a preparative separation of the cis enantiomeric pair of benzyl-2,3 dihydroxypiperidine-1-carboxylate using supercritical-fluid chromatography (SFC) with methanol modifier, significant degradation of the products in the collected fractions was observed when a Waters SFC-350(r) (Milford, MA, USA) was used, but same was not observed when a Waters SFC-80q(r) (Milford, MA, USA) was used. Through a systematic investigation, we discovered that the compound degraded over time under an acidic condition created by the formation of methyl carbonic acid from methanol and CO2. The extent of the product degradation was dependent on the time and the concentration of CO2 remained in the product fraction, which was governed by the efficiency of CO2-methanol separation during the fraction collection. Hence, we demonstrated that the different designs of CO2-solvent separator (high pressurized cyclone in Waters SFC-350(r) and low-pressurized vortexing separator in Waters SFC-80q(r)(r)) had a significant impact on the degradation of an acid-sensitive compound. The acidity caused by CO2 in methanol was supported by diminished degradation after a nitrogen purging or after neutralizing the collected fractions with a base. Three different solutions to overcome the degradation problem of the acid sensitive compounds using SFC-350(r) with the high pressurized separator were investigated and demonstrated. The degraded products were isolated as four enantiomers and their relative stereochemistry were established based on 2D NMR data along with the plausible mechanism of degradation. PMID- 29162235 TI - Synthesis and chromatographic characteristics of iminodisuccinic acid functionalized silica stationary phase. AB - In this study, we developed a multifunctional chromatographic medium by using iminodisuccinic acid (IDS) as ligand, gamma-glycidoxypropyltrimethoxysilane (gamma-GLDP) as spacer arm and silica as matrix. The medium was characterized by fourier transform infrared spectrometry (FT-IR). Binding capacity of IDS on chromatographic medium was determined by potentiometric titration. The effect of mass ratios (w/w) between silica and IDS on the medium synthesis was discussed. The optimal ratio of matrix, spacer arm and ligand was 1.5g: 2.0mL: 4.6g. Based on different chromatographic modes, protein mixtures of bovine serum albumin, ribonuclease and lysozyme were successfully separated with IDS-Silica column and IDS-Cu(II)-Silica column, respectively. To examine metal chelating behavior of IDS-Silica stationary phase, optimal geometries and related parameters of complexes formed by IDS with Fe3+, Cu2+, Ni2+, Zn2+, Co2+ and Ca2+ were achieved by quantum computing. The stabilities of the complexes were predicted according to the results of theoretical calculation. Sorption capacities of IDS-Silica stationary phase for metal ions were determined by using offline frontal chromatography (FC) combined with inductively coupled plasma atomic emission spectrometry (ICP-AES). A good agreement was found between simulating results and experimental observations. The order of chelating strength of IDS-Silica medium for metal ions was Fe3+>Cu2+>Ni2+>Zn2+>Co2+>Ca2+. Compared with IDA-Silica, Asp Silica and Glu-Silica stationary phases, IDS-Silica displayed a stronger chelating property for metal ion. PMID- 29162236 TI - Scientific societies and the third industrial revolution - The future role of the OTC. PMID- 29162237 TI - Inter-individual gene variants associated with trabecular bone plasticity: A step forward in the personal genomics of degenerative bone disease. AB - Continuing tissue destruction in osteoarthrosis is maintained by molecular pathways related to an unbalanced chondrocyte metabolism, the loss of reactive oxygen species (ROS) homeostasis, increase catabolism in a degraded matrix and the limited response to growth factors due to cell aging. Rare deleterious gene variants driving relevant molecular pathways may play a key role in the pathogenesis and genetic control of common diseases and may also influence the common gene variants observed in GWAS. We use molecular profiling technologies based on massive sequencing of genes to interrogate clinical samples for a variety of molecules involved in the pathogenesis pathways of OA and also to derive new insights for drug targeting discovery at an early stage of the disease. By whole-exome sequencing performed in OA patients with extreme phenotypes and in non-related individuals without clinical evidence of OA, the most predominant of the rare gene variants found were non-synonymous single nucleotide variants (SNV) from exonic DNA regions and with missense functional effects predicting a moderate impact on protein function. A total of 629, 577, and 639 gene variants for the TPF, COA, and ANHNF patients, respectively, were found not to be shared with the 20 non-disease-related individuals. After subtraction of the 306 variants shared among the OA patients, we obtained the individual profiles of 323, 271, and 333 gene variants, for the TPF, COA, and ANHNF patients, respectively. After filtering by the bioinformatics, genetic, and biological criteria established to assess the clinical consequences, comparative analysis of trio sequences using integrative genome visualization tool clearly demonstrate the differences between patients. Analysis of the collagen gene variants identified 78, 20, and 43 genetic collagen variants for the three extreme phenotypes. Rare gene variants encoding for proteins that are less abundant in the trabecular bone matrix, together with those responsible for the control and regulation of bone turnover and plasticity of subchondral trabecular bone, play important roles in OA and help to define the clinical phenotype. PMID- 29162238 TI - Nanostructure in the trabecular bone of postmenopausal women: Mechanical and chemical analysis. AB - The possibility of diagnosis and prediction of multiple disorders in trabecular bone through nano-biomechanics and chemical analysis are summarized. Improvements to the understating of the compositional contributors of bone mineral and organic components to mechanical competence are crucial. Viscoelastic properties and Raman characterization have been used to evaluate possible alterations of the trabecular bone associated with aging, disease, or injury. In this study, the trabecular bone of postmenopausal women has been analyzed throughout. (a) Nanomechanical characterization, by using nano-DMA: complex modulus, tan delta, loss modulus (E'), and storage modulus (E'); and (b) Raman analysis: relative presence of minerals, carbonate-to-phosphate ratio (both from the mineral components), the crosslinking and nature/secondary structure of collagen (both from the organic components). Complementary nano-morphological studies were done assessing roughness (SRa) and collagen fibrils width, on this trabecular bone. A general idea of the behavior of the viscoelastic performance can be obtained by the Tan delta (E"/E'), that achieved 0.98GPa of damping. 249nm and 0.898MUm of SRa roughness and fibrils width were obtained, respectively. The relative presence of minerals, the carbonate-to-phosphate ratio, the crosslinking and the nature/secondary structure of collagen, between 700 and 1700cm-1, were also obtained, in order to propose a study protocol for trabecular bone characterization. PMID- 29162239 TI - Biomechanical study of pelvic discontinuity in failed total hip arthroplasty. Lessons learnt from the treatment of pelvic fractures. AB - Pelvic discontinuity is a rare but serious problem in orthopedic surgery. Acetabular reconstruction in case of severe bone loss after failed total hip arthroplasty is technically difficult, especially in segmental loss type III (anterior or posterior) or pelvic discontinuity (type IV). Acetabular reinforcement devices are frequently used as load-sharing devices to allow allograft incorporation and in order to serve as support of acetabular implants. This study tries to show, by means of biomechanic work, the efficiency of reinforced plate in anterior column in a segmental pelvic loss, illustrated with a clinical case, which shows the socket stability of hip prosthesis. PMID- 29162240 TI - Influence of gap size, screw configuration, and nail materials in the stability of anterograde reamed intramedullary nail in femoral transverse fractures. AB - Femoral shaft fractures are among the most severe injuries of the skeleton. They are associated with high morbidity and mortality. The most appropriate treatment depending on the type of fracture and location level should be chosen. A finite element model of the femur has been developed, analyzing various types of fractures in the subtrochanteric and diaphyseal supracondylar area, with several gap sizes, being stabilized with a single combination of screws for the intramedullary nail. The mechanical strength of the nail against bending and compression efforts was studied comparing two materials for the nail: stainless steel and titanium alloy. Beside the finite elements (FE) simulations, a clinical follow-up was carried out, considering a sample of 55 patients, 24 males, and 31 females, with mean age of 52.5 years. Localizations of fractures were 22 in the right femur and 33 in the left one, respectively. A good agreement between clinical results and the simulated fractures in terms of gap size was found. Non comminuted fractures have a mean consolidation time of 4.1 months, which coincides with the appropriate mobility at fracture site obtained in the FE simulations, whereas comminuted fractures have a higher mean consolidation period estimated in 7.1 months, corresponding to the excessive mobility at fracture site obtained by means of FE simulations. The obtained results between both nail materials (stainless steel and titanium alloy) show a higher mobility when using titanium nails, which produce a higher rate of strains at the fracture site, amplitude of micromotions and bigger global movements compared to stainless-steel nails. Steel nails provide stiffer osteosyntheses than the titanium nails. In conclusion, anterograde locked nail is particularly useful in the treatment of a wide range of supracondylar fractures with proximal extension into the femoral diaphysis. PMID- 29162241 TI - Influence of screw combination and nail materials in the stability of anterograde reamed intramedullary nail in distal femoral fractures. AB - Intramedullary nailing (IM) is a technique universally accepted to treat femoral diaphyseal fractures. The treatment of fractures located in the distal third remains a controversial issue though. A finite element model of the femur has been developed, analyzing distal fractures with several gap sizes combined with different interlocking combinations of distal screws with one oblique screw proximally to stabilize the intramedullary nail. The mechanical strength of the nail against bending and compression efforts was also studied. Beside the FE simulations, a clinical follow-up of 15 patients, 6 males and 9 females, with mean age of 53.2 years was carried out. Localizations of fractures were 10 in the right femur and 5 in the left femur, respectively. A fairly good correspondence agreement between clinical results and the simulated fractures in terms of gap size was found. Non-comminuted fractures had a mean consolidation time of 20.5 weeks (4.8 months), a tendency corresponding well to the mobility obtained in the FE simulations; Comminuted fractures on the other hand exhibited a higher mean consolidation period of 22.2 weeks (5.2 months) secondary to the excessive mobility at fracture site obtained by means of FE simulations. The best stability at fracture site was found for the system with three distal screws and the system with two distal screws placed medial lateral. The highest leverage of distal screws was obtained maximizing the distance between them and choosing the coronal plane for their orientation. The results obtained with both nail materials (stainless steel and titanium alloy) show a higher mobility when using titanium nails. Steel nails provide stiffer osteosyntheses than the titanium nails. In conclusion, the best screw combination in terms of stability to produce fracture healing and the least difficulties during treatment is the one which had one oblique proximal screw with two distal lateral screw implanted in the coronal plane. PMID- 29162242 TI - Current concepts in spondylopelvic dissociation. AB - INTRODUCTION: Spondylopelvic dissociation is an uncommon and complex injury that results from high-energy trauma with axial overloading through the sacrum. Due to the life-threatening nature of these injuries, standard Advanced Trauma Life Support(r) (ATLS) protocol must be used in the trauma setting as part of the initial management of these patients. The key to diagnosis is a good physical exam coupled with high level of suspicion. Radicular neurological deficits commonly are present in spondylopelvic dissociation (L5's roots) and should be documented for future evaluations. Radiographic views and CT-scan is preferred for the diagnosis. BIOMECHANICS AND CLASSIFICATION: The authors briefly describe the anatomy and biomechanics of the pelvis, and present the main classifications used to define this rare lesion. TREATMENT: Discussion about setting the boundaries of surgical stabilization, if there is still a role for conservative treatment, the importance of the initial treatment and the timing of intervention. Decompression is mandatory in the presence of canal compromise and progressive neurological deficit, regardless of biomechanical criteria for surgery. Kyphotic deformity occurs at the site of sacral transverse fracture and also reduces anteroposterior pelvis diameter. The technique of reduction and posterior surgical stabilization is emphasized. If residual kyphosis remains after bilateral lumbopelvic fixation by shifting of the lower sacral segment, we use S2 and/or S3 screws connected to transitional rods to additional reduction. An illustrated case is shown. COMPLICATIONS: The infection of the wound and the failure of the implants are the most frequent complications of this surgical treatment. CONCLUSION: Posterior stabilization is widely recognized as crucial in the treatment of pelvic disruptions. The concept of circumferential restoration of pelvic ring by bilateral lumbopelvic fixation and anterior fixation seems to be a nice option to increase stabilization and avoid bone misalignment. PMID- 29162243 TI - Influence of the number and position of stripped screws on plate-screw construct biomechanical properties. AB - INTRODUCTION: Screw stripping is a common situation in fracture fixation, particularly in osteopenic bone treatment. Surgeons' perception of screw stripping is relatively poor and the real number of loose screws in every plate screw construct is unknown. The biomechanical and clinical implications of the different possible screw-stripping situations are also unidentified. In this study, construct stiffness in different scenarios of stripped screws is investigated. METHOD: A bone surrogate comminuted osteoporotic fracture was fixed with four screws in both sides of the fracture gap in 75 specimens. In four groups, one or two screws closest or distal to the gap were over-tightened and left in place in one part of the construct and the remaining screws were tightened with 0.3N m torque (four groups). In the fifth group (control), all the screws were tightened with 0.3N m torque. Construct stiffness was tested in terms of compression, bending, and torsion for 1000 cycles. RESULTS: When one or two screws closest to the gap were stripped, stiffness only decreased by, respectively, 5.7% or 7.6% under compression and 4.7% or 6.7% under bending; however, stiffness in torsion was 15.1% or 32%, respectively, lower than the initial stiffness. When a screw distal to the gap was stripped, the stiffness decreased by 28% under bending and 10% under compression; no change was noted under torsion. When two screws distal to the gap were stripped, the stiffness decreased by 11% in compression, collapsed under bending, and decreased by 8% under torsion. CONCLUSIONS: Position and number of stripped screws affect the biomechanical properties of a construct in different ways, depending on the acting forces. PMID- 29162244 TI - Locking versus non-locking one-third tubular plates for treating osteoporotic distal fibula fractures: a comparative study. AB - INTRODUCTION: Ankle fractures represent the third most common fracture in elderly patients, after hip and wrist fractures. Distal fibula fractures in this population are closely related to osteoporosis, which renders commonly used methods of internal fixation technically demanding and prone to failure. Currently there is a tendency to fix osteoporotic metaphyseal and epiphyseal fractures with locking plates. However, published accounts about the use of this technology in osteoporotic distal fibula fractures are scarce. In this study we compare the results of two groups of patients who underwent surgery for these types of fracture, one group received locking and the other non-locking screws, both using one-third tubular plates. METHODS: Sixty-two patients, aged over 64 years, underwent surgery for osteoporotic distal fibula fractures between 2011 and 2014. Forty-five of them were stabilized with a non-locking plate and the remaining 17 with a locking plate fixation. Follow-up was performed at 4, 8, 12, 26, and 52 weeks. Results were assessed according to the AOFAS Ankle-Hindfoot Score and radiological criteria for consolidation. RESULTS: Average time to union and AOFAS scores at 6 and 12 months were similar in both groups, including for the individual categories: function, pain, mobility, and alignment. Only time until partial weight bearing was significantly lower in the locking plate group (4.69 +/- 2.63 vs 7.77 +/- 4.30, p = 0.03). The most common complications were wound dehiscence and superficial infection (two cases of both). CONCLUSIONS: Both locking and conventional non-locking plates achieved similar treatment outcomes in this group of osteoporotic patients aged over 64. However, locking plates may offer more benefits in cases that have to take into account immobilization time and concomitant soft-tissue damage. PMID- 29162245 TI - Ultrasound-guided supra-acetabular pin placement in pelvic external fixation: description of a surgical technique and results. AB - INTRODUCTION: Pelvic fracture in trauma patients can lead to hemodynamic instability. External fixation is a treatment capable of stabilizing these injuries in the context of damage control surgery. Supra-acetabular pin offers the greater biomechanical stability but requires the use of intraoperative fluoroscopy. The aim of this study was to analyze our results for an ultrasound guided supra-acetabular pinning. MATERIAL AND METHODS: Cross-sectional study with cadaveric specimens. Ultrasound-guided pin placement assessed by fluoroscopy and dissection. RESULTS: Fourteen ultrasound-guided supra-acetabular pins were placed in seven cadaveric specimens. Excellent placement in all cases, evaluated with radiological control. Good qualitative bone fixation after dissection. One femoral cutaneous nerve was not found during anatomic dissection and was assumed injured. CONCLUSION: Ultrasound-guided supra-acetabular pin placement is a feasible and effective technique. Our study indicates that pin placement without intraoperative fluoroscopy is feasible without compromising the reliability of its placement. PMID- 29162246 TI - Floating hip and associated injuries. AB - AIM: To describe our experience in treating patients diagnosed with floating hip injury and to communicate the outcomes achieved and the rate of complications. A secondary aim is to compare the results of this group in terms of quality of life with those of patients presenting with a fracture either of the pelvis or of the acetabulum, but in which the femoral segment is not involved. PATIENTS AND METHODS: This is a descriptive study of the patients diagnosed with floating hip injury (25 patients) who were treated at our hospital between 2004 and 2007, with a minimum follow-up of seven years. The results are compared with those of a control group of 56 patients diagnosed with an isolated pelvic or acetabular injury. We describe the injuries and the associated lesion. The patients' quality of life was assessed using the EUROQOL tool. RESULTS: Among the floating hip group of patients, three suffered an additional arterial lesion and were later treated with a supracondylar amputation. Seven patients presented heterotopic ossification. No significant difference was observed between the study and control groups, according to the EUROQOL tool, although the scores for every dimension were lower among the floating hip patients. Among the patients in the control group, the quality of life scores were also affected in every dimension of the EUROQOL scale. DISCUSSION AND CONCLUSIONS: The addition of a femoral fracture to a pelvic or acetabular injury, the so-called floating hip, is a devastating injury which has an important impact on patients' quality of life, going beyond that experienced by patients with isolated injuries. Nevertheless, our results did not reflect statistically significant differences in the quality of life among the three groups analyzed: isolated fractures, floating hip and floating hip resulting in amputation. PMID- 29162247 TI - Severe tibial plateau fractures (Schatzker V-VI): open reduction and internal fixation versus hybrid external fixation. AB - Tibial plateau fractures (TPF) are highly prone to complications and adverse effects. Their treatment has long been a matter of controversy, as fracture patterns and possible damage to soft tissues can easily aggravate complications. On the one hand, open reduction and internal fixation (ORIF) techniques provide a good approach to joint shape restoration and biomechanics, but they may also provoke a higher rate of soft-tissue complications. On the other, hybrid external fixation (HEF), although allowing little facility for reduction, may, theoretically, produce much less damage to the soft tissues. We present 93 cases of TPF classified as type V or VI that were followed up for at least 24 months. There were no statistical differences among them in relation to consolidation, secondary malalignment or range of motion, according to whether ORIF or HEF was employed. However, when external fixation followed open reduction, both superficial and deep-infection rates were higher. PMID- 29162248 TI - Predicting syndesmotic injuries in ankle fractures: a new system based on the medial malleolar focus. AB - The early establishment of the diagnosis of a syndesmotic injury is essential for treatment selection. However, such injuries may not be apparent radiographically. Previous studies have attempted to describe correlations between medial malleolar fracture geometry and syndesmotic disruption. The main objective of this study was to create predictive models for assessing syndesmotic injuries based on an originally described angle, i.e., the medial crural-focal angle (MCFA). This study included 138 ankle fractures involving the medial malleolus. Any measure from the plain radiograph that could potentially lead to the suspicion of a syndesmotic disruption was recorded, and the newly described MCFA (formed by the main line of the medial malleolus fracture and a line perpendicular to the bearing surface of the tibial plafond) was also recorded. The inter- and intraobserver reliabilities were obtained using Krippendorff's alpha coefficients. To examine the predictive abilities of every parameter, several statistical methods were applied including logistic regression, an ad hoc clinical rule, and discriminant analysis. After variable selection, we obtained the best possible logistic model. The variables that were found to be statistically significant were the MCFA, the tibiofibular clear space (TFCS) and the type of injury in the Lauge-Hansen (L-H) classification. This model was tested by cross validation, which revealed a mean percentage of correctly classified patients of 88%. A simpler and more intuitive alternative model was sought that was based solely on the influences of the MCFA and the TFCS. Our study revealed that an absence of syndesmotic disruptions when the MCFA was under 60 degrees , and there were no uninjured patients with tibiofibular clear space values over 6mm. Cross-validation revealed that the mean percentage of patients who were correctly classified with this model was 86%. The application of discriminant analysis to this combination of variables resulted in a function was able to correctly classify a mean of 84% of patients. In conclusion, three models that can predict syndesmotic injury using parameters from preoperative plain radiographs were obtained and validated. The MCFA measurement was in these models and found to be a reliable technique. PMID- 29162250 TI - Emerging Nanomedical Solutions for Angiogenesis Regulation. PMID- 29162249 TI - Functional outcome after calcaneus fractures: a comparison between polytrauma patients and isolated fractures. AB - BACKGROUND: Displaced intra-articular calcaneal fractures (DIACFs) can have long term consequences in terms of foot pain and disability. This injury frequently occurs in the context of polytrauma patients and its influence in long-term functional prognosis is well known. The purpose of this study is to compare the etiology, severity, and functional outcome of the operated DIACFs between polytrauma patients and isolated cases. METHODS: Eighty-six patients with operated displaced intra-articular calcaneal fractures through open reduction and internal fixation (ORIF) were managed at our institution between January 1, 2008 and December 31, 2015. Eighty patients completed the follow-up, nine of them with both calcaneus operated (89 calcaneus) by ORIF with a plate. Two groups were established; one included 11 (14%) polytrauma patients, three of them with operated bilateral calcaneus, and 69 (86%) patients without polytrauma diagnosis. Severity of trauma, injury patterns, psychiatric background, associated fractures, second surgeries and functional questionnaire (adjusted American Orthopedic Foot and Ankle Society - AOFAS - ankle-hindfoot scale and SF-36) were collected. A detailed comparative statistical analysis is provided. RESULTS: There was significant statistical relationship between polytrauma patients and those with psychiatric comorbidities, severe trauma or severe injury, but not with second surgeries, later subtalar arthrodesis or outcome measures. Only calcaneal fractures with comminution according to Sanders classification was associated with second surgeries and later subtalar arthrodesis. The AOFAS score was solely related to trauma severity (71.5 vs 77; p = 0.29) and calcaneal fracture's comminution according to Sanders classification (79.4 type II and 79.3 type III vs 69.2 type IV; p = 0.000 and p = 0.008, respectively) and SF-36 score only with trauma severity (67.4 vs 78.1; p = 0.00) and psychiatric comorbidities (62.2 vs 75.8; p = 0.048). CONCLUSION: No differences in outcome measures and second surgeries were found between polytrauma patients and isolated fractures. For DIACFs, the severity of the impact was correlated with a higher number of second surgeries and worse functional outcomes. Following a DIACF, patients with psychiatric comorbidities presented worse health-related quality of life than people without this background. PMID- 29162251 TI - ? PMID- 29162252 TI - [Prematurity, progress and challenges]. AB - Prematurity is one of the main causes of neonatal mortality and comorbidities, and longer term sequalae. The survival rate and quality of life of premature babies has however progressed significantly and infants benefit from improved monitoring and long-term follow-up. Notable advances have been made in the area of developmental care, although their implementation in units needs to be improved. Innovations in perinatology should emerge in the years ahead. PMID- 29162253 TI - [Supporting the establishment of the parent-child bond in cases of prematurity]. AB - The evolution of the care of premature babies is having an effect on a particular difficulty, that of the development of parenthood and the parent-baby relationship hampered by an early birth. The short- and long-term consequences of any disruption to these two dimensions can be considerable and the hospital must take into account the issue when caring for parents and their premature baby. PMID- 29162254 TI - [Alliance of skills to fight pain of premature babies]. AB - Premature babies are particularly vulnerable and exposed to pain and discomfort. To improve the quality of care, an alliance of skills between nurses, children's nurses and the psychomotor therapist has been set up in a neonatal intensive care unit. PMID- 29162255 TI - [Oral feeding difficulties in neonatal medicine and intensive care]. AB - Oral feeding difficulties represent a major health issue for the future of babies born prematurely. In a neonatal intensive care unit at the Hopital Cochin, a multi-disciplinary group of professionals regularly meet to initiate team actions. Infants vulnerabilities and quality of life and parents supports are essential for patient management. PMID- 29162256 TI - [Prematurity and nursing care in neonatal intensive care]. AB - In neonatal intensive care, the management of babies born prematurely requires particular vigilance from caregivers. Specific care procedures include enteral feeding and the development of the diet, the monitoring of vital signs, venous access management, blood withdrawal, phototherapy and obligatory screening. The nursing role is essential in this context. PMID- 29162257 TI - [Developmental care for the premature newborn]. AB - Prematurity is linked to risks of developmental disorders later in life. Developmental care aims to improve the comfort of premature babies and to support their physiological, neurological, behavioural and relational skills. Centred on the infant and their parents, it is based on scientific evidence. PMID- 29162258 TI - [An innovative position during skin-to-skin contact in neonatology]. AB - Skin-to-skin is, by its very nature, the only relational care entirely devoted to the parent-baby relationship, from the infant's time in neonatal intensive care. However, current practice is unsuited to visual and tactile exchange. A simple change to the baby's positioning helps to improve the quality of the immediate interaction between the infant and the mother, benefiting the development of the baby and parenthood. PMID- 29162259 TI - ? PMID- 29162260 TI - ? PMID- 29162261 TI - ["Valentin was born prematurely"]. AB - Anne-Charlotte B. is the proud mother of Valentin, born prematurely seven years ago. Despite the complications of the birth, the initial separation and the difficult start to breastfeeding, Valentin gradually gained weight and has never suffered any sequelae. The family has since grown. PMID- 29162262 TI - [Understanding of the parents' perception of a hospitalised infant about their skills]. AB - The hospitalisation of a child involves the whole family. The parents' perception is therefore a suitable indicator to help improve family-centered helpgiving practices. A study was carried out in 2014 in a paediatric unit in Switzerland, in order to guide the cultural adaptation of a tool for measuring the practices in place to support the parents of hospitalised children. The purpose is also that they know better their abilities. PMID- 29162263 TI - ? PMID- 29162264 TI - Retraction notice to NAD(P)H:QUINONE OXIOREDUCTASE 1 PROTECTS LUNGS FROM OXIDANT INDUCED EMPHYSEMA IN MICE [FRB 52/3 (2012) 705 - 715]. PMID- 29162265 TI - The impact of antegrade intramedullary nailing start site using the SIGN nail in proximal femoral fractures: A prospective cohort study. AB - INTRODUCTION: In many low and middle-income countries (LMICs) SIGN nail is commonly used for antegrade femoral intramedullary (IM) nailing, using a start site either at the tip of the greater trochanter or piriformis fossa. While a correct start site is considered an essential technical step; few studies have evaluated the impact of using an erroneous start site. This is particularly relevant in settings with limited access to fluoroscopy to aid in creating a nail entry point. The purpose of this study was to evaluate the impact of antegrade SIGN IM nailing start site on radiographic alignment and health-related quality of life. METHODS: In this prospective cohort study, adult patients with proximal femur fractures (OTA 32, subtrochanteric zone) treated with antegrade IM SIGN nail at Muhimbili Orthopaedic Institute (MOI), Dar es Salaam, Tanzania were enrolled. Start site was determined on the immediate postoperative X-ray and was graded on a continuous scale based on distance of the IM nail center from the greater trochanteric tip. The primary outcome measurement was coronal alignment on the post-operative x-ray. The secondary outcomes were reoperation rates, RUST scores and EQ5D scores at one year follow-up. RESULTS: Seventy-nine patients were enrolled. 50 of them (63.3%) had complete data at 1year and were included in the final data analysis. Of the fifty patients, nine (18%) had IM nails placed laterally, 26 (52%) medially and 15 (30%) directly over the tip of the greater trochanter. Compared to a start site at the tip or medial to the greater trochanter, a lateral start site was 9 times more likely to result in a varus malalignment (95% CI: 1.42-57.70, p=0.021). CONCLUSIONS: Lateral start site was associated with varus malalignment. Although lateral start site was not significantly associated with reoperation, varus deformity was associated with higher reoperation rates. Surgeons should consider avoiding a start site lateral to the tip of the greater trochanter or allow the nail to rotate to avoid malalignment when using the SIGN nail for proximal femur fractures. PMID- 29162267 TI - The prehospital management of hypothermia - An up-to-date overview. AB - BACKGROUND: Accidental hypothermia concerns a body core temperature of less than 35 degrees C without a primary defect in the thermoregulatory system. It is a serious threat to prehospital patients and especially injured patients, since it can induce a vicious cycle of the synergistic effects of hypothermia, acidosis and coagulopathy; referred to as the trauma triad of death. To prevent or manage deterioration of a cold patient, treatment of hypothermia should ideally begin prehospital. Little effort has been made to integrate existent literature about prehospital temperature management. The aim of this study is to provide an up-to date systematic overview of the currently available treatment modalities and their effectiveness for prehospital hypothermia management. DATA SOURCES: Databases PubMed, EMbase and MEDLINE were searched using the terms: "hypothermia", "accidental hypothermia", "Emergency Medical Services" and "prehospital". Articles with publications dates up to October 2017 were included and selected by the authors based on relevance. RESULTS: The literature search produced 903 articles, out of which 51 focused on passive insulation and/or active heating. The most effective insulation systems combined insulation with a vapor barrier. Active external rewarming interventions include chemical, electrical and charcoal-burning heat packs; chemical or electrical heated blankets; and forced air warming. Mildly hypothermic patients, with significant endogenous heat production from shivering, will likely be able to rewarm themselves with only insulation and a vapor barrier, although active warming will still provide comfort and an energy-saving benefit. For colder, non-shivering patients, the addition of active warming is indicated as a non-shivering patient will not rewarm spontaneously. All intravenous fluids must be reliably warmed before infusion. CONCLUSION: Although it is now accepted that prehospital warming is safe and advantageous, especially for a non-shivering hypothermic patient, this review reveals that no insulation/heating combinations stand significantly above all the others. However, modern designs of hypothermia wraps have shown promise and battery-powered inline fluid warmers are practical devices to warm intravenous fluids prior to infusion. Future research in this field is necessary to assess the effectiveness expressed in patient outcomes. PMID- 29162266 TI - Plasma free carnitine in severe trauma: Influence of the association with traumatic brain injury. AB - BACKGROUND: Metabolic response to severe trauma requires early nutritional resuscitation. Carnitine is essential for lipolysis, the energy source during this hypercatabolic phase. However l-carnitine is not present in nutritional replacement solutions. Furthermore, free carnitine depletion, defined as carnitine plasma level under 36MUmol/L, was not adequately reported in adult patients with severe trauma. The aim of this study was to assess plasma free carnitine levels and factors of variation in severe trauma. METHOD: Our observational study concerned 38 trauma patients including 18 with traumatic brain injury (TBI). On the third day after trauma, plasma free carnitine concentration was determined (by enzymatic method) while patients received artificial nutrition. RESULTS: Low plasmatic free carnitine concentration was evidenced in 95% of the patients with a median value of 18MUmol/L (11-47). Univariate analysis showed that mean arterial pressure, serum urea, CKD-EPI and patients with TBI were significantly associated with plasma free carnitine concentration less than 18MUmol/L. Lower plasma free carnitine concentration was observed in the group of patients with TBI with 17.72MUmol/L (11-36) versus 21.5MUmol/L (11-47) for others patients (p=0.031). Logistic regression analysis showed that severe trauma with TBI and CKD-EPI above 94mL/min/1.73m2 appeared to be independent predictor of lower free carnitine plasmatic concentration (Goodness of fit=0.87 and AUC=0.89). CONCLUSION: Our observations support hypotheses that plasma free carnitine concentration is lowered in severe injured patients especially for TBI patients and patients with estimated GFR above 94mL/min/1.73m2. PMID- 29162268 TI - Diabetes and Healing Outcomes in Lower Extremity Fractures: A Systematic Review. AB - OBJECTIVE: The purpose of this study was to review the rates of adverse healing outcomes following surgical fixation of lower extremity fractures in diabetic patients and matched controls. MATERIALS AND METHODS: Searches of PubMed, MEDLINE, CINAHL and Embase were performed for studies published between the date of database inception and July 6, 2015. Patient characteristics and the incidence of adverse healing outcomes (nonunion, malunion, delayed union, infection and reoperation) were extracted from each study. The occurrence of each fracture healing complication was pooled and analyzed for comparisons between diabetic and non-diabetic patients. An odds ratio with a 95% confidence interval for each healing outcome was calculated between the diabetic and non-diabetic groups. RESULTS: Diabetes was found to significantly increase rates of malunion, infection and reoperation in patients with surgically treated lower extremity fractures. In addition, when only peripheral lower extremity fractures (i.e. below the knee) were examined, diabetes significantly increased the rates of nonunion. CONCLUSION: Diabetes substantially alters bone metabolism and soft tissue healing, posing a risk of adverse fracture healing and other complications. This systematic review provides evidence that the presence of diabetes significantly increases the risks of infection, malunion, nonunion and re-operation across a wide variety of surgically treated lower extremity fractures. This study provides prognostic information for clinicians and may aid in guiding treatment for this population. PMID- 29162269 TI - Trans-articular Kirschner wire fixation in treating complex tibial plateau fractures complicated by multiple ligaments injuries: A case report and literature review. AB - There is no guideline and consensus about when and how to treat accompanying multi-ligaments injuries, especially anterior and/or posterior cruciate ligaments, in tibial plateau fractures. We report one case of fracture and dislocation of tibial plateau, treated by open reduction and internal plates fixation, augmented by trans-articular Kirschner wire fixation to overcome instability and malrotation of the knee joints discovered intraoperatively. The Kirschner wire was removed about four weeks after the index operation, and the patient begun functional exercise from then on. The fracture united uneventfully, the knee joint regained full range of motion without malalignment. The patient reported excellent knee function and satisfied with the operations. We suppose that trans-articular Kirschner wires fixation combined with open reduction internal plates fixation maybe is a treatment solution in treating complex tibial plateau fractures complicated by multiple ligamentous injuries. PMID- 29162270 TI - Epsilon gamma delta beta thalassemia: A rare cause of fetal and neonatal anemia. PMID- 29162271 TI - Familial pancreatic cancer asociated to germline mutation of BRCA2. PMID- 29162272 TI - Use of intravenous iron in critically ill patients with anemia. PMID- 29162273 TI - Ten-year survival of nonagenarians after a hospital discharge. PMID- 29162274 TI - Maxillar osteonecrosis associated to denosumab in a patient with systemic mastocytosis. PMID- 29162275 TI - Different tools for the diagnosis and molecular follow-up of leukemias and lymphomas. PMID- 29162277 TI - [Necrotising fasciitis in an elderly oncologic patient]. PMID- 29162276 TI - [Oropharyngeal dysphagia, a new geriatric syndrome]. PMID- 29162278 TI - [Considerations for the determination of sample size in instrumental research in geriatrics and gerontology]. PMID- 29162279 TI - Clinical decision support of radiotherapy treatment planning: A data-driven machine learning strategy for patient-specific dosimetric decision making. AB - BACKGROUND AND PURPOSE: Clinical decision support systems are a growing class of tools with the potential to impact healthcare. This study investigates the construction of a decision support system through which clinicians can efficiently identify which previously approved historical treatment plans are achievable for a new patient to aid in selection of therapy. MATERIAL AND METHODS: Treatment data were collected for early-stage lung and postoperative oropharyngeal cancers treated using photon (lung and head and neck) and proton (head and neck) radiotherapy. Machine-learning classifiers were constructed using patient-specific feature-sets and a library of historical plans. Model accuracy was analyzed using learning curves, and historical treatment plan matching was investigated. RESULTS: Learning curves demonstrate that for these datasets, approximately 45, 60, and 30 patients are needed for a sufficiently accurate classification model for radiotherapy for early-stage lung, postoperative oropharyngeal photon, and postoperative oropharyngeal proton, respectively. The resulting classification model provides a database of previously approved treatment plans that are achievable for a new patient. An exemplary case, highlighting tradeoffs between the heart and chest wall dose while holding target dose constant in two historical plans is provided. CONCLUSIONS: We report on the first artificial-intelligence based clinical decision support system that connects patients to past discrete treatment plans in radiation oncology and demonstrate for the first time how this tool can enable clinicians to use past decisions to help inform current assessments. Clinicians can be informed of dose tradeoffs between critical structures early in the treatment process, enabling more time spent on finding the optimal course of treatment for individual patients. PMID- 29162280 TI - Catheter-related bacteraemia caused by Raoultella ornithinolytica. AB - Infections in humans by Raoultella spp. are rare and the effect that Raoultella spp. might have as a human pathogen is currently unknown. A clinical case is presented of catheter-related bacteraemia caused by Raoultella ornithinolytica, treated successfully with applied antibiotic therapy (intravenous cefepime and sealed the catheter with amikacin). PMID- 29162281 TI - Targeted next-generation sequencing identified ADAMTS5 as novel genetic substrate in patients with bicuspid aortic valve. AB - BACKGROUND: Bicuspid Aortic Valve (BAV) is the most common congenital heart disease, affecting >1% of the general population. Up to date, three genes, NOTCH1, GATA5 and SMAD6, have been linked to the isolated form of BAV. However, potential genetic determinants remain largely unknown in most BAV patients. MATERIAL AND METHODS: Targeted next-generation sequencing of 7 BAV candidate genes (NOTCH1, GATA5, SMAD6, NOS3, ADAMTS5, Alk2 and SMAD2) was performed in 32 BAV patients. Additional 35 BAV patients and 238 tricuspid aortic valve (TAV) patients, consisting of 107 patients from the transcatheter aortic valve implantation (TAVI) registry and 131 patients from the coronary artery disease (CAD) registry, were selected for further genotyping. RESULTS: We found 2 rare non-synonymous variants in 2/7 genes in 3 BAV patients: one was NOTCH1:c.4297G>A and the other one was ADMTS5:c.935C>A that shared by two patients. NOTCH1:c.4297G>A has not been reported previously. ADMTS5:c.935C>A was predicted to be pathogenic by all applied algorithms. Alignment of protein sequences from all available species revealed that ADMTS5:p.Arg312Leu, produced by ADMTS5:c.935C>A, is located in a highly conserved region. The minor allele frequency of ADMTS5:c.935C>A in BAV patients was significantly higher than the matched population in TAV group (0.015 vs. 0, P=0.048). CONCLUSION: Our results suggested that ADMTS5:c.935C>A are potentially associated with BAV. Further studies, such as large sample case-control replication test and functional research, are needed to explore the role of this rare variant in the development of BAV. PMID- 29162282 TI - Interruption of cardiac resynchronization therapy by atrial premature complexes. AB - Biotronik devices used for cardiac resynchronization therapy (CRT) combined with defibrillation function (CRT-D) are capable of left ventricular (LV) sensing. Under certain circumstances, LV sensing may cause loss of CRT. The third generation of the Biotronik i-family CRT-Ds enables the recording of event triggered tracings of the electrogram particularly those involving "CRT pacing interrupt" episodes. We report three cases of a sudden "CRT pacing interrupt" initiated by an atrial premature complex. This was caused by realignment of the LV timing cycles induced by the APCs whereupon LV pacing was inhibited and a self perpetuating desynchronization process was initiated. In all cases it is the repeated occurrence of LV sensed events that prevents the emission of LV paced events because it displaces the LV upper rate interval from its normal position. Prevention of desynchronization requires programming an LV upper rate faster than the maximum sensor-driven rate or right ventricular upper rate. PMID- 29162283 TI - [Bilateral cataract caused by electrocution: A case report]. PMID- 29162284 TI - [Vitreous hemorrhage, persistent fetal vasculature and Incontinentia Pigmenti]. PMID- 29162285 TI - [Proptosis as presenting sign of craniofacial fibrous dysplasia]. PMID- 29162286 TI - Medical management of a subretinal Klebsiella pneumoniae abscess with excellent visual outcome without performing vitrectomy. AB - OBJECTIVE: To report the case of a Klebsiella pneumoniae endogenous endophthalmitis (KPEE) of hepatic and urinary origin that was successfully treated with systemic antibiotherapy and 13 intravitreal antibiotics injections without performing a vitrectomy. PATIENT AND METHOD: Case report of a 60-year-old man with a subretinal abscess in the left eye that developed 3 days after initial presentation for K. pneumoniae bacteremia, liver abscess and urinary tract infection. RESULTS: Ophthalmic examination of the left eye showed anterior uveitis and a single subretinal abscess located in mid-peripheral temporal retina. BCVA dropped to 20/50. Follow-up was made with clinical examination and multimodal imaging (SD-OCT, FA, ICGA) with high field photographs. A total of 13 intravitreal injections (IVI) of ceftazidime were performed, and no vitrectomy was required. Ocular signs regressed and prognosis was excellent with 20/20 of final BCVA. CONCLUSION: KPEE is a rare but severe condition with a typically poor ocular prognosis. When diagnosis is made early, subretinal abscess with partially conserved BCVA could be treated successfully with medical management that includes systemic antibiotics and repeated intravitreal injections without requiring vitrectomy. PMID- 29162287 TI - Sustained attention in school-age children with congenital hypothyroidism: Influence of episodes of overtreatment in the first three years of life. AB - INTRODUCTION: Children with congenital hypothyroidism (CH) are at risk of developing mild cognitive impairment despite normal overall intellectual performance. These deficits may be caused by disease-related and treatment related factors. This study explores the impact of abnormal thyroid function during the first 3 years of life on attention performance at school age. METHODS: We included 49 children diagnosed with CH and receiving treatment for the condition: 14 boys (mean age 9.5+/-2.8 years) and 35 girls (9.6+/-2.6 years). The number of episodes of normal, under-, and overtreatment were estimated based on TSH levels during their first 3 years of life (at 12, 18, 24, 30, and 36 months). Children were assessed using a computerised version of a Sustained attention test. General linear models were calculated with the attention index as the dependent variable and sex, aetiology, and number of episodes of normal, under-, and overtreatment as independent variables. RESULTS: Higher numbers of episodes of overtreatment (low TSH level) were associated with poorer attention performance at school age (P=.005, r=-0.45). CONCLUSIONS: Children with CH should be monitored closely during the first 3 years of life in order to prevent not only hypothyroidism but also any adverse effects of overtreatment that may affect attentional function at school age. PMID- 29162289 TI - Apelin-APJ system is responsible for stress-induced increase in atrial natriuretic peptide expression in rat heart. AB - BACKGROUND: The cardiovascular system is a primary target of stress and stress is the most important etiologic factor in cardiovascular diseases. Stressors increase expressions of atrial natriuretic peptide (ANP) and apelin in cardiac tissue. AIM: The aim of the present study was to investigate whether stress induced apelin has an effect on the expression of ANP in the right atrium of rat heart. METHODS: The rats were divided into the control, stress and F13A+stress groups. In the stress and F13A+stress groups, the rats were subjected to water immersion and restraint stress (WIRS) for 6h. In the F13A+stress group, apelin receptor antagonist F13A, was injected intravenously immediately before application of WIRS. The plasma samples were obtained for the measurement of corticosterone and atrial natriuretic peptide. The atrial samples were used for immunohistochemistry and western blot analysis. RESULTS: F13A administration prevented the rise of plasma corticosterone and ANP levels induced by WIRS. While WIRS application increased the expressions of apelin, HIF-1alpha and ANP in atrial tissue, while F13A prevented the stress-induced increase in the expression of HIF-1alpha and ANP. CONCLUSION: Stress-induced apelin induces ANP expression in atrial tissue and may play a role in cardiovascular homeostasis by increasing ANP expression under WIRS conditions. PMID- 29162290 TI - Reduction of pharmaceutical expenditure by a drug appropriateness intervention in polymedicated elderly subjects in Catalonia (Spain). AB - OBJECTIVE: To assess the monetary savings resulting from a pharmacist intervention on the appropriateness of prescribed drugs in community-dwelling polymedicated (>=8 drugs) elderly people (>=70 years). METHOD: An evaluation of pharmaceutical expenditure reduction was performed within a randomised, multicentre clinical trial. The study intervention consisted of a pharmacist evaluation of all drugs prescribed to each patient using the "Good Palliative Geriatric Practice" algorithm and the "Screening Tool of Older Persons Prescriptions/Screening Tool to Alert doctors to Right Treatment" criteria (STOPP/START). The control group followed the routine standard of care. A time horizon of one year was considered and cost elements included human resources and drug expenditure. RESULTS: 490 patients (245 in each group) were analysed. Both groups experienced a decrease in drug expenditure 12 months after the study started, but this decrease was significantly higher in the intervention group than in the control group (-14.3% vs.-7.7%; p=0.041). Total annual drug expenditure decreased 233.75 ?/patient (95% confidence interval [95%CI]: 169.83 297.67) in the intervention group and 169.40 ?/patient (95%CI: 103.37-235.43) in the control group over a one-year period, indicating that 64.30 ? would be the drug expenditure savings per patient a year attributable to the study intervention. The estimated return per Euro invested in the programme would be 2.38 ? per patient a year on average. CONCLUSIONS: The study intervention is a cost-effective alternative to standard care that could generate a positive return of investment. PMID- 29162291 TI - The efficacy of self-disinfecting bedrail covers in an intensive care unit. AB - BACKGROUND: Hospital surfaces are considered important vectors in the spread of nosocomial pathogens. This study evaluated microbial counts on novel antimicrobial bedrail covers over a 2-week period in a critical care environment. METHODS: Disposable bedrail covers (Aionx Inc, Hershey, PA) made of a copper and silver polymer and capable of conducting an imperceptible surface potential, were installed in a case-control manner on a series of occupied intensive care unit beds. Seventeen bedrails were covered with the study bedrail surface, and 17 were left uncovered. Two hundred seventy-two microbial surface cultures were obtained from both study and control bedrails and analyzed for microbial growth by bacterial enumeration and speciation. RESULTS: The bedrails covered with the study surface demonstrated >80% average decrease in colony forming units across the study period of 15 days. CONCLUSIONS: These novel, detachable bedrail covers successfully demonstrated significant bacterial count reduction in an intensive care unit setting. This may have implications for acquisition of hospital acquired infections. PMID- 29162292 TI - Posterior reversible encephalopathy syndrome in IgA vasculitis: Neuroimaging of a 14-year-old child. AB - IgA vasculitis (IgAV) is a leukocytoclastic vasculitis and characterized by involvement of small vessels in skin, gastrointestinal system, joints, kidneys, and less frequently other organs. It is the commonest vasculitis in childhood and etiology is not completely known. Neurological manifestations of IgAV are very rare and usually seen in patients with severe hypertension or as an uncommon feature such as peripheral neuropathy. Posterior reversible encephalopathy syndrome (PRES) is a clinic-radiologic entity characterized with temporary vasogenic edema developing typically in posterior circulation of the brain and has been reported as a rare manifestation of IgAV. In this paper, a PRES case of 14-year-old male with IgAV is reported and etiopathogenesis was discussed with literature. Diagnosis was made by magnetic resonance imaging because of the existence of neurological symptoms (headache and visual loss) during the course of disease. His radiological findings have resolved with therapy. Although neurological involvement is a rare manifestation in IgAV, we recommend magnetic resonance imaging in such patients for diagnosis and evaluation of complications. PMID- 29162293 TI - [Difficult laryngoscopy and tracheal intubation: observational study]. AB - INTRODUCTION: Since anesthesia complications associated with unexpected difficult airway are potentially catastrophic, they should be avoided. The modified Mallampati test and jaw-thrust maneuver enable the identification of difficult airway. The aim of this study was to associate the modified Mallampati test and the jaw-thrust maneuver with laryngoscopy (Cormack-Lehane) in an attempt to identify a better predictor of difficult airway in an adult population undergoing elective surgery. METHOD: A cross-sectional study in which 133 adult patients undergoing elective surgery requiring tracheal intubation were analyzed. The accuracy and specificity of the modified Mallampati test and jaw-thrust maneuver were assessed by correlating them with difficult laryngoscopy (Cormack-Lehane Degrees 3 and 4). RESULTS: In the 133 patients evaluated the difficult intubation rate found was 0.8%; there was association between the two predictive tests proposed (p=0.012). The values of 94.5% for specificity and 95.4% for accuracy were found for the jaw-thrust maneuver and for the modified Mallampati test, the values found were 81.1% and 81.2%, respectively. Kappa agreement identified a result of 0.240 between jaw-thrust maneuver and Cormarck-Lehane, which was considered reasonable. On the other hand, a poor agreement (kappa=0.06) was seen between modified Mallampati test and Cormarck-Lehane test. CONCLUSION: The jaw thrust maneuver presented superior accuracy and agreement than the modified Mallampati test, showing the ability to identify a difficult airway. It is necessary to emphasize the association of tests in the evaluation of patients, emphasizing their complementarity to minimize the negative consequences of repeated laryngoscopies. PMID- 29162294 TI - Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy. AB - Mesoamerican nephropathy is a devastating disease of unknown etiology that affects mostly young agricultural workers in Central America. An understanding of the mechanism of injury and the early disease process is urgently needed and will aid in identification of the underlying cause and direct treatment and prevention efforts. We sought to describe the renal pathology in Mesoamerican nephropathy at its earliest clinical appearance in prospectively identified acute case patients in Nicaragua. We considered those with elevated (or increased at least 0.3 mg/dL or 1.5-fold from baseline) serum creatinine, leukocyturia, and either leukocytosis or neutrophilia for inclusion in this biopsy study. Renal tissue was obtained by ultrasound-guided biopsy for examination by light, immunofluorescence, and electron microscopy. All 11 individuals who underwent renal biopsy showed tubulointerstitial nephritis, with varying degrees of inflammation and chronicity. Interstitial cellular infiltrates (predominantly T lymphocytes and monocytes), mostly in the corticomedullary junction; neutrophilic accumulation in the tubular lumens; largely preserved glomeruli; few mild ischemic changes; and no immune deposits were noted. The acute components of tubulointerstitial nephritis were acute tubular cell injury, interstitial edema, and early fibrosis. Chronic tubulointerstitial nephritis included severe tubular atrophy, thickened tubular basement membrane, and interstitial fibrosis. Thus, renal histopathology in Mesoamerican nephropathy reveals primary interstitial disease with intact glomeruli. PMID- 29162295 TI - Male with Toothache. PMID- 29162296 TI - Early Outcomes of Vein Grafting for Reconstruction of Brachial Arterial Injuries in Children. AB - PURPOSE: We postulated that, with microsurgical technique, vascular reconstruction with interpositional vein grafts in the pediatric population is safe and results in sustained vascular patency and excellent midterm outcomes. METHODS: Twenty children with brachial artery injuries were treated with interpositional vein grafting at a tertiary pediatric hospital from 1995 to 2013. Medical records were evaluated for demographic, clinical, and radiographic data. Ten patients were available for longer-term follow-up. Pain at rest, pain with exercise, and temperature intolerance were assessed with visual analog scale (VAS) (range, 0-5). Functional outcomes were assessed using the Pediatric Outcomes Data Collection Instrument (PODCI) and Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaires. Graft patency and flow were characterized via duplex sonography. Peak flow velocity and resistive index (RI) were compared with the contralateral extremity. Median patient age at the time of injury was 7.75 years (range, 4.6-11.5 years) and median follow-up was 1.75 years (range, 0.3-6.3 years). RESULTS: All patients had perfused hands with palpable radial pulses at follow-up. There were no clinically meaningful differences in motion, sensibility, or strength between affected and unaffected limbs. Mean VAS scores for pain at rest, pain with exercise, and temperature intolerance were 0.4, 0.4, and 0.6, respectively. Mean global PODCI and DASH scores were 98.0 and 5.1, respectively. Nine of 10 patients had patent arteries with normal flow patterns. In the patient with graft occlusion, there was collateralization around the elbow with normal reconstitution of the distal vessels. Mean peak flow velocity proximal and distal to the graft were 77.7 cm/s and 66.5 cm/s, respectively. Mean RI of the graft were 0.84 and 0.77, respectively. CONCLUSIONS: Brachial artery reconstruction using interpositional vein graft and microsurgical technique is safe and effective and results in excellent functional outcomes in children. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 29162297 TI - Administrative Evidence-based Practices in State Chronic Disease Practitioners. AB - INTRODUCTION: Research and lessons from community implementation have informed evidence-based practices that can improve the effectiveness of health initiatives. Administrative evidence-based practices (A-EBPs) facilitate the role of public health departments in implementing the most effective programs and policies. The purpose of this study is to describe A-EBPs in relation to characteristics of chronic disease practitioners in state health departments. METHODS: Randomly selected chronic disease practitioners who worked in state health departments were invited to complete an online survey in 2016. The survey included questions on five domains of A-EBPs: workforce development, leadership, culture and climate, relationships and partners, and financial practices. State level variables that could potentially affect the use of A-EBPs were collected and used in a regression model. RESULTS: Analysis was conducted in 2016 on data from 571 respondents. Mean percentages of those who strongly agreed/agreed were lowest for financial practices (41.49%) and leadership (42.33%) with higher means for culture and climate (54.52%) and relationships and partners (58.71%). State poverty level was the only significant predictor of A-EBP scores after adjusting for other covariates in a regression model. CONCLUSIONS: These results show several areas of high agreement with A-EBP within the domains measured as well as opportunities for improvement. Highlighting the importance of A-EBPs to public health leadership level may enhance practice. There is also need for developing plans for an aging workforce and cultivating partnerships with health care and other sectors. Findings can be used to target training for enhancement of A-EBPs within state health departments. PMID- 29162298 TI - On the Bayesian approach to forensic age estimation of living individuals. AB - Forensic age estimation, a branch of forensic science, has received renewed attention lately mainly due to societal migration phenomena. And yet, the interpretation of age-related evidence is still largely neglected as a field, the literature being usually limited to technical discussions strictly pertaining to the statistical methodologies to be used in estimation process. This short communication aims to highlight the fundamental role of evidence evaluation and interpretation in forensic age estimation. We illustrate why the Bayesian approach represents the best choice in such a perspective. PMID- 29162299 TI - 3D MnO2 hollow microspheres ozone-catalysis coupled with flat-plate membrane filtration for continuous removal of organic pollutants: Efficient heterogeneous catalytic system and membrane fouling control. AB - A heterogeneous catalytic ozonation/membrane filtration (HCOMF) system was fabricated by integrating a flat-plate polyvinylidene fluoride (PVDF) membrane module along with a slurry catalytic ozonation reactor. The performance and catalytic activity of HCOMF was evaluated for degradation of model wastewater containing bisphenol A (BPA) and humid acid (HA) under different permeation flux in long-term continuous experiments. The membrane fouling was investigated by trans-membranous pressure (TMP), membrane filtration resistance, scanning electronic microscopy (SEM), and fluorescence spectra. The results showed that HCOMF system exhibited an excellent and stable catalytic activity in long-term continuous experiments owning to integration of 3D MnO2 hollow microsphere ozone catalysis with flat-plate membrane filtration. The TMP of HCOMF system didn't increase significantly, and the membrane resistance Rp and Rc declined from 4% and 16% to 1% and 4%, respectively, thus, the membrane fouling of HCOMF system was mitigated compared to MF system. The mitigation of membrane fouling in HCOMF system was attributed to the increase of hydrophilicity of membrane surface and change of HA fractions. PMID- 29162301 TI - [Validation of the technique based on Dot blot for the detection of Cercospora kikuchii in soybean plants]. AB - Cercospora kikuchii is a common pathogen in soybean plants that causes crop spoilage. Its early and precise identification would prevent the misuse of pesticides and allow the initiation of an appropriate treatment. A quick, economical and easy-to-execute technique is the Dot blot, capable of recognizing the presence of a genus-specific protein called CFP (Cercosporin Facilitator Protein). The objective was to validate this technique to guarantee the reliability of the results. For that purpose, 29 infected soybean plants and 31 healthy plants were processed, taking into account a 95% desired confidence level and a permissible error of 5%. The technique provided a diagnostic sensitivity of 93.3% and a diagnostic specificity of 96.7%. The efficiency was 95% and positive and negative predictive values were 96.6% and 93.5%, respectively. These results postulate it as a useful resource for the early detection of C. kikuchii in soybean plants. PMID- 29162300 TI - Reduced subcortical volumes among preschool-age girls and boys with ADHD. AB - Anomalous brain structure and function are implicated in children with attention deficit/hyperactivity disorder (ADHD). Most neuroimaging research, however, has examined school-aged children, despite the typical onset of symptoms in early childhood. This study compared the volumes of subcortical structures (caudate nucleus, putamen, globus pallidus, and thalamus) among preschoolers with ADHD and typically developing (TD) children. High resolution T1-weighted 3D MPRAGE images covering the whole brain were acquired on a 3T scanner and subcortical volumes were automatically extracted. Analyses were conducted in a total of 87 medication naive preschoolers, ages 4-5 years (47 with ADHD, 40 controls; 63% boys). ADHD was diagnosed using modified DSM-IV criteria based on review of developmental history, structured psychiatric interview and caregiver ratings. Compared to typically developing children, subcortical volumes were reduced among preschoolers with ADHD, with largest reductions in the caudate, globus pallidus, and thalamus. Among girls (but not boys) with ADHD, putamen and thalamus volumes were associated with ADHD symptom severity. The observed patterns of subcortical differences in preschoolers with ADHD (larger reductions in girls), contrasted with differences observed among school-aged children, (larger reductions in boys) suggests that children with ADHD show sexual dimorphism in neuroanatomical development that parallels early trajectory of symptom onset and attenuation. PMID- 29162302 TI - Native yeasts for alternative utilization of overripe mango pulp for ethanol production. AB - Mango fruits (Mangifera indica L.) are highly perishable, causing postharvest losses and producing agroindustrial waste. In the present work, native yeasts were used to evaluate ethanol production in overripe mango pulp. The two isolated strains showed similar sequences in the 18S rDNA region corresponding to Kluyveromyces marxianus, being different to the data reported in the NCBI database. Values of up to 5% ethanol (w/v) were obtained at the end of fermentation, showing a productivity of 4g/l/day, a yield of up to 49% of ethanol and a process efficiency of 80%. These results represent a viable option for using the surplus production and all the fruits that have suffered mechanical injury that are not marketable and are considered as agroindustrial waste, thus achieving greater income and less postharvest losses. PMID- 29162303 TI - Cervical intradural disc herniation: A systematic review. AB - BACKGROUND: Cervical intradural disc herniation (CIDH) is rare, and diagnosis and treatment are challenging. We conducted a systematic review and meta-analysis of the literature on the diagnosis and treatment of CIDH. METHOD: The presentation, imaging manifestations, diagnosis, management, prognosis and possible pathogenesis were reviewed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. English-language studies and case reports published from inception to 2017 were retrieved. Data on presentation, imaging characteristics, diagnosis, management, outcomes and pathogenesis were extracted. RESULTS: Twenty articles involving 23 patients were selected. The most common involved level was C5-6 (43.5%), followed by C6-7 (30.4%), C4-5 (13%), and C3-4 (13%). Spontaneous IDH occurred in 61% of the patients, and relevant cervical trauma was present in 39%. Brown-Sequard's syndrome (56.5%), quadriparesis (34.8%), and radiculopathy (8.7%) were the main presentations. Magnetic resonance imaging (MRI) was the most commonly used diagnostic technique, and the "halo" and "Y-sign" were strong indicators of CIDH. Three (13%) patients were diagnosed as having CIDH preoperatively, and 87% were confirmed intraoperatively. All patients underwent surgical intervention primarily (73.9%) through an anterior approach. Neurological function improved postoperatively in all patients but one. Dural and arachnoid mater tears were managed by direct suture or covering with a substitute, and only one patient sustained cerebrospinal fluid (CSF) leakage after surgery. CONCLUSION: IDH mostly involves the lower cervical spine. More than half of the patients had spontaneous CIDH, and some had a relevant cervical trauma history. BSS was the main presentation. It is difficult to diagnose CIDH depending on clinical presentations and radiographic findings. Surgery was an effective treatment for CIDH and can provide a definitive diagnosis. With meticulous management of dural and arachnoid tears, the postoperative incidence of CSF leakage was found to be low. PMID- 29162304 TI - Letter to the editor in response to "Prevention of skin injuries associated with non-invasive mechanical ventilation". PMID- 29162305 TI - Quantifying success after total shoulder arthroplasty: the minimal clinically important difference. AB - BACKGROUND: Knowledge of the minimal clinically important difference (MCID) for different shoulder outcome metrics and range of motion after total shoulder arthroplasty (TSA) can be useful to establish a minimum threshold of improvement that defines successful treatment. This study quantifies how MCID varies with different prosthesis types, patient age, gender, and length of follow-up after TSA. METHODS: A total of 466 anatomic TSA (aTSA) and reverse TSA (rTSA) with 2 year minimum follow-up were performed by 13 shoulder surgeons. The MCID for the American Shoulder and Elbow Surgeons, Constant, University of California Los Angeles Shoulder Rating Scale, Simple Shoulder Test, Shoulder Pain and Disability Index, global shoulder function, and visual analog scale for pain scores, as well as active abduction, forward flexion, and external rotation, were calculated for different prosthesis types and patient cohorts using an anchor-based method. RESULTS: The anchor-based MCID results were American Shoulder and Elbow Surgeons = 13.6 +/- 2.3, Constant score = 5.7 +/- 1.9, University of California Los Angeles Shoulder Rating Scale = 8.7 +/- 0.6, Simple Shoulder Test score = 1.5 +/- 0.3, Shoulder Pain and Disability Index score = 20.6 +/- 2.6, global shoulder function = 1.4 +/- 0.3, pain visual analog scale = 1.6 +/- 0.3, active abduction = 7 degrees +/- 4 degrees , active forward flexion = 12 degrees +/- 4 degrees , and active external rotation = 3 degrees +/- 2 degrees . Female gender and rTSA were associated with lower MCID values compared with male gender and aTSA patients. CONCLUSION: The minimum improvement necessary for patients to achieve a result they believe is clinically meaningful after aTSA and rTSA is nominal and was achieved by at least 80% of the patients. Future endeavors should investigate the influence of different anchor questions on the MCID calculation. PMID- 29162306 TI - Osteosynthesis of AO/OTA 13-C3 distal humeral fractures in patients older than 70 years. AB - OBJECTIVE: The purpose of this retrospective case series was to examine the AO Foundation and Orthopaedic Trauma Association (AO/OTA) 13-C3 distal humeral fractures treated with open reduction-internal fixation (ORIF) in patients older than 70 years. METHODS: During an 8-year period, 21 patients older than 70 years with AO/OTA 13-C3 distal humeral fractures were treated with ORIF performed by 2 senior upper extremity traumatologists. There were 16 patients with >1 year of follow-up, with a mean age of 78 (70-84) years. RESULTS: At a mean follow-up of 4 years (1-8 years), all 16 patients demonstrated radiographic signs of bone union. Three patients underwent reoperations, including irrigation and debridement for postoperative infections (n = 2) and removal of implant for symptomatic olecranon intramedullary screw (n = 1). The mean postoperative total arc of ulnohumeral motion was 97 degrees (80 degrees -145 degrees ), including a mean flexion of 117 degrees (106 degrees -126 degrees ) and flexion contracture of 20 degrees (14 degrees -26 degrees ). The mean pronation was 69 degrees (55 degrees -85 degrees ), and supination was 78 degrees (74 degrees -9 degrees 0). The mean Quick Disabilities of the Arm, Shoulder, and Hand score was 19 (standard deviation, 6.9; confidence interval, 15.4-22.8), and the mean Mayo Elbow Performance Score was 91 (standard deviation, 8.2; confidence interval, 86-95). CONCLUSIONS: ORIF remains a reliable option for treatment of AO/OTA 13-C3 distal humeral fractures in elderly patients. Excellent clinical outcomes can be achieved with preservation of motion and arm function through anatomic reduction, rigid internal fixation, and early mobilization. PMID- 29162307 TI - Cortactin: Cell Functions of A Multifaceted Actin-Binding Protein. AB - Cortactin fulfills many functions in various cell types. These functions have been considered to derive from its ability to activate the Actin-related protein 2/3 (Arp2/3) complex, and are regulated by post-translational modifications, including phosphorylation and acetylation. New evidence suggests that cortactin regulates cell migration by controlling the deposition of extracellular matrix proteins rather than lamellipodial Arp2/3 activation, and that cortactin also functions in GTPase signaling, vesicular trafficking, and actomyosin contractility. These recent new findings and concepts are relevant for physiological and pathological cell functions, but have not yet been put into mechanistic context. Here, we reconsider current thinking on cortactin functions in different cell types during health and disease, and discuss potential directions of future research in cortactin biology. PMID- 29162308 TI - A novel series of enoyl reductase inhibitors targeting the ESKAPE pathogens, Staphylococcus aureus and Acinetobacter baumannii. AB - S. aureus and A. baumannii are among the ESKAPE pathogens that are increasingly difficult to treat due to the rise in the number of drug resistant strains. Novel therapeutics targeting these pathogens are much needed. The bacterial enoyl reductase (FabI) is as potentially significant drug target for developing pathogen-specific antibiotics due to the presence of alternate FabI isoforms in many other bacterial species. We report the identification and development of a novel N-carboxy pyrrolidine scaffold targeting FabI in S. aureus and A. baumannii, two pathogens for which FabI essentiality has been established. This scaffold is unrelated to other known antibiotic families, and FabI is not targeted by any currently approved antibiotic. Our data shows that this scaffold displays promising enzyme inhibitory activity against FabI from both S. aureus and A. baumannii, as well as encouraging antibacterial activity in S. aureus. Compounds also display excellent synergy when combined with colistin and tested against A. baumannii. In this combination the MIC of colistin is reduced by 10 fold. Our first generation compound displays promising enzyme inhibition, targets FabI in S. aureus with a favorable selectivity index (ratio of cytotoxicity to MIC), and has excellent synergy with colistin against A. baumannii, including a multidrug resistant strain. PMID- 29162309 TI - Design and synthesis of aminoester heterodimers containing flavone or chromone moieties as modulators of P-glycoprotein-based multidrug resistance (MDR). AB - In this study, a new series of heterodimers was synthesized. These derivatives are N,N-bis(alkanol)amine aryl esters or N,N-bis(ethoxyethanol)amine aryl esters carrying a methoxylated aryl residue combined with a flavone or chromone moiety. The new compounds were studied to evaluate their P-gp modulating activity on a multidrug-resistant leukemia cell line. Some of the new compounds show a good MDR reversing activity; interestingly this new series of compounds does not comply with the structure-activity relationships (SAR) outlined by previously synthesized analogs carrying different aromatic moieties. In the case of the compounds described in this paper, activity is linked to different features, in particular the characteristics of the spacer, which seem to be critical for the interaction with the pump. This fact indicates that the presence of a flavone or chromone residue influences the SAR of these series of products, and that flexible molecules can find different productive binding modes with the P-gp recognition site. These results support the synthesis of new compounds that might be useful leads for the development of drugs to control P-gp-dependent MDR. PMID- 29162310 TI - Therapeutic Mechanisms of Glucocorticoids. AB - Glucocorticoids (GCs) have been used clinically for decades as potent anti inflammatory and immunosuppressive agents. Nevertheless, their use is severely hampered by the risk of developing side effects and the occurrence of glucocorticoid resistance (GCR). Therefore, efforts to understand the complex mechanisms underlying GC function and GCR are ongoing. The goal is to generate new glucocorticoid receptor (GR) ligands that can dissociate anti-inflammatory from metabolic side effects and/or overcome GCR. In this review paper we discuss recent insights into GR-mediated actions in GCR and novel therapeutic strategies for acute and chronic inflammatory diseases. PMID- 29162311 TI - Berlin Heart Explant in an Infant. PMID- 29162312 TI - Severe Mitral Regurgitation Due to a "Folded" Anterior Mitral Valve Leaflet After Bentall Procedure Requiring Mitral Valve Replacement. PMID- 29162313 TI - Efficacy and Efficiency of Perioperative Stellate Ganglion Blocks in Cardiac Surgery: A Pilot Study. PMID- 29162314 TI - Clinical characteristics and outcomes of nonurothelial cell carcinoma of the bladder: Results from the National Cancer Data Base. AB - OBJECTIVES: To determine the clinical characteristics, treatment patterns, and outcomes of patients with nonurothelial cell bladder cancer (NUBC) in the United States. METHODS: A total of 163,683 patients with bladder cancer from 1998 to 2014 in the National Cancer Data Base were identified. Of all, 153,262 had urothelial cell (UC) carcinoma (93.6%) and 10,421 had NUBC (6.4%) further classified as: squamous cell carcinoma (SC, 2.4%), adenocarcinoma (AC, 1.7%), neuroendocrine (NE, 1.3%), micropapillary (MP, a UC variant histology, 0.3%), lymphoid/haematopoietic (LH, 0.3%), and sarcoma/mesenchymal (SM, 0.3%). Analyses were run on the entire cohort, those with non-muscle-invasive disease (T0-1, N0, M0), muscle-invasive disease (MIBC, T2-4A, N0, M0), and metastatic disease (T4B or N+ or M+). Clinical characteristics and treatment received (surgery, chemotherapy, and radiation) were reported by histologic subtype. Survival analysis was performed via Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: Patients with NE, SC, MP, and AC were more likely to be diagnosed with metastatic disease (11.5% for UC vs. 40%, 31.3%, 17.8%, and 30.6%, respectively, P<0.001). Patients with NUBC were also more likely to have MIBC compared to UC (43% vs. 32.5%, respectively). For all patients, those with UC may be less likely to undergo cystectomy, chemotherapy, and radiation therapy (P<0.001). For all patients, NUBC, with the exception of LH, SM, and MP, was associated with inferior survival compared to UC (P<0.001). CONCLUSIONS: This encompassing clinical characterization and prognosis of NUBC patients in the United States shows NUBC patients have significantly different disease characteristics compared to those with UC, and present with more advanced disease, receive more treatment, and overall have inferior outcomes. Further work is needed to help improve outcomes for these patients. PMID- 29162315 TI - Mannose-binding lectin deficiency associated with numerous paraspinal neurofibromas. PMID- 29162316 TI - The association of maternal prenatal vitamin D levels and child current wheeze. PMID- 29162317 TI - Dexamethasone for inpatient childhood asthma exacerbations is as effective as short-acting corticosteroid treatment. PMID- 29162318 TI - Schnitzler syndrome with IgG gammopathy and elevated IL-1beta and IL-17 in skin biopsy. PMID- 29162319 TI - Impact of rotavirus vaccine on acute gastroenteritis in children under 5 years in Senegal: Experience of sentinel site of the Albert Royer Children's Hospital in Dakar. AB - BACKGROUND: Acute gastroenteritis (AGE) is a leading cause of morbidity and mortality among children <5 years of age in developing countries, with rotavirus being the most common infectious etiology. In November 2014, monovalent rotavirus vaccine was introduced in Senegal. We determined the impact of rotavirus vaccine on hospitalizations for all-cause and rotavirus related AGE in children <60 months of age. METHODS: We examined two data sources from the national referral hospital. Using sentinel surveillance data from March 2011 to February 2017, we examined the proportion of AGE hospitalizations among children <60 months of age attributable to rotavirus, stratified by age groups (0-11, 12-23 and 24-59 months). Using pediatric logbook data from March 2010 to February 2017, we examined the proportion of all childhood hospitalizations attributable to AGE, among the same age groups. RESULTS: In sentinel surveillance, 673 patients <60 months were hospitalized for AGE, with 30% (203/673) due to rotavirus. In pre vaccine years, the median proportion of rotavirus-positive hospitalizations was 42%; this proportion declined by 76% to 10% rotavirus positive in 2015-2016 (p < .001) and by 59% to 17% in 2016-2017 (p < .001). From the logbook data, among all children <60 months, a median of 11% of all hospitalizations in the pre-vaccine period were due to AGE, with 2015-2016 seeing a 16% decline (p < .001), to 9% of all hospitalizations, and 2016-2017 seeing a 39% decline (p < .001), to 7% of all hospitalizations. Declines in both rotavirus-associated and all-cause AGE hospitalizations were most marked among infants, with a suggestion of herd effect among older children seen in the surveillance data. CONCLUSION: Rotavirus vaccine demonstrated a significant impact on rotavirus-associated hospitalizations and all-cause AGE hospitalizations in the first two seasons after vaccine introduction in Senegal. Our data support the continued use of this vaccine in national immunization program. PMID- 29162320 TI - Controlled human infections: A report from the controlled human infection models workshop, Leiden University Medical Centre 4-6 May 2016. AB - The principle of deliberately infecting humans with infectious agents in a controlled setting, so-called controlled human infections (CHI), is not novel. Many CHI models have a long history and were established decades ago such as the intentional exposure to yellow fever and dengue performed in the 1900's (Reed, 1902) [2]. In these times bioethics and scientific reasoning were in their infancy. Nowadays, clinical trials are highly regulated and CHI are executed worldwide. Controlled human malaria infections and influenza infections are the two most frequently practiced. Others are experiencing a revival or are being carefully developed. Because CHI models test the efficacy of promising vaccine or drug candidates early in clinical development, they offer the potential to decrease the number of failing phase 2 and 3 trials, reducing risks for patients and saving costs and efforts. In addition, CHI models provide unprecedented opportunities to dissect the physiological, immunological and metabolic changes that occur upon infection. However, it is clear that controlled infections require careful deliberation of safety, ethics, quarantine, scientific output and the production of infectious material. An independent international workshop was hosted by the Leiden University Medical Centre in The Netherlands, bringing together clinical investigators, basic scientists, regulators, funders and policy makers from 22 different countries to discuss the opportunities and challenges in CHI. The aim of the workshop was to discuss CHI as a tool to advance science, drug and vaccine development, share the challenges of establishing a CHI model with specific focus on neglected tropical diseases and the possibilities to transfer models to endemic sites. Noticeably, among the 128 participants were clinical investigators from ten different countries in Sub-Saharan Africa. An important dimension of the meeting was to give the floor to young established clinicians and scientists to voice their perspective on the future of CHI models. PMID- 29162321 TI - A cluster randomized trial to determine the effectiveness of a novel, digital pendant and voice reminder platform on increasing infant immunization adherence in rural Udaipur, India. AB - BACKGROUND: Five hundred thousand children under the age of 5 die from vaccine preventable diseases in India every year. More than just improving coverage, increasing timeliness of immunizations is critical to ensuring infant health in the first year of life. Novel, culturally appropriate community engagement strategies are worth exploring to close the immunization gap. In our study, a digital NFC (Near Field Communication) pendant worn on black thread and voice call reminder system was tested for the effectiveness in improving DTP3 adherence within 2 monthly camps from DTP1 administration. METHOD: A cluster randomized controlled trial was conducted in which 96 village health camps were randomized to 3 arms: NFC sticker, NFC pendant, and NFC pendant with voice call reminder in local dialect. Randomization was done across 5 blocks in the Udaipur District serviced by Seva Mandir from August 2015 to April 2016. RESULTS: In terms of our three primary outcomes related to DTP3 adherence, point estimates show conflicting results. Two outcomes presented adherence in the control. DTP3 completion within two camps after DTP1 showed higher adherence in the Control (Sticker) (74.2%) arm compared to the Pendant (67.2%) and Pendant and Voice arms (69.3%). Likewise, the estimate for DTP3 completion within 180 days of birth in the Control (Sticker) (69.4%) arm was higher than estimates in the Pendant (57.4%) and Pendant and Voice arms (58.7%). However, one outcome displayed higher adherence in the intervention. DTP3 completion within two months from the time of registration was higher in the Pendant (37.7%) and Pendant and Voice arms (38.7%) compared to the Control (Sticker) arm (27.4%). In all primary outcomes, differences in adherence were statistically insignificant both before and after controlling for confounding factors. In terms of secondary outcomes, our results suggest that providing a necklace generated significant community discussion (H = 8.8796, df = 2, p = .0118), had strong satisfaction among users (chi2=26.039, df = 4, p < .0001), and resulted in increased visibility within families (grandmothers:chi2=34.023, df = 2, p < .0001, fathers: chi2=34.588, df = 2, p < .0001). CONCLUSION: Neither the NFC necklace nor the necklace with additional voice call reminders in the local dialect directly resulted in an increase in infant immunization timeliness through DTP3, the primary outcome. Still our process outcomes suggest that our culturally symbolic necklace has potential to be an assistive tool in immunization campaigns. Follow-on work will seek to examine whether positive behavior change towards vaccines can be fostered with earlier engagement of this platform beginning in the prenatal stage, under a continuum of care framework. PMID- 29162322 TI - Do Long-Lived Plasma Cells Maintain a Healthy Microbiota in the Gut? AB - Disruptions to the gut microbiota have been associated with a variety of diseases. Understanding the underlying mechanisms that regulate the maintenance of a healthy microbiota may therefore have therapeutic implications. Secretory IgA play a unique role in immune-microbiota crosstalk by directly binding to bacteria in the gut lumen. Microbe-specific IgA responses co-develop with the assembly of the gut microbiota during infancy, and resemble those of adults by 2 years postnatally in the healthy host. We propose here that microbiota-specific IgA-producing gut plasma cells generated during infancy live for many decades and contribute to a stable microbiota community. We furthermore suggest that members of the microbiota that induce long-lasting IgA responses in the gut are putative targets for therapeutic interventions. PMID- 29162324 TI - Modulation of human macrophage activity by Ascaris antigens is dependent on macrophage polarization state. AB - Parasitic worms (helminths) are known to actively modulate host immune responses and inflammation. The aim of this study was to investigate if adult body fluid (ABF) from the helminth Ascaris suum has immunomodulatory effects on different subtypes of human monocyte-derived macrophages (Mphi) in vitro. Mphis were exposed to A. suum ABF at different stages of their differentiation and/or polarization. Mphi were first differentiated from monocytes into either uncommitted (M-), classically activated (M(GM-CSF)) or alternatively activated (M(M-CSF)) phenotypes and then stimulated with lipopolysaccharide (LPS). ABF strongly suppressed LPS-induced TNF-alpha, IL-6 and IL-10 secretion in M(GM CSF)s, however in M(M-CSF)s only TNF-alpha was suppressed, with these cells secreting high levels of IL-10 which was not affected by ABF treatment. To determine if ABF modulated the differentiation of previously uncommitted Mphi to either type 1 or type 2 Mphi, monocytes were differentiated with human serum into (M-)s and then polarized by IFN-gamma/LPS or IL-4 treatment in the presence of ABF. Under these conditions, ABF did not modulate cytokine secretion but did reduce CD80 expression in IFNgamma/LPS-polarized cells but not IL-4-polarized cells. Finally, we demonstrate that when monocytes are differentiated into M(GMCSF)s in the presence of ABF, subsequent inflammatory responses are markedly suppressed. Our data suggest that ABF inhibits cytokine secretion and co stimulatory molecule expression in classically activated Mphi but not in alternatively activated Mphi, indicating selective action of ABF depending on Mphi subtype. Moreover, ABF appears to exert stronger activity when acting upon Mphi that have already been polarized to the type 1 phenotype, rather than influencing the polarization process per se. PMID- 29162323 TI - Chemokine-Mediated Choreography of Thymocyte Development and Selection. AB - As they differentiate, thymocytes encounter spatially restricted cues critical for differentiation and selection of a functional, self-tolerant T cell repertoire. Sequential migration of developing T cells through distinct thymic microenvironments is enforced by the ordered expression of chemokine receptors. Herein, we provide an updated perspective on T cell differentiation through the lens of recent advances that illuminate the dynamics of chemokine-driven thymocyte migration, localization, and interactions with stromal cells. We consider these findings in the context of earlier groundwork exploring the contribution of chemokines to T cell development, recent advances regarding the specificity of chemokine signaling, and novel techniques for evaluating the T cell repertoire. We suggest future research should amalgamate visualization of localized cellular interactions with downstream molecular signals. PMID- 29162326 TI - Identifying perceptions of academic reform in pharmacy using a four-frame organizational change model. AB - BACKGROUND: In an ever-changing environment, pharmacy education is in the race to catch up and excel to produce competent pharmacists. Examining academic institutions, including schools of pharmacy, their internal systems and framework, it seems appropriate to view these institutions using multiple lenses. Bolman and Deal conceptualized a method to examine organizations using four constructs (structural, human resource, political, and symbolic). The Eastern Mediterranean Region (EMR), with deep-rooted pharmacy education and practice was the setting for this research. OBJECTIVES: To explore factors affecting academic reform in undergraduate pharmacy education in the EMR from stakeholders' and students' perspectives; and to apply Bolman and Deal's four-frame organizational change model to explore how these issues might be viewed. METHODS: A multiple method approach was employed and involved collecting, analyzing and integrating qualitative semi-structured interview data with open-ended questions in a survey. Cross-sector stakeholder sample from various EMR countries was recruited and interviewed. Final year pharmacy students from one school of pharmacy in Jordan were surveyed. RESULTS: Emergent themes were indicative that academic reform was addressed by all frames of the Bolman and Deal model. Structural and political frames received substantial weighing pointing to the importance of curricular reform, collaboration and leadership. A need for skillful and role-model teaching academic staff was highlighted, and in harmony with the human resource frame. Issues within the symbolic frame were readily apparent in the data and spanned the other three frames in relation to heritage, customs and cultural barriers. CONCLUSIONS: Issues pertinent to academic reform in pharmacy were presented. Viewing change in pharmacy schools from multiple perspectives highlighted the need for structural changes to pharmacy programs, human resource management, political will, leadership, and collaboration. The importance of understanding cultural aspects of organizations is critical as it is these that provide identity to any organization and help reformers better manage change. PMID- 29162327 TI - E-learning teaches attendings "how to" objectively assess pediatric urology trainees' surgery skills for orchiopexy. AB - INTRODUCTION: Established methods to train pediatric urology surgery by residency training programs require updating in response to administrative changes such as new, reduced trainee duty hours. Therefore, new objective methods must be developed to teach trainees. We approached this need by creating e-learning to teach attendings objective assessment of trainee skills using the Zwisch scale, an established assessment tool. The aim of this study was to identify whether or not e-learning is an appropriate platform for effective teaching of this assessment tool, by assessing inter-rater correlation of assessments made by the attendings after participation in the e-learning. Pediatric orchiopexy was used as the index case. METHODS: An e-learning tool was created to teach attending surgeons objective assessment of trainees' surgical skills. First, e-learning content was created which showed the assessment method videotape of resident surgery done in the operating room. Next, attendings were enrolled to e-learn this method. Finally, the ability of enrollees to assess resident surgery skill performance was tested. Namely, test video was made showing a trainee performing inguinal orchiopexy. All enrollees viewed the same online videos. Assessments of surgical skills (Zwisch scale) were entered into an online survey. Data were analyzed by intercorrelation coefficient kappa analysis (strong correlation was ICC >= 0.7). RESULTS: A total of 11 attendings were enrolled. All accessed the online learning and then made assessments of surgical skills trainees showed on videotapes. The e-learning comprised three modules: 1. "Core concepts," in which users learned the assessment tool methods; 2. "Learn to assess," in which users learned how to assess by watching video clips, explaining the assessment method; and 3. "Test," in which users tested their skill at making assessments by watching video clips and then actively inputting their ratings of surgical and global skills as viewed in the video clips (Figure). A total of 89 surgical skill ratings were performed with 56 (65%) exact matches between raters and 89 (100%) matched within one rank. Interclass correlation coefficient (ANOVA) showed statistically significant correlation. (r = 0.725, 95% CI 0.571-0.837, F = 3.976, p <= 0.00001). Kappa analysis of inter-rater reliability showed strong consensus between attendings for average measures with ICC = 0.71, 95% CI 0.46-0.95 (p = 0.03). CONCLUSION: We launched e-learning to teach pediatric urology attendings "how to" assess trainee surgical skills objectively (Zwisch scale). After e learning, there was strong inter-rater correlation in assessments made. We plan to extend such e-learning to pediatric urology surgical training programs. PMID- 29162325 TI - Scriptaid improves the reprogramming of donor cells and enhances canine-porcine interspecies embryo development. AB - Histone methylation, histone acetylation, and DNA methylation are the important factors for somatic cell nuclear transfer (SCNT). Histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have been used to improve cloning efficiency. In particular, scriptaid, an HDACi, has been shown to improve SCNT efficiency. However, no studies have been performed on canines. Here, we evaluated the effects of scriptaid on histone modification in canine ear fibroblasts (cEFs) and cloned canine embryos derived from cEFs. The early development of cloned canine-porcine interspecies SCNT (iSCNT) embryos was also examined. cEFs were treated with scriptaid (0, 100, 250, 500, 750, and 1000nM) in a medium for 24h. Scriptaid treatment (all concentrations) did not significantly affect cell apoptosis. Treatment with 500nM scriptaid caused a significant increase in the acetylation of H3K9, H3K14, and H4K5. cEFs treated with 500nM scriptaid showed significantly decreased Gcn5, Hat1, Hdac6, and Bcl2 and increased Oct4 and Sox2 expression levels. After SCNT with canine oocytes, H3K14 acetylation was significantly increased in the one- and two-cell cloned embryos from scriptaid-treated cEFs. In iSCNT, the percentage of embryos in the 16-cell stage was significantly higher in the scriptaid-treated group (21.6+/-2.44%) than in the control (7.5+/-2.09%). The expression levels of Oct4, Sox2, and Bcl2 were significantly increased in 16-cell iSCNT embryos, whereas that of Hdac6 was decreased. These results demonstrated that scriptaid affected the reprogramming of canine donor and cloned embryos, as well as early embryo development in canine porcine iSCNT, by regulating reprogramming and apoptotic genes. PMID- 29162328 TI - Response to commentary re 'Primary female epispadias: Perineal approach or Kelly repair?' PMID- 29162329 TI - Author Reply. PMID- 29162330 TI - Editorial Comment. PMID- 29162331 TI - The effect of load on Achilles tendon structure in novice runners. AB - OBJECTIVES: To observe the changes in Achilles tendon structure in novice runners, with loading prescriptions of 100% body weight compared to 20% body weight. DESIGN: Randomised crossover. METHODS: Twenty novice runners participated in two separate running bouts spaced 14days apart, one of high load at 100% body weight, and one of low load at 20% body weight. Tendon structure was measured by ultrasonographic tissue characterisation on 6 occasions; immediately prior to each run, 2 and 7days after each run. RESULTS: The interaction effect of time and condition was not found to be significant for echotypes I-IV [Wald chi square=2.8, d.f.=2, P=0.247; Wald chi-square=2.888, d.f.=2, P=0.236; Wald chi square=1.385, d.f.=2, P=0.5; Wald chi-square=4.19, d.f.=2, P=0.123], respectively. A significant effect of time was found for echotypes III [Wald chi square=6.785, d.f.=2, P=0.0.034] and IV [Wald chi-square=7.491, d.f.=2, P=0.0.024]. CONCLUSIONS: The decrease in echotypes III and IV suggest that moderate loads can be applied to the Achilles tendon without compromising tendon structure. Low to moderate loads may be beneficial in the management of Achilles tendinopathy. Further studies should focus on protocols with higher loading and/or repetitive loading in athletic populations with and without Achilles tendinopathy to assess any differences in tendon structure. PMID- 29162332 TI - Integrating Downstaging in the Risk Assessment of Patients With Locally Advanced Rectal Cancer Treated With Neoadjuvant Chemoradiotherapy: Validation of Valentini's Nomograms and the Neoadjuvant Rectal Score. AB - BACKGROUND: Adjuvant chemotherapy is controversial in patients with locally advanced rectal cancer after preoperative chemoradiation. Valentini et al developed 3 nomograms (VN) to predict outcomes in these patients. The neoadjuvant rectal score (NAR) was developed after VN to predict survival. We aimed to validate these tools in a retrospective cohort at an academic institution. PATIENTS AND METHODS: VN and the NAR were applied to 158 consecutive patients with locally advanced rectal cancer treated with chemoradiation followed by surgery. According to the score, they were divided into low, intermediate, or high risk of relapse or death. For statistical analysis, we performed Kaplan Meier curves, log-rank tests, and Cox regression analysis. RESULTS: Five-year overall survival was 83%, 77%, and 67% for low-, intermediate-, and high-risk groups, respectively (P = .023), according to VN, and 84%, 71%, and 59% for low-, intermediate-, and high-risk groups, respectively (P = .004), according to NAR. When the score was considered as a continuous variable, a significant association with the risk of death was observed (NAR: hazard ratio, 1.04; P < .001; VN: hazard ratio, 1.10; P < .001). CONCLUSION: We confirmed the value of these scores to stratify patients according to their individual risk when designing new trials. PMID- 29162333 TI - Evaluation of a Mindful Eating Intervention Curriculum Among Elementary School Children and their Parents. PMID- 29162334 TI - Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients. AB - BACKGROUND: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile. STUDY DESIGN: Randomized prospective crossover study. SETTING & PARTICIPANTS: 50 African American maintenance kidney recipients on stable IR-Tac dosing. INTERVENTION: Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose. OUTCOMES: Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype. MEASUREMENTS: CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles. RESULTS: ~80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4). LIMITATIONS: This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes. CONCLUSIONS: Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, with study number NCT01962922. PMID- 29162335 TI - The Precision of Standardized Hospitalization, Readmission, and Mortality Ratios for Dialysis Facilities. PMID- 29162336 TI - Insights From the 2016 Peer Kidney Care Initiative Report: Still a Ways to Go to Improve Care for Dialysis Patients. AB - Although outcomes improved during the past decade for patients receiving maintenance dialysis, gains were few in certain key areas, as highlighted in the 2016 Peer Kidney Care Initiative Report. Overall incidence rates of dialysis therapy initiation in adults remained relatively stable (~42 per 100,000 US population, 2009-2013), but rates varied more than 2-fold, from 26 to 54, across US geographic regions. Hospitalization rates in incident patients decreased from 261 hospitalizations per 100 patient-years in 2003 to 207 in 2012, but observation stay rates increased from 40 to 67, attenuating the decline in hospitalizations by half. Decreases in prevalent patient hospitalizations for heart failure, from 15.6 per 100 patient-years in 2004 to 9.5 in 2013, were partially offset by increases in hospitalizations for volume overload, from 3.0 in 2004 to 6.1 in 2013. Prevalent patient rates of hospitalizations for arrhythmias (~4.6 per 100 patient-years) did not improve during the past decade, whereas sudden cardiac death as a proportion of total cardiovascular deaths increased from 53% to 73%. Hospitalization rates for pneumonia/influenza, at about 8.3 per 100 patient-years in prevalent patients, did not decrease during this period, while hospitalization rates for bacteremia/sepsis increased from 8.6 to 12.0. If decreases in mortality rates are to be sustained, novel approaches to these challenges will be required. PMID- 29162337 TI - Hip Fracture Trends in Japanese Dialysis Patients, 2008-2013. AB - BACKGROUND: Contrary to observations of decreasing rates in Western nations for the past 2 decades, age-adjusted rates of hip fracture in the general population in Japan have continually increased. This study aimed to analyze recent changes in trends of hip fracture incidence among Japanese dialysis patients between 2008 and 2013. STUDY DESIGN, SETTING, & PARTICIPANTS: Using data from the Japanese Society for Dialysis Therapy Renal Data Registry database from 2007 to 2013, we created a point-prevalent study cohort for each study year. Prevalent dialysis cohorts included patients 20 years or older without a history of hip fracture who were receiving maintenance dialysis in Japan on December 31 of each year. FACTORS: Age, sex, and calendar year. OUTCOMES: Hip fracture incidence rates. MEASUREMENTS: Unadjusted hip fracture rates were estimated using number of events per 1,000 patient-years in each year and then standardized for age to the 2013 dialysis population. Average annual percentage of change in rates and corresponding 95% CI were computed for trend by joinpoint regression analysis. RESULTS: During the study period, 6,615 and 4,963 hip fractures were recorded among female and male dialysis patients, respectively. Age-standardized hip fracture rates decreased steadily from 2008 (21.1/1,000 patient-years) to 2013 (17.7/1,000 patient-years) among women, but remained constant from 2008 (8.6/1,000 patient-years) through 2013 (8.2/1,000 patient-years) among men. Decreases in the joinpoint trend for hip fracture were significant among female ( 3.6% [95% CI, -6.9 to -0.2] per year), but not among male, dialysis patients ( 1.4% [95% CI, -5.7 to 3.0] per year) from 2008 through 2013. LIMITATIONS: Only the first hip fracture event was considered in calculations of fracture rates. CONCLUSIONS: In contrast to the increasing incidence of hip fracture in the general Japanese population, we found that the incidence of hip fracture in Japanese dialysis patients between 2008 and 2013 decreased among women, but did not change in men. PMID- 29162338 TI - Interstitial Nephritis Secondary to Vedolizumab Treatment in Crohn Disease and Safe Rechallenge Using Steroids: A Case Report. AB - Vedolizumab is a gut-selective humanized monoclonal antibody that binds selectively to the alpha4 beta7 integrin and acts as a lymphocyte-homing antagonist. It is indicated in ulcerative colitis and Crohn disease. We report a case of acute interstitial nephritis following vedolizumab infusion in a 55-year old white woman treated for severe Crohn disease resistant to several therapies. Other kidney disease causes were ruled out. Glucocorticoids were administrated, leading to full renal recovery. In the absence of other therapeutic options, vedolizumab was re-administered along with transient corticosteroids; this treatment was well tolerated. Fewer than 10 cases of immunoallergic acute interstitial nephritis following treatment with monoclonal antibody have previously been reported in the literature. The pathophysiology of delayed-type hypersensitivity secondary to monoclonal antibody therapeutics is discussed in this case report. PMID- 29162339 TI - Acute Kidney Injury and Risk of Incident Heart Failure Among US Veterans. AB - BACKGROUND: Acute kidney injury (AKI) is common and associated with poor outcomes. Heart failure is a leading cause of cardiovascular disease among patients with chronic kidney disease. The relationship between AKI and heart failure remains unknown and may identify a novel mechanistic link between kidney and cardiovascular disease. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: We studied a national cohort of 300,868 hospitalized US veterans (2004-2011) without a history of heart failure. PREDICTOR: AKI was the predictor and was defined as a 0.3-mg/dL or 50% increase in serum creatinine concentration from baseline to the peak hospital value. Patients with and without AKI were matched (1:1) on 28 in- and outpatient covariates using optimal Mahalanobis distance matching. OUTCOMES: Incident heart failure was defined as 1 or more hospitalization or 2 or more outpatient visits with a diagnosis of heart failure within 2 years through 2013. RESULTS: There were 150,434 matched pairs in the study. Patients with and without AKI during the index hospitalization were well matched, with a median preadmission estimated glomerular filtration rate of 69mL/min/1.73m2. The overall incidence rate of heart failure was 27.8 (95% CI, 19.3-39.9) per 1,000 person-years. The incidence rate was higher in those with compared with those without AKI: 30.8 (95% CI, 21.8-43.5) and 24.9 (95% CI, 16.9 36.5) per 1,000 person-years, respectively. In multivariable models, AKI was associated with 23% increased risk for incident heart failure (HR, 1.23; 95% CI, 1.19-1.27). LIMITATIONS: Study population was primarily men, reflecting patients seen at Veterans Affairs hospitals. CONCLUSIONS: AKI is an independent risk factor for incident heart failure. Future studies to identify underlying mechanisms and modifiable risk factors are needed. PMID- 29162341 TI - [Novel insights into the role of APOL1 in the kidney]. PMID- 29162342 TI - Giant popliteal vein aneurysm in Parkes-Weber syndrome. PMID- 29162340 TI - Effects of Intensive Blood Pressure Treatment on Acute Kidney Injury Events in the Systolic Blood Pressure Intervention Trial (SPRINT). AB - BACKGROUND: Treating to a lower blood pressure (BP) may increase acute kidney injury (AKI) events. STUDY DESIGN: Data for AKI resulting in or during hospitalization or emergency department visits were collected as part of the serious adverse events reporting process of the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING & PARTICIPANTS: 9,361 participants 50 years or older with 1 or more risk factors for cardiovascular disease. INTERVENTIONS: Participants were randomly assigned to a systolic BP target of <120 (intensive arm) or <140mmHg (standard arm). OUTCOMES & MEASUREMENTS: Primary outcome was the number of adjudicated AKI events. Secondary outcomes included severity of AKI and degree of recovery of kidney function after an AKI event. Baseline creatinine concentration was defined as the most recent SPRINT outpatient creatinine value before the date of the AKI event. RESULTS: There were 179 participants with AKI events in the intensive arm and 109 in the standard arm (3.8% vs 2.3%; HR, 1.64; 95% CI, 1.30-2.10; P<0.001). Of 288 participants with an AKI event, 248 (86.1%) had a single AKI event during the trial. Based on modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria for severity of AKI, the number of AKI events in the intensive versus standard arm by KDIGO stage was 128 (58.5%) versus 81 (62.8%) for AKI stage 1, 42 (19.2%) versus 18 (14.0%) for AKI stage 2, and 42 (19.2%) versus 25 (19.4%) for AKI stage 3 (P=0.5). For participants with sufficient data, complete or partial resolution of AKI was seen for 169 (90.4%) and 9 (4.8%) of 187 AKI events in the intensive arm and 86 (86.9%) and 4 (4.0%) of 99 AKI events in the standard arm, respectively. LIMITATIONS: Trial results are not generalizable to patients with diabetes mellitus or without risk factors for cardiovascular disease. CONCLUSIONS: More intensive BP lowering resulted in more frequent episodes of AKI. Most cases were mild and most participants had complete recovery of kidney function. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01206062. PMID- 29162343 TI - Long-term voice quality outcomes after total thyroidectomy: a prospective multicenter study. AB - BACKGROUND: Postthyroidectomy voice disorders can occur without any recurrent laryngeal nerve injury, and probably are the most frequent complication after thyroidectomy. We report the long-term voice quality outcomes after total thyroidectomy without vocal cord palsy using a simple self-assessment tool: the voice handicap index self-questionnaire. METHODS: This observational prospective multicenter study included 203 patients from the "ThyrQoL" study (ClinicalTrial NCT02167529), who underwent total thyroidectomy between October 2014 and August 2015 in 3 French Hospitals (Nantes, La Roche-sur-Yon, and Limoges). Exclusion criteria included confirmed malignant disease, age <18 years, and preoperative voice troubles with confirmed vocal cord palsy. Direct flexible laryngoscopy was performed after surgery. Nineteen patients with a postoperative vocal cord palsy were excluded from analysis. RESULTS: One hundred and seventy-six patients with no vocal cord palsy were analyzed. Voice handicap index scores were significantly altered on postoperative month 2 compared with preoperative values (7.02 +/- 11.56 vs 14.41 +/- 19.44; P<.0001). Voice handicap index scores were not significantly different on postoperative month 6 compared with preoperative values (7.02 +/- 11.56 vs 7.61 +/- 14.02; P=.381). Thirty-six patients (20.5%) described significant voice impairment 2 months after total thyroidectomy. Nine patients (5.7%) still experienced significant discomfort at 6 months. CONCLUSION: Twenty percent of patients had initial voice impairment at 2 months postthyroidectomy, with a progressive recovery to preoperative levels at 6 months with <6% with persistent voice complaints. PMID- 29162344 TI - Disentangling the prognostic heterogeneity of stage III colorectal cancer through histologic stromal categorization. AB - BACKGROUND: Growing evidence suggests the importance of stroma in determining cancer biology and recent studies have identified that genes closely associated with poor prognosis subtypes of colorectal cancer are expressed by the stroma rather than epithelial cancer cells. We aimed to clarify the prognostic value of the novel histologic classification of desmoplastic reaction in stage III colorectal cancer. METHODS: A pathologic review was conducted for 466 stage III colorectal cancer patients in a single Japanese institution (1999-2006). Desmoplastic reaction was classified as mature, intermediate, or immature according to existence of hyalinized collagen bundles and myxoid stroma, both appear exclusively at the desmoplastic front. An additional 432 patients treated at four independent institutions (2007-2008) were examined as a second cohort to validate the results. RESULTS: According to desmoplastic reaction, 164, 133, and 169 patients were classified as mature, intermediate, and immature, respectively. Five-year relapse-free survival rates were highest in the mature group (86.0%), followed by the intermediate (73.7%) and immature (50.9%) groups. An adverse prognostic impact of desmoplastic reaction was invariably observed in stage IIIB, which contained 71% of stage III cases. Harrell's concordance index for relapse free survival was greater in desmoplastic reaction (0.66) than any conventional tumor-associated prognostic factors including tumor node metastasis substage (0.62) and tumor grade (0.53). Similar results were observed in the second cohort, wherein desmoplastic reaction categorization was the most influential prognostic factor. CONCLUSION: Histologic desmoplastic reaction categorization could be a key to solve the issue of prognostic heterogeneity in stage III colorectal cancer, thereby enhancing the value of tumor node metastasis stage. PMID- 29162345 TI - Postacute Care after Pediatric Hospitalizations for a Primary Mental Health Condition. AB - OBJECTIVES: To determine the proportion of US children hospitalized for a primary mental health condition who are discharged to postacute care (PAC); whether PAC discharge is associated with demographic, clinical, and hospital characteristics; and whether PAC use varies by state. STUDY DESIGN: Retrospective cohort study of a nationally representative sample of US acute care hospitalizations for children ages 2-20 years with a primary mental health diagnosis, using the 2009 and 2012 Kids' Inpatient Databases. Discharge to PAC was used as a proxy for transfer to an inpatient mental health facility. We derived adjusted logistic regression models to assess the association of patient and hospital characteristics with discharge to PAC. RESULTS: In 2012, 14.7% of hospitalized children (n = 248 359) had a primary mental health diagnosis. Among these, 72% (n = 178 214) had bipolar disorder, depression, or psychosis, of whom 4.9% (n = 8696) were discharged to PAC. The strongest predictors of PAC discharge were homicidal ideation (aOR, 24.9; 96% CI, 4.1-150.4), suicide and self-injury (aOR, 15.1; 95% CI, 11.7-19.4), and substance abuse-related medical illness (aOR, 5.0; 95% CI, 4.5-5.6). PAC use varied widely by state, ranging from 2.2% to 36.3%. CONCLUSIONS: The majority of children hospitalized primarily for a mood disorder or psychosis were not discharged to PAC, and safety-related conditions were the primary drivers of the relatively few PAC discharges. There was substantial state-to-state variation. Target areas for quality improvement include improving access to PAC for children hospitalized for mood disorders or psychosis and equitable allocation of appropriate PAC resources across states. PMID- 29162346 TI - Self-Management Measurement and Prediction of Clinical Outcomes in Pediatric Transplant. AB - OBJECTIVE: To further refine a measure of self-management, the Responsibility and Familiarity with Illness Survey (REFILS), and to determine if this score predicts medication adherence and, thus, fewer instances of allograft rejection among pediatric liver transplant recipients. STUDY DESIGN: Participants were 400 liver transplant recipients and their parents recruited for the Medication Adherence in Children Who Had a Liver Transplant study, from 5 US pediatric transplant centers. The REFILS was administered to participants (ages 9-17 years) and their parents at enrollment (n = 213 completed dyads). The REFILS scores, and a discrepancy score calculated between patient and parent report of the patient's self-management, were used to predict Medication Level Variability Index (MLVI), a measure of medication adherence (higher MLVI = more variability in medication levels) and central pathologist-diagnosed rejection over a 2-year follow-up. RESULTS: When patients reported greater self-management, their adherence was lower (higher MLVI, r = 0.26, P < .01). Discrepancies between patient and parent report (patients endorsing higher levels than parents) were associated with lower adherence (r = 0.20, P < .01). Greater patient-reported self-management and higher discrepancy scores also predicted rejection. CONCLUSIONS: We found that when patients endorse more responsibility for their care, clinical outcomes are worse, indicating that indiscriminate promotion of self-management by adolescents may not be advisable. A discrepancy between patient and parent perception of self management emerged as a novel strategy to gauge the degree of risk involved in transitioning care responsibilities to the child. PMID- 29162347 TI - Trypanosoma cruzi tryparedoxin II interacts with different peroxiredoxins under physiological and oxidative stress conditions. AB - Trypanosoma cruzi, the etiologic agent of Chagas disease, has to cope with reactive oxygen and nitrogen species during its life cycle in order to ensure its survival and infection. The parasite detoxifies these species through a series of pathways centered on trypanothione that depend on glutathione or low molecular mass dithiol proteins such as tryparedoxins. These proteins transfer reducing equivalents to peroxidases, including mitochondrial and cytosolic peroxiredoxins, TcMPx and TcCPx, respectively. In T. cruzi two tryparedoxins have been identified, TXNI and TXNII with different intracellular locations. TXNI is a cytosolic protein while TXNII due to a C-terminal hydrophobic tail is anchored in the outer membrane of the mitochondrion, endoplasmic reticulum and glycosomes. TXNs have been suggested to be involved in a majority of biological processes ranging from redox mechanisms to protein translation. Herein, a comparison of the TXNII interactomes under physiological and oxidative stress conditions was examined. Under physiological conditions, apart from the proteins with unknown biological process annotation, the majority of the identified proteins are related to cell redox homeostasis and biosynthetic processes, while under oxidative stress conditions, are involved in stress response, cell redox homeostasis, arginine biosynthesis and microtubule based process. Interestingly, although TXNII interacts with both peroxiredoxins under physiological conditions, upon oxidative stress, TcMPx interaction prevails. The relevance of the interactions is discussed opening a new perspective of TXNII functions. PMID- 29162348 TI - Human aniridia limbal epithelial cells lack expression of keratins K3 and K12. AB - Aniridia is a rare disease of the eye that affects the iris, lens and the cornea. In about 90% of the cases, patients showed a loss of PAX6 function. Patients with aniridia often develop aniridia-related keratopathy (ARK), due to limbal stem cell insufficiency. The aim of this study was to determine the differentiation status of limbal epithelial cells (LECs) in patients with ARK. Epithelial cells were isolated from the limbus region of two patients with aniridia and cultured in KSFM medium supplemented with EGF and BPE. Normal cells were obtained from limbus region of cadaveric control patients. Cells were analyzed with RT-PCR, qPCR and Western blot to evaluate expression of the developmental transcription factor, PAX6, potential stem cell markers, DeltaNp63alpha and ABCG2, and corneal differentiation markers, keratin 12 (K12) and K3. Conjunctival differentiation markers, keratin 13 (K13) and K19 were also investigated. Cells were immunostained to evaluate K3, PAX6, and p63alpha protein expression. Protein coding sequence of PAX6 from patient LEC-cDNA was cloned and sequenced. RT-PCR showed that K3 and K12 transcripts were absent from patient cells, but present in healthy control preparations. Transcription levels of PAX6, ABCG2, and p63alpha of aniridia patients show no differences compared to normal control cells. Western blot showed reduced PAX6, protein levels in aniridia-LECs compared to control-LECs. Immunostaining also showed reduced PAX6 and K3 expression in aniridia-LECs compared to control-LECs. One aniridia patient showed a loss of stop codon in half of the cloned transcripts. In the second aniridia patient mRNA degradation through nonsense mediated decay seems to be very likely since we could not identify the mutation c.174C > T (Refseq. NM_000280), or misspliced transcripts in cDNA. We identified decreased PAX6 protein levels in aniridia patients in addition to decreased K12 mRNA levels compared to control cells. This result indicates an altered differentiation of limbal epithelial cells of aniridia patients. Further studies are necessary to evaluate the mechanism of differentiation of limbal epithelial cells in aniridia. PMID- 29162349 TI - Agreement between parents and clinicians on the communication function levels and relationship of classification systems of children with cerebral palsy. AB - BACKGROUND: Functional classification systems have generally been used by clinicians and recently by parents to classify various functions of children with cerebral palsy (CP). OBJECTIVE: This study evaluated the agreement between clinicians and parents when classifying the communication function of children with CP using the Communication Function Classification System (CFCS). In addition, the relationships between the Gross Motor Function Classification System - Expanded and Revised (GMFCS-E&R), the Manual Ability Classification System (MACS), and CFCS were investigated. METHODS: This study was a cross sectional study and included 102 children aged 4-18 years with CP and their parents. The parents and clinician classified the communication of children by using the Turkish language version of CFCS. Furthermore GMFCS-E&R and MACS were used for classification only by the clinician. RESULTS: The weighted Kappa agreement between CFCS results of the parents and clinicians was 0.95 (95% CI 0.95-0.96, p < 0.001). GMFCS-E&R levels were highly correlated with CFCS levels (r = 0.78 (95%CI 0.68-0.84, p < 0.001)). MACS and CFCS results were also highly correlated (r = 0.73 (95%CI 0.63-0.81, p < 0.001). CONCLUSION: The child's communication was classified as indicating higher functioning by the parents compared with the clinicians. The excellent agreement between parents and clinicians with the Turkish language version of CFCS for children with CP indicated that parents and clinicians could use the same language while classifying the communication function of children. PMID- 29162350 TI - Re: Fertility Outcomes After Extended Searches for Ejaculated Spermatozoa in Men with Virtual Azoospermia. PMID- 29162351 TI - Refining the Assessment and Implications of AR-V7 in Castrate-resistant Prostate Cancer. PMID- 29162352 TI - [Facing a serious disease during adolescence despite a defective parental support: The experience of cancer]. AB - Facing a serious somatic disease during adolescence without any parental support is a very difficult life event. In this paper, we discuss the situation of teenagers facing deep emotional deprivation that existed prior to the illness and is reinforced by the lack of parental support during treatment. After analyzing the psychopathological mechanisms involved in such situations - in parents, teenagers, and healthcare teams - we hypothesize that the absence of involvement of parents can sometimes represent, for those who are not able to meet their child's emotional needs, a paradoxical way to take care of him. PMID- 29162353 TI - [Emergency child psychiatry response following the 14 July 2016 terrorist attack in Nice, France]. AB - The attack on 14 July 2016 in Nice on the Promenade des Anglais caused major trauma for individuals directly or indirectly impacted by the horror of the terrorist attack, mainly families and children. It was the first time in France that a pediatric population aged from several months to 18 years was impacted by an event of such magnitude. The literature underlines the importance of taking into account, over the longer term, the side effects of such a psychotrauma in the pediatric population, especially in children under 6 years of age. From the night of 14 July 2016, a pediatric medical and psychological emergency unit (CUMP) was set up within the CHU-Lenval pediatric hospital. This has been a unique experience in Europe, which mobilized 227 caregivers. A total of 728 individuals were seen in consultations, including 385 children between 3 months and 17.7 years. The article outlines the main lines of its organization and its objectives. PMID- 29162354 TI - [Cryptosporidiosis, a cause of acute diarrhea: A review and retrospective study of cases in Rouen university hospital's pediatrics department]. AB - Cryptosporidium is the most important diarrhea-causing protozoan parasite, with severe health consequences for very young, malnourished children living in endemic areas and for immunocompromised individuals. Cryptosporidium is widely distributed and disease transmission can occur through person-to-person or animal to-person contact, or contaminated food or water (drinking or swimming), leading to large outbreaks. The zoonotic Cryptosporidium parvum and the anthroponotic Cryptosporidium hominis are responsible for the majority of human cases. Specific therapy, primarily nitazoxanide, has some effect in healthy individuals, but drugs effectively preventing or controlling this disease in all clinical situations are not yet available. In France, as elsewhere in Europe, little epidemiological and molecular information is available regarding the burden of cryptosporidiosis in children. Cryptosporidium is usually not tested in all fecal samples submitted for routine parasitological examination and only tested on special request, primarily in immunocompromised patients. Between January 2007 and October 2014, out of a total of 5337 immunocompetent children with diarrhea in Rouen university hospital's pediatrics department, the prevalence of Cryptosporidium infection was 0.97 % (52 infected children). The median age of infected children was 3 years (range, 5 months to 11 years) and 80 % of the cases occurred between July and November. Thirty-six (69.2 %) and 16 (30.8 %) infections were due to C. parvum and C. hominis, respectively. The fact that the species C. parvum, mainly the IIaA15G2R1 subtype, was detected in most locally infected children suggests that cryptosporidiosis must primarily be considered as a zoonotic disease in Upper Normandy. PMID- 29162355 TI - [Hot tub lung: A case report]. AB - Hot tub lung is a type of hypersensitivity pneumonitis caused by inhalational exposure to the Mycobacterium avium complex. We report the case of a 14-year-old boy presenting dyspnea with hypoxemia, whose medical history and clinical course helped make the diagnosis. Infectious causes were considered first, and antibiotics were initiated without success. Further questioning and explorations led to discussing a hypersensitivity pneumonitis diagnosis. Relapse after exposure to a hot tub enabled us to confirm hot tub lung. Hypersensitivity pneumonitis is a rare cause of pulmonary disorder, especially in children. It should be discussed with unusually severe and progressive cough or dyspnea. Further explorations should therefore be undertaken (CT, fibroscopy). Taking a precise medical history allows early diagnosis, leading to a quick withdrawal from the allergenic source and appropriate treatments. PMID- 29162356 TI - The Perception of Breathiness in the Voices of Pediatric Speakers. AB - BACKGROUND: The perception of pediatric voice quality has been investigated using clinical protocols developed for adult voices and acoustic analyses designed to identify important physical parameters associated with normal and dysphonic pediatric voices. Laboratory investigations of adult dysphonia have included sophisticated methods, including a psychoacoustic approach that involves a single variable matching task (SVMT), characterized by high inter- and intra-listener reliability, and analyses that include bio-inspired models of auditory perception that have provided valuable information regarding adult voice quality. OBJECTIVES: To establish the utility of a psychoacoustic approach to the investigation of voice quality perception in the context of pediatric voices? METHODS: Six listeners judged the breathiness of 20 synthetic vowel stimuli using an SVMT. To support comparisons with previous data, stimuli were modeled after four pediatric speakers and synthesized using Klatt with five parameter settings that influence the perception of breathiness. The population average breathiness judgments were modeled with acoustic measures of loudness ratio, pitch strength, and cepstral peak. RESULTS: Listeners reliably judged the perceived breathiness of pediatric voices, as with previous investigations of breathiness in adult dysphonic voices. Breathiness judgments were accurately modeled by loudness ratio (r2 = 0.93), pitch strength (r2 = 0.91), and cepstral peak (r2 = 0.82). Model accuracy was not affected significantly by including stimulus fundamental frequency and was slightly higher for pediatric than for adult voices. CONCLUSIONS: The SVMT proved robust for pediatric voices spanning a wide range of breathiness. The data indicate that this is a promising approach for future investigation of pediatric voice quality. PMID- 29162357 TI - 2017 Guidelines for the management of arterial hypertension in primary health care in Portuguese-speaking countries. AB - The World Health Organization goal's to reduce mortality due to chronic non communicable diseases by 2% per year demands a huge effort from member countries. This challenge for health professionals requires global political action on implementation of social measures, with cost-effective population interventions to reduce chronic non-communicable diseases and their risk factors. Systemic arterial hypertension is highly prevalent in Portuguese-speaking countries, and is a major risk factor for complications such as stroke, acute myocardial infarction and chronic kidney disease, rivaling dyslipidemia and obesity in importance for the development of atherosclerotic disease. Joint actions to implement primary prevention measures can reduce outcomes related to hypertensive disease, especially ischemic heart disease and stroke. It is essential to ensure the implementation of guidelines for the management of systemic hypertension via a continuous process involving educational actions, lifestyle changes and guaranteed access to pharmacological treatment. PMID- 29162358 TI - Heart transplantation for Chagas cardiomyopathy. AB - Chagas disease is an endemic disease in Latin America that is increasingly found in non-endemic areas all over the world due to the flow of migrants from Central and South America. We present the case of a Brazilian immigrant in Portugal who underwent orthotopic heart transplantation for end-stage Chagas cardiomyopathy. Immunosuppressive therapy included prednisone, mycophenolate mofetil and tacrolimus. Twelve months after the procedure she is asymptomatic, with good graft function, and with no evidence of complications such as graft rejection, opportunistic infections, neoplasms or reactivation of Trypanosoma cruzi infection. By reporting the first case in Portugal of heart transplantation for Chagas cardiomyopathy, we aim to increase awareness of Chagas disease as an emerging global problem and of Chagas cardiomyopathy as a serious complication for which heart transplantation is a valuable therapeutic option. PMID- 29162359 TI - The freedom of clinicians and the art of the impossible. PMID- 29162360 TI - Sleep-disordered breathing in heart failure: The state of the art after the SERVE HF trial. AB - Heart failure (HF) is one of the most prevalent conditions worldwide and despite therapeutic advances, its prognosis remains poor. Among the multiple comorbidities in HF, sleep-disordered breathing (SDB) is frequent and worsens the prognosis. Preliminary observational studies suggested that treatment of SDB could modify the prognosis of HF, and the issue has gained importance in recent years. The diagnosis of SDB is expensive, slow and suboptimal, and there is thus a need for screening devices that are easier to use and validated in this population. The first-line treatment involves optimization of medical therapy for heart failure. Continuous positive airway pressure (CPAP) is used in patients who mainly suffer from obstructive sleep apnea. In patients with predominantly central sleep apnea, CPAP is not sufficient and adaptive servo-ventilation (ASV), despite promising results in observational studies, showed no benefit in patients with symptomatic HF and reduced ejection fraction in the SERVE-HF randomized trial; on the contrary, there was unexpectedly increased mortality in the ASV group compared to controls, and so ASV is contraindicated in these patients, calling into question the definition and pathogenesis of SDB and risk stratification in these patients. There are many gaps in the evidence, and so further research is needed to better understand this issue: definitions, simple screening methods, and whether and how to treat SDB in patients with HF. PMID- 29162361 TI - Impaired beta cell sensitivity to incretins in type 2 diabetes is insufficiently compensated by higher incretin response. AB - BACKGROUND AND AIMS: The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors. METHODS AND RESULTS: Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the incretin effect, representing potentiation of insulin secretion by incretins (PINCR), was determined by mathematical modelling as the time-dependent fold increase in insulin secretion during OGTT compared to IIGI. The time course of PINCR was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled incretin concentration, PIC), as the slope of the relationship between PINCR and PIC. SINCR was reduced in T2D (p < 0.01). In the whole group, mean PIC, GIP and GLP-1 concentrations during the OGTT were inversely correlated with SINCR, but T2D had lower PIC, GIP and GLP-1 levels at the same SINCR (p < 0.05). CONCLUSION: Relative incretin insensitivity is partly compensated for by higher incretin secretory responses. However, T2D shows both impairment in incretin sensitivity and abnormal compensation by incretin secretion. PMID- 29162362 TI - Prediabetes is associated with lower brain gray matter volume in the general population. The Study of Health in Pomerania (SHIP). AB - BACKGROUND AND AIMS: We investigated the associations of fasting (FG) and 2-h postload (2HG) plasma glucose from oral glucose tolerance test (OGTT) with gray (GMV) and white (WMV) matter volume. METHODS AND RESULTS: We analyzed data from 1330 subjects without known diabetes mellitus, aged 21 to 81, from the second cohort (SHIP-Trend-0) of the population-based Study of Health in Pomerania (SHIP). Following the OGTT, individuals were classified in five groups (according to the American Diabetes Association criteria): normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i IGT), combined IFG and IGT (IFG + IGT) and unknown type 2 diabetes mellitus (UDM). GMV and WMV were determined by magnetic resonance imaging. FG, 2HG and OGTT groups were associated with GMV and WMV by linear regression models adjusted for confounders. FG and 2HG were inversely associated with GMV. The adjusted mean GMV, when compared with the NGT group (584 ml [95% CI: 581 to 587]), was significantly lower in the groups i-IFG (578 ml [95% CI: 573 to 582]; p = 0.035) and UDM (562 ml [95% CI: 551 to 573]; p < 0.001), but not different in the i-IGT (586 ml [95% CI: 576 to 596]; p = 0.688) and IFG + IGT (579 ml [95% CI: 571 to 586]; p = 0.209) groups. There were no associations of FG, 2HG and OGTT parameters with WMV. CONCLUSION: Our findings suggest that elevated FG levels, even within the prediabetic range, might already have some harmful effects on GMV. PMID- 29162363 TI - Sex differences in associations between blood lipids and cerebral small vessel disease. AB - BACKGROUND AND AIMS: Dyslipidemia predicts higher risk of coronary events and stroke and might be associated with cerebral small vessel disease (SVD). Previous studies linking blood lipids and SVD have yielded inconsistent results, which may be attributable to sex differences in lipids metabolism. The aim of this study was to investigate the relationships between blood lipids and SVD in neurologically healthy men and women. METHODS AND RESULTS: Consecutive 817 people aged 50 years or more were enrolled and underwent magnetic resonance imaging scans to evaluate the periventricular white matter lesions (PVWMLs), deep white matter lesions (DWMLs) and silent brain infarction (SBI). Fasting total cholesterol, triglyceride, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol, apolipoprotein A-1 (apoA-1) and apolipoprotein B were assessed. Multivariable logistic regression analyses were performed to determine the associations of blood lipids with PVWMLs, DWMLs and SBI. HDL-C (for PVWMLs: OR 0.36, 95% CI 0.19-0.71; for DWMLs: OR 0.35, 95% CI 0.20-0.63) and apoA 1 (for PVWMLs: OR 0.27, 95% CI 0.11-0.66; for DWMLs: OR 0.22, 95% CI 0.10-0.48) were inversely associated with the severity of PVWMLs and DWMLs in women but not in men after adjustment for age, hypertension, diabetes, current smoking, daily drinking, body mass index and uric acid. Additionally, no blood lipids were significantly associated with SBI. CONCLUSIONS: Our findings demonstrate that sex differences may exist in the associations between lipids and SVD. HDL-C and apoA 1 levels were inversely associated with the severity of PVWMLs and DWMLs in women. PMID- 29162364 TI - Is There an Association Between Noncontact Anterior Cruciate Ligament Injuries and Decreased Hip Internal Rotation or Radiographic Femoroacetabular Impingement? A Systematic Review. AB - PURPOSE: To perform a systematic review to determine if there is (1) an association between decreased hip internal rotation and anterior cruciate ligament (ACL) tear rates; (2) an association between radiographic femoroacetabular impingement (FAI) and ACL tear rates; and (3) biomechanical evidence demonstrating increased strain in the ACL of patients with decreased hip internal rotation. METHODS: A systematic review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies investigating relationships between hip motion, hip radiographs, and ACL tear were sought. Studies with Levels of evidence I-IV were eligible for inclusion. Study methodology/evidence were evaluated using Methodological Index for Non-Randomized Studies (MINORS), Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. RESULTS: Eleven studies were analyzed (2 cadaveric in vitro models, 8 clinical studies measuring hip internal rotation (2 concurrently assessing radiographic FAI), and 1 clinical study assessing radiographic FAI alone). Mean MINORS, STROBE, and GRADE for the studies was 82.4%, 20.9 out of 22, and "low," respectively. A total of 959 subjects (84.8% male; mean age 23.6 +/- 3.8 years) were analyzed. Overall, 378 subjects sustained 427 ACL tears (399 primary ACL ruptures, 28 reruptures). Six of 8 clinical studies identified a significant association between limited rotation (internal rotation [IR; loss greater than 10 degrees -20 degrees ], external rotation [ER], or combined IR + ER [loss greater than 20 degrees ]) and ACL tears. Two studies found an association between ACL ruptures and radiographic cam/pincer impingement. Two cadaveric models found a significant association between ACL strain and limited hip internal rotation. CONCLUSIONS: This systematic review identified a significant association between ACL tear and both limited hip rotation and radiographic FAI. LEVEL OF EVIDENCE: Level IV, systematic review of Levels II-IV studies. PMID- 29162365 TI - Ankle fracture controversies: Do the foot and ankle specialists have a different vision? AB - OBJECTIVE: To analyse the differences in the management of ankle fractures between orthopaedic/trauma surgeons and foot and ankle specialists. MATERIAL AND METHOD: An e-mail survey was performed asking some of the country's orthopaedic surgeons controversial questions regarding the analysis of 5 clinical cases of different ankle fractures. RESULTS: Seventy-two surgeons responded to the questionnaire (response rate of 24.2%): 37 foot and ankle specialists and 35 non specialist orthopaedic surgeons. For trimalleolar fracture, 40.5% of the specialists would request a computed tomography scan compared to 14% of the non specialists (P=.01). Ninety-four percent of all the respondents would synthesise the posterior malleolus; 91% of the non-specialists would use an antero-posterior approach, either with a plate or with screws (P=.006). No differences were found between groups in the treatment of syndesmotic injuries (P>.05). For trans syndesmotic fracture (Weber B) with signs of medial instability, 54% of the non specialists would revise the internal lateral ligament compared to only 32% of the specialists (P=.06). CONCLUSIONS: The foot and ankle specialists ask for more complementary tests to diagnose ankle fractures. In turn, they use a greater diversity of surgical techniques in synthesis of the posterior malleolus (posterior plate) and the medial malleolus (cerclage wires). Finally, they indicated a lower revision rate of the internal lateral ligament. PMID- 29162366 TI - Resurfacing arthroplasty as an alternative to the posttraumatic sequelae of fractures of the external column of the humerus in the young adult. AB - Symptomatic posttraumatic arthritis of the elbow in young patients is a disorder for which there is currently no satisfactory solution. In this case report we show the evolution of a comminuted fracture of the capitellum with trochlear extension (McKee typeIV) treated initially with open reduction and internal fixation that eventually required a resurfacing hemiarthroplasty of the capitellum and reconstruction of the lateral ligament complex. After this surgical procedure, the patient had evident improvement of pain and of elbow range of motion, keeping the possibility of performing other rescue techniques open if they were to be necessary in the future. PMID- 29162367 TI - Arterial reconstructions for chronic lower extremity ischemia in preadolescent and adolescent children. AB - OBJECTIVE: Chronic lower extremity ischemia in pediatric patients is uncommon. The intent of this study was to better define the arterial reconstructive options and their long-term durability in preadolescent and adolescent children having clinically relevant arterial occlusions affecting the lower extremity. METHODS: The medical records of 33 consecutive pediatric patients who underwent lower extremity revascularization for chronic ischemia at the University of Michigan from 1974 to 2016 were reviewed. Patients were categorized by age, clinical manifestation, surgical intervention undertaken, and outcomes. RESULTS: Operative treatments involved 26 preadolescent children (mean age, 6.1 years; range, 3-9 years) and 7 adolescent children (mean age, 13.9 years; range, 10-17 years). Occlusions were due to earlier injury related to catheter (14), cannula (2), or both catheter and cannula (14); penetrating trauma (2); and vasculitis (1). Preoperative manifestations included symptomatic extremity ischemia (25), growth retardation manifested by documented limb length discrepancies (21), and scoliosis (5). Primary arterial reconstructions were delayed after the precipitating vascular event an average of 5.3 and 11.2 years in the preadolescent and adolescent children, respectively. Primary procedures involved revascularizations of 36 extremities (in preadolescents and adolescents) including autologous vein (26/5), polyethylene terephthalate (Dacron; 1/0), and expanded polytetrafluoroethylene (0/3) bypasses and vein patch angioplasty (0/1). Vein grafts traversing the abdominal cavity (15) were wrapped with a synthetic mesh. Excluding one early graft occlusion, there were no major early postoperative complications after the primary procedures. Secondary operations followed 31% of the primary operations, being performed an average of 8.8 and 6.7 years later (in 8 preadolescent and 3 adolescent children, respectively) for late graft occlusions (6), graft stenoses (3), aneurysmal vein grafts (2), and anastomotic pseudoaneurysm (1). The unassisted primary graft patency rate was 69%, and the assisted secondary graft patency rate was 94%. Symptomatic ischemia resolved in all but two children. Mean postoperative ankle-brachial indices improved to 1.08 from 0.76 preoperatively. Among children having postoperative documentation of limb lengths, the limb length discrepancies became less (11), were unchanged (1), or progressed (3). Follow-up averaged 8.0 years. There was no operative mortality in this experience. CONCLUSIONS: Primary lower extremity arterial reconstructions in children with chronic lower extremity ischemia can be successfully undertaken with excellent results. Nevertheless, the potential for late primary graft failures, evident in nearly a third of this experience, mandates careful long-term follow-up and may necessitate secondary interventions to maintain satisfactory outcomes. PMID- 29162368 TI - Role of hydroxyl groups in the B-ring of flavonoids in stabilization of the Hoogsteen paired third strand of Poly(U).Poly(A)*Poly(U) triplex. AB - We have reported the interaction of two flavonoids namely quercetin (Q) and morin (M) with double stranded poly(A).poly(U) (herein after A.U) and triple stranded poly(U).poly(A)*poly(U) (herein after U.A*U, dot represents the Watson-Crick and asterisk represents Hoogsteen base pairing respectively) in this article. It has been observed that relative positions of hydroxyl groups on the B-ring of the flavonoids affect the stabilization of RNA. The double strand as well as the triple strand of RNA-polymers become more stabilized in presence of Q, however both the duplex and triplex remain unaffected in presence of M. The presence of catechol moiety on the B-ring of Q is supposed to be responsible for the stabilization. Moreover, after exploiting a series of biophysical experiments, it has been found that, triple helical RNA becomes more stabilized over its parent duplex in presence of Q. Fluorescence quenching, viscosity measurement and helix melting results establish the fact that Q binds with both forms of RNA through the mode of intercalation while M does not bind at all to either forms of RNA. PMID- 29162369 TI - Carney complex review: Genetic features. AB - Carney complex is a multiple neoplasia syndrome having endocrine and non endocrine manifestations. Diagnostic criteria include myxoma, lentigines, and primary pigmented nodular adrenocortical disease, amongst other signs/symptoms. In most cases it is an autosomal dominant disease, and diagnosis therefore requires study and follow-up of the family members. Inactivating mutations of the PRKAR1A gene were identified as the main cause of the disease, although since 2015 other disease-related genes, including PRKACA and PRKACB activating mutations, have also been related with Carney complex. This review will address the genetic aspects related to Carney complex. PMID- 29162370 TI - Lipid discordance and carotid plaque in obese patients in primary prevention. AB - INTRODUCTION: Obese patients with lipid discordance (non-HDL cholesterol levels 30mg/dL above the LDL-c value) may have a greater prevalence of carotid atherosclerotic plaque (CAP). Our study objectives were: 1) To assess the prevalence of lipid discordance in a primary prevention population of obese patients; 2) To investigate the association between lipid discordance and presence of CAP. METHODS: Obese subjects aged >18 years (BMI >=30kg/m2) with no cardiovascular disease, diabetes, or lipid-lowering treatment from six cardiology centers were included. Lipid discordance was defined when, regardless of the LDL c level, the non-HDL cholesterol value exceeded the LDL-c value by 30mg/dL. Presence of CAP was identified by ultrasonography. Univariate and multivariate analyses were performed to explore the association between lipid discordance and presence of CAP. RESULTS: The study simple consisted of 325 obese patients (57.2% men; mean age, 52.3 years). Prevalence of lipid discordance was 57.9%. CAP was found in 38.6% of patients, but the proportion was higher in subjects with lipid discordance as compared to those without this lipid pattern (44.4% vs. 30.7%, P=.01). In both the univariate (OR: 1.80; 95% CI: 1.14-2.87; P=.01) and the multivariate analysis (OR: 2.07; 95% CI: 1.22-3.54; P=.007), presence of lipid discordance was associated to an increased probability of CAP. CONCLUSION: In these obese patients, lipid discordance was associated to greater prevalence of CAP. Evaluation of obese patients with this strategy could help identify subjects with higher residual cardiovascular risk. PMID- 29162371 TI - The role of caveolin-1 in lipid droplets and their biogenesis. AB - We address unresolved questions of the energetics and mechanism of lipid droplet (LD) biogenesis, and of the role of caveolins in the endoplasmic reticulum (ER) and in mature LDs. LDs are eukaryotic repositories of neutral lipids, which are believed to be synthesised in the ER. We investigate the effects of a curvature inducing protein, caveolin-1, on the formation and structure of a spontaneously aggregated triolein (TO) lipid lens in a flat lipid bilayer using molecular dynamics (MD) simulations. A truncated form of caveolin-1 (Cav1) localises on the interface between the spontaneously formed TO aggregate and the bulk bilayer, and thins the bilayer at the edge of the aggregate, which may contribute to lowering the energy barrier for pinching off the aggregate from the host bilayer. Simulations of fully mature LDs do not conclusively establish the optimal localisation of Cav1 in LDs, but when Cav1 is in the LD core, the distribution of both neutral lipids in the LD core, and of phospholipids on the engulfing monolayer are altered significantly. Our simulations provide an unprecedented molecular description of the distribution and dynamics of various lipid species in both mature LDs and in the nascent LD inside the bilayer. PMID- 29162372 TI - Genetics, environment, and asthma associated with celiac disease in the extended family of an affected child. AB - INTRODUCTION: Celiac disease (CD) is an autoimmune enteropathy associated with gluten ingestion. In extended families of celiac patients that live in close proximity of one another, shared genetic and environmental factors can predispose them to CD. AIM: The aim of this study was to provide evidence about the genetic and environmental factors involved in the development of CD in the extended family of a pediatric patient. METHODS: The medical history, environmental conditions, and participant weight, height, and peripheral blood samples were evaluated. The HLA-DQ2/DQ8 haplotypes were genotyped through qPCR testing and the IgA anti-gliadin and anti-transglutaminase antibodies were quantified using the ELISA test. RESULTS: Twelve close-living maternal relatives of the index case participated in the study. Eight of them presented with the HLA-DQ2 haplotype, inherited from the grandfather, and 7/12 and 9/12 were positive for IgA anti gliadin and IgA anti-transglutaminase antibodies, respectively. The main intestinal symptoms stated by the participants were abdominal bloating, excess flatulence, constipation, and gastroesophageal reflux. The most frequent extra intestinal symptoms were fatigue, stress, and anxiety. In addition, 6/13 participants had bronchial asthma. CONCLUSION: The extended family living in close proximity of one another shared a genetic predisposition, environmental conditions, and asthma, which could have predisposed them to celiac disease. PMID- 29162373 TI - Stabilisation and dewatering of primary sludge using ferrate(VI) pre-treatment followed by freeze-thaw in simulated drainage beds. AB - This study evaluated the ability of potassium ferrate(VI) and freeze-thaw to stabilise and dewater primary sludge. Potassium ferrate(VI) additions of 0.5 and 5.0 g/L were used as a pre-treatment prior to freeze-thaw. Samples were frozen at -10, -20 and -30 degrees C, and were kept frozen for 1, 8 and 15 days. The samples were subsequently thawed at room temperature in a setup which allowed meltwater to be separated from the sludge cake via gravity drainage. The meltwater was characterised in terms of fecal coliform, soluble chemical oxygen demand (COD), soluble proteins, soluble carbohydrates, pH and turbidity. The sludge cake was characterised in terms of fecal coliform, total solids (TS) and volatile solids (VS). Freeze-thaw with gravity meltwater drainage reduced the sludge volume by up to 79%. After being frozen for only 1 day, the concentrations of fecal coliform in many of the primary sludge samples were reduced to <1000 MPN/g dry solids (DS), representing >3-log inactivation in some cases. However, pre-treatment of the primary sludge with <=5.0 g/L potassium ferrate(VI) resulted in significant increases in soluble proteins, soluble carbohydrates, and sCOD, and reduced the effectiveness of stand-alone freeze-thaw. Follow-up experiments using higher doses ranging from 5.1 to 24.9 g/L of potassium ferrate(VI) demonstrated that >5-log inactivation of fecal coliform in raw primary sludge can be achieved within 15 min using 15 g/L of potassium ferrate(VI), and the resulting concentration of fecal coliform in the sludge was 1023 MPN/g DS. Pre treatment with 22.0 g/L of potassium ferrate(VI), followed by freeze-thaw, with only 3 days frozen, reduced the concentration of fecal coliform to below the detection limit in the meltwater and the sludge cake. This demonstrates that potassium ferrate(VI) and freeze-thaw offers the flexibility to adjust the ferrate(VI) dose to meet treatment requirements for land application, and can be used as a stand-alone sludge treatment technology for primary sludge that achieves both treatment and dewatering. PMID- 29162375 TI - The sometimes competing retrieval and Van Hamme & Wasserman models predict the selective role of within-compound associations in retrospective revaluation. AB - The correlation between blocking and within-compound memory is stronger when compound training occurs before elemental training (i.e., backward blocking) than when the phases are reversed (i.e., forward blocking; Melchers et al., 2004, 2006). This trial order effect is often interpreted as problematic for performance-focused models that assume a critical role for within-compound associations in both retrospective revaluation and traditional cue competition. The present manuscript revisits this issue using a computational modeling approach. The fit of sometimes competing retrieval (SOCR; Stout & Miller, 2007) was compared to the fit of an acquisition-focused model of retrospective revaluation and cue competition. These simulations reveal that SOCR explains this trial order effect in some situations based on its use of local error reduction. PMID- 29162374 TI - The efficiency and mechanism of N-octyl-O, N-carboxymethyl chitosan-based micelles to enhance the oral absorption of silybin. AB - This study demonstrates the preparation of a silybin-loaded N-octyl-O, N carboxymethyl chitosan micelle (OCC-SLB) to enhance the oral absorption efficiency of silybin (SLB) and investigate the related mechanisms of enhancement. Firstly, the physicochemical properties of OCC and OCC-SLB micelles, including critical micelle concentration (CMC), particle size, zeta potential, drug-loading, etc., were determined. Results of pharmacokinetic studies on rats then confirmed a desirable enhancement in the oral bioavailability of SLB by OCC SLB micelles compared with a stock SLB suspension solution. Subsequently, uptake studies on the Caco-2 cell line demonstrated that OCC-SLB micelles effectively accumulated SLB or rhodamine-123 into cells through clathrin and caveolae mediated endocytosis and the inhibition of P-glycoprotein (P-gp) efflux. In addition, results of the Caco-2 transport study further clarified that OCC-SLB micelles enhanced the permeability of SLB via tight junction opening and clathrin mediated transcytosis across the endothelium. These findings indicated the OCC micelle platform as a potential delivery vehicle for oral administration of P-gp substrates such as SLB. PMID- 29162376 TI - Developmental song learning as a model to understand neural mechanisms that limit and promote the ability to learn. AB - Songbirds famously learn their vocalizations. Some species can learn continuously, others seasonally, and still others just once. The zebra finch (Taeniopygia guttata) learns to sing during a single developmental "Critical Period," a restricted phase during which a specific experience has profound and permanent effects on brain function and behavioral patterns. The zebra finch can therefore provide fundamental insight into features that promote and limit the ability to acquire complex learned behaviors. For example, what properties permit the brain to come "on-line" for learning? How does experience become encoded to prevent future learning? What features define the brain in receptive compared to closed learning states? This piece will focus on epigenomic, genomic, and molecular levels of analysis that operate on the timescales of development and complex behavioral learning. Existing data will be discussed as they relate to Critical Period learning, and strategies for future studies to more directly address these questions will be considered. Birdsong learning is a powerful model for advancing knowledge of the biological intersections of maturation and experience. Lessons from its study not only have implications for understanding developmental song learning, but also broader questions of learning potential and the enduring effects of early life experience on neural systems and behavior. PMID- 29162377 TI - Smartphone-based accelerometry is a valid tool for measuring dynamic changes in knee extension range of motion. AB - INTRODUCTION: Measurement of static joint range of motion is used extensively in orthopaedic and rehabilitative communities to benchmark treatment efficacy. Static measures are, however, insufficient in providing detailed information about patient impairments. Dynamic range of motion measures could provide more detailed information about patient impairments thus leading to better clinical assessments. Reliable and valid methods are available, but due to limitations in the present technology, dynamic measures are seldom performed in clinical settings. The objective of this study was to determine the validity of smartphone based accelerometry measuring the dynamic range of motion of the knee joint during a passively executed extension movement. MATERIALS AND METHODS: Dynamic knee extension range of motion was examined three consecutive times in twenty-one healthy male subjects utilising an isokinetic dynamometer to generate passively the extension motion. Measurements of joint angles in dynamic knee extension were performed using two methods: (i) isokinetic dynamometer (gold-standard method, Biodex System 4 Pro) and (ii) smartphone (iPhone 6, attached to the tibia) accelerometry data. RESULTS: Tests of validity showed excellent correlation (rs=0.899) between methods, with a low standard error of measurement of 0.62deg. and limits of agreement ranging from -9.1 to 8.8deg. Interclass correlation coefficients showed excellent between-measures reliability (ICC>0.862) for both methods. CONCLUSIONS: Smartphone-based accelerometry is a valid tool for measuring the range of motion at the knee joint during dynamic extension movements. This method enables the clinician to carry out simple, low cost, and valid clinical measurements of dynamic knee extension range of motion. PMID- 29162378 TI - Arthroscopic medial meniscal repair with or without concurrent anterior cruciate ligament reconstruction: A subgroup analysis. AB - BACKGROUND: There are few large-scale, long-term studies comparing medial meniscal repairs with or without concurrent anterior cruciate ligament (ACL) reconstruction. METHODS: A total of 140 patients who underwent arthroscopic medial meniscal repair were divided into two groups: Group A, meniscus repair only and Group B, meniscus repair with concurrent ACL reconstruction. Clinical assessments in- cluded physical examination findings, Lysholm score, and the International Knee Documentation Committee (IKDC) form. Barret criteria were used for the clinical assessment of healing status. Magnetic resonance imaging (MRI)was obtained to confirmhealing and failure. Subgroups of participants were compared in terms of suture technique, type of tear, and location of tear. KT 2000 arthrometer testing was used for objective evaluation of anterior-posterior knee movement. RESULTS: Mean follow-up duration was 61 (34-85) months. Clinical outcomes in both groups were significantly improved compared to baseline (P=0.001 vs. P=0.001); however, there was no significant between-group difference in postoperative Lysholm and IKDC scores (P=0.830). The outcomes of three participants (seven percent) in Group A and 11 (11.3%) in Group B were considered as treatment failures (P=0.55). Red-red zone tears had higher scores. Mean postoperative KT2000 arthrometer values of failed participants in Groups A and B were 4.66mm (range, four to six) and 5.2mm (range, two to seven), respectively. CONCLUSION: Concurrentmedialmeniscus repair and ACL reconstruction did not have clinical superiority over meniscus repair alone. Repairs in the red-red zone appeared to be associated with better outcomes. PMID- 29162379 TI - [Epidemiology of urolithiasis in French West Indies: A retrospective study]. AB - INTRODUCTION: The incidence of urolithiasis is increasing with dietary changes especially in developed countries. Guadeloupe is a French department overseas where western diet meets traditional local food. The objective was to describe and analyze the epidemiology of urolithiasis in Guadeloupe. MATERIAL AND METHODS: We conducted a retrospective single-center study throughout the year 2015 on patients hospitalized for urolithiasis at University Hospital of Pointe-a-Pitre. Data of the patients, treatments performed and the types of stones were recorded. According to their mineral content, groups were composed. RESULTS: In total, 165 patients were included. The sex ratio was 1.61. The median body mass index (BMI) was 26.5kg/m2. The most common stone was oxalocalcic (64.7%). Mixed stones (24.7%) were in second place. There were only 3.5% of uric acid urolithiasis. Calcium oxalate stones were predominantly monohydrate. The oxalocalcic stones were significantly more frequent in men (80% versus 47.5%, P=0.01) and in the age group over 50 years old (72.2% versus 51.6%, P=0.04). There was no association between the type of stone and the BMI. CONCLUSION: Epidemiology of urolithiasis in our French Caribbean island is, therefore, similar to continental France. However, our population is distinguished by the proportion of women affected and by the different proportions among each type of stone. Other studies on larger samples are needed to study these specificities. LEVEL OF EVIDENCE: 4. PMID- 29162380 TI - [Results of conservative surgical management of ureteral injuries]. AB - INTRODUCTION: The ureter is a retroperitoneal organ. Ureteral injuries are rare, with a prevalence of 0.083% of surgical interventions over 10 years. The objective of this study was to evaluate the surgical management of ureteric injuries according to the time of discovery, their size and their location. We also evaluated the results of this management on the renal repercussion as well as the predictive factors of the severity of the ureteric injuries. MATERIAL AND METHODS: This was a monocentric retrospective study carried out on the basis of a systematic review of the CHU surgery files. RESULTS: The average follow-up was 30 months. The average hospital stay was 8 days. Thirty-four patients (73.9%) underwent initial endoscopic management by attempting a double J probe. Only 20 patients received this double J probe and only 11 patients (55%) did not recidivate the ureteral injury with a median duration of maintenance of the double J probe of 90 days (28-240). Thirty-five patients received open surgical management (76.1%). We found 57% ureterovesical reimplantations (n=20), corresponding to pelvic ureteral injuries (n=32). We also found 20% of nephrectomies. No patient had recurrence of the ureteral injury. Eight patients had secondary dilatation of the pyelocalicious cavities (28.57%). The success of surgical treatment was therefore 57%. CONCLUSION: The management of surgically treated ureter injuries provides good results but remains relatively diversified due to the different lesion levels. It was effective in 57% of cases including nephrectomies as failure of treatment. LEVEL OF EVIDENCE: 4. PMID- 29162382 TI - [Patients cultural diversity role in clinical practice guidelines]. PMID- 29162381 TI - Strategies adopted by younger and older adults while operating a non-pedal tricycle. AB - BACKGROUND: Exercises that could prevent gait impairment of older adults should be implemented in such a way that practitioners can keep motivation and adherence independent of older adults fitness levels. OBJECTIVE: This study describes how younger and older adults use a non-pedal tricycle to transport their bodies along a pathway. METHODS: Nine younger (24+/-4.9y) and nine older (66+/-4.0y) adults participated in this study. They moved along a straight pathway at a self selected comfortable speed with reflective markers on their main lower limb landmarks. A computerized gait analysis system with infrared cameras was used to obtain kinematic data to calculate spatial-temporal parameters and lower limb angles. RESULTS: Overall, participants from both groups were able to perform the task moving at a similar mean speed, with similar stride length and ankle joint excursion. Older adults had higher cadence (mean difference of 17steps/min; 95% CI=0.99-1.15) and hip excursion (mean difference of 12 degrees ; 95% CI=28-33), longer stance duration (mean difference of 3.4%; 95% CI=56.2-59.5), and lower knee excursion (mean difference of 6 degrees ; 95% CI=47.9-53.8) than younger adults. CONCLUSION: Older adults were able to transport their body with a non pedal tricycle with more hip and less knee excursion than younger adults. Professionals that work with the older population should look at and take into consideration the use of non-pedal tricycles in exercise protocols and investigate the long-term impacts. PMID- 29162383 TI - Inhibition of AMPAR endocytosis alleviates pentobarbital-induced spatial memory deficits and synaptic depression. AB - Our previous study has shown that pentobarbital causes memory deficits and impairs hippocampal synaptic plasticity. The Tat-GluA23Y peptide (GluA23Y) prevents activity-dependent alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) endocytosis. It enables early-phase long-term potentiation (LTP) to proceed to late-phase LTP allowing short-term memory to convert to long term memory. The purpose of this study is to explore the potential effects of GluA23Y on pentobarbital-induced memory deficits through behavioral and electrophysiological paradigms. We found that in vivo intrahippocampal infusion of GluA23Y (100MUM, 1MUl per hippocampus) 30min prior to pentobarbital administration (8mM, 1MUl per hippocampus) significantly rescued the pentobarbital-induced deficit of memory retrieval in rats during the Morris water maze test. Pre-incubation of GluA23Y (10MUM) partially rescued bath application of pentobarbital-induced synaptic transmission of the CA3-CA1 pathway in hippocampal slices. More importantly, GluA23Y selectively upregulated the synaptic GluA2 expression that was suppressed by pentobarbital. Together, these results suggest that inhibition of GluA2-containing AMPAR endocytosis by GluA23Y increases the pentobarbital-suppressed basal synaptic transmission by upregulating the synaptic GluA2, and then subsequently alleviates spatial memory deficits. Therefore, inhibition of AMPAR endocytosis may be a potential therapeutic way to treat memory disorders caused by anesthetics. PMID- 29162384 TI - Relevance-dependent modulation of tactile suppression during active, passive and pantomime reach-to-grasp movements. AB - When we move, our ability to detect tactile events on the moving limb is reduced (e.g., movement-related tactile suppression). This process prevents unimportant sensory information from bombarding our central nervous system. This study investigated whether movement-related suppression can be modulated according to task relevance, while introducing a novel motor-driven complex upper limb movement. In three experiments, participants performed volitional self-driven and passive motor-driven reaching and grasping movements. Over the course of the movement, weak electrical stimulation was presented at task-relevant (i.e., index finger) and irrelevant sites (i.e., forearm) on the moving limb. In Experiment 1, participants displayed reduced detectability during movement (90% resting detection). This was true for all locations on the moving limb irrespective of task-relevance and during both self and motor-driven movements. In Experiments 2 and 3 a range of stimulus amplitudes were presented to one task-relevant location during both self and motor-driven movements (Experiment 2A), to a task-relevant and irrelevant site (Experiment 2B) and during a targeted and pantomime/no target reach (Experiment 3). This allowed us to estimate perceptual thresholds and assess the magnitude of movement-related suppression. During both self and motor driven movements participants exhibited movement-related suppression. Suppression was greater at the irrelevant site (forearm) than at the relevant site (index finger) of the limb. Further, the magnitude of suppression varied with task relevance such that pantomime movements elicited more suppression than targeted movements. Collectively, these experiments suggest that although tactile suppression may be a general consequence of movement, suppression can be modulated in a relevance-dependent manner. PMID- 29162385 TI - New method of detecting hydrophobic interaction between C-terminal binding domain and biomacromolecules. AB - The C-terminal domains of proteases play crucial roles in hydrolysis, substrate adsorption and targeted binding. Identifying and characterizing interactions between C-terminal domains and biomacromolecules can help to examine the diversity as well as the substrate-binding ability of C-terminal domains and to explore novel functions. The bacterial pre-peptidase C-terminal (PPC) domain is a typical C-terminal domain normally found at the C-terminus of bacterial secreted proteases. In this work, we successfully demonstrated that 8-anilinonaphthalene-1 sulfonic acid (ANS) could be used to rapidly determine the interactions between this C-terminal domain and biomacromolecules. The time-resolved ANS fluorescence of PPC and collagen interaction could be used for quantitative analysis of the collagen-binding capability based on the slope of the time-scanning curve. Using this method, we found that PPC domains had an obvious affinity to fibrillar proteins but had little or no capacity to bind polysaccharides or linear DNAs. Docking studies proved that collagen bound to the same hydrophobic site of PPC as the ANS probe, causing a decrease in the emission intensity. This method is simple and cost effective and provides an effective detection technique to analyze the interaction between this C-terminal domain and biomolecules. PMID- 29162386 TI - The scientific dry eye disease journey: From the beginning to the end of the beginning. PMID- 29162387 TI - Detecting the needs of working women with fibromyalgia from a primary care perspective. PMID- 29162388 TI - Quality of clinical practice guidelines of lower extremity venous ulcers. AB - The clinical variability and professional uncertainty in the prevention and treatment of lower extremity venous ulcers (VU) has as a main consequence, the fact that patients can be subjected to diagnostic and therapeutic tests, sometimes of dubious utility, these may even be harmful to the health of the patient and that, at other times, certain procedures or processes that may be appropriate to the patient's situation and needs may be omitted. It is for this reason that a series of specific documents called clinical practice guidelines for the approach of VU (CPG-VU) have been created, with the aim of improving the effectiveness and quality of care, reducing unjustified variability and establishing homogeneous criteria for its handling. Nevertheless, the literature shows that not all CPGs have the same methodological and evidence-drawing criteria. Many of them are of poor scientific quality and editorial rigor. This implies that CPGs should be periodically reviewed and updated based on the most current evidence and their quality contrasted with validated instruments such as AGREE-II. After an analysis of the quality of six CPG-VU available today, it has been possible to identify what guidelines are recommended for its implementation in the practice of care, which should be modified to improve their applicability and development of the evidence. PMID- 29162389 TI - Is cryptogenic cirrhosis different from NASH cirrhosis? AB - BACKGROUND & AIMS: We hypothesized that patients currently diagnosed with cryptogenic cirrhosis (CC) have truly 'cryptogenic' liver disease, which is unlikely to have evolved from NASH. The aim of this study is to characterize patients with CC, and compare their characteristics to patients with cirrhosis of other etiologies. METHODS: To investigate this, we compared the clinical characteristics of adults with CC (n = 7,999) to those with cirrhosis caused by non-alcoholic steatohepatitis (NASH) (n = 11,302), alcohol (n = 21,714) and autoimmune hepatitis (n = 3,447), using the UNOS database from 2002-16. We performed an age, gender and year of listing matched comparison of CC and NASH (n = 7,201 in each group), and also stratified patients by the presence of obesity or diabetes mellitus (DM). RESULTS: From 2002 to 2016, patients listed with a diagnosis of NASH increased from about 1% to 16% while CC decreased from 8% to 4%. A logistic regression model using the entire United Network for Organ Sharing data (n = 138,021) suggested that the strongest predictors of NASH were type 2 DM, obesity, age >=60 years, female gender and white race. Type 2 DM was more common in patients with NASH (53%) than those with CC (29%), alcoholic cirrhosis (16%) and autoimmune hepatitis (16%), and obesity was more common in NASH (65.3%) compared to the other three groups (33-42%). There were more white individuals (82.3%) in the NASH group and a lower prevalence of black, Hispanic and Asian individuals, compared to the other three groups. Hepatocellular carcinoma was more commonly seen in NASH (19% vs. 9-13% in the other groups) and this is not influenced by obesity and type 2 DM. The differences between CC and NASH remained unchanged even when two groups were matched for age, gender and year of listing, or when stratified by the presence or absence of obesity or type 2DM. CONCLUSIONS: Based on risk perspectives, CC should not be equated with the term 'NASH cirrhosis'. LAY SUMMARY: We hypothesized that cryptogenic cirrhosis is a distinct condition from cirrhosis caused by non-alcoholic steatohepatitis (NASH). By comparing cryptogenic cirrhosis with cirrhosis of other causes, we found clear clinical differences. Therefore, cryptogenic cirrhosis should not be considered the same as NASH cirrhosis. Further investigations are required to identify unknown causes of cirrhosis. PMID- 29162391 TI - Impact of HIV-1 Envelope Conformation on ADCC Responses. AB - HIV-1 envelope glycoproteins (Env) represent the only virus-specific antigen exposed at the surface of infected cells. In its unliganded form, Env from primary viruses samples a 'closed' conformation (State 1), which is preferentially recognized by broadly neutralizing antibodies (bNAbs). CD4 engagement drives Env into an intermediate 'partially open' (State 2) and then into the 'open' CD4-bound conformation (State 3). Emerging evidence suggests a link between Env conformation and Ab-dependent cellular cytotoxicity (ADCC). HIV 1-infected cells exposing Env in the CD4-bound conformation are susceptible to ADCC mediated by CD4-induced Abs and HIV+sera. Cells exposing State 1 Env are susceptible to ADCC mediated by bNAbs. Here, we discuss how Env conformation affects ADCC responses and in vitro measurements. PMID- 29162392 TI - Hematological phenotypes in children according to the alpha-globin genotypes. AB - Limited information is available on the hematological characterization of the alpha-thalassemia carrier in pediatric age. The objective of this report was to evaluate the red cell indices according to the alpha-globin genotype in a cohort of children evaluated in Sardinia. Moreover, we verified the frequency of different alpha-globin genotypes in this cohort. A total of 453 subjects were investigated for hematological indices and for the most common alpha-globin defects present in Sardinia. Of them, 352 with HbA2<=3.2%, and no iron deficiency anemia were taken into consideration to evaluate the red cell indices according to the alpha-globin genotype in pediatric age. A total of 11 different alpha genotypes were detected, confirming the wide heterogeneity of alpha-thalassemia in Sardinia. Moreover, our results showed that the hematological parameters in normal children may be conditioned by the clinically occult coinheritance of mild alpha-thalassemia alleles as already described in the adult population while microcytosis and hypocromia in children without iron deficiency should suggest the coexistence of two alpha-globin defects. We concluded that recognizing the alpha-globin gene mutations for a particular population with their particular red cell indices may help pediatricians to perform a correct diagnosis distinguishing among physiological and pathological types of microcytosis and hypocromia. PMID- 29162390 TI - Opposing Functions of Heparanase-1 and Heparanase-2 in Cancer Progression. AB - Heparanase, the sole heparan sulfate (HS)-degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, metastasis, angiogenesis, and inflammation. Heparanase accomplishes this by degrading HS and thereby regulating the bioavailability of heparin-binding proteins; priming the tumor microenvironment; mediating tumor-host crosstalk; and inducing gene transcription, signaling pathways, exosome formation, and autophagy that together promote tumor cell performance and chemoresistance. By contrast, heparanase-2, a close homolog of heparanase, lacks enzymatic activity, inhibits heparanase activity, and regulates selected genes that promote normal differentiation, endoplasmic reticulum stress, tumor fibrosis, and apoptosis, together resulting in tumor suppression. The emerging premise is that heparanase is a master regulator of the aggressive phenotype of cancer, while heparanase-2 functions as a tumor suppressor. PMID- 29162393 TI - PCR-based discrimination of emerging Streptococcus pneumoniae serotypes 22F and 33F. AB - Serotyping of Streptococcus pneumoniae is important to monitor disease epidemiology and assess the impact of pneumococcal vaccines. Traditionally, the Quellung reaction used serotype-specific antibodies to classify S. pneumoniae based on differences in capsular antigens. More recently, PCR-based serotype deduction relying on serotype-specific capsule biosynthesis genes has been broadly applied for pneumococcal surveillance. However, PCR-based serotyping lacks discrimination for certain S. pneumoniae serotypes, including the differentiation of serotype 22F from 22A, and serotype 33F from 33A and 37. Serotypes 22F and 33F are emerging serotypes that are absent in the currently licensed 13-valent pneumococcal conjugate vaccine, but present in the new candidate 15-valent formulation. This study validated novel PCR reactions to detect and discriminate S. pneumoniae serotypes 22F and 33F. In order to differentiate S. pneumoniae serotypes 22F or 33F from genetically similar serotypes, two novel PCR reactions were designed and validated. The specificity of all PCR targets was evaluated using all 92 different S. pneumoniae serotypes, as well as 32 other streptococci. Reproducibility was evaluated using geographically and genetically diverse strains of S. pneumoniae serotypes 22F and 22A, or serotypes 33F, 33A, and 37 that were previously characterized by reputable reference laboratories. Overall, S. pneumoniae serotypes 22F and 33F could be accurately and reproducibly be detected and discriminated using PCR alone. Such a molecular serotyping approach provides a valuable diagnostic tool that is feasible in any molecular laboratory, to enable pneumococcal serotype surveillance and subsequent assessment of the impact of the new 15-valent candidate pneumococcal vaccine. PMID- 29162394 TI - What is the role of apheresis technology in stem cell transplantation? AB - Since the demonstration that hematopoietic cells are present in circulating blood, peripheral blood stem cell transplantation (PBSCT) has become an area of interest. The invention of growth factors such as the granulocyte colony stimulating factor (G-CSF) and the availability of apheresis techniques allowed the wide application of peripheral blood stem cells (PBSC) in both autologous and allogeneic hematopoietic stem cell transplantation settings. It has been since 1986 that clinically introduced, peripheral blood stem cells replaced bone marrow as a stem-cell source to nearly 100% in the autologous and to approximately 75% in the allogeneic transplantation setting. During this period of time, remarkable development occurred in both stem cell mobilizing agents (i.e. CXCR4 antagonists) and apheresis techniques. Currently, apheresis technology is being increasingly used in not only for collection of PBSC or blood product support, but also for treatment and/or prevention of several transplantations related complications. Apheresis technology also allows to manipulate stem cells and thus provides opportunity to curative treatment of certain diseases. PMID- 29162395 TI - Automated red blood cell depletion in ABO incompatible grafts in the pediatric setting. AB - Bone marrow ABO incompatible transplantations require graft manipulation prior to infusion to avoid potentially lethal side effects. We analyzed the influence of pre-manipulation factors (temperature at arrival, transit time, time of storage at 4 degrees C until processing and total time from collection to red blood cell depletion) on the graft quality of 21 red blood cell depletion procedures in ABO incompatible pediatric transplants. Bone marrow collections were processed using the Spectra Optia(r) (Terumo BCT) automated device. Temperature at arrival ranged between 4 degrees C and 6 degrees C, median transit time was 9.75h (range 0.33 28), median time of storage at 4 degrees -6 degrees C until processing was 1.8h (range 0.41-18.41) and median time from collection to RBC depletion was 21h (range1-39.4). Median percentage of red blood cell depletion was 97.7 (range 95.4 98.5), median mononuclear cells recovery was 92.2% (range 40-121.2), median CD34+ cell recovery was 93% (range 69.9-161.2), median cell viability was 97.7% (range 94-99.3) and median volume reduction was 83.9% (range 82-92). Graft quality was not significantly different between BM units median age. Our preliminary data show that when all good manifacturing practices are respected the post manipulation graft quality is excellent also for those units processed after 24h. PMID- 29162396 TI - Factors associated with peripheral blood stem cell yield in healthy pediatric donors. AB - BACKGROUND AND OBJECTIVES: Although several studies have reported on the use of children as donors for peripheral blood stem cells (PBSC), data on the predictive factors of CD34+ stem cell yield in healthy pediatric donors are very limited. DESIGN AND METHOD: We retrospectively analyzed factors predicting the yield for a target CD34 cell dose of >3*106/kg recipient body weight in 140 apheresis in 100 healthy pediatric donors. The donors were evaluated in four groups assigned according to their ages of being 0-4 years, 5-9 years, 10-14 years and 15-18 years. 38 donors underwent second apheresis, two of which required third apheresis. RESULTS: Median age and body weight were 9.8 years (range: 2-18 years) and 35.8kg (range 11-84kg), respectively. The median number of CD34+ cells in first apheresis was 3.9*106/kg of recipient body weight (RBW) (range: 0.03 33*106/kg RBW). Sixty-two out of 100 donors (62%) needed only one apheresis. The CD34+ cell count in stem cell product and the amount of CD34+ cell yield considering donors' body weight obtained from the first apheresis was not statistically different among defined age groups. On multivariate analysis, variables that had a significant impact on CD34+ cell collection being more than 3*106kg RBW were donor to recipient weight ratio and periperal CD34+ cell count. CONCLUSION: Our data suggest that CD34+ stem cell yield can be predicted from circulating CD34+ cell concentration on apheresis day and donor to recipient weight ratio in healthy pediatric donors. PMID- 29162398 TI - Hematopoietic progenitor cell mobilization. PMID- 29162397 TI - Biosimilar filgrastim (leucostim(r)) have similar efficacy in steady-state hematopoietic progenitor cell mobilization compared to original filgrastim (neupogen(r)) and lenograstim (granocyte(r)): A retrospective multicenter study. AB - Biosimilar filgrastim (Leucostim(r)) was shown to be similar in terms of efficacy and safety in hematopoietic progenitor cell mobilization (HPCM) compared to originator filgrastim (Neupogen(r)) and lenograstim (Granocyte(r)) in healthy donors and chemomobilization settings. Here we report our retrospective experience with Leucostim(r) (n: 43) compared to Neupogen(r) (n: 71) and Granocyte(r) (n: 32) in steady-state mobilization of patients presenting with Hodgkin lymphoma, non-Hodgkin lymphoma and multiple myeloma. The median age of patients on Leucostim(r) (56) arm was significantly higher compared to patients who received Neupogen(r) (50) and Granocyte(r) (49) (p: 0.039). Patients who underwent HPCM with Leucostim(r) received less chemotherapy lines (p: 0.026) and courses (p: 0.046) compared to others. Otherwise the study cohort was homogenous in terms of gender, primary diagnosis and various risk factors for mobilization failure. Mobilization failure was defined as failure to achieve a minimum threshold (10/MUL) for peripheral blood CD34+ cell concentration to initiate leukapheresis or 0.5*106/kg, 0.8*106/kg and 2*106/kg CD34+ cells in first, second and fourth days of apheresis, respectively. The study groups were similar in terms of median number of CD34+ progenitor cell yield (*106/kg) (Neupogen(r): 6.18, Granocyte(r): 6.2 and Leucostim(r): 6.2) (p: 0.959) and median number of leukapheresis sessions (p: 0.615). The treatment arms were also similar in terms of mobilization failure (Neupogen(r) 11.3% - Granocyte(r) 21.9% - Leucostim(r) 16.3%; p: 0.366). No patient experienced any severe adverse effect during HPCM. Leucostim(r) is equally effective and safe in HPCM compared to originator G-CSF (Neupogen(r)) and lenograstim (Granocyte(r)) in steady-state HPCM setting. PMID- 29162399 TI - Laboratory assessment of Activated Protein C Resistance/Factor V-Leiden and performance characteristics of a new quantitative assay. AB - Activated Protein C Resistance is mainly associated to a factor V mutation (RQ506), which induces a deficient inactivation of activated factor V by activated protein C, and is associated to an increased risk of venous and arterial thrombosis in affected individuals, caused by the prolonged activated factor V survival. Its prevalence is mainly in Caucasians (about 5%), and this mutation is absent in Africans and Asians. Presence of Factor V-Leiden is usually evidenced with clotting methods, using a two-step APTT assay performed without or with APC: prolongation of blood coagulation time is decreased if this factor is present. The R506Q Factor V-Leiden mutation is now usually characterized using molecular biology, and this technique tends to become the first intention assay for characterization of patients. Both techniques are qualitative, and allow classifying tested individuals as heterozygotes or homozygotes for the mutation, when present. A new quantitative assay for Factor V-Leiden, using a one-step clotting method, has been developed, and designed with highly purified human coagulation proteins. Clotting is triggered with human Factor Xa, in presence of calcium and phospholipids (mixture which favours APC action over clotting process). Diluted tested plasma, is supplemented with a clotting mixture containing human fibrinogen, prothrombin, and protein S at a constant concentration. APC is added, and clotting is initiated with calcium. Calibration is performed with a pool of plasmas from patients carrying the R506Q Factor V mutation, and its mixtures with normal plasma. Homozygous patients have clotting times of about <40sec; heterozygous patients have clotting times of about 40 60sec and normal individuals yield clotting times >70sec. Factor V-Leiden concentration is usually >75% in homozygous patients, 30-60% in heterozygous patients and below 5% in normal. The assay is insensitive to clotting factor deficiencies (II, VII, VIII: C, IX, X), dicoumarol or heparin therapies, and has no interference with lupus anticoagulant (LA). This new assay for Factor V-Leiden can be easily used in any coagulation laboratory, is performed as a single test, and is quantitative. This assay has a high robustness, is accurate and presents a good intra- (<3%) and inter-assay (<5%) variability. It contributes solving most of the laboratory issues faced when testing factor V-Leiden. Quantitation of Factor V-L could contribute to a better assessment of thrombotic risk in affected patients, as this complication is first associated to and caused by the presence of a defined amount of FVa. PMID- 29162400 TI - An alternative method for custom prime: A case report of successful peripheral blood stem cell harvesting from two low-weight child donors. AB - Allogeneic peripheral blood stem cell (APBSCs) transplantation is an effective treatment for hematological malignancies. However low-weight donor children meet some complications. In the current report, PBSCs were harvested from a 14-month old child (9.8Kg) for a 6years old sibling recipient suffering from pre-B type of acute lymphoblastic leukemia (ALL) and also 24 months old male child donor (12Kg) for a haploidentical recipient suffering from acute myeloid leukemia (AML-M4EO). The PBSC harvesting was performed using SpectraTM Optia(r) apheresis software with continuous mononuclear cell (CMNC) procedure. The results were completely promising and both recipients underwent an acceptable transplantation. PMID- 29162401 TI - Risk factors for poor mobilization in solid tumors: How effectively can we mobilize patients with solid tumors? AB - BACKGROUND: In the literature, risk factors for poor mobilization were tried to identify. However, most of the studies consisted heterogeneous group of patients including both hematologic and oncologic malignancies. In this study, we aimed to identify the risk factors for poor mobilization in adults with solid tumors. METHODS: We enrolled 49(47 men, 2 women) adult patients with solid tumor who were mobilized between September 2007 and February 2017. All the mobilization procedures were performed with G-CSF(10MUg/kg/day) with chemotherapy. Mobilization insufficiency was defined as peripheral blood CD34+stem cell number less than 10/MUl and/or total collected CD34+cells less than 2.5*10 6/kg. RESULTS: The patients were divided into two groups, patients with successful mobilization at the first attempt(group 1, 36 patients,73.5%) and poor mobilizers (group 2, 13 patients 26.5%). Second and third mobilization attempt was needed in 11 and 2 patients, respectively. The median number of CD34+cells collected was 7,08*106/kg(0,6-19) with a median 4(1-6) apheresis. There was no statistical difference between two groups in terms of patient's and mobilization characteristics. Only number of CD 34+stem cells collected was statistically different (median 9,07*106/kg CD34+cells in group 1 versus 2,14*106/kg in group 2, p<0.05). The only possible risk factor that we could define was presence of organ metastasis. CONCLUSIONS: Since several methods and new drugs are available for peripheral stem cell collecting, risk factors should be identified clearly in adult population with solid tumors. So multicenter studies should be constructed for resolving this problem. PMID- 29162402 TI - Peripheral blood stem cell collection for allogeneic hematopoietic stem cell transplantation: Practical implications after 200 consequent transplants. AB - BACKGROUND: Proper stem cell mobilization is one of the most important steps in hematopoietic stem cell transplantation (HSCT). The aim of this paper is to share our 6 years' experience and provide practical clinical approaches particularly for stem cell mobilization and collection within the series of more than 200 successive allogeneic HSCT at our transplant center. SUBJECTS & METHODS: Two hundred and seven consecutive patients who underwent allogeneic peripheral blood stem cell transplantation were included in this study. Age, sex, weight, complete blood counts, CD34+ cell counts, total collected amount of CD34+ cells, CD34+ cells per 10l processed, mobilization failure and adverse events were reviewed. RESULTS: Median age was 40.2+/-12.9 (21-68) years and 46.4+/-13.4 (17-67) years for donors and patients, respectively. The number of donors who had undergone adequate CD34+ cell harvesting and completed the procedure on the fourth day was 67 (32.8% of all patients). Only 12 patients required cell apheresis both on day 5 and 6. Apheresis was completed on day 4 and/or day 5 in 94.2% of all our donors. There was no significant association between CD34+ stem cell volume and age, gender and weight values of donors. Mobilization failure was not seen in our series. CONCLUSIONS: G-CSF is highly effective in 1/3 of the donors on the 4th day in order to collect enough number of stem cells. We propose that peripheral stem cell collection might start on day 4th of G-CSF treatment for avoiding G-CSF related side effects and complications. PMID- 29162403 TI - Cope's sign and complete heart block in a 78-year-old patient with biliary colic. AB - INTRODUCTION: Acute cholecystitis and biliary colic may have signs and symptoms similar to those of Acute Coronary Syndrome(ACS) along with ischemic ECG changes. Cholecystitis and/or biliary colic have been both reported as trigger factors for bradyarrhythmia in the literature. CASE REPORT: A 78-year-old male patient was admitted to our Emergency Department (ED) due to acute abdominal pain. The ECG on admission showed sinus bradycardia with a rate of 40 beats per minute (bpm) without signs of acute ischemia and a brief period (7 s) of complete atrioventricular (AV) block. He was initially treated with analgesics. After the remission of the pain, a subsequent ECG was performed which showed sinus bradycardia of 55 bpm. The AV block terminated one hour after the patient's admission. The patient remained hemodynamically stable during the episode. He underwent an ultrasound of the abdomen in the ED which revealed sludge and one stone in the gallbladder without signs of inflammation. Laboratory test results for D-dimer and troponin were negative, while the coronary angiography showed coronary vessels without significant lesions. CONCLUSION: Biliary colic can cause severe reversible reflex bradycardia (Cope's Sign), even complete heart block. Pain relief is very important in the management of such cases. PMID- 29162404 TI - Neglected Tropical Diseases, Neglected Communities, and Conflict: How Do We Leave No One Behind? AB - Most well established neglected tropical disease (NTD) programs have seen great progress towards disease control or elimination. Areas in conflict, however, are a looming challenge to reaching control and elimination targets. To be successful, programs and partners need to creatively adapt to local circumstances and embrace new colleagues not traditionally seen as NTD implementers. PMID- 29162405 TI - Identification of target risk groups for population-based Clostridium difficile infection prevention strategies using a population attributable risk approach. AB - OBJECTIVES: We aimed to determine risk factors associated with Clostridium difficile infection (CDI) and assess the contributions of these factors on CDI burden. METHODS: We conducted a 1:4 matched case-control study using a national claims dataset. Cases were incident CDI without a history of CDI in the previous 84 days, and were age- and sex-matched with control patients. We ascertained exposure, defined as a history of morbidities and drug use within 90 days. The population attributable risk (PAR) percent for risk factors was estimated using odds ratios (ORs) obtained from the case-control study. RESULTS: Overall, the strongest CDI-associated risk factors, which have significant contributions to the CDI burden as well, were the experience of gastroenteritis (OR=5.08, PAR%=17.09%) and use of antibiotics (OR=1.69, PAR%=19.00%), followed by the experiences of female pelvic infection, irritable bowel syndrome, inflammatory bowel disease, and pneumonia, and use of proton-pump inhibitors (OR=1.52-2.37, PAR%=1.95-2.90). CONCLUSIONS: The control of risk factors that had strong association with CDI and affected large proportions of total CDI cases would be beneficial for CDI prevention. We suggest performing CDI testing for symptomatic patients with gastroenteritis and implementing antibiotics stewardship. PMID- 29162407 TI - A predictive model to distinguish malignant and benign thyroid nodules based on age, gender and ultrasonographic features. AB - INTRODUCTION: A discussion in literature about a standardized decision support tool for the management of thyroid nodules remains. OBJECTIVE: The purpose of this study was to create a statistical prediction model for thyroid nodules management. METHODS: Two hundred and four benign and 57 malignant thyroid nodules were selected for a retrospective study. The variables age, gender and ultrasonographic features were examined using univariate and multivariate models. A statistical formula was used to calculate the risk of cancer of each case. RESULTS: In multivariate analysis, irregular shape, absence of halo, lower mean age, homogeneous echotexture, microcalcifications and solid content were associated with cancer. After applying the formula, 20 cases (7.6%) with a calculated risk for malignancy <=3.0% were found, all of them benign. Setting the calculated risk in >=80%, 21 (8.0%) cases were selected, and in 85.7% of them cancer was confirmed in histopathology. Internal accuracy of the prediction formula was 92.5%. CONCLUSIONS: The prediction formula reached high accuracy and may be an alternative to other decision support tools for thyroid nodule management. PMID- 29162406 TI - Novel anti-suprabasin antibodies may contribute to the pathogenesis of neuropsychiatric systemic lupus erythematosus. AB - Neuropsychiatric systemic lupus erythematosus (NPSLE) is often difficult to diagnose and distinguish from other diseases, because no NPSLE-specific antibodies have been identified. We developed a novel proteomic strategy for identifying and profiling antigens in immune complexes in the cerebrospinal fluid (CSF), and applied this strategy to 26 NPSLE patients. As controls, we also included 25 SLE patients without neuropsychiatric manifestations (SLE), 15 with relapsing remitting multiple sclerosis (MS) and 10 with normal pressure hydrocephalus (NPH). We identified immune complexes of suprabasin (SBSN) in the CSF of the NPSLE group. The titer of anti-SBSN antibodies was significantly higher in the CSF of the NPSLE group compared to those of the SLE, MS and NPH groups. Microarray data showed that the senescence and autophagy pathways were significantly changed in astrocytes exposed to anti-SBSN antibodies. Our findings indicate that SBSN could be a novel autoantibody for the evaluation of suspected NPSLE. PMID- 29162408 TI - Downregulation of Notch4 - a prognostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma. AB - INTRODUCTION: Oral verrucous carcinoma is a special form of well-differentiated squamous cell carcinoma which possesses specific clinical, morphologic and cytokinetic features that differ from other types of oral cancers and hence diagnosis requires immense experience in histopathology. Hence it is certainly important to distinguish such a lesion from other oral tumors as treatment strategies vary widely between them. OBJECTIVE: In search of a critical diagnostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma, Notch4 receptor, one of the key regulatory molecules of the Notch signaling family has been aberrantly activated in the progression of several types of tumors. However its function in oral verrucous carcinoma remains unexplored. Thus the present study aims in determining the differential expression pattern of Notch4 in oral verrucous carcinoma and oral squamous cell carcinoma. METHODS: Ten patients reported positive for oral cancer (5 patients with oral verrucous carcinoma and 5 patients with oral squamous cell carcinoma). Five normal tissue samples were also obtained and evaluated for clinicopathological parameters and immunohistochemistry, western blotting and real time polymerase chain reaction for Notch4 expression. RESULTS: Our results reveal that the expression of Notch4 was considerably high in oral squamous cell carcinoma lesions compared to normal tissue, whereas in oral verrucous carcinoma, irrespective of the clinicopathological features, complete regulacao descendente of Notch4 was observed. CONCLUSIONS: These preliminary findings strongly support the fact that Notch4 is downregulated in oral verrucous carcinoma and could be considered as a suitable prognostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma. This distinguishing marker can help in improving therapeutic options in patients diagnosed with oral verrucous carcinoma. PMID- 29162409 TI - High level expression and characterization of tannase tan7 using Aspergillus niger SH-2 with low-background endogenous secretory proteins as the host. AB - Tannin acyl hydrolase (tannase, EC3.1.1.20) catalyzes the hydrolysis of hydrolyzable tannins. It is used in the manufacture of instant tea and in the production of gallic acid. In this study, we reported that the overexpression, purification and characterization of an Aspergillus niger tannase. The tannase gene was cloned from A. niger SH-2 and expressed in the A. niger strain Bdel4 which is low-background of secreted proteins. The recombinant tannase was purified by desalting, followed by gel filtration for characterization. The tannase activity achieved 111.5 U/mL at 168 h, and the purity of the enzyme in the broth supernatant was estimated to be over 70%. The optimum temperature and pH of the recombinant tannase was ~40 degrees C and 7.0, respectively. The tannase activity was inhibited by Mg2+, Ca2+, Cu2+, Ba2+, Ni2+ and EDTA, and was enhanced by Mn2+ and Co2+. Since A. niger is a GRAS microorganism, the recombinant tannase could be purification-free due to its high purity. The results of this study suggested that this recombinant strain could be subjected to large-scale production of A. niger tannase. PMID- 29162410 TI - Diagnostic performance of contrast-enhanced ultrasound for pancreatic neoplasms: A systematic review and meta-analysis. AB - BACKGROUND: Early diagnosis of pancreatic cancer is essential to optimize treatment strategies. OBJECTIVES: To evaluate the diagnostic performance of contrast-enhanced ultrasound for benign and malignant pancreatic neoplasms. DATA SOURCES: Pubmed, Embase, Web of Science, and Cochrane Library databases. STUDY ELIGIBILITY CRITERIA: Retrospective or prospective studies. PARTICIPANTS: Patients with a confirmed diagnosis of benign and malignant pancreatic neoplasms. INTERVENTION: Contrast-enhanced ultrasound. STUDY APPRAISAL AND SYNTHESIS: Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic risk ratio, and corresponding 95% confidence intervals; summary receiver operating characteristic (SROC) curve; a Fagan nomogram. RESULTS: Ten studies involving 641 patients were included. Pooled sensitivity, specificity, and positive and negative predictive values were 91% (95% CI: 87%, 93%), 87% (95% CI: 78%, 93%), 7.2 (95% CI: 4.3, 12.3), and 0.11 (95% CI: 0.08, 0.15), respectively; and the odds ratio for diagnosis was 67 (95% CI: 34, 113). Contrast enhanced ultrasound had good diagnostic ability and accuracy. Pre- and post-test probability of disease was 50% and 88%, respectively, when the positive likelihood ratio was 7. CONCLUSION: Contrast-enhanced ultrasound can be used for qualitative diagnosis of benign and malignant pancreatic neoplasms. IMPLICATIONS OF KEY FINDINGS: CEUS should be considered as an important imaging tool for the characterization of pancreatic tumors. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42017070434 (PROSPERO). PMID- 29162411 TI - An unusual primary omental tumor: Mixed germ cell tumor. PMID- 29162412 TI - The discovery of the "Etruscan intestine". PMID- 29162413 TI - [Frontoethmoidal encephalocele detected after meningitis caused by two microorganisms]. PMID- 29162414 TI - [Insertion of a central venous reservoir using an exclusively ultrasound guided technique: Preliminary experience]. PMID- 29162415 TI - Novel mutations in the cartilage oligomeric matrix protein gene identified in two Taiwanese patients with pseudoachondroplasia and multiple epiphyseal dysplasia. PMID- 29162416 TI - Crosstalk Complexities between Auxin, Cytokinin, and Ethylene in Arabidopsis Root Development: From Experiments to Systems Modeling, and Back Again. AB - Understanding how hormones and genes interact to coordinate plant growth in a changing environment is a major challenge in plant developmental biology. Auxin, cytokinin, and ethylene are three important hormones that regulate many aspects of plant development. This review critically evaluates the crosstalk between the three hormones in Arabidopsis root development. We integrate a variety of experimental data into a crosstalk network, which reveals multiple layers of complexity in auxin, cytokinin, and ethylene crosstalk. In particular, data integration reveals an additional, largely overlooked link between the ethylene and cytokinin pathways, which acts through a phosphorelay mechanism. This proposed link addresses outstanding questions on whether ethylene application promotes or inhibits receptor kinase activity of the ethylene receptors. Elucidating the complexity in auxin, cytokinin, and ethylene crosstalk requires a combined experimental and systems modeling approach. We evaluate important modeling efforts for establishing how crosstalk between auxin, cytokinin, and ethylene regulates patterning in root development. We discuss how a novel methodology that iteratively combines experiments with systems modeling analysis is essential for elucidating the complexity in crosstalk of auxin, cytokinin, and ethylene in root development. Finally, we discuss the future challenges from a combined experimental and modeling perspective. PMID- 29162417 TI - A rare complication associated with the endotracheal tube during extubation in a cat. PMID- 29162419 TI - Leveraging Twitter to Maximize the Radiology Meeting Experience. AB - Over recent years, social media engagement has proliferated among physicians, health care systems, scientific journals, professional societies, and patients. In radiology, Twitter (Twitter Inc, San Francisco, California) has rapidly become the preferred social media engagement tool and is now an essential activity at many large radiology society meetings. Twitter offers a versatile, albeit simple, platform for anyone interested in engaging with others, regardless of title, stature, or geography. In radiology and other medical specialties, year-after year increases in Twitter engagement before, during, and after professional society meetings continue with widespread positive feedback. This short-form messaging tool also allows users to connect and interact with high-impact individuals and organizations on an ongoing basis (rather than once a year during large meetings). Through live-polling, Twitter also has the power to gather global opinions on issues highly relevant to radiology's future, such as the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) or breast cancer screening. Also increasingly popular is "live-tweeting" of curated meeting content, which makes information from the meeting accessible to a global audience. Despite the promise of growing professional networks and enabling discussions that cross geographic boundaries, the risks of Twitter use during radiology meetings must be recognized and mitigated. These include posting of unpublished data without consent (eg, slide content captured on camera phones), propagation of misinformation, and copyright infringement. Despite these issues and with an eye towards professionalism, Twitter can nonetheless be used effectively to increase engagement among radiologists, radiology societies, and patients. PMID- 29162420 TI - Documenting Web-Based Learning Modules as Scholarly Activity for Promotion. PMID- 29162418 TI - Nerve Stimulation: Immunomodulation and Control of Inflammation. AB - Neuronal stimulation is an emerging field in modern medicine to control organ function and re-establish physiological homeostasis during illness. Transdermal nerve stimulation with electroacupuncture is currently endorsed by the World Health Organization (WHO) and the National Institutes of Health (NIH), and is used by millions of people to control pain and inflammation. Recent advances in electroacupuncture may permit activation of specific neuronal networks to prevent organ damage in inflammatory and infectious disorders. Experimental studies of nerve stimulation are also providing new information on the functional organization of the nervous system to control inflammation and its clinical implications in infectious and inflammatory disorders. These studies may allow the design of novel non-invasive techniques for nerve stimulation to help to control immune and organ functions. PMID- 29162421 TI - Past, Current, and Future Incidence Rates and Burden of Metastatic Prostate Cancer in the United States. AB - BACKGROUND: Metastatic prostate cancer (PCA) remains a highly lethal malignancy in the USA. As prostate-specific antigen testing declines nationally, detailed assessment of current age- and race-specific incidence trends and quantitative forecasts are needed. OBJECTIVE: To evaluate the current trends of metastatic PCA by age and race, and forecast the number of new cases (annual burden) and future trends. DESIGN, SETTING, AND PARTICIPANTS: We derived incidence data for men aged >=45 yr who were diagnosed with metastatic PCA from the population-based Surveillance, Epidemiology, and End Results registries. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We examined the current trends of metastatic PCA from 2004 to 2014, and forecast the annual burden and incidence rates by age and race for 2015-2025, using age-period-cohort models and population projections. We also examined alternative forecasts (2012-2025) using trends prior to the revised screening guidelines issued in 2012. RESULTS AND LIMITATIONS: Metastatic PCA, steadily declining from 2004 to 2007 by 1.45%/yr, began to increase by 0.58%/yr after 2008, which accelerated to 2.74%/yr following the 2012 United States Preventive Services Task Force recommendations-a pattern that was magnified among men aged <=69 yr and white men. Forecasts project the incidence to increase by 1.03%/yr through 2025, with men aged 45-54 yr (2.29%/yr) and 55-69 yr (1.53%/yr) increasing more rapidly. Meanwhile, the annual burden is expected to increase 42% by 2025. Our forecasts estimated an additional 15 891 metastatic cases from 2015 to 2025 compared with alternative forecasts using trends prior to 2012. CONCLUSIONS: The recent uptick in metastatic PCA rates has resulted in forecasts that project increasing rates through 2025, particularly among men aged <=69 yr. Moreover, racial disparities are expected to persist and the annual burden will increase considerably. The impact of the prior and current PCA screening recommendations on metastatic PCA rates requires continued examination. PATIENT SUMMARY: In this report, we assessed how the incidence of metastatic prostate cancer has changed over recent years, and forecast future incidence trends and the number of new cases expected each year. We found that the incidence of metastatic prostate cancer has been increasing more rapidly since 2012, resulting in a rise in both future incidence and the number of new cases by 2025. Future incidence rates and the number of new cases were reduced in alternative forecasts using data prior to the 2012 United States Preventive Services Task Force (USPSTF) recommendations against prostate-specific antigen (PSA) testing for prostate cancer. There is a need for additional research that examines whether national declines in PSA testing contributed to increases in rates of metastatic disease. The incidence of metastatic disease in black men is still expected to occur at considerably higher rates compared with that in white men. PMID- 29162422 TI - Chlamydiales, Anaplasma and Bartonella: persistence and immune escape of intracellular bacteria. AB - Intracellular bacteria, such as Chlamydiales, Anaplasma or Bartonella, need to persist inside their host in order to complete their developmental cycle and to infect new hosts. In order to escape from the host immune system, intracellular bacteria have developed diverse mechanisms of persistence, which can directly impact the health of their host. PMID- 29162423 TI - Manipulating Aggregation Behavior of the Uncharged Peptide Carbetocin. AB - Peptides are usually administered through subcutaneous injection. For low potency drugs, this may require high concentration formulations increasing the risk of peptide aggregation, especially for compounds without any intrinsic chargeable groups. Carbetocin was used as a model to study the behavior of uncharged peptides at high concentrations. Manipulation of the aggregation behavior of 70 mg/mL carbetocin was attempted by selecting excipients which interact with hydrophobic groups in carbetocin, and cover hydrophobic surfaces and interfaces. Peptide aggregation was induced by shaking stress and followed over time. Carbetocin solutions showed significant visible particle formation already after 4 h of shaking stress. This particle formation was not due to supersaturation or phase separation but suggested a nucleated aggregation process. None of the excipients prevented carbetocin aggregation, though altered aggregation behavior was observed, such as induction of fibril formation for most, but not all, charged excipients. Sodium dodecyl sulfate was found to accelerate peptide aggregation both below and above the critical micelle concentration in half filled vials. However, in the absence of an air headspace, sodium dodecyl sulfate above the critical micelle concentration was capable of preventing shaking induced carbetocin aggregation. Our study highlights the complexity in rational excipient selection to stabilize uncharged peptides at high concentration. PMID- 29162426 TI - Current Status and Unanswered Questions for Food Allergy Treatments. AB - Although there is no FDA approved therapy for food allergy, over the past decades, several routes of immunotherapy have been investigated for food allergy. Thus far, these therapies have shown variable levels of efficacy at desensitizing to foods, with oral immunotherapy (OIT) far more successful than sublingual immunotherapy (SLIT) or epicutaneous immunotherapy (EPIT). However, desensitization tends to be temporary, and safety remains a major concern with OIT. Moreover, although it seems logical that desensitization will result in fewer reactions, it is not clear whether OIT or other immunotherapies are associated with an overall lower or higher risk of reactions over the long term. Eosinophilic esophagitis is a known complication of OIT, and may also be a risk with SLIT and possibly EPIT, although it has not been reported in the relatively few patients treated thus far. Adjuvants such as omalizumab or probiotics may improve the safety and/or efficacy of immunotherapy for food allergy, but more research is needed. In the future, biomarkers may identify subsets of patients who are better candidates for specific treatments. As therapies become commercially available, patients and providers will need to consider whether the benefits justify the risks and burdens of these treatments. PMID- 29162424 TI - Injectable Hydrogels for Localized Chemotherapy and Radiotherapy in Brain Tumors. AB - Overall survival of patients with newly diagnosed glioblastoma (GBM) remains dismal at 16 months with state-of-the-art treatment that includes surgical resection, radiation, and chemotherapy. GBM tumors are highly heterogeneous, and mechanisms for overcoming tumor resistance have not yet fully been elucidated. An injectable chitosan hydrogel capable of releasing chemotherapy (temozolomide [TMZ]) while retaining radioactive isotopes agents (iodine, [131I]) was used as a vehicle for localized radiation and chemotherapy, within the surgical cavity. Release from hydrogels loaded with TMZ or 131I was characterized in vitro and in vivo and their efficacy on tumor progression and survival on GBM tumors was also measured. The in vitro release of 131I was negligible over 42 days, whereas the TMZ was completely released over the first 48 h. 131I was completely retained in the tumor bed with negligible distribution in other tissues and that when delivered locally, the chemotherapy accumulated in the tumor at 10-fold higher concentrations than when delivered systemically. We found that the tumors were significantly decreased, and survival was improved in both treatment groups compared to the control group. Novel injectable chemo-radio-hydrogel implants may potentially improve the local control and overall outcome of aggressive, poor prognosis brain tumors. PMID- 29162425 TI - Usefulness of basophil activation test for the diagnosis of IgE mediated hypersensitivity to tetanus toxoid vaccine. AB - A great number of vaccinated patients develop specific anti-tetanus toxoid IgE, but usually do not undergo any adverse effect. Most of the allergic reactions to tetanus toxoid vaccine usually present with unspecific symptoms of local inflammation. In the presence of severe reactions, and in a special way if the vaccine is provided together with other drugs, it is difficult to establish which is the harmful drug responsible for IgE-mediated adverse reaction. A patient with an anaphylactic reaction after the administration of Toxoid Tetanic (TT) along with several drugs is described. All skin test were negative. The basophils activation test (BAT) in a clear way, identified TT as the allergen that triggered anaphylaxis. The results achieved demonstrates the usefulness of BAT to clarify patients with hypersensibility to tetanus toxoide when the clinic is severe and the vaccine has been administered together with other drugs. PMID- 29162427 TI - Disulfide bond mapping of Pfs25, a recombinant malaria transmission blocking vaccine candidate. AB - A liquid chromatography tandem-mass spectrometry method was developed to map the eleven disulfide bonds in Pfs25, a malaria transmission-blocking vaccine candidate. The compact and complex nature of Pfs25 has led to difficulties in prior peptide mapping efforts. Here, we report confirmation of proper disulfide pairing of a recombinant Pfs25, by optimizing denaturation and digestion with trypsin/Lys-C. The digested peptides were separated by reversed phase HPLC to obtain the peptide map and elucidate the disulfide linkages. MSE fragmentation confirmed the digested peptides and disulfide bonds. The eleven disulfide bonds and locations matched the predicted Pvs25 crystal structure, a Pfs25 homologue. PMID- 29162429 TI - Studies with psychedelic drugs in human volunteers. AB - Scientific curiosity and fascination have played a key role in human research with psychedelics along with the hope that perceptual alterations and heightened insight could benefit well-being and play a role in the treatment of various neuropsychiatric disorders. These motivations need to be tempered by a realistic assessment of the hurdles to be cleared for therapeutic use. Development of a psychedelic drug for treatment of a serious psychiatric disorder presents substantial although not insurmountable challenges. While the varied psychedelic agents described in this chapter share some properties, they have a range of pharmacologic effects that are reflected in the gradation in intensity of hallucinogenic effects from the classical agents to DMT, MDMA, ketamine, dextromethorphan and new drugs with activity in the serotonergic system. The common link seems to be serotonergic effects modulated by NMDA and other neurotransmitter effects. The range of hallucinogens suggest that they are distinct pharmacologic agents and will not be equally safe or effective in therapeutic targets. Newly synthesized specific and selective agents modeled on the legacy agents may be worth considering. Defining therapeutic targets that represent unmet medical need, addressing market and commercial issues, and finding treatment settings to safely test and use such drugs make the human testing of psychedelics not only interesting but also very challenging. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'. PMID- 29162428 TI - Can Mindfulness Training Improve Medication Adherence? Integrative Review of the Current Evidence and Proposed Conceptual Model. AB - Medication adherence is a complex, multi-determined behavior that is often influenced by system- (e.g., cost), drug- (e.g., regimen complexity), and patient related (e.g., depression) factors. System-level approaches (e.g., making medications more affordable) are critically important but do not address patient level factors that can undermine adherence. In this paper, we identify patient level determinants of non-adherence and discuss whether mindfulness-training approaches that target these determinants can help to improve adherence to medical treatment. We highlight two chronic medical conditions (viz., heart failure and HIV) where poor adherence is a significant concern, and examine the evidence regarding the use of mindfulness interventions to improve medication adherence in these two conditions. We also discuss the theoretical underpinnings of mindfulness training with respect to medication adherence, and conclude by suggesting directions for future research. PMID- 29162430 TI - Spontaneous activity, singly bound states and the impact of alpha1Phe64 mutation on GABAAR gating in the novel kinetic model based on the single-channel recordings. AB - GABAA receptor is the primary mediator of inhibition in the adult mammalian brain. Our recent studies revealed that a classic gating scheme for GABAAR needed to be updated with an intermediate step (flipping) and that the alpha1Phe64 mutation at the GABA binding site affects this transition. However, description of flipping at the single-channel level remains incomplete. In particular, its role in singly-bound and spontaneous activity remains unknown. We have performed thus single-channel recordings over wide range of agonist concentration for wild type alpha1beta2gamma2L receptors and alpha1Phe64 mutants. For WT receptors we observed relatively frequent brief spontaneous openings which were also present at low [GABA]. However, closed times distributions for spontaneous activity and at low [GABA] were clearly different indicating that a proportion of short-lived openings were due to liganded, most likely singly bound receptors. Increasing [GABA] resulted in prolongation of bursts and increased occurrence of bursts with long openings and short closures. Mutations of alpha1Phe64 residue dramatically affected the open and closed time distributions at high and saturating [GABA], especially in the case of cysteine mutants. However, this mutation weakly affected spontaneous or singly bound activity. Model fitting of our single channel data led us to propose a novel and, to our knowledge, most complete GABAAR kinetic model in which flipping occurs in singly and doubly bound states. However, spontaneous activity did not reveal involvement of flipping. Moreover, we report that alpha1Phe64 mutation affects not only the flipping but also the opening/closing transitions indicating its generalized impact on the receptor gating. PMID- 29162431 TI - Adenine accelerated the diabetic wound healing by PPAR delta and angiogenic regulation. AB - Wound healing is one of the major complications of diabetes, and problems with wound healing in diabetics often lead to amputation and even death. AMP-activated protein kinase (AMPK) is a protein involved in intracellular metabolism. Activated AMPK can reduce visceral fat and cholesterol synthesis and even inhibit hepatic gluconeogenesis. Activation of AMPK has been widely used in the treatment of type II diabetes. We applied an AMPK activator (Adenine) to human fibroblasts and to the wounds of streptozotocin-induced diabetic mice. We applied Adenine ointment to the wounds on 7 consecutive days and observed the healing status as well as activation of AMPK and angiogenic factors. Based on the appearance of the wounds, the results showed that after 7 days of treatment the wound area was smaller in the Adenine-treated group relative to the control group. The results for tissue protein expression showed that, compared to the control group, angiogenic related protein, PPARdelta were increased and receptor for advanced glycation endproducts (RAGE) was decreased in the Adenine-treated group. Our studies indicate that Adenine has the potential to become a useful drug in the treatment of diabetic wound healing. PMID- 29162432 TI - Renal damage in the metabolic syndrome (MetSx): Disorders implicated. AB - The prevalence of metabolic syndrome is increasing worldwide and has become a risk factor for the development of chronic kidney disease. The complex linkage between metabolic syndrome and chronic kidney disease is under research and the factors involved beyond the biological pathogenesis include demographic, sociological and psychological factors that are related to the metabolic syndrome prevalence. The social context of disease causation is as relevant to today's clinical scientist and practitioner as biomarker-directed risk stratification and therapy. The aim of this review is to compare the criteria for diagnosis among different international health organizations, identifying all factors that contribute to the development of this association between metabolic syndrome and chronic kidney disease, and categorizing them by those that could be useful for preventive strategies. In addition, patients with metabolic syndrome have microvascular disease characterized by microalbuminuria, decreased glomerular filtration rate, tubular atrophy, interstitial fibrosis, and glomerulosclerosis. These effects may be due to insulin resistance, hypertension, dyslipidemias, activation of inflammatory processes, fibrotic, dysbiosis and generation of oxidative stress; which cause an imbalance in the main vasoactive factors and thus endothelial dysfunction, deteriorating the renal function. Furthermore, since unhealthy eating habits and a sedentary lifestyle are among the strongest risk factors related to these diseases, lifestyle interventions programs have been recommended for facilitating positive changes in behavior at the individual level. However, further research is needed to promote multiple social, economic and political transformations, shifting the intervention emphasis from individual education, counseling, regimens and medications to community, national and global institutions. PMID- 29162433 TI - Triptonide potently suppresses pancreatic cancer cell-mediated vasculogenic mimicry by inhibiting expression of VE-cadherin and chemokine ligand 2 genes. AB - Various aggressive cancers, including pancreatic cancer, produce functional blood vessels by neovascularization. Tumor vasculogenic mimicry (VM) promotes cancer progression and is closely associated with the poor prognosis of the cancer patients. Therefore, tumor VM is a sensible target for novel anti-cancer drug discovery. However, there is a lack of effective anti-tumor VM drugs in the clinical setting. In this study, we aim to explore novel agents to effectually inhibit pancreatic cancer cell-mediated tumor VM for anti-cancer therapy. Pancreatic cancer cell lines Patu8988 and Panc1 were utilized as a model. A mouse model was used for in vitro capillary-like structure formation and in vivo Matrigel plug assays to evaluate the anti-tumor VM efficacy of a small molecule triptonide from traditional Chinese herbs. Various methods, including RT-PCR, immunohistochemical staining, and the luciferase gene transcription reporter system, were applied to study the mechanisms of triptonide-exerted anti-tumor VM. Triptonide effectively inhibited pancreatic cancer cell-formed capillary-like structures in vitro and blood vessels in vivo through suppressing pancreatic cancer cell migration, invasion, and VM via inhibiting expression of tumor VM master gene VE-cadherin and pro-migratory gene chemokine C-X-C motif ligand 2 (CXCL2), mainly via reduction of gene promoter activity. Triptonide potently suppresses pancreatic cancer cell-mediated VM by reducing tumor cell migration and invasion and inhibiting expression of VE-cadherin and CXCL2 genes. Our results provide a novel and potent anti-tumor VM drug candidate for further development of effective anti-pancreatic cancer therapy. PMID- 29162434 TI - Oxytocin inhibited stress induced visceral hypersensitivity, enteric glial cells activation, and release of proinflammatory cytokines in maternal separated rats. AB - Visceral hypersensitivity (VH) is a significant contributor to irritable bowel syndrome (IBS). Oxytocin (OT) possesses analgesic effects on the central nervous system (CNS) and attenuates microglial activation, however, little is known about its peripheral effects and involvement in VH of IBS. Reactive enteric glial cells (EGCs) contributes to abnormal motility in gastrointestinal (GI) diseases. The aim of this study was to evaluate the peripheral use of OT to maintain VH and activation of EGCs through involvement of the Toll-like receptor (TLR) 4/MyD88/NF kappaB signaling. After assessing a baseline visceromotor response (VMR) to colorectal distension (CRD), rats were exposed to a 1h water avoidance stress (WAS) session. Before each WAS session, intraperitoneal injection of OT (1mg/kg body weight, in phosphate-buffered saline (PBS)) atosiban (0.5mg/kg body weight, in PBS) or PBS (as a vehicle control, 1ml/kg body weight) was administered. Animas are killed 24h after the last WAS session. EGCs activity, relative OT receptor expression, glial fibrillary acidic protein (GFAP) expression and TLR4/MyD88/NF-kappaB signaling were evaluated. Neonatal maternal separation (MS) significantly increased the OT receptor expression and enhanced VMR to CRD. WAS improved VMR to CRD only during neonatal MS. OT treatment prevented WAS-induced higher VMRs to CRD, which was reversed by an OT receptor antagonist administration. Compared to the vehicle, OT pre-treated rats reduced EGCs activation, GFAP expression and TLR4/MyD88/NF-kappaB signaling. We conclude that neonatal MS induces VH and visceral pain in rats. Furthermore, exogenous OT attenuated stress-induced VH and EGCs activation, which was mediated by TLR4/MyD88/NF-kappaB signaling. PMID- 29162435 TI - Pioglitazone reduces mortality, prevents depressive-like behavior, and impacts hippocampal neurogenesis in the 6-OHDA model of Parkinson's disease in rats. AB - Deficiencies in adult hippocampal neurogenesis have been suggested to be a possible pathophysiological mechanism that underlies depressive symptoms that are often observed in patients with Parkinson's disease (PD). Pioglitazone, a selective peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, has been shown to exert antiinflammatory and antidepressant effects and modulate neural plasticity in several neurodegenerative disorders. The present study investigated the effects of pioglitazone on depressive phenotypes and adult hippocampal neurogenesis in a rat model of PD that was induced by bilateral 6 hydroxydopamine (6-OHDA) infusions in the substantia nigra pars compact (SNpc). Rats with SNpc and ventral tegmental area (VTA) neurodegeneration exhibited despair-like behavior, concomitant with persistent microglial activation in the hippocampus. Pioglitazone reduced the rate of mortality and attenuated microglial activation in the early phase of 6-OHDA-induced nigral lesions. Pioglitazone exerted antidepressant-like effects and increased the survival of neurons in the hippocampus in rats with nigral lesions. These results indicate that pioglitazone exerts neuroprotective effects by facilitating hippocampal neurogenesis in 6-OHDA lesioned rats, which might contribute to its antidepressant-like effect. PMID- 29162436 TI - Effect of intermedin/adrenomedullin2 on the pulmonary vascular bed in hypoxia induced pulmonary hypertensive rats. AB - AIMS: This study aimed to investigate the effect and mechanism of action of intermedin/adrenomedullin2 (IMD/AM2) on the pulmonary vascular bed in pulmonary hypertensive rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were exposed to hypobaric hypoxia for 3 weeks to induce pulmonary hypertension (PHT). The development of PHT was confirmed by histopathological analyses and measurement of hematocrit, basal perfusion pressure, and right ventricle hypertrophy. Subsequently, the effect of IMD/AM2 in pulmonary hypertensive rats was assessed with both, isolated organ bath and isolated lung perfusion studies. KEY FINDINGS: In the PHT group, the basal perfusion pressure and % hematocrit were increased, and right ventricle hypertrophy occurred after 3 weeks of hypoxia exposure. Increased medial wall thickness was also observed in the pulmonary artery with histopathological analysis. In the PHT, the nitric oxide-mediated vasodilation caused by IMD/AM2 in the pulmonary vascular bed and this was as potent as the control group. Acetylcholine responses were also protected in pulmonary hypertensive rats. SIGNIFICANCE: Our results showed for the first time in in vitro studies that IMD/AM2 administration causes potent, concentration-dependent vasodilation in the main and resistance pulmonary arteries of rats with PHT. Based on these results, IMD/AM2 might be considered as a future therapeutic target for PHT treatment. PMID- 29162439 TI - No pain, no gain ... a diagnosis of acute aortic dissection. PMID- 29162440 TI - Automated external defibrillators in the hospital: A case of medical reversal. AB - Automated external defibrillators (AEDs) emerged in the 1980s as an important innovation in pre-hospital emergency cardiac care (ECC). In the years since, the American Heart Association (AHA) and the International Liaison Committee for Resuscitation (ILCOR) have promoted AED technology for use in hospitals as well, resulting in the widespread purchase and use of AED-capable defibrillators. In hospital use of AEDs now appears to have decreased survival from cardiac arrests. This article will look at the use of AEDs in hospitals as a case of "medical reversal." Medical reversal occurs when an accepted, widely used treatment is found to be ineffective or even harmful. This article will discuss the issue of AEDs in the hospital using a conceptual framework provided by recent work on medical reversal. It will go on to consider the implications of the reversal for in-hospital resuscitation programs and emergency medicine more generally. PMID- 29162438 TI - Peri-intubation factors affecting emergency physician choice of paralytic agent for rapid sequence intubation of trauma patients. AB - INTRODUCTION: No study has assessed predictors of physician choice between the succinylcholine (Succ) and rocuronium (Roc) for rapid sequence intubation (RSI) during the initial resuscitation of trauma patients in the emergency department (ED). METHODS: We retrospectively evaluated of the use of Succ and Roc for adult trauma patients undergoing RSI at a Level 1 trauma center. The primary outcome was to identify factors affecting physician choice of paralytic agent for RSI analyzed by cluster analysis using pre-intubation vital signs and early mortality. The secondary outcome was to identify factors influencing physician choice of paralytic agent using a logistic regression model reported as adjusted odds ratios (aOR). RESULTS: The analysis included 215 patients, including 148 receiving Succ and 67 receiving Roc. The two groups were similar in regard to age, provider level of training, mean GCS (10 vs. 10) and median ISS (27 vs. 27). Cluster analysis using peri-intubation patient vital signs and early mortality indicates that patients with predominantly abnormal vital signs and early mortality were more likely to receive Roc (74%) than those without abnormal vital signs prior to intubation or early mortality (24%). Hypoxemia prior to RSI (aOR 12.3 [2.5-60.9]) and the use of video laryngoscopy (VL) (aOR 5.5 [1.2-24.6]) were associated with the choice to use Roc. CONCLUSIONS: Roc was more frequently chosen for paralysis in the patient cluster with predominantly abnormal peri intubation vital signs and higher rate of early ED mortality. The use of Roc was associated with hypoxemia prior to RSI and VL. PMID- 29162437 TI - Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations. AB - BACKGROUND & AIMS: Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms. METHODS: Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines. RESULTS: Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch expressing cells to JAG1Ndr, compared with JAG1, led to hypomorphic Notch signaling, based on transcriptome analysis. JAG1-expressing cells, but not JAG1Ndr-expressing cells, bound soluble Notch1 extracellular domain, quantified by flow cytometry. However, JAG1 and JAG1Ndr cells each bound NOTCH2, and signaling from NOTCH2 signaling was reduced but not completely inhibited, in response to JAG1Ndr compared with JAG1. CONCLUSIONS: In mice, expression of a missense mutant of Jag1 (Jag1Ndr) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology. JAG1Ndr does not bind NOTCH1, but binds NOTCH2, and elicits hypomorphic signaling. This mouse model can be used to study other features of Alagille syndrome and organ development. PMID- 29162441 TI - Treatment and complication of giant cell arteritis. PMID- 29162442 TI - Utility of common bile duct measurement in ED point of care ultrasound: A prospective study. AB - BACKGROUND: Measurement of the common bile duct (CBD) is considered a fundamental component of biliary point-of-care ultrasound (POCUS), but can be technically challenging. OBJECTIVE: The primary objective of this study was to determine whether CBD diameter contributes to the diagnosis of complicated biliary pathology in emergency department (ED) patients with normal laboratory values and no abnormal biliary POCUS findings aside from cholelithiasis. METHODS: We performed a prospective, observational study of adult ED patients undergoing POCUS of the right upper quadrant (RUQ) and serum laboratory studies for suspected biliary pathology. The primary outcome was complicated biliary pathology occurring in the setting of normal laboratory values and a POCUS demonstrating the absence of gallbladder wall thickening (GWT), pericholecystic fluid (PCF) and sonographic Murphy's sign (SMS). The association between CBD dilation and complicated biliary pathology was assessed using logistic regression to control for other factors, including laboratory findings, cholelithiasis and other sonographic abnormalities. RESULTS: A total of 158 patients were included in the study. 76 (48.1%) received non-biliary diagnoses and 82 (51.9%) were diagnosed with biliary pathology. Complicated biliary pathology was diagnosed in 39 patients. Sensitivity of CBD dilation for complicated biliary pathology was 23.7% and specificity was 77.9%. CONCLUSION: Of patients diagnosed with biliary pathology, none had isolated CBD dilatation. In the absence of abnormal laboratory values and GWT, PCF or SMS on POCUS, obtaining a CBD measurement is unlikely to contribute to the evaluation of this patient population. PMID- 29162443 TI - Visualization of the inferoposterior thoracic wall (VIP) and boomerang signs novel sonographic signs of right pleural effusion. AB - OBJECTIVES: This study is to present the diagnostic values of the novel sonographic visualization of the inferoposterior thoracic wall (VIP) and boomerang signs in detecting right pleural effusion by sonologists with little to no experience in ultrasound. METHODS: A prospective analysis of a convenience sample of patients who were assessed by junior intensive care physicians was performed. The patients all underwent computed tomography (CT) of the chest or abdomen with lung bases as part of their care regardless of indication; the results were interpreted by radiologists and were considered the gold standard. Sonography was performed to assess for the presence of the VIP and boomerang signs. Sonographic and chest radiographic findings were compared against CT results. RESULTS: 73 patients were enrolled. The sensitivity and specificity for the VIP sign were 0.85 (95% confidence interval [CI], 0.67-0.94) and 0.86 (95% CI, 0.70-0.95). The sensitivity and specificity for the boomerang sign were 0.78 (95% CI, 0.60-0.90) and 0.87 (95% CI, 0.71-0.95). However, the sensitivity and specificity for the traditional approach of detecting an anechoic collection above the diaphragm to indicate pleural effusion were only 0.54 (95% CI, 0.37 0.71) and 0.86 (95% CI, 0.80-0.99). CONCLUSIONS: Despite inexperience in sonography, the novel VIP and boomerang signs show high diagnostic values in detecting right pleural effusion compared to the traditional methods. PMID- 29162444 TI - A qualitative analysis of the needs and expectations of patients who present to the emergency department for management of migraine. PMID- 29162445 TI - The neuromorphological caudate-putaminal clustering of neostriate interneurons: Kohonen self-organizing maps and supervised artificial neural networks with multivariate analysis. AB - AIMS: The objective of this study is to investigate the possibility of the neuromorphotopological clustering of neostriate interneurons (NSIN) and their consequent classification into caudate (CIN) and putaminal neuron type (PIN), according to the nuclear localization of the neurons. It tends to discover whether these two topological neuron types are morphologically different. MATERIAL AND METHODS: The binary images of adult human NSIN are used for the purposes of the analysis. The total of the 46 neuromorphological parameters is used. They can be divided into the following classes: neuron surface/size, shape, compartmental length, dendritic branching, neuromorphological organization and complexity. The clustering is performed by an algorithm which consists of the steps of predictor extraction, multivariate cluster analysis set and cluster identification. RESULTS: Unifactor analysis extracted as significant the following parameters: neurosoma/perikaryon size (AS), the size of a dendritic tree (ADT), the size of a dendritic field area (ADF), the size of an entire neuron field area (ANF), the size of a perineuronal space (APNS), the fractal dimension of a neuron (DN), the index of perikaryon asymmetry (MS), total dendritic length (L), standardized total dendritic length (Lst), standardized dendritic width (DWDTHst), dendritic centrifugal branching order (DCBO), branching polarization index (MDCBO), dendritic partial surface (DSP), the fractal dimension of a skeletonized neuron image (DS), the index of maximal complex density of a dendritic tree (NMAX) and standardized dendritic branching pattern complexity (CDF/ADFst). The cluster analysis set together with Kohonen self-organizing maps and backpropagation feed-forward artificial neural networks confirmed the classification on both unsupervised and supervised manner, respectively. As a final step, the cluster identification is performed by an assignment of each neuron to a particular cluster. CONCLUSION: NSIN can be classified neuromorphologically into CIN and PIN type. Differences are expected since the two nuclei have different functional roles in processing the information involved in volitional movement control. PMID- 29162446 TI - Multi-step regulation of transcription kinetics explains the non-linear relation between RNA polymerase II density and mRNA expression in dosage compensation. AB - In heterogametic organisms, expression of unequal number of X chromosomes in males and females is balanced by a process called dosage compensation. In Drosophila and mammals, dosage compensation involves nearly two-fold up regulation of the X chromosome mediated by dosage compensation complex (DCC). Experimental studies on the role of DCC on RNA polymerase II (Pol II) transcription in mammals disclosed a non-linear relationship between Pol II densities at different transcription steps and mRNA expression. An ~20-30% increase in Pol II densities corresponds to a rough 200% increase in mRNA expression and two-fold up-regulation. Here, using a simple kinetic model of Pol II transcription calibrated by in vivo measured rate constants of different transcription steps in mammalian cells, we demonstrate how this non-linearity can be explained by multi-step transcriptional regulation. Moreover, we show how multi-step enhancement of Pol II transcription can increase mRNA production while leaving Pol II densities unaffected. Our theoretical analysis not only recapitulates experimentally observed Pol II densities upon two-fold up regulation but also points to erroneous interpretations of Pol II profiles from chromatin immunoprecipitation sequencing (ChIP-seq) or global run-on assays. PMID- 29162447 TI - Co-administration of liposomal fasudil and tissue plasminogen activator ameliorated ischemic brain damage in occlusion model rats prepared by photochemically induced thrombosis. AB - Delivery of neuroprotectants with liposomes has been shown to be effective for the treatment of ischemic stroke. We have recently revealed that intravenous administration of liposomal fasudil (Fasudil-Lip), a Rho-kinase inhibitor, prior to thrombolysis with tissue plasminogen activator (t-PA) can extend the narrow therapeutic time window (TTW) of t-PA. In the present study, we examined the influence of t-PA treatment on liposomal accumulation into the ischemic region and cerebroprotective effect of combined treatment with Fasudil-Lip and t-PA performed at the same timing after the onset of ischemia in middle cerebral artery occlusion (MCAO) prepared by photochemically induced thrombosis. The t-PA administration into MCAO rats 3 h after occlusion brought about significantly higher accumulation of intravenously injected PEGylated liposomes in wide area of ischemic region. Confocal images showed that extravasation of the liposomes from cerebral vessels into brain parenchyma was markedly facilitated by the t-PA treatment which increased blood flow in cerebral vessels. Importantly, co administration of Fasudil-Lip and t-PA after 3 h occlusion, beyond the TTW of t PA in MCAO rats, significantly suppressed brain cell damage compared with t-PA treatment alone. These findings suggest that co-administration of Fasudil-Lip and t-PA should lead to prolong t-PA's TTW and become a useful therapeutic option for ischemic stroke. PMID- 29162448 TI - Intracellular cholesterol level regulates sensitivity of glioblastoma cells against temozolomide-induced cell death by modulation of caspase-8 activation via death receptor 5-accumulation and activation in the plasma membrane lipid raft. AB - Development of resistance against temozolomide (TMZ) in glioblastoma (GBM) after continuous treatment with TMZ is one of the critical problems in clinical GBM therapy. Intracellular cholesterol regulates cancer cell biology, but whether intracellular cholesterol is involved in TMZ resistance of GBM cells remains unclear. The involvement of intracellular cholesterol in acquired resistance against TMZ in GBM cells was investigated. Intracellular cholesterol levels were measured in human U251 MG cells with acquired TMZ resistance (U251-R cells) and TMZ-sensitive control U251 MG cells (U251-Con cells), and found that the intracellular cholesterol level was significantly lower in U251-R cells than in U251-Con cells. In addition, treatment by intracellular cholesterol remover, methyl-beta cyclodextrin (MbetaCD), or intracellular cholesterol inducer, soluble cholesterol (Chol), regulated TMZ-induced U251-Con cell death in line with changes in intracellular cholesterol level. Involvement of death receptor 5 (DR5), a death receptor localized in the plasma membrane, was evaluated. TMZ without or with MbetaCD and/or Chol caused accumulation of DR5 into the plasma membrane lipid raft and formed a complex with caspase-8, an extrinsic caspase cascade inducer, reflected in the induction of cell death. In addition, treatment with caspase-8 inhibitor or knockdown of DR5 dramatically suppressed U251-Con cell death induced by combination treatment with TMZ, MbetaCD, and Chol. Combined treatment of Chol with TMZ reversed the TMZ resistance of U251-R cells and another GBM cell model with acquired TMZ resistance, whereas clinical antihypercholesterolemia agents at physiological concentrations suppressed TMZ induced cell death of U251-Con cells. These findings suggest that intracellular cholesterol level affects TMZ treatment of GBM mediated via a DR5-caspase-8 mechanism. PMID- 29162449 TI - Characterization of the oxidative protein folding activity of a unique plant oxidoreductase, Arabidopsis protein disulfide isomerase-11. AB - Protein disulfide isomerases (PDIs) can catalyze disulfide bond formation in nascent secretory proteins and membrane proteins and can introduce correct disulfide bonds into substrate proteins containing mispaired disulfides. The functions of mammalian PDIs have been extensively studied; however, relative to mammalian PDIs, the systematic characterization of PDIs for their oxidoreductase activity in plants is still lacking. Arabidopsis protein disulfide isomerases-11 (AtPDI11), with the structure of a-a'-D, has no ortholog in animals or yeast. In this study, we demonstrated that AtPDI11 has oxidoreductase activity in vitro using a GSSG/GSH-mediated oxidative protein folding system. Moreover, the active site in the a' domain of AtPDI11 is critical for its oxidative folding activity. AtPDI11 is present in four redox forms in vivo, which are determined by the active site cysteines (Cys52 and Cys55 in the a domain, and Cys171 and Cys174 in the a' domain). Genetic evidence suggests that AtPDI11 is required for plant growth under reducing conditions. Our work provides an example for studying the oxidoreductase function of other plant PDIs. PMID- 29162450 TI - Visualization of local phosphatidylcholine synthesis within hippocampal neurons using a compartmentalized culture system and imaging mass spectrometry. AB - Neurons extend neurites with an increased synthesis of phosphatidylcholine (PC) that is not only a membrane component but also a functional regulator with specific fatty acid composition. To analyze the local synthesis of the PC molecular species within neurons, we combined a compartmentalized culture system with matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS). We observed that a newly synthesized PC, which contains exogenously administered palmitic acid-d3, is accumulated at the cell bodies and the tips of the distal neurites. The local accumulation within distal neurites is formed by distinct metabolic activity from cell bodies, suggesting that the local extracellular composition of free fatty acid can be a key to regulate specific functions of each PC molecular species. We expect our simple method to be a starting point for more sophisticated in vitro analytical methods for unveiling detailed lipid metabolisms within neurons. PMID- 29162451 TI - Hydrostatic pressure incubation affects barrier properties of mammary epithelial cell monolayers, in vitro. AB - During lactation, accumulation of milk in mammary glands (MG) causes hydrostatic pressure (HP) and concentration of bioactive compounds. Previously, a changed expression of tight junction (TJ) proteins was observed in mice MGs by accumulation of milk, in vivo. The TJ primarily determines the integrity of the MG epithelium. The present study questioned whether HP alone can affect the TJ in a mammary epithelial cell model, in vitro. Therefore, monolayers of HC11, a mammary epithelial cell line, were mounted into modified Ussing chambers and incubated with 10 kPa bilateral HP for 4 h. Short circuit current and transepithelial resistance were recorded and compared to controls, and TJ proteins were analyzed by Western blotting and immunofluorescent staining. In our first approach HC11 cells could withstand the pressure incubation and a downregulation of occludin was observed. In a second approach, using prolactin- and dexamethasone-induced cells, a decrease of short circuit current was observed, beginning after 2 h of incubation. With the addition of 1 mM barium chloride to the bathing solution the decrease could be blocked temporarily. On molecular level an upregulation of ZO-1 could be observed in hormone-induced cells, which was downregulated after the incubation with barium chloride. In conclusion, bilateral HP incubation affects mammary epithelial monolayers, in vitro. Both, the reduction of short circuit current and the change in TJ proteins may be interpreted as physiological requirements for lactation. PMID- 29162452 TI - DT-13 ameliorates TNF-alpha-induced nitric oxide production in the endothelium in vivo and in vitro. AB - The steroidal saponin DT-13 (25(R,S)-ruscogenin-1-O-[beta-d-glucopyranosyl-(1 -> 2)][beta-d-xylopyranosyl-(1 -> 3)]-beta-d-fucopyranoside), one of the major active compounds of the herb Liriope muscari (Decne.), exhibits significant anti inflammatory, anti-tumor and cardioprotective effects. This study aimed to explore the protective effect of DT-13 on endothelium through regulating of nitric oxide production induced by Tumor necrosis factor-alpha (TNF-alpha). The results demonstrated that DT-13 inhibited inflammatory cell infiltration and thus played a protective effect on endothelial cells in vivo, as shown by hematoxylin eosin (H&E) staining and immunohistochemical staining. Enzyme-linked immunosorbent assay (ELISA) results demonstrated that DT-13 could suppress the TNF-alpha-induced upregulation of reactive oxygen species (ROS), tumor necrosis factor receptor (TNFR), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and nitric oxide in vivo dose-dependently and suppressed production of nitric oxide in vitro as shown by DAF-FMDA. Western blotting results indicated that DT-13 could down-regulate phosphorylation of endothelial nitric oxide synthase (eNOS) significantly in TNF-alpha-induced human umbilical vein endothelial cells (HUVECs). Taken together, we speculate that DT-13 inhibits endothelium vascular inflammation through regulating nitric oxide production and the expression of ROS, TNFR, IL-8, MCP-1, which are associated with inflammation. PMID- 29162453 TI - Combined hypoxia and hypercapnia, but not hypoxia alone, suppresses neurotransmission from orexin to hypothalamic paraventricular spinally-projecting neurons in weanling rats. AB - Both orexin neurons in the lateral hypothalamus and spinally-projecting pre sympathetic neurons (PSNs) in the paraventricular nucleus of the hypothalamus (PVN) play an important role in the regulation of cardiovascular function under normal conditions and during cardiovascular challenges such as hypoxia and/or hypercapnia. We have previously established, using selective optogenetic excitation of orexin neurons and pathways, there is a heterogeneous neurotransmission from orexin neurons to PSNs in the PVN. This study was undertaken to test whether this pathway is altered by acute exposure to hypoxia alone and/or combined hypoxia and hypercapnia (H/H). To test this hypothesis, we selectively expressed channelrhodopsin-2 (ChR2) in orexin neurons in the lateral hypothalamus and photoactivated ChR2-expressing fibers to evoke postsynaptic currents in spinally-projecting PSNs in an in vitro slice preparation in rats. In accordance with previously published data, two subpopulations of spinally projecting PSNs were established, including those with glutamatergic or GABAergic inputs from orexin neurons. Hypoxia alone did not alter the peak amplitude of either glutamatergic or GABAergic neurotransmission, however, H/H significantly inhibited both glutamatergic and GABAergic neurotransmission from orexin neurons to SPNs. In conclusion, H/H may modulate cardiovascular function by affecting heterogeneous pathways from orexin neurons to spinally-projecting PSNs in the PVN. PMID- 29162454 TI - The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as inhibitors of HCV NS3 protease. AB - Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued. PMID- 29162455 TI - Synthesis and biological evaluation of water-soluble derivatives of chiral gossypol as HIV fusion inhibitors targeting gp41. AB - A series of novel or known water-soluble derivatives of chiral gossypol were synthesized and screened in vitro for their anti-HIV-1 activity. (-)-gossypol derivative was more active against HIV-1 than the corresponding (+)-gossypol derivative, respectively. Among these derivatives, d-glucosamine derivative of ( )-gossypol, oligopeptide derivative of (-)-gossypol and taurine derivative of (-) gossypol, such as compounds 1a, 3a and 14a, showed significant inhibitory activities against HIV-1 replication, HIV-1 mediated cell-cell fusion and HIV gp41 6-helix bundle formation as some amino acid derivatives of (-)-gossypol. PMID- 29162456 TI - Selective incorporation of foreign functionality into fibrin gels through a chemically modified DNA aptamer. AB - We found for the first time that a thrombin-binding DNA aptamer (TBA) is selectively entrapped in fibrin gels during the gel growth reaction catalyzed by thrombin. Furthermore, using this phenomenon, we successfully demonstrated multiple incorporation of amphiphilic aliphatic groups into fibrin gels via chemically modified TBA. PMID- 29162458 TI - Electrophysiological impact of multiple concussions in asymptomatic athletes: A re-analysis based on alpha activity during a visual-spatial attention task. AB - Most EEG studies used event-related potentials to assess long-term and cumulative effects of sport-related concussions on brain activity. Time-frequency methods provide another approach that allows the detection of subtle shifts in types and patterns of brain oscillations. We sought to discover whether event-related alpha activity would be significantly affected in asymptomatic multi-concussed athletes. We measured the amplitude of alpha activity (8-12Hz) from the EEG recorded during a visual-spatial attention task to compare event-related alpha perturbations in 13 multi-concussed athletes and 14 age-equivalent, non-concussed teammates. Relative to non-concussed athletes, multi-concussed athletes showed significantly less event-related perturbations time-locked to stimulus presentation. Alpha activity alterations were closely related to the number of concussions sustained. Event-related alpha activity differed in asymptomatic multi-concussed athletes when compared to controls. Our study suggests that low level neurophysiological underpinnings of the deployment of visual-spatial attention are affected in multi-concussed athletes even though their last concussion occurred on average 30 months prior to testing. PMID- 29162457 TI - Antiplasmodial alkaloids from bulbs of Amaryllis belladonna Steud. AB - A bioassay-guided fractionation and chemical investigation of Amaryllis belladonna Steud. bulbs resulted in the isolation and identification of the new crinane alkaloid 1,4-dihydroxy-3-methoxy powellan (1), along with the 3 known crinane alkaloids 2-4 and the two lycorane alkaloids 5-6. The structures were elucidated by interpretation of combined HR-ESIMS, CD and 2D NMR spectroscopic data. Among these isolated compounds the lycorane-type alkaloid acetylcaranine (5) exhibited strong antiplasmodial activity, while compounds 3 and 4 were moderately active, and compounds 1 and 6 were inactive. PMID- 29162459 TI - EEG-neurofeedback training of beta band (12-22Hz) affects alpha and beta frequencies - A controlled study of a healthy population. AB - The frequency-function relation of various EEG bands has inspired EEG neurofeedback procedures intending to improve cognitive abilities in numerous clinical groups. In this study, we administered EEG-neurofeedback (EEG-NFB) to a healthy population to determine the efficacy of this procedure. We evaluated feedback manipulation in the beta band (12-22Hz), known to be involved in visual attention processing. Two groups of healthy adults were trained to either up- or down-regulate beta band activity, thus providing mutual control. Up-regulation training induced increases in beta and alpha band (8-12Hz) amplitudes during the first three sessions. Group-independent increases in the activity of both bands were observed in the later phase of training. EEG changes were not matched by measured behavioural indices of attention. Parallel changes in the two bands challenge the idea of frequency-specific EEG-NFB protocols and suggest their interdependence. Our study exposes the possibility (i) that the alpha band is more prone to manipulation, and (ii) that changes in the bands' amplitudes are independent from specified training. We therefore encourage a more comprehensive approach to EEG-neurofeedback training embracing physiological and/or operational relations among various EEG bands. PMID- 29162460 TI - Physical exercise in cirrhotic patients: Towards prehabilitation on waiting list for liver transplantation. A systematic review and meta-analysis. AB - BACKGROUND: Early survival after Liver Transplantation (LT) is reduced among sarcopenic patients. Despite, Adapted Physical Activity (APA) before LT is rarely proposed for the risk to impair portal hypertension and its resulting complications. OBJECTIVES: To assess the effects of APA program in adults affected by End Stage Liver Disease (ESLD) on hospital stay, 1-year mortality and morbidity after LT, adverse events (Primary outcomes). Secondary outcomes were changes in VO2 peak, muscle morphology, 6minutes walking distance test (6MWD), Body Mass Index (BMI), MELD, CHILD score and Hepatic Venous Pressure Gradient (HVPG). SEARCH METHODS: MEDLINE, EMBASE, Google Scholar and the Cochrane Library database were explored for randomized clinical trials (RCT). DATA COLLECTION AND ANALYSIS: Data were collected by one review author on the type of study, participants, treatments used for primary and secondary outcomes. Review Manager 5.2 was used for the analysis. MAIN RESULTS: Four RCT with 81 patients were included. Primary outcomes: no severe adverse event was observed, but no published data were available on hospital stay or mortality after LT. SECONDARY OUTCOMES: CHILD, MELD and BMI were not worsened by physical activity. No significant muscle diameter, 6MWD and VO2 peak changes were observed after exercise. Significant reduction in HVPG in the treatment group was observed in a single study (MD-2.5mmHg; 95%CI [-04.76, -0.24]; P=0.03). AUTHORS' CONCLUSIONS: Knowledge in this field is still at an early stage. Evidence derived from small trials of medium quality on ESLD patients suggests that APA is safe, without increasing portal hypertension. Further research is very likely to have an important impact on our confidence in the intervention effect. PMID- 29162461 TI - Compressed collagen constructs with optimized mechanical properties and cell interactions for tissue engineering applications. AB - In this study, we are introducing a simple, fast and reliable add-in to the technique of plastic compression to obtain collagen sheets with decreased fibrillar densities, representing improved cell-interactions and mechanical properties. Collagen hydrogels with different initial concentrations (1.64mg/mL 0.41mg/mL) were compressed around an electrospun sheet of PLGA. The scaffolds were then studied as non-seeded, or seeded with 3T3 fibroblast cells and cultured for 7days. Confocal microscopy and TEM imaging of non-seeded scaffolds showed that by decreasing the share of collagen in the hydrogel formula, collagen sheets with similar thickness but lower fibrous densities were achieved. Nanomechanical characterization of compressed collagen sheets by AFM showed that Young's modulus was inversely proportional to the final concentration of collagen. Similarly, according to SEM, MTS, and cell nuclei counting, all the scaffolds supported cell adhesion and proliferation, whilst the highest metabolic activities and proliferation were seen in the scaffolds with lowest collagen content in hydrogel formula. We conclude that by decreasing the collagen content in the formula of collagen hydrogel for plastic compression, not only a better cell environment and optimum mechanical properties are achieved, but also the application costs of this biopolymer is reduced. PMID- 29162462 TI - Functional role of the conserved glycine residues, Gly481 and Gly482, of the gamma-glutamyltranspeptidase from Bacillus licheniformis. AB - Six mutants bearing single amino acid substitutions in the small subunit of Bacillus licheniformis gamma-glutamyltranspeptudase (BlGGT) have been constructed by site-directed mutagenesis. The resultant enzymes were overexpressed in Escherichia coli and purified by affinity chromatography for biochemical and biophysical characterizations. Replacing Gly481 by either Ala or Glu did affect both autocatalytic processing and catalytic activity of the enzyme, but the substitution of this residue to arginine resulted in an unprocessed enzyme with insignificant catalytic activity. The replacement of another conserved glycine residue, Gly482, by either Ala or Glu caused a significant change in the functional integrity of the enzyme. Moreover, the mutation of Gly482 to arginine led to a marked reduction in the autocatalytic processing. Structural analyses revealed that the fluorescence and circular dichroism properties of mutant proteins were basically consistent with those of BlGGT. However, guanidine hydrochloride (GdnHCl)-induced transitions of most mutants were profoundly reduced in comparison with that of wild-type enzyme. Molecular modeling suggests that the conserved Gly481 and Gly482 residues of BlGGT are located at critical positions to create an environment suitable for both autoprocessing and catalytic reactions. PMID- 29162463 TI - Bioactivity of glycolipopeptide cell-bound biosurfactants against skin pathogens. AB - The antimicrobial and anti-adhesive activities of the cell-bound biosurfactants, produced by Lactobacillus pentosus (PEB), characterized as glycolipopeptide macromolecules, were evaluated against several microorganisms present in the skin microflora, envisaging its potential use as a "natural" ingredient in cosmetic and personal care formulations. Their performance was compared with another cell bound biosurfactants also characterized as glycolipopeptides produced by Lactobacillus paracasei (PAB). At concentrations of 50mg/mL, the PEB showed an important antimicrobial activity against Pseudomonas aeruginosa (85% when extracted with phosphate buffer (PB) and 100% when extracted with phosphate buffer saline (PBS)), Streptococcus agalactiae (100% for both extracts), Staphylococcus aureus (67% when extracted with PBS and 100% when extracted with PB), Escherichia coli (72% when extracted with PB and 89% when extracted with PBS), Streptococcus pyogenes (about 85% for both extracts) and Candida albicans (around 70% for both extracts), comparable with that obtained for the PAB. However, at lower concentrations the PAB exhibited in general higher antimicrobial activities. Biosurfactants produced by both microorganisms also showed significant anti-adhesive properties against all the microorganisms under study, except for E. coli and C. albicans (less than 30%). Overall, these cell bound biosurfactants could be used as potential antimicrobial and anti-adhesive agents in cosmetic and pharmaceutical formulations. PMID- 29162464 TI - Biochemical and Biophysical characterization of curcumin binding to human mitotic kinesin Eg5: Insights into the inhibitory mechanism of curcumin on Eg5. AB - In this study we have characterized the biochemical and biophysical interactions of curcumin with the mitotic kinesin Eg5 which plays a pivotal role in the separation of centrosomes during cell division. Curcumin bound to the purified Eg5 (Eg5-437H) with a Kd value of 7.8MUM. The temperature dependent binding analysis and evaluation of thermodynamic parameters indicated the involvement of static quenching mechanism in the binding process. Evidences from competition experiment with monastrol indicated that curcumin bound to Eg5 at a novel druggable site. Using Forster resonance energy transfer the distance between curcumin and monastrol binding site from TRP127 on Eg5-437H was found to be 33A and 17A respectively. Curcumin inhibited the ATPase activity of Eg5 motor and perturbed the dynamic interactions between Eg5 and microtubules. Results from circular dichroism studies and molecular dynamics simulations suggest that curcumin binding might perturb the Eg5-437H secondary structure which could be the reason behind its inhibitory effects on Eg5. Cell culture studies performed in HeLa cells indicated that curcumin potentiated the mitotic arrest and monopolar spindle formation in synergism with monastrol, indicating that both ligands could bind simultaneously to the same target. PMID- 29162465 TI - Linoleic acid enhance the production of moncolin K and red pigments in Monascus ruber by activating mokH and mokA, and by accelerating cAMP-PkA pathway. AB - Monacolin K, an inhibitor of HMG-CoA reductase, is a secondary metabolite synthesized by polyketide synthases (PKS) from Monascus ruber. The mokH gene encoding Zn(II)2Cys6 binding protein and mokA gene encoding polyketide synthase are presumed to activate monacolin K production. In this study, linoleic acid could be a quorum sensing signaling molecule to increase monacolin K production in the cyclic AMP(cAMP)-protein kinase A(PKA) signaling pathway. Analysis of the PKA activity and the cAMP concentration shows that linoleic acid could increase cAMP concentration and activate PKA. Analysis of the RT-qPCR products demonstrates that 256MUM and 512MUM linoleic acid can up-regulate mokH and mokA gene transcript levels. Especially with 512MUM linoleic acid addition, linoleic acid increase 1.35 folds of monacolin K production, but 64MUM linoleic acid increase 1.94 folds of red pigment production in Monascus ruber. These results show the cAMP-PkA pathway activity can up-regulate mokA and mokH gene, which enhance the yield of Monacolin K. PMID- 29162466 TI - Specific inhibitory effects of myricetin on human proton-coupled folate transporter: Comparison with its effects on rat proton-coupled folate transporter and human riboflavin transporter 3. AB - Myricetin is a flavonoid that inhibits human proton-coupled folate transporter (hPCFT) in a transient manner, in which inhibition is manifested in its presence, and also in a sustained manner, in which inhibition induced in its presence persists after its removal. In an effort to elucidate the mechanisms involved in those, we examined if myricetin might or might not act similarly on some other transporters. Transporters examined for that, in comparison with hPCFT, were its rat ortholog (rPCFT) and human riboflavin transporter 3 (hRFVT3). Experiments were conducted, using human embryonic kidney 293 cells transiently expressing the transporter to be examined, to assess the effects of myricetin (100 MUM) on the uptake of folate by the PCFTs and riboflavin by hRFVT3. For hPCFT, myricetin was confirmed to induce a transient inhibition and also a sustained inhibition. However, myricetin induced neither transient nor sustained type of rPCFT inhibition. hRFVT3 was inhibited by myricetin in a transient manner, but not in a sustained manner. These results suggest the involvement of a hPCFT-specific mechanism in the sustained inhibition. The transient inhibition may be induced by a mechanism specific to hPCFT and also hRFVT3. PMID- 29162467 TI - Return to Play After Injuries: A Survey on the Helpfulness of Various Forms of Assistance in the Shared Decision-Making Process in Semiprofessional Athletes in Germany. AB - OBJECTIVE: To assess how different decision-guiding factors, such as health- and performance-related stakeholders, as well as evidence-based guidelines, support the process-oriented final positive return-to-play (RTP) decision of head coaches responsible for semiprofessional sport teams. DESIGN: Cross-sectional survey. SETTING: Team sport. PARTICIPANTS: A survey consisting of questions on the importance of different decision-guiding factors used when making the RTP decision after injuries was administered to and completed by head coaches (N=238) of semiprofessional players' teams. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: With respect to helpfulness in the RTP decision-making process, the coaches rated both the importance of the opinions of physicians, physiotherapists, strength and conditioning coaches, and the athletes themselves, and the importance of the general and injury-specific RTP guidelines. RESULTS: Our survey revealed that the head coaches rely on physicians and physiotherapists to a large extent, to the athletes and to themselves to a medium extent, and to strength and conditioning coaches and RTP guidelines to a small but still relevant extent. The coaches' efforts to seek a shared decision-making process in RTP are, hence, partially evident. CONCLUSIONS: A multitude of actuators intervene when making the RTP decision. The professionalization of the RTP process in semiprofessional sports includes the athletes themselves, the head coaches, the (external) physicians, the (external) physiotherapists, and the strength and conditioning coaches based on general RTP decision-making models and specific criteria related to injury type, sports type, level, and playing position. The development of awareness and implementation strategies of RTP models should be subject to further research. PMID- 29162469 TI - Response to Editor: Regarding Foster et al., Neonatal C57BL/6J and parkin mice respond differently following developmental manganese exposure: Result of a high dose pilot study. PMID- 29162468 TI - Assessment of Rehabilitation Infrastructure in Peru. AB - OBJECTIVE: To assess rehabilitation infrastructure in Peru in terms of the World Health Organization (WHO) health systems building blocks. DESIGN: Anonymous quantitative survey; questions were based on the WHO's Guidelines for Essential Trauma Care and rehabilitation professionals' input. SETTING: Large public hospitals and referral centers and an online survey platform. PARTICIPANTS: Convenience sample of hospital personnel working in rehabilitation and neurology (N=239), recruited through existing contacts and professional societies. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Outcome measures were for 4 WHO domains: health workforce, health service delivery, essential medical products and technologies, and health information systems. RESULTS: Regarding the domain of health workforce, 47% of physical therapists, 50% of occupational therapists, and 22% of physiatrists never see inpatients. Few reported rehabilitative nurses (15%) or prosthetist/orthotists (14%) at their hospitals. Even at the largest hospitals, most reported <=3 occupational therapists (54%) and speech-language pathologists (70%). At hospitals without speech-language pathologists, physical therapists (49%) or nobody (34%) perform speech-language pathology roles. At hospitals without occupational therapists, physical therapists most commonly (59%) perform occupational therapy tasks. Alternate prosthetist/orthotist task performers are occupational therapists (26%), physical therapists (19%), and physicians (16%). Forty-four percent reported interdisciplinary collaboration. Regarding the domain of health services, the most frequent inpatient and outpatient rehabilitation barriers were referral delays (50%) and distance/transportation (39%), respectively. Regarding the domain of health information systems, 28% reported rehabilitation service data collection. Regarding the domain of essential medical products and technologies, electrophysical agents (88%), gyms (81%), and electromyography (76%) were most common; thickened liquids (19%), swallow studies (24%), and cognitive training tools (28%) were least frequent. CONCLUSIONS: Rehabilitation emphasis is on outpatient services, and there are comparatively adequate numbers of physical therapists and physiatrists relative to rehabilitation personnel. Financial barriers seem low for accessing existing services. There appear to be shortages of inpatient rehabilitation, specialized services, and interdisciplinary collaboration. These may be addressed by redistributing personnel and investing in education and equipment for specialized services. Further examination of task sharing's role in Peru's rehabilitation services is necessary to evaluate its potential to address deficiencies. PMID- 29162470 TI - Incorporation of metabolic enzymes to improve predictivity of reporter gene assay results for estrogenic and anti-androgenic activity. AB - Identification and monitoring of so-called endocrine-disrupting compounds has received ample attention; both the OECD and the United States Environmental Protection Agency (US EPA) have designed tiered testing approaches, involving in vitro bioassays to prioritize and partly replace traditional animal experiments. Since the estrogen (ER) and androgen (AR) receptor are frequent targets of endocrine disrupting chemicals, bioassays detecting interaction with these receptors have a high potential to be of use in risk assessment of endocrine active compounds. However, in many bioassays in vivo hepatic metabolism is not accounted for, which hampers extrapolation to the in vivo situation. In the present study, we have developed a metabolic module using rat liver S9 as an add on to human cell-based reporter gene assays. The method was applied to reporter gene assays for detection of (anti-) estrogens and (anti-) androgens, but can be extended to cell-based reporter gene assays covering a variety of endpoints related to endocrine disruption. PMID- 29162471 TI - Reply to letter by Trupp et al. PMID- 29162472 TI - [Self-perception of disease in patients with chronic diseases]. AB - OBJECTIVE: The aim of this study is to assess the self-perception of disease by patients with chronic diseases and determine factors related to their perception of disease. MATERIAL AND METHODS: Cross-sectional descriptive study performed between September 2014 and April 2015 in nine (6 urban and 3 rural) Health Centres of Navarra, Spain. The participants were recruited by convenience sampling of 196 patients aged over 65 years with at least one chronic disease. The outcome variable was: Perception of disease evaluated through The Brief Illness Perception Questionnaire (9 items. Assessment of the cognitive and emotional representation of the disease. A higher total score indicates a greater threat of disease to the patient). Explanatory variables: Evaluation of the care received through the Patient Assessment of Chronic Illness Care, Katz index, Gijon's socio-family evaluation scale and quality of life using the EQ5D questionnaire. Other variables studied were: gender, age, education, Charlson index, and number of chronic diseases. The association between the total The Brief Illness Perception Questionnaire value and the rest of the variables was calculated. RESULTS: The self-perception of disease is more negative for a larger number of diseases (rho: 0.242; p=.001), greater patient dependence (rho: -0.193; P=.007), and a poorer self-perceived quality of life (EQ VAS rho: -0.484; P<.001. EQ5D5L Index value rho: -0.507; P<.001). CONCLUSIONS: The perception that chronic patients have about their disease worsens as their diseases and their dependence increase, and also worsens their quality of life. PMID- 29162473 TI - [Neurological manifestations associated with spina bifida in adults]. PMID- 29162474 TI - [Acute epiglottitis in adult. Presentation of several clinical cases]. PMID- 29162475 TI - [Thyrotropin reference ranges during pregnancy in the province of Huelva, Spain]. AB - OBJECTIVE: The correct diagnosis of hypothyroidism during pregnancy requires knowledge of the local trimester-specific thyrotropin (TSH) reference ranges. When these are not available, the guidelines recommend upper limits of 2.5, 3.0, and 3.0MUU/ml for the 1st, 2nd, and 3rd trimesters, respectively. The aim is to establish the reference range for our local population. MATERIAL AND METHODS: A population-based observational study was performed on healthy pregnant women from 11 healthcare centres in the province of Huelva. Women were recruited consecutively during 2016 through the pregnancy process. Women were excluded who had a history of thyroid or medical disease, a poor obstetric history, multiple pregnancy, thyroid autoimmunity, and extreme TSH values (<0.4MUU/ml or>10MUU/ml), as well as women treated with levothyroxine for thyroid dysfunction. RESULTS: The study included a total of 186 pregnant women, with a mean age of 30.7 years (95% CI: 29.8-31.6) and a body mass index (BMI) of 23.6 (95% CI: 23.2-24.0). Most of them had the first laboratory tests performed before week 11 of pregnancy. Valid subjects for analysis were 145, 105, and 67 pregnant women in the 1st, 2nd, and 3rd trimesters, respectively, after excluding those due to abortion (18.9%), autoimmunity (6.5%), hypo/hyperthyroidism (2.2%), and levothyroxine treatment during the 2nd/3rd trimester (18.6%). The 97.5% TSH percentile for the 1st, 2nd, and 3rd trimester was 4.68, 4.83, and 4.57MUU/ml, respectively. Thyroid dysfunction was identified in 80 women (55.2%), 33 of whom received treatment with Levothyroxine (22.7%). With the new criteria, thyroid dysfunction prevalence would be reduced to 6.2%, and the need for treatment to 4.1%. CONCLUSION: The reference range for TSH in our population differs from that proposed by the guidelines. Unnecessary treatment was being given to 18.6% of pregnant women. PMID- 29162476 TI - Prevention and treatment of respiratory viral infections: Presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference. AB - The International Society for Influenza and other Respiratory Virus Diseases held its 5th Antiviral Group (isirv-AVG) Conference in Shanghai, China, in conjunction with the Shanghai Public Health Center and Fudan University from 14-16 June 2017. The three-day programme encompassed presentations on some of the clinical features, management, immune responses and virology of respiratory infections, including influenza A(H1N1)pdm09 and A(H7N9) viruses, MERS-CoV, SARS-CoV, adenovirus Type 80, enterovirus D68, metapneumovirus and respiratory syncytial virus (RSV). Updates were presented on several therapeutics currently in clinical trials, including influenza polymerase inhibitors pimodivir/JNJ6362387, S033188, favipiravir, monoclonal antibodies MHAA45449A and VIS410, and host directed strategies for influenza including nitazoxanide, and polymerase ALS-008112 and fusion inhibitors AK0529, GS-5806 for RSV. Updates were also given on the use of the currently licensed neuraminidase inhibitors. Given the location in China, there were also presentations on the use of Traditional Chinese Medicines. Following on from the previous conference, there were ongoing discussions on appropriate endpoints for severe influenza in clinical trials from regulators and clinicians, an issue which remains unresolved. The aim of this conference summary is to provide information for not only conference participants, but a detailed referenced review of the current status of clinical trials, and pre-clinical development of therapeutics and vaccines for influenza and other respiratory diseases for a broader audience. PMID- 29162477 TI - MiR-301b-3p/3584-5p enhances low-dose mono-n-butyl phthalate (MBP)-induced proliferation by targeting Rasd1 in Sertoli cells. AB - To investigate the possible molecular mechanism of low concentration plasticizer mono-n-butyl phthalate (MBP) -induced juvenile Sertoli cells (SCs) proliferation, we evaluated global alterations of miRNA and mRNA expression in rat SCs treated with 0.1mM MBP. Microarray analysis revealed that miR-3584-5p and miR-301b-3p were up-regulated and their common target gene Dexamethasone-induced Ras-related protein 1 (Rasd1) was down-regulated. Further work suggested that SCs proliferation induced by low concentration MBP in vitro might be mediated by Rasd1 regulating ERK1/2 signaling pathway. The present study is first to investigate the effect of low-dose MBP on SCs proliferation and may enhance our understanding on the modes of action of low concentration MBP on male reproductive system. We hope the results will contribute to explain the causes of precocious puberty and testicular tumors induced by exogenous chemicals. PMID- 29162478 TI - Liposomes assembled from dimeric retinoic acid phospholipid with improved pharmacokinetic properties. AB - All-trans-retinoic acid (ATRA) exhibits potent cytotoxicities against different cancer cells by binding to retinoic acid receptors (RARs), which is regarded as the first example of targeted therapy in acute promyelocytic leukemia (APL). However, its extensive clinical applications have been limited because of poor aqueous solubility, short half-life time and side effects. In this report, dimeric ATRA phosphorylcholine prodrug (Di-ATRA-PC) was designed and assembled into nanoliposomes to improve its pharmacokinetic properties. Di-ATRA-PC prodrug was synthesized by a facile esterification and characterized by mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR). The Di-ATRA-PC assembled liposomes were prepared by thin film hydration method with ATRA loading efficiency up to 73wt%. The liposomes have a uniform particle size (73.1+/-3.6nm) with negatively charged surface (-20.5+/-2.5mV) and typical lipid bilayer structure as measured by dynamic light scattering (DLS), transmission electron microscope (TEM) and cryogenic transmission electron microscope (cryo-TEM). In vitro drug release study confirmed that Di-ATRA-PC liposomes could sustainedly release free ATRA in a weakly acidic condition. Furthermore, cellular uptake, MTT and cell apoptosis analysis demonstrated that the liposomes could be successfully internalized into tumor cells to induce apoptosis of MCF-7 and HL-60 cells. More importantly, in vivo pharmacokinetic assay indicated that Di-ATRA-PC liposomes had much longer retention time in comparison with ATRA. In conclusion, Di-ATRA-PC liposomal formulation could be a potential drug delivery system of ATRA with enhanced pharmacokinetic properties. PMID- 29162480 TI - Dual-targeting immunoliposomes using angiopep-2 and CD133 antibody for glioblastoma stem cells. AB - Glioblastoma stem cells (GSCs), which are identified as subpopulation of CD133+/ALDH1+, are known to show resistance to the most of chemotherapy and radiation therapy, leading to the recurrence of tumor in glioblastoma multiforme (GBM) patients. Also, delivery of temozolomide (TMZ), a mainline treatment of GBM, to the GBM site is hampered by various barriers including the blood-brain barrier (BBB). A dual-targeting immunoliposome encapsulating TMZ (Dual-LP-TMZ) was developed by using angiopep-2 (An2) and anti-CD133 monoclonal antibody (CD133 mAb) for BBB transcytosis and specific delivery to GSCs, respectively. The size, zeta potential and drug encapsulation efficiency of Dual-LP-TMZ were 203.4nm in diameter, -1.6mV and 99.2%, respectively. The in vitro cytotoxicity of Dual-LP TMZ against U87MG GSCs was increased by 425- and 181-folds when compared with that of free TMZ and non-targeted TMZ liposome (LP-TMZ) (10.3MUM vs. 4380MUM and 1869MUM in IC50, respectively). Apoptosis and anti-migration ability of Dual-LP TMZ in U87MG GSCs were also significantly enhanced comparing with those of free TMZ or LP-TMZ. In vivo study clearly showed a significant reduction in tumor size after intravenous administrations of Dual-LP-TMZ to the orthotopically-implanted brain tumor mice when compared with free TMZ or LP-TMZ. Increased life span (ILS) and median survival time (MST) of tumor-bearing mice were also increased when treated with Dual-LP-TMZ (211.2% in ILS and 49.2days in MST) than with free TMZ (0% in ILS and 23.3day in MST). These data indicate that conjugation of both An2 peptide and CD133 mAb to TMZ-encapsulating liposome is very effective in delivering the TMZ to GSCs via BBB, suggesting a potential use of Dual-LP-TMZ as a therapeutic modality for GBM. PMID- 29162479 TI - MiR-145 ameliorates neuropathic pain via inhibiting inflammatory responses and mTOR signaling pathway by targeting Akt3 in a rat model. AB - Neuropathic pain perplexes a large population of patients with various diseases. Inflammation plays a key role in the physiopathology of neuropathic pain. Anti inflammatory can be a promising strategy to treat neuropathic pain. We generated a chronic constriction injury rat model to mimic neuropathic pain by ligating the left ischiadic nerves of rats. Then we performed intrathecal injection of miR-145 mimics to treat these rats for seven consecutive days. Pain behavior tests including mechanical allodynia and thermal hyperalgesia, pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 were analyzed. Quantitative polymerase chain reaction and immunoblotting were performed to detect the changes of signaling pathway after miR-145 mimic treatment. Targeting of Akt3 by miR-145 was studied by dual-luciferase reporter gene assays. MiR-145 mimics injection significantly mollified both mechanical allodynia and thermal hyperalgesia in rats, and down-regulated secretion of TNF alpha, IL-1beta and IL-6. We confirmed that miR-145 directly targeted Akt3, inhibiting NF-kappaB and mTOR downstream genes in rat dorsal root ganglia. MiR 145 can mollify neuropathic pain in a chronic constriction injury rat model by reducing inflammation and ion channel overexpression through Akt3/mTOR and Akt3/NF-kappaB signaling pathways. PMID- 29162481 TI - Dissociation of mono- and co-culture spheroids into single cells for subsequent flow cytometric analysis. AB - BACKGROUND: Spheroids are considered to reflect the natural organization of cells better than 2D cell cultures, but their analysis by flow cytometry requires dissociation into single cells. METHODS: We established protocols for dissociation of mono- and co-culture spheroids consisting of human fibroblasts and human endothelial cells. Cell recovery rate and viability after dissociation were evaluated with hemocytometer and by flow cytometry. The diameter of cells and the amount of cell aggregates were quantified by Casy(r)-technology and the cellular composition was analyzed by flow cytometry. RESULTS: Optimal dissociation conditions with low cell aggregation were determined by size, cultivation time and cellular composition of the spheroids. Smaller spheroids (10,000 cells) could be dissociated with Accutase(r), whereas larger spheroids (50,000 cells) required more stringent dissociation conditions. The size of the cells decreased with increasing cultivation time. Cell recovery rate was dependent upon cellular composition and spheroid size. The highest cell recovery rate was found for co-culture spheroids. The highest cell viability was detected for dissociated fibroblast spheroids. A quantitative analysis of the cellular composition of dissociated co-culture spheroids was possible. DISCUSSION: Spheroids can be successfully dissociated into singular cells for subsequent flow cytometric analysis. Dissociation conditions as well as cell recovery rate and cell viability depend on size, cultivation time and cellular composition of the spheroids. The observed decrease in cell size in spheroids over time might be responsible for the well-known time-dependent decrease in spheroid size. PMID- 29162482 TI - Antimicrobial activity of Melaleuca alternifolia nanoparticles in polymicrobial biofilm in situ. AB - Microbial biofilms represent a challenge in the treatment of infections, due to the low efficacy of the antimicrobials. This study evaluated the antimicrobial effect of nanoparticles of Melaleuca alternifolia (TTO) in dental biofilm. Thirty eight volunteers used an oral device in situ in situ including four bovine enamel specimens for 07 days. From the fifth day four solutions were applied randomly for each specimen: Physiological Saline Solution (0.85% NaCl) (C+), Chlorhexidine 0.12% (CHX), M. alternifolia oil 0.3% (TTO), and a nanoparticle solution of 0.3% M. alternifolia oil (NPTTO). The nanoparticles of TTO were characterized for pH, IPD, medium size, zeta potential and Transmission Electron Microscopy. Antimicrobial activity was evaluated by viable microorganisms count and the structure of the biofilm by atomic force microscopy. The NPTTO presented pH 6.4, particle diameter of 197.9 +/- 1 nm, polydispersion index of 0.242 +/- 0.005, zeta potential of -7.12 mV and +/-0:27 spherical shape. The C+ resulted in 100% of bacterial vitality, while CHX, TTO and NPTTO showed 34.2%, 51.4% and 25.8%, respectively. The AFM images showed biofilms with an average roughness of 350 nm for C+, 275 nm for CHX, 500 nm for TTO and 100 nm for NPTTO. The NPTTO demonstrated excellent antimicrobial activity in the biofilm formed in situ and will possibly be used in future for the treatment/prevention of oral biofilms. PMID- 29162483 TI - Altered expression of CXCR1 (IL-8R) in macrophages utilizing cell surface TNFR1 and IL-1 receptor during Staphylococcus aureus infection. AB - Currently, very few studies are available on the expression of CXCR1 in mouse macrophages having both intact TNFR1 and IL-1R or their deficiency in relation to acute S. aureus infection. Peritoneal macrophages from mice neutralized singly for TNFR1or IL-1R, or for both TNFR1 and IL-1R were infected with S. aureus in vitro and their ability to secrete cytokines and reactive oxygen species (ROS) were determined. It was observed that the release of TNF-alpha and IL-1beta in response to S. aureus infection was decreased in macrophages when both TNFR1 and IL-1R were neutralized. The amount of H2O2, superoxide anion, nitric oxide release and bacterial CFU were significantly decreased in TNFR1 plus IL-1R blocked macrophages when compared with macrophages having intact receptors at 60 min of S. aureus infection. There was decrement of CXCL8 (IL-8) release and expression of CXCR1 in macrophages during dual receptor (TNFR1 plus IL-1R) blocking prior to stimulation with S. aureus. Expression of CXCR1 on murine peritoneal macrophages was evaluated by immunoblots from lysate at 60 min after S. aureus infection. It was observed that at 60 min after S. aureus infection in murine peritoneal macrophages, the expression of CXCR1 was increased significantly (p < 0.05) in comparison to the control groups. CXCR1 expression was decreased significantly (p < 0.05) in macrophages pre-incubated separately with anti-TNFR1 antibody (10 MUg/ml) or IL-1R antagonist protein (240 ng/ml) at 60 min after S. aureus infection. However, blocking of both TNFR1 as well as IL 1R in macrophages downregulated the CXCR1expression in comparison to the groups either pre-incubated with anti-TNFR1 antibody or IRAP alone. PMID- 29162485 TI - Expression and regulation of CYP17A1 and 3beta-hydroxysteroid dehydrogenase in cells of the nervous system: Potential effects of vitamin D on brain steroidogenesis. AB - Steroids are reported to have diverse functions in the nervous system. Enzymatic production of steroid hormones has been reported in different cell types, including astrocytes and neurons. However, the information on some of the steroidogenic enzymes involved is insufficient in many respects. Contradictory results have been reported concerning the relative importance of different cell types in the nervous system for expression of CYP17A1 and 3beta-hydroxysteroid dehydrogenase (3beta-HSD). 3beta-HSD is important in all basic steroidogenic pathways and CYP17A1 is required to form sex hormones. In the current investigation we studied the expression of these enzymes in cultured primary rat astrocytes, in neuron-enriched cells from rat cerebral cortex and in human neuroblastoma SH-SY5Y cells, a cell line often used as an in vitro model of neuronal function and differentiation. As part of this study we also examined potential effects on CYP17A1 and 3beta-HSD by vitamin D, a compound previously shown to have regulatory effects in steroid hormone-producing cells outside the brain. The results of our study indicate that astrocytes are a major site for expression of 3beta-HSD whereas expression of CYP17A1 is found in both astrocytes and neurons. The current data suggest that neurons, contrary to some previous reports, are not involved in 3beta-HSD reactions. Previous studies have shown that vitamin D can influence gene expression and hormone production by steroidogenic enzymes in some cells. We found that vitamin D suppressed CYP17A1 mediated activity by 20% in SH-SY5Ycells and astrocytes. Suppression of CYP17A1 mRNA levels was considerably stronger, about 50% in SH-SY5Y cells and 75% in astrocytes. In astrocytes 3beta-HSD was also suppressed by vitamin D, about 20% at the enzyme activity level and 60% at the mRNA level. These data suggest that vitamin D-mediated regulation of CYP17A1 and 3beta-HSD, particularly on the transcriptional level, may play a role in the nervous system. PMID- 29162484 TI - Differential homologous desensitization of the human histamine H3 receptors of 445 and 365 amino acids expressed in CHO-K1 cells. AB - Histamine H3 receptors (H3Rs) signal through Galphai/o proteins and are found in neuronal cells as auto- and hetero-receptors. Alternative splicing of the human H3R (hH3R) originates 20 isoforms, and the mRNAs of two receptors of 445 and 365 amino acids (hH3R445 and hH3R365) are widely expressed in the human brain. We previously showed that the hH3R445 stably expressed in CHO-K1 cells experiences homologous desensitization. The hH3R365 lacks 80 residues in the third intracellular loop, and in this work we therefore studied whether this isoform also experiences homologous desensitization and the possible differences with the hH3R445. In clones of CHO-K1 cells stably expressing similar receptor levels (211 +/- 12 and 199 +/- 16 fmol/mg protein for hH3R445 and hH3R365, respectively), there were no differences in receptor affinity for selective H3R ligands or for agonist-induced [35S]-GTPgammaS binding to membranes and inhibition of forskolin stimulated cAMP accumulation in intact cells. For both cell clones, pre incubation with the H3R agonist RAMH (1 MUM) resulted in functional receptor desensitization, as indicated by cAMP accumulation assays, and loss of receptors from the cell surface and reduced affinity for the agonist immepip in cell membranes, evaluated by radioligand binding. However, functional desensitization differed in the maximal extent (96 +/- 15% and 58 +/- 8% for hH3R445 and hH3R365, respectively) and the length of pre-exposure required to reach the maximum desensitization (60 and 30 min, respectively). Furthermore, the isoforms differed in their recovery from desensitization. These results indicate that the hH3R365 experiences homologous desensitization, but that the process differs between the isoforms in time-course, magnitude and re-sensitization. PMID- 29162486 TI - Cadmium body burden and pregnancy-induced hypertension. AB - Previous studies provided a strong evidence of the association between environmental exposure to cadmium (Cd) and hypertension in the general population. However, the role of Cd in pregnancy-induced hypertension (PIH) remains unclear. A total of 5429 pregnant women was selected from a birth cohort in Wuhan, China to investigate the association between Cd exposure and risk of PIH. Among them, 199 (3.7%) women were diagnosed with PIH. The Cd concentrations in maternal urine collected at delivery were measured by inductively coupled plasma mass spectrometry. Multivariable logistic regression was performed on Cd concentrations as a continuous variable (natural logarithm transformed) or as a categorical variable (tertiles). For about 3-fold increase in urinary Cd concentrations, there was 75% increase in the odds of PIH after adjusting for potential confounders (odds ratio (OR) =1.75; 95% confidence interval (CI): 1.45, 2.11). Women in the highest tertile of urinary Cd had 2.2-fold increased OR of PIH, compared with women in the lowest tertile (2.24; 95% CI: 1.47, 3.41). Furthermore, we found a significant interaction between Cd exposure and maternal socioeconomic status on PIH (P for interaction=0.04). Our findings indicate that higher Cd exposure might increase the risk of PIH, and the association might be modified by socioeconomic status. PMID- 29162487 TI - Molecular pathways of cell-mediated degradation of fibrillar collagen. AB - Fibrillar collagens are the most abundant components of the extracellular matrix and provide stability to connective tissues, such as bone, cartilage and skin. An imbalance in collagen turnover inevitably affects the function of these tissues. Therefore, the molecular and cellular mechanisms involved in the synthesis and degradation of collagen have received increasing attention. This short review attempts to summarize our present understanding of how different pathways of collagen degradation are used by different cell types. PMID- 29162488 TI - Transcription analysis of the interaction between chicken thymus and recombinant avian leukosis virus isolate FJ15HT0. AB - Avian leukosis virus (ALV) induces multiple avian tumors, growth decrease and immune suppression. Previously, a novel natural recombinant ALV isolate FJ15HT0 was proven to be associated with significant body weight decrease, immune suppression and lymphocytoma in infected SPF chickens. In order to uncover the interaction between virus and host, we compared differences in the transcriptomes of the thymuses from the mock chickens and simulated congenitally infected chickens at 5days (d), 13d and 21d of age by RNA-seq analysis of the thymuses. Signaling pathways including cytokine-cytokine receptor interactions, peroxisome proliferator-activated receptor (PPAR) signaling pathway, Janus tyrosine kinase/signal transducers and activators of transcription (Jak-STAT) signaling pathway and fatty acid degradation were involved in the interaction between FJ15HT0 and SPF chickens. Interestingly, fold change of ciliary neurotrophic factor receptor alpha (CNTFRalpha) in infected donor collected from 2d to 21d showed a significant positive correlation with the corresponding expression of the viral gp85 gene in thymuses (r=0.656, P<0.01) and in livers (r=0.525, P<0.05). It will provide new insights for the molecular pathogenesis of ALV infection. PMID- 29162489 TI - In-silico evaluation based on public data: In search of forensically efficient tri- and tetrallelic X-SNPs. PMID- 29162490 TI - Qualitative and quantitative assessment of cartilage degeneration using full field optical coherence tomography ex vivo. AB - OBJECTIVE: The purpose of this study was to investigate the ability of full-field optical coherence tomography (FFOCT) to qualitatively and quantitatively evaluate cartilage degeneration using the qualitative evaluation of histology sections as the reference. DESIGN: Thirty-three human knee cartilage samples of variable degeneration were included in the study. A closely matching histology and FFOCT image was acquired for each sample. The cartilage degeneration was qualitatively evaluated by assigning a grade to each histology and FFOCT image. The relevance of the performed grading was assessed by calculating the intra- and inter observer reproducibility and calculating the concordance between the histology and FFOCT grades. A near-automatic algorithm was developed to quantitatively characterize the cartilage surface in each image. The correlation between the quantitative results and the reference qualitative histology was calculated. RESULTS: An almost perfect agreement was achieved for both the intra- and inter reproducibility of the histology and FFOCT qualitative grading (kappa >= 0.91). A high and statistically significant level of agreement was measured between the histology and FFOCT grades (W = 0.95, P < 0.05). Strong and statistically significant correlations were measured between the quantitative results and the reference qualitative histology grades (rho >= 0.75, P < 0.05). CONCLUSIONS: We have demonstrated that FFOCT is an alternative approach to conventional optical coherence tomography (OCT) that is as well adapted for the qualitative and quantitative assessment of human cartilage as the reference gold standard - histology. This study constitutes the first promising results towards developing a new diagnostic tool in the field of osteoarthritis. PMID- 29162491 TI - Effectiveness of individual strategies for the empowerment of patients with diabetes mellitus: A systematic review with meta-analysis. AB - AIMS: To identify and evaluate the effectiveness of individual empowerment strategies in patients with diabetes mellitus (DM). METHODS: A systematic review was performed in the PubMed, Scopus, Science Direct and BVS. For meta-analysis and evaluation of Cochrane Risk and Bias, Revman V 5.2 software was used. RESULTS: Eleven studies of 1073 publications met the inclusion criteria. The strategies used were individual consultations, phone calls, sessions via a website and use of a booklet. Glycemic Hemoglobin (HbA1c) was used to evaluate the effectiveness of the strategies, and 45.4% of the studies also used the Diabetes Empowerment Scale. Five studies (45.5%) showed significant improvements in HbA1c reduction, improvements in self-efficacy (18.2%), knowledge levels of DM (18.2%), quality of life (18.2%). However, after meta-analysis, no statistically significant improvement was found for HbA1c. CONCLUSION: This systematic review showed that individual strategies for DM empowerment were not effective in reducing HbA1c, despite contributing to improvements in psychosocial parameters. Therefore, individual strategies need to be reviewed so that they become effective in DM control. PMID- 29162492 TI - Field testing of a novel colour indicator added to chlorine solutions used for decontamination of surfaces in Ebola treatment units. AB - Disinfection with chlorine solution was used in West Africa to prevent transmission of Ebola virus disease. This study surveyed 94 healthcare personnel and community leaders in Liberia and Guinea to assess understanding of disinfection and evaluate feedback on the perceived usefulness of Highlight, a new colour indicator designed to improve chlorine disinfection procedures. Using a Likert-type scale questionnaire, respondents agreed or strongly agreed (P<0.0001) that Highlight improved coverage of chlorine solution and feelings of confidence. PMID- 29162493 TI - Outbreak of gentamicin-resistant, meticillin-susceptible Staphlococcus aureus on a neonatal unit. AB - BACKGROUND: This report describes an outbreak of gentamicin-resistant, meticillin resistant Staphylococcus aureus (GR MSSA) which occurred on a 21-bed neonatal unit (NNU) in Ninewells Hospital, Dundee, UK. METHODS: An outbreak investigation was triggered by two new GR MSSA isolates from babies admitted directly to the NNU who had acquired this organism during their stay. Data on MSSA cases and antibiograms of patient isolates were flagged as an alert, and microbiology records were trawled to detect previous cases. FINDINGS: Eight babies were affected by the outbreak strain over six months. Typing of all isolates by pulsed field gel electrophoresis and spa typing showed that all were clonal complex 30, spa type t012. None of the outbreak strains were associated with bacteraemia, apart from one baby who was born at 24 weeks of gestation with a birth weight of 500 g. Observation of practice and environmental swabbing of an incubator suggested that this was the most likely source of spread of the outbreak strain. Three of 11 surfaces sampled were positive for the outbreak strain. On inspection, it was found that the impeller was not removed routinely during cleaning, and debris was seen in the housing. Swabs that were taken from the impeller and housing yielded the outbreak strain. CONCLUSION: GR MSSA isolates from the NNU have been set up as an alert organism on the infection control system. No further cases were detected over one year of follow-up after full compliance with the new guidelines for cleaning and disinfection of incubators was implemented. PMID- 29162494 TI - Prevalence of multidrug-resistant organisms in migrant children admitted to an Italian cardiac surgery department, 2015-2016. AB - Screening on hospital admission to identify multidrug-resistant organism (MDRO) colonization is a frequently discussed topic. We report the results of microbiological screening in 141 Italian and 354 migrant children candidates for cardiac surgery conducted in 2015-2016. In all, 25% of Italian children and more than 65.4% of African and Romanian children carried at least one MDRO (meticillin resistant Staphylococcus aureus; extended-spectrum beta-lactamase enzymes; carbapenemase producers; and vancomycin-resistant enterococci). Based on our findings, we propose that non-geographically limited approaches are needed to improve infection prevention and control. PMID- 29162495 TI - The morphology of mouthparts, wings and genitalia of Paleozoic insect families Protohymenidae and Scytohymenidae reveals new details and supposed function. AB - Megasecoptera is an extinct group of insects with specialized rostrum-like mouthparts, which is a synapomorphy shared with all members of the Late Paleozoic Palaeodictyopterida, and markedly slender wings that are unable to flex backwards. Here we describe the close up morphology of Protohymenidae and Scytohymenidae and uncover new aspects of the endoskeleton (tentorium) of the head, structure of the mouthparts with discernible proximal part of stylets controlled by muscles, surface of compound eyes that consist of a hexagonal pattern of large facets, structure and microstructures on the wings and reconstruct male and female external genitalia using ESEM and light stereomicroscopy. Furthermore, we describe Protohymen novokshonovi sp. n. based on an exceptionally well preserved fossil from the early Permian at Tshekarda in Russia, which shows crucial details, and the earliest species of Protohymenidae, Carbohymen testai gen. et sp. n. from a late Carboniferous siderite nodule at Mazon Creek in Illinois, USA. Our comparative study confirmed a set of structural and microstructural details on their wings, such as the composite anterior wing margin, development of an apical cell and the previously unknown external genitalia. Based on the results and comparison of homologous structures known primarily for extant relatives, such as mayflies and dragonflies, we outline for the first time the function of the mouthparts, in particular, the stylets, structure of the tentorium, vision provided by large hexagonal ommatidia and male copulatory structures bearing curved claspers for holding a female during copulation and penial lobes with seminal grooves. PMID- 29162498 TI - The validation of a sensitive, non-toxic in vivo metabolic assay applicable across zebrafish life stages. AB - Energy expenditure and metabolism, is a well-studied field as it is linked to many diseases as dysregulation of metabolism is associated with cancer, neurodegeneration, and aging. Classical methods of studying metabolism in vivo are well established, but most are tedious and expensive, thus, finding methods of accurately measuring metabolism in living organisms that is quick and non invasive is of strong interest. In this work, we validate the use of resazurin; a compound that is conformationally changed into fluorescent resorufin upon metabolic reduction by NADH2, as a metabolic assay for adult zebrafish. This assay is based on the principle that increases in resorufin fluorescence intensity (FI) conveys relative changes in metabolic output of the organisms. We demonstrate the effectiveness of resazurin in measuring metabolic changes in zebrafish larvae and adults in relation to number of pooled fish, as well as temperature alteration. Moreover, we provide details on the appropriate and optimized diluents and concentrations of resazurin. Further, by using a novel sample collection technique, we can increase the temporal possibilities that were previously limited, as well as show that samples can be stored and measured at a later time point with no decrease in accuracy. Thus, the validation of this assay in adult zebrafish may increase the versatility and complexity of the types of experiments that can be performed and have many practical applications in the field. PMID- 29162499 TI - Metabolic strategies for the degradation of the neuromodulator agmatine in mammals. AB - Agmatine (1-amino-4-guanidinobutane), a precursor for polyamine biosynthesis, has been identified as an important neuromodulator with anticonvulsant, antineurotoxic and antidepressant actions in the brain. In this context it has emerged as an important mediator of addiction/satiety pathways associated with alcohol misuse. Consequently, the regulation of the activity of key enzymes in agmatine metabolism is an attractive strategy to combat alcoholism and related addiction disorders. Agmatine results from the decarboxylation of L-arginine in a reaction catalyzed by arginine decarboxylase (ADC), and can be converted to either guanidine butyraldehyde by diamine oxidase (DAO) or putrescine and urea by the enzyme agmatinase (AGM) or the more recently identified AGM-like protein (ALP). In rat brain, agmatine, AGM and ALP are predominantly localised in areas associated with roles in appetitive and craving (drug-reinstatement) behaviors. Thus, inhibitors of AGM or ALP are promising agents for the treatment of addictions. In this review, the properties of DAO, AGM and ALP are discussed with a view to their role in the agmatine metabolism in mammals. PMID- 29162496 TI - Clinical information extraction applications: A literature review. AB - BACKGROUND: With the rapid adoption of electronic health records (EHRs), it is desirable to harvest information and knowledge from EHRs to support automated systems at the point of care and to enable secondary use of EHRs for clinical and translational research. One critical component used to facilitate the secondary use of EHR data is the information extraction (IE) task, which automatically extracts and encodes clinical information from text. OBJECTIVES: In this literature review, we present a review of recent published research on clinical information extraction (IE) applications. METHODS: A literature search was conducted for articles published from January 2009 to September 2016 based on Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Scopus, Web of Science, and ACM Digital Library. RESULTS: A total of 1917 publications were identified for title and abstract screening. Of these publications, 263 articles were selected and discussed in this review in terms of publication venues and data sources, clinical IE tools, methods, and applications in the areas of disease- and drug-related studies, and clinical workflow optimizations. CONCLUSIONS: Clinical IE has been used for a wide range of applications, however, there is a considerable gap between clinical studies using EHR data and studies using clinical IE. This study enabled us to gain a more concrete understanding of the gap and to provide potential solutions to bridge this gap. PMID- 29162497 TI - Expression signatures of early-stage and advanced medaka melanomas. AB - Melanoma is one of the most aggressive tumors with a very low survival rate once metastasized. The incidence of newly detected cases increases every year suggesting the necessity of development and application of innovative treatment strategies. Human melanoma develops from melanocytes localized in the epidermis of the skin to malignant tumors because of deregulated effectors influencing several molecular pathways. Despite many advances in describing the molecular changes accompanying melanoma formation, many critical and clinically relevant molecular features of the transformed pigment cells and the underlying mechanisms are largely unknown. To contribute to a better understanding of the molecular processes of melanoma formation, we use a transgenic medaka melanoma model that is well suited for the investigation of melanoma tumor development because fish and human melanocytes are both localized in the epidermis. The purpose of our study was to gain insights into melanoma development from the first steps of tumor formation up to melanoma progression and to identify gene expression patterns that will be useful for monitoring treatment effects in drug screening approaches. Comparing transcriptomes from juvenile fish at the tumor initiating stage with nevi and advanced melanoma of adults, we identified stage specific expression signatures and pathways that are characteristic for the development of medaka melanoma, and are also found in human malignancies. PMID- 29162501 TI - Comparison of the effects of local anesthesia and epidural anesthesia for percutaneous transforaminal endoscopic discectomy in elderly patients over 65 years old. AB - BACKGROUND: Local anesthesia (LA) is recommended for percutaneous transforaminal endoscopic discectomy (PTED) but clinical practice indicates that LA cannot achieve satisfactory pain management during PTED. OBJECTIVES: The study aimed to investigate the comparisons between LA and EA for PTED in elderly population over 65 years old. METHODS: We performed a retrospective analysis of patients over 65 years old received PTED from May 2013 to December 2014. And patients were divided into two groups according to the anesthesia method. The data collected for analysis including operative time, fluoroscopy time, postoperative bed time, visual analog scale (VAS), Oswestry Back Pain Disability Index (ODI), the global outcome based on the Macnab outcome criteria, satisfaction rate of anesthesia, and complications. RESULTS: A total of 132 consecutive patients were enrolled in this study. There were 65 patients in LA group and 67 patients in EA group. Compared to LA group, EA group had longer operative time (P < 0.001) and postoperative bed time (P < 0.001) but shorter fluoroscopy time, (P < 0.001), smaller VAS score of lumbar pain intraoperatively (P < 0.001), 1-h postoperatively (P < 0.001) and 1-week postoperatively (P < 0.001). Similarly, EA group had lower VAS score of leg pain intraoperatively (P < 0.001) and 1-h postoperatively (P < 0.001). In additions, higher satisfaction rate of anesthesia was observed in EA group (P = 0.029). CONCLUSIONS: EA and LA for PTED achieved comparable clinical outcomes in elderly population over 65 years old. However, compared to LA for PTED, EA had a better performance in pain management. PMID- 29162502 TI - Vagus nerve magnetic modulation facilitates dysphagia recovery in patients with stroke involving the brainstem - A proof of concept study. AB - BACKGROUND & AIMS: Stroke involving the brainstem (SBS) causes severe oropharyngeal dysphagia (OD). Research on the therapeutic efficacy of vagus nerve modulation (VNM) by using repetitive transcranial magnetic stimulation (rTMS) in SBS patients with OD has been limited thus far. We aimed to assess the effect of VNM by using rTMS in improving swallowing function after SBS. METHOD: We conducted a sham-controlled, double-blinded, parallel pilot study in 28 SBS patients with OD randomly allocated to a real rTMS group (n = 13; TMSreal) or a sham group (n = 15; TMSsham). For VNM, 5-Hz rTMS was applied to the left mastoid in 10 sessions. We evaluated all patients for swallowing function before and after rTMS conditioning, assessed on the 8-point Penetration-Aspiration Scale (PAS) through videofluoroscopy and the Australian Therapy Outcome Measures Swallowing scale (AusTOMs). We measured the amplitude and latency of cricopharyngeal motor evoked potentials (CP-MEPs) as the neurophysiological parameters. RESULTS: TMSreal exhibited significant improvement in all swallowing outcomes-neurophysiological, radiological, and functional-compared with TMSsham: We noted higher CP-MEP amplitude (p = 0.004), shorter CP-MEP latency (p = 0.004), a lower PAS score (p = 0.001), and a higher AusTOMs score (p < 0.001) following rTMS in TMSreal. Moreover, the neurophysiological improvements were significantly correlated with the functional outcomes (p < 0.05). CONCLUSIONS: Our results encourage the application of VNM by using rTMS for improving swallowing function after SBS. The immediate therapeutic effects suggest that this novel intervention can be an effective complementary therapy to traditional oropharyngeal rehabilitation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02893033. PMID- 29162500 TI - The emerging role of immune dysfunction in mitochondrial diseases as a paradigm for understanding immunometabolism. AB - Immunometabolism aims to define the role of intermediary metabolism in immune cell function, with bioenergetics and the mitochondria recently taking center stage. To date, the medical literature on mitochondria and immune function extols the virtues of mouse models in exploring this biologic intersection. While the laboratory mouse has become a standard for studying mammalian biology, this model comprises part of a comprehensive approach. Humans, with their broad array of inherited phenotypes, serve as a starting point for studying immunometabolism; specifically, patients with mitochondrial disease. Using this top-down approach, the mouse as a model organism facilitates further exploration of the consequences of mutations involved in mitochondrial maintenance and function. In this review, we will discuss the emerging phenotype of immune dysfunction in mitochondrial disease as a model for understanding the role of the mitochondria in immune function in available mouse models. PMID- 29162503 TI - Global structural integrity and effective connectivity in patients with disorders of consciousness. AB - BACKGROUND: Previous studies have separately reported impaired functional, structural, and effective connectivity in patients with disorders of consciousness (DOC). The perturbational complexity index (PCI) is a transcranial magnetic stimulation (TMS) derived marker of effective connectivity. The global fractional anisotropy (FA) is a marker of structural integrity. Little is known about how these parameters are related to each other. OBJECTIVE: We aimed at testing the relationship between structural integrity and effective connectivity. METHODS: We assessed 23 patients with severe brain injury more than 4 weeks post onset, leading to DOC or locked-in syndrome, and 14 healthy subjects. We calculated PCI using repeated single pulse TMS coupled with high-density electroencephalography, and used it as a surrogate of effective connectivity. Structural integrity was measured using the global FA, derived from diffusion weighted imaging. We used linear regression modelling to test our hypothesis, and computed the correlation between PCI and FA in different groups. RESULTS: Global FA could predict 74% of PCI variance in the whole sample and 56% in the patients' group. No other predictors (age, gender, time since onset, behavioural score) improved the models. FA and PCI were correlated in the whole population (r = 0.86, p < 0.0001), the patients, and the healthy subjects subgroups. CONCLUSION: We here demonstrated that effective connectivity correlates with structural integrity in brain-injured patients. Increased structural damage level decreases effective connectivity, which could prevent the emergence of consciousness. PMID- 29162506 TI - Expression of the BRAF L597Q mutation in sporadic neurofibromas of the upper extremity. AB - The pathogenesis of neurofibromas is poorly understood outside of neurofibromatosis (NF). The BRAF proto-oncogene has been implicated in malignant peripheral nerve sheath tumors (PNSTs), however its role in neurofibromas has not been described. In this study, we identify a BRAF mutation in a 61-year old non NF patient with a history of sporadic and recurrent neurofibromas localized to the right upper extremity. Despite repeat resections to establish local control, he developed median nerve neuropathy secondary to a 13*4cm plexiform neurofibroma. Genetic sequencing of the neurofibroma revealed the expression of a novel BRAF L597Q mutation. This study is the first to describe the BRAF L597Q mutation in PNSTs and the first to implicate a BRAF mutation in neurofibroma biology. We hypothesize that BRAF mutations may identify a molecularly-distinct subset of recurrent neurofibromas and may provide potential for targeted therapeutics. PMID- 29162505 TI - Salivary proteins alter taste-guided behaviors and taste nerve signaling in rat. AB - Taste stimuli are normally dissolved in saliva prior to interacting with their respective receptor targets. There are hundreds of proteins in saliva, and it has been hypothesized that these proteins could interact with either taste stimuli or taste receptors to alter taste signaling and diet acceptance. However, the impact of these proteins on feeding has been relatively unexplored using rodent models. We have developed a novel technique for saliva collection that allows us to link salivary protein expression with feeding behavior. First, we monitored the microstructure of rats' feeding patterns on a 0.375% quinine diet (Q-diet) while tracking changes in salivary protein expression. We found 5 protein bands were upregulated by diet exposure to Q-diet and upregulation of a subset of these bands were statistically related to increased diet acceptance, including changes in behavioral measures that are thought to represent both orosensory and postingestive signaling. In a second experiment, we measured the licking to a range of quinine solutions (0.01-1.0mM) before and after the animals were exposed to a tannic acid diet that altered salivary protein expression. Rats found the quinine solutions less aversive after salivary protein altering diets. In a third experiment we recorded the response of the chorda tympani (CT) nerve while delivering quinine solutions (0.3-30mM) to the front of the tongue dissolved in either "donor saliva" containing salivary proteins or donor saliva which has had the salivary proteins removed. Donor saliva was collected from a separate group of animals using isoproterenol and pilocarpine. The samples containing salivary proteins resulted in lower nerve responses than those without salivary proteins. Together these data suggest that salivary proteins are capable of altering taste guided behaviors and taste nerve signaling. PMID- 29162507 TI - Biomechanical property and modelling of venous wall. AB - Human saphenous vein has long been used as coronary artery bypass grafts to survive a heart arrested by blocked coronary arteries. Biomechanical properties of the saphenous vein can be critical because mismatch in the biomechanical property between a coronary artery and a graft will reduce graft patency and speed up disease development in the graft. In this paper hence the active and passive biomechanical behaviours of the human saphenous vein and other venous walls were reviewed extensively and comprehensively. The existing in vitro uniaxial, bulge, planar and tubular biaxial tensile testing methods, in vivo testing cases, property variables, various tested results, constitutive models and their mathematical modelling methods, viscoelasticity, and residual strain/stress are highlighted and summarized. It is demonstrated that the biomechanical properties of the human saphenous vein and other venous walls are not well documented, and their modelling approaches are limited and subjected to be updated in a great deal. Additionally, a few important research issues are proposed. The paper has provided a piece of useful information to investigation into coronary artery bypass grafts. PMID- 29162508 TI - Targeted delivery of nucleic acids into xenograft tumors mediated by novel folate equipped liposomes. AB - Folate receptors (FR) are cellular markers highly expressed in various cancer cells. Here, we report on the synthesis of a novel folate-containing lipoconjugate (FC) built of 1,2-di-O-ditetradecyl-rac-glycerol and folic acid connected via a PEG spacer, and the evaluation of the FC as a targeting component of liposomal formulations for nucleic acid (NA) delivery into FR expressing tumor cells. FR-targeting liposomes, based on polycationic lipid 1,26-bis(cholest-5-en 3beta-yloxycarbonylamino)-7,11,16,20-tetraazahexacosan tetrahydrochloride (2X3), lipid helper dioleoylphosphatidylethanolamine (DOPE) and novel FC, formed small compact particles in solution with diameters of 60 +/- 22 nm, and were not toxic to cells. Complexes of NAs with the liposomes were prepared at various nitrogen to phosphate ratios (N/P) to optimize liposome/cell interactions. We showed that FR-mediated delivery of different nucleic acids mediated by 2X3-DOPE/FC liposomes occurs in vitro at low N/P (1/1 and 2/1); under these conditions FC-containing liposomes display 3-4-fold higher transfection efficiency in comparison with conventional formulation. Lipoplexes formed at N/P 1/1 by targeted liposomes and cargo (Cy7-labeled siRNA targeting MDR1 mRNA) in vivo efficiently accumulate in tumor (~15-18% of total amount), and kidneys (71%), and were retained there for more than 24 h, causing efficient downregulation of p-glycoprotein expression (to 40% of control) in tumors. Thus, FC containing liposomes provide effective targeted delivery of nucleic acids into tumor cells in vitro and in xenograft tumors in vivo. PMID- 29162504 TI - Checks and Balances between Autophagy and Inflammasomes during Infection. AB - Autophagy and inflammasome complex assembly are physiological processes that control homeostasis, inflammation, and immunity. Autophagy is a ubiquitous pathway that degrades cytosolic macromolecules or organelles, as well as intracellular pathogens. Inflammasomes are multi-protein complexes that assemble in the cytosol of cells upon detection of pathogen- or danger-associated molecular patterns. A critical outcome of inflammasome assembly is the activation of the cysteine protease caspase-1, which activates the pro-inflammatory cytokine precursors pro-IL-1beta and pro-IL-18. Studies on chronic inflammatory diseases, heart diseases, Alzheimer's disease, and multiple sclerosis revealed that autophagy and inflammasomes intersect and regulate each other. In the context of infectious diseases, however, less is known about the interplay between autophagy and inflammasome assembly, although it is becoming evident that pathogens have evolved multiple strategies to inhibit and/or subvert these pathways and to take advantage of their intricate crosstalk. An improved appreciation of these pathways and their subversion by diverse pathogens is expected to help in the design of anti-infective therapeutic interventions. PMID- 29162509 TI - Efficient production of solid dispersions by spray drying solutions of high solid content using a 3-fluid nozzle. AB - To evaluate the feasibility of producing solid dispersions with 3-fluid nozzle spray drying to improve the dissolution behavior of lipophilic drugs, 60 experiments were performed based on a Design of Experiment. Solid dispersions with mannitol as a hydrophilic matrix and diazepam as a model drug with a drug load of 20 wt-% were produced. The variables of the experiments were the water/organic solvent ratio, liquid feed flow, total solid content, atomizing airflow and type of organic solvent (ethanol or ethyl acetate). The responses measured were dissolution rate, yield, actual drug load, particle size and crystallinity of diazepam and mannitol. Increasing water/organic solvent ratio was found to be the main factor for enhancing the dissolution rate. The total solid content of the solutions to be spray dried did not affect any of the responses, which means that processing solutions of high concentrations is possible. The choice of organic solvent did not affect the responses as well, i.e. both the fully water miscible solvent ethanol and the poorly water miscible solvent ethyl acetate could be used which makes this production method highly versatile. PMID- 29162510 TI - Unravelling the link between embryogenesis and cancer metastasis. AB - PURPOSE: Cancer as opposed to embryonic development is characterized by dysregulated, uncontrolled and clonal growth of cells. Inspite of that they share certain commonality in gene expression patterns and a number of cellular & molecular features. Consequently, in the present study we aimed to evaluate the role of a definite set of genes in fetal liver, primary liver cancers and metastatic liver tissue. METHODS: The relative expression of fourteen candidate genes obtained by data mining and manual curation of published data (CXCL12, CXCR4, CK7, CDH1, CTNNB1, CLDN4, VEGFA, HIF1A, MMP9, p53, OPN, CDKN2A, TGFBR2, MUC16, beta-actin) were performed on 62 tissues (32 liver metastasis tissues and 30 primary Liver cancer tissues), Fetal liver tissues (below and above 20weeks of gestation) and 2 sets of control samples by real-time quantitative reverse transcription PCR (qRT-PCR). RESULTS: Results showed significant down-regulation of MMP9 and TP53 in Fetal liver above 20weeks of gestation whereas it was up regulated in fetal liver below 20weeks of gestation, primary liver cancers and liver metastasis. Contradictory to that OPN and CDKN2A were significantly up regulated in primary liver cancer, liver metastasis; down-regulated in fetal liver above 20weeks of gestation but were not expressed during early embryo development (below 20weeks of gestation). Moreover, MMP9 and TP53 demonstrated a strong correlation with MUC16 whereas CDKN2A and OPN showed correlation with CXCL12/CXCR4 signifying that MUC16, CXCL12/CXCR4 might be involved in the complex process of cancer metastasis. CONCLUSION: MMP9, OPN, TP53 and CDKN2A were the identified markers that were expressed in a similar pattern in early embryonic development and cancer development & invasion suggesting that these genes are activated during embryogenesis and might be re-expressed in cancer metastasis. Moreover, these genes govern a pathway that might be activated during cancer metastasis. Thus, targeting these molecules may provide better treatment for metastatic liver cancers. PMID- 29162511 TI - The thymidylate synthase enhancer region (TSER) polymorphism increases the risk of thymic lymphoid hyperplasia in patients with Myasthenia Gravis. AB - BACKGROUND: Myasthenia Gravis (MG) is caused, in approximately 80% of the patients, by autoantibodies against the nicotinic acetylcholine receptor (AChR). The disease is often associated with pathological changes of the thymus: thymic epithelial tumours are present in about 10-20% of the patients, while up to 80% of the patients with early disease onset have thymic hyperplasia. Folate metabolism is required for the production of DNA precursors and for proper DNA methylation reactions, and impaired folate metabolism has been often associated with cellular growth and cancer. METHODS: We investigated if major polymorphisms of folate-related genes, namely MTHFR c.677C>T, MTR c.2756A>G, MTRR c.66A>G and TYMS TSER (a 28-bp tandem repeat in the 5' promoter enhancer region of TYMS) increase the risk of pathological changes of the thymus in AChR+ MG patients. A total of 526 AChR+ MG patients, including 132 patients with normal (involuted) thymus, 146 patients with thymic hyperplasia, and 248 patients with a thymoma were included in the study. Allele and genotype comparisons were performed among the three study groups, after correcting for multiple testing. RESULTS: The frequency of the TYMS TSER 3R allele was significantly higher in MG patients with thymic hyperplasia (P=0.004), and the TYMS TSER 3R3R genotype was significantly associated with increased risk of thymic hyperplasia [OR 2.71 (95% CI: 1.34 5.47)]. CONCLUSIONS: The 3R allele in the thymidylate synthase promoter enhancer region results in increased protein production, required for the synthesis of DNA precursors. The present study suggests that the TYMS TSER 3R allele increases the risk of thymic lymphoid hyperplasia in AChR+ MG patients. PMID- 29162513 TI - Homeostatic effect of laughter on diabetic cardiovascular complications: The myth turned to fact. AB - AIMS: Laughter has been used for centuries to alleviate pain in morbid conditions. It was not until 1976 that scientists thought about laughter as a form of therapy that can modulate hormonal and immunological parameters that affect the outcome of many serious diseases. Moreover, laughter therapy was shown to be beneficial in type 2 diabetes mellitus (T2DM) by delaying the onset of many diabetic complications. Laughter is also described to influence the cardiovascular and endothelial functions and thus may protect against diabetic cardiovascular complications. In this review, we outline the different biochemical, physiological and immunological mechanisms by which laughter may influence the overall state of wellbeing and enhance disease prognosis. We also focus on the biological link between laughter therapy and diabetic cardiovascular complications as well as the underlying mechanisms involved in T2DM. METHODS: Reviewing all the essential databases for "laughter" and "type 2 diabetes mellitus". RESULTS: Although laughter therapy is still poorly investigated, recent studies show that laughter may retard the onset of diabetic complications, enhance cardiovascular functions and rectify homeostatic abnormalities associated with T2DM. CONCLUSIONS: Laughter therapy is effective in delaying diabetic complications and should be used as an adjuvant therapy. PMID- 29162512 TI - MMP9 gene expression regulation by intragenic epigenetic modifications in breast cancer. AB - Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Metastasis remains a major challenge for the clinical management and prognosis of patients with cancer. The metalloprotease MMP-9 plays a critical role in the first step of metastasis through extracellular matrix degradation. In this study, our goal was to determine the effect of epigenetic mechanisms in the promoter and intragenic region of this gene and to correlate it to the levels of expression of MMP9 in breast cancer cell lines. We have identified that MMP9 was highly expressed in the breast cancer cell lines MCF7 and MDA-MB-436 after 5-aza-2'-deoxycytidine (5-azadC) treatment. Sequencing of the promoter region as well as the CGI intronic CpG islands showed a specific sequence in CGI2, between CpGs 12-30 that was demethylated after 5-azadC treatment. This specific region was studied in breast cancer samples that revealed similar results with demethylation in positive MMP-9 breast cancer samples. Furthermore, the histone methylation marker of open chromatin (H3K4me3) was found in the promoter and intronic regions of MMP9 after 5-azadC treatment. Taken together these results showed a mechanism of DNA methylation and gene expression regulation by epigenetic marks present in the intronic DNA region of MMP9. PMID- 29162514 TI - Increased sugar intake as a form of compensatory hyperphagia in patients with type 2 diabetes under dapagliflozin treatment. AB - AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) cause substantially less weight loss than would be expected based on their caloric deficits, probably due to enhanced appetite regulation known as "compensatory hyperphagia," which occurs to offset the negative energy balance caused by increased glycosuria. We examined whether any specific nutrients contributed to the compensatory hyperphagia in diabetic patients taking SGLT2i. METHODS: Sixteen patients with type 2 diabetes were newly administered dapagliflozin 5 mg daily as the experimental SGLT2i group. Sixteen age-, sex- and BMI-matched type 2 diabetes patients not receiving dapagliflozin served as controls. A brief-type self-administered diet history questionnaire (BDHQ) was undertaken just before and 3 months after study initiation to evaluate changes of energy and nutrient intakes in each group. RESULTS: At 3 months, daily intakes of total calories and the proportions of the three major nutrients were not significantly increased in either group. However, daily sucrose intake was significantly increased after treatment versus the baseline value in the SGLT2i group (p = .003), but not in controls. The calculated intakes of all other nutrients were not significantly changed in either group. CONCLUSIONS: Dapagliflozin treatment specifically increased sucrose intake, which might be an ideal target for nutritional approaches to attenuate compensatory hyperphagia. PMID- 29162515 TI - Whole-exome sequencing in a Japanese family with highly aggregated diabetes identifies a candidate susceptibility mutation in ADAMTSL3. AB - AIMS: The aim of this study was to clarify the genetic background of a family with multiple cases of diabetes accompanied by absolute insulin deficiency using whole-exome sequencing (WES). METHODS: In a Japanese family, WES was performed in four affected members with absolute insulin deficiency and two unaffected members. We focused on variants that were predicted to be disease-causing by bioinformatics and were shared by all of the four affected members but were not present in the two unaffected members. We assumed that the familial clustering of diabetes was caused by rare variants excluding those with allele frequency of more than 0.01 in the 1000 Genomes Project, the Human Genetic Variation Database, or a cohort of 105 normoglycemic controls in Japan. The rare variants were then genotyped in 2102 Japanese without diabetes and 119 Japanese with diabetes. RESULTS: Among the variants detected by WES and predicted to be disease-causing, 16 variants shared by all of the four of the affected members and not present in the two unaffected members were confirmed to be rare. Genotyping of the 16 rare variants revealed that only A137T in ADAMTSL3 (rs181914721) was observed more frequently in the 119 subjects with diabetes than in the 105 normoglycemic controls, and the allele frequency of the variant was significantly higher in the 119 subjects with diabetes than in another cohort of 2102 Japanese without diabetes. CONCLUSIONS: We propose that A137T in ADAMTSL3 is a candidate mutation for susceptibility to diabetes in this family and in the Japanese population. PMID- 29162516 TI - Structure and function of a novel antioxidant peptide from the skin of tropical frogs. AB - The amphibian skin plays an important role protecting the organism from external harmful factors such as microorganisms or UV radiation. Based on biorational strategies, many studies have investigated the cutaneous secretion of anurans as a source of bioactive molecules. By a peptidomic approach, a novel antioxidant peptide (AOP) with in vitro free radical scavenging ability was isolated from Physalaemus nattereri. The AOP, named antioxidin-I, has a molecular weight [M+H]+ = 1543.69Da and a TWYFITPYIPDK primary amino acid sequence. The gene encoding the antioxidin-I precursor was expressed in the skin tissue of three other Tropical frog species: Phyllomedusa tarsius, P. distincta and Pithecopus rohdei. cDNA sequencing revealed highly homologous regions (signal peptide and acidic region). Mature antioxidin-I has a novel primary sequence with low similarity compared with previously described amphibian's AOPs. Antioxidin-I adopts a random structure even at high concentrations of hydrophobic solvent, it has poor antimicrobial activity and poor performance in free radical scavenging assays in vitro, with the exception of the ORAC assay. However, antioxidin-I presented a low cytotoxicity and suppressed menadione-induced redox imbalance when tested with fibroblast in culture. In addition, it had the capacity to substantially attenuate the hypoxia-induced production of reactive oxygen species when tested in hypoxia exposed living microglial cells, suggesting a potential neuroprotective role for this peptide. PMID- 29162518 TI - Ripe for solution: Delayed development of multisensory processing in autism and its remediation. AB - Difficulty integrating inputs from different sensory sources is commonly reported in individuals with Autism Spectrum Disorder (ASD). Accumulating evidence consistently points to altered patterns of behavioral reactions and neural activity when individuals with ASD observe or act upon information arriving through multiple sensory systems. For example, impairments in the integration of seen and heard speech appear to be particularly acute, with obvious implications for interpersonal communication. Here, we explore the literature on multisensory processing in autism with a focus on developmental trajectories. While much remains to be understood, some consistent observations emerge. Broadly, sensory integration deficits are found in children with an ASD whereas these appear to be much ameliorated, or even fully recovered, in older teenagers and adults on the spectrum. This protracted delay in the development of multisensory processing raises the possibility of applying early intervention strategies focused on multisensory integration, to accelerate resolution of these functions. We also consider how dysfunctional cross-sensory oscillatory neural communication may be one key pathway to impaired multisensory processing in ASD. PMID- 29162517 TI - Elevated plasma 8-iso-prostaglandin F2alpha levels in human smokers originate primarily from enzymatic instead of non-enzymatic lipid peroxidation. AB - It is widely accepted that free radicals in tobacco smoke lead to oxidative stress and generate the popular lipid peroxidation biomarker 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha). However, 8-iso-PGF2alpha can simultaneously be produced in vivo by the prostaglandin-endoperoxide synthases (PGHS) induced by inflammation. This inflammation-dependent mechanism has never been considered as a source of elevated 8-iso-PGF2alpha in tobacco smokers. The goal of this study is to quantify the distribution of chemical- and PGHS-dependent 8-iso-PGF2alpha formation in the plasma of tobacco smokers and non-smokers. The influences of gender and hormonal contraceptive use were accounted for. The distribution was determined by measuring the 8-iso-PGF2alpha/prostaglandin F2alpha (PGF2alpha) ratio. When comparing smokers (n = 28) against non-smokers (n = 30), there was a statistically significant increase in the 8-iso-PGF2alpha concentration. The source of this increased 8-iso-PGF2alpha was primarily from PGHS. When stratifying for gender, the increase in 8-iso-PGF2alpha in male smokers (n = 9) was primarily from PGHS. Interestingly, female smokers on hormonal contraceptives had increased 8-iso-PGF2alpha in both pathways, whereas those not on hormonal contraceptives did not have increased 8-iso-PGF2alpha. In conclusion, increased plasma 8-iso-PGF2alpha in tobacco smokers has complex origins, with PGHS dependent formation as the primary source. Accounting for both pathways provides a definitive measurement of both oxidative stress and inflammation. PMID- 29162520 TI - Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: A systematic review and meta-analysis. AB - A systematic review with meta-analyses was performed to: 1) quantify the association between ADHD and risk of unintentional physical injuries in children/adolescents ("risk analysis"); 2) assess the effect of ADHD medications on this risk ("medication analysis"). We searched 114 databases through June 2017. For the risk analysis, studies reporting sex-controlled odds ratios (ORs) or hazard ratios (HRs) estimating the association between ADHD and injuries were combined. Pooled ORs (28 studies, 4,055,620 individuals without and 350,938 with ADHD) and HRs (4 studies, 901,891 individuals without and 20,363 with ADHD) were 1.53 (95% CI=1.40,1.67) and 1.39 (95% CI=1.06,1.83), respectively. For the medication analysis, we meta-analysed studies that avoided the confounding-by indication bias [four studies with a self-controlled methodology and another comparing risk over time and groups (a "difference in differences" methodology)]. The pooled effect size was 0.879 (95% CI=0.838,0.922) (13,254 individuals with ADHD). ADHD is significantly associated with an increased risk of unintentional injuries and ADHD medications have a protective effect, at least in the short term, as indicated by self-controlled studies. PMID- 29162519 TI - Meta-analysis of regional white matter volume in bipolar disorder with replication in an independent sample using coordinates, T-maps, and individual MRI data. AB - Converging evidence suggests that bipolar disorder (BD) is associated with white matter (WM) abnormalities. Meta-analyses of voxel based morphometry (VBM) data is commonly performed using published coordinates, however this method is limited since it ignores non-significant data. Obtaining statistical maps from studies (T maps) as well as raw MRI datasets increases accuracy and allows for a comprehensive analysis of clinical variables. We obtained coordinate data (7 studies), T-Maps (12-studies, including unpublished data) and raw MRI datasets (5 studies) and analysed the 24 studies using Seed-based d Mapping (SDM). A VBM analysis was conducted to verify the results in an independent sample. The meta analysis revealed decreased WM volume in the posterior corpus callosum extending to WM in the posterior cingulate cortex. This region was significantly reduced in volume in BD patients in the independent dataset (p=0.003) but there was no association with clinical variables. We identified a robust WM volume abnormality in BD patients that may represent a trait marker of the disease and used a novel methodology to validate the findings. PMID- 29162521 TI - Intrinsic insula network engagement underlying children's reading and arithmetic skills. AB - The neural substrates of children's reading and arithmetic skills have long been of great interest to cognitive neuroscientists. However, most previous studies have focused on the contrast between these skills as specific domains. Here, we investigate the potentially shared processes across these domains by focusing on how the neural circuits associated with cognitive control influence reading and arithmetic proficiency in 8-to-10-year-old children. Using a task-free resting state approach, we correlated the intrinsic functional connectivity of the right anterior insula (rAI) network with performance on assessments of Chinese character recognition, reading comprehension, subtraction, and multiplication performance. A common rAI network strengthened for reading and arithmetic skill, including the right middle temporal gyrus (MTG) and superior temporal gyrus (STG) in the lateral temporal cortex, as well as the inferior frontal gyrus (IFG). In addition, performance measures evidenced rAI network specializations. Single character recognition was uniquely associated with connectivity to the right superior parietal lobule (SPL). Reading comprehension only, rather than character recognition, was associated with connectivity to the right IFG, MTG and angular gyrus (AG). Furthermore, subtraction was associated with connectivity to premotor cortex whereas multiplication was associated with the supramarginal gyrus. Only reading comprehension and multiplication were associated with hyper connectivity within local rAI network. These results indicate that during a critical period for children's acquisition of reading and arithmetic, these skills are supported by both intra-network synchronization and inter-network connectivity of rAI circuits. Domain-general intrinsic insular connectivity at rest contained also, functional components that segregated into different sets of skill-related networks. The embedded components of cognitive control may be essential to understanding the interplay of multiple functional circuits necessary to more fully characterize cognitive skill acquisition. PMID- 29162522 TI - Loss of consciousness is related to hyper-correlated gamma-band activity in anesthetized macaques and sleeping humans. AB - Loss of consciousness can result from a wide range of causes, including natural sleep and pharmacologically induced anesthesia. Important insights might thus come from identifying neuronal mechanisms of loss and re-emergence of consciousness independent of a specific manipulation. Therefore, to seek neuronal signatures of loss of consciousness common to sleep and anesthesia we analyzed spontaneous electrophysiological activity recorded in two experiments. First, electrocorticography (ECoG) acquired from 4 macaque monkeys anesthetized with different anesthetic agents (ketamine, medetomidine, propofol) and, second, stereo-electroencephalography (sEEG) from 10 epilepsy patients in different wake sleep stages (wakefulness, NREM, REM). Specifically, we investigated co activation patterns among brain areas, defined as correlations between local amplitudes of gamma-band activity. We found that resting wakefulness was associated with intermediate levels of gamma-band coupling, indicating neither complete dependence, nor full independence among brain regions. In contrast, loss of consciousness during NREM sleep and propofol anesthesia was associated with excessively correlated brain activity, as indicated by a robust increase of number and strength of positive correlations. However, such excessively correlated brain signals were not observed during REM sleep, and were present only to a limited extent during ketamine anesthesia. This might be related to the fact that, despite suppression of behavioral responsiveness, REM sleep and ketamine anesthesia often involve presence of dream-like conscious experiences. We conclude that hyper-correlated gamma-band activity might be a signature of loss of consciousness common across various manipulations and independent of behavioral responsiveness. PMID- 29162523 TI - Specific visualization of neuromelanin-iron complex and ferric iron in the human post-mortem substantia nigra using MR relaxometry at 7T. AB - Neuromelanin (NM) is an endogenous iron chelating molecule of pigmented neurons in the human substantia nigra (SN). Along with the increase in iron deposition, the reduction in NM-containing dopaminergic neurons and the variation of iron load on NM are generally considered to be important factors participating to pathogenesis of Parkinson's disease (PD). The aim of this study was to non invasively delineate the spatial distributions of paramagnetic magnetic susceptibility perturbers, such as NM-iron complex and ferric iron in SN. Multiple quantitative MR parameters of T1, T2, T2*, susceptibility weighted image (SWI), quantitative susceptibility map (QSM), and T1 weighted image with magnetization transfer (MT) effects were acquired for six post-mortem SN samples without a history of neurological disease. Co-registered quantitative histological validations were performed to identify and correlate NM pigments, iron deposits, and myelin distributions with respect to associated MR parameters. The regions with NM pigments and iron deposits showed positive magnetic susceptibility (paramagnetic) values, while myelinated areas showed negative magnetic susceptibility (diamagnetic) values from the QSM. The region of reduced T2 values in SN mostly coincided with high iron deposits, but not necessarily with the NM pigments. The correlations between T2*/T2 (or T2*/T22) values and NM pigments were higher than those between T2* values and NM pigments, due to the effective size differences between NM-iron complex and ferric iron. Consequently, separate segmentations of ferric iron from the T2 map and NM-iron complex from the T2*/T2 map (or T2*/T22 map) were possible with the boundary of the SN determined from the T1 weighted image. PMID- 29162524 TI - The Impact of Aneurysm Location on Incidence and Etiology of Hyponatremia Following Subarachnoid Hemorrhage. AB - BACKGROUND: Hyponatremia is the most common electrolyte abnormality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt wasting (CSW) are the most common etiologies. Whether or not the location of the ruptured aneurysm is associated with the etiology of hyponatremia is unknown. We sought to determine whether or not the incidence of SIADH and CSW after aSAH differed based on aneurysm location. METHODS: Retrospective analysis of 335 consecutive patients who presented with aSAH at a single institution was performed. Patients were included if they developed hyponatremia before postbleed day 14. Electronic health records were reviewed to obtain data regarding aneurysm location, treatment, etiology of hyponatremia, and modified Rankin Scale score at hospital discharge. RESULTS: Inclusion criteria were met by 114 patients. There were 67 (59%) anterior circulation aneurysms and 47 (41%) posterior circulation aneurysms. Of patients, 85 (75%) had hyponatremia owing to SIADH, 14 (12%) had CSW, and 15 (13%) did not fit either etiology. SIADH was more common than CSW in anterior circulation aneurysms (90%) compared with posterior circulation aneurysms (75%). This trended toward, but did not reach, statistical significance (P = 0.08). More severe Hunt and Hess grades were associated with the development of CSW rather than SIADH (P = 0.002). CONCLUSIONS: SIADH is much more common than CSW in patients with aSAH. Anterior circulation aneurysms may be associated with a higher rate of SIADH than posterior circulation aneurysms. PMID- 29162525 TI - Surgical Outcome of Very Small Intracranial Aneurysms Utilizing the Double Clip Technique. AB - OBJECTIVES: To report the outcome of patients with very small intracranial aneurysm (VSIA) undergoing surgical clipping using a double-clip technique. METHODS: This cross-sectional study was conducted in Namazi Hospital, the main referral neurovascular center in Southern Iran during a 6-year period from September 2010 to March 2016. All patients with VSIAs (<=3 mm) undergoing surgery with double-clip technique were included. This technique reduces the clip slippage. The short- and long-term outcomes determined by Glasgow outcome score (GOS), modified Rankin Scale (MRS), and complications. RESULTS: Operations were performed on 32 VSIAs in 26 patients with a mean +/- SD age of 55.7 +/- 10.1 years. Middle cerebral artery was the most common location for VSIA (50.0%). There was no neck remnant, and the complete occlusion rate was 100%. The rate of intraoperative aneurysm rupture was 30.8%, and none of the patients experienced rebleeding. The 6-month mortality rate was 0% in ruptured VSIAs and 6.25% in unruptured VSIAs. Most of the patients had favorable outcomes (88.5%), and the overall mortality rate was 11.5%. The rate of permanent neurologic deficit was 10.0% in ruptured and 12.5% in unruptured VSIAs. Multivariate logistic regression analysis revealed no association between baseline and clinical characteristics and outcome in this series. CONCLUSION: VSIAs are difficult to treat because of their small sizes; therefore, with a double-clip technique, one can reduce complications related to the treatment of small aneurysms. PMID- 29162526 TI - Surgical Resection of Anterior and Posterior Butterfly Glioblastoma. AB - BACKGROUND: Evidence suggests a survival benefit for patients with glioblastoma who undergo maximal safe surgical resection. Not all glioblastomas are amenable to surgical resection and anatomic location is one potentially limiting factor. Glioblastomas that invade the corpus callosum and cross midline to the contralateral hemisphere-butterfly glioblastomas (bGBMs)-are one subgroup of tumors traditionally deemed inoperable. METHODS: We evaluate the management of bGBMs at our institution to assess whether surgical resection is feasible, safe, and more effective than biopsy. We retrospectively reviewed our institutional brain tumor registry for all adult patients treated for glioblastoma (World Health Organization grade IV) between 2004 and 2016 to identify all bGBMs. RESULTS: Survival between biopsy and resection was assessed using the Kaplan Meier model. Twenty-nine (3.8%) of 764 newly diagnosed GBMs were identified as bGBM. Of these, 9 patients (31.0%) underwent surgical resection and 20 patients (69.0%) underwent biopsy. Five patients (55.6%) in the surgical resection group had 98% extent of resection or greater. Median survival of our entire cohort of patients was 3.3 months. Median survival was higher in the surgical resection groups (7.8 vs. 2.8 months; P = 0.0019). Increased age is independently associated with increased risk of death, and adjuvant therapy is independently associated with prolonged survival. CONCLUSIONS: Surgical resection of butterfly glioblastoma prolongs survival without increased risk of permanent neurologic deficit. Both anterior and posterior bGBMs can be resected safely. PMID- 29162527 TI - Usefulness of 18F-fluorodeoxyglucose-Positron Emission Tomography in Comparison with Methionine-Positron Emission Tomography in Differentiating Solid Hemangioblastoma from Adult Cerebellar Tumors. AB - BACKGROUND AND PURPOSE: Among adults with posterior fossa tumors, an intraaxial location of the tumor is less common than an extraaxial location. Moreover, the differential diagnosis of a single cerebellar tumor in adults is sometimes difficult by conventional magnetic resonance imaging. We aimed to report the findings of positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) and methionine in adult patients with intraaxial and solitary metastatic brain tumors. MATERIALS AND METHODS: FDG-PET was performed on 12 patients with posterior fossa tumors: 4 had solid hemangioblastoma (HB), 3 had primary central nervous system lymphomas, 1 had a glioblastoma, and 4 had single metastatic brain tumors (METs). Methionine-PET was performed on 9 patients except for 1 patient with a MET. The maximum standardized uptake value (SUVmax) of the tumor was measured and compared with pathologic findings. RESULTS: The SUVmax of FDG in HB was lower compared with that of other tumors (P = 0.001). On the other hand, the SUVmax of methionine in the HB cases was almost the same as that in other tumors (P = 0.07). CONCLUSION: FDG-PET was helpful in differentiating HBs from adult cerebellar tumors. PMID- 29162528 TI - Risk Factors Associated with Readmission and Reoperation in Patients Undergoing Spine Surgery. AB - OBJECTIVE: Reoperation and readmission are often avoidable, costly, and difficult to predict. We sought to identify risk factors for readmission and reoperation after spine surgery and to use these factors to develop a scoring system predictive of readmission and reoperation. METHODS: The National Surgical Quality Improvement Project database for years 2012 to 2014 was reviewed for patients undergoing spinal surgery, and 68 perioperative characteristics were analyzed. RESULTS: A total of 111,892 patients who underwent spinal surgery were identified. The rate of reoperation was 3.1%, the rate of readmission was 5.2%, and the occurrence of either was 6.6%. Multivariate analysis found 20 perioperative factors significantly associated with both readmission and reoperation. Preoperative and operative factors found significant included age >60 years, African-American race, recent weight loss, chronic steroid use, on dialysis, blood transfusion required, American Society of Anesthesiologists classification >=3, contaminated wound, >10% probability of experiencing morbidity, and operative time >3 hours. Postoperative associations identified included urinary tract infection, stroke, dehiscence, pulmonary embolism, sepsis, septic shock, deep and superficial surgical site infection, reintubation, and failure to wean from ventilator. An unweighted and weighted risk score were generated that yielded receiver operating characteristic curves with areas under the curve of 0.707 (95% confidence interval [CI]: 0.701-0.713) and 0.743 (95% CI: 0.736-0.749) 0.708 (95% CI: 0.702-0.715), respectively. CONCLUSIONS: Patients with an unweighted score >=7 had a more than 20-fold increased risk of reoperation or readmission and a more than 1000-fold increased risk of mortality than did patients with a score of 0. PMID- 29162529 TI - Vulvar Nodules: A Rare Presentation of Mastocytosis. AB - BACKGROUND: Mastocytosis is a rare benign disorder characterized by the finding of mast cells in the skin and other organs, occurring in adult as well as pediatric age groups. The cutaneous form is the most common presentation in childhood and is rarely located on the vulva. CASE: A 9-year-old prepubertal girl presented with bilateral vulvar nodules found incidentally by her pediatrician. Biopsy and histopathologic review confirmed mastocytosis. Her lesions significantly diminished over the following year. SUMMARY AND CONCLUSION: Mastocytosis should be on the differential for lesions on the vulva in children, in addition to the more common disorders such as condyloma acuminata and molluscum contagiosum. It is a benign condition in children, and conservative, symptomatic management is recommended. PMID- 29162530 TI - A Retrospective Chart Review of Contraceptive Use among Adolescents with Opioid Use Disorder. AB - STUDY OBJECTIVE: To describe contraceptive use among female adolescents initiating outpatient treatment for opioid use disorder. DESIGN: Retrospective chart review. SETTING: Outpatient clinic providing medication-assisted treatment for substance use disorders to adolescents and young adults. PARTICIPANTS: Nonpregnant female adolescents who presented for treatment from January 1, 2013 to January 31, 2016 (N = 123). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prescription contraceptive use at baseline and initiation of a new method within 90 days. RESULTS: Of 123 female adolescents who presented for treatment of opioid use disorder, 113 (91.9%) reported sexual activity and 80 (65.0%) were not using prescription contraception at intake. Previous pregnancy was reported by 43 (35.0%) and 20 (16.3%) were positive for a sexually transmitted infection. Contraceptive counseling was not documented for 73 (59.3%) patients. Among patients with no prescription contraception at baseline, 56 of 80 (70.0%) initiated a method within the study window. Significant predictors (odds ratio [OR]; 95% confidence interval) of contraceptive initiation included previous pregnancy (8.6; 1.39-52.99), education of less than a high school diploma/general equivalency diploma (7.4; 1.63-33.41), and return for follow-up visit (9.8; 2.18 43.69). CONCLUSION: Young women who presented for opioid use disorder treatment were at high risk of adverse reproductive health outcomes. Most were sexually active and not using prescription contraception. Findings underscore the need for contraceptive counseling in this patient population. Optimally, these services would be provided in conjunction with substance use treatment. Improved contraceptive counseling documentation will allow evaluation of effective contraceptive counseling strategies for adolescents with opioid use disorders and might serve to inform future interventions. PMID- 29162531 TI - MyLARC: A Theory-Based Interactive Smartphone App to Support Adolescents' Use of Long-Acting Reversible Contraception. AB - STUDY OBJECTIVE: Develop and test the feasibility of a Health Belief Model theory based interactive smartphone application (app) aimed at providing information and support to adolescents with long-acting reversible contraception (LARC). DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Using a mixed-method design, we conducted 30 in-person interviews with adolescent LARC users who were enrolled in school-based health centers in New York City. Interviews were conducted in 2 phases: during phase 1, 12 participants viewed a pilot version of the app (MyLARC); during phase 2, 18 additional participants interacted with an expanded version of the app. Phase 2 participants downloaded MyLARC onto their smartphone and app usage was tracked. MAIN OUTCOME MEASURES: Participants' responses to the in-person interviews and data usage of MyLARC from phase 2 determined the feasibility and acceptability of using MyLARC to support young women's satisfaction and continuation of LARC methods. RESULTS: Noneducational games were recommended as an approach to provide information to adolescents in an engaging way, as well as educational graphics and visually appealing content. Data tracking of MyLARC usage among phase 2 participants revealed a total of 67 unique logins to the app with 18 average page visits per unique login. The total amount of times MyLARC was opened was 1197. The most frequented features were 'Info about LARC' (95 unique visits) and 'Games' (80 unique plays). CONCLUSION: A theory-based interactive smartphone app with LARC-specific information and support is an appropriate and appealing medium to provide information and support to adolescents using LARC. Games represented a novel opportunity to engage adolescents with health information. PMID- 29162532 TI - The Value of Prostate-Specific Antigen in Diagnosis of Polycystic Ovarian Syndrome in Adolescent Girls. AB - STUDY OBJECTIVE: This study was designed to evaluate and compare the serum total prostate-specific antigen (PSA) levels in adolescent girls in with and without polycystic ovarian syndrome (PCOS) to show whether evaluation of PSA levels have a diagnostic benefit over existing diagnostic criteria. DESIGN: Case-control study. SETTING: A territory referral center. PARTICIPANTS: A total of 89 (15-19 years) nonobese (body mass index, 18-24.9) adolescents with PCOS (n = 42) and controls without PCOS (n = 47) were enrolled in the study. INTERVENTIONS: Pathophysiological features of PCOS and serum total PSA levels were determined at the time of study enrollment. MAIN OUTCOME MEASURES: Determination, comparison, and diagnostic performance of serum total PSA levels in diagnosis of PCOS in adolescent girls were the main outcome measures of the study. RESULTS: The serum total PSA levels of adolescents with PCOS were detected to be higher than for control participants (0.63 +/- 1.38 ng/mL vs 0.48 +/- 0.95 ng/mL) without meeting statistical significance (P = .923). There was a correlation between total PSA levels and indices of insulin resistance like the homeostasis insulin resistance model (r = 0.414; P = .010). The serum total PSA level was not a discriminative parameter for diagnosis of PCOS in adolescent girls (area under the curve, 0.559; P = .476). CONCLUSION: The serum total PSA level was not a predictor of PCOS in adolescent girls. This finding might be related to the extemporal nature of tissues capable of PSA production and lack of sufficient exposure interval to hyperandrogenemia, rather than lack of stimulatory relationship between serum androgens. PMID- 29162533 TI - Derivation of an oral reference dose (RfD) for di 2-ethylhexyl cyclohexan-1,4 dicarboxylate (DEHCH), an alternative to phthalate plasticizers. AB - Di 2-ethylhexyl cyclohexane-1,4-dicarboxylate (DEHCH, CAS 84731-70-4) is an ester of polycarboxylic acid assessed in a variety of mammalian toxicity assays as a substitute for phthalate ester-type plasticizers. An OECD 422 combined systemic toxicity study with a reproductive/developmental toxicity screening test in SD rats found minimal effects on the liver, spleen, and thyroid and no indication that DEHCH is a developmental or reproductive toxicant. In a 90-day feeding study in SD rats, no toxicologically relevant effects were noted. Low genotoxic potential of DEHCH is indicated by the lack of mutagenicity or clastogenicity in vitro. No studies assessing mode of action were identified. Where data gaps exist for DEHCH, a read-across approach was used to assess other toxicological endpoints of interest. Di-ethylhexyl terephthalate (DEHT, CAS 6422-86-2) and 1,2 cyclohexane dicarboxylic acid, diisononyl ester (DINCH, CAS 474919-59-0) have higher tiered studies to supplant the data lacking for health-based standard setting. DEHT and DINCH were chosen as the source substances due to similar physical/chemical properties and thus anticipated metabolism and toxicological characteristics. An oral reference dose (RfD) for DEHCH was calculated using the human equivalent NOAEL from the OECD 422 study. A total uncertainty factor of 100 was comprised of interspecies (3x), intraspecies (10x), subchronic to chronic (1x), LOAEL to NOAEL uncertainty (1x) and database uncertainty (3x) factors, resulting in an RfD of 0.3 mg/kg-day. PMID- 29162534 TI - Nano- and micro-materials in the treatment of internal bleeding and uncontrolled hemorrhage. AB - Internal bleeding is defined as the loss of blood that occurs inside of a body cavity. After a traumatic injury, hemorrhage accounts for over 35% of pre hospital deaths and 40% of deaths within the first 24 hours. Coagulopathy, a disorder in which the blood is not able to properly form clots, typically develops after traumatic injury and results in a higher rate of mortality. The current methods to treat internal bleeding and coagulopathy are inadequate due to the requirement of extensive medical equipment that is typically not available at the site of injury. To discover a potential route for future research, several current and novel treatment methods have been reviewed and analyzed. The aim of investigating different potential treatment options is to expand available knowledge, while also call attention to the importance of research in the field of treatment for internal bleeding and hemorrhage due to trauma. PMID- 29162535 TI - CT Screening for Lung Cancer: Successful Trial, but Failed Understanding. PMID- 29162537 TI - Venous endothelium reactivity to Angiotensin II: A study in primary endothelial cultures of rat vena cava and portal vein. AB - The role of the vascular endothelium in modulating the arterial system has been widely investigated, but poorly explored at the venous site. In the present work, primary cultures of venous endothelium from rat Vena Cava (VC) and Portal Vein (PV) were established, characterized and analyzed according to their growth pattern and ability to produce nitric oxide (NO) and prostanoids (PGF2 alpha and PGI2), at basal state and after stimulation with Angiotensin II (Ang II, 1MUmol/L). Basal NO was detected in all examined cells in culture. Pre-incubation with Ang II increased NO production in cells from VC (but not in PV cultures), through activation of both AT1 and AT2 receptors. Both cultures exhibited detectable levels of PGF2 alpha at resting conditions, which were similarly enhanced by Ang II. Basal PGI2 levels were higher in PV, but increased after Ang II treatment in VC, with no further effect on PV cells. We conclude that endothelial cells from VC and PV exhibit important properties and react to Ang II, probably influencing the whole circulatory system. This experimental cell model gives support to further studies concerning intracellular pathways of the venous endothelium, analyzed in separate from the vascular smooth muscle wall. PMID- 29162536 TI - Functional Mitral Regurgitation: Imaging Insights, Clinical Outcomes and Surgical Principles. AB - Functional mitral regurgitation (MR; FMR) is the most common type of MR and its development is associated with increased morbidity and mortality. Leaflet tethering with apical shift of the papillary muscle due to adverse left ventricular remodeling and loss of normal leaflet coaptation is the principal mechanism of FMR. Echocardiography plays a central role in the assessment of the FMR. The development of 3D echocardiography has allowed for assessment of the geometric changes of mitral valve morphology and spatial relationship with the left ventricle that accompanies FMR. 2D/3D echocardiographic findings, clinical outcomes of FMR are reviewed and role of surgical intervention is discussed. PMID- 29162538 TI - Metformin promotes the proliferation and differentiation of murine preosteoblast by regulating the expression of sirt6 and oct4. AB - Osteopenia, osteoporosis and bone salt metabolism disorder are common diseases in the aged and diabetics. From case reports of patients with T2DM, we have observed that metformin can decrease risk of bone fracture and promote bone formation. However, the underlying mechanism of metformin's effect on bone metabolism remains unknown. In our research, we show that metformin can promote proliferation of murine preosteoblast by regulating AMPK-mTORC2 and AKT-mTORC1 signaling axis. Furthermore, we have observed that metformin can promote SIRT6 expression before and during differentiation of murine preosteoblast. The interaction between SIRT6 and NF-kappaB is highly important in osteoblast differentiation just as the relationship between OPG and RANKL in the process of bone formation. During differentiation, we show that SIRT6 inhibits phosphorylation of NF-kappaB and that OPG increases while RANKL decrease in HG groups. In addition, ablation of sirt6 in mice causes phosphorylation of NF kappaB at high-levels and RANKL increases slightly in femur bone cells. However, other bone formation marker proteins such as RUNX2, OSTERIX and OPG appear at low levels in sirt6 KO mice. It has been confirmed that downregulation of OCT4 is critical incident in the differentiation of embryonic stem cells. Fortunately, we observe that SIRT6 can suppress OCT4 expression in murine preosteoblast and the expression of OCT4 is at high-level in sirt6 KO mice. Taken together, this study's results illuminate metformin's effect on bone metabolism under HG condition and help to elucidate why metformin can promote bone fracture healing of patients with T2DM. PMID- 29162539 TI - Modulation of diverse oncogenic transcription factors by thymoquinone, an essential oil compound isolated from the seeds of Nigella sativa Linn. AB - Thymoquinone (TQ), isolated almost fifty years ago, is the main bioactive constituent of black seed essential oil extracted from the seed of Nigella sativa. TQ has been shown to have promising effects against a variety of inflammatory diseases and cancer. Cancer development is a multistep process where normal cells acquire qualities that enable the cells to proliferate continuously and migrate to distant sites in the human body. Drugs that interfere with this process are considered potential anti-cancer therapeutics, which may ultimately result in their clinical usage. TQ is once such compound which has been reported to modulate several major signaling pathways and key oncogenic molecules that play a prominent role in cancer initiation, progression, invasion, metastasis, and angiogenesis. Various studies have reported that TQ can enhance the anti cancer potential when co-administered with several chemotherapeutic agents while reducing their toxic side effects. In addition, TQ has been shown to inhibit the growth of breast, prostate, pancreatic, colon, lung, and hematological malignancies in different mouse models of cancer. This review focuses on TQ's chemical and pharmacological properties, its diverse molecular targets and also provides clear evidence on its promising potential under preclinical and clinical settings. PMID- 29162540 TI - Genomic analysis of NF-kappaB signaling pathway reveals its complexity in Crassostrea gigas. AB - NF-kappaB signaling pathway is an evolutionarily conserved pathway that plays highly important roles in several developmental, cellular and immune response processes. With the recent release of the draft Pacific oyster (Crassostra gigas) genome sequence, we have sought to identify the various components of the NF kappaB signaling pathway in these mollusks and investigate their gene structure. We further constructed phylogenetic trees to establish the evolutionary relationship of the oyster proteins with their homologues in vertebrates and invertebrates using BLASTX and neighbor-joining method. We report the presence of two classic NF-kappaB/Rel homologues in the pacific oyster namely Cgp100 and CgRel, which possess characteristic RHD domain and a consensus nuclear localization signal, similar to mammalian homologues and an additional CgRel-like protein, unique to C. gigas. Further, in addition to two classical IkappaB homologues, CgIkappaB1 and CgIkappaB2, we have identified three atypical IkappaB family members namely CgIkappaB3, CgIkappaB4 and CgBCL3 which lack the IkappaB degradation motif and consist of only one exon that might have arisen by retrotransposition from CgIkappaB1. Finally, we report the presence of three IKKs and one NEMO genes in oyster genome, named CgIKK1, CgIKK2, CgIKK3 and CgNEMO, respectively. While CgIKK1 and CgIKK3 domain structure is similar to their mammalian homologues, CgIKK2 was found to lack the HLH and NBD domains. Overall, the high conservation of the NF-kappaB/Rel, IkappaB and IKK family components in the pacific oyster and their structural similarity to the vertebrate and invertebrate homologues underline the functional importance of this pathway in regulation of critical cellular processes across species. PMID- 29162541 TI - A mini review on immune role of chemokines and its receptors in snakehead murrel Channa striatus. AB - Chemokines are ubiquitous cytokine molecules involved in migration of cells during inflammation and normal physiological processes. Though the study on chemokines in mammalian species like humans have been extensively studied, characterization of chemokines in teleost fishes is still in the early stage. The present review provides an overview of chemokines and its receptors in a teleost fish, Channa striatus. C. striatus is an air breathing freshwater carnivore, which has enormous economic importance. This species is affected by an oomycete fungus, Aphanomyces invadans and a Gram negative bacteria Aeromonas hydrophila is known to cause secondary infection. These pathogens impose immune changes in the host organism, which in turn mounts several immune responses. Of these, the role of cytokines in the immune response is immense, due to their involvement in several activities of inflammation such as cell trafficking to the site of inflammation and antigen presentation. Given that importance, chemokines in fishes do have significant role in the immunological and other physiological functions of the organism, hence there is a need to understand the characteristics, activities and performace of these small molecules in details. PMID- 29162542 TI - Silencing tyrosine hydroxylase retards depression of immunocompetence of Litopenaeus vannamei under hypothermal stress. AB - Tyrosine hydroxylase (TH), the first and rate-limiting step in the synthesis of catecholamines, is required in catecholamine synthesis of the neuroendocrine regulatory network against stress in shrimp. The immunocompetence, catecholamine biosynthesis, and carbohydrate metabolites were evaluated in Litopenaeus vannamei received L. vannamei TH (LvTH) double-stranded (ds)RNA, diethyl pyrocarbonate water, or non-targeted dsRNA for 3 days then transferred from 28 to 20 or 28 degrees C. The immunocompetence of LvTH-depleted shrimp held at 28 degrees C was promoted, and those were downregulated under hypothermal stress and revealed higher level than the other two dsRNA treatments. Meanwhile, the decrease of catecholamine biosynthesis was observed in LvTH-depleted shrimp held at 28 degrees C, and those were elevated under hypothermal stress and revealed lower levels, compared to two dsRNA treatments. The reduced carbohydrate metabolites was observed in LvTH-depleted shrimp held at 28 degrees C, and those were upregulated under hypothermal stress and showed lower levels than the other two dsRNA treatments. It was therefore concluded that LvTH-depleted shrimp revealed enhanced immunocompetence and reduced carbohydrate metabolites when exposed to a hypothermal stress condition, and in the meantime, even though catecholamine biosynthesis was downregulated, no significant difference was observed in DA or NE levels. PMID- 29162543 TI - Identification, expression analysis, and antibacterial activity of NK-lysin from common carp Cyprinus carpio. AB - Natural killer lysin (NK-lysin), produced by cytotoxic T lymphocytes and natural killer cells, is a cationic antimicrobial peptide that has a broad antimicrobial spectrum, including bacteria, viruses, and parasites. Nevertheless, the implication of NK-lysin in the protection against bacterial infection is not aware in common carp. In this study, six different NK-lysin genes (nkl1, nkl2, nkl3, nkl4, nkl5 and nkl6) were identified in the common carp genome. Each of the mature peptides of common carp NK-lysin has six well-conserved cysteine residues, and shares a Saposin B domain, characteristic of saposin-like protein (SALIP) family. The gene nkl1 contains 5 extrons and 4 introns, and nkl2, nkl3, nkl4 or nkl5 contains 4 extrons and 3 introns, however, the nkl6 has 3 extrons and 2 introns. By quantitative real-time PCR, nkl2 transcripts were predominantly expressed in spleen of healthy common carp, while elevated mainly in gill and spleen upon Aeromonas hydrophila infection. The recombinant NK-lysin-2 purified from Pichia pastoris shows antibacterial activity against Staphylococcus aureus (Gram-positive), and Escherichia coli M15, Aeromonas hydrophila, as well as Edwardsiella tarda (Gram-negative), the latter two are important pathogens of aquaculture. Our results indicate that NK-lysin in common carp might play an important role in fish immune response by enhancing antibacterial defense against bacterial pathogens. PMID- 29162544 TI - Immunostimulation and yellow head virus (YHV) disease resistance induced by a lignin-based pulping by-product in black tiger shrimp (Penaeus monodon Linn.). AB - Yellow head virus (YHV) is classified as one of the most serious pathogens causing a harmful disease in many penaeids, especially black tiger shrimp (Penaeus monodon), with high economic loss. To determine a potent and practical prophylactic strategy for controlling this disease, the toxicity of the by product kraft lignin and its ability to control severe YHV infection were investigated in juvenile black tiger shrimp (15.9 +/- 1.2 g body weight). The median lethal dosage at 96 h (96-hrs LD50) of lignin in shrimp was 297 mg/L. Lignin was further added to shrimp diets via top-dressing to assess its ability to elicit immune stimulation activity. At 14 days after feeding, shrimp fed 1, 3, 5 and 10 g of lignin/kg of diet exhibited significantly higher levels of phagocytic activity (PA) than the control group (P < 0.05). However, differences in total hemocyte count among treatments were not significant during the experimental period (P > 0.05). Additionally, lignin supplementation at 1-10 g/kg for 14 days failed to protect experimental shrimp against YHV infection. The antiviral activity of lignin against YHV in black tiger shrimp was notable in vitro because compared to control shrimp (96.7 +/- 5.8%; P < 0.05), shrimp injected with a pre-incubated solution of YHV and lignin at 1, 5, 10 and 20 mg/L exhibited significantly lower mortality rates, 23.3 +/- 5.8, 16.7 +/- 5.8, 23.3 +/- 5.8, and 20.0 +/- 0.0%, respectively, after a lethal dose of YHV at 14-20 days after injection. These potent effects were clearly supported and confirmed by histopathological and RT-PCR analyses. Based on these results, the pulping by product kraft lignin efficiently inhibits YHV infection in black tiger shrimp. This information will facilitate the development of practical methods to control yellow head disease in the marine shrimp culture industry. PMID- 29162545 TI - Gene expression analysis of Ruditapes philippinarum haemocytes after experimental Perkinsus olseni zoospore challenge and infection in the wild. AB - The production of Manila clam (Ruditapes philippinarum) is seriously threatened by the protistan parasite Perkinsus olseni. We characterized and compared gene expression of Manila clam haemocytes in response to P. olseni in a time-course (10 h, 24 h, 8 d) controlled laboratory challenge (LC), representing the first step of infection, and in a more complex infection in the wild (WI), using a validated oligo-microarray containing 11,232 transcripts, mostly annotated. Several immune-genes involved in NIK/NF-kappaB signalling, Toll-like receptor signalling and apoptosis were activated at LC-10 h. However, down-regulation of genes encoding lysozyme, histones, cathepsins and heat shock proteins indicated signals of immunodepression, which persisted at LC-24 h, when only down-regulated genes were detected. A rebound of haemocyte activity occurred at LC-8 d as shown by up-regulation of genes involved in cytoskeleton organization and cell survival. The WI study showed a more complex picture, and several immune-relevant processes including cytoskeleton organization, cell survival, apoptosis, encapsulation, cell redox- and lipid-homeostasis were activated, illustrating the main mechanism of host response. Our results provide useful information, including potential biomarkers, to develop strategies for controlling Manila clam perkinsosis. PMID- 29162546 TI - Evaluation of probiotic Bacillus aerius B81e isolated from healthy hybrid catfish on growth, disease resistance and innate immunity of Pla-mong Pangasius bocourti. AB - Infectious diseases have been found to be a major cause of mortality in fish hatcheries. Probiotics have been introduced to replace antibiotics commonly used for treatment of bacterial infection in aquaculture. This study was conducted to isolate, screen, and evaluate the probiotic Bacillus spp. for potential use as a feed supplement to enhance fish growth, disease resistance and innate immunity of Pla-mong Pangasius bocourti. Bacillus aerius strain B81e was selectively isolated from the intestine of healthy catfish and chosen based on its probiotic properties both in vitro and in vivo. This bacterium produced a bacteriocin-like substance and exhibited a broad-spectrum antibacterial activity inhibiting both Gram-positive and Gram-negative bacteria especially the fish pathogens Aeromonas hydrophila and Streptococcus agalactiae. The susceptibility to all 8 antibiotics tested implies that it is unlikely to be an antibiotic-resistant bacterium. B. aerius strain B81e possessed interesting adhesion properties as shown by its high percentages of hydrophobicity, auto-aggregation, co-aggregation with fish pathogens A. hydrophila FW52 and S. agalactiae F3S and mucin binding. The strain B81e survived simulated gastrointestinal conditions, producing protease and lipase but not beta-haemolysin. The study also evaluated the effects of dietary supplementation with strain B81e on growth performance, innate immunity, and the disease resistance of P. bocourti against A. hydrophila infection. Fish with a mean body weight of 69 g were fed strain B81e at 0 (control) and 107 CFU g-1 feed (test) for 60 days. Various growth and immune parameters were examined at 30 and 60 days post-feeding. Fish were challenged with A. hydrophila 60 days post feeding and mortalities were recorded over 14 days post-infection. Results showed that the administration of strain B81e for 60 days had significant effects (p < 0.05) on weight gain, specific growth rate and feed utilization efficiency of P. bocourti. Dietary administration of strain B81e increased the serum lysozyme and bactericidal activities of P. bocourti significantly throughout the experimental period whereas the alternative complement, phagocytic and respiratory burst activities were significantly (p < 0.05) higher in the test fish compared to the control fish after 60 days of feeding. In addition, the fish fed a strain B81e supplemented diet had a significantly higher (p < 0.05) post-challenge survival rate than the control fish. The results in this study indicate that B. aerius B81e has beneficial effects on growth performance, innate immunity and disease resistance of P. bocourti. This is the first report on the probiotic roles of B. aerius in aquaculture. PMID- 29162547 TI - Compact in-line lensfree digital holographic microscope. AB - Phase imaging provides intensity contrast to visualize transparent samples such as found in biology without any staining. Among them, digital holographic microscopy (DHM) is a well-known quantitative phase method. Lensfree implementations of DHMs offer the added advantage to provide large field of views (several mm2 compared to several hundred MUm2) and more compact setups that traditional DHM which have high quality microscope objectives. In this article, a lensfree DHM is presented using a side illumination technique in order to further reduce the device size. Its practical use is described and results on a transparent (phase only) sample are shown. PMID- 29162548 TI - Navigating in the vast and deep oceans of high-dimensional biological data. PMID- 29162549 TI - Diversification dynamics and transoceanic Eurasian-Australian disjunction in the genus Picris (Compositae) induced by the interplay of shifts in intrinsic/extrinsic traits and paleoclimatic oscillations. AB - Understanding transcontinental biogeographic patterns has been one of the main foci of the field of biogeography. While multiple explanations for transcontinental disjunctions have been proposed, little is still known about the relative importance of intrinsic and extrinsic traits for the diversification dynamics of disjunct taxa. Here, we study the evolutionary history of the genus Picris L. (Compositae), a great model for investigating the diversification dynamics of transoceanic bipolar disjunct organisms. Ancestral state reconstructions indicate that the most recent common ancestor (MRCA) of Picris was a semelparous and heterocarpic herb that lived in unpredictable environments of North Africa and West Asia. Diversification analyses suggest a significant shift in speciation ca. 1 million years ago, likely associated with the onset of the mid-Pleistocene revolution. Longevity characters are correlated with the evolution of particular fruit types and with environmental conditions. Heterocarpic species are mostly semelparous herbs strongly linked with unpredictable habitats, while homocarpic taxa are mostly iteroparous plants occurring in predictable environments. Binary-state speciation and extinction analyses suggest that homocarpy, iteroparity, and habitats predictability accelerate diversification. Although the combination of homocarpy and iteroparity evolved in several lineages, only members of the P. hieracioides group were able to colonise Eurasia and expand to Australia by transoceanic dispersal. Those findings indicate that large-scale colonisation events depend on a complex interplay of intrinsic and extrinsic factors. PMID- 29162550 TI - Discovery of an old, archipelago-wide, endemic radiation of Philippine snakes. AB - The extraordinarily rich land vertebrate biodiversity of the Philippines includes at least 112 species of terrestrial snakes (74% of which are endemic to the archipelago) in 41 genera (12% endemic). Endemic Philippine snake genera include Cyclocorus (two species), Hemibungarus (three species), Hologerrhum (two species), Oxyrhabdium (two species), and Myersophis (monotypic). Although Hemibungarus and Oxyrhabdium have been included in previous species-level phylogenies, the affinities of the other three Philippine endemic genera are completely unknown. We generated novel DNA sequences for six species from four genera and analyzed these in conjunction with data from earlier studies to infer a phylogeny for the group containing Colubridae, Elapoidea (Elapidae + Lamprophiidae), and Homalopsidae. We present a novel phylogenetic result that strongly supports the existence of an entirely endemic Philippine radiation of elapoid snakes that originated 35-25 million years ago. We provide a revised, phylogeny-based classification to accommodate the new clade, transfer Cyclocorus, Hologerrhum, and Myersophis to Lamprophiidae, and provide the first estimate of the evolutionary relationships among these genera and the related Oxyrhabdium, setting the stage for future investigation of this entirely endemic, novel Philippine elapoid radiation. PMID- 29162551 TI - Using a new RAD-sequencing approach to study the evolution of Micromeria in the Canary islands. AB - As found in other oceanic islands, the Canary Islands include a large number of single island endemic species, some of which form clades that are broadly distributed within the archipelago. The genus Micromeria (Lamiaceae), for instance, includes groups of morphologically similar but ecologically diverse species on each island, representing a great model to investigate niche shifts and adaptation within the Canary Archipelago. Previous attempts to reconstruct phylogenetic relationships within the genus did not lead to robust phylogenies, presumably due to introgression and/or incomplete lineage sorting. In this study, we use a newly developed RAD-sequencing method to improve phylogenetic resolution and to better understand relationships among the Canary Island endemic Micromeria. Overall, we obtained 3571 loci that were genotyped for a total of 46 individuals of Micromeria. Our data reconstructed a highly resolved phylogeny, and corroborated the latest species reclassification of the M. varia s.l. species complex, the taxonomically most complicated group within the genus. Furthermore, taxa occupying similar ecological conditions in different islands, were shown to be closely related. This is the case of taxa from the laurel forest from La Gomera and Gran Canaria, suggesting that the laurel forest likely worked as a filter, only allowing the establishment of colonizers already pre-adapted to these conditions. We also found introgression between these species so it is also possible that the genes that facilitated the adaptation to laurel forest were swapped between Gran Canaria and La Gomera. The observations obtained in this study also allowed us to explain the role of introgression in the origin of M. varia s.l. species complex. PMID- 29162552 TI - The challenge of species delimitation in the diploid-polyploid complex Veronica subsection Pentasepalae. AB - A reliable taxonomic framework and the identification of evolutionary lineages are essential for effective decisions in conservation biodiversity programs. However, phylogenetic reconstruction becomes extremely difficult when polyploidy and hybridization are involved. Veronica subsection Pentasepalae is a diploid polyploid complex of ca. 20 species with ploidy levels ranging from 2x to 10x. Here, DNA-ploidy level estimations and AFLP fingerprinting were used to determine the evolutionary history, and species boundaries were reviewed in an integrated approach including also previous data (mainly morphology and sequence-based phylogenetic reconstructions). Molecular analyses were performed for 243 individuals from 95 populations, including for the first time all taxa currently recognized within the subsection. Phylogenetic reconstruction identified four main groups corresponding almost completely to the four clusters identified by genetic structure analyses. Multiple autopolyploidization events have occurred in the tetraploid V. satureiifolia giving rise to octoploid entities in central Europe and north of Spain, whereas hybridization is demonstrated to have occurred in several populations from the Balkan Peninsula. Furthermore, our study has established the taxonomic status of taxa, for the most part recovered as monophyletic. Cryptic taxa within the group have been identified, and a new species, Veronica dalmatica, is fully described. This study highlights the implications of polyploidy in species delimitation, and illustrates the importance to conserve polyploid populations as potential sources of diversification due to evolutionary significance of genome duplications in plant evolution. PMID- 29162553 TI - Exhaled nitric oxide and vascular endothelial growth factor as predictors of cold symptoms after stress. AB - OBJECTIVE: Prior research has demonstrated that psychosocial stress is associated with respiratory infections. Immunologic, endocrine, and cardiovascular predictors of such infections have been explored with varying success. We therefore sought to study the unexplored role of airway mucosal immunity factors, nitric oxide (NO) and vascular endothelial growth factor (VEGF). NO is secreted by airway epithelial cells as part of the first line of defense against bacteria, viruses, and fungi. VEGF is expressed by mast cells in respiratory infections and recruits immune cells to infected sites, but in excess lead to vulnerability of the airway epithelium. METHODS: In this proof-of-concept study we measured exhaled NO, exhaled breath condensate (EBC) VEGF, salivary VEGF, and salivary cortisol in 36 students undergoing final academic examinations at three occasions: a low-stress baseline during the term, an early phase of finals, and a late phase of finals. Participants also reported on cold symptoms at these time points and approximately 5 and 10days after their last academic examination. RESULTS: Higher baseline NO was associated with fewer cold symptoms after stress, whereas higher baseline VEGF in EBC and saliva were associated with more cold symptoms after stress. Perceived stress at baseline as well as salivary VEGF and cortisol late in the finals also contributed to the prediction of later cold symptoms. CONCLUSION: Basal levels of NO and VEGF may inform about mucosal immunocompetence and add to preventative treatments against airway infections from periods of stress in daily life. PMID- 29162554 TI - Sustained administration of corticosterone at stress-like levels after stroke suppressed glial reactivity at sites of thalamic secondary neurodegeneration. AB - Secondary neurodegeneration (SND) is an insidious and progressive condition involving the death of neurons in regions of the brain that were connected to but undamaged by the initial stroke. Our group have published compelling evidence that exposure to psychological stress can significantly exacerbate the severity SND, a finding that has considerable clinical implications given that stroke survivors often report experiencing high and unremitting levels of psychological stress. It may be possible to use one or more targeted pharmacological approaches to limit the negative effects of stress on the recovery process but in order to move forward with this approach the most critical stress signals have to be identified. Accordingly, in the current study we have directed our attention to examining the potential effects of corticosterone, delivered orally at stress like levels. Our interest is to determine how similar the effects of corticosterone are to stress on repair and remodelling that is known to occur after stroke. The study involved 4 groups, sham and stroke, either administered corticosterone or normal drinking water. The functional impact was assessed using the cylinder task for paw asymmetry, grid walk for sensorimotor function, inverted grid for muscle strength and coordination and open field for anxiety like behaviour. Biochemically and histologically, we considered disturbances in main cellular elements of the neurovascular unit, including microglia, astrocytes, neurons and blood vessels using both immunohistochemistry and western blotting. In short, we identified that corticosterone delivery after stroke results in significant suppression of key microglial and astroglial markers. No changes were observed on the vasculature and in neuronal specific markers. No changes were identified for sensorimotor function or anxiety-like behaviour. We did, however, observe a significant change in motor function as assessed using the inverted grid walk test. Collectively, these results suggest that pharmacologically targeting corticosterone levels in the future may be warranted but that such an approach is unlikely to limit all the negative effects associated with exposure to chronic stress. PMID- 29162555 TI - 11beta-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation. AB - Chronically elevated glucocorticoid levels impair cognition and are pro inflammatory in the brain. Deficiency or inhibition of 11beta-hydroxysteroid dehydrogenase type-1 (11beta-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11beta-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11beta-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11beta-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3 phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11beta-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging. PMID- 29162556 TI - Recombinant Netrin-1 binding UNC5B receptor attenuates neuroinflammation and brain injury via PPARgamma/NFkappaB signaling pathway after subarachnoid hemorrhage in rats. AB - Neuroinflammation is an essential mechanism involved in the pathogenesis of subarachnoid hemorrhage (SAH)-induced brain injury. Recently, Netrin-1 (NTN-1) is well established to exert anti-inflammatory property in non-nervous system diseases through inhibiting infiltration of neutrophil. The present study was designed to investigate the effects of NTN-1 on neuroinflammation, and the potential mechanism in a rat model of SAH. Two hundred and ninety-four male Sprague Dawley rats (weight 280-330 g) were subjected to the endovascular perforation model of SAH. Recombinant human NTN-1 (rh-NTN-1) was administered intravenously. Small interfering RNA (siRNA) of NTN-1 and UNC5B, and a selective PPARgamma antagonist bisphenol A diglycidyl ether (BADGE) were applied. Post-SAH evaluations included neurobehavioral function, brain water content, Western blot analysis, and immunohistochemistry. Our results showed that endogenous NTN-1 and its receptor UNC5B level were increased after SAH. Administration of rh-NTN-1 reduced brain edema, ameliorated neurological impairments, and suppressed microglia activation after SAH, which were concomitant with PPARgamma activation, inhibition of NFkappaB, and decrease in TNF-alpha, IL-6, and ICAM-1, as well as myeloperoxidase (MPO). Knockdown of endogenous NTN-1 increased expression of pro inflammatory mediators and MPO, and aggravated neuroinflammation and brain edema. Moreover, knockdown of UNC5B using specific siRNA and inhibition of PPARgamma with BADGE blocked the protective effects of rh-NTN-1. In conclusion, our findings indicated that exogenous rh-NTN-1 treatment attenuated neuroinflammation and neurological impairments through inhibiting microglia activation after SAH in rats, which is possibly mediated by UNC5B/PPARgamma/NFkappaB signaling pathway. Exogenous NTN-1 may be a novel therapeutic agent to ameliorating early brain injury via its anti-inflammation effect. PMID- 29162557 TI - Self-Management and Clinical Decision Support for Patients With Complex Chronic Conditions Through the Use of Smartphone-Based Telemonitoring: Randomized Controlled Trial Protocol. AB - BACKGROUND: The rising prevalence of chronic illnesses hinders the sustainability of the health care system because of the high cost of frequent hospitalizations of patients with complex chronic conditions. Clinical trials have demonstrated that telemonitoring can improve health outcomes, but they have generally been limited to single conditions such as diabetes, hypertension, or heart failure. Few studies have examined the impact of telemonitoring on complex patients with multiple chronic conditions, although these patients may benefit the most from this technology. OBJECTIVE: The aim of this study is to investigate the impact of a smartphone-based telemonitoring system on the clinical care and health outcomes of complex patients across several chronic conditions. METHODS: A mixed-methods, 6-month randomized controlled trial (RCT) of a smartphone-based telemonitoring system is being conducted in specialty clinics. The study will include patients who have been diagnosed with one or more of any of the following conditions: heart failure, chronic obstructive pulmonary disease, chronic kidney disease, uncontrolled hypertension, or insulin-requiring diabetes. The primary outcome will be the health status of patients as measured with SF-36. Patients will be randomly assigned to either the control group receiving usual care (n=73) or the group using the smartphone-based telemonitoring system in addition to usual care (n=73). RESULTS: Participants are currently being recruited for the trial. Data collection is anticipated to be completed by the fall of 2018. CONCLUSIONS: This RCT will be among the first trials to provide evidence of the impact of telemonitoring on costs and health outcomes of complex patients who may have multiple chronic conditions. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 41238563; http://www.isrctn.com/ISRCTN41238563 (Archived by WebCite at http://www.webcitation.org/6ug2Sk0af) and Clinicaltrials.gov NCT03127852; https://clinicaltrials.gov/ct2/show/NCT03127852 (Archived by WebCite at http://www.webcitation.org/6uvjNosBC). PMID- 29162558 TI - Surgical Interventions for the Treatment of Supracondylar Humerus Fractures in Children: Protocol of a Systematic Review. AB - BACKGROUND: The treatment of supracondylar humerus fracture in children (SHFC) is associated with complications such as functional deficit, residual deformity, and iatrogenic neurological damage. The standard treatment is closed reduction and percutaneous Kirschner wire fixation with different configurations. Despite this fact, there is still no consensus on the most effective technique for the treatment of these fractures. OBJECTIVE: The aim of this systematic review will be to evaluate the effect of surgical interventions on the treatment of Gartland type II and III SHFC by assessing function, complications, and error as primary outcomes. Clinical outcomes such as range of motion and pain and radiographic outcomes will also be judged. METHODS: A systematic review of randomized controlled trials or quasi-randomized controlled trials evaluating the surgical treatment of SHFC will be carried out in the Cochrane Central Register of Controlled Trials, PubMed, Literatura Latino-Americana e do Caribe em Ciencias da Saude, and Excerpta Medica Database. The search will also occur at ongoing and recently completed clinical trials in selected databases. Data management and extraction will be performed using a data withdrawal form and by analyzing the following: study method characteristics, participant characteristics, intervention characteristics, results, methodological domains, and risk of bias. To assess the risk of bias of the included trials, the Cochrane Risk of Bias Tool will be used. Dichotomous outcome data will be analyzed as risk ratios, and continuous outcome data will be expressed as mean differences, both with 95% confidence intervals. Also, whenever possible, subgroup analysis, sensitivity analysis, and assessment of heterogeneity will be performed. RESULTS: Following the publication of this protocol, searches will be run and included studies will be deeply analyzed. We hope to obtain final results in the next few months and have the final paper published by the end of 2018. This study was funded by a government-based noncommercial agency, Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP). CONCLUSIONS: This study may provide surgical treatment effects evidence for SHFC. The results will assist clinical practice by demonstrating the effectiveness and potential complications of these interventions and might serve as a reference for future clinical trials on the topic. TRIAL REGISTRATION: PROSPERO CRD42014009304; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=9304 (Archived by WebCite at http://www.webcitation.org/6usiDHzD7). PMID- 29162559 TI - Enhancing the Usability of an Optical Reader System to Support Point-of-Care Rapid Diagnostic Testing: An Iterative Design Approach. AB - BACKGROUND: In today's health care environment, increasing costs and inadequate medical resources have created a worldwide need for more affordable diagnostic tools that are also portable, fast, and easy to use. To address this issue, numerous research and commercial efforts have focused on developing rapid diagnostic technologies; however, the efficacy of existing systems has been hindered by usability problems or high production costs, making them infeasible for deployment in at-home, point-of-care (POC), or resource-limited settings. OBJECTIVE: The aim of this study was to create a low-cost optical reader system that integrates with any smart device and accepts any type of rapid diagnostic test strip to provide fast and accurate data collection, sample analysis, and diagnostic result reporting. METHODS: An iterative design methodology was employed by a multidisciplinary research team to engineer three versions of a portable diagnostic testing device that were evaluated for usability and overall user receptivity. RESULTS: Repeated design critiques and usability studies identified a number of system requirements and considerations (eg, software compatibility, biomatter contamination, and physical footprint) that we worked to incrementally incorporate into successive system variants. Our final design phase culminated in the development of Tidbit, a reader that is compatible with any Wi Fi-enabled device and test strip format. The Tidbit includes various features that support intuitive operation, including a straightforward test strip insertion point, external indicator lights, concealed electronic components, and an asymmetric shape, which inherently signals correct device orientation. Usability testing of the Tidbit indicates high usability for potential user communities. CONCLUSIONS: This study presents the design process, specification, and user reception of the Tidbit, an inexpensive, easy-to-use, portable optical reader for fast, accurate quantification of rapid diagnostic test results. Usability testing suggests that the reader is usable among and can benefit a wide group of potential users, including in POC contexts. Generally, the methodology of this study demonstrates the importance of testing these types of systems with potential users and exemplifies how iterative design processes can be employed by multidisciplinary research teams to produce compelling technological solutions. PMID- 29162560 TI - Diabetes Data Management System to Improve Glycemic Control in People With Type 1 Diabetes: Prospective Cohort Study. AB - BACKGROUND: Smartphone and Web technology can improve the health care process, especially in chronic diseases. OBJECTIVE: The aim of this study was to investigate whether the use of blood glucose (BG) data management system, which enables connection to smartphones, the Web, the cloud, and downloading, can improve glycemic control in subjects with type 1 diabetes mellitus (T1DM). METHODS: This study was a prospective, single-arm, cohort feasibility study with 6 months of duration. T1DM subjects enrolled had experience in self-monitoring blood glucose, but were download data naive. Fasting BG and glycated hemoglobin (HbA1c) were collected at the enrollment and at follow-up. Subjects were divided into Downloader (DL) and No-downloader (NDL). RESULTS: A total of 63 subjects were analyzed, of which 30 were classified as DL and 33 as NDL. At the end of the study, DL had significantly lower HbA1c, mean daily glucose, standard deviation, percentage of BG values above target, and pre- and postprandial (lunch and dinner) values compared with NDL (all P<.05). The percentage of BG values within treatment target was significantly higher in DL compared with NDL (47% [SD 9] vs 37% [SD 13]; P=.001). CONCLUSIONS: The findings suggest that, in T1DM, downloading of BG from data management system, which enables connection to smartphones, the Web, and the cloud, might be a valuable contributor to improved glycemic control. PMID- 29162561 TI - Minimum unit pricing for alcohol clears final legal hurdle in Scotland. PMID- 29162562 TI - Metabolic Effects of Bariatric Surgery. AB - BACKGROUND: Obesity can be defined as a chronic subcortical brain disease, as there is an important neurophysiological component to its etiology based on changes in the functioning of those areas of the brain controlling food intake and reward. Extensive metabolic changes accompany bariatric surgery-based treatment of obesity. Consequently, the term "metabolic" surgery is being increasingly adopted in relation to the beneficial effects these procedures have on chronic diseases like type 2 diabetes. CONTENT: In the present review, we focus on the key biochemical and physiological changes induced by metabolic surgery and highlight the beneficial effects accrued systemically with the use of an organ-based approach. Understanding the impact on and interactions between the gut, brain, adipose tissue, liver, muscle, pancreas, and kidney is key to understanding the sum of the metabolic effects of these operations. SUMMARY: Further mechanistic studies are essential to assess the true potential of metabolic surgery to treat metabolic comorbidities of obesity beyond type 2 diabetes. Approaches that may mitigate the metabolic side effects of surgery also require attention. Understanding the positive impact of metabolic surgery on metabolic health may result in a wider acceptance of this intervention as treatment for metabolic, comorbid conditions. PMID- 29162564 TI - Poziotinib Shows Promise for Rare Lung Cancer. AB - Poziotinib, an EGFR inhibitor that was previously shelved as ineffective against non-small cell lung cancer, is showing promising activity in a subset of patients with EGFR exon 20 insertions. According to preliminary data from a phase II trial, the drug led to a 73% overall response rate in patients with this disease subtype, which is typically highly resistant to standard therapy. PMID- 29162565 TI - Towards evidence based medicine for paediatricians. PMID- 29162567 TI - Government shops will sell recreational marijuana in Ontario and Quebec. PMID- 29162568 TI - David Oliver: We need statutory duty of candour and transparency for NHS executives. PMID- 29162563 TI - FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor. AB - The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behavior and shapes treatment responses in distinct cancer types. Here, we uncover that in gastrointestinal stromal tumor (GIST), the forkhead family member FOXF1 directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor interstitial cells of Cajal lineage specification and GIST tumorigenesis. Further, FOXF1 colocalizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST lineage-specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance, and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth in vitro and murine GIST tumor growth and maintenance in vivo The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage restricted clinical behavior and treatment response.Significance: We uncover that FOXF1 defines the core-regulatory circuitry in GIST through both direct transcriptional regulation and pioneer factor function. The unique and simultaneous control of signaling and transcriptional circuitry by FOXF1 sets up an enforced transcriptional addiction to FOXF1 in GIST, which can be exploited diagnostically and therapeutically. Cancer Discov; 8(2); 234-51. (c)2017 AACR.See related commentary by Lee and Duensing, p. 146This article is highlighted in the In This Issue feature, p. 127. PMID- 29162569 TI - Sensitivity analysis for mistakenly adjusting for mediators in estimating total effect in observational studies. AB - OBJECTIVES: In observational studies, epidemiologists often attempt to estimate the total effect of an exposure on an outcome of interest. However, when the underlying diagram is unknown and limited knowledge is available, dissecting bias performances is essential to estimating the total effect of an exposure on an outcome when mistakenly adjusting for mediators under logistic regression. Through simulation, we focused on six causal diagrams concerning different roles of mediators. Sensitivity analysis was conducted to assess the bias performances of varying across exposure-mediator effects and mediator-outcome effects when adjusting for the mediator. SETTING: Based on the causal relationships in the real world, we compared the biases of varying across the effects of exposure mediator with those of varying across the effects of mediator-outcome when adjusting for the mediator. The magnitude of the bias was defined by the difference between the estimated effect (using logistic regression) and the total effect of the exposure on the outcome. RESULTS: In four scenarios (a single mediator, two series mediators, two independent parallel mediators or two correlated parallel mediators), the biases of varying across the effects of exposure-mediator were greater than those of varying across the effects of mediator-outcome when adjusting for the mediator. In contrast, in two other scenarios (a single mediator or two independent parallel mediators in the presence of unobserved confounders), the biases of varying across the effects of exposure-mediator were less than those of varying across the effects of mediator outcome when adjusting for the mediator. CONCLUSIONS: The biases were more sensitive to the variation of effects of exposure-mediator than the effects of mediator-outcome when adjusting for the mediator in the absence of unobserved confounders, while the biases were more sensitive to the variation of effects of mediator-outcome than those of exposure-mediator in the presence of an unobserved confounder. PMID- 29162570 TI - Relationship between socioeconomic status and HIV infection: findings from a survey in the Free State and Western Cape Provinces of South Africa. AB - BACKGROUND: Studies have shown a mixed association between socioeconomic status (SES) and prevalent HIV infection across and within settings in sub-Saharan Africa. In general, the relationship between years of formal education and HIV infection changed from a positive to a negative association with maturity of the HIV epidemic. Our objective was to determine the association between SES and HIV in women of reproductive age in the Free State (FSP) and Western Cape Provinces (WCP) of South Africa (SA). STUDY DESIGN: Cross-sectional. SETTING: SA. METHODS: We conducted secondary analysis on 1906 women of reproductive age from a 2007 to 2008 survey that evaluated effectiveness of Prevention of Mother-to-Child HIV Transmission Programmes. SES was measured by household wealth quintiles, years of formal education and employment status. Our analysis principally used logistic regression for survey data. RESULTS: There was a significant negative trend between prevalent HIV infection and wealth quintile in WCP (P<0.001) and FSP (P=0.025). In adjusted analysis, every additional year of formal education was associated with a 10% (adjusted OR (aOR) 0.90 (95% CI 0.85 to 0.96)) significant reduction in risk of prevalent HIV infection in WCP but no significant association was observed in FSP (aOR 0.99; 95% CI 0.89 to 1.11). There was no significant association between employment and prevalent HIV in each province: (aOR 1.54; 95% CI 0.84 to 2.84) in WCP and (aOR 0.96; 95% CI 0.71 to 1.30) in FSP. CONCLUSION: The association between HIV infection and SES differed by province and by measure of SES and underscores the disproportionately higher burden of prevalent HIV infection among poorer and lowly educated women. Our findings suggest the need for re-evaluation of whether current HIV prevention efforts meet needs of the least educated (in WCP) and the poorest women (both WCP and FSP), and point to the need to investigate additional or tailored strategies for these women. PMID- 29162571 TI - Classroom Promotion of Oral Language (CPOL): protocol for a cluster randomised controlled trial of a school-based intervention to improve children's literacy outcomes at grade 3, oral language and mental health. AB - INTRODUCTION: Oral language and literacy competence are major influences on children's developmental pathways and life success. Children who do not develop the necessary language and literacy skills in the early years of school then go on to face long-term difficulties. Improving teacher effectiveness may be a critical step in lifting oral language and literacy outcomes. The Classroom Promotion of Oral Language trial aims to determine whether a specifically designed teacher professional learning programme focusing on promoting oral language can lead to improved teacher knowledge and practice, and advance outcomes in oral language and literacy for early years school children, compared with usual practice. METHODS AND ANALYSIS: This is a two-arm cluster multisite randomised controlled trial conducted within Catholic and Government primary schools across Victoria, Australia. The intervention comprises 4 days of face-to face professional learning for teachers and ongoing implementation support via a specific worker. The primary outcome is reading ability of the students at grade 3, and the secondary outcomes are teacher knowledge and practice, student mental health, reading comprehension and language ability at grade 1; and literacy, writing and numeracy at grade 3. Economic evaluation will compare the incremental costs of the intervention to the measured primary and secondary outcomes. ETHICS AND DISSEMINATION: This trial was approved by the Monash University Human Research Ethics Committee #CF13/2634-2013001403 and later transferred to the University of Melbourne #1545540. The investigators (including Government and Catholic partners) will communicate trial results to stakeholders, collaborators and participating schools and teachers via appropriate presentations and publications. TRIAL REGISTRATION NUMBER: ISRCTN77681972; Pre-results. PMID- 29162572 TI - Protocol: a cluster randomised control trial study exploring stigmatisation and recovery-based perspectives regarding mental illness and substance use problems among primary healthcare providers across Toronto, Ontario. AB - INTRODUCTION: Primary care settings are often the first and only point of contact for persons with mental health and/or substance use problems. However, staff experience and training in this area are often limited. These factors as well as a multitude of other components such as structural and systemic stigma experienced by staff can lead to clients being stigmatised, leading to poorer outcomes. By developing a comprehensive intervention for primary care staff working at community health centres (CHCs) aimed at reducing stigma towards people with mental health and substance use problems (MHSUP), we sought to test an innovative and contact-based intervention consisting of staff training, raising awareness, a recovery-focused art programme and an analysis of internal policies and procedures. All of these components can inform and support staff so they can provide better care for people who are experiencing MHSUP. CHC staff members and clients will be included in this project as active participants. METHODS AND ANALYSIS: This mixed-methods project will consist of repeated surveys of staff and clients, as well as in-depth, semistructured interviews with a sample of clients and staff. A cluster randomised control trial design will test the effectiveness of an antistigma intervention for CHCs in Toronto, Canada. Six CHCs-three receiving the intervention and three controls-will be included in the study. Using a variety of measures, including the Opening Minds Scale for Health Care Providers (OMS-HC), Mental Illness: Clinicians Attitudes (MICA) Scale, Modified Bogardus Social Distance Scale, Perceived Devaluation-Discrimination Scale, Discrimination Experience subscale of the Internalized Stigma of Mental Illness (ISMI) Scale and the Recovery Assessment Scale (RAS), we hope to gain a thorough understanding of staff members' attitudes and beliefs and clients' perceptions of staff beliefs and behaviours. In-depth interviews will reveal important themes related to clients' experiences of stigma both within and outside the healthcare setting. ETHICS AND DISSEMINATION: If demonstrated to be successful, this intervention can be used as a model for future initiatives aimed at reducing MHSUP-related stigma among healthcare providers in an organisational context. Adapting this work in other settings is a key strategic goal of this project. The project will also advance knowledge about stigma reduction and the experience of encountering stigma within a healthcare setting. TRIAL REGISTRATION: NCT03043417; Post-results. PMID- 29162573 TI - Data quality and 30-day survival for out-of-hospital cardiac arrest in the UK out of-hospital cardiac arrest registry: a data linkage study. AB - OBJECTIVES: The Out-of-Hospital Cardiac Arrest Outcomes (OHCAO) project aims to understand the epidemiology and outcomes of out-of-hospital cardiac arrest (OHCA) across the UK. This data linkage study is a subproject of OHCAO. The aim was to establish the feasibility of linking OHCAO data to National Health Service (NHS) patient demographic data and Office for National Statistics (ONS) date of death data held on the NHS Personal Demographics Service (PDS) database to improve OHCAO demographic data quality and enable analysis of 30-day survival from OHCA. DESIGN AND SETTING: Data were collected from 1 January 2014 to 31 December 2014 as part of a prospective, observational study of OHCA attended by 10 English NHS Ambulance Services. 28 729 OHCA cases had resuscitation attempted by Emergency Medical Services and were included in the study. Data linkage was carried out using a data linkage service provided by NHS Digital, a national provider of health-related data. To assess data linkage feasibility a random sample of 3120 cases was selected. The sample was securely transferred to NHS Digital to be matched using OHCAO patient demographic data to return previously missing demographic data and provide ONS date of death data. RESULTS: A total of 2513 (80.5%) OHCAO cases were matched to patients in the NHS PDS database. Using the linkage process, missing demographic data were retrieved for 1636 (72.7%) out of 2249 OHCAO cases that had previously incomplete demographic data. Returned ONS date of death data allowed analysis of 30-day survival status. The results showed a 30-day survival rate of 9.3%, reducing unknown survival status from 46.1% to 8.5%. CONCLUSIONS: In this sample, data linkage between the OHCAO registry and NHS PDS database was shown to be feasible, improving demographic data quality and allowing analysis of 30-day survival status. PMID- 29162574 TI - Doctors' perception of support and the processes involved in complaints investigations and how these relate to welfare and defensive practice: a cross sectional survey of the UK physicians. AB - OBJECTIVE: How adverse outcomes and complaints are managed may significantly impact on physician well-being and practice. We aimed to investigate how depression, anxiety and defensive medical practice are associated with doctors actual and perceived support, behaviour of colleagues and process issues regarding how complaints investigations are carried out. DESIGN: A survey study. Respondents were classified into three groups: no complaint, recent/current complaint (within 6 months) or past complaint. Each group completed specific surveys. SETTING: British Medical Association (BMA) members were invited to complete an online survey. PARTICIPANTS: 95 636 members of the BMA were asked to participate. 7926 (8.3%) completed the survey, of whom 1780 (22.5%) had no complaint, 3889 (49.1%) had a past complaint and 2257 (28.5%) had a recent/current complaint. We excluded those with no complaints leaving 6144 in the final sample. PRIMARY OUTCOMES MEASURES: We measured anxiety and depression using the Generalised Anxiety Disorder Scale 7 and Physical Health Questionnaire 9. Defensive practice was assessed using a new measure for avoidance and hedging. RESULTS: Most felt supported by colleagues (61%), only 31% felt supported by management. Not following process (56%), protracted timescales (78%), vexatious complaints (49%), feeling bullied (39%) or victimised for whistleblowing (20%), and using complaints to undermine (31%) were reported. Perceived support by management (relative risk (RR) depression: 0.77, 95% CI 0.71 to 0.83; RR anxiety: 0.80, 95% CI 0.74 to 0.87), speaking to colleagues (RR depression: 0.64, 95% CI 0.48 to 0.84 and RR anxiety: 0.69, 95% CI 0.51 to 0.94, respectively), fair/accurate documentation (RR depression: 0.80, 95% CI 0.75 to 0.86; RR anxiety: 0.81, 95% CI 0.75 to 0.87), and being informed about rights (RR depression 0.96 (0.89 to 1.03) and anxiety 0.94 (0.87 to 1.02), correlated positively with well-being and reduced defensive practice. Doctors worried most about professional humiliation following a complaint investigation (80%). CONCLUSION: Poor process, prolonged timescales and vexatious use of complaints systems are associated with decreased psychological welfare and increased defensive practice. In contrast, perceived support from colleagues and management is associated with a reduction in these effects. PMID- 29162575 TI - Patient and practice characteristics predicting attendance and completion at a specialist weight management service in the UK: a cross-sectional study. AB - OBJECTIVE: To determine the association between patient and referring practice characteristics and attendance and completion at a specialist health service weight management service (WMS). DESIGN: Cross-sectional study. SETTING: Regional specialist WMS located in the West of Scotland. PARTICIPANTS: 9677 adults with obesity referred between 2012 and 2014; 3250 attending service and 2252 completing. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measure was attendance at the WMS; secondary outcome was completion, defined as attending four or more sessions. ANALYSIS: Multilevel binary logistic regression models constructed to determine the association between patient and practice characteristics and attendance and completion. RESULTS: Approximately one-third of the 9677 obese adults referred attended at least one session (n=3250, 33.6%); only 2252 (23%) completed by attending four or more sessions. Practice referrals ranged from 1 to 257. Patient-level characteristics were strongest predictors of attendance; odds of attendance increased with age (OR 4.14, 95% CI 3.27 to 5.26 for adults aged 65+ compared with those aged 18-24), body mass index (BMI) category (OR 1.83, 95% CI 1.56 to 2.15 for BMI 45+ compared with BMI 30-35) and increasing affluence (OR 1.96, 95% CI 1.17 to 3.28). Practice-level characteristics most strongly associated with attendance were being a non training practice, having a larger list size and not being located in the most deprived areas. CONCLUSIONS: There was wide variation in referral rates across general practice, suggesting that there is still much to do to improve engagement with weight management by primary care practitioners. The high attrition rate from referral to attendance and from attendance to completion suggests ongoing barriers for patients, particularly those from the most socioeconomically deprived areas. Patient and practice-level characteristics can help us understand the observed variation in attendance at specialist WMS following general practitioner (GP) referral and the underlying explanations for these differences merit further investigation. PMID- 29162576 TI - Functional visual fields: a cross-sectional UK study to determine which visual field paradigms best reflect difficulty with mobility function. AB - OBJECTIVES: To develop an appropriate method of assessing visual field (VF) loss which reflects its functional consequences, this study aims to determine which method(s) of assessing VF best reflect mobility difficulty. SETTING: This cross sectional observational study took place within a single primary care setting. Participants attended a single session at a University Eye Clinic, Cambridge, UK, with data collected by a single researcher (HS), a qualified optometrist. PARTICIPANTS: 50 adult participants with peripheral field impairment were recruited for this study. Individuals with conditions not primarily affecting peripheral visual function, such as macular degeneration, were excluded from the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants undertook three custom and one standard binocular VF tests assessing VF to 60 degrees , and also integrated monocular threshold 24-2 visual fields (IVF). Primary VF outcomes were average mean threshold, percentage of stimuli seen and VF area. VF outcomes were compared with self-reported mobility function assessed with the Independent Mobility Questionnaire, and time taken and patient acceptability were also considered. Receiver operating characteristic (ROC) curves determined which tests best predicted difficulty with mobility tasks. RESULTS: Greater VF loss was associated with greater self-reported mobility difficulty with all field paradigms (R2 0.38-0.48, all P<0.001). All four binocular tests were better than the IVF at predicting difficulty with at least three mobility tasks in ROC analysis. Mean duration of the tests ranged from 1 min 26 s (+/-9 s) for kinetic assessment to 9 min 23 s (+/-24 s) for IVF. CONCLUSIONS: The binocular VF tests extending to 60 degrees eccentricity all relate similarly to self-reported mobility function, and slightly better than integrated monocular VFs. A kinetic assessment of VF area is quicker than and as effective at predicting mobility function as static threshold assessment. PMID- 29162578 TI - Five minutes with . . . Chris Carey. PMID- 29162577 TI - Cohort profile: the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) in Olmsted County, Minnesota (USA). AB - PURPOSE: This cohort study was established to investigate the effects of unilateral and bilateral oophorectomy on the ageing processes in women. PARTICIPANTS: We used the records-linkage system of the Rochester Epidemiology Project (REP, http://www.rochesterproject.org) to identify 570 women who underwent unilateral oophorectomy and 1653 women who underwent bilateral oophorectomy in Olmsted County, Minnesota from 1988 through 2007 (20 years). Each woman was matched by age (+/-1 year) to a population-based referent woman who had not undergone any oophorectomy (570 referent women) or bilateral oophorectomy (1653 referent women). These four cohorts are being followed to assess morbidity and mortality and to study imaging and biological markers related to ageing. FINDINGS TO DATE: An extensive medical record abstraction using the REP has been completed for each woman to obtain demographic, reproductive and adult life characteristics and extensive clinical information about the surgical procedure and subsequent oestrogen replacement therapy (or other sex steroid therapy). The cohorts have been used to date to study the accumulation of multiple chronic conditions following bilateral oophorectomy in women with or without chronic conditions at the time of the oophorectomy (or index date). From the cohorts, we have also derived a sample of 128 pairs of women for a case-control study linking adverse childhood or adult experiences to the risk of bilateral oophorectomy. FUTURE PLANS: We hypothesise that the abrupt hormonal changes caused by bilateral oophorectomy in younger women have a major effect on the ageing processes across the full body. Therefore, we plan to investigate the risk of a wide range of chronic conditions following bilateral oophorectomy. Specific studies are underway for kidney diseases, psychiatric diseases and neurological diseases. In addition, we plan to invite a subsample of women from the bilateral oophorectomy cohort to participate in an in-person study involving brain imaging and the collection of biomarkers. PMID- 29162580 TI - In This Issue of Diabetes Care. PMID- 29162579 TI - In This Issue: November. PMID- 29162581 TI - Maturation of CGM and Glycemic Measurements Beyond HbA1c-A Turning Point in Research and Clinical Decisions. PMID- 29162582 TI - Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 Diabetes: A Consensus Report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange. AB - OBJECTIVE: To identify and define clinically meaningful type 1 diabetes outcomes beyond hemoglobin A1c (HbA1c) based upon a review of the evidence, consensus from clinical experts, and input from researchers, people with type 1 diabetes, and industry. Priority outcomes include hypoglycemia, hyperglycemia, time in range, diabetic ketoacidosis (DKA), and patient-reported outcomes (PROs). While priority outcomes for type 1 and type 2 diabetes may overlap, type 1 diabetes was the focus of this work. RESEARCH AND METHODS: A Steering Committee-comprising representatives from the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange-was the decision-making body for the Type 1 Diabetes Outcomes Program. Their work was informed by input from researchers, industry, and people with diabetes through Advisory Committees representing each stakeholder group. Stakeholder surveys were used to identify priority outcomes. The outcomes prioritized in the surveys were hypoglycemia, hyperglycemia, time in range, DKA, and PROs. To develop consensus on the definitions of these outcomes, the Steering Committee relied on published evidence, their clinical expertise, and feedback from the Advisory Committees. RESULTS: The Steering Committee developed definitions for hypoglycemia, hyperglycemia, time in range, and DKA in type 1 diabetes. The definitions reflect their assessment of the outcome's short- and long-term clinical impact on people with type 1 diabetes. Knowledge gaps to be addressed by future research were identified. The Steering Committee discussed PROs and concluded that further type 1 diabetes-specific development is needed. CONCLUSIONS: The Steering Committee recommends use of the defined clinically meaningful outcomes beyond HbA1c in the research, development, and evaluation of type 1 diabetes therapies. PMID- 29162584 TI - Individualized Glycemic Goals and an Expanded Classification of Severe Hypoglycemia in Diabetes. AB - The view that a hemoglobin A1c (A1C) level <7% (55 mmol/mol) is the accepted glycemic goal for most people with diabetes sometimes conflicts with the view that glycemic goals should be individualized and, thus, that somewhat higher A1C levels are appropriate for some, particularly many at risk for iatrogenic hypoglycemia because of treatment with insulin, a sulfonylurea, or a glinide. The relationship between A1C and chronic complications of diabetes is curvilinear, A1C is a relatively weak predictor of cardiovascular disease, and minor elevations of A1C above 7% have not been found to be associated with increased mortality. Iatrogenic hypoglycemia causes recurrent morbidity in diabetes and is sometimes fatal. In those at risk for hypoglycemia, a reasonable individualized glycemic goal is the lowest A1C that does not cause severe hypoglycemia and preserves awareness of hypoglycemia, preferably with little or no symptomatic or even asymptomatic hypoglycemia, at a given stage in the evolution of the individual's diabetes. A somewhat higher A1C level is appropriate in those who have previously experienced hypoglycemia or have potential high risk for hypoglycemia, have a long duration of diabetes, and have a short life expectancy, among other traits. Given the importance of severe hypoglycemia in selecting glycemic goals, it is proposed to expand the classification of severe hypoglycemia beyond a hypoglycemic event requiring assistance from another person to include a measured glucose concentration <50 mg/dL (2.8 mmol/L), a level associated with sudden death. PMID- 29162585 TI - Diet Behavior Change Techniques in Type 2 Diabetes: A Systematic Review and Meta analysis. AB - OBJECTIVE: Dietary behavior is closely connected to type 2 diabetes. The purpose of this meta-analysis was to identify behavior change techniques (BCTs) and specific components of dietary interventions for patients with type 2 diabetes associated with changes in HbA1c and body weight. RESEARCH DESIGN AND METHODS: The Cochrane Library, CINAHL, Embase, PubMed, PsycINFO, and Scopus databases were searched. Reports of randomized controlled trials published during 1975-2017 that focused on changing dietary behavior were selected, and methodological rigor, use of BCTs, and fidelity and intervention features were evaluated. RESULTS: In total, 54 studies were included, with 42 different BCTs applied and an average of 7 BCTs used per study. Four BCTs-"problem solving," "feedback on behavior," "adding objects to the environment," and "social comparison"-and the intervention feature "use of theory" were associated with >0.3% (3.3 mmol/mol) reduction in HbA1c. Meta-analysis revealed that studies that aimed to control or change the environment showed a greater reduction in HbA1c of 0.5% (5.5 mmol/mol) (95% CI 0.65, -0.34), compared with 0.32% (3.5 mmol/mol) (95% CI -0.40, -0.23) for studies that aimed to change behavior. Limitations of our study were the heterogeneity of dietary interventions and poor quality of reporting of BCTs. CONCLUSIONS: This study provides evidence that changing the dietary environment may have more of an effect on HbA1c in adults with type 2 diabetes than changing dietary behavior. Diet interventions achieved clinically significant reductions in HbA1c, although initial reductions in body weight diminished over time. If appropriate BCTs and theory are applied, dietary interventions may result in better glucose control. PMID- 29162583 TI - International Consensus on Use of Continuous Glucose Monitoring. AB - Measurement of glycated hemoglobin (HbA1c) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA1c testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA1c measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes. PMID- 29162587 TI - Comment on Farren et al. The Prevention of Gestational Diabetes Mellitus With Antenatal Oral Inositol Supplementation: A Randomized Controlled Trial. Diabetes Care 2017;40:759-763. PMID- 29162588 TI - Response to Comment on Farren et al. The Prevention of Gestational Diabetes Mellitus With Antenatal Oral Inositol Supplementation: A Randomized Controlled Trial. Diabetes Care 2017;40:759-763. PMID- 29162589 TI - Comment on Kaul. Mitigating Cardiovascular Risk in Type 2 Diabetes With Antidiabetes Drugs: A Review of Principal Cardiovascular Outcome Results of EMPA REG OUTCOME, LEADER, and SUSTAIN-6 Trials. Diabetes Care 2017;40:821-831. PMID- 29162590 TI - Response to Comment on Kaul. Mitigating Cardiovascular Risk in Type 2 Diabetes With Antidiabetes Drugs: A Review of Principal Cardiovascular Outcome Results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 Trials. Diabetes Care 2017;40:821-831. PMID- 29162591 TI - Perspectives on the Strengths and Weaknesses of the National Kidney Allocation System. PMID- 29162592 TI - Early Experience with the New Kidney Allocation System: A Perspective from a Transplant Center. PMID- 29162593 TI - Early Experience with New Kidney Allocation System: A Perspective from the Organ Procurement Agency. PMID- 29162594 TI - Early Experience with the New Kidney Allocation System: A Perspective from UNOS. AB - PODCAST: This article contains a podcast at https://www.asn online.org/media/podcast/CJASN/2017_11_21_CJASNPodcast_18_1_v.mp3. PMID- 29162595 TI - Predicting Outcome in Patients with Anti-GBM Glomerulonephritis. AB - BACKGROUND AND OBJECTIVES: Large studies on long-term kidney outcome in patients with anti-glomerular basement membrane (anti-GBM) GN are lacking. This study aimed to identify clinical and histopathologic parameters that predict kidney outcome in these patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective analysis included a total of 123 patients with anti-GBM GN between 1986 and 2015 from six centers worldwide. Their kidney biopsy samples were classified according to the histopathologic classification for ANCA-associated GN. Clinical data such as details of treatment were retrieved from clinical records. The primary outcome parameter was the occurrence of ESRD. Kidney survival was analyzed using the log-rank test and Cox regression analyses. RESULTS: The 5-year kidney survival rate was 34%, with an improved rate observed among patients diagnosed after 2007 (P=0.01). In patients with anti-GBM GN, histopathologic class and kidney survival were associated (P<0.001). Only one of 15 patients with a focal class biopsy sample (>=50% normal glomeruli) developed ESRD. Patients with a sclerotic class biopsy sample (>=50% globally sclerotic glomeruli) and patients with 100% cellular crescents did not recover from dialysis dependency at presentation. In multivariable analysis, dialysis dependency at presentation (hazard ratio [HR], 3.17; 95% confidence interval [95% CI], 1.59 to 6.32), percentage of normal glomeruli (HR, 0.97; 95% CI, 0.95 to 0.99), and extent of interstitial infiltrate (HR, 2.02; 95% CI, 1.17 to 3.50) were predictors of ESRD during follow-up. CONCLUSIONS: Dialysis dependency, low percentage of normal glomeruli, and large extent of interstitial infiltrate are associated with poor kidney outcome in anti-GBM GN. Kidney outcome has improved during recent years; the success rate doubled after 2007. PODCAST: This article contains a podcast at https://www.asn online.org/media/podcast/CJASN/2017_11_21_CJASNPodcast_18_1_v.mp3. PMID- 29162596 TI - Lactadherin promotes microvesicle clearance to prevent coagulopathy and improves survival of severe TBI mice. AB - Coagulopathy is common in patients with traumatic brain injury (TBI) and predicts poor clinical outcomes. We have shown that brain-derived extracellular microvesicles, including extracellular mitochondria, play a key role in the development of TBI-induced coagulopathy. Here, we further show in mouse models that the apoptotic cell-scavenging factor lactadherin, given at a single dose of 400 MUg/kg 30 minutes before (preconditioning) or 30 minutes after cerebral fluid percussion injury, prevented coagulopathy as defined by clotting time, fibrinolysis, intravascular fibrin deposition, and microvascular bleeding of the lungs. Lactadherin also reduced cerebral edema, improved neurological function, and increased survival. It achieved these protective effects by enhancing the clearance of circulating microvesicles through phosphatidylserine-mediated phagocytosis. Together, these results identify the scavenging system for apoptotic cells as a potential therapeutic target to prevent TBI-induced coagulopathy and improve the outcome of TBI. PMID- 29162598 TI - Mitochondrial Respiration and Atherosclerosis: R-E-S-P-I-R-E. Find Out What it Means to Mphi (and VSMC). PMID- 29162597 TI - Prevalence and clinical profile of microcephaly in South America pre-Zika, 2005 14: prevalence and case-control study. AB - Objective To describe the prevalence and clinical spectrum of microcephaly in South America for the period 2005-14, before the start of the Zika epidemic in 2015, as a baseline for future surveillance as the Zika epidemic spreads and as other infectious causes may emerge in future.Design Prevalence and case-control study.Data sources ECLAMC (Latin American Collaborative Study of Congenital Malformations) database derived from 107 hospitals in 10 South American countries, 2005 to 2014. Data on microcephaly cases, four non-malformed controls per case, and all hospital births (all births for hospital based prevalence, resident within municipality for population based prevalence). For 2010-14, head circumference data were available and compared with Intergrowth charts.Results 552 microcephaly cases were registered, giving a hospital based prevalence of 4.4 (95% confidence interval 4.1 to 4.9) per 10 000 births and a population based prevalence of 3.0 (2.7 to 3.4) per 10 000. Prevalence varied significantly between countries and between regions and hospitals within countries. Thirty two per cent (n=175) of cases were prenatally diagnosed; 29% (n=159) were perinatal deaths. Twenty three per cent (n=128) were associated with a diagnosed genetic syndrome, 34% (n=189) polymalformed without a syndrome diagnosis, 12% (n=65) with associated neural malformations, and 26% (n=145) microcephaly only. In addition, 3.8% (n=21) had a STORCH (syphilis, toxoplasmosis, other including HIV, rubella, cytomegalovirus, and herpes simplex) infection diagnosis and 2.0% (n=11) had consanguineous parents. Head circumference measurements available for 184/235 cases in 2010-14 showed 45% (n=82) more than 3 SD below the mean, 24% (n=44) between 3 SD and 2 SD below the mean, and 32% (n=58) larger than -2 SD.Conclusion Extrapolated to the nearly 7 million annual births in South America, an estimated 2000-2500 microcephaly cases were diagnosed among births each year before the Zika epidemic began in 2015. Clinicians are using more than simple metrics to make microcephaly diagnoses. Endemic infections are important enduring causes of microcephaly. PMID- 29162600 TI - Letter by Wu et al Regarding Article, "Mechanical Activation of Hypoxia-Inducible Factor 1alpha Drives Endothelial Dysfunction at Atheroprone Sites". PMID- 29162601 TI - Response by Feng et al to Letter Regarding Article, "Mechanical Activation of Hypoxia-Inducible Factor 1alpha Drives Endothelial Dysfunction at Atheroprone Sites". PMID- 29162599 TI - Redox Control of Vascular Function. PMID- 29162602 TI - Rosuvastatin Reduces Aortic Sinus and Coronary Artery Atherosclerosis in SR-B1 (Scavenger Receptor Class B Type 1)/ApoE (Apolipoprotein E) Double Knockout Mice Independently of Plasma Cholesterol Lowering. AB - OBJECTIVE: Rosuvastatin has been widely used in the primary and secondary prevention of coronary heart disease. However, its antiatherosclerotic properties have not been tested in a mouse model that could mimic human coronary heart disease. The present study was designed to test the effects of rosuvastatin on coronary artery atherosclerosis and myocardial fibrosis in SR-B1 (scavenger receptor class B type 1) and apoE (apolipoprotein E) double knockout mice. APPROACH AND RESULTS: Three-week-old SR-B1-/-/apoE-/- mice were injected daily with 10 mg/kg of rosuvastatin for 2 weeks. Compared with saline-treated mice, rosuvastatin-treated mice showed increased levels of hepatic PCSK9 (proprotein convertase subtilisin/kexin type-9) and LDLR (low-density lipoprotein receptor) message, increased plasma PCSK9 protein but decreased levels of hepatic LDLR protein and increased plasma total cholesterol associated with apoB (apolipoprotein B) 48-containing lipoproteins. In spite of this, rosuvastatin treatment was associated with decreased atherosclerosis in both the aortic sinus and coronary arteries and reduced platelet accumulation in atherosclerotic coronary arteries. Cardiac fibrosis and cardiomegaly were also attenuated in rosuvastatin-treated SR-B1-/-/apoE-/- mice. Two-week treatment with rosuvastatin resulted in significant decreases in markers of oxidized phospholipids in atherosclerotic plaques. In vitro analysis showed that incubation of bone marrow derived macrophages with rosuvastatin substantially downregulated cluster of differentiation (CD)36 and inhibited oxidized LDL-induced foam cell formation. CONCLUSIONS: Rosuvastatin protected SR-B1-/-/apoE-/- mice against atherosclerosis and platelet accumulation in coronary arteries and attenuated myocardial fibrosis and cardiomegaly, despite increased plasma total cholesterol. The ability of rosuvastatin to reduce oxidized phospholipids in atherosclerotic plaques and inhibit macrophage foam cell formation may have contributed to this protection. PMID- 29162603 TI - Exogenous Insulin Infusion Can Decrease Atherosclerosis in Diabetic Rodents by Improving Lipids, Inflammation, and Endothelial Function. AB - OBJECTIVE: The objective of this study is to evaluate whether exogenously induced hyperinsulinemia may increase the development of atherosclerosis. APPROACH AND RESULTS: Hyperinsulinemia, induced by exogenous insulin implantation in high-fat fed (60% fat HFD) apolipoprotein E-deficient mice (ApoE-/-) mice, exhibited insulin resistance, hyperglycemia, and hyperinsulinemia. Atherosclerosis was measured by the accumulation of fat, macrophage, and extracellular matrix in the aorta. After 8 weeks on HFD, ApoE-/- mice were subcutaneously implanted with control (sham) or insulin pellet, and phlorizin, a sodium glucose cotransporters inhibitor (1/2)inhibitor, for additional 8 weeks. Intraperitoneal glucose tolerance test showed that plasma glucose levels were lower and insulin and IGF-1 (insulin-like growth factor-1) levels were 5.3- and 3.3-fold higher, respectively, in insulin-implanted compared with sham-treated ApoE-/- mice. Plasma triglyceride, cholesterol, and lipoprotein levels were decreased in mice with insulin implant, in parallel with increased lipoprotein lipase activities. Atherosclerotic plaque by en face and complexity staining showed significant reductions of fat deposits and expressions of vascular adhesion molecule-1, tumor necrosis factor-alpha, interleukin 6, and macrophages in arterial wall while exhibiting increased activation of pAKT and endothelial nitric oxide synthase (P<0.05) comparing insulin-implanted versus sham HFD ApoE-/- mice. No differences were observed in atherosclerotic plaques between phlorizin-treated and sham HFD ApoE-/- mice, except phlorizin significantly lowered plasma glucose and glycated hemoglobin levels while increased glucosuria. Endothelial function was improved only by insulin treatment through endothelial nitric oxide synthase/nitric oxide activations and reduced proinflammatory (M1) and increased anti-inflammatory (M2) macrophages, which were inhibited by endothelial nitric oxide synthase inhibitor. CONCLUSIONS: Exogenous insulin decreased atherosclerosis by lowering inflammatory cytokines, macrophages, and plasma lipids in HFD-induced hyperlipidemia, insulin resistant and mildly diabetic ApoE-/- mice. PMID- 29162604 TI - Suppression of Hepatic FLOT1 (Flotillin-1) by Type 2 Diabetes Mellitus Impairs the Disposal of Remnant Lipoproteins via Syndecan-1. AB - OBJECTIVE: Type 2 diabetes mellitus (T2DM) and the atherometabolic syndrome exhibit a deadly dyslipoproteinemia that arises in part from impaired hepatic disposal of C-TRLs (cholesterol- and triglyceride-rich remnant apoB [apolipoprotein B] lipoproteins). We previously identified syndecan-1 as a receptor for C-TRLs that directly mediates endocytosis via rafts, independent from coated pits. Caveolins and flotillins form rafts but facilitate distinct endocytotic pathways. We now investigated their participation in syndecan-1 mediated disposal of C-TRLs and their expression in T2DM liver. APPROACH AND RESULTS: In cultured liver cells and nondiabetic murine livers, we found that syndecan-1 coimmunoprecipitates with FLOT1 (flotillin-1) but not with CAV1 (caveolin-1). Binding of C-TRLs to syndecan-1 on the surface of liver cells enhanced syndecan-1/FLOT1 association. The 2 molecules then trafficked together into the lysosomes, implying limited if any recycling back to the cell surface. The interaction requires the transmembrane/cytoplasmic region of syndecan-1 and the N-terminal hydrophobic domain of FLOT1. Knockdown of FLOT1 in cultured liver cells substantially inhibited syndecan-1 endocytosis. Livers from obese, T2DM KKAy mice exhibited 60% to 70% less FLOT1 protein and mRNA than in nondiabetic KK livers. An adenoviral construct to enhance hepatic expression of wild-type FLOT1 in T2DM mice normalized plasma triglycerides, whereas a mutant FLOT1 missing its N-terminal hydrophobic domain had no effect. Moreover, the adenoviral vector for wild-type FLOT1 lowered plasma triglyceride excursions and normalized retinyl excursions in T2DM KKAy mice after a corn oil gavage, without affecting postprandial production of C-TRLs. CONCLUSIONS: FLOT1 is a novel participant in the disposal of harmful C-TRLs via syndecan-1. Low expression of FLOT1 in T2DM liver may contribute to metabolic dyslipoproteinemia. PMID- 29162606 TI - Support mounts for paediatrician whom GMC wants struck off. PMID- 29162605 TI - Changes in High-Density Lipoprotein Cholesterol Efflux Capacity After Bariatric Surgery Are Procedure Dependent. AB - OBJECTIVE: High-density lipoprotein cholesterol efflux capacity (CEC) is inversely associated with incident cardiovascular events, independent of high density lipoprotein cholesterol. Obesity is often characterized by impaired high density lipoprotein function. However, the effects of different bariatric surgical techniques on CEC have not been compared. This study sought to determine the effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on CEC. APPROACH AND RESULTS: We prospectively studied severely obese, nondiabetic, premenopausal Hispanic women not using lipid medications undergoing RYGB (n=31) or SG (n=36). Subjects were examined before and at 6 and 12 months after surgery. There were no differences in baseline characteristics between surgical groups. Preoperative CEC correlated most strongly with Apo A1 (apolipoprotein A1) concentration but did not correlate with body mass index, waist:hip, high sensitivity C-reactive protein, or measures of insulin resistance. After 6 months, SG produced superior response in high-density lipoprotein cholesterol and Apo A1 quantity, as well as global and non-ABCA1 (ATP-binding cassette transporter A1)-mediated CEC (P=0.048, P=0.018, respectively) versus RYGB. In multivariable regression models, only procedure type was predictive of changes in CEC (P=0.05). At 12 months after SG, CEC was equivalent to that of normal body mass index control subjects, whereas it remained impaired after RYGB. CONCLUSIONS: SG and RYGB produce similar weight loss, but contrasting effects on CEC. These findings may be relevant in discussions about the type of procedure that is most appropriate for a particular obese patient. Further study of the mechanisms underlying these changes may lead to improved understanding of the factors governing CEC and potential therapeutic interventions to maximally reduce cardiovascular disease risk in both obese and nonobese patients. PMID- 29162607 TI - Computational study on the effect of malalignment of the tibial component on the biomechanics of total knee arthroplasty: A Finite Element Analysis. AB - OBJECTIVES: Malalignment of the tibial component could influence the long-term survival of a total knee arthroplasty (TKA). The object of this study was to investigate the biomechanical effect of varus and valgus malalignment on the tibial component under stance-phase gait cycle loading conditions. METHODS: Validated finite element models for varus and valgus malalignment by 3 degrees and 5 degrees were developed to evaluate the effect of malalignment on the tibial component in TKA. Maximum contact stress and contact area on a polyethylene insert, maximum contact stress on patellar button and the collateral ligament force were investigated. RESULTS: There was greater total contact stress in the varus alignment than in the valgus, with more marked difference on the medial side. An increase in ligament force was clearly demonstrated, especially in the valgus alignment and force exerted on the medial collateral ligament also increased. CONCLUSION: These results highlight the importance of accurate surgical reconstruction of the coronal tibial alignment of the knee joint. Varus and valgus alignments will influence wear and ligament stability, respectively in TKA.Cite this article: D-S. Suh, K-T. Kang, J. Son, O-R. Kwon, C. Baek, Y-G. Koh. Computational study on the effect of malalignment of the tibial component on the biomechanics of total knee arthroplasty: A Finite Element Analysis. Bone Joint Res 2017;6:623-630. DOI: 10.1302/2046-3758.611.BJR-2016-0088.R2. PMID- 29162608 TI - Robotic arm-assisted versus conventional unicompartmental knee arthroplasty: Exploratory secondary analysis of a randomised controlled trial. AB - OBJECTIVES: This study reports on a secondary exploratory analysis of the early clinical outcomes of a randomised clinical trial comparing robotic arm-assisted unicompartmental knee arthroplasty (UKA) for medial compartment osteoarthritis of the knee with manual UKA performed using traditional surgical jigs. This follows reporting of the primary outcomes of implant accuracy and gait analysis that showed significant advantages in the robotic arm-assisted group. METHODS: A total of 139 patients were recruited from a single centre. Patients were randomised to receive either a manual UKA implanted with the aid of traditional surgical jigs, or a UKA implanted with the aid of a tactile guided robotic arm-assisted system. Outcome measures included the American Knee Society Score (AKSS), Oxford Knee Score (OKS), Forgotten Joint Score, Hospital Anxiety Depression Scale, University of California at Los Angeles (UCLA) activity scale, Short Form-12, Pain Catastrophising Scale, somatic disease (Primary Care Evaluation of Mental Disorders Score), Pain visual analogue scale, analgesic use, patient satisfaction, complications relating to surgery, 90-day pain diaries and the requirement for revision surgery. RESULTS: From the first post-operative day through to week 8 post-operatively, the median pain scores for the robotic arm assisted group were 55.4% lower than those observed in the manual surgery group (p = 0.040).At three months post-operatively, the robotic arm-assisted group had better AKSS (robotic median 164, interquartile range (IQR) 131 to 178, manual median 143, IQR 132 to 166), although no difference was noted with the OKS.At one year post-operatively, the observed differences with the AKSS had narrowed from a median of 21 points to a median of seven points (p = 0.106) (robotic median 171, IQR 153 to 179; manual median 164, IQR 144 to 182). No difference was observed with the OKS, and almost half of each group reached the ceiling limit of the score (OKS > 43). A greater proportion of patients receiving robotic arm-assisted surgery improved their UCLA activity score.Binary logistic regression modelling for dichotomised outcome scores predicted the key factors associated with achieving excellent outcome on the AKSS: a pre-operative activity level > 5 on the UCLA activity score and use of robotic-arm surgery. For the same regression modelling, factors associated with a poor outcome were manual surgery and pre operative depression. CONCLUSION: Robotic arm-assisted surgery results in improved early pain scores and early function scores in some patient-reported outcomes measures, but no difference was observed at one year post-operatively. Although improved results favoured the robotic arm-assisted group in active patients (i.e. UCLA ? 5), these do not withstand adjustment for multiple comparisons.Cite this article: M. J. G. Blyth, I. Anthony, P. Rowe, M. S. Banger, A. MacLean, B. Jones. Robotic arm-assisted versus conventional unicompartmental knee arthroplasty: Exploratory secondary analysis of a randomised controlled trial. Bone Joint Res 2017;6:631-639. DOI: 10.1302/2046-3758.611.BJR-2017 0060.R1. PMID- 29162609 TI - Health of health care workers in Canadian nursing homes and pediatric hospitals: a cross-sectional study. AB - BACKGROUND: Poor health of health care workers affects quality of care, but research and health data for health care workers are scarce. Our aim was to compare physical/mental health among health care worker groups 1) within nursing homes and pediatric hospitals, 2) between the 2 settings and 3) with the physical/mental health of the Canadian population. METHODS: Using cross-sectional data collected as part of the Translating Research in Elder Care program and the Translating Research on Pain in Children program, we examined the health of health care workers. In nursing homes, 169 registered nurses, 139 licensed practical nurses, 1506 care aides, 145 allied health care providers and 69 managers were surveyed. In pediatric hospitals, 63 physicians, 747 registered nurses, 155 allied health care providers, 49 nurse educators and 22 managers were surveyed. After standardization of the data for age and sex, we applied analyses of variance and general linear models, adjusted for multiple testing. RESULTS: Nursing home workers and registered nurses in pediatric hospitals had poorer mental health than the Canadian population. Scores were lowest for registered nurses in nursing homes (mean difference -4.4 [95% confidence interval -6.6 to 2.6]). Physicians in pediatric hospitals and allied health care providers in nursing homes had better physical health than the general population. We also found important differences in physical/mental health for care provider groups within and between care settings. INTERPRETATION: Mental health is especially poor among nursing home workers, who care for a highly vulnerable and medically complex population of older adults. Strategies including optimized work environments are needed to improve the physical and mental health of health care workers to ameliorate quality of patient care. PMID- 29162610 TI - Angiography Versus Hemodynamics to Predict the Natural History of Coronary Stenoses: Fractional Flow Reserve Versus Angiography in Multivessel Evaluation 2 Substudy. AB - BACKGROUND: Among patients with documented stable coronary artery disease and in whom no revascularization was performed, we compared the respective values of angiographic diameter stenosis (DS) and fractional flow reserve (FFR) in predicting natural history. METHODS: The present analysis included the 607 patients from the FAME 2 trial (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation 2) in whom no revascularization was performed. FFR varied from 0.20 to 1.00 (average 0.74+/-0.16), and DS (by quantitative coronary analysis) varied from 8% to 98% (average 53+/-15). The primary end point, defined as vessel-oriented clinical end point (VOCE) at 2 years, was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent, and not urgent revascularization. The stenoses were divided into 4 groups according to FFR and %DS values: positive concordance (FFR<=0.80; DS>=50%), negative concordance (FFR>0.80; DS<50%), positive mismatch (FFR<=0.80; DS<50%), and negative mismatch (FFR>0.80; DS>=50%). RESULTS: The rate of VOCE was highest in the positive concordance group (log rank: X2=80.96; P=0.001) and lowest in the negative concordance group. The rate of VOCE was higher in the positive mismatch group than in the negative mismatch group (hazard ratio, 0.38; 95% confidence interval, 0.21-0.67; P=0.001). There was no significant difference in VOCE between the positive concordance and positive mismatch groups (FFR<=0.80; hazard ratio, 0.77; 95% confidence interval, 0.57 1.09; P=0.149) and no significant difference in rate of VOCE between the negative mismatch and negative concordance groups (FFR>0.80; hazard ratio, 1.89; 95% confidence interval, 0.96-3.74; P=0.067). CONCLUSIONS: In patients with stable coronary disease, physiology (FFR) is a more important determinant of the natural history of coronary stenoses than anatomy (DS). CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT01132495. PMID- 29162612 TI - Pharmacist who helped his father die walks free after being acquitted of murder. PMID- 29162611 TI - High-Density Lipoprotein Subspecies Defined by Presence of Apolipoprotein C-III and Incident Coronary Heart Disease in Four Cohorts. AB - BACKGROUND: The causal role of high-density lipoprotein (HDL) cholesterol in cardioprotection has been questioned by genetic and randomized studies. Novel measures that relate to HDL function may contribute new information to the prediction of cardiovascular risk. Apolipoprotein C-III (apoC-III) is a key regulator of lipoprotein metabolism. We investigated whether subspecies of HDL defined by apoC-III are associated with coronary heart disease (CHD). METHODS: We used immunoaffinity chromatography to measure the apoA-I concentrations of HDL that contains and lacks apoC-III in 2 prospective studies of adults free of CHD. In MESA (Multi-Ethnic Study of Atherosclerosis), 5657 participants (52% women, 52 72 years of age) were followed for risk of CHD from 2000 to 2002 through 2013. In a case-cohort study nested within the DCH study (Danish Diet, Cancer, and Health), 3642 participants (47% women, 51-64 years of age) were followed from 1994 to 1997 through 2010. Subsequently, we conducted a meta-analysis that combined these results with the previously published findings from 2 cohort studies that used similar laboratory methodology to measure lipoproteins, totaling 2997 incident cases. RESULTS: ApoC-III was found on 6% to 8% of apoA-I. The 2 HDL subspecies showed opposing associations, with risk of CHD in each of the individual cohorts and in the meta-analysis (P heterogeneity between the 2 subspecies <0.01). HDL that contains apoC-III was associated with a higher risk of CHD (pooled relative risk per standard deviation, 1.09; 95% confidence interval, 1.01-1.18), whereas HDL that lacks apoC-III was associated with lower risk (relative risk, 0.76; 95% confidence interval, 0.70-0.83). The relative risk for HDL lacking apoC-III was even more negative than the relative risk for total HDL (relative risk, 0.80; 95% confidence interval, 0.74-0.87). CONCLUSIONS: Our findings from 4 prospective studies support the hypothesis that apoC-III may mark a subfraction of HDL that is associated with higher risk of CHD. New measures reflecting HDL structure and function may provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations. PMID- 29162613 TI - The JAK1/2 Inhibitor Ruxolitinib Reverses Interleukin-6-Mediated Suppression of Drug-Detoxifying Proteins in Cultured Human Hepatocytes. AB - The inflammatory cytokine interleukin (IL)-6, which basically activates the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) signaling pathway, is well known to repress expression of hepatic cytochromes P-450 (P450s) and transporters. Therapeutic proteins, like monoclonal antibodies targeting IL-6 or its receptor, have consequently been demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract the repressing effects of IL-6 toward hepatic detoxifying systems. Ruxolitinib was found to fully inhibit IL-6 mediated repression of P450 (CYP1A2, CYP2B6, and CYP3A4) and transporter (NTCP, OATP1B1, and OCT1) mRNA levels in primary human hepatocytes and differentiated hepatoma HepaRG cells. Such effects were dose-dependent, with ruxolitinib EC50 values around 1.0-1.2 MUM and thus close to ruxolitinib plasma levels that can be reached in patients. Moreover, they were associated with concomitant restoration of P450 and drug transporter activities in IL-6-exposed HepaRG cells. By contrast, ruxolitinib failed to suppress the repression of drug-detoxifying protein mRNA levels caused by IL-1beta The JAK inhibitor and anti-rheumatoid arthritis compound tofacitinib was additionally found to reverse IL-6-mediated suppression of P450 and transporter mRNA expressions. Taken together, our results demonstrated that small drugs acting as JAK inhibitors, like ruxolitinib, counteract IL-6-mediated repression of drug-metabolizing enzymes and drug transporters in cultured human hepatocytes. These JAK inhibitors may consequently be hypothesized to restore hepatic detoxification capacity for patients suffering from inflammatory diseases, which may in turn cause idDDIs. PMID- 29162614 TI - Discovery and Validation of Pyridoxic Acid and Homovanillic Acid as Novel Endogenous Plasma Biomarkers of Organic Anion Transporter (OAT) 1 and OAT3 in Cynomolgus Monkeys. AB - Perturbation of organic anion transporter (OAT) 1- and OAT3-mediated transport can alter the exposure, efficacy, and safety of drugs. Although there have been reports of the endogenous biomarkers for OAT1/3, none of these have all of the characteristics required for a clinical useful biomarker. Cynomolgus monkeys were treated with intravenous probenecid (PROB) at a dose of 40 mg/kg in this study. As expected, PROB increased the area under the plasma concentration-time curve (AUC) of coadministered furosemide, a known substrate of OAT1 and OAT3, by 4.1 fold, consistent with the values reported in humans (3.1- to 3.7-fold). Of the 233 plasma metabolites analyzed using a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics method, 29 metabolites, including pyridoxic acid (PDA) and homovanillic acid (HVA), were significantly increased after either 1 or 3 hours in plasma from the monkeys pretreated with PROB compared with the treated animals. The plasma of animals was then subjected to targeted LC-MS/MS analysis, which confirmed that the PDA and HVA AUCs increased by approximately 2- to 3-fold by PROB pretreatments. PROB also increased the plasma concentrations of hexadecanedioic acid (HDA) and tetradecanedioic acid (TDA), although the increases were not statistically significant. Moreover, transporter profiling assessed using stable cell lines constitutively expressing transporters demonstrated that PDA and HVA are substrates for human OAT1, OAT3, OAT2 (HVA), and OAT4 (PDA), but not OCT2, MATE1, MATE2K, OATP1B1, OATP1B3, and sodium taurocholate cotransporting polypeptide. Collectively, these findings suggest that PDA and HVA might serve as blood-based endogenous probes of cynomolgus monkey OAT1 and OAT3, and investigation of PDA and HVA as circulating endogenous biomarkers of human OAT1 and OAT3 function is warranted. PMID- 29162615 TI - Precision Oncology: Between Vaguely Right and Precisely Wrong. AB - Precision Oncology seeks to identify and target the mutation that drives a tumor. Despite its straightforward rationale, concerns about its effectiveness are mounting. What is the biological explanation for the "imprecision?" First, Precision Oncology relies on indiscriminate sequencing of genomes in biopsies that barely represent the heterogeneous mix of tumor cells. Second, findings that defy the orthodoxy of oncogenic "driver mutations" are now accumulating: the ubiquitous presence of oncogenic mutations in silent premalignancies or the dynamic switching without mutations between various cell phenotypes that promote progression. Most troublesome is the observation that cancer cells that survive treatment still will have suffered cytotoxic stress and thereby enter a stem cell like state, the seeds for recurrence. The benefit of "precision targeting" of mutations is inherently limited by this counterproductive effect. These findings confirm that there is no precise linear causal relationship between tumor genotype and phenotype, a reminder of logician Carveth Read's caution that being vaguely right may be preferable to being precisely wrong. An open-minded embrace of the latest inconvenient findings indicating nongenetic and "imprecise" phenotype dynamics of tumors as summarized in this review will be paramount if Precision Oncology is ultimately to lead to clinical benefits. Cancer Res; 77(23); 6473-9. (c)2017 AACR. PMID- 29162617 TI - NHS was overcharged for thyroid drug after company raised price by 6000. PMID- 29162616 TI - The Biology of Cancer Exosomes: Insights and New Perspectives. AB - Exosomes are a subclass of extracellular vesicles involved in intercellular communication that are released by all cell types, including cancer cells. Cancer exosomes carry malignant information in the form of proteins, lipids, and nucleic acids that can reprogram recipient cells. Exosomes have emerged as putative biological mediators in cancer contributing to major steps of disease progression. A leading role exists for cancer exosomes in specific aspects of tumor progression: modulation of immune response, tumor microenvironment reprogramming, and metastasis. This review will address the functions attributed to cancer exosomes in these three aspects of cancer biology, highlighting recent advances and potential limitations. Finally, we explore alternative strategies to develop better models to study cancer exosomes biology. Cancer Res; 77(23); 6480 8. (c)2017 AACR. PMID- 29162619 TI - Updated systematic review of exercise studies in breast cancer survivors: attention to the principles of exercise training. AB - OBJECTIVES: To update our previous evaluation of the exercise interventions used in randomised controlled trials of breast cancer survivors in relation to (1) the application of the principles of exercise training in the exercise prescription; (2) the reporting of the components of the exercise prescription; and (3) the reporting of adherence of participants to the prescribed interventions. DESIGN: Systematic review. DATA SOURCES: The OVID Medline, Embase, CINAHL and SPORTDiscus electronic databases were searched from January 2010 to January 2017. ELIGIBILITY CRITERIA: Randomised controlled trials of at least 4 weeks of aerobic and/or resistance exercise in women diagnosed with breast cancer, reporting on physical fitness or body composition outcomes. RESULTS: Specificity was appropriately applied by 84%, progression by 29%, overload by 38% and initial values by 67% of newly identified studies. Reversibility was reported by 3% anddiminishing returns by 22% of newly identified studies. No studies reported all components of the exercise prescription in the methods, or adherence to the prescribed intervention in the results. Reporting of reversibility has increased from 2010, but no other improvements in reporting were noted from the previous review. SUMMARY/CONCLUSION: No studies of exercise in women with breast cancer attended to all principles of exercise training, or reported all components of the exercise prescription in the methods, or adherence to the prescription in the results. Full reporting of the exercise prescribed and completed is essential for study replication in research and translating research findings into the community, and should be prioritised in future trials. PMID- 29162618 TI - Tackler's head position relative to the ball carrier is highly correlated with head and neck injuries in rugby. AB - OBJECTIVES: To characterise the tackler's head position during one-on-one tackling in rugby and to determine the incidence of head, neck and shoulder injuries through analysis of game videos, injury records and a questionnaire completed by the tacklers themselves. METHODS: We randomly selected 28 game videos featuring two university teams in competitions held in 2015 and 2016. Tackles were categorised according to tackler's head position. The 'pre-contact phase' was defined; its duration and the number of steps taken by the ball carrier prior to a tackle were evaluated. RESULTS: In total, 3970 tackles, including 317 (8.0%) with the tackler's head incorrectly positioned (ie, in front of the ball carrier) were examined. Thirty-two head, neck or shoulder injuries occurred for an injury incidence of 0.8% (32/3970). The incidence of injury in tackles with incorrect head positioning was 69.4/1000 tackles; the injury incidence with correct head positioning (ie, behind or to one side of the ball carrier) was 2.7/1000 tackles. Concussions, neck injuries, 'stingers' and nasal fractures occurred significantly more often during tackles with incorrect head positioning than during tackles with correct head positioning. Significantly fewer steps were taken before tackles with incorrect head positioning that resulted in injury than before tackles that did not result in injury. CONCLUSION: Tackling with incorrect head position relative to the ball carrier resulted in a significantly higher incidence of concussions, neck injuries, stingers and nasal fractures than tackling with correct head position. Tackles with shorter duration and distance before contact resulted in more injuries. PMID- 29162620 TI - Distinguishing between causal and non-causal associations: implications for sports medicine clinicians. PMID- 29162622 TI - Evidence from 1970 on sugar's effects on health never saw light of day. PMID- 29162621 TI - Needle-use declarations at the Olympic Games Rio 2016. AB - AIM: We report on the results of the 'IOC Needle Policy' applied during the course of the Games of the XXXI Summer Olympiad in Rio de Janeiro, Brazil. The policy was intended to empower physicians to ensure appropriate clinical use of needles within team medical environments, enhance the safety of those responsible for housekeeping services and others in the Olympic environment, and permit documentation of such procedures as an adjunct to the doping control programme. Any needle use required the submission of an 'Injection Declaration Form' to IOC medical officials. METHOD: All 'Injection Declaration Forms' were reviewed and archived. The declarations provided basic information regarding the nature of the needle use and the product(s) involved, the physician, athlete and respective National Olympic Committee (NOC). The details of the declarations were subsequently categorised. RESULTS: A total of 367 declarations were received from physicians representing 49 NOCs. Needle-use declarations were more common in athletics, gymnastics, football and aquatics. A single product was administered in 60% of the cases, and more than one product was administered in 40%. The majority of declarations indicated the use of local anaesthetics, glucocorticoids, non-steroidal anti-inflammatory drugs and analgesics. CONCLUSION: The introduction of a 'Needle Policy' in the Olympic Games setting was intended to minimise the use of needles by non-physicians, promote evidence based practice and to deter needle-based doping practices. Declarations were received from 49 of 209 NOCs suggesting either that needle use is minimal among certain teams or opportunities remain to enhance compliance with such policies at future games. PMID- 29162623 TI - Elimination of classically-activated macrophages in tumor-conditioned medium by alternatively-activated macrophages. AB - Cellular interactions are critical during development, tissue fitness and epithelial tumor development. The expression levels of specific genes confer to tumoral cells a survival advantage versus the normal neighboring cells. As a consequence, cells surrounding tumors are eliminated and engulfed by macrophages. We propose a novel scenario in which circulating cells facing a tumor can reproduce these cellular interactions. In vitro cultured macrophages from murine bone marrow were used to investigate this hypothesis. M1 macrophages in tumoral medium upregulated markers of a suboptimal condition, such as Sparc and TyrRS, and undergo apoptosis. However, M2 macrophages display higher Myc expression levels and proliferate at the expense of M1. Resulting M1 apoptotic debris is engulfed by M2 in a Sparc- and TyrRS-dependent manner. These findings suggest that tumor-dependent macrophage elimination could deplete immune response against tumors. This possibility could be relevant for macrophage based anti-tumoral strategies. PMID- 29162624 TI - MRCKalpha is activated by caspase cleavage to assemble an apical actin ring for epithelial cell extrusion. AB - Extrusion of apoptotic cells from epithelial tissues requires orchestrated morphological rearrangements of the apoptotic cell and its neighbors. However, the connections between the apoptotic cascade and events leading to extrusion are not fully understood. Here, we characterize an apoptotic extrusion apical actin ring (EAAR) that is assembled within the apoptotic cell and drives epithelial extrusion. Caspase-mediated cleavage of myotonic dystrophy kinase-related CDC42 binding kinase-alpha (MRCKalpha) triggers a signaling pathway that leads to the assembly of EAAR that pulls actin bundles, resulting in the compaction and removal of the cell body. We provide a detailed portrait of the EAAR including F actin flow, the contribution of myosin contraction, and actin polymerization at bundles' terminals when the product of MRCKalpha cleavage is expressed. These results add to our understanding of the mechanisms controlling the process of epithelial extrusion by establishing a causal relationship between the triggering events of apoptosis, the activation of MRCKalpha, and its subsequent effects on the dynamics of actomyosin cytoskeleton rearrangement. PMID- 29162625 TI - Sgs1 Binding to Rad51 Stimulates Homology-Directed DNA Repair in Saccharomyces cerevisiae. AB - Accurate repair of DNA breaks is essential to maintain genome integrity and cellular fitness. Sgs1, the sole member of the RecQ family of DNA helicases in Saccharomyces cerevisiae, is important for both early and late stages of homology dependent repair. Its large number of physical and genetic interactions with DNA recombination, repair, and replication factors has established Sgs1 as a key player in the maintenance of genome integrity. To determine the significance of Sgs1 binding to the strand-exchange factor Rad51, we have identified a single amino acid change at the C-terminal of the helicase core of Sgs1 that disrupts Rad51 binding. In contrast to an SGS1 deletion or a helicase-defective sgs1 allele, this new separation-of-function allele, sgs1-FD, does not cause DNA damage hypersensitivity or genome instability, but exhibits negative and positive genetic interactions with sae2Delta, mre11Delta, exo1Delta, srs2Delta, rrm3Delta, and pol32Delta that are distinct from those of known sgs1 mutants. Our findings suggest that the Sgs1-Rad51 interaction stimulates homologous recombination (HR). However, unlike sgs1 mutations, which impair the resection of DNA double-strand ends, negative genetic interactions of the sgs1-FD allele are not suppressed by YKU70 deletion. We propose that the Sgs1-Rad51 interaction stimulates HR by facilitating the formation of the presynaptic Rad51 filament, possibly by Sgs1 competing with single-stranded DNA for replication protein A binding during resection. PMID- 29162628 TI - Etiopathogenesis and Pharmacological Prevention of a Type-2 Diabetes Model in Male Mice. AB - We describe a stress-derived type-2 diabetes model in male mice, and formulate new hypotheses on how the model was induced, how diabetes-like alterations were prevented through specific pharmacological treatments, and how its possible neuroendocrine pathogenesis could be hypothesized. Pregnant females arrived in our laboratory on their 14th day of conceptional age. After birth, control mice never showed any apparent behavioral-metabolic-endocrine alterations. However, application of postnatal stress (brief mother deprivation, plus sham injection, daily from birth to weaning), was followed in adult male mice by two series of diabetes-like alterations. Some alterations (e.g., body overweight, immune, neurophysiologic, neurobehavioral alterations) were selectively prevented by opioid antagonist naloxone daily administered during nursing period. The aforementioned alterations plus several others (e.g., hyperglycemia, neuroendocrine alterations) were prevented by administration of specific antisense oligodeoxinucleotide, which modulated synthesis-hyperfunction of proopiomelanocortin-derived corticotropin (ACTH)-corticosterone and endorphins in the pituitary. Surprisingly, together with metabolic alterations, enduring increment of neurophysiologic/neurobehavioral brain performances were observed, accompanied by energy compensative reactions, and brain mitochondria hyperfunction. Thus, increased glycemia/lipidemia appeared to furnish fuel necessary to cope with increased request of energy. Diabetes-like alterations were accompanied by enduring hyperfunction of opioid- and ACTH-corticosterone endogenous structures in the brain, which were apparently due to failure of negative feedback hormone mechanisms in the pituitary, for the control of the hypothalamus-pituitary-adrenal axis. In conclusion, for the first time we can hypothesize that a diabetes-like syndrome is produced by enduring hyperfunction of two proopiomelanocortin-dependent endogenous systems (brain opioid- and ACTH corticosterone systems), following failure of pituitary feedback hormonal control, after complex stress procedures. PMID- 29162627 TI - A Combination of G Protein-Coupled Receptor Modulators Protects Photoreceptors from Degeneration. AB - Degeneration of retinal photoreceptor cells can arise from environmental and/or genetic causes. Since photoreceptor cells, the retinal pigment epithelium (RPE), neurons, and glial cells of the retina are intimately associated, all cell types eventually are affected by retinal degenerative diseases. Such diseases often originate either in rod and/or cone photoreceptor cells or the RPE. Of these, cone cells located in the central retina are especially important for daily human activity. Here we describe the protection of cone cells by a combination therapy consisting of the G protein-coupled receptor modulators metoprolol, tamsulosin, and bromocriptine. These drugs were tested in Abca4-/-Rdh8-/- mice, a preclinical model for retinal degeneration. The specificity of these drugs was determined with an essentially complete panel of human G protein-coupled receptors. Significantly, the combination of metoprolol, tamsulosin, and bromocriptine had no deleterious effects on electroretinographic responses of wild-type mice. Moreover, putative G protein-coupled receptor targets of these drugs were shown to be expressed in human and mouse eyes by RNA sequencing and quantitative polymerase chain reaction. Liquid chromatography together with mass spectrometry using validated internal standards confirmed that metoprolol, tamsulosin, and bromocriptine individually or together penetrate the eye after either intraperitoneal delivery or oral gavage. Collectively, these findings support human trials with combined therapy composed of lower doses of metoprolol, tamsulosin, and bromocriptine designed to safely impede retinal degeneration associated with certain genetic diseases (e.g., Stargardt disease). The same low dose combination also could protect the retina against diseases with complex or unknown etiologies such as age-related macular degeneration. PMID- 29162629 TI - We're on a road to nowhere: Culture and adaptation to the environment are driving human evolution, but the destination of this journey is unpredictable. PMID- 29162626 TI - Identification of Isthmin 1 as a Novel Clefting and Craniofacial Patterning Gene in Humans. AB - Orofacial clefts are one of the most common birth defects, affecting 1-2 per 1000 births, and have a complex etiology. High-resolution array-based comparative genomic hybridization has increased the ability to detect copy number variants (CNVs) that can be causative for complex diseases such as cleft lip and/or palate. Utilizing this technique on 97 nonsyndromic cleft lip and palate cases and 43 cases with cleft palate only, we identified a heterozygous deletion of Isthmin 1 in one affected case, as well as a deletion in a second case that removes putative 3' regulatory information. Isthmin 1 is a strong candidate for clefting, as it is expressed in orofacial structures derived from the first branchial arch and is also in the same "synexpression group" as fibroblast growth factor 8 and sprouty RTK signaling antagonist 1a and 2, all of which have been associated with clefting. CNVs affecting Isthmin 1 are exceedingly rare in control populations, and Isthmin 1 scores as a likely haploinsufficiency locus. Confirming its role in craniofacial development, knockdown or clustered randomly interspaced short palindromic repeats/Cas9-generated mutation of isthmin 1 in Xenopus laevis resulted in mild to severe craniofacial dysmorphologies, with several individuals presenting with median clefts. Moreover, knockdown of isthmin 1 produced decreased expression of LIM homeobox 8, itself a gene associated with clefting, in regions of the face that pattern the maxilla. Our study demonstrates a successful pipeline from CNV identification of a candidate gene to functional validation in a vertebrate model system, and reveals Isthmin 1 as both a new human clefting locus as well as a key craniofacial patterning gene. PMID- 29162631 TI - Misuse of gabapentin and pregabalin may be underestimated. PMID- 29162632 TI - Sixty seconds on . . . digital drugs. PMID- 29162633 TI - Use of prostaglandins in duct-dependent congenital heart conditions. AB - Congenital heart disease (CHD) remains a leading cause of infant mortality, which is even higher in infants with undiagnosed duct-dependent CHDs. Up to 39%-50% of infants with critical CHD are being discharged undiagnosed from the hospital. Infants with duct-dependent critical CHD remain well during the fetal period and may deteriorate when the ductus arteriosus (commonly called 'duct') closes after birth. It is critical to open or maintain ductus arteriosus patent in infants with duct-dependent CHDs. Prostaglandin E1 (alprostadil marketed as 'Prostin VR ') and prostaglandin E2 (dinoprostone) are used to maintain a patent ductus arteriosus and the dose of medication depends on the clinical presentation. Delay in starting prostaglandin infusion can have deleterious effects on infants and can even lead to death. These infants often present as an emergency, and professionals caring for these infants need to have a good understanding of these conditions and medications used for ductal patency. PMID- 29162634 TI - Update on Myosin Motors: Molecular Mechanisms and Physiological Functions. PMID- 29162635 TI - Oxygen Sensing and Integrative Stress Signaling in Plants. PMID- 29162636 TI - Quantitative Proteomic Profiling Reveals Novel Plasmodium falciparum Surface Antigens and Possible Vaccine Candidates. AB - Despite recent efforts toward control and elimination, malaria remains a major public health problem worldwide. Plasmodium falciparum resistance against artemisinin, used in front line combination drugs, is on the rise, and the only approved vaccine shows limited efficacy. Combinations of novel and tailored drug and vaccine interventions are required to maintain the momentum of the current malaria elimination program. Current evidence suggests that strain-transcendent protection against malaria infection can be achieved using whole organism vaccination or with a polyvalent vaccine covering multiple antigens or epitopes. These approaches have been successfully applied to the human-infective sporozoite stage. Both systemic and tissue-specific pathology during infection with the human malaria parasite P. falciparum is caused by asexual blood stages. Tissue tropism and vascular sequestration are the result of specific binding interactions between antigens on the parasite-infected red blood cell (pRBC) surface and endothelial receptors. The major surface antigen and parasite ligand binding to endothelial receptors, PfEMP1 is encoded by about 60 variants per genome and shows high sequence diversity across strains. Apart from PfEMP1 and three additional variant surface antigen families RIFIN, STEVOR, and SURFIN, systematic analysis of the infected red blood cell surface is lacking. Here we present the most comprehensive proteomic investigation of the parasitized red blood cell surface so far. Apart from the known variant surface antigens, we identified a set of putative single copy surface antigens with low sequence diversity, several of which are validated in a series of complementary experiments. Further functional and immunological investigation is underway to test these novel P. falciparum blood stage proteins as possible vaccine candidates. PMID- 29162638 TI - The relationship between pectoral fin ray stiffness and swimming behavior in Labridae: insights into design, performance and ecology. AB - The functional capabilities of flexible, propulsive appendages are directly influenced by their mechanical properties. The fins of fishes have undergone extraordinary evolutionary diversification in structure and function, which raises questions of how fin mechanics relate to swimming behavior. In the fish family Labridae, pectoral fin swimming behavior ranges from rowing to flapping. Rowers are more maneuverable than flappers, but flappers generate greater thrust at high speeds and achieve greater mechanical efficiency at all speeds. Interspecific differences in hydrodynamic capability are largely dependent on fin kinematics and deformation, and are expected to correlate with fin stiffness. Here we examine fin ray stiffness in two closely related species that employ divergent swimming behaviors, the flapping Gomphosus varius and the rowing Halichoeres bivittatus To determine the spatial distribution of flexural stiffness across the fin, we performed three-point bending tests at the center of the proximal, middle and distal regions of four equally spaced fin rays. Pectoral fin ray flexural stiffness ranged from 0.0001 to 1.5109 uN m2, and the proximal regions of G. varius fin rays were nearly an order of magnitude stiffer than those of H. bivittatus In both species, fin ray flexural stiffness decreased exponentially along the proximodistal span of fin rays, and flexural stiffness decreased along the fin chord from the leading to the trailing edge. Furthermore, the proportion of fin area occupied by fin rays was significantly greater in G. varius than in H. bivittatus, suggesting that the proportion of fin ray to fin area contributes to differences in fin mechanics. PMID- 29162639 TI - At What Point Is the Accumulated Evidence Sufficient to Change Maintenance Intravenous Fluid Prescribing Practice in Children? How About Yesterday? PMID- 29162640 TI - Outcomes of a Clinical Pathway to Standardize Use of Maintenance Intravenous Fluids. AB - OBJECTIVES: Improper use of maintenance intravenous fluids (IVFs) may cause serious hospital-acquired harm. We created an evidence-based clinical pathway to guide providers on the indications for IVF, its preferred composition, and appropriate clinical monitoring. METHODS: Pathway implementation was supported by the creation of an electronic order set (PowerPlan) and hospital-wide education. Outcomes were measured among pathway-eligible patients for the years before (July 1, 2014-June 30, 2015) and after (July 1, 2015-June 30, 2016) implementation. An interrupted time series analysis was used to evaluate monthly trends related to IVF use, including the following: median duration, proportions of isotonic and hypotonic IVF, adherence to monitoring recommendations, incidence of associated severe dysnatremia, potassium-containing IVF use in the emergency department, and costs. RESULTS: There were 11 602 pathway-eligible encounters (10 287 patients) across the study. Median IVF infusion hours did not change. Isotonic maintenance IVF use increased significantly from 9.3% to 50.6%, whereas the use of any hypotonic fluid decreased from 94.2% to 56.6%. There were significant increases in daily weight measurement and recommended serum sodium testing. Cases of dysnatremia increased from 2 to 4 among pathway-eligible patients and were mostly associated with hypotonic IVF use. Patients in the emergency department had a significant increase in the number of potassium-containing IVF bags (52.9% to 75.3%). Total hospitalization and laboratory test costs did not change significantly. CONCLUSIONS: This is the first report of outcomes of a clinical pathway to standardize IVF use. Implementation was feasible in both medical and surgical units, with sustained improvements for 1 year. Future improvement work includes increasing PowerPlan use and developing clinical assessment tools. PMID- 29162637 TI - Analysis of Mammalian O-Glycopeptides-We Have Made a Good Start, but There is a Long Way to Go. AB - Glycosylation is perhaps the most common post-translational modification. Recently there has been growing interest in cataloging the glycan structures, glycoproteins, and specific sites modified and deciphering the biological functions of glycosylation. Although the results are piling up for N glycosylation, O-glycosylation is seriously trailing behind. In our review we reiterate the difficulties researchers have to overcome in order to characterize O-glycosylation. We describe how an ingenious cell engineering method delivered exciting results, and what could we gain from "wild-type" samples. Although we refer to the biological role(s) of O-glycosylation, we do not provide a complete inventory on this topic. PMID- 29162641 TI - Discovery of noncanonical translation initiation sites through mass spectrometric analysis of protein N termini. AB - Translation initiation generally occurs at AUG codons in eukaryotes, although it has been shown that non-AUG or noncanonical translation initiation can also occur. However, the evidence for noncanonical translation initiation sites (TISs) is largely indirect and based on ribosome profiling (Ribo-seq) studies. Here, using a strategy specifically designed to enrich N termini of proteins, we demonstrate that many human proteins are translated at noncanonical TISs. The large majority of TISs that mapped to 5' untranslated regions were noncanonical and led to N-terminal extension of annotated proteins or translation of upstream small open reading frames (uORF). It has been controversial whether the amino acid corresponding to the start codon is incorporated at the TIS or methionine is still incorporated. We found that methionine was incorporated at almost all noncanonical TISs identified in this study. Comparison of the TISs determined through mass spectrometry with ribosome profiling data revealed that about two thirds of the novel annotations were indeed supported by the available ribosome profiling data. Sequence conservation across species and a higher abundance of noncanonical TISs than canonical ones in some cases suggests that the noncanonical TISs can have biological functions. Overall, this study provides evidence of protein translation initiation at noncanonical TISs and argues that further studies are required for elucidation of functional implications of such noncanonical translation initiation. PMID- 29162643 TI - Identification of an Oleanane-Type Triterpene Hedragonic Acid as a Novel Farnesoid X Receptor Ligand with Liver Protective Effects and Anti-inflammatory Activity. AB - Farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor 1 (GPBAR1) are two important bile acid (BA) receptors. As non-BAs drug template for GPBAR1, none of the natural oleanane-type triterpenes have been reported as FXR ligands, despite FXR and GPBAR1 having similar binding pockets for BAs. Here, we report the natural triterpene hedragonic acid that has been isolated from the stem and root of Celastrus orbiculatus Thunb. (COT) as an effective agonist for FXR. Both biochemical amplified luminescent proximity homogeneous assay and cell-based reporter assays showed that hedragonic acid regulated the transcriptional activity of FXR. Circular dichroism spectroscopy further suggested the conformational changes of FXR upon the binding of hedragonic acid. Interestingly, the crystal structure of hedragonic acid-bound FXR revealed a unique binding mode with hedragonic acid occupying a novel binding pocket different from the classic binding position. The structural comparison between hedragonic acid-bound FXR and oleanolic acid-bound GPBAR1 explained the molecular basis for the selectivity of oleanane-type triterpenes for FXR. Moreover, hedragonic acid treatment protected mice from liver injury induced by acetaminophen overdose and decreased hepatic inflammatory responses in an FXR-dependent manner, suggesting that hedragonic acid might be one of the major components of COT for its multifunctional pharmaceutical uses. In conclusion, our results provide novel structure templates for drug design based on natural triterpenes by targeting FXR and/or GPBAR1 with pharmaceutical values. PMID- 29162642 TI - ABCA4 midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease. AB - Stargardt disease is caused by variants in the ABCA4 gene, a significant part of which are noncanonical splice site (NCSS) variants. In case a gene of interest is not expressed in available somatic cells, small genomic fragments carrying potential disease-associated variants are tested for splice abnormalities using in vitro splice assays. We recently discovered that when using small minigenes lacking the proper genomic context, in vitro results do not correlate with splice defects observed in patient cells. We therefore devised a novel strategy in which a bacterial artificial chromosome was employed to generate midigenes, splice vectors of varying lengths (up to 11.7 kb) covering almost the entire ABCA4 gene. These midigenes were used to analyze the effect of all 44 reported and three novel NCSS variants on ABCA4 pre-mRNA splicing. Intriguingly, multi-exon skipping events were observed, as well as exon elongation and intron retention. The analysis of all reported NCSS variants in ABCA4 allowed us to reveal the nature of aberrant splicing events and to classify the severity of these mutations based on the residual fraction of wild-type mRNA. Our strategy to generate large overlapping splice vectors carrying multiple exons, creating a toolbox for robust and high-throughput analysis of splice variants, can be applied to all human genes. PMID- 29162644 TI - A role for astroglia in prion diseases. AB - In this issue of JEM, Krejciova et al. (https://doi.org/10.1084/jem.20161547) report that astrocytes derived from human iPSCs can replicate human CJD prions. These observations provide a new, potentially very valuable model for studying human prions in cellula and for identifying antiprion compounds that might serve as clinical candidates. Furthermore, they add to the evidence that astrocytes may not be just innocent bystanders in prion diseases. PMID- 29162645 TI - The amazing brain drain. AB - In this issue of JEM, Antila et al. (https://doi.org/10.1084/jem.20170391) demonstrate that central nervous system lymphatics develop in the mouse meninges during early postnatal periods and display remarkable plasticity in adult periods through manipulation of VEGF-C-VEGFR3 signaling. PMID- 29162646 TI - NKG2D-Dependent Antitumor Effects of Chemotherapy and Radiotherapy against Glioblastoma. AB - Purpose: NKG2D is a potent activating immune cell receptor, and glioma cells express the cognate ligands (NKG2DL). These ligands are inducible by cellular stress and temozolomide (TMZ) or irradiation (IR), the standard treatment of glioblastoma, could affect their expression. However, a role of NKG2DL for the efficacy of TMZ and IR has never been addressed.Experimental Design: We assessed the effect of TMZ and IR on NKG2DL in vitro and in vivo in a variety of murine and human glioblastoma models, including glioma-initiating cells, and a cohort of paired glioblastoma samples from patients before and after therapy. Functional effects were studied with immune cell assays. The relevance of the NKG2D system for the efficacy of TMZ and IR was assessed in vivo in syngeneic orthotopic glioblastoma models with blocking antibodies and NKG2D knockout mice.Results: TMZ or IR induced NKG2DL in vitro and in vivo in all glioblastoma models, and glioblastoma patient samples had increased levels of NKG2DL after therapy with TMZ and IR. This enhanced the immunogenicity of glioma cells in a NGK2D-dependent manner, was independent from cytotoxic or growth inhibitory effects, attenuated by O6-methylguanine-DNA-methyltransferase (MGMT), and required the DNA damage response. The survival benefit afforded by TMZ or IR relied on an intact NKG2D system and was decreased upon inhibition of the NKG2D pathway.Conclusions: The immune system may influence the activity of convential cancer treatments with particular importance of the NKG2D pathway in glioblastoma. Our data provide a rationale to combine NKG2D-based immunotherapies with TMZ and IR. Clin Cancer Res; 24(4); 882-95. (c)2017 AACR. PMID- 29162648 TI - Biological age of the endometrium using DNA methylation. AB - Age has a detrimental effect on reproduction and as an increasing number of women postpone motherhood, it is imperative to assess biological age in terms of fertility prognosis and optimizing fertility treatment individually. Horvath's epigenetic clock is a mathematical algorithm that calculates the biological age of human cells, tissues or organs based on DNA methylation levels. The clock, however, was previously shown to be highly inaccurate for the human endometrium, most likely because of the hormonal responsive nature of this tissue. The aim of this study was to determine if epigenetically based biological age of the human endometrium correlated with chronological age, when strictly timed to the same time point in the menstrual cycle. Endometrial biopsies from nine women were obtained in two consecutive cycles, both strictly timed to the LH surge (LH + 7) and additionally, peripheral whole blood samples were analyzed. Using the Illumina HumanMethylation 450 K array and Horvath's epigenetic clock, we found a significant correlation between the biological age of the endometrium and the chronological age of the participants, although the endometrial biological age was accelerated by comparison with blood and chronological age. Moreover, similar biological ages were found in pairs of consecutive biopsies, indicating that an endometrial biopsy does not alter the biological age in the following cycle. In conclusion, as long as endometrial samples are timed to the same time point in the menstrual cycle, Horvath's epigenetic clock could be a powerful new biomarker of reproductive aging in the human endometrium. PMID- 29162649 TI - Effects of sympathectomy on ovarian follicular development and steroid secretion. AB - Recently, the influence of adrenergic activity over ovarian function, and thus fertility, has begun to gain importance. Previous studies have shown that adrenergic activity through norepinephrine (NE) participates in the control of follicular development and steroidal secretion from the ovary, among other functions. To examine this phenomenon, the denervation of the gonad has been widely used to observe changes in the ovary's performance. Nevertheless, the effect of the absence of adrenergic nerves in the ovary has only been studied in short times periods. In the present work, we used guanethidine (a drug that produces an irreversible sympathectomy) during the infantile period of rats, and we observed its effects in the adult rat (6 months old). Our results indicate that ovarian NE content is recovered at 6 months old, alongside with an increase of the adrenal content of NE and a dysfunctional celiac ganglion. Together, these results suggest that the recovery of ovarian NE does not come from a neural origin. In addition, ovarian performance was impaired because the changes in follicular development and steroidal secretion are not recovered despite the recovery of ovarian NE content. In conclusion, these results suggest that the nerve-ovarian connections, which are established during infantile development, are necessary for the accurate response of the ovary to sympathetic stimulation. PMID- 29162650 TI - Steric hindrance in the upper 50 kDa domain of the motor Myo2p leads to cytokinesis defects in fission yeast. AB - Cytokinesis in many eukaryotes requires a contractile actomyosin ring that is placed at the division site. In fission yeast, which is an attractive organism for the study of cytokinesis, actomyosin ring assembly and contraction requires the myosin II heavy chain Myo2p. Although myo2-E1, a temperature-sensitive mutant defective in the upper 50 kDa domain of Myo2p, has been studied extensively, the molecular basis of the cytokinesis defect is not understood. Here, we isolate myo2-E1-Sup2, an intragenic suppressor that contains the original mutation in myo2-E1 (G345R) and a second mutation in the upper 50 kDa domain (Y297C). Unlike myo2-E1-Sup1, a previously characterized myo2-E1 suppressor, myo2-E1-Sup2 reverses actomyosin ring contraction defects in vitro and in vivo Structural analysis of available myosin motor domain conformations suggests that a steric clash in myo2-E1, which is caused by the replacement of a glycine with a bulky arginine, is relieved in myo2-E1-Sup2 by mutation of a tyrosine to a smaller cysteine. Our work provides insight into the function of the upper 50 kDa domain of Myo2p, informs a molecular basis for the cytokinesis defect in myo2-E1, and may be relevant to the understanding of certain cardiomyopathies. PMID- 29162651 TI - Transoceanic Management and Treatment of Aneurysmal Subarachnoid Hemorrhage: A 10 Year Experience. AB - BACKGROUND AND PURPOSE: Because of the small number of yearly cases of ruptured cerebral aneurysms, endovascular treatment is not performed in Martinique. Therefore, patients from Martinique are sent 7000 km to Paris on commercial flights as soon as possible, where treatment is performed. Nontransportable patients are treated locally with either surgery or symptomatic care. The objective of our study was to assess patient outcomes and safety of this treatment strategy. METHODS: We retrospectively examined all cases of aneurysmal subarachnoid hemorrhage in Martinique diagnosed during 2004 to 2013. Medical case records were searched for the type and location of treatment, clinical status, and transfer duration. RESULTS: A total of 119 patients had an aneurysmal subarachnoid hemorrhage during the 10-year period. Of these, 91 were transferred to Paris, 12 were surgically treated locally, and 16 received symptomatic treatment. None of the transferred patients experienced any hemorrhagic recurrence, and none suffered a significant complication related to the air transportation. The median time between aneurysmal subarachnoid hemorrhage diagnosis and arrival at the referral center was 32 hours. The 30-day case fatality rate for treated cases was 14.6% (8.8% for those treated in Paris and 58.3% for those treated locally). CONCLUSIONS: Our treatment strategy for aneurysmal subarachnoid hemorrhage resulted in a 30-day case fatality rate similar to those observed elsewhere, despite an 8-hour flight and a median treatment delay of 32 hours. This strategy therefore seems to be safe and reliable for isolated regions with small populations. PMID- 29162647 TI - A unifying biology of sex steroid-induced apoptosis in prostate and breast cancers. AB - Prostate and breast cancer are the two cancers with the highest incidence in men and women, respectively. Here, we focus on the known biology of acquired resistance to antihormone therapy of prostate and breast cancer and compare laboratory and clinical similarities in the evolution of the disease. Laboratory studies and clinical observations in prostate and breast cancer demonstrate that cell selection pathways occur during acquired resistance to antihormonal therapy. Following sex steroid deprivation, both prostate and breast cancer models show an initial increased acquired sensitivity to the growth potential of sex steroids. Subsequently, prostate and breast cancer cells either become dependent upon the antihormone treatment or grow spontaneously in the absence of hormones. Paradoxically, the physiologic sex steroids now kill a proportion of selected, but vulnerable, resistant tumor cells. The sex steroid receptor complex triggers apoptosis. We draw parallels between acquired resistance in prostate and breast cancer to sex steroid deprivation. Clinical observations and patient trials confirm the veracity of the laboratory studies. We consider therapeutic strategies to increase response rates in clinical trials of metastatic disease that can subsequently be applied as a preemptive salvage adjuvant therapy. The goal of future advances is to enhance response rates and deploy a safe strategy earlier in the treatment plan to save lives. The introduction of a simple evidence-based enhanced adjuvant therapy as a global healthcare strategy has the potential to control recurrence, reduce hospitalization, reduce healthcare costs and maintain a healthier population that contributes to society. PMID- 29162652 TI - Elucidating the pathogenesis of synchronous and metachronous tumors in a woman with endometrioid carcinomas using a whole-exome sequencing approach. AB - Synchronous endometrial and ovarian (SEO) carcinomas involve endometrioid neoplasms in both the ovary and uterus at the time of diagnosis. Patients were traditionally classified as having independent primary SEO lesions or as having metastatic endometrioid carcinoma. Recent studies have supported that SEO tumors result from the dissemination of cells from one organ site to another. However, whether this can be considered a "metastasis" or "dissemination" remains unclear. In this report, we performed whole-exome sequencing of tumor samples from a woman with well-differentiated endometrioid SEO tumors and a clinical "recurrent" poorly differentiated peritoneal tumor that was diagnosed 8 years after the complete resection of the SEO tumors. Somatic mutation analysis identified 132, 171, and 1214 nonsynonymous mutations in the endometrial, ovarian, and peritoneal carcinomas, respectively. A unique mutation signature associated with mismatch repair deficiency was observed in all three tumors. The SEO carcinomas shared 57 nonsynonymous mutations, whereas the clinically suspected recurrent carcinoma shared only eight nonsynonymous mutations with the SEO tumors. One of the eight shared somatic mutations involved PTEN; these shared mutations represent the earliest genetic alteration in the ancestor cell clone. Based on analysis of the phylogenetic tree, we predicted that the so-called recurrent peritoneal tumor was derived from the same endometrial ancestor clone as the SEO tumors, and that this clone migrated and established benign peritoneal endometriosis where the peritoneal tumor later arose. This case highlights the usefulness of next generation sequencing in defining the etiology and clonal relationships of synchronous and metachronous tumors from patients, thus providing valuable insight to aid in the clinical management of rare or ambiguous tumors. PMID- 29162653 TI - De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism. AB - Using whole-exome sequencing, we identified seven unrelated individuals with global developmental delay, hypotonia, dysmorphic facial features, and an increased frequency of short stature, ataxia, and autism with de novo heterozygous frameshift, nonsense, splice, and missense variants in the Early B cell Transcription Factor Family Member 3 (EBF3) gene. EBF3 is a member of the collier/olfactory-1/early B-cell factor (COE) family of proteins, which are required for central nervous system (CNS) development. COE proteins are highly evolutionarily conserved and regulate neuronal specification, migration, axon guidance, and dendritogenesis during development and are essential for maintaining neuronal identity in adult neurons. Haploinsufficiency of EBF3 may affect brain development and function, resulting in developmental delay, intellectual disability, and behavioral differences observed in individuals with a deleterious variant in EBF3. PMID- 29162654 TI - The impact of hereditary cancer gene panels on clinical care and lessons learned. AB - Mutations in hereditary cancer syndromes account for a modest fraction of all cancers; however, identifying patients with these germline mutations offers tremendous health benefits to both patients and their family members. There are about 60 genes that confer a high lifetime risk of specific cancers, and this information can be used to tailor prevention, surveillance, and treatment. With advances in next-generation sequencing technologies and the elimination of gene patents for evaluating genetic information, we are now able to analyze multiple genes simultaneously, leading to the widespread clinical use of gene panels for germline cancer testing. Over the last 4 years since these panels were introduced, we have learned about the diagnostic yield of testing, the expanded phenotypes of the patients with mutations, and the clinical utility of genetic testing in patients with cancer and/or without cancer but with a family history of cancer. We have also experienced challenges including the large number of variants of unknown significance (VUSs), identification of somatic mutations and need to differentiate these from germline mutations, technical issues with particular genes and mutations, insurance coverage and reimbursement issues, lack of access to data, and lack of clinical management guidelines for newer and, especially, moderate and low-penetrance genes. The lessons learned from cancer genetic testing panels are applicable to other clinical areas as well and highlight the problems to be solved as we advance genomic medicine. PMID- 29162655 TI - Cardiovascular effects of small peptides of the renin angiotensin system. AB - The renin-angiotensin system (RAS) is a unique hormonal cascade which is composed by multiple enzymes and effector peptides. Recently, new peptides presenting biological activity have been discovered, increasing the complexity of the RAS Here, we evaluated the effects of small peptides of the RAS in coronary bed of rats. Firstly, we examined the direct effect of small angiotensinergic peptides [Angiotensin (Ang) -(1-5), Ang-(1-4) Ang-(1-3), and Ang-(1-2)] in coronary vessels. Noteworthy, it was observed that Ang-(1-4), Ang-(1-3), and Ang-(1-2) caused a significant reduction in pressure perfusion. Because Ang-(1-2) was the smallest peptide tested and presented the major effect, we decided to investigate its mechanisms of action. The effect of Ang-(1-2) was partially dependent on the Mas receptor, nitric oxide release and angiotensin-converting enzyme. Importantly, Ang-(1-2) reduced the blood pressure of Wistar rats and SHR Interestingly, SHR presented a more pronounced decrease in blood pressure levels than Wistar rats. Altogether, these data showed that angiotensinergic small peptides hold biological activities in coronary bed of rats. PMID- 29162656 TI - Leishmania LABCG2 transporter is involved in ATP-dependent transport of thiols. AB - The Leishmania LABCG2 transporter has a key role in the redox metabolism of these protozoan parasites. Recently, the involvement of LABCG2 in virulence, autophagy and oxidative stress has been described. Null mutant parasites for LABCG2 present an increase in the intracellular levels of glutathione (GSH) and trypanothione [T(SH)2]. On the other hand, parasites overexpressing LABCG2 transporter export non-protein thiols to the extracellular medium. To explore if LABCG2 may mediate an active transport of non-protein thiols, the effect of these molecules on ATPase activity of LABCG2 as well as the ability of LABCG2 to transport them was determined using a baculovirus-Sf9 insect cell system. Our results indicate that all thiols tested [GSH, T(SH)2] as well as their oxidized forms GSSG and TS2 (trypanothione disulfide) stimulate LABCG2-ATPase basal activity. We have measured the transport of [3H]-GSH in inside-out Sf9 cell membrane vesicles expressing LABCG2-GFP (green fluorescence protein), finding that LABCG2 was able to mediate a rapid and concentration-dependent uptake of [3H]-GSH in the presence of ATP. Finally, we have analyzed the ability of different thiol species to compete for this uptake, T(SH)2 and TS2 being the best competitors. The IC50 value for [3H]-GSH uptake in the presence of increasing concentrations of T(SH)2 was less than 100 MUM, highlighting the affinity of this thiol for LABCG2. These results provide the first direct evidence that LABCG2 is an ABC transporter of reduced and oxidized non-protein thiols in Leishmania, suggesting that this transporter can play a role in the redox metabolism and related processes in this protozoan parasite. PMID- 29162657 TI - Implementation of a Guideline to Decrease Use of Acid-Suppressing Medications in the NICU. AB - BACKGROUND AND OBJECTIVES: Acid-suppressing medications are used extensively in term and preterm newborns despite limited efficacy data and increasing evidence for potential harm. We sought to reduce nonindicated use of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) in our level III/IV NICU by developing and implementing a guideline for their use. Our specific aim was to reduce prescriptions among infants <1 month corrected age from a baseline of 7.5 to 4 per month by December 2016. METHODS: Our outcome measures were number of nonindicated PPI/H2RA prescriptions per month, total (indicated and nonindicated) prescriptions per month and percent of patient days with PPI/H2RA therapy. We also tracked potential complications associated with PPIs/H2RAs as secondary outcomes and gastrointestinal bleed as a balancing measure. Interventions and plan-do-study-act cycles included implementation of the initial guideline, guideline revision based on staff feedback, and staff education. By using statistical process control charts and interrupted time series analysis, we compared outcomes over an 8-month baseline period and 2 postimplementation periods spanning 19 months. RESULTS: Nonindicated prescription of PPIs/H2RAs decreased from mean 7.5 per month to 0 (P = .001). Concurrently, total PPI/H2RA prescriptions decreased from mean 11.5 per month to 2.5 (P = .002). Rates of the balancing measure and potentially related complications remained stable over time. CONCLUSIONS: Implementation of an evidence-based guideline in our unit led to a significant decrease in nonindicated use of acid suppressing medications and reduced the burden of exposure to PPIs/H2RAs. This intervention could feasibly be implemented in other similar inpatient settings. PMID- 29162658 TI - Hand and Wrist Injuries Among US High School Athletes: 2005/06-2015/16. AB - BACKGROUND: The risk of hand/wrist injuries is present across various sports. Little is known about the epidemiology of such injuries. The objective of this study was to calculate the rates of hand/wrist injuries and investigate injury patterns among high school athletes. METHODS: Athlete exposure (AE) and hand/wrist injury data were collected during 11 academic years, 2005/06 through 2015/16, from a large sample of US high schools as part of the National High School Sports-Related Injury Surveillance Study. RESULTS: There were 6723 hand/wrist injuries sustained during 40 195 806 AEs, a rate of 1.7 per 10 000 AEs. The rate of injury in competition (3.3) was higher than in practice (1.1) (95% confidence interval: 2.8-3.1). Rates of hand/wrist injuries varied by sport, with the highest rates in football (4.3), boys' lacrosse (1.9), girls' softball (1.9), wrestling (1.8), girls' field hockey (1.7), boys' ice hockey (1.7), and girls' basketball (1.7). The most common injuries were fracture (45.0%), contusion (11.6%), and ligament sprain (9.0%). Athletes most frequently returned to play in <7 days (45.7%), but 12.4% of injuries kept athletes out >=3 weeks. CONCLUSIONS: High school athletes are at risk for hand/wrist injuries. Such injuries can keep athletes out of play and many require substantial medical treatment. Stick and ball or puck sports and full contact sports have high rates of hand/wrist injuries relative to other sports, which is indicative of a need for sport-specific prevention efforts. PMID- 29162659 TI - Clinical Variability in Neonatology: Context Matters. PMID- 29162662 TI - I sit in the Diabetic Clinic. PMID- 29162660 TI - Survival in Very Preterm Infants: An International Comparison of 10 National Neonatal Networks. AB - OBJECTIVES: To compare survival rates and age at death among very preterm infants in 10 national and regional neonatal networks. METHODS: A cohort study of very preterm infants, born between 24 and 29 weeks' gestation and weighing <1500 g, admitted to participating neonatal units between 2007 and 2013 in the International Network for Evaluating Outcomes of Neonates. Survival was compared by using standardized ratios (SRs) comparing survival in each network to the survival estimate of the whole population. RESULTS: Network populations differed with respect to rates of cesarean birth, exposure to antenatal steroids and birth in nontertiary hospitals. Network SRs for survival were highest in Japan (SR: 1.10; 99% confidence interval: 1.08-1.13) and lowest in Spain (SR: 0.88; 99% confidence interval: 0.85-0.90). The overall survival differed from 78% to 93% among networks, the difference being highest at 24 weeks' gestation (range 35% 84%). Survival rates increased and differences between networks diminished with increasing gestational age (GA) (range 92%-98% at 29 weeks' gestation); yet, relative differences in survival followed a similar pattern at all GAs. The median age at death varied from 4 days to 13 days across networks. CONCLUSIONS: The network ranking of survival rates for very preterm infants remained largely unchanged as GA increased; however, survival rates showed marked variations at lower GAs. The median age at death also varied among networks. These findings warrant further assessment of the representativeness of the study populations, organization of perinatal services, national guidelines, philosophy of care at extreme GAs, and resources used for decision-making. PMID- 29162663 TI - The team that plays together stays together: the effect of departmental Christmas party attendance on team cohesion within a healthcare setting. AB - OBJECTIVES: To understand the effect of attendance at departmental Christmas parties on cohesion and teamwork within the healthcare setting. METHOD DESIGN/SETTING/PARTICIPANTS/INTERVENTIONS/OUTCOME MEASURES: We used the 'Team Development Measure' questionnaire to assess team cohesiveness among healthcare professionals before and after departmental Christmas parties took place. A pooled mean score (PMS) of responses was used to compare between groups. RESULTS: There were no significant differences in perceived measures of team cohesion when comparing responses before (PMSbefore=1.86+/-0.20) and after (PMSafter=1.91+/ 0.22) the departmental Christmas party (p=0.37), nor was there a significant difference when comparing responses from attendees (PMSbefore=1.83+/-0.23, PMSafter=1.89+/-0.24, p=0.52) or non-attendees (PMSbefore=1.84+/-1.47, PMSafter=1.83+/-0.15, p=0.91). No difference was observed between professional groups (PMSdoctors=1.85+/-0.23, PMSnurses=1.95+/-0.18, p=0.064). CONCLUSION: Attendance at departmental Christmas parties does not seem to result in improved team cohesion. PMID- 29162664 TI - Christmas Connections. PMID- 29162665 TI - The beneficial effects of curcumin in cirrhotic rats with portal hypertension. AB - In liver cirrhosis with portal hypertension, the uneven distribution of vasoactive substances leads to increased intrahepatic vascular resistance and splanchnic vasodilatation. Angiogenesis also induces increased portal inflow and portosystemic collaterals. The collaterals may induce lethal complications such as gastroesophageal variceal hemorrhage, but the therapeutic effect of vasoconstrictors is still suboptimal due to poor collateral vasoresponsivenss. Curcumin has aroused much attention for its antifibrosis, vasoactive, and anti angiogenesis actions. However, whether it affects the aforementioned aspects is unknown. Liver cirrhosis was induced by common bile duct ligation (CBDL) in Sprague-Dawley rats. Sham-operated rats were controls. CBDL and sham rats were randomly allocated to receive curcumin (600 mg/kg per day) or vehicle since the 15th day after BDL. On the 29th day, portal hypertension related parameters were surveyed. Portosystemic collateral in situ perfusion was performed to evaluate vascular activity. Chronic curcumin treatment decreased portal pressure (PP), cardiac index (CI) and increased systemic vascular resistance (SVR) in cirrhotic rats. In splanchnic system, curcumin decreased superior mesenteric artery (SMA) flow and increased SMA resistance. Mesenteric angiogenesis was attenuated by curcumin. Acute administration of curcumin significantly induced splanchnic vasoconstriction. The mesenteric protein expressions of p-endothelial nitric oxide synthase (eNOS), cyclooxygenase (COX) 2 (COX2), vascular endothelial growth factor (VEGF), p-VEGF receptor 2 (VEGFR2), and p-Erk were down-regulated. In collateral system, curcumin decreased portosystemic shunting and induced vasoconstriction. In conclusion, chronic curcumin administration in cirrhotic rats ameliorated portal hypertension related hemodynamic derangements and portosystemic collaterals. Curcumin also attenuated splanchnic hyperdynamic circulation by inducing vasoconstriction through inhibition of eNOS activation and by decreasing mesenteric angiogenesis via VEGF pathway blockade. PMID- 29162666 TI - Molecular characterization and expression analysis of CSalphabeta defensin genes from the scorpion Mesobuthus martensii. AB - Defensins are important components of innate host defence system against bacteria, fungi, parasites and viruses. Here, we predicted six potential defensin genes from the genome of the scorpion Mesobuthus martensii and then validated four genes from them via the combination of PCR and genomic sequence analysis. These four scorpion defensin genes share the same gene organization and structure of two exons and one phase-I intron with the GT-AG rule. Conserved motif and phylogenetic analysis showed that they belonged to the members of the invertebrate cysteine-stabilized alpha-helix/beta-sheet motif defensin (CSalphabeta) defensin family. All these four CSalphabeta defensin genes have the expression feature of constitutive transcription (CON) by the whole scorpion infection model, promoter sequence analysis and dual luciferase assays. Further evolution and comparison analysis found that the invertebrate CSalphabeta defensin genes from most of arachnids and mollusks appear to share the expression pattern of CON, but those from insects and lower invertebrates (nematodes, annelids, cnidarians and sponges) seem to have identical inducible transcription (IND) after being challenged by microorganisms. Together, we identified four scorpion CSalphabeta defensin genes with the expression feature of CON, and characterized the diversified expression patterns of the invertebrate CSalphabeta defensin genes, which will shed insights into the evolution of the invertebrate CSalphabeta defensin genes and their expression patterns. PMID- 29162667 TI - Reperfusion of occluded branch retinal arteries by transluminal Nd:YAG laser embolysis combined with intravenous thrombolysis of urokinase. AB - PURPOSE: To report successful treatment with transluminal Nd:YAG laser embolysis (TYE) combined with urokinase thrombolysis for reperfusion of occluded branch retinal arteries with visible emboli. METHODS: A total of 34 eyes from 34 patients with acute, severe vision loss secondary to a branch retinal artery occlusion with visible emboli and retinal whitening were examined. Each patient was administered TYE therapy, which focused on the embolus, using an ocular contact lens; a 0.3-0.9 mJ laser pulse was delivered directly and gradually according to the reaction. Fundus photographs and fundus fluorescein angiography (FFA) were obtained before and immediately after the laser treatment. All patients received urokinase thrombolysis therapy drops intravenously for 5 days at 10-20 u/d. The follow-up period ranged from 6 to 14 months after therapy. The morphological characteristics of FFA associated with obstruction recovery of arterial fluorescence filling and visual function were analyzed. RESULTS: After TYE therapy, FFA examinations showed that the retinal artery and its branches exhibited completely restored blood flow without obstruction in 13 eyes, accounting for 38.2% of the cases. The blood flow was mostly recovered in 11 eyes (32.4% of patients). FFA examinations following the combined intravenous urokinase thrombolysis therapy showed that the retinal artery and its branches exhibited completely restored blood flow after obstruction in 16 eyes (47.1% of patients). The blood flow was mostly recovered in 15 eyes (44.1% of patients). CONCLUSION: TYE combined with urokinase thrombolysis is effective for reperfusion of occluded branch retinal arteries and improving visual recovery in patients with visible emboli. PMID- 29162668 TI - Huai Qi Huang corrects the balance of Th1/Th2 and Treg/Th17 in an ovalbumin induced asthma mouse model. AB - The present study is designed to determine whether Huai Qi Huang has immunoregulatory effects on the (helper T (Th)) Th1/Th2 and regulatory T cell (Treg)/Th17 balance in ovalbumin (OVA)-induced asthma model mice. Asthma model mice were constructed by OVA treatment and Huai Qi Huang was administered. The amount of migrated inflammatory cells in the bronchoalveolar lavage fluid (BALF) from the OVA mice was counted. The total IgE in the sera was detected by the IgE ELISA kit. Cell suspensions from the lung were stained with antibodies specific for CD4 and the master transcription factors for Th1 (T-box expressed in T cells (T-bet)), Th2 (GATA-binding protein 3 (Gata-3)), Th17 (retinoic acid related orphan receptor gammat (RORgammat)), and Treg (forkhead box p3 (Foxp3)). The left lobe of the lung was used to prepare a single-cell suspension for flow cytometry to determine whether Huai Qi Huang influenced CD4+ T-cell subsets. Histological analyses were performed by using Hematoxylin and Eosin staining. The mRNA expression levels of the transcription factors were detected by using qRT-PCR. Huai Qi Huang inhibited infiltration of inflammatory cells into the lung, reduced influx of eosinophils (EOSs), lymphocytes (LYMs), neutrophils (NEUs), and macrophages (MACs) in the BALF, and decreased IgE in the serum in OVA-treated mice. Huai Qi Huang could regulate Th1/Th2 and Treg/Th17 via the re-balance of cytokine profiles and change the mRNA expression levels of the transcription factors, T-bet/Gata-3 and Foxp3/RORgammat in OVA-treated mice. Our results showed that Huai Qi Huang could correct the imbalance of Th1/Th2 and Treg/Th17 in OVA induced asthma model mice, indicating its effects on inhibiting the development and severity of asthma. PMID- 29162669 TI - Non-labeled lensless micro-endoscopic approach for cellular imaging through highly scattering media. AB - We describe an imaging approach based on an optical setup made up of a miniature, lensless, minimally invasive endoscope scanning a sample and matching post processing techniques that enable enhanced imaging capabilities. The two main scopes of this article are that this approach enables imaging beyond highly scattering medium and increases the resolution and signal to noise levels reaching single cell imaging. Our approach has more advantages over ordinary endoscope setups and other imaging techniques. It is not mechanically limited by a lens, the stable but flexible fiber can acquire images over long time periods (unlike current imaging methods such as OCT etc.), and the imaging can be obtained at a certain working distance above the surface, without interference to the imaged object. Fast overlapping scans enlarge the region of interest, enhance signal to noise levels and can also accommodate post-processing, super-resolution algorithms. Here we present that due to the setup properties, the overlapping scans also lead to dramatic enhancement of non-scattered signal to scattered noise. This enables imaging through highly scattering medium. We discuss results obtained from in vitro investigation of weak signals of ARPE cells, rat retina, and scattered signals from polydimethylsiloxane (PDMS) microchannels filled with hemoglobin and covered by intralipids consequently mimicking blood capillaries and the epidermis of human skin. The development of minimally invasive procedures and methodologies for imaging through scattering medium such as tissues can vastly enhance biomedical diagnostic capabilities for imaging internal organs. We thereby propose that our method may be used for such tasks in vivo. PMID- 29162672 TI - Introduction to the Newborn Screening, Diagnosis, and Treatment for Pompe Disease Guidance Supplement. PMID- 29162670 TI - PU.1-deficient mice are resistant to thioacetamide-induced hepatic fibrosis: PU.1 finely regulates Sirt1 expression via transcriptional promotion of miR-34a and miR-29c in hepatic stellate cells. AB - PU box binding protein (PU.1) is a critical transcription factor involved in many pathological processes. However, its exact role in activation of hepatic stellate cells (HSCs) and liver fibrosis was rarely reported. Here, we found that, in HSCs of PU.1+/- mice, Sirt1 mRNA expression was not changed but Sirt1 protein was significantly increased, suggesting its promoting role in Sirt1 translation. We then isolated HSCs from wild-type (WT) and PU.1+/- mice, and the pcDNA-PU.1 expression vector was transfected into PU.1+/- HSCs. We checked the levels of miR 34a and miR-29c, two Sirt1-targetting miRNAs, and protein levels of PU.1 and Sirt1. The results showed that miR-34a/-29c were significantly reduced and Sirt1 protein was increased in PU.1+/- HSCs, compared with WT HSCs. Besides, PU.1 overexpression inversed the reduction in miR-34a/-29c levels and the increase in Sirt1 protein in both PU.1+/- HSCs and WT HSCs. Additionally, ChIP-quantitive real-time PCR (qPCR) assay comfirmed that PU.1 was directly bound to both the promoter regions of miR-34a and miR-29c Importantly, PU.1 overexpression promoted the proliferation, migration, activation, oxidative stress and inflammatory response in WT HSCs, while the promotion could be inversed by either overexpression of Sirt1 or inhibition of miR-34a/-29c Moreover, animal model of liver fibrosis was established by intraperitoneal injections of thioacetamide (TAA) in WT and PU.1+/- mice, respectively. Compared with the WT mice, PU.1+/- mice displayed a lower fibrotic score, less collagen content, better liver function, and lower levels of oxidative stress and inflammatory response. In conclusion, PU.1 suppresses Sirt1 translation via transcriptional promotion of miR-34a/-29c, thus promoting Sirt1-mediated HSC activation and TAA-induced hepatic fibrosis. PMID- 29162673 TI - Newborn Screening for Pompe Disease. AB - Started in 1963 by Robert Guthrie, newborn screening (NBS) is considered to be one of the great public health achievements. Its original goal was to screen newborns for conditions that could benefit from presymptomatic treatment, thereby reducing associated morbidity and mortality. With advances in technology, the number of disorders included in NBS programs increased. Pompe disease is a good candidate for NBS. Because decisions regarding which diseases should be included in NBS panels are made regionally and locally, programs and efforts for NBS for Pompe disease have been inconsistent both in the United States and globally. In this article, published in the "Newborn Screening, Diagnosis, and Treatment for Pompe Disease" guidance supplement, the Pompe Disease Newborn Screening Working Group, an international group of experts in both NBS and Pompe disease, review the methods used for NBS for Pompe disease and summarize results of current and ongoing NBS programs in the United States and other countries. Challenges and potential drawbacks associated with NBS also are discussed. PMID- 29162674 TI - The Initial Evaluation of Patients After Positive Newborn Screening: Recommended Algorithms Leading to a Confirmed Diagnosis of Pompe Disease. AB - Newborn screening (NBS) for Pompe disease is done through analysis of acid alpha glucosidase (GAA) activity in dried blood spots. When GAA levels are below established cutoff values, then second-tier testing is required to confirm or refute a diagnosis of Pompe disease. This article in the "Newborn Screening, Diagnosis, and Treatment for Pompe Disease" guidance supplement provides recommendations for confirmatory testing after a positive NBS result indicative of Pompe disease is obtained. Two algorithms were developed by the Pompe Disease Newborn Screening Working Group, a group of international experts on both NBS and Pompe disease, based on whether DNA sequencing is performed as part of the screening method. Using the recommendations in either algorithm will lead to 1 of 3 diagnoses: classic infantile-onset Pompe disease, late-onset Pompe disease, or no disease/not affected/carrier. Mutation analysis of the GAA gene is essential for confirming the biochemical diagnosis of Pompe disease. For NBS laboratories that do not have DNA sequencing capabilities, the responsibility of obtaining sequencing of the GAA gene will fall on the referral center. The recommendations for confirmatory testing and the initial evaluation are intended for a broad global audience. However, the Working Group recognizes that clinical practices, standards of care, and resource capabilities vary not only regionally, but also by testing centers. Individual patient needs and health status as well as local/regional insurance reimbursement programs and regulations also must be considered. PMID- 29162675 TI - Management of Confirmed Newborn-Screened Patients With Pompe Disease Across the Disease Spectrum. AB - After a Pompe disease diagnosis is confirmed in infants identified through newborn screening (NBS), when and if to start treatment with enzyme replacement therapy (ERT) with alglucosidase alfa must be determined. In classic infantile onset Pompe disease, ERT should start as soon as possible. Once started, regular, routine follow-up is necessary to monitor for treatment effects, disease progression, and adverse effects. Decision-making for when or if to start ERT in late-onset Pompe disease (LOPD) is more challenging because patients typically have no measurable signs or symptoms or predictable time of symptom onset at NBS. With LOPD, adequate, ongoing follow-up and assessments for onset or progression of signs and symptoms are important to track disease state and monitor and adjust care before and after treatment is started. Because numerous tests are used to monitor patients at variable frequencies, a standardized approach across centers is lacking. Significant variability in patient assessments may result in missed opportunities for early intervention. Management of Pompe disease requires a comprehensive, multidisciplinary approach with timely disease-specific interventions that target the underlying disease process and symptom-specific manifestations. Regardless of how identified, all patients who have signs or symptoms of the disease require coordinated medical care and follow-up tailored to individual needs throughout their lives. The Pompe Disease Newborn Screening Working Group identifies key considerations before starting and during ERT; summarizes what comprises an indication to start ERT; and provides guidance on how to determine appropriate patient management and monitoring and guide the frequency and type of follow-up assessments for all patients identified through NBS. PMID- 29162676 TI - The Role of Genetic Counseling in Pompe Disease After Patients Are Identified Through Newborn Screening. AB - An important part of the coordinated care by experienced health care teams for all Pompe disease patients, whether diagnosed through newborn screening (NBS), clinical diagnosis, or prenatal diagnosis, is genetic counseling. Genetic counseling helps families better understand medical recommendations and options presented by the patient's health care team so they can make informed decisions. In addition to providing important information about the inheritance and genetic risks, genetic counseling also provides information about Pompe disease and available treatments and resources and should be offered to families with an affected child and all adults diagnosed with Pompe disease. Although the need for genetic counseling after a positive newborn screen for Pompe disease is recognized, the role that genetic counseling plays for both families of affected patients and health care teams is not fully understood. Consistent best genetic counseling practices also are lacking. The guidance in this article in the "Newborn Screening, Diagnosis, and Treatment for Pompe Disease" supplement is derived from expert consensus from the Pompe Disease Newborn Screening Working Group. It is intended to help guide genetic counseling efforts and provide a clear understanding of the role for families or carriers of Pompe disease identified through NBS; explain special considerations (eg, diagnosis of late onset Pompe disease before the appearance of symptoms) and the impact and implications associated with a diagnosis (eg, determination of genetic risk and carrier status and preconception counseling); and provide health care teams caring for patients with a framework for a standardized approach to genetic counseling for patients and at-risk family members. PMID- 29162677 TI - Feasibility of Urgent-Start Peritoneal Dialysis in Older Patients with End-Stage Renal Disease: A Single-Center Experience. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) frequently require urgent-start dialysis. Recent evidence suggests that peritoneal dialysis (PD) might be a feasible alternative to hemodialysis (HD) in these patients, including in older patients. METHODS: This retrospective study enrolled patients aged > 65 years with ESRD who underwent urgent dialysis without functional vascular access or PD catheter at a single center, from January 2011 to December 2014. Patients were grouped based on their dialysis modality (PD or HD). Patients unable to tolerate PD catheter insertion or wait for PD were excluded. Each patient was followed for at least 30 days after catheter insertion. Short-term (30-day) dialysis-related complications and patient survival were compared between the 2 groups. RESULTS: A total of 94 patients were enrolled, including 53 (56.4%) who underwent PD. The incidence of dialysis-related complications during the first 30 days was significantly lower in PD compared with HD patients (3 [5.7%] vs 10 [24.4%], p = 0.009). Logistic regression identified urgent-start HD as an independent risk factor for dialysis-related complications compared with urgent start PD (odds ratio 4.760 [1.183 - 19.147], p = 0.028). The 6-, 12-, 24-, and 36 month survival rates in the PD and HD groups were 92.3% vs 94.6%, 82.4% vs 81.3%, 75.7% vs 74.2%, and 69.5% vs 60.6%, respectively, with no significant differences between the groups (log-rank = 0.011, p = 0.915). CONCLUSION: Urgent-start PD was associated with fewer short-term dialysis-related complications and similar survival to urgent-start HD in older patients with ESRD. Peritoneal dialysis may thus be a safe and effective dialysis modality for older ESRD patients requiring urgent dialysis. PMID- 29162678 TI - Stability of Ceftazidime and Heparin in Four Different Types of Peritoneal Dialysis Solutions. AB - BACKGROUND: Intraperitoneal (IP) administration of ceftazidime is recommended for the treatment of peritoneal dialysis-associated peritonitis (PDAP) from Pseudomonas. Patients with PDAP may also need IP heparin to overcome problems with drainage of turbid peritoneal dialysis (PD) fluids and blockage of catheters with fibrin. Physico-chemical stability of ceftazidime and heparin, and biological stability of heparin in many types of PD solutions is unknown. Therefore, we investigated the stability of ceftazidime and heparin in 4 types of PD solutions. METHODS: A total of 12 PD bags (3 for each type of solution) containing ceftazidime and heparin were prepared and stored at 4 degrees C for 120 hours, and then at 25 degrees C for 6 hours, and finally at 37 degrees C for 12 hours. An aliquot was withdrawn after predefined time points and analyzed for the concentration of ceftazidime and heparin using high-performance liquid chromatography (HPLC). Samples were assessed for pH, color changes, particle content, and anticoagulant activity of heparin. RESULTS: Ceftazidime and heparin retained more than 91% of their initial concentration when stored at 4 degrees C for 120 hours followed by storage at 25 degrees C for 6 hours and then at 37 degrees C for 12 hours. Heparin retained more than 95% of its initial activity throughout the study period. Particle formation was not detected at any time under the storage conditions. The pH and color remained essentially unchanged throughout the study. CONCLUSIONS: Ceftazidime-heparin admixture retains its stability over long periods of storage at different temperatures, allowing its potential use for PDAP treatment in outpatient and remote settings. PMID- 29162679 TI - Safety of Peritoneal Dialysis after Nonrenal Solid-Organ Transplantation. AB - BACKGROUND: End-stage renal disease is a well-known complication after solid organ transplantation, mostly as a result of calcineurin-inhibitor therapy. Among recipients of solid-organ transplants other than kidneys, peritoneal dialysis (PD) has been considered an accessory technique as an increased risk of infectious complications has been reported. The aim of our study was to evaluate the outcome of patients with a liver, heart, or lung transplant who underwent PD for replacement therapy. METHODS: This was a retrospective, monocentric study. Every adult patient starting PD between January 1, 2001, and December 31, 2016, at our center was included. The history of previous solid-organ transplantation was determined. For the statistical analysis, we considered 2 groups of patients: 1 group having a history of transplantation of an organ other than the kidney (lung, heart, liver), and 1 group that was starting dialysis without any prior history of organ transplantation. Patients who had previously undergone kidney transplantation were excluded. The events of interest were the first peritonitis episode, death, and PD failure, defined as transfer to hemodialysis. RESULTS: A total of 383 patients started PD during this period, 13 of whom had a history of organ transplantation. We found no significant difference between the solid-organ transplantation patients and those without a history of transplantation in terms of the occurrence of peritonitis (HR [hazard ratio] 0.91 [0.37 - 2.22]), death (HR 0.83 [0.26 - 2.63]), and PD failure (HR 1.01 [0.32 - 3.22]). CONCLUSION: Peritoneal dialysis appears to be an effective replacement therapy for patients with a previous history of solid-organ transplantation. PMID- 29162680 TI - Peritoneal Dialysis in Orthotopic Liver Transplantation Recipients. AB - BACKGROUND: In many dialysis programs, there is resistance to initiating peritoneal dialysis (PD) in liver transplant patients needing renal replacement therapy. This retrospective study reviews the outcome of PD in liver transplant patients at a major transplantation and dialysis center. METHOD: We performed a retrospective cohort study in patients who underwent liver transplants and received PD between 1991 and 2016. Patient demographics, laboratory parameters, and adverse events were collected from our electronic database. RESULTS: Between 1991 and 2016, 14 patients underwent liver transplants and subsequently received PD. The mean age was 59.0 +/- 7.1 years; 42.8% women; the mean time from transplant to PD initiation was 9.7 +/- 2.8 years; average follow-up on PD was 31.3 months (range: 9 - 87 months). Hepatitis C was the main cause of liver failure necessitating the transplant (8 patients). Calcineurin inhibitor toxicity was the lead cause of end-stage renal disease (ESRD) (12 patients). The overall peritonitis rate was 39.8 patient-months (0.3 episodes per year at risk). There was 1 patient with relapsing peritonitis, and 1 patient had severe peritonitis and died. Mean survival was 58.9 +/- 11.3 months, 4 patients died, 4 received a kidney transplant, 1 patient was transitioned to hemodialysis due to poor ultrafiltration, 1 patient was transferred to another program, 2 remained on PD and 2 patients recovered renal function. Eight patients underwent liver biopsies during their time on PD without complication. CONCLUSION: There appears to be no specific concern related to liver transplant patients undergoing PD. Peritonitis and mortality rates were no different from other solid organ recipients or even from the general PD population. The hepatic graft was never threatened, even during peritonitis. Therefore, these patients should not be denied the option of PD. PMID- 29162681 TI - Clusters of Practice in Peritoneal Dialysis in France: Data from the Catheter Section of the RDPLF. AB - BACKGROUND: Peritonitis is a major cause of peritoneal dialysis (PD) failure. Recommendations for the prevention of peritonitis are available, but wide variations exist in the peritonitis rate among countries and PD units. The objective of this study was to describe the different pattern of practices in France. METHODS: This was a retrospective, multicenter study based on data from the French Language Peritoneal Dialysis Registry. Center practices were described and mapped. Clusters of practices were sought in a hierarchical analysis and centers belonging to the same clusters of practices were mapped. RESULTS: Data from 2,770 catheters placed in 64 centers in France between 1 February 2012 and 31 December 2016 were considered. A median of 34 (ranging from 5 to 133) catheters was reported in each center. Twenty-eight (43.8%) centers routinely administered a prophylactic antibiotic prior to catheter placement, and 8 (12.5%) centers applied a local prophylactic antibiotic at the exit site, as recommended by International guidelines. The presence of a PD nurse specialized in PD or PD referent nephrologist was not associated with better adherence to guidelines. Practices were heterogeneous across centers. We identified 5 clusters of centers according to practice. Geographical proximity was not associated with homogeneity in practices. CONCLUSION: Peritoneal dialysis practices are heterogeneous in France, even those that are subject to International guidelines. Studies to identify associations between center-specific practices and PD patient outcomes remain mandatory. Efforts should be made to standardize the PD standards of care in France. PMID- 29162682 TI - Caenorhabditis elegans DBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling. AB - Metabolic homeostasis is coordinately controlled by diverse inputs. Understanding these regulatory networks is vital to combating metabolic disorders. The nematode Caenorhabditis elegans has emerged as a powerful, genetically tractable model system for the discovery of lipid regulatory mechanisms. Here we introduce DBL-1, the C. elegans homolog of bone morphogenetic protein 2/4 (BMP2/4), as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL 1/BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively with the level of DBL 1/BMP signaling. Regulation of lipid accumulation in the intestine occurs through non-cell-autonomous signaling, since expression of SMA-3, a Smad signal transducer, in the epidermis (hypodermis) is sufficient to rescue the loss of lipid accumulation. Finally, genetic evidence indicates that DBL-1/BMP functions upstream of Insulin/IGF-1 Signaling in lipid metabolism. We conclude that BMP signaling regulates lipid metabolism in C. elegans through interorgan signaling to the Insulin pathway, shedding light on a less well-studied regulatory mechanism for metabolic homeostasis. PMID- 29162683 TI - Rapid Gene Family Evolution of a Nematode Sperm Protein Despite Sequence Hyper conservation. AB - Reproductive proteins are often observed to be the most rapidly evolving elements within eukaryotic genomes. The major sperm protein (MSP) is unique to the phylum Nematoda and is required for proper sperm locomotion and fertilization. Here, we annotate the MSP gene family and analyze their molecular evolution in 10 representative species across Nematoda. We show that MSPs are hyper-conserved across the phylum, having maintained an amino acid sequence identity of 83.5 97.7% for over 500 million years. This extremely slow rate of evolution makes MSPs some of the most highly conserved genes yet identified. However, at the gene family level, we show hyper-variability in both gene copy number and genomic position within species, suggesting rapid, lineage-specific gene family evolution. Additionally, we find evidence that extensive gene conversion contributes to the maintenance of sequence identity within chromosome-level clusters of MSP genes. Thus, while not conforming to the standard expectation for the evolution of reproductive proteins, our analysis of the molecular evolution of the MSP gene family is nonetheless consistent with the widely repeatable observation that reproductive proteins evolve rapidly, in this case in terms of the genomic properties of gene structure, copy number, and genomic organization. This unusual evolutionary pattern is likely generated by strong pleiotropic constraints acting on these genes at the sequence level, balanced against expansion at the level of the whole gene family. PMID- 29162684 TI - Rice TSV3 Encoding Obg-Like GTPase Protein Is Essential for Chloroplast Development During the Early Leaf Stage Under Cold Stress. AB - The Spo0B-associated GTP-binding (Obg) proteins are essential for the viability of nearly all bacteria. However, the detailed roles of Obg proteins in higher plants have not yet been elucidated. In this study, we identified a novel rice (Oryza sativa L.) thermo-sensitive virescent mutant (tsv3) that displayed an albino phenotype at 20 degrees before the three-leaf stage while being a normal green at 32 degrees or even at 20 degrees after the four-leaf stage. The mutant phenotype was consistent with altered chlorophyll content and chloroplast structure in leaves. Map-based cloning and complementation experiments showed that TSV3 encoded a small GTP-binding protein. Subcellular localization studies revealed that TSV3 was localized to the chloroplasts. Expression of TSV3 was high in leaves and weak or undetectable in other tissues, suggesting a tissue-specific expression of TSV3 In the tsv3 mutant, expression levels of genes associated with the biogenesis of the chloroplast ribosome 50S subunit were severely decreased at the three-leaf stage under cold stress (20 degrees ), but could be recovered to normal levels at a higher temperature (32 degrees ). These observations suggest that the rice nuclear-encoded TSV3 plays important roles in chloroplast development at the early leaf stage under cold stress. PMID- 29162685 TI - Tobacco, alcohol and illicit drugs during pregnancy and risk of neuroblastoma: systematic review. AB - OBJECTIVE: To determine whether prenatal and perinatal maternal consumption of alcohol, tobacco and/or illicit drugs is associated with risk of neuroblastoma. DATA SOURCES: Medline and Embase (both from inception to February 2017), and reference lists of included studies. STUDY SELECTION: To be eligible, a study had to be an original report including data on intake of alcohol, tobacco smoking and/or consumption of illicit drugs during pregnancy and risk of neuroblastoma in the child. DATA EXTRACTION: From eligible studies, data study characteristics as well as effect measures and confounders were extracted. We assessed unadjusted and confounder-adjusted estimates, performed risk of bias analysis, constructed random-effects models and assessed heterogeneity. RESULTS: We identified 14 case control studies (1987-2016) involving a total of 3114 children with neuroblastoma. Meta-analysis of unadjusted estimates showed an association between alcohol (OR 1.26; 95% CI 1.07 to 1.49), tobacco (OR 1.22; 95% CI 1.04 to 1.44) and illicit drug consumption during pregnancy and risk of neuroblastoma during childhood, with illicit drug consumption showing the strongest association (OR 3.26; 95% CI 1.36 to 7.86). However, adjusted estimates were highly heterogeneous. LIMITATIONS: All studies were at high risk of bias. CONCLUSIONS: Smoking, alcohol or illicit drugs during pregnancy might play a role in the development of neuroblastoma. However, well-designed studies are needed to assess whether these exposures are causal and whether time period during pregnancy, dose or co-consumption of substances is critical. TRIAL REGISTRATION NUMBER: Registration number CRD42016036165. PMID- 29162687 TI - The power of negative [theoretical] results. PMID- 29162688 TI - Differential effects of global and local climate data in assessing environmental drivers of epidemic outbreaks. PMID- 29162686 TI - Atypical activation of dendritic cells by Plasmodium falciparum. AB - Dendritic cells (DCs) are activated by pathogens to initiate and shape immune responses. We found that the activation of DCs by Plasmodium falciparum, the main causative agent of human malaria, induces a highly unusual phenotype by which DCs up-regulate costimulatory molecules and secretion of chemokines, but not of cytokines typical of inflammatory responses (IL-1beta, IL-6, IL-10, TNF). Similar results were obtained with DCs obtained from malaria-naive US donors and malaria experienced donors from Mali. Contact-dependent cross-talk between the main DC subsets, plasmacytoid and myeloid DCs (mDCs) was necessary for increased chemokine and IFN-alpha secretion in response to the parasite. Despite the absence of inflammatory cytokine secretion, mDCs incubated with P. falciparum infected erythrocytes activated antigen-specific naive CD4+ T cells to proliferate and secrete Th1-like cytokines. This unexpected response of human mDCs to P. falciparum exhibited a transcriptional program distinct from a classical LPS response, pointing to unique P. falciparum-induced activation pathways that may explain the uncharacteristic immune response to malaria. PMID- 29162689 TI - Shifts in time and space interact as climate warms. PMID- 29162690 TI - Multiple pathways in pressure-induced phase transition of coesite. AB - High-pressure single-crystal X-ray diffraction method with precise control of hydrostatic conditions, typically with helium or neon as the pressure transmitting medium, has significantly changed our view on what happens with low density silica phases under pressure. Coesite is a prototype material for pressure-induced amorphization. However, it was found to transform into a high pressure octahedral (HPO) phase, or coesite-II and coesite-III. Given that the pressure is believed to be hydrostatic in two recent experiments, the different transformation pathways are striking. Based on molecular dynamic simulations with an ab initio parameterized potential, we reproduced all of the above experiments in three transformation pathways, including the one leading to an HPO phase. This octahedral phase has an oxygen hcp sublattice featuring 2 * 2 zigzag octahedral edge-sharing chains, however with some broken points (i.e., point defects). It transforms into alpha-PbO2 phase when it is relaxed under further compression. We show that the HPO phase forms through a continuous rearrangement of the oxygen sublattice toward hcp arrangement. The high-pressure amorphous phases can be described by an fcc and hcp sublattice mixture. PMID- 29162691 TI - Dabbling with Piezo2 for mechanosensation. PMID- 29162692 TI - Phosphorylation of huntingtin at residue T3 is decreased in Huntington's disease and modulates mutant huntingtin protein conformation. AB - Posttranslational modifications can have profound effects on the biological and biophysical properties of proteins associated with misfolding and aggregation. However, their detection and quantification in clinical samples and an understanding of the mechanisms underlying the pathological properties of misfolding- and aggregation-prone proteins remain a challenge for diagnostics and therapeutics development. We have applied an ultrasensitive immunoassay platform to develop and validate a quantitative assay for detecting a posttranslational modification (phosphorylation at residue T3) of a protein associated with polyglutamine repeat expansion, namely Huntingtin, and characterized its presence in a variety of preclinical and clinical samples. We find that T3 phosphorylation is greatly reduced in samples from Huntington's disease models and in Huntington's disease patients, and we provide evidence that bona-fide T3 phosphorylation alters Huntingtin exon 1 protein conformation and aggregation properties. These findings have significant implications for both mechanisms of disease pathogenesis and the development of therapeutics and diagnostics for Huntington's disease. PMID- 29162693 TI - DeltaNp63-mediated regulation of hyaluronic acid metabolism and signaling supports HNSCC tumorigenesis. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and several molecular pathways that underlie the molecular tumorigenesis of HNSCC have been identified. Among them, amplification or overexpression of DeltaNp63 isoforms is observed in the majority of HNSCCs. Here, we unveiled a DeltaNp63-dependent transcriptional program able to regulate the metabolism and the signaling of hyaluronic acid (HA), the major component of the extracellular matrix (ECM). We found that ?Np63 is capable of sustaining the production of HA levels in cell culture and in vivo by regulating the expression of the HA synthase HAS3 and two hyaluronidase genes, HYAL-1 and HYAL-3. In addition, ?Np63 directly regulates the expression of CD44, the major HA cell membrane receptor. By controlling this transcriptional program, ?Np63 sustains the epithelial growth factor receptor (EGF-R) activation and the expression of ABCC1 multidrug transporter gene, thus contributing to tumor cell proliferation and chemoresistance. Importantly, p63 expression is positively correlated with CD44, HAS3, and ABCC1 expression in squamous cell carcinoma datasets and p63-HA pathway is a negative prognostic factor of HNSCC patient survival. Altogether, our data shed light on a ?Np63-dependent pathway functionally important to the regulation of HNSCC progression. PMID- 29162694 TI - An endogenous retroviral envelope syncytin and its cognate receptor identified in the viviparous placental Mabuya lizard. AB - Syncytins are envelope genes from endogenous retroviruses that have been captured during evolution for a function in placentation. They have been found in all placental mammals in which they have been searched, including marsupials. Placental structures are not restricted to mammals but also emerged in some other vertebrates, most frequently in lizards, such as the viviparous Mabuya Scincidae. Here, we performed high-throughput RNA sequencing of a Mabuya placenta transcriptome and screened for the presence of retroviral env genes with a full length ORF. We identified one such gene, which we named "syncytin-Mab1," that has all the characteristics expected for a syncytin gene. It encodes a membrane-bound envelope protein with fusogenic activity ex vivo, is expressed at the placental level as revealed by in situ hybridization and immunohistochemistry, and is conserved in all Mabuya species tested, spanning over 25 My of evolution. Its cognate receptor, required for its fusogenic activity, was searched for by a screening assay using the GeneBridge4 human/Chinese hamster radiation hybrid panel and found to be the MPZL1 gene, previously identified in mammals as a signal-transducing transmembrane protein involved in cell migration. Together, these results show that syncytin capture is not restricted to placental mammals, but can also take place in the rare nonmammalian vertebrates in which a viviparous placentotrophic mode of reproduction emerged. It suggests that similar molecular tools have been used for the convergent evolution of placentation in independently evolved and highly distant vertebrates. PMID- 29162695 TI - Parallel epigenetic modifications induced by hatchery rearing in a Pacific salmon. AB - Wild stocks of Pacific salmonids have experienced sharp declines in abundance over the past century. Consequently, billions of fish are released each year for enhancing abundance and sustaining fisheries. However, the beneficial role of this widely used management practice is highly debated since fitness decrease of hatchery-origin fish in the wild has been documented. Artificial selection in hatcheries has often been invoked as the most likely explanation for reduced fitness, and most studies to date have focused on finding signatures of hatchery induced selection at the DNA level. We tested an alternative hypothesis, that captive rearing induces epigenetic reprogramming, by comparing genome-wide patterns of methylation and variation at the DNA level in hatchery-reared coho salmon (Oncorhynchus kisutch) with those of their wild counterparts in two geographically distant rivers. We found a highly significant proportion of epigenetic variation explained by the rearing environment that was as high as the one explained by the river of origin. The differentially methylated regions show enrichment for biological functions that may affect the capacity of hatchery-born smolts to migrate successfully in the ocean. Shared epigenetic variation between hatchery-reared salmon provides evidence for parallel epigenetic modifications induced by hatchery rearing in the absence of genetic differentiation between hatchery and natural-origin fish for each river. This study highlights epigenetic modifications induced by captive rearing as a potential explanatory mechanism for reduced fitness in hatchery-reared salmon. PMID- 29162697 TI - EB1-binding-myomegalin protein complex promotes centrosomal microtubules functions. AB - Control of microtubule dynamics underlies several fundamental processes such as cell polarity, cell division, and cell motility. To gain insights into the mechanisms that control microtubule dynamics during cell motility, we investigated the interactome of the microtubule plus-end-binding protein end binding 1 (EB1). Via molecular mapping and cross-linking mass spectrometry we identified and characterized a large complex associating a specific isoform of myomegalin termed "SMYLE" (for short myomegalin-like EB1 binding protein), the PKA scaffolding protein AKAP9, and the pericentrosomal protein CDK5RAP2. SMYLE was associated through an evolutionarily conserved N-terminal domain with AKAP9, which in turn was anchored at the centrosome via CDK5RAP2. SMYLE connected the pericentrosomal complex to the microtubule-nucleating complex (gamma-TuRC) via Galectin-3-binding protein. SMYLE associated with nascent centrosomal microtubules to promote microtubule assembly and acetylation. Disruption of SMYLE interaction with EB1 or AKAP9 prevented microtubule nucleation and their stabilization at the leading edge of migrating cells. In addition, SMYLE depletion led to defective astral microtubules and abnormal orientation of the mitotic spindle and triggered G1 cell-cycle arrest, which might be due to defective centrosome integrity. As a consequence, SMYLE loss of function had a profound impact on tumor cell motility and proliferation, suggesting that SMYLE might be an important player in tumor progression. PMID- 29162698 TI - Ideals, practices, and future prospects of stakeholder involvement in sustainability science. AB - This paper evaluates current stakeholder involvement (SI) practices in science through a web-based survey among scholars and researchers engaged in sustainability or transition research. It substantiates previous conceptual work with evidence from practice by building on four ideal types of SI in science. The results give an interesting overview of the varied landscape of SI in sustainability science, ranging from the kinds of topics scientists work on with stakeholders, over scientific trade-offs that arise in the field, to improvements scientists wish for. Furthermore, the authors describe a discrepancy between scientists' ideals and practices when working with stakeholders. On the conceptual level, the data reflect that the democratic type of SI is the predominant one concerning questions on the understanding of science, the main goal, the stage of involvement in the research process, and the science-policy interface. The fact that respondents expressed agreement to several types shows they are guided by multiple and partly conflicting ideals when working with stakeholders. We thus conclude that more conceptual exchange between practitioners, as well as more qualitative research on the concepts behind practices, is needed to better understand the stakeholder-scientist nexus. PMID- 29162700 TI - Double-strand DNA breaks are mainly repaired by the homologous recombination pathway in early developing swine embryos. AB - DNA double-strand breaks (DSBs) are less frequent than single-strand breaks but have more harmful consequences on cell survival and physiology. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are the two main pathways that are responsible for DSB repair in eukaryotic cells, but their importance for the preservation of genome stability in totipotent blastomeres of early developing embryos has not been determined. In this study, we observed that the chemical inhibition of HR or both pathways, but not NHEJ alone, increased the number of DSBs, reduced embryo development to the blastocyst stage, and resulted in embryos with higher proportions of apoptotic cells. Targeted knockdown of ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related; HR regulators) and DNA-dependent protein kinase (NHEJ regulator) mRNAs revealed that the attenuation of HR or both HR and NHEJ regulators severely impaired blastocyst formation and quality. Attenuation of ATM alone resulted in a higher incidence of DSBs, lower development and embryo quality, and increased mRNA abundance of genes that are involved in either repair pathway. These findings indicate that HR is the main pathway responsible for the promotion of DSB repair in early developing embryos, and that ATM seems to be more important than ATR in the regulation of the HR pathway in mammalian embryos.-Bohrer, R. C., Dicks, N., Gutierrez, K., Duggavathi, R., Bordignon, V. Double-strand DNA breaks are mainly repaired by the homologous recombination pathway in early developing swine embryos. PMID- 29162696 TI - Expansion microscopy of zebrafish for neuroscience and developmental biology studies. AB - Expansion microscopy (ExM) allows scalable imaging of preserved 3D biological specimens with nanoscale resolution on fast diffraction-limited microscopes. Here, we explore the utility of ExM in the larval and embryonic zebrafish, an important model organism for the study of neuroscience and development. Regarding neuroscience, we found that ExM enabled the tracing of fine processes of radial glia, which are not resolvable with diffraction-limited microscopy. ExM further resolved putative synaptic connections, as well as molecular differences between densely packed synapses. Finally, ExM could resolve subsynaptic protein organization, such as ring-like structures composed of glycine receptors. Regarding development, we used ExM to characterize the shapes of nuclear invaginations and channels, and to visualize cytoskeletal proteins nearby. We detected nuclear invagination channels at late prophase and telophase, potentially suggesting roles for such channels in cell division. Thus, ExM of the larval and embryonic zebrafish may enable systematic studies of how molecular components are configured in multiple contexts of interest to neuroscience and developmental biology. PMID- 29162701 TI - Glycosylation stabilizes hERG channels on the plasma membrane by decreasing proteolytic susceptibility. AB - The human ether-a-go-go related gene ( hERG)-encoded channel hERG undergoes N linked glycosylation at position 598, which is located in the unusually long S5 pore linker of the channel. In other work we have demonstrated that hERG is uniquely susceptible to proteolytic cleavage at the S5-pore linker by proteinase K (PK) and calpain (CAPN). The scorpion toxin BeKm-1, which binds to the S5-pore linker of hERG, protects hERG from such cleavage. In the present study, our data revealed that, compared with normal glycosylated hERG channels, nonglycosylated hERG channels were significantly more susceptible to cleavage by extracellular PK. Furthermore, the protective effect of BeKm-1 on hERG from PK-cleavage was lost when glycosylation of hERG was inhibited. The inactivation-deficient mutant hERG channels S620T and S631A were resistant to PK cleavage, and inhibition of glycosylation rendered both mutants susceptible to PK cleavage. Compared with normal glycosylated channels, nonglycosylated hERG channels were also more susceptible to cleavage mediated by CAPN, which was present in the medium of human embryonic kidney cells under normal culture conditions. Inhibition of CAPN resulted in an increase of nonglycosylated hERG current. In summary, our results revealed that N-linked glycosylation protects hERG against protease-mediated degradation and thus contributes to hERG channel stability on the plasma membrane.-Lamothe, S. M., Hulbert, M., Guo, J., Li, W., Yang, T., Zhang, S. Glycosylation stabilizes hERG channels on the plasma membrane by decreasing proteolytic susceptibility. PMID- 29162699 TI - DNAJB1-PRKACA fusion kinase interacts with beta-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. AB - A segmental deletion resulting in DNAJB1-PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here we implement CRISPR-Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of either the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC. Notably, overexpression of the wild-type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1-PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression. Tumorigenesis was significantly enhanced by genetic activation of beta-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with the hepatotoxin 3,5-diethoxycarbonyl-1,4 dihydrocollidine, which causes tissue injury, inflammation, and fibrosis. Our study validates the DNAJB1-PRKACA fusion kinase as an oncogenic driver and candidate drug target for FL-HCC, and establishes a practical model for preclinical studies to identify strategies to treat this disease. PMID- 29162703 TI - Deformability of breast cancer cells in correlation with surface markers and cell rolling. AB - Although the cancer stem cell (CSC) hypothesis has been around for many years, the reliability of cell-surface markers to classify CSCs has remained debatable. The finding that cancerous cells are significantly more deformable than healthy ones has provided motivation to consider mechanical properties as a possible biomarker for stemness. In this study, using the micropipette aspiration technique, mechanical properties of multiple breast cancer cell lines were investigated and correlated with breast cancer stem cell (BCSC) marker, CD44+/CD24-/ALDH1+. The results indicated that Hs578T and MDA-MB-231 cell lines with CD44+/CD24-/ALDH1+ phenotype were significantly more deformable than the MDA MB-468 cell line, which did not express the BCSC marker. The BT-20 cell line with intermediate deformability did not express any CD44+/CD24- phenotype, but it expressed aldehyde dehydrogenase-1 activity. In addition, more-deformable cell lines were found to roll with shear-independent velocities on E-selectin-coated substrates in a parallel-plate flow chamber, which might be a mediating factor for firm adhesion of CSCs to endothelium during metastasis. Our results indicate that rheological properties can be considered as a biomechanical marker in addition to, or as a complement of, surface markers to find more-definitive evidence of CSC characteristics within tumors.-Mohammadalipour, A., Burdick, M. M., Tees, D. F. J. Deformability of breast cancer cells in correlation with surface markers and cell rolling. PMID- 29162702 TI - Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule. AB - The acetylcholine-activated inward rectifier potassium current ( IKACh) is constitutively active in persistent atrial fibrillation (AF). We tested the hypothesis that the blocking of IKACh with the small molecule chloroquine terminates persistent AF. We used a sheep model of tachypacing-induced, persistent AF, molecular modeling, electrophysiology, and structural biology approaches. The 50% inhibition/inhibitory concentration of IKACh block with chloroquine, measured by patch clamp, was 1 MUM. In optical mapping of sheep hearts with persistent AF, 1 MUM chloroquine restored sinus rhythm. Molecular modeling suggested that chloroquine blocked the passage of a hydrated potassium ion through the intracellular domain of Kir3.1 (a molecular correlate of IKACh) by interacting with residues D260 and F255, in proximity to I228, Q227, and L299. 1H 15N heteronuclear single-quantum correlation of purified Kir3.1 intracellular domain confirmed the modeling results. F255, I228, Q227, and L299 underwent significant chemical-shift perturbations upon drug binding. We then crystallized and solved a 2.5 A X-ray structure of Kir3.1 with F255A mutation. Modeling of chloroquine binding to the mutant channel suggested that the drug's binding to the pore becomes off centered, reducing its ability to block a hydrated potassium ion. Patch clamp validated the structural and modeling data, where the F255A and D260A mutations significantly reduced IKACh block by chloroquine. With the use of numerical and structural biology approaches, we elucidated the details of how a small molecule could block an ion channel and exert antiarrhythmic effects. Chloroquine binds the IKACh channel at a site formed by specific amino acids in the ion-permeation pathway, leading to decreased IKACh and the subsequent termination of AF.-Takemoto, Y., Slough, D. P., Meinke, G., Katnik, C., Graziano, Z. A., Chidipi, B., Reiser, M., Alhadidy, M. M., Ramirez, R., Salvador-Montanes, O., Ennis, S., Guerrero-Serna, G., Haburcak, M., Diehl, C., Cuevas, J., Jalife, J., Bohm, A., Lin,Y.-S., Noujaim, S. F. Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule. PMID- 29162704 TI - Tropomyosin-related kinase C (TrkC) enhances podocyte migration by ERK-mediated WAVE2 activation. AB - Podocyte malfunction is central to glomerular diseases and is marked by defective podocyte intercellular junctions and actin cytoskeletal dynamics. Podocytes share many morphologic features with neurons, so that similar sets of proteins appear to regulate cell process formation. One such protein is the tropomyosin-related kinase C (TrkC). TrkC deficiency in mice leads to proteinuria as a surrogate of defective kidney filter function. Activation of endogenous TrkC by its ligand neurotrophin-3 resulted in increased podocyte migration-a surrogate of podocyte actin dynamics in vivo. Employing a mutagenesis approach, we found that the Src homologous and collagen-like (Shc) binding site Tyr516 within the TrkC cytoplasmic domain was necessary for TrkC-induced migration of podocytes. TrkC activation led to a mobility shift of Wiskott-Aldrich syndrome family verprolin homologous protein (WAVE)-2 which is known to orchestrate Arp2/3 activation and actin polymerization. Chemical inactivation of Erk or mutagenesis of 2 of 4 known Erk target sites within WAVE2, Thr346 and Ser351, abolished the TrkC-induced WAVE2 mobility shift. Knockdown of WAVE2 by shRNA abolished TrkC-induced podocyte migration. In summary, TrkC signals to the podocyte actin cytoskeleton to induce migration by phosphorylating WAVE2 Erk dependently. This signaling mechanism may be important for TrkC-mediated cytoskeletal dynamics in podocyte disease. Gromnitza, S., Lepa, C., Weide, T., Schwab, A., Pavenstadt, H., George, B. Tropomyosin-related kinase C (TrkC) enhances podocyte migration by ERK-mediated WAVE2 activation. PMID- 29162705 TI - Three-Dimensional Superresolution Imaging of the FtsZ Ring during Cell Division of the Cyanobacterium Prochlorococcus. AB - Superresolution imaging has revealed subcellular structures and protein interactions in many organisms. However, superresolution microscopy with lateral resolution better than 100 nm has not been achieved in photosynthetic cells due to the interference of a high-autofluorescence background. Here, we developed a photobleaching method to effectively reduce the autofluorescence of cyanobacterial and plant cells. We achieved lateral resolution of ~10 nm with stochastic optical reconstruction microscopy (STORM) in the sphere-shaped cyanobacterium Prochlorococcus and the flowering plant Arabidopsis thaliana During the cell cycle of Prochlorococcus, we characterized the three-dimensional (3D) organization of the cell division protein FtsZ, which forms a ring structure at the division site and is important for cytokinesis of bacteria and chloroplasts. Although the FtsZ ring assembly process in rod-shaped bacteria has been studied extensively, it has rarely been studied in sphere-shaped bacteria. Similarly to rod-shaped bacteria, our results with Prochlorococcus also showed the assembly of FtsZ clusters into incomplete rings and then complete rings during cell division. Differently from rod-shaped bacteria, the FtsZ ring diameter was not found to decrease during Prochlorococcus cell division. We also discovered a novel double-Z-ring structure, which may be the Z rings of two daughter cells in a predivisional mother cell. Our results showed a quantitative picture of the in vivo Z ring organization of sphere-shaped bacteria.IMPORTANCE Superresolution microscopy has not been widely used to study photosynthetic cells due to their high-autofluorescence background. Here, we developed a photobleaching method to reduce the autofluorescence of cyanobacteria and plant cells. After photobleaching, we performed superresolution imaging in the cyanobacterium Prochlorococcus and the flowering plant Arabidopsis thaliana with ~10-nm resolution, which is the highest resolution in a photosynthetic cell. With this method, we characterized the 3D organization of the cell division protein FtsZ in Prochlorococcus We found that the morphological variation of the FtsZ ring during cell division of the sphere-shaped cyanobacterium Prochlorococcus is similar but not identical to that of rod-shaped bacteria. Our method might also be applicable to other photosynthetic organisms. PMID- 29162706 TI - Vaccine Effects on Heterogeneity in Susceptibility and Implications for Population Health Management. AB - Heterogeneity in host susceptibility is a key determinant of infectious disease dynamics but is rarely accounted for in assessment of disease control measures. Understanding how susceptibility is distributed in populations, and how control measures change this distribution, is integral to predicting the course of epidemics with and without interventions. Using multiple experimental and modeling approaches, we show that rainbow trout have relatively homogeneous susceptibility to infection with infectious hematopoietic necrosis virus and that vaccination increases heterogeneity in susceptibility in a nearly all-or-nothing fashion. In a simple transmission model with an R0 of 2, the highly heterogeneous vaccine protection would cause a 35 percentage-point reduction in outbreak size over an intervention inducing homogenous protection at the same mean level. More broadly, these findings provide validation of methodology that can help to reduce biases in predictions of vaccine impact in natural settings and provide insight into how vaccination shapes population susceptibility.IMPORTANCE Differences among individuals influence transmission and spread of infectious diseases as well as the effectiveness of control measures. Control measures, such as vaccines, may provide leaky protection, protecting all hosts to an identical degree, or all-or-nothing protection, protecting some hosts completely while leaving others completely unprotected. This distinction can have a dramatic influence on disease dynamics, yet this distribution of protection is frequently unaccounted for in epidemiological models and estimates of vaccine efficacy. Here, we apply new methodology to experimentally examine host heterogeneity in susceptibility and mode of vaccine action as distinct components influencing disease outcome. Through multiple experiments and new modeling approaches, we show that the distribution of vaccine effects can be robustly estimated. These results offer new experimental and inferential methodology that can improve predictions of vaccine effectiveness and have broad applicability to human, wildlife, and ecosystem health. PMID- 29162708 TI - Lactobacillus acidophilus Metabolizes Dietary Plant Glucosides and Externalizes Their Bioactive Phytochemicals. AB - Therapeutically active glycosylated phytochemicals are ubiquitous in the human diet. The human gut microbiota (HGM) modulates the bioactivities of these compounds, which consequently affect host physiology and microbiota composition. Despite a significant impact on human health, the key players and the underpinning mechanisms of this interplay remain uncharacterized. Here, we demonstrate the growth of Lactobacillus acidophilus on mono- and diglucosyl dietary plant glycosides (PGs) possessing small aromatic aglycones. Transcriptional analysis revealed the upregulation of host interaction genes and identified two loci that encode phosphotransferase system (PTS) transporters and phospho-beta-glucosidases, which mediate the uptake and deglucosylation of these compounds, respectively. Inactivating these transport and hydrolysis genes abolished or severely reduced growth on PG, establishing the specificity of the loci to distinct groups of PGs. Following intracellular deglucosylation, the aglycones of PGs are externalized, rendering them available for absorption by the host or for further modification by other microbiota taxa. The PG utilization loci are conserved in L. acidophilus and closely related lactobacilli, in correlation with versatile growth on these compounds. Growth on the tested PG appeared more common among human gut lactobacilli than among counterparts from other ecologic niches. The PGs that supported the growth of L. acidophilus were utilized poorly or not at all by other common HGM strains, underscoring the metabolic specialization of L. acidophilus These findings highlight the role of human gut L. acidophilus and select lactobacilli in the bioconversion of glycoconjugated phytochemicals, which is likely to have an important impact on the HGM and human host.IMPORTANCE Thousands of therapeutically active plant derived compounds are widely present in berries, fruits, nuts, and beverages like tea and wine. The bioactivity and bioavailability of these compounds, which are typically glycosylated, are altered by microbial bioconversions in the human gut. Remarkably, little is known about the bioconversion of PGs by the gut microbial community, despite the significance of this metabolic facet to human health. Our work provides the first molecular insights into the metabolic routes of diet relevant and therapeutically active PGs by Lactobacillus acidophilus and related human gut lactobacilli. This taxonomic group is adept at metabolizing the glucoside moieties of select PG and externalizes their aglycones. The study highlights an important role of lactobacilli in the bioconversion of dietary PG and presents a framework from which to derive molecular insights into their metabolism by members of the human gut microbiota. PMID- 29162707 TI - CD4+ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis. AB - Cryptococcus neoformans is a major fungal pathogen that disseminates to the central nervous system (CNS) to cause fatal meningoencephalitis, but little is known about immune responses within this immune-privileged site. CD4+ T cells have demonstrated roles in anticryptococcal defenses, but increasing evidence suggests that they may contribute to clinical deterioration and pathology in both HIV-positive (HIV+) and non-HIV patients who develop immune reconstitution inflammatory syndrome (IRIS) and post-infectious inflammatory response syndrome (PIIRS), respectively. Here we report a novel murine model of cryptococcal meningoencephalitis and a potential damaging role of T cells in disseminated cryptococcal CNS infection. In this model, fungal burdens plateaued in the infected brain by day 7 postinfection, but activation of microglia and accumulation of CD45hi leukocytes was significantly delayed relative to fungal growth and did not peak until day 21. The inflammatory leukocyte infiltrate consisted predominantly of gamma interferon (IFN-gamma)-producing CD4+ T cells, conventionally believed to promote fungal clearance and recovery. However, more than 50% of mice succumbed to infection and neurological dysfunction between days 21 and 35 despite a 100-fold reduction in fungal burdens. Depletion of CD4+ cells significantly impaired IFN-gamma production, CD8+ T cell and myeloid cell accumulation, and fungal clearance from the CNS but prevented the development of clinical symptoms and mortality. These findings conclusively demonstrate that although CD4+ T cells are necessary to control fungal growth, they can also promote significant immunopathology and mortality during CNS infection. The results from this model may provide important guidance for development and use of anti-inflammatory therapies to minimize CNS injury in patients with severe cryptococcal infections.IMPORTANCE CNS infection with the fungal pathogen Cryptococcus neoformans often results in debilitating brain injury and has a high mortality rate despite antifungal treatment. Treatment is complicated by the fact that immune responses needed to eliminate infection are also thought to drive CNS damage in a subset of both HIV+ and non-HIV patients. Thus, physicians need to balance efforts to enhance patients' immune responses and promote microbiological control with anti-inflammatory therapy to protect the CNS. Here we report a novel model of cryptococcal meningoencephalitis demonstrating that fungal growth within the CNS does not immediately cause symptomatic disease. Rather, accumulation of antifungal immune cells critically mediates CNS injury and mortality. This model demonstrates that antifungal immune responses in the CNS can cause detrimental pathology and addresses the urgent need for animal models to investigate the specific cellular and molecular mechanisms underlying cryptococcal disease in order to better treat treat patients with CNS infections. PMID- 29162709 TI - Ehrlichia chaffeensis and Its Invasin EtpE Block Reactive Oxygen Species Generation by Macrophages in a DNase X-Dependent Manner. AB - The obligatory intracellular pathogen Ehrlichia chaffeensis lacks most genes that confer resistance to oxidative stress but can block reactive oxygen species (ROS) generation by host monocytes-macrophages. Bacterial and host molecules responsible for this inhibition have not been identified. To infect host cells, Ehrlichia uses the C terminus of its surface invasin, entry-triggering protein of Ehrlichia (EtpE; EtpE-C), which directly binds the mammalian cell surface receptor glycosylphosphatidylinositol-anchored protein DNase X. We investigated whether EtpE-C binding to DNase X blocks ROS production by mouse bone marrow derived macrophages (BMDMs). On the basis of a luminol-dependent chemiluminescence assay, E. chaffeensis inhibited phorbol myristate acetate (PMA) induced ROS generation by BMDMs from wild-type, but not DNase X-/-, mice. EtpE-C is critical for inhibition, as recombinant EtpE-C (rEtpE-C)-coated latex beads, but not recombinant N-terminal EtpE-coated or uncoated beads, inhibited PMA induced ROS generation by BMDMs from wild-type mice. DNase X is required for this inhibition, as none of these beads inhibited PMA-induced ROS generation by BMDMs from DNase X-/- mice. Previous studies showed that E. chaffeensis does not block ROS generation in neutrophils, a cell type that is a potent ROS generator but is not infected by E. chaffeensis Human and mouse peripheral blood neutrophils did not express DNase X. Our findings point to a unique survival mechanism of ROS sensitive obligate intramonocytic bacteria that involves invasin EtpE binding to DNase X on the host cell surface. This is the first report of bacterial invasin having such a subversive activity on ROS generation.IMPORTANCEEhrlichia chaffeensis preferentially infects monocytes-macrophages and causes a life threatening emerging tick-transmitted infectious disease called human monocytic ehrlichiosis. Ehrlichial infection, and hence the disease, depends on the ability of this bacterium to avoid or overcome powerful microbicidal mechanisms of host monocytes-macrophages, one of which is the generation of ROS. Our findings reveal that an ehrlichial surface invasin, EtpE, not only triggers bacterial entry but also blocks ROS generation by host macrophages through its host cell receptor, DNase X. As ROS sensitivity is an Achilles' heel of this group of pathogens, understanding the mechanism by which E. chaffeensis rapidly blocks ROS generation suggests a new approach for developing effective anti-infective measures. The discovery of a ROS-blocking pathway is also important, as modulation of ROS generation is important in a variety of ailments and biological processes. PMID- 29162710 TI - UDP-4-Keto-6-Deoxyglucose, a Transient Antifungal Metabolite, Weakens the Fungal Cell Wall Partly by Inhibition of UDP-Galactopyranose Mutase. AB - Can accumulation of a normally transient metabolite affect fungal biology? UDP-4 keto-6-deoxyglucose (UDP-KDG) represents an intermediate stage in conversion of UDP-glucose to UDP-rhamnose. Normally, UDP-KDG is not detected in living cells, because it is quickly converted to UDP-rhamnose by the enzyme UDP-4-keto-6 deoxyglucose-3,5-epimerase/-4-reductase (ER). We previously found that deletion of the er gene in Botrytis cinerea resulted in accumulation of UDP-KDG to levels that were toxic to the fungus due to destabilization of the cell wall. Here we show that these negative effects are at least partly due to inhibition by UDP-KDG of the enzyme UDP-galactopyranose mutase (UGM), which reversibly converts UDP galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). An enzymatic activity assay showed that UDP-KDG inhibits the B. cinerea UGM enzyme with a Ki of 221.9 uM. Deletion of the ugm gene resulted in strains with weakened cell walls and phenotypes that were similar to those of the er deletion strain, which accumulates UDP-KDG. Galf residue levels were completely abolished in the Deltaugm strain and reduced in the Deltaer strain, while overexpression of the ugm gene in the background of a Deltaer strain restored Galf levels and alleviated the phenotypes. Collectively, our results show that the antifungal activity of UDP-KDG is due to inhibition of UGM and possibly other nucleotide sugar-modifying enzymes and that the rhamnose metabolic pathway serves as a shunt that prevents accumulation of UDP-KDG to toxic levels. These findings, together with the fact that there is no Galf in mammals, support the possibility of developing UDP-KDG or its derivatives as antifungal drugs.IMPORTANCE Nucleotide sugars are donors for the sugars in fungal wall polymers. We showed that production of the minor sugar rhamnose is used primarily to neutralize the toxic intermediate compound UDP-KDG. This surprising finding highlights a completely new role for minor sugars and other secondary metabolites with undetermined function. Furthermore, the toxic potential of predicted transition metabolites that never accumulate in cells under natural conditions are highlighted. We demonstrate that UDP-KDG inhibits the UDP-galactopyranose mutase enzyme, thereby affecting production of Galf, which is one of the components of cell wall glycans. Given the structural similarity, UDP-KDG likely inhibits additional nucleotide sugar-utilizing enzymes, a hypothesis that is also supported by our findings. Our results suggest that UDP-KDG could serve as a template to develop antifungal drugs. PMID- 29162711 TI - Expression and Cleavage of Middle East Respiratory Syndrome Coronavirus nsp3-4 Polyprotein Induce the Formation of Double-Membrane Vesicles That Mimic Those Associated with Coronaviral RNA Replication. AB - Betacoronaviruses, such as Middle East respiratory syndrome coronavirus (MERS CoV), are important pathogens causing potentially lethal infections in humans and animals. Coronavirus RNA synthesis is thought to be associated with replication organelles (ROs) consisting of modified endoplasmic reticulum (ER) membranes. These are transformed into double-membrane vesicles (DMVs) containing viral double-stranded RNA and into other membranous elements such as convoluted membranes, together forming a reticulovesicular network. Previous evidence suggested that the nonstructural proteins (nsp's) 3, 4, and 6 of the severe acute respiratory syndrome coronavirus (SARS-CoV), which contain transmembrane domains, would all be required for DMV formation. We have now expressed MERS-CoV replicase self-cleaving polyprotein fragments encompassing nsp3-4 or nsp3-6, as well as coexpressed nsp3 and nsp4 of either MERS-CoV or SARS-CoV, to characterize the membrane structures induced. Using electron tomography, we demonstrate that for both MERS-CoV and SARS-CoV coexpression of nsp3 and nsp4 is required and sufficient to induce DMVs. Coexpression of MERS-CoV nsp3 and nsp4 either as individual proteins or as a self-cleaving nsp3-4 precursor resulted in very similar DMVs, and in both setups we observed proliferation of zippered ER that appeared to wrap into nascent DMVs. Moreover, when inactivating nsp3-4 polyprotein cleavage by mutagenesis, we established that cleavage of the nsp3/nsp4 junction is essential for MERS-CoV DMV formation. Addition of the third MERS-CoV transmembrane protein, nsp6, did not noticeably affect DMV formation. These findings provide important insight into the biogenesis of coronavirus DMVs, establish strong similarities with other nidoviruses (specifically, the arteriviruses), and highlight possible general principles in viral DMV formation.IMPORTANCE The RNA replication of positive stranded RNA viruses of eukaryotes is thought to take place at cytoplasmic membranous replication organelles (ROs). Double-membrane vesicles are a prominent type of viral ROs. They are induced by coronaviruses, such as SARS-CoV and MERS-CoV, as well as by a number of other important pathogens, yet little is known about their biogenesis. In this study, we explored the viral protein requirements for the formation of MERS-CoV- and SARS-CoV-induced DMVs and established that coexpression of two of the three transmembrane subunits of the coronavirus replicase polyprotein, nonstructural proteins (nsp's) 3 and 4, is required and sufficient to induce DMV formation. Moreover, release of nsp3 and nsp4 from the polyprotein by proteolytic maturation is essential for this process. These findings provide a strong basis for further research on the biogenesis and functionality of coronavirus ROs and may point to more general principles of viral DMV formation. PMID- 29162712 TI - Persistence of an Oncogenic Papillomavirus Genome Requires cis Elements from the Viral Transcriptional Enhancer. AB - Human papillomavirus (HPV) genomes are replicated and maintained as extrachromosomal plasmids during persistent infection. The viral E2 proteins are thought to promote stable maintenance replication by tethering the viral DNA to host chromatin. However, this has been very difficult to prove genetically, as the E2 protein is involved in transcriptional regulation and initiation of replication, as well as its assumed role in genome maintenance. This makes mutational analysis of viral trans factors and cis elements in the background of the viral genome problematic and difficult to interpret. To circumvent this problem, we have developed a complementation assay in which the complete wild type HPV18 genome is transfected into primary human keratinocytes along with subgenomic or mutated replicons that contain the minimal replication origin. The wild-type genome provides the E1 and E2 proteins in trans, allowing us to determine additional cis elements that are required for long-term replication and partitioning of the replicon. We found that, in addition to the core replication origin (and the three E2 binding sites located therein), additional sequences from the transcriptional enhancer portion of the URR (upstream regulatory region) are required in cis for long-term genome replication.IMPORTANCE Human papillomaviruses infect cutaneous and mucosal epithelial cells of the host, and this results in very-long-lived, persistent infection. The viral genomes are small, circular, double-stranded DNA molecules that replicate extrachromosomally in concert with cellular DNA. This replication strategy requires that the virus has a robust mechanism to partition and retain the viral genomes in dividing cells. This has been difficult to study, because viral transcription, replication, and partitioning are regulated by the same viral proteins and involve overlapping elements in the viral genome. We developed a complementation assay that allows us to separate these functions and define the elements required for long-term replication and stable maintenance replication of the HPV genome. This has important implications, as disruption of viral maintenance replication can eliminate viral genomes from infected cells, thus curing persistent HPV infection. PMID- 29162713 TI - Capsular Polysaccharide Interferes with Biofilm Formation by Pasteurella multocida Serogroup A. AB - Pasteurella multocida is an important multihost animal and zoonotic pathogen that is capable of causing respiratory and multisystemic diseases, bacteremia, and bite wound infections. The glycosaminoglycan capsule of P. multocida is an essential virulence factor that protects the bacterium from host defenses. However, chronic infections (such as swine atrophic rhinitis and the carrier state in birds and other animals) may be associated with biofilm formation, which has not been characterized in P. multocida Biofilm formation by clinical isolates was inversely related to capsule production and was confirmed with capsule deficient mutants of highly encapsulated strains. Capsule-deficient mutants formed biofilms with a larger biomass that was thicker and smoother than the biofilm of encapsulated strains. Passage of a highly encapsulated, poor-biofilm forming strain under conditions that favored biofilm formation resulted in the production of less capsular polysaccharide and a more robust biofilm, as did addition of hyaluronidase to the growth medium of all of the strains tested. The matrix material of the biofilm was composed predominately of a glycogen exopolysaccharide (EPS), as determined by gas chromatography-mass spectrometry, nuclear magnetic resonance, and enzymatic digestion. However, a putative glycogen synthesis locus was not differentially regulated when the bacteria were grown as a biofilm or planktonically, as determined by quantitative reverse transcriptase PCR. Therefore, the negatively charged capsule may interfere with biofilm formation by blocking adherence to a surface or by preventing the EPS matrix from encasing large numbers of bacterial cells. This is the first detailed description of biofilm formation and a glycogen EPS by P. multocidaIMPORTANCEPasteurella multocida is an important pathogen responsible for severe infections in food animals, domestic and wild birds, pet animals, and humans. P. multocida was first isolated by Louis Pasteur in 1880 and has been studied for over 130 years. However, aspects of its lifecycle have remained unknown. Although formation of a biofilm by P. multocida has been proposed, this report is the first to characterize biofilm formation by P. multocida Of particular interest is that the biofilm matrix material contained a newly reported amylose-like glycogen as the exopolysaccharide component and that production of capsular polysaccharide (CPS) was inversely related to biofilm formation. However, even highly mucoid, poor biofilm-forming strains could form abundant biofilms by loss of CPS or following in vitro passage under biofilm growth conditions. Therefore, the carrier state or subclinical chronic infections with P. multocida may result from CPS downregulation with concomitant enhanced biofilm formation. PMID- 29162714 TI - Ablation of an Ovarian Tumor Family Deubiquitinase Exposes the Underlying Regulation Governing the Plasticity of Cell Cycle Progression in Toxoplasma gondii. AB - The Toxoplasma genome encodes the capacity for distinct architectures underlying cell cycle progression in a life cycle stage-dependent manner. Replication in intermediate hosts occurs by endodyogeny, whereas a hybrid of schizogony and endopolygeny occurs in the gut of the definitive feline host. Here, we characterize the consequence of the loss of a cell cycle-regulated ovarian tumor (OTU family) deubiquitinase, OTUD3A of Toxoplasma gondii (TgOTUD3A; TGGT1_258780), in T. gondii tachyzoites. Rather than the mutation being detrimental, mutant parasites exhibited a fitness advantage, outcompeting the wild type. This phenotype was due to roughly one-third of TgOTUD3A-knockout (TgOTUD3A-KO) tachyzoites exhibiting deviations from endodyogeny by employing replication strategies that produced 3, 4, or 5 viable progeny within a gravid mother instead of the usual 2. We established the mechanistic basis underlying these altered replication strategies to be a dysregulation of centrosome duplication, causing a transient loss of stoichiometry between the inner and outer cores that resulted in a failure to terminate S phase at the attainment of 2N ploidy and/or the decoupling of mitosis and cytokinesis. The resulting dysregulation manifested as deviations in the normal transitions from S phase to mitosis (S/M) (endopolygeny-like) or M phase to cytokinesis (M/C) (schizogony like). Notably, these imbalances are corrected prior to cytokinesis, resulting in the generation of normal progeny. Our findings suggest that decisions regarding the utilization of specific cell cycle architectures are controlled by a ubiquitin-mediated mechanism that is dependent on the absolute threshold levels of an as-yet-unknown target(s). Analysis of the TgOTUD3A-KO mutant provides new insights into mechanisms underlying the plasticity of apicomplexan cell cycle architecture.IMPORTANCE Replication by Toxoplasma gondii can occur by 3 distinct cell cycle architectures. Endodyogeny is used by asexual stages, while a hybrid of schizogony and endopolygeny is used by merozoites in the definitive feline host. Here, we establish that the disruption of an ovarian-tumor (OTU) family deubiquitinase, TgOTUD3A, in tachyzoites results in dysregulation of the mechanism controlling the selection of replication strategy in a subset of parasites. The mechanistic basis for these altered cell cycles lies in the unique biology of the bipartite centrosome that is associated with the transient loss of stoichiometry between the inner and outer centrosome cores in the TgOTUD3A-KO mutant. This highlights the importance of ubiquitin-mediated regulation in the transition from the nuclear to the budding phases of the cell cycle and provides new mechanistic insights into the regulation of the organization of the apicomplexan cell cycle. PMID- 29162716 TI - Erratum for Schloss et al., "Support Science by Publishing in Scientific Society Journals". PMID- 29162715 TI - Bacteriophage Transcytosis Provides a Mechanism To Cross Epithelial Cell Layers. AB - Bacterial viruses are among the most numerous biological entities within the human body. These viruses are found within regions of the body that have conventionally been considered sterile, including the blood, lymph, and organs. However, the primary mechanism that bacterial viruses use to bypass epithelial cell layers and access the body remains unknown. Here, we used in vitro studies to demonstrate the rapid and directional transcytosis of diverse bacteriophages across confluent cell layers originating from the gut, lung, liver, kidney, and brain. Bacteriophage transcytosis across cell layers had a significant preferential directionality for apical-to-basolateral transport, with approximately 0.1% of total bacteriophages applied being transcytosed over a 2-h period. Bacteriophages were capable of crossing the epithelial cell layer within 10 min with transport not significantly affected by the presence of bacterial endotoxins. Microscopy and cellular assays revealed that bacteriophages accessed both the vesicular and cytosolic compartments of the eukaryotic cell, with phage transcytosis suggested to traffic through the Golgi apparatus via the endomembrane system. Extrapolating from these results, we estimated that 31 billion bacteriophage particles are transcytosed across the epithelial cell layers of the gut into the average human body each day. The transcytosis of bacteriophages is a natural and ubiquitous process that provides a mechanistic explanation for the occurrence of phages within the body.IMPORTANCE Bacteriophages (phages) are viruses that infect bacteria. They cannot infect eukaryotic cells but can penetrate epithelial cell layers and spread throughout sterile regions of our bodies, including the blood, lymph, organs, and even the brain. Yet how phages cross these eukaryotic cell layers and gain access to the body remains unknown. In this work, epithelial cells were observed to take up and transport phages across the cell, releasing active phages on the opposite cell surface. Based on these results, we posit that the human body is continually absorbing phages from the gut and transporting them throughout the cell structure and subsequently the body. These results reveal that phages interact directly with the cells and organs of our bodies, likely contributing to human health and immunity. PMID- 29162717 TI - Reference Values for the 6-min Walk Distance in Healthy Children Age 7 to 12 Years in Brazil: Main Results of the TC6minBrasil Multi-Center Study. AB - INTRODUCTION: Brazil is a country with great climatic, socioeconomic, and cultural differences that does not yet have a reference value for the 6-min walk test (6MWT) in healthy children. To avoid misinterpretation, the use of equations to predict the maximum walk distance should be established in each country. OBJECTIVES: We sought to establish reference values and to develop an equation to predict the 6-min walk distance for healthy children in Brazil. METHODS: This is a cross-sectional multi-center study that included 1,496 healthy children, aged 7 to 12 y, assessed across 11 research sites in all regions of Brazil, and recruited from public and private schools in their respective regions. Each child was assessed for weight and height. Walk distance was our main outcome. An open source software environment for statistical computing was used for statistical analysis. RESULTS: We observed a higher average distance walked by boys (531.1 m) than by girls (506.2 m), with a difference of 24.9 m (P < .001). We established 6MWT reference values for boys with the following equation: Distance = (16.86 * age) + (1.89 * Delta heart rate) - (0.80 * weight) + (336.91 * R1) + (360.91 * R2). For girls the equation is as follows: Distance = (13.54 * age) + (1.62 * Delta heart rate) - (1.28 * weight) + (352.33 * R1) + (394.81 * R2). CONCLUSION: Reference values were established for the 6MWT in healthy children aged 7-12 y in Brazil. PMID- 29162718 TI - Delay Between Shaking and Actuation of a Hydrofluoroalkane Fluticasone Pressurized Metered-Dose Inhaler. AB - BACKGROUND: Inhaled corticosteroids are used to treat pediatric asthma. The shaking of a pressurized metered-dose inhaler (pMDI) is required to ensure consistency of emitted dose. Delays between shaking and actuating the pMDI are frequent during administration of aerosols to children where a valved holding chamber is used. METHODS: In a recent clinical trial, we used a monitoring device to record shaking and actuation of the pMDI and the inhalation profiles of children with asthma while they were inhaling fluticasone hydrofluoroalkane from a valved holding chamber onto an external filter. During the procedure, in vitro and transport samples were generated without a delay between shaking and actuating the pMDI. Emitted dose, expressed as percentage of ex-actuator nominal dose, obtained from the second actuation following a recorded shake-actuation interval for subjects and from in vitro/transport samples (no delay) were compared. RESULTS: The mean emitted dose was 158.6% (95% CI 150.1-167.2%) (subjects) and 106.8% (95% CI 104.7-108.9%) (in vitro + transport) of the ex actuator nominal dose (P < .001). The mean delay between shaking and actuating the pMDI was 12.9 s (95% CI 11.9-13.9 s) for the subject samples. A strong correlation was observed between shake and actuation delay and the emitted dose of the second actuation following the delay (Spearman correlation coefficient = 0.61). A 10-, 20-, and 30-s delay resulted in an emitted dose of the second actuation following the delay of 147, 187, and 227% of the ex-actuator nominal dose, respectively. CONCLUSIONS: Delays between shaking and actuating a corticosteroid suspension pMDI resulted in an increase in the emitted dose of the second actuation following the delay. This can be a common occurrence when doses are administered by a caregiver to a patient via a holding chamber. This should be addressed by practitioners educating patients and parents on proper inhaler use. (ClinicalTrials.gov registration NCT01714063.). PMID- 29162719 TI - Limiting Factors in Walking Performance of Subjects With COPD. AB - INTRODUCTION: Exercise intolerance is the most predominant symptom in patients with COPD. Nevertheless, it is unclear whether walking economy and gait variability are altered in these patients. Thus, our main objective was to compare the cost of transport and gait variability as a function of speed, including the self-selected walking speed, in subjects with COPD relative to healthy subjects. METHODS: 22 subjects, 11 with COPD (FEV1 = 45 +/- 17% of predicted) and 11 age- and sex-matched healthy subjects undertook an evaluation that involved walking on a treadmill at 6 speeds (at 3.2 km/h, at a self-selected walking speed, and at 2 speeds below and 2 speeds above the self-selected walking speed) and measuring the cost of transport (the oxygen consumption normalized by mass and distance), gait variability, perceived dyspnea, and leg fatigue. RESULTS: In subjects with COPD, the cost of transport decreased with increasing walking speed, contrary to healthy subjects, who presented a minimum at the self selected walking speed. No difference was found in cost of transport between the experimental groups at the same absolute velocity (P = .62). In subjects with COPD, dyspnea sensation rose above the self-selected walking speed, doubling at the maximal walking velocity (P = .03), and gait variability was higher at low speeds. CONCLUSION: Subjects with COPD choose their walking speed so as to keep the dyspnea sensation tolerable and to keep gait variability and cost of transport at an acceptable level. These outcomes suggest that interventions acting on dyspnea and gait pattern may increase patients' self-selected walking speed and improve their quality of life. PMID- 29162720 TI - Direct interactions of mitotic arrest deficient 1 (MAD1) domains with each other and MAD2 conformers are required for mitotic checkpoint signaling. AB - As a sensitive signaling system, the mitotic checkpoint ensures faithful chromosome segregation by delaying anaphase onset even when a single kinetochore is unattached to mitotic spindle microtubules. The key signal amplification reaction for the checkpoint is the conformational conversion of "open" mitotic arrest deficient 2 (O-MAD2) into "closed" MAD2 (C-MAD2). The reaction has been suggested to be catalyzed by an unusual catalyst, a MAD1:C-MAD2 tetramer, but how the catalysis is executed and regulated remains elusive. Here, we report that in addition to the well-characterized middle region of MAD1 containing the MAD2 interaction motif (MIM), both N- and C-terminal domains (NTD and CTD) of MAD1 also contribute to mitotic checkpoint signaling. Unlike the MIM, which stably associated only with C-MAD2, the NTD and CTD in MAD1 surprisingly bound both O- and C-MAD2, suggesting that these two domains interact with both substrates and products of the O-to-C conversion. MAD1NTD and MAD1CTD also interacted with each other and with the MPS1 protein kinase, which phosphorylated both NTD and CTD. This phosphorylation decreased the NTD:CTD interaction and also CTD's interaction with MPS1. Of note, mutating the phosphorylation sites in the MAD1CTD, including Thr-716, compromised MAD2 binding and the checkpoint responses. We further noted that Ser-610 and Tyr-634 also contribute to the mitotic checkpoint signaling. Our results have uncovered that the MAD1NTD and MAD1CTD directly interact with each other and with MAD2 conformers and are regulated by MPS1 kinase, providing critical insights into mitotic checkpoint signaling. PMID- 29162721 TI - Loss of alphaB-crystallin function in zebrafish reveals critical roles in the development of the lens and stress resistance of the heart. AB - Genetic mutations in the human small heat shock protein alphaB-crystallin have been implicated in autosomal cataracts and skeletal myopathies, including heart muscle diseases (cardiomyopathy). Although these mutations lead to modulation of their chaperone activity in vitro, the in vivo functions of alphaB-crystallin in the maintenance of both lens transparency and muscle integrity remain unclear. This lack of information has hindered a mechanistic understanding of these diseases. To better define the functional roles of alphaB-crystallin, we generated loss-of-function zebrafish mutant lines by utilizing the CRISPR/Cas9 system to specifically disrupt the two alphaB-crystallin genes, alphaBa and alphaBb We observed lens abnormalities in the mutant lines of both genes, and the penetrance of the lens phenotype was higher in alphaBa than alphaBb mutants. This finding is in contrast with the lack of a phenotype previously reported in alphaB crystallin knock-out mice and suggests that the elevated chaperone activity of the two zebrafish orthologs is critical for lens development. Besides its key role in the lens, we uncovered another critical role for alphaB-crystallin in providing stress tolerance to the heart. The alphaB-crystallin mutants exhibited hypersusceptibility to develop pericardial edema when challenged by crowding stress or exposed to elevated cortisol stress, both of which activate glucocorticoid receptor signaling. Our work illuminates the involvement of alphaB crystallin in stress tolerance of the heart presumably through the proteostasis network and reinforces the critical role of the chaperone activity of alphaB crystallin in the maintenance of lens transparency. PMID- 29162722 TI - Docosahexaenoic acid lowers cardiac mitochondrial enzyme activity by replacing linoleic acid in the phospholipidome. AB - Cardiac mitochondrial phospholipid acyl chains regulate respiratory enzymatic activity. In several diseases, the rodent cardiac phospholipidome is extensively rearranged; however, whether specific acyl chains impair respiratory enzyme function is unknown. One unique remodeling event in the myocardium of obese and diabetic rodents is an increase in docosahexaenoic acid (DHA) levels. Here, we first confirmed that cardiac DHA levels are elevated in diabetic humans relative to controls. We then used dietary supplementation of a Western diet with DHA as a tool to promote cardiac acyl chain remodeling and to study its influence on respiratory enzyme function. DHA extensively remodeled the acyl chains of cardiolipin (CL), mono-lyso CL, phosphatidylcholine, and phosphatidylethanolamine. Moreover, DHA lowered enzyme activities of respiratory complexes I, IV, V, and I+III. Mechanistically, the reduction in enzymatic activities were not driven by a dramatic reduction in the abundance of supercomplexes. Instead, replacement of tetralinoleoyl-CL with tetradocosahexaenoyl-CL in biomimetic membranes prevented formation of phospholipid domains that regulate enzyme activity. Tetradocosahexaenoyl-CL inhibited domain organization due to favorable Gibbs free energy of phospholipid mixing. Furthermore, in vitro substitution of tetralinoleoyl-CL with tetradocosahexaenoyl-CL blocked complex-IV binding. Finally, reintroduction of linoleic acid, via fusion of phospholipid vesicles to mitochondria isolated from DHA-fed mice, rescued the major losses in the mitochondrial phospholipidome and complexes I, IV, and V activities. Altogether, our results show that replacing linoleic acid with DHA lowers select cardiac enzyme activities by potentially targeting domain organization and phospholipid-protein binding, which has implications for the ongoing debate about polyunsaturated fatty acids and cardiac health. PMID- 29162723 TI - The transcription factor Foxc1a in zebrafish directly regulates expression of nkx2.5, encoding a transcriptional regulator of cardiac progenitor cells. AB - Cardiogenesis is a tightly controlled biological process required for formation of a functional heart. The transcription factor Foxc1 not only plays a crucial role in outflow tract development in mice, but is also involved in cardiac structure formation and normal function in humans. However, the molecular mechanisms by which Foxc1 controls cardiac development remain poorly understood. Previously, we reported that zebrafish embryos deficient in foxc1a, an ortholog of mammalian Foxc1, display pericardial edemas and die 9-10 days postfertilization. To further investigate Foxc1a's role in zebrafish cardiogenesis and identify its downstream target genes during early heart development, we comprehensively analyzed the cardiovascular phenotype of foxc1a null zebrafish embryos. Our results confirmed that foxc1a-null mutants exhibit disrupted cardiac morphology, structure, and function. Performing transcriptome analysis on the foxc1a mutants, we found that the expression of the cardiac progenitor marker gene nkx2.5 was significantly decreased, but the expression of germ layer-patterning genes was unaffected. Dual-fluorescence in situ hybridization assays revealed that foxc1a and nkx2.5 are co-expressed in the anterior lateral plate mesoderm at the somite stage. Chromatin immunoprecipitation and promoter truncation assays disclosed that Foxc1a regulates nkx2.5 expression via direct binding to two noncanonical binding sites in the proximal nkx2.5 promoter. Moreover, functional rescue experiments revealed that developmental stage-specific nkx2.5 overexpression partially rescues the cardiac defects of the foxc1a-null embryos. Taken together, our results indicate that during zebrafish cardiogenesis, Foxc1a is active directly upstream of nkx2.5. PMID- 29162724 TI - Progesterone receptor A promotes invasiveness and metastasis of luminal breast cancer by suppressing regulation of critical microRNAs by estrogen. AB - Distal metastasis of luminal breast cancer is frequent and incurable, yet the metastasis mechanisms are poorly understood. Estrogen, even at postmenopausal concentrations, suppresses invasiveness of luminal breast cancer cells through the estrogen receptor (ER). Invasive tumors overexpress the short progesterone receptor A (PR-A) isoform. Even at postmenopausal concentrations, progesterone activates PR-A, inducing invasiveness by counteracting estrogen's effects, particularly when cells are hypersensitized to progesterone by PR-A overexpression. To interrogate the role of this cross-talk in metastasis, we investigated selective cross-talk mechanisms of PR-A with ER. We developed a quantitative PCR-based lymph node infiltration assay to address the slowness of metastasis of tumor xenografts. We found that 15 microRNAs (miRNAs) are regulated by progesterone via PR-A, but not the longer PR-B isoform, with increased progesterone sensitivity when PR-A was overexpressed. Two of these miRNAs whose induction (miR-92a-3p) or repression (miR-26b-5p) by estrogen was suppressed by progesterone plus PR-A were critical for the PR-A-ER cross-talk causing a gene regulatory pattern of invasiveness and metastasis and complete rescue of invasiveness in vitro Constitutive expression of miR-92a-3p or inhibition of miR 26b-5p profoundly suppressed metastasis. Finally, in primary breast tumors, PR-A expression was correlated negatively with miR-92a-3p expression and positively with miR-26b-5p expression. Therefore, hormonal cross-talk of PR-A with ER is probably a fundamental mechanism that enables metastasis of luminal breast cancer. Moreover, miRNA biomarkers of hyperactive PR-A may help predict metastatic potential of luminal breast tumors. Further, miR-92a-3p and miR-26b-5p may reveal target pathways for selective intervention to suppress hormone regulated metastasis, both pre- and postmenopause. PMID- 29162725 TI - Src homology 2 domains enhance tyrosine phosphorylation in vivo by protecting binding sites in their target proteins from dephosphorylation. AB - Phosphotyrosine (pTyr)-dependent signaling is critical for many cellular processes. It is highly dynamic, as signal output depends not only on phosphorylation and dephosphorylation rates but also on the rates of binding and dissociation of effectors containing phosphotyrosine-dependent binding modules such as Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains. Previous in vitro studies suggested that binding of SH2 and PTB domains can enhance protein phosphorylation by protecting the sites bound by these domains from phosphatase-mediated dephosphorylation. To test whether this occurs in vivo, we used the binding of growth factor receptor bound 2 (GRB2) to phosphorylated epidermal growth factor receptor (EGFR) as a model system. We analyzed the effects of SH2 domain overexpression on protein tyrosine phosphorylation by quantitative Western and far-Western blotting, mass spectrometry, and computational modeling. We found that SH2 overexpression results in a significant, dose-dependent increase in EGFR tyrosine phosphorylation, particularly of sites corresponding to the binding specificity of the overexpressed SH2 domain. Computational models using experimentally determined EGFR phosphorylation and dephosphorylation rates, and pTyr-EGFR and GRB2 concentrations, recapitulated the experimental findings. Surprisingly, both modeling and biochemical analyses suggested that SH2 domain overexpression does not result in a major decrease in the number of unbound phosphorylated SH2 domain binding sites. Our results suggest that signaling via SH2 domain binding is buffered over a relatively wide range of effector concentrations and that SH2 domain proteins with overlapping binding specificities are unlikely to compete with one another for phosphosites in vivo. PMID- 29162727 TI - Measuring and understanding the attitudes of Australian gay and bisexual men towards biomedical HIV prevention using cross-sectional data and factor analyses. AB - INTRODUCTION: Contemporary responses to HIV embrace biomedical prevention, particularly treatment as prevention (TasP) and pre-exposure prophylaxis (PrEP). However, large-scale implementation of biomedical prevention should be ideally preceded by assessments of their community acceptability. We aimed to understand contemporary attitudes of gay and bisexual men (GBM) in Australia towards biomedical-based HIV prevention and propose a framework for their measurement and ongoing monitoring. METHODS: A cross-sectional, online survey of GBM >=18 years has been conducted annually in Victoria, Australia, since 2008. In 2016, 35 attitudinal items on biomedical HIV prevention were added. Items were scored on five-point Likert scales. We used principal factor analysis to identify key constructs related to GBM's attitudes to biomedical HIV prevention and use these to characterise levels of support for TasP and PrEP. RESULTS: A total of 462 HIV negative or HIV-status-unknown men, not using PrEP, provided valid responses for all 35 attitudinal items. We extracted four distinct and interpretable factors we named: 'Confidence in PrEP', 'Judicious approach to PrEP', 'Treatment as prevention optimism' and 'Support for early treatment'. High levels of agreement were seen across PrEP-related items; 77.9% of men agreed that PrEP prevented HIV acquisition and 83.6% of men agreed that users were protecting themselves. However, the agreement levels for HIV TasP items were considerably lower, with <20% of men agreeing treatment (undetectable viral load) reduced HIV transmission risk. CONCLUSIONS: Better understanding of community attitudes is crucial for shaping policy and informing initiatives that aim to improve knowledge, acceptance and uptake of biomedical prevention. Our analyses suggest confidence in, acceptability of and community support for PrEP among GBM. However, strategies to address scepticism towards HIV treatment when used for prevention may be needed to optimise combination biomedical HIV prevention. PMID- 29162726 TI - Foxj1a is expressed in ependymal precursors, controls central canal position and is activated in new ependymal cells during regeneration in zebrafish. AB - Zebrafish are able to regenerate the spinal cord and recover motor and sensory functions upon severe injury, through the activation of cells located at the ependymal canal. Here, we show that cells surrounding the ependymal canal in the adult zebrafish spinal cord express Foxj1a. We demonstrate that ependymal cells express Foxj1a from their birth in the embryonic neural tube and that Foxj1a activity is required for the final positioning of the ependymal canal. We also show that in response to spinal cord injury, Foxj1a ependymal cells actively proliferate and contribute to the restoration of the spinal cord structure. Finally, this study reveals that Foxj1a expression in the injured spinal cord is regulated by regulatory elements activated during regeneration. These data establish Foxj1a as a pan-ependymal marker in development, homeostasis and regeneration and may help identify the signals that enable this progenitor population to replace lost cells after spinal cord injury. PMID- 29162728 TI - Evaluating the Value of the Respiratory Therapist: Where Is the Evidence? Focus on the Barnes-Jewish Hospital Experience. AB - Currently, >20 million people in the United States have asthma, and approximately 15 million adults have been diagnosed with COPD, with approximately the same number not yet having been diagnosed with this condition. Moreover, the overall burden of respiratory diseases is still increasing, in part due to environmental factors, such as air pollution. At the same time, the number of patients requiring hospitalization as well as the number of individuals admitted to ICUs from emergency departments has been on the rise over the last decade. Because of the cost to the health-care system, the burden of respiratory diseases, hospitalizations, and ICU admissions also falls on society; it is paid for with tax dollars, higher health insurance rates, and lost productivity. Respiratory therapists (RTs) are in a unique position to influence health-care delivery in a number of settings that include acutely ill hospitalized patients and those with chronic conditions in ambulatory settings. Clinical studies have demonstrated the value of RTs in specific areas, including the performance of medical procedures, the development and implementation of protocols aimed at weaning patients from mechanical ventilation and providing lung-protective ventilation, optimal delivery of in-patient respiratory treatments, the application of disease management programs for COPD, and as part of rapid response teams. However, due to increasing scrutiny of health-care expenditures and limited resources, there is a growing need to document the impact of health-care providers in terms of clinical outcomes. As a profession, RTs should continue to describe the impact they have on patient outcomes and the value they bring to our health-care system. Promoting such investigative outcomes research, along with enhancing the professional aspects of the field of respiratory care, will ensure that the value of RTs does not go unappreciated. PMID- 29162729 TI - The Strong Cough: Is It a Signpost on the Road to Extubation or Just a Dead End? PMID- 29162730 TI - The First Necessity of Progress. PMID- 29162731 TI - Optimizing Mechanical Ventilation in the Neonatal ICU. PMID- 29162733 TI - In This Issue of Diabetes. PMID- 29162734 TI - Granzyme A in the Pathogenesis of Type 1 Diabetes: The Yes and the No. PMID- 29162735 TI - Direct Analysis of Insulin-Specific T Cells Provides New Insights. PMID- 29162736 TI - Erratum. Mediobasal Hypothalamic SIRT1 Is Essential for Resveratrol's Effects on Insulin Action in Rats. Diabetes 2011;60:2691-2700. PMID- 29162738 TI - Science and Culture: Researchers find history in the diagrams of Euclid's Elements. PMID- 29162739 TI - Inner Workings: Medical microrobots have potential in surgery, therapy, imaging, and diagnostics. PMID- 29162741 TI - Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype. AB - The cell surface protein CD44 is involved in diverse physiological processes, and its aberrant function is linked to various pathologies such as cancer, immune dysregulation, and fibrosis. The diversity of CD44 biological activity is partly conferred by the generation of distinct CD44 isoforms through alternative splicing. We identified an unexpected function for the ubiquitous hyaluronan degrading enzyme, hyaluronidase 2 (HYAL2), as a regulator of CD44 splicing. Standard CD44 is associated with fibrotic disease, and its production is promoted through serine-arginine-rich (SR) protein-mediated exon exclusion. HYAL2 nuclear translocation was stimulated by bone morphogenetic protein 7, which inhibits the myofibroblast phenotype. Nuclear HYAL2 displaced SR proteins from the spliceosome, thus enabling HYAL2, spliceosome components (U1 and U2 small nuclear ribonucleoproteins), and CD44 pre-mRNA to form a complex. This prevented double exon splicing and facilitated the inclusion of CD44 exons 11 and 12, which promoted the accumulation of the antifibrotic CD44 isoform CD44v7/8 at the cell surface. These data demonstrate previously undescribed mechanisms regulating CD44 alternative splicing events that are relevant to the regulation of cellular phenotypes in progressive fibrosis. PMID- 29162743 TI - AKAP95-mediated nuclear anchoring of PKA mediates cortisol-induced PTGS2 expression in human amnion fibroblasts. AB - Phosphorylation of the transcription factors cyclic adenosine monophosphate response element-binding protein (CREB) and signal transducer and activator of transcription 3 (STAT3) by protein kinase A (PKA) is required for the cortisol induced production of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in human amnion fibroblasts, which critically mediates human parturition (labor). We found that PKA was confined in the nucleus by A-kinase-anchoring protein 95 (AKAP95) in amnion fibroblasts and that this localization was key to the cortisol induced expression of PTGS2, the gene encoding COX-2. Cortisol increased the abundance of nuclear PKA by stimulating the expression of the gene encoding AKAP95. Knockdown of AKAP95 not only reduced the amounts of nuclear PKA and phosphorylated CREB but also attenuated the induction of PTGS2 expression in primary human amnion fibroblasts treated with cortisol, whereas the phosphorylation of STAT3 in response to cortisol was not affected. The abundances of AKAP95, phosphorylated CREB, and COX-2 were markedly increased in human amnion tissue after labor compared to those in amnion tissues from cesarean sections without labor. These results highlight an essential role for PKA that is anchored in the nucleus by AKAP95 in the phosphorylation of CREB and the consequent induction of COX-2 expression by cortisol in amnion fibroblasts, which may be important in human parturition. PMID- 29162742 TI - Microtubules tune mechanotransduction through NOX2 and TRPV4 to decrease sclerostin abundance in osteocytes. AB - The adaptation of the skeleton to its mechanical environment is orchestrated by mechanosensitive osteocytes, largely by regulating the abundance of sclerostin, a secreted inhibitor of bone formation. We defined a microtubule-dependent mechanotransduction pathway that linked fluid shear stress to reactive oxygen species (ROS) and calcium (Ca2+) signals that led to a reduction in sclerostin abundance in cultured osteocytes. We demonstrated that microtubules stabilized by detyrosination, a reversible posttranslational modification of polymerized alpha tubulin, determined the stiffness of the cytoskeleton, which set the mechanoresponsive range of cultured osteocytes to fluid shear stress. We showed that fluid shear stress through the microtubule network activated NADPH oxidase 2 (NOX2)-generated ROS that target the Ca2+ channel TRPV4 to elicit Ca2+ influx. Furthermore, tuning the abundance of detyrosinated tubulin affected cytoskeletal stiffness to define the mechanoresponsive range of cultured osteocytes to fluid shear stress. Finally, we demonstrated that NOX2-ROS elicited Ca2+ signals that activated the kinase CaMKII to decrease the abundance of sclerostin protein. Together, these discoveries may identify potentially druggable targets for regulating osteocyte mechanotransduction to affect bone quality. PMID- 29162744 TI - ATP promotes the fast migration of dendritic cells through the activity of pannexin 1 channels and P2X7 receptors. AB - Upon its release from injured cells, such as infected, transformed, inflamed, or necrotic cells, extracellular adenosine-5'-triphosphate (ATP) acts as a danger signal that recruits phagocytes, such as neutrophils, macrophages, and dendritic cells (DCs), to the site of injury. The sensing of extracellular ATP occurs through purinergic (P2) receptors. We investigated the cellular mechanisms linking purinergic signaling to DC motility. We found that ATP stimulated fast DC motility through an autocrine signaling loop, which was initiated by the activation of P2X7 receptors and further amplified by pannexin 1 (Panx1) channels. Upon stimulation of the P2X7 receptor by ATP, Panx1 contributed to fast DC motility by increasing the permeability of the plasma membrane, which resulted in supplementary ATP release. In the absence of Panx1, DCs failed to increase their speed of migration in response to ATP, despite exhibiting a normal P2X7 receptor-mediated Ca2+ response. In addition to DC migration, Panx1 channel- and P2X7 receptor-dependent signaling was further required to stimulate the reorganization of the actin cytoskeleton. In vivo, functional Panx1 channels were required for the homing of DCs to lymph nodes, although they were dispensable for DC maturation. These data suggest that P2X7 receptors and Panx1 channels are crucial players in the regulation of DC migration to endogenous danger signals. PMID- 29162745 TI - Does sympathetic dysfunction occur before denervation in pure autonomic failure? AB - Pure autonomic failure (PAF) is a rare sporadic disorder characterized by autonomic failure in the absence of a movement disorder or dementia and is associated with very low plasma norepinephrine (NE) levels-suggesting widespread sympathetic denervation, however due to its rarity the pathology remains poorly elucidated. We sought to correlate clinical and neurochemical findings with sympathetic nerve protein abundances, accessed by way of a forearm vein biopsy, in patients with PAF and in healthy controls and patients with multiple systems atrophy (MSA) in whom sympathetic nerves are considered intact. The abundance of sympathetic nerve proteins, extracted from forearm vein biopsy specimens, in 11 patients with PAF, 8 patients with MSA and 9 age-matched healthy control participants was performed following a clinical evaluation and detailed evaluation of sympathetic nervous system function, which included head-up tilt (HUT) testing with measurement of plasma catecholamines and muscle sympathetic nerve activity (MSNA) in addition to haemodynamic assessment to confirm the clinical phenotype. PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (P<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (P<0.05) protein expression compared with control and MSA participants. These findings were associated with a significantly higher ratio of plasma 3,4 dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (P<0.05). The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis. The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves and suggests that sympathetic dysfunction may occur ahead of denervation. PMID- 29162746 TI - Vascular dysfunction in the stroke-prone spontaneously hypertensive rat is dependent on constrictor prostanoid activity and Y chromosome lineage. AB - Vascular dysfunction is a hallmark of hypertension and the strongest risk factor to date for coronary artery disease. As Y chromosome lineage has emerged as one of the strongest genetic predictors of cardiovascular disease risk to date, we investigated if Y chromosome lineage modulated this important facet in the stroke prone spontaneously hypertensive rat (SHRSP) using consomic strains. Here, we show that vascular dysfunction in the SHRSP is attributable to differential cyclooxygenase (COX) activity with nitric oxide (NO) levels playing a less significant role. Measurement of prostacyclin, the most abundant product of COX in the vasculature, confirmed the augmented COX activity in the SHRSP aorta. This was accompanied by functional impairment of the vasodilatory prostacyclin (IP) receptor, while inhibition of the thromboxane (TP) receptor significantly ameliorated vascular dysfunction in the SHRSP, suggesting this is the downstream target responsible for constrictor prostanoid activity. Importantly, Y chromosome lineage was shown to modulate vascular function in the SHRSP through influencing COX activity, prostacyclin levels and IP dysfunction. Vascular dysfunction in the renal and intrarenal arteries was also found to be prostanoid and Y chromosome dependent. Interestingly, despite no apparent differences in agonist-stimulated NO levels, basal NO levels were compromised in the SHRSP aorta, which was also Y chromosome dependent. Thus, in contrast with the widely held view that COX inhibition is deleterious for the vasculature due to inhibition of the vasodilator prostacyclin, we show that COX inhibition abolishes vascular dysfunction in three distinct vascular beds, with IP dysfunction likely being a key mechanism underlying this effect. We also delineate a novel role for Y chromosome lineage in regulating vascular function through modulation of COX and basal NO levels. PMID- 29162748 TI - Theorizing medical practice for India. PMID- 29162747 TI - Therapeutic effect of a novel Wnt pathway inhibitor on cardiac regeneration after myocardial infarction. AB - After myocardial infarction (MI), the heart is difficult to repair because of great loss of cardiomyoctyes and lack of cardiac regeneration. Novel drug candidates that aim at reducing pathological remodeling and stimulating cardiac regeneration are highly desirable. In the present study, we identified if and how a novel porcupine inhibitor CGX1321 influenced MI and cardiac regeneration. Permanent ligation of left anterior descending (LAD) coronary artery was performed in mice to induce MI injury. Cardiac function was measured by echocardiography, infarct size was examined by TTC staining. Fibrosis was evaluated with Masson's trichrome staining and vimentin staining. As a result, CGX1321 administration blocked the secretion of Wnt proteins, and inhibited both canonical and non-canonical Wnt signaling pathways. CGX1321 improved cardiac function, reduced myocardial infarct size, and fibrosis of post-MI hearts. CGX1321 significantly increased newly formed cardiomyocytes in infarct border zone of post-MI hearts, evidenced by the increased EdU+ cardiomyocytes. Meanwhile, CGX1321 increased Ki67+ and phosphohistone H3 (PH3+) cardiomyocytes in culture, indicating enhanced cardiomyocyte proliferation. The mRNA microarray showed that CGX1321 up-regulated cell cycle regulating genes such as Ccnb1 and Ccne1 CGX1321 did not alter YAP protein phosphorylation and nuclear translocation in cardiomyocytes. In conclusion, porcupine inhibitor CGX1321 reduces MI injury by limiting fibrosis and promoting regeneration. It promotes cardiomyocyte proliferation by stimulating cell cycle regulating genes with a Hippo/YAP independent pathway. PMID- 29162749 TI - Role of synaptophysin in the intraoperative assessment of quadrantic innervation of the proximal doughnut in Hirschsprung disease. AB - BACKGROUND: Symptoms may persist in a retained aganglionic segment of the colon after corrective (pull-through) surgery in Hirschsprung disease (HD). Thus, it is important to assess the proximal doughnut for innervation abnormalities intraoperatively by frozen sections stained with conventional haematoxylin and eosin stain and supported by rapid acetylcholinesterase (AChE) histochemistry. When the doughnut is proximal to the sigmoid colon, AChE is not useful and requires ratification by yet another rapid technique and hence this study. METHODS: Two pathologists independently evaluated fresh doughnuts from the proximal bowel clinically assumed to be of normal innervation intraoperatively and chosen for anastomosis in patients with HD along with controls using AChE and synaptophysin (SY) immunohistochemistry. RESULTS: From 38 patients with HD, 28 doughnuts (63.7%) showed normal innervation with intense SY activity in the mucosa, the muscularis and the ganglion cells. The circumferential aganglionic doughnuts (abnormal innervation) (n= 6, 13.6%) showed neither SY-positive fibres in the mucosa nor in the muscularis. The abnormal transition zone doughnuts (n=10, 22.7%) showed involvement of three quadrants of the doughnut in one, two quadrants in three and one quadrant in six with decreased SY-positive fibres in the muscularis and scattered ganglion cells with a statistically significant measure of agreement of (kappa=0.973) between the two. CONCLUSION: The pattern, intensity and distribution of SY-positive fibres in the muscularis propria of the doughnut of the proximal bowel chosen intraoperatively for anastomosis in HD can identify sectors with abnormal innervation allowing the surgeon to seek normal innervation status more proximally to avoid complications. PMID- 29162750 TI - Psychometric validation of a Hindi version of a chronic obstructive pulmonary disease (COPD) assessment test in patients in northern India. AB - BACKGROUND: We aimed to validate a Hindi version of a chronic obstructive pulmonary disease (COPD) assessment test (CAT) for assessing the health status of patients in northern India. METHODS: Of the 178 patients studied, 171 with COPD self-completed CAT twice at a 4-week interval. The patients also self-completed the Hindi versions of the abbreviated World Health Organization Quality of Life questionnaire (WHOQOL-Bref) and St George's Respiratory Questionnaire (SGRQ) at the initial assessment. Baseline clinical details and spirometric data were recorded. Acceptability, validity, internal consistency, test-retest reproducibility and responsiveness were assessed using standard tools. RESULTS: The study population of 178 had 167 (93.8%) males and 1 59 (89.3%) smokers. One hundred and twenty- seven (71.3%) patients completed the second assessment, of whom the condition of 19 had worsened. Each of the eight CAT items correlated strongly with the total CAT score (Pearson coefficients 0.59-0.73). The total CAT score correlated well with the dyspnoea grade, SGRQ domain scores and the physical domain score of WHOQOL-Bref. Cronbach's alpha coefficient had a high value of 0.83. The intraclass correlation coefficient for 101 patients with stable disease between the two assessments was high (0.83), but the effect size in the 19 patients who recovered from an exacerbation was moderate (0.45). CONCLUSION: The Hindi version of CAT has good validity and reliability and can be used to quantify the health impact of COPD among patients in northern India. PMID- 29162751 TI - Population-based estimate of urinary stones from Ballabgarh, northern India. AB - BACKGROUND: Stones in the urinary tract are a common condition but there is paucity of data on their population-based estimates in India. We describe our findings of the burden of urinary stones during a cross-sectional study with another primary goal. METHODS: We conducted the study at Ballabgarh Health and Demographic Surveillance System, Haryana, among residents aged 18 years or above. We used simple random sampling to enrol participants. Self-reported history of urinary stones was elicited through an interview schedule. Results of the descriptive analysis were described as proportions with 95% confidence intervals (CI) or as mean wherever applicable. Bivariate analysis was done using t-test and chi-square test as applicable. RESULTS: The response rate for our study was 86.6%; lifetime prevalence (95% CI) of urinary stones was 7.9% (5.7, 10.8). In a majority of participants, urinary stones were diagnosed at an age of 20-40 years (55.9%), mostly by an ultrasonography examination (94.1%). CONCLUSIONS: A high burden of urinary stones is indicated in the working-age population in northern India at the community level. Untreated urinary stones can lead to an acute emergency (colic) or may have long-term adverse consequences, e.g. hydronephrosis, which have implications for the healthcare delivery system. PMID- 29162752 TI - Systemic thrombosis due to pulmonary tuberculosis. AB - Pulmonary tuberculosis (TB) is an established cause of venous thrombosis. A few instances have been described with arterial thrombosis as well. It has been speculated that TB causes systemic hypercoagulability, which may lead to venous thrombosis. This may be the presenting phenomenon, may occur shortly after diagnosis of TB, or even after starting antitubercular therapy. We describe a patient of pulmonary TB, who presented with pulmonary thromboembolism, with both arterial as well as venous thrombosis, which resolved on antitubercular therapy. PMID- 29162754 TI - ESPAC-4 trial: A summary. PMID- 29162753 TI - Assessment of pain in the elderly: A literature review. AB - BACKGROUND: Pain perception is highly subjective, and effective pain management can be challenging in the elderly. We aimed to identify a set of practical measures that could be used to assess pain in elderly patients with or without cognitive impairment, as the first step towards effectively managing their pain. METHODS: We used the PRISMA guidelines for this literature review. Two reviewers independently assessed titles, abstracts and full-text articles, and a third reviewer resolved any disagreements. RESULTS: A total of 11 285 abstracts and 103 full-text articles were assessed. Forty-one studies met the inclusion criteria. The Numeric Rating Scale, Visual Analogue Scale, Face Pain Scale and Verbal Descriptor Scale have proven valid in the elderly. The Abbey pain scale, Doloplus 2, Pain Assessment in Advanced Dementia scale, Pain Assessment Checklist for Seniors with Limited Ability to Communicate, Checklist of Nonverbal Pain Indicators, Pain Assessment for the Dementing Elderly rating tool and the Clinical Utility of the CNA Pain Assessment Tool are used in elderly patients with cognitive impairment. CONCLUSIONS: We identified a number of reliable and valid methods for pain assessment in the elderly. Elderly patients can receive treatment in a variety of settings, and frequently it is administered by a caregiver or family member, rather than a medical employee. The development of a pain assessment tool that is not subject to variations arising from differences in settings or caregivers is needed to assess pain accurately in elderly patients, and provide timely treatment. Natl Med J India 2017;30:203-7. PMID- 29162755 TI - Standardized patient method in tuberculosis research. PMID- 29162756 TI - Integrating medical biostatistics into postgraduate medical curriculum. AB - BACKGROUND: Knowledge of biostatistics is important for a health professional to understand research methods, analyse new information presented in scientific journals and to assess its relevance for their clinical practice. METHODS: We discuss the implementation of biostatistics in medical curricula, give perspectives on medical education in India, and narrate our own experience of integration of biostatistics into the medical curriculum. RESULTS: Biostatistics is still not a part of all postgraduate curricula in spite of its growing importance for all medical practitioners in the 21st century. CONCLUSION: The need for a reliable tool in research and evidence-based medicine is recognized in most postgraduate medical curricula in developed countries to improve teaching learning outcomes. PMID- 29162757 TI - Low-fidelity simulation to enhance understanding of infection control among undergraduate medical students. AB - BACKGROUND: Developing economies are stressing institutional care for better health outcomes but its advantages are dampened by healthcare-associated infections (HAIs). Besides other undesired complications, the economic cost of HAIs is enormous. Developing countries have higher HAI rates compared with Europe or the USA. The knowledge and practice of infection control is poor among medical students. Based on introspection of 'Infection Control Module' for undergraduates introduced in 2012, we tested emotional sensitization using low-fidelity techniques to enhance its effectiveness. METHODS: All medical undergraduate students in their second year (n=102) were randomly divided into three groups using balanced randomization (two test and one control). Test groups were made to realize the emotional, social and financial consequences of HAI on patients and their families through low-fidelity simulation in the form of case discussions and video demonstrations. Pre- and postintervention empathy scores were calculated using Toronto empathy questionnaire (TEQ) for all the 102 students. Postintervention, all students were subjected to an infection control module and knowledge test. Perceptions of the intervention groups were recorded. Descriptive statistics and ANOVA were applied for data analysis. RESULTS: Of the 102 students, 93 (91.1%) participated in the study. There was no significant difference in the pre-test TEQ score (p=0.87) but there was a significant difference in the post-test TEQ (p = 0.026) and knowledge test score (p = 0.016) among the groups. Both the simulation exercises were well appreciated by the students. CONCLUSION: Emotional sensitization using low-fidelity simulation served as a catalyst in understanding infection control among medical undergraduate students. PMID- 29162758 TI - Public health challenges for the 21st century: Convergence of demography, economics, environment and biology: Nalanda distinguished lecture. AB - The rapidly changing and interdependent world under the mega-force of globalization presents unique challenges and opportunities for public health. Focusing on the example of type 2 diabetes, I argue that an appreciation for the evolution of demographic and economic contexts is essential to appropriately address today's dynamic and complex health challenges. For the vast majority of the past 2000 years, India and China were the world's largest economies until the rise of western European nations in the 18th century and later the USA. In the case of India, inflation-adjusted per capita income remained flat between 1700 and 1950, while in the same period that of the UK grew more than 7-fold, although the population of the UK relatively grew 3-times faster than that of India in the same period. This 250-year gap in industrial and economic development may be central to understanding the large burden of diabetes among individuals of Indian descent, and should be taken into account in a wider context to understand the divergence in health development between India and parts of the world which benefited from early industrial progress and accompanying improvements in food supply, hygiene and living conditions. Lessons from high-income countries support a strong emphasis on public health to achieve important populationwide health gains, and offer insights into the broader determinants of health such as economic and food security, equity, urban infrastructure, health-promoting environments, and access to high-quality health systems. Critical to contemporary public health is also strong data systems and evidence-based decision-making. PMID- 29162760 TI - Autonomy for Medical Institutes in India: A view from history. PMID- 29162759 TI - Pattern and profile of children using substances in India: Insights and recommendations. AB - India has one of the largest proportion of children and adolescents in the world, but the threat posed by child substance use remains under-researched. Only recently a large study, the first of its kind in India, was carried out with a sample of nearly 4000 children using substances (school-going, out-of-school as well as street children) across more than a hundred cities/towns. We discuss (i) the existing knowledge on the prevalence of child substance abuse in India; (ii) perspectives and insights gained from the recent nation-wide study on its pattern and profile; and (iii) recommendations for substance use prevention and treatment among children in the Indian context. A multipronged approach involving all stakeholders is required to address the issues of prevention and treatment. PMID- 29162761 TI - Letter from Glasgow. PMID- 29162762 TI - Letter from Chennai. PMID- 29162763 TI - Incidental cytodiagnosis of microfilaria from subcutaneous nodule. PMID- 29162764 TI - Extensive commotio retinae involving peripheral retina. PMID- 29162766 TI - Production and rearing of germ-free X-SCID pigs. AB - Pigs with X-linked severe combined immunodeficiency (X-SCID) caused by a mutation of the interleukin-2 receptor gamma chain gene (IL2RG) are of value for a wide range of studies. However, they do not survive longer than 8 weeks because of their susceptibility to infections. To allow longer survival of X-SCID pigs, the animals must be born and reared under germ-free conditions. Here, we established an efficient system for piglet derivation by hysterectomy and used it to obtain and maintain a germ-free X-SCID pig. In four trials using pregnant wild-type pigs, 66% of piglets after hysterectomy started spontaneous breathing (range of 20-100% per litter). The resuscitation rate was found to negatively correlate with elapsed time from the uterus excision to piglet derivation (r=-0.97, P<0.05). Therefore, it is critical to deliver piglets within 5 min to achieve a high resuscitation rate (82% estimated from regression analysis). In a fifth trial with an IL2RG+/- pig, four piglets were delivered within 4.2 min of uterus excision and three were alive (75%). One of the live born piglets was genotypically and phenotypically determined to be X-SCID and was reared for 12 weeks. The X-SCID piglet was free from both bacteria and fungi at all time points tested by microbial culture and grew without any abnormal signs or symptoms. This study showed successful production and rearing of germ-free pigs, enabling experiments involving long-term follow-up of X-SCID pigs. PMID- 29162767 TI - An increasing electromechanical window is a predictive marker of ventricular fibrillation in anesthetized rabbit with ischemic heart. AB - The QTc interval is widely used in Safety Pharmacological studies to predict arrhythmia risk, and the electromechanical window (EMW) and short-term variability of QT intervals (STVQT) have been studied as new biomarkers for drug induced Torsades de Pointes (TdP). However, the use of EMW and STVQT to predict ventricular fibrillation (VF) has not been elucidated. This study aimed to evaluate EMW and STVQT to predict VF in anesthetized rabbit model of VF. VF was induced by ligation of the left anterior descending and a descending branch of the left circumflex coronary arteries in a sample population of rabbits (n=18). VF was developed 55.6% (10/18). In rabbit with VF, the EMW was significantly higher than in rabbits without VF (96.3 +/- 15.6 ms and 49.5 +/- 5.6 ms, respectively, P<0.05). STVQT had significantly increased before the onset of VF in rabbits that experienced VF, but not in rabbits that did not experience VF (11.7 +/- 1.8 ms and 3.7 +/- 0.4 ms, respectively, P<0.05). The EMW and STVQT had better predictive power for VF with higher sensitivity and specificity than the QTc measure. The result suggested that the increasing of EMW, as well as the elevation of STVQT, can potentially be used as biomarkers for predicting of VF. PMID- 29162769 TI - [Chinese Journal of Nuclear Medicine and Molecular Imaging Volume 37, Number 10, October 25, 2017]. PMID- 29162768 TI - Coexistence of Trunk or Lower Extremity Pain with Elbow and/or Shoulder Pain among Young Overhead Athletes: A Cross-Sectional Study. AB - Elbow or shoulder injuries are common in overhead sports. Because energy derived from the lower extremity passes through the trunk to the upper extremity in overhead motion, a break in such a kinetic chain could lead to arm injuries. However, there is only limited information about the role of the trunk and lower extremity support in preventing elbow or shoulder injuries. This study aimed to explore the association of trunk and lower extremity pain with elbow/shoulder pain among young overhead athletes. We conducted a cross-sectional study using self-reported questionnaires mailed to young athletes belonging to the Miyagi Amateur Sports Association. The final study population comprised 2,215 young athletes playing baseball (n = 1,422), volleyball (n = 546), softball (n = 14), handball (n = 28), tennis (n = 110), or badminton (n = 95). The median age of the participants was 11 years (range: 6 to 15 years). Multiple logistic regression analysis revealed the higher prevalence of elbow and/or shoulder pain in athletes with back pain (OR = 5.52, 95% CI = 3.51-8.69), hip pain (OR = 6.13, 95% CI = 3.35-11.22), knee pain (OR = 2.28, 95% CI = 1.48-3.51), and foot pain (OR = 3.03, 95% CI = 1.95-4.72), compared with those without pain. We propose that trunk or lower extremity pain is significantly associated with elbow or shoulder pain among young overhead athletes. Assessing for pain in trunk or lower extremity, as well as elbow and/or shoulder pain, may help prevent serious injuries in young overhead athletes. PMID- 29162770 TI - Correlation of the Blood Test Results Obtained between Assays Using Microliter scale Fingertip Blood Samples Collected with a Novel Blood Collection Device and Conventional Venous Blood Assays: a Secondary Publication in English. AB - In this study, we investigated the correlations between biochemical and hematological test results obtained using microliter-scale fingertip blood samples collected with a newly developed blood collection device and those obtained using conventional venous blood. Eighty volunteer subjects were enrolled in this study. Blood samples were drawn from the fingertip of the ring finger by a single puncture, and 60-uL samples were promptly and accurately aspirated into a blood collection chip. Then the chip was tightly sealed in a chip container and was shaken to mix the contents without dispersion. For biochemical tests other than that for HbA1c, blood was collected without anticoagulant and centrifuged to obtain 15 uL of serum which was then diluted with 190 uL of physiological saline for the assay. For hematological tests and the test for HbA1c, the sample was assayed with blood collected using EDTA-2 K. Good correlations were obtained between the test results of the assay using fingertip blood and that using venous blood. The correlation coefficients were >=0.97 for TG, T-CHO, HDL-C, LDL-C, GLU, ALT, gamma-GTP, UA, BUN, and HbA1c and >=0.95 for WBC, RBC, Hgb, and Hct. These results suggest that our microliter-scale blood testing system is comparable to assays using venous blood and may be useful as a rapid and simple test to determine basic clinical parameters that are close to the reference intervals. PMID- 29162771 TI - In vivo evidence for possible up-regulating roles of lysophosphatidic acid around fertilization in rats. AB - Lysophosphatidic acid (LPA) produced by autotaxin (ATX) is recognized as a multi functional mediator in mammalian reproduction. This study focused on possible effect(s) of LPA on ovulated cumulus-oocyte complexes (COCs) around fertilization in rats in vivo. Immunohistochemistry revealed the cell-type-dependent localization of candidates of synthetic enzymes, ATX and two phospholipases A2 isofroms, and LPA receptors LPA1-4 in ovulated COCs and in oviductal epithelium. The eggs ovulated with a form of COCs became denuded of cumulus cells and underwent fragmentation in the absence of fertilization. In vivo experiments of local administration in non-copulated rats demonstrated that eggs denudation was increased by LPA and decreased by anti-ATX antibody and that fragmentation was inhibited by LPA and stimulated by an ATX chemical inhibitor. Furthermore, LPA administration in adult copulated rats increased the rate of cleaved embryos significantly. Obtained results suggest the presence of LPA synthesis and action system in ovulated COCs within the oviductal ampulla and positive actions of LPA possibly at multiple sites around fertilization in rats. PMID- 29162772 TI - Functional alteration of canine isocitrate dehydrogenase 2 (IDH2) via an R174K mutation. AB - Gliomas are common intracranial neoplasias in dogs. However, the underlying pathogenic mechanisms remain unclear. In humans, isocitrate dehydrogenase 2 (IDH2) is often mutated in gliomas. Although almost human IDH2 mutations have been identified at the Arg172 codon, few studies have reported structural, functional or mutational information for canine IDH2. In this study, we cloned the full-length canine IDH2 (cIDH2) cDNA and substituted wild type Arg174 (cIDH2 WT: corresponding to R172 of human IDH2) with Lys (cIDH2 R174K). The cIDH2 WT and R174K proteins were overexpressed in HeLa cells, and their presence was confirmed using an anti-human IDH2-WT mAb (clone: KrMab-3) and an anti-IDH2-R172K mAb (clone: KMab-1). The IDH2 activity between cIDH2 WT and cIDH2 R174K transfectants was compared by measuring the production of NADH and NADPH. NADPH production was lower for cIDH2 R174K than that for cIDH2 WT transfectants. Finally, we detected increased expression of hypoxia inducible factor-1 alpha (HIF-1alpha) in cIDH2 R174K transfectants. This indicates that mutations at R174 can potentially induce carcinogenesis in canine somatic cells. PMID- 29162774 TI - The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks. AB - In mammals, DNA double-strand breaks (DSBs) are primarily repaired by classical non-homologous end joining (C-NHEJ), although homologous recombination repair and alternative NHEJ (A-NHEJ), which involve DSB processing, can also occur. These pathways are tightly regulated to maintain chromosome integrity. The ends of chromosomes, called telomeres, contain telomeric DNA that forms a cap structure in cooperation with telomeric proteins to prevent the activation of the DNA damage response and chromosome fusion at chromosome termini. Telomeres and subtelomeric regions are poor substrates for DNA replication; therefore, regions near telomeres are prone to replication fork stalling and chromosome breakage. Moreover, DSBs near telomeres are poorly repaired. As a result, when DSBs occur near telomeres in normal cells, the cells stop proliferating, while in cancer cells, subtelomeric DSBs induce rearrangements due to the absence of cell cycle checkpoints. The sensitivity of subtelomeric regions to DSBs is due to the improper regulation of processing, because although C-NHEJ is functional at subtelomeric DSBs, excessive processing results in an increased frequency of large deletions and chromosome rearrangements involving A-NHEJ. PMID- 29162773 TI - A High-Fat and High-Cholesterol Diet Induces Cardiac Fibrosis, Vascular Endothelial, and Left Ventricular Diastolic Dysfunction in SHRSP5/Dmcr Rats. AB - AIM: Non-alcoholic steatohepatitis (NASH) increases cardiovascular risk regardless of risk factors in metabolic syndrome. However, the intermediary factors between NASH and vascular disease are still unknown because a suitable animal model has never been established. The stroke-prone (SP) spontaneously hypertensive rat, SHRSP5/Dmcr, simultaneously develops hypertension, acute arterial lipid deposits in mesenteric arteries, and NASH when feed with a high fat and high-cholesterol (HFC) diet. We investigated whether SHRSP5/Dmcr affected with NASH aggravates the cardiac or vascular dysfunction. METHOD: Wister Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 rats each, and fed with a SP or HFC diet. After 8 weeks of HFC or SP diet feeding, glucose and insulin resistance, echocardiography, blood biochemistry, histopathological staining, and endothelial function in aorta were evaluated. RESULTS: We demonstrate that SHRSP5/Dmcr rats fed with a HFC diet presented with cardiac and vascular dysfunction caused by cardiac fibrosis, endothelial dysfunction, and left ventricular diastolic dysfunction, in association with NASH and hypertension. These cardiac and vascular dysfunctions were aggravated and not associated with the presence of hypertension, glucose metabolism disorder, and/or obesity. CONCLUSIONS: SHRSP5/Dmcr rats may be a suitable animal model for elucidating the organ interaction between NASH and cardiac or vascular dysfunction. PMID- 29162775 TI - Effect of methyl p-hydroxybenzoate on the culture of mammalian cell. AB - Several chemicals, such as methyl p-hydroxybenzoate (MHB), have been widely used as preservatives in the water baths of CO2 incubators used for mammalian cell culture, and they are not considered to produce any biological effects. However, no detailed analyses of the effects of these compounds on cultured cells have been reported. In this study, we thus examined whether MHB in the incubator water bath affects cell viability or genome-wide gene expression in mouse embryonic stem cells under control conditions [using only dimethyl sulfoxide (DMSO) in the culture medium] and under chemical-treated conditions using benzene and chloroform; conditions that simulate a cell-based toxicity assay. We found that (i) MHB significantly altered cell growth rate, and (ii) MHB affected gene expression levels related to pathways that modulate cell growth and basic molecular processes, not only under control conditions but also the chemical treated conditions. Furthermore, Gene Ontology term analyses revealed that the effects of MHB cannot be accounted for by subtracting the gene expression pattern in the control conditions from that in the chemical-treated conditions. Thus, we suggest that the use of MHB or other preservatives in a CO2 incubator water bath is reconsidered in terms of potential confounding effects on cultured cells. PMID- 29162776 TI - Erratum for "Sushi repeat-containing protein X-linked 2 promotes angiogenesis through the urokinase-type plasminogen activator receptor dependent integrin alphavbeta3/focal adhesion kinase pathways" by Liu KL et al. (Drug Discov Ther. 2017; 11(4):212-217). AB - In the article entitled "Sushi repeat-containing protein X-linked 2 promotes angiogenesis through the urokinase-type plasminogen activator receptor dependent integrin alphavbeta3/focal adhesion kinase pathways" by Liu KL et al. (Drug Discov Ther. 2017; 11(4):212-217.), a mistake in Figure 3a (alphavbeta3) has been identified. Figure 3 is printed below. PMID- 29162777 TI - Long-Term Favorable Course of Aspergillus Endo-, Myo-, and Pericarditis. AB - Here, we report on a healthy 30-year-old man with no significant medical history, who tested negative for human immunodeficiency virus antigenemia but developed Aspergillus pancarditis. A case of this kind is extremely rare, and to the best of our knowledge, this is the first report of a patient with Aspergillus pancarditis, which generally leads to a very poor outcome, who had a long-term favorable clinical course. A biopsy from the right atrium of hypertrophied atrial septum was essential for obtaining the definitive diagnosis. Long-term administration of an effective antifungal oral agent might account for the patient's favorable outcome. PMID- 29162778 TI - Ryanodine Receptor Type 2 Plays a Role in the Development of Cardiac Fibrosis under Mechanical Stretch Through TGFbeta-1. AB - Ryanodine receptor type 2 (RyR-2), the main Ca2+ release channel from sarcoplasmic reticulum in cardiomyocytes, plays a vital role in the regulation ofmyocardial contractile function and cardiac hypertrophy. However, the role of RyR-2 in cardiac fibrosis during the development of cardiac hypertrophy remains unclear.In this study, we examined whether RyR-2 regulates TGFbeta1, which is secreted from cardiomyocytes and exerts on cardiac fibrosis using cultured cardiomyocytes and cardiac fibroblasts of neonatal rats. The expression of RyR-2 was found only in cardiomyocytesbut not in cardiac fibroblasts. Mechanical stretch induced upregulation of TGFbeta1 in cardiomyocytes and RyR-2 knockdown significantly suppressed the upregulation of TGFbeta1 expression. The transcript levels of collagen genes were also decreased in fibroblasts compare with wild type, although the expression of both two kinds was higher than those in stationary cardiomyocytes (non-stretch). With the inhibition of the TGFbeta1 neutralizing antibody, the expression of collagen genes has no significant difference between the mechanically stretched cardiomyocytes and non stretchedones. These results indicate that RyR-2 regulated TGFbeta1 expression in mechanically stretched cardiomyocytes and TGFbeta1 promoted collagen formation of cardiac fibroblasts by a paracrine mechanism.RyR-2 in mechanical stretch could promote the development of cardiac fibrosis involving TGFbeta1-dependent paracrine mechanism. Our findings provided more insight into comprehensively understanding the molecular role of RyR-2 in regulating cardiac fibrosis. PMID- 29162779 TI - Gender-Adjustment and Cutoff Values of Cornell Product in Hypertensive Japanese Patients. AB - In the Japanese population, the electrocardiographic (ECG) Cornell voltage and product predict cardiovascular events at lower values (Cornell voltage of 2.04 mV in males and 1.71 mV in females, and Cornell product of 158.7 mV* msec) than in the guidelines (2.8 mV, 2.0 mV, and 244 mV* msec, respectively). We evaluated the ECG criteria for left ventricular hypertrophy (LVH) corresponding to echocardiographic LVH (Echo-LVH) in Japanese patients.We reviewed data on 345 consecutive hypertensive patients who underwent echocardiography, and evaluated the Cornell voltage (S in leads V3 + R in leads aVL), Cornell product [ (Cornell voltage + 0.6 mV for females) * QRS duration], and left ventricular mass index (LVMI) (Echo-LVH: LVMI >= 116 g/m2 in males and >= 96 g/m2 in females).The mean age was 63.8 +/- 12.5 years (174 males/172 females). Echo-LVH was found in 22.7% of males and 37.2% of females. The equations for estimating LVMI from the Cornell voltage were (1) LVMI = 14.5 * Cornell voltage + 78.9 for males and (2) LVMI = 21.5 * Cornell voltage + 61.5 for females. The Cornell voltage corresponding to Echo-LVH was 2.6 mV in males and 1.6 mV in females, which were below the guideline levels and close to the values indicating cardiovascular risk. The equation for estimating LVMI from the Cornell product was LVMI = 0.15 * Cornell product + 68.8. The Cornell product corresponding to Echo-LVH was 170 mV* msec (sensitivity: 0.730, specificity: 0.601), which was also close to the cardiovascular risk level.Cornell voltage and product values indicating Echo-LVH are lower than those in the current guidelines and closer to the cardiovascular risk levels. PMID- 29162780 TI - Prolonged Inflation Technique Using a Scoring Balloon for Severe Calcified Lesion. AB - Percutaneous coronary intervention for the treatment of a severe calcified lesion is still one of the most technically challenging areas of interventional cardiology. Calcified lesions are a cause of stent underexpansion, which significantly increases the subsequent risks of in-stent restenosis and thrombosis, even when drug-eluting stents are used. In this report, we describe the usefulness of prolonged inflations using a scoring balloon catheter (Scoreflex) for severe calcified lesions. Prolonged inflation using a scoring balloon enables an adequate dilation for treatment of a severe calcified plaque that was unresponsive to conventional technique with or without rotational atherectomy. PMID- 29162781 TI - Successful Withdrawal from Dobutamine by Canagliflozin in a Diabetic Patient with Stage D Heart Failure. AB - Patients with stage D heart failure (HF) frequently become dependent on high doses of diuretics and inotropic agents. Recently, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), an oral antidiabetic agent, has been demonstrated to have favorable effects in preventing HF. However, it remains unknown whether SGLT2i is reliable for patients with decompensated HF. We experienced a case of a patient with stage D HF for whom attempting intravenous dobutamine withdrawal was difficult even after the administration of all conventional pharmacological treatment. Administration of canagliflozin produced an additive diuretic action and correction of volume overload in combination with azosemide and tolvaptan, and resulted in successful withdrawal of dobutamine. Thus, SGLT2i might be promising for the treatment of patients with congestive HF who are refractory to conventional diuretic treatment. PMID- 29162782 TI - Recurrent Early Coronary Stent Thrombosis under Chronic Disseminated Intravascular Coagulation. AB - A 62-year-old Japanese man presented with chest pain indicating that acute myocardial infarction had occurred. Eleven years earlier, he underwent a splenectomy due to idiopathic portal hypertension. Coronary angiography revealed diffuse stenosis, with calcification in the left anterior descending coronary artery (LAD). We performed a primary percutaneous coronary intervention (PCI). We deployed two drug-eluting stents with sufficient minimal cross-sectional stent area by intravascular ultrasound and thrombolysis in myocardial infarction (TIMI) 3 flow. The initial laboratory examination revealed chronic disseminated intravascular coagulation (DIC). On the 8th hospital day, he developed chest pain indicating early coronary stent thrombosis, although he had been prescribed dual antiplatelet therapy. We performed an emergent second PCI, and the TIMI flow grade improved from 0 to 3. Clopidogrel was replaced with prasugrel. On the 18th hospital day, we detected a repeated coronary stent thrombosis again. We performed a third PCI and the TIMI flow grade improved from 0 to 3. After anticoagulation therapy with warfarin, the DIC was improved and his condition ran a benign course without the recurrence of stent thrombosis for 1 month. Contrast enhanced CT showed portal vein thrombosis. This patient's case reveals the possibility that the condition of chronic DIC can lead to recurrent stent thrombosis. Stent thrombosis is infrequent, but remains a serious complication in terms of morbidity and mortality. Although stent thrombosis is multifactorial, the present case suggests that DIC is a factor in stent thrombosis. To prevent stent thrombosis after PCI under DIC, anticoagulation might be a treatment option in addition to antiplatelet therapy. PMID- 29162784 TI - Quantitative analysis of chronological changes in the volume of flaps used for reconstruction of oral cavity defects. AB - Reconstruction of oral defects using flaps following resection of oral cancer has become a standard approach for restoration of oral function. The purpose of this study was to investigate chronological changes in the volume of such flaps used for reconstruction and the factors affecting flap volume. We performed a retrospective analysis of 17 patients who had undergone oral cancer resection and reconstruction with flaps. Measurements were performed using data from computed tomography, and the flaps were selected semi-automatically using a computer operated region-of-interest system. The data indicated that the change in total flap volume at 1 year after surgery was 30.6%, and that body weight loss was a risk factor for volume reduction. Our results suggested that flaps should be at least 30% larger than the defects they are intended to repair. However, as large flaps have the potential to cause upper airway obstruction, flap volume should be determined on an individual basis according to defect size and location. PMID- 29162783 TI - Impact of macroprolactin on galactorrhea and the rate of patients possibly affected by macroprolactin. AB - The clinical influence of macroprolactin (MPRL) is not clearly understood and the rate of patients potentially affected by MPRL is unknown. We investigated the influence of MPRL on the onset of galactorrhea and estimated the rate of patients with a proportion of MPRL fraction that may possibly affect galactorrhea. Data of patients with obstetric or gynecological symptoms who had undergone PRL fractionation testing were retrospectively analyzed. To evaluate factors influencing galactorrhea, a multivariate logistic regression analysis was performed and the adjusted odds ratios of MPRL for galactorrhea were calculated. Cutoff values for the total PRL level and the proportion of MPRL fractions for galactorrhea were determined by ROC analysis using a multivariate logistic model. The prevalence of patients with a proportion of MPRL fraction greater than or equal to the cutoff value for galactorrhea was estimated. The median proportion of MPRL fraction was 30.1% and increased as PRL level increased. Total PRL and MPRL had a significant influence on the onset of galactorrhea and the adjusted odds ratio was 1.09 in total PRL and 0.94 in MPRL. The rate of patients with a proportion of MPRL fraction that may possibly affect galactorrhea was estimated to be 33.5% of the study population, and thus found to be twelve times or more the number of macroprolactinemia patients. Future prospects for hyperprolactinemia may require diagnostic criteria using free prolactin levels and so MPRL fraction measurement is important for the diagnosis and treatment of patients with obstetric and gynecological symptoms. PMID- 29162785 TI - Relevance of surface characteristics in the adhesiveness of polymicrobial biofilms to crown restoration materials. AB - We used a polymicrobial (PM) biofilm model to examine associations of bacterial adhesiveness with surface characteristics of various dental materials. Four types of dental materials (apatite pellet, zirconia, ceramic, and composite resin) with rough and mirror surfaces were used. Surface roughness, surface free energy, zeta potential, and colony-forming units (CFUs) of the biofilm formations were measured. Biofilms were cultured for 24 h under anaerobic conditions, plated onto blood agar medium, and anaerobically cultured for 4 days. After culturing, CFU per mm2 was calculated, and samples were observed under a scanning electron microscope. Means and standard deviations of the experimental data were estimated, and one-way ANOVA and Tukey multiple comparison assays were performed. Pearson correlation coefficients were obtained for the CFU and surface characteristics. Surface roughness and surface free energy appeared to affect generation of PM biofilms on oral materials, and zeta potential was involved in generation of PM biofilms on mirror-ground oral materials. PMID- 29162786 TI - Are there early signs that predict development of temporomandibular joint disease? AB - Temporomandibular joint disorders (TMJD) involve orofacial pain and functional limitations that may limit important daily activities such as chewing and speaking. This observational case-control study attempted to identify factors associated with TMJD development, particularly inflammation. The study participants were patients treated at Karolinska University Hospital, Stockholm, Sweden. The cases were patients who received a diagnosis of TMJD, chronic closed lock, or painful clicking and were treated surgically during the period from 2007 through 2011. The control group was randomly selected from among patients who had undergone tooth extraction and was matched by age and sex. A total of 146 cases and 151 controls were included in the analyses. The response rate was 55.3% for the case group and 21.8% for the control group. The male:female ratio for patients with TMJD was 1:4.4. TMJD was significantly associated with pneumonia (odds ratio [OR], 2.1), asthma (OR, 2.1), allergies (OR, 1.8), headache (OR, 3.1), general joint hypermobility (OR, 3.8), orofacial trauma (OR, 3.9), rheumatism (OR, 2.5), and orthodontic treatment (OR, 2.4) (P < 0.05 for all outcomes). In conclusion, autoimmune diseases and inflammatory conditions are associated with increased risk of TMJD. Moreover, certain lung disorders may predict subsequent development of TMJD. PMID- 29162787 TI - The economics of biological therapy for inflammatory bowel disease and the case for equality. PMID- 29162788 TI - Early onset and persistent progression of coronary artery disease of unknown etiology in a 30-year-old man. PMID- 29162789 TI - Solitary retroperitoneal neurofibroma: not as small as it seems. PMID- 29162790 TI - The safety and utility of magnetic resonance imaging in a patient with conventional cardiac resynchronization therapy device. PMID- 29162791 TI - Autologous artificial tears used for treatment of dry eye syndrome in patients with chronic graft versus host disease. PMID- 29162792 TI - Association of skin autofluorescence with periodontal inflammation in adults with type 1 diabetes. PMID- 29162793 TI - Omalizumab is effective and available for treatment of patients with severe allergic asthma in Poland. PMID- 29162794 TI - Liver Transplantation from Female Donors Provokes Higher Complement Component C5a Activity. PMID- 29162795 TI - Semiconductor Sequencing Analysis of Chromosomal Copy Number Variations in Spontaneous Miscarriage. AB - BACKGROUND Array CGH is the criterion standard for identifying copy number variations (CNV), but the restrictive requirement of DNA quality and relatively high cost prevent the use of this method as a general assay in hospitals in developing countries. Our principal objective was to determine whether the semiconductor sequencing platform (SSP) could be an alternative method in CNV detection for spontaneous miscarriage. MATERIAL AND METHODS A total of 443 spontaneous miscarriage samples were collected and subjected to low-coverage (0.1X) whole-genome analysis by SSP. These samples were verified by array CGH and 8 low-quality DNA samples were analyzed by SSP and validated by MLPA. RESULTS SSP detected 195 chromosomal numerical abnormalities, 74 CNVs, and 9 mosaicisms among the 435 samples. Among 74 CNV abnormalities, SSP detected an equal number (56) of CNVs 56 >1 Mb with array CGH. However, SSP missed more 6 cases CNVs <1 Mb than array CGH (12 vs. 18). SSP detected more mosaicisms than array CGH (9 vs. 7, p=0.5). Interestingly, SSP detected the mosaicism which had only 8% X monosomy, which was much lower than the minimal percentage of monosomy that was detected by array CGH. CONCLUSIONS SSP is of equivalent efficacy as array CGH in detecting CNVs >1 Mb, and performs better in identifying mosaicism. With the merits of low cost and less demand of input DNA, SSP is a good alternative for use in genetic diagnosis. PMID- 29162796 TI - Deconvoluting interrelationships between concentrations and chemical shifts in urine provides a powerful analysis tool. AB - The NMR chemical shifts of a substance in a complex mixture strongly depend on the composition of the mixture itself, as many weak interactions occur that are hardly predictable. Chemical shift variability is the major obstacle to automatically assigning, and subsequently quantitating, metabolite signals in body fluids, particularly urine. Here we demonstrate that the chemical shifts of signals in urine are actually predictable. This is achieved by constructing ca. 4000 artificial mixtures where the concentrations of 52 most abundant urine metabolites-including 11 inorganic ions-are varied, to sparsely but efficiently populate an N-dimensional concentration matrix. A strong relationship is established between the concentration matrix and the chemical shift matrix, so that chemical shifts of > 90 metabolite signals can be accurately predicted in real urine samples. The concentrations of the invisible inorganic ions are also accurately predicted, along with those of albumin and of several other abundant urine components. PMID- 29162797 TI - 3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry. AB - The topographical organization of collagen within the tumor microenvironment has been implicated in modulating cancer cell migration and independently predicts progression to metastasis. Here, we show that collagen matrices with small pores and short fibers, but not Matrigel, trigger a conserved transcriptional response and subsequent motility switch in cancer cells resulting in the formation of multicellular network structures. The response is not mediated by hypoxia, matrix stiffness, or bulk matrix density, but rather by matrix architecture-induced beta1-integrin upregulation. The transcriptional module associated with network formation is enriched for migration and vasculogenesis-associated genes that predict survival in patient data across nine distinct tumor types. Evidence of this gene module at the protein level is found in patient tumor slices displaying a vasculogenic mimicry (VM) phenotype. Our findings link a collagen-induced migration program to VM and suggest that this process may be broadly relevant to metastatic progression in solid human cancers. PMID- 29162798 TI - Persistence and reversal of plasmid-mediated antibiotic resistance. AB - In the absence of antibiotic-mediated selection, sensitive bacteria are expected to displace their resistant counterparts if resistance genes are costly. However, many resistance genes persist for long periods in the absence of antibiotics. Horizontal gene transfer (primarily conjugation) could explain this persistence, but it has been suggested that very high conjugation rates would be required. Here, we show that common conjugal plasmids, even when costly, are indeed transferred at sufficiently high rates to be maintained in the absence of antibiotics in Escherichia coli. The notion is applicable to nine plasmids from six major incompatibility groups and mixed populations carrying multiple plasmids. These results suggest that reducing antibiotic use alone is likely insufficient for reversing resistance. Therefore, combining conjugation inhibition and promoting plasmid loss would be an effective strategy to limit conjugation-assisted persistence of antibiotic resistance. PMID- 29162799 TI - Structure-based design of native-like HIV-1 envelope trimers to silence non neutralizing epitopes and eliminate CD4 binding. AB - Elicitation of broadly neutralizing antibodies (bnAbs) is a primary HIV vaccine goal. Native-like trimers mimicking virion-associated spikes present nearly all bnAb epitopes and are therefore promising vaccine antigens. However, first generation native-like trimers expose epitopes for non-neutralizing antibodies (non-nAbs), which may hinder bnAb induction. We here employ computational and structure-guided design to develop improved native-like trimers that reduce exposure of non-nAb epitopes in the V3-loop and trimer base, minimize both CD4 reactivity and CD4-induced non-nAb epitope exposure, and increase thermal stability while maintaining bnAb antigenicity. In rabbit immunizations with native-like trimers of the 327c isolate, improved trimers suppress elicitation of V3-directed and tier-1 neutralizing antibodies and induce robust autologous tier 2 neutralization, unlike a first-generation trimer. The improved native-like trimers from diverse HIV isolates, and the design methods, have promise to assist in the development of a HIV vaccine. PMID- 29162800 TI - Discovery and characterization of stable and toxic Tau/phospholipid oligomeric complexes. AB - The microtubule-associated protein Tau plays a central role in the pathogenesis of Alzheimer's disease. Although Tau interaction with membranes is thought to affect some of its physiological functions and its aggregation properties, the sequence determinants and the structural and functional consequences of such interactions remain poorly understood. Here, we report that the interaction of Tau with vesicles results in the formation of highly stable protein/phospholipid complexes. These complexes are toxic to primary hippocampal cultures and are detected by MC-1, an antibody recognizing pathological Tau conformations. The core of these complexes is comprised of the PHF6* and PHF6 hexapeptide motifs, the latter in a beta-strand conformation. Studies using Tau-derived peptides enabled the design of mutants that disrupt Tau interactions with phospholipids without interfering with its ability to form fibrils, thus providing powerful tools for uncoupling these processes and investigating the role of membrane interactions in regulating Tau function, aggregation and toxicity. PMID- 29162802 TI - Nanoscale tomography reveals the deactivation of automotive copper-exchanged zeolite catalysts. AB - Copper-exchanged zeolite chabazite (Cu-SSZ-13) was recently commercialized for the selective catalytic reduction of NO X with ammonia in vehicle emissions as it exhibits superior reaction performance and stability compared to all other catalysts, notably Cu-ZSM-5. Herein, the 3D distributions of Cu as well as framework elements (Al, O, Si) in both fresh and aged Cu-SSZ-13 and Cu-ZSM-5 are determined with nanometer resolution using atom probe tomography (APT), and correlated with catalytic activity and other characterizations. Both fresh catalysts contain a heterogeneous Cu distribution, which is only identified due to the single atom sensitivity of APT. After the industry standard 135,000 mile simulation, Cu-SSZ-13 shows Cu and Al clustering, whereas Cu-ZSM-5 is characterized by severe Cu and Al aggregation into a copper aluminate phase (CuAl2O4 spinel). The application of APT as a sensitive and local characterization method provides identification of nanometer scale heterogeneities that lead to catalytic activity and material deactivation. PMID- 29162801 TI - Characterizing a thermostable Cas9 for bacterial genome editing and silencing. AB - CRISPR-Cas9-based genome engineering tools have revolutionized fundamental research and biotechnological exploitation of both eukaryotes and prokaryotes. However, the mesophilic nature of the established Cas9 systems does not allow for applications that require enhanced stability, including engineering at elevated temperatures. Here we identify and characterize ThermoCas9 from the thermophilic bacterium Geobacillus thermodenitrificans T12. We show that in vitro ThermoCas9 is active between 20 and 70 degrees C, has stringent PAM-preference at lower temperatures, tolerates fewer spacer-protospacer mismatches than SpCas9 and its activity at elevated temperatures depends on the sgRNA-structure. We develop ThermoCas9-based engineering tools for gene deletion and transcriptional silencing at 55 degrees C in Bacillus smithii and for gene deletion at 37 degrees C in Pseudomonas putida. Altogether, our findings provide fundamental insights into a thermophilic CRISPR-Cas family member and establish a Cas9-based bacterial genome editing and silencing tool with a broad temperature range. PMID- 29162803 TI - mDia1 senses both force and torque during F-actin filament polymerization. AB - Formins, an important family of force-bearing actin-polymerizing factors, function as homodimers that bind with the barbed end of actin filaments through a ring-like structure assembled from dimerized FH2 domains. It has been hypothesized that force applied to formin may facilitate transition of the FH2 ring from an inhibitory closed conformation to a permissive open conformation, speeding up actin polymerization. We confirm this hypothesis for mDia1 dependent actin polymerization by stretching a single-actin filament in the absence of profilin using magnetic tweezers, and observe that increasing force from 0.5 to 10 pN can drastically speed up the actin polymerization rate. Further, we find that this force-promoted actin polymerization requires torsionally unconstrained actin filament, suggesting that mDia1 also senses torque. As actin filaments are subject to complex mechanical constraints in living cells, these results provide important insights into how formin senses these mechanical constraints and regulates actin organization accordingly. PMID- 29162804 TI - High-velocity projectile impact induced 9R phase in ultrafine-grained aluminium. AB - Aluminium typically deforms via full dislocations due to its high stacking fault energy. Twinning in aluminium, although difficult, may occur at low temperature and high strain rate. However, the 9R phase rarely occurs in aluminium simply because of its giant stacking fault energy. Here, by using a laser-induced projectile impact testing technique, we discover a deformation-induced 9R phase with tens of nm in width in ultrafine-grained aluminium with an average grain size of 140 nm, as confirmed by extensive post-impact microscopy analyses. The stability of the 9R phase is related to the existence of sessile Frank loops. Molecular dynamics simulations reveal the formation mechanisms of the 9R phase in aluminium. This study sheds lights on a deformation mechanism in metals with high stacking fault energies. PMID- 29162805 TI - The key role of Au-substrate interactions in catalytic gold subnanoclusters. AB - The development of gold catalysis has allowed significant levels of activity and complexity in organic synthesis. Recently, the use of very active small gold subnanoclusters (Au n , n < 10) has been reported. The stabilization of such nanocatalysts to prevent self-aggregation represents a true challenge that has been partially remediated, for instance, by their immobilization in polymer matrices. Here, we describe the transient stabilization of very small gold subnanoclusters (Au n , n < 5) by alkyl chains or aromatic groups appended to the reactive pi bond of simple alkynes. The superior performance toward Bronsted acid free hydration of medium to long aliphatic alkynes (1-hexyne and 1-docecyne) and benzylacetylene with respect to phenylacetylene is demonstrated experimentally and investigated computationally. A cooperative network of dispersive Au...C-H and/or Au...pi interactions, supported by quantum mechanical calculations and time-resolved luminescence experiments, is proposed to be at the origin of this stabilization. PMID- 29162806 TI - Publisher Correction: Mergeable nervous systems for robots. AB - The original version of this Article contained an error in the author contributions section, whereby credit for design of the experiments was not attributed to N.M. This error has now been corrected in both the PDF and HTML versions of the Article. PMID- 29162807 TI - Molecular basis of AKAP79 regulation by calmodulin. AB - AKAP79/150 is essential for coordinating second messenger-responsive enzymes in processes including synaptic long-term depression. Ca2+ directly regulates AKAP79 through its effector calmodulin (CaM), but the molecular basis of this regulation was previously unknown. Here, we report that CaM recognizes a '1-4-7-8' pattern of hydrophobic amino acids starting at Trp79 in AKAP79. Cross-linking coupled to mass spectrometry assisted mapping of the interaction site. Removal of the CaM binding sequence in AKAP79 prevents formation of a Ca2+-sensitive interface between AKAP79 and calcineurin, and increases resting cellular PKA phosphorylation. We determined a crystal structure of CaM bound to a peptide encompassing its binding site in AKAP79. CaM adopts a highly compact conformation in which its open Ca2+-activated C-lobe and closed N-lobe cooperate to recognize a mixed alpha/310 helix in AKAP79. The structure guided a bioinformatic screen to identify potential sites in other proteins that may employ similar motifs for interaction with CaM. PMID- 29162808 TI - A multiplexable TALE-based binary expression system for in vivo cellular interaction studies. AB - Binary expression systems have revolutionised genetic research by enabling delivery of loss-of-function and gain-of-function transgenes with precise spatial temporal resolution in vivo. However, at present, each existing platform relies on a defined exogenous transcription activator capable of binding a unique recognition sequence. Consequently, none of these technologies alone can be used to simultaneously target different tissues or cell types in the same organism. Here, we report a modular system based on programmable transcription activator like effector (TALE) proteins, which enables parallel expression of multiple transgenes in spatially distinct tissues in vivo. Using endogenous enhancers coupled to TALE drivers, we demonstrate multiplexed orthogonal activation of several transgenes carrying cognate variable activating sequences (VAS) in distinct neighbouring cell types of the Drosophila central nervous system. Since the number of combinatorial TALE-VAS pairs is virtually unlimited, this platform provides an experimental framework for highly complex genetic manipulation studies in vivo. PMID- 29162809 TI - Full-scale evaluation of methane production under oxic conditions in a mesotrophic lake. AB - Oxic lake surface waters are frequently oversaturated with methane (CH4). The contribution to the global CH4 cycle is significant, thus leading to an increasing number of studies and stimulating debates. Here we show, using a mass balance, on a temperate, mesotrophic lake, that ~90% of CH4 emissions to the atmosphere is due to CH4 produced within the oxic surface mixed layer (SML) during the stratified period, while the often observed CH4 maximum at the thermocline represents only a physically driven accumulation. Negligible surface CH4 oxidation suggests that the produced 110 +/- 60 nmol CH4 L-1 d-1 efficiently escapes to the atmosphere. Stable carbon isotope ratios indicate that CH4 in the SML is distinct from sedimentary CH4 production, suggesting alternative pathways and precursors. Our approach reveals CH4 production in the epilimnion that is currently overlooked, and that research on possible mechanisms behind the methane paradox should additionally focus on the lake surface layer. PMID- 29162810 TI - DNA methylation signatures follow preformed chromatin compartments in cardiac myocytes. AB - Storage of chromatin in restricted nuclear space requires dense packing while ensuring DNA accessibility. Thus, different layers of chromatin organization and epigenetic control mechanisms exist. Genome-wide chromatin interaction maps revealed large interaction domains (TADs) and higher order A and B compartments, reflecting active and inactive chromatin, respectively. The mutual dependencies between chromatin organization and patterns of epigenetic marks, including DNA methylation, remain poorly understood. Here, we demonstrate that establishment of A/B compartments precedes and defines DNA methylation signatures during differentiation and maturation of cardiac myocytes. Remarkably, dynamic CpG and non-CpG methylation in cardiac myocytes is confined to A compartments. Furthermore, genetic ablation or reduction of DNA methylation in embryonic stem cells or cardiac myocytes, respectively, does not alter genome-wide chromatin organization. Thus, DNA methylation appears to be established in preformed chromatin compartments and may be dispensable for the formation of higher order chromatin organization. PMID- 29162811 TI - Evolution of tribo-induced interfacial nanostructures governing superlubricity in a-C:H and a-C:H:Si films. AB - Hydrogenated amorphous carbon (a-C:H) is capable of providing a near-frictionless lubrication state when rubbed in dry sliding contacts. Nevertheless, the mechanisms governing superlubricity in a-C:H are still not well comprehended, mainly due to the lack of spatially resolved structural information of the buried contact surface. Here, we present structural analysis of the carbonaceous sliding interfaces at the atomic scale in two superlubricious solid lubricants, a-C:H and Si-doped a-C:H (a-C:H:Si), by probing the contact area using state-of-the-art scanning electron transmission microscopy and electron energy-loss spectroscopy. The results emphasize the diversity of superlubricity mechanisms in a-C:Hs. They suggest that the occurrence of a superlubricious state is generally dependent on the formation of interfacial nanostructures, mainly a tribolayer, by different carbon rehybridization pathways. The evolution of such anti-friction nanostructures highly depends on the contact mechanics and the counterpart material. These findings enable a more effective manipulation of superlubricity and developments of new carbon lubricants with robust lubrication properties. PMID- 29162812 TI - Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis. AB - Previous studies have proposed that epithelial to mesenchymal transition (EMT) in breast cancer cells regulates metastasis, stem cell properties and chemo resistance; most studies were based on in vitro culture of cell lines and mouse transgenic cancer models. However, the identity and function of cells expressing EMT-associated genes in normal murine mammary gland homeostasis and human breast cancer still remains under debate. Using in vivo lineage tracing and triple negative breast cancer (TNBC) patient derived xenografts we demonstrate that the repopulating capacity in normal mammary epithelial cells and tumorigenic capacity in TNBC is independent of expression of EMT-associated genes. In breast cancer, while a subset of cells with epithelial and mesenchymal phenotypes have stem cell activity, in many cells that have lost epithelial characteristics with increased expression of mesenchymal genes, have decreased tumor-initiating capacity and plasticity. These findings have implications for the development of effective therapeutic agents targeting tumor-initiating cells. PMID- 29162813 TI - Chemogenomic analysis reveals key role for lysine acetylation in regulating Arc stability. AB - The role of Arc in synaptic plasticity and memory consolidation has been investigated for many years with recent evidence that defects in the expression or activity of this immediate-early gene may also contribute to the pathophysiology of brain disorders including schizophrenia and fragile X syndrome. These results bring forward the concept that reversing Arc abnormalities could provide an avenue to improve cognitive or neurological impairments in different disease contexts, but how to achieve this therapeutic objective has remained elusive. Here, we present results from a chemogenomic screen that probed a mechanistically diverse library of small molecules for modulators of BDNF-induced Arc expression in primary cortical neurons. This effort identified compounds with a range of influences on Arc, including promoting its acetylation-a previously uncharacterized post-translational modification of this protein. Together, our data provide insights into the control of Arc that could be targeted to harness neuroplasticity for clinical applications. PMID- 29162814 TI - TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response. AB - Adult neurogenesis persists in the rodent dentate gyrus and is stimulated by chronic treatment with conventional antidepressants through BDNF/TrkB signaling. Ketamine in low doses produces both rapid and sustained antidepressant effects in patients. Previous studies have shed light on post-transcriptional synaptic NMDAR mediated mechanisms underlying the acute effect, but how ketamine acts at the cellular level to sustain this anti-depressive function for prolonged periods remains unclear. Here we report that ketamine accelerates differentiation of doublecortin-positive adult hippocampal neural progenitors into functionally mature neurons. This process requires TrkB-dependent ERK pathway activation. Genetic ablation of TrkB in neural stem/progenitor cells, or pharmacologic disruption of ERK signaling, or inhibition of adult neurogenesis, each blocks the ketamine-induced behavioral responses. Conversely, enhanced ERK activity via Nf1 gene deletion extends the response and rescues both neurogenic and behavioral deficits in mice lacking TrkB. Thus, TrkB-dependent neuronal differentiation is involved in the sustained antidepressant effects of ketamine. PMID- 29162815 TI - Organic carbon burial in global lakes and reservoirs. AB - Burial in sediments removes organic carbon (OC) from the short-term biosphere atmosphere carbon (C) cycle, and therefore prevents greenhouse gas production in natural systems. Although OC burial in lakes and reservoirs is faster than in the ocean, the magnitude of inland water OC burial is not well constrained. Here we generate the first global-scale and regionally resolved estimate of modern OC burial in lakes and reservoirs, deriving from a comprehensive compilation of literature data. We coupled statistical models to inland water area inventories to estimate a yearly OC burial of 0.15 (range, 0.06-0.25) Pg C, of which ~40% is stored in reservoirs. Relatively higher OC burial rates are predicted for warm and dry regions. While we report lower burial than previously estimated, lake and reservoir OC burial corresponded to ~20% of their C emissions, making them an important C sink that is likely to increase with eutrophication and river damming. PMID- 29162817 TI - Surface plasmon induced direct detection of long wavelength photons. AB - Millimeter and terahertz wave photodetectors have long been of great interest due to a wide range of applications, but they still face challenges in detection performance. Here, we propose a new strategy for the direct detection of millimeter and terahertz wave photons based on localized surface-plasmon polariton (SPP)-induced non-equilibrium electrons in antenna-assisted subwavelength ohmic metal-semiconductor-metal (OMSM) structures. The subwavelength OMSM structure is used to convert the absorbed photons into localized SPPs, which then induce non-equilibrium electrons in the structure, while the antenna increases the number of photons coupled into the OMSM structure. When the structure is biased and illuminated, the unidirectional flow of the SPP-induced non-equilibrium electrons forms a photocurrent. The energy of the detected photons is determined by the structure rather than the band gap of the semiconductor. The detection scheme is confirmed by simulation and experimental results from the devices, made of gold and InSb, and a room temperature noise equivalent power (NEP) of 1.5 * 10-13 W Hz-1/2 is achieved. PMID- 29162818 TI - The roles of photo-carrier doping and driving wavelength in high harmonic generation from a semiconductor. AB - High-harmonic generation from gases produces attosecond bursts and enables high harmonic spectroscopy to explore electron dynamics in atoms and molecules. Recently, high-harmonic generation from solids has been reported, resulting in novel phenomena and unique control of the emission, absent in gas-phase media. Here we investigate high harmonics from semiconductors with controllable induced photo-carrier densities, as well as the driving wavelengths. We demonstrate that the dominant generation mechanism can be identified by monitoring the variation of the harmonic spectra with the carrier density. Moreover, the harmonic spectral dependence on the driving wavelength is reported and a different dependence from the well-known one in gas-phase media is observed. Our study provides distinct control of the harmonic process from semiconductors, sheds light on the underlying mechanism and helps optimize the harmonic properties for future solid state attosecond light sources. PMID- 29162816 TI - Impairments of spatial memory in an Alzheimer's disease model via degeneration of hippocampal cholinergic synapses. AB - Choline acetyltransferase neurons in the vertical diagonal band of Broca (vChATs) degenerate in the early stage of Alzheimer's disease (AD). Here, we report that vChATs directly innervate newly generated immature neurons (NGIs) in the dorsal hippocampus (dNGIs) of adult mice and regulate both the dNGIs survival and spatial pattern separation. In a mouse model that exhibits amyloid-beta plaques similar to AD patients, cholinergic synaptic transmission, dNGI survival and spatial pattern separation are impaired. Activation of vChATs with theta burst stimulation (TBS) that alleviates the decay in cholinergic synaptic transmission effectively protects against spatial pattern separation impairments in the AD mice and this protection was completely abolished by inhibiting the dNGIs survival. Thus, the impairments of pattern separation-associated spatial memory in AD mice are in part caused by degeneration of cholinergic synaptic transmission that modulates the dNGIs survival. PMID- 29162820 TI - The formation and evolution of Titan's winter polar vortex. AB - Saturn's largest moon Titan has a substantial nitrogen-methane atmosphere, with strong seasonal effects, including formation of winter polar vortices. Following Titan's 2009 northern spring equinox, peak solar heating moved to the northern hemisphere, initiating south-polar subsidence and winter polar vortex formation. Throughout 2010-2011, strengthening subsidence produced a mesospheric hot-spot and caused extreme enrichment of photochemically produced trace gases. However, in 2012 unexpected and rapid mesospheric cooling was observed. Here we show extreme trace gas enrichment within the polar vortex dramatically increases mesospheric long-wave radiative cooling efficiency, causing unusually cold temperatures 2-6 years post-equinox. The long time-frame to reach a stable vortex configuration results from the high infrared opacity of Titan's trace gases and the relatively long atmospheric radiative time constant. Winter polar hot-spots have been observed on other planets, but detection of post-equinox cooling is so far unique to Titan. PMID- 29162819 TI - Exocytosis-coordinated mechanisms for tip growth underlie pollen tube growth guidance. AB - Many tip-growing cells are capable of responding to guidance cues, during which cells precisely steer their growth toward the source of guidance signals. Though several players in signal perception have been identified, little is known about the downstream signaling that controls growth direction during guidance. Here, using combined modeling and experimental studies, we demonstrate that the growth guidance of Arabidopsis pollen tubes is regulated by the signaling network that controls tip growth. Tip-localized exocytosis plays a key role in this network by integrating guidance signals with the ROP1 Rho GTPase signaling and coordinating intracellular signaling with cell wall mechanics. This model reproduces the high robustness and responsiveness of pollen tube guidance and explains the connection between guidance efficiency and the parameters of the tip growth system. Hence, our findings establish an exocytosis-coordinated mechanism underlying the cellular pathfinding guided by signal gradients and the mechanistic linkage between tip growth and guidance. PMID- 29162821 TI - Widely tunable black phosphorus mid-infrared photodetector. AB - Lately rediscovered orthorhombic black phosphorus (BP) exhibits promising properties for near- and mid-infrared optoelectronics. Although recent electrical measurements indicate that a vertical electric field can effectively reduce its transport bandgap, the impact of the electric field on light-matter interaction remains unclear. Here we show that a vertical electric field can dynamically extend the photoresponse in a 5 nm-thick BP photodetector from 3.7 to beyond 7.7 MUm, leveraging the Stark effect. We further demonstrate that such a widely tunable BP photodetector exhibits a peak extrinsic photo-responsivity of 518, 30, and 2.2 mA W-1 at 3.4, 5, and 7.7 MUm, respectively, at 77 K. Furthermore, the extracted photo-carrier lifetime indicates a potential operational speed of 1.3 GHz. Our work not only demonstrates the potential of BP as an alternative mid infrared material with broad optical tunability but also may enable the compact, integrated on-chip high-speed mid-infrared photodetectors, modulators, and spectrometers. PMID- 29162822 TI - Increased rise time of electron temperature during adiabatic plasmon focusing. AB - Decay of plasmons to hot carriers has recently attracted considerable interest for fundamental studies and applications in quantum plasmonics. Although plasmon assisted hot carriers in metals have already enabled remarkable physical and chemical phenomena, much remains to be understood to engineer devices. Here, we present an analysis of the spatio-temporal dynamics of hot electrons in an emblematic plasmonic device, the adiabatic nanofocusing surface-plasmon taper. With femtosecond-resolution measurements, we confirm the extraordinary capability of plasmonic tapers to generate hot carriers by slowing down plasmons at the taper apex. The measurements also evidence a substantial increase of the "lifetime" of the electron gas temperature at the apex. This interesting effect is interpreted as resulting from an intricate heat flow at the apex. The ability to harness the "lifetime" of hot-carrier gases with nanoscale circuits may provide a multitude of applications, such as hot-spot management, nonequilibrium hot-carrier generation, sensing, and photovoltaics. PMID- 29162823 TI - Manufacture of highly loaded silica-supported cobalt Fischer-Tropsch catalysts from a metal organic framework. AB - The development of synthetic protocols for the preparation of highly loaded metal nanoparticle-supported catalysts has received a great deal of attention over the last few decades. Independently controlling metal loading, nanoparticle size, distribution, and accessibility has proven challenging because of the clear interdependence between these crucial performance parameters. Here we present a stepwise methodology that, making use of a cobalt-containing metal organic framework as hard template (ZIF-67), allows addressing this long-standing challenge. Condensation of silica in the Co-metal organic framework pore space followed by pyrolysis and subsequent calcination of these composites renders highly loaded cobalt nanocomposites (~ 50 wt.% Co), with cobalt oxide reducibility in the order of 80% and a good particle dispersion, that exhibit high activity, C5 + selectivity and stability in Fischer-Tropsch synthesis. PMID- 29162824 TI - Watt-level 10-gigahertz solid-state laser enabled by self-defocusing nonlinearities in an aperiodically poled crystal. AB - Femtosecond modelocked lasers with multi-gigahertz pulse repetition rates are attractive sources for all applications that require individually resolvable frequency comb lines or high sampling rates. However, the modelocked laser architectures demonstrated so far have several issues, including the need for single-mode pump lasers, limited output power, Q-switching instabilities and challenging cavity geometries. Here, we introduce a technique that solves these issues. In a two-dimensionally patterned quasi-phase-matching (QPM) device, we create a large, low-loss self-defocusing nonlinearity, which simultaneously provides SESAM-assisted soliton modelocking in the normal dispersion regime and suppresses Q-switching induced damage. We demonstrate femtosecond passive modelocking at 10-GHz pulse repetition rates from a simple straight laser cavity, directly pumped by a low-cost highly spatially multimode pump diode. The 10.6-GHz Yb:CaGdAlO4 (Yb:CALGO) laser delivers 166-fs pulses at 1.2 W of average output power. This enables a new class of femtosecond modelocked diode-pumped solid state lasers with repetition rates at 10 GHz and beyond. PMID- 29162825 TI - Outcomes of patients with sarcoma enrolled in clinical trials of pazopanib combined with histone deacetylase, mTOR, Her2, or MEK inhibitors. AB - Pazopanib is US FDA approved for the treatment of advanced soft tissue sarcomas. All patients with this disease ultimately develop resistance to therapy. Mechanisms of resistance include activation of the mTOR, histone deacetylase (HDAC), MAPK, and ERBB4 pathways. We hypothesized that combining pazopanib with other targeted agents inhibiting these pathways would increase response rates. We retrospectively evaluated the safety and efficacy of pazopanib plus vorinostat, everolimus, lapatinib or trastuzumab, and MEK inhibitor in patients with advanced sarcoma. The Cancer Geneome Atlas (TCGA) data was analyzed for HDAC, PI3K, HER2, and MAPK/RAS/RAF gene alterations from sarcoma TCGA. Of the 44 advanced sarcoma patients in these trials, 27 (61%) were male; 18 (41%) had bone sarcoma, and 26 (59%) had soft tissue sarcoma. Best response was partial response (PR) in four patients [(overall response rate (ORR) = 9%, 95% confidence interval [CI] 3% to 22%)]. The median progression-free survival (PFS) for all patients was 9.6 weeks (95% CI 8.0 to 15.7 weeks). Analysis of TCGA data revealed HDAC, PI3K, HER2, and MAPK/RAS/RAF gene alterations in 112/243 (46%) of patients predominantly HDAC1-11 (41%) alterations. Pazopanib combinations did demonstrate safety in combination with other agents. TCGA data suggests further evaluation of epigenetic pathway inhibitors in sarcoma. PMID- 29162826 TI - Carrageenan catabolism is encoded by a complex regulon in marine heterotrophic bacteria. AB - Macroalgae contribute substantially to primary production in coastal ecosystems. Their biomass, mainly consisting of polysaccharides, is cycled into the environment by marine heterotrophic bacteria using largely uncharacterized mechanisms. Here we describe the complete catabolic pathway for carrageenans, major cell wall polysaccharides of red macroalgae, in the marine heterotrophic bacterium Zobellia galactanivorans. Carrageenan catabolism relies on a multifaceted carrageenan-induced regulon, including a non-canonical polysaccharide utilization locus (PUL) and genes distal to the PUL, including a susCD-like pair. The carrageenan utilization system is well conserved in marine Bacteroidetes but modified in other phyla of marine heterotrophic bacteria. The core system is completed by additional functions that might be assumed by non orthologous genes in different species. This complex genetic structure may be the result of multiple evolutionary events including gene duplications and horizontal gene transfers. These results allow for an extension on the definition of bacterial PUL-mediated polysaccharide digestion. PMID- 29162827 TI - Intranasal infection and contact transmission of Zika virus in guinea pigs. AB - Zika virus (ZIKV) is primarily transmitted to humans through mosquito bites or sexual contact. The excretion and persistence of contagious ZIKV in various body fluids have been well documented in ZIKV patients; however, the risk of direct contact exposure remains unclear. Here, we show that guinea pigs are susceptible to ZIKV infection via subcutaneous inoculation route; infected guinea pigs exhibit seroconversion and significant viral secretion in sera, saliva, and tears. Notably, ZIKV is efficiently transmitted from infected guinea pigs to naive co-caged animals. In particular, intranasal inoculation of ZIKV is fully capable of establishing infection in guinea pigs, and viral antigens are detected in multiple tissues including brain and parotid glands. Cynomolgus macaques also efficiently acquire ZIKV infection via intranasal and intragastric inoculation routes. These collective results from animal models highlight the risk of exposure to ZIKV contaminants and raise the possibility of close contact transmission of ZIKV in humans. PMID- 29162828 TI - Selenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models. AB - Selenoprotein P (SeP) functions as a selenium (Se)-supply protein. SeP is identified as a hepatokine, promoting insulin resistance in type 2 diabetes. Thus, the suppression of Se-supply activity of SeP might improve glucose metabolism. Here, we develop an anti-human SeP monoclonal antibody AE2 as with neutralizing activity against SeP. Administration of AE2 to mice significantly improves glucose intolerance and insulin resistance that are induced by human SeP administration. Furthermore, excess SeP administration significantly decreases pancreas insulin levels and high glucose-induced insulin secretion, which are improved by AE2 administration. Epitope mapping reveals that AE2 recognizes a region of human SeP adjacent to the first histidine-rich region (FHR). A polyclonal antibody against the mouse SeP FHR improves glucose intolerance and insulin secretion in a mouse model of diabetes. This report describes a novel molecular strategy for the development of type 2 diabetes therapeutics targeting SeP. PMID- 29162829 TI - Single-molecule visualization of conformational changes and substrate transport in the vitamin B12 ABC importer BtuCD-F. AB - ATP-binding cassette (ABC) transporters form the largest class of active membrane transport proteins. Binding and hydrolysis of ATP by their highly conserved nucleotide-binding domains drive conformational changes of the complex that mediate transport of substrate across the membrane. The vitamin B12 importer BtuCD-F in Escherichia coli is an extensively studied model system. The periplasmic soluble binding protein BtuF binds the ligand; the transmembrane and ATPase domains BtuCD mediate translocation. Here we report the direct observation at the single-molecule level of ATP, vitamin B12 and BtuF-induced events in the transporter complex embedded in liposomes. Single-molecule fluorescence imaging techniques reveal that membrane-embedded BtuCD forms a stable complex with BtuF, regardless of the presence of ATP and vitamin B12. We observe that a vitamin B12 molecule remains bound to the complex for tens of seconds, during which several ATP hydrolysis cycles can take place, before it is being transported across the membrane. PMID- 29162830 TI - Numerical Simulation of Hemodynamic Changes in Central Veins after Tunneled Cuffed Central Venous Catheter Placement in Patients under Hemodialysis. AB - The tunneled central venous catheter (CVC) plays an important role for hemodialysis patients, but CVC-related thrombosis in the central veins remain problematic. This study is the first try to numerically find out what hemodynamic parameters are predisposed to the initiation and formation of thrombus after CVC insertion. And the potential relationship between hemodynamic parameters and the incidence rates of thrombosis occurrence was explored. The results revealed that the CVC insertion led to a significant increase of hydraulic resistance, wide ranging abnormally high wall shear stress (WSS), and a great loss of flow rotation in the vein. Moreover, the clinical data showed that thrombosis mainly occurred at sections where most blood flow lost spiral rotation after the CVC insertion, but no corresponding match was observed between the occurrence of thrombosis and the flow velocity or WSS. We speculate that the destruction of the flow rotation in the central vein is a precursor to the thrombus formation around CVC, and an introduction of spiral flow with the CVC insertion may possibly help to protect the central vein from thrombosis. Further animal and clinical experiments should be carried out to test and verify this speculation. PMID- 29162831 TI - Cisplatin is retained in the cochlea indefinitely following chemotherapy. AB - Cisplatin chemotherapy causes permanent hearing loss in 40-80% of treated patients. It is unclear whether the cochlea has unique sensitivity to cisplatin or is exposed to higher levels of the drug. Here we use inductively coupled plasma mass spectrometry (ICP-MS) to examine cisplatin pharmacokinetics in the cochleae of mice and humans. In most organs cisplatin is detected within one hour after injection, and is eliminated over the following days to weeks. In contrast, the cochlea retains cisplatin for months to years after treatment in both mice and humans. Using laser ablation coupled to ICP-MS, we map cisplatin distribution within the human cochlea. Cisplatin accumulation is consistently high in the stria vascularis, the region of the cochlea that maintains the ionic composition of endolymph. Our results demonstrate long-term retention of cisplatin in the human cochlea, and they point to the stria vascularis as an important therapeutic target for preventing cisplatin ototoxicity. PMID- 29162832 TI - The roles of plasticity versus dominance in maintaining polymorphism in mating strategies. AB - Although natural selection is expected to reduce variability, polymorphism is common in nature even under strong selective regimes. Discrete polymorphisms in mating strategies are widespread and offer a good opportunity to understand the genetic processes that allow the maintenance of polymorphism in relatively simple systems. Here we explored the genetic mechanism underlying the expression of discrete mating strategies in the rock-paper-scissors (RPS) game. Heterozygotes carry the genetic information for two different strategies, yet little attention has been devoted to the mechanisms underpinning heterozygote phenotype and its consequences for allele frequency dynamics. We explored the maintenance of polymorphism under 1) genetic dominance or 2) plasticity, as mechanisms driving the expression of alternative strategies in males. We developed an alternative mating strategy model and analysed allele frequency dynamics using time series analyses. Our results show that both genetic mechanisms can maintain polymorphism depending on population demographic characteristics but that plasticity can enhance the likelihood that polymorphism is maintained relative to dominance. Time series analysis on simulation outcomes show that the RPS game is mostly driven by a single strategy, but the importance of this strategy on long term dynamics is stronger when gene expression shows dominance rather than plasticity. PMID- 29162834 TI - Publisher Correction: Synthesis method of asymmetric gold particles. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29162833 TI - The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia. AB - Cytarabine (AraC) represents the most effective single agent treatment for AML. Nevertheless, overriding AraC resistance in AML remains an unmet medical need. Here we show that the CHK1 inhibitor (CHK1i) GDC-0575 enhances AraC-mediated killing of AML cells both in vitro and in vivo, thus abrogating any potential chemoresistance mechanisms involving DNA repair. Importantly, this combination of drugs does not affect normal long-term hematopoietic stem/progenitors. Moreover, the addition of CHK1i to AraC does not generate de novo mutations and in patients' samples where AraC is mutagenic, addition of CHK1i appears to eliminate the generation of mutant clones. Finally, we observe that persistent residual leukemic cells are quiescent and can become responsive to the treatment when forced into cycle via granulocyte colony-stimulating factor (G-CSF) administration. This drug combination (AraC+CHK1i+G-CSF) will open the doors for a more efficient treatment of AML in the clinic. PMID- 29162836 TI - Optically driven ultra-stable nanomechanical rotor. AB - Nanomechanical devices have attracted the interest of a growing interdisciplinary research community, since they can be used as highly sensitive transducers for various physical quantities. Exquisite control over these systems facilitates experiments on the foundations of physics. Here, we demonstrate that an optically trapped silicon nanorod, set into rotation at MHz frequencies, can be locked to an external clock, transducing the properties of the time standard to the rod's motion with a remarkable frequency stability f r/Deltaf r of 7.7 * 1011. While the dynamics of this periodically driven rotor generally can be chaotic, we derive and verify that stable limit cycles exist over a surprisingly wide parameter range. This robustness should enable, in principle, measurements of external torques with sensitivities better than 0.25 zNm, even at room temperature. We show that in a dilute gas, real-time phase measurements on the locked nanorod transduce pressure values with a sensitivity of 0.3%. PMID- 29162835 TI - A signal-amplifiable biochip quantifies extracellular vesicle-associated RNAs for early cancer detection. AB - Detection of extracellular vesicle (EV)-associated RNAs with low expression levels in early-stage cancer remains a challenge and is highly valuable. Here, we report a nanoparticle-based biochip that could capture circulating EVs without isolation, brighten encapsulated RNAs, and amplify fluorescence signals in situ in a single step. We confine catalyzed hairpin DNA circuit (CHDC) in cationic lipid-polymer hybrid nanoparticles (LPHNs) that are tethered on a chip. LPHN features a core-shell-corona structure that facilitates the transfer and mixing of CHDC with EV-associated RNAs when forming the LPHN-EV nanocomplex. CHDC is triggered upon target RNA binding and quickly generate amplified signals. The signal amplification efficiency of LPHN-CHDC is demonstrated in artificial EVs, cancer cells, and cancer cell-derived EVs. We show that LPHN-CHDC biochip with signal amplification capability could selectively and sensitively identify low expression glypican-1 mRNA in serum EVs, distinguishing patients with early- and late-stage pancreatic cancer from healthy donors and patients with benign pancreatic disease. PMID- 29162838 TI - Author Correction: Metabolic Biomarkers for Prognostic Prediction of Pre diabetes: results from a longitudinal cohort study. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29162837 TI - L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease. AB - Lysosomal storage disorders are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. 573C10 is a Schwann cell line derived from a mouse model of Niemann-Pick type C disease-1, NPC (-/-). Under serum-starved conditions, NPC (-/-) cells manifested impaired autophagy accompanied by an increase in the amount of p62 and lysosome enlargement. Addition of L-leucine to serum-starved NPC (-/-) cells ameliorated the enlargement of lysosomes and the p62 accumulation. Similar autophagy defects were observed in NPC (-/-) cells even without serum starvation upon the knockdown of Spinster-like 1 (SPNS1), a putative transporter protein thought to function in lysosomal recycling. Conversely, SPNS1 overexpression impeded the enlargement of lysosomes, p62 accumulation and mislocalization of the phosphorylated form of the mechanistic Target of rapamycin in NPC (-/-) cells. In addition, we found a reduction in endogenous SPNS1 expression in fibroblasts derived from NPC-1 patients compared with normal fibroblasts. We propose that SPNS1-dependent L leucine export across the lysosomal membrane is a key step for triggering autophagy, and that this mechanism is impaired in NPC-1. PMID- 29162839 TI - Hypoxia induces epithelial-mesenchymal transition in colorectal cancer cells through ubiquitin-specific protease 47-mediated stabilization of Snail: A potential role of Sox9. AB - During the metastatic phase, cancer cells require the dissolution of cadherin mediated cell-cell adhesion and a dramatic re-organization of the cytoskeleton through epithelial-mesenchymal transition (EMT), thereby acquiring migratory and invasive capabilities. In most tumors, EMT is accompanied by hypoxia. However, the intracellular signaling molecule that mediates hypoxia-induced EMT remained overlooked. By utilizing the microarray database system of the Cancer Genome Atlas, we identified ubiquitin-specific protease 47 (USP47), a deubiquitinating enzyme, as a potential mediator of hypoxia-induced EMT. Immunofluorescence staining of human colorectal tissue microarrays revealed that USP47 is overexpressed in colorectal adenocarcinoma tissues compared with normal adjacent tissues. The expression of USP47 was found to be elevated in three different human colorectal cancer cell lines. The enhancement of USP47 in colorectal cancer cells under hypoxic conditions induced the disassembly of E-cadherin and promoted EMT through deubiquitination of Snail. Silencing of USP47 accelerated the proteasomal degradation of Snail and inhibited EMT. Notably, hypoxia-induced USP47 upregulation was mediated by Sox9. These results demonstrate, for the first time, the role for USP47, as a novel target of Sox9, in the regulation of EMT and metastasis of colorectal cancer cells. PMID- 29162840 TI - Whey Protein Concentrate Renders MDA-MB-231 Cells Sensitive to Rapamycin by Altering Cellular Redox State and Activating GSK3beta/mTOR Signaling. AB - Whey protein concentrate (WPC) is an amino acid-rich supplement that has been shown to increase cellular antioxidant capacity. Mammalian target of rapamycin (mTOR) is a crucial regulator of signaling in mammalian cells, and serves as a therapeutic target for triple-negative breast cancer (TNBC). This study was designed to investigate the effect of combining WPC with rapamycin on MDA-MB-231 human breast cancer cells. These cells were found to be insensitive to rapamycin and exhibited higher glutathione (GSH) and reactive oxygen species levels than non-tumorigenic MCF-10A cells. However, for MDA-MB-231 cells, the half maximal inhibitory concentration of rapamycin was lower when this drug was administered in combination with WPC than when used alone. Furthermore, combining WPC with rapamycin depleted GSH levels and reduced Nrf2 nuclear accumulation. In addition, WPC activated GSK3beta/mTOR signaling, and GSK3beta appeared to be involved in the WPC-mediated Nrf2 reduction and mTOR activation. In conclusion, WPC induced rapamycin sensitivity in MDA-MB-231 cells by altering their redox state and activating GSK3beta/mTOR signaling. These results not only suggest a novel therapeutic approach for breast cancer treatment, but also provide insight into the critical pathways affecting the resistance to mTOR inhibition observed in a subgroup of TNBC patients. PMID- 29162841 TI - Detection of Somatic Mutations in Exome Sequencing of Tumor-only Samples. AB - Due to lack of normal samples in clinical diagnosis and to reduce costs, detection of small-scale mutations from tumor-only samples is required but remains relatively unexplored. We developed an algorithm (GATKcan) augmenting GATK with two statistics and machine learning to detect mutations in cancer. The averaged performance of GATKcan in ten experiments outperformed GATK in detecting mutations of randomly sampled 231 from 241 TCGA endometrial tumors (EC). In external validations, GATKcan outperformed GATK in TCGA breast cancer (BC), ovarian cancer (OC) and melanoma tumors, in terms of Matthews correlation coefficient (MCC) and precision, where MCC takes both sensitivity and specificity into account. Further, GATKcan reduced high fractions of false positives detected by GATK. In mutation detection of somatic variants, classified commonly by VarScan 2 and MuTect from the called variants in BC, OC and melanoma, ranked by adjusted MCC (adjusted precision) GATKcan was the top 1, followed by MuTect, VarScan 2 and GATK. Importantly, GATKcan enables detection of mutations when alternate alleles exist in normal samples. These results suggest that GATKcan trained by a cancer is able to detect mutations in future patients with the same type of cancer and is likely applicable to other cancers with similar mutations. PMID- 29162842 TI - Trophic position and dietary breadth of bats revealed by nitrogen isotopic composition of amino acids. AB - Bats perform important ecosystem services, but it remains difficult to quantify their dietary strategies and trophic position (TP) in situ. We conducted measurements of nitrogen isotopes of individual amino acids (delta 15NAA) and bulk-tissue carbon (delta 13Cbulk) and nitrogen (delta 15Nbulk) isotopes for nine bat species from different feeding guilds (nectarivory, frugivory, sanguivory, piscivory, carnivory, and insectivory). Our objective was to assess the precision of delta 15NAA-based estimates of TP relative to other approaches. TPs calculated from delta 15N values of glutamic acid and phenylalanine, which range from 8.3 33.10/00 and 0.7-15.40/00 respectively, varied between 1.8 and 3.8 for individuals of each species and were generally within the ranges of those anticipated based on qualitative dietary information. The delta 15NAA approach reveals variation in TP within and among species that is not apparent from delta 15Nbulk data, and delta 15NAA data suggest that two insectivorous species (Lasiurus noctivagans and Lasiurus cinereus) are more omnivorous than previously thought. These results indicate that bats exhibit a trophic discrimination factor (TDF) similar to other terrestrial organisms and that delta 15NAA provides a reliable approach for addressing questions about variation in the TP of bats that have heretofore proven elusive. PMID- 29162843 TI - Behavioral responses of honey bees (Apis mellifera) to natural and synthetic xenobiotics in food. AB - While the natural foods of the western honey bee (Apis mellifera) contain diverse phytochemicals, in contemporary agroecosystems honey bees also encounter pesticides as floral tissue contaminants. Whereas some ubiquitous phytochemicals in bee foods up-regulate detoxification and immunity genes, thereby benefiting nestmates, many agrochemical pesticides adversely affect bee health even at sublethal levels. How honey bees assess xenobiotic risk to nestmates as they forage is poorly understood. Accordingly, we tested nine phytochemicals ubiquitous in nectar, pollen, or propolis, as well as five synthetic xenobiotics that frequently contaminate hives-two herbicides (atrazine and glyphosate) and three fungicides (boscalid, chlorothalonil, and prochloraz). In semi-field free flight experiments, bees were offered a choice between paired sugar water feeders amended with either a xenobiotic or solvent only (control). Among the phytochemicals, foragers consistently preferred quercetin at all five concentrations tested, as evidenced by both visitation frequency and consumption rates. This preference may reflect the long evolutionary association between honey bees and floral tissues. Of pesticides eliciting a response, bees displayed a preference at specific concentrations for glyphosate and chlorothalonil. This paradoxical preference may account for the frequency with which these pesticides occur as hive contaminants and suggests that they present a greater risk factor for honey bee health than previously suspected. PMID- 29162844 TI - DNA nanomapping using CRISPR-Cas9 as a programmable nanoparticle. AB - Progress in whole-genome sequencing using short-read (e.g., <150 bp), next generation sequencing technologies has reinvigorated interest in high-resolution physical mapping to fill technical gaps that are not well addressed by sequencing. Here, we report two technical advances in DNA nanotechnology and single-molecule genomics: (1) we describe a labeling technique (CRISPR-Cas9 nanoparticles) for high-speed AFM-based physical mapping of DNA and (2) the first successful demonstration of using DVD optics to image DNA molecules with high speed AFM. As a proof of principle, we used this new "nanomapping" method to detect and map precisely BCL2-IGH translocations present in lymph node biopsies of follicular lymphoma patents. This HS-AFM "nanomapping" technique can be complementary to both sequencing and other physical mapping approaches. PMID- 29162845 TI - Helicobacter pylori targets mitochondrial import and components of mitochondrial DNA replication machinery through an alternative VacA-dependent and a VacA independent mechanisms. AB - Targeting mitochondria is a powerful strategy for pathogens to subvert cell physiology and establish infection. Helicobacter pylori is a bacterial pathogen associated with gastric cancer development that is known to target mitochondria directly and exclusively through its pro-apoptotic and vacuolating cytotoxin VacA. By in vitro infection of gastric epithelial cells with wild-type and VacA deficient H. pylori strains, treatment of cells with purified VacA proteins and infection of a mouse model, we show that H. pylori deregulates mitochondria by two novel mechanisms, both rather associated with host cell survival. First, early upon infection VacA induces transient increase of mitochondrial translocases and a dramatic accumulation of the mitochondrial DNA replication and maintenance factors POLG and TFAM. These events occur when VacA is not detected intracellularly, therefore do not require the direct interaction of the cytotoxin with the organelle, and are independent of the toxin vacuolating activity. In vivo, these alterations coincide with the evolution of gastric lesions towards severity. Second, H. pylori also induces VacA-independent alteration of mitochondrial replication and import components, suggesting the involvement of additional H. pylori activities in mitochondria-mediated effects. These data unveil two novel mitochondrial effectors in H. pylori-host interaction with links on gastric pathogenesis. PMID- 29162846 TI - Intensification of terrestrial carbon cycle related to El Nino-Southern Oscillation under greenhouse warming. AB - The El Nino/Southern Oscillation (ENSO) drives interannual variation in the global carbon cycle. However, the relationship between ENSO and the carbon cycle can be modulated by climate change due to anthropogenic forcing. We show herein that the sensitivity of the terrestrial carbon flux to ENSO will be enhanced under greenhouse warming by 44% ( +/- 15%), indicating a future amplification of carbon-climate interactions. Separating the contributions of the changes in carbon sensitivity reveals that the response of land surface temperature to ENSO and the sensitivity of gross primary production to local temperature are significantly enhanced under greenhouse warming, thereby amplifying the ENSO carbon-cycle coupling. In a warm climate, depletion of soil moisture increases temperature response in a given ENSO event. These findings suggest that the ENSO related carbon cycle will be enhanced by hydroclimate changes caused by anthropogenic forcing. PMID- 29162847 TI - Clinical and immunopathological findings during long term follow-up in Leishmania infantum experimentally infected dogs. AB - Canine Visceral Leishmaniasis (CVL) is caused by Leishmania infantum, which in the New World is transmitted by Lutzomyia longipalpis. While prospective clinical and immunological assessments of dogs experimentally challenged with L. infantum have been previously reported over a relatively short follow-up period, the long term characterization of infected animals has not been performed to date. We evaluated dogs in a subclinical state for six years following experimental infection with L. infantum and Lu. longipalpis saliva, via an intradermal route, to characterize clinical, parasitological and immunological parameters arising from L. infantum experimental infection. We also assess these parameters in a group of naturally infected animals. The immune profiles of the experimentally and naturally infected animals exhibited increases of IFN-gamma, IL-6 and IL-18, and decreases in TNF, IL-2, IL-8 and CXCL1, compared to controls. Our results indicate that over a six-year follow-up post-challenge, subclinically infected dogs presented low CVL clinical scores despite the persistence of Leishmania parasites in the lymph nodes, spleen and skin. Similarities observed among immune profiles in the context of experimental and natural infection seem to suggest that an enduring activation of the host immune response may lead to the control of parasite growth, thereby limiting disease severity. PMID- 29162848 TI - miRDDCR: a miRNA-based method to comprehensively infer drug-disease causal relationships. AB - Revealing the cause-and-effect mechanism behind drug-disease relationships remains a challenging task. Recent studies suggested that drugs can target microRNAs (miRNAs) and alter their expression levels. In the meanwhile, the inappropriate expression of miRNAs will lead to various diseases. Therefore, targeting specific miRNAs by small-molecule drugs to modulate their activities provides a promising approach to human disease treatment. However, few studies attempt to discover drug-disease causal relationships through the molecular level of miRNAs. Here, we developed a miRNA-based inference method miRDDCR to comprehensively predict drug-disease causal relationships. We first constructed a three-layer drug-miRNA-disease heterogeneous network by combining similarity measurements, existing drug-miRNA associations and miRNA-disease associations. Then, we extended the algorithm of Random Walk to the three-layer heterogeneous network and ranked the potential indications for drugs. Leave-one-out cross validations and case studies demonstrated that our method miRDDCR can achieve excellent prediction power. Compared with related methods, our causality discovery-based algorithm showed superior prediction ability and highlighted the molecular basis miRNAs, which can be used to assist in the experimental design for drug development and disease treatment. Finally, comprehensively inferred drug-disease causal relationships were released for further studies. PMID- 29162849 TI - Erratum: Chlamydia trachomatis neither exerts deleterious effects on spermatozoa nor impairs male fertility. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29162851 TI - Results of a 15-year systematic survey of commensal rodents in English dwellings. AB - Population trends for commensal rodents are the subject of interest and speculation but accurate data are rarely available. Here we report data from a 15 year systematic survey of rats and mice in English dwellings and present national level estimates of prevalence for 1996-2010. We found evidence for peaks in prevalence of mice inside and rats around dwellings in 2002 and 2008. Models containing twelve variables relating to the dwelling and local area explained some but not all of the variation in prevalence. Older dwellings, those in rural areas, those with litter, drainage faults and pets or other animals outdoors tended to have higher levels of rodent prevalence. Regional differences were found but there were no seasonal trends apart from lower prevalence of mice during summer. Rodent prevalence was generally higher in rented (compared to owner-occupied) dwellings, although apparently not due to reduced tendency to carry out rodent control. The percentage of households having taken some form of action against active rodent problems varied according to prevalence at the national level, and therefore appropriate data on number of rodent control treatments carried out each year could likely act as a useful index of household rodent prevalence. PMID- 29162852 TI - Predicting nosocomial lower respiratory tract infections by a risk index based system. AB - Although belonging to one of the most common type of nosocomial infection, there was currently no simple prediction model for lower respiratory tract infections (LRTIs). This study aims to develop a risk index based system for predicting nosocomial LRTIs based on data from a large point-prevalence survey. Among the 49328 patients included, the prevalence of nosocomial LRTIs was 1.70% (95% confidence interval [CI], 1.64% to 1.76%). The areas under the receiver operating characteristic (ROC) curve for logistic regression and fisher discriminant analysis were 0.907 (95% CI, 0.897 to 0.917) and 0.902 (95% CI, 0.892 to 0.912), respectively. The constructed risk index based system also displayed excellent discrimination (area under the ROC curve: 0.905 [95% CI, 0.895 to 0.915]) to identify LRTI in internal validation. Six risk levels were generated according to the risk score distribution of study population, ranging from 0 to 5, the corresponding prevalence of nosocomial LRTIs were 0.00%, 0.39%, 3.86%, 12.38%, 28.79% and 44.83%, respectively. The sensitivity and specificity of prediction were 0.87 and 0.79, respectively, when the best cut-off point of risk score was set to 14. Our study suggested that this newly constructed risk index based system might be applied to boost more rational infection control programs in clinical settings. PMID- 29162853 TI - IGF-1-mediated PKM2/beta-catenin/miR-152 regulatory circuit in breast cancer. AB - Dysregulation of miRNAs is important in breast cancer initiation and malignant progression. Recently we showed that miR-152 downregulation is associated with breast cancer development, yet the underlying mechanism of miR-152 remains to be well elucidated. In this study, we identified beta-catenin as a new direct target of miR-152. MiR-152 inhibited cell proliferation by targeting and inhibiting both beta-catenin and PKM2 expression. We found that miR-152 expression sensitized the breast cancer cells to paclitaxel treatment by inhibiting beta-catenin and PKM2 expression. Intriguingly, IGF-1 induced beta-catenin and PKM2 expression and enhanced beta-catenin and PKM2 interaction. Subsequently, IGF-1-induced beta catenin and PKM2 complex translocated into the nucleus, which in turn activated expression of miR-152. These results suggested a regulatory circuit between miR 152, beta-catenin and PKM2 in breast cancer. By using human clinical specimens, we also showed that miR-152 expression levels were negatively correlated with beta-catenin and PKM2 levels in breast cancer tissues. Our findings provide new insights into a mechanism of miR-152 involved in beta-catenin and PKM2 inhibition which would have clinical implication for the cancer development and new treatment option in the future. PMID- 29162850 TI - Whole Exome Sequencing reveals new candidate genes in host genomic susceptibility to Respiratory Syncytial Virus Disease. AB - Respiratory syncytial virus (RSV) is an important cause of serious lower respiratory tract disease in infants. Several studies have shown evidence pointing to the genome of the host as an important factor determining susceptibility to respiratory disease caused by RSV. We sequenced the complete exomes of 54 patients infected by RSV that needed hospitalization due to development of severe bronchiolitis. The Iberian sample (IBS) from The 1000 Genomes Project (1000G) was used as control group; all the association results were pseudo-replicated using other 1000G-European controls and Spanish controls. The study points to SNP rs199665292 in the olfactory receptor (OR) gene OR13C5 as the best candidate variant (P-value = 1.16 * 10-12; OR = 5.56). Genetic variants at HLA genes (HLA-DQA1, HLA-DPB1), and in the mucin 4 gene (MUC4) also emerge as susceptibility candidates. By collapsing rare variants in genes and weighing by pathogenicity, we obtained confirmatory signals of association in the OR gene OR8U1/OR8U8, the taste receptor TAS2R19, and another mucin gene (MUC6). Overall, we identified new predisposition variants and genes related to RSV infection. Of special interest is the association of RSV to olfactory and taste receptors; this finding is in line with recent evidence pointing to their role in viral infectious diseases. PMID- 29162854 TI - Human eye-inspired soft optoelectronic device using high-density MoS2-graphene curved image sensor array. AB - Soft bioelectronic devices provide new opportunities for next-generation implantable devices owing to their soft mechanical nature that leads to minimal tissue damages and immune responses. However, a soft form of the implantable optoelectronic device for optical sensing and retinal stimulation has not been developed yet because of the bulkiness and rigidity of conventional imaging modules and their composing materials. Here, we describe a high-density and hemispherically curved image sensor array that leverages the atomically thin MoS2 graphene heterostructure and strain-releasing device designs. The hemispherically curved image sensor array exhibits infrared blindness and successfully acquires pixelated optical signals. We corroborate the validity of the proposed soft materials and ultrathin device designs through theoretical modeling and finite element analysis. Then, we propose the ultrathin hemispherically curved image sensor array as a promising imaging element in the soft retinal implant. The CurvIS array is applied as a human eye-inspired soft implantable optoelectronic device that can detect optical signals and apply programmed electrical stimulation to optic nerves with minimum mechanical side effects to the retina. PMID- 29162855 TI - Three Dimensional Honeycomb Patterned Fibrinogen Based Nanofibers Induce Substantial Osteogenic Response of Mesenchymal Stem Cells. AB - Stem cells therapy offers a viable alternative for treatment of bone disorders to the conventional bone grafting. However clinical therapies are still hindered by the insufficient knowledge on the conditions that maximize stem cells differentiation. Hereby, we introduce a novel 3D honeycomb architecture scaffold that strongly support osteogenic differentiation of human adipose derived mesenchymal stem cells (ADMSCs). The scaffold is based on electrospun hybrid nanofibers consisting of poly (L-lactide epsilon-caprolactone) and fibrinogen (PLCL/FBG). Classical fibers orientations, random or aligned were also produced and studied for comparison. The overall morphology of ADMSC's generally followed the nanofibers orientation and dimensionality developing regular focal adhesions and direction-dependent actin cytoskeleton bundles. However, there was an initial tendency for cells rounding on honeycomb scaffolds before ADMSCs formed a distinct bridging network. This specific cells organization appeared to have significant impact on the differentiation potential of ADMSCs towards osteogenic lineage, as indicated by the alkaline phosphatase production, calcium deposition and specific genes expression. Collectively, it was observed synergistic effect of nanofibers with honeycomb architecture on the behavior of ADMSCs entering osteogenic path of differentiation which outlines the potential benefits from insertion of such bioinspired geometrical cues within scaffolds for bone tissue engineering. PMID- 29162856 TI - An organic fluorophore-nanodiamond hybrid sensor for photostable imaging and orthogonal, on-demand biosensing. AB - Organic fluorescent probes are widely used to detect key biomolecules; however, they often lack the photostability required for extended intracellular imaging. Here we report a new hybrid nanomaterial (peroxynanosensor, PNS), consisting of an organic fluorescent probe bound to a nanodiamond, that overcomes this limitation to allow concurrent and extended cell-based imaging of the nanodiamond and ratiometric detection of hydrogen peroxide. Far-red fluorescence of the nanodiamond offers continuous monitoring without photobleaching, while the green fluorescence of the organic fluorescent probe attached to the nanodiamond surface detects hydrogen peroxide on demand. PNS detects basal production of hydrogen peroxide within M1 polarised macrophages and does not affect macrophage growth during prolonged co-incubation. This nanosensor can be used for extended bio imaging not previously possible with an organic fluorescent probe, and is spectrally compatible with both Hoechst 33342 and MitoTracker Orange stains for hyperspectral imaging. PMID- 29162857 TI - Temporal expression pattern of genes during the period of sex differentiation in human embryonic gonads. AB - The precise timing and sequence of changes in expression of key genes and proteins during human sex-differentiation and onset of steroidogenesis was evaluated by whole-genome expression in 67 first trimester human embryonic and fetal ovaries and testis and confirmed by qPCR and immunohistochemistry (IHC). SRY/SOX9 expression initiated in testis around day 40 pc, followed by initiation of AMH and steroidogenic genes required for androgen production at day 53 pc. In ovaries, gene expression of RSPO1, LIN28, FOXL2, WNT2B, and ETV5, were significantly higher than in testis, whereas GLI1 was significantly higher in testis than ovaries. Gene expression was confirmed by IHC for GAGE, SOX9, AMH, CYP17A1, LIN28, WNT2B, ETV5 and GLI1. Gene expression was not associated with the maternal smoking habits. Collectively, a precise temporal determination of changes in expression of key genes involved in human sex-differentiation is defined, with identification of new genes of potential importance. PMID- 29162858 TI - BdorOBP2 plays an indispensable role in the perception of methyl eugenol by mature males of Bactrocera dorsalis (Hendel). AB - Bactrocera dorsalis (Hendel) is a fruit-eating pest that causes substantial economic damage to the fresh produce industry in tropical and sub-tropical countries. Methyl eugenol (ME) is a powerful attractant for mature males of B. dorsalis, and has been widely used for detecting, luring and eradicating B. dorsalis populations worldwide. However, the molecular mechanism underlying the olfactory perception of ME remains largely unknown. Here, we analyzed the differential proteomics profiling of the antennae between ME-responsive and ME non-responsive males by using isobaric tags for relative and absolute quantitation (iTRAQ). In total, 4622 proteins were identified, of which 277 proteins were significant differentially expressed, with 192 up-regulated and 85 down-regulated in responsive male antennae. Quantitative real-time PCR (qRT-PCR) analysis confirmed the authenticity and accuracy of the proteomic analysis. Based on the iTRAQ and qRT-PCR results, we found that the odorant-binding protein 2 (BdorOBP2) was abundantly expressed in responsive male antennae. Moreover, BdorOBP2 was significantly up-regulated by ME in male antennae. Mature males showed significantly greater taxis toward ME than did mature females. Silencing BdorOBP2 reduced mature males' responsiveness to ME. These results indicate that BdorOBP2 may play an essential role in the molecular mechanism underlying B. dorsalis olfactory perception of ME. PMID- 29162859 TI - Ferroquine, the next generation antimalarial drug, has antitumor activity. AB - Despite the tremendous progress in medicine, cancer remains one of the most serious global health problems awaiting new effective therapies. Here we present ferroquine (FQ), the next generation antimalarial drug, as a promising candidate for repositioning as cancer therapeutics. We report that FQ potently inhibits autophagy, perturbs lysosomal function and impairs prostate tumor growth in vivo. We demonstrate that FQ negatively regulates Akt kinase and hypoxia-inducible factor-1alpha (HIF-1alpha) and is particularly effective in starved and hypoxic conditions frequently observed in advanced solid cancers. FQ enhances the anticancer activity of several chemotherapeutics suggesting its potential application as an adjuvant to existing anticancer therapy. Alike its parent compound chloroquine (CQ), FQ accumulates within and deacidifies lysosomes. Further, FQ induces lysosomal membrane permeabilization, mitochondrial depolarization and caspase-independent cancer cell death. Overall, our work identifies ferroquine as a promising new drug with a potent anticancer activity. PMID- 29162861 TI - New insight on the structural features of the cytotoxic auristatins MMAE and MMAF revealed by combined NMR spectroscopy and quantum chemical modelling. AB - Antibody-drug conjugates (ADCs) are emerging as a promising class of selective drug delivery systems in the battle against cancer and other diseases. The auristatins monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) appear as the cytotoxic drug in almost half of the state-of-the-art ADCs on the market or in late stage clinical trials. Here, we present the first complete NMR spectroscopic characterisation of these challenging molecules, and investigate their structural properties by a combined NMR and quantum chemical modelling approach. We find that in solution, half of the drug molecules are locked in an inactive conformation, severely decreasing their efficiency, and potentially increasing the risk of side-effects. Furthermore, we identify sites susceptible to future modification, in order to potentially improve the performance of these drugs. PMID- 29162860 TI - Transcriptomics reveals multiple resistance mechanisms against cotton leaf curl disease in a naturally immune cotton species, Gossypium arboreum. AB - Cotton leaf curl disease (CLCuD), caused by cotton leaf curl viruses (CLCuVs), is among the most devastating diseases in cotton. While the widely cultivated cotton species Gossypium hirsutum is generally susceptible, the diploid species G. arboreum is a natural source for resistance against CLCuD. However, the influence of CLCuD on the G. arboreum transcriptome and the interaction of CLCuD with G. arboreum remains to be elucidated. Here we have used an RNA-Seq based study to analyze differential gene expression in G. arboreum under CLCuD infestation. G. arboreum plants were infested by graft inoculation using a CLCuD infected scion of G. hirsutum. CLCuD infested asymptomatic and symptomatic plants were analyzed with RNA-seq using an Illumina HiSeq. 2500. Data analysis revealed 1062 differentially expressed genes (DEGs) in G. arboreum. We selected 17 genes for qPCR to validate RNA-Seq data. We identified several genes involved in disease resistance and pathogen defense. Furthermore, a weighted gene co-expression network was constructed from the RNA-Seq dataset that indicated 50 hub genes, most of which are involved in transport processes and might have a role in the defense response of G. arboreum against CLCuD. This fundamental study will improve the understanding of virus-host interaction and identification of important genes involved in G. arboreum tolerance against CLCuD. PMID- 29162862 TI - TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity. AB - STAT3 is a pleiotropic transcription factor involved in homeostatic and host defense processes in the human body. It is activated by numerous cytokines and growth factors and generates a series of cellular effects. Of the STAT-mediated signal transduction pathways, STAT3 transcriptional control is best understood. Jak kinase dependent activation of STAT3 relies on Y705 phosphorylation triggering a conformational switch that is stabilized by intermolecular interactions between SH2 domains and the pY705 motif. We here show that a second tyrosine phosphorylation within the SH2 domain at position Y640, induced by Tyk2, negatively controls STAT3 activity. The Y640F mutation leads to stabilization of activated STAT3 homodimers, accelerated nuclear translocation and superior transcriptional activity following IL-6 and LIF stimulation. Moreover, it unlocks type I IFN-dependent STAT3 signalling in cells that are normally refractory to STAT3 transcriptional activation. PMID- 29162863 TI - Pulse frequency dependency of photobiomodulation on the bioenergetic functions of human dental pulp stem cells. AB - Photobiomodulation (PBM) therapy contributes to pain relief, wound healing, and tissue regeneration. The pulsed wave (PW) mode has been reported to be more effective than the continuous wave (CW) mode when applying PBM to many biological systems. However, the reason for the higher effectiveness of PW-PBM is poorly understood. Herein, we suggest using delayed luminescence (DL) as a reporter of mitochondrial activity after PBM treatment. DL originates mainly from mitochondrial electron transport chain systems, which produce reactive oxygen species (ROS) and adenosine triphosphate (ATP). The decay time of DL depends on the pulse frequencies of applied light, which correlate with the biological responses of human dental pulp stem cells (hDPSCs). Using a low-power light whose wavelength is 810 nm and energy density is 38 mJ/cm2, we find that a 300-Hz pulse frequency prolonged the DL pattern and enhanced alkaline phosphatase activity. In addition, we analyze mitochondrial morphological changes and their volume density and find evidence supporting mitochondrial physiological changes from PBM treatment. Our data suggest a new methodology for determining the effectiveness of PBM and the specific pulse frequency dependency of PBM in the differentiation of hDPSCs. PMID- 29162864 TI - Dual-Mode Manipulating Multicenter Photoluminescence in a Single-Phased Ba9Lu2Si6O24:Bi3+, Eu3+ Phosphor to Realize White Light/Tunable Emissions. AB - A Bi3+ and Eu3+ ion co-doped Ba9Lu2Si6O24 single-phased phosphor was synthesized successfully via a conventional high-temperature solid-state reaction. X-ray diffraction, crystal structure analysis, diffuse reflectance and luminescent spectra, quantum efficiency measurements, and thermal stability analysis were applied to investigate the phase, structure, luminescent and thermal stability properties. From the analyses of the crystal structure and luminescent spectra, we observed four discernible Bi3+ luminescent centers with peaks at ~363.3, ~403.1, ~437.7, and ~494.5 nm. Moreover, due to the complex energy transfer processes among these Bi3+ centers, their relative emission intensity tightly depended on the incident excitation wavelength. Interestingly, the as-prepared phosphor could generate warm white light/tunable emission by changing the concentration of Eu3+ ions or adjusting the excitation wavelength. The energy transfer mechanism from Bi3+ to Eu3+ was confirmed via an electric dipole-dipole interaction, the energy transfer efficiencies [Formula: see text] from Bi3+ to Eu3+ were 50.84% and 40.17% monitoring at 410 and 485 nm, respectively. The internal quantum efficiency of the optimized Ba9Lu2Si6O24:Bi3+, Eu3+ phosphor was calculated to be 42.6%. In addition, the configurational coordinate model was carried out to explain the energy decrease of the phonon-electron coupling effect. PMID- 29162865 TI - GABA A Receptor Coupling Junction and Pore GABRB3 Mutations are Linked to Early Onset Epileptic Encephalopathy. AB - GABAA receptors are brain inhibitory chloride ion channels. Here we show functional analyses and structural simulations for three de novo missense mutations in the GABAA receptor beta3 subunit gene (GABRB3) identified in patients with early-onset epileptic encephalopathy (EOEE) and profound developmental delay. We sought to obtain insights into the molecular mechanisms that might link defects in GABAA receptor biophysics and biogenesis to patients with EOEE. The mutant residues are part of conserved structural domains such as the Cys-loop (L170R) and M2-M3 loop (A305V) that form the GABA binding/channel gating coupling junction and the channel pore (T288N), which are functionally coupled during receptor activation. The mutant coupling junction residues caused rearrangements and formation of new hydrogen bonds in the open state, while the mutant pore residue reshaped the pore cavity. Whereas mutant coupling junction residues uncoupled during activation and caused gain of function, the mutant pore residue favoured low conductance receptors and differential sensitivity to diazepam and loss of function. These data reveal novel molecular mechanisms by which EOEE-linked mutations affect GABAA receptor function. PMID- 29162866 TI - Trophic and tectonic limits to the global increase of marine invertebrate diversity. AB - The marine invertebrate fossil record provides the most comprehensive history of how the diversity of animal life has evolved through time. One of the main features of this record is a modest rise in diversity over nearly a half-billion years. The long-standing view is that ecological interactions such as resource competition and predation set upper limits to global diversity, which, in the absence of external perturbations, is maintained indefinitely at equilibrium. However, the effect of mechanisms associated with the history of the seafloor, and their influence on the creation and destruction of marine benthic habitats, has not been explored. Here we use statistical methods for causal inference to investigate the drivers of marine invertebrate diversity dynamics through the Phanerozoic. We find that diversity dynamics responded to secular variations in marine food supply, substantiating the idea that global species richness is regulated by resource availability. Once diversity was corrected for changes in food resource availability, its dynamics were causally linked to the age of the subducting oceanic crust. We suggest that the time elapsed between the formation (at mid-ocean ridges) and destruction (at subduction zones) of ocean basins influences the diversity dynamics of marine invertebrates and may have contributed to constrain their diversification. PMID- 29162867 TI - Broad-spectrum antiviral agents: secreted phospholipase A2 targets viral envelope lipid bilayers derived from the endoplasmic reticulum membrane. AB - Hepatitis C virus (HCV), dengue virus (DENV) and Japanese encephalitis virus (JEV) belong to the family Flaviviridae. Their viral particles have the envelope composed of viral proteins and a lipid bilayer acquired from budding through the endoplasmic reticulum (ER). The phospholipid content of the ER membrane differs from that of the plasma membrane (PM). The phospholipase A2 (PLA2) superfamily consists of a large number of members that specifically catalyse the hydrolysis of phospholipids at a particular position. Here we show that the CM-II isoform of secreted PLA2 obtained from Naja mossambica mossambica snake venom (CM-II-sPLA2) possesses potent virucidal (neutralising) activity against HCV, DENV and JEV, with 50% inhibitory concentrations (IC50) of 0.036, 0.31 and 1.34 ng/ml, respectively. In contrast, the IC50 values of CM-II-sPLA2 against viruses that bud through the PM (Sindbis virus, influenza virus and Sendai virus) or trans Golgi network (TGN) (herpes simplex virus) were >10,000 ng/ml. Moreover, the 50% cytotoxic (CC50) and haemolytic (HC50) concentrations of CM-II-sPLA2 were >10,000 ng/ml, implying that CM-II-sPLA2 did not significantly damage the PM. These results suggest that CM-II-sPLA2 and its derivatives are good candidates for the development of broad-spectrum antiviral drugs that target viral envelope lipid bilayers derived from the ER membrane. PMID- 29162868 TI - Via mucosa incision EUS-guided sampling for the diagnosis of conventional endoscopic biopsy-negative gastric wall thickening. AB - Abnormal thickened lesions of the gastric wall are usually covered with normal mucosa. Conventional endoscopic biopsies often do not yield sufficient positive histological results for clinical treatment. To increase the rate of diagnosis of conventional endoscopic biopsy-negative gastric wall thickening, we used an endoscopic submucosal dissection (ESD)-like sampling method under endoscopic ultrasound (EUS) guidance to obtain tissue of gastric wall-thickening lesions. Between 2012 and 2016, patients with gastric wall thickening (as identified by computed tomography (CT), EUS or other imaging methods that showed no positive findings in repeating conventional endoscopic biopsy) underwent via mucosa incision EUS-guided sampling. Final diagnosis was determined after surgical or biopsy pathology. A total of 10 patients with gastric wall thickening were included in this study. Eight cases received definite results, whereas in two cases the biopsy results were ambiguous and in these two patients poorly differentiated adenocarcinoma was determined by postoperative pathology. The results of the cases presented in this study demonstrated that via mucosa incision EUS-guided sampling provided a complementary option for the diagnosis of conventional endoscopic biopsy-negative gastric wall thickening. PMID- 29162869 TI - Novel, one-step synthesis of zwitterionic polymer nanoparticles via distillation precipitation polymerization and its application for dye removal membrane. AB - In this work, poly(MBAAm-co-SBMA) zwitterionic polymer nanoparticles were synthesized in one-step via distillation-precipitation polymerization (DPP) and were characterized. [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA) as monomer and N, N'-methylene bis(acrylamide) (MBAAm) as cross linker are used for the synthesis of nanoparticles. As far as our knowledge, this is the first such report on the synthesis of poly(MBAAm-co-SBMA) nanoparticles via DPP. The newly synthesized nanoparticles were further employed for the surface modification of polysulfone (PSF) hollow fiber membranes for dye removal. The modified hollow fiber membrane exhibited the improved permeability (56 L/ m2 h bar) and dye removal (>98% of Reactive Black 5 and >80.7% of Reactive orange 16) with the high permeation of salts. Therefore, the as-prepared membrane can have potential application in textile and industrial wastewater treatment. PMID- 29162870 TI - HDL particles incorporate into lipid bilayers - a combined AFM and single molecule fluorescence microscopy study. AB - The process, how lipids are removed from the circulation and transferred from high density lipoprotein (HDL) - a main carrier of cholesterol in the blood stream - to cells, is highly complex. HDL particles are captured from the blood stream by the scavenger receptor, class B, type I (SR-BI), the so-called HDL receptor. The details in subsequent lipid-transfer process, however, have not yet been completely understood. The transfer has been proposed to occur directly at the cell surface across an unstirred water layer, via a hydrophobic channel in the receptor, or after HDL endocytosis. The role of the target lipid membrane for the transfer process, however, has largely been overlooked. Here, we studied at the single molecule level how HDL particles interact with synthetic lipid membranes. Using (high-speed) atomic force microscopy and fluorescence correlation spectroscopy (FCS) we found out that, upon contact with the membrane, HDL becomes integrated into the lipid bilayer. Combined force and single molecule fluorescence microscopy allowed us to directly monitor the transfer process of fluorescently labelled amphiphilic lipid probe from HDL particles to the lipid bilayer upon contact. PMID- 29162872 TI - European catfish (Silurus glanis) as a freshwater apex predator drives ecosystem via its diet adaptability. AB - Apex predators play a key role in ecosystem stability across environments but their numbers in general are decreasing. By contrast, European catfish (Silurus glanis), the European freshwater apex predator, is on the increase. However, studies concerning apex predators in freshwaters are scarce in comparison to those in terrestrial and marine ecosystems. The present study combines stomach content and stable isotope analyses with diet preferences of catfish to reveal its impact on the ecosystem since stocking. Catfish niche width is extremely wide in comparison to the typical model predator, Northern pike (Esox lucius). Catfish and pike have different individual dietary specialization that results in different functional roles in coupling or compartmentalizing distinct food webs. The role of both species in the ecosystem is irreplaceable due to multiple predator effects. The impact of catfish is apparent across the entire aquatic ecosystem, but herbivores are the most affected ecological group. The key feature of catfish, and probably a common feature of apex predators in general, is utilization of several dietary strategies by individuals within a population: long-term generalism or specialization and also short-term specialization. Catfish, similar to other large-bodied apex predators, have two typical features: enormous generalism and adaptability to new prey sources. PMID- 29162871 TI - Allometric scaling of skin thickness, elasticity, viscoelasticity to mass for micro-medical device translation: from mice, rats, rabbits, pigs to humans. AB - Emerging micro-scale medical devices are showing promise, whether in delivering drugs or extracting diagnostic biomarkers from skin. In progressing these devices through animal models towards clinical products, understanding the mechanical properties and skin tissue structure with which they interact will be important. Here, through measurement and analytical modelling, we advanced knowledge of these properties for commonly used laboratory animals and humans (~30 g to ~150 kg). We hypothesised that skin's stiffness is a function of the thickness of its layers through allometric scaling, which could be estimated from knowing a species' body mass. Results suggest that skin layer thicknesses are proportional to body mass with similar composition ratios, inter- and intra-species. Experimental trends showed elastic moduli increased with body mass, except for human skin. To interpret the relationship between species, we developed a simple analytical model for the bulk elastic moduli of skin, which correlated well with experimental data. Our model suggest that layer thicknesses may be a key driver of structural stiffness, as the skin layer constituents are physically and therefore mechanically similar between species. Our findings help advance the knowledge of mammalian skin mechanical properties, providing a route towards streamlined micro-device research and development onto clinical use. PMID- 29162873 TI - Rapid in situ imaging and whole genome sequencing of biofilm in neonatal feeding tubes: A clinical proof of concept. AB - The bacterial flora of nasogastric feeding tubes and faecal samples were analysed for a low-birth weight (725 g) neonate EGA 25 weeks in intensive care. Samples were collected at age 6 and 8 weeks of life. Optical coherence tomography (OCT) was used to visualise bacterial biofilms inside the nasogastric feeding tubes. The biofilm was heterogeneously distributed along the tube lumen wall, and had a depth of up to 500 um. The bacterial biofilm and faecal samples included Enterococcus faecalis and Enterobacter hormaechei. Representative strains, recovered from both feeding tubes and faecal samples, were whole genome sequenced using Illumina, Mi-Seq, which revealed indistinguishable strains, each with less than 28 SNP differences, of E. faecalis and E. hormaechei. The E. faecalis strains were from two sequence types (ST191 and ST211) and encoded for a number of traits related to biofilm formation (BopD), adherence (Epb pili), virulence (cps loci, gelatinase, SprE) and antibiotic resistances (IsaA, tetM). The E. hormaechei were all ST106, and encoded for blaACT-15 beta-lactamase and fosfomycin resistance (fosA). This proof of concept study demonstrates that bacterial flora within the neonatal feeding tubes may influence the bacterial colonisation of the intestinal tract and can be visualised non-destructively using OCT. PMID- 29162874 TI - Information processing in the NF-kappaB pathway. AB - The NF-kappaB pathway is known to transmit merely 1 bit of information about stimulus level. We combined experimentation with mathematical modeling to elucidate how information about TNF concentration is turned into a binary decision. Using Kolmogorov-Smirnov distance, we quantified the cell's ability to discern 8 TNF concentrations at each step of the NF-kappaB pathway, to find that input discernibility decreases as signal propagates along the pathway. Discernibility of low TNF concentrations is restricted by noise at the TNF receptor level, whereas discernibility of high TNF concentrations it is restricted by saturation/depletion of downstream signaling components. Consequently, signal discernibility is highest between 0.03 and 1 ng/ml TNF. Simultaneous exposure to TNF or LPS and a translation inhibitor, cycloheximide, leads to prolonged NF-kappaB activation and a marked increase of transcript levels of NF-kappaB inhibitors, IkappaBalpha and A20. The impact of cycloheximide becomes apparent after the first peak of nuclear NF-kappaB translocation, meaning that the NF-kappaB network not only relays 1 bit of information to coordinate the all-or-nothing expression of early genes, but also over a longer time course integrates information about other stimuli. The NF-kappaB system should be thus perceived as a feedback-controlled decision-making module rather than a simple information transmission channel. PMID- 29162875 TI - Effect of aerobic exercise and diet on liver fat in pre-diabetic patients with non-alcoholic-fatty-liver-disease: A randomized controlled trial. AB - The study aimed to assess whether aerobic exercise (AEx) training and a fibre enriched diet can reduce hepatic fat content (HFC) and increase glycaemic control in pre-diabetic patients with non-alcoholic fatty liver disease (NAFLD). Six hundred-and-three patients from seven clinics in Yangpu district, Shanghai, China were recruited. Of them 115 individuals aged 50-65-year fulfilled the inclusion criteria (NAFLD with impaired fasting glucose or impaired glucose tolerance) and were randomly assigned into exercise (AEx n = 29), diet (Diet n = 28), exercise plus diet (AED n = 29), or no-intervention (NI n = 29) groups. Progressive supervised AEx training (60-75% VO2max intensity) was given 2-3 times/week in 30 60 min/sessions, and the diet intervention was provided as lunch with 38% carbohydrate and diet fibre of 12 g/day for 8.6-month. HFC was assessed by 1H MRS. We found that HFC was significantly reduced in the AEx (-24.4%), diet ( 23.2%), and AED (-47.9%) groups by contrast to the 20.9% increase in the NI group (p = 0.001 for all) after intervention. However, only AED group significantly decreased HbA1c (-4.4%, p = 0.01) compared with the NI group (-0.6%). Aerobic exercise training combined with fibre-enriched diet can reduce HFC more effectively than either exercise or increased fibre-intake alone in pre-diabetic patients with NAFLD. PMID- 29162877 TI - Energy Reduction Effect of the South-to-North Water Diversion Project in China. AB - The North China Plain, with a population of approximately 150 million, is facing severe water scarcity. The over-exploitation of groundwater in the region, with accumulation amounts reaching more than 150 billion m3, causes a series of hydrological and geological problems together with the consumption of a significant amount of energy. Here, we highlight the energy and greenhouse gas related environmental co-benefits of the South-to-North Water Diversion Project (SNWDP). Moreover, we evaluate the energy-saving effect of SNWDP on groundwater exploitation based on the groundwater-exploitation reduction program implemented by the Chinese government. Our results show that the transferred water will replace about 2.97 billion m3 of exploited groundwater in the water reception area by 2020 and hence reduce energy consumption by 931 million kWh. Further, by 2030, 6.44 billion m3 of groundwater, which accounts for 27% of the current groundwater withdrawal, will save approximately 7% of Beijing's current thermal power generation output. PMID- 29162876 TI - Transcriptome analysis of the salivary glands of the grain aphid, Sitobion avenae. AB - Aphid saliva plays important roles in aphid-host interactions, such as assisting aphid digestion, detoxification, activating or suppressing plant defenses. The grain aphid, Sitobion avenae, is one of the most devastating pests of cereals worldwide. In this study, we performed the transcriptome analysis of salivary glands of S. avenae. A total of 33,079 assembled unigenes were identified in the salivary glands of aphids. Of the all obtained unigenes, 15,833(47.86%) and 10,829(32.73%) unigenes showed high similarity to known proteins in Nr and Swiss Prot databases respectively. 526 unigenes were predicted to encode secretory proteins, including some digestive and detoxifying enzymes and potential effectors. The RT-PCR and RT-qPCR results showed that all of the 15 most highly expressed putative secretory proteins specifically expressed in salivary glands. Interestingly, 11 of the 15 most highly expressed putative secretory proteins were still not matched to function-known proteins. We also detected the expression of 9 interested putative secretory proteins in aphid different tissues, including some digestive and detoxifying enzymes, effectors and Ca2+ binding proteins. The results showed that only glutathione-S-transferase 1 was specifically expressed in salivary glands. These findings provide a further insight into the identification of potential effectors involving in aphid-cereals interactions. PMID- 29162878 TI - Comparative analysis of cytokine/chemokine regulatory networks in patients with hippocampal sclerosis (HS) and focal cortical dysplasia (FCD). AB - Experimental and clinical evidence have demonstrated aberrant expression of cytokines/chemokines and their receptors in patients with hippocampal sclerosis (HS) and focal cortical dysplasia (FCD). However, there is limited information regarding the modulation of cytokine/chemokine-regulatory networks, suggesting contribution of miRNAs and downstream transcription factors/receptors in these pathologies. Hence, we studied the levels of multiple inflammatory mediators (IL1beta, IL1Ra, IL6, IL10, CCL3, CCL4, TNFalpha and VEGF) along with transcriptional changes of nine related miRNAs and mRNA levels of downstream effectors of significantly altered cytokines/chemokines in brain tissues obtained from patients with HS (n = 26) and FCD (n = 26). Up regulation of IL1beta, IL6, CCL3, CCL4, STAT-3, C-JUN and CCR5, and down regulation of IL 10 were observed in both HS and FCD cases (p < 0.05). CCR5 was significantly up regulated in FCD as compared to HS (p < 0.001). Both, HS and FCD presented decreased miR-223-3p, miR 21-5p, miR-204-5p and let-7a-5p and increased miR-155-5p expression (p < 0.05). As compared to HS, miR-204-5p (upstream to CCR5 and IL1beta) and miR-195-5p (upstream to CCL4) were significantly decreased in FCD patients (p < 0.01). Our results suggest differential alteration of cytokine/chemokine regulatory networks in HS and FCD and provide a rationale for developing pathology specific therapy. PMID- 29162879 TI - MiR-30e inhibits tumor growth and chemoresistance via targeting IRS1 in Breast Cancer. AB - MicroRNA-30e (miR-30e) is downregulated in various tumor types. However, its mechanism in inhibiting tumor growth of breast cancer remains to be elucidated. In this study, we found that miR-30e was significantly downregulated in tumor tissues of breast cancer (BC) patients and cell lines, and overexpression of miR 30e inhibited cell proliferation, migration and invasion. To understand the potential mechanism of miR-30e in inhibiting tumor growth, we showed that miR-30e blocked the activation of AKT and ERK1/2 pathways, and the expression of HIF 1alpha and VEGF via directly targeting IRS1. Moreover, miR-30e regulates cell proliferation, migration, invasion and increases chemosensitivity of MDA-MB-231 cells to paclitaxel by inhibiting its target IRS1. MiR-30e also inhibited tumor growth and suppressed expression of IRS1, AKT, ERK1/2 and HIF-1alpha in mouse xenograft tumors. To test the clinical relevance of these results, we used 40 pairs of BC tissues and adjacent normal tissues, analyzed the levels of miR-30e and IRS1 expression in these tissues, and found that miR-30e levels were significantly inversely correlated with IRS1 levels in these BC tissues, suggesting the important implication of our findings in translational application for BC diagnostics and treatment in the future. PMID- 29162880 TI - FSCN1 gene polymorphisms: biomarkers for the development and progression of breast cancer. AB - Breast cancer is a major cause of cancer mortality worldwide. Fascin-1 (FSCN1) is an actin-binding protein found in mammalian cells, including endothelial, neuronal and mesenchymal cells. FSCN1 overexpression has been indicated in breast cancer patients. However, scant information is available regarding the association between FSCN1 single nucleotide polymorphisms (SNPs) and the risk or prognosis of breast cancer. We report on the association between 6 SNPs of the FSCN1 gene (rs56156320, rs8772, rs3801004, rs2966447, rs852479 and rs1640233) and breast cancer susceptibility as well as clinical outcomes in 316 patients with breast cancer and in 222 healthy controls. Carriers of the AC or AC + CC allele of the variant rs56156320 were at greater risk of breast cancer compared with wild-type (AA) carriers. Moreover, carriers of at least one G allele in rs3801004 were likely to progress to stage III/IV disease and lymph node metastasis. Individuals with at least one T allele at FSCN1 SNP rs2966447 were at higher risk of developing pathologic grade G3 disease. Furthermore, individuals bearing the C/C haplotype at SNPs rs56156320 and rs3801004 had nearly twice the risk of breast cancer. Our results indicate that genetic variations in the FSCN1 gene may serve as an important predictor of early-stage breast cancer. PMID- 29162881 TI - Discrimination of CRISPR/Cas9-induced mutants of rice seeds using near-infrared hyperspectral imaging. AB - Identifying individuals with target mutant phenotypes is a significant procedure in mutant exploitation for implementing genome editing technology in a crop breeding programme. In the present study, a rapid and non-invasive method was proposed to identify CRISPR/Cas9-induced rice mutants from their acceptor lines (huaidao-1 and nanjing46) using hyperspectral imaging in the near-infrared (NIR) range (874.41-1733.91 nm) combined with chemometric analysis. The hyperspectral imaging data were analysed using principal component analysis (PCA) for exploratory purposes, and a support vector machine (SVM) and an extreme learning machine (ELM) were applied to build discrimination models for classification. Meanwhile, PCA loadings and a successive projections algorithm (SPA) were used for extracting optimal spectral wavelengths. The SVM-SPA model achieved best performance, with classification accuracies of 93% and 92.75% being observed for calibration and prediction sets for huaidao-1 and 91.25% and 89.50% for nanjing46, respectively. Furthermore, the classification of mutant seeds was visualized on prediction maps by predicting the features of each pixel on individual hyperspectral images based on the SPA-SVM model. The above results indicated that NIR hyperspectral imaging together with chemometric data analysis could be a reliable tool for identifying CRISPR/Cas9-induced rice mutants, which would help to accelerate selection and crop breeding processes. PMID- 29162882 TI - Sublethal effects of imidacloprid on targeting muscle and ribosomal protein related genes in the honey bee Apis mellifera L. AB - A sublethal concentration of imidacloprid can cause chronic toxicity in bees and can impact the behavior of honey bees. The nectar- and water-collecting, and climbing abilities of bees are crucial to the survival of the bees and the execution of responsibilities in bee colonies. Besides behavioral impact, data on the molecular mechanisms underlying the toxicity of imidacloprid, especially by the way of RNA-seq at the transcriptomic level, are limited. We treated Apis mellifera L. with sublethal concentrations of imidacloprid (0.1, 1 and 10 ppb) and determined the effect on behaviors and the transcriptomic changes. The sublethal concentrations of imidacloprid had a limited impact on the survival and syrup consumption of bees, but caused a significant increase in water consumption. Moreover, the climbing ability was significantly impaired by 10 ppb imidacloprid at 8 d. In the RNA-seq analysis, gene ontology (GO) term enrichment indicated a significant down-regulation of muscle-related genes, which might contribute to the impairment in climbing ability of bees. The enriched GO terms were attributed to the up-regulated ribosomal protein genes. Considering the ribosomal and extra-ribosomal functions of the ribosomal proteins, we hypothesized that imidacloprid also causes cell dysfunction. Our findings further enhance the understanding of imidacloprid sublethal toxicity. PMID- 29162883 TI - Protocadherin-alphaC2 is required for diffuse projections of serotonergic axons. AB - Serotonergic axons extend diffuse projections throughout various brain areas, and serotonergic system disruption causes neuropsychiatric diseases. Loss of the cytoplasmic region of protocadherin-alpha (Pcdh-alpha) family proteins, products of the diverse clustered Pcdh genes, causes unbalanced distributions (densification and sparsification) of serotonergic axons in various target regions. However, which Pcdh-alpha member(s) are responsible for the phenotype is unknown. Here we demonstrated that Pcdh-alphaC2 (alphaC2), a Pcdh-alpha isoform, was highly expressed in serotonergic neurons, and was required for normal diffusion in single-axon-level analyses of serotonergic axons. The loss of alphaC2 from serotonergic neurons, but not from their target brain regions, led to unbalanced distributions of serotonergic axons. Our results suggest that alphaC2 expressed in serotonergic neurons is required for serotonergic axon diffusion in various brain areas. The alphaC2 extracellular domain displays homophilic binding activity, suggesting that its homophilic interaction between serotonergic axons regulates axonal density via alphaC2's cytoplasmic domain. PMID- 29162884 TI - Copolymers enhance selective bacterial community colonization for potential root zone applications. AB - Managing the impact of anthropogenic and climate induced stress on plant growth remains a challenge. Here we show that polymeric hydrogels, which maintain their hydrous state, can be designed to exploit functional interactions with soil microorganisms. This microbial enhancement may mitigate biotic and abiotic stresses limiting productivity. The presence of mannan chains within synthetic polyacrylic acid (PAA) enhanced the dynamics and selectivity of bacterial ingress in model microbial systems and soil microcosms. Pseudomonas fluorescens exhibiting high mannan binding adhesins showed higher ingress and localised microcolonies throughout the polymeric network. In contrast, ingress of Bacillus subtilis, lacking adhesins, was unaltered by mannan showing motility comparable to bulk liquids. Incubation within microcosms of an agricultural soil yielded hydrogel populations significantly increased from the corresponding soil. Bacterial diversity was markedly higher in mannan containing hydrogels compared to both control polymer and soil, indicating enhanced selectivity towards microbial families that contain plant beneficial species. Here we propose functional polymers applied to the potential root zone which can positively influence rhizobacteria colonization and potentially plant growth as a new approach to stress tolerance. PMID- 29162885 TI - An increased chloride level in hypochloremia is associated with decreased mortality in patients with severe sepsis or septic shock. AB - Only a few observational studies investigated the association between hypochloremia and mortality in critically ill patients, and these studies included small number of septic patients. Also, no study has evaluated the effect of an increase in chloride (Cl-) concentration in hypochloremia on the mortality. A total of 843 Korean septic patients were divided into three groups based on their baseline Cl- level, and Cox analyses were performed to evaluate the 28-day mortality. Moreover, the change in Cl- level (DeltaCl) from baseline to 24, 48, or 72 hour was determined, and Cox analyses were also conducted to evaluate the relationship of DeltaCl with mortality. 301 (35.7%) patients were hypochloremic (Cl- < 97 mEq/L), and 38 (4.5%) patients were hyperchloremic (Cl- > 110 mEq/L). During the follow-up period, 119 (14.1%) patients died. Hypochloremia was significantly associated with an increased mortality after adjusting for several variables, but an 1 mEq/L increase of DeltaCl within 24 hour in patients with hypochloremia was significantly related to a decreased mortality. Caution might be required in severe septic patients with hypochloremia considering their increased mortality rate. However, an increased Cl- concentration might decrease the mortality rate of such patients. PMID- 29162886 TI - Association of Human Leukocyte Antigen Class 1 genes with Stevens Johnson Syndrome with severe ocular complications in an Indian population. AB - Stevens Johnson syndrome (SJS) is part of a spectrum of adverse drug reactions resulting in the destruction of skin, mucous membranes, and the ocular surface. A similar, more severe form of the disorder included in this spectrum is toxic epidermal necrolysis (TEN). Approximately 35% of patients suffer chronic sequelae such as vascularization, corneal scarring, conjunctival inversion to the cornea, keratinization, symblepharon, scarring of the palpebral conjunctiva, trichiasis, and severe dry eye. We focused on 80 Indian patients with SJS/TEN with severe ocular complications (SOC) and investigated the association of alleles at HLA -A, HLA-B and HLA-C loci; the controls were 50 healthy Indian volunteers. Genotyping at HLA-A, HLA-B, and HLA-C loci showed a significant positive association with HLA-A*33:03, HLA-B*44:03, and HLA-C*07:01 alleles, and a significant negative association with HLA-B*57:01 and HLA-C*06:02. This indicates that HLA-A*33:03, HLA-B*44:03 and HLA-C*07:01 are risk alleles, and HLA-B*57:01 and HLA-C*06:02 are protective alleles in this population. We also found that the haplotypes consisting of HLA-B*44:03 and HLA-C*07:01 were strongly associated with SJS/TEN with SOC in our Indian population (p = 1.1 * 10-7, odds ratio = 11.0). Describing the association of the haplotype could facilitate the understanding of increased risk factors for developing SJS/TEN with SOC. PMID- 29162887 TI - The WD40-domain containing protein CORO2B is specifically enriched in glomerular podocytes and regulates the ventral actin cytoskeleton. AB - Podocytes are highly specialized epithelial cells essentially required to establish and maintain the kidney filtration barrier. Due to their complex cellular architecture these cells rely on an elaborated cytoskeletal apparatus providing plasticity as well as adaptive adhesion properties to withstand significant physical filtration forces. However, our knowledge about podocyte specific components of the cytoskeletal machinery is still incomplete. Employing cross-analysis of various quantitative omics-data sets we identify the WD40 domain containing protein CORO2B as a podocyte enriched protein. Furthermore, we demonstrate the distinct localization pattern of CORO2B to the ventral actin cytoskeleton serving as a physical linkage module to cell-matrix adhesion sites. Analysis of a novel Coro2b knockout mouse revealed that CORO2B modulates stress response of podocytes in an experimental nephropathy model. Using quantitative focal adhesome proteomics we identify the recruitment of CFL1 via CORO2B to focal adhesions as an underlying mechanism. Thus, we describe CORO2B as a novel podocyte enriched protein influencing cytoskeletal plasticity and stress adaptation. PMID- 29162888 TI - miR-500a-5p regulates oxidative stress response genes in breast cancer and predicts cancer survival. AB - MicroRNAs (miRNAs) are small regulatory non-coding RNAs with a diversity of cellular functions, and are frequently dysregulated in cancer. Using a novel computational method (ActMir) that we recently developed, the "activity" of miRNA hsa-miR-500a was implicated in estrogen receptor (ER) positive breast cancer; however its targets and functional impact remain poorly understood. Here, we performed an extensive gene expression analysis in ER+ breast cancer cell lines, to reveal the targets of miR-500a-5p after experimental modulation of its levels. We found that among mRNAs targeted by miR-500a-5p there was enrichment in oxidative stress response genes. Moreover, in vitro exposure to oxidative stress using H2O2 induces miR-500a-5p overexpression and downregulation of the oxidative stress targets TXNRD1 and NFE2L2. Finally, expression of several of the identified miR-500a-5p targets related to oxidative stress, including TXNRD1, was associated with ER+ breast cancer survival in multiple datasets. Overall, we identify miR-500a-5p as an oxidative stress response miRNA whose activity may define breast cancer progression and survival. PMID- 29162889 TI - Identification of microRNAs as potential cellular monocytic biomarkers in the early phase of myocardial infarction: a pilot study. AB - MicroRNA has been increasingly suggested to be involved in vascular inflammation. The aim of this study was to assess the expression profile of miRs as possible novel cellular biomarkers in circulating monocytes in patients with ST-segment elevation myocardial infarction (STEMI). Microarray techniques and TaqMan polymerase chain reaction were used to analyse the global expression of 352 miRNAs in peripheral blood monocytes from healthy donors (n = 20) and patients (n = 24) with acute STEMI. The expression level of miR-143 in monocytes from STEMI patients compared to healthy controls was increased, whereas the expression of miR-1, -92a, -99a, and -223 was reduced significantly. During 3.5 +/- 1.5 months of follow-up miR-1 and -223 were back to baseline, whereas miR-92a and -99a return to normal levels over 3 months, but remained lower than healthy controls. Furthermore, monocytic expression of miR-143 was positively correlated with hs CRP (R2 = 0.338; P < 0.031), but not with cTnT. Importantly, treatment of monocytes isolated from healthy individuals with INFgamma, but not LPS or TNFalpha caused an upregulation of miR-143 and downregulation of miR-1. Our findings identify circulating monocytes as putative biomarkers and as novel carriers for the cell-specific transfer of miRs in the early phase of myocardial infarction. PMID- 29162890 TI - Reconstructing molar growth from enamel histology in extant and extinct Equus. AB - The way teeth grow is recorded in dental enamel as incremental marks. Detailed analysis of tooth growth is known to provide valuable insights into the growth and the pace of life of vertebrates. Here, we study the growth pattern of the first lower molar in several extant and extinct species of Equus and explore its relationship with life history events. Our histological analysis shows that enamel extends beyond the molar's cervix in these mammals. We identified three different crown developmental stages (CDS) in the first lower molars of equids characterised by different growth rates and likely to be related to structural and ontogenetic modifications of the tooth. Enamel extension rate, which ranges from ~400 MUm/d at the beginning of crown development to rates of ~30 MUm/d near the root, and daily secretion rate (~17 MUm/d) have been shown to be very conservative within the genus. From our results, we also inferred data of molar wear rate for these equids that suggest higher wear rates at early ontogenetic stages (13 mm/y) than commonly assumed. The results obtained here provide a basis for future studies of equid dentition in different scientific areas, involving isotope, demographic and dietary studies. PMID- 29162891 TI - Electrochemical performance and interfacial properties of Li-metal in lithium bis(fluorosulfonyl)imide based electrolytes. AB - Successful usage of lithium metal as the negative electrode or anode in rechargeable batteries can be an important step to increase the energy density of lithium batteries. Performance of lithium metal in a relatively promising electrolyte solution composed of lithium bis(fluorosulfonyl)imide (LiN(SO2F)2; LiFSI) salt dissolved in 1,2-dimethoxyethane (DME) is here studied. The influence of the concentration of the electrolyte salt -1 M or 4 M LiFSI- is investigated by varying important electrochemical parameters such as applied current density and plating capacity. X-ray photoelectron spectroscopy analysis as a surface sensitive technique is here used to analyze that how the composition of the solid electrolyte interphase varies with the salt concentration and with the number of cycles. PMID- 29162892 TI - Silencing of OsGRXS17 in rice improves drought stress tolerance by modulating ROS accumulation and stomatal closure. AB - Glutaredoxins (GRXs) modulate redox-dependent signaling pathways and have emerged as key mediators in plant responses to environmental stimuli. Here we report that RNAi-mediated suppression of Oryza sativa GRXS17 (OsGRXS17) improved drought tolerance in rice. Gene expression studies showed that OsGRXS17 was present throughout the plant and that transcript abundance increased in response to drought stress and abscisic acid (ABA) treatment. Localization studies, utilizing GFP-OsGRXS17 fusion proteins, indicated that OsGRXS17 resides in both the cytoplasm and the nuclear envelope. Under drought stress conditions, rice plants with reduced OsGRXS17 expression showed lower rates of water loss and stomatal conductance, higher relative water content, and enhanced survival compared to wild-type controls. Further characterization of the OsGRXS17 down-regulated plants revealed an elevation in H2O2 production within the guard cells, increased sensitivity to ABA, and a reduction in stomatal apertures. The findings demonstrate a critical link between OsGRXS17, the modulation of guard cell H2O2 concentrations, and stomatal closure, expanding our understanding of the mechanisms governing plant responses to drought. PMID- 29162893 TI - Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14alpha-demethylase. AB - Mucormycoses are emerging and potentially lethal infections. An increase of breakthrough infections has been found in cohorts receiving short-tailed azoles prophylaxis (e.g. voriconazole (VCZ)). Although VCZ is ineffective in vitro and in vivo, long-tailed triazoles such as posaconazole remain active against mucormycetes. Our goal was to validate the molecular mechanism of resistance to short-tailed triazoles in Mucorales. The paralogous cytochrome P450 genes (CYP51 F1 and CYP51 F5) of Rhizopus arrhizus, Rhizopus microsporus, and Mucor circinelloides were amplified and sequenced. Alignment of the protein sequences of the R. arrhizus, R. microsporus, and M. circinelloides CYP51 F1 and F5 with additional Mucorales species (n = 3) and other fungi (n = 16) confirmed the sequences to be lanosterol 14alpha-demethylases (LDMs). Sequence alignment identified a pan-Mucorales conservation of a phenylalanine129 substitution in all CYP51 F5s analyzed. A high resolution X-ray crystal structure of Saccharomyces cerevisiae LDM in complex with VCZ was used for generating a homology model of R. arrhizus CYP51 F5. Structural and functional knowledge of S. cerevisiae CYP51 shows that the F129 residue in Mucorales CYP51 F5 is responsible for intrinsic resistance of Mucorales against short-tailed triazoles, with a V to A substitution in Helix I also potentially playing a role. PMID- 29162894 TI - Temporary Diverting Stoma Improves Recovery of Anastomotic Leakage after Anterior Resection for Rectal Cancer. AB - Temporary diverting stoma might be a protective factor for the prevention of anastomotic leakage (AL) after anterior resection. Its role in leakage recovery is unknown. This study aimed to evaluate the effect of temporary diverting stoma on anastomotic leakage severity and recovery. We analyzed 323 patients who underwent anterior resection for rectal cancer and developed anastomotic leakage, in which 44 had temporary diverting stoma. Association between diverting stoma and occurrence of anastomotic leakage, recovery time, length of hospital stay, overall costs, local and distant relapse-free survival were further studied. In non-severe AL group, temporary diverting stoma improved leakage recovery by 4 days (mean: 20.7 days vs. 16.1 days, p = 0.031), especially in patients who did not receive neoadjuvant treatment (mean time: 20.9 days vs. 14.4 days, p = 0.016). However, it did not delay the occurrence of anastomotic leakage. Moreover, no significant difference was found in the overall length of hospital stay and costs among patients with versus without a diverting stoma. In severe AL group, however, no difference was detected. The advantage of shortened leakage recovery did not reduce the local and distant relapse-free survival. In conclusion, our findings indicated the recovery benefit from diverting stoma in patients with anterior resection. PMID- 29162895 TI - Publisher Correction: Novel detection of post-translational modifications in human monocyte-derived dendritic cells after chronic alcohol exposure: Role of inflammation regulator H4K12ac. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29162896 TI - beta-adrenergic stimulation augments transmural dispersion of repolarization via modulation of delayed rectifier currents IKs and IKr in the human ventricle. AB - Long QT syndrome (LQTS) is an inherited or drug induced condition associated with delayed repolarization and sudden cardiac death. The cardiac potassium channel, IKr, and the adrenergic-sensitive cardiac potassium current, IKs, are two primary contributors to cardiac repolarization. This study aimed to elucidate the role of beta-adrenergic (beta-AR) stimulation in mediating the contributions of IKr and IKs to repolarizing the human left ventricle (n = 18). Optical mapping was used to measure action potential durations (APDs) in the presence of the IKs blocker JNJ-303 and the IKr blocker E-4031. We found that JNJ-303 alone did not increase APD. However, under isoprenaline (ISO), both the application of JNJ-303 and additional E-4031 significantly increased APD. With JNJ-303, ISO decreased APD significantly more in the epicardium as compared to the endocardium, with subsequent application E-4031 increasing mid- and endocardial APD80 more significantly than in the epicardium. We found that beta-AR stimulation significantly augmented the effect of IKs blocker JNJ-303, in contrast to the reduced effect of IKr blocker E-4031. We also observed synergistic augmentation of transmural repolarization gradient by the combination of ISO and E-4031. Our results suggest beta-AR-mediated increase of transmural dispersion of repolarization, which could pose arrhythmogenic risk in LQTS patients. PMID- 29162898 TI - Equivalent model optimization with cyclic correction approximation method considering parasitic effect for thermoelectric coolers. AB - As thermoelectric coolers (TECs) have become highly integrated in high-heat-flux chips and high-power devices, the parasitic effect between component layers has become increasingly obvious. In this paper, a cyclic correction method for the TEC model is proposed using the equivalent parameters of the proposed simplified model, which were refined from the intrinsic parameters and parasitic thermal conductance. The results show that the simplified model agrees well with the data of a commercial TEC under different heat loads. Furthermore, the temperature difference of the simplified model is closer to the experimental data than the conventional model and the model containing parasitic thermal conductance at large heat loads. The average errors in the temperature difference between the proposed simplified model and the experimental data are no more than 1.6 K, and the error is only 0.13 K when the absorbed heat power Q c is equal to 80% of the maximum achievable absorbed heat power Q max . The proposed method and model provide a more accurate solution for integrated TECs that are small in size. PMID- 29162897 TI - GWAS, QTL mapping and gene expression analyses in Brassica napus reveal genetic control of branching morphogenesis. AB - Branch number is an important trait in plant architecture that can influence crop yield and quality in Brassica napus. Here, we detected the QTLs responsible for branch number in a DH population and its reconstructed F2 population over two years. Further, a GWAS research on branch number was performed using a panel of 327 accessions with 33186 genomic SNPs from the 60 K Brassica Illumina(r) Infinium SNP array. Through combining linkage analysis and association mapping, a new QTL was fine mapped onto C03. Subsequently, we tested the correlations between the SNP polymorphisms and mRNA expression levels of genes in the target interval to identify potential loci or genes that control branch number through expression. The results show that 4 SNP loci are associated with the corresponding gene expression levels, and one locus (BnaC03g63480D) exhibited a significant correlation between the phenotype variation and gene expression levels. Our results provide insights into the genetic basis for branching morphogenesis and may be valuable for optimizing architecture in rapeseed breeding. PMID- 29162899 TI - Remapping high-capacity, pre-attentive, fragile sensory memory. AB - Humans typically make several saccades per second. This provides a challenge for the visual system as locations are largely coded in retinotopic (eye-centered) coordinates. Spatial remapping, the updating of retinotopic location coordinates of items in visuospatial memory, is typically assumed to be limited to robust, capacity-limited and attention-demanding working memory (WM). Are pre-attentive, maskable, sensory memory representations (e.g. fragile memory, FM) also remapped? We directly compared trans-saccadic WM (tWM) and trans-saccadic FM (tFM) in a retro-cue change-detection paradigm. Participants memorized oriented rectangles, made a saccade and reported whether they saw a change in a subsequent display. On some trials a retro-cue indicated the to-be-tested item prior to probe onset. This allowed sensory memory items to be included in the memory capacity estimate. The observed retro-cue benefit demonstrates a tFM capacity considerably above tWM. This provides evidence that some, if not all sensory memory was remapped to spatiotopic (world-centered, task-relevant) coordinates. In a second experiment, we show backward masks to be effective in retinotopic as well as spatiotopic coordinates, demonstrating that FM was indeed remapped to world-centered coordinates. Together this provides conclusive evidence that trans-saccadic spatial remapping is not limited to higher-level WM processes but also occurs for sensory memory representations. PMID- 29162900 TI - Air-oxidation from sulfur to sulfone-bridged Schiff-base macrocyclic complexes showing enhanced antimicrobial activities. AB - Two embedded sulfur atoms in a novel [2 + 2] Schiff-base macrocyclic dinuclear Zn(II) complex were found to be easily autoxidized to the sulfone units on air exposure, and the resultant sulfone-functionalized macrocyclic complex was obtained by the post-modification strategy exhibiting enhanced antimicrobial activities because of the presence of dual active sites in comparison with the sulfur-containing Schiff-base macrocycle. PMID- 29162901 TI - microRNA-449a modulates medullary thymic epithelial cell differentiation. AB - Medullary thymic epithelial cells (mTECs) ectopically express a diversity of peripheral tissue-restricted antigens (PTAs) and provide unique cues for the expansion, maturation and selection of a repertoire of functionally diverse T lymphocytes. Genetic deletion of all mature microRNAs in thymic epithelial cells (TECs) results in premature thymic involution, progressive disorganisation of the thymic epithelium, and alteration in thymic T cell lineage commitment, consequently eliciting autoimmune disorders. In the present study, we identified that microRNA-449a (miR-449a), a member of miR-449 cluster, regulated mTEC differentiation. Expression of miR-449a was induced by RANK ligand in mouse fetal thymus. In in vitro studies, overexpression of miR-449a induced thymic epithelial progenitor cells (TEPCs) differentiation into mature mTECs. Despite abundant expression of miR-449a in developing thymus, miR-449a-mutant mice exhibited normal thymic development. This might be partially due to in miR-449a-mutant thymus the up-regulation of miR-34a which shared similar seed sequence with miR 449a. However, thymic expression of miR-449/34 sponge which was able to neutralize the function of miR-449/34 family members significantly reduced the number of mature Ly51-MHCIIhi mTECs. Taken together, our data suggested that miR 449a modulated mTEC differentiation, and members of miR-34 cluster functioned redundantly to rescue miR-449a deficiency in thymus development. PMID- 29162902 TI - Shear Stress Regulates TRPV4 Channel Clustering and Translocation from Adherens Junctions to the Basal Membrane. AB - Localized Ca2+ influx via TRPV4 on the surface of endothelial cells greatly influences endothelial adaptation to blood flow, but how mechanical stress from blood flow controls TRPV4 integration into this physiological function is not fully understood. Here, we studied the spatial organization of TRPV4 and its relationship to the adherens junction component beta-catenin using single- and dual-color direct stochastic optical reconstruction microscopy (dSTORM). In non stimulated endothelial cells, TRPV4 is clustered in small protein islands, as is beta-catenin. Using dual-color imaging, we found that TRPV4 and beta-catenin reside in similar islands and can be found at both the basolateral and basal membranes. Following shear stress stimulation, TRPV4 molecules formed smaller clusters, with the majority residing outside of clusters. Further shear stress stimulation changed the molecular distribution of TRPV4 molecules, limiting them to the basal membrane. This redistribution and the smaller clusters resulted in the segregation of TRPV4 from beta-catenin. Furthermore, TRPV4 trafficking was controlled by focal adhesion kinase and activation of the alpha5beta1 integrin. These highly differentiated spatial redistributions suggest that mechanotransduction of blood flow is controlled via a more complex hierarchy than previously thought. PMID- 29162903 TI - The LATERAL ORGAN BOUNDARIES Domain gene family in grapevine: genome-wide characterization and expression analyses during developmental processes and stress responses. AB - LATERAL ORGAN BOUNDARIES (LOB) DOMAIN (LBD) constitute a family of plant-specific transcription factors with key roles in the regulation of plant organ development, pollen development, plant regeneration, pathogen response, and anthocyanin and nitrogen metabolisms. However, the role of LBDs in fruit ripening and in grapevine (Vitis vinifera L.) development and stress responses is poorly documented. By performing a model curation of LBDs in the latest genome annotation 50 genes were identified. Phylogenetic analysis showed that LBD genes can be grouped into two classes mapping on 16 out of the 19 V. vinifera chromosomes. New gene subclasses were identified that have not been characterized in other species. Segmental and tandem duplications contributed significantly to the expansion and evolution of the LBD gene family in grapevine as noticed for other species. The analysis of cis-regulatory elements and transcription factor binding sites in the VviLBD promoter regions suggests the involvement of several hormones in the regulation of LBDs expression. Expression profiling suggest the involvement of LBD transcription factors in grapevine development, berry ripening and stress responses. Altogether this study provides valuable information and robust candidate genes for future functional analysis aiming to clarify mechanisms responsible for the onset of fruit ripening and fruit defense strategies. PMID- 29162905 TI - Parvalbumin-Expressing Neurons in the Nucleus Accumbens: A New Player in Amphetamine Sensitization and Reward. PMID- 29162904 TI - Whole Y-chromosome sequences reveal an extremely recent origin of the most common North African paternal lineage E-M183 (M81). AB - E-M183 (E-M81) is the most frequent paternal lineage in North Africa and thus it must be considered to explore past historical and demographical processes. Here, by using whole Y chromosome sequences from 32 North African individuals, we have identified five new branches within E-M183. The validation of these variants in more than 200 North African samples, from which we also have information of 13 Y STRs, has revealed a strong resemblance among E-M183 Y-STR haplotypes that pointed to a rapid expansion of this haplogroup. Moreover, for the first time, by using both SNP and STR data, we have provided updated estimates of the times-to the-most-recent-common-ancestor (TMRCA) for E-M183, which evidenced an extremely recent origin of this haplogroup (2,000-3,000 ya). Our results also showed a lack of population structure within the E-M183 branch, which could be explained by the recent and rapid expansion of this haplogroup. In spite of a reduction in STR heterozygosity towards the West, which would point to an origin in the Near East, ancient DNA evidence together with our TMRCA estimates point to a local origin of E-M183 in NW Africa. PMID- 29162906 TI - Characterisation of the semi-volatile component of Dissolved Organic Matter by Thermal Desorption - Proton Transfer Reaction - Mass Spectrometry. AB - Proton Transfer Reaction - Mass Spectrometry (PTR-MS) is a sensitive, soft ionisation method suitable for qualitative and quantitative analysis of volatile and semi-volatile organic vapours. PTR-MS is used for various environmental applications including monitoring of volatile organic compounds (VOCs) emitted from natural and anthropogenic sources, chemical composition measurements of aerosols, etc. Here we apply thermal desorption PTR-MS for the first time to characterise the chemical composition of dissolved organic matter (DOM). We developed a clean, low-pressure evaporation/sublimation system to remove water from samples and coupled it to a custom-made thermal desorption unit to introduce the samples to the PTR-MS. Using this system, we analysed waters from intact and degraded peat swamp forest of Kalimantan, Indonesian Borneo, and an oil palm plantation and natural forest in Sarawak, Malaysian Borneo. We detected more than 200 organic ions from these samples and principal component analysis allowed clear separation of the different sample origins based on the composition of organic compounds. The method is sensitive, reproducible, and provides a new and comparatively cheap tool for a rapid characterisation of water and soil DOM. PMID- 29162907 TI - Physicochemical characteristics and toxicity of surface-modified zinc oxide nanoparticles to freshwater and marine microalgae. AB - Because of wide applications of surface-modified zinc oxide nanoparticles (ZnO NPs) in commercial sunscreens and their easiness of being released into water, concerns have been raised over their potential effects on aquatic organisms. This study compared physicochemical properties of silane-coated and uncoated ZnO-NPs to elucidate their toxic potencies toward three freshwater and three marine microalgae. Surfaces of ZnO-NPs (20 nm) were modified by coating with 3 aminopropyltrimethoxysilane (A-ZnO-NPs) that provides the particles with a more hydrophilic surface, or dodecyltrichlorosilane (D-ZnO-NPs) that turns the particles to hydrophobic. Uncoated ZnO-NPs formed larger aggregates and released more Zn2+ than did either of the two coated ZnO-NPs. The three nanoparticles formed larger aggregates but released less Zn2+ at pH 8 than at pH 7. Although sensitivities varied among algal species, A-ZnO-NPs and uncoated ZnO-NPs were more potent at inhibiting growth of algal cells than were D-ZnO-NPs after 96-h exposure to ZnO, uncoated ZnO-NPs, each of the coated ZnO-NPs or ZnSO4 at 10 concentrations ranging from 0.1 to 100 mg/L. The marine diatom Thalassiosira pseudonana exposed to ZnO-NPs, A-ZnO-NPs or D-ZnO-NPs resulted in differential expressions of genes, suggesting that each of the coatings resulted in ZnO-NPs acting through different mechanisms of toxic action. PMID- 29162908 TI - Human canonical CD157/Bst1 is an alternatively spliced isoform masking a previously unidentified primate-specific exon included in a novel transcript. AB - CD157/Bst1 is a dual-function receptor and beta-NAD+-metabolizing ectoenzyme of the ADP-ribosyl cyclase family. Expressed in human peripheral blood neutrophils and monocytes, CD157 interacts with extracellular matrix components and regulates leukocyte diapedesis via integrin-mediated signalling in inflammation. CD157 also regulates cell migration and is a marker of adverse prognosis in epithelial ovarian cancer and pleural mesothelioma. One form of CD157 is known to date: the canonical sequence of 318 aa from a 9-exon transcript encoded by BST1 on human chromosome 4. Here we describe a second BST1 transcript, consisting of 10 exons, in human neutrophils. This transcript includes an unreported exon, exon 1b, located between exons 1 and 2 of BST1. Inclusion of exon 1b in frame yields CD157 002, a novel proteoform of 333 aa: exclusion of exon 1b by alternative splicing generates canonical CD157, the dominant proteoform in neutrophils and other tissues analysed here. In comparative functional analyses, both proteoforms were indistinguishable in cell surface localization, specific mAb binding, and behaviour in cell adhesion and migration. However, NAD glycohydrolase activity was detected in canonical CD157 alone. Comparative phylogenetics indicate that exon 1b is a genomic innovation acquired during primate evolution, pointing to the importance of alternative splicing for CD157 function. PMID- 29162909 TI - Association of serum sodium and risk of all-cause mortality in patients with chronic kidney disease: A meta-analysis and sysematic review. AB - Studies on the association of dysnatraemia with all-cause mortality risk in chronic kidney disease (CKD) patients have yielded inconsistent results. This meta-analysis aimed to evaluate the association of hyponatremia or hypernatremia with all-cause mortality risk in CKD patients. An electronic literature search was performed in Web of Science, Pubmed and Embase databases from inception to March 2017 for available observational studies evaluating the association of dysnatraemia with all-cause mortality risk in CKD patients. Pooled hazard risk (HR) with 95% confidence interval (CI) was calculated for hyponatremia or hypernatremia vs. normonatremia. Seven studies that enrolled 742,979 CKD patients were identified. Baseline hyponatremia (HR 1.34; 95% CI: 1.15-1.57), and not hypernatremia (HR 1.12; 95%: CI 0.93-1.34), was independently associated with increased risk of all-cause mortality, when compared than the normonatremia category. In time-dependent analyses, both time-averaged hyponatremia (HR 1.65; 95% CI: 1.27-2.15) and hypernatremia (HR 1.41; 95% CI: 1.20-1.65) had a higher independent risk of all-cause mortality. Furthermore, subgroup analyses by type of patients, study design, sample size and follow-up duration revealed similar results across most of these analyses. Baseline hyponatremia and time-dependent hyponatremia or hypernatremia were independently associated with increased all cause mortality risk in CKD patients. PMID- 29162910 TI - A library of chemically defined human N-glycans synthesized from microbial oligosaccharide precursors. AB - Synthesis of homogenous glycans in quantitative yields represents a major bottleneck to the production of molecular tools for glycoscience, such as glycan microarrays, affinity resins, and reference standards. Here, we describe a combined biological/enzymatic synthesis that is capable of efficiently converting microbially-derived precursor oligosaccharides into structurally uniform human type N-glycans. Unlike starting material obtained by chemical synthesis or direct isolation from natural sources, which can be time consuming and costly to generate, our approach involves precursors derived from renewable sources including wild-type Saccharomyces cerevisiae glycoproteins and lipid-linked oligosaccharides from glycoengineered Escherichia coli. Following deglycosylation of these biosynthetic precursors, the resulting microbial oligosaccharides are subjected to a greatly simplified purification scheme followed by structural remodeling using commercially available and recombinantly produced glycosyltransferases including key N-acetylglucosaminyltransferases (e.g., GnTI, GnTII, and GnTIV) involved in early remodeling of glycans in the mammalian glycosylation pathway. Using this approach, preparative quantities of hybrid and complex-type N-glycans including asymmetric multi-antennary structures were generated and subsequently used to develop a glycan microarray for high throughput, fluorescence-based screening of glycan-binding proteins. Taken together, these results confirm our combined synthesis strategy as a new, user friendly route for supplying chemically defined human glycans simply by combining biosynthetically-derived precursors with enzymatic remodeling. PMID- 29162911 TI - Ultrasonographic measurement of the optic nerve sheath diameter and its association with eyeball transverse diameter in 585 healthy volunteers. AB - The optic nerve sheath diameter (ONSD) is considered as an indirect marker for intracranial pressure (ICP). However, the optimal cut-off value for an abnormal ONSD indicating elevated ICP and its associated factors have been unclear. Thus, we investigated normative values for the ONSD using ultrasonography and investigate the potential factors affecting it. We prospectively recruited healthy volunteers between September 2016 and March 2017. A total of 585 individuals were included, in which the mean ONSD was 4.11 mm [95% confidence interval (CI), 4.09-4.14 mm]. Although ONSD was correlated with sex (p = 0.015), height (p = 0.003), and eyeball transverse diameter (ETD) (p < 0.001) in simple linear regression analyses, multiple linear regression analysis revealed that only ETD was independently associated with ONSD (p < 0.001). Accordingly, we further established a normative value for the ONSD/ETD ratio and its associated factors. The mean ONSD/ETD ratio was 0.18 (95% CI, 0.18-0.18), but the ONSD/ETD ratio was not correlated with sex, height, weight, body mass index, and head circumference. Our findings suggest that the ONSD had a strong correlation with ETD, and ONSD/ETD ratio might provide more reliable data than ONSD itself as a marker of ICP. PMID- 29162912 TI - Histamine N-methyltransferase regulates aggression and the sleep-wake cycle. AB - Histamine is a neurotransmitter that regulates diverse physiological functions including the sleep-wake cycle. Recent studies have reported that histaminergic dysfunction in the brain is associated with neuropsychiatric disorders. Histamine N-methyltransferase (HNMT) is an enzyme expressed in the central nervous system that specifically metabolises histamine; yet, the exact physiological roles of HNMT are unknown. Accordingly, we phenotyped Hnmt knockout mice (KO) to determine the relevance of HNMT to various brain functions. First, we showed that HNMT deficiency enhanced brain histamine concentrations, confirming a role for HNMT in histamine inactivation. Next, we performed comprehensive behavioural testing and determined that KO mice exhibited high aggressive behaviours in the resident intruder and aggressive biting behaviour tests. High aggression in KO mice was suppressed by treatment with zolantidine, a histamine H2 receptor (H2R) antagonist, indicating that abnormal H2R activation promoted aggression in KO mice. A sleep analysis revealed that KO mice exhibited prolonged bouts of awakening during the light (inactive) period and compensatory sleep during the dark (active) period. Abnormal sleep behaviour was suppressed by treatment with pyrilamine, a H1R antagonist, prior to light period, suggesting that excessive H1R activation led to the dysregulation of sleep-wake cycles in KO mice. These observations inform the physiological roles of HNMT. PMID- 29162913 TI - CT dose reduction factors in the thousands using X-ray phase contrast. AB - Phase-contrast X-ray imaging can improve the visibility of weakly absorbing objects (e.g. soft tissues) by an order of magnitude or more compared to conventional radiographs. Combining phase retrieval with computed tomography (CT) can increase the signal-to-noise ratio (SNR) by up to two orders of magnitude over conventional CT at the same radiation dose, without loss of image quality. Our experiments reveal that as the radiation dose decreases, the relative improvement in SNR increases. We show that this enhancement can be traded for a reduction in dose greater than the square of the gain in SNR. Upon reducing the dose 300 fold, the phase-retrieved SNR was still up to 9.6 +/- 0.2 times larger than the absorption contrast data with spatial resolution in the tens of microns. We show that this theoretically reveals the potential for dose reduction factors in the tens of thousands without loss in image quality, which would have a profound impact on medical and industrial imaging applications. PMID- 29162914 TI - A small molecule screen to identify regulators of let-7 targets. AB - The let-7 family of miRNAs has been shown to be crucial in many aspects of biology, from the regulation of developmental timing to cancer. The available methods to regulate this family of miRNAs have so far been mostly genetic and therefore not easily performed experimentally. Here, we describe a small molecule screen designed to identify regulators of let-7 targets in human cells. In particular, we focused our efforts on the identification of small molecules that could suppress let-7 targets, as these could serve to potentially intercede in tumors driven by loss of let-7 activity. After screening through roughly 36,000 compounds, we identified a class of phosphodiesterase inhibitors that suppress let-7 targets. These compounds stimulate cAMP levels and raise mature let-7 levels to suppress let-7 target genes in multiple cancer cell lines such as HMGA2 and MYC. As a result, these compounds also show growth inhibitory activity on cancer cells. PMID- 29162915 TI - Extensive gene flow of white-backed planthopper in the Greater Mekong Subregion as revealed by microsatellite markers. AB - The white-backed planthopper (WBPH), Sogatella furcifera (Horvath), is a destructive pest of rice in the Greater Mekong Subregion (GMS) countries including Cambodia, Laos, Myanmar, Thailand, Vietnam, and China's Yunnan Province. Our previous study not only confirmed the immigration sources of the WBPH in China's Yunnan Province were from Myanmar, Vietnam, and Laos, but also indicated that Cambodia was likely an additional migration source. To further clarify the migration sources and patterns of the WBPH in the GMS, we investigated the genetic structure of 42 WBPH populations using microsatellite loci markers. The analysis of genetic diversity, heterozygosity deficit, and heterozygosity excess based on the nuclear markers suggest that there is extensive gene flow between the 42 sampled populations from the GMS. The genetic structure confirmed the immigration sources of WBPH as revealed by mitochondrial markers and trajectory analyses methods in previous studies. These findings will aid in the sustainable regional management of this insect pest in the GMS. PMID- 29162916 TI - AFM-based detection of glycocalyx degradation and endothelial stiffening in the db/db mouse model of diabetes. AB - Degradation of the glycocalyx and stiffening of endothelium are important pathophysiological components of endothelial dysfunction. However, to our knowledge, these events have not been investigated in tandem in experimental diabetes. Here, the mechanical properties of the glycocalyx and endothelium in ex vivo mouse aorta were determined simultaneously in indentation experiments with an atomic force microscope (AFM) for diabetic db/db and control db/+ mice at ages of 11-19 weeks. To analyze highly heterogeneous aorta samples, we developed a tailored classification procedure of indentation data based on a bi-layer brush model supplemented with Hertz model for quantification of nanomechanics of endothelial regions with and without the glycocalyx surface. In db/db mice, marked endothelial stiffening and reduced glycocalyx coverage were present already in 11-week-old mice and persisted in older animals. In contrast, reduction of the effective glycocalyx length was progressive and was most pronounced in 19-week-old db/db mice. The reduction of the glycocalyx length correlated with an increasing level of glycated haemoglobin and decreased endothelial NO production. In conclusion, AFM nanoindentation analysis revealed that stiffening of endothelial cells and diminished glycocalyx coverage occurred in early diabetes and were followed by the reduction of the glycocalyx length that correlated with diabetes progression. PMID- 29162917 TI - Keratin-water-NMF interaction as a three layer model in the human stratum corneum using in vivo confocal Raman microscopy. AB - The secondary and tertiary structure of keratin and natural moisturizing factor (NMF) are of great importance regarding the water regulating functions in the stratum corneum (SC). In this in vivo study, the depth-dependent keratin conformation and its relationship to the hydrogen bonding states of water and its content in the SC, are investigated using confocal Raman microscopy. Based on the obtained depth-profiles for the beta-sheet/alpha-helix ratio, the stability of disulphide bonds, the amount of cysteine forming disulphide bonds, the buried/exposed tyrosine and the folding/unfolding states of keratin, a "three layer model" of the SC, regarding the keratin-water-NMF interaction is proposed. At the uppermost layers (30-0% SC depth), the keratin filaments are highly folded, entailing limited water binding sites, and NMF is mostly responsible for binding water. At the intermediate layers (70-30% SC depth), the keratin filaments are unfolded, have the most water binding sites and are prone to swelling. At the bottom layers (100-80% SC depth), the water binding sites are already occupied with water and cannot swell substantially. The hydrogen bonding states of water molecules can only be explained by considering both, the molecular structure of keratin and the contribution of NMF as a holistic system. PMID- 29162918 TI - Partial loss-of-function of NAL1 alters canopy photosynthesis by changing the contribution of upper and lower canopy leaves in rice. AB - Little is known about the genetic basis of leaf and canopy photosynthesis. Here we aimed to detect novel quantitative trait loci (QTL) controlling photosynthesis by increasing leaf nitrogen content (LNC) per leaf area and analysed its effect on leaf and canopy photosynthesis. To identify QTL that increase photosynthetic rate in leaves, we screened chromosome segment substitution lines (CSSLs) of Oryza sativa ssp. japonica cultivar Koshihikari and O. sativa ssp. indica cultivar Nona Bokra using LNC per leaf area as the phenotype indicator. Locus leaf nitrogen content on chromosome four (qLNC4) is associated with increased LNC and photosynthetic rate per leaf area. Moreover, a non-synonymous amino acid substitution was identified in the NARROW LEAF 1 (NAL1) gene located in the qLNC4 region. This NAL1 allele increases LNC and photosynthetic rate per leaf area in flag leaves but does not increase whole-leaf photosynthesis. This NAL1 allele also increases light capture and whole-leaf nitrogen content of the lower leaves and is associated with slower senescence in flag leaves. These results suggest that this NAL1 allele does not increase whole-leaf photosynthesis but plays a role in regulating spatial and temporal trade-offs among traits at the whole plant level. PMID- 29162919 TI - Production of recombinant human procollagen type I C-terminal propeptide and establishment of a sandwich ELISA for quantification. AB - Procollagen type I carboxy-terminal propeptide (PICP), derived from type I procollagen, has been identified as an indicator of type I collagen synthesis in bone matrix formation and skin recovery. PICP is a heterotrimeric glycoprotein consisting of two alpha1 chains (PICPalpha1) and one alpha2 chain (PICPalpha2). Here, we report the recombinant expression of human PICP using a mammalian expression system. Co-expression of PICPalpha1 and PICPalpha2 in HEK293F cells resulted in the production of functional PICP in the correctly assembled heterotrimeric form. Using the recombinant PICP as an antigen, we isolated PICP specific human monoclonal antibodies from phage-displayed antibody libraries and raised rabbit polyclonal antibodies. Using those antibodies, we then developed a sandwich ELISA for PICP with a limit of detection of 1 ng/mL and a measurable range of 1-640 ng/mL. Both intra- and inter-assay imprecision values were <10%. For measuring PICP levels in human fibroblast cellular extracts and culture supernatants and a human serum, the developed ELISA kit displayed comparable performance to that of a commercialized kit. Our results provide an efficient production strategy for recombinant PICP, facilitating the generation of PICP specific antibodies and development of PICP sandwich ELISA, with potential use in clinical diagnosis of serum samples and testing of cosmeceutical ingredients in fibroblast cell cultures. PMID- 29162920 TI - The corepressor NCOR1 regulates the survival of single-positive thymocytes. AB - Nuclear receptor corepressor 1 (NCOR1) is a transcriptional regulator bridging repressive chromatin modifying enzymes with transcription factors. NCOR1 regulates many biological processes, however its role in T cells is not known. Here we show that Cd4-Cre-mediated deletion of NCOR1 (NCOR1 cKOCd4) resulted in a reduction of peripheral T cell numbers due to a decrease in single-positive (SP) thymocytes. In contrast, double-positive (DP) thymocyte numbers were not affected in the absence of NCOR1. The reduction in SP cells was due to diminished survival of NCOR1-null postselection TCRbetahiCD69+ and mature TCRbetahiCD69- thymocytes. NCOR1-null thymocytes expressed elevated levels of the pro-apoptotic factor BIM and showed a higher fraction of cleaved caspase 3-positive cells upon TCR stimulation ex vivo. However, staphylococcal enterotoxin B (SEB)-mediated deletion of Vbeta8+ CD4SP thymocytes was normal, suggesting that negative selection is not altered in the absence of NCOR1. Finally, transgenic expression of the pro-survival protein BCL2 restored the population of CD69+ thymocytes in NCOR1 cKOCd4 mice to a similar percentage as observed in WT mice. Together, these data identify NCOR1 as a crucial regulator of the survival of SP thymocytes and revealed that NCOR1 is essential for the proper generation of the peripheral T cell pool. PMID- 29162922 TI - Coulomb-like elastic interaction induced by symmetry breaking in nematic liquid crystal colloids. AB - It is generally thought that colloidal particles in a nematic liquid crystal do not generate the first multipole term called deformation elastic charge as it violates the mechanical equilibrium. Here, we demonstrate theoretically and experimentally that this is not the case, and deformation elastic charges, as well as dipoles and quadrupoles, can be induced through anisotropic boundary conditions. We report the first direct observation of Coulomb-like elastic interactions between colloidal particles in a nematic liquid crystal. The behaviour of two spherical colloidal particles with asymmetric anchoring conditions induced by asymmetric alignment is investigated experimentally; the interaction of two particles located at the boundary of twist and parallel aligned regions is observed. We demonstrate that such particles produce deformation elastic charges and interact by Coulomb-like interactions. PMID- 29162921 TI - Predictive value of thrombus volume for recanalization in stent retriever thrombectomy. AB - This retrospective study investigated whether the volume or density of the thrombus is predictive of recanalization in stent retriever (SR) treatment. Consecutive patients treated with SR thrombectomy as the first endovascular modality were enrolled. The thrombus volume and density were measured on thin section noncontrast computed tomography using 3-dimensional software. The patients were grouped by recanalization status and the number of SR passes. Among 165 patients, recanalization was achieved with the first pass in 68 (50.0%), 2-3 passes in 43 (31.6%), and >=4 passes in 25 (18.4%) patients. The thrombus volume was smaller in patients with (107.5 mm3) than without (173.7 mm3, p = 0.025) recanalization, and tended to be larger with increasing number of passes (p for trend = 0.001). The thrombus volume was an independent predictor of first-pass recanalization (odds ratio 0.93 per 10 mm3, 95% confidence interval 0.89-0.97). However, the thrombus density was not associated with recanalization success. Recanalization within 3 passes was associated with a favorable outcome. In conclusion, the thrombus volume was significantly related to recanalization in SR thrombectomy. Measuring the thrombus volume was particularly predictive of first pass recanalization, which was associated with a higher likelihood of a favorable outcome. PMID- 29162923 TI - Overexpression of suppressive microRNAs, miR-30a and miR-200c are associated with improved survival of breast cancer patients. AB - Some microRNAs (miRNAs) are known to suppress breast cancer. However, whether the expressions of these tumor suppressive miRNAs translate to patient survival were not investigated in large cohort. Nine miRNAs (miR-30a, miR-30c, miR-31, miR-126, miR-140, miR-146b, miR-200c, miR-206, and miR-335) known to be tumor suppressive miRNAs in breast cancer were investigated in Genomic Data Common data portal miRNA-Seq dataset and The Cancer Genome Atlas (TCGA) (n = 1052). Of the 9 miRNAs, miR-30a, miR-30c, miR-126, miR-140, miR-206, and miR-335 were found to have significantly lower expression in breast cancer tissues compared to paired normal breast tissue. High expression of miR-30a or miR-200c was associated with significantly better overall survival (OS). Gene Set Enrichment Analysis (GSEA) demonstrated that low expression levels of miR-30a had the tendency to associate with gene enrichment of EMT, while miR-200c did not, in TCGA cohort, and our findings support the need of validation using large cohort to use miRNA as prognostic biomarker for patients with breast cancer. PMID- 29162924 TI - Dysbiosis of the microbiome in gastric carcinogenesis. AB - The gastric microbiome has been proposed as an etiological factor in gastric carcinogenesis. We compared the gastric microbiota in subjects presenting with gastric cancer (GC, n = 12) and controls (functional dyspepsia (FD), n = 20) from a high GC risk population in Singapore and Malaysia. cDNA from 16S rRNA transcripts were amplified (515F-806R) and sequenced using Illumina MiSeq 2 * 250 bp chemistry. Increased richness and phylogenetic diversity but not Shannon's diversity was found in GC as compared to controls. nMDS clustered GC and FD subjects separately, with PERMANOVA confirming a significant difference between the groups. H. pylori serological status had a significant impact on gastric microbiome alpha-diversity and composition. Several bacterial taxa were enriched in GC, including Lactococcus, Veilonella, and Fusobacteriaceae (Fusobacterium and Leptotrichia). Prediction of bacterial metabolic contribution indicated that serological status had a significant impact on metabolic function, while carbohydrate digestion and pathways were enriched in GC. Our findings highlight three mechanisms of interest in GC, including enrichment of pro-inflammatory oral bacterial species, increased abundance of lactic acid producing bacteria, and enrichment of short chain fatty acid production pathways. PMID- 29162925 TI - Toxicological and biochemical responses of the earthworm Eisenia fetida to cyanobacteria toxins. AB - Irrigation with eutrophic water containing cyanobacteria toxins poses a potential risk to soil animals. To evaluate ecotoxicological effect of microcystins (MCs) on earthworms, filter paper acute toxicity test, avoidance test and a 14-d artificial soil test were carried out. No acute toxicity was found in the filter paper test, and earthworms showed no avoidance response to MCs exposure. In the artificial soil test, Eisenia fetida were allowed to grow in presence or absence of MCs (0, 1, 10, 100, 1000 MUg kg-1 of soil) for 1, 7, and 14 d. Results showed that MCs could bioaccumulated in earthworm. A stimulatory effect on catalase and glutathione oxidase activities induced by MCs was found on day 1, and both of them were significantly inhibited at 100 and 1000 MUg kg-1 on days 14. The superoxide dismutase activity was relatively insensitive. Significant increase of malondialdehyde content and decrease of neutral red retention time were observed at 100 and 1000 MUg kg-1 on days 7 and 14. Our results suggest that MCs induces oxidative stress on earthworms, which leads to disruption of the antioxidant system and lipid peroxidation, as well as alterations in lysosomal membrane stability. PMID- 29162926 TI - The relationship between soluble CD40 ligand level and atherosclerosis in white coat hypertension. AB - This study was designed to examine the distribution of plasma soluble CD40 ligand (sCD40L), and its relationship with carotid intima-media thickness (CIMT) in healthy controls and subjects with white-coat hypertension (WCH) or hypertension (HT). Thirty-five patients with HT, 35 patients with WCH, and 35 healthy controls were enrolled. The normal group (CIMT < 0.9 mm), subclinical atherosclerosis group (0.9 mm <= CIMT < 1.2 mm) and atherosclerosis group (CIMT >= 1.2 mm) were grouped based on the value of CIMT. The highest level of sCD40L was observed in HT group, followed by WCH group and healthy controls. The level of sCD40L was significantly increased in atherosclerosis group compared with subclinical atherosclerosis group and healthy controls. In the WCH group, sCD40L level was significantly and positively correlated with CIMT and systolic blood pressure. Multiple logistic regression indicated that sCD40L was a risk factor for increased CIMT (odds ratio, 1.504; 95% confidence interval, 1.054-1.956, P < 0.001). The data provided evidence that sCD40L levels in subjects with WCH and HT were significantly and consistently higher than those in healthy controls. SCD40L may represent a potential non-invasive atherosclerosis marker in WCH patients. PMID- 29162927 TI - Dislocation Multiplications in Extremely Small Hexagonal-structured Titanium Nanopillars Without Dislocation Starvation. AB - "Smaller is stronger" has been commonly observed in cubic structured and hexagonal close-packed (HCP) structured materials. Dislocation starvation phenomenon is highly responsible for the increase of strength at smaller scale in cubic materials. However, by using quantitative in situ transmission electron microscope (TEM) nano-mechanical testing on cylindrical titanium nano-pillars with diameters of ~150 nm but varied orientations and three dimensional dislocation tomography, we found that dislocation nucleation and multiplication dominate the plastic deformation of the nano-pillars with no sign of dislocation starvation, resulting in much better ability of dislocation storage and plastic stability of HCP structured materials at extremely small scale. PMID- 29162928 TI - Motor actions influence subsequent sensorimotor decisions. AB - Sensorimotor decisions are influenced by factors beyond the current sensory input, but little is known about the effect of preceding motor actions. Here, we show that choice-unrelated motor actions influence subsequent sensorimotor decisions. By instructing participants to perform choice-unrelated motor responses before visuomotor decisions, we could manipulate upcoming decisions in a directed fashion. Subjects tended not to repeat the instructed motor response. Our results show that simple motor behaviors can influence subsequent sensorimotor decision. PMID- 29162929 TI - Genomic assessment in Lactobacillus plantarum links the butyrogenic pathway with glutamine metabolism. AB - The butyrogenic capability of Lactobacillus (L.) plantarum is highly dependent on the substrate type and so far not assigned to any specific metabolic pathway. Accordingly, we compared three genomes of L. plantarum that showed a strain specific capability to produce butyric acid in human cells growth media. Based on the genomic analysis, butyric acid production was attributed to the complementary activities of a medium-chain thioesterase and the fatty acid synthase of type two (FASII). However, the genomic islands of discrepancy observed between butyrogenic L. plantarum strains (S2T10D, S11T3E) and the non-butyrogenic strain O2T60C do not encompass genes of FASII, but several cassettes of genes related to sugar metabolism, bacteriocins, prophages and surface proteins. Interestingly, single amino acid substitutions predicted from SNPs analysis have highlighted deleterious mutations in key genes of glutamine metabolism in L. plantarum O2T60C, which corroborated well with the metabolic deficiency suffered by O2T60C in high-glutamine growth media and its consequent incapability to produce butyrate. In parallel, the increase of glutamine content induced the production of butyric acid by L. plantarum S2T10D. The present study reveals a previously undescribed metabolic route for butyric acid production in L. plantarum, and a potential involvement of the glutamine uptake in its regulation. PMID- 29162930 TI - Chemopreventive effects of Ku-jin tea against AOM-induced precancerous colorectal lesions in rats and metabolomic analysis. AB - Ku-jin tea (KJT) is a health beverage prepared from the leaves of the plant Acer tataricum subsp. ginnala that has been consumed in some regions of China for thousands of years. KJT contains high levels of anti-inflammatory and antioxidative compounds such as ginnalins, but little is known about the chemopreventive effect of KJT on colon cancer. In this study, we investigated the preventive effects of KJT on colon carcinogenesis using the azoxymethane (AOM) induced precancerous colorectal lesion model in rats. The results showed that the number of aberrant crypts, aberrant crypt foci (ACF) and crypts/focus in rats of the KJT + AOM group were significantly decreased compared with rats of the AOM group (p < 0.01). Further exploration of the prevention mechanism of KJT by UPLC QTOF/MS-based urinary metabolomics showed that 5 metabolic pathways were modulated, including purine metabolism and amino acid metabolism, in the group with KJT. In addition, the levels of the immunomodulatory cytokines IL-1alpha and IL-10 were significantly decreased, and the levels of IL-2 in the serum of AOM rats increased after KJT treatment. Our present data suggest that KJT can inhibit AOM-induced colonic ACF formation and might be a useful chemopreventive agent against colorectal carcinogenesis. PMID- 29162931 TI - Comparison of clinical outcomes with InterTan vs Gamma nail or PFNA in the treatment of intertrochanteric fractures: A meta-analysis. AB - Intertrochanteric fractures are common injuries in the elderly. Conventional intramedullary nails including Gamma 3 locking nail and proximal femoral nail antirotation (PFNA) were designed for unstable intertrochanteric fractures. The InterTan (IT) nail system, introduced in 2005, has been reported superior biomechanical and clinical outcomes compared with 1-screw nailing system. However, some recent studies have reported that IT did not improve functional recovery in patients with intertrochanteric fractures. Randomized controlled trials (RCTs) or prospective cohort studies were included in our meta-analysis. We used the PRISMA guidelines and Cochrane Handbook to evaluate the quality of included studies to ensure that the pooled data of our meta-analysis were reliable and veritable. Our pooled data analysis demonstrated that IT was as effective as the control group in terms of Harris Hip Score (HHS), blood loss, total complications, union time, length of hospital stay, revision rate, and fluoroscopy time. IT shows less implant cut-out rate and femoral fractures when compared with control groups. PMID- 29162933 TI - Deep characterization of a common D4Z4 variant identifies biallelic DUX4 expression as a modifier for disease penetrance in FSHD2. AB - Facioscapulohumeral muscular dystrophy is caused by incomplete repression of the transcription factor DUX4 in skeletal muscle as a consequence of D4Z4 macrosatellite repeat contraction in chromosome 4q35 (FSHD1) or variants in genes encoding D4Z4 chromatin repressors (FSHD2). A clinical hallmark of FSHD is variability in onset and progression suggesting the presence of disease modifiers. A well-known cis modifier is the polymorphic DUX4 polyadenylation signal (PAS) that defines FSHD permissive alleles: D4Z4 chromatin relaxation on non-permissive alleles which lack the DUX4-PAS cannot cause disease in the absence of stable DUX4 mRNA. We have explored the nature and relevance of a common variant of the major FSHD haplotype 4A161, which is defined by 1.6 kb size difference of the most distal D4Z4 repeat unit. While the short variant (4A161S) has been extensively studied, we demonstrate that the long variant (4A161L) is relatively common in the European population, is capable of expressing DUX4, but that DUX4 mRNA processing differs from 4A161S. While we do not find evidence for a difference in disease severity between FSHD carriers of an 4A161S or 4A161L allele, our study does uncover biallelic DUX4 expression in FSHD2 patients. Compared to control individuals, we observed an increased frequency of FSHD2 patients homozygous for disease permissive alleles, and who are thus capable of biallelic DUX4 expression, while SMCHD1 variant carriers with only one permissive allele were significantly more often asymptomatic. This suggests that biallelic DUX4 expression lowers the threshold for disease presentation and is a modifier for disease severity in FSHD2. PMID- 29162934 TI - Decision making and experiences of young adults undergoing presymptomatic genetic testing for familial cancer: a longitudinal grounded theory study. AB - Enabling informed choice is an essential component of care when offering young adults presymptomatic testing for a genetic condition. A systematic review on this topic revealed that many young adults grew up with little information regarding their genetic risk and that parents had applied pressure to them during the testing decision-making process. However, none of the studies retrieved were conducted in South European countries. To address this gap, we undertook a qualitative study based on grounded theory to explore the psychosocial implications of presymptomatic testing for hereditary cancer in Italian young adults aged 18-30 years. Interviews were conducted on three occasions: 1 month before counselling, and 2 weeks and 6 months after results. Data were coded and grouped under themes. A total of 42 interviews were conducted. Four themes emerged: knowledge, genetic counselling process, decision making and dealing with test results. Although participants grew up with little or no information about their genetic risk, none expressed regret at having the test at a young age. Pre test counselling was appreciated as a source of information, rather than support for decision making. Decisions were often made autonomously and sometimes conflicted with parents' wishes. Participants reported no changes in health behaviours after testing. This evidence highlights the need for a comprehensive, longitudinal counselling process with appropriate timing and setting, which supports 'parent-to-offspring' risk communication first and decision making by young adults about presymptomatic testing and risk management afterwards. In conclusion, it is clear that counselling approaches for presymptomatic testing may require modification both for young adults and their parents. PMID- 29162936 TI - Liver cancer: A complex interplay between inflammation and immunity in liver cancer. PMID- 29162937 TI - Spontaneous body contractions are modulated by the microbiome of Hydra. AB - Spontaneous contractile activity, such as gut peristalsis, is ubiquitous in animals and is driven by pacemaker cells. In humans, disruption of the contraction pattern leads to gastrointestinal conditions, which are also associated with gut microbiota dysbiosis. Spontaneous contractile activity is also present in animals lacking gastrointestinal tract. Here we show that spontaneous body contractions in Hydra are modulated by symbiotic bacteria. Germ free animals display strongly reduced and less regular contraction frequencies. These effects are partially restored by reconstituting the natural microbiota. Moreover, soluble molecule(s) produced by symbiotic bacteria may be involved in contraction frequency modulation. As the absence of bacteria does not impair the contractile ability itself, a microbial effect on the pacemakers seems plausible. Our findings indicate that the influence of bacteria on spontaneous contractile activity is present in the early-branching cnidarian hydra as well as in Bilateria, and thus suggest an evolutionary ancient origin of interaction between bacteria and metazoans, opening a window into investigating the roots of human motility disorders. PMID- 29162935 TI - Hepatitis E virus: advances and challenges. AB - At least 20 million hepatitis E virus (HEV) infections occur annually, with >3 million symptomatic cases and ~60,000 fatalities. Hepatitis E is generally self limiting, with a case fatality rate of 0.5-3% in young adults. However, it can cause up to 30% mortality in pregnant women in the third trimester and can become chronic in immunocompromised individuals, such as those receiving organ transplants or chemotherapy and individuals with HIV infection. HEV is transmitted primarily via the faecal-oral route and was previously thought to be a public health concern only in developing countries. It is now also being frequently reported in industrialized countries, where it is transmitted zoonotically or through organ transplantation or blood transfusions. Although a vaccine for HEV has been developed, it is only licensed in China. Additionally, no effective, non-teratogenic and specific treatments against HEV infections are currently available. Although progress has been made in characterizing HEV biology, the scarcity of adequate experimental platforms has hampered further research. In this Review, we focus on providing an update on the HEV life cycle. We will further discuss existing cell culture and animal models and highlight platforms that have proven to be useful and/or are emerging for studying other hepatotropic (viral) pathogens. PMID- 29162939 TI - Intravesicular administration of sodium hyaluronate ameliorates the inflammation and cell proliferation of cystitis cystica et glandularis involving interleukin 6/JAK2/Stat3 signaling pathway. AB - Cystitis cystica et glandularis (CCEG) is a chronic cystitis that causes extreme agony in affected patients. However, there are lack of effective conservative treatments. In this study, it is evident that intravesicular sodium hyaluronate (SH) therapy significantly improved the clinical symptoms of CCEG patients and ameliorated the bladder mucosal inflammation and cell proliferation characteristics of the disease. Immunohistochemical staining showed that the staining intensities of hyaluronidase (HYAL 1/2), CD44, IL-6 and phosphorylated signal transducer and activator of transcription 3 (p-Stat3) in bladder mucosal tissue were significantly increased in CCEG patients compared with control patients and that intravesicular SH treatment suppressed these protein expression. We established a CCEG rat model by treating rats with E. coli intravesicularly, and we found that HYAL 1/2 and CD44 expression levels were significantly increased in the E. coli group compared with the NC group. Activation of the IL-6/JAK2/Stat3 pathway and the expression levels of the downstream pro-apoptotic proteins Mcl-1 and Bcl-xL were also significantly increased in the E. coli group compared with the NC group. The above changes were significantly mitigated by intravesicular SH treatment. Therefore, SH may serve as an effective therapy for CCEG by inhibiting bladder mucosal inflammation and proliferation. PMID- 29162940 TI - Trophy hunting certification. PMID- 29162938 TI - RNA metabolism is the primary target of formamide in vivo. AB - The synthesis, processing and function of coding and non-coding RNA molecules and their interacting proteins has been the focus of a great deal of research that has boosted our understanding of key molecular pathways that underlie higher order events such as cell cycle control, development, innate immune response and the occurrence of genetic diseases. In this study, we have found that formamide preferentially weakens RNA related processes in vivo. Using a non-essential Schizosaccharomyces pombe gene deletion collection, we identify deleted loci that make cells sensitive to formamide. Sensitive deletions are significantly enriched in genes involved in RNA metabolism. Accordingly, we find that previously known temperature-sensitive splicing mutants become lethal in the presence of the drug under permissive temperature. Furthermore, in a wild type background, splicing efficiency is decreased and R-loop formation is increased in the presence of formamide. In addition, we have also isolated 35 formamide-sensitive mutants, many of which display remarkable morphology and cell cycle defects potentially unveiling new players in the regulation of these processes. We conclude that formamide preferentially targets RNA related processes in vivo, probably by relaxing RNA secondary structures and/or RNA-protein interactions, and can be used as an effective tool to characterize these processes. PMID- 29162941 TI - Aerobic performance in tinamous is limited by their small heart. A novel hypothesis in the evolution of avian flight. AB - Some biomechanical studies from fossil specimens suggest that sustained flapping flight of birds could have appeared in their Mesozoic ancestors. We challenge this idea because a suitable musculoskeletal anatomy is not the only requirement for sustained flapping flight. We propose the "heart to fly" hypothesis that states that sustained flapping flight in modern birds required an enlargement of the heart for the aerobic performance of the flight muscles and test it experimentally by studying tinamous, the living birds with the smallest hearts. The small ventricular size of tinamous reduces cardiac output without limiting perfusion pressures, but when challenged to fly, the heart is unable to support aerobic metabolism (quick exhaustion, larger lactates and post-exercise oxygen consumption and compromised thermoregulation). At the same time, cardiac growth shows a crocodilian-like pattern and is correlated with differential gene expression in MAPK kinases. We integrate this physiological evidence in a new evolutionary scenario in which the ground-up, short and not sustained flapping flight displayed by tinamous represents an intermediate step in the evolution of the aerobic sustained flapping flight of modern birds. PMID- 29162942 TI - Developmental evolution facilitates rapid adaptation. AB - Developmental evolution has frequently been identified as a mode for rapid adaptation, but direct observations of the selective benefits and associated mechanisms of developmental evolution are necessarily challenging to obtain. Here we show rapid evolution of greatly increased rates of dispersal by developmental changes when populations experience stringent selection. Replicate populations of the filamentous fungus Trichoderma citrinoviride underwent 85 serial transfers, under conditions initially favoring growth but not dispersal. T. citrinoviride populations shifted away from multicellular growth toward increased dispersal by producing one thousand times more single-celled asexual conidial spores, three times sooner than the ancestral genotype. Conidia of selected lines also germinated fifty percent faster. Gene expression changed substantially between the ancestral and selected fungi, especially for spore production and growth, demonstrating rapid evolution of tight regulatory control for down-regulation of growth and up-regulation of conidia production between 18 and 24 hours of growth. These changes involved both developmentally fixed and plastic changes in gene expression, showing that complex developmental changes can serve as a mechanism for rapid adaptation. PMID- 29162943 TI - Leukaemia: Crowd control. PMID- 29162944 TI - Immunotherapy: Rewiring cancer cells. PMID- 29162945 TI - Metabolism: Conscious decoupling. PMID- 29162947 TI - Tumour biomarkers: A mark is a marker. PMID- 29162946 TI - Targeting immunosuppressive adenosine in cancer. PMID- 29162948 TI - Association between Recipient IL-15 Genetic Variant and the Prognosis of HBV Related Hepatocellular Carcinoma after Liver Transplantation. AB - Objective: To investigate the association of donor and recipient IL-15 genetic variants with HCC recurrence and prognosis after LT. Methods: A total of 112 liver transplant patients with HBV-related HCC were enrolled. IL-15 rs10519613 and rs13122930 were genotyped in donors and recipients. Results: Recipient IL-15 rs10519613 polymorphism was found to be significantly related to HCC recurrence after LT. In multivariate analysis, tumor thrombus, UCSF criteria, and recipient IL-15 rs10519613 genotypes were independent predictive factors of HCC recurrence after LT. Kaplan-Meier survival analysis demonstrated that patients with recipient IL-15 rs10519613 CA/AA genotypes had a decreased disease-free survival and overall survival than those with the CC genotype. Recipient IL-15 rs10519613 genetic variant could improve survival prediction when combined with the UCSF criteria. Furthermore, Cox proportional hazard regression analysis revealed that tumor size (p = 0.012, p = 0.623), tumor thrombus (p = 0.011, p = 0.015), UCSF criteria (p = 0.471, p = 0.013), and recipient IL-15 rs10519613 genotype (p = 0.039, p = 0.008) were independent factors of predicting DFS and OS. Conclusions: Recipient IL-15 rs10519613 polymorphism was associated with HCC recurrence after LT and might be a potential genetic marker for the clinical outcome of HCC patients treated with LT. PMID- 29162950 TI - Intrauterine Insemination: Fundamentals Revisited. AB - Intrauterine insemination (IUI) is an assisted conception technique that involves the deposition of a processed semen sample in the upper uterine cavity, overcoming natural barriers to sperm ascent in the female reproductive tract. It is a cost-effective, noninvasive first-line therapy for selected patients with functionally normal tubes, and infertility due to a cervical factor, anovulation, moderate male factor, unexplained factors, immunological factor, and ejaculatory disorders with clinical pregnancy rates per cycle ranging from 10 to 20%. It, however, has limited use in patients with endometriosis, severe male factor infertility, tubal factor infertility, and advanced maternal age >= 35 years. IUI may be performed with or without ovarian stimulation. Controlled ovarian stimulation, particularly with low-dose gonadotropins, with IUI offers significant benefit in terms of pregnancy outcomes compared with natural cycle or timed intercourse, while reducing associated COH complications such as multiple pregnancies and ovarian hyperstimulation syndrome. Important prognostic indicators of success with IUI include age of patient, duration of infertility, stimulation protocol, infertility etiology, number of cycles, timing of insemination, number of preovulatory follicles on the day of hCG, processed total motile sperm > 10 million, and insemination count > 1 * 106 with > 4% normal spermatozoa. Alternative insemination techniques, such as Fallopian tube sperm perfusion, intracervical insemination, and intratubal insemination, provide no additional benefit compared to IUI. A complete couple workup that includes patient history, physical examination, and clinical and laboratory investigations is mandatory to justify the choice in favor of IUI and guide alternative patient management, while individualizing the treatment protocol according to the patient characteristics with a strict cancelation policy to limit multi-follicular development may help optimize IUI pregnancy outcomes. PMID- 29162951 TI - Down Syndrome Screening in India: Are We There Yet? AB - Down syndrome is the most common cause of intellectual disability among live born children and is amenable to prenatal detection. Screening for Down syndrome on a population basis requires a thorough understanding of the principles involved in the screening tests. We discuss the rationale behind the commonly available screening tests and the Indian scenario in this setting. PMID- 29162952 TI - Oral Health Status and Fertility Treatment Including IVF. AB - Oral health is extremely important for the general wellbeing of the individual. From a number of research articles, it is established that there is a definitive connection between periodontal health and many systemic diseases, like type II diabetes, cardiovascular diseases and even preterm labor and low birth weight of babies. The significant rate of failure in the treatment of infertility and IVF (in vitro fertilization) even with multiple advancements in the last decade has made scientist take interest in newer parameters of health, an important one among them being periodontal health. From the limited number of studies available on the relationship between periodontitis and reproductive health, it can be inferred that periodontitis can act as a focus of infection leading to bacteremia which can lead to complications in conceiving naturally or through IVF in women. A limited number of studies have also reported an association between male factor infertility (MFI) and dental health status of men. Although more research is needed to understand and explore this connection, this article reviews the current literature available linking poor oral health to infertility and poor outcomes of IVF. PMID- 29162949 TI - Neuromuscular Electrical Stimulation for Treatment of Muscle Impairment: Critical Review and Recommendations for Clinical Practice. AB - Purpose: In response to requests from physiotherapists for guidance on optimal stimulation of muscle using neuromuscular electrical stimulation (NMES), a review, synthesis, and extraction of key data from the literature was undertaken by six Canadian physical therapy (PT) educators, clinicians, and researchers in the field of electrophysical agents. The objective was to identify commonly treated conditions for which there was a substantial body of literature from which to draw conclusions regarding the effectiveness of NMES. Included studies had to apply NMES with visible and tetanic muscle contractions. Method: Four electronic databases (CINAHL, Embase, PUBMED, and SCOPUS) were searched for relevant literature published between database inceptions until May 2015. Additional articles were identified from bibliographies of the systematic reviews and from personal collections. Results: The extracted data were synthesized using a consensus process among the authors to provide recommendations for optimal stimulation parameters and application techniques to address muscle impairments associated with the following conditions: stroke (upper or lower extremity; both acute and chronic), anterior cruciate ligament reconstruction, patellofemoral pain syndrome, knee osteoarthritis, and total knee arthroplasty as well as critical illness and advanced disease states. Summaries of key details from each study incorporated into the review were also developed. The final sections of the article outline the recommended terminology for describing practice using electrical currents and provide tips for safe and effective clinical practice using NMES. Conclusion: This article provides physiotherapists with a resource to enable evidence-informed, effective use of NMES for PT practice. PMID- 29162953 TI - Evaluation of Spot Urinary Albumin-Creatinine Ratio as Screening Tool in Prediction of Pre-eclampsia in Early Pregnancy. AB - Objective: The aim of this study was to establish whether a spot urinary albumin/creatinine ratio (ACR) measured between 20 and 28 weeks of gestation can predict subsequent pre-eclampsia in asymptomatic pregnant women. Design: Prospective observational study. Subjects: The patients included sixty-two women with singleton pregnancy, normal renal function and no evident proteinuria, attending antenatal clinics between 20 and 28 weeks of gestation in a tertiary care hospital. Methods: The ACR was determined from midstream urine sample taken between 20 and 28 weeks of gestation. Estimation of albumin was done by immunoturbidimetric microalbumin method and creatinine by modified Jaffe's method. Results: Incidence of pre-eclampsia in the study group was 12.90%. The cut-off value for ACR was taken as 35.5 mg/mol. The mean ACR in normotensive group was 19.26 +/- 7.99, and in pre-eclampsia group it was 51.95 +/- 18.78. For pre-eclampsia, screening in early pregnancy, spot ACR cut-off >=35.5 mg/mol has sensitivity of 87.5%, specificity of 96.30%, PPV of 77.78% and NPV of 98.11%. Conclusions: Spot urinary ACR values are higher in asymptomatic women in early pregnancy, who developed pre-eclampsia later on. When measured early in the second trimester, an ACR >= 35.5 mg/mmol predicted pre-eclampsia well before the onset of clinical manifestations with high sensitivity and specificity. It can be used as a good screening tool for predicting pre-eclampsia in early pregnancy. PMID- 29162954 TI - Analyses of Nutrients and Body Mass Index as Risk Factor for Preeclampsia. AB - Background: Little is known about the pathogenesis of preeclampsia. Many factors are identified as risk factors for preeclampsia including nutrients and obesity. The aim of this study was to assess whether nutrients and body mass index (BMI) are risk factors for preeclampsia. Methods: This was a case-control study at the Department of Obstetric and Gynecology in Dr. M. Djamil Hospital, Padang, Indonesia. A total of 140 patients were enrolled in this study with 70 cases and 70 controls. All subjects completed an interview for their nutritional status and prepregnancy BMI after delivery. The nutritional status was assessed by Food Frequency Questionnaire and then analyzed by Nutrisurvey Program. The independent samples t test was used for nutritional status, and Chi-square test was used for BMI. For nutrients, logistic regression procedures were employed to calculate potential risk factors associated with preeclampsia. Results: Prevalence of abnormal BMI was more common in the preeclampsia group compared with those without preeclampsia 19 (27.1%) versus 12 (17.1%) but not found as a significant risk factor in this study (p = 0.222). Deficiency of vitamin E (OR 1.76, 95% CI 10.2 +/- 30.5), zinc (OR 99.4, 95% CI 1.37 +/- 7219), fat (OR 59.1, 95% CI 3.14 +/- 500), calcium (OR 109, 95% CI 0.29 +/- 40,041), vitamin C (OR 19.5, 95% CI 2.52 +/- 151) were associated with increased risk of preeclampsia. Excess of carbohydrate was associated with increased risk of preeclampsia (OR 52.9, 95% CI 0.801 +/- 3495). Conclusions: Deficiency of vitamin E, zinc, fat, calcium, and vitamin C, and excess of calories and carbohydrate were associated with increased risk of preeclampsia. PMID- 29162955 TI - Diagnosis and Management of 'Cornual' Pregnancies from 2002 to 2015 at a Tertiary Referral Centre in South India: Insights from Introspection. AB - Purpose: Interstitial, angular and rudimentary horn pregnancies have all been referred to as cornual pregnancies despite definite diagnostic criteria. Angular pregnancies can be followed up expectantly under close surveillance while interstitial and rudimentary horn pregnancies are terminated by medical or surgical methods. This study aimed to assess accuracy of ultrasound in the diagnosis of 'cornual pregnancy' and evaluate management. Methods: Data pertaining to clinical features, ultrasound findings and treatment modalities of the aforementioned conditions between January 2002 and December 2015 at a tertiary perinatal centre were retrieved from the medical records. The ultrasound images and surgical videos were reviewed by the authors. Results: Of 62 cases, 35 were interstitial, 26 were angular/eccentric intrauterine, and 1 was a rudimentary horn pregnancy. The accuracy of ultrasonography in the diagnosis of interstitial and angular pregnancies was 71.0 and 46.8%, respectively. Medical management was successful in 33.3% of interstitial pregnancies. Fifteen women with interstitial pregnancy had subsequent pregnancies and nine (75.0%) were Caesarean deliveries. Rupture and recurrence rates of interstitial pregnancy were 34.2 and 2.9%, respectively. The rudimentary horn pregnancy was managed by laparoscopic excision followed by a subsequent term delivery. Conclusion: This study identified frequent occurrences of imprecise nomenclature that resulted in mismanagement of a few potentially viable angular pregnancies. It is imperative for clinicians and sonologists to use unambiguous nomenclature and avoid the term 'cornual pregnancy' altogether. PMID- 29162956 TI - Risk Assessment at 11-14-Week Antenatal Visit: A Tertiary Referral Center Experience from South India. AB - Background: Present study carried out in a tertiary referral hospital in South India attempts to determine the predictive value of integrated screening at 11-14 week antenatal visit. Objectives: To determine the detection rate of fetal abnormalities at 11-14 weeks and also to predict the placental dysfunction disorders based on early integrated evaluation. Method: Integrated screening performed on 440 women between 11 and 14 weeks, including detailed maternal history [medical history, bad obstetric history (BOH)], body mass index (BMI), mean arterial pressure (MAP), detailed ultrasound and maternal serum biochemistry as part of combined first-trimester screening for aneuploidy. Results: There were two proven Down's syndrome foetuses; both detected with combined screening test. There were 12 fetuses with major anomalies, out of whom 7 (58.3%) detected in 11 14-week scan. Among 440, 114 pregnancies (25.9%) developed complications in pregnancy, including 33 (7.5%) gestational hypertension, 8 (1.8%) pre-eclampsia, 41 (9.38%) SGA, 13 (2.9%) abortions, 22 (5%) indicated and 9 (2.04%) spontaneous preterm deliveries, 38 (8.63%) GDM and 3 (0.6%) stillbirth/IUD. Among the risk factors, age >35 years, BMI >23 kg/m2, BOH, MAP >105 mmHg and PAPP-A <0.5 MoM correlated well with adverse outcome. Using early integrated screening, 78.9% of obstetric complications could be predicted although 306 (69.5%) were labeled high risk, among whom 90 (29.4%) developed adverse pregnancy outcomes. Conclusions: Majority of fetal abnormalities can be detected, and majority adverse pregnancy outcomes can be predicted at 11-14-week antenatal visit, although this study shows high screen positivity and low specificity in a tertiary referral unit. PMID- 29162957 TI - Geriatric Pelvic Organ Prolapse Surgery: Going the Extra Mile. AB - Background: To assess the quality of life in geriatric patients after reconstructive and obliterative vaginal surgery for advanced pelvic organ prolapse (POP). Methods: Prospective observational study was conducted between January 2009 and December 2014 at the department of Urogynaecology, Government Kasturbha Gandhi Hospital. A total of 424 women (between the age group of 60 and 94 years) with advanced pelvic organ prolapse underwent vaginal hysterectomy along with vaginal apical suspension procedures which were McCalls culdoplasty (35.02%), sacrospinous ligament suspension (8.3%), high uterosacral ligament suspension (26.2%), iliococcygeus fixation (4.6%) for stage 3-4 POP. Abdominal sacrocolpopexy (3.2%) was done for stage 3-4 vaginal vault prolapse. Patients with medical comorbidities underwent Leeforts partial colpocleisis (8.1%) and total colpocleisis (2%) for stage 3 and 4 POP. Site-specific repair (12.5%) was done for stage 3/4 cystocele and rectocele. The main outcomes measured were subjective cure (no prolapse), subjective improvements in pelvic floor symptoms as per the pelvic floor impact questionnaire, and objective cure (no prolapse of vaginal segment on maximum straining). Results: Mean age of the patient was 64.29 years. The major complication rates were less than 1%. 85% were examined at 3 and 12 months. The subjective cure rate at 12 months is 92% and the objective cure rate is 94.5%. Conclusion: The geriatric patients who underwent either reconstructive or obliterative procedures were relieved of their preoperative symptoms and their quality of life had greatly improved. PMID- 29162958 TI - Serous Tubal Carcinogenesis: The Recent Concept of Origin of Ovarian, Primary Peritoneal and Fallopian Tube High-Grade Serous Carcinoma. AB - Background: Pelvic (non-uterine) high-grade serous carcinomas (PHGSC) including ovarian, tubal and primary peritoneal serous carcinomas have increased death: incidence ratio due to presentation at advanced stage, rapid progression, poor prognosis and high morbidity. Ambiguity regarding their pathogenesis and lack of a proper screening method is the cause of their late detection and high fatality rate. This study was undertaken to assess the fallopian tube for the presence of precursor lesions in pelvic serous carcinoma. Methods: This was a prospective case-control study carried out in a tertiary care center. Consecutive specimens of 55 cases of pelvic high-grade serous carcinoma and 41 controls inclusive of 21 low-grade serous carcinoma, 10 benign adnexal masses and 10 normal adnexa were included in the study. Both side fallopian tubes in each case were subjected to histopathological examination and p53, Ki67 immunohistochemistry. Results: There were 55 cases of PHGSC comprising of 50 cases of ovarian HGSC, two cases of primary peritoneal carcinoma (PPC) and three cases of tubal carcinoma. Serous tubal intraepithelial carcinoma (STIC) was detected in 14 cases (28%), p53 signature in 13 cases (26%) and tubal intraepithelial lesion in transition in 10 cases (20%) of ovarian HGSC. One case (50%) of PPC and one (33%) case of tubal carcinoma revealed the presence of STIC. None of the controls exhibited any precursor lesion except ovarian low-grade serous carcinoma where p53 was detected in 20% of cases. Conclusion: This revelation concludes that fallopian tubes are the sites of precursors of PHGSC to a large extent. In the absence of a proper screening method of HGSC, prophylactic bilateral salpingectomy at hysterectomy for benign diseases can achieve ultimate goal of reduction in incidence of PHGSC. PMID- 29162959 TI - Breast Cancer in Pregnancy. PMID- 29162960 TI - A Rare Report of Concurrent Serous and Mucinous Cystadenomas in Bilateral Ovaries. PMID- 29162961 TI - Pisat's Visual Vasopressor Injection Needle: A New Device for Increasing Patient Safety in Laparoscopic Myomectomy. AB - Introduction: The use of vasopressin and other vasoconstrictive agents to reduce blood loss during laparoscopic myomectomy significantly reduces blood loss and operative time. However, serious cardiovascular complications following the use of intra-myometrial injection of vasopressin solution have also been reported. Most of these side effects are believed to be due to inadvertent intravascular injection of vasopressin solution. Aims and Objectives: To describe a new design of an injection needle, Pisat's Visual Vasopressor Injection Needle (VVIN), that can be used during laparoscopic myomectomy to minimise the incidence of an inadvertent intravascular injection of a vasoconstrictor solution. Results: A total of 53 patients who underwent laparoscopic myomectomy at various hospitals in Mumbai, India, were studied over a period of two years. Out of these, 23 patients were operated upon using a standard 5-mm laparoscopic injection needle, and 30 patients were operated upon by using a VVIN. Out of the 23 patients in whom a regular needle was used, four patients (17.39%) demonstrated a significant (over 20 percent of pre-injection value) but transient elevation in pulse and blood pressure readings at 1-min post-injection. This gradually returned to baseline at 10 min after the injection. None of the 30 patients in whom VVIN was used after confirming a negative aspiration demonstrated any significant change in post-injection pulse or blood pressure recordings. Conclusions: Using a VVIN during a laparoscopic myomectomy enables the surgeon to detect an inadvertent vascular puncture very early, even in a small calibre blood vessel, and with much more sensitivity than a regular needle. This increases patient safety during the intra-myometrial injection of a vasoconstrictive agent during myomectomy and reduces the incidence of catastrophic complications. PMID- 29162962 TI - Comment on "Panicker's Vacuum Suction Hemostatic Device for Treating Postpartum Hemorrhage". PMID- 29162963 TI - Molecular modeling and simulation of three important components of Plant Pathogen Interaction cascade in Vigna mungo. AB - Plant pathogen interaction plays a great role in plant immunity. The regulation of various components of plant pathogen interactions is quite complicated and is very important in establishing relationship among components of this system. Yellow Mosaic Disease is common among legumes such as Vigna mungo. Mungbean Yellow Mosaic India Virus (MYMIV) and whitefly (Bemisia tabaci) is a vector causing the disease. Therefore, it is of interest to document the molecule models of three different components of Plant Pathogen interaction cascade- MAP kinase1, MAP kinase 2 and WRKY33 from V. mungo resistant to MYMIV. Both the MAP kinases were sequenced for this study while WRKY 33 was extracted and modeled from transcripts generated from two different transcriptome libraries, one set MYMIV- challenged, the other fed with aviruliferous whitefly. Post simulation studies revealed that MAPKs contained less percentage of disordered residues and were structurally more stable and than WRKY33. PMID- 29162964 TI - Robust Feature Selection Approach for Patient Classification using Gene Expression Data. AB - Patient classification through feature selection (FS) based on gene expression data (GED) has already become popular to the research communities. T-test is the well-known statistical FS method in GED analysis. However, it produces higher false positives and lower accuracies for small sample sizes or in presence of outliers. To get rid from the shortcomings of t-test with small sample sizes, SAM has been applied in GED. But, it is highly sensitive to outliers. Recently, robust SAM using the minimum beta-divergence estimators has overcome all the problems of classical t-test & SAM and it has been successfully applied for identification of differentially expressed (DE) genes. But, it was not applied in classification. Therefore, in this paper, we employ robust SAM as a feature selection approach along with classifiers for patient classification. We demonstrate the performance of the robust SAM in a comparison of classical t-test and SAM along with four popular classifiers (LDA, KNN, SVM and naive Bayes) using both simulated and real gene expression datasets. The results obtained from simulation and real data analysis confirm that the performance of the four classifiers improve with robust SAM than the classical t-test and SAM. From a real Colon cancer dataset we identified 21 additional DE genes using robust SAM that were not identified by the classical t-test or SAM. To reveal the biological functions and pathways of these 21 genes, we perform KEGG pathway enrichment analysis and found that these genes are involved in some important pathways related to cancer disease. PMID- 29162965 TI - Host Infection beyond the Traditional Range of Sclerotium (Athelia) rolfsii with Physalis minima. AB - Physalis minima is an herbaceous plant and inhabitant of the porous and organic matter containing soil of bunds in crop fields, wastelands, around the houses, and on the roadsides. S. rolfsii is soil borne and it can infect over 500 plant species of different families. It is of interest to study the pathogenesis of S. rolfsii on P. minima. The S. rolfsii isolated from P. minima (physr1) was characterized by morphology and sequence of Internal Transcribed Spacer (ITS) region. The population structure determination and phylogenetic analysis showed the isolate physr1 significantly differs from other isolates. The null hypothesis of equal evolutionary rate was rejected throughout the Maximum likelihood (ML) tree topology of different S. rolfsii ITS sequences. The site-specific mean (relative) evolutionary rate analysis showed that most of the sites (80.59 % sites) evolved at a slower rate than average. Finally, the result of Tajima's neutrality test indicated that the population of S. rolfsii has recently begun to expand and that's why the pathogen was infecting the new host P. minima and pose a serious threat of infecting several other cropped and non-cropped hosts. PMID- 29162966 TI - A QSAR model of Olanzapine derivatives as potential inhibitors for 5-HT2A Receptor. AB - Schizophrenia is a complex, chronic mental disorder, affecting about 21 million people worldwide. It is characterized by symptoms, including distortions in thinking, perception, emotions, disorganized speech, sense of self and behavior. Recently, a numbers of marketed drugs for Schizophrenia are available against dopamine D2 and serotonin 5-HT2A receptors. Here, we docked Olanzapine derivatives (collected from literature) with 5-HT2A Receptor using the program AutoDock 4.2. The docked protein inhibitor complex structure was optimized using molecular dynamics simulation for 5ps with the CHARMM-22 force field using NAMD (NAnoscale Molecular Dynamics program) incorporated in visual molecular dynamics (VMD 1.9.2) and then evaluating the stability of complex structure by calculating RMSD values. NAMD is a parallel, object-oriented molecular dynamics code designed for high-performance simulation of large biomolecular systems. A quantitative structure activity relationship (QSAR) model was built using energy-based descriptors as independent variable and pKi value as dependent variable of eleven known Olanzapine derivatives with 5-HT2A Receptor, yielding correlation coefficient r2 of 0.63861. The predictive performance of QSAR model was assessed using different crossvalidation procedures. Our results suggest that a ligand receptor binding interaction for 5-HT2A receptor using a QSAR model is promising approach to design more potent 5-HT2A receptor inhibitors prior to their synthesis. PMID- 29162967 TI - Lubricin: A Principal Modulator of the Psychoneuroendocrine - Osteoimmune Interactome - Implications for Novel Treatments of Osteoarthritic Pathologies. AB - Lubricin is a synovial glycoprotein that contributes to joint lubrication. We propose the hypothesis that lubricin is a key modulator of the psychoneuroendocrine-osteoimmune interactome, with important clinical relevance for osteoarthritic pathologies. We consider a variety of neuroendocrine-immune factors, including inflammatory cytokines and chemokines that may contribute to the modulation of lubricin in rheumatic complications. Based on our preliminary immunocytochemistry and fractal analysis data, and in the context of translational research of modern healthcare, we propose that molecular lubricin gene expression modification by means of the novel CRISPR/Cas system be considered for osteoarthritic therapies. PMID- 29162968 TI - Cholera host response gene networks: preliminary studies. AB - Gene network analysis was performed based on published literature describing genes that are possibly interconnected with cholera vaccine responses in vitro in cell culture and in vivo in human patient punch biopsies as well as DNA extracted from blood. These studies produced divergent results. The differences should be replicated and studied further. Included in such studies, patient ethnicities, states of stress, nutrition, and health, as well as the precise characteristics of the various cholera vaccines and modes of delivery need to be considered as well. PMID- 29162969 TI - Clinical Immunology of Cholera - Current Trends and Directions for Future Advancement. AB - Cholera remains a feared, aggressive, infectious and lethal disease today, despite several decades of intense research, concerted public health modalities designed to prevent, and to control outbreaks, availability of efficacious vaccines aimed at containing its contagious spread, and effective patient centered medical interventions for reducing morbidity and mortality. Despite these advances, cholera still strikes communities around the world, especially in countries and regions of the globe where medical and nursing care cannot be as effectively proffered to the population at risk as in First World economies. Case in point, the number of suspected cholera cases that currently afflicts Yemen escalates at an "unprecedented rate", according to the World Health Organization. Here, following a brief introduction of the history of the medical knowledge about cholera, we discuss current trends of our understanding of clinical immune surveillance against the bacillus that causes cholera, vibrio Cholera (vCh). We cite the current state of best available evidence about anticholera vaccines, and outline certain directions for future study to characterize the clinical immunology of cholera. PMID- 29162970 TI - FICE in Predicting Colorectal Flat Lesion Histology. AB - Background and Objectives: Colonoscopy is the gold standard for detection of polyps and is preventive against colorectal cancers. Flat adenomas are small, superficial lesions and have a high rate of going undetected during conventional white-light endoscopy. This article adds to the scant body of literature in English regarding in vivo detection and diagnosis of flat adenomas using Fujinon intelligent color enhancement (FICE) system. In this study, we investigated the diagnosis of flat lesions via the FICE endoscopy system and in vivo histologic diagnostic estimations of flat lesions. Methods: This prospective study was conducted in patients who underwent colonoscopy that found flat adenomas. Lesions were classified morphologically with regard to the Paris Classification and sent for histopathologic examination after in vivo histologic diagnostic estimations were made according to Kudo's pit pattern classification. The positive predictive value (PPV), negative predictive value (NPV), specificity, sensitivity, and accuracy of in vivo endoscopic diagnostic estimations of flat lesions with the FICE system were analyzed. Results: A total of 217 flat lesions were identified in 137 patients. Of the lesions, 85.7% were Paris type 0-IIa, and 59.4% were Kudo pit pattern type III. When the FICE diagnostic estimations of flat lesions and final pathology results were considered, PPV was 68.5%, NPV value was 89.6%, sensitivity was 94.7%, specificity was 50.9%, and accuracy was 74.2%. Conclusions: Biologic importance of flat lesions is obscure, as they are usually missed during colonoscopy. The use of novel endoscopic techniques may improve their detection and diagnosis rates. PMID- 29162971 TI - Long-Term Patient-Reported Outcomes of Paraesophageal Hernia Repair. AB - Background and Objectives: There is a lack of consensus on the optimal repair technique and the definition of good outcomes in paraesophageal hernia (PEH) repair. We reviewed long-term patient-reported outcomes of open and laparoscopic PEH repair to assist with our future surgical consent process. Methods: This was a retrospective case-control study including all patients with PEH repair performed from 2000 through 2012 at a single center without the use of mesh. We mailed questionnaires to patients to assess reoperation, symptom control, and satisfaction. Results: Chart review identified 217 patients who underwent PEH repair. Nineteen died during the follow-up period. Of the 106 returning the questionnaire, 87 underwent laparoscopic repair, and 19 had open repair, with follow-up of 6.6 (SD 3.9) years and 7.0 (SD 4.1) years, respectively. Reoperation rates were 9.9% and 5.3%, respectively (P = .720). Dysphagia, heartburn, and regurgitation improved in 95.4% of patients after laparoscopic repair and 89.5% after open repair (P = .318). Medication for symptom control was necessary in 54.0% of patients after laparoscopic repair and 26.3% after open repair (P = .029). In each group, 90% stated that they would still choose to have the operation (P = .713). Conclusions: Long-term patient-specific outcomes showed comparable, encouraging results between open and laparoscopic repair of PEH without mesh reinforcement. However, half of those undergoing laparoscopic repair required the use of medication for symptom control. This study adds to the literature describing long-term patient-specific outcomes and can be useful when counseling patients about PEH repair. PMID- 29162972 TI - Clinical Outcomes of Upper Gastrointestinal Stents and Review of Current Literature. AB - Background and Objectives: The self-expandable metal stent (SEMS) is an alternative for several possible surgical and palliative treatments of upper gastrointestinal obstructions that occur in several disease states. The present study was performed to describe a single-center experience with upper gastrointestinal stents. Methods: All patients at a single center who had an SEMS placed for the treatment of obstruction over a 3-year period were retrospectively evaluated. Pre- and postoperative dysphagia scoring was calculated and used to evaluate postprocedure improvement in quality of life. Procedural success and early and late complication rates were investigated. Results: A total of 171 endoscopic procedures were performed in 73 patients. Procedural success was 95.8% (n = 69) and dilatation was performed in 80 patients. The rate of perioperative complication was 26% (n = 19). After 1 month, stents were patent in all patients (n = 73). Stent obstruction was noted in 6 patients: 2 each at 2, 7, and 10 months. Conclusion: SEMS usage for palliative and curative purposes in benign or malignant upper gastrointestinal system obstructions is an efficient and reliable treatment method with advantages, such as shortening hospital stay, decreased pain, cost-effectiveness, and low mortality-morbidity rates when compared to surgical procedures, and a high rate of clinical success. PMID- 29162974 TI - Nonmonotonic Pathway Gene Expression Analysis Reveals Oncogenic Role of p27/Kip1 at Intermediate Dose. AB - The mechanistic basis by which the level of p27Kip1 expression influences tumor aggressiveness and patient mortality remains unclear. To elucidate the competing tumor-suppressing and oncogenic effects of p27Kip1 on gene expression in tumors, we analyzed the transcriptomes of squamous cell papilloma derived from Cdkn1b nullizygous, heterozygous, and wild-type mice. We developed a novel functional pathway analysis method capable of testing directional and nonmonotonic dose response. This analysis can reveal potential causal relationships that might have been missed by other nondirectional pathway analysis methods. Applying this method to capture dose-response curves in papilloma gene expression data, we show that several known cancer pathways are dominated by low-high-low gene expression responses to increasing p27 gene doses. The oncogene cyclin D1, whose expression is elevated at an intermediate p27 dose, is the most responsive gene shared by these cancer pathways. Therefore, intermediate levels of p27 may promote cellular processes favoring tumorigenesis-strikingly consistent with the dominance of heterozygous mutations in CDKN1B seen in human cancers. Our findings shed new light on regulatory mechanisms for both pro- and anti-tumorigenic roles of p27Kip1. Functional pathway dose-response analysis provides a unique opportunity to uncover nonmonotonic patterns in biological systems. PMID- 29162975 TI - Computational Model of the Effect of a Surface-Binding Site on the Saccharomycopsis fibuligera R64 alpha-Amylase to the Substrate Adsorption. AB - alpha-Amylase is one of the important enzymes in the starch-processing industry. However, starch processing requires high temperature, thus resulting in high cost. The high adsorptivity of alpha-amylase to the substrate allows this enzyme to digest the starch at a lower temperature. alpha-Amylase from Saccharomycopsis fibuligera R64 (Sfamy R64), a locally sourced enzyme from Indonesia, has a high amylolytic activity but low starch adsorptivity. The objective of this study was to design a computational model of Sfamy R64 with increased starch adsorptivity using bioinformatics method. The model structure of Sfamy R64 was compared with the positive control, ie, Aspergillus niger alpha-amylase. The structural comparison showed that Sfamy R64 lacks the surface-binding site (SBS). An SBS was introduced to the structure of Sfamy R64 by S383Y/S386W mutations. The dynamics and binding affinity of the SBS of mutant to the substrate were also improved and comparable with that of the positive control. PMID- 29162973 TI - Going and stopping: Dichotomies in behavioral control by the prefrontal cortex. AB - The rodent dorsal medial prefrontal cortex (PFC), specifically the prelimbic cortex (PL), regulates the expression of conditioned fear and behaviors interpreted as reward-seeking. Meanwhile, the ventral medial PFC, namely the infralimbic cortex (IL), is essential to extinction conditioning in both appetitive and aversive domains. Here we review evidence that supports, or refutes, this "PL-go/IL-stop" dichotomy. We focus on the extinction of conditioned fear and the extinction and reinstatement of cocaine- or heroin reinforced responding. We then synthesize evidence that the PL is essential for developing goal-directed response strategies, while the IL supports habit behavior. Finally, we propose that some functions of the orbital PFC parallel those of the medial PFC in the regulation of response selection. Integration of these discoveries may provide points of intervention for inhibiting untethered drug seeking in drug use disorders, failures in extinction in Post-traumatic Stress Disorder, or co-morbidities between the two. PMID- 29162976 TI - Linking Air Quality and Human Health Effects Models: An Application to the Los Angeles Air Basin. AB - Proposed emission control strategies for reducing ozone and particulate matter are evaluated better when air quality and health effects models are used together. The Community Multiscale Air Quality (CMAQ) model is the US Environmental Protection Agency's model for determining public policy and forecasting air quality. CMAQ was used to forecast air quality changes due to several emission control strategies that could be implemented between 2008 and 2030 for the South Coast Air Basin that includes Los Angeles. The Environmental Benefits Mapping and Analysis Program-Community Edition (BenMAP-CE) was used to estimate health and economic impacts of the different emission control strategies based on CMAQ simulations. BenMAP-CE is a computer program based on epidemiologic studies that link human health and air quality. This modeling approach is better for determining optimum public policy than approaches that only examine concentration changes. PMID- 29162977 TI - Perioperative Management of Patients with Diabetes. AB - Hyperglycemia has long been recognized to have detrimental effects on postoperative outcomes in patients undergoing surgery. The manifestations of uncontrolled diabetes are manifold and can include risk of hyperglycemic crises, postoperative infection, poor wound healing, and increased mortality. There is substantial literature supporting the role of diligent glucose control in the prevention of adverse surgical outcomes, but considerable debate remains as to the optimal glucose targets. Hence, most organizations advocate the avoidance of hypoglycemia while striving for adequate glucose control in the perioperative period. These objectives can be accomplished with careful preoperative evaluation, clear patient instructions the day of surgery, frequent blood glucose monitoring during the perioperative period, and use of effective strategies for insulin initiation and titration. This article highlights the major issues concerning patients with diabetes undergoing surgery and reviews the management recommendations put forth by general consensus guidelines and expert opinion. PMID- 29162978 TI - Exploring the Interaction of Drosophila TDP-43 and the Type II Voltage-Gated Calcium Channel, Cacophony, in Regulating Motor Function and Behavior. AB - Amyotrophic lateral sclerosis (ALS) is the most common adult onset motor neurodegenerative disease. The cause of the disease remains obscure, and as such there is no effective treatment or cure. Amyotrophic lateral sclerosis and other neurodegenerative diseases are frequently characterized by dysfunction of the RNA binding protein, TDP-43. Using model systems to understand the mechanisms underlying TDP-43 dysfunction should accelerate identification of therapeutic targets. A recent report has shown that motor defects caused by the deletion of the Drosophila TDP-43 ortholog, tbph, are not driven by changes in the physiology at the neuromuscular junction. Rather, defective motor burst rhythmicity and coordination, displayed by tbph mutants, are rescued by genetically restoring a voltage-gated calcium channel to either motor neurons or just a single pair of neurons in the brain. If these effects are mirrored in human TDP-43 proteinopathies, these observations could open new avenues to investigate alternative therapeutic targets for these neurodegenerative diseases. PMID- 29162979 TI - Association of Tissue-Specific DNA Methylation Alterations with alpha-Thalassemia Southeast Asian Deletion. AB - In the wild-type allele, DNA methylation levels of 10 consecutive CpG sites adjacent to the upstream 5'-breakpoint of alpha-thalassemia Southeast Asian (SEA) deletion are not different between placenta and leukocytes. However, no previous study has reported the map of DNA methylation in the SEA allele. This report aims to show that the SEA mutation is associated with DNA methylation changes, resulting in differential methylation between placenta and leukocytes. Methylation-sensitive high-resolution analysis was used to compare DNA methylation among placenta, leukocytes, and unmethylated control DNA. The result indicates that the DNA methylation between placenta and leukocyte DNA is different and shows that the CpG status of both is not fully unmethylated. Mapping of individual CpG sites was performed by targeted bisulfite sequencing. The DNA methylation level of the 10 consecutive CpG sites was different between placenta and leukocyte DNA. When the 10th CpG of the mutation allele was considered as a hallmark for comparing DNA methylation level, it was totally different from the unmethylated 10th CpG of the wild-type allele. Finally, the distinct DNA methylation patterns between both DNA were extracted. In total, 24 patterns were found in leukocyte samples and 9 patterns were found in placenta samples. This report shows that the large deletion is associated with DNA methylation change. In further studies for clinical application, the distinct DNA methylation pattern might be a potential marker for detecting cell-free fetal DNA. PMID- 29162980 TI - Functional Studies of CCAAT/Enhancer Binding Protein Site Located Downstream of the Transcriptional Start Site. AB - Previous studies have identified a CCAAT/enhancer binding protein (C/EBP) site located downstream of the transcriptional start site (DS3). The role of the DS3 element with respect to HIV-1 transactivation by Tat and viral replication has not been characterized. We have demonstrated that DS3 was a functional C/EBPbeta binding site and mutation of this site to the C/EBP knockout DS3-9C variant showed lower HIV-1 long terminal repeat (LTR) transactivation by C/EBPbeta. However, it was able to exhibit similar or even higher transcription levels by Tat compared to the parental LTR. C/EBPbeta and Tat together further enhanced the transcription level of the parental LAI-LTR and DS3-9C LTR, with higher levels in the DS3-9C LTR. HIV molecular clone viruses carrying the DS3-9C variant LTR demonstrated a decreased replication capacity and delayed rate of replication. These results suggest that DS3 plays a role in virus transcriptional initiation and provides new insight into C/EBP regulation of HIV-1. PMID- 29162981 TI - The Impact of Complications on Patients' Assessment of the Outcome of Tension Free Vaginal Tape Procedure. AB - Introduction: Our study aimed to assess the impact of managed complications of tension-free vaginal tape (TVT) on the patients' assessment of the results as measured by Patient Global Impression of Improvement (PGI-I). Materials and methods: This was a retrospective study, supplemented with a telephone interview, comparing patients who had complications of TVT procedures with those where no complications recorded. The primary outcome was the PGI-I score in the 2 groups. Results: A total of 118 invitations were sent. In all, 60 patients returned the signed consent and completed the telephone interview with one of the authors (response rate = 50.8%). Complications were recorded in 21 patients (group 1) and no complications in 39 patients (group 2). There was no statistically significant difference between PGI-I in both groups. Conclusions: Managed complications of TVT do not seem to affect patients' assessment of outcome as measured by PGI-I score. PMID- 29162982 TI - Future Directions and Molecular Basis of Ventilator Associated Pneumonia. AB - Mechanical ventilation is a lifesaving treatment and has complications such as ventilator associated pneumonia (VAP) that lead to high morbidity and mortality. Moreover VAP is the second most common hospital-acquired infection in pediatric intensive care units. Although it is still not well understood, understanding molecular pathogenesis is essential for preventing and treating pneumonia. A lot of microbes are detected as a causative agent of VAP. The most common isolated VAP pathogens in pediatric patients are Staphylococcus aureus, Pseudomonas aeruginosa, and other gram negative bacteria. All of the bacteria have different pathogenesis due to their different virulence factors and host reactions. This review article focused on mechanisms of VAP with molecular pathogenesis of the causative bacteria one by one from the literature. We hope that we know more about molecular pathogenesis of VAP and we can investigate and focus on the management of the disease in near future. PMID- 29162984 TI - "We are the best to stand in for patients": a qualitative study on nurses' advocacy characteristics in Ghana. AB - Background: Patient advocacy has been identified as a core duty of the nurse, and certain nurse characteristics influence the performance of the role. However, these characteristics have not been adequately explored in Ghana. This study aimed to explore the perspectives of nurses about the characteristics of nurses that influence their role as patient advocates. Methods: An exploratory descriptive qualitative study was conducted among 15 nurses from a regional hospital in Ghana. Purposive sampling was used to select participants and individual in-depth interviews were conducted in English using a semi-structured interview guide. The interviews were audio-taped and transcribed. Data analysis was done concurrently employing the principles of thematic analysis. Ethical approval was obtained for the study from the Noguchi Memorial Institute of Medical Research and the Ghana Health Service Ethical Review Committee. Results: Themes generated revealed nurse traits which enhanced the advocacy role of nurses such as being empathetic, nurturing, ethical, assertive and persistent and nurse states which hindered the performance of the role such as fatigue and frustration. However, "compassionate" emerged as an additional nurse trait from this study. Out of empathy, participants availed themselves for patients to share their problems with them. In their nurturing roles, spending more time with patients and providing personal care fostered closeness which helped in identifying patients' problems. Helping patients navigate the health system was also found. They perceived patient advocacy as a moral responsibility and identified good communication skills and determination to help patients get their problems solved as important in patient advocacy. Some participants also described compassion-based activities such as pleading on patients' behalf, providing material and financial assistance, facilitating care and providing emotional support in their advocacy. However, heavy workload and lack of appreciation from patients were found to hinder the performance of the advocacy role. Conclusions: We concluded that nurse characteristics that influence patient advocacy are comparable to those identified internationally such as being empathetic, assertiveness and fatigue. Enhancing these characteristics could help nurses overcome the negative states that undermine the patient advocacy role of nurses. PMID- 29162985 TI - CBFA2T2 is associated with a cancer stem cell state in renal cell carcinoma. AB - Background: Renal cell carcinoma (RCC) is the most common kidney cancer, accounting for approximately 80-90% of all primary kidney cancer. Treatment for patients with advanced RCC remains unsatisfactory. Rare cancer stem cells (CSCs) are proposed to be responsible for failure of current treatment. Methods: OncoLnc was used as a tool for interactively exploring survival correlations. Gene manipulation and expression analysis were carried out using siRNA, RT-PCR and Western blotting. Wound healing and invasion assays were used for phenotypical characterization. Aldefluor assay and FACS sorting Sphere culture were used to determine the "stemness" of CSCs. Co-Immunoprecipitation (Co-IP) was used to examine the interaction between OCT4 and CBFA2T2. Student's t-test and Chi square test was used to analyze statistical significance. Results: CBFA2T2 expression can significantly predict the survival of RCC patients. Knocking-down of CBFA2T2 can inhibit cell migration and invasion in RCC cells in vitro, and reduce ALDHhigh CSCs populations. CBFA2T2 expression is necessary for sphere-forming ability and cancer stem cells marker expression in RCC cell lines. Conclusions: Our data suggest that CBFA2T2 expression correlates with aggressive characteristics of RCC and CBFA2T2 is required for maintenance of "stemness" through regulation of stem cells factors, thereby highlighting CBFA2T2 as a potential therapeutic target for RCC treatment. PMID- 29162986 TI - Hyperoside attenuates dextran sulfate sodium-induced colitis in mice possibly via activation of the Nrf2 signalling pathway. AB - Background: Hyperoside (Hyp) is a flavonoid glycoside compound that has been demonstrated to have anti-inflammatory, anti-apoptotic and antioxidant effects. However, the impact of Hyp on inflammatory bowel disease (IBD) has not been previously explored. Thus, we evaluated the role of Hyp in dextran sodium sulfate (DSS)-induced acute colitis in mice. Methods: We established a mouse model of experimental acute colitis by treating mice with drinking water supplemented with 3.0% DSS for 7 days. The disease activity index (DAI), colon length, histological features and colonic malondialdehyde (MDA) levels were examined using appropriate methods, and COX-2 expression was examined by immunohistochemistry. TNF-alpha, IL 4, IL-6, IL-10, NF-kappaB p65, Bcl-2, Bax, Caspase-3, nuclear factor-erythroid 2 related factor 2 (Nrf2), hemeoxygenase-1 (HO-1) and superoxide dismutase (SOD) levels in colorectal tissues were detected by RT-PCR and western blotting. Results: Hyp significantly attenuated DSS-induced changes in the DAI as well as DSS-induced colonic shortening and histological changes. Hyp also inhibited inflammation, a change reflected by decreases in TNF-alpha, IL-6, COX-2 and NF kappaB p65 expression and increases in IL-10 expression. Hyp suppressed increases in the levels of apoptosis-related proteins, such as Caspase-3 and Bax, but upregulated the level of the anti-apoptotic protein Bcl2. In addition, Hyp also exerted antioxidant effects. The MDA content was decreased, and the expression of Nrf2 and its downstream targets HO-1 and SOD were increased by Hyp. Conclusions: Based on these findings, Hyp possesses the ability to attenuate colitis, possibly by mitigating colonic inflammation and apoptosis via activation of the Nrf2 signaling pathway. PMID- 29162988 TI - Suture-assisted punctoplasty. AB - Purpose: To describe a surgical technique in which a suture, instead of forceps, is used to improve access for the introduction of scissors and more easily achieve an appropriately-sized punctoplasty. Materials and Methods: In this technique, a new modification of the 2-snip punctoplasty, a 6-0 polyglactin 910 suture is passed through the posterior wall of the punctum to apply traction. A video of the technique is provided. Results: This technique improves the surgical field of view and eases access for introduction of Vannas scissors into the punctum to perform the punctoplasty. Conclusions: This simple and practical modification of the 2-snip punctoplasty improves instrument access so that an appropriately-sized punctoplasty can be performed with ease. PMID- 29162987 TI - Systematic approaches for reviewing neuro-imaging scans in ophthalmology. AB - Neuroimaging is an important tool in ophthalmology, but many ophthalmologists are uncomfortable evaluating actual scans. Unfortunately, exclusive reliance on a radiologist's report can lead to diagnostic and management errors. We outline a methodology for equipping ophthalmologists with the skills necessary to read neuroimaging studies with respect to specific clinical questions. PMID- 29162989 TI - A retrospective study on the outcomes of Ahmed valve versus Ahmed valve combined with fluocinolone implant in uveitic glaucoma. AB - Purpose: To compare the intraocular pressure (IOP) outcomes of Ahmed glaucoma valve (AGV) surgery alone versus AGV with fluocinolone implant in uveitic glaucoma patients. Methods: We identified uveitic glaucoma patients with AGV surgery alone and AGV surgery combined with fluocinolone implant from the Massachusetts Eye and Ear Ocular Inflammation Database. Demographic information, visual acuity, and IOP were recorded at preoperative visits and 1, 6, and 12 months after surgery. Incidence of hypertensive phase, defined as an IOP of >21 mm Hg or use of additional treatment to lower IOP occurring any time between 7 days to 6 months postoperatively, was investigated. Multilevel mixed effects models were performed to compare the outcomes between groups. Results: Eighteen eyes of 13 uveitic glaucoma patients with 1-year follow-up data were included. There were 11 eyes of 9 patients (mean age, 56.5 years; 63.6% male) in the AGV group and 7 eyes of 4 patients (mean age, 61.3 years; 71.4% male) in the AGV + fluocinolone group. There was no significant difference in visual acuity change at 1 year after surgery between groups (P = 0.25), although visual acuity improvement was significant in the AGV group (P = 0.01). The hypertensive phase occurred in 91% of AGV patients and 43% of AGV + fluocinolone patients (P = 0.30), with onset of 8-40 days (mean, 18 days) after surgery. IOP and number of glaucoma medications decreased at the 1-year postoperative visits in both the AGV group (P < 0.0001, P < 0.0001) and the AGV + fluocinolone group (P = 0.001, P < 0.0001). Compared to the AGV group, the AGV + fluocinolone group used fewer glaucoma medications (0.28 vs 1.30 [P = 0.01]) and had better inflammation control (P = 0.02). The surgical complication rates were similar between groups. Conclusions: In uveitic glaucoma, AGV with fluocinolone achieves a similar, desired IOP control but with fewer glaucoma medications than AGV alone. PMID- 29162990 TI - A microbubble of gas as an early indication of macular hole formation after vitrectomy surgery for retinal detachment repair. AB - We present a novel case of a 67-year-old man who developed a full-thickness macular hole in the presence of a microbubble after repair of rhegmatogenous retinal detachment. PMID- 29162991 TI - Magnusiomyces capitatus: a new and emerging pathogen linked to keratomycosis. AB - We describe our experience managing a case of fungal keratitis in a 71-year-old immunocompetent woman. Intracameral cultures isolated Magnusiomyces capitatus, a dimorphic commensal microbe with limited pathogenicity, in an immune competent patient. Repeated corneal cultures for bacteria and fungus were negative. Initial broad-spectrum topical fortified antibiotics were eventually escalated to include topical natamycin and voriconazole and oral voriconazole. The patient underwent emergent corneal transplantation, but recurrent infection eventually required anterior chamber washout and intracameral injection of amphotericin B. A combination of topical, systemic, intracameral administration of voriconazole, intracameral administration of amphotericin B, anterior chamber washout, and penetrating keratoplasty were required to clear the infection. PMID- 29162992 TI - A 45-year-old man with spontaneous hyphema of the right eye. PMID- 29162993 TI - A 61-year-old man with cystoid macular edema and chorioretinal folds after cataract surgery. PMID- 29162994 TI - A 71-year-old man with bilateral vision loss. PMID- 29162995 TI - A 5-day-old-newborn with a large right upper eyelid coloboma. PMID- 29162996 TI - Combination of beta Adrenergic Receptor Block and Renin-Angiotensin System Inhibition Diminished the Angiotensin II-Induced Vasoconstriction and Increased Bradykinin-Induced Vasodilation in Hypertension. AB - In hypertension, the combination therapy is frequently used to obtain a better therapeutic effect and reduce adverse effects. One effective combination is with inhibitors and beta-blockers of renin-angiotensin system. Although the mechanisms of action of each drug are already known, the antihypertensive mechanism is more complex and therefore the combined treatment mechanism is unclear. Specifically, the effect of the treatments of angiotensin-converting enzyme inhibitor or AT1 receptor antagonist with beta-blocker on the angiotensin II and bradykinin reactivity has not been studied. For this reason, we evaluated the interaction between propranolol and captopril or losartan on vascular reactivity to bradykinin and angiotensin II in spontaneously hypertensive rat. We constructed concentration-response curves to angiotensin II and bradykinin after treatment of SHR with propranolol-captopril or propranolol-losartan by using rat aortic rings. While losartan or captopril with propranolol potentiated bradykinin-induced vasodilation effect, the propranolol-losartan interaction decreased the angiotensin II-induced vasoconstriction. In addition, the combinations did not reduce the heart rate significantly. These results suggest that the combined therapy decreased blood pressure to normotensive values and showed less effect for angiotensin II and greater effect for bradykinin than monotherapy which could contribute in the antihypertensive effect. PMID- 29162997 TI - Association between employer's knowledge and attitude towards smoking cessation and voluntary promotion in workplace: a survey study. AB - Background: Workplace smoking cessation (SC) intervention is effective in increasing quit rate but little was known about the factors associated with voluntary SC promotion. Comprehensive smoke-free legislation, including banning smoking in all indoor area of workplaces, has been enforced in Hong Kong. This survey investigated the prevalence of company's compliance with smoke-free legislation and examined the relation between voluntary SC promotion in workplace and employer's knowledge of and attitude towards smoking and SC. Methods: Half (50.3%, n = 292) of a convenience sample of companies completed a self administered questionnaire on company's voluntary SC promotion in the workplace. Factors investigated included company's characteristics (size, type, and number of smoking employees); employers' knowledge of smoking, second-hand smoke and SC effects on health; perceived responsibility in assisting employees to quit smoking and smoking prohibition in workplace (smoke free policy). Logistic regression yielded adjusted odds ratio (aOR) for voluntary SC promotion. Results: A notable proportion of companies (14.7%) showed non-compliance with the smoke free workplace ordinance and only 10% voluntarily promoted SC. Perceived greater negative impact of smoking on the company (adjusted odds ratio[aOR] 1.94, 95% confidence interval [CI] 1.18-3.20) and better knowledge of smoking (aOR 1.40, 95%CI 1.00-1.94) were associated with voluntary SC promotion. Positive but non significant associations were observed between perceived responsibility of assisting employees to quit, workplace smoke free policy and voluntary SC promotion. Company characteristics were generally not associated with voluntary SC promotion except white collar companies were less likely to promote SC (aOR 0.26, 95% CI 0.08-0.85). Conclusions: This is the first survey on company's SC promotion in the Chinese population. A notable proportion of companies was not compliant with the smoke-free workplace ordinance. Employers with a higher level of knowledge and perceived impact of smoking on companies and from blue-collar companies were more likely to promote SC in workplace. The findings inform future workplace intervention design and policy. Trial registration: The study was retrospectively registered at ClinicalTrials.gov (NCT02179424) dated 27 June 2014. PMID- 29162998 TI - Symptomatic first-degree atrioventricular block in a young woman after taking a fat burner supplement. AB - A 22-year-old woman collapsed at home and was brought to the accident and emergency department. History revealed that she was fit and taken T5 capsule the night before the collapse. There was no history of similar collapses or seizure. Examination revealed blood pressure (BP) of 104/69 mmHg and a heart rate (HR) of 70 bpm. Chest, cardiovascular, and neurology examination were unremarkable. However, on standing, her HR increased to 120 bpm, and her BP dropped to 62/40 mmHg. Blood Na, K, Ca, Mg, phosphate, creatinine, complete blood count, T4 cortisol, and thyroid-stimulating hormone (TSH) were normal. The electrocardiogram (ECG) on the ambulance revealed sinus rhythm with normal morphology but a significant first-degree atrioventricular block with a PR interval of 280-300 ms. The patient was treated for orthostatic hypotension with intravenous fluids. Her symptoms gradually improved. The repeat ECG taken 24 h after admission showed reduced PR interval to 230ms. The patient was followed up in the clinic after 1 week with normal ECG with a PR interval of 200 ms and a normal echocardiogram. The findings are discussed. PMID- 29162999 TI - Language Experience with a Native-Language Phoneme Sequence Modulates the Effects of Attention on Cortical Sensory Processing. AB - Auditory evoked potentials (AEP) reflect spectro-temporal feature changes within the spoken word and are sufficiently reliable to probe deficits in auditory processing. The current research assessed whether attentional modulation would alter the morphology of these AEPs and whether native-language experience with phoneme sequences would influence the effects of attention. Native-English and native-Polish adults listened to nonsense word pairs that contained the phoneme sequence onsets /st/, /set/, /pet/ that occur in both the Polish and English languages and the phoneme sequence onset /pt/ that occurs in the Polish language, but not the English language. Participants listened to word pairs within two experimental conditions designed to modulate attention. In one condition, participants listened to word pairs and performed a behavioral task to the second word in the pairs ("with task") and in the alternate condition participants listened to word pairs without performing a task ("without task"). Conditions were counterbalanced so that half the English and Polish subjects performed the "without task" condition as the first testing session and the "with task" condition as the second testing session. The remaining English and Polish subjects performed the tasks in the reverse order. Two or more months separated the testing sessions. Task conditions did not modulate the morphology of the AEP. Attention, however, modulated the AEP by producing a negative shift in the overall waveform. This effect of attention was modulated by experience with a native-language phoneme sequence. Thus, only Polish listeners showed an effect of attention to the native language /pt/ onset when the behavioral task occurred as the second testing session for which attention demands were reduced. This effect began at 400 ms and suggests a mechanism at intermediate stages within auditory cortex that facilitates recognition of the native language for comprehension. PMID- 29163000 TI - Convergence of Cortical, Thalamocortical, and Callosal Pathways during Human Fetal Development Revealed by Diffusion MRI Tractography. AB - There has been evidence that during brain development, emerging thalamocortical (TC) and corticothalamic (CT) pathways converge in some brain regions and follow each other's trajectories to their final destinations. Corpus callosal (CC) pathways also emerge at a similar developmental stage, and are known to converge with TC pathways in specific cortical regions in mature brains. Given the functional relationships between TC and CC pathways, anatomical convergence of the two pathways are likely important for their functional integration. However, it is unknown (1) where TC and CT subcortically converge in the human brain, and (2) where TC and CC converge in the cortex of the human brain, due to the limitations of non-invasive methods. The goals of this study were to describe the spatio-temporal relationships in the development of the TC/CT and CC pathways in the human brain, using high-angular resolution diffusion MR imaging (HARDI) tractography. Emerging cortical, TC and CC pathways were identified in postmortem fetal brains ranging from 17 gestational weeks (GW) to 30 GW, as well as in vivo 34-40 GW newborns. Some pathways from the thalami were found to be converged with pathways from the cerebral cortex as early as 17 GW. Such convergence was observed mainly in anterior and middle regions of the brain until 21 GW. At 22 GW and onwards, posterior pathways from the thalami also converged with cortical pathways. Many CC pathways reached the full length up to the cortical surface as early as 17 GW, while pathways linked to thalami (not only TC axons but also including pathways linked to thalamic neuronal migration) reached the cortical surface at and after 20 GW. These results suggest that CC pathways developed earlier than the TC pathways. The two pathways were widespread at early stages, but by 40 GW they condensed and formed groups of pathways that projected to specific regions of the cortex and overlapped in some brain regions. These results suggest that HARDI tractography has the potential to identify developing TC/CT and CC pathways with the timing and location of their convergence in fetal stages persisting in postnatal development. PMID- 29163001 TI - Implantation of 3D Constructs Embedded with Oral Mucosa-Derived Cells Induces Functional Recovery in Rats with Complete Spinal Cord Transection. AB - Spinal cord injury (SCI), involving damaged axons and glial scar tissue, often culminates in irreversible impairments. Achieving substantial recovery following complete spinal cord transection remains an unmet challenge. Here, we report of implantation of an engineered 3D construct embedded with human oral mucosa stem cells (hOMSC) induced to secrete neuroprotective, immunomodulatory, and axonal elongation-associated factors, in a complete spinal cord transection rat model. Rats implanted with induced tissue engineering constructs regained fine motor control, coordination and walking pattern in sharp contrast to the untreated group that remained paralyzed (42 vs. 0%). Immunofluorescence, CLARITY, MRI, and electrophysiological assessments demonstrated a reconnection bridging the injured area, as well as presence of increased number of myelinated axons, neural precursors, and reduced glial scar tissue in recovered animals treated with the induced cell-embedded constructs. Finally, this construct is made of bio compatible, clinically approved materials and utilizes a safe and easily extractable cell population. The results warrant further research with regards to the effectiveness of this treatment in addressing spinal cord injury. PMID- 29163002 TI - Serotonin Coordinates Responses to Social Stress-What We Can Learn from Fish. AB - Social interaction is stressful and subordinate individuals are often subjected to chronic stress, which greatly affects both their behavior and physiology. In teleost fish the social position of an individual may have long-term effects, such as effects on migration, age of sexual maturation or even sex. The brain serotonergic system plays a key role in coordinating autonomic, behavioral and neuroendocrine stress responses. Social subordination results in a chronic activation of the brain serotonergic system an effect, which seems to be central in the subordinate phenotype. However, behavioral effects of short-term acute activation of the serotonergic system are less obvious. As in other vertebrates, divergent stress coping styles, often referred to as proactive and reactive, has been described in teleosts. As demonstrated by selective breeding, stress coping styles appear to be partly heritable. However, teleost fish are characterized by plasticity, stress coping style being affected by social experience. Again, the brain serotonergic system appears to play an important role. Studies comparing brain gene expression of fish of different social rank and/or displaying divergent stress coping styles have identified several novel factors that seem important for controlling aggressive behavior and stress coping, e.g., histamine and hypocretin/orexin. These may also interact with brain monoaminergic systems, including serotonin. PMID- 29163004 TI - Cardiac Concomitants of Feedback and Prediction Error Processing in Reinforcement Learning. AB - Successful learning hinges on the evaluation of positive and negative feedback. We assessed differential learning from reward and punishment in a monetary reinforcement learning paradigm, together with cardiac concomitants of positive and negative feedback processing. On the behavioral level, learning from reward resulted in more advantageous behavior than learning from punishment, suggesting a differential impact of reward and punishment on successful feedback-based learning. On the autonomic level, learning and feedback processing were closely mirrored by phasic cardiac responses on a trial-by-trial basis: (1) Negative feedback was accompanied by faster and prolonged heart rate deceleration compared to positive feedback. (2) Cardiac responses shifted from feedback presentation at the beginning of learning to stimulus presentation later on. (3) Most importantly, the strength of phasic cardiac responses to the presentation of feedback correlated with the strength of prediction error signals that alert the learner to the necessity for behavioral adaptation. Considering participants' weight status and gender revealed obesity-related deficits in learning to avoid negative consequences and less consistent behavioral adaptation in women compared to men. In sum, our results provide strong new evidence for the notion that during learning phasic cardiac responses reflect an internal value and feedback monitoring system that is sensitive to the violation of performance-based expectations. Moreover, inter-individual differences in weight status and gender may affect both behavioral and autonomic responses in reinforcement-based learning. PMID- 29163003 TI - A Complex Interplay of Vitamin B1 and B6 Metabolism with Cognition, Brain Structure, and Functional Connectivity in Older Adults. AB - Aging is associated with brain atrophy, functional brain network reorganization and decline of cognitive performance, albeit characterized by high interindividual variability. Among environmental influencing factors accounting for this variability, nutrition and particularly vitamin supply is thought to play an important role. While evidence exists that supplementation of vitamins B6 and B1 might be beneficial for cognition and brain structure, at least in deficient states and neurodegenerative diseases, little is known about this relation during healthy aging and in relation to reorganization of functional brain networks. We thus assessed the relation between blood levels of vitamins B1 and B6 and cognitive performance, cortical folding, and functional resting-state connectivity in a large sample of older adults (N > 600; age: 55-85 years), drawn from the population-based 1000BRAINS study. In addition to blood sampling, subjects underwent structural and functional resting-state neuroimaging as well as extensive neuropsychological testing in the domains of executive functions, (working) memory, attention, and language. Brain regions showing changes in the local gyrification index as calculated using FreeSurfer in relation to vitamin levels were used for subsequent seed-based resting-state functional connectivity analysis. For B6, a positive correlation with local cortical folding was found throughout the brain, while only slight changes in functional connectivity were observed. Contrarily, for B1, a negative correlation with cortical folding as well as problem solving and visuo-spatial working memory performance was found, which was accompanied by pronounced increases of interhemispheric and decreases of intrahemispheric functional connectivity. While the effects for B6 expand previous knowledge on beneficial effects of B6 supplementation on brain structure, they also showed that additional effects on cognition might not be recognizable in healthy older subjects with normal B6 blood levels. The cortical atrophy and pronounced functional reorganization associated with B1, contrarily, was more in line with the theory of a disturbed B1 metabolism in older adults, leading to B1 utilization deficits, and thus, an effective B1 deficiency in the brain, despite normal to high-normal blood levels. PMID- 29163006 TI - MATLAB Toolboxes for Reference Electrode Standardization Technique (REST) of Scalp EEG. AB - Reference electrode standardization technique (REST) has been increasingly acknowledged and applied as a re-reference technique to transform an actual multi channels recordings to approximately zero reference ones in electroencephalography/event-related potentials (EEG/ERPs) community around the world in recent years. However, a more easy-to-use toolbox for re-referencing scalp EEG data to zero reference is still lacking. Here, we have therefore developed two open-source MATLAB toolboxes for REST of scalp EEG. One version of REST is closely integrated into EEGLAB, which is a popular MATLAB toolbox for processing the EEG data; and another is a batch version to make it more convenient and efficient for experienced users. Both of them are designed to provide an easy-to-use for novice researchers and flexibility for experienced researchers. All versions of the REST toolboxes can be freely downloaded at http://www.neuro.uestc.edu.cn/rest/Down.html, and the detailed information including publications, comments and documents on REST can also be found from this website. An example of usage is given with comparative results of REST and average reference. We hope these user-friendly REST toolboxes could make the relatively novel technique of REST easier to study, especially for applications in various EEG studies. PMID- 29163005 TI - In Vivo Imaging of Tau Pathology Using Magnetic Resonance Imaging Textural Analysis. AB - Background: Non-invasive characterization of the pathological features of Alzheimer's disease (AD) could enhance patient management and the development of therapeutic strategies. Magnetic resonance imaging texture analysis (MRTA) has been used previously to extract texture descriptors from structural clinical scans in AD to determine cerebral tissue heterogeneity. In this study, we examined the potential of MRTA to specifically identify tau pathology in an AD mouse model and compared the MRTA metrics to histological measures of tau burden. Methods: MRTA was applied to T2 weighted high-resolution MR images of nine 8.5 month-old rTg4510 tau pathology (TG) mice and 16 litter matched wild-type (WT) mice. MRTA comprised of the filtration-histogram technique, where the filtration step extracted and enhanced features of different sizes (fine, medium, and coarse texture scales), followed by quantification of texture using histogram analysis (mean gray level intensity, mean intensity, entropy, uniformity, skewness, standard-deviation, and kurtosis). MRTA was applied to manually segmented regions of interest (ROI) drawn within the cortex, hippocampus, and thalamus regions and the level of tau burden was assessed in equivalent regions using histology. Results: Texture parameters were markedly different between WT and TG in the cortex (E, p < 0.01, K, p < 0.01), the hippocampus (K, p < 0.05) and in the thalamus (K, p < 0.01). In addition, we observed significant correlations between histological measurements of tau burden and kurtosis in the cortex, hippocampus and thalamus. Conclusions: MRTA successfully differentiated WT and TG in brain regions with varying degrees of tau pathology (cortex, hippocampus, and thalamus) based on T2 weighted MR images. Furthermore, the kurtosis measurement correlated with histological measures of tau burden. This initial study indicates that MRTA may have a role in the early diagnosis of AD and the assessment of tau pathology using routinely acquired structural MR images. PMID- 29163007 TI - From Mice to Mole-Rats: Species-Specific Modulation of Adult Hippocampal Neurogenesis. AB - Rodent populations living in their natural environments have very diverse ecological and life history profiles that may differ substantially from that of conventional laboratory rodents. Free-living rodents show species-specific neurogenesis that are dependent on their unique biology and ecology. This perspective aims to illustrate the benefit of studying wild rodent species in conjunction with laboratory rodents. African mole-rats are discussed in terms of habitat complexity, social structures, and longevity. African mole-rats are a group of subterranean rodents, endemic to Africa, that show major differences in both intrinsic and extrinsic traits compared to the classical rodent models. Mole rats exhibit a spectrum of sociality within a single family, ranging from solitary to eusocial. This continuum of sociality provides a platform for comparative testing of hypotheses. Indeed, species differences are apparent both in learning ability and hippocampal neurogenesis. In addition, social mole-rat species display a reproductive division of labor that also results in differential hippocampal neurogenesis, independent of age, offering further scope for comparison. In conclusion, it is evident that neurogenesis studies on conventional laboratory rodents are not necessarily representative, specifically because of a lack of diversity in life histories, uniform habitats, and low genetic variability. The observed level of adult neurogenesis in the dentate gyrus is the result of an intricate balance between many contributing factors, which appear to be specific to distinct groups of animals. The ultimate understanding of the functional and adaptive role of adult neurogenesis will involve research on both laboratory animals and natural rodent populations. PMID- 29163008 TI - Antioxidative and Antiapoptotic Effects of Delta-Opioid Peptide [D-Ala2, D-Leu5] Enkephalin on Spinal Cord Ischemia-Reperfusion Injury in Rabbits. AB - Background: In our previous study, we found that regional administration of delta opioid peptide [D-Ala2, D-Leu5] enkephalin (DADLE) could provide dose-dependent protection on spinal cord ischemia-reperfusion (I/R) injury in rabbits. However, the relative protective molecular mechanisms underlying this neuroprotection remain unclear. The purpose of this study was to investigate whether DADLE provided the protection in spinal cord I/R injury through its antioxidant property by decreasing malondialdehyde (MDA) and nitric oxide (NO) levels and increasing glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) levels and through its antiapoptotic capacity by inhibiting caspase-3 and p53 expression. Methods: The rabbits were divided into three groups. The animals in Group NS and Group DADLE were administered with normal saline (NS) or DADLE via aorta during 30 min of ischemia respectively, while the one in Group Sham received no intervention. During the period of reperfusion, the rabbit's blood samples were collected for enzyme-linked immunoabsorbent assay (ELISA) examinations of MDA, NO, GSH-Px and SOD. At 48 h after reperfusion, the lumbar spinal cords were harvested for immunohistochemical, real-time polymerase chain reaction (PCR) and western blot studies to detect the caspase-3 and p53 expressions. Results: The activities of serum MDA and NO showed significant reductions in the DADLE group as compared with the control group. By contrast, the levels of serum GSH-Px and SOD were significantly higher in the DADLE group than those in the NS group. In addition, caspase-3 and p53 expression were significantly increased in the NS group, while DADLE mitigated these changes. Conclusions: The protective effects of DADLE at the dosage of 0.05 mg/kg may be related to its antioxidant and antiapoptosis properties in the rabbit model of spinal cord I/R injury. PMID- 29163010 TI - An Axiology of Information Security for Futuristic Neuroprostheses: Upholding Human Values in the Context of Technological Posthumanization. AB - Previous works exploring the challenges of ensuring information security for neuroprosthetic devices and their users have typically built on the traditional InfoSec concept of the "CIA Triad" of confidentiality, integrity, and availability. However, we argue that the CIA Triad provides an increasingly inadequate foundation for envisioning information security for neuroprostheses, insofar as it presumes that (1) any computational systems to be secured are merely instruments for expressing their human users' agency, and (2) computing devices are conceptually and practically separable from their users. Drawing on contemporary philosophy of technology and philosophical and critical posthumanist analysis, we contend that futuristic neuroprostheses could conceivably violate these basic InfoSec presumptions, insofar as (1) they may alter or supplant their users' biological agency rather than simply supporting it, and (2) they may structurally and functionally fuse with their users to create qualitatively novel "posthumanized" human-machine systems that cannot be secured as though they were conventional computing devices. Simultaneously, it is noted that many of the goals that have been proposed for future neuroprostheses by InfoSec researchers (e.g., relating to aesthetics, human dignity, authenticity, free will, and cultural sensitivity) fall outside the scope of InfoSec as it has historically been understood and touch on a wide range of ethical, aesthetic, physical, metaphysical, psychological, economic, and social values. We suggest that the field of axiology can provide useful frameworks for more effectively identifying, analyzing, and prioritizing such diverse types of values and goods that can (and should) be pursued through InfoSec practices for futuristic neuroprostheses. PMID- 29163009 TI - Regulatory Pathways of Monoamine Oxidase A during Social Stress. AB - Social stress has a high impact on many biological systems in the brain, including serotonergic (5-HT) system-a major drug target in the current treatment for depression. Hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis and monoamine oxidase A (MAO-A) are well-known stress responses, which are involved in the central 5-HT system. Although, many MAO-A inhibitors have been developed and used in the therapeutics of depression, effective management of depression by modulating the activity of MAO-A has not been achieved. Identifying the molecular pathways that regulate the activity of MAO-A in the brain is crucial for developing new drug targets for precise control of MAO-A activity. Over the last few decades, several regulatory pathways of MAO-A consisting of Kruppel like factor 11 (KLF11), Sirtuin1, Ring finger protein in neural stem cells (RINES), and Cell division cycle associated 7-like protein (R1) have been identified, and the influence of social stress on these regulatory factors evaluated. This review explores various aspects of these pathways to expand our understanding of the roles of the HPA axis and MAO-A regulatory pathways during social stress. The first part of this review introduces some components of the HPA axis, explains how stress affects them and how they interact with the 5-HT system in the brain. The second part summarizes the novel regulatory pathways of MAO-A, which have high potential as novel therapeutic targets for depression. PMID- 29163011 TI - Optimised PDMS Tunnel Devices on MEAs Increase the Probability of Detecting Electrical Activity from Human Stem Cell-Derived Neuronal Networks. AB - Measurement of the activity of human pluripotent stem cell (hPSC)-derived neuronal networks with microelectrode arrays (MEAs) plays an important role in functional in vitro brain modelling and in neurotoxicological screening. The previously reported hPSC-derived neuronal networks do not, however, exhibit repeatable, stable functional network characteristics similar to rodent cortical cultures, making the interpretation of results difficult. In earlier studies, microtunnels have been used both to control and guide cell growth and amplify the axonal signals of rodent neurons. The aim of the current study was to develop tunnel devices that would facilitate signalling and/or signal detection in entire hPSC-derived neuronal networks containing not only axons, but also somata and dendrites. Therefore, MEA-compatible polydimethylsiloxane (PDMS) tunnel devices with 8 different dimensions were created. The hPSC-derived neurons were cultured in the tunnel devices on MEAs, and the spontaneous electrical activity of the networks was measured for 5 weeks. Although the tunnel devices improved the signal-to-noise ratio only by 1.3-fold at best, they significantly increased the percentage of electrodes detecting neuronal activity (52-100%) compared with the controls (27%). Significantly higher spike and burst counts were also obtained using the tunnel devices. Neuronal networks inside the tunnels were amenable to pharmacological manipulation. The results suggest that tunnel devices encompassing the entire neuronal network can increase the measured spontaneous activity in hPSC-derived neuronal networks on MEAs. Therefore, they can increase the efficiency of functional studies of hPSC-derived networks on MEAs. PMID- 29163012 TI - Iron Oxide Nanoparticle Delivery of Peptides to the Brain: Reversal of Anxiety during Drug Withdrawal. AB - Targeting neuropeptide systems is important for future advancements in treatment of neurological and psychiatric illnesses. However, many of the peptides and their analogs do not cross the blood-brain barrier (BBB) efficiently. Nanoparticles such as iron oxide can cross the BBB, and here we describe a novel method for the conjugation of a peptide antisauvagine-30 (ASV-30) to iron oxide nanoparticles. Previous research has shown that direct infusion of ASV-30 into the brain reduces anxiety-like behavior in animal models via actions on corticotropin releasing factor type 2 (CRF2) receptors. Therefore, we tested whether iron oxide+ASV-30 complexes cross the BBB of rats and then determined whether iron oxide+ASV-30 nanoparticles are localized with CRF2-expressing neurons. Finally we tested the hypothesis that systemic infusion of iron oxide+ASV-30 can reduce anxiety-like behavior. First we describe the synthesis and demonstrate the stability of iron oxide-peptide nanoparticle complexes. Next, nanoparticles (87.7 MUg/kg Fe2O3) with or without ASV-30 (200 MUg/kg, ip) were injected into male rats 30 min prior to transcardial perfusion and brain fixation for immunohistochemical analysis, or before testing on the elevated plus maze (EPM) in an amphetamine withdrawal model of anxiety. Systemically administered iron oxide+ASV-30 particles were present in the brain and associated with neurons, including those that express CRF2 receptors, but did not localize with the iron storage protein ferritin. Furthermore, systemic administration of ironoxide+ASV-30 reduced amphetamine withdrawal-induced anxiety without affecting locomotion, suggesting that the anxiolytic effects of ASV-30 were preserved and the bioavailability of ASV-30 was sufficient. The findings demonstrate a novel approach to peptide delivery across the BBB and provide insight as to the neural distribution and efficacy of this nanotechnology. PMID- 29163013 TI - Motor Areas Show Altered Dendritic Structure in an Amyotrophic Lateral Sclerosis Mouse Model. AB - Objective: Motor neurons (MNs) die in amyotrophic lateral sclerosis (ALS), a clinically heterogeneous neurodegenerative disease of unknown etiology. In human or rodent studies, MN loss is preceded by increased excitability. As increased neuronal excitability correlates with structural changes in dendritic arbors and spines, we have examined longitudinal changes in dendritic structure in vulnerable neuron populations in a mouse model of familial ALS. Methods: We used a modified Golgi-Cox staining method to determine the progressive changes in dendritic structure of hippocampal CA1 pyramidal neurons, striatal medium spiny neurons, and resistant (trochlear, IV) or susceptible (hypoglossal, XII; lumbar) MNs from brainstem and spinal cord of mice over-expressing the human SOD1G93A (SOD1) mutation, in comparison to wild-type (WT) mice, at four postnatal (P) ages of 8-15, 28-35, 65-75, and 120 days. Results: In SOD1 mice, dendritic changes occur at pre-symptomatic ages in both XII and spinal cord lumbar MNs. Spine loss without dendritic changes was present in striatal neurons from disease onset. Spine density increases were present at all ages studied in SOD1 XII MNs. Spine density increased in neonatal lumbar MNs, before decreasing to control levels by P28-35 and was decreased by P120. SOD1 XII MNs and lumbar MNs, but not trochlear MNs showed vacuolization from the same time-points. Trochlear MN dendrites were unchanged. Interpretation: Dendritic structure and spine alterations correlate with the neuro-motor phenotype in ALS and with cognitive and extra-motor symptoms seen in patients. Prominent early changes in dendritic arbors and spines occur in susceptible cranial and spinal cord MNs, but are absent in MNs resistant to loss in ALS. PMID- 29163014 TI - Downregulation of DmMANF in Glial Cells Results in Neurodegeneration and Affects Sleep and Lifespan in Drosophila melanogaster. AB - In Drosophila melanogaster, mesencephalic astrocyte-derived neurotrophic factor (DmMANF) is an evolutionarily conserved ortholog of mammalian MANF and cerebral dopamine neurotrophic factor (CDNF), which have been shown to promote the survival of dopaminergic neurons in the brain. We observed especially high levels of DmMANF in the visual system of Drosophila, particularly in the first optic neuropil (lamina). In the lamina, DmMANF was found in glial cells (surface and epithelial glia), photoreceptors and interneurons. Interestingly, silencing of DmMANF in all neurons or specifically in photoreceptors or L2 interneurons had no impact on the structure of the visual system. However, downregulation of DmMANF in glial cells induced degeneration of the lamina. Remarkably, this degeneration in the form of holes and/or tightly packed membranes was observed only in the lamina epithelial glial cells. Those membranes seem to originate from the endoplasmic reticulum, which forms autophagosome membranes. Moreover, capitate projections, the epithelial glia invaginations into photoreceptor terminals that are involved in recycling of the photoreceptor neurotransmitter histamine, were less numerous after DmMANF silencing either in neurons or glial cells. The distribution of the alpha subunit of Na+/K+-ATPase protein in the lamina cell membranes was also changed. At the behavioral level, silencing of DmMANF either in neurons or glial cells affected the daily activity/sleep pattern, and flies showed less activity during the day but higher activity during the night than did controls. In the case of silencing in glia, the lifespan of flies was also shortened. The obtained results showed that DmMANF regulates many functions in the brain, particularly those dependent on glial cells. PMID- 29163015 TI - Resveratrol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage via Inhibition of NLRP3 Inflammasome Activation. AB - Previous studies have demonstrated resveratrol (RSV) has beneficial effects in early brain injury (EBI) after subarachnoid hemorrhage (SAH). However, the beneficial effects of RSV and the underlying mechanisms have not been clearly identified. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation plays a crucial role in the EBI pathogenesis. The aim of this study was to investigate the role of RSV on the NLRP3 inflammasome signaling pathway and EBI in rats after SAH. A prechiasmatic cistern injection model was established in rats, and the primary cultured cortical neurons were stimulated with oxyhemoglobin (oxyHb) to induce SAH in vitro. It showed that the NLRP3 inflammasome components, including NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, mature interleukin-1beta (IL-1beta), and interleukin-18 (IL-18) were upregulated after SAH, and the enhanced NLRP3 after SAH was mainly located in microglia. Treatment with 60 or 90 mg/kg RSV after SAH dramatically inhibited the expression of NLRP3, but there was no significant difference in the expression of NLRP3 between the SAH + 60 mg/kg RSV and SAH + 90 mg/kg RSV groups. In addition, treatment with 30 mg/kg RSV did not significantly reduced the expression of NLRP3. We next evaluated the neuroprotective effects of RSV against SAH. We determined that SAH-induced NLRP3 inflammasome activation was significantly inhibited in the SAH + 60 mg/kg RSV group. Meanwhile, 60 mg/kg RSV administration could markedly inhibit microglia activation and neutrophils infiltration after SAH. Concomitant with the decreased cerebral inflammation, RSV evidently reduced cortical apoptosis, brain edema, and neurobehavioral impairment after SAH. In vitro experiments, RSV treatment also clearly protected primary cortical neurons against oxyHb insults, including reduced the proportion of neuronal apoptosis, alleviated neuronal degeneration, and improved cell viabilities. These in vitro data further confirm that RSV has an efficient neuroprotection against SAH. Taken together, these in vivo and in vitro findings suggested RSV could protect against EBI after SAH, at least partially via inhibiting NLRP3 inflammasome signaling pathway. PMID- 29163016 TI - Session-RPE Method for Training Load Monitoring: Validity, Ecological Usefulness, and Influencing Factors. AB - Purpose: The aim of this review is to (1) retrieve all data validating the Session-rating of perceived exertion (RPE)-method using various criteria, (2) highlight the rationale of this method and its ecological usefulness, and (3) describe factors that can alter RPE and users of this method should take into consideration. Method: Search engines such as SPORTDiscus, PubMed, and Google Scholar databases in the English language between 2001 and 2016 were consulted for the validity and usefulness of the session-RPE method. Studies were considered for further analysis when they used the session-RPE method proposed by Foster et al. in 2001. Participants were athletes of any gender, age, or level of competition. Studies using languages other than English were excluded in the analysis of the validity and reliability of the session-RPE method. Other studies were examined to explain the rationale of the session-RPE method and the origin of RPE. Results: A total of 950 studies cited the Foster et al. study that proposed the session RPE-method. 36 studies have examined the validity and reliability of this proposed method using the modified CR-10. Conclusion: These studies confirmed the validity and good reliability and internal consistency of session-RPE method in several sports and physical activities with men and women of different age categories (children, adolescents, and adults) among various expertise levels. This method could be used as "standing alone" method for training load (TL) monitoring purposes though some recommend to combine it with other physiological parameters as heart rate. PMID- 29163017 TI - Electrical Neuroimaging of Music Processing Reveals Mid-Latency Changes with Level of Musical Expertise. AB - This original research focused on the effect of musical training intensity on cerebral and behavioral processing of complex music using high-density event related potential (ERP) approaches. Recently we have been able to show progressive changes with training in gray and white matter, and higher order brain functioning using (f)MRI [(functional) Magnetic Resonance Imaging], as well as changes in musical and general cognitive functioning. The current study investigated the same population of non-musicians, amateur pianists and expert pianists using spatio-temporal ERP analysis, by means of microstate analysis, and ERP source imaging. The stimuli consisted of complex musical compositions containing three levels of transgression of musical syntax at closure that participants appraised. ERP waveforms, microstates and underlying brain sources revealed gradual differences according to musical expertise in a 300-500 ms window after the onset of the terminal chords of the pieces. Within this time window, processing seemed to concern context-based memory updating, indicated by a P3b-like component or microstate for which underlying sources were localized in the right middle temporal gyrus, anterior cingulate and right parahippocampal areas. Given that the 3 expertise groups were carefully matched for demographic factors, these results provide evidence of the progressive impact of training on brain and behavior. PMID- 29163018 TI - Brain Networks Implicated in Seasonal Affective Disorder: A Neuroimaging PET Study of the Serotonin Transporter. AB - Background: Seasonal Affective Disorder (SAD) is a subtype of Major Depressive Disorder characterized by seasonally occurring depression that often presents with atypical vegetative symptoms such as hypersomnia and carbohydrate craving. It has recently been shown that unlike healthy people, patients with SAD fail to globally downregulate their cerebral serotonin transporter (5-HTT) in winter, and that this effect seemed to be particularly pronounced in female S-carriers of the 5-HTTLPR genotype. The purpose of this study was to identify a 5-HTT brain network that accounts for the adaption to the environmental stressor of winter in females with the short 5-HTTLPR genotype, a specific subgroup previously reported to be at increased risk for developing SAD. Methods: Nineteen females, either S' carriers (LG- and S-carriers) without SAD (N = 13, mean age 23.6 +/- 3.2 year, range 19-28) or S' carriers with SAD (N = 6, mean age 23.7 +/- 2.4, range 21-26) were PET-scanned with [11C]DASB during both summer and winter seasons (asymptomatic and symptomatic phase, 38 scans in total) in randomized order, defined as a 12-week interval centered on summer or winter solstice. We used a multivariate Partial Least Squares (PLS) approach with NPAIRS split-half cross validation, to identify and map a whole-brain pattern of 5-HTT levels that distinguished the brains of females without SAD from females suffering from SAD. Results: We identified a pattern of 5-HTT levels, distinguishing females with SAD from those without SAD; it included the right superior frontal gyrus, brainstem, globus pallidus (bilaterally) and the left hippocampus. Across seasons, female S' carriers without SAD showed nominally higher 5-HTT levels in these regions compared to female S' carriers with SAD, but the group difference was only significant in the winter. Female S' carriers with SAD, in turn, displayed robustly increased 5-HTT levels in the ventral striatum (bilaterally), right orbitofrontal cortex, middle frontal gyrus (bilaterally), extending to the left supramarginal gyrus, left precentral gyrus and left postcentral gyrus during winter compared to female S' carriers without SAD. Limitations: The study is preliminary and limited by small sample size in the SAD group (N = 6). Conclusions: These findings provide novel exploratory evidence for a wintertime state-dependent difference in 5-HTT levels that may leave SAD females with the short 5-HTTLPR genotype more vulnerable to persistent stressors like winter. The affected brain regions comprise a distributed set of areas responsive to emotion, voluntary, and planned movement, executive function, and memory. The preliminary findings provide additional insight into the neurobiological components through which the anatomical distribution of serotonergic discrepancies between individuals genetically predisposed to SAD, but with different phenotypic presentations during the environmental stressor of winter, may constitute a potential biomarker for resilience against developing SAD. PMID- 29163020 TI - What Drives Bird Vision? Bill Control and Predator Detection Overshadow Flight. AB - Although flight is regarded as a key behavior of birds this review argues that the perceptual demands for its control are met within constraints set by the perceptual demands of two other key tasks: the control of bill (or feet) position, and the detection of food items/predators. Control of bill position, or of the feet when used in foraging, and timing of their arrival at a target, are based upon information derived from the optic flow-field in the binocular region that encompasses the bill. Flow-fields use information extracted from close to the bird using vision of relatively low spatial resolution. The detection of food items and predators is based upon information detected at a greater distance and depends upon regions in the retina with relatively high spatial resolution. The tasks of detecting predators and of placing the bill (or feet) accurately, make contradictory demands upon vision and these have resulted in trade-offs in the form of visual fields and in the topography of retinal regions in which spatial resolution is enhanced, indicated by foveas, areas, and high ganglion cell densities. The informational function of binocular vision in birds does not lie in binocularity per se (i.e., two eyes receiving slightly different information simultaneously about the same objects) but in the contralateral projection of the visual field of each eye. This ensures that each eye receives information from a symmetrically expanding optic flow-field centered close to the direction of the bill, and from this the crucial information of direction of travel and time-to contact can be extracted, almost instantaneously. Interspecific comparisons of visual fields between closely related species have shown that small differences in foraging techniques can give rise to different perceptual challenges and these have resulted in differences in visual fields even within the same genus. This suggests that vision is subject to continuing and relatively rapid natural selection based upon individual differences in the structure of the optical system, retinal topography, and eye position in the skull. From a sensory ecology perspective a bird is best characterized as "a bill guided by an eye" and that control of flight is achieved within constraints on visual capacity dictated primarily by the demands of foraging and bill control. PMID- 29163019 TI - Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System. AB - Bile acids are best known as detergents involved in the digestion of lipids. In addition, new data in the last decade have shown that bile acids also function as gut hormones capable of influencing metabolic processes via receptors such as FXR (farnesoid X receptor) and TGR5 (Takeda G protein-coupled receptor 5). These effects of bile acids are not restricted to the gastrointestinal tract, but can affect different tissues throughout the organism. It is still unclear whether these effects also involve signaling of bile acids to the central nervous system (CNS). Bile acid signaling to the CNS encompasses both direct and indirect pathways. Bile acids can act directly in the brain via central FXR and TGR5 signaling. In addition, there are two indirect pathways that involve intermediate agents released upon interaction with bile acids receptors in the gut. Activation of intestinal FXR and TGR5 receptors can result in the release of fibroblast growth factor 19 (FGF19) and glucagon-like peptide 1 (GLP-1), both capable of signaling to the CNS. We conclude that when plasma bile acids levels are high all three pathways may contribute in signal transmission to the CNS. However, under normal physiological circumstances, the indirect pathway involving GLP-1 may evoke the most substantial effect in the brain. PMID- 29163021 TI - Schizophrenia Shows Disrupted Links between Brain Volume and Dynamic Functional Connectivity. AB - Studies featuring multimodal neuroimaging data fusion for understanding brain function and structure, or disease characterization, leverage the partial information available in each of the modalities to reveal data variations not exhibited through the independent analyses. Similar to other complex syndromes, the characteristic brain abnormalities in schizophrenia may be better understood with the help of the additional information conveyed by leveraging an advanced modeling method involving multiple modalities. In this study, we propose a novel framework to fuse feature spaces corresponding to functional magnetic resonance imaging (functional) and gray matter (structural) data from 151 schizophrenia patients and 163 healthy controls. In particular, the features for the functional and structural modalities include dynamic (i.e., time-varying) functional network connectivity (dFNC) maps and the intensities of the gray matter (GM) maps, respectively. The dFNC maps are estimated from group independent component analysis (ICA) network time-courses by first computing windowed functional correlations using a sliding window approach, and then estimating subject specific states from this windowed data using temporal ICA followed by spatio temporal regression. For each subject, the functional data features are horizontally concatenated with the corresponding GM features to form a combined feature space that is subsequently decomposed through a symmetric multimodal fusion approach involving a combination of multiset canonical correlation analysis (mCCA) and joint ICA (jICA). Our novel combined analyses successfully linked changes in the two modalities and revealed significantly disrupted links between GM volumes and time-varying functional connectivity in schizophrenia. Consistent with prior research, we found significant group differences in GM comprising regions in the superior parietal lobule, precuneus, postcentral gyrus, medial/superior frontal gyrus, superior/middle temporal gyrus, insula and fusiform gyrus, and several significant aberrations in the inter-regional functional connectivity strength as well. Importantly, structural and dFNC measures have independently shown changes associated with schizophrenia, and in this work we begin the process of evaluating the links between the two, which could shed light on the illness beyond what we can learn from a single imaging modality. In future work, we plan to evaluate replication of the inferred structure-function relationships in independent partitions of larger multi-modal schizophrenia datasets. PMID- 29163023 TI - Perinatal Asphyxia in Rat Alters Expression of Novel Schizophrenia Risk Genes. AB - Epidemiological studies suggest that obstetric complications, particularly those related to hypoxia during labor and delivery, are a risk factor for development of schizophrenia. The impact of perinatal asphyxia on postnatal life has been studied in a rodent model of global hypoxia, which is accompanied by cesarean section birth. This asphyxia model shows several behavioral, pharmacological, neurochemical, and neuroanatomical abnormalities in adulthood that have relevance to schizophrenia. Further, it is suggested that schizophrenia has a strong genetic component, and indeed novel candidate genes were recently identified by a genome-wide association study. Here, we examined alteration in the novel schizophrenia risk genes, CNNM2, CSMD1, and MMP16 in the brains of rats undergoing cesarean section with or without global hypoxia. The brain regions studied were the prefrontal cortex, striatum, and hippocampus, which are all relevant to schizophrenia. Risk gene expression was measured at three time periods: neonatal, adolescence, and adulthood. We also performed an in vitro analysis to determine involvement of these genes in CNS maturation during differentiation of human neuronal and glial cell lines. Cnnm2 expression was altered in the brains of asphyxia model rats. However, Csmd1 and Mmp16 showed altered expression by exposure to cesarean section only. These findings suggest that altered expression of these risk genes via asphyxia and cesarean section may be associated, albeit through distinct pathways, with the pathobiology of schizophrenia. PMID- 29163024 TI - PET/MR Imaging: New Frontier in Alzheimer's Disease and Other Dementias. AB - Alzheimer's disease (AD) is the most common form of dementia; a progressive neurodegenerative disease that currently lacks an effective treatment option. Early and accurate diagnosis, in addition to quick elimination of differential diagnosis, allows us to provide timely treatments that delay the progression of AD. Imaging plays an important role for the early diagnosis of AD. The newly emerging PET/MR imaging strategies integrate the advantages of PET and MR to diagnose and monitor AD. This review introduces the development of PET/MR imaging systems, technical considerations of PET/MR imaging, special considerations of PET/MR in AD, and the system's potential clinical applications and future perspectives in AD. PMID- 29163026 TI - Generation of Urine Cell-Derived Non-integrative Human iPSCs and iNSCs: A Step-by Step Optimized Protocol. AB - Objective: Establishing a practical procedure to generate induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) from human urine cells (UCs). In this report, we optimized a non-integrative protocol to generate patient-specific iPSC and iNSC lines with high reprogramming efficiency. Methods: UCs were electroporated with the pEP4-EO2S-ET2K and pEP4-M2L plasmids containing the OCT4, SOX2, KLF4, SV40LT, c-MYC, and LIN28 genes, and then cultured with N2B27 medium plus four small molecule compounds (A83-01, PD0325901, Thiazovivin, and CHIR99021). When iPSC or iNSC clones emerged, the medium was replaced with mTeSR1 or neural growth medium. Morphological changes were seen at day 4-7. After day 10, the clones were picked up when the clone diameter exceeded 1 mm. Results: iPSCs and iNSCs were successfully derived from UCs with up to 80 clones/well. These iPSCs and iNSCs showed typical hESC or NSC morphology and were self renewable. The iPSCs had pluripotency to differentiate into the three germinal layers and displayed high levels of expression of pluripotency markers SOX2, NANOG, OCT4, SSEA-4, TRA-1-60, TRA-1-81, and alkaline phosphatase (AP). They maintained normal karyotype and had no transgene expression or genomic integration. The iNSCs were positive for NSC markers NESTIN, PAX6, SOX2, and OLIG2. Conclusion: The optimized protocol is an easy and fast procedure to yield both iPSC and iNSC lines from a convenient source of human urine in a single experiment. PMID- 29163025 TI - BDNF/trkB Induction of Calcium Transients through Cav2.2 Calcium Channels in Motoneurons Corresponds to F-actin Assembly and Growth Cone Formation on beta2 Chain Laminin (221). AB - Spontaneous Ca2+ transients and actin dynamics in primary motoneurons correspond to cellular differentiation such as axon elongation and growth cone formation. Brain-derived neurotrophic factor (BDNF) and its receptor trkB support both motoneuron survival and synaptic differentiation. However, in motoneurons effects of BDNF/trkB signaling on spontaneous Ca2+ influx and actin dynamics at axonal growth cones are not fully unraveled. In our study we addressed the question how neurotrophic factor signaling corresponds to cell autonomous excitability and growth cone formation. Primary motoneurons from mouse embryos were cultured on the synapse specific, beta2-chain containing laminin isoform (221) regulating axon elongation through spontaneous Ca2+ transients that are in turn induced by enhanced clustering of N-type specific voltage-gated Ca2+ channels (Cav2.2) in axonal growth cones. TrkB-deficient (trkBTK-/-) mouse motoneurons which express no full-length trkB receptor and wildtype motoneurons cultured without BDNF exhibited reduced spontaneous Ca2+ transients that corresponded to altered axon elongation and defects in growth cone morphology which was accompanied by changes in the local actin cytoskeleton. Vice versa, the acute application of BDNF resulted in the induction of spontaneous Ca2+ transients and Cav2.2 clustering in motor growth cones, as well as the activation of trkB downstream signaling cascades which promoted the stabilization of beta-actin via the LIM kinase pathway and phosphorylation of profilin at Tyr129. Finally, we identified a mutual regulation of neuronal excitability and actin dynamics in axonal growth cones of embryonic motoneurons cultured on laminin-221/211. Impaired excitability resulted in dysregulated axon extension and local actin cytoskeleton, whereas upon beta-actin knockdown Cav2.2 clustering was affected. We conclude from our data that in embryonic motoneurons BDNF/trkB signaling contributes to axon elongation and growth cone formation through changes in the local actin cytoskeleton accompanied by increased Cav2.2 clustering and local calcium transients. These findings may help to explore cellular mechanisms which might be dysregulated during maturation of embryonic motoneurons leading to motoneuron disease. PMID- 29163022 TI - The Insula and Taste Learning. AB - The sense of taste is a key component of the sensory machinery, enabling the evaluation of both the safety as well as forming associations regarding the nutritional value of ingestible substances. Indicative of the salience of the modality, taste conditioning can be achieved in rodents upon a single pairing of a tastant with a chemical stimulus inducing malaise. This robust associative learning paradigm has been heavily linked with activity within the insular cortex (IC), among other regions, such as the amygdala and medial prefrontal cortex. A number of studies have demonstrated taste memory formation to be dependent on protein synthesis at the IC and to correlate with the induction of signaling cascades involved in synaptic plasticity. Taste learning has been shown to require the differential involvement of dopaminergic GABAergic, glutamatergic, muscarinic neurotransmission across an extended taste learning circuit. The subsequent activation of downstream protein kinases (ERK, CaMKII), transcription factors (CREB, Elk-1) and immediate early genes (c-fos, Arc), has been implicated in the regulation of the different phases of taste learning. This review discusses the relevant neurotransmission, molecular signaling pathways and genetic markers involved in novel and aversive taste learning, with a particular focus on the IC. Imaging and other studies in humans have implicated the IC in the pathophysiology of a number of cognitive disorders. We conclude that the IC participates in circuit-wide computations that modulate the interception and encoding of sensory information, as well as the formation of subjective internal representations that control the expression of motivated behaviors. PMID- 29163028 TI - The Neuronal and Peripheral Expressed Membrane-Bound UNC93A Respond to Nutrient Availability in Mice. AB - Many transporters such as the solute carriers belonging to the Major facilitator superfamily Pfam clan are orphans in that their tissue and cellular localization as well as substrate profile and function are still unknown. Here we have characterized the putative solute carrier UNC93A. We aimed to investigate the expression profile on both protein and mRNA level of UNC93A in mouse since it has not been clarified. UNC93A staining was found in cortex, hippocampus and cerebellum. It was found to be expressed in many neurons, but not all, with staining located in close proximity to the plasma membrane. Furthermore, we aimed to extend the starvation data available for Unc93a in hypothalamic cell cultures from mouse. We investigated the Unc93a alterations with focus on amino acid deprivation in embryonic cortex cells from mice as well as 24 h starvation in adult male mice and compared it to recently studied putative and known solute carriers. Unc93a expression was found both in the brain and peripheral organs, in low to moderate levels in the adult mice and was affected by amino acid deprivation in embryonic cortex cultures and starvation in in vivo samples. In conclusion, the membrane-bound UNC93A is expressed in both the brain and peripheral tissues and responds to nutrient availability in mice. PMID- 29163027 TI - Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models. AB - Pain due to osteoarthritis (OA) is one of the most frequent causes of chronic pain. However, the mechanisms of OA pain are poorly understood. This review addresses the mechanisms which are thought to be involved in OA pain, derived from studies on pain mechanisms in humans and in experimental models of OA. Three areas will be considered, namely local processes in the joint associated with OA pain, neuronal mechanisms involved in OA pain, and general factors which influence OA pain. Except the cartilage all structures of the joints are innervated by nociceptors. Although the hallmark of OA is the degradation of the cartilage, OA joints show multiple structural alterations of cartilage, bone and synovial tissue. In particular synovitis and bone marrow lesions have been proposed to determine OA pain whereas the contribution of the other pathologies to pain generation has been studied less. Concerning the peripheral neuronal mechanisms of OA pain, peripheral nociceptive sensitization was shown, and neuropathic mechanisms may be involved at some stages. Structural changes of joint innervation such as local loss and/or sprouting of nerve fibers were shown. In addition, central sensitization, reduction of descending inhibition, descending excitation and cortical atrophies were observed in OA. The combination of different neuronal mechanisms may define the particular pain phenotype in an OA patient. Among mediators involved in OA pain, nerve growth factor (NGF) is in the focus because antibodies against NGF significantly reduce OA pain. Several studies show that neutralization of interleukin-1beta and TNF may reduce OA pain. Many patients with OA exhibit comorbidities such as obesity, low grade systemic inflammation and diabetes mellitus. These comorbidities can significantly influence the course of OA, and pain research just began to study the significance of such factors in pain generation. In addition, psychologic and socioeconomic factors may aggravate OA pain, and in some cases genetic factors influencing OA pain were found. Considering the local factors in the joint, the neuronal processes and the comorbidities, a better definition of OA pain phenotypes may become possible. Studies are under way in order to improve OA and OA pain monitoring. PMID- 29163030 TI - Tcf12 Is Involved in Early Cell-Fate Determination and Subset Specification of Midbrain Dopamine Neurons. AB - The basic helix-loop-helix (bHLH) protein family has previously been shown to be involved in the development of mesodiencephalic dopaminergic (mdDA) neurons in the murine midbrain. Specifically, Ngn2 and Mash1 are known to have a role in the specification of neural progenitors in the ventricular zone (VZ) of the midbrain towards an mdDA neuronal cell-fate. Furthermore, other members of the bHLH protein family, the E-box factors, are expressed in the developing midbrain and are thought to have a role in neuronal differentiation. Here we show that the E box factor Tcf12 is implicated in early and late development of mdDA neurons. Tcf12 is expressed in the midbrain and in young TH-expressing mdDA neurons throughout development. Tcf12lox/lox;En1cre/+ embryos, that lose Tcf12 at ~embryonic day (E)9 throughout the En1 expression domain, have a changed spatial expression of Lmx1a and Nurr1 and a consistent loss of rostral TH expression. Expression of the subset marker Ahd2 is initially delayed, but recovers during development, eventually showing an ~10% increase in AHD2-expressing cells at postnatal day (P)30. Tcf12lox/lox;Pitx3cre/+ embryos, that lose Tcf12 at ~E12 in post-mitotic mdDA neurons, show no effect on the amount of TH-expressing neurons in the developing midbrain. However, similar as to Tcf12lox/lox;En1cre/+ embryos, subset specification is delayed during development. Taken together, we have identified Tcf12 as a novel factor in mdDA neuronal development. It serves a dual function; one in early cell-fate commitment of neural progenitors and one late in subset specification. PMID- 29163029 TI - MicroRNAs and Target Genes As Biomarkers for the Diagnosis of Early Onset of Parkinson Disease. AB - Among the neurodegenerative disorders, Parkinson's disease (PD) ranks as the second most common disorder with a higher prevalence in individuals aged over 60 years old. Younger individuals may also be affected with PD which is known as early onset PD (EOPD). Despite similarities between the characteristics of EOPD and late onset PD (LODP), EOPD patients experience much longer disease manifestations and poorer quality of life. Although some individuals are more prone to have EOPD due to certain genetic alterations, the molecular mechanisms that differentiate between EOPD and LOPD remains unclear. Recent findings in PD patients revealed that there were differences in the genetic profiles of PD patients compared to healthy controls, as well as between EOPD and LOPD patients. There were variants identified that correlated with the decline of cognitive and motor symptoms as well as non-motor symptoms in PD. There were also specific microRNAs that correlated with PD progression, and since microRNAs have been shown to be involved in the maintenance of neuronal development, mitochondrial dysfunction and oxidative stress, there is a strong possibility that these microRNAs can be potentially used to differentiate between subsets of PD patients. PD is mainly diagnosed at the late stage, when almost majority of the dopaminergic neurons are lost. Therefore, identification of molecular biomarkers for early detection of PD is important. Given that miRNAs are crucial in controlling the gene expression, these regulatory microRNAs and their target genes could be used as biomarkers for early diagnosis of PD. In this article, we discussed the genes involved and their regulatory miRNAs, regarding their roles in PD progression, based on the findings of significantly altered microRNAs in EOPD studies. We also discussed the potential of these miRNAs as molecular biomarkers for early diagnosis. PMID- 29163031 TI - MicroRNA-Mediated Regulation of ITGB3 and CHL1 Is Implicated in SSRI Action. AB - Background: Selective serotonin reuptake inhibitor (SSRI) antidepressant drugs are the first-line of treatment for major depressive disorder (MDD) but are effective in <70% of patients. Our earlier genome-wide studies indicated that two genes encoding for cell adhesion proteins, close homolog of L1 (CHL1) and integrin beta-3 (ITGB3), and microRNAs, miR-151a-3p and miR-221/222, are implicated in the variable sensitivity and response of human lymphoblastoid cell lines (LCL) from unrelated individuals to SSRI drugs. Methods: The microRNAs miR 221, miR-222, and miR-151-a-3p, along with their target gene binding sites, were explored in silico using miRBase, TargetScan, microRNAviewer, and the UCSC Genome Browser. Luciferase reporter assays were conducted for demonstrating the direct functional regulation of ITGB3 and CHL1 expression by miR-221/222 and miR-151a 3p, respectively. A human LCL exhibiting low sensitivity to paroxetine was utilized for studying the phenotypic effect of CHL1 regulation by miR-151a-3p on SSRI response. Results: By showing direct regulation of CHL1 and ITGB3 by miR 151a-3p and miR-221/222, respectively, we link these microRNAs and genes with cellular SSRI sensitivity phenotypes. We report that miR-151a-3p increases cell sensitivity to paroxetine via down-regulating CHL1 expression. Conclusions: miR 151a-3p, miR-221/222 and their (here confirmed) respective target-genes, CHL1 and ITGB3, are implicated in SSRI responsiveness, and possibly in the clinical response to antidepressant drugs. PMID- 29163033 TI - Phosphorylation at S153 as a Functional Switch of Phosphatidylethanolamine Binding Protein 1 in Cerebral Ischemia-Reperfusion Injury in Rats. AB - This study aimed to estimate the role of phosphatidylethanolamine binding protein 1 (PEBP1) in cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms. Middle cerebral artery occlusion/reperfusion (MCAO/R) model in adult male Sprague Dawley rats (250-280 g) were established and cultured neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic I/R injury in vitro. Expression vectors encoding wild-type PEBP1 and PEBP1 with Ser153Ala mutation (S153A), PEBP1 specific siRNAs, and human recombinant PEBP1 (rhPEBP1) were administered intracerebroventricularly. Endogenous PEBP1 level and its phosphorylation at Ser153 were increased within penumbra tissue and cultured neurons after I/R, accompanied by decreased interaction between PEBP1 and Raf-1. There was a trend toward increased Raf-1/MEK/ERK/NF-kappaB signaling pathway and phosphatidylcholine-phospholipase C (PC-PLC) activity after I/R, which was enhanced by wild-type PEBP1overexpression and rhPEBP1 treatment and inhibited by PEBP1 (S153A) overexpression. And PEBP1 (S153A) overexpression increased its interaction with Raf-1, reduced infarct size, neuronal death and inflammation, and improved neurological function after I/R, while wild-type PEBP1overexpression exerted opposite effects, suggesting that phosphorylation at Ser153 may exert as a functional switch of PEBP1 by switching PEBP1 from Raf-1 inhibition to PC-PLC activation following I/R. Compared with PEBP1 knockdown, PEBP1 (S153A) overexpression exerted a better rescue effect on I/R injury, which further proved that PEBP1 may be a good protein gone bad with phosphorylation at S153 as a functional switch following I/R. Collectively, our findings suggest that PEBP1 contributed to neuronal death and inflammation after I/R. Selective inhibition of PEBP1 phosphorylation may be a novel approach to ameliorate I/R injury. PMID- 29163032 TI - Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases. AB - Lysosomal storage diseases (LSDs) are a heterogeneous group of rare inherited metabolic diseases that are frequently triggered by the accumulation of lipids inside organelles of the endosomal-autophagic-lysosomal system (EALS). There is now a growing realization that disrupted lysosomal homeostasis (i.e., lysosomal cacostasis) also contributes to more common neurodegenerative disorders such as Parkinson disease (PD). Lipid deposition within the EALS may also participate in the pathogenesis of some additional neurodegenerative diseases of the motor system. Here, I will highlight the lipid abnormalities and clinical manifestations that are common to LSDs and several diseases of the motor system, including amyotrophic lateral sclerosis (ALS), atypical forms of spinal muscular atrophy, Charcot-Marie-Tooth disease (CMT), hereditary spastic paraplegia (HSP), multiple system atrophy (MSA), PD and spinocerebellar ataxia (SCA). Elucidating the underlying basis of intracellular lipid mislocalization as well as its consequences in each of these disorders will likely provide innovative targets for therapeutic research. PMID- 29163034 TI - Direct Reprogramming Rather than iPSC-Based Reprogramming Maintains Aging Hallmarks in Human Motor Neurons. AB - In vitro generation of motor neurons (MNs) is a promising approach for modeling motor neuron diseases (MNDs) such as amyotrophic lateral sclerosis (ALS). As aging is a leading risk factor for the development of neurodegeneration, it is important to recapitulate age-related characteristics by using MNs at pathogenic ages. So far, cell reprogramming through induced pluripotent stem cells (iPSCs) and direct reprogramming from primary fibroblasts are two major strategies to obtain populations of MNs. While iPSC generation must go across the epigenetic landscape toward the pluripotent state, directly converted MNs might have the advantage of preserving aging-associated features from fibroblast donors. In this study, we confirmed that human iPSCs reset the aging status derived from their old donors, such as telomere attrition and cellular senescence. We then applied a set of transcription factors to induce MNs from either primary fibroblasts or iPSC-derived neural progenitor cells. The results revealed that directly reprogrammed MNs, rather than iPSC-derived MNs, maintained the aging hallmarks of old donors, including extensive DNA damage, loss of heterochromatin and nuclear organization, and increased SA-beta-Gal activity. iPSC-derived MNs did not regain those aging memories from old donors. Collectively, our study indicates rejuvenation in the iPSC-based model, as well as aging maintenance in direct reprogramming of MNs. As such, the directly reprogrammed MNs may be more suitable for modeling the late-onset pathogenesis of MNDs. PMID- 29163035 TI - NPAS2 Regulation of Anxiety-Like Behavior and GABAA Receptors. AB - Abnormal circadian rhythms and circadian genes are strongly associated with several psychiatric disorders. Neuronal PAS Domain Protein 2 (NPAS2) is a core component of the molecular clock that acts as a transcription factor and is highly expressed in reward- and stress-related brain regions such as the striatum. However, the mechanism by which NPAS2 is involved in mood-related behaviors is still unclear. We measured anxiety-like behaviors in mice with a global null mutation in Npas2 (Npas2 null mutant mice) and found that Npas2 null mutant mice exhibit less anxiety-like behavior than their wild-type (WT) littermates (in elevated plus maze, light/dark box and open field assay). We assessed the effects of acute or chronic stress on striatal Npas2 expression, and found that both stressors increased levels of Npas2. Moreover, knockdown of Npas2 in the ventral striatum resulted in a similar reduction of anxiety-like behaviors as seen in the Npas2 null mutant mouse. Additionally, we identified Gabra genes as transcriptional targets of NPAS2, found that Npas2 null mutant mice exhibit reduced sensitivity to the GABAa positive allosteric modulator, diazepam and that knockdown of Npas2 reduced Gabra1 expression and response to diazepam in the ventral striatum. These results: (1) implicate Npas2 in the response to stress and the development of anxiety; and (2) provide functional evidence for the regulation of GABAergic neurotransmission by NPAS2 in the ventral striatum. PMID- 29163036 TI - Amino-Terminal beta-Amyloid Antibody Blocks beta-Amyloid-Mediated Inhibition of the High-Affinity Choline Transporter CHT. AB - Alzheimer's disease (AD) is a common age-related neurodegenerative disorder that is characterized by progressive cognitive decline. The deficits in cognition and attentional processing that are observed clinically in AD are linked to impaired function of cholinergic neurons that release the neurotransmitter acetylcholine (ACh). The high-affinity choline transporter (CHT) is present at the presynaptic cholinergic nerve terminal and is responsible for the reuptake of choline produced by hydrolysis of ACh following its release. Disruption of CHT function leads to decreased choline uptake and ACh synthesis, leading to impaired cholinergic neurotransmission. We report here that cell-derived beta-amyloid peptides (Abeta) decrease choline uptake activity and cell surface CHT protein levels in SH-SY5Y neural cells. Moreover, we make the novel observation that the amount of CHT protein localizing to early endosomes and lysosomes is decreased significantly in cells that have been treated with cell culture medium that contains Abeta peptides released from neural cells. The Abeta-mediated loss of CHT proteins from lysosomes is prevented by blocking lysosomal degradation of CHT with the lysosome inhibitor bafilomycin A1 (BafA1). BafA1 also attenuated the Abeta-mediated decrease in CHT cell surface expression. Interestingly, however, lysosome inhibition did not block the effect of Abeta on CHT activity. Importantly, neutralizing Abeta using an anti-Abeta antibody directed at the N terminal amino acids 1-16 of Abeta, but not by an antibody directed at the mid region amino acids 22-35 of Abeta, attenuates the effect of Abeta on CHT activity and trafficking. This indicates that a specific N-terminal Abeta epitope, or specific conformation of soluble Abeta, may impair CHT activity. Therefore, Abeta immunotherapy may be a more effective therapeutic strategy for slowing the progression of cognitive decline in AD than therapies designed to promote CHT cell surface levels. PMID- 29163037 TI - Commentary: alpha-Synuclein Interacts with Lipoproteins in Plasma. PMID- 29163039 TI - Commentary: Prenatal Ethanol Exposure Persistently Alters Endocannabinoid Signaling and Endocannabinioid-Mediated Excitatory Synaptic Plasticity in Ventral Tegmental Area Dopamine Neurons. PMID- 29163038 TI - Electroacupuncture Suppresses the NF-kappaB Signaling Pathway by Upregulating Cylindromatosis to Alleviate Inflammatory Injury in Cerebral Ischemia/Reperfusion Rats. AB - Electroacupuncture (EA) may reduce inflammatory injury by inhibiting nuclear factor-kappa B (NF-kappaB) signaling pathway activation after ischemic stroke. Thus, we explored temporal and spatial expression of cylindromatosis (CYLD), a negative feedback inhibitor of the NF-kappaB signaling pathway, to learn whether CYLD is essential for EA and reduction of inflammatory injury after focal cerebral ischemia/reperfusion. A middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in male Sprague-Dawley (SD) rats and CYLD gene interference was used to investigate a potential role of neuroprotection. Rats were treated with EA (1 mA, 20 Hz for 5 min, 2 Hz for 30 min) at Baihui (GV 20), Hegu (LI 4) and Taichong (LR 3) acupoints, once daily, beginning 2 h after focal cerebral ischemia. Microglial activation and co-expression of CYLD and NF-kappaB were measured with immunofluorescence. Neuronal CX3CL1 expression was assayed to investigate the role of EA in the interaction between neurons and microglia via upregulation of CYLD. Then, CYLD, NF-kappaB p65 and p-IkappaBalpha protein expression was measured with Western blot. CYLD was mainly expressed in neurons of the peri-ischemic area after MCAO/R in rats and EA upregulated CYLD mRNA and protein from 24 to 72 h after focal cerebral ischemia/reperfusion. In addition, CYLD overexpression was positively correlated to neurobehavior and negatively connected with infarct volume and pro-inflammatory cytokines (TNF-alpha and IL 1beta). Upregulation of CYLD by EA prevented NF-kappaB nuclear translocation and inhibition of neuronal CX3CL1 expression, which repressed activation of microglia. Finally, CYLD silencing significantly weakened suppression of the NF kappaB signaling pathway by EA. In conclusion, upregulation of CYLD may underlie how EA could alleviate inflammatory injury after focal cerebral ischemia/reperfusion. PMID- 29163040 TI - Cdk7 Is Required for Activity-Dependent Neuronal Gene Expression, Long-Lasting Synaptic Plasticity and Long-Term Memory. AB - In the brain, de novo gene expression driven by learning-associated neuronal activities is critical for the formation of long-term memories. However, the signaling machinery mediating neuronal activity-induced gene expression, especially the rapid transcription of immediate-early genes (IEGs) remains unclear. Cyclin-dependent kinases (Cdks) are a family of serine/threonine kinases that have been firmly established as key regulators of transcription processes underling coordinated cell cycle entry and sequential progression in nearly all types of proliferative cells. Cdk7 is a subunit of transcriptional initiation factor II-H (TFIIH) and the only known Cdk-activating kinase (CAK) in metazoans. Recent studies using a novel Cdk7 specific covalent inhibitor, THZ1, revealed important roles of Cdk7 in transcription regulation in cancer cells. However, whether Cdk7 plays a role in the regulation of transcription in neurons remains unknown. In this study, we present evidence demonstrating that, in post-mitotic neurons, Cdk7 activity is positively correlated with neuronal activities in cultured primary neurons, acute hippocampal slices and in the brain. Cdk7 inhibition by THZ1 significantly suppressed mRNA levels of IEGs, selectively impaired long-lasting synaptic plasticity induced by 4 trains of high frequency stimulation (HFS) and prevented the formation of long-term memories. PMID- 29163041 TI - Revisiting the Quantum Brain Hypothesis: Toward Quantum (Neuro)biology? AB - The nervous system is a non-linear dynamical complex system with many feedback loops. A conventional wisdom is that in the brain the quantum fluctuations are self-averaging and thus functionally negligible. However, this intuition might be misleading in the case of non-linear complex systems. Because of an extreme sensitivity to initial conditions, in complex systems the microscopic fluctuations may be amplified and thereby affect the system's behavior. In this way quantum dynamics might influence neuronal computations. Accumulating evidence in non-neuronal systems indicates that biological evolution is able to exploit quantum stochasticity. The recent rise of quantum biology as an emerging field at the border between quantum physics and the life sciences suggests that quantum events could play a non-trivial role also in neuronal cells. Direct experimental evidence for this is still missing but future research should address the possibility that quantum events contribute to an extremely high complexity, variability and computational power of neuronal dynamics. PMID- 29163042 TI - Impairment of Hepcidin Upregulation by Lipopolysaccharide in the Interleukin-6 Knockout Mouse Brain. AB - To find out whether the Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is involved in the expression of hepcidin in the mouse brain in vivo, we investigated the phosphorylation of STAT3, as well as the expression of hepcidin mRNA, ferroportin 1 (Fpn1) and ferritin light chain (Ft-L) proteins in the cortex and hippocampus of LPS-treated wild type (IL-6+/+) and IL-6 knockout (IL-6-/-) mice. We demonstrated that IL-6 knockout could significantly reduce the response of hepcidin mRNA, phospho-STAT3, Fpn1 and Ft-L protein expression to LPS treatment, in both the cortex and hippocampus of mice. Also, Stattic, an inhibitor of STAT3, significantly reduced the expression of phospho-STAT3 and hepcidin mRNA in the cortex and hippocampus of the LPS-treated wild type mice. These findings provide in vivo evidence for the involvement of the IL-6/STAT3 signaling pathway in the expression of hepcidin. PMID- 29163043 TI - Combination Therapy in Fragile X Syndrome; Possibilities and Pitfalls Illustrated by Targeting the mGluR5 and GABA Pathway Simultaneously. AB - Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability and autism. The disorder is characterized by altered synaptic plasticity in the brain. Synaptic plasticity is tightly regulated by a complex balance of different synaptic pathways. In FXS, various synaptic pathways are disrupted, including the excitatory metabotropic glutamate receptor 5 (mGluR5) and the inhibitory gamma-aminobutyric acid (GABA) pathways. Targeting each of these pathways individually, has demonstrated beneficial effects in animal models, but not in patients with FXS. This lack of translation might be due to oversimplification of the disease mechanisms when targeting only one affected pathway, in spite of the complexity of the many pathways implicated in FXS. In this report we outline the hypothesis that targeting more than one pathway simultaneously, a combination therapy, might improve treatment effects in FXS. In addition, we present a glance of the first results of chronic combination therapy on social behavior in Fmr1 KO mice. In contrast to what we expected, targeting both the mGluR5 and the GABAergic pathways simultaneously did not result in a synergistic effect, but in a slight worsening of the social behavior phenotype. This does implicate that both pathways are interconnected and important for social behavior. Our results underline the tremendous fine-tuning that is needed to reach the excitatory-inhibitory balance in the synapse in relation to social behavior. We believe that alternative strategies focused on combination therapy should be further explored, including targeting pathways in different cellular compartments or cell-types. PMID- 29163044 TI - Partial Aminoglycoside Lesions in Vestibular Epithelia Reveal Broad Sensory Dysfunction Associated with Modest Hair Cell Loss and Afferent Calyx Retraction. AB - Although the effects of aminoglycoside antibiotics on hair cells have been investigated for decades, their influences on the dendrites of primary afferent neurons have not been widely studied. This is undoubtedly due to the difficulty in disassociating pathology to dendritic processes from that resulting from loss of the presynaptic hair cell. This was overcome in the present investigation through development of a preparation using Chinchilla laniger that enabled direct perilymphatic infusion. Through this strategy we unmasked gentamicin's potential effects on afferent calyces. The pathophysiology of the vestibular neuroepithelia after post-administration durations of 0.5 through 6 months was assessed using single-neuron electrophysiology, immunohistochemistry, and confocal microscopy. Hair cell densities within cristae central zones (0.5-, 1-, 2-, and 6-months) and utricle peri- and extrastriola (6-months) regions were determined, and damage to calretinin-immunoreactive calyces was quantified. Gentamicin-induced hair cell loss exhibited a profile that reflected elimination of a most-sensitive group by 0.5-months post-administration (18.2%), followed by loss of a second group (20.6%) over the subsequent 5.5 months. The total hair cell loss with this gentamicin dose (approximately 38.8%) was less than the estimated fraction of type I hair cells in the chinchilla's crista central zone (approximately 60%), indicating that viable type I hair cells remained. Extensive lesions to afferent calyces were observed at 0.5-months, though stimulus-evoked modulation was intact at this post-administration time. Widespread compromise to calyx morphology and severe attenuation of stimulus-evoked afferent discharge modulation was found at 1 month post-administration, a condition that persisted in preparations examined through the 6-month post-administration interval. Spontaneous discharge was robust at all post-administration intervals. All calretinin-positive calyces had retracted at 2 and 6 months post-administration. We found no evidence of morphologic or physiologic recovery. These results indicate that gentamicin induced partial lesions to vestibular epithelia include hair cell loss (ostensibly reflecting an apoptotic effect) that is far less extensive than the compromise to stimulus-evoked afferent discharge modulation and retraction of afferent calyces (reflecting non-apoptotic effects). Additionally, calyx retraction cannot be completely accounted for by loss of type I hair cells, supporting the possibility for direct action of gentamicin on the afferent dendrite. PMID- 29163045 TI - Down-regulation of NTPDase2 and ADP-sensitive P2 Purinoceptors Correlate with Severity of Symptoms during Experimental Autoimmune Encephalomyelitis. AB - The present study explores tissue and cellular distribution of ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) and the gene and protein expression in rat spinal cord during the course of experimental autoimmune encephalomyelitis (EAE). Given that NTPDase2 hydrolyzes ATP with a transient accumulation of ADP, the expression of ADP-sensitive P2 purinoceptors was analyzed as well. The autoimmune disease was actively induced in Dark Agouti female rats and the changes were analyzed 10, 15 and 29 days after the induction. These selected time points correspond to the onset ( Eo ), peak ( Ep ) and recovery ( Er ) from EAE. In control animals, NTPDase2 was confined in the white matter, in most of the glial fibrillary acidic protein (GFAP)-immunoreactive (ir) astrocytes and in a considerable number of nestin-ir cells, while the other cell types were immunonegative. Immunoreactivity corresponding to NTPDase2 decreased significantly at Eo and Ep and then returned to the baseline levels at Er . The preservation of the proportion of GFAP single-labeled and GFAP/NTPDase2 double labeled elements along the course of EAE indicated that changes in NTPDase2-ir occurred at fibrous astrocytes that typically express NTPDase2 in normal conditions. Significant downregulation of P2Y1 and P2Y12 receptor proteins at Eo and several-fold induction of P2Y12 and P2Y13 receptor proteins at Ep and/or Er were observed implying that the pathophysiological process in EAE may be linked to ADP signaling. Cell-surface expression of NTPDase2, NTPDase1/CD39 and ecto-5' nucleotidase (eN/CD73) was analyzed in CD4+ T cells of a draining lymph node by fluorescence-activated cell sorting. The induction of EAE was associated with a transient decrease in a number of CD4+ NTPDase2+ T cells in a draining lymph node, whereas the recovery was characterized by an increase in NTPDase2+ cells in both CD4+ and CD4- cell populations. The opposite was found for NTPDase1/CD39+ and eN/CD73+ cells, which slightly increased in number with progression of the disease, particularly in CD4- cells, and then decreased in the recovery. Finally, CD4+ NTPDase2+ cells were never observed in the spinal cord parenchyma. Taken together, our results suggest that the process of neuroinflammation in EAE may be associated with altered ADP signaling. PMID- 29163046 TI - RIM-Binding Protein 2 Promotes a Large Number of CaV1.3 Ca2+-Channels and Contributes to Fast Synaptic Vesicle Replenishment at Hair Cell Active Zones. AB - Ribbon synapses of inner hair cells (IHCs) mediate high rates of synchronous exocytosis to indefatigably track the stimulating sound with sub-millisecond precision. The sophisticated molecular machinery of the inner hair cell active zone realizes this impressive performance by enabling a large number of synaptic voltage-gated CaV1.3 Ca2+-channels, their tight coupling to synaptic vesicles (SVs) and fast replenishment of fusion competent SVs. Here we studied the role of RIM-binding protein 2 (RIM-BP2)-a multidomain cytomatrix protein known to directly interact with Rab3 interacting molecules (RIMs), bassoon and CaV1.3-that is present at the inner hair cell active zones. We combined confocal and stimulated emission depletion (STED) immunofluorescence microscopy, electron tomography, patch-clamp and confocal Ca2+-imaging, as well as auditory systems physiology to explore the morphological and functional effects of genetic RIM-BP2 disruption in constitutive RIM-BP2 knockout mice. We found that RIM-BP2 (1) positively regulates the number of synaptic CaV1.3 channels and thereby facilitates synaptic vesicle release and (2) supports fast synaptic vesicle recruitment after readily releasable pool (RRP) depletion. However, Ca2+-influx exocytosis coupling seemed unaltered for readily releasable SVs. Recordings of auditory brainstem responses (ABR) and of single auditory nerve fiber firing showed that RIM-BP2 disruption results in a mild deficit of synaptic sound encoding. PMID- 29163047 TI - Biphasic Regulation of Caveolin-1 Gene Expression by Fluoxetine in Astrocytes: Opposite Effects of PI3K/AKT and MAPK/ERK Signaling Pathways on c-fos. AB - Previously, we reported that fluoxetine acts on 5-HT2B receptor and induces epidermal growth factor receptor (EGFR) transactivation in astrocytes. Recently, we have found that chronic treatment with fluoxetine regulates Caveolin-1 (Cav 1)/PTEN/PI3K/AKT/glycogen synthase kinase 3beta (GSK-3beta) signaling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At low concentrations fluoxetine down-regulates Cav-1 gene expression, decreases membrane content of PTEN, increases PI3K activity and increases phosphorylation of GSK-3beta and increases its activity; at high concentrations fluoxetine acts on PTEN/PI3K/AKT/GSK-3beta in an inverse fashion. Here, we present the data indicating that acute treatment with fluoxetine at lower concentrations down-regulates c-Fos gene expression via PI3K/AKT signaling pathway; in contrast at higher concentrations fluoxetine up-regulates c-Fos gene expression via MAPK/extracellular-regulated kinase (ERK) signaling pathway. However, acute treatment with fluoxetine has no effect on Cav-1 protein content. Similarly, chronic effects of fluoxetine on Cav-1 gene expression are suppressed by inhibitor of PI3K at lower concentrations, but by inhibitor of MAPK at higher concentrations, indicating that the mechanism underlying bi-phasic regulation of Cav-1 gene expression by fluoxetine is opposing effects of PI3K/AKT and MAPK/ERK signal pathways on c-Fos gene expression. The effects of fluoxetine on Cav-1 gene expression at both lower and higher concentrations are abolished by AG1478, an inhibitor of EGFR, indicating the involvement of 5-HT2B receptor induced EGFR transactivation as we reported previously. However, PP1, an inhibitor of Src only abolished the effect by lower concentrations, suggesting the relevance of Src with PI3K/AKT signal pathway during activation of EGFR. PMID- 29163048 TI - Nicotinic Acetylcholine Receptor Subtype Alpha-9 Mediates Triple-Negative Breast Cancers Based on a Spontaneous Pulmonary Metastasis Mouse Model. AB - Triple-negative breast cancer (TNBC) subtype is associated with poor prognosis and a high risk of recurrence-related death in women. Despite the aggressiveness of TNBCs, targeted TNBC therapy is not yet available in the clinic. To overcome this challenge, we generated highly metastatic TNBC cells (LM) derived from metastasized lung cells via a serial spontaneous pulmonary metastasis animal model to identify targetable molecules for attenuating the progression of TNBC metastasis. Gene analysis of primary tumor (P), first-round (1LM) and second round (2LM) metastasized lung cells revealed that mesenchymal-related genes were significantly expressed in LM cells, especially in 2LM cells. Interestingly, alpha9-nAChR gene expression was also dramatically induced in LM cells, confirming our previous finding that alpha9-nAChR plays important roles in receptor-mediated carcinogenic signals in human breast cancer development. Using alpha9-nAChR as a biomarker, we transfected 2LM cells with CRISPR/Cas9 lentivirus targeting the alpha9-nAChR genomic region (2LM-alpha9-nAChR-null), showing that mesenchymal markers and the migration and invasion abilities of 2LM cells were significantly attenuated in 2LM-alpha9-nAChR-null cells both in vitro and in vivo. In addition, the high efficiency of editing the alpha9-nAChR gene using a CRISPR/Cas9 lentivirus was demonstrated by gene sequencing, genomic indel frequency and protein expression analyses. Collectively, these results confirmed those of our previous study that advanced-stage breast tumors are associated with substantially higher levels of alpha9-nAChR gene expression, indicating that alpha9-nAChR expression is essential for mediating TNBC metastasis during cancer development and may potentially act as a biomarker for targeted therapy in clinical investigations. PMID- 29163049 TI - Tagging of Endogenous BK Channels with a Fluorogen-Activating Peptide Reveals beta4-Mediated Control of Channel Clustering in Cerebellum. AB - BK channels are critical regulators of neuronal activity, controlling firing, neurotransmitter release, cerebellar function, and BK channel mutations have been linked to seizure disorders. Modulation of BK channel gating is well characterized, regulated by accessory subunit interactions, intracellular signaling pathways, and membrane potential. In contrast, the role of intracellular trafficking mechanisms in controlling BK channel function, especially in live cells, has been less studied. Fluorogen-activating peptides (FAPs) are well-suited for trafficking and physiological studies due to the binding of malachite green (MG)-based dyes with sub-nanomolar affinity to the FAP, resulting in bright, photostable, far-red fluorescence. Cell-excluded MG dyes enable the selective tagging of surface protein and tracking through endocytic pathways. We used CRISPR to insert the FAP at the extracellular N terminus of BKalpha in the first exon of its native locus, enabling regulation by the native promoter elements and tag incorporation into multiple splice isoforms. Motor coordination was found to be normal; however, BK channel expression seems to be reduced in some locations. Alternate start site selection or post translational proteolytic processing resulted in incomplete FAP tagging of the BKalpha proteins in brain tissues. In Purkinje cell somata, FAP revealed BK channel clustering previously only observed by electron microscopy. Measurement of these clusters in beta4+/- and beta4-/- mice showed that puncta number and cluster fluorescence intensity on the soma are reduced in beta4-/- knockout animals. This novel mouse line provides a versatile fluorescent platform for studying endogenous BK channels in living and fixed tissues. Future studies could apply this line to ex vivo neuronal cultures to study live-cell channel trafficking. PMID- 29163051 TI - Young Human Cholinergic Neurons Respond to Physiological Regulators and Improve Cognitive Symptoms in an Animal Model of Alzheimer's Disease. AB - The degeneration of cholinergic neurons of the nucleus basalis of Meynert (NBM) in the basal forebrain (BF) is associated to the cognitive decline of Alzheimer's disease (AD) patients. To date no resolutive therapies exist. Cell-based replacement therapy is a strategy currently under consideration, although the mechanisms underlying the generation of stem cell-derived NBM cholinergic neurons able of functional integration remain to be clarified. Since fetal brain is an optimal source of neuronal cells committed towards a specific phenotype, this study is aimed at isolating cholinergic neurons from the human fetal NBM (hfNBMs) in order to study their phenotypic, maturational and functional properties. Extensive characterization confirmed the cholinergic identity of hfNBMs, including positivity for specific markers (such as choline acetyltransferase) and acetylcholine (Ach) release. Electrophysiological measurements provided the functional validation of hfNBM cells, which exhibited the activation of peculiar sodium (INa) and potassium (IK) currents, as well as the presence of functional cholinergic receptors. Accordingly, hfNBMs express both nicotinic and muscarinic receptors, which were activated by Ach. The hfNBMs cholinergic phenotype was regulated by the nerve growth factor (NGF), through the activation of the high affinity NGF receptor TrkA, as well as by 17-beta-estradiol through a peculiar recruitment of its own receptors. When intravenously administered in NBM-lesioned rats, hfNBMs determined a significant improvement in memory functions. Histological examination of brain sections showed that hfNBMs (labeled with PKH26 fluorescent dye prior to administration) reached the damaged brain areas. The study provides a useful model to study the ontogenetic mechanisms regulating the development and maintenance of the human brain cholinergic system and to assess new lines of research, including disease modeling, drug discovery and cell-based therapy for AD. PMID- 29163050 TI - Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection. AB - Evidence of significant hearing loss during the early days of use of cisplatin as a chemotherapeutic agent in cancer patients has stimulated research into the causes and treatment of this side effect. It has generally been accepted that hearing loss is produced by excessive generation of reactive oxygen species (ROS) in cell of the cochlea, which led to the development of various antioxidants as otoprotective agents. Later studies show that ROS could stimulate cochlear inflammation, suggesting the use of anti-inflammatory agents for treatment of hearing loss. In this respect, G-protein coupled receptors, such as adenosine A1 receptor and cannabinoid 2 receptors, have shown efficacy in the treatment of hearing loss in experimental animals by increasing ROS scavenging, suppressing ROS generation, or by decreasing inflammation. Inflammation could be triggered by activation of transient receptor potential vanilloid 1 (TRPV1) channels in the cochlea and possibly other TRP channels. Targeting TRPV1 for knockdown has also been shown to be a useful strategy for ensuring otoprotection. Cisplatin entry into cochlear hair cells is mediated by various transporters, inhibitors of which have been shown to be effective for treating hearing loss. Finally, cisplatin induced DNA damage and activation of the apoptotic process could be targeted for cisplatin-induced hearing loss. This review focuses on recent development in our understanding of the mechanisms underlying cisplatin-induced hearing loss and provides examples of how drug therapies have been formulated based on these mechanisms. PMID- 29163052 TI - The Thymus/Neocortex Hypothesis of the Brain: A Cell Basis for Recognition and Instruction of Self. AB - The recognition of internal and external sources of stimuli, the self from non self, seems to be an intrinsic property to the adequate functioning of the immune system and the nervous system, both complex network systems that have evolved to safeguard the self biological identity of the organism. The mammalian brain development relies on dynamic and adaptive processes that are now well described. However, the rules dictating this highly constrained developmental process remain elusive. Here we hypothesize that there is a cellular basis for brain selfhood, based on the analogy of the global mechanisms that drive the self/non-self recognition and instruction by the immune system. In utero education within the thymus by multi-step selection processes discard overly low and high affinity T lymphocytes to self stimuli, thus avoiding expendable or autoreactive responses that might lead to harmful autoimmunity. We argue that the self principle is one of the chief determinants of neocortical brain neurogenesis. According to our hypothesis, early-life education on self at the subcortical plate of the neocortex by selection processes might participate in the striking specificity of neuronal repertoire and assure efficiency and self tolerance. Potential implications of this hypothesis in self-reactive neurological pathologies are discussed, particularly involving consciousness-associated pathophysiological conditions, i.e., epilepsy and schizophrenia, for which we coined the term autophrenity. PMID- 29163053 TI - Functional Characterization of Lamina X Neurons in ex-Vivo Spinal Cord Preparation. AB - Functional properties of lamina X neurons in the spinal cord remain unknown despite the established role of this area for somatosensory integration, visceral nociception, autonomic regulation and motoneuron output modulation. Investigations of neuronal functioning in the lamina X have been hampered by technical challenges. Here we introduce an ex-vivo spinal cord preparation with both dorsal and ventral roots still attached for functional studies of the lamina X neurons and their connectivity using an oblique LED illumination for resolved visualization of lamina X neurons in a thick tissue. With the elaborated approach, we demonstrate electrophysiological characteristics of lamina X neurons by their membrane properties, firing pattern discharge and fiber innervation (either afferent or efferent). The tissue preparation has been also probed using Ca2+ imaging with fluorescent Ca2+ dyes (membrane-impermeable or -permeable) to demonstrate the depolarization-induced changes in intracellular calcium concentration in lamina X neurons. Finally, we performed visualization of subpopulations of lamina X neurons stained by retrograde labeling with aminostilbamidine dye to identify sympathetic preganglionic and projection neurons in the lamina X. Thus, the elaborated approach provides a reliable tool for investigation of functional properties and connectivity in specific neuronal subpopulations, boosting research of lamina X of the spinal cord. PMID- 29163054 TI - Motor Deficits and Cerebellar Atrophy in Elovl5 Knock Out Mice. AB - Spino-Cerebellar-Ataxia type 38 (SCA38) is caused by missense mutations in the very long chain fatty acid elongase 5 gene, ELOVL5. The main clinical findings in this disease are ataxia, hyposmia and cerebellar atrophy. Mice in which Elovl5 has been knocked out represent a model of the loss of function hypothesis of SCA38. In agreement with this hypothesis, Elovl5 knock out mice reproduced the main symptoms of patients, motor deficits at the beam balance test and hyposmia. The cerebellar cortex of Elovl5 knock out mice showed a reduction of thickness of the molecular layer, already detectable at 6 months of age, confirmed at 12 and 18 months. The total perimeter length of the Purkinje cell (PC) layer was also reduced in Elovl5 knock out mice. Since Elovl5 transcripts are expressed by PCs, whose dendrites are a major component of the molecular layer, we hypothesized that an alteration of their dendrites might be responsible for the reduced thickness of this layer. Reconstruction of the dendritic tree of biocytin-filled PCs, followed by Sholl analysis, showed that the distribution of distal dendrites was significantly reduced in Elovl5 knock out mice. Dendritic spine density was conserved. These results suggest that Elovl5 knock out mice recapitulate SCA38 symptoms and that their cerebellar atrophy is due, at least in part, to a reduced extension of PC dendritic arborization. PMID- 29163055 TI - Study of Sex Differences in Duloxetine Efficacy for Depression in Transgenic Mouse Models. AB - Clinical evidences show sex differences in risk of developing depressive disorders as well as effect of antidepressants in depression treatment. However, whether such a sex-dependent risk of depression and efficacy of antidepressants is dependent on endogenous estrogen level remain elusive. The aim of this study is to explore the molecular mechanisms of sex differences in antidepressant duloxetine. In the present study, we used genetic knockout or overexpression estrogen-synthesizing enzyme aromatase (Ar) gene as models for endogenous estrogen deficiency and elevation endogenous estrogen, respectively, to examine the anti-depressive efficacy of duloxetine in males and females by force swimming test (FST). We also measured the sex-specific effect of duloxetine on dopamine and serotonin (5-HT) metabolisms in frontal cortex and hippocampus (HPC). Elevation of brain endogenous estrogen in male and female mice showed a reduction of immobility time in FST compared to control mice. Estrogen deficiency in females showed poor response to duloxetine treatment compared to sex-matched wildtype (WT) or aromatase transgenic mice. In contrast, male mice with estrogen deficiency showed same anti-depressive response to duloxetine treatments as aromatase transgenic mice. Our data showed that the sex different effect of endogenous estrogen on duloxetine-induced anti-depressive behavioral change is associated with brain region-specific changes of dopamine (DA) and 5-HT system. Endogenous estrogen exerts antidepressant effects in both males and females. Lacking of endogenous estrogen reduced antidepressive effect of duloxetine in females only. The endogenous estrogen level alters 5-HT system in female mainly, while both DA and 5-HT metabolisms were regulated by endogenous estrogen levels after duloxetine administration. PMID- 29163056 TI - Commentary: Analysis of SUMO1-conjugation at synapses. PMID- 29163057 TI - Synchronicity and Rhythmicity of Purkinje Cell Firing during Generalized Spike and-Wave Discharges in a Natural Mouse Model of Absence Epilepsy. AB - Absence epilepsy is characterized by the occurrence of generalized spike and wave discharges (GSWDs) in electrocorticographical (ECoG) recordings representing oscillatory activity in thalamocortical networks. The oscillatory nature of GSWDs has been shown to be reflected in the simple spike activity of cerebellar Purkinje cells and in the activity of their target neurons in the cerebellar nuclei, but it is unclear to what extent complex spike activity is implicated in generalized epilepsy. Purkinje cell complex spike firing is elicited by climbing fiber activation and reflects action potential firing in the inferior olive. Here, we investigated to what extent modulation of complex spike firing is reflected in the temporal patterns of seizures. Extracellular single-unit recordings in awake, head-restrained homozygous tottering mice, which suffer from a mutation in the voltage-gated CaV2.1 calcium channel, revealed that a substantial proportion of Purkinje cells (26%) showed increased complex spike activity and rhythmicity during GSWDs. Moreover, Purkinje cells, recorded either electrophysiologically or by using Ca2+-imaging, showed a significant increase in complex spike synchronicity for both adjacent and remote Purkinje cells during ictal events. These seizure-related changes in firing frequency, rhythmicity and synchronicity were most prominent in the lateral cerebellum, a region known to receive cerebral input via the inferior olive. These data indicate profound and widespread changes in olivary firing that are most likely induced by seizure related activity changes in the thalamocortical network, thereby highlighting the possibility that olivary neurons can compensate for pathological brain-state changes by dampening oscillations. PMID- 29163058 TI - Adaptive Changes in the Vestibular System of Land Snail to a 30-Day Spaceflight and Readaptation on Return to Earth. AB - The vestibular system receives a permanent influence from gravity and reflexively controls equilibrium. If we assume gravity has remained constant during the species' evolution, will its sensory system adapt to abrupt loss of that force? We address this question in the land snail Helix lucorum exposed to 30 days of near weightlessness aboard the Bion-M1 satellite, and studied geotactic behavior of postflight snails, differential gene expressions in statocyst transcriptome, and electrophysiological responses of mechanoreceptors to applied tilts. Each approach revealed plastic changes in the snail's vestibular system assumed in response to spaceflight. Absence of light during the mission also affected statocyst physiology, as revealed by comparison to dark-conditioned control groups. Readaptation to normal tilt responses occurred at ~20 h following return to Earth. Despite the permanence of gravity, the snail responded in a compensatory manner to its loss and readapted once gravity was restored. PMID- 29163059 TI - Oxygen and Glucose Deprivation Induces Bergmann Glia Membrane Depolarization and Ca2+ Rises Mainly Mediated by K+ and ATP Increases in the Extracellular Space. AB - During brain ischemia, intense energy deficiency induces a complex succession of events including pump failure, acidosis and exacerbated glutamate release. In the cerebellum, glutamate is the principal mediator of Purkinje neuron anoxic depolarization during episodes of oxygen and glucose deprivation (OGD). Here, the impact of OGD is studied in Bergmann glia, specialized astrocytes closely associated to Purkinje neurons. Patch clamp experiments reveal that during OGD Bergmann glial cells develop a large depolarizing current that is not mediated by glutamate and purinergic receptors but is mainly due to the accumulation of K+ in the extracellular space. Furthermore, we also found that increases in the intracellular Ca2+ concentration appear in Bergmann glia processes several minutes following OGD. These elevations require, in an early phase, Ca2+ mobilization from internal stores via P2Y receptor activation, and, over longer periods, Ca2+ entry through store-operated calcium channels. Our results suggest that increases of K+ and ATP concentrations in the extracellular space are primordial mediators of the OGD effects on Bergmann glia. In the cerebellum, glial responses to energy deprivation-triggering events are therefore highly likely to follow largely distinct rules from those of their neuronal counterparts. PMID- 29163060 TI - NMDA Receptors Regulate the Development of Neuronal Intrinsic Excitability through Cell-Autonomous Mechanisms. AB - Maturation of neuronal and synaptic functions during early life is essential for the development of neuronal circuits and behaviors. In newborns synaptic transmission at excitatory synapses is primarily mediated by N-methyl-D-aspartate receptors (NMDARs), and NMDAR-mediated signaling plays an important role in synaptic maturation. Concomitant with synapse development, the intrinsic properties of neurons undergo dramatic changes during early life. However, little is known about the role of NMDARs in the development of intrinsic excitability. By using mosaic deletion of the obligatory GluN1 subunit of NMDARs in the thalamus of newborn mice, we showed that NMDARs regulate neuronal excitability during postnatal development. Compared with neighboring control neurons, neurons lacking NMDARs exhibit hyperexcitability and this effect is present throughout early life. Morphological analyses show that thalamic neurons without NMDARs have smaller soma size and fewer dendritic branches. Deletion of NMDARs causes a reduction of hyperpolarization-activated cation (HCN) channel function in thalamic neurons, and pharmacologically blocking HCN channels in wild type neurons mimics the effects of GluN1 deletion on intrinsic excitability. Deletion of GluN1 down-regulated mechanistic target of rapamycin (mTOR) signaling in thalamic neurons, and mosaic deletion of mTOR recapitulated the effects of GluN1 deletion. Our results demonstrate that NMDARs regulate intrinsic excitability and morphology of thalamic neurons through cell autonomous mechanisms that implicate mTOR signaling. PMID- 29163061 TI - Cyclodextrins and Iatrogenic Hearing Loss: New Drugs with Significant Risk. AB - Cyclodextrins are a family of cyclic oligosaccharides with widespread usage in medicine, industry and basic sciences owing to their ability to solubilize and stabilize guest compounds. In medicine, cyclodextrins primarily act as a complexing vehicle and consequently serve as powerful drug delivery agents. Recently, uncomplexed cyclodextrins have emerged as potent therapeutic compounds in their own right, based on their ability to sequester and mobilize cellular lipids. In particular, 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) has garnered attention because of its cholesterol chelating properties, which appear to treat a rare neurodegenerative disorder and to promote atherosclerosis regression related to stroke and heart disease. Despite the potential health benefits, use of HPbetaCD has been linked to significant hearing loss in several species, including humans. Evidence in mice supports a rapid onset of hearing loss that is dose-dependent. Ototoxicity can occur following central or peripheral drug delivery, with either route resulting in the preferential loss of cochlear outer hair cells (OHCs) within hours of dosing. Inner hair cells and spiral ganglion cells are spared at doses that cause ~85% OHC loss; additionally, no other major organ systems appear adversely affected. Evidence from a first-to-human phase 1 clinical trial mirrors animal studies to a large extent, indicating rapid onset and involvement of OHCs. All patients in the trial experienced some permanent hearing loss, although a temporary loss of function can be observed acutely following drug delivery. The long-term impact of HPbetaCD use as a maintenance drug, and the mechanism(s) of ototoxicity, are unknown. beta-cyclodextrins preferentially target membrane cholesterol, but other lipid species and proteins may be directly or indirectly involved. Moreover, as cholesterol is ubiquitous in cell membranes, it remains unclear why OHCs are preferentially susceptible to HPbetaCD. It is possible that HPbetaCD acts upon several targets-for example, ion channels, tight junctions (TJ), membrane integrity, and bioenergetics-that collectively increase the sensitivity of OHCs over other cell types. PMID- 29163062 TI - Difference in Perseverative Errors during a Visual Attention Task with Auditory Distractors in Alpha-9 Nicotinic Receptor Subunit Wild Type and Knock-Out Mice. AB - The auditory efferent system is a neural network that originates in the auditory cortex and projects to the cochlear receptor through olivocochlear (OC) neurons. Medial OC neurons make cholinergic synapses with outer hair cells (OHCs) through nicotinic receptors constituted by alpha9 and alpha10 subunits. One of the physiological functions of the alpha9 nicotinic receptor subunit (alpha9-nAChR) is the suppression of auditory distractors during selective attention to visual stimuli. In a recent study we demonstrated that the behavioral performance of alpha-9 nicotinic receptor knock-out (KO) mice is altered during selective attention to visual stimuli with auditory distractors since they made less correct responses and more omissions than wild type (WT) mice. As the inhibition of the behavioral responses to irrelevant stimuli is an important mechanism of the selective attention processes, behavioral errors are relevant measures that can reflect altered inhibitory control. Errors produced during a cued attention task can be classified as premature, target and perseverative errors. Perseverative responses can be considered as an inability to inhibit the repetition of an action already planned, while premature responses can be considered as an index of the ability to wait or retain an action. Here, we studied premature, target and perseverative errors during a visual attention task with auditory distractors in WT and KO mice. We found that alpha9-KO mice make fewer perseverative errors with longer latencies than WT mice in the presence of auditory distractors. In addition, although we found no significant difference in the number of target error between genotypes, KO mice made more short-latency target errors than WT mice during the presentation of auditory distractors. The fewer perseverative error made by alpha9-KO mice could be explained by a reduced motivation for reward and an increased impulsivity during decision making with auditory distraction in KO mice. PMID- 29163063 TI - Acetylcholine Neuromodulation in Normal and Abnormal Learning and Memory: Vigilance Control in Waking, Sleep, Autism, Amnesia and Alzheimer's Disease. AB - Adaptive Resonance Theory, or ART, is a neural model that explains how normal and abnormal brains may learn to categorize and recognize objects and events in a changing world, and how these learned categories may be remembered for a long time. This article uses ART to propose and unify the explanation of diverse data about normal and abnormal modulation of learning and memory by acetylcholine (ACh). In ART, vigilance control determines whether learned categories will be general and abstract, or specific and concrete. ART models how vigilance may be regulated by ACh release in layer 5 neocortical cells by influencing after hyperpolarization (AHP) currents. This phasic ACh release is mediated by cells in the nucleus basalis (NB) of Meynert that are activated by unexpected events. The article additionally discusses data about ACh-mediated tonic control of vigilance. ART proposes that there are often dynamic breakdowns of tonic control in mental disorders such as autism, where vigilance remains high, and medial temporal amnesia, where vigilance remains low. Tonic control also occurs during sleep-wake cycles. Properties of Up and Down states during slow wave sleep arise in ACh-modulated laminar cortical ART circuits that carry out processes in awake individuals of contrast normalization, attentional modulation, decision-making, activity-dependent habituation, and mismatch-mediated reset. These slow wave sleep circuits interact with circuits that control circadian rhythms and memory consolidation. Tonic control properties also clarify how Alzheimer's disease symptoms follow from a massive structural degeneration that includes undermining vigilance control by ACh in cortical layers 3 and 5. Sleep disruptions before and during Alzheimer's disease, and how they contribute to a vicious cycle of plaque formation in layers 3 and 5, are also clarified from this perspective. PMID- 29163064 TI - Turtle Flexion Reflex Motor Patterns Show Windup, Mediated Partly by L-type Calcium Channels. AB - Windup is a form of multisecond temporal summation in which identical stimuli, delivered seconds apart, trigger increasingly strong neuronal responses. L-type Ca2+ channels have been shown to play an important role in the production of windup of spinal cord neuronal responses, initially in studies of turtle spinal cord and later in studies of mammalian spinal cord. L-type Ca2+ channels have also been shown to contribute to windup of limb withdrawal reflex (flexion reflex) in rats, but flexion reflex windup has not previously been described in turtles and its cellular mechanisms have not been studied. We studied windup of flexion reflex motor patterns, evoked with weak mechanical and electrical stimulation of the dorsal hindlimb foot skin and assessed via a hip flexor (HF) nerve recording, in spinal cord-transected and immobilized turtles in vivo. We found that an L-type Ca2+ channel antagonist, nifedipine, applied at concentrations of 50 MUM or 100 MUM to the hindlimb enlargement spinal cord, significantly reduced windup of flexion reflex motor patterns, while lower concentrations of nifedipine had no such effect. Nifedipine similarly reduced the amplitude of an individual flexion reflex motor pattern evoked by a stronger mechanical stimulus, in a dose-dependent manner, suggesting that L-type Ca2+ channels contribute to each flexion reflex as well as to multisecond summation of flexion reflex responses in turtles. We also found that we could elicit flexion reflex windup consistently using a 4-g von Frey filament, which is not usually considered a nociceptive stimulus. Thus, it may be that windup can be evoked by a wide range of tactile stimuli and that L-type calcium channels contribute to multisecond temporal summation of diverse tactile stimuli across vertebrates. PMID- 29163065 TI - The Lesioned Spinal Cord Is a "New" Spinal Cord: Evidence from Functional Changes after Spinal Injury in Lamprey. AB - Finding a treatment for spinal cord injury (SCI) focuses on reconnecting the spinal cord by promoting regeneration across the lesion site. However, while regeneration is necessary for recovery, on its own it may not be sufficient. This presumably reflects the requirement for regenerated inputs to interact appropriately with the spinal cord, making sub-lesion network properties an additional influence on recovery. This review summarizes work we have done in the lamprey, a model system for SCI research. We have compared locomotor behavior (swimming) and the properties of descending inputs, locomotor networks, and sensory inputs in unlesioned animals and animals that have received complete spinal cord lesions. In the majority (~90%) of animals swimming parameters after lesioning recovered to match those in unlesioned animals. Synaptic inputs from individual regenerated axons also matched the properties in unlesioned animals, although this was associated with changes in release parameters. This suggests against any compensation at these synapses for the reduced descending drive that will occur given that regeneration is always incomplete. Compensation instead seems to occur through diverse changes in cellular and synaptic properties in locomotor networks and proprioceptive systems below, but also above, the lesion site. Recovery of locomotor performance is thus not simply the reconnection of the two sides of the spinal cord, but reflects a distributed and varied range of spinal cord changes. While locomotor network changes are insufficient on their own for recovery, they may facilitate locomotor outputs by compensating for the reduction in descending drive. Potentiated sensory feedback may in turn be a necessary adaptation that monitors and adjusts the output from the "new" locomotor network. Rather than a single aspect, changes in different components of the motor system and their interactions may be needed after SCI. If these are general features, and where comparisons with mammalian systems can be made effects seem to be conserved, improving functional recovery in higher vertebrates will require interventions that generate the optimal spinal cord conditions conducive to recovery. The analyses needed to identify these conditions are difficult in the mammalian spinal cord, but lower vertebrate systems should help to identify the principles of the optimal spinal cord response to injury. PMID- 29163066 TI - From Structure to Behavior in Basolateral Amygdala-Hippocampus Circuits. AB - Emotion influences various cognitive processes, including learning and memory. The amygdala is specialized for input and processing of emotion, while the hippocampus is essential for declarative or episodic memory. During emotional reactions, these two brain regions interact to translate the emotion into particular outcomes. Here, we briefly introduce the anatomy and functions of amygdala and hippocampus, and then present behavioral, electrophysiological, optogenetic and biochemical evidence from recent studies to illustrate how amygdala and hippocampus work synergistically to form long-term memory. With recent technological advances, the causal investigations of specific neural circuit between amygdala and hippocampus will help us understand the brain mechanisms of emotion-regulated memories and improve clinical treatment of emotion-associated memory disorders in patients. PMID- 29163067 TI - The BAF45D Protein Is Preferentially Expressed in Adult Neurogenic Zones and in Neurons and May Be Required for Retinoid Acid Induced PAX6 Expression. AB - Adult neurogenesis is important for the development of regenerative therapies for human diseases of the central nervous system (CNS) through the recruitment of adult neural stem cells (NSCs). NSCs are characterized by the capacity to generate neurons, astrocytes, and oligodendrocytes. To identify key factors involved in manipulating the adult NSC neurogenic fate thus has crucial implications for the clinical application. Here, we report that BAF45D is expressed in the subgranular zone (SGZ) of the dentate gyrus, the subventricular zone (SVZ) of the lateral ventricle, and the central canal (CC) of the adult spinal cord. Coexpression of BAF45D with glial fibrillary acidic protein (GFAP), a radial glial like cell marker protein, was identified in the SGZ, the SVZ and the adult spinal cord CC. Quantitative analysis data indicate that BAF45D is preferentially expressed in the neurogenic zone of the LV and the neurons of the adult CNS. Furthermore, during the neuroectoderm differentiation of H9 cells, BAF45D is required for the expression of PAX6, a neuroectoderm determinant that is also known to regulate the self-renewal and neuronal fate specification of adult neural stem/progenitor cells. Together, our results may shed new light on the expression of BAF45D in the adult neurogenic zones and the contribution of BAF45D to early neural development. PMID- 29163068 TI - Larger Subcortical Gray Matter Structures and Smaller Corpora Callosa at Age 5 Years in HIV Infected Children on Early ART. AB - Sub-Saharan Africa is home to 90% of HIV infected (HIV+) children. Since the advent of antiretroviral therapy (ART), HIV/AIDS has transitioned to a chronic condition where central nervous system (CNS) damage may be ongoing. Although, most guidelines recommend early ART to reduce CNS viral reservoirs, the brain may be more vulnerable to potential neurotoxic effects of ART during the rapid development phase in the first years of life. Here we investigate differences in subcortical volumes between 5-year-old HIV+ children who received early ART (before age 18 months) and uninfected children using manual tracing of Magnetic Resonance Images. Participants included 61 Xhosa children (43 HIV+/18 uninfected, mean age = 5.4 +/- 0.3 years, 25 male) from the children with HIV early antiretroviral (CHER) trial; 27 children initiated ART before 12 weeks of age (ART-Before12Wks) and 16 after 12 weeks (ART-After12Wks). Structural images were acquired on a 3T Allegra MRI in Cape Town and manually traced using MultiTracer. Volumetric group differences (HIV+ vs. uninfected; ART-Before12Wks vs. ART After12Wks) were examined for the caudate, nucleus accumbens (NA), putamen (Pu), globus pallidus (GP), and corpus callosum (CC), as well as associations within infected children of structure volumes with age at ART initiation and CD4/CD8 as a proxy for immune health. HIV+ children had significantly larger NA and Pu volumes bilaterally and left GP volumes than controls, whilst CC was smaller. Bilateral Pu was larger in both treatment groups compared to controls, while left GP and bilateral NA were enlarged only in ART-After12Wks children. CC was smaller in both treatment groups compared to controls, and smaller in ART-After12Wks compared to ART-Before12Wks. Within infected children, delayed ART initiation was associated with larger Pu volumes, effects that remained significant when controlling for sex and duration of treatment interruption (left beta = 0.447, p = 0.005; right beta = 0.325, p = 0.051), and lower CD4/CD8 with larger caudates controlling for sex (left beta = -0.471, p = 0.002; right beta = -0.440, p = 0.003). Volumetric differences were greater in children who initiated ART after 12 weeks. Results suggest damage is ongoing despite early ART and viral load suppression; however, earlier treatment is neuroprotective. PMID- 29163070 TI - Origin and Migration of Olfactory Cajal-Retzius Cells. AB - Early telencephalic development involves the migration of diverse cell types that can be identified by specific molecular markers. Most prominent among them are Cajal-Retzius (CR) cells that emanate mainly from the cortical hem and to a lesser extent from rostrolateral, septal and caudo-medial regions. One additional territory proposed to give rise to CR cells that migrate dorsally into the neocortex lies at the ventral pallium, although contradictory results question this notion. With the use of a cell-permeable fluorescent tracer in cultured embryos, we identified novel migratory paths of putative CR cells and other populations that originate from the rostrolateral telencephalon at its olfactory region. Moreover, extensive labeling on the lateral telencephalon along its rostro-caudal extent failed to reveal a dorsally-migrating CR cell population from the ventral pallium at the stages analyzed. Hence, this work reveals a novel olfactory CR cell migration and supports the idea that the ventral pallium, where diverse types of neurons converge, does not actually generate CR cells. PMID- 29163069 TI - Notes on the Recent History of Neuroscience in Africa. AB - Neuroscience began with neuroanatomy and neurosurgery in Egypt more than 5000 years ago. Knowledge grew over time and specialized neurosurgery centers were established in north Africa in the eleventh century. However, it was not until the twentieth century that neuroscience research became established in sub Saharan Africa. In most African countries, clinical research focused on understanding the rationale and improving treatment of epilepsy, infections, nutritional neuropathies, stroke and tumors. Significant advances were made. In the twenty-first century, African knowledge expanded to include all branches of neuroscience, contributing to genetic, biochemical and inflammatory determinants of brain disorders. A major focus of basic neuroscience research has been, and is, investigation of plant extracts, drugs and stress in animal models, providing insight and identifying potential novel therapies. A significant event in the history of African neuroscience was the founding of the Society of Neuroscientists of Africa (SONA) in 1993. The International Brain Research Organization (IBRO) supported SONA conferences, as well as workshops and neuroscience training schools in Africa. Thanks to their investment, as well as that of funding agencies, such as the National Institutes of Health (NIH), International Society for Neurochemistry (ISN), World Federation of Neurosurgical Societies (WFNS), World Federation of Neurology (WFN) and the International League Against Epilepsy (ILAE), neuroscience research is well-established in Africa today. However, in order to continue to develop, African neuroscience needs continued international support and African neuroscientists need to engage in policy and decision-making to persuade governments to fund studies that address the unique regional needs in Africa. PMID- 29163071 TI - Systematic Morphometry of Catecholamine Nuclei in the Brainstem. AB - Catecholamine nuclei within the brainstem reticular formation (RF) play a pivotal role in a variety of brain functions. However, a systematic characterization of these nuclei in the very same experimental conditions is missing so far. Tyrosine hydroxylase (TH) immune-positive cells of the brainstem correspond to dopamine (DA)-, norepinephrine (NE)-, and epinephrine (E)-containing cells. Here, we report a systematic count of TH-positive neurons in the RF of the mouse brainstem by using stereological morphometry. All these nuclei were analyzed for anatomical localization, rostro-caudal extension, volume, neuron number, neuron density, and mean neuronal area for each nucleus. The present data apart from inherent informative value wish to represent a reference for neuronal mapping in those studies investigating the functional anatomy of the brainstem RF. These include: the sleep-wake cycle, movement control, muscle tone modulation, mood control, novelty orienting stimuli, attention, archaic responses to internal and external stressful stimuli, anxiety, breathing, blood pressure, and innumerable activities modulated by the archaic iso-dendritic hard core of the brainstem RF. Most TH immune-positive cells fill the lateral part of the RF, which indeed possesses a high catecholamine content. A few nuclei are medial, although conventional nosography considers all these nuclei as part of the lateral column of the RF. Despite the key role of these nuclei in psychiatric and neurological disorders, only a few of them aspired a great attention in biomedical investigation, while most of them remain largely obscure although intense research is currently in progress. A simultaneous description of all these nuclei is not simply key to comprehend the variety of brainstem catecholamine reticular neurons, but probably represents an intrinsically key base for understanding brain physiology and physiopathology. PMID- 29163072 TI - Altered Functional Brain Connectomes between Sporadic and Familial Parkinson's Patients. AB - Familial Parkinson's disease (PD) is often caused by mutation of a certain gene, while sporadic PD is associated with variants of genes which can influence the susceptibility to PD. The goal of this study was to investigate the difference between the two forms of PD in terms of brain abnormalities using resting-state functional MRI and graph theory. Thirty-one familial PD patients and 36 sporadic PD patients underwent resting-state functional MRI scanning. Frequency-dependent functional connectivity was calculated for each subject using wavelet-based correlations of BOLD signal over 246 brain regions from Brainnetome Atlas. Graph theoretical analysis was then performed to analyze the topology of the functional network, and functional connectome differences were identified with a network based statistical approach. Our results revealed a frequency-specific (0.016 and 0.031 Hz) connectome difference between familial and sporadic forms of PD, as indicated by an increase in assortativity and decrease in the nodal strength in the left medial amygdala of the familial PD group. In addition, the familial PD patients also showed a distinctive functional network between the left medial amygdala and regions related to retrieval of motion information. The present study indicates that the medial amygdala might be most vulnerable to both sporadic and familial PD. Our findings provide some new insights into disrupted resting-state functional connectomes between sporadic PD and familial PD. PMID- 29163073 TI - Neocortical Lamination: Insights from Neuron Types and Evolutionary Precursors. AB - The neocortex is characterized by lamination of its neuron cell bodies in six layers, but there are few clues as to how this comes about and what is its function. Recent studies provide evidence that evolution from simple three-layer cortex may give insight into this problem. Three-layer cortex arose in the olfactory, hippocampal and dorsal cortex of the early amniote forebrain based on a cortical module of excitatory and inhibitory inputs to an intratelencephalic (IT) type of pyramidal neuron with feedback excitation and inhibition and related interneurons. We summarize recent evidence suggesting the hypothesis that the developmental program of three-layer olfactory cortex was co-opted to form six layer mammalian neocortex, elaborating IT cortical units in layers 2-6 while adding layer 4 stellate cells, layer 5B pyramidal tract (PT) cells and layer 6 corticothalamic (CT) cells. PMID- 29163074 TI - The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy. AB - The paravascular pathway, also known as the "glymphatic" pathway, is a recently described system for waste clearance in the brain. According to this model, cerebrospinal fluid (CSF) enters the paravascular spaces surrounding penetrating arteries of the brain, mixes with interstitial fluid (ISF) and solutes in the parenchyma, and exits along paravascular spaces of draining veins. Studies have shown that metabolic waste products and solutes, including proteins involved in the pathogenesis of neurodegenerative diseases such as amyloid-beta, may be cleared by this pathway. Consequently, a growing body of research has begun to explore the association between glymphatic dysfunction and various disease states. However, significant controversy exists in the literature regarding both the direction of waste clearance as well as the anatomical space in which the waste-fluid mixture is contained. Some studies have found no evidence of interstitial solute clearance along the paravascular space of veins. Rather, they demonstrate a perivascular pathway in which waste is cleared from the brain along an anatomically distinct perivascular space in a direction opposite to that of paravascular flow. Although possible explanations have been offered, none have been able to fully reconcile the discrepancies in the literature, and many questions remain. Given the therapeutic potential that a comprehensive understanding of brain waste clearance pathways might offer, further research and clarification is highly warranted. PMID- 29163075 TI - Pauses in Striatal Cholinergic Interneurons: What is Revealed by Their Common Themes and Variations? AB - Striatal cholinergic interneurons, the so-called tonically active neurons (TANs), pause their firing in response to sensory cues and rewards during classical conditioning and instrumental tasks. The respective pause responses observed can demonstrate many commonalities, such as constant latency and duration, synchronous occurrence in a population of cells, and coincidence with phasic activities of midbrain dopamine neurons (DANs) that signal reward predictions and errors. Pauses can however also show divergent properties. Pause latencies and durations can differ in a given TAN between appetitive vs. aversive outcomes in classical conditioning, initial excitation can be present or absent, and a second pause can variably follow a rebound. Despite more than 20 years of study, the functions of these pause responses are still elusive. Our understanding of pause function is hindered by an incomplete understanding of how pauses are generated. In this mini-review article, we compare pause types, as well as current key hypotheses for inputs underlying pauses that include dopamine-induced inhibition through D2-receptors, a GABA input from ventral tegmental area, and a prolonged afterhyperpolarization induced by excitatory input from the cortex or from the thalamus. We review how each of these mechanisms alone explains some but not all aspects of pause responses. These mechanisms might need to operate in specific but variable sets of sequences to generate a full range of pause responses. Alternatively, these mechanisms might operate in conjunction with an underlying control mechanism within cholinergic interneurons which could potentially provide a framework to generate the common themes and variations seen amongst pause responses. PMID- 29163076 TI - Disentangling the Role of the MEC and LEC in the Processing of Spatial and Non Spatial Information: Contribution of Lesion Studies. AB - It is now widely accepted that the entorhinal cortex (EC) plays a pivotal role in the processing of spatial information and episodic memory. The EC is segregated into two sub-regions, the medial EC (MEC) and the lateral EC (LEC) but a comprehensive understanding of their roles across multiple behavioral contexts remains unclear. Considering that it is still useful to investigate the impact of lesions of EC on behavior, we review the contribution of lesion approach to our knowledge of EC functions. We show that the MEC and LEC play different roles in the processing of spatial and non-spatial information. The MEC is necessary to the use of distal but not proximal landmarks during navigation and is crucial for path integration, in particular integration of linear movements. Consistent with predominant hypothesis, the LEC is important for combining the spatial and non spatial aspects of the environment. However, object exploration studies suggest that the functional segregation between the MEC and the LEC is not as clearly delineated and is dependent on environmental and behavioral factors. Manipulation of environmental complexity and therefore of cognitive demand shows that the MEC and the LEC are not strictly necessary to the processing of spatial and non spatial information. In addition we suggest that the involvement of these sub regions can depend on the kind of behavior, i.e., navigation or exploration, exhibited by the animals. Thus, the MEC and the LEC work in a flexible manner to integrate the "what" and "where" information in episodic memory upstream the hippocampus. PMID- 29163077 TI - Revisiting Vision Rehabilitation. AB - Low vision is a condition caused by eye or brain disease, in which visual acuity is 20/70 (3/10 or 6/18) or poorer in the better-seeing eye and cannot be corrected or improved with regular eyeglasses. It impacts personal ability to perform vision-dependent tasks as activities of daily living, walking, reading or using a computer. Rehabilitation is a multidisciplinary training dedicated to improve patients' functional abilities and quality of life. It has to be personalized to every individual situation, whatever the underlying pathology. PMID- 29163078 TI - Natural Translating Locomotion Modulates Cortical Activity at Action Observation. AB - The present study verified if the translational component of locomotion modulated cortical activity recorded at action observation. Previous studies focusing on visual processing of biological motion mainly presented point light walker that were fixed on a spot, thus removing the net translation toward a goal that yet remains a critical feature of locomotor behavior. We hypothesized that if biological motion recognition relies on the transformation of seeing in doing and its expected sensory consequences, a significant effect of translation compared to centered displays on sensorimotor cortical activity is expected. To this aim, we explored whether EEG activity in the theta (4-8 Hz), alpha (8-12 Hz), beta 1 (14-20 Hz) and beta 2 (20-32 Hz) frequency bands exhibited selectivity as participants viewed four types of stimuli: a centered walker, a centered scrambled, a translating walker and a translating scrambled. We found higher theta synchronizations for observed stimulus with familiar shape. Higher power decreases in the beta 1 and beta 2 bands, indicating a stronger motor resonance was elicited by translating compared to centered stimuli. Finally, beta bands modulation in Superior Parietal areas showed that the translational component of locomotion induced greater motor resonance than human shape. Using a Multinomial Logistic Regression classifier we found that Dorsal-Parietal and Inferior-Frontal regions of interest (ROIs), constituting the core of action-observation system, were the only areas capable to discriminate all the four conditions, as reflected by beta activities. Our findings suggest that the embodiment elicited by an observed scenario is strongly mediated by horizontal body displacement. PMID- 29163079 TI - Neural Correlates of Rewarded Response Inhibition in Youth at Risk for Problematic Alcohol Use. AB - Risk for substance use disorder (SUD) is associated with poor response inhibition and heightened reward sensitivity. During adolescence, incentives improve performance on response inhibition tasks and increase recruitment of cortical control areas (Geier et al., 2010) associated with SUD (Chung et al., 2011). However, it is unknown whether incentives moderate the relationship between response inhibition and trait-level psychopathology and personality features of substance use risk. We examined these associations in the current project using a rewarded antisaccade (AS) task (Geier et al., 2010) in youth at risk for substance use. Participants were 116 adolescents and young adults (ages 12-21) from the University of Pittsburgh site of the National Consortium on Adolescent Neurodevelopment and Alcohol [NCANDA] study, with neuroimaging data collected at baseline and 1 year follow up visits. Building upon previous work using this task in normative developmental samples (Geier et al., 2010) and adolescents with SUD (Chung et al., 2011), we examined both trial-wise BOLD responses and those associated with individual task-epochs (cue presentation, response preparation, and response) and associated them with multiple substance use risk factors (externalizing and internalizing psychopathology, family history of substance use, and trait impulsivity). Results showed that externalizing psychopathology and high levels of trait impulsivity (positive urgency, SUPPS-P) were associated with general decreases in antisaccade performance. Accompanying this main effect of poor performance, positive urgency was associated with reduced recruitment of the frontal eye fields (FEF) and inferior frontal gyrus (IFG) in both a priori regions of interest and at the voxelwise level. Consistent with previous work, monetary incentive improved antisaccade behavioral performance and was associated with increased activation in the striatum and cortical control areas. However, incentives did not moderate the association between response inhibition behavioral performance and any trait-level psychopathology and personality factor of substance use risk. Reward interactions were observed for BOLD responses at the task-epoch level, however, they were inconsistent across substance use risk types. The results from this study may suggest poor response inhibition and heightened reward sensitivity are not overlapping neurocognitive features of substance use risk. Alternatively, more subtle, common longitudinal processes might jointly explain reward sensitivity and response inhibition deficits in substance use risk. PMID- 29163080 TI - Behavioral and Neurochemical Phenotyping of Mice Incapable of Homer1a Induction. AB - Immediate early and constitutively expressed products of the Homer1 gene regulate the functional assembly of post-synaptic density proteins at glutamatergic synapses to influence excitatory neurotransmission and synaptic plasticity. Earlier studies of Homer1 gene knock-out (KO) mice indicated active, but distinct, roles for IEG and constitutively expressed Homer1 gene products in regulating cognitive, emotional, motivational and sensorimotor processing, as well as behavioral and neurochemical sensitivity to cocaine. More recent characterization of transgenic mice engineered to prevent generation of the IEG form (a.k.a Homer1a KO) pose a critical role for Homer1a in cocaine-induced behavioral and neurochemical sensitization of relevance to drug addiction and related neuropsychiatric disorders. Here, we extend our characterization of the Homer1a KO mouse and report a modest pro-depressant phenotype, but no deleterious effects of the KO upon spatial learning/memory, prepulse inhibition, or cocaine induced place-conditioning. As we reported previously, Homer1a KO mice did not develop cocaine-induced behavioral or neurochemical sensitization within the nucleus accumbens; however, virus-mediated Homer1a over-expression within the nucleus accumbens reversed the sensitization phenotype of KO mice. We also report several neurochemical abnormalities within the nucleus accumbens of Homer1a KO mice that include: elevated basal dopamine and reduced basal glutamate content, Group1 mGluR agonist-induced glutamate release and high K+-stimulated release of dopamine and glutamate within this region. Many of the neurochemical anomalies exhibited by Homer1a KO mice are recapitulated upon deletion of the entire Homer1 gene; however, Homer1 deletion did not affect NAC dopamine or alter K+-stimulated neurotransmitter release within this region. These data show that the selective deletion of Homer1a produces a behavioral and neurochemical phenotype that is distinguishable from that produced by deletion of the entire Homer1 gene. Moreover, the data indicate a specific role for Homer1a in regulating cocaine induced behavioral and neurochemical sensitization of potential relevance to the psychotogenic properties of this drug. PMID- 29163081 TI - Activation of D1/5 Dopamine Receptors in the Dorsal Medial Prefrontal Cortex Promotes Incubated-Like Aversive Responses. AB - It is well established that neurons of the mammalian medial prefrontal cortex (mPFC) modulate different behavioral outputs, including several memory types. This behavioral modulation is, at least in part, under the control of the D1-like Dopamine (DA) receptor (D1/5R) which comprises D1 and D5-specific subtypes (D1R and D5R, respectively). Here, combining a set of behavioral assays with pharmacology, we determined whether the activation of D1/5R in the mPFC during almost neutral or weak negative-valence experiences induces aversive behaviors. The intra mPFC bilateral infusion of the D1/5R agonist SKF 38393 (6.25 MUg/side) immediately after exposing rats to the white compartment of a place conditioning apparatus promotes a incubated-like aversive memory when tested 7 days thereafter, but it was not seen 24 h after conditioning. No signs of fear or changes in the anxiety state were observed after the exposure to the white compartment. This aversive response is observed only when the experience paired with the mPFC D1/5R activation has a context component involved. By using specific agonists for D1R or D5R subtypes we suggest that D5R mediate the induction of the aversive behavior. No aversive effects were observed when the D1/5R agonist was infused into the dorsal hippocampus (HP), the nucleus accumbens (NAcc) or the basolateral amygdala (BLA) of rats exposed to the white compartment. Taken together, our present findings endorse the idea that activation of mPFC D1/5R is sufficient to induce incubated-like aversive memories after exposing rats to an apparent neutral or weak negative-valence environment and that mPFC might be considered a key brain region involved in providing adaptive emotional behaviors in response to an ever-changing environment. PMID- 29163082 TI - The Way Dogs (Canis familiaris) Look at Human Emotional Faces Is Modulated by Oxytocin. An Eye-Tracking Study. AB - Dogs have been shown to excel in reading human social cues, including facial cues. In the present study we used eye-tracking technology to further study dogs' face processing abilities. It was found that dogs discriminated between human facial regions in their spontaneous viewing pattern and looked most to the eye region independently of facial expression. Furthermore dogs played most attention to the first two images presented, afterwards their attention dramatically decreases; a finding that has methodological implications. Increasing evidence indicates that the oxytocin system is involved in dogs' human-directed social competence, thus as a next step we investigated the effects of oxytocin on processing of human facial emotions. It was found that oxytocin decreases dogs' looking to the human faces expressing angry emotional expression. More interestingly, however, after oxytocin pre-treatment dogs' preferential gaze toward the eye region when processing happy human facial expressions disappears. These results provide the first evidence that oxytocin is involved in the regulation of human face processing in dogs. The present study is one of the few empirical investigations that explore eye gaze patterns in naive and untrained pet dogs using a non-invasive eye-tracking technique and thus offers unique but largely untapped method for studying social cognition in dogs. PMID- 29163083 TI - Effective Connectivity Analysis of the Brain Network in Drivers during Actual Driving Using Near-Infrared Spectroscopy. AB - Driving a vehicle is a complex activity that requires high-level brain functions. This study aimed to assess the change in effective connectivity (EC) between the prefrontal cortex (PFC), motor-related areas (MA) and vision-related areas (VA) in the brain network among the resting, simple-driving and car-following states. Twelve young male right-handed adults were recruited to participate in an actual driving experiment. The brain delta [HbO2] signals were continuously recorded using functional near infrared spectroscopy (fNIRS) instruments. The conditional Granger causality (GC) analysis, which is a data-driven method that can explore the causal interactions among different brain areas, was performed to evaluate the EC. The results demonstrated that the hemodynamic activity level of the brain increased with an increase in the cognitive workload. The connection strength among PFC, MA and VA increased from the resting state to the simple-driving state, whereas the connection strength relatively decreased during the car following task. The PFC in EC appeared as the causal target, while the MA and VA appeared as the causal sources. However, l-MA turned into causal targets with the subtask of car-following. These findings indicate that the hemodynamic activity level of the cerebral cortex increases linearly with increasing cognitive workload. The EC of the brain network can be strengthened by a cognitive workload, but also can be weakened by a superfluous cognitive workload such as driving with subtasks. PMID- 29163084 TI - Sex Matters: Robust Sex Differences in Signal Detection in the HIV-1 Transgenic Rat. AB - Sex differences in human immunodeficiency virus type-1 (HIV-1) have been repeatedly suggested. Females, who account for 51% of HIV-1 seropositive individuals, are inadequately represented in clinical and preclinical studies, as well as in the description of HIV-1 associated neurocognitive disorders (HAND). Direct comparisons of neurocognitive decline in women and men must be made to address this underrepresentation. The effect of biological sex (i.e., the biological factors, including chromosomes and hormones, determining male or female characteristics; WHO, 2017) on sustained attention, which is commonly impaired in HIV-1 seropositive individuals, was investigated in intact HIV-1 transgenic (Tg) and control animals using a signal detection operant task. Analyses revealed a robust sex difference in the rate of task acquisition, collapsed across genotype, with female animals meeting criteria in shaping (at least 60 reinforcers for three consecutive or five non-consecutive sessions) and signal detection (70% accuracy for five consecutive or seven non-consecutive sessions) significantly more slowly than male animals. Presence of the HIV-1 transgene also had a significant effect on shaping and signal detection acquisition, with HIV-1 Tg animals displaying significant deficits in the rate of acquisition relative to control animals-deficits that were more prominent in female HIV-1 Tg animals. Once the animals' reached asymptotic performance in the signal detection task, female animals achieved a lower percent accuracy across test sessions and exhibited a decreased response rate relative to male animals, although there was no compelling evidence for any effect of transgene. Results indicate that the factor of biological sex may be a moderator of the influence of the HIV-1 transgene on signal detection. Understanding the impact of biological sex on neurocognitive deficits in HIV-1 is crucial for the development of sex based therapeutics and cure strategies. PMID- 29163085 TI - Involvement of the Avian Dorsal Thalamic Nuclei in Homing Pigeon Navigation. AB - The navigational ability of birds has been a focus of popular and scientific interest for centuries, but relatively little is known about the neuronal networks that support avian navigation. In the brain, regions like the piriform cortex, olfactory bulbs, hippocampal formation, vestibular nuclei, and the wulst, are among the brain regions often discussed as involved in avian navigation. However, despite large literature showing a prominent role of some anterior and dorsal thalamic nuclei in mammalian spatial navigation, little is known about the role of the thalamus in avian navigation. Here, we analyzed a possible role of the dorsal anterior thalamic nuclei in avian navigation by combining olfactory manipulations during the transport of young homing pigeons to a release site and c-Fos immunohistochemistry for the mapping brain activity. The results reveal that odor modulated neurons in the avian dorsolateral lateral (DLL) subdivision of the anterior thalamic nuclei are actively involved in processing outward journey, navigational information. Outward journey information is used by pigeons to correctly determine the homeward direction. DLL participation in acquiring path-based information, and its modulation by olfactory exposure, broadens our understanding of the neural pathways underlying avian navigation. PMID- 29163086 TI - Adolescent Exposure to Methylphenidate Increases Impulsive Choice Later in Life. AB - Background: The psychostimulant methylphenidate (MPH) is known to temporarily reduce impulsive choice and promote self-control. What is not sufficiently understood is how repeated treatment with MPH affects impulsive choice in the long run, and whether any such effect is contingent on exposure at certain developmental stages. Methods: Using an animal model for impulsive choice, we examined first whether giving MPH through early adolescence alters delay discounting, an operational measure of impulsive choice, later in adulthood. We then tested whether equivalent long-term effects are observed if exposure to the drug occurred during adulthood. Starting on postnatal day 25 or postnatal day 60, male rats received one of a range of doses of MPH for 10 consecutive days. Twenty six days later, all rats were trained to choose between a lever that produced a small immediate reward and a lever that produced a large reward after a range of delays. Results: Rats showed a long-term decrease in the selection of the delayed larger reward when treated with moderate doses of MPH during early adolescence, but not when treated with the lower or higher doses. In contrast, no differences were observed in the selection of the delayed larger reward in animals that were treated with various doses of MPH during adulthood. Conclusions: Our findings suggest effects of MPH on impulsive choice that are contingent on dosage and on the developmental period of exposure. When administered during adolescence, moderate doses of MPH increase impulsive choice long after the end of treatment, whereas these same doses administered during adulthood were without effect. PMID- 29163087 TI - Localized Fluctuant Oscillatory Activity by Working Memory Load: A Simultaneous EEG-fMRI Study. AB - Working memory (WM) is a resource-limited memory system for temporary storage and processing of brain information during the execution of cognitive tasks. Increased WM load will increase the amount and difficulty of memory information. Several studies have used electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) to explore load-dependent cognition processing according to the time courses of electrophysiological activity or the spatial pattern of blood oxygen metabolic activity. However, the relationships between these two activities and the underlying neural mechanism are still unclear. In this study, using simultaneously collected EEG and fMRI data under an n-back verbal WM task, we modeled the spectral perturbation of EEG oscillation and fMRI activation through joint independent component analysis (JICA). Multi-channel oscillation features were also introduced into the JICA model for further analysis. The results showed that time-locked activity of theta and beta were modulated by memory load in the early stimuli evaluation stage, corresponding to the enhanced activation in the frontal and parietal lobe, which were involved in stimulus discrimination, information encoding and delay-period activity. In the late response selection stage, alpha and gamma activity changes dependent on the load correspond to enhanced activation in the areas of frontal, temporal and parietal lobes, which played important roles in attention, information extraction and memory retention. These findings suggest that the increases in memory load not only affect the intensity and time course of the EEG activities, but also lead to the enhanced activation of brain regions which plays different roles during different time periods of cognitive process of WM. PMID- 29163088 TI - Simultaneous Reality Filtering and Encoding of Thoughts: The Substrate for Distinguishing between Memories of Real Events and Imaginations? AB - Any thought, whether it refers to the present moment or reflects an imagination, is again encoded as a new memory trace. Orbitofrontal reality filtering (ORFi) denotes an on-line mechanism which verifies whether upcoming thoughts relate to ongoing reality or not. Its failure induces reality confusion with confabulations and disorientation. If the result of this process were simultaneously encoded, it would easily explain later distinction between memories relating to a past reality and memories relating to imagination, a faculty called reality monitoring. How the brain makes this distinction is unknown but much research suggests that it depends on processes active when information is encoded. Here we explored the precise timing between ORFi and encoding as well as interactions between the involved brain structures. We used high-density evoked potentials and two runs of a continuous recognition task (CRT) combining the challenges of ORFi and encoding. ORFi was measured by the ability to realize that stimuli appearing in the second run had not appeared in this run yet. Encoding was measured with immediately repeated stimuli, which has been previously shown to induce a signal emanating from the medial temporal lobe (MTL), which has a protective effect on the memory trace. We found that encoding, as measured with this task, sets in at about 210 ms after stimulus presentation, 35 ms before ORFi. Both processes end at about 330 ms. Both were characterized by increased coherence in the theta band in the MTL during encoding and in the orbitofrontal cortex (OFC) during ORFi. The study suggests a complex interaction between OFC and MTL allowing for thoughts to be re-encoded while they undergo ORFi. The combined influence of these two processes at 200-300 ms may leave a memory trace that allows for later effortless reality monitoring in most everyday situations. PMID- 29163089 TI - The BACHD Rat Model of Huntington Disease Shows Specific Deficits in a Test Battery of Motor Function. AB - Rationale: Huntington disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and neuropsychiatric symptoms. HD is usually diagnosed by the appearance of motor deficits, resulting in skilled hand use disruption, gait abnormality, muscle wasting and choreatic movements. The BACHD transgenic rat model for HD represents a well-established transgenic rodent model of HD, offering the prospect of an in-depth characterization of the motor phenotype. Objective: The present study aims to characterize different aspects of motor function in BACHD rats, combining classical paradigms with novel high throughput behavioral phenotyping. Methods: Wild-type (WT) and transgenic animals were tested longitudinally from 2 to 12 months of age. To measure fine motor control, rats were challenged with the pasta handling test and the pellet reaching test. To evaluate gross motor function, animals were assessed by using the holding bar and the grip strength tests. Spontaneous locomotor activity and circadian rhythmicity were assessed in an automated home-cage environment, namely the PhenoTyper. We then integrated existing classical methodologies to test motor function with automated home-cage assessment of motor performance. Results: BACHD rats showed strong impairment in muscle endurance at 2 months of age. Altered circadian rhythmicity and locomotor activity were observed in transgenic animals. On the other hand, reaching behavior, forepaw dexterity and muscle strength were unaffected. Conclusions: The BACHD rat model exhibits certain features of HD patients, like muscle weakness and changes in circadian behavior. We have observed modest but clear-cut deficits in distinct motor phenotypes, thus confirming the validity of this transgenic rat model for treatment and drug discovery purposes. PMID- 29163091 TI - Mind Your Grip: Even Usual Dexterous Manipulation Requires High Level Cognition. AB - Simultaneous execution of cognitive and sensorimotor tasks is critical in daily life. Here, we examined whether dexterous manipulation, a highly habitual and seemingly automatic behavior, involves high order cognitive functions. Specifically, we explored the impact of reducing available cognitive resources on the performance of a precision grip-lift task in healthy participants of three age groups (18-30, 30-60 and 60-75 years). Participants performed a motor task in isolation (M), in combination with a low-load cognitive task (M + L), and in combination with a high-load cognitive task (M + H). The motor task consisted in grasping, lifting and holding an apparatus instrumented with force sensors to monitor motor task performance. In the cognitive task, a list of letters was shown briefly before the motor task. After completing the motor task, one letter of the list was shown, and participants reported the following letter of the list. In M + L, letters in the list followed the alphabetical order. In M + H, letters were presented in random order. Performing the high-load task thus required maintaining information in working memory. Temporal and dynamic parameters of grip and lift forces were compared across conditions. During the cognitive tasks, there was a significant alteration of movement initiation and a significant increase of grip force (GF) throughout the grip-lift task. There was no interaction with "age". Our results demonstrate that planning and the on-line control of dexterous manipulation is not an automatic behavior and, instead, that it interacts with high-level cognitive processes such as those involved in working memory. PMID- 29163090 TI - Community Violence Exposure and Conduct Problems in Children and Adolescents with Conduct Disorder and Healthy Controls. AB - Exposure to community violence through witnessing or being directly victimized has been associated with conduct problems in a range of studies. However, the relationship between community violence exposure (CVE) and conduct problems has never been studied separately in healthy individuals and individuals with conduct disorder (CD). Therefore, it is not clear whether the association between CVE and conduct problems is due to confounding factors, because those with high conduct problems also tend to live in more violent neighborhoods, i.e., an ecological fallacy. Hence, the aim of the present study was: (1) to investigate whether the association between recent CVE and current conduct problems holds true for healthy controls as well as adolescents with a diagnosis of CD; (2) to examine whether the association is stable in both groups when including effects of aggression subtypes (proactive/reactive aggression), age, gender, site and socioeconomic status (SES); and (3) to test whether proactive or reactive aggression mediate the link between CVE and conduct problems. Data from 1178 children and adolescents (62% female; 44% CD) aged between 9 years and 18 years from seven European countries were analyzed. Conduct problems were assessed using the Kiddie-Schedule of Affective Disorders and Schizophrenia diagnostic interview. Information about CVE and aggression subtypes was obtained using self report questionnaires (Social and Health Assessment and Reactive-Proactive aggression Questionnaire (RPQ), respectively). The association between witnessing community violence and conduct problems was significant in both groups (adolescents with CD and healthy controls). The association was also stable after examining the mediating effects of aggression subtypes while including moderating effects of age, gender and SES and controlling for effects of site in both groups. There were no clear differences between the groups in the strength of the association between witnessing violence and conduct problems. However, we found evidence for a ceiling effect, i.e., individuals with very high levels of conduct problems could not show a further increase if exposed to CVE and vice versa. Results indicate that there was no evidence for an ecological fallacy being the primary cause of the association, i.e., CVE must be considered a valid risk factor in the etiology of CD. PMID- 29163092 TI - How Well Can Saliency Models Predict Fixation Selection in Scenes Beyond Central Bias? A New Approach to Model Evaluation Using Generalized Linear Mixed Models. AB - Since the turn of the millennium, a large number of computational models of visual salience have been put forward. How best to evaluate a given model's ability to predict where human observers fixate in images of real-world scenes remains an open research question. Assessing the role of spatial biases is a challenging issue; this is particularly true when we consider the tendency for high-salience items to appear in the image center, combined with a tendency to look straight ahead ("central bias"). This problem is further exacerbated in the context of model comparisons, because some-but not all-models implicitly or explicitly incorporate a center preference to improve performance. To address this and other issues, we propose to combine a-priori parcellation of scenes with generalized linear mixed models (GLMM), building upon previous work. With this method, we can explicitly model the central bias of fixation by including a central-bias predictor in the GLMM. A second predictor captures how well the saliency model predicts human fixations, above and beyond the central bias. By subject and by-item random effects account for individual differences and differences across scene items, respectively. Moreover, we can directly assess whether a given saliency model performs significantly better than others. In this article, we describe the data processing steps required by our analysis approach. In addition, we demonstrate the GLMM analyses by evaluating the performance of different saliency models on a new eye-tracking corpus. To facilitate the application of our method, we make the open-source Python toolbox "GridFix" available. PMID- 29163093 TI - Neuromoral Diversity: Individual, Gender, and Cultural Differences in the Ethical Brain. PMID- 29163094 TI - Where Are You Throwing the Ball? I Better Watch Your Body, Not Just Your Arm! AB - The ability to intercept or avoid a moving object, whether to catch a ball, snatch one's prey, or avoid the path of a predator, is a skill that has been acquired throughout evolution by many species in the animal kingdom. This requires processing early visual cues in order to program anticipatory motor responses tuned to the forthcoming event. Here, we explore the nature of the early kinematics cues that could inform an observer about the future direction of a ball projected with an unconstrained overarm throw. Our goal was to pinpoint the body segments that, throughout the temporal course of the throwing action, could provide key cues for accurately predicting the side of the outgoing ball. We recorded whole-body kinematics from twenty non-expert participants performing unconstrained overarm throws at four different targets placed on a vertical plane at 6 m distance. In order to characterize the spatiotemporal structure of the information embedded in the kinematics of the throwing action about the outgoing ball direction, we introduced a novel combination of dimensionality reduction and machine learning techniques. The recorded kinematics clearly shows that throwing styles differed considerably across individuals, with corresponding inter individual differences in the spatio-temporal structure of the thrower predictability. We found that for most participants it is possible to predict the region where the ball hit the target plane, with an accuracy above 80%, as early as 400-500 ms before ball release. Interestingly, the body parts that provided the most informative cues about the action outcome varied with the throwing style and during the time course of the throwing action. Not surprisingly, at the very end of the action, the throwing arm is the most informative body segment. However, cues allowing for predictions to be made earlier than 200 ms before release are typically associated to other body parts, such as the lower limbs and the contralateral arm. These findings are discussed in the context of the sport science literature on throwing and catching interactive tasks, as well as from the wider perspective of the role of sensorimotor coupling in interpersonal social interactions. PMID- 29163095 TI - The Functional Architecture of the Brain Underlies Strategic Deception in Impression Management. AB - Impression management, as one of the most essential skills of social function, impacts one's survival and success in human societies. However, the neural architecture underpinning this social skill remains poorly understood. By employing a two-person bargaining game, we exposed three strategies involving distinct cognitive processes for social impression management with different levels of strategic deception. We utilized a novel adaptation of Granger causality accounting for signal-dependent noise (SDN), which captured the directional connectivity underlying the impression management during the bargaining game. We found that the sophisticated strategists engaged stronger directional connectivity from both dorsal anterior cingulate cortex and retrosplenial cortex to rostral prefrontal cortex, and the strengths of these directional influences were associated with higher level of deception during the game. Using the directional connectivity as a neural signature, we identified the strategic deception with 80% accuracy by a machine-learning classifier. These results suggest that different social strategies are supported by distinct patterns of directional connectivity among key brain regions for social cognition. PMID- 29163096 TI - Tai Chi Chuan and Baduanjin Mind-Body Training Changes Resting-State Low Frequency Fluctuations in the Frontal Lobe of Older Adults: A Resting-State fMRI Study. AB - Age-related cognitive decline is a significant public health concern. Recently, non-pharmacological methods, such as physical activity and mental training practices, have emerged as promising low-cost methods to slow the progression of age-related memory decline. In this study, we investigated if Tai Chi Chuan (TCC) and Baduanjin modulated the fractional amplitude of low-frequency fluctuations (fALFF) in different frequency bands (low-frequency: 0.01-0.08 Hz; slow-5: 0.01 0.027 Hz; slow-4: 0.027-0.073 Hz) and improved memory function. Older adults were recruited for the randomized study. Participants in the TCC and Baduanjin groups received 12 weeks of training (1 h/day for 5 days/week). Participants in the control group received basic health education. Each subject participated in memory tests and fMRI scans at the beginning and end of the experiment. We found that compared to the control group: (1) TCC and Baduanjin groups demonstrated significant improvements in memory function; (2) TCC increased fALFF in the dorsolateral prefrontal cortex (DLPFC) in the slow-5 and low-frequency bands; and (3) Baduanjin increased fALFF in the medial PFC in the slow-5 and low-frequency bands. This increase was positively associated with memory function improvement in the slow-5 and low-frequency bands across the TCC and Baduanjin groups. Our results suggest that TCC and Baduanjin may work through different brain mechanisms to prevent memory decline due to aging. PMID- 29163097 TI - The Role of Motivation in Cognitive Reappraisal for Depressed Patients. AB - Background: People engage in emotion regulation in service of motive goals (typically, to approach a desired emotional goal or avoid an undesired emotional goal). However, how motives (goals) in emotion regulation operate to shape the regulation of emotion is rarely known. Furthermore, the modulatory role of motivation in the impaired reappraisal capacity and neural abnormalities typical of depressed patients is not clear. Our hypothesis was that (1) approach and avoidance motivation may modulate emotion regulation and the underlying neural substrates; (2) approach/avoidance motivation may modulate emotion regulation neural abnormalities in depressed patients. Methods: Twelve drug-free depressed patients and fifteen matched healthy controls reappraised emotional pictures with approach/avoidant strategies and self-rated their emotional intensities during fMRI scans. Approach/avoidance motivation was measured using Behavioral Inhibition System and Behavioral Activation System (BIS/BAS) Scale. We conducted whole-brain analyses and correlation analyses of regions of interest to identify alterations in regulatory prefrontal-amygdala circuits which were modulated by motivation. Results: Depressed patients had a higher level of BIS and lower levels of BAS-reward responsiveness and BAS-drive. BIS scores were positively correlated with depressive severity. We found the main effect of motivation as well as the interactive effect of motivation and group on the neural correlates of emotion regulation. Specifically, hypoactivation of IFG underlying the group differences in the motivation-related neural correlates during reappraisal may be partially explained by the interaction between group and reappraisal. Consistent with our prediction, dlPFC and vmPFC was differentially between groups which were modulated by motivation. Specifically, the avoidance motivation of depressed patients could predict the right dlPFC activation during decreasing positive emotion, while the approach motivation of normal individuals could predict the right vmPFC activation during decreasing negative emotion. Notably, striatal regions were observed when examining the neural substrates underlying the main effect of motivation (lentiform nucleus) and the interactive effect between motivation and group (midbrain). Conclusions: Our findings highlight the modulatory role of approach and avoidance motivation in cognitive reappraisal, which is dysfunctional in depressed patients. The results could enlighten the CBT directed at modifying the motivation deficits in cognitive regulation of emotion. PMID- 29163098 TI - A Systematic Review of Investigations into Functional Brain Connectivity Following Spinal Cord Injury. AB - Background: Complete or incomplete spinal cord injury (SCI) results in varying degree of motor, sensory and autonomic impairment. Long-lasting, often irreversible disability results from disconnection of efferent and afferent pathways. How does this disconnection affect brain function is not so clear. Changes in brain organization and structure have been associated with SCI and have been extensively studied and reviewed. Yet, our knowledge regarding brain connectivity changes following SCI is overall lacking. Methods: In this study we conduct a systematic review of articles regarding investigations of functional brain networks following SCI, searching on PubMed, Scopus and ScienceDirect according to PRISMA-P 2015 statement standards. Results: Changes in brain connectivity have been shown even during the early stages of the chronic condition and correlate with the degree of neurological impairment. Connectivity changes appear as dynamic post-injury procedures. Sensorimotor networks of patients and healthy individuals share similar patterns but new functional interactions have been identified as unique to SCI networks. Conclusions: Large scale, multi-modal, longitudinal studies on SCI patients are needed to understand how brain network reorganization is established and progresses through the course of the condition. The expected insight holds clinical relevance in preventing maladaptive plasticity after SCI through individualized neurorehabilitation, as well as the design of connectivity-based brain-computer interfaces and assistive technologies for SCI patients. PMID- 29163099 TI - A Computational Analysis of Neural Mechanisms Underlying the Maturation of Multisensory Speech Integration in Neurotypical Children and Those on the Autism Spectrum. AB - Failure to appropriately develop multisensory integration (MSI) of audiovisual speech may affect a child's ability to attain optimal communication. Studies have shown protracted development of MSI into late-childhood and identified deficits in MSI in children with an autism spectrum disorder (ASD). Currently, the neural basis of acquisition of this ability is not well understood. Here, we developed a computational model informed by neurophysiology to analyze possible mechanisms underlying MSI maturation, and its delayed development in ASD. The model posits that strengthening of feedforward and cross-sensory connections, responsible for the alignment of auditory and visual speech sound representations in posterior superior temporal gyrus/sulcus, can explain behavioral data on the acquisition of MSI. This was simulated by a training phase during which the network was exposed to unisensory and multisensory stimuli, and projections were crafted by Hebbian rules of potentiation and depression. In its mature architecture, the network also reproduced the well-known multisensory McGurk speech effect. Deficits in audiovisual speech perception in ASD were well accounted for by fewer multisensory exposures, compatible with a lack of attention, but not by reduced synaptic connectivity or synaptic plasticity. PMID- 29163100 TI - Resting Heart Rate Variability, Facets of Rumination and Trait Anxiety: Implications for the Perseverative Cognition Hypothesis. AB - The perseverative cognition hypothesis (PCH) posits that perseveration, defined as the repetitive or sustained activation of cognitive representations of a real or imagined stressor, is a primary mechanism linking psychological (or stress) vulnerability with poor health and disease. Resting vagally mediated heart rate variability (vmHRV) is an important indicator of self-regulatory abilities, stress vulnerability and overall health. Those with lower resting vmHRV are more vulnerable to stress, and thus more likely to engage in perseverative cognition and experience subsequent negative mental health outcomes such as anxiety. Recent research suggests that rumination-one of the core mechanisms underlying perseveration-is a construct containing (at least) two maladaptive (depressive and brooding) and one adaptive (reflective) types of rumination. However, to date, research has not examined how the association between resting vmHRV may differ between these three facets of rumination, in addition to these facets' mechanistic role in linking lower resting vmHRV with greater trait anxiety. The current cross-sectional study explores these relationships in a sample of 203 participants (112 females, 76 ethnic minorities, mean age = 19.43, standard deviation = 1.87). Resting vmHRV was assessed during a 5-min-resting period using an Electrocardiogram (ECG). Both trait rumination (including the three facets) and anxiety were assessed via self-report scales. Significant negative associations were found between resting vmHRV and maladaptive, but not adaptive, forms of perseveration. Similarly, mediation analyses showed a significant indirect relationship between resting vmHRV and anxiety through maladaptive, but not adaptive, facets of rumination. Our findings support the PCH such that those with stress vulnerability, as indexed by lower resting vmHRV, are more likely to engage in maladaptive perseverative cognition and thus experience negative outcomes such as anxiety. Our data also lend a novel outlook on the PCH; resting vmHRV is not related to reflective rumination and thus, this facet of perseveration may be a neutral, but not beneficial, factor in the link between stress vulnerability and psychological well-being. PMID- 29163102 TI - Illuminating Artistic Processes toward Transdisciplinary Discourse. PMID- 29163101 TI - EEG Frequency Changes Prior to Making Errors in an Easy Stroop Task. AB - Background: Mind-wandering is a form of off-task attention that has been associated with negative affect and rumination. The goal of this study was to assess potential electroencephalographic markers of task-unrelated thought, or mind-wandering state, as related to error rates during a specialized cognitive task. We used EEG to record frontal frequency band activity while participants completed a Stroop task that was modified to induce boredom, task-unrelated thought, and therefore mind-wandering. Methods: A convenience sample of 27 older adults (50-80 years) completed a computerized Stroop matching task. Half of the Stroop trials were congruent (word/color match), and the other half were incongruent (mismatched). Behavioral data and EEG recordings were assessed. EEG analysis focused on the 1-s epochs prior to stimulus presentation in order to compare trials followed by correct versus incorrect responses. Results: Participants made errors on 9% of incongruent trials. There were no errors on congruent trials. There was a decrease in alpha and theta band activity during the epochs followed by error responses. Conclusion: Although replication of these results is necessary, these findings suggest that potential mind-wandering, as evidenced by errors, can be characterized by a decrease in alpha and theta activity compared to on-task, accurate performance periods. PMID- 29163103 TI - Sensory Feedback Interferes with Mu Rhythm Based Detection of Motor Commands from Electroencephalographic Signals. AB - Background: Electroencephalogram (EEG)-based brain-computer interfaces (BCI) represent a promising component of restorative motor therapies in individuals with partial paralysis. However, in those patients, sensory functions such as proprioception are at least partly preserved. The aim of this study was to investigate whether afferent feedback interferes with the BCI-based detection of efferent motor commands during execution of movements. Methods: Brain activity of 13 able-bodied subjects (age: 29.1 +/- 4.8 years; 11 males) was compared between a motor task (MT) consisting of an isometric, isotonic grip and a somatosensory electrical stimulation (SS) of the fingertips. Modulation of the mu rhythm (8-13 Hz) was investigated to identify changes specifically related to the generation of efferent commands. A linear discriminant analysis (LDA) was used to investigate the activation pattern on a single-trial basis. Classifiers were trained with MT vs. REST (periods without MT/SS) and tested with SS and vice versa to quantify the impact of afferent feedback on the classification results. Results: Few differences in the spatial pattern between MT and SS were found in the modulation of the mu rhythm. All were characterized by event-related desynchronization (ERD) peaks at electrodes C3, C4, and CP3. Execution of the MT was associated with a significantly stronger ERD in the majority of sensorimotor electrodes [C3 (p < 0.01); CP3 (p < 0.05); C4 (p < 0.01)]. Classification accuracy of MT vs. REST was significantly higher than SS vs. REST (77% and 63%; p < 10-8). Classifiers trained on MT vs. REST were able to classify SS trials significantly above chance even though no motor commands were present during SS. Classifiers trained on SS performed better in classifying MT instead of SS. Conclusion: Our results challenge the notion that the modulation of the mu rhythm is a robust phenomenon for detecting efferent commands when afferent feedback is present. Instead, they indicate that the mu ERD caused by the processing of afferent feedback generates ERD patterns in the sensorimotor cortex that are masking the ERD patterns caused by the generation of efferent commands. Thus, processing of afferent feedback represents a considerable source of false positives when the mu rhythm is used for the detection of efferent commands. PMID- 29163104 TI - Transcranial Random Noise Stimulation Does Not Improve Behavioral and Neurophysiological Measures in Patients with Subacute Vegetative-Unresponsive Wakefulness State (VS-UWS). AB - Background: The absence of efficient treatments capable to promote central nervous system recovery in patients in vegetative state (VS) due to a severe acquired brain injury highlights the need of exploring alternative neuromodulatory treatments that can lead to neurobehavioral gains. Some encouraging preliminary observations suggest that transcranial direct current stimulation could be effective in disorders of consciousness (DoC) patients, especially when applied on the dorsolateral prefrontal cortex (DLPFC) in patients with minimally conscious state (MCS) but not in those with VS. Objective: The primary aim of the present study was to verify if the application of transcranial random noise stimulation (tRNS) on the DLPFC might favor improvements of consciousness recovery in subacute VS-UWS. Methods: Nine patients with DoC due to traumatic brain injury (n = 1), anoxia (n = 3), and vascular damage (n = 5), have undergone a randomized, double-blind, sham-controlled, neuromodulatory trial with tRNS of bilateral DLPFC. All patients were in a post-acute phase and the DoC onset ranged from 30 days to 4 months. The diagnosis of DoC was based on internationally established criteria from the Multi-Society Task Force on PVS, and classified as VS or MCS using the JFK Coma Recovery Scale-Revised scores (CRS R). We used CRS-R, Synek Scale, Ad-Hoc semi-quantitative scale and the Clinical Global Impression-Improvement scale to measure behavioral and electrophysiological changes during tRNS intervention. All patients were also treated with daily conventional rehabilitation treatment. Results: No significant differences emerged between active and sham groups regarding improvements of level of consciousness, as well as on electroencephalographic data. Only one patient showed emergence from VS-UWS, evolving from VS to MCS after the tRNS stimulation, at a distance of 3 weeks from the enrolment into the study. Conclusion: Repeated applications of tRNS of the DLPFC, even if applied in a subacute phase of VS-UWS state, did not modify behavioral and neurophysiological outcomes differently than sham stimulation. PMID- 29163105 TI - Seeing a Blush on the Visible and Invisible Spectrum: A Functional Thermal Infrared Imaging Study. AB - So far blushing has been examined in the context of a negative rather than a positive reinforcement where visual displays of a blush were based on subjective measures. The current study used infrared imaging to measure thermal patterns of the face while with the use of a video camera quantified on the visible spectrum alterations in skin color related to a compliment. To elicit a blush a three phase dialog was adopted ending or starting with a compliment on a female sample (N = 22). When the dialog ended with a compliment results showed a linear increase in temperature for the cheek, and forehead whereas for the peri-orbital region a linear decrease was observed. The compliment phase marked the highest temperature on the chin independent of whether or not the experiment started with a compliment contrary to other facial regions, which did not show a significant change when the experiment started with a compliment. Analyses on the visible spectrum showed that skin pigmentation was getting deep red in the compliment condition compared to the serious and social dialog conditions for both the forehead and the cheeks. No significant association was observed between temperature values and erythrocyte displays on the forehead and cheek. Heat is the physiological product of an arousing social scenario, however, preconceived notions about blushing propensity seem to drive erythrocyte displays and not necessarily conscious awareness of somatic sensations. PMID- 29163106 TI - Recent Advances in Non-invasive Brain Stimulation for Major Depressive Disorder. AB - Non-invasive brain stimulation (NBS) is a promising treatment for major depressive disorder (MDD), which is an affective processing disorder involving abnormal emotional processing. Many studies have shown that repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) over the prefrontal cortex can play a regulatory role in affective processing. Although the clinical efficacy of NBS in MDD has been demonstrated clinically, the precise mechanism of action remains unclear. Therefore, this review article summarizes the current status of NBS methods, including rTMS and tDCS, in the treatment of MDD. The article explores possible correlations between depressive symptoms and affective processing, highlighting the relevant affective processing mechanisms. Our review provides a reference for the safety and efficacy of NBS methods in the clinical treatment of MDD. PMID- 29163110 TI - Modeling Uncertainties in EEG Microstates: Analysis of Real and Imagined Motor Movements Using Probabilistic Clustering-Driven Training of Probabilistic Neural Networks. AB - Part of the process of EEG microstate estimation involves clustering EEG channel data at the global field power (GFP) maxima, very commonly using a modified K means approach. Clustering has also been done deterministically, despite there being uncertainties in multiple stages of the microstate analysis, including the GFP peak definition, the clustering itself and in the post-clustering assignment of microstates back onto the EEG timecourse of interest. We perform a fully probabilistic microstate clustering and labeling, to account for these sources of uncertainty using the closest probabilistic analog to KM called Fuzzy C-means (FCM). We train softmax multi-layer perceptrons (MLPs) using the KM and FCM inferred cluster assignments as target labels, to then allow for probabilistic labeling of the full EEG data instead of the usual correlation-based deterministic microstate label assignment typically used. We assess the merits of the probabilistic analysis vs. the deterministic approaches in EEG data recorded while participants perform real or imagined motor movements from a publicly available data set of 109 subjects. Though FCM group template maps that are almost topographically identical to KM were found, there is considerable uncertainty in the subsequent assignment of microstate labels. In general, imagined motor movements are less predictable on a time point-by-time point basis, possibly reflecting the more exploratory nature of the brain state during imagined, compared to during real motor movements. We find that some relationships may be more evident using FCM than using KM and propose that future microstate analysis should preferably be performed probabilistically rather than deterministically, especially in situations such as with brain computer interfaces, where both training and applying models of microstates need to account for uncertainty. Probabilistic neural network-driven microstate assignment has a number of advantages that we have discussed, which are likely to be further developed and exploited in future studies. In conclusion, probabilistic clustering and a probabilistic neural network-driven approach to microstate analysis is likely to better model and reveal details and the variability hidden in current deterministic and binarized microstate assignment and analyses. PMID- 29163112 TI - Reduced Attention Allocation during Short Periods of Partially Automated Driving: An Event-Related Potentials Study. AB - Research on partially automated driving has revealed relevant problems with driving performance, particularly when drivers' intervention is required (e.g., take-over when automation fails). Mental fatigue has commonly been proposed to explain these effects after prolonged automated drives. However, performance problems have also been reported after just a few minutes of automated driving, indicating that other factors may also be involved. We hypothesize that, besides mental fatigue, an underload effect of partial automation may also affect driver attention. In this study, such potential effect was investigated during short periods of partially automated and manual driving and at different speeds. Subjective measures of mental demand and vigilance and performance to a secondary task (an auditory oddball task) were used to assess driver attention. Additionally, modulations of some specific attention-related event-related potentials (ERPs, N1 and P3 components) were investigated. The mental fatigue effects associated with the time on task were also evaluated by using the same measurements. Twenty participants drove in a fixed-base simulator while performing an auditory oddball task that elicited the ERPs. Six conditions were presented (5-6 min each) combining three speed levels (low, comfortable and high) and two automation levels (manual and partially automated). The results showed that, when driving partially automated, scores in subjective mental demand and P3 amplitudes were lower than in the manual conditions. Similarly, P3 amplitude and self-reported vigilance levels decreased with the time on task. Based on previous studies, these findings might reflect a reduction in drivers' attention resource allocation, presumably due to the underload effects of partial automation and to the mental fatigue associated with the time on task. Particularly, such underload effects on attention could explain the performance decrements after short periods of automated driving reported in other studies. However, further studies are needed to investigate this relationship in partial automation and in other automation levels. PMID- 29163111 TI - Association between Slip Severity and Muscle Synergies of Slipping. AB - Falls impose significant negative impacts to the US population and economy. A significant number of falls may be prevented via appropriate slip-responses since a strong relation exists between slips and falls. More importantly, as severe slips are more prone to result in a fall, identifying severe slippers along with the responsible factors for their adverse motor control and severe slipping should be the highest priority in fall prevention process. Previous studies have suggested that muscle synergies may be building blocks of the central nervous system in controlling motor tasks. Muscle synergies observed during slipping ('post-slip-initiation synergies' or 'just briefly,' 'slipping muscle synergies'), may represent the fundamental blocks of the neural control during slipping. Hence, studying the differences in slipping muscle synergies of mild and severe slippers can potentially reveal the differences in their neural control and subsequently, indicate the responsible factors for the adverse post slip response in severe slippers. Even though the slipping muscle synergies have been investigated before, it still remains unclear on how the slip severity is associated with the slipping muscle synergies. More importantly, muscle synergies can be interpreted not only as neural blocks but also as physical sub-tasks of the main motor task. Hence, studying the differences of slipping synergies of mild and severe slippers would reveal the discrepancies in sub-tasks of their post-slip response. These discrepancies help pinpoint the malfunctioning sub function associated with inadequate motor response seen in severe slippers. Twenty healthy subjects were recruited and underwent an unexpected slip (to extract their slipping synergies). Subjects were classified into mild and severe slippers based on their Peak Heel Speed. An independent t-test revealed several significant inter-group differences for muscle synergies of mild and severe slippers indicating differences in their neural control of slipping. A forward dynamic simulation was utilized to reveal the functionality of each synergy. Decomposition of slipping into sub-tasks (synergies), and finding the malfunctioning sub-task in severe slippers is important as it results in a novel targeted motor-rehabilitation technique that only aims to re-establish the impaired sub-task responsible for the adverse motor-response in severe slippers. PMID- 29163108 TI - Alterations in White Matter Integrity in Young Adults with Smartphone Dependence. AB - Smartphone dependence (SPD) is increasingly regarded as a psychological problem, however, the underlying neural substrates of SPD is still not clear. High resolution magnetic resonance imaging provides a useful tool to help understand and manage the disorder. In this study, a tract-based spatial statistics (TBSS) analysis on diffusion tensor imaging (DTI) was used to measure white matter integrity in young adults with SPD. A total of 49 subjects were recruited and categorized into SPD and control group based on their clinical behavioral tests. To localize regions with abnormal white matter integrity in SPD, the voxel-wise analysis of fractional anisotropy (FA) and mean diffusivity (MD) on the whole brain was performed by TBSS. The correlation between the quantitative variables of brain structures and the behavior measures were performed. Our result demonstrated that SPD had significantly lower white matter integrity than controls in superior longitudinal fasciculus (SLF), superior corona radiata (SCR), internal capsule, external capsule, sagittal stratum, fornix/stria terminalis and midbrain structures. Correlation analysis showed that the observed abnormalities in internal capsule and stria terminalis were correlated with the severity of dependence and behavioral assessments. Our finding facilitated a primary understanding of white matter characteristics in SPD and indicated that the structural deficits might link to behavioral impairments. PMID- 29163113 TI - Changes of Attention during Value-Based Reversal Learning Are Tracked by N2pc and Feedback-Related Negativity. AB - Previously learned reward values can have a pronounced impact, behaviorally and neurophysiologically, on the allocation of selective attention. All else constant, stimuli previously associated with a high value gain stronger attentional prioritization than stimuli previously associated with a low value. The N2pc, an ERP component indicative of attentional target selection, has been shown to reflect aspects of this prioritization, by changes of mean amplitudes closely corresponding to selective enhancement of high value target processing and suppression of high value distractor processing. What has remained unclear so far is whether the N2pc also reflects the flexible and repeated behavioral adjustments needed in a volatile task environment, in which the values of stimuli are reversed often and unannounced. Using a value-based reversal learning task, we found evidence that the N2pc amplitude flexibly and reversibly tracks value based choices during the learning of reward associated stimulus colors. Specifically, successful learning of current value-contingencies was associated with reduced N2pc amplitudes, and this effect was more apparent for distractor processing, compared with target processing. In addition, following a value reversal the feedback related negativity(FRN), an ERP component that reflects feedback processing, was amplified and co-occurred with increased N2pc amplitudes in trials following low-value feedback. Importantly, participants that showed the greatest adjustment in N2pc amplitudes based on feedback were also the most efficient learners. These results allow further insight into how changes in attentional prioritization in an uncertain and volatile environment support flexible adjustments of behavior. PMID- 29163116 TI - A Sensitivity Analysis of an Inverted Pendulum Balance Control Model. AB - Balance control models are used to describe balance behavior in health and disease. We identified the unique contribution and relative importance of each parameter of a commonly used balance control model, the Independent Channel (IC) model, to identify which parameters are crucial to describe balance behavior. The balance behavior was expressed by transfer functions (TFs), representing the relationship between sensory perturbations and body sway as a function of frequency, in terms of amplitude (i.e., magnitude) and timing (i.e., phase). The model included an inverted pendulum controlled by a neuromuscular system, described by several parameters. Local sensitivity of each parameter was determined for both the magnitude and phase using partial derivatives. Both the intrinsic stiffness and proportional gain shape the magnitude at low frequencies (0.1-1 Hz). The derivative gain shapes the peak and slope of the magnitude between 0.5 and 0.9 Hz. The sensory weight influences the overall magnitude, and does not have any effect on the phase. The effect of the time delay becomes apparent in the phase above 0.6 Hz. The force feedback parameters and intrinsic stiffness have a small effect compared with the other parameters. All parameters shape the TF magnitude and phase and therefore play a role in the balance behavior. The sensory weight, time delay, derivative gain, and the proportional gain have a unique effect on the TFs, while the force feedback parameters and intrinsic stiffness contribute less. More insight in the unique contribution and relative importance of all parameters shows which parameters are crucial and critical to identify underlying differences in balance behavior between different patient groups. PMID- 29163107 TI - The Complexity of H-wave Amplitude Fluctuations and Their Bilateral Cross Covariance Are Modified According to the Previous Fitness History of Young Subjects under Track Training. AB - The Hoffmann reflex (H-wave) is produced by alpha-motoneuron activation in the spinal cord. A feature of this electromyography response is that it exhibits fluctuations in amplitude even during repetitive stimulation with the same intensity of current. We herein explore the hypothesis that physical training induces plastic changes in the motor system. Such changes are evaluated with the fractal dimension (FD) analysis of the H-wave amplitude-fluctuations (H-wave FD) and the cross-covariance (CCV) between the bilateral H-wave amplitudes. The aim of this study was to compare the H-wave FD as well as the CCV before and after track training in sedentary individuals and athletes. The training modality in all subjects consisted of running three times per week (for 13 weeks) in a concrete road of 5 km. Given the different physical condition of sedentary vs. athletes, the running time between sedentary and athletes was different. After training, the FD was significantly increased in sedentary individuals but significantly reduced in athletes, although there were no changes in spinal excitability in either group of subjects. Moreover, the CCV between bilateral H waves exhibited a significant increase in athletes but not in sedentary individuals. These differential changes in the FD and CCV indicate that the plastic changes in the complexity of the H-wave amplitude fluctuations as well as the synaptic inputs to the Ia-motoneuron systems of both legs were correlated to the previous fitness history of the subjects. Furthermore, these findings demonstrate that the FD and CCV can be employed as indexes to study plastic changes in the human motor system. PMID- 29163120 TI - The Myosuit: Bi-articular Anti-gravity Exosuit That Reduces Hip Extensor Activity in Sitting Transfers. AB - Muscle weakness-which can result from neurological injuries, genetic disorders, or typical aging-can affect a person's mobility and quality of life. For many people with muscle weakness, assistive devices provide the means to regain mobility and independence. These devices range from well-established technology, such as wheelchairs, to newer technologies, such as exoskeletons and exosuits. For assistive devices to be used in everyday life, they must provide assistance across activities of daily living (ADLs) in an unobtrusive manner. This article introduces the Myosuit, a soft, wearable device designed to provide continuous assistance at the hip and knee joint when working with and against gravity in ADLs. This robotic device combines active and passive elements with a closed-loop force controller designed to behave like an external muscle (exomuscle) and deliver gravity compensation to the user. At 4.1 kg (4.6 kg with batteries), the Myosuit is one of the lightest untethered devices capable of delivering gravity support to the user's knee and hip joints. This article presents the design and control principles of the Myosuit. It describes the textile interface, tendon actuators, and a bi-articular, synergy-based approach for continuous assistance. The assistive controller, based on bi-articular force assistance, was tested with a single subject who performed sitting transfers, one of the most gravity intensive ADLs. The results show that the control concept can successfully identify changes in the posture and assist hip and knee extension with up to 26% of the natural knee moment and up to 35% of the knee power. We conclude that the Myosuit's novel approach to assistance using a bi-articular architecture, in combination with the posture-based force controller, can effectively assist its users in gravity-intensive ADLs, such as sitting transfers. PMID- 29163118 TI - Semi-automated Anatomical Labeling and Inter-subject Warping of High-Density Intracranial Recording Electrodes in Electrocorticography. AB - In this article, we introduce img_pipe, our open source python package for preprocessing of imaging data for use in intracranial electrocorticography (ECoG) and intracranial stereo-EEG analyses. The process of electrode localization, labeling, and warping for use in ECoG currently varies widely across laboratories, and it is usually performed with custom, lab-specific code. This python package aims to provide a standardized interface for these procedures, as well as code to plot and display results on 3D cortical surface meshes. It gives the user an easy interface to create anatomically labeled electrodes that can also be warped to an atlas brain, starting with only a preoperative T1 MRI scan and a postoperative CT scan. We describe the full capabilities of our imaging pipeline and present a step-by-step protocol for users. PMID- 29163126 TI - Editorial: Clearance Pathways for Amyloid-beta. Significance for Alzheimer's Disease and Its Therapy. PMID- 29163117 TI - Deep Learning Predicts Correlation between a Functional Signature of Higher Visual Areas and Sparse Firing of Neurons. AB - Visual information in the visual cortex is processed in a hierarchical manner. Recent studies show that higher visual areas, such as V2, V3, and V4, respond more vigorously to images with naturalistic higher-order statistics than to images lacking them. This property is a functional signature of higher areas, as it is much weaker or even absent in the primary visual cortex (V1). However, the mechanism underlying this signature remains elusive. We studied this problem using computational models. In several typical hierarchical visual models including the AlexNet, VggNet, and SHMAX, this signature was found to be prominent in higher layers but much weaker in lower layers. By changing both the model structure and experimental settings, we found that the signature strongly correlated with sparse firing of units in higher layers but not with any other factors, including model structure, training algorithm (supervised or unsupervised), receptive field size, and property of training stimuli. The results suggest an important role of sparse neuronal activity underlying this special feature of higher visual areas. PMID- 29163114 TI - Interaction between BDNF Polymorphism and Physical Activity on Inhibitory Performance in the Elderly without Cognitive Impairment. AB - Background: In the elderly, physical activity (PA) enhances cognitive performances, increases brain plasticity and improves brain health. The neurotrophic hypothesis is that the release of brain-derived neurotrophic factor (BDNF), which is implicated in brain plasticity and cognition, is triggered by PA because motoneurons secrete BDNF into the bloodstream during exercise. Individual differences in cognitive performance may be explained by individual differences in genetic predisposition. A single nucleotide polymorphism on the BDNF gene, BDNFVal66Met, affects activity-dependent BDNF secretion. This study investigated the influence of the BDNFVal66Met polymorphism on the relationship between PA and controlled inhibition performance in older adults. Methods: A total of 114 healthy elderly volunteers (mean age = 71.53 years old) were evaluated. Participants were genotyped for the BDNFVal66Met polymorphism. We evaluated inhibitory performance using choice reaction times (RT) and error rates from a Simon-like task and estimated their PA using two self-reported questionnaires. We established four groups according to PA level (active vs. inactive) and BDNFVal66Met genotype (Met carriers vs. Val-homozygous). The results were analyzed using ANOVA and ANCOVA, including age, gender and body mass index as covariates. Results: The BDNFVal66Met polymorphism interacted with PA on controlled inhibition performance. More specifically, inactive Val-homozygous participants exhibited a lower inhibition performance than active Val homozygotes and inactive Met carriers; the former had a higher error rate without differences in RT. Conclusion: Differences between individuals on inhibitory performance may be partially understood by the interaction between genetic influence in BDNF secretion and PA level. The results of this study clearly support the neurotrophic hypothesis that BDNF synthesis is an important mechanism underlying the influence of physical activity on brain structure and functions. PMID- 29163121 TI - Joint Learning of Binocularly Driven Saccades and Vergence by Active Efficient Coding. AB - This paper investigates two types of eye movements: vergence and saccades. Vergence eye movements are responsible for bringing the images of the two eyes into correspondence, whereas saccades drive gaze to interesting regions in the scene. Control of both vergence and saccades develops during early infancy. To date, these two types of eye movements have been studied separately. Here, we propose a computational model of an active vision system that integrates these two types of eye movements. We hypothesize that incorporating a saccade strategy driven by bottom-up attention will benefit the development of vergence control. The integrated system is based on the active efficient coding framework, which describes the joint development of sensory-processing and eye movement control to jointly optimize the coding efficiency of the sensory system. In the integrated system, we propose a binocular saliency model to drive saccades based on learned binocular feature extractors, which simultaneously encode both depth and texture information. Saliency in our model also depends on the current fixation point. This extends prior work, which focused on monocular images and saliency measures that are independent of the current fixation. Our results show that the proposed saliency-driven saccades lead to better vergence performance and faster learning in the overall system than random saccades. Faster learning is significant because it indicates that the system actively selects inputs for the most effective learning. This work suggests that saliency-driven saccades provide a scaffold for the development of vergence control during infancy. PMID- 29163119 TI - Running Neuroimaging Applications on Amazon Web Services: How, When, and at What Cost? AB - The contribution of this paper is to identify and describe current best practices for using Amazon Web Services (AWS) to execute neuroimaging workflows "in the cloud." Neuroimaging offers a vast set of techniques by which to interrogate the structure and function of the living brain. However, many of the scientists for whom neuroimaging is an extremely important tool have limited training in parallel computation. At the same time, the field is experiencing a surge in computational demands, driven by a combination of data-sharing efforts, improvements in scanner technology that allow acquisition of images with higher image resolution, and by the desire to use statistical techniques that stress processing requirements. Most neuroimaging workflows can be executed as independent parallel jobs and are therefore excellent candidates for running on AWS, but the overhead of learning to do so and determining whether it is worth the cost can be prohibitive. In this paper we describe how to identify neuroimaging workloads that are appropriate for running on AWS, how to benchmark execution time, and how to estimate cost of running on AWS. By benchmarking common neuroimaging applications, we show that cloud computing can be a viable alternative to on-premises hardware. We present guidelines that neuroimaging labs can use to provide a cluster-on-demand type of service that should be familiar to users, and scripts to estimate cost and create such a cluster. PMID- 29163115 TI - Anodal tDCS Enhances Verbal Episodic Memory in Initially Low Performers. AB - The left dorsolateral prefrontal cortex (DLPFC) is involved in encoding and retrieval of episodic memories, and thus, is frequently targeted in non-invasive brain stimulation paradigms, aiming for its functional modulation. Anodal transcranial direct current stimulation (tDCS), that boosts neuronal excitability in stimulated cortical areas, has been found to increase cognitive skills differentially, depending on the initial performance. We hypothesize that the benefit of tDCS on verbal episodic memory can be extrapolated from the participants' baseline performance. In the present randomized, double-blind, parallel group study, healthy young adults (n = 43) received either real anodal or sham tDCS over their left DLPFC during the encoding phase of a verbal episodic memory task. Forty words were presented visually thrice with immediate vocal retrieval after each block and an additional delayed recall. We conducted a moderation analysis to test the modulating effect of initial episodic memory retrieval, adjusted for primacy and recency effects, on delayed recall under real or sham stimulation. Despite the absence of a significantly beneficial tDCS effect at the group level, we found that the number of remembered midlist words in the first retrieval significantly moderated the stimulation effect in such a way that initially low performers experienced the highest gain from real stimulation. These results suggest that anodal tDCS to the left DLPFC improves memory functions only so far. While only marginal stimulation-induced gains occur in cognitively unimpaired populations, greater stimulation benefits might be expected in individuals with clinically relevant deficiencies in the verbal episodic memory domain. PMID- 29163123 TI - Closed-Loop Hybrid Gaze Brain-Machine Interface Based Robotic Arm Control with Augmented Reality Feedback. AB - Brain-machine interface (BMI) can be used to control the robotic arm to assist paralysis people for performing activities of daily living. However, it is still a complex task for the BMI users to control the process of objects grasping and lifting with the robotic arm. It is hard to achieve high efficiency and accuracy even after extensive trainings. One important reason is lacking of sufficient feedback information for the user to perform the closed-loop control. In this study, we proposed a method of augmented reality (AR) guiding assistance to provide the enhanced visual feedback to the user for a closed-loop control with a hybrid Gaze-BMI, which combines the electroencephalography (EEG) signals based BMI and the eye tracking for an intuitive and effective control of the robotic arm. Experiments for the objects manipulation tasks while avoiding the obstacle in the workspace are designed to evaluate the performance of our method for controlling the robotic arm. According to the experimental results obtained from eight subjects, the advantages of the proposed closed-loop system (with AR feedback) over the open-loop system (with visual inspection only) have been verified. The number of trigger commands used for controlling the robotic arm to grasp and lift the objects with AR feedback has reduced significantly and the height gaps of the gripper in the lifting process have decreased more than 50% compared to those trials with normal visual inspection only. The results reveal that the hybrid Gaze-BMI user can benefit from the information provided by the AR interface, improving the efficiency and reducing the cognitive load during the grasping and lifting processes. PMID- 29163127 TI - Post-stroke Fatigue and Depressive Symptoms Are Differentially Related to Mobility and Cognitive Performance. AB - Background: Fatigue and depressive symptoms are common and often inter-related stroke sequelae. This study investigates how they are related, directly or indirectly, to mobility and cognitive outcomes within 6 months of stroke. Methods: Participants were recruited from 4 stroke centers in Ontario, Canada. Post-stroke fatigue was assessed using the Fatigue Assessment Scale (FAS). Depressive symptoms were screened using the Center for Epidemiological Studies Scale for Depression (CES-D). Factor analyses were used to construct scores from mobility (distance traveled during a 2-min walk test, Chedoke-McMaster Stroke Assessment leg score, and Berg Balance Scale total score) and cognitive (Montreal Cognitive Assessment, Trail-Making Tests A and B, and five-word free recall) tests. Direct associations were assessed in linear regression models and indirect effects were assessed in path models. Covariates were age, sex, education, antidepressant use, days since stroke, and stroke severity (National Institute of Health Stroke Severity Scale score). Results: Fatigue and depressive symptoms were highly correlated (r > 0.51, p < 0.0001). Depressive symptoms were associated with cognition (beta = -0.184, p = 0.04) and indirectly with mobility, mediated by fatigue (indirect effect = -0.0142, 95% CI: -0.0277 to -0.0033). Fatigue was associated with mobility (beta = -0.253, p = 0.01), and indirectly with cognition, mediated by depressive symptoms (indirect effect = -0.0113, 95% CI: -0.0242 to -0.0023). Conclusions: Fatigue and depressive symptoms are related distinctly to cognitive and mobility impairments post-stroke. Fatigue was associated with poorer lower limb motor function, and with cognition indirectly via depressive symptoms. PMID- 29163125 TI - "Cerebellar Challenge" for Older Adults: Evaluation of a Home-Based Internet Intervention. AB - There is converging evidence that maintenance of function in the multiple connectivity networks involving the cerebellum is a key requirement for healthy aging. The present study evaluated the effectiveness of a home-based, internet administered "cerebellar challenge" intervention designed to create progressive challenges to vestibular function, multi-tasking, and dynamic coordination. Participants (n = 98, mean age 68.2, SD 6.6) were randomly allocated to either intervention (the cerebellar challenge training for 10 weeks) or no intervention. All participants undertook an initial series of pre-tests, and then an identical set of post-tests following the intervention period. The test battery comprised five suites of tests designed to evaluate cognitive-sensori-motor-affective functions, including Physical Coordination, Memory, Language Dexterity, Fluid Thinking and Affect. The intervention group showed significant pre- to post improvements in 9 of the 18 tests, whereas the controls improved significantly on one only. Furthermore, the intervention group showed significantly greater improvement than the controls on the "Physical Coordination" suite of tests, with evidence also of differential improvement on the Delayed Picture Recall test. Frequency of intervention use correlated significantly with the improvement in balance and in peg-moving speed. It is concluded that an internet-based cerebellar challenge programme for older adults can lead to benefits in balance, coordination and declarative memory. Limitations and directions for further research are outlined. PMID- 29163129 TI - Biomarkers of Presbycusis and Tinnitus in a Portuguese Older Population. AB - Introduction: Presbycusis or age-related hearing loss (ARHL) is a ubiquitous health problem. It is estimated that it will affect up to 1.5 billion people by 2025. In addition, tinnitus occurs in a large majority of cases with presbycusis. Glutamate metabotropic receptor 7 (GRM7) and N-acetyltransferase 2 (NAT2) are some of the genetic markers for presbycusis. Objectives: To explore patterns of hearing loss and the role of GRM7 and NAT2 as possible markers of presbycusis and tinnitus in a Portuguese population sample. Materials and Methods: Tonal and speech audiometry, tinnitus assessment, clinical interview, and DNA samples were obtained from patients aged from 55 to 75 with or without tinnitus. GRM7 analysis was performed by qPCR. Genotyping of single nucleotide polymorphisms (SNPs) in NAT2 was performed by PCR amplification followed by Sanger sequencing or by qPCR. Results: We screened samples from 78 individuals (33 men and 45 women). T allele at GRM7 gene was the most observed (60.3% T/T and 33.3% A/T). Individuals with a T/T genotype have a higher risk for ARHL and 33% lower risk for tinnitus, compared to individuals with A/A and A/T genotype, respectively. Being a slow acetylator (53%) was the most common NAT2 phenotype, more common in men (55.8%). Intermediate acetylator was the second most common phenotype (35.9%) also more frequent in men (82.6%). Noise exposed individuals and individuals with 'high frequency' hearing loss seem to have a higher risk for tinnitus. Our data suggests that allele AT of GRM7 can have a statistically significant influence toward the severity of tinnitus. Conclusion: For each increasing year of age the chance of HL increases by 9%. The risk for ARHL was not significantly associated with GRM7 neither NAT2. However, we cannot conclude from our data whether the presence of T allele at GRM7 increases the odds for ARHL or whether the A allele has a protective effect. Genotype A/T at GRM7 could potentially be considered a biomarker of tinnitus severity. This is the first study evaluating the effect of GRM7 and NAT2 gene in tinnitus. PMID- 29163124 TI - The Search for an Effective Therapy to Treat Fragile X Syndrome: Dream or Reality? AB - Fragile X Syndrome (FXS) is the most common form of intellectual disability and a primary cause of autism. It originates from the lack of the Fragile X Mental Retardation Protein (FMRP), which is an RNA-binding protein encoded by the Fragile X Mental Retardation Gene 1 (FMR1) gene. Multiple roles have been attributed to this protein, ranging from RNA transport (from the nucleus to the cytoplasm, but also along neurites) to translational control of mRNAs. Over the last 20 years many studies have found a large number of FMRP mRNA targets, but it is still not clear which are those playing a critical role in the etiology of FXS. So far, no therapy for FXS has been found, making the quest for novel targets of considerable importance. Several pharmacological approaches have been attempted, but, despite some promising preclinical results, no strategy gave successful outcomes, due either to the induction of major side effects or to the lack of improvement of the phenotypes. However, these studies suggested that, in order to measure the effectiveness of a specific treatment, trials should be redesigned and new endpoints defined in FXS patients. Nevertheless, the search for new therapeutic targets for FXS is very active. In this context, the advances in animal modeling, coupled with better understanding of neurobiology and physiopathology of FXS, are of crucial importance in developing new selected treatments. Here, we discuss the pathways that were recently linked to the physiopathology of FXS (mGluR, GABAR, insulin, Insulin-like Growth Factor 1 (IGF 1), MPP-9, serotonin, oxytocin and endocannabinoid signaling) and that suggest new approaches to find an effective therapy for this disorder. Our goal with this review article is to summarize some recent relevant findings on FXS treatment strategies in order to have a clearer view of the different pathways analyzed to date emphasizing those shared with other synaptic disorders. PMID- 29163109 TI - On the Role of Physical Interaction on Performance of Object Manipulation by Dyads. AB - Human physical interactions can be intrapersonal, e.g., manipulating an object bimanually, or interpersonal, e.g., transporting an object with another person. In both cases, one or two agents are required to coordinate their limbs to attain the task goal. We investigated the physical coordination of two hands during an object-balancing task performed either bimanually by one agent or jointly by two agents. The task consisted of a series of static (holding) and dynamic (moving) phases, initiated by auditory cues. We found that task performance of dyads was not affected by different pairings of dominant and non-dominant hands. However, the spatial configuration of the two agents (side-by-side vs. face-to-face) appears to play an important role, such that dyads performed better side-by-side than face-to-face. Furthermore, we demonstrated that only individuals with worse solo performance can benefit from interpersonal coordination through physical couplings, whereas the better individuals do not. The present work extends ongoing investigations on human-human physical interactions by providing new insights about factors that influence dyadic performance. Our findings could potentially impact several areas, including robotic-assisted therapies, sensorimotor learning and human performance augmentation. PMID- 29163133 TI - Frequency-Specific Abnormalities of Intrinsic Functional Connectivity Strength among Patients with Amyotrophic Lateral Sclerosis: A Resting-State fMRI Study. AB - The classical concept that amyotrophic lateral sclerosis (ALS) is a degenerative disorder characterized by the loss of upper and lower motor neurons is agreed. However, more and more studies have suggested the involvement of some extra-motor regions. The aim of this study is to investigate the frequency-related alteration pattern of intrinsic functional connectivity strength (FCS) at the voxel-wise level in the relatively early-stage of ALS on a whole brain scale. In this study, 21 patients with ALS and 21 well-matched healthy control subjects were enrolled to examine the intrinsic FCS in the different frequencies (slow-4: 0.027-0.073 Hz; slow-5: 0.01-0.027 Hz, and typical band: 0.01-0.1 Hz). Compared with the control subjects, the ALS patients showed a significantly decreased FCS in the left prefrontal cortex (PFC) and the bilateral superior frontal gyrus. In the slow-5 band, the patients with ALS showed decreased FCS in the left lingual gyrus, as well as increased FCS in the left postcentral gyrus/paracentral lobule (PoCG/PARC). In the slow-4 band, the ALS patients presented decreased FCS in the left and right ventrolateral PFC. Moreover, the increased FCS in the left PoCG/PARC in the slow-5 band was positively correlated with the ALSFRS-r score (P = 0.015). Our results demonstrated that the FCS changes in ALS were wide spread and frequency dependent. These findings may provide some evidences that ALS patients have the consistent impairment in some extra-motor regions at a relatively early-stage. PMID- 29163135 TI - Neuroprotective Effect of Ligustilide through Induction of alpha-Secretase Processing of Both APP and Klotho in a Mouse Model of Alzheimer's Disease. AB - Emerging evidence suggests that alpha-processing single transmembrane proteins, amyloid precursor protein (APP) and anti-aging protein Klotho, are likely to be involved in the progression of Alzheimer's disease (AD). The natural phthalide Ligustilide (LIG) has been demonstrated to protect against aging- and amyloid beta (Abeta)-induced brain dysfunction in animal models. The present study is to investigate the effects of LIG on cognitive deficits and metabolism of both APP and Klotho and its underlying mechanism in AD double-transgenic (APP/PS1) mice and cultured human cells. Our results show that treatment with LIG significantly ameliorated memory impairment and Abeta levels and plaques burden. Specifically, LIG might act as a potent enhancer of alpha-secretase, disintegrin, and metalloprotease 10 (ADAM10), leading to upregulation of alpha-processing of both APP and Klotho and subsequent increases in the levels of both soluble APP fragment (sAPPalpha) and soluble Klotho (sKL) with inhibition of IGF-1/Akt/mTOR signaling in AD mice and cultured cells. Moreover, the specific ADAM10 inhibitor (G1254023X) effectively reversed LIG-induced alpha-processing of both APP and Klotho in vitro, while Klotho gene knockdown by small interfering RNA significantly blunted LIG-mediated inhibition of IGF-1/Akt/mTOR signaling in vitro. Taken together with the reported neuroprotective effects of both sAPPalpha and sKL as well as autophagy induction by Akt/mTOR pathway inhibition, our findings suggest that neuroprotection of LIG against AD is associated with induction alpha-processing of APP and Klotho and potential Abeta clearance. Whether LIG might induce Abeta autophagic clearance and the underlying mechanisms need to be further studied. PMID- 29163130 TI - Sex Differences in the Cognitive and Hippocampal Effects of Streptozotocin in an Animal Model of Sporadic AD. AB - More than 95% of Alzheimer's disease (AD) belongs to sporadic AD (sAD), and related animal models are the important research tools for investigating the pathogenesis and developing new drugs for sAD. An intracerebroventricular infusion of streptozotocin (ICV-STZ) is commonly employed to generate sporadic AD animal model. Moreover, the potential impact of sex on brain function is now emphasized in the field of AD. However, whether sex differences exist in AD animal models remains unknown. Here we reported that ICV-STZ remarkably resulted in learning and memory impairment in the Sprague-Dawley male rats, but not in the female rats. We also found tau hyperphosphorylation, an increase of Abeta40/42 as well as increase in both GSK-3beta and BACE1 activities, while a loss of dendritic and synaptic plasticity was observed in the male STZ rats. However, STZ did not induce above alterations in the female rats. Furthermore, estradiol levels of serum and hippocampus of female rats were much higher than that of male rats. In conclusion, sex differences exist in this sporadic AD animal model (Sprague-Dawley rats induced by STZ), and this should be considered in future AD research. PMID- 29163131 TI - Task-Irrelevant Novel Sounds have Antithetical Effects on Visual Target Processing in Young and Old Adults. AB - In young adults, primary visual task processing can be either enhanced or disrupted by novel auditory stimuli preceding target events, depending on task demands. Little is known about this phenomenon in older individuals, who, in general, are more susceptible to distraction. In the current study, age-related differences in the electrophysiological effects of task-irrelevant auditory stimuli on visual target processing were examined. Under both low and high primary task loads, the categorization/updating process in response to visual targets preceded by auditory novels, as indexed by the target P3 component, was enhanced in young, but diminished in old adults. In both age groups, the alerting/orienting response to novel auditory stimuli, as measured by the P3a, was smaller under high task load, whereas redirecting attention to the visual task after a novel auditory event, as indexed by the reorienting negativity (RON), tended to be augmented under high task load. Old subjects generated a smaller P3a and RON. We conclude that task irrelevant novel auditory stimuli have the opposite effect on the processing of visual targets in young and old adults. This finding may help explain age-related increases in the disruption of primary task activity by irrelevant, but salient auditory events. PMID- 29163134 TI - Geographic Variations in the Incidence of Glioblastoma and Prognostic Factors Predictive of Overall Survival in US Adults from 2004-2013. AB - Objective: The purpose of this study was to evaluate variations in the regional incidence of glioblastoma in US adults in 2004-2013. Study Design and Setting: We evaluated 24,262 patients with primary glioblastoma. Data were categorized based on geographic regions that included different SEER registry sites as follows: (1) Northeast: Connecticut, New Jersey (3,977 patients); (2) South: Kentucky, Louisiana, Metropolitan Atlanta, Rural Georgia, Greater Georgia (excluding AT and RG) (5,212 patients); (3) North Central: Metropolitan Detroit, Iowa (2,320 patients); (4) West: Hawaii, New Mexico, Seattle (Puget Sound), Utah, San Francisco-Oakland SMSA, San Jose-Monterey, Los Angeles, Greater California (excluding SF, LA, and SJ), Alaska (12,753 patients). Results: Statistically significant differences in the rates of overall patient survival (P < 0.001) and the incidence of glioblastoma (24.31, 22.6, 20.35, 15.03 per 100,000/year in the South, Northeast, West, North Central regions, respectively) were identified between geographic regions. Multivariate Cox regression analysis demonstrated that overall survival was better in patients of Asian or Pacific Islander race. In addition, age, registry site, marital status, tumor laterality, histological classification, the extent of disease, tumor size, tumor extension, and treatment methods were identified as significant prognostic factors. Conclusion: Glioblastoma incidence is geographic region and race/ethnicity-dependent. PMID- 29163137 TI - Multiple Evidences for Association between Cognitive Impairment and Dysglycemia in Parkinson's Disease: Implications for Clinical Practice. AB - Background and purpose: It remains unclear about the etiopathogenesis of cognitive impairment (CI) in Parkinson's disease (PD). Since diabetes mellitus (DM) has been shown to be associated with CI in several diseases, we examined the association between CI and dysglycemia in PD. Methods: Enrolled PD patients completed a series of clinical and neuropsychological assessments. Motor symptoms were determined by Hohen-Yahr staging (H-Y staging) and Unified Parkinson's Disease Rating Scale - motor score (UPDRS-III). Neuropsychological functions were evaluated by the Mini Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Hamilton Anxiety and Depression Scales. Moreover, fasting glucose, fasting insulin, glycosylated hemoglobin A1c (HbA1c) and oral glucose tolerance test were performed to assess glucose metabolism. Results: MoCA and MMSE scores in PD patients with DM group (PD-DM) were significantly lower than those in PD patients without DM group (PD-nDM). Consistently, PD-DM group showed significantly higher constituent ratio of CI than PD-nDM group. In addition, MoCA scores in HbA1c >= 6.5% group and HbA1c >= 7% group were significantly lower than those in the corresponding control groups. MoCA score in IR >= 3 group was significantly lower than that in IR < 3 group. Furthermore, MoCA score was negatively correlated with H-Y staging, HbA1c and insulin resistance, respectively. Finally, regression analysis indicated that H-Y staging and HbA1c >= 7% were independent risk factors of CI in PD. Conclusion: CI may be tightly associated with dysglycemia in, at least partially, PD patients. Importantly, H-Y staging and HbA1c >= 7%, two independent risk factors of CI in PD, may serve as key biomarkers in future PD clinical practice. PMID- 29163132 TI - The Influence of Negative Emotion on Cognitive and Emotional Control Remains Intact in Aging. AB - Healthy aging is characterized by a gradual decline in cognitive control and inhibition of interferences, while emotional control is either preserved or facilitated. Emotional control regulates the processing of emotional conflicts such as in irony in speech, and cognitive control resolves conflict between non affective tendencies. While negative emotion can trigger control processes and speed up resolution of both cognitive and emotional conflicts, we know little about how aging affects the interaction of emotion and control. In two EEG experiments, we compared the influence of negative emotion on cognitive and emotional conflict processing in groups of younger adults (mean age = 25.2 years) and older adults (69.4 years). Participants viewed short video clips and either categorized spoken vowels (cognitive conflict) or their emotional valence (emotional conflict), while the visual facial information was congruent or incongruent. Results show that negative emotion modulates both cognitive and emotional conflict processing in younger and older adults as indicated in reduced response times and/or enhanced event-related potentials (ERPs). In emotional conflict processing, we observed a valence-specific N100 ERP component in both age groups. In cognitive conflict processing, we observed an interaction of emotion by congruence in the N100 responses in both age groups, and a main effect of congruence in the P200 and N200. Thus, the influence of emotion on conflict processing remains intact in aging, despite a marked decline in cognitive control. Older adults may prioritize emotional wellbeing and preserve the role of emotion in cognitive and emotional control. PMID- 29163136 TI - Effects of Video Game Training on Measures of Selective Attention and Working Memory in Older Adults: Results from a Randomized Controlled Trial. AB - Video game training with older adults potentially enhances aspects of cognition that decline with aging and could therefore offer a promising training approach. Although, previous published studies suggest that training can produce transfer, many of them have certain shortcomings. This randomized controlled trial (RCT; Clinicaltrials.gov ID: NCT02796508) tried to overcome some of these limitations by incorporating an active control group and the assessment of motivation and expectations. Seventy-five older volunteers were randomly assigned to the experimental group trained for 16 sessions with non-action video games from Lumosity, a commercial platform (http://www.lumosity.com/) or to an active control group trained for the same number of sessions with simulation strategy games. The final sample included 55 older adults (30 in the experimental group and 25 in the active control group). Participants were tested individually before and after training to assess working memory (WM) and selective attention and also reported their perceived improvement, motivation and engagement. The results showed improved performance across the training sessions. The main results were: (1) the experimental group did not show greater improvements in measures of selective attention and working memory than the active control group (the opposite occurred in the oddball task); (2) a marginal training effect was observed for the N-back task, but not for the Stroop task while both groups improved in the Corsi Blocks task. Based on these results, one can conclude that training with non-action games provide modest benefits for untrained tasks. The effect is not specific for that kind of training as a similar effect was observed for strategy video games. Groups did not differ in motivation, engagement or expectations. PMID- 29163122 TI - Selectivity and Longevity of Peripheral-Nerve and Machine Interfaces: A Review. AB - For those individuals with upper-extremity amputation, a daily normal living activity is no longer possible or it requires additional effort and time. With the aim of restoring their sensory and motor functions, theoretical and technological investigations have been carried out in the field of neuroprosthetic systems. For transmission of sensory feedback, several interfacing modalities including indirect (non-invasive), direct-to-peripheral nerve (invasive), and cortical stimulation have been applied. Peripheral nerve interfaces demonstrate an edge over the cortical interfaces due to the sensitivity in attaining cortical brain signals. The peripheral nerve interfaces are highly dependent on interface designs and are required to be biocompatible with the nerves to achieve prolonged stability and longevity. Another criterion is the selection of nerves that allows minimal invasiveness and damages as well as high selectivity for a large number of nerve fascicles. In this paper, we review the nerve-machine interface modalities noted above with more focus on peripheral nerve interfaces, which are responsible for provision of sensory feedback. The invasive interfaces for recording and stimulation of electro neurographic signals include intra-fascicular, regenerative-type interfaces that provide multiple contact channels to a group of axons inside the nerve and the extra-neural-cuff-type interfaces that enable interaction with many axons around the periphery of the nerve. Section Current Prosthetic Technology summarizes the advancements made to date in the field of neuroprosthetics toward the achievement of a bidirectional nerve-machine interface with more focus on sensory feedback. In the Discussion section, the authors propose a hybrid interface technique for achieving better selectivity and long-term stability using the available nerve interfacing techniques. PMID- 29163138 TI - Perspective Insights into Disease Progression, Diagnostics, and Therapeutic Approaches in Alzheimer's Disease: A Judicious Update. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive accumulation of beta-amyloid fibrils and abnormal tau proteins in and outside of neurons. Representing a common form of dementia, aggravation of AD with age increases the morbidity rate among the elderly. Although, mutations in the ApoE4 act as potent risk factors for sporadic AD, familial AD arises through malfunctioning of APP, PSEN-1, and-2 genes. AD progresses through accumulation of amyloid plaques (Abeta) and neurofibrillary tangles (NFTs) in brain, which interfere with neuronal communication. Cellular stress that arises through mitochondrial dysfunction, endoplasmic reticulum malfunction, and autophagy contributes significantly to the pathogenesis of AD. With high accuracy in disease diagnostics, Abeta deposition and phosphorylated tau (p-tau) are useful core biomarkers in the cerebrospinal fluid (CSF) of AD patients. Although five drugs are approved for treatment in AD, their failures in achieving complete disease cure has shifted studies toward a series of molecules capable of acting against Abeta and p-tau. Failure of biologics or compounds to cross the blood brain barrier (BBB) in most cases advocates development of an efficient drug delivery system. Though liposomes and polymeric nanoparticles are widely adopted for drug delivery modules, their use in delivering drugs across the BBB has been overtaken by exosomes, owing to their promising results in reducing disease progression. PMID- 29163140 TI - Simultaneous Imaging of Cerebrovascular Structure and Function in Hypertensive Rats Using Synchrotron Radiation Angiography. AB - Hypertension has a profound influence on the structure and function of blood vessels. Cerebral vessels undergo both structural and functional changes in hypertensive animals. However, dynamic changes of cerebrovasculature and the factors involved in this process are largely unknown. In this study, we explored the dynamic changes of vascular structure in hypertensive rats using novel synchrotron radiation angiography. Twenty-four spontaneously hypertensive rats (SHR) and 24 Sprague-Dawley (SD) rats underwent synchrotron radiation (SR) angiography. Each group had 8 animals. We studied the cerebral vascular changes in SHR over a time period of 3-12-month and performed quantitative analysis. No vascular morphology differences between SHR and SD rats were observed in the early stage of hypertension. The number of twisted blood vessels in the front brain significantly increased at the 9- and 12-month observation time-points in the SHR compared to the SD rats (p < 0.01). The vessel density of the cortex and the striatum in SHR was consistently higher than that in SD rats at time points of 3-, 9-, and 12-month (p < 0.001). Vascular elasticity decreased both in SHR and SD rats with aging. There were statistically significant differences in the relative vascular elasticity of extracranial/intracranial internal carotid artery, middle cerebral artery, posterior cerebral artery and anterior cerebral artery between SHR and SD rats at 12-month (p < 0.01). We concluded that the dynamic vascular alterations detected by SR angiography provided novel imaging data for the study of hypertension in vivo. The longer the course of hypertension was, the more obvious the vascular differences between the SHR and the SD rats became. PMID- 29163141 TI - Disrupted Functional Connectivity of Basal Ganglia across Tremor-Dominant and Akinetic/Rigid-Dominant Parkinson's Disease. AB - It is well known that disruption of basal ganglia function generates the motor symptoms in PD, however, these are presented in a heterogeneous manner; patients can be divided into tremor-dominant and akinesia/rigidity-dominant subtypes. To date, it is unknown if these differences in the motor symptoms could be explained by differences on the functional connectivity of basal ganglia with specific brain regions. In this study, we aimed to explore the alterations of the network based and global functional connectivity linking to basal ganglia between the PD TD and PD-AR patients. One hundred and six PD patients and 52 normal controls were recruited. According to the subscales of UPDRS motor scale, PD patients were divided into the PD-TD (n = 57) and PD-AR (n = 49) subtypes. We performed independent component analysis to identify basal ganglia network (BGN) involving connected brain regions having coactivation with basal ganglia. Eigenvector centrality mapping were processed and the eigenvector centrality in the subcortical component of BGN including the bilateral caudate nuclei, putamen, thalami and pallidum were extracted to measure the global connectivity. Compared with controls, whole PD patients or PD subtypes showed decreases of functional connectivity within the subcortical component of BGN, e.g., thalamus, pallidum and putamen. Compared with controls, decreased functional connectivity of precuneus and amygdala with basal ganglia was observed in the PD-TD while that of occipital lobule and precuneus was observed in the PD-AR. Compared with the PD TD, significantly decreased functional connectivity between occipital lobule and cerebellum posterior lobule and basal ganglia was observed in the PD-AR, and such connectivity had positive correlations with tremor and negative correlations with akinesia/rigidity. We also observed enhanced global connectivity in the caudate nucleus and thalamus in the PD subtypes compared with controls. In conclusion, PD patients independent of motor subtypes consistently express similar alterations of functional connectivity within the subcortical component of BGN including network-based connectivity and global connectivity. Functional connectivity of cerebellum posterior lobule and occipital lobule with basal ganglia play important roles in the modulation of parkinsonian motor symptoms. PMID- 29163128 TI - Insulin Resistance and Alzheimer's Disease: Bioenergetic Linkages. AB - Metabolic dysfunction is a well-established feature of Alzheimer's disease (AD), evidenced by brain glucose hypometabolism that can be observed potentially decades prior to the development of AD symptoms. Furthermore, there is mounting support for an association between metabolic disease and the development of AD and related dementias. Individuals with insulin resistance, type 2 diabetes mellitus (T2D), hyperlipidemia, obesity, or other metabolic disease may have increased risk for the development of AD and similar conditions, such as vascular dementia. This association may in part be due to the systemic mitochondrial dysfunction that is common to these pathologies. Accumulating evidence suggests that mitochondrial dysfunction is a significant feature of AD and may play a fundamental role in its pathogenesis. In fact, aging itself presents a unique challenge due to inherent mitochondrial dysfunction and prevalence of chronic metabolic disease. Despite the progress made in understanding the pathogenesis of AD and in the development of potential therapies, at present we remain without a disease-modifying treatment. In this review, we will discuss insulin resistance as a contributing factor to the pathogenesis of AD, as well as the metabolic and bioenergetic disruptions linking insulin resistance and AD. We will also focus on potential neuroimaging tools for the study of the metabolic dysfunction commonly seen in AD with hopes of developing therapeutic and preventative targets. PMID- 29163142 TI - Low Serum Phosphorus Correlates with Cerebral Abeta Deposition in Cognitively Impaired Subjects: Results from the KBASE Study. AB - Alzheimer's disease (AD), characterized by progressive cognitive decline, is the most prevalent neurodegenerative disease in the elderly. Cerebral beta-amyloid (Abeta) deposition is the major pathological hallmark of AD. Recent studies also have shown that the serum level of phosphorus correlates to the risk of incident dementia. To date, the linkage between cerebral Abeta deposition and the serum phosphorus level remains unknown. In this study, we analyzed the levels of serum phosphorus in 109 mild cognitive impairment (MCI) and 73 AD dementia (ADD) subjects. All subjects underwent Pittsburgh compound B positron emission tomography (PiB-PET) imaging to measure cerebral Abeta deposition. The results with Abeta deposition was compared with the serum levels of phosphorus. The subjects with cerebral Abeta deposition showed lower levels of serum phosphorus than those without Abeta deposition. Furthermore, multiple regression analyses showed that a low level of serum phosphorus correlated with cerebral Abeta deposition, even when age, sex, apolipoprotein E epsilon4 genotype, and MMSE z score were controlled for. Serum levels of other ions, including calcium, iron, zinc, and copper, showed no such correlation. In conclusion, our results suggest that the serum level of phosphorus may be used as an easily accessible blood biomarker for cerebral Abeta deposition in a cognitively impaired population. PMID- 29163154 TI - Biotransformation of Flavonoid Conjugates with Fatty Acids and Evaluations of Their Functionalities. AB - Enzymatic conjugation with fatty acids including omega-3 polyunsaturated fatty acids (omega-3 PUFAs) derived from fish oil to three citrus fruit-derived flavonoids: grapefruit extract, naringin, and neohesperidin dihydrochalcone were investigated. The conversions were achieved over 85% under the catalysis of lipase Novozyme 435 in acetone at 45 degrees C at semi-preparative scale. The conjugates were purified via solvent partition and silica gel chromatography and achieved 90-98% in purity. The NMR analysis of the conjugates confirmed that the fatty acid carbon chain was linked onto the primary -OH group on the glucose moiety of the flavonoids. The purified flavonoid conjugates alongside their original flavonoids were analyzed for antioxidant activities via 2,2-diphenyl-1 picrylhydrazyl scavenging assay, and anti-peroxidation test via peroxide values measured during a 1-week fish oil storage trial. Vascular endothelial growth factor (VEGF) assay was conducted with 1, 10, and 100 MUM of naringin and grapefruits and their conjugates, respectively, and total VEGF levels were measured at 24 and 48 h, respectively, using ELISA and dot blot analysis. The results from these functionality experiments demonstrated that flavonoid FA conjugates have at least comparable (if not higher) antioxidant activity, anti peroxidation activity, and anti-angiogenic activity. PMID- 29163144 TI - The Relationship of Cognitive Performance and the Theta-Alpha Power Ratio Is Age Dependent: An EEG Study of Short Term Memory and Reasoning during Task and Resting-State in Healthy Young and Old Adults. AB - Objective: The Theta-Alpha ratio (TAR) is known to differ based upon age and cognitive ability, with pathological electroencephalography (EEG) patterns routinely found within neurodegenerative disorders of older adults. We hypothesized that cognitive ability would predict EEG metrics differently within healthy young and old adults, and that healthy old adults not showing age expected EEG activity may be more likely to demonstrate cognitive deficits relative to old adults showing these expected changes. Methods: In 216 EEG blocks collected in 16 young and 20 old adults during rest (eyes open, eyes closed) and cognitive tasks (short-term memory [STM]; matrix reasoning [RM; Raven's matrices]), models assessed the contributing roles of cognitive ability, age, and task in predicting the TAR. A general linear mixed-effects regression model was used to model this relationship, including interaction effects to test whether increased cognitive ability predicted TAR differently for young and old adults at rest and during cognitive tasks. Results: The relationship between cognitive ability and the TAR across all blocks showed age-dependency, and cognitive performance at the CZ midline location predicted the TAR measure when accounting for the effect of age (p < 0.05, chi-square test of nested models). Age significantly interacted with STM performance in predicting the TAR (p < 0.05); increases in STM were associated with increased TAR in young adults, but not in old adults. RM showed similar interaction effects with aging and TAR (p < 0.10). Conclusion: EEG correlates of cognitive ability are age-dependent. Adults who did not show age-related EEG changes were more likely to exhibit cognitive deficits than those who showed age-related changes. This suggests that healthy aging should produce moderate changes in Alpha and TAR measures, and the absence of such changes signals impaired cognitive functioning. PMID- 29163149 TI - GYY4137, an H2S Slow-Releasing Donor, Prevents Nitrative Stress and alpha Synuclein Nitration in an MPTP Mouse Model of Parkinson's Disease. AB - The neuromodulator hydrogen sulfide (H2S) was shown to exert neuroprotection in different models of Parkinson's disease (PD) via its anti-inflammatory and anti apoptotic properties. In this study, we evaluated the effect of an H2S slow releasing compound GYY4137 (GYY) on a mouse PD model induced by acute injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). GYY was intraperitoneally (i.p.) injected once daily into male C57BL/6J mice 3 days before and 2 weeks after MPTP (14 mg/kg, four times at 2-h intervals, i.p.) administration. Saline was given as a control. Behavioral tests (rotarod, balance beam, and grid walking) showed that 50 mg/kg GYY significantly ameliorated MPTP caused motor impairments. At lower doses (12.5 and 25 mg/kg) GYY exhibited a less obvious effect. Consistent with this, immunohistochemistry and western blot analysis demonstrated that 50 mg/kg GYY attenuated the loss of tyrosine hydroxylase (TH) positive neurons in the substantia nigra and the decrease of TH expression in the striatum of MPTP-treated mice. Moreover, at this regimen GYY relieved the nitrative stress, as indicated by the decreases in nitric oxide (NO) generation and neuronal NO synthase (nNOS) upregulation elicited by MPTP in the striatum. The suppression of GYY on nNOS expression was verified in vitro, and the results further revealed that Akt activation may participate in the inhibition by GYY on nNOS upregulation. More important, GYY reduced the nitrated modification of alpha-synuclein, a PD-related protein, in MPTP-induced mice. Overall, our findings suggest that GYY attenuated dopaminergic neuron degeneration and reduced alpha-synuclein nitration in the midbrain, thus exerting neuroprotection in MPTP-induced mouse model of PD. PMID- 29163148 TI - Methadone as a "Tumor Theralgesic" against Cancer. AB - Methadone has beneficial characteristics as an analgesic against cancer pain, including high bioavailability, multiple receptor affinities, and lack of active metabolites that might induce adverse side effects. However, methadone has an own pharmacological profile that should be considered in the treatment of cancer patients. There is evidence from preclinical studies that methadone could also elicit antitumor activity by downregulating the threshold of apoptosis and to enhance the effects of different chemotherapeutic agents. This confirms the concept of using methadone as a chemosensitizer in the future treatment of cancer. Our article discusses major issues about the role of methadone as a possible "tumor theralgesic," combining tumor therapeutic and analgesic activities. PMID- 29163155 TI - Intracellular Hyper-Acidification Potentiated by Hydrogen Sulfide Mediates Invasive and Therapy Resistant Cancer Cell Death. AB - Slow and continuous release of H2S by GYY4137 has previously been demonstrated to kill cancer cells by increasing glycolysis and impairing anion exchanger and sodium/proton exchanger activity. This action is specific for cancer cells. The resulting lactate overproduction and defective pH homeostasis bring about intracellular acidification-induced cancer cell death. The present study investigated the potency of H2S released by GYY4137 against invasive and radio- as well as chemo-resistant cancers, known to be glycolytically active. We characterized and utilized cancer cell line pairs of various organ origins, based on their aggressive behaviors, and assessed their response to GYY4137. We compared glycolytic activity, via lactate production, and intracellular pH of each cancer cell line pair after exposure to H2S. Invasive and therapy resistant cancers, collectively termed aggressive cancers, are receptive to H2S-mediated cytotoxicity, albeit at a higher concentration of GYY4137 donor. While lactate production was enhanced, intracellular pH of aggressive cancers was only modestly decreased. Inherently, the magnitude of intracellular pH decrease is a key determinant for cancer cell sensitivity to H2S. We demonstrated the utility of coupling GYY4137 with either simvastatin, known to inhibit monocarboxylate transporter 4 (MCT4), or metformin, to further boost glycolysis, in bringing about cell death for aggressive cancers. Simvastatin inhibiting lactate extrusion thence contained excess lactate induced by GYY4137 within intracellular compartment. In contrast, the combined exposure to both GYY4137 and metformin overwhelms cancer cells with lactate over-production exceeding its expulsion rate. Together, GYY4137 and simvastatin or metformin synergize to induce intracellular hyper-acidification-mediated cancer cell death. PMID- 29163147 TI - Chronic Psychological Stress Was Not Ameliorated by Omega-3 Eicosapentaenoic Acid (EPA). AB - Background: Chronic psychological stress and mental health disorders are endemic in Western culture where population dietary insufficiencies of omega-3 fatty acids (n-3FA) from seafood have been observed. Objective: This study was designed to test for a causal relationship between one of the most active components of fish oil, eicosapentaenoic acid (EPA), and chronic psychological stress. Method: A randomized double-blind, placebo-controlled clinical trial with parallel assignment to two groups was designed (Trial Id: ACTRN12610000404022). The interventions were four EPA-rich fish oil capsules per day, delivering 2.2 g/d EPA (and 0.44 g/d DHA), or identical placebo (low-phenolic olive oil capsules with 5% fish oil to aid blinding). The primary outcome was the between-group difference on the Perceived Stress Scale (PSS-10) after 12 weeks supplementation. An a priori power analysis determined that group sizes of 43 would provide 80% power to detect a significant between-group difference of 12.5%, at alpha = 0.05. Ninety community members (64 females, 26 males) reporting chronic work stress were recruited via public advertising in northern NSW, Australia. Results: At baseline the omega-3 index (EPA + DHA as % to total fatty acids in red blood cell membranes) was 5.2% in both groups (SD = 1.6% control group; 1.8% active group). After supplementation this remained stable at 5.3% (SD = 1.6%) for the control group but increased to 8.9% (SD = 1.5%) for the active group, demonstrating successful incorporation of EPA into cells. Intention-to-treat (ITT) analysis found no significant between-group differences in PSS outcome scores post intervention (b = 1.21, p = 0.30) after adjusting for sex (b = 2.36, p = 0.079), baseline PSS (b = 0.42, p = 0.001) and baseline logEPA [b = 1.41, p = 0.185; F(3, 86) = 8.47, p < 0.01, n = 89, R-square = 0.243]. Discussion: Treatment increased cell membrane EPA but, contrary to the hypothesis, there was no effect on perceived stress. Limitations included an imbalance of gender in groups after randomization (68% of the males were in the placebo group). While we found no significant interaction between sex and group on the outcome after adjusting for baseline PSS, larger studies with groups stratified for gender may be required to further confirm these findings. Conclusion: This study demonstrated that 2. 2 g/day of EPA for 12 weeks did not reduce chronic psychological stress. PMID- 29163156 TI - Role of Translocator 18 KDa Ligands in the Activation of Leukotriene B4 Activated G-Protein Coupled Receptor and Toll Like Receptor-4 Pathways in Neutrophils. AB - TSPO (Translocator 18 KDa; tryptophan-rich sensory protein oxygen sensor) is a constitutive outer mitochondrial membrane protein overexpressed in inflammatory cells during local or systemic processes. Despite its expression is characterized, role of TSPO in inflammation remains elusive. For this study, we investigated the role of TSPO ligands on neutrophil functions elicited by two different inflammatory pathways. Peritoneal neutrophils were isolated from male Balb-C mice, treated with TSPO ligand diazepam, Ro5-4864 or PK11195 (1,100 or 1000 nM; 2 h) and further stimulated with lipopolysaccharide from Escherichia coli (LPS), a binding for Toll-Like Receptor-4 (TLR4), or leukotriene B4 (LTB4), a G-protein coupled receptor (GPCR) ligand. LPS treatment did not lead to overexpression of TSPO on neutrophils, and pre-treatment with any TSPO ligand did not alter cytokine expression, adhesion molecule expression, or the production of reactive oxygen and nitrogen species caused by LPS stimulation. Conversely, all TSPO ligands impaired LTB4's actions, as visualized by reductions in L-selectin shedding, beta2 integrin overexpression, neutrophil chemotaxis, and actin filament assembly. TSPO ligands showed distinct intracellular effects on LTB4 induced neutrophil locomotion, with diazepam enhancing cofilin but not modifying Arp2/3 expression, and Ro5-4864 and PK11195 reducing both cofilin and Arp2/3 expression. Taken together, our data exclude a direct role of TSPO ligands in TLR4-elicited pathways, and indicate that TSPO activation inhibits GPCR inflammatory pathways in neutrophils, with a relevant role in neutrophil influx into inflammatory sites. PMID- 29163152 TI - The Hinge Segment of Human NADPH-Cytochrome P450 Reductase in Conformational Switching: The Critical Role of Ionic Strength. AB - NADPH-cytochrome P450 reductase (CPR) is a redox partner of microsomal cytochromes P450 and is a prototype of the diflavin reductase family. CPR contains 3 distinct functional domains: a FMN-binding domain (acceptor reduction), a linker (hinge), and a connecting/FAD domain (NADPH oxidation). It has been demonstrated that the mechanism of CPR exhibits an important step in which it switches from a compact, closed conformation (locked state) to an ensemble of open conformations (unlocked state), the latter enabling electron transfer to redox partners. The conformational equilibrium between the locked and unlocked states has been shown to be highly dependent on ionic strength, reinforcing the hypothesis of the presence of critical salt interactions at the interface between the FMN and connecting FAD domains. Here we show that specific residues of the hinge segment are important in the control of the conformational equilibrium of CPR. We constructed six single mutants and two double mutants of the human CPR, targeting residues G240, S243, I245 and R246 of the hinge segment, with the aim of modifying the flexibility or the potential ionic interactions of the hinge segment. We measured the reduction of cytochrome c at various salt concentrations of these 8 mutants, either in the soluble or membrane-bound form of human CPR. All mutants were found capable of reducing cytochrome c yet with different efficiency and their maximal rates of cytochrome c reduction were shifted to lower salt concentration. In particular, residue R246 seems to play a key role in a salt bridge network present at the interface of the hinge and the connecting domain. Interestingly, the effects of mutations, although similar, demonstrated specific differences when present in the soluble or membrane-bound context. Our results demonstrate that the electrostatic and flexibility properties of the hinge segment are critical for electron transfer from CPR to its redox partners. PMID- 29163146 TI - Influence of Sequential vs. Simultaneous Dual-Task Exercise Training on Cognitive Function in Older Adults. AB - Emerging research indicates that exercise combined with cognitive training may improve cognitive function in older adults. Typically these programs have incorporated sequential training, where exercise and cognitive training are undertaken separately. However, simultaneous or dual-task training, where cognitive and/or motor training are performed simultaneously with exercise, may offer greater benefits. This review summary provides an overview of the effects of combined simultaneous vs. sequential training on cognitive function in older adults. Based on the available evidence, there are inconsistent findings with regard to the cognitive benefits of sequential training in comparison to cognitive or exercise training alone. In contrast, simultaneous training interventions, particularly multimodal exercise programs in combination with secondary tasks regulated by sensory cues, have significantly improved cognition in both healthy older and clinical populations. However, further research is needed to determine the optimal characteristics of a successful simultaneous training program for optimizing cognitive function in older people. PMID- 29163159 TI - Larvicidal, Histopathological Efficacy of Penicillium daleae against Larvae of Culex quinquefasciatus and Aedes aegypti Plus Biotoxicity on Artemia nauplii a Non-target Aquatic Organism. AB - Mosquitoes can transmit the terrible diseases to human beings. Soil-borne fungal products act as potential source for low-cost chemicals, used for developing eco friendly control agents against mosquito-vector borne diseases. The prime aim of study was to check the larvicidal potential of fungus mycelia (by ethyl acetate solvent) extract from Penicillium daleae (KX387370) against Culex quinquefasciatus and Aedes aegypti and to test the toxicity of brine shrimp Artemia nauplii, by observing the physiological activity. The ethyl acetate extract of P. daleae mycelia (after 15 days) from Potato dextrose broth (PDB) medium revealed better result with least LC50 and LC90 values of I-IV instars larvae of Cx. quinquefasciatus (LC50 = 127.441, 129.087, 108.683, and 93.521; LC90 = 152.758, 158.169, 139.091, and 125.918 MUg/ml) and Ae. aegypti (LC50 = 105.077, 83.943, 97.158, and 76.513; LC90 = 128.035, 106.869, 125.640, and 104.606 MUg/ml) respectively. At higher concentration (1000 MUg/ml) of extracts, mortality begins at 18 h of exposure and attained 100% mortality after 48 h exposure. Overall, the activity was depends on the dose and time of exposure to the extracts. The stereomicroscopic and histopathological analysis of Ae. aegypti and Cx. quinquefasciatus larvae treated with mycelium ethyl acetate extract showed complete disintegration of abdominal region, particularly the midgut and caeca, loss of cuticular parts and caudal hairs. Morphological characterization of the fungi was performed and taxonomically identified through 5.8s rDNA technique. The phylogenetic analysis of rDNA sequence was carried out to find out the taxonomic and the evolutionary sketch of isolate in relation to earlier described genus Penicillium. Behavior and swimming speed alteration was analyzed together with mortality. The results of the experiment indicates that swimming behavior recorder (SBR) is a appropriate tool to detect individual swimming speed of the A. nauplii organisms, since the values have been obtained in accordance with control monitored results showed the 2.75 mm s-1 and after 24 h treated found to be 0.72 mm s-1, respectively. The extract-exposed to A. nauplii showed changes in body structures, i.e., intestine enlargement, eye formation, outer shell malformations and loss of antennae. In the present study, we aimed to investigate the toxicity of the ethyl acetate extract of P. daleae on A. nauplii larvae by performing the mortality, behavior and alterations in swimming responses. This is the first time report on the larvicidal efficacy of P. daleae ethyl acetate extract against Cx. quinquefasciatus and Ae. aegypti larvae. PMID- 29163145 TI - Insulin-Like Growth Factor-1 and Neuroinflammation. AB - Insulin-like growth factor-1 (IGF-1) effects on aging and neurodegeneration is still controversial. However, it is widely admitted that IGF-1 is involved in the neuroinflammatory response. In peripheral tissues, several studies showed that IGF-1 inhibited the expression of inflammatory markers, although other studies concluded that IGF-1 has proinflammatory functions. Furthermore, proinflammatory cytokines such as TNF-alpha impaired IGF-1 signaling. In the brain, there are controversial results on effects of IGF-1 in neuroinflammation. In addition to direct protective effects on neurons, several studies revealed anti-inflammatory effects of IGF-1 acting on astrocytes and microglia, and that IGF-1 may also inhibit blood brain barrier permeability. Altogether suggests that the aging related decrease in IGF-1 levels may contribute to the aging-related pro inflammatory state. IGF-1 inhibits the astrocytic response to inflammatory stimuli, and modulates microglial phenotype (IGF-1 promotes the microglial M2 and inhibits of M1 phenotype). Furthermore, IGF-1 is mitogenic for microglia. IGF-1 and estrogen interact to modulate the neuroinflammatory response and microglial and astrocytic phenotypes. Brain renin-angiotensin and IGF-1 systems also interact to modulate neuroinflammation. Induction of microglial IGF-1 by angiotensin, and possibly by other pro-inflammatory inducers, plays a major role in the repression of the M1 microglial neurotoxic phenotype and the enhancement of the transition to an M2 microglial repair/regenerative phenotype. This mechanism is impaired in aged brains. Aging-related decrease in IGF-1 may contribute to the loss of capacity of microglia to undergo M2 activation. Fine tuning of IGF-1 levels may be critical for regulating the neuroinflammatory response, and IGF-1 may be involved in inflammation in a context-dependent mode. PMID- 29163153 TI - Ketogal: A Derivative Ketorolac Molecule with Minor Ulcerogenic and Renal Toxicity. AB - Ketorolac is a powerful non-steroidal anti-inflammatory drug (NSAID), with a great analgesic activity, present on the Italian market since 1991. Despite the excellent therapeutic activity, the chronic use of ketorolac has long been limited owing to the high incidence of gastrointestinal and kidney side events. In our previous study, we demonstrated that ketorolac-galactose conjugate (ketogal), synthesized and tested in a single-dose study, was able to reduce ulcerogenicity, while preserving the high pharmacological efficacy of its parent drug. In this paper, in order to verify the suitability of this compound, for repeated administration, ex vivo experiments on naive mice were performed. Mice were treated for 5 or 7 days with the highest doses of two drugs (ketorolac 10 mg/kg and ketogal 16.3 mg/kg), and the expression of both gastric COX-1 and PGsyn was evaluated. Results showed that oral ketorolac treatment significantly reduced both enzymes; surprisingly, oral treatment with ketogal did not produce significant variation in the expression of the two constitutive enzymes. Moreover, histological experiments on stomach and kidneys clearly indicated that repeated administration of ketogal induced lower toxicity than ketorolac. At same time, in vivo results clearly showed that both ketorolac and ketogal had a similar therapeutic activity in a model of inflammation and in pain perception. These effects were accompanied by the reduction of enzyme expression such as COX 2 and iNOS, and by the modulation of levels of nuclear NF-kappaB and cytosolic IkappaB-alpha in the inflamed paws. These very encouraging results demonstrate for the first time that ketogal could represent a valid and novel therapeutic alternative to the ketorolac and might pave the way for clinical studies. PMID- 29163158 TI - Shengjiang Xiexin Decoction Alters Pharmacokinetics of Irinotecan by Regulating Metabolic Enzymes and Transporters: A Multi-Target Therapy for Alleviating the Gastrointestinal Toxicity. AB - Shengjiang Xiexin decoction (SXD), a classic traditional Chinese medical formula chronicled in Shang Han Lun, is used in modern clinical practice to decrease gastrointestinal toxicity induced by the chemotherapeutic drug irinotecan (CPT 11). In this study, the effect of SXD on the pharmacokinetics of CPT-11 and its active metabolites (SN-38 and SN-38G), and the underlying mechanisms were further examined. An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous quantification of CPT-11, SN-38, and SN-38G in the plasma, bile, liver, intestine, and intestinal contents of control and SXD-pre-treated rats after intravenous administration of CPT-11. SXD pretreatment increased the area under the curve (AUC) and the initial plasma concentration (C0) of CPT-11 but decreased the plasma clearance (CL). The AUC and the maximum plasma concentration (Cmax) of SN-38 decreased, whereas the Cmax of SN-38G increased. Compared with that of the control group, the biliary excretion of CPT-11, SN-38, and SN-38G was inhibited. The CPT-11, SN-38, and SN-38G concentrations in the liver, intestine, and intestinal contents were different between the two groups. Furthermore, the hepatic expression of multidrug resistance-associated protein-2 (Mrp-2), P glycoprotein (P-gp), and carboxylesterase 2 (CES2) was significantly down regulated by SXD, while the hepatic and jejunal uridine diphosphate (UDP) glucuronosyltransferase 1A1 (UGT1A1) expression was elevated. The hydrolysis of CPT-11 to SN-38 by CES and the glucuronidation of SN-38 to SN-38G by UGT were affected by liver and jejunum S9 fractions from rats pre-treated with SXD. Therefore, this study demonstrated for the first time that SXD could alter the pharmacokinetics of CPT-11 and its metabolites to alleviate CPT-11-induced diarrhea. And the underlying mechanism of drug interaction between CPT-11 and SXD involves decreasing hepatic Mrp-2 and P-gp expression and altering the activities of CES and UGT. PMID- 29163143 TI - Distinct Aging Effects on Motion Repulsion and Surround Suppression in Humans. AB - Elderly exhibit accumulating deficits in visual motion perception, which is critical for humans to interact with their environment. Previous studies have suggested that aging generally reduces neuronal inhibition in the visual system. Here, we investigated how aging affects the local intra-cortical inhibition using a motion direction discrimination task based on the motion repulsion phenomenon. Motion repulsion refers to the phenomenon by which observers overestimate the perceived angle when two superimposed dot patterns are moving at an acute angle. The misperception has been interpreted as local mutual inhibition between nearby direction-tuned neurons within the same cortical area. We found that elderly exhibited much stronger motion repulsion than young adults. We then compared this effect to how aging affects the global inter-cortical inhibition by adopting the surround suppression paradigm previously used by Betts et al. (2005). We found that elderly showed less change in the discrimination threshold when the size of a high-contrast drifting Gabor was increased, indicating reduced surround suppression compared to young adults. Our results indicate that aging may not always lead to a decrease of neuronal inhibition in the visual system. These distinct effects of aging on inhibitory functions might be one of the reasons that elderly people often exhibit deficits of motion perception in a real-world situation. PMID- 29163151 TI - Ongoing Initiatives to Improve the Quality and Efficiency of Medicine Use within the Public Healthcare System in South Africa; A Preliminary Study. AB - Introduction: South Africa has an appreciable burden of both communicable and non communicable diseases as well as high maternal, neonatal, and child morbidity. In recent years there have been significant strides with improving the public health system, and addressing current inequalities, with the right to health a constitutional provision in South Africa. Initiatives include the introduction of National Health Insurance, programmes to enhance access to medicines for patients with chronic diseases, as well as activities to improve care in hospitals, including improving pharmacovigilance. Consequently, the objective of this paper is to review ongoing initiatives within the public healthcare sector in South Africa and their influence to provide future direction. Method: Principally a structured review of current and planned activities. Results: There have been a number of major activities and initiatives surrounding the availability and access to medicines in the public system in recent years in South Africa. This includes a National Surveillance Centre and an innovative early warning system for the supply of medicines as well as the development of a National Health Care Pricing Authority and initiatives to improve contracting. There have also been developments to improve the supply chain including instigating Medicine Procurement Units in the provinces and enhancing forecasting capabilities. Access to medicines is improving though the instigation of stable chronic disease management initiatives to increase the number of external pick-up points for medicines. There are also ongoing programmes to enhance adherence to medicines as well as enhance adherence to the Standard Treatment Guidelines and the Essential Medicines List with their increasing availability. In addition, there is a movement to enhance the role of health technology assessment in future decision making. Hospital initiatives include increased focus on reducing antimicrobial resistance through instigating stewardship programmes as well as improving adverse drug reaction reporting and associated activities. Conclusion: Overall, there are an appreciable number of ongoing activities within the public healthcare system in South Africa attempting to ensure and sustain universal healthcare. It is too early to assess their impact, which will be the subject of future research. PMID- 29163139 TI - Exercise-Induced Neuroprotection of the Nigrostriatal Dopamine System in Parkinson's Disease. AB - Epidemiological studies indicate that physical activity and exercise may reduce the risk of developing Parkinson's disease (PD), and clinical observations suggest that physical exercise can reduce the motor symptoms in PD patients. In experimental animals, a profound observation is that exercise of appropriate timing, duration, and intensity can reduce toxin-induced lesion of the nigrostriatal dopamine (DA) system in animal PD models, although negative results have also been reported, potentially due to inappropriate timing and intensity of the exercise regimen. Exercise may also minimize DA denervation-induced medium spiny neuron (MSN) dendritic atrophy and other abnormalities such as enlarged corticostriatal synapse and abnormal MSN excitability and spiking activity. Taken together, epidemiological studies, clinical observations, and animal research indicate that appropriately dosed physical activity and exercise may not only reduce the risk of developing PD in vulnerable populations but also benefit PD patients by potentially protecting the residual DA neurons or directly restoring the dysfunctional cortico-basal ganglia motor control circuit, and these benefits may be mediated by exercise-triggered production of endogenous neuroprotective molecules such as neurotrophic factors. Thus, exercise is a universally available, side effect-free medicine that should be prescribed to vulnerable populations as a preventive measure and to PD patients as a component of treatment. Future research needs to establish standardized exercise protocols that can reliably induce DA neuron protection, enabling the delineation of the underlying cellular and molecular mechanisms that in turn can maximize exercise induced neuroprotection and neurorestoration in animal PD models and eventually in PD patients. PMID- 29163157 TI - A Dual Role of P53 in Regulating Colistin-Induced Autophagy in PC-12 Cells. AB - This study aimed to investigate the mechanism of p53 in regulating colistin induced autophagy in PC-12 cells. Importantly, cells were treated with 125 MUg/ml colistin for 12 and 24 h after transfection with p53 siRNA or recombinant plasmid. The hallmarks of autophagy and apoptosis were examined by real-time PCR and western blot, fluorescence/immunofluorescence microscopy, and electron microscopy. The results showed that silencing of p53 leads to down-regulation of Atg5 and beclin1 for 12 h while up-regulation at 24 h and up-regulation of p62 noted. The ratio of LC3-II/I and autophagic vacuoles were significantly increased at 24 h, but autophagy flux was blocked. The cleavage of caspase3 and PARP (poly ADP-ribose polymerase) were enhanced, while PC-12-sip53 cells exposed to 3-MA showed down-regulation of apoptosis. By contrast, the expression of autophagy related genes and protein reduced in p53 overexpressing cells following a time dependent manner. Meanwhile, there was an increase in the expression of activated caspase3 and PARP, condensed and fragmented nuclei were evident. Conclusively, the data supported that silencing of p53 promotes impaired autophagy, which acts as a pro-apoptotic induction factor in PC-12 cells treated with colistin for 24 h, and overexpression of p53 inhibits autophagy and accelerates apoptosis. Hence, it has been suggested that p53 could not act as a neuro-protective target in colistin-induced neurotoxicity. PMID- 29163150 TI - Targeting DNA Repair through Podophyllotoxin and Rutin Formulation in Hematopoietic Radioprotection: An in Silico, in Vitro, and in Vivo Study. AB - Drug discovery field has tremendously progressed during last few decades, however, an effective radiation countermeasure agent for the safe administration to the victims of radiation exposure is still unavailable. This multi-model study is aimed at elucidating the mechanistic aspects of a novel podophyllotoxin and rutin combination (henceforth referred as G-003M) in the hematopoietic radioprotection and its involvement in the DNA damage and repair signaling pathways. Using in silico study, we identified the binding sites and structural components of G-003M and validated in vitro. We further studied various in vivo endpoints related to the DNA repair and cell death pathways in mice pre administered with G-003M, irradiated and subsequently euthanized to collect blood and bone marrow cells. In silico study showed the binding of podophyllotoxin to beta-tubulin and presence of a functional hydroxyl group in the rutin, suggested their involvement in G2/M arrest and the free radical scavenging respectively. This experimentation was further validated through in vitro studies. In vivo mice studies confirmed that G-003M pre-administration attenuated DNA damage and enhanced repair after whole body exposure. We further noticed a decrease in the levels of gammaH2AX, p53BP1, and ATM kinase and an increase in the levels of DNA pk, Ku 80, Ligase IV, Mre 11, Rad 50 and NBS 1 in the blood and bone marrow cells of the G-003M pre-administered and irradiated mice. We noticed an overall increase in the pro-survival factors in the G-003M pre-treated and irradiated groups establishing the radioprotective efficacy of this formulation. The lead obtained from this study will certainly help in developing this formulation as a safe and effective radioprotector which could be used for humans against any planned or emergency exposure of radiation. PMID- 29163160 TI - Aberrant Wnt/Beta-Catenin Pathway Activation in Dialysate-Induced Peritoneal Fibrosis. AB - Peritoneal dialysis (PD)-associated peritoneal fibrosis is a chronic progress which induces ultrafiltration failure. It remains a challenge to prevent the progression of PD-associated fibrosis in clinic practice. Wnt/beta-catenin pathway plays important role in many severe fibrotic diseases, here we investigated its contribution to the development of peritoneal damage. We isolated mesothelial cells (MC) from the effluent of PD patients and found that the expressions of Wnt1, Wnt5a, beta-catenin, and LEF1 were increased in patients with more than 1-year PD compared with patients who just started with PD (<1 month). The elevated expressions of Wnts and beta-catenin were accompanied with changes in the expressions of E-cadherin, alpha-SMA, COL-I, and FN mRNA and proteins, which are known related to mesothelial-mesenchymal transition (MMT). In addition, treatment with high glucose significantly increased the expression of Wnt1, Wnt5a, beta-catenin, and LEF1 as well as the expression of alpha-SMA, COL I, and FN in human peritoneal mesothelial cells (HPMC), whereas the expression of E-cadherin was reduced. Dickkopf-1 (DKK-1) is an endogenous inhibitor of Wnt/beta catenin signaling. Overexpression of DKK1 transgene significantly decreased the expression of beta-catenin and attenuated the process of MMT as indicated by the decreased expression of alpha-SMA, COL-I, and FN and the increased expression of E-cadherin. Furthermore, TGF-beta1 treatment significantly activated the Wnt/beta catenin pathway in HPMCs, while DKK1 blocked the TGF-beta1-induced Wnt signaling activation and significantly inhibited the process of MMT. These data suggest that the canonical Wnt/beta-catenin pathway plays an important role in the MMT and fibrosis induced by PD. PMID- 29163162 TI - A Randomized, Double-Blinded, Clinical Trial on Effects of a Vitis vinifera Extract on Cognitive Function in Healthy Older Adults. AB - Introduction: Gradual population aging is creating a new set of needs in the general population. Memory capacity decreases with age, and memory deficits are considered an early symptom of Alzheimer's Disease (AD), one of the most prevalent cognitive disorders in older people. Numerous studies have shown that grape polyphenolic compounds (GPs) are able to attenuate cognitive impairment and reduce brain lesions in experimental AD animal models. These GP effects are associated with improvement in brain antioxidant status and prevention of free radical-induced neuronal damage. We designed a randomized, double-blind, placebo controlled clinical trial to investigate the potential beneficial effects of a Vitis vinifera-based dietary supplement on cognitive function and neuropsychological status in healthy older adults. Methods: One-hundred eleven subjects were recruited and randomly divided in two groups: one group received the V. vinifera-based dietary supplement Cognigrape(r) for 12 weeks (250 mg/day) and the second group received placebo over the same period of time. Before and after the end of the supplementation period, cognitive function and neuropsychological status were evaluated using the Mini-Mental State Examination (MMSE), Beck Depression Inventory (BDI), Hamilton Anxiety Rating Scale (HARS), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) evaluations. Results: MMSE scores were significantly improved after supplementation with Cognigrape(r) in comparison with baseline levels (p < 0.0001) and placebo (r = 0.59, 0.95% CI 0.11, 1.22; p < 0.0001). Cognigrape(r) supplementation produced a significant reduction in BDI (-15.8%) and HARS ( 24.9%) scores with respect to baseline levels (p < 0.0001) and placebo (p < 0.0001 for BDI and p < 0.05 for HARS). RBANS total score was significantly improved by Cognigrape(r) with respect to baseline levels and placebo (r = 0.55, 0.95% CI 0.48, 6.07; p < 0.0001). The comparison with the placebo revealed improvements in several parameters among participants receiving Cognigrape(r): attention (p < 0.001); language (p < 0.05); immediate memory (p < 0.0001); and delayed memory (p < 0.0001). Visuospatial/constructional abilities were not modified. During the study, no adverse effects were detected. Conclusion: The results show that 12 weeks of Cognigrape(r) supplementation is safe, can improve physiological cognitive profiles, and can concurrently ameliorate negative neuropsychological status in healthy older adults. PMID- 29163165 TI - The Modulatory Properties of Chronic Antidepressant Drugs Treatment on the Brain Chemokine - Chemokine Receptor Network: A Molecular Study in an Animal Model of Depression. AB - An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokine - chemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1alpha), CX3CL1 (fractalkine) and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF beta, a molecular pathway related to fractalkine receptor (CX3CR1), was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine administration. Tianeptine modulate also brain TGF-beta signaling in the prenatal stress-induced animal model of depression. Our results provide new evidence that not only prenatal stress-induced behavioral disturbances but also changes of CXCL12 and their receptor and at less extend in CX3CL1-CX3CR1 expression may be normalized by chronic antidepressant drug treatment. In particular, the effect on the CXCL12 and their CXCR4 and CXCR7 receptors requires additional studies to elucidate the possible biological consequences. PMID- 29163163 TI - Guanxin Danshen Formulation Protects against Myocardial Ischemia Reperfusion Injury-Induced Left Ventricular Remodeling by Upregulating Estrogen Receptor beta. AB - Background: Guanxin Danshen formulation (GXDSF) is a traditional Chinese herbal recipe recorded in the Chinese Pharmacopeia since 1995 edition, which consists of Salviae miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma and Dalbergiae odoriferae Lignum. Our previous research suggested GXDSF had positive effect on cardiovascular disease. Therefore, the aim of this study was to elucidate the effects of GXDSF on myocardial ischemia reperfusion injury-induced left ventricular remodelling (MIRI-LVR). Methods: The effects of GXDSF on cardiac function were detected by haemodynamics and echocardiograms. The effects of GXDSF on biochemical parameters (AST, LDH and CK-MB) were analyzed. Histopathologic examinations were performed to evaluate the effect of GXDSF on cardiac structure. In addition, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to predict the main target of GXDSF. Target validation was conducted by using western blots and immunofluorescent double staining assays. Results: We found that +dp/dt and LVSP were significantly elevated in the GXDSF treated groups compared with the MIRI-LVR model group. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were increased in the GXDSF-treated groups compared with the model group. All biochemical parameters (AST, LDH and CK-MB) were considerably decreased in the GXDSF-treated groups compared with the model group. Fibrosis parameters (collagen I and III, alpha-SMA, and left ventricular fibrosis percentage) were decreased to different degrees in the GXDSF-treated groups compared with the model group, and the collagen III/I ratio was elevated by the same treatments. TCMSP database prediction and western blot results indicated that estrogen receptor beta (ERbeta) could be the main target of GXDSF. PHTPP, a selective antagonist of ERbeta, could inhibit the expression of ERbeta and the phosphorylation of PI3K and Akt in myocardial tissue induced by GXDSF, and partly normalize the improving effects of GXDSF on +dp/dt, LVEF, LVFS, LDH, CK-MB, alpha-SMA and myocardial fibrosis. Conclusion: Collectively, GXDSF showed therapeutic potential for use in the prevention and treatment of myocardial ischemia reperfusion injury-induced ventricular remodeling by upregulating ERbeta via PI3K/Akt signaling. Moreover, these findings may be valuable in understand the mechanism of disease and provide a potential therapy of MIRI-IVR. PMID- 29163164 TI - LASSBio-897 Reduces Lung Injury Induced by Silica Particles in Mice: Potential Interaction with the A2A Receptor. AB - Silicosis is a lethal fibro-granulomatous pulmonary disease highly prevalent in developing countries, for which no proper therapy is available. Among a small series of N-acylhydrazones, the safrole-derived compound LASSBio-897 (3 thienylidene-3, 4-methylenedioxybenzoylhydrazide) raised interest due to its ability to bind to the adenosine A2A receptor. Here, we evaluated the anti inflammatory and anti-fibrotic potential of LASSBio-897, exploring translation to a mouse model of silicosis and the A2A receptor as a site of action. Pulmonary mechanics, inflammatory, and fibrotic changes were assessed 28 days after intranasal instillation of silica particles in Swiss-Webster mice. Glosensor cAMP HEK293G cells, CHO cells stably expressing human adenosine receptors and ligand binding assay were used to evaluate the pharmacological properties of LASSBio-897 in vitro. Molecular docking studies of LASSBio-897 were performed using the genetic algorithm software GOLD 5.2. We found that the interventional treatment with the A2A receptor agonist CGS 21680 reversed silica particle-induced airway hyper-reactivity as revealed by increased responses of airway resistance and lung elastance following aerosolized methacholine. LASSBio-897 (2 and 5 mg/kg, oral) similarly reversed pivotal lung pathological features of silicosis in this model, reducing levels of airway resistance and lung elastance, granuloma formation and collagen deposition. In competition assays, LASSBio-897 decreased the binding of the selective A2A receptor agonist [3H]-CGS21680 (IC50 = 9.3 MUM). LASSBio-897 (50 MUM) induced modest cAMP production in HEK293G cells, but it clearly synergized the cAMP production by adenosine in a mechanism sensitive to the A2A antagonist SCH 58261. This synergism was also seen in CHO cells expressing the A2A, but not those expressing A2B, A1 or A3 receptors. Based on the evidence that LASSBio-897 binds to A2A receptor, molecular docking studies were performed using the A2A receptor crystal structure and revealed possible binding modes of LASSBio 897 at the orthosteric and allosteric sites. These findings highlight LASSBio-897 as a lead compound in drug development for silicosis, emphasizing the role of the A2A receptor as its putative site of action. PMID- 29163166 TI - Saxagliptin Attenuates Albuminuria by Inhibiting Podocyte Epithelial- to Mesenchymal Transition via SDF-1alpha in Diabetic Nephropathy. AB - The dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin has been found to reduce progressive albuminuria, but the exact mechanism of inhibition is unclear. Podocyte epithelial-to-mesenchymal transition (EMT) has emerged as a potential pathway leading to proteinuria in diabetic nephropathy (DN). Stromal cell-derived factor-1alpha (SDF-1alpha), one of the substrates of DPP-4, can activate the protein kinase A pathway and subsequently inhibit its downstream effector, transforming growth factor-beta1 (TGF-beta1), which induces podocyte EMT. Thus, this study was designed to test the hypothesis that saxagliptin reduces progressive albuminuria by preventing podocyte EMT through inhibition of SDF 1alpha cleavage in DN. The results of a series of assays, including ELISA, western blotting, and immunochemistry/immunofluorescence, showed that saxagliptin treatment obviously ameliorated urinary microalbumin excretion and renal histological changes in high-fat diet/streptozotocin-induced diabetic rats. Furthermore, saxagliptin-treated diabetic rats presented with suppression of DPP 4 activity/protein expression accompanied by restoration of SDF-1alpha levels, which subsequently hindered NOX2 expression and podocyte EMT. In vitro, we consistently observed that saxagliptin significantly inhibited increased DPP-4 activity/expression, oxidative stress and podocyte EMT. Application of an SDF 1alpha receptor inhibitor (AMD3100) to cultured podocytes further confirmed the essential role of SDF-1alpha in podocyte EMT inhibition. In sum, we demonstrated for the first time that saxagliptin treatment plays an essential role in ameliorating progressive DN by preventing podocyte EMT through a SDF-1alpha related pathway, suggesting that saxagliptin could offer renoprotection and that SDF-1alpha might be a potential therapeutic target for DN. PMID- 29163170 TI - European Drug Users at Risk from Illicit Fentanyls Mix. PMID- 29163161 TI - Inhibition of miR-128-3p by Tongxinluo Protects Human Cardiomyocytes from Ischemia/reperfusion Injury via Upregulation of p70s6k1/p-p70s6k1. AB - Background and Aims: Tongxinluo (TXL) is a multifunctional traditional Chinese medicine that has been widely used to treat cardiovascular and cerebrovascular diseases. However, no studies have explored whether TXL can protect human cardiomyocytes (HCMs) from ischemia/reperfusion (I/R) injury. Reperfusion Injury Salvage Kinase (RISK) pathway activation was previously demonstrated to protect the hearts against I/R injury and it is generally activated via Akt or (and) Erk 1/2, and their common downstream protein, ribosomal protein S6 kinase (p70s6k). In addition, prior studies proved that TXL treatment of cells promoted secretion of VEGF, which could be stimulated by the increased phosphorylation of one p70s6k subtype, p70s6k1. Consequently, we hypothesized TXL could protect HCMs from I/R injury by activating p70s6k1 and investigated the underlying mechanism. Methods and Results: HCMs were exposed to hypoxia (18 h) and reoxygenation (2 h) (H/R), with or without TXL pretreatment. H/R reduced mitochondrial membrane potential, increased bax/bcl-2 ratios and cytochrome C levels and induced HCM apoptosis. TXL preconditioning reversed these H/R-induced changes in a dose-dependent manner and was most effective at 400 MUg/mL. The anti-apoptotic effect of TXL was abrogated by rapamycin, an inhibitor of p70s6k. However, inhibitors of Erk1/2 (U0126) or Akt (LY294002) failed to inhibit the protective effect of TXL. TXL increased p70s6k1 expression and, thus, enhanced its phosphorylation. Furthermore, transfection of cardiomyocytes with siRNA to p70s6k1 abolished the protective effects of TXL. Among the micro-RNAs (miR-145-5p, miR-128-3p and miR-497-5p) previously reported to target p70s6k1, TXL downregulated miR-128-3p in HCMs during H/R, but had no effects on miR-145-5p and miR-497-5p. An in vivo study confirmed the role of the p70s6k1 pathway in the infarct-sparing effect of TXL, demonstrating that TXL decreased miR-128-3p levels in the rat myocardium during I/R. Transfection of HCMs with a hsa-miR-128-3p mimic eliminated the protective effects of TXL. Conclusions: The miR-128-3p/p70s6k1 signaling pathway is involved in protection by TXL against HCM apoptosis during H/R. Overexpression of p70s6k1 is, therefore, a potential new strategy for alleviating myocardial reperfusion injury. PMID- 29163168 TI - Atheroregressive Potential of the Treatment with a Chimeric Monoclonal Antibody against Sulfated Glycosaminoglycans on Pre-existing Lesions in Apolipoprotein E Deficient Mice. AB - The retention of lipoprotein particles in the intima, in particular to glycosaminoglycan side chains of proteoglycans, is a critical step in atherosclerosis initiation. Administration of chP3R99, a chimeric mouse/human monoclonal antibody inducing an anti-idiotypic network response against glycosaminoglycans was previously shown to prevent atherosclerotic lesion progression, yet its effect in the late-stage progression of lesions remains unknown. This study investigated the effect of chP3R99 at a late stage of disease development in apolipoprotein E-deficient mice and the vascular mechanisms involved. Male apolipoprotein E-deficient mice were fed a high-fat high cholesterol diet from 4 to 19 weeks old, at which time mice were fed normal chow and 5 doses of chP3R99 (50 MUg) or isotype-matched IgG (hR3) were administered subcutaneously weekly for the first 3 administrations, then at weeks 24 and 26 before sacrifice (week 28). Lesions progression was reduced by 88% in treated mice with no change in total plasma cholesterol levels, yet with increased sera reactivity to chP3R99 idiotype and heparin, suggesting the induction of an anti idiotype antibody cascade against glycosaminoglycans, which was likely related with the atheroprotective effect. chP3R99 treatment initiated regression in a significant number of mice. Circulating levels of interleukin-6 were reduced along with a striking diminution of inflammatory cell accumulation in the vessel wall, and of VCAM-1 labeling in vivo. The ratio of IL-10/iNOS gene expression in aortas increased in chP3R99-treated mice. In conclusion, our results show that treatment with chP3R99 reduces vascular inflammatory burden and halts lesion progression with potential for regression in the late phase of the disease in atherosclerotic mice, and support the therapeutic intervention against glycosaminoglycans as a novel strategy to reverse atherosclerosis. PMID- 29163167 TI - Experimental Evaluation of the Transport Mechanisms of PoIFN-alpha in Caco-2 Cells. AB - For the development of an efficient intestinal delivery system for Porcine interferon-alpha (PoIFN-alpha), the understanding of transport mechanisms of which in the intestinal cell is essential. In this study, we investigated the absorption mechanisms of PoIFN-alpha in intestine cells. Caco-2 cells and fluorescein isothiocyanate-labeled (FITC)-PoIFN-alpha were used to explore the whole transport process, including endocytosis, intracellular trafficking, exocytosis, and transcytosis. Via various techniques, the transport pathways of PoIFN-alpha in Caco-2 cells and the mechanisms were clarified. Firstly, the endocytosis of PoIFN-alpha by Caco-2 cells was time, concentration and temperature dependence. And the lipid raft/caveolae endocytosis was the most likely endocytic pathway for PoIFN-alpha. Secondly, both Golgi apparatus and lysosome were involved in the intracellular trafficking of PoIFN-alpha. Thirdly, the treatment of indomethacin resulted in a significant decrease of exocytosis of PoIFN-alpha, indicating the participation of cyclooxygenase. Finally, to evaluate the efficiency of PoIFN-alpha transport, the transepithelial electrical resistance (TEER) value was measured to investigate the tight junctional integrity of the cell monolayers. The fluorescence microscope results revealed that the transport of PoIFN-alpha across the Caco-2 cell monolayers was restricted. In conclusion, this study depicts a probable picture of PoIFN-alpha transport in Caco-2 cells characterized by non-specificity, partial energy dependency and low transcytosis. PMID- 29163169 TI - Icariin Enhances Bone Repair in Rabbits with Bone Infection during Post-infection Treatment and Prevents Inhibition of Osteoblasts by Vancomycin. AB - Vancomycin is an effective antibiotic for treatment of bone infection caused by Staphylococcus aureus, however, a high local concentration of vancomycin might induce a delay in bone union. Icariin has been reported to suppress osteoclastogenes and promote osteogenesis. Our study aimed to investigate the effect of icariin on bone repair after anti-infection treatment in vivo and to explore the resisting effect of icariin on rat calvarial osteoblasts (ROBs) inhibited with high doses of vancomycin. Rabbits with bone infection of S. aureus were treated with implanted vancomycin-calcium sulfate (VCS) and icariin at 10.86 mg/kg/day for consecutive 8 weeks. Micro-CT, morphology, blood biochemistry were evaluated. In addition, ROBs were treated with vancomycin and icariin at different doses. Cell proliferation and differentiation capabilities, BMP2, Runx2, OPG, RANKL mRNA levels and protein expression were assessed. The results indicated that high dose of vancomycin significantly decreased bone mass and inhibited osteocalcin secretion; icariin increased these indicators compared with the single vancomycin treatment. Over 0.1 mg/mL of vancomycin inhibited the proliferation and differentiation of ROBs, while icariin resisted the inhibition of vancomycin by regulating cell cycle and promoting the Alkaline phosphatase (ALP) activity. Moreover, icariin promote bone formation by up-regulating BMP2/Runx2 and OPG/RANKL pathways. Icariin exhibited osteoplastic properties on osteoblasts that had been inhibited with high doses of vancomycin. Therefore, icariin is helpful for post-infection treatment of bone infection. PMID- 29163171 TI - The Sooner, the Better: The Establishment of a Treatment Paradigm in Prostate Cancer. PMID- 29163174 TI - Sustained Complete Response to Metronomic Chemotherapy in a Child with Refractory Atypical Teratoid Rhabdoid Tumor: A Case Report. AB - Atypical teratoid rhabdoid tumor (ATRT) is a rare and highly aggressive embryonal tumor of the central nervous system with a dismal prognosis and no definitive guidelines for treatment, especially at relapse or in case of refractory disease. Metronomic chemotherapy (MC) has emerged as a new treatment option in solid malignancies, with lower toxicity and is frequently combined with drug repositioning. We report a case of ATRT in an 8-year-old boy who progressed during multimodal therapy including surgical resection, chemotherapy and radiotherapy. He was treated with MC involving continuous oral celecoxib with alternating metronomic etoposide and cyclophosphamide, in combination with biweekly bevacizumab and monthly intrathecal liposomal cytarabine. To date, he remains clinically and symptomatically disease-free with a follow-up of 10 months. The treatment was well-tolerated. Metronomics represent a possible alternative regimen for children with recurrent or progressive ATRT. PMID- 29163173 TI - Investigation of Liver Injury of Polygonum multiflorum Thunb. in Rats by Metabolomics and Traditional Approaches. AB - Liver injury induced by Polygonum multiflorum Thunb. (PM) have been reported since 2006, which aroused widespread concern. However, the toxicity mechanism of PM liver injury remained unclear. In this study, the mechanism of liver injury induced by different doses of PM after long-term administration was investigated in rats by metabolomics and traditional approaches. Rats were randomly divided into control group and PM groups. PM groups were oral administered PM of low (10 g/kg), medium (20 g/kg), high (40 g/kg) dose, while control group was administered distilled water. After 28 days of continuous administration, the serum biochemical indexes in the control and three PM groups were measured and the liver histopathology were analyzed. Also, UPLC-Q-TOF-MS with untargeted metabolomics was performed to identify the possible metabolites and pathway of liver injury caused by PM. Compared with the control group, the serum levels of ALT, AST, ALP, TG, and TBA in middle and high dose PM groups were significantly increased. And the serum contents of T-Bil, D-Bil, TC, TP were significantly decreased. However, there was no significant difference between the low dose group of PM and the control group except serum AST, TG, T-Bil, and D-Bil. Nine biomarkers were identified based on biomarkers analysis. And the pathway analysis indicated that fat metabolism, amino acid metabolism and bile acid metabolism were involved in PM liver injury. Based on the biomarker pathway analysis, PM changed the lipid metabolism, amino acid metabolism and bile acid metabolism and excretion in a dose-dependent manner which was related to the mechanism of liver injury. PMID- 29163175 TI - Evaluation of the Antioxidant and Antiglycation Effects of Lactarius deterrimus and Castanea sativa Extracts on Hepatorenal Injury in Streptozotocin-Induced Diabetic Rats. AB - The present study aimed to investigate the beneficial effects of the treatment with extracts from the edible mushroom Lactarius deterrimus (Ld) and the chestnut Castanea sativa (Cs), separately and in combination (MIX Ld/Cs), on oxidative stress and advanced glycation end-product (AGE)-mediated hepatorenal injury in a rat model of streptozotocin (STZ)-induced diabetes by examining pathways responsible for maintenance of redox homeostasis. An experimental model of diabetes was induced in rats by the administration of 40 mg/kg STZ intraperitoneally (i.p.) for 5 consecutive days. The examined extracts were applied separately at a dose of 60 mg/kg i.p. and in combination (60 mg/kg each extract; i.p.) for 4 weeks, starting from the last day of STZ administration. The improvement of hepatorenal function in diabetic rats treated with the extracts was associated with an improved glycemic and lipid status and suppression of oxidative stress and thereby oxidative damage of lipids and DNA. Besides the fact that both extracts inhibited protein glycation and AGE formation in vitro, they also reduced non-enzymatic glycosylation in diabetic rats in vivo. The observed antiglycation activity of the examined extracts (separately and in combination) was accompanied with the inhibition of CML-mediated RAGE/NF-kappaB activation and reduction of enzymatic O-GlcNAcylation in liver and kidney tissues of diabetic rats. Taken together, these results reveal that the administration of chestnut and mushroom extracts, either individually or together, activates a coordinated cytoprotective response against diabetes-induced hepatorenal injury not only through recovery of the antioxidant defense system of the cell, but also through a marked antiglycation activity. PMID- 29163172 TI - Central Administration of 5Z-7-Oxozeaenol Protects Experimental Autoimmune Encephalomyelitis Mice by Inhibiting Microglia Activation. AB - Transforming growth factor beta-activated kinase 1 (TAK1), a vital upstream integrator of multiple pro-inflammatory signaling pathways, mediates the production of pro-inflammatory cytokines, chemokines, and adhesion molecules. Investigations targeting TAK1 provide new therapeutic options for chronic inflammatory disorders, autoimmune diseases, and cancer. However, the role and mechanism of the TAK1 inhibitor 5Z-7-oxozeaenol in treating autoimmune demyelinating diseases remain unclear. This work aimed to identify whether 5Z-7 oxozeaenol exerts neuroprotective effects on experimental autoimmune encephalomyelitis (EAE) in mice. Here, we demonstrate that 5Z-7-oxozeaenol efficiently alleviates the symptoms of EAE by decreasing the levels of pro inflammatory cytokines in splenocytes and central nervous system, diminishing the number of activated microglia and inhibiting the p38MAPK, JNK, and ERK signaling pathways. Furthermore, we demonstrate that administration during the symptomatic time window is required for 5Z-7-oxozeaenol efficacy. These results suggest that TAK1 inhibition may provide a potent approach toward treating autoimmune demyelinating diseases. PMID- 29163176 TI - Jiang Tang Xiao Ke Granule Play an Anti-diabetic Role in Diabetic Mice Pancreatic Tissue by Regulating the mRNAs and MicroRNAs Associated with PI3K-Akt Signaling Pathway. AB - Purpose: To investigate the effect of JTXK granule on the expression pattern of miRNA in pancreatic tissue of KKAy diabetic mice, and to explore the molecular mechanism and pathways of JTXK granule in anti-diabetic effect. Methods: We used high fat diet (HFD) to induce the KKAy diabetic mice and screened the differentially expressed miRNAs (DEMs) between JTXK-treated group (n = 6) and the diabetic group (n = 6) using MicroRNA (miRNA) Microarray. C57BL/6J mice were given a normal diet as the control group (n = 6). Subsequently, miRNA target gene prediction, GO and Pathway analysis were used to explore the function of DEMs. Finally, the mechanism of anti-diabetic effects of JTXK granule was tested by in vitro INS-1 pancreatic beta-cell experiment. Results: The blood glucose and body weight of JTXK-treated group was significantly lower compared with the model group. Moreover, a total of 45 miRNAs with significant differences were detected in the model group and the JTXK-treated group (P <= 0.05, Fold Change > 2). Further, miRNA-mRNA analysis showed that the differential expression of mmu-miR 192-5p, mmu-miR-291a-3p, mmu-miR-320-3p, mmu-miR-139-5p and mmu-miR-378a-3p are closely related to pancreatic histological changes. In addition, pathway analysis showed that the DEMs were closely related to PI3K-Akt Signaling Pathway. Furthermore, the levels of serine/threonine-protein kinase (Akt), phosphorylated Akt (p-Akt) and phosphorylated forkhead transcription factor O1 (p-Foxo1) in INS 1-FOXO1 overexpressing model cells were lower than those in normal group, while JTXK granules could increase the expression of Akt, p-Akt and p-Foxo1. Conclusions: The results showed that JTXK granule could play an anti-diabetic role by regulating the mRNA and miRNAs associated with PI3K-Akt pathway in diabetic mice pancreatic tissue. PMID- 29163177 TI - Assessment of Pharmacogenomic Panel Assay for Prediction of Taxane Toxicities: Preliminary Results. AB - Backbone: Paclitaxel and docetaxel are the primary taxane anticancer drugs regularly used to treat, breast, gastric, ovarian, head/neck, lung, and genitourinary neoplasm. Suspension of taxane treatments compromising patient benefits is more frequently caused by peripheral neuropathy and allergy, than to tumor progression. Several strategies for preventing toxicity have been investigated so far. Recently, findings on the genetic variants associated with toxicity and resistance to taxane-based chemotherapy have been reported. Methods: An extensive panel of five polymorphisms on four candidate genes (ABCB1, CYP2C8*3, CYP3A4*1B, XRCC3), previously validated as significant markers related to paclitaxel and Docetaxel toxicity, are analyzed and discussed. We genotyped 76 cancer patients, and 35 of them received paclitaxel or docetaxel-based therapy. What is more, an early outline evaluation of the genotyping costs and benefit was assessed. Results: Out of 35 patients treated with a taxane, six (17.1%) had adverse neuropathy events. Pharmacogenomics analysis showed no correlation between candidate gene polymorphisms and toxicity, except for the XRCC3 AG+GG allele [OR 2.61 (95% CI: 0.91-7.61)] which showed a weak significant trend of risk of neurotoxicities vs. the AG allele [OR 1.52 (95% CI: 0.51-4.91)] P = 0.03. Summary: Based on our experimental results and data from the literature, we propose a useful and low-cost genotyping panel assay for the prevention of toxicity in patients undergoing taxane-based therapy. With the individual pharmacogenomics profile, clinicians will have additional information to plan the better treatment for their patients to minimize toxicity and maximize benefits, including determining cost-effectiveness for national healthcare sustainability. PMID- 29163179 TI - In Silico Assessment of Efficacy and Safety of IKur Inhibitors in Chronic Atrial Fibrillation: Role of Kinetics and State-Dependence of Drug Binding. AB - Current pharmacological therapy against atrial fibrillation (AF), the most common cardiac arrhythmia, is limited by moderate efficacy and adverse side effects including ventricular proarrhythmia and organ toxicity. One way to circumvent the former is to target ion channels that are predominantly expressed in atria vs. ventricles, such as KV1.5, carrying the ultra-rapid delayed-rectifier K+ current (IKur). Recently, we used an in silico strategy to define optimal KV1.5-targeting drug characteristics, including kinetics and state-dependent binding, that maximize AF-selectivity in human atrial cardiomyocytes in normal sinus rhythm (nSR). However, because of evidence for IKur being strongly diminished in long standing persistent (chronic) AF (cAF), the therapeutic potential of drugs targeting IKur may be limited in cAF patients. Here, we sought to simulate the efficacy (and safety) of IKur inhibitors in cAF conditions. To this end, we utilized sensitivity analysis of our human atrial cardiomyocyte model to assess the importance of IKur for atrial cardiomyocyte electrophysiological properties, simulated hundreds of theoretical drugs to reveal those exhibiting anti-AF selectivity, and compared the results obtained in cAF with those in nSR. We found that despite being downregulated, IKur contributes more prominently to action potential (AP) and effective refractory period (ERP) duration in cAF vs. nSR, with ideal drugs improving atrial electrophysiology (e.g., ERP prolongation) more in cAF than in nSR. Notably, the trajectory of the AP during cAF is such that more IKur is available during the more depolarized plateau potential. Furthermore, IKur block in cAF has less cardiotoxic effects (e.g., AP duration not exceeding nSR values) and can increase Ca2+ transient amplitude thereby enhancing atrial contractility. We propose that in silico strategies such as that presented here should be combined with in vitro and in vivo assays to validate model predictions and facilitate the ongoing search for novel agents against AF. PMID- 29163178 TI - NF-kappabeta: A Potential Target in the Management of Vascular Complications of Diabetes. AB - Diabetes is a metabolic disorder affecting large percentage of population worldwide. NF-kappabeta plays key role in pathogenesis of vascular complications of diabetes. Persistent hyperglycemia activates NF-kappabeta that triggers expression of various cytokines, chemokines and cell adhesion molecules. Over expression of TNF-alpha, interleukins, TGF-beta, Bcl2 and other pro-inflammatory proteins and pro-apoptotic genes by NF-kappabeta is key risk factor in vascular dysfunction. NF-kappabeta over-expression also triggers calcification of endothelial cells leading to endothelial dysfunction and further vascular complications. Inhibition of NF-kappabeta pro-inflammatory pathway is upcoming novel target for management of vascular complications of diabetes. Various natural and synthetic inhibitors of NF-kappabeta have been studied in management of diabetic complications. Recent preclinical and clinical studies validate NF kappabeta as promising target in the management of vascular complications of diabetes. PMID- 29163180 TI - Risk Factors of Hypersensitivity to Carboplatin in Patients with Gynecologic Malignancies. AB - We evaluated the prevalence of and risk factors for hypersensitivity reactions related to carboplatin, which is commonly used to treat gynecological malignancies. All women with pathologically documented ovarian, fallopian tube, or primary peritoneal cancer treated with carboplatin alone or a carboplatin based combination chemotherapy regimen at a single hospital between January 2006 and December 2013 were retrospectively recruited. We analyzed the incidence, characteristics, risk factors, management, and outcomes of carboplatin-related hypersensitivity reactions among these patients. Among 735 eligible women, 75 (10.2%) experienced a total of 215 carboplatin-related hypersensitivity reaction events. The annual incidence of carboplatin-related hypersensitivity reactions gradually increased from 0.88% in 2006 to 5.42% in 2013. The incidence of carboplatin-related hypersensitivity was higher in patients with advanced stage disease (P < 0.001, Kruskal-Wallis test), serous and mixed histological types (P = 0.003, Kruskal-Wallis test), malignant ascites (P = 0.009, chi-square test), and history of other drug allergy (P < 0.001, chi-square test). Compared to women without hypersensitivity reactions, women who experienced hypersensitivity reactions had a significantly greater median cycle number (12 vs. 6, P < 0.001, independent sample t-test) and dose (6,816 vs. 3,844 mg, P < 0.001, independent sample t-test). The cumulative incidence of carboplatin-related hypersensitivity reactions dramatically increased with >8 cycles or dose >3,500 mg. Therefore, disease severity, histological type, malignant ascites, past drug allergies, and cumulative carboplatin dose are risk factors for carboplatin-related hypersensitivity reactions. Such reactions could potentially be reduced or prevented by slowing the infusion rate and using a desensitization protocol involving anti-allergy medications. PMID- 29163181 TI - Shengfu Oil Enhances the Healing of Full-Thickness Scalded Skin Accompanying the Differential Regulation of beta-Catenin, Dlk1, and COX-2. AB - Shengfu oil is a traditional Chinese medicine formula containing 16 ingredients, including Scutellariae radix, Olibanum, and Rehmanniae radix. In this study, we aimed to enhance the wound healing of rabbit full-thickness scalded skin by Shengfu oil and to elucidate its regulatory effects on beta-catenin, Dlk1, and COX-2. We found that Shengfu oil exhibited significant anti-inflammatory, analgesic, and antimicrobial activities. The structure of wound tissues in Shengfu oil group was intact, including regenerated cutaneous appendages, indicating better healing capability of Shengfu oil compared to the controls. The protein expression of beta-catenin, Dlk1, and COX-2 in wound tissues were investigated by immunohistochemistry staining and were further quantitated with the use of multispectral imaging analysis. The protein expression of beta-catenin and Dlk1 in the Shengfu oil group was higher than that in the sesame oil group in early wound repair, accompanied by the lower expression of COX-2; the protein expression of beta-catenin decreased in the middle of wound healing; the protein expression of beta-catenin and Dlk1 increased at the end of wound healing. These results strongly suggest that Shengfu oil can enhance wound healing by regulating the expression of beta-catenin, Dlk1, and COX-2 due to its excellent anti inflammatory, analgesic, and antimicrobial activities. PMID- 29163182 TI - The Natural Antiangiogenic Compound AD0157 Induces Caspase-Dependent Apoptosis in Human Myeloid Leukemia Cells. AB - Evasion of apoptosis is a hallmark of cancer especially relevant in the development and the appearance of leukemia drug resistance mechanisms. The development of new drugs that could trigger apoptosis in aggressive hematological malignancies, such as AML and CML, may be considered a promising antileukemic strategy. AD0157, a natural marine pyrrolidinedione, has already been described as a compound that inhibits angiogenesis by induction of apoptosis in endothelial cells. The crucial role played by defects in the apoptosis pathways in the pathogenesis, progression and response to conventional therapies of several forms of leukemia, moved us to analyze the effect of this compound on the growth and death of leukemia cells. In this work, human myeloid leukemia cells (HL60, U937 and KU812F) were treated with AD0157 ranging from 1 to 10 MUM and an experimental battery was applied to evaluate its apoptogenic potential. We report here that AD0157 was highly effective to inhibit cell growth by promotion of apoptosis in human myeloid leukemia cells, and provide evidence of its mechanisms of action. The apoptogenic activity of AD0157 on leukemia cells was verified by an increased chromatin condensation and DNA fragmentation, and confirmed by an augmentation in the apoptotic subG1 population, translocation of the membrane phosphatidylserine from the inner face of the plasma membrane to the cell surface and by cleavage of the apoptosis substrates PARP and lamin-A. In addition, AD0157 in the low micromolar range significantly enhanced the activities of the initiator caspases 8 and -9, and the effector caspases-3/-7 in a dose-dependent manner. Results presented here throw light on the apoptogenic mechanism of action of AD0157, mediated through caspase-dependent cascades, with an especially relevant role played by mitochondria. Altogether, these results suggest the therapeutic potential of this compound for the treatment of human myeloid leukemia. PMID- 29163183 TI - Pharmacological Therapy of Osteoporosis: A Systematic Current Review of Literature. AB - Osteoporosis is the most common bone disease affecting millions of people worldwide, particularly in elderly or in post-menopausal women. The pathogenesis is useful to understand the possible mechanism of action of anti-osteoporotic drugs. Early diagnosis, possible with several laboratory and instrumental tests, allows a major accuracy in the choice of anti-osteoporosis drugs. Treatment of osteoporosis is strictly related to severity of pathology and consists on prevention of fragility fractures with a correct lifestyle and adequate nutritional supplements, and use of pharmacological therapy, started in patients with osteopenia and history of fragility fracture of the hip or spine. The purpose of this review is to focus on main current pharmacological products to treat osteoporotic patients. PMID- 29163184 TI - Silencing of NAC1 Expression Induces Cancer Cells Oxidative Stress in Hypoxia and Potentiates the Therapeutic Activity of Elesclomol. AB - In order to survive under conditions of low oxygen, cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial respiration in order to reduce oxygen consumption and prevent excessive amounts of reactive oxygen species (ROS) production. Nucleus accumbens-1 (NAC1), a nuclear protein of the BTB/POZ gene family, has pivotal roles in cancer development. Here, we identified that NAC1-PDK3 axis as necessary for suppression of mitochondrial function, oxygen consumption, and more harmful ROS generation and protects cancer cells from apoptosis in hypoxia. We show that NAC1 mediates suppression of mitochondrial function in hypoxia through inducing expression of pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1alpha at the transcriptional level, thereby inactivating pyruvate dehydrogenase and attenuating mitochondrial respiration. Re expression of PDK3 in NAC1 absent cells rescued cells from hypoxia-induced metabolic stress and restored the activity of glycolysis in a xenograft mouse model, and demonstrated that silencing of NAC1 expression can enhance the antitumor efficacy of elesclomol, a pro-oxidative agent. Our findings reveal a novel mechanism by which NAC1 facilitates oxidative stress resistance during cancer progression, and chemo-resistance in cancer therapy. PMID- 29163186 TI - A High Fat Diet during Adolescence in Male Rats Negatively Programs Reproductive and Metabolic Function Which Is Partially Ameliorated by Exercise. AB - An interaction between obesity, impaired glucose metabolism and sperm function in adults has been observed but it is not known whether exposure to a diet high in fat during the peri-pubertal period can have longstanding programmed effects on reproductive function and gonadal structure. This study examined metabolic and reproductive function in obese rats programmed by exposure to a high fat (HF) diet during adolescence. The effect of physical training (Ex) in ameliorating this phenotype was also assessed. Thirty-day-old male Wistar rats were fed a HF diet (35% lard w/w) for 30 days then subsequently fed a normal fat diet (NF) for a 40-day recovery period. Control animals were fed a NF diet throughout life. At 70 days of life, animals started a low frequency moderate exercise training that lasted 30 days. Control animals remained sedentary (Se). At 100 days of life, biometric, metabolic and reproductive parameters were evaluated. Animals exposed to HF diet showed greater body weight, glucose intolerance, increased fat tissue deposition, reduced VO2max and reduced energy expenditure. Consumption of the HF diet led to an increase in the number of abnormal seminiferous tubule and a reduction in seminiferous epithelium height and seminiferous tubular diameter, which was reversed by moderate exercise. Compared with the NF-Se group, a high fat diet decreased the number of seminiferous tubules in stages VII-VIII and the NF-Ex group showed an increase in stages XI-XIII. HF-Se and NF-Ex animals showed a decreased number of spermatozoa in the cauda epididymis compared with animals from the NF-Se group. Animals exposed to both treatments (HF and Ex) were similar to all the other groups, thus these alterations induced by HF or Ex alone were partially prevented. Physical training reduced fat pad deposition and restored altered reproductive parameters. HF diet consumption during the peri-pubertal period induces long-term changes on metabolism and the reproductive system, but moderate and low frequency physical training is able to recover adipose tissue deposition and reproductive system alterations induced by high fat diet. This study highlights the importance of a balanced diet and continued physical activity during adolescence, with regard to metabolic and reproductive health. PMID- 29163185 TI - Orthostatic Intolerance in Older Persons: Etiology and Countermeasures. AB - Orthostatic challenge produced by upright posture may lead to syncope if the cardiovascular system is unable to maintain adequate brain perfusion. This review outlines orthostatic intolerance related to the aging process, long-term bedrest confinement, drugs, and disease. Aging-associated illness or injury due to falls often leads to hospitalization. Older patients spend up to 83% of hospital admission lying in bed and thus the consequences of bedrest confinement such as physiological deconditioning, functional decline, and orthostatic intolerance represent a central challenge in the care of the vulnerable older population. This review examines current scientific knowledge regarding orthostatic intolerance and how it comes about and provides a framework for understanding of (patho-) physiological concepts of cardiovascular (in-) stability in ambulatory and bedrest confined senior citizens as well as in individuals with disease conditions [e.g., orthostatic intolerance in patients with diabetes mellitus, multiple sclerosis, Parkinson's, spinal cord injury (SCI)] or those on multiple medications (polypharmacy). Understanding these aspects, along with cardio postural interactions, is particularly important as blood pressure destabilization leading to orthostatic intolerance affects 3-4% of the general population, and in 4 out of 10 cases the exact cause remains elusive. Reviewed also are countermeasures to orthostatic intolerance such as exercise, water drinking, mental arithmetic, cognitive training, and respiration training in SCI patients. We speculate that optimally applied countermeasures such as mental challenge maintain sympathetic activity, and improve venous return, stroke volume, and consequently, blood pressure during upright standing. Finally, this paper emphasizes the importance of an active life style in old age and why early re-mobilization following bedrest confinement or bedrest is crucial in preventing orthostatic intolerance, falls and falls-related injuries in older persons. PMID- 29163187 TI - Prognostic Values of Long Noncoding RNA GAS5 in Various Carcinomas: An Updated Systematic Review and Meta-Analysis. AB - The growth arrest-specific transcript 5 (GAS5) is a long noncoding RNA with low expression in multiple cancers. This meta-analysis aims to explore the association between GAS5 expression levels and cancer patients' prognosis. We collected all the relevant literatures about GAS5 expression levels associated with overall survival (OS), lymph node metastasis (LNM) and high tumor stage (II/III/IV) (HTS) from the PubMed and Web of Science. The hazard ratio (HR) and the corresponding 95% confidence interval (CI) were calculated to evaluate the link strength between GAS5 and cancer prognosis. A total of 934 patients from 14 studies were included to the present meta-analysis, according to the inclusion and exclusion criteria. The results demonstrated that low expression of GAS5 could predict poor OS in cancer patients (HR = 1.955, 95% CI: 1.551-2.465, P < 0.001). Meanwhile we also analyzed the following cancers independently: hepatocellular carcinoma (HR = 1.893, 95% CI: 1.103-3.249, P = 0.021) and urothelial carcinoma (HR = 1.653, 95% CI: 1.185-2.306, P = 0.003). Compared to the high GAS5 expression group, additionally, patients with low GAS5 expression in tumor tissues were more prone to lymph node metastasis (OR = 0.234, 95%CI: 0.153-0.358, P < 0.001) and high tumor stage (OR = 0.185, 95% CI:0.102-0.333, P < 0.001). In conclusion, this meta-analysis showed that GAS5 might be served as a novel biomarker for predicting prognosis in various types of cancers. PMID- 29163189 TI - Commentary: Managing Thoracic Aortic Aneurysm in Patients with Bicuspid Aortic Valve Based on Aortic Root-Involvement. PMID- 29163188 TI - Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease. AB - The diagnosis and treatment of bone disorders in patients with chronic kidney disease (CKD) represent a clinical challenge. CKD leads to mineral and bone complications starting early in the course of renal failure. Recently, we have observed the positive relationship between intensified central kynurenine turnover and bone strength in rats with subtotal 5/6 nephrectomy (5/6 Nx)-induced CKD. The aim of the present study was to determine the association between peripheral kynurenine pathway metabolites and bone strength in rats with 5/6 Nx induced CKD. The animals were sacrificed 1 and 3 months after 5/6 Nx or sham operation. Nephrectomized rats presented higher concentrations of serum creatinine, urea nitrogen, and parathyroid hormone both 1 and 3 months after nephrectomy. These animals revealed higher concentrations of kynurenine and 3 hydroxykynurenine in the serum and higher gene expression of aryl hydrocarbon receptor (AhR) as a physiological receptor for kynurenine and AhR-dependent cytochrome in the bone tissue. Furthermore, nephrectomy significantly increased the number of osteoclasts in the bone without affecting their resorptive activity measured in serum. These changes were particularly evident in rats 1 month after 5/6 Nx. The main bone biomechanical parameters of the tibia were unchanged between nephrectomized and sham-operated rats but were significantly increased in older compared to younger animals. A similar trend was observed for geometrical parameters measured with calipers, bone mineral density based on Archimedes' method and image of bone microarchitecture obtained from micro-computed tomography analyses of tibial cortical bone. In nephrectomized animals, peripheral kynurenine levels correlated negatively with the main parameters of bone biomechanics, bone geometry, and bone mineral density values. In conclusion, our data suggest that CKD-induced elevated levels of peripheral kynurenine cause pathological changes in bone structure via AhR pathway. This finding opens new opportunities for the treatment/prevention of osteoporosis in CKD. PMID- 29163190 TI - SR-BI Mediated Transcytosis of HDL in Brain Microvascular Endothelial Cells Is Independent of Caveolin, Clathrin, and PDZK1. AB - The vascular endothelium supplying the brain exhibits very low paracellular and transcellular permeability and is a major constituent of the blood-brain barrier. High-density lipoprotein (HDL) crosses the blood-brain barrier by transcytosis, but technical limitations have made it difficult to elucidate its regulation. Using a combination of spinning-disc confocal and total internal reflection fluorescence microscopy, we examined the uptake and transcytosis of HDL by human primary brain microvascular endothelial cell monolayers. Using these approaches, we report that HDL internalization requires dynamin but not clathrin heavy chain and that its internalization and transcytosis are saturable. Internalized HDL partially co-localized with the scavenger receptor BI (SR-BI) and knockdown of SR BI significantly attenuated HDL internalization. However, we observed that the adaptor protein PDZK1-which is critical to HDL-SR-BI signaling in other tissues is not required for HDL uptake in these cells. Additionally, while these cells express caveolin, the abundance of caveolae in this tissue is negligible and we find that SR-BI and caveolin do not co-fractionate. Furthermore, direct silencing of caveolin-1 had no impact on the uptake of HDL. Finally, inhibition of endothelial nitric oxide synthase increased HDL internalization while increasing nitric oxide levels had no impact. Together, these data indicate that SR-BI mediated transcytosis in brain microvascular endothelial cells is distinct from uptake and signaling pathways described for this receptor in other cell types. PMID- 29163191 TI - Phoenix from the Ashes: Fire, Torpor, and the Evolution of Mammalian Endothermy. PMID- 29163192 TI - Cycling before and after Exhaustion Differently Affects Cardiac Autonomic Control during Heart Rate Matched Exercise. AB - During cycling before (PRE) and after exhaustion (POST) different modes of autonomic cardiac control might occur due to different interoceptive input and altered influences from higher brain centers. We hypothesized that heart rate variability (HRV) is significantly affected by an interaction of the experimental period (PRE vs. POST) and exercise intensity (HIGH vs. LOW; HIGH = HR > HR at the lactate threshold (HRLT), LOW = HR <= HRLT) despite identical average HR. Methods: Fifty healthy volunteers completed an incremental cycling test until exhaustion. Workload started with 30 W at a constant pedaling rate (60 revolutions . min-1) and was gradually increased by 30 W . 5 min-1. Five adjacent 60 s inter-beat (R-R) interval segments from the immediate recovery period (POST 1-5 at 30 W and 60 rpm) were each matched with their HR-corresponding 60 s segments during the cycle test (PRE 1-5). An analysis of covariance was carried out with one repeated-measures factor (PRE vs. POST exhaustion), one between subject factor (HIGH vs. LOW intensity) and respiration rate as covariate to test for significant effects (p < 0.050) on the natural log-transformed root mean square of successive differences between adjacent R-R intervals (lnRMSSD60s). Results: LnRMSSD60s was significantly affected by the interaction of experimental period * intensity [F(1, 242) = 30.233, p < 0.001, eta p2 = 0.111]. LnRMSSD60s was higher during PRE compared to POST at LOW intensity (1.6 +/- 0.6 vs. 1.4 +/- 0.6 ms; p < 0.001). In contrast, at HIGH intensity lnRMSSD60s was lower during PRE compared to POST (1.0 +/- 0.4 vs. 1.2 +/- 0.4 ms; p < 0.001). Conclusion: Identical net HR during cycling can result from distinct autonomic modulation patterns. Results suggest a pronounced sympathetic-parasympathetic coactivation immediately after the cessation of peak workload compared to HR-matched cycling before exhaustion at HIGH intensity. On the opposite, at LOW intensity cycling, a stronger coactivational cardiac autonomic modulation pattern occurs during PRE exhaustion if compared to POST-exhaustion cycling. The different autonomic modes during these phases might be the result of different afferent and/or central inputs to the cardiovascular control centers in the brainstem. PMID- 29163193 TI - Changes in Muscle and Cerebral Deoxygenation and Perfusion during Repeated Sprints in Hypoxia to Exhaustion. AB - During supramaximal exercise, exacerbated at exhaustion and in hypoxia, the circulatory system is challenged to facilitate oxygen delivery to working tissues through cerebral autoregulation which influences fatigue development and muscle performance. The aim of the study was to evaluate the effects of different levels of normobaric hypoxia on the changes in peripheral and cerebral oxygenation and performance during repeated sprints to exhaustion. Eleven recreationally active participants (six men and five women; 26.7 +/- 4.2 years, 68.0 +/- 14.0 kg, 172 +/- 12 cm, 14.1 +/- 4.7% body fat) completed three randomized testing visits in conditions of simulated altitude near sea-level (~380 m, FIO2 20.9%), ~2000 m (FIO2 16.5 +/- 0.4%), and ~3800 m (FIO2 13.3 +/- 0.4%). Each session began with a 12-min warm-up followed by two 10-s sprints and the repeated cycling sprint (10-s sprint: 20-s recovery) test to exhaustion. Measurements included power output, vastus lateralis, and prefrontal deoxygenation [near-infrared spectroscopy, delta (Delta) corresponds to the difference between maximal and minimal values], oxygen uptake, femoral artery blood flow (Doppler ultrasound), hemodynamic variables (transthoracic impedance), blood lactate concentration, and rating of perceived exertion. Performance (total work, kJ; -27.1 +/- 25.8% at 2000 m, p < 0.01 and 49.4 +/- 19.3% at 3800 m, p < 0.001) and pulse oxygen saturation (-7.5 +/- 6.0%, p < 0.05 and -18.4 +/- 5.3%, p < 0.001, respectively) decreased with hypoxia, when compared to 400 m. Muscle Delta hemoglobin difference ([Hbdiff]) and Delta tissue saturation index (TSI) were lower (p < 0.01) at 3800 m than at 2000 and 400 m, and lower Delta deoxyhemoglobin resulted at 3800 m compared with 2000 m. There were reduced changes in peripheral [Delta[Hbdiff], DeltaTSI, Delta total hemoglobin ([tHb])] and greater changes in cerebral (Delta[Hbdiff], Delta[tHb]) oxygenation throughout the test to exhaustion (p < 0.05). Changes in cerebral deoxygenation were greater at 3800 m than at 2000 and 400 m (p < 0.01). This study confirms that performance in hypoxia is limited by continually decreasing oxygen saturation, even though exercise can be sustained despite maximal peripheral deoxygenation. There may be a cerebral autoregulation of increased perfusion accounting for the decreased arterial oxygen content and allowing for task continuation, as shown by the continued cerebral deoxygenation. PMID- 29163194 TI - On the Metabolism of Exogenous Ketones in Humans. AB - Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low carbohydrate "ketogenic" diet, but adherence to such diets can be difficult. An alternative way to increase blood D-beta-hydroxybutyrate (D-betaHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3 hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium betaHB. Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of betaHB. Both drinks elevated blood D betaHB concentrations (D-betaHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3-4 h. KS drinks were found to contain 50% of the L betaHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-betaHB and L-betaHB was <1.5% of the total betaHB ingested and was in proportion to the blood AUC. D-betaHB, but not L-betaHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-betaHB concentrations was determined in 16 participants. Food lowered blood D-betaHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-betaHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-betaHB AUC of 1.3-1.4 moles.min. Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis. PMID- 29163195 TI - Members of Bitter Taste Receptor Cluster Tas2r143/Tas2r135/Tas2r126 Are Expressed in the Epithelium of Murine Airways and Other Non-gustatory Tissues. AB - The mouse bitter taste receptors Tas2r143, Tas2r135, and Tas2r126 are encoded by genes that cluster on chromosome 6 and have been suggested to be expressed under common regulatory elements. Previous studies indicated that the Tas2r143/Tas2r135/Tas2r126 cluster is expressed in the heart, but other organs had not been systematically analyzed. In order to investigate the expression of this bitter taste receptor gene cluster in non-gustatory tissues, we generated a BAC (bacterial artificial chromosome) based transgenic mouse line, expressing CreERT2 under the control of the Tas2r143 promoter. After crossing this line with a mouse line expressing EGFP after Cre-mediated recombination, we were able to validate the Tas2r143-CreERT2 transgenic mouse line and monitor the expression of Tas2r143. EGFP-positive cells, indicating expression of members of the cluster, were found in about 47% of taste buds, and could also be found in several other organs. A population of EGFP-positive cells was identified in thymic epithelial cells, in the lamina propria of the intestine and in vascular smooth muscle cells of cardiac blood vessels. EGFP-positive cells were also identified in the epithelium of organs readily exposed to pathogens including lower airways, the gastrointestinal tract, urethra, vagina, and cervix. With respect to the function of cells expressing this bitter taste receptor cluster, RNA-seq analysis in EGFP positive cells isolated from the epithelium of trachea and stomach showed expression of genes related to innate immunity. These data further support the concept that bitter taste receptors serve functions outside the gustatory system. PMID- 29163196 TI - An Inertial Sensor-Based Method for Estimating the Athlete's Relative Joint Center Positions and Center of Mass Kinematics in Alpine Ski Racing. AB - For the purpose of gaining a deeper understanding of the relationship between external training load and health in competitive alpine skiing, an accurate and precise estimation of the athlete's kinematics is an essential methodological prerequisite. This study proposes an inertial sensor-based method to estimate the athlete's relative joint center positions and center of mass (CoM) kinematics in alpine skiing. Eleven inertial sensors were fixed to the lower and upper limbs, trunk, and head. The relative positions of the ankle, knee, hip, shoulder, elbow, and wrist joint centers, as well as the athlete's CoM kinematics were validated against a marker-based optoelectronic motion capture system during indoor carpet skiing. For all joints centers analyzed, position accuracy (mean error) was below 110 mm and precision (error standard deviation) was below 30 mm. CoM position accuracy and precision were 25.7 and 6.7 mm, respectively. Both the accuracy and precision of the system to estimate the distance between the ankle of the outside leg and CoM (measure quantifying the skier's overall vertical motion) were found to be below 11 mm. Some poorer accuracy and precision values (below 77 mm) were observed for the athlete's fore-aft position (i.e., the projection of the outer ankle-CoM vector onto the line corresponding to the projection of ski's longitudinal axis on the snow surface). In addition, the system was found to be sensitive enough to distinguish between different types of turns (wide/narrow). Thus, the method proposed in this paper may also provide a useful, pervasive way to monitor and control adverse external loading patterns that occur during regular on-snow training. Moreover, as demonstrated earlier, such an approach might have a certain potential to quantify competition time, movement repetitions and/or the accelerations acting on the different segments of the human body. However, prior to getting feasible for applications in daily training, future studies should primarily focus on a simplification of the sensor setup, as well as a fusion with global navigation satellite systems (i.e., the estimation of the absolute joint and CoM positions). PMID- 29163197 TI - Variation in Enamel Formation Genes Influences Enamel Demineralization In Vitro in a Streptococcus mutans Biofilm Model. AB - Genetic studies have shown that variations in enamel formation genes are associated with caries susceptibility. The aim of this study was to test in vitro whether variants in these genes are associated with dental enamel demineralization in a Streptococcus mutans biofilm model. DNA and enamel samples were obtained from 213 individuals. DNA was extracted from saliva, and 16 single nucleotide polymorphisms were analyzed. The physical and chemical properties of sound enamel samples and the mineral loss and the lesion depth of the demineralized enamel samples under cariogenic challenge were analyzed. Microhardness, enamel chemicals, mineral loss and demineralization depth were compared between different genotypes at each single nucleotide polymorphism. The GG genotype of TUFT1 (rs17640579) and the GT genotype of MMP20 (rs1612069) exhibited increased microhardness (p = 0.044 and 0.016, respectively). The GG genotype of AMBN (rs7694409) had a higher magnesium level, while the CT genotype of TFIP11 (rs2097470) had a lower magnesium level (p = 0.044 and 0.046, respectively). The GT genotype of MMP20 (rs1612069) had a higher calcium level (p = 0.034). The GG genotype of AMBN (rs13115627), the AG genotype of ENAM (rs12640848) and the AA genotype of MMP20 (rs2292730) had a lower phosphorus level (p = 0.012, 0.006, and 0.023, respectively). The GG genotype of AMBN (rs13115627) was also associated with a higher calcium-phosphorus ratio (p = 0.034). Individuals with the CC genotype of TFIP11 (rs134143) exhibited significantly more mineral loss (p = 0.011) and a deeper lesions (p = 0.042). Individuals with the TT genotype of TFIP11 (rs2097470) had more mineral loss (p = 0.018). Individuals with the GG genotype of TUFT1 (rs17640579) exhibited a shallower demineralization depth (p = 0.047). Individuals with the GT genotype of MMP20 (rs1612069) exhibited a shallower demineralization depth (p = 0.042). Individuals with the GG genotype of ENAM (rs12640848) exhibited less mineral loss (p = 0.01) and a shallower demineralization depth (p = 0.03). Genetic variations in TFIP11, TUFT1, MMP20, and ENAM influenced enamel demineralization in a Streptococcus mutans biofilm model. PMID- 29163198 TI - Ankyrins and Spectrins in Cardiovascular Biology and Disease. AB - Ankyrins are adaptor proteins critical for the expression and targeting of cardiac membrane proteins, signaling molecules, and cytoskeletal elements. Findings in humans and animal models have highlighted the in vivo roles for ankyrins in normal physiology and in cardiovascular disease, most notably in cardiac arrhythmia. For example, human ANK2 loss-of-function variants are associated with a complex array of electrical and structural phenotypes now termed "ankyrin-B syndrome," whereas alterations in the ankyrin-G pathway for Nav channel targeting are associated with human Brugada syndrome. Further, both ankyrin-G and -B are now linked with acquired forms of cardiovascular disease including myocardial infarction and atrial fibrillation. Spectrins are ankyrin associated proteins and recent studies support the critical role of ankyrin spectrin interactions in normal cardiac physiology as well as regulation of key ion channel and signaling complexes. This review will highlight the roles of ankyrins and spectrins in cardiovascular physiology as well as illustrate the link between the dysfunction in ankyrin- and spectrin-based pathways and disease. PMID- 29163200 TI - A Pulse Wave Velocity Based Method to Assess the Mean Arterial Blood Pressure Limits of Autoregulation in Peripheral Arteries. AB - Background: Constant blood flow despite changes in blood pressure, a phenomenon called autoregulation, has been demonstrated for various organ systems. We hypothesized that by changing hydrostatic pressures in peripheral arteries, we can establish these limits of autoregulation in peripheral arteries based on local pulse wave velocity (PWV). Methods: Electrocardiogram and plethysmograph waveforms were recorded at the left and right index fingers in 18 healthy volunteers. Each subject changed their left arm position, keeping the right arm stationary. Pulse arrival times (PAT) at both fingers were measured and used to calculate PWV. We calculated DeltaPAT (DeltaPWV), the differences between the left and right PATs (PWVs), and compared them to the respective calculated blood pressure at the left index fingertip to derive the limits of autoregulation. Results: DeltaPAT decreased and DeltaPWV increased exponentially at low blood pressures in the fingertip up to a blood pressure of 70 mmHg, after which changes in DeltaPAT and DeltaPWV were minimal. The empirically chosen 20 mmHg window (75 95 mmHg) was confirmed to be within the autoregulatory limit (slope = 0.097, p = 0.56). DeltaPAT and DeltaPWV within a 20 mmHg moving window were not significantly different from the respective data points within the control 75-95 mmHg window when the pressure at the fingertip was between 56 and 110 mmHg for DeltaPAT and between 57 and 112 mmHg for DeltaPWV. Conclusions: Changes in hydrostatic pressure due to changes in arm position significantly affect peripheral arterial stiffness as assessed by DeltaPAT and DeltaPWV, allowing us to estimate peripheral autoregulation limits based on PWV. PMID- 29163199 TI - Slow Breathing Can Be Operantly Conditioned in the Rat and May Reduce Sensitivity to Experimental Stressors. AB - In humans, exercises involving slowed respiratory rate (SRR) counter autonomic sympathetic bias and reduce responses to stressors, including in individuals with various degrees of autonomic dysfunction. In the rat, we examined whether operant conditioning could lead to reductions in respiratory rate (RR) and performed preliminary studies to assess whether conditioned SRR was sufficient to decrease physiological and behavioral responsiveness to stressors. RR was continuously monitored during 20 2-h sessions using whole body plethysmography. SRR conditioned, but not yoked control rats, were able to turn off aversive visual stimulation (intermittent bright light) by slowing their breathing below a preset target of 80 breaths/min. SRR conditioned rats greatly increased the incidence of breaths below the target RR over training, with average resting RR decreasing from 92 to 81 breaths/min. These effects were significant as a group and vs. yoked controls. Preliminary studies in a subset of conditioned rats revealed behavioral changes suggestive of reduced reactivity to stressful and nociceptive stimuli. In these same rats, intermittent sessions without visual reinforcement and a post-training priming stressor (acute restraint) demonstrated that conditioned rats retained reduced RR vs. controls in the absence of conditioning. In conclusion, we present the first successful attempt to operantly condition reduced RR in an animal model. Although further studies are needed to clarify the physio-behavioral concomitants of slowed breathing, the developed model may aid subsequent neurophysiological inquiries on the role of slow breathing in stress reduction. PMID- 29163201 TI - Short-Term High- and Moderate-Intensity Training Modifies Inflammatory and Metabolic Factors in Response to Acute Exercise. AB - Purpose: To compare the acute and chronic effects of high intensity intermittent training (HIIT) and steady state training (SST) on the metabolic profile and inflammatory response in physically active men. Methods: Thirty recreationally active men were randomly allocated to a control group (n = 10), HIIT group (n = 10), or SST group (n = 10). For 5 weeks, three times per week, subjects performed HIIT (5 km 1-min at 100% of maximal aerobic speed interspersed by 1-min passive recovery) or SST (5 km at 70% of maximal aerobic speed) while the control group did not perform training. Blood samples were collected at fasting (~12 h), pre exercise, immediately post, and 60 min post-acute exercise session (pre- and post 5 weeks training). Blood samples were analyzed for glucose, non-ester fatty acid (NEFA), and cytokine (IL-6, IL-10, and TNF-alpha) levels through a three-way analysis (group, period, and moment of measurement) with repeated measures in the second and third factors. Results: The results showed an effect of moment of measurement (acute session) with greater values to TNF-alpha and glucose immediately post the exercise when compared to pre exercise session, independently of group or training period. For IL-6 there was an interaction effect for group and moment of measurement (acute session) the increase occurred immediately post-exercise session and post-60 min in the HIIT group while in the SST the increase was observed only 60 min post, independently of training period. For IL-10, there was an interaction for training period (pre- and post-training) and moment of measurement (acute session), in which in pre-training, pre-exercise values were lower than immediately and 60 min post-exercise, in post-training period pre-exercise values were lower than immediately post-exercise and immediately post-exercise lower than 60 min post, it was also observed that values immediately post-exercise were lower pre- than post-training, being all results independently of intensity (group). Conclusion: Our main result point to an interaction (acute and chronic) for IL-10 showing attenuation post-training period independent of exercise intensity. PMID- 29163202 TI - Comparison of Peak Oxygen Uptake and Test-Retest Reliability of Physiological Parameters between Closed-End and Incremental Upper-Body Poling Tests. AB - Objective: To compare peak oxygen uptake (VO2peak) and the test-retest reliability of physiological parameters between a 1-min and a 3-min closed-end and an incremental open-end upper-body poling test. Methods: On two separate test days, 24 healthy, upper-body trained men (age: 28.3 +/- 9.3 years, body mass: 77.4 +/- 8.9 kg, height: 182 +/- 7 cm) performed a 1-min, a 3-min and an incremental test to volitional exhaustion in the same random order. Respiratory parameters, heart rate (HR), blood lactate concentration (BLa), rating of perceived exertion (RPE), and power output were measured. VO2peak was determined as the single highest 30-s average. Relative reliability was assessed with the intra-class correlation coefficient (ICC2, 1) and absolute reliability with the standard error of measurement (SEM) and smallest detectable change (SDC). Results: The incremental (3.50 +/- 0.46 L.min-1 and 45.4 +/- 5.5 mL.kg-1.min-1) and the 3-min test (3.42 +/- 0.47 L.min-1 and 44.5 +/- 5.5 mL.kg-1.min-1) resulted in significantly higher absolute and body-mass normalized VO2peak compared to the 1-min test (3.13 +/- 0.40 L.min-1 and 40.4 +/- 5.0 mL.kg-1.min-1) (all comparisons, p < 0.001). Furthermore, the incremental test resulted in a significantly higher VO2peak as compared to the 3-min test (p < 0.001). VO2peak was significantly higher on day 1 than day 2 for the 1-min test (p < 0.05) and displayed a trend toward higher values on day 2 for the incremental test (p = 0.07). High and very high ICCs across all physiological parameters were found for the 1-min (0.827-0.956), the 3-min (0.916-0.949), and the incremental test (0.728 0.956). The SDC was consistently small for HR (1-min: 4%, 3-min: 4%, incremental: 3%), moderate for absolute and body-mass normalized VO2peak (1-min: 5%, 3-min: 6%, incremental: 7%) and large for BLa (1-min: 20%, 3-min: 12%, incremental: 22%). Conclusions: Whereas both the 3-min and the incremental test display high relative reliability, the incremental test induces slightly higher VO2peak. However, the 3-min test seems to be more stable with respect to day-to-day differences in VO2peak. The 1-min test would provide a reliable alternative when short test-duration is desirable, but is not recommended for testing VO2peak due to the clearly lower values. PMID- 29163203 TI - Cyclic Stretch Alters Vascular Reactivity of Mouse Aortic Segments. AB - Large, elastic arteries buffer the pressure wave originating in the left ventricle and are constantly exposed to higher amplitudes of cyclic stretch (10%) than muscular arteries (2%). As a crucial factor for endothelial and smooth muscle cell function, cyclic stretch has, however, never been studied in ex vivo aortic segments of mice. To investigate the effects of cyclic stretch on vaso reactivity of mouse aortic segments, we used the Rodent Oscillatory Tension Set up to study Arterial Compliance (ROTSAC). The aortic segments were clamped at frequencies of 6-600 bpm between two variable preloads, thereby mimicking dilation as upon left ventricular systole and recoiling as during diastole. The preloads corresponding to different transmural pressures were chosen to correspond to a low, normal or high amplitude of cyclic stretch. At different time intervals, cyclic stretch was interrupted, the segments were afterloaded and isometric contractions by alpha1-adrenergic stimulation with 2 MUM phenylephrine in the absence and presence of 300 MUM L-NAME (eNOS inhibitor) and/or 35 MUM diltiazem (blocker of voltage-gated Ca2+ channels) were measured. As compared with static or cyclic stretch at low amplitude (<10 mN) or low frequency (0.1 Hz), cyclic stretch at physiological amplitude (>10 mN) and frequency (1-10 Hz) caused better ex vivo conservation of basal NO release with time after mounting. The relaxation of PE-precontracted segments by addition of ACh to stimulate NO release was unaffected by cyclic stretch. In the absence of basal NO release (hence, presence of L-NAME), physiological in comparison with aberrant cyclic stretch decreased the baseline tension, attenuated the phasic contraction by phenylephrine in the absence of extracellular Ca2+ and shifted the smaller tonic contraction more from a voltage-gated Ca2+ channel-mediated to a non-selective cation channel-mediated. Data highlight the need of sufficient mechanical activation of endothelial and vascular smooth muscle cells to maintain basal NO release and low intracellular Ca2+ in the smooth muscle cells in large arteries. Both phenomena may play a vital role in maintaining the high compliance of large arteries. PMID- 29163204 TI - The Effect of Being Aerobically Active vs. Inactive on Cutaneous Vascular Conductance during Local Heat Stress in an Older Population. AB - Objective: To test the hypothesis that long- term aerobically trained elderly individuals have a greater amount of bioavailable nitric oxide (NO) and have a larger cutaneous vasodilation during local heat stress compared to their inactive elderly counterparts. Methods: Eight aerobically trained and 8 inactive older men (>60 years old) participated in this study. NO bioavailability in blood and intradermal dialysate were measured with an ozone based chemiluminescence NO analyzer. Cutaneous vasodilator response to local heating was obtained using laser Doppler velocimetry. Results: Whole blood NO were similar in older- trained and inactive subjects (0.75 +/- 0.56 and 0.38 +/- 0.32 MUM, respectively; Mann Whitney, p = 0.153), as was intradermal dialysate NO before (7.82 +/- 6.32 and 4.18 +/- 1.89 MUM, respectively) and after local heating (7.16 +/- 6.27 and 5.88 +/- 3.97 MUM, respectively, p = 0.354). The cutaneous vasodilator response of the older- inactive group was smaller than the older- trained group [Group-Time interaction, F(24, 264) = 12.0, p < 0.0001]. When compared to a young group the peak vasodilator response of the older- trained subjects was similar. However, the time to initial dilation was 3.1 and 2.2 times longer (p < 0.05) in older- inactive and older- trained subjects, respectively, compared to young subjects. Conclusions: Our data support the hypothesis that the age-related reductions in cutaneous vasodilation can possibly be restored by maintaining an aerobic training regimen (at least 3 years). However, some residual effects of aging remain, specifically a delayed cutaneous vasodilator response to local heating is still present in active older adults. We found no evidence for an increase in systemic or local NO-bioavailability with an extended commitment to aerobic fitness. PMID- 29163205 TI - Localization and Interaction between Kinin B1 Receptor and NADPH Oxidase in the Vascular System of Diabetic Rats. AB - Kinin B1 receptor (B1R) enhanced superoxide anion ([Formula: see text]) production in the vasculature of diabetic rats. This study investigates the induction and distribution of B1R in diabetic blood vessels and addresses the hypothesis that B1R is co-localized with NADPH oxidase (NOX1 and NOX2) and produces its activation via protein kinase C (PKC). Diabetes was induced in rats with streptozotocin (STZ 65 mg.kg-1, i.p.). Two weeks later, the production of [Formula: see text] was measured in aorta rings in response to the B1R agonist (Sar[D-Phe8]-des-Arg9-BK, 20 MUM) by the method of lucigenin-enhanced chemiluminescence. Various inhibitors were added (10 MUM) to block PKCtotal (Ro 31-8220), PKCbeta1/2 (LY333531), or NADPH oxidase (Diphenyleneiodonium). The cellular localization of B1R was studied in the aorta, popliteal artery, and renal glomerulus/arteries by immunofluorescence and confocal microscopy with markers of endothelial cells (anti-RECA-1), macrophages (anti-CD11), vascular smooth muscle cells (anti-SMA), and NADPH oxidase (anti-NOX1 and NOX2). Although B1R was largely distributed in resistant vessels, it was sparsely expressed in the aorta's endothelium. The greater basal production of [Formula: see text] in STZ-diabetic aorta was significantly enhanced by the B1R agonist (15-45 min). The peak response to the agonist (30 min) was inhibited by all inhibitors. Immunofluorescent staining for B1R, NOX1, and NOX2 was significantly increased in endothelial cells, vascular smooth muscle cells, and macrophages of STZ-diabetic aorta on which they were found co-localized. Data showed that B1R enhanced [Formula: see text] by activating vascular NADPH oxidase through PKCbeta1/2. This was substantiated by the cellular co-localization of B1R with NOX1 and NOX2 and opens the possibility that B1R-enhanced oxidative stress is derived from vascular and infiltrating immune cells in diabetes. PMID- 29163206 TI - Hepatocyte Ploidy Is a Diversity Factor for Liver Homeostasis. AB - Polyploidy, the existence of cells containing more than one pair of chromosomes, is a well-known feature of mammalian hepatocytes. Polyploid hepatocytes are found either as cells with a single polyploid nucleus or as multinucleated cells with diploid or even polyploid nuclei. In this study, we evaluate the degree of polyploidy in the murine liver by accounting both DNA content and number of nuclei per cell. We demonstrate that mouse hepatocytes with diploid nuclei have distinct metabolic characteristics compared to cells with polyploid nuclei. In addition to strong differential gene expression, comprising metabolic as well as signaling compounds, we found a strongly decreased insulin binding of nuclear polyploid cells. Our observations were associated with nuclear ploidy but not with total ploidy within a cell. We therefore suggest ploidy of the nuclei as an new diversity factor of hepatocytes and hypothesize that hepatocytes with polyploid nuclei may have distinct biological functions than mono-nuclear ones. This diversity is independent from the well-known heterogeneity related to the cells' position along the porto-central liver-axis. PMID- 29163207 TI - A New Personalized Cooling Protocol to Activate Brown Adipose Tissue in Young Adults. AB - Brown adipose tissue (BAT) activity is induced when humans are exposed to cold. Therefore, cold exposure prior to the 18F-FDG-PET/CT scan is used as a tool to quantify BAT. Several cooling protocols, including fixed and personalized ones are currently in use. The aim of the present study was to determine the effect of a new personalized cooling protocol where the shivering threshold was measured on a separate day, on BAT volume and activity in young adults. A total of 47 adults (n = 28 women) aged 22 +/- 2 years participated in the study. We determined participants' shivering threshold (visually and self-reported) using a water perfused cooling vest in an air-conditioned cold room. 48-72 h later, participants wore the cooling vest set at ~4 degrees C above the shivering threshold for 60 min prior to injection of 18F-FDG and ~5 degrees C above the shivering threshold for ~60 min after injection, until PET/CT scan. We quantified BAT following BARCIST 1.0 recommendations. We identified 40 participants (85%, n = 25 women) as PET+ and 7 (n = 3 women) as PET-. The PET+ group presented significantly higher BAT volume and activity than PET- group (all P < 0.05). PET+ women had higher BAT mean activity than PET+ men (SUVmean: 5.0 +/- 1.6 vs. 3.6 +/ 0.9 g/ml respectively, P = 0.003), and there were no significant sex differences in BAT volume (P = 0.161). A total of 9 out of 47 participants did not shiver during the shivering threshold test. Our findings are similar to previous cold stimulated human BAT studies; therefore, we conclude that our personalized cooling protocol is able to activate BAT in young adults. PMID- 29163208 TI - Circadian Alterations in a Murine Model of Hypothalamic Glioma. AB - The mammalian circadian system is controlled by a central oscillator located in the suprachiasmatic nuclei (SCN) of the hypothalamus, in which glia appears to play a prominent role. Gliomas originate from glial cells and are the primary brain tumors with the highest incidence and mortality. Optic pathway/hypothalamic gliomas account for 4-7% of all pediatric intracranial tumors. Given the anatomical location, which compromises both the circadian pacemaker and its photic input pathway, we decided to study whether the presence of gliomas in the hypothalamic region could alter circadian behavioral outputs. Athymic nude mice implanted with LN229 human glioma cells showed an increase in the endogenous period of the circadian clock, which was also less robust in terms of sustaining the free running period throughout 2 weeks of screening. We also found that implanted mice showed a slower resynchronization rate after an abrupt 6 h advance of the light-dark (LD) cycle, advanced phase angle, and a decreased direct effect of light in general activity (masking), indicating that hypothalamic tumors could also affect photic sensitivity of the circadian clock. Our work suggests that hypothalamic gliomas have a clear impact both on the endogenous pacemaking of the circadian system, as well as on the photic synchronization of the clock. These findings strongly suggest that the observation of altered circadian parameters in patients might be of relevance for glioma diagnosis. PMID- 29163209 TI - The Role of Cholecystokinin in Peripheral Taste Signaling in Mice. AB - Cholecystokinin (CCK) is a gut hormone released from enteroendocrine cells. CCK functions as an anorexigenic factor by acting on CCK receptors expressed on the vagal afferent nerve and hypothalamus with a synergistic interaction between leptin. In the gut, tastants such as amino acids and bitter compounds stimulate CCK release from enteroendocrine cells via activation of taste transduction pathways. CCK is also expressed in taste buds, suggesting potential roles of CCK in taste signaling in the peripheral taste organ. In the present study, we focused on the function of CCK in the initial responses to taste stimulation. CCK was coexpressed with type II taste cell markers such as Galpha-gustducin, phospholipase Cbeta2, and transient receptor potential channel M5. Furthermore, a small subset (~30%) of CCK-expressing taste cells expressed a sweet/umami taste receptor component, taste receptor type 1 member 3, in taste buds. Because type II taste cells are sweet, umami or bitter taste cells, the majority of CCK expressing taste cells may be bitter taste cells. CCK-A and -B receptors were expressed in both taste cells and gustatory neurons. CCK receptor knockout mice showed reduced neural responses to bitter compounds compared with wild-type mice. Consistently, intravenous injection of CCK-Ar antagonist lorglumide selectively suppressed gustatory nerve responses to bitter compounds. Intravenous injection of CCK-8 transiently increased gustatory nerve activities in a dose-dependent manner whereas administration of CCK-8 did not affect activities of bitter sensitive taste cells. Collectively, CCK may be a functionally important neurotransmitter or neuromodulator to activate bitter nerve fibers in peripheral taste tissues. PMID- 29163210 TI - A "Wearable" Test for Maximum Aerobic Power: Real-Time Analysis of a 60-m Sprint Performance and Heart Rate Off-Kinetics. AB - Maximum aerobic power ([Formula: see text]) as an indicator of body fitness is today a very well-known concept not just for athletes but also for the layman. Unfortunately, the accurate measurement of that variable has remained a complex and exhaustive laboratory procedure, which makes it inaccessible to many active people. In this paper we propose a quick estimate of it, mainly based on the heart rate off-kinetics immediately after an all-out 60-m sprint run. The design of this test took into account the recent availability of wrist wearable, heart band free, multi-sensor smart devices, which could also inertially detect the different phases of the sprint and check the distance run. 25 subjects undertook the 60-m test outdoor and a [Formula: see text] test on the laboratory treadmill. Running average speed, HR excursion during the sprint and the time constant (tau) of HR exponential decay in the off-kinetics were fed into a multiple regression, with measured [Formula: see text] as the dependent variable. Statistics revealed that within the investigated range (25-55 ml O2/(kg min)), despite a tendency to overestimate low values and underestimate high values, the three predictors confidently estimate individual [Formula: see text] (R2 = 0.65, p < 0.001). The same analysis has been performed on a 5-s averaged time course of the same measured HR off-kinetics, as these are the most time resolved data for HR provided by many modern smart watches. Results indicate that despite of the substantial reduction in sample size, predicted [Formula: see text] still explain 59% of the variability of the measured [Formula: see text]. PMID- 29163211 TI - Oxidative Stress in the Local and Systemic Events of Apical Periodontitis. AB - Oxidative stress is involved in the pathogenesis of a variety of inflammatory disorders. Apical periodontitis (AP) usually results in the formation of an osteolytic apical lesion (AL) caused by the immune response to endodontic infection. Reactive oxygen species (ROS) produced by phagocytic cells in response to bacterial challenge represent an important host defense mechanism, but disturbed redox balance results in tissue injury. This mini review focuses on the role of oxidative stress in the local and associated systemic events in chronic apical periodontitis. During endodontic infection, ligation of Toll-like receptors (TLRs) on phagocytes' surface triggers activation, phagocytosis, synthesis of ROS, activation of humoral and cellular responses, and production of inflammatory mediators, such as, cytokines and matrix metalloproteinases (MMPs). The increment in ROS perturbs the normal redox balance and shifts cells into a state of oxidative stress. ROS induce molecular damage and disturbed redox signaling, that result in the loss of bone homeostasis, increased pro inflammatory mediators, and MMP overexpression and activation, leading to apical tissue breakdown. On the other hand, oxidative stress has been strongly involved in the pathogenesis of atherosclerosis, where a chronic inflammatory process develops in the arterial wall. Chronic AP is associated with an increased risk of cardiovascular diseases (CVD) and especially atherogenesis. The potential mechanisms linking these diseases are also discussed. PMID- 29163213 TI - Effect of Human Amnion Epithelial Cells on the Acute Inflammatory Response in Fetal Sheep. AB - Intra-amniotic (IA) lipopolysaccharide (LPS) injection in sheep induces inflammation in the fetus. Human amnion epithelial cells (hAECs) moderate the effect of IA LPS on fetal development, but their influence on the acute inflammatory response to IA LPS is unknown. We aimed to determine the effects of hAECs on the acute fetal inflammatory response to IA LPS. After surgical instrumentation at 116 days' gestation (d) ewes were randomized to 1 of 4 groups at 123 d: IA LPS (10 mg) and intravenous (IV) saline (n = 8), IA LPS and IV hAECs (n = 6), IA saline and IV saline (n = 5) or IA saline and IV hAECs (n = 5). IV injections were administered immediately after IA injections. Serial fetal blood samples were collected. At 125 d, placental, fetal lung and liver samples were collected. IA LPS increased inflammatory cell recruitment in the placenta and lungs, increased IL-1beta and IL-8 mRNA levels in the lungs and increased serum amyloid A3 (SAA3) and C-reactive protein (CRP) mRNA levels in the liver. IV hAECs reduced fetal lung inflammatory cell recruitment but did not otherwise alter indices of placental, fetal lung or liver inflammation. The acute fetal inflammatory response to IA LPS is not substantially altered by IV hAEC treatment. PMID- 29163212 TI - Regulation of Skeletal Muscle Plasticity by Protein Arginine Methyltransferases and Their Potential Roles in Neuromuscular Disorders. AB - Protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the methylation of arginine residues on target proteins, thereby mediating a diverse set of intracellular functions that are indispensable for survival. Indeed, full-body knockouts of specific PRMTs are lethal and PRMT dysregulation has been implicated in the most prevalent chronic disorders, such as cancers and cardiovascular disease (CVD). PRMTs are now emerging as important mediators of skeletal muscle phenotype and plasticity. Since their first description in muscle in 2002, a number of studies employing wide varieties of experimental models support the hypothesis that PRMTs regulate multiple aspects of skeletal muscle biology, including development and regeneration, glucose metabolism, as well as oxidative metabolism. Furthermore, investigations in non-muscle cell types strongly suggest that proteins, such as peroxisome proliferator-activated receptor-gamma coactivator-1alpha, E2F transcription factor 1, receptor interacting protein 140, and the tumor suppressor protein p53, are putative downstream targets of PRMTs that regulate muscle phenotype determination and remodeling. Recent studies demonstrating that PRMT function is dysregulated in Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and amyotrophic lateral sclerosis (ALS) suggests that altering PRMT expression and/or activity may have therapeutic value for neuromuscular disorders (NMDs). This review summarizes our understanding of PRMT biology in skeletal muscle, and identifies uncharted areas that warrant further investigation in this rapidly expanding field of research. PMID- 29163214 TI - Predictive Value of Dynamic Cerebral Autoregulation Assessment in Surgical Management of Patients with High-Grade Carotid Artery Stenosis. AB - Dynamic cerebral autoregulation (DCA) capacity along with the degree of internal carotid artery (ICA) stenosis and characteristics of the plaque can also play an important role in selection of appropriate treatment strategy. This study aims to classify the patients with severe ICA stenosis according to preoperative state of DCA and to assess its dynamics after surgery. Thirty-five patients with severe ICA stenosis having different clinical type of disease underwent reconstructive surgery. DCA was assessed with transfer function analysis (TFA) by calculating phase shift (PS) between Mayer waves of blood flow velocity (BFV) and blood pressure (BP) before and after operation. In 18 cases, regardless of clinical type, preoperative PS on ipsilateral side was within the normal range and did not change considerably after surgery. In other 17 cases preoperative PS was reliably lower both in patients with symptomatic and asymptomatic stenosis. Surgical reconstruction led to restoration of impaired DCA evidenced by significant increase of PS in postoperative period. Our data suggest that regardless clinical type of disease various state of DCA may be present in patients with severe ICA stenosis. This finding can contribute to establishing the optimal treatment strategy, and first of all for asymptomatic patients. Patients with compromised DCA should be considered as ones with higher risk of stroke and first candidates for reconstructive surgery. PMID- 29163215 TI - Implantable Cardioverter-Defibrillator in Dilated Cardiomyopathy after the DANISH Trial Lesson. A Poly-Parametric Risk Evaluation Is Needed to Improve the Selection of Patients. PMID- 29163216 TI - Distinct Mechanism of Cysteine Oxidation-Dependent Activation and Cold Sensitization of Human Transient Receptor Potential Ankyrin 1 Channel by High and Low Oxaliplatin. AB - Oxaliplatin, a third-generation platinum-based chemotherapeutic agent, displays unique acute peripheral neuropathy triggered or enhanced by cold, and accumulating evidence suggests that transient receptor potential ankyrin 1 (TRPA1) is responsible. TRPA1 is activated by oxaliplatin via a glutathione sensitive mechanism. However, oxaliplatin interrupts hydroxylation of a proline residue located in the N-terminal region of TRPA1 via inhibition of prolyl hydroxylase (PHD), which causes sensitization of TRPA1 to reactive oxygen species (ROS). Furthermore, PHD inhibition endows cold-insensitive human TRPA1 (hTRPA1) with ROS-dependent cold sensitivity. Since cysteine oxidation and proline hydroxylation regulate its activity, their association with oxaliplatin-induced TRPA1 activation and acquirement of cold sensitivity were investigated in the present study. A high concentration of oxaliplatin (1 mM) induced outward rectifier whole-cell currents and increased the intracellular Ca2+ concentration in hTRPA1-expressing HEK293 cells, but did not increase the probability of hTRPA1 channel opening in the inside-out configuration. Oxaliplatin also induced the rapid generation of hydrogen peroxide, and the resultant Ca2+ influx was prevented in the presence of glutathione and in cysteine-mutated hTRPA1 (Cys641Ser)-expressing cells, whereas proline-mutated hTRPA1 (Pro394Ala) expressing cells showed similar whole-cell currents and Ca2+ influx. By contrast, a lower concentration of oxaliplatin (100 MUM) did not increase the intracellular Ca2+ concentration but did confer cold sensitivity on hTRPA1-expressing cells, and this was inhibited by PHD2 co-overexpression. Cold sensitivity was abolished by the mitochondria-targeting ROS scavenger mitoTEMPO and was minimal in cysteine mutated hTRPA1 (Cys641Ser or Cys665Ser)-expressing cells. Thus, high oxaliplatin evokes ROS-mediated cysteine oxidation-dependent hTRPA1 activation independent of PHD activity, while a lower concentration induces cold-induced cysteine oxidation dependent opening of hTRPA1 via PHD inhibition. PMID- 29163217 TI - Different Principles of ADP-Ribose-Mediated Activation and Opposite Roles of the NUDT9 Homology Domain in the TRPM2 Orthologs of Man and Sea Anemone. AB - A decisive element in the human cation channel TRPM2 is a region in its cytosolic C-terminus named NUDT9H because of its homology to the NUDT9 enzyme, a pyrophosphatase degrading ADP-ribose (ADPR). In hTRPM2, however, the NUDT9H domain has lost its enzymatic activity but serves as a binding domain for ADPR. As consequence of binding, gating of the channel is initiated. Since ADPR is produced after oxidative DNA damage, hTRPM2 mediates Ca2+ influx in response to oxidative stress which may lead to cell death. In the genome of the sea anemone Nematostella vectensis (nv), a preferred model organism for the evolution of key bilaterian features, a TRPM2 ortholog has been identified that contains a NUDT9H domain as well. Heterologous expression of nvTRPM2 in HEK-293 cells reveals a cation channel with many close similarities to the human counterpart. Most notably, nvTRPM2 is activated by ADPR, and Ca2+ is a co-agonist. However, the intramolecular mechanisms of ADPR gating as well as the role of NUDT9H are strikingly different in the two species. Whereas already subtle changes of NUDT9H abolish ADPR gating in hTRPM2, the region can be completely removed from nvTRPM2 without loss of responses to ADPR. An alternative ADPR binding site seems to be present but has not yet been characterized. The ADP-ribose pyrophosphatase (ADPRase) function of nvNUDT9H has been preserved but can be abolished by numerous genetic manipulations. All these manipulations create channels that are sensitive to hydrogen peroxide which fails to induce channel activity in wild type nvTRPM2. Therefore, the function of NUDT9H in nvTRPM2 is the degradation of ADPR, thereby reducing agonist concentration in the presence of oxidative stress. Thus, the two TRPM2 orthologs have evolved divergently but nevertheless gained analogous functional properties, i.e., gating by ADPR with Ca2+ as co-factor. Opposite roles are played by the respective NUDT9H domains, either binding of ADPR and mediating channel activity, or controlling the availability of ADPR at the binding site located in a different domain. PMID- 29163218 TI - Exosomes and Metabolic Function in Mice Exposed to Alternating Dark-Light Cycles Mimicking Night Shift Work Schedules. AB - Sleep is an important modulator of metabolic function. Disruptions of sleep in circadian rhythm are common in modern societies and are associated with increased risk of developing cardiometabolic disorders. Exosomes are ubiquitous extracellular vesicles that may play a mechanistic role in metabolic derangements. We hypothesized that alternating dark-light cycles mimicking shift work in mice would alter fecal microbiota and colonic epithelium permeability and alter plasma exosome cargo and metabolic function. C57BL/6 mice were randomly assigned to (i) control day light (CL), or (ii) inverted dark-light every 2 weeks for 8 weeks (IN). Body weight, fat mass and HOMA-IR were measured, along with Tregs, metabolic, and resident macrophages in visceral white adipose tissue (vWAT). Fecal water samples were incubated with confluent colonic epithelium cell cultures in electric cell-substrate impedance sensing (ECIS) arrays, and plasma exosomes were added to differentiated adipocytes and insulin-induced pAKT/AKT expression changes were assessed by western blots. Mice exposed to IN showed elevated HOMA-IR, and their fecal samples showed altered microbiota which promote increased permeability of the colonic epithelial cell barrier. Plasma exosomes decreased pAKT/AKT responses to exogenous insulin compared to CL, and altered expression of circadian clock genes. Inflammatory macrophages (Ly-6chigh) were increased in IN-exposed vWAT, while Tregs were decreased. Thus, gut microbiota and the cargo of plasma exosomes are altered by periodic shifts in environmental lighting, and effectively alter metabolic function, possibly via induction of systemic inflammation and altered clock expression in target tissues. Further exploration of exosomal miRNA signatures in shift workers and their putative metabolic organ cell targets appears warranted. PMID- 29163219 TI - Neuromuscular Training Improves Lower Extremity Biomechanics Associated with Knee Injury during Landing in 11-13 Year Old Female Netball Athletes: A Randomized Control Study. AB - The purpose of this study was to examine the effects of a neuromuscular training (NMT) program on lower-extremity biomechanics in youth female netball athletes. The hypothesis was that significant improvements would be found in landing biomechanics of the lower-extremities, commonly associated with anterior cruciate ligament (ACL) injury, following NMT. Twenty-three athletes (age = 12.2 +/- 0.9 years; height = 1.63 +/- 0.08 m; mass = 51.8 +/- 8.5 kg) completed two testing sessions separated by 7-weeks and were randomly assigned to either a experimental or control group. Thirteen athletes underwent 6-weeks of NMT, while the remaining 10 served as controls and continued their regular netball training. Three dimensional lower-extremity kinematics and vertical ground reaction force (VGRF) were measured during two landing tasks, a drop vertical jump and a double leg broad jump with a single leg landing. The experimental group significantly increased bilateral knee marker distance during the bilateral landing task at maximum knee-flexion range of motion. Knee internal rotation angle during the unilateral landing task at maximum knee flexion-extension range of motion was significantly reduced (p <= 0.05, g > 1.00). The experimental group showed large, significant decreases in peak vertical ground reaction force in both landing tasks (p <= 0.05, g > -1.30). Control participants did not demonstrate any significant pre-to-post-test changes in response to the 6-week study period. Results of the study affirm the hypothesis that a 6-week NMT program can enhance landing biomechanics associated with ACL injury in 11-13 year old female netball athletes. PMID- 29163220 TI - Evaluation of Optogenetic Electrophysiology Tools in Human Stem Cell-Derived Cardiomyocytes. AB - Current cardiac drug safety assessments focus on hERG channel block and QT prolongation for evaluating arrhythmic risks, whereas the optogenetic approach focuses on the action potential (AP) waveform generated by a monolayer of human cardiomyocytes beating synchronously, thus assessing the contribution of several ion channels on the overall drug effect. This novel tool provides arrhythmogenic sensitizing by light-induced pacing in combination with non-invasive, all-optical measurements of cardiomyocyte APs and will improve assessment of drug-induced electrophysiological aberrancies. With the help of patch clamp electrophysiology measurements, we aimed to investigate whether the optogenetic modifications alter human cardiomyocytes' electrophysiology and how well the optogenetic analyses perform against this gold standard. Patch clamp electrophysiology measurements of non-transduced stem cell-derived cardiomyocytes compared to cells expressing the commercially available optogenetic constructs Optopatch and CaViar revealed no significant changes in action potential duration (APD) parameters. Thus, inserting the optogenetic constructs into cardiomyocytes does not significantly affect the cardiomyocyte's electrophysiological properties. When comparing the two methods against each other (patch clamp vs. optogenetic imaging) we found no significant differences in APD parameters for the Optopatch transduced cells, whereas the CaViar transduced cells exhibited modest increases in APD-values measured with optogenetic imaging. Thus, to broaden the screen, we combined optogenetic measurements of membrane potential and calcium transients with contractile motion measured by video motion tracking. Furthermore, to assess how optogenetic measurements can predict changes in membrane potential, or early afterdepolarizations (EADs), cells were exposed to cumulating doses of E-4031, a hERG potassium channel blocker, and drug effects were measured at both spontaneous and paced beating rates (1, 2 Hz). Cumulating doses of E-4031 produced prolonged APDs, followed by EADs and drug-induced quiescence. These observations were corroborated by patch clamp and contractility measurements. Similar responses, although more modest were seen with the IKs potassium channel blocker JNJ-303. In conclusion, optogenetic measurements of AP waveforms combined with optical pacing compare well with the patch clamp gold standard. Combined with video motion contractile measurements, optogenetic imaging provides an appealing alternative for electrophysiological screening of human cardiomyocyte responses in pharmacological efficacy and safety testings. PMID- 29163221 TI - The Superficial Dermis May Initiate Keloid Formation: Histological Analysis of the Keloid Dermis at Different Depths. AB - Several studies have reported on certain aspects of the characteristics of different sites within a keloid lesion, but detailed studies on the keloid dermis at different depths within a keloid lesion are scarce. The aim of this study was to investigate the histology of the keloid dermis at different depths. This study included 19 keloid tissue samples that were collected from 19 patients and 19 normal skin samples, which were harvested from subjects without keloids or hypertrophic scar. Samples were studied by light microscopy using routine hematoxylin and eosin histochemical staining, and immunohistochemistry to detect CD20-positive B-lymphocytes and CD3-positive T-lymphocytes. Sirius Red histochemical staining was used to determine the type of collagen in keloid tissue and normal skin samples. The migratory properties of fibroblasts within the keloid dermis at different depths was compared, using an in vitro migration assay. The findings of this study showed that although the papillary and reticular dermis could be clearly distinguished in normal skin, three tissue layers were identified in the keloid dermis. The superficial dermis of keloid was characterized by active fibroblasts and lymphocytes; the middle dermis contained dense extracellular matrix (ECM) with large numbers fibroblasts, and the deep dermis was poorly cellular and characterized by hyalinized collagen bundles. In the keloid samples, from the superficial to the deep dermis, type I collagen increased and type III collagen decreased, and fibroblasts from the superficial dermis of the keloid were found to migrate more rapidly. In conclusion, the findings of this study showed that different depths within the keloid dermis displayed different biological features. The superficial dermis may initiate keloid formation, in which layer intralesional injection of pharmaceuticals and other treatments should be performed for keloid. PMID- 29163222 TI - An Update on Sec61 Channel Functions, Mechanisms, and Related Diseases. AB - The membrane of the endoplasmic reticulum (ER) of nucleated human cells harbors the protein translocon, which facilitates membrane integration or translocation of almost every newly synthesized polypeptide targeted to organelles of the endo- and exocytotic pathway. The translocon comprises the polypeptide-conducting Sec61 channel and several additional proteins and complexes that are permanently or transiently associated with the heterotrimeric Sec61 complex. This ensemble of proteins facilitates ER targeting of precursor polypeptides, modification of precursor polypeptides in transit through the Sec61 complex, and Sec61 channel gating, i.e., dynamic regulation of the pore forming subunit to mediate precursor transport and calcium efflux. Recently, cryoelectron tomography of translocons in native ER membrane vesicles, derived from human cell lines or patient fibroblasts, and even intact cells has given unprecedented insights into the architecture and dynamics of the native translocon and the Sec61 channel. These structural data are discussed in light of different Sec61 channel activities including ribosome receptor function, membrane insertion, and translocation of newly synthesized polypeptides as well as the putative physiological roles of the Sec61 channel as a passive ER calcium leak channel. Furthermore, the structural insights into the Sec61 channel are incorporated into an overview and update on Sec61 channel-related diseases-the Sec61 channelopathies-and novel therapeutic concepts for their treatment. PMID- 29163224 TI - Editorial: Physiology and Clinical Potential of Eccentric Exercise. PMID- 29163223 TI - Have the Findings from Clinical Risk Prediction and Trials Any Key Messages for Safety Pharmacology? AB - Anti-arrhythmic drugs are a mainstay in the management of symptoms related to arrhythmias, and are adjuncts in prevention and treatment of life-threatening ventricular arrhythmias. However, they also have the potential for pro-arrhythmia and thus the prediction of arrhythmia predisposition and drug response are critical issues. Clinical trials are the latter stages in the safety testing and efficacy process prior to market release, and as such serve as a critical safeguard. In this review, we look at some of the lessons to be learned from approaches to arrhythmia prediction in patients, clinical trials of drugs used in the treatment of arrhythmias, and the implications for the design of pre-clinical safety pharmacology testing. PMID- 29163227 TI - Editorial: Sedentary Behavior in Human Health and Disease. PMID- 29163225 TI - Human Locomotion in Hypogravity: From Basic Research to Clinical Applications. AB - We have considerable knowledge about the mechanisms underlying compensation of Earth gravity during locomotion, a knowledge obtained from physiological, biomechanical, modeling, developmental, comparative, and paleoanthropological studies. By contrast, we know much less about locomotion and movement in general under sustained hypogravity. This lack of information poses a serious problem for human space exploration. In a near future humans will walk again on the Moon and for the first time on Mars. It would be important to predict how they will move around, since we know that locomotion and mobility in general may be jeopardized in hypogravity, especially when landing after a prolonged weightlessness of the space flight. The combination of muscle weakness, of wearing a cumbersome spacesuit, and of maladaptive patterns of locomotion in hypogravity significantly increase the risk of falls and injuries. Much of what we currently know about locomotion in hypogravity derives from the video archives of the Apollo missions on the Moon, the experiments performed with parabolic flight or with body weight support on Earth, and the theoretical models. These are the topics of our review, along with the issue of the application of simulated hypogravity in rehabilitation to help patients with deambulation problems. We consider several issues that are common to the field of space science and clinical rehabilitation: the general principles governing locomotion in hypogravity, the methods used to reduce gravity effects on locomotion, the extent to which the resulting behavior is comparable across different methods, the important non-linearities of several locomotor parameters as a function of the gravity reduction, the need to use multiple methods to obtain reliable results, and the need to tailor the methods individually based on the physiology and medical history of each person. PMID- 29163226 TI - Adenosine A2A Receptor Modulates the Activity of Globus Pallidus Neurons in Rats. AB - The globus pallidus is a central nucleus in the basal ganglia motor control circuit. Morphological studies have revealed the expression of adenosine A2A receptors in the globus pallidus. To determine the modulation of adenosine A2A receptors on the activity of pallidal neurons in both normal and parkinsonian rats, in vivo electrophysiological and behavioral tests were performed in the present study. The extracellular single unit recordings showed that micro pressure administration of adenosine A2A receptor agonist, CGS21680, regulated the pallidal firing activity. GABAergic neurotransmission was involved in CGS21680-induced modulation of pallidal neurons via a PKA pathway. Furthermore, application of two adenosine A2A receptor antagonists, KW6002 or SCH442416, mainly increased the spontaneous firing of pallidal neurons, suggesting that endogenous adenosine system modulates the activity of pallidal neurons through adenosine A2A receptors. Finally, elevated body swing test (EBST) showed that intrapallidal microinjection of adenosine A2A receptor agonist/antagonist induced ipsilateral/contralateral-biased swing, respectively. In addition, the electrophysiological and behavioral findings also revealed that activation of dopamine D2 receptors by quinpirole strengthened KW6002/SCH442416-induced excitation of pallidal activity. Co-application of quinpirole with KW6002 or SCH442416 alleviated biased swing in hemi-parkinsonian rats. Based on the present findings, we concluded that pallidal adenosine A2A receptors may be potentially useful in the treatment of Parkinson's disease. PMID- 29163228 TI - GMSC-Derived Exosomes Combined with a Chitosan/Silk Hydrogel Sponge Accelerates Wound Healing in a Diabetic Rat Skin Defect Model. AB - Background: Delayed wound healing in diabetic patients is one of the most challenging complications in clinical medicine, as it poses a greater risk of gangrene, amputation and even death. Therefore, a novel method to promote diabetic wound healing is of considerable interest at present. Previous studies showed that injection of MSC-derived exosomes has beneficial effects on wound healing. In current studies, we aimed to isolate exosomes derived from gingival mesenchymal stem cells (GMSCs) and then loading them to the chitosan/silk hydrogel sponge to evaluate the effects of this novel non-invasive method on skin defects in diabetic rats. Methods: GMSCs were isolated from human gingival connective tissue and characterized by surface antigen analysis and in vitro multipotent differentiation. The cell supernatant was collected to isolate the exosomes. The exosomes were characterized by transmission electron microscopy, Western blot and size distribution analysis. The chitosan/silk-based hydrogel sponge was prepared using the freeze-drying method and then structural and physical properties were characterized. Then, the exosomes were added to the hydrogel and tested in a diabetic rat skin defect model. The effects were evaluated by wound area measurement, histological, immunohistochemical and immunofluorescence analysis. Results: We have successfully isolated GMSCs and exosomes with a mean diameter of 127 nm. The chitosan/silk hydrogel had the appropriate properties of swelling and moisture retention capacity. The in vivo studies showed that the incorporating of GMSC-derived exosomes to hydrogel could effectively promote healing of diabetic skin defects. The histological analysis revealed more neo-epithelium and collagen in the hydrogel-exosome group. In addition, the hydrogel-exosome group had the highest microvessel density and nerve density. Conclusions: The combination of GMSC-derived exosomes and hydrogel could effectively promote skin wound healing in diabetic rats by promoting the re epithelialization, deposition and remodeling of collagen and by enhancing angiogenesis and neuronal ingrowth. These findings not only provide new information on the role of the GMSC-derived exosomes in wound healing but also provide a novel non-invasive application method of exosomes with practical value for skin repair. PMID- 29163229 TI - Cx43 Isoform GJA1-20k Promotes Microtubule Dependent Mitochondrial Transport. AB - Connexin 43 (Cx43, encoded by GJA1) is a cell-cell communication gap junction protein expressed in all organ systems. It was recently found that GJA1 mRNA undergoes alternative translation to generate N-terminal truncated isoforms, of which GJA1-20k is the most abundant. Here we report a surprising finding that, unlike full length GJA1-43k, GJA1-20k has a strong tropism for mitochondria. Exploring function, we found that GJA1-20k appears to be an organelle chaperone and that overexpression of GJA1-20k is sufficient to rescue mitochondrial localization to the cell periphery upon exposure to hydrogen peroxide, which effectively limits the network fragmentation that occurs with oxidative stress. By high-resolution fluorescent imaging and electron microscopy, we determined that GJA1-20k is enriched at the interface between mitochondria and microtubules, appearing to load organelles for transport. Mutagenesis experiments revealed that although the microtubule-binding domain (MTBD) in GJA1-20k is not necessary for protein localization to mitochondria, the MTBD is essential for GJA1-20k to facilitate mitochondrial transport and maintain mitochondrial localization at the periphery. These results reveal an unexpected role for the alternatively translated isoform of the Cx43 gap junction protein, GJA1-20k, which is to facilitate microtubule-based mitochondrial transport and to maintain mitochondrial network integrity during cellular stress. PMID- 29163230 TI - Physiological Levels of Nitric Oxide Diminish Mitochondrial Superoxide. Potential Role of Mitochondrial Dinitrosyl Iron Complexes and Nitrosothiols. AB - Mitochondria are the major source of superoxide radicals and superoxide overproduction contributes to cardiovascular diseases and metabolic disorders. Endothelial dysfunction and diminished nitric oxide levels are early steps in the development of these pathological conditions. It is known that physiological production of nitric oxide reduces oxidative stress and inflammation, however, the precise mechanism of "antioxidant" effect of nitric oxide is not clear. In this work we tested the hypothesis that physiological levels of nitric oxide diminish mitochondrial superoxide production without inhibition of mitochondrial respiration. In order to test this hypothesis we analyzed effect of low physiological fluxes of nitric oxide (20 nM/min) on superoxide and hydrogen peroxide production by ESR spin probes and Amplex Red in isolated rat brain mitochondria. Indeed, low levels of nitric oxide substantially attenuated both basal and antimycin A-stimulated production of reactive oxygen species in the presence of succinate or glutamate/malate as mitochondrial substrates. Furthermore, slow releasing NO donor DPTA-NONOate (100 MUM) did not change oxygen consumption in State 4 and State 3. However, the NO-donor strongly inhibited oxygen consumption in the presence of uncoupling agent CCCP, which is likely associated with inhibition of the over-reduced complex IV in uncoupled mitochondria. We have examined accumulation of dinitrosyl iron complexes and nitrosothiols in mitochondria treated with fast-releasing NO donor MAHMA NONOate (10 MUM) for 30 min until complete release of NO. Following treatment with NO donor, mitochondria were frozen for direct detection of dinitrosyl iron complexes using Electron Spin Resonance (ESR) while accumulation of nitrosothiols was measured by ferrous-N-Methyl-D-glucamine dithiocarbamate complex, Fe(MGD)2, in lysed mitochondria. Treatment of mitochondria with NO-donor gave rise to ESR signal of dinitrosyl iron complexes while ESR spectra of Fe(MGD)2 supplemented mitochondrial lysates showed presence of both dinitrosyl iron complexes and nitrosothiols. We suggest that nitric oxide attenuates production of mitochondrial superoxide by post-translational modifications by nitrosylation of protein cysteine residues and formation of protein dinitrosyl iron complexes with thiol-containing ligands and, therefore, nitric oxide reduction in pathological conditions associated with endothelial dysfunction may increase mitochondrial oxidative stress. PMID- 29163231 TI - Role of Cyclic Nucleotide Phosphodiesterases in Inner Ear and Hearing. PMID- 29163232 TI - Considerations on the Assessment and Use of Cycling Performance Metrics and their Integration in the Athlete's Biological Passport. AB - Over the past few decades the possibility to capture real-time data from road cyclists has drastically improved. Given the increasing pressure for improved transparency and openness, there has been an increase in publication of cyclists' physiological and performance data. Recently, it has been suggested that the use of such performance biometrics may be used to strengthen the sensitivity and applicability of the Athlete Biological Passport (ABP) and aid in the fight against doping. This is an interesting concept which has merit, although there are several important factors that need to be considered. These factors include accuracy of the data collected and validity (and reliability) of the subsequent performance modeling. In order to guarantee high quality standards, the implementation of well-structured Quality-Systems within sporting organizations should be considered, and external certifications may be required. Various modeling techniques have been developed, many of which are based on fundamental intensity/time relationships. These models have increased our understanding of performance but are currently limited in their application, for example due to the largely unaccounted effects of environmental factors such as, heat and altitude. In conclusion, in order to use power data as a performance biometric to be integrated in the biological passport, a number of actions must be taken to ensure accuracy of the data and better understand road cycling performance in the field. This article aims to outline considerations in the quantification of cycling performance, also presenting an alternative method (i.e., monitoring race results) to allow for determination of unusual performance improvements. PMID- 29163233 TI - Symptom Overlap and Screening for Symptoms of Attention-Deficit/Hyperactivity Disorder and Psychosis Risk in Help-Seeking Psychiatric Patients. AB - Symptoms of attention-deficit/hyperactivity disorder (ADHD) and psychosis risk share features which might represent an early vulnerability marker for schizophrenia. Early detection of individuals with this symptomatic overlap is relevant and may assist clinicians in their decision making for diagnosis and treatment. This study sought to analyze the capability of different instruments in the screening of patients for ADHD symptoms or at psychosis risk, assess their classification accuracy, and describe the extent of symptoms overlap between them. 243 adult patients completed one instrument screening for ADHD and two instruments screening for psychosis risk symptoms [Adult ADHD Self-Report Scale Symptom Checklist (ASRS-v1.1); Prodromal Questionnaire Brief Version (PQ-16); Self-Screen Prodrome (SPro)]. The ability of these instruments to distinguish between the symptomaticity of these patients appears modest. The most satisfactory scale to identify subjects at psychosis risk was SPro with its subscale psychosis risk. ASRS-v1.1 showed good reliability in assessing individuals as not having ADHD symptoms and had higher probability to achieve its own and the cut-off of another questionnaire. Subjects having symptoms of psychosis risk and ADHD showed elevated symptomatology. Reliable instruments capable of separating ADHD symptoms from those of psychosis risk are needed to better identify the symptomatic overlap of this two conditions. PMID- 29163234 TI - A Comparison of Treatment-Seeking Behavioral Addiction Patients with and without Parkinson's Disease. AB - The administration of dopaminergic medication to treat the symptoms of Parkinson's disease (PD) is associated with addictive behaviors and impulse control disorders. Little is known, however, on how PD patients differ from other patients seeking treatments for behavioral addictions. The aim of this study was to compare the characteristics of behavioral addiction patients with and without PD. N = 2,460 treatment-seeking men diagnosed with a behavioral addiction were recruited from a university hospital. Sociodemographic, impulsivity [Barratt Impulsiveness Scale (BIS-11)], and personality [Temperament and Character Inventory-Revised (TCI-R)] measures were taken upon admission to outpatient treatment. Patients in the PD group were older and had a higher prevalence of mood disorders than patients without PD. In terms of personality characteristics and impulsivity traits, PD patients appeared to present a more functional profile than PD-free patients with a behavioral addiction. Our results suggest that PD patients with a behavioral addiction could be more difficult to detect than their PD-free counterparts in behavioral addiction clinical setting due to their reduced levels of impulsivity and more standard personality traits. As a whole, this suggests that PD patients with a behavioral addiction may have different needs from PD-free behavioral addiction patients and that they could potentially benefit from targeted interventions. PMID- 29163235 TI - Electrophysiological Anomalies in Face-Name Memory Encoding in Young Binge Drinkers. AB - A growing body of evidence indicates that the intake of large amounts of alcohol during one session may have structural and functional effects on the still maturing brains of young people. These effects are particularly pronounced in prefrontal and hippocampal regions, which appear to be especially sensitive to the neurotoxic effects of alcohol. However, to date, few studies have used the event-related potentials (ERPs) technique to analyze the relationship between binge drinking (BD) and associative memory. The objective of this study was to examine brain activity during memory encoding using the Subsequent memory paradigm in subjects who have followed a BD pattern of alcohol consumption for at least 2 years. A total of 50 undergraduate students (mean age = 20.6 years), i.e., 25 controls (12 females) and 25 binge drinkers (BDs; 11 females), with no personal or family history of alcoholism or psychopathological disorders, performed a visual face-name association memory task. The task used enables assessment of the Difference due to memory effect (Dm), a measure of memory encoding based on comparison of the neural activity associated with subsequent successful and unsuccessful retrieval. In ERP studies, study items that are subsequently remembered elicit larger positive amplitudes at midline parieto frontal sites than those items that are subsequently forgotten. The Dm effect generally appears in the latency range of about 300-800 ms. The results showed a Dm effect in posterior regions in the 350-650 ms latency range in the Control group. However, in the BD group, no significant differences were observed in the electrophysiological brain activity between remembered and forgotten items during the encoding process. No differences between groups were found in behavioral performance. These findings show that young BDs display abnormal pattern of ERP brain activity during the encoding phase of a visual face-name association task, possibly suggesting a different neural signature of successful memory encoding. PMID- 29163236 TI - Poor Illness Perceptions Are a Risk Factor for Depressive and Anxious Symptomatology in Fibromyalgia Syndrome: A Longitudinal Cohort Study. AB - Background: Patients with widespread pain, such as in fibromyalgia, are vulnerable for depression and anxiety, which composes a relevant public health problem. Identifying risk factors for the onset of depression and anxiety is therefore warranted. Objective of this study was to determine whether severe pain, maladaptive coping, and poor illness perceptions are associated with depressive and anxious symptomatology in fibromyalgia. Method: Consecutive patients referred to an outpatient clinic completed sets of physical and psychological questionnaires at baseline and at 18-month follow-up. A total of 452 patients with fibromyalgia syndrome (FMS) were eligible for inclusion, and subsequently, 280 patients returned the baseline questionnaire. Depressive and anxious symptomatology was measured with the Hospital Anxiety and Depression Scale. To measure pain severity, coping style, and illness perceptions, the Fibromyalgia Impact Questionnaire, Pain Coping Inventory, and the Illness Perception Questionnaire-Revised (IPQ-R) were used, respectively. Multivariable logistic regression analyses, bootstrapping and calibration, were performed to examine the association of pain severity, pain coping, and illness perception with depressive and anxiety symptoms at follow-up, adjusted for sociodemographic variables. Initial level of depressive and anxiety symptoms was selected as covariates. Results: Mean age was 42.6 years and 95.4% were female. At 18-month follow-up, 68 (of the 195) patients were depressed and 80 (of the 197) were anxious. Only the IPQ-R subscale "emotional representations" showed a significant positive association with depressive symptoms at follow-up (OR = 1.10), next to the initial level of depressive symptoms (OR = 1.30). In case of anxiety, only the IPQ-R subscale "treatment control" showed a significant negative association with anxiety symptoms at follow-up (OR = 0.87), next to the initial level of anxiety symptoms (OR = 1.45). Conclusion: Our data suggest that not pain severity or maladaptive coping, but poor illness perceptions are important in elevated depressive and anxious symptomatology. Patients with fibromyalgia who think their illness negatively affects their mental well-being are at increased risk for more depressive symptoms, and those who think treatment of their illness will not be effective are at increased risk for more anxiety symptoms. Strengthening illness beliefs and reducing catastrophic thinking, therefore, seem crucial factors in the treatment of patients with FMS. PMID- 29163237 TI - [18F]-Fluorodeoxyglucose-Positron Emission Tomography in Rats with Prolonged Cocaine Self-Administration Suggests Potential Brain Biomarkers for Addictive Behavior. AB - The DSM5-based dimensional diagnostic approach defines substance use disorders on a continuum from recreational drug use to habitual and ultimately addicted behavior. Biomarkers that are indicative of recreational drug use and addicted behavior are lacking. We performed a translational [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) study in the multi-dimensional 0/3crit model of cocaine addiction. Addict-like (3crit) and non-addict-like (0crit) rats, which shared identical life conditions and levels of cocaine self-administration, were acquired for FDG-PET under baseline conditions and following cocaine and yohimbine challenges. Compared to cocaine-naive control rats, 0crit animals showed higher glucose uptake in the caudate putamen (CPu) and medial prefrontal cortex (mPFC) respect to naive controls. 3crit animals did not show this adaptive higher glucose utilization, but had lower uptake in several cortical areas. Both cocaine and yohimbine challenges affected glucose uptake in control rats in several brain sites, but not in 0crit and 3crit rats, indicating that impaired glucose mobilization in response to these challenges is not specifically associated with addictive behavior. Compared to 0crit, 3crit rats showed higher reinstatement responses, which were negatively associated with glucose uptake in the ventral tegmental area. Data indicate that cocaine non-addict- and addict like phenotypes are associated with several potential biomarkers. Specifically, we propose that increased glucose uptake in the CPu and mPFC is a function of controlled drug use, whereas a loss of striatal and prefrontal metabolic activity and reduced uptake in cortical areas are indicative of addictive behavior. PMID- 29163238 TI - Impairment of Working Memory, Decision-making, and Executive Function in the First-Degree Relatives of People with Panic Disorder: A Pilot Study. AB - Background: Panic disorder (PD) patients present impairments of working memory, decision-making, and executive function. However, whether the first-degree relatives (FDRs) of people with PD present abnormal characteristics, including clinical and neuropsychological aspects, in comparison to the general population, has not been studied. Investigation and understanding of the abnormal neuropsychological characteristics of the FDRs of people with PD will contribute to the prevention and treatment of PD. Objective: The purpose of this paper is to compare the working memory, decision-making, and executive function among people with PD, their FDRs, and controls. Materials and methods: Neuropsychological functions of 30 people with PD, 30 FDRs of people with PD, and 30 controls were measured with a digit span task, Iowa Gambling Task (IGT), and Wisconsin Card Sorting Test (WCST). Results: Perseverative errors, failure to maintain set scores, and number of cards chosen from decks A, B, C, and D were higher for People with PD and their FDRs than those of controls. Furthermore, error rates for these tests were higher for people with PD than their FDRs. Forward scores and backward scores, percentage of conceptual level responses, the number of categories completed, choices from advantageous minus disadvantageous decks, and mean amount of money earned of people with PD and their FDRs were all lower than those of controls. Scores for these tests were also lower for people with PD than for their FDRs. Conclusion: People with PD as well as their FDRs present different degrees of impairments of working memory, decision-making, and executive function. Impaired performance on three tasks appears to be associated with the diathesis for PD and may be a valuable indicator of susceptibility for this disorder. PMID- 29163239 TI - Editorial: Trauma, Psychosis and Posttraumatic Stress Disorder. PMID- 29163240 TI - Interleukin-6 in Schizophrenia-Is There a Therapeutic Relevance? AB - Renewing interest in immune aspects of schizophrenia and new findings about the brain-fat axis encourage us to discuss the possible role of interleukin-6 (IL-6) in schizophrenia. Previously, it was suggested that a primary alteration of the innate immune system may be relevant in schizophrenia. Functional dichotomy of IL 6 suggests that this chemical messenger may be responsible for regulating the balance between pro- and anti-inflammatory responses, with tissue-specific properties at the periphery and in the central nervous system. Specific phase of this chronic and deteriorating disorder must be considered, which can involve IL 6 in acute or possible chronic inflammation and/or autoimmunity. We give an overview of IL-6 role in the onset and progression of this disorder, also considering cognitive impairment and metabolic changes in patients with schizophrenia. Data suggest that decreased serum level of IL-6 following antipsychotic therapy could be predisposing factor for the development of obesity and obesity-related metabolic disorders in schizophrenia. As we reviewed, the IL 6 plays significant role in disease genesis and progression, so the use of specific inhibitors may not only be beneficial for exacerbation and alleviation of positive symptoms, but may attenuate cognitive impairment in patients with schizophrenia. PMID- 29163241 TI - Posttraumatic Stress Disorder: An Immunological Disorder? AB - Patients with posttraumatic stress disorder (PTSD) exhibit an increased state of inflammation. Various animal models for PTSD have shown some of the same immune imbalances as have been shown in human subjects with PTSD, and some of these studies are discussed in this review. However, animal studies can only indirectly implicate immune involvement in PTSD in humans. This review of mainly studies with human subjects focuses on dissecting the immunological role in the pathogenesis of PTSD following initial trauma exposure. It addresses both the inflammatory state associated with PTSD and the immune imbalance between stimulatory and inhibitory immune mediators, as well as variables that can lead to discrepancies between analyses. The concept of immunological treatment approaches is proposed for PTSD, as new treatments are needed for this devastating disorder that is affecting unprecedented numbers of Veterans from the long-standing wars in the Middle East and which affects civilians following severe trauma. PMID- 29163242 TI - Alexithymia Is Associated with Tinnitus Severity. AB - Objective: Alexithymia is considered to be a personality trait with a tendency to express psychological distress in somatic rather than emotional form and, therefore, may play a vital role in somatization. Although, such a propensity can be found in patients suffering from tinnitus, the relationship between alexithymic characteristics and the subjective experience of tinnitus severity remains yet unclear. Our aim was to evaluate which alexithymic characteristics are linked to the subjective experience of tinnitus symptomatology. Methods: We evaluated tinnitus severity (Tinnitus Handicap Inventory, THI), alexithymia (20 item Toronto Alexithymia Scale, TAS-20), and depression (Beck Depression Inventory, BDI) in 207 outpatients with tinnitus. Correlation analyses and multiple regression analyses were calculated in order to investigate the relationship between alexithymic characteristics, tinnitus severity, and depression. Results: Highly significant positive correlations were found between THI total score and TAS-20 total score as well as BDI score. Regarding the TAS-20 subscales, multiple regression analyses showed that only the TAS-20 subscale "difficulty in identifying feelings" (DIF) and the BDI significantly predicted the subjective experience of tinnitus severity. Regarding the THI subscales, only higher scores of the THI subscale "functional" demonstrated an independent moderate association with higher scores for DIF. Conclusion: We found an independent association between the subjective experience of tinnitus severity and alexithymic characteristics, particularly with regard to limitations in the fields of mental, social, and physical functioning because of tinnitus and the difficulty of identifying feelings facet of alexithymia. These findings are conducive to a better understanding of affect regulation that may be important for the psychological adaptation of patients suffering from tinnitus. PMID- 29163243 TI - Functional Alterations of Postcentral Gyrus Modulated by Angry Facial Expressions during Intraoral Tactile Stimuli in Patients with Burning Mouth Syndrome: A Functional Magnetic Resonance Imaging Study. AB - Previous findings suggest that negative emotions could influence abnormal sensory perception in burning mouth syndrome (BMS). However, few studies have investigated the underlying neural mechanisms associated with BMS. We examined activation of brain regions in response to intraoral tactile stimuli when modulated by angry facial expressions. We performed functional magnetic resonance imaging on a group of 27 BMS patients and 21 age-matched healthy controls. Tactile stimuli were presented during different emotional contexts, which were induced via the continuous presentation of angry or neutral pictures of human faces. BMS patients exhibited higher tactile ratings and greater activation in the postcentral gyrus during the presentation of tactile stimuli involving angry faces relative to controls. Significant positive correlations between changes in brain activation elicited by angry facial images in the postcentral gyrus and changes in tactile rating scores by angry facial images were found for both groups. For BMS patients, there was a significant positive correlation between changes in tactile-related activation of the postcentral gyrus elicited by angry facial expressions and pain intensity in daily life. Findings suggest that neural responses in the postcentral gyrus are more strongly affected by angry facial expressions in BMS patients, which may reflect one possible mechanism underlying impaired somatosensory system function in this disorder. PMID- 29163245 TI - The Training of Morphological Decomposition in Word Processing and Its Effects on Literacy Skills. AB - This study set out to examine the effects of a morpheme-based training on reading and spelling in fifth and sixth graders (N = 47), who present poor literacy skills and speak German as a second language. A computerized training, consisting of a visual lexical decision task (comprising 2,880 items, presented in 12 sessions), was designed to encourage fast morphological analysis in word processing. The children were divided between two groups: the one underwent a morpheme-based training, in which word-stems of inflections and derivations were presented for a limited duration, while their pre- and suffixes remained on screen until response. Another group received a control training consisting of the same task, except that the duration of presentation of a non-morphological unit was restricted. In a Word Disruption Task, participants read words under three conditions: morphological separation (with symbols separating between the words' morphemes), non-morphological separation (with symbols separating between non-morphological units of words), and no-separation (with symbols presented at the beginning and end of each word). The group receiving the morpheme-based program improved more than the control group in terms of word reading fluency in the morphological condition. The former group also presented similar word reading fluency after training in the morphological condition and in the no-separation condition, thereby suggesting that the morpheme-based training contributed to the integration of morphological decomposition into the process of word recognition. At the same time, both groups similarly improved in other measures of word reading fluency. With regard to spelling, the morpheme-based training group showed a larger improvement than the control group in spelling of trained items, and a unique improvement in spelling of untrained items (untrained word-stems integrated into trained pre- and suffixes). The results further suggest some contribution of the morpheme-based training to performance in a standardized spelling task. The morpheme-based training did not, however, show any unique effect on comprehension. These results suggest that the morpheme-based training is effective in enhancing some basic literacy skill in the population examined, i.e., morphological analysis in word processing and the access to orthographic representations in spelling, with no specific effects on reading fluency and comprehension. PMID- 29163244 TI - Peripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment Resistant Schizophrenia. AB - Investigation of peripheral gene expression patterns of transcripts within the NRG-ErbB signaling pathway, other than neuregulin-1 (NRG1), among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS) is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFalpha, EGFbeta, and type I(Ig2) containing transcripts in TRS by investigating 11 NRG-ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1) in whole blood of TRS patients (N = 71) and healthy controls (N = 57). We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs) from 15 healthy individuals. Five transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1) were significantly elevated in TRS patients compared to healthy controls but only expression of P70S6K (Pcorrected = 0.018), a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini Hochberg method. Investigation of clinical factors revealed that ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our in vitro PBMC clozapine exposure experiment. Taken together with previously published NRG1 results, our findings suggest an overall upregulation of transcripts within the NRG-ErbB signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the NRG-ErbB signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia. PMID- 29163246 TI - Screening Protocol for Early Identification of Brazilian Children at Risk for Dyslexia. AB - Early identification of students at risk of dyslexia has been an educational challenge in the past years. This research had two main goals. First, we aimed to develop a screening protocol for early identification of Brazilian children at risk for dyslexia; second, we aimed to identify the predictive variables of this protocol using Principal Component Analysis. The major step involved in developing this protocol was the selection of variables, which were chosen based on the literature review and linguistic criteria. The screening protocol was composed of seven cognitive-linguistic skills: Letter naming; Phonological Awareness (which comprises the following subtests: Rhyme production, Rhyme identification, Syllabic segmentation, Production of words from a given phoneme, Phonemic Synthesis, and Phonemic analysis); Phonological Working memory, Rapid naming Speed; Silent reading; Reading of words and non-words; and Auditory Comprehension of sentences from pictures. A total of 149 children, aged from 6 years to 6 and 11, of both genders who were enrolled in the 1st grade of elementary public schools were submitted to the screening protocol. Principal Component Analysis revealed four factors, accounting for 64.45% of the variance of the Protocol variables: first factor ("pre-reading"), second factor ("decoding"), third factor ("Reading"), and fourth factor "Auditory processing." The factors found corroborate those reported in the National and International literature and have been described as early signs of dyslexia and reading problems. PMID- 29163247 TI - How to Dax? Preschool Children's Prosocial Behavior, But Not Their Social Norm Enforcement Relates to Their Peer Status. AB - The current study examined correlates of preschool children's (n = 82) peer status. In particular, we assessed children's prosocial behavior, social problem behavior, norm enforcement, language abilities, and temperament. Children's prosocial behavior, pragmatic language abilities, and gender correlated with peer status. A regression analysis revealed that prosocial behavior and gender were independent predictors. There was some evidence for a mediation effect: The link between pragmatic language and peer status was mediated by prosocial behavior. Children's norm enforcement was not related to peer status, neither was it related to any other factor such as temperament or language. Overall, the study supports approaches claiming that prosocial behavior plays a role in children's social functioning and are in line with social-interactionist accounts to social and social-cognitive development. PMID- 29163248 TI - Montessori Preschool Elevates and Equalizes Child Outcomes: A Longitudinal Study. AB - Quality preschool programs that develop the whole child through age-appropriate socioemotional and cognitive skill-building hold promise for significantly improving child outcomes. However, preschool programs tend to either be teacher led and didactic, or else to lack academic content. One preschool model that involves both child-directed, freely chosen activity and academic content is Montessori. Here we report a longitudinal study that took advantage of randomized lottery-based admission to two public Montessori magnet schools in a high-poverty American city. The final sample included 141 children, 70 in Montessori and 71 in other schools, most of whom were tested 4 times over 3 years, from the first semester to the end of preschool (ages 3-6), on a variety of cognitive and socio emotional measures. Montessori preschool elevated children's outcomes in several ways. Although not different at the first test point, over time the Montessori children fared better on measures of academic achievement, social understanding, and mastery orientation, and they also reported relatively more liking of scholastic tasks. They also scored higher on executive function when they were 4. In addition to elevating overall performance on these measures, Montessori preschool also equalized outcomes among subgroups that typically have unequal outcomes. First, the difference in academic achievement between lower income Montessori and higher income conventionally schooled children was smaller at each time point, and was not (statistically speaking) significantly different at the end of the study. Second, defying the typical finding that executive function predicts academic achievement, in Montessori classrooms children with lower executive function scored as well on academic achievement as those with higher executive function. This suggests that Montessori preschool has potential to elevate and equalize important outcomes, and a larger study of public Montessori preschools is warranted. PMID- 29163249 TI - Are Empowered Employees More Proactive? The Contingency of How They Evaluate Their Leader. AB - Finding ways to enhance employee proactive behavior is a focal concern for academics and practitioners. Previous studies have found a positive association between empowering leadership and proactive behavior (Martin et al., 2013; Li et al., 2017). However, these studies lack elaboration on mechanisms and do not rule out the effect of employees' proactive personality during empirical testing. We investigate empowering leadership from individual perspective due to the variation of empowerment levels even in the same team. Our research proposes a more elaborated theoretical model that explains why, and when, empowering leadership might promote employee proactive behavior. Specifically, we examine mediating mechanisms based on social cognitive theory and propose trust in leader competency as boundary condition. Using a sample of 280 leader-follower dyads from a large state-owned Chinese company, our results revealed that (1) empowering leadership was positively related to proactive behavior, with role breadth self-efficacy acting as a mediator for this relationship; (2) employees' trust in leader competency moderated both the empowering leadership-subordinate proactive behavior relationship and the mediating effect of role breadth self efficacy, such that the empowering leadership-subordinate proactive behavior relationship was weaker, and the mediating effect of role breadth self-efficacy was stronger, for employees with high levels of trust in leader competency. PMID- 29163250 TI - Beyond Verb Meaning: Experimental Evidence for Incremental Processing of Semantic Roles and Event Structure. AB - We present an event-related potentials (ERP) study that addresses the question of how pieces of information pertaining to semantic roles and event structure interact with each other and with the verb's meaning. Specifically, our study investigates German verb-final clauses with verbs of motion such as fliegen 'fly' and schweben 'float, hover,' which are indeterminate with respect to agentivity and event structure. Agentivity was tested by manipulating the animacy of the subject noun phrase and event structure by selecting a goal adverbial, which makes the event telic, or a locative adverbial, which leads to an atelic reading. On the clause-initial subject, inanimates evoked an N400 effect vis-a-vis animates. On the adverbial phrase in the atelic (locative) condition, inanimates showed an N400 in comparison to animates. The telic (goal) condition exhibited a similar amplitude like the inanimate-atelic condition. Finally, at the verbal lexeme, the inanimate condition elicited an N400 effect against the animate condition in the telic (goal) contexts. In the atelic (locative) condition, items with animates evoked an N400 effect compared to inanimates. The combined set of findings suggest that clause-initial animacy is not sufficient for agent identification in German, which seems to be completed only at the verbal lexeme in our experiment. Here non-agents (inanimates) changing their location in a goal directed way and agents (animates) lacking this property are dispreferred and this challenges the assumption that change of (locational) state is generally a defining characteristic of the patient role. Besides this main finding that sheds new light on role prototypicality, our data seem to indicate effects that, in our view, are related to complexity, i.e., minimality. Inanimate subjects or goal arguments increase processing costs since they have role or event structure restrictions that animate subjects or locative modifiers lack. PMID- 29163251 TI - Consumer Neuroscience-Based Metrics Predict Recall, Liking and Viewing Rates in Online Advertising. AB - The purpose of the present study is to investigate whether the effectiveness of a new ad on digital channels (YouTube) can be predicted by using neural networks and neuroscience-based metrics (brain response, heart rate variability and eye tracking). Neurophysiological records from 35 participants were exposed to 8 relevant TV Super Bowl commercials. Correlations between neurophysiological-based metrics, ad recall, ad liking, the ACE metrix score and the number of views on YouTube during a year were investigated. Our findings suggest a significant correlation between neuroscience metrics and self-reported of ad effectiveness and the direct number of views on the YouTube channel. In addition, and using an artificial neural network based on neuroscience metrics, the model classifies (82.9% of average accuracy) and estimate the number of online views (mean error of 0.199). The results highlight the validity of neuromarketing-based techniques for predicting the success of advertising responses. Practitioners can consider the proposed methodology at the design stages of advertising content, thus enhancing advertising effectiveness. The study pioneers the use of neurophysiological methods in predicting advertising success in a digital context. This is the first article that has examined whether these measures could actually be used for predicting views for advertising on YouTube. PMID- 29163252 TI - The Paradox of Isochrony in the Evolution of Human Rhythm. AB - Isochrony is crucial to the rhythm of human music. Some neural, behavioral and anatomical traits underlying rhythm perception and production are shared with a broad range of species. These may either have a common evolutionary origin, or have evolved into similar traits under different evolutionary pressures. Other traits underlying rhythm are rare across species, only found in humans and few other animals. Isochrony, or stable periodicity, is common to most human music, but isochronous behaviors are also found in many species. It appears paradoxical that humans are particularly good at producing and perceiving isochronous patterns, although this ability does not conceivably confer any evolutionary advantage to modern humans. This article will attempt to solve this conundrum. To this end, we define the concept of isochrony from the present functional perspective of physiology, cognitive neuroscience, signal processing, and interactive behavior, and review available evidence on isochrony in the signals of humans and other animals. We then attempt to resolve the paradox of isochrony by expanding an evolutionary hypothesis about the function that isochronous behavior may have had in early hominids. Finally, we propose avenues for empirical research to examine this hypothesis and to understand the evolutionary origin of isochrony in general. PMID- 29163253 TI - Coping with Childbirth: Brain Structural Associations of Personal Growth Initiative. AB - Major life events require psychological adaptations and can be accompanied by brain structural and functional changes. The goal of the current study was to investigate the association of personal growth initiative (PGI) as a form of proactive coping strategy before childbirth, with gray matter volume after delivery. Childbirth is one of the few predictable major life events, which, while being one of the most positive experiences for many, is also accompanied by multidimensional stress for the mother. Previous research has shown that high stress is associated with reductions in gray matter volume in limbic cortices as well as the prefrontal cortex (PFC). We hypothesized that PGI before childbirth is positively related to gray matter volume after delivery, especially in the ventromedial PFC (vmPFC). In a prospective study, 22 first-time mothers answered questionnaires about their PGI level 1 month before birth (T1) and 1 month after delivery (T2). Four months after giving birth, a follow-up assessment was applied with 16 of these mothers (T3). Structural brain data were acquired at both postpartal measurement occasions. Voxel-based morphometry was used to correlate prenatal PGI levels with postpartal gray matter volume. Higher PGI levels before delivery were positively associated with larger gray matter volume in the vmPFC directly after childbirth. Previous structural neuroimaging research in the context of major life events focused primarily on pathological reactions to stress (e.g., post-traumatic stress disorder; PTSD). The current study gives initial indications that proactive coping may be positively associated with gray matter volume in the vmPFC, a brain region which shows volumetric reductions in PTSD patients. PMID- 29163254 TI - Using Self-Generated Cues to Facilitate Recall: A Narrative Review. AB - We draw upon the Associative Network model of memory, as well as the principles of encoding-retrieval specificity, and cue distinctiveness, to argue that self generated cue mnemonics offer an intuitive means of facilitating reliable recall of personally experienced events. The use of a self-generated cue mnemonic allows for the spreading activation nature of memory, whilst also presenting an opportunity to capitalize upon cue distinctiveness. Here, we present the theoretical rationale behind the use of this technique, and highlight the distinction between a self-generated cue and a self-referent cue in autobiographical memory research. We contrast this mnemonic with a similar retrieval technique, Mental Reinstatement of Context, which is recognized as the most effective mnemonic component of the Cognitive Interview. Mental Reinstatement of Context is based upon the principle of encoding-retrieval specificity, whereby the overlap between encoded information and retrieval cue predicts the likelihood of accurate recall. However, it does not incorporate the potential additional benefit of self-generated retrieval cues. PMID- 29163255 TI - Positive Emotion Facilitates Cognitive Flexibility: An fMRI Study. AB - Cognitive flexibility is the ability to switch rapidly between multiple goals. By using a task-switching paradigm, the present study investigated how positive emotion affected cognitive flexibility and the underlying neural mechanisms. After viewing pictures of different emotional valence (positive, negative, or neutral), participants discriminated whether a target digit in a specific color was odd or even. After a series of trials, the color of target stimuli was changed, i.e., the switch condition. Switch costs were measured by the increase of reaction times (RTs) in the switch trials compared to those in the repeat trials. Behavior results indicated that switch costs significantly decreased in the positive emotional condition, and increased in the negative emotional condition, compared with those in the neutral condition. Imaging data revealed enhanced activation in the dorsal anterior cingulate cortex (dACC) in switch trials than those in repeat trials. Moreover, the interaction between emotion (positive, negative, neutral) and trial type (repeat vs. switch) was significant. For switch trials, the activation of dACC decreased significantly in the positive condition, while increased significantly in the negative condition compared to neutral condition. By contrast, for repeat trials, no significant difference was observed for the activation of dACC among three emotional conditions. Our results showed that positive emotions could increase the cognitive flexibility and reduce the conflict by decreasing the activation of dACC. PMID- 29163256 TI - From Discovery to Justification: Outline of an Ideal Research Program in Empirical Psychology. AB - The gold standard for an empirical science is the replicability of its research results. But the estimated average replicability rate of key-effects that top tier psychology journals report falls between 36 and 39% (objective vs. subjective rate; Open Science Collaboration, 2015). So the standard mode of applying null-hypothesis significance testing (NHST) fails to adequately separate stable from random effects. Therefore, NHST does not fully convince as a statistical inference strategy. We argue that the replicability crisis is "home made" because more sophisticated strategies can deliver results the successful replication of which is sufficiently probable. Thus, we can overcome the replicability crisis by integrating empirical results into genuine research programs. Instead of continuing to narrowly evaluate only the stability of data against random fluctuations (discovery context), such programs evaluate rival hypotheses against stable data (justification context). PMID- 29163258 TI - The Structure of the Chinese Material Value Scale: An Eastern Cultural View. AB - This study investigated the structure of the Chinese Material Value Scale (MVS). A two-factor structure, rather than the original three-factor structure, was proposed for China by means of confirmatory factor analysis. Direct evidence showed that the dimensions of success and happiness could be merged together. Both explicit and implicit methods were used to examine the relationship between success and happiness based on possession. In particular, as an implicit method, the dot-probe paradigm recording participants' response time supported the idea that the two-factors could be merged together. The results also showed that for Chinese people, success to an extent means happiness, while the converse is not necessarily true. Chinese are much more concerned about social evaluation than their own feelings, and this cultural characteristic is reflected in our findings. PMID- 29163257 TI - Free Will and the Brain Disease Model of Addiction: The Not So Seductive Allure of Neuroscience and Its Modest Impact on the Attribution of Free Will to People with an Addiction. AB - Free will has been the object of debate in the context of addiction given that addiction could compromise an individual's ability to choose freely between alternative courses of action. Proponents of the brain-disease model of addiction have argued that a neuroscience perspective on addiction reduces the attribution of free will because it relocates the cause of the disorder to the brain rather than to the person, thereby diminishing the blame attributed to the person with an addiction. Others have worried that such displacement of free will attribution would make the person with a drug addiction less responsible. Using the paradigmatic literature on the seductive allure of neuroscience explanations, we tested whether neuroscience information diminishes attributions of free will in the context of addiction and whether respondent characteristics influence these attributions and modulate the effect of neuroscience information. We performed a large-scale, web-based experiment with 2,378 German participants to explore how attributions of free will in the context of addiction to either alcohol or cocaine are affected by: (1) a text with a neurobiological explanation of addiction, (2) a neuroimage showing effects of addiction on the brain, and (3) a combination of a text and a neuroimage, in comparison to a control group that received no information. Belief in free will was measured using the FAD-Plus scale and was, subsequent to factor analysis, separated into two factors: responsibility and volition. The investigated respondent characteristics included gender, age, education, self-reported knowledge of neuroscience, substance-use disorder (SUD), and having a friend with SUD. We found that attributions of volition (in the cocaine-subsample) were reduced in the text and neuroimage treatment compared to the control group. However, respondent characteristics such as education and self-reported knowledge of neuroscience were associated with lower attributions of responsibility for both substances, and education was associated with lower attribution of volition for the alcohol sub-sample. Interaction analyses showed that knowledge of neuroscience was found to generally decrease attribution of responsibility. Further research on attribution of free will should consider the effects of context and respondent characteristics, which appeared surprisingly larger than those induced by experimental treatments. PMID- 29163259 TI - Commentary: Exercise-dependent BDNF as a Modulatory Factor for the Executive Processing of Individuals in Course of Cognitive Decline. A Systematic Review. PMID- 29163261 TI - A Sentence Repetition Task for Catalan-Speaking Typically-Developing Children and Children with Specific Language Impairment. AB - It is common to find that so-called minority languages enjoy fewer (if any) diagnostic tools than the so-called majority languages. This has repercussions for the detection and proper assessment of children with Specific Language Impairment (SLI) brought up in these languages. With a view to remedy this situation for Catalan, I developed a sentence repetition task to assess grammatical maturity in school-age children; in current practice, Catalan speaking children are assessed with tests translated from Spanish, with disregard of the fact that the markers of SLI may differ substantially from one language to another, even between closely related languages. The test proposed here is inspired by SASIT [School-Age Sentence Imitation Test - English], designed for English by Marinis et al. (2011); some of the constructions targeted are challenging in a subset of languages, but not others, and are included because they are indeed affected in Catalan SLI; other constructions appear to be disrupted universally. The test involves canonical SVO sentences, sentences with third person accusative clitics (known to be problematic in Catalan SLI, but not in Spanish), passives, wh- interrogatives, subordinate clauses, subject and object relatives and conditionals. The test was administered to thirty typically developing 6- and 7-year-olds (as reported in Gavarro et al., 2012b), and five children diagnosed with SLI (mean age 10;7). The results of the task were scored under two systems: (i) identical vs. non-identical repetition and (ii) identical, grammatical and ungrammatical repetition, with detail regarding the error type. The results for typically developing and SLI children showed differences between the groups: identical repetition was found in 88.9% of cases for typically developing children but only 48% for SLI children. Ungrammatical productions were higher for the SLI group, and so were grammatical but different repetitions, a trend which was found in every child individually. The results are compared to those available in the literature for similar languages and I discuss the impact of grammatical variation in language performance, in both typical and impaired development. PMID- 29163260 TI - The Economic Utility of Clinical Psychology in the Multidisciplinary Management of Pain. PMID- 29163262 TI - The Effects of Psychotherapist's and Clients' Interpersonal Behaviors during a First Simulated Session: A Lab Study Investigating Client Satisfaction. AB - The purpose of this study was to examine the effects of psychotherapists' behaviors during a first simulated therapy session on clients' satisfaction, including their intention to pursue or drop out from therapy. The importance of psychotherapists' warmth on clients' satisfaction was examined to check previous findings stressing this determining factor. Examining the role of warm behaviors is however insufficient according to the interpersonal perspective. We therefore tested the role of the psychotherapist's agentic behaviors since only a few studies provide contradictory results about the role of this interpersonal dimension on clients' satisfaction and how it is influenced by matching up client and therapist's profiles. To test our hypotheses and control for alternative therapy-related explanatory variables, we used different videos as experimental conditions manipulating the therapist's behaviors. Seventy-five participants had to imagine themselves as potential clients arriving for a first therapy session. They successively watched a role-playing therapist behaving according to five randomized interpersonal profiles. Results confirmed that warmth was a major dimension predicting client satisfaction. They revealed that agency was also a determinant of client satisfaction and that its effects depended on the client's own interpersonal agentic profile. Dominant clients were found to be more satisfied with the dominant psychotherapist than the submissive one while submissive clients preferred only the warm psychotherapist. These findings are discussed and suggest that therapists may need to be flexible and adapt their behaviors according to their client's interpersonal profile to increase their client satisfaction and decrease drop outs. PMID- 29163263 TI - Editorial: Understanding the Successful Coordination of Team Behavior. PMID- 29163264 TI - Psychocultural Mechanisms of the Propensity toward Criminal Homicide: A Multidimensional View of the Culture of Honor. AB - Introduction: Theory of the Culture of Honor is one of the few models in criminology specifically geared toward homicide. It proposes that, in certain societies, men must never show weakness and are required to react violently to any perceived threats to their reputation, thereby increasing their probability of committing a homicide. This has been suggested as the main explanation for the high rates of this type of crime in Brazil, particularly in the Northeast. Underlying this explanation there are complex mechanisms and processes that have yet to be clarified. Objectives: The present research aimed to investigate the workings of the possible psychocultural mechanisms underlying the culture of honor and the process through which they might affect the individual propensity toward homicide. Methods: A total of 336 Brazilian adults were assessed regarding a broad range of sociodemographic, psychological, and sociocultural variables, including their attitudes toward homicide. The resulting dataset was analyzed using Smallest Space Analysis and Facet Theory. Results: It seems that certain cultural elements associated to traditional masculinity and enhanced anger tend to promote negative personality traits and increase one's propensity toward committing homicide. Conclusion: The findings obtained not only confirm the Theory of the Culture of Honor for the propensity toward homicide, but also explicit and clarify some of the psychocultural processes and mechanisms involved, suggesting a new scientific framework. PMID- 29163265 TI - Designing Interventions that Last: A Classification of Environmental Behaviors in Relation to the Activities, Costs, and Effort Involved for Adoption and Maintenance. AB - Policy makers draw on behavioral research to design interventions that promote the voluntary adoption of environmental behavior in societies. Many environmental behaviors will only be effective if they are maintained over the long-term. In the context of climate change and concerns about future water security, behaviors that involve reducing energy consumption and improving water quality must be continued indefinitely to mitigate global warming and preserve scarce resources. Previous reviews of environmental behavior have focused exclusively on factors related to adoption. This review investigates the factors that influence both adoption and maintenance, and presents a classification of environmental behaviors in terms of the activities, costs, and effort required for both adoption and maintenance. Three categories of behavior are suggested. One-off behaviors involve performing an activity once, such as purchasing an energy efficient washing machine, or signing a petition. Continuous behaviors involve the performance of the same set of behaviors for adoption and for maintenance, such as curbside recycling. Dynamic behaviors involve the performance of different behaviors for adoption and maintenance, such as revegetation. Behaviors can also be classified into four categories related to cost and effort: those that involve little cost and effort for adoption and maintenance, those that involve moderate cost and effort for adoption and maintenance, those that involve a high cost or effort for adoption and less for maintenance, and those that involve less cost or effort for adoption and a higher amount for maintenance. In order to design interventions that last, policy makers should consider the factors that influence the maintenance as well as the adoption of environmental behaviors. PMID- 29163266 TI - Linking the Positivity Effect in Attention with Affective Outcomes: Age Group Differences and the Role of Arousal. AB - Despite its assumed importance for emotional well-being, studies investigating the positivity effect (PE) in older adults' information processing rarely tested its relationship with immediate or general affective outcome measures like emotional reactivity or emotional well-being. Moreover, the arousal level of the to-be-processed emotional stimuli has rarely been taken into account as a moderator for the occurrence of the PE and its relationship with affective outcomes. Age group differences (young vs. old) in attention (i.e., fixation durations using eye tracking) and subjective emotional reactions (i.e., pleasantness ratings) were investigated in response to picture stimuli systematically varied in valence (positive vs. negative) and arousal (low vs. high). We examined whether there is a link between age group differences in fixation durations and affective outcomes (i.e., subjective emotional reactions as well as emotional well-being). Older compared to young adults fixated less on the most emotional part in negative but not in positive low-arousing pictures. This age difference did not occur under high arousal. While age group differences in fixation duration did not translate into age group differences in subjective emotional reactions, we found a positive relationship between fixation duration on negative low-arousing pictures and emotional well-being, i.e., negative affect. The present study replicated the well-known PE in attention and emotional reactivity. In line with the idea that the PE reflects top-down-driven processing of affective information, age group differences in fixation durations decreased under high arousal. The present findings are consistent with the idea that age related changes in the processing of emotional information support older adults' general emotional well-being. PMID- 29163268 TI - Sex Differences in Intergenerational Income Transmission and Educational Attainment: Testing the Trivers-Willard Hypothesis. AB - From an evolutionary point of view, sex differences in intergenerational transmission of income may be influenced by the Trivers-Willard (T-W) effect: Low status parents should invest more in daughters, whereas high status parents are expected to invest more in sons. This bias in parental investment may result in status-dependent sex biased parental support for higher education and educational attainment and should therefore affect the level of intergenerational income transmission for the sons and daughters. We used the data from the Wisconsin Longitudinal Study (WLS) to model the effect of parental financial investment on the child's income and educational attainment controlling for the number of siblings. The observed sex differences in intergenerational income transmission demonstrate that sons profited more from parental income and education in terms of their own income than daughters. Furthermore, we showed that fathers with a high socioeconomic index (SEI) invest more in their sons' education in terms of completed years of education and financial support during college. In contrast daughters of low SEI fathers completed more years of education and received more financial support than sons of low SEI fathers. However, the pattern in intergenerational income transmission might be better explained as a product of sociological factors and reproductive trade-offs in later life rather than as a consequence of the T-W effect. PMID- 29163267 TI - Binge Eating, But Not Other Disordered Eating Symptoms, Is a Significant Contributor of Binge Drinking Severity: Findings from a Cross-Sectional Study among French Students. AB - Many studies have suggested the co-occurrence of eating disorders and alcohol use disorders but in which extent binge eating (BE) and other disordered eating symptoms (DES) are associated with the severity of binge drinking (BD) remains unknown. We conducted a online cross-sectional study among 1,872 French students. Participants were asked their age, gender, tobacco and cannabis use status. They completed the Alcohol Use Questionnaire (AUQ), Eating Disorder Examination Questionnaire (EDE-Q), and UPPS impulsive behavior questionnaire. BD score was calculated using the AUQ. Three items of the EDE-Q were used to construct a BE score. The predictors of the BD score were determined using a linear regression model. Our results showed that the BE score was correlated with the BD score (beta0 = 0.051 +/- 0.022; p = 0.019), but no other DES was associated with BD, including purging behaviors. The severity of BD was also correlated with younger age, male gender, tobacco and cannabis use, and with the 'positive urgency,' 'premeditation,' and 'sensation seeking' UPPS subscores (R2 of the model: 25%). Within DES, BE appeared as an independent determinant of the BD severity. This is in line with the recent hypothesis that BE is not a subtype of DES, but more a general vulnerability factor of emotional dysregulation, which could be shared by different behavioral and addictive disorders. PMID- 29163269 TI - A Systematic Review of the Effectiveness of Intergenerational Programs. AB - Purpose of the study: The objective of the present review study is to identify the determinant elements of the effectiveness of empirically based interventions (EBI) in the field of intergenerational work, contrasting face-to-face and combined (face-to-face and virtual) intervention modalities against variables relating to this field according to EBI indicators. Design and Methods: An extensive literature search returned a total of 553 studies. Of these, just 50 studies met the inclusion criteria of being an empirical investigation of the effectiveness of intergenerational programs that contain appropriate elaboration on theoretical constructs and methods. Results: The descriptive and multivariate analysis conducted demonstrates that programs with a greater number of EBI controls have the greatest effectiveness, regardless of the intervention mode employed, and that this effectiveness is also modulated by other variables such as the participants' disabilities, their literacy level, or their membership of an organization. Conclusions: We examined the implications of these findings, noting the need to increase the number of virtual interventions that could improve the efficiency of the activities undertaken, and at the same time ensuring that EBI indicators are also fulfilled. PMID- 29163270 TI - Facial Shape Analysis Identifies Valid Cues to Aspects of Physiological Health in Caucasian, Asian, and African Populations. AB - Facial cues contribute to attractiveness, including shape cues such as symmetry, averageness, and sexual dimorphism. These cues may represent cues to objective aspects of physiological health, thereby conferring an evolutionary advantage to individuals who find them attractive. The link between facial cues and aspects of physiological health is therefore central to evolutionary explanations of attractiveness. Previously, studies linking facial cues to aspects of physiological health have been infrequent, have had mixed results, and have tended to focus on individual facial cues in isolation. Geometric morphometric methodology (GMM) allows a bottom-up approach to identifying shape correlates of aspects of physiological health. Here, we apply GMM to facial shape data, producing models that successfully predict aspects of physiological health in 272 Asian, African, and Caucasian faces - percentage body fat (21.0% of variance explained), body mass index (BMI; 31.9%) and blood pressure (BP; 21.3%). Models successfully predict percentage body fat and blood pressure even when controlling for BMI, suggesting that they are not simply measuring body size. Predicted values of BMI and BP, but not percentage body fat, correlate with health ratings. When asked to manipulate the shape of faces along the physiological health variable axes (as determined by the models), participants reduced predicted BMI, body fat and (marginally) BP, suggesting that facial shape provides a valid cue to aspects of physiological health. PMID- 29163271 TI - Self-Presentation Strategies, Fear of Success and Anticipation of Future Success among University and High School Students. AB - The backlash avoidance model (BAM) suggests women insufficiently self-promote because they fear backlash for behavior which is incongruent with traditional gender roles. Avoiding self-promoting behavior is also potentially related to associating success with negative consequences. In two studies we tested whether self-promotion and fear of success will be predictors of lower salaries and anticipation of lower chances of success in an exam. In study 1, prior to the exam they were about to take, we asked 234 students about their predictions concerning exam results and their future earnings. They also filled scales measuring their associations with success (fear of success) and tendency for self promotion. The tested model proved that in comparison to men, women expect lower salaries in the future, anticipate lower test performance and associate success with more negative consequences. Both tendency for self-promotion and fear of success are related to anticipation of success in test performance and expectations concerning future earnings. In study 2 we repeated the procedure on a sample of younger female and male high school pupils (N = 100) to verify whether associating success with negative consequences and differences in self promotion strategies are observable in a younger demographic. Our results show that girls and boys in high school do not differ with regard to fear of success, self-promotion or agency levels. Girls and boys anticipated to obtain similar results in math exam results, but girls expected to have higher results in language exams. Nevertheless, school pupils also differed regarding their future earnings but only in the short term. Fear of success and agency self-ratings were significant predictors of expectations concerning future earnings, but only among high school boys and with regard to earnings expected just after graduation. PMID- 29163272 TI - Perceived Emotional Intelligence and Learning Strategies in Spanish University Students: A New Perspective from a Canonical Non-symmetrical Correspondence Analysis. AB - Recent studies have revealed that emotional competences are relevant to the student's learning process and, more specifically, in the use of learning strategies (LSs). The aim of this study is twofold. First, we aim to analyze the relationship between perceived emotional intelligence (PEI) and LSs applying the scales TMMS-24 and Abridged ACRA to a sample of 2334 Spanish university students, whilst also exploring possible gender differences. Second, we aim to propose a methodological alternative based on the Canonical non-symmetrical correspondence analysis (CNCA), as an alternative to the methods traditionally used in Psychology and Education. Our results show that PEI has an impact on the LS of the students. Male participants with high scores on learning support strategies are positively related to high attention, clarity, and emotional repair. However, the use of cognitive and control LS is related to low values on the PEI dimensions. For women, high scores on cognitive, control, and learning support LS are related to high emotional attention, whereas dimensions such as study habits and learning support are related to adequate emotional repair. Participants in the 18-19 and 22-23 years age groups showed similar behavior. High scores on learning support strategies are related to high values on three dimensions of the PEI, and high values of study habits show high values for clarity and low values for attention and repair. The 20-21 and older than 24 years age groups behaved similarly. High scores on learning support strategies are related to low values on clarity, and study habits show high values for clarity and repair. This article presents the relationship between PEI and LS in university students, the differences by gender and age, and CNCA as an alternative method to techniques used in this field to study this association. PMID- 29163273 TI - Implications of a Culturally Evolved Self for Notions of Free Will. AB - Most schools in psychology have emphasized individual choice despite evidence of genetic and cultural determinism. It is suggested in this paper that the rejection of classical behaviorism by psychology and other humanities flowed from deeply held cultural assumptions about volition and free will. While compatibilists have suggested that notions of free will and determinism are not mutually exclusive, the psychological mechanisms by which such an accommodation could be explained have been inadequately explored. Drawing on research into classical cultures, this paper builds an argument that the notion of free will was adaptive flowing from culturally evolved changes to the self, and that this "evolved self," containing assumptions of personal volition, continuity, and reason, became benchmarks of what it means to be human. The paper proposes a model of a culturally evolved self that is compatible with understandings of free will and determinism. Implications for therapeutic practice and future research are discussed. PMID- 29163274 TI - The Relationship between Job Demands and Employees' Counterproductive Work Behaviors: The Mediating Effect of Psychological Detachment and Job Anxiety. AB - This study aims to explore the relation between job demands and counterproductive work behaviors (CWBs). A cross-sectional sample of 439 coal miners completed a self-report questionnaire that assessed their job demands, psychological detachment, job anxiety, and CWBs in a Chinese context. The conceptual model, based on the stressor-detachment model, was examined using structural equation modeling. The results suggest that psychological detachment mediates not only the relation between job demands and job anxiety but also that between job demands and CWBs. Furthermore, the relation between job demands and CWBs is sequentially mediated by psychological detachment and job anxiety. Our findings validate the effectiveness of the stressor-detachment model. Moreover, we demonstrate that the underlying mechanism of the relation between job demands and CWBs can be explained by psychological detachment and job anxiety. PMID- 29163275 TI - Evaluation of the Acoustic Coordinated Reset (CR(r)) Neuromodulation Therapy for Tinnitus: Update on Findings and Conclusions. PMID- 29163276 TI - A Joint Prosodic Origin of Language and Music. AB - Vocal theories of the origin of language rarely make a case for the precursor functions that underlay the evolution of speech. The vocal expression of emotion is unquestionably the best candidate for such a precursor, although most evolutionary models of both language and speech ignore emotion and prosody altogether. I present here a model for a joint prosodic precursor of language and music in which ritualized group-level vocalizations served as the ancestral state. This precursor combined not only affective and intonational aspects of prosody, but also holistic and combinatorial mechanisms of phrase generation. From this common stage, there was a bifurcation to form language and music as separate, though homologous, specializations. This separation of language and music was accompanied by their (re)unification in songs with words. PMID- 29163277 TI - The Effect of Task Duration on Event-Based Prospective Memory: A Multinomial Modeling Approach. AB - Remembering to perform an action when a specific event occurs is referred to as Event-Based Prospective Memory (EBPM). This study investigated how EBPM performance is affected by task duration by having university students (n = 223) perform an EBPM task that was embedded within an ongoing computer-based color matching task. For this experiment, we separated the overall task's duration into the filler task duration and the ongoing task duration. The filler task duration is the length of time between the intention and the beginning of the ongoing task, and the ongoing task duration is the length of time between the beginning of the ongoing task and the appearance of the first Prospective Memory (PM) cue. The filler task duration and ongoing task duration were further divided into three levels: 3, 6, and 9 min. Two factors were then orthogonally manipulated between-subjects using a multinomial processing tree model to separate the effects of different task durations on the two EBPM components. A mediation model was then created to verify whether task duration influences EBPM via self reminding or discrimination. The results reveal three points. (1) Lengthening the duration of ongoing tasks had a negative effect on EBPM performance while lengthening the duration of the filler task had no significant effect on it. (2) As the filler task was lengthened, both the prospective and retrospective components show a decreasing and then increasing trend. Also, when the ongoing task duration was lengthened, the prospective component decreased while the retrospective component significantly increased. (3) The mediating effect of discrimination between the task duration and EBPM performance was significant. We concluded that different task durations influence EBPM performance through different components with discrimination being the mediator between task duration and EBPM performance. PMID- 29163279 TI - Life Themes and Interpersonal Motivational Systems in the Narrative Self construction. AB - What makes unique and unrepeatable individuals is their ability to write their own story attributing meaning, sharing it through narration, giving coherence to the information related to the interpersonal motivational systems, and creating alternative hierarchies to those biologically provided by the genetic code. Through clinical narratives and narrative literature, we can observe the recurrence of specific topics, across time and different cultures. Hence, we wondered whether there are some evolutionary suggestions that guide us in the construction of the narrative-autobiographical contents. In this article we proposed a theoretical-clinical hypothesis about the existence of a biological disposition to identify as fundamental six Life Themes (LTs) that contribute to defining the image of the self and the world: Love, Personal Value, Power, Justice, Truth, and Freedom. Besides the innumerable narratives dependent upon context, there may be many ways of telling stories that, instead, would be reported to these few essential themes. A narrative review of the literature about these concepts follows the systematic explanation of the perspective about the LTs as attractors of meaning. The manuscript considers also the process of co construction of meanings within the interpersonal relationships and the influences of these on the narratives. In particular, we focused on the importance of episodic and autobiographical memory related to the attachment and significant figures, in the construction of the personal story and the LTs. We also explained the possible clinical implications of the theoretical hypothesis of LTs. Within clinical conversations, the LTs could be expressed rigidly or, otherwise, in a confused way. The lack of narrative integration may lead to the dominance of chaos or rigidity that generates suffering. A better comprehension of the LTs in patients' narrations could be useful to identify a narrative profile about the areas of greatest suffering related to the idea of self and the world, as well as to construct an adequate care plan. PMID- 29163278 TI - Can Limitations of Visuospatial Attention Be Circumvented? A Review. AB - In daily life, humans are bombarded with visual input. Yet, their attentional capacities for processing this input are severely limited. Several studies have investigated factors that influence these attentional limitations and have identified methods to circumvent them. Here, we provide a review of these findings. We first review studies that have demonstrated limitations of visuospatial attention and investigated physiological correlates of these limitations. We then review studies in multisensory research that have explored whether limitations in visuospatial attention can be circumvented by distributing information processing across several sensory modalities. Finally, we discuss research from the field of joint action that has investigated how limitations of visuospatial attention can be circumvented by distributing task demands across people and providing them with multisensory input. We conclude that limitations of visuospatial attention can be circumvented by distributing attentional processing across sensory modalities when tasks involve spatial as well as object based attentional processing. However, if only spatial attentional processing is required, limitations of visuospatial attention cannot be circumvented by distributing attentional processing. These findings from multisensory research are applicable to visuospatial tasks that are performed jointly by two individuals. That is, in a joint visuospatial task requiring object-based as well as spatial attentional processing, joint performance is facilitated when task demands are distributed across sensory modalities. Future research could further investigate how applying findings from multisensory research to joint action research may facilitate joint performance. Generally, findings are applicable to real-world scenarios such as aviation or car-driving to circumvent limitations of visuospatial attention. PMID- 29163280 TI - Production Is Only Half the Story - First Words in Two East African Languages. AB - Theories of early learning of nouns in children's vocabularies divide into those that emphasize input (language and non-linguistic aspects) and those that emphasize child conceptualisation. Most data though come from production alone, assuming that learning a word equals speaking it. Methodological issues can mean production and comprehension data within or across input languages are not comparable. Early vocabulary production and comprehension were examined in children hearing two Eastern Bantu languages whose grammatical features may encourage early verb knowledge. Parents of 208 infants aged 8-20 months were interviewed using Communicative Development Inventories that assess infants' first spoken and comprehended words. Raw totals, and proportions of chances to know a word, were compared to data from other languages. First spoken words were mainly nouns (75-95% were nouns versus less than 10% verbs) but first comprehended words included more verbs (15% were verbs) than spoken words did. The proportion of children's spoken words that were verbs increased with vocabulary size, but not the proportion of comprehended words. Significant differences were found between children's comprehension and production but not between languages. This may be for pragmatic reasons, rather than due to concepts with which children approach language learning, or directly due to the input language. PMID- 29163281 TI - Academic Self-Efficacy Partially Mediates the Relationship between Scottish Index of Multiple Deprivation and Composite Attainment Score. AB - A developing literature continues to testify to the relationship between higher socio-economic status (SES) and better academic attainment. However, the literature is complex in terms of the variety of SES and attainment indicators used. Against the backdrop of a Scottish Government initiative to close the attainment gap between higher and lower SES children, the present study examined the relationship between individual-level Scottish Index of Multiple Deprivation (SIMD) and National Lower Tariff Score in school children in the West of Scotland. Results showed a practically significant relationship between SIMD and Tariff Score. This relationship was partially mediated by higher academic self efficacy, so that higher belief in academic competency partially mediated the SIMD-Tariff Score relationship. Further, this partial mediation was robust to the influence of gender, sensation seeking, level of school attendance and past month frequency of Heavy Episodic Drinking. It is suggested that increasing attendance and perceived academic competence are viable ways (among others) of attempting to close the attainment gap. PMID- 29163282 TI - From Querulous to Suicidal: Self-immolation in Public Places as a Symbolic Response to the Feeling of Injustice. AB - Aim: This paper sheds light on the context that leads some querulous patients to self-immolate in front of, or into, public buildings (e.g., tribunals, city halls, and employment agencies). Method: The author defines paranoid querulousness. A psychoanalytic perspective, but also a judicial and a psychiatric point of view, over querulous claimants is presented. The links between political or social claims and self-immolation are studied. The expression of suicidal thoughts voiced by four querulous subjects is analyzed. Eight examples of self-immolation are presented. Results: The querulous subjects' self-aggressive behaviors seem to be caused by a loss of hope to obtain compensation for a prejudice they allegedly suffered. Querulous individuals tend to self-immolate in front of, or into, public buildings when no answer is given to their claims. These gestures may be both a consequence of some personal distress and triggered by a difficult social or professional context. Discussion: Five sets of assumptions derived from Freudian and Lacanian psychoanalytic theories are advanced. The status of the object over which the querulous claimants wish to assert their rights is clarified. The meaning of self aggressive gestures is outlined by making reference to the concepts of instinct for mastery, symbolic other, chain of signifiers, masochism, pleasure principle, and reality principle. Conclusion: Prevention of self-immolation could involve that members of the legal professions, social workers, civil servants, and mental health professionals in contact with querulous subjects openly show their will to listen to these claimants' voice: self-aggressive gestures might be avoided by supporting the querulous person's hope to obtain compensation for the prejudice allegedly suffered. PMID- 29163283 TI - The Influence of Background Music on Learning in the Light of Different Theoretical Perspectives and the Role of Working Memory Capacity. AB - This study investigates how background music influences learning with respect to three different theoretical approaches. Both the Mozart effect as well as the arousal-mood-hypothesis indicate that background music can potentially benefit learning outcomes. While the Mozart effect assumes a direct influence of background music on cognitive abilities, the arousal-mood-hypothesis assumes a mediation effect over arousal and mood. However, the seductive detail effect indicates that seductive details such as background music worsen learning. Moreover, as working memory capacity has a crucial influence on learning with seductive details, we also included the learner's working memory capacity as a factor in our study. We tested 81 college students using a between-subject design with half of the sample listening to two pop songs while learning a visual text and the other half learning in silence. We included working memory capacity in the design as a continuous organism variable. Arousal and mood scores before and after learning were collected as potential mediating variables. To measure learning outcomes we tested recall and comprehension. We did not find a mediation effect between background music and arousal or mood on learning outcomes. In addition, for recall performance there were no main effects of background music or working memory capacity, nor an interaction effect of these factors. However, when considering comprehension we did find an interaction between background music and working memory capacity: the higher the learners' working memory capacity, the better they learned with background music. This is in line with the seductive detail assumption. PMID- 29163284 TI - Creative Motor Actions As Emerging from Movement Variability. AB - In cognitive science, creative ideas are defined as original and feasible solutions in response to problems. A common proposal is that creative ideas are generated across dedicated cognitive pathways. Only after creative ideas have emerged, they can be enacted to solve the problem. We present an alternative viewpoint, based upon the dynamic systems approach to perception and action, that creative solutions emerge in the act rather than before. Creative actions, thus, are as much a product of individual constraints as they are of the task and environment constraints. Accordingly, we understand creative motor actions as functional movement patterns that are new to the individual and/or group and adapted to satisfy the constraints on the motor problem at hand. We argue that creative motor actions are promoted by practice interventions that promote exploration by manipulating constraints. Exploration enhances variability of functional movement patterns in terms of either coordination or control solutions. At both levels, creative motor actions can emerge from finding new and degenerate adaptive motor solutions. Generally speaking, we anticipate that in most cases, when exposed to variation in constraints, people are not looking for creative motor actions, but discover them while doing an effort to satisfy constraints. For future research, this paper achieves two important aspects: it delineates how adaptive (movement) variability is at the heart of (motor) creativity, and it sets out methodologies toward stimulating adaptive variability. PMID- 29163285 TI - Effects of Phonological Training on the Reading and Reading-Related Abilities of Hong Kong Children with Dyslexia. AB - This study aimed to investigate phonological awareness training by examining outcomes among Chinese children who learn Chinese without phonetic system training. Fifty-six Hong Kong children from the 3rd to 6th grades were recruited. Two-thirds of the children had been officially identified as dyslexic by the local government, and the remainder were considered high risk for dyslexia. The children were divided equally into a control group and an experimental group, with the groups matched as closely as possible by age and gender. Children in the experimental group were trained by onset-rime-level phonological training. The training lasted ~3 weeks, with 15 daily sessions lasting ~20 min each. Our results indicated that children in the experimental group made significant improvements in Chinese character reading, onset awareness, rime awareness, and rapid naming after training. The association between phonological awareness and Chinese character reading, especially the association between rime awareness and Chinese character reading, also changed after training. The benefits of phonological awareness training were more obvious for children younger than 10 years old. The results of the present study can be extended to provide another approach to Chinese learning for children suffering from reading difficulties who are not responding to the usual approach in their region. PMID- 29163286 TI - Perception of Western Musical Modes: A Chinese Study. AB - The major mode conveys positive emotion, whereas the minor mode conveys negative emotion. However, previous studies have primarily focused on the emotions induced by Western music in Western participants. The influence of the musical mode (major or minor) on Chinese individuals' perception of Western music is unclear. In the present experiments, we investigated the effects of musical mode and harmonic complexity on psychological perception among Chinese participants. In Experiment 1, the participants (N = 30) evaluated 24 musical excerpts in five dimensions (pleasure, arousal, dominance, emotional tension, and liking). In Experiment 2, the participants (N = 40) evaluated 48 musical excerpts. Perceptions of the musical excerpts differed significantly according to mode, even if the stimuli were Western musical excerpts. The major-mode music induced greater pleasure and arousal and produced higher liking ratings than the minor mode music, whereas the minor-mode music induced greater tension than the major mode music. Mode did not influence the dominance rating. Perception of Western music was not influenced by harmonic complexity. Moreover, preference for musical mode was influenced by previous exposure to Western music. These results confirm the cross-cultural emotion induction effects of musical modes in Western music. PMID- 29163287 TI - Corporate Social Responsibility and Employee Outcomes: A Moderated Mediation Model of Organizational Identification and Moral Identity. AB - Corporate social responsibility (CSR) research is not new, but its importance to today's socially conscious market environment is even more evident in recent years. This study moves beyond CSR as simply the socially responsible actions and policies of organizations and focuses on the complex psychology of CSR as it relates to individuals within the organization. Given CSR can positively affect both the individuals within the organization and the organization itself, better understanding and leveraging the mechanisms and conditions of CSR that facilitate desired employee outcomes is crucial for organizational performance. However, scholars lack consensus in determining a theoretical framework for understanding how and under what conditions CSR will make an impact on employees and ultimately organizational performance. This study adds clarity by exploring the effect of perceived CSR on a more comprehensive set of employees' attitudinal and behavioral reactions (i.e., turnover intention, in-role job performance, and helping behavior) via the mediating mechanism of organizational identification and the moderating condition of moral identity. Hypotheses were derived using social identity theory. Results were based on data obtained from 340 Chinese manufacturing employee-supervisor dyads. This study found that employees' perceived CSR had an indirect relationship via organizational identification with each of the variables: (1) turnover intention, (2) in-role job performance, and (3) helping behavior. Specifically, the negative relationship between perceived CSR and turnover intention was stronger when employees had higher moral identity and the positive relationship between perceived CSR and in-role job performance and helping behavior was amplified by moral identity. Our findings show how the mediating mechanism of organizational identity and the moderating condition of moral identity work together to improve organizational effectiveness. The findings reveal several ways in which organizations can strategically focus their CSR and human resource efforts, such as applying this model and focusing on moral identity as a key indicator when evaluating employees. PMID- 29163288 TI - Linguistic and Cognitive Effects of Bilingualism with Regional Minority Languages: A Study of Sardinian-Italian Adult Speakers. AB - This study explores the effects of bilingualism in Sardinian as a regional minority language on the linguistic competence in Italian as the dominant language and on non-linguistic cognitive abilities. Sardinian/Italian adult speakers and monolingual Italian speakers living in the same geographical area of Sardinia were compared in two kinds of tasks: (a) verbal and non-verbal cognitive tasks targeting working memory and attentional control and (b) tasks of linguistic abilities in Italian focused on the comprehension of sentences differing in grammatical complexity. Although no difference was found between bilinguals and monolinguals in the cognitive control of attention, bilinguals performed better on working memory tasks. Bilinguals with lower formal education were found to be faster at comprehension of one type of complex sentence (center embedded object relative clauses). In contrast, bilinguals and monolinguals with higher education showed comparable slower processing of complex sentences. These results show that the effects of bilingualism are modulated by type of language experience and education background: positive effects of active bilingualism on the dominant language are visible in bilinguals with lower education, whereas the effects of higher literacy in Italian obliterate those of active bilingualism in bilinguals and monolinguals with higher education. PMID- 29163289 TI - Network Approach to Understanding Emotion Dynamics in Relation to Childhood Trauma and Genetic Liability to Psychopathology: Replication of a Prospective Experience Sampling Analysis. AB - Background: The network analysis of intensive time series data collected using the Experience Sampling Method (ESM) may provide vital information in gaining insight into the link between emotion regulation and vulnerability to psychopathology. The aim of this study was to apply the network approach to investigate whether genetic liability (GL) to psychopathology and childhood trauma (CT) are associated with the network structure of the emotions "cheerful," "insecure," "relaxed," "anxious," "irritated," and "down"-collected using the ESM method. Methods: Using data from a population-based sample of twin pairs and siblings (704 individuals), we examined whether momentary emotion network structures differed across strata of CT and GL. GL was determined empirically using the level of psychopathology in monozygotic and dizygotic co-twins. Network models were generated using multilevel time-lagged regression analysis and were compared across three strata (low, medium, and high) of CT and GL, respectively. Permutations were utilized to calculate p values and compare regressions coefficients, density, and centrality indices. Regression coefficients were presented as connections, while variables represented the nodes in the network. Results: In comparison to the low GL stratum, the high GL stratum had significantly denser overall (p = 0.018) and negative affect network density (p < 0.001). The medium GL stratum also showed a directionally similar (in-between high and low GL strata) but statistically inconclusive association with network density. In contrast to GL, the results of the CT analysis were less conclusive, with increased positive affect density (p = 0.021) and overall density (p = 0.042) in the high CT stratum compared to the medium CT stratum but not to the low CT stratum. The individual node comparisons across strata of GL and CT yielded only very few significant results, after adjusting for multiple testing. Conclusions: The present findings demonstrate that the network approach may have some value in understanding the relation between established risk factors for mental disorders (particularly GL) and the dynamic interplay between emotions. The present finding partially replicates an earlier analysis, suggesting it may be instructive to model negative emotional dynamics as a function of genetic influence. PMID- 29163290 TI - Children's Mathematics and Verbal Self-concepts and Externalizing Behaviors: The Moderating Role of Peer Rejection at School. AB - Previous research has found a strong correlation between children's academic self concept and their behavioral problems. The present study examined whether children's peer rejection moderated the relationship between children's math and verbal self-concepts and their behavioral problems at school. We expected that children's social competence, as measured by peer rejection, moderated the negative effect of low self-concept on children's externalizing behaviors. Participants were 173 children (males = 93, Mage = 10.31 years, SD = 1.43). The main findings showed that peer rejection moderated the effect of both low verbal and math self-concepts on children's externalizing behavior. The results are discussed in terms of the protective factor played by children's social competence reducing the impact of low self-concept on children's externalizing behaviors. PMID- 29163291 TI - Implicit Attitudes toward the Self Over Time in Chinese Undergraduates. AB - Although the explicit attitudes of Chinese people toward the self over time are known (i.e., past = present < future), little is known about their implicit attitudes. Two studies were conducted to measure the implicit subjective temporal trajectory (STT) of Chinese undergraduates. Study 1 used a Go/No-go association task to measure participants' implicit attitudes toward their past, present, and future selves. The obtained implicit STT was different from the explicit pattern found in former research. It showed that the future self was viewed to be identical to the present self and participants implicitly evaluated their present self as better than the past self. Since this comparison of the past and present selves suggested a cultural difference, we aimed to replicate this finding in Study 2. Using an implicit association test, we again found that the present self was more easily associated with positive valence than the past self. Overall, both studies reveal an implicitly inclining-flat STT (i.e., past < present = future) for Chinese undergraduates. Implications of this difference in explicit implicit measures and the cultural differences of temporal self appraisals are discussed. PMID- 29163292 TI - Further Evidence That the Effects of Repetition on Subjective Time Depend on Repetition Probability. AB - Repeated stimuli typically have shorter apparent duration than novel stimuli. Most explanations for this effect have attributed it to the repeated stimuli being more expected or predictable than the novel items, but an emerging body of work suggests that repetition and expectation exert distinct effects on time perception. The present experiment replicated a recent study in which the probability of repetition was varied between blocks of trials. As in the previous work, the repetition effect was smaller when repeats were common (and therefore more expected) than when they were rare. These results add to growing evidence that, contrary to traditional accounts, expectation increases apparent duration whereas repetition compresses subjective time, perhaps via a low-level process like adaptation. These opposing processes can be seen as instances of a more general "processing principle," according to which subjective time is a function of the perceptual strength of the stimulus representation, and therefore depends on a confluence of "bottom-up" and "top-down" variables. PMID- 29163293 TI - Adaptation and Validation of the ADOS-2, Polish Version. AB - Autism Diagnostic Observation Schedule (ADOS) is one of the most popular instruments used world-widely in the diagnosis of autism spectrum disorders (ASD). Unfortunately, there are only a few studies of the psychometric properties of non-English language versions of this instrument and none of the adaptation of its second edition (ADOS-2). The objective of this study was to verify the psychometric properties of the Polish version of the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2-PL). The authors recruited 401 participants: 193 with ASDs (ASD group) and 78 with non-spectrum disorders, plus 130 typically developing participants (control group). ADOS-2-PL was found to have high interrater reliability, internal consistency and test-retest reliability. Confirmatory factor analysis confirmed a good fit of the Polish data to the two-factor model of ADOS-2. As no significant differences were found between participants with childhood autism and other ASDs, only one cut-off was established for Modules 1-4. The sensitivity, specificity and positive predictive value of ADOS-2-PL are high: sensitivity was over 90% (only for the "Older with some words" algorithm in the Toddler Module the sensitivity was 71% and "Aged 5 years or older" algorithm in Module 2 sensitivity was 84%), specificity was above 80% (with the exception of the Module 4 and Module 2 "Aged 5 years or older" algorithm where it was above 70%). The results support the use of ADOS-2-PL in clinical practice and scientific research. To the best of our knowledge, there have been no reports to date about adaptations of ADOS-2 and the psychometric properties of non-English language versions. As such, this constitutes the first attempt at adapting ADOS-2, and its results could be of interest for researchers outside of Poland. PMID- 29163294 TI - Constructing a Reward-Related Quality of Life Statistic in Daily Life-a Proof of Concept Study Using Positive Affect. AB - Background: Mental healthcare needs person-tailored interventions. Experience Sampling Method (ESM) can provide daily life monitoring of personal experiences. This study aims to operationalize and test a measure of momentary reward-related Quality of Life (rQoL). Intuitively, quality of life improves by spending more time on rewarding experiences. ESM clinical interventions can use this information to coach patients to find a realistic, optimal balance of positive experiences (maximize reward) in daily life. rQoL combines the frequency of engaging in a relevant context (a 'behavior setting') with concurrent (positive) affect. High rQoL occurs when the most frequent behavior settings are combined with positive affect or infrequent behavior settings co-occur with low positive affect. Methods: Resampling procedures (Monte Carlo experiments) were applied to assess the reliability of rQoL using various behavior setting definitions under different sampling circumstances, for real or virtual subjects with low-, average and high contextual variability. Furthermore, resampling was used to assess whether rQoL is a distinct concept from positive affect. Virtual ESM beep datasets were extracted from 1,058 valid ESM observations for virtual and real subjects. Results: Behavior settings defined by Who-What contextual information were most informative. Simulations of at least 100 ESM observations are needed for reliable assessment. Virtual ESM beep datasets of a real subject can be defined by Who-What-Where behavior setting combinations. Large sample sizes are necessary for reliable rQoL assessments, except for subjects with low contextual variability. rQoL is distinct from positive affect. Conclusion: rQoL is a feasible concept. Monte Carlo experiments should be used to assess the reliable implementation of an ESM statistic. Future research in ESM should asses the behavior of summary statistics under different sampling situations. This exploration is especially relevant in clinical implementation, where often only small datasets are available. PMID- 29163295 TI - How Much of Language Acquisition Does Operant Conditioning Explain? AB - Since the 1950s, when Chomsky argued that Skinner's arguments could not explain syntactic acquisition, psychologists have generally avoided explicitly invoking operant or instrumental conditioning as a learning mechanism for language among human children. In this article, we argue that this is a mistake. We focus on research that has been done on language learning in human infants and toddlers in order to illustrate our points. Researchers have ended up inventing learning mechanisms that, in actual practice, not only resemble but also in fact are examples of operant conditioning (OC) by any other name they select. We argue that language acquisition researchers should proceed by first ruling out OC before invoking alternative learning mechanisms. While it is possible that OC cannot explain all of the language acquisition, simple learning mechanisms that work across species may have some explanatory power in children's language learning. PMID- 29163296 TI - Post-event Processing Predicts Impaired Cortisol Recovery Following Social Stressor: The Moderating Role of Social Anxiety. AB - There is growing evidence that individuals with social anxiety show impaired cortisol recovery after experiencing social evaluative stressors. Yet, little is known regarding the cognitive processes underlying such impaired cortisol recovery. The present study examined the effect of post-event processing (PEP), referred to as repetitive thinking about social situations, on cortisol recovery following a social stressor. Forty-two non-clinical university students (23 women, 19 men, mean age = 22.0 +/- 2.0 years) completed the Trier Social Stress Test (TSST), followed by a thought sampling procedure which assessed the frequency of PEP reflecting the TSST. A growth curve model showed PEP and social anxiety interactively predicted cortisol recovery. In particular, PEP predicted impaired cortisol recovery in those with low levels of social anxiety but not in those with high levels of social anxiety, which contradicted the initial hypothesis. These findings suggest that PEP is differentially associated with cortisol recovery depending on levels of social anxiety. The possible mechanisms underlying these findings were discussed in terms of protective inhibition framework. PMID- 29163297 TI - Customer Orientation and Leadership in the Health Service Sector: The Role of Workplace Social Support. AB - Health care is a critical context due to unpredictable situations, demanding clients, workload, and intrinsic organizational complexity. One key to improve the quality of health services is connected to the shift in organization perspective of viewing patients as active consumers rather than passive users. Therefore, higher levels of customer orientation (CO) are expected to improve organizational service effectiveness. According to a cultural perspective to CO, the aim of the study was to explore how different leaders' behaviors (task oriented and relationship-oriented) interact with CO of health organizations. Specifically, the aim of the paper was to contribute to this topic, by considering the leaders' point of view. Since leader's experience of CO is influenced by social processes in the work environment, workplace social support (WSS) was inserted as moderator in the relationship between leader behavior and CO. A survey study was conducted among 57 Health Department directors belonging to the National Health Service in the North of Italy in 2016. Findings showed that WSS moderated the influence of leadership concern for relationship on CO. Practical implications of the study are discussed. PMID- 29163298 TI - The Effects of Cognitive Reappraisal and Expressive Suppression on Memory of Emotional Pictures. AB - In the field of emotion research, the influence of emotion regulation strategies on memory with emotional materials has been widely discussed in recent years. However, existing studies have focused exclusively on regulating negative emotion but not positive emotion. Therefore, in the present study, we investigated the influence of emotion regulation strategies for positive emotion on memory. One hundred and twenty college students were selected as participants. Emotional pictures (positive, negative and neutral) were selected from Chinese Affective Picture System (CAPS) as experimental materials. We employed a mixed, 4 (emotion regulation strategies: cognitive up-regulation, cognitive down-regulation, expressive suppression, passive viewing) * 3 (emotional pictures: positive, neutral, negative) experimental design. We investigated the influences of different emotion regulation strategies on memory performance, using free recall and recognition tasks with pictures varying in emotional content. The results showed that recognition and free recall memory performance of the cognitive reappraisal groups (up-regulation and down-regulation) were both better than that of the passive viewing group for all emotional pictures. No significant differences were reported in the two kinds of memory scores between the expressive suppression and passive viewing groups. The results also showed that the memory performance with the emotional pictures differed according to the form of memory test. For the recognition test, participants performed better with positive images than with neutral images. Free recall scores with negative images were higher than those with neutral images. These results suggest that both cognitive reappraisal regulation strategies (up-regulation and down-regulation) promoted explicit memories of the emotional content of stimuli, and the form of memory test influenced performance with emotional pictures. PMID- 29163299 TI - Behavioral Evidence for Enhanced Processing of the Minor Component of Binary Odor Mixtures in Larval Drosophila. AB - A fundamental problem in deciding between mutually exclusive options is that the decision needs to be categorical although the properties of the options often differ but in grade. We developed an experimental handle to study this aspect of behavior organization. Larval Drosophila were trained such that in one set of animals odor A was rewarded, but odor B was not (A+/B), whereas a second set of animals was trained reciprocally (A/B+). We then measured the preference of the larvae either for A, or for B, or for "morphed" mixtures of A and B, that is for mixtures differing in the ratio of the two components. As expected, the larvae showed higher preference when only the previously rewarded odor was presented than when only the previously unrewarded odor was presented. For mixtures of A and B that differed in the ratio of the two components, the major component dominated preference behavior-but it dominated less than expected from a linear relationship between mixture ratio and preference behavior. This suggests that a minor component can have an enhanced impact in a mixture, relative to such a linear expectation. The current paradigm may prove useful in understanding how nervous systems generate discrete outputs in the face of inputs that differ only gradually. PMID- 29163300 TI - Relations among Temperament, Self-regulatory Strategies and Gender in Predicting Delay of Gratification. AB - Self-regulation is associated with many positive outcomes, but there is limited information about individual difference regarding children's spontaneous use of strategies to self-regulate and the relative success of those strategies. In the current study, we examined whether temperament and gender are associated with self-regulation and explored the types of spontaneous strategies children use during Mischel's delay of gratification protocol. In addition, we investigated whether spontaneous strategy use during the task could moderate the effects of temperament on self-regulation and whether temperament would mediate the effect of gender on self-regulation. Participants were 349 9-year-olds (182 boys, Mage = 9.18, SD = 1.17). Mothers reported on children's temperament and the Delay of Gratification task was used to assess self-regulation. Both temperament and child's gender were significantly associated with children's delay time. Girls were able to delay longer than boys, and children scoring high on activity level were less able to delay. Activity level also mediated the relationship between gender and delay time. Finally, we found an interaction effect between activity level and certain strategies in relation to self-regulatory behavior. PMID- 29163301 TI - The Relationship between Defense Patterns and DSM-5 Maladaptive Personality Domains. AB - Aim: Research has extensively examined the relationship between defense mechanisms (DM) and personality traits. However, no study to date has explored if specific defenses (alone or in combination) are able to predict dysfunctional variants of personality domains, as conceived in the alternative DSM-5 model for personality disorders. This study aimed to investigate the relationship between DMs and DSM-5 maladaptive personality domains among adults. Materials and Methods: Three hundred and twenty-eight adults aged between 18 and 64 years old completed measures on DMs and maladapive personality domains. Regression analyses were performed to determine which DMs predicted the maladaptive personality domains of negative affectivity, detachment, antagonism, disinhibition, and psychoticism. Results: According to psychoanalytic literature, results showed that immature defenses positively predicted maladaptive personality domain scores, whereas mature defenses were generally related with better personality functioning. Moreover, different defense patterns emerged as significant predictors of the maladaptive personality domains comprised in the alternative DSM-5 model for personality disorder. Discussion: Our findings support the view that defense patterns represent core components of personality and its disorders, and suggest that an increased use of immature defenses and a reduced use of mature defenses have a negative impact on the development of personality. PMID- 29163302 TI - Irrational Delay Revisited: Examining Five Procrastination Scales in a Global Sample. AB - Scales attempting to measure procrastination focus on different facets of the phenomenon, yet they share a common understanding of procrastination as an unnecessary, unwanted, and disadvantageous delay. The present paper examines in a global sample (N = 4,169) five different procrastination scales - Decisional Procrastination Scale (DPS), Irrational Procrastination Scale (IPS), Pure Procrastination Scale (PPS), Adult Inventory of Procrastination Scale (AIP), and General Procrastination Scale (GPS), focusing on factor structures and item functioning using Confirmatory Factor Analysis and Item Response Theory. The results indicated that The PPS (12 items selected from DPS, AIP, and GPS) measures different facets of procrastination even better than the three scales it is based on. An even shorter version of the PPS (5 items focusing on irrational delay), corresponds well to the nine-item IPS. Both scales demonstrate good psychometric properties and appear to be superior measures of core procrastination attributes than alternative procrastination scales. PMID- 29163303 TI - Attentional Orientation Patterns toward Emotional Faces and Temperamental Correlates of Preschool Oppositional Defiant Problems: The Moderating Role of Callous-Unemotional Traits and Anxiety Symptoms. AB - The present study examined the independent contributions and the interaction effects of oppositional defiant problems (ODD), callous unemotional traits (CU) and anxiety symptoms on attentional orienting to emotional faces, in a community sample of preschoolers. Additionally, based on Rothbart's (2007) model of temperament, we analyzed whether fine-grained dimensions of reactivity (fear, anger, discomfort, sadness, activity level, approach, high intensity pleasure, impulsivity) and self-regulation (attentional shifting, attentional focusing, inhibitory control), as well as the higher order temperamental factors of negative affectivity, surgency and effortful control are associated with CU traits and ODD-related problems. Attentional orienting to emotional faces was assessed with pictorial Dot-probe task, while teachers rated CU traits and ODD related problems. Also, parents reported on ODD-related problems, anxiety and temperament. Results indicated significant interaction effects between ODD related problems and CU, as well as between CU and anxiety, in predicting attentional orientation patterns for angry, fearful and happy faces. Moreover, temperamental reactivity was positively associated with CU traits and ODD-related problems, whereas temperamental self-regulation was negatively related to CU traits and ODD-related problems. Results of this study have implications for early intervention and prevention approaches targeting preschool oppositional defiant problems. PMID- 29163305 TI - Editorial: Hand and Touch: Evolution, Ability, and Preference. PMID- 29163304 TI - Do Different Mental Models Influence Cybersecurity Behavior? Evaluations via Statistical Reasoning Performance. AB - Cybersecurity research often describes people as understanding internet security in terms of metaphorical mental models (e.g., disease risk, physical security risk, or criminal behavior risk). However, little research has directly evaluated if this is an accurate or productive framework. To assess this question, two experiments asked participants to respond to a statistical reasoning task framed in one of four different contexts (cybersecurity, plus the above alternative models). Each context was also presented using either percentages or natural frequencies, and these tasks were followed by a behavioral likelihood rating. As in previous research, consistent use of natural frequencies promoted correct Bayesian reasoning. There was little indication, however, that any of the alternative mental models generated consistently better understanding or reasoning over the actual cybersecurity context. There was some evidence that different models had some effects on patterns of responses, including the behavioral likelihood ratings, but these effects were small, as compared to the effect of the numerical format manipulation. This points to a need to improve the content of actual internet security warnings, rather than working to change the models users have of warnings. PMID- 29163306 TI - Quantifying Contextual Interference and Its Effect on Skill Transfer in Skilled Youth Tennis Players. AB - The contextual interference effect is a well-established motor learning phenomenon. Most of the contextual interference effect literature has addressed simple skills, while less is known about the role of contextual interference in complex sport skill practice, particularly with respect to skilled performers. The purpose of this study was to assess contextual interference when practicing the tennis serve. Study 1 evaluated tennis serve practice of nine skilled youth tennis players using a novel statistical metric developed specifically to measure between-skill and within-skill variability as sources of contextual interference. This metric highlighted that skilled tennis players typically engaged in serve practice that featured low contextual interference. In Study 2, 16 skilled youth tennis players participated in 10 practice sessions that aimed to improve serving "down the T." Participants were stratified into a low contextual interference practice group (Low CI) and a moderate contextual interference practice group (Moderate CI). Pre- and post-tests were conducted 1 week before and 1 week after the practice period. Testing involved a skill test, which assessed serving performance in a closed setting, and a transfer test, which assessed serving performance in a match-play setting. No significant contextual interference differences were observed with respect to practice performance. However, analysis of pre- and post-test serve performance revealed significant Group * Time interactions. The Moderate CI group showed no change in serving performance (service displacement from the T) from pre- to post-test in the skill test, but did display improvements in the transfer test. Conversely, the Low CI group improved serving performance (service displacement from the T) in the skill test but not the transfer test. Results suggest that the typical contextual interference effect is less clear when practicing a complex motor skill, at least with the tennis serve skill evaluated here. We encourage researchers and applied sport scientists to use our statistical metric to measure contextual interference. PMID- 29163307 TI - On Nomological Validity and Auxiliary Assumptions: The Importance of Simultaneously Testing Effects in Social Cognitive Theories Applied to Health Behavior and Some Guidelines. AB - Tests of social cognitive theories provide informative data on the factors that relate to health behavior, and the processes and mechanisms involved. In the present article, we contend that tests of social cognitive theories should adhere to the principles of nomological validity, defined as the degree to which predictions in a formal theoretical network are confirmed. We highlight the importance of nomological validity tests to ensure theory predictions can be disconfirmed through observation. We argue that researchers should be explicit on the conditions that lead to theory disconfirmation, and identify any auxiliary assumptions on which theory effects may be conditional. We contend that few researchers formally test the nomological validity of theories, or outline conditions that lead to model rejection and the auxiliary assumptions that may explain findings that run counter to hypotheses, raising potential for 'falsification evasion.' We present a brief analysis of studies (k = 122) testing four key social cognitive theories in health behavior to illustrate deficiencies in reporting theory tests and evaluations of nomological validity. Our analysis revealed that few articles report explicit statements suggesting that their findings support or reject the hypotheses of the theories tested, even when findings point to rejection. We illustrate the importance of explicit a priori specification of fundamental theory hypotheses and associated auxiliary assumptions, and identification of the conditions which would lead to rejection of theory predictions. We also demonstrate the value of confirmatory analytic techniques, meta-analytic structural equation modeling, and Bayesian analyses in providing robust converging evidence for nomological validity. We provide a set of guidelines for researchers on how to adopt and apply the nomological validity approach to testing health behavior models. PMID- 29163308 TI - Disclosure and Exposure of Alcohol on Social Media and Later Alcohol Use: A Large Scale Longitudinal Study. AB - This article aims to investigate whether alcohol-related disclosure and exposure on social media can predict later alcohol use, and to identify covariates in these relationships. Data were collected by online surveys (two waves) among students in Bergen, Norway. The first survey was administered in fall 2015. The follow-up took place during fall 2016. A total of 5,217 students participated in both waves. The surveys included questions about demographics, personality, alcohol use, alcohol-related cognitions (e.g., attitudes and norms), social media use, and disclosure and exposure of alcohol on social media. Bivariate comparisons were conducted to assess differences in alcohol use between the frequent (i.e., monthly or more often) disclosure and exposure groups and low frequent disclosure and exposure groups. Crude and adjusted linear regressions were employed to investigate if disclosure and exposure of alcohol could predict later alcohol use, when controlling for a range of covariates. Compared to the low-frequent disclosure and exposure groups, participants which frequently disclosed or were frequently exposed to alcohol-related content had higher alcohol use at baseline and 1 year later (p < 0.001), when no covariates were controlled for. Frequent disclosure of content reflecting positive aspects of alcohol predicted stable or slightly increased alcohol use at Time 2 (p < 0.01), even when all covariates (i.e., demographics, personality, alcohol use, alcohol related cognitions, and social media use) were controlled for. In conclusion, frequent disclosure and/or exposure to alcohol-related content predicted alcohol use over time. Alcohol disclosure/exposure on social media could for the most part not predict later alcohol use when baseline alcohol use was controlled for. High alcohol use and alcohol disclosure/exposure on social media appear to be strongly intertwined, which hampers identification of directionality between alcohol use and disclosure/exposure. Disclosing content reflecting positive aspects of alcohol was the only independent variable that could predict further alcohol use when other factors, like baseline alcohol use, were held constant. This finding suggests that disclosure of alcohol content reflecting positive aspects of alcohol might have a self-enhancing effect on the sharers' further alcohol consumption, or that disclosing such content could indicate lenient alcohol-related cognitions not detected by the current measurements. PMID- 29163309 TI - Eye Movement Desensitization and Reprocessing and Slow Wave Sleep: A Putative Mechanism of Action. AB - Eye Movement Desensitization and Reprocessing (EMDR) is considered highly efficacious for the treatment of Post-traumatic Stress Disorder and has proved to be a valid treatment approach with a wide range of applications. However, EMDR's mechanisms of action is not yet fully understood. This is an active area of clinical and neurophysiological research, and several different hypotheses have been proposed. This paper discusses a conjecture which focuses on the similarity between the delta waves recorded by electroencephalography during Slow Wave Sleep (SWS) and those registered upon typical EMDR bilateral stimulation (eye movements or alternate tapping) during recurrent distressing memories of an emotionally traumatic event. SWS appears to have a key role in memory consolidation and in the reorganization of distant functional networks, as well as Eye Movements seem to reduce traumatic episodic memory and favor the reconsolidation of new associated information. The SWS hypothesis may put forward an explanation of how EMDR works, and is discussed also in light of other theories and neurobiological findings. PMID- 29163310 TI - Perception Accuracy of Affiliative Relationships in Elementary School Children and Young Adolescents. AB - There has been a rapid growth of studies focused on selection and socialization processes of peer groups, mostly due to the development of stochastic actor-based models to analyze longitudinal social network data. One of the core assumptions of these models is that individuals have an accurate knowledge of the dyadic relationships within their network (i.e., who is and is not connected to whom). Recent cross-sectional findings suggest that elementary school children are very inaccurate in perceiving their classmates' dyadic relationships. These findings question the validity of stochastic actor-based models to study the developmental dynamics of children and carry implications for future research as well as for the interpretation of past findings. The goal of the present study was thus to further explore the adequacy of the accuracy assumption, analysing data from three longitudinal samples of different age groups (elementary school children and adolescents). Our results support the validity of stochastic actor-based models to study the network of adolescents and suggest that the violation of the accuracy assumption for elementary school children is not as severe as previously thought. PMID- 29163311 TI - Auditory and Visual Memories in PTSD Patients Targeted with Eye Movements and Counting: The Effect of Modality-Specific Loading of Working Memory. AB - Introduction: Eye movement desensitization and reprocessing (EMDR) therapy is an evidence-based treatment for post-traumatic stress disorder (PTSD). A key element of this therapy is simultaneously recalling an emotionally disturbing memory and performing a dual task that loads working memory. Memories targeted with this therapy are mainly visual, though there is some evidence that auditory memories can also be targeted. Objective: The present study tested whether auditory memories can be targeted with EMDR in PTSD patients. A second objective was to test whether taxing the patient (performing a dual task while recalling a memory) in a modality specific way (auditory demanding for auditory memories and visually demanding for visual memories) was more effective in reducing the emotionality experienced than taxing in cross-modality. Methods: Thirty-six patients diagnosed with PTSD were asked to recall two disturbing memories, one mainly visual, the other one mainly auditory. They rated the emotionality of the memories before being exposed to any condition. Both memories were then recalled under three alternating conditions [visual taxation, auditory taxation, and a control condition (CC), which comprised staring a non-moving dot] - counterbalanced in order - and patients rerated emotionality after each condition. Results: All three conditions were equally effective in reducing the emotionality of the auditory memory. Auditory loading was more effective in reducing the emotionality in the visual intrusion than the CC, but did not differ from the visual load. Conclusion: Auditory and visual aversive memories were less emotional after working memory taxation (WMT). This has some clinical implications for EMDR therapy, where mainly visual intrusions are targeted. In this study, there was no benefit of modality specificity. Further fundamental research should be conducted to specify the best protocol for WMT. PMID- 29163312 TI - A New Standardized Emotional Film Database for Asian Culture. AB - Researchers interested in emotions have endeavored to elicit emotional responses in the laboratory and have determined that films were one of the most effective ways to elicit emotions. The present study presented the development of a new standardized emotional film database for Asian culture. There were eight kinds of emotion: fear, disgust, anger, sadness, neutrality, surprise, amusement, and pleasure. Each kind included eight film clips, and a total of 64 emotional films were viewed by 110 participants. We analyzed both the subjective experience (valence, arousal, motivation, and dominance) and physiological response (heart rate and respiration rate) to the presentation of each film. The results of the subjective ratings indicated that our set of 64 films successfully elicited the target emotions. Heart rate declined while watching high-arousal films compared to neutral ones. Films that expressed amusement elicited the lowest respiration rate, whereas fear elicited the highest. The amount and category of emotional films in this database were considerable. This database may help researchers choose applicable emotional films for study according to their own purposes and help in studies of cultural differences in emotion. PMID- 29163313 TI - Intuitive Choices Lead to Intensified Positive Emotions: An Overlooked Reason for "Intuition Bias"? AB - People have, for many well-documented reasons, a tendency to overemphasize their intuitions and to follow them, even when they should not. This "intuition bias" leads to several kinds of specific intuitive biases in judgments and decision making. Previous studies have shown that characteristics of the decision process have a tendency to "leak" into the experience of the choice outcome. We explore whether intuitive choices influence the experience of the choice outcomes differently from "non-intuitive," analytic choices. Since intuition is feeling based, we examine in particular if intuitive choices have stronger affective consequences than non-intuitive ones. Participants in two scenario studies (N = 90; N = 126) rated the feelings of decision makers who experienced a conflict between two options, one intuitively appealing and another that appeared preferable on analytic grounds. Choosing the intuitive alternative was anticipated to lead to somewhat more regret after negative outcomes and, in particular, much more satisfaction with positive outcomes. In two autobiographical studies, one with psychology students (N = 88) and the other with experienced engineers (N = 99), participants were asked to provide examples of choice conflicts between an intuitive and a non-intuitive option from their own private or professional lives. Both groups showed a tendency to report stronger emotions, in particular positive, after intuitive choices. One well established explanation for intuition bias focuses on the nature of people's anticipated negative counterfactual thoughts if their decisions were to turn out badly. The present data indicate that intuitive choices intensify positive emotions, anticipated and real, after successful outcomes much more than negative emotions after failures. Positive outcomes are also more commonly expected than negative ones, when we make choices. We argue that markedly amplified emotions, mediated by stronger personal involvement, in the positive outcomes of intuitive versus non-intuitive choices, is an overlooked reason for intuition bias. PMID- 29163314 TI - Dual-Routes and the Cost of Determining Least-Costs. AB - Theories of cognition that posit complementary dual-route processes afford better fits to the data when each route explains a part of the data not explained by the other route. However, such theories must also explain why each route is invoked, lest one can fit any data set with enough alternatives. One possible explanation is that route selection is based on a least-cost principle: the route that requires fewer cognitive resources (including time) relative to the goal at hand. We investigated this explanation with a dual-display version of visual search, where the target could be identified via opposing (easy or hard forms of) feature and conjunction search conditions. The data support a contextualized version of the least-cost principle in that the cost of computing least-cost also influences route selection: participants assessed alternatives, but only when the cost of that assessment was relatively low. PMID- 29163315 TI - Does Short-Term Hunger Increase Trust and Trustworthiness in a High Trust Society? AB - We build on the social heuristics hypothesis, the literature on the glucose model of self-control, and recent challenges on these hypotheses to investigate whether individuals exhibit a change in degree of trust and reciprocation after consumption of a meal. We induce short-term manipulation of hunger followed by the trust game and a decision on whether to leave personal belongings in an unlocked and unsupervised room. Our results are inconclusive. While, we report hungry individuals trusting and reciprocating more than those who have just consumed a meal in a high trust society, we fail to reject the null with small number of observations (N = 101) and experimental sessions (N = 8). In addition, we find no evidence of short-term hunger having an impact on charitable giving or decisions in public good game. PMID- 29163316 TI - Modeling Psychological Contract Violation using Dual Regime Models: An Event based Approach. AB - A good understanding of the dynamics of psychological contract violation requires theories, research methods and statistical models that explicitly recognize that violation feelings follow from an event that violates one's acceptance limits, after which interpretative processes are set into motion, determining the intensity of these violation feelings. Whereas theories-in the form of the dynamic model of the psychological contract-and research methods-in the form of daily diary research and experience sampling research-are available by now, the statistical tools to model such a two-stage process are still lacking. The aim of the present paper is to fill this gap in the literature by introducing two statistical models-the Zero-Inflated model and the Hurdle model-that closely mimic the theoretical process underlying the elicitation violation feelings via two model components: a binary distribution that models whether violation has occurred or not, and a count distribution that models how severe the negative impact is. Moreover, covariates can be included for both model components separately, which yields insight into their unique and shared antecedents. By doing this, the present paper offers a methodological-substantive synergy, showing how sophisticated methodology can be used to examine an important substantive issue. PMID- 29163317 TI - A Field Experimental Design of a Strengths-Based Training to Overcome Academic Procrastination: Short- and Long-Term Effect. AB - This study reports on the effect of a newly developed 4-week strengths-based training approach to overcome academic procrastination, given to first-year elementary teacher education students (N = 54). The training was based on a strengths-based approach, in which elements of the cognitive behavioral approach were also used. The purpose of the training was to promote awareness of the personal strengths of students who experience academic procrastination regularly and to teach them how to use their personal strengths in situations in which they usually tend to procrastinate. With a pretest-posttest control group design (two experimental groups: n = 31, control group: n = 23), the effect of the training on academic procrastination was studied after 1, 11, and 24 weeks. Results of a one-way analysis of covariance revealed a significant short-term effect of the training. In the long term (after 11 and 24 weeks), the scores for academic procrastination for the intervention groups remained stable, whereas the scores for academic procrastination for the control group decreased to the same level as those of the intervention groups. The findings of this study suggest that a strengths-based approach can be helpful to students at an early stage of their academic studies to initiate their individual process of dealing with academic procrastination. The findings for the long term show the importance of measuring the outcomes of an intervention not only shortly after the intervention but also in the long term. Further research is needed to find out how the short-term effect can be maintained in the long-term. PMID- 29163318 TI - Anger as a Basic Emotion and Its Role in Personality Building and Pathological Growth: The Neuroscientific, Developmental and Clinical Perspectives. AB - Anger is probably one of the mostly debated basic emotions, owing to difficulties in detecting its appearance during development, its functional and affective meaning (is it a positive or a negative emotion?), especially in human beings. Behaviors accompanied by anger and rage serve many different purposes and the nuances of aggressive behaviors are often defined by the symbolic and cultural framework and social contexts. Nonetheless, recent advances in neuroscientific and developmental research, as well as clinical psychodynamic investigation, afford a new view on the role of anger in informing and guiding many aspects of human conducts. Developmental studies have confirmed the psychophysiological, cognitive and social acquisition that hesitate in the pre-determined sequence appearance of anger and rage in the first 2 years of life. The so-called affective neurosciences have shown the phylogenetic origin of the two circuits underlying the emergence of anger along with its evolutionary role for promoting survival. This view has been integrated by the psychodynamic theory of motivational systems that attribute a double role to anger: on the one hand, this affect works as an inwardly directed signal concerning a pressure to overcome an obstacle or an aversive situation; on the other hand, anger is also an outwardly directed communicative signal establishing differentiation and conflict within interpersonal relationships and affective bonds. Of course, human peculiar mental functioning requires the appraisal of such signals by higher cortical functions and, there is little doubt that the meaning that orientates individual behaviors is, eventually, construed on a social and cultural level. At the same time, everyday life experiences as well as clinical insights into psychopathic, narcissistic and borderline personality pathology clearly illustrate the necessity to correctly interpret and give answers to the basic questions raised around the topic of anger as a basic emotion. PMID- 29163319 TI - Functional Relations Modulate the Responsiveness to Affordances Despite the Impact of Conflicting Stimulus-Response Mappings. AB - The study investigated how conflicting stimulus-response mappings influenced affordance processing given a manipulation of the functional relations. Participants performed a task involving consistent-inconsistent stimulus-response mappings: Implicit Relational Assessment Procedure (IRAP). They were instructed to confirm or to deny a relation between words and tool-objects (consistent blocks) or to provide non-conventional responses (inconsistent blocks). The relations between stimuli could functionally match (e.g., Kitchen - Spatula) or not (e.g., Kitchen - Hammer), as well as the spatial relations (e.g., a match or a mismatch between participants' hand response and the tool-object orientation). The results showed faster reaction times (RTs) when functional relations between stimuli matched both in consistent and inconsistent blocks. Differences in RTs and accuracy between consistent and inconsistent blocks were only found when the functional relation between stimuli matched. No modulation of the performance was observed for mismatching functional relations and spatial relations between blocks. These results support the hypothesis that the responsiveness to affordances is strongly modulated by matching functional relations, despite the impact of conflicting stimulus-response mappings. PMID- 29163320 TI - Morpheme-Based Reading and Writing in Spanish Children with Dyslexia. AB - It has been well documented that morphemic structure (roots and affixes) have an impact in reading, but effects seem to depend on the reading experience of readers and lexical characteristics of the stimuli. Specifically, it has been reported that morphemes constitute reading units for developing readers and children with dyslexia when they encounter a new word. In addition, recent studies have stated that the effect of morphology is also present in spelling, as morphological information facilitates spelling accuracy and influences handwriting times. The goal of this study was to investigate the role of morphology in reading and spelling fluency in Spanish children with dyslexia. For that purpose, a group of 24 children with dyslexia was compared with an age matched group of 24 children without reading disabilities in performing a word naming task and a spelling-to-dictation task of isolated words. Morphological condition (high frequency base, low frequency base, simple) and lexicality (words vs. pseudowords) were manipulated. We considered, for the naming task, reading latencies, reading durations, reading critical segment (three first phonemes) durations and naming accuracy; and, for the spelling task, written latencies, writing durations for the whole word, writing critical segment (three first letters) durations and spelling accuracy. Results showed that Spanish children (with and without dyslexia) benefit from a high frequency base to initiate reading and writing responses, showing that they are familiar with the letter chunks that constitute a morpheme. In addition, base frequency impacts reading critical segment duration only for children with dyslexia, but for both groups in writing. In summary, children with dyslexia benefit from a high frequency base to read and spell unfamiliar stimuli. PMID- 29163321 TI - Does Ability to Defend Moderate the Association between Exposure to Bullying and Symptoms of Anxiety? AB - In the context of workplace bullying, the ability to defend refers to whether or not a target feels able to deal with those negative behaviors that typically constitute bullying. The aim of this study was to determine whether the perceived ability to defend oneself moderates the association between exposure to bullying behaviors at work and symptoms of anxiety as predicted by the definition of workplace bullying. It was hypothesized that exposure to bullying behaviors would be more strongly related to symptoms of anxiety among targets feeling unable to defend oneself than among targets who do feel that they are able to defend themselves in the actual situation. This survey study was based on a probability sample of 1,608 Norwegian employees (response rate 32%). Only respondents exposed to at least one bullying behavior were included (N = 739). In contrast to hypothesis, the findings showed that ability to defend only had a protective effect on the relationship between exposure to bullying behaviors and anxiety in cases of low exposure. In cases of high exposure, there was a stronger increase in anxiety among employees able to defend themselves than among those who generally felt unable to defend. Hence, the ability to defend against exposure to bullying behaviors does not seem to protect high-exposed targets against symptoms of anxiety. Organization should therefore intervene against bullying in early stages rather than relying on the individual resilience of those exposed. PMID- 29163322 TI - Second Language Interference during First Language Processing by Arabic-English Bilinguals. AB - The research investigated whether a bilinguals' second language (L2) is activated during a task involving only the first language (L1). We tested the hypothesis that the amount of L2 interference can vary across settings, with less interference occurring in testing locations where L2 is rarely used. In Experiment 1, we compared language processing for 50 Arabic-English bilinguals tested in Saudi Arabia and 49 Arabic-English tested in the United States. In the task, participants viewed a picture and judged whether a phoneme presented over headphones was part of the L1 picture name. The results showed no effect of testing location on processing. For both groups of bilinguals, we observed L2 interference in mean error rates, but not in mean response times. We also found evidence for L2 interference in correlational analyses between response times and (a) participants' weekly L2 usage and (b) frequency of English picture names. A second experiment with 24 Arabic monolinguals supported the conclusion that the results with bilinguals were due to L2 interference. Implications for theories of bilingual memory are discussed. PMID- 29163323 TI - The Impact of Topic Characteristics and Threat on Willingness to Engage with Wikipedia Articles: Insights from Laboratory Experiments. AB - A growing body of research aims to identify the factors that motivate people to make contributions in Wikipedia. We conducted two laboratory experiments to investigate the connections between topic characteristics, perception of threat, and willingness to engage with Wikipedia articles. In Study 1 (N = 83), we examined how topic familiarity, topic controversiality, and mortality salience influenced participants' willingness to engage with Wikipedia articles. We presented the introduction parts of 20 Wikipedia articles and asked participants to rate each article with respect to familiarity and controversiality. In addition, we experimentally manipulated participants' level of mortality salience in terms of the amount of threat they experienced when reading the article. Participants also indicated their willingness to engage with a particular article. The results revealed that familiar and controversial topics increased the willingness to engage with Wikipedia articles. Although mortality salience increased accessibility of death-related thoughts, it did not result in any changes in people's willingness to work with the articles. The aim of Study 2 (N = 90) was to replicate the effects of topic characteristics by following a similar procedure. We additionally manipulated uncertainty salience by assigning participants to three experimental conditions: uncertainty salience, certainty salience, and non-salience. As expected, familiar and controversial topics were of high interest in terms of willingness to contribute. However, the manipulation of uncertainty salience did not yield any significant results despite the emergence of negative emotional states. In sum, we demonstrated that topic characteristics were factors that substantially influenced people's willingness to engage with Wikipedia articles whereas perceived threat was not. PMID- 29163324 TI - Practice and Preparation Time Facilitate System-Switching in Perceptual Categorization. AB - Mounting evidence suggests that category learning is achieved using different psychological and biological systems. While existing multiple-system theories and models of categorization may disagree about the number or nature of the different systems, all assume that people can switch between systems seamlessly. However, little empirical data has been collected to test this assumption, and recent available data suggest that system-switching is difficult. The main goal of this article is to identify factors influencing the proportion of participants who successfully learn to switch between procedural and declarative systems on a trial-by-trial basis. Specifically, we tested the effects of preparation time and practice, two factors that have been useful in task-switching, in a system switching experiment. The results suggest that practice and preparation time can be beneficial to system-switching (as calculated by a higher proportion of switchers and lower switch costs), especially when they are jointly present. However, this improved system-switching comes at the cost of a larger button switch interference when changing the location of the response buttons. The article concludes with a discussion of the implications of these findings for empirical research on system-switching and theoretical work on multiple-systems of category learning. PMID- 29163325 TI - An Illustration of the Exploratory Structural Equation Modeling (ESEM) Framework on the Passion Scale. AB - While exploratory factor analysis (EFA) provides a more realistic presentation of the data with the allowance of item cross-loadings, confirmatory factor analysis (CFA) includes many methodological advances that the former does not. To create a synergy of the two, exploratory structural equation modeling (ESEM) was proposed as an alternative solution, incorporating the advantages of EFA and CFA. The present investigation is thus an illustrative demonstration of the applicability and flexibility of ESEM. To achieve this goal, we compared CFA and ESEM models, then thoroughly tested measurement invariance and differential item functioning through multiple-indicators-multiple-causes (MIMIC) models on the Passion Scale, the only measure of the Dualistic Model of Passion (DMP) which differentiates between harmonious and obsessive forms of passion. Moreover, a hybrid model was also created to overcome the drawbacks of the two methods. Analyses of the first large community sample (N = 7,466; 67.7% females; Mage = 26.01) revealed the superiority of the ESEM model relative to CFA in terms of improved goodness-of fit and less correlated factors, while at the same time retaining the high definition of the factors. However, this fit was only achieved with the inclusion of three correlated uniquenesses, two of which appeared in previous studies and one of which was specific to the current investigation. These findings were replicated on a second, comprehensive sample (N = 504; 51.8% females; Mage = 39.59). After combining the two samples, complete measurement invariance (factor loadings, item intercepts, item uniquenesses, factor variances-covariances, and latent means) was achieved across gender and partial invariance across age groups and their combination. Only one item intercept was non-invariant across both multigroup and MIMIC approaches, an observation that was further corroborated by the hybrid model. While obsessive passion showed a slight decline in the hybrid model, harmonious passion did not. Overall, the ESEM framework is a viable alternative of CFA that could be used and even extended to address substantially important questions and researchers should systematically compare these two approaches to identify the most suitable one. PMID- 29163326 TI - Systematic Review of Traumatic Brain Injuries in Baseball and Softball: A Framework for Prevention. AB - Background: Traumatic brain injuries (TBIs) are an important public health challenge. The classification of baseball and softball as low contact sports and their association with extremity injuries cause individuals to overlook the risk of TBI in baseball and softball. Purpose: To summarize our knowledge of the epidemiology and risk factors of TBIs associated with baseball and softball with an aim to better design and implement preventive strategies. Methods: A search algorithm containing keywords that were synonymous to the terms "TBI," "baseball" was applied to the following nine databases: MEDLINE, Scopus, PubMed, EMBASE, CINAHL, Healthstar, PsychINFO, AMED, Cochrane library. Cited reference lists of identified articles were also consulted yielding a total of eighty-eight articles for full review. The search was concluded on November 14, 2016. The level of evidence was evaluated according to the guidelines from Strengthening the Reporting of Observational Studies in Epidemiology statement. Results: Twenty nine articles published between 2000 and 2016 met the criteria for analysis. Collectively, they examined the years 1982-2015 and identified 242,731 baseball and softball-related TBIs. The most explored outcome of TBI was concussion. The average injury rate per 1,000 athletic exposures was 0.13 (range 0.03-0.46). The most common mechanism of injury was being struck by bat for younger players and being struck by ball for older athletes (adolescent and beyond). Rates of TBI were on average 4.17 times greater in games compared to practices. Females were on average 2.04 times more likely to sustain a TBI than males. Severity of TBIs varied considerably from mild and returning to the field on the same day, to immediate death. Generally, there is poor compliance with helmet use and return to-play post-concussion guidelines. An increase TBI rates was observed over time. Multifaceted preventive strategies must be implemented to reduce the frequency and burden of these injuries. Conclusion: It is difficult to compare the epidemiologic trends of TBI in baseball and softball due critical differences in the methods employed across the studies. Additional research is needed to provide a greater understanding of baseball- and softball-related TBI and to aid in the development of prevention and management modules. PMID- 29163327 TI - The State of Neurocritical Care Fellowship Training and Attitudes toward Accreditation and Certification: A Survey of Neurocritical Care Fellowship Program Directors. AB - Neurocritical care as a recognized and distinct subspecialty of critical care has grown remarkably since its inception in the 1980s. As of 2016, there were 61 fellowship training programs accredited by the United Council for Neurologic Subspecialties (UCNS) in the United States and more than 1,000 UCNS-certified neurointensivists from diverse medical backgrounds. In late 2015, the Program Accreditation, Physician Certification, and Fellowship Training (PACT) Committee of the Neurocritical Care Society (NCS) was convened to promote and support excellence in the training and certification of neurointensivists. One of the first tasks of the committee was to survey neurocritical care fellowship training program directors to ascertain the current state of fellowship training and attitudes regarding transition to Accreditation Council for Graduate Medical Education (ACGME) accreditation of training programs and American Board of Medical Specialties (ABMS) certification of physicians. First, the survey revealed significant heterogeneities in the manner of neurocritical care training and a lack of consistency in requirements for fellow procedural competency. Second, although a majority of the 33 respondents indicated that a move toward ACGME accreditation/ABMS certification would facilitate further growth and mainstreaming of training in neurocritical care, many programs do not currently meet administrative requirements and do not receive the level of institutional support that would be needed for such a transition. In summary, the results revealed that there is an opportunity for future harmonization of training standards and that a transition to ACGME accreditation/ABMS certification is preferred. While the results reflect the opinions of more than half of the survey respondents, they represent only a small sample of neurointensivists. PMID- 29163328 TI - Parkinson's Disease Severity at 3 Years Can Be Predicted from Non-Motor Symptoms at Baseline. AB - Objective: The aim of this study is to present a predictive model of Parkinson's disease (PD) global severity, measured with the Clinical Impression of Severity Index for Parkinson's Disease (CISI-PD). Methods: This is an observational, longitudinal study with annual follow-up assessments over 3 years (four time points). A multilevel analysis and multiple imputation techniques were performed to generate a predictive model that estimates changes in the CISI-PD at 1, 2, and 3 years. Results: The clinical state of patients (CISI-PD) significantly worsened in the 3-year follow-up. However, this change was of small magnitude (effect size: 0.44). The following baseline variables were significant predictors of the global severity change: baseline global severity of disease, levodopa equivalent dose, depression and anxiety symptoms, autonomic dysfunction, and cognitive state. The goodness-of-fit of the model was adequate, and the sensitive analysis showed that the data imputation method applied was suitable. Conclusion: Disease progression depends more on the individual's baseline characteristics than on the 3-year time period. Results may contribute to a better understanding of the evolution of PD including the non-motor manifestations of the disease. PMID- 29163329 TI - Dystonic Dysarthria in Wilson Disease: Efficacy of Zolpidem. AB - Wilson disease (WD) is a rare genetic disorder characterized by copper overload in the liver and the brain. Neurological presentations are mainly related to the accumulation of copper in the basal ganglia, the brainstem, and the cerebellum. Dysarthria is a frequent symptom, with dystonic, spastic, or parkinsonian components and is usually resistant to medical or voice rehabilitation therapies. Here, we report the case of a patient with WD diagnosed at the age of 12, who presented a severe and constant dysarthria from dystonic origin which was unresponsive to benzodiazepines and anticholinergic drugs. When she was 25-year old, she tried zolpidem at bedtime for sleeping difficulties and reported a paradoxical effect of this drug on her voice. To confirm the effect of zolpidem on her dystonic dysarthria, we realized a full evaluation of her dysarthria at baseline without zolpidem and after 4 days of treatment by 10 mg twice a day. Lexical access was evaluated by the semantic fluency; dysarthria by the Intelligibility Score, the spontaneous speech and reading rates, the maximum phonation time on the sustained vowel [a] and by a perceptive evaluation. Two hours after the intake of zolpidem, improvement of all the parameters tested, with the exception of the maximum phonation time, was observed. Semantic fluency increased by 59%, the spontaneous speech rate by 88% and the reading rate by 76%. General dystonia remained unchanged and the tolerance of zolpidem was satisfactory. Since then, the patient takes zolpidem 5 mg five times a day, and 4 years later shows persistent improvement in oral communication and a good drug tolerance. In this single-case study, we showed that regular daytime intake of zolpidem could have a persisting effect on a complex dystonic dysarthria that was resistant to usual medical treatments. PMID- 29163330 TI - White Matter Changes in HIV+ Women with a History of Cocaine Dependence. AB - Cocaine use is associated with the transmission of human immunodeficiency (HIV) virus through risky sexual behavior. In HIV+ individuals, cocaine use is linked with poor health outcomes, including HIV-medication non-adherence and faster disease progression. Both HIV and cocaine dependence are associated with reduced integrity of cerebral white matter (WM), but the effects of HIV during cocaine abstinence have not yet been explored. We used diffusion tensor imaging (DTI) to understand the effect of combined HIV+ serostatus and former cocaine dependence on cerebral WM integrity. DTI data obtained from 15 HIV+ women with a history of cocaine dependence (COC+/HIV+) and 21 healthy females were included in the analysis. Diffusion-based measures [fractional anisotropy (FA), radial diffusivity (RD), mean diffusivity, and axial diffusivity] were examined using tract-based spatial statistics and region-of-interest analyses. In a whole-brain analysis, COC+/HIV+ women showed significantly reduced FA and increased RD in all major WM tracts, except the left corticospinal tract for RD. The tract with greatest percentage of voxels showing significant between-group differences was the forceps minor (FA: 75.6%, RD: 59.7%). These widespread changes in diffusion measures indicate an extensive neuropathological effect of HIV and former cocaine dependence on WM. PMID- 29163331 TI - The Mobility Assessment Course for the Diagnosis of Spatial Neglect: Taking a Step Forward? AB - Spatial neglect after stroke can be a challenging syndrome to diagnose under standard neuropsychological assessment. There is now sufficient evidence that those affected might demonstrate neglect behavior in everyday settings despite showing no signs of neglect during common neglect tasks. This discrepancy is attributed to the simplified and unrealistic nature of common pen and paper based tasks that do not match the demanding, novel, and complex environment of everyday life. As such, increasing task demands under more ecologically valid scenarios has become an important method of increasing test sensitivity. The main aim of the current study was to evaluate the diagnostic utility of the Mobility Assessment Course (MAC), an ecological task, for the assessment of neglect. If neglect becomes more apparent under more challenging task demands the MAC could prove to be more diagnostically accurate at detecting neglect than conventional methods, particularly as the time from initial brain damage increases. Data collected by Guide Dogs of SA/NT were retrospectively analyzed. The Receiver Operating Characteristic (ROC) curve, a measure of sensitivity and specificity, was used to investigate the diagnostic utility of the MAC and a series of paper and pencil tests in 67 right hemisphere stroke survivors. While the MAC proved to be a more sensitive neglect test (74.2%) when compared to the Star Cancellation (43.3%) and Line Bisection (35.7%) tests, this was at the expense of relatively low specificity. As a result, the ROC curve analysis showed no statistically discernable differences between tasks (p > 0.12), or between subacute and chronic groups for individual tasks (p > 0.45). It is concluded that, while the MAC is an ecologically valid alternative for assessing neglect, regarding its diagnostic accuracy, there is currently not enough evidence to suggest that it is a big step forward in comparison to the accuracy of conventional tests. PMID- 29163333 TI - Mutation Analysis of Consanguineous Moroccan Patients with Parkinson's Disease Combining Microarray and Gene Panel. AB - During the last two decades, 15 different genes have been reported to be responsible for the monogenic form of Parkinson's disease (PD), representing a worldwide frequency of 5-10%. Among them, 10 genes have been associated with autosomal recessive PD, with PRKN and PINK1 being the most frequent. In a cohort of 145 unrelated Moroccan PD patients enrolled since 2013, 19 patients were born from a consanguineous marriage, of which 15 were isolated cases and 4 familial. One patient was homozygous for the common LRRK2 G2019S mutation and the 18 others who did not carry this mutation were screened for exon rearrangements in the PRKN gene using Affymetrix Cytoscan HD microarray. Two patients were determined homozygous for PRKN exon-deletions, while another patient presented with compound heterozygous inheritance (3/18, 17%). Two other patients showed a region of homozygosity covering the 1p36.12 locus and were sequenced for the candidate PINK1 gene, which revealed two homozygous point mutations: the known Q456X mutation in exon 7 and a novel L539F variation in exon 8. The 13 remaining patients were subjected to next-generation sequencing (NGS) that targeted a panel of 22 PD-causing genes and overlapping phenotypes. NGS data showed that two unrelated consanguineous patients with juvenile-onset PD (12 and 13 years) carried the same homozygous stop mutation W258X in the ATP13A2 gene, possibly resulting from a founder effect; and one patient with late onset (76 years) carried a novel heterozygous frameshift mutation in SYNJ1. Clinical analysis showed that patients with the ATP13A2 mutation developed juvenile-onset PD with a severe phenotype, whereas patients having either PRKN or PINK1 mutations displayed early-onset PD with a relatively mild phenotype. By identifying pathogenic mutations in 45% (8/18) of our consanguineous Moroccan PD series, we demonstrate that the combination of chromosomal microarray analysis and NGS is a powerful approach to pinpoint the genetic bases of autosomal recessive PD, particularly in countries with a high rate of consanguinity. PMID- 29163332 TI - Clinical Use of Cerebral Microdialysis in Patients with Aneurysmal Subarachnoid Hemorrhage-State of the Art. AB - Objective: To review the published literature on the clinical application of cerebral microdialysis (CMD) in aneurysmal subarachnoid hemorrhage (SAH) patients and to summarize the evidence relating cerebral metabolism to pathophysiology, secondary brain injury, and outcome. Methods: Study selection: Two reviewers identified all manuscripts reporting on the clinical use of CMD in aneurysmal SAH patients from MEDLINE. All identified studies were grouped according to their focus on brain metabolic changes during the early and subacute phase after SAH, their association with mechanisms of secondary brain injury and outcome. Results: The review demonstrated: (1) limited literature is available in the very early phase before the aneurysm is secured. (2) Brain metabolic changes related to early and delayed secondary injury mechanisms may be used in addition to other neuromonitoring parameters in the critical care management of SAH patients. (3) CMD markers of ischemia may detect delayed cerebral ischemia early (up to 16 h before onset), underlining the importance of trend analysis. (4) Various CMD derived parameters may be associated with patient outcome at 3-12 months, including CMD-lactate-to-pyruvate-ratio, CMD-glucose, and CMD-glutamate. Conclusion: The clinical use of CMD is an emerging area in the literature of aneurysmal SAH patients. Larger prospective multi-center studies on interventions based on CMD findings are needed. PMID- 29163334 TI - Improvement of Upper Extremity Deficit after Constraint-Induced Movement Therapy Combined with and without Preconditioning Stimulation Using Dual-hemisphere Transcranial Direct Current Stimulation and Peripheral Neuromuscular Stimulation in Chronic Stroke Patients: A Pilot Randomized Controlled Trial. AB - In this study, we investigated the effects of dual-hemisphere transcranial direct current stimulation (dual-tDCS) of both the affected (anodal tDCS) and non affected (cathodal tDCS) primary motor cortex, combined with peripheral neuromuscular electrical stimulation (PNMES), on the effectiveness of constraint induced movement therapy (CIMT) as a neurorehabilitation intervention in chronic stroke. We conducted a randomized controlled trial of feasibility, with a single blind assessor, with patients recruited from three outpatient clinics. Twenty chronic stroke patients were randomly allocated to the control group, receiving conventional CIMT, or the intervention group receiving dual-tDCS combined with PNMES before CIMT. Patients in the treatment group first underwent a 20-min period of dual-tDCS, followed immediately by PNMES, and subsequent CIMT for 2 h. Patients in the control group only received CIMT (with no pretreatment stimulation). All patients underwent two CIMT sessions, one in the morning and one in the afternoon, each lasting 2 h, for a total of 4 h of CIMT per day. Upper extremity function was assessed using the Fugl-Meyer Assessment (primary outcome), as well as the amount of use (AOU) and quality of movement (QOM) scores, obtained via the Motor Activity Log (secondary outcome). Nineteen patients completed the study, with one patient withdrawing after allocation. Compared to the control group, the treatment improvement in upper extremity function and AOU was significantly greater in the treatment than control group (change in upper extremity score, 9.20 +/- 4.64 versus 4.56 +/- 2.60, respectively, P < 0.01, eta2 = 0.43; change in AOU score, 1.10 +/- 0.65 versus 0.62 +/- 0.85, respectively, P = 0.02, eta2 = 0.52). There was no significant effect of the intervention on the QOM between the intervention and control groups (change in QOM score, 1.00 +/- 0.62 versus 0.71 +/- 0.72, respectively, P = 0.07, eta2 = 0.43; treatment versus control). Our findings suggest a novel pretreatment stimulation strategy based on dual-tDCS and PNMES may enhance the therapeutic benefit of CIMT. PMID- 29163335 TI - Alopecia Universalis following Alemtuzumab Treatment in Multiple Sclerosis: A Barely Recognized Manifestation of Secondary Autoimmunity-Report of a Case and Review of the Literature. AB - Secondary autoimmunity is the most frequent adverse event occurring in almost every other alemtuzumab-treated multiple sclerosis patient. We report a case of a patient with relapsing-remitting multiple sclerosis who reported smooth, circular areas of complete hair loss on both thighs 6 months after the second treatment cycle with alemtuzumab. The patient was diagnosed as having alopecia areata (AA). Within 3 months, AA progressed to complete loss of all body hair (alopecia universalis). Current literature rarely connects alemtuzumab with the onset of alopecia of autoimmune origin. Here, we report a little-noticed autoimmune disease affecting the skin, very likely being associated with alemtuzumab. We emphasize the necessity of careful clinical surveillance of alemtuzumab-treated patients for yet undescribed autoimmune diseases. PMID- 29163336 TI - Two Novel Mutations Associated With Ataxia-Telangiectasia Identified Using an Ion AmpliSeq Inherited Disease Panel. AB - Ataxia-telangiectasia (A-T), or Louis-Bar syndrome, is a rare neurodegenerative disorder associated with immunodeficiency. For families with at least one affected child, timely A-T genotyping during any subsequent pregnancy allows the parents to make an informed decision about whether to continue to term when the fetus is affected. Mutations in the ATM gene, which is 150 kb long, give rise to A-T; more than 600 pathogenic variants in ATM have been characterized since 1990 and new mutations continue to be discovered annually. Therefore, limiting genetic screening to previously known SNPs by PCR or hybridization with microarrays may not identify the specific pathogenic genotype in ATM for a given A-T family. However, recent developments in next-generation sequencing technology offer prompt high-throughput full-length sequencing of genomic fragments of interest. This allows the identification of the whole spectrum of mutations in a gene, including any novel ones. We report two A-T families with affected children and current pregnancies. Both families are consanguineous and originate from Caucasian regions of Russia and Azerbaijan. Before our study, no ATM mutations had been identified in the older children of these families. We used ion semiconductor sequencing and an Ion AmpliSeqTM Inherited Disease Panel to perform complete ATM gene sequencing in a single member of each family. Then we compared the experimentally determined genotype with the affected/normal phenotype distribution in the whole family to provide unambiguous evidence of pathogenic mutations responsible for A-T. A single novel SNP was allocated to each family. In the first case, we found a mononucleotide deletion, and in the second, a mononucleotide insertion. Both mutations lead to truncation of the ATM protein product. Identification of the pathogenic mutation in each family was performed in a timely fashion, allowing the fetuses to be tested and diagnosed. The parents chose to continue with both pregnancies as both fetuses had a healthy genotype and thus were not at risk of A-T. PMID- 29163337 TI - Disrupted Gamma Synchrony after Mild Traumatic Brain Injury and Its Correlation with White Matter Abnormality. AB - Mild traumatic brain injury (mTBI) has been firmly associated with disrupted white matter integrity due to induced white matter damage and degeneration. However, comparatively less is known about the changes of the intrinsic functional connectivity mediated via neural synchronization in the brain after mTBI. Moreover, despite the presumed link between structural and functional connectivity, no existing studies in mTBI have demonstrated clear association between the structural abnormality of white matter axons and the disruption of neural synchronization. To investigate these questions, we recorded resting state EEG and diffusion tensor imaging (DTI) from a cohort of military service members. A newly developed synchronization measure, the weighted phase lag index was applied on the EEG data for estimating neural synchronization. Fractional anisotropy was computed from the DTI data for estimating white matter integrity. Fifteen service members with a history of mTBI within the past 3 years were compared to 22 demographically similar controls who reported no history of head injury. We observed that synchronization at low-gamma frequency band (25-40 Hz) across scalp regions was significantly decreased in mTBI cases compared with controls. The synchronization in theta (4-7 Hz), alpha (8-13 Hz), and beta (15-23 Hz) frequency bands were not significantly different between the two groups. In addition, we found that across mTBI cases, the disrupted synchronization at low gamma frequency was significantly correlated with the white matter integrity of the inferior cerebellar peduncle, which was also significantly reduced in the mTBI group. These findings demonstrate an initial correlation between the impairment of white matter integrity and alterations in EEG synchronization in the brain after mTBI. The results also suggest that disruption of intrinsic neural synchronization at low-gamma frequency may be a characteristic functional pathology following mTBI and may prove useful for developing better methods of diagnosis and treatment. PMID- 29163338 TI - Radial Peripapillary Capillary Network in Patients with Retinitis Pigmentosa: An Optical Coherence Tomography Angiography Study. AB - Purpose: To investigate radial peripapillary capillary (RPC) network in patients affected by retinitis pigmentosa (RP). Methods: Eleven patients (22 eyes) with previous diagnosis of RP and 16 age-matched healthy subjects (16 eyes) were enrolled. The diagnosis of RP was made based on both clinical features and electrophysiological examination. All patients underwent a complete ophthalmologic examination, including optical coherence tomography angiography and visual field (VF). The primary outcomes were the RPC vessel density in the peripapillary and disk areas; the secondary outcomes were the peripapillary retinal nerve fiber layer (RNFL) thickness and the mean defect at VF. Results: A total of 19 eyes of 11 RP patients (5 males, 6 females) and 16 eyes of 16 healthy subjects (10 males, 6 females) were included for the analysis. RPC vessel density in the disk area was 46.5 +/- 7.1% in the RP group and 45.4 +/- 10.6% in the control group (p = 0.754). RPC vessel density in the peripapillary area was significantly reduced in the RP group after the comparison with the control group (52.5 +/- 5.0 and 57.2 +/- 5.1%, respectively, p = 0.011). RNFL thickness was 85.9 +/- 20.4 MUm in the RP group and 104.0 +/- 6.4 MUm in the control group (p = 0.002). RPC vessel density was significantly correlated with RNFL thickness values in RP patients, both in the disk and in the peripapillary area (Rho = 0.599 and p = 0.007 in the disk area, Rho = 0.665 and p = 0.002 in the peripapillary area, respectively). Conclusion: We showed that density of RPC is reduced in these patients in the peripapillary area. Moreover, the RPC vessel density correlates with the RNFL thickness. PMID- 29163339 TI - Predictors of Infarct Growth in Patients with Large Vessel Occlusion Treated with Endovascular Therapy. AB - Introduction: Endovascular therapy (EVT) is now evidence based in anterior circulation stroke caused by large vessel occlusion. Outcome is related to infarct size, but data on predictors of infarct growth is limited. We analyzed our cohort of EVT treated patients primarily selected by magnetic resonance imaging (MRI) to examine predictors of infarct growth and the association between infarct size and outcome. Methods: We identified 342 patients with anterior circulation stroke from 2004 to 2014 in our prospectively collected EVT database. Baseline infarct size was available for 281 (measured by MRI) while final infarct size was available for 312 patients. Functional outcome was defined by modified Rankin Score (mRS) after 90 days and good outcome was defined as mRS 0-2. Predictors of infarct growth were examined by regression analysis. Results: Successful reperfusion [odds ratio (OR) 0.17, 95% confidence interval (CI) (0.09 0.33)] was the strongest predictor of reduction of infarct growth. Receiving intravenous thrombolysis and a short time span from symptom onset to scanning also reduced infarct growth. Occlusion of the internal carotid artery (ICA) intracranially predicted infarct growth (OR = 7.29, 95% CI: 2.36-22.53). EVT under general anesthesia and having a NIHSS between 10 and 15 were also associated with infarct growth. Discussion: Failure of reperfusion resulted in an average infarct growth of approximately 50 ml. Lack of reperfusion generally results in a poor outcome likely due to infarct growth. Occlusion of the intracranial ICA and EVT under general anesthesia predicted infarct growth, while successful reperfusion, getting intraveneous thrombolysis, and a short time span from onset to scan protected against growth. A median infarct size of 52 ml best discriminates between a good and a bad outcome. PMID- 29163340 TI - The Dominant-Subthalamic Nucleus Phenomenon in Bilateral Deep Brain Stimulation for Parkinson's Disease: Evidence from a Gait Analysis Study. AB - Background: It has been suggested that parkinsonian [Parkinson's disease (PD)] patients might have a "dominant" (DOM) subthalamic nucleus (STN), whose unilateral electrical stimulation [deep brain stimulation (DBS)] could lead to an improvement in PD symptoms similar to bilateral STN-DBS. Objectives: Since disability in PD patients is often related to gait problems, in this study, we wanted to investigate in a group of patients bilaterally implanted for STN-DBS: (1) if it was possible to identify a subgroup of subjects with a dominant STN; (2) in the case, if the unilateral stimulation of the dominant STN was capable to improve gait abnormalities, as assessed by instrumented multifactorial gait analysis, similarly to what observed with bilateral stimulation. Methods: We studied 10 PD patients with bilateral STN-DBS. A clinical evaluation and a kinematic, kinetic, and electromyographic (EMG) analysis of overground walking were performed-off medication-in four conditions: without stimulation, with bilateral stimulation, with unilateral right or left STN-DBS. Through a hierarchical agglomerative cluster analysis based on motor Unified Parkinson's Disease Rating Scale scores, it was possible to separate patients into two groups, based on the presence (six patients, DOM group) or absence (four patients, NDOM group) of a dominant STN. Results: In the DOM group, both bilateral and unilateral stimulation of the dominant STN significantly increased gait speed, stride length, range of motion of lower limb joints, and peaks of moment and power at the ankle joint; moreover, the EMG activation pattern of distal leg muscles was improved. The unilateral stimulation of the non-dominant STN did not produce any significant effect. In the NDOM group, only bilateral stimulation determined a significant improvement of gait parameters. Conclusion: In the DOM group, the effect of unilateral stimulation of the dominant STN determined an improvement of gait parameters similar to bilateral stimulation. The pre-surgical identification of these patients, if possible, could allow to reduce the surgical risks and side effects of DBS adopting a unilateral approach. PMID- 29163341 TI - Effects of Transcranial Direct Current Stimulation, Transcranial Pulsed Current Stimulation, and Their Combination on Brain Oscillations in Patients with Chronic Visceral Pain: A Pilot Crossover Randomized Controlled Study. AB - Objective: Chronic visceral pain (CVP) syndromes are persistently painful disorders with a remarkable lack of effective treatment options. This study aimed at evaluating the effects of different neuromodulation techniques in patients with CVP on cortical activity, through electreocephalography (EEG) and on pain perception, through clinical tests. Design: A pilot crossover randomized controlled study. Settings: Out-patient. Subjects: Adults with CVP (>3 months). Methods: Participants received four interventions in a randomized order: (1) transcranial pulsed current stimulation (tPCS) and active transcranial direct current stimulation (tDCS) combined, (2) tPCS alone, (3) tDCS alone, and (4) sham condition. Resting state quantitative electroencephalography (qEEG) and pain assessments were performed before and after each intervention. Results were compared with a cohort of 47 healthy controls. Results: We enrolled six patients with CVP for a total of 21 visits completed. Compared with healthy participants, patients with CVP showed altered cortical activity characterized by increased power in theta, alpha and beta bands, and a significant reduction in the alpha/beta ratio. Regarding tES, the combination of tDCS with tPCS had no effect on power in any of the bandwidths, nor brain regions. Comparing tPCS with tDCS alone, we found that tPCS induced higher increase in power within the theta and alpha bandwidths. Conclusion: This study confirms that patients with CVP present abnormal EEG-indexed cortical activity compared with healthy controls. Moreover, we showed that combining two types of neurostimulation techniques had no effect, whereas the two interventions, when applied individually, have different neural signatures. PMID- 29163342 TI - Novel Anterior Brainstem Magnetic Resonance Imaging Findings in Non-Small Cell Lung Cancer with Leptomeningeal Carcinomatosis. AB - Leptomeningeal carcinomatosis (LC) is found in around 4% of patients with non small cell lung cancer (NSCLC). The most common radiological finding of LC is diffuse leptomeningeal enhancement on contrast-enhanced brain magnetic resonance imaging (MRI). Herein, we report a novel brain MRI finding-non-enhanced, band like, symmetric restricted diffusion along the anterior surface of the brainstem of LC in four patients with NSCLC. We also identified three additional cases with similar MRI findings in a literature review. We hypothesized that the restricted diffusion along the anterior brainstem was caused by malignant cells concentrating in the cistern around the brainstem and infiltrating into the circumferential perforating arteries along the anterior brainstem surface, which then resulted in microinfarctions. PMID- 29163343 TI - Data-Driven Sequence of Changes to Anatomical Brain Connectivity in Sporadic Alzheimer's Disease. AB - Model-based investigations of transneuronal spreading mechanisms in neurodegenerative diseases relate the pattern of pathology severity to the brain's connectivity matrix, which reveals information about how pathology propagates through the connectivity network. Such network models typically use networks based on functional or structural connectivity in young and healthy individuals, and only end-stage patterns of pathology, thereby ignoring/excluding the effects of normal aging and disease progression. Here, we examine the sequence of changes in the elderly brain's anatomical connectivity over the course of a neurodegenerative disease. We do this in a data-driven manner that is not dependent upon clinical disease stage, by using event-based disease progression modeling. Using data from the Alzheimer's Disease Neuroimaging Initiative dataset, we sequence the progressive decline of anatomical connectivity, as quantified by graph-theory metrics, in the Alzheimer's disease brain. Ours is the first single model to contribute to understanding all three of the nature, the location, and the sequence of changes to anatomical connectivity in the human brain due to Alzheimer's disease. Our experimental results reveal new insights into Alzheimer's disease: that degeneration of anatomical connectivity in the brain may be a viable, even early, biomarker and should be considered when studying such neurodegenerative diseases. PMID- 29163344 TI - Systemic and Local Cytokine Profile following Spinal Cord Injury in Rats: A Multiplex Analysis. AB - Our study of the changes in cytokine profile in blood serum and in the spinal cord after traumatic spinal cord injury (SCI) has shown that an inflammatory reaction and immunological response are not limited to the CNS, but widespread. This fact was confirmed by changes detected in a cytokine profile in blood serum samples [MIP-1alpha, interleukin 1 (IL-1) alpha, IL-2, IL-5, IL-1beta, MCP-1, RANTES]. There were also changes in the levels of MIP-1alpha, IL-1alpha, IL-2, IL 5, IL-18, GM-colony-stimulating factor, IL-17alpha, IFN-gamma, IL-10, IL-13, MCP 1, and GRO KC CINC-1 in samples of the rat injured spinal cord. The results underscore the complex cytokine network imbalance exhibited after SCI and show significant changes in the concentrations of 14 cytokines/chemokines with different inflammatory and immunological activities. PMID- 29163345 TI - Fluid Distribution Pattern in Adult-Onset Congenital, Idiopathic, and Secondary Normal-Pressure Hydrocephalus: Implications for Clinical Care. AB - Objective: In spite of growing evidence of idiopathic normal-pressure hydrocephalus (NPH), a viewpoint about clinical care for idiopathic NPH is still controversial. A continuous divergence of viewpoints might be due to confusing classifications of idiopathic and adult-onset congenital NPH. To elucidate the classification of NPH, we propose that adult-onset congenital NPH should be explicitly distinguished from idiopathic and secondary NPH. Methods: On the basis of conventional CT scan or MRI, idiopathic NPH was defined as narrow sulci at the high convexity in concurrent with enlargement of the ventricles, basal cistern and Sylvian fissure, whereas adult-onset congenital NPH was defined as huge ventricles without high-convexity tightness. We compared clinical characteristics and cerebrospinal fluid distribution among 85 patients diagnosed with idiopathic NPH, 17 patients with secondary NPH, and 7 patients with adult-onset congenital NPH. All patients underwent 3-T MRI examinations and tap-tests. The volumes of ventricles and subarachnoid spaces were measured using a 3D workstation based on T2-weighted 3D sequences. Results: The mean intracranial volume for the patients with adult-onset congenital NPH was almost 100 mL larger than the volumes for patients with idiopathic and secondary NPH. Compared with the patients with idiopathic or secondary NPH, patients with adult-onset congenital NPH exhibited larger ventricles but normal sized subarachnoid spaces. The mean volume ratio of the high-convexity subarachnoid space was significantly less in idiopathic NPH than in adult-onset congenital NPH, whereas the mean volume ratio of the basal cistern and Sylvian fissure in idiopathic NPH was >2 times larger than that in adult-onset congenital NPH. The symptoms of gait disturbance, cognitive impairment, and urinary incontinence in patients with adult-onset congenital NPH tended to progress more slowly compared to their progress in patients with idiopathic NPH. Conclusion: Cerebrospinal fluid distributions and disease progression were significantly different among the patients with adult-onset congenital NPH, idiopathic NPH and secondary NPH. This finding indicates that the pathogenesis of adult-onset congenital NPH may differ from those of idiopathic and secondary NPH. Therefore, adult-onset congenital NPH should be definitively distinguished from the categories of idiopathic and secondary NPH. PMID- 29163346 TI - Paroxysmal Symptoms As the First Manifestation of Multiple Sclerosis Mimicking a Transient Ischemic Attack: A Report of Two Cases. AB - Paroxysmal symptoms are unusual manifestations of multiple sclerosis (MS). When presented as the first clinical manifestation, paroxysmal symptoms may easily be mistaken for transient ischemic attack (TIA). Previously, several cases of MS that reported with paroxysmal symptoms were misdiagnosed as TIA. Here, we report two additional cases, focusing on the clinical characteristics of paroxysmal symptoms in MS. Both cases had paroxysmal symptoms as their first manifestation; one presented with transient dizziness, left face numbness, and right limb weakness, and the other presented with episodic lightheadedness, blurred vision, nausea, palpitations, and tremulousness upon standing. Both of the patients' symptoms were mistaken for TIA at first, based on microembolic signals recorded by transcranial Doppler, but were later correctly diagnosed with MS based on neuroimaging and lumbar puncture. The paroxysmal symptoms responded to carbamazepine and were relieved completely after administration of intravenous methylprednisolone and interferon. Herein, we aim to summarize the differences between paroxysmal symptoms seen in MS and TIA, to facilitate a timely differential diagnosis and recommend an early appropriate treatment. PMID- 29163347 TI - Long-term Treatment Benefits and Prolonged Efficacy of OnabotulinumtoxinA in Patients Affected by Chronic Migraine and Medication Overuse Headache over 3 Years of Therapy. AB - Background: Chronic migraine (CM) affects about the 2% of the general population and it has been recognized as one of the most-disabling conditions worldwide by the World Health Organization. CM is often associated with the overuse of abortive medication, which determines the worsening of headache itself and the development of a secondary headache called medication overuse headache. The management of these associated conditions is difficult, but a growing amount of evidence is pointing out the effectiveness and the good safety profile of OnabotulinumtoxinA (OnabotA). Despite this, data on OnabotA effects and safety in long-term use lack. The purpose of the present article is to retrospectively assess the efficacy and safety of OnabotA in a cohort of chronic migraineurs with drug overuse from the 18th month of treatment until the third year. Materials and methods: 90 chronic migraineurs with medication overuse were enrolled between January 2013 and February 2017. All patients were treated with OnabotA according to PREEMPT dictates. Before every injection session the headache index, the analgesic consumption, the visual analog scale for pain score, the 36-items short form health survey questionnaire score, the 6-items headache impact test (HIT-6) score and the Zung self-rating anxiety and depression scale scores were collected. Adverse events were carefully registered. A simple linear regression was performed to explore the mean changes in the abovementioned parameters for a single injection session and mean comparison tests were performed using the one way analysis of variance followed by Tukey-Kramer post-hoc test. Results: A significantly improvement for a single injection was registered for all the above mentioned parameters. Headache index, analgesic consumption, visual analog pain scale, and 6-items HIT-6 scores were significantly lower than baseline from the 18th month of treatment onwards. The 36-items short form health survey questionnaire scores were significantly higher than baseline at every injections session from the 18th months onwards. Zung scales did not change. No serious adverse events were assessed and no adverse events-related drop-outs were seen. Conclusion: OnabotA effectiveness and safety last until 3 years of therapy, raising the possibility of the use of this therapy even for many years in CM prevention. PMID- 29163348 TI - Intermediate Latency-Evoked Potentials of Multimodal Cortical Vestibular Areas: Galvanic Stimulation. AB - Introduction: Human multimodal vestibular cortical regions are bilaterally anterior insulae and posterior opercula, where characteristic vestibular-related cortical potentials were previously reported under acoustic otolith stimulation. Galvanic vestibular stimulation likely influences semicircular canals preferentially. Galvanic stimulation was compared to previously established data under acoustic stimulation. Methods: 14 healthy right-handed subjects, who were also included in the previous acoustic potential study, showed normal acoustic and galvanic vestibular-evoked myogenic potentials. They received 2,000 galvanic binaural bipolar stimuli for each side during EEG recording. Results: Vestibular cortical potentials were found in all 14 subjects and in the pooled data of all subjects ("grand average") bilaterally. Anterior insula and posterior operculum were activated exclusively under galvanic stimulation at 25, 35, 50, and 80 ms; frontal regions at 30 and 45 ms. Potentials at 70 ms in frontal regions and at 110 ms at all of the involved regions could also be recorded; these events were also found using acoustic stimulation in our previous study. Conclusion: Galvanic semicircular canal stimulation evokes specific potentials in addition to those also found with acoustic otolith stimulation in identically located regions of the vestibular cortex. Vestibular cortical regions activate differently by galvanic and acoustic input at the peripheral sensory level. Significance: Differential effects in vestibular cortical-evoked potentials may see clinical use in specific vertigo disorders. PMID- 29163350 TI - Differential Diagnosis of Vertigo in the Emergency Department: A Prospective Validation Study of the STANDING Algorithm. AB - Objective: We investigated the reliability and accuracy of a bedside diagnostic algorithm for patients presenting with vertigo/unsteadiness to the emergency department. Methods: We enrolled consecutive adult patients presenting with vertigo/unsteadiness at a tertiary hospital. STANDING, the acronym for the four step algorithm we have previously described, based on nystagmus observation and well-known diagnostic maneuvers includes (1) the discrimination between SponTAneous and positional nystagmus, (2) the evaluation of the Nystagmus Direction, (3) the head Impulse test, and (4) the evaluation of equilibrium (staNdinG). Reliability of each step was analyzed by Fleiss' K calculation. The reference standard (central vertigo) was a composite of brain disease including stroke, demyelinating disease, neoplasm, or other brain disease diagnosed by initial imaging or during 3-month follow-up. Results: Three hundred and fifty-two patients were included. The incidence of central vertigo was 11.4% [95% confidence interval (CI) 8.2-15.2%]. The leading cause was ischemic stroke (70%). The STANDING showed a good reliability (overall Fleiss K 0.83), the second step showing the highest (0.95), and the third step the lowest (0.74) agreement. The overall accuracy of the algorithm was 88% (95% CI 85-88%), showing high sensitivity (95%, 95% CI 83-99%) and specificity (87%, 95% CI 85-87%), very high negative predictive value (99%, 95% CI 97-100%), and a positive predictive value of 48% (95% CI 41-50%) for central vertigo. Conclusion: Using the STANDING algorithm, non-sub-specialists achieved good reliability and high accuracy in excluding stroke and other threatening causes of vertigo/unsteadiness. PMID- 29163349 TI - Kainic Acid-Induced Post-Status Epilepticus Models of Temporal Lobe Epilepsy with Diverging Seizure Phenotype and Neuropathology. AB - The aim of epilepsy models is to investigate disease ontogenesis and therapeutic interventions in a consistent and prospective manner. The kainic acid-induced status epilepticus (KASE) rat model is a widely used, well-validated model for temporal lobe epilepsy (TLE). As we noted significant variability within the model between labs potentially related to the rat strain used, we aimed to describe two variants of this model with diverging seizure phenotype and neuropathology. In addition, we evaluated two different protocols to induce status epilepticus (SE). Wistar Han (Charles River, France) and Sprague-Dawley (Harlan, The Netherlands) rats were subjected to KASE using the Hellier kainic acid (KA) and a modified injection scheme. Duration of SE and latent phase were characterized by video-electroencephalography (vEEG) in a subgroup of animals, while animals were sacrificed 1 week (subacute phase) and 12 weeks (chronic phase) post-SE. In the 12 weeks post-SE groups, seizures were monitored with vEEG. Neuronal loss (neuronal nuclei), microglial activation (OX-42 and translocator protein), and neurodegeneration (Fluorojade C) were assessed. First, the Hellier protocol caused very high mortality in WH/CR rats compared to SD/H animals. The modified protocol resulted in a similar SE severity for WH/CR and SD/H rats, but effectively improved survival rates. The latent phase was significantly shorter (p < 0.0001) in SD/H (median 8.3 days) animals compared to WH/CR (median 15.4 days). During the chronic phase, SD/H rats had more seizures/day compared to WH/CR animals (p < 0.01). However, neuronal degeneration and cell loss were overall more extensive in WH/CR than in SD/H rats; microglia activation was similar between the two strains 1 week post-SE, but higher in WH/CR rats 12 weeks post-SE. These neuropathological differences may be more related to the distinct neurotoxic effects of KA in the two rat strains than being the outcome of seizure burden itself. The divergences in disease progression and seizure outcome, in addition to the histopathological dissimilarities, further substantiate the existence of strain differences for the KASE rat model of TLE. PMID- 29163351 TI - Computed Tomography Perfusion Alberta Stroke Program Early Computed Tomography Score Is Associated with Hemorrhagic Transformation after Acute Cardioembolic Stroke. AB - Alberta Stroke Program Early Computed Tomography (CT) score (ASPECTS) has been applied to CT perfusion (CTP) with good interrater agreement to predict early ischemic stroke, and it can be useful in decision making in acute ischemic stroke. The aim of the present study was to assess the predictive value of CTP ASPECTS of hemorrhagic transformation (HT) in acute cardioembolic stroke. This is a single-enter, retrospective study. All patients hospitalized with acute cardioembolic stroke from January 2008 to September 2013 were included. ASPECTS of baseline non-contrast CT, CTP maps of cerebral blood volume (CBV), cerebral blood flow, and mean transit time were collected from 52 consecutive patients with less than 12-h anterior circulation ischemic stroke. MRI scan was performed within 72 h of symptom onset after index stroke including T2*-weighted gradient echo to identify HT. For bleeding risk assessment, CTP and diffusion-weighted imaging ASPECTS were categorized into 0-7 or 8-10. Baseline characteristics, ASPCETS scores and HT were compared. Eighteen (34.6%) patients had HT and four (7.7%) developed symptomatic HT. On univariate analysis, the proportion of patients with CBV-ASPECTS 0-7 was significantly higher in HT patients as compared to patients without HT (44 versus 9%, P = 0.005). CBV ASPECTS 0-7 remained independent prognostic factors for HT after adjustment for clinical baseline variables. CBV ASPECTS could be of value to predict HT risk after acute cardioembolic stroke and may be a quick risk assessment approach before reperfusion therapy. PMID- 29163352 TI - Parahippocampal Involvement in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis: A Proof of Concept from Memory-Guided Saccades. AB - Objective: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) may involve extrahippocampal areas of structural damage and dysfunction. The accuracy of medium-term spatial memory can be tested by memory-guided saccades (MGS) to evaluate a functional impairment of the parahippocampal cortex (PHC), while voxel based morphometry (VBM) analysis can be used to detect a structural damage of the latter region. Methods: MGS with 3- and 30-s memorization delays were compared between 7 patients affected by right MTLE-HS (r-MTLE-HS), 6 patients affected by left MTLE-HS, and 13 healthy controls. The same subjects underwent brain MRI for a VBM analysis. Correlation analysis was performed between the results of VBM and MGS and with patients' clinical data. Results: Right MTLE-HS patients showed impaired accuracy of leftward MGS with a 30-s memorization delay; their gray matter volume was reduced in the right hippocampus and inferior temporal gyrus, and bilaterally in the cerebellum. Left MTLE-HS patients had normal MGS accuracy; their gray-matter volume was reduced in the left hippocampus, in the right inferior temporal gyrus and corpus callosus, and bilaterally in the insular cortex and in the cerebellum. The difference between right and left parahippocampal volumes correlated with MGS accuracy, while right and left hippocampal volumes did not. Hippocampal and parahippocampal volume did not correlate with clinical variables such as febrile seizures, age at disease onset, disease duration, and seizure frequency. Conclusion: MGS abnormalities suggested the functional involvement of the right PHC in patients with r-MTLE-HS, supporting a right lateralization of spatial memory control and showing a relation between functional impairment and degree of atrophy. PMID- 29163353 TI - Primary Ewing Sarcoma of the Thyroid-Eight Cases in a Decade: A Case Report and Literature Review. AB - Sarcomas represent less than 1% of all malignant tumors found in the thyroid. Of these, primary extraosseoussarcoma has been reported only a few times in the past decade. We present the case of a 34-year-old male who had a fast-growing hard mass in the lower left neck. FNA was inconclusive. Core needle biopsy revealed the diagnosis of an Ewing sarcoma/primitive neuroectodermal tumor. Mutation of EWSR1 was confirmed using the FISH method. Following treatment by neoadjuvant chemotherapy, we observed clinical, radiological, and finally histopathological remission. This was followed by a left-sided isthmolobectomy with unilateral cervical lymph node dissection by lateral lymphadenectomy, which revealed no residual disease. Posttreatment radiotherapy was administered but discontinued upon the patient's request. After 18 months of observation, the patient had no recurrence or metastasis and required l-thyroxine supplementation. We discuss our case using a comparative literature review to the few other known case reports. PMID- 29163355 TI - Regulation of Gonadotropin-Releasing Hormone-(1-5) Signaling Genes by Estradiol Is Age Dependent. AB - Gonadotropin-releasing hormone (GnRH) is a key regulatory molecule of the hypothalamus-pituitary (PIT)-gonadal (HPG) axis that ultimately leads to the downstream release of estradiol (E2) and progesterone (P). These gonadal steroids feed back to the hypothalamus and PIT to regulate reproductive function and behavior. While GnRH is thought to be the master regulator of reproduction, its metabolic product GnRH-(1-5) is also biologically active. Thimet oligopeptidase 1 (also known as EP24.15) cleaves GnRH to form GnRH-(1-5). GnRH-(1-5) is involved in regulation of the HPG axis, exerting its actions through a pair of orphan G protein-coupled receptors, GPR101 and GPR173. The physiological importance of GnRH-(1-5) signaling has been studied in several contexts, but its potential role during reproductive senescence is poorly understood. We used an ovariectomized (OVX) rat model of reproductive senescence to assess whether and how GnRH-(1-5) signaling genes in hypothalamic subnuclei change in response to aging and/or different estradiol replacement regimens designed to model clinical hormone replacement in women. We found that Gpr101 and Gpr173 mRNA expression was increased with age in the arcuate nucleus, while expression of Gpr173 and EP24.15 increased with age in the medial preoptic area. Treatment with E2 in younger OVX animals increased expression of Gpr101, Gpr173, and EP24.15. However, older animals treated with E2 showed decreased expression of these GnRH-(1-5) signaling genes, displaying an age-related decline in responsiveness to E2. To our knowledge, this is the first study to systematically assess the effects of age and different clinically relevant regimens of E2 replacement on GnRH-(1-5) signaling genes. PMID- 29163354 TI - Diabetes and Sepsis: Risk, Recurrence, and Ruination. AB - Sepsis develops when an infection surpasses local tissue containment. A series of dysregulated physiological responses are generated, leading to organ dysfunction and a 10% mortality risk. When patients with sepsis demonstrate elevated serum lactates and require vasopressor therapy to maintain adequate blood pressure in the absence of hypovolemia, they are in septic shock with an in-hospital mortality rate >40%. With improvements in intensive care treatment strategies, overall sepsis mortality has diminished to ~20% at 30 days; however, mortality continues to steadily climb after recovery from the acute event. Traditionally, it was thought that the complex interplay between inflammatory and anti inflammatory responses led to sepsis-induced organ dysfunction and mortality. However, a closer examination of those who die long after sepsis subsides reveals that many initial survivors succumb to recurrent, nosocomial, and secondary infections. The comorbidly challenged, physiologically frail diabetic individuals suffer the highest infection rates. Recent reports suggest that even after clinical "recovery" from sepsis, persistent alterations in innate and adaptive immune responses exists resulting in chronic inflammation, immune suppression, and bacterial persistence. As sepsis-associated immune defects are associated with increased mortality long-term, a potential exists for immune modulatory therapy to improve patient outcomes. We propose that diabetes causes a functional immune deficiency that directly reduces immune cell function. As a result, patients display diminished bactericidal clearance, increased infectious complications, and protracted sepsis mortality. Considering the substantial expansion of the elderly and obese population, global adoption of a Western diet and lifestyle, and multidrug resistant bacterial emergence and persistence, diabetic mortality from sepsis is predicted to rise dramatically over the next two decades. A better understanding of the underlying diabetic-induced immune cell defects that persist following sepsis are crucial to identify potential therapeutic targets to bolster innate and adaptive immune function, prevent infectious complications, and provide more durable diabetic survival. PMID- 29163357 TI - A Journey through the Gonadotropin-Inhibitory Hormone System of Fish. AB - Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that belongs to the RFamide peptide family and was first identified in the quail brain. From the discovery of avian GnIH, orthologous GnIH peptides have been reported in a variety of vertebrates, including mammals, amphibians, teleosts and agnathans, but also in protochordates. It has been clearly established that GnIH suppresses reproduction in avian and mammalian species through its inhibitory actions on brain GnRH and pituitary gonadotropins. In addition, GnIH also appears to be involved in the regulation of feeding, growth, stress response, heart function and social behavior. These actions are mediated via G protein-coupled GnIH receptors (GnIH-Rs), of which two different subtypes, GPR147 and GPR74, have been described to date. With around 30,000 species, fish represent more than one half of the total number of recognized living vertebrate species. In addition to this impressive biological diversity, fish are relevant because they include model species with scientific and clinical interest as well as many exploited species with economic importance. In spite of this, the study of GnIH and its physiological effects on reproduction and other physiological processes has only been approached in a few fish species, and results obtained are in some cases conflicting. In this review, we summarize the information available in the literature on GnIH sequences identified in fish, the distribution of GnIH and GnIH-Rs in central and peripheral tissues, the physiological actions of GnIH on the reproductive brain-pituitary-gonadal axis, as well as other reported effects of this neuropeptide, and existing knowledge on the regulatory mechanisms of GnIH in fish. PMID- 29163356 TI - Sonic Hedgehog Signaling in Thyroid Cancer. AB - Thyroid cancer is the most common malignancy of the endocrine system. The initiation of thyroid cancer is often triggered by a genetic mutation in the phosphortidylinositol-3 kinase (PI3K) or mitogen-activated protein kinase (MAPK) pathway, such as RAS and BRAF, or by the rearrangement of growth factor receptor tyrosine kinase genes such as RET/PTC. The sonic hedgehog (Shh) pathway is evolutionarily conserved and plays an important role in the embryonic development of normal tissues and organs. Gene mutations in the Shh pathway are involved in basal cell carcinomas (BCC). Activation of the Shh pathway due to overexpression of the genes encoding the components of this pathway stimulates the growth and spread of a wide range of cancer types. The Shh pathway also plays an important role in cancer stem cell (CSC) self-renewal. GDC-0449 and LDE-225, two inhibitors of this pathway, have been approved for treating BCC and are being tested as a single agent or in combination with other drugs for treating various other cancers. Here, we review the recent findings on activation of the Shh pathway in thyroid cancer and its role in maintaining thyroid CSC self-renewal. We also summarize the recent developments on crosstalk of the Shh pathway with the MAPK and PI3K oncogenic pathways, and its implications for combination therapy. PMID- 29163358 TI - Reactive Oxygen Species Link Gonadotropin-Releasing Hormone Receptor Signaling Cascades in the Gonadotrope. AB - Biological rhythms lie at the center of regulatory schemes that control many aspects of living systems. At the cellular level, meaningful responses to external stimuli depend on propagation and quenching of a signal to maintain vigilance for subsequent stimulation or changes that serve to shape and modulate the response. The hypothalamus-pituitary-gonad endocrine axis that controls reproductive development and function relies on control through rhythmic stimulation. Central to this axis is the pulsatile stimulation of the gonadotropes by hypothalamic neurons through episodic release of the neuropeptide gonadotropin-releasing hormone. Alterations in pulsatile stimulation of the gonadotropes result in differential synthesis and secretion of the gonadotropins LH and FSH and changes in the expression of their respective hormone subunit genes. The requirement to amplify signals arising from activation of the gonadotropin-releasing hormone (GnRH) receptor and to rapidly quench the resultant signal to preserve an adaptive response suggests the need for rapid activation and feedback control operating at the level of intracellular signaling. Emerging data suggest that reactive oxygen species (ROS) can fulfill this role in the GnRH receptor signaling through activation of MAP kinase signaling cascades, control of negative feedback, and participation in the secretory process. Results obtained in gonadotrope cell lines or other cell models indicate that ROS can participate in each of these regulatory cascades. We discuss the potential advantage of reactive oxygen signaling for modulating the gonadotrope response to GnRH stimulation and the potential mechanisms for this action. These observations suggest further targets of study for regulation in the gonadotrope. PMID- 29163359 TI - Attitudes of Palestinian Health-Care Professionals in Gaza to Clinical Practice Guideline for Diagnosis and Treatment of Diabetes Mellitus. AB - Background: Despite the huge numbers of the internationally produced and implemented Clinical Practice Guidelines (CPGs), the compliance with them is still low in health care. This study aimed at assessing the attitudes of Palestinian health-care professionals toward the most perceived factors influencing the adherence to the CPG for Diabetes Mellitus in the Primary Health care centers of the Ministry of Health (PHC-MoH) and the Primary Health-care centers of the United Nations Relief and Works Agency for Palestine Refugees (PHC UNRWA) using a validated questionnaire. Methods: A cross-sectional design was employed with a census sample of all Palestinian family doctors and nurses (n = 323). The Cabana theoretical framework was used to develop a study questionnaire. A cross cultural adaptation framework was followed to develop the Arabic version questionnaire. The psychometric properties of Arabic version were finally assessed. Results: The Arabic version questionnaire showed a good construct validity and internal consistency reliability. The overall adherence level to the diabetic guideline was disappointingly suboptimal 51.5% (47.3% in the PHC-MoH and 55.5% in the PHC-UNRWA) P = 0.000. The most frequently perceived barriers in the PHC-MoH were lack of incentives, lack of resources, and lack of guideline trustworthiness, whereas the lack of time and the lack of guideline trustworthiness were the most prominent barriers in the PHC-UNRWA. In spite of the lack of trustworthiness of the diabetic guideline, most respondents in both settings had a positive attitude toward guidelines in general, but this attitude was not a predictor of guideline adherence. Conclusion: The good validity and reliability of our questionnaire can provide support for the accuracy of our findings. Multifaceted implementation strategies targeting the main barriers elicited from this study are required for addressing the lack of incentives, organizational resources, lack of confidence in the guideline, and time constraints. PMID- 29163361 TI - Girls with a History of Premature Adrenarche Have Advanced Growth and Pubertal Development at the Age of 12 Years. AB - Background: Premature adrenarche (PA) has been linked to early thelarche and menarche, but longitudinal data on growth and pubertal development after PA are insufficient. Methods: Growth and pubertal development of mostly full-term and appropriate for gestational age-born 43 PA (36 girls) and 63 control children (52 girls) were analyzed prospectively. Children examined first at the mean age of 7.6 years were reexamined at the mean age of 12.0 years. Results: The PA girls but not the boys were taller and had higher body mass index (BMI) than the controls. A higher proportion of the PA than control girls had reached menarche, while the same percentage of the PA and control boys were at Tanner genital stage >=2. The PA girls with premature pubarche (PP) were taller but not heavier and had more often reached menarche by the age of 12 years than the PA girls without PP. The PA girls with menarche had lower birth length (BL) and higher prepubertal insulin-like growth factor 1 (IGF-1) concentrations compared with non-menarcheal PA girls. In logistic regression analyses for all girls, lower BL standard deviation score, earlier maternal menarche, and higher prepubertal IGF-1 were independently associated with menarche. Conclusion: At 12 years of age, the PA girls had higher BMI, advanced linear growth, and accelerated pubertal development with earlier menarche than the control girls. The PA girls with PP were taller and had earlier menarche than the PA girls without PP. Lower BL and higher prepubertal IGF-1 concentration were predictive factors for menarche by the age of 12 years. PMID- 29163360 TI - Vitiligo and Autoimmune Thyroid Disorders. AB - Vitiligo represents the most common cause of acquired skin, hair, and oral depigmentation, affecting 0.5-1% of the population worldwide. It is clinically characterized by the appearance of disfiguring circumscribed skin macules following melanocyte destruction by autoreactive cytotoxic T lymphocytes. Patients affected by vitiligo usually show a poorer quality of life and are more likely to suffer from depressive symptoms, particularly evident in dark-skinned individuals. Although vitiligo is a non-fatal disease, exposure of affected skin to UV light increases the chance of skin irritation and predisposes to skin cancer. In addition, vitiligo has been associated with other rare systemic disorders due to the presence of melanocytes in other body districts, such as in eyes, auditory, nervous, and cardiac tissues, where melanocytes are thought to have roles different from that played in the skin. Several pathogenetic models have been proposed to explain vitiligo onset and progression, but clinical and experimental findings point mainly to the autoimmune hypothesis as the most qualified one. In this context, it is of relevance the strong association of vitiligo with other autoimmune diseases, in particular with autoimmune thyroid disorders, such as Hashimoto thyroiditis and Graves' disease. In this review, after a brief overview of vitiligo and its pathogenesis, we will describe the clinical association between vitiligo and autoimmune thyroid disorders and discuss the possible underlying molecular mechanism(s). PMID- 29163362 TI - Obesity and Breast Cancer: Current Insights on the Role of Fatty Acids and Lipid Metabolism in Promoting Breast Cancer Growth and Progression. AB - Obesity and excess accumulation of adipose tissue are known risk factors for several types of cancer, including breast cancer. With the incidence of obesity constantly rising worldwide, understanding the molecular details of the interaction between adipose tissue and breast tumors, the most common tumors in women, becomes an urgent task. In terms of lipid metabolism, most of the studies conducted so far focused on upregulated de novo lipid synthesis in cancer cells. More recently, the use of extracellular lipids as source of energy came into focus. Especially in obesity, associated dysfunctional adipose tissue releases increased amounts of fatty acids, but also dietary lipids can be involved in promoting tumor growth and progression. In addition, it was shown that breast cancer cells and adipocytes, which are a major component of the stroma of breast tumors, are able to directly interact with each other. Breast cancer cells and adjacent adipocytes exchange molecules such as growth factors, chemokines, and interleukins in a reciprocal manner. Moreover, it was shown that breast cancer cells can access and utilize fatty acids produced by neighboring adipocytes. Thus adipocytes, and especially hypertrophic adipocytes, can act as providers of lipids, which can be used as a source of energy for fatty acid oxidation and as building blocks for tumor cell growth. PMID- 29163363 TI - Human Prolactin Point Mutations and Their Projected Effect on Vasoinhibin Generation and Vasoinhibin-Related Diseases. AB - Background: A dysregulation of the generation of vasoinhibin hormones by proteolytic cleavage of prolactin (PRL) has been brought into context with diabetic retinopathy, retinopathy of prematurity, preeclampsia, pregnancy-induced hypertension, and peripartum cardiomyopathy. Factors governing vasoinhibin generation are incompletely characterized, and the composition of vasoinhibin isoforms in human tissues or compartments, such as the circulation, is unknown. The aim of this study was to determine the possible contribution of PRL point mutations to the generation of vasoinhibins as well as to project their role in vasoinhibin-related diseases. Methods: Prolactin sequences, point mutations, and substrate specificity information about the PRL cleaving enzymes cathepsin D, matrix metalloproteinases 8 and 13, and bone-morphogenetic protein 1 were retrieved from public databases. The consequences of point mutations in regard to their possible effect on vasoinhibin levels were projected on the basis of a score indicating the suitability of a particular sequence for enzymatic cleavage that result in vasoinhibin generation. The relative abundance and type of vasoinhibin isoforms were estimated by comparing the relative cleavage efficiency of vasoinhibin-generating enzymes. Results: Six point mutations leading to amino acid substitutions in vasoinhibin-generating cleavage sites were found and projected to either facilitate or inhibit vasoinhibin generation. Four mutations affecting vasoinhibin generation in cancer tissues were found. The most likely composition of the relative abundance of vasoinhibin isoforms is projected to be 15 > 17.2 > 16.8 > 17.7 > 18 kDa vasoinhibin. Conclusion: Prolactin point mutations are likely to influence vasoinhibin levels by affecting the proteolysis efficiency of vasoinhibin-generating enzymes and should be monitored in patients with vasoinhibin-related diseases. Attempts to characterize vasoinhibin-related diseases should include the 15, 17.2, 16.8, 17.7, and 18 kDa vasoinhibin isoforms. PMID- 29163364 TI - Telomere Length in Preterm Infants: A Promising Biomarker of Early Adversity and Care in the Neonatal Intensive Care Unit? AB - Preterm infants present an immature neurobehavioral profile at birth, even in absence of severe brain injuries and perinatal complications. As such, they require a long-lasting hospitalization in the Neonatal Intensive Care Unit (NICU), which is thought to grant at-risk newborns' survival, but still entails a number of physical, painful, and socio-emotional stressors. Hence, preterm birth and NICU stay represent an early adverse experience, which has been linked to detrimental consequences for neurological, neuro-endocrinal, behavioral, and socio-emotional development, as well as to disease later in life. Recent advances in the behavioral epigenetic field are helping us to unveil the potential mechanisms through which early NICU-related stress may lead to negative developmental outcomes. From this perspective, telomere regulation might be a key programming mechanism. Telomeres are the terminal portion of chromosomes and are known to get shorter with age. Moreover, telomere length (TL) is affected by the exposure to stress during early development. As such, TL might be an innovative biomarker of early adverse exposures in young infants and children. Unfortunately, there is paucity of studies investigating TL in populations of preterm infants and its association with known NICU-related stressors remains unexplored. In the present paper, the potential relevance of TL for research and clinical work with preterm infants will be underlined in the light of recent contributions linking progressive telomere shortening and early exposure to adverse experiences and stressful environments in humans. Finally, insights will be provided to guide clinically relevant translational research on TL in the field of VPT birth and NICU stay. PMID- 29163366 TI - Clinical, Genetic, and Protein Structural Aspects of Familial Dysalbuminemic Hyperthyroxinemia and Hypertriiodothyroninemia. AB - Familial dysalbuminemic hyperthyroxinemia (FDH-T4) and hypertriiodothyroninemia (FDH-T3) are dominantly inherited syndromes characterized by a high concentration of thyroid hormone in the blood stream. The syndromes do not cause disease, because the concentration of free hormone is normal, but affected individuals are at risk of erroneous treatment. FDH-T4 is the most common cause of euthyroid hyperthyroxinemia in Caucasian populations in which its prevalence is about 1 in 10,000 individuals, but the prevalence can be much higher in some ethnic groups. The condition is caused by a genetic variant of human serum albumin (HSA); Arg218 is mutated to histidine, proline, or serine or Arg222 is changed to isoleucine. The disorder is characterized by greater elevation in serum l-thyroxine (T4) than in serum triiodothyronine (T3); T4 can be increased by a factor 8-15. The high serum concentration of T4 is due to modification of a binding site located in the N-terminal half of HSA (in subdomain IIA). Thus, mutating Arg218 or Arg222 for a smaller amino acid reduces the steric restrictions in the site and creates a high affinity binding site. The mutations can also affect binding of other ligands and can perhaps cause modified pharmacokinetics of albumin-binding drugs. In normal HSA, the high-affinity site has another location (in subdomain IIIB). Different locations of these sites imply that persons with and without FDH-T4 can have different types of interactions, and thereby complications, when given albumin binding drugs. FDH-T3 is caused by a leucine to proline mutation in position 66 of HSA, which results in a large increment of the binding affinity for T3 but not for T4. For avoiding unwanted treatment of euthyroid persons with hyperthyroxinemia or hypertriiodothyroninemia, protein sequencing and/or sequencing of the albumin gene should be performed. PMID- 29163365 TI - Functional Mitochondria in Health and Disease. AB - The ability to rapidly adapt cellular bioenergetic capabilities to meet rapidly changing environmental conditions is mandatory for normal cellular function and for cancer progression. Any loss of this adaptive response has the potential to compromise cellular function and render the cell more susceptible to external stressors such as oxidative stress, radiation, chemotherapeutic drugs, and hypoxia. Mitochondria play a vital role in bioenergetic and biosynthetic pathways and can rapidly adjust to meet the metabolic needs of the cell. Increased demand is met by mitochondrial biogenesis and fusion of individual mitochondria into dynamic networks, whereas a decrease in demand results in the removal of superfluous mitochondria through fission and mitophagy. Effective communication between nucleus and mitochondria (mito-nuclear cross talk), involving the generation of different mitochondrial stress signals as well as the nuclear stress response pathways to deal with these stressors, maintains bioenergetic homeostasis under most conditions. However, when mitochondrial DNA (mtDNA) mutations accumulate and mito-nuclear cross talk falters, mitochondria fail to deliver critical functional outputs. Mutations in mtDNA have been implicated in neuromuscular and neurodegenerative mitochondriopathies and complex diseases such as diabetes, cardiovascular diseases, gastrointestinal disorders, skin disorders, aging, and cancer. In some cases, drastic measures such as acquisition of new mitochondria from donor cells occurs to ensure cell survival. This review starts with a brief discussion of the evolutionary origin of mitochondria and summarizes how mutations in mtDNA lead to mitochondriopathies and other degenerative diseases. Mito-nuclear cross talk, including various stress signals generated by mitochondria and corresponding stress response pathways activated by the nucleus are summarized. We also introduce and discuss a small family of recently discovered hormone-like mitopeptides that modulate body metabolism. Under conditions of severe mitochondrial stress, mitochondria have been shown to traffic between cells, replacing mitochondria in cells with damaged and malfunctional mtDNA. Understanding the processes involved in cellular bioenergetics and metabolic adaptation has the potential to generate new knowledge that will lead to improved treatment of many of the metabolic, degenerative, and age-related inflammatory diseases that characterize modern societies. PMID- 29163368 TI - Editorial: Leptin Resistance in Metabolic Disorders: Possible Mechanisms and Treatments. PMID- 29163367 TI - A Testis-Specific Long Non-Coding RNA, lncRNA-Tcam1, Regulates Immune-Related Genes in Mouse Male Germ Cells. AB - Spermatogenesis is precisely controlled by hormones from the hypothalamus pituitary-gonadal axis and testis-specific genes, but the regulatory mechanism is not fully understood. Recently, a large number of long non-coding RNAs (lncRNAs) are found to be transcribed at each stage of meiosis of male germ cells, and their functions in spermatogenesis have yet to be fully investigated. lncRNA testicular cell adhesion molecule 1 (lncRNA-Tcam1) is a nuclear lncRNA which is specifically expressed in mouse male germ cells and presumed to play a role in gene regulation during meiosis. Here, we present the identification of potential target genes of lncRNA-Tcam1 using spermatocyte-derived GC-2spd(ts) cells. Initially, 55 target gene candidates were detected by RNA-sequencing of two GC 2spd(ts) cell clones that were stably transfected with transgenes to express lncRNA-Tcam1 at different levels. Expression of 21 genes of the candidates was found to be correlated with lncRNA-Tcam1 at 7-14 postnatal days, when lncRNA Tcam1 expression was elevated. Subsequently, we examined expression levels of the 21 genes in other two GC-2spd(ts) clones, and 11 genes exhibited the correlation with lncRNA-Tcam1. Induction of lncRNA-Tcam1 transcription using the Tet-off system verified that six genes, Trim30a, Ifit3, Tgtp2, Ifi47, Oas1g, and Gbp3, were upregulated in GC-2spd(ts) cells, indicating that lncRNA-Tcam1 is responsible for the regulation of gene expression of the six genes. In addition, five of the six genes, namely, Ifit3, Tgtp2, Ifi47, Oas1g, and Gbp3, are immune response genes, and Trim30a is a negative regulator of immune response. Altogether, the present study suggests that lncRNA-Tcam1 is responsible for gene regulation for the immune response during spermatogenesis. PMID- 29163369 TI - Preconception Prebiotic and Sitagliptin Treatment in Obese Rats Affects Pregnancy Outcomes and Offspring Microbiota, Adiposity, and Glycemia. AB - Maternal obesity is associated with increased risk of pregnancy complications and greater risk of obesity in offspring, but studies designed to examine preconception weight loss are limited. The objective of this study was to determine if a combined dietary [oligofructose (OFS)] and pharmacological (sitagliptin) preconception intervention could mitigate poor pregnancy outcomes associated with maternal obesity and improve offspring metabolic health and gut microbiota composition. Diet-induced obese female Sprague-Dawley rats were randomized to one of four intervention groups for 8 weeks: (1) Obese-Control (consumed control diet during intervention); (2) Obese-OFS (10% OFS diet); (3) Obese-S (sitagliptin drug); (4) Obese-OFS + S (combination treatment). Two reference groups were also included: (5) Obese-HFS (untreated obese consumed high fat/sucrose diet throughout study); (6) Lean-Control (lean reference group that were never obese and consumed control diet throughout). Offspring consumed control diet until 11 weeks of age followed by HFS diet until 17 weeks of age. The Obese-OFS + S rats lost weight during the intervention phase whereas the OFS and S treatments attenuated weight gain compared with Obese-HFS (p < 0.05). Gestational weight gain was lowest in Obese-OFS + S rats and highest in Obese-HFS rats (p < 0.05). Prepregnancy intervention did not affect reproductive parameters but did affect pregnancy outcomes including litter size. Male Obese-OFS offspring had significantly lower percent body fat than Obese-HFS at 17 weeks. Female Obese S and Obese-OFS offspring had significantly lower fasting glucose at 17 weeks compared with Obese-Control and Obese-HFS. Clostridium cluster XI was higher in Obese-HFS and Obese-S dams at birth compared with all other groups. Dams with an adverse pregnancy outcome had significantly lower (p = 0.035) Lactobacillus spp. compared with dams with normal or small litters. At weaning, male offspring of Obese-HFS had higher levels of Methanobrevibacter than all other groups except Obese-S and female Obese-HFS offspring had higher Enterobacteriaceae compared with all other groups. At 11 and 17 weeks of age, Bacteroides/Prevotella spp. was significantly lower in male and female offspring of Obese-HFS dams compared with all other groups except Obese-OFS + S. Modest weight loss induced with a diet drug combination did not affect maternal fecundity but did have sex-specific effects on offspring adiposity and glycemia that may be linked to changes in offspring microbiota. PMID- 29163370 TI - Small Ubiquitin-Like Modifier 4 (SUMO4) Gene M55V Polymorphism and Type 2 Diabetes Mellitus: A Meta-analysis Including 6,823 Subjects. AB - Background: Many studies suggest that the small ubiquitin-like modifier 4 (SUMO4) M55V gene polymorphism (rs237025) may be associated with an increased risk of type 2 diabetes mellitus (T2DM). However, due to other conflicting results, a clear consensus is lacking in the matter. Objective and methods: A meta-analysis consisting of 6,823 subjects from 10 studies was conducted to elucidate relationship between the SUMO4 M55V gene polymorphism and T2DM. Depending on the heterogeneity of the data, either a fixed or random-effects model would be used to assess the combined odds ratio (ORs) and their corresponding 95% confidence interval (CI). Results: SUMO4 gene M55V polymorphism was significantly associated with T2DM in the whole population under allelic (OR: 1.18, 95% CI: 1.10-1.28, P = 1.63 * 10-5), recessive (OR: 1.59, 95% CI: 1.14-2.23, P = 0.006), dominant (OR: 0.815, 95% CI: 0.737-0.901, P = 6.89 * 10-5), homozygous (OR: 1.415, 95% CI: 1.170-1.710, P = 0.0003), heterozygous (OR: 1.191, 95% CI: 1.072-1.323, P = 0.001), and additive genetic models (OR: 1.184, 95% CI: 1.097-1.279, P = 1.63 * 10-5). In our subgroup analysis, a significant association was found again in the Chinese population, but not in Japanese or Iranian population. Conclusion: SUMO4 gene M55V polymorphism may correlate with increased T2DM risk. Chinese carriers of the V allele of the SUMO4 gene M55V polymorphism may be predisposed to developing T2DM. PMID- 29163371 TI - Cofactors As Metabolic Sensors Driving Cell Adaptation in Physiology and Disease. AB - Chromatin architectures and epigenetic fingerprint regulation are fundamental for genetically determined biological processes. Chemical modifications of the chromatin template sensitize the genome to intracellular metabolism changes to set up diverse functional adaptive states. Accumulated evidence suggests that the action of epigenetic modifiers is sensitive to changes in dietary components and cellular metabolism intermediates, linking nutrition and energy metabolism to gene expression plasticity. Histone posttranslational modifications create a code that acts as a metabolic sensor, translating changes in metabolism into stable gene expression patterns. These observations support the notion that epigenetic reprograming-linked energy input is connected to the etiology of metabolic diseases and cancer. In the present review, we introduce the role of epigenetic cofactors and their relation with nutrient intake and we question the links between epigenetic regulation and the development of metabolic diseases. PMID- 29163372 TI - Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2. AB - Background: Epidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa) and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and hyperglycemia: we investigated whether some of the exposures associated with disturbed metabolism can also affect the frequency of this gene fusion. Methods: Fusion was induced in LNCaP PCa cells in normal or high levels of glucose, with or without insulin-like growth factor binding protein-2 (IGFBP-2) silenced or the presence of insulin like growth factor-1 (IGF-I), insulin, or epidermal growth factor (EGF). RNA was extracted for analysis by nested PCR. Abundance of IGFBP-2, gammaH2AX, DNA dependent protein kinase catalytic subunit (DNAPKcs), and beta-actin were analyzed by Western immunoblotting. Results: Our data suggest that hyperglycemia induced IGFBP-2 increased the frequency of the gene fusion that was accompanied by decreased levels of DNAPKcs implying that they were mediated by alterations in the rate of repair of double-strand breaks. In contrast insulin, IGF-I and EGF all decreased gene fusion events. Conclusion: These novel observations may represent a further mechanism by which obesity can exert an effect aggravating PCa progression. PMID- 29163374 TI - Erratum: Arginine Vasopressin Effects on Subjective Judgments and Neural Responses to Same and Other-Sex Faces in Men and Women. AB - [This corrects the article on p. 200 in vol. 8, PMID: 28871239.]. PMID- 29163373 TI - Placental Nutrient Transport in Gestational Diabetic Pregnancies. AB - Maternal obesity during pregnancy is rising and is associated with increased risk of developing gestational diabetes mellitus (GDM), defined as glucose intolerance first diagnosed in pregnancy (1). Fetal growth is determined by the maternal nutrient supply and placental nutrient transfer capacity. GDM-complicated pregnancies are more likely to be complicated by fetal overgrowth or excess adipose deposition in utero. Infants born from GDM mothers have an increased risk of developing cardiovascular and metabolic disorders later in life. Diverse factors, such as ethnicity, age, fetal sex, clinical treatment for glycemic control, gestational weight gain, and body mass index among others, represent a challenge for studying underlying mechanisms in GDM subjects. Determining the individual roles of glucose intolerance, obesity, and other factors on placental function and fetal growth remains a challenge. This review provides an overview of changes in placental macronutrient transport observed in human pregnancies complicated by GDM. Improved knowledge and understanding of the alterations in placenta function that lead to pathological fetal growth will allow for development of new therapeutic interventions and treatments to improve pregnancy outcomes and lifelong health for the mother and her children. PMID- 29163375 TI - Isolation and Characterization of Pseudomonas spp. Strains That Efficiently Decompose Sodium Dodecyl Sulfate. AB - Due to their particular properties, detergents are widely used in household cleaning products, cosmetics, pharmaceuticals, and in agriculture as adjuvants tailoring the features of pesticides or other crop protection agents. The continuously growing use of these various products means that water soluble detergents have become one of the most problematic groups of pollutants for the aquatic and terrestrial environments. Thus it is important to identify bacteria having the ability to survive in the presence of large quantities of detergent and efficiently decompose it to non-surface active compounds. In this study, we used peaty soil sampled from a surface flow constructed wetland in a wastewater treatment plant to isolate bacteria that degrade sodium dodecyl sulfate (SDS). We identified and initially characterized 36 Pseudomonas spp. strains that varied significantly in their ability to use SDS as their sole carbon source. Five isolates having the closest taxonomic relationship to the Pseudomonas jessenii subgroup appeared to be the most efficient SDS degraders, decomposing from 80 to 100% of the SDS present in an initial concentration 1 g/L in less than 24 h. These isolates exhibited significant differences in degree of SDS degradation, their resistance to high detergent concentration (ranging from 2.5 g/L up to 10 g/L or higher), and in chemotaxis toward SDS on a plate test. Mass spectrometry revealed several SDS degradation products, 1-dodecanol being dominant; however, traces of dodecanal, 2-dodecanol, and 3-dodecanol were also observed, but no dodecanoic acid. Native polyacrylamide gel electrophoresis zymography revealed that all of the selected isolates possessed alkylsulfatase-like activity. Three isolates, AP3_10, AP3_20, and AP3_22, showed a single band on native PAGE zymography, that could be the result of alkylsulfatase activity, whereas for isolates AP3_16 and AP3_19 two bands were observed. Moreover, the AP3_22 strain exhibited a band in presence of both glucose and SDS, whereas in other isolates, the band was visible solely in presence of detergent in the culture medium. This suggests that these microorganisms isolated from peaty soil exhibit exceptional capabilities to survive in, and break down SDS, and they should be considered as a valuable source of biotechnological tools for future bioremediation and industrial applications. PMID- 29163377 TI - Wild Grape-Associated Yeasts as Promising Biocontrol Agents against Vitis vinifera Fungal Pathogens. AB - The increasing level of hazardous residues in the environment and food chains has led the European Union to restrict the use of chemical fungicides. Thus, exploiting new natural antagonistic microorganisms against fungal diseases could serve the agricultural production to reduce pre- and post-harvest losses, to boost safer practices for workers and to protect the consumers' health. The main aim of this work was to evaluate the antagonistic potential of epiphytic yeasts against Botrytis cinerea, Aspergillus carbonarius, and Penicillium expansum pathogen species. In particular, yeast isolation was carried out from grape berries of Vitis vinifera ssp sylvestris populations, of the Eurasian area, and V. vinifera ssp vinifera cultivars from three different farming systems (organic, biodynamic, and conventional). Strains able to inhibit or slow the growth of pathogens were selected by in vitro and in vivo experiments. The most effective antagonist yeast strains were subsequently assayed for their capability to colonize the grape berries. Finally, possible modes of action, such as nutrients and space competition, iron depletion, cell wall degrading enzymes, diffusible and volatile antimicrobial compounds, and biofilm formation, were investigated as well. Two hundred and thirty-one yeast strains belonging to 26 different species were isolated; 20 of them, ascribed to eight species, showed antagonistic action against all molds. Yeasts isolated from V. vinifera ssp sylvestris were more effective (up to 50%) against B. cinerea rather than those isolated from V. vinifera ssp vinifera. Six strains, all isolated from wild vines, belonging to four species (Meyerozyma guilliermondii, Hanseniaspora uvarum, Hanseniaspora clermontiae, and Pichia kluyveri) revealed one or more phenotypical characteristics associated to the analyzed modes of antagonistic action. PMID- 29163378 TI - Circulating Aspergillus fumigatus DNA Is Quantitatively Correlated to Galactomannan in Serum. AB - The performance of antigen galactomannan (GM) for diagnosing invasive aspergillosis (IA) is hampered by the occurrence of false-positive results. Quantitative PCR has been proposed to improve the diagnosis of IA. Therefore, we analyzed the value of performing a PCR test to the GM-positive serum sample. Using a quantitative PCR assay specific for Aspergillus fumigatus 28S ribosomal DNA, we retrospectively tested 422 GM-positive (Platelia Bio-Rad kit) serum samples collected over 1 year from 147 patients. The cases were classified based on EORTC criteria as "proven," "probable," and "no-IA" before availability of the PCR results. After exclusion of 65 samples for non-reproducibility of GM positivity (n = 62) or PCR inhibition (n = 3), 75 (21.0%) of the remaining 357 samples were PCR-positive. GM and fungal DNA showed a significantly positive correlation (p < 0.0001, R2 = 0.27, slope = 0.98 +/- 0.19). At least one PCR positive result was observed in 63.3% (31/49) of IA patients and in 13.2% (13/98) of non-IA patients (p < 0.0001). The PCR positivity was also associated with the presence of other microbiological criteria among the 44 patients with IA and complete mycological workup (p = 0.014), as well as a higher mortality rate at six months among the 135 patients with hematological conditions (p = 0.0198). Overall, we found a quantitative correlation between serum GM and circulating DNA with an increased likelihood of IA when both were positive. A PCR-positive result also supported a higher fungal load when GM was already positive. We advocate adding a PCR test for every confirmed GM-positive serum sample. PMID- 29163376 TI - Complete Genome Sequence Analysis of Enterobacter sp. SA187, a Plant Multi-Stress Tolerance Promoting Endophytic Bacterium. AB - Enterobacter sp. SA187 is an endophytic bacterium that has been isolated from root nodules of the indigenous desert plant Indigofera argentea. SA187 could survive in the rhizosphere as well as in association with different plant species, and was able to provide abiotic stress tolerance to Arabidopsis thaliana. The genome sequence of SA187 was obtained by using Pacific BioScience (PacBio) single-molecule sequencing technology, with average coverage of 275X. The genome of SA187 consists of one single 4,429,597 bp chromosome, with an average 56% GC content and 4,347 predicted protein coding DNA sequences (CDS), 153 ncRNA, 7 rRNA, and 84 tRNA. Functional analysis of the SA187 genome revealed a large number of genes involved in uptake and exchange of nutrients, chemotaxis, mobilization and plant colonization. A high number of genes were also found to be involved in survival, defense against oxidative stress and production of antimicrobial compounds and toxins. Moreover, different metabolic pathways were identified that potentially contribute to plant growth promotion. The information encoded in the genome of SA187 reveals the characteristics of a dualistic lifestyle of a bacterium that can adapt to different environments and promote the growth of plants. This information provides a better understanding of the mechanisms involved in plant-microbe interaction and could be further exploited to develop SA187 as a biological agent to improve agricultural practices in marginal and arid lands. PMID- 29163379 TI - Medfly Gut Microbiota and Enhancement of the Sterile Insect Technique: Similarities and Differences of Klebsiella oxytoca and Enterobacter sp. AA26 Probiotics during the Larval and Adult Stages of the VIENNA 8D53+ Genetic Sexing Strain. AB - The Mediterranean fruit fly, Ceratitis capitata, is a major agricultural pest worldwide. The development of genetic sexing strains (GSSs) for this species that allows male-only sterile insects releases has boosted the effectiveness of the environmental friendly pest control method known as the sterile insect technique. The last generation of these strains, the VIENNA 7 and VIENNA 8, are currently used in all mass rearing facilities worldwide and are considered as models for such pest control applications. The sterile insect technique depends on the rearing of sufficient numbers of adequate "biological quality" laboratory flies to be released in the field. Currently, there is an increasing amount of studies focusing on the characterization of the symbiotic communities and development of probiotic diets. In our study, two bacterial isolates, an Enterobacter sp. (strain AA26) and a Klebsiella oxytoca strain, were used as probiotics in larval and adult diet. These strains have been shown to be beneficial, affecting several aspects related to the rearing efficiency and biological quality of the medfly VIENNA 8D53+ GSS. Our results demonstrate the effect of K. oxytoca on the developmental duration of the immature stages and, to some extent, on flight ability. On the other hand, our study does not support the presence of any beneficial effect of (a) K. oxytoca on pupal and adult recovery and adults' survival under stress conditions when provided as a larval diet supplement and (b) K. oxytoca and Enterobacter sp. AA26 on mating competitiveness when provided as adult diet supplements. Possible explanations for inconsistencies with previous studies and the need for universalizing protocols are discussed. Our findings, combined with previous studies can support the sterile insect technique, through the improvement of different aspects of mass rearing and biological properties of laboratory reared insect pests. PMID- 29163380 TI - Focused Review: Cytotoxic and Antioxidant Potentials of Mangrove-Derived Streptomyces. AB - Human life expectancy is rapidly increasing with an associated increasing burden of chronic diseases, such as neurodegenerative diseases and cancer. However, there is limited progress in finding effective treatment for these conditions. For this reason, members of the genus Streptomyces have been explored extensively over the past decades as these filamentous bacteria are highly efficient in producing bioactive compounds with human health benefits. Being ubiquitous in nature, streptomycetes can be found in both terrestrial and marine environments. Previously, two Streptomyces strains (MUSC 137T and MUM 256) isolated from mangrove sediments in Peninsular Malaysia demonstrated potent antioxidant and cytotoxic activities against several human cancer cell lines on bioactivity screening. These results illustrate the importance of streptomycetes from underexplored regions aside from the terrestrial ecosystem. Here we provide the insights and significance of Streptomyces species in the search of anticancer and/or chemopreventive agents and highlight the impact of next generation sequencing on drug discovery from the Streptomyces arsenal. PMID- 29163381 TI - Functional Characterization of Acinetobacter baumannii Lacking the RNA Chaperone Hfq. AB - The RNA chaperone Hfq is involved in the riboregulation of diverse genes via small RNAs. Recent studies have demonstrated that Hfq contributes to the stress response and the virulence of several pathogens, and the roles of Hfq vary among bacterial species. Here, we attempted to elucidate the role of Hfq in Acinetobacter baumannii ATCC 17978. In the absence of hfq, A. baumannii exhibited retarded cell growth and was highly sensitive to environmental stress, including osmotic and oxidative pressure, pH, and temperature. Compared to the wild-type, the Hfq mutant had reduced outer membrane vesicles secretion and fimbriae production as visualized by atomic force microscopy. The absence of hfq reduced biofilm formation, airway epithelial cell adhesion and invasion, and survival in macrophage. Further, the hfq mutant induced significantly higher IL-8 levels in airway epithelial cells, which would promote bacterial clearance by the host. In addition to results similar to those reported for other bacteria, our findings demonstrate that Hfq is required in the regulation of the iron-acquisition system via downregulating the bauA and basD genes, the stress-related outer membrane proteins carO, A1S_0820, ompA, and nlpE, and the stress-related cytosolic proteins uspA and groEL. Our data indicate that Hfq plays a critical role in environmental adaptation and virulence in A. baumannii by modulating stress responses, surface architectures, and virulence factors. This study is the first to illustrate the functional role of Hfq in A. baumannii. PMID- 29163382 TI - Immune Cell Responses and Cytokine Profile in Intestines of Mice Infected with Trichinella spiralis. AB - The intestinal phase is critical for trichinellosis caused by Trichinella spiralis (T. spiralis), as it determines both process and consequences of the disease. Several previous studies have reported that T. spiralis induces the initial predominance of a Th1 response during the intestine stage and a subsequent predominance of a Th2 response during the muscle stage. In the present study, immune cells and cytokine profile were investigated in the intestine of mice infected with T. spiralis. The results showed that the number of eosinophils, goblet cells, mucosal mast cells, and 33D1+ dendritic cells (DCs) increased during the intestinal phase of the infection. Among these, eosinophils, goblet cells, and mucosal mast cells continued to increase until 17 days post infection (dpi), and the number of 33D1+ DCs increased compared to wild type; however, it did not change with the days of infection. The mRNA and protein levels of Th1 cytokines IL-2, IL-12, and IFN-gamma and the Th2 cytokines IL-4, IL 5, IL-10, IL-13, and TGF-beta were all increased in the tissues of the small intestine in infected mice; however, in general, Th2 cytokines increased more than Th1 cytokines. In conclusion, our findings suggest that T. spiralis infection can induce an increase of small intestine mucosal immune cells and add further evidence to show that the intestinal mucosal immune system of infected mice was induced toward mixed Th1/Th2 phenotypes with the predominance of Th2 response at the early stage of infection. PMID- 29163383 TI - Microbial Taxa Distribution Is Associated with Ecological Trophic Cascades along an Elevation Gradient. AB - The elevational pattern of soil microbial diversity along mountain slopes has received considerable interest over the last decade. An increasing amount of taxonomic data on soil microbial community composition along elevation gradients have been collected, however the trophic patterns and environmental drivers of elevational changes remain largely unclear. Here, we examined the distribution patterns of major soil bacterial and fungal taxa along the northern slope of Changbai Mountain, Northeast China, at five typical vegetation types located between 740 and 2,691 m above sea level. Elevational patterns of the relative abundance of specific microbial taxa could be partially explained by the oligotrophic-copiotrophic theory. Specifically, two dark-coniferous forests, located at mid-elevation sites, were considered to be oligotrophic habitats, with relatively higher soil C/N ratio and [Formula: see text]-N concentrations. As expected, oligotrophic microbial taxa, belonging to the bacterial phyla Acidobacteria and Gemmatimonadetes, and fungal phylum Basidiomycota, were predominant in the two dark-coniferous forests, exhibiting a mid-elevation maximum pattern. In contrast, the broad leaf-Korean pine mixed forest located at the foot of the mountain, Betula ermanii-dominated forest located below the tree line, and alpine tundra at the highest elevation were considered more copiotrophic habitats, characterized by higher substrate-induced-respiration rates and [Formula: see text]-N concentrations. Microbial taxa considered to be so called copiotrophic members, such as bacterial phyla Proteobacteria and Actinobacteria, and fungal phylum Ascomycota, were relatively abundant in these locations, resulting in a mid-elevation minimum pattern. At finer taxonomic levels, the two most abundant proteobacterial classes, alpha- and beta Proteobacteria, along with Acidobacteria Gp1, 2, 3, 15, and the Basidiomycotal class of Tremellomycetes were classified with the copiotrophic group. Gamma- and delta-Proteobacteria, Acidobacteria Gp4, 6, 7, 16, and Basidiomycotal class of Agaricomycetes were classified as oligotrophic taxa. This work uses the oligotrophic-copiotrophic theory to explain the elevational distribution pattern of the relative abundance of specific microbial taxa, confirming some of the existing trophic classifications of microbial taxa and expanding on the theory to include a broader range of taxonomic levels. PMID- 29163384 TI - Bacillus subtilis Biofilm Development - A Computerized Study of Morphology and Kinetics. AB - Biofilm is commonly defined as accumulation of microbes, embedded in a self secreted extra-cellular matrix, on solid surfaces or liquid interfaces. In this study, we analyze several aspects of Bacillus subtilis biofilm formation using tools from the field of image processing. Specifically, we characterize the growth kinetics and morphological features of B. subtilis colony type biofilm formation and compare these in colonies grown on two different types of solid media. Additionally, we propose a model for assessing B. subtilis biofilm complexity across different growth conditions. GFP-labeled B. subtilis cells were cultured on agar surfaces over a 4-day period during which microscopic images of developing colonies were taken at equal time intervals. The images were used to perform a computerized analysis of few aspects of biofilm development, based on features that characterize the different phenotypes of B. subtilis colonies. Specifically, the analysis focused on the segmented structure of the colonies, consisting of two different regions of sub-populations that comprise the biofilm a central "core" region and an "expanding" region surrounding it. Our results demonstrate that complex biofilm of B. subtillis grown on biofilm-promoting medium [standard lysogeny broth (LB) supplemented with manganese and glycerol] is characterized by rapidly developing three-dimensional complex structure observed at its core compared to biofilm grown on standard LB. As the biofilm develops, the core size remains largely unchanged during development and colony expansion is mostly attributed to the expansion in area of outer cell sub-populations. Moreover, when comparing the bacterial growth on biofilm-promoting agar to that of colonies grown on LB, we found a significant decrease in the GFP production of colonies that formed a more complex biofilm. This suggests that complex biofilm formation has a diminishing effect on cell populations at the biofilm core, likely due to a combination of reduced metabolic rate and increased levels of cell death within this region. PMID- 29163385 TI - Synergistic Response of Rifampicin with Hydroperoxides on Mycobacterium: A Mechanistic Study. AB - Prolonged chemotherapy as well as rapid development of antimicrobial resistance are two of the major concerns for treatment of mycobacterial infections. To enhance the effectiveness of current drug regimens, search for compounds having synergistic interaction with anti-mycobacterial drugs has become indispensable. Here, we have investigated the intervention by oxidative stress, a major factor in mycobacterial pathogenesis, in combination with rifampicin (RIF), a first-line drug used against Mycobacterium tuberculosis. We have observed that a sub inhibitory concentration of cumene hydroperoxide (CHP), a hydrophobic oxidant, synergistically reduced the minimum inhibitory concentration of RIF by fourfold, with a Fractional Inhibitory Concentration Index (FICI) of 0.45. Also, this interaction was found to be robust and synergistic against different strains of M. smegmatis as well as on M. bovis BCG, with FICI ranging from 0.3 to 0.6. Various physiological, biochemical and molecular parameters were explored to understand the mechanism of synergy. It was observed that increased membrane permeability owing to the presence of the oxidant, led to higher uptake of the drug. Moreover, downregulation of the hydroperoxide reductases by RIF, a transcriptional inhibitor, prevented quenching of the reactive oxygen species produced in the presence of CHP. The lipid soluble reactive species triggered autocatalytic lipid peroxidation (LPO), observed here as extensive membrane damage eventually leading to growth inhibition. Furthermore, it was seen that in combination with hydrogen peroxide (H2O2), the effect was only additive, establishing LPO as a key aspect leading toward synergism. To conclude, this work suggests that targeting the bacterial membrane by a radical species can have a significant impact on the treatment of tuberculosis. PMID- 29163386 TI - Evaluating Production of Cyclopentyl Tetraethers by Marine Group II Euryarchaeota in the Pearl River Estuary and Coastal South China Sea: Potential Impact on the TEX86 Paleothermometer. AB - TEX86 [TetraEther indeX of glycerol dialkyl glycerol tetraethers (GDGTs) with 86 carbon atoms] has been widely applied to reconstruct (paleo-) sea surface temperature. Marine Group I (MG-I) Thaumarchaeota were thought to be the primary source of GDGTs constituting the TEX86 formula; however, recent research has suggested that Marine Group II (MG-II) Euryarchaeota may also contribute significantly to the GDGT pool in the ocean. Little is known regarding the potential impact of MG-II Euryarchaeota-derived GDGTs on TEX86 values recorded in marine sediments. In this study, we assessed the relationship between distributions of GDGTs and MG-II Euryarchaeota and evaluated its potential effect on the TEX86 proxy. Lipid and DNA analyses were performed on suspended particulate matter and surface sediments collected along a salinity gradient from the lower Pearl River (river water) and its estuary (mixing water) to the coastal South China Sea (SCS, seawater). TEX86-derived temperatures from the water column and surface sediments were significantly correlated and both were lower than satellite-based temperatures. The ring index (RI) values in these environments were higher than predicted from the calculated TEX86-RI correlation, indicating that the GDGT pool in the water column of the PR estuary and coastal SCS comprises relatively more cyclopentane rings, which thereby altered TEX86 values. Furthermore, the abundance of MG-II Euryarchaeota 16S rRNA gene in the mixing water was two to three orders of magnitude higher than those observed in the river or seawater. Significant linear correlations were observed between the gene abundance ratio of MG-II Euryarchaeota to total archaea and the fractional abundance of GDGTs with cyclopentane rings. Collectively, these results suggest that MG-II Euryarchaeota likely produce a large proportion of GDGTs with 1-4 cyclopentane moieties, which may bias TEX86 values in the water column and sediments. As such, valid interpretation of TEX86 values in the sediment record, particularly in coastal oceans, should consider the contribution from MG-II Euryarchaeota. PMID- 29163387 TI - A Multiplex SYBR Green Real-Time PCR Assay for the Detection of Three Colistin Resistance Genes from Cultured Bacteria, Feces, and Environment Samples. AB - The aim of the study was to develop a multiplex assay for rapid detection of mcr 1, mcr-2, and mcr-3, a group of genes of conferring resistance to colistin mediated by plasmid in Enterobacteriaceae. A SYBR Green based real-time PCR assay has been designed to detect the mcr genes, and applied to cultured bacteria, feces and soil samples. All three mcr genes could be detected with a lower limit of 102 cultured bacteria. This test was highly specific and sensitive, and generated no false-positive results. The assay was also conclusive when applied to feces and soil samples containing mcr-1-positive Escherichia coli, which could facilitate the screening of mcr genes not only in the bacteria, but also directly from the environment. This simple, rapid, sensitive, and specific multiplex assay will be useful for rapid screening of the colistin resistance in both clinical medicine and animal husbandry. PMID- 29163388 TI - Genomic Comparison of Two Family-Level Groups of the Uncultivated NAG1 Archaeal Lineage from Chemically and Geographically Disparate Hot Springs. AB - Recent progress based on single-cell genomics and metagenomic investigations of archaea in a variety of extreme environments has led to significant advances in our understanding of the diversity, evolution, and metabolic potential of archaea, yet the vast majority of archaeal diversity remains undersampled. In this work, we coordinated single-cell genomics with metagenomics in order to construct a near-complete genome from a deeply branching uncultivated archaeal lineage sampled from Great Boiling Spring (GBS) in the U.S. Great Basin, Nevada. This taxon is distantly related (distinct families) to an archaeal genome, designated "Novel Archaeal Group 1" (NAG1), which was extracted from a metagenome recovered from an acidic iron spring in Yellowstone National Park (YNP). We compared the metabolic predictions of the NAG1 lineage to better understand how these archaea could inhabit such chemically distinct environments. Similar to the NAG1 population previously studied in YNP, the NAG1 population from GBS is predicted to utilize proteins as a primary carbon source, ferment simple carbon sources, and use oxygen as a terminal electron acceptor under oxic conditions. However, GBS NAG1 populations contained distinct genes involved in central carbon metabolism and electron transfer, including nitrite reductase, which could confer the ability to reduce nitrite under anaerobic conditions. Despite inhabiting chemically distinct environments with large variations in pH, GBS NAG1 populations shared many core genomic and metabolic features with the archaeon identified from YNP, yet were able to carve out a distinct niche at GBS. PMID- 29163389 TI - Genome Replication in Thermococcus kodakarensis Independent of Cdc6 and an Origin of Replication. AB - The initiation of DNA replication is typically tightly regulated by proteins that form initiation complexes at specific sequences known as replication origins. In Archaea and Eukaryotes, Cdc6, a near-universally conserved protein binds and facilitates the origin-dependent assembly of the replicative apparatus. TK1901 encodes Cdc6 in Thermococcus kodakarensis but, as we report here, TK1901 and the presumed origin of replication can be deleted from the genome of this hyperthermophilic Archaeon without any detectable effects on growth, genetic competence or the ability to support autonomous plasmid replication. All regions of the genome were equally represented in the sequences generated by whole genome sequencing of DNA isolated from T. kodakarensis strains with or without TK1901, inconsistent with DNA initiation occurring at one or few origins, and instead suggestive of replication initiating at many sites distributed throughout the genome. We were unable to generate strains lacking the recombination factors, RadA or RadB, consistent with T. kodakarensis cells, that are oligoploid (7-19 genomes per cell), employing a recombination-based mechanism of DNA replication. Deletion of the previously presumed origin region reduced the long-term viability of cultures supporting the possibility that retaining an origin-based mechanism of DNA initiation provides a survival mechanism for stationary phase cells with only one genome. PMID- 29163390 TI - Comparative Genomics Reveals Specific Genetic Architectures in Nicotine Metabolism of Pseudomonas sp. JY-Q. AB - Microbial degradation of nicotine is an important process to control nicotine residues in the aqueous environment. In this study, a high active nicotine degradation strain named Pseudomonas sp. JY-Q was isolated from tobacco waste extract (TWE). This strain could completely degrade 5.0 g l-1 nicotine in 24 h under optimal culture conditions, and it showed some tolerance even at higher concentrations (10.0 g l-1) of nicotine. The complete genome of JY-Q was sequenced to understand the mechanism by which JY-Q could degrade nicotine and tolerate such high nicotine concentrations. Comparative genomic analysis indicated that JY-Q degrades nicotine through putative novel mechanisms. Two candidate gene cluster duplications located separately at distant loci were predicted to be responsible for nicotine degradation. These two nicotine (Nic) degradation-related loci (AA098_21325-AA098_21340, AA098_03885-AA098_03900) exhibit nearly completely consistent gene organization and component synteny. The nicotinic acid (NA) degradation gene cluster (AA098_17770-AA098_17790) and Nic like clusters were both predicted to be flanked by mobile genetic elements (MGE). Furthermore, we analyzed the regions of genomic plasticity (RGP) in the JY-Q strain and found a dynamic genome carrying a type VI secretion system (T6SS) that promotes nicotine metabolism and tolerance based on transcriptomics and used in silico methods to identify the T6SS effector protein. Thus, a novel nicotine degradation mechanism was elucidated for Pseudomonas sp. JY-Q, suggesting its potential application in the bioremediation of nicotine-contaminated environments, such as TWEs. PMID- 29163391 TI - Colletotrichum gloeosporioides- Contaminated Tea Infusion Blocks Lipids Reduction and Induces Kidney Damage in Mice. AB - When the homogenate of fresh tea tree leaves was fermented to produce black tea beverage, the Colletotrichum gloeosporioides (main pathogen or endophyte of Camellia sinensis) may be mixed into the fermentation liquor. However, it was unclear whether C. gloeosporioides-contaminated tea beverage would damage human health. Therefore, we investigated the changes of functional components and the influences on mice. C. gloeosporioides was added to the green tea infusion. After cultivation of 48 h, tea polyphenols, caffeine, and L-theanine decreased by 31.0, 26.2, and 8.3%, respectively. The contaminated tea infusion showed brown stain, and produced a group of toxic materials named phthalic acid esters. The animal study showed that green tea without contamination significantly decreased levels of alanine aminotransferase, triglycerides, free fatty acids, low-density lipoprotein, and increased insulin level compared with obese mice. On the contrary, contaminated tea lost the effects on these indicators. Furthermore, the urea nitrogen and serum creatinine levels significantly increased in the contaminated tea-drinking mice. Altogether, our results indicate that C. gloeosporioides contamination can reduce the amount of functional components of green tea. Therefore, it inhibits some health-care function of lipid-lowering. In addition, the toxic components in contaminated tea infusion might induce renal damage. PMID- 29163392 TI - Clonal Expansion of Biofilm-Forming Salmonella Typhimurium ST34 with Multidrug Resistance Phenotype in the Southern Coastal Region of China. AB - To disclose the antibiotics susceptibility and wide adaptability of commonly occurring genotypes of Salmonella Typhimurium, the antibiotic resistance and biofilm formation of different multi-locus sequence typing (MLST) types of a collection of 240 S. Typhimurium isolates (33 food and 207 clinical ones) during 2010-2014 in Shenzhen were analyzed. Among these strains, 167 was ST34 (69.58%), and 57 was ST19 (23.75%), respectively. A total of 159 (95.21%) ST34 strains displayed the multidrug resistant phenotype (>= three classes of antibiotic), whereas only 23 (40.35%) ST19 ones did (P < 0.01). Moreover, a relative high proportion (72.46%) of ST34 isolates was classified as moderate to strong biofilm producers, while only 15.79% of ST19 (P < 0.01) was. Among the food isolates, more than half (51.52%) were from livestock products, among which 41.18% classified as moderate to strong biofilm-producers. In summary, this study highlights the expansion of S. Typhimurium ST34 of strong biofilm-forming ability and multidrug resistance in the southern coastal region of China. Therefore, monitoring the occurrence of ST34 S. Typhimurium in food sources, especially in livestock products, and taking appropriate measures to control Salmonella spp. infections via decreasing biofilm formation should be addressed. PMID- 29163394 TI - Cadaver Thanatomicrobiome Signatures: The Ubiquitous Nature of Clostridium Species in Human Decomposition. AB - Human thanatomicrobiome studies have established that an abundant number of putrefactive bacteria within internal organs of decaying bodies are obligate anaerobes, Clostridium spp. These microorganisms have been implicated as etiological agents in potentially life-threatening infections; notwithstanding, the scale and trajectory of these microbes after death have not been elucidated. We performed phylogenetic surveys of thanatomicrobiome signatures of cadavers' internal organs to compare the microbial diversity between the 16S rRNA gene V4 hypervariable region and V3-4 conjoined regions from livers and spleens of 45 cadavers undergoing forensic microbiological studies. Phylogenetic analyses of 16S rRNA gene sequences revealed that the V4 region had a significantly higher mean Chao1 richness within the total microbiome data. Permutational multivariate analysis of variance statistical tests, based on unweighted UniFrac distances, demonstrated that taxa compositions were significantly different between V4 and V3-4 hypervariable regions (p < 0.001). Of note, we present the first study, using the largest cohort of criminal cases to date, that two hypervariable regions show discriminatory power for human postmortem microbial diversity. In conclusion, here we propose the impact of hypervariable region selection for the 16S rRNA gene in differentiating thanatomicrobiomic profiles to provide empirical data to explain a unique concept, the Postmortem Clostridium Effect. PMID- 29163393 TI - The 5BSL3.2 Functional RNA Domain Connects Distant Regions in the Hepatitis C Virus Genome. AB - Viral genomes are complexly folded entities that carry all the information required for the infective cycle. The nucleotide sequence of the RNA virus genome encodes proteins and functional information contained in discrete, highly conserved structural units. These so-called functional RNA domains play essential roles in the progression of infection, which requires their preservation from one generation to the next. Numerous functional RNA domains exist in the genome of the hepatitis C virus (HCV). Among them, the 5BSL3.2 domain in the cis-acting replication element (CRE) at the 3' end of the viral open reading frame has become of particular interest given its role in HCV RNA replication and as a regulator of viral protein synthesis. These functionalities are achieved via the establishment of a complex network of long-distance RNA-RNA contacts involving (at least as known to date) the highly conserved 3'X tail, the apical loop of domain IIId in the internal ribosome entry site, and/or the so-called Alt region upstream of the CRE. Changing contacts promotes the execution of different stages of the viral cycle. The 5BSL3.2 domain thus operates at the core of a system that governs the progression of HCV infection. This review summarizes our knowledge of the long-range RNA-RNA interaction network in the HCV genome, with special attention paid to the structural and functional consequences derived from the establishment of different contacts. The potential implications of such interactions in switching between the different stages of the viral cycle are discussed. PMID- 29163395 TI - Role of Soluble Innate Effector Molecules in Pulmonary Defense against Fungal Pathogens. AB - Fungal infections of the lung are life-threatening but rarely occur in healthy, immunocompetent individuals, indicating efficient clearance by pulmonary defense mechanisms. Upon inhalation, fungi will first encounter the airway surface liquid which contains several soluble effector molecules that form the first barrier of defense against fungal infections. These include host defense peptides, like LL 37 and defensins that can neutralize fungi by direct killing of the pathogen, and collectins, such as surfactant protein A and D, that can aggregate fungi and stimulate phagocytosis. In addition, these molecules have immunomodulatory activities which can aid in fungal clearance from the lung. However, existing observations are based on in vitro studies which do not reflect the complexity of the lung and its airway surface liquid. Ionic strength, pH, and the presence of mucus can have strong detrimental effects on antifungal activity, while the potential synergistic interplay between soluble effector molecules is largely unknown. In this review, we describe the current knowledge on soluble effector molecules that contribute to antifungal activity, the importance of environmental factors and discuss the future directions required to understand the innate antifungal defense in the lung. PMID- 29163396 TI - Synergistic Antifungal Effect of Fluconazole Combined with Licofelone against Resistant Candida albicans. AB - Candida albicans (C. albicans) is one of the important opportunistic fungal pathogens that is closely associated with disseminated or chronic infections. The objective of this study is to evaluate the synergistic antifungal effect of licofelone, which is dual microsomal prostaglandin E2 synthase/lipoxygenase (mPGES-1/LOX) inhibitor in combination with fluconazole against C. albicans. Here our results showed that licofelone (16 MUg/mL) can synergistically work with fluconazole (1 MUg/mL) against planktonic cells of fluconazole-resistant C. albicans. The two-drug combination inhibited the C. albicans biofilm formation over 12 h, and reduced the expression of extracellular phospholipase genes, biofilm-specific genes and RAS/cAMP/PKA pathway related genes. In addition, the two-drug combination inhibited the transition from yeast to hyphal growth form, and decreased the secreted aspartyl proteinase activity, while not affecting the drug efflux pumps activity. Galleria mellonella model was also used to confirm the antifungal activity of the drug combination in vivo. This study first indicates that the combination of fluconazole and licofelone has synergistic effect against resistant C. albicans and could be a promising therapeutic strategy for the antifungal treatment. PMID- 29163397 TI - Functionality of Root-Associated Bacteria along a Salt Marsh Primary Succession. AB - Plant-associated bacteria are known for their high functional trait diversity, from which many are likely to play a role in primary and secondary succession, facilitating plant establishment in suboptimal soils conditions. Here we used an undisturbed salt marsh chronosequence that represents over 100 years of soil development to assess how the functional traits of plant associated bacteria respond to soil type, plant species and plant compartment. We isolated and characterized 808 bacterial colonies from the rhizosphere soil and root endosphere of two salt marsh plants, Limonium vulgare and Artemisia maritima, along the chronosequence. From these, a set of 59 strains (with unique BOX-PCR patterns, 16S rRNA sequence and unique to one of the treatments) were further screened for their plant growth promoting traits (siderophore production, IAA production, exoprotease production and biofilm formation), traits associated with bacterial fitness (antibiotic and abiotic stress resistance - pH, osmotic and oxidative stress, and salinity) and metabolic potential. An overall view of functional diversity (multivariate analysis) indicated that the distributional pattern of bacterial functional traits was driven by soil type. Samples from the late succession (Stage 105 year) showed the most restricted distribution, harboring strains with relatively low functionalities, whereas the isolates from intermediate stage (35 year) showed a broad functional profiles. However, strains with high trait performance were largely from stage 65 year. Grouping the traits according to category revealed that the functionality of plant endophytes did not vary along the succession, thus being driven by plant rather than soil type. In opposition, the functionality of rhizosphere isolates responded strongly to variations in soil type as observed for antibiotic resistance (P = 0.014). Specifically, certain Pseudomonas sp. and Serratia sp. strains revealed high resistance against abiotic stress and antibiotics and produce more siderophores, confirming the high plant-growth promoting activity of these two genera. Overall, this study contributes to a better understanding of the functional diversity and adaptation of the microbiome at typical salt marsh plant species across soil types. Specifically, soil type was influential only in the rhizosphere but not on the endosphere, indicating a strong plant-driven effect on the functionality of endophytes. PMID- 29163398 TI - Phytohormones and Beneficial Microbes: Essential Components for Plants to Balance Stress and Fitness. AB - Plants are subjected to various abiotic stresses, such as drought, extreme temperature, salinity, and heavy metals. Abiotic stresses have negative impact on the physiology and morphology of plants through defects in the genetic regulation of cellular pathways. Plants employ several tolerance mechanisms and pathways to avert the effects of stresses that are triggered whenever alterations in metabolism are encountered. Phytohormones are among the most important growth regulators; they are known for having a prominent impact on plant metabolism, and additionally, they play a vital role in the stimulation of plant defense response mechanisms against stresses. Exogenous phytohormone supplementation has been adopted to improve growth and metabolism under stress conditions. Recent investigations have shown that phytohormones produced by root-associated microbes may prove to be important metabolic engineering targets for inducing host tolerance to abiotic stresses. Phytohormone biosynthetic pathways have been identified using several genetic and biochemical methods, and numerous reviews are currently available on this topic. Here, we review current knowledge on the function of phytohormones involved in the improvement of abiotic stress tolerance and defense response in plants exposed to different stressors. We focus on recent successes in identifying the roles of microbial phytohormones that induce stress tolerance, especially in crop plants. In doing so, this review highlights important plant morpho-physiological traits that can be exploited to identify the positive effects of phytohormones on stress tolerance. This review will therefore be helpful to plant physiologists and agricultural microbiologists in designing strategies and tools for the development of broad spectrum microbial inoculants supporting sustainable crop production under hostile environments. PMID- 29163399 TI - MinION Nanopore Sequencing Enables Correlation between Resistome Phenotype and Genotype of Coliform Bacteria in Municipal Sewage. AB - Wastewater treatment plants (WWTPs) functioned as the intersection between the human society and nature environment, are receiving increasingly more attention on risk assessment of the acquisition of environmental antibiotic resistance genes (ARGs) by pathogenetic populations during treatment. However, because of the general lack of robust resistome profiling methods, genotype, and resistance phenotype is still poorly correlated in human pathogens of sewage samples. Here we applied MinION sequencing to quantify the resistance genes of multiple antibiotic resistant (MAR) coliform bacteria, a common indicator for human enteric pathogens in sewage samples. Our pipeline could deliver the results within 30 h from sample collection and the resistome quantification was consistent to that based on the Illumina platform. Additionally, the long nanopore reads not only enabled a simultaneous identification of the carrier populations of ARGs detected, but also facilitated the genome reconstruction of a representative MAR strain, from which we identified an instance of chromosomal integration of environmental resistance gene obtained by plasmid exchange with a porcine pathogen. This study demonstrated the utilization of MinION sequencing in quick monitoring and simultaneous phylogenetic tracking of environmental ARGs to address potential health risk associated with them. PMID- 29163400 TI - Prevalence and Antibiotic Resistance of Non-typhoidal Salmonella Isolated from Raw Chicken Carcasses of Commercial Broilers and Spent Hens in Tai'an, China. AB - The present study was aimed to determine the prevalence and characteristics of Salmonella isolated from meat samples of commercial broilers (CB) and spent hens (SH). Between March and June 2016, 200 retail raw chicken carcasses (100 from CB and 100 from SH) were obtained from local supermarkets in Tai'an city of China, and Salmonella isolates were then analyzed for antibiotic resistance, serotype, beta-lactamase genes, and the presence of class 1 integron. Forty Salmonella strains were obtained in this study (CB: 21/100, 21%; SH: 19/100, 19%). Three serotypes were identified in 40 Salmonella, and S. Enteritidis (CB: 15/21, 71.4%; SH: 10/19, 52.6%) was the dominant serotype, followed by S. Typhimurium (CB: 4/21, 19%; SH: 6/19, 31.6%) and S. Derby (CB: 2/21, 9.5%; SH: 3/19, 15.8%). Among 21 Salmonella isolated from CB, high antibiotic resistance rates were found for ampicillin (20/21, 95.2%), nalidixic acid (18/21, 85.7%), cefotaxime (17/21, 81%), and tetracycline (13/21, 61.9%); class 1 integron was observed in seven isolates (7/21, 33.3%), and gene cassettes included an empty integron (0.15 kb, n = 1), aadA2 (1.2 kb, n = 3), drfA1-aadA1 (1.4 kb, n = 1), and drfA17-aadA5 (1.7 kb, n = 2); blaTEM-1 was the dominant beta-lactamase gene (21/21, 100%), followed by blaCTX-M-55 (7/21, 33.3%). Among 19 Salmonella isolated from SH, high antibiotic resistance rates were found for nalidixic acid (19/19, 100%), tetracycline (19/19, 100%), ampicillin (18/19, 94.7%), and ciprofloxacin (13/19, 68.4%); class 1 integron was observed in two isolates (2/19, 10.5%), and gene cassettes included drfA17-aadA5 (1.7 kb, n = 1) and drfA1-aadA1 (1.4 kb, n = 1); blaTEM-1 was the dominant beta-lactamase gene (19/19, 100%), followed by blaCTX-M 55 (2/19, 10.5%) and blaCMY-2 (1/19, 5.3%). Collectively, antibiotic-resistant Salmonella can be widely detected in retail raw chicken carcasses of CB and SH, and therefore can pose a serious risk to public health. PMID- 29163401 TI - The Relationship among Tyrosine Decarboxylase and Agmatine Deiminase Pathways in Enterococcus faecalis. AB - Enterococci are considered mainly responsible for the undesirable accumulation of the biogenic amines tyramine and putrescine in cheeses. The biosynthesis of tyramine and putrescine has been described as a species trait in Enterococcus faecalis. Tyramine is formed by the decarboxylation of the amino acid tyrosine, by the tyrosine decarboxylase (TDC) route encoded in the tdc cluster. Putrescine is formed from agmatine by the agmatine deiminase (AGDI) pathway encoded in the agdi cluster. These biosynthesis routes have been independently studied, tyrosine and agmatine transcriptionally regulate the tdc and agdi clusters. The objective of the present work is to study the possible co-regulation among TDC and AGDI pathways in E. faecalis. In the presence of agmatine, a positive correlation between putrescine biosynthesis and the tyrosine concentration was found. Transcriptome studies showed that tyrosine induces the transcription of putrescine biosynthesis genes and up-regulates pathways involved in cell growth. The tyrosine modulation over AGDI route was not observed in the mutant Deltatdc strain. Fluorescence analyses using gfp as reporter protein revealed PaguB (the promoter of agdi catabolic genes) was induced by tyrosine in the wild-type but not in the mutant strain, confirming that tdc cluster was involved in the tyrosine induction of putrescine biosynthesis. This study also suggests that AguR (the transcriptional regulator of agdi) was implicated in interaction among the two clusters. PMID- 29163402 TI - Pharmacological Induction of Heme Oxygenase-1 Impairs Nuclear Accumulation of Herpes Simplex Virus Capsids upon Infection. AB - Heme oxygenase-1 (HO-1) is an inducible enzyme that is expressed in response to physical and chemical stresses, such as ultraviolet radiation, hyperthermia, hypoxia, reactive oxygen species (ROS), as well as cytokines, among others. Its activity can be positively modulated by cobalt protoporphyrin (CoPP) and negatively by tin protoporphirin (SnPP). Once induced, HO-1 degrades iron containing heme into ferrous iron (Fe2+), carbon monoxide (CO) and biliverdin. Importantly, numerous products of HO-1 are cytoprotective with anti-apoptotic, anti-oxidant, anti-inflammatory, and anti-cancer effects. The products of HO-1 also display antiviral properties against several viruses, such as the human immunodeficiency virus (HIV), influenza, hepatitis B, hepatitis C, and Ebola virus. Here, we sought to assess the effect of modulating HO-1 activity over herpes simplex virus type 2 (HSV-2) infection in epithelial cells and neurons. There are no vaccines against HSV-2 and treatment options are scarce in the immunosuppressed, in which drug-resistant variants emerge. By using HSV strains that encode structural and non-structural forms of the green fluorescent protein (GFP), we found that pharmacological induction of HO-1 activity with CoPP significantly decreases virus plaque formation and the expression of virus encoded genes in epithelial cells as determined by flow cytometry and western blot assays. CoPP treatment did not affect virus binding to the cell surface or entry into the cytoplasm, but rather downstream events in the virus infection cycle. Furthermore, we observed that treating cells with a CO-releasing molecule (CORM-2) recapitulated some of the anti-HSV effects elicited by CoPP. Taken together, these findings indicate that HO-1 activity interferes with the replication cycle of HSV and that its antiviral effects can be recapitulated by CO. PMID- 29163403 TI - Modeling the Effect of Modified Atmospheres on Conidial Germination of Fungi from Dairy Foods. AB - Modified atmosphere packaging (MAP) is commonly applied to extend food shelf life. Despite growth of a wide variety of fungal contaminants has been previously studied in relation to modified-atmospheres, few studies aimed at quantifying the effects of dioxygen (O2) and carbon dioxide (CO2) partial pressures on conidial germination in solid agar medium. In the present study, an original culture method was developed, allowing microscopic monitoring of conidial germination under modified-atmospheres in static conditions. An asymmetric model was utilized to describe germination kinetics of Paecilomyces niveus, Mucor lanceolatus, Penicillium brevicompactum, Penicillium expansum, and Penicillium roquefoti, using two main parameters, i.e., median germination time (tau) and maximum germination percentage (Pmax ). These two parameters were subsequently modeled as a function of O2 partial pressure ranging from 0 to 21% and CO2 partial pressure ranging from 0.03 to 70% (8 tested levels for both O2 and CO2). Modified atmospheres with residual O2 or CO2 partial pressures below 1% and up to 70%, respectively, were not sufficient to totally inhibit conidial germination,. However, O2 levels < 1% or CO2 levels > 20% significantly increased tau and/or reduced Pmax , depending on the fungal species. Overall, the present method and results are of interest for predictive mycology applied to fungal spoilage of MAP food products. PMID- 29163404 TI - Do Viruses Exchange Genes across Superkingdoms of Life? AB - Viruses can be classified into archaeoviruses, bacterioviruses, and eukaryoviruses according to the taxonomy of the infected host. The host constrained perception of viruses implies preference of genetic exchange between viruses and cellular organisms of their host superkingdoms and viral origins from host cells either via escape or reduction. However, viruses frequently establish non-lytic interactions with organisms and endogenize into the genomes of bacterial endosymbionts that reside in eukaryotic cells. Such interactions create opportunities for genetic exchange between viruses and organisms of non-host superkingdoms. Here, we take an atypical approach to revisit virus-cell interactions by first identifying protein fold structures in the proteomes of archaeoviruses, bacterioviruses, and eukaryoviruses and second by tracing their spread in the proteomes of superkingdoms Archaea, Bacteria, and Eukarya. The exercise quantified protein structural homologies between viruses and organisms of their host and non-host superkingdoms and revealed likely candidates for virus to-cell and cell-to-virus gene transfers. Unexpected lifestyle-driven genetic affiliations between bacterioviruses and Eukarya and eukaryoviruses and Bacteria were also predicted in addition to a large cohort of protein folds that were universally shared by viral and cellular proteomes and virus-specific protein folds not detected in cellular proteomes. These protein folds provide unique insights into viral origins and evolution that are generally difficult to recover with traditional sequence alignment-dependent evolutionary analyses owing to the fast mutation rates of viral gene sequences. PMID- 29163405 TI - Overexpression of the Prunus sogdiana NBS-LRR Subgroup Gene PsoRPM2 Promotes Resistance to the Root-Knot Nematode Meloidogyne incognita in Tobacco. AB - Root-knot nematodes (RKNs), particularly Meloidogyne incognita, are the most devastating soil-borne pathogens that significantly affect the production of Prunus spp. fruit. RKN infection is difficult to control and consequently causes massive yield losses each year. However, several germplasms of wild Prunus spp. have been shown to display resistance to M. incognita. Consequently, both the isolation of novel plant resistance (R) genes and the characterization of their resistance mechanisms are important strategies for future disease control. R proteins require the co-chaperone protein HSP90-SGT1-RAR1 to achieve correct folding, maturation, and stabilization. Here, we used homologous cloning to isolate the R gene PsoRPM2 from the RKN-resistant species Prunus sogdiana. PsoRPM2 was found to encode a TIR-NB-LRR-type protein and react with significantly elevated PsoRPM2 expression levels in response to RKN infection. Transient expression assays indicated PsoRPM2 to be located in both the cytoplasm and the nucleus. Four transgenic tobacco lines that heterologously expressed PsoRPM2 showed enhanced resistance to M. incognita. Yeast two-hybrid analysis and bimolecular fluorescence complementation analysis demonstrated that both PsoRAR1 and PsoRPM2 interacted with PsoHSP90-1 and PsoSGT1, but not with one another. These results indicate that the observed PsoRPM2-mediated RKN resistance requires both PsoHSP90-1 and PsoSGT1, further suggesting that PsoRAR1 plays a functionally redundant role in the HSP90-SGT1-RAR1 co-chaperone. PMID- 29163406 TI - Analysis of Microbiome Data in the Presence of Excess Zeros. AB - Motivation: An important feature of microbiome count data is the presence of a large number of zeros. A common strategy to handle these excess zeros is to add a small number called pseudo-count (e.g., 1). Other strategies include using various probability models to model the excess zero counts. Although adding a pseudo-count is simple and widely used, as demonstrated in this paper, it is not ideal. On the other hand, methods that model excess zeros using a probability model often make an implicit assumption that all zeros can be explained by a common probability models. As described in this article, this is not always recommended as there are potentially three types/sources of zeros in a microbiome data. The purpose of this paper is to develop a simple methodology to identify and accomodate three different types of zeros and to test hypotheses regarding the relative abundance of taxa in two or more experimental groups. Another major contribution of this paper is to perform constrained (directional or ordered) inference when there are more than two ordered experimental groups (e.g., subjects ordered by diet or age groups or environmental exposure groups). As far as we know this is the first paper that addresses such problems in the analysis of microbiome data. Results: Using extensive simulation studies, we demonstrate that the proposed methodology not only controls the false discovery rate at a desired level of significance while competing well in terms of power with DESeq2, a popular procedure derived from RNASeq literature. As expected, the method using pseudo-counts tends to be very conservative and the classical t-test that ignores the underlying simplex structure in the data has an inflated FDR. PMID- 29163407 TI - A Therapeutic Antiviral Antibody Inhibits the Anterograde Directed Neuron-to-Cell Spread of Herpes Simplex Virus and Protects against Ocular Disease. AB - Herpes simplex virus (HSV) is a leading cause of blindness and viral encephalitis in the developed world. Upon reactivation from sensory neurons, HSV returns via axonal transport to peripheral tissues where it causes, e.g., severe, potentially blinding ocular diseases. In the present study we investigated whether the HSV 1/2 glycoprotein B-specific antibody mAb 2c or its humanized counterpart mAb hu2c can protect from ocular disease in a mouse model of HSV-1-induced acute retinal necrosis (ARN). In this model the viral spread from the initially infected to the contralateral eye resembles the routes taken in humans upon HSV reactivation. Systemic antibody treatment prior or early after infection effectively protected the mice from the development of ARN. These observations suggest that the antibody potently neutralized the infection and inhibited the viral transmission, since there was almost no virus detectable in the contralateral eyes and trigeminal ganglia of antibody treated mice. Besides of neutralizing free virus or limiting the infection via activating the complement or cellular effector functions, blocking of the anterograde directed neuron-to-cell spread of HSV represents a viable mode of action how mAb 2c protected the mice from ARN. We proved this hypothesis using a microfluidic chamber system. Neurons and epithelial cells were cultured in two separate compartments where the neurons sent axons via connecting microgrooves to the epithelial cells. Neurons were infected with a reporter HSV-1 strain expressing mCherry, and the co-culture was treated with neutralizing antibodies. In contrast to commercial polyclonal human HSV-neutralizing immunoglobulins, mAb 2c effectively blocked the anterograde directed neuron-to-cell transmission of the virus. Our data suggest that the humanized HSV-1/2-gB antibody protects mice from ocular disease by blocking the neuronal spread of HSV. Therefore, mAb hu2c may become a potent novel therapeutic option for severe ocular HSV infections. PMID- 29163408 TI - Environmental Nutrient Supply Directly Alters Plant Traits but Indirectly Determines Virus Growth Rate. AB - Ecological stoichiometry and resource competition theory both predict that nutrient rates and ratios can alter infectious disease dynamics. Pathogens such as viruses hijack nutrient rich host metabolites to complete multiple steps of their epidemiological cycle. As the synthesis of these molecules requires nitrogen (N) and phosphorus (P), environmental supply rates, and ratios of N and P to hosts can directly limit disease dynamics. Environmental nutrient supplies also may alter virus epidemiology indirectly by changing host phenotype or the dynamics of coinfecting pathogens. We tested whether host nutrient supplies and coinfection control pathogen growth within hosts and transmission to new hosts, either directly or through modifications of plant tissue chemistry (i.e., content and stoichiometric ratios of nutrients), host phenotypic traits, or among pathogen interactions. We examined two widespread plant viruses (BYDV-PAV and CYDV-RPV) in cultivated oats (Avena sativa) grown along a range of N and of P supply rates. N and P supply rates altered plant tissue chemistry and phenotypic traits; however, environmental nutrient supplies and plant tissue content and ratios of nutrients did not directly alter virus titer. Infection with CYDV-RPV altered plant traits and resulted in thicker plant leaves (i.e., higher leaf mass per area) and there was a positive correlation between CYDV-RPV titer and leaf mass per area. CYDV-RPV titer was reduced by the presence of a competitor, BYDV PAV, and higher CYDV-RPV titer led to more severe chlorotic symptoms. In our experimental conditions, virus transmission was unaffected by nutrient supply rates, co-infection, plant stoichiometry, or plant traits, although nutrient supply rates have been shown to increase infection and coinfection rates. This work provides a robust test of the role of plant nutrient content and ratios in the dynamics of globally important pathogens and reveals a more complex relationship between within-host virus growth and alterations of plant traits. A deeper understanding of the differential effects of environmental nutrient supplies on virus epidemiology and ecology is particularly relevant given the rapid increase of nutrients flowing into Earth's ecosystems as a result of human activities. PMID- 29163409 TI - Seasonal Shifts in Bacterial Community Responses to Phytoplankton-Derived Dissolved Organic Matter in the Western Antarctic Peninsula. AB - Bacterial consumption of dissolved organic matter (DOM) drives much of the movement of carbon through the oceanic food web and the global carbon cycle. Understanding complex interactions between bacteria and marine DOM remains an important challenge. We tested the hypothesis that bacterial growth and community succession would respond differently to DOM additions due to seasonal changes in phytoplankton abundance in the environment. Four mesocosm experiments were conducted that spanned the spring transitional period (August-December 2013) in surface waters of the Western Antarctic Peninsula (WAP). Each mesocosm consisted of nearshore surface seawater (50 L) incubated in the laboratory for 10 days. The addition of DOM, in the form of cell-free exudates extracted from Thalassiosira weissflogii diatom cultures led to changes in bacterial abundance, production, and community composition. The timing of each mesocosm experiment (i.e., late winter vs. late spring) influenced the magnitude and direction of bacterial changes. For example, the same DOM treatment applied at different times during the season resulted in different levels of bacterial production and different bacterial community composition. There was a mid-season shift from Collwelliaceae to Polaribacter having the greatest relative abundance after incubation. This shift corresponded to a modest but significant increase in the initial relative abundance of Polaribacter in the nearshore seawater used to set up experiments. This finding supports a new hypothesis that starting community composition, through priority effects, influenced the trajectory of community succession in response to DOM addition. As strong inter-annual variability and long-term climate change may shift the timing of WAP phytoplankton blooms, and the corresponding production of DOM exudates, this study suggests a mechanism by which different seasonal successional patterns in bacterial communities could occur. PMID- 29163410 TI - Modeling Reveals the Role of Aging and Glucose Uptake Impairment in L1A1 Listeria monocytogenes Biofilm Life Cycle. AB - Listeria monocytogenes is a food-borne pathogen that can persist in food processing plants by forming biofilms on abiotic surfaces. The benefits that bacteria can gain from living in a biofilm, i.e., protection from environmental factors and tolerance to biocides, have been linked to the biofilm structure. Different L. monocytogenes strains build biofilms with diverse structures, and the underlying mechanisms for that diversity are not yet fully known. This work combines quantitative image analysis, cell counts, nutrient uptake data and mathematical modeling to provide a mechanistic insight into the dynamics of the structure of biofilms formed by L. monocytogenes L1A1 (serotype 1/2a) strain. Confocal laser scanning microscopy (CLSM) and quantitative image analysis were used to characterize the structure of L1A1 biofilms throughout time. L1A1 forms flat, thick structures; damaged or dead cells start appearing early in deep layers of the biofilm and rapidly and massively loss biomass after 4 days. We proposed several reaction-diffusion models to explain the system dynamics. Model candidates describe biomass and nutrients evolution including mechanisms of growth and cell spreading, nutrients diffusion and uptake and biofilm decay. Data fitting was used to estimate unknown model parameters and to choose the most appropriate candidate model. Remarkably, standard reaction-diffusion models could not describe the biofilm dynamics. The selected model reveals that biofilm aging and glucose impaired uptake play a critical role in L1A1 L. monocytogenes biofilm life cycle. PMID- 29163411 TI - Diversity within Italian Cheesemaking Brine-Associated Bacterial Communities Evidenced by Massive Parallel 16S rRNA Gene Tag Sequencing. AB - This study explored the bacterial diversity of brines used for cheesemaking in Italy, as well as their physicochemical characteristics. In this context, 19 brines used to salt soft, semi-hard, and hard Italian cheeses were collected in 14 commercial cheese plants and analyzed using a culture-independent amplicon sequencing approach in order to describe their bacterial microbiota. Large NaCl concentration variations were observed among the selected brines, with hard cheese brines exhibiting the highest values. Acidity values showed a great variability too, probably in relation to the brine use prior to sampling. Despite their high salt content, brine microbial loads ranged from 2.11 to 6.51 log CFU/mL for the total mesophilic count. Microbial community profiling assessed by 16S rRNA gene sequencing showed that these ecosystems were dominated by Firmicutes and Proteobacteria, followed by Actinobacteria and Bacteroidetes. Cheese type and brine salinity seem to be the main parameters accountable for brine microbial diversity. On the contrary, brine pH, acidity and protein concentration, correlated to cheese brine age, did not have any selective effect on the microbiota composition. Nine major genera were present in all analyzed brines, indicating that they might compose the core microbiome of cheese brines. Staphylococcus aureus was occasionally detected in brines using selective culture media. Interestingly, bacterial genera associated with a functional and technological use were frequently detected. Indeed Bifidobacteriaceae, which might be valuable probiotic candidates, and specific microbial genera such as Tetragenococcus, Corynebacterium and non-pathogenic Staphylococcus, which can contribute to sensorial properties of ripened cheeses, were widespread within brines. PMID- 29163412 TI - Different Non-Saccharomyces Yeast Species Stimulate Nutrient Consumption in S. cerevisiae Mixed Cultures. AB - The growing interest of the winemaking industry on the use of non-Saccharomyces starters has prompted several studies about the physiological features of this diverse group of microorganisms. The fact that the proposed use of these new starters will almost invariably involve either simultaneous or sequential inoculation with Saccharomyces cerevisiae has also driven the attention to the potential biological interactions between different starters during wine fermentation. Our current understanding is that alternative yeast starters will affect wine features by both direct and indirect mechanisms (through metabolic or other types of interactions with S. cerevisiae). There are still few studies addressing the question of yeast-yeast interactions in winemaking by a transcriptomic approach. In a previous report, we revealed early responses of S. cerevisiae and Torulaspora delbrueckii to the presence of each other under anaerobic conditions, mainly the overexpression of genes related with sugar consumption and cell proliferation. We have now studied the response, under aerobic conditions, of S. cerevisiae to other two non-Saccharomyces species, Hanseniaspora uvarum and Candida sake, keeping T. delbrueckii as a reference; and always focusing on the early stages of the interaction. Results point to some common features of the way S. cerevisiae modifies its transcriptome in front of other yeast species, namely activation of glucose and nitrogen metabolism, being the later specific for aerobic conditions. PMID- 29163413 TI - Lipoprotein Glycosylation by Protein-O-Mannosyltransferase (MAB_1122c) Contributes to Low Cell Envelope Permeability and Antibiotic Resistance of Mycobacterium abscessus. AB - Lipoproteins are important components of the mycobacterial cell envelope due to their function in cell wall homeostasis and bacterial virulence. They are post translationally modified with lipid- and glycosyl-residues in various species and interference with acylation or glycosylation leads to reduced growth and attenuated virulence in Mycobacterium tuberculosis. Lipoproteins are also expressed in the emerging and highly drug resistant pathogen Mycobacterium abscessus which frequently affects the lungs of patients with chronic pulmonary disease or cystic fibrosis. We investigated post-translational modification, acylation and glycosylation, of heterologously expressed (M. tuberculosis LppX and Mpt83) and endogenous (SodC) lipoproteins at the molecular level in M. abscessus and identified MAB_1122c as protein O-mannosyltransferase (Pmt). Both, heterologous and endogenous lipoproteins carried a characteristic lipid anchor with palmitic acid (C16), palmitoleic acid (C16:1), oleic acid (C18), or tuberculostearic acid (C19) modifications. Multiple hexose-moieties were detected in the N-terminal region of the model lipoproteins expressed in M. abscessus. Conservation of lipoprotein glycosylation in M. tuberculosis and M. abscessus was revealed and points toward the existence of an O-glycosylation motif or other regulatory mechanisms regarding this post-translational modification. Deletion of MAB_1122c prevented glycosylation and affected susceptibility to specific antibiotics which are large or target peptidoglycan synthesis and to lysozyme. Cell envelope permeability of M. abscessus Deltapmt was increased and mutant bacteria showed reduced survival inside macrophages. The results provide a link between post-translational modification of lipoproteins and the permeability of the mycobacterial cell envelope which stresses the importance of lipoproteins as components of this complex structure. PMID- 29163414 TI - Control of Antimicrobial Resistance Requires an Ethical Approach. AB - Ethical behavior encompasses actions that benefit both self and society. This means that tackling antimicrobial resistance (AMR) becomes an ethical obligation, because the prospect of declining anti-infectives affects everyone. Without preventive action, loss of drugs that have saved lives over the past century, will condemn ourselves, people we know, and people we don't know, to unacceptable risk of untreatable infection. Policies aimed at extending antimicrobial life should be considered within an ethical framework, in order to balance the choice, range, and quality of drugs against stewardship activities. Conserving availability and effectiveness for future use should not compromise today's patients. Practices such as antimicrobial prophylaxis for healthy people 'at risk' should receive full debate. There are additional ethical considerations for AMR involving veterinary care, agriculture, and relevant bio-industries. Restrictions for farmers potentially threaten the quality and quantity of food production with economic consequences. Antibiotics for companion animals do not necessarily spare those used for humans. While low-income countries cannot afford much-needed drugs, pharmaceutical companies are reluctant to develop novel agents for short-term return only. Public demand encourages over-the-counter, internet, black market, and counterfeit drugs, all of which compromise international control. Prescribers themselves require educational support to balance therapeutic choice against collateral damage to both body and environment. Predicted mortality due to AMR provides justification for international co operation, commitment and investment to support surveillance and stewardship along with development of novel antimicrobial drugs. Ethical arguments for, and against, control of antimicrobial resistance strategies are presented and discussed in this review. PMID- 29163415 TI - Combination Susceptibility Testing of Common Antimicrobials in Vitro and the Effects of Sub-MIC of Antimicrobials on Staphylococcus aureus Biofilm Formation. AB - The current study was conducted to evaluate the antibacterial combination efficacies, and whether the sub-inhibitory concentrations (sub-MIC) of antibiotics can influent on the biofilm formation of S. aureus. The minimum inhibitory concentration (MIC) of common antibacterial drugs was determined in vitro against clinical isolates of Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and Pasteurella multocida (P. multocida) alone and in combination with each other by using the broth microdilution method and the checkerboard micro-dilution method analyzed with the fractional inhibitory concentration index (FICI), respectively. Regarding these results, antibacterial drug combinations were categorized as synergistic, interacting, antagonistic and indifferent, and most of the results were consistent with the previous reports. Additionally, the effects of sub-MIC of seven antimicrobials (kanamycin, acetylisovaleryltylosin tartrate, enrofloxacin, lincomycin, colistin sulfate, berberine, and clarithromycin) on S. aureus biofilm formation were determined via crystal violet staining, scanning electron microscopy (SEM) and real-time PCR. Our results demonstrate that all antibiotics, except acetylisovaleryltylosin tartrate, effectively reduced the S. aureus biofilm formation. In addition, real-time reverse transcriptase PCR was used to analyze the relative expression levels of S. aureus biofilm-related genes such as sarA, fnbA, rbf, lrgA, cidA, and eno after the treatment at sub-MIC with all of the six antimicrobials. All antibiotics significantly inhibited the expression of these biofilm-related genes except for acetylisovaleryltylosin tartrate, which efficiently up-regulated these transcripts. These results provide the theoretical parameters for the selection of effective antimicrobial combinations in clinical therapy and demonstrate how to correctly use antibiotics at sub-MIC as preventive drugs. PMID- 29163416 TI - Diagnostic Evasion of Highly-Resistant Microorganisms: A Critical Factor in Nosocomial Outbreaks. AB - Highly resistant microorganisms (HRMOs) may evade screening strategies used in routine diagnostics. Bacteria that have evolved to evade diagnostic tests may have a selective advantage in the nosocomial environment. Evasion of resistance detection can result from the following mechanisms: low-level expression of resistance genes not resulting in detectable resistance, slow growing variants, mimicry of wild-type-resistance, and resistance mechanisms that are only detected if induced by antibiotic pressure. We reviewed reports on hospital outbreaks in the Netherlands over the past 5 years. Remarkably, many outbreaks including major nation-wide outbreaks were caused by microorganisms able to evade resistance detection by diagnostic screening tests. We describe various examples of diagnostic evasion by several HRMOs and discuss this in a broad and international perspective. The epidemiology of hospital-associated bacteria may strongly be affected by diagnostic screening strategies. This may result in an increasing reservoir of resistance genes in hospital populations that is unnoticed. The resistance elements may horizontally transfer to hosts with systems for high level expression, resulting in a clinically significant resistance problem. We advise to communicate the identification of HRMOs that evade diagnostics within national and regional networks. Such signaling networks may prevent inter hospital outbreaks, and allow collaborative development of adapted diagnostic tests. PMID- 29163417 TI - CSFV Infection Up-Regulates the Unfolded Protein Response to Promote Its Replication. AB - Classical swine fever (CSF) is an OIE-listed, highly contagious animal disease caused by classical swine fever virus (CSFV). The endoplasmic reticulum (ER) is an organelle in which the replication of many RNA viruses takes place. During viral infection, a series of events elicited in cells can destroy the ER homeostasis that cause ER stress and induce an unfolded protein response (UPR). In this study, we demonstrate that ER stress was induced during CSFV infection as several UPR-responsive elements such as XBP1(s), GRP78 and CHOP were up regulated. Specifically, CSFV transiently activated IRE1 pathway at the initial stage of infection but rapidly switched off, likely due to the reduction in cytoplasm Ca2+ after viral incubation. Additionally, our data show that the ER stress induced by CSFV can promote CSFV production, which the IRE1 pathway play an important role in it. Evidence of ER stress in vivo was also confirmed by the marked elevation of GRP78 in CSFV-infected pig PBMC and tissues. Collectively, these data indicate that the ER stress was induced upon CSFV infection and that the activation of the IRE1 pathway benefits CSFV replication. PMID- 29163418 TI - Pharmacodynamics, Pharmacokinetics, and Antiviral Activity of BAY 81-8781, a Novel NF-kappaB Inhibiting Anti-influenza Drug. AB - Influenza is a respiratory disease that causes annual epidemics. Antiviral treatment options targeting the virus exist, but their efficiency is limited and influenza virus strains easily develop resistance. Thus, new treatment strategies are urgently needed. In the present study, we investigated the anti-influenza virus properties of D,L-lysine acetylsalicylate ? glycine (BAY 81-8781; LASAG) that is approved as Aspirin i.v. for intravenous application. Instead of targeting the virus directly BAY 81-8781 inhibits the activation of the NF-kappaB pathway, which is required for efficient influenza virus propagation. Using highly pathogenic avian influenza virus strains we could demonstrate that BAY 81 8781 was able to control influenza virus infection in vitro. In the mouse infection model, inhalation of BAY 81-8781 resulted in reduced lung virus titers and protection of mice from lethal infection. Pharmacological studies demonstrated that the oral route of administration was not suitable to reach the sufficient concentrations of BAY 81-8781 for a successful antiviral effect in the lung. BAY 81-8781 treatment of mice infected with influenza virus started as late as 48 h after infection was still effective in protecting 50% of the animals from death. In summary, the data represent a successful proof of the novel innovative antiviral concept of targeting a host cell signaling pathway that is required for viral propagation instead of viral structures. PMID- 29163419 TI - Reconstruction of Diverse Verrucomicrobial Genomes from Metagenome Datasets of Freshwater Reservoirs. AB - The phylum Verrucomicrobia contains freshwater representatives which remain poorly studied at the genomic, taxonomic, and ecological levels. In this work we present eighteen new reconstructed verrucomicrobial genomes from two freshwater reservoirs located close to each other (Tous and Amadorio, Spain). These metagenome-assembled genomes (MAGs) display a remarkable taxonomic diversity inside the phylum and comprise wide ranges of estimated genome sizes (from 1.8 to 6 Mb). Among all Verrucomicrobia studied we found some of the smallest genomes of the Spartobacteria and Opitutae classes described so far. Some of the Opitutae family MAGs were small, cosmopolitan, with a general heterotrophic metabolism with preference for carbohydrates, and capable of xylan, chitin, or cellulose degradation. Besides, we assembled large copiotroph genomes, which contain a higher number of transporters, polysaccharide degrading pathways and in general more strategies for the uptake of nutrients and carbohydrate-based metabolic pathways in comparison with the representatives with the smaller genomes. The diverse genomes revealed interesting features like green-light absorbing rhodopsins and a complete set of genes involved in nitrogen fixation. The large diversity in genome sizes and physiological properties emphasize the diversity of this clade in freshwaters enlarging even further the already broad eco physiological range of these microbes. PMID- 29163420 TI - Microbial Diversity and Community Structure of Sulfate-Reducing and Sulfur Oxidizing Bacteria in Sediment Cores from the East China Sea. AB - Sulfate-reducing bacteria (SRB) and sulfur-oxidizing bacteria (SOB) have been studied extensively in marine sediments because of their vital roles in both sulfur and carbon cycles, but the available information regarding the highly diverse SRB and SOB communities is not comprehensive. High-throughput sequencing of functional gene amplicons provides tremendous insight into the structure and functional potential of complex microbial communities. Here, we explored the community structure, diversity, and abundance of SRB and SOB simultaneously through 16S rRNA, dsrB and soxB gene high-throughput sequencing and quantitative PCR analyses of core samples from the East China Sea. Overall, high-throughput sequencing of the dsrB and soxB genes achieved almost complete coverage (>99%) and revealed the high diversity, richness, and operational taxonomic unit (OTU) numbers of the SRB and SOB communities, which suggest the existence of an active sulfur cycle in the study area. Further analysis demonstrated that rare species make vital contributions to the high richness, diversity, and OTU numbers obtained. Depth-based distributions of the dsrB, soxB, and 16S rRNA gene abundances indicated that the SRB abundance might be more sensitive to the sedimentary dynamic environment than those of total bacteria and SOB. In addition, the results of unweighted pair group method with arithmetic mean (UPGMA) clustering analysis and redundancy analysis revealed that environmental parameters, such as depth and dissolved inorganic nitrogen concentrations, and the sedimentary dynamic environment, which differed between the two sampling stations, can significantly influence the community structures of total bacteria, SRB, and SOB. This study provided further comprehensive information regarding the characteristics of SRB and SOB communities. PMID- 29163421 TI - Arbuscular Mycorrhizal Fungal Community Composition in Carludovica palmata, Costus scaber and Euterpe precatoria from Weathered Oil Ponds in the Ecuadorian Amazon. AB - Arbuscular mycorrhizal fungi (AMF) are ubiquitous to most natural and anthropized ecosystems, and are often found in polluted environments. However, their occurrence and community composition in highly weathered petroleum-polluted soils has been infrequently reported. In the present study, two ponds of weathered crude oil and their surrounding soil from the Charapa field in the Amazon region of Ecuador were selected and root colonization by AMF of their native plants investigated. The AMF community was further analyzed in three selected plant species (i.e., Carludovica palmata, Costus scaber and Euterpe precatoria) present in the two ponds and the surrounding soil. A fragment covering partial SSU, the whole ITS and partial LSU rDNA region was amplified (i.e., 1.5 kb), cloned and sequenced from the roots of each host species. AMF root colonization exceeded 56% in all plant species examined and no significant difference was observed between sites or plants. For AMF community analysis, a total of 138 AMF sequences were obtained and sorted into 32 OTUs based on clustering (threshold >=97%) by OPTSIL. The found OTUs belonged to the genera Rhizophagus (22%), Glomus (31%), Acaulospora (25%) and Archaeospora (22%). Glomus and Archaeospora were always present regardless of the plant species or the site. Acaulospora was found in the three plant species and in the two ponds while Rhizophagus was revealed only in the surrounding soil in one plant species (Euterpe precatoria). Our study contributed to the molecular community composition of AMF and revealed an unexpected high presence of four AMF genera which have established a symbiosis with roots of native plants from the Amazon forest under high polluted soil conditions. PMID- 29163422 TI - A Novel IncA/C1 Group Conjugative Plasmid, Encoding VIM-1 Metallo-Beta-Lactamase, Mediates the Acquisition of Carbapenem Resistance in ST104 Klebsiella pneumoniae Isolates from Neonates in the Intensive Care Unit of V. Monaldi Hospital in Naples. AB - The emergence of carbapenemase producing Enterobacteriaceae has raised major public health concern. The aim of this study was to investigate the molecular epidemiology and the mechanism of carbapenem resistance acquisition of multidrug resistant Klebsiella pneumoniae isolates from 20 neonates in the neonatal intensive care unit (NICU) of the V. Monaldi Hospital in Naples, Italy, from April 2015 to March 2016. Genotype analysis by pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST) identified PFGE type A and subtypes A1 and A2 in 17, 2, and 1 isolates, respectively, and assigned all isolates to sequence type (ST) 104. K. pneumoniae isolates were resistant to all classes of beta-lactams including carbapenems, fosfomycin, gentamicin, and trimethoprim sulfamethoxazole, but susceptible to quinolones, amikacin, and colistin. Conjugation experiments demonstrated that resistance to third-generation cephems and imipenem could be transferred along with an IncA/C plasmid containing the extended spectrum beta-lactamase blaSHV -12 and carbapenem-hydrolyzing metallo beta-lactamase blaV IM-1 genes. The plasmid that we called pIncAC_KP4898 was 156,252 bp in size and included a typical IncA/C backbone, which was assigned to ST12 and core genome (cg) ST12.1 using the IncA/C plasmid MLST (PMLST) scheme. pIncAC_KP4898 showed a mosaic structure with blaV IM-1 into a class I integron, blaSHV -12 flanked by IS6 elements, a mercury resistance and a macrolide 2' phosphotransferase clusters, ant(3"), aph(3"), aacA4, qnrA1, sul1, and dfrA14 conferring resistance to aminoglycosides, quinolones, sulfonamides, and trimethoprim, respectively, several genes predicted to encode transfer functions and proteins involved in DNA transposition. The acquisition of pIncAC_KP4898 carrying blaV IM-1 and blaSHV -12 contributed to the spread of ST104 K. pneumoniae in the NICU of V. Monaldi Hospital in Naples. PMID- 29163423 TI - Microbial Community Composition and Functional Capacity in a Terrestrial Ferruginous, Sulfate-Depleted Mud Volcano. AB - Terrestrial mud volcanoes (MVs) are an important natural source of methane emission. The role of microbial processes in methane cycling and organic transformation in such environments remains largely unexplored. In this study, we aim to uncover functional potentials and community assemblages across geochemical transitions in a ferruginous, sulfate-depleted MV of eastern Taiwan. Geochemical profiles combined with 16S rRNA gene abundances indicated that anaerobic oxidation of methane (AOM) mediated by ANME-2a group coincided with iron/manganese reduction by Desulfuromonadales at shallow depths deprived of sulfate. The activity of AOM was stimulated either by methane alone or by methane and a range of electron acceptors, such as sulfate, ferrihydrite, and artificial humic acid. Metagenomic analyses revealed that functional genes for AOM and metal reduction were more abundant at shallow intervals. In particular, genes encoding pili expression and electron transport through multi-heme cytochromes were prevalent, suggesting potential intercellular interactions for electron transport involved in AOM. For comparison, genes responsible for methanogenesis and degradation of chitin and plant-derived molecules were more abundant at depth. The gene distribution combined with the enhanced proportions of 16S rRNA genes related to methanogens and heterotrophs, and geochemical characteristics suggest that particulate organic matter was degraded into various organic entities that could further fuel in situ methanogenesis. Finally, genes responsible for aerobic methane oxidation were more abundant in the bubbling pool and near-surface sediments. These methane oxidizers account for the ultimate attenuation of methane discharge into the atmosphere. Overall, our results demonstrated that various community members were compartmentalized into stratified niches along geochemical gradients. These community members form a metabolic network that cascades the carbon transformation from the upstream degradation of recalcitrant organic carbon with fermentative production of labile organic entities and methane to downstream methane oxidation and metal reduction near the surface. Such a metabolic architecture enables effective methane removal under ferruginous, sulfate-depleted conditions in terrestrial MVs. PMID- 29163424 TI - The Bacillus subtilis Conjugative Plasmid pLS20 Encodes Two Ribbon-Helix-Helix Type Auxiliary Relaxosome Proteins That Are Essential for Conjugation. AB - Bacterial conjugation is the process by which a conjugative element (CE) is transferred horizontally from a donor to a recipient cell via a connecting pore. One of the first steps in the conjugation process is the formation of a nucleoprotein complex at the origin of transfer (oriT), where one of the components of the nucleoprotein complex, the relaxase, introduces a site- and strand specific nick to initiate the transfer of a single DNA strand into the recipient cell. In most cases, the nucleoprotein complex involves, besides the relaxase, one or more additional proteins, named auxiliary proteins, which are encoded by the CE and/or the host. The conjugative plasmid pLS20 replicates in the Gram-positive Firmicute bacterium Bacillus subtilis. We have recently identified the relaxase gene and the oriT of pLS20, which are separated by a region of almost 1 kb. Here we show that this region contains two auxiliary genes that we name aux1LS20 and aux2LS20 , and which we show are essential for conjugation. Both Aux1LS20 and Aux2LS20 are predicted to contain a Ribbon-Helix Helix DNA binding motif near their N-terminus. Analyses of the purified proteins show that Aux1LS20 and Aux2LS20 form tetramers and hexamers in solution, respectively, and that they both bind preferentially to oriTLS20 , although with different characteristics and specificities. In silico analyses revealed that genes encoding homologs of Aux1LS20 and/or Aux2LS20 are located upstream of almost 400 relaxase genes of the RelLS20 family (MOBL) of relaxases. Thus, Aux1LS20 and Aux2LS20 of pLS20 constitute the founding member of the first two families of auxiliary proteins described for CEs of Gram-positive origin. PMID- 29163425 TI - Features of CRISPR-Cas Regulation Key to Highly Efficient and Temporally-Specific crRNA Production. AB - Bacterial immune systems, such as CRISPR-Cas or restriction-modification (R-M) systems, affect bacterial pathogenicity and antibiotic resistance by modulating horizontal gene flow. A model system for CRISPR-Cas regulation, the Type I-E system from Escherichia coli, is silent under standard laboratory conditions and experimentally observing the dynamics of CRISPR-Cas activation is challenging. Two characteristic features of CRISPR-Cas regulation in E. coli are cooperative transcription repression of cas gene and CRISPR array promoters, and fast non specific degradation of full length CRISPR transcripts (pre-crRNA). In this work, we use computational modeling to understand how these features affect the system expression dynamics. Signaling which leads to CRISPR-Cas activation is currently unknown, so to bypass this step, we here propose a conceptual setup for cas expression activation, where cas genes are put under transcription control typical for a restriction-modification (R-M) system and then introduced into a cell. Known transcription regulation of an R-M system is used as a proxy for currently unknown CRISPR-Cas transcription control, as both systems are characterized by high cooperativity, which is likely related to similar dynamical constraints of their function. We find that the two characteristic CRISPR-Cas control features are responsible for its temporally-specific dynamical response, so that the system makes a steep (switch-like) transition from OFF to ON state with a time-delay controlled by pre-crRNA degradation rate. We furthermore find that cooperative transcription regulation qualitatively leads to a cross-over to a regime where, at higher pre-crRNA processing rates, crRNA generation approaches the limit of an infinitely abrupt system induction. We propose that these dynamical properties are associated with rapid expression of CRISPR-Cas components and efficient protection of bacterial cells against foreign DNA. In terms of synthetic applications, the setup proposed here should allow highly efficient expression of small RNAs in a narrow time interval, with a specified time-delay with respect to the signal onset. PMID- 29163426 TI - Sugar Metabolism of the First Thermophilic Planctomycete Thermogutta terrifontis: Comparative Genomic and Transcriptomic Approaches. AB - Xanthan gum, a complex polysaccharide comprising glucose, mannose and glucuronic acid residues, is involved in numerous biotechnological applications in cosmetics, agriculture, pharmaceuticals, food and petroleum industries. Additionally, its oligosaccharides were shown to possess antimicrobial, antioxidant, and few other properties. Yet, despite its extensive usage, little is known about xanthan gum degradation pathways and mechanisms. Thermogutta terrifontis, isolated from a sample of microbial mat developed in a terrestrial hot spring of Kunashir island (Far-East of Russia), was described as the first thermophilic representative of the Planctomycetes phylum. It grows well on xanthan gum either at aerobic or anaerobic conditions. Genomic analysis unraveled the pathways of oligo- and polysaccharides utilization, as well as the mechanisms of aerobic and anaerobic respiration. The combination of genomic and transcriptomic approaches suggested a novel xanthan gum degradation pathway which involves novel glycosidase(s) of DUF1080 family, hydrolyzing xanthan gum backbone beta-glucosidic linkages and beta-mannosidases instead of xanthan lyases, catalyzing cleavage of terminal beta-mannosidic linkages. Surprisingly, the genes coding DUF1080 proteins were abundant in T. terrifontis and in many other Planctomycetes genomes, which, together with our observation that xanthan gum being a selective substrate for many planctomycetes, suggest crucial role of DUF1080 in xanthan gum degradation. Our findings shed light on the metabolism of the first thermophilic planctomycete, capable to degrade a number of polysaccharides, either aerobically or anaerobically, including the biotechnologically important bacterial polysaccharide xanthan gum. PMID- 29163427 TI - Antimycobacterial and Anti-inflammatory Mechanisms of Baicalin via Induced Autophagy in Macrophages Infected with Mycobacterium tuberculosis. AB - Tuberculosis (TB) remains a leading killer worldwide among infectious diseases and the effective control of TB is still challenging. Autophagy is an intracellular self-digestion process which has been increasingly recognized as a major host immune defense mechanism against intracellular microorganisms like Mycobacterium tuberculosis (Mtb) and serves as a key negative regulator of inflammation. Clinically, chronic inflammation surrounding Mtb can persist for decades leading to lung injury that can remain even after successful treatment. Adjunct host-directed therapy (HDT) based on both antimycobacterial and anti inflammatory interventions could be exploited to improve treatment efficacy and outcome. Autophagy occurring in the host macrophages represents a logical host target. Here, we show that herbal medicine, baicalin, could induce autophagy in macrophage cell line Raw264.7 and caused increased killing of intracellular Mtb. Further, baicalin inhibited Mtb-induced NLRP3 inflammasome activation and subsequent inflammasome-derived IL-1beta. To investigate the molecular mechanisms of baicalin, the signaling pathways associated with autophagy were examined. Results indicated that baicalin decreased the levels of phosphorylated protein kinase B (p-Akt) and phosphorylated mammalian target of rapamycin (p-mTOR) at Ser473 and Ser2448, respectively, but did not alter the phosphorylation of p38, JNK, or ERK both in Raw264.7 and primary peritoneal macrophages. Moreover, baicalin exerted an obvious inhibitory effect on nuclear factor-kappa B (NF kappaB) activity. Finally, immunofluorescence studies demonstrated that baicalin promoted the co-localization of inflammasome with autophagosome may serve as the underlying mechanism of autophagic degradative effect on reducing inflammasome activation. Together, baicalin definitely induces the activation of autophagy on the Mtb-infected macrophages through PI3K/Akt/mTOR pathway instead of MAPK pathway. Furthermore, baicalin inhibited the PI3K/Akt/NF-kappaB signal pathway, and both autophagy induction and NF-kappaB inhibition contribute to limiting the NLRP3 inflammasome as well as subsequent production of pro-inflammatory cytokine IL-1beta. Based on these results, we conclude that baicalin is a promising antimycobacterial and anti-inflammatory agent which can be a novel candidate for the development of new adjunct drugs targeting HDT for possible improved treatment. PMID- 29163428 TI - HHV-6A/6B Infection of NK Cells Modulates the Expression of miRNAs and Transcription Factors Potentially Associated to Impaired NK Activity. AB - Natural killer (NK) cells have a critical role in controlling virus infections, and viruses have evolved several mechanisms to escape NK cell functions. In particular, Human herpesvirus 6 (HHV-6) is associated with diseases characterized by immune dysregulation and has been reported to infect NK cells. We recently found that HHV-6 in vitro infection of human thyroid follicular epithelial cells and T-lymphocytes modulates several miRNAs associated with alterations in immune response. Since miRNAs are key regulators of many immune pathways, including NK cell functions, we aimed to study the impact of HHV-6A and -6B in vitro infection on the intracellular mediators correlated to NK cell function. To this purpose, a human NK cell line (NK-92) was infected in vitro with HHV-6A or 6B and analyzed for alterations in the expression of miRNAs and transcription factors. The results showed that both viruses establish lytic replication in NK-92 cells, as shown by the presence of viral DNA, expression of lytic transcripts and antigens, and by the induction of an evident cytopathic effect. Notably, both viruses, although with species-specific differences, induced significant modifications in miRNA expression of miRNAs known for their role in NK cell development, maturation and effector functions (miR-146, miR-155, miR-181, miR-223), and on at least 13 miRNAs with recognized role in inflammation and autoimmunity. Also the expression of transcription factors was significantly modified by HHV-6A/6B infection, with an early increase of ATF3, JUN and FOXA2 by both species, whereas HHV-6A specifically induced a 15-fold decrease of POU2AF1, and HHV-6B an increase of FOXO1 and a decrease of ESR1. Overall, our data show that HHV-6A and -6B infections have a remarkable effect on the expression of miRNAs and transcription factors, which might be important in the induction of NK cell function impairment, virus escape strategies and related pathologies. PMID- 29163429 TI - Relationship between Gingival Crevicular Fluid Microbiota and Cytokine Profile in Periodontal Host Homeostasis. AB - As potential biomarkers in periodontitis, microbiome, and cytokines have recently been extensively investigated, but combined analyses of the variations between the microbial structure and cytokine composition are rare. The present study aimed to investigate whether there are differences in the combined profile of microbiome and cytokines in individuals with or without periodontitis. The microbiome and cytokine composition in gingival crevicular fluid (GCF) from 16 patients and 15 controls from Jishi Shan (Gansu, China) were analyzed using 454 pyrosequencing and RayBio Quantibody Arrays. The results showed that a higher co occurrence of genera in periodontitis group compared with the healthy group, as evaluated by Schoener's abundance-based co-occurrence index. C-reactive protein (CRP) was significantly (P < 0.05) higher in the GCF of the periodontitis group while interleukin (IL)-8 was significantly (P < 0.01) higher in the GCF of the healthy group. The Mantel test revealed a significant concordance between cytokines and microbiota, in the healthy group (Mantel statistic r = 0.36, P <= 0.05) but not in the periodontitis group (Mantel statistic r = 0.013, P = 0.434). The results were further confirmed by the Procrustes test. Matrix metalloproteinase (MMP)-9, osteoactivin, IL-8, and macrophage inflammatory protein (MIP)-1a were significantly associated with bacterial composition at the phylum, class, order, family, and genus levels. CRP was also associated with bacterial composition at the species level. In conclusion, alterations in the polymicrobial community structure leads to disruption in the healthy correlation between cytokines and microbiomes. This dysbiosis between the microbiota and the immune response could be one of the major etiological mechanisms underlying periodontitis. PMID- 29163430 TI - PdtaS Deficiency Affects Resistance of Mycobacteria to Ribosome Targeting Antibiotics. AB - Two-component regulatory systems (TCSSs) are key regulatory elements responsible for the adaptation of bacteria to environmental stresses. A classical TCSS is typically comprised of a sensory histidine kinase and a corresponding response regulator. Here, we used homologous recombination to construct a Mycobacterium smegmatis mutant defective in the synthesis of cytosolic histidine kinase PdtaS (Msmeg_1918). The resulting DeltapdtaS mutant strain was tested in the Phenotype Microarray screening system, which allowed us to identify aminoglycoside antibiotic sensitivity, tetracyclines antibiotic resistance as well as membrane transport and respiration, as the main processes affected by removal of pdtaS. The antibiotic sensitivity profiles were confirmed by survival assessment and complementation studies. To gain insight into the molecular mechanisms responsible for the observed phenotype, we compared ribosomal RNA and protein profiles of the mutant and wild-type strains. We carried out Northern blotting and qRT-PCR to compare rRNA levels and analyzed ribosome sedimentation patterns of the wild-type and mutant strains on sucrose gradients. Isolated ribosomes were further used to estimate relative abundance of individual proteins in the ribosomal subunits using label free mass spectrometry analysis. Additionally, the DeltapdtaS mutant revealed lower activity of the respiratory chain as measured by the rate of TTC (triphenyltetrazolium chloride) reduction, while at the same time showing only insignificant changes in the uptake of aminoglycosides. We postulate that deficiency of PdtaS affects the oxidative respiration rates and ribosomal composition causing relevant changes to intrinsic resistance or susceptibility to antibiotics targeting ribosomes, which are commonly used to treat mycobacterial infections. PMID- 29163431 TI - Camelina Seed Supplementation at Two Dietary Fat Levels Change Ruminal Bacterial Community Composition in a Dual-Flow Continuous Culture System. AB - This experiment aimed to determine the effects of camelina seed (CS) supplementation at different dietary fat levels on ruminal bacterial community composition and how it relates to changes in ruminal fermentation in a dual-flow continuous culture system. Diets were randomly assigned to 8 fermenters (1,200 1,250 mL) in a 2 * 2 factorial arrangement of treatments in a replicated 4 * 4 Latin square with four 10-day experimental periods that consisted of 7 days for diet adaptation and 3 days for sample collection. Treatments were: (1) no CS at 5% ether extract (EE, NCS5); (2) no CS at 8% EE (NCS8); (3) 7.7% CS at 5% EE (CS5); and (4) 17.7% CS at 8% EE (CS8). Megalac was used as a control to adjust EE levels. Diets contained 55% orchardgrass hay and 45% concentrate, and fermenters were equally fed a total of 72 g/day (DM basis) twice daily. The bacterial community was determined by sequencing the V4 region of the 16S rRNA gene using the Illumina MiSeq platform. Sequencing data were analyzed using mothur and statistical analyses were performed in R and SAS. The most abundant phyla across treatments were the Bacteroidetes and Firmicutes, accounting for 49 and 39% of the total sequences, respectively. The bacterial community composition in both liquid and solid fractions of the effluent digesta changed with CS supplementation but not by dietary EE. Including CS in the diets decreased the relative abundances of Ruminococcus spp., Fibrobacter spp., and Butyrivibrio spp. The most abundant genus across treatments, Prevotella, was reduced by high dietary EE levels, while Megasphaera and Succinivibrio were increased by CS supplementation in the liquid fraction. Correlatively, the concentration of acetate was decreased while propionate increased; C18:0 was decreased and polyunsaturated fatty acids, especially C18:2 n-6 and C18:3 n-3, were increased by CS supplementation. Based on the correlation analysis between genera and fermentation end products, this study revealed that CS supplementation could be energetically beneficial to dairy cows by increasing propionate-producing bacteria and suppressing ruminal bacteria associated with biohydrogenation. However, attention should be given to avoid the effects of CS supplementation on suppressing cellulolytic bacteria. PMID- 29163432 TI - Stratified Bacterial and Archaeal Community in Mangrove and Intertidal Wetland Mudflats Revealed by High Throughput 16S rRNA Gene Sequencing. AB - The stratified distribution of bacterial and archaeal communities has been detected in many sediment profiles from various natural environments. A better understanding of microbial composition and diversity pattern in coastal mangrove wetlands in relation to physicochemical and spatial-temporal influences could provide more insights into the ecological functions of microbes in coastal wetlands. In this study, seasonal variations of microbial communities within sediment profiles from two sediment types (mangrove forest and intertidal mudflats) at three sampling locations in coastal Mai Po wetland were characterized using MiSeq high throughput sequencing and 16S rRNA quantitative PCR methods. Bacterial 16S rRNA gene abundance showed clear decreasing trends with increasing depth for all sites, seasonality and sediment types. There is a weak seasonal dynamic of bacterial and archaeal community abundance in both seasons. Seasonality imposed more influence on the beta diversity pattern of bacterial community than archaeal community. The five most abundant phyla within bacterial and archaeal community remain stable between two distinctive seasons. Sediment depth and seasonality are the most influential factors affecting bacterial community composition and diversity. The pH is the most influential factor on shaping the archaeal community. Stratified distribution of bacterial community including aerobic and anaerobic bacterial taxa is largely represented in the surface layers and the subsurface layers, respectively. For archaeal stratification, Thaumarchaeota Marine Group I is the dominant member in surface sediments while Bathyarchaeota and MBG-B dominate in subsurface sediments. Such stratified distribution patterns are irrespective of sediment types, sampling locations or seasonality, but significantly correlated to the sediment depth, which might be shaped by oxygen availability and the distribution of other terminal electron accepters along the depth profile. PMID- 29163433 TI - What Goes Around, Comes Around - HSV-1 Replication in Monocyte-Derived Dendritic Cells. AB - HSV-1 is a very successful human pathogen, known for its high sero-prevalence and the ability to infect a wide range of different cell types, including dendritic cells (DCs). As very potent antigen-presenting cells DCs play an important role in the induction of antiviral immune responses and therefore represent a strategic target for viral-mediated immune escape mechanisms. It is known that HSV-1 completes its gene expression profile in immature as well as in mature DCs, while lytic infection is only found in immature DCs (iDCs). Notably, HSV-1 infected mature DCs (mDCs) fail to release infectious progeny virions into the supernatant. Apart from HSV-1 dissemination via extracellular routes cell-to-cell spread counteracts a yet unknown mechanism by which the virus is trapped in mDCs and not released into the supernatant. The dissemination in a cell-cell contact dependent manner enables HSV-1 to infect bystander cells without the exposure toward the extracellular environment. This supports the virus to successfully infect the host and establish latency. In this review the mechanism of HSV-1 replication in iDCs and mDCs and its immunological as well as virological implications, will be discussed. PMID- 29163434 TI - Neglected Australian Arboviruses and Undifferentiated Febrile Illness: Addressing Public Health Challenges Arising From the 'Developing Northern Australia' Government Policy. AB - The Australian Government is currently promoting the development of Northern Australia, with an associated increase in the local population. Consequent to this is the public health threat posed by heightened human exposure to many previously neglected arboviruses that are indigenous to the region. This initiative to support economic activity in the tropical north of the continent is leading to the accelerated expansion of an infection-naive human population into hitherto un-encountered ecosystems inhabited by reservoir animals and vectors for these arboviruses. Combined with an apparent rise in the number and impact of dramatic climate events, such as tropical cyclones and floods caused by torrential monsoonal rainfall, this heightens the potential for viral transmission to humans. More than 75 arboviruses have been identified in Australia, some of which are associated with human disease but for which routine tests are not available to diagnose infection. Here, we describe briefly the neglected Australian arboviruses that are most likely to emerge as significant agents of human disease in the coming decades. We also advocate the establishment of a thorough surveillance and diagnostic protocol, including developing new pan viral rapid tests for primary care use to assist in the early diagnosis and correct treatment of affected patients. We propose that the implementation of these activities will enhance our understanding of the geographical range, prevalence, identification and control of neglected Australian arboviruses. This would minimise and limit the possibility of large-scale outbreaks with these agents as population and economic growth expands further into Australia's tropical north. PMID- 29163435 TI - Evolutionary Analysis of HIV-1 Pol Proteins Reveals Representative Residues for Viral Subtype Differentiation. AB - RNA viruses have been used as model systems to understand the patterns and processes of molecular evolution because they have high mutation rates and are genetically diverse. Human immunodeficiency virus 1 (HIV-1), the etiological agent of acquired immune deficiency syndrome, is highly genetically diverse, and is classified into several groups and subtypes. However, it has been difficult to use its diverse sequences to establish the overall phylogenetic relationships of different strains or the trends in sequence conservation with the construction of phylogenetic trees. Our aims were to systematically characterize HIV-1 subtype evolution and to identify the regions responsible for HIV-1 subtype differentiation at the amino acid level in the Pol protein, which is often used to classify the HIV-1 subtypes. In this study, we systematically characterized the mutation sites in 2,052 Pol proteins from HIV-1 group M (144 subtype A; 1,528 subtype B; 380 subtype C), using sequence similarity networks. We also used spectral clustering to group the sequences based on the network graph structures. A stepwise analysis of the cluster hierarchies allowed us to estimate a possible evolutionary pathway for the Pol proteins. The subtype A sequences also clustered according to when and where the viruses were isolated, whereas both the subtype B and C sequences remained as single clusters. Because the Pol protein has several functional domains, we identified the regions that are discriminative by comparing the structures of the domain-based networks. Our results suggest that sequence changes in the RNase H domain and the reverse transcriptase (RT) connection domain are responsible for the subtype classification. By analyzing the different amino acid compositions at each site in both domain sequences, we found that a few specific amino acid residues (i.e., M357 in the RT connection domain and Q480, Y483, and L491 in the RNase H domain) represent the differences among the subtypes. These residues were located on the surface of the RT structure and in the vicinity of the amino acid sites responsible for RT enzymatic activity or function. PMID- 29163436 TI - Promoting Simultaneous Onset of Viral Gene Expression Among Cells Infected with Herpes Simplex Virus-1. AB - Synchronous viral infection facilitates the study of viral gene expression, viral host interactions, and viral replication processes. However, the protocols for achieving synchronous infections were hardly ever tested in proper temporal resolution at the single-cell level. We set up a fluorescence-based, time lapse microscopy assay to study sources of variability in the timing of gene expression during herpes simplex virus-1 (HSV-1) infection. We found that with the common protocol, the onset of gene expression within different cells can vary by more than 3 h. We showed that simultaneous viral genome entry to the nucleus can be achieved with a derivative of the previously characterized temperature sensitive mutant tsB7, however, this did not improve gene expression synchrony. We found that elevating the temperature in which the infection is done and increasing the multiplicity of infection (MOI) significantly promoted simultaneous onset of viral gene expression among infected cells. Further, elevated temperature result in a decrease in the coefficient of variation (a standardized measure of dispersion) of viral replication compartments (RCs) sizes among cells as well as a slight increment of viral late gene expression synchrony. We conclude that simultaneous viral gene expression can be improved by simple modifications to the infection process and may reduce the effect of single-cell variability on population-based assays. PMID- 29163437 TI - Transport Deficiency Is the Molecular Basis of Candida albicans Resistance to Antifungal Oligopeptides. AB - Oligopeptides incorporating N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), an inhibitor of glucosamine-6-phosphate synthase, exhibited growth inhibitory activity against Candida albicans, with minimal inhibitory concentration values in the 0.05-50 MUg mL-1 range. Uptake by the peptide permeases was found to be the main factor limiting an anticandidal activity of these compounds. Di- and tripeptide containing FMDP (F2 and F3) were transported by Ptr2p/Ptr22p peptide transporters (PTR) and FMDP-containing hexa-, hepta-, and undecapeptide (F6, F7, and F11) were taken up by the oligopeptide transporters (OPT) oligopeptide permeases, preferably by Opt2p/Opt3p. A phenotypic, apparent resistance of C. albicans to FMDP-oligopeptides transported by OPT permeases was triggered by the environmental factors, whereas resistance to those taken up by the PTR system had a genetic basis. Anticandidal activity of longer FMDP oligopeptides was strongly diminished in minimal media containing easily assimilated ammonium sulfate or L-glutamine as the nitrogen source, both known to downregulate expression of the OPT genes. All FMDP-oligopeptides tested were more active at lower pH and this effect was slightly more remarkable for peptides F6, F7, and F11, compared to F2 and F3. Formation of isolated colonies was observed inside the growth inhibitory zones induced by F2 and F3 but not inside those induced by F6, F7, and F11. The vast majority (98%) of those colonies did not originate from truly resistant cells. The true resistance of 2% of isolates was due to the impaired transport of di- and to a lower extent, tripeptides. The resistant cells did not exhibit a lower expression of PTR2, PTR22, or OPT1-3 genes, but mutations in the PTR2 gene resulting in T422H, A320S, D119V, and A320S substitutions in the amino acid sequence of Ptr2p were found. PMID- 29163438 TI - Culture Strategies for Isolation of Fastidious Leptospira Serovar Hardjo and Molecular Differentiation of Genotypes Hardjobovis and Hardjoprajitno. AB - The Leptospira serovar Hedjo belongs to the serogroup sejroe and this serovar is the most prevalent in bovine herds worldwide. The sejroe serogroup is the most frequently detected by serology in Brazilian cattle herds suggesting that it is due serovar Hardjo. In the molecular classification, this serovar has two genotypes: Hardjobovis and Hardjoprajitno. This serovar is as considered as fastidious pathogens, and their isolation is one of the bottlenecks in leptospirosis laboratories. In addition, its molecular characterization using genomic approaches is oftentimes not simple and time-consuming. This study describes a method for isolating the two genotypes of serovar Hardjo using culture medium formulations and suggests a get-at-able molecular characterization. Ten cows naturally infected which were seropositive were selected from small dairy farms, and their urine was collected for bacterial isolation. We evaluated three modifications of liquid Leptospira medium culture supplemented with sodium pyruvate, superoxide dismutase enzyme and fetal bovine serum, and the isolates were characterized by molecular techniques. After isolation and adaptation in standard culture medium, the strains were subcultured for 1 week in the three modified culture media for morphologic evaluation using electronic microscopy. Strains were molecularly identified by multilocus variable number tandem-repeat analysis (MLVA), partial sequencing and phylogenic analyses of gene sec Y. Combining the liquid culture medium formulations allowed growth of the Leptospira serovar Hardjo in three tubes. Two isolates were identified as genotype Hardjobovis, and the other as genotype Hardjoprajitno. Morphologically, compared with control media, cells in the medium supplemented with the superoxide dismutase enzyme were more elongated and showed many cells in division. The cells in the medium supplemented with fetal bovine serum were fewer and lost their spirochete morphology. This indicated that the additional supplementation with fetal bovine serum assisted in the initial growth and maintenance of the viable leptospires and the superoxide dismutase enzyme allowed them to adapt to the medium. These culture strategies allowed for the isolation and convenient molecular characterization of two genotypes of serovar Hardjo, creating new insight into the seroepidemiology of leptospirosis and its specific genotypes. It also provides new information for the immunoprophylaxis of bovine leptospirosis. PMID- 29163439 TI - Phosphomannosylation and the Functional Analysis of the Extended Candida albicans MNN4-Like Gene Family. AB - Phosphomannosylation is a modification of cell wall proteins that occurs in some species of yeast-like organisms, including the human pathogen Candida albicans. These modified mannans confer a negative charge to the wall, which is important for the interactions with phagocytic cells of the immune systems and cationic antimicrobial peptides. In Saccharomyces cerevisiae, the synthesis of phosphomannan relies on two enzymes, the phosphomannosyltransferase Ktr6 and its positive regulator Mnn4. However, in C. albicans, at least three phosphomannosyltransferases, Mnn4, Mnt3 and Mnt5, participate in the addition of phosphomannan. In addition to MNN4, C. albicans has a MNN4-like gene family composed of seven other homologous members that have no known function. Here, using the classical mini-Ura-blaster approach and the new gene knockout CRISPR Cas9 system for gene disruption, we generated mutants lacking single and multiple genes of the MNN4 family; and demonstrate that, although Mnn4 has a major impact on the phosphomannan content, MNN42 was also required for full protein phosphomannosylation. The reintroduction of MNN41, MNN42, MNN46, or MNN47 in a genetic background lacking MNN4 partially restored the phenotype associated with the mnn4Delta null mutant, suggesting that there is partial redundancy of function between some family members and that the dominant effect of MNN4 over other genes could be due to its relative abundance within the cell. We observed that additional copies of alleles number of any of the other family members, with the exception of MNN46, restored the phosphomannan content in cells lacking both MNT3 and MNT5. We, therefore, suggest that phosphomannosylation is achieved by three groups of proteins: [i] enzymes solely activated by Mnn4, [ii] enzymes activated by the dual action of Mnn4 and any of the products of other MNN4-like genes, with exception of MNN46, and [iii] activation of Mnt3 and Mnt5 by Mnn4 and Mnn46. Therefore, although the MNN4-like genes have the potential to functionally redundant with Mnn4, they apparently do not play a major role in cell wall mannosylation under most in vitro growth conditions. In addition, our phenotypic analyses indicate that several members of this gene family influence the ability of macrophages to phagocytose C. albicans cells. PMID- 29163440 TI - Nutrient Composition Promotes Switching between Pellicle and Bottom Biofilm in Salmonella. AB - Salmonella is one of the most frequently reported causes of foodborne illness worldwide. Non-typhoidal serovars cause gastroenteritis in humans. Salmonella can grow on surfaces forming biofilms, contributing to its persistence since biofilms are difficult to eradicate due to the high resistance to antimicrobials and disinfectants. It has been described that there are two crucial biofilm promoting factors in Salmonella: curli and cellulose. The expression of both factors is coordinately regulated by the transcriptional regulator CsgD. Most biofilm studies of Salmonella have been performed by growing bacteria in low osmolarity rich medium and low temperature (25 degrees C). In such conditions, the biofilm is formed at the air-liquid interface (pellicle biofilm). Remarkably, when Salmonella grow in minimal medium, biofilm formation switches from the air-liquid interface to the solid-liquid interface (bottom biofilm). In this report, the switching between pellicle and bottom biofilm has been characterized. Our data indicate that curli, but not cellulose, is crucial for the formation of both kinds of biofilms. In minimal medium, conditions promoting formation of bottom biofilm, a high transcriptional expression of csgD and consequently of the genes involved in the synthesis of curli and cellulose was detected. The nutritional status of the cells seems to be pivotal for the spatial distribution of the biofilms formed. When bacteria is growing in minimal medium the addition of amino acids downregulates the expression of csgB and causes the switch between bottom and pellicle biofilm. The crosstalk between general metabolism and biofilm formation is also highlighted by the fact that the metabolic sensor cAMP modulates the type of biofilm generated by Salmonella. Moreover, cAMP regulates transcriptional expression of csgD and stimulates pellicle biofilm formation, suggesting that the physiological conditions define the type of biofilm formed by Salmonella. The consequences of the switching between pellicle and bottom biofilm during either infection or survival in natural environments remain undercover. PMID- 29163441 TI - Antifungal and Anti-Biofilm Activity of Essential Oil Active Components against Cryptococcus neoformans and Cryptococcus laurentii. AB - Cryptococcosis is an emerging and recalcitrant systemic infection occurring in immunocompromised patients. This invasive fungal infection is difficult to treat due to the ability of Cryptococcus neoformans and Cryptococcus laurentii to form biofilms resistant to standard antifungal treatment. The toxicity concern of these drugs has stimulated the search for natural therapeutic alternatives. Essential oil and their active components (EO-ACs) have shown to possess the variety of biological and pharmacological properties. In the present investigation the effect of six (EO-ACs) sourced from Oregano oil (Carvacrol), Cinnamon oil (Cinnamaldehyde), Lemongrass oil (Citral), Clove oil (Eugenol), Peppermint oil (Menthol) and Thyme oil (thymol) against three infectious forms; planktonic cells, biofilm formation and preformed biofilm of C. neoformans and C. laurentii were evaluated as compared to standard drugs. Data showed that antibiofilm activity of the tested EO-ACs were in the order: thymol>carvacrol>citral>eugenol=cinnamaldehyde>menthol respectively. The three most potent EO-ACs, thymol, carvacrol, and citral showed excellent antibiofilm activity at a much lower concentration against C. laurentii in comparison to C. neoformans indicating the resistant nature of the latter. Effect of the potent EO ACs on the biofilm morphology was visualized using scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM), which revealed the absence of extracellular polymeric matrix (EPM), reduction in cellular density and alteration in the surface morphology of biofilm cells. Further, to realize the efficacy of the EO-ACs in terms of human safety, cytotoxicity assays and co culture model were evaluated. Thymol and carvacrol as compared to citral were the most efficient in terms of human safety in keratinocyte- Cryptococcus sp. co culture infection model suggesting that these two can be further exploited as cost-effective and non-toxic anti-cryptococcal drugs. PMID- 29163442 TI - The Rationale for a Preventative HCV Virus-Like Particle (VLP) Vaccine. AB - HCV represents a global health problem with ~200 million individuals currently infected, worldwide. With the high cost of antiviral therapies, the global burden of chronic hepatitis C infection (CHCV) infection will be substantially reduced by the development of an effective vaccine for HCV. The field of HCV vaccines is generally divided into proponents of strategies to induce neutralizing antibodies (NAb) and those who propose to elicit cell mediated immunity (CMI). However, for a hepatitis C virus (HCV) vaccine to be effective in preventing infection, it must be capable of generating cross-reactive CD4+, CD8+ T cell, and NAb responses that will cover the major viral genotypes. Simulation models of hepatitis C have predicted that a vaccine of even modest efficacy and coverage will significantly reduce the incidence of hepatitis C. A HCV virus like particle (VLP) based vaccine would fulfill the requirement of delivering critical conformational neutralizing epitopes in addition to providing HCV specific CD4+ and CD8+ epitopes. Several approaches have been reported including insect cell-derived genotype 1b HCV VLPs; a human liver-derived quadrivalent genotype 1a, 1b, 2, and 3a vaccine; a genotype 1a HCV E1 and E2 glycoprotein/MLV Gag pseudotype VLP vaccine; and chimeric HBs-HCV VLP vaccines. All to result in the production of cross-NAb and/or T cell responses against HCV. This paper summarizes the evidence supporting the development of a HCV VLP based vaccine. PMID- 29163444 TI - Progressive Colonization of Bacteria and Degradation of Rice Straw in the Rumen by Illumina Sequencing. AB - The aim of this study was to improve the utilization of rice straw as forage in ruminants by investigating the degradation pattern of rice straw in the dairy cow rumen. Ground up rice straw was incubated in situ in the rumens of three Holstein cows over a period of 72 h. The rumen fluid at 0 h and the rice straw at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 h were collected for analysis of the bacterial community and the degradation of the rice straw. The bacterial community and the carbohydrate-active enzymes in the rumen fluid were analyzed by metagenomics. The diversity of bacteria loosely and tightly attached to the rice straw was investigated by scanning electron microscopy and Miseq sequencing of 16S rRNA genes. The predominant genus in the rumen fluid was Prevotella, followed by Bacteroides, Butyrivibrio, unclassified Desulfobulbaceae, Desulfovibrio, and unclassified Sphingobacteriaceae. The main enzymes were members of the glycosyl hydrolase family, divided into four categories (cellulases, hemicellulases, debranching enzymes, and oligosaccharide-degrading enzymes), with oligosaccharide degrading enzymes being the most abundant. No significant degradation of rice straw was observed between 0.5 and 6 h, whereas the rice straw was rapidly degraded between 6 and 24 h. The degradation then gradually slowed between 24 and 72 h. A high proportion of unclassified bacteria were attached to the rice straw and that Prevotella, Ruminococcus, and Butyrivibrio were the predominant classified genera in the loosely and tightly attached fractions. The composition of the loosely attached bacterial community remained consistent throughout the incubation, whereas a significant shift in composition was observed in the tightly attached bacterial community after 6 h of incubation. This shift resulted in a significant reduction in numbers of Bacteroidetes and a significant increase in numbers of Firmicutes. In conclusion, the degradation pattern of rice straw in the dairy cow rumen indicates a strong contribution by tightly attached bacteria, especially after 6 h incubation, but most of these bacteria were not taxonomically characterized. Thus, these bacteria should be further identified and subjected to functional analysis to improve the utilization of crop residues in ruminants. PMID- 29163443 TI - Parasite-Derived Proteins for the Treatment of Allergies and Autoimmune Diseases. AB - The morbidity associated with atopic diseases and immune dysregulation disorders such as asthma, food allergies, multiple sclerosis, atopic dermatitis, type 1 diabetes mellitus, and inflammatory bowel disease has been increasing all around the world over the past few decades. Although the roles of non-biological environmental factors and genetic factors in the etiopathology have been particularly emphasized, they do not fully explain the increase; for example, genetic factors in a population change very gradually. Epidemiological investigation has revealed that the increase also parallels a decrease in infectious diseases, especially parasitic infections. Thus, the reduced prevalence of parasitic infections may be another important reason for immune dysregulation. Parasites have co-evolved with the human immune system for a long time. Some parasite-derived immune-evasion molecules have been verified to reduce the incidence and harmfulness of atopic diseases in humans by modulating the immune response. More importantly, some parasite-derived products have been shown to inhibit the progression of inflammatory diseases and consequently alleviate their symptoms. Thus, parasites, and especially their products, may have potential applications in the treatment of autoimmune diseases. In this review, the potential of parasite-derived products and their analogs for use in the treatment of atopic diseases and immune dysregulation is summarized. PMID- 29163447 TI - Revisiting the Mechanisms Involved in Calcium Chloride Induced Bacterial Transformation. PMID- 29163445 TI - In Silico Analysis of Putrefaction Pathways in Bacteria and Its Implication in Colorectal Cancer. AB - Fermentation of undigested proteins in human gastrointestinal tract (gut) by the resident microbiota, a process called bacterial putrefaction, can sometimes disrupt the gut homeostasis. In this process, essential amino acids (e.g., histidine, tryptophan, etc.) that are required by the host may be utilized by the gut microbes. In addition, some of the products of putrefaction, like ammonia, putrescine, cresol, indole, phenol, etc., have been implicated in the disease pathogenesis of colorectal cancer (CRC). We have investigated bacterial putrefaction pathways that are known to be associated with such metabolites. Results of the comprehensive in silico analysis of the selected putrefaction pathways across bacterial genomes revealed presence of these pathways in limited bacterial groups. Majority of these bacteria are commonly found in human gut. These include Bacillus, Clostridium, Enterobacter, Escherichia, Fusobacterium, Salmonella, etc. Interestingly, while pathogens utilize almost all the analyzed pathways, commensals prefer putrescine and H2S production pathways for metabolizing the undigested proteins. Further, comparison of the putrefaction pathways in the gut microbiomes of healthy, carcinoma and adenoma datasets indicate higher abundances of putrefying bacteria in the carcinoma stage of CRC. The insights obtained from the present study indicate utilization of possible microbiome-based therapies to minimize the adverse effects of gut microbiome in enteric diseases. PMID- 29163446 TI - More Than Gliding: Involvement of GldD and GldG in the Virulence of Flavobacterium psychrophilum. AB - A fascinating characteristic of most members of the genus Flavobacterium is their ability to move over surfaces by gliding motility. Flavobacterium psychrophilum, an important pathogen of farmed salmonids worldwide, contains in its genome the 19 gld and spr genes shown to be required for gliding or spreading in Flavobacterium johnsoniae; however, their relative role in its lifestyle remains unknown. In order to address this issue, two spreading deficient mutants were produced as part of a Tn4351 mutant library in F. psychrophilum strain THCO2-90. The transposons were inserted in gldD and gldG genes. While the wild-type strain is proficient in adhesion, biofilm formation and displays strong proteolytic activity, both mutants lost these characteristics. Extracellular proteome comparisons revealed important modifications for both mutants, with a significant reduction of the amounts of proteins likely transported through the outer membrane by the Type IX secretion system, indicating that GldD and GldG proteins are required for an effective activity of this system. In addition, a significant decrease in virulence was observed using rainbow trout bath and injection infection models. Our results reveal additional roles of gldD and gldG genes that are likely of importance for the F. psychrophilum lifestyle, including virulence. PMID- 29163448 TI - Real-Time qPCR as a Method for Detection of Antibody-Neutralized Phage Particles. AB - The most common method for phage quantitation is the plaque assay, which relies on phage ability to infect bacteria. However, non-infective phage particles may preserve other biological properties; specifically, they may enter interactions with the immune system of animals and humans. Here, we demonstrate real-time quantitative polymerase chain reaction (qPCR) detection of bacteriophages as an alternative to the plaque assay. The closely related staphylococcal bacteriophages A3R and 676Z and the coliphage T4 were used as model phages. They were tested in vivo in mice, ex vivo in human sera, and on plastic surfaces designed for ELISAs. T4 phage was injected intravenously into pre-immunized mice. The phage was completely neutralized by specific antibodies within 5 h (0 pfu/ml of serum, as determined by the plaque assay), but it was still detected by qPCR in the amount of approximately 107 pfu/ml of serum. This demonstrates a substantial timelapse between "microbiological disappearance" and true clearance of phage particles from the circulation. In human sera ex vivo, qPCR was also able to detect neutralized phage particles that were not detected by the standard plaque assay. The investigated bacteriophages differed considerably in their ability to immobilize on plastic surfaces: this difference was greater than one order of magnitude, as shown by qPCR of phage recovered from plastic plates. The ELISA did not detect differences in phage binding to plates. Major limitations of qPCR are possible inhibitors of the PCR reaction or free phage DNA, which need to be considered in procedures of phage sample preparation for qPCR testing. We propose that phage pharmacokinetic and pharmacodynamic studies should not rely merely on detection of antibacterial activity of a phage. Real-time qPCR can be an alternative for phage detection, especially in immunological studies of bacteriophages. It can also be useful for studies of phage-based drug nanocarriers or biosensors. PMID- 29163450 TI - Autophosphorylation and Cross-Phosphorylation of Protein Kinases from the Crenarchaeon Sulfolobus islandicus. AB - Protein phosphorylation, one of the most important post-translational modifications, regulates almost every cellular process. Although signal transduction by protein phosphorylation is extensively studied in Eukaryotes and Bacteria, the knowledge of this process in archaea is greatly lagging behind, especially for Ser/Thr/Tyr phosphorylation by eukaryotic-like protein kinases (ePKs). So far, only a few studies on archaeal ePKs have been reported, most of which focused on the phosphorylation activities in vitro, but their physiological functions and interacting network are still largely unknown. In this study, we systematically investigated the autophosphorylation and cross-phosphorylation activities of ePKs from Sulfolobus islandicus REY15A using proteins expressed in Escherichia coli or S. islandicus. In vitro kinase assay showed that 7 out of the 11 putative ePKs have autophosphorylation activity. A protein Ser/Thr phosphatase, SiRe_1009, was able to dephosphorylate various autophosphorylated ePKs, confirming that these proteins are Ser/Thr kinases. Two ePKs, SiRe_2030 and SiRe_2056, homologs of typical eukaryotic PKs involved in peptide synthesis in response to various cellular stresses, exhibit highly efficient phosphorylation activities on both themselves and other ePKs. Overexpression of the protein kinases in vivo revealed that elevated level of either SiRe_1531 or SiRe_2056 inhibited the cell growth of S. islandicus cells. Finally, a phosphorylation network of the protein kinases was proposed and their putative physiological roles were discussed. PMID- 29163449 TI - Dietary and Microbial Metabolites in the Regulation of Host Immunity. AB - Mucosal surfaces in the body, especially the intestine, are constantly exposed to trillions of microbiomes. Accumulating evidence has revealed that changes in the composition of the gut microbiome, especially that of the commensal bacteria population, are frequently associated with immunologic disorders. These changes coincide with changes in the production of certain dietary metabolites. Recent studies have uncovered the molecular and cellular mechanisms underlying the relationships among diet, commensal bacteria, and the host immune system. In this review, we describe how dietary and microbial metabolites modulate host immunity. PMID- 29163451 TI - Non-Saccharomyces Yeasts Nitrogen Source Preferences: Impact on Sequential Fermentation and Wine Volatile Compounds Profile. AB - Nitrogen sources in the must are important for yeast metabolism, growth, and performance, and wine volatile compounds profile. Yeast assimilable nitrogen (YAN) deficiencies in grape must are one of the main causes of stuck and sluggish fermentation. The nitrogen requirement of Saccharomyces cerevisiae metabolism has been described in detail. However, the YAN preferences of non-Saccharomyces yeasts remain unknown despite their increasingly widespread use in winemaking. Furthermore, the impact of nitrogen consumption by non-Saccharomyces yeasts on YAN availability, alcoholic performance and volatile compounds production by S. cerevisiae in sequential fermentation has been little studied. With a view to improving the use of non-Saccharomyces yeasts in winemaking, we studied the use of amino acids and ammonium by three strains of non-Saccharomyces yeasts (Starmerella bacillaris, Metschnikowia pulcherrima, and Pichia membranifaciens) in grape juice. We first determined which nitrogen sources were preferentially used by these yeasts in pure cultures at 28 and 20 degrees C (because few data are available). We then carried out sequential fermentations at 20 degrees C with S. cerevisiae, to assess the impact of the non-Saccharomyces yeasts on the availability of assimilable nitrogen for S. cerevisiae. Finally, 22 volatile compounds were quantified in sequential fermentation and their levels compared with those in pure cultures of S. cerevisiae. We report here, for the first time, that non-Saccharomyces yeasts have specific amino-acid consumption profiles. Histidine, methionine, threonine, and tyrosine were not consumed by S. bacillaris, aspartic acid was assimilated very slowly by M. pulcherrima, and glutamine was not assimilated by P. membranifaciens. By contrast, cysteine appeared to be a preferred nitrogen source for all non-Saccharomyces yeasts. In sequential fermentation, these specific profiles of amino-acid consumption by non Saccharomyces yeasts may account for some of the interactions observed here, such as poorer performances of S. cerevisiae and volatile profile changes. PMID- 29163452 TI - The Opportunistic Pathogen Vibrio vulnificus Produces Outer Membrane Vesicles in a Spatially Distinct Manner Related to Capsular Polysaccharide. AB - Vibrio vulnificus, a bacterial species that inhabits brackish waters, is an opportunistic pathogen of humans. V. vulnificus infections can cause acute gastroenteritis, invasive septicemia, tissue necrosis, and potentially death. Virulence factors associated with V. vulnificus include the capsular polysaccharide (CPS), lipopolysaccharide, flagellum, pili, and outer membrane vesicles (OMVs). The aims of this study were to characterize the morphology of V. vulnificus cells and the formation and arrangement of OMVs using cryo-electron microscopy (cryo-EM). cryo-EM and cryo-electron tomography imaging of V. vulnificus strains grown in liquid cultures revealed the presence of OMVs (diameters of ~45 nm for wild-type, ~30 nm for the unencapsulated mutant, and ~50 nm for the non-motile mutant) in log-phase growth. Production of OMVs in the stationary growth phase was limited and irregular. The spacing of the OMVs around the wild-type cells was in regular, concentric rings. In wild-type cells and a non-motile mutant, the spacing between the cell envelope and the first ring of OMVs was ~200 nm; this spacing was maintained between subsequent OMV layers. The size, arrangement, and spacing of OMVs in an unencapsulated mutant was irregular and indicated that the polysaccharide chains of the capsule regulate aspects of OMV production and order. Together, our results revealed the distinctive organization of V. vulnificus OMVs that is affected by expression of the CPS. PMID- 29163453 TI - An Integrated Insight into the Relationship between Soil Microbial Community and Tobacco Bacterial Wilt Disease. AB - The soil microbial communities play an important role in plant health, however, the relationship between the below-ground microbiome and above-ground plant health remains unclear. To reveal such a relationship, we analyzed soil microbial communities through sequencing of 16S rRNA gene amplicons from 15 different tobacco fields with different levels of wilt disease in the central south part of China. We found that plant health was related to the soil microbial diversity as plants may benefit from the diverse microbial communities. Also, those 15 fields were grouped into 'healthy' and 'infected' samples based upon soil microbial community composition analyses such as unweighted paired-group method with arithmetic means (UPGMA) and principle component analysis, and furthermore, molecular ecological network analysis indicated that some potential plant beneficial microbial groups, e.g., Bacillus and Actinobacteria could act as network key taxa, thus reducing the chance of plant soil-borne pathogen invasion. In addition, we propose that a more complex soil ecology network may help suppress tobacco wilt, which was also consistent with highly diversity and composition with plant-beneficial microbial groups. This study provides new insights into our understanding the relationship between the soil microbiome and plant health. PMID- 29163454 TI - Low-Molecular-Weight Chitosan Supplementation Increases the Population of Prevotella in the Cecal Contents of Weanling Pigs. AB - Low-molecular-weight chitosan (LC) promoted growth in weaned piglets as an alternative to feed-grade antibiotics. To investigate the influence of LC supplementation on piglets' gut microbiome and compare the differences in community composition between LC and antibiotics with ZnO addition, we assessed the cecal microbial community by 16S rRNA gene sequencing with three treatments consisting of basal diet (CTR group), basal diet with low-molecular-weight chitosan (LC group), and basal diet with antibiotic and ZnO (AZ group). LC decreased pH more than AZ did in the cecum (both compared to CTR). Beta diversity analysis showed that community structure was distinctly different among the CTR, LC, and AZ treatments, indicating that either LC or AZ treatment modulated the piglet microbiota. Bacteroidetes, Firmicutes, and Proteobacteria dominated the community [>98% of operational taxonomic units (OTUs)] in piglet cecal contents. Compared to CTR, both LC, and AZ increased the relative abundance of Bacteroidetes while they decreased the count of Firmicutes and AZ decreased the population of Proteobacteria. In CTR the top four abundant genera were Prevotella (~10.4%), Succinivibrio (~6.2%), Lactobacillus (~5.6%), and Anaerovibrio (5.4%). Both LC and AZ increased the relative abundance of Prevotella but decreased the ratio of Lactobacillus when they compared with CTR. Moreover, LC increased the relative abundance of Succinivibrio and Anaerovibrio while AZ decreased them. The microbial function prediction showed LC enriched more pathways in the metabolism of cofactors and vitamins than CTR or AZ did. LC may potentially function as an alternative to feed-grade antibiotics in weaned piglets due to its beneficial regulation of the intestinal microbiome. PMID- 29163455 TI - Designing and Creating a Synthetic Omega Oxidation Pathway in Saccharomyces cerevisiae Enables Production of Medium-Chain alpha, omega-Dicarboxylic Acids. AB - Medium-chain (C8-C14) alpha, omega-dicarboxylic acids (alpha, omega-DCAs), which have numerous applications as raw materials for producing various commodities and polymers in chemical industry, are mainly produced from chemical or microbial conversion of petroleum-derived alkanes or plant-derived fatty acids at present. Recently, significant attention has been gained to microbial production of medium chain alpha, omega-DCAs from simple renewable sugars. Here, we designed and created a synthetic omega oxidation pathway in Saccharomyces cerevisiae to produce C10 and C12 alpha, omega-DCAs from renewable sugars and fatty acids by introducing a heterogeneous cytochrome P450 CYP94C1 and cytochrome reductase ATR1. Furthermore, the deletion of fatty acyl-CoA synthetase genes FAA1 and FAA4 increased the production of medium-chain alpha, omega-DCAs from 4.690 +/- 0.088 mg/L to 12.177 +/- 0.420 mg/L and enabled the production of C14 and C16 alpha, omega-DCAs at low percentage. But blocking beta-oxidation pathway by deleting fatty-acyl coenzyme A oxidase gene POX1 and overexpressing different thioesterase genes had no significant impact on the production and the composition of alpha, omega-dicarboxylic acids. Overall, our study indicated the potential of microbial production of medium-chain alpha, omega-DCAs from renewable feedstocks using engineered yeast. PMID- 29163456 TI - miR-194 Inhibits Innate Antiviral Immunity by Targeting FGF2 in Influenza H1N1 Virus Infection. AB - Fibroblast growth factor 2 (FGF2 or basic FGF) regulates a wide range of cell biological functions including proliferation, angiogenesis, migration, differentiation, and injury repair. However, the roles of FGF2 and the underlying mechanisms of action in influenza A virus (IAV)-induced lung injury remain largely unexplored. In this study, we report that microRNA-194-5p (miR-194) expression is significantly decreased in A549 alveolar epithelial cells (AECs) following infection with IAV/Beijing/501/2009 (BJ501). We found that miR-194 can directly target FGF2, a novel antiviral regulator, to suppress FGF2 expression at the mRNA and protein levels. Overexpression of miR-194 facilitated IAV replication by negatively regulating type I interferon (IFN) production, whereas reintroduction of FGF2 abrogated the miR-194-induced effects on IAV replication. Conversely, inhibition of miR-194 alleviated IAV-induced lung injury by promoting type I IFN antiviral activities in vivo. Importantly, FGF2 activated the retinoic acid-inducible gene I signaling pathway, whereas miR-194 suppressed the phosphorylation of tank binding kinase 1 and IFN regulatory factor 3. Our findings suggest that the miR-194-FGF2 axis plays a vital role in IAV-induced lung injury, and miR-194 antagonism might be a potential therapeutic target during IAV infection. PMID- 29163458 TI - Molecular Biology Can Change the Classic Laboratory Approach for Intestinal Protozoan Infections. AB - For many years microscopy has been considered the mainstay of the diagnosis of parasitic infections. In our laboratory, before the advent of molecular biology, the approach for the identification of parasitic infections in stools was the microscopic exam of three samples. Once we adopted molecular biology, a real-time PCR on one single sample was added to the classical coproparasitological exam of three samples. Given the high sensitivity of real-time PCR (Rt-PCR), we then decided to evaluate if a change of our routine was justified. In detail, we intended to assess if a much more practical routine, based on the analysis of a single fecal sample, was sufficiently sensitive to replace the routine described above. The new approach to be evaluated included, on the same and unique fecal sample, a classical coproparasitological exam plus Rt-PCR. The data obtained showed that the sensitivity of the new proposed approach remains very high, despite the reduction of coproparasitological exams from three to one, with the advantage of reducing costs and saving time, both for patients and for the laboratory. PMID- 29163457 TI - The Agr Quorum Sensing System Represses Persister Formation through Regulation of Phenol Soluble Modulins in Staphylococcus aureus. AB - The opportunistic pathogen Staphylococcus aureus has become an increasing threat to public health. While the Agr quorum sensing (QS) system is a master regulator of S. aureus virulence, its dysfunction has been frequently reported to promote bacteremia and mortality in clinical infections. Here we show that the Agr system is involved in persister formation in S. aureus. Mutation of either agrCA or agrD but not RNAIII resulted in increased persister formation of stationary phase cultures. RNA-seq analysis showed that in stationary phase AgrCA/AgrD and RNAIII mutants showed consistent up-regulation of virulence associated genes (lip and splE, etc.) and down-regulation of metabolism genes (bioA and nanK, etc.). Meanwhile, though knockout of agrCA or agrD strongly repressed expression of phenol soluble modulin encoding genes psmalpha1-4, psmbeta1-2 and phenol soluble modulins (PSM) transporter encoding genes in the pmt operon, mutation of RNAIII enhanced expression of the genes. We further found that knockout of psmalpha1-4 or psmbeta1-2 augmented persister formation and that co-overexpression of PSMalphas and PSMbetas reversed the effects of AgrCA mutation on persister formation. We also detected the effects on persister formation by mutations of metabolism genes (arcA, hutU, narG, nanK, etc.) that are potentially regulated by Agr system. It was found that deletion of the ManNAc kinase encoding gene nanK decreased persister formation. Taken together, these results shed new light on the PSM dependent regulatory role of Agr system in persister formation and may have implications for clinical treatment of MRSA persistent infections. PMID- 29163459 TI - CRISPR/Cas9 System as a Valuable Genome Editing Tool for Wine Yeasts with Application to Decrease Urea Production. AB - An extensive repertoire of molecular tools is available for genetic analysis in laboratory strains of S. cerevisiae. Although this has widely contributed to the interpretation of gene functionality within haploid laboratory isolates, the genetics of metabolism in commercially-relevant polyploid yeast strains is still poorly understood. Genetic engineering in industrial yeasts is undergoing major changes due to Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein (Cas) engineering approaches. Here we apply the CRISPR/Cas9 system to two commercial "starter" strains of S. cerevisiae (EC1118, AWRI796), eliminating the CAN1 arginine permease pathway to generate strains with reduced urea production (18.5 and 35.5% for EC1118 and AWRI796, respectively). In a wine-model environment based on two grape musts obtained from Chardonnay and Cabernet Sauvignon cultivars, both S. cerevisiae starter strains and CAN1 mutants completed the must fermentation in 8-12 days. However, recombinant strains carrying the can1 mutation failed to produce urea, suggesting that the genetic modification successfully impaired the arginine metabolism. In conclusion, the reduction of urea production in a wine-model environment confirms that the CRISPR/Cas9 system has been successfully established in S. cerevisiae wine yeasts. PMID- 29163460 TI - Links between Soil Fungal Diversity and Plant and Soil Properties on the Loess Plateau. AB - Previous studies have revealed inconsistent correlations between fungal diversity and plant/soil properties from local to global scales. Here, we investigated the internal relationships between soil fungal diversity and plant/soil properties on the Loess Plateau following vegetation restoration, using Illumina sequencing of the internal transcribed spacer 2 (ITS2) region for fungal identification. We found significant effects of land use types (Af, Artificial forest; Ns, Natural shrub; Ag, Artificial grassland; Ng, Natural grassland; Sc, slope cropland) on soil fungal communities composition, and the dominant phyla were Ascomycota, Basidiomycota, and Zygomycota, which transitioned from Basidiomycota-dominant to Ascomycota-dominant community due to vegetation restoration. The Chao1 richness, Shannon's diversity and ACE indices were significantly influenced by land use types with the order of Ns > Af > Ng > Ag > Sc, and the total number of OTUs varied widely. In contrast, Good's coverage and Simpson's diversity indicated no significant difference among land use types (p > 0.05). Correlation analysis showed that plant and soil properties were closely related to fungal diversity regardless of land use types. In addition, soil organic carbon (SOC) and Hplant (plant richness, Shannon-Wiener index) were strong driving factors that explained fungal diversity. As revealed by the structural equation model (SEM) and generalized additive models (GAMs), fungal diversity was directly and indirectly affected by soil and plant properties, respectively, providing evidence for strong links between soil fungal diversity and plant and soil properties on the Loess Plateau. PMID- 29163462 TI - Impact of Preformed Donor-Specific Anti-Human Leukocyte Antigen Antibody C1q Binding Ability on Kidney Allograft Outcome. AB - The consolidation of single antigen beads (SAB-panIgG) assay in the detection of preformed anti-human leukocyte antigen (HLA) antibodies has improved transplantation success. However, its high sensitivity has limited the allograft allocation for sensitized patients, increasing their waiting time. A modification of the standard SAB-panIgG assay allows the detection of that subset of antibodies capable of binding C1q (SAB-C1q assay). However, the clinical usefulness of SAB-C1q assay for determining the unacceptable mismatches is under discussion. We retrospectively analyzed the impact of preformed donor-specific anti-HLA antibodies (DSA) according to the C1q-binding ability on allograft outcome, examining 389 single-kidney transplanted patients from deceased donors. Recipients with preformed C1q-binding DSA showed the lowest allograft survival up to 7 years (40.7%) compared to patients with preformed non-C1q-binding DSA (73.4%; p = 0.001) and without DSA (79.1%; p < 0.001). Allograft survival rate was similar between patients with preformed non-C1q-binding DSA and patients without preformed DSA (p = 0.403). Interestingly, among the high-mean fluorescence intensity DSA (>=10,000) population (n = 46), those patients whose DSA were further capable of binding C1q showed a poorer allograft outcome (38.4 vs. 68.9%; p = 0.041). Moreover, in our multivariate predictive model for assessing the risk of allograft loss, the presence of C1q-binding DSA (HR 4.012; CI 95% 2.326-6.919; p < 0.001) but not of non-C1q-binding DSA (HR 1.389; CI 95% 0.784-2.461; p = 0.260) remained an independent predictor after stratifying the DSA population according to the C1q-binding ability and adjusting the model for other pre-transplantation predictive factors including donor age, cold-ischemia time, and HLA-DR mismatches. In conclusion, the unacceptable mismatch definition according to the SAB-C1q assay would improve the risk stratification of allograft loss and increase the limited allograft allocation of highly sensitized patients, shortening their waiting time. PMID- 29163461 TI - Factors Affecting the FcRn-Mediated Transplacental Transfer of Antibodies and Implications for Vaccination in Pregnancy. AB - At birth, neonates are particularly vulnerable to infection and transplacental transfer of immunoglobulin G (IgG) from mother to fetus provides crucial protection in the first weeks of life. Transcytosis of IgG occurs via binding with the neonatal Fc receptor (FcRn) in the placental synctiotrophoblast. As maternal vaccination becomes an increasingly important strategy for the protection of young infants, improving our understanding of transplacental transfer and the factors that may affect this will become increasingly important, especially in low-income countries where the burden of morbidity and mortality is highest. This review highlights factors of relevance to maternal vaccination that may modulate placental transfer-IgG subclass, glycosylation of antibody, total maternal IgG concentration, maternal disease, infant gestational age, and birthweight-and outlines the conflicting evidence and questions that remain regarding the complexities of these relationships. Furthermore, the intricacies of the Ab-FcRn interaction remain poorly understood and models that may help address future research questions are described. PMID- 29163463 TI - Selective Glucocorticoid Receptor Properties of GSK866 Analogs with Cysteine Reactive Warheads. AB - Synthetic glucocorticoids (GC) are the mainstay therapy for treatment of acute and chronic inflammatory disorders. Due to the high adverse effects associated with long-term use, GC pharmacology has focused since the nineties on more selective GC ligand-binding strategies, classified as selective glucocorticoid receptor (GR) agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). In the current study, GSK866 analogs with electrophilic covalent binding warheads were developed with potential SEGRA properties to improve their clinical safety profile for long-lasting topical skin disease applications. Since the off-rate of a covalently binding drug is negligible compared to that of a non covalent drug, its therapeutic effects can be prolonged and typically, smaller doses of the drug are necessary to reach the same level of therapeutic efficacy, thereby potentially reducing systemic side effects. Different analogs of SEGRA GSK866 coupled to cysteine reactive warheads were characterized for GR potency and selectivity in various biochemical and cellular assays. GR- and NFkappaB dependent reporter gene studies show favorable anti-inflammatory properties with reduced GR transactivation of two non-steroidal GSK866 analogs UAMC-1217 and UAMC 1218, whereas UAMC-1158 and UAMC-1159 compounds failed to modulate cellular GR activity. These results were further supported by GR immuno-localization and S211 phospho-GR western analysis, illustrating significant GR phosphoactivation and nuclear translocation upon treatment of GSK866, UAMC-1217, or UAMC-1218, but not in case of UAMC-1158 or UAMC-1159. Furthermore, mass spectrometry analysis of tryptic peptides of recombinant GR ligand-binding domain (LBD) bound to UAMC-1217 or UAMC-1218 confirmed covalent cysteine-dependent GR binding. Finally, molecular dynamics simulations, as well as glucocorticoid receptor ligand-binding domain (GR-LBD) coregulator interaction profiling of the GR-LBD bound to GSK866 or its covalently binding analogs UAMC-1217 or UAMC-1218 revealed subtle conformational differences that might underlie their SEGRA properties. Altogether, GSK866 analogs UAMC-1217 and UAMC-1218 hold promise as a novel class of covalent-binding SEGRA ligands for the treatment of topical inflammatory skin disorders. PMID- 29163464 TI - NLRP3 Inflammasome Mediates Dormant Neutrophil Recruitment following Sterile Lung Injury and Protects against Subsequent Bacterial Pneumonia in Mice. AB - Sterile lung injury is an important clinical problem that complicates the course of severely ill patients. Interruption of blood flow, namely ischemia-reperfusion (IR), initiates a sterile inflammatory response in the lung that is believed to be maladaptive. The rationale for this study was to elucidate the molecular basis for lung IR inflammation and whether it is maladaptive or beneficial. Using a mouse model of lung IR, we demonstrate that sequential blocking of inflammasomes [specifically, NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)], inflammatory caspases, and interleukin (IL)-1beta, all resulted in an attenuated inflammatory response. IL-1beta production appeared to predominantly originate in conjunction with alveolar type 2 epithelial cells. Lung IR injury recruited unactivated or dormant neutrophils producing less reactive oxygen species thereby challenging the notion that recruited neutrophils are terminally activated. However, lung IR inflammation was able to limit or reduce the bacterial burden from subsequent experimentally induced pneumonia. Notably, inflammasome-deficient mice were unable to alter this bacterial burden following IR. Thus, we conclude that the NLRP3 inflammasome, through IL-1beta production, regulates lung IR inflammation, which includes recruitment of dormant neutrophils. The sterile IR inflammatory response appears to serve an important function in inducing resistance to subsequent bacterial pneumonia and may constitute a critical part of early host responses to infection in trauma. PMID- 29163466 TI - Cigarette Smoking Triggers Colitis by IFN-gamma+ CD4+ T Cells. AB - The increased incidence of Crohn's disease in smokers has been recently reported, suggesting a strong association of cigarette smoke (CS) with colitis. However, the mechanism of the action of CS on colitis has not yet been explored. Here, we demonstrate that CS exposure is sufficient to induce colitis in mice. Interestingly, the colitis is mainly mediated by Th1, but not Th17, responses. CD4+ T-cell depletion or T-bet/IFN-gamma deficiency protects against the development of colitis induced by CS. Additionally, IFN-gamma-producing CD4+ T cells play a substantial role in CS-induced colitis. The adoptive transfer (AT) of effector T cells from CS-exposed WT mice into colitis-prone mice caused these mice to develop colitis, while the AT of effector T cells from IFN-gamma knock out mice did not. These findings have implications for broadening our understanding of CS-induced pathology and for the development of novel therapeutic strategies to treat Crohn's disease. PMID- 29163465 TI - B-Cell-Activating Factor and the B-Cell Compartment in HIV/SIV Infection. AB - With the goal to design effective HIV vaccines, intensive studies focused on broadly neutralizing antibodies, which arise in a fraction of HIV-infected people. Apart from identifying new vulnerability sites in the viral envelope proteins, these studies have shown that a fraction of these antibodies are produced by self/poly-reactive B-cells. These findings prompted us to revisit the B-cell differentiation and selection process during HIV/SIV infection and to consider B-cells as active players possibly shaping the helper T-cell program within germinal centers (GCs). In this context, we paid a particular attention to B-cell-activating factor (BAFF), a key cytokine in B-cell development and immune response that is overproduced during HIV/SIV infection. As it does in autoimmune diseases, BAFF excess might contribute to the abnormal rescue of self-reactive B cells at several checkpoints of the B-cell development and impair memory B-cell generation and functions. In this review, we first point out what is known about the functions of BAFF/a proliferation-inducing ligand and their receptors [B-cell maturation, transmembrane activator and CAML interactor (TACI), and BAFF-R], in physiological and pathophysiological settings, in mice and humans. In particular, we highlight recent results on the previously underappreciated regulatory functions of TACI and on the highly regulated production of soluble TACI and BAFF R that act as decoy receptors. In light of recent data on BAFF, TACI, and BAFF-R, we then revisit the altered phenotypes and functions of B-cell subsets during the acute and chronic phase of HIV/SIV infection. Given the atypical phenotype and reduced functions of memory B-cells in HIV/SIV infection, we particularly discuss the GC reaction, a key checkpoint where self-reactive B-cells are eliminated and pathogen-specific memory B-cells and plasmablasts/cells are generated in physiological settings. Through its capacity to differentially bind and process BAFF-R and TACI on GC B-cells and possibly on follicular helper T-cells, BAFF appears as a key regulator of the physiological GC reaction. Its local excess during HIV/SIV infection could play a key role in B-cell dysregulations. PMID- 29163467 TI - The Immune System Bridges the Gut Microbiota with Systemic Energy Homeostasis: Focus on TLRs, Mucosal Barrier, and SCFAs. AB - The gut microbiota is essential for the development and regulation of the immune system and the metabolism of the host. Germ-free animals have altered immunity with increased susceptibility to immunologic diseases and show metabolic alterations. Here, we focus on two of the major immune-mediated microbiota influenced components that signal far beyond their local environment. First, the activation or suppression of the toll-like receptors (TLRs) by microbial signals can dictate the tone of the immune response, and they are implicated in regulation of the energy homeostasis. Second, we discuss the intestinal mucosal surface is an immunologic component that protects the host from pathogenic invasion, is tightly regulated with regard to its permeability and can influence the systemic energy balance. The short chain fatty acids are a group of molecules that can both modulate the intestinal barrier and escape the gut to influence systemic health. As modulators of the immune response, the microbiota-derived signals influence functions of distant organs and can change susceptibility to metabolic diseases. PMID- 29163469 TI - Induction of Broad-Spectrum Protective Immunity against Disparate Cryptococcus Serotypes. AB - Cryptococcosis is a fungal disease caused by multiple Cryptococcus serotypes; particularly C. neoformans (serotypes A and D) and C. gattii (serotypes B and C). To date, there is no clinically available vaccine to prevent cryptococcosis. Mice given an experimental pulmonary vaccination with a C. neoformans serotype A strain engineered to produce interferon-gamma, denoted H99gamma, are protected against a subsequent otherwise lethal experimental infection with C. neoformans serotype A. Thus, we determined the efficacy of immunization with C. neoformans strain H99gamma to elicit broad-spectrum protection in BALB/c mice against multiple disparate Cryptococcus serotypes. We observed significantly increased survival rates and significantly decreased pulmonary fungal burden in H99gamma immunized mice challenged with Cryptococcus serotypes A, B, or D compared to heat killed H99gamma (HKH99gamma) immunized mice. Results indicated that prolonged protection against Cryptococcus serotypes B or D in H99gamma immunized mice was CD4+ T cell dependent and associated with the induction of predominantly Th1-type cytokine responses. Interestingly, immunization with H99gamma did not elicit greater protection against challenge with the Cryptococcus serotype C tested either due to low overall virulence of this strain or enhanced capacity of this strain to evade host immunity. Altogether, these studies provide "proof-of concept" for the development of a cryptococcal vaccine that provides cross protection against multiple disparate serotypes of Cryptococcus. PMID- 29163470 TI - Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now? AB - Cells expressing IDO suppress innate and adaptive immunity to promote tolerance by catabolizing the amino acid tryptophan (Trp) and other indole compounds. Interferon type I (IFN-I) and type II (IFN-II) produced at sites of inflammation or by activated immune cells are potent IDO inducers because mammalian IDO genes contain IFN response elements. Elevated IDO expression by dendritic cells (DCs) is of particular significance because IDO activity converts mature DCs into tolerogenic APCs that suppress effector T cells (Teff) and promote regulatory T cells (Tregs), thereby promoting tolerance. Local Trp depletion and production of immune suppressive Trp catabolites contribute to tolerogenic processes by activating metabolic pathways responsive to amino acid withdrawal and aryl hydrocarbon signaling, respectively. Sustained IDO elevation creates local immune privilege that protects tissues from immune-mediated damage and allows tissues to heal. This response occurs in lymphoid tissues when DNA released by dying tissue cells is sensed to induce specialized DC subsets to acquire tolerogenic phenotypes. The tolerogenic effects of IDO also promote tumorigenesis and help establish immune checkpoints in cancer, as malignant cells are protected from immune surveillance. Similar processes may attenuate host immunity to some pathogens that persist in immunocompetent individuals. However, if inflammation with IDO involvement is not resolved, chronic immune activation at such sites causes progressive tissue damage over time. Another effect of sustained IDO activity is enhanced pain sensitivity, as some Trp catabolites produced by cells expressing IDO are neuroactive. In this review, we summarize links between IDO and chronic inflammatory diseases and discuss prospects for exploiting IDO and Trp catabolism to suppress immunity and promote tolerance for clinical benefit, with particular emphasis on protecting tissues from destructive autoimmunity. PMID- 29163468 TI - The Role of Natural Antibodies to CC Chemokine Receptor 5 in HIV Infection. AB - The CC chemokine receptor 5 (CCR5) is responsible for immune and inflammatory responses by mediation of chemotactic activity in leukocytes, although it is expressed on different cell types. It has been shown to act as co-receptor for the human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV). Natural reactive antibodies (Abs) recognizing first loop (ECL1) of CCR5 have been detected in several pools of immunoglobulins from healthy donors and from several cohorts of either HIV-exposed but uninfected subjects (ESN) or HIV-infected individuals who control disease progression (LTNP) as well. The reason of development of anti-CCR5 Abs in the absence of autoimmune disease is still unknown; however, the presence of these Abs specific for CCR5 or for other immune receptors and mediators probably is related to homeostasis maintenance. The majority of anti-CCR5 Abs is directed to HIV binding site (N-terminus and ECL2) of the receptor. Conversely, it is well known that ECL1 of CCR5 does not bind HIV; thus, the anti-CCR5 Abs directed to ECL1 elicit a long-lasting internalization of CCR5 but not interfere with HIV binding directly; these Abs block HIV infection in either epithelial cells or CD4+ T lymphocytes and the mechanism differs from those ones described for all other CCR5-specific ligands. The Ab-mediated CCR5 internalization allows the formation of a stable signalosome by interaction of CCR5, beta-arrestin2 and ERK1 proteins. The signalosome degradation and the subsequent de novo proteins synthesis determine the CCR5 reappearance on the cell membrane with a very long-lasting kinetics (8 days). The use of monoclonal Abs to CCR5 with particular characteristics and mode of action may represent a novel mode to fight viral infection in either vaccinal or therapeutic strategies. PMID- 29163471 TI - Innate B-1 B Cells Are Not Enriched in Red Blood Cell Autoimmune Mice: Importance of B Cell Receptor Transgenic Selection. AB - Autoimmune hemolytic anemia (AIHA) results from breakdown of humoral tolerance to RBC antigens. Past analyses of B-cell receptor transgenic (BCR-Tg) mice that recognize RBC autoantigens led to a paradigm in which autoreactive conventional B 2 B cells are deleted whereas extramedullary B-1 B cells escape deletion due to lack of exposure to RBCs. However, BCR-Tg mice utilized to shape the current paradigm were unable to undergo receptor editing or class-switching. Given the importance of receptor editing as mechanism to tolerize autoreactive B cells during central tolerance, we hypothesized that expansion of autoreactive B-1 B cells is a consequence of the inability of the autoreactive BCR to receptor edit. To test this hypothesis, we crossed two separate strains of BCR-Tg mice with transgenic mice expressing the BCR target on RBCs. Both BCR-Tg mice express the same immunoglobulin and, thus, secrete antibodies with identical specificity, but one strain (SwHEL) has normal receptor editing, whereas the other (IgHEL) does not. Similar to other AIHA models, the autoreactive IgHEL strain showed decreased B-2 B cells, an enrichment of B-1 B cells, and detectable anti-RBC autoantibodies and decreased RBC hematocrit and hemoglobin values. However, autoreactive SwHEL mice had induction of tolerance in both B-2 and B-1 B cells with anti-RBC autoantibody production without anemia. These data generate new understanding and challenge the existing paradigm of B cell tolerance to RBC autoantigens. Furthermore, these findings demonstrate that immune responses vary when BCR-Tg do not retain BCR editing and class-switching functions. PMID- 29163473 TI - Treadmill Slope Modulates Inflammation, Fiber Type Composition, Androgen, and Glucocorticoid Receptors in the Skeletal Muscle of Overtrained Mice. AB - Overtraining (OT) may be defined as an imbalance between excessive training and adequate recovery period. Recently, a downhill running-based overtraining (OTR/down) protocol induced the nonfunctional overreaching state, which is defined as a performance decrement that may be associated with psychological and hormonal disruptions and promoted intramuscular and systemic inflammation. To discriminate the eccentric contraction effects on interleukin 1beta (IL-1beta), IL-6, IL-10, IL-15, and SOCS-3, we compared the release of these cytokines in OTR/down with other two OT protocols with the same external load (i.e., the product between training intensity and volume), but performed in uphill (OTR/up) and without inclination (OTR). Also, we evaluated the effects of these OT models on the muscle morphology and fiber type composition, serum levels of fatigue markers and corticosterone, as well as androgen receptor (AR) and glucocorticoid receptor (GR) expressions. For extensor digitorum longus (EDL), OTR/down and OTR groups increased the cytokines and exhibited micro-injuries with polymorphonuclear infiltration. While OTR/down group increased the cytokines in soleus muscle, OTR/up group only increased IL-6. All OT groups presented micro injuries with polymorphonuclear infiltration. In serum, while OTR/down and OTR/up protocols increased IL-1beta, IL-6, and tumor necrosis factor alpha, OTR group increased IL-1beta, IL-6, IL-15, and corticosterone. The type II fibers in EDL and soleus, total and phosphorylated AR levels in soleus, and total GR levels in EDL and soleus were differentially modulated by the OT protocols. In summary, the proinflammatory cytokines were more sensitive for OTR/down than for OTR/up and OTR. Also, the specific treadmill inclination of each OT model influenced most of the other evaluated parameters. PMID- 29163474 TI - Aged Gut Microbiota Contributes to Systemical Inflammaging after Transfer to Germ Free Mice. AB - Advanced age is associated with chronic low-grade inflammation, which is usually referred to as inflammaging. Elderly are also known to have an altered gut microbiota composition. However, whether inflammaging is a cause or consequence of an altered gut microbiota composition is not clear. In this study, gut microbiota from young or old conventional mice was transferred to young germ-free (GF) mice. Four weeks after gut microbiota transfer immune cell populations in spleen, Peyer's patches, and mesenteric lymph nodes from conventionalized GF mice were analyzed by flow cytometry. In addition, whole-genome gene expression in the ileum was analyzed by microarray. Gut microbiota composition of donor and recipient mice was analyzed with 16S rDNA sequencing. Here, we show by transferring aged microbiota to young GF mice that certain bacterial species within the aged microbiota promote inflammaging. This effect was associated with lower levels of Akkermansia and higher levels of TM7 bacteria and Proteobacteria in the aged microbiota after transfer. The aged microbiota promoted inflammation in the small intestine in the GF mice and enhanced leakage of inflammatory bacterial components into the circulation was observed. Moreover, the aged microbiota promoted increased T cell activation in the systemic compartment. In conclusion, these data indicate that the gut microbiota from old mice contributes to inflammaging after transfer to young GF mice. PMID- 29163472 TI - The Kynurenine Pathway As a Novel Link between Allergy and the Gut Microbiome. AB - In the past few decades, the indoleamine 2,3 dioxygenase (IDO) subset of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism has been the subject of much research in the area of immune tolerance. In this review, we aim to incorporate new findings on this pathway in relation to allergy and the gut microbiome, while providing a comprehensive overview of the pathway itself. Stimulated by interferon gamma, IDO acts as a tolerogenic, immunosuppressive enzyme to attenuate allergic responses by the induction of the KYN-IDO pathway, resultant depletion of TRP, and elevation in KYN metabolites. Acting through the aryl hydrocarbon receptor, KYN metabolites cause T-cell anergy and apoptosis, proliferation of Treg and Th17 cells, and deviation of the Th1/Th2 response, although the outcome is highly dependent on the microenvironment. Moreover, new evidence from germ-free mice and human infants shows that gut microbiota and breast milk are key in determining the functioning of the KYN-IDO pathway. As such, we recommend further research on how this pathway may be a critical link between the microbiome and development of allergy. PMID- 29163475 TI - Critical Role for Very-Long Chain Sphingolipids in Invariant Natural Killer T Cell Development and Homeostasis. AB - The role of sphingolipids (SLs) in the immune system has come under increasing scrutiny recently due to the emerging contributions that these important membrane components play in regulating a variety of immunological processes. The acyl chain length of SLs appears particularly critical in determining SL function. Here, we show a role for very-long acyl chain SLs (VLC-SLs) in invariant natural killer T (iNKT) cell maturation in the thymus and homeostasis in the liver. Ceramide synthase 2-null mice, which lack VLC-SLs, were susceptible to a hepatotropic strain of lymphocytic choriomeningitis virus, which is due to a reduction in the number of iNKT cells. Bone marrow chimera experiments indicated that hematopoietic-derived VLC-SLs are essential for maturation of iNKT cells in the thymus, whereas parenchymal-derived VLC-SLs are crucial for iNKT cell survival and maintenance in the liver. Our findings suggest a critical role for VLC-SL in iNKT cell physiology. PMID- 29163476 TI - Induction of Peripheral Tolerance in Ongoing Autoimmune Inflammation Requires Interleukin 27 Signaling in Dendritic Cells. AB - Peripheral tolerance to autoantigens is induced via suppression of self-reactive lymphocytes, stimulation of tolerogenic dendritic cells (DCs) and regulatory T (Treg) cells. Interleukin (IL)-27 induces tolerogenic DCs and Treg cells; however, it is not known whether IL-27 is important for tolerance induction. We immunized wild-type (WT) and IL-27 receptor (WSX-1) knockout mice with MOG35-55 for induction of experimental autoimmune encephalomyelitis and intravenously (i.v.) injected them with MOG35-55 after onset of disease to induce i.v. tolerance. i.v. administration of MOG35-55 reduced disease severity in WT mice, but was ineffective in Wsx-/- mice. IL-27 signaling in DCs was important for tolerance induction, whereas its signaling in T cells was not. Further mechanistic studies showed that IL-27-dependent tolerance relied on cooperation of distinct subsets of spleen DCs with the ability to induce T cell-derived IL-10 and IFN-gamma. Overall, our data show that IL-27 is a key cytokine in antigen induced peripheral tolerance and may provide basis for improvement of antigen specific tolerance approaches in multiple sclerosis and other autoimmune diseases. PMID- 29163478 TI - Editorial: Cross-Talk Mechanisms of Wnt/Beta-Catenin Signaling Components with TLR-Activated Signaling Molecules in the Inflammatory Response. PMID- 29163477 TI - Genes Critical for Developing Periodontitis: Lessons from Mouse Models. AB - Since the etiology of periodontitis in humans is not fully understood, genetic mouse models may pinpoint indispensable genes for optimal immunological protection of the periodontium against tissue destruction. This review describes the current knowledge of genes that are involved for a proper maintenance of a healthy periodontium in mice. Null mutations of genes required for leukocyte cell cell recognition and extravasation (e.g., Icam-1, P-selectin, Beta2 integrin/Cd18), for pathogen recognition and killing (e.g., Tlr2, Tlr4, Lamp-2), immune modulatory molecules (e.g., Cxcr2, Ccr4, IL-10, Opg, IL1RA, Tnf-alpha receptor, IL-17 receptor, Socs3, Foxo1), and proteolytic enzymes (e.g., Mmp8, Plasmin) cause periodontitis, most likely due to an inefficient clearance of bacteria and bacterial products. Several mechanisms resulting in periodontitis can be recognized: (1) inefficient bacterial control by the polymorphonuclear neutrophils (defective migration, killing), (2) inadequate antigen presentation by dendritic cells, or (3) exaggerated production of pro-inflammatory cytokines. In all these cases, the local immune reaction is skewed toward a Th1/Th17 (and insufficient activation of the Th2/Treg) with subsequent osteoclast activation. Finally, genotypes are described that protect the mice from periodontitis: the SCID mouse, and mice lacking Tlr2/Tlr4, the Ccr1/Ccr5, the Tnf-alpha receptor p55, and Cathepsin K by attenuating the inflammatory reaction and the osteoclastogenic response. PMID- 29163479 TI - Discriminating between Interstitial and Circulating Leukocytes in Tissues of the Murine Oral Mucosa Avoiding Nasal-Associated Lymphoid Tissue Contamination. AB - Periodontitis is a chronic inflammatory response to a microbial biofilm that destroys bone and soft tissues supporting the teeth. Murine models of periodontitis based on Porphyromonas gingivalis (Pg) colonization have shown that extravasation of leukocytes into oral tissue is critical to driving alveolar bone destruction. Identifying interstitial leukocytes is key to understanding the immunopathogenesis of periodontitis. Here, we describe a robust flow cytometry assay based on intravenous FITC-conjugated anti-mouse CD45 mAb that distinguishes interstitial leukocytes in the oral mucosa of mice from those circulating within the vasculature or in post-dissection contaminating blood. Unaccounted circulating leukocytes skewed the relative frequency of B cells and granulocytes and inflated the numbers of all leukocyte cell types. We also describe a dissection technique that avoids contamination of oral mucosal tissues with nasal associated lymphoid tissues (NALT), a B cell rich organ that can inflate leukocyte numbers at least 10-fold and skew the assessment of interstitial CD4 T cell phenotypes. Unlike circulating CD4 T cells, interstitial CD4 T cells were almost exclusively antigen-experienced cells (CD44hi). We report for the first time the presence of antigen-experienced Pg-specific CD4 T cells in NALT following oral feeding of mice with Pg. This new combined flow cytometry and dissection approach allows identification of leukocytes infiltrating the connective tissues of the murine oral mucosa and avoids confounding analyses of leukocytes not recruited to inflamed oral mucosal tissues in disease conditions like periodontitis, candidiasis, or sialadenitis. PMID- 29163480 TI - Differentiation of IL-17-Producing Invariant Natural Killer T Cells Requires Expression of the Transcription Factor c-Maf. AB - c-Maf belongs to the large Maf family of transcription factors and plays a key role in the regulation of cytokine production and differentiation of TH2, TH17, TFH, and Tr1 cells. Invariant natural killer T (iNKT) cells can rapidly produce large quantity of TH-related cytokines such as IFN-gamma, IL-4, and IL-17A upon stimulation by glycolipid antigens, such as alpha-galactosylceramide (alpha GalCer). However, the role of c-Maf in iNKT cells and iNKT cells-mediated diseases remains poorly understood. In this study, we demonstrate that alpha GalCer-stimulated iNKT cells express c-Maf transcript and protein. By using c-Maf deficient fetal liver cell-reconstituted mice, we further show that c-Maf deficient iNKT cells produce less IL-17A than their wild-type counterparts after alpha-GalCer stimulation. While c-Maf deficiency does not affect the development and activation of iNKT cells, c-Maf is essential for the induction of IL-17 producing iNKT (iNKT17) cells by IL-6, TGF-beta, and IL-1beta, and the optimal expression of RORgammat. Accordingly, c-Maf-deficient iNKT17 cells lose the ability to recruit neutrophils into the lungs. Taken together, c-Maf is a positive regulator for the expression of IL-17A and RORgammat in iNKT17 cells. It is a potential therapeutic target in iNKT17 cell-mediated inflammatory disease. PMID- 29163481 TI - Pro-Resolving Mediators in Regulating and Conferring Macrophage Function. AB - Macrophages are central in coordinating the host response to both sterile and infective insults. Clearance of apoptotic cells and cellular debris is a key biological action preformed by macrophages that paves the way to the resolution of local inflammation, repair and regeneration of damaged tissues, and re establishment of function. The essential fatty acid-derived autacoids termed specialized pro-resolving mediators (SPM) play central roles in promoting these processes. In the present article, we will review the role of microvesicles in controlling macrophage efferocytosis and SPM production. We will also discuss the role of both apoptotic cells and microvesicles in providing substrate for transcellular biosynthesis of several SPM families during efferocyotsis. In addition, this article will discuss the biological actions of the recently uncovered macrophage-derived SPM termed maresins. These mediators are produced via 14-lipoxygenation of docosahexaenoic acid that is either enzymatically converted to mediators carrying two hydroxyl groups or to autacoids that are peptide-lipid conjugates, coined maresin conjugates in tissue regeneration. The formation of these mediators is temporally regulated during acute self-limited infectious-inflammation where they promote the uptake and clearance of apoptotic cells, regulate several aspects of the tissue repair and regeneration, and display potent anti-nociceptive actions. PMID- 29163483 TI - CD4 T-Cell Dysregulation in Psoriatic Arthritis Reveals a Regulatory Role for IL 22. AB - Dysregulation of interleukin-22 (IL-22) has been associated with autoimmune diseases but divergent effects upon inflammation have hampered efforts to define its contribution to pathogenesis. Here, we examined the role of IL-22 in patients with psoriatic arthritis (PsA). In the peripheral blood of PsA patients, there was a decrease in IL-22+CD4+ T cells compared with healthy controls resulting in a heightened CD4+ IFNgamma+/IL-22+ ratio accompanied by diminished CCR6 expression. IL-22 expressing cells were depleted primarily from the central memory CD4 T-cell subset in PsA patients. Paradoxically IL-22 and particularly interferon-gamma (IFNgamma) production were elevated within a CD4+ T-cell subset with phenotypic markers characteristic of naive T cells (CD3+CD4+CD27+CD45RA+CCR7+CD95-IL-2Rbeta-) from PsA patients with the highest IFNgamma+/IL-22+ ratio of all the CD4 subsets. These unconventional "naive" CD4+ T cells from PsA patients displayed some phenotypic and functional characteristics of memory cells including a marked proliferative response. Increased IFNgamma production from these unconventional "naive" T cells from PsA patients promoted greater expression of the chemo-attractant CXCL9 by HaCaT keratinocytes compared with their healthy counterparts. Treatment with anti-TNF therapy reversed these abnormalities in this T-cell subset though did not affect the frequency of IL-22+ T cells overall. Furthermore, blockade of IL-22 enhanced the IFNgamma mediated release of CXCL-9. These results reveal CD4+ T-cell dysregulation in patients with PsA which can be reversed by anti-TNF and highlight the regulatory properties of IL-22 with important implications for therapeutic approaches that inhibit its production. PMID- 29163484 TI - Tracking Human Immunodeficiency Virus-1 Infection in the Humanized DRAG Mouse Model. AB - Humanized mice are emerging as an alternative model system to well-established non-human primate (NHP) models for studying human immunodeficiency virus (HIV)-1 biology and pathogenesis. Although both NHP and humanized mice have their own strengths and could never truly reflect the complex human immune system and biology, there are several advantages of using the humanized mice in terms of using primary HIV-1 for infection instead of simian immunodeficiency virus or chimera simian/HIV. Several different types of humanized mice have been developed with varying levels of reconstitution of human CD45+ cells. In this study, we utilized humanized Rag1KO.IL2RgammacKO.NOD mice expressing HLA class II (DR4) molecule (DRAG mice) infused with HLA-matched hematopoietic stem cells from umbilical cord blood to study early events after HIV-1 infection, since the mucosal tissues of these mice are highly enriched for human lymphocytes and express the receptors and coreceptors needed for HIV-1 entry. We examined the various tissues on days 4, 7, 14, and 21 after an intravaginal administration of a single dose of purified primary HIV-1. Plasma HIV-1 RNA was detected as early as day 7, with 100% of the animals becoming plasma RNA positive by day 21 post infection. Single cells were isolated from lymph nodes, bone marrow, spleen, gut, female reproductive tissue, and brain and analyzed for gag RNA and strong stop DNA by quantitative (RT)-PCR. Our data demonstrated the presence of HIV-1 viral RNA and DNA in all of the tissues examined and that the virus was replication competent and spread rapidly. Bone marrow, gut, and lymph nodes were viral RNA positive by day 4 post-infection, while other tissues and plasma became positive typically between 7 and 14 days post-infection. Interestingly, the brain was the last tissue to become HIV-1 viral RNA and DNA positive by day 21 post-infection. These data support the notion that humanized DRAG mice could serve as an excellent model for studying the trafficking of HIV-1 to the various tissues, identification of cells harboring the virus, and thus could serve as a model system for HIV-1 pathogenesis and reservoir studies. PMID- 29163485 TI - A Novel Affinity Tag, ABTAG, and Its Application to the Affinity Screening of Single-Domain Antibodies Selected by Phage Display. AB - ABTAG is a camelid single-domain antibody (sdAb) that binds to bovine serum albumin (BSA) with low picomolar affinity. In surface plasmon resonance (SPR) analyses using BSA surfaces, bound ABTAG can be completely dissociated from the BSA surfaces at low pH, over multiple cycles, without any reduction in the capacity of the BSA surfaces to bind ABTAG. A moderate throughput, SPR-based, antibody screening assay exploiting the unique features of ABTAG is described. Anti-carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) sdAbs were isolated from a phage-displayed sdAb library derived from the heavy chain antibody repertoire of a llama immunized with CEACAM6. Following one or two rounds of panning, enriched clones were expressed as ABTAG fusions in microtiter plate cultures. The sdAb-ABTAG fusions from culture supernatants were captured on BSA surfaces and CEACAM6 antigen was then bound to the captured molecules. The SPR screening method gives a read-out of relative expression levels of the fusion proteins and kinetic and affinity constants for CEACAM6 binding by the captured molecules. The library was also panned and screened by conventional methods and positive clones were subcloned and expressed for SPR analysis. Compared to conventional panning and screening, the SPR-based ABTAG method yielded a considerably higher diversity of binders, some with affinities that were three orders of magnitude higher affinity than those identified by conventional panning. PMID- 29163482 TI - Current Advances in gammadelta T Cell-Based Tumor Immunotherapy. AB - gammadelta T cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of gammadelta T cells: those that express Vdelta1 gene, paired with different Vgamma elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells. Conversely, gammadelta T cells expressing the Vdelta2 gene paired with the Vgamma9 chain are the predominant (50-90%) gammadelta T cell population in the peripheral blood and recognize phosphoantigens (PAgs) derived from the mevalonate pathway of mammalian cells, which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote gammadelta T cell activation. gammadelta T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that alphabeta T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-gamma and tumor necrosis factor-alpha and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of gammadelta T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of gammadelta T cell-based immunotherapy in different types of cancer after the application of PAgs or n-BPs plus interleukin-2 in vivo or after adoptive transfer of ex vivo-expanded gammadelta T cells, particularly the Vgamma9Vdelta2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that gammadelta T cell-based therapy is safe, but long-term clinical results to date are inconsistent. In this review, we will discuss the major achievements and pitfalls of the gammadelta T cell-based immunotherapy of cancer. PMID- 29163486 TI - Structure and Diversity of the Rhesus Macaque Immunoglobulin Loci through Multiple De Novo Genome Assemblies. AB - The rhesus macaque is a critically important animal model in biomedical research, most recently playing a key role in the development of vaccines against human immunodeficiency virus-1. Nevertheless, the immunoglobulin (Ig) loci of macaques are as yet incompletely determined and our understanding of differences between human and macaque humoral immunity remains deficient. We completed a high coverage, high-quality whole genome sequencing and assembly project with a single rhesus macaque of Indian origin, and partial genome assemblies using genomic molecular targeting of the Ig loci in nine other rhesus macaques of Indian origin. These data indicate that the macaque Ig loci are substantially more diverse than those in humans, including greater sequence diversity and copy number variation between individuals. It appears likely that such copy-number variation even occurs between allelic loci within individuals. Different Ig gene families in the macaque show distinct relationships to the corresponding human gene families and appear to evolve under different mechanisms. These results raise intriguing questions about the evolution of antigen receptors in primates but also have important practical implications for the design and interpretation of biomedical studies. PMID- 29163487 TI - Baicalin Inhibits NOD-Like Receptor Family, Pyrin Containing Domain 3 Inflammasome Activation in Murine Macrophages by Augmenting Protein Kinase A Signaling. AB - The flavonoid baicalin has been reported to possess potent anti-inflammatory activities by suppressing inflammatory signaling pathways. However, whether baicalin can suppress the activation of NOD-like receptor (NLR) family, pyrin containing domain 3 (NLRP3) inflammasome in macrophages is largely unknown. Here, we showed that baicalin treatment dose-dependently inhibited adenosine triphosphate (ATP) or nigericin-induced NLRP3 inflammasome activation, as revealed by the decreased release of mature interleukin (IL)-1beta, active caspase-1p10, and high-mobility group box-1 protein from lipopolysaccharide (LPS) primed bone marrow-derived macrophages. The formation of ASC specks, a critical marker of NLRP3 inflammasome assembly, was robustly inhibited by baicalin in the macrophages upon ATP or nigericin stimulation. All these inhibitory effects of baicalin could be partly reversed by MDL12330A or H89, both of which are inhibitors of the protein kinase A (PKA) signaling pathway. Consistent with this, baicalin strongly enhanced PKA-mediated phosphorylation of NLRP3, which has been suggested to prevent ASC recruitment into the inflammasome. Of note, the PKA inhibitor H89 could block baicalin-induced NLRP3 phosphorylation on PKA-specific sites, further supporting PKA's role in this process. In addition, we showed that when administered pre and post exposure to Escherichia coli infection baicalin treatment significantly improved mouse survival in bacterial sepsis. Baicalin administration also significantly reduced IL-1beta levels in the sera of bacterial infected mice. Altogether, our results revealed that baicalin inhibited NLRP3 inflammasome activation at least partly through augmenting PKA signaling, highlighting its therapeutic potential for the treatment of NLRP3-related inflammatory diseases. PMID- 29163488 TI - Late-Onset Cryopyrin-Associated Periodic Syndromes Caused by Somatic NLRP3 Mosaicism-UK Single Center Experience. AB - Cryopyrin-associated periodic syndrome (CAPS) is caused by gain-of-function NLRP3 mutations. Recently, somatic NLRP3 mosaicism has been reported in some CAPS patients who were previously classified as "mutation-negative." We describe here the clinical and laboratory findings in eight British adult patients who presented with symptoms typical of CAPS other than an onset in mid-late adulthood. All patients underwent comprehensive clinical and laboratory investigations, including analysis of the NLRP3 gene using Sanger and amplicon based deep sequencing (ADS) along with measurements of extracellular apoptosis associated speck-like protein with CARD domain (ASC) aggregates. The clinical phenotype in all subjects was consistent with mid-spectrum CAPS, except a median age at disease onset of 50 years. Sanger sequencing of NLRP3 was non-diagnostic but ADS detected a somatic NLRP3 mutation in each case. In one patient, DNA isolated from blood demonstrated an increase in the mutant allele from 5 to 45% over 12 years. ASC aggregates in patients' serum measured during active disease were significantly higher than healthy controls. This series represents 8% of CAPS patients diagnosed in a single center, suggesting that acquired NLRP3 mutations may not be an uncommon cause of the syndrome and should be sought in all patients with late-onset symptoms otherwise compatible with CAPS. Steadily worsening CAPS symptoms in one patient were associated with clonal expansion of the mutant allele predominantly affecting myeloid cells. Two patients developed AA amyloidosis, which previously has only been reported in CAPS in association with life-long germline NLRP3 mutations. PMID- 29163489 TI - Ameliorating Amyloid-beta Fibrils Triggered Inflammation via Curcumin-Loaded Polymeric Nanoconstructs. AB - Inflammation is a common hallmark in several diseases, including atherosclerosis, cancer, obesity, and neurodegeneration. In Alzheimer's disease (AD), growing evidence directly correlates neuronal damage with inflammation of myeloid brain cells, such as microglia. Here, polymeric nanoparticles were engineered and characterized for the delivery of anti-inflammatory molecules to macrophages stimulated via direct incubation with amyloid-beta fibers. 200 nm spherical polymeric nanoconstructs (SPNs) and 1,000 nm discoidal polymeric nanoconstructs (DPNs) were synthesized using poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and lipid chains as building blocks. First, the internalization propensity in macrophages of both nanoparticles was assessed via cytofluorimetric and confocal microscopy analyses, demonstrating that SPNs are by far more rapidly taken up as compared to DPNs (99.6 +/- 0.11 vs 14.4 +/- 0.06%, within 24 h). Then, Curcumin-loaded SPNs (Curc-SPNs) were realized by encapsulating Curcumin, a natural anti-inflammatory molecule, within the PLGA core of SPNs. Finally, Curc SPNs were shown to diminish up to 6.5-fold the production of pro-inflammatory cytokines-IL-1beta; IL-6, and TNF-alpha-in macrophages stimulated via amyloid beta fibers. Although more sophisticated in vitro models and systematic analyses on the blood-brain barrier permeability are critically needed, these findings hold potential in the development of nanoparticles for modulating inflammation in AD. PMID- 29163490 TI - Immune Checkpoint Molecules on Tumor-Infiltrating Lymphocytes and Their Association with Tertiary Lymphoid Structures in Human Breast Cancer. AB - There is an exponentially growing interest in targeting immune checkpoint molecules in breast cancer (BC), particularly in the triple-negative subtype where unmet treatment needs remain. This study was designed to analyze the expression, localization, and prognostic role of PD-1, PD-L1, PD-L2, CTLA-4, LAG3, and TIM3 in primary BC. Gene expression analysis using the METABRIC microarray dataset found that all six immune checkpoint molecules are highly expressed in basal-like and HER2-enriched compared to the other BC molecular subtypes. Flow cytometric analysis of fresh tissue homogenates from untreated primary tumors show that PD-1 is principally expressed on CD4+ or CD8+ T cells and CTLA-4 is expressed on CD4+ T cells. The global proportion of PD-L1+, PD-L2+, LAG3+, and TIM3+ tumor-infiltrating lymphocytes (TIL) was low and detectable in only a small number of tumors. Immunohistochemically staining fixed tissues from the same tumors was employed to score TIL and tertiary lymphoid structures (TLS). PD-L1+, PD-L2+, LAG3+, and TIM3+ cells were detected in some TLS in a pattern that resembles secondary lymphoid organs. This observation suggests that TLS are important sites of immune activation and regulation, particularly in tumors with extensive baseline immune infiltration. Significantly improved overall survival was correlated with PD-1 expression in the HER2-enriched and PD-L1 or CTLA-4 expression in basal-like BC. PD-1 and CTLA-4 proteins were most frequently detected on TIL, which supports the correlations observed between their gene expression and improved long-term outcome in basal-like and HER2-enriched BC. PD L1 expression by tumor or immune cells is uncommon in BC. Overall, the data presented here distinguish PD-1 as a marker of T cell activity in both the T and B cell areas of BC associated TLS. We found that immune checkpoint molecule expression parallels the extent of TIL and TLS, although there is a noteworthy amount of heterogeneity between tumors even within the same molecular subtype. These data indicate that assessing the levels of immune checkpoint molecule expression in an individual patient has important implications for the success of therapeutically targeting them in BC. PMID- 29163491 TI - Suppression of Natural Killer Cell Activity by Regulatory NKT10 Cells Aggravates Alcoholic Hepatosteatosis. AB - We and others have found that the functions of hepatic natural killer (NK) cells are inhibited but invariant NKT (iNKT) cells become activated after alcohol drinking, leaving a possibility that there exists interplay between NK cells and iNKT cells during alcoholic liver disease. Here, in a chronic plus single-binge ethanol consumption mouse model, we observed that NK cells and interferon-gamma (IFN-gamma) protected against ethanol-induced liver steatosis, as both wild-type (WT) mice treated with anti-asialo GM1 antibody and IFN-gamma-deficient GKO mice developed more severe alcoholic fatty livers. As expected, IFN-gamma could directly downregulate lipogenesis in primary hepatocytes in vitro. On the contrary, iNKT cell-deficient Jalpha18-/- or interleukin-10 (IL-10)-/- mice showed fewer alcoholic steatosis, along with the recovered number and IFN-gamma release of hepatic NK cells, and exogenous IL-10 injection was sufficient to compensate for iNKT cell deficiency. Furthermore, NK cell depletion in Jalpha18-/ or IL-10-/- mice caused more severe hepatosteatosis, implying NK cells are the direct effector cells to inhibit liver steatosis. Importantly, adoptive transfer of iNKT cells purified from normal but not IL-10-/- mice resulted in suppression of the number and functions of NK cells and aggravated alcoholic liver injury in Jalpha18-/- mice, indicating that IL-10-producing iNKT (NKT10) cells are the regulators on NK cells. Conclusion: Ethanol exposure-triggered NKT10 cells antagonize the protective roles of NK cells in alcoholic hepatosteatosis. PMID- 29163492 TI - T-Cell Composition of the Lymph Node Is Associated with the Risk for Early Rejection after Renal Transplantation. AB - Background: The T-cell composition within the lymph node (LN) of end-stage renal disease (ESRD) patients differs from the composition within the circulation. Activation of the alloreactive T-cell response within secondary lymphoid organs is important after organ transplantation. However, to date no data are present on LN T-cell subsets and the risk for acute rejection after kidney transplantation. Methods: T cells from LNs of ESRD patients were analyzed for frequency of recent thymic emigrants, relative telomere length, expression of differentiation markers, and were related to the development of early acute rejection (EAR), occurring within 3 months after renal transplantation (RT). Furthermore, the alloreactive potential of mononuclear cells isolated from the LN and peripheral blood of 10 patients was analyzed. Measures of alloreactive potential included proliferation, cytokine production, frequencies of interferon-gamma-producing cells, and the presence of cytotoxic molecules. Results: Patients with EAR were younger (p = 0.019), cytomegalovirus-seropositive (p = 0.037) and usually received dialysis prior to RT (p = 0.030). Next to this, patients with EAR showed a lower CD4:CD8 ratio (p = 0.027) within the LN. T cells from the LN were similar with regard to alloreactive capacity compared with those within the circulation. Univariate regression analysis showed that the CD4:CD8 ratio (OR: 0.67, p = 0.039), patient age (OR: 0.93, p = 0.024), and preemptive RT (OR: 0.11, p = 0.046) were associated with EAR. After a multivariate analysis, only the CD4:CD8 ratio (OR: 0.58, p = 0.019) and preemptive RT (OR:0.05, p = 0.012) were associated with EAR. Conclusion: A lower CD4:CD8 ratio in the LN is associated with a higher risk for the development of rejection within 3 months after RT. PMID- 29163493 TI - Alpha-Galactosylceramide/CD1d-Antibody Fusion Proteins Redirect Invariant Natural Killer T Cell Immunity to Solid Tumors and Promote Prolonged Therapeutic Responses. AB - Major progress in cancer immunotherapies have been obtained by the use of tumor targeting strategies, in particular with the development of bi-functional fusion proteins such as ImmTacs or BiTes, which engage effector T cells for targeted elimination of tumor cells. Given the significance of invariant natural killer T (iNKT) cells in bridging innate and adaptive immunity, we have developed a bi functional protein composed of the extracellular part of CD1d molecule that was genetically fused to an scFv fragment from high affinity antibodies against HER2 or CEA. Systemic treatments with the CD1d-antitumor fusion proteins loaded with the agonist alpha-galactosylceramide (alphaGalCer) led to specific iNKT cell activation, resulting in a sustained growth inhibition of established tumors expressing HER2 or CEA, while treatment with the free alphaGalCer was ineffective. Importantly, we discovered that alphaGalCer/CD1d-antitumor fusion proteins were able to maintain iNKT cells reactive to multiple re-stimulations in contrast to their anergic state induced after a single injection of free alphaGalCer. We further demonstrated that the antitumor effects by alphaGalCer/CD1d-antitumor fusion proteins were largely dependent on the iNKT cell-mediated transactivation of NK cells. Moreover, prolonged antitumor effects could be obtained when combining the CD1d-antitumor fusion protein treatment with a therapeutic peptide/CpG cancer vaccine, which favored the capacity of iNKT cells to transactivate cross-presenting DCs for efficient priming of tumor specific CD8 T cells. We will also summarize these pre-clinical results with a special focus on the cellular mechanisms underlying iNKT cell unresponsiveness to antigen re-challenge. Finally, we will discuss the perspectives regarding iNKT cell-mediated tumor targeting strategy in cancer immunotherapy. PMID- 29163494 TI - Reproducibility and Reuse of Adaptive Immune Receptor Repertoire Data. AB - High-throughput sequencing (HTS) of immunoglobulin (B-cell receptor, antibody) and T-cell receptor repertoires has increased dramatically since the technique was introduced in 2009 (1-3). This experimental approach explores the maturation of the adaptive immune system and its response to antigens, pathogens, and disease conditions in exquisite detail. It holds significant promise for diagnostic and therapy-guiding applications. New technology often spreads rapidly, sometimes more rapidly than the understanding of how to make the products of that technology reliable, reproducible, or usable by others. As complex technologies have developed, scientific communities have come together to adopt common standards, protocols, and policies for generating and sharing data sets, such as the MIAME protocols developed for microarray experiments. The Adaptive Immune Receptor Repertoire (AIRR) Community formed in 2015 to address similar issues for HTS data of immune repertoires. The purpose of this perspective is to provide an overview of the AIRR Community's founding principles and present the progress that the AIRR Community has made in developing standards of practice and data sharing protocols. Finally, and most important, we invite all interested parties to join this effort to facilitate sharing and use of these powerful data sets (join@airr-community.org). PMID- 29163495 TI - Human CD141+ Dendritic Cell and CD1c+ Dendritic Cell Undergo Concordant Early Genetic Programming after Activation in Humanized Mice In Vivo. AB - Human immune cell subsets develop in immunodeficient mice following reconstitution with human CD34+ hematopoietic stem cells. These "humanized" mice are useful models to study human immunology and human-tropic infections, autoimmunity, and cancer. However, some human immune cell subsets are unable to fully develop or acquire full functional capacity due to a lack of cross reactivity of many growth factors and cytokines between species. Conventional dendritic cells (cDCs) in mice are categorized into cDC1, which mediate T helper (Th)1 and CD8+ T cell responses, and cDC2, which mediate Th2 and Th17 responses. The likely human equivalents are CD141+ DC and CD1c+ DC subsets for mouse cDC1 and cDC2, respectively, but the extent of any interspecies differences is poorly characterized. Here, we exploit the fact that human CD141+ DC and CD1c+ DC develop in humanized mice, to further explore their equivalency in vivo. Global transcriptome analysis of CD141+ DC and CD1c+ DC isolated from humanized mice demonstrated that they closely resemble those in human blood. Activation of DC subsets in vivo, with the TLR3 ligand poly I:C, and the TLR7/8 ligand R848 revealed that a core panel of genes consistent with DC maturation status were upregulated by both subsets. R848 specifically upregulated genes associated with Th17 responses by CD1c+ DC, while poly I:C upregulated IFN-lambda genes specifically by CD141+ DC. MYCL expression, known to be essential for CD8+ T cell priming by mouse DC, was specifically induced in CD141+ DC after activation. Concomitantly, CD141+ DC were superior to CD1c+ DC in their ability to prime naive antigen-specific CD8+ T cells. Thus, CD141+ DC and CD1c+ DC share a similar activation profiles in vivo but also have induce unique signatures that support specialized roles in CD8+ T cell priming and Th17 responses, respectively. In combination, these data demonstrate that humanized mice provide an attractive and tractable model to study human DC in vitro and in vivo. PMID- 29163496 TI - Activation and Role of NACHT, LRR, and PYD Domains-Containing Protein 3 Inflammasome in RNA Viral Infection. AB - NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation and effects during ribonucleic acid (RNA) viral infection are the focus of a wide range of research currently. Both the pathogen-associated molecule pattern derived from virions and intracellular stress molecules involved in the process of viral infection lead to activation of the NLRP3 inflammasome, which in turn triggers inflammatory responses for antiviral defense and tissue healing. However, aberrant activation of the NLRP3 inflammasome can instead support viral pathogenesis and promote disease progression. Here, we summarize and expound upon the recent literature describing the molecular mechanisms underlying the activation and effects of the NLRP3 inflammasome in RNA viral infection to highlight how it provides protection against RNA viral infection. PMID- 29163497 TI - Interactions between Innate Lymphoid Cells and Cells of the Innate and Adaptive Immune System. AB - Type 2 innate lymphoid cells (ILC2s) are a major source of cytokines, which are also produced by Th2 cells and several cell types of the innate immune system. Work over the past few years indicates that ILC2s play a central role in regulating type 2 immune responses against allergens and helminths. ILC2s can interact with a variety of cells types of the innate and adaptive immune system by cell-cell contacts or by communication via soluble factors. In this review, we provide an overview about recent advances in our understanding how ILC2s orchestrate type 2 immune responses with focus on direct interactions between ILC2s and other cells of the immune system. PMID- 29163499 TI - FcepsilonRI gamma-Chain Negatively Modulates Dectin-1 Responses in Dendritic Cells. AB - The inhibitory effect of immunoreceptor tyrosine-based activation motif (ITAM) containing adapters DAP12 and FcepsilonRI gamma-chain (FcRgamma) has been found in many immune functions. Herein, we have further explored the role of these adapters in C-type lectin receptors response. We identified that FcRgamma, but not DAP12, could negatively regulate the Dectin-1 responses in dendritic cells (DCs). Loss of FcRgamma or both DAP12 and FcRgamma enhanced the maturation and cytokine production in DCs upon Dectin-1 activation compared to normal cells, whereas DCs lacking only DAP12 showed little changes. In addition, increments of T cell activation and T helper 17 polarization induced by FcRgamma-deficient DCs were observed both in vitro and in vivo. Examining the Dectin-1 signaling, we revealed that the activations of several signaling molecules were augmented in FcRgamma-deficient DCs stimulated with Dectin-1 ligands. Furthermore, we demonstrated that the association of phosphatases SHP-1 and PTEN with FcRgamma may contribute to the negative regulation of FcRgamma in Dectin-1 activation in DCs. These results extend the inhibitory effect of ITAM-containing adapters to Dectin-1 response in immune functions, even though Dectin-1 contains an ITAM-like intracellular domain. According to the role of Dectin-1 in responding to microbes and tumor cells, our finding may have applications in the development of vaccine and cancer therapy. PMID- 29163500 TI - Antibodies to Senescent Antigen and C3 Are Not Required for Normal Red Blood Cell Lifespan in a Murine Model. AB - Red blood cells (RBCs) have a well-defined lifespan, indicating a mechanism by which senescent cells of a certain age are removed from circulation. However, the specifics by which senescent cells are recognized and removed are poorly understood. There are multiple competing hypotheses for this process, perhaps the most commonly cited is that senescent RBCs expose neoantigens [or senescent antigen(s)] that are then recognized by naturally occurring antibodies, which opsonize the senescent cells and result in clearance from circulation. While there are a large volume of published data to indicate that older RBCs accumulate increased levels of antibody on their surface, to the best of our knowledge, the causal role of such antibodies in clearance has not been rigorously assessed. In the current report, we demonstrate that RBC lifespan and clearance patterns are not altered in mice deficient in antibodies, in C3 protein, or missing both. These data demonstrate that neither antibody nor C3 is required for clearance of senescent RBCs, and questions if they are even involved, in a murine model of RBC lifespan. PMID- 29163498 TI - Cytokine Profiles of Severe Influenza Virus-Related Complications in Children. AB - Rationale: Effective immunomodulatory therapies for children with life threatening "cytokine storm" triggered by acute influenza infection are lacking. Understanding the immune profiles of children progressing to severe lung injury and/or septic shock could provide insight into pathogenesis. Objectives: To compare the endotracheal and serum cytokine profiles of children with influenza related critical illness and to identify their associations with severe influenza associated complications. Methods: Children with influenza-related critical illness were enrolled across 32 hospitals in development (N = 171) and validation (N = 73) cohorts (December 2008 through May 2016). Concentrations of 42 cytokines were measured in serum and endotracheal samples and clustered into modules of covarying cytokines. Relative concentrations of cytokines and cytokine modules were tested for associations with acute lung injury (ALI), shock requiring vasopressors, and death/ECMO. Measurements and main results: Modules of covarying cytokines were more significantly associated with disease severity than individual cytokines. In the development cohort, increased levels of a serum module containing IL6, IL8, IL10, IP10, GCSF, MCP1, and MIP1alpha [shock odds ratio (OR) = 3.37, family-wise error rate (FWER) p < 10-4], and decreased levels of a module containing EGF, FGF2, SCD40L, and PAI-1 (shock OR = 0.43, FWER p = 0.002), were both associated with ALI, shock, and death-ECMO independent of age and bacterial coinfection. Both of these associations were confirmed in the validation cohort. Endotracheal and serum cytokine associations differed markedly and were differentially associated with clinical outcomes. Conclusion: We identified strong positive and negative associations of cytokine modules with the most severe influenza-related complications in children, providing new insights into the pathogenesis of influenza-related critical illness in children. Effective therapies may need to target mediators of both inflammation and repair. PMID- 29163501 TI - Herceptin Enhances the Antitumor Effect of Natural Killer Cells on Breast Cancer Cells Expressing Human Epidermal Growth Factor Receptor-2. AB - Optimal adoptive cell therapy (ACT) should contribute to effective cancer treatment. The unique ability of natural killer (NK) cells to kill cancer cells independent of major histocompatibility requirement makes them suitable as ACT tools. Herceptin, an antihuman epidermal growth factor receptor-2 (anti-HER2) monoclonal antibody, is used to treat HER2+ breast cancer. However, it has limited effectiveness and possible severe cardiotoxicity. Given that Herceptin may increase the cytotoxicity of lymphocytes, we explored the possible augmentation of NK cell cytotoxicity against HER2+ breast cancer cells by Herceptin. We demonstrated that Herceptin could interact with CD16 on NK cells to expand the cytotoxic NK (specifically, CD56dim) cell population. Additionally, Herceptin increased NK cell migration and cytotoxicity against HER2+ breast cancer cells. In a pilot study, Herceptin-treated NK cells shrunk lung nodular metastasis in a woman with HER2+ breast cancer who could not tolerate the cardiotoxic side effects of Herceptin. Our findings support the therapeutic potential of Herceptin-treated NK cells in patients with HER2+ and Herceptin intolerant breast cancer. PMID- 29163502 TI - Regulating Immunogenicity and Tolerogenicity of Bone Marrow-Derived Dendritic Cells through Modulation of Cell Surface Glycosylation by Dexamethasone Treatment. AB - Dendritic cellular therapies and dendritic cell vaccines show promise for the treatment of autoimmune diseases, the prolongation of graft survival in transplantation, and in educating the immune system to fight cancers. Cell surface glycosylation plays a crucial role in the cell-cell interaction, uptake of antigens, migration, and homing of DCs. Glycosylation is known to change with environment and the functional state of DCs. Tolerogenic DCs (tDCs) are commonly generated using corticosteroids including dexamethasone, however, to date, little is known on how corticosteroid treatment alters glycosylation and what functional consequences this may have. Here, we present a comprehensive profile of rat bone marrow-derived dendritic cells, examining their cell surface glycosylation profile before and after Dexa treatment as resolved by both lectin microarrays and lectin-coupled flow cytometry. We further examine the functional consequences of altering cell surface glycosylation on immunogenicity and tolerogenicity of DCs. Dexa treatment of rat DCs leads to profoundly reduced expression of markers of immunogenicity (MHC I/II, CD80, CD86) and pro-inflammatory molecules (IL-6, IL 12p40, inducible nitric oxide synthase) indicating a tolerogenic phenotype. Moreover, by comprehensive lectin microarray profiling and flow cytometry analysis, we show that sialic acid (Sia) is significantly upregulated on tDCs after Dexa treatment, and that this may play a vital role in the therapeutic attributes of these cells. Interestingly, removal of Sia by neuraminidase treatment increases the immunogenicity of immature DCs and also leads to increased expression of pro-inflammatory cytokines while tDCs are moderately protected from this increase in immunogenicity. These findings may have important implications in strategies aimed at increasing tolerogenicity where it is advantageous to reduce immune activation over prolonged periods. These findings are also relevant in therapeutic strategies aimed at increasing the immunogenicity of cells, for example, in the context of tumor specific immunotherapies. PMID- 29163504 TI - Butyrate Conditions Human Dendritic Cells to Prime Type 1 Regulatory T Cells via both Histone Deacetylase Inhibition and G Protein-Coupled Receptor 109A Signaling. AB - Recently, it has become clear that short-chain fatty acids (SCFAs), and in particular butyrate, have anti-inflammatory properties. Murine studies have shown that butyrate can promote regulatory T cells via the induction of tolerogenic dendritic cells (DCs). However, the effects of SCFAs on human DCs and how they affect their capacity to prime and polarize T-cell responses have not been addressed. Here, we report that butyrate suppresses LPS-induced maturation and metabolic reprogramming of human monocyte-derived DCs (moDCs) and conditions them to polarize naive CD4+ T cells toward IL-10-producing type 1 regulatory T cells (Tr1). This effect was dependent on induction of the retinoic acid-producing enzyme retinaldehyde dehydrogenase 1 in DCs. The induction of retinaldehyde dehydrogenase activity and Tr1 cell differentiation by butyrate was dependent on simultaneous inhibition of histone deacetylases and signaling through G protein coupled receptor 109A. Taken together, we reveal that butyrate is a potent inducer of tolerogenic human DCs, thereby shedding new light on the cellular and molecular mechanisms through which SCFAs can exert their immunomodulatory effects in humans. PMID- 29163505 TI - IL17eScan: A Tool for the Identification of Peptides Inducing IL-17 Response. AB - IL-17 cytokines are pro-inflammatory cytokines and are crucial in host defense against various microbes. Induction of these cytokines by microbial antigens has been investigated in the case of ischemic brain injury, gingivitis, candidiasis, autoimmune myocarditis, etc. In this study, we have investigated the ability of amino acid sequence of antigens to induce IL-17 response using machine-learning approaches. A total of 338 IL-17-inducing and 984 IL-17 non-inducing peptides were retrieved from Immune Epitope Database. 80% of the data were randomly selected as training dataset and rest 20% as validation dataset. To predict the IL-17-inducing ability of peptides/protein antigens, different sequence-based machine-learning models were developed. The performance of support vector machine (SVM) and random forest (RF) was compared with different parameters to predict IL 17-inducing epitopes (IIEs). The dipeptide composition-based SVM-model displayed an accuracy of 82.4% with Matthews correlation coefficient = 0.62 at polynomial (t = 1) kernel on 10-fold cross-validation and outperformed RF. Amino acid residues Leu, Ser, Arg, Asn, and Phe and dipeptides LL, SL, LK, IL, LI, NL, LR, FK, SF, and LE are abundant in IIEs. The present tool helps in the identification of IIEs using machine-learning approaches. The induction of IL-17 plays an important role in several inflammatory diseases, and identification of such epitopes would be of great help to the immunologists. It is freely available at http://metagenomics.iiserb.ac.in/IL17eScan/ and http://metabiosys.iiserb.ac.in/IL17eScan/. PMID- 29163503 TI - Efferocytosis and Outside-In Signaling by Cardiac Phagocytes. Links to Repair, Cellular Programming, and Intercellular Crosstalk in Heart. AB - Phagocytic sensing and engulfment of dying cells and extracellular bodies initiate an intracellular signaling cascade within the phagocyte that can polarize cellular function and promote communication with neighboring non phagocytes. Accumulating evidence links phagocytic signaling in the heart to cardiac development, adult myocardial homeostasis, and the resolution of cardiac inflammation of infectious, ischemic, and aging-associated etiology. Phagocytic clearance in the heart may be carried out by professional phagocytes, such as macrophages, and non-professional cells, including myofibrolasts and potentially epithelial cells. During cardiac development, phagocytosis initiates growth cues for early cardiac morphogenesis. In diseases of aging, including myocardial infarction, heightened levels of cell death require efficient phagocytic debridement to salvage further loss of terminally differentiated adult cardiomyocytes. Additional risk factors, including insulin resistance and other systemic risk factors, contribute to inefficient phagocytosis, altered phagocytic signaling, and delayed cardiac inflammation resolution. Under such conditions, inflammatory presentation of myocardial antigen may lead to autoimmunity and even possible rejection of transplanted heart allografts. Increased understanding of these basic mechanisms offers therapeutic opportunities. PMID- 29163506 TI - The Significance of Type-I Interferons in the Pathogenesis and Therapy of Human Immunodeficiency Virus 1 Infection. AB - Type-I interferons (IFN-I) are a widely expressed family that could promote antivirus immunity in the process of pathogens invasion. In a human immunodeficiency virus 1 (HIV-1)-infected individual, the production of IFN-I can be detected as early as the acute phase and will persist throughout the course of infection. However, sustained stimulation of immune system by IFN-I also contributes greatly to host-mediated immunopathology and diseases progression. Although the protective effects of IFN-I in the acute phase of HIV-1 infection have been observed, more studies recently focus on their detrimental role in the chronic stage. Inhibition of IFN-I signaling may reverse HIV-1-induced immune hyperactivation and furthermore reduce HIV-1 reservoirs, which suggest this strategy may provide a potential way to enhance the therapeutic effect of antiretroviral therapy. Therefore, we review the role of IFN-I in HIV-1 progression, their effects on different immunocytes, and therapeutic prospects targeting the IFN-I system. PMID- 29163507 TI - Impact of Chronic Viral Infection on T-Cell Dependent Humoral Immune Response. AB - During the last decades, considerable efforts have been done to decipher mechanisms supported by microorganisms or viruses involved in the development, differentiation, and function of immune cells. Pathogens and their associated secretome as well as the continuous inflammation observed in chronic infection are shaping both innate and adaptive immunity. Secondary lymphoid organs are functional structures ensuring the mounting of adaptive immune response against microorganisms and viruses. Inside these organs, germinal centers (GCs) are the specialized sites where mature B-cell differentiation occurs leading to the release of high-affinity immunoglobulin (Ig)-secreting cells. Different steps are critical to complete B-cell differentiation process, including proliferation, somatic hypermutations in Ig variable genes, affinity-based selection, and class switch recombination. All these steps require intense interactions with cognate CD4+ helper T cells belonging to follicular helper lineage. Interestingly, pathogens can disturb this subtle machinery affecting the classical adaptive immune response. In this review, we describe how viruses could act directly on GC B cells, either through B-cell infection or by their contribution to B-cell cancer development and maintenance. In addition, we depict the indirect impact of viruses on B-cell response through infection of GC T cells and stromal cells, leading to immune response modulation. PMID- 29163508 TI - Interferon-alpha-Enhanced CD100/Plexin-B1/B2 Interactions Promote Natural Killer Cell Functions in Patients with Chronic Hepatitis C Virus Infection. AB - Background: CD100, also known as Sema4D, is an immune semaphorin constitutively expressed on natural killer (NK) cells and T cells. As an immune activation molecule, CD100 has important immunoregulatory effects on NK functions by enhancing the interactions between NK cells and target cells. The aim of this study was to investigate whether hepatitis C virus (HCV) infection affects CD100 expression, and whether interferon-alpha treatment enhances NK killing activity to facilitate HCV clearance via CD100. Methods: Expression of CD100 on NK cells was evaluated by flow cytometry in patients with chronic HCV infection, with or without pegylated interferon-alpha-based therapy. NK cell cytotoxicity and interferon (IFN)-gamma production were measured by flow cytometry upon culturing the NK cells with K562 and Huh7.5 or HCV JFH-1-infected Huh7.5 cells. Results: The frequency of CD100+ NK cells in HCV-infected individuals was slightly suppressed compared to healthy subjects. IFN-alpha treatment could significantly upregulate CD100 expression, which was confirmed by in vitro studies using peripheral blood mononuclear cells cocultured with HCV-expressing Huh7.5 cells or IFN-alpha. Importantly, the expression of CD100 on NK cells from HCV patients was inversely associated with the HCV-RNA levels in the early phase of IFN-alpha therapy, and the IFN-alpha upregulated CD100 led to an enhanced NK killing activity through ligations with its receptors plexin-B1/B2 on target cells. Conclusion: These results implied a novel mechanism by which IFN-alpha enhanced CD100/Plexin-B1/B2 interaction plays an important role in promoting NK functions in patients with chronic hepatitis C. PMID- 29163509 TI - Downregulated IL-21 Response and T Follicular Helper Cell Exhaustion Correlate with Compromised CD8 T Cell Immunity during Chronic Toxoplasmosis. AB - CD8 T cells are important for maintaining the chronicity of Toxoplasma gondii infection. In a T. gondii encephalitis susceptible model, we recently demonstrated that CD4 T cells play an essential helper role in the maintenance of the effector response and CD8 T cell dysfunctionality was linked to CD4 T cell exhaustion. However, CD4 T cells are constituted of different subsets with various functions and the population(s) providing help to the CD8 T cells has not yet been determined. In the present study, T follicular helper cells (Tfh), which are known to be essential for B cell maturation and are one of the main sources of IL-21, were significantly increased during chronic toxoplasmosis. However, at week 7 p.i., when CD8 T cells are exhausted, the Tfh population exhibited increased expression of several inhibitory receptors and levels of IL-21 in the serum were decreased. The importance of IL-21 in the maintenance of CD8 T cells function after T. gondii infection was further demonstrated in IL-21R KO mouse model. Interestingly, while CD8 T cells from both knockout (KO) and wild-type mice expressed similar levels of PD-1, animals with defective IL-21 signaling exhibited lower polyfunctionality than wild-type controls. This reduced polyfunctional ability observed in CD8 T cells from KO mice was associated with a significant increase in other inhibitory receptors like Tim-3, LAG-3, and 2B4. Furthermore, the animals exhibited greater signs of Toxoplasma reactivation manifested by the reduced number of cysts and increased expression of tachyzoite (replicative form of the parasite) specific genes (SAG1 and ENO2) in the brain. Also, IL-21R KO mice displayed a higher frequency of tachyzoite-infected monocytes in the blood and spleen. Our findings suggest the importance of Tfh and IL-21 during chronic toxoplasmosis and establish a critical role for this cytokine in regulating CD8 T cell dysfunction by preventing the co-expression of multiple inhibitory receptors during chronic parasitic infection. PMID- 29163510 TI - The Equivocal Role of Th17 Cells and Neutrophils on Immunopathogenesis of Leishmaniasis. AB - Advances in the understanding of leishmaniasis progression indicate that cellular interactions more complex than the Th1/Th2 paradigm define the course of infection. Th17 cells are a crucial modulator of adaptive immunity against Leishmania parasites acting mainly on neutrophil recruitment and playing a dual role at the site of infection. This review describes the roles of both these cell types in linking innate defense responses to the establishment of specific immunity. We focus on the Th17-neutrophil interaction as a crucial component of anti-Leishmania immunity, and the clinical evolution of cutaneous or visceral leishmaniasis. To date, information obtained through experimental models and patient evaluations suggests that the influence of the presence of interleukin (IL)-17 (the main cytokine produced by Th17 cells) and neutrophils during Leishmania infections is strictly dependent on the tissue (skin or liver/spleen) and parasite species. Also, the time at which neutrophils are recruited, and the persistence of IL-17 in the infection microenvironment, may also be significant. A clearer understanding of these interactions will enable better measurement of the influence of IL-17 and its regulators, and contribute to the identification of disease/resistance biomarkers. PMID- 29163512 TI - Carboxyl-Terminal Residues N478 and V479 Required for the Cytolytic Activity of Listeriolysin O Play a Critical Role in Listeria monocytogenes Pathogenicity. AB - Listeria monocytogenes is a facultative intracellular pathogen that secretes the cytolysin listeriolysin O (LLO), which enables the bacteria to cross the phagosomal membrane. L. monocytogenes regulates LLO activity in the phagosome and minimizes its activity in the host cytosol. Mutants that fail to compartmentalize LLO activity are cytotoxic and have attenuated virulence. Here, we showed that residues N478 and V479 of LLO are required for LLO hemolytic activity and bacterial virulence. A single N478A mutation (LLON478A) significantly increased the hemolytic activity of LLO at a neutral pH, while no difference was observed at the optimum acidic pH, compared with wild-type LLO. Conversely, the mutant LLOV479A exhibited lower hemolytic activity at the acidic pH, but not at the neutral pH. The double mutant LLON478AV479A showed a greater decrease in hemolytic activity at both the acidic and neutral pHs. Interestingly, strains producing LLON478A or LLOV479A lysed erythrocytes similarly to the wild-type strain. Surprisingly, bacteria-secreting LLON478AV479A had barely detectable hemolytic activity, but exhibited host cell cytotoxicity, escaped from the phagosome, grew intracellularly, and spread cell-to-cell with the same efficiency as the wild-type strain, but were highly attenuated in virulence in mice. These data demonstrate that these two residues are required for LLO hemolytic activity and pathogenicity in mice, but not for escape from the phagosome and cell-to-cell spreading. The finding that the nearly non-hemolytic LLON478AV479A mutant grew intracellularly indicates that mutagenesis of a virulence determinant is a novel approach for the development of live vaccine strains. PMID- 29163513 TI - MicroRNA-4443 Causes CD4+ T Cells Dysfunction by Targeting TNFR-Associated Factor 4 in Graves' Disease. AB - Context: Aberrant CD4+ T cell function plays a critical role in the process of Graves' disease (GD). MicroRNAs (miRNAs) are important regulators of T cell activation, proliferation, and cytokine production. However, the contribution of miRNAs to CD4+ T cell dysfunction in GD remains unclear. Objective: To investigate how certain miRNA causes aberrant CD4+ T cell function in GD patients. Methods: We compared the expression pattern of miRNAs in CD4+ T cells from untreated GD (UGD) patients with those from healthy controls. The most significantly dysregulated miRNAs were selected and their correlations with clinical parameters were analyzed. The effect of miR-4443 on CD4+ T cells cytokines production and proliferation was assessed. The potential gene target was identified and validated. Results: GD patients had unique pattern of miRNA expression profile in CD4+ T cells comparing to healthy subjects. miR-10a, miR 125b, and miR-4443 were the three most significantly dysregulated miRNAs. The elevated miR-4443 levels were strongly correlated with clinical parameters in an independent dataset of UGD patients (N = 40), while miR-4443 was normally expressed in GD patients with euthyroidism and negative TRAb level. We found that miR-4443 directly inhibited TNFR-associated factor (TRAF) 4 expression to increase CD4+ T cells cytokines secretion as well as proliferation through the NF kappaB pathway. Furthermore, the TRAF4 levels in GD patients were inversely correlated with miR-4443, and knocking down TRAF4 had a similar effect with miR 4443 overexpression. Conclusion: The increased expression of miR-4443 induced CD4+ T cells dysfunction by targeting TRAF4, which may cause GD. PMID- 29163511 TI - Lactoferrin in a Context of Inflammation-Induced Pathology. AB - Much progress has been achieved to elucidate the function of lactoferrin (LTF), an iron-binding glycoprotein, in the milieu of immune functionality. This review represents a unique examination of LTF toward its importance in physiologic homeostasis as related to development of disease-associated pathology. The immunomodulatory nature of this protein derives from its unique ability to "sense" the immune activation status of an organism and act accordingly. Underlying mechanisms are proposed whereby LTF controls disease states, thereby pinpointing regions of entry for LTF in maintenance of various physiological pathways to limit the magnitude of tissue damage. LTF is examined as a first line mediator in immune defense and response to pathogenic and non-pathogenic injury, as well as a molecule critical for control of oxidative cell function. Mechanisms of interaction of LTF with its receptors are examined, with a focus on protective effects via regulation of enzyme activities and reactive oxygen species production, immune deviation, and prevention of cell apoptosis. Indeed, LTF serves as a critical control point in physiologic homeostasis, functioning as a sensor of immunological performance related to pathology. Specific mediation of tissue pathophysiology is described for maintenance of intestinal integrity during endotoxemia, elicited airway inflammation due to allergens, and pulmonary damage during tuberculosis. Finally, the role of LTF to alter differentiation of adaptive immune function is examined, with specific recognition of its utility as a vaccine adjuvant to control subsequent lymphocytic reactivity. Overall, it is clear that while the ability of LTF to both sequester iron and to direct reactive oxygen intermediates is a major factor in lessening damage due to excessive inflammatory responses, further effects are apparent through direct control over development of higher order immune functions that regulate pathology due to insult and injury. This culminates in attenuation of pathological damage during inflammatory injury. PMID- 29163514 TI - An Unexpected Major Role for Proteasome-Catalyzed Peptide Splicing in Generation of T Cell Epitopes: Is There Relevance for Vaccine Development? AB - Efficient and safe induction of CD8+ T cell responses is a desired characteristic of vaccines against intracellular pathogens. To achieve this, a new generation of safe vaccines is being developed accommodating single, dominant antigens of pathogens of interest. In particular, the selection of such antigens is challenging, since due to HLA polymorphism the ligand specificities and immunodominance hierarchies of pathogen-specific CD8+ T cell responses differ throughout the human population. A recently discovered mechanism of proteasome mediated CD8+ T cell epitope generation, i.e., by proteasome-catalyzed peptide splicing (PCPS), expands the pool of peptides and antigens, presented by MHC class I HLA molecules. On the cell surface, one-third of the presented self peptides are generated by PCPS, which coincides with one-fourth in terms of abundance. Spliced epitopes are targeted by CD8+ T cell responses during infection and, like non-spliced epitopes, can be identified within antigen sequences using a novel in silico strategy. The existence of spliced epitopes, by enlarging the pool of peptides available for presentation by different HLA variants, opens new opportunities for immunotherapies and vaccine design. PMID- 29163515 TI - Nanobody-Based Delivery Systems for Diagnosis and Targeted Tumor Therapy. AB - The development of innovative targeted therapeutic approaches are expected to surpass the efficacy of current forms of treatments and cause less damage to healthy cells surrounding the tumor site. Since the first development of targeting agents from hybridoma's, monoclonal antibodies (mAbs) have been employed to inhibit tumor growth and proliferation directly or to deliver effector molecules to tumor cells. However, the full potential of such a delivery strategy is hampered by the size of mAbs, which will obstruct the targeted delivery system to access the tumor tissue. By serendipity, a new kind of functional homodimeric antibody format was discovered in camelidae, known as heavy-chain antibodies (HCAbs). The cloning of the variable domain of HCAbs produces an attractive minimal-sized alternative for mAbs, referred to as VHH or nanobodies (Nbs). Apart from their dimensions in the single digit nanometer range, the unique characteristics of Nbs combine a high stability and solubility, low immunogenicity and excellent affinity and specificity against all possible targets including tumor markers. This stimulated the development of tumor targeted therapeutic strategies. Some autonomous Nbs have been shown to act as antagonistic drugs, but more importantly, the targeting capacity of Nbs has been exploited to create drug delivery systems. Obviously, Nb-based targeted cancer therapy is mainly focused toward extracellular tumor markers, since the membrane barrier prevents antibodies to reach the most promising intracellular tumor markers. Potential strategies, such as lentiviral vectors and bacterial type 3 secretion system, are proposed to deliver target-specific Nbs into tumor cells and to block tumor markers intracellularly. Simultaneously, Nbs have also been employed for in vivo molecular imaging to diagnose diseased tissues and to monitor the treatment effects. Here, we review the state of the art and focus on recent developments with Nbs as targeting moieties for drug delivery systems in cancer therapy and cancer imaging. PMID- 29163517 TI - Prophenoloxidase-Mediated Ex Vivo Immunity to Delay Fungal Infection after Insect Ecdysis. AB - Skin immunity protects animals from airborne pathogen infection. Unlike mammals, arthropods, including insects, undergo periodic ecdysis to grow and develop. Newly molted insects emerge with unsclerotized thin cuticles but successfully escape pathogenic infections during the post-molt period. Here we show that prophenoloxidases (PPOs) in molting fluids remain bioactive on the integument and impede fungal infection after ecdysis. We found that the purified plasma PPOs or recombinant PPOs could effectively bind to fungal spores (conidia) by targeting the cell wall components chitin and beta-1,3-glucan. Pretreatment of the spores of the fungal pathogen Beauveria bassiana with PPOs increased spore hydrophilicity and reduced spore adhesion activity, resulting in a significant decrease in virulence as compared with mock infection. We also identified a spore secreted protease BPS8, a member of peptidase S8 family of protease that degrade PPOs at high levels to benefit fungal infection, but which at lower doses activate PPOs to inhibit spore germination after melanization. These data indicate that insects have evolved a distinct strategy of ex vivo immunity to survive pathogen infections after ecdysis using PPOs in molting fluids retained on the underdeveloped and tender integument of newly molted insects for protection against airborne fungal infection. PMID- 29163518 TI - Mixed Signals: Co-Stimulation in Invariant Natural Killer T Cell-Mediated Cancer Immunotherapy. AB - Invariant natural killer T (iNKT) cells are an integral component of the immune system and play an important role in antitumor immunity. Upon activation, iNKT cells can directly kill malignant cells as well as rapidly produce cytokines that stimulate other immune cells, making them a front line defense against tumorigenesis. Unfortunately, iNKT cell number and activity are reduced in multiple cancer types. This anergy is often associated with upregulation of co inhibitory markers such as programmed death-1. Similar to conventional T cells, iNKT cells are influenced by the conditions of their activation. Conventional T cells receive signals through the following three types of receptors: (1) T cell receptor (TCR), (2) co-stimulation molecules, and (3) cytokine receptors. Unlike conventional T cells, which recognize peptide antigen presented by MHC class I or II, the TCRs of iNKT cells recognize lipid antigen in the context of the antigen presentation molecule CD1d (Signal 1). Co-stimulatory molecules can positively and negatively influence iNKT cell activation and function and skew the immune response (Signal 2). This study will review the background of iNKT cells and their co-stimulatory requirements for general function and in antitumor immunity. We will explore the impact of monoclonal antibody administration for both blocking inhibitory pathways and engaging stimulatory pathways on iNKT cell mediated antitumor immunity. This review will highlight the incorporation of co stimulatory molecules in antitumor dendritic cell vaccine strategies. The use of co-stimulatory intracellular signaling domains in chimeric antigen receptor-iNKT therapy will be assessed. Finally, we will explore the influence of innate-like receptors and modification of immunosuppressive cytokines (Signal 3) on cancer immunotherapy. PMID- 29163516 TI - Restoring Natural Killer Cell Immunity against Multiple Myeloma in the Era of New Drugs. AB - Transformed plasma cells in multiple myeloma (MM) are susceptible to natural killer (NK) cell-mediated killing via engagement of tumor ligands for NK activating receptors or "missing-self" recognition. Similar to other cancers, MM targets may elude NK cell immunosurveillance by reprogramming tumor microenvironment and editing cell surface antigen repertoire. Along disease continuum, these effects collectively result in a progressive decline of NK cell immunity, a phenomenon increasingly recognized as a critical determinant of MM progression. In recent years, unprecedented efforts in drug development and experimental research have brought about emergence of novel therapeutic interventions with the potential to override MM-induced NK cell immunosuppression. These NK-cell enhancing treatment strategies may be identified in two major groups: (1) immunomodulatory biologics and small molecules, namely, immune checkpoint inhibitors, therapeutic antibodies, lenalidomide, and indoleamine 2,3-dioxygenase inhibitors and (2) NK cell therapy, namely, adoptive transfer of unmanipulated and chimeric antigen receptor-engineered NK cells. Here, we summarize the mechanisms responsible for NK cell functional suppression in the context of cancer and, specifically, myeloma. Subsequently, contemporary strategies potentially able to reverse NK dysfunction in MM are discussed. PMID- 29163519 TI - Repertoire of BALB/c Mice Natural Anti-Carbohydrate Antibodies: Mice vs. Humans Difference, and Otherness of Individual Animals. AB - One of the most common genetic backgrounds for mice used as a model to investigate human diseases is the inbred BALB/c strain. This work is aimed to characterize the pattern of natural anti-carbohydrate antibodies present in the serum of 20 BALB/c mice by printed glycan array technology and to compare their binding specificities with that of human natural anti-carbohydrate antibodies. Natural antibodies (NAbs) from the serum of BALB/c mice interacted with 71 glycans from a library of 419 different carbohydrate structures. However, only seven of these glycans were recognized by the serum of all the animals studied, and other five glycans by at least 80% of mice. The pattern of the 12 glycans mostly recognized by the circulating antibodies of BALB/c mice differed significantly from that observed with natural anti-carbohydrate antibodies in humans. This lack of identical repertoires of natural anti-carbohydrate antibodies between individual inbred mice, and between mice and humans, should be taken into consideration when mouse models are intended to be used for investigation of NAbs in biomedical research. PMID- 29163520 TI - The Injury-Related Activation of Hedgehog Signaling Pathway Modulates the Repair Associated Inflammation in Liver Fibrosis. AB - Liver fibrosis is a wound healing response initiated by inflammation responding for different iterative parenchymal damages caused by diverse etiologies. Immune cells, which exert their ability of either inducing injury or promoting repair, have been regarded as crucial participants in the fibrogenic response. A characteristic feature of the fibrotic microenvironment associated with chronic liver injury is aberrant activation of hedgehog (Hh) signaling pathway. Growing evidence from a number of different studies in vivo and in vitro has indicated that immune-mediated events involved in liver fibrogenesis are regulated by Hh signaling pathway. In this review, we emphasize the impacts of injury-activated Hh signaling on liver fibrogenesis through modulating repair-related inflammation and focus on the regulatory action of aberrant Hh signaling on repair-related inflammatory responses mediated by hepatic classical and non-classical immune cell populations in the progression of liver fibrosis. Moreover, we also assess the potentiality of Hh pathway inhibitors as good candidates for anti-fibrotic therapeutic agents because of their immune regulation actions for fibrogenic liver repair. The identification of immune-modulatory mechanisms of Hh signaling pathway underlying the fibrotic process of chronic liver diseases might provide a basis for Hh-centered therapeutic strategies for liver fibrosis. PMID- 29163521 TI - CD4+ and Perivascular Foxp3+ T Cells in Glioma Correlate with Angiogenesis and Tumor Progression. AB - Background: Angiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL) and tumor blood-vasculatures in the context of glioma progression. Methods: Paired tumor tissues of 44 patients from three tumor recurrent groups: diffuse astrocytomas (DA) recurred as DA, DA recurred as glioblastomas (GBM), and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naive recurrent GBM were also evaluated and compared. Results: Upon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naive recurrent tumors). Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS) (HR = 4.199, 95% CI 1.522-11.584, p = 0.006). Conclusion: The minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3+ TILs associate with tumor angiogenesis and tumor progression in glioma patients. Our results suggest that combining antiangiogenic agents with immunotherapeutic approaches may help improve the antitumor efficacy for patients with malignant gliomas. PMID- 29163523 TI - Interleukin-5 Mediates Parasite-Induced Protection against Experimental Autoimmune Encephalomyelitis: Association with Induction of Antigen-Specific CD4+CD25+ T Regulatory Cells. AB - Objective: To examine if the protective effect of parasite infection on experimental autoimmune encephalomyelitis (EAE) was due to interleukin (IL)-5, a cytokine produced by a type-2 response that induces eosinophilia. We hypothesize that, in parasite infections, IL-5 also promotes expansion of antigen-specific T regulatory cells that control autoimmunity. Methods: Nippostrongylus brasiliensis larvae were used to infect Lewis rats prior to induction of EAE by myelin basic protein. Animals were sham treated, or given blocking monoclonal antibodies to interleukin 4 or 5 or to deplete CD25+ T cells. Reactivity of CD4+CD25+ T regulatory cells from these animals was examined. Results: Parasite-infected hosts had reduced severity and length of EAE. The beneficial effect of parasitic infection was abolished with an anti-IL-5 or an anti-CD25 monoclonal antibody (mAb), but not anti-IL-4 mAb. Parasite-infected animals with EAE developed antigen-specific CD4+CD25+ T regulatory cells earlier than EAE controls and these expressed more Il5ra than controls. Treatment with IL-5 also reduced the severity of EAE and induced Il5ra expressing CD4+CD25+ T regulatory cells. Interpretation: The results of this study suggested that IL-5 produced by the type-2 inflammatory response to parasite infection promoted induction of autoantigen-specific CD25+Il5ra+ T regulatory cells that reduced the severity of autoimmunity. Such a mechanism may explain the protective effect of parasite infection in patients with multiple sclerosis where eosinophilia is induced by IL-5, produced by the immune response to parasites. PMID- 29163522 TI - The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract. AB - The vagus nerve (VN) is the longest nerve of the organism and a major component of the parasympathetic nervous system which constitutes the autonomic nervous system (ANS), with the sympathetic nervous system. There is classically an equilibrium between the sympathetic and parasympathetic nervous systems which is responsible for the maintenance of homeostasis. An imbalance of the ANS is observed in various pathologic conditions. The VN, a mixed nerve with 4/5 afferent and 1/5 efferent fibers, is a key component of the neuro-immune and brain-gut axes through a bidirectional communication between the brain and the gastrointestinal (GI) tract. A dual anti-inflammatory role of the VN is observed using either vagal afferents, targeting the hypothalamic-pituitary-adrenal axis, or vagal efferents, targeting the cholinergic anti-inflammatory pathway. The sympathetic nervous system and the VN act in synergy, through the splenic nerve, to inhibit the release of tumor necrosis factor-alpha (TNFalpha) by macrophages of the peripheral tissues and the spleen. Because of its anti-inflammatory effect, the VN is a therapeutic target in the treatment of chronic inflammatory disorders where TNFalpha is a key component. In this review, we will focus on the anti-inflammatory role of the VN in inflammatory bowel diseases (IBD). The anti inflammatory properties of the VN could be targeted pharmacologically, with enteral nutrition, by VN stimulation (VNS), with complementary medicines or by physical exercise. VNS is one of the alternative treatments for drug resistant epilepsy and depression and one might think that VNS could be used as a non-drug therapy to treat inflammatory disorders of the GI tract, such as IBD, irritable bowel syndrome, and postoperative ileus, which are all characterized by a blunted autonomic balance with a decreased vagal tone. PMID- 29163525 TI - A Novel Vascular Endothelial Growth Factor Receptor Participates in White Spot Syndrome Virus Infection in Litopenaeus vannamei. AB - Vascular endothelial growth factor (VEGF) signaling pathway is known to play key roles in endothelial cell proliferation, migration, angiogenesis, vascular permeability, inhibition of apoptosis, and virus infection. In the present study, a novel VEGFR gene (LvVEGFR2) was identified and characterized from Litopenaeus vannamei. The deduced amino acid sequence of LvVEGFR2 possessed typical features of VEGFRs reported in other species, including six IG-like domains, a transmembrane motif, a protein kinase (PK) domain, and one tyrosine-PK active site. The transcripts of LvVEGFR2 were mainly detected in hemocytes and lymphoid organ (Oka). Subcellular localization analysis showed that LvVEGFR2 was a membrane protein. Its expression level was obviously upregulated in hemocytes and Oka of the shrimp after white spot syndrome virus (WSSV) infection. Knockdown of LvVEGFR2 gene expression by double-strand RNA mediated interference could lead to a decrease of virus copy number in WSSV-infected shrimp. The interaction between LvVEGFR2 and different LvVEGFs (LvVEGF1, LvVEGF2, and LvVEGF3) in shrimp was analyzed at the transcription level and protein level, respectively. Knockdown of LvVEGF2 or LvVEGF3 could downregulate the expression level of LvVEGFR2, and injection of the recombinant LvVEGF2 or LvVEGF3 could upregulate the expression level of LvVEGFR2. Yeast two-hybrid analysis showed that LvVEGFR2 could interact with LvVEGF2 and LvVEGF3 directly. The study improved our understanding on the VEGF signaling pathway of shrimp and its role during WSSV infection. PMID- 29163524 TI - T Helper 17 Promotes Induction of Antigen-Specific Gut-Mucosal Cytotoxic T Lymphocytes following Adenovirus Vector Vaccination. AB - Few current vaccines can establish antigen (Ag)-specific immune responses in both mucosal and systemic compartments. Therefore, development of vaccines providing defense against diverse infectious agents in both compartments is of high priority in global health. Intramuscular vaccination of an adenovirus vector (Adv) has been shown to induce Ag-specific cytotoxic T lymphocytes (CTLs) in both systemic and gut-mucosal compartments. We previously found that type I interferon (IFN) signaling is required for induction of gut-mucosal, but not systemic, CTLs following vaccination; however, the molecular mechanism involving type I IFN signaling remains unknown. Here, we found that T helper 17 (Th17)-polarizing cytokine expression was down-regulated in the inguinal lymph nodes (iLNs) of Ifnar2-/- mice, resulting in the reduction of Ag-specific Th17 cells in the iLNs and gut mucosa of the mice. We also found that prior transfer of Th17 cells reversed the decrease in the number of Ag-specific gut-mucosal CTLs in Ifnar2-/- mice following Adv vaccination. Additionally, prior transfer of Th17 cells into wild-type mice enhanced the induction of Ag-specific CTLs in the gut mucosa, but not in systemic compartments, suggesting a gut mucosa-specific mechanism where Th17 cells regulate the magnitude of vaccine-elicited Ag-specific CTL responses. These data suggest that Th17 cells translate systemic type I IFN signaling into a gut-mucosal CTL response following vaccination, which could promote the development of promising Adv vaccines capable of establishing both systemic and gut-mucosal protective immunity. PMID- 29163526 TI - Nucleated Teleost Erythrocytes Play an Nk-Lysin- and Autophagy-Dependent Role in Antiviral Immunity. AB - With the exception of mammals, vertebrate erythrocytes are nucleated. Nevertheless, these cells are usually considered as mere carriers of hemoglobin. In this work, however, we describe for the first time an unrecognized role of teleost red blood cells (RBCs). We found that Nk-lysin (Nkl), an antimicrobial peptide produced by NK-cells and cytotoxic T-lymphocytes, was also expressed in flatfish turbot (Scophthalmus maximus) erythrocytes. Although the antiviral role of Nkl remains to be elucidated, we found a positive correlation between the transcription of nkl and the resistance to an infection with Rhabdovirus in a teleost fish. Surprisingly, Nkl was found to be present in the autophagolysosomes of erythrocytes, and therefore this higher resistance provided by Nkl could be related to autophagy. The organelles of RBCs are degraded through autophagy during the maturation process of these cells. In this work, we observed that the blockage of autophagy increased the replication of viral hemorrhagic septicemia virus in nucleated teleost erythrocytes, which suggests that this mechanism may also be a key process in the defense against viruses in these cells. Nkl, which possesses membrane-perturbing ability and was affected by this modulation of RBC autophagy, could also participate in this process. For the first time, autophagy has been described not only as a life cycle event during the maturation of erythrocytes but also as a pivotal antiviral mechanism in nucleated erythrocytes. These results suggest a role of erythrocytes and Nkl in the antiviral immunity of fish and other vertebrates with nucleated RBCs. PMID- 29163527 TI - Engineered Tolerance: Tailoring Development, Function, and Antigen-Specificity of Regulatory T Cells. AB - Regulatory T cells (Tregs) are potent suppressors of immune responses and are currently being clinically tested for their potential to stop or control undesired immune responses in autoimmunity, hematopoietic stem cell transplantation, and solid organ transplantation. Current clinical approaches aim to boost Tregs in vivo either by using Treg-promoting small molecules/proteins and/or by adoptive transfer of expanded Tregs. However, the applicability of Treg based immunotherapies continues to be hindered by technical limitations related to cell isolation and expansion of a pure, well-characterized, and targeted Treg product. Efforts to overcome these limitations and improve Treg-directed therapies are now under intense investigation in animal models and pre-clinical studies. Here, we review cell and protein engineering-based approaches that aim to target different aspects of Treg biology including modulation of IL-2 signaling or FOXP3 expression, and targeted antigen-specificity using transgenic T cell receptors or chimeric antigen receptors. With the world-wide interest in engineered T cell therapy, these exciting new approaches have the potential to be rapidly implemented and developed into therapies that can effectively fine-tune immune tolerance. PMID- 29163529 TI - NLRP10 Enhances CD4+ T-Cell-Mediated IFNgamma Response via Regulation of Dendritic Cell-Derived IL-12 Release. AB - NLRP10 is a nucleotide-binding oligomerization domain-like receptor that functions as an intracellular pattern recognition receptor for microbial products. Here, we generated a Nlrp10-/- mouse to delineate the role of NLRP10 in the host immune response and found that Nlrp10-/- dendritic cells (DCs) elicited sub-optimal IFNgamma production by antigen-specific CD4+ T cells compared to wild type (WT) DCs. In response to T-cell encounter, CD40 ligation or Toll-like receptor 9 stimulation, Nlrp10-/- DCs produced low levels of IL-12, due to a substantial decrease in NF-kappaB activation. Defective IL-12 production was also evident in vivo and affected IFNgamma production by CD4+ T cells. Upon Mycobacterium tuberculosis (Mtb) infection, Nlrp10-/- mice displayed diminished T helper 1-cell responses and increased bacterial growth compared to WT mice. These data indicate that NLRP10-mediated IL-12 production by DCs is critical for IFNgamma induction in T cells and contributes to promote the host defense against Mtb. PMID- 29163528 TI - The Role of Transforming Growth Factor Beta-1 in the Progression of HIV/AIDS and Development of Non-AIDS-Defining Fibrotic Disorders. AB - Even after attainment of sustained viral suppression following implementation of highly active antiretroviral therapy, HIV-infected persons continue to experience persistent, low-grade, systemic inflammation. Among other mechanisms, this appears to result from ongoing microbial translocation from a damaged gastrointestinal tract. This HIV-related chronic inflammatory response is paralleled by counteracting, but only partially effective, biological anti inflammatory processes. Paradoxically, however, this anti-inflammatory response not only exacerbates immunosuppression but also predisposes for development of non-AIDS-related, non-communicable disorders. With respect to the pathogenesis of both sustained immunosuppression and the increased frequency of non-AIDS-related disorders, the anti-inflammatory/profibrotic cytokine, transforming growth factor beta1 (TGF-beta1), which remains persistently elevated in both untreated and virally suppressed HIV-infected persons, may provide a common link. In this context, the current review is focused on two different, albeit related, harmful activities of TGF-beta1 in HIV infection. First, on the spectrum of anti inflammatory/immunosuppressive activities of TGF-beta1 and the involvement of this cytokine, derived predominantly from T regulatory cells, in driving disease progression in HIV-infected persons via both non-fibrotic and profibrotic mechanisms. Second, the possible involvement of sustained elevations in circulating and tissue TGF-beta1 in the pathogenesis of non-AIDS-defining cardiovascular, hepatic, pulmonary and renal disorders, together with a brief comment on potential TGF-beta1-targeted therapeutic strategies. PMID- 29163530 TI - Sense and Immunity: Context-Dependent Neuro-Immune Interplay. AB - The sensory nervous and immune systems, historically considered autonomous, actually work in concert to promote host defense and tissue homeostasis. These systems interact with each other through a common language of cell surface G protein-coupled receptors and receptor tyrosine kinases as well as cytokines, growth factors, and neuropeptides. While this bidirectional communication is adaptive in many settings, helping protect from danger, it can also become maladaptive and contribute to disease pathophysiology. The fundamental logic of how, where, and when sensory neurons and immune cells contribute to either health or disease remains, however, unclear. Our lab and others' have begun to explore how this neuro-immune reciprocal dialog contributes to physiological and pathological immune responses and sensory disorders. The cumulative results collected so far indicate that there is an important role for nociceptors (noxious stimulus detecting sensory neurons) in driving immune responses, but that this is highly context dependent. To illustrate this concept, we present our findings in a model of airway inflammation, in which nociceptors seem to have major involvement in type 2 but not type 1 adaptive immunity. PMID- 29163532 TI - Biodistribution and Immunogenicity of Allogeneic Mesenchymal Stem Cells in a Rat Model of Intraarticular Chondrocyte Xenotransplantation. AB - Xenogeneic chondrocytes and allogeneic mesenchymal stem cells (MSC) are considered a potential source of cells for articular cartilage repair. We here assessed the immune response triggered by xenogeneic chondrocytes when injected intraarticularly, as well as the immunoregulatory effect of allogeneic bone marrow-derived MSC after systemic administration. To this end, a discordant xenotransplantation model was established by injecting three million porcine articular chondrocytes (PAC) into the femorotibial joint of Lewis rats and monitoring the immune response. First, the fate of MSC injected using various routes was monitored in an in vivo imaging system. The biodistribution revealed a dependency on the injection route with MSC injected intravenously (i.v.) succumbing early after 24 h and MSC injected intraperitoneally (i.p.) lasting locally for at least 5 days. Importantly, no migration of MSC to the joint was detected in rats previously injected with PAC. MSC were then administered either i.v. 1 week before PAC injection or i.p. 3 weeks after to assess their immunomodulatory function on humoral and adaptive immune parameters. Anti-PAC IgM and IgG responses were detected in all PAC-injected rats with a peak at week 2 postinjection and reactivity remaining above baseline levels by week 18. IgG2a and IgG2b were the predominant and long-lasting IgG subtypes. By contrast, no anti-MSC antibody response was detected in the cohort injected with MSC only, but infusion of MSC before PAC injection temporarily augmented the anti-PAC antibody response. Consistent with a cellular immune response to PAC in PAC-injected rats, cytokine/chemokine profiling in serum by antibody array revealed a distinct pattern relative to controls characterized by elevation of multiple markers at week 2, as well as increases in proliferation in draining lymph nodes. Notably, systemic administration of allogeneic MSC under the described conditions did not diminish the immune response. IL-2 measurements in cocultures of rat peripheral blood lymphocytes with PAC indicated that PAC injection induced some T-cell hyporesponsiveness that was not enhanced in the cohorts additionally receiving MSC. Thus, PAC injected intraarticularly in Lewis rats induced a cellular and humoral immune response that was not counteracted by the systemic administration of allogeneic MSC under the described conditions. PMID- 29163531 TI - Impaired Resolution of Inflammation in Alzheimer's Disease: A Review. AB - Alzheimer's disease (AD) remains the leading cause of dementia worldwide, and over the last several decades, the role of inflammation in the pathogenesis of this neurodegenerative disorder has been increasingly elucidated. The initiation of the acute inflammatory response is counterbalanced by an active process termed resolution. This process is designed to restore homeostasis and promote tissue healing by the activation of neutrophilic apoptosis, promotion of neutrophil clearance by macrophages, and increasing anti-inflammatory cytokine levels, while concurrently leading to a diminution in pro-inflammatory mediators. The switch from the initiation to the resolution phase of inflammation is initially characterized by increased production of arachidonic acid-derived pro-resolving lipoxins and decreases in pro-inflammatory prostaglandin and leukotriene levels, subsequently followed by increases in specialized pro-resolving lipid mediators derived from omega-3 fatty acids (omega-3 FAs). There is mounting evidence that in AD, the resolution of inflammation is impaired, resulting in chronic inflammation and the exacerbation of the AD-related pathology. In this review, we examine preclinical and clinical evidence supporting the hypothesis that AD is a neurodegenerative disorder where the impairment or failure of resolution contributes to the disease process. Moreover, we review the literature supporting the potential therapeutic role of omega-3 FAs and specialized pro-resolving lipid mediators in the management of the disease. Lastly, we highlight areas that could strengthen the association of failed resolution to AD and should, therefore, be the focus of future scientific investigations in this research field. PMID- 29163533 TI - Chronic NKG2D Engagement In Vivo Differentially Impacts NK Cell Responsiveness by Activating NK Receptors. AB - Immunosuppression is a typical hallmark of cancer and frequently includes perturbations of the NKG2D tumor recognition system as well as impaired signaling by other activating NK cell receptors. Several in vitro studies suggested that sustained engagement of the NKG2D receptor, as it is occurring in the tumor microenvironment, not only impairs expression and function of NKG2D but also impacts signaling by other activating NK receptors. Here, we made use of a transgenic mouse model of ubiquitous NKG2D ligand expression (H2-Kb-MICA mice) to investigate consequences of chronic NKG2D engagement in vivo for functional responsiveness by other activating NK receptors such as NKp46 and Ly49D. Unexpectedly, we found no evidence for an impairment of NKp46 expression and function in H2-Kb-MICA mice, as anticipated from previous in vitro experiments. However, we observed a marked downregulation and dysfunction of the activating receptor Ly49D in activated NK cells from H2-Kb-MICA mice. Ly49D shares the adaptor proteins DAP10 and DAP12 with NKG2D possibly explaining the collateral impairment of Ly49D function in situations of chronic NKG2D engagement. Altogether, our results demonstrate that persistent engagement of NKG2D in vivo, as often observed in tumors, can selectively impair functions of unrelated NK receptors and thereby compromise NK responsiveness to third-party antigens. PMID- 29163535 TI - Chronic Inflammation Increases the Sensitivity of Mouse Treg for TNFR2 Costimulation. AB - TNF receptor type 2 (TNFR2) has gained attention as a costimulatory receptor for T cells and as critical factor for the development of regulatory T cells (Treg) and myeloid suppressor cells. Using the TNFR2-specific agonist TNCscTNF80, direct effects of TNFR2 activation on myeloid cells and T cells were investigated in mice. In vitro, TNCscTNF80 induced T cell proliferation in a costimulatory fashion, and also supported in vitro expansion of Treg cells. In addition, activation of TNFR2 retarded differentiation of bone marrow-derived immature myeloid cells in culture and reduced their suppressor function. In vivo application of TNCscTNF80-induced mild myelopoiesis in naive mice without affecting the immune cell composition. Already a single application expanded Treg cells and improved suppression of CD4 T cells in mice with chronic inflammation. By contrast, multiple applications of the TNFR2 agonist were required to expand Treg cells in naive mice. Improved suppression of T cell proliferation depended on expression of TNFR2 by T cells in mice repeatedly treated with TNCscTNF80, without a major contribution of TNFR2 on myeloid cells. Thus, TNFR2 activation on T cells in naive mice can lead to immune suppression in vivo. These findings support the important role of TNFR2 for Treg cells in immune regulation. PMID- 29163534 TI - Membrane Rafts in T Cell Activation: A Spotlight on CD28 Costimulation. AB - Spatiotemporal compartmentalization of signaling pathways and second messengers is pivotal for cell biology and membrane rafts are, therefore, required for several lymphocyte functions. On the other hand, T cells have the specific necessity of tuning signaling amplification depending on the context in which the antigen is presented. In this review, we discuss of membrane rafts in the context of T cell signaling, focusing on CD28-mediated costimulation. PMID- 29163536 TI - Drug Hypersensitivity and Anaphylaxis in Cancer and Chronic Inflammatory Diseases: The Role of Desensitizations. AB - Drug allergy is a rising problem in the twenty-first century which affects all populations and races, children, and adults, and for which the recognition, diagnosis, management, and treatment is still not well standardized. Classical and new chemotherapy drugs, monoclonal antibodies (MoAbs), and small molecules to treat cancer and chronic inflammatory diseases are aimed at improving quality of life and life expectancy of patients, but an increasing number of reactions including anaphylaxis precludes their use in targeted populations. Women are more affected by drug allergy and up to 27% of women with ovarian and breast cancer develop carboplatin allergy after multiple cycles of treatment. Carriers of BRCA genes develop drug allergy after fewer exposures and can present with severe reactions, including anaphylaxis. Atopic patients are at increased risk for chemotherapy and MoAbs drug allergy and the current patterns of treatment with recurrent and intermittent drug exposures may favor the development of drug allergies. To overcome drug allergy, desensitization has been developed, a novel approach which provides a unique opportunity to protect against anaphylaxis and to improve clinical outcomes. There is evidence that inhibitory mechanisms blocking IgE/antigen mast cell activation are active during desensitization, enhancing safety. Whether desensitization modulates drug allergic and anaphylactic responses facilitating tolerance is currently being investigated. This review provides insight into the current knowledge of drug allergy and anaphylaxis to cancer and chronic inflammatory diseases drugs, the mechanisms of drug desensitization and its applications to personalized medicine. PMID- 29163537 TI - MYCN Amplification Is Associated with Repressed Cellular Immunity in Neuroblastoma: An In Silico Immunological Analysis of TARGET Database. AB - Purpose: RNA and DNA sequencing data are traditionally used to discern intrinsic cellular pathways in cancer pathogenesis, their utility for investigating the tumor microenvironment (TME) has not been fully explored. This study explores the use of sequencing data to investigate immunity within the TME. Experimental design: Here, we use immune cell fraction estimation analysis to determine the immune profiles in the microenvironment of neuroblastoma (NB) based on RNA-seq data in the TARGET database. The correlation between immune cell transcripts and prognosis in pediatric NB is also investigated. Results: In silico analysis revealed a strong inverse correlation between MYCN amplification and leukocyte infiltration. This finding was validated by immunohistochemistry analysis in tumor samples. Moreover, the abundance of CD4 T cells strongly associated with better patient survival regardless of MYCN gene amplification, while those of CD8 T cells, NK or B cells do not. Based on characteristic cytokine expression of CD4 subsets in tumors, the Th2 rather than Th1 levels were associated with better prognosis. Conclusion: We found that the in silico analysis of TARGET database reflected tumor immunity and was validated by the immunohistochemical tumor data. Our results reveal the association of MYCN amplification with repressed cellular immunity and the potential prognostic value of infiltrating CD4 T cell transcripts in pediatric NB. This analysis illustrates the potential role of MYCN in NB as a regulator of immune privilege and characterizes the power of in silico analysis for delineating cancer immunology and risk stratification. PMID- 29163539 TI - HLA Class I or Class II and Disease Association: Catch the Difference If You Can. PMID- 29163538 TI - Efficacy and Safety of a Multistrain Probiotic Formulation Depends from Manufacturing. AB - Background: Variability in probiotics manufacturing may affect their properties, with potential implications for their efficacy and safety. This is of particular concern with probiotic products destined for use in patients with serious medical conditions, including human immunodeficiency virus (HIV) infection. The purpose of the study was to carry out a series of experiments comparing the properties of the US-made probiotic formulation originally commercialized under the brand name VSL#3(r), with those of the Italian-made formulation now commercialized under the same name. The US-made formulation has previously shown beneficial effects at the intestinal and neurological levels in HIV-infected subjects as well as in patients with inflammatory bowel diseases and hepatic encephalopathy. Methods: Eleven subjects receiving combined antiretroviral therapy for HIV-1 were treated for 6 months with the US-made VSL#3 formulation. At baseline and 6 months, T cells were analyzed for phenotype and activation markers, and fecal samples were analyzed for bifidobacteria, lactobacilli, and their metabolites. The fecal metabolome was assessed using 1H-NMR spectroscopy. Production of metabolites of interest by bacteria obtained from sachets of the two formulations was compared in vitro and their effects on a rat intestinal epithelial cell line (IEC-6) were assessed. Particular attention was paid to the metabolite 1,3-dihydroxyacetone (DHA). Results: At 6 months, fecal samples showed a significant increase in the specific bacterial genera contained in the probiotic supplement. Immune activation was reduced as shown by a significant reduction in the percentage of CD4+CD38+HLA-DR+ T-cells at 6 months. Fecal concentrations of DHA decreased significantly. In vitro, significant differences in the production and metabolism of DHA were found between bacteria from the US-made and Italian-made formulations: the US-made formulation was able to metabolize DHA whereas the bacteria in the Italian-made formulation were producing DHA. DHA reduced the viability of Streptococcus thermophilus, reduced IEC-6 cell viability in a dose dependent manner, and also led to a lower rate of repair to scratched IEC-6 cell monolayer. Conclusion: Our data, in conjunction with previously published findings, confirm that the new Italian-made formulation of VSL#3(r) is different from the previous US-made VSL#3 and therefore its efficacy and safety in HIV infected subjects is still unproven. PMID- 29163540 TI - Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer. AB - Local irradiation of cancer through radiotherapy can induce spontaneous regression of non-directly irradiated lesions, suggesting the involvement of systemic antitumor immune responses. In oligometastatic breast cancer (BC) patients, the use of stereotactic body radiotherapy (SBRT) favors the local control of treated lesions and may contribute to break local tolerance and release tumor-associated antigens (TAAs), improving host antitumor immunity. We performed a detailed immunomonitoring of BC patients undergoing SBRT to verify its ability to "switch on" the anti-tumor immunity both systemically, in peripheral blood, and locally, employing in vitro BC models. Twenty-one BC patients with <=6 metastases were treated with 3 daily doses of 10 Gy with SBRT. Blood samples for immune profiling were collected before and after treatment. One month after treatment a third of patients displayed the boosting or even the de novo appearance of polyfunctional CD4+ and CD8+ T cell responses against known BC TAAs (survivin, mammaglobin-A, HER2), through intracellular staining in flow cytometry. Half of patients showed increased numbers of activated natural killer (NK) cells, measured with multispectral flow cytometry, immediately after the first dose of SBRT. Interestingly, high levels of activated NK cells at diagnosis correlated with a longer progression-free survival. BC in vitro models, treated with the same SBRT modality, showed enhanced expression of MHC class-I and class II, major histocompatibility complex class I-related chain A/B, and Fas molecules, and increased release of pro-inflammatory cytokines, such as IL-1beta and TNF-alpha. Consistently, we noticed enhanced production of perforin by CD4+ T cells when patients' lymphocytes were cultured in the presence of irradiated BC cell line, compared to untreated targets. Besides immunogenic effects, SBRT also enhanced the percentages of circulating regulatory T cells, and increased indoleamine 2,3 dioxygenase and PD-L1 expression in BC in vitro models. These results suggest that SBRT may boost host antitumor immune responses also in an advanced disease setting such as oligometastatic BC, by inducing immunomodulating effects both locally and systemically. However, the concomitant induction of immunosuppressive pathways suggests that a combination with immunotherapy could further enhance the in situ vaccination ability of radiotherapy, possibly further improving the curative potential of SBRT in this subset of patients. PMID- 29163541 TI - Nucleotide-Binding Oligomerization Domain 2 Contributes to Limiting Growth of Mycobacterium abscessus in the Lung of Mice by Regulating Cytokines and Nitric Oxide Production. AB - Mycobacterium abscessus is a prominent cause of pulmonary infection in immunosuppressed patients and those with cystic fibrosis. Nucleotide-binding oligomerization domain (NOD) 2 is a cytosolic receptor which senses a bacterial peptidoglycan component, muramyl dipeptide (MDP). Although nucleotide-binding oligomerization domain 2 (NOD2) contributes to protect host against various microbial infections, it is still unclear whether NOD2 is essential to regulate host immune responses against M. abscessus infection. In this study, we sought to clarify the role of NOD2 and the underlying mechanism in host defense against M. abscessus infection. Mice were infected intranasally with M. abscessus and sacrificed at indicated time points. Bacterial survival, cytokines production, and pathology in the lungs were determined. Bone marrow-derived macrophages were used to clarify cellular mechanism of NOD2-mediated immune response. Bacterial clearance was impaired, and pathology was more severe in the lungs of NOD2 deficient mice compared with the wild-type mice. In macrophages, NOD2-mediated activation of p38 and JNK were required for production of proinflammatory cytokines and nitric oxide (NO) and expression of iNOS in response to M. abscessus. NO was critical for limiting intracellular growth of the pathogen. Intranasal administration of MDP reduced in vivo bacterial replication and thus improved lung pathology in M. abscessus-infected mice. This study offers important new insights into the potential roles of the NOD2 in initiating and potentiating innate immune response against M. abscessus pulmonary infection. PMID- 29163542 TI - Effects of Food Additives on Immune Cells As Contributors to Body Weight Gain and Immune-Mediated Metabolic Dysregulation. AB - Food additives are compounds used in order to improve food palatability, texture, and shelf life. Despite a significant effort to assure safety of use, toxicological analysis of these substances, generally, rely on their direct toxicity to target organs (liver and kidney) or their genotoxic effects. Much less attention is paid to the effects of these compounds on cells of the immune system. This is of relevance given that metabolic dysregulation and obesity have a strong immune-mediated component. Obese individuals present a state of chronic low-grade inflammation that contributes to the establishment of insulin resistance and other metabolic abnormalities known as the metabolic syndrome. Obesity and metabolic syndrome are currently recognized as worldwide epidemics that pose a profound socioeconomic impact and represent a concern to public health. Cells of the immune system contribute to both the maintenance of "lean homeostasis" and the metabolic dysregulation observed in obese individuals. Although much attention has been drawn in the past decades to obesity and metabolic syndrome as a result of ingesting highly processed food containing large amounts of fat and simple sugars, mounting evidence suggest that food additives may also be important contributors to metabolic derangement. Herein, we review pieces of evidence from the literature showing that food additives have relevant effects on cells of the immune system that could contribute to immune mediated metabolic dysregulation. Considering their potential to predispose individuals to develop obesity and metabolic syndrome, their use should be taken with caution or maybe revisited. PMID- 29163543 TI - Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells. AB - Background: Epithelial ovarian cancer (EOC) remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs) in ascites are correlated with tumor progression and reduced survival. Malignant ascites harbors high levels of Tregs expressing the tumor necrosis factor receptor 2 (TNFR2), as well as pro-inflammatory factors such as interleukin 6 (IL-6) and tumor necrosis factor (TNF). IL-6 is also associated with poor prognosis. Herein, we study the effect of IL-6 and TNF present in ascites on the modulation of TNFR2 expression on T cells, and specifically Tregs. Methods: Ascites and respective peripheral blood sera were collected from 18 patients with advanced EOC and soluble biomarkers, including IL-6, sTNFR2, IL-10, TGF-beta, and TNF, were quantified using multiplexed bead-based immunoassay. Peripheral blood mononuclear cells (PBMC) from healthy donors were incubated with cell-free ascites for 48 h (or media as a negative control). In some experiments, IL-6 or TNF within the ascites were neutralized by using monoclonal antibodies. The phenotype of TNFR2+ Tregs and TNFR2- Tregs were characterized post incubation in ascites. In some experiments, cell sorted Tregs were utilized instead of PBMC. Results: High levels of immunosuppressive (sTNFR2, IL-10, and TGF-beta) and pro inflammatory cytokines (IL-6 and TNF) were present in malignant ascites. TNFR2 expression on all T cell subsets was higher in post culture in ascites and highest on CD4+CD25hiFoxP3+ Tregs, resulting in an increased TNFR2+ Treg/effector T cell ratio. Furthermore, TNFR2+ Tregs conditioned in ascites expressed higher levels of the functional immunosuppressive molecules programmed cell death ligand 1, CTLA-4, and GARP. Functionally, TNFR2+ Treg frequency was inversely correlated with interferon-gamma (IFN-gamma) production by effector T cells, and was uniquely able to suppress TNFR2+ T effectors. Blockade of IL-6, but not TNF, within ascites decreased TNFR2+ Treg frequency. Results indicating malignant ascites promotes TNFR2 expression, and increased suppressive Treg activity using PBMC were confirmed using purified Treg subsets. Conclusion: IL-6 present in malignant ovarian cancer ascites promotes increased TNFR2 expression and frequency of highly suppressive Tregs. PMID- 29163546 TI - Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications. AB - G6PC3 deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phenotypes that are typical for a systemic autoinflammatory syndrome. The index case presented with combination of unexplained fevers, severe mucosal ulcers, abdominal symptoms, and inflammatory arthritis. He eventually fully responded to anti-TNF therapy. In this study, we show that compared with healthy controls, neutrophils and monocytes from patients have reduced glycolytic reserve. Considering that healthy myeloid cells have been shown to switch their metabolic pathways to glycolysis in response to inflammatory cues, we studied what impact this might have on production of the inflammatory cytokines. We have demonstrated that patients' monocytes, in response to lipopolysaccharide, show significantly increased production of IL-1beta and IL-18, which is NLRP3 inflammasome dependent. Furthermore, additional whole blood assays have also shown an enhanced production of IL-6 and TNF from the patients' cells. These cases provide further proof that autoinflammatory complications are also seen within the spectrum of primary immune deficiencies, and resulting from a wider dysregulation of the immune responses. PMID- 29163544 TI - Macrophage Autophagy and Bacterial Infections. AB - Autophagy is a well-conserved lysosomal degradation pathway that plays key roles in bacterial infections. One of the most studied is probably xenophagy, the selective capture and degradation of intracellular bacteria by lysosomes. However, the impact of autophagy goes beyond xenophagy and involves intensive cross-talks with other host defense mechanisms. In addition, autophagy machinery can have non-canonical functions such as LC3-associated phagocytosis. In this review, we intend to summarize the current knowledge on the many functions of autophagy proteins in cell defenses with a focus on bacteria-macrophage interaction. We also present the strategies developed by pathogens to evade or to exploit this machinery in order to establish a successful infection. Finally, we discuss the opportunities and challenges of autophagy manipulation in improving therapeutics and vaccines against bacterial pathogens. PMID- 29163545 TI - CD40L Expression Allows CD8+ T Cells to Promote Their Own Expansion and Differentiation through Dendritic Cells. AB - CD8+ T cells play an important role in providing protective immunity against a wide range of pathogens, and a number of different factors control their activation. Although CD40L-mediated CD40 licensing of dendritic cells (DCs) by CD4+ T cells is known to be necessary for the generation of a robust CD8+ T cell response, the contribution of CD8+ T cell-expressed CD40L on DC licensing is less clear. We have previously shown that CD8+ T cells are able to induce the production of IL-12 p70 by DCs in a CD40L-dependent manner, providing some evidence that CD8+ T cell-mediated activation of DCs is possible. To better understand the role of CD40L on CD8+ T cell responses, we generated and characterized CD40L-expressing CD8+ T cells both in vitro and in vivo. We found that CD40L was expressed on 30-50% of effector CD8+ T cells when stimulated and that this expression was transient. The expression of CD40L on CD8+ T cells promoted the proliferation and differentiation of both the CD40L-expressing CD8+ T cells and the bystander effector CD8+ T cells. This process occurred via a cell extrinsic manner and was mediated by DCs. These data demonstrate the existence of a mechanism where CD8+ T cells and DCs cooperate to maximize CD8+ T cell responses. PMID- 29163547 TI - Natural Killer Cells from the Subcutaneous Adipose Tissue Underexpress the NKp30 and NKp44 in Obese Persons and Are Less Active against Major Histocompatibility Complex Class I Non-Expressing Neoplastic Cells. AB - There are many types of leukocytes reside in subcutaneous adipose tissue (SAT), and among them, natural killer cells (NKs) comprise a major part. We show that the NKs that reside in the SAT (adipose tissue-derived NK cells; ADNKs) of the abdominal region found with phenotypic differences from the NKs circulating in the peripheral blood derived NK cells (PBNKs). In this survey, flow cytometry phenotyping was used to study the differences between the natural cytotoxicity receptor expression on ADNKs and PBNKs of both obese and lean persons. Also, their cytotoxicity and cytokine production patterns were evaluated. The activation experiments on isolated and expanded NKs with IL-2, IL-15, and IL-21 cytokines revealed the main population of the CD56dim within the total ADNKs of obese persons has an under-expression of NKp30 and NKp44 despite the unchanged levels of NKG2D. The data suggest the suppressive condition of the adipose tissue niche on the NKs response against sensitive major histocompatibility complex class I non-expressing neoplastic cells. As the NKs are the first line of the body's defense vs tumor formation, this change may lead to the development of transformed cells into the tumors. PMID- 29163548 TI - Emodin Alleviates Sodium Taurocholate-Induced Pancreatic Acinar Cell Injury via MicroRNA-30a-5p-Mediated Inhibition of High-Temperature Requirement A/Transforming Growth Factor Beta 1 Inflammatory Signaling. AB - Pancreatitis is an inflammatory disease that is responsible for substantial morbidity and mortality, and it can induce pancreatic necrosis that starts within pancreatic acinar cells in severe cases. Emodin, a pleiotropic natural product isolated from the Chinese herb Rheum palmatum L., has effective anti-inflammatory activities. In this paper, we investigated the protective effects and molecular mechanism of emodin against sodium taurocholate (STC)-induced pancreatic acinar cells injury in vitro and in vivo; and the results showed that emodin could significantly alleviate STC-induced pancreatic acinar cells injury through decreasing trypsin, amylase and the release of inflammatory factors (tumor necrosis factor alpha, interleukin-1beta, and interleukin-6). Also, we found that emodin could significantly downregulate the HTRA1, interleukin-33, myeloid differentiation primary response gene 88, TNF receptor-associated factor-6, and nuclear factor kappa-B protein levels, but upregulate the transforming growth factor beta 1 (TGF-beta1) protein level. These results indicated that emodin alleviated pancreatic acinar cells injury mainly through inhibiting HTRA1/TGF beta1 signaling pathway, and this finding was further proved by the HTRA1 overexpression experiments. In addition, the inflammatory regulator microRNA-30a 5p (miR-30a-5p) was confirmed to be a transcriptional brake that controls the HTRA1 gene through using a dual luciferase reporter assay, and it was upregulated by emodin in pancreatic acinar cells. Furthermore, the pancreatic protective effects and anti-inflammatory activities of emodin were all abrogated with both miR-30a-5p inhibitor in vitro and miR-30a-5p antagomir in vivo. Collectively, these results demonstrate that miR-30a-5p/HTRA1 are the target of emodin-mediated attenuation of pancreatic acinar cell injury in pancreatitis, thus providing the foundation for further development of this natural product for medical therapy. PMID- 29163549 TI - Commentary: Cytokine-Regulation of Na+-K+-Cl- Cotransporter 1 and Cystic Fibrosis Transmembrane Conductance Regulator-Potential Role in Pulmonary Inflammation and Edema Formation. PMID- 29163550 TI - Evaluation of Alpha-1 Antitrypsin Levels and SERPINA1 Gene Polymorphisms in Sickle Cell Disease. AB - Alpha-1 antitrypsin (AAT) is an inhibitor of neutrophil elastase and a member of the serine proteinase inhibitor (serpin) superfamily, and little is known about its activity in sickle cell disease (SCD). We hypothesize that AAT may undergo changes in SCD because of the high oxidative stress and inflammation associated with the disease. We have found high AAT levels in SCD patients compared to controls, while mutant genotypes of SERPINA1 gene had decreased AAT levels, in both groups. AAT showed negative correlation with red blood cells, hemoglobin (Hb), hematocrit, high-density lipoprotein cholesterol, urea, creatinine, and albumin and was positively correlated with mean corpuscular Hb concentration, white blood cells, neutrophils, Hb S, bilirubin, lactate dehydrogenase, ferritin, and C-reactive protein. Patients with higher levels of AAT had more infection episodes (OR = 1.71, CI: 1.05-2.65, p = 0.02), gallstones (OR = 1.75, CI: 1.03 2.97, p = 0.02), and had more blood transfusions (OR = 2.35, CI: 1.51-3.65, p = 0.0001). Our data on AAT association with laboratory indices of hemolysis and inflammation suggest that it may be positively associated with SCD severity; the negative correlations with renal parameters suggest a cytoprotective mechanism in SCD patients. In summary, AAT may need to be included in studies related to SCD and in the discussion of further therapeutic strategies. PMID- 29163553 TI - PPARgamma Deficiency Counteracts Thymic Senescence. AB - Thymic senescence contributes to increased incidence of infection, cancer and autoimmunity at senior ages. This process manifests as adipose involution. As with other adipose tissues, thymic adipose involution is also controlled by PPARgamma. This is supported by observations reporting that systemic PPARgamma activation accelerates thymic adipose involution. Therefore, we hypothesized that decreased PPARgamma activity could prevent thymic adipose involution, although it may trigger metabolic adverse effects. We have confirmed that both human and murine thymic sections show marked staining for PPARgamma at senior ages. We have also tested the thymic lobes of PPARgamma haplo-insufficient and null mice. Supporting our working hypothesis both adult PPARgamma haplo-insufficient and null mice show delayed thymic senescence by thymus histology, thymocyte mouse T cell recombination excision circle qPCR and peripheral blood naive T-cell ratio by flow-cytometry. Delayed senescence showed dose-response with respect to PPARgamma deficiency. Functional immune parameters were also evaluated at senior ages in PPARgamma haplo-insufficient mice (null mice do not reach senior ages due to metabolic adverse affects). As expected, sustained and elevated T-cell production conferred oral tolerance and enhanced vaccination efficiency in senior PPARgamma haplo-insufficient, but not in senior wild-type littermates according to ELISA IgG measurements. Of note, humans also show increased oral intolerance issues and decreased protection by vaccines at senior ages. Moreover, PPARgamma haplo-insufficiency also exists in human known as a rare disease (FPLD3) causing metabolic adverse effects, similar to the mouse. When compared to age- and metabolic disorder-matched other patient samples (FPLD2 not affecting PPARgamma activity), FPLD3 patients showed increased human Trec (hTrec) values by qPCR (within healthy human range) suggesting delayed thymic senescence, in accordance with mouse results and supporting our working hypothesis. In summary, our experiments prove that systemic decrease of PPARgamma activity prevents thymic senescence, albeit with metabolic drawbacks. However, thymic tissue-specific PPARgamma antagonism would likely solve the issue. PMID- 29163551 TI - Host Antimicrobial Peptides: The Promise of New Treatment Strategies against Tuberculosis. AB - Tuberculosis (TB) continues to be a devastating infectious disease and remerges as a global health emergency due to an alarming rise of antimicrobial resistance to its treatment. Despite of the serious effort that has been applied to develop effective antitubercular chemotherapies, the potential of antimicrobial peptides (AMPs) remains underexploited. A large amount of literature is now accessible on the AMP mechanisms of action against a diversity of pathogens; nevertheless, research on their activity on mycobacteria is still scarce. In particular, there is an urgent need to integrate all available interdisciplinary strategies to eradicate extensively drug-resistant Mycobacterium tuberculosis strains. In this context, we should not underestimate our endogenous antimicrobial proteins and peptides as ancient players of the human host defense system. We are confident that novel antibiotics based on human AMPs displaying a rapid and multifaceted mechanism, with reduced toxicity, should significantly contribute to reverse the tide of antimycobacterial drug resistance. In this review, we have provided an up to date perspective of the current research on AMPs to be applied in the fight against TB. A better understanding on the mechanisms of action of human endogenous peptides should ensure the basis for the best guided design of novel antitubercular chemotherapeutics. PMID- 29163552 TI - T Follicular Helper Cells As a New Target for Immunosuppressive Therapies. AB - Over the past decade, antibody-mediated (humoral) rejection has been recognized as a common cause of graft dysfunction after organ transplantation and an important determinant for graft loss. In humoral alloimmunity, T follicular helper (Tfh) cells play a crucial role, because they help naive B cells to differentiate into memory B cells and alloantibody-producing plasma cells within germinal centers. In this way, they contribute to the induction of donor-specific antibodies, which are responsible for the humoral immune response to the allograft. In this article, we provide an overview of the current knowledge on the effects of immunosuppressive therapies on Tfh cell development and function, and discuss possible new approaches to influence the activity of Tfh cells. In addition, we discuss the potential use of Tfh cells as a pharmacodynamic biomarker to improve alloimmune-risk stratification and tailoring of immunosuppression to individualize therapy after transplantation. PMID- 29163554 TI - Isoliquiritigenin Activates Nuclear Factor Erythroid-2 Related Factor 2 to Suppress the NOD-Like Receptor Protein 3 Inflammasome and Inhibits the NF-kappaB Pathway in Macrophages and in Acute Lung Injury. AB - Among the cellular response mechanisms, the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway is considered a survival pathway that alleviates oxidative injury, while both the NOD-like receptor protein 3 (NLRP3) and NF kappaB pathways are pro-inflammatory pathways that cause damage to cells. These pathways are implicated in the development and resolution of acute lung injury (ALI). Isoliquiritigenin (ISL), a flavonoid from the liquorice compound, is suggested to be a regulator of the above pathways, but the mechanisms of how the NLRP3/NF-kappaB pathway interacts with Nrf2 and its protective effects in ALI remain unknown. In the present study, ISL inhibited reactive oxygen species (ROS) generation and cytotoxicity induced by t-BHP and pro-inflammatory enzymes production induced by LPS in RAW 264.7 cells. Such cytoprotective effects coincided with the induction of AMP-activated protein kinase (AMPK)/Nrf2/antioxidant response element (ARE) signaling and the suppression of the NLRP3 and NF-kappaB pathways. Consistent with these findings, ISL treatment significantly alleviated lung injury in LPS-induced ALI mice, which was reflected by reductions in histopathological changes, pulmonary edema, and protein leakage. At the same time, the increased levels of inflammatory cell exudation and pro inflammatory mediators, the enhanced production of ROS, myeloperoxidase, and malondialdehyde, and the depleted expression of GSH and superoxide dismutase induced by LPS were ameliorated by ISL. Furthermore, ISL notably activated AMPK/Nrf2/ARE signaling and inhibited LPS-induced NLRP3 and NF-kappaB activation in the lung. Moreover, although inhibition of the LPS-induced histopathological changes and ROS production were attenuated in Nrf2-deficient mice, the repression of the NLRP3 and NF-kappaB pathways by ISL was Nrf2-dependent and Nrf2 independent, respectively. In conclusion, our results are the first to highlight the beneficial role and relevant mechanisms of ISL in LPS-induced ALI and provide novel insight into its application. PMID- 29163555 TI - TTT and PIKK Complex Genes Reverted to Single Copy Following Polyploidization and Retain Function Despite Massive Retrotransposition in Maize. AB - The TEL2, TTI1, and TTI2 proteins are co-chaperones for heat shock protein 90 (HSP90) to regulate the protein folding and maturation of phosphatidylinositol 3 kinase-related kinases (PIKKs). Referred to as the TTT complex, the genes that encode them are highly conserved from man to maize. TTT complex and PIKK genes exist mostly as single copy genes in organisms where they have been characterized. Members of this interacting protein network in maize were identified and synteny analyses were performed to study their evolution. Similar to other species, there is only one copy of each of these genes in maize which was due to a loss of the duplicated copy created by ancient allotetraploidy. Moreover, the retained copies of the TTT complex and the PIKK genes tolerated extensive retrotransposon insertion in their introns that resulted in increased gene lengths and gene body methylation, without apparent effect in normal gene expression and function. The results raise an interesting question on whether the reversion to single copy was due to selection against deleterious unbalanced gene duplications between members of the complex as predicted by the gene balance hypothesis, or due to neutral loss of extra copies. Uneven alteration of dosage either by adding extra copies or modulating gene expression of complex members is being proposed as a means to investigate whether the data supports the gene balance hypothesis or not. PMID- 29163556 TI - Identification of MsHsp20 Gene Family in Malus sieversii and Functional Characterization of MsHsp16.9 in Heat Tolerance. AB - Heat shock proteins (Hsps) are common molecular chaperones present in all plants that accumulate in response to abiotic stress. Small heat shock proteins (sHsps) play important roles in alleviating diverse abiotic stresses, especially heat stress. However, very little is known about the MsHsp20 gene family in the wild apple Malus sieversii, a precious germplasm resource with excellent resistance characteristics. In this study, 12 putative M. sieversii Hsp20 genes were identified from RNA-Seq data and analyzed in terms of gene structure and phylogenetic relationships. A new Hsp20 gene, MsHsp16.9, was cloned and its function studied in response to stress. MsHsp16.9 expression was strongly induced by heat, and transgenic Arabidopsis plants overexpressing MsHsp16.9 displayed improved heat resistance, enhanced antioxidant enzyme activity, and decreased peroxide content. Overexpression of MsHsp16.9 did not alter the growth or development under normal conditions, or the hypersensitivity to exogenous ABA. Gene expression analysis indicated that MsHsp16.9 mainly modulates the expression of proteins involved in antioxidant enzyme synthesis, as well as ABA-independent stress signaling in 35S:MsHsp16.9-L11. However, MsHsp16.9 could activate ABA dependent signaling pathways in all transgenic plants. Additionally, MsHsp16.9 may function alongside AtHsp70 to maintain protein homeostasis and protect against cell damage. Our results suggest that MsHsp16.9 is a protein chaperone that positively regulates antioxidant enzyme activity and ABA-dependent and independent signaling pathway to attenuate plant responses to severe stress. Transgenic plants exhibited luxuriant growth in high temperature environments. PMID- 29163557 TI - History of Tree Growth Declines Recorded in Old Trees at Two Sacred Sites in Northern China. AB - Old forests are an important component in sacred sites, yet they are at risk of growth decline from ongoing global warming and increased human activities. Growth decline, characterized by chronic loss of tree vigor, is not a recent phenomenon. Knowledge of past occurrence of declines is useful for preparing conservation plans because it helps understand if present day forests are outside the natural range of variation in tree health. We report a dendroecological study of growth decline events in the past two centuries at two sacred sites, Hengshan and Wutaishan, in Shanxi province of northern China. Tree rings collected at both sites show distinct periods of declining growth evident as narrow rings. These occurred in the 1830s in both sites, in the 1920s in Wutaishan and in the 2000s in Hengshan. By comparing the pattern of grow declines at the two sites, we hypothesize that resistance of tree growth to external disturbances is forest size dependent, and increased human activity might be a factor additional to climatic droughts in causing the recent strong growth decline at Hengshan Park. Despite these past declines, the forests at both sites have high resilience to disturbances as evidenced by the ability of trees to recover their growth rates to levels comparable to the pre-decline period. Managers should consider reducing fragmentation and restoring natural habitat of old forests, especially in areas on dry sites. PMID- 29163559 TI - Genome-Wide Association Study of Calcium Accumulation in Grains of European Wheat Cultivars. AB - Mineral concentrations in cereals are important for human health, especially for people who depend mainly on consuming cereal diet. In this study, we carried out a genome-wide association study (GWAS) of calcium concentrations in wheat (Triticum aestivum L.) grains using a European wheat diversity panel of 353 varieties [339 winter wheat (WW) plus 14 of spring wheat (SW)] and phenotypic data based on two field seasons. High genotyping densities of single-nucleotide polymorphism (SNP) markers were obtained from the application of the 90k iSELECT ILLUMINA chip and a 35k Affymetrix chip. Inductively coupled plasma optical emission spectrometry (ICP-OES) was used to measure the calcium concentrations of the wheat grains. Best linear unbiased estimates (BLUEs) for calcium were calculated across the seasons and ranged from 288.20 to 647.50 among the varieties (MUg g-1 DW) with a mean equaling 438.102 (MUg g-1 DW), and the heritability was 0.73. A total of 485 SNP marker-trait associations (MTAs) were detected in data obtained from grains cultivated in both of the two seasons and BLUE values by considering associations with a -log10 (P-value) >=3.0. Among these SNP markers, we detected 276 markers with a positive allele effect and 209 markers with a negative allele effect. These MTAs were found on all chromosomes except chromosomes 3D, 4B, and 4D. The most significant association was located on chromosome 5A (114.5 cM) and was linked to a gene encoding cation/sugar symporter activity as a potential candidate gene. Additionally, a number of candidate genes for the uptake or transport of calcium were located near significantly associated SNPs. This analysis highlights a number of genomic regions and candidate genes for further analysis as well as the challenges faced when mapping environmentally variable traits in genetically highly diverse variety panels. The research demonstrates the feasibility of the GWAS approach for illuminating the genetic architecture of calcium-concentration in wheat grains and for identifying putative candidate genes underlying this trait. PMID- 29163560 TI - Conservation and Dispersion of Genes Conferring Resistance to Tomato Begomoviruses between Tomato and Pepper Genomes. AB - In the present climate change scenario, controlling plant disease through exploitation of host plant resistance could contribute toward the sustainable crop production and global food security. In this respect, the identification of new sources of resistance and utilization of genetic diversity within the species may help in the generation of cultivars with improved disease resistance. Begomoviruses namely, Tomato yellow leaf curl virus (TYLCV) and Chilli leaf curl virus (ChLCV) are known to cause major yield losses in several economically important crop plants of the family Solanaceae. Though co-occurrence, association and synergistic interactions among these viruses in the host plants is reported, whether orthologous genetic loci in related host plants could be responsible for conferring resistance to these viruses has not been investigated yet. Several loci including Ty1, Ty2, Ty3, Ty4, and ty5 have been reported to confer resistance to leaf curl viruses in tomato. Here, we examined the pepper orthologous markers, corresponding to these QTL regions, for polymorphism between ChLCV susceptible and resistant genotypes of pepper. Further, to examine if the polymorphic markers are segregating with the disease resistance, Bulk Segregant Analysis (BSA) was performed on F2 population derived from crosses between resistant and susceptible lines. However, none of the markers showed polymorphism in BSA suggesting that the tested markers are not linked to genes/QTLs responsible for conferring resistance to ChLCV in the selected genotypes. In silico analysis was performed to study the synteny and collinearity of genes located within these QTL regions in tomato and pepper genomes, which revealed that more than 60% genes located in Ty2 and Ty4, 13.71% genes in Ty1, 23.07% in Ty3, and 44.77% genes located within ty5 QTL region in tomato are conserved in pepper genome. However, despite such a high conservation in gene content, the linkage relationship in these regions seems to be greatly affected by gross rearrangements in both the species. PMID- 29163558 TI - Current Status and Challenges in Identifying Disease Resistance Genes in Brassica napus. AB - Brassica napus is an economically important crop across different continents including temperate and subtropical regions in Europe, Canada, South Asia, China and Australia. Its widespread cultivation also brings setbacks as it plays host to fungal, oomycete and chytrid pathogens that can lead to serious yield loss. For sustainable crop production, identification of resistance (R) genes in B. napus has become of critical importance. In this review, we discuss four key pathogens affecting Brassica crops: Clubroot (Plasmodiophora brassicae), Blackleg (Leptosphaeria maculans and L. biglobosa), Sclerotinia Stem Rot (Sclerotinia sclerotiorum), and Downy Mildew (Hyaloperonospora parasitica). We first review current studies covering prevalence of these pathogens on Brassica crops and highlight the R genes and QTL that have been identified from Brassica species against these pathogens. Insights into the relationships between the pathogen and its Brassica host, the unique host resistance mechanisms and how these affect resistance outcomes is also presented. We discuss challenges in identification and deployment of R genes in B. napus in relation to highly specific genetic interactions between host subpopulations and pathogen pathotypes and emphasize the need for common or shared techniques and research materials or tighter collaboration between researchers to reconcile the inconsistencies in the research outcomes. Using current genomics tools, we provide examples of how characterization and cloning of R genes in B. napus can be carried out more effectively. Lastly, we put forward strategies to breed resistant cultivars through introgressions supported by genomic approaches and suggest prospects that can be implemented in the future for a better, pathogen-resistant B. napus. PMID- 29163561 TI - Expression of Separate Proteins in the Same Plant Leaves and Cells Using Two Independent Virus-Based Gene Vectors. AB - Plant viral vectors enable the expression of proteins at high levels in a relatively short time. For many purposes (e.g., cell biological interaction studies) it may be desirable to express more than one protein in a single cell but that is often not feasible when using a single virus vector. Such a co expression strategy requires the simultaneous delivery by two compatible and non competitive viruses that can co-exist to each express a separate protein. Here, we report on the use of two agro-launchable coat-protein gene substitution GFP expressing virus vector systems based on Tomato bushy stunt virus (TBSV) referred to as TG, and Tobacco mosaic virus (TMV) annotated as TRBO-G. TG expressed GFP in Nicotiana benthamiana, tomato, lettuce and cowpea, whereas expression from TRBO-G was detected only in the first two species. Upon co-infiltration of the two vectors co-expression was monitored by: molecular detection of the two slightly differently sized GFPs, suppressor-complementation assays, and using TG in combination with TRBO-RFP. All the results revealed that in N. benthamiana and tomato the TBSV and TMV vectors accumulated and expressed proteins in the same plants, the same leaves, and in the same cells. Therefore, co-expression by these two vectors provides a platform for fast and high level expression of proteins to study their cell biology or other properties. PMID- 29163563 TI - Genetic Dissection of the Major Quantitative Trait Locus (qSE11), and Its Validation As the Major Influence on the Rate of Stigma Exsertion in Rice (Oryza sativa L.). AB - The rate of stigma exsertion (SE) is an important trait in rice breeding because the efficiency of hybrid rice seed production can be improved by increasing the percentage of stigmas that exsert. In this study, we developed a near isogenic line (NIL) from two parents, XieqingzaoB (XQZB) and Zhonghoi9308 (ZH9308), which have high and low SE rates in that order. In our previous study, we employed 75 chromosome segment substitution lines (CSSLs) and analyzed quantitative trait loci (QTLs) for their influence on SE rate. The single gene QTL (qSE11), which is located on chromosome 11, was responsible for this trait. In this study, we focused on one of the CSSLs (C65), namely, the NIL (qSE11XB). It contains an introgression segment of XQZB in the genetic background of ZH9308, and exhibits a significantly higher SE rate than that of the parents. We demonstrated that qSE11 regulated both the single and the dual SE rates. They both contribute to the total SE rate. Genetic analysis revealed that qSE11 acted as a single Mendelian factor and that the allele from XQZB increased the SE rate. The validity of our conclusions was established when C65 was used to develop secondary F2 (BC5F2) and F2:3 (BC5F2:3) populations by backcrossing to ZH9308, with subsequent selfing. We entered 3600 plants from the F2 population and 3200 from the F2:3 populations into a genetic dissection program and dissected the major QTL qSE11 to a 350.7-kb region located on chromosome 11. This study will contribute to the future isolation of candidate genes of SE and will play a vital role in future hybrid rice seed production programs. PMID- 29163562 TI - Combined Field Inoculations of Pseudomonas Bacteria, Arbuscular Mycorrhizal Fungi, and Entomopathogenic Nematodes and their Effects on Wheat Performance. AB - In agricultural ecosystems, pest insects, pathogens, and reduced soil fertility pose major challenges to crop productivity and are responsible for significant yield losses worldwide. Management of belowground pests and diseases remains particularly challenging due to the complex nature of the soil and the limited reach of conventional agrochemicals. Boosting the presence of beneficial rhizosphere organisms is a potentially sustainable alternative and may help to optimize crop health and productivity. Field application of single beneficial soil organisms has shown satisfactory results under optimal conditions. This might be further enhanced by combining multiple beneficial soil organisms, but this remains poorly investigated. Here, we inoculated wheat plots with combinations of three beneficial soil organisms that have different rhizosphere functions and studied their effects on crop performance. Plant beneficial Pseudomonas bacteria, arbuscular mycorrhizal fungi (AMF), and entomopathogenic nematodes (EPN), were inoculated individually or in combinations at seeding, and their effects on plant performance were evaluated throughout the season. We used traditional and molecular identification tools to monitor their persistence over the cropping season in augmented and control treatments, and to estimate the possible displacement of native populations. In three separate trials, beneficial soil organisms were successfully introduced into the native populations and readily survived the field conditions. Various Pseudomonas, mycorrhiza, and nematode treatments improved plant health and productivity, while their combinations provided no significant additive or synergistic benefits compared to when applied alone. EPN application temporarily displaced some of the native EPN, but had no significant long-term effect on the associated food web. The strongest positive effect on wheat survival was observed for Pseudomonas and AMF during a season with heavy natural infestation by the frit fly, Oscinella frit, a major pest of cereals. Hence, beneficial impacts differed between the beneficial soil organisms and were most evident for plants under biotic stress. Overall, our findings indicate that in wheat production under the test conditions the three beneficial soil organisms can establish nicely and are compatible, but their combined application provides no additional benefits. Further studies are required, also in other cropping systems, to fine-tune the functional interactions among beneficial soil organisms, crops, and the environment. PMID- 29163564 TI - Non-replicative Integral Membrane Proteins Encoded by Plant Alpha-Like Viruses: Emergence of Diverse Orphan ORFs and Movement Protein Genes. AB - Fast accumulation of sequencing data on plant virus genomes and plant transcriptomes demands periodic re-evaluation of current views on the genome evolution of viruses. Here, we substantiate and further detail our previously mostly speculative model on the origin and evolution of triple gene block (TGB) encoding plant virus movement proteins TGB1, TGB2, and TGB3. Recent experimental data on functional competence of transport gene modules consisting of two proteins related to TGB1 and TGB2, as well as sequence analysis data on similarity of TGB2 and TGB3 encoded by a viral genome and virus-like RNAs identified in a plant transcriptomes, suggest that TGB evolution involved events of gene duplication and gene transfer between viruses. In addition, our analysis identified that plant RNA-seq data assembled into RNA virus-like contigs encode a significant variety of hydrophobic proteins. Functions of these orphan proteins are still obscure; however, some of them are obviously related to hydrophobic virion proteins of recently sequenced invertebrate (mostly insect) viruses, therefore supporting the current view on a common origin for many groups of plant and insect RNA-containing viruses. Moreover, these findings may suggest that the function of at least some orphan hydrophobic proteins is to provide plant viruses with the ability to infect insect hosts. In general, our observations emphasize that comparison of RNA virus sequences in a large variety of land plants and algae isolated geographically and ecologically may lead to experimental confirmation of previously purely speculative schemes of evolution of single genes, gene modules, and whole genomes. PMID- 29163565 TI - Genotypic Variation in Nitrogen Utilization Efficiency of Oilseed Rape (Brassica napus) Under Contrasting N Supply in Pot and Field Experiments. AB - Oilseed rape (Brassica napus) characteristically has high N uptake efficiency and low N utilization efficiency (NUtE, seed yield/shoot N accumulation). Determining the NUtE phenotype of various genotypes in different growth conditions is a way of finding target traits to improve oilseed rape NUtE. The aim of this study was to compare oilseed rape genotypes grown on contrasting N supply rates in pot and field experiments to investigate the genotypic variations of NUtE and to identify indicators of N efficient genotypes. For 50 oilseed rape genotypes, NUtE, dry matter and N partitioning, morphological characteristics, and the yield components were investigated under high and low N supplies in a greenhouse pot experiment and a field trial. Although the genotype rankings of NUtE were different between the pot experiment and the field trial, some genotypes performed consistently in both two environments. N-responder, N-nonresponder, N efficient and N-inefficient genotypes were identified from these genotypes with consistent NUtE. The correlations between the pot experiment and the field trial in NUtE were only 0.34 at high N supplies and no significant correlations were found at low N supplies. However, Pearson coefficient correlation (r) and principal component analysis showed NUtE had similar genetic correlations with other traits across the pot and field experiment. Among the yield components, only seeds per silique showed strong and positive correlations with NUtE under varying N supply in both experiments (r = 0.47**; 0.49**; 0.47**; 0.54**). At high and low N supply, NUtE was positively correlated with seed yield (r = 0.45**; 0.53**; 0.39**; 0.87**), nitrogen harvest index (NHI, r = 0.68**; 0.82**; 0.99**; 0.89**), and harvest index (HI, r = 0.79**; 0.83**; 0.90**; 0.78**) and negatively correlated with biomass distribution to stem and leaf (r = -0.34**; 0.45**; -0.37**; 0.62**), all aboveground plant section N concentration (r from 0.30* to -0.80**), N distribution to the vegetative parts (silique husk, stem and leaf) (r from -0.40** to -0.83**). N-efficient (N-responder) genotypes produced more seeds per silique and had significantly higher NHI and HI than did N inefficient (N-nonresponder) genotypes. In conclusion, across the pot and field experiments, the 50 genotypes had similar underlying traits correlated with NUtE and seeds per silique may be a good indicator of NUtE. PMID- 29163566 TI - Cultivar Diversity of Grape Skin Polyphenol Composition and Changes in Response to Drought Investigated by LC-MS Based Metabolomics. AB - Phenolic compounds represent a large family of plant secondary metabolites, essential for the quality of grape and wine and playing a major role in plant defense against biotic and abiotic stresses. Phenolic composition is genetically driven and greatly affected by environmental factors, including water stress. A major challenge for breeding of grapevine cultivars adapted to climate change and with high potential for wine-making is to dissect the complex plant metabolic response involved in adaptation mechanisms. A targeted metabolomics approach based on ultra high-performance liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-QqQ-MS) analysis in the Multiple Reaction Monitoring (MRM) mode has been developed for high throughput profiling of the phenolic composition of grape skins. This method enables rapid, selective, and sensitive quantification of 96 phenolic compounds (anthocyanins, phenolic acids, stilbenoids, flavonols, dihydroflavonols, flavan-3-ol monomers, and oligomers...), and of the constitutive units of proanthocyanidins (i.e., condensed tannins), giving access to detailed polyphenol composition. It was applied on the skins of mature grape berries from a core-collection of 279 Vitis vinifera cultivars grown with or without watering to assess the genetic variation for polyphenol composition and its modulation by irrigation, in two successive vintages (2014-2015). Distribution of berry weights and delta13C values showed that non irrigated vines were subjected to a marked water stress in 2014 and to a very limited one in 2015. Metabolomics analysis of the polyphenol composition and chemometrics analysis of this data demonstrated an influence of water stress on the biosynthesis of different polyphenol classes and cultivar differences in metabolic response to water deficit. Correlation networks gave insight on the relationships between the different polyphenol metabolites and related biosynthetic pathways. They also established patterns of polyphenol response to drought, with different molecular families affected either positively or negatively in the different cultivars, with potential impact on grape and wine quality. PMID- 29163567 TI - Soil Type Has a Stronger Role than Dipterocarp Host Species in Shaping the Ectomycorrhizal Fungal Community in a Bornean Lowland Tropical Rain Forest. AB - The role that mycorrhizal fungal associations play in the assembly of long-lived tree communities is poorly understood, especially in tropical forests, which have the highest tree diversity of any ecosystem. The lowland tropical rain forests of Southeast Asia are characterized by high levels of species richness within the family Dipterocarpaceae, the entirety of which has been shown to form obligate ectomycorrhizal (ECM) fungal associations. Differences in ECM assembly between co occurring species of dipterocarp have been suggested, but never tested in adult trees, as a mechanism for maintaining the coexistence of closely related tree species in this family. Testing this hypothesis has proven difficult because the assembly of both dipterocarps and their ECM associates co-varies with the same edaphic variables. In this study, we used high-throughput DNA sequencing of soils and Sanger sequencing of root tips to evaluate how ECM fungi were structured within and across a clay-sand soil nutrient ecotone in a mixed-dipterocarp rain forest in Malaysian Borneo. We compared assembly patterns of ECM fungi in bulk soil to ECM root tips collected from three ecologically distinct species of dipterocarp. This design allowed us to test whether ECM fungi are more strongly structured by soil type or host specificity. As with previous studies of ECM fungi on this plot, we observed that clay vs. sand soil type strongly structured both the bulk soil and root tip ECM fungal communities. However, we also observed significantly different ECM communities associated with two of the three dipterocarp species evaluated on this plot. These results suggest that ECM fungal assembly on these species is shaped by a combination of biotic and abiotic factors, and that the soil edaphic niche occupied by different dipterocarp species may be mediated by distinct ECM fungal assemblages. PMID- 29163568 TI - Canopy Chlorophyll Density Based Index for Estimating Nitrogen Status and Predicting Grain Yield in Rice. AB - Canopy chlorophyll density (Chl) has a pivotal role in diagnosing crop growth and nutrition status. The purpose of this study was to develop Chl based models for estimating N status and predicting grain yield of rice (Oryza sativa L.) with Leaf area index (LAI) and Chlorophyll concentration of the upper leaves. Six field experiments were conducted in Jiangsu Province of East China during 2007, 2008, 2009, 2013, and 2014. Different N rates were applied to generate contrasting conditions of N availability in six Japonica cultivars (9915, 27123, Wuxiangjing 14, Wuyunjing 19, Yongyou 8, and Wuyunjing 24) and two Indica cultivars (Liangyoupei 9, YLiangyou 1). The SPAD values of the four uppermost leaves and LAI were measured from tillering to flowering growth stages. Two N indicators, leaf N accumulation (LNA) and plant N accumulation (PNA) were measured. The LAI estimated by LAI-2000 and LI-3050C were compared and calibrated with a conversion equation. A linear regression analysis showed significant relationships between Chl value and N indicators, the equations were as follows: PNA = (0.092 * Chl) - 1.179 (R2 = 0.94, P < 0.001, relative root mean square error (RRMSE) = 0.196), LNA = (0.052 * Chl) - 0.269 (R2 = 0.93, P < 0.001, RRMSE = 0.185). Standardized method was used to quantity the correlation between Chl value and grain yield, normalized yield = (0.601 * normalized Chl) + 0.400 (R2 = 0.81, P < 0.001, RRMSE = 0.078). Independent experimental data also validated the use of Chl value to accurately estimate rice N status and predict grain yield. PMID- 29163569 TI - Olive Cultivation in the Southern Hemisphere: Flowering, Water Requirements and Oil Quality Responses to New Crop Environments. AB - Olive (Olea europaea L.) is a crop well adapted to the environmental conditions prevailing in the Mediterranean Basin. Nevertheless, the increasing international demand for olive oil and table olives in the last two decades has led to expansion of olive cultivation in some countries of the southern hemisphere, notably in Argentina, Chile, Peru and Australia. While the percentage of world production represented by these countries is still low, many of the new production regions do not have typical Mediterranean climates, and some are located at subtropical latitudes where there is relatively little information about crop function. Thus, the primary objective of this review was to assess recently published scientific literature on olive cultivation in these new crop environments. The review focuses on three main aspects: (a) chilling requirements for flowering, (b) water requirements and irrigation management, and (c) environmental effects on fruit oil concentration and quality. In many arid and semiarid regions of South America, temperatures are high and rainfall is low in the winter and early spring months compared to conditions in much of the Mediterranean Basin. High temperatures have often been found to have detrimental effects on olive flowering in many olive cultivars that have been introduced to South America, and a better understanding of chilling requirements is needed. Lack of rainfall in the winter and spring also has resulted in an urgent need to evaluate water requirements from the flower differentiation period in the winter to early fruit bearing. Additionally, in some olive growing areas of South America and Australia, high early season temperatures affect the timing of phenological events such that the onset of oil synthesis occurs sooner than in the Mediterranean Basin with most oil accumulation taking place in the summer when temperatures are very high. Increasing mean daily temperatures have been demonstrated to decrease fruit oil concentration (%) and negatively affect some aspects of oil quality based on both correlative field studies and manipulative experiments. From a practical standpoint, current findings could be used as approximate tools to determine whether the temperature conditions in a proposed new growing region are appropriate for achieving sustainable oil productivity and quality. PMID- 29163570 TI - Metabolic Pathway Assignment of Plant Genes based on Phylogenetic Profiling-A Feasibility Study. AB - Despite many developed experimental and computational approaches, functional gene annotation remains challenging. With the rapidly growing number of sequenced genomes, the concept of phylogenetic profiling, which predicts functional links between genes that share a common co-occurrence pattern across different genomes, has gained renewed attention as it promises to annotate gene functions based on presence/absence calls alone. We applied phylogenetic profiling to the problem of metabolic pathway assignments of plant genes with a particular focus on secondary metabolism pathways. We determined phylogenetic profiles for 40,960 metabolic pathway enzyme genes with assigned EC numbers from 24 plant species based on sequence and pathway annotation data from KEGG and Ensembl Plants. For gene sequence family assignments, needed to determine the presence or absence of particular gene functions in the given plant species, we included data of all 39 species available at the Ensembl Plants database and established gene families based on pairwise sequence identities and annotation information. Aside from performing profiling comparisons, we used machine learning approaches to predict pathway associations from phylogenetic profiles alone. Selected metabolic pathways were indeed found to be composed of gene families of greater than expected phylogenetic profile similarity. This was particularly evident for primary metabolism pathways, whereas for secondary pathways, both the available annotation in different species as well as the abstraction of functional association via distinct pathways proved limiting. While phylogenetic profile similarity was generally not found to correlate with gene co-expression, direct physical interactions of proteins were reflected by a significantly increased profile similarity suggesting an application of phylogenetic profiling methods as a filtering step in the identification of protein-protein interactions. This feasibility study highlights the potential and challenges associated with phylogenetic profiling methods for the detection of functional relationships between genes as well as the need to enlarge the set of plant genes with proven secondary metabolism involvement as well as the limitations of distinct pathways as abstractions of relationships between genes. PMID- 29163572 TI - Root and Rhizosphere Bacterial Phosphatase Activity Varies with Tree Species and Soil Phosphorus Availability in Puerto Rico Tropical Forest. AB - Tropical forests generally occur on highly weathered soils that, in combination with the immobility of phosphorus (P), often result in soils lacking orthophosphate, the form of P most easily metabolized by plants and microbes. In these soils, mineralization of organic P can be the major source for orthophosphate. Both plants and microbes encode for phosphatases capable of mineralizing a range of organic P compounds. However, the activity of these enzymes depends on several edaphic factors including P availability, tree species, and microbial communities. Thus, phosphatase activity in both roots and the root microbial community constitute an important role in P mineralization and P nutrient dynamics that are not well studied in tropical forests. To relate phosphatase activity of roots and bacteria in tropical forests, we measured phosphatase activity in roots and bacterial isolates as well as bacterial community composition from the rhizosphere. Three forests in the Luquillo Mountains of Puerto Rico were selected to represent a range of soil P availability as measured using the resin P method. Within each site, a minimum of three tree species were chosen to sample. Root and bacterial phosphatase activity were both measured using a colorimetric assay with para-nitrophenyl phosphate as a substrate for the phosphomonoesterase enzyme. Both root and bacterial phosphatase were chiefly influenced by tree species. Though tree species was the only significant factor in root phosphatase activity, there was a negative trend between soil P availability and phosphatase activity in linear regressions of average root phosphatase and resin P. Permutational multivariate analysis of variance of bacterial community composition based on 16S amplicon sequencing indicated that bacterial composition was strongly controlled by soil P availability (p-value < 0.05). These results indicate that although root and bacterial phosphatase activity were influenced by tree species; bacterial community composition was chiefly influenced by P availability. Although the sample size is limited given the tremendous diversity of tropical forests, our study indicates the importance of roots and bacterial function to understanding phosphatase activity. Future work will broaden the diversity of tree species and microbial members sampled to provide insight into P mineralization and model representation of tropical forests. PMID- 29163571 TI - Setting Up Shop: The Formation and Function of the Viral Factories of Cauliflower mosaic virus. AB - Similar to cells, viruses often compartmentalize specific functions such as genome replication or particle assembly. Viral compartments may contain host organelle membranes or they may be mainly composed of viral proteins. These compartments are often termed: inclusion bodies (IBs), viroplasms or viral factories. The same virus may form more than one type of IB, each with different functions, as illustrated by the plant pararetrovirus, Cauliflower mosaic virus (CaMV). CaMV forms two distinct types of IBs in infected plant cells, those composed mainly of the viral proteins P2 (which are responsible for transmission of CaMV by insect vectors) and P6 (required for viral intra-and inter-cellular infection), respectively. P6 IBs are the major focus of this review. Much of our understanding of the formation and function of P6 IBs comes from the analyses of their major protein component, P6. Over time, the interactions and functions of P6 have been gradually elucidated. Coupled with new technologies, such as fluorescence microscopy with fluorophore-tagged viral proteins, these data complement earlier work and provide a clearer picture of P6 IB formation. As the activities and interactions of the viral proteins have gradually been determined, the functions of P6 IBs have become clearer. This review integrates the current state of knowledge on the formation and function of P6 IBs to produce a coherent model for the activities mediated by these sophisticated virus-manufacturing machines. PMID- 29163574 TI - Invader Competition with Local Competitors: Displacement or Coexistence among the Invasive Khapra Beetle, Trogoderma granarium Everts (Coleoptera: Dermestidae), and Two Other Major Stored-Grain Beetles? AB - Local potential competitor species are important determinants of the invasibility of an environment even when widely recognized invasive species are concerned since it may compromise its establishment. Thus, the outcome of the direct competition among the invasive khapra beetle, Trogoderma granarium, and the cosmopolitan species lesser grain borer, Rhyzopertha dominica and rice weevil, Sitophilus oryzae, and thus the likelihood of establishment of T. granarium under their co-occurrence, was here explored in paddy rice and wheat, at temperatures between 25 and 35 degrees C and through 200 days of storage. Insect infestations were higher in wheat rather than in paddy rice. Trogoderma granarium was unable to displace any of the competing species under two and three-species competition experiments retaining lower adult population than both local competitors at the lowest temperature level. Rhyzopertha dominica prevailed in paddy rice, while S. oryzae prevailed in wheat. Paradoxically, T. granarium adults retained low population growth but contributed more for the total frass production and grain loss, much more than that recorded for R. dominica. Nonetheless, T. granarium larvae exhibited high population numbers 130 days after the introduction of the parental individuals. At higher temperature levels (30 and 35 degrees C) the numbers of T. granarium larvae were extremely high even after 65 days, while the numbers of the other two species rapidly declined. Interestingly, the simultaneous presence of R. dominica and S. oryzae was beneficial for the population growth of T. granarium. Consequently, T. granarium has the ability to outperform other primary stored-product insects at high temperatures, while its presence at low temperatures remains for long periods apparently unaffected by other co-occurring species. Hence, T. granarium, in wheat, is able to outcompete other major species of stored-product insects at elevated temperatures, while at 25 degrees C this species can maintain low numbers of individuals for long periods, which can rapidly produce population outbursts when the prevailing conditions are suitable for its development. PMID- 29163573 TI - Mitochondrial Uncoupling Protein 1 Overexpression Increases Yield in Nicotiana tabacum under Drought Stress by Improving Source and Sink Metabolism. AB - Mitochondrial uncoupling proteins (UCPs) sustain mitochondrial respiration independent of intracellular ATP concentration. Uncoupled respiration is particularly beneficial under stress conditions, during which both photosynthesis and respiration may be impaired. Sustaining carbon fixation during the reproductive phase is essential for plants to develop viable pollen grains and for seed setting. Here, we examined whether UCP1 overexpression (UCP1-oe) would help tobacco plants cope with drought stress during reproductive development. We observed that WT and UCP1-oe plants lost water at the same rate under moderate drought stress, but that UCP1-oe lines regained water faster upon rewatering. UCP1-oe plants maintained higher levels of respiration and photosynthesis and decreased H2O2 content in the leaves during the drought stress period. We examined whether UCP1-oe impacts reproductive tissues and seed production by monitoring the progress of flower development, focusing on the early stages of pollen formation. UCP1-oe lines induced the expression of mitochondrial genes and increased mtDNA content in reproductive tissues, which increased the consumption of carbohydrates and reduced H2O2 content and pollen disturbances. Finally, the beneficial impact of UCP1-oe on the source and sink organs resulted in an increased seed size and number under both control conditions and drought stress. PMID- 29163576 TI - Quantitative Trait Loci and Maternal Effects Affecting the Strong Grain Dormancy of Wild Barley (Hordeum vulgare ssp. spontaneum). AB - Wild barley (Hordeum vulgare ssp. spontaneum) has strong grain dormancy, a trait that may enhance its survival in non-cultivated environments; by contrast, cultivated barley (Hordeum vulgare ssp. vulgare) has weaker dormancy, allowing uniform germination in cultivation. Malting barley cultivars have been bred for especially weak dormancy to optimize their use in malt production. Here, we analyzed the genetic mechanism of this difference in seed dormancy, using recombinant inbred lines (RILs) derived from a cross between the wild barley accession 'H602' and the malting barley cultivar 'Kanto Nakate Gold (KNG)'. Grains of H602 and KNG harvested at physiological maturity and dried at 30 degrees C for 7 days had germination of approximately 0 and 100%, respectively. Analysis of quantitative trait loci (QTL) affecting grain dormancy identified the well-known major dormancy QTL SD1 and SD2 (located near the centromeric region and at the distal end of the long arm of chromosome 5H, respectively), and QTL at the end of the long arm of chromosome 4H and in the middle of the long arm of chromosome 5H. We designated these four QTL Qsd1-OK, Qsd2-OK, Qsdw-4H, and Qsdw 5H, and they explained approximately 6, 38, 3, and 13% of the total phenotypic variation, respectively. RILs carrying H602 alleles showed increased dormancy levels for all QTL. The QTL acted additively and did not show epistasis or QTL environment interactions. Comparison of QTL locations indicated that all QTL except Qsdw-5H are likely the same as the QTL previously detected in the doubled haploid population from a cross between the malting cultivar 'Haruna Nijo' and 'H602.' We further examined Qsd2-OK and Qsdw-5H by analyzing the segregation of phenotypes and genotypes of F2 progenies derived from crosses between RILs carrying specific segments of chromosome 5H from H602 in the KNG background. This analysis confirmed that the two genomic regions corresponding to these QTL are involved in the regulation of grain dormancy. Germination tests of F1 grains derived from reciprocal crosses between H602 and KNG revealed that the H602 strong dormancy phenotype shows maternal inheritance with incomplete dominance. These results provide new insight into the mechanisms regulating grain dormancy in barley. PMID- 29163575 TI - Quantitative Resistance to Plant Pathogens in Pyramiding Strategies for Durable Crop Protection. AB - Quantitative resistance has gained interest in plant breeding for pathogen control in low-input cropping systems. Although quantitative resistance frequently has only a partial effect and is difficult to select, it is considered more durable than major resistance (R) genes. With the exponential development of molecular markers over the past 20 years, resistance QTL have been more accurately detected and better integrated into breeding strategies for resistant varieties with increased potential for durability. This review summarizes current knowledge on the genetic inheritance, molecular basis, and durability of quantitative resistance. Based on this knowledge, we discuss how strategies that combine major R genes and QTL in crops can maintain the effectiveness of plant resistance to pathogens. Combining resistance QTL with complementary modes of action appears to be an interesting strategy for breeding effective and potentially durable resistance. Combining quantitative resistance with major R genes has proven to be a valuable approach for extending the effectiveness of major genes. In the plant genomics era, improved tools and methods are becoming available to better integrate quantitative resistance into breeding strategies. Nevertheless, optimal combinations of resistance loci will still have to be identified to preserve resistance effectiveness over time for durable crop protection. PMID- 29163577 TI - Combination of the Endogenous lhcsr1 Promoter and Codon Usage Optimization Boosts Protein Expression in the Moss Physcomitrella patens. AB - The moss Physcomitrella patens is used both as an evo-devo model and biotechnological production system for metabolites and pharmaceuticals. Strong in vivo expression of genes of interest is important for production of recombinant proteins, e.g., selectable markers, fluorescent proteins, or enzymes. In this regard, the choice of the promoter sequence as well as codon usage optimization are two important inside factors to consider in order to obtain optimum protein accumulation level. To reliably quantify fluorescence, we transfected protoplasts with promoter:GFP fusion constructs and measured fluorescence intensity of living protoplasts in a plate reader system. We used the red fluorescent protein mCherry under 2x 35S promoter control as second reporter to normalize for different transfection efficiencies. We derived a novel endogenous promoter and compared deletion variants with exogenous promoters. We used different codon-adapted green fluorescent protein (GFP) genes to evaluate the influence of promoter choice and codon optimization on protein accumulation in P. patens, and show that the promoter of the gene of P. patens chlorophyll a/b binding protein lhcsr1 drives expression of GFP in protoplasts significantly (more than twofold) better than the commonly used 2x 35S promoter or the rice actin1 promoter. We identified a shortened 677 bp version of the lhcsr1 promoter that retains full activity in protoplasts. The codon optimized GFP yields significantly (more than twofold) stronger fluorescence signals and thus demonstrates that adjusting codon usage in P. patens can increase expression strength. In combination, new promotor and codon optimized GFP conveyed sixfold increased fluorescence signal. PMID- 29163578 TI - Transpiration Response and Growth in Pearl Millet Parental Lines and Hybrids Bred for Contrasting Rainfall Environments. AB - Under conditions of high vapor pressure deficit (VPD) and soil drying, restricting transpiration is an important avenue to gain efficiency in water use. The question we raise in this article is whether breeding for agro-ecological environments that differ for the rainfall have selected for traits that control plant water use. These are measured in pearl millet materials bred for zones varying in rainfall (8 combinations of parent and F1-hybrids, 18 F1-hybrids and then 40 F1-hybrids). In all cases, we found an agro-ecological variation in the slope of the transpiration response to increasing VPD, and parental line variation in the transpiration response to soil drying within hybrids/parent combinations. The hybrids adapted to lower rainfall had higher transpiration response curves than those from the highest rainfall zones, but showed no variation in how transpiration responded to soil drying. The genotypes bred for lower rainfall zones showed lower leaf area, dry matter, thicker leaves, root development, and exudation, than the ones bred for high rainfall zone when grown in the low VPD environment of the greenhouse, but there was no difference in their root length neither on the root/shoot index in these genotypes. By contrast, when grown under high VPD conditions outdoors, the lower rainfall hybrids had the highest leaf, tiller, and biomass development. Finally, under soil drying the genotypes from the lower rainfall accumulated less biomass than the ones from higher rainfall zone, and so did the parental lines compared to the hybrids. These differences in the transpiration response and growth clearly showed that breeding for different agro-ecological zones also bred for different genotype strategies in relation to traits related to plant water use. Highlights: * Variation in transpiration response reflected breeding for agro-ecological zones * Different growth strategies depended on the environmental conditions * Different ideotypes reflected rainfall levels in specific agro-ecological zones. PMID- 29163579 TI - Arabidopsis Phosphatidic Acid Phosphohydrolases Are Essential for Growth under Nitrogen-Depleted Conditions. AB - The Arabidopsis homologs of mammalian lipin, PAH1 and PAH2, are cytosolic phosphatidic acid phosphohydrolases that are involved in phospholipid biosynthesis and are essential for growth under phosphate starvation. Here, pah1 pah2 double-knockout mutants were found to be hypersensitive to nitrogen (N) starvation, whereas transgenic plants overexpressing PAH1 or PAH2 in the pah1 pah2 mutant background showed a similar growth phenotype as compared with wild type (WT) under N starvation. The chlorophyll content of pah1 pah2 was significantly lower than that of WT, whereas the chlorophyll content and photosynthetic activity of the transgenic plants were significantly higher than those of WT under N-depleted conditions. Membrane glycerolipid composition of the pah1 pah2 mutants showed a significant decrease in the mole percent of chloroplast lipids to other phospholipids, whereas membrane lipid composition did not differ between transgenic plants and WT plants. Pulse-chase labeling experiments using plants grown under N-depleted conditions showed that, in pah1 pah2 plants, the labeling percent of chloroplast lipids such as phosphatidylglycerol and monogalactosyldiacylglycerol in the total glycerolipids was significantly lower than in WT. Moreover, N starvation-induced degradation of chloroplast structure was enhanced in pah1 pah2 mutants, and the membrane structure was recovered by complementation with PAH1. Thus, PAH is involved in maintaining chloroplast membrane structure and is required for growth under N depleted conditions. PMID- 29163580 TI - Testing of Auxotrophic Selection Markers for Use in the Moss Physcomitrella Provides New Insights into the Mechanisms of Targeted Recombination. AB - The moss Physcomitrella patens is unique among plants in that homologous recombination can be used to knock out genes, just like in yeast. Furthermore, transformed plasmids can be rescued from Physcomitrella back into Escherichia coli, similar to yeast. In the present study, we have tested if a third important tool from yeast molecular genetics, auxotrophic selection markers, can be used in Physcomitrella. Two auxotrophic moss strains were made by knocking out the PpHIS3 gene encoding imidazoleglycerol-phosphate dehydratase, and the PpTRP1 gene encoding phosphoribosylanthranilate isomerase, disrupting the biosynthesis of histidine and tryptophan, respectively. The resulting PpHIS3Delta and PpTRP1Delta knockout strains were unable to grow on medium lacking histidine or tryptophan. The PpHIS3Delta strain was used to test selection of transformants by complementation of an auxotrophic marker. We found that the PpHIS3Delta strain could be complemented by transformation with a plasmid expressing the PpHIS3 gene from the CaMV 35S promoter, allowing the strain to grow on medium lacking histidine. Both linearized plasmids and circular supercoiled plasmids could complement the auxotrophic marker, and plasmids from both types of transformants could be rescued back into E. coli. Plasmids rescued from circular transformants were identical to the original plasmid, whereas plasmids rescued from linearized transformants had deletions generated by recombination between micro-homologies in the plasmids. Our results show that cloning by complementation of an auxotrophic marker works in Physcomitrella, which opens the door for using auxotrophic selection markers in moss molecular genetics. This will facilitate the adaptation of shuttle plasmid dependent methods from yeast molecular genetics for use in Physcomitrella. PMID- 29163581 TI - Identification of Substitutions and Small Insertion-Deletions Induced by Carbon Ion Beam Irradiation in Arabidopsis thaliana. AB - Heavy-ion beam irradiation is one of the principal methods used to create mutants in plants. Research on mutagenic effects and molecular mechanisms of radiation is an important subject that is multi-disciplinary. Here, we re-sequenced 11 mutagenesis progeny (M3) Arabidopsis thaliana lines derived from carbon-ion beam (CIB) irradiation, and subsequently focused on substitutions and small insertion deletion (INDELs). We found that CIB induced more substitutions (320) than INDELs (124). Meanwhile, the single base INDELs were more prevalent than those in large size (>=2 bp). In details, the detected substitutions showed an obvious bias of C > T transitions, by activating the formation of covalent linkages between neighboring pyrimidine residues in the DNA sequence. An A and T bias was observed among the single base INDELs, in which most of these were induced by replication slippage at either the homopolymer or polynucleotide repeat regions. The mutation rate of 200-Gy CIB irradiation was estimated as 3.37 * 10-7 per site. Different from previous researches which mainly focused on the phenotype, chromosome aberration, genetic polymorphism, or sequencing analysis of specific genes only, our study revealed genome-wide molecular profile and rate of mutations induced by CIB irradiation. We hope our data could provide valuable clues for explaining the potential mechanism of plant mutation breeding by CIB irradiation. PMID- 29163582 TI - Deep Learning for Image-Based Cassava Disease Detection. AB - Cassava is the third largest source of carbohydrates for human food in the world but is vulnerable to virus diseases, which threaten to destabilize food security in sub-Saharan Africa. Novel methods of cassava disease detection are needed to support improved control which will prevent this crisis. Image recognition offers both a cost effective and scalable technology for disease detection. New deep learning models offer an avenue for this technology to be easily deployed on mobile devices. Using a dataset of cassava disease images taken in the field in Tanzania, we applied transfer learning to train a deep convolutional neural network to identify three diseases and two types of pest damage (or lack thereof). The best trained model accuracies were 98% for brown leaf spot (BLS), 96% for red mite damage (RMD), 95% for green mite damage (GMD), 98% for cassava brown streak disease (CBSD), and 96% for cassava mosaic disease (CMD). The best model achieved an overall accuracy of 93% for data not used in the training process. Our results show that the transfer learning approach for image recognition of field images offers a fast, affordable, and easily deployable strategy for digital plant disease detection. PMID- 29163583 TI - Mathematical Modeling and Optimizing of in Vitro Hormonal Combination for G * N15 Vegetative Rootstock Proliferation Using Artificial Neural Network-Genetic Algorithm (ANN-GA). AB - The efficiency of a hybrid systems method which combined artificial neural networks (ANNs) as a modeling tool and genetic algorithms (GAs) as an optimizing method for input variables used in ANN modeling was assessed. Hence, as a new technique, it was applied for the prediction and optimization of the plant hormones concentrations and combinations for in vitro proliferation of Garnem (G * N15) rootstock as a case study. Optimizing hormones combination was surveyed by modeling the effects of various concentrations of cytokinin-auxin, i.e., BAP, KIN, TDZ, IBA, and NAA combinations (inputs) on four growth parameters (outputs), i.e., micro-shoots number per explant, length of micro-shoots, developed callus weight (CW) and the quality index (QI) of plantlets. Calculation of statistical values such as R2 (coefficient of determination) related to the accuracy of ANN GA models showed a considerably higher prediction accuracy for ANN models, i.e., micro-shoots number: R2 = 0.81, length of micro-shoots: R2 = 0.87, CW: R2 = 0.88, QI: R2 = 0.87. According to the results, among the input variables, BAP (19.3), KIN (9.64), and IBA (2.63) showed the highest values of variable sensitivity ratio for proliferation rate. The GA showed that media containing 1.02 mg/l BAP in combination with 0.098 mg/l IBA could lead to the optimal proliferation rate (10.53) for G * N15 rootstock. Another objective of the present study was to compare the performance of predicted and optimized cytokinin-auxin combination with the best optimized obtained concentrations of our other experiments. Considering three growth parameters (length of micro-shoots, micro-shoots number, and proliferation rate), the last treatment was found to be superior to the rest of treatments for G * N15 rootstock in vitro multiplication. Very little difference between the ANN predicted and experimental data confirmed high capability of ANN-GA method in predicting new optimized protocols for plant in vitro propagation. PMID- 29163584 TI - Spatiotemporal Expression and Substrate Specificity Analysis of the Cucumber SWEET Gene Family. AB - The functions of SWEET (Sugar Will Eventually be Exported Transporter) proteins have been studied in a number of crops, but little is known about their roles in cucumber (Cucumis sativus L.), a model plant for studying stachyose metabolism and phloem function. Here, we identified 17 cucumber SWEET genes (CsSWEETs), located on chromosomes 1-6, and classified them into four clades. Two genes from each clade were selected for spatiotemporal expression, subcellular localization, and substrate specificity analyses. Clade I and II proteins were all hexose transporters and targeted to the plasma membrane, while clade III proteins also localized to the plasma membrane, but used sucrose as a substrate. Clade IV SWEET proteins were localized to the tonoplast, and used hexose as a substrate. The eight tested CsSWEET genes were most highly expressed in flower, which represents a large sink in plants. However, each gene also showed specific expression patterns: three of the eight tested genes were highly expressed in mature leaves, two in roots, two in fruit, two in stems, and one was detected in all tested organs. The likely biological roles of each are discussed based on the above results. PMID- 29163585 TI - The Arabidopsis Cysteine-Rich Receptor-Like Kinase CRK36 Regulates Immunity through Interaction with the Cytoplasmic Kinase BIK1. AB - Receptor-like kinases are important signaling components that regulate a variety of cellular processes. In this study, an Arabidopsis cDNA microarray analysis led to the identification of the cysteine-rich receptor-like kinase CRK36 responsive to the necrotrophic fungal pathogen, Alternaria brassicicola. To determine the function of CRK36 in plant immunity, T-DNA-insertion knockdown (crk36) and overexpressing (CRK36OE) plants were prepared. CRK36OE plants exhibited increased hypersensitive cell death and ROS burst in response to avirulent pathogens. Treatment with a typical pathogen-associated molecular pattern, flg22, markedly induced pattern-triggered immune responses, notably stomatal defense, in CRK36OE plants. The immune responses were weakened in crk36 plants. Protein-protein interaction assays revealed the in vivo association of CRK36, FLS2, and BIK1. CRK36 enhanced flg22-triggered BIK1 phosphorylation, which showed defects with Cys mutations in the DUF26 motifs of CRK36. Disruption of BIK1 and RbohD/RbohF genes further impaired CRK36-mediated stomatal defense. We propose that CRK36, together with BIK1 and NADPH oxidases, may form a positive activation loop that enhances ROS burst and leads to the promotion of stomatal immunity. PMID- 29163586 TI - Photosynthetic Entrainment of the Circadian Clock Facilitates Plant Growth under Environmental Fluctuations: Perspectives from an Integrated Model of Phase Oscillator and Phloem Transportation. AB - Plants need to avoid carbon starvation and resultant growth inhibition under fluctuating light environments to ensure optimal growth and reproduction. As diel patterns of carbon metabolism are influenced by the circadian clock, appropriate regulation of the clock is essential for plants to properly manage their carbon resources. For proper adjustment of the circadian phase, higher plants utilize environmental signals such as light or temperature and metabolic signals such as photosynthetic products; the importance of the latter as phase regulators has been recently elucidated. A mutant of Arabidopsis thaliana that is deficient in phase response to sugar has been shown, under fluctuating light conditions, to be unable to adjust starch turnover and to realize carbon homeostasis. Whereas, the effects of light entrainment on growth and survival of higher plants are well studied, the impact of phase regulation by sugar remains unknown. Here we show that endogenous sugar entrainment facilitates plant growth. We integrated two mathematical models, one describing the dynamics of carbon metabolism in A. thaliana source leaves and the other growth of sink tissues dependent on sucrose translocation from the source. The integrated model predicted that sugar sensitive plants grow faster than sugar-insensitive plants under constant as well as changing photoperiod conditions. We found that sugar entrainment enables efficient carbon investment for growth by stabilizing sucrose supply to sink tissues. Our results highlight the importance of clock entrainment by both exogenous and endogenous signals for optimizing growth and increasing fitness. PMID- 29163587 TI - Global DNA Methylation Patterns Can Play a Role in Defining Terroir in Grapevine (Vitis vinifera cv. Shiraz). AB - Understanding how grapevines perceive and adapt to different environments will provide us with an insight into how to better manage crop quality. Mounting evidence suggests that epigenetic mechanisms are a key interface between the environment and the genotype that ultimately affect the plant's phenotype. Moreover, it is now widely accepted that epigenetic mechanisms are a source of useful variability during crop varietal selection that could affect crop performance. While the contribution of DNA methylation to plant performance has been extensively studied in other major crops, very little work has been done in grapevine. To study the genetic and epigenetic diversity across 22 vineyards planted with the cultivar Shiraz in six wine sub-regions of the Barossa, South Australia. Methylation sensitive amplified polymorphisms (MSAPs) were used to obtain global patterns of DNA methylation. The observed epigenetic profiles showed a high level of differentiation that grouped vineyards by their area of provenance despite the low genetic differentiation between vineyards and sub regions. Pairwise epigenetic distances between vineyards indicate that the main contributor (23-24%) to the detected variability is associated to the distribution of the vineyards on the N-S axis. Analysis of the methylation profiles of vineyards pruned with the same system increased the positive correlation observed between geographic distance and epigenetic distance suggesting that pruning system affects inter-vineyard epigenetic differentiation. Finally, methylation sensitive genotyping by sequencing identified 3,598 differentially methylated genes in grapevine leaves that were assigned to 1,144 unique gene ontology terms of which 8.6% were associated with response to environmental stimulus. Our results suggest that DNA methylation differences between vineyards and sub-regions within The Barossa are influenced both by the geographic location and, to a lesser extent, by pruning system. Finally, we discuss how epigenetic variability can be used as a tool to understand and potentially modulate terroir in grapevine. PMID- 29163589 TI - Changes in Rice Grain Quality of Indica and Japonica Type Varieties Released in China from 2000 to 2014. AB - China is the first country to use heterosis successfully for commercial rice production. This study compared the main quality characteristics (head rice rate, chalky rice rate, chalkiness degree, gel consistency, amylose content, and length to-width ratio) of 635 rice varieties (not including upland and glutinous rice) released from 2000 to 2014 to establish the quality status and offer suggestions for future rice breeding for grain quality in China. In the past 15 years, grain quality in japonica rice and indica hybrid rice has improved. In japonica rice, inbred varieties have increased head rice rates and decreased chalkiness degree over time, while hybrid rice varieties have decreased chalky rice rates and chalkiness degree. In indica hybrid rice, the chalkiness degree and amylose contents have decreased and gel consistency has increased. Improvements in grain quality in indica inbred rice have been limited, with some increases in head rice rate and decreases in chalky rice rate and amylose content. From 2010 to 2014, the percentage of indica varieties meeting the Grade III national standard of rice quality for different quality traits was low, especially for chalky rice rate and chalkiness degree. Japonica varieties have more superior grain quality than indica rice in terms of higher head rice rates and gel consistency, lower chalky rice rates and chalkiness degree, and lower amylose contents, which may explain why the Chinese prefer japonica rice. The japonica rice varieties, both hybrid and inbred, had similar grain qualities, but this varied in indica rice with the hybrid varieties having higher grain quality than inbred varieties due to significantly better head rice rates and lower chalkiness degree. For better quality rice in future, the chalky rice rate and chalkiness degree should be improved in japonica rice along with most of the quality traits in indica rice. PMID- 29163588 TI - Genome-Wide Analysis of japonica Rice Performance under Limited Water and Permanent Flooding Conditions. AB - A rice GWAS panel of 281 accessions of japonica rice was phenotypically characterized for 26 traits related to phenology, plant and seed morphology, physiology and yield for 2 years in field conditions under permanent flooding (PF) and limited water (LW). A genome-wide analysis uncovered a total of 160 significant marker-trait associations (MTAs), of which 32 were LW-specific, 59 were PF-specific, and 69 were in common between the two water management systems. LW-specific associations were identified for several agronomic traits including days to maturation, days from flowering to maturation, leaf traits, plant height, panicle and seed traits, hundred grain weight, yield and tillering. Significant MTAs were detected across all the 12 rice chromosomes, while clusters of effects influencing different traits under LW or in both watering conditions were, respectively, observed on chromosomes 4, 8, and 12 and on chromosomes 1, 3, 4, 5, and 8. The analysis of genes annotated in the Nipponbare reference sequence and included in the regions associated to traits related to plant morphology, grain yield, and physiological parameters allowed the identification of genes that were demonstrated to affect the respective traits. Among these, three (OsOFP2, Dlf1, OsMADS56) and seven (SUI1, Sd1, OsCOL4, Nal1, OsphyB, GW5, Ehd1) candidate genes were, respectively, identified to co-localize with LW-specific associations and associations in common between the two water treatments. For several LW-specific MTAs, or in common among the two treatments, positional co-localizations with previously identified QTLs for rice adaptation to water shortages were observed, a result that further supports the role of the loci identified in this work in conferring adaptation to LW. The most robust associations identified here could represent suitable targets for genomic selection approaches to improve yield related traits under LW. PMID- 29163590 TI - Multiple Copies of a Simple MYB-Binding Site Confers Trans-regulation by Specific Flavonoid-Related R2R3 MYBs in Diverse Species. AB - In apple, the MYB transcription factor MYB10 controls the accumulation of anthocyanins. MYB10 is able to auto-activate its expression by binding its own promoter at a specific motif, the R1 motif. In some apple accessions a natural mutation, termed R6, has more copies of this motif within the MYB10 promoter resulting in stronger auto-activation and elevated anthocyanins. Here we show that other anthocyanin-related MYBs selected from apple, pear, strawberry, petunia, kiwifruit and Arabidopsis are able to activate promoters containing the R6 motif. To examine the specificity of this motif, members of the R2R3 MYB family were screened against a promoter harboring the R6 mutation. Only MYBs from subgroups 5 and 6 activate expression by binding the R6 motif, with these MYBs sharing conserved residues in their R2R3 DNA binding domains. Insertion of the apple R6 motif into orthologous promoters of MYB10 in pear (PcMYB10) and Arabidopsis (AtMY75) elevated anthocyanin levels. Introduction of the R6 motif into the promoter region of an anthocyanin biosynthetic enzyme F3'5'H of kiwifruit imparts regulation by MYB10. This results in elevated levels of delphinidin in both tobacco and kiwifruit. Finally, an R6 motif inserted into the promoter the vitamin C biosynthesis gene GDP-L-Gal phosphorylase increases vitamin C content in a MYB10-dependent manner. This motif therefore provides a tool to re-engineer novel MYB-regulated responses in plants. PMID- 29163591 TI - Transcriptomic and Hormonal Analyses Reveal that YUC-Mediated Auxin Biogenesis Is Involved in Shoot Regeneration from Rhizome in Cymbidium. AB - Cymbidium, one of the most important orchid genera in horticulture, can be classified into epiphytic and terrestrial species. Generally, epiphytic Cymbidium seedlings can be easily propagated by tissue culture, but terrestrial seedlings are difficult to propagate. To date, the molecular mechanisms underlying the differences in the ease with which terrestrial and epiphytic cymbidiums can be propagated are largely unknown. Using RNA-sequencing, quantitative reverse transcription PCR and enzyme-linked immunosorbent assay, Cymbidium 'Xiaofeng' (CXF), which can be efficiently micropropagated, and terrestrial Cymbidium sinense 'Qijianbaimo' (CSQ), which has a low regeneration ability, were used to explore the molecular mechanisms underlying the micropropagation ability of Cymbidium species. To this end, 447 million clean short reads were generated, and 31,264 annotated unigenes were obtained from 10 cDNA libraries. A total of 1,290 differentially expressed genes (DEGs) were identified between CXF and CSQ during shoot induction. Gene ontology (GO) enrichment analysis indicated that the DEGs were significantly enriched in auxin pathway-related GO terms. Further analysis demonstrated that YUC and GH3 family genes, which play crucial roles in the regulation of auxin/IAA (indole-3-acetic acid) metabolism, acted quickly in response to shoot induction culture in vitro and were closely correlated with variation in shoot regeneration between CXF and CSQ. In addition, the study showed that IAA accumulated rapidly and significantly during shoot induction in CXF compared to that in CSQ; in contrast, no significant changes in other hormones were observed between CXF and CSQ. Furthermore, shoot regeneration in CXF was inhibited by a yucasin-auxin biosynthesis inhibitor, indicating that increased IAA level is required for high-frequency shoot regeneration in CXF. In conclusion, our study revealed that YUC-mediated auxin biogenesis is involved in shoot regeneration from rhizome in Cymbidium. PMID- 29163592 TI - Reciprocal Interactions between Cadmium-Induced Cell Wall Responses and Oxidative Stress in Plants. AB - Cadmium (Cd) pollution renders many soils across the world unsuited or unsafe for food- or feed-orientated agriculture. The main mechanism of Cd phytotoxicity is the induction of oxidative stress, amongst others through the depletion of glutathione. Oxidative stress can damage lipids, proteins, and nucleic acids, leading to growth inhibition or even cell death. The plant cell has a variety of tools to defend itself against Cd stress. First and foremost, cell walls might prevent Cd from entering and damaging the protoplast. Both the primary and secondary cell wall have an array of defensive mechanisms that can be adapted to cope with Cd. Pectin, which contains most of the negative charges within the primary cell wall, can sequester Cd very effectively. In the secondary cell wall, lignification can serve to immobilize Cd and create a tougher barrier for entry. Changes in cell wall composition are, however, dependent on nutrients and conversely might affect their uptake. Additionally, the role of ascorbate (AsA) as most important apoplastic antioxidant is of considerable interest, due to the fact that oxidative stress is a major mechanism underlying Cd toxicity, and that AsA biosynthesis shares several links with cell wall construction. In this review, modifications of the plant cell wall in response to Cd exposure are discussed. Focus lies on pectin in the primary cell wall, lignification in the secondary cell wall and the importance of AsA in the apoplast. Regarding lignification, we attempt to answer the question whether increased lignification is merely a consequence of Cd toxicity, or rather an elicited defense response. We propose a model for lignification as defense response, with a central role for hydrogen peroxide as substrate and signaling molecule. PMID- 29163593 TI - OsARM1, an R2R3 MYB Transcription Factor, Is Involved in Regulation of the Response to Arsenic Stress in Rice. AB - Bioaccumulation of arsenic (As) in rice (Oryza sativa) increases human exposure to this toxic, carcinogenic element. Recent studies identified several As transporters, but the regulation of these transporters remains unclear. Here, we show that the rice R2R3 MYB transcription factor OsARM1 (ARSENITE-RESPONSIVE MYB1) regulates As-associated transporters genes. Treatment with As(III) induced OsARM1 transcript accumulation and an OsARM1-GFP fusion localized to the nucleus. Histochemical analysis of OsARM1pro::GUS lines indicated that OsARM1 was expressed in the phloem of vascular bundles in basal and upper nodes. Knockout of OsARM1 (OsARM1-KO CRISPR/Cas9-generated mutants) improved tolerance to As(III) and overexpression of OsARM1 (OsARM1-OE lines) increased sensitivity to As(III). Measurement of As in As(III)-treated plants showed that under low As(III) conditions (2 MUM), more As was transported from the roots to the shoots in OsARM1-KOs. By contrast, more As accumulated in the roots in OsARM1-OEs in response to high As(III) exposure (25 MUM). In particular, the As(III) levels in node I were significantly higher in OsARM1-KOs, but significantly lower in OsARM1 OEs, compared to wild-type plants, implying that OsARM1 is important for the regulation of root-to-shoot translocation of As. Moreover, OsLsi1, OsLsi2, and OsLsi6, which encode key As transporters, were significantly downregulated in OsARM1-OEs and upregulated in OsARM1-KOs compared to wild type. Chromatin immunoprecipitation-quantitative PCR of OsARM1-OEs indicated that OsARM1 binds to the conserved MYB-binding sites in the promoters or genomic regions of OsLsi1, OsLsi2, and OsLsi6 in rice. Our findings suggest that the OsARM1 transcription factor has essential functions in regulating As uptake and root-to-shoot translocation in rice. PMID- 29163594 TI - Expression of MEP Pathway Genes and Non-volatile Sequestration Are Associated with Circadian Rhythm of Dominant Terpenoids Emission in Osmanthus fragrans Lour. Flowers. AB - Osmanthus fragrans Lour. is one of the top 10 traditional ornamental flowers in China famous for its unique fragrance. Preliminary study proved that the terpenoids including ionone, linalool, and ocimene and their derivatives are the dominant aroma-active compounds that contribute greatly to the scent bouquet. Pollination observation implies the emission of aromatic terpenoids may follow a circadian rhythm. In this study, we investigated the variation of volatile terpenoids and its potential regulators. The results showed that both volatile and non-volatile terpenoids presented circadian oscillation with high emission or accumulation during the day and low emission or accumulation during the night. The volatile terpenoids always increased to reach their maximum values at 12:00 h, while free and glycosylated compounds continued increasing throughout the day. The depletion of non-volatile pool might provide the substrates for volatile emission at 0:00-6:00, suggesting the sequestration of non-volatile compounds acted like a buffer regulating emission of terpenoids. Further detection of MEP pathway genes demonstrated that their expressions increased significantly in parallel with the evident increase of both volatile and non-volatile terpenoids during the day, indicating that the gene expressions were also closely associated with terpenoid formation. Thus, the expression of MEP pathway genes and internal sequestration both played crucial roles in modulating circadian rhythm of terpenoid emission in O. fragrans. PMID- 29163595 TI - Alfalfa Root Growth Rate Correlates with Progression of Microtubules during Mitosis and Cytokinesis as Revealed by Environmental Light-Sheet Microscopy. AB - Cell division and expansion are two fundamental biological processes supporting indeterminate root growth and development of plants. Quantitative evaluations of cell divisions related to root growth analyses have been performed in several model crop and non-crop plant species, but not in important legume plant Medicago sativa. Light-sheet fluorescence microscopy (LSFM) is an advanced imaging technique widely used in animal developmental biology, providing efficient fast optical sectioning under physiological conditions with considerably reduced phototoxicity and photobleaching. Long-term 4D imaging of living plants offers advantages for developmental cell biology not available in other microscopy approaches. Recently, LSFM was implemented in plant developmental biology studies, however, it is largely restricted to the model plant Arabidopsis thaliana. Cellular and subcellular events in crop species and robust plant samples have not been studied by this method yet. Therefore we performed LSFM long-term live imaging of growing root tips of transgenic alfalfa plants expressing the fluorescent molecular marker for the microtubule-binding domain (GFP-MBD), in order to study dynamic patterns of microtubule arrays during mitotic cell division. Quantitative evaluations of cell division progress in the two root tissues (epidermis and cortex) clearly indicate that root growth rate is correlated with duration of cell division in alfalfa roots. Our results favor non invasive environmental LSFM as one of the most suitable methods for qualitative and quantitative cellular and developmental imaging of living transgenic legume crops. PMID- 29163596 TI - Editorial: Phytohormones and the Regulation of Stress Tolerance in Plants: Current Status and Future Directions. PMID- 29163597 TI - Morphology, Carbohydrate Distribution, Gene Expression, and Enzymatic Activities Related to Cell Wall Hydrolysis in Four Barley Varieties during Simulated Malting. AB - Many biological processes, such as cell wall hydrolysis and the mobilisation of nutrient reserves from the starchy endosperm, require stringent regulation to successfully malt barley (Hordeum vulgare) grain in an industrial context. Much of the accumulated knowledge defining these events has been collected from individual, unrelated experiments, and data have often been extrapolated from Petri dish germination, rather than malting, experiments. Here, we present comprehensive morphological, biochemical, and transcript data from a simulated malt batch of the three elite malting cultivars Admiral, Navigator, and Flagship, and the feed cultivar Keel. Activities of lytic enzymes implicated in cell wall and starch depolymerisation in germinated grain have been measured, and transcript data for published cell wall hydrolytic genes have been provided. It was notable that Flagship and Keel exhibited generally similar patterns of enzyme and transcript expression, but exhibited a few key differences that may partially explain Flagship's superior malting qualities. Admiral and Navigator also showed matching expression patterns for these genes and enzymes, but the patterns differed from those of Flagship and Keel, despite Admiral and Navigator having Keel as a common ancestor. Overall (1,3;1,4)-beta-glucanase activity differed between cultivars, with lower enzyme levels and concomitantly higher amounts of (1,3;1,4)-beta-glucan in the feed variety, Keel, at the end of malting. Transcript levels of the gene encoding (1,3;1,4)-beta-glucanase isoenzyme EI were almost three times higher than those encoding isoenzyme EII, suggesting a previously unrecognised importance for isoenzyme EI during malting. Careful morphological examination showed that scutellum epithelial cells in mature dry grain are elongated but expand no further as malting progresses, in contrast to equivalent cells in other cereals, perhaps demonstrating a morphological change in this critical organ over generations of breeding selection. Fluorescent immuno histochemical labelling revealed the presence of pectin in the nucellus and, for the first time, significant amounts of callose throughout the starchy endosperm of mature grain. PMID- 29163598 TI - An RNA Sequencing Transcriptome Analysis of Grasspea (Lathyrus sativus L.) and Development of SSR and KASP Markers. AB - Grasspea (Lathyrus sativus L., 2n = 14) has great agronomic potential because of its ability to survive under extreme conditions, such as drought and flood. However, this legume is less investigated because of its sparse genomic resources and very slow breeding process. In this study, 570 million quality-filtered and trimmed cDNA sequence reads with total length of over 82 billion bp were obtained using the Illumina NextSeqTM 500 platform. Approximately two million contigs and 142,053 transcripts were assembled from our RNA-Seq data, which resulted in 27,431 unigenes with an average length of 1,250 bp and maximum length of 48,515 bp. The unigenes were of high-quality. For example, the stay-green (SGR) gene of grasspea was aligned with the SGR gene of pea with high similarity. Among these unigenes, 3,204 EST-SSR primers were designed, 284 of which were randomly chosen for validation. Of these validated unigenes, 87 (30.6%) EST-SSR primers produced polymorphic amplicons among 43 grasspea accessions selected from different geographical locations. Meanwhile, 146,406 SNPs were screened and 50 SNP loci were randomly chosen for the kompetitive allele-specific PCR (KASP) validation. Over 80% (42) SNP loci were successfully transformed to KASP markers. Comparison of the dendrograms according to the SSR and KASP markers showed that the different marker systems are partially consistent with the dendrogram constructed in our study. PMID- 29163599 TI - A Growing Stem Inhibits Bud Outgrowth - The Overlooked Theory of Apical Dominance. AB - Three theories of apical dominance, direct, diversion, and indirect, were proposed in the 1930s to explain how auxin synthesized in the shoot apex might inhibit axillary bud outgrowth, and thus shoot branching. The direct and diversion theories of apical dominance have been investigated in detail, and they are replaced with the current auxin transport canalization and second messenger theories, respectively. These two current theories still cannot entirely explain the phenomenon of apical dominance. Although there is ample evidence that the inhibition of bud outgrowth by auxin from the shoot apex is linked to stem elongation and highly branched auxin biosynthesis or signaling mutants are dwarf, the third theory proposed in the 1930s, the indirect theory, that explains apical dominance as auxin-induced stem growth indirectly inhibits bud outgrowth has been overlooked. The indirect theory did not propose how a growing stem might inhibit bud outgrowth. Recent discoveries indicate bud dormancy (syn. quiescence, paradormancy) in response to intrinsic and environmental factors in diverse species is linked to enhanced growth of the main shoot and reduced sugar level in the buds. Since a growing stem is a strong sink for sugars, and sugar is indispensable for shoot branching, the indirect theory of apical dominance might now be explained as auxin-induced stem growth inhibits bud outgrowth by diverting sugars away from buds. Detailed study of the indirect theory and the effect of source-sink status on dormancy and outgrowth of axillary buds will advance our knowledge of apical dominance and shoot branching in plants. PMID- 29163600 TI - Plastome Rearrangements in the "Adenocalymma-Neojobertia" Clade (Bignonieae, Bignoniaceae) and Its Phylogenetic Implications. AB - The chloroplast is one of the most important organelles of plants. This organelle has a circular DNA with approximately 130 genes. The use of plastid genomic data in phylogenetic and evolutionary studies became possible with high-throughput sequencing methods, which allowed us to rapidly obtain complete genomes at a reasonable cost. Here, we use high-throughput sequencing to study the "Adenocalymma-Neojobertia" clade (Bignonieae, Bignoniaceae). More specifically, we use Hi-Seq Illumina technology to sequence 10 complete plastid genomes. Plastomes were assembled using selected plastid reads and de novo approach with SPAdes. The 10 assembled genomes were analyzed in a phylogenetic context using five different partition schemes: (1) 91 protein-coding genes ("coding"); (2) 76 introns and spacers with alignment manually edited ("non-coding edited"); (3) 76 non-coding regions with poorly aligned regions removed using T-Coffee ("non coding filtered"); (4) 91 coding regions plus 76 non-coding regions edited ("coding + non-coding edited"); and, (5) 91 protein-coding regions plus the 76 filtered non-coding regions ("coding + non-coding filtered"). Fragmented regions were aligned using Mafft. Phylogenetic analyses were conducted using Maximum Likelihood (ML) and Bayesian Criteria (BC). The analyses of the individual plastomes consistently recovered an expansion of the Inverted Repeated (IRs) regions and a compression of the Small Single Copy (SSC) region. Major genomic translocations were observed at the Large Single Copy (LSC) and IRs. ML phylogenetic analyses of the individual datasets led to the same topology, with the exception of the analysis of the "non-coding filtered" dataset. Overall, relationships were strongly supported, with the highest support values obtained through the analysis of the "coding + non-coding edited" dataset. Four regions at the LSC, SSC, and IR were selected for primer development. The "Adenocalymma Neojobertia" clade shows an unusual pattern of plastid structure variation, including four major genomic translocations. These rearrangements challenge the current view of conserved plastid genome architecture in terms of gene order. It also complicates both genomic assemblies using reference genomes and sequence alignments using whole plastomes. Therefore, strategies that employ de novo assemblies and manual evaluation of sequence alignments are required to prevent assembly and alignment errors. PMID- 29163601 TI - Genome-Wide Constitutively Expressed Gene Analysis and New Reference Gene Selection Based on Transcriptome Data: A Case Study from Poplar/Canker Disease Interaction. AB - A number of transcriptome datasets for differential expression (DE) genes have been widely used for understanding organismal biology, but these datasets also contain untapped information that can be used to develop more precise analytical tools. With the use of transcriptome data generated from poplar/canker disease interaction system, we describe a methodology to identify candidate reference genes from high-throughput sequencing data. This methodology will improve the accuracy of RT-qPCR and will lead to better standards for the normalization of expression data. Expression stability analysis from xylem and phloem of Populus bejingensis inoculated with the fungal canker pathogen Botryosphaeria dothidea revealed that 729 poplar transcripts (1.11%) were stably expressed, at a threshold level of coefficient of variance (CV) of FPKM < 20% and maximum fold change (MFC) of FPKM < 2.0. Expression stability and bioinformatics analysis suggested that commonly used house-keeping (HK) genes were not the most appropriate internal controls: 70 of the 72 commonly used HK genes were not stably expressed, 45 of the 72 produced multiple isoform transcripts, and some of their reported primers produced unspecific amplicons in PCR amplification. RT qPCR analysis to compare and evaluate the expression stability of 10 commonly used poplar HK genes and 20 of the 729 newly-identified stably expressed transcripts showed that some of the newly-identified genes (such as SSU_S8e, LSU_L5e, and 20S_PSU) had higher stability ranking than most of commonly used HK genes. Based on these results, we recommend a pipeline for deriving reference genes from transcriptome data. An appropriate candidate gene should have a unique transcript, constitutive expression, CV value of expression < 20% (or possibly 30%) and MFC value of expression <2, and an expression level of 50-1,000 units. Lastly, when four of the newly identified HK genes were used in the normalization of expression data for 20 differential expressed genes, expression analysis gave similar values to Cufflinks output. The methods described here provide an alternative pathway for the normalization of transcriptome data, a process that is essential for integrating analyses of transcriptome data across environments, laboratories, sequencing platforms, and species. PMID- 29163602 TI - Effects of Ridge-Furrow System Combined with Different Degradable Mulching Materials on Soil Water Conservation and Crop Production in Semi-Humid Areas of China. AB - In China, the ridge-furrow water conservation planting (RC) system is advantageous for improving crop yields and rainwater use efficiency. In RC planting system, plastic film-mulched ridges are employed for water harvesting while the furrows serve as infiltration and planting belts. To optimize the RC system and to overcome problems due to the lack of water in semi-humid areas at risk of drought, we mulched the furrows with 8% biodegradable film (RCSB), liquid film (RCSL), or no mulching in the furrows (RCSN), while conventional flat planting (CF) was employed as the control. After 4 year (2007-2010) consecutive field study, the results showed that the soil water storage level in the 0-100 cm layer with four treatments was ranked as follow: RCSB > RCSL > RCSN > CF, while the RCSB and RCSL were 26.3 and 12.2 mm greater than RCSN, respectively. Compared with CF, the average soil temperature was significantly (P < 0.05) higher by 3.1, 1.7, and 1.5 degrees C under the RC planting treatments (RCSB, RCSL, and RCSN) during each year, respectively. The average ET rate of RC treatments were all lower than CF in each experimental year, and the average decreased by 8.0% (P < 0.05). The average yields with RCSB, RCSL, and RCSN increased by 2,665, 1,444, and 1,235 kg ha-1, respectively, and the water use efficiency (WUE) increased by 51.6, 25.6, and 21.1%, compared with CF. RCSB obtained the highest economic benefit, the average net income was higher than CF by 4,020 Yuan ha-1. In conclusion, we found that RC planting with biodegradable film mulching in the furrows is the best cultivation pattern in the semi-humid areas of China in terms of both environmental and economic benefits. PMID- 29163603 TI - Novel Ribonuclease Activity Differs between Fibrillarins from Arabidopsis thaliana. AB - Fibrillarin is one of the most important nucleolar proteins that have been shown as essential for life. Fibrillarin localizes primarily at the periphery between fibrillar center and dense fibrillar component as well as in Cajal bodies. In most plants there are at least two different genes for fibrillarin. In Arabidopsis thaliana both genes show high level of expression in transcriptionally active cells. Here, we focus on two important differences between A. thaliana fibrillarins. First and most relevant is the enzymatic activity by AtFib2. The AtFib2 shows a novel ribonuclease activity that is not seen with AtFib1. Second is a difference in the ability to interact with phosphoinositides and phosphatidic acid between both proteins. We also show that the novel ribonuclease activity as well as the phospholipid binding region of fibrillarin is confine to the GAR domain. The ribonuclease activity of fibrillarin reveals in this study represents a new role for this protein in rRNA processing. PMID- 29163604 TI - Root Traits Enhancing Rice Grain Yield under Alternate Wetting and Drying Condition. AB - Reducing water requirements and lowering environmental footprints require attention to minimize risks to food security. The present study was conducted with the aim to identify appropriate root traits enhancing rice grain yield under alternate wetting and drying conditions (AWD) and identify stable, high-yielding genotypes better suited to the AWD across variable ecosystems. Advanced breeding lines, popular rice varieties and drought-tolerant lines were evaluated in a series of 23 experiments conducted in the Philippines, India, Bangladesh, Nepal and Cambodia in 2015 and 2016. A large variation in grain yield under AWD conditions enabled the selection of high-yielding and stable genotypes across locations, seasons and years. Water savings of 5.7-23.4% were achieved without significant yield penalty across different ecosystems. The mean grain yield of genotypes across locations ranged from 3.5 to 5.6 t/ha and the mean environment grain yields ranged from 3.7 (Cambodia) to 6.6 (India) t/ha. The best-fitting Finlay-Wilkinson regression model identified eight stable genotypes with mean grain yield of more than 5.0 t/ha across locations. Multidimensional preference analysis represented the strong association of root traits (nodal root number, root dry weight at 22 and 30 days after transplanting) with grain yield. The genotype IR14L253 outperformed in terms of root traits and high mean grain yield across seasons and six locations. The 1.0 t/ha yield advantage of IR14L253 over the popular cultivar IR64 under AWD shall encourage farmers to cultivate IR14L253 and also adopt AWD. The results suggest an important role of root architectural traits in term of more number of nodal roots and root dry weight at 10-20 cm depth on 22-30 days after transplanting (DAT) in providing yield stability and preventing yield reduction under AWD compared to continuous flooded conditions. Genotypes possessing increased number of nodal roots provided higher yield over IR64 as well as no yield reduction under AWD compared to flooded irrigation. The identification of appropriate root architecture traits at specific depth and specific growth stage shall help breeding programs develop better rice varieties for AWD conditions. PMID- 29163605 TI - The Verticillium dahliae SnodProt1-Like Protein VdCP1 Contributes to Virulence and Triggers the Plant Immune System. AB - During pathogenic infection, hundreds of proteins that play vital roles in the Verticillium dahliae-host interaction are secreted. In this study, an integrated proteomic analysis of secreted V. dahliae proteins was performed, and a conserved secretory protein, designated VdCP1, was identified as a member of the SnodProt1 phytotoxin family. An expression analysis of the vdcp1 gene revealed that the transcript is present in every condition studied and displays elevated expression throughout the infection process. To investigate the natural role of VdCP1 in V. dahliae, two vdcp1 knockout mutants and their complementation strains were generated. Bioassays of these mutants revealed no obvious phenotypic differences from the wild-type (WT) in terms of mycelial growth, conidial production or mycelial/spore morphology. However, compared with the WT, the vdcp1 knockout mutants displayed attenuated pathogenicity in cotton plants. Furthermore, treating plants with purified recombinant VdCP1 protein expressed in Pichia pastoris induced the accumulation of reactive oxygen species (ROS), expression of several defense-related genes, leakage of ion electrolytes, enhancement of defense-related enzyme activity and production of salicylic acid. Moreover, VdCP1 conferred resistance to Botrytis cinerea and Pseudomonas syringae pv. tabaci in tobacco and to V. dahliae in cotton. Further research revealed that VdCP1 possesses chitin-binding properties and that the growth of vdcp1 knockout mutants was more affected by treatments with chitinase, indicating that VdCP1 could protect V. dahliae cell wall from enzymatic degradation, which suggests an effector role of VdCP1 in infecting hosts. PMID- 29163607 TI - Increasing Leaf Vein Density via Mutagenesis in Rice Results in an Enhanced Rate of Photosynthesis, Smaller Cell Sizes and Can Reduce Interveinal Mesophyll Cell Number. AB - Improvements to leaf photosynthetic rates of crops can be achieved by targeted manipulation of individual component processes, such as the activity and properties of RuBisCO or photoprotection. This study shows that simple forward genetic screens of mutant populations can also be used to rapidly generate photosynthesis variants that are useful for breeding. Increasing leaf vein density (concentration of vascular tissue per unit leaf area) has important implications for plant hydraulic properties and assimilate transport. It was an important step to improving photosynthetic rates in the evolution of both C3 and C4 species and is a foundation or prerequisite trait for C4 engineering in crops like rice (Oryza sativa). A previous high throughput screen identified five mutant rice lines (cv. IR64) with increased vein densities and associated narrower leaf widths (Feldman et al., 2014). Here, these high vein density rice variants were analyzed for properties related to photosynthesis. Two lines were identified as having significantly reduced mesophyll to bundle sheath cell number ratios. All five lines had 20% higher light saturated photosynthetic capacity per unit leaf area, higher maximum carboxylation rates, dark respiration rates and electron transport capacities. This was associated with no significant differences in leaf thickness, stomatal conductance or CO2 compensation point between mutants and the wild-type. The enhanced photosynthetic rate in these lines may be a result of increased RuBisCO and electron transport component amount and/or activity and/or enhanced transport of photoassimilates. We conclude that high vein density (associated with altered mesophyll cell length and number) is a trait that may confer increased photosynthetic efficiency without increased transpiration. PMID- 29163606 TI - Transgenic Peanut (Arachis hypogaea L.) Overexpressing mtlD Gene Showed Improved Photosynthetic, Physio-Biochemical, and Yield-Parameters under Soil-Moisture Deficit Stress in Lysimeter System. AB - Peanut, an important oilseed crop, frequently encounters drought stress (DS) during its life cycle. In this study, four previously developed mtlD transgenic (T) peanut lines were used for detailed characterization under DS, at the reproductive stage using lysimeter system under controlled greenhouse conditions. In dry-down experiments, T lines maintained better photosynthetic machinery, such as, photosynthesis rate, stomatal conductance, transpiration rate, and SPAD (Soil Plant Analyses Development) values, and had lower oxidative damage, including lipid membrane peroxidation and hydrogen peroxide and superoxide radical accumulation than WT, when exposed to 24 days of DS. WT plants had a more negative water potential (WP; up to -3.22 MPa) than T lines did (-2.56 to -2.71 MPa) at day 24 of DS treatment. During recovery, T lines recovered easily whereas 67% of WT plants failed to recover. In T lines, the rate of photosynthesis strongly and positively correlated with the transpiration rate (r = 0.92), RWC (r = 0.90), WP (r = 0.86), and total chlorophyll content (r = 0.75), suggesting its strong correlation with water retention-related parameters. Furthermore, yield parameters such as, pod weight and harvest index of T lines were up to 2.19 and 1.38 times more than those of WT plants, respectively. Thus, the significantly better performance of mtlD T peanut lines than of WT plants under DS could be attributed to the accumulation of mannitol, which in turn helped in maintaining the osmoregulation and ROS scavenging activity of mannitol and ultimately conferred water-economizing capacity and higher yield in T lines than in WT plants. PMID- 29163608 TI - OsHAK1, a High-Affinity Potassium Transporter, Positively Regulates Responses to Drought Stress in Rice. AB - Drought is one of the environmental factors that severely restrict plant distribution and crop production. Recently, we reported that the high-affinity potassium transporter OsHAK1 plays important roles in K acquisition and translocation in rice over low and high K concentration ranges, however, knowledge on the regulatory roles of OsHAK1 in osmotic/drought stress is limited. Here, transcript levels of OsHAK1 were found transiently elevated by water deficit in roots and shoots, consistent with the enhanced GUS activity in transgenic plants under stress. Under drought conditions, OsHAK1 knockout mutants (KO) presented lower tolerance to the stress and displayed stunted growth at both the vegetative and reproductive stages. Phenotypic analysis of OsHAK1 overexpression seedlings (Ox) demonstrated that they present better tolerance to drought stress than wild-type (WT). Compared to WT seedlings, OsHAK1 overexpressors had lower level of lipid peroxidation, higher activities of antioxidant enzymes (POX and CAT) and higher proline accumulation. Furthermore, qPCR analysis revealed that OsHAK1 act as a positive regulator of the expression of stress-responsive genes as well as of two well-known rice channel genes (OsTPKb and OsAKT1) involved in K homeostasis and stress responses in transgenic plants under dehydration. Most important, OsHAK1-Ox plants displayed enhanced drought tolerance at the reproductive stage, resulting in 35% more grain yield than WT under drought conditions, and without exhibiting significant differences under normal growth conditions. Consequently, OsHAK1 can be considered to be used in molecular breeding for improvement of drought tolerance in rice. PMID- 29163609 TI - Selenium Biofortification in Fragaria * ananassa: Implications on Strawberry Fruits Quality, Content of Bioactive Health Beneficial Compounds and Metabolomic Profile. AB - Selenium (Se) is an essential nutrient for humans, due to its antioxidant properties, whereas, to date, its essentiality to plants still remains to be demonstrated. Nevertheless, if added to the cultivation substrate, plants growth resulted enhanced. However, the concentration of Se in agricultural soils is very variable, ranging from 0.01 mg kg-1 up to 10 mg kg-1 in seleniferous areas. Therefore several studies have been performed aimed at bio-fortifying crops with Se and the approaches exploited were mainly based on the application of Se fertilizers. The aim of the present research was to assess the biofortification potential of Se in hydroponically grown strawberry fruits and its effects on qualitative parameters and nutraceutical compounds. The supplementation with Se did not negatively affect the growth and the yield of strawberries, and induced an accumulation of Se in fruits. Furthermore, the metabolomic analyses highlighted an increase in flavonoid and polyphenol compounds, which contributes to the organoleptic features and antioxidant capacity of fruits; in addition, an increase in the fruits sweetness also was detected in biofortified strawberries. In conclusion, based on our observations, strawberry plants seem a good target for Se biofortification, thus allowing the increase in the human intake of this essential micronutrient. PMID- 29163611 TI - Genetic and Cytological Analyses of the Natural Variation of Seed Number per Pod in Rapeseed (Brassica napus L.). AB - Seed number is one of the key traits related to plant evolution/domestication and crop improvement/breeding. In rapeseed germplasm, the seed number per pod (SNPP) shows a very wide variation from several to nearly 30; however, the underlying causations/mechanisms for this variation are poorly known. In the current study, the genetic and cytological bases for the natural variation of SNPP in rapeseed was firstly and systematically investigated using the representative four high SNPP and five low-SNPP lines. The results of self- or cross-pollination experiment between the high- and low-SNPP lines showed that the natural variation of SNPP was mainly controlled by maternal effect (mean = 0.79), followed by paternal effect (mean = 0.21). Analysis of the data using diploid seed embryo cytoplasmic-maternal model further showed that the maternal genotype, embryo, and cytoplasm effects, respectively, explained 47.6, 35.2, and 7.5% of the genetic variance. In addition, the analysis of combining ability showed that for the SNPP of hybrid F1 was mainly determined by the general combining ability of parents (63.0%), followed by special combining ability of parental combination (37.0%). More importantly, the cytological observation showed that the SNPP difference between the high- and low-SNPP lines was attributable to the accumulative differences in its components. Of which, the number of ovules, the proportion of fertile ovules, the proportion of fertile ovules to be fertilized, and the proportion of fertilized ovules to develop into seeds accounted for 30.7, 18.2, 7.1, and 43.9%, respectively. The accordant results of both genetic and cytological analyses provide solid evidences and systematic insights to further understand the mechanisms underlying the natural variation of SNPP, which will facilitate the development of high-yield cultivars in rapeseed. PMID- 29163610 TI - Single-Molecule Fluorescence Methods to Study Plant Hormone Signal Transduction Pathways. AB - Plant-hormone-initiated signaling pathways are extremely vital for plant growth, differentiation, development, and adaptation to environmental stresses. Hormonal perception by receptors induces downstream signal transduction mechanisms that lead to plant responses. However, conventional techniques-such as genetics, biochemistry, and physiology methods-that are applied to elucidate these signaling pathways can only provide qualitative or ensemble-averaged quantitative results, and the intrinsic molecular mechanisms remain unclear. The present study developed novel methodologies based on in vitro single-molecule fluorescence assays to elucidate the complete and detailed mechanisms of plant hormone signal transduction pathways. The proposed methods are based on multicolor total internal reflection fluorescence microscopy and a flow cell model for gas environment control. The methods validate the effectiveness of single-molecule approaches for the extraction of abundant information, including oligomerization, specific gas dependence, and the interaction kinetics of different components. PMID- 29163612 TI - Variability in Susceptibility to Anthracnose in the World Collection of Olive Cultivars of Cordoba (Spain). AB - Anthracnose of olive (Olea europaea ssp. europaea L.), caused by Colletotrichum species, is a serious disease causing fruit rot and branch dieback, whose epidemics are highly dependent on cultivar susceptibility and environmental conditions. Over a period of 10 years, there have been three severe epidemics in Andalusia (southern Spain) that allowed us to complete the assessment of the World Olive Germplasm Bank of Cordoba, one of the most important cultivar collections worldwide.A total of 308 cultivars from 21 countries were evaluated, mainly Spain (174 cvs.), Syria (29 cvs.), Italy (20 cvs.), Turkey (15 cvs.), and Greece (16 cvs.). Disease assessments were performed using a 0-10 rating scale, specifically developed to estimate the incidence of symptomatic fruit in the tree canopy. Also, the susceptibility of five reference cultivars was confirmed by artificial inoculation. Because of the direct relationship between the maturity of the fruit and their susceptibility to the pathogen, evaluations were performed at the end of fruit ripening, which forced coupling assessments according to the maturity state of the trees. By applying the cluster analysis to the 308 cultivars, these were classified as follows: 66 cvs. highly susceptible (21.4%), 83 cvs. susceptible (26.9%), 66 cvs. moderately susceptible (21.4%), 61 cvs. resistant (19.8%), and 32 cvs. highly resistant (10.4%). Representative cultivars of these five categories are "Ocal," "Lechin de Sevilla," "Arbequina," "Picual," and "Frantoio," respectively. With some exceptions, such as cvs. Arbosana, Empeltre and Picual, most of the Spanish cultivars, such as "Arbequina," "Cornicabra," "Hojiblanca," "Manzanilla de Sevilla," "Morisca," "Picudo," "Farga," and "Verdial de Huevar" are included in the categories of moderately susceptible, susceptible or highly susceptible. The phenotypic evaluation of anthracnose reaction is a limiting factor for the selection of olive cultivars by farmers, technicians, and breeders. PMID- 29163614 TI - Long-Distance Transport of Prosystemin Messenger RNA in Tomato. AB - Main conclusion: The transcripts of transgenic prosystemin (PS) gene are mobile and the PS mRNA can be translated into protein in tomato and tobacco plants. Systemin (SYS) and its precursor protein, prosystemin (PS), are upstream components of the wound-induced signaling pathway in tomato. Although the mobile signal(s) for wound responses has been the subject of considerable research, its identity remains controversial. Intensive studies have revealed the essential role of mRNA on plant systemic signaling. We hypothesize that PS mRNA can act as a transmissible signal in tomato. Herein, we demonstrated that transgenic PS mRNA occurs in leaves located at considerable distances from the initial site of its generation by a transient Agrobacterium-infiltration assay system. We also showed that PS protein is present in the vascular bundle of the distant leaves. Our results indicate that transgenic PS mRNA may be functional as a long-distance signal to modulate systemic defense responses in tomato, providing novel insights into the multifaceted systems by which SYS signaling transports. PMID- 29163613 TI - A Comparison of Petiole Hydraulics and Aquaporin Expression in an Anisohydric and Isohydric Cultivar of Grapevine in Response to Water-Stress Induced Cavitation. AB - We report physiological, anatomical and molecular differences in two economically important grapevine (Vitis vinifera L.) cultivars cv. Grenache (near-isohydric) and Chardonnay (anisohydric) in their response to water-stress induced cavitation. The aim of the study was to compare organ vulnerability (petiole and stem) to cavitation by measuring ultrasonic acoustic emissions (UAE) and percent loss of conductance of potted grapevines subject to the onset of water-stress. Leaf (psiL) and stem water potential (psiS), stomatal conductance (gs), transpiration (E), petiole hydraulics (KPet), and xylem diameter were also measured. Chardonnay displayed hydraulic segmentation based on UAE, with cavitation occurring at a less negative psiL in the petiole than in the stem. Vulnerability segmentation was not observed in Grenache, with both petioles and stems equally vulnerable to cavitation. Leaf water potential that induced 50% of maximum UAE was significantly different between petioles and stems in Chardonnay (psi50Petiole = -1.14 and psi50Stem = -2.24 MPa) but not in Grenache (psi50Petiole = -0.73 and psi50Stem = -0.78 MPa). Grenache stems appeared more susceptible to water-stress induced cavitation than Chardonnay stems. Grenache displayed (on average) a higher KPet likely due to the presence of larger xylem vessels. A close relationship between petiole hydraulic properties and vine water status was observed in Chardonnay but not in Grenache. Transcriptional analysis of aquaporins in the petioles and leaves (VvPIP1;1, VvPIP2;1, VvPIP2;2 VvPIP2;3, VvTIP1;1, and VvTIP2;1) showed differential regulation diurnally and in response to water-stress. VvPIP2;1 showed strong diurnal regulation in the petioles and leaves of both cultivars with expression highest predawn. Expression of VvPIP2;1 and VvPIP2;2 responded to psiL and psiS in both cultivars indicating the expression of these two genes are closely linked to vine water status. Expression of several aquaporin genes correlated with gas exchange measurements, however, these genes differed between cultivars. In summary, the data shows two contrasting responses in petiole hydraulics and aquaporin expression between the near-isohydric cultivar, Grenache and anisohydric cultivar, Chardonnay. PMID- 29163615 TI - Assessing the Pathogenic Ability of Ralstonia pseudosolanacearum (Ralstonia solanacearum Phylotype I) from Ornamental Rosa spp. Plants. AB - Ralstonia pseudosolanacearum (Ralstonia solanacearum phylotype I) isolates found in stunted, yellowing, and wilted ornamental rose (Rosa spp.) were assessed for their pathogenic ability in two rose cultivars (cv. "Armando" and cv. "Red Naomi") and in four solanaceous crops: tomato (Solanum lycopersicum cv. "Money Maker"), tobacco (Nicotiana tabacum cv. "White Burley"), eggplant (Solanum melongena cv. "Black Beauty") and sweet pepper (Capsicum annum cv. "Yolo Wonder"). Significant differences were observed in susceptibility between the two rose cultivars as well as between the two modes of inoculation performed. The cultivar "Armando" was significantly more susceptible than cultivar "Red Naomi," exhibiting higher disease severity and incidence. Similarly, stem inoculation after wounding was found to be significantly more effective than soil drenching, resulting in higher disease severity. Additionally, a temperature dependency in susceptibility was observed for both cultivars irrespective of the mode of inoculation, however, this was significantly more pronounced upon soil drenching. The solanaceous crops all showed to be susceptible to the R. pseudosolanacearum isolates originated from the Rosa spp. plants. Furthermore, both rose cultivars were able to harbor symptomless infections with other R. pseudosolanacearum and R. solanacearum isolates than those isolated from rose. Our results clearly demonstrated that latent infections in a rose cultivar such as cv. "Red Naomi" do occur even at temperatures as low as 20 degrees C. This latency poses high risks for the entire floricultural industry as latently infected Rosa spp. plants are propagated and distributed over various continents, including areas where climatic conditions are optimal for the pathogen. PMID- 29163616 TI - Co-expression of Arabidopsis NHX1 and bar Improves the Tolerance to Salinity, Oxidative Stress, and Herbicide in Transgenic Mungbean. AB - Mungbean is an important pulse crop extensively cultivated in Southeast Asia for supply of easily digestible protein. Salinity severely limits the growth and productivity of mungbean, and weeding poses nutritional and disease constraints to mungbean cultivation. To pyramid both salt tolerance and protection against herbicide in mungbean, the AtNHX1 encoding tonoplast Na+/H+ antiporter from Arabidopsis, and bar gene associated with herbicide resistance were co-expressed through Agrobacterium-mediated transformation. Stress inducible expression of AtNHX1 significantly improved tolerance under salt stress to ionic, osmotic, and oxidative stresses in transgenic mungbean plants compared to the wild type (WT) plants, whereas constitutive expression of bar provided resistance to herbicide. Compared to WT, transgenic mungbean plants grew better with higher plant height, foliage, dry mass and seed yield under high salt stress (200 mM NaCl) in the greenhouse. The improved performance of transgenic plants under salt stress was associated with enhanced sequestration of Na+ in roots by vacuolar Na+/H+ antiporter and limited transport of toxic Na+ to shoots, possibly by restricting Na+ influx into shoots. Transgenic plants showed better intracellular ion homeostasis, osmoregulation, reduced cell membrane damage, improved photosynthetic capacity, and transpiration rate as compared to WT when subjected to salt stress. Reduction in hydrogen peroxide and oxygen radical production indicated enhanced protection of transgenic plants to both salt- and methyl vialogen (MV)-induced oxidative stress. This study laid a firm foundation for improving mungbean yield in saline lands in Southeast Asia. PMID- 29163617 TI - Phenylpropanoid Scent Compounds in Petunia x hybrida Are Glycosylated and Accumulate in Vacuoles. AB - Floral scent has been studied extensively in the model plant Petunia. However, little is known about the intracellular fate of scent compounds. Here, we characterize the glycosylation of phenylpropanoid scent compounds in Petunia x hybrida. This modification reduces scent compounds' volatility, reactivity, and autotoxicity while increasing their water-solubility. Gas chromatography-mass spectrometry (GC-MS) analyses revealed that flowers of petunia cultivars accumulate substantial amounts of glycosylated scent compounds and that their increasing level parallels flower development. In contrast to the pool of accumulated aglycones, which drops considerably at the beginning of the light period, the collective pool of glycosides starts to increase at that time and does not decrease thereafter. The glycoside pool is dynamic and is generated or catabolized during peak scent emission, as inferred from phenylalanine isotope feeding experiments. Using several approaches, we show that phenylpropanoid scent compounds are stored as glycosides in the vacuoles of petal cells: ectopic expression of Aspergillus niger beta-glucosidase-1 targeted to the vacuole resulted in decreased glycoside accumulation; GC-MS analysis of intact vacuoles isolated from petal protoplasts revealed the presence of glycosylated scent compounds. Accumulation of glycosides in the vacuoles seems to be a common mechanism for phenylpropanoid metabolites. PMID- 29163618 TI - The Ralstonia solanacearum Type III Effector RipAY Is Phosphorylated in Plant Cells to Modulate Its Enzymatic Activity. AB - Most bacterial pathogens subvert plant cellular functions using effector proteins delivered inside plant cells. In the plant pathogen Ralstonia solanacearum, several of these effectors contain domains with predicted enzymatic activities, including acetyltransferases, phosphatases, and proteases, among others. How these enzymatic activities get activated inside plant cells, but not in the bacterial cell, remains unknown in most cases. In this work, we found that the R. solanacearum effector RipAY is phosphorylated in plant cells. One phosphorylated serine residue, S131, is required for the reported gamma-glutamyl cyclotransferase activity of RipAY, responsible for the degradation of gamma glutamyl compounds (such as glutathione) inside host cells. Accordingly, non phosphorylable mutants in S131 abolish RipAY-mediated degradation of glutathione in plant cells and the subsequent suppression of plant immune responses. In this article, we examine our results in relation to the recent reports on the biochemical activities of RipAY, and discuss the potential implications of phosphorylation in plant cells as a mechanism to modulate the enzymatic activity of RipAY. PMID- 29163619 TI - FAR-RED INSENSITIVE 219/JAR1 Contributes to Shade Avoidance Responses of Arabidopsis Seedlings by Modulating Key Shade Signaling Components. AB - To receive an ample amount of light, plants use elongation growth in response to vegetation shade. The combined interaction of light and hormones, including jasmonic acid (JA) signaling controls this elongation. However, the detailed molecular mechanisms underlying the response are still emerging. FAR-RED INSENSITIVE 219/JASMONATE RESISTANCE 1 (FIN219/JAR1), a cytoplasmic localized JA conjugating enzyme, integrates far-red light and JA signaling. Here, we report that FIN219/JAR1 negatively regulates shade-induced hypocotyl elongation and gene expression in Arabidopsis seedlings in response to shade. In turn, simulated shade reduces FIN219 protein accumulation. Analysis of phyA 211 fin219-2 double mutants indicated that FIN219 and phyA are synergistic in regulating shade induced hypocotyl elongation and gene expression. Moreover, FIN219 differentially affected the expression of the shade-signaling bHLH factors PIF5 and PAR1, thereby increasing the expression of the auxin-response genes IAA29 and SAUR68 on exposure to shade. Furthermore, the protein level of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) was affected in both fin219 mutants and overexpression lines as compared with the wild type under shade. Intriguingly, ectopic expression of FIN219 inhibited the nuclear accumulation of COP1 in response to shade. Further co-immunoprecipitation studies revealed that FIN219 interacted with COP1 and phyA under shade. Therefore, FIN219/JAR1 may play a vital role in modulating the Arabidopsis response to simulated shade via multiple layers of molecular mechanisms. PMID- 29163620 TI - An Oleuropein beta-Glucosidase from Olive Fruit Is Involved in Determining the Phenolic Composition of Virgin Olive Oil. AB - Phenolic composition of virgin olive oil is determined by the enzymatic and/or chemical reactions that take place during olive fruit processing. Of these enzymes, beta-glucosidase activity plays a relevant role in the transformation of the phenolic glycosides present in the olive fruit, generating different secoiridoid derivatives. The main goal of the present study was to characterize olive fruit beta-glucosidase genes and enzymes responsible for the phenolic composition of virgin olive oil. To achieve that, we have isolated an olive beta glucosidase gene from cultivar Picual (OepGLU), expressed in Nicotiana benthamiana leaves and purified its corresponding recombinant enzyme. Western blot analysis showed that recombinant OepGLU protein is detected by an antibody raised against the purified native olive mesocarp beta-glucosidase enzyme, and exhibits a deduced molecular mass of 65.0 kDa. The recombinant OepGLU enzyme showed activity on the major olive phenolic glycosides, with the highest levels with respect to oleuropein, followed by ligstroside and demethyloleuropein. In addition, expression analysis showed that olive GLU transcript level in olive fruit is spatially and temporally regulated in a cultivar-dependent manner. Furthermore, temperature, light and water regime regulate olive GLU gene expression in olive fruit mesocarp. All these data are consistent with the involvement of OepGLU enzyme in the formation of the major phenolic compounds present in virgin olive oil. PMID- 29163621 TI - Transcript Profiling of Hevea brasiliensis during Latex Flow. AB - Latex exploitation enhances latex regeneration in rubber trees. The latex exploitation-caused latex flow lasts from 10 min to a few hours, which is convenient for exploring the transcript profiling of latex metabolism-related genes at the different stages of latex flow. In the present study, the expression pattern of 62 latex metabolism-related genes involved in water transportation, carbohydrate metabolism, natural rubber biosynthesis, hormone signaling, ROS generation and scavenging, and latex coagulum across three stages of latex flow between rubber tree clones CATAS7-33-97 and CATAS8-79 were comparatively analyzed by quantitative real-time PCR. The two clones show differences in latex regeneration and have a different duration of latex flow. The results showed that the expression levels of 38 genes were significantly higher in CATAS8-79 latex than in CATAS7-33-97 during latex regeneration, while 45 genes had a notably higher expression level in CATAS8-79 latex during latex flow. Together with the activation of the MEP pathway and jasmonate pathway in CATAS8-79 latex, HbPIP1;3, HbPIP1;4, HbSUT3, HbSus3, HbHMGS1-2, HbMK should contribute to the high latex regeneration ability. The up-regulation of ethylene signaling and Hb44KD and the down-regulation of latex coagulation-related genes in CATAS8-79 latex might contribute to its longer latex flow duration. This study provides some cues for revealing the regulation of latex metabolism in rubber trees. PMID- 29163622 TI - Transcriptome and Metabolome Analyses Provide Insights into the Occurrence of Peel Roughing Disorder on Satsuma Mandarin (Citrus unshiu Marc.) Fruit. AB - Roughing disorder (RD) is a significant quality barrier in citrus fruit, prevalent on easy-peeling mandarins. As RD is not yet well-understood, this study aimed to examine the changes and synergic molecular processes involved in peel RD. Peel with RD was induced by severely defruiting Satsuma mandarin trees. Morphology observations, RNA-sequencing, and targeted and untargeted metabolic analyses were conducted. The results showed that the primary metabolites of sugars, organic acids and amino acids are dramatically changed in RD peel. The RD peel was always characterized by higher magnesium content during development. Comparative transcriptome profiling was performed for CK and RD peels at 30, 80, and 170 days after full bloom (DAFB) which represented fruit at cell division stage, cell enlargement stage and fruit maturity stage, respectively. Physiological and molecular biological evidence suggested that the month after full bloom is a crucial stage for RD initiation. A total of 4,855 differentially expressed genes (DEGs) in RD peel, relative to CK peel were detected at cell division stage, about 2 to 4-fold more than other stages had. Among the differentially expressed transcription factors, the bHLH family were affected most by RD, and six bHLH transcription factors functionally involved in GA metabolism were assessed to associate with RD occurrence. Gene set enrichment analysis suggested that RD significantly altered starch and GA metabolism in peel. Higher starch content and hydrolysed chain status were found in RD peel at cell division stage. RD occurrence on the peel was influenced significantly by GA, especially abundant GA before July. These changes may mean a significant alteration in sink strength of RD peel. The findings of this study provide insights into the emergence, development and molecular mechanisms of RD. PMID- 29163623 TI - Accession-Dependent CBF Gene Deletion by CRISPR/Cas System in Arabidopsis. AB - The CRISPR/Cas system became a powerful genome editing tool for basic plant research and crop improvement. Thus far, CRISPR/Cas has been applied to many plants, including Arabidopsis, rice and other crop plants. It has been reported that CRISPR/Cas efficiency is generally high in many plants. In this study, we compared the genome editing efficiency of CRISPR/Cas in three different Arabidopsis accessions [Col-0, Ler, and C24RDLUC (C24 accession harboring the stress-responsive RD29A promoter-driven luciferase reporter)]. For the comparison, we chose to target the cold-responsive C-repeat/DRE-Binding Factor (CBF) genes. CBF1, CBF2, and CBF3 genes are tandemly located on Arabidopsis chromosome 4 with redundant functions as the key transcription factors functioning in cold stress signaling and tolerance. Due to the close proximity of these CBFs on the chromosome, it is impossible to generate cbf1, cbf2, cbf3 triple mutants (cbf123) by traditional genetic crosses. Therefore, using the CRISPR/Cas tool, we aimed to generate cbf123 mutants and compared the genome editing efficiency in different Arabidopsis accessions. Among the accessions, Ler was the most resilient to the CRISPR/Cas deletion with the lowest gene deletion ratio in both T1 and T2 generations. Interestingly, while C24RDLUC showed a high CBF123 deletion frequency in T2 only when the gene deletion was observed in T1 generation, Col-0 displayed high ratios of the CBF123 deletions in T2 regardless of the presence or absence of the CBF123 deletion in T1. Isolated cbf123 mutants in C24RDLUC background showed no expression of CBF1, CBF2, and CBF3 genes and proteins with reduction in the CBF target gene expression under cold stress. PMID- 29163624 TI - Phytohormone and Light Regulation of Chlorophyll Degradation. AB - Degreening, due to the net loss of chlorophyll (Chl), is the most prominent symptom during the processes of leaf senescence, fruit ripening, and seed maturation. Over the last decade or so, extensive identifications of Chl catabolic genes (CCGs) have led to the revelation of the biochemical pathway of Chl degradation. As such, exploration of the regulatory mechanism of the degreening process is greatly facilitated. During the past few years, substantial progress has been made in elucidating the regulation of Chl degradation, particularly via the mediation of major phytohormones' signaling. Intriguingly, ethylene and abscisic acid's signaling have been demonstrated to interweave with light signaling in mediating the regulation of Chl degradation. In this review, we briefly summarize this progress, with an effort on providing a framework for further investigation of multifaceted and hierarchical regulations of Chl degradation. PMID- 29163625 TI - Genome-Wide Association Study Reveals Novel Genes Associated with Culm Cellulose Content in Bread Wheat (Triticum aestivum, L.). AB - Plant cell wall formation is a complex, coordinated and developmentally regulated process. Cellulose is the most dominant constituent of plant cell walls. Because of its paracrystalline structure, cellulose is the main determinant of mechanical strength of plant tissues. As the most abundant polysaccharide on earth, it is also the focus of cellulosic biofuel industry. To reduce culm lodging in wheat and for improved ethanol production, delineation of the variation for stem cellulose content could prove useful. We present results on the analysis of the stem cellulose content of 288 diverse wheat accessions and its genome-wide association study (GWAS). Cellulose concentration ranged from 35 to 52% (w/w). Cellulose content was normally distributed in the accessions around a mean and median of 45% (w/w). Genome-wide marker-trait association study using 21,073 SNPs helped identify nine SNPs that were associated (p < 1E-05) with cellulose content. Four strongly associated (p < 8.17E-05) SNP markers were linked to wheat unigenes, which included beta-tubulin, Auxin-induced protein 5NG4, and a putative transmembrane protein of unknown function. These genes may be directly or indirectly involved in the formation of cellulose in wheat culms. GWAS results from this study have the potential for genetic manipulation of cellulose content in bread wheat and other small grain cereals to enhance culm strength and improve biofuel production. PMID- 29163626 TI - Genetic, Physical and Comparative Mapping of the Powdery Mildew Resistance Gene Pm21 Originating from Dasypyrum villosum. AB - Pm21, originating from wheat wild relative Dasypyrum villosum, confers immunity to all known races of Blumeria graminis f. sp. tritici (Bgt) and has been widely utilized in wheat breeding. However, little is known on the genetic basis of the Pm21 locus. In the present study, four seedling-susceptible D. villosum lines (DvSus-1 ~ DvSus-4) were identified from different natural populations. Based on the collinearity among genomes of Brachypodium distachyon, Oryza, and Triticeae, a set of 25 gene-derived markers were developed declaring the polymorphisms between DvRes-1 carrying Pm21 and DvSus-1. Fine genetic mapping of Pm21 was conducted by using an extremely large F2 segregation population derived from the cross DvSus-1/DvRes-1. Then Pm21 was narrowed to a 0.01-cM genetic interval defined by the markers 6VS-08.4b and 6VS-10b. Three DNA markers, including a resistance gene analog marker, were confirmed to co-segregate with Pm21. Moreover, based on the susceptible deletion line Y18-S6 induced by ethyl methanesulfonate treatment conducted on Yangmai 18, Pm21 was physically mapped into a similar interval. Comparative analysis revealed that the orthologous regions of the interval carrying Pm21 were narrowed to a 112.5 kb genomic region harboring 18 genes in Brachypodium, and a 23.2 kb region harboring two genes in rice, respectively. This study provides a high-density integrated map of the Pm21 locus, which will contribute to map-based cloning of Pm21. PMID- 29163627 TI - Effects of Competition, Drought Stress and Photosynthetic Productivity on the Radial Growth of White Spruce in Western Canada. AB - Understanding the complex interactions of competition, climate warming-induced drought stress, and photosynthetic productivity on the radial growth of trees is central to linking climate change impacts on tree growth, stand structure and in general, forest productivity. Using a mixed modeling approach, a stand-level photosynthetic production model, climate, stand competition and tree-ring data from mixedwood stands in western Canada, we investigated the radial growth response of white spruce [Picea glauca (Moench.) Voss] to simulated annual photosynthetic production, simulated drought stress, and tree and stand level competition. The long-term (~80-year) radial growth of white spruce was constrained mostly by competition, as measured by total basal area, with minor effects from drought. There was no relation of competition and drought on tree growth but dominant trees increased their growth more strongly to increases in modeled photosynthetic productivity, indicating asymmetric competition. Our results indicate a co-limitation of drought and climatic factors inhibiting photosynthetic productivity for radial growth of white spruce in western Canada. These results illustrate how a modeling approach can separate the complex factors regulating both multi-decadal average radial growth and interannual radial growth variations of white spruce, and contribute to advance our understanding on sustainable management of mixedwood boreal forests in western Canada. PMID- 29163628 TI - A Conserved Basal Transcription Factor Is Required for the Function of Diverse TAL Effectors in Multiple Plant Hosts. AB - Many Xanthomonas bacteria use transcription activator-like effector (TALE) proteins to activate plant disease susceptibility (S) genes, and this activation contributes to disease. We recently reported that rice basal transcription factor IIA gamma subunit, OsTFIIAgamma5, is hijacked by TALE-carrying Xanthomonas oryzae infecting the plants. However, whether TFIIAgammas are also involved in TALE carrying Xanthomonas-caused diseases in other plants is unknown. Here, molecular and genetic approaches were used to investigate the role of TFIIAgammas in other plants. We found that TFIIAgammas are also used by TALE-carrying Xanthomonas to cause disease in other plants. The TALEs of Xanthomonas citri pv. citri (Xcc) causing canker in citrus and Xanthomonas campestris pv. vesicatoria (Xcv) causing bacterial spot in pepper and tomato interacted with corresponding host TFIIAgammas as in rice. Transcriptionally suppressing TFIIAgamma led to resistance to Xcc in citrus and Xcv in pepper and tomato. The 39th residue of OsTFIIAgamma5 and citrus CsTFIIAgamma is vital for TALE-dependent induction of plant S genes. As mutated OsTFIIAgamma5V 39E, CsTFIIAgammaV 39E, pepper CaTFIIAgammaV 39E, and tomato SlTFIIAgammaV 39E also did not interact with TALEs to prevent disease. These results suggest that TALE-carrying bacteria share a common mechanism for infecting plants. Using TFIIAgammaV 39E-type mutation could be a general strategy for improving resistance to TALE-carrying pathogens in crops. PMID- 29163629 TI - High-Throughput Field Phenotyping of Leaves, Leaf Sheaths, Culms and Ears of Spring Barley Cultivars at Anthesis and Dough Ripeness. AB - To optimize plant architecture (e.g., photosynthetic active leaf area, leaf-stem ratio), plant physiologists and plant breeders rely on destructively and tediously harvested biomass samples. A fast and non-destructive method for obtaining information about different plant organs could be vehicle-based spectral proximal sensing. In this 3-year study, the mobile phenotyping platform PhenoTrac 4 was used to compare the measurements from active and passive spectral proximal sensors of leaves, leaf sheaths, culms and ears of 34 spring barley cultivars at anthesis and dough ripeness. Published vegetation indices (VI), partial least square regression (PLSR) models and contour map analysis were compared to assess these traits. Contour maps are matrices consisting of coefficients of determination for all of the binary combinations of wavelengths and the biomass parameters. The PLSR models of leaves, leaf sheaths and culms showed strong correlations (R2 = 0.61-0.76). Published vegetation indices depicted similar coefficients of determination; however, their RMSEs were higher. No wavelength combination could be found by the contour map analysis to improve the results of the PLSR or published VIs. The best results were obtained for the dry weight and N uptake of leaves and culms. The PLSR models yielded satisfactory relationships for leaf sheaths at anthesis (R2 = 0.69), whereas only a low performance for all of sensors and methods was observed at dough ripeness. No relationships with ears were observed. Active and passive sensors performed comparably, with slight advantages observed for the passive spectrometer. The results indicate that tractor-based proximal sensing in combination with optimized spectral indices or PLSR models may represent a suitable tool for plant breeders to assess relevant morphological traits, allowing for a better understanding of plant architecture, which is closely linked to the physiological performance. Further validation of PLSR models is required in independent studies. Organ specific phenotyping represents a first step toward breeding by design. PMID- 29163630 TI - Nitrogen Addition Changes the Stoichiometry and Growth Rate of Different Organs in Pinus tabuliformis Seedlings. AB - Background: Nitrogen (N) deposition could influence plant stoichiometry and growth rate and thus alter the structure and function of the ecosystem. However, the mechanism by which N deposition changes the stoichiometry and relative growth rate (RGR) of plant organs, especially roots with different diameters, is unclear. Methods: We created a gradient of N availability (0-22.4 g N m-2 year-1) for Pinus tabuliformis seedlings for 3 years and examined changes in the carbon (C):N:phosphorus (P) ratios and RGRs of the leaves, stems, and roots with four diameter classes (finest roots, <0.5 mm; finer roots, 0.5-1 mm; middle roots, 1-2 mm; and coarse roots, >2 mm). Results: (1) N addition significantly increased the C and N contents of the leaves and whole roots, the C content of the stems, the N:P ratios of the leaves and stems, and the C:P ratio of the whole roots. (2) In the root system, the C:N ratio of the finest roots and the C:P ratios of the finest and finer roots significantly changed with N addition. The N:P ratios of the finest, finer, and middle roots significantly increased with increasing amount of N added. The stoichiometric responses of the roots were more sensitive to N addition than those of the other organs (3) The RGR of all the organs significantly increased at low N addition levels (2.8-11.2 g N m-2 year-1) but decreased at high N addition levels (22.4 g N m-2 year-1). (4) The RGRs of the whole seedlings and leaves were not significantly correlated with their N:P ratios at low and high N addition levels. By contrast, the RGRs of the stems and roots showed a significantly positive correlation with their own N:P ratio only at low N addition level. Conclusion: Addition of N affected plant growth by altering the contents of C and N; the ratios of C, N, and P; and the RGRs of the organs. RGR is correlated with the N:P ratios of the stems and roots at low N addition level but not at high N addition level. This finding is inconsistent with the growth rate hypothesis. PMID- 29163631 TI - Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size? AB - Here we describe a case of a prenatal diagnosis of a male fetus that inherited the unstable allele from his full mutation mosaic mother (29, 160, >200 CGG repeats) reduced to a normal size range (19 CGG repeats). Haplotype analysis showed that the fetus 19 CGG repeats allele derived from the maternal unstable allele which was inherited from his maternal grandmother. No size mosaicism was detected by testing the DNA from in vitro cultured samples, including seventh passage culture as well as from two amniocentesis samples. Sequence analysis confirmed that the allele was 19 CGG repeats long. Methylation assay showed no methylation. Although none of the techniques used in this study can provide with absolute certainty the diagnosis, the results strongly indicate the presence in the fetus of an allele with a CGG repeat number in the normal range. Because this is a prenatal diagnosis case, the crucial question is whether the 19 CGG allele derived from the maternal unstable expanded allele, which contracted to the normal range, became a normal stable allele or a normal unstable allele which could expand in the next generation. It is also possible that allele size mosaicism of the FMR1 gene that went undetected exists. Because this is a prenatal diagnosis case, we cannot with certainty exclude the presence of an undetected expanded allele of the FMR1 gene, in addition to the 19 CGG allele derived from an unstable expanded allele, which contracted to the normal range. PMID- 29163632 TI - Editorial: GPCRs and Cancer. PMID- 29163633 TI - New Tools in Orthology Analysis: A Brief Review of Promising Perspectives. AB - Nowadays defying homology relationships among sequences is essential for biological research. Within homology the analysis of orthologs sequences is of great importance for computational biology, annotation of genomes and for phylogenetic inference. Since 2007, with the increase in the number of new sequences being deposited in large biological databases, researchers have begun to analyse computerized methodologies and tools aimed at selecting the most promising ones in the prediction of orthologous groups. Literature in this field of research describes the problems that the majority of available tools show, such as those encountered in accuracy, time required for analysis (especially in light of the increasing volume of data being submitted, which require faster techniques) and the automatization of the process without requiring manual intervention. Conducting our search through BMC, Google Scholar, NCBI PubMed, and Expasy, we examined more than 600 articles pursuing the most recent techniques and tools developed to solve most the problems still existing in orthology detection. We listed the main computational tools created and developed between 2011 and 2017, taking into consideration the differences in the type of orthology analysis, outlining the main features of each tool and pointing to the problems that each one tries to address. We also observed that several tools still use as their main algorithm the BLAST "all-against-all" methodology, which entails some limitations, such as limited number of queries, computational cost, and high processing time to complete the analysis. However, new promising tools are being developed, like OrthoVenn (which uses the Venn diagram to show the relationship of ortholog groups generated by its algorithm); or proteinOrtho (which improves the accuracy of ortholog groups); or ReMark (tackling the integration of the pipeline to turn the entry process automatic); or OrthAgogue (using algorithms developed to minimize processing time); and proteinOrtho (developed for dealing with large amounts of biological data). We made a comparison among the main features of four tool and tested them using four for prokaryotic genomas. We hope that our review can be useful for researchers and will help them in selecting the most appropriate tool for their work in the field of orthology. PMID- 29163634 TI - Evidence Suggesting Absence of Mitochondrial DNA Methylation. AB - Methylation of nuclear genes encoding mitochondrial proteins participates in the regulation of mitochondria function. The existence of cytosine methylation in the mitochondrial genome is debated. To investigate whether mitochondrial DNA (mtDNA) is methylated, we used both targeted- and whole mitochondrial genome bisulfite sequencing in cell lines and muscle tissue from mouse and human origin. While unconverted cytosines were detected in some portion of the mitochondrial genome, their abundance was inversely associated to the sequencing depth, indicating that sequencing analysis can bias the estimation of mtDNA methylation levels. In intact mtDNA, few cytosines remained 100% unconverted. However, removal of supercoiled structures of mtDNA with the restriction enzyme BamHI prior to bisulfite sequencing decreased cytosine unconversion rate to <1.5% at all the investigated regions: D-loop, tRNA-F+12S, 16S, ND5 and CYTB, suggesting that mtDNA supercoiled structure blocks the access to bisulfite conversion. Here, we identified an artifact of mtDNA bisulfite sequencing that can lead to an overestimation of mtDNA methylation levels. Our study supports that cytosine methylation is virtually absent in mtDNA. PMID- 29163635 TI - Departure from Hardy Weinberg Equilibrium and Genotyping Error. AB - Objective: Departure from Hardy Weinberg Equilibrium (HWE) may occur due to a variety of causes, including purifying selection, inbreeding, population substructure, copy number variation or genotyping error. We searched for specific characteristics of HWE-departure due to genotyping error. Methods: Genotypes of a random set of genetic variants were obtained from the Exome Aggregation Consortium (ExAC) database. Variants with <80% successful genotypes or with minor allele frequency (MAF) <1% were excluded. HWE-departure (d-HWE) was considered significant at p < 10E-05 and classified as d-HWE with loss of heterozygosity (LoH d-HWE) or d-HWE with excess heterozygosity (gain of heterozygosity: GoH d HWE). Missing genotypes, variant type (single nucleotide polymorphism (SNP) vs. insertion/deletion); MAF, standard deviation (SD) of MAF across populations (MAF SD) and copy number variation were evaluated for association with HWE-departure. Results: The study sample comprised 3,204 genotype distributions. HWE-departure was observed in 134 variants: LoH d-HWE in 41 (1.3%), GoH d-HWE in 93 (2.9%) variants. LoH d-HWE was more likely in variants located within deletion polymorphisms (p < 0.001) and in variants with higher MAF-SD (p = 0.0077). GoH d HWE was associated with low genotyping rate, with variants of insertion/deletion type and with high MAF (all at p < 0.001). In a sub-sample of 2,196 variants with genotyping rate >98%, LoH d-HWE was found in 29 (1.3%) variants, but no GoH d-HWE was detected. The findings of the non-random distribution of HWE-violating SNPs along the chromosome, the association with common deletion polymorphisms and indel-variant type, and the finding of excess heterozygotes in genomic regions that are prone to cross-hybridization were confirmed in a large sample of short variants from the 1,000 Genomes Project. Conclusions: We differentiated between two types of HWE-departure. GoH d-HWE was suggestive for genotyping error. LoH d HWE, on the contrary, pointed to natural variabilities such as population substructure or common deletion polymorphisms. PMID- 29163636 TI - A Pipeline for High-Throughput Concentration Response Modeling of Gene Expression for Toxicogenomics. AB - Cell-based assays are an attractive option to measure gene expression response to exposure, but the cost of whole-transcriptome RNA sequencing has been a barrier to the use of gene expression profiling for in vitro toxicity screening. In addition, standard RNA sequencing adds variability due to variable transcript length and amplification. Targeted probe-sequencing technologies such as TempO Seq, with transcriptomic representation that can vary from hundreds of genes to the entire transcriptome, may reduce some components of variation. Analyses of high-throughput toxicogenomics data require renewed attention to read-calling algorithms and simplified dose-response modeling for datasets with relatively few samples. Using data from induced pluripotent stem cell-derived cardiomyocytes treated with chemicals at varying concentrations, we describe here and make available a pipeline for handling expression data generated by TempO-Seq to align reads, clean and normalize raw count data, identify differentially expressed genes, and calculate transcriptomic concentration-response points of departure. The methods are extensible to other forms of concentration-response gene expression data, and we discuss the utility of the methods for assessing variation in susceptibility and the diseased cellular state. PMID- 29163637 TI - Association between TGF-beta1 Polymorphisms and Head and Neck Cancer Risk: A Meta Analysis. AB - Background and Objective: Studies have been conducted to explore the association between the single nucleotide polymorphisms (SNPs) in transforming growth factor beta 1 (TGF-beta1) and head and neck cancer (HNC) susceptibility, however the findings are still inconclusive. Therefore, we conduct this meta-analysis to quantitatively assess the association. Methods: Embase and PubMed were searched for all eligible clinical studies. The odds ratio (OR) and 95% confidence interval (CI) of each study were pooled to estimate the association between SNPs in the TGF-beta1 and the HNC risk. Subgroup analysis was used to explore whether particular characteristics were related to the value of overall ORs and 95% CIs. Results: Seven case-control studies, including three SNPs (-509C/T, 869T/C, and 915G/C), were examined. Overall, this meta-analysis failed to identify a significant association between TGF-beta1-509C/T, 915G/C polymorphism and HNC risk in any models. As for the 869T/C polymorphism, significant associations were observed in the allelic model (C vs. T: OR = 1.351, 95%CI: 1.030-1.772), the homozygote model (CC vs. TT: OR = 1.585, 95%CI: 1.026-2.449) and the dominant model (CT/CC vs. TT: OR = 1.398, 95%CI: 1.008-1.937). This polymorphism was also found in the Asian group as well (C vs. T: OR = 1.400, 95%CI: 1.003-1.956, CC vs. TT: OR = 1.814, 95%CI: 1.018-3.233). Conclusion: Meta-analysis failed to show a statistical association between TGF-beta1-509C/T, 915G/C polymorphism, and HNC risk in any genetic models. However, it was found that TGF-beta1 869C/T polymorphism may be involved in susceptibility to HNC, especially in Asian patients. However, given the limitations of this meta-analysis, further well designed studies are required in the future. PMID- 29163638 TI - Network Analysis Reveals Putative Genes Affecting Meat Quality in Angus Cattle. AB - Improvements in eating satisfaction will benefit consumers and should increase beef demand which is of interest to the beef industry. Tenderness, juiciness, and flavor are major determinants of the palatability of beef and are often used to reflect eating satisfaction. Carcass qualities are used as indicator traits for meat quality, with higher quality grade carcasses expected to relate to more tender and palatable meat. However, meat quality is a complex concept determined by many component traits making interpretation of genome-wide association studies (GWAS) on any one component challenging to interpret. Recent approaches combining traditional GWAS with gene network interactions theory could be more efficient in dissecting the genetic architecture of complex traits. Phenotypic measures of 23 traits reflecting carcass characteristics, components of meat quality, along with mineral and peptide concentrations were used along with Illumina 54k bovine SNP genotypes to derive an annotated gene network associated with meat quality in 2,110 Angus beef cattle. The efficient mixed model association (EMMAX) approach in combination with a genomic relationship matrix was used to directly estimate the associations between 54k SNP genotypes and each of the 23 component traits. Genomic correlated regions were identified by partial correlations which were further used along with an information theory algorithm to derive gene network clusters. Correlated SNP across 23 component traits were subjected to network scoring and visualization software to identify significant SNP. Significant pathways implicated in the meat quality complex through GO term enrichment analysis included angiogenesis, inflammation, transmembrane transporter activity, and receptor activity. These results suggest that network analysis using partial correlations and annotation of significant SNP can reveal the genetic architecture of complex traits and provide novel information regarding biological mechanisms and genes that lead to complex phenotypes, like meat quality, and the nutritional and healthfulness value of beef. Improvements in genome annotation and knowledge of gene function will contribute to more comprehensive analyses that will advance our ability to dissect the complex architecture of complex traits. PMID- 29163639 TI - Genetic Diversity in Insect Metal Tolerance. AB - Insects encounter a variety of metals in their environment, many of which are required at some concentration for normal organismal homeostasis, but essentially all of which are toxic at higher concentrations. Insects have evolved a variety of genetic, and likely epigenetic, mechanisms to deal with metal stress. A recurring theme in all these systems is complexity and diversity; even simple, single gene, cases are complex. Of the known gene families, the metallothioneins are perhaps the best understood and provide good examples of how diverse metal response is. Interestingly, there is considerable diversity across taxa in these metal-responsive systems, including duplications to form small gene families and complex expression of single loci. Strikingly, different species have evolved different mechanisms to cope with the same, or similar, stress suggesting both independent derivation of, and plasticity in, the pathways involved. It is likely that some metal-response systems evolved early in evolutionary time and have been conserved, while others have diverged, and still others evolved more recently and convergently. In addition to conventional genetics, insects likely respond to environmental metal through a variety of epigenetic systems, but direct tests are lacking. Ultimately, it is likely that classical genetic and epigenetic factors interact in regulating insect metal responses. In light of this diversity across species, future studies including a broad-based examination of gene expression in non-model species in complex environments will likely uncover additional genes and genetic and epigenetic mechanisms. PMID- 29163640 TI - A Review of Pathway-Based Analysis Tools That Visualize Genetic Variants. AB - Pathway analysis is a powerful method for data analysis in genomics, most often applied to gene expression analysis. It is also promising for single-nucleotide polymorphism (SNP) data analysis, such as genome-wide association study data, because it allows the interpretation of variants with respect to the biological processes in which the affected genes and proteins are involved. Such analyses support an interactive evaluation of the possible effects of variations on function, regulation or interaction of gene products. Current pathway analysis software often does not support data visualization of variants in pathways as an alternate method to interpret genetic association results, and specific statistical methods for pathway analysis of SNP data are not combined with these visualization features. In this review, we first describe the visualization options of the tools that were identified by a literature review, in order to provide insight for improvements in this developing field. Tool evaluation was performed using a computational epistatic dataset of gene-gene interactions for obesity risk. Next, we report the necessity to include in these tools statistical methods designed for the pathway-based analysis with SNP data, expressly aiming to define features for more comprehensive pathway-based analysis tools. We conclude by recognizing that pathway analysis of genetic variations data requires a sophisticated combination of the most useful and informative visual aspects of the various tools evaluated. PMID- 29163641 TI - Isolation and Characterization of Thermophilic Bacteria from Jordanian Hot Springs: Bacillus licheniformis and Thermomonas hydrothermalis Isolates as Potential Producers of Thermostable Enzymes. AB - The aim of this study was the isolation and characterization of thermophilic bacteria from hot springs in Jordan. Ten isolates were characterized by morphological, microscopic, biochemical, molecular, and physiological characteristics. Sequencing of the 16S rDNA of the isolates followed by BLAST search revealed that nine strains could be identified as Bacillus licheniformis and one isolate as Thermomonas hydrothermalis. This is the first report on the isolation of Thermomonas species from Jordanian hot springs. The isolates showed an ability to produce some thermostable enzymes such as amylase, protease, cellulose, gelatins, and lecithin. Moreover, the UPGMA dendrogram of the enzymatic characteristics of the ten isolates was constructed; results indicated a high phenotypic diversity, which encourages future studies to explore further industrial and environmental applications. PMID- 29163644 TI - Evaluation of amprolium and toltrazuril efficacy in controlling natural intestinal rabbit coccidiosis. AB - This trial was undertaken with the objective to evaluate the efficacy of amprolium, toltrazuril and their combination in rabbits naturally infected with Eimeria species (32 * 103 +/- 4.63 oocysts per gram (OPG) of faeces). Thirty-six rabbits (11 weeks old with average body weight (BW) 2000 +/- 75 g), were randomly allocated into six groups (six kits each), namely, negative untreated and was retained as negative control (group 1), infected and kept untreated (group 2), treated with single oral dose of amprolium at 50 mg/kg BW for 5 days (group 3), received toltrazuril at 5 mg/kg BW for 2 days (group 4), treated orally with toltrazuril at 2.5 mg/kg BW, two doses with 5 day interval (group 5) and given oral doses of both amprolium and toltrazuril at 50 mg and 5 mg/kg BW (group 6), respectively. Clinical signs, mortalities, production data (feed consumption, feed conversion rate, BW, body weight gain (BWG), and performance index (PI)), OPG of faeces and the percentage of OPG reduction were recorded. The results indicated that both toltrazuril, amprolium and their concurrent use significantly (P<0.05) reduced OPG and effectively controlled coccidiosis related mortality, fully abolished the clinical signs, improved feed consumption, BW, weight gain and feed conversion rate. From the observations of the present study it can be concluded that the oral administration of both drugs and their combined use ameliorated the adverse impacts of intestinal coccidiosis in rabbits as therapeutic, but the concurrent use of both drugs was more superior. PMID- 29163642 TI - Potential Role of Exosomes in Mending a Broken Heart: Nanoshuttles Propelling Future Clinical Therapeutics Forward. AB - Stem cell transplantation therapy is a promising adjunct for regenerating damaged heart tissue; however, only modest improvements in cardiac function have been observed due to poor survival of transplanted cells in the ischemic heart. Therefore, there remains an unmet need for therapies that can aid in attenuating cardiac damage. Recent studies have demonstrated that exosomes released by stem cells could serve as a potential cell-free therapeutic for cardiac repair. These exosomes/nanoshuttles, once thought to be merely a method of waste disposal, have been shown to play a crucial role in physiological functions including short- and long-distance intercellular communication. In this review, we have summarized studies demonstrating the potential role of exosomes in improving cardiac function, attenuating cardiac fibrosis, stimulating angiogenesis, and modulating miRNA expression. Furthermore, exosomes carry an important cargo of miRNAs and proteins that could play an important role as a diagnostic marker for cardiovascular disease post-myocardial infarction. Although there is promising evidence from preclinical studies that exosomes released by stem cells could serve as a potential cell-free therapeutic for myocardial repair, there are several challenges that need to be addressed before exosomes could be fully utilized as off-the-shelf therapeutics for cardiac repair. PMID- 29163643 TI - Persistent bovine viral diarrhea virus (BVDV) infection in cattle herds. AB - Bovine viral diarrhea virus (BVDV) is a significant pathogen associated with gastrointestinal, respiratory, and reproductive diseases of cattle worldwide. It causes continuous economic losses to the cattle industry primarily due to decreased reproductive performance. The ability of virus to cross the placenta during early pregnancy can result in the birth of persistently infected (PI) calves. Persistently infected animals are generally much more efficient transmitters of BVDV than transiently or acutely infected animals because they are capable of shedding large quantities of virus throughout their lives and are considered the primary reservoirs for BVDV. Due to the nature of viral infections, there is no treatment to fully cure an animal of a viral infection. All control programs which are in use in many countries of the world, mainly depend upon the detection of PI animals, eliminating them and preventing their return into the herds. Detection of PI animals at early stage, particularly soon after birth is of significant benefit to implement BVDV control programs. Available diagnostic tests such as virus isolation (VI), immunohistochemistry (IHC), Antigen-Capture ELISA (ACE), and reverse transcriptase polymerase chain reaction (RT-PCR) are used for detection of PI cattle. Each method to detect BVDV has advantages, disadvantages, and applicability for different diagnostic situations. The reliability of diagnostic tests is optimized by choosing the appropriate sampling strategy on the basis of animal age. PMID- 29163645 TI - Hypervitaminosis D3 in broiler chicks: histopathological, immunomodulatory and immunohistochemical approach. AB - The present study was undertaken to investigate the toxic effects of higher doses (1,00,000 IU i.e. 2.5 mg/kg body weight (BW)) of vitamin D3, concomitantly with bacterial endotoxins (lipopolysaccharides: LPS) to study the immunomodulatory potential of vitamin D3 in IBL-80 broiler chicks. The chicks were divided into four groups [group I (NSS), group II (LPS), group III (Vit. D3 + NSS), and group IV (Vit. D3 + LPS)] containing eight chicks in each group, treated accordingly for 21 days. Birds were kept under close observation for apparent clinical signs and symptoms. Clinically, vitamin D3 treated chicks were dull, off feed, showed polydipsia, polyuria, watery faeces, rigidity of limbs, severe dehydration, weakness and significant progressive emaciation. Grossly, the bones were soft whereas most organs revealed congestion and hemorrhages in visceral organs. Histopathologically, renal tubular epithelium showed coagulative necrosis and metastatic calcification. The lung parenchyma and bronchi showed hemorrhages, congestion with diffuse heterophilic cell infiltration in inter-alveolar septa and infiltration of heterophils in alveoli along with proteinacious fluid in LPS treated chicks of treatment group, suggesting immunomodulatory action of vitamin D3. Vitamin D3 treated chicks showed strong expression of Calbindin D28k in intestine and kidney but weak expression in lung, which can be linked to nephrocalcinosis seen in kidney and from its prospective role in cellular calcium homeostasis. PMID- 29163646 TI - Prevalence of Campylobacter jejuni and Campylobacter coli in captive wildlife species of India. AB - Campylobacteriosis is an important zoonotic disease and the prevalence of Campylobacter is largely unknown in the wildlife of India. A total of 370 samples, comprising of 314 fresh faecal samples from apparently healthy captive wild animals and birds, 30 stool swabs from animal care takers and 26 samples of the animals' food and water were collected from G. B. Pant High Altitude Zoo, Nainital, Kanpur Zoo, Wildlife Park, IVRI and the Post Graduate Research Institute in Animal Sciences (PGRIAS), Chennai, Tamilnadu from August 2014 to May 2015. Samples were processed for cultural isolation, direct PCR and multiplex PCR for species confirmation. To decipher the genetic diversity, the 16S rRNA gene was amplified, sequenced and analyzed. Based on isolation, the overall occurrence rate of Campylobacter spp. was 0.8% (3/370), being 2.94% (3/102) for captive wild birds. Three Campylobacter jejuni were isolated from silver pheasants, lady amherest pheasants and saras cranes. Direct PCR assay showed the overall occurrence rate of Campylobacter spp. to be 4.77% (15/315), being 1.58% (2/126) for captive wild ruminants, 5.81% (5/86) for non-ruminants and 7.84% (8/102) for birds. All the isolates were identified as C. jejuni. PMID- 29163647 TI - Comparison of diagnostic tests for the detection of bovine brucellosis in the natural cases of abortion. AB - Rapid and precise diagnosis in natural field cases of bovine abortion caused by Brucella abortus warrants the use of the most sensitive and reliable diagnostic methods. In the present study, bacterial isolation, serology, gross, histopathology, immunohistochemistry and polymerase chain reaction technique(s) were applied. Sero-prevalence studies showed the rate of 28.86% positive cases using the competitive ELISA. Histopathological changes were mainly seen in the placenta, fetal lungs, kidney, liver and spleen. Immunohistochemical (IHC) staining of Brucella spp. was evident as brown, finely granular intracytoplasmic staining in trophoblasts of placental sections and in section(s) of liver, lung, kidney and spleen. Twenty-eight out of the 103 samples (17 from stomach contents, 3 from placental cotyledons, 2 from vaginal discharges and 6 from pooled fetal tissues) produced 193 bp amplicon specific for Brucella genus. Moreover, the species-specific primers amplified a 498 bp amplicon which corresponded to B. abortus. Comparison of diagnostic tests revealed PCR and IHC provide a reliable test for the diagnosis of bovine brucellosis in aborted fetal tissue and placental cotyledons whereas serology is most important for detection of Brucella positive animals in a herd. PMID- 29163648 TI - Fiber gene based molecular and biological characterization of hydropericardium hepatitis syndrome associated avian adenoviruses. AB - This study was designed to perform biological and molecular characterization of avian adenoviruses (AAVs) recovered from suspected cases of hydropericardium hepatitis syndrome (HHS) in commercial poultry. Initially the samples were screened by Agar Gel Precipitation Test (AGPT) for the presence of AAVs followed by its confirmation and typing through polymerase chain reaction (PCR) focusing on already reported serotypes AAV-4, AAV-8 and AAV-10 elsewhere. These PCR positive samples were further subjected to amplification of fiber gene, followed by conducting restriction fragment length polymorphism (RFLP) using restriction enzyme Alu. The selected isolates were further propagated through cell culture and pathogenic potential of selected isolates was determined by infecting chickens. In this study, out of a total 190 samples, 57.8% of suspected cases were found positive for AAV presence through AGPT while sub-type identification using PCR revealed 46.3% for these viruses belonging to AAV-4, 41.8% to AAV-8 and 11.8% showed co-infection of AAV-4 and AAV-8. AAV-10 was not detected in any of the tested samples. On the basis of RFLP pattern, AAV-4 isolates were further divided into four sub-groups (A-D) while AAV-8 isolates had identical RFLP pattern. To further evaluate the pathogenic potential of these sub-groups of AAV 4 isolates, specific pathogen free (SPF) chicks were challenged with selected isolates belonging to each of the sub-groups, resulting in variable pattern of pathogenicity. It is concluded that any variation in the fiber gene of AAV-4 isolates may affect its pathogenicity and eventually specificity of the vaccines used against such infections. Therefore, regular monitoring of the circulating AAV serotypes may be helpful in understanding the pathogenic potential of emerging AAVs, which may lead to development of more effective response strategies accordingly. PMID- 29163649 TI - Immunopathological evaluation of recombinant mycobacterial antigen Hsp65 expressed in Lactococcus lactis as a novel vaccine candidate. AB - Bovine tuberculosis (TBB) is a zoonotic disease distributed worldwide and is of great importance for public health and the livestock industry. Several experimental vaccines against this disease have been evaluated in recent years, yielding varying results. An example is the Bacillus Calmette-Guerin (BCG) vaccine, which has been used extensively in humans and tested in cattle showing mixed results related to protection (0-80%) against Mycobacterium bovis. In this study, we used the food-grade bacterium Lactococcus lactis as an expression system for production of mycobacterial protein Hsp65. For this purpose, the construction of a replicable plasmid in strain NZ9000 L. lactis (pVElepr) was conducted, which expressed the Mycobacterium leprae Hsp65 antigen, and was recognized by traded anti-Hsp65 antibodies. The strain NZ9000-pVElepr was applied to calves that were negative to tuberculin test and the immune response was monitored. The results showed that immune response was not significantly increased in calves with NZ9000-pVElepr with respect to control groups, and no injury was observed in any lung or lymph of the calves. Finally, this study suggest that the recombinant NZ9000 strain of L. lactis may protect against the development of M. bovis infection, although studies with longer exposure to this pathogen are necessary to conclude the matter. PMID- 29163650 TI - Cumulus cell expansion and ultrastructural changes in in vitro matured bovine oocytes under heat stress. AB - Cumulus-oocyte complexes (COCs) from cows were matured under normal (38.5 degrees C) and elevated temperatures (41 degrees C) simulating heat stress and their maturation was assessed based on measurement of cumulus expansion in both groups. There was a significant reduction (P<0.01) in maturation rate in the heat stressed oocytes. The ultrastructural events associated with in vitro oocyte maturation and changes associated with elevated temperature were also studied by transmission electron microscopy (TEM). Normal maturation cellular events were marked by migration of Golgi and mitochondria from the cortical regions, and conversely by a migration of cortical granules from the inner regions to a sub perivitelline zone. Heat stressed oocytes (41 degrees C) were not only marked by a reduction in rate and less cumulus cell expansion, but also by a reduction in cortical granule migration. The mitochondria appeared swollen with cristolysis. Ribosomal disruption and an abundance of free ribosomes were also seen. Changes in the cumulus cells include nuclear chromatin margination, condensation and karyolysis, formation of nuclear and cell membrane blebs, and typical membrane bound vesicles enclosing cell fragments indistinguishable from apoptosis. Evidently, heat stress can be associated with reduced cytoplasmic events of oocyte maturation, thereby decreasing the oocyte competence and can be associated with apoptosis of the cumulus cells and therefore compromise the survival of the oocyte itself. PMID- 29163651 TI - Molecular detection of virulence genes and multi-drug resistance patterns in Escherichia coli (STEC) in clinical bovine mastitis: Alborz province, Iran. AB - The aim of this study was to identify virulence genes and antimicrobial resistance of Escherichia coli isolated from bovine clinical mastitis in dairy herds in Iran. Sampling was done from 86 inflamed quarters of dairy cows in 8 commercial farms of Alborz province, Iran in summer 2015. Shiga toxin-producing E. coli (STEC) virulence genes were detected by multiplex PCR and multi-drug resistance profiles were confirmed using disk diffusion method. Among 60 E. coli isolated from examined samples, 13 (21.6%) of them were STEC. The results of PCR assay showed that eaeA gene was carried by 4 (30.8%) of STEC isolates. Although stx1 in combination with eaeA gene was detected from 7 (53.8%) of STEC isolates, stx1 and stx2 genes were detected from only 1 (7.7%) of the examined samples. The result of the disk diffusion method showed that all E. coli isolates were resistant to penicillin, tylosin, oxytetracycline, erythromycin, ampicillin, streptomycin and neomycin. However all isolates were susceptible to enrofloxacin. Therefore, according to the results establishing a regular monitoring system for identification of cases with clinical mastitis and conducting antibiotic sensitivity tests are recommended. PMID- 29163652 TI - Phylogenic analysis of serotype Asia1 foot-and-mouth disease virus from Sulaimani/Iraq using VP1 protein: heterogeneity with vaccine strain As1/Shamir/89. AB - Foot-and-mouth disease virus (FMDV) serotypes O, A and Asia1 are responsible for a significant number of disease outbreaks in Iraq. The current study can be considered as the first molecular characterization of serotype Asia1 in Iraq. The present investigation reports the detection of serotype FMDV Asia1 from local farms in Sulaimani districts in 2012 and 2014 outbreaks. Phylogenetic analysis of the complete VP1 gene has shown that FMDV Asia1 field isolates were under genetic novel variant Sindh-08 (group VII) including PAK/iso/11 and TUR/13 strains. The VP1 protein sequence of circulatory FMDV Asia1 genotype showed heterogeneity of nine amino acid substitutions within the G-H loop with the vaccine strain As1/Shamir/89 (JF739177) that is currently used in vaccination program in Iraq. Our result indicated that differences in VP1 protein at G-H loop of the locally circulated FMDV serotype Asia1 strain may be a reason for current vaccination failure. PMID- 29163653 TI - Axial pattern flaps, using the deep circumflex iliac artery, superficial brachial and cranial superficial epigastric direct cutaneous arteries in the dog. AB - Three dogs (Boxer, Labrador Retriever and German Shepherd) between the age of 7 10 years were presented with the history of tumour masses on right caudo-lateral thigh, right cranial forearm and left cranial and caudal thoracic mammary gland region, respectively. Fine needle aspiration cytology of the tumour masses and the sentinel regional lymph nodes were done. Plain radiography was done to rule out distant metastasis. In all the three cases the tumour masses were large in size, firmly adherent to the tissues underneath and sufficient loose skin was not available to close the skin defect following surgery. Hence axial pattern flaps were chosen to close the skin defect, following wide margin excision of tumour masses, leaving 3 cm from all the dimensions including healthy tissue. Deep circumflex iliac axial pattern flap, superficial brachial axial pattern flap and cranial superficial epigastric axial pattern flap were chosen to close the skin defect in case 1, case 2 and case 3, respectively. Post-operatively the dogs were admitted in in-patient unit for 5 days to restrict movement of the dog for immobilization of the flap and for wound dressing. All the cases recovered uneventfully with few complications. PMID- 29163654 TI - Editorial. PMID- 29163655 TI - Vector velocity estimation of blood flow - A new application in medical ultrasound. AB - Vector flow techniques in the field of ultrasound encompass different pulse emission and estimation strategies. Numerous techniques have been introduced over the years, and recently commercial implementations usable in the clinic have been made. A number of clinical papers using different vector velocity approaches have been published. This review will give an overview of the most significant in vivo results achieved with ultrasound vector flow techniques, and will outline some of the possible clinical applications for vector velocity estimation in the future. PMID- 29163656 TI - The usefulness of thoracic ultrasonography in diagnosis and staging of bronchogenic carcinoma. AB - Aim: To evaluate (1) the usefulness of thoracic ultrasound in diagnosis and staging of bronchogenic carcinoma by comparing lesion detectability between thoracic- ultrasound and computed tomography and (2) the outcome of thoracic ultrasound-guided biopsy in diagnosing bronchogenic carcinoma. Methods: We conducted a cross-sectional study on 53 patients of confirmed bronchogenic carcinoma. All patients had been investigated by thoracic-ultrasound and chest computed tomography; data regarding the presence of mass (its size, necrosis), lymph nodes invasion, peritumoural atelectasis, consolidations, pleural effusion, chest wall invasion, and paralysis of the diaphragm were recorded. Thoracic ultrasound-guided biopsy was done for 41 patients. Results: Thoracic-ultrasound had significantly higher detection rate of peritumoural atelectasis, paralysis of the diaphragm, and supraclavicular lymph nodes invasion, while it has significantly lower detection rate of pulmonary masses and mediastinal lymph nodes invasion than computed tomography. It has nonsignificant higher detection rate of pleural effusion, consolidations, chest wall invasion and necrosis within mass than computed tomography. Thoracic-ultrasound detects static air-bronchogram and/or fluid bronchogram in 53.3% of bronchogenic carcinoma-associated consolidation. Thoracic-ultrasound-guided biopsy revealed positive yield in 78.0% (32/41) of patients. All patients with negative thoracic-ultrasound biopsy had mass size >5 cm with necrosis within the mass. Self-limited complications occurred in 26.8% after thoracic-ultrasound-guided biopsy (haemoptysis 22.0%, pneumothorax 2.4% and subcutaneous emphysema 2.4%). Conclusion: Thoracic ultrasound has a significant complementary role to computed tomography in diagnosis and staging of bronchogenic carcinoma. Thoracic-ultrasound-guided biopsy revealed good positive yield (78%), its yield was negatively affected by mass size and necrosis. It is a simple, practical and accurate procedure without significant patients' risks. PMID- 29163657 TI - A sonographic Doppler study of the hepatic vein, portal vein and hepatic artery in liver cirrhosis: Correlation of hepatic hemodynamics with clinical Child Pugh score in Singapore. AB - Objective: Liver cirrhosis has been a rising complication of chronic liver disease in Singapore. Ultrasound has been widely accepted as a non-invasive imaging modality for the evaluation of hepatic haemodynamics. This study aims to correlate the Doppler ultrasound values with the progression of liver cirrhosis to allow further understanding and possible prediction of clinical events for timely intervention. Methods: Study sample of 56 eligible patients with liver cirrhosis was divided according to their Child-Pugh clinical score into Child's A (n = 29 patients), B (n = 19 patients) and C (n = 8 patients). The maximum portal vein velocity, maximum hepatic vein velocity, maximum hepatic artery velocity and hepatic artery resistive index were assessed by Doppler ultrasound. Results: The incidence of ascites increases with the severity of cirrhosis. Flattening of the hepatic vein waveforms was dependant on degree of liver cirrhosis. Maximum hepatic vein velocity was higher in cirrhotic patients (where p = 0.05). Maximum portal vein velocity was found to be lower in cirrhosis (where p < 0.001) and mean maximum portal vein velocity decreases as severity of cirrhosis worsens. Hepatic artery resistive index was significantly higher in cirrhosis (where p < 0.001). Significant association was found between maximum hepatic vein velocity and maximum hepatic artery velocity and significant negative correlation was observed with the maximum portal vein velocity and hepatic artery resistive index. Conclusion: The study demonstrated that these parameters can supplement the evaluation of liver cirrhosis and will be able to distinguish the different grades of liver cirrhosis using Doppler ultrasound. PMID- 29163658 TI - Shear wave elastography in the pronator quadratus muscle following distal radial fracture fixation: A feasibility study comparing the operated versus nonoperated sides. AB - The aim of this study was to assess changes in shear wave velocity within the pronator quadratus muscle in patients following volar plate fixation for distal radial fractures compared to the contralateral nonoperated side. Shear wave velocity values were obtained in the short and long axis of the pronator quadratus muscle, which were analyzed separately. Patients were also stratified by age below or above 66 years. Statistical analysis was performed using paired sample Wilcoxon signed rank and t tests. Pearson and Spearman rank correlations were also used. Seventeen patients (nine women and eigth men; age range 33-82, mean 62.4 years) were prospectively assessed following open reduction volar plate fixation of distal radial fracture. A statistically significant reduction in the velocities of the treated versus the nontreated side was observed in the long axis of the muscle (3.29 versus 3.59 m/second; t test p = 0.035). The data provide evidence for shear wave elastography as a quantitative measure to assess postoperative changes in muscle and a potential tool to monitor the efficacy of rehabilitation. PMID- 29163659 TI - Automated quality control of ultrasound based on in-air reverberation patterns. AB - Ultrasound image degradation originates primarily from transducer defects and potentially undermines reliable image interpretation. Systematic quantitative quality control is often neglected due to the limited resources available for this task. We propose a quantitative quality control based on in-air reverberation images. These images serve as an initial indication of image degradation. They are easily generated for any (curvi-)linear transducer independent of the level of expertise of the operator. Automated analysis is presented to extract quality parameters based on the in-air reverberation pattern. Static images acquired by the clinical user are transferred to a server where analysis is performed. The results are available to the sonographer prior to clinical use and transducer status can be remotely monitored with trend analysis over time. The method was evaluated for normal functioning and defect transducers. A pilot study was performed over a period of three weeks to assess reproducibility and practical feasibility. All reverberation images were successfully analysed for different transducer types and vendor-specific image presentation. The proposed quality parameters are sensitive to signal loss and allow differentiation of type and severity of image degradation. The pilot study was well received by the sonographers for the simplicity of the method and the measurements were consistent over time. The proposed automated analysis method of ultrasound quality control can monitor (curvi-)linear transducer status in the entire hospital, overcoming previous limitations for periodic quality control. Implementation of the method can reduce the number of defective transducers routinely used in clinical practice. PMID- 29163660 TI - Testing a new surfactant in a widely-used blood mimic for ultrasound flow imaging. AB - Background: A blood-mimicking fluid developed by Ramnarine et al. has been widely used in flow phantoms for ultrasound flow imaging research, and it has also been cited by IEC 61685 as a reference for making blood-mimicking fluid.However, the surfactant material Synperonic N in this blood-mimicking fluid recipe is phased out from the European market due to environmental issues. The aim of this study is to test whether Synperonic N can be substituted by biodegradable Synperonic A7 in making blood-mimicking fluid for ultrasound flow imaging research. Methods and materials: A flow phantom was fabricated to test the blood-mimicking fluid with Synperonic N and Synperonic A7 as surfactants separately. Doppler images and velocity data were collected using a clinical ultrasound scanner under constant and pulsatile flows; and images and measured velocities were compared. Results: It was found that both blood mimics can provide exactly the same images under spectral Doppler ultrasound and colour Doppler ultrasound in terms of their image qualities. The maximum velocities under constant flow were measured by the spectral Doppler ultrasound as 0.4714 +/- 0.001 m.s-1 and 0.4644 +/- 0.001 m.s-1 for blood-mimicking fluid with Synperonic N and blood-mimicking fluid with Synperonic A7, respectively. Measured velocities using the two different blood mimicking fluids were statistically different (p < 0.001), but this difference was less than 2%. The Synperonic A7 can be used as a substitute for Synperonic N as a surfactant material in making the blood-mimicking fluid for ultrasound flow imaging research. PMID- 29163661 TI - Ultrasound-guided removal of hypopharyngeal foreign body in the emergency department. AB - Foreign body impaction at the cricopharyngeal level can be a life-threatening emergency. While traditionally, removal of these is performed in the operating room setting, patients with relatively unstable airways or significant discomfort may require immediate extraction to prevent further injury. This is the case of an 85-year-old man who presented to the emergency department in significant discomfort following aspiration of a large partial denture. We report here the first known use of ultrasound in an emergent airway situation to rapidly localize and retrieve an aspirated foreign body. PMID- 29163662 TI - A case report of lung ultrasound missing a pneumothorax due to patient positioning. AB - Lung ultrasound is increasingly utilized as a diagnostic tool for the detection of a pneumothorax. The effect of small changes in patient positioning on the accuracy of lung ultrasound to detect a pneumothorax is not well studied. We present the first known case of lung ultrasound missing a pneumothorax because of suboptimal patient positioning, and discuss the implications of our findings for clinicians that utilize lung ultrasound and for future research. PMID- 29163663 TI - An unusual and rare form of truncus arteriosus in an asymptomatic woman. AB - Persistent truncus arteriosus is a rare congenital cardiac malformation. It is characterized by a single great artery arising from the heart which supplies the aorta, the origin of coronary arteries and pulmonary arteries. Without surgery, prognosis is poor and 90% of these patients die before one year of age. We report a rare case of an asymptomatic 35-year-old woman with uncorrected persistent truncus arteriosus and hypoplastic right and left pulmonary arteries. Hypoplastic branch pulmonary arteries prevented the development of severe pulmonary arterial hypertension. PMID- 29163665 TI - Chlorinative stress in age-related diseases: a literature review. AB - Aging is an agglomerate of biological long-lasting processes that result being inevitable. Main actors in this scenario are both long-term inflammation and oxidative stress. It has been proved that oxidative stress induce alteration in proteins and this fact itself is critically important in the pathophysiological mechanisms leading to diseases typical of aging. Among reactive species, chlorine ones such as hypochlorous acid (HOCl) are cytotoxic oxidants produced by activated neutrophils during chronic inflammation processes. HOCl can also cause damages by reacting with biological molecules. HOCl is generated by myeloperoxidase (MPO) and augmented serum levels of MPO have been described in acute and chronic inflammatory conditions in cardiovascular patients and has been implicated in many inflammatory diseases such as atherosclerosis, neurodegenerative conditions, and some cancers. Due to these data, we decided to conduct an up-to-date review evaluating chlorinative stress effects on every age related disease linked; potential anti-oxidant countermeasures were also assessed. Results obtained associated HOCl generation to the aging processes and confirmed its connection with diseases like neurodegenerative and cardiovascular pathologies, atherosclerosis and cancer; chlorination was mainly linked to diseases where molecular (protein) alteration constitute the major suspected cause: i.e. inflammation, tissue lesions, DNA damages, apoptosis and oxidative stress itself. According data collected, a healthy lifestyle together with some dietary suggestion and/or the administration of nutracetical antioxidant integrators could balance the effects of chlorinative stress and, in some cases, slow down or prevent the onset of age-releated diseases. PMID- 29163666 TI - Addressing culture and context in humanitarian response: preparing desk reviews to inform mental health and psychosocial support. AB - Delivery of effective mental health and psychosocial support programs requires knowledge of existing health systems and socio-cultural context. To respond rapidly to humanitarian emergencies, international organizations often seek to design programs according to international guidelines and mobilize external human resources to manage and deliver programs. Familiarizing international humanitarian practitioners with local culture and contextualizing programs is essential to minimize risk of harm, maximize benefit, and optimize efficient use of resources. Timely literature reviews on traditional health practices, cultural beliefs and attitudes toward mental health and illness, local health care systems and previous experiences with humanitarian interventions can provide international practitioners with crucial background information to improve their capacity to work efficiently and with maximum benefit. In this paper, we draw on experience implementing desk review guidance from the World Health Organization (WHO) and UNHCR, the United Nations Refugee Agency (2012) in four diverse humanitarian crises (earthquakes in Haiti and Nepal; forced displacement among Syrians and Congolese). We discuss critical parameters for the design and implementation of desk reviews, and discuss current challenges and future directions to improve mental health care and psychosocial support in humanitarian emergencies. PMID- 29163667 TI - Understanding the unique experiences, perspectives and sexual and reproductive health needs of very young adolescents: Somali refugees in Ethiopia. AB - Background: Kobe Refugee camp hosts roughly 39,000 refugees displaced from Somalia during the 2011-2012 Horn of Africa Crisis. Sexual and reproductive health, as with the greater issues of health and well-being for adolescents displaced from this crisis remain largely unknown and neglected. In 2013, the Women's Refugee Commission, Johns Hopkins University, and International Medical Corps in Ethiopia, implemented qualitative and quantitative research to explore the factors and risks that impact the health of very young adolescents (VYAs), those 10-14 years of age, in this setting. This paper presents findings from the qualitative effort. Methods: Focus group discussions (FGD), incorporating community mapping and photo elicitation activities, were conducted with 10-12 and 13-14 year-olds to obtain information about their own perspectives, experiences and values. FGDs were also implemented with 15-16 year-olds and adults, to consider their perspectives on the sexual and reproductive health needs and risks of VYAs. Results: This research identified several factors that were found to influence the health and well-being of VYAs in Kobe refugee camp, including newfound access to education and security, combined with gender divisions and parental communication around early SRH and puberty that remained intact from traditional Somali culture. Girls were found to face an additional risk of child marriage and early pregnancy exacerbated since displacement, which significantly limited their ability to access education and achieve future aspirations. Conclusion: Findings from this study could help to inform future programs in Kobe and similar contexts involving long-term displacement from conflict, focusing on the health and development needs of VYAs. Future programs should consider the determinants of positive VYA health and development, including access to education, gender equity, and safety.By better understanding the unique experiences, perspectives and needs of VYAs, practitioners, policy makers and donors can invest in the individual and community assets that reinforce positive behaviors established in early adolescence, in order to achieve long-term SRH impacts. PMID- 29163668 TI - Sexual and reproductive health needs and risks of very young adolescent refugees and migrants from Myanmar living in Thailand. AB - Background: The very young adolescent (VYA) population age 10-14 years is often neglected in the field of sexual and reproductive health (SRH) research due to the combined sensitivity of the topic and the young age group, resulting in little data about the SRH needs and concerns of VYA. In 2013, the Women's Refugee Commission (WRC), Johns Hopkins University (JHU), Adolescent and Reproductive Health Network (ARHN) and Karen Youth Organization (KYO) implemented qualitative participatory research to explore the SRH needs and risks of VYA. The study was conducted in Mae Sot town and Mae La refugee camp, both in Thailand, with migrant populations and refugees, respectively. Methods: A total of 22 focus group discussions (FGD) were conducted with 176 participants. FGD were implemented with girls and boys aged 10-16, and adults in both settings. The FGD with 10-14 year olds included community mapping and photo elicitation interviews. These activities gathered information about their own perspectives, experiences and values regarding SRH, as well as SRH risks. The FGD with 15-16 year olds and adults focused on their perspectives regarding the SRH needs and risks of VYA. Results: Fourteen (64%) of FGD were conducted in Mae Sot town, and 8 (36%) were conducted in Mae La refugee camp.Schools, youth centers and religious institutions were identified as key locations for obtaining SRH information. Schools are most promising, but access to schools is unequal between boys and girls. Parents can provide support and education to adolescents if they are supported to do so and if trust and comfort can be built between adolescents and parents around SRH. Conclusions: To a large degree, the same themes emerged from both locations, in terms of the awareness of body changes and puberty, the centrality of peer influences, and the value of education. These findings call for rigorous study of youth-directed programs and policies that meaningfully involve key influential adults identified by vulnerable young adolescents and utilize the specific places young adolescents, themselves, voice as being critical settings for obtaining information on SRH issues. PMID- 29163670 TI - How does technology pathway choice influence economic viability and environmental impacts of lignocellulosic biorefineries? AB - Background: The need for liquid fuels in the transportation sector is increasing, and it is essential to develop industrially sustainable processes that simultaneously address the tri-fold sustainability metrics of technological feasibility, economic viability, and environmental impacts. Biorefineries based on lignocellulosic feedstocks could yield high-value products such as ethyl acetate, dodecane, ethylene, and hexane. This work focuses on assessing biochemical and biomass to electricity platforms for conversion of Banagrass and Energycane into valuable fuels and chemicals using the tri-fold sustainability metrics. Results: The production cost of various products produced from Banagrass was $1.19/kg ethanol, $1.00/kg ethyl acetate, $3.01/kg dodecane (jet fuel equivalent), $2.34/kg ethylene and $0.32/kW-h electricity. The production cost of different products using Energycane as a feedstock was $1.31/kg ethanol, $1.11/kg ethyl acetate, $3.35/kg dodecane, and $2.62/kg ethylene. The sensitivity analysis revealed that the price of the main product, feedstock cost and cost of ethanol affected the profitability the overall process. Banagrass yielded 11% higher ethanol compared to Energycane, which could be attributed to the differences in the composition of these lignocellulosic biomass sources. Acidification potential was highest when ethylene was produced at the rate of 2.56 * 10-2 and 1.71 * 10-2 kg SO2 eq. for Banagrass and Energycane, respectively. Ethanol production from Banagrass and Energycane resulted in a global warming potential of - 12.3 and - 40.0 g CO2 eq./kg ethanol. Conclusions: Utilizing hexoses and pentoses from Banagrass to produce ethyl acetate was the most economical scenario with a payback period of 11.2 years and an ROI of 8.93%, respectively. Electricity production was the most unprofitable scenario with an ROI of - 29.6% using Banagrass/Energycane as a feedstock that could be attributed to high feedstock moisture content. Producing ethylene or dodecane from either of the feedstocks was not economical. The moisture content and composition of biomasses affected overall economics of the various pathways studied. Producing ethanol and ethyl acetate from Energycane had a global warming potential of - 3.01 kg CO2 eq./kg ethyl acetate. PMID- 29163671 TI - Lignocellulose binding of a Cel5A-RtCBM11 chimera with enhanced beta-glucanase activity monitored by electron paramagnetic resonance. AB - Background: The Bacillus subtilis endo-beta-1,4-glucanase (BsCel5A) hydrolyzes beta-1,3-1,4-linked glucan, and the enzyme includes a family 3 carbohydrate binding module (CBM3) that binds beta-1,4-linked glucan. Methods: Here we investigate the BsCel5A beta-1,3-1,4 glucanase activity after exchanging the CBM3 domain for the family 11 CBM from Ruminiclostridium thermocellum celH (RtCBM11) having beta-1,3-1,4 glucan affinity. Results: The BsCel5A-RtCBM11 presents a 50.4% increase in Vmax, a 10% reduction in K0.5, and a 2.1-fold increase in catalytic efficiency. Enzyme mobility and binding to barley beta-1,3-1,4 glucan and pre-treated sugarcane bagasse were investigated using Electron Paramagnetic Resonance (EPR) with Site-Directed Spin Labeling (SDSL) of the binding site regions of the CBM3 and RtCBM11 domains in the BsCel5A-CBM3 and BsCel5A-RtCBM11, respectively. Although higher mobility than the RtCBM11 was shown, no interaction of the spin-labeled CBM3 with beta-1,3-1,4 glucan was observed. In contrast, a Ka value of 0.22 mg/mL was estimated from titration of the BsCel5A-RtCBM11 with beta 1,3-1,4 glucan. Enzyme binding as inferred from altered EPR spectra of the BsCel5A-RtCBM11 was observed only after xylan or lignin extraction from sugarcane bagasse. Binding to xylan- or lignin-free lignocellulose was correlated with a 4.5- to 5-fold increase in total reducing sugar release as compared to the milled intact sugarcane bagasse, suggesting that xylan impedes enzyme access to the beta 1,3-1,4 glucan. Conclusions: These results show that the non-specific binding of the BsCel5A-RtCBM11 to the lignin component of the cell wall is minimal, and represent the first reported use of EPR to directly study the interaction of glycoside hydrolyse enzymes with natural insoluble substrates. PMID- 29163669 TI - Current status and perspectives of genome editing technology for microalgae. AB - Genome editing techniques are critical for manipulating genes not only to investigate their functions in biology but also to improve traits for genetic engineering in biotechnology. Genome editing has been greatly facilitated by engineered nucleases, dubbed molecular scissors, including zinc-finger nuclease (ZFN), TAL effector endonuclease (TALEN) and clustered regularly interspaced palindromic sequences (CRISPR)/Cas9. In particular, CRISPR/Cas9 has revolutionized genome editing fields with its simplicity, efficiency and accuracy compared to previous nucleases. CRISPR/Cas9-induced genome editing is being used in numerous organisms including microalgae. Microalgae have been subjected to extensive genetic and biological engineering due to their great potential as sustainable biofuel and chemical feedstocks. However, progress in microalgal engineering is slow mainly due to a lack of a proper transformation toolbox, and the same problem also applies to genome editing techniques. Given these problems, there are a few reports on successful genome editing in microalgae. It is, thus, time to consider the problems and solutions of genome editing in microalgae as well as further applications of this exciting technology for other scientific and engineering purposes. PMID- 29163672 TI - Contribution of riboflavin supply pathways to Vibrio cholerae in different environments. AB - Background: The waterborne diarrheagenic bacterium Vibrio cholerae, cause of the pandemic cholera disease, thrives in a variety of environments ranging from estuarine waters to the human intestinal tract. This species has two ways to obtain the essential micronutrient riboflavin, de novo biosynthesis and environmental uptake through the RibN importer. The way these functions interrelate to fulfill riboflavin needs in different conditions in this species is unknown. Results: This study analyzed the contributions of riboflavin biosynthesis and transport to the culturability of Vibrio cholerae in river and seawater in vitro and in the Caenorhabditis elegans nematode host model. Elimination of the ribD riboflavin biosynthetic gene renders the bacteria riboflavin-auxotrophic, while a ribN mutant strain has no growth defect in minimal media. When growing in river water, deletion of ribD causes an impairment in culturability. In this condition, the ?ribN strain has a defect to compete against a wild type strain but outcompetes the ?ribD strain. The latter effect is inverted by the addition of riboflavin to the water. In contrast, growth in seawater causes a loss in culturability independent of riboflavin biosynthesis or transport. In the C. elegans model, only the ?ribD strain is attenuated. Conclusion: Results indicate that while riboflavin biosynthesis seems to outweigh riboflavin uptake, the latter may still provide a selective advantage to V. cholerae in some environments. PMID- 29163673 TI - Effects of pioglitazone therapy on blood parameters, weight and BMI: a meta analysis. AB - Background: Type 2 diabetes mellitus (T2DM) is one of the most common diseases worldwide and insulin insufficiency and insulin resistance are two main metabolic issues connected with it. The dyslipidemia associated with insulin resistance and T2DM is characterized by higher triglycerides (TGs), higher very-low-density lipoprotein cholesterol and lower apo A1. Pioglitazone, a member of the thiazolidinedione class, with a proven antihyperglycemic effect, is known to positively influence insulin sensitivity and beta-cell function and to have the potential to alter the lipid profile. Methods: The aim of our meta-analysis is to summarize and determine the influence of pioglitazone on the glycemic profile and lipoprotein metabolism as well as on weight and BMI in order to highlight the benefit of pioglitazone therapy in patients with T2DM. A comprehensive literature search was conducted through the electronic databases PubMed, MEDLINE, Scopus, PsyInfo, eLIBRARY.ru (from 2000 until February 2016) to identify studies that investigate the effect of pioglitazone on the glycemic and lipid profile and on the weight and BMI. We chose the random-effects method as the primary analysis. Forest plots depict estimated results from the studies included in the analysis and funnel plots are used to evaluate publication bias. Sensitivity analyses were performed in order to evaluate the degree of influence of the consequent elimination of each individual study on the final result. Results: Of the 1536 identified sources only 15 randomised trials were included in the meta-analysis. Pioglitazone treatment was associated with improvement in the glycemic profile. It reduced FPG levels by a mean of 1.1-2 mmol/l and HbA1c by a mean of 0.9-1.3%. Our results reaffirmed the hypothesis that pioglitazone has a positive influence on the lipid profile of T2DM patients with increase in TC and HDL, no significant changes in LDL and notable decrease in TGs. Results also showed that pioglitazone therapy led to increase in both weight and BMI (WMD 1.755, 95% CI 0.674 to 2.837 and 1.145, 95% CI 0.389 to 1.901 respectively). Conclusion: Our results prove that the PPAR gamma agonist pioglitazone has the potential to be beneficial to patients with T2DM. PMID- 29163674 TI - Clinical value of homodynamic numerical simulation applied in the treatment of cerebral aneurysm. AB - Our objective was to evaluate the clinical value of numerical simulation in diagnosing cerebral aneurysm based on the analysis of numerical simulation of hemodynamic model. The experimental method used was the numerical model of cerebral aneurysm hemodynamic, and the numerical value of blood flow at each point was analyzed. The results showed that, the wall shear stress (WSS) value on the top of CA1 was significantly lower than that of the top (P<0.05), the WSS value of each point on the CA2 tumor was significantly lower than that of tumor neck (P<0.05); the pressure value on the tumor top and tumor neck between CA1 and CA2 had no significant difference (P>0.05); the unsteady index of shear (UIS) value at the points of 20 had distinctly changed, the wave range was 0.6-1.5; the unsteady index of pressure value of every point was significantly lower than UIS value, the wave range was 0.25-0.40. In conclusion, the application of cerebral aneurysm hemodynamic research can help doctors to diagnose cerebral aneurysm more precisely and to grasp the opportunity of treatment during the formulating of the treatment strategies. PMID- 29163675 TI - Effects of different concentrations of type-I collagen hydrogel on the growth and differentiation of chondrocytes. AB - The objective of this study was to analyze the effects of type-I collagen hydrogel of different concentrations on the growth and differentiation of rabbit chondrocytes. Articular cartilage from New Zealand white rabbits was harvested and cultured. Second-generation chondrocytes were collected for in vitro culture with 10, 7, and 5 mg/ml type-I collagen hydrogel, respectively (denoted as groups A, B, and C). After in vitro culture for 1 day, chondrocytes were stained with fluorescein diacetate (FDA)/propidium iodide (PI), and cell viability was observed by laser confocal microscopy. After in vitro culture for 14 days, the histological patterns were observed by H&E and toluidine blue staining. The expression of chondrocyte-related genes were measured by real-time quantitative RT-PCR. After in vitro culture for 1 day, FDA/PI staining showed that the cell density of group A was significantly higher than that of group B and C. After in vitro culture for 14 days, H&E staining showed that chondrocytes showed obvious aggregation in group A, partial proliferation and aggregation in group B, and uniform distribution in group C. Toluidine blue staining showed that chondrocytes in group A had aggregation areas and some were stained purple-red, fewer chondrocytes were aggregated with different staining around them in group B, and the aggregation of chondrocytes was not obvious. However, the distribution of chondrocytes was uniform with different staining in group C. After in vitro culture for 2 weeks, the levels of polymerized proteoglycan and type-II collagen mRNA were not significantly different between the three groups (P>0.05). The levels of type-I collagen, type-X collagen, and Sox9 mRNA in group A were significantly higher than those in group B and C (P<0.05). In conclusion, high concentration type-I collagen hydrogel can promote chondrocyte fibrosis and upregulation of type-I collagen, type-X collagen, and Sox9 mRNA. PMID- 29163676 TI - Effects of calcium channel on ovarian cancer cells. AB - The aim of the present study was to examine the effects of calcium channel protein on ovarian cancer cells. The expression of calcium channel protein in normal ovarian cells and ovarian cancer cells was detected by fluorescence quantitative PCR. Subsequently, the ovarian cancer cells were added to calcium channel protein activator media at various concentrations of 0, 1, 4, 8, 12, 16 and 20 mmol/l. The concentration of calcium ion in different samples was produced, and using an MTT assay, ovarian cancer cell activity in various samples was detected. Finally, a flow cytometer was used to explore the apoptosis rate. It was found that there was a significant difference between the expression of calcium channel protein in normal ovarian tissue and ovarian cancer cells (P<0.05), as well as a significant difference of calcium concentration among various samples (P<0.05). When the concentrations of calcium channel activator were 1, 4, 8, 12, 16 and 20 mmol/l, the values of the ovarian cancer cell inhibition rates were 4.6, 21.3, 48.3, 67.9, 52.8 and 31.8%, respectively. It showed that the calcium channel activator inhibited the proliferation of ovarian cancer cells to a certain extent, in a dose-dependent manner, especially when the concentration was at 12 mmol/l at which the intracellular calcium concentration was similar to that in normal ovarian cells. In conclusion, calcium ions play an important role in promoting cell proliferation of ovarian cancer cells, and they were involved in apoptosis of ovarian cancer cells to some extent, which regulates apoptosis by controlling the content of intracellular calcium. PMID- 29163677 TI - TRIM37 promotes tumor cell proliferation and drug resistance in pediatric osteosarcoma. AB - Osteosarcoma (OS) is among the most frequently occurring bone tumors, particularly in children. Clinical treatment of OS is limited due to several factors including resistance to chemotherapy drugs and metastasis, and the underlying molecular mechanisms remain unclear. In the present study, tripartite motif containing 37 (TRIM37) expression levels were upregulated in tumor samples and associated with the development of drug resistance in OS. Furthermore, chemotherapy drug treatment (doxorubicin, cisplatin and methotrexate) induced TRIM37 expression in OS cells in vitro. TRIM37 mRNA and protein were upregulated in 41 pediatric osteosarcoma clinical specimens. To further elucidate the effect of TRIM37, gain and loss-of-function analysis was performed. Overexpression of TRIM37 induced cell proliferation and drug resistance ability of OS cells, whilst TRIM37 knockdown suppressed cell growth rate and restored chemosensitivity. TRIM37-regulated genes were subsequently analyzed by expression microarray and gene set enrichment analysis. Using the Wnt/beta-catenin inhibitor XAV-939, the present study demonstrated that TRIM37-induced chemoresistance is partially dependent on the activation of the Wnt/beta-catenin signaling pathway. Collectively, the results of the present study suggest that TRIM37 may have a key role in the development of OS and in the ability for the cells to acquire drug resistance, thus it may be a novel target for the treatment of OS. PMID- 29163678 TI - MicroRNA-497 inhibits tumor growth through targeting insulin receptor substrate 1 in colorectal cancer. AB - MicroRNAs (miRNAs) have been demonstrated to serve an important role in diverse biological processes and cancer progression. Downregulation of microRNA-497 (miR 497) has been observed in human colorectal cancer (CRC) tissues, but the function of miR-497 in CRC has not been well investigated. In the present study, it was demonstrated that expression of miR-497 was significantly downregulated in human CRC tissues compared to adjacent normal tissues. Enforced expression of miR-497 inhibited proliferation, migration and invasion abilities of CRC cell lines SW1116 and SW480. Furthermore, overexpression of miR-497 inhibited phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling by targeting insulin receptor substrate 1 (IRS1). In human clinical specimens, IRS1 was inversely correlated with miR-497 in CRC tissues. Collectively, the results of the present study demonstrate that miR-497 is a tumor suppressor miRNA and indicate its potential application for the treatment of human CRC in the future. PMID- 29163679 TI - Identification of molecular mechanisms of glutamine in pancreatic cancer. AB - The aim of the present study was to explore the critical genes and molecular mechanisms in pancreatic cancer (PC) cells with glutamine. By analyzing microarray data GSE17632 from the Gene Expression Omnibus database, the DEGs between PC cells treated with glutamine and without glutamine were evaluated. Additionally, function enrichment analyses and protein-protein interaction (PPI) network construction of DEGs were performed. Network module and literature mining analyses were performed to analyze the critical DEGs in PC cells. In total, 495 genes were selected as DEGs between control and glutamine cells in PC. These DEGs were mainly enriched in several Gene Ontology (GO) terms in biological process, cellular components and molecular function. Additionally, they were also enriched in certain pathways, including metabolic pathways and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. MYC, heat shock 70kDa protein 5 (HSPA5), interleukin 8 (IL8), and chemokine (C-X-C motif) receptor 4 (CXCR4) were hub genes in the PPI network. Furthermore, two sub network modules of PPI network and two co-occurrence networks were obtained. The DEGs of MYC, HSPA5, IL18 and CXCR4 may exert important roles in molecular mechanisms of PC cells with glutamine. PMID- 29163680 TI - Yi-qi-yang-yin-tang increases the sensitivity of KG1a leukemia stem cells to daunorubicin by promoting cell cycle progression and regulating the expression of PTEN, TOPOII and mTOR. AB - The present study aimed to investigate the effects of serum containing a combination of yi-qi-yang-yin-tang (YQYYT) and daunorubicin (DNR) on multidrug resistance in KG1a leukemia stem cells (LSCs). The effects of YQYYT and DNR on proliferation, cell cycle progression and the expression of phosphatase and tensin homolog (PTEN), topoisomerase II (Topo II) and mechanistic target of rapamycin (mTOR) in KG1a cells were investigated in vitro using cell counting kit 8 assay, flow cytometry, reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. It was revealed that YQYYT containing serum did not affect proliferation of KG1a cells compared with the blank group. Furthermore, there were no significant differences on the inhibition of proliferation among different groups at various concentrations of YQYYT. Treatment with YQYYT-containing serum (volume, 20 and 40 ul) and DNR was able to significantly inhibit the proliferation of KG1a cells compared with the blank group. The inhibition rate in the treatment group with YQYYT-containing serum (40 ul) and DNR for 48 h (72.5%) was higher compared with treatment for 24 h (60.4%, P<0.01). Treatment with YQYYT-containing serum was able to promote G0 phase of KG1a cells into cell cycle in a dose- and time-dependent manner, and significantly upregulated the mRNA expression of PTEN and Topo II, but did not affect mTOR expression compared with the blank group. Treatment with serum containing YQYYT alone did not directly affect the proliferation of KG1a cells, but when the cells were treated with a combination of YQYYT-containing serum and DNR, the proliferation of KG1a cells was significantly inhibited in a dose- and time-dependent manner. Furthermore, treatment with YQYYT-containing serum was able to promote cell cycle progression of KG1a cells in the G0 phase and upregulate the expression of the negative regulatory genes PTEN and Topo II. These results indicated the potential of YQYYT to reverse multidrug resistance in LSCs. PMID- 29163681 TI - The prognostic value of neutrophil to lymphocyte and platelet to lymphocyte ratios for patients with lung cancer. AB - As the leading cause of cancer-associated mortality globally among males in 2012, lung cancer is a disease of particular concern. Previously, the neutrophil-to lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) were revealed to be prognostic factors for various types of cancer, including lung cancer. In the present study, a retrospective review was conducted with patients who were diagnosed with lung cancer between January 1, 2000 and December 31, 2005 in the Fourth Hospital of Hebei Medical University. A total of 695 patients were included, and the optimal cutoffs of the NLR and the PLR were 6.0 and 248.0, respectively. There were statistically significant associations between tumor node-metastasis (TNM) stage, surgery, metastasis incidence and NLR (P<0.001). The associations between TNM stage, surgery incidence and PLR were also revealed to be statistically significant (P<0.001). Patients in the low NLR group demonstrated longer overall survival (OS) than patients in the high NLR group (819.57 days vs. 629.86 days, P=0.041). The NLR at diagnosis was demonstrated to be an independent prognostic factor for OS. Thus, the NLR may be a promising approach for predicting the prognosis of patients with lung cancer. PMID- 29163682 TI - Hypoxia induces the expression of TET enzymes in HepG2 cells. AB - Hypoxia promotes tumor malignancy in solid tumors. One key mechanism by which this occurs is via epigenetic alteration. The present study demonstrates that hypoxia upregulates the expression of the ten-eleven-translocation 5 methylcytosine dioxygenase (TET) enzymes, which catalyze the conversion of 5 methylcytosine to 5-hydroxymethylcytosine (5-hmC), thereby leading to elevated cellular 5-hmC levels in hepatoblastoma HepG2 cells. Hypoxia inducible factor 1alpha (HIF-1alpha) is the main transcription factor activated by hypoxia. A chemical inducer of HIF-1alpha, CoCl2, also increases the expression of TET enzymes. Knockdown of HIF-1alpha attenuates the hypoxia-induced expression of TET enzymes. These results indicate that hypoxia controls DNA methylation through HIF 1alpha-mediated TET enzyme regulation in HepG2 cells. PMID- 29163683 TI - Knockdown of HMGN5 increases the chemosensitivity of human urothelial bladder cancer cells to cisplatin by targeting PI3K/Akt signaling. AB - High-mobility group nucleosome-binding domain 5 (HMGN5) is the latest member of the HMGN family of proteins. Numerous studies have confirmed the carcinogenic role of HMGN5 in cancer, but its function in the regulation of chemosensitivity is largely unknown and controversial. A previous study by the authors of the present study demonstrated that HMGN5 contributes to the progression of urothelial bladder cancer (UBC) through regulating the expression of E-cadherin and vascular endothelial growth factor (VEGF)-C, which are associated with the sensitivity of tumor cells to cisplatin. Therefore, the present study aimed to elucidate the mechanisms underlying the regulation of HMGN5 and investigate the involvement of HMGN5 in cisplatin treatment. The results of the present study revealed that HMGN5 is able to positively regulate the expression of phosphorylated (p-)Akt in UBC cells. In addition, HMGN5 expression was negatively associated with the response of UBC cells to cisplatin. The findings indicated that HMGN5 may be a potential therapeutic target of cisplatin treatment, since cisplatin treatment reduced HMGN5 expression in a dose-dependent manner. It was also confirmed that the knockdown of HMGN5 decreased the viability, colony formation and invasion of 5637 cells but increased apoptosis under cisplatin treatment. The changes caused by HMGN5 knockdown in 5637 cells were able to be reversed by treatment with insulin-like growth factor-1 (IGF-1), which is a phosphoinositide 3-kinase (PI3K)/Akt signaling activator. Additionally, with the decreased expression of HMGN5, the expression of p-Akt, slug, E-cadherin and VEGF C was subsequently inhibited. By contrast, the expression of cytochrome c, cleaved-caspase-3 and cleaved-poly ADP ribose polymerase was increased following HMGN5 knockdown. Consistently, these changes in protein expression were able to be reversed by IGF-1 treatment. In conclusion, findings from the in vitro experiments indicate that HMGN5 may a target of cisplatin treatment and that the inhibition of HMGN5 increases the chemosensitivity of UBC cells by inhibiting PI3K/Akt signaling. PMID- 29163684 TI - Novel peptide screened from a phage display library antagonizes the activity of CC chemokine receptor 9. AB - CC chemokine receptor 9 (CCR9) serves a role in the drug resistance and metastasis of tumors. In the present study, a peptide specifically bound to CCR9 was obtained and the effect on tumor cells was observed. A Ph.D.-12 phage display peptide library was used to screen for peptides binding specifically to the second extracellular loop of CCR9. The ratios of the input and output of phage clones increased gradually following three rounds of biopanning. A total of 8 positive phage clones were identified from DNA analysis. A phage clone, C-4, was identified which exhibited higher affinity and specificity for the second extracellular loop of CCR9 in vitro compared with other clones. A peptide (P1; VHWDFRQWWQPS) was identified which may inhibit the corresponding phage, C-4, binding to the second extracellular loop of CCR9. Furthermore, P1 was able to bind specifically with MOLT4 cells which exhibit marked expression of CCR9. In addition, P1 promoted the apoptosis of MOLT4 cells induced by doxorubicin, and inhibited the migration of MOLT4 cells in the presence of chemokine (C-C motif) ligand 25. It was suggested that decreased activity in the phosphorylation of protein kinase B in MOLT4 cells may be responsible for the inhibition. In conclusion, the peptide P1 derived from a screened phage is able to specifically bind to CCR9 and inhibit the activity of CCR9. It has potential use as an antagonist in the treatment of CCR9-overexpressed carcinoma. PMID- 29163685 TI - Expression of cancer/testis antigens MAGE-A, MAGE-C1, GAGE and CTAG1B in benign and malignant thyroid diseases. AB - Despite considerable advances in the understanding of thyroid gland biology, correctly diagnosing thyroid nodules and treating high-grade thyroid carcinoma remains challenging. Cancer/testis (CT) antigens have emerged as potential diagnostic tools as well as targets of potential cancer vaccinations. In the present study, a total of 117 patients who underwent surgical therapy for thyroid disease were available for analysis. The expression levels of melanoma-associated antigen (MAGE) A, MAGE-C1/CT7, cancer/testis antigen 1B (CTAG1B) and G antigen (GAGE) were analyzed by immunohistochemistry. None of the CT antigens were expressed in the normal thyroid or goiter. In papillary and follicular carcinoma, MAGE-A was present in 8.1% of cases, GAGE in 10.8% and CT/7MAGE-C1 and CTAG1B in 2.7% each. In medullary carcinoma, CT antigen expression was as follows: MAGE-A in 42.9% of patients; MAGE-C1/CT7 in 46.5%; GAGE in 92.9%; and CTAG1B in 3.6%. A statistically significant association was observed between the expression of G MAGE-C1/CT7 and patient gender as well as patient clinical stage (P=0.029 and 0.031, respectively). In poorly differentiated and anaplastic carcinoma cases, CT antigen expression was as follows: MAGE-A in 61.8% of cases; MAGE-C1 in 57.1%; GAGE in 66.7%; and CTAG1B in 14.4%. There was a statistically significant association between expression of GAGE and gender (P=0.043). However, there was no association between CT antigen expression and patient survival in any of the tumor entities analyzed. The current study identified a distinct expression pattern of CT antigens in malignant thyroid tumors indicating that CT antigens have the potential to outperform existing thyroid cancer biomarkers. The prevalence of CT antigens in high-grade carcinomas suggests that they serve an important biological role within malignant tumors. PMID- 29163686 TI - Characterization of distinct types of KRAS mutation and its impact on first-line platinum-based chemotherapy in Chinese patients with advanced non-small cell lung cancer. AB - We performed this retrospective study to investigate whether the KRAS mutation status and its subtypes could predict the effect of first-line platinum-based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC). Patients received who had KRAS mutations were enrolled. Correlations between KRAS mutations, specific mutant subtypes and responses to chemotherapy were analyzed using Kaplan-Meier and Cox proportional hazard methods. A total of 2,183 cases who received KRAS mutation detection were included. A total of 218 of these cases were indicated to have KRAS mutations. KRAS mutations were identified more commonly in males compared with females (P=0.035). The most common subtypes were G12C, G12D and G12V. Among 73 KRAS mutant patients and 100 EGFR/ALK/KRAS wild type patients with advanced NSCLC, KRAS-mutant NSCLC patients had a significantly shorter progression-free survival (P=0.007) compared with NSCLC patients with KRAS wild-type. In addition, there was a shorter but marginally statistically significant progression-free survival (PFS) in KRAS mutant patients with adenocarcinoma compared with those with non-adenocarcinoma (P=0.051). In the KRAS mutant group, patients with the KRAS G12V mutation had the poorest PFS compared with non-G12V mutant cases (P=0.045). In conclusion, KRAS mutation was a negative predictive factor of PFS in Chinese patients with advanced NSCLC who received first platinum-based chemotherapy. Patients with KRAS G12V mutations exhibited the poorest PFS compared with those with other KRAS mutant types. PMID- 29163687 TI - Stromal regulation of prostate cancer cell growth by mevalonate pathway enzymes HMGCS1 and HMGCR. AB - It has been suggested that the tumor microenvironment plays an important role in tumor progression, acquisition of androgen independence, and distant metastasis in prostate cancer (PC). However, little is known about the transcriptional basis of cellular interactions in the human PC microenvironment. To clarify the mechanism of PC progression and metastasis, we investigated the interaction of PC, epithelial, and stromal cells using genome-wide gene expression profiling. We hypothesized that PC cells could induce stromal cells to differentiate into so called cancer-associated fibroblasts (CAFs), which might contribute to cancer invasion and metastasis. Genes upregulated in normal human prostate stromal cells (PrSC) co-cultured with human PC cells (LNCaP) included the mevalonate pathway enzymes 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and 3-hydroxy-3 methylglutaryl-CoA reductase (HMGCR). Knockdown of endogenous HMGCS1 or HMGCR in PC cells by shRNA resulted in a significant reduction of PC cell viability. Importantly, exogenous overexpression of HMGCS1 or HMGCR in either PC cells or prostate stromal cells stimulated PC cell growth, suggesting a possible autocrine/paracrine mechanism of action. Immunohistochemical analysis confirmed that HMGCS1 and HMGCR were overexpressed in PC stroma, especially in early stage PC. These results provide clues to the molecular mechanisms underlying PC invasion and metastasis, and suggest that HMGCS1 and HMGCR in PC, as well as in PC stroma, might serve as molecular targets for the treatment of PC. PMID- 29163688 TI - FoxM1 is associated with metastasis in colorectal cancer through induction of the epithelial-mesenchymal transition. AB - The aim of the present study was to investigate the role of forkhead box M1 (FoxM1) in epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer (CRC). Immunohistochemical assays were performed to detect FoxM1 and epithelial (E-) cadherin protein expression in 92 CRC, 61 colonic adenoma and 32 wild-type colonic tissue samples. Quantitative polymerase chain reaction (qPCR) assays were performed to determine the expression levels of FoxM1 and E-cadherin mRNAs in 30 CRC and adjacent normal mucosal tissues. RNA interference was used to knock down endogenous FoxM1 expression in CRC cell lines, and the migratory and invasive capacity of the CRC cells was analyzed. The expression of FoxM1, E cadherin and neuronal (N-) cadherin in the CRC cell lines was evaluated using qPCR and Western blot analysis. The relative expression levels of FoxM1 mRNA and protein were significantly increased in the CRC tissues compared with those in the colonic adenoma and wild-type mucosal tissue samples (P<0.01). In contrast, the relative expression levels of E-cadherin mRNA and protein were significantly decreased in the CRC tissues compared with in the colonic adenoma and normal mucosal tissues (P<0.01). FoxM1 overexpression and decreased E-cadherin expression were significantly associated with poor colonic tissue differentiation, lymph node metastasis and an advanced tumor-node-metastasis stage. Additionally, the increased expression of FoxM1 was associated with a decrease in E-cadherin expression (P<0.01). Furthermore, RNA interference mediated FoxM1 knockdown significantly inhibited the proliferation, migration and invasion of CRC cells. Downregulation of FoxM1 expression significantly increased E-cadherin expression and decreased N-cadherin expression. The results of the present study suggest that FoxM1 overexpression in tumor tissues is significantly associated with metastasis in CRC through the induction of EMT. PMID- 29163689 TI - Aurora kinase A inhibitor TCS7010 demonstrates pro-apoptotic effect through the unfolded protein response pathway in HCT116 colon cancer cells. AB - Aurora kinase A (AURKA) is essential for regulating mitosis and is frequently amplified in various cancer cell types. However, the effect of AURKA inhibition on the induction of apoptosis remains unclear. In the present study, it was reported that treatment with TCS7010, a specific inhibitor of AURKA, resulted in the accumulation of cells in the sub-G0/G1 phase of the cell cycle and increased the percentage of annexin V-binding cells. The cleavage of caspase-2, caspase-7, and poly(ADP-ribose)polymerase (PARP) significantly increased in a time-dependent manner following TCS7010 treatment. In addition, TCS7010 resulted in the production of reactive oxygen species (ROS) and stimulation of the unfolded protein response (UPR), leading to the upregulation of CCAAT/enhancer-binding protein-homologous protein (CHOP), and its downstream target BCL2 like 11 (BIM). Pretreatment with N-acetylcystein, a ROS scavenger, significantly abrogated TCS7010-induced accumulation of CHOP, BIM, cleaved caspase-7 and cleaved PARP. These results suggest that TCS7010 triggers apoptosis through the ROS-mediated UPR signaling pathway. PMID- 29163690 TI - Delisheng induces antiproliferation and apoptosis effects in Hep3B cells via modulation of angiogenic proteins. AB - Delisheng is a widely used antineoplastic agent in China. Although previous studies revealed that Delisheng exhibits numerous pharmacological effects including the inhibition of cancer cell differentiation and enhancement of immune function with the lowest toxicity, the precise anticancer mechanisms of Delisheng in human hepatocellular carcinoma (HCC) cells remains largely unknown. The present study investigated the potential mechanisms underlying the anticancer properties of Delisheng on Hep3B cells. Delisheng demonstrated a strong anti proliferation effect on Hep3B cells compared with normal liver HL-7702 cells, as detected by MTT assays. In addition, Delisheng arrested the cells in G/G1 phase. Furthermore, it exhibited a pro-apoptotic effect on Hep3B cells, as detected by flow cytometry. When exposed to Delisheng, Hep3B cells demonstrated decreased vascular endothelial growth factor (VEGF) and osteopontin (OPN) and increased endostatin (ES) protein expressions, as detected using immunocytochemistry staining and western blotting. These data suggest that Delisheng induces antiproliferation and apoptosis of Hep3B cells via modulation of VEGF, OPN and ES protein expression. It is hypothesized that Delisheng may be used as a novel anticancer therapeutic in HCC. PMID- 29163691 TI - Autophagy inhibition contributes to Endostar sensitization in esophageal squamous cell carcinoma. AB - Endostar is a novel artificially-synthesized anti-angiogenesis drug, and has been approved for clinical use. Previous studies have indicated that patients with esophageal cancer could benefit from Endostar combined with chemotherapy or chemoradiotherapy. However, the most advantageous use of this drug remains to be elucidated. The role of autophagy in cancer treatment remains controversial. The results of the present study demonstrated that Endostar promotes autophagy activation, which is regulated via phosphorylation inhibition of the downstream signaling molecules of the vascular endothelial growth factor, AKT serine/threonine kinase and mechanistic target of rapamycin signaling pathways. Furthermore, inhibiting autophagy using the pharmacological inhibitor chloroquine facilitated the antiproliferative effect of Endostar and increased the number of apoptotic cells, compared with Endostar monotherapy. Taken together, the results of the present study suggest that autophagy activation induced by Endostar serves a protective role in human esophageal cancer treatment, and that autophagy inhibition promotes the antiproliferative role of Endostar. Therefore, the combination of Endostar with an autophagy inhibitor may be a novel prospective approach to improving the efficacy of Endostar for the treatment of patients with esophageal cancer. PMID- 29163692 TI - Clinical significance and biological role of Wnt10a in ovarian cancer. AB - Ovarian cancer is one of the five most malignant types of cancer in females, and the only currently effective therapy is surgical resection combined with chemotherapy. Wnt family member 10A (Wnt10a) has previously been identified to serve an oncogenic function in several tumor types, and was revealed to have clinical significance in renal cell carcinoma; however, there is still only limited information regarding the function of Wnt10a in the carcinogenesis of ovarian cancer. The present study identified increased expression levels of Wnt10a in two cell lines, SKOV3 and A2780, using reverse transcription-polymerase chain reaction. Functional analysis indicated that the viability rate and migratory ability of SKOV3 cells was significantly inhibited following Wnt10a knockdown using short interfering RNA (siRNA) technology. The viability rate of SKOV3 cells decreased by ~60% compared with the control and the migratory ability was only ~30% of that in the control. Furthermore, the expression levels of beta catenin, transcription factor 4, lymphoid enhancer binding factor 1 and cyclin D1 were significantly downregulated in SKOV3 cells treated with Wnt10a-siRNA3 or LGK 974, a specific inhibitor of the canonical Wnt signaling pathway. However, there were no synergistic effects observed between Wnt10a siRNA3 and LGK-974, which indicated that Wnt10a activated the Wnt/beta-catenin signaling pathway in SKOV3 cells. In addition, using quantitative PCR, Wnt10a was overexpressed in the tumor tissue samples obtained from 86 patients with ovarian cancer when compared with matching paratumoral tissues. Clinicopathological association analysis revealed that Wnt10a was significantly associated with high-grade (grade III, P=0.031) and late-stage (T4, P=0.008) ovarian cancer. Furthermore, the estimated 5-year survival rate was 18.4% for patients with low Wnt10a expression levels (n=38), whereas for patients with high Wnt10a expression (n=48) the rate was 6.3%. The results of the present study suggested that Wnt10a serves an oncogenic role during the carcinogenesis and progression of ovarian cancer via the Wnt/beta catenin signaling pathway. PMID- 29163693 TI - Association between spectral computed tomography images and clinicopathological features in advanced gastric adenocarcinoma. AB - To investigate the role of spectral computed tomography (CT)-generated iodine concentration (IC) in the evaluation of clinicopathological features of advanced gastric adenocarcinoma (AGC), 42 patients who underwent abdominal enhanced CT with spectral imaging mode were selected for the present study. The IC of the primary lesion in the arterial phase (ICAP) and portal venous phase (ICVP) was measured and the IC of the aorta was used for a normalized iodine concentration (nIC). Micro-vessel density (MVD) and lymphatic vessel density (LVD) were detected using immunohistochemical assays against cluster of differentiation 34 and D2-40, respectively. Other clinicopathological characteristics were also documented. The IC parameters were revealed to be significantly increased in the high-MVD group, particularly for the nICVP (P=0.002). Additionally, the nICAP revealed a significant difference (P=0.041) between the high- and low-LVD group. The nICAP and nICVP were increased in the poorly differentiated group compared with the moderately differentiated group (P=0.040 and P=0.011, respectively). The ICs and MVD demonstrated a statistically significant positive linear correlation. nICVP was able to be used to discriminate between the moderately and poorly differentiated carcinomas, with an area under the receiver operating characteristic curve of 0.759. However, IC demonstrated no correlation with serosal involvement, lymph node metastasis, LVD, and nodular or metastatic tumors. The results of the present study suggest that the nICVP value may serve as a non-invasive marker for the angiogenesis of, and the differentiations between, patients with AGC. PMID- 29163694 TI - Exploration of the mechanism of colorectal cancer metastasis using microarray analysis. AB - The aim of the present study was to investigate the mechanism of metastasis in colorectal cancer (CRC) using microRNA (miRNA) and mRNA expression profiles. The mRNA and miRNA expression profiles of the GSE2509 and GSE56350 datasets were obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified using the limma software package. The Database for Annotation, Visualization and Integrated Discovery was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs. The predicted target genes associated with the DEMs were identified using the miRWalk database and the enrichment analysis was conducted using the clusterProfiler package. The miRNA gene molecular interaction network was visualized using the Cytoscape software platform. A total of 544 DEGs and 42 DEMs were identified. DEGs were annotated in 320 GO terms and 11 KEGG pathways. Overall, 366 miRNA-gene pairs were identified and the miRNA-gene network was visualized. Furthermore, the predicted target genes were mainly classified in 12 pathways. The results of the present study suggest that fibronectin type III domain-containing 3B, cysteine rich transmembrane BMP regulator 1 and forkhead box J2 may be potential therapeutic and prognostic targets of metastatic CRC. In addition, pathways in cancer, the Wnt signaling pathway and extracellular matrix-receptor interaction may play a critical role in CRC metastasis. PMID- 29163695 TI - Ouabain targets the Na+/K+-ATPase alpha3 isoform to inhibit cancer cell proliferation and induce apoptosis. AB - Ouabain has been used for the treatment of heart failure and atrial fibrillation. Its potential anticancer effect has also attracted great interest. The aim of the present study was to evaluate the anticancer effect of ouabain and investigate its molecular target. The effects of ouabain on the viability of and induction of cellular death on OS-RC-2 renal cancer cells were examined using the MTT assay and acridine orange/ethidium bromide staining. The levels of Ca2+ and reactive oxygen species were determined using Fura-3-acetoxymethyl ester and dichloro dihydro-fluorescein diacetate probes, respectively. Apoptosis was examined using annexin V-fluorescein isothiocyanate/propidium iodide staining and western blotting. The expression profile of the different Na+/K+-ATPase (NKA) isoforms in NCI-H446 small cell lung cancer cells was determined using immunocytochemistry and reverse transcription polymerase chain reaction analysis. In the present study, it was demonstrated that ouabain inhibited cancer cell proliferation and induced apoptosis while no significant difference in the expression of NKA alpha1 and alpha3 isoforms was detected following 48 h of ouabain treatment. Furthermore, expression of NKA alpha3 but not the alpha1 isoform was associated with ouabain sensitivity. The results of the present study indicated that ouabain targets the NKA alpha3 isoform, inhibits cancer cell proliferation and induces apoptosis. PMID- 29163696 TI - Effectiveness of 125I seed implantation in the treatment of non-small cell lung cancer during R2 resection. AB - The aim of the present study was to investigate the effectiveness of 125I particle implantation during R2resection for non-small cell lung cancer (NSCLC). Data from 23 patients with NSCLC and macroscopic residual diseasefollowing surgery (R2 resection) between March 2010 and May 2014 were retrospectively analyzed. Among these patients, 12 patients [4 with T-residual disease (incomplete resection of primary tumor but complete dissection of regional lymph node), 8 with N-residual disease (complete resection of primary tumor but incomplete resection of metastatic regional lymph node)] underwent 125I particle implantation during the operation, while the other 11 (4 with T-residual disease and 7 with N-residual disease) received postoperative conventional radiotherapy. The local control rate, overall survival, and distant metastasis were evaluated. Additionally, the efficacy and safety of brachytherapy using 125I particle implantation during surgery for locally advanced NSCLC were investigated. The 23 patients were followed up for 3-40 months. For the 125I group, the 2-year local control rate was 100%, and the median survival time was 24 months. The 1-2-year survival rates were 83.3 and 58.33%, respectively. For the postoperative radiotherapy group, the median survival time was 12 months, andthe 1- and 2-year survival rates were 54.5 and 27.7%, respectively. No statistically significant difference in 2-year survival rates was detected between the two treatment groups, but the particle implantation group exhibited a higher survival rate trend. For patients with T-residual disease, the survival rate was higher for the 125I seed implantation group compared with the postoperative radiotherapy group. However, there was no significant difference in the rates of metastasis between the two groups for patients with N-residual disease. Therefore, intraoperative implantation of 125I particles during R2 resection of NSCLC may be a safer and more reliable method to reduce the local recurrence rate compared with conventional radiotherapy. Although not statistically significant, the overall survival rate of patients in the 125I seed implantation group was higher compared with the postoperative radiotherapy group. PMID- 29163697 TI - Reoperation following the use of non-standardized procedures for malignant parotid tumors. AB - Non-standardized or conservative procedures are employed when parotid tumors involving the facial nerve or parotid carcinoma are misdiagnosed as benign parotid tumors prior to or during surgery. Remedial measures are usually required when the pathological diagnosis of a malignant parotid tumor is confirmed following surgery. The aim of the present study was to systematically evaluate reoperation subsequent to treatment with non-standardized procedures for malignant parotid tumors, and to explore the preoperative diagnoses, the primary procedure selection and the necessity of reoperation following non-standardized procedures in malignant parotid tumors. A total of 30 patients who met the inclusion criteria, were diagnosed with a malignant parotid tumor and underwent reoperation following the use of a non-standardized procedure were included in the present study. Surgical conditions and clinical data were analyzed. Among the patients with a malignant parotid tumor who underwent reoperation subsequent to a non-standardized procedure, the incidence of residual tumor, as confirmed by pathological examination, was 63.3% (19/30). The intact facial nerve preservation rate was 83.3% (25/30), the facial nerve branch resection rate was 6.7% (2/30), the facial partial nerve resection rate was 6.7% (2/30) and the facial nerve resection rate was 3.3% (1/30). In total, 3 patients underwent facial nerve reconstruction, 3 patients underwent a local flap repair of skin defects in the parotid region and 3 patients underwent pectoralis major muscle flap repair. The current findings indicate that the qualitative diagnosis of malignant parotid tumors prior to surgery is difficult, there is a high incidence of residual tumor following non-standardized procedures, and that reoperation in a timely manner is required in such cases. PMID- 29163698 TI - Cytokeratin 17 mRNA as a prognostic marker of oral squamous cell carcinoma. AB - Despite diagnostic and therapeutic advances, the 5-year survival rate of oral squamous cell carcinoma (OSCC) remains between 70-80% due to recurrences and secondary metastases to cervical lymph nodes. It is difficult to find these recurrences and metastases postoperatively, thus, careful follow-up is recommended. Cytokeratins (CKs) are intermediate filaments of the cytoskeleton and candidate prognostic biomarkers for OSCC, as they are overexpressed in OSCC compared with normal mucosa. The aim of the present study was to determine the relative levels of occurrence of 3 CK mRNA (CK17, CK19, CK20) transcripts in peripheral blood mononuclear cells (PBMC) using reverse transcription quantitative polymerase chain reaction. The study comprised pre- and post operative PBMC samples from 19 OSCC patients. In the good-prognosis group, 10 of 13 patients demonstrated reduced CK17 mRNA expression post-operatively, compared with pre-operative samples, conversely, only 3 of 6 patients in the poor prognosis group had reduced post-operative CK17 mRNA expression. This difference was statistically significant (P<0.01). The disease-free survival rate of the group with reduced post-operative CK17 mRNA expression was significantly increased compared with the elevated CK17 mRNA group (P<0.01); however, the overall survival rates of the two groups were not significantly different. Neither CK19 mRNA nor CK20 mRNA were significantly expressed in the PBMC of OSCC patients. Overall, CK17 mRNA expression may be a useful prognostic biomarker for OSCC. PMID- 29163699 TI - Comparison of adjuvant FOLFOX4 chemotherapy and oral UFUR/LV following adjuvant FOLFOX4 chemotherapy in patients with stage III colon cancer subsequent to radical resection. AB - The present study aimed to demonstrate the potential advantage of oral uracil tegafur (UFUR)/leucovorin (LV) as the subsequent therapy in patients with stage III colon cancer following adjuvant LV, 5-fluorouracil and oxaliplatin (FOLFOX4) chemotherapy. Of a total 143 patients, 62 patients received only FOLFOX adjuvant chemotherapy (FOLFOX4 biweekly * 12 cycles for 6 months), and 81 patients received FOLFOXU adjuvant treatment (which consisted of FOLFOX4 biweekly * 12 cycles for 6 months followed by oral UFUR/LV for an additional 6 months). The 3 year disease-free survival (DFS) rate of the FOLFOXU group was 74.3%; which was superior to that of the FOLFOX4 group (59.9%). The average DFS time of the FOLFOXU group was superior to that of the FOLFOX4 group (P=0.003). The 5-year overall survival (OS) rate of the FOLFOXU group was 76.9%, which was also superior to that of the FOLFOX4 group (63.8%). The average OS time of patients in the FOLFOXU group was longer than that of the patients in the FOLFOX4 group (hazard ratio, 0.155; 95% confidence interval, 0.054-0.450; P=0.001). In comparison to the FOLFOX regimen, the FOLFOXU regimen achieved a more favorable response and survival time without a significant increase of toxicities in patients with stage III colon cancer as the adjuvant chemotherapy. PMID- 29163700 TI - Carbohydrate antigen 19-9 as a prognostic biomarker in pancreatic neuroendocrine tumors. AB - Carbohydrate antigen 19-9 (CA19-9) is not generally considered to be a biomarker in pancreatic neuroendocrine tumors (pNETs), as the majority of pNETs present with a normal range of CA19-9. The present study aimed to evaluate the role of serum CA19-9 levels as a prognostic factor in a relatively large number of patients with pNETs. Consecutive patients were retrospectively collected from a single institution between June 2006 and February 2015. The receiver operating characteristic (ROC) curve and the area under the ROC curve were used to select the cut-off values for the baseline CA19-9 levels. The primary end point was set as overall survival. Potential factors associated with the abnormal elevation of CA19-9 expression levels in pNETs were also investigated. The cut-off value for CA19-9 was 16 U/ml as determined by the ROC curve, and for the area under the ROC curve it was 0.68. In total, 32.7% of patients (51/156) had CA19-9 expression levels higher than the cut-off value. Univariate analysis demonstrated that CA19 9 >16 U/ml was an adverse prognostic factor for patients' overall survival. The CA19-9 >16 U/ml group had a statistically higher proportion of tumor node metastasis (TNM) stage III or IV, as compared with the CA19-9 <=16 U/ml group. To the best of our knowledge, the present study is the first to demonstrate that CA19-9 is a prognostic biomarker of pNETs, one that may reflect its aggressiveness and severity. PMID- 29163701 TI - High levels of DEPDC1B predict shorter biochemical recurrence-free survival of patients with prostate cancer. AB - DEP domain-containing protein 1B (DEPDC1B) has been reported to serve important functions in breast cancer and non-small cell lung cancer. However, its involvement in the development of prostate cancer (PCa) remains unclear. Therefore, the present study aimed to investigate the expression and clinical significance of DEPDC1B in tumor tissues from patients diagnosed with PCa. A total of 80 prostate tissue samples were collected following prostatectomy to generate a tissue microarray for immunohistochemical analysis of DEPDC1B protein expression. High throughput sequencing of mRNAs from 179 prostate tissue samples, either from patients with PCa or from healthy controls, was included in the Taylor dataset. The expression levels of DEPDC1B in tumor tissues from patients with PCa were revealed to be significantly increased compared with those in normal prostate tissues (P=0.039). Increased expression of DEPDC1B was significantly associated with advanced clinical stage (P=0.006), advanced T stage (P=0.012) and lymph node metastasis (P=0.004). Kaplan-Meier analysis demonstrated that patients with high levels of DEPDC1B mRNA had significantly shorter biochemical recurrence (BCR)-free survival times. Multivariate analysis using Cox proportional hazards model revealed that levels of DEPDC1B mRNA were significant independent predictors of BCR-free survival time of patients with PCa. Therefore, the expression of DEPDC1B may be used as an independent predictor of biochemical recurrence-free survival time of patients with PCa. PMID- 29163702 TI - Beclin 1 expression is associated with the occurrence and development of esophageal squamous cell carcinoma. AB - Beclin 1 has a central role in the regulation of autophagy, differentiation, apoptosis resistance, tumorigenesis and cancer progression. The role of Beclin 1 in the development of esophageal squamous cell carcinoma (ESCC) and its subsequent progression is not fully characterized. In the present study, the role of Beclin 1 and autophagy in ESCC was evaluated. The expression of Beclin 1 mRNA and protein levels in human ESCC tumor and adjacent normal esophageal tissue was measured. Beclin 1 mRNA and protein were significantly lower in tumor tissue than in normal esophageal tissue (P<0.05). Cells of the less differentiated esophageal tumors expressed lower Beclin 1 mRNA and protein (P<0.05). Tumors from patients in early clinical stages (I/II) exhibited significantly higher Beclin 1 mRNA and protein expression levels than patients with tumors in mid-to-late stages (III/IV; P<0.05). Tumors from patients with lymph node metastasis exhibited significantly lower Beclin 1 mRNA and protein expression levels compared with tumors from patients without lymph node involvement (P<0.05). Beclin 1 downregulation was demonstrated to significantly upregulate invasion by ESCC EC9706 cells (P<0.01), and downregulate the number of acidic vesicular organelles, a process associated with autophagy. These results suggest that the expression of Beclin 1 is associated with the occurrence and development of ESCC. Measuring the Beclin 1 expression of tumors from patient may improve the understanding of the prognosis of patients with ESCC. PMID- 29163703 TI - The downregulation of c-Myc and its target gene hTERT is associated with the antiproliferative effects of baicalin on HL-60 cells. AB - Baicalin is a flavonoid compound isolated from Scutellaria baicalensis, a Chinese traditional medicinal herb, and is used as an anti-inflammatory, antibacterial, anxiolytic and hepatoprotective drug. Accumulating evidence has demonstrated that baicalin exhibits potent antitumor properties by suppressing cell growth, arresting cell cycle progression and inducing differentiation or apoptosis in leukemia cell lines. However, whether or not the extrinsic pathway is involved in baicalin-induced apoptosis of leukemia cells and the mechanisms underlying the antitumor activity of baicalin remain unclear. In the present study, the effect of baicalin on the expression of caspase-8, Fas cell surface death receptor (Fas) and Fas ligand in HL-60 cells was assessed, and it was demonstrated that the Fas mediated extrinsic pathway was also involved in baicalin-triggered cell apoptosis, in addition to the intrinsic pathway. Furthermore, baicalin was able to inhibit the proliferation of HL-60 cells by arresting the cell cycle at the G0/G1 phase, and by down-regulating Myc proto-oncogene protein (c-Myc) along with its target gene, human telomerase reverse transcriptase. In summary, the results of the present study demonstrated that baicalin was able to inhibit the growth of HL-60 cells through blockade of the G0/G1 phase of the cell cycle, and significantly induce the apoptosis of cells by activating the intrinsic and extrinsic pathways. The inhibition of HL-60 cell growth was also demonstrated to be mediated by telomerase inhibition through suppression of c-Myc. The results of the present study highlight the possibility of baicalin as a promising regimen for the treatment of AML. PMID- 29163704 TI - Riparsaponin isolated from Homonoia riparia Lour induces apoptosis of oral cancer cells. AB - Homonoia riparia Lour (Euphorbiaceae) is a known source of herbal medicine in China, and riparsaponin (RSP) is an active constituent isolated from H. riparia. The aim of the present study was to investigate the antitumor effect of RSP on human oral carcinoma cells and its potential underlying molecular mechanism. RSP was isolated from roots of H. riparia and identified using nuclear magnetic resonance. An MTT assay was used to evaluate the cytotoxicity of RSP on human oral carcinoma cells. Subsequently, DAPI staining was performed to investigate the apoptotic effect of RSP. To investigate the potential underlying molecular mechanism of action of RSP, western blotting was performed to determine the expression of cleaved caspase 3/9, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), Bcl-2-associated death promoter (Bad), epithelial cadherin (E CAD), c-MET, matrix metalloproteinase (MMP)-2 and MMP-9. RSP exhibited a significant anti-proliferative effect on oral carcinoma cells at concentrations between 10 and 200 ug/ml via apoptosis. Following treatment with RSP (20, 40 and 80 ug/ml), expression of cleaved caspase-3 (P<0.05, P<0.01 and P<0.01, respectively), cleaved caspase-9 (P<0.01), Bad (P<0.01), Bax (P<0.01), c-MET (P<0.01), MMP-2 (P<0.01) and MMP-9 (P<0.01) in oral carcinoma cells was increased significantly compared with the control group, whereas expression of Bcl-2 (P<0.01) and E-CAD (P<0.01) was decreased. These results suggest that RSP possessed notable antitumor activity against oral squamous cell carcinoma by inducing mitochondria-mediated apoptosis. PMID- 29163705 TI - Beclin-1 suppresses gastric cancer progression by promoting apoptosis and reducing cell migration. AB - To investigate Beclin-1 expression in gastric cancer and its clinical relevance, 60 samples were collected from patients with gastric carcinoma, which were subjected to immunohistochemical staining and analysis. Associations of Beclin-1 expression with the clinical parameters of the patients, including tumor size, histological differentiation and metastatic status, were examined by statistical analysis. The results demonstrated that Beclin-1 expression in gastric carcinoma tissue was significantly associated with the tumor, node, metastasis stage and tumor invasion status. Further experiments indicated that Beclin-1 overexpression promoted MKN-45 gastric cancer cell apoptosis and inhibited their migration. These data suggested that Beclin-1 was a suppressor of tumorigenesis in gastric cancer and a potential therapeutic target for patients with gastric cancer. PMID- 29163706 TI - IGFBP-4 expression is adversely associated with lung cancer prognosis. AB - Insulin-like growth factor binding protein-4 (IGFBP-4) was reported to be associated with prognosis in several types of cancer; however, to the best of our knowledge, whether it is correlated with lung cancer has yet to be reported. In the present study, 102 pairs of lung cancer tissues and surrounding non-cancerous tissues (SNCTs) were collected. The IGFBP-4 levels in tissues were detected with immunohistochemistry. The relevance of IGFBP-4 to the survival of patients was assessed. The IGFBP-4 gene was knocked down, and its function in the proliferation of lung cancer cells was measured. The percentage of lung cancer tissues with higher IGFBP-4 expression than SNCTs (51.9%) was increased compared with the percentage with similar (11.76%) or lower (36.27%) IGFBP-4 expression. Patients with higher IGFBP-1 expression exhibited a shorter median survival time. IGFBP-1 was associated with metastasis, lung cancer stages and malignancy, but not with age, sex or tumor size. Lung cancer cells with stably knocked down IGFBP 4 showed an inhibitory proliferation rate. The present study identified that IGFBP-4 was adversely associated with the prognosis of lung cancer patients. IGFBP-4 knockdown prohibited lung cancer cell growth. The present study provides a potential marker for lung cancer diagnosis and a possible target for lung cancer therapy. PMID- 29163707 TI - N-Myc downstream-regulated gene 2 restrains glycolysis and glutaminolysis in clear cell renal cell carcinoma. AB - Glycolysis and glutaminolysis are heavily involved in the metabolic reprogramming of cancer cells. The activation of oncogenes and inactivation of tumor suppressor genes has a marked effect on the cellular metabolic processes glycolysis and glutaminolysis. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor gene that previous studies have demonstrated can inhibit the growth, proliferation and metastasis of clear cell renal cell carcinoma (ccRCC) cells. However, the function of NDRG2 in ccRCC metabolism remains unknown. In the present study, NDRG2 significantly inhibited the consumption of glucose and glutamine, as well as the production of lactate and glutamate in ccRCC. NDRG2 significantly suppressed the expression of glucose transporter 1, hexokinase 2, pyruvate kinase M2, lactate dehydrogenase A, glutamine transporter ASC amino acid transporter 2 and glutaminase 1 at the mRNA (by quantitative polymerase chain reaction) and protein level (by western blot analysis), all of which are key regulators and enzymes in glycolysis and glutaminolysis. Data from the present study also revealed that overexpression of NDRG2 suppressed cell proliferation in ccRCC in vitro and in vivo, demonstrated by colony formation assays, wound healing assay and nude mouse transplantation tumor experiment. The present findings demonstrate for the first time that NDRG2 acts as a key inhibitor of glycolysis and glutaminolysis in ccRCC and could be a promising target for the metabolic treatment of ccRCC. PMID- 29163708 TI - miR-20b promotes cellular proliferation and migration by directly regulating phosphatase and tensin homolog in prostate cancer. AB - MicroRNAs are small non-coding RNAs, which are critical regulators of carcinogenesis and tumor progression. Previous studies have identified that microRNA-20b (miR-20b) acts as an oncogene in numerous cancers. However, the role of miR-20b in prostate cancer remains unclear. The present study aimed to investigate the expression of miR-20b in prostate cancer and to examine whether modulating miR-20b expression impacts prostate cancer cellular proliferation and migration. It was revealed that miR-20b was strongly expressed in prostate cancer tissues compared with adjacent normal prostate tissues (P<0.05). Knockdown of miR 20b expression by miR-20b inhibitor inhibited VCaP and PC-3 cell growth and migration. Through bioinformatics analysis, phosphatase and tensin homolog (PTEN) was predicted as a target gene of miR-20b in prostate cancer cells, which was validated by dual-luciferase reporter assay and western blot analysis. In addition, restoration of PTEN expression levels did not affect endogenous miR-20b expression in prostate cancer cells. In conclusion, the present study indicated that miR-20b promotes cellular proliferation and migration by directly regulating PTEN in prostate cancer. PMID- 29163709 TI - The anti-hepatocellular carcinoma activity of Mel-P15 is mediated by natural killer cells. AB - Mel-P15 is a peptide derived from melittin, the main toxic component in the venom of the European honeybee Apis mellifera. In the present study, the antitumor effects of Mel-P15 and the underlying molecular mechanisms of these effects in vivo were investigated. Mel-P15 directly stimulated natural killer (NK) cell cytotoxicity in vitro, which was increased to 55.45% at a 4 ug/ml dose of Mel P15. In the mouse liver cancer (H22) xenograft mice model, Mel-P15 suppressed tumor growth in vivo; the tumor inhibitory rate was 61.15% following treatment with 2 mg/kg Mel-P15. In addition, the immune response was activated following Mel-P15 treatment. Mel-P15 treatment increased the spleen and thymus indices, promoted splenocyte proliferation, stimulated NK cytotoxicity and upregulated the secretion of cytokines, including interleukin-2, interferon-gamma and tumor necrosis factor-alpha. In addition, the tumor inhibitory effect of Mel-P15 on BEL 7402-bearing nude mice was abrogated by the selective depletion of NK cells via the intraperitoneal injection of an anti-asialo GM-1 antibody. The results suggest that Mel-P15 inhibits tumor growth in vivo by promoting NK cell cytotoxicity. Mel-P15 may therefore be a potential immunotherapy candidate for the treatment of hepatocellular carcinoma. PMID- 29163710 TI - Combination of histoculture drug response assay and qPCR as an effective method to screen biomarkers for personalized chemotherapy in esophageal cancer. AB - Personalized chemotherapy with the use of biomarkers helps to maximize clinical efficiency. Therefore, the present study aimed to identify a potential method for identifying biomarkers in esophageal cancer. A total of 49 freshly resected tumor tissues and 72 paraffin-embedded specimens from patients with esophageal cancer were obtained. mRNA expression levels of ERCC1, BRCA1, TUBB3, FBW7, RRM1, MDM2, TS and TOP1 were measured quantitative reverse transcription polymerase chain reaction (RT-qPCR). In vitro chemosensitivity to cisplatin, docetaxel, gemcitabine, etoposide, fluorouracil and irinotecan were tested using histoculture drug response assay (HDRA). BRCA1 mRNA levels were positively correlated with resistance to cisplatin (P=0.027) and sensitivity to docetaxel (P=0.002). TS mRNA levels were inversely correlated with fluorouracil sensitivity (P=0.044), and TOP1 mRNA expression was positively correlated with irinotecan sensitivity (P=0.008). In addition, high BRCA1 mRNA levels correlated with decreased median overall survival (mOS; P<0.001) and response rate (RR; P=0.002) in cisplatin-fluorouracil chemotherapy group and also correlated with increased mOS (P<0.001) and RR (P=0.023) in docetaxel-fluorouracil chemotherapy group. Overall, these results suggested that HDRA combined with RT-qPCR may serve as an effective method for screening biomarkers in personalized chemotherapy for esophageal cancer. PMID- 29163711 TI - Identification of a protein associated with the activity of cytokine-induced killer cells. AB - Cytokine-induced killer cells (CIKs) adoptive immunotherapy for efficient antitumor ability is used clinically, but details regarding the proteins associated with CIK activity remain unclear. In the current study, the cytotoxicity of CIKs on hepatoma was identified to be significantly downregulated by 1.61-fold following gentamincin treatment. Further research revealed that a differentially expressed protein (P43) was significantly downregulated by 1.22 fold using one-dimensional gel electrophoresis analysis. Of these, the P43 was identified as human haptoglobin using liquid chromatography-mass spectrometry. Western blotting demonstrated that the haptoglobin specifically reacted with rabbit anti-human-haptoglobin. Furthermore, western blotting results verified that the haptoglobin was significantly downregulated by 1.17-fold compared with the control group. In addition, the expression of haptoglobin mRNA was significantly downregulated by 1.73-fold following gentamincin treatment. Taken together, the results of the present study demonstrated that the expression of haptoglobin protein was associated with the activity of CIKs, and the results will be beneficial to the further investigation of CIK activity-enhancement mechanism. PMID- 29163712 TI - Combinations of elevated tissue miRNA-17-92 cluster expression and serum prostate specific antigen as potential diagnostic biomarkers for prostate cancer. AB - The aim of the present study was to investigate the effectiveness of the miR-17 92 cluster as a disease progression marker in prostate cancer (PCa). Reverse transcription-quantitative polymerase chain reaction analysis was used to detect the microRNA (miR)-17-92 cluster expression levels in tissues from patients with PCa or benign prostatic hyperplasia (BPH), in addition to in PCa and BPH cell lines. Spearman correlation was used for comparison and estimation of correlations between miRNA expression levels and clinicopathological characteristics such as the Gleason score and prostate-specific antigen (PSA). Receiver operating curve (ROC) analysis was performed for evaluation of specificity and sensitivity of miR-17-92 cluster expression levels for discriminating patients with PCa from patients with BPH. Kaplan-Meier analysis was plotted to investigate the predictive potential of miR-17-92 cluster for PCa biochemical recurrence. Expression of the majority of miRNAs in the miR-17-92 cluster was identified to be significantly increased in PCa tissues and cell lines. Bivariate correlation analysis indicated that the high expression of unregulated miRNAs was positively correlated with Gleason grade, but had no significant association with PSA. ROC curves demonstrated that high expression of miR-17-92 cluster predicted a higher diagnostic accuracy compared with PSA. Improved discriminating quotients were observed when combinations of unregulated miRNAs with PSA were used. Survival analysis confirmed a high combined miRNA score of miR-17-92 cluster was associated with shorter biochemical recurrence interval. miR-17-92 cluster could be a potential diagnostic and prognostic biomarker for PCa, and the combination of the miR-17-92 cluster and serum PSA may enhance the accuracy for diagnosis of PCa. PMID- 29163713 TI - MicroRNA-154/ADAM9 axis inhibits the proliferation, migration and invasion of breast cancer cells. AB - Breast cancer is the leading cause for cancer-associated mortality in women. Although great progress has been made in the earlier diagnosis and systemic therapy of patients with breast cancer in recent years, recurrence or distant metastasis continue to present major barriers to the successful treatment of breast cancer. Therefore, fully understanding the molecular mechanisms underlying the progression of breast cancer may be critical for the development of effective therapeutic strategies against breast cancer. The aim of the present study was to explore the expression, function and molecular mechanisms of microRNA-154 (miR 154) in human breast cancer. It was demonstrated that miR-154 was significantly downregulated in breast cancer tissue and cell lines. The restoration of miR-154 expression suppressed the proliferation, migration and invasion of breast cancer cells. ADAM metallopeptidase domain 9 (ADAM9) was identified as a novel direct target for miR-154 in breast cancer. It was demonstrated that miR-154 acted as a tumor suppressor in breast cancer by targeting ADAM9. The results of the present study suggest that the restoration of miR-154 expression may be an effective therapeutic strategy for the treatment of breast cancer in the future. PMID- 29163714 TI - Downregulation of eukaryotic initiation factor 4A1 improves radiosensitivity by delaying DNA double strand break repair in cervical cancer. AB - Expression of eukaryotic initiation factor 4A1 (eIF4A1) following brachytherapy has been reported to predict improved radiosensitivity and tumor-specific survival in cervical cancer. Therefore, the present study investigated the function of eIF4A1 in cervical cancer and the mechanism by which eIF4A1 regulates cervical cancer radiosensitivity. It was determined that the downregulation of eIF4A1 in HeLa and SiHa cells notably attenuated cell proliferation, in addition to repressing cervical cancer migration and invasion, and promoting cell apoptosis. In vitro and in vivo studies have demonstrated that silencing eIF4A1 improves cervical cancer radiosensitivity. Detection of gamma-H2AX using western blot analysis at 0, 0.5, 1, 6 and 24 h following the exposure of cervical cancer cells to X-rays illustrated that eIF4A1-knockdown results in postponed radiation induced DNA double strand break (DSB) repair. Overall, the results of the present study demonstrated that downregulated eIF4A1 improves cervical cancer radiosensitivity by delaying cancer cell DSB repair. In conclusion, the data indicated that eIF4A1 performs a vital role in cervical cancer progression and radiosensitivity. Therefore, eIF4A1 may be a potential therapeutic target in patients with cervical cancer. PMID- 29163715 TI - The ultimate opportunity for advancing pharmacy practice. PMID- 29163716 TI - Erratum. AB - [This corrects the article DOI: 10.1177/1715163516642209.]. PMID- 29163718 TI - Drug costs in Canada. PMID- 29163717 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/1715163517701770.]. PMID- 29163719 TI - Drug costs in Canada. PMID- 29163720 TI - Authors' response. PMID- 29163721 TI - The role of spirometry in the management of obstructive airways disease: How pharmacists should get involved. PMID- 29163722 TI - Innovative pharmacy practice: Lonni Johnson. PMID- 29163723 TI - CANImmunize: A digital tool to help patients manage their immunizations. PMID- 29163724 TI - Part 3: Perspectives of pharmacy technicians on practice change. PMID- 29163725 TI - 2016 Guidelines for the management of dyslipidemia and the prevention of cardiovascular disease in adults by pharmacists. PMID- 29163726 TI - Beyond equality: Providing equitable care for persons with disabilities. AB - Background: Almost 14% of Canadians have a disability, and older adults are most commonly affected. People living with disabilities have challenges accessing health care services, including medications and other services provided in pharmacies. Methods: A literature review was conducted regarding disability and pharmacy services. Resources regarding accessibility were also incorporated. Results: A number of organizations provide guidance on caring for those with disabilities. A primary concern for these vulnerable individuals relates to being invisible or overlooked by the health care system. There are also the stresses of physical, communication and attitudinal barriers. Pharmacists may be unaware of these barriers and may actually be contributing to them. To understand their patients' accessibility needs, pharmacists can consider physical and nonphysical barriers and engage in education, advocacy and communications training to improve their patient-centred care for individuals with disabilities. Discussion and Conclusion: Pharmacists can improve the care of individuals with disabilities by learning more about accessibility. Within the community pharmacy environment, there are physical and nonphysical interventions that pharmacists can implement to ensure that patient-centred care is prioritized. PMID- 29163727 TI - PHArmacists' perspective oN the Take hOme naloxone prograM (The PHANTOM Study). AB - Objective: To evaluate pharmacists' attitudes toward the Take Home Naloxone (THN) program and identify areas that could be improved to support pharmacists' involvement. Methods: Pharmacists on the Alberta College of Pharmacists' directory were invited to complete an online survey between July 10 and August 8, 2016. The survey consisted of 19 questions. Descriptive statistics were used to analyze the data. Results: Four hundred seventy pharmacists completed the survey (response rate = 11.2%). A total of 76.8% of respondents strongly agreed or agreed that pharmacists should be screening patients to identify those at risk of opioid overdose. Full-time pharmacists were more likely to agree (p = 0.02). A total of 79.8% of respondents strongly agreed or agreed that pharmacists should be recommending THN kits. Pharmacists working in large population centres (p = 0.008) and full-time pharmacists (p = 0.02) were more likely to agree with this statement. Furthermore, 60.6% of pharmacists were extremely willing or very willing to participate in the THN program. Pharmacists in practice for <=15 years were more willing to participate in the THN program than pharmacists in practice >15 years (p = 0.03). The most common perceived barriers to implementation of the THN program were lack of time in pharmacists' current work environment and education about the program. Conclusions: Overall, pharmacists had positive attitudes toward screening patients to identify those at risk of opioid overdose, recommending THN kits and willingness to participate in the program. Factors that may facilitate increased participation in the program include addressing time issues and improving education about the THN program. PMID- 29163728 TI - Results of a Quality Improvement Project Aimed at Eliminating Healthcare Waste by Changing Medical Resident Test Ordering Behavior. AB - Background: In light of rising healthcare costs and evidence of inefficient use of medical resources, there is growing interest in reducing healthcare waste by clinicians. Unwarranted lab tests may lead to further tests, prolonged hospital stays, unnecessary referrals and procedures, patient discomfort, and iatrogenic anemia, resulting in significant economic and clinical effects. Blood tests are essential in guiding medical decisions, but they are also associated with significant financial and clinical costs. We designed a quality improvement study that attempted to decrease inappropriate ordering of laboratory tests while maintaining quality of care in a large residency program. Methods: An algorithm outlining indications for complete blood count (CBC), coagulation profile (PT/INR) and basic metabolic profile (BMP) was created by the study team. Data from 1,312 patients over a 3-month period in the pre-intervention phase and 1,255 patients during the selected intervention phase were analyzed. The primary endpoint was mortality rate and secondary endpoints were length of stay and laboratory costs. Results: There were significant decreases in the number of PT/INR orders (20.6%), followed by BMP orders (12.4%), and CBC orders (9.3%). The mortality rate was 5.3% for the pre-intervention phase and 5.8% for the selected intervention phase, with a difference of 0.5% (P = 0.44). Conclusion: Our approach leads to a decrease in costs, preventing unnecessary downstream testing, and improving patient experience. It also brought a mental discipline while ordering blood tests amongst residents. PMID- 29163729 TI - Prevalence, Comorbidity and Investigation of Anemia in the Primary Care Office. AB - Background: Anemia has a myriad of causes and its prevalence is growing. Anemia is associated with increased all-cause hospitalization and mortality in community dwelling individuals above age 65 years. Our aim was to determine the prevalence and severity of anemia in adult patients in our primary care office and to determine the relationship between anemia and medical comorbidities. Methods: Electronic medical records of 499 adult patients in our suburban internal medicine office were reviewed who had had at least one hemoglobin value and did not undergo moderate to high-risk surgery in the preceding 30 days. Results: About one-fifth (21.1%) of the patients had anemia. The mean age of patients with anemia was 62.6 years. Among all patients with anemia, 20.3% were males and 79.6% were females. Of these patients, 60.1% had mild anemia (hemoglobin 11 - 12.9 g/dL) and 39.8% had moderate anemia (hemoglobin 8 - 10.9 g/dL). For every year of increase in age, there was 1.8% increased odds of having anemia. African-American race had 5.2 times greater odds of having anemia than the Caucasian race. Hispanic race had 3.2 times greater odds of having anemia compared to the Caucasian race. Patients with anemia had a greater average number of comorbidities compared to patients without anemia (1.74 and 0.96, respectively; P < 0.05). There was a statistically greater percentage of patients with essential hypertension, hypothyroidism, chronic kidney disease, malignancy, rheumatologic disease, congestive heart failure, and coronary artery disease in the anemic population as compared to the non-anemic population. Of the patients, 41% with mild anemia and 62% with moderate anemia underwent additional diagnostic studies. Of the patients, 14.8% had resolution of anemia without therapy in 1 year, 15.7% were on iron replacement therapy, and 6.5% were on cobalamin therapy. No specific etiology of anemia was found in 24% of patients. Conclusion: A higher prevalence of anemia was associated with advancing age, African-American and Hispanic ethnicity, and comorbidities, such as essential hypertension, hypothyroidism, chronic kidney disease, malignancy, rheumatologic disease, congestive heart failure, and coronary artery disease. It is important to be aware of the demographic factors and their relationship to anemia in primary care. PMID- 29163730 TI - Association Between Dental Caries and Body Mass Index in Schoolchildren Aged Between 14 and 16 Years in Riyadh, Saudi Arabia. AB - Background: Dental caries and obesity are multifactorial diseases that have common risk factors. Studies worldwide reported varied outcomes about the association between dental caries and obesity. There is no published study that investigates this association among schoolchildren in Arabic countries. The aim of this study was to evaluate the relationship between dental caries (DMFT) and body mass index (BMI) for children aged between 14 and 16 years old in Riyadh, Saudi Arabia. The role of oral hygiene habits, parent's education, sugar consumption and physical activity in causing both diseases was also evaluated. Methods: This is a cross-sectional study that involved 610 schoolchildren aged between 14 and 16 years. The children were selected from 12 boy's intermediate schools distributed in Riyadh city. A questionnaire that asked about demographic data, oral hygiene habits, parents' education, sugar consumption and physical activity was distributed. Then, the mean DMFT and BMI were calculated by collecting the information from dental examination, body weight and height. Multivariate logistic regression model was used to explain the relationship between the teeth health and the BMI. Moreover, multivariate linear regression was conducted to model the relationship between DMFT and BMI and the socioeconomic score, sugar consumption and physical activity. Results: The prevalence of dental caries (DMFT > 0) was 54.1%. Around 32% of the schoolchildren were either overweight or obese. A statistically significant association between dental caries (DMFT) and BMI was found (P = 0.008). It was found that obese schoolchildren are 1.79 times higher to be with healthy teeth (P = 0.02). In addition, it was found that schoolchildren with higher socioeconomic status are 1.26 times higher to be with healthy teeth group (P = 0.005). Similarly, schoolchildren who reported that they are using the fluoridated toothpaste were 1.63 times higher to be within the healthy teeth group (DMFT = 0) when everything else is controlled. Physical activity level affects the schoolchildren BMI significantly (P < 0.001). Conclusions: The study showed a statistically significant association between dental caries and BMI for this study sample. Obese schoolchildren showed healthier teeth than others did. Fluoride toothpaste usage and socioeconomic score were associated significantly with dental caries. PMID- 29163731 TI - Acute Abdominal Pain Assessment in the Emergency Department: The Experience of a Greek University Hospital. AB - Background: Acute abdominal pain (AAP) is a common symptom in the emergency department (ED). Because abdominal pain can be caused by a wide spectrum of underlying pathology, evaluation of abdominal pain in the ED requires a comprehensive approach, based on patient history, physical examination, laboratory tests and imaging studies. The aim of this study was to investigate predictive factors for admission to the hospital in patients who presented to the ED with AAP as the main symptom. Methods: This prospective observational study enrolled 125 patients who presented with AAP in the ED of the Patras University Hospital in western Greece. The sample of patients who enrolled in the study was representative of patients who receive care in this academic institution. All patients underwent clinical examination, laboratory testing and radiological assessment. Clinical and laboratory data were analyzed in an attempt to identify clinical or laboratory factors predicting hospital admission. Results: Based on clinical, laboratory and radiologic evaluation, 37.6% of patients enrolled in the study were admitted to the hospital, whereas 62.4% were not admitted. Compared to patients who were not admitted, patients admitted to the hospital had higher age and significantly higher inflammatory markers, white blood count and C-reactive protein (CRP). Binary logistic regression analysis showed that abnormal imaging findings (odds ratio (OR) = 6.47, 95% confidence interval (CI): 2.11 - 19.77, P < 0.001) and elevated serum CRP levels (OR = 6.24, 95% CI: 2.16 - 18.03, P < 0.001) were significant predictive factors for hospital admission. Conclusions: Assessment of AAP remains a challenging problem in the ED. Comprehensive history combined with detailed clinical examination, appropriate laboratory testing and radiologic imaging facilitates effective assessment of patients who present in the ED with AAP and guides the decision to admit patients to the hospital for further care. PMID- 29163732 TI - A Comparison of the Effects and Side Effects of Oral Betahistine with Injectable Promethazine in the Treatment of Acute Peripheral Vertigo in Emergency. AB - Background: Vertigo is an illusion of rotation that is caused by the asymmetry of neurological function of the right and left vestibular nuclei. The aim of this study was to compare the efficacy and side effects of oral betahistine with injectable promethazine in treatment of acute peripheral vertigo. Methods: In this double-blind clinical trial study, the patients with acute peripheral vertigo were assigned in the two groups: receiving promethazine intramuscularly at a dose of 25 mg (group A) and receiving 8 mg betahistine tablets (group B) and the severity of their vertigo was evaluated on the visual analog scale (VAS) scoring system. In addition, adverse events in both groups of patients were compared and evaluated. Results: A total of 162 patients (82 subjects in group A) participated in this study. The mean age, gender distribution, intensity and symptoms of vertigo were similar in both groups before the intervention. At 2 and 3 h after the intervention, the score of VAS in patients taking betahistine was significantly higher than promethazine. In addition, the clinical symptoms after taking betahistine were significantly less. Side effects seen in patients taking the promethazine include mainly drowsiness. After taking betahistine, the most common complication was abdominal problems (nausea and vomiting). Conclusion: The results of this study show that betahistine is a safe and effective drug in controlling patients with acute vertigo and its impact is more than promethazine. PMID- 29163733 TI - Can Antioxidative Status Be Involved in Type 1 Diabetes? AB - Background: Type 1 diabetes mellitus (T1DM) is an autoimmune disease with beta cell destruction, resulting in insulin deficiency. It is now clear that environmental factors also play a role in disease development. The prevalence of type 1 diabetes in children and young people in Portugal is 0.16% between 0 and 19 years of age. The main cause of death in T1DM is cardiovascular disease, and early endothelial dysfunction is its pathophysiologycal precursor. Hyperglycemia is associated with increased production of free radicals and increased oxidative stress. The aim of this study was to analyze the antioxidant status in a pediatric portuguese diabetic population. Methods: The study was conducted to characterize and compare the antioxidant status in children aged 2 - 10 years old, with type 1 diabetes and healthy children. Plasmatic profile of total phenolic content (TPC), ferric reducing antioxidant power (FRAP), Trolox equivalent antioxidant capacity (TEAC) in children with diabetes and controls, pre-pubescent, and with BMI < 85th centile were evaluated. Results: FRAP values were significantly lower in diabetic children compared with healthy controls (P < 0.001). There was not any statistical significant difference in the TPC and the TEAC determinations. Conclusions: Young Portuguese diabetic children have a lower antioxidant status than healthy children. PMID- 29163734 TI - Risk of Obstructive Sleep Apnea Assessment Among Patients With Type 2 Diabetes in Taif, Saudi Arabia. AB - Background: Obstructive sleep apnea (OSA) is a common condition in middle-aged persons worldwide. The major factor risk of this disease is obesity. Methods: A cross-sectional study was performed at King Abdul-Aziz Specialist Hospital. A STOP-BANG questionnaire formed of eight questions was used to assess the risk of OSA among type 2 diabetic patients. The scoring scale is categorized into three groups: low (0 - 2), intermediate (3 - 4) and high (5 - 8), respectively. By this study, we aimed to assess the risk of OSA among diabetes patients in Taif city. Results: Of the patients, 57.9% had mild risk, 26.9% had moderate risk and 15.2% had severe risk for OSA. There was a moderate positive relationship between age and STOP-BANG score. There was no significant correlation between the score and last fasting blood sugar and HbA1c's level, with P values of 0.554 and 0.335, respectively. There was a significant relationship between the type of treatment and the risk of developing OSA (P < 0.001). Percentage of patients with severe risk was significantly higher in those taking both insulin and oral drugs than those taking insulin alone or oral drugs alone. Conclusions: The OSA risk and prevalence is much higher in diabetics than in general population, with the risk increasing with age. The risk is higher in diabetic patients who are receiving both oral hypoglycemic drugs and insulin. The screening of OSA among diabetic patients is necessary to identify those at severe risk and manage this problem, which may remain undiagnosed in many patients. PMID- 29163735 TI - Urate-Lowering Therapy Ameliorates Kidney Function in Type 2 Diabetes Patients With Hyperuricemia. AB - Background: Hyperuricemia often causes kidney dysfunction which increases serum urate, forming a vicious cycle in the kidney. In this study, urate-lowering therapy was demonstrated in type 2 diabetic patients with hyperuricemia to evaluate the effect on diabetic nephropathy. Methods: Type 2 diabetic patients with hyperuricemia (n = 34) were treated by urate-lowering drugs. Serum urate levels, estimated glomerular filtration rate (eGFR), blood pressure, HbA1c, and urinary albumin-to-creatinine ratio (UACR) were measured for 52 weeks. The parameters at the endpoint when serum urate decreased to below 6.0 mg/dL and at 52 weeks were compared to the initial levels at week 0. Results: Serum urate level decreased to the endpoint in all patients and was maintained at under 6.0 mg/dL throughout the observation period. eGFR significantly increased at the endpoint and also at 52 weeks. Overall UACR did not change after 52 weeks; however, the treatment decreased UACR significantly in patients with no microalbuminuria. There was a negative relationship between the change of serum urate levels and the change of eGFR, and a negative relationship between the baseline UACR and the change of UACR when patients with macroalbuminuria were excluded. There were no changes in HbA1c levels and blood pressure before and after the treatment. Conclusions: There were significant improvements in kidney function by lowering serum urate levels to under 6.0 mg/dL and the effect was maintained for at least 52 weeks. This treatment may be one strategy to slow the progression of nephropathy in type 2 diabetic patients with hyperuricemia. PMID- 29163736 TI - Association of Glycosylated Hemoglobin Levels With Vitamin D Status. AB - Background: The discovery of vitamin D is one of medicine's great achievements. Despite all the positive evidence emerging about the beneficial effect of vitamin D, we still find many are vitamin D deficient. The purposes of this study were to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and glycosylated hemoglobin (HbA1c) levels, to test the hypothesis that lower 25(OH)D levels are associated with poorer glucose control in diabetes mellitus (DM) patients and to investigate the effect of vitamin D supplementation on HbA1c levels. Methods: This was a prospective observational cohort study of all patients with type 1 and type 2 diabetes (above 12 years) who attended the outpatient clinics of a tertiary center in Riyadh. HbA1c and vitamin D levels were recorded prior to supplementation and after 9 months of supplementation with vitamin D. All patients were divided into four groups according to their vitamin D level and an association between 25(OH)D and HbA1c was tested. Results: Results showed that 73.1% of the patients had 25(OH)D levels < 50 nmol/L. We observed lowering of HbA1c after vitamin D supplementation (from mean HbA1c of 10.55 to 7.70). We found HbA1c to be inversely related to serum vitamin D levels (r = 0.14 (P < 0.0000002) before supplementation and -0.16 (P < 0.000001) after supplementation with vitamin D). Conclusions: Advising patients with higher HbA1c to test their vitamin D level and correct any deficiency will result in better blood glucose control and benefit the patient's overall health. PMID- 29163737 TI - The Mechanisms Underlying Changes in Broad Dimensions of Psychopathology During Cognitive Behavioral Therapy for Social Anxiety Disorder. AB - Background: Social anxiety disorder (SAD) patients commonly have broad dimensions of psychopathology. This study investigated the relationship between a wide range of psychopathology and attention or cognitions during cognitive behavioral therapy (CBT) for SAD. Methods: We treated 96 SAD patients with group CBT. Using multiple regression analysis, we examined the associations between the changes in broad dimensions of psychopathology and the changes in self-focused attention or maladaptive cognitions in the course of CBT. Results: The reduction in self focused attention was related to the decreases in somatization, obsessive compulsive, interpersonal sensitivity, anxiety, phobic anxiety, and global severity index. The reduction in maladaptive cognitions was associated with decreases in interpersonal sensitivity, depression, and global severity index. Conclusions: The present study suggests that changes in self-focused attention and maladaptive cognitions may predict broad dimensions of psychopathology changes in SAD patients over the course of CBT. For the purpose of improving a wide range of psychiatric symptoms with SAD patients in CBT, it may be useful to decrease self-focus attention and maladaptive cognitions. PMID- 29163738 TI - A Case of Moderate Sprue-Like Enteropathy Associated With Telmisartan. AB - Sprue-like enteropathy associated with olmesartan medoxomil use has been recently reported. Its clinical manifestations include diarrhea, weight loss and malabsorption. Duodenal biopsies show villous atrophy (VA) with or without intraepithelial lymphocytosis and inflammation of the lamina propria. Serology for celiac disease (CD) is negative and gluten-free diet does not result in clinical improvement. Symptoms resolve after olmesartan discontinuation. Follow up biopsies show recovery/improvement of the duodenum. Whether sprue-like enteropathy is a specific adverse reaction to olmesartan or rather a class effect of angiotensin-receptor blockers (ARBs) remains a controversial issue. We report a case of sprue-like enteropathy associated with telmisartan. A 52-year-old man presented with chronic diarrhea, abdominal discomfort and significant weight loss. In the last 3 years, he had been treated with telmisartan 40 mg/day for hypertension after right adrenalectomy for an aldosterone-producing adenoma. Laboratory investigations showed no significant abnormalities: Hb 13.6 g/dL, serum albumin 3.9 g/dL, total cholesterol 193 mg/dL, serum creatinine 0.99 mg/dL, sodium 143.6 mmol/L, K+ 4.3 mmol/L, calcium 9.3 mg/dL, phosphorus 3.9 mg/dL and 25-OH-D3 27.7 ng/mL. Duodenal histology showed subtotal VA and inflammation of the lamina propria. CD serology was negative. HLA-DQ typing showed absence of the DQ2/DQ8 haplotypes. After telmisartan discontinuation, patient's symptoms subsided, and his body weight increased despite persistence of a gluten containing diet. Follow-up biopsies at 3 showed progressive duodenal recovery. Very few cases of sprue-like enteropathy associated with ARBs other than olmesartan have been reported. Our case of telmisartan-associated enteropathy further suggests that sprue-like disease may be a class effect of ARBs. PMID- 29163739 TI - Obsessive-Compulsive Disorder in a 19-Year-Old Female Adolescent With Turner Syndrome. AB - Obsessive-compulsive disorder (OCD) in patients with Turner syndrome (TS) is an uncommon neuropsychiatric presentation that has not been well characterized in the scientific literature. Though no clear psychiatric component is syndromic to TS, the clinical manifestations of certain neuropsychiatric disorders, including mood, anxiety and eating disorders, have all been well documented in patients with TS. However, the presence of OCD in these patients has not been previously described. This report details a 19-year-old TS patient who presented with OCD since the age of 13, comorbid with several other psychiatric pathologies, including bipolar I disorder, anorexia nervosa and attention deficit hyperactivity disorder (ADHD). It will also discuss those comorbidities in relation to the patient's genetic syndrome and mention the contribution it makes to her multiple disabilities diagnosis as well as her patient-specific therapy. Patients with TS often present to treating physicians for overwhelming somatic complaints, likely resulting in poor recognition of psychiatric disorders. Thus, OCD may be significantly under-diagnosed in patients with TS and should be explored by clinicians treating this vulnerable population. PMID- 29163740 TI - The Application of Sodium-Glucose Cotransporter 2 Inhibitors to Chronic Kidney Disease Stage 4. PMID- 29163741 TI - Correction: Validation of Skeletal Muscle Volume as a Nutritional Assessment in Patients With Gastric or Colorectal Cancer Before Radical Surgery. AB - [This corrects the article DOI: 10.14740/jocmr3129w.]. PMID- 29163742 TI - Endovascular Treatment of Spontaneous Intracranial Internal Carotid Dissection in a Young Patient Affected by Systemic Lupus Erythematosus: A Case Report. AB - Systemic lupus erythematosus (SLE) increases the risk of cerebrovascular events due to vascular changes, resulting in the weakening of the vessel walls. Moreover, patients with SLE have more incidence of arterial lesions such as dissections. Internal carotid dissection (ICA) is an infrequent cause of ischemic stroke, representing 2% of all ischemic events. We present a case of ischemic stroke, caused by a spontaneous dissection of intracranial ICA, treated with endovascular stent implantation, in a 22-year-old woman affected by SLE, newly diagnosed. ICA dissection with consequent ischemic stroke is an unusual first presentation of SLE disease. Our case highlights how, despite an infrequent occurrence, ICA dissection should be considered for young adults presenting with ischemic stroke, especially in those affected by SLE. This paper also shows the good technical result in the use of stenting in case of intracranial ICA dissection. PMID- 29163743 TI - Comparison of Endovascular Treatment with Intravenous Thrombolysis for Isolated M2 Segment of Middle Cerebral Artery Occlusion in Acute Ischemic Stroke. AB - Background: The benefit of endovascular treatment for distal large artery ischemic occlusions such as M2 segment of middle cerebral artery is not clear. Methods: We retrospectively analyzed data from 51 subjects who had an isolated M2 segment occlusion on baseline computed tomographic (CT) angiogram who were randomized to either intravenous (IV) recombinant tissue plasminogen activator (rt-PA) followed by endovascular treatment or IV rt-PA alone in a multicenter trial. We determined the effect of endovascular treatment on occurrence of excellent [mRS (modified Rankin scale) scores of 0-1] functional outcomes at three months and any death within 3 and 12 months. We also performed proportional odds logistic regression analysis to compare the distribution of mRS scores between the two groups. Each of the analyses was adjusted for age, baseline Alberta stroke program early CT score strata, and baseline National Institutes of Health Stroke scale score strata. Results: At three months, the rate of excellent functional outcome (38.2% versus 17.6%, unadjusted odds ratio 2.9; 95% confidence interval ; 0.7-12.1; p = 0.15) was non-significantly higher among subjects with M2 segment occlusion who were randomized to endovascular treatment. In multivariate analysis, the odds of excellent functional outcome at three months were non-significantly higher among subjects who were randomized to endovascular treatment at three months (OR 2.7; 95% CI; 0.6-13.6; p = 0.22). There was a trend toward lower disability grades in subject randomized to endovascular treatment when distribution of the mRS score at three months were compared (common OR 2.6; p = 0.084), adjusting for potential confounders. The rates of any death within 3 (adjusted OR 0.1; 95% CI; 0.1-0.8; p = 0.031) and within 12 months (adjusted OR 0.1; 95% CI; 0.1-0.7; p = 0.022) were significantly lower among those who were randomized to endovascular treatment. Conclusion: In this post-hoc analysis, acute ischemic stroke subjects who had isolated M2 segment occlusion randomized to endovascular treatment appeared to have lower mortality and a trend toward lower grades of disability. PMID- 29163744 TI - Spinal Arteriovenous Fistula. PMID- 29163745 TI - Possible Reversible Cerebral Vasoconstriction Syndrome Associated with Eucalyptus: Case Report. AB - Background: Reversible cerebral vasoconstrictive syndrome (RCVS) has characteristic clinical features, brain imaging and Angiographic features. The majority of RCVS cases are associated with the use of antidepressants, polysubstance abuse, and nasal decongestants. We here present a case that highlights the use of eucalyptus herbs as a possible precipitant factor for RCVS formation. Case Presentation: A 42-year-old woman presented to the emergency department with a tingling sensation on the right-hand side of her body and a two week progressive throbbing severe holocranial headache radiating to the neck, with associated nausea, photophobia, and phonophobia. She denied any seizures and recent trauma or fevers. She was not taking scheduled medications, but she had used inhaling vapors obtained from boiling eucalyptus leaves to alleviate sinus congestion. Initial imaging revealed subarachnoid hemorrhage at bilateral posterior parietal convexity leading to her admission into the intensive care unit. Further work up disclosed the presence of findings consistent with RCVS. Conclusion: In conclusion, we hereby postulate that some herbal remedies used in alternative medicine, including eucalyptus, could play a role in causing serotonergic symptoms including dizziness, diarrhea, and cerebral vasoconstriction. Understanding that eucalyptus has the potential to contribute to RCVS due to its serotoninergic activity may be of importance in the diagnosis and management of these patients. PMID- 29163748 TI - Transradial Approach for Deployment of a Flow Diverter for an Intracranial Aneurysm in a Patient with a Type-3 Aortic Arch. AB - Background: Flow diversion with the Pipeline embolization device (PED) is an effective treatment for giant and wide-neck intracranial aneurysms, but the standard transfemoral approach may not be feasible in patients with Type-3 aortic arches. Case Report: An 84-year-old woman presented with a right internal carotid artery (ICA) giant aneurysm and a Type-3 aortic arch, necessitating a transradial approach for access to the right common carotid artery. A triaxial catheter system made for a stable platform for the deployment of two telescoping PEDs to treat the patient's right ICA giant aneurysm. The procedure was technically successful, and there were no immediate complications. Conclusion: The transradial approach allows for carotid access in patients with challenging aortic arches, and this report demonstrates its effectiveness for deployment of flow diverters, especially with a triaxial catheter system. The peripheral access point facilitates hemostasis, which is of great importance in patients on antiplatelet medications to prevent thrombotic complications of flow diverters. PMID- 29163746 TI - Genetic Insights into Cerebrovascular Disorders: A Comprehensive Review. PMID- 29163747 TI - Endovascular Stenting of Tandem Carotid Artery Origin and Bifurcation Stenotic Lesions Using Flow Reversal. AB - Background: The treatment of tandem lesions involving severe stenosis of the internal carotid artery with concomitant stenosis of the ipsilateral common carotid artery (CCA) origin represents an ongoing challenge. Current options for the treatment of tandem carotid artery origin and bifurcation stenotic lesions include open surgical endarterectomy, endovascular stenting, balloon angioplasty, and hybrid procedures combining both modalities. However, these options are either associated with high peri-operative risks or not always anatomically feasible. Case Description: We report, for the first time in North America (to the best of our knowledge), an alternative treatment modality that involves obtaining access through a direct carotid cut-down, with serial treatment of the tandem lesions through a combination of retrograde and anterograde endovascular stenting. Conclusion: This technique obviates the need for navigating the aortic arch in patients with difficult arch anatomy and permits the use of distal embolic protection devices, thus decreasing the risk of peri-operative ischemic events. PMID- 29163749 TI - Isolated Extracranial Vasospasm and Intracranial Dissection: An Unusual Imaging Manifestation of Reversible Cerebral Vasoconstriction Syndrome. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is a distinct clinical syndrome characterized by thunderclap headache and reversible cerebral vasoconstriction. An association between RCVS and arterial dissection has emerged in recent years, where dissection typically involves the cervical vertebral arteries. In this vignette, we describe isolated reversible vasoconstriction, involving the extracranial arteries and intracranial dissection-a combination hitherto never reported. PMID- 29163750 TI - Long Acting Liposomal Bupivacaine for Percutaneous Sympathetic Stellate Ganglion Blockade: A Technical Note. AB - Introduction: We describe the use of long acting liposomal bupivacaine for percutaneous stellate ganglion blockade to treat severe headaches following internal carotid artery dissection. Methods: A 43-year old woman developed right sided refractory headache after right internal carotid artery dissection. Patient underwent percutaneous stellate ganglion block using bupivacaine hydrochloride (0.25%-20 ml) in the past with short acting relief. Liposomal bupivacaine (EXPAREL) 13.3 mg/mL (1.3%) solution diluted with preservative-free normal saline: a total solution of 20 ml (52 mg of bupivacaine) was injected at the level of the lower portion of body of the sixth cervical vertebra, medial to the right internal carotid artery. The response to sympathetic block was assessed by a neurologist not involved in the procedure. Results: After the stellate ganglion block with bupivacaine hydrochloride, patient was headache free immediately after the block but with recurrence of pain on Day 3 with return to peak intensity by Day 4. After the stellate ganglion blockade with liposomal bupivacaine hydrochloride, patient reported recurrence of pain on Day 15 post injection with return to peak intensity by Day 17. The patient reported an episode of aura which consisted of visual scintillations on Day 2 which lasted for five days and resolved spontaneously. Conclusion: Liposomal bupivacaine injection for stellate ganglion blockade can result in a more prolonged effect compared with bupivacaine hydrochloride. PMID- 29163751 TI - Extracranial Four-Vessel Dissection with Reversible Cerebral Vasoconstriction Syndrome in a Habitual Cocaine User Presenting with Thunderclap Headache. PMID- 29163753 TI - Cytoprotective Effects of Citicoline and Homotaurine against Glutamate and High Glucose Neurotoxicity in Primary Cultured Retinal Cells. AB - Citicoline and homotaurine are renowned compounds that exhibit potent neuroprotective activities through distinct molecular mechanisms. The present study was undertaken to demonstrate whether cotreatment with citicoline and homotaurine affects cell survival in primary retinal cultures under experimental conditions simulating retinal neurodegeneration. Primary cultures were obtained from the retina of fetal rats and exposed to citicoline plus homotaurine (100 MUM). Subsequently, neurotoxicity was induced using excitotoxic levels of glutamate and high glucose concentrations. The effects on retinal cultures were assessed by cell viability and immunodetection of apoptotic oligonucleosomes. The results showed that a combination of citicoline and homotaurine synergistically decreases proapoptotic effects associated with glutamate- and high glucose treated retinal cultures. This study provides an insight into the potential application of citicoline and homotaurine as a valuable tool to exert neuroprotective effects against retinal damage. PMID- 29163752 TI - Cytotoxicity, Oxidative Stress, Cell Cycle Arrest, and Mitochondrial Apoptosis after Combined Treatment of Hepatocarcinoma Cells with Maleic Anhydride Derivatives and Quercetin. AB - The inflammatory condition of malignant tumors continually exposes cancer cells to reactive oxygen species, an oxidizing condition that leads to the activation of the antioxidant defense system. A similar activation occurs with glutathione production. This oxidant condition enables tumor cells to maintain the energy required for growth, proliferation, and evasion of cell death. The objective of the present study was to determine the effect on hepatocellular carcinoma cells of a combination treatment with maleic anhydride derivatives (prooxidants) and quercetin (an antioxidant). The results show that the combination of a prooxidant/antioxidant had a cytotoxic effect on HuH7 and HepG2 liver cancer cells, but not on either of two normal human epithelial cell lines or on primary hepatocytes. The combination treatment triggered apoptosis in hepatocellular carcinoma cells by activating the intrinsic pathway and causing S phase arrest during cell cycle progression. There is also clear evidence of a modification in cytoskeletal actin and nucleus morphology at 24 and 48 h posttreatment. Thus, the current data suggest that the combination of two anticarcinogenic drugs, a prooxidant followed by an antioxidant, can be further explored for antitumor potential as a new treatment strategy. PMID- 29163754 TI - Troxerutin Reduces Kidney Damage against BDE-47-Induced Apoptosis via Inhibiting NOX2 Activity and Increasing Nrf2 Activity. AB - 2,2,4,4-Tetrabromodiphenyl ether (BDE-47), one of the persistent organic pollutants, seriously influences the quality of life; however, its pathological mechanism remains unclear. Troxerutin is a flavonoid with pharmacological activity of antioxidation and anti-inflammation. In the present study, we investigated troxerutin against BDE-47-induced kidney cell apoptosis and explored the underlying mechanism. The results show that troxerutin reduced renal cell apoptosis and urinary protein secretion in BDE-47-treated mice. Western blot analysis shows that troxerutin supplement enhanced the ratio of Bcl-2/Bax; inhibited the release of cytochrome c from mitochondria, the activation of procaspase-9 and procaspase-3, and the cleavage of PARP; and reduced FAS, FASL, and caspase-8 levels induced by BDE-47. In addition, troxerutin decreased the production of reactive oxygen species (ROS) and increased the activities of antioxidative enzymes. Furthermore, troxerutin blunted Nrf2 ubiquitylation, enhanced the activity of Nrf2, decreased the activity of NOX2, and ameliorated kidney oxidant status of BDE-47-treated mice. Together, these results confirm that troxerutin could alleviate the cytotoxicity of BDE-47 through antioxidation and antiapoptosis, which suggests that its protective mechanism is involved in the inhibition of apoptosis via suppressing NOX2 activity and increasing Nrf2 signaling pathway. PMID- 29163758 TI - Ribosomal proteins: a novel class of oncogenic drivers. PMID- 29163757 TI - Cancer drugs in LMICs: cheap but unaffordable. PMID- 29163755 TI - Uncoupling Protein 2: A Key Player and a Potential Therapeutic Target in Vascular Diseases. AB - Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane protein that belongs to the uncoupling protein family and plays an important role in lowering mitochondrial membrane potential and dissipating metabolic energy with prevention of oxidative stress accumulation. In the present article, we will review the evidence that UCP2, as a consequence of its roles within the mitochondria, represents a critical player in the predisposition to vascular disease development in both animal models and in humans, particularly in relation to obesity, diabetes, and hypertension. The deletion of the UCP2 gene contributes to atherosclerosis lesion development in the knockout mice, also showing significantly shorter lifespan. The UCP2 gene downregulation is a key determinant of higher predisposition to renal and cerebrovascular damage in an animal model of spontaneous hypertension and stroke. In contrast, UCP2 overexpression improves both hyperglycemia- and high-salt diet-induced endothelial dysfunction and ameliorates hypertensive target organ damage in SHRSP. Moreover, drugs (fenofibrate and sitagliptin) and several vegetable compounds (extracts from Brassicaceae, berberine, curcumin, and capsaicin) are able to induce UCP2 expression level and to exert beneficial effects on the occurrence of vascular damage. As a consequence, UCP2 becomes an interesting therapeutic target for the treatment of common human vascular diseases. PMID- 29163756 TI - Effect of Chronic Administration of Resveratrol on Cognitive Performance during Aging Process in Rats. AB - The increase in the elderly population has generated concern to meet health demands. The research efforts to elucidate the mechanisms of damage associated with aging have also been significantly increased, especially in order to avoid the reduction of the cognitive abilities in geriatric patients, resulting from the damage generated mainly at the level of the hippocampus during old age. At present, many studies describe resveratrol as an antiaging component. There are reports that it can activate the Sirt1 gene related to antiaging, emulating the effects obtained by caloric restriction in rodents. The aim of the study was to evaluate the effect of chronic administration of resveratrol (10 mg/kg) on cognitive performance in behavioral tests after 8 months of treatment and on the preservation of cerebral integrity in the cytoarchitecture of regions CA1 and CA2. Results showed that the cytoarchitecture of the CA1 and CA2 regions in the hippocampus retained their integrity over time in rats treated with resveratrol, and the behavioral test performed revealed that chronic resveratrol administration for 8 months showed improvements in cognitive performance. The results indicate that resveratrol may exhibit therapeutic potential for age related conditions. PMID- 29163759 TI - HO-1 inhibits migration of leukemic cells. PMID- 29163760 TI - TSH-independent release of thyroid hormones through cold exposure in aging rats. AB - Thyroid function decreases and cold exposure response becomes impaired with increasing age. We investigated the age-related changes in thyroid structure and function and cold-induced changes in the thyroid activity of aging rats. Thirty two male Sprague-Dawley rats were randomly divided into four groups (8 rats per group): young (7 months) and old (22 months) groups exposed to room temperature and cold stress. The active follicle ratio and serum free T3, T4 and TSH, and TSH receptor (TSHR) concentrations in the thyroid tissues of the rats from each group were compared. At room temperature, old rats had significantly lower active follicle ratio and free T3 and T4 concentrations than young rats. Furthermore, old rats displayed higher TSH level than young. Exposure to cold temperature led to significantly increased active colloid ratio and free T3 and T4 concentrations among old rats, but no significant differences were found among young rats. Additionally, no significant changes in the TSH and TSHR levels were observed after cold exposure in both young and old rats. Old rats have lower thyroid function than young rats under normal temperature. Aging rats are more susceptible to cold stress than young rats, and cold-induced thyroid activation occurs independently of TSH. We investigated the age-related changes in the thyroid structure and function and cold-induced changes in the thyroid activity of aging rats. Aging rats have structurally less active thyroid follicles and functionally lower thyroid hormone levels than young rats. Furthermore, old rats are more susceptible to cold stress than young rats, and cold-induced thyroid activation occurs independently of TSH. PMID- 29163761 TI - E3 ligase mahogunin (MGRN1) influences amyloid precursor protein maturation and secretion. AB - Altered processing of the Amyloid Precursor Protein (APP) is a well-recognized central pathogenic mechanism in Alzheimer's Disease (AD), and regulation of APP processing is a major focus of research in the AD field. However, how age associated cellular and molecular changes contribute to changes in the amyloidogenic processing of APP have not been extensively clarified so far. We here provide evidence that the processing of APP is influenced by the e3 ubiquitin ligase Mahogunin (MGRN1), a neuroprotective molecule whose levels decrease with aging. Specifically, the expression of MGRN1 inhibits the maturation of APP by sequestering it in the secretory pathway. This sequestration significantly delayed the proteolytic processing of APP, resulting in a reduced beta-amyloid (Abeta) peptide release into the extracellular environment. Accordingly, a reduction of MGRN1 levels in hippocampal neurons, as it occurs during physiological aging, leads to an increased Abeta40 and Abeta42 release. We therefore propose that age contributes to the amyloidogenic processing of APP by altering its intracellular trafficking along the secretory pathway due in part to the down-regulation of MGRN1. PMID- 29163762 TI - BMAL1 facilitates trophoblast migration and invasion via SP1-DNMT1/DAB2IP pathway in recurrent spontaneous abortion. AB - The underlying mechanism about rhythms and epigenetics leading to aberrant trophoblast migration and invasion in recurrent spontaneous abortion (RSA) remains unknown. Brain and muscle ARNT-like protein 1 (BMAL1) is considered as a crucial role in fertility, and polymorphism of BMAL1 gene has been reported to be associated with risk of miscarriage. However, the functional role of BMAL1 in RSA is not fully understood. Previous study shows the descended expression of DNA 5' cytosine-methyltransferases 1 (DNMT1) in the villous of early pregnancy loss. Thus, understanding of the regulation of DNMT1 expression may be of significance for the elucidation of the process of RSA. Using HTR-8/SVneo and JEG-3 cell lines, we certified the induction of specificity protein 1 (SP1) to DNMT1 and DAB2 interaction protein (DAB2IP), respectively, both of which further activated matrix metallo-proteinase 2/9 (MMP2/9), bringing out changes in trophoblast migration and invasion. Notably, BMAL1 functioned as a positive upstream factor of SP1 only in HTR-8/SVneo cells but not in JEG-3 cells, inducing SP1 DNMT1/DAB2IP pathway and facilitating migration and invasion of trophoblasts. In addition, progesterone might restore the down-regulation of BMAL1 and downstream pathway in a dose-dependent manner. Last but not least, the decreased abundance of BMAL1 was correlated positively with that of SP1, DNMT1, DAB2IP, MMP2 and MMP9 in human villous specimens of RSA. Our results demonstrate that the induction of BMAL1 to SP1 contributes to the expression of DNMT1 and DAB2IP, respectively, activating trophoblast migration and invasion. The deregulation of the BMAL1 mediated pathway in RSA can be rescued by progesterone. PMID- 29163763 TI - PD-L1 expression and CD8+ tumor-infiltrating lymphocytes are associated with ALK rearrangement and clinicopathological features in inflammatory myofibroblastic tumors. AB - Background: Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal neoplasms that are composed of myofibroblastic cells accompanied by inflammatory infiltrate. We investigated the immune profiles of IMTs, including PD-L1 expression and proportion of CD8+ tumor-infiltrating lymphocytes (TILs), as well as its clinicopathological characteristics according to ALK gene rearrangementstatus. Methods: Twenty-eight IMTs from 25 patients were retrieved from our pathology files (2005-2015), and their clinicopathological parameters and outcomes were analyzed. Immunohistochemistry (IHC) was performed using whole tissue sections to detect PD-L1 and CD8 expression, and fluorescent in situ hybridization (FISH) analysis and IHC were performed using tissue microarrays to identify rearrangements in the ALK, ROS1, and RET genes. Results: ALK rearrangement was observed in 11 cases (44.0%), and all cases exhibited diffuse cytoplasmic ALK expression during IHC. ROS1 or RET rearrangement was not detected using IHC or FISH. IMTs harboring ALK rearrangement (ALK-positive) were located in the lungs (n = 7), genitourinary tract (n = 2), and mesentery (n = 1). The mean patient age was 33.2 years for ALK-positive IMTs and 53.1 years for ALK negative IMTs. All patients with ALK-positive IMTs survived without recurrence or metastasis. IMTs with metastasis and/or recurrence were ALK-negative and exhibited elevated PD-L1 expression (positive tumor cells: 70.0% vs. 21.3%, P = 0.023; H-score: 107.5 vs. 26.3, P = 0.005). In addition, ALK-negative IMTs had a more CD8+ TILs, compared to ALK-positive IMTs (23.3% vs. 8.9%, P = 0.027). Conclusion: ALK-positive IMTs are characterized by younger age, well-defined margins, frequent involvement of the lung, and fewer CD8+ TILs. Greater PD-L1 expression was observed in IMTs with tumor necrosis and metastasis/recurrence, which were also negative for ALK rearrangement. These results suggest that immune checkpoint inhibitors may be a novel option for treating patients with advanced IMT. PMID- 29163764 TI - Inhibition of autoimmune Th17 cell responses by pain killer ketamine. AB - Ketamine is widely used in animals and humans as a systemic anesthetic. Although several immune-modulatory functions of ketamine have been reported, the effects of ketamine on the differentiation of Th17 cell are unknown. We found that ketamine significantly diminished the frequency of IL-17-producers among CD4+ T cells stimulated under Th17-skewing conditions. Mechanistic studies showed that ketamine had little effect on the production of Th17-inducing cytokines by dendritic cells and the proliferation of T cells in response to anti-CD3; however it significantly hampered IL-21 expression as well as STAT3 phosphorylation in T cells upon IL-6 stimulation. Moreover, MOG-reactive CD4+ T cells expanded in the presence of ketamine produced reduced amounts of Th17 cytokines, leading to diminished EAE severity when transferred into TCRbeta-deficient mice in comparison to those treated with vehicle. These findings demonstrate that ketamine suppresses autoimmune Th17 cell responses by inhibiting the differentiation as well as the reactivation of Th17 cells. PMID- 29163765 TI - B cells regulate thymic CD8+T cell differentiation in lupus-prone mice. AB - Previous studies have shown that under normal physiological conditions thymic B cells play a critical function in T cell negative selection. We tested the effect of thymic B cells on thymic T-cell differentiation in autoimmune diseases including systemic lupus erythematosus (SLE). We found that thymic B cells and CD8- CD4+ and CD4-CD8+T cells increased, whereas CD4+CD8+T cells decreased in lupus-prone mice. Once B cells were reduced, the change was reversed. Furthermore, we found that B cells blocked thymic immature single positive (ISP) CD4-CD8+CD3lo/-RORgammat- T cells progression into CD4+CD8+T cells. Interestingly, we found a novel population of thymic immature T cells (CD4 CD8+CD3loRORgammat+) that were induced into mature CD4-CD8+CD3+RORgammat+T cells by B cells in lupus-prone mice. Importantly, we found that IgG, produced by thymic B cells, played a critical role in the differentiation of thymic CD8+ISP and mature RORgammat+CD8+ T cells in lupus-prone mice. In conclusion, B cells blocked the differentiation from thymic CD8+ISP and induced the differentiation of a novel immature CD4-CD8+CD3loRORgammat+T cells into mature RORgammat+CD8+ T cells by secreting IgG antibody in lupus-prone mice. PMID- 29163766 TI - Epigallocatechin-3-gallate (EGCG) up-regulates miR-15b expression thus attenuating store operated calcium entry (SOCE) into murine CD4+ T cells and human leukaemic T cell lymphoblasts. AB - CD4+ T cells are key elements in immune responses and inflammation. Activation of T cell receptors in CD4+ T cells triggers cytosolic Ca2+ release with subsequent store operated Ca2+ entry (SOCE), which is accomplished by the pore forming Ca2+ release activated Ca2+ (CRAC) channel Orai1 and its regulator stromal cell interaction molecule 2 (STIM2). Green tea polyphenol epigallocatechin-3-gallate (EGCG) acts as a potent anti-inflammatory and anti-oxidant agent for various types of cells including immune cells. However, how post-transcriptional gene regulators such as miRNAs are involved in the regulation of Ca2+ influx into murine CD4+ T cells and human Jurkat T cells through EGCG is not defined. EGCG treatment of murine CD4+ T cells significantly down-regulated the expression of STIM2 and Orai1 both at mRNA and protein levels. Furthermore, EGCG significantly decreased SOCE in both murine and human T cells. EGCG treatment increased miRNA 15b (miR-15b) abundance in both murine and human T cells. Bioinformatics analysis reveals that miR-15b, which has a STIM2 binding site, is involved in the down regulation of SOCE. Overexpression of miR-15b significantly decreased the mRNA and protein expression of STIM2 and Orai1 in murine T cells. Treatment of Jurkat T cells with 10 MUM EGCG further decreased mTOR and PTEN protein levels. EGCG decreased mitochondrial membrane potential (MMP) in both human and murine T cells. In conclusion, the observations suggest that EGCG inhibits the Ca2+ entry into murine and human T cells, an effect accomplished at least in part by up regulation of miR-15b. PMID- 29163767 TI - Immunology repertoire study of pulmonary sarcoidosis T cells in CD4+, CD8+ PBMC and tissue. AB - Sarcoidosis is a systemic granulomatous disorder highly related with immune response. The diversity and stability of the immune system could be measured by hypervariable complementarity-determining region 3 (CDR3) segments of the T cell receptor (TCR). Here we used a combination of multiplex PCR and next-generation sequencing to conduct a good quality analysis of the T-cell receptor BV complementarity-determining region 3 (TCR BV CDR3) gene in peripheral blood mononuclear cells (PBMCs) from 7 sarcoidosis patients and lung sarcoidosis tissue from 6 patients. The length distribution of CDR3 sequences identified a significant difference among CD4+, CD8+ and tissue samples. The analysis of Gini coefficient, Shannon entropy and HEC number showed that they all presents in sarcoidosis tissue group clones in a more skewed manner than that of in PMBCs groups. 2 nucleotide sequences and 2 amino acid sequences were shared by all samples. The comparison of TRBV, TRBJ usage and VJ combination frequency identified 2 TRBV genes, 2 TRBJ genes differentially expressed among different groups and different higher usage and lower usage of V-J combinations between each group. PMID- 29163768 TI - Inhibitor of growth protein 4 interacts with Beclin 1 and represses autophagy. AB - Beclin 1 (BECN1) is a multifunctional protein that activates the pro-autophagic class III phosphatidylinositol 3-kinase (PIK3C3, best known as VPS34), yet also interacts with multiple negative regulators. Here we report that BECN1 interacts with inhibitor of growth family member 4 (ING4), a tumor suppressor protein that is best known for its capacity to interact with the tumor suppressor protein p53 (TP53) and the acetyltransferase E1A binding protein p300 (EP300). Removal of TP53 or EP300 did not affect the BECN1/ING4 interaction, which however was lost upon culture of cells in autophagy-inducing, nutrient free conditions. Depletion of ING4 stimulated the enzymatic activity of PIK3C3, as visualized by means of a red fluorescent protein-tagged short peptide (FYVE) that specifically binds to phosphatidylinositol-3-phosphate (PI3P)-containing subcellular vesicles and enhanced autophagy, as indicated by an enhanced lipidation of microtubule associated proteins 1A/1B light chain 3 beta (LC3B) and the redistribution of a green-fluorescent protein (GFP)-LC3B fusion protein to cytoplasmic puncta. The generation of GFP-LC3B puncta stimulated by ING4 depletion was reduced by simultaneous depletion, or pharmacological inhibition, of PIK3C3/VPS34. In conclusion, ING4 acts as a negative regulator of the lipid kinase activity of the BECN1 complex, and starvation-induced autophagy is accompanied by the dissociation of the ING4/BECN1 interaction. PMID- 29163769 TI - YAP1 is essential for tumor growth and is a potential therapeutic target for EGFR dependent lung adenocarcinomas. AB - Epidermal growth factor receptor (EGFR) mutations are found in lung adenocarcinomas leading to tumor cells proliferation and survival. EGFR tyrosine kinase inhibitors (TKIs) that block EGFR activity are effective therapeutics for EGFR-mutant lung adenocarcinoma patients, but TKI-resistance inevitably occurs. The YES-associated protein (YAP1) transcription coactivator has been implicated as an oncogene and is amplified in human cancers and provides tumor cells strong proliferation and survival cues. This study investigated the roles of YAP1 in lung adenocarcinoma by exploring its regulation and functions mediated by EGFR signaling. In this study, we detected a correlation between YAP1 level and EGFR mutation status in lung adenocarcinoma tissues. Using lung adenocarcinoma cell lines, enhanced YAP1 expression and activity mediated by EGFR signaling was detected through enhanced protein stability. A SRC family protein, YES, was involved in EGFR-regulated YAP1 expression and this pathway was crucial for proliferation in EGFR-dependent cells. Small molecules that reduced YAP1 levels by mechanisms bypassing EGFR signaling were effective in reducing viability in EGFR-dependent cells including those with EGFR T790M, the major cause of TKI resistance. These observations unveiled the significance of YAP1 in EGFR mutant lung adenocarcinomas and identified YAP1 as a promising therapeutic target for EGFR-dependent lung adenocarcinoma patients, including those with EGFR T790M caused TKI resistance. PMID- 29163770 TI - Role of microenvironmental periostin in pancreatic cancer progression. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic reaction. Pancreatic stellate cells (PSCs) are the principal effector cells responsible for stroma production. Aberrant up-regulation of periostin expression has been reported in activated PSCs. In this study, we investigated the role of periostin and the mechanisms underlying its aberrant upregulation in PDAC. We used lentiviral shRNA and human recombinant periostin protein to down and up regulate periostin expression in vitro. Specific oncogenic signaling pathways such as EGFR-Akt and EGFR-Erk-c-Myc were assessed in vitro and in vivo. Tissue microarray immunohistochemical assays including 80 pancreatic cancer tissues and paired normal tissues were used to understand the function relationship between periostin expression and PDAC pathologic stage and overall survival. We found that periostin was strongly expressed in PSCs and the stroma of PDAC tumors. We also observed a significant decrease in proliferation, metastasis, and clonality of pancreatic cancer cells when co-cultured with supernatant of periostin shRNA-transfected PSCs. Specifically, the biological behavior of periostin correlated with EGFR-Akt and EGER-Erk-c-Myc signaling pathways. Moreover, increased periostin expression significantly associated with advanced disease stage and decreased survival rate in PDAC patients. Together, our findings provide novel insights into the role of microenvironmental periostin in pancreatic cancer progression, and periostin may serve as a prognostic biomarker for PDAC. PMID- 29163771 TI - Inhibition of HOX/PBX dimer formation leads to necroptosis in acute myeloid leukemia cells. AB - The HOX genes encode a family of transcription factors that have key roles in both development and malignancy. Disrupting the interaction between HOX proteins and their binding partner, PBX, has been shown to cause apoptotic cell death in a range of solid tumors. However, despite HOX proteins playing a particularly significant role in acute myeloid leukemia (AML), the relationship between HOX gene expression and patient survival has not been evaluated (with the exception of HOXA9), and the mechanism by which HOX/PBX inhibition induces cell death in this malignancy is not well understood. In this study, we show that the expression of HOXA5, HOXB2, HOXB4, HOXB9, and HOXC9, but not HOXA9, in primary AML samples is significantly related to survival. Furthermore, the previously described inhibitor of HOX/PBX dimerization, HXR9, is cytotoxic to both AML derived cell lines and primary AML cells from patients. The mechanism of cell death is not dependent on apoptosis but instead involves a regulated form of necrosis referred to as necroptosis. HXR9-induced necroptosis is enhanced by inhibitors of protein kinase C (PKC) signaling, and HXR9 combined with the PKC inhibitor Ro31 causes a significantly greater reduction in tumor growth compared to either reagent alone. PMID- 29163772 TI - Increased cFLIP expression in thymic epithelial tumors blocks autophagy via NF kappaB signalling. AB - The anti-apoptotic cellular FLICE-like inhibitory protein cFLIP plays a pivotal role in normal tissues homoeostasis and the development of many tumors, but its role in normal thymus (NT), thymomas and thymic carcinomas (TC) is largely unknown. Expression, regulation and function of cFLIP were analyzed in biopsies of NT, thymomas, thymic squamous cell carcinomas (TSCC), thymic epithelial cells (TECs) derived thereof and in the TC line 1889c by qRT-PCR, western blot, shRNA techniques, and functional assays addressing survival, senescence and autophagy. More than 90% of thymomas and TSCCs showed increased cFLIP expression compared to NT. cFLIP expression declined with age in NTs but not in thymomas. During short term culture cFLIP expression levels declined significantly slower in neoplastic than non-neoplastic primary TECs. Down-regulation of cFLIP by shRNA or NF-kappaB inhibition accelerated senescence and induced autophagy and cell death in neoplastic TECs. The results suggest a role of cFLIP in the involution of normal thymus and the development of thymomas and TSCC. Since increased expression of cFLIP is a known tumor escape mechanism, it may serve as tissue-based biomarker in future clinical trials, including immune checkpoint inhibitor trials in the commonly PD-L1high thymomas and TCs. PMID- 29163773 TI - Tumor response of temozolomide in combination with morphine in a xenograft model of human glioblastoma. AB - Despite multimodal treatments comprising, radiation therapy (RT) and chemotherapy with temozolomide (TMZ), the prognosis of glioblastoma multiforme (GBM) remains dismal and consolidated therapy yields a median survival of 14.6 months. Blood Brain Barrier (BBB) mediated chemoresistance and high dose related toxicity make necessary the development of new therapeutic approach to sensitize GBM to TMZ. The aim of the present study was to investigate the potential of the treatment morphine plus TMZ metronmic doses (1,77 and 0,9 mg/kg) in GBM therapy. The effect of morphine, on tumor cell growth and P-glycoprothein (P-gp) activity, was investigate in in vitro models. The results demonstrated that GBM cells growth is not influenced by morphine treatment and, for the first time, we show that morphine is an inhibitor of the activity of P-gp efflux transporter who is markedly expressed on BBB. In vivo, response to the treatments TMZ plus morphine was investigated in an orthotopic nude mice model of GBM. Animals treated with TMZ metronomic doses showed a significant tumor growth inhibition compared to untreated mice and association with morphine appears to improve TMZ efficacy. Moreover, the combination of morphine with lower dose of TMZ result in a cytostatic effect on tumor growth over the period of the pharmacological treatments. In conclusion this novel approach could be a successful strategy to overcome chemoresistance and side effects TMZ mediated, reducing drug dosage and improving long term response, in GBM therapy. PMID- 29163774 TI - Integrative analysis of novel hypomethylation and gene expression signatures in glioblastomas. AB - Molecular and clinical heterogeneity critically hinders better treatment outcome for glioblastomas (GBMs); integrative analysis of genomic and epigenomic data may provide useful information for improving personalized medicine. By applying training-validation approach, we identified a novel hypomethylation signature comprising of three CpGs at non-CpG island (CGI) open sea regions for GBMs. The hypomethylation signature consistently predicted poor prognosis of GBMs in a series of discovery and validation datasets. It was demonstrated as an independent prognostic indicator, and showed interrelationships with known molecular marks such as MGMT promoter methylation status, and glioma CpG island methylator phenotype (G-CIMP) or IDH1 mutations. Bioinformatic analysis found that the hypomethylation signature was closely associated with the transcriptional status of an EGFR/VEGFA/ANXA1-centered gene network. The integrative molecular analysis finally revealed that the gene network defined two distinct clinically relevant molecular subtypes reminiscent of different immature neuroglial lineages in GBMs. The novel hypomethylation signature and relevant gene network may provide new insights into prognostic classification, molecular characterization, and treatment development for GBMs. PMID- 29163775 TI - Loss of Sun2 promotes the progression of prostate cancer by regulating fatty acid oxidation. AB - The role of Sun2 has been described by previous studies in various types of cancers, including breast cancer and lung cancer. However, its role and potential molecular mechanism in the progression of prostate cancer have not been fully elucidated. In the present study, we found that Sun2 expression was reduced in prostate cancer tissues compared with paired normal tissues, and that low expression of Sun2 was significantly correlated with Higher Gleason scores, postoperative T stage (pT), Lymph nodal invasion and Clinical pathological stages. In addition, reduced Sun2 Expression predicts poor survival of prostate cancer patients and could serve as an independent predictor of prostate cancer patients overall survival (OS).Furthermore, Sun2 overexpression inhibits the prostate cancer cells growth, and Sun2 knockdown promotes the prostate cancer cells growth both in vitro and vivo. Mechanical silencing of , Sun2 promoted fatty acid oxidation (FAO) in prostate cancer, prostate cancer cells growth promoted by Sun2 silencing could be reversed by the FAO inhibitor Etomoxir. Additionally, we also showed that serum amyloid A1 (SAA1) play a vital role in FAO, ATP and cell growth promoted by Sun2 loss in prostate cancer. These results suggest that Loss of Sun2 promoted the prostate cancer progression by regulating FAO. PMID- 29163776 TI - MiR-1268b confers chemosensitivity in breast cancer by targeting ERBB2-mediated PI3K-AKT pathway. AB - Chemoresistance represents a major obstacle to effective therapy for breast cancer. Emerging evidences associated aberrantly expressed miRNAs with tumor development and chemoresistance. MiR-1268b has never been studied in any cancers before, and its roles in mediating tumor progression and drug resistance are still unclear. Selected from miRNA microarray and confirmed by real-time quantitative PCR (RT-qPCR), miR-1268b was found to be significantly upregulated in drug sensitive and ERBB2 negative tissues, as well as in breast cancer patients with low clinical stage. And miR-1268b had a higher expression in chemosensitive breast cancer cell lines, compared with the chemoresistant cell line. Moreover, the results revealed that miR-1268b induced breast cancer cell apoptosis and increased cell chemosensitivity. ERBB2 was demonstrated to be the target gene of miR-1268b by dual-luciferase reporter assays, western blot, and immunocytochemistry. Furthermore, PI3KCA, AKT, BCL2 in the ERBB2-PI3K-AKT signaling pathway were found to be downstream effectors of miR-1268b. In conclusion, miR-1268b increased chemosensitivity, at least in part, via modulation of PI3K-AKT pathway by targeting ERBB2. MiR-1268b may serve as a potential therapeutic target for patients with breast cancers. PMID- 29163777 TI - DHX15 is associated with poor prognosis in acute myeloid leukemia (AML) and regulates cell apoptosis via the NF-kB signaling pathway. AB - The role of DHX15, a newly identified DEAH-box RNA helicase, in leukemogenesis remains elusive. Here, we identified a recurrent mutation in DHX15 (NM_001358:c.664C>G: p.(R222G)) in one familial AML patient and 4/240 sporadic AML patients. Additionally, DHX15 was commonly overexpressed in AML patients and associated with poor overall survival (OS) (P=0.019) and relapse-free survival (RFS) (P=0.032). In addition, we found a distinct expression pattern of DHX15. DHX15 was highly expressed in hematopoietic stem cells and leukemia cells but was lowly expressed in mature blood cells. DHX15 was down-regulated when AML patients achieved disease remission or when leukemia cell lines were induced to differentiate. DHX15 silencing greatly inhibited leukemia cell proliferation and induced cell apoptosis and G1-phase arrest. In contrast, the restoration of DHX15 expression rescued cell viability and reduced cell apoptosis. In addition, we found that DHX15 was down-regulated when cell apoptosis was induced by ATO (arsenic trioxide); overexpression of DHX15 caused dramatic resistance to ATO induced cell apoptosis, suggesting an important role for DHX15 in cell apoptosis. We further explored the mechanism of DHX15 in apoptosis and found that overexpression of DHX15 activated NF-kB transcription. Knockdown of DHX15 inhibited the nuclear translocation and activation of the NF-kB subunit P65 in leukemia cells. Several downstream targets of the NF-kB pathway were also down regulated, and apoptosis-associated genes CASP3 and PARP were activated. In conclusion, this study represents the first demonstration that DHX15 plays an important role in leukemogenesis via the NF-kB signaling pathway and may serve as an independent prognostic marker for AML. PMID- 29163778 TI - A study on the expression of apoptotic molecules related to death receptor and endoplasmic reticulum pathways in the jejunum of AFB1-intoxicated chickens. AB - Aflatoxin B1 (AFB1) is a common contaminant of poultry feeds in tropical and subtropical climates. Early researches have well established the hepatotoxic, carcinogenic, and immunotoxic effects of AFB1 on humans and animals. Recently, it has been shown that AFB1 could cause the up- or down-alteration of mitochondrial pathway molecule expression. However, the information on the expression of death receptor and endoplasmic reticulum molecules in the jejunal apoptosis induced by AFB1 were unavailable. So the present study was conducted to explore the expression of apoptotic molecules related to death receptor and endoplasmic reticulum in the jejunal cells of chickens exposed to AFB1 diet for 3 weeks. Total of 144 one-day-old chickens was randomly divided into two groups, namely control group (containing 0 mg/kg AFB1) and AFB1 group (containing 0.6 mg/kg AFB1). Histopathological observation and microscopic quantitative analysis revealed morphological changes in the jejunum such as the shedding of the mucosal epithelial cells in the apical region of villi along with the decrease of villus height, villus area and villus/crypt ratio in the AFB1 group. Both TUNEL and flow cytometry assays showed that AFB1 intake induced excessive apoptosis of jejunal cells. Quantitative real-time PCR test displayed the general upregulation of death receptors (FAS, FASL, TNF-alpha and TNF-R1), endoplasmic reticulum signals (GRP78 and GRP94) as well as initiator and executioner caspases (CASPASE-10, CASPASE-8 and CASPASE-3) in the jejunum of AFB1-intoxicated chickens. It's the first study demonstrating that AFB1 induced apoptosis of chickens' jejunum accompanied by the alteration of death receptor and endoplasmic reticulum molecule expression. PMID- 29163779 TI - Maternal dietary manganese protects chick embryos against maternal heat stress via epigenetic-activated antioxidant and anti-apoptotic abilities. AB - Maternal heat stress induced the aberrant epigenetic patterns resulting in the abnormal development of offspring embryos. It is unclear whether maternal dietary manganese supplementation as an epigenetic modifier could protect the chick embryonic development against maternal heat stress via epigenetic mechanisms. To test this hypothesis using an avian model, a completely randomized design with a 2 (maternal normal and high environmental temperatures of 21 and 32 degrees C, respectively) * 3 (maternal dietary manganese sources, the control diet without manganese supplementation and the control diet + 120 mg/kg as either inorganic or organic manganese) factorial arrangement was adopted. Maternal environmental hyperthermia increased mRNA expressions of heat shock proteins 90 and 70, cyclin dependent kinase 6 and B-cell CLL/lymphoma 2-associated X protein displaying oxidative damage and apoptosis in the embryonic heart. Maternal environmental hyperthermia impaired the embryonic development associated with the alteration of epigenetic status, as evidenced by global DNA hypomethylation and histone 3 lysine 9 hypoacetylation in the embryonic heart. Maternal dietary manganese supplementation increased the heart anti-apoptotic gene B-cell CLL/lymphoma 2 expressions under maternal environmental hyperthermia and manganese superoxide dismutase enzyme activity in the embryonic heart. Maternal dietary organic Mn supplementation effectively eliminated the impairment of maternal environmental hyperthermia on the embryonic development. Maternal dietary manganese supplementation up-regulated manganese superoxide dismutase mRNA expression by reducing DNA methylation and increasing histone 3 lysine 9 acetylation of its promoter. It is suggested that maternal dietary manganese addition could protect the chick embryonic development against maternal heat stress via enhancing epigenetic-activated antioxidant and anti-apoptotic abilities. PMID- 29163780 TI - Hypoxia-inducible factor-1alpha activation in HPV-positive head and neck squamous cell carcinoma cell lines. AB - Purpose: Human papillomavirus (HPV) is a causative agent for a rising number of head and neck squamous cell carcinomas (HNSCC), which are characterized by distinct tumor biology. Hypoxia inducible-factor (HIF) signaling influences initiation and progression of carcinogenesis and HPV oncoproteins have evolved to highjack cellular pathways for viral reproduction. Therefore, we investigated whether HPV activates HIF-1alpha expression in HNSCC. Experimental Technique: HPV positive and -negative HNSCC cells were examined for adaptive responses to hypoxia. Expression of HIF-1alpha, prolyl hydroxylase-domain protein 2 (PHD2) and E-cadherin was analyzed by Western blotting, immunofluorescence (IF) microscopy and migration/wound healing assays. Results: HPV-positive HNSCC cells showed higher HIF-1alpha and PHD2 protein levels under normoxia and hypoxia. HIF-1alpha hydroxylation was reduced in HPV-positive HNSCC cell lines under PHD and proteasomal inhibition. In vitro wound healing assays showed impairment of migration and proliferation by HIF-1alpha pathway activation in HPV-negative cell lines only. In contrast, migration and proliferation in HPV-positive cell lines was impaired by HIF-1alpha specific siRNA. Conclusions: HPV-positive HNSCC cells show activation of the HIF pathway and adaptation to HIF-1alpha upregulation, representing potential therapeutic targets in this emerging tumor entity. PMID- 29163781 TI - SYNJ2BP promotes the degradation of PTEN through the lysosome-pathway and enhances breast tumor metastasis via PI3K/AKT/SNAI1 signaling. AB - SYNJ2BP plays an important role in breast cancer metastasis. However, the molecular mechanism associated with the function of SYNJ2BP in metastasis remains unclear. In this study, we investigated the role of SYNJ2BP in tumor metastasis and established the associated underlying mechanism. Over-expression of SYNJ2BP promoted both cell migration and invasion. In contrast, silencing SYNJ2BP caused the suppression of cell migration and invasion. SYNJ2BP increased the levels of phosphorylation for AKT and GSK3beta, which could be inhibited by the PI3K inhibitor, LY294002, and the GSK3beta inhibitor, LiCl, and regulated the accumulation of SNAI1 in the nucleus and the expression of the SNAI1 target gene, E-cadherin (EMT marker). It is known that the stability of PTEN is regulated by ubiquitination. However, in this study, we additionally demonstrated that SYNJ2BP mediated the degradation of PTEN protein by the lysosome-pathway and induced the activation of PI3K/AKT signaling by promoting the co-localization of PTEN with autophagy-lysosomes and the expression of LC3-II and p62. In vivo study, the overexpression of SYNJ2BP significantly increased the metastasis of 4T1 cells in BALB/c mice. In addition, SYNJ2BP was highly expressed in breast carcinoma (p = 0.0031), but not in normal breast tissue, while analysis of tissue samples taken from SNAI1-positive human breast cancers showed a significant correlation between the expression of SYNJ2BP and that of p-AKT (p < 0.005). Collectively, our data identified a tumor inducer, SYNJ2BP, which could activate the PI3K/AKT/GSK3beta/SNAI1 signaling pathway through the lysosome-mediated degradation of PTEN, and promote both EMT and tumor metastasis during the progression of breast cancer. PMID- 29163783 TI - Abundant expression of TIM-3, LAG-3, PD-1 and PD-L1 as immunotherapy checkpoint targets in effusions of mesothelioma patients. AB - Malignant pleural mesothelioma (MPM) is an aggressive cancer with an increasing incidence, poor prognosis and limited effective treatment options. Hence, new treatment strategies are warranted which include immune checkpoint blockade approaches with encouraging preliminary data. Research on the immunological aspects of the easily accessible mesothelioma microenvironment could identify prognostic and/or predictive biomarkers and provide useful insights for developing effective immunotherapy. In this context, we investigated the immune cell composition of effusions (pleural and ascites fluids) from 11 different chemotherapy-treated MPM patients. We used multicolor flow cytometry to describe different subsets of immune cells and their expression of immune checkpoint molecules TIM-3, LAG-3, PD-1 and PD-L1. We demonstrate a patient-dependent inter- and intraspecific variation comparing pleural and ascites fluids in immune cell composition and immune checkpoint expression. We found CD4+ and CD8+ T cells, B cells, macrophages, natural killer cells, dendritic cells and tumor cells in the fluids. To the best of our knowledge, we are the first to report TIM-3 and LAG-3 expression and we confirm PD-1 and PD-L1 expression on different MPM effusion resident immune cells. Moreover, we identified two MPM effusion-related factors with clinical value: CD4+ T cells were significantly correlated with better response to chemotherapy, while the percentage of PD-L1+ podoplanin (PDPN)+ tumor cells is a significant prognostic factor for worse outcome. Our data provide a basis for more elaborate research on MPM effusion material in the context of treatment follow-up and prognostic biomarkers and the development of immune checkpoint-targeted immunotherapy. PMID- 29163782 TI - BMI1 reduces ATR activation and signalling caused by hydroxyurea. AB - BMI1 facilitates DNA damage response (DDR) induced by double strand DNA breaks; however, it remains unknown whether BMI1 functions in single strand DNA (ssDNA) lesions-initiated DDR. We report here that BMI1 reduces hydroxyurea-elicited ATR activation, thereby reducing the S-phase checkpoints. Hydroxyurea induces ssDNA lesions, which activate ATR through binding TOPBP1 as evidenced by phosphorylation of ATR at threonine 1989 (ATRpT1989). ATR subsequently phosphorylates H2AX at serine 139 (gammaH2AX) and CHK1 at serine 345 (CHK1pS345), leading to phosphorylation of CDK1 at tyrosine 15 (CDK1pY15) and S-phase arrest. BMI1 overexpression reduced gammaH2AX, CHK1pS345, CDK1pY15, S-phase arrest, and ATR activation in HU-treated MCF7 and DU145 cells, whereas BMI1 knockdown enhanced these events. BMI1 contains a ring finger, helix-turn, proline/serine domain and two nuclear localization signals (NLS). Individual deletion of these domains did not abolish BMI1-derived reductions of CHK1pS345 in MCF7 cells following HU exposure, suggesting that these structural features are not essential for BMI1 to attenuate ATR-mediated CHK1pS345. BMI1 interacts with both TOPBP1 and ATR. Furthermore, all of our BMI1 mutants associate with endogenous TOPBP1. It has previously been established that association of TOPBP1 and ATR is required for ATR activation. Thus, our results suggest that BMI1 decreases ATR activation through a mechanism that involves binding to TOPBP1 and/or ATR. PMID- 29163784 TI - IMP2/IGF2BP2 expression, but not IMP1 and IMP3, predicts poor outcome in patients and high tumor growth rate in xenograft models of gallbladder cancer. AB - Overexpression of the oncofetal insulin-like growth factor 2 mRNA-binding protein 2 (IMP2/IGF2BP2) has been described in different cancer types. Gallbladder carcinoma (GBC) is a rare but highly aggressive cancer entity with late clinical detection and poor prognosis. The aim of this study was to investigate the role of IMP2 in human GBC. Tissue microarrays (TMAs) of an international multi-center GBC sample collection from n = 483 patients were analyzed by immunohistochemistry. IMP2 immunoreactivity was found in 74.3% of the tumor samples on TMA, of which 14.0% showed strong and 86.0% low staining intensity. 72.4% of the tumor samples were IMP1 positive, but IMP1 showed lower expression in tumor tissue compared to control tissues. IMP3 immunoreactivity was observed in 92.7% of all tumors, of which 53.6% revealed strong IMP3 expression. Kaplan Meier analysis linked high IMP2 expression to shorter survival time (p = 0.033), whereas neither IMP1 nor IMP3 expression was linked to a decreased survival time. Eight different human biliary tract cancer (BTC) cell lines were evaluated for tumor growth kinetics in mouse xenografts. Cell lines with high IMP2 expression levels showed the fastest increase in tumor volumes in murine xenografts. Furthermore, IMP2 expression in these cells correlated with the generation of reactive oxygen species (ROS) and RAC1 expression in BTC cells, suggesting RAC1 induced ROS generation as a potential mechanism of IMP2-promoted progression of GBC. In conclusion, IMP2 is frequently overexpressed in GBC and significantly associated with poor prognosis and growth rates in vivo. IMP2 might therefore represent a new target for the treatment of advanced GBC. PMID- 29163785 TI - TM5441, a plasminogen activator inhibitor-1 inhibitor, protects against high fat diet-induced non-alcoholic fatty liver disease. AB - Recent evidences showed that elevation of plasminogen activator inhibitor 1 (PAI 1) was responsible in mediating obesity-induced non-alcoholic fatty liver disease (NAFLD) and metabolic disorders. Here, we investigated the effect of TM5441, an oral PAI-1 inhibitor that lacks of bleeding risk, on high-fat diet (HFD)-induced NAFLD. HFD-fed C57BL/6J mice was daily treated with 20 mg/kg TM5441. To examine the preventive effect, 10-week-treatment was started along with initiation of HFD; alternatively, 4-week-treatment was started in mice with glucose intolerance in the interventional strategy. In vivo study showed that early and delayed treatment decreased hepatic steatosis. Particularly, early treatment prevented the progression of hepatic inflammation and fibrosis in HFD mice. Interestingly, both strategies abrogated hepatic insulin resistance and mitochondrial dysfunction, presented by enhanced p-Akt and p-GSK3beta, reduced p-JNK signaling, along with p-AMPK and PGC-1alpha activation. Consistently, TM5441 treatment in the presence of either PAI-1 exposure or TNF-alpha stimulated-PAI-1 activity showed a restoration of mitochondrial biogenesis related genes expression on HepG2 cells. Thus, improvement of insulin sensitivity and mitochondrial function was imperative to partially explain the therapeutic effects of TM5441, a novel agent targeting HFD-induced NAFLD. PMID- 29163786 TI - Axl inhibition induces the antitumor immune response which can be further potentiated by PD-1 blockade in the mouse cancer models. AB - Immune checkpoint blockers (ICB) have emerged as a promising new class of antitumor agents which significantly change the treatment landscape in a range of tumors; however, cancer patients benefited from ICB-based immunotherapy remains limited, scoring the need to explore the combination treatments with synergistic mechanisms of action. Axl receptor tyrosine kinase critically involves in the carcinogenesis of multiple cancers due to its dual roles in both promoting cancer invasion and metastasis and suppressing myeloid cell activation and function. Here, we found that Axl inhibition by tyrosine kinase inhibitors induces antitumor efficacy critically depending on immune effector mechanisms in two highly clinical relevant murine tumor models. Mechanistic investigation defined that Axl inhibition reprograms the immunological microenvironment leading to the increased proliferation, activation and effector function of tumor-infiltrating CD4+ and CD8+ T cells possibly through preferential accumulation and activation of CD103+ cross-presenting dendritic cells. More importantly, we show that Axl inhibition induces an adaptive immune resistance evidenced by unregulated PD-L1 expression on tumor cells and combined Axl inhibition with PD-1 blockade mounts a potent synergistic antitumor efficacy leading to tumor eradication. Thus, Axl directed therapy in Axl expressing tumors could hold a great potential to subvert the innate and/or adaptive resistance to and broaden the coverage of population benefited from ICB-based immunotherapy. PMID- 29163788 TI - MIND4-17 protects retinal pigment epithelium cells and retinal ganglion cells from UV. AB - Nrf2 activation would efficiently protect retinal cells from UV radiation (UVR). Recent studies have developed a Nrf2-targeting thiazole-containing compound MIND4 17, which activates Nrf2 through blocking its association with Keap1. In the current study, we demonstrated that pretreatment with MIND4-17 efficiently protected retinal pigment epithelium (RPE) cells (RPEs) and retinal ganglion cells (RGCs) from UVR. UVR-induced apoptosis in the retinal cells was also largely attenuated by MIND4-17 pretreatment. MIND4-17 presumably separated Nrf2 from Keap1, allowing its stabilization and accumulation in retinal cells, which then translocated to cell nuclei and promoted transcription of ARE-dependent anti oxidant genes, including HO1, NQO1 and GCLM. Significantly, shRNA-mediated knockdown of Nrf2 almost completely abolished MIND4-17-induced cytoprotection against UVR. Further studies showed that MIND4-17 largely ameliorated UVR-induced ROS production, lipid peroxidation and DNA damages in RPEs and RGCs. Together, MIND4-17 protects retinal cells from UVR by activating Nrf2 signaling. PMID- 29163787 TI - Neural crest derived progenitor cells contribute to tumor stroma and aggressiveness in stage 4/M neuroblastoma. AB - Pediatric tumors arise upon oncogenic transformation of stem/progenitor cells during embryonic development. Given this scenario, the existence of non tumorigenic stem cells included within the aberrant tumoral niche, with a potential role in tumor biology, is an intriguing and unstudied possibility. Here, we describe the presence and function of non-tumorigenic neural crest derived progenitor cells in aggressive neuroblastoma (NB) tumors. These cells differentiate into neural crest typical mesectodermal derivatives, giving rise to tumor stroma and promoting proliferation and tumor aggressiveness. Furthermore, an analysis of gene expression profiles in stage 4/M NB revealed a neural crest stem cell (NCSC) gene signature that was associated to stromal phenotype and high probability of relapse. Thus, this NCSC gene expression signature could be used in prognosis to improve stratification of stage 4/M NB tumors. Our results might facilitate the design of new therapies by targeting NCSCs and their contribution to tumor stroma. PMID- 29163789 TI - Prostaglandin E2 and PD-1 mediated inhibition of antitumor CTL responses in the human tumor microenvironment. AB - Accumulating evidence indicates that inflammation plays a critical role in cancer development; however, mechanisms of immunosuppression hinder productive anti tumor immunity to limit immunopathology. Tumor-specific cytotoxic T lymphocyte (CTL) dysfunction or exhaustion by upregulating inhibitory receptors such as programmed cell death 1 (PD-1) in tumor-bearing hosts is one such mechanism. Identification and blockade of the pathways that induce CTL dysfunction has been shown to partially restore CTL function in tumor-bearing hosts. Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme for prostanoid biosynthesis, including prostaglandin E2 (PGE2), and plays a key role in both inflammation and cancer. The disruption of COX2/PGE2 signaling using COX2 inhibitors or PGE2 receptors EP2 and EP4 antagonists, combined with anti-PD-1 blockade was therapeutic in terms of improving eradication of tumors and augmenting the numbers of functional tumor specific CTLs. Thus, COX2/PGE2 axis inhibition is a promising adjunct therapy to PD-1 blockade for immune-based therapies in cancer. PMID- 29163790 TI - A combination of circulating miRNAs for the early detection of ovarian cancer. AB - Ovarian cancer is the leading cause of gynecologic cancer mortality, due to the difficulty of early detection. Current screening methods lack sufficient accuracy, and it is still challenging to propose a new early detection method that improves patient outcomes with less-invasiveness. Although many studies have suggested the utility of circulating microRNAs in cancer detection, their potential for early detection remains elusive. Here, we develop novel predictive models using a combination of 8 circulating serum miRNAs. This method was able to successfully distinguish ovarian cancer patients from healthy controls (area under the curve, 0.97; sensitivity, 0.92; and specificity, 0.91) and early-stage ovarian cancer from patients with benign tumors (0.91, 0.86 and 0.83, respectively). This method also enables subtype classification in 4 types of epithelial ovarian cancer. Furthermore, it is found that most of the 8 miRNAs were packaged in extracellular vesicles, including exosomes, derived from ovarian cancer cells, and they were circulating in murine blood stream. The circulating miRNAs described in this study may serve as biomarkers for ovarian cancer patients. Early detection and subtype determination prior to surgery are crucial for clinicians to design an effective treatment strategy for each patient, as is the goal of precision medicine. PMID- 29163791 TI - Abnormal CYP11A1 gene expression induces excessive autophagy, contributing to the pathogenesis of preeclampsia. AB - Objective: In this study, we investigated the exact mechanism by which excessive CYP11A1 expression impairs the placentation process and whether this causes preeclampsia (PE) in an in vivo model. Setting and Design: In order to study CYP11A1 overexpression, BeWo cells were transfected with CYP11A1. Pregnenolone, progesterone, and testosterone levels were measured by enzyme linked immunosorbent assays, and levels of autophagy markers were quantified by western blotting and immunofluorescence. Trophoblastic cell invasion was assessed using transwell assays; BeWo cells were treated with testosterone and an androgen receptor (AR) inhibitor (flutamide) to elucidate the invasion mechanism. An adenovirus overexpression rat model was established to investigate CYP11A1 overexpression in vivo and the phenotype was examined. Furthermore, human placenta samples (n = 24) were used to determine whether PE patient placentas showed altered CYP11A1 and autophagy marker expression. Results: BeWo cells overexpressing CYP11A1 had significantly increased levels of pregnenolone, progesterone, and testosterone. Additionally, the expression levels of autophagy markers in CYP11A1-overexpressing BeWo cells were significantly increased. Trophoblast invasion was significantly reduced in CYP11A1-overexpressing cells as well as in cells treated with high testosterone. This reduction could be significantly rescued when cells were pretreated with flutamide. Overexpression of CYP11A1 in rat pregnancies led to PE-like symptoms and an over-activation of the AR-mediated pathway in the placenta. Elevated expression of CYP11A1 and autophagy markers could also be detected in PE placenta samples. Conclusions: These results suggest that abnormally high expression of CYP11A1 induces trophoblast autophagy and inhibits trophoblastic invasion, which is associated with the etiology of PE. PMID- 29163792 TI - Dual-targeting nanoparticles with excellent gene transfection efficiency for gene therapy of peritoneal metastasis of colorectal cancer. AB - Colorectal cancer has been one of the most common cancers in the worldwide. Poor patient compliance and serious side effects often associated with conventional therapy (e.g. surgery, radiation, and chemotherapy). Gene therapy may be an alternative strategy. Herein, we developed a dual-targeting nanoparticle with excellent gene transfection efficiency for gene therapy of peritoneal metastasis of colorectal cancer. This nanoparticle can facilitate efficient cellular uptake and promote penetration into nucleus. Meanwhile, this nanoparticle mediated efficient gene transfection in medium with or without serum, which significantly surpassed that of commercial transfection reagents, Lipofectamine 2000 and Lipofectamine 3000. After systemic administration, this nanoparticle loaded with hTRAIL plasmid significantly inhibited peritoneal metastasis of colorectal cancer in vivo. In conclusion, this dual-targeting nanoparticle has great potential to be a gene delivery vector for colorectal cancer therapy. PMID- 29163793 TI - Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy. AB - Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization. PMID- 29163794 TI - Association of FOXF2 gene polymorphisms with ischemic stroke in Chinese Han population. AB - Recently, a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with an increased risk of stroke in European populations was identified. However, whether polymorphisms in FOXF2 are also associated with the incidence of ischemic stroke in other populations remains unknown. In this case-control study, 803 Chinese Han patients with ischemic stroke and 803 matched control individuals were enrolled. Four tag SNPs and rs12204590 located in or near FOXF2 were selected, and the associations between genotypes/alleles and ischemic stroke were analyzed. In our study, we did not detect an association between the previously reported locus rs12204590 and ischemic stroke. By the genotype analysis, a novel SNP rs1711972, near FOXF2, was observed to be associated with an increased risk of ischemic stroke(CA genotype, adjusted OR = 1.35; 95% CI, 1.07 to 1.70), but not significantly after Bonferroni corrections for multiple tests. However, in the subgroup analysis, we discovered that rs1711972 was associated with an increased risk of large-artery atherosclerotic stroke in the additive model (P = 0.020; CA genotype, adjusted OR = 1.50; 95%CI, 1.09 to 2.07) and dominant model (P = 0.010; OR = 1.47; 95%CI, 1.09 to 1.99). Collectively, these results indicate that a novel SNP near FOXF2 may influence the risk of large-artery atherosclerotic stroke in Chinese Han population. PMID- 29163795 TI - Oral 4-(N)-stearoyl gemcitabine nanoparticles inhibit tumor growth in mouse models. AB - In spite of recent advances in targeted tumor therapy, systemic chemotherapy with cytotoxic agents remains a vital cancer treatment modality. Gemcitabine is a nucleoside analog commonly used in the treatment of various solid tumors, but an oral gemcitabine dosage form remain unavailable. Previously, we developed the 4 (N)-stearoyl gemcitabine solid lipid nanoparticles (GemC18-SLNs) by incorporating 4-(N)-stearoyl gemcitabine (GemC18), an amide prodrug of gemcitabine, into solid lipid nanoparticles. GemC18-SLNs, when administered intravenously, showed strong antitumor activity against various human and mouse tumors in mouse models. In the present study, we defined the plasma pharmacokinetics of gemcitabine when GemC18 SLNs were given orally to healthy mice and evaluated the antitumor activity of GemC18-SLNs when given orally in mouse models of lung cancer. In mice orally gavaged with GemC18-SLNs, plasma gemcitabine concentration followed an absorption phase and then clearance phase, with a Tmax of ~2 h. The absolute oral bioavailability of gemcitabine in the GemC18-SLNs was ~70% (based on AUC0-24 h values). In mice with pre-established tumors (i.e. mouse TC-1 or LLC lung cancer cells), oral GemC18-SLNs significantly inhibited the tumor growth and increased mouse survival time, as compared to the molar equivalent dose of gemcitabine hydrochloride or GemC18 in vegetable oil or in Tween 20. Immunohistostaining revealed that oral GemC18-SLNs also have significant antiproliferative, antiangiogenic, and proapoptotic activity in LLC tumors. Formulating a lipophilic amide prodrug of gemcitabine into solid lipid nanoparticles may represent a viable approach toward developing a safe and efficacious gemcitabine oral dosage form. PMID- 29163796 TI - Plasminogen activator inhibitor-1 is an independent prognostic factor of ovarian cancer and IMD-4482, a novel plasminogen activator inhibitor-1 inhibitor, inhibits ovarian cancer peritoneal dissemination. AB - In the present study, the therapeutic potential of targeting plasminogen activator inhibitor-1 (PAI-1) in ovarian cancer was tested. Tissues samples from 154 cases of ovarian carcinoma were immunostained with anti-PAI-1 antibody, and the prognostic value was analyzed. Among the samples, 67% (104/154) showed strong PAI-1 expression; this was significantly associated with poor prognosis (progression-free survival: 20 vs. 31 months, P = 0.0033). In particular, among patients with stage II-IV serous adenocarcinoma, PAI-1 expression was an independent prognostic factor. The effect of a novel PAI-1 inhibitor, IMD-4482, on ovarian cancer cell lines was assessed and its therapeutic potential was examined using a xenograft mouse model of ovarian cancer. IMD-4482 inhibited in vitro cell adhesion to vitronectin in PAI-1-positive ovarian cancer cells, followed by the inhibition of extracellular signal-regulated kinase and focal adhesion kinase phosphorylation through dissociation of the PAI-urokinase receptor complex from integrin alphaVbeta3. IMD-4482 caused G0/G1 cell arrest and inhibited the proliferation of PAI-1-positive ovarian cancer cells. In the xenograft model, IMD-4482 significantly inhibited peritoneal dissemination with the reduction of PAI-1 expression and the inhibition of focal adhesion kinase phosphorylation. Collectively, the functional inhibition of PAI-1 significantly inhibited ovarian cancer progression, and targeting PAI-1 may be a potential therapeutic strategy in ovarian cancer. PMID- 29163797 TI - PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients. AB - Background: Anti-immune programmed death-ligand 1 (PD-L1) pathway is used by the tumor to overcome immune system and serves as immunotherapy target in various malignancies. Aim: To investigate the expression of PD-L1 in vulvar squamous cell carcinoma (vSCC) and to assess it's clinicopathological and prognostic significance. Methods: Immunohistochemical PD-L1 expression was evaluated in 84 vSCCs with previously defined status of p16 and DNA-HPV, infiltration of immune cells: CD8+, CD4+, FOXP3+, CD56+, CD68+, and GZB+ cells. PD-L1 positivity was defined as >=5% of PD-L1-positive cells. Survival analyses included the Kaplan Meier method, log-rank test and Cox proportional hazards model. Results: PD-L1 expression was detected on cancer and peritumoral immune cells. PD-L1-positivity of cancer nests (27/84, 32.1%) was correlated with higher infiltration of CD4+ (p=0.037), CD8+ (p=0.02), FOXP3+ (p=0.007), CD68+ (p=0.021) cells, while PD-L1 positivity of peritumoral immune cells (51/84, 60.7%) was correlated with higher infiltration of intraepithelial FOXP3+ cells only (p=0.037).PD-L1-positivity of cancer cells but not immune cells, was more frequently observed in p16-negative tumors (p=0.004). High-risk HPV-status did not correlate with the PD-L1 status of cancer and immune cells (p=1.000) and (p=1.000) respectively). Median follow up was 89.20 months (range 1.7-189.5). PD-L1 positivity of peritumoral immune cells was found to be an independent favorable prognostic factor for OS. Conclusion: This study highlights the importance of comprehensive PD-L1 assessment in both cancer and immune cells. PD-L1 expression on peritumoral immune cells seems to be an additional prognostic factor in vSCC patients and may influence the results by anti-PD-L1 treatment. PMID- 29163798 TI - MicroRNA-144-3p inhibits bone formation in distraction osteogenesis through targeting Connexin 43. AB - Distraction osteogenesis (DO), one of effective therapies for bone regeneration, has been received more attention in recent years. However, the underlying mechanism remains elusive. Recently, microRNAs (miRNAs) have been reported to play important roles in regulating osteogenesis and bone formation. We therefore provided the hypothesis that miRNAs could involve in the DO-mediated bone regeneration. After successfully established the DO model of rats, a miRNA microarray was performed to find the differently expressed miRNAs in DO and control groups in this study. As one of the most downregulated miRNAs, miR-144-3p was found to be decreased during osteogenic differentiation in mesenchymal stem cells of rats (rBMSCs) and DO model. And miR-144-3p overexpression suppressed the osteogenesis while its inhibitor promoted osteogenesis. Furthermore, Connexin-43, an essential regulator for osteogenesis, was validated to be a novel target for miR-144-3p. Finally, miR-144-3p inhibitor modified MSCs promoted mineralization of distracted bone in rat DO model. In conclusion, miR-144-3p was found to regulate osteogenesis and inhibition of miR-144-3p resulted in acceleration of mineralization of DO, which not only give clues to understanding the mechanism of DO but also provide a potential therapeutic target in clinical practice. PMID- 29163800 TI - End-of-life care in children with hematologic malignancies. AB - Introduction: Hematologic malignancies (HM) represent the most common neoplasms in childhood. Despite improved overall survival rates, they are still a major contributor to cancer death in children. Aims: To determine the proportion of children with HM in pediatric palliative care (PPC) and to identify the clinical characteristics and symptoms in comparison to children with extracranial solid tumors (non HM patients). Patients and Methods: This study was conducted as a single-center retrospective cohort study of patients in the care of a large specialized PPC team. Results: Fifteen HM and 50 non HM patients were included. Symptoms in which HM patients scored significantly higher than non HM patients were mucositis, difficulty moving, somnolence, fatigue, petechiae and paleness. Blood transfusions were more frequently administered to HM patients, but large external hemorrhage was not observed in any child. A large variety of drugs and appliances were needed by the patients, with morphine being the most frequently prescribed drug. During the study period, a much larger and over the years even increasing number of HM patients (not in the care of the PPC team) died in hospital with an (assumed) curative intent, with two thirds dying in the ICU. Conclusions: Children with HM were referred to outpatient PPC with almost the full clinical picture of advanced leukemia. Noteworthy, the number of children with HM dying at home is decreasing in our center, instead a substantial proportion received high-intensity medical hospital care including novel anticancer therapies. These patients thus seem to be at an increased risk of dying in hospital as the right time to transfer them to palliative care is oftentimes missed. PMID- 29163799 TI - JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia. AB - JAK2 abnormalities may serve as target for precision medicines in pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL). In the current study we performed a screening for JAK2 mutations and translocations, analyzed the clinical outcome and studied the efficacy of two JAK inhibitors in primary BCP ALL cells. Importantly, we identify a number of limitations of JAK inhibitor therapy. JAK2 mutations mainly occurred in the poor prognostic subtypes BCR-ABL1 like and non- BCR-ABL1-like B-other (negative for sentinel cytogenetic lesions). JAK2 translocations were restricted to BCR-ABL1-like cases. Momelotinib and ruxolitinib were cytotoxic in both JAK2 translocated and JAK2 mutated cells, although efficacy in JAK2 mutated cells highly depended on cytokine receptor activation by TSLP. However, our data also suggest that the effect of JAK inhibition may be compromised by mutations in alternative survival pathways and microenvironment-induced resistance. Furthermore, inhibitors induced accumulation of phosphorylated JAK2Y1007, which resulted in a profound re-activation of JAK2 signaling upon release of the inhibitors. This preclinical evidence implies that further optimization and evaluation of JAK inhibitor treatment is necessary prior to its clinical integration in pediatric BCP-ALL. PMID- 29163801 TI - Long non-coding RNA CCAT1 modulates neuropathic pain progression through sponging miR-155. AB - Neuropathic pain is caused by dysfunction or primary injury of the somatosensory nervous system. Long noncoding RNAs (lncRNAs) play important roles in the development of neuropathic pain. However, the effects of lncRNA colon cancer associated transcript-1 (CCAT1) in neuropathic pain have not been reported. The model of bilateral sciatic nerve chronic constriction injuries (bCCI) is regarded as long-lasting mechanical hypersensitivity and cold allodynia, which is the representative symptom in the human subjects suffering from the neuropathic pain. In this study, we found that CCAT1 expression was decreased in the spinal dorsal horn, dorsal root ganglion (DRG), hippocampus, and anterior cingulate cortex (ACC) of rats with bCCI. The rats of bCCI presented the cold allodynia after the 14th day of postoperation. We furtherly showed that lncRNA CCAT1 decreased miR 155 expression and enhanced Serum and glucocorticoid regulated protein kinase 3 (SGK3) expression in the NGF-differentiated PC12 cell. We found that miR-155 expression was increased in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. However, SGK3 expression was downregulated in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. Moreover, lncRNA CCAT1 overexpression could alleviate the pain thresholds and inhibited expression of SGK3 could rescue this effect. In conclusion, these results suggested the crucial roles of CCAT1 and SGK3 in the neuropathic pain. PMID- 29163802 TI - Evaluation of somatostatin, CXCR4 chemokine and endothelin A receptor expression in a large set of paragangliomas. AB - Paragangliomas are predominantly benign tumors, but in some cases invasive growth and also metastasis are observed. Given the limited number of nonsurgical treatment options, novel target structures for diagnostics and therapy of this tumor entity are urgently needed. In the present study, expression of all five somatostatin receptor (SST) subtypes, chemokine receptor CXCR4 and endothelin receptor type A (ETA) was assessed by means of immunohistochemistry in a total of 66 paraffin-embedded paraganglioma samples from 55 patients. The stainings were rated by means of the Immunoreactive Score and correlated to clinical data and to succinate dehydrogenase subunit B (SDHB) expression. SST2A was by far the most prominent receptor in the paragangliomas investigated. It was present in 89% of the tumors at a high intensity, followed by SST5, SST3, SST1 and SST4, which were detected in 47%, 35%, 35% and 13% of the samples, respectively. SDHB positive tumors exhibited significantly higher SST2A and SST3 expression as compared to SDHB negative cases. There was no correlation between SST and Ki-67 expression or grading of the tumors and no difference in SST expression between primary tumors and metastases. Cell surface expression of CXCR4 and ETA was detected only in few samples. On tumor capillaries, however, exceptionally strong staining for these two receptors was noticed in the vast majority of the tumors. In conclusion, paragangliomas are well suited for SST2A-based diagnostics and treatment modalities. An indirect targeting of these highly vascularized tumors via CXCR4 or ETA may also represent a promising future strategy. PMID- 29163803 TI - HAT1 induces lung cancer cell apoptosis via up regulating Fas. AB - The dysfunction of apoptosis is one of the factors contributing to lung cancer (LC) growth. Histone acetyltransferase HAT1 can up regulate cell apoptosis. This study aims to investigate the mechanism by which HAT1 induces LC cell (LCC) apoptosis via up regulating the expression of Fas. In this study, the surgically removed human LC tissues were collected. LCCs were isolated from the LC tissues and analyzed for the expression of HAT1 and Fas by RT-qPCR and Western blotting. We observed that the expression of Fas was negatively correlated with PAR2 in LCCs. Activation of PAR2 suppressed the expression of Fas in normal lung epithelial cells. The expression of HAT1 was lower and positively correlated with Fas expression and negatively correlated with PAR2 expression in LCCs. Activation of PAR2 suppressed Fas expression in lung epithelial cells via inhibiting HAT1. Restoration of HAT1 expression restored Fas expression in LCCs and induced LCC apoptosis. In conclusion, less expression of HAT1 in LCCs was associated with the pathogenesis of LC. Up regulation of HAT1 expression in LCCs can induce LCCs apoptosis, which may be a potential novel therapy for the treatment of LC. PMID- 29163804 TI - Circulating tumor cells as liquid biomarker for high HCC recurrence risk after curative liver resection. AB - Background: Early hepatocellular carcinoma (HCC) has a limited prognosis due to recurrence rates of more than 50% after liver resection. Recurrence within two years is believed to be caused by untraceable micro metastases at the time of resection. The objective of this study was to investigate EpCAM-positive circulating tumor cells (CTC) as liquid biomarker to identify patients with high risk of recurrence after liver resection. Methods: 61 patients undergoing resection between 2011 and 2015 were consecutively enrolled. Blood specimens were obtained prior to surgery and processed with the CellSearchTM system, detecting EpCAM-positive CTC. The primary endpoint was recurrence-free survival (RFS). Results: 13 women and 44 men (63.6 +/- 11.1 years) were finally evaluated. CTC positive patients had a significantly higher risk of recurrence with a hazard ratio (HR) of 2.3 (p=0.027), and a shorter RFS compared to CTC-negative patients (5.0 +/- 1.5 vs. 12.0 +/- 2.5 months, p=0.039). As expected, incomplete resection (R1) was also associated with shorter RFS (HR=2.6, p=0.035), but vascular invasion was not. However, the predictive power of CTC status was independent of R1. Conclusion: Bloodstream detection of CTC prior to curative-intended liver resection discloses an elevated risk of HCC recurrence and could identify patients, who might benefit from adjuvant treatment. PMID- 29163805 TI - Thymine DNA Glycosylase (TDG) is involved in the pathogenesis of intestinal tumors with reduced APC expression. AB - Thymine DNA Glycosylase (TDG) is a base excision repair enzyme that acts as a thymine and uracil DNA N-glycosylase on G:T and G:U mismatches, thus protecting CpG sites in the genome from mutagenesis by deamination. In addition, TDG has an epigenomic function by removing the novel cytosine derivatives 5-formylcytosine and 5-carboxylcytosine (5caC) generated by Ten-Eleven Translocation (TET) enzymes during active DNA demethylation. We and others previously reported that TDG is essential for mammalian development. However, its involvement in tumor formation is unknown. To study the role of TDG in tumorigenesis, we analyzed the effects of its inactivation in a well-characterized model of tumor predisposition, the ApcMin mouse strain. Mice bearing a conditional Tdgflox allele were crossed with Fabpl::Cre transgenic mice, in the context of the ApcMin mutation, in order to inactivate Tdg in the small intestinal and colonic epithelium. We observed an approximately 2-fold increase in the number of small intestinal adenomas in the test Tdg-mutant ApcMin mice in comparison to control genotypes (p=0.0001). This increase occurred in female mice, and is similar to the known increase in intestinal adenoma formation due to oophorectomy. In the human colorectal cancer (CRC) TCGA database, the subset of patients with TDG and APC expression in the lowest quartile exhibits an excess of female cases. We conclude that TDG inactivation plays a role in intestinal tumorigenesis initiated by mutation/underexpression of APC. Our results also indicate that TDG may be involved in sex-specific protection from CRC. PMID- 29163806 TI - Interferon-inducible CXC-chemokines are crucial immune modulators and survival predictors in colorectal cancer. AB - Tumor-infiltrating T-cells are strongly associated with prognosis in colorectal cancer, but the mechanisms governing intratumoral lymphocyte recruitment are unclear. We investigated the clinical relevance and functional contribution of interferon-regulated CXC-chemokines CXCL9, CXCL10, and CXCL11, described as T cells attractants. Their expression was significantly elevated in tumors as compared to normal colon in 163 patients with colon cancer, represented an independent positive predictor of post-operative survival, and was highly significantly correlated with the presence of tumor-infiltrating cytotoxic CD8+ T cells and CD4+ TH1-effector cells. The regulation of chemokine expression was investigated in established cell lines and in tissue explants from resected tumor specimen (n=22). All colorectal cancer cell lines tested, as well as stroma or endothelial cells, produced CXC-chemokines in response to cytokine stimulation. Moreover, resected tumor explants could be stimulated to produce CXC-chemokines, even in cases with initially low CXC-levels. Lastly, a causative role of chemokine expression was evaluated with an orthotopic mouse model, based on isogenic rectal CT26 cancer cells, engineered to express CXCL10. The orthotopic model demonstrated a protective and anti-metastatic role of intratumoral CXCL10 expression, mediated mainly by adaptive immunity. PMID- 29163807 TI - Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia. AB - The crosstalk between chronic lymphocytic leukemia (CLL) cells and tumor microenvironment is essential for leukemic clone maintenance, supporting CLL cells survival, proliferation and protection from drug-induced apoptosis. Over the past years, the role of several soluble factors involved in these processes has been studied. CLL cells express higher levels of endothelin 1 (ET-1) and ETA receptor as compared to normal B cells. Upon ET-1 stimulation, CLL cells improve their survival and proliferation and reduce their sensitivity to the phosphoinositide-3-kinase delta inhibitor idelalisib and to fludarabine. Here, we demonstrate that CLL cells express not only ETA receptor but also ETB receptor. ET-1 acts as a homing factor supporting CLL cells migration and adhesion to microenvironmental cells. In addition, ET-1 stimulates a pro-angiogenic profile of CLL cells increasing VEGF expression through hypoxia-inducible factor-1 (HIF 1alpha) accumulation in CLL cells. Macitentan, a specific dual inhibitor of ETA and ETB receptors, targets CLL cells affecting leukemic cells migration and adhesion and overcoming the pro-survival and proliferation signals mediated by microenvironment. Furthermore, macitentan cooperates with ibrutinib inhibiting the BCR pathway and with ABT-199 disrupting BCL2 pathway. Our data describe the biological effects of a new drug, macitentan, able to counteract essential processes in CLL pathobiology as survival, migration, trafficking and drug resistance. These findings envision the possibility to interfere with ET receptors activity using macitentan as a possible novel therapeutic strategy for CLL patients. PMID- 29163808 TI - CD4+T cell specific B7-H1 selectively inhibits proliferation of naive T cells and Th17 differentiation in experimental autoimmune encephalomyelitis. AB - It is widely acknowledged that interleukin 17-producing T helper (Th17) cells are critically participant in the pathogenesis of multiple sclerosis. In the current study, we identified that the expression of CD4+T cells specific co-inhibitory molecule B7-homologue 1(B7-H1) in spleenocytes and mononuclear cells isolated from brains and spinal cord were positive correlated with Th1 and Th17 cells generation and disease severity in experimental autoimmune encephalomyelitis (EAE). Furthermore, B7-H1 transgenic mice developed milder EAE symptoms and fewer Th17 cells than B7-H1 wild type mice. We also found the proliferation of naive CD4+CD62+T cells isolated from B7-H1 transgenic mice was inhibited. And naive T cells isolated from B7-H1 transgenic mice produced fewer Th17 cells than WT mice in Th17-polarizing conditions, but the Th1, Th2, and inducible Treg differentiation were the similar in naive T cells isolated from B7-H1 transgenic mice and WT mice. In conclusion, our study show CD4+T cells specific B7-H1 is a slective inhibitor in proliferation of naive T cells, Th17 differentiation and pathogenesis of multiple sclerosis. PMID- 29163809 TI - Distinct signaling events promote resistance to mitoxantrone and etoposide in pediatric AML: a Children's Oncology Group report. AB - Despite aggressive chemotherapy including mitoxantrone and etoposide, relapse occurs for almost half of children with acute myeloid leukemia (AML). Since both drugs inhibit topoisomerase II and cause DNA double strand breaks, resistance could be achieved by enhanced DNA damage repair (DDR), via homologous recombination (HR) and/or non-homologous end joining (NHEJ). An important source of extrinsic chemoresistance is the bone marrow stroma. We aimed to reveal intrinsic and stroma-induced signaling pathways that contribute to chemoresistance. Sixty diagnostic pediatric AML samples were cultured on or off stromal cells, with or without chemotherapy. We measured apoptosis, DNA damage signaling, and NHEJ/HR pathway activity by FACS analysis of intracellular cleaved PARP, gammaH2AX, pDNA-PKcs and pATM, respectively. Mitoxantrone strongly increased gammaH2AX and pDNA-PKcs. Neither chemotherapy drug induced pATM. DNA-PK inhibition alleviated mitoxantrone resistance for AML cells on and off stromal cells. Regarding stroma-induced signaling pathways, ERK1/2 was most consistently activated in primary AML cells by stromal cells. ERK1/2 inactivation partially restored chemosensitivity to AML cells on stromal cells. Additionally, low stroma induced STAT3 activity and strong stroma-induced mitoxantrone resistance were associated with inferior clinical outcome. Taken together, the NHEJ DDR and ERK1/2 pathways are potential targets for reducing intrinsic and extrinsic chemotherapy resistance in pediatric AML. PMID- 29163810 TI - Myeloid ecotropic viral integration site 1 inhibits cell proliferation, invasion or migration in human gastric cancer. AB - Myeloid ecotropic viral integration site 1 (MEIS1) has been identified to be a potential tumor suppressor in some cancers. However, the mechanisms underlying MEIS1-induced cancer development and progression were not clear. Here, we investigated the expression and role of MEIS1 in gastric cancer. In vivo, we analyzed tumor growth using nude mice model. In the present study, MEIS1 expression was obviously decreased in GC cell lines compared with that in normal gastric cell lines (all p<0.001). MEIS1 overexpression inhibited cell proliferation and G1/S transition accompanied by decreased Cyclin D1 and Cyclin A expression. Furthermore, MEIS1 overexpression decreased the expression of Survivin, and induced cell apoptosis (p<0.001). Transwell migration assay revealed that MEIS1 affects cell invasion and migration, and inhibited epithelial mesenchymal transition (EMT). Finally, MEIS1 inhibits MKN28 cell growth in nude mice model. In conclusion, our study suggested that MEIS1 plays an important role in regulating cell survival, proliferation, anchorage-independent growth, cell cycle, apoptosis and metastasis. Thus, MEIS1 might be recommended as an effective target for GC patients. PMID- 29163811 TI - Impaired GABAB-mediated presynaptic inhibition increases excitatory strength and alters short-term plasticity in synapsin knockout mice. AB - Synapsins are a family of synaptic vesicle phosphoproteins regulating synaptic transmission and plasticity. SYN1/2 genes are major epilepsy susceptibility genes in humans. Consistently, synapsin I/II/III triple knockout (TKO) mice are epileptic and exhibit severe impairments in phasic and tonic GABAergic inhibition that precede the appearance of the epileptic phenotype. These changes are associated with an increased strength of excitatory transmission that has never been mechanistically investigated. Here, we observed that an identical effect in excitatory transmission could be induced in wild-type (WT) Schaffer collateral CA1 pyramidal cell synapses by blockade of GABAB receptors (GABABRs). The same treatment was virtually ineffective in TKO slices, suggesting that the increased strength of the excitatory transmission results from an impairment of GABAB presynaptic inhibition. Exogenous stimulation of GABABRs in excitatory autaptic neurons, where GABA spillover is negligible, demonstrated that GABABRs were effective in inhibiting excitatory transmission in both WT and TKO neurons. These results demonstrate that the decreased GABA release and spillover, previously observed in TKO hippocampal slices, removes the tonic brake of presynaptic GABABRs on glutamate transmission, making the excitation/inhibition imbalance stronger. PMID- 29163812 TI - Identification of metastasis-associated microRNAs in serum from rectal cancer patients. AB - MicroRNAs (miRNAs) are promising prognostic and diagnostic biomarkers due to their high stability in blood. Here we investigate the expression of miRNAs and other noncoding (nc) RNAs in serum of rectal cancer patients. Serum from 96 rectal cancer patients was profiled using small RNA sequencing and expression of small RNAs was correlated with the clinicopathological characteristics of the patients. Multiple classes of RNAs were detected, including miRNAs and fragments of tRNAs, snoRNAs, long ncRNAs, and other classes of RNAs. Several miRNAs, miRNA variants (isomiRs) and other ncRNAs were differentially expressed between Stage IV and Stage I-III rectal cancer patients, including several members of the miR 320 family. Furthermore, we show that high expression of miR-320d as well as one tRNA fragment is associated with poor survival. We also show that several miRNAs and isomiRs are differentially expressed between patients receiving preoperative chemoradiotherapy and patients who did not receive any treatment before serum collection. In summary, our study shows that the expression of miRNAs and other small ncRNAs in serum may be used to predict distant metastasis and survival in rectal cancer. PMID- 29163813 TI - The novel ZIP4 regulation and its role in ovarian cancer. AB - Our RNAseq analyses revealed that ZIP4 is a top gene up-regulated in more aggressive ovarian cancer cells. ZIP4's role in cancer stem cells has not been reported in any type of cancer. In addition, the role and regulation of ZIP4, a zinc transporter, have been studied in the context of extracellular zinc transporting. Factors other than zinc with ZIP4 regulatory effects are essentially unknown. ZIP4 expression and its regulation in epithelial ovarian cancer cells was assessed by immunoblotting, quantitative PCR, or immunohistochemistry staining in human ovarian tissues. Cancer stem cell-related activities were examined to evaluate the role of ZIP4 in human high-grade serous ovarian cancer cells in vitro and in vivo. RNAi and CRISPR techniques were used to knockdown or knockout ZIP4 and related genes. Ovarian cancer tissues overexpressed ZIP4 when compared with normal and benign tissues. ZIP4 knockout significantly reduced several cancer stem cell-related activities in EOC cells, including proliferation, anoikis-resistance, colony-formation, spheroid formation, drug-resistance, and side-population in vitro. ZIP4-expressing side population highly expressed known CSC markers ALDH1 and OCT4. ZIP4 knockout dramatically reduced tumorigenesis and ZIP4 overexpression increased tumorigenesis in vivo. In addition, the ZIP4-expressing side-population had the tumor initiating activity. Moreover, the oncolipid lysophosphatic acid effectively up-regulated ZIP4 expression via the nuclear receptor peroxisome proliferator-activated receptor gamma and lysophosphatic acid 's promoting effects in cancer stem cell-related activities in HGSOC cells was at least partially mediated by ZIP4 in an extracellular zinc-independent manner. Our critical data imply that ZIP4 is a new and important cancer stem cell regulator in ovarian cancer. Our data also provide an innovative interpretation for the apparent disconnection between low levels of zinc and up-regulation of ZIP4 in ovarian cancer tissues. PMID- 29163814 TI - Multivalent cationic pseudopeptide polyplexes as a tool for cancer therapy. AB - In this study, a novel anticancer reagent based on polyplexes nanoparticles was developed. These nanoparticles are obtained by mixing negatively charged polyelectrolytes with the antitumour cationically-charged pseudopeptide N6L. Using two in vivo experimental tumor pancreatic models based upon PANC-1 and mPDAC cells, we found that the antitumour activity of N6L is significantly raised via its incorporation in polyplexed nanoparticles. Study of the mechanism of action using affinity isolation and si-RNA experiments indicated that N6L polyplexes are internalized through their interaction with nucleolin. In addition, using a very aggressive model of pancreatic cancer in which gemcitabine, a standard of care for this type of cancer, has a weak effect on tumour growth, we observed that N6L-polyplexes administration has a stronger efficacy than gemcitabine. Biodistribution studies carried out in tumour-bearing mice indicated that N6L-polyplexes localises in tumour tissue, in agreement with its antitumour effect. These results support the idea that N6L nanoparticles could develop into a promising strategy for the treatment of cancer, especially hard-to-treat pancreatic cancers. PMID- 29163815 TI - PD-L1 expression heterogeneity in non-small cell lung cancer: evaluation of small biopsies reliability. AB - Immunotherapy with checkpoint inhibitors, allowing recovery of effector cells function, has demonstrated to be highly effective in many tumor types and represents a true revolution in oncology. Recently, the anti-PD1 agent pembrolizumab was granted FDA approval for the first line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors show PD-L1 expression in >= 50% of neoplastic cells and as a second line treatment for patients with NSCLC expressing PD-L1 in >=1% of neoplastic cells, evaluated with a validated assay. For the large majority of patients such evaluation is made on small biopsies. However, small tissue samples such as core biopsies might not be representative of tumors and may show divergent results given the possible heterogeneous immunoexpression of the biomarker. We therefore sought to evaluate PD-L1 expression concordance in a cohort of 239 patients using tissue microarrays (TMA) as surrogates of biopsies stained with a validated PD-L1 immunohistochemical assay (SP263) and report the degree of discordance among tissue cores in order to understand how such heterogeneity could affect decisions regarding therapy. We observed a discordance rate of 20% and 7.9% and a Cohen's kappa value of 0.53 (moderate) and 0,48 (moderate) for >= 1% and >= 50% cutoffs, respectively. Our results suggest that caution must be taken when evaluating single biopsies from patients with advanced NSCLC eligible for immunotherapy; moreover, at least 4 biopsies are necessary in order to minimize the risk of tumor misclassification. PMID- 29163816 TI - Sestrin2 and sestrin3 suppress NK-92 cell-mediated cytotoxic activity on ovarian cancer cells through AMPK and mTORC1 signaling. AB - Ovarian cancer is one of the major cancer types. NK-92 cell line, which has consistently and reproducibly high anti-tumor cytotoxicity, may be used for immunotherapy against ovarian cancer. Understanding the mechanisms that regulate the anti-tumor activity of NK-92 cells is important for developing novel therapeutic strategies. In the current study, using an ovarian cancer xenograft mouse model, we identified the up-regulation of sestrin2 (SESN2) and sestrin3 (SESN3) in intratumoral NK-92 cells. Lentivirus-transduced NK-92 cells, which overexpressed SESN2 or SESN3 after doxycycline treatment, exhibited less expression of activating receptors, perforin and granzyme B. Overexpression of SESN2 and SESN3 impaired tumoricidal effect of NK-92 cells both in vitro and in vivo. Furthermore, overexpression of SESN2 and SESN3 inhibited mTORC1 signaling while promoting AMPK signaling in NK-92 cells. Taken together, our data highlights the crucial effects of SESN2 and SESN3 on NK-92 cell-mediated anti ovarian cancer activity. This study might be valuable for designing a novel therapeutic strategy for ovarian cancer. PMID- 29163817 TI - Characteristics and genetic diversity of multi-drug resistant extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolated from bovine mastitis. AB - A characterization of the drug resistance profiles, identification of PCR-based replicon typing, and multilocus sequence typing (MLST) and analysis of 46 ESBL producing Escherichia coli from cows with mastitis are described. All multidrug resistant isolates of various phylogenetic groups (A = 31, B1= 3, B2 = 2, D = 10) were ESBL-producers of genotypes CTX-M-15 (29), CTX-M-55 (4), CTX-M-14 (4), CTX-M 3 (1), CTX-M-1 (1), TEM (22) and SHV (8) that were found on conjugative plasmids of diverse incompatibility groups (primarily IncF). Transconjugation experiments indicated successful (100%) trans-conjugation, which was verified phenotypically and genotypically. A total of 28 sequence types (ST) were identified, with 10% of isolates being ST410, and 9 other ST that were assigned arbitrary numbers, reflecting the degree of diversity. Multilocus sequence analysis revealed two lineages, a dominant and a small lineage. Split-decomposition showed intraspecies recombination clearly contributed in genetic recombination generating genotypic diversity among the isolates, and a lack of interspecies recombination. This coherent analysis on genetic structure of multidrug-resistant pathogenic E. coli population isolated from mastitic-milk weaponized with resistance elements from a large, rapidly developing country will be a helpful contribution for epidemiology and surveillance of drug resistance patterns, and understanding their global diversity. PMID- 29163818 TI - Pediatric brain tumor cells release exosomes with a miRNA repertoire that differs from exosomes secreted by normal cells. AB - High-grade gliomas (HGGs) are very aggressive brain tumors with a cancer stem cell component. Cells, including cancer stem cells, release vesicles called exosomes which contain small non-coding RNAs such as microRNAs (miRNAs). These are thought to play an important role in cell-cell communication. However, we have limited knowledge of the types of exosomal miRNAs released by pediatric HGG stem cells; a prerequisite for exploring their potential roles in HGG biology. Here we isolated exosomes released by pediatric glioma stem cells (GSCs) and compared their repertoire of miRNAs to genetically normal neural stem cells (NSCs) exosomes, as well as their respective cellular miRNA content. Whereas cellular miRNAs are similar, we find that the exosomal miRNA profiles differ between normal and tumor cells, and identify several differentially expressed miRNAs. Of particular interest is miR-1290 and miR-1246, which have previously been linked to 'stemness' and invasion in other cancers. We demonstrate that GSC secreted exosomes influence the gene expression of receiving NSCs, particularly targeting genes with a role in cell fate and tumorigenesis. Thus, our study shows that GSCs and NSCs have similar cellular miRNA profiles, yet differ significantly in the repertoire of exosomal miRNAs and these could influence malignant features of HGG. PMID- 29163819 TI - Exploring the model of PC12 apoptosis induced by OGSD/R through in vitro experiments. AB - Aims: To explicit cell apoptosis trend in PC12 oxygen-glucose-serum deprivation/restoration (OGSD/R) model and provide experimental bases for neural cell simulation in ischemia reperfusion injury in vitro. Methods: OGSD/R model was constructed using the passage PC12 cells in vitro. The profile of cell apoptosis was estimated by DAPI staining, Annexin V-FITC and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, as well as the levels of apoptosis-related proteins, including procaspase-3 and caspase-12. Results: PC12 apoptosis was induced by OGSD and aggravated after restoration. CCK8 assay indicated that cell activity reached minimum after 1h of oxygen glucose-serum restoration (OGR). DAPI staining suggested that apoptosis was the most serious after 1h of OGR, causing apoptotic cell nucleus pyknosis, particle spot formation, and fracture of cells with serious apoptosis forming pieces, and nucleus disintegration. The percentage of apoptotic cells exhibited increased trend after restoration, and reached the highest at 1h of OGR. Moreover, the expression of procaspase-3 and caspase-12 were extremely enhanced after OGD, especially 1h after OGR. Conclusions: PC12 apoptosis is induced by OGSD and aggravated after restoration. The apoptosis of PC12 reaches the highest at 1h after OGR, which may provide experimental bases for spinal cord ischemia reperfusion injury treatment. PMID- 29163820 TI - Role of drug-dependent transporter modulation on the chemosensitivity of cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with limited therapeutic options. Curative therapy is limited to surgery whereas chemotherapy treatments are the election option for unresectable or metastatic cholangiocarcinoma. Cisplatin plus gemcitabine is the reference chemotherapy regimen, albeit the contribution to the median overall survival barely reaches one year. Drug transporters are undoubtedly a limiting step for drug bioavailability and have been clearly related to chemoresistance. Several members of the SoLute Carrier (SLC) superfamily involved in the uptake of anticancer drugs used to treat cholangiocarcinoma are downregulated in these tumors. This study shows the increase in the expression of specific drug transporters exerted by cisplatin treatment thereby enhancing their transport activity. Combination treatments of cisplatin with selected drugs as gemcitabine and sorafenib take in by these transporters at the desired combination schedule induced synergy. These data support the concept that proper administration pattern could favor treatment outcome. PMID- 29163821 TI - The clinical use of circulating microRNAs as non-invasive diagnostic biomarkers for lung cancers. AB - Many studies have investigated the diagnostic role of circulating microRNAs (miRNAs) in patients with lung cancer; however, the results still remain inconclusive. An updated system review and meta-analysis was necessary to give a comprehensive evaluation of diagnostic role of circulating miRNAs in lung cancer. Eligible studies were searched in electronical databases. The sensitivity and specificity were used to plot the summary receiver operator characteristic (SROC) curve and calculate the area under the curve (AUC). The between-study heterogeneity was evaluated by Q test and I2 statistics. Subgroup analyses and meta-regression were further performed to explore the potential sources of heterogeneity. A total of 134 studies from 65 articles (6,919 patients with lung cancer and 7,064 controls) were included for analysis. Overall analysis showed that circulating miRNAs had a good diagnostic performance in lung cancers, with a sensitivity of 0.83, a specificity of 0.84, and an AUC of 0.90. Subgroup analysis suggested that combined miRNAs and Caucasian populations may yield relatively higher diagnostic performance. In addition, we found serum might serve as an ideal material to detecting miRNA as good diagnostic performance. We also found the diagnostic role of miRNAs in early stage lung cancer was still relatively high (the sensitivity, specificity and an AUC of stage I/II was 0.81, 0.82 and 0.88; and for stage I, it was 0.80, 0.81, and 0.88). We also identified a panel of miRNAs such as miR-21-5p, miR-223-3p, miR-155-5p and miR-126-3p might serve as potential biomarkers for lung cancer. As a result, circulating miRNAs, particularly the combination of multiple miRNAs, may serve as promising biomarkers for the diagnosis of lung cancer. PMID- 29163822 TI - Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab. AB - Monoclonal antibodies targeting PD-1/PD-L1 signaling pathway have achieved unprecedented success in cancer treatment over the last few years. Atezolizumab is the first PD-L1 monoclonal antibody approved by US FDA for cancer therapy; however the molecular basis of atezolizumab in blocking PD-1/PD-L1 interaction is not fully understood. Here we have solved the crystal structure of PD L1/atezolizumab complex at 2.9 angstrom resolution. The structure shows that atezolizumab binds the front beta-sheet of PD-L1 through three CDR loops from the heavy chain and one CDR loop from the light chain. The binding involves extensive hydrogen-bonding and hydrophobic interactions. Notably there are multiple aromatic residues from the CDR loops forming Pi-Pi stacking or cation-Pi interactions within the center of the binding interface and the buried surface area is more than 2000 A2, which is the largest amongst all the known PD L1/antibody structures. Mutagenesis study revealed that two hot-spot residues (E58, R113) of PD-L1 contribute significantly to the binding of atezolizumab. The structure also shows that atezolizumab binds PD-L1 with a distinct heavy and light chain orientation and it blocks PD-1/PD-L1 interaction through competing with PD-1 for the same PD-L1 surface area. Taken together, the complex structure of PD-L1/atezolizumab solved here revealed the molecular mechanism of atezolizumab in immunotherapy and provides basis for future monoclonal antibody optimization and rational design of small chemical compounds targeting PD-L1 surface. PMID- 29163823 TI - MYC is downregulated by a mitochondrial checkpoint mechanism. AB - The MYC proto-oncogene serves as a rheostat coupling mitogenic signaling with the activation of genes regulating growth, metabolism and mitochondrial biogenesis. Here we describe a novel link between mitochondria and MYC levels. Perturbation of mitochondrial function using a number of conventional and novel inhibitors resulted in the decreased expression of MYC mRNA. This decrease in MYC mRNA occurred concomitantly with an increase in the levels of tumor-suppressive miRNAs such as members of the let-7 family and miR-34a-5p. Knockdown of let-7 family or miR-34a-5p could partially restore MYC levels following mitochondria damage. We also identified let-7-dependent downregulation of the MYC mRNA chaperone, CRD-BP (coding region determinant-binding protein) as an additional control following mitochondria damage. Our data demonstrates the existence of a homeostasis mechanism whereby mitochondrial function controls MYC expression. PMID- 29163824 TI - Targeting cyclophilin-D by compound 19 protects neuronal cells from oxygen glucose deprivation/re-oxygenation. AB - Oxygen and glucose deprivation (OGD) with re-oxygenation (OGDR) is applied to neuronal cells to mimic ischemia-reperfusion injuries. Activation of cyclophilin D (Cyp-D)-dependent programmed necrosis pathway mediates OGDR-induced neuronal cell damages. Here, we tested the potential effect of Compound 19 (C19), a novel Cyp-D inhibitor, in this process. In both established neuronal cell lines (Neuro 2a and NB41A3 cells) and the primary murine CA1 hippocampal neurons, pretreatment with C19 largely attenuated OGDR-induced cell viability reduction and cell death. Significantly, C19 was ineffective in Cyp-D-silenced Neuro-2a cells. OGDR induced mitochondria-dependent programmed necrosis in neuronal cells. OGDR induced p53 translocation to mitochondria and association with Cyp-D, causing mitochondrial depolarization, cytochrome C release and reactive oxygen species production. Such effects were largely attenuated with pre-treatment of C19. Importantly, C19 was significantly more efficient than other known Cyp-D inhibitors in protecting neuronal cells from OGDR. These results suggest that targeting Cyp-D by C19 protects neuronal cells from OGDR. PMID- 29163825 TI - Maternal histone acetyltransferase KAT8 is required for porcine preimplantation embryo development. AB - K (lysine) acetyltransferase 8 (KAT8), an acetyltransferase that specifically catalyzes histone H4 lysine 16 acetylation, is critical for key biological processes including cell proliferation and maintenance of genome stability. However, the role of KAT8 during preimplantation development in pigs remains unclear. Results herein showed that KAT8 mRNA is maternally derived and it is required for successful development of early embryos. An abundance of KAT8 transcripts are expressed in oocytes and its abundance continuously decreases throughout meiotic maturation and preimplantation development. In addition, KAT8 expression is insensitive to RNA polymerase II inhibitor after embryonic genome activation, suggesting its maternal origin. The levels of KAT8 mRNA and H4K16 acetylation were effectively knocked down by siRNA microinjection. Knockdown of KAT8 significantly reduced the blastocyst formation rate and total cell number per blastocyst. Analysis of trophectoderm lineage and marker of DNA double-strand breaks revealed that the impaired developmental competence and quality of embryos might be attributed to defects in both the first two lineages development and genome integrity. Taken together, these results demonstrate that maternal KAT8 is indispensible for porcine early embryo development potentially through maintaining the proliferation of the first two lineages and genome integrity. PMID- 29163826 TI - HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibody in vivo. AB - Patients whose NSCLC tumors become afatinib resistant presently have few effective therapeutic options to extend their survival. Afatinib resistant NSCLC cells were sensitive to clinically relevant concentrations of the irreversible pan-HER inhibitor neratinib, but not by the first generation ERBB1/2/4 inhibitor lapatinib. In multiple afatinib resistant NSCLC clones, HDAC inhibitors reduced the expression of ERBB1/3/4, but activated c-SRC, which resulted in higher total levels of ERBB1/3 phosphorylation. Neratinib also rapidly reduced the expression of ERBB1/2/3/4, c-MET and of mutant K-/N-RAS; K-RAS co-localized with phosphorylated ATG13 and with cathepsin B in vesicles. Combined exposure of cells to [neratinib + HDAC inhibitors] caused inactivation of mTORC1 and mTORC2, enhanced autophagosome and subsequently autolysosome formation, and caused an additive to greater than additive induction of cell death. Knock down of Beclin1 or ATG5 prevented HDAC inhibitors or neratinib from reducing ERBB1/3/4 and K-/N RAS expression and reduced [neratinib + HDAC inhibitor] lethality. Neratinib and HDAC inhibitors reduced the expression of multiple HDAC proteins via autophagy that was causal in the reduced expression of PD-L1, PD-L2 and ornithine decarboxylase, and increased expression of Class I MHCA. In vivo, neratinib and HDAC inhibitors interacted to suppress the growth of 4T1 mammary tumors, an effect that was enhanced by an anti-PD-1 antibody. Our data support the premises that neratinib lethality can be enhanced by HDAC inhibitors, that neratinib may be a useful therapeutic tool in afatinib resistant NSCLC, and that [neratinib + HDAC inhibitor] exposure facilitates anti-tumor immune responses. PMID- 29163827 TI - Fluorescence contrast-enhanced proliferative lesion imaging by enema administration of indocyanine green in a rat model of colon carcinogenesis. AB - The fluorescent contrast agent indocyanine green (ICG) is approved by the Food and Drug Administration for clinical applications. We previously reported that cultured human colon tumor cells preferentially take up ICG by endocytic activity in association with disruption of their tight junctions. The present study explored ICG availability in fluorescence imaging of the colon to identify proliferative lesions during colonoscopy. The cellular uptake of ICG in cultured rat colon tumor cells was examined using live-cell imaging. Colon lesions in rats administered an ICG-containing enema were further assessed in rats with azoxymethane-induced colon carcinogenesis, using in vivo endoscopy, ex vivo microscopy, and immunofluorescence microscopy. The uptake of ICG by the cultured cells was temperature-dependent. The intracellular retention of the dye in the membrane trafficking system suggested endocytosis as the uptake mechanism. ICG administered via enema accumulated in colon proliferative lesions ranging from tiny aberrant crypt foci to adenomas and localized in proliferating cells. Fluorescence endoscopy detected these ICG-positive colonic proliferative lesions in vivo. The immunoreactivity of the tight-junction molecule occludin was altered in the proliferative lesions, suggesting the disruption of the integrity of tight junctions. These results suggest that fluorescence contrast-enhanced imaging following the administration of an ICG-containing enema can enhance the detection of mucosal proliferative lesions of the colon during colonoscopy. The tissue preference of ICG in the rat model evaluated in this study can be attributed to the disruption of tight junctions, which in turn promotes endocytosis by proliferative cells and the cellular uptake of ICG. PMID- 29163828 TI - Surrogate endpoint for overall survival in assessment of adjuvant therapies after curative treatment for hepatocellular carcinoma: a re-analysis of meta-analyses of individual patients' data. AB - The gold standard endpoint to evaluate the effect of treatment for hepatocellular carcinoma (HCC) is overall survival (OS), but it requires a longer follow-up period to observe. This study aimed to identify whether disease-free survival (DFS) could be used as a surrogate endpoint for OS to assess the efficacy of adjuvant therapies after curative treatment (surgical resection and ablation) for HCC patients. A systematic review was conducted to identify trials about curative treatment combined with or without adjuvant therapies (interferon, IFN; or transarterial chemoembolization, TACE) for HCC. Total of 2211 patients' data from 17 trials were analyzed. At the individual study level, DFS was strongly correlated to OS (rho = 0.988 and 0.930, 95% CI: 0.965-0.996 and 0.806-0.976 for the studies comparing Radiofrequency ablation (RFA) + TACE to RFA alone; and for the studies comparing curative treatment + IFN to curative treatment alone, respectively). At the trial level, the effects of treatment on DFS and OS were also strongly correlated to each other (R = 0.815 and 0.854, 95% CI: 0.536-0.934 and 0.621-0.948, respectively). In conclusion, DFS could be used as a potential surrogate endpoint for OS to assess the effect of adjuvant therapies after curative treatment for HCC. PMID- 29163829 TI - Meta-analysis of the prognostic value of lncRNA ZFAS1 in patients with solid tumors. AB - Expression of ZFAS1, a newly identified long noncoding RNA (lncRNA), is dysregulated in several types of cancer. Here we assessed the prognostic value of ZFAS1 in solid tumors. A comprehensive literature search was performed by screening the PubMed, EMBASE, MEDLINE, Cochrane Library, CNKI, and Wanfang databases. A total of 874 patients from 10 studies were included. The pooled analysis demonstrated that patients with high ZFAS1 expression had a significantly shorter overall survival (OS) (HR, 1.58; 95% CI, 1.28-1.97; P < 0.001) and recurrence-free survival (RFS) (HR, 1.90; 95% CI, 1.29-2.79; P = 0.001). Moreover, elevated ZFAS1 expression correlated with tumor size, tumor node-metastasis (TNM) stage, and lymph node metastasis (LNM). These results demonstrate that increased ZFAS1 expression correlates with a poor prognosis in cancer patients, which suggests ZFAS1 might be useful as a potential prognostic biomarker in patients with solid tumors. PMID- 29163830 TI - Systematic review and meta-analysis comparing zoledronic acid administered at 12 week and 4-week intervals in patients with bone metastasis. AB - Zoledronic acid is used to treat patients with bone metastasis, but the optimal dosing interval remains controversial. We therefore performed a systematic review and meta-analysis to compare the efficacy and safety of a 12-week interval of zoledronic acid with the standard 4-week interval. Three randomized controlled trials comprising 2650 patients were analyzed. Using a random-effects model, pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. No differences in the occurrence of skeletal-related events (SREs: RR = 0.98; 95% CI = 0.86-1.12; P = 0.80) or grade 3/4 adverse events (RR = 0.91; 95% CI = 0.69 1.20; P = 0.52) were observed between the 12-week and 4-week groups. The 12-week group tended to have lower incidences of osteonecrosis of the jaw [13 (0.98%) vs. 23 (1.73%)] and kidney dysfunction [21 (1.68%) vs. 31 (2.45%)] than the 4-week group, though the difference did not reach statistical significance (RR = 0.58, 95% CI: 0.30-1.12; P = 0.11); (RR = 0.67, 95% CI: 0.39-1.15, P = 0.15). These data show that zoledronic acid administered at 12-week intervals instead of 4 week intervals does not increase the risk of SREs, and may reduce the incidence of osteonecrosis of the jaw and kidney dysfunction. This suggests the 12-week interval with zoledronic acid may be an acceptable treatment option. PMID- 29163831 TI - MUC1 overexpression predicts worse survival in patients with non-small cell lung cancer: evidence from an updated meta-analysis. AB - Background: Previous studies on the prognostic role of MUC1 expression in non small cell lung cancer (NSCLC) remain controversial. We conducted a meta-analysis to appraise the clinicopathological and prognostic effect of MUC1 in NSCLC patients. Materials and Methods: Searches of PubMed, EMBASE and CNKI (Chinese National Knowledge Infrastructure) were conducted and relevant studies were extracted. The pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence intervals (CIs) were used to estimate effects. Heterogeneity among studies and publication bias were also evaluated. Results: A total of 15 studies with 1,682 patients were included in this meta-analysis. The pooled HRs indicated that elevated MUC1 expression was associated with poorer overall survival (HR = 2.12, 95% CI: 1.47-3.05; P < 0.001) and progression-free survival (HR = 2.00, 95% CI: 1.53-2.62; P < 0.001) in patients with NSCLC. Significant associations were also found in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (HR = 3.16, 95% CI: 2.21-4.52, P < 0.001) and with a platinum-based regimen (HR = 4.35, 95% CI: 2.45-7.72, P < 0.001). Additionally, MUC1 overexpression was significantly associated with performance status (OR = 2.32, 95% CI: 1.13-4.73, P = 0.021). Conclusions: MUC1 could be a valuable biomarker of the prognoses of NSCLC patients. PMID- 29163832 TI - Neoadjuvant chemotherapy followed by surgery versus upfront surgery in non metastatic non-small cell lung cancer: systematic review and meta-analysis of randomized controlled trials. AB - Background: The favorable effect of postoperative chemotherapy on long-term survival has been well acknowledged in non-small cell lung cancer (NSCLC), while the role of neoadjuvant chemotherapy (NAC) remains obscure. This meta-analysis enrolling high-quality randomized controlled trials (RCTs) aimed at comparing NAC followed by surgery with upfront surgery (US) in efficacy and safety among non metastatic NSCLC patients. Materials and Methods: Relevant literatures were searched systematically from MEDLINE, EMBASE, and the Cochrane Library. We also screened references of relevant publications and conference proceedings. Primary outcomes were overall survival (OS), disease free survival (DFS), 3-year and 5 year survival rates, mortality, and recurrence. Secondary outcomes included tumor free (R0) resection rates, response rate, and postoperative complications. Subgroup analysis according to ethnicity was further conducted. Results: A total of 11 eligible RCTs comparing NAC (n = 1624) with US (n = 1639) and published from 1998 to 2013 were included. Compared to US, NAC contributed to longer OS and DFS, higher 3-year and 5-year DFS rates, and lower incidences of total mortality, overall recurrence and metastasis, and tended to cause higher 5-year OS rates. NAC was associated with reduced risks in recurrence compared to US. Patients receiving NAC had lower surgery and resection rates, but higher R0 resection incidence among resected cases. NAC especially benefited occident patients. The overall NAC response rate was 52.1%, and NAC-related toxicity rate was 58.3%. Conclusion: NAC may provide better survival, reduced recurrence, and improved R0 resection rates among NSCLC patients who had surgery, especially in occident patients. Further studies are needed to clarify the ethnic differences. PMID- 29163833 TI - A systematic review and meta-analysis of effectiveness and safety of therapy for overactive bladder using botulinum toxin A at different dosages. AB - Purpose: To assess the effectiveness and safety of botulinum toxin A (BTX-A) at different dosages for overactive bladder (OAB). Materials and Methods: The MEDLINE, EMBASE, and Cochrane Controlled Trials Register databases were searched through November 3, 2016 to identify relevant randomized controlled trials (RCTs). Results: Eleven studies were identified in this meta-analysis. Compared with placebo, the urinary incontinence (UI) episodes per week as the primary outcomes, urodynamic parameters including maximum cystometric capacity (MCC), and maximum detrusor pressure (MDP) for neurogenic detrusor overactivity (NDO) at 6 weeks, and for idiopathic detrusor overactivity (IDO) at 36 weeks were evaluated. These and other outcomes for effectiveness of BTX-A at different dosages in two observation periods indicate that a dose greater than 50 U is significantly more effective for certain symptoms of OAB compared with placebo. However, there were no significant differences between some dosages. Compared with placebo, the outcomes of total adverse events for NDO and for IDO show that doses of 300 U and 200 U for NDO are associated with more complications. Conclusions: In consideration that the treatments of BTX-A were with minimal, local, and manageable adverse effects, this meta-analysis demonstrates that BTX-A 200 U is recommended for management of NDO for short-term treatment for there was no significant difference from the larger dose of 300U. The short-term efficacies of BTX-A for IDO remain to be investigated. PMID- 29163834 TI - Prognostic value of c-Met overexpression in hepatocellular carcinoma: a meta analysis and review. AB - The overexpression of c-Met protein has been detected in hepatocellular carcinoma (HCC). However, its prognostic impact remains uncertain. We performed this meta analysis to evaluate the prognostic value of c-Met overexpression in patients who underwent curative surgical resection for HCC. A systematic computerized search of the electronic databases was carried out. From 5 studies, 1,408 patients who underwent surgical resection for HCC were included in the meta-analysis. Compared with patients with HCC having low c-Met expression, patients with c-Met-high tumor showed significantly worse relapse-free survival (hazard ratio = 1.26 [95% confidence interval, 1.02-1.56], P = 0.03) and overall survival (hazard ratio = 1.16 [95% confidence interval, 1.03-1.31], P = 0.01). In conclusion, our meta analysis indicates that c-Met overexpression is a significant adverse prognostic factor for recurrence and survival in patients who underwent surgical resection for HCC. PMID- 29163835 TI - CD147 expression was positively linked to aggressiveness and worse prognosis of gastric cancer: a meta and bioinformatics analysis. AB - CD147 (also named as Basigin or EMMPRIN) might promote cancer invasion and metastasis by inducing MMP and VEGF synthesis in tumor microenvironment. We performed a systematic meta and bioinformatics analysis through multiple online databases up to March 14, 2017. Up-regulated CD147 expression was found in gastric cancer, compared with normal mucosa (p < 0.05). The male patients with gastric cancer showed higher CD147 expression than the female ones (p < 0.0001). CD147 expression was positively correlated with tumor size, depth of invasion, lymph node metastasis, TNM staging and unfavorable prognosis of gastric cancer (p < 0.05). At mRNA level, CD147 expression was higher in intestinal-type and mixed type gastric carcinomas than normal tissues (p < 0.05). CD147 mRNA expression was negatively associated with histological grading and dedifferentiation of gastric cancer (p < 0.05). A higher CD147 mRNA expression was negatively correlated with overall and progression-free survival rates of all cancer patients, even stratified by clinicopathological features (p < 0.05). These findings indicated that CD147 expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis. PMID- 29163836 TI - Kinetics of plasma von Willebrand factor in acute myocardial infarction patients: a meta-analysis. AB - Previous studies have shown a variation in plasma level of von Willebrand factor (vWF) in acute myocardial infarction (AMI) patients but with contentious results. In this study, we performed a meta-analysis to evaluate the kinetics of plasma vWF after AMI. A total of 11 qualified studies were obtained through systematical search in PubMed, Web of science, Cochrane Library database and CNKI, followed by search of reference lists, involving 519 AMI patients and 466 non-AMI controls. The standard mean difference (SMD) and 95% confidence intervals (95% CI) were calculated using random-effects model. Results indicated that the plasma vWF was significantly increased in the first several hours after onset of AMI (SMD = 1.94, 95% CI = 1.39-2.48, P < 0.001) and stayed at high level until 24 h (SMD = 1.17, 95% CI = 0.45-1.89, P = 0.001). Elevated level of vWF appeared to persist for one week and reduced to normal until the fourteenth day after AMI (SMD = 0.44, 95% CI = -0.14-1.02, P = 0.14). Subgroup analysis revealed that the high level of vWF lasted just for 1 day in patients with a symptom duration <= 6 h before admission. For patients with a symptom duration > 6 h, elevated vWF was found in all 7 days except day 1. Our findings determined the kinetics of plasma vWF after AMI, and might provide a new insight in monitoring AMI progression. PMID- 29163837 TI - The use of neutrophil to lymphocyte ratio as a predictor for clinical outcomes in spontaneous intracerebral hemorrhage. AB - Objective: Neutrophil to lymphocyte ratio (NLR) is used as an independent predictor for clinical outcomes in cancers, cardiovascular disorders and ischemic stroke. The prognostic role of NLR in spontaneous intracerebral hemorrhage (sICH) is still controversial. The aim of this report is to conduct a meta-analysis to evaluate the prognostic significance NLR in patients with sICH. Materials and Methods: All related articles were searched on PubMed, EMBASE, Cochrane Central Register of Controlled Trials followed the PRISMA flow diagram. The quality of eligible studies were evaluated and the related data were extracted by two reviewers independently. The end points included the mortality and poor outcomes and subgroup analyses were performed. Results: Five studies with 1944 subjects were included and had acceptable quality. The high NLR had a higher risk of in hospital mortality (OR: 0.97; 95% CI: 0.94-0.99, p = 0.02) and 90-day mortality (OR: 2.43; 95% CI: 1.01-5.83, p = 0.047); without association with the poor outcomes (OR: 1.17; 95% CI: 0.93-1.47, p = 0.18). After subgroup analyses, the high NLR correlated with an increased 90-day mortality in the high cut-off group (OR: 1.56; 95% CI: 1.15-2.13, p = 0.005). The high NLR additionally predicts poor outcomes in smaller hematoma group (OR: 1.16; 95% CI: 1.01-1.32, p = 0.04) and the high cut-off group (OR: 2.20; 95% CI: 1.54-3.14, p < 0.001). Conclusions: The high NLR was significantly associated with in-hospital and 90-day mortality in patients with sICH. The NLR with cut-off of 7.5 had statistically significant potential for predicting mortality and poor outcomes, regardless of country, time of laboratory test and hematoma volumes. PMID- 29163838 TI - Combining des-gamma-carboxyprothrombin and alpha-fetoprotein for hepatocellular carcinoma diagnosing: an update meta-analysis and validation study. AB - Controversies about the combination of des-gamma-carboxyprothrombin (DCP) and alpha-fetoprotein (AFP) for hepatocellular carcinoma diagnosing still exist. Hence, we performed this updated meta-analysis to estimate the diagnostic value of DCP , AFP and DCP + AFP in HCC. In addition, we conducted a validation study to analyze the performance of the candidate makers. After a systematic literature review, 27 studies from 20 articles were identified from four major databases. The pooled sensitivity and specificity were 69% and 89%, respectively, for DCP; for AFP, they were 65% and 88%, respectively; and they were 82% and 85%, respectively, for DCP + AFP. The values of the area under the curve (AUC) for DCP, AFP, DCP + AFP, respectively, were 0.88, 0.75, and 0.90. The validation study confirmed that the performance of DCP + AFP (sensitivity = 84%, specificity = 86%; AUC = 0.887) was higher than that of DCP (sensitivity = 76%, specificity = 92%; AUC = 0.843) or AFP (sensitivity = 73%, specificity = 92%; AUC = 0.837) alone. PMID- 29163839 TI - Prognostic value of intratumoral metabolic heterogeneity on F-18 fluorodeoxyglucose positron emission tomography/computed tomography in locally advanced cervical cancer patients treated with concurrent chemoradiotherapy. AB - Objective: To evaluate the prognostic value for predicting tumor recurrence of intratumoral metabolic heterogeneity and traditional quantitative metabolic parameters on pre-treatment F-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with locally advanced cervical cancer treated with concurrent chemoradiotherapy (CCRT). Materials and Methods: Ninety-three patients with biopsy-proven cervical cancer and treated with CCRT (FIGO stage IIB-IV) were enrolled in this study. The traditional metabolic parameters of the primary tumor, regional lymph node, and whole body (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], and total lesion glycolysis), and intratumoral heterogeneity factor (HF) were measured on pre-treatment 18F-FDG PET/CT images. Univariate and multivariate analyses for disease-free survival (DFS) were performed using clinical and metabolic parameters. The additional HF prognostic value was evaluated by means of time-dependent receiver operating characteristic curve, integrated discrimination improvement, and net reclassification improvement. Results: On multivariate analysis, nodal SUVmax (hazard ratio 3.60; 95% CI, 1.66-7.85; p = 0.0012) and whole body MTV (WBMTV; hazard ratio 3.15; 95% CI, 1.17-8.53; p = 0.0236) were significant prognostic factors for DFS. When HF was combined with nodal SUVmax and WBMTV, a significant improvement in discrimination for recurrence was observed compared with nodal SUVmax alone (area under curve 0.817 vs. 0.732; p = 0.0028). Conclusions: HF did not show superiority over traditional metabolic parameters. However, when HF was combined with nodal SUVmax and WBMTV, the predictive value for tumor recurrence improved. Therefore, HF may be a useful additional prognostic biomarker to improve the prognostic value of traditional metabolic parameters on 18F-FDG PET/CT. PMID- 29163840 TI - An improved nerve-sparing radical hysterectomy technique for cervical cancer using the paravesico-vaginal space as a new surgical landmark. AB - Bladder dysfunction remains a major postoperative challenge for early stage cervical cancer patients. The present prospective phase 2 trial in patients with stage IB1 and IIA1 cervical cancer follows up on our previous, unpublished work describing a new surgical landmark, the paravesico-vaginal space. We describe a novel nerve-sparing radical hysterectomy (NSRH) approach to treat early stage cervical cancer without compromising local control rate or survival. Between September 2015 and August 2016, 49 patients were enrolled to receive NSRH. The bladder catheter was routinely removed on postoperative day 4. The primary endpoints were rate of postvoid residual urine volume (PVR) <= 50 ml and proportion of patients with successful catheter removal (ClinicalTrials.gov Identifier: NCT02562729). Anatomically, from ventral to dorsal, the terminal ureter, deep uterine vein, and cardinal ligament were the three markers of the paravesico-vaginal space. The median operative time was 100 min, and the median blood loss was 200 ml. Thirty-four patients (69.4%) had successful catheter removal on postoperative day 4, and 17 patients (34.7%) had a PVR <= 50 ml. Our results suggest that by accessing the paravesico-vaginal space landmark, the bladder branch of the inferior hypogastric plexus can be completely preserved, contributing to greater NSRH efficiency without compromising outcomes for patients with early stage cervical cancer. PMID- 29163841 TI - Assessing right ventricular function in pulmonary hypertension patients and the correlation with the New York Heart Association (NYHA) classification. AB - This investigation aimed to compare the pressure-volume loop (PV loop) measurements in three less symptomatic categories (New York Heart Association classes , NYHA I, II, and III) of pulmonary hypertension (PH) patients since NYHA classification system performance is limited by the shortcomings discussed above. Thirty-six patients were enrolled in this study with PV loop measurement acquisition via micro-conductance catheters. Functional classification according to NYHA was determined with comprehensive assessing function and activity. Catheterization and MRI was applied to obtain variables on right ventricle (RV) functions. Correlation test was applied to test the relationship between measured PV loop measurements and NYHA classification. A group of PV loop measurements, including end-systolic pressure (RVESP) RV end-diastolic pressure (RVEDP), and RV arterial elastance (RVEa), are well correlated with three NYHA classes (I, II, and III). Moreover, RVESP and RVEa significantly correlated with two groups of NYHA classes (I and II/III) while RVEDP, RV end-diastolic volume (RVEDV), and RV end-systolic volume (RVESV) significantly moderately correlated with two groups of NYHA classes (I/II and III). This study suggests the promising role of PV loop analysis in assessing functional capacity in progressive but less symptomatic PH patients. PMID- 29163842 TI - Real-world experience of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. AB - We evaluated the real-world efficacy and side effects of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. The medical records of patients receiving afatinib as a first-line therapy after National Health Insurance reimbursement between May 2014 and January 2016 were reviewed, and information on patient characteristics and treatment courses were collected consecutively. Rebiopsy tissue was collected for EGFR mutation and MET amplification analyses. MET amplification was detected by fluorescence in situ hybridization and immunohistochemistry. In total, 140 patients were enrolled (median follow-up, 18.0 months). No significant differences in side effects, treatment responses, progression-free survival, or brain metastasis control were observed between patients receiving 40 mg versus < 40 mg of afatinib during the first 6 months. Patients with significant pretreatment weight loss (> 10.0% in 6 months) had a shorter median progression-free survival. Patients with brain metastases had a poorer Eastern Cooperative Oncology Group performance status and were associated with a shorter median progression-free survival. Nine patients (32.1%) had a p.T790M mutation and only 1 patient gained MET amplifications after disease progression. Afatinib is effective as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. Afatinib dosage does not affect clinical efficacy and drug-related side effects. PMID- 29163843 TI - Effect of subclinical hypothyroidism on the skeletal system and improvement with short-term thyroxine therapy. AB - The purpose of the study was to observe changes in the skeletal system of rats with subclinical hypothyroidism (SCH) and to determine whether L-thyroxine (L-T4) administration suppresses those changes. Sixty male Wistar rats were randomly divided into control, SCH, and SCH+T4 groups. SCH was induced in rats by administration of methimazole (MMI), and rats in the SCH+T4 group were treated with L-T4 after 45 days of MMI administration. The SCH group had higher thyroid stimulating hormone (TSH) level than the control and SCH+T4 groups. There were no differences in serum thyroid hormone (FT4 and FT3) levels among the three groups. Bone mineral density; serum levels of BALP and TRACP-5b, two bone metabolic markers; and the biomechanical properties of the femurs were lower in the SCH group than in the control group. After L-T4 treatment, serum BALP and TRACP-5b levels and the femur biomechanical properties were higher in the SCH+T4 than the SCH group. Histopathological examination revealed damage to the structure of the femur trabecular bone network in rats with SCH, and L-T4 treatment improved this condition to some extent. These findings demonstrate that L-T4 treatment ameliorates the destructive effects of SCH on the skeletal system in rats. PMID- 29163844 TI - Identifying current and remitted major depressive disorder with the Hurst exponent: a comparative study on two automated anatomical labeling atlases. AB - Major depressive disorder (MDD) is a leading world-wide psychiatric disorder with high recurrence rate, therefore, it is desirable to identify current MDD (cMDD) and remitted MDD (rMDD) for their appropriate therapeutic interventions. In the study, 19 cMDD, 19 rMDD and 19 well-matched healthy controls (HC) were enrolled and scanned with the resting-state functional magnetic resonance imaging (rs fMRI). The Hurst exponent (HE) of rs-fMRI in AAL-90 and AAL-1024 atlases were calculated and compared between groups. Then, a radial basis function (RBF) based support vector machine was proposed to identify every pair of the cMDD, rMDD and HC groups using the abnormal HE features, and a leave-one-out cross-validation was used to evaluate the classification performance. Applying the proposed method with AAL-1024 and AAL-90 atlas respectively, 87% and 84% subjects were correctly identified between cMDD and HC, 84% and 71% between rMDD and HC, and 89% and 74% between cMDD and rMDD. Our results indicated that the HE was an effective feature to distinguish cMDD and rMDD from HC, and the recognition performances with AAL 1024 parcellation were better than that with the conventional AAL-90 parcellation. PMID- 29163845 TI - Improved medical expenditure and survival with integration of traditional Chinese medicine treatment in patients with heart failure: A nationwide population-based cohort study. AB - Background: No previous studies have evaluated the effects of traditional Chinese medicine (TCM) treatment on patients with heart failure (HF). Hence, in this study, we determined whether TCM treatment affects the healthcare burden and survival of HF patients. Methods: Samples were retrieved from the registry of catastrophic illness patients of the Taiwan National Health Insurance Research Database (NHIRD). Based on a frequency (1:1) matched case-control design, patients with HF between 2000 and 2010 were designated as cases (TCM users) and controls (non-TCM users). TCM treatment for patients with HF was analyzed. Results: Among these patients, 312 used TCM for HF treatment and exhibited significantly increased 5-year survival (p < .0001), with multivariate adjustment, compared with those without TCM use. Mean outpatient clinic visits at 1 year and 5 years after HF diagnosis were higher in TCM users, and accumulated medical costs were lower than in non-TCM users at 1 year. The hospitalization cost at 1-year follow-up was lower for TCM users than for non-TCM users. We found that, compared with non-TCM users, TCM users had an 86% reduction in risk of mortality in the compensated group, and a 68% reduction in the decompensated group receiving TCM treatment (aHR 0.32, 95% CI 0.20-0.52). The hazard ratio (HR) of Chinese herbal medicine (CHM) users with HF was significantly lower than that of non-users (aHR 0.24, 95% CI 0.16-0.35). We also analyzed the most commonly used herbal products as well as the HRs associated with their use, thus providing future research avenues. Conclusions: This nationwide retrospective cohort study finds that combined therapy with TCM may improve survival in HF patients. This study also suggests that TCM may be used as an integral element of HF interventions on health care costs. PMID- 29163846 TI - Does the type of anesthesia really affect the recurrence-free survival after breast cancer surgery? AB - Background: Although previous studies have suggested that propofol inhibits cancer recurrence and metastasis, the association between anesthetic agents and the recurrence of breast cancer has not been clearly investigated. We compared total intravenous anesthesia and balanced anesthesia with volatile agents to investigate the differences in their effects on recurrence-free survival and overall survival after breast cancer surgery. Materials and Methods: The electronic medical records of 2,729 patients who underwent breast cancer surgery between November 2005 and December 2010 were retrospectively reviewed to analyze the factors associated with recurrence-free survival after surgery. Cox proportional hazards models were used to identify the risk factors for cancer recurrence and overall mortality after breast cancer surgery. Results: Data from 2,645 patients were finally analyzed. The recurrence-free survival rate in this study was 91.2%. Tumor-node-metastasis staging exhibited the strongest association with breast cancer recurrence. However, we were unable to identify significant differences between the preventive effects of total intravenous anesthesia and those of volatile agents on postoperative breast cancer recurrence using Cox regression analyses and propensity score matching. Furthermore, the survival probability with regard to postoperative recurrence and mortality showed no significant differences among anesthetic agents. Conclusions: Our findings suggest that the effects of total intravenous anesthesia are comparable with those of volatile agents with regard to postoperative recurrence-free survival and overall survival in patients with breast cancer. PMID- 29163847 TI - A relative increase in circulating platelets following chemoradiation predicts for poor survival of patients with glioblastoma. AB - Background: Thrombocytosis is triggered by and promotes tumor growth. The relationship between the change in circulating platelets after chemoradiation therapy (CRT) or adjuvant temozolomide (TMZ) and survival in glioblastoma remains unclear. We hypothesized that an increase in platelets after these treatments would be predictive of a shorter survival. Methods: We retrospectively reviewed data on 122 patients with newly diagnosed, pathologically proven glioblastoma who had been treated with surgery, followed by CRT and adjuvant TMZ, from 2007 to 2016. The association between the changes in blood count levels and survival was analyzed by the log-rank test. To adjust for confounding, we performed a multivariate analysis using known prognostic co-variates. Results: Patients were dichotomized on the basis of the relative change in platelets after CRT from the baseline: <=30% increase, low (n = 101) vs >30% increase, high (n = 12). The median survival for high vs. low platelets were 11 vs 28 months (p = 0.0062). No significant survival differences were observed on the basis of platelet changes during adjuvant TMZ. Similarly, changes in lymphocyte counts were not significantly prognostic. On multivariate analysis, MGMT, performance status, and an increase in platelets after CRT were significantly associated with survival (HR for platelets, 4.5; 95% confidence interval, 1.6-12.6). Conclusions: Increased platelet counts after CRT are predictive of poor survival in glioblastoma. The effect is platelet specific and does not reflect bone marrow changes, as lymphocyte changes were not significantly prognostic. These results suggest an interaction between platelets and tumor aggressiveness. Thus, platelets serve as a novel, minimally invasive liquid biopsy for predicting outcome. PMID- 29163848 TI - Radiation therapy and serum salivary amylase in head and neck cancer. AB - Radiation therapy (RT) is a valid treatment option for head and neck cancer (HNC). The risk of RT-induced toxicities is significant, especially due to extended treatment fields. The raise in amylase activity is strictly dependent on the volume of salivary glands included in the irradiated target volume and it is firmly related to the dose. The aim of this review is to report the effects on salivary amylase activity after radiation exposure of salivary glands, in patients with HNC. PMID- 29163850 TI - Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: challenges and opportunities. AB - Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have been shown to have unprecedented efficacy in B cell malignancies, most notably in B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate using anti-CD19 CAR-T cells. However, CAR T-cell therapy for solid tumors currently is faced with numerous challenges such as physical barriers, the immunosuppressive tumor microenvironment and the specificity and safety. The clinical results in solid tumors have been much less encouraging, with multiple cases of toxicity and a lack of therapeutic response. In this review, we will discuss the current stats and challenges of CAR-T cell therapy for solid tumors, and propose possibl e solutions and future perspectives. PMID- 29163849 TI - The therapeutic potential of cell cycle targeting in multiple myeloma. AB - Proper cell cycle progression through the interphase and mitosis is regulated by coordinated activation of important cell cycle proteins (including cyclin dependent kinases and mitotic kinases) and several checkpoint pathways. Aberrant activity of these cell cycle proteins and checkpoint pathways results in deregulation of cell cycle progression, which is one of the key hallmarks of cancer. Consequently, intensive research on targeting these cell cycle regulatory proteins identified several candidate small molecule inhibitors that are able to induce cell cycle arrest and even apoptosis in cancer cells. Importantly, several of these cell cycle regulatory proteins have also been proposed as therapeutic targets in the plasma cell malignancy multiple myeloma (MM). Despite the enormous progress in the treatment of MM the past 5 years, MM still remains most often incurable due to the development of drug resistance. Deregulated expression of the cyclins D is observed in virtually all myeloma patients, emphasizing the potential therapeutic interest of cyclin-dependent kinase inhibitors in MM. Furthermore, other targets have also been identified in MM, such as microtubules, kinesin motor proteins, aurora kinases, polo-like kinases and the anaphase promoting complex/cyclosome. This review will provide an overview of the cell cycle proteins and checkpoint pathways deregulated in MM and discuss the therapeutic potential of targeting proteins or protein complexes involved in cell cycle control in MM. PMID- 29163851 TI - Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity. AB - Context: Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors. Materials and Methods: We analyzed all available evidence supporting the role of tumor microenvironment (TME) in EC development and the therapeutic implications offered by immune checkpoint inhibitors in this setting. We performed a review on Pubmed with Mesh keywords 'endometrial cancer' and the name of each checkpoint inhibitor discussed in the article. The same search was operated on clinicaltrial.gov to identify ongoing clinical trials exploring PD-1/PD-L1 and CTLA-4 axis in EC, particularly focusing on POLE-ultra-muted and MSI-H cancer types. Results: POLE-ultra-mutated and MSI-H ECs showed an active TME expressing high number of neo-antigens and an elevated amount of tumor infiltrating lymphocytes (TILs). Preliminary results from a phase 1 clinical trial (KEYNOTE-028) demonstrated antitumor activity of Pembrolizumab in EC. Moreover, both Pembrolizumab and Nivolumab reported durable clinical responses in POLE-ultra-mutated patients. Conclusions: Immune checkpoint inhibitors are an attractive option in POLE-ultra-mutated and MSI-H ECs. Future investigations in these subgroups include combinations of checkpoints inhibitors with chemotherapy and small tyrosine kinase inhibitors (TKIs) to enhance a more robust intra-tumoral immune response. PMID- 29163852 TI - Melatonin as a potential inhibitory agent in head and neck cancer. AB - Melatonin is a molecule secreted by the pineal gland; it is an important regulator of sleep and circadian rhythms. Through multiple interrelated mechanisms, melatonin exhibits various inhibitory properties at different stages of tumor progression. Many studies have explored the oncostatic effects of melatonin on hormone-dependent tumors. In this review, we highlight recent advances in understanding the effects of melatonin on the development of head and neck cancers, including molecular mechanisms identified through experimental and clinical observations. Because melatonin exerts a wide range of effects, melatonin may influence many mechanisms that influence the development of cancer. These include cell proliferation, apoptosis, angiogenesis, extracellular matrix remodeling through matrix metalloproteinases, and genetic polymorphism. Thus, the evidence discussed in this article will serve as a basis for basic and clinical research to promote the use of melatonin for understanding and controlling the development of head and neck cancers. PMID- 29163853 TI - Mechanisms of resistance to irreversible epidermal growth factor receptor tyrosine kinase inhibitors and therapeutic strategies in non-small cell lung cancer. AB - Epidermal growth factor receptor (EGFR) T790M mutation is the most frequent mechanism which accounts for about 60% of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients harboring EGFR activating mutations. Irreversible EGFR-TKIs which include the second-generation and third-generation EGFR-TKIs are developed to overcome T790M mediated resistance. The second-generation EGFR-TKIs inhibit the wide type (WT) EGFR combined with dose-limiting toxicity which limits its application in clinics, while the development of third-generation EGFR-TKIs brings inspiring efficacy either in vitro or in vivo. The acquired resistance, however, will also occur and limit their response. Understanding the mechanisms of resistance to irreversible EGFR-TKIs plays an important role in the choice of subsequent treatment. In this review, we show the currently known mechanisms of resistance which can be summarized as EGFR dependent and independent mechanisms and potential therapeutic strategies to irreversible EGFR-TKIs. PMID- 29163855 TI - Correction: Compliance with the enhanced recovery after surgery protocol and prognosis after colorectal cancer surgery: A prospective cohort study. AB - [This corrects the article DOI: 10.18632/oncotarget.18602.]. PMID- 29163856 TI - Participant experiences of Eye Movement Desensitisation and Reprocessing vs. Cognitive Behavioural Therapy for grief: similarities and differences. AB - Background and Objective: Previous research has used quantitative methods to assess the impact of grief therapy. However, rarely have participants been asked about how they have been affected by treatment using qualitative methods. This study sought to explore participants' experiences of two therapeutic approaches to grief: Cognitive Behavioural Therapy (CBT) and Eye Movement Desensitisation and Reprocessing (EMDR). Method: Nineteen participants were randomly allocated to receive seven weekly therapy sessions of either CBT or EMDR. Approximately two weeks after completing therapy, a semi-structured interview was conducted with each participant. Interviews were transcribed and a thematic analysis was performed. Results: Participant reports common to both therapies included developments in insight, a positive shift in emotions, increased activity, improved self-confidence and a healthier mental relationship to the deceased. Participants also responded by describing experiences that were unique to each therapy. Those who completed CBT described the acquisition of emotion regulation tools and shifting from being in an ongoing state of grief to feeling that they were at a new stage in their lives. Participants who completed EMDR reported that distressing memories were less clear and felt more distant from such memories following treatment. Conclusions: Although both therapies resulted in some similar changes for participants, there were unique experiences associated with each therapy. These findings are discussed in terms of implications for the underlying key processes of each therapy and the processes of recovery in grief. PMID- 29163857 TI - Italian translation and cross-cultural comparison with the Childhood Attachment and Relational Trauma Screen (CARTS). AB - Background: The Childhood Attachment and Relational Trauma Screen (CARTS) is a computer-administered survey designed to assess retrospectively the socio ecological context in which instances of child abuse may have occurred. To date, studies supporting the validity of the CARTS have only been undertaken in English speaking North American populations. Validation projects in other countries and cross-cultural comparisons are therefore warranted. Objective: Develop and preliminarily evaluate the psychometric properties of an Italian version of the CARTS on college students and compare such observations to data acquired from Canadian students. Method: Seventy-nine undergraduate students from the University of Padua (Italy) completed an Italian translation of the CARTS as well as measures of childhood experiences, mental health and attachment, responses to which were compared to those obtained in 288 Canadian students who completed the CARTS in English. Results: Internal consistency and convergent validity with the Childhood Trauma Questionnaire and Parental Bonding Instrument were found to be acceptable for the Italian translation. Within the Italian sample, correlation analyses suggested that CARTS Mother ratings referring to attachment and abuse were associated with romantic attachment, whereas CARTS Father ratings were significantly correlated to PTSD symptoms and other symptoms of psychopathology distress. Significant differences between Italian and Canadian students across the relationship types for the CARTS abuse and attachment scales were found, indicating that Italian students rated their mothers and fathers as simultaneously less abusive, but also less as a source of secure attachment. Conclusions: The results of this preliminary study seem to suggest convergent validity of the Italian CARTS and the association between childhood attachment related experiences and romantic attachment. Cultural variations were identified between Canadian and Italian students in both attachment and abuse scales. Future studies to investigate cross-cultural variations in the relational context of childhood abuse and in order to boost Italian CARTS psychometric features are warranted. PMID- 29163858 TI - Investigating institutional abuse survivors' help-seeking attitudes with the Inventory of Attitudes towards Seeking Mental Health Services. AB - Background: Although effective treatments exist, many trauma survivors delay or avoid professional help. Attitudes towards help-seeking are associated with intentions to and actual treatment use, but were neglected in research on trauma survivors so far. Objective: This study aimed to investigate the reliability, construct validity, and predictive power of the Inventory of Attitudes towards Seeking Mental Health Services (IASMHS) and to investigate attitudes of adult institutional abuse survivors. Method: A total of 220 adult survivors of institutional abuse were interviewed using IASMHS, the PTSD Checklist for DSM-5 (PCL-5), the Childhood Trauma Questionnaire Short-Form (CTQ-SF), the Life Events Checklist (LEC-5), and the depression-subscale of the Brief Symptom Inventory (BSI-18). They were further asked about their current mental health service use. We assessed the fit of different models of IASMHS with confirmatory factor analyses and predicted current mental health service use with a binominal logistic regression model. Results: The three-factor structure of IASMHS provided the best fit. One of the three scales (help-seeking propensity), the PTSD intrusion scale, and the depression scale significantly contributed to the prediction of current mental health service use. Single items of the psychological openness scale loaded weakly on the according factor. Our sample showed a similar IASMHS profile compared to other samples with mental health problems. Conclusion: Overall, IASMHS appears to be a useful instrument to assess attitudes towards seeking mental health services in trauma survivors. It can be used to investigate help-seeking attitudes and its correlates to better understand and facilitate survivors' treatment use. PMID- 29163859 TI - Virtual agent-mediated appraisal training: a single case series among Dutch firefighters. AB - Background: First responders are a prime example of professionals that are at a high risk of being exposed to traumatic experiences. Reappraisal as a coping strategy might help first responders to better cope with their emotional responses to traumatic events. Objective: This study investigated the effects of repeated sessions of a digital reappraisal training among seven firefighters. The training consisted of four sessions supported by a virtual agent, conducted at home or at work, over a two-week period in a single case series. Method: Sixteen data points were collected from each participant in the eight days pre- and post training. Results: Significantly more themes were used at post-training than at pre-training, implying more flexibility and confirming the main hypothesis of the study. Negative side effects were not reported during or in the week after the training. Conclusions: More controlled studies into the short- and long-term effects of a training of this nature are needed. Furthermore, it provides a reference for developers in this field. PMID- 29163854 TI - Interactions between TGF-beta1, canonical WNT/beta-catenin pathway and PPAR gamma in radiation-induced fibrosis. AB - Radiation therapy induces DNA damage and inflammation leading to fibrosis. Fibrosis can occur 4 to 12 months after radiation therapy. This process worsens with time and years. Radiation-induced fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during fibrosis process. In this review, we discussed the interplays between transforming growth factor-beta1 (TGF-beta1), canonical WNT/beta-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR gamma) in regulating the molecular mechanisms underlying the radiation-induced fibrosis, and the potential role of PPAR gamma agonists. Overexpression of TGF-beta and canonical WNT/beta-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR gamma expression decreases due to the opposite interplay of canonical WNT/beta-catenin pathway. Both TGF-beta1 and canonical WNT/beta-catenin pathway stimulate each other through the Smad pathway and non Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/beta-catenin pathway and PPAR gamma interact in an opposite manner. PPAR gamma agonists decrease beta-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 beta) and dickkopf-related protein 1 (DKK1). PPAR gamma agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-beta1 and PI3K/Akt pathways. PPAR gamma agonists by activating Smad7 decrease Smads pathway and then TGF-beta signaling leading to decrease radiation induced fibrosis. TGF-beta1 and canonical WNT/beta-catenin pathway promote radiation-induced fibrosis whereas PPAR gamma agonists can prevent radiation induced fibrosis. PMID- 29163860 TI - Assessing therapeutic change in patients with severe dissociative disorders: the progress in treatment questionnaire, therapist and patient measures. AB - Background: Treatment research for dissociative identity disorder (DID) and closely related severe dissociative disorders (DD) is rare, and has been made more difficult by the lack of a reliable, valid measure for assessing treatment progress in these populations. Objective: This paper presents psychometric data for therapist and patient report measures developed to evaluate therapeutic progress and outcomes for individuals with DID and other DD: the Progress in Treatment Questionnaire - Therapist (PITQ-t; a therapist report measure) and the Progress in Treatment Questionnaire - Patient (PITQ-p; a patient self-report measure). Method: We examined the data of 177 patient-therapist pairs (total N = 354) participating in the TOP DD Network Study, an online psychoeducation programme aimed at helping patients with DD establish safety, regulate emotions, and manage dissociative and posttraumatic symptoms. Results: The PITQ-t and PITQ p demonstrated good internal consistency and evidence of moderate convergent validity in relation to established measures of emotional dysregulation, dissociation, posttraumatic stress disorder, and psychological quality of life, which are characteristic difficulties for DD patients. The measures also demonstrated significant relationships in the hypothesized directions with positive emotions, social relations, and self-harm and dangerous behaviours. The patient-completed PITQ-p, which may be used as an ongoing assessment measure to guide treatment planning, demonstrated evidence of stronger relationships with established symptom measures than the PITQ-t. Conclusions: The PITQ-t and PITQ-p merit use, additional research, and refinement in relation to the assessment of therapeutic progress with patients with DD. PMID- 29163861 TI - Peritraumatic reactions in relation to trauma exposure and symptoms of posttraumatic stress in high school students. AB - Background: Exposure to traumatic events is clearly associated with a diversity of subsequent mental health problems, with posttraumatic stress disorder (PTSD) as the most prevalent disorder. Epidemiologically, trauma exposure rates are more prevalent than PTSD, indicating that most trauma victims do not develop PTSD. More knowledge is needed to understand the development of the different posttraumatic pathways including the significance of pretraumatic, peritraumatic and posttraumatic risk factors. Objective: To study peritraumatic reactions in relation to trauma exposure and symptoms of posttraumatic stress and to enhance our understanding of peritraumatic reactions as mediators between trauma and later symptomatology. Method: The study was composed of a representative community sample of 5332 second year high school students (mean age 17.3 years) who completed the Juvenile Victimization Questionnaire (SAQ/JVQ), Trauma Symptom Checklist for Children (TSCC) and answered questions about peritraumatic reactions. Mediation effects of peritraumatic reactions on the trauma exposure relationship to symptoms was tested using the PROCESS macro for SPSS. Results: Traumatic events are common (84.1%) and are accompanied in three-quarters of the students with at least one form of peritraumatic reaction. Peritraumatic reactions, especially peritraumatic dissociative reactions, mediate the relationship between trauma exposure and symptoms, and gender moderates the effect of peritraumatic dissociation. This moderating effect was found to be larger for boys than for girls, indicating gender differences in response to trauma. Conclusions: The results indicate the need to screen for peritraumatic reactions as early as possible after a traumatic event in order to identify those at risk for PTSD. PMID- 29163862 TI - Comparison of DSM-5 and proposed ICD-11 criteria for PTSD with DSM-IV and ICD-10: changes in PTSD prevalence in military personnel. AB - Background: Recently, changes have been introduced to the diagnostic criteria for posttraumatic stress disorder (PTSD) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD). Objectives:This study investigated the effect of the diagnostic changes made from DSM-IV to DSM-5 and from ICD-10 to the proposed ICD-11. The concordance of provisional PTSD prevalence between the diagnostic criteria was examined in a convenience sample of 100 members of the German Armed Forces. Method: Based on questionnaire measurements, provisional PTSD prevalence was assessed according to DSM-IV, DSM-5, ICD-10, and proposed ICD-11 criteria. Consistency of the diagnostic status across the diagnostic systems was statistically evaluated. Results: Provisional PTSD prevalence was the same for DSM-IV and DSM-5 (both 56%) and comparable under DSM-5 versus ICD-11 proposal (48%). Agreement between DSM-IV and DSM-5, and between DSM-5 and the proposed ICD-11, was high (both p < .001). Provisional PTSD prevalence was significantly increased under ICD-11 proposal compared to ICD-10 (30%) which was mainly due to the deletion of the time criterion. Agreement between ICD-10 and the proposed ICD-11 was low (p = .014). Conclusion: This study provides preliminary evidence for a satisfactory concordance between provisional PTSD prevalence based on the diagnostic criteria for PTSD that are defined using DSM-IV, DSM-5, and proposed ICD-11. This supports the assumption of a set of PTSD core symptoms as suggested in the ICD-11 proposal, when at the same time a satisfactory concordance between ICD-11 proposal and DSM was given. The finding of increased provisional PTSD prevalence under ICD-11 proposal in contrast to ICD-10 can be of guidance for future epidemiological research on PTSD prevalence, especially concerning further investigations on the impact, appropriateness, and usefulness of the time criterion included in ICD-10 versus the consequences of its deletion as proposed for ICD-11. PMID- 29163863 TI - Cognitive therapy and eye movement desensitization and reprocessing for reducing psychopathology among disaster-bereaved individuals: study protocol for a randomized controlled trial. AB - Background: Confrontation with a traumatic (e.g. disaster-related) loss is a risk factor for the development of psychopathology, including symptoms of prolonged grief (PG), posttraumatic stress (PTS), and depression. Although interventions have been developed for reducing post-loss psychopathology, more research into the effectiveness of treatment is needed to improve care for bereaved persons. Cognitive therapy (CT) and eye movement desensitization and reprocessing (EMDR) have been shown to be effective in trauma-exposed populations. We hypothesize that CT and EMDR are also effective in reducing symptoms among people exposed to traumatic loss. Objective: In this article we describe the rationale of a randomized controlled trial (RCT) to examine (1) treatment effects of CT and EMDR for reducing PG, PTS, and depression among traumatically bereaved people, and (2) the associations between improvements in PG, PTS, and depression symptoms on the one hand and tentative mechanisms of change, including a sense of unrealness, negative cognitions, avoidance behaviour, and intrusive memories, on the other hand. Method: A two-armed (intervention versus waiting list controls) RCT will be conducted. Participants will be asked to fill in questionnaires prior to treatment, during treatment, and one, 12, and 24 weeks post-treatment. Potential participants are people who have lost one or multiple significant other(s) in the Ukrainian plane disaster in 2014 with clinically significant levels of self-rated PG, PTS, and/or depression. Multiple regression, including analysis of covariance, and multilevel regression analyses will be used. Discussion: There is a need for treatment for psychopathology following traumatic loss. Strengths of this study are the development of a treatment that targets grief and trauma related complaints and the examination of potential mechanisms of change in CT and EMDR. Bereaved people, clinicians, and researchers could benefit from the results of this study. PMID- 29163864 TI - Pathways into mental health care for UK veterans: a qualitative study. AB - Background: It is well established that veterans suffering from mental health difficulties under use mental health services. Objective: This study aimed to understand more about the barriers that prevent veterans from seeking professional help and the enablers that assist veterans in seeking professional help. It also aimed to explore potential mechanisms to improve veterans' help seeking and pathways to care. Method: The study employed a qualitative design whereby 17 veterans who had recently attended specialist veteran mental health services took part in semi-structured interviews. The resultant data were analysed using grounded theory. Results: Participants described two distinct stages to their help-seeking: initial help-seeking and pathways through treatment. Specific barriers and enablers to help-seeking were identified at each stage. Initial barriers included recognizing that there is a problem, self-stigma and anticipated public stigma. Initial enablers included being in crisis, social support, motivation and the media. Treatment pathway barriers included practical factors and negative beliefs about health services and professionals. Treatment pathway enablers included having a diagnosis, being seen in a veteran-specific service and establishing a good therapeutic relationship. Participants provided some suggestions for interventions to improve veterans' help-seeking in future; these focussed on enhancing both veterans and health professionals' knowledge regarding mental health difficulties. Conclusions: This study identified a number of barriers and enablers that may impact a veteran's journey in seeking help from professional services for mental health difficulties. Enablers such as reaching a crisis point, social support, the media, having a diagnosis of PTSD and veteran specific mental health services appeared to be important in opposing stigma related beliefs and in supporting veterans to engage in help-seeking behaviours. PMID- 29163865 TI - Associations between neurocognitive functioning and social and occupational resilience among South African women exposed to childhood trauma. AB - Background: Prior research on adaptation after early trauma among black South African women typically assessed resilience in ways that lacked contextual specificity. In addition, the neurocognitive correlates of social and occupational resilience have not been investigated. Objective: The primary aim of this exploratory study was to identify domains of neurocognitive functioning associated with social and occupational resilience, defined as functioning at a level beyond what would be expected given exposure to childhood trauma. Methods: A sample of black South African women, N = 314, completed a neuropsychological battery, a questionnaire assessing exposure to childhood trauma, and self-report measures of functional status. We generated indices of social and occupational resilience by regressing childhood trauma exposure on social and occupational functioning, saving the residuals as indices of social and occupational functioning beyond what would be expected given exposure to childhood trauma. Results: Women with lower non-verbal memory evidenced greater social and occupational resilience above and beyond the effects attributable to age, education, HIV status, and depressive and posttraumatic stress symptoms. In addition, women with greater occupational resilience exhibited lower semantic language fluency and processing speed. Conclusion: Results are somewhat consistent with prior studies implicating memory effects in impairment following trauma, though our findings suggest that reduced abilities in these domains may be associated with greater resilience. Studies that use prospective designs and objective assessment of functional status are needed to determine whether non verbal memory, semantic fluency, and processing speed are implicated in the neural circuitry of post-traumatic exposure resilience. PMID- 29163866 TI - Multidisciplinary treatment for traumatized refugees in a naturalistic setting: symptom courses and predictors. AB - Background: Multidisciplinary treatment approaches are commonly used in specialized psychosocial centres for the treatment of traumatized refugees, but empirical evidence for their efficacy is inconsistent. Objective: In order to obtain more evidence on the development of mental health and well-being of traumatized refugees who receive multidisciplinary treatment, symptom courses of posttraumatic stress disorder (PTSD), anxiety, depression and somatoform symptoms as well as in the subjective quality of life were investigated in the course of a multidisciplinary treatment. In addition, it was analysed if sociodemographic variables were predictors for possible changes in symptomatology and quality of life. Method: N = 76 patients of the outpatient clinic of a psychosocial centre for traumatized refugees receiving regular multidisciplinary treatment were surveyed using standardized questionnaires at three measurement points (at the beginning of treatment, and after an average of 7 and 14 months of treatment) in a single-group design. Results: Multilevel analysis showed significant improvements of symptoms of PTSD (p < .001), depression (p < .001), anxiety (p < .001), and somatoform symptoms (p = .002) as well as of the subjective quality of life (p < .001) over time. Among the tested predictors (gender, age, country of origin), age was a significant predictor for the course of somatoform symptoms (p < .05). Younger patients showed greater improvements in symptomatology over time than older ones. Conclusions: The results suggest that the received multidisciplinary treatment had a positive effect on trauma-related symptoms as well as on quality of life of traumatized refugees. There was no indication that sociodemographic characteristics predicted the symptom courses of the patients, except for somatoform symptoms. Younger patients benefitted more from multidisciplinary treatment than older ones. PMID- 29163868 TI - The effectiveness of psychosocial interventions in war-traumatized refugee and internally displaced minors: systematic review and meta-analysis. AB - Background: The United Nations reported that in 2016 over 65 million people worldwide have forcibly left home. Over 50% are children and adolescents; a substantial number has been traumatized and displaced by war. Objective: To provide an overview of the effectiveness of psychosocial interventions in this group we conducted a narrative review and a meta-analysis of intervention studies providing data on posttraumatic stress symptoms (PTSS), depression, anxiety, grief, and general distress. Method: We searched PILOTS, MEDLINE, WoS, Embase, CENTRAL, LILACS, PsycINFO, ASSIA, CSA, and SA for studies on treatment outcomes for war-traumatized displaced children and adolescents. Between-group effect sizes (ES) and pre-post ES were reconstructed for each trial. Overall pre-post ES were calculated using a random effects model. Results: The narrative review covers 23 studies with a variety of treatments. Out of the 35 calculated between group ES, only six were significant, all compared to untreated controls. Two of them indicated significant adverse effects on symptoms of general distress or depression. When calculating pre-post effect sizes, the positive between-group results of cognitive behavioural therapy (CBT) and interpersonal therapy (IPT) were reproduced and singular other treatments showed significant positive effects. However, the mean pre-post effects for PTSS and depression could not be interpreted due to the high heterogeneity of the included studies (PTSS: ES = 0.78; I2 = 88.6%; depression: ES = 0.35; I2 = 93.1%). Only the mean pre-post effect for seven active CBT treatment groups for depression (ES = 0.30, 95% CI [0.18, 0.43]) was interpretable (Q = 3.3, df = 6, p = .77). Conclusion: Given the large number of children and adolescents displaced by war there were regrettably few treatment studies available, and many of them were of low methodological quality. The effect sizes lagged behind the effects observed in traumatized minors in general, and often were small or non-significant. However, CBT and IPT showed promising results that need further replication. PMID- 29163867 TI - Strengthening mental health care systems for Syrian refugees in Europe and the Middle East: integrating scalable psychological interventions in eight countries. AB - The crisis in Syria has resulted in vast numbers of refugees seeking asylum in Syria's neighbouring countries as well as in Europe. Refugees are at considerable risk of developing common mental disorders, including depression, anxiety, and posttraumatic stress disorder (PTSD). Most refugees do not have access to mental health services for these problems because of multiple barriers in national and refugee specific health systems, including limited availability of mental health professionals. To counter some of challenges arising from limited mental health system capacity the World Health Organization (WHO) has developed a range of scalable psychological interventions aimed at reducing psychological distress and improving functioning in people living in communities affected by adversity. These interventions, including Problem Management Plus (PM+) and its variants, are intended to be delivered through individual or group face-to-face or smartphone formats by lay, non-professional people who have not received specialized mental health training, We provide an evidence-based rationale for the use of the scalable PM+ oriented programmes being adapted for Syrian refugees and provide information on the newly launched STRENGTHS programme for adapting, testing and scaling up of PM+ in various modalities in both neighbouring and European countries hosting Syrian refugees. PMID- 29163869 TI - Efficient identification of mental health problems in refugees in Germany: the Refugee Health Screener. AB - Background: A substantial number of refugees present with mental disorders. This appears particularly acute in the currently increasing refugee populations in Europe. Although EU guidelines demand the identification and support of vulnerable individuals such as survivors of trauma, no adequately validated and comprehensive mental health screening instruments for refugees residing in Europe currently exist. Objective: We studied the feasibility, validity, and reliability of the Refugee Health Screener-15 (RHS-15) - a time-efficient and easy-to implement screening developed by Hollifield et al. (2013) - as a self-rating and interview instrument. Methods: A sample of refugees from different countries (N = 86), representative of those who had arrived around the turn of the year 2015/2016 in Germany, filled in the RHS-15 on their own. A semi-structured clinical interview was later conducted with a random subsample (n = 56). Results: Fifty-two percent of the refugees examined screened positive in the RHS-15, thus indicating current mental health problems. The RHS-15 showed a good feasibility, reliability, and validity in both the self-rating and the interview version. It detected clinically relevant mental health problems when PTSD, depression, anxiety, or somatization problems were present. A shorter 13-item version proved to be equally valid. Conclusions: Together with previous research on the RHS in refugees living in the US, this suggests that the RHS is a time-efficient and accurate instrument that is able to detect common mental health problems in a wide range of refugees. Prospectively, the RHS could be used as an instrument for identifying vulnerable refugees, for example, by integrating it in the initial medical examination in the host community, thereby initiating support. PMID- 29163870 TI - Transdiagnostic culturally adapted CBT with Farsi-speaking refugees: a pilot study. AB - Background: Approximately half of all asylum seekers suffer from trauma-related disorders requiring treatment, among them Posttraumatic Stress Disorder (PTSD), depression, anxiety, and somatic symptoms. There is a lack of easily accessible, low-threshold treatments taking the cultural background into account. Culturally Adapted CBT (CA CBT) is a well evaluated, transdiagnostic group intervention for refugees, using psychoeducation, meditation, and Yoga-like exercises. Objective: An uncontrolled pilot study with male Farsi-speaking refugees from Afghanistan and Iran was conducted to investigate feasibility with this ethnic group; a group for which no previous CBT trials have been reported. Method: The participants were nine Farsi-speaking, male refugees with M.I.N.I./DSM-IV diagnoses comprising PTSD, major depressive disorder, and anxiety disorders. Treatment components were adapted to the specific cultural framework of perception of symptoms, causes, ideas of healing, and local therapeutic processes. Before and after 12 weeks of treatment, the primary outcome was assessed using the General Health Questionnaire (GHQ-28). Secondary outcome measures were the Posttraumatic Checklist, Patient Health Questionnaire, Somatic Symptom Scale, World Health Organization Quality of Life Questionnaire (WHOQOL-BREF), Affective Style Questionnaire (ASQ), and Emotion Regulation Scale (ERS). Results: Seven participants completed treatment. In the completer analysis, improvements were found on almost all questionnaires. Large effect sizes were seen for the GHQ-28 (d = 2.0), WHOQOL-BREF scales (d = 1.0-2.3), ASQ tolerating subscale (d = 2.2), and ERS (d = 1.7). With respect to feasibility, cultural adaptation seemed to be a crucial means to promote effectiveness. Conclusion: CA CBT may reduce general psychopathological distress and improve quality of life. Improvement in emotion regulation strategies may mediate treatment effects. More support should be provided to enhance coping with the uncertainty of asylum status and stressful housing conditions. CA CBT appears to be a promising transdiagnostic treatment, serving as an initial low-threshold therapy in a stepped care approach. PMID- 29163871 TI - Grief rumination mediates the association between self-compassion and psychopathology in relatives of missing persons. AB - Background: The disappearance of a loved one is a unique type of loss, also termed 'ambiguous loss', which may heighten the risk for developing prolonged grief (PG), depression, and posttraumatic stress (PTS) symptoms. Little is known about protective and risk factors for psychopathology among relatives of missing persons. A potential protective factor is self-compassion, referring to openness toward and acceptance of one's own pain, failures, and inadequacies. One could reason that self-compassion is associated with lower levels of emotional distress following ambiguous loss, because it might serve as a buffer for getting entangled in ruminative thinking about the causes and consequences of the disappearance ('grief rumination'). Objective: In a sample of relatives of missing persons we aimed to examine (1) the prediction that greater self compassion is related to lower symptom-levels of PG, depression, and PTS and (2) to what extent these associations are mediated by grief rumination. Method: Dutch and Belgian relatives of long-term missing persons (N = 137) completed self report measures tapping self-compassion, grief rumination, PG, depression, and PTS. Mediation analyses were conducted. Results: Self-compassion was significantly, negatively, and moderately associated with PG, depression, and PTS levels. Grief rumination significantly mediated the associations of higher levels of self-compassion with lower levels of PG (a*b = -0.11), depression (a*b = 0.07), and PTS (a*b = -0.11). Specifically, 50%, 32%, and 32% of the effect of self-compassion on PG, depression, and PTS levels, respectively, was accounted for by grief rumination. Conclusions: Findings suggest that people with more self compassion experience less severe psychopathology, in part because these people are less strongly inclined to engage in ruminative thinking related to the disappearance. Strengthening a self-compassionate attitude using, for instance, mindfulness-based interventions may therefore be a useful intervention to reduce emotional distress associated with the disappearance of a loved one. PMID- 29163872 TI - CIT-7, a crystalline, molecular sieve with pores bounded by 8 and 10-membered rings. AB - A new crystalline molecular sieve, denoted CIT-7, is synthesized using an imidazolium-based diquaternary organic structure directing agent (OSDA). The framework structure is determined from a combination of rotation electron diffraction and synchrotron X-ray powder diffraction data. The structure has 10 crystallographically unique tetrahedral atoms (T-atoms) in the unit cell, and can be described as an ordered arrangement of the [425462] mtw building unit and a previously unreported [4452] building unit. The framework contains a 2 dimensional pore system that is bounded by 10 T-atom rings (10-ring, 5.1 A * 6.2 A opening) that are connected with oval 8-rings (2.9 A * 5.5 A opening) through medium-sized cavities (~7.9 A) at the channel intersections. CIT-7 can be synthesized over a broad range of compositions including pure-silica and heteroatom, e.g., aluminosilicate and titanosilicate, containing variants. PMID- 29163873 TI - Mechanism, reactivity, and selectivity of the iridium-catalyzed C(sp3)-H borylation of chlorosilanes. AB - The iridium-catalyzed C(sp3)-H borylation of methylchlorosilanes is investigated by means of density functional theory, using the B3LYP and M06 functionals. The calculations establish that the resting state of the catalyst is a seven coordinate Ir(v) species that has to be converted into an Ir(iii)tris(boryl) complex in order to effect the oxidative addition of the C-H bond. This is then followed by a C-B reductive elimination to yield the borylated product, and the catalytic cycle is finally completed by the regeneration of the active catalyst over two facile steps. The two employed functionals give somewhat different conclusions concerning the nature of the rate-determining step, and whether reductive elimination occurs directly or after a prior isomerization of the Ir(v) hydride intermediate complex. The calculations reproduce quite well the experimentally-observed trends in the reactivities of substrates with different substituents. It is demonstrated that the reactivity can be correlated to the Ir C bond dissociation energies of the corresponding Ir(v) hydride intermediates. The effect of the chlorosilyl group is identified to originate from the alpha carbanion-stabilizing effect of the silicon, which is further reinforced by the presence of an electron-withdrawing chlorine substituent. Furthermore, the source of selectivity for the borylation of primary over secondary C(sp3)-H can be explained on a steric basis, by repulsion between the alkyl group and the Ir/ligand moiety. Finally, the difference in the reactivity between C(sp3)-H and C(sp2)-H borylation is investigated and rationalized in terms of distortion/interaction analysis. PMID- 29163874 TI - A facile route to electronically conductive polyelectrolyte brushes as platforms of molecular wires. AB - A facile strategy for the synthesis of conjugated polyelectrolyte brushes grafted from a conductive surface is presented. Such brushes form a platform of molecular wires oriented perpendicularly to the surface, enabling efficient directional transport of charge carriers. As the synthesis of conjugated polymer brushes using chain-growth polymerization via a direct "grafting from" approach is very challenging, we developed a self-templating surface-initiated method. It is based on the formation of multimonomer template chains in the first surface-initiated polymerization step, followed by the second polymerization leading to conjugated chains in an overall ladder-like architecture. This strategy exploits the extended conformation of the surface-grafted brushes, thereby enabling alignment of the pendant polymerizable groups along the template chains. We synthesized a new bifunctional monomer and used the developed approach to obtain quaternized poly(ethynylpyridine) chains on a conductive indium tin oxide surface. A catalyst free quaternization polymerization was for the first time used here for surface grafting. The presence of charged groups makes the obtained brushes both ionically and electronically conductive. After doping with iodine, the brushes exhibited electronic conductivity, in the direction perpendicular to the surface, as high as 10-1-100 S m-1. Tunneling AFM was used for mapping the surface conductivity and measuring the conductivity in the spectroscopic mode. The proposed synthetic strategy is very versatile as a variety of monomers with pendant polymerizable groups and various polymerization techniques may be applied, leading to platforms of molecular wires with the desired characteristics. PMID- 29163875 TI - Catalysis of water oxidation in acetonitrile by iridium oxide nanoparticles. AB - Water oxidation catalysed by iridium oxide nanoparticles (IrO2 NPs) in water acetonitrile mixtures using [RuIII(bpy)3]3+ as oxidant was studied as a function of the water content, the acidity of the reaction media and the catalyst concentration. It was observed that under acidic conditions (HClO4) and at high water contents (80% (v/v)) the reaction is slow, but its rate increases as the water content decreases, reaching a maximum at approximately equimolar proportions (~25% H2O (v/v)). The results can be rationalized based on the structure of water in water-acetonitrile mixtures. At high water fractions, water is present in highly hydrogen-bonded arrangements and is less reactive. As the water content decreases, water clustering gives rise to the formation of water rich micro-domains, and the number of bonded water molecules decreases monotonically. The results presented herein indicate that non-bonded water present in the water micro-domains is considerably more reactive towards oxygen production. Finally, long term electrolysis of water-acetonitrile mixtures containing [RuII(bpy)3]2+ and IrO2 NPs in solution show that the amount of oxygen produced is constant with time demonstrating that the redox mediator is stable under these experimental conditions. PMID- 29163876 TI - Discovery of potent inhibitors of human beta-tryptase from pre-equilibrated dynamic combinatorial libraries. AB - Pre-equilibrated dynamic combinatorial libraries based on acyl hydrazone interchange of peptide-derived hydrazides and di- and tri-aldehydes have been used to discover potent inhibitors with nanomolar affinities for beta-tryptase. To identify potent inhibitors the activity of the full library containing 95 members was compared with those of sub-libraries in which individual building blocks were missing. The most active library members contain a rigid central aromatic scaffold with three cationic peptide arms. The arms of the best inhibitors also contained a tailor-made GCP oxoanion binding motif attached to a lysine side chain. The most potent tri-armed hydrazones with peptide arms GKWR or GKWK(GCP) were shown to inhibit beta-tryptase (Kica. 10-20 nM) reversibly, non competitively and selectively (compared to related serine proteases, e.g. trypsin and chymotrypsin), most likely by binding to the protein surface, also in agreement with molecular modelling calculations. These new inhibitors are one order of magnitude more efficient than related tetravalent inhibitors obtained from previous work on a split-mix-combinatorial library and were identified with significantly less effort, demonstrating the usefulness of this approach for the identification of enzyme inhibitors in general. PMID- 29163877 TI - Interconvertible multiple photoluminescence color of a gold(i) isocyanide complex in the solid state: solvent-induced blue-shifted and mechano-responsive red shifted photoluminescence. AB - In this study, we report the interconvertible tetracolored solid state photoluminescence of gold(i) isocyanide complex 2 upon various external stimuli through solid state structural changes. Soaking complex 2 in acetone yields blue emission as a result of the formation of 2B. The subsequent removal of acetone yields 2G through a crystal-to-crystal phase transition, which exhibits green emission. This green-emitting solid 2G exhibits stepwise emission color changes to yellow and then to orange upon mechanical stimulation by ball-milling, which corresponds to the formation of 2Y and 2O, respectively. 2B could be recovered upon the addition of acetone to 2G, 2Y, and 2O. Thus, these four emitting solid states of 2 can be switched between repeatedly by means of acetone soaking and the application of mechanical stimulation. Importantly, single crystal and powder X-ray diffraction (PXRD) studies fully show the detailed molecular arrangements of 2B, 2G, and 2Y. This is the first mechanochromic compound to show interconvertible four color emission in the solid state. We also present the first example of using PXRD measurements and the Rietveld refinement technique for the structural analysis of a ground powder in a luminescence mechanochromism study. We obtained complete molecular-level structural information of the crystalline states of 2B, 2G, 2Y, and 2O. In comparison with a more solvophobic analogue 1, we suggest that the weak interaction of 2 with acetone in the solid state would allow a solvent inclusion/release mode, which is an important structural factor for the unprecedented multicolor mechanochromic luminescence. PMID- 29163878 TI - Redefining q: quaternary ammonium cross sectional area (XSA) as a general descriptor for transport-limiting PTC rate approximations. AB - The relationships of several key molecular descriptors with the rate of the O'Donnell alkylation under phase transfer catalysis (PTC) have been investigated. The most common parameter used to predict PTC rates, the ammonium ion accessibility, q , is defined in such a way that limits its use to straight-chain tetraalkylammonium catalysts. To find a general descriptor of rate, eight linear, symmetrical tetraalkylammonium cations were examined to determine if a model containing broadly applicable descriptors could be found. The catalytic activity of these salts was determined under PTC conditions (operating under an interfacial, transport-rate limiting mechanism) and was compared with these molecular descriptors. Models could be generated from the ammonium ion accessibility parameter q and the amphiphilic cross sectional area descriptor (XSA), and each gave a correlative model predicting the rate of alkylation. However, a similar model cannot be generated from a descriptor that is a direct measure of ammonium ion accessibility, the solvent accessible ammonium surface area (NC4_SA). These models lead to the conclusion that q must approximate catalyst properties other than ammonium ion accessibility. Additionally, the relationship between XSA and rate demonstrates that XSA approximates the complex behavior of ammonium ions at the interfacial region of a biphasic system, allowing for its use as a general descriptor for transport-limiting PTC rate approximations. PMID- 29163879 TI - Plasmonic giant quantum dots: hybrid nanostructures for truly simultaneous optical imaging, photothermal effect and thermometry. AB - Hybrid semiconductor-metal nanoscale constructs are of both fundamental and practical interest. Semiconductor nanocrystals are active emitters of photons when stimulated optically, while the interaction of light with nanosized metal objects results in scattering and ohmic damping due to absorption. In a combined structure, the properties of both components can be realized together. At the same time, metal-semiconductor coupling may intervene to modify absorption and/or emission processes taking place in the semiconductor, resulting in a range of effects from photoluminescence quenching to enhancement. We show here that photostable 'giant' quantum dots when placed at the center of an ultrathin gold shell retain their key optical property of bright and blinking-free photoluminescence, while the metal shell imparts efficient photothermal transduction. The latter is despite the highly compact total particle size (40-60 nm "inorganic" diameter and <100 nm hydrodynamic diameter) and the very thin nature of the optically transparent Au shell. Importantly, the sensitivity of the quantum dot emission to local temperature provides a novel internal thermometer for recording temperature during infrared irradiation-induced photothermal heating. PMID- 29163880 TI - Recent developments in the selective dispersion of single-walled carbon nanotubes using conjugated polymers. AB - A significant barrier that impedes the commercialization of single-walled carbon nanotube-related applications is that all known synthetic methods produce a complicated mixture of semiconducting and metallic species. For device applications, pure semiconducting or pure metallic samples are desirable. Thus far, the purification methods that have been identified are capable of separating individual carbon nanotube species on a microgram scale, but purification on a large scale has remained elusive. The use of conjugated polymers to selectively disperse specific nanotube species is a promising approach to resolve the scalability issue, but a comprehensive understanding of the selectivity mechanism has not yet been achieved. Here, several of the trends reported in the literature are outlined to further the rational design of conjugated polymers for nanotube sorting. Numerous variables influence dispersion selectivity, including polymer structure and molecular weight, nanotube type used, sonication temperature, amount of polymer relative to nanotube, and solvent. We have organized these seemingly disparate parameters into two simple categories: conjugated polymer structure, and dispersion preparation conditions. Most importantly, we consider the mechanistic arguments that have been proposed, and provide additional insights based on the observations in the literature. PMID- 29163881 TI - Displacement and hybridization reactions in aptamer-functionalized hydrogels for biomimetic protein release and signal transduction. AB - A variety of hydrogels have been synthesized for controlling the release of signaling molecules in applications such as drug delivery and regenerative medicine. However, it remains challenging to synthesize hydrogels with the ability to control the release of signaling molecules sequentially or periodically under physiological conditions as living cells do in response to the variation of metabolism. The purpose of this work was to study a novel biomimetic hydrogel system with the ability of recapitulating the procedure of cellular signal transduction and controlling the sequential release of signaling molecules under physiological conditions. In the presence of a small chemical, the signaling molecule is regulated to change from a DNA-bound state to a free state and the freed signaling molecule is able to regulate intracellular signal transduction and cell migration. Moreover, periodic exposure of the hydrogel system to the small chemical leads to sequential protein release. Since signaling molecules are important for every activity of the cell, this hydrogel system holds potential as a metabolism-responsive platform for controlled release of signaling molecules and cell regulation in various applications. PMID- 29163882 TI - Rapid and precise determination of zero-field splittings by terahertz time-domain electron paramagnetic resonance spectroscopy. AB - Zero-field splitting (ZFS) parameters are fundamentally tied to the geometries of metal ion complexes. Despite their critical importance for understanding the magnetism and spectroscopy of metal complexes, they are not routinely available through general laboratory-based techniques, and are often inferred from magnetism data. Here we demonstrate a simple tabletop experimental approach that enables direct and reliable determination of ZFS parameters in the terahertz (THz) regime. We report time-domain measurements of electron paramagnetic resonance (EPR) signals associated with THz-frequency ZFSs in molecular complexes containing high-spin transition-metal ions. We measure the temporal profiles of the free-induction decays of spin resonances in the complexes at zero and nonzero external magnetic fields, and we derive the EPR spectra via numerical Fourier transformation of the time-domain signals. In most cases, absolute values of the ZFS parameters are extracted from the measured zero-field EPR frequencies, and the signs can be determined by zero-field measurements at two different temperatures. Field-dependent EPR measurements further allow refined determination of the ZFS parameters and access to the g-factor. The results show good agreement with those obtained by other methods. The simplicity of the method portends wide applicability in chemistry, biology and material science. PMID- 29163883 TI - Effects of electron transfer on the stability of hydrogen bonds. AB - The measurement of the dimerization constants of hydrogen-bonded ruthenium complexes (12, 22, 32) linked by a self-complementary pair of 4-pyridylcarboxylic acid ligands in different redox states is reported. Using a combination of FTIR and UV/vis/NIR spectroscopies, the dimerization constants (KD) of the isovalent, neutral states, 12, 22, 32, were found to range from 75 to 130 M-1 (DeltaG0 = 2.56 to -2.88 kcal mol-1), while the dimerization constants (K2-) of the isovalent, doubly-reduced states, (12)2-, (22)2-, (32)2-, were found to range from 2000 to 2500 M-1 (DeltaG0 = -4.5 to -4.63 kcal mol-1). From the aforementioned values and the comproportionation constant for the mixed-valent dimers, the dimerization constants (KMV) of the mixed-valent, hydrogen-bonded dimers, (12)-, (22)-, (32)-, were found to range from 0.5 * 106 to 1.2 * 106 M-1 (DeltaG0 = -7.78 to -8.31 kcal mol-1). On average, the hydrogen-bonded, mixed valent states are stabilized by -5.27 (0.04) kcal mol-1 relative to the isovalent, neutral, hydrogen-bonded dimers and -3.47 (0.06) kcal mol-1 relative to the isovalent, dianionic hydrogen bonded dimers. Electron exchange in the mixed valence states imparts significant stability to hydrogen bonding. This is the first quantitative measurement of the strength of hydrogen bonds in the presence and absence of electronic exchange. PMID- 29163884 TI - Magnetic control of cellular processes using biofunctional nanoparticles. AB - Remote control of cellular functions is a key challenge in biomedical research. Only a few tools are currently capable of manipulating cellular events at distance, at spatial and temporal scales matching their naturally active range. A promising approach, often referred to as 'magnetogenetics', is based on the use of magnetic fields, in conjunction with targeted biofunctional magnetic nanoparticles. By triggering molecular stimuli via mechanical, thermal or biochemical perturbations, magnetic actuation constitutes a highly versatile tool with numerous applications in fundamental research as well as exciting prospects in nano- and regenerative medicine. Here, we highlight recent studies, comment on the advancement of magnetic manipulation, and discuss remaining challenges. PMID- 29163886 TI - Chromium complexes for luminescence, solar cells, photoredox catalysis, upconversion, and phototriggered NO release. AB - Some complexes of Cr(iii) and Cr(0) have long been known to exhibit interesting photophysical and photochemical properties, but in the past few years important conceptual progress was made. This Perspective focuses on the recent developments of Cr(iii) complexes as luminophores and dyes for solar cells, their application in photoredox catalysis, their use as sensitizers in upconversion processes, and their performance as photochemical nitric oxide sources. The example of a luminescent Cr(0) isocyanide complex illustrates the possibility of obtaining photoactive analogues of d6 metal complexes that are commonly made from precious metals such as Ru(ii) or Ir(iii). The studies highlighted herein illustrate the favorable excited-state properties of robust first-row transition metal complexes with broad application potential. PMID- 29163885 TI - Molecular design of upconversion nanoparticles for gene delivery. AB - Due to their large anti-Stokes shifts, sharp emission spectra and long excited state lifetimes, upconversion nanoparticles (UCNPs) have attracted an increasing amount of research interests, and have shown great potential for enhancing the practical utility of gene therapy, whose versatility has been limited by existing gene delivery technologies that are basically mono-functional in nature. Despite this, up to now in-depth analysis of the development of UCNPs for gene delivery has been scant in the literature, even though there has been an upsurge of reviews on the chemistry of UCNPs and their applications in bioimaging and drug delivery. To fill this gap, this review aims to present the latest advances in the development and applications of UCNPs as gene carriers. Prior to describing the prominent works published in the field, a critical view on the properties, chemistry and molecular design of UCNPs for gene delivery is provided. With a synopsis of the recent advances in UCNP-mediated gene delivery, challenges and opportunities could be illuminated for clinical translation of works in this nascent field of research. PMID- 29163887 TI - A novel peptide stapling strategy enables the retention of ring-closing amino acid side chains for the Wnt/beta-catenin signalling pathway. AB - The all-hydrocarbon peptide stapling strategy has recently been extensively explored in drug discovery. There remains the potential for improvement regarding the retention of the amino acid side chains at the stapled positions. Herein, we describe a new series of amino acids that not only contain the native side chains, but also carry the alkenyl arms that are needed for the ring-closing stapling chemistry. We incorporate the new amino acids into a beta-catenin binding domain of Axin (469-482) and develop a new category of stapled peptides with the retention of the native side chains. These stapled peptides exhibit high alpha-helicity, strong proteolytic stability and good cell permeability. Biochemical experiments demonstrate that these stapled peptides can activate beta catenin more efficiently than canonical stapled peptides due to the presence of extra side chains. We expect that the new side-chain-retention stapling method would expand the scope of the all-hydrocarbon stapled peptide strategy by retaining some important peripheral residues for protein-protein interactions or preserving key hydrophilic side chains to improve solubility. PMID- 29163888 TI - Theoretical predictions suggest carbon dioxide phases III and VII are identical. AB - Solid carbon dioxide exhibits a rich phase diagram at high pressures. Metastable phase III is formed by compressing dry ice above ~10-12 GPa. Phase VII occurs at similar pressures but higher temperatures, and its stability region is disconnected from III on the phase diagram. Comparison of large-basis-set quasi harmonic second-order Moller-Plesset perturbation theory calculations and experiment suggests that the long-accepted structure of phase III is problematic. The experimental phase III and VII structures both relax to the same phase VII structure. Furthermore, Raman spectra predicted for phase VII are in good agreement with those observed experimentally for both phase III and VII, while those for the purported phase III structure agree poorly with experimental observations. Crystal structure prediction is employed to search for other potential structures which might account for phase III, but none are found. Together, these results suggest that phases III and VII are likely identical. PMID- 29163889 TI - Determination of protonation states of iminosugar-enzyme complexes using photoinduced electron transfer. AB - A series of N-alkylated analogues of 1-deoxynojirimycin containing a fluorescent 10-chloro-9-anthracene group in the N-alkyl substituent were prepared. The anthracene group acted as a reporting group for protonation at the nitrogen in the iminosugar because an unprotonated amine was found to quench fluorescence by photoinduced electron transfer. The new compounds were found to inhibit beta glucosidase from Phanerochaete chrysosporium and alpha-glucosidase from Aspergillus niger, with Ki values in the low micro- to nanomolar range. Fluorescence and inhibition versus pH studies of the beta-glucosidase-iminosugar complexes revealed that the amino group in the inhibitor is unprotonated when bound, while one of the active site carboxylates is protonated. PMID- 29163890 TI - All-metal aromatic cationic palladium triangles can mimic aromatic donor ligands with Lewis acidic cations. AB - We present that cationic rings can act as donor ligands thanks to suitably delocalized metal-metal bonds. This could grant parent complexes with the peculiar properties of aromatic rings that are crafted with main group elements. We assembled Pd nuclei into equilateral mono-cationic triangles with unhindered faces. Like their main group element counterparts and despite their positive charge, these noble-metal rings form stable bonding interactions with other cations, such as positively charged silver atoms, to deliver the corresponding tetranuclear dicationic complexes. Through a mix of modeling and experimental techniques we propose that this bonding mode is an original coordination-like one rather than a 4-centre-2-electron bond, which have already been observed in three dimensional aromatics. The present results thus pave the way for the use of suitable metal rings as ligands. PMID- 29163891 TI - Identification of new quorum sensing autoinducer binding partners in Pseudomonas aeruginosa using photoaffinity probes. AB - Many bacterial species, including the human pathogen Pseudomonas aeruginosa, employ a mechanism of intercellular communication known as quorum sensing (QS), which is mediated by signalling molecules termed autoinducers. The Pseudomonas Quinolone Signal (PQS) and 2-Heptyl-3H-4-Quinolone (HHQ) are autoinducers in P. aeruginosa, and they are considered important factors in the progress of infections by this clinically relevant organism. Herein, we report the development of HHQ and PQS photoaffinity-based probes for chemical proteomic studies. Application of these probes led to the identification of previously unsuspected putative HHQ and PQS binders, thereby providing new insights into QS at a proteomic level and revealing potential new small molecule targets for virulence attenuation strategies. Notably, we found evidence that PQS binds RhlR, the cognate receptor in the Rhl QS sub-system of P. aeruginosa. This is the first indication of interaction between the Rhl and PQS systems at the protein/ligand level, which suggests that RhlR should be considered a highly attractive target for antivirulence strategies. PMID- 29163892 TI - The photochemical alkylation and reduction of heteroarenes. AB - The functionalization of heteroarenes has been integral to the structural diversification of medicinally active molecules such as quinolines, pyridines, and phenanthridines. Electron-deficient heteroarenes are electronically compatible to react with relatively nucleophilic free radicals such as hydroxyalkyl. However, the radical functionalization of such heteroarenes has been marked by the use of transition-metal catalyzed processes that require initiators and stoichiometric oxidants. Herein, we describe the photochemical alkylation of quinolines, pyridines and phenanthridines, where through direct excitation of the protonated heterocycle, alcohols and ethers, such as methanol and THF, can serve as alkylating agents. We also report the discovery of a photochemical reduction of these heteroarenes using only iPrOH and HCl. Mechanistic studies to elucidate the underlying mechanism of these transformations, and preliminary results on catalytic methylations are also reported. PMID- 29163893 TI - Crystalline boron-linked tetraaminoethylene radical cations. AB - Single-electron oxidation of neutral boryl-linked tetraaminoethylene derivatives 4 led to the formation of radical cations 4+ , which have been isolated and fully characterized. X-ray diffraction analysis, EPR spectroscopy, and computational studies revealed that the unpaired electron is delocalized over the B2N4C2 skeleton and the spin density mainly resides on the carbon and boron atoms. PMID- 29163894 TI - Comparisons of lanthanide/actinide +2 ions in a tris(aryloxide)arene coordination environment. AB - A new series of Ln3+ and Ln2+ complexes has been synthesized using the tris(aryloxide)arene ligand system, ((Ad,MeArO)3mes)3-, recently used to isolate a complex of U2+. The triphenol precursor, (Ad,MeArOH)3mes, reacts with the Ln3+ amides, Ln(NR2)3 (R = SiMe3), to form a series of [((Ad,MeArO)3mes)Ln] complexes, 1-Ln. Crystallographic characterization was achieved for Ln = Nd, Gd, Dy, and Er. The complexes 1-Ln can be reduced with potassium graphite in the presence of 2.2.2-cryptand (crypt) to form highly absorbing solutions with properties consistent with Ln2+ complexes, [K(crypt)][((Ad,MeArO)3mes)Ln], 2-Ln. The synthesis of the Nd2+ complex [K(crypt)][((Ad,MeArO)3mes)Nd], 2-Nd, was unambiguously confirmed by X-ray crystallography. In the case of the other lanthanides, crystals were found to contain mixtures of 2-Ln co-crystallized with either a Ln3+ hydride complex, [K(crypt)][((Ad,MeArO)3mes)LnH], 3-Ln, for Ln = Gd, Dy, and Er, or a hydroxide complex, [K(crypt)][((Ad,MeArO)3mes)Ln(OH)], 4-Ln, for Ln = Dy. A Dy2+ complex with 18-crown-6 as the potassium chelator, [K(18 crown-6)(THF)2][((Ad,MeArO)3mes)Dy], 5-Dy, was isolated as a co-crystallized mixture with the Dy3+ hydride complex, [K(18-crown 6)(THF)2][((Ad,MeArO)3mes)DyH], 6-Dy. Structural comparisons of 1-Ln and 2-Ln are presented with respect to their uranium analogs and correlated with density functional theory calculations on their electronic structures. PMID- 29163895 TI - Trapping intermediate MLCT states in low-symmetry {Ru(bpy)} complexes. AB - The picosecond excited state dynamics of [Ru(tpm)(bpy)(NCS)]+ (RubNCS+ ) and [Ru(tpm)(bpy)(CN)]+ (RubCN+ ) (tpm = tris(1-pyrazolyl)methane, bpy = 2,2' bipyridine) have been analyzed by means of transient absorption measurements and spectroelectrochemistry. Emissive 3MLCTs with (GS)HOMO(h+)-(GS)LUMO(e-) configurations are the lowest triplet excited states regardless of whether 387 or 505 nm photoexcitation is used. 387 nm photoexcitation yields, after a few picoseconds, the emissive 3MLCTs. In contrast, 505 nm photoexcitation populates an intermediate excited state that we assign as a 3MLCT state, in which the hole sits in a metal-centered orbital of different symmetry, prior to its conversion to the emissive 3MLCTs. The disparities in terms of electronic configuration between the intermediate and the emissive 3MLCTs have two important consequences. On one hand, both states feature very different fingerprint absorptions in transient absorption measurements. On the other hand, the reconfiguration is impeded by a kinetic barrier. As such, the conversion is followed spectroscopically and kinetically on the 300 ps timescale. PMID- 29163896 TI - Fluorogenic labeling and single-base resolution analysis of 5-formylcytosine in DNA. AB - 5-Formylcytosine (5fC), which plays an important role in epigenetic functions, has received widespread attention in many related fields. Here, we demonstrate a new design for both the fluorogenic switch-on detection and single-base resolution analysis of 5fC through selectively reacting a reagent with 5fC to yield an intramolecular cyclization nucleobase. The generated product, bearing a similar benzothiazole-iminocoumarin scaffold, is highly fluorescent and enables us to qualitatively and quantitatively detect 5fC moieties in gamma-irradiated calf thymus DNA. Additionally, losing the exocyclic 4-amino group in 5fC causes the incorporation of dATP through base pairing with the generated nucleobase during polymerase extension, which helped us to analyze the 5fC sites in both single- and double-stranded oligonucleotides. Our Sanger and Illumina sequencing results show great potential in single-base resolution analysis of 5fC. It is hopeful that a similar design may be used for more detection targets. PMID- 29163897 TI - Preferential targeting of i-motifs and G-quadruplexes by small molecules. AB - i-Motifs and G-quadruplexes are dynamic nucleic acid secondary structures, which are believed to play key roles in gene expression. We herein report two peptidomimetic ligands (PBP1 and PBP2) that selectively target i-motifs and G quadruplexes over double-stranded DNA. These peptidomimetics, regioisomeric with respect to the position of triazole/prolinamide motifs, have been synthesized using a modular method involving Cu(i)-catalyzed azide and alkyne cycloaddition. The para-isomer, PBP1 exhibits high selectivity for i-motifs while the meta isomer PBP2 binds selectively to G-quadruplex structures. Interestingly, these ligands have the ability to induce G-quadruplex or i-motif structures from the unstructured single-stranded DNA conformations, as observed using single molecule Forster resonance energy transfer (smFRET) studies. The quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and dual-luciferase assays indicate that PBP1 upregulates and PBP2 downregulates BCL-2 gene expression in cancer cells. PMID- 29163898 TI - Self-quenched ferrocenyl diketopyrrolopyrrole organic nanoparticles with amplifying photothermal effect for cancer therapy. AB - Organic nanoparticles (NPs) with near-infrared absorbance possess high photothermal conversion (PTC) efficiency and an excellent photoacoustic signal, presenting a great prospect for photoacoustic imaging (PAI)-guided photothermal therapy (PTT). Herein, a novel diketopyrrolopyrrole derivative (DPPCN-Fc) is synthesized for use as a PTT agent with PAI performance. Due to photo-induced electron transfer (PET), the two flanked ferrocene moieties significantly quench the radiative decay and intersystem crossing process, resulting in an enhanced nonradiative transition, and an amplifying photothermal effect is observed. Exposing the DPPCN-Fc NP aqueous dispersion (100 MUg mL-1) to 730 nm (1.0 W cm-2) laser radiation results in a temperature elevation of 33.4 degrees C within 10 min and the PTC efficiency reaches up to 59.1%, which is higher than most reported photothermal therapeutic agents. Furthermore, under irradiation from 730 nm lasers, cancer cells could be completely killed in vivo due to the amplifying photothermal effects. Therefore, the as-prepared DPPCN-Fc NPs are a promising cancer theranostic agent for photoacoustic imaging-guided cancer photothermal therapy. PMID- 29163899 TI - Design, crystal structure and atomic force microscopy study of thioether ligated d,l-cyclic antimicrobial peptides against multidrug resistant Pseudomonas aeruginosa. AB - Here we report a new family of cyclic antimicrobial peptides (CAMPs) targeting MDR strains of Pseudomonas aeruginosa. These CAMPs are cyclized via a xylene double thioether bridge connecting two cysteines placed at the ends of a linear amphiphilic alternating d,l-sequence composed of lysines and tryptophans. Investigations by transmission electron microscopy (TEM), dynamic light scattering and atomic force microscopy (AFM) suggest that these peptide macrocycles interact with the membrane to form lipid-peptide aggregates. Amphiphilic conformations compatible with membrane disruption are observed in high resolution X-ray crystal structures of fucosylated derivatives in complex with lectin LecB. The potential for optimization is highlighted by N-methylation of backbone amides leading to derivatives with similar antimicrobial activity but lower hemolysis. PMID- 29163901 TI - Violations of Lowenstein's rule in zeolites. AB - Zeolites, microporous aluminosilicates, are amongst the most widely used catalysts in the petrochemical industry. Zeolite catalytic functionality is influenced by the location of tetrahedral alumina and associated counter-cations in the aluminosilicate framework, yet little is definitively known about the factors that govern the framework aluminium arrangement. It is generally accepted that all zeolites obey Lowenstein's rule of "aluminium avoidance", and that -Al-O Al- bond formation is forbidden. Here, we describe an unprecedented screening of aluminium distribution in catalytically active zeolite SSZ-13 (CHA) in both its protonated and sodium-containing forms, H-SSZ-13 and Na-SSZ-13, using density functional theory (DFT). We predict violations of Lowenstein's rule in high and low silica H-SSZ-13 and other protonated frameworks considered in this investigation: H-LTA, H-RHO, H-ABW and H-MOR. The synthetic realisation of these zeolites could spur the development of new catalytic routes and materials, and the optimisation of existing zeolite catalysts. PMID- 29163900 TI - Manganese complex-catalyzed oxidation and oxidative kinetic resolution of secondary alcohols by hydrogen peroxide. AB - The highly efficient catalytic oxidation and oxidative kinetic resolution (OKR) of secondary alcohols has been achieved using a synthetic manganese catalyst with low loading and hydrogen peroxide as an environmentally benign oxidant in the presence of a small amount of sulfuric acid as an additive. The product yields were high (up to 93%) for alcohol oxidation and the enantioselectivity was excellent (>90% ee) for the OKR of secondary alcohols. Mechanistic studies revealed that alcohol oxidation occurs via hydrogen atom (H-atom) abstraction from an alpha-CH bond of the alcohol substrate and a two-electron process by an electrophilic Mn-oxo species. Density functional theory calculations revealed the difference in reaction energy barriers for H-atom abstraction from the alpha-CH bonds of R- and S-enantiomers by a chiral high-valent manganese-oxo complex, supporting the experimental result from the OKR of secondary alcohols. PMID- 29163902 TI - Tertiary amine synthesis via reductive coupling of amides with Grignard reagents. AB - A new iridium catalyzed reductive coupling reaction of Grignard reagents and tertiary amides affording functionalised tertiary amine products via an efficient and technically-simple one-pot, two-stage experimental protocol, is reported. The reaction - which can be carried out on gram-scale using as little as 1 mol% Vaska's complex [IrCl(CO)(PPh3)2] and TMDS as the terminal reductant for the initial reductive activation step - tolerates a broad range of tertiary amides from (hetero)aromatic to aliphatic (branched, unbranched and formyl) and a wide variety of alkyl (linear, branched), vinyl, alkynyl and (hetero)aryl Grignard reagents. The new methodology has been applied directly to bioactive molecule synthesis and the high chemoselectivity of the reductive coupling of amide has been exploited in late stage functionalization of drug molecules. This reductive functionalisation of tertiary amides provides a new and practical solution to tertiary amine synthesis. PMID- 29163903 TI - Hydrogen generation from methanol at near-room temperature. AB - As a promising hydrogen storage medium methanol has many advantages such as a high hydrogen content (12.5 wt%) and low-cost. However, conventional methanol water reforming methods usually require a high temperature (>200 degrees C). In this research, we successfully designed an effective strategy to fully convert methanol to hydrogen for at least 1900 min (~32 h) at near-room temperature. The strategy involves two main procedures, which are CH3OH -> HCOOH -> H2 and CH3OH > NADH -> H2. HCOOH and the reduced form of nicotinamide adenine dinucleotide (NADH) are simultaneously produced through the dehydrogenation of methanol by the cooperation of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Subsequently, HCOOH is converted to H2 by a new iridium polymer complex catalyst and an enzyme mimic is used to convert NADH to H2 and nicotinamide adenine dinucleotide (NAD+). NAD+ can then be reconverted to NADH by repeating the dehydrogenation of methanol. This strategy and the catalysts invented in this research can also be applied to hydrogen production from other small organic molecules (e.g. ethanol) or biomass (e.g. glucose), and thus will have a high impact on hydrogen storage and applications. PMID- 29163904 TI - Protonation tuning of quantum interference in azulene-type single-molecule junctions. AB - The protonation of azulene derivatives with quantum interference effects is studied by the conductance measurements of single-molecule junctions. Three azulene derivatives with different connectivities are synthesized and reacted with trifluoroacetic acid to form the protonated states. It is found that the protonated azulene molecular junctions produce more than one order of magnitude higher conductance than the neutral states, while the molecules with destructive interference show more significant changes. These experimental observations are supported by our recently-developed parameter free theory of connectivity, which suggests that the largest conductance change occurs when destructive interference near the Fermi energy in the neutral state is alleviated by protonation. PMID- 29163905 TI - Laboratory-scale photoredox catalysis using hydrated electrons sustainably generated with a single green laser. AB - The ruthenium-tris-bipyridyl dication as catalyst combined with the ascorbate dianion as bioavailable sacrificial donor provides the first regenerative source of hydrated electrons for chemical syntheses on millimolar scales. This electron generator is operated simply by illumination with a frequency-doubled Nd:YAG laser (532 nm) running at its normal repetition rate. Much more detailed information than by product studies alone was obtained by photokinetical characterization from submicroseconds (time-resolved laser flash photolysis) up to one hour (preparative photolysis). The experiments on short timescales established a reaction mechanism more complex than previously thought, and proved the catalytic action by unchanged concentration traces of the key transients over a number of flashes so large that the accumulated electron total surpassed the catalyst concentration many times. Preparative photolyses revealed that the sacrificial donor greatly enhances the catalyst stability through quenching the initial metal-to-ligand charge-transfer state before destructive dd states can be populated from it, such that the efficiency of this electron generator is no longer limited by catalyst decomposition but by electron scavenging by the accumulating oxidation products of the ascorbate. Applications covered dechlorinations of selected aliphatic and aromatic chlorides and the reduction of a model ketone. All these substrates are impervious to photoredox catalysts exhibiting lower reducing power than the hydrated electron, but the combination of an extremely negative standard potential and a long unquenched life allowed turnover numbers up to 1400 with our method. PMID- 29163906 TI - Biosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity. AB - Griselimycins (GMs) are depsidecapeptides with superb anti-tuberculosis activity. They contain up to three (2S,4R)-4-methyl-prolines (4-MePro), of which one blocks oxidative degradation and increases metabolic stability in animal models. The natural congener with this substitution is only a minor component in fermentation cultures. We showed that this product can be significantly increased by feeding the reaction with 4-MePro and we investigated the molecular basis of 4-MePro biosynthesis and incorporation. We identified the GM biosynthetic gene cluster as encoding a nonribosomal peptide synthetase and a sub-operon for 4-MePro formation. Using heterologous expression, gene inactivation, and in vitro experiments, we showed that 4-MePro is generated by leucine hydroxylation, oxidation to an aldehyde, and ring closure with subsequent reduction. The crystal structures of the leucine hydroxylase GriE have been determined in complex with substrates and products, providing insight into the stereospecificity of the reaction. PMID- 29163907 TI - Nb2(c)Au6: a molecular wheel with a short Nb 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 Nb triple bond coordinated by an Au6 ring and reinforced by sigma aromaticity. AB - We report a photoelectron spectroscopy and high-resolution photoelectron imaging study of a bimetallic Nb2Au6- cluster. Theoretical calculations, in conjunction with the experimental data, reveal that Nb2Au6-/0 possess high-symmetry D6h structures featuring a Nb-Nb axis coordinated equatorially by an Au6 ring. Chemical bonding analyses show that there are two pi bonds and one sigma bond in the Nb2 moiety in Nb2(c)Au6, as well as five totally delocalized sigma bonds. The Nb 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 Nb triple bond is strengthened significantly by the delocalized sigma bonds, resulting in an extremely short Nb-Nb bond length comparable to the quintuple bond in gaseous Nb2. The totally delocalized sigma bonding in Nb2(c)Au6 is reminiscent of sigma aromaticity, representing a new bonding mode in metal-ligand systems. The unusually short Nb-Nb bond length in Nb2 PMID- 29163908 TI - Photosensitizer-free visible light-mediated gold-catalysed cis difunctionalization of silyl-substituted alkynes. AB - A new photosensitizer-free visible light-mediated gold-catalysed cis difunctionalization reaction is developed. The reaction was chemoselective towards silyl-substituted alkynes with excellent regioselectivity and good functional group compatibility, giving a series of silyl-substituted quinolizinium derivatives as products. The newly synthesized fluorescent quinolizinium compounds, named JR-Fluor-1, possessed tunable emission properties and large Stokes shifts. With unique photophysical properties, the fluorophores have been applied in photooxidative amidations as efficient photocatalysts and cellular imaging with switchable subcellular localization properties. PMID- 29163909 TI - Selective photocatalytic hydroxylation and epoxidation reactions by an iron complex using water as the oxygen source. AB - The iron complex [(bTAML)FeIII-OH2]- (1) selectively catalyses the photocatalytic hydroxylation and epoxidation reactions of alkanes and alkenes, respectively, using water as the oxygen-atom source. Upon the oxidation of unactivated alkanes, which included several substrates including natural products, hydroxylation was observed mostly at the 3 degrees C-H bonds with 3 degrees : 2 degrees selectivity up to ~100 : 1. When alkenes were used as the substrates, epoxides were predominantly formed with high yields. In the presence of H218O, more than 90% of the 18O-labelled oxygen atoms were incorporated into the hydroxylated and epoxide product indicating that water was the primary oxygen source. Mechanistic studies indicate the formation of an active [{(bTAML)FeIV}2-MU-oxo]2- (2) dimer from the starting complex 1via PCET. The subsequent disproportionation of 2 upon addition of substrate, leading to the formation of FeV(O), renders the high selectivity observed in these reactions. PMID- 29163910 TI - Cholesterol-directed nanoparticle assemblies based on single amino acid peptide mutations activate cellular uptake and decrease tumor volume. AB - Peptide drugs have been difficult to translate into effective therapies due to their low in vivo stability. Here, we report a strategy to develop peptide-based therapeutic nanoparticles by screening a peptide library differing by single-site amino acid mutations of lysine-modified cholesterol. Certain cholesterol-modified peptides are found to promote and stabilize peptide alpha-helix formation, resulting in selectively cell-permeable peptides. One cholesterol-modified peptide self-assembles into stable nanoparticles with considerable alpha-helix propensity stabilized by intermolecular van der Waals interactions between inter peptide cholesterol molecules, and shows 68.3% stability after incubation with serum for 16 h. The nanoparticles in turn interact with cell membrane cholesterols that are disproportionately present in cancer cell membranes, inducing lipid raft-mediated endocytosis and cancer cell death. Our results introduce a strategy to identify peptide nanoparticles that can effectively reduce tumor volumes when administered to in in vivo mice models. Our results also provide a simple platform for developing peptide-based anticancer drugs. PMID- 29163911 TI - Hyperfine adjustment of flexible pore-surface pockets enables smart recognition of gas size and quadrupole moment. AB - The pore size and framework flexibility of hosts are of vital importance for molecular recognition and related applications, but accurate control of these parameters is very challenging. We use the slight difference of metal ion size to achieve continuous hundredth-nanometer pore-size adjustments and drastic flexibility modulations in an ultramicroporous metal-organic framework, giving controllable N2 adsorption isotherm steps, unprecedented/reversed loading dependence of H2 adsorption enthalpy, quadrupole-moment sieving of C2H2/CO2, and an exceptionally high working capacity for C2H2 storage under practical conditions (98 times that of an empty cylinder). In situ single-crystal X-ray diffraction measurements and multilevel computational simulations revealed the importance of pore-surface pockets, which utilize their size and electrostatic potential to smartly recognize the molecular sizes and quadruple moments of gas molecules to control their accessibility to the strongest adsorption sites. PMID- 29163912 TI - Magnetically activated adhesives: towards on-demand magnetic triggering of selected polymerisation reactions. AB - On-demand initiation of chemical reactions is becoming increasingly popular in many areas. The use of a magnetic field to trigger reactions is an intriguing concept, with vast potential in both research and industrial settings, though it remains a challenge as yet unsolved. Here we report the first example of on demand magnetic activation of a polymerisation process using an anaerobic adhesive formulation as an example of this new approach toward triggering polymerisation reactions using an external magnetic field. Our strategy involves the use of a colloidal system comprising functional methacrylate ester monomers, peroxide and CuII-salt as polymerisation initiators and magnetic nanoparticles coated with an oxidising shell. This unique combination prevents reduction of the reactive transition metal (CuII) ion by the metal substrates (steel or aluminium) to be joined - hence inhibiting the redox radical initiated cationic polymerisation reaction and efficiently preventing adhesion. The polymerisation and corresponding adhesion process can be triggered by removal of the functional magnetic particles using a permanent external magnet either prior to formulation application or at the joint to be adhered, enabling the polymerisation to proceed through CuII-mediated reduction. This new approach enables on-demand magnetically triggered reaction initiation and holds potential for a range of useful applications in chemistry, materials science and relevant industrial manufacturing. PMID- 29163913 TI - Cross-linking Zr-based metal-organic polyhedra via postsynthetic polymerization. AB - Metal organic polyhedra (MOPs) have potential as supramolecular building blocks, but utilizing MOPs for postsynthetic polymerization has not been explored. Although MOPs with flexible organic moieties have been recently reported to target enhanced processability, permanent porosity has not been demonstrated. Here, a novel synthetic strategy involving the cross-linking of MOPs via a covalent bond is demonstrated by exploiting a condensation reaction between the MOP and flexible organic linkers. An amine-functionalized Zr-based MOP is cross linked with acyl chloride linkers in the crystalline state to form cross-linked MOPs. The condensation reaction results in a cross-linked system without significant changes to the structure of the Zr-based MOP. Such cross-linked MOPs provide a microporous tetrahedral cage based on gas sorption analysis. This cross linking strategy highlights the potential of MOPs as building blocks and provides access to a new class of porous material. PMID- 29163914 TI - Increase of enzyme activity through specific covalent modification with fragments. AB - Modulation of enzyme activity is a powerful means of probing cellular function and can be exploited for diverse applications. Here, we explore a method of enzyme activation where covalent tethering of a small molecule to an enzyme can increase catalytic activity (kcat/KM) up to 35-fold. Using a bacterial glycoside hydrolase, BtGH84, we demonstrate how small molecule "fragments", identified as activators in free solution, can be covalently tethered to the protein using Michael-addition chemistry. We show how tethering generates a constitutively activated enzyme-fragment conjugate, which displays both improved catalytic efficiency and increased susceptibility to certain inhibitor classes. Structure guided modifications of the tethered fragment demonstrate how specific interactions between the fragment and the enzyme influence the extent of activation. This work suggests that a similar approach may be used to modulate the activity of enzymes such as to improve catalytic efficiency or increase inhibitor susceptibility. PMID- 29163916 TI - A new face of phenalenyl-based radicals in the transition metal-free C-H arylation of heteroarenes at room temperature: trapping the radical initiator via C-C sigma-bond formation. AB - The radical-mediated transition metal-free approach for the direct C-H bond functionalization of arenes is considered as a cost effective alternative to transition metal-based catalysis. An organic ligand-based radical plays a key role by generating an aryl radical which undergoes a subsequent functionalization process. The design principle of the present study takes advantage of a relatively stable odd alternant hydrocarbon-based phenalenyl (PLY) radical. In this study, the first transition metal-free catalyzed direct C-H arylation of a variety of heteroarenes such as azoles, furan, thiophene and pyridine at room temperature has been reported using a phenalenyl-based radical without employing any photoactivation step. This protocol has been successfully applied to the gram scale synthesis of core moieties of bioactive molecules. The phenalenyl-based radical initiator has been characterized crystallographically by trapping it via the formation of a C-C sigma-bond between the phenalenyl radical and solvent based radical species. PMID- 29163915 TI - Field-deployable, quantitative, rapid identification of active Ebola virus infection in unprocessed blood. AB - The West African Ebola virus outbreak underlined the importance of delivering mass diagnostic capability outside the clinical or primary care setting in effectively containing public health emergencies caused by infectious disease. Yet, to date, there is no solution for reliably deploying at the point of need the gold standard diagnostic method, real time quantitative reverse transcription polymerase chain reaction (RT-qPCR), in a laboratory infrastructure-free manner. In this proof of principle work, we demonstrate direct performance of RT-qPCR on fresh blood using far-red fluorophores to resolve fluorogenic signal inhibition and controlled, rapid freeze/thawing to achieve viral genome extraction in a single reaction chamber assay. The resulting process is entirely free of manual or automated sample pre-processing, requires no microfluidics or magnetic/mechanical sample handling and thus utilizes low cost consumables. This enables a fast, laboratory infrastructure-free, minimal risk and simple standard operating procedure suited to frontline, field use. Developing this novel approach on recombinant bacteriophage and recombinant human immunodeficiency virus (HIV; Lentivirus), we demonstrate clinical utility in symptomatic EBOV patient screening using live, infectious Filoviruses and surrogate patient samples. Moreover, we evidence assay co-linearity independent of viral particle structure that may enable viral load quantification through pre-calibration, with no loss of specificity across an 8 log-linear maximum dynamic range. The resulting quantitative rapid identification (QuRapID) molecular diagnostic platform, openly accessible for assay development, meets the requirements of resource-limited countries and provides a fast response solution for mass public health screening against emerging biosecurity threats. PMID- 29163917 TI - 3D hole-transporting materials based on coplanar quinolizino acridine for highly efficient perovskite solar cells. AB - Over the past five years, perovskite solar cells (PSCs) have gained intense worldwide attention in the photovoltaic community due to their low cost and high power conversion efficiencies (PCEs). One of the most significant issues in achieving high PCEs of PSCs is the development of suitable low-cost hole transporting materials (HTMs). Here, we put forward a new concept of HTMs for PSCs: a 3D structure with a core of coplanar quinolizino acridine, derived from the conventional concept of 2D triphenylamine HTMs. A cheaper Ag nanolayer was utilized to replace Au as the counter electrodes, and the title HTM TDT-OMeTAD was synthesized via an easy four-step synthesis (total yield: 61%) to achieve the low cost and convenient manufacture of PSCs. Compared with the conventional 2D triphenylamine HTM, TTPA-OMeTPA, PSC devices based on the 3D HTM TDT-OMeTPA showed a significant improvement in PCE from 10.8% to 16.4%, even outperforming Spiro-OMeTAD (14.8%). TDT-OMeTAD's highest PCE mainly results from it having the highest open-circuit voltage (Voc) of 1.01 V in this work, which is proven to be due to the higher hole mobility, matching energy levels, higher hydrophobicity and the smaller dark current. Moreover, an incident photon-current conversion efficiency (IPCE) test and time-resolved photoluminescence (TRPL) have been carried out to observe the better hole injecting efficiency and photoelectric conversion capability of TDT-OMeTPA based PSCs than Spiro-OMeTAD. The TDT-OMeTPA based PSCs exhibited >75% reproducibility (PCE > 15%) and retained 93.2% of the initial PCE after >500 hours. PMID- 29163918 TI - Assembly of strongly phosphorescent hetero-bimetallic and -trimetallic [2]catenane structures based on a coinage metal alkynyl system. AB - Homo-metallic metal alkynyl complexes exhibit interesting catenane structures, but their hetero-metallic catenane counterparts are under-developed. In this work, we report rare examples of bimetallic Au-Cu (DtbpC 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 C- ligand; Dtbp = 3,5-di-tert-butylphenyl), Au-Ag ( t BuC 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 C- ligand), and Au-Cu, Au-Ag (C6-FluoC 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 C- ligand; C6-Fluo = 9,9-dihexyl-9H-fluoren-2-yl) complexes as well as a trimetallic Au-Ag Cu (C6-FluoC 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 C- ligand) complex, which feature [2]catenane structures. The formation of the [2]catenane structure is significantly affected by the coinage metal ion(s) and change of the structure of the alkynyl ligand. These hetero-metallic [2]catenane structures are strongly luminescent with tunable emission lambdamax from 503 to 595 nm and Phi values up to 0.83. PMID- 29163919 TI - Effects of vibrational excitation on the F + H2O -> HF + OH reaction: dissociative photodetachment of overtone-excited [F-H-OH]. AB - The reaction F + H2O -> HF + OH is a four-atom system that provides an important benchmark for reaction dynamics. Hydrogen atom transfer at the transition state for this reaction is expected to exhibit a strong dependence on reactant vibrational excitation. In the present study, the vibrational effects are examined by photodetachment of vibrationally excited F-(H2O) precursor anions using photoelectron-photofragment coincidence (PPC) spectroscopy and compared with full six-dimensional quantum dynamical calculations on ab initio potential energy surfaces. Prior to photodetachment at hnuUV = 4.80 eV, the overtone of the ionic hydrogen bond mode in the precursor F-(H2O), 2nuIHB at 2885 cm-1, was excited using a tunable IR laser. Experiment and theory show that vibrational energy in the anion can be effectively carried away by the photoelectron upon a Franck-Condon photodetachment, and also show evidence for an increase of branching into the F + H2O reactant channel. The experimental results suggest a greater role for product rotational excitation than theory. Improved potential energy surfaces and longer wavepacket propagation times would be helpful to further examine the nature of the discrepancy. PMID- 29163920 TI - Harnessing fungal nonribosomal cyclodepsipeptide synthetases for mechanistic insights and tailored engineering. AB - Nonribosomal peptide synthetases represent potential platforms for the design and engineering of structurally complex peptides. While previous focus has been centred mainly on bacterial systems, fungal synthetases assembling drugs like the antifungal echinocandins, the antibacterial cephalosporins or the anthelmintic cyclodepsipeptide (CDP) PF1022 await in-depth exploitation. As various mechanistic features of fungal CDP biosynthesis are only partly understood, effective engineering of NRPSs has been severely hampered. By combining protein truncation, in trans expression and combinatorial swapping, we assigned important functional segments of fungal CDP synthetases and assessed their in vivo biosynthetic capabilities. Hence, artificial assembly line components comprising of up to three different synthetases were generated. Using Aspergillus niger as a heterologous expression host, we obtained new-to-nature octa-enniatin (4 mg L-1) and octa-beauvericin (10.8 mg L-1), as well as high titers of the hybrid CDP hexa bassianolide (1.3 g L-1) with an engineered ring size. The hybrid compounds showed up to 12-fold enhanced antiparasitic activity against Leishmania donovani and Trypanosoma cruzi compared to the reference drugs miltefosine and benznidazole, respectively. Our findings thus contribute to a rational engineering of iterative nonribosomal assembly lines. PMID- 29163921 TI - The short device lifetimes of blue PhOLEDs: insights into the photostability of blue Ir(iii) complexes. AB - Using Ir(iii) complexes as dopants in phosphorescent organic light-emitting diodes (PhOLEDs) is the most successful strategy to attain long-lasting and highly-performant electroluminescent devices. Whilst highly efficient blue PhOLEDs are accessible, their limited operational lifetimes still restraint their practical use in lighting and displays. These short lifetimes are directly related to the low intrinsic photostability of blue Ir(iii) complexes. This work uses first principles to unveil the mechanisms of degradation of blue phosphors arising from energetically hot excited states (?6.0 eV), and to propose a strategy for improving the stability of blue phosphors. PMID- 29163922 TI - Bright and sensitive ratiometric fluorescent probe enabling endogenous FA imaging and mechanistic exploration of indirect oxidative damage due to FA in various living systems. AB - As a notorious toxin, formaldehyde (FA) poses an immense threat to human health. Aberrantly elevated FA levels lead to serious pathologies, including organ damage, neurodegeneration, and cancer. Unfortunately, current techniques limit FA imaging to general comparative studies, instead of a mechanistic exploration of its biological role, and this is presumably due to the lack of robust molecular tools for reporting FA in living systems. More importantly, despite being reductive, FA, however, can induce oxidative damage to organisms, thus providing a challenge to the mechanistic study of FA using fluorescence imaging. Herein, we presented the design and multi-application of a bright sensitive ratiometric fluorescent probe 1-(4-(1H-phenanthro[9,10-d]imidazol-2-yl)phenyl) but-3-en-1 amine (PIPBA). With a pi-extended phenylphenanthroimidazole fluorophore and an allylamine group, PIPBA exhibited high quantum yield (phi = 0.62) in blue fluorescent emission and selective reactivity toward FA. When sensing FA, PIPBA transformed to PIBE, which is a product capable of releasing bright green fluorescence (phi = 0.51) with its enhanced intramolecular charge transfer (ICT). Transformation of PIPBA to PIBE contributed to 80 nm of red shift in emission wavelength and a highly sensitive ratiometric response (92.2-fold), as well as a quite low detection limit (0.84 MUM). PIPBA was successfully applied to various living systems, realizing, for the first time, ratiometric quantification (in cells), in vivo imaging (zebrafish), and living tissue imaging (vivisectional mouse under anaesthetic) of endogenous FA that was spontaneously generated by biological systems. Furthermore, with the aid of PIPBA, we obtained visual evidence for the oxidative damage of FA in both HeLa cells and renal tissue of a living mouse. The results demonstrated that FA exerted indirect oxidative damage by interacting with free radicals, thus producing more oxidizing species, which eventually caused aggravated oxidative damage to the organism. The indirect oxidative damage due to FA could be alleviated by an exogenous or endogenous antioxidant. The excellent behaviors of PIPBA demonstrate that a chemical probe can detect endogenous FA in cells/tissue/vivo, promising to be an effective tool for further exploration of the biological mechanism of FA in living systems. PMID- 29163923 TI - Size and charge effect of guest cations in the formation of polyoxopalladates: a theoretical and experimental study. AB - The development of rational synthetic procedures with desired nuclearity and high selectivity is a critical issue in inorganic chemistry. Here we demonstrate a comprehensive understanding of the template effect induced by metal cations in the formation mechanism of the class of polyoxopalladates ({MPd12L8} nanocube and {MPd15L10} nanostar) by combining computational and experimental techniques. The capture of a M n+ guest ion by a peripheral palladium(ii)-oxo shell leads to a competition between the parent Pd2+ addenda ion and the respective guest metal ion. The present study reveals that (i) the selection of the incorporated guest ion has a thermodynamic control, (ii) the main factors governing the formation of a particular polyanion are the charge and size of the guest cation, (iii) the electrostatic interaction between the cation and the surrounding oxo ligands and (iv) the dehydration ability of the cation. As expected from the number of observed {M n+Pd12L8} species, trivalent cations M3+ were found to be good templates resulting in several examples of {M3+Pd12L8}, whereas monovalent cations M+ are much less prone to form {M+Pd12L8}. For tetravalent cations the dehydration energies are very large, however, the formation of {M4+Pd12L8} nanocubes is found to be still energetic favourable. Fully consistent with computational predictions, four novel polyoxo-12-palladates were synthesized: the La3+-centered nanocube [LaPd12O8(PhAsO3)8]5- (LaPd12-closed), the La3+-centered "open" nanocube [LaPd12O6(OH)3(PhAsO3)6(OAc)3]3- (LaPd12-open), the Ga3+-centered [GaPd12O8(PhAsO3)8]5- (GaPd12 ), and the In3+-analogue [InPd12O8(PhAsO3)8]5- (InPd12 ). All four compounds were fully characterized in the solid state and in solution by a multitude of physicochemical techniques, including 71Ga and 115In NMR as well as mass spectrometry. The experimentally observed selective incorporation of only In3+ ions in the presence of Ga3+ and In3+ confirmed the thermodynamic control of the formation mechanism, which we had predicted by theory. PMID- 29163924 TI - Synthesis of a terminal Ce(iv) oxo complex by photolysis of a Ce(iii) nitrate complex. AB - Reaction of [Ce(NR2)3] (R = SiMe3) with LiNO3 in THF, in the presence of 2,2,2 cryptand, results in the formation of the Ce(iii) "ate" complex, [Li(2,2,2 cryptand)][Ce(kappa2-O2NO)(NR2)3] (1) in 38% yield. Photolysis of 1 at 380 nm affords [Li(2,2,2-cryptand)][Ce(O)(NR2)3] (2), in 33% isolated yield after reaction work-up. Complex 2 is the first reported example of a Ce(iv) oxo complex where the oxo ligand is not supported by hydrogen bonding or alkali metal coordination. Also formed during photolysis are [Li(2,2,2-cryptand)]2[(MU3 O){Ce(MU-O)(NR2)2}3] (3) and [Li(2,2,2-cryptand)][Ce(OSiMe3)(NR2)3] (4). Their identities were confirmed by X-ray crystallography. Complex 4 can also be prepared via reaction of [Ce(NR2)3] with LiOSiMe3 in THF, in the presence of 2,2,2-cryptand. When synthesized in this fashion, 4 can be isolated in 47% yield. To rationalize the presence of 2, 3, and 4 in the reaction mixture, we propose that photolysis of 1 first generates 2 and NO2, via homolytic cleavage of the N-O bond in its nitrate co-ligand. Complex 2 then undergoes decomposition via two separate routes: (1) ligand scrambling and oligomerization to form 3; and, (2) abstraction of a trimethylsilyl cation to form a transient Ce(iv) silyloxide, [CeIV(OSiMe3)(NR2)3], followed by 1e- reduction to form 4. Alternatively, complex 4 could form directly via .SiMe3 abstraction by 2. PMID- 29163925 TI - Quantitative first principles calculations of protein circular dichroism in the near-ultraviolet. AB - Vibrational structure in the near-UV circular dichroism (CD) spectra of proteins is an important source of information on protein conformation and can be exploited to study structure and folding. A fully quantitative theory of the relationship between protein conformation and optical spectroscopy would facilitate deeper interpretation of and insight into biophysical and simulation studies of protein dynamics and folding. We have developed new models of the aromatic side chain chromophores toluene, p-cresol and 3-methylindole, which incorporate ab initio calculations of the Franck-Condon effect into first principles calculations of CD using an exciton approach. The near-UV CD spectra of 40 proteins are calculated with the new parameter set and the correlation between the computed and the experimental intensity from 270 to 290 nm is much improved. The contribution of individual chromophores to the CD spectra has been calculated for several mutants and in many cases helps rationalize changes in their experimental spectra. Considering conformational flexibility by using families of NMR structures leads to further improvements for some proteins and illustrates an informative level of sensitivity to side chain conformation. In several cases, the near-UV CD calculations can distinguish the native protein structure from a set of computer-generated misfolded decoy structures. PMID- 29163926 TI - Design of template-stabilized active and earth-abundant oxygen evolution catalysts in acid. AB - Oxygen evolution reaction (OER) catalysts that are earth-abundant and are active and stable in acid are unknown. Active catalysts derived from Co and Ni oxides dissolve at low pH, whereas acid stable systems such as Mn oxides (MnO x ) display poor OER activity. We now demonstrate a rational approach for the design of earth-abundant catalysts that are stable and active in acid by treating activity and stability as decoupled elements of mixed metal oxides. Manganese serves as a stabilizing structural element for catalytically active Co centers in CoMnO x films. In acidic solutions (pH 2.5), CoMnO x exhibits the OER activity of electrodeposited Co oxide (CoO x ) with a Tafel slope of 70-80 mV per decade while also retaining the long-term acid stability of MnO x films for OER at 0.1 mA cm-2. Driving OER at greater current densities in this system is not viable because at high anodic potentials, Mn oxides convert to and dissolve as permanganate. However, by exploiting the decoupled design of the catalyst, the stabilizing structural element may be optimized independently of the Co active sites. By screening potential-pH diagrams, we replaced Mn with Pb to prepare CoFePbO x films that maintained the high OER activity of CoO x at pH 2.5 while exhibiting long-term acid stability at higher current densities (at 1 mA cm-2 for over 50 h at pH 2.0). Under these acidic conditions, CoFePbO x exhibits OER activity that approaches noble metal oxides, thus establishing the viability of decoupling functionality in mixed metal catalysts for designing active, acid stable, and earth-abundant OER catalysts. PMID- 29163927 TI - Nickel-catalyzed asymmetric hydrogenation of beta-acylamino nitroolefins: an efficient approach to chiral amines. AB - An efficient approach for synthesizing chiral beta-amino nitroalkanes has been developed via the Ni-catalyzed asymmetric hydrogenation of challenging beta-amino nitroolefins under mild conditions, affording the desired products in excellent yields and with high enantioselectivities. This protocol had good compatibility with the wide substrate scope and a range of functional groups. The synthesis of chiral beta-amino nitroalkanes on a gram scale has also been achieved. In addition, the reaction mechanism was elucidated using a combined experimental and computational study, and it involved acetate-assisted heterolytic H2 cleavage followed by 1,4-hydride addition and protonation to achieve the nitroalkanes. PMID- 29163928 TI - Understanding single enzyme activity via the nano-impact technique. AB - To evaluate the possible detection of single enzyme activity via electrochemical methods, a combined finite difference and random walk simulation is used to model individual enzyme-electrode collisions where such events are monitored amperometrically via the measurement of products formed by the enzyme in solution. It is found that the observed signal is highly sensitive to both the enzyme turnover number, the size of the electrode and the bandwidth of the electronics. Taking single catalase impacts as an example, simulation results are compared with experimental data. Our work shows the requirement for the detection of electrochemically active product formed by individual enzymes and gives guidance for the design of experiments. PMID- 29163929 TI - Nickel-catalyzed transamidation of aliphatic amide derivatives. AB - Transamidation, or the conversion of one amide to another, is a long-standing challenge in organic synthesis. Although notable progress has been made in the transamidation of primary amides, the transamidation of secondary amides has remained underdeveloped, especially when considering aliphatic substrates. Herein, we report a two-step approach to achieve the transamidation of secondary aliphatic amides, which relies on non-precious metal catalysis. The method involves initial Boc-functionalization of secondary amide substrates to weaken the amide C-N bond. Subsequent treatment with a nickel catalyst, in the presence of an appropriate amine coupling partner, then delivers the net transamidated products. The transformation proceeds in synthetically useful yields across a range of substrates. A series of competition experiments delineate selectivity patterns that should influence future synthetic design. Moreover, the transamidation of Boc-activated secondary amide derivatives bearing epimerizable stereocenters underscores the mildness and synthetic utility of this methodology. This study provides the most general solution to the classic problem of secondary amide transamidation reported to date. PMID- 29152221 TI - PubRunner: A light-weight framework for updating text mining results. AB - Biomedical text mining promises to assist biologists in quickly navigating the combined knowledge in their domain. This would allow improved understanding of the complex interactions within biological systems and faster hypothesis generation. New biomedical research articles are published daily and text mining tools are only as good as the corpus from which they work. Many text mining tools are underused because their results are static and do not reflect the constantly expanding knowledge in the field. In order for biomedical text mining to become an indispensable tool used by researchers, this problem must be addressed. To this end, we present PubRunner, a framework for regularly running text mining tools on the latest publications. PubRunner is lightweight, simple to use, and can be integrated with an existing text mining tool. The workflow involves downloading the latest abstracts from PubMed, executing a user-defined tool, pushing the resulting data to a public FTP or Zenodo dataset, and publicizing the location of these results on the public PubRunner website. We illustrate the use of this tool by re-running the commonly used word2vec tool on the latest PubMed abstracts to generate up-to-date word vector representations for the biomedical domain. This shows a proof of concept that we hope will encourage text mining developers to build tools that truly will aid biologists in exploring the latest publications. PMID- 29163930 TI - Cobalt-catalysed reductive C-H alkylation of indoles using carboxylic acids and molecular hydrogen. AB - The direct CH-alkylation of indoles using carboxylic acids is presented for the first time. The catalytic system based on the combination of Co(acac)3 and 1,1,1 tris(diphenylphosphinomethyl)-ethane (Triphos, L1), in the presence of Al(OTf)3 as co-catalyst, is able to perform the reductive alkylation of 2-methyl-1H-indole with a wide range of carboxylic acids. The utility of the protocol was further demonstrated through the C3 alkylation of several substituted indole derivatives using acetic, phenylacetic or diphenylacetic acids. In addition, a careful selection of the reaction conditions allowed to perform the selective C3 alkenylation of some indole derivatives. Moreover, the alkenylation of C2 position of 3-methyl-1H-indole was also possible. Control experiments indicate that the aldehyde, in situ formed from the carboxylic acid hydrogenation, plays a central role in the overall process. This new protocol enables the direct functionalization of indoles with readily available and stable carboxylic acids using a non-precious metal based catalyst and hydrogen as reductant. PMID- 29152222 TI - Preprocessed Consortium for Neuropsychiatric Phenomics dataset. AB - Here we present preprocessed MRI data of 265 participants from the Consortium for Neuropsychiatric Phenomics (CNP) dataset. The preprocessed dataset includes minimally preprocessed data in the native, MNI and surface spaces accompanied with potential confound regressors, tissue probability masks, brain masks and transformations. In addition the preprocessed dataset includes unthresholded group level and single subject statistical maps from all tasks included in the original dataset. We hope that availability of this dataset will greatly accelerate research. PMID- 29163933 TI - A novel glomerular basement membrane segmentation using neutrsophic set and shearlet transform on microscopic images. AB - Purpose: Glomerular basement membrane segmentation is an ultimate step in several image processing applications for kidney diseases and abnormalities in microscopic images. However, extracting the glomerular basement membrane (GBM) regions accurately is considered challenging because of the large variants in the microscopic images. The contribution of this work is to propose a computer-aided detection system to provide accurate GBM segmentation. Methods: A novel GBM segmentation algorithm is developed based on neutrsophic set and shearlet transform. Firstly, the shearlet features are extracted from the microscopic image samples using shearlet transform. Afterward, the neutrosophic image is defined using shearlet features, and the indeterminacy on the neutrosophic image is reduced using an alpha-mean operation. Lastly, the k-means clustering algorithm is applied to segment the neutrsophic image and the GBM is identified using its intensity feature. Results: Three metrics, namely the average distance (AvgDist), the Hausdorff distance (Hdist), and percentage overlap area (POA); were employed to assess the proposed method performance. The results established that the proposed method achieved smaller distance errors and larger POAs. For the tested image, the average of AvgDist, HDist and POA are 1.99204, 4.59535 and 0.67857, respectively. The results established that the cases were segmented accurately using the proposed NS based shearlet transform. Conclusions: The new method utilizing the shearlet features and neutrosophic set improved the accuracy of GBM segmentation. Further study is underway to improve an automated CAD system using the refined segmentation results. PMID- 29163934 TI - Determinants of Integrated Management of Childhood Illness (IMCI) non-severe pneumonia classification and care in Malawi health facilities: Analysis of a national facility census. AB - Background: Research shows inadequate Integrated Management of Childhood Illness (IMCI)-pneumonia care in various low-income settings but evidence is largely from small-scale studies with limited evidence of patient-, provider- and facility levels determinants of IMCI non-severe pneumonia classification and its management. Methods: The Malawi Service Provision Assessment 2013-2014 included 3149 outpatients aged 2-59 months with completed observations, interviews and re examinations. Mixed-effects logistic regression models quantified the influence of patient-, provider and facility-level determinants on having IMCI non-severe pneumonia and its management in observed consultations. Findings: Among 3149 eligible outpatients, 590 (18.7%) had IMCI non-severe pneumonia classification in re-examination. 228 (38.7%) classified cases received first-line antibiotics and 159 (26.9%) received no antibiotics. 18.6% with cough or difficult breathing had 60-second respiratory rates counted during consultations, and conducting this assessment was significantly associated with IMCI training ever received (odds ratio (OR) = 2.37, 95% confidence interval (CI): 1.29-4.31) and negative rapid diagnostic test results (OR = 3.21, 95% CI: 1.45-7.13). Older children had lower odds of assessments than infants (OR = 48-59 months: 0.35, 95% CI: 0.16-0.75). Children presenting with any of the following complaints also had reduced odds of assessment: fever, diarrhea, skin problem or any danger sign. First-line antibiotic treatment for classified cases was significantly associated with high temperatures (OR = 3.26, 95% CI: 1.24-8.55) while older children had reduced odds of first-line treatment compared to infants (OR = 48-59 months: 0.29, 95% CI: 0.10-0.83). RDT-confirmed malaria was a significant predictor of no antibiotic receipt for IMCI non-severe pneumonia (OR = 10.65, 95% CI: 2.39-47.36). Conclusions: IMCI non-severe pneumonia care was sub-optimal in Malawi health facilities in 2013-2014 with inadequate assessments and prescribing practices that must be addressed to reduce this leading cause of mortality. Child's symptoms and age, malaria diagnosis and provider training were primary influences on assessment and treatment practices. Current evidence could be used to better target IMCI training and support to improve pneumonia care for sick children in Malawi facilities. PMID- 29163935 TI - The cost of diabetes in Latin America and the Caribbean in 2015: Evidence for decision and policy makers. AB - BACKGROUND: The financial implications of the increase in the prevalence of diabetes in middle-income countries represents one of the main challenges to health system financing and to the society as a whole. The objective of this study was to estimate the economic cost of diabetes in Latin America and the Caribbean (LAC) in 2015. METHODS: The study used a prevalence-based approach to estimate the direct and indirect costs related to diabetes in 29 LAC countries in 2015. Direct costs included health care expenditures such as medications (insulin and oral hypoglycemic agents), tests, consultations, hospitalizations, emergency visits and treating complications. Two different scenarios (S1 and S2) were used to analyze direct cost. S1 assumed conservative estimates while S2 assumed broader coverage of medication and services. Indirect costs included lost resources due to premature mortality, temporary and permanent disabilities. RESULTS: In 2015 over 41 million adults (20 years of age and more) were estimated to have Diabetes Mellitus in LAC. The total indirect cost attributed to Diabetes was US$ 57.1 billion, of which US$ 27.5 billion was due to premature mortality, US$16.2 billion to permanent disability, and US$ 13.3 billion to temporary disability. The total direct cost was estimated between US$ 45 and US$ 66 billion, of which the highest estimated cost was due to treatment of complications (US$ 1 616 to US$ 26 billion). Other estimates indicated the cost of insulin between US$ 6 and US$ 11 billion; oral medication US$ 4 to US$ 6 billion; consultations between US$ 5 and US$ 6 billion; hospitalization US$ 10 billion; emergency visits US$ 1 billion; test and laboratory exams between US$ 1 and US$ 3 million. The total cost of diabetes in 2015 in LAC was estimated to be between US$ 102 and US$ 123 billion. On average, the annual cost of treating one case of diabetes mellitus (DM) in LAC was estimated between US$ 1088 and US$ 1818. Per capita National Health Expenditures averaged US$ 1061 in LAC. CONCLUSIONS: Diabetes represented a major economic burden to the countries of Latin America and the Caribbean in 2015. The estimates presented here are key information for decision-making that can be used in the formulation of policies and programs to achieve greater efficiency and effectiveness in the use of resources for diabetes prevention in the 29 countries of LAC. PMID- 29163936 TI - Quality of antenatal care service provision in health facilities across sub Saharan Africa: Evidence from nationally representative health facility assessments. AB - Background: Utilization of antenatal care (ANC) services has increased over the past two decades. Continued gains in maternal and newborn health will require an understanding of both access and quality of ANC services. We linked health facility and household survey data to examine the quality of service provision for five ANC interventions across health facilities in sub-Saharan Africa. Methods: Using data from 20 nationally representative health facility assessments - the Service Provision Assessment (SPA) and the Service Availability and Readiness Assessment (SARA), we estimated facility level readiness to deliver five ANC interventions: tetanus toxoid vaccine for pregnant women, intermittent preventive treatment for malaria in pregnancy (IPTp), syphilis detection and treatment in pregnancy, iron supplementation and hypertensive disease case management. Facility level indicators were stratified by health facility type, managing authority and location, then linked to estimates of ANC utilization in that stratum from the corresponding Demographic and Health Surveys (DHS) to generate population level estimates of the 'likelihood of appropriate care'. Finally, the association between estimates of the 'likelihood of appropriate care' from the linking approach and estimates of coverage levels from the DHS were assessed. Findings: A total of 10 534 health facilities were surveyed in the 20 health facility assessments, of which 8742 reported offering ANC services and were included in the analysis. Health facility readiness to deliver IPTp, iron supplementation, and tetanus toxoid vaccination was higher (median: 84.1%, 84.9% and 82.8% respectively) than readiness to deliver hypertensive disease case management and syphilis detection and treatment (median: 23.0% and 19.9% respectively). Coverage of at least 4 ANC visits ranged from 24.8% to 75.8%. Estimates of the likelihood of appropriate care derived from linking health facility and household survey data showed marked gaps for all interventions, particularly hypertensive disease case management and syphilis detection and treatment. There was fairly good concordance between our estimates of high likelihood of appropriate care and DHS estimates of coverage for iron supplementation, IPTp, and tetanus toxoid vaccination. Conclusion: Linking household surveys to health facility assessments revealed marked gaps in population-level coverage of quality ANC interventions and underscored the need for a double-pronged approach to increase ANC utilization and improve the quality of ANC services. PMID- 29163937 TI - Development and validation of a simplified algorithm for neonatal gestational age assessment - protocol for the Alliance for Maternal Newborn Health Improvement (AMANHI) prospective cohort study. AB - Objective: The objective of the Alliance for Maternal and Newborn Health Improvement (AMANHI) gestational age study is to develop and validate a programmatically feasible and simple approach to accurately assess gestational age of babies after they are born. The study will provide accurate, population based rates of preterm birth in different settings and quantify the risks of neonatal mortality and morbidity by gestational age and birth weight in five South Asian and sub-Saharan African sites. Methods: This study used on-going population-based cohort studies to recruit pregnant women early in pregnancy (<20 weeks) for a dating ultrasound scan. Implementation is harmonised across sites in Ghana, Tanzania, Zambia, Bangladesh and Pakistan with uniform protocols and standard operating procedures. Women whose pregnancies are confirmed to be between 8 to 19 completed weeks of gestation are enrolled into the study. These women are followed up to collect socio-demographic and morbidity data during the pregnancy. When they deliver, trained research assistants visit women within 72 hours to assess the baby for gestational maturity. They assess for neuromuscular and physical characteristics selected from the Ballard and Dubowitz maturation assessment scales. They also measure newborn anthropometry and assess feeding maturity of the babies. Computer machine learning techniques will be used to identify the most parsimonious group of signs that correctly predict gestational age compared to the early ultrasound date (the gold standard). This gestational age will be used to categorize babies into term, late preterm and early preterm groups. Further, the ultrasound-based gestational age will be used to calculate population-based rates of preterm birth. Importance of the study: The AMANHI gestational age study will make substantial contribution to improve identification of preterm babies by frontline health workers in low- and middle- income countries using simple evaluations. The study will provide accurate preterm birth estimates. This new information will be crucial to planning and delivery of interventions for improving preterm birth outcomes, particularly in South Asia and sub-Saharan Africa. PMID- 29163939 TI - Infection prevention and control measures and tools for the prevention of entry of carbapenem-resistant Enterobacteriaceae into healthcare settings: guidance from the European Centre for Disease Prevention and Control. AB - Background: Infections with carbapenem-resistant Enterobacteriaceae (CRE) are increasingly being reported from patients in healthcare settings. They are associated with high patient morbidity, attributable mortality and hospital costs. Patients who are "at-risk" may be carriers of these multidrug-resistant Enterobacteriaceae (MDR-E).The purpose of this guidance is to raise awareness and identify the "at-risk" patient when admitted to a healthcare setting and to outline effective infection prevention and control measures to halt the entry and spread of CRE. Methods: The guidance was created by a group of experts who were functioning independently of their organisations, during two meetings hosted by the European Centre for Disease Prevention and Control. A list of epidemiological risk factors placing patients "at-risk" for carriage with CRE was created by the experts. The conclusions of a systematic review on the prevention of spread of CRE, with the addition of expert opinion, were used to construct lists of core and supplemental infection prevention and control measures to be implemented for "at-risk" patients upon admission to healthcare settings. Results: Individuals with the following profile are "at-risk" for carriage of CRE: a) a history of an overnight stay in a healthcare setting in the last 12 months, b) dialysis dependent or cancer chemotherapy in the last 12 months, c) known previous carriage of CRE in the last 12 months and d) epidemiological linkage to a known carrier of a CRE.Core infection prevention and control measures that should be considered for all patients in healthcare settings were compiled. Preliminary supplemental measures to be implemented for "at-risk" patients on admission are: pre-emptive isolation, active screening for CRE, and contact precautions. Patients who are confirmed positive for CRE will need additional supplemental measures. Conclusions: Strengthening the microbiological capacity, surveillance and reporting of new cases of CRE in healthcare settings and countries is necessary to monitor the epidemiological situation so that, if necessary, the implemented CRE prevention strategies can be refined in a timely manner. Creating a large communication network to exchange this information would be helpful to understand the extent of the CRE reservoir and to prevent infections in healthcare settings, by applying the principles outlined here.This guidance document offers suggestions for best practices, but is in no way prescriptive for all healthcare settings and all countries. Successful implementation will result if there is local commitment and accountability. The options for intervention can be adopted or adapted to local needs, depending on the availability of financial and structural resources. PMID- 29163938 TI - Understanding biological mechanisms underlying adverse birth outcomes in developing countries: protocol for a prospective cohort (AMANHI bio-banking) study. AB - Objectives: The AMANHI study aims to seek for biomarkers as predictors of important pregnancy-related outcomes, and establish a biobank in developing countries for future research as new methods and technologies become available. Methods: AMANHI is using harmonised protocols to enrol 3000 women in early pregnancies (8-19 weeks of gestation) for population-based follow-up in pregnancy up to 42 days postpartum in Bangladesh, Pakistan and Tanzania, with collection taking place between August 2014 and June 2016. Urine pregnancy tests will be used to confirm reported or suspected pregnancies for screening ultrasound by trained sonographers to accurately date the pregnancy. Trained study field workers will collect very detailed phenotypic and epidemiological data from the pregnant woman and her family at scheduled home visits during pregnancy (enrolment, 24-28 weeks, 32-36 weeks & 38+ weeks) and postpartum (days 0-6 or 42 60). Trained phlebotomists will collect maternal and umbilical blood samples, centrifuge and obtain aliquots of serum, plasma and the buffy coat for storage. They will also measure HbA1C and collect a dried spot sample of whole blood. Maternal urine samples will also be collected and stored, alongside placenta, umbilical cord tissue and membrane samples, which will both be frozen and prepared for histology examination. Maternal and newborn stool (for microbiota) as well as paternal and newborn saliva samples (for DNA extraction) will also be collected. All samples will be stored at -80 degrees C in the biobank in each of the three sites. These samples will be linked to numerous epidemiological and phenotypic data with unique study identification numbers. Importance of the study: AMANHI biobank proves that biobanking is feasible to implement in LMICs, but recognises that biobank creation is only the first step in addressing current global challenges. PMID- 29163940 TI - Sub-minimum inhibitory concentration of rifampin: a potential risk factor for resuscitation of Mycobacterium tuberculosis. AB - Background: Mycobacterium tuberculosis possesses five resuscitation-promoting factors, Rpf A to E, which are required for the resuscitation of dormancy in mycobacteria. This study explores the transcriptional profile of all five rpfs of M. tuberculosis, in response to sub-MIC concentration of rifampin, in multidrug and mono-rifampin resistant clinical isolates. Methods: Thirteen multidrug and two rifampin mono resistant clinical isolates were analyzed. Drug susceptibility testing and determination of MIC were performed. The relative expression of rpfs was measured, by real-time quantitative PCR. Results: A significant upregulation of relative expression (p < 0.05) was observed, as follows: 7/15(46.66%); 5/15(33.33%); 9/15(60%); 10/15(66.66%) and 9/15(60%) in rpfA, rpfB, rpfC, rpfD and rpfE, respectively. Conclusion: Our results showed that the rpfs could be overexpressed in some extent in the presence of sub-MIC concentration of rifampin in multidrug and mono drug resistant M. tuberculosis. These results highlight the potential risk of sub-MIC rifampin concentrations, as a risk factor for tuberculosis reactivation. PMID- 29163941 TI - Exploring the effects of a family admissions program for adolescents with anorexia nervosa. AB - Background: This study investigated patient experience in a Family Admissions Program (FAP) - a pilot treatment program for adolescents with Anorexia Nervosa at the Children's Hospital, Westmead. Based on Maudsley Family Based Treatment (FBT), the FAP involves an adolescent and his/her family undergoing a two-week family-based hospital admission at the outset of treatment. The program aims to increase intensity and support to a level needed by some families struggling to engage with or access FBT. Method: Narrative Inquiry and Interpretative Phenomenological Analysis were used as a dual methodological approach to explore the prospective expectations and retrospective experiences of participants partaking in the program. Results: Results indicated that in cases where the family unit has been particularly fractured as a result of the eating disorder, the FAP offers an opportunity for relational strengthening and reunification. Combined with the program's intensive support and proximity to hospital services, this serves to provide struggling families with enhanced skills and a stronger foundation for outpatient FBT. Conclusions: For families deemed at risk of unsuccessful outcomes with FBT, the FAP can be considered as an appropriate treatment adjunct to place alongside or before the commencement of FBT. PMID- 29163942 TI - Development of non-invasive ventilation treatment practice for patients with chronic obstructive pulmonary disease:Results from a participatory research project. AB - Objectives: Non-invasive ventilation treatment for patients with acute exacerbation of chronic obstructive pulmonary disease is well documented. Communication with patients during treatment is inhibited because of the mask, the noise from the machine and patient distress. Assessing life expectancy and identifying end-stage chronic obstructive pulmonary disease posed difficulties and caused doubts concerning initiation and continuation of non-invasive ventilation as life-sustaining treatment. Health professionals expressed a need for knowledge of patients' perspectives and attitude towards non-invasive ventilation. Methods: The study adheres to principles of Critical psychological practice research. Data on patients' and health professionals' perspectives were obtained from observations from the ward and semi-structured interviews with 16 patients. A group of health professionals was set up to form a co-researcher group. The co-researcher group described and analysed treatment practice at the department, drawing on research literature, results from observations and patients' interviews. Results: Interviews revealed that 15 patients evaluated treatment with non-invasive ventilation positively, although 13 had experienced fear and 14 discomfort during treatment. The co-researcher group described health professionals' perspectives and analysed treatment practice based on data from patients' perspectives developing new management strategies in clinical practice with non-invasive ventilation. Conclusion: The participatory approach enabled continuous and complementary development of knowledge and treatment practice. The investigation of patient perspectives was particularly productive in qualifying cooperation among health professionals. The study resulted in preparing, and implementing, new clinical strategies. PMID- 29163943 TI - Rehabilitation for patients with rheumatic diseases: Patient experiences of a structured goal planning and tailored follow-up programme. AB - Objective: To explore the significance of the content of rehabilitation in terms of achieving a personal outcome, and to understand the significance of tailored follow-up interventions for individual efforts to prolong health behaviour change after rehabilitation. Design: Semi-structured interviews with patients who had received an extended rehabilitation programme. All interviews were transcribed verbatim. A thematic analysis was applied. Subjects: A purposeful sample of 18 patients with rheumatic diseases who had attended specialized multidisciplinary rehabilitation with an extended programme consisting of a self-help booklet, structured goal-setting talks and tailored follow-up calls based on motivational interviewing. Results: Four overarching and interrelated themes were identified. Experienced Person-centred interventions represented a basis for the patients' motivation and personal outcomes. Confident self-management describes a new confident approach to exercise and illness management after rehabilitation with person-centred interventions. For many, this included reaching a different mindset, a change of illness perception. Continuity of the personal outcomes describes the importance of follow-up telephone calls to maintain the focus on goals and continued efforts. Building on established relationships and practising person-centred communication were essential. Conclusion: Tailoring of communication and rehabilitation interventions may be a premise for enhancing health behaviour, including a beneficial illness perception. Structured goal setting and follow-up telephone calls using motivational interviewing enhance motivation and may contribute to prolonged goal attainment. PMID- 29163944 TI - Pediatric sleep and autonomic complaints. AB - Objectives: Little is known about the relationship between autonomic dysfunction and sleep disturbances. This study aimed to identify patterns of sleep disturbances and autonomic dysfunction in children. Methods: A retrospective chart review of 14 children who underwent sleep and autonomic testing was performed. Subjects were divided into three groups based on sudomotor Composite Autonomic Severity Score Scale score and postural tachycardia syndrome criteria. Sleep quality, sleep architecture, and number of comorbidities were analyzed. Results: There were no statistically significant differences between groups in measures of sleep quality, sleep architecture, and number of comorbidities. Conclusion: Patients with postural tachycardia syndrome and autonomic dysfunction experience multiple sleep-related complaints. The low power of our study did not allow firm conclusions, but there is no pattern to these abnormalities. PMID- 29163945 TI - Pregnancy associated death in record linkage studies relative to delivery, termination of pregnancy, and natural losses: A systematic review with a narrative synthesis and meta-analysis. AB - Objectives: Measures of pregnancy associated deaths provide important guidance for public health initiatives. Record linkage studies have significantly improved identification of deaths associated with childbirth but relatively few have also examined deaths associated with pregnancy loss even though higher rates of maternal death have been associated with the latter. Following PRISMA guidelines we undertook a systematic review of record linkage studies examining the relative mortality risks associated with pregnancy loss to develop a narrative synthesis, a meta-analysis, and to identify research opportunities. Methods: MEDLINE and SCOPUS were searched in July 2015 using combinations of: mortality, maternal death, record linkage, linked records, pregnancy associated mortality, and pregnancy associated death to identify papers using linkage of death certificates to independent records identifying pregnancy outcomes. Additional studies were identified by examining all citations for relevant studies. Results: Of 989 studies, 11 studies from three countries reported mortality rates associated with termination of pregnancy, miscarriage or failed pregnancy. Within a year of their pregnancy outcomes, women experiencing a pregnancy loss are over twice as likely to die compared to women giving birth. The heightened risk is apparent within 180 days and remains elevated for many years. There is a dose effect, with exposure to each pregnancy loss associated with increasing risk of death. Higher rates of death from suicide, accidents, homicide and some natural causes, such as circulatory diseases, may be from elevated stress and risk taking behaviors. Conclusions: Both miscarriage and termination of pregnancy are markers for reduced life expectancy. This association should inform research and new public health initiatives including screening and interventions for patients exhibiting known risk factors. PMID- 29163946 TI - Vertebral body segmentation with GrowCut: Initial experience, workflow and practical application. AB - Objectives: Spinal diseases are very common; for example, the risk of osteoporotic fracture is 40% for White women and 13% for White men in the United States during their lifetime. Hence, the total number of surgical spinal treatments is on the rise with the aging population, and accurate diagnosis is of great importance to avoid complications and a reappearance of the symptoms. Imaging and analysis of a vertebral column is an exhausting task that can lead to wrong interpretations. The overall goal of this contribution is to study a cellular automata-based approach for the segmentation of vertebral bodies between the compacta and surrounding structures yielding to time savings and reducing interpretation errors. Methods: To obtain the ground truth, T2-weighted magnetic resonance imaging acquisitions of the spine were segmented in a slice-by-slice procedure by several neurosurgeons. Subsequently, the same vertebral bodies have been segmented by a physician using the cellular automata approach GrowCut. Results: Manual and GrowCut segmentations have been evaluated against each other via the Dice Score and the Hausdorff distance resulting in 82.99% +/- 5.03% and 18.91 +/- 7.2 voxel, respectively. Moreover, the times have been determined during the slice-by-slice and the GrowCut course of actions, indicating a significantly reduced segmentation time (5.77 +/- 0.73 min) of the algorithmic approach. Conclusion: In this contribution, we used the GrowCut segmentation algorithm publicly available in three-dimensional Slicer for three-dimensional segmentation of vertebral bodies. To the best of our knowledge, this is the first time that the GrowCut method has been studied for the usage of vertebral body segmentation. In brief, we found that the GrowCut segmentation times were consistently less than the manual segmentation times. Hence, GrowCut provides an alternative to a manual slice-by-slice segmentation process. PMID- 29163947 TI - Mechanical diagnosis and therapy enhances attitude toward self-management in people with musculoskeletal disorders: A preliminary evidence with a before-after design. AB - Objectives: Mechanical diagnosis and therapy is one of the most common approaches for the management of low back pain. In mechanical diagnosis and therapy, a great emphasis is placed on patient education so that patients can manage their problems by themselves. However, there has been no evidence that mechanical diagnosis and therapy actually enhances patient's self-management skills. This study aimed to preliminarily investigate whether self-reported skills of self management for musculoskeletal problems are enhanced through the course of mechanical diagnosis and therapy. Method: Outpatients with musculoskeletal disorders in a local orthopedic clinic were included. The primary outcome measures were the "Self-monitoring and Insight" and "Skill and Technique Acquisition" scores of the Health Education Impact Questionnaire, where higher scores indicate greater self-management skills. Mechanical diagnosis and therapy was undertaken up to a maximum of twice per week for 1 month. The Self-monitoring and Insight and Skill and Technique Acquisition scores before and 1 month after the mechanical diagnosis and therapy interventions were compared. Proportions of patients who exceed the threshold for "reliable change" in the Health Education Impact Questionnaire scores (% >positive "reliable change") and proportions of patients with the net positive "reliable change" (% net positive "reliable change") were investigated. Results: Forty-five patients participated and 97.8% completed the 1-month follow-up. The Self-monitoring and Insight and Skill and Technique Acquisition scores significantly increased at the follow-up (Self monitoring and Insight, p = 0.002; Skill and Technique Acquisition, p < 0.001. The % >positive "reliable change" (Self-monitoring and Insight = 22.2%, Skill and Technique Acquisition = 48.9%) and % net positive "reliable change" (Self monitoring and Insight = 13.3%, Skill and Technique Acquisition = 46.7%) in this study were comparative to or greater than self-management programs in previous studies (%> positive "reliable change': Self-monitoring and Insight = 20.5%, Skill and Technique Acquisition = 30.7%; % net positive "reliable change": Self monitoring and Insight = 14.1%, Skill and Technique Acquisition = 23.0%). Conclusion: This study provides a preliminary evidence that mechanical diagnosis and therapy enhances patient's self-management skills, particularly in the self monitoring skills for symptoms/functions and the self-management skill for symptoms/problems. PMID- 29163948 TI - The heart matters in diabetes: 10-Year outcomes of peripheral artery disease. AB - Objectives: Mortality rates at 10 years are higher in diabetic patients with chronic lower extremity peripheral arterial disease than in non-diabetic peripheral arterial disease patients. We tested the hypothesis that the predictors of mortality differ between diabetic and non-diabetic peripheral arterial disease patients. Methods: We studied 331 consecutive patients who were <75 years of age, symptomatic for peripheral arterial disease, and admitted to a tertiary care hospital. Our cohort included 216 patients without diabetes mellitus and 115 with diabetes mellitus. The outcome measure was all-cause mortality at 10 years post-admission. Results: Mortality rates at 10 years were 29% among non-diabetic peripheral arterial disease patients and 58% among diabetic peripheral arterial disease patients. We identified the following independent predictors of death in the 216 peripheral arterial disease patients without diabetes: age >=65 years (risk ratio: 2.15; 95% confidence interval: 1.28 3.59), ankle brachial index <0.60 mmHg/mmHg (risk ratio: 1.88; 95% confidence interval: 1.14-3.08), history of peripheral arterial disease-specific intervention (risk ratio: 1.81; 95% confidence interval: 1.10-2.97), and high sensitivity C-reactive protein >=5.0 mg/L (risk ratio: 2.11; 95% confidence interval: 1.28-3.47). For the 115 peripheral arterial disease patients with diabetes, independent predictors of mortality were as follows: age >=65 years (risk ratio: 1.72; 95% confidence interval: 1.05-2.83) and amino-terminal pro-B type natriuretic peptide >=125 ng/L (risk ratio: 2.10; 95% confidence interval: 1.22-3.60). Conclusion: In this study, the predictors of death at 10 years differed between peripheral arterial disease patients with and without diabetes. Among the biomarkers tested, high-sensitivity C-reactive protein was independently associated with outcomes in non-diabetic patients, whereas amino terminal pro-B-type natriuretic peptide was an independent predictor of death in patients with diabetes. Our findings suggest that in future studies, risk assessment and treatment strategies should be differentially applied to the two peripheral arterial disease subgroups. PMID- 29163949 TI - Health benefits of Quran memorization for older men. AB - Objective: To examine the association between Quran memorization and health among older men. Methods: This cross-sectional study included older Saudi men (age >= 55 years) from Buraidah, Al-Qassim. The neighborhoods were selected randomly (20 out of 96); eligible men from the mosques were recruited. Demographics, lifestyle, and depression were assessed with standardized questionnaires; height, weight, blood pressure, and random blood glucose (glucometer) were measured with standard protocol. Results: The mean and standard deviation for age, body mass index, and Quran memorization were 63 years (7.5), 28.9 kg/m2 (4.8), and 4.3 sections (6.9). Prevalence of hypertension, diabetes, and depression were 71%, 29%, and 22%, respectively. Those who memorized at least 10 sections of Quran were 64%, 71%, and 81% less likely to have hypertension, diabetes, and depression compared to those who memorized less than 0.5 sections, after controlling for covariates. Conclusion: There was a strong linear association between Quran memorization and hypertension, diabetes, and depression indicating that those who had memorized a larger portion of the Quran were less likely to have one of these chronic diseases. Future studies should explore the potential health benefits of Quran memorization and the underlying mechanisms. PMID- 29163950 TI - A retrospective epidemiologic study to define risk factors, microbiology, and clinical outcomes of infective endocarditis in a large tertiary-care teaching hospital. AB - Objective: This study aims to define risk factors as well as their association with microbiology and clinical outcomes in a large US infective endocarditis population. Methods: Hospital records were searched for appropriate infective endocarditis-related ICD codes from 16 July 2007 to 13 August 2015. A total of 363 cases were retrospectively identified that met definite Modified Duke Criteria for infective endocarditis and were analyzed by age group, causative organism, and associated risk factors for use of valvular surgical intervention, 30/90/180-day mortality after admission, and embolic phenomena. Results: Chronic hemodialysis was the most common risk factor (26.7% of cases). Of all age groups, those aged 78+ years had the lowest 30-day mortality but those aged 58-77 years had the highest mortality (p = 0.039). Staphylococcus aureus was the most prevalent causative organism. Those aged 78-97 years were more likely to have enterococcal infective endocarditis than those aged 18-27 years (p = 0.0144). Chronic hemodialysis associated infective endocarditis was more likely to be caused by coagulase-negative staphylococcus (p = 0.0121) and have a higher 30-day mortality (p = 0.141) than intravenous drug use associated infective endocarditis. Intravenous drug use and chronic hemodialysis were similarly likely to be caused by S. aureus. Intravenous drug use associated infective endocarditis was more likely to be caused by viridans group streptococci (p = 0.0001). Fungal infective endocarditis was most likely to embolize. Chronic hemodialysis patients were less likely to undergo valvular surgery (p = 0.001) and those with chronic hemodialysis who did had lower mortality than those only managed medically that did not reach statistical significance (p = 0.2991). Infective endocarditis caused by coagulase-negative staphylococci had the greatest 30-day mortality at 31.3% but did not reach statistical significance over all other causative organisms (p = 0.060). Conclusion: In our infective endocarditis population, S. aureus is the predominant causative organism. Chronic hemodialysis is the most common risk factor present in infective endocarditis populations and has greater association with coagulase-negative staphylococci and 30-day mortality. Intravenous drug use had the lowest mortality among risk factors with a similar proportion of S. aureus infective endocarditis compared to chronic hemodialysis but a higher proportion of viridans group streptococci infective endocarditis cases. Further study will need to be performed on prevention and treatment of infective endocarditis in chronic hemodialysis patients. PMID- 29163951 TI - Coronary artery anomalies: Unusually high incidence of anomalies with a malignant course in an Asian population. AB - Objectives: Coronary artery anomalies are uncommon, but important cardiac malformations, representing the second commonest cause of death in young athletes. Methods: We utilized computerized tomographic angiography to screen and precisely delineate coronary artery anomalies in patients with minimal cardiac symptoms. Results: During 3.5-year period, we performed 2888 computerized tomographic angiographies. A total of 33 (1.1%; 95% confidence interval = 0.7 1.5) cases of coronary artery anomalies were identified (mean age = 44 +/- 13.5 (15-70) years). In total, 23 patients (mean age = 43 years) had malignant coronary artery anomalies with an inter-arterial course of the aberrant vessel: of which 3 had left main coronary artery arising from right coronary sinus and 20 right coronary artery from left sinus; 19 patients were of Asian and 14 were of Arab origins. Of interest, 21 out of 33 patients had chest pain, 5 had palpitations, and 2 had breathlessness. There were no examples of sudden cardiac death. All patients received appropriate advice regarding physical exertion and medical management, and remained well for 2-5 years of follow-up. Of 33 patients, 4 had significant symptomatic coronary artery disease requiring intervention: 1 percutaneous coronary intervention and 3 coronary artery bypass graft surgery. Conclusion: There is a relatively high incidence of coronary artery anomalies with malignant course in Asians. The vast majority were managed conservatively. PMID- 29163952 TI - In-office arthroscopy for the evaluation of chronic knee pain: A case report. AB - This is a case report detailing the use of in-office needle arthroscopy (mi-eye 2TM) in a patient with chronic knee pain and inconclusive magnetic resonance imaging findings. The patient is a 40-year-old male who presented to our clinic after an extended history of right knee pain along the medial aspect with previous failed treatments. Magnetic resonance imaging without contrast had demonstrated full-thickness chondral fissuring of the lateral patellar facet, mild abnormal signals of the proximal patellar tendon and Hoffa's fat pad, and intact anterior cruciate ligament and posterior cruciate ligament. The patient was previously treated with an ultrasound-guided injection of 2 cm3 of 1% lidocaine without epinephrine and 1 cm3 of Kenalog-40 and scheduled for follow up. At follow-up, clinical examination showed antalgic gait, minimal tenderness along medial joint line, medial pain in deep flexion, and no pain when in varus or valgus. Due to continued discomfort with a negative magnetic resonance imaging, in-office diagnostic arthroscopy was performed using mi-eye 2 revealing a tear of the mid-body of the medial meniscus. The patient subsequently underwent arthroscopic repair and is recovering well with complete resolution of medial joint pain. This report highlights the clinical utility of in-office diagnostic arthroscopy in the management of patients with persistent knee pain and negative or equivocal findings on magnetic resonance imaging. PMID- 29163953 TI - Hypokalemia: A potentially life-threatening complication of tenofovir therapy. AB - Tenofovir is a nucleotide analog reverse transcriptase inhibitor approved for the treatment of HIV and hepatitis B infections. It is widely prescribed and an integral part of the recommended regimens for the treatment of HIV infection in antiretroviral-naive patients. Tenofovir is implicated in renal proximal tubular dysfunction, which can be associated with Fanconi syndrome and hypokalemia. When the hypokalemia is severe, it can lead to life-threatening complications. We describe the case of a 59-year-old woman who suffered a cardiac arrest secondary to severe hypokalemia from tenofovir use. PMID- 29163954 TI - Successful management of life-threatening bleeding of intraductal papillary mucinous neoplasms in the pancreatic head. AB - Complications associated with intraductal papillary mucinous neoplasms, such as acute pancreatitis, perforation, and fistula formation, have been documented. Intraductal papillary mucinous neoplasm with intratumoral hemorrhage is rare. To the best of our knowledge, there have been no previous reports of intraductal papillary mucinous neoplasm rupture and bleeding with intra-abdominal hemorrhage. A 74-year-old woman complained of acute upper right abdominal pain. She was under follow-up for an intraductal papillary mucinous neoplasm in the pancreatic head. Contrast-enhanced computed tomography revealed intraductal papillary mucinous neoplasm rupture and bleeding with intra-abdominal hemorrhage. The bleeding was treated with selective endovascular embolization of a branch of the gastroduodenal artery. Follow-up examinations are recommended even for intraductal papillary mucinous neoplasm patients without malignant findings because of the potential risk of rupture and bleeding with intra-abdominal hemorrhage. Clinicians should be aware of this possibility to ensure that patients are appropriately treated. PMID- 29163955 TI - Extra-osseous 99mTc methylene diphosphonate uptake detected enlargement of the knee joint in patient with polyarthritis. AB - Bone scintigraphy is a nuclear scanning test used to find abnormalities in the skeleton. Certain abnormal processes involving soft tissues can also cause skeletal accumulation of radiotracer during bone scintigraphy. We present a case of periarticular knee soft tissue 99mTc methylene diphosphonate uptake in a patient with asymmetric polyarthritis. A 33-year-old patient with asymmetric polyarthritis, skin lesions and joint pain underwent bone scintigraphy. Total body examination showed an extra-osseous uptake in periarticular soft tissue of knees joints. A detailed history checkup, physical examination and laboratory tests were carried out to understand the link between the extra-osseous uptake and the phosphonate binding in periarticular soft tissue. To improve the anatomical description of the soft tissue of the knees and to clarify the nature of the extra-skeletal 99mTc methylene diphosphonate uptake, magnetic resonance imaging scan was performed. 99mTc-labeled phosphonate binding has been reported in a number of extra-osseous conditions, but to our knowledge, there are a few cases showing bone tracer uptake in polyarthritis. In polyarthritic patients, whole-body bone scintigraphy were useful in examining the whole joints and detecting possible dubious extra-osseous uptake; in fact, it is able to select subjects who require further in-depth analysis, for example, magnetic resonance imaging. PMID- 29163956 TI - Eversion endarterectomy under full prasugrel treatment. AB - The third-generation thienopyridine prasugrel has much stronger antiplatelet effect compared to other current antiplatelet inhibitors and exhibits practically zero resistance in healthy people. Prasugrel is used as a pre- and post-treatment in percutaneous coronary or neurovascular interventions with parallel aspirin regime. However, as there is a higher reported bleeding with intraluminal interventions and meticulous technique is recommended, there is nearly non existent international experience of open surgery under full prasugrel treatment. We present, herein, a case of open carotid endarterectomy with the eversion technique in an asymptomatic patient with carotid stenosis, who was receiving dual antiplatelet therapy with aspirin and prasugrel, due to a previous insertion of two newer drug-eluting stents at the left anterior descending artery and the right coronary artery. The resistance test to prasugrel showed complete inhibition of platelet function. Open surgery was performed under continuation of prasugrel treatment and interruption of aspirin for 3 days before surgery. No perioperative and postoperative neurologic or cardiologic event occurred. No bleeding at the cervical or cerebral area was noted. PMID- 29163957 TI - New therapeutic options provided by off-label deployment of stent graft for tailored arteriovenous access salvage: Two cases. AB - A tailored therapy to patient requirements by combining endovascular and surgical steps can be necessary to prolong the life of a vascular access. Stent grafts play a growing role for the therapy of dialytic access complications. Randomized multi-center trials, however, support the on-label use of stent grafts in the treatment of graft venous outflow and in-stent restenosis. The main contraindication to their use is an ongoing infection. We report two cases of new off-label application of Viabahn (Gore, flagstaff, USA) stent graft. In the first case, the failure of a radiocephalic early cannulation graft was treated by stent graft placement on the arterial inflow anastomosis, when emergent angiographic examination revealed the previously unknown high takeoff of the radial artery from the axillary artery. At 13-month follow-up, the target lesion remained untreated. In the second case, elbow stent graft occlusion with extended thrombosis occurred in a right radiocephalic fistula after 3 years of unassisted patency. Being the last option for vascular access, successful endovascular recanalization was carried out. After 3 months, however, the clinical setting relapsed. A two-stage hybrid strategy with vascular surgeon was arranged due to ongoing signs of local infection. Flow was restored by emergent thromboaspiration associated with a new stent graft placement as a endovascular bridge to subsequent surgical treatment. After 2 days, the overlapped stent grafts were excised as planned. Surgical rerouting was completed by polytetrafluoroethylene prosthetic bridge implantation across the elbow. At 4 months, the follow-up remained uneventful. In selected instances, the off-label use of stent grafts may expand the therapeutic options of the vascular access team. PMID- 29163958 TI - Systematic review and meta-analysis: Sodium picosulphate with magnesium citrate as bowel preparation for colonoscopy. AB - Background: An effective and tolerable bowel preparation is important to secure quality of colonoscopies. It remains unclear if sodium picosulphate with magnesium citrate (SPMC), which is considered a tolerable bowel preparation agent, is also an effective alternative for polyethylene glycol (PEG) and sodium phosphate (NaP). Aim: The aim of this article is to compare effectiveness of SPMC to PEG and NaP through assessment of quality of bowel cleansing measured by validated tools. Methods: We searched electronic databases up to January 2015. Only randomised controlled trials (RCTs) were included. Two authors independently performed selection of studies, risk of bias assessment and data extraction. Results: Thirteen RCTs were included, with overall good quality, but large heterogeneity. SPMC had slightly better quality of bowel cleansing than PEG (pooled RR 1.06; 95% CI 1.02 to 1.11). In most trials SPMC was significantly better tolerated than PEG. There were no significant differences in effectiveness or tolerability between SPMC and NaP. Side effects were similar between agents, except for dizziness (pooled RR 1.71; 95% CI 1.32 to 2.21 in favour of PEG vs. SPMC) and vomiting (pooled RR 0.35; 95% CI 0.13 to 0.95 in favour of single-dose SPMC vs. split-dose). Conclusions: SPMC is equally effective to NaP and little superior to PEG in terms of bowel cleansing. SPMC preparations were better tolerated than PEG preparations. SPMC may be considered as standard bowel preparation for colonoscopy. PMID- 29163959 TI - The gut microbiota: A new potential driving force in liver cirrhosis and hepatocellular carcinoma. AB - The gut microbiota has recently been recognized as a major environmental factor in the pathophysiology of many human diseases. The anatomical and function connection existing between gut and liver provides the theoretical basis to assume the liver is a major target for gut microbes. In the last decades, numerous studies reported an altered composition of gut microbiota in patients with liver cirrhosis and a progressively marked dysbiosis with worsening of the liver disease. The risk of developing hepatocellular carcinoma, the deadliest complication of liver cirrhosis, is widely variable among cirrhotic patients, thus suggesting a complexity of genetic and environmental factors implicated in hepatocarcinogenesis. Gut microbiota is now emerging as a plausible candidate to explain this variability. In this manuscript we review the human and the experimental evidence supporting the potential implication of gut microbiota in the promotion, progression and complication of liver disease. PMID- 29163960 TI - When to let the fellow do the procedure. AB - Background and aims: In complex endoscopies, the initial attempt is often associated with the highest success and subsequent attempts to achieve the same outcome have a higher failure rate. An attending physician needs to decide how the ultimate success may become compromised by letting a fellow start the procedure. A decision analysis is aimed to shed light on this issue. Methods: A formula is derived to calculate the point in time when to switch the instrument between an attending and fellow physician. This time point is determined by the ratio of benefit to the patient over benefit to the fellow, the difference in probability of achieving success by an attending versus a fellow, and the decline in probability of success during consecutive procedural attempts. Results: The attending should undertake the first attempts at doing the procedure, if the fellow is inexperienced and the difference in success rate between attending and fellow is still large, if the procedure is risky, and if the benefit of a successful outcome outweighs the benefit of a teaching experience to the fellow. Vice versa, fellows should take the lead, if they have become well trained and the difference in their procedural success rate compared with the attendings' has grown relatively small. The fellow should also be trusted to lead in all instances where the risk to the patient is small. Conclusions: Such rules can serve as general guidance when to pass the endoscope to a fellow physician. Medical decision analysis is helpful to enlighten complex situations during training of fellows. PMID- 29163961 TI - The risk of Clostridium difficile infection in patients with pernicious anaemia: a retrospective cohort study using primary care database. AB - Background: Studies have found an association between proton pump inhibitor (PPI) use and Clostridium difficile infection. The purpose of this study was to determine whether the mechanism by which PPIs induce an increased risk of C. difficile infection is supported by the same mechanism acting in another cause of achlorhydria, pernicious anaemia. Methods: Using a database of anonymised primary care records between 1990 and 2013, we selected exposed patients with a diagnosis of pernicious anaemia treated with vitamin B12 therapy. Each exposed patient was matched by age, gender and general practice to up to 10 controls. Cox regression analysis was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for C. difficile infection with pernicious anaemia, adjusted for potential confounders. Results: We identified 45,467 exposed patients matched to 449,635 controls. The crude incidence rate of C. difficile infection was 1.85/1000 person years for the exposed cohort and 1.09/1000 person-years for controls. Patients with pernicious anaemia had a greater risk of C. difficile infection than the controls (adjusted HR 1.57, 95% CI 1.40-1.76). Conclusions: Pernicious anaemia patients have an increased risk of C. difficile infection. This supports the theory that severe achlorhydria is the mechanism that increases the risk of C. difficile infection in long-term PPI users. PMID- 29163962 TI - Chronic anemia due to gastrointestinal bleeding: when do gastroenterologists transfuse? AB - Background: The hypothesis is that decision-making for transfusion varies considerably among gastroenterologists. The aim is to identify preferences and predictors of transfusion decision-making in chronic anemia. Study design and methods: Between February and April of 2015, a computerized adaptive choice-based conjoint survey was administered to gastroenterologists in the Netherlands. The survey included seven patient attributes: hemoglobin levels, hemoglobin stability, age, iron indices, the presence of anemia-related symptoms, cardiovascular comorbidities, and the number of transfusions in the past half year. Predictors of transfusion preferences were assessed by multivariable regression. Results: 113 gastroenterologists completed the survey (response rate = 29%; mean age = 47 years; 24% women). Absolute hemoglobin level was the most important incentive of transfusion, accounting for 42% of decision-making, followed by age (15%), hemoglobin stability (12%), anemia-related symptoms (10%), and cardiovascular comorbidities (10%). A hemoglobin level >9.6 g/dL is an inflection point, where gastroenterologists would not prescribe transfusions. Age of the patient is more important in the decision-making process to younger gastroenterologists (OR -2.9, 95% CI -5.3 to -0.5). Conclusion: Absolute hemoglobin level is the most important factor to transfusion decision-making. This is contradictory to transfusion guidelines for chronic anemia which address the importance of symptoms. PMID- 29163964 TI - Occult liver disease burden: Analysis from a large general practitioners' database. AB - Background: Cirrhosis represents the end stage of chronic liver disease, characterized by high mortality and morbidity. The prevalence of liver disease is difficult to assess, given its clinical latency up to the late stage. Objective: We aimed to assess the prevalence of unrecognized chronic liver disease and cirrhosis using surrogate indicators from medical records of family physicians. Methods: Medical records of 139,104 subjects, collected from 99 family physicians of the Veneto region, were used. Persistently high transaminases were used as indicators of occult chronic liver disease; thrombocytopenia, unrelated to haematological malignancies, was used as indicator of occult cirrhosis. Diagnosis of chronic liver disease and cirrhosis was assessed using ICD9-CM-1997 codes. Results: Alteration of transaminases was found in 32.7% of the subjects, and among them only one-third had an already diagnosed liver disease. Patients with diagnosis of cirrhosis were 0.3%, while thrombocytopenia, indicator of occult cirrhosis, was detected in 1.3% of the remaining population. Patients with overt and occult cirrhosis showed a higher metabolic profile, with significantly higher prevalence of arterial hypertension, obesity and diabetes than the general population. Conclusion: A large proportion of patients with chronic liver disease is still undiagnosed. Surrogate biochemical indicators might be useful for disease recognition. PMID- 29163963 TI - Capsule endoscopy in young patients with iron deficiency anaemia and negative bidirectional gastrointestinal endoscopy. AB - Background: Recent data imply young patients (age <=50 years) undergoing small bowel (SB) capsule endoscopy (CE) for iron deficiency anaemia (IDA) show higher diagnostic yield (DY) for sinister pathology. We aimed to investigate DY of CE in a large cohort of young IDA patients, and evaluate factors predicting significant SB pathology. Materials and methods: This was a retrospective, multicentre study (2010-2015) in consecutive, young patients (<=50 years) from 18 centres/12 countries, with negative bidirectional gastrointestinal (GI) endoscopy undergoing SBCE for IDA. Exclusion criteria: previous/ongoing obscure-overt GI bleeding; age <19 or >50 years; comorbidities associated with IDA. Data retrieved: SBCE indications; prior investigations; medications; SBCE findings; final diagnosis. Clinical and laboratory data were analysed by multivariate logistic regression. Results: Data on 389 young IDA patients were retrieved. In total, 169 (43.4%) were excluded due to incomplete clinical data; data from 220 (122F/98M; mean age 40.5 +/- 8.6 years) patients were analysed. Some 71 patients had at least one clinically significant SBCE finding (DY: 32.3%). They were divided into two groups: neoplastic pathology (10/220; 4.5%), and non-neoplastic but clinically significant pathology (61/220; 27.7%). The most common significant but non neoplastic pathologies were angioectasias (22/61) and Crohn's disease (15/61). On multivariate analysis, weight loss and lower mean corpuscular volume(MCV) were associated with significant SB pathology (OR: 3.87; 95%CI: 1.3-11.3; p = 0.01; and OR: 0.96; 95%CI: 0.92-0.99; p = 0.03; respectively). Our model also demonstrates association between use of antiplatelets and significant SB pathology, although due to the small number of patients, definitive conclusions cannot be drawn. Conclusion: In IDA patients <=50 years with negative bidirectional GI endoscopy, overall DY of SBCE for clinically significant findings was 32.3%. Some 5% of our cohort was diagnosed with SB neoplasia; lower MCV or weight loss were associated with higher DY for SB pathology. PMID- 29163965 TI - Use of inhibitors of the renin-angiotensin system is associated with longer survival in patients with hepatocellular carcinoma. AB - Background: Inhibition of the renin-angiotensin system (RAS) was associated with longer survival in patients with different solid malignancies. Objective: The objective of this study was to investigate the effect of RAS inhibitor (RASi) treatment (angiotensin-converting enzyme inhibitors or angiotensin-II-receptor blockers) on survival of patients with hepatocellular carcinoma (HCC). Methods: Patients diagnosed with HCC and Child-Pugh A between 1992 and 2013 who received sorafenib, experimental therapy, or best supportive care were eligible for the Vienna cohort. The Mainz cohort included patients with HCC and Child-Pugh A who received sorafenib treatment between 2007 and 2016. The association between RASi and overall survival (OS) was evaluated in univariate and multivariate analyses. Results: In the Vienna cohort, 43 of 156 patients received RASi for hypertension. RASi treatment was associated with longer OS (11.9 vs. 6.8 months (mo); p = 0.014) and remained a significant prognostic factor upon multivariate analysis (HR = 0.6; 95% CI 0.4-0.9; p = 0.011). In subgroup analysis, patients treated with sorafenib plus RASi had better median OS (19.5 mo) compared to those treated with either sorafenib (10.9 mo) or RASi (9.7 mo) alone (p = 0.043). The beneficial effect of RASi on survival was confirmed in the Mainz cohort (n = 76). Conclusion: RAS inhibition is associated with longer survival in HCC patients with Child-Pugh class A. PMID- 29163966 TI - Risk factors and survival outcomes of biliary complications after adult-to-adult living donor liver transplantation. AB - The objective of this study was to evaluate the risk factors and survival outcomes of biliary complications (BCs) after living donor liver transplantation (LDLT) based on our single-center experience. From 2007 to 2010, 112 adult patients were assessed. Forty-nine patients (43.8%) experienced at least one episode of BCs, including biliary stricture and bile leak, occurring in 37.5% and 16.1% of the patients, respectively. Multivariate analysis indicated that hepatic artery thrombosis (relative risk (RR), 5.692; 95% CI, 2.132 to 15.201; p < 0.001), a hepatic duct diameter of less than 3 mm (RR, 2.523; 95% CI, 1.295 to 4.914; p = 0.005), ductoplasty (RR, 2.175; 95% CI, 1.134 to 4.174; p = 0.018), and cytomegalovirus infection (RR, 4.452; 95% CI, 1.868 to 10.613; p = 0.001) were independent risk factors for the development of BCs. However, these factors and BCs showed no prominent impact on the overall survival (OS) and graft survival (GS). In addition, the patients who developed vascular complications demonstrated poor outcomes in terms of OS (five-year, 56.3% vs. 78.1%; p = 0.017), GS (five-year, 56.3% vs. 77.1%; p = 0.023), and BC-free survival (five year, 25.0% vs. 63.5%; p = 0.007) compared with patients without vascular complications. In conclusion, BCs remain a common problem after LDLT, especially for patients using duct-to-duct anastomosis. Hepatic artery thrombosis, a short duct diameter, ductoplasty, and cytomegalovirus infection lead to an increased incidence of BCs. The occurrence of BCs manifested no significant influence on the long-term survival outcomes. However, our findings await verification through large-scale randomized studies regarding the risk factors for the development of BCs and their impact on the prognosis. PMID- 29163967 TI - The prevalence of pancreatic cystic lesions in patients with liver cirrhosis is double that in controls. AB - Background and aims: Pancreatic cystic lesions (PCLs) are commonly diagnosed incidentally and are often preneoplastic. Their presence may influence the management of patients with chronic diseases such as liver cirrhosis (LC). This study evaluated the prevalence and nature of PCLs in LC patients. Methods: The images of 192 LC patients and 192 controls who underwent either computed tomography scan or nuclear magnetic resonance were reviewed for the presence and nature of PCLs. The prevalence of PCLs in both groups and differences between LC patients with and without PCLs were analysed. Multiple logistic regression analysis was used to investigate factors associated with PCLs. Results: Thirty five of 192 LC patients (18%) and 19/192 controls (10%) had PCLs (p = .027). The prevalence of presumptive intraductal pancreatic mucinous neoplasm (IPMN) was double in LC patients compared with controls (14% vs 7%; p = .065). In multivariate analysis, age, LC and having undergone a magnetic resonance cholangiopancreatography were factors associated with PCLs and IPMNs. LC patients with PCLs were older at the time of imaging and had a longer history of liver disease (67 vs. 43 months; p = 0.039) compared with LC patients without PCLs. Conclusions: PCLs are more common in LC patients than in controls, and most are IPMNs. The occurrence of PCLs in LC patients seems to be related to age and disease duration. PMID- 29163968 TI - Brushing the distal biliary stricture in the surrounding of the papilla increased the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis: A retrospective study using propensity score analysis. AB - Background and aims: Brushing cytology is useful for diagnosing biliary strictures. With regard to biliary stricture brushing at the distal common bile duct in the surrounding of the papilla, the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis is unknown. Our study aimed to evaluate the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis by using this procedure. Methods: A total of 150 endoscopic retrograde cholangiopancreatography-naive patients undergoing endoscopic retrograde cholangiopancreatography including biliary stricture brushing were retrospectively analyzed. Patients were divided into two groups: the surrounding of the papilla group (n = 25) and the other group (n = 125). The primary outcome was the post-endoscopic retrograde cholangiopancreatography pancreatitis incidence. We analyzed the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis by using inverse probability of treatment weighting based on propensity scores to adjust for selection bias. Results: The overall incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis was 11.3%, and post-endoscopic retrograde cholangiopancreatography pancreatitis of the surrounding of the papilla group occurred significantly more frequently than in the other group (32.0% vs 7.2%, p < 0.01). Multivariate analysis showed that this procedure was a risk factor for post-endoscopic retrograde cholangiopancreatography pancreatitis (odds ratio, 10.6; 95% confidence interval, 2.82-40.2; p < 0.01). In the propensity-weighted model, this procedure was an independent risk factor for post-endoscopic retrograde cholangiopancreatography pancreatitis (odds ratio, 8.42; 95% confidence interval, 2.12-32.4; p < 0.01) by multivariate analysis. Conclusions: Biliary stricture brushing at the distal common bile duct in the surrounding of the papilla may increase the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis compared with brushing other portions. PMID- 29163969 TI - ERCP in infants, children and adolescents is feasible and safe: results from a tertiary care center. AB - Background: Indications for endoscopic retrograde cholangiopancreatography (ERCP) in children differ from adults. Paucity of data and concerns about potential lower effectiveness and more side effects limit its use even in high volume centers. We retrospectively analyzed indications, success rates, limitations, and side effects of ERCPs in children <18 years. Methods: From January 2012 to March 2015, 54 ERCPs were performed in 31 children (median age 11 (0-17) years; median weight 22 (3.3-142.7) kg) with suspected choledocholithiasis (n = 13 interventions in 9 patients), post-transplantation anastomotic stenosis (10/4), malignancy (10/5), chronic pancreatitis (7/1), biliary atresia (6/6), anomaly (2/2), leak (4/3), or primary sclerosing cholangitis (PSC) (2/1). All patients were followed up as inpatients. Results: Thirty-six therapeutic and 18 diagnostic procedures were performed by adult ERCP expert endoscopists. Successful intervention was achieved in 90.7% of cases. Failed cannulation (n = 4) was associated with lower body weight (p = 0.023). In children younger than 1 year, ERCP was significantly more often diagnostic than in patients >1 year (p < 0.001). In three of six infants with suspected atresia, surgical exploration was avoided. Five complications were recorded (9.3%), and included four episodes of mild pancreatitis (7.4% post-ERCP pancreatitis (PEP) rate) and one cholangitis in PSC. A trend towards a protective effect of pancreatic stents on PEP was observed. All complications were managed conservatively. No complications were attributed to mechanical stress on the gastrointestinal tract. Conclusions: ERCP in newborns, infants, and adolescents can be safely performed with high technical and clinical success. Endoscopists must be aware of differing spectrum of pediatric diseases. Failed cannulation was associated with lower body weight of young children. Complications were similar to rates reported in adults. PMID- 29163970 TI - Effect of low-dose aspirin use on pancreatic cancer development and morphological changes on imaging in IPMN: A long-term cohort study. AB - Background: Aspirin use may reduce the incidence of pancreatic cancer (PC), but no data are available regarding its chemopreventive effects on intraductal papillary mucinous neoplasm (IPMN). We aimed to determine whether low-dose aspirin (LDA) reduces PC development and morphological changes on imaging in IPMN patients. Methods: A cohort of 448 IPMN patients periodically followed up with imaging tests was analyzed. We used one-to-two propensity score matching to adjust for differences between an LDA group (n = 63) and a non-LDA group (n = 385). Outcomes included increasing cyst diameter, increasing main pancreatic duct (MPD) diameter, mural nodule (MN) appearance and PC development. Results: After matching, 63 LDA and 126 non-LDA patients were selected. During follow-up (median, 5.5 years), no significant differences were found in increasing cyst diameter, MN appearance, or PC development. However, there were significantly fewer cases of increasing MPD diameter in the LDA group (4.8% vs. 12.7%; p = 0.02). After adjustment for age and sex, LDA still decreased the risk of increasing MPD diameter (hazard ratio, 0.17; p = 0.02). Conclusion: Our results do not support a chemopreventive effect of LDA on PC development. However, LDA reduces further MPD dilation in IPMN patients. PMID- 29163971 TI - Dexmedetomidine vs propofol for gastrointestinal endoscopy: A meta-analysis. AB - Background and aim: Several randomized controlled trials have compared sedation with dexmedetomidine and propofol in gastrointestinal endoscopy, with contradictory results. We conducted a meta-analysis of data from randomized controlled trials that compared dexmedetomidine with propofol. Methods: We searched PubMed, the Cochrane library, and the Igaku-chuo-zasshi database for randomized trials eligible for inclusion in our meta-analysis. We identified six eligible randomized trials from the database search, and compared the effect of propofol versus dexmedetomidine with respect to: (a) patient's satisfaction level, (b) body movement or gagging, (c) cardiopulmonary complications, and (d) change in heart rate. Data from eligible studies were combined to calculate pooled risk difference (RD) or weighted mean difference (WMD). Results: Compared to propofol, dexmedetomidine significantly decreased the patient's satisfaction level (WMD: -0.678, 95% confidence interval (CI): -1.149 to -0.207, p = 0.0048), and there was no significant heterogeneity among the trial results. The pooled RD for developing body movement or gagging when using dexmedetomidine was 0.107 (95% CI: -0.09 to 0.305, p = 0.288), with no significant differences. Compared with propofol, the pooled RD for hypotension, hypoxia, and bradycardia with dexmedetomidine sedation were -0.029 (95% CI: -0.11 to 0.05), -0.080 (95% CI: 0.178 to 0.018), and 0.022 (95% CI: -0.027 to 0.07), respectively, with no significant differences. Compared to propofol, dexmedetomidine significantly decreased the heart rate (WMD: -10.41, 95% CI: -13.77 to -7.051, p <= 0.0001), without significant heterogeneity. Conclusions: In gastrointestinal endoscopy, patient satisfaction level was higher in propofol administration, when compared to dexmedetomidine. The risk of complications was similar. PMID- 29163972 TI - Prevalence of fecal incontinence in a cohort of systemic sclerosis patients within a regional referral network. AB - Background: The prevalence of gastrointestinal involvement in systemic sclerosis is higher than 75%. The estimated prevalence of fecal incontinence varies from 22% to 77%, but suffers from recruitment bias and patient reluctance. Our goal was to evaluate the prevalence of fecal incontinence in systemic sclerosis, and to identify associated risk factors. Methods: Patients were recruited in the referral systemic sclerosis network of the Lyon University Hospitals, using self administered questionnaires including constipation, fecal incontinence and Bristol Stool scales, quality of life, anxiety and depression. The cohort was compared with the historical ORALIA cohort that established the prevalence of fecal incontinence in the general population of the Rhone-Alpes region (France). Results: Seventy-seven patients were included (mean age: 60 years, range: 32-84), and 86% were female. These were compared to 153 ORALIA individuals matched for age and sex. Fecal incontinence was present in 38% of patients and 6% of the general population. A longer duration of systemic sclerosis was the only characteristic associated with fecal incontinence. Abnormal stool consistency was more frequent in patients with fecal incontinence. Conclusion: Fecal incontinence and abnormal stool consistency are common in systemic sclerosis and should be systematically addressed. PMID- 29163974 TI - Major advances in gastroenterology and hepatology over the last 25 Years: Review of 25th UEG Week Anniversary Session. PMID- 29163973 TI - Young gastrointestinal angle: Study design in gastroenterology. PMID- 29163976 TI - Availability, prices and affordability of UN Commission's lifesaving medicines for reproductive and maternal health in Uganda. AB - Background: Uganda was one of seven countries in which the United Nations Commission on Life Saving Commodities (UNCoLSC) initiative was implemented starting from 2013. A nationwide survey was conducted in 2015 to determine availability, prices and affordability of essential UNCoLSC maternal and reproductive health (MRH) commodities. Methods: The survey at health facilities in Uganda was conducted using an adapted version of the standardized methodology co-developed by World Health Organisation (WHO) and Health Action International (HAI). In this study, six maternal and reproductive health commodities, that were part of the UNCoLSC initiative, were studied in the public, private and mission health sectors. Median price ratios were calculated with Management Sciences for Health International Drug Price Indicator prices as reference. Maternal and reproductive health commodity stocks were reviewed from stock cards for their availability for a period of 6 months preceding the survey. Affordability was measured using wages of the lowest paid government worker. Results: Overall none of the six maternal and reproductive commodities was found in the surveyed health facilities. Public sector had the highest availability (52%), followed by mission sector (36%) and then private sector had the least (30%). Stock outs ranged from 7 to 21 days in public sector; 2 to 23 days in private sector and 3 to 27 days in mission sector. During the survey, maternal health commodities were more available and had less number of stock out days than reproductive health commodities. Median price ratios (MPR) indicated that medicines and commodities were more expensive in Uganda compared to international reference prices. Furthermore, MRH medicines and commodities were more expensive and less affordable in private sector compared to mission sector. Conclusion: Access to MRH commodities is inadequate in Uganda. Maternal health commodities were more available, cheaper and thus more affordable than reproductive health commodities in the current study. Efforts should be undertaken by the Ministry of Health and stakeholders to improve availability, prices and affordability of MRH commodities in Uganda to ensure that sustainable Development Goals are met. PMID- 29163977 TI - Patient-centred outcomes research: perspectives of patient stakeholders. AB - Objective: To elicit patient stakeholders' experience and perspectives about patient-centred care. Design: Qualitative. Setting: A large urban healthcare system. Participants: Four patient stakeholders who are prostate cancer survivors. Main outcome measures: Experience and perspectives of patient stakeholders regarding patient-centred care and treatment decisions. Results: Our patient stakeholders represented a diverse socio-demographic group. The patient stakeholders identified engagement and dialogue with physicians as crucial elements of patient-centred care model. The degree of patient-centred care was observed to be dependent on the situations. High severity conditions warranted a higher level of patient involvement, compared to mild conditions. They agreed that patient-centred care should not mean that patients can demand inappropriate treatments. Conclusions: An important attribute of patient-centred outcomes research model is the involvement of stakeholders. However, we have limited knowledge about the experience of patient stakeholders in patient-centred outcomes research. Our study indicates that patient stakeholders offer a unique perspective as researchers and policy-makers aim to precisely define patient centred research and care. PMID- 29163975 TI - On the descent of the epididymo-testicular unit, cryptorchidism, and prevention of infertility. AB - This comprehensive review provides in-depth coverage of progress made in understanding the molecular mechanisms underlying cryptorchidism, a frequent pathology first described in about 1786 by John Hunter. The first part focuses on the physiology, embryology, and histology of epididymo-testicular descent. In the last 20 years epididymo-testicular descent has become the victim of schematic drawings with an unjustified rejection of valid histological data. This part also includes discussion on the roles of gonadotropin-releasing hormone, fibroblast growth factors, Mullerian inhibiting substance, androgens, inhibin B, and insulin like 3 in epididymo-testicular descent. The second part addresses the etiology and histology of cryptorchidism as well as the importance of mini-puberty for normal fertility development. A critical view is presented on current clinical guidelines that recommend early orchidopexy alone as the best possible treatment. Finally, by combining classical physiological information and the output of cutting-edge genomics data into a complete picture the importance of hormonal treatment in preventing cryptorchidism-induced infertility is underscored. PMID- 29163978 TI - Same features, different diagnosis: A case of ilio-iliac arteriovenous fistula presenting as decompensated heart failure. AB - In case of high output cardiac failure, an arteriovenous fistula should be considered. PMID- 29163979 TI - Use of a social media network to reduce early neonatal mortality: a preliminary report from a quality improvement project in Yaounde, Cameroon. AB - Background: Perinatal networks have yielded substantial contribution in decreasing the neonatal mortality rate. We present here the process of implementation of a perinatal network in Yaounde (Cameroon) based on the WhatsApp messenger application as well as some preliminary results and achievements. Methods: In December 2016, the Yaounde Perinatal Network was launched, regrouping a multidisciplinary team of health professionals dealing with perinatal care in Yaounde, Cameroon. The network takes advantage of WhatsApp facilities and is coordinated by 5 administrators. One of their main duties is to have a twice daily updated status of the available equipment (incubators, oxygen and phototherapy) and bed capacities across the Yaounde pediatric units. Once a request is sent through the network, other members react, either by giving advice or by telling where the desired equipment or expertise is available at that moment. Then, the baby is immediately prepared for transfer, occurring once the receiving pediatric unit has attested that it is already prepared to receive the new patient. Results: From December 18, 2016 to July 31, 2017, 139 members representing all the principal maternities and tertiary pediatric units in Yaounde were already included in the network. The network permitted instant sharing of knowledge and information between its members for an optimal delivery of care. Two hundred and seventeen neonates were transferred using the network; the median time of response after a request had been sent was 19.5 min and the delay in transferring a neonate averaged 70 min. Conclusion: Taking account of the preliminary promising notes, there is hope that the Yaounde Perinatal Network will help to reduce neonatal mortality in our context. Lessons learned from its implementation will serve to replicate this innovative health action in other towns of the country. Moreover, this experience could be a source of inspiration for other countries facing similar challenges. PMID- 29163980 TI - Follow-up monitoring in a cat with leishmaniosis and coinfections with Hepatozoon felis and 'Candidatus Mycoplasma haemominutum'. AB - Case summary: A 6-year-old female neutered domestic shorthair cat from Cyprus was presented with multiple ulcerated skin nodules. Cytology and histopathology of the lesions revealed granulomatous dermatitis with intracytoplasmic organisms, consistent with amastigotes of Leishmania species. Biochemistry identified a mild hyperproteinaemia. Blood extraction and PCR detected Leishmania species, Hepatozoon species and 'Candidatus Mycoplasma haemominutum' (CMhm) DNA. Subsequent sequencing identified Hepatozoon felis. Additionally, the rRNA internal transcribed spacer 1 locus of Leishmania infantum was partially sequenced and phylogeny showed it to cluster with species derived from dogs in Italy and Uzbekistan, and a human in France. Allopurinol treatment was administered for 6 months. Clinical signs resolved in the second month of treatment with no deterioration 8 months post-treatment cessation. Quantitative PCR and ELISA were used to monitor L infantum blood DNA and antibody levels. The cat had high L infantum DNA levels pretreatment that gradually declined during treatment but increased 8 months post-treatment cessation. Similarly, ELISA revealed high levels of antibodies pretreatment, which gradually declined during treatment and increased slightly 8 months post-treatment cessation. The cat remained PCR positive for CMhm and Hepatozoon species throughout the study. There was no clinical evidence of relapse 24 months post-treatment. Relevance and novel information: To our knowledge, this is the first clinical report of a cat with leishmaniosis with H felis and CMhm coinfections. The high L infantum DNA levels post-treatment cessation might indicate that although the lesions had resolved, prolonged or an alternative treatment could have been considered. PMID- 29163981 TI - A comparison of isometric, isotonic concentric and isotonic eccentric exercises in the physiotherapy management of subacromial pain syndrome/rotator cuff tendinopathy: study protocol for a pilot randomised controlled trial. AB - Background: Subacromial pain syndrome (SPS) involving rotator cuff tendinopathy is a common cause of shoulder pain and disability. Evidence suggests that structured physiotherapy may be as effective as surgery in this condition with significant improvements demonstrated in trials involving scapular retraining, rotator cuff strengthening and flexibility exercises. Most published programs typically utilise isotonic concentric and/or eccentric strengthening modes. Recently, immediate analgesic effects and muscle strength gains following heavy load isometric exercises in lower limb tendinopathy conditions have been observed. It is pertinent to ascertain whether such outcomes can be replicated in SPS/rotator cuff tendinopathy. The primary aim of this study is to establish the feasibility of undertaking a full-scale randomised controlled trial (RCT) that compares the effects of isometric, isotonic concentric and isotonic eccentric rotator cuff contractions when used as part of a semi-standardised exercise-based physiotherapy program in patients diagnosed with SPS. The secondary aim is to explore potential trends or treatment effects of the exercise intervention. Methods: Thirty-six participants diagnosed with SPS will be randomised to one of three intervention groups and undergo a one-on-one exercise-based physiotherapy intervention, involving scapular and rotator cuff muscle retraining and strengthening. Each group will utilise a different mode of rotator cuff strengthening-isometric, isotonic concentric or isotonic eccentric. Rotator cuff tendon responses to isometric loading are not yet established in the literature; hence, individualised, progressive loading will be used in this pilot study in accordance with symptoms. The intervention will involve two phases: during Phase 1 (weeks 1-6) participants undertake the active group-specific physiotherapy treatment; in Phase 2 (weeks 6-12), they undertake a progressive, but no longer group-specific exercise program. To determine feasibility, an evaluation of key study parameters including (a) ease of recruitment (rate and number as well as suitability of the assessment algorithm), (b) adherence to all phases of the exercise intervention including home program compliance and logbook completion, (c) participant non-completion (drop out number and rate) and (d) adverse events (nature and number) will be undertaken. Secondary outcomes will measure immediate effects: (i) within-treatment changes in pain perception (verbal rating scale (VRS) and shoulder muscle strength (hand-held dynamometer) as well as longer-term changes: (ii) shoulder-related symptoms and disability (Western Ontario Rotator Cuff Index (WORC) and Shoulder Pain and Disability Index (SPADI)), (iii) perception of pain (11-point numerical rating scale (NRS), (iv) shoulder muscle strength (hand-held dynamometer) and (v) perceived global rating of change score. The immediate within-treatment assessment of pain and muscle strength will be undertaken in treatments 2 and 3, and the longer term measures will be collected at the primary (conclusion of Phase 1 at 6 weeks) and secondary (conclusion of Phase 2 at 12 weeks) end-points of the study. Discussion: The findings of this pilot study will permit evaluation of this study design for a full-scale RCT. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12616001676404. PMID- 29163982 TI - Individual differences in schizophrenia. AB - Background: Whether there are distinct subtypes of schizophrenia is an important issue to advance understanding and treatment of schizophrenia. Aims: To understand and treat individuals with schizophrenia, the aim was to advance understanding of differences between individuals, whether there are discrete subtypes, and how first-episode patients (FEP) may differ from multiple episode patients (MEP). Method: These issues were analysed in 687 FEP and 1880 MEP with schizophrenia using the Positive and Negative Syndrome Scale for (PANSS) schizophrenia before and after antipsychotic medication for 6 weeks. Results: The seven Negative Symptoms were correlated with each other and with P2 (conceptual disorganisation), G13 (disturbance of volition), and G7 (motor retardation). The main difference between individuals was in the cluster of seven negative symptoms, which had a continuous unimodal distribution. Medication decreased the PANSS scores for all the symptoms, which were similar in the FEP and MEP groups. Conclusions: The negative symptoms are a major source of individual differences, and there are potential implications for treatment. Declaration of interests: L.P. received speaker fees from Otsuka Canada and educational grant from Janssen Canada in 2017. Copyright and usage: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 29163984 TI - Retrospective cohort follow-up study of individuals detained under Section 136. AB - Background: An original cohort study found that over half of the individuals detained under Section 136 (S136) of the Mental Health Act 1983 were discharged home after assessment, and nearly half were intoxicated. Aims: To investigate whether the cohort was followed up by psychiatric services, characterise those repeatedly detained and assess whether substance use was related to these outcomes. Method: Data were retrospectively collected from the notes of 242 individuals, who presented after S136 detention to a place of safety over a 6 month period, and were followed up for 1 year. Results: After 1 year, 48% were in secondary care. Those with psychosis were the most likely to be admitted. Diagnoses of personality disorder or substance use were associated with multiple detentions; however, few were in contact with secondary services. Conclusions: Crisis and long-term care pathways for these groups need to be developed to reduce repeated and unnecessary police detention. Declaration of interest: None. Copyright and usage: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 29163983 TI - Cognitive ability and risk of post-traumatic stress disorder after military deployment: an observational cohort study. AB - Background: Studies of the association between pre-deployment cognitive ability and post-deployment post-traumatic stress disorder (PTSD) have shown mixed results. Aims: To study the influence of pre-deployment cognitive ability on PTSD symptoms 6-8 months post-deployment in a large population while controlling for pre-deployment education and deployment-related variables. Method: Study linking prospective pre-deployment conscription board data with post-deployment self reported data in 9695 Danish Army personnel deployed to different war zones in 1997-2013. The association between pre-deployment cognitive ability and post deployment PTSD was investigated using repeated-measure logistic regression models. Two models with cognitive ability score as the main exposure variable were created (model 1 and model 2). Model 1 was only adjusted for pre-deployment variables, while model 2 was adjusted for both pre-deployment and deployment related variables. Results: When including only variables recorded pre-deployment (cognitive ability score and educational level) and gender (model 1), all variables predicted post-deployment PTSD. When deployment-related variables were added (model 2), this was no longer the case for cognitive ability score. However, when educational level was removed from the model adjusted for deployment-related variables, the association between cognitive ability and post deployment PTSD became significant. Conclusions: Pre-deployment lower cognitive ability did not predict post-deployment PTSD independently of educational level after adjustment for deployment-related variables. Declaration of interest: None. Copyright and usage: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 29163985 TI - Response to inhaled loxapine in patients with schizophrenia or bipolar I disorder: PANSS-EC responder analyses. AB - Background: Efficacy of inhaled loxapine 5 or 10 mg in treating agitation was shown using the Positive and Negative Syndrome Scale - Excited Component (PANSS EC) in two Phase III randomised, double-blind, placebo-controlled trials in 344 agitated patients with schizophrenia and 314 patients with bipolar I disorder (Clinicaltrials.gov: NCT00628589, NCT00721955). Aims: To examine the five individual items comprising the PANSS-EC and the percentage of patients achieving a clinical response (reduction of >=40%) in PANSS-EC (Response-40) for these two studies. Method: Response-40 was examined at the primary end-point (2 h) and over time. Results: Response-40 and each PANSS-EC item score were statistically significant v. placebo at 2 h and at each assessment time point for both doses. Conclusions: Inhaled loxapine produced rapid improvement in agitated patients with schizophrenia or bipolar I disorder, achieving Response-40 at the first assessment (10 min post dose). These results highlight the effectiveness of loxapine across all components of agitation as measured by the PANSS-EC. Declaration of interest: S.Z. is a member of the speakers bureau for Grupo Ferrer. L.Z. has been a speaker and grant recipient for Teva Pharmaceuticals. J.V.C. and D.A.S. were employees of Alexza Pharmaceuticals during execution of the studies, and are currently paid consultants for and have received stock and/or stock options from Alexza Pharmaceuticals. P.P.Y. is a full-time employee and receives stock options from Teva Pharmaceuticals. Copyright and usage: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 29163986 TI - The salt-taste threshold in untreated hypertensive patients. AB - Background: The salt-taste threshold can influence the salt appetite, and is thought to be another marker of sodium intake. Many studies have mentioned the relationship between the sodium intake and blood pressure (BP). The aim of this study was to evaluate the relationship between the salt-taste threshold and urinary sodium excretion in normotensive and hypertensive groups. Methods: We analyzed 199 patients (mean age 52 years, male 47.3%) who underwent 24-h ambulatory BP monitoring (ABPM). Hypertension was diagnosed as an average daytime systolic BP of >=135 mmHg or diastolic BP of >=85 mmHg by the ABPM. We assessed the salt-taste threshold using graded saline solutions. The salt-taste threshold, 24-h urinary sodium and potassium excretion, and echocardiographic data were compared between the control and hypertensive groups. Results: The detection and recognition threshold of the salt taste did not significantly differ between the control and hypertensive groups. The 24-h urinary sodium excretion of hypertensive patients was significantly higher than that of the control group (140.9 +/- 59.8 vs. 117.9 +/- 57.2 mEq/day, respectively, p = 0.011). Also, the urinary sodium-potassium ratio was significantly higher in the hypertensive patients. There was no correlation between the salt-taste threshold and 24-h urinary sodium excretion. Conclusions: The salt-taste threshold might not be related to the BP status as well as the 24-h urinary sodium excretion. PMID- 29163987 TI - Medial collateral ligament calcification: a rare knee pain entity with literature review. AB - Medial knee pain can originate from both osseous and non-osseous soft tissue structures including medial collateral ligament (MCL), creating a raft for patients' sufferings. Previously published works demonstrated MCL calcification as a rare medial knee pain entity. Alongside physical examination, radio-imaging techniques, namely conventional X-ray, CT/MRI scanning, etc. have been reported to be useful in recognizing MCL calcification. The present study demonstrates MCL calcification in a 60-year-old Asian-Bangladeshi woman, using high frequency diagnostic ultrasonogram and is the first reported study in the literature. To have available literature review, PubMed, Cochrane, Embase, and Scopus databases were used. PMID- 29163988 TI - Effect of MT3 on Retinal and Choroidal TGF-beta2 and HAS2 Expressions in Form Deprivation Myopia of Guinea Pig. AB - Purpose: To confirm its dose-dependent effect on form deprivation myopia and evaluate the effect of MT3 at different tissue concentrations on changes in mRNA and protein expression for TGF-beta2 and HAS2. Methods: MT3 was intravitreally injected into deprived eyes at two-day intervals. Refraction was measured by streak retinoscopy after cycloplegia. The axial dimensions were measured by A scan ultrasound. The quantitative RT-PCR and Western blot were used to detect the changes of TGF-beta2 and HAS2 expressions in the retina and choroid of guinea pigs. Results: MT3 treatment produced a significant dose-dependent reduction in relative myopia compared to FD group (both p < 0.001). There were statistically significant increases in retinal and choroidal mRNA levels for both TGF-beta2 and HAS2 after injections of 10 MUM of MT3, when compared to the FD group. There were no significant differences in retinal and choroidal TGF-beta2 protein expression levels between the MT3 treatment groups and FD group (all p > 0.05). The injections of 10 MUM of MT3 caused a marked decrease in retinal HAS2 protein expression level, when compared to the FD group (p = 0.001). Conclusion: MT3 can inhibit form deprivation myopia, and MT3 treatment can result in changes of retinal and choroidal TGF-beta2 and HAS2 mRNA and protein expressions. PMID- 29163989 TI - Axial Length and Ocular Development of Premature Infants without ROP. AB - Purpose: To investigate the ocular parameters of premature infants without ROP at gestational age (GA) more than 28 weeks and their relationship with growth parameters. Methods: 76 preterm infants without ROP and 65 term infants were involved to undergo portable slit lamp, RetCam3, ultrasonic A-scan biometry, and cycloplegic streak examination at their 40 weeks' postconceptional ages (PCA). Ocular parameters of infants' right eye and growth parameters were used for analysis. Results: All the infants were examined at 40 weeks' PCA. No significant difference was found between male and female in axial length of preterm infants (p = 0.993) and term infants (p = 0.591). Significant differences were found in axial length (AL), anterior chamber depth (ACD), lens thickness (LT), and vitreous depth (VD) between preterm and term infants. No significant correlation was found between AL and spherical equivalent in preterm infants' group. In preterm group, AL was significantly correlated with gestational age (GA), birth weight (BW), and head circumference (HC). Conclusions: Preterm infants had shorter AL, shallow ACD, thicker LT, and thinner VD compared to term infants. Refractive error in preterm infants at GA between 28 to 37 weeks was not related to axial length. Among all the growth parameters of preterm infants, GA, BW, and HC had effect on axial length. PMID- 29163990 TI - Interventional Pain Management in Multidisciplinary Chronic Pain Clinics: A Prospective Multicenter Cohort Study with One-Year Follow-Up. AB - Background: Interventional Pain Management (IPM) is performed in multidisciplinary chronic pain clinics (MCPC), including a range of invasive techniques to diagnose and treat chronic pain (CP) conditions. Current patterns of use of those techniques in MCPC have not yet been reported. Objective: We aimed to describe quantitatively and qualitatively the use of IPM and other therapeutic procedures performed on-site at four Portuguese MCPC. Methods: A prospective cohort study with one-year follow-up was performed in adult patients. A structured case report form was systematically completed at baseline and six and 12 months. Results: Among 808 patients referred to the MCPC, 17.2% had been prescribed IPM. Patients with IPM were on average younger and had longer CP duration and lower levels of maximum pain and pain interference/disability. The three main diagnoses were low back pain (n = 28), postoperative CP, and knee pain (n = 16 each). From 195 IPM prescribed, nerve blocks (n = 108), radiofrequency (n = 31), and viscosupplementation (n = 22) were the most prevalent. Some IPM techniques were only available in few MCPC. One MCPC did not provide IPM. Conclusions: IPM are seldom prescribed in Portuguese MCPC. Further studies on IPM safety and effectiveness are necessary for clear understanding the role of these techniques in CP management. PMID- 29163991 TI - An Undiagnosed Paraganglioma in a 58-Year-Old Female Who Underwent Tumor Resection. AB - Paragangliomas and pheochromocytomas are rare neuroendocrine tumors that can have high morbidity and mortality if undiagnosed. Here we report a case of an undiagnosed paraganglioma in a 58-year-old female who underwent tumor resection. The patient became severely hypertensive intraoperatively with paroxysmal swings in blood pressure and then later became acutely hypotensive after tumor removal. She was managed in the surgical intensive care unit (SICU) postoperatively and discharged from the hospital without acute complications. We briefly discuss the epidemiology, clinical presentation, perioperative management, and possible complications of these tumors to assist healthcare providers if one were to encounter them. PMID- 29163992 TI - CD56-Negative Aggressive NK Cell Leukemia Relapsing as Multiple Cranial Nerve Palsies: Case Report and Literature Review. AB - Background: Aggressive natural killer cell leukemia (ANKL) is extremely rare and habitually manifests as a systemic disease with multiorgan failure that rapidly evolves to death. The neoplastic natural killer (NK) cells usually harbor the Epstein-Barr virus (EBV) with a latent viral infection pattern type II; they often have a cytoplasmic CD3epsilon+ and surface CD3-, CD2+, and CD56+ immunophenotype, and they show complex genetic abnormalities affecting multiple tumor suppressor genes and oncogenes. We present a rare case of CD56-negative ANKL and review the clinical and laboratorial criteria for the diagnosis, as well as the available therapies. Case Presentation: A European 36-year-old male presented with acute onset fever, pallor, weakness, and jaundice. He had hepatosplenomegaly, severe pancytopenia, hepatic cytolysis, and very high serum lactic dehydrogenase levels. The bone marrow studies resulted in the diagnosis of an EBV-positive, CD56-negative ANKL. The patient failed to respond to gemcitabine and cisplatin-based polychemotherapy, dying three months later with leukemic meningitis and multiple cranial nerves palsies. Conclusions: The diagnosis of ANKL is difficult and requires both clinical suspicion and an extensive laboratorial approach. Absence of CD56 expression on the neoplastic NK cells may impose difficulties in the diagnosis, which requires morphological, immunophenotypic, histopathological, immunohistochemical, cytogenetic, and molecular studies. PMID- 29163993 TI - 21-Year-Old Pregnant Woman with MODY-5 Diabetes. AB - The term "Maturity-Onset Diabetes of the Young" (MODY) was first described in 1976 and is currently referred to as monogenic diabetes. There are 14 known entities accounting for 1-2% of diabetes and they are frequently misdiagnosed as either type 1 or type 2 diabetes. MODY-5 is an entity of monogenic diabetes that is associated with genitourinary malformations and should be considered by obstetricians in pregnant women with a screen positive for diabetes, genitourinary malformations, and fetal renal anomalies. Correct diagnosis of monogenic diabetes has implications on managing patients and their families. We are reporting a case of a 21-year-old pregnant woman with a bicornuate uterus, fetal renal anomalies, and a family history of diabetes that were suggestive of a MODY-5 diabetes. PMID- 29163994 TI - Lumbar Spondylodiscitis Caused by Burkholderia cepacia in a Previously Healthy Patient. AB - Burkholderia cepacia spondylodiscitis is a rare entity that has been reported in only four cases. We hereby report the case of a 43-year-old, previously healthy, woman who was found to have a B. cepacia spondylodiscitis after a cholecystectomy. She was treated with a three-month regimen of ceftazidime and ciprofloxacin with complete clinical, biological, and radiological remission. PMID- 29163995 TI - Delayed Tibial Osteomyelitis after Anterior Cruciate Ligament Reconstruction with Hamstrings Autograft and Bioabsorbable Interference Screw: A Case Report and Review of the Literature. AB - Osteomyelitis following arthroscopically assisted anterior cruciate ligament (ACL) reconstruction has rarely been reported in the literature. We report a case of a 20-year-old female who had delayed tibial osteomyelitis and a pretibial cyst with culture-positive, oxacillin sensitive Staphylococcus epidermidis 15 months after an ACL reconstruction with hamstring autograft. Soft tissue fixation within the tibial tunnel was with a poly-L-D-lactic acid (PLDLA) bioabsorbable interference screw. The patient underwent surgical treatment with curettage, debridement, hardware removal, and bone grafting of the tibial tunnel followed by a course of intravenous antibiotics. Arthroscopic evaluation demonstrated an intact ACL graft without any evidence of intra-articular infection. The patient returned to collegiate athletics without any complications. While the most common biologic complications include pretibial cysts, granuloma formation, tunnel widening, and inflammatory reactions, infection is exceedingly rare. Late infection and osteomyelitis are also rare but can occur and should be considered in the differential diagnosis. PMID- 29163996 TI - Lymphangiomatous Polyp Presenting as Tonsillar Mass. AB - A 19-year-old female presented to ENT OPD of Dhulikhel Hospital, Kathmandu University Hospital, with history of foreign body sensation in throat for 2 weeks and mass in left tonsil for 1 week. There is no history of difficulty swallowing or recurrent throat infection. Physical examination revealed a pedunculated mass arising from upper pole of left tonsil. Bilateral tonsillectomy was done under general anaesthesia. Grossly, 2.5 * 1.5 * 1 cm polypoidal mass, soft in consistency, was found to be attached to left tonsil. Histopathology report was consistent with lymphangiomatous polyp of tonsil. Postoperative period was uneventful and she was normal during her follow-up at 1 month with bilateral healthy tonsillar fossa. PMID- 29163997 TI - Evans Syndrome Complicated by Intratubular Hemoglobin Cast Nephropathy. AB - Evans syndrome (ES) is a rare autoimmune disorder whose exact pathophysiology is unknown. It is characterized by the simultaneous or subsequent development of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Intravascular hemolysis, with hemoglobinemia, is known to produce acute kidney injury; however, the development of intratubular hemoglobin casts (hemoglobin cast nephropathy) in the setting of acute hemolysis is uncommon. Likewise, the association of ES and acute renal failure is equally uncommon. We present a case of a 7-year-old girl with ES who developed acute kidney injury in the setting of intravascular hemolysis and had widespread intratubular hemoglobin casts. PMID- 29163998 TI - Multifocal Pulmonary Granular Cell Tumor Presenting with Postobstructive Pneumonia. AB - Granular cell tumor (GCT) is a neoplasm of Schwann cell origin. Its presence in the aerodigestive tract is uncommon and becomes a diagnostic challenge on initial presentation. Our case is of a 59-year-old woman who presented to the emergency department with a history of productive cough and dyspnea associated with fever and chest pain. An initial chest X-ray (CXR) showed a right middle lobe consolidation with follow-up Computed Tomography (CT) scan showing a mass in the right bronchus. Bronchoscopy revealed a polypoid, sessile granular mass in the right bronchus intermedius with multiple white lesions in trachea, left main bronchus, and right upper bronchi. Histology revealed a benign GCT. Bronchoalveolar lavage from the right middle lobe grew Streptococcus pneumoniae. Patient was treated with intravenous levofloxacin during hospital stay and discharged on a 7-day course of oral antibiotics to be followed as outpatient but was lost to follow-up. GCT can present as a polypoid tumor causing recurrent postobstructive pneumonia. Surgical resection is the most successful treatment option. The tumor is more common in third and fourth decade of life and our patient is the oldest patient, according to our knowledge, to have a GCT. PMID- 29163999 TI - Childhood lupus nephritis: 12 years of experience from a developing country's perspective. AB - Objective: To assess the long-term outcome of lupus nephritis in children with systemic lupus erythematosus followed up over 12 years at a tertiary care teaching hospital in Eastern India. Material and Methods: This is a retrospective observational study of the clinicopathological presentation, management, and outcome in 46 children with lupus nephritis over a period of 12 years at a tertiary teaching hospital in Eastern India. Mortality was compared between different lupus classes and therapy groups with Kaplan-Meier analysis and log rank test. Results: The incidence of lupus nephritis was 58.97% [95% confidence interval (CI) 48.06%-59.89%] with the mean age at presentation being 10.2+/-2.43 years (range 5.5-14.5) years. Majority belonged to class IV (30.43%), followed by class II (26.91%), class III (23.91), and class V (8.70%). Outcome analysis of children with lupus nephritis over 12 years revealed that 24 (52.17%) achieved complete remission of disease activity, 5 attained partial remission, 4 continued to have active disease, 5 developed end-stage renal disease (ESRD), and 8 died. Overall mortality thus observed was 17.39% with septicemia in the background of ESRD being the commonest cause. No significant difference in mortality was observed between different lupus nephritis classes or therapy arm groups. Conclusion: The study throws light on various aspects of lupus nephritis and their long-term outcome patterns in children from developing countries such as India. PMID- 29164000 TI - Late ventricular potentials in familial Mediterranean fever with and without AA amyloidosis. AB - Objective: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by episodic and chronic inflammation that may lead to both accelerated coronary atherosclerosis and cardiac AA amyloidosis. We hypothesized that late ventricular potentials (LPs), an established electrocardiographic susceptibility marker of ventricular arrhythmias, will be more common in FMF than in the adjusted normal population due to these two types of inflammation associated cardiac effects. Therefore, we aimed to evaluate the occurrence of LPs in FMF patients with and without amyloidosis. Material and Methods: Signal averaged electrocardiography was performed in consecutive patients with FMF using the Frank corrected orthogonal lead system. At least 200 consecutive beats were digitally recorded and averaged, and the presence of LPs was determined according to acceptable thresholds. Results: There were 54 patients with colchicine-treated FMF, of whom 14 had biopsy-proven AA amyloidosis. None of the uncomplicated FMF patients and 2 of the 14 FMF amyloidosis patients had abnormal or borderline LPs. Conclusion: Based on LPs as a susceptibility marker for arrhythmia, FMF patients, including the large majority of FMF patients with amyloidosis, are seemingly not at an increased risk to develop arrhythmias. PMID- 29164001 TI - Paradoxical elevation of serum TRACP5b levels despite increase in lumbar spine bone mineral density during anti-TNFalpha therapy in patients with inflammatory rheumatic disease: a 2-year prospective assessment of bone mass, bone metabolism, and the trabecular bone score. AB - Objective: To examine the impact of long-term anti-TNFalpha therapy on bone mass, bone metabolism, and the trabecular bone score (TBS) in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS). Material and Methods: In eight patients with RA and 12 with AS, bone mineral densities (BMDs) of the lumbar spine (LS), left and right femoral neck, and total skeleton were measured using dual X-ray absorptiometry at baseline and then at 6, 12, and 24 months after anti TNFalpha therapy. The TBS was also calculated. At baseline and at 1, 3, 6, 12, 18, and 24 months, bone metabolism was assessed by measurements of pro-collagen-I carboxyterminal propeptide (PICP), osteocalcin, and bone alkaline phosphatase levels in the serum, which are indicative of bone formation and beta-isomerized carboxy-terminal telopeptide of type-I collagen (beta-CTX-I) and serum isoform 5b of tartrate-resistant acid phosphatase (TRACP5b) levels in the serum, which are indicative of bone resorption. Results: In patients with RA, the LS T-score increased (3.2%, p<0.001) and the TBS progressively decreased (-3.9%, p=0.03). In patients with AS, the LS BMD and T-score increased (4.3% and 6.2%, respectively; p<0.001) with no significant change in the TBS. Serum TRACP5b levels dramatically increased in both groups (227% in patients with RA and 150% in those with AS, p<0.001), while beta-CTX-I levels did not change. Serum osteocalcin and PICP levels showed a transitory increase in patients with AS. Conclusion: Long-term anti-TNFalpha therapy increased LS bone mass and affected bone quality (TBS) with little impact on bone remodeling. Conversely, TRACP5b levels dramatically increased during anti-TNFalpha therapy but without any detrimental effect on bone mass. PMID- 29164002 TI - Biological therapy in arthritis patients with hepatitis B or C infection: a multicenter retrospective case series. AB - Objective: Reactivation of viral hepatitis B (HBV) and C (HCV) has been reported in various case reports of patients with arthritis on biological therapy. The objective of this study was to describe the clinical characteristics and outcomes of arthritis patients with HBV or HCV treated with biological therapy. Material and Methods: This is a retrospective case series including all patients above 13 years of age with arthritis patients from four centers in Saudi Arabia with concurrent chronic viral hepatitis infection (HBV or HCV) who received biological agents in the rheumatology clinics during their course of their disease from duration of the disease onset until last outpatient visit up to November 2015. Demographic information, full details about the hepatitis status of each patient, rheumatic disease diagnosis and different therapies used were reviewed. Results: We identified 10 cases each with HBV and HCV on biological therapy. The mean age in the HBV group was 51 (34-85) years and 80% were females. Eight patients had rheumatoid arthritis (RA), one patient had RA/systemic lupus erythematosus, and one had human immunodeficiency virus related-arthritis. Seven were chronic inactive HBsAg carriers and three had chronic active HBV. Nine HBV patients received prophylactic antiviral therapy. Two cases with chronic HBV had reactivation with no elevation of the transaminases.The mean age in the HCV group was 54 (23-79) years and all were female RA patients. Three had detectable hepatitis C virus-ribonuecleic acid (HCV-RNA) before the start of biological therapy. Nine HCV patients received antiviral treatment and seven had a sustained virologic response (SVR) before start of biological treatment. Three patients had detectable HCV-RNA during the course of biological therapy. One of the three was a non-responder and two were relapsers. One of the patients with HCV relapse was started on sofosbuvir plus ribavirin and achieved SVR on follow-up. Conclusion: We report the successful use of biological therapy in arthritis patients with hepatitis B infection with antiviral therapy with no detoriation of their viral status. Due to the lack of sufficient prospective studies demonstrating the rate of HCV flare on biological therapy, caution should be exercised and careful monitoring with liver enzymes and viral load is mandated in vulnerable HCV RNA patients. Treatment should be individualized by the rheumatologist in collaboration with the hepatologist to minimize complications. PMID- 29164004 TI - Primary lipoma arborescens of the knee. AB - Lipoma arborescens is a rare and benign intra-articular lesion of unknown etiology; it is characterized by synovial villous proliferation and sub-synovial connective tissue replacement by mature fatty tissue. It is part of the differential diagnosis in patients with an articulation affected by a slow, progressive, and chronically inflamed affection. We report primary knee involvement in a patient without significant articulate antecedents. Lipoma arborescens was diagnosed after knee magnetic resonance imaging and was confirmed by an anatomopathological study of the surgical specimen. PMID- 29164005 TI - Study of systemic disease IgG4. Usefulness of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography for staging, selection of biopsy site, evaluation of treatment response and follow-up. AB - Immunoglobulin G4-related systemic disease (IgG4-RSD) is a recently emerging disorder characterized by swelling lesions with storiform fibrosis and lymphoplasmacytic infiltration enriched with IgG4-positive plasma cells. IgG4-RSD has been found in multiple organs/tissues. The diagnosis requires the integration of clinical, serological, imaging, histopathological, and immunohistological features. The 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (18F-FDG PET/CT) enables the acquisition of whole body images and provides functional information about disease activity. However, its current role in IgG4-RSD is not well established in clinical practice. In our case, we studied a patient with systemic symptoms, submaxillary adenopathy, and imaging explorations that initially guided toward a lymphoproliferative process. However, the differential diagnosis with an autoimmune systemic disease type IgG4 was considered because of elevated levels of serum immunoglobulins. The study was completed with 18F-FDG PET/CT that not only allowed us to assess the extension disease and to locate the best lesion for biopsy but also allowed us to evaluate the response to treatment and to diagnose the suspicion of recurrence. In this case, PET/CT shows its usefulness in clinical practice. PMID- 29164003 TI - The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease. AB - Pain is the most common manifestation of both acute and chronic inflammation that often challenges patients with rheumatic disease. Simply, we attribute this to local joint changes of pH in joints, the formation of radicals, enhanced joint pressure, or cytokine release acting on local nerves to produce pain. However, there is a more complex interplay of interactions between cytokines, mediators of inflammation, and ion channels that influence the final immune response and our perception of pain. Endocannabinoids, a group of less well-known endogenous bioactive lipids, have such manifold immunomodulatory effects able to influence both inflammation and pain. In this review, we overview the endocannabinoid system, its role in pain, inflammation, and immune regulation, and highlight the emerging challenges and therapeutic hopes. PMID- 29164006 TI - Guest Editor's Message: Tripler Army Medical Center Research Symposium. PMID- 29164007 TI - Adult-Onset Still's Disease: Is This Truly a Diagnosis of Exclusion? AB - Adult-onset Still's Disease is a rare, idiopathic, inflammatory disorder characterized by arthralgia, evanescent, salmon-colored rash, and daily fevers as well as lymphadenopathy, pharyngitis, splenomegaly, myalgias, and serositis. The inciting etiology of this syndrome is unknown, though it has been hypothesized that infection triggers an autoimmune response. The Yamaguchi Criteria, the most sensitive and widely used diagnostic criteria, requires both a minimum set of criteria to be met as well other potential etiologies to be excluded. By definition, evidence of concomitant infection, malignancy, vasculitis, or connective tissue disease precludes the diagnosis of Adult-onset Still's Disease from being made. We present a very rare case of a patient who met all diagnostic criteria for Adult-onset Still's Disease, had a protracted course refractory to numerous immunosuppressant treatments, and also had evidence of coxsackie B infection with fourfold rise in viral titers on two occasions (both associated with disease flare). Although coxsackie B virus has been linked to Adult-onset Still's Disease at disease presentation, this case is unique in its protracted course and serological evidence of infection temporally related to disease flare. While accepted diagnostic criteria call for this disease to be a diagnosis of exclusion, our case supports the fact that ongoing infection may in fact be an important antigenic driver in persistent and refractory Adult-onset Still's Disease. PMID- 29164008 TI - Spontaneous Endometriosis Within a Primary Umbilical Hernia. AB - Umbilical hernias are rather common in the General Surgery clinic; however, endometriosis of an umbilical hernia is rare. It is especially unusual to have endometriosis of an umbilical hernia spontaneously occur compared to occurring at a site of a prior surgery. We present a case of spontaneous endometriosis of an umbilical hernia without prior surgery to her umbilicus. She had not presented with the usual symptoms of endometriosis and it was not considered as a diagnosis prior to surgery. Umbilical endometriosis is rare but usually occurs after prior laparoscopic surgery. We believe this is the second reported case in the English literature and the first such case reported from North America of spontaneous endometriosis of an umbilical hernia. This case highlights the importance of a full review of systems and qualifying the type and occurrence of pain. Additionally, it is always important to analyze surgical specimens in pathology to avoid errors in diagnosis. PMID- 29164009 TI - Next-Generation Gene Sequencing Differentiates Hypoplastic Myelodysplastic Syndrome from Aplastic Anemia. AB - Hypoplastic Myelodysplastic Syndrome (h-MDS) comprises 15% of all MDS and has traditionally been difficult to distinguish from aplastic anemia (AA) by current testing. Accurate differentiation is important because treatment and prognosis differ. Since the publication of the 2008 World Health Organization classification of MDS, next-generation DNA sequencing has discovered novel mutations strongly associated with AA and MDS. Recent research supports the utility of identifying these mutations in the diagnosis and management of MDS; however, use of next-generation sequencing is not yet recommended in guidelines and the study is not routinely performed. We present a case where next-generation sequencing performed on a peripheral blood specimen aided the diagnosis and management of a 74-year-old man with h-MDS. This case adds to the growing body of evidence supporting the utility of next-generation DNA sequencing in the evaluation of MDS and h-MDS, particularly when diagnosis remains unclear after standard testing. PMID- 29164010 TI - Chewing the Fat: A Case Report of Therapeutic Plasma Exchange in Hypertriglyceridemia-Induced Pancreatitis. AB - Hypertriglyceridemia is the third most common etiology of acute pancreatitis, but lacks a clear, evidence-based treatment approach. We present the case of a 25 year-old man who was admitted eleven times over seven years for hypertriglyceridemia-induced pancreatitis. In his first ten admissions, he received conservative therapy. During his eleventh admission, he underwent therapeutic plasma exchange with lowering of serum triglycerides from 5080 to 332 mg/dL. He was discharged on hospital day five and was noted to have persistently lowered triglyceride levels upon follow up. The case affirms plasma exchange's ability to rapidly lower serum triglyceride levels and provides future research opportunities for examining the long-term effects of this treatment. PMID- 29164011 TI - DaT's Awesome: Hawai'i's First Dopamine Transporter (DaT) Nuclear Medicine Study. AB - Parkinsonian Syndromes are difficult to accurately diagnose and distinguish from other neurological processes such as essential tremor. Until now, physical exam and clinical presentation have been the gold standard for diagnosis (bradykinesia, tremor, rigidity, and postural instability).1 However, this leads to over- or under diagnosis and improper treatment due to variability in presentation and symptoms.1 A nuclear medicine study using I-123 Ioflupane (DaTSCAN) has been developed, which allows accurate differentiation of Parkinsonian Syndromes from other etiologies.1 This study is now widely performed on the mainland, but has never been done in Hawai'i due to its East Coast sourcing and relatively short physical half-life. Through a highly coordinated logistical effort, Tripler Army Medical Center's Nuclear Medicine Department conducted the first DaTSCAN in Hawai'i in April 2016. PMID- 29164012 TI - Benign Granuloma Masquerading as Squamous Cell Carcinoma Due to a "Floater". AB - Pathology specimen cross-contamination is a rare phenomenon in diagnostic pathology. Such "floaters" may result in delayed, missed or erroneous diagnoses. We describe the case of a patient with benign granuloma of the lung initially misdiagnosed as squamous cell carcinoma due to a "floater." PMID- 29164013 TI - Physician Adherence to Sexually Transmitted Infection Screening Guidelines in an OB/GYN Teaching Clinic in Hawai'i. AB - Rates of chlamydia (CT) and gonorrhea (GC) have risen for the first time in the United States since 2006. Certain population groups are disproportionately affected by these sexually transmitted infections (STIs) as well as HIV. The Centers for Disease Control and Prevention (CDC) and professional societies have published screening guidelines for these STIs for women under the age of 25. We aimed to quantify physician adherence to GC/CT and HIV screening guidelines and to determine demographic factors associated with GC/CT and HIV screening recommendations among women 14-25 years old in Honolulu, Hawai'i. We conducted a retrospective chart review of all visits to an OB/GYN teaching clinic in 2014 to determine rates of STI screening recommendations and evaluate differences in screening recommendations by demographic factors such as patient age, race, insurance type, visit type, and visit number during the study period. Electronic medical records of 726 visits by 446 patients were reviewed. Among visits by patients with indications for screening, 71.0% and 21.6% received screening recommendations for GC/CT and HIV, respectively. Age group, race, and visit type were significantly associated with receiving screening recommendations. A lack of appropriate documentation regarding the assessment of risk factors for GC/CT and HIV screening was observed. Emphasis should be placed on more thorough ascertainment and documentation of patients' risk factors for STI acquisition to determine screening needs at each clinical visit based on professional guidelines, as substantial public health benefits may be gained through the identification and prompt treatment of GC/CT and HIV infections. PMID- 29164014 TI - Patient Communication, Satisfaction, and Trust Before and After Use of a Standardized Birth Plan. AB - The birth plan was developed as a way for pregnant women to communicate their desires and expectations for labor and delivery. Standardized birth plans have been used by some birth facilities as a communication tool. In this quality improvement project, we sought to describe communication, trust, and satisfaction scores after delivery in a group of patients who used a standardized birth plan. All pregnant women at 24 or more weeks of gestation were asked to complete a short, standardized birth plan. Communication, trust, and satisfaction were assessed before and after delivery. Descriptive analyses showed that communication, trust, and satisfaction scores were high following delivery. Scores for all three factors increased significantly following delivery though increases were modest. Most patients (84%) indicated they would use a birth plan with a subsequent delivery. PMID- 29164015 TI - Medical School Hotline: Advancing Suicide Prevention in Hawai'i. PMID- 29164016 TI - Insights in Public Health: Ambulatory Blood Pressure Monitoring: Underuse in Clinical Practice in Hawai'i. AB - Hypertension is one of the leading causes of death and disability worldwide. Blood pressure reduction and control are associated with reduced risk of stroke and cardiovascular disease. To achieve optimal reduction and control, reliable and valid methods for blood pressure measurement are needed. Office based measurements can result in 'white coat' hypertension, which is when a patient's blood pressure in a clinical setting is higher than in other settings, or 'masked' hypertension, which occurs when a patient's blood pressure is normal in a clinical setting, but elevated outside the clinical setting. In 2015, the US Preventative Services Task Force recommended Ambulatory Blood Pressure Monitoring (ABPM) as the "best method" for measuring blood pressure, endorsing its use both for confirming the diagnosis of hypertension and for excluding 'white coat' hypertension. ABPM is a safe, painless and non-invasive test wherein patients wear a small digital blood pressure machine attached to a belt around their body and connected to a cuff around their upper arm that enables multiple automated blood pressure measurements at designated intervals (typically every 15 to 30 minutes) throughout the day and night for a specified period (eg, 24 hours). Patients can go about their typical daily activities wearing the device as much as possible, except when they are bathing, showering, or engaging in heavy exercise. Given the importance of blood pressure monitoring and control to population public health, this article provides details on the relevance and challenges of blood pressure measurement broadly then describes ABPM generally and specifically in the Hawai'i context. PMID- 29164017 TI - The Daniel K. Inouye College of Pharmacy Scripts: Targeted Nanocarrier Based Systems for the Treatment of Lung Cancer. AB - In Hawai'i, lung cancer is among the top cancers diagnosed and a leading cause of death. Despite current understanding and modern surgery, radiology, and chemotherapy techniques, the survival of those suffering from lung cancer remains low. Current anticancer drugs have poor tumor tissue selectivity and toxicity issues that contribute to their overall low efficacy, detrimental effects to normal tissues, and drug resistance. A potential way of mitigating cancer is through RNA interference (RNAi) by the delivery of small interfering RNA (siRNA) to target select proteins or genes involved in cancer progression, known as oncoproteins or oncogenes, respectively. However, the clinical utility of delivering unformulated siRNA has been hindered due to poor cell penetration, nonspecific effects, rapid degradation, and short half-life. As an alternate for conventional chemotherapy, nanoparticles (AKA nanocarriers) may be designed to localize within the tumor environment and increase targeted cell internalization, thus reducing systemic adverse effects and increasing efficacy. Nanoparticles play important roles in drug delivery and have been widely studied for cancer therapy and diagnostics, termed collectively as theranostics. Nanoparticles composed of natural and artificial polymers, proteins, lipids, metals, and carbon based materials have been developed for the delivery of siRNA. Cancer targeting has been improved by nanoparticle surface modification or conjugation with biomolecules that are attracted to or stimulate therapeutic agent release within cancer tissues or cells. In this mini-review article, we present recent progress in nanocarrier-mediated siRNA delivery systems that include lipid, polymer, metallic and carbon-based nanoparticles for lung cancer therapy. PMID- 29164019 TI - Quantitative Analysis of Electro-Anatomical Maps: Application to an Experimental Model of Left Bundle Branch Block/Cardiac Resynchronization Therapy. AB - Electro-anatomical maps (EAMs) are commonly acquired in clinical routine for guiding ablation therapies. They provide voltage and activation time information on a 3-D anatomical mesh representation, making them useful for analyzing the electrical activation patterns in specific pathologies. However, the variability between the different acquisitions and anatomies hampers the comparison between different maps. This paper presents two contributions for the analysis of electrical patterns in EAM data from biventricular surfaces of cardiac chambers. The first contribution is an integrated automatic 2-D disk representation (2-D bull's eye plot) of the left ventricle (LV) and right ventricle (RV) obtained with a quasi-conformal mapping from the 3-D EAM meshes, that allows an analysis of cardiac resynchronization therapy (CRT) lead positioning, interpretation of global (total activation time), and local indices (local activation time (LAT), surrogates of conduction velocity, inter-ventricular, and transmural delays) that characterize changes in the electrical activation pattern. The second contribution is a set of indices derived from the electrical activation: speed maps, computed from LAT values, to study the electrical wave propagation, and histograms of isochrones to analyze regional electrical heterogeneities in the ventricles. We have applied the proposed methods to look for the underlying physiological mechanisms of left bundle branch block (LBBB) and CRT, with the goal of optimizing the therapy by improving CRT response. To better illustrate the benefits of the proposed tools, we created a set of synthetically generated and fully controlled activation patterns, where the proposed representation and indices were validated. Then, the proposed analysis tools are used to analyze EAM data from an experimental swine model of induced LBBB with an implanted CRT device. We have analyzed and compared the electrical activation patterns at baseline, LBBB, and CRT stages in four animals: two without any structural disease and two with an induced infarction. By relating the CRT lead location with electrical dyssynchrony, we evaluated current hypotheses about lead placement in CRT and showed that optimal pacing sites should target the RV lead close to the apex and the LV one distant from it. PMID- 29164020 TI - Efficacy and Safety of Methylprednisolone Sodium Succinate in Acute Spinal Cord Injury: A Systematic Review. AB - Study Design: Systematic review and meta-analysis. Objective: The objective of this study was to conduct a systematic review to assess the comparative effectiveness and safety of high-dose methylprednisolone sodium succinate (MPSS) versus no pharmacological treatment in patients with traumatic spinal cord injury (SCI). Methods: A systematic search was performed in PubMed and the Cochrane Collaboration Library for literature published between January 1956 and June 17, 2015. Included studies were critically appraised, and Grades of Recommendation Assessment, Development and Evaluation methods were used to determine the overall quality of evidence for primary outcomes. Previous systematic reviews on this topic were collated and evaluated using the Assessment of Multiple Systematic Reviews scoring system. Results: The search yielded 723 citations, 13 of which satisfied inclusion criteria. Among these, 6 were primary research articles and 7 were previous systematic reviews. Based on the included research articles, there was moderate evidence that the 24-hour NASCIS II (National Acute Spinal Cord Injury Studies) MPSS regimen has no impact on long-term neurological recovery when all postinjury time points are considered. However, there is also moderate evidence that subjects receiving the same MPSS regimen within 8 hours of injury achieve an additional 3.2 points (95% confidence interval = 0.10 to 6.33; P = .04) of motor recovery compared with patients receiving placebo or no treatment. Conclusion: Although safe to administer, a 24-hour NASCIS II MPSS regimen, when all postinjury time points are considered, has no impact on indices of long-term neurological recovery. When commenced within 8 hours of injury, however, a high dose 24-hour regimen of MPSS confers a small positive benefit on long-term motor recovery and should be considered a treatment option for patients with SCI. PMID- 29164021 TI - Efficacy, Safety, and Timing of Anticoagulant Thromboprophylaxis for the Prevention of Venous Thromboembolism in Patients With Acute Spinal Cord Injury: A Systematic Review. AB - Study Design: Systematic review. Objectives: The objective of this study was to answer 5 key questions: What is the comparative effectiveness and safety of (1a) anticoagulant thromboprophylaxis compared to no prophylaxis, placebo, or another anticoagulant strategy for preventing deep vein thrombosis (DVT) and pulmonary embolism (PE) after acute spinal cord injury (SCI)? (1b) Mechanical prophylaxis strategies alone or in combination with other strategies for preventing DVT and PE after acute SCI? (1c) Prophylactic inferior vena cava filter insertion alone or in combination with other strategies for preventing DVT and PE after acute SCI? (2) What is the optimal timing to initiate and/or discontinue anticoagulant, mechanical, and/or prophylactic inferior vena cava filter following acute SCI? (3) What is the cost-effectiveness of these treatment options? Methods: A systematic literature search was conducted to identify studies published through February 28, 2015. We sought randomized controlled trials evaluating efficacy and safety of antithrombotic strategies. Strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Results: Nine studies satisfied inclusion criteria. We found a trend toward lower risk of DVT in patients treated with enoxaparin. There were no significant differences in rates of DVT, PE, bleeding, and mortality between patients treated with different types of low-molecular-weight heparin or between low-molecular weight heparin and unfractionated heparin. Combined anticoagulant and mechanical prophylaxis initiated within 72 hours of SCI resulted in lower risk of DVT than treatment commenced after 72 hours of injury. Conclusion: Prophylactic treatments can be used to lower the risk of venous thromboembolic events in patients with acute SCI, without significant increase in risk of bleeding and mortality and should be initiated within 72 hours. PMID- 29164022 TI - Impact of Baseline Magnetic Resonance Imaging on Neurologic, Functional, and Safety Outcomes in Patients With Acute Traumatic Spinal Cord Injury. AB - Study Design: Systematic review. Objective: To perform a systematic review to evaluate the utility of magnetic resonance imaging (MRI) in patients with acute spinal cord injury (SCI). Methods: An electronic search of Medline, EMBASE, the Cochrane Collaboration Library, and Google Scholar was conducted for literature published through May 12, 2015, to answer key questions associated with the use of MRI in patients with acute SCI. Results: The literature search yielded 796 potentially relevant citations, 8 of which were included in this review. One study used MRI in a protocol to decide on early surgical decompression. The MRI protocol group showed improved outcomes; however, the quality of evidence was deemed very low due to selection bias. Seven studies reported MRI predictors of neurologic or functional outcomes. There was moderate-quality evidence that longer intramedullary hemorrhage (2 studies) and low-quality evidence that smaller spinal canal diameter at the location of maximal spinal cord compression and the presence of cord swelling are associated with poor neurologic recovery. There was moderate-quality evidence that clinical outcomes are not predicted by SCI lesion length and the presence of cord edema. Conclusions: Certain MRI characteristics appear to be predictive of outcomes in acute SCI, including length of intramedullary hemorrhage (moderate-quality evidence), canal diameter at maximal spinal cord compression (low-quality evidence), and spinal cord swelling (low-quality evidence). Other imaging features were either inconsistently (presence of hemorrhage, maximal canal compromise, and edema length) or not associated with outcomes. The paucity of literature highlights the need for well-designed prospective studies. PMID- 29164023 TI - Type and Timing of Rehabilitation Following Acute and Subacute Spinal Cord Injury: A Systematic Review. AB - Objectives: The objective of this study was to conduct a systematic review of the literature to address the following clinical questions: In adult patients with acute and subacute complete or incomplete traumatic SCI, (1) does the time interval between injury and commencing rehabilitation affect outcome?; (2) what is the comparative effectiveness of different rehabilitation strategies, including different intensities and durations of treatment?; (3) are there patient or injury characteristics that affect the efficacy of rehabilitation?; and (4) what is the cost-effectiveness of various rehabilitation strategies? Methods: A systematic search was conducted for literature published through March 31, 2015 that evaluated rehabilitation strategies in adults with acute or subacute traumatic SCI at any level. Studies were critically appraised individually and the overall strength of evidence was evaluated using methods proposed by the GRADE (Grades of Recommendation Assessment, Development and Evaluation) working group. Results: The search strategy yielded 384 articles, 19 of which met our inclusion criteria. Based on our results, there was no difference between body weight-supported treadmill training and conventional rehabilitation with respect to improvements in Functional Independence Measure (FIM) Locomotor score, Lower Extremity Motor Scores, the distance walked in 6 minutes or gait velocity over 15.2 m. Functional electrical therapy resulted in slightly better FIM Motor, FIM Self-Care, and Spinal Cord Independence Measure Self-Care subscores compared with conventional occupational therapy. Comparisons using the Toronto Rehabilitation Institute Hand Function Test demonstrated no differences between groups in 7 of 9 domains. There were no clinically important differences in Maximal Lean Test, Maximal Sidewards Reach Test, T-shirt Test, or the Canadian Occupational Performance Measure between unsupported sitting training and standard in-patient rehabilitation. Conclusion: The current evidence base for rehabilitation following acute and subacute spinal cord injury is limited. Methodological challenges have contributed to this and further research is still needed. PMID- 29164024 TI - A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury and Central Cord Syndrome: Recommendations on the Timing (<=24 Hours Versus >24 Hours) of Decompressive Surgery. AB - Objective: To develop recommendations on the timing of surgical decompression in patients with traumatic spinal cord injury (SCI) and central cord syndrome. Methods: A systematic review of the literature was conducted to address key relevant questions. A multidisciplinary guideline development group used this information, along with their clinical expertise, to develop recommendations for the timing of surgical decompression in patients with SCI and central cord syndrome. Based on GRADE, a strong recommendation is worded as "we recommend," whereas a weak recommendation is presented as "we suggest." Results: Conclusions from the systematic review included (1) isolated studies reported statistically significant and clinically important improvements following early decompression at 6 months and following discharge from inpatient rehabilitation; (2) in one study on acute central cord syndrome without instability, a marginally significant improvement in total motor scores was reported at 6 and 12 months in patients managed with early versus late surgery; and (3) there were no significant differences in length of acute care/rehabilitation stay or in rates of complications between treatment groups. Our recommendations were: "We suggest that early surgery be considered as a treatment option in adult patients with traumatic central cord syndrome" and "We suggest that early surgery be offered as an option for adult acute SCI patients regardless of level." Quality of evidence for both recommendations was considered low. Conclusions: These guidelines should be implemented into clinical practice to improve outcomes in patients with acute SCI and central cord syndrome by promoting standardization of care, decreasing the heterogeneity of management strategies, and encouraging clinicians to make evidence-informed decisions. PMID- 29164025 TI - A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Use of Methylprednisolone Sodium Succinate. AB - Introduction: The objective of this guideline is to outline the appropriate use of methylprednisolone sodium succinate (MPSS) in patients with acute spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to the use of MPSS in acute SCI. A multidisciplinary Guideline Development Group used this information, in combination with their clinical expertise, to develop recommendations for the use of MPSS. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest." Results: The main conclusions from the systematic review included the following: (1) there were no differences in motor score change at any time point in patients treated with MPSS compared to those not receiving steroids; (2) when MPSS was administered within 8 hours of injury, pooled results at 6- and 12-months indicated modest improvements in mean motor scores in the MPSS group compared with the control group; and (3) there was no statistical difference between treatment groups in the risk of complications. Our recommendations were: (1) "We suggest not offering a 24-hour infusion of high dose MPSS to adult patients who present after 8 hours with acute SCI"; (2) "We suggest a 24-hour infusion of high-dose MPSS be offered to adult patients within 8 hours of acute SCI as a treatment option"; and (3) "We suggest not offering a 48-hour infusion of high-dose MPSS to adult patients with acute SCI." Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and reduce morbidity in SCI patients. PMID- 29164026 TI - A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Type and Timing of Anticoagulant Thromboprophylaxis. AB - Introduction: The objective of this study is to develop evidence-based guidelines that recommend effective, safe and cost-effective thromboprophylaxis strategies in patients with spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions relating to thromboprophylaxis in SCI. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest." Results: Based on conclusions from the systematic review and expert panel opinion, the following recommendations were developed: (1) "We suggest that anticoagulant thromboprophylaxis be offered routinely to reduce the risk of thromboembolic events in the acute period after SCI;" (2) "We suggest that anticoagulant thromboprophylaxis, consisting of either subcutaneous low-molecular-weight heparin or fixed, low-dose unfractionated heparin (UFH) be offered to reduce the risk of thromboembolic events in the acute period after SCI. Given the potential for increased bleeding events with the use of adjusted-dose UFH, we suggest against this option;" (3) "We suggest commencing anticoagulant thromboprophylaxis within the first 72 hours after injury, if possible, in order to minimize the risk of venous thromboembolic complications during the period of acute hospitalization." Conclusions: These guidelines should be implemented into clinical practice in patients with SCI to promote standardization of care, decrease heterogeneity of management strategies and encourage clinicians to make evidence-informed decisions. PMID- 29164027 TI - A Clinical Practice Guideline for the Management of Degenerative Cervical Myelopathy: Introduction, Rationale, and Scope. AB - Degenerative cervical myelopathy (DCM) is a progressive spine disease and the most common cause of spinal cord dysfunction in adults worldwide. Patients with DCM may present with common signs and symptoms of neurological dysfunction, such as paresthesia, abnormal gait, decreased hand dexterity, hyperreflexia, increased tone, and sensory dysfunction. Clinicians across several specialties encounter patients with DCM, including primary care physicians, rehabilitation specialists, therapists, rheumatologists, neurologists, and spinal surgeons. Currently, there are no guidelines that outline how to best manage patients with mild (defined as a modified Japanese Orthopedic Association (mJOA) score of 15-17), moderate (mJOA = 12-14), or severe (mJOA <= 11) myelopathy, or nonmyelopathic patients with evidence of cord compression. This guideline provides evidence-based recommendations to specify appropriate treatment strategies for these populations. The intent of our recommendations is to (1) help identify patients at high risk of neurological deterioration, (2) define the role of nonoperative and operative management in each patient population, and (3) determine which patients are most likely to benefit from surgical intervention. The ultimate goal of these guidelines is to improve outcomes and reduce morbidity in patients with DCM by promoting standardization of care and encouraging clinicians to make evidence-informed decisions. PMID- 29164030 TI - The Natural History of Degenerative Cervical Myelopathy and the Rate of Hospitalization Following Spinal Cord Injury: An Updated Systematic Review. AB - Study Method: Systematic review (update). Objective: Degenerative cervical myelopathy (DCM) is a degenerative spine disease and the most common cause of spinal cord dysfunction in adults worldwide. The objective of this study is to determine the natural history of DCM by updating the systematic review by Karadimas et al. The specific aims of this review were (1) to describe the natural history of DCM and (2) to determine potential risk factors of disease progression. Method: An updated search based on a previous protocol was conducted in PubMed and the Cochrane Collaboration library for studies published between November 2012 and February 15, 2015. Results: The updated search yielded 3 additional citations that met inclusion criteria and reported the incidence of spinal cord injury and severe disability in patients with DCM. Based on 2 retrospective cohort studies, the incidence rate of hospitalization for spinal cord injury is 13.9 per 1000 person-years in patients with cervical spondylotic myelopathy and 4.8 per 1000 person-years in patients with myelopathy secondary to ossification of the posterior longitudinal ligament (OPLL). In a third small prospective study, the risk of being wheelchair bound or bedridden was 66.7% in DCM patients with OPLL. Conclusion: The overall level of evidence for these estimated rates of hospitalization following spinal cord injury was rated as low. PMID- 29164028 TI - A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Role of Baseline Magnetic Resonance Imaging in Clinical Decision Making and Outcome Prediction. AB - Introduction: The objective of this guideline is to outline the role of magnetic resonance imaging (MRI) in clinical decision making and outcome prediction in patients with traumatic spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to the use of MRI in patients with traumatic SCI. This review focused on longitudinal studies that controlled for baseline neurologic status. A multidisciplinary Guideline Development Group (GDG) used this information, their clinical expertise, and patient input to develop recommendations on the use of MRI for SCI patients. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest." Results: Based on the limited available evidence and the clinical expertise of the GDG, our recommendations were: (1) "We suggest that MRI be performed in adult patients with acute SCI prior to surgical intervention, when feasible, to facilitate improved clinical decision-making" (quality of evidence, very low) and (2) "We suggest that MRI should be performed in adult patients in the acute period following SCI, before or after surgical intervention, to improve prediction of neurologic outcome" (quality of evidence, low). Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and prognostication for patients with SCI. PMID- 29164031 TI - Nonoperative Versus Operative Management for the Treatment Degenerative Cervical Myelopathy: An Updated Systematic Review. AB - Study Design: Systematic review (update). Objective: Degenerative cervical myelopathy (DCM) is a progressive degenerative spine disease that is increasingly managed surgically. The objective of this study is to determine the role of nonoperative treatment in the management of DCM by updating a systematic review published by Rhee and colleagues in 2013. The specific aims of this review were (1) to determine the comparative efficacy, effectiveness, and safety of nonoperative and surgical treatment; (2) to assess whether myelopathy severity differentially affects outcomes of nonoperative treatment; and (3) to evaluate whether activities or minor injuries are associated with neurological deterioration. Methods: Methods from the original review were used to search for new literature published between July 20, 2012, and February 12, 2015. Results: The updated search yielded 2 additional citations that met inclusion criteria and compared the efficacy of conservative management and surgical treatment. Based on a single retrospective cohort, there were no significant differences in posttreatment Japanese Orthopaedic Association (JOA) or Neck Disability Index scores or JOA recovery ratios between patients treated nonoperatively versus operatively. A second retrospective study indicated that the incidence rate of hospitalization for spinal cord injury was 13.9 per 1000 person-years in a nonoperative group compared with 9.4 per 1000 person-years in a surgical group (adjusted hazard ratio = 1.57; 95% confidence interval = 1.11-2.22; P = .011). Conclusion: Nonoperative management results in similar outcomes as surgical treatment in patients with a modified JOA >= 13, single-level myelopathy and intramedullary signal change on T2-weighted magnetic resonance imaging. Furthermore, patients managed nonoperatively for DCM have higher rates of hospitalization for spinal cord injury than those treated surgically. The overall level of evidence for these findings was rated as low. PMID- 29164029 TI - A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Type and Timing of Rehabilitation. AB - Introduction: The objective of this study is to develop guidelines that outline the appropriate type and timing of rehabilitation in patients with acute spinal cord injury (SCI). Methods: A systematic review of the literature was conducted to address key questions related to rehabilitation in patients with acute SCI. A multidisciplinary guideline development group used this information, and their clinical expertise, to develop recommendations for the type and timing of rehabilitation. Based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation), a strong recommendation is worded as "we recommend," whereas a weaker recommendation is indicated by "we suggest. Results: Based on the findings from the systematic review, our recommendations were: (1) We suggest rehabilitation be offered to patients with acute spinal cord injury when they are medically stable and can tolerate required rehabilitation intensity (no included studies; expert opinion); (2) We suggest body weight-supported treadmill training as an option for ambulation training in addition to conventional overground walking, dependent on resource availability, context, and local expertise (low evidence); (3) We suggest that individuals with acute and subacute cervical SCI be offered functional electrical stimulation as an option to improve hand and upper extremity function (low evidence); and (4) Based on the absence of any clear benefit, we suggest not offering additional training in unsupported sitting beyond what is currently incorporated in standard rehabilitation (low evidence). Conclusions: These guidelines should be implemented into clinical practice to improve outcomes and reduce morbidity in patients with SCI by promoting standardization of care, decreasing the heterogeneity of management strategies and encouraging clinicians to make evidence-informed decisions. PMID- 29164032 TI - Change in Function, Pain, and Quality of Life Following Structured Nonoperative Treatment in Patients With Degenerative Cervical Myelopathy: A Systematic Review. AB - Study Design: Systematic review. Objectives: The objective of this study was to conduct a systematic review to determine (1) change in function, pain, and quality of life following structured nonoperative treatment for degenerative cervical myelopathy (DCM); (2) variability of change in function, pain, and quality of life following different types of structured nonoperative treatment; (3) differences in outcomes observed between certain subgroups (eg, baseline severity score, duration of symptoms); and (4) negative outcomes and harms resulting from structured nonoperative treatment. Methods: A systematic search was conducted in Embase, PubMed, and the Cochrane Collaboration for articles published between January 1, 1950, and February 9, 2015. Studies were included if they evaluated outcomes following structured nonoperative treatment, including therapeutic exercise, manual therapy, cervical bracing, and/or traction. The quality of each study was evaluated using the Newcastle-Ottawa Scale, and strength of the overall body of evidence was rated using guidelines outlined by the Grading of Recommendation Assessment, Development and Evaluation Working Group. Results: Of the 570 retrieved citations, 8 met inclusion criteria and were summarized in this review. Based on our results, there is very low evidence to suggest that structured nonoperative treatment for DCM results in either a positive or negative change in function as evaluated by the Japanese Orthopaedic Association score. Conclusion: There is a lack of evidence to determine the role of nonoperative treatment in patients with DCM. However, in the majority of studies, patients did not achieve clinically significant gains in function following structured nonoperative treatment. Furthermore, 23% to 54% of patients managed nonoperatively subsequently underwent surgical treatment. PMID- 29164034 TI - Guidelines for the Management of Degenerative Cervical Myelopathy and Spinal Cord Injury: An Introduction to a Focus Issue. AB - Study Design: Introduction to a guidelines project. Objectives: The objective of this focus issue is to present guidelines that outline how to best manage patients with degenerative cervical myelopathy (DCM) and spinal cord injury (SCI). Topics addressed in this focus issue include: 1) management strategies for patients with mild, moderate and severe DCM; and 2a) timing of surgical decompression; b) the use of methylprednisolone sodium succinate; c) the type and timing of anticoagulation strategies; d) the role of magnetic resonance imaging in clinical decision making and outcome prediction; and e) the type and timing of rehabilitation in patients with SCI. Methods: Systematic reviews were conducted to address key clinical questions and to synthesize the current body of evidence. A multidisciplinary guideline development group used the results of these reviews, along with their clinical expertise, to develop clinical practice guidelines, in a process that adhered to methodology proposed by the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group. Results: The multidisciplinary guideline development group combined the systematic review findings with their clinical expertise and opinions to formulate recommendations on how to manage patients with DCM and SCI. Conclusions: These guidelines will serve as tools to assist clinicians in their decision making by offering a perspective that combines the available evidence, expertise from a variety of clinicians, and patient values. PMID- 29164033 TI - Change in Functional Impairment, Disability, and Quality of Life Following Operative Treatment for Degenerative Cervical Myelopathy: A Systematic Review and Meta-Analysis. AB - Study Design: Systematic review. Objectives: The primary objective of this systematic review was to define the change in impairment, disability, and pain following surgical intervention in patients with degenerative cervical myelopathy (DCM). Secondary objectives included to assess the impact of preoperative disease severity and duration of symptoms on outcomes and to summarize complications associated with surgery. Methods: A systematic literature search was conducted to identify prospective studies evaluating the effectiveness and safety of operative treatment in patients with DCM. Outcomes of interest were functional status, disability, pain, and complications. The quality of each study was evaluated using the Newcastle-Ottawa Scale, and the strength of the overall body of evidence was rated using guidelines outlined by the Grading of Recommendation Assessment, Development and Evaluation (GRADE) Working Group. Results: Of the 385 retrieved citations, 32 met inclusion criteria and are summarized in this review. Based on our results, pooled standard mean differences showed a large effect for improvement in Japanese Orthopaedic Association or modified Japanese Orthopaedic Association score from baseline at short-, medium-, and long-term follow-up: 6 to 12 months (1.92; 95% confidence interval [CI] = 1.41 to 2.43), 13 to 36 months (1.40; 95% CI = 1.12 to 1.67), and >=36 months (1.92; 95% CI = 1.14 to 2.69) (moderate evidence). Surgery also resulted in significant improvements in Nurick, Neck Disability Index, and Visual Analogue Scale scores (low to very low evidence). The cumulative incidence of complications was low (14.1%; 95% CI = 10.1% to 18.2%). Conclusion: Surgical intervention for DCM results in significant improvements in functional impairment, disability, and pain and is associated with an acceptably low rate of complications. PMID- 29164036 TI - A Clinical Practice Guideline for the Management of Acute Spinal Cord Injury: Introduction, Rationale, and Scope. AB - Acute spinal cord injury (SCI) is a traumatic event that results in disturbances to normal sensory, motor, or autonomic function and ultimately affects a patient's physical, psychological, and social well-being. The management of patients with SCI has drastically evolved over the past century as a result of increasing knowledge on injury mechanisms, disease pathophysiology, and the role of surgery. There still, however, remain controversial areas surrounding available management strategies for the treatment of SCI, including the use of corticosteroids such as methylprednisolone sodium succinate, the optimal timing of surgical intervention, the type and timing of anticoagulation prophylaxis, the role of magnetic resonance imaging, and the type and timing of rehabilitation. This lack of consensus has prevented the standardization of care across treatment centers and among the various disciplines that encounter patients with SCI. The objective of this guideline is to form evidence-based recommendations for these areas of controversy and outline how to best manage patients with SCI. The ultimate goal of these guidelines is to improve outcomes and reduce morbidity in patients with SCI by promoting standardization of care and encouraging clinicians to make evidence-informed decisions. PMID- 29164035 TI - A Clinical Practice Guideline for the Management of Patients With Degenerative Cervical Myelopathy: Recommendations for Patients With Mild, Moderate, and Severe Disease and Nonmyelopathic Patients With Evidence of Cord Compression. AB - Study Design: Guideline development. Objectives: The objective of this study is to develop guidelines that outline how to best manage (1) patients with mild, moderate, and severe myelopathy and (2) nonmyelopathic patients with evidence of cord compression with or without clinical symptoms of radiculopathy. Methods: Five systematic reviews of the literature were conducted to synthesize evidence on disease natural history; risk factors of disease progression; the efficacy, effectiveness, and safety of nonoperative and surgical management; the impact of preoperative duration of symptoms and myelopathy severity on treatment outcomes; and the frequency, timing, and predictors of symptom development. A multidisciplinary guideline development group used this information, and their clinical expertise, to develop recommendations for the management of degenerative cervical myelopathy (DCM). Results: Our recommendations were as follows: (1) "We recommend surgical intervention for patients with moderate and severe DCM." (2) "We suggest offering surgical intervention or a supervised trial of structured rehabilitation for patients with mild DCM. If initial nonoperative management is pursued, we recommend operative intervention if there is neurological deterioration and suggest operative intervention if the patient fails to improve." (3) "We suggest not offering prophylactic surgery for non-myelopathic patients with evidence of cervical cord compression without signs or symptoms of radiculopathy. We suggest that these patients be counseled as to potential risks of progression, educated about relevant signs and symptoms of myelopathy, and be followed clinically." (4) "Non-myelopathic patients with cord compression and clinical evidence of radiculopathy with or without electrophysiological confirmation are at a higher risk of developing myelopathy and should be counselled about this risk. We suggest offering either surgical intervention or nonoperative treatment consisting of close serial follow-up or a supervised trial of structured rehabilitation. In the event of myelopathic development, the patient should be managed according to the recommendations above." Conclusions: These guidelines will promote standardization of care for patients with DCM, decrease the heterogeneity of management strategies and encourage clinicians to make evidence-informed decisions. PMID- 29164037 TI - Guidelines for the Management of Degenerative Cervical Myelopathy and Acute Spinal Cord Injury: Development Process and Methodology. AB - The Institute of Medicine defines clinical practice guidelines as "statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options." Guidelines help clinicians implement best evidence into practice and encourage informed shared decision making with patients. Guidelines are intended to enhance the quality of patient care by discouraging ineffective and potentially harmful interventions and standardizing practice. Standards for the development and appraisal of guidelines, such as those proposed by the Institute of Medicine and other organizations, help assure guideline quality and credibility. Primary standards include establishing transparency, managing conflicts of interest, forming a multidisciplinary guideline development group, conducting methodologically sound systematic reviews, developing evidence based recommendations, balancing risks and harms, and rating the strength of recommendations based on the confidence in the evidence. Furthermore, the guideline document must be appraised internally and externally and updated when new evidence arises. The Grading of Recommendation, Assessment, Development and Evaluation process helps appraise the existing body of evidence as well as provide an interactive framework for weighing the benefits and harms of treatment options and translating evidence to recommendations. This article summarizes the methodology used to develop clinical practice guidelines for the management of degenerative cervical myelopathy and acute spinal cord injury. PMID- 29164039 TI - Not One for All. PMID- 29164038 TI - Timing of Decompression in Patients With Acute Spinal Cord Injury: A Systematic Review. AB - Study Design: Systematic review. Objective: To conduct a systematic review and synthesis of the literature to assess the comparative effectiveness, safety, and cost-effectiveness of early (<=24 hours) versus late decompression (>24 hours) in adults with acute spinal cord injury (SCI). Methods: A systematic search was conducted of Medline, EMBASE, the Cochrane Collaboration Library, and Google Scholar to identify studies published through November 6, 2014. Studies published in any language, in humans, and with an abstract were considered for inclusion. Included studies were critically appraised and the overall strength of evidence was determined using methods proposed by the Grading of Recommendation Assessment, Development and Evaluation working group. Results: The search yielded 449 potentially relevant citations. Sixteen additional primary studies were identified through other sources. Six studies met inclusion criteria. All but 2 studies were considered to have moderately high risk of bias. Across studies and injury levels, the impact of early surgical decompression (<=24 hours) on clinically important improvement in neurological status was variable. Isolated studies reported statistically significant and clinically important improvements at 6 months (cervical injury, low strength of evidence) and following discharge from inpatient rehabilitation (all levels, very low strength of evidence) but not at other time points; another study observed a statistically significant 6 point improvement in ASIA Impairment Scale (AIS) among patients with AIS B, C, or D, but not for those with AIS A (very low strength of evidence). In one study of acute central cord syndrome without instability, a clinically and statistically meaningful improvement in total motor scores was reported at 6 and 12 months in patients treated early (versus late). There were, however, no significant differences in AIS improvement between early and late surgical groups at 6- or 12 months (very low strength of evidence). One of 3 studies found a shorter length of hospital stay associated with early surgical decompression. Of 3 studies reporting on safety, no significant differences in rates of complications (including mortality, neurologic deterioration, pneumonia or pressure ulcers) were noted between early and late decompression groups. Conclusions: Results surrounding the efficacy of early versus late decompressive surgery, as well as the quality of evidence available, were variable depending on the level of SCI, timing of follow-up, and specific outcome considered. Existing evidence supports improved neurological recovery among cervical SCI patients undergoing early surgery; however, evidence regarding remaining SCI populations and clinical outcomes was inconsistent. PMID- 29164040 TI - Regional Disparity and Factors Influencing Unmet Medical Needs: A Study Based on the Sixth Korea National Health and Nutrition Examination Survey (2015). AB - Objectives: This study aimed to determine regional differences and the factors that affect unmet medical needs. Methods: Data from the 6th Korea National Health and Nutrition Examination Survey (2015) were used, and 4,946 health survey participants who provided responses on medical utilization and health behavior were included in the study. Results: A statistically significant difference was observed in the incidence rate of unmet medical needs in terms of region. The independent variables that affected unmet medical needs were sex, age, education, region, household income, insurance type, smoking status, self-reported health status, and stress awareness. Gender (female), lower education level, rural residents, lowest household income, poor self-reported health status, and stress awareness increased the probability of unmet medical needs. Conclusion: Our findings suggested that different policies and approaches should be considered for each population that is at risk to address the primary cause of the unmet medical needs. Further studies that include medical expenses and the relevant variables of an area should be conducted in the future. PMID- 29164041 TI - Prevalence and Risk Factors of Intestinal Parasite Infection among Schoolchildren in the Peripheral Highland Regions of Huanuco, Peru. AB - Objectives: Schoolchildren in developing countries are at greater risk of intestinal parasitic infections. This study aimed to estimate the prevalence and assess the risk factors of intestinal parasite infection among schoolchildren in rural areas of Peru. Methods: A volunteer team from the Korea International Cooperation Agency (KOICA) conducted a campaign for parasite eradication called "Chao parasitos" at five schools in the peripheral highland regions of Huanuco in October 2013. The study collected questionnaires and stool samples from children of participating schools. Entamoeba coli, Iodamoeba buschii, and Chilomastix mesnil were classified as nonpathogenic parasites. Results: The overall prevalence of intestinal parasite infection in the students was 100% (185/185). Among them, 25.9% (48/185) were infected only with nonpathogenic parasites whereas 74.1% (137/185) were infected with at least one pathogenic parasite. Ascaris lumbricoides was the most commonly detected (37.3%, 69/185), followed by Giardia lamblia (15.1%, 28/185) and I. buschii (11.9%, 22/185). Among lifestyle practices associated with parasitic infection, the rate of washing hands before meals was significantly lower in the students with pathogenic parasites compared to those with nonpathogenic parasites (77.4%, 106/137 vs. 93.8%, 45/48, p = 0.025). Conclusion: The prevalence of intestinal parasite was 100%. Both personal hygiene and water supply facilities are required to eradicate parasite infection in rural areas of Peru. PMID- 29164042 TI - Different Effects of Cognitive and Non-exercise Physical Leisure Activities on Cognitive Function by Age in Elderly Korean Individuals. AB - Objectives: We aimed to examine the effects of various leisure activities on cognitive impairment in young-old (aged 65-74 years) and old-old (aged >= 75 years) adults. Methods: In total, 10,279 elderly Korean individuals from the 2014 Korean National Survey on Older Adults' cohort were enrolled in our study. Cognitive impairment was assessed using the standardized score of the Mini-Mental State Examination for Dementia Screening, whereas leisure activities were recorded via self-reporting of the extent and type of leisure activity the subjects involved in over the past year. Multivariate logistic regression was used to assess the effect of leisure activities on cognitive impairment, while controlling for potential covariates. Results: The subjects were more likely to participate in cognitive activities than in non-exercise physical activities. After controlling for selected covariates, involvement in cognitive activities was found to be a significant predictor of cognitive impairment in both the groups, whereas involvement in non-exercise physical activities was not a predictor of cognitive impairment in individuals aged >= 75 years. Moreover, depressive symptoms, rural residence, and hearing difficulties were common predictors of cognitive impairment among elderly-Korean-individuals. Conclusion: Leisure activity involvement may help delay cognitive impairment, which is often concomitant with aging. Hence, an early intervention service may significantly benefit both young-old and old-old individuals. PMID- 29164044 TI - Characterization of Clostridium difficile Strains Isolated from Patients with C. difficile-associated Disease in Korea. AB - Objectives: Studies on Clostridium difficile are rare in Korea. We investigated the epidemiological characteristics of C. difficile isolates from patients with C. difficile-associated disease (CDAD) in Korea. Methods: Multiplex polymerase chain reaction was performed to detect the presence of tcdA and tcdB toxin genes. Antimicrobial susceptibility test was carried out by the disk-dilution method. C. difficile strains were subtyped by automated repetitive-element palindromic PCR (rep-PCR). Results: Among patients with CDAD, 73 (25.8%), 32 (11.3%), 32 (11.3%), and 26 (9.2%) suffered from pneumonia, cancer or neoplasm, diabetes, and colitis, respectively. Of all stool samples, 43 samples (15.2%) were positive for C. difficile strains. We observed two expression patterns of toxin genes: tcdA+/tcdB+ (86% isolates) and tcdA-/tcdB+ (14% isolates), with all isolates expressing tcdB. Furthermore, some isolates were resistant to clindamycin (65%), ampicillin (56%), and cefazolin (40%), but all were susceptible to vancomycin and metronidazole. The tested samples were classified into diverse clusters using automated rep-PCR. Conclusion: Our findings revealed the characteristics and antibiotic resistance of C. difficile isolates from patients in Korea. The epidemiological data may provide valuable insight into development of treatment strategies for C. difficile infections in Korea. PMID- 29164043 TI - Antiviral Activity of Itraconazole against Echovirus 30 Infection In Vitro. AB - Objectives: Echovirus 30 is a major cause of meningitis in children and adults. The aim of this study was to investigate whether the antifungal drug itraconazole could exhibit antiviral activity against echovirus 30. Methods: The cytopathic effect and viral RNA levels were assessed in RD cells as indicators of viral replication. The effects of itraconazole were compared to those of two known antiviral drugs, rupintrivir and pleconaril. The time course and time-of-addition assays were used to approximate the time at which itraconazole exerts its activity in the viral cycle. Results: Itraconazole and rupintrivir demonstrated the greatest potency against echovirus 30, demonstrating concentration-dependent activity, whereas pleconaril showed no antiviral activity. Itraconazole did not directly inactivate echovirus 30 particles or impede viral uptake into RD cells, but did affect the initial stages of echovirus 30 infection through interference with viral replication. Conclusion: Itraconazole can be considered a lead candidate for the development of antiviral drugs against echovirus 30 that may be used during the early stages of echovirus 30 replication. PMID- 29164045 TI - Factors Related to Healthcare Service Quality in Long-term Care Hospitals in South Korea: A Mixed-methods Study. AB - Objectives: The environment of long-term care hospitals (LTCHs) is critical to the management of the quality of their services and to patient safety, as highlighted by international studies. However, there is a lack of evidence on this topic in South Korea. This study aimed to examine the factors affecting healthcare quality in LTCHs and to explore the effectiveness of their quality management. Methods: This study used a mixed methods approach with quantitative data collected in a national survey and qualitative data from semi-structured interviews with practice-based managers. The samples included 725 nationally representative LTCHs in South Korea for the quantitative analysis and 15 administrators for the in-depth interviews. Results: A higher installation rate of patient-safety and hygiene-related facilities and staff with longer-tenures, especially nurses, were more likely to have better healthcare quality and education for both employees and patients. Conclusion: The need for patient safety- and hygiene-related facilities in LTCHs that serve older adults reflects their vulnerability to certain adverse events (e.g., infections). Consistent and skillful nursing care to improve the quality of LTCHs can be achieved by developing relevant educational programs for staff and patients, thereby strengthening the relationships between them. PMID- 29164046 TI - Comparative Analysis of the Trends in Medical Utilization of Cancer Inpatients in Korea. AB - Objectives: Cancer has attracted worldwide attention. The incidence and prevalence are increasing, and it is the main cause of death. The purpose of this study was to identify the characteristics of hospitalized cancer patients. Methods: This study is a secondary data study using the Korean National Hospital Discharge In-depth Injury Survey Data conducted annually by the Korea Centers for Disease Control and Prevention. Using these data, we extracted inpatients who principal diagnosis is cancer for nine years from 2005 to 2013. Results: According to the analysis, the annual trend of cancer inpatients is steadily increasing. In 2025, it is expected to increase to about 670,000 inpatients. A cancer diagnosis created a change in medical utilization depending on the characteristics of patients and hospital. Men are more at risk of cancer than women. The number of hospital beds and hospital days were inversely proportional to cancer inpatients. There was also a difference in the equity of medical utilization by region. Other cancer management policies should be based on sex. Conclusion: Populations between the ages of 45 and 64 years should be a priority in cancer policy. Because of the long-term hospitalization of patients with death as the outcome, a terminal cancer patient care facility is needed. These conclusions can provide a basis for various health policies. PMID- 29164047 TI - Cost of Tuberculosis Treatment: Evidence from Iran's Health System. AB - Objectives: This study aimed to estimate the cost of smear-positive drug susceptible pulmonary tuberculosis (TB) treatment of the patients in the Azadshahr district, Golestan Province, Iran. Methods: In this retrospective study, all new smear positive pulmonary TB patients who had been registered at the district's health network between April, 2013 and December, 2015 and had successfully completed their treatment were entered into the study (45 patients). Treatment costs were estimated from the provider's perspective using an activity based costing (ABC) method. Results: The cost of treating a new smear-positive pulmonary TB patient was US dollar (USD) 1,409.00 (Iranian Rial, 39,438,260), which can be divided into direct and indirect costs (USD 1,226.00 [87%] and USD 183.00 [13%], respectively). The highest cost (58.1%) was related to care and management of TB patients (including 46.1% human resources costs and 12% directly observed treatment, short course implementation) and then respectively related to hospitalization (12.1%), supportive activity centers (11.4%), transportation (6.5%), medicines (5.3%), and laboratory tests and radiography (3.2%). Conclusion: Using disease-specific cost studies can help the healthcare system management to have correct insight into the financial burden created by the disease. This can subsequently be used in prioritization, planning, operational budgeting, economic evaluation of programs, interventions, and ultimately in disease management. PMID- 29164048 TI - A Retrospective Mid- and Long-term Follow-up Study on the Changes in Hematologic Parameters in the Highly Exposed Residents of the Hebei Spirit Oil Spill in Taean, South Korea. AB - Objectives: This study aimed to analyze changes in hematologic parameters in the residents of the areas highly contaminated by the Hebei Spirit Oil Spill in 2007 and those who participated in the clean-up activities. Methods: According to demographic characteristics, health status and behavior, and level of exposure to oil, we compared the hematologic results in 2009 and 2012 among 701 residents. The hematologic parameters were composed of white blood cell (WBC) count, and levels of hemoglobin, hematocrit (Hct), aspartate aminotransferase (AST), alanine aminotransferase (ALT), glucose, glycosylated hemoglobin (HbA1c), blood urea nitrogen (BUN), creatinine (Cr), total cholesterol (T-chol), high-density lipoprotein (HDL), and triglyceride (TG). Results: Paired t-test revealed that the WBC count and levels of Hct, AST, ALT, glucose, and HbA1c significantly increased, whereas the BUN, Cr, HDL, and TG levels significantly decreased. Multiple linear regression modelling showed a relationship between the level of exposure to oil and temporal changes in Hct, glucose, HbA1c, and BUN levels. Conclusion: Our results suggest a relationship between level of exposure to oil and changes in hematologic parameters over 3 years. Further studies should be conducted to determine the impact of oil spill on health such as the occurrence of diseases. PMID- 29164049 TI - Polyphenols Treatment in Patients with Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) affects 25-30% of the general population worldwide and this high prevalence is linked with lifestyle and dietetic changes, not only in Western countries, but also in the urban areas of developing countries. Several pharmacological approaches were proposed in the treatment of NAFLD, but the reported results are inconclusive. International guidelines recommended the reduction of dietary fat and fructose, in association with some physical activity. In this context, it was reported that the protective effects of traditional Mediterranean diet, related to the high concentration of antioxidant compounds, particularly of polyphenols. Polyphenols are a heterogeneous class of plant derived compounds, with some proven hepatoprotective effects. Our opinion is that the adherence to traditional Mediterranean diet characterized by the consumption of antioxidant-rich foods in general and of polyphenols in particular, can be considered as a potential new approach in the treatment of NAFLD. PMID- 29164050 TI - Colorectal Stenting for Obstruction due to Retrorectal Tumor in a Patient Unsuitable for Surgery. AB - Fund of knowledge on palliative treatment of unresectable retrorectal tumors is scare. Here, we reported a non-surgical treatment of a huge retrorectal malignant tumor in an aged and debilitated patient complicated with colorectal obstruction. An 86-year-old male with severe comorbidities was admitted with acute colorectal obstruction owing to an untreated retrorectal malign epithelial tumor. There was a lobulated retrorectal mass, 20 cm * 15 cm at largest size, extending to the superior iliac bifurcation level, caused an obstruction of the rectal lumen. He was not suitable for surgical excision because of the severe comorbidities. Rectal obstruction was palliated by two self-expandable metallic stents. He tolerated the procedures well and post-procedural course was uneventful. After four months, stents were patent and the patient was continent. Stenting for colorectal obstruction owing to a retrorectal tumor can be feasible in patients who are not suitable for surgery (aged, debilitated, advanced tumor). It avoided the surgical trauma to a high-risk patient and ensured the continuity of continence. As far as we know, this was the first report on colorectal stenting for a retrorectal tumor. PMID- 29164051 TI - Anti-inflammatory Microglia/Macrophages As a Potential Therapeutic Target in Brain Metastasis. AB - Brain metastasis is a common complication of cancer patients and is associated with poor survival. Histological data from patients with brain metastases suggest that microglia are the major immune population activated around the metastatic foci. Microglia and macrophages have the ability to polarize to different phenotypes and to exert both tumorigenic and cytotoxic effects. However, the role of microglia/macrophages during the early stages of metastatic growth in the brain has not yet been determined. The aim of this study was to profile microglial/macrophage activation in a mouse model of breast cancer brain metastasis during the early stages of tumor growth, and to assess the role of the anti-inflammatory microglial/macrophage population, specifically, during this phase. Following intracerebral injection of 5 * 103 4T1-GFP mammary carcinoma cells into female BALB/c mice, robust microglial/macrophage activation around the 4T1 metastatic foci was evident throughout the time-course studied (28 days) and correlated positively with tumor volume (R2 = 0.67). Populations of classically (proinflammatory) and alternatively (anti-inflammatory) activated microglia/macrophages were identified immunohistochemically by expression of either induced nitric oxide synthase/cyclooxygenase 2 or mannose receptor 1/arginase 1, respectively. Temporally, levels of both pro- and anti-inflammatory cells were broadly stable across the time-course. Subsequently, selective depletion of the anti-inflammatory microglia/macrophage population by intracerebral injection of mannosylated clodronate liposomes significantly reduced metastatic tumor burden (p < 0.01). Moreover, increased levels of apoptosis were associated with tumors in clodronate liposome treated animals compared to controls (p < 0.05). These findings suggest that microglia/macrophages are important effectors of the inflammatory response in the early stages of brain metastasis, and that targeting the anti-inflammatory microglial/macrophage population may offer an effective new therapeutic avenue for patients with brain metastases. PMID- 29164052 TI - Development of Novel Patient-Derived Xenografts from Breast Cancer Brain Metastases. AB - Brain metastases are an increasing burden among breast cancer patients, particularly for those with HER2+ and triple negative (TN) subtypes. Mechanistic insight into the pathophysiology of brain metastases and preclinical validation of therapies has relied almost exclusively on intracardiac injection of brain homing cells derived from highly aggressive TN MDA-MB-231 and HER2+ BT474 breast cancer cell lines. Yet, these well characterized models are far from representing the tumor heterogeneity observed clinically and, due to their fast progression in vivo, their suitability to validate therapies for established brain metastasis remains limited. The goal of this study was to develop and characterize novel human brain metastasis breast cancer patient-derived xenografts (BM-PDXs) to study the biology of brain metastasis and to serve as tools for testing novel therapeutic approaches. We obtained freshly resected brain metastases from consenting donors with breast cancer. Tissue was immediately implanted in the mammary fat pad of female immunocompromised mice and expanded as BM-PDXs. Brain metastases from 3/4 (75%) TN, 1/1 (100%) estrogen receptor positive (ER+), and 5/9 (55.5%) HER2+ clinical subtypes were established as transplantable BM-PDXs. To facilitate tracking of metastatic dissemination using BM-PDXs, we labeled PDX dissociated cells with EGFP-luciferase followed by reimplantation in mice, and generated a BM-derived cell line (F2-7). Immunohistologic analyses demonstrated that parental and labeled BM-PDXs retained expression of critical clinical markers such as ER, progesterone receptor, epidermal growth factor receptor, HER2, and the basal cell marker cytokeratin 5. Similarly, RNA sequencing analysis showed clustering of parental, labeled BM-PDXs and their corresponding cell line derivative. Intracardiac injection of dissociated cells from BM-E22-1, resulted in magnetic resonance imaging-detectable macrometastases in 4/8 (50%) and micrometastases (8/8) (100%) mice, suggesting that BM-PDXs remain capable of colonizing the brain at high frequencies. Brain metastases developed 8-12 weeks after ic injection, located to the brain parenchyma, grew around blood vessels, and elicited astroglia activation characteristic of breast cancer brain metastasis. These novel BM-PDXs represent heterogeneous and clinically relevant models to study mechanisms of brain metastatic colonization, with the added benefit of a slower progression rate that makes them suitable for preclinical testing of drugs in therapeutic settings. PMID- 29164053 TI - Synergistic Protective Activity of Tumor-Specific Epitopes Engineered in Bacterial Outer Membrane Vesicles. AB - Introduction: Bacterial outer membrane vesicles (OMVs) are naturally produced by all Gram-negative bacteria and, thanks to their plasticity and unique adjuvanticity, are emerging as an attractive vaccine platform. To test the applicability of OMVs in cancer immunotherapy, we decorated them with either one or two protective epitopes present in the B16F10EGFRvIII cell line and tested the protective activity of OMV immunization in C57BL/6 mice challenged with B16F10EGFRvIII. Materials and methods: The 14 amino acid B cell epitope of human epidermal growth factor receptor variant III (EGFRvIII) and the mutation-derived CD4+ T cell neo-epitope of kif18b gene (B16-M30) were used to decorate OMVs either alone or in combination. C57BL/6 were immunized with the OMVs and then challenged with B16F10EGFRvIII cells. Immunogenicity and protective activity was followed by measuring anti-EGFRvIII antibodies, M30-specific T cells, tumor infiltrating cell population, and tumor growth. Results: Immunization with engineered EGFRvIII-OMVs induced a strong inhibition of tumor growth after B16F10EGFRvIII challenge. Furthermore, mice immunized with engineered OMVs carrying both EGFRvIII and M30 epitopes were completely protected from tumor challenge. Immunization was accompanied by induction of high anti-EGFRvIII antibody titers, M30-specific T cells, and infiltration of CD4+ and CD8+ T cells at the tumor site. Conclusion: OMVs can be decorated with tumor antigens and can elicit antigen-specific, protective antitumor responses in immunocompetent mice. The synergistic protective activity of multiple epitopes simultaneously administered with OMVs makes the OMV platform particularly attractive for cancer immunotherapy. PMID- 29164054 TI - Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates. AB - Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG), patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB). We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED) may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment) of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%)-carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole-are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG. PMID- 29164056 TI - Prostate Cancer Imaging and Biomarkers Guiding Safe Selection of Active Surveillance. AB - Background: Active surveillance (AS) is a widely adopted strategy to monitor men with low-risk, localized prostate cancer (PCa). Current AS inclusion criteria may misclassify as many as one in four patients. The advent of multiparametric magnetic resonance imaging (mpMRI) and novel PCa biomarkers may offer improved risk stratification. We performed a review of recently published literature to characterize emerging evidence in support of these novel modalities. Methods: An English literature search was conducted on PubMed for available original investigations on localized PCa, AS, imaging, and biomarkers published within the past 3 years. Our Boolean criteria included the following terms: PCa, AS, imaging, biomarker, genetic, genomic, prospective, retrospective, and comparative. The bibliographies and diagnostic modalities of the identified studies were used to expand our search. Results: Our review identified 222 original studies. Our expanded search yielded 244 studies. Among these, 70 met our inclusion criteria. Evidence suggests mpMRI offers improved detection of clinically significant PCa, and MRI-fusion technology enhances the sensitivity of surveillance biopsies. Multiple studies demonstrate the promise of commercially available screening assays for prediction of AS failure, and several novel biomarkers show promise in this setting. Conclusion: In the era of AS for men with low-risk PCa, improved strategies for proper stratification are needed. mpMRI has dramatically enhanced the detection of clinically significant PCa. The advent of novel biomarkers for prediction of aggressive disease and AS failure has shown some initial promise, but further validation is warranted. PMID- 29164055 TI - microRNAs and Acute Myeloid Leukemia Chemoresistance: A Mechanistic Overview. AB - Up until the early 2000s, a functional role for microRNAs (miRNAs) was yet to be elucidated. With the advent of increasingly high-throughput and precise RNA sequencing techniques within the last two decades, it has become well established that miRNAs can regulate almost all cellular processes through their ability to post-transcriptionally regulate a majority of protein-coding genes and countless other non-coding genes. In cancer, miRNAs have been demonstrated to play critical roles by modifying or controlling all major hallmarks including cell division, self-renewal, invasion, and DNA damage among others. Before the introduction of anthracyclines and cytarabine in the 1960s, acute myeloid leukemia (AML) was considered a fatal disease. In decades since, prognosis has improved substantially; however, long-term survival with AML remains poor. Resistance to chemotherapy, whether it is present at diagnosis or induced during treatment is a major therapeutic challenge in the treatment of this disease. Certain mechanisms such as DNA damage response and drug targeting, cell cycling, cell death, and drug trafficking pathways have been shown to be further dysregulated in treatment resistant cancers. miRNAs playing key roles in the emergence of these drug resistance phenotypes have recently emerged and replacement or inhibition of these miRNAs may be a viable treatment option. Herein, we describe the roles miRNAs can play in drug resistant AML and we describe miRNA-transcript interactions found within other cancer states which may be present within drug resistant AML. We describe the mechanisms of action of these miRNAs and how they can contribute to a poor overall survival and outcome as well. With the precision of miRNA mimic- or antagomir-based therapies, miRNAs provide an avenue for exquisite targeting in the therapy of drug resistant cancers. PMID- 29164057 TI - Diagnostic and Prognostic Significance of Methionine Uptake and Methionine Positron Emission Tomography Imaging in Gliomas. AB - The present most common image diagnostic tracer in clinical practice for glioma is 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for brain tumors diagnosis and prognosis. PET is a promising molecular imaging technique, which provides real-time information on the metabolic behavior of the tracer. The diffusive nature of glioblastoma (GBM) and heterogeneity often make the radiographic detection by FDG-PET inaccurate, and there is no gold standard. FDG PET often leads to several controversies in making clinical decisions due to their uptake by normal surrounding tissues, and pose a challenge in delineating treatment-induced necrosis, edema, inflammation, and pseudoprogression. Thus, it is imperative to find new criteria independent of conventional morphological diagnosis to demarcate normal and tumor tissues. We have provided proof of concept studies for 11C methionine-PET (MET-PET) imaging of gliomas, along with prognostic and diagnostic significance. MET-PET is not widely used in the United States, though clinical trials from Japan and Germany suggesting the diagnostic ability of MET-PET imaging are superior to FDG-PET imaging for brain tumors. A major impediment is the availability of the onsite cyclotron and isotopic carbon chemistry facilities. In this article, we have provided the scientific rationale and advantages of the use of MET-PET as GBM tracers. We extend our discussion on the expected pitfalls of using MET-PET and ways to overcome them by incorporating a translational component of profiling gene status in the methionine metabolic pathway. This translational correlative component to the MET-PET clinical trials can lead to a better understanding of the existing controversies and can enhance our knowledge for future randomization of GBM patients based on their tumor gene signatures to achieve better prognosis and treatment outcome. PMID- 29164058 TI - Delineation of the HPV11E6 and HPV18E6 Pathways in Initiating Cellular Transformation. AB - Although high-risk human papillomaviruses (HPVs) are the major risk factors for cervical cancer they have been associated with several other cancers, such as head and neck and oral cancers. Since integration of low-risk HPV11 DNA has been demonstrated in esophageal tumor genomes, this study compared the effects of low risk HPV11E6 and high-risk HPV18E6 on cellular gene expression. The HPV11E6 and HPV18E6 genes were cloned into an adenoviral vector and expressed in human keratinocytes (HaCaT) in order to investigate early events and to eliminate possible artifacts introduced by selective survival of fast growing cells in stable transfection experiments. HPV11E6 had very little effect on p21 and p53 gene expression, while HPV18E6 resulted in a marked reduction in both these proteins. Both HPV11E6 and HPV18E6 enabled growth of colonies in soft agar, but the level of colony formation was higher in HPV18E6 infected cells. DNA microarray analysis identified significantly differentially regulated genes involved in the cellular transformation signaling pathways. These findings suggest that HPV11E6 and HPV18E6 are important in initiating cellular transformation via deregulation of signaling pathways such as PI3K/AKT and pathways that are directly involved in DNA damage repair, cell survival, and cell proliferation. This study shows that the low-risk HPV11E6 may have similar effects as the high-risk HPV18E6 during the initial stages of infection, but at a much reduced level. PMID- 29164059 TI - Intravesical Gemcitabine versus Intravesical Bacillus Calmette-Guerin for the Treatment of Non-Muscle Invasive Bladder Cancer: An Evaluation of Efficacy and Toxicity. AB - Background: Intravesical Bacillus Calmette-Guerin (BCG) remains the standard adjuvant treatment for non-muscle invasive bladder cancer (NMIBC) following transurethral resection; however, BCG failure and related toxicities are common. Objectives: To compare the efficacy and toxicity of intravesical BCG and gemcitabine in the treatment of NMIBC. Methods: Retrospective data were collected in the region of Canberra, Australia from January 2010 to December 2015. The survival cutoff was December 2016. Primary end point was disease-free survival (DFS) and secondary end point was toxicity. After optimal transurethral resection all patients received weekly intravesical BCG or gemcitabine for 6 weeks and maintenance treatment according to their risk. The recurrence was defined as histology proven tumor recurrence (any grade), or appearance of carcinoma in situ. Results: One hundred and three patients were evaluable, 52 treated with BCG and 51 with gemcitabine with a median age of 77 and 78, and were mostly male. Approximately half of each received maintenance therapy. The groups were well balanced, apart from some difference in cancer risk groups. Twenty-one percent in the BCG group and 29% in the gemcitabine group had received prior BCG. Median follow up was 15.0 months. Median DFS was 19.6 months for BCG, whereas median DFS was not reached with gemcitabine. There was a trend toward improved DFS with gemcitabine in multivariate analysis, HR: 0.49 (95% CI: 0.22-1.06, p = 0.07). Adverse events were significantly less frequent with gemcitabine (7 versus 44%, p <= 0.05). There were four cases of systemic BCG infection. Conclusion: Intravesical gemcitabine was associated with a trend toward better DFS with significantly lower toxicity when compared with BCG. Intravesical BCG remains the standard first-line adjuvant therapy; however, intravesical gemcitabine could be a reasonable alternative in cases where BCG is contraindicated and for patients who are intolerant or refractory to BCG. A prospective phase 3 trial is needed to confirm the benefits of gemcitabine over BCG. PMID- 29164060 TI - Tissue Factor-Expressing Tumor-Derived Extracellular Vesicles Activate Quiescent Endothelial Cells via Protease-Activated Receptor-1. AB - Tissue factor (TF)-expressing tumor-derived extracellular vesicles (EVs) can promote metastasis and pre-metastatic niche formation, but the mechanisms by which this occurs remain largely unknown. We hypothesized that generation of activated factor X (FXa) by TF expressed on tumor-derived EV could activate protease-activated receptors (PARs) on non-activated endothelial cells to induce a pro-adhesive and pro-inflammatory phenotype. We obtained EV from TF-expressing breast (MDA-MB-231) and pancreatic (BxPC3 and Capan-1) tumor cell lines. We measured expression of E-selectin and secretion of interleukin-8 (IL-8) in human umbilical vein endothelial cells after exposure to EV and various immunologic and chemical inhibitors of TF, FXa, PAR-1, and PAR-2. After 6 h of exposure to tumor derived EV (pretreated with factor VIIa and FX) in vitro, endothelial cells upregulated E-selectin expression and secreted IL-8. These changes were decreased with an anti-TF antibody, FXa inhibitors (FPRCK and EGRCK), and PAR-1 antagonist (E5555), demonstrating that FXa generated by TF-expressing tumor-derived EV was signaling through endothelial PAR-1. Due to weak constitutive PAR-2 expression, these endothelial responses were not induced by a PAR-2 agonist peptide (SLIGKV) and were not inhibited by a PAR-2 antagonist (FSLLRY) after exposure to tumor derived EV. In conclusion, we found that TF-expressing cancer-derived EVs activate quiescent endothelial cells, upregulating E-selectin and inducing IL-8 secretion through generation of FXa and cleavage of PAR-1. Conversion of resting endothelial cells to an activated phenotype by TF-expressing cancer-derived EV could promote cancer metastases. PMID- 29164062 TI - Preleukemic Hematopoietic Stem Cells in Human Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow characterized by an uncontrolled proliferation of undifferentiated myeloid lineage cells. Decades of research have demonstrated that AML evolves from the sequential acquisition of genetic alterations within a single lineage of hematopoietic cells. More recently, the advent of high-throughput sequencing has enabled the identification of a premalignant phase of AML termed preleukemia. Multiple studies have demonstrated that AML can arise from the accumulation of mutations within hematopoietic stem cells (HSCs). These HSCs have been termed "preleukemic HSCs" as they represent the evolutionary ancestors of the leukemia. Through examination of the biological and clinical characteristics of these preleukemic HSCs, this review aims to shed light on some of the unexplored questions in the field. We note that some of the material discussed is speculative in nature and is presented in order to motivate future work. PMID- 29164061 TI - The Landscape of mtDNA Modifications in Cancer: A Tale of Two Cities. AB - Mitochondria from normal and cancerous cells represent a tale of two cities, wherein both execute similar processes but with different cellular and molecular effects. Given the number of reviews currently available which describe the functional implications of mitochondrial mutations in cancer, this article focuses on documenting current knowledge in the abundance and distribution of somatic mitochondrial mutations, followed by elucidation of processes which affect the fate of mutations in cancer cells. The conclusion includes an overview of translational implications for mtDNA mutations, as well as recommendations for future research uniting mitochondrial variants and tumorigenesis. PMID- 29164063 TI - Monitoring the Efficacy of Oncolytic Viruses via Gene Expression. AB - With the recent success of oncolytic viruses in clinical trials, efforts toward improved monitoring of the viruses and their mechanism have intensified. Four main gene expression strategies have been employed to date including: analyzing overall gene expression in tumor cells, looking at gene expression of a few specific genes in the tumor cells, focusing on gene expression of specific transgenes introduced into the virus, and following gene expression of certain viral genes. Each strategy presents certain advantages and disadvantages over the others. Various methods to organize the dysregulated genes into clusters have provided a window into the mechanism of action for these viruses. Methodologically, the combined approach of looking at both overall gene expression, the tumor cells and gene expression of viral genes, enables researchers to assess correlation between the introduction of the virus and the changes in the tumor. This would seem to be the most productive approach for future studies, providing much information on mechanism and timing. PMID- 29164064 TI - Quantitative Mass Spectrometry-Based Proteomic Profiling for Precision Medicine in Prostate Cancer. AB - Prostate cancer (PCa) is one of the most frequently diagnosed cancer among men in the western societies. Many PCa patients bear tumors that will not threat their lives if left untreated or if treatment is delayed. Our inability for early identification of these patients has resulted in massive overtreatment. Therefore, there is a great need of finding biomarkers for patient stratification according to prognostic risk; as well as there is a need for novel targets that can allow the development of effective treatments for patients that progress to castration-resistant PCa. Most biomarkers in cancer are proteins, including the widely-used prostate-specific antigen (PSA). Recent developments in mass spectrometry allow the identification and quantification of thousands of proteins and posttranslational modifications from small amounts of biological material, including formalin-fixed paraffin-embedded tissues, and biological fluids. Novel diagnostic and prognostic biomarkers have been identified in tissue, blood, urine, and seminal plasma of PCa patients, and new insights in the ethology and progression of this disease have been achieved using this technology. In this review, we summarize these findings and discuss the potential of this technology to pave the way toward the clinical implementation of precision medicine in PCa. PMID- 29164065 TI - Transcriptional and Microenvironmental Regulation of Lineage Ambiguity in Leukemia. AB - Leukemia is characterized by the uncontrolled production of leukemic cells and impaired normal hematopoiesis. Although the combination of chemotherapies and hematopoietic stem cell transplantation has significantly improved the outcome of leukemia patients, a proportion of patients still suffer from relapse after treatment. Upon relapse, a phenomenon termed "lineage switch" is observed in a subset of leukemia patients, in which conversion of lymphoblastic leukemia to myeloid leukemia or vice versa is observed. A rare entity of leukemia called mixed-phenotype acute leukemia exhibits co-expression of markers representing two or three lineages. These two phenotypes regarding the lineage ambiguity suggest that the fate of some leukemia retain or acquire a certain degree of plasticity. Studies using animal models provide insight into how lineage specifying transcription factors can enforce or convert a fate in hematopoietic cells. Modeling lineage conversion in normal hematopoietic progenitor cells may improve our current understanding of how lineage switch occurs in leukemia. In this review, we will summarize the role of transcription factors and microenvironmental signals that confer fate plasticity to normal hematopoietic progenitor cells, and their potential to regulate lineage switching in leukemias. Future efforts to uncover the mechanisms contributing to lineage conversion in both normal hematopoiesis and leukemia may pave the way to improve current therapeutic strategies. PMID- 29164066 TI - Application of ImmunoScore Model for the Differentiation between Active Tuberculosis and Latent Tuberculosis Infection as Well as Monitoring Anti tuberculosis Therapy. AB - Tuberculosis (TB) is a leading global public health problem. To achieve the end TB strategy, non-invasive markers for diagnosis and treatment monitoring of TB disease are urgently needed, especially in high-endemic countries such as China. Interferon-gamma release assays (IGRAs) and tuberculin skin test (TST), frequently used immunological methods for TB detection, are intrinsically unable to discriminate active tuberculosis (ATB) from latent tuberculosis infection (LTBI). Thus, the specificity of these methods in the diagnosis of ATB is dependent upon the local prevalence of LTBI. The pathogen-detecting methods such as acid-fast staining and culture, all have limitations in clinical application. ImmunoScore (IS) is a new promising prognostic tool which was commonly used in tumor. However, the importance of host immunity has also been demonstrated in TB pathogenesis, which implies the possibility of using IS model for ATB diagnosis and therapy monitoring. In the present study, we focused on the performance of IS model in the differentiation between ATB and LTBI and in treatment monitoring of TB disease. We have totally screened five immunological markers (four non specific markers and one TB-specific marker) and successfully established IS model by using Lasso logistic regression analysis. As expected, the IS model can effectively distinguish ATB from LTBI (with a sensitivity of 95.7% and a specificity of 92.1%) and also has potential value in the treatment monitoring of TB disease. PMID- 29164067 TI - Tick-Borne Transmission of Murine Gammaherpesvirus 68. AB - Herpesviruses are a large group of DNA viruses infecting mainly vertebrates. Murine gammaherpesvirus 68 (MHV68) is often used as a model in studies of the pathogenesis of clinically important human gammaherpesviruses such as Epstein Barr virus and Kaposi's sarcoma-associated herpesvirus. This rodent virus appears to be geographically widespread; however, its natural transmission cycle is unknown. Following detection of MHV68 in field-collected ticks, including isolation of the virus from tick salivary glands and ovaries, we investigated whether MHV68 is a tick-borne virus. Uninfected Ixodes ricinus ticks were shown to acquire the virus by feeding on experimentally infected laboratory mice. The virus survived tick molting, and the molted ticks transmitted the virus to uninfected laboratory mice on which they subsequently fed. MHV68 was isolated from the tick salivary glands, consistent with transmission via tick saliva. The virus survived in ticks without loss of infectivity for at least 120 days, and subsequently was transmitted vertically from one tick generation to the next, surviving more than 500 days. Furthermore, the F1 generation (derived from F0 infected females) transmitted MHV68 to uninfected mice on which they fed, with MHV68 M3 gene transcripts detected in blood, lung, and spleen tissue of mice on which F1 nymphs and F1 adults engorged. These experimental data fulfill the transmission criteria that define an arthropod-borne virus (arbovirus), the largest biological group of viruses. Currently, African swine fever virus (ASFV) is the only DNA virus recognized as an arbovirus. Like ASFV, MHV68 showed evidence of pathogenesis in ticks. Previous studies have reported MHV68 in free living ticks and in mammals commonly infested with I. ricinus, and neutralizing antibodies to MHV68 have been detected in large mammals (e.g., deer) including humans. Further studies are needed to determine if these reports are the result of tick-borne transmission of MHV68 in nature, and whether humans are at risk of infection. PMID- 29164068 TI - Comparative Pan-Genome Analysis of Piscirickettsia salmonis Reveals Genomic Divergences within Genogroups. AB - Piscirickettsia salmonis is the etiological agent of salmonid rickettsial septicemia, a disease that seriously affects the salmonid industry. Despite efforts to genomically characterize P. salmonis, functional information on the life cycle, pathogenesis mechanisms, diagnosis, treatment, and control of this fish pathogen remain lacking. To address this knowledge gap, the present study conducted an in silico pan-genome analysis of 19 P. salmonis strains from distinct geographic locations and genogroups. Results revealed an expected open pan-genome of 3,463 genes and a core-genome of 1,732 genes. Two marked genogroups were identified, as confirmed by phylogenetic and phylogenomic relationships to the LF-89 and EM-90 reference strains, as well as by assessments of genomic structures. Different structural configurations were found for the six identified copies of the ribosomal operon in the P. salmonis genome, indicating translocation throughout the genetic material. Chromosomal divergences in genomic localization and quantity of genetic cassettes were also found for the Dot/Icm type IVB secretion system. To determine divergences between core-genomes, additional pan-genome descriptions were compiled for the so-termed LF and EM genogroups. Open pan-genomes composed of 2,924 and 2,778 genes and core-genomes composed of 2,170 and 2,228 genes were respectively found for the LF and EM genogroups. The core-genomes were functionally annotated using the Gene Ontology, KEGG, and Virulence Factor databases, revealing the presence of several shared groups of genes related to basic function of intracellular survival and bacterial pathogenesis. Additionally, the specific pan-genomes for the LF and EM genogroups were defined, resulting in the identification of 148 and 273 exclusive proteins, respectively. Notably, specific virulence factors linked to adherence, colonization, invasion factors, and endotoxins were established. The obtained data suggest that these genes could be directly associated with inter-genogroup differences in pathogenesis and host-pathogen interactions, information that could be useful in designing novel strategies for diagnosing and controlling P. salmonis infection. PMID- 29164070 TI - Generation of an Attenuated Tiantan Vaccinia Virus Strain by Deletion of Multiple Genes. AB - An attenuated vaccinia virus-MVTTEAB-was constructed by deletion of non-essential gene segments related to the immunomodulatory and virulence functions of the vaccinia virus Tiantan strain (VVTT). The shuttle plasmids pTC-EGFP, pTE-EGFP, pTA35-EGFP, pTB-EGFP, and pTA66-EGFP were constructed and combined with the early and late strong promoter pE/L and EGFP as an exogenous selectable marker. Then, through the homologous recombination technology and Cre/loxP system, the following gene fragments were gradually knocked out one by one: TC7L-TK2L, TE3L, TA35R, TB13R, and TA66R. Ultimately, the five-segment-deleted attenuated strain MVTTEAB was obtained. Knockout of these segments and genetic stability of MVTTEAB were confirmed, and it was also shown that knockout of these segments did not affect the replication ability of the virus. Further, a series of in vivo and in vitro experiments demonstrated that the virulence of MVTTEAB was attenuated significantly, but at same time, high immunogenicity was maintained. These results indicate that MVTTEAB has potential for clinical use as a safe viral vector or vaccine with good attenuation and immunogenicity. PMID- 29164069 TI - Iron Acquisition Mechanisms and Their Role in the Virulence of Burkholderia Species. AB - Burkholderia is a genus within the beta-Proteobacteriaceae that contains at least 90 validly named species which can be found in a diverse range of environments. A number of pathogenic species occur within the genus. These include Burkholderia cenocepacia and Burkholderia multivorans, opportunistic pathogens that can infect the lungs of patients with cystic fibrosis, and are members of the Burkholderia cepacia complex (Bcc). Burkholderia pseudomallei is also an opportunistic pathogen, but in contrast to Bcc species it causes the tropical human disease melioidosis, while its close relative Burkholderia mallei is the causative agent of glanders in horses. For these pathogens to survive within a host and cause disease they must be able to acquire iron. This chemical element is essential for nearly all living organisms due to its important role in many enzymes and metabolic processes. In the mammalian host, the amount of accessible free iron is negligible due to the low solubility of the metal ion in its higher oxidation state and the tight binding of this element by host proteins such as ferritin and lactoferrin. As with other pathogenic bacteria, Burkholderia species have evolved an array of iron acquisition mechanisms with which to capture iron from the host environment. These mechanisms include the production and utilization of siderophores and the possession of a haem uptake system. Here, we summarize the known mechanisms of iron acquisition in pathogenic Burkholderia species and discuss the evidence for their importance in the context of virulence and the establishment of infection in the host. We have also carried out an extensive bioinformatic analysis to identify which siderophores are produced by each Burkholderia species that is pathogenic to humans. PMID- 29164071 TI - Galectin-3: A Friend but Not a Foe during Trypanosoma cruzi Experimental Infection. AB - Trypanosoma cruzi interacts with host cells, including cardiomyocytes, and induces the production of cytokines, chemokines, metalloproteinases, and glycan binding proteins. Among the glycan-binding proteins is Galectin-3 (Gal-3), which is upregulated after T. cruzi infection. Gal-3 is a member of the lectin family with affinity for beta-galactose containing molecules; it can be found in both the nucleus and the cytoplasm and can be either membrane-associated or secreted. This lectin is involved in several immunoregulatory and parasite infection process. Here, we explored the consequences of Gal-3 deficiency during acute and chronic T. cruzi experimental infection. Our results demonstrated that lack of Gal-3 enhanced in vitro replication of intracellular parasites, increased in vivo systemic parasitaemia, and reduced leukocyte recruitment. Moreover, we observed decreased secretion of pro-inflammatory cytokines in spleen and heart of infected Gal-3 knockout mice. Lack of Gal-3 also led to elevated mast cell recruitment and fibrosis of heart tissue. In conclusion, galectin-3 expression plays a pivotal role in controlling T. cruzi infection, preventing heart damage and fibrosis. PMID- 29164072 TI - A New Strain Collection for Improved Expression of Outer Membrane Proteins. AB - Almost all integral membrane proteins found in the outer membranes of Gram negative bacteria belong to the transmembrane beta-barrel family. These proteins are not only important for nutrient uptake and homeostasis, but are also involved in such processes as adhesion, protein secretion, biofilm formation, and virulence. As surface exposed molecules, outer membrane beta-barrel proteins are also potential drug and vaccine targets. High production levels of heterologously expressed proteins are desirable for biochemical and especially structural studies, but over-expression and subsequent purification of membrane proteins, including outer membrane proteins, can be challenging. Here, we present a set of deletion mutants derived from E. coli BL21(DE3) designed for the over-expression of recombinant outer membrane proteins. These strains harbor deletions of four genes encoding abundant beta-barrel proteins in the outer membrane (OmpA, OmpC, OmpF, and LamB), both single and in all combinations of double, triple, and quadruple knock-outs. The sequences encoding these outer membrane proteins were deleted completely, leaving only a minimal scar sequence, thus preventing the possibility of genetic reversion. Expression tests in the quadruple mutant strain with four test proteins, including a small outer membrane beta-barrel protein and variants thereof as well as two virulence-related autotransporters, showed significantly improved expression and better quality of the produced proteins over the parent strain. Differences in growth behavior and aggregation in the presence of high salt were observed, but these phenomena did not negatively influence the expression in the quadruple mutant strain when handled as we recommend. The strains produced in this study can be used for outer membrane protein production and purification, but are also uniquely useful for labeling experiments for biophysical measurements in the native membrane environment. PMID- 29164073 TI - Streptococcus equi subsp. zooepidemicus Invades and Survives in Epithelial Cells. AB - Streptococcus equi subsp. zooepidemicus (S. zooepidemicus) is an opportunistic pathogen of several species including humans. S. zooepidemicus is found on mucus membranes of healthy horses, but can cause acute and chronic endometritis. Recently S. zooepidemicus was found able to reside in the endometrium for prolonged periods of time. Thus, we hypothesized that an intracellular phase may be part of the S. zooepidemicus pathogenesis and investigated if S. zooepidemicus was able to invade and survive inside epithelial cells. HEp-2 and HeLa cell lines were co-cultured with two S. zooepidemicus strains (1-4a and S31A1) both originating from the uterus of mares suffering from endometritis. Cells were fixed at different time points during the 23 h infection assay and field emission scanning electron microscopy (FESEM) was used to characterize adhesion and invasion mechanisms. The FESEM images showed three morphologically different types of invasion for both bacterial strains. The main port of entry was through large invaginations in the epithelial cell membrane. Pili-like bacterial appendages were observed when the S. zooepidemicus cells were in close proximity to the epithelial cells indicating that attachment and invasion were active processes. Adherent and intracellular S. zooepidemicus, and bacteria in association with lysosomes was determined by immunofluorescence staining techniques and fluorescence microscopy. Quantification of intracellular bacteria was determined in penicillin protection assays. Both S. zooepidemicus strains investigated were able to invade epithelial cells although at different magnitudes. The immunofluorescence data showed significantly higher adhesion and invasion rates for strain 1-4a when compared to strain S31A1. S. zooepidemicus was able to survive intracellularly, but the survival rate decreased over time in the cell culture system. Phagosome-like compartments containing S. zooepidemicus at some stages fused with lysosomes to form a phagolysosome. The results indicate that an intracellular phase may be one way S. zooepidemicus survives in the host, and could in part explain how S. zooepidemicus can cause recurrent/persistent infections. Future studies should reveal the ability of S. zooepidemicus to internalize and survive in primary equine endometrial cells and during in vivo conditions. PMID- 29164074 TI - Systemic Responses of Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii Following Exposure to the Antimicrobial Peptide Cathelicidin-BF Imply Multiple Intracellular Targets. AB - Cathelicidin-BF, derived from the banded krait (Bungarus fasciatus), is a typically cationic, amphiphilic and alpha-helical antimicrobial peptide (AMP) with 30 amino acids that exerts powerful effects on multidrug-resistant (MDR) clinical isolates, including Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, but whether it targets plasma membranes or intracellular targets to kill bacteria is still controversial. In the present study, we demonstrated that the disruption of bacterial membranes with high concentrations of cathelicidin-BF was the cause of bacterial death, as with conventional antibiotics at high concentrations. At lower concentrations, cathelicidin-BF did not cause bacterial plasma membrane disruption, but it was able to cross the membrane and aggregate at the nucleoid regions. Functional proteins of the transcription processes of P. aeruginosa and A. baumannii were affected by sublethal doses of cathelicidin-BF, as demonstrated by comparative proteomics using isobaric tags for relative and absolute quantification and subsequent gene ontology (GO) analysis. Analysis using the Kyoto Encyclopedia of Genes and Genomes showed that cathelicidin-BF mainly interferes with metabolic pathways related to amino acid synthesis, metabolism of cofactors and vitamins, metabolism of purine and energy supply, and other processes. Although specific targets of cathelicidin-BF must still be validated, our study offers strong evidence that cathelicidin-BF may act upon intracellular targets to kill superbugs, which may be helpful for further efforts to discover novel antibiotics to fight against them. PMID- 29164076 TI - Correction. AB - [This corrects the article DOI: 10.7860/JCDR/2015/11613.5775.]. PMID- 29164075 TI - Disruption of Two-component System LytSR Affects Forespore Engulfment in Bacillus thuringiensis. AB - Two-component regulatory systems (TCSs) play pivotal roles in bacteria sensing many different stimuli from environment. Here, we investigated the role of the LytSR TCS in spore formation in Bacillus thuringiensis (Bt) subsp. kurstaki HD73. lacZ gene fusions revealed that the transcription of the downstream genes, lrgAB, encoding two putative membrane-associated proteins, is regulated by LytSR. The sporulation efficiency of a lytSR mutant was significantly lower than that of wild-type HD73. A confocal microscopic analysis demonstrated that LytSR modulates the process of forespore engulfment. Moreover, the transcription of the lytSR operon is regulated by the mother-cell transcription factor SigE, whereas the transcription of the sporulation gene spoIIP was reduced in the lytSR mutant, as demonstrated with a beta-galactosidase activity assay. These results suggest that LytSR modulates forespore engulfment by affecting the transcription of the spoIIP gene in Bt. PMID- 29164077 TI - Glucose variability for cardiovascular risk factors in type 2 diabetes: a meta analysis. AB - Aims: It is consensus that glucose variability (GV) plays an important role in maccomplications of type 2 diabetes, but whether GV has a causal role is not yet clear for cardiovascular disease (CVD). This study sought to explore the effect on GV for CVD risk factors with type 2 diabetes. Methods: The systematic literature search was performed to identify all GV and CVD risk factors, including total cholesterol (TC), LDL cholesterol (LDL-C), triglyceride (TG), HDL cholesterol (HDL-C), Body Mass Index (BMI), waist circumference (WC), High Sensitivity C-reactive protein (Hs-CRP), Homeostasis model assessment (HOMA) and carotid intima-media thickness (IMT). Preferred Reporting Items was synthesized for Systematic reviews and Meta Analyses guideline. And the pooled analyses were undertaken using Review Manager 5.3. Results: Twenty two studies were included with a total of 1143 patients in high glucose variability group (HGVG) and 1275 patients low glucose variability group (LGVG). Among these selected CVD risk factors, HOMA-IR and reduced IMT were affected by GV. HOMA-IR level was significantly lower in LGVG than in HGVG (MD = 0.58, 95% CI: 0.26 to 0.91, P = 0.0004), with evidence of heterogeneity between studies (I2 = 0%; P = 0.47).Reduced IMT level was significantly lower in LGVG than in HGVG (SMD = 0.28, 95% CI: 0.09 to 0.47, P = 0.003), with evidence of heterogeneity between studies (I2 = 0%; P = 0.48). However, the others were no significant statistical difference. Conclusions: Among these selected CVD risk factors in type 2 diabetes, minimizing GV could improve insulin resistance and reduced IMT, consistent with a lowering in risk of CVD. PMID- 29164078 TI - Internal Hernia Masquerading As Necrotizing Enterocolitis. AB - In extremely preterm infants, acute abdominal emergencies are fortunately less common with improving care. Spontaneous intestinal perforation and necrotizing enterocolitis are conditions where emergency surgery is most often needed. Conservative medical management and placement of temporary drain are often used in the initial management. Internal hernia (IH) is an uncommon cause of bowel obstruction in neonates, is difficult to diagnose and unfortunately are found only at autopsy. The presentation in preterm infants, distinction between these conditions, and the need for early diagnosis of IH are discussed. PMID- 29164079 TI - Cognitive and Behavioral Disorders in Children with Neurofibromatosis Type 1. AB - Aim: The last systematic review of research on the behavior of children with neurofibromatosis type 1 (NF1) was in 2012. Since then, several important findings have been published. Therefore, the study aim was to synthesize recent relevant work related to this issue. Method: We conducted a systematic review of the literature. Relevant articles were identified using the electronic databases PubMed, PsycINFO, and Scopus and a manual search of references lists. Thirty of 156 articles identified met the inclusion criteria. A quality evaluation of the articles was performed and the information was synthesized using a narrative approach. Results: Compared with controls, children and adolescents with NF1 present significant alterations in language, reading, visuospatial skills, motor function, executive function, attention, behavior, emotion, and social skills. The prevalence of attention-deficit/hyperactivity disorder (ADHD) is important and can affect cognition and executive function variables. A high prevalence of autistic traits and autistic spectrum disorder were reported. The benefits of using statins to treat cognitive deficits are unclear. However, children with NF1 and ADHD seem to benefit from methylphenidate treatment. The presence of hyperintensities in brain magnetic resonance imaging data seem to be related to poor cognitive performance. Analysis of these lesions could help to predict cognitive alterations in children with NF1. Interpretation: There has been important progress to evaluate cognitive characteristics of children with NF1 and to determine the physiological mechanisms of the concomitant disorders. However, discrepancies in relation to intelligence, learning disabilities, attention deficits, and treatment remain. Further investigations on this topic are recommended. PMID- 29164080 TI - The Incidence and Short-term Outcomes of Acute Respiratory Illness with Cough in Children from a Socioeconomically Disadvantaged Urban Community in Australia: A Community-Based Prospective Cohort Study. AB - Background: Acute respiratory illnesses with cough (ARIwC) are predominant causes of morbidity in Australian Indigenous children; however, data on disease burden in urban communities are scarce. This study aimed to determine the incidence of ARIwC, the predictors of recurrent (>=4 episodes) ARIwC, and development of chronic cough following an ARIwC in urban, predominantly Indigenous, children aged <5 years from northern Brisbane, Australia. Methods: Prospective cohort study of children aged <5 years registered with a primary healthcare center. ARIwC episodes and outcomes were collected for 12 months. Recurrent ARIwC was defined as >=4 episodes in 12 months. Chronic cough was defined as cough lasting >4 weeks. Children who developed chronic cough were reviewed by a pediatric pulmonologist. Incidence densities per child-month of observation were calculated and predictors of recurrent ARIwC and chronic cough were evaluated in logistic regression models. Results: Between February 2013 and November 2015, 200 children were enrolled; median age of 18.1 months, range (0.7-59.7 months) and 90% identified as Indigenous. A total of 1,722 child-months of observation were analyzed (mean/child = 8.58, 95% CI 8.18-9.0). The incidence of ARIwC was 24.8/100 child-months at risk (95% CI 22.3-27.5). Twenty-one children (10.5%) experienced recurrent ARIwC. Chronic cough was identified in 70/272 (25.7%) episodes of ARIwC. Predictors of recurrent ARIwC were presence of eczema, mold in the house, parent/carer employment status, and having an Aboriginal and Torres Strait Islander mother/non-Aboriginal and Torres Strait Islander father (compared to both parents being Aboriginal and Torres Strait Islander). Predictors of chronic cough included being aged <12 months, eczema, childcare attendance, previous history of cough of >4 weeks duration, having an Aboriginal and Torres Strait Islander mother/non-Aboriginal and Torres Strait Islander father (compared to both parents being Aboriginal and Torres Strait Islander), and a low income. Of those with chronic cough reviewed by a pediatric pulmonologist, a significant underlying disorder was found in 14 children (obstructive sleep apnea = 1, bronchiectasis = 2, pneumonia = 2, asthma = 3, tracheomalacia = 6). Discussion: This community of predominantly Aboriginal and Torres Strait Islander and socially disadvantaged children bear a considerable burden of ARIwC. One in 10 children will experience more than three episodes over a 12-month period and 1 in five children will develop chronic cough post ARIwC, some with a serious underlying disorder. Further larger studies that include a broader population base are needed. PMID- 29164081 TI - Delayed Development of Feeding Skills in Children with Feeding Difficulties-Cross sectional Study in a Brazilian Reference Center. AB - Background: Delays in gross motor development, sensory processing issues, and organic and behavioral problems are known to interfere in the development of feeding skills (FS); and-therefore-in the success of the process of feeding a child. Children with feeding difficulties (FD) commonly present inadequacy of FS. Objectives: Assessment of five FS in Brazilian children with FD, and search of associations with types of FD. Methods: Cross-sectional study with 70 children below 10 years old. Data were obtained from medical records: age, gender, age at texture transitions, feeding phase (breastfeeding, weaning to solids or full solids) at first complaint; characteristics of the meal (duration, environment, and shared meals with adults), self-feeding practices, use of feeding equipment and bottle, mouthing, feeding position and FD diagnosis. Skills were categorized according to standards for age. Chi-Square, Anova Test (or non-parametric equivalent) and Multinomial logistic regression tests were used, with a significance level of 5%. Results: There was no difference in FS (p > 0.05) or in the number of FS inadequateness (p = 0.84) according to FD diagnosis. The majority (94%) of children presented at least one delayed development of FS; 1/3 presented delays in more than half of the FS. The most prevalent inadequacies in FS were inadequate feeding position (73.5%), prolonged bottle feeding (56.9%), and inadequate self-feeding practices (37.9%). Feeding complaints first appeared at 10.9 +/- 11.4 months, and picky eating was the most prevalent type of FD (37.1%). Most children were fed in inadequate environments (55.2%), without the company of adults (78%). Transition to solid foods occurred at 16 +/- 5.6 months. Multinomial logistic regression showed no difference in likelihood of presenting any type of FD compared to picky eating, according to FS. Age at texture transition both from breastfeeding to complementary feeding (p = 0.95), and from complementary feeding to solid foods (p = 0.43) did not vary according to FD diagnosis. Conclusion: FS development or number of FS inadequateness did not vary according to FD diagnosis. Identification of these inadequacies could help the discussion for multi-professional treatment of patients with FD. PMID- 29164082 TI - Acute Septic Arthritis of the Knee Caused by Kingella kingae in a 5-Year-Old Cameroonian Boy. AB - Kingella kingae is an important cause of invasive infections in young children from Western countries. Although increasing reports indicate that this organism is the leading agent of bone and joint infections in early childhood, data on K. kingae infections from resource-limited settings are scarce, and none has yet been reported in Africa. We herein report the diagnostic and epidemiological investigations of the first case of K. kingae arthritis identified in a child from sub-Saharan Africa. A 5-year-old Cameroonian boy presented with a sudden painful limp which appeared in the course of a mild rhinopharyngitis. He lived in Cameroon where he had been vaccinated with BCG at birth and moved to France for holidays 4 days before consultation. There was no history of trauma and he did not have any underlying medical condition. Upon admission, he had a temperature of 36.7 degrees C, and clinical examination revealed right-sided knee tenderness and effusion that was confirmed by ultrasound imaging. Laboratory results showed a white blood cell count of 5,700 cells/mm3, C-reactive protein level of 174 mg/L, and platelet count of 495,000 cells/mm3. He underwent an arthrocentesis and was immediately given intravenous amoxicillin-clavulanate. Conventional cultures from blood samples and synovial fluids were negative. Polymerase chain reaction (PCR) assay targeting the broad-range 16S rRNA gene and real-time quantitative PCR assays targeting Mycobacterium species were negative. Surprisingly, real-time PCR assays targeting the cpn60, rtxA, and rtxB genes of K. kingae were positive. Multicolor fluorescence in situ hybridization specific for K. kingae identified the presence of numerous coccobacilli located within the synovial fluid. Finally, multilocus sequence typing analysis performed on deoxyribonucleic acid directly extracted from joint fluid disclosed a novel K. kingae sequence-type complex. This case report demonstrates that K. kingae may be considered as a potential cause of septic arthritis in children living in sub-Saharan Africa, and hence the burden of K. kingae infection may be not limited to the Western countries. Further studies are required to determine the prevalence of K. kingae infection and carriage in Africa. PMID- 29164083 TI - Ovotesticular Differences of Sex Development: Surgery or Not Surgery? That Is the Question. PMID- 29164085 TI - Commentary: Left Ventricular Hypertrophy in Pediatric Hypertension: A Mini Review. PMID- 29164084 TI - Pretreatment with Human Chorionic Gonadotropin Protects the Neonatal Brain against the Effects of Hypoxic-Ischemic Injury. AB - Introduction: Though the human fetus is exposed to placentally derived human chorionic gonadotropin (hCG) throughout gestation, the role of hCG on the fetal brain is unknown. Review of the available literature appears to indicate that groups of women with higher mean levels of hCG during pregnancy tend to have offspring with lower cerebral palsy (CP) risk. Given that newborn cerebral injury often precedes the development of CP, we aimed to determine whether hCG may protect against the neurodegenerative effects of neonatal brain injury. Methods: We utilized the Rice-Vannucci model of neonatal cerebral hypoxia-ischemia (HI) in postnatal day 7 mice to examine whether intraperitoneal administration of hCG 15 18 h prior, 1 h after or immediately following HI decrease brain tissue loss 7 days after injury. We next studied whether hCG has pro-survival and trophic properties in neurons by exposing immature cortical and hippocampal neurons to hCG in vitro and examining neurite sprouting and neuronal survival prior and after glutamate receptor-mediated excitotoxic injury. Results: We found that intraperitoneal injection of hCG 15 h prior to HI, but not at or 1 h after HI induction, resulted in a significant decrease in hippocampal and striatal tissue loss 7 days following brain injury. Furthermore, hCG reduced N-methyl-d-aspartate (NMDA)-mediated neuronal excitotoxicity in vitro when neurons were continuously exposed to this hormone for 10 days or when given at the time and following neuronal injury. In addition, continuous in vitro administration of hCG for 6-9 days increased neurite sprouting and basal neuronal survival as assessed by at least a 1-fold increase in MAP2 immunoreactivity and a 2.5-fold increase in NeuN + immunoreactivity. Conclusion: Our findings suggest that hCG can decrease HI associated immature neural degeneration. The mechanism of action for this neuroprotective effect may partly involve inhibition of NMDA-dependent excitotoxic injury. This study supports the hypothesis that hCG during pregnancy has the potential for protecting the developing brain against HI, an important CP risk factor. PMID- 29164086 TI - A Novel Missense Mutation of the NSD1 Gene Associated with Overgrowth in Three Generations of an Italian Family: Case Report, Differential Diagnosis, and Review of Mutations of NSD1 Gene in Familial Sotos Syndrome. AB - Sotos syndrome (SoS) is characterized by overgrowth of prenatal onset, learning disability, and characteristic facial appearance; it is usually due to haploinsufficiency of NSD1 gene at chromosome 5q35. An Italian child was born at 37 weeks of gestation (weight 2,910 g, 25th-50th centiles; length 50 cm, 75th centile; head circumference 36 cm, 97th centile) showing cryptorchidism on the right side, hypertelorism, dolichocephaly, broad and prominent forehead, and narrow jaw; the pregnancy was worsened by maternal preeclampsia and gestational diabetes, and his mother had a previous history of four early miscarriages. The patient showed neonatal jaundice, hypotonia, feeding difficulties, frequent vomiting, and gastroesophageal reflux. After the age of 6 months, his weight, length, and head circumference were above the 97th centile; psychomotor development was delayed. At the age of 9 years, the patient showed also joint laxity and scoliosis. DNA sequence analysis of NSD1 gene detected a novel heterozygous mutation (c.521T>A, p.Val174Asp) in exon 2. The same mutant allele was also found in the mother and in the maternal grandfather of the proband; both the mother and the maternal grandfather of the proband showed isolated overgrowth with height above the 97th centile in absence of other features of SoS. At present 23 familial cases of SoS have been described (two cases with mutation in exon 2 of NSD1 gene); no familial cases of SoS with mutation of NSD1 gene and isolated overgrowth have been reported. Probably, point mutations of NSD1 gene, and particularly mutations between exon 20 and exon 23, are not likely to affect reproductive fitness. Epigenetic mechanisms and intrauterine environment may influence phenotypes, therefore genetic tests are not useful to predict the phenotype but they are indispensable for the diagnosis of SoS. This is the first Italian familial case of SoS with genetic confirmation and the third report in which a missense mutation of NSD1 gene is found in three generations of the same family. PMID- 29164087 TI - Plasma Brain-Derived Neurotrophic Factor Levels in Newborn Infants with Neonatal Abstinence Syndrome. AB - Background: Brain-derived neurotrophic factor (BDNF) is a type of growth factor that promotes growth and survival of neurons. Fetal exposure to opiates can lead to postnatal withdrawal syndrome, which is referred as neonatal abstinence syndrome (NAS). Preclinical and clinical studies have shown an association between opiates exposure and alteration in BDNF expression in the brain and serum levels in adult. However, to date, there are no data available on the effects of opiate exposure on BDNF levels in infant who are exposed to opiates in utero and whether BDNF level may correlate with the severity of NAS. Objective: To compare plasma BDNF levels among NAS and non-NAS infants and to determine the correlation of BDNF levels and the severity of NAS. Methods: This is a prospective cohort study with no intervention involved. Infants >=35 weeks of gestation were enrolled. BDNF level was measured using enzyme-linked immunosorbent assay technique from blood samples drawn within 48 h of life. The severity of NAS was determined by the length of hospital stay, number of medications required to treat NAS. Results: 67 infants were enrolled, 34 NAS and 33 non-NAS. Mean gestational age did not differ between the two groups. Mean birth weight of NAS infants was significantly lower than the non-NAS infants (3,070 +/- 523 vs. 3,340 +/- 459 g, p = 0.028). Mean BDNF level in NAS group was 252.2 +/- 91.6 ng/ml, significantly higher than 211.3 +/- 66.3 ng/ml in the non-NAS group (p = 0.04). There were no differences in BDNF levels between NAS infants that required one medication vs. more than one medication (254 +/- 91 vs. 218 +/- 106 ng/ml, p = 0.47). There was no correlation between the BDNF levels and length of hospital stay (p = 0.68) among NAS infants. Overall, there were no significant correlations between BDNF levels and NAS scores except at around 15 h after admission (correlation 0.35, p = 0.045). Conclusion: Plasma BDNF level was significantly increased in NAS infants during the first 48 h when compared to non NAS infants. The correlations between plasma BDNF levels and the severity of NAS warrant further study. These results suggest that BDNF may play a neuromodulatory role during withdrawal after in utero opiate exposure. PMID- 29164088 TI - Step-Initiation Deficits in Children with Faulty Posture Diagnosed with Neurodevelopmental Disorders during Infancy. AB - Background: Early detection of movement deficits during step initiation will facilitate the selection of the optimal physiotherapy management strategy. The main aim of the study was to assess potential differences in step initiation between 5- and 6-year-old children with faulty posture who had been diagnosed with neurodevelopmental disorders during infancy and healthy children. Methods: The experimental group consisted of 19 children aged 5-6 years with faulty posture, who had been diagnosed with neurodevelopmental disorders during infancy and were given physiotherapy in the first year of their lives. The control group comprised 19 nursery school children aged 5-6 years with no postural defects, no history of postural control or movement deficits, and no physiotherapy interventions in the first year of their lives. Step initiation was performed on force platforms under various conditions, i.e., with and without an obstacle, stepping up onto a platform placed at a higher level, stepping down onto a platform placed on a lower level. The recording of center of foot pressure (COP) displacements was divided into three phases: phase 1 (P1)-quiet standing before step initiation, phase 2 (P2)-transit, phase 3 (P3)-quiet standing until measurement completion. Results: The Tukey post hoc test showed that the means of sway range (raCOP) and mean velocity (vCOP) in sagittal (AP) plane for phase 1 and vCOP in frontal (ML) plane for phase 3 registered in the step-up trial were significantly higher (p < 0.05) in children with faulty posture compared to children with typical development. P1vCOPML, P3vCOPAP, P3raCOPML, and P3vCOPMLof the step-down trial were also significantly higher in children with faulty posture (p < 0.05). Conclusion: Inclusion of functional movement exercises (stair walking tasks) in physiotherapy interventions for children with postural defects seems well justified.The trial was registered in the Australian and New Zealand Clinical Trials Registry (no. ACTRN12617001068358). PMID- 29164089 TI - Pulmonary Hypoplasia Caused by Fetal Ascites in Congenital Cytomegalovirus Infection Despite Fetal Therapy. AB - We report two cases of pulmonary hypoplasia due to fetal ascites in symptomatic congenital cytomegalovirus (CMV) infections despite fetal therapy. The patients died soon after birth. The pathogenesis of pulmonary hypoplasia in our cases might be thoracic compression due to massive fetal ascites as a result of liver insufficiency. Despite aggressive fetal treatment, including multiple immunoglobulin administration, which was supposed to diminish the pathogenic effects of CMV either by neutralization or immunomodulatory effects, the fetal ascites was uncontrollable. To prevent development of pulmonary hypoplasia in symptomatic congenital CMV infections, further fetal intervention to reduce ascites should be considered. PMID- 29164090 TI - Feasibility of Classifying Life Stages and Searching for the Determinants: Results from the Medical Expenditure Panel Survey 1996-2011. AB - Background: Life stages are not clearly defined and significant determinants for the identification of stages are not discussed. This study aims to test a data driven approach to define stages and to identify the major determinants. Methods: This study analyzed the data on the Medical Expenditure Panel Survey interviewees from 1996 to 2011 in the United States. This study first selected features with the Spearman's correlation to remove redundant variables and to increase computational feasibility. The retained 430 variables were log transformed, if applicable. Sixty-four nominal variables were replaced with 164 binominal variables. This led to 525 variables that were available for principal component analysis (PCA). Life stages were proposed to be periods of ages with significantly different values of principal components (PCs). Results: After retaining subjects followed throughout the panels, 244,089 were eligible for PCA, and the number of civilians was estimated to be 4.6 billion. The age ranged from 0 to 90 years old (mean = 35.88, 95% CI = 35.67-36.09). The values of the first PC were not significant from age of 6 to 13, 30 to 41, 46 to 60, and 76 to 90 years (adjusted p > 0.5), and the major determinants were related to functional status, employment, and poverty. Conclusion: Important stages and their major determinants, including the status of functionality and cognition, income, and marital status, can be identified. Identifying stages of stability or transition will be important for research that relies on a research population with similar characteristics to draw samples for observation or intervention. Contribution: This study sets an example of defining stages of transition and stability across ages with social and health data. Among all available variables, cognitive limitations, income, and poverty are important determinants of these stages. PMID- 29164091 TI - Review of the Campaign to Prevent Falls in Construction. AB - Roofing is one of the most dangerous activities in the construction industry according to the US Bureau of Labor Statistics. Although injuries are manifold in this industry element, the vast majority of them occur as a result of falls from elevation (1, 2). These events lead to physical injury, fatalities, and financial burdens to the individual injured, their families, the employer, and the construction market as a whole (3, 4). In order to reduce construction worker falls, Occupational Health and Safety Administration launched the nationwide Campaign to Prevent Falls in Construction on April 26, 2012 (5). The campaign applied several learning theories that are utilized and proven effective in public health interventions. However, the initiative fails to address a key subpopulation. Further critical assessment of this campaign is now needed to evaluate overall effectiveness. PMID- 29164092 TI - The Nuisance Mosquito Anopheles plumbeus (Stephens, 1828) in Germany-A Questionnaire Survey May Help Support Surveillance and Control. AB - The mosquito species Anopheles plumbeus is an aggressive biter and a potential vector of malaria parasites and West Nile virus. It occurs naturally at low population densities, as its larval development is adapted to the specific water qualities found in tree holes. However, probably owing to environmental changes, it has recently been observed in several European countries to use increasingly often artificial breeding habitats that may lead to mass development and severe annoyance to humans living close by. The perception of mosquito nuisance, however, is very subjective, and breeding habitats are not always known, thus impeding targeted surveillance and control. To relate nuisance by An. plumbeus to specific environmental conditions, a questionnaire survey was carried out addressing persons who had submitted specimens of this particular mosquito species to the German citizen science project "Mueckenatlas", an instrument of passive mosquito surveillance. The questionnaire was intended to find out whether a nuisance situation linked to An. plumbeus had existed, whether mosquito breeding habitats could be identified and whether control measures had been conducted. Despite some efforts, the participants who claimed to suffer from an An. plumbeus nuisance problem had rarely identified the source of the mosquitoes. Once control measures had been performed on abandoned manure pits, however, the nuisance problem disappeared or mosquito abundance was at least significantly reduced. Nevertheless, no significant effect of abandoned manure pits on the probability of an An. plumbeus nuisance could be demonstrated in a multivariate logistic regression model testing various variables. Instead, a significant positive effect of a disused farm nearby was found. The reason is probably that manure pits as the most frequent source of An. plumbeus mass development are often located on disused farms, without most people's knowledge about their existence. Disused farms are therefore appropriate candidates to consider when it comes to public health issues connected to An. plumbeus such as surveillance of mass development and implementation of control measures. PMID- 29164093 TI - Application of the Intervention Mapping Framework to Develop an Integrated Twenty first Century Core Curriculum-Part Three: Curriculum Implementation and Evaluation. AB - Public health professionals have been challenged to radically reform public health training to meet evolving demands of twenty-first century public health. Such a transformation requires a systems thinking approach with an interdisciplinary focus on problem solving, leadership, management and teamwork, technology and information, budgeting and finance, and communication. This article presents processes for implementing and evaluating a revised public health curriculum and outlines lessons learned from this initiative. To date, more than 200 students have participated in the initial pilot testing of this program. A rigorous process and outcome evaluation plan was developed and employed. Results from the evaluation were used to enhance the resulting curriculum. Specifically, all instructional materials were evaluated by both the students who received the materials and the faculty who presented the materials. As each successive pilot is delivered, both enrollment and faculty involvement has increased. Through this process, the value of committed faculty, the importance of engaging learners in the evaluation of an education program, and the need to implement curriculum that has been carefully evaluated and evidence informed in nature has emerged. We credit our successful transformation of the Masters in Public Health core to the challenge provided by the Framing the Future task force, the commitment of our College of Public Health leadership, the engagement of our faculty, and the time we allowed for the process to unfold. Ultimately, we believe this transformed curriculum will result in better trained public health professionals, interdisciplinary practitioners who can see public health challenges in new and different ways. PMID- 29164094 TI - Application of the Intervention Mapping Framework to Develop an Integrated Twenty first Century Core Curriculum-Part Two: Translation of MPH Core Competencies into an Integrated Theory-Based Core Curriculum. AB - In the twenty-first century, the dynamics of health and health care are changing, necessitating a commitment to revising traditional public health curricula to better meet present day challenges. This article describes how the College of Public Health at the University of South Florida utilized the Intervention Mapping framework to translate revised core competencies into an integrated, theory-driven core curriculum to meet the training needs of the twenty-first century public health scholar and practitioner. This process resulted in the development of four sequenced courses: History and Systems of Public Health and Population Assessment I delivered in the first semester and Population Assessment II and Translation to Practice delivered in the second semester. While the transformation process, moving from traditional public health core content to an integrated and innovative curriculum, is a challenging and daunting task, Intervention Mapping provides the ideal framework for guiding this process. Intervention mapping walks the curriculum developers from the broad goals and objectives to the finite details of a lesson plan. Throughout this process, critical lessons were learned, including the importance of being open to new ideologies and frameworks and the critical need to involve key-stakeholders in every step of the decision-making process to ensure the sustainability of the resulting integrated and theory-based curriculum. Ultimately, as a stronger curriculum emerged, the developers and instructors themselves were changed, fostering a stronger public health workforce from within. PMID- 29164095 TI - Application of the Intervention Mapping Framework to Develop an Integrated Twenty First Century Core Curriculum-Part 1: Mobilizing the Community to Revise the Masters of Public Health Core Competencies. AB - Twenty-first century health challenges have significantly altered the expanding role and functions of public health professionals. Guided by a call from the Association of Schools and Programs of Public Health's (ASPPH) and the Framing the Future: The Second 100 Years of Education for Public Health report to adopt new and innovative approaches to prepare public health leaders, the University of South Florida College of Public Health aimed to self-assess the current Masters of Public Health (MPH) core curriculum with regard to preparing students to meet twenty-first century public health challenges. This paper describes how Intervention Mapping was employed as a framework to increase readiness and mobilize the COPH community for curricular change. Intervention Mapping provides an ideal framework, allowing organizations to access capacity, specify goals, and guide the change process from curriculum development to implementation and evaluation of competency-driven programs. The steps outlined in this paper resulted in a final set of revised MPH core competencies that are interdisciplinary in nature and fulfill the emergent needs to address changing trends in both public health education and challenges in population health approaches. Ultimately, the competencies developed through this process were agreed upon by the entire College of Public Health faculty, signaling one college's readiness for change, while providing the impetus to revolutionize the delivery of public health education at the University of South Florida. PMID- 29164097 TI - Tacrolimus Utilization and Expenditure in Serbia. AB - Background: Increasing immunosuppressant consumption and expenditure is a quite a challenge in transplantation medicine. The aim of the study was to characterize the utilization and expenditure of tacrolimus, backbone, and standard of care in immunosuppression regimen in Serbian solid organ transplant recipients. Methods: This study was performed as retrospective cross-sectional study during a 3-year period (from 2013 to 2015) in Serbia. The Anatomical Therapeutic Chemical Classification/Defined Daily Doses (ATC/DDD) international system was used for consumption evaluation. Results: Two hundred and sixty-nine patients were transplanted in Serbia from 2013 to 2015 (185 recipients from deceased donors and 84 recipients from living donors). Total number of deceased donors in this period was 81. The consumption of tacrolimus increased (from 0.051 DDD/1,000 inhabitants/day to 0.069 DDD/1,000 inhabitants/day in 2013 and 2015, respectively). The total cost of tacrolimus was also increased; from 1,206,816? to 1,483,472? in 2013 and 2015, respectively. On the other hand, the number of all new solid organ transplants (from deceased and living donors) per million population per year was decreased from 17.39 to 10.02, from 2013 to 2015, respectively. Conclusion: In spite downward trend in the number of solid organ transplants, tacrolimus consumption and expenditure in the examined 3-year period in Serbia increased. Since tacrolimus is a high-cost and life-preserving drug, its increasing utilization and expenditure will most likely continue consuming an enhancing share of Serbian pharmaceutical expenditure, as well as its health care, as a whole. PMID- 29164096 TI - The Prevalence of Overfat Adults and Children in the US. AB - The overfat condition is defined as excess body fat sufficient to impair health. The problem exists in most overweight and obese individuals and can also occur in those who are normal-weight and non-obese, often due to excess abdominal fat. Despite previous indications that the prevalence overweight and obesity is leveling, these conditions are currently at their highest levels in US history. Our review estimated the number of overfat Americans at 91% for adults and 69% for children. The primary purpose of this review was to build upon previous estimations of overfat prevalence in developed countries by using new data from the Centers for Disease Control and Prevention to estimate the overfat prevalence in American adults (>=20 years) and children (2-19 years), and to expand the definition of overfat as excess body fat associated with at least one additional risk factor of impaired cardiometabolic or physical health. The secondary goals are to highlight the role of dietary sugar as a primary cause of the overfat pandemic and mention new data showing the increased prevalence of exercise that parallels the rising prevalence of overfat to further emphasize the secondary role exercise may play in fat loss. Current public health guidelines to address the overfat pandemic may require more emphasis on reducing the consumption of refined carbohydrates, including added sugars. PMID- 29164098 TI - The Highs and Lows of Making a Bucket List-Quantifying Potential Mosquito Breeding Habitats in Metropolitan Backyards. AB - While the development of land for residential housing along the Swan and Canning Rivers in Perth, WA, Australia has reduced natural mosquito breeding sites, the role of backyard container breeding remains a relatively unknown factor. Local Governments responsible for these areas focus management and control efforts on low lying, tidally driven mosquito habitats to control Aedes vigilax (Skuse) and Aedes camptorhynchus (Thomson) mosquitoes in an effort to reduce both the nuisance and disease risk to residents. In spite of their efforts, Local Governments continue to receive complaints regarding mosquito nuisance, even when environmental conditions do not favor hatching and development of the two species in the Swan River tidal flats. In this study, 150 backyard inspections were conducted in the residential suburb of Bassendean, Perth, WA, Australia, situated in close proximity to the Swan River tidal plain. The occurrence and species composition of the mosquito fauna found in residential backyards was documented. Of the backyards inspected, 94% were found to possess containers capable of breeding mosquitoes, although only 3% contained mosquito larvae. Nine species of mosquito were collected from containers ranging in capacity from 0.05 to 50 L across the study area. Additionally, encephalitis virus surveillance trapping was conducted within residential properties and compared to the tidally driven natural habitat at Ashfield Flats and a tidally influenced brackish creekline at Bindaring Park. The species composition of the fauna at the three habitat types differed significantly, with Aedes notoscriptus (Skuse) dominating residential lots and A. vigilax more prevalent at the saltmarsh site. Bindaring Park had an adult composition at the mid-point of these two habitats, reflecting its proximity to both the Swan River and residential lots. PMID- 29164099 TI - The Effectiveness of Brief Information and Self-Efficacy-Based Interventions in Influencing Snack Choices in Homeless Individuals. AB - Background: Homeless adults frequently experience poor nutrition. Research suggests raising self-efficacy and nutritional knowledge can increase healthy eating but that the choice of specific behavioral change techniques (BCTs) is also critical. This study investigated how BCTs, operationalized to increase nutrition knowledge and self-efficacy, might influence the choice of homeless adults when presented with a "healthy" and an "unhealthy" snack. Methods: A total of 125 homeless adults were randomly allocated to watch 1 of 4 brief films: "control," "[nutrition] information only," "self-efficacy" (aimed at increasing self-efficacy and general healthy eating knowledge), and "enhanced self-efficacy" (as "self-efficacy," but the presenter identified themselves as a homeless adult). Post-film, participants were invited to choose between a healthy and an unhealthy snack. Data were analyzed using ANOVA and chi square. Results: Participants in the "enhanced self-efficacy" condition were significantly more likely to choose the healthy option compared to those in the control condition; for the "self-efficacy" condition, the difference was marginally significant. Perceived knowledge and self-efficacy were significantly associated and those with high self-efficacy were significantly more likely to choose a healthy snack regardless of condition. Conclusion: Homeless adults are more likely to make healthy snack choices if their nutritional self-efficacy is increased through encouragement by a peer. PMID- 29164100 TI - Grand Challenges for Nanoscience and Nanotechnology in Energy and Health. PMID- 29164101 TI - The Promoting Role of Different Carbon Allotropes Cocatalysts for Semiconductors in Photocatalytic Energy Generation and Pollutants Degradation. AB - Semiconductor based photocatalytic process is of great potential for solving the fossil fuels depletion and environmental pollution. Loading cocatalysts for the modification of semiconductors could increase the separation efficiency of the photogenerated hole-electron pairs, enhance the light absorption ability of semiconductors, and thus obtain new composite photocatalysts with high activities. Kinds of carbon allotropes, such as activated carbon, carbon nanotubes, graphene, and carbon quantum dots have been used as effective cocatalysts to enhance the photocatalytic activities of semiconductors, making them widely used for photocatalytic energy generation, and pollutants degradation. This review focuses on the loading of different carbon allotropes as cocatalysts in photocatalysis, and summarizes the recent progress of carbon materials based photocatalysts, including their synthesis methods, the typical applications, and the activity enhancement mechanism. Moreover, the cocatalytic effect among these carbon cocatalysts is also compared for different applications. We believe that our work can provide enriched information to harvest the excellent special properties of carbon materials as a platform to develop more efficient photocatalysts for solar energy utilization. PMID- 29164102 TI - Anti-tumor and Anti-angiogenic Ergosterols from Ganoderma lucidum. AB - This study was carried out to isolate chemical constituents from the lipid enriched fraction of Ganoderma lucidum extract and to evaluate their anti proliferative effect on tumor cells and human umbilical vein endothelial cells (HUVECs). Ergosterol derivatives (1-14) were isolated and purified from the lipid enriched fraction of G. lucidum. Their chemical structures were established by spectroscopic analyses or by comparison of mass and NMR spectral data with those reported previously. Amongst, compound 1 was purified and identified as a new one. All the compounds were evaluated for their anti-proliferative effect on human tumor cells and HUVECs in vitro. Compounds 9-13 displayed inhibitory activity against two types of human tumor cells and HUVECs, which indicated that these four compounds had both anti-tumor and anti-angiogenesis activities. Compound 2 had significant selective inhibition against two tumor cell lines, while 3 exhibited selective inhibition against HUVECs. The structure-activity relationships for inhibiting human HepG2 cells were revealed by 3D-QASR. Ergosterol content in different parts of the raw material and products of G. lucidum was quantified. This study provides a basis for further development and utilization of ergosterol derivatives as natural nutraceuticals and functional food ingredients, or as source of new potential antitumor or anti-angiogenesis chemotherapy agent. PMID- 29164103 TI - The Human Antimicrobial Peptides Dermcidin and LL-37 Show Novel Distinct Pathways in Membrane Interactions. AB - Mammals protect themselves from inflammation triggered by microorganisms through secretion of antimicrobial peptides (AMPs). One mechanism by which AMPs kill bacterial cells is perforating their membranes. Membrane interactions and pore formation were investigated for alpha-helical AMPs leading to the formulation of three basic mechanistic models: the barrel stave, toroidal, and carpet model. One major drawback of these models is their simplicity. They do not reflect the real in vitro and in vivo conditions. To challenge and refine these models using a structure-based approach we set out to investigate how human cathelicidin (LL-37) and dermcidin (DCD) interact with membranes. Both peptides are alpha-helical and their structures have been solved at atomic resolution. DCD assembles in solution into a hexameric pre-channel complex before the actual membrane targeting and integration step can occur, and the complex follows a deviation of the barrel stave model. LL-37 interacts with lipids and shows the formation of oligomers generating fibril-like supramolecular structures on membranes. LL-37 further assembles into transmembrane pores with yet unknown structure expressing a deviation of the toroidal pore model. Both of their specific targeting mechanisms will be discussed in the context of the "old" models propagated in the literature. PMID- 29164104 TI - Targeting Dengue Virus NS-3 Helicase by Ligand based Pharmacophore Modeling and Structure based Virtual Screening. AB - Dengue fever is an emerging public health concern, with several million viral infections occur annually, for which no effective therapy currently exist. Non structural protein 3 (NS-3) Helicase encoded by the dengue virus (DENV) is considered as a potential drug target to design new and effective drugs against dengue. Helicase is involved in unwinding of dengue RNA. This study was conducted to design new NS-3 Helicase inhibitor by in silico ligand- and structure based approaches. Initially ligand-based pharmacophore model was generated that was used to screen a set of 1201474 compounds collected from ZINC Database. The compounds matched with the pharmacophore model were docked into the active site of NS-3 helicase. Based on docking scores and binding interactions, 25 compounds are suggested to be potential inhibitors of NS3 Helicase. The pharmacokinetic properties of these hits were predicted. The selected hits revealed acceptable ADMET properties. This study identified potential inhibitors of NS-3 Helicase in silico, and can be helpful in the treatment of Dengue. PMID- 29164105 TI - Platelet-Rich Plasma Derived Growth Factors Contribute to Stem Cell Differentiation in Musculoskeletal Regeneration. AB - Stem cell treatment and platelet-rich plasma (PRP) therapy are two significant issues in regenerative medicine. Stem cells such as bone marrow mesenchymal stem cells, adipose-derived stem cells and periodontal ligament stem cells can be successfully applied in the field of tissue regeneration. PRP, a natural product isolated from whole blood, can secrete multiple growth factors (GFs) for regulating physiological activities. These GFs can stimulate proliferation and differentiation of different stem cells in injury models. Therefore, combination of both agents receives wide expectations in regenerative medicine, especially in bone, cartilage and tendon repair. In this review, we thoroughly discussed the interaction and underlying mechanisms of PRP derived GFs with stem cells, and assessed their functions in cell differentiation for musculoskeletal regeneration. PMID- 29164106 TI - Complementary Sample Preparation Strategies for Analysis of Cereal beta-Glucan Oxidation Products by UPLC-MS/MS. AB - The oxidation of cereal (1->3,1->4)-beta-D-glucan can influence the health promoting and technological properties of this linear, soluble homopolysaccharide by introduction of new functional groups or chain scission. Apart from deliberate oxidative modifications, oxidation of beta-glucan can already occur during processing and storage, which is mediated by hydroxyl radicals (HO*) formed by the Fenton reaction. We present four complementary sample preparation strategies to investigate oat and barley beta-glucan oxidation products by hydrophilic interaction ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), employing selective enzymatic digestion, graphitized carbon solid phase extraction (SPE), and functional group labeling techniques. The combination of these methods allows for detection of both lytic (C1, C3/4, C5) and non-lytic (C2, C4/3, C6) oxidation products resulting from HO*-attack at different glucose carbons. By treating oxidized beta-glucan with lichenase and beta-glucosidase, only oxidized parts of the polymer remained in oligomeric form, which could be separated by SPE from the vast majority of non-oxidized glucose units. This allowed for the detection of oligomers with mid-chain glucuronic acids (C6) and carbonyls, as well as carbonyls at the non-reducing end from lytic C3/C4 oxidation. Neutral reducing ends were detected by reductive amination with anthranilic acid/amide as labeled glucose and cross-ring cleaved units (arabinose, erythrose) after enzyme treatment and SPE. New acidic chain termini were observed by carbodiimide-mediated amidation of carboxylic acids as anilides of gluconic, arabinonic, and erythronic acids. Hence, a full characterization of all types of oxidation products was possible by combining complementary sample preparation strategies. Differences in fine structure depending on source (oat vs. barley) translates to the ratio of observed oxidized oligomers, with in-depth analysis corroborating a random HO*-attack on glucose units irrespective of glycosidic linkage and neighborhood. The method was demonstrated to be (1) sufficiently sensitive to allow for the analysis of oxidation products also from a mild ascorbate-driven Fenton reaction, and (2) to be specific for cereal beta glucan even in the presence of other co-oxidized polysaccharides. This opens doors to applications in food processing to assess potential oxidations and provides the detailed structural basis to understand the effect oxidized functional groups have on beta-glucan's health promoting and technological properties. PMID- 29164107 TI - Poly(ethylene glycol) and Cyclodextrin-Grafted Chitosan: From Methodologies to Preparation and Potential Biotechnological Applications. AB - Chitosan, a polyaminosaccharide obtained by alkaline deacetylation of chitin, possesses useful properties including biodegradability, biocompatibility, low toxicity, and good miscibility with other polymers. It is extensively used in many applications in biology, medicine, agriculture, environmental protection, and the food and pharmaceutical industries. The amino and hydroxyl groups present in the chitosan backbone provide positions for modifications that are influenced by factors such as the molecular weight, viscosity, and type of chitosan, as well as the reaction conditions. The modification of chitosan by chemical methods is of interest because the basic chitosan skeleton is not modified and the process results in new or improved properties of the material. Among the chitosan derivatives, cyclodextrin-grafted chitosan and poly(ethylene glycol)-grafted chitosan are excellent candidates for a range of biomedical, environmental decontamination, and industrial purposes. This work discusses modifications including chitosan with attached cyclodextrin and poly(ethylene glycol), and the main applications of these chitosan derivatives in the biomedical field. PMID- 29164108 TI - Salicylic Acid Alleviates Aluminum Toxicity in Soybean Roots through Modulation of Reactive Oxygen Species Metabolism. AB - As an important signal molecule, salicylic acid (SA) improves plant tolerance to aluminum (Al) stress. The objective of this study was to investigate the effects of exogenous SA application on the dynamics of endogenous SA and reactive oxygen species in soybean (Glycine max L.) exposed to Al stress. The roots of soybean seedlings were exposed to a combination of AlCl3 (30 MUM) and SA (10 MUM)/PAC (100 MUM, paclobutrazol, SA biosynthesis inhibitor) for 3, 6, 9, and 12 h. Al stress induced an increase in endogenous SA concentration in a time-dependent manner, also verified by the up-regulated expression of GmNPR1, an SA-responsive gene. Al stress increased the activities of phenylalanine ammonia-lyase (PAL) and benzoic acid 2-hydroxylase (BA2H), and the contents of SA, [Formula: see text] and malondialdehyde (MDA) in the root apex. The application of exogenous SA increased PAL and BA2H, and reduced [Formula: see text] and MDA contents in soybean roots under Al stress. PAC inhibited the SA induced increase in BA2H activity. In addition, the SA application resulted in a rapid increase in hydrogen peroxide (H2O2) concentration under Al stress, followed by a sharp decrease. Compared with the plants exposed to Al alone, Al+SA plants possessed higher activities of superoxide dismutase, peroxidase, and ascorbate peroxidase, and lower catalase activity, indicating that SA alleviated Al-induced oxidative damage. These results suggested that PAL and BA2H were involved in Al-induced SA production and showed that SA alleviated the adverse effects of Al toxicity by modulating the cellular H2O2 level and the antioxidant enzyme activities in the soybean root apex. PMID- 29164109 TI - Identification of Directed Interactions in Kinematic Data during Running. AB - The knowledge of motion dynamics during running activity is crucial to enhance the development of rehabilitation techniques and injury prevention programs. Recent studies investigated the interaction between joints, using several analysis techniques, as cross-correlation, sensitivity analysis, among others. However, the direction of the joints pairing is still not understood. This paper proposes a study of the influence direction pattern in healthy runners by using kinematic data together with partial directed coherence, a frequency approach of Granger causality. The analysis was divided into three anatomical planes, sagittal, frontal, and transverse, and using data from ankle, knee, hip, and trunk segments. Results indicate a predominance of proximal to distal influence during running, reflecting a centralized anatomic source of movements. These findings highlight the necessity of managing proximal joints movements, in addition to motor control and core (trunk and hip) strengthening training to lumbar spine, knee, and ankle injuries prevention and rehabilitation. PMID- 29164110 TI - It Takes Two to Tango: Coupling of Angiogenesis and Osteogenesis for Bone Regeneration. AB - Bone regeneration is a complex process requiring highly orchestrated interactions between different cells and signals to form new mineralized tissue. Blood vessels serve as a structural template, around which bone development takes place, and also bring together the key elements for bone homeostasis into the osteogenic microenvironment, including minerals, growth factors and osteogenic progenitor cells. Vascular endothelial growth factor (VEGF) is the master regulator of vascular growth and it is required for effective coupling of angiogenesis and osteogenesis during both skeletal development and postnatal bone repair. Here, we will review the current state of knowledge on the molecular cross-talk between angiogenesis and osteogenesis. In particular, we will focus on the role of VEGF in coupling these two processes and how VEGF dose can control the outcome, addressing in particular: (1) the direct influence of VEGF on osteogenic differentiation of mesenchymal progenitors; (2) the angiocrine functions of endothelium to regulate osteoprogenitors; (3) the role of immune cells, e.g., myeloid cells and osteoclast precursors, recruited by VEGF to the osteogenic microenvironment. Finally, we will discuss emerging strategies, based on the current biological understanding, to ensure rapid vascularization and efficient bone formation in regenerative medicine. PMID- 29164111 TI - Cartilage and Muscle Cell Fate and Origins during Lizard Tail Regeneration. AB - Introduction: Human cartilage is an avascular tissue with limited capacity for repair. By contrast, certain lizards are capable of musculoskeletal tissue regeneration following tail loss throughout all stages of their lives. This extraordinary ability is the result of a complex process in which a blastema forms and gives rise to the tissues of the regenerate. Blastemal cells have been shown to originate either from dedifferentiated tissues or from existing progenitor cells in various species, but their origin has not been determined in lizards. As reptiles, lizards are the closest relatives to mammals with enhanced regenerative potential, and the origin of blastemal cells has important implications for the regenerative process. Hence, the aim of this study is to determine the cellular origin of regenerated cartilage and muscle tissues in reptiles using the mourning gecko lizard as the regenerative model. Methods: To trace the fate and differentiation potential of cartilage during tail regeneration, cartilage cells pre-labeled with the fluorescent tracer Dil were injected into lizard tails, and the contribution of cartilage cells to regenerated tail tissues was assessed by histologic examination at 7, 14, and 21 days post-tail amputation. The contribution of muscle cells to regenerated tail tissues was evaluated using muscle creatine kinase promoter-driven Cre recombinase in conjunction with the Cre-responsive green-to-red fluorescence shift construct CreStoplight. 21 days after amputation, tail tissues were analyzed by histology for red fluorescent protein (RFP)-positive cells. Results: At 7 days post-amputation, Dil-labeled cartilage cells localized to the subapical space contributing to the blastema. At 14 and 21 days post-amputation, Dil labeled cells remained in the subapical space and colocalized with Collagen type II (Col2) staining in the cartilage tube and myosin heavy chain (MHC) staining in regenerated muscle. Lineage tracing of myocytes showed colocalization of RFP with Col2 and MHC in differentiated tissues at 21 days post-amputation. Conclusion: This study demonstrates that differentiated cartilage cells contribute to both regenerated muscle and cartilage tissues following tail loss, and in turn, differentiated muscle cells contribute to both tissue types as well. These findings suggest that dedifferentiation and/or transdifferentiation are at least partially responsible for the regenerative outcome in the mourning gecko. PMID- 29164112 TI - Details Matter: Noise and Model Structure Set the Relationship between Cell Size and Cell Cycle Timing. AB - Organisms across all domains of life regulate the size of their cells. However, the means by which this is done is poorly understood. We study two abstracted "molecular" models for size regulation: inhibitor dilution and initiator accumulation. We apply the models to two settings: bacteria like Escherichia coli, that grow fully before they set a division plane and divide into two equally sized cells, and cells that form a bud early in the cell division cycle, confine new growth to that bud, and divide at the connection between that bud and the mother cell, like the budding yeast Saccharomyces cerevisiae. In budding cells, delaying cell division until buds reach the same size as their mother leads to very weak size control, with average cell size and standard deviation of cell size increasing over time and saturating up to 100-fold higher than those values for cells that divide when the bud is still substantially smaller than its mother. In budding yeast, both inhibitor dilution or initiator accumulation models are consistent with the observation that the daughters of diploid cells add a constant volume before they divide. This "adder" behavior has also been observed in bacteria. We find that in bacteria an inhibitor dilution model produces adder correlations that are not robust to noise in the timing of DNA replication initiation or in the timing from initiation of DNA replication to cell division (the C+D period). In contrast, in bacteria an initiator accumulation model yields robust adder correlations in the regime where noise in the timing of DNA replication initiation is much greater than noise in the C + D period, as reported previously (Ho and Amir, 2015). In bacteria, division into two equally sized cells does not broaden the size distribution. PMID- 29164113 TI - Chemokine Signaling during Midline Epithelial Seam Disintegration Facilitates Palatal Fusion. AB - Disintegration of the midline epithelial seam (MES) is crucial for palatal fusion, and failure results in cleft palate. Palatal fusion and wound repair share many common signaling pathways related to epithelial-mesenchymal cross talk. We postulate that chemokine CXCL11, its receptor CXCR3, and the cytoprotective enzyme heme oxygenase (HO), which are crucial during wound repair, also play a decisive role in MES disintegration. Fetal growth restriction and craniofacial abnormalities were present in HO-2 knockout (KO) mice without effects on palatal fusion. CXCL11 and CXCR3 were highly expressed in the disintegrating MES in both wild-type and HO-2 KO animals. Multiple apoptotic DNA fragments were present within the disintegrating MES and phagocytized by recruited CXCR3-positive wt and HO-2 KO macrophages. Macrophages located near the MES were HO-1-positive, and more HO-1-positive cells were present in HO-2 KO mice compared to wild-type. This study of embryonic and palatal development provided evidence that supports the hypothesis that the MES itself plays a prominent role in palatal fusion by orchestrating epithelial apoptosis and macrophage recruitment via CXCL11-CXCR3 signaling. PMID- 29164114 TI - Interorganelle Communication between Mitochondria and the Endolysosomal System. AB - The function of mitochondria and lysosomes has classically been studied separately. However, evidence has now emerged of intense crosstalk between these two organelles, such that the activity or stress status of one organelle may affect the other. Direct physical contacts between mitochondria and the endolysosomal compartment have been reported as a rapid means of interorganelle communication, mediating lipid or other metabolite exchange. Moreover, mitochondrial derived vesicles can traffic obsolete mitochondrial proteins into the endolysosomal system for their degradation or secretion to the extracellular milieu as exosomes, representing an additional mitochondrial quality control mechanism that connects mitochondria and lysosomes independently of autophagosome formation. Here, we present what is currently known about the functional and physical communication between mitochondria and lysosomes or lysosome-related organelles, and their role in sustaining cellular homeostasis. PMID- 29164115 TI - Cross-sectional Associations of Fatigue with Cerebral beta-Amyloid in Older Adults at Risk of Dementia. AB - Fatigue is a common symptom in the elderly and has also been associated with impaired cognition in older adults. Hence, we sought to explore the cross sectional relationship between fatigue and cerebral beta-amyloid (Abeta) in 269 elderly individuals reporting subjective memory complaints from the Multidomain Alzheimer Preventive Trial. Standard uptake value ratios (SUVRs) were generated by [18F] florbetapir positron emission tomography (PET) using the cerebellum as a reference. Cortical-to-cerebellar SUVRs (cortical-SUVRs) were obtained using the mean signal from the frontal cortex, temporal cortex, parietal cortex, precuneus, anterior cingulate, and posterior cingulate. Other brain regions independently assessed were the anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval center, and temporal cortex. Fatigue was defined according to two questions retrieved from the Center for Epidemiological Studies-Depression scale. Chronic fatigue was defined as meeting fatigue criteria at two consecutive clinical visits 6 months apart between study baseline and 1 year (visits were performed at baseline, 6 months and 1 year then annually). Cross-sectional associations between fatigue variables and cerebral Abeta were explored using fully adjusted multiple linear regression models. We found no statistically significant cross-sectional associations between fatigue assessed at the clinical visit closest to PET and Abeta in any brain region. Similarly, chronic fatigue was not significantly associated with Abeta load. Sensitivity analysis in subjects with a Clinical Dementia Rating of 0.5 showed that fatigue reported at the clinical visit closest to PET was, however, weakly associated with increased Abeta in the hippocampus (B-coefficient: 0.07, 95% CI: 0.01, 0.12, p = 0.016). These preliminary results suggest that fatigue might be associated with Abeta in brain regions associated with Alzheimer's disease in subjects in the early stages of disease. PMID- 29164116 TI - Potential of Metformin to Improve Cardiac Risk in Postpartum Women with Gestational Diabetes. AB - Objective: Pregnancy is associated with an increase in total cholesterol, high density lipoproteins (HDL), and low-density lipoproteins (LDL). Postpartum, HDL and LDL decrease over the first 12 weeks postpartum. Oxidized LDL (ox-LDL) is a marker of oxidative stress-related inflammation, which is associated with obesity and also with development of cardiovascular disease. Cardiovascular protection and weight loss are benefits from metformin, especially in women with diabetes. The objective of this study was to compare changes in lipid profiles and biomarkers for obesity during the initial 6 weeks postpartum between women with gestational diabetes mellitus (GDM) treated with metformin versus placebo. Methods: This was a planned ancillary study of a randomized controlled trial compares metformin versus placebo in women with GDM for postpartum weight loss. Two 3 mL blood samples were collected within 24 h of delivery and 6 weeks postpartum immediately processed after collection then stored at -20 degrees C until completion of clinical trial prior to analysis. Change in the median plasma concentrations of total cholesterol, HDL, ox-LDL, glucose, insulin, leptin, and unacylated ghrelin were compared between study groups. Results: Of the 77 postpartum women were included, 35 received metformin and 42 received placebo. There was less of a reduction in HDL in the metformin group compared to placebo ( 2.3 versus -7.5 mg/dL, p = 0.019). In addition, there was a greater reduction in ox-LDL in those receiving metformin (-12.2 versus -3.8 mg/dL, p = 0.038). No other differences were observed in the selected biomarkers evaluated. Conclusion: Biomarker levels of HDL and ox-LDL were positively affected during the initial 6 weeks postpartum in GDM women treated with metformin. Additional studies with a longer duration of metformin treatment in the postpartum period are warranted to evaluate long-term potential benefits. PMID- 29164117 TI - Active Aging in Very Old Age and the Relevance of Psychological Aspects. AB - Background: Active aging encompasses a socially and individually designed mix of different domains that range from personal and familial, to social and professional. In being a key policy concept often focused on the young-old individuals, efforts in studying its dimensions in advanced ages have seldom been made. Nevertheless, there is a recognized need to promote adequate responses to the growing number of individuals reaching advanced ages and to recognize their specific dependability on health-related aspects, services attendance, social interactions, or on psychological characteristics for what it means to "age actively." Objective and methods: This study provides a secondary analysis of data and follows the preceding work on the operationalization of the World Health Organization's (WHO) active aging model by means of an assessment protocol to measure which variables, within the model's determinants, contribute the most for an active aging process (1). Authors used the achieved model (composed by six factors: health, psychological component, cognitive performance, social relationships, biological component, and personality) and performed multi-group analysis of structural invariance to examine hypothetical differences between age groups (<75 years vs. >=75 years) and to contrast obtained findings with the originally achieved model for the total sample (1,322 individuals aged 55 +). Results: The structural covariances for the two age groups were statistically different. The comparison of components between age groups revealed a major relevance of the psychological component for the older age group. Conclusion: These findings reinforce the importance of psychological functioning in active aging in oldest old, and the need for further research on specific psychological features underlying the subjective meaning of active aging in more advanced ages. PMID- 29164120 TI - Expression of Mitochondrial-Encoded Genes in Blood Differentiate Acute Renal Allograft Rejection. AB - Despite potent immunosuppression, clinical and biopsy confirmed acute renal allograft rejection (AR) still occurs in 10-15% of recipients, ~30% of patients demonstrate subclinical rejection on biopsy, and ~50% of them can show molecular inflammation, all which increase the risk of chronic dysfunction and worsened allograft outcomes. Mitochondria represent intracellular endogenous triggers of inflammation, which can regulate immune cell differentiation, and expansion and cause antigen-independent graft injury, potentially enhancing the development of acute rejection. In the present study, we investigated the role of mitochondrial DNA encoded gene expression in biopsy matched peripheral blood (PB) samples from kidney transplant recipients. Quantitative PCR was performed in 155 PB samples from 115 unique pediatric (<21 years) and adult (>21 years) renal allograft recipients at the point of AR (n = 61) and absence of rejection (n = 94) for the expression of 11 mitochondrial DNA encoded genes. We observed increased expression of all genes in adult recipients compared to pediatric recipients; separate analyses in both cohorts demonstrated increased expression during rejection, which also differentiated borderline rejection and showed an increasing pattern in serially collected samples (0-3 months prior to and post rejection). Our results provide new insights on the role of mitochondria during rejection and potentially indicate mitochondria as targets for novel immunosuppression. PMID- 29164119 TI - Spontaneous Reversion of Clinical Conditions Measuring the Risk Profile of the Individual: From Frailty to Mild Cognitive Impairment. AB - The number of people living with disabilities worldwide is rapidly growing due to a longer life expectancy and the subsequent increasing burden of chronic diseases. The need of developing and implementing effective strategies aimed at delaying or preventing disability has been repeatedly underlined and is currently the main focus of several health-care policies. In this scenario, a special attention is addressed to the identification of specific clinical conditions measuring the risk profile of the individual of developing an overt disability and other negative outcomes. These risk profiles can indeed become promising targets for developing and implementing preventive interventions. When the disabling cascade is fully established, in fact, the reversing/attenuating the process becomes more challenging. However, the exact nature of these relatively new constructs is not yet sufficiently clear, and several related issues remain poorly explored. In particular, these entities tend to be considered as unequivocally prodromal stages of a future disease, neglecting and underestimating their fluctuations/transitions over time and their potential to clinically improve/revert. This unbalanced judgment did probably contribute to an ambiguous and biased use of these conditions. Considering them as an early stage of an unavoidable future disease, in fact, determined a tendency to start a targeted intervention as if in presence of the disease itself, with the subsequent risk of over-diagnosis and over-treatment. In the present article, we discuss the dynamics underlying the reversion from a clinical at-risk condition to normality and its implications, specifically focusing on the examples of frailty and mild cognitive impairment. PMID- 29164121 TI - A Pragmatic Study Shows Failure of Dental Composite Fillings Is Genetically Determined: A Contribution to the Discussion on Dental Amalgams. AB - Composite resins for posterior tooth restorations have become a viable alternative to dental amalgam. Failures sometimes cannot be easily explained, and we hypothesize that a genetic component may influence longevity of restorations. We aimed to determine if there is any evidence for a difference in the performance of amalgams versus composite resin in extensive posterior restorations. We also aimed to determine if risk factors such as age, sex, smoking tobacco, alcohol drinking, diabetes status, and periodontal health status may have a role in the failures of extensive anterior composite restorations. Finally, we investigated if genetic variation in matrix metalloproteinases that are present in the mineralized dentin is associated with failure of composite resin. The data used to perform this research were obtained from the Dental Registry and DNA Repository project after screening 4,856 patients. All restorations were evaluated at times of 1, 2, and 5 years after the restoration placement. 6,266 amalgam and 2,010 composite restorations were analyzed in a total of 807 patients in a period of approximately 10 years (period corresponding to the database existence). An additional 443 extensive direct composite resin restorations in anterior teeth were also studied. Failure rates of amalgam and composite restorations are similar, and by the end of 5 years, composites outperformed amalgams slightly. Failures of anterior composite restorations occurred more often in males who smoked tobacco (p = 0.05), despite a similar number of females and males that smoked tobacco in the sample (116 individuals smoked tobacco, 54 females and 62 males). Alcohol drinking increased failure rate within 2 years (p = 0.03). We found a statistically significant association between matrix metalloproteinase 2 rs9923304 and failure of composite restorations (p = 0.007). Composite resins can replace amalgam restorations. Smoking tobacco and drinking alcohol will increase the chance of restoration failure. PMID- 29164118 TI - Infections Caused by Antimicrobial Drug-Resistant Saprophytic Gram-Negative Bacteria in the Environment. AB - Background: Drug-resistance genes found in human bacterial pathogens are increasingly recognized in saprophytic Gram-negative bacteria (GNB) from environmental sources. The clinical implication of such environmental GNBs is unknown. Objectives: We conducted a systematic review to determine how often such saprophytic GNBs cause human infections. Methods: We queried PubMed for articles published in English, Spanish, and French between January 2006 and July 2014 for 20 common environmental saprophytic GNB species, using search terms "infections," "human infections," "hospital infection." We analyzed 251 of 1,275 non-duplicate publications that satisfied our selection criteria. Saprophytes implicated in blood stream infection (BSI), urinary tract infection (UTI), skin and soft tissue infection (SSTI), post-surgical infection (PSI), osteomyelitis (Osteo), and pneumonia (PNA) were quantitatively assessed. Results: Thirteen of the 20 queried GNB saprophytic species were implicated in 674 distinct infection episodes from 45 countries. The most common species included Enterobacter aerogenes, Pantoea agglomerans, and Pseudomonas putida. Of these infections, 443 (66%) had BSI, 48 (7%) had SSTI, 36 (5%) had UTI, 28 (4%) had PSI, 21 (3%) had PNA, 16 (3%) had Osteo, and 82 (12%) had other infections. Nearly all infections occurred in subjects with comorbidities. Resistant strains harbored extended-spectrum beta lactamase (ESBL), carbapenemase, and metallo-beta-lactamase genes recognized in human pathogens. Conclusion: These observations show that saprophytic GNB organisms that harbor recognized drug-resistance genes cause a wide spectrum of infections, especially as opportunistic pathogens. Such GNB saprophytes may become increasingly more common in healthcare settings, as has already been observed with other environmental GNBs such as Acinetobacter baumannii and Pseudomonas aeruginosa. PMID- 29164122 TI - Changes in Expression of the CLOCK Gene in Obstructive Sleep Apnea Syndrome Patients Are Not Reverted by Continuous Positive Airway Pressure Treatment. AB - Purpose: Metabolic syndrome and cardiovascular disease are strongly associated with obstructive sleep apnea syndrome (OSAS), which causes substantial changes to normal circadian physiological functions, including metabolic pathways. Because core clock genes are known to be modulated by sleep/vigilance cycles, we asked whether the expression level of mRNA coding for clock genes is altered in non treated OSAS patients and if it can be corrected by standard continuous positive airway pressure (CPAP) treatment. Methods: Peripheral blood was collected from male patients diagnosed with severe OSAS (apnea-hypopnea index >= 30/h) before and after treatment initiation. qPCR was used to measure mRNA levels of genes associated with the central circadian pacemaker including CLOCK, BMAL1, Cry1, Cry2, and three Period genes (Per 1, 2, 3) in peripheral blood mononuclear cells (PBMCs). Results: We found statistically significant differences for CLOCK (p value = 0.022) expression in PBMCs of OSAS patients which were not reverted by treatment with CPAP. We have also found a substantial decrease in the slow wave sleep (SWS) content in OSAS patients (p-value < 0.001) that, contrary to REM sleep, was not corrected by CPAP (p-value = 0.875). Conclusion: CPAP treatment does not correct substantial changes in expression of core clock genes in OSAS patients. Because CPAP treatment is also unable to normalize the SWS in these patients, it is likely that additional therapeutic interventions that increase SWS content and complement the benefits of CPAP are required to more effectively reduce the known increased cardiovascular risk associated with OSAS patients. PMID- 29164124 TI - Sterile Reverse Osmosis Water Combined with Friction Are Optimal for Channel and Lever Cavity Sample Collection of Flexible Duodenoscopes. AB - Introduction: Simulated-use buildup biofilm (BBF) model was used to assess various extraction fluids and friction methods to determine the optimal sample collection method for polytetrafluorethylene channels. In addition, simulated-use testing was performed for the channel and lever cavity of duodenoscopes. Materials and methods: BBF was formed in polytetrafluorethylene channels using Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa. Sterile reverse osmosis (RO) water, and phosphate-buffered saline with and without Tween80 as well as two neutralizing broths (Letheen and Dey-Engley) were each assessed with and without friction. Neutralizer was added immediately after sample collection and samples concentrated using centrifugation. Simulated-use testing was done using TJF-Q180V and JF-140F Olympus duodenoscopes. Results: Despite variability in the bacterial CFU in the BBF model, none of the extraction fluids tested were significantly better than RO. Borescope examination showed far less residual material when friction was part of the extraction protocol. The RO for flush-brush-flush (FBF) extraction provided significantly better recovery of E. coli (p = 0.02) from duodenoscope lever cavities compared to the CDC flush method. Discussion and conclusion: We recommend RO with friction for FBF extraction of the channel and lever cavity of duodenoscopes. Neutralizer and sample concentration optimize recovery of viable bacteria on culture. PMID- 29164123 TI - Income Gradient in Renal Disease Mortality in the United States. AB - Background: Non-communicable diseases and associated mortality follow a social gradient and chronic kidney disease is not an exception to this rule. Intermediate behavioral and medical factors that may explain such social gradients are, however, still unknown. Objectives: Using nationally representative data in the United States, this study was conducted to investigate the mediating effect of medical and behavioral risk factors on the association between socioeconomic status (SES) and renal disease mortality. Patients and methods: Americans' Changing Lives Study (ACL), 1986-2011, is a 25-year nationally representative prospective cohort study. ACL followed 3,361 adults for up to 25 years. Income, education, and unemployment were the main predictors of interest. Death due to renal disease was the main outcome. Health behaviors (smoking, drinking, and exercise) and medical risk factors (diabetes, hypertension, and obesity) were the mediators. Cox proportional hazards models were used for data analysis. Results: Higher income (HR = 0.75; 95% CI = 0.62 0.89) was associated with lower risk of death due to renal disease over the 25 year follow-up period. Although health behaviors and medical risk factors at baseline were also predictors of the outcome, they failed to explain the effect of income on death due to renal disease. That is, income was associated with death due to renal disease above and beyond all potential mediators including behavioral and medical risk factors. Conclusion: Socioeconomic inequalities in the United States cause disparities in renal disease mortality; however, such differences are not due to health behaviors (smoking and drinking) and medical risk factors (hypertension and diabetes). To reduce disparities in renal disease mortality in the United States, policies should go beyond health behaviors and medical risk factors. While programs should help low-income individuals maintain exercise and avoid smoking, reduction of income disparities should be regarded as a strategy for reduction of disparities in renal disease mortality. By increasing minimum pay and minimizing the income gap, we may reduce disparities in renal disease mortality. PMID- 29164125 TI - Malnutrition upon Hospital Admission in Geriatric Patients: Why Assess It? AB - Objective: To assess the prevalence of malnutrition according to the new ESPEN definition in a population of geriatric hospital patients and to determine how malnutrition affects the length of hospital stay (LOS) and hospital mortality. Design: A retrospective analysis of data gathered during nutritional screening surveys carried out three consecutive years, from 2012 to 2014, in an Italian geriatric research hospital (INRCA, Ancona) was performed. On the day of the study, demographic data, data on clinical conditions and the nutritional status of newly admitted patients were collected. Patients were screened for malnutrition risk using the Malnutrition Universal Screening Tool (MUST). Subsequently, malnutrition was diagnosed, for subjects at high risk, following the criteria suggested by the European Association for Clinical Nutrition and Metabolism [body mass index (BMI) < 18.5 kg/m2 or different combinations of unintentional weight loss over time and BMI values]. Sensitivity, specificity, positive and negative predictive value of MUST compared to ESPEN criteria were assessed. The characteristics of patients with a diagnosis of malnutrition were compared to those of non-malnourished patients. The impact of malnutrition on LOS and hospital mortality was investigated through logistic and linear regression models. Setting: The study was performed in an Italian geriatric research hospital (INRCA, Ancona). Subjects: Two hundred eighty-four newly hospitalized geriatric patients from acute care wards (mean age 82.8 +/- 8.7 years), who gave their written consent to participate in the study, were enrolled. Results: According to the MUST, high risk of malnutrition at hospitalization was found in 28.2% of patients. Malnutrition was diagnosed in 24.6% of subjects. The malnutrition was an independent predictor of both the LOS and hospital mortality. The multivariate analyses-linear and logistic regression-were performed considering different potential confounders contemporarily. The results showed that the malnutrition is an independent predictor of LOS and hospital mortality. Malnourished subjects were hospitalized almost 3 days longer compared to non malnourished patients (p = 0.047; CI 0.04-5.80). The risk of death during hospitalization was 55% higher for malnourished patients (p = 0.037; CI 0.21 0.95). Conclusion: A new ESPEN consensus of malnutrition was easily applicable in a population of geriatric hospital patients. Given that the nutritional status of geriatric patients was strongly correlated with the LOS and hospital mortality, the use of this simple and non-time consuming tool is highly recommended in clinical practice. PMID- 29164126 TI - Overweight and Cognitive Performance: High Body Mass Index Is Associated with Impairment in Reactive Control during Task Switching. AB - The prevalence of weight problems is increasing worldwide. There is growing evidence that high body mass index (BMI) is associated with frontal lobe dysfunction and deficits in cognitive control. The present study aims to clarify the association between weight status and the degree of impairment in cognitive flexibility, i.e., the ability to efficiently switch from one task to another, by disentangling the preparatory and residual domains of task switching. Twenty-six normal weight (BMI < 25, five males) and twenty-six overweight (BMI >= 25, seven males) university students performed a task-switching paradigm that provides a relatively well-established diagnostic measure of proactive vs. reactive control with regard to cognitive flexibility. Compared to individuals with a BMI lower than 25, overweight (i.e., >=25) was associated with increased switching costs in the reactive switching condition (i.e., when preparation time is short), representing reduced cognitive flexibility in the preparatory domain. In addition, the overweight group reported significantly more depression and binge eating symptoms, although still indicating minimal depression. No between-group differences were found with regard to self-reported autism spectrum symptoms, impulsiveness, state- and trait anxiety, and cognitive reactivity to depression. The present findings are consistent with and extend previous literature showing that elevated BMI in young, otherwise healthy individuals is associated with significantly more switching costs due to inefficiency in the retrieval, implementation, and maintenance of task sets, indicating less efficient cognitive control functioning. PMID- 29164128 TI - Peptides Released from Foremilk and Hindmilk Proteins by Breast Milk Proteases Are Highly Similar. AB - Human milk contains active proteases that initiate hydrolysis of milk proteins within the mammary gland. Milk expressed at the beginning of feeding is known as foremilk and that at the end of feeding is known as hindmilk. As hindmilk contains higher fat, vitamins A and E, and higher calories than foremilk, feeding only hindmilk initially and reserving foremilk for later are practiced in some neonatal intensive care units. This study investigated the difference in peptide profiles, predicted milk protease activities, and bioactive peptides between foremilk and hindmilk. Bioactive peptides are short fragments of proteins that influence biological processes. Four mothers pumped 10 mL of their foremilk and 10 mL of their hindmilk into iced containers prepared with antiproteases and the samples were immediately frozen. The peptide profile of each sample was analyzed by liquid chromatography nano-electrospray ionization Orbitrap Fusion tandem mass spectrometry. Peptide abundance (sum of ion intensities) and count (number of unique peptide sequences) in each milk sample were determined from this analysis. The specific enzymes that participated in peptide release were predicted based on the amino acids positioned at each cleavage site. Peptide bioactivity was predicted based on homology to a known functional peptide database and two bioactivity prediction algorithms. Hindmilk contained a higher count of peptides than foremilk. The higher number of unique peptide sequences in hindmilk was related to hydrolysis of beta-casein, osteopontin, alphas1-casein and mucin-1 via plasmin and elastase cleavage, and possible aminopeptidase and carboxypeptidase activities. Though hindmilk contained a greater number of peptides than foremilk, the overall peptide abundance did not differ and most of the total peptide abundance derived from peptide sequences that were present in both milk types. The presence of higher numbers of predicted bioactive peptides in the hindmilk could indicate that the practice of providing hindmilk rather than foremilk to premature infants could positively impact health outcomes; however, as there are few differences in overall peptide abundance, the overall effect is likely limited. PMID- 29164127 TI - Antidiabetic Effects of Aronia melanocarpa and Its Other Therapeutic Properties. AB - Diabetes is a global pandemic which warrants urgent attention due to its rising prevalence and economic burden. Thus, many alternative therapies are being researched for antidiabetic properties, given the inefficacy of current medicinal treatments. From this perspective, Aronia melanocarpa or black chokeberry has been investigated for its therapeutic properties in many studies, especially for its ability to combat hyperglycemia-induced oxidative stress and the macrovascular complications of diabetes including cardiovascular disease. Though A. melanocarpa is native to the eastern areas of North America, it has been planted extensively in Europe and Asia as well. Several in vivo studies have displayed the antioxidant properties of A. melanocarpa berry juice and plant extract in rat models where oxidative stress markers were observed to have significant reductions. Some of the potent bioactive compounds present in the fruits and other parts of the plant were identified as (-)-epicatechin, chlorogenic acid, neochlorogenic acid, and cyanidin-3-galactoside. Overall, A. melanocarpa could be considered a good source of antioxidants which is effective in combating hyperglycemia-induced oxidative stress. PMID- 29164129 TI - A Commercially Available Portion-Controlled Diet Program Is More Effective for Weight Loss than a Self-Directed Diet: Results from a Randomized Clinical Trial. AB - Objective: To examine changes in weight and related outcomes in response to a commercial weight loss program compared to a self-directed diet in adults with overweight or obesity. Design: Participants were randomly assigned [stratified by body mass index (BMI) and age] to a commercial weight loss program (n = 38) or to a self-directed Dietary Approaches to Stop Hypertension (DASH) diet (n = 40) for a 16-week period. Daily energy intake goals were 1,500 kcal/d for men and 1,200 kcal/d for women, except for the first week of the commercial program (1,000 kcal/d). This study was registered at http://ClinicalTrials.gov (NCT03017443). Participants: Primarily Caucasian (71%) women (n = 61) and men (n = 17) from the greater metropolitan area of the city of Chicago, IL, USA. with a mean baseline BMI of 34.4 kg/m2, body weight of 95.7 kg, and age of 50.4 years. Results: Data = mean (95% CI). At week 16, the commercial program group lost significantly more body weight [-5.9 (-7.5, -4.3) kg vs. -1.8 (-2.9, -0.8) kg; or -6.4 vs. -1.8% of initial body weight, respectively], fat mass [-4.4 (-5.7, -3.1) kg vs. -1.2 ( 2.1, -0.4) kg] and total body circumference (chest + waist + hip + upper arm + thigh) [-16.9 (-21.5, -12.3) cm vs. -5.8 (-9.0, -2.6) cm] (p < 0.01 for all). Additionally, more participants in the commercial program group lost a clinically meaningful amount of weight, defined as >=5% of initial body weight, at week 16 (58% vs. 13%, p < 0.001). Conclusion: The commercial program resulted in greater weight loss and improvements in body composition/anthropometric parameters compared to a self-directed DASH diet over a 16-week period. Some important limitations were that no objective measurements of dietary intake or physical activity were collected to potentially ascertain the independent or combined effects of these components on weight loss (or lack thereof). Additionally, future research is warranted in order to understand the effects of this program, and similar programs, on longer term changes in body weight, in particular weight loss maintenance, as weight regain is common following the cessation of a structured weight loss intervention. PMID- 29164130 TI - Comparison of an Innovative Rehabilitation, Combining Reduced Conventional Rehabilitation with Balneotherapy, and a Conventional Rehabilitation after Anterior Cruciate Ligament Reconstruction in Athletes. AB - Background: Instability of the knee, related to anterior cruciate ligament injury, is treated by surgical reconstruction. During recovery, a loss of proprioceptive input can have a significant impact. Few studies have evaluated the benefits of rehabilitation of the knee in aquatic environment on functional outcomes. Objective: This study aimed to compare an innovative rehabilitation protocol combining reduced conventional rehabilitation with aquatic rehabilitation, with a conventional rehabilitation, according to the National French Health Authority, in terms of kinetics, development of proprioceptive skills, and functional improvement of the knee. Methods: 67 patients, who were amateur or professional athletes, were randomized into two groups: 35 patients followed the conventional rehabilitation protocol (Gr1) and 32 patients followed the innovative rehabilitation protocol (Gr2). Patients were evaluated before surgery, and at 2 weeks, 1, 2, and 6 months after surgery using posturography, and evaluation of muscular strength, walking performance and proprioception. This study is multicenter, prospective, randomized, and controlled with a group of patients following conventional rehabilitation (level of evidence I). Results: For the same quality of postural control, Gr2 relied more on somesthesia than Gr1 at 6 months. The affected side had an impact on postural control and in particular on the preoperative lateralization, at 2 weeks and at 1 month. Lateralization depended on the affected knee, with less important lateralization in Gr2 preoperatively and at 1 month. The quadriceps muscular strength was higher in Gr2 than in Gr1 at 2 and 6 months and muscle strength of the external hamstring was greater in Gr2 than in Gr1 at 6 months. The isokinetic test showed a greater quadriceps muscular strength in Gr2. Gr2 showed a greater walking distance than Gr1 at one month. Gr2 showed an improvement in the proprioceptive capacities of the operated limb in flexion for the first 2 months. Conclusion: The effectiveness of the innovative rehabilitation program permits faster recovery, allowing for an earlier return to social, sporting, and professional activities. Faster retrieval of knee function following aquatic rehabilitation would prevent both short-term risk of lesions of the contralateral limb due to overcompensation and long-term risk of surgery due to osteoarthritis. Registration of clinical trials: NCT02225613. PMID- 29164131 TI - Continuous Laparoscopic Closure of the Linea Alba with Barbed Sutures Combined with Laparoscopic Mesh Implantation (IPOM Plus Repair) As a New Technique for Treatment of Abdominal Hernias. AB - Despite extensive experience and significant reduction of complications in recent years, laparoscopic treatment of complex abdominal hernias is a challenge even for the experienced endoscopic surgeon. Patients with severe incisional hernias or symptomatic rectus diastasis benefit from the closure of the linea alba as a morphological and physiological reconstruction of the abdominal wall followed by mesh implantation. Occasionally, an additional component separation is necessary. In open surgery, this is associated with very large wound areas, postoperative seromas, poor wound healing and, in the worst case, mesh infections. To avoid these complications, we operate these complex reconstructions completely endoscopically. Our concept is based on a laparoscopic closure of the linea alba through an ongoing, barbed non-resorbable 1-0 suture (polybutester) and final reinforcement by an intraperitoneal-onlay mesh (IPOM-Plus). For the treatment of complex abdominal hernias with a width of more than 10 cm, we performed an endoscopic anterior bilateral component separation. This allows the surgeon to combine the advantages of the open abdominal wall reconstruction with those of laparoscopic hernia repair. Between May 2015 and June 2017, we treated 42 patients with abdominal hernias by laparoscopic continuous hernia defect closure and complementary mesh implantation, whereby a complex reconstruction with additional endoscopic anterior component separation was performed in five patients. In this article, we will present this innovative technique of endoscopic/laparoscopic hernia repair in complex abdominal hernias. PMID- 29164132 TI - Conserved Molecular Mechanism of TyrA Dehydrogenase Substrate Specificity Underlying Alternative Tyrosine Biosynthetic Pathways in Plants and Microbes. AB - L-Tyrosine (Tyr) is an aromatic amino acid synthesized de novo in plants and microbes. In animals, Tyr must be obtained through their diet or synthesized from L-phenylalanine. In addition to protein synthesis, Tyr serves as the precursor of neurotransmitters (e.g., dopamine and epinephrine) in animals and of numerous plant natural products, which serve essential functions in both plants and humans (e.g., vitamin E and morphine). Tyr is synthesized via two alternative routes mediated by a TyrA family enzyme, prephenate, or arogenate dehydrogenase (PDH/TyrAp or ADH/TyrAa), typically found in microbes and plants, respectively. Although ADH activity is also found in some bacteria, the origin of arogenate specific TyrAa enzymes is unknown. We recently identified an acidic Asp222 residue that confers ADH activity in plant TyrAs. In this study, structure-guided phylogenetic analyses identified bacterial homologs, closely-related to plant TyrAs, that also have an acidic 222 residue and ADH activity. A more distant archaeon TyrA that preferred PDH activity had a non-acidic Gln, whose substitution to Glu introduced ADH activity. These results indicate that the conserved molecular mechanism operated during the evolution of arogenate-specific TyrAa in both plants and microbes. PMID- 29164133 TI - Role of Dietary Antioxidants in the Preservation of Vascular Function and the Modulation of Health and Disease. AB - In vascular diseases, including hypertension and atherosclerosis, vascular endothelial dysfunction (VED) occurs secondary to altered function of endothelial nitric oxide synthase (eNOS). A novel redox regulated pathway was identified through which eNOS is uncoupled due to S-glutathionylation of critical cysteine residues, resulting in superoxide free radical formation instead of the vasodilator molecule, nitric oxide. In addition, the redox sensitive cofactor tetrahydrobiopterin, BH4, is also essential for eNOS coupling. Antioxidants, either individually or combined, can modulate eNOS uncoupling by scavenging free radicals or impairing specific radical generating pathways, thus preventing oxidative stress and ameliorating VED. Epidemiological evidence and dietary guidelines suggest that diets high in antioxidants, or antioxidant supplementation, could preserve vascular health and prevent cardiovascular diseases (CVDs). Therefore, the purpose of this review is to highlight the possible role of dietary antioxidants in regulating eNOS function and uncoupling which is critical for maintenance of vascular health with normal blood flow/circulation and prevention of VED. We hypothesize that a conditioned dietary approach with suitable antioxidants may limit systemic oxidation, maintain a beneficial ratio of reduced to oxidized glutathione, and other redox markers, and minimize eNOS uncoupling serving to prevent CVD and possibly other chronic diseases. PMID- 29164134 TI - Cancer and Thrombotic Risk: The Platelet Paradigm. AB - Hematologic malignancies and solid tumors increase the risk of venous and arterial thrombosis and contribute greatly to patient morbidity and mortality. Thrombosis occurs when the intricate balance of circulating antithrombotic and prothrombotic blood elements are disrupted. In recent years, the interplay between paraneoplastic cells and platelets has become apparent, with a change in platelet phenotype causing dysregulated platelet activity. This review discusses mechanism of thrombosis in cancer, evidence for using drug therapy, and exciting research efforts to understand and hopefully control aberrant thrombotic events in patients with cancer. PMID- 29164135 TI - A Protocol for Improved Precision and Increased Confidence in Nanoparticle Tracking Analysis Concentration Measurements between 50 and 120 nm in Biological Fluids. AB - Nanoparticle tracking analysis (NTA) can be used to quantitate extracellular vesicles (EVs) in biological samples and is widely considered a useful diagnostic tool to detect disease. However, accurately profiling EVs can be challenging due to their small size and heterogeneity. Here, we aimed to provide a protocol to facilitate high-precision particle quantitation by NTA in plasma, the supernatant of activated purified platelets [the platelet releasate (PR)] and in serum, to increase confidence in NTA particle enumeration. The overall variance and the precision of NTA measurements were quantified by root mean square error and relative standard error. Using a bootstrapping approach, we found that increasing video replicates from 5 s * 60 s to 25 s * 60 s captures led to a reduction in overall variance and a reproducible increase in the precision of NTA particle concentration quantitation for all three biofluids. We then validated our approach in an extended cohort of 32 healthy donors. Our results indicate that for vesicles sized between 50 and 120 nm, the precision of routine NTA measurements in serum, plasma, and PR can be significantly improved by increasing the number of video replicates captured. Our protocol provides a common platform to statistical compare particle size distribution profiles in the exosomal vesicle size range across a variety of biofluids and in both healthy donor and patient groups. PMID- 29164136 TI - Factors Associated With Health-Related Quality of Life among Hypertensive Patients in Kathmandu, Nepal. AB - Introduction: Nepal has a high prevalence of hypertension. While improving the overall health-related quality of life (HRQOL) is a central tenet to public health plans in developed nations, this focus has yet to be articulated in Nepal. Therefore, this study aims to identify the factors associated with HRQOL among hypertensive patients in Nepal. Method: The EuroQol-5Dimension HRQOL survey was administered to 180 hypertensive patients, attending the outpatient clinic at Shahid Gangalal National Heart Center in Kathmandu, Nepal. Multiple linear regression models, adjusted for age and sex, were used to identify factors associated with HRQOL. Results: The mean age and EuroQol visual analytic scale of the participants were 53.2 years and 63.7, respectively. Age [beta = -0.56; 95% confidence interval (CI): -0.75 to -0.37], income (beta = 0.02; 95% CI: 0.01, 0.03), family size (beta = -0.98; 95% CI: -1.89, -0.07), number of antihypertensive drugs use (beta = 4.62; 95% CI: 1.33, 7.90), and compliance to dietary salt advise (beta = 4.86; 95% CI: 0.29, 9.43) were significant factors associated with HRQOL among participants. In addition, levels of education and self-perceived health were associated in a positive gradient to HRQOL. In mediation analysis, both, dietary low salt compliance and use of antihypertensive drugs, had a significant direct effect on HRQOL, and the use of antihypertensive drugs did not significantly mediate the relationship between dietary salt compliance and HRQOL. Conclusion: Various factors were found to be associated with HRQOL among hypertensive patients in Kathmandu. Assessing HRQOL is a valuable technique to identify populations in need of services and interventions. This assessment can serve as a baseline, and in conjunction with multiple stakeholders, can guide public health policy, planning, and practices, especially those aimed toward improving the HRQOL of Nepalese with hypertension. PMID- 29164137 TI - Urban Livestock Keeping in the City of Nairobi: Diversity of Production Systems, Supply Chains, and Their Disease Management and Risks. AB - Urban livestock keeping in developing cities have an important role in food security and livelihoods but can also pose a significant threat to the environment and health of urban dwellers. The aim of this study was to identify the different livestock systems in Nairobi, their supply chains, and their management and food safety risks. Seven focus group discussions with livestock production officers in charge of each major Nairobi sub-county were conducted. Data were collected on the type of systems existing for each livestock species and their supply chains, disease management, food safety risks, and general husbandry and gender factors. Supply chain flow diagrams and thematic analysis of the data was done. Results of the study show a large variability of livestock keeping in Nairobi. The majority were small scale with: <5 dairy cows, 1-6 dairy goats, <10 small ruminants, <20 pigs, 200-500 broilers, 300-500 layers, <10 indigenous chickens, or <20 rabbits. Beef keeping was mainly described as a "by the way" system or done by traders to fatten animals for 3 month. Supply chain analysis indicated that most dairy farmers sold milk directly to consumers due to "lack of trust" of these in traders. Broiler and pig farmers sold mainly to traders but are dependent on few large dominating companies for their replacement or distribution of products. Selling directly to retailers or consumers (including own consumption), with backyard slaughtering, were important chains for small-scale pig, sheep and goat, and indigenous chicken keepers. Important disease risk practices identified were associated with consumption of dead and sick animals, with underground network of brokers operating for ruminant products. Qualified trained health managers were used mainly by dairy farmers, and large commercial poultry and pig farmers, while use of unqualified health managers or no treatment were common in small-scale farming. Control of urban livestock keepers was reported difficult due to their "feeling of being outlaws," "lack of trust" in government, "inaccessibility" in informal settlements, "lack of government funding," or "understaffing." Findings are useful for designing policies to help to control urban livestock production and minimize its associated health and environment risks. PMID- 29164138 TI - Modeling the Costs of Postpartum Dysgalactia Syndrome and Locomotory Disorders on Sow Productivity and Replacement. AB - Postpartum dysgalactia syndrome (PPDS) and locomotory disorders are common health problems in sows. Previous research suggests that they can cause substantial losses, reduce sow welfare, and result in premature removal of the sow from the herd. However, economic consequences of PPDS and locomotory disorders have not been investigated thoroughly. The goal of this study was to examine economic losses caused by PPDS and locomotory disorders and their impacts on sow longevity. A stochastic dynamic programming model, which maximizes return on sow space unit and assesses sow replacement under several scenarios, was developed. The state variables were litter size, parity number, and sow's health status. The model describes changes in the production parameters such as the number of piglets born and piglet mortality. Herd data originating from commercial sow herds and from a research farm were used to parameterize the model. Sow longevity, health, and economic results are related to each other. Eliminating the risk of PPDS from the model increased the value of sow space unit by ?279 when compared to the baseline scenario. Eliminating the risk of locomotory disorders increased value by ?110. Results suggest that these estimates correspond to about ?29.1 and ?11.5 in economic costs per housed sow during her lifetime. The estimated magnitude of losses was ?300-?470 per affected sow for PPDS and ?290-?330 per affected sow for locomotory disorders. However, realistically speaking, not all of these costs are avoidable. Due to premature replacement associated with these two disorders, the average number of litters that the sow would deliver during her lifetime is decreased by about 0.1-0.4 litters depending on the scenario. We also observed that the optimal lifetime of a sow is not a fixed number, but it depends on her productivity level as well as health status. In general, a healthy sow could stay in the herd until she has produced 6-10 litters. Research is needed to understand the structures and interactions underlying health impairments, performance, replacement policies, and farm economics, and to provide pork producers with management recommendations. PMID- 29164139 TI - Associations between Antibacterial Treatment and the Prevalence of Tail-Biting Related Sequelae in Danish Finishers at Slaughter. AB - Secondary infections as a result of tail biting cause substantial economic losses in pig production and are a subject of concern for animal welfare. The use of first-choice antibacterial agents in the treatment of tail biting in finishing pigs is hypothesized to be negatively correlated with the development of systemic infection. This would be expected to reduce the prevalence of post-mortem pyemic sequelae (such as osteomyelitis and abscesses) in finishers with tail-bite lesions. We performed a register-based study that included three Danish databases, holding information on the purchase of antibacterials at herd level (VetStat), herd demographics (Central Husbandry Register), and relevant observations at slaughter (meat inspection data). We included all finishers from indoor production finisher herds that met the inclusion criterion of at least one slaughtered finisher with a recorded tail-bite observation during 2015 at the single largest Danish abattoir. The final dataset held 1,070 herds with one or more tail-bite observations, from which 14,411 of 2,906,626 finishers (0.50%) had an individual record of a tail bite. Within this group of finishers with tail bite observations, the recorded tail-biting-related sequelae included osteomyelitis (8.1%), abscesses in the hindquarters (10.5%), abscesses in the forequarters (2.3%), abscesses in the mid-section of the carcass (2.9%), abscesses in the limbs (2.4%), and chronic arthritis (0.5%). Due to a high-herd prevalence (>25%), osteomyelitis and abscesses in the hindquarters were selected for further analysis. The occurrence of osteomyelitis and hindquarter abscesses in individual finishers with tail-bite observations was described using a generalized linear mixed effects model with binomial response and logit link. Herd was included as a random effect, while herd size and various antibacterial treatments were tested for inclusion in the model as fixed effects. The final models indicated a significant association between herd size and both osteomyelitis (p = 0.014) and hindquarter abscesses (p < 0.001), with larger herds (2,001-12,000 registered finisher pigs) showing a reduced risk. Further, a negative association was found between the occurrence of hindquarter abscesses and the use of oral pleuromutilin (p = 0.022). The significant association with herd size highlights the potential importance of management factors in reducing the occurrence of tail-bite lesions in finishing pigs. PMID- 29164140 TI - Phenotypic and Genotypic Features of a Salmonella Heidelberg Strain Isolated in Broilers in Brazil and Their Possible Association to Antibiotics and Short-Chain Organic Acids Resistance and Susceptibility. AB - Salmonella enterica serovar Heidelberg is a human pathogen also found in broilers. A strain (UFPR1) has been associated with field reports of resistance to short-chain organic acids (SCOA) in broilers in the South of Brazil, but was susceptible to a Bacillus subtilis-based probiotic added in feed in a related study. This work aimed to (i) report clinical symptoms caused by SH UFPR1 in broilers, (ii) study its susceptibility to some antibiotics in vitro, and (iii) SCOA in vivo; and (iv) relate these phenotypic observations with its genome characteristics. Two in vivo trials used 1-day-old chicks housed for 21 days in 8 sterilized isolated negative pressure rooms with 4 battery cages of 12 birds each. Birds were challenged or not with 107 CFU/bird of SH UFPR1 orally and exposed or not to SCOA in a 2 * 2 factorial design. Zootechnical parameters were unaffected (P > 0.05), no clinical signs were observed, and few cecal and hepatic histologic and immune-related alterations were seen, in birds challenged with SH. Formic and propionic acids added together in drinking water, fumaric and benzoic acid in feed (Trial 1), and coated calcium butyrate in feed (Trial 2) did not reduce the SH isolation frequencies seen in cecum and liver in broilers after SH challenge (P > 0.05). SH UFPR1 was susceptible to amikacin, amoxicillin + clavulanate, ceftiofur, cephalexin, doxycycline and oxytetracycline; and mildly susceptible to ampicillin + sulbactam, cephalothin, ciprofloxacin, enrofloxacin, and gentamycin in an in vitro minimum inhibitory concentration model using Mueller-Hinton agar. The whole genome of SH UFPR1 was sequenced and consisted of a circular chromosome, spanning 4,760,321 bp with 52.18% of GC-content encoding 84 tRNA, 22 rRNA, and 4,427 protein-coding genes. The comparison between SH UFPR1 genome and a multidrug-resistant SL476 strain revealed 11 missing genomic fragments and 5 insertions related to bgt, bgr, and rpoS genes. The deleted genes codify proteins associated with cell cycle regulation, virulence, drug resistance, cellular adhesion, and salt efflux which collectively reveal key aspects of the evolution and adaptation of SH strains such as organic acids resistance and antibiotic sensitivity and provide information relevant to the control of SH in poultry. PMID- 29164141 TI - Replacement Beef Cow Valuation under Data Availability Constraints. AB - Economists are often tasked with estimating the benefits or costs associated with livestock production losses; however, lack of available data or absence of consistent reporting can reduce the accuracy of these valuations. This work looks at three potential estimation techniques for determining the value for replacement beef cows with varying types of market data to proxy constrained data availability and discusses the potential margin of error for each technique. Oklahoma bred replacement cows are valued using hedonic pricing based on Oklahoma bred cow data-a best case scenario-vector error correction modeling (VECM) based on national cow sales data and cost of production (COP) based on just a representative enterprise budget and very limited sales data. Each method was then used to perform a within-sample forecast of 2016 January to December, and forecasts are compared with the 2016 monthly observed market prices in Oklahoma using the mean absolute percent error (MAPE). Hedonic pricing methods tend to overvalue for within-sample forecasting but performed best, as measured by MAPE for high quality cows. The VECM tended to undervalue cows but performed best for younger animals. COP performed well, compared with the more data intensive methods. Examining each method individually across eight representative replacement beef female types, the VECM forecast resulted in a MAPE under 10% for 33% of forecasted months, followed by hedonic pricing at 24% of the forecasted months and COP at 14% of the forecasted months for average quality beef females. For high quality females, the hedonic pricing method worked best producing a MAPE under 10% in 36% of the forecasted months followed by the COP method at 21% of months and the VECM at 14% of the forecasted months. These results suggested that livestock valuation method selection was not one-size-fits-all and may need to vary based not only on the data available but also on the characteristics (e.g., quality or age) of the livestock being valued. PMID- 29164143 TI - Valence of Facial Cues Influences Sheep Learning in a Visual Discrimination Task. AB - Sheep are one of the most studied farm species in terms of their ability to process information from faces, but little is known about their face-based emotion recognition abilities. We investigated (a) whether sheep could use images of sheep faces taken in situation of varying valence as cues in a simultaneous discrimination task and (b) whether the valence of the situation affects their learning performance. To accomplish this, we photographed faces of sheep in three situations inducing emotional states of neutral (ruminating in the home pen) or negative valence (social isolation or aggressive interaction). Sheep (n = 35) first had to learn a discrimination task with colored cards. Animals that reached the learning criterion (n = 16) were then presented with pairs of images of the face of a single individual taken in the neutral situation and in one of the negative situations. Finally, sheep had to generalize what they had learned to new pairs of images of faces taken in the same situation, but of a different conspecific. All sheep that learned the discrimination task with colored cards reached the learning criterion with images of faces. Sheep that had to associate a negative image with a food reward learned faster than sheep that had to associate a neutral image with a reward. With the exception of sheep from the aggression-rewarded group, sheep generalized this discrimination to images of faces of different individuals. Our results suggest that sheep can perceive the emotional valence displayed on faces of conspecifics and that this valence affects learning processes. PMID- 29164142 TI - Pathogenesis, Molecular Genetics, and Genomics of Mycobacterium avium subsp. paratuberculosis, the Etiologic Agent of Johne's Disease. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of Johne's disease in ruminants causing chronic diarrhea, malnutrition, and muscular wasting. Neonates and young animals are infected primarily by the fecal-oral route. MAP attaches to, translocates via the intestinal mucosa, and is phagocytosed by macrophages. The ensuing host cellular immune response leads to granulomatous enteritis characterized by a thick and corrugated intestinal wall. We review various tissue culture systems, ileal loops, and mice, goats, and cattle used to study MAP pathogenesis. MAP can be detected in clinical samples by microscopy, culturing, PCR, and an enzyme-linked immunosorbent assay. There are commercial vaccines that reduce clinical disease and shedding, unfortunately, their efficacies are limited and may not engender long-term protective immunity. Moreover, the potential linkage with Crohn's disease and other human diseases makes MAP a concern as a zoonotic pathogen. Potential therapies with anti mycobacterial agents are also discussed. The completion of the MAP K-10 genome sequence has greatly improved our understanding of MAP pathogenesis. The analysis of this sequence has identified a wide range of gene functions involved in virulence, lipid metabolism, transcriptional regulation, and main metabolic pathways. We also review the transposons utilized to generate random transposon mutant libraries and the recent advances in the post-genomic era. This includes the generation and characterization of allelic exchange mutants, transcriptomic analysis, transposon mutant banks analysis, new efforts to generate comprehensive mutant libraries, and the application of transposon site hybridization mutagenesis and transposon sequencing for global analysis of the MAP genome. Further analysis of candidate vaccine strains development is also provided with critical discussions on their benefits and shortcomings, and strategies to develop a highly efficacious live-attenuated vaccine capable of differentiating infected from vaccinated animals. PMID- 29164145 TI - Aspergillus fumigatus-specific immunoglobulin levels in BALF of CF patients. AB - IgE responses to Aspergillus fumigatus in cystic fibrosis lungs http://ow.ly/XXwv30furqs. PMID- 29164144 TI - Intensive care unit patients with lower respiratory tract nosocomial infections: the ENIRRIs project. AB - The clinical course of intensive care unit (ICU) patients may be complicated by a large spectrum of lower respiratory tract infections (LRTI), defined by specific epidemiological, clinical and microbiological aspects. A European network for ICU related respiratory infections (ENIRRIs), supported by the European Respiratory Society, has been recently established, with the aim at studying all respiratory tract infective episodes except community-acquired ones. A multicentre, observational study is in progress, enrolling more than 1000 patients fulfilling the clinical, biochemical and radiological findings consistent with a LRTI. This article describes the methodology of this study. A specific interest is the clinical impact of non-ICU-acquired nosocomial pneumonia requiring ICU admission, non-ventilator-associated LRTIs occurring in the ICU, and ventilator-associated tracheobronchitis. The clinical meaning of microbiologically negative infectious episodes and specific details on antibiotic administration modalities, dosages and duration are also highlighted. Recently released guidelines address many unresolved questions which might be answered by such large-scale observational investigations. In light of the paucity of data regarding such topics, new interesting information is expected to be obtained from our network research activities, contributing to optimisation of care for critically ill patients in the ICU. PMID- 29164146 TI - Extracorporeal Shock Wave Rebuilt Subchondral Bone In Vivo and Activated Wnt5a/Ca2+ Signaling In Vitro. AB - Background: This study aimed to identify the optimal extracorporeal shock wave (ESW) intensity and to investigate its effect on subchondral bone rebuilt in vivo and Wnt5a/Ca2+ signaling in vitro using an osteoarthritis (OA) rat model and bone marrow mesenchymal stem cells (BMMSCs), respectively. Methods: OA rats treated with (OA + ESW group) or without (OA group) ESW (n = 12/group) were compared with healthy controls (control group, n = 12). Gait patterns and subchondral trabecular bone changes were measured. Western blot and quantitative real-time polymerase chain reaction detected protein expression and gene transcription, respectively. Results: The gait disturbances of OA + ESW group were significantly improved compared with the OA group at 6th and 8th weeks. The micro-CT analysis indicated that the BMD, BSV/BV, BV/TV, Tr.S, and Tr.Th are significantly different between OA group and OA + ESW group. Expression of Wnt5a was increased rapidly after ESW treatment at 0.6 bar and peaked after 30 min. Conclusions: ESW were positive for bone remodeling in joint tibial condyle subchondral bone of OA rat. ESW prevented histological changes in OA and prevented gait disturbance associated with OA progression. Optimal intensity of ESW induced changes in BMMSCs via activation of the Wnt5a/Ca2+ signaling pathway. PMID- 29164147 TI - Dissection of Factors Affecting the Variability of the Peptide Bond Geometry and Planarity. AB - Proteins frequently assume complex three-dimensional structures characterized by marginal thermodynamic stabilities. In this scenario, deciphering the folding code of these molecular giants with clay feet is a cumbersome task. Studies performed in last years have shown that the interplay between backbone geometry and local conformation has an important impact on protein structures. Although the variability of several geometrical parameters of protein backbone has been established, the role of the structural context in determining these effects has been hitherto limited to the valence bond angle tau (NC alpha C). We here investigated the impact of different factors on the observed variability of backbone geometry and peptide bond planarity. These analyses corroborate the notion that the local conformation expressed in terms of (phi, psi) dihedrals plays a predominant role in dictating the variability of these parameters. The impact of secondary structure is limited to bond angles which involve atoms that are usually engaged in H-bonds and, therefore, more susceptible to the structural context. Present data also show that the nature of the side chain has a significant impact on angles such as NC alpha C beta and C beta C alpha C. In conclusion, our analyses strongly support the use of variability of protein backbone geometry in structure refinement, validation, and prediction. PMID- 29164148 TI - Relative and Absolute Interrater Reliabilities of a Hand-Held Myotonometer to Quantify Mechanical Muscle Properties in Patients with Acute Stroke in an Inpatient Ward. AB - Introduction: The reliability of using MyotonPRO to quantify muscles mechanical properties in a ward setting for the acute stroke population remains unknown. Aims: To investigate the within-session relative and absolute interrater reliability of MyotonPRO. Methods: Mechanical properties of biceps brachii, brachioradialis, rectus femoris, and tibialis anterior were recorded at bedside. Participants were within 1 month of the first occurrence of stroke. Relative reliability was assessed by intraclass correlation coefficient (ICC). Absolute reliability was assessed by standard error of measurement (SEM), SEM%, smallest real difference (SRD), SRD%, and the Bland-Altman 95% limits of agreement. Results: ICCs of all studied muscles ranged between 0.63 and 0.97. The SEM of all muscles ranged within 0.30-0.88 Hz for tone, 0.07-0.19 for decrement, 6.42-20.20 N/m for stiffness, and 0.04-0.07 for creep. The SRD of all muscles ranged within 0.70-2.05 Hz for tone, 0.16-0.45 for decrement, 14.98-47.15 N/m for stiffness, and 0.09-0.17 for creep. Conclusions: MyotonPRO demonstrated acceptable relative and absolute reliability in a ward setting for patients with acute stroke. However, results must be interpreted with caution, due to the varying level of consistency between different muscles, as well as between different parameters within a muscle. PMID- 29164149 TI - Bioinformatics Genes and Pathway Analysis for Chronic Neuropathic Pain after Spinal Cord Injury. AB - It is well known spinal cord injury (SCI) can cause chronic neuropathic pain (NP); however its underlying molecular mechanisms remain elusive. This study aimed to disclose differentially expressed genes (DEGs) and activated signaling pathways in association with SCI induced chronic NP, in order to identify its diagnostic and therapeutic targets. Microarray dataset GSE5296 has been downloaded from Gene Expression Omnibus (GEO) database. Significant analysis of microarray (SAM), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and pathway network analysis have been used to compare changes of DEGs and signaling pathways between the SCI and sham-injury group. As a result, DEGs analysis showed there were 592 DEGs with significantly altered expression; among them Ccl3 expression showed the highest upregulation which implicated its association with SCI induced chronic NP. Moreover, KEGG analysis found 209 pathways changed significantly; among them the most significantly activated one is MAPK signaling pathway, which is in line with KEGG analysis results. Our results show Ccl3 is highly associated with SCI induced chronic NP; as the exosomes with Ccl3 can be easily and efficiently detected in peripheral blood, Ccl3 may serve as a potential prognostic target for the diagnosis and treatment of SCI induced chronic NP. PMID- 29164150 TI - Potential Anticancer Mechanisms of a Novel EGFR/DNA-Targeting Combi-Molecule (JDF12) against DU145 Prostate Cancer Cells: An iTRAQ-Based Proteomic Analysis. AB - The development of multitargeting drugs is an emerging trend in cancer research. To promote further development and clinical application of multitargeting drugs, this research was performed. MTT assay and flow cytometry of Annexin V/propidium iodide staining were used to confirm the proapoptotic efficacy of a novel combi targeting molecule, JDF12, against DU145 prostate cancer (PCa) cells. Differentially expressed proteins between control and JDF12-treated cultures were revealed by isobaric tags for relative and absolute quantitation (iTRAQ), and part of them was confirmed by quantitative PCR. Differentially expressed proteins were further analyzed for function, pathway association, and protein-protein interactions using GO, KEGG, and STRING databases. A total of 119 differentially expressed proteins, 70 upregulated and 49 downregulated, were implicated in the anticancer effects of JDF12. Many of these proteins are involved in biosynthesis, response to stress, energy metabolism, and signal transduction. This study provides important information for understanding the anti-PCa mechanisms of JDF12, and well-designed combi-targeting drugs may possess stronger anticancer efficacy than single-targeting drugs and are thus promising candidates for clinical application. PMID- 29164151 TI - Naturally Occurring Resistance-Associated Variants to Hepatitis C Virus Direct Acting Antiviral Agents in Treatment-Naive HCV Genotype 6a-Infected Patients. AB - Background and Objective: The direct-acting antiviral agents (DAAs) antiviral therapy has drastically improved the prognosis of hepatitis C virus (HCV) patients. However, the viral drug resistance-associated variants (RAVs) can limit the efficacy of DAAs. For the HCV-6a is not the predominant prevalent genotype; the data on the prevalence of naturally occurring RAVs in it is scarce. Our study aims to assess the prevalence of RAVs in treatment-naive HCV-6a patients. Methods: Nested PCR assays were performed on 95 HCV-6a patients to amplify HCV viral regions of NS3, NS5A, and NS5B. Results: In NS3/4A region, we detected Q80K in 95.5% isolates (84/88) and D168E in 2.3% isolates (2/88). In NS5A region, we detected Q30R in 93.2% isolates (82/88), L31M in 4.6% isolates (4/88), and H58P in 6.8% isolates (6/88). In NS5B region, we detected A15G in 2.3% isolates (2/88), S96T in 1.1% isolates (1/88), and S282T in 20.7% isolates (17/88) and we detected I482L in 100% isolates (4/4), V494A in 50% isolates (2/4), and V499A in 100% isolates (4/4). Conclusions: RAVs to DAAs preexist in treatment-naive HCV-6a patients. Further studies should address the issue of the impact of RAVs in response to DAA therapies for HCV-6a patients. PMID- 29164152 TI - Foot Complications in a Representative Australian Inpatient Population. AB - We investigated the prevalence and factors independently associated with foot complications in a representative inpatient population (adults admitted for any reason with and without diabetes). We analysed data from the Foot disease in inpatients study, a sample of 733 representative inpatients. Previous amputation, previous foot ulceration, peripheral arterial disease (PAD), peripheral neuropathy (PN), and foot deformity were the foot complications assessed. Sociodemographic, medical, and foot treatment history were collected. Overall, 46.0% had a foot complication with 23.9% having multiple; those with diabetes had higher prevalence of foot complications than those without diabetes (p < 0.01). Previous amputation (4.1%) was independently associated with previous foot ulceration, foot deformity, cerebrovascular accident, and past surgeon treatment (p < 0.01). Previous foot ulceration (9.8%) was associated with PN, PAD, past podiatry, and past nurse treatment (p < 0.02). PAD (21.0%) was associated with older age, males, indigenous people, cancer, PN, and past surgeon treatment (p < 0.02). PN (22.0%) was associated with older age, diabetes, mobility impairment, and PAD (p < 0.05). Foot deformity (22.4%) was associated with older age, mobility impairment, past podiatry treatment, and PN (p < 0.01). Nearly half of all inpatients had a foot complication. Those with foot complications were older, male, indigenous, had diabetes, cerebrovascular accident, mobility impairment, and other foot complications or past foot treatment. PMID- 29164153 TI - SIRT1 Regulates Cognitive Performance and Ability of Learning and Memory in Diabetic and Nondiabetic Models. AB - Type 2 diabetes mellitus is a complex age-related metabolic disease. Cognitive dysfunction and learning and memory deficits are main characteristics of age related metabolic diseases in the central nervous system. The underlying mechanisms contributing to cognitive decline are complex, especially cognitive dysfunction associated with type 2 diabetes mellitus. SIRT1, as one of the modulators in insulin resistance, is indispensable for learning and memory. In the present study, deacetylation, oxidative stress, mitochondrial dysfunction, inflammation, microRNA, and tau phosphorylation are considered in the context of mechanism and significance of SIRT1 in learning and memory in diabetic and nondiabetic murine models. In addition, future research directions in this field are discussed, including therapeutic potential of its activator, resveratrol, and application of other compounds in cognitive improvement. Our findings suggest that SIRT1 might be a potential therapeutic target for the treatment of cognitive impairment induced by type 2 diabetes mellitus. PMID- 29164154 TI - The Application of Dextran Sedimentation as an Initial Step in Neutrophil Purification Promotes Their Stimulation, due to the Presence of Monocytes. AB - The purification of human neutrophils for in vitro studies is challenging as they are easily activated through ex vivo manipulations. The technique of erythrocyte sedimentation combined with density gradient centrifugation remains widely practiced and was the subject of this study. Since in the sedimentation step the leukocytes are incubated with dextran, we have raised the likelihood that cellular activation would occur with mediator release leading to neutrophil activation. By comparing the activity of neutrophils purified from whole blood by the classical 2-step method of dextran sedimentation followed by low-density Ficoll-Hypaque (1.077 g/mL) medium, and the 1-step high-density Ficoll-Hypaque (1.114 g/mL) gradient centrifugation, we found that neutrophils from the 2-step method had a significant increase in cell surface CD11b expression and CD62L shedding and a marked increase in adhesion. Decreased random migration and chemotaxis and raised baseline oxidative burst activity were also observed. The effect was not specific to dextran, as using Ficoll for erythrocyte sedimentation replicated the elevated neutrophil adherence. Through the depletion of monocytes, lymphocytes, and platelets prior to sedimentation, we deduced that monocytes were responsible for the neutrophil activation. Our findings suggest that care needs to be exercised in choosing the method of neutrophil purification for functional studies. PMID- 29164156 TI - Disseminated Mycobacterium avium-Intracellulare Complex Infection Presenting With Disseminated Intravascular Coagulation in an AIDS Patient. AB - Disseminated Mycobacterium avium-intracellulare complex (MAC) infection is one of the relatively common opportunistic infections seen in severely immunocompromised AIDS patients. A constellation of clinical, laboratory, and pathological features involving multiple organ systems are often present in disseminated MAC infection but disseminated intravascular coagulation (DIC) has not been previously described in association with this condition. To our knowledge, this is the first reported case of DIC complicating disseminated MAC infection in an AIDS patient. In this article, we present the case of a 33-year-old AIDS patient with high viral load, CD4 lymphocyte count of 1/mm3, who presented with nonspecific symptoms, anemia, thrombocytopenia, and increased lactate dehydrogenase, alkaline phosphatase, and ferritin. She also had abnormal coagulation parameters and features compatible with chronic DIC. Bone marrow biopsy assisted in making the correct diagnosis. She also later grew MAC from blood and sputum cultures. There were no other factors identified after a complete workup to explain DIC in this patient. After commencement of appropriate MAC therapy, she initially had a good response with some improvement of her coagulation parameters. Few months later, however, probably attributable to poor medication compliance, her condition deteriorated with development of thromboembolism, full-fledged DIC, sepsis, and an eventual fatal outcome. This case illustrates the importance of including disseminated MAC in the differential diagnosis of DIC in an AIDS patient. PMID- 29164157 TI - Inflammatory Breast Cancer and Warm Antibody Autoimmune Hemolytic Anemia: A Rare Paraneoplastic Syndrome. AB - Autoimmune hemolytic anemia (AIHA) is a disease process that involves the destruction of red blood cells mediated by the humoral immune system. It can be characterized as a cold agglutinin syndrome, paroxysmal cold hemoglobinuria, and warm, mixed type, and drug-induced AIHA. Although a well-established relationship exists between the presence of AIHA and lymphoproliferative malignancy, AIHA rarely presents in association with solid malignancies. An analysis of the limited number of published cases of AIHA in association with solid malignancies performed showed that AIHA may present before the diagnosis of a solid malignancy, concurrently with the presence of a solid malignancy, or even on resolution of a solid malignancy. Few cases of solid cancers associated with AIHA have been reported. AIHA rarely presents as a paraneoplastic syndrome indicating existence of a solid cancer. We report a case of inflammatory breast cancer with AIHA. PMID- 29164155 TI - New Insights into the Mechanisms of Chinese Herbal Products on Diabetes: A Focus on the "Bacteria-Mucosal Immunity-Inflammation-Diabetes" Axis. AB - Diabetes, especially type 2, has been rapidly increasing all over the world. Although many drugs have been developed and used to treat diabetes, side effects and long-term efficacy are of great challenge. Therefore, natural health product and dietary supplements have been of increasing interest alternatively. In this regard, Chinese herbs and herbal products have been considered a rich resource of product development. Although increasing evidence has been produced from various scientific studies, the mechanisms of action are lacking. Here, we have proposed that many herbal monomers and formulae improve glucose homeostasis and diabetes through the BMID axis; B represents gut microbiota, M means mucosal immunity, I represents inflammation, and D represents diabetes. Chinese herbs have been traditionally used to treat diabetes, with minimal side and toxic effects. Here, we reviewed monomers such as berberine, ginsenoside, M. charantia extract, and curcumin and herbal formulae such as Gegen Qinlian Decoction, Danggui Liuhuang Decoction, and Huanglian Wendan Decoction. This review was intended to provide new perspectives and strategies for future diabetes research and product. PMID- 29164158 TI - Development of Multiple Aortic Mycotic Aneurysms After Cardiac Catheterization. AB - A 71-year-old male with a past medical history of coronary artery bypass surgery developed multiple, infected pseudoaneurysms of the ascending aorta and aortic root 1 year after cardiac catheterization. He underwent aortic root replacement with a 24-mm homograft. Tissue culture from operative specimens revealed invasive Aspergillus fumigatus infection. He was treated with voriconazole for 3 months. After 1 year, he had no recurrence of symptoms, pseudoaneurysm, or fungal infection. PMID- 29164159 TI - Gastric Pouch Mixed Adenoneuroendocrine Carcinoma With a Mixed Adenocarcinoma Component After Roux-en-Y Gastric Bypass. AB - The Roux-en-Y gastric bypass is one of the most common procedures currently performed for surgical treatment of patients with severe obesity. Gastric cancer after bariatric surgery is not common, with most of them arising in the excluded stomach. Gastric mixed adenoneuroendocrine carcinomas are a rare type of stomach malignancy, composed of both adenocarcinoma and neuroendocrine tumor-cell components, with the latter comprising at least 30% of the whole neoplasm. In this article, we report a unique case of a mixed adenoneuroendocrine carcinoma with a mixed adenocarcinoma (tubular and poorly cohesive) component arising in the gastric pouch of a patient who underwent previous Roux-en-Y gastric bypass for glycemic control. Since stomach cancer is not usual in patients who have formerly undergone bariatric surgery and symptoms tend to be nonspecific, such diagnosis is often rendered at an advanced stage. Full assessment of these patients when presenting such vague symptoms is critical for an early cancer diagnosis. PMID- 29164160 TI - Use of Phenobarbital in Delirium Tremens. AB - The standard of care for alcohol withdrawal centers on the use of escalating doses of benzodiazepines until clinical improvement is achieved. However, there is no established standard in the care of patients with severe alcohol withdrawal and delirium tremens that is refractory to benzodiazepine therapy. One potential therapy that is gaining traction is the use of phenobarbital, which may be mechanistically superior to benzodiazepines in treating delirium tremens because of its effects on GABA and N-methyl-D-aspartate receptors. The dosing of phenobarbital and its subsequent taper, however, is still unclear and the side effect profile is not well characterized. In this case report, we present the case of a 37-year-old Hispanic male who presented with alcohol withdrawal and subsequent delirium tremens who was treated with phenobarbital with positive clinical response and minimal side effects. PMID- 29164161 TI - Determining the Most Important Factors Involved in Ranking Orthopaedic Sports Medicine Fellowship Applicants. AB - Background: Orthopaedic surgery residencies and certain fellowships are becoming increasingly competitive. Several studies have identified important factors to be taken into account when selecting medical students for residency interviews. Similar information for selecting orthopaedic sports medicine fellows does not exist. Purpose: To determine the most important factors that orthopaedic sports medicine fellowship program directors (PDs) take into account when ranking applicants. Study Design: Cross-sectional study. Methods: A brief survey was distributed electronically to PDs of the 92 orthopaedic sports medicine fellowship programs that are accredited by the Accreditation Council for Graduate Medical Education (ACGME). Each PD was asked to rank, in order, the 5 most important factors taken into account when ranking applicants based on a total list of 13 factors: the interview, the applicant's residency program, letters of recommendation (LORs), personal connections made through the applicant, research experience, an applicant's geographical ties to the city/town of the fellowship program, United States Medical Licensing Examination (USMLE) scores, Orthopaedic In-Training Examination (OITE) scores, history of being a competitive athlete in college, extracurricular activities/hobbies, volunteer experience, interest in a career in academics, and publications/research/posters. Factors were scored from 1 to 5, with a score of 5 representing the most important factor and 1 representing the fifth-most important factor. Results: Of the 92 PDs contacted, 57 (62%) responded. Thirty-four PDs (37%) listed the interview as the most important factor in ranking fellowship applicants (overall score, 233). LORs (overall score, 196), an applicant's residency program (overall score, 133), publications/research/posters (overall score, 115), and personal connections (overall score, 90) were reported as the second- through fifth-most important factors, respectively. Conclusion: According to orthopaedic sports medicine fellowship PDs, the fellowship interview is the most important factor in determining how an applicant will be ranked. Other factors, including LORs, the applicant's residency program, research production, and personal connections, were also considered to be important. This information provides orthopaedic sports medicine fellowship applicants with a better understanding of which areas to focus on when preparing for the fellowship interview and matching process. PMID- 29164162 TI - Functional Outcomes After the Surgical Management of Isolated Anterolateral Leg Chronic Exertional Compartment Syndrome. AB - Background: Failure rates of up to 20% have been reported after fasciotomy for chronic exertional compartment syndrome (CECS). There is some evidence that postoperative failure and complication rates are higher in the posterior compartments of the lower leg than the anterolateral compartments. Isolated compartment surgery may put patients at risk of requiring revision surgery because of the risk of developing posterior compartment disease. Hypothesis: Isolated anterolateral fasciotomy for CECS, in the absence of posterior compartment symptoms, produces satisfactory functional outcomes. Study Design: Case series; Level of evidence, 4. Methods: Between 2006 and 2012, patients who had positive intracompartment pressure-testing findings and who underwent isolated anterolateral fasciotomy release for CECS were given a self-administered questionnaire. The minimum follow-up was 3 years. The questionnaire addressed time to return to sport and ongoing symptoms. A visual analog scale was used to assess pain during exercise before and after surgery (score: 0, no pain; 10, worst pain imaginable); overall satisfaction with the procedure was assessed as well. Of 31 eligible patients, 20 patients (36 legs operated on) were assessed. Results: Postoperatively, 90% of participants returned to the same or higher level of sport. The mean pain score during exercise before surgery was 8.17, whereas it was 1.74 after surgery. The overall mean patient satisfaction score was 8.64. Only 1 leg (2.8%) went on to develop posterior compartment syndrome. Conclusion: Isolated anterolateral fasciotomy for CECS produced excellent functional outcomes. Our rate of recurrence was low compared with those found in the literature, and 90% of participants returned to their same or higher level of sport postoperatively. PMID- 29164163 TI - Neurocognitive Deficits of Concussed Adolescent Athletes at Self-reported Symptom Resolution in the Zurich Guidelines Era. AB - Background: Previous studies have evaluated high school and collegiate athletes in the pre-Zurich guidelines era; whether adolescent athletes demonstrate similar neurocognitive decrements in the current concussion management era remains unclear. Purpose: To assess for the presence of neurocognitive deficits in adolescents with a sport-related concussion at the time of self-reported symptom resolution. Study Design: Cross-sectional study; Level of evidence, 3. Methods: We conducted a prospective cohort study of 32 patients, aged 13 to 18 years, who sustained concussions during ice hockey and who were referred to 3 sports medicine clinics between September 1, 2012, and March 31, 2015. Demographic, anthropometric, and injury data were collected at the time of the initial postconcussion evaluation. To document symptoms, patients completed the Post Concussion Symptom Scale (PCSS) at initial and follow-up visits. Baseline and postinjury neurocognitive function were assessed using computerized neurocognitive testing (Immediate Post-Concussion Assessment and Cognitive Test [ImPACT]), and a reliable change index was used to determine significant changes in composite scores. Statistical comparisons were conducted using the Student t test and Mann-Whitney U test. Results: A total of 9 of 32 athletes (28.1%; 95% CI, 14.8%-46.9%) demonstrated continued neurocognitive impairment on >=1 composite score when no longer reporting concussion-related symptoms, while only 2 of 32 athletes (6.3%; 95% CI, 1.4%-23.2%) demonstrated continued neurocognitive impairment on >=2 composite scores. Conclusion: Neurocognitive deficits persist in adolescent athletes who no longer report concussion-related symptoms, at rates similar to those of collegiate athletes but at longer time intervals. This finding provides further evidence that adolescent athletes with a sport-related concussion demonstrate a protracted recovery and resolution of neurocognitive deficits compared with collegiate and professional athletes. Computer-based neurocognitive testing as part of a multifaceted approach continues to play an important role in return-to-play decision making after a sport-related concussion in adolescent athletes. Test-taking strategies may erroneously identify asymptomatic athletes as exhibiting neurocognitive impairment. PMID- 29164164 TI - Female Sex Is a Risk Factor for Failure of Hip Arthroscopy Performed for Acetabular Retroversion. AB - Background: The success of hip surgery in treating acetabular retroversion depends on the severity of the structural deformity and on selecting the correct patient for open or arthroscopic procedures. Purpose: To compare a group of patients with retroverted hips treated successfully with hip arthroscopy with a group of patients with retroverted hips that failed arthroscopic surgery, with special emphasis on (1) patient characteristics, (2) perioperative radiographic parameters, (3) intraoperative findings and concomitant procedures, and (4) patient sex. Study Design: Case-control study; Level of evidence, 3. Methods: We retrospectively reviewed the charts of 47 adult patients (47 hips) with acetabular retroversion who had undergone hip arthroscopy. Retroversion was based on the presence of an ischial spine sign in addition to either a crossover or posterior wall sign on a well-positioned anteroposterior pelvic radiograph. A total of 24 hips (50%) (16 females, 8 males; mean patient age, 31 years) had failed arthroscopy, defined as modified Harris Hip Score (mHHS) <80 or need for subsequent procedure. Twenty-three hips (8 females, 15 males; mean patient age, 29 years) were considered successful, defined as having no subsequent procedures and an mHHS >80 at the time of most recent follow-up. Perioperative variables, radiographic characteristics, and intraoperative findings were compared between the groups, in addition to a subgroup analysis based on sex. Results: The mean follow-up for successful hips was 30 months (SD, 11 months), with a mean mHHS of 95. In the failure group, 6 patients required subsequent procedures (4 anteverting periacetabular osteotomies and 2 total hip arthroplasties). The mean overall time to failure was 21 months, and the mean time to a second procedure was 24 months (total hip arthroplasty, 29.5 months; periacetabular osteotomy, 21.2 months); 18 hips failed on the basis of a low mHHS (mean, 65; range, 27-79) at last follow-up. Factors significantly different between the success and failure groups included patient sex, with males being more likely than females to have a successful outcome (P < .02), as well as undergoing femoral osteoplasty (P < .02). Intraoperative variables that were associated with worse outcome included isolated labral debridement (P < .002). In a subgroup analysis, males were more likely than their female counterparts to have a successful outcome with both isolated cam and combined cam-pincer resection (P < .05). Level of crossover correction on postoperative radiographs had no correlation with outcome. Conclusion: Acetabular retroversion remains a challenging pathoanatomy to treat arthroscopically. If hip arthroscopy is to be considered in select cases, we recommend labral preservation when possible. Male patients with correction of cam deformities did well, while females with significant retroversion appeared to be at greater risk for failure of arthroscopic treatment. PMID- 29164165 TI - Platelet-Rich Plasma for Primary Treatment of Partial Ulnar Collateral Ligament Tears: MRI Correlation With Results. AB - Background: Jobe revolutionized the treatment of medial ulnar collateral ligament (MUCL) tears with his reconstruction technique. However, not all MUCL injuries require operative management; Rettig showed that 42% of MUCL injuries respond to conservative management. This was improved by Podesta, who showed that augmentation of nonoperative management with platelet-rich plasma (PRP) and magnetic resonance imaging (MRI) for detecting partial MUCL tears resulted in significantly higher success rates. Their series used a single injection of leukocyte-rich PRP. However, to our knowledge, no study has established optimal dosing and composition of PRP for augmentation of soft tissue healing. We present a series of patients with partial MUCL tears of the elbow treated with a series of 2 leukocyte-rich PRP injections, bracing, physical therapy, and a structured return-to-throwing protocol. Hypothesis: Nonoperative management of acute or subacute partial MUCL tears of the elbow with a formal treatment protocol will allow the injured ligament to heal without surgery and will permit a rapid return to sport. Study Design: Case series; Level of evidence, 4. Methods: Patients with symptomatic MUCL instability and magnetic resonance arthrography demonstrating grade 2 MUCL tears at the proximal or distal aspect were treated with varus loading elbow bracing, activity restriction, and physical therapy, supplemented by 2 injections of PRP. The injections were separated by 2 weeks. Two weeks after the second injection, a repeat examination and magnetic resonance arthrogram were obtained to evaluate the response to treatment. Results: A total of 25 athletes (23 baseball athletes, 2 softball athletes [1 participant also danced]) underwent PRP injections and guided rehabilitation. Of these patients, 23 were diagnosed with primary grade 2 injuries of the MUCL; 22 patients with primary injuries (96%) demonstrated stability of the MUCL after treatment and returned to play at the same or higher level of competition without further intervention. Repeat MRI demonstrated reconstitution of the ligament in all patients, although 2 patients demonstrated only partial reconstitution. Patients were released to play at 6 weeks; due to vagaries of sports seasons, the mean time to return to competitive play was 82 days. Two of the 25 patients had undergone prior surgery (1 MUCL reconstruction and 1 repair). These patients remained unstable and symptomatic on examination after this treatment regimen, did not show complete reconstitution of the ligament on subsequent MRI, and required MUCL reconstruction. Conclusion: Ouf of 23 primary injury patients who received PRP injections and nonoperative measures, 22 (96%) were able to return to play and demonstrated reconstitution of the MUCL on MRI. Two of the 3 patients for whom PRP therapy failed had undergone previous MUCL surgery. We conclude that a 2-injection regimen of leukocyte-rich PRP is a safe and effective treatment for partial MUCL tears, but it appears to be less effective in patients with previous surgery for MUCL repair or reconstruction. PMID- 29164166 TI - Juvenile Osteochondritis Dissecans of the Knee: Does Magnetic Resonance Imaging Instability Correlate With the Need for Surgical Intervention? AB - Background: Several magnetic resonance imaging (MRI) classification systems have been developed to determine the degree of instability of juvenile osteochondritis dissecans (JOCD) lesions. Our current practice involves correlating the patients' symptoms with their MRI findings, but there are many cases in which this correlation is poor and results in incorrect classification of the stability of a JOCD lesion. Purpose: To determine whether certain MRI findings of JOCD instability are associated with the necessity for arthroscopic intervention to assess lesion stability. A secondary objective was to determine the interobserver agreement of the Kijowski et al (2008) MRI criteria for osteochondritis dissecans (OCD) instability. Study Design: Case series; Level of evidence, 4. Methods: A retrospective review was performed of patients who had documented femoral condyle OCD lesions, had open growth plates, and had been evaluated with serial MRI examinations. Each OCD lesion on MRI was classified according to the Kijowski classification as either stable or likely unstable. Results: The study included 16 patients (17 knees) with 49 MRI examinations. The initial MRI lesion was graded as stable in 59% (10/17), and 7 of these remained stable throughout the study period, with only 1 requiring operative intervention. Two became unstable on MRI, with 1 requiring surgery and 1 reverting back to stable with nonoperative management. The initial MRI lesion was graded as unstable in 41% (7/17) of the knees, with 2 of these becoming stable on MRI during the follow-up period with nonoperative management. The other 5 lesions remained unstable, with 3 eventually requiring surgery. The most important finding in this study was that MRI instability is a poor predictor of the necessity for surgery for JOCD lesions. The correlation between a nonradiologist and a trained musculoskeletal radiologist in the interpretation of the MRI criteria by Kijowski et al showed only substantial agreement for multiple cysts. Conclusion: MRI criteria for OCD instability in the pediatric knee do not always correlate with the necessity for surgery. They are, at times, a helpful adjunct to the management of these patients; however, care must be taken to interpret all available clinical and radiographic information in surgical decision making. PMID- 29164167 TI - Single-Leg Hop Test Performance and Isokinetic Knee Strength After Anterior Cruciate Ligament Reconstruction in Athletes. AB - Background: Isokinetic strength and hop tests are commonly used to assess athletes' readiness to return to sport after knee surgery. Purpose/Hypothesis: The purpose of this study was to investigate the results of single-leg hop and isokinetic knee strength testing in athletes who underwent anterior cruciate ligament reconstruction (ACLR) upon returning to sport participation as well as to study the correlation between these 2 test batteries. The secondary purpose was to compare the test results by graft type (patellar tendon or hamstring). It was hypothesized that there would be no statistically significant limb difference in either isokinetic knee strength or single-leg hop tests, that there would be a moderate to strong correlation between the 2 test batteries, and that there would be no significant difference between graft types. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Twenty-nine high school and collegiate athletes who underwent ACLR participated in this study. At the time of return to full sport participation, a series of hop tests and knee extension/flexion isokinetic strength measurements were conducted. The results were analyzed using analysis of variance and Pearson correlation (r). Results: The timed 6-m hop test was the only hop test that showed a significant difference between the involved and uninvolved limbs (2.3 and 2.2 seconds, respectively; P = .02). A significant difference between limbs in knee strength was found for flexion peak torque/body weight at 180 deg/s (P = .03), flexion total work/body weight at 180 deg/s (P = .04), and flexion peak torque/body weight at 300 deg/s (P = .03). The strongest correlation between the hop tests and knee strength was found between the total distance of the hop tests and flexion total work/body weight at 300 deg/s (r = 0.69) and between the timed 6-m hop test and flexion peak torque/body weight at 300 deg/s (r = -0.54). There was no statistically significant difference in hop test performance or isokinetic knee strength between graft types. Conclusion: The single-leg hop tests and isokinetic strength measurements were both useful for a bilateral comparison of knee functional performance and strength. Knee flexion strength deficits and flexion-to-extension ratios seemed to be correlated with single-leg hop test performance. There was no difference in postoperative hop test performance or knee strength according to graft type. PMID- 29164168 TI - AIDS-Related Endemic Mycoses in Western Cape, South Africa, and Clinical Mimics: A Cross-Sectional Study of Adults With Advanced HIV and Recent-Onset, Widespread Skin Lesions. AB - Background: Skin lesions are common in advanced HIV infection and are sometimes caused by serious diseases like systemic mycoses (SM). AIDS-related SM endemic to Western Cape, South Africa, include emergomycosis (formerly disseminated emmonsiosis), histoplasmosis, and sporotrichosis. We previously reported that 95% of patients with AIDS-related emergomycosis had skin lesions, although these were frequently overlooked or misdiagnosed clinically. Prospective studies are needed to characterize skin lesions of SM in South Africa and to help distinguish these from common HIV-related dermatoses. Methods: We prospectively enrolled HIV infected adult patients living in Western Cape, South Africa, with CD4 counts <=100 cells/MUL and widespread skin lesions present <=6 months that were deemed clinically compatible with SM. We obtained skin biopsies for histopathology and fungal culture and collected epidemiological and clinical data. Results: Of 34 patients enrolled and in whom a diagnosis could be made, 25 had proven SM: 14 had emergomycosis, and 3 each had histoplasmosis and sporotrichosis; for 5 additional patients, the fungal species could not be identified. Antiretroviral therapy (ART) had been initiated in the preceding 4 weeks for 11/25 (44%) patients with SM (vs no patients without SM). Plaques and scale crust occurred more frequently in patients with SM (96% vs 25%, P = .0002; and 67% vs 13%, P = .01, respectively). Conclusions: Recent ART initiation and presence of plaques or scale crust should make clinicians consider SM in patients with advanced HIV infection in this geographic area. Clinical overlap between SM and other dermatoses makes early skin biopsy critical for timely diagnosis and treatment. PMID- 29164169 TI - Tuberculosis Patients Who Are A Potential Source for Unprotected Exposure in Health Care Systems: A Multicenter Case Control Study. AB - Setting: Five health care systems in Texas. Objective: To describe the epidemiology of inadequate isolation for pulmonary tuberculosis leading to tuberculosis (TB) exposures from confirmed TB patients and the patient factors that led to the exposures. Design: A retrospective cohort and case-control study of adult patients with TB resulting in exposures (cases) vs those TB patients who did not result in exposures (controls) during January 2005 to December 2012. Results: There were 335 patients with pulmonary TB disease, 199 cases and 136 controls. There was no difference between groups in age (46 +/- 14.6 vs 45 +/- 17 years; P > .05), race, or substance abuse. Cases were more likely to be transplant recipients (adjusted odds ratio [AOR], 18.90; 95% CI, 1.9-187.76), have typical TB chest radiograph (AOR, 2.23; 95% CI, 1.1-4.51), and have positive acid-fast bacilli stains (AOR, 2.36; 95% CI, 1.31-4.27). Cases were less likely to have extrapulmonary disease (AOR, 0.47; 95% CI, 0.24-0.95). Conclusions: TB exposure resulting from inadequate isolation is frequent in health care settings. Extrapulmonary involvement resulted in earlier airborne isolation. Being a transplant recipient, having chest radiograph findings typical for TB, and sputum positivity acid-fast bacilli upon staining were associated with increased risk of inadequate isolation. PMID- 29164170 TI - Impact of Procalcitonin-Guided Antibiotic Management on Antibiotic Exposure and Outcomes: Real-world Evidence. AB - Background: Delayed pathogen identification and nonspecific clinical findings make definitive decisions regarding antibiotics challenging. The stimuli of bacterial toxins and inflammation make procalcitonin (PCT) unique in its ability to differentiate bacterial infection from other causes of inflammation, and thus it is useful for antibiotic management. The objective of our study was to evaluate the impact of a PCT algorithm (PCT-A) on current practice. Methods: A single-center, retrospective cohort study was conducted to evaluate the impact of adding PCT-A to stewardship practices. Data from 4 years prior to and after PCT-A implementation were compared in critical and acute care patients of all ages receiving parenteral antibiotics for a DRG coded for infection. A baseline PCT was obtained on admission in patients with suspected bacterial infection. Serial PCT measurements were repeated daily to evaluate effectiveness of therapy. Outcomes of interest were antibiotic exposure, hospital mortality, 30-day readmission, Clostridium difficile infection (CDI), and adverse drug events during hospitalization. Results: A total of 985 patients (pre-PCT-A group) were compared with 1167 patients (post-PCT-A group). Antimicrobial stewardship alone (pre-PCT-A) resulted in a median days of therapy (DOT) of 17 (interquartile range [IQR], 8.5-22.5) vs 9.0 (IQR, 6.5-12) in the post-PCT-A group (P < .0001). Secondary outcomes were also significantly reduced in the post-PCT-A group. Conclusion: The addition of PCT in a facility with an established stewardship program resulted in a significant reduction in antibiotic exposure and adverse outcomes. PCT may improve antibiotic management when diagnostic clarity and resolution of infection are lacking. PMID- 29164172 TI - Hallucinations Are Real to Patients With Dementia. AB - : In this case study, we present a patient with preexistent posttraumatic stress disorder and psychosis who has been recently diagnosed with Dementia with Lewy Bodies. He is experiencing vivid hallucinations. What went wrong between him and his wife as a result of these hallucinations is presented. Alternative actions that could have been used are suggested. Objectives: At the end of this case study, readers will know the following:The characteristic clinical features of Dementia with Lewy Bodies (DLB).Patients experiencing hallucinations should not be contradicted, to them, these hallucinations are real.Easy distractibility and short attention span can be exploited to avert or defuse potentially catastrophic situations.Patients with dementia should not have access to loaded guns. PMID- 29164171 TI - Health Care Students' Attitudes About Alcohol Consumption During Pregnancy: Responses to Narrative Vignettes. AB - This article explores medical, midwifery, and nurse practitioner students' attitudes about women who may consume alcohol throughout their pregnancies. Twenty-one health care students responded to a scenario-based vignette addressing alcohol consumption during pregnancy, as well as a semistructured interview, which were analyzed using Braun and Clarke's thematic analysis approach. Two primary themes related to students' attitudes concerning alcohol consumption during pregnancy were identified: (a) divergent recommendations for different women, based on perceptions of their level of education, culture/ethnicity, and ability to stop drinking; and (b) understanding the social determinants of health, including the normalization of women's alcohol consumption and potential partner violence. Health care professionals in training need further education about the risks of alcohol consumption during pregnancy and fetal alcohol spectrum disorder (FASD). In addition, health care students need training in how to engage in reflective practice to identify their own stereotypical beliefs and attitudes and how these attitudes may affect their practice. PMID- 29164173 TI - Factors Related to the Severity of Delirium in the Elderly Patients With Infection. AB - Objective: Delirium is a common neuropsychiatric syndrome in the elderly characterized by concurrent impairments in cognition and behavior. Infection is one of the most important risk factors for delirium. The objective of this study is to elaborate the factors related to the severity of delirium in the elderly patients with infection. Method: An observational study on the relationship of several clinical parameters and the severity of delirium in elderly patients (more than 60 years) with infection was conducted at Geriatric Inpatient Ward, Sanglah Hospital. Delirium was defined by the Memorial Delirium Assessment Scale (MDAS). Charlson Age Comorbidity Index (CACI) scores were calculated as proposed by Charlson et al. Infection was confirmed by clinical, laboratory, and radiographic findings. Results: During 3 months, there were 60 elderly patients (35 men and 25 women) who were hospitalized with infection and delirium. In all, 33 (55.0%), 16 (26.7%), and 11 (18.3%) patients had pneumonia, urinary tract infection, and other infections, respectively, and 44 out of 60 (73.3%) patients had sepsis. There was no significant difference found in MDAS score between male and female patients and among different types of infection, but patients with sepsis had higher MDAS score significantly compared with patients without sepsis (19.48 +/- 3.72 vs. 15.88 +/- 2.82; p < .001). This study revealed that of several clinical parameters, only CACI (R = .533; p < .001), blood urea nitrogen (BUN; R = .230; p = .040), and interleukin 6 (IL-6) levels (R = .499; p < .001) were correlated with MDAS score significantly. By multiple linear regression test, CACI, IL-6, and sepsis have significant role, meanwhile, BUN has no role, on the severity of delirium. Conclusions: The CACI score, IL-6 levels, and sepsis have strong relationship with the severity of delirium, but BUN only has weak role in the severity of delirium in the elderly patients with infection. PMID- 29164174 TI - Early-Life Pseudomonas aeruginosa Infection in Cystic Fibrosis and Lung Disease Progression. AB - Lung disease in cystic fibrosis (CF) starts early, with studies identifying abnormalities on chest computed tomography (CT) scan even in infancy. In this retrospective study, abnormal chest CT was the main outcome; body mass index (BMI) z score and forced expiratory volume percent predicted (FEV1%) predicted at age 6 to 7 years were secondary outcomes. Pseudomonas aeruginosa infection prior to 12 months of age was the main explanatory variable. There was no association between early P aeruginosa infection and abnormal CT after adjustment for CFTR (cystic fibrosis transmembrane conductance regulator) functional mutation class, gender, and other pathogens (odds ratio = 0.30; 95% confidence interval = 0.07 1.35; P = .11). No significant associations were demonstrated for BMI z score and FEV1% predicted. Children with class I-III CFTR mutations had increased risk of abnormal CT findings (odds ratio = 11.67; 95% confidence interval = 1.11-115.06; P = .035) and lower FEV1% predicted (P = .04). In the current era, early-life P aeruginosa infection in CF might not influence the severity of lung disease in school age as much as previously. Larger studies are needed to confirm this finding. PMID- 29164175 TI - Aeromedical Transport of Critically Ill Infants Less Than 3 Months of Age. PMID- 29164176 TI - Needs Assessment for a Medical Home Curriculum for Pediatric Residents. AB - Several studies and the Accreditation Council for Graduate Medical Education recommend integration of medical home (MH) concepts into pediatric resident training. There is a paucity of research depicting the current landscape of pediatric resident MH education. We hypothesized formal MH curricula in pediatric residency education are limited and pediatric residency programs desire incorporating MH education into curricula. A national needs assessment of pediatric residency programs was conducted assessing inclusion of MH concepts in training. Outcomes assessed were perceived importance of including MH concepts, satisfaction of current curriculum, content taught, resources available, and barriers encountered. Fifty-six programs (28%) completed the survey, majority academic programs. Nearly 75% indicated interest in incorporating MH concepts. Fifty-one percent of programs reported faculty knowledgeable in MH concepts/implementation and 11% reported access to readily available resources. Barriers included resident schedules, faculty teaching time, funding, and not faculty priority. Pediatric program directors report interest and need for improved MH training but identify implementation barriers. PMID- 29164177 TI - A Systems Medicine Approach: Translating Emerging Science into Individualized Wellness. AB - In today's aging society, more people are living with lifestyle-related noncommunicable diseases (NCDs) such as cardiovascular disease, type 2 diabetes, obesity, and cancer. Numerous opinion-leader organizations recommend lifestyle medicine as the first-line approach in NCD prevention and treatment. However, there is a strong need for a personalized approach as "one-size-fits-all" public health recommendations have been insufficient in addressing the interindividual differences in the diverse populations. Advancement in systems biology and the "omics" technologies has allowed comprehensive analysis of how complex biological systems are impacted upon external perturbations (e.g., nutrition and exercise), and therefore is gradually pushing personalized lifestyle medicine toward reality. Clinicians and healthcare practitioners have a unique opportunity in advocating lifestyle medicine because patients see them as a reliable source of advice. However, there are still numerous technical and logistic challenges to overcome before personal "big data" can be translated into actionable and clinically relevant solutions. Clinicians are also facing various issues prior to bringing personalized lifestyle medicine to their practice. Nevertheless, emerging ground-breaking research projects have given us a glimpse of how systems thinking and computational methods may lead to personalized health advice. It is important that all stakeholders work together to create the needed paradigm shift in healthcare before the rising epidemic of NCDs overwhelm the society, the economy, and the dated health system. PMID- 29164178 TI - The Amazon region. AB - This is an editorial for the special series. PMID- 29164179 TI - Schroth physiotherapeutic scoliosis-specific exercises for adolescent idiopathic scoliosis: how many patients require treatment to prevent one deterioration? - results from a randomized controlled trial - "SOSORT 2017 Award Winner". AB - Background: Recent randomized controlled trials (RCTs) support using physiotherapeutic scoliosis-specific exercises (PSSE) for adolescents with idiopathic scoliosis (AIS). All RCTs reported statistically significant results favouring PSSE but none reported on clinical significance. The number needed to treat (NNT) helps determine if RCT results are clinically meaningful. The NNT is the number of patients that need to be treated to prevent one bad outcome in a given period. A low NNT suggests that a therapy has positive outcomes in most patients offered the therapy. The objective was to determine how many patients require Schroth PSSE added to standard care (observation or brace treatment) to prevent one progression (NNT) of the Largest Curve (LC) or Sum of Curves (SOC) beyond 5 degrees and 10 degrees , respectively over a 6-month interval. Methods: This was a secondary analysis of a RCT. Fifty consecutive participants from a scoliosis clinic were randomized to the Schroth PSSE + standard of care group (n = 25) or the standard of care group (n = 25).We included males and females with AIS, age 10-18 years, all curve types, with curves 10 degrees - 45 degrees , with or without brace, and all maturity levels. We excluded patients awaiting surgery, having had surgery, having completed brace treatment and with other scoliosis diagnoses. The local ethics review board approved the study (Pro00011552).The Schroth intervention consisted of weekly 1-h supervised Schroth PSSE sessions and a daily home program delivered over six months in addition to the standard of care. A prescription algorithm was used to determine which exercises patients were to perform. Controls received only standard of care.Cobb angles were measured using a semi-automatic system from posterior-anterior standing radiographs at baseline and 6 months.We calculated absolute risk reduction (ARR) and relative risk reduction (RRR). The NTT was calculated as: NNT = 1/ARR. Patients with missing values (PSSE group; n = 2 and controls; n = 4) were assumed to have had curve progression (worst case scenario). The RRR is calculated as RRR = ARR/CER. Results: For LC, NNT = 3.6 (95% CI 2.0-28.2), and for SOC, NNT = 3.1 (95% CI 1.9-14.2). The corresponding ARR was 28% for LC and 32% for the SOC. The RRR was 70% for LC and 73% for the SOC. Patients with complete follow-up attended 85% of prescribed visits and completed 82.5% of the home program. Assuming zero compliance after dropout, 76% of visits were attended and 73% of the prescribed home exercises were completed. Conclusions: The short term of Schroth PSSE intervention added to standard care provided a large benefit as compared to standard care alone. Four (LC and SOC) patients require treatment for the additional benefit of a 6-month long Schroth intervention to be observed beyond the standard of care in at least one patient. Trial registration: NCT01610908 April 2, 2012. PMID- 29164180 TI - You can't burn the house down because of one bedbug: a qualitative study of changing gender norms in the prevention of violence against women and girls in an urban informal settlement in India. AB - Background: The contribution of structural inequalities and societal legitimisation to violence against women, which 30% of women in India survive each year, is widely accepted. There is a consensus that interventions should aim to change gender norms, particularly through community mobilisation. How this should be done is less clear. Methods: We did a qualitative study in a large informal settlement in Mumbai, an environment that characterises 41% of households. After reviewing the anonymised records of consultations with 1653 survivors of violence, we conducted 5 focus group discussions and 13 individual interviews with 71 women and men representing a range of age groups and communities. We based the interviews on fictitious biographical vignettes to elicit responses and develop an understanding of social norms. We wondered whether, in trying to change norms, we might exploit the disjunction between descriptive norms (beliefs about what others actually do) and injunctive norms (beliefs about what others think one ought to do), focusing program activities on evidence that descriptive norms are changing. Results: We found that descriptive and injunctive norms were relatively similar with regard to femininity, masculinity, the need for marriage and childbearing, resistance to separation and divorce, and disapproval of friendships between women and men. Some constraints on women's dress and mobility were relaxing, but there were more substantial differences between descriptive and injunctive norms around women's education, control of income and finances, and premarital sexual relationships. Conclusions: Programmatically, we hope to exploit these areas of mismatch in the context of injunctive norms generally inimical to violence against women. We propose that an under-appreciated strategy is expansion of the reference group: induction of relatively isolated women and men into broader social groups whose descriptive and injunctive norms do not tolerate violence. PMID- 29164181 TI - Gingival depigmentation using Er:YAG laser and scalpel technique: A six-month prospective clinical study. AB - OBJECTIVE: To compare the 6-month clinical efficacy of Er:YAG laser and standard scalpel technique in treating gingival hyperpigmentation. METHOD AND MATERIALS: Patients requesting treatment for moderate to severe gingival hyperpigmentation in the maxilla were enrolled in this split-mouth study. The contralateral maxillary sides were randomly assigned to receive either Er:YAG laser (continuous wavelength of 2,940 nm) with a noncontact tip or the standard scalpel technique. Dummett oral pigmentation index (DOPI) and Hedin melanin index (HMI) were compared at the baseline and at 1 and 2 weeks, and 1, 3, and 6 months following the treatment. Bleeding Index, total treatment time, patient preference, pain perception at the first 3 days, wound healing, and level of satisfaction were also compared. Mann-Whitney test, Kruskal-Wallis test, and chi-square test were used to test the significance between variables. A P value of less than or equal to .05 was considered statistically significant. RESULTS: Of the 22 patients enrolled, 20 completed this study. After assessing DOPI and HMI at 1 and 2 weeks, and at 1-, 3-, and 6-month follow-up appointments, both Er:YAG laser and scalpel were significantly effective in treating gingival hyperpigmentation when compared to baseline (P < .001) but with no statistically significant difference between the two treatment methods (P > .05). More patients preferred the scalpel technique as it was associated with slightly shorter treatment time and less postoperative pain when compared to Er:YAG laser, but with no statistical significance (P > .05). Er:YAG laser sites showed minimal bleeding and more rapid wound healing (P < .001). CONCLUSION: Both Er:YAG laser and scalpel technique achieved similar outcomes regarding the efficacy of gingival depigmentation, postoperative pain perception, and the time required for the treatment. Laser therapy requires more advanced technology and is associated with higher financial costs. Therefore, the scalpel technique is still considered the gold standard treatment for gingival depigmentation. PMID- 29164182 TI - Replantation of an avulsed tooth after one day of storage in adverse extraoral dry conditions: Acceptable outcome after a 10-year follow-up. AB - This article reports a clinical case of a 10-year-old boy who sustained an avulsion of the maxillary right central incisor. The avulsed tooth was kept in adverse extraoral dry conditions for 26 hours from the moment of trauma until its replantation. Treatment guidelines for avulsed mature permanent teeth with closed apex were only partially followed. However, the clinical and radiographic findings after 10 years revealed acceptable functional outcome, in spite of ankylosis and root resorption of the replanted tooth, which was eventually treated cosmetically. PMID- 29164183 TI - Removal of a severely impacted mandibular third molar minimizing the risks of compromised periodontium, nerve injury, and mandibular fracture. AB - : A technique is presented for severely impacted and dentigerous-cyst-related mandibular third molar removal, avoiding any associated risks. CASE PRESENTATION: A healthy patient complained about unpleasant smell and taste in the mouth and unilateral extraoral palpation of a protuberance, at the right corner of the mandible. Restricted field CBCT showed a severely impacted third molar, which penetrated the inferior cortical bone of the mandibular corner and was associated with a dentigerous cyst that had resorbed considerable bone in the region. Surgical exposure of the impacted tooth and cyst marsupialization procedures under local anesthesia were combined with orthodontic extrusion of the impacted tooth to facilitate third molar removal. Treatment resulted in successful bone formation and safe tooth removal. The symptoms gradually improved after the first surgery and were eliminated by 14 months later, when the third molar was removed. Follow-up examination 1 year after removal showed favorable periodontal conditions. CONCLUSION: Although it is not normally the first treatment of choice, orthodontically assisted impacted tooth removal is an alternative that can minimize the risk of compromised periodontium or injury to the adjacent tooth and the inferior alveolar nerve, as well as the risk of mandibular fracture, in complicated cases. PMID- 29164184 TI - Interpretations of complications following third molar extraction. AB - OBJECTIVE: Surgical removal of third molars is often associated with complications. The aim of the present study was to analyze the incidence of complications following extraction of third molars relative to the risk factors. METHOD AND MATERIALS: This retrospective study included 463 patients who had mandibular third molar extraction (performed by a single surgeon, DSA) in the years 2001 to 2011. In total, 665 mandibular third molars were extracted. The average patient's age was 29 +/- 11.30 years, median 26 years, and the patient age ranged from 13 to 75 years. Patients' records were obtained for medical/general data. RESULTS: The overall prevalence of postsurgical complications was 17%. Dry sockets showed the highest incidence (11.6%). Partially impacted teeth showed the highest incidence of complications (67.3%). Cigarette smoking correlated with increased complications and dry sockets, and complications were more prevalent on the left side (62.8%). CONCLUSION: Complications after mandibular third molar extraction increase with age, level of impaction, side of extraction, and cigarette smoking. PMID- 29164185 TI - Ruthenium catalyzed remote C4-selective C-H functionalisation of carbazoles via sigma-activation. AB - We report the C4-selective C-H alkylation of carbazole derivatives furnished with a pyrimidine directing group at N9. This was realized using ruthenium catalyzed sigma-activation methodology, whereby C-H activation at C1 enables the interaction of this ruthenacycle, at the para position to the metal center, with tertiary alkyl radicals. PMID- 29164186 TI - Phenylalanine and derivatives as versatile low-molecular-weight gelators: design, structure and tailored function. AB - Phenylalanine (Phe) is an essential amino acid classified as neutral and nonpolar due to the hydrophobic nature of the benzyl side chain. In the field of materials science, the chemical modification of phenylalanine at C or N terminus has enabled to synthesize a large number of low-molecular-weight gelators over the past decade. Thus, many physical (or supramolecular) softgel materials have been fabricated by self-assembly of Phe-derived building blocks, which can be programmed with atomic level information and modification. The process of self assembly and gelation must balance the parameters that influence the solubility as well as the contrasting forces that dictate epitaxial growth into entangled fibrillar aggregates. Gelator-gelator and solvent-gelator interactions are known to be highly important for the gelation process, and the non-covalent nature of these interactions provides physical gels with important properties such as reversible phase transitions and responsiveness towards external stimuli. Among other applications, these gels have been used for drug delivery, as extracellular matrix for tissue engineering, for oil spills recovery, removal of dyes, extraction of heavy metals or pollutants, and for the detection of explosives. In this tutorial review, we highlight the advances in the design, synthesis and applications of supramolecular gels made of Phe and derivatives. PMID- 29164187 TI - Fluorous photosensitizers enhance photodynamic therapy with perfluorocarbon nanoemulsions. AB - Photodynamic therapy (PDT) requires a photosensitizer, light, and oxygen to induce cell death. The majority of efforts to advance PDT focus only on the first two components. Here, we employ perfluorocarbon nanoemulsions to simultaneously deliver oxygen and a photosensitizer. We find that the implementation of fluorous soluble photosensitizers enhances the efficacy of PDT. PMID- 29164188 TI - Facile immobilization of DNA using an enzymatic his-tag mimic. AB - Methods for immobilization of DNA on solid supports are in high demand. Herein, we present a generally applicable enzymatic method for the immobilization of DNA without any prior chemical derivatization. This strategy relies on the homopolymerization of the modified triphosphate dImTP by the TdT. The resulting enzymatic his-tag mimic ensures binding of DNA on Ni-NTA agarose. The usefulness of this method is highlighted by the immobilization of functional nucleic acids without impairing their specific activities. PMID- 29164189 TI - Structural analysis of elastically bent organic crystals using in situ indentation and micro-Raman spectroscopy. AB - The structural dynamics of two elastically bendable, halogenated N benzylideneaniline organic crystals were studied using an in situ three-point bending test and Raman spectroscopy. This study reveals the inhomogeneous molecular distribution in the elastic crystal lattice during the bent stage and further validates the known qualitative mechanistic model of elastic bendable crystals. PMID- 29164190 TI - Upgrading well plates using open microfluidic patterning. AB - Cellular communication between multiple cell types is a ubiquitous process that is responsible for vital physiological responses observed in vivo (e.g., immune response, organ function). Many in vitro coculture strategies have been developed, both in traditional culture and microscale systems, and have shown the potential to recreate some of the physiological behaviors of organs or groups of cells. A fundamental limitation of current systems is the difficulty of reconciling the additional engineering requirements for creating soluble factor signaling systems (e.g., segregated cell culture) with the use of well characterized materials and platforms that have demonstrated successful results and biocompatibility in assays. We present a new open-microfluidic platform, the Monorail Device, that is placed in any existing well plate or Petri dish and enables patterning of segregated coculture regions, thereby allowing the direct upgrade of monoculture experiments into multiculture assays. Our platform patterns biocompatible hydrogel walls via microfluidic spontaneous capillary flow (SCF) along a rail insert set inside commercially available cultureware, creating customized pipette-accessible cell culture chambers that require fewer cells than standard macroscale culture. Importantly, the device allows the use of native surfaces without additional modification or treatments, while creating permeable dividers for the diffusion of soluble factors. Additionally, the ease of patterning afforded by our platform makes reconfiguration of the culture region as simple as changing the rail insert. We demonstrate the ability of the device to pattern flows on a variety of cell culture surfaces and create hydrogel walls in complex and precise shapes. We characterize the physical parameters that enable a reproducible SCF-driven flow and highlight specialized design features that increase the ease of use of the device and control of the open microfluidic flow. Further, we present the performance of our platform according to useful coculture criteria, including permeability and integrity of our hydrogel walls and surface-sensitive cell culture. Lastly, we show the potential of this type of platform to create modular multikingdom culture systems that can be used to study soluble factor signaling between mammalian cells, bacteria, and fungi, as well as the potential for adaptation of this technology by researchers across multiple fields. PMID- 29164192 TI - Synthesis of nitrogen and sulfur co-doped hierarchical porous carbons and metal free oxidative coupling of silanes with alcohols. AB - Hierarchically porous N and S co-doped carbon was prepared by using 2,5-dihydroxy 1,4-benzoquinone as the carbon source, thiourea as the N and S source, and SiO2 particles as the template. Using the material as the catalyst, oxidative coupling of silanes with alcohols was conducted for the first time under metal-free conditions. PMID- 29164191 TI - Characterising the evaporation kinetics of water and semi-volatile organic compounds from viscous multicomponent organic aerosol particles. AB - The physicochemical changes experienced by organic aerosol particles undergoing dehydration into the surrounding gas phase can be drastic, forcing rapid vitrification of the particle and suppressing internal diffusion. Until recently, experimental studies have concentrated on quantifying diffusional mixing of either water or non-volatile components, while relatively little attention has been paid to the role of semivolatile organic component (SVOC) diffusion and volatilisation in maintaining the equilibrium between the gas and particle phases. Here we present methods to simultaneously investigate diffusivities and volatilities in studies of evolving single ternary aerosol particle size and composition. Analysing particles of ternary composition must account for the multiple chemical species that volatilise in response to a step change in gas phase water activity. In addition, treatments of diffusion in multicomponent mixtures are necessary to represent evolving heterogeneities in particle composition. We find that the contributions to observed size behaviour from volatilisation of water and a SVOC can be decoupled and treated separately. Employing Fickian diffusion modelling, we extract the compositional dependence of the diffusion constant of water and compare the results to recently published parametrisations in binary aerosol particles. The treatment of ideality and activity in each case is discussed, with reference to use in multicomponent core shell models. Meanwhile, the evaporation of an SVOC into an unsaturated gas flow may be treated by Maxwell's equation, with slow diffusional transport manifesting as a suppression in the extracted vapour pressure. PMID- 29164193 TI - Two-step kinetic model of the self-assembly mechanism for diphenylalanine micro/nanotube formation. AB - Peptide nanostructures compose a new class of materials that have gained attention due to their interesting properties. Among them, nanotubes of diphenylalanine (FF) and its analogues have been one of the most studied structures in the last few years. Their importance originates from the need to better understand the formation of beta-amyloid fibrils which are associated with Alzheimer's disease. In this work, the FF self-assembly process was probed using time-resolved Raman microscopy. The changes in the Raman spectra are followed over time after injecting water into a FF-film until micro/nanotubes (MNTs) are formed. Specific features of the Raman spectra clearly suggest that FF-molecules after water injection form an intermediate species before forming FF-MNTs. The broad Raman bands observed for the intermediate species suggest the presence of very heterogeneous structures based on FF. The FF-MNTs appear almost instantaneously (detected via the rise of the typical Raman bands of FF-MNTs at 761, 1249 and 1426 cm-1) after the intermediate structures are formed. This delayed formation of FF-MNTs supports a nucleation process. The formation via nucleation of FF-MNTs is further corroborated by a simulation of the Raman spectra based on a 2-step kinetic model and the respective vibrational Raman modes are identified using Density Functional Theory vibrational calculations. Our results indicate that the driving force for the FF-MNT patterning process is the electric dipole re-orientation originating from the FF dipeptide unit connectivity over time. PMID- 29164194 TI - N-Heterocyclic carbene-catalyzed sulfa-Michael addition of enals. AB - An efficient N-heterocyclic carbene (NHC) catalyzed sulfa-Michael addition (SMA) between enals and thiols has been developed. Under the catalysis of 10 mol% stable free carbene IPr and with 20 mol% hexafluoroisopropanol (HFIP) as an additive, enals react with a variety of thiols to afford the SMA adducts in 54 98% yields. In this process, the free carbene preferentially interacts with thiols through hydrogen-bonding and no NHC-catalyzed extended Umpolung transformations were observed. PMID- 29164195 TI - Nanochannels as molecular check valves. AB - A molecular check valve is a nanomachine that enables unidirectional molecular transport. In this work, we report a novel molecular check valve fabricated by asymmetric modification of a silica nanoporous membrane (SNM) consisting of parallel nanochannels with a diameter of 2-3 nm. Asymmetric modification refers to the thermal deposition of hydrophobic polydimethylsiloxane (PDMS) only on one side of the SNM to generate hydrophobic nanoorifices. Such an asymmetric nanostructure, designated as PDMS-SNM, could synergistically exert a hydrophobic force on the molecules by PDMS nanoorifices and an electrostatic force by naked silica nanochannels, resulting in unidirectional molecular transport under specific circumstances. Typically, only positively charged molecules were able to transport across the PDMS-SNM from the PDMS nanoorifice side, while backward transport from the other side was prohibited. In the former case, positively charged molecules were subject to electrostatic attraction from naked silica channels, which could exceed the hydrophobic rejection from PDMS nanoorifices to pull the molecule across the PDMS-SNM. However, in the latter case the electrostatic attraction is no longer a driving force to overcome the hydrophobic rejection from PDMS nanoorifices to promote the molecular transport. On the other hand, the PDMS-SNM based molecular check valve can be shut down to prevent any molecular transport from either side of the PDMS-SNM under certain conditions, such as a high salt concentration or an appropriate pH (e.g., pH 3). We believe that it could be applied to convert natural fluctuation energy into directed motion, as well as to prevent backward transport in batteries and fuel cells. PMID- 29164196 TI - Supramolecular polymeric biomaterials. AB - Polymeric chains crosslinked through supramolecular interactions-directional and reversible non-covalent interactions-compose an emerging class of modular and tunable biomaterials. The choice of chemical moiety utilized in the crosslink affords different thermodynamic and kinetic parameters of association, which in turn illustrate the connectivity and dynamics of the system. These parameters, coupled with the choice of polymeric architecture, can then be engineered to control environmental responsiveness, viscoelasticity, and cargo diffusion profiles, yielding advanced biomaterials which demonstrate rapid shear-thinning, self-healing, and extended release. In this review we examine the relationship between supramolecular crosslink chemistry and biomedically relevant macroscopic properties. We then describe how these properties are currently leveraged in the development of materials for drug delivery, immunology, regenerative medicine, and 3D-bioprinting (253 references). PMID- 29164197 TI - Theoretical study of the photothermal behaviour of self-assembled magnetic plasmonic chain structures. AB - We study the field-directed self-assembly and photothermal behavior of one dimensional (1D) chains of core-shell Fe3O4@Au magnetic-plasmonic nanoparticles. Monte Carlo analysis is used to predict the self-assembly of the nanoparticles when they are subjected to a uniform magnetic field and confined to a fluidic nanochannel. A coupled photonic and thermodynamic analysis is performed to analyze the optical and photothermal properties of the 1D chain structures. We show for the first time that the assembled chain structures exhibit a pronounced dip in their absorption spectrum at a wavelength that is strongly sensitive to changes in the refractive index of the surrounding medium. The plasmon enhanced features of these structures are well suited for a variety of theranostic modalities as we discuss. PMID- 29164198 TI - Aptamer-modified selenium nanoparticles for dark-field microscopy imaging of nucleolin. AB - Selenium nanoparticles (SeNPs) with strong green scattering light serving as light scattering nanoprobes for dark-field microscopy imaging are developed for the first time. The SeNPs show good stability, excellent biocompatibility, and high light-producing power, and can precisely and specifically target cancer cells with overexpressed nucleolin (NCL) after modification with aptamers, revealing that the SeNPs can act as a good light scattering nanoprobe for bioimaging and biolabeling. PMID- 29164199 TI - Monitoring of Au(iii) species in plants using a selective fluorescent probe. AB - A colorimetric and ratiometric probe with a push-pull chromophore dicyanoisophorone system, AuP, has been developed for the detection of Au(iii) species with highly sensitive and selective response to real-water samples and living tissues of Arabidopsis thaliana. PMID- 29164200 TI - Visualizing rotational wave functions of electronically excited nitric oxide molecules by using an ion imaging technique. AB - Here we report the dissociative ionization imaging of electronically excited nitric oxide (NO) molecules to visualize rotational wave functions in the electronic excited state (A 2Sigma+). The NO molecules were excited to a single rotational energy eigenstate in the first electronic excited state by a resonant nanosecond ultraviolet pulse. The molecules were then irradiated by a strong, circularly polarized femtosecond imaging pulse. Spatial distribution of the ejected N+ and O+ fragment ions from the dissociative NO2+ was recorded as a direct measure of the molecular axis distribution using a high-resolution slice ion imaging apparatus. The circularly polarized probe pulse realizes the isotropic ionization and thus undistorted shapes of the functions can be visualized. Due to the higher ionization efficiency of the excited molecules relative to the ground state ones, signals from the excited NO were enhanced. We can, therefore, extract shapes of the square of rotational wave functions in the electronic excited state although the unexcited ground state molecules are the majority in an ensemble. The observed images show s-function-like and p-function like shapes depending on the excitation wavelengths. These shapes well reflect the rotational (angular momentum) character of the prepared states. The present approach directly leads to the evaluation method of the molecular axis alignment in photo-excited ensembles, and it could also lead to a visualization method for excited state molecular dynamics. PMID- 29164201 TI - Impacts of cloud water droplets on the OH production rate from peroxide photolysis. AB - Understanding the difference between observed and modeled concentrations of HOx radicals in the troposphere is a current major issue in atmospheric chemistry. It is widely believed that existing atmospheric models miss a source of such radicals and several potential new sources have been proposed. In recent years, interest has increased on the role played by cloud droplets and organic aerosols. Computer modeling of ozone photolysis, for instance, has shown that atmospheric aqueous interfaces accelerate the associated OH production rate by as much as 3-4 orders of magnitude. Since methylhydroperoxide is a main source and sink of HOx radicals, especially at low NOx concentrations, it is fundamental to assess what is the influence of clouds on its chemistry and photochemistry. In this study, computer simulations for the photolysis of methylhydroperoxide at the air-water interface have been carried out showing that the OH production rate is severely enhanced, reaching a comparable level to ozone photolysis. PMID- 29164202 TI - Fundamental peak disappears upon binding of a noble gas: a case of the vibrational spectrum of PtCO in an argon matrix. AB - Anharmonic vibrational state calculations were performed for PtCO and Ar-PtCO via the direct vibrational configuration interaction (VCI) method based on CCSD(T) energies and CCSD dipole moments at tens of thousands of grids, to get insights into the anomalous effect of a solid argon matrix on the vibrational spectra of PtCO. It was shown that, through the binding of Ar to PtCO via a strong van der Waals interaction, the Pt-C-O bending fundamental level drastically loses the infrared intensity although the corresponding overtone band shows a relatively large intensity. The origin of this phenomenon was analyzed based on the dipole moment surfaces and electron densities around the equilibrium structure. The present computations have solved the inconsistency between the gas-phase and the matrix-isolation experiments for PtCO. PMID- 29164203 TI - Interfacial electronic structure of Cl6SubPc non-fullerene acceptors in organic photovoltaics using soft X-ray spectroscopies. AB - In organic photovoltaics (OPVs), determining the energy-level alignment of a donor and an acceptor is particularly important since the interfacial energy gap between the highest occupied molecular orbital (HOMO) level of a donor and the lowest unoccupied molecular orbital (LUMO) level of an acceptor (E-E) gives the theoretical maximum value of the open-circuit voltage (VOC). To increase the E-E, non-fullerene acceptors, which have a lower electron affinity (EA) than C60, are receiving increasing attention. In this study, we investigated the energy-level alignment at the interface of a boron chloride subphthalocyanine (SubPc) donor and a halogenated SubPc (Cl6SubPc) acceptor using soft X-ray spectroscopy techniques. The estimated E-E of Cl6SubPc/SubPc was 1.95 eV, which was significantly higher than that of 1.51 eV found at the interface of C60/SubPc. This increased E-E was the origin of the enhanced VOC in OPVs. Additionally, we studied the molecular orientation of Cl6SubPc using angle-dependent X-ray absorption spectroscopy. The highly disordered Cl6SubPc molecules result in low carrier mobility, which contributes to the lower short-circuit current density of the Cl6SubPc acceptor OPVs than the C60 acceptor OPVs. PMID- 29164204 TI - Antipseudomonal activity enhancement of luminescent iridium(iii) dipyridylamine complexes under visible blue light. AB - Cyclometallated iridium(iii) dipyridylamine complexes present antibacterial activity against P. aeruginosa, a highly resistant pathogenic bacterium. This activity is increased when the complex is conjugated to biotin, a bacterial nutrient, and a MIC of 4 MUM (4 MUg mL-1) has been observed. The irradiation of P. aeruginosa cultures with blue LED light potentiates the anti-bacterial activities of these iridium(iii) complexes when they are conjugated to a glycoside. PMID- 29164205 TI - Theory of SERS enhancement: general discussion. PMID- 29164206 TI - Coupled relaxation channels of excitons in monolayer MoSe2. AB - Using ultrafast degenerate pump-probe spectroscopy, we have investigated the ultrafast exciton dynamics of monolayer MoSe2 at different pump fluences. The exciton-exciton annihilation, typically occurring tens of picoseconds after pump excitation, has been found to have a substantial correlation with the initial relaxation process dominated by the defect trapping of excitons. A new exciton exciton annihilation model has been proposed by introducing a coupling term that accounts for the initial relaxation contribution. This coupling term can be tuned by varying the pump excitation intensity and at a high intensity it vanishes due to the full occupation of the defect states. At the same time, the final electron hole recombination is found to be affected by the heat accumulation effect originating from the high intensity pump pulses. PMID- 29164207 TI - A phototactic micromotor based on platinum nanoparticle decorated carbon nitride. AB - In this paper, we report a unique phototactic (both positive and negative) micromotor based on platinum nanoparticle decorated carbon nitride. The phototaxis relies on the self-diffusiophoretic mechanism and different surface modifications. The micromotor reported in the current study does not require the addition of any external fuels and shows versatile motion behaviour, i.e. start, stop, directional and programmable motion, which is controlled by light. In addition, since the actuation of the precipitated micromotors at the bottom of a solution using light results in the opacity changes from transparent to translucent, we anticipate that the current micromotor may have potential application in the field of smart windows. PMID- 29164208 TI - Performing multi-step chemical reactions in microliter-sized droplets by leveraging a simple passive transport mechanism. AB - Despite the increasing importance of positron emission tomography (PET) imaging in research and clinical management of disease, access to myriad new radioactive tracers is severely limited due to their short half-lives (which requires daily production) and the high cost and complexity of tracer production. The application of droplet microfluidics based on electrowetting-on-dielectric (EWOD) to the field of radiochemistry can significantly reduce the amount of radiation shielding necessary for safety and the amount of precursor and other reagents needed for the synthesis. Furthermore, significant improvements in the molar activity of the tracers have been observed. However, widespread use of this technology is currently hindered in part by the high cost of prototype chips and the operating complexity. To address these issues, we developed a novel microfluidic device based on patterned wettability for multi-step radiochemical reactions in microliter droplets and implemented automated systems for reagent loading and collection of the crude product after synthesis. In this paper, we describe a simple and inexpensive method for fabricating the chips, demonstrate the feasibility of prototype chips for performing multi-step radiochemical reactions to produce the PET tracers [18F]fallypride and [18F]FDG, and further show that synthesized [18F]fallypride can be used for in vivo mouse imaging. PMID- 29164209 TI - Tuning the cytotoxicity of ruthenium(ii) para-cymene complexes by mono substitution at a triphenylphosphine/phenoxydiphenylphosphine ligand. AB - The new complexes [RuCl2(eta6-p-cymene)(kappaP-Ph2PR)] [R = 4-C6H4OSiMe2tBu, 1; R = 4-C6H4Br, 2; R = OC([double bond, length as m-dash]O)CHCl2, 3; R = OPh, 4; R = O(2-C6H4SiMe2tBu), 5] and [Ru(C2O4)(eta6-p-cymene){kappaP-Ph2PO(2 C6H4(SiMe2tBu))}], 6, were obtained in 83-98% yield from Ru(ii) arene precursors by three different synthetic strategies. The unprecedented phosphine Ph2P(O(2 C6H4SiMe2tBu)) was synthesized in 86% yield from 2-C6H4Br(OSiMe2tBu) and Ph2PCl, via intramolecular oxygen to carbon 1,3 migration of the silyl group (retro-Brook rearrangement). All the complexes were fully characterized by analytical and spectroscopic methods, and by single crystal X-ray diffraction in the cases of 3, 4, 5 and 6. Complexes 1-6 and the model compounds [RuCl2(eta6-p-cymene)(kappaP PPh3)] (Ru-PPh3) and [Ru(C2O4)(eta6-p-cymene)(kappaP-PPh3)] (Ru-PPh3-O) underwent slow degradation in chloroform solutions upon air contact; the mixed valence complex [(eta6-p-cymene)Ru(MU-Cl)3RuCl2(kappaP-PPh3)], 7, was isolated from a solution of Ru-PPh3 in CHCl3, and X-ray identified. The antiproliferative activity of 1-6 and Ru-PPh3, Ru-PPh3-O and [RuCl2(eta6-p-cymene)(kappaP-PTA)] (RAPTA-C) was assessed towards the triple-negative breast cancer cell line MDA-MB 231, the ovarian carcinoma cell line A2780 and human skin fibroblasts (HSF). Complexes 1, 2, 5 and 6 displayed IC50 values significantly lower than that of cisplatin, with 2 providing a more potent cytotoxic effect on MDA-MB-231 and A2780 cancer cells compared to the noncancerous cell line (HSF). The stability of all complexes in DMSO/water solution was elucidated by NMR and conductivity measurements, and in particular 35Cl NMR spectroscopy was helpful to check the possible chloride dissociation. The stability studies suggest that the cytotoxic activity in vitro of the compounds is mainly ascribable to Ru(ii) species still bound to the phosphorus ligand. PMID- 29164210 TI - High-efficiency near-infrared enabled planar perovskite solar cells by embedding upconversion nanocrystals. AB - Integration of the upconversion effect in perovskite solar cells (PSCs) is a facile approach towards extending the spectral absorption from the visible to the near infrared (NIR) range and reducing the non-absorption loss of solar photons. However, the big challenge for practical application of UCNCs in planar PSCs is the poor compatibility between UCNCs and the perovskite precursor. Herein, we have subtly overcome the tough compatibility issue using a ligand-exchange strategy. For the first time, beta-NaYF4:Yb,Er UCNCs have been embedded in situ into a CH3NH3PbI3 layer to fabricate NIR-enabled planar PSCs. The CH3NH3I-capped UCNCs generated from the ligand-exchange were mixed with the perovskite precursor and served as nucleation sites for the UCNC-mediated heteroepitaxial growth of perovskite; moreover, the in situ embedding of UCNCs into the perovskite layer was realized during a spin-coating process. The resulting UCNC-embedded perovskite layer attained a uniform pinhole-free morphology with enlarged crystal grains and enabled NIR absorption. It also contributed to the energy transfer from the UCNCs to the perovskite and electron transport to the collecting electrode surface. The device fabricated using the UCNC-embedded perovskite film achieved an average power-conversion efficiency of 18.60% (19.70% for the best) under AM 1.5G and 0.37% under 980 nm laser, corresponding to 54% and 740-fold increase as compared to that of its counterpart without UCNCs. PMID- 29164211 TI - Various polyoxomolybdate-based hybrids induced by pH and solvents: structures, adsorption activities for dyes and bifunctional electrocatalytic properties. AB - By changing the pH values and solvents of reaction systems, four polyoxomolybdate based compounds, [CoL(H2O)2][beta-Mo8O26]0.5 (1), {[Co2L2(H2O)3][Mo7O23]}.3H2O (2), [Co2L3][delta-Mo8O26]0.5[beta-Mo8O26]0.5.10H2O (3), [Co2L3][H4Mo8O28].4DMA.2H2O (4), (L = 1,3-bis(1H-imidazole-4 carboxamido)metaphenylene, DMA = N,N'-dimethylacetamide), have been synthesized in the presence of the Co2+ ion, L ligand and Mo7O246-. Compounds 1 and 2 were obtained under hydrothermal conditions; the different pH values result in two kinds of polyoxomolybdate anions, [beta-Mo8O26]4- in 1 and [Mo14O46]8- in 2, and the similar [CoL(H2O)2]2+ or [Co2L2(H2O)3]4+ metal-organic chains. Compounds 3 and 4 were synthesized under mixed-solvent conditions. There are two kinds of octamolybdate isomers in 3, [beta-Mo8O26]4- and [delta-Mo8O26]4- anions, but only one kind of [Mo8O28]8- anion in 4, but the two compounds have a similar metal organic cage [Co2L3]4+. The results reveal that the pH values and different solvents play key roles in tuning the diverse architectures of polyoxomolybdate anions and metal-organic motifs. The adsorption activities for organic dyes, crystal violet (CV), methylene blue (MB) and Congo red (CR), and the electrocatalytic properties of hydrogen peroxide (H2O2) and ascorbic acid (AA) of compounds 1-4 are reported here. PMID- 29164212 TI - Elemental sulfur mediated 2-substituted benzothiazole formation from 2 aminobenzenethiols and arylacetylenes or styrenes under metal-free conditions. AB - An oxidative cyclization of 2-aminothiophenols and arylacetylenes or styrenes for the synthesis of 2-alkylbenzothiazoles and 2-acylbenzothiazoles has been developed. Elemental sulfur was used as the effective oxidant to give the corresponding product in good yield under metal-free conditions. PMID- 29164213 TI - Strain-induced alignment and phase behavior of blue phase liquid crystals confined to thin films. AB - We report on the influence of surface confinement on the phase behavior and strain-induced alignment of thin films of blue phase liquid crystals (BPs). Confining surfaces comprised of bare glass, dimethyloctadecyl [3 (trimethoxysilyl)propyl] ammonium chloride (DMOAP)-functionalized glass, or polyvinyl alcohol (PVA)-coated glass were used with or without mechanically rubbing to influence the azimuthal anchoring of the BPs. These experiments reveal that confinement can change the phase behavior of the BP films. For example, in experiments performed with rubbed-PVA surfaces, we measured the elastic strain of the BPs to change the isotropic-BPII phase boundary, suppressing formation of BPII for film thicknesses incommensurate with the BPII lattice. In addition, we observed strain-induced alignment of the BPs to exhibit a complex dependence on both the surface chemistry and azimuthal alignment of the BPs. For example, when using bare glass surfaces causing azimuthally degenerate and planar anchoring, BPI oriented with (110) planes of the unit cell parallel to the contacting surfaces for thicknesses below 3 MUm but transitioned to an orientation with (200) planes aligned parallel to the contacting surfaces for thicknesses above 4 MUm. In contrast, BPI aligned with (110) planes parallel to confining surfaces for all other thicknesses and surface treatments, including bare glass with uniform azimuthal alignment. Complementary simulations based on minimization of the total free energy (Landau-de Gennes formalism) confirmed a thickness dependent reorientation due to strain of BPI unit cells within a window of surface anchoring energies and in the absence of uniform azimuthal alignment. In contrast to BPI, BPII did not exhibit thickness-dependent orientations but did exhibit orientations that were dependent on the surface chemistry, a result that was also captured in simulations by varying the anchoring energies. Overall, the results in this paper reveal that the orientations assumed by BPs in thin films reflect a complex interplay of surface interactions and elastic energies associated with strain of the BP lattice. The results also provide new principles and methods to control the structure and properties of BP thin films, which may find use in BP-templated material synthesis, and BP-based optical and electronic devices. PMID- 29164214 TI - Withapubesides A-D: natural inducible nitric oxide synthase (iNOS) inhibitors from Physalis pubescens. AB - Four new steroid glycosides, withapubesides A-D (1-4), were isolated from the stems of Physalis pubescens L. Their structures were elucidated primarily by NMR experiments. The absolute configurations of 1 and 2 were deduced by single crystal X-ray diffraction and ECD data analysis, respectively. Compound 3 has shown significant inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages with an IC50 value of 12.8 MUM and moderate cytostatic activity against human carcinoma cells (786-O, C4-2B, 22Rvl, A375 and A375S2) with IC50 values in the range of 3.05-9.47 MUM. Molecular docking simulation demonstrated that 3 is bound in the inducible nitric oxide synthase (iNOS) active site heme pocket very well, which suggests that 3 might be a candidate for the development of iNOS inhibitors. PMID- 29164216 TI - Improved synthesis of symmetrically & asymmetrically N-substituted pyridinophane derivatives. AB - The N,N'-di(toluenesulfonyl)-2,11-diaza[3,3](2,6)pyridinophane (TsN4) precursor was sought after as a starting point for the preparation of various symmetric and asymmetric pyridinophane-derived ligands. Various procedures to synthesize TsN4 had been published, but the crucial problem had been the purification of TsN4 from the larger 18- and 24-membered azamacrocycles. Most commonly, column chromatography or other laborious methods have been utilized for this separation, yet we have found an alternate selective dissolution method upon protonation which allows for multi-gram scale output of TsN4.HCl. This optimized synthesis of TsN4 also led to the development of symmetric RN4 derivatives as well as the asymmetric derivative N-(tosyl)-2,11-diaza[3,3](2,6)pyridinophane (TsHN4). Using this TsHN4 precursor, different N-substituents can be added to create a library of asymmetric RR'N4 macrocyclic ligands. These asymmetric RR'N4 derivatives expand the utility of the RN4 framework in coordination chemistry and the ability to study the electronic, steric, and denticity effects of these pyridinophane ligands on the metal center. PMID- 29164215 TI - Controlling miRNA-like off-target effects of an siRNA with nucleobase modifications. AB - SiRNAs can cause unintended gene silencing due to miRNA-like effects because of the similarity in function of an siRNA guide strand and a miRNA. Here we evaluate the effect on miRNA-like off targeting of introducing the adenosine derivative 7 EAA and triazoles prepared from 7-EAA at different positions in an siRNA guide strand. We find that a sterically demanding triazole placed in the RNA duplex major groove at position six of the guide strand dramatically reduces miRNA-like off targeting potency. A high-resolution structure of an RNA duplex bearing a novel, major-groove localized triazole is reported, which suggests that modified triazoles could be disrupting the hAgo2-guide-target RNA ternary complex. Five different triazole modifications were tested at the guide strand 6-position for effects on on-target and miRNA-like off target knockdown potency. A 7-EAA triazole bearing a benzylamine substituent displayed on-target knockdown activity as potent as the native siRNA, while having an IC50 against a miRNA-like off target >100-fold higher. Melting temperature studies revealed no obvious correlation between potency in knockdown assays and a modification's effect on duplex stability. These results, along with known structures of hAgo2-guide target ternary complexes, are used to rationalize the effect of 7-EAA triazoles on miRNA-like off target effects. PMID- 29164217 TI - Enhanced energy transfer in heterogeneous nanocrystals for near infrared upconversion photocurrent generation. AB - The key to produce inorganic heterogeneous nanostructures, and to integrate multiple functionalities, is to enhance or at least retain the functionalities of different components of materials. However, this ideal scenario is often deteriorated at the interface of the heterogeneous nanostructures due to lattice mismatches, resulting in downgraded performance in most hybrid nanomaterials. Here, we report that there is a narrow window in controlling temperature in a Lewis acid-base reaction process to facilitate epitaxial alignment during the synthesis of hybrid nanomaterials. We demonstrate a perfectly fused NaYF4:Yb,Tm@ZnO heterogeneous nanostructure, in which the semiconductor ZnO shell can be epitaxially grown onto lanthanide-doped upconversion nanoparticles. By achieving a matched crystal lattice, the interface defects and crystalline grain boundaries are minimized to enable more efficient energy transfer from the upconversion nanoparticles to the semiconductor, resulting in both enhanced upconversion luminescence intensity and superior photoelectrochemical properties. This strategy provides an outstanding approach to endow lanthanide-doped upconversion nanoparticles with versatile properties. PMID- 29164218 TI - Charge regulation of nonpolar colloids. AB - Individual colloids often carry a charge as a result of the dissociation (or adsorption) of weakly-ionized surface groups. The magnitude depends on the precise chemical environment surrounding a particle, which in a concentrated dispersion is a function of the colloid packing fraction eta. Theoretical studies have suggested that the effective charge Zeff in regulated systems could, in general, decrease with increasing eta. We test this hypothesis for nonpolar dispersions by determining Zeff(eta) over a wide range of packing fractions (10-5 <= eta <= 0.3) using a combination of small-angle X-ray scattering and electrophoretic mobility measurements. All dispersions remain entirely in the fluid phase regime. We find a complex dependence of the particle charge as a function of the packing fraction, with Zeff initially decreasing at low concentrations before finally increasing at high eta. We attribute the non monotonic density dependence to a crossover from concentration-independent screening at low eta, to a high packing fraction regime in which counterions outnumber salt ions and electrostatic screening becomes eta-dependent. The efficiency of charge stabilization at high concentrations may explain the unusually high stability of concentrated nanoparticle dispersions which has been reported. PMID- 29164219 TI - Conformational isomerism in cyclic peptoids and its specification. AB - Most of the structural studies made on the secondary structure of peptoids describe their geometric attributes in terms of the classic Ramachandran plot (based on the local analysis of omega, psi, chi, phi dihedral angles). However, little intuitive understanding is available from internal coordinates when stereochemistry is involved. In this contribution we list all the conformationally stable cyclic peptoids reported up to the year 2017 and propose a simple method to define their geometric arrangement in terms of planar chirality. Evidence of conformational isomerism (due to the long average time of single bond rotation) and conformational chirality (induced by the absence of roto-reflection axes) in this promising class of synthetic macrocycles is provided by NMR spectroscopy (using Pirkle's alcohol as chiral solvating agent) and careful evaluation of X-ray crystallographic studies. The full understanding of the oligomeric macrocycles' structural properties and the clear framing of their conformational isomerism in a proper conceptual scheme is fundamental for future application of peptoids in asymmetric synthesis, chiral recognition and supramolecular chemistry. PMID- 29164220 TI - Polycrystalline soft carbon semi-hollow microrods as anode for advanced K-ion full batteries. AB - Soft carbon, which possesses the advantages of low cost and considerable potassium storage capacity, has been widely studied as an anode in K-ion batteries (KIBs). Herein, we constructed a novel polycrystalline semi-hollow microrods-structured soft carbon as an anode in KIBs, which exhibited both high capacity and excellent cycling stability. PMID- 29164221 TI - Selective C-H bond electro-oxidation of benzylic acetates and alcohols to benzaldehydes. AB - A chemical oxidant-free and mediator-free, direct electro-oxidation of both benzylic alcohols and benzylic esters are reported. The scope of the reaction is explored as a function of both steric and electronic effects. Expansion of the scope to non-benzylic and heteroaryl substrates is investigated. Functionalisation of esters and alcohols selectively to the aldehyde oxidation level using a traceless electron approach is reported. PMID- 29164222 TI - Strain-stiffening gels based on latent crosslinking. AB - Gels represent an increasingly important class of soft materials with applications ranging from regenerative medicine to commodity materials. However, gels typically exhibit relative mechanical weakness, which worsens under repeated strain. Here we report a new class of responsive gels with latent crosslinking moieties that exhibit strain-stiffening behavior. This property results from the lability of disulfides, initially isolated in a protected state, then activated to crosslink on-demand. The thiol groups are induced to form inter-chain crosslinks when subjected to mechanical compression, resulting in a gel that strengthens under strain. Molecular shielding design elements regulate the strain sensitivity and spontaneous crosslinking tendencies of the polymer network. These strain-responsive gels represent a rational design of new advanced materials with on-demand stiffening properties and potential applications in elastomers, adhesives, foams, films, and fibers. PMID- 29164223 TI - Output optimized electret nanogenerators for self-powered long-distance optical communication systems. AB - High-speed optical communication systems are built for real-time, massive and remote information exchange. However, any power outage will paralyse the systems and cause a huge loss. Here we constructed a self-powered long-distance optical communication system (SLOCS) utilizing output enhanced parallel connected electret nanogenerators (NGs) as a backup power for the power outage. The output current of the electret NG was promoted from 1.45 MUA to 8.14 MUA through optimizing the thickness of the electret film. In the SLOCS, a coded message was successfully transmitted for 50 meters by pressing electret NGs. The as fabricated SLOCS paves the way to a simple and cost-effective strategy for developing a reliable emergency communication system in case of power outage, simultaneously promoting the progress of self-powered electronics. PMID- 29164224 TI - Surface coatings of silver nanowires lead to effective, high conductivity, high strain, ultrathin sensors. AB - Integrated sensors for bodily measurements require a sensing material that is highly conductive, flexible, thin and sensitive. It is important that these materials are non-invasive in application but robust in nature to allow for effective, continuous measurement. Herein, we report a comparative study of two simple, scalable methods to produce silver nanowire (AgNW) polyurethane (PU) composite materials: layer-by-layer (LBL) and mixed filtration. Both types of composites formed were ultrathin (~50 MUm) and highly conductive (104 S m-1), with the LBL method ultimately found to be superior due to its low percolation threshold. Electrical resistance of the LBL composites was found to vary with strain, making these materials suitable for strain sensing. LBL composites displayed a working strain up to ~250% and a high gauge factor (G), with values of G ~70 reported. The sensors reported here were ~109-times more conductive and ~104-times thinner than their carbon-based composite sensor counterparts with similar gauge factor. This made the strain sensors presented here among one of the most flexible, highly sensitive, thinnest, conductive materials in literature. We demonstrated that with these properties, the LBL composites formed were ideal for bodily motion detection. PMID- 29164225 TI - Amorphous red phosphorus nanosheets anchored on graphene layers as high performance anodes for lithium ion batteries. AB - A facile solution-based method was developed to combine the advantage of amorphous nanoscale red P sheets and highly conductive graphene, forming a high performance P/graphene composite anode for advanced lithium ion batteries. Graphene can be easily expanded into a 3D framework in solution with rich interior porosity and abundant adsorption points, which enables a large percentage of red P to be loaded and form a uniform P/graphene hybrid structure. The nanoscale and amorphous features of red P effectively reduce the volume expansion and mechanical stress within individual P sheets, thereby alleviating P pulverization during cycling. The well dispersed graphene serves as a buffer layer to accommodate the volume expansion and adsorb the stress during electrochemical reactions, thereby maintaining a robust electrode structure. Besides, the highly conductive graphene greatly enhances the ionic/electronic conductivity of the electrode, which favors efficient redox reactions and high P utilization. Based on the superior composite structure, the potentials of both components can be fully exerted, resulting in excellent electrochemical performance. The P/graphene electrode delivered a high reversible capacity of 1286 mA h g-1 based on the weight of the composite after 100 cycles at 200 mA g 1. Even at a high current density of 1000 mA g-1, the composite electrode exhibits a high capacity of 1125 mA h g-1, revealing its potential as a high performance P-carbon composite anode for advanced lithium ion batteries. PMID- 29164226 TI - Nicking enzyme-controlled toehold regulation for DNA logic circuits. AB - DNA strand displacement is widely used in DNA-related nanoengineering for its remarkable specificity and predictability. We report a nicking enzyme-assisted mechanism to regulate strand displacement, where DNA toeholds are dynamically controlled. To demonstrate the strategy, a protein/DNA-based Boolean operation system is constructed and based on it a two-channel multiplexer controlled by three different nicking enzymes is realized. The proposed regulatory mechanism can be used for switch logic statement and bridges protein and DNA logic circuits. PMID- 29164227 TI - Self-assembled monolayer field-effect transistors based on oligo-9,9' dioctylfluorene phosphonic acids. AB - The use of functional oligomers of pi-conjugated oligofluorenes led to a region selective assembly of amorphous monolayers which exhibit robust lateral charge transport pathways in self-assembled monolayer field-effect transistors over long distances and even in mixed monolayers of semiconducting and insulating molecules. This oligomer concept might stimulate a new molecular design of self assembling semiconducting materials. PMID- 29164229 TI - Dermatology Practice Consolidation Fueled by Private Equity Investment: Potential Consequences for the Specialty and Patients. PMID- 29164228 TI - Electromyography-Driven Forward Dynamics Simulation to Estimate In Vivo Joint Contact Forces During Normal, Smooth, and Bouncy Gaits. AB - Computational models that predict in vivo joint loading and muscle forces can potentially enhance and augment our knowledge of both typical and pathological gaits. To adopt such models into clinical applications, studies validating modeling predictions are essential. This study created a full-body musculoskeletal model using data from the "Sixth Grand Challenge Competition to Predict in vivo Knee Loads." This model incorporates subject-specific geometries of the right leg in order to concurrently predict knee contact forces, ligament forces, muscle forces, and ground contact forces. The objectives of this paper are twofold: (1) to describe an electromyography (EMG)-driven modeling methodology to predict knee contact forces and (2) to validate model predictions by evaluating the model predictions against known values for a patient with an instrumented total knee replacement (TKR) for three distinctly different gait styles (normal, smooth, and bouncy gaits). The model integrates a subject specific knee model onto a previously validated generic full-body musculoskeletal model. The combined model included six degrees-of-freedom (6DOF) patellofemoral and tibiofemoral joints, ligament forces, and deformable contact forces with viscous damping. The foot/shoe/floor interactions were modeled by incorporating shoe geometries to the feet. Contact between shoe segments and the floor surface was used to constrain the shoe segments. A novel EMG-driven feedforward with feedback trim motor control strategy was used to concurrently estimate muscle forces and knee contact forces from standard motion capture data collected on the individual subject. The predicted medial, lateral, and total tibiofemoral forces represented the overall measured magnitude and temporal patterns with good root mean-squared errors (RMSEs) and Pearson's correlation (p2). The model accuracy was high: medial, lateral, and total tibiofemoral contact force RMSEs = 0.15, 0.14, 0.21 body weight (BW), and (0.92 < p2 < 0.96) for normal gait; RMSEs = 0.18 BW, 0.21 BW, 0.29 BW, and (0.81 < p2 < 0.93) for smooth gait; and RMSEs = 0.21 BW, 0.22 BW, 0.33 BW, and (0.86 < p2 < 0.95) for bouncy gait, respectively. Overall, the model captured the general shape, magnitude, and temporal patterns of the contact force profiles accurately. Potential applications of this proposed model include predictive biomechanics simulations, design of TKR components, soft tissue balancing, and surgical simulation. PMID- 29164230 TI - Intraocular Pressure and Glaucomatous Optic Neuropathy in High Myopia. AB - Purpose: To examine the association between intraocular pressure (IOP) and the prevalence of glaucomatous optic neuropathy (GON) in high myopia. Methods: The hospital-based observational study consisted of patients treated in the Tokyo High Myopia Clinics and for whom fundus photographs and IOP readings were available. The appearance of the optic nerve head on fundus photographs was the basis for the definition of GON. Results: Among 517 eyes of 261 patients (mean age: 62.1 +/- 14.2 years; range: 13-89 years; mean axial length: 29.5 +/- 2.2 mm; range: 23.2-35.3 mm), GON was present in 141 eyes (27.3%; 95% confidence intervals [CIs]: 23.4, 31.0). Mean IOP did not differ significantly (P = 0.53) between the glaucoma group (14.5 +/- 3.3 mm Hg; median: 14 mm Hg; range: 8-38 mm Hg) and the nonglaucomatous group (14.7 +/- 2.5 mm Hg; median: 14 mm Hg; range: 6 23 mm Hg). In eyes with an axial length of <=27.4 mm, higher presence of GON was correlated only with higher IOP (P = 0.037; odds ratio [OR]:1.35; 95% CI: 1.02, 1.80). In eyes with an axial length of >=27.5 mm, presence of GON was correlated with older age (P < 0.001; OR: 1.05; 95% CI :1.03, 1.08), longer axial length (P < 0.001; OR: 1.60; 95% CI: 1.34, 1.91), shorter vertical diameter of the temporal arterial arcade (P = 0.009; OR: 0.82; 95% CI: 0.71, 0.95), and longer minimal optic disc diameter (P = 0.002; OR: 3.07; 95% CI: 1.52, 6.21). If IOP was added to the model, it was not significantly associated with the prevalence of GON (P = 0.97; OR: 1.00; 95% CI: 0.91, 1.10). Conclusions: GON was associated with elevated IOP in myopic eyes with an axial length of <=27.4 mm, while in more highly myopic eyes (axial length >=27.5 mm), larger optic disc, longer axial elongation and older age-but not IOP mostly within its normal range-were factors associated with GON. Future studies may examine an abnormally low IOP to be associated with a lower GON prevalence in highly myopic eyes. PMID- 29164231 TI - Storage of Porcine Cornea in an Innovative Bioreactor. AB - Purpose: To quantify cell survival and tissue structure preservation of porcine cornea stored in a bioreactor (BR) that recreates a transcorneal pressure gradient equivalent to intraocular pressure (IOP) and renews the medium. Methods: A BR comprising endothelial and epithelial chambers was machined in a biocompatible material. The porcine cornea, securely held, separated the chambers. Medium flow and pressure inside the endothelial chamber were maintained by a peristaltic pump. In the epithelial chamber, the corneal surface was alternatively exposed to air and a specific medium. Two transparent windows allowed thickness measurement by optical coherence tomography without opening the BR. Porcine corneas stored in the BR-on (pressure 20 mm Hg, flow 5 MUL/min, temperature 31 degrees C) were compared with (1) BR-off (no pressure or flow); (2) organ culture; and (3) Petri dish with agar on the endothelial side. Epithelial and limbal structure and differentiation, corneal transparency and thickness, and endothelial viability were compared after 7 days of storage and with fresh corneas. Results: Corneas stored in the BR-on were thinner and more transparent than those stored with the other methods. The BR-on preserved a stratified and differentiated (K3/K12+) corneal epithelium and undifferentiated basal limbal cells with stemness markers (K3/K12-; ABCB5, K14, p75+), as well as endothelial integrity. Conclusions: By recreating equivalent IOP and medium renewal, the BR obtained unprecedented storage quality of porcine corneas and preserved their main epithelial, limbal, and endothelial characteristics. PMID- 29164232 TI - Mast Cell-Derived Tryptase in Geographic Atrophy. AB - Purpose: Our previous study demonstrated significantly more degranulating mast cells (MCs) in choroids from subjects with age-related macular degeneration compared to aged controls. This study examined the immunolocalization of tryptase, the most abundant MC secretory granule-derived serine protease, in aged control eyes and eyes with geographic atrophy (GA). Methods: Postmortem human eyes with and without GA were obtained from the National Disease Research Interchange. Tissue was fixed, cryopreserved, sectioned, and immunostained with a monoclonal antibody against tryptase. Sections were imaged on a Zeiss 710 Confocal Microscope. Results: In the posterior pole of all aged control eyes, tryptase was confined to choroidal MCs, which were located primarily in Sattler's layer. In eyes with GA, many MCs were located in the inner choroid near choriocapillaris and Bruch's membrane (BM). Tryptase was found not only in MCs but also diffusely around them in stroma, suggesting they had degranulated. In contrast with aged control eyes, eyes with GA also had strong tryptase staining in BM. Tryptase was observed within BM in regions of RPE atrophy, at the border of atrophy, and extending well into the nonatrophic region. Conclusions: Our results demonstrate that tryptase, released during choroidal MC degranulation, binds to BM in GA in advance of RPE atrophy. Tryptase activates MMPs that can degrade extracellular matrix (ECM) and basement membrane components found in BM. ECM modifications are likely to have a profound effect on the function and health of RPE and choroidal thinning in GA. PMID- 29164234 TI - Author Response: Concerning Manuscript "Bright Light Suppresses Form-Deprivation Myopia Development With Activation of Dopamine D1 Receptor Signaling in the ON Pathway in Retina". PMID- 29164233 TI - Concerning Manuscript "Bright Light Suppresses Form-Deprivation Myopia Development With Activation of Dopamine D1 Receptor Signaling in the ON Pathway in Retina". PMID- 29164235 TI - Incidence, Progression, and Risk Factors for Cataract in Type 2 Diabetes. AB - Purpose: We report the 4-year incidence, progression, and risk factors of cataract subtypes in type 2 diabetes. Methods: A total of 779 subjects completed baseline and 4-year follow-up. Results: The incidences of nuclear opalescence (NO), nuclear color (NC), cortical cataract (CC), and posterior subcapsular cataract (PSC) were 70%, 55.2%, 25.7%, and 7.3%, respectively. One-step progressions of NO, NC, CC, and PSC were 14.3%, 16.1%, 8.8%, and 8.1%, respectively, and two-step or more progressions were 5.0%, 6.0%, 0.8%, and 6.0%, respectively. Incident NO was seen in patients 50 to 59 (odds ratio [OR] = 3.3), NC in those 50 to 59 (OR = 2.7) and 60 to 69 (OR = 3.9), and CC in those 60 to 69 (OR = 3.3) years old. A lower hemoglobin A1c (HbA1c; OR = 0.7), longer diabetes duration (OR = 1.1), and hyperopia (OR = 4.0) were associated with incident PSC. Women (OR = 1.7) and patients with higher total cholesterol (OR = 1.3) at baseline showed one-step NO progression. Patients 60 to 69 (OR = 2.8) and >=70 (OR = 3.8) years old showed one-step NC progression, while those 60 to 69 years old showed one-step CC progression (OR = 6.3). A lower HbA1c (OR = 0.3) was associated with one-step PSC progression. A higher low-density lipoprotein (OR = 1.6) was associated with two-step or more NO progression. Patients 60 to 69 years old (OR = 6.7) had a greater risk, while those with hyperopia at baseline (OR = 0.2) had lower risk of two-step or more NC progression. Patients 40 to 49 years old constituted the reference group for all. Conclusions: The 4-year cumulative incidence of cataract is higher than that of progression. Greater age is a risk factor for incidence and progression of most types of cataract. PMID- 29164236 TI - Posttranscriptional Regulation of LOXL1 Expression Via Alternative Splicing and Nonsense-Mediated mRNA Decay as an Adaptive Stress Response. AB - Purpose: Alternative mRNA splicing coupled to nonsense-mediated decay (NMD) is a common mRNA surveillance pathway also known to dynamically modulate gene expression in response to cellular stress. Here, we investigated the involvement of this pathway in the regulation of lysyl oxidase-like 1 (LOXL1) expression in response to pseudoexfoliation (PEX)-associated pathophysiologic factors. Methods: Transcript levels of LOXL1 isoforms were determined in ocular tissues obtained from donor eyes without and with PEX syndrome. Pseudoexfoliation-relevant cell types, including human Tenon's capsule fibroblasts (hTCF) and trabecular meshwork cells (hTMC), were exposed to puromycin, caffeine, TGF-beta1, homocysteine, IL-6, retinoic acid, UV-B radiation, oxidative stress, and mechanical stress for up to 48 hours. Western blot analysis was carried out using antibodies against LOXL1, (phosphorylated-) eukaryotic initiation factor 2-alpha (eIF2-alpha), and regulator of nonsense transcripts 2 (UPF2). RNA interference was used to knockdown UPF1-3 and Serine/threonine-protein kinase (SMG1). Results: Constitutive expression of wild-type LOXL1 and alternatively spliced LOXL1-a transcripts was detected in all ocular tissues showing highest levels in trabecular meshwork and differential expression between PEX and control specimens. LOXL1-a transcripts were upregulated in hTCF and hTMC by NMD inhibitors puromycin and caffeine (>=6-fold; P < 0.01) or after knockdown of NMD core factors (>=2-fold; P < 0.05), whereas mRNA and protein levels of LOXL1 were reduced (<=0.8 fold; P < 0.05). Exposure of cells to various PEX-associated (stress) factors, including TGF-beta1, UV-B light, oxidative stress, mechanical stress, and retinoic acid enhanced LOXL1-a transcript levels (>=1.5-fold; P < 0.05), while partially downregulating LOXL1 levels (<=0.7-fold; P < 0.05). Stress induced inhibition of NMD was dependent on phosphorylation of eIF2alpha. Conclusions: These findings provide evidence for a functional role of alternative splicing coupled to NMD in the posttranscriptional regulation of LOXL1 gene expression and suggest this mechanism to represent a dynamic mode of adapting LOXL1 expression to PEX-associated environmental and nutritional cues. PMID- 29164238 TI - Relief for Central Sleep Apnea. PMID- 29164237 TI - Feasibility Study of the 3D Visualization at High Resolution of Intra-Cranial Rabbit Eyes With X-Ray CT Phase-Contrast Imaging. AB - Purpose: The intracranial three-dimensional (3D) visualization of the whole volume of the eyeball at micrometric resolution has not been achieved yet either in clinical nor in preclinical diagnostic research. Overcoming this limitation may provide a new tool for clinical and preclinical studies of different pathologies of the various sections of the eye. The aim of this work is to give the first insight of a volumetric visualization at the high resolution of the entire enucleated and intracranial postmortem rabbit eyeballs. Methods: X-ray computed tomography phase-contrast imaging was used to obtain 3D models of enucleated and intracranial rabbit eyes. Images were compared with the ones measured by using optical coherence tomography (OCT) images. The experiment was carried out at the European Synchrotron Radiation Facility. Results: Combining the unique possibilities offered by phase-contrast imaging, microtomography, and the properties of synchrotron radiation, the 3D visualization of the whole eyeball, at an isotropic voxel size of 3.1 MUm3, is reported here for the first time. Conclusions: High image contrast is achieved without the necessity of injection of contrast agents, thanks to the superior performances, achieved by x ray phase-contrast imaging with respect to the conventional radiographic imaging. The measurement protocol developed within this work opens the way for in vivo high-resolution visualization of the entire organ. PMID- 29164240 TI - Eye Tracking in Surgical Robotics. PMID- 29164239 TI - Twice the Power in New MRI. PMID- 29164241 TI - Advancing High Performance in Veterans Affairs Health Care. PMID- 29164242 TI - Mendelian Randomization. PMID- 29164244 TI - Building Blocks for Addressing Social Determinants of Health. PMID- 29164245 TI - The Soldiers' and Sailors' Insurance Law. PMID- 29164246 TI - Trends in Emergency Department Visits for Nonfatal Self-inflicted Injuries Among Youth Aged 10 to 24 Years in the United States, 2001-2015. PMID- 29164247 TI - Consequences of Reductions in Hospital Readmissions. PMID- 29164248 TI - Patient-Reported Symptom Monitoring During Chemotherapy. PMID- 29164249 TI - Medical Device Identification in Claims Data. PMID- 29164250 TI - Consequences of Reductions in Hospital Readmissions-Reply. PMID- 29164251 TI - Patient-Reported Symptom Monitoring During Chemotherapy-Reply. PMID- 29164253 TI - Pancreatic Enzyme Replacement Products. PMID- 29164252 TI - Medical Device Identification in Claims Data-Reply. PMID- 29164256 TI - Treatments for Food Allergies. PMID- 29164254 TI - Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes: A Randomized Clinical Trial. AB - Importance: Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect. Objective: To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes. Design, Setting, and Participants: Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016. Interventions: Randomization to receive 7.5 mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186). Main Outcome and Measures: The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported. Results: Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7 12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5-4.6 years) in the main study group, diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes was not significantly different between the 2 groups (hazard ratio [HR], 0.87; 95% CI, 0-1.2; P = .21). In secondary stratum 1 (n = 55), diabetes was diagnosed in 13 participants (48.1%) in the oral insulin group and in 19 participants (70.3%) in the placebo group. The time to diabetes was significantly longer with oral insulin (HR, 0.45; 95% CI, 0-0.82; P = .006). The HR for time to diabetes for the between-group comparisons for the 116 participants in the other secondary stratum was 1.03 (95% CI, 0-2.11; P = .53) and for the entire cohort of 560 participants was 0.83 (95% CI, 0-1.07; P = .11), which were not significantly different. The most common adverse event was infection (n = 254), with 134 events in the oral insulin group and 120 events in the placebo group, but no significant study-related adverse events occurred. Conclusions and Relevance: Among autoantibody-positive relatives of patients with type 1 diabetes, oral insulin at a dose of 7.5 mg/d, compared with placebo, did not delay or prevent the development of type 1 diabetes over 2.7 years. These findings do not support oral insulin as used in this study for diabetes prevention. Trial Registration: clinicaltrials.gov Identifier: NCT00419562. PMID- 29164258 TI - My Tenuous Relationship With an Octopus. PMID- 29164255 TI - Effect of an Indwelling Pleural Catheter vs Talc Pleurodesis on Hospitalization Days in Patients With Malignant Pleural Effusion: The AMPLE Randomized Clinical Trial. AB - Importance: Indwelling pleural catheter and talc pleurodesis are established treatments for malignant pleural effusions among patients with poor prognosis. Objective: To determine whether indwelling pleural catheters are more effective than talc pleurodesis in reducing total hospitalization days in the remaining lifespan of patients with malignant pleural effusion. Design, Setting, and Participants: This open-label, randomized clinical trial included participants recruited from 9 centers in Australia, New Zealand, Singapore, and Hong Kong between July 2012 and October 2014; they were followed up for 12 months (study end date: October 16, 2015). Patients (n = 146) with symptomatic malignant pleural effusion who had not undergone indwelling pleural catheter or pleurodesis treatment were included. Interventions: Participants were randomized (1:1) to indwelling pleural catheter (n = 74) or talc pleurodesis (n = 72), minimized by malignancy (mesothelioma vs others) and trapped lung (vs not), and stratified by region (Australia vs Asia). Main Outcomes and Measures: The primary end point was the total number of days spent in hospital from procedure to death or to 12 months. Secondary outcomes included further pleural interventions, patient reported breathlessness, quality-of-life measures, and adverse events. Results: Among the 146 patients who were randomized (median age, 70.5 years; 56.2% male), 2 withdrew before receiving the randomized intervention and were excluded. The indwelling pleural catheter group spent significantly fewer days in hospital than the pleurodesis group (median, 10.0 [interquartile range [IQR], 3-17] vs 12.0 [IQR, 7-21] days; P = .03; Hodges-Lehmann estimate of difference, 2.92 days; 95% CI, 0.43-5.84). The reduction was mainly in effusion-related hospitalization days (median, 1.0 [IQR, 1-3] day with the indwelling pleural catheter vs 4.0 (IQR, 3 6) days with pleurodesis; P < .001; Hodges-Lehmann estimate, 2.06 days; 95% CI, 1.53-2.58). Fewer patients randomized to indwelling pleural catheter required further ipsilateral invasive pleural drainages (4.1% vs 22.5%; difference, 18.4%; 95% CI, 7.7%-29.2%). There were no significant differences in improvements in breathlessness or quality of life offered by indwelling pleural catheter or talc pleurodesis. Adverse events were seen in 22 patients in the indwelling pleural catheter group (30 events) and 13 patients in the pleurodesis group (18 events). Conclusions and Relevance: Among patients with malignant pleural effusion, treatment with an indwelling pleural catheter vs talc pleurodesis resulted in fewer hospitalization days from treatment to death, but the magnitude of the difference is of uncertain clinical importance. These findings may help inform patient choice of management for pleural effusion. Trial Registration: anzctr.org.au Identifier: ACTRN12611000567921. PMID- 29164260 TI - Two Southeast Asian Countries Eliminate Trachoma. PMID- 29164261 TI - High Mercury Levels Found in Women Around the World. PMID- 29164262 TI - Child Mortality Rates Decrease in India. PMID- 29164263 TI - Plasma Leptin and Premenstrual Syndrome: A Review. AB - Importance: Premenstrual syndrome (PMS) is characterized by physical and psychological symptoms in the luteal phase. Leptin can influence PMS as it acts on the hypothalamic-pituitary-gonadal axis. Objective: The aim of this study was to evaluate data in the literature about the profile of plasma leptin in women with PMS. Evidence Acquisition: We performed a search of databases using both descriptors. Three studies were identified. They included 181 participants. Two of these studies found higher leptin levels in women with PMS. Results: Conflicting results were found regarding the leptin levels in the luteal phase and the correlation between leptin, estradiol, and progesterone levels. Conclusions and Relevance: Leptin could have a role in the pathophysiology of PMS and indicate degree of severity of PMS. Future studies on the role of leptin in PMS are needed. PMID- 29164264 TI - Risks and Benefits of Salpingectomy at the Time of Sterilization. AB - Importance: Bilateral salpingectomy reduces the risk ovarian cancer. The Society of Gynecologic Oncology has recommended surgeons discuss salpingectomy with patients desiring sterilization. Objective: This review summarizes current literature on the benefits and risks of bilateral salpingectomy to reduce ovarian cancer risk. Areas of insufficient evidence and directions for further research are discussed. Evidence Acquisition: We examined the benefits and risks of bilateral salpingectomy for female surgical sterilization, using a PubMed and EMBASE literature review. Search parameters included articles in English language and keywords "salpingectomy" or "ovarian cancer" combined with "contraception," "sterilization," or "tubal ligation." Results: We reviewed 4 high-quality studies that investigated the increased risk reduction of bilateral salpingectomy compared with traditional sterilization. Overall, evidence shows that salpingectomy moderately decreases the risk of ovarian cancer compared with traditional sterilization. An additional 4 studies, including a meta-analysis, showed salpingectomy likely does not have significant long-term impact on ovarian reserve. Additional benefits include improved contraceptive efficacy and elimination of subsequent ectopic pregnancies. Risks include need for in vitro fertilization for patients experiencing sterilization regret, increases in operative time, and potential increases in surgical risks. Conclusions: Bilateral salpingectomy can reduce ovarian cancer risk compared with traditional sterilization; however, research regarding other outcomes is limited. Challenges to implementation include physician concern regarding surgical risks and patient education. Studies investigating patient-based outcomes are lacking. Relevance: Bilateral salpingectomy for surgical sterilization is a reasonable option when patients are appropriately informed. Ovarian cancer risk reduction should be one of several factors considered when patients choose a surgical sterilization method. PMID- 29164265 TI - The Power and Pitfalls of Big Data Research in Obstetrics and Gynecology: A Consumer's Guide. AB - Importance: Research in obstetrics and gynecology (OB/GYN) increasingly relies on "big data" and observational study designs. There is a gap in practitioner relevant guides to interpret and critique such research. Objective: This guide is an introduction to interpreting research using observational data and provides explanations and context for related terminology. In addition, it serves as a guide for critiquing OB/GYN studies that use observational data by outlining how to assess common pitfalls of experimental and observational study designs. Lastly, the piece provides a compendium of observational data resources commonly used within OB/GYN research. Evidence Acquisition: Review of literature was conducted for the collection of definitions and examples of terminology related to observational data research. Data resources were collected via Web search and researcher recommendations. Next, each data resource was reviewed and analyzed for content and accessibility. Contents of data resources were organized into summary tables and matched to relevant literature examples. Results: We identified 26 observational data resources frequently used in secondary analysis for OB/GYN research. Cost, accessibility considerations for software/hardware capabilities, and contents of each data resource varied substantially. Conclusions and Relevance: Observational data sources can provide researchers with a variety of options in tackling their research questions related to OB/GYN practice, patient health outcomes, trends in utilization of medications/procedures, or prevalence estimates of disease states. Insurance claims data resources are useful for population-level prevalence estimates and utilization trends, whereas electronic health record-derived data and patient survey data may be more useful for exploring patient behaviors and trends in practice. PMID- 29164266 TI - Nationwide study highlights a second peak in ACL tears for women in their early forties. AB - PURPOSE: Anterior cruciate ligament (ACL) rupture continues to be a focus of research on knee injuries. Despite this, data on the total number of ruptures on a national basis including both reconstructed (ACLR) and non-reconstructed injuries are limited. The purpose of this study was to describe the national incidence of MRI diagnosed ACL ruptures in Iceland and its subsequent rate of operation with regard to sex and age. METHODS: All MRI knee reports taken in Iceland between 2006 and 2011 were gathered to identify ACL ruptures. Software was written to search for phrases relating to ACL rupture. Duplicate records were removed and yearly incidence for sex and age groups was determined. Data from the Icelandic Social Insurance Administration were used identify all those who were operated and to determine the yearly incidence of ACLR. General additive models were used assuming either a Poisson or binomial distribution to model ACL rupture incidence and ACLR rate, respectively. RESULTS: The average age was 33.9 (95% CI 33.1-34.6; Table 1). The average incidence of ACL tears per year was 75.1 (95% CI 71.3-79.1) per 100,000 person-years. For males the peak incidence was in their early twenties. Females showed two peaks, one in their teens and another in their forties resulting in an older average age at rupture compared to males (35 +/- 16 vs 33 +/- 13, p = 0.06). The main effects of age and sex and their interaction were significant (p < 0.001). The average incidence of ACLR was 39.4 (95% CI 36.7 42.4) per 100,000 person-years. Those operated were significantly younger than those who were not (27 +/- 10 vs 42 +/- 15 years, p < 0.001). The main effects of age and the interaction between sex and age were significant (p < 0.001). CONCLUSION: This nationwide study indicates that ACL rupture incidence may be higher than previously thought, implying an underestimated impact of the burden of this serious knee injury. The incidence of injury peaked twice in the female population, a result not previously reported. Older persons are less likely to undergo ACLR and, therefore, sex-dependent differences in overall mean age at injury are contrary to previous reports. These data suggest that prevention programs focused solely on young girls should be extended to older women who are returning to sports. LEVEL OF EVIDENCE: II. PMID- 29164267 TI - Intracellular apoptotic pathways: a potential target for reducing joint damage in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that results in both local and systemic bone erosion, causing significant joint deformities and functional disability. The increased number of synovial fibroblasts, inflammatory cells and osteoclasts in RA is associated with reduced apoptosis in these cells. The ability to modulate the cell proliferation or death (particularly apoptosis) is recognised for its immense therapeutic potential. Identifying new therapeutics to assist in stimulating apoptosis within the synovial joints therefore may be beneficial in reducing inflammation and bone loss in RA patients. In this review, the roles of anti-apoptotic proteins that are upregulated in RA synovial joints will be discussed in relation to their actions on bone destruction and inflammation. Evidence recently published suggests that intracellular apoptotic inhibitory molecules can be targeted by current or new therapeutics to reduce joint damage in RA. However, the therapeutics that target these molecules are yet to reach clinical trial stages. Even so it is evident that understanding the upregulation of anti-apoptotic molecules in RA is required to improve treatments currently available for RA patients. PMID- 29164268 TI - Mapping of the binding sites of human diamine oxidase (DAO) monoclonal antibodies. AB - OBJECTIVE: Recently we characterized five mouse monoclonal antibodies that allow the specific and sensitive detection of human diamine oxidase (DAO). To understand differences in binding characteristics and recognition of enzyme variants, we mapped the antibody binding sites. METHODS: Fragments of human DAO were expressed as glutathione-S-transferase fusion proteins that were used for testing antibody binding on immunoblots. Combined information from species cross reactivity, sequence comparison and binding site-prediction software were used to localize the epitope recognized by each antibody. RESULTS: All five monoclonal DAO antibodies bound to linear epitopes between the N3 and enzymatic domains of the 732 amino acid protein. The binding sites could be mapped onto amino acid regions V262-E278 and P279-R288, respectively, which exhibit considerable sequence variation in mammals explaining the fact that the human DAO antibodies do not cross-react with DAO from other species. The antibodies efficiently bind only denatured human DAO but not the native protein. CONCLUSIONS: Characterization of the binding sites of the DAO antibodies revealed that the antibodies bind two adjacent epitopes and exhibit similar binding characteristics and species cross-reactivity. As the epitopes do not overlap any of the amino acid substitutions described for clinically significant DAO gene polymorphisms, our antibodies will also be useful for analyses of the mutant DAO proteins. PMID- 29164269 TI - [Postoperative radiation therapy for prostate cancer : Still no genomic risk profiling for clinical routine]. PMID- 29164270 TI - Long-term outcomes in patients younger than 60 years of age treated with brachytherapy for prostate cancer. AB - PURPOSE: The purpose of the study was to report the outcomes and late toxicities in patients younger than 60 years of age with long-term follow-up treated with low dose rate (LDR) brachytherapy for localized prostate cancer. METHODS: Between January 2000 and December 2009, 270 consecutive patients were treated with favourable localized prostate cancer; the median follow-up was 111 months (range 21-206). All patients received one implant of LDR brachytherapy. Toxicity was reported according to the Common Toxicity Criteria for Adverse Events, Version 4.0 (CTAE v4.02) by the National Cancer Institute. RESULTS: The overall survival according to Kaplan-Meier estimates was 99 (+/-1%) at 17 years. The 17-year rate for failure in tumour-free survival (TFS) was 97% (+/-1%), whereas for biochemical control it was 95% (+/-1%) at 17 years, 97% (+/-1%) of patients being free of local recurrence. No intraoperative or perioperative complications occurred. Acute genitourinary (GU) grade II toxicity was 4% at 12 months. No other chronic toxicity was observed after treatment. At 6 months, 94% of patients reported no change in bowel function. CONCLUSIONS: LDR brachytherapy provides patients younger than 60 years of age with low and intermediate-risk prostate cancer excellent outcomes and has a low risk of significant long-term GU or gastrointestinal morbidity. PMID- 29164271 TI - Bacteriophages targeting intestinal epithelial cells: a potential novel form of immunotherapy. AB - In addition to their established role as a physical barrier to invading pathogens and other harmful agents, intestinal epithelial cells (IEC) are actively involved in local immune reactions. In the past years, evidence has accumulated suggesting the role of IEC in the immunopathology of intestinal inflammatory disorders (IBD). Recent advances in research on bacteriophages strongly suggest that-in addition to their established antibacterial activity-they have immunomodulating properties that are potentially useful in the clinic. We suggest that these immunomodulating phage activities targeting IEC may open novel treatment perspectives in disorders of the alimentary tract, particularly IBD. PMID- 29164273 TI - Mapping and characterization of wheat stem rust resistance genes SrTm5 and Sr60 from Triticum monococcum. AB - KEY MESSAGE: The new stem rust resistance gene Sr60 was fine-mapped to the distal region of chromosome arm 5AmS, and the TTKSK-effective gene SrTm5 could be a new allele of Sr22. The emergence and spread of new virulent races of the wheat stem rust pathogen (Puccinia graminis f. sp. tritici; Pgt), including the Ug99 race group, is a serious threat to global wheat production. In this study, we mapped and characterized two stem rust resistance genes from diploid wheat Triticum monococcum accession PI 306540. We mapped SrTm5, a previously postulated gene effective to Ug99, on chromosome arm 7AmL, completely linked to Sr22. SrTm5 displayed a different race specificity compared to Sr22 indicating that they are distinct. Sequencing of the Sr22 homolog in PI 306540 revealed a novel haplotype. Characterization of the segregating populations with Pgt race QFCSC revealed an additional resistance gene on chromosome arm 5AmS that was assigned the official name Sr60. This gene was also effective against races QTHJC and SCCSC but not against TTKSK (a Ug99 group race). Using two large mapping populations (4046 gametes), we mapped Sr60 within a 0.44 cM interval flanked by sequenced-based markers GH724575 and CJ942731. These two markers delimit a 54.6-kb region in Brachypodium distachyon chromosome 4 and a 430-kb region in the Chinese Spring reference genome. Both regions include a leucine-rich repeat protein kinase (LRRK123.1) that represents a potential candidate gene. Three CC-NBS-LRR genes were found in the colinear Brachypodium region but not in the wheat genome. We are currently developing a Bacterial Artificial Chromosome library of PI 306540 to determine which of these candidate genes are present in the T. monococcum genome and to complete the cloning of Sr60. PMID- 29164274 TI - Detection and Sizing of Ti-Containing Particles in Recreational Waters Using Single Particle ICP-MS. AB - Single particle inductively coupled plasma mass spectrometry (spICP-MS) was used to detect Ti-containing particles in heavily-used bathing areas of a river (Salt River) and five swimming pools. Ti-containing particle concentrations in swimming pools ranged from 2.8 * 103 to 4.4 * 103 particles/mL and were an order of magnitude lower than those detected in the Salt River. Measurements from the Salt River showed an 80% increase in Ti-containing particle concentration over baseline concentration during peak recreational activity (at 16:00 h) in the river. Cloud point extraction followed by transmission electron microscopy with energy dispersive X-ray analysis confirmed presence of aggregated TiO2 particles in river samples, showing morphological similarity to particles present in an over-the-counter sunscreen product. The maximum particle mass concentration detected in a sample from the Salt River (659 ng/L) is only slightly lower than the predicted no effect concentration for TiO2 to aquatic organisms (< 1 MUg/L). PMID- 29164276 TI - Physical Activity and Heart Rate Variability in Adolescents with Abdominal Obesity. AB - Physical activity is a protective factor for autonomic dysfunction. However, whether this occurs in adolescents with abdominal obesity is still unclear. Thus, the aim of this study was to analyze the association between physical activity and heart rate variability (HRV) in adolescents with and without abdominal obesity. This cross-sectional study included 1152 boys (age: 17 +/- 1 years). HRV measures of time (root mean square of the squared differences between adjacent normal RR intervals-RMSSD and the percentage of adjacent intervals over 50 ms PNN50) and frequency domains (balance sympathetic-vagal-LF/HF) were evaluated, as well as total physical activity, commuting physical activity, leisure-time physical activity, and abdominal obesity. All physical activity domains were associated with better RMSSD, PNN50, and LF/HF in normal weight adolescents (p < 0.05), whereas in adolescents with abdominal obesity only leisure-time physical activity was associated with better PNN50 (b = 0.174, p = 0.035) independent of age, period of the day, body mass index, and blood pressure. In conclusion, higher leisure-time physical activity, but not total and commuting physical activity levels, was associated with improved HRV in adolescents with abdominal obesity. PMID- 29164275 TI - DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA1c levels: a systematic review and replication in a case-control sample of the Lifelines study. AB - AIMS/HYPOTHESIS: Epigenetic mechanisms may play an important role in the aetiology of type 2 diabetes. Recent epigenome-wide association studies (EWASs) identified several DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA1c levels. Here we present a systematic review of these studies and attempt to replicate the CpG sites (CpGs) with the most significant associations from these EWASs in a case-control sample of the Lifelines study. METHODS: We performed a systematic literature search in PubMed and EMBASE for EWASs to test the association between DNA methylation and type 2 diabetes and/or glycaemic traits and reviewed the search results. For replication purposes we selected 100 unique CpGs identified in peripheral blood, pancreas, adipose tissue and liver from 15 EWASs, using study-specific Bonferroni-corrected significance thresholds. Methylation data (Illumina 450K array) in whole blood from 100 type 2 diabetic individuals and 100 control individuals from the Lifelines study were available. Multivariate linear models were used to examine the associations of the specific CpGs with type 2 diabetes and glycaemic traits. RESULTS: From the 52 CpGs identified in blood and selected for replication, 15 CpGs showed nominally significant associations with type 2 diabetes in the Lifelines sample (p < 0.05). The results for five CpGs (in ABCG1, LOXL2, TXNIP, SLC1A5 and SREBF1) remained significant after a stringent multiple-testing correction (changes in methylation from -3% up to 3.6%, p < 0.0009). All associations were directionally consistent with the original EWAS results. None of the selected CpGs from the tissue specific EWASs were replicated in our methylation data from whole blood. We were also unable to replicate any of the CpGs associated with HbA1c levels in the healthy control individuals of our sample, while two CpGs (in ABCG1 and CCDC57) for fasting glucose were replicated at a nominal significance level (p < 0.05). CONCLUSIONS/INTERPRETATION: A number of differentially methylated CpGs reported to be associated with type 2 diabetes in the EWAS literature were replicated in blood and show promise for clinical use as disease biomarkers. However, more prospective studies are needed to support the robustness of these findings. PMID- 29164272 TI - Signaling pathways and mesenchymal transition in pediatric high-grade glioma. AB - Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal types of cancer in children. In recent years, it has become evident that these tumors are driven by epigenetic events, mainly mutations involving genes encoding Histone 3, setting them apart from their adult counterparts. These tumors are exceptionally resistant to chemotherapy and respond only temporarily to radiotherapy. Moreover, their delicate location and diffuse growth pattern make complete surgical resection impossible. In many other forms of cancer, chemo- and radioresistance, in combination with a diffuse, invasive phenotype, are associated with a transcriptional program termed the epithelial-to-mesenchymal transition (EMT). Activation of this program allows cancer cells to survive individually, invade surrounding tissues and metastasize. It also enables them to survive exposure to cytotoxic therapy, including chemotherapeutic drugs and radiation. We here suggest that EMT plays an important, yet poorly understood role in the biology and therapy resistance of pHGG and DIPG. This review summarizes the current knowledge on the major signal transduction pathways and transcription factors involved in the epithelial-to mesenchymal transition in cancer in general and in pediatric HGG and DIPG in particular. Despite the fact that the mesenchymal transition has not yet been specifically studied in pHGG and DIPG, activation of pathways and high levels of transcription factors involved in EMT have been described. We conclude that the mesenchymal transition is likely to be an important element of the biology of pHGG and DIPG and warrants further investigation for the development of novel therapeutics. PMID- 29164277 TI - High prevalence of dengue antibodies and the arginine variant of the FcgammaRIIa polymorphism in asymptomatic individuals in a population of Minas Gerais State, Southeast Brazil. AB - Dengue is the most prevalent arthropod-borne viral illness in humans worldwide. Single-nucleotide polymorphisms (SNPs) in genes involved in the immune response, such as dendritic cell-specific intercellular adhesion molecule-3-grabbing non integrin (DC-SIGN), IgG Fc receptor II-A (FcgammaRIIa), vitamin D receptor (VDR), and tumor necrosis factor alpha (TNF-alpha), were previously reported to be associated with susceptibility to dengue disease in different human populations. Therefore, due to the relevant association of host immune and genetic status with disease susceptibility/severity of dengue, this work aims to verify the frequency of anti-dengue virus antibodies and some dengue-associated risk SNPs in a population in Minas Gerais State, Southeast Brazil. A total of 1560 individuals were genotyped for polymorphisms in DC-SIGN (rs4804803), FcgammaRIIa (rs1801274), VDR (rs7975232), and TNF-alpha (rs1800629). The presence of anti-dengue antibodies (IgM and/or IgG) in these samples was also assayed. Anti-dengue antibodies were detected at an overall frequency of 16.86%, indicating a virus infection in asymptomatic individuals. The genotypic frequencies of all SNPs studied did not differ between the asymptomatic and control groups. Regarding the allelic frequencies of the four SNPs analyzed, a higher frequency was detected of the G allele of FcgammaRIIa/rs1801274 in the asymptomatic individuals when compared to that in the control group (p = 0.03). Therefore, the results showed a high prevalence of asymptomatic individuals in Minas Gerais State, with a potential association between the presence of the G allele of FcgammaRIIa/rs1801274 and protection against symptomatic disease. PMID- 29164278 TI - Metals and Organohalogen Contaminants in Bald Eagles (Haliaeetus leucocephalus) from Ontario, 1991-2008. AB - We examined the degree of exposure of lead (Pb), mercury (Hg), and several organohalogen contaminants and its potential impact on survival of bald eagles in Ontario from 1991 to 2008. Overall, results for 43 dead or dying bald eagles collected in the province indicate that 23% (10/43) of birds died of Pb poisoning and 9% (4/43) died of suspected Hg poisoning. Pb poisoning was diagnosed based on exceedances of toxicity thresholds in liver and kidney and supported by clinical observations, necropsy results, and histology findings when available. Evidence for Hg poisoning in eagles was limited; however, Hg concentrations exceeded the toxicity threshold in kidney. Pb concentrations ranged widely in liver and kidney. Total Hg concentrations were relatively higher in kidney compared with liver and were significantly correlated with selenium (Se) concentrations in both tissues. Concentrations of p,p'-DDE and sum PCBs in livers of 12 bald eagles collected from 2001 to 2004 were likely below concentrations associated with adverse effects. Hepatic concentrations of total polybrominated diphenyl ethers were generally higher in birds collected from southern Ontario compared with northern Ontario. Potential impacts of exposure to these flame retardants and others are not known. Elevated metal exposure appears to influence survivorship and may affect the recovery of bald eagles in the province, particularly in southern Ontario and along the Great Lakes where a disproportionate number of poisoned eagles were collected. Increased efforts are needed to identify sources of exposure and develop measures to reduce metal exposure in this top predator. PMID- 29164279 TI - Elemental Concentrations in Roadside Dust Along Two National Highways in Northern Vietnam and the Health-Risk Implication. AB - There is a need to assess the risk of exposure to metals via roadside dust in Vietnam where many people live along the road/highways and are constantly exposed to roadside dust. In this study, we collected dust samples at 55 locations along two major Highways in north-east Vietnam, which passed through different land use areas. Samples were sieved into three different particle sizes and analyzed for concentrations of eight metals using a X-ray fluorescence instrument. The concentrations and environmental indices (EF, I geo) of metals were used to evaluate the degree of pollution in the samples. Among different land uses, industrial areas could be highly polluted with heavy metals in roadside dust, followed by commerce and power plants. Additionally, the traffic density probably played an important role; higher concentrations were observed in samples from Highway No. 5 where traffic is several times higher than Highway No. 18. According to the risk assessment, Cr poses the highest noncarcinogenic risk even though the health hazard index values of assessed heavy metals in this study were within the acceptable range. Our assessment also found that the risk of exposure to heavy metals through roadside dust is much higher for children than for adults. PMID- 29164280 TI - Functional brain networks involved in decision-making under certain and uncertain conditions. AB - PURPOSE: The aim of this study was to describe imaging markers of decision-making under uncertain conditions in normal individuals, in order to provide baseline activity to compare to impaired decision-making in pathological states. METHODS: In this cross-sectional study, 19 healthy subjects ages 18-35 completed a novel decision-making card-matching task using a Phillips T3 Scanner and a 32-channel head coil. Functional data were collected in six functional runs. In one condition of the task, the participant was certain of the rule to apply to match the cards; in the other condition, the participant was uncertain. We performed cluster-based comparison of the two conditions using FSL fMRI Expert Analysis Tool and network-based analysis using MATLAB. RESULTS: The uncertain > certain comparison yielded three clusters-a midline cluster that extended through the midbrain, the thalamus, bilateral prefrontal cortex, the striatum, and bilateral parietal/occipital clusters. The certain > uncertain comparison yielded bilateral clusters in the insula, parietal and temporal lobe, as well as a medial frontal cluster. A larger, more connected functional network was found in the uncertain condition. CONCLUSION: The involvement of the insula, parietal cortex, temporal cortex, ventromedial prefrontal cortex, and orbitofrontal cortex of the certain condition reinforces the notion that certainty is inherently rewarding. For the uncertain condition, the involvement of the prefrontal cortex, parietal cortex, striatum, thalamus, amygdala, and hippocampal involvement was expected, as these are areas involved in resolving uncertainty and rule updating. The involvement of occipital cortical involvement and midbrain involvement may be attributed to increased visual attention and increased motor control. PMID- 29164281 TI - Monitoring of post-mortem changes of saliva N-glycosylation by nano LC/MS. AB - The estimation of post-mortem interval (PMI) is a crucial part for investigations of crime and untimely deaths in forensic science. However, standard methods of PMI estimation are easily confounded by extenuating circumstances and/or environmental factors. Therefore, a panel of PMI markers obtained from a more acceptable and accurate method is necessary to definitely determine time of death. Saliva, one of the vital fluids encountered at crime scenes, contains various glycoproteins that are highly affected by biochemical environment. Here, we investigated saliva N-glycans between live and dead rats to determine the alteration of N-glycans using an animal model system because of the limitation of saliva collection from recently deceased humans. Rat saliva samples were collected both before and after death. N-Glycans were enzymatically released by PNGase F without any glycoprotein extraction. Released native glycans were purified and enriched by PGC-SPE. About 100 N-glycans were identified, profiled, and structurally elucidated by nano LC/MS and tandem MS. Sialylated N-glycans were exclusively present in abundance in live rat saliva whereas non-sialylated N glycans including LacdiNAc disaccharides were detected in high level following death. Through in-depth investigations using quantitative comparison and statistical analysis, 14 N-glycans that significantly changed after death were identified as the potential marker candidates for PMI estimation. To the best of our knowledge, this is the first study to monitor the post-mortem changes of saliva glycosylation, with obvious forensic applications. PMID- 29164282 TI - Analysis of bronopol (2-bromo-2-nitropropan-1, 3-diol) residues in rice (Oryza sativa L.) by SPE using Bond Elut Plexa and liquid chromatography-tandem mass spectrometry. AB - A novel method has been developed for the direct, sensitive, and rapid detection of bronopol in rice using a simple solid-phase extraction (SPE) procedure followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), with electrospray ionization (ESI). Bronopol was stable under acidic conditions, and an acidic environment was thus needed before sample loading to ensure the stability of bronopol. Rice extracts containing bronopol were pretreated using a hydrophilic-lipophilic balanced (Bond Elut Plexa) cartridge to reduce the matrix effect. An XDB-C18 column (150 mm * 2.1 mm, 3.5 MUm) was used for chromatographic separations, with a mobile phase comprising methanol and aqueous ammonium formate (5 mM). The linearity of the method was satisfactory with regression coefficient (R 2) = 0.9992. The limit of quantification was 3.3 MUg kg-1. Three spiked levels (25, 125 and 625 MUg kg-1) were used to determine the recovery of bronopol, which was found to be 73.3-96.7%, with relative standard deviations (RSD) in the range 1.2-7.9%. The RSD for intra-day precision (n = 7) was 7.6% and the RSD for inter day precision (n = 15) was 8.3%. The newly developed analytical method was successfully used to quantify bronopol in rice samples. PMID- 29164283 TI - Gastric cancer metastatic to neck lipoma: a case report with imaging consideration. AB - A 71-year-old man visited our hospital for examination of a soft neck mass. Computed tomography and magnetic resonance imaging scans showed a well circumscribed large lipomatous tumor with multiple nodules inside. Atypical lipomatous tumor or lipoma involving the lymph nodes was considered. Pathological examination of the surgical specimen suggested typical lipoma including multiple metastatic foci from gastric cancer. Subsequent endoscopy revealed a gastric tumor, which was histologically proven to be signet-ring cell carcinoma. Considering these findings, this case was diagnosed as tumor-to-tumor metastasis to lipoma. We present the first such case with imaging and clinical characteristics. PMID- 29164284 TI - Uncommon observation of bifocal giant subchondral cysts in the hip: diagnostic role of CT arthrography and MRI, with pathological correlation. AB - Subchondral cysts (or geodes) are common in osteoarthritis (OA), usually in association with other typical signs, i.e., joint space narrowing, subchondral bone sclerosis, and osteophytosis. However, large lesions without the typical signs of OA or lesions located outside the weight-bearing areas are unusual and may be confused for other conditions, in particular, those of tumoral origin. We report the findings in a 48-year-old man who had been complaining of left buttock pain for 3 years, getting worse over the last year, and an evolutive limited range of motion of the hip. The pain was increased by weight-bearing and was not relieved by nonsteroidal anti-inflammatory drugs. Radiographs and CT showed a large multilocular lytic lesion within the femoral head and a large lytic lesion in the left ilio-ischiatic ramus, raising the question of bifocal tumoral involvement. On MRI, the lesions had low signal intensity on T1- and high signal intensity on T2-weighted MR images, with subtle peripheral enhancement on post contrast T1-weighted images. CT arthrography, by demonstrating a communication between the femoral head and ischiatic cysts and the joint space allowed us to definitively rule out malignant conditions and to make the diagnosis of subchondral bone cysts. Total hip arthroplasty was performed. Pathological analysis of the resected femoral head and of material obtained at curettage of the ischiatic lesion confirmed the diagnosis of degenerative geodes. This case illustrates an atypical bifocal location of giant subchondral cysts in the hip joint mimicking lytic tumors, in the absence of osteoarthritis or rheumatoid arthritis, and highlights the role of CT arthrography in identifying this condition. PMID- 29164287 TI - Prolonged hospital stay before hip fracture surgery in the elderly: a single parameter but multiple roles. PMID- 29164285 TI - Referent control of the orientation of posture and movement in the gravitational field. AB - This study addresses the question of how posture and movement are oriented with respect to the direction of gravity. It is suggested that neural control levels coordinate spatial thresholds at which multiple muscles begin to be activated to specify a referent body orientation (RO) at which muscle activity is minimized. Under the influence of gravity, the body is deflected from the RO to an actual orientation (AO) until the emerging muscle activity and forces begin to balance gravitational forces and maintain body stability. We assumed that (1) during quiet standing on differently tilted surfaces, the same RO and thus AO can be maintained by adjusting activation thresholds of ankle muscles according to the surface tilt angle; (2) intentional forward body leaning results from monotonic ramp-and-hold shifts in the RO; (3) rhythmic oscillation of the RO about the ankle joints during standing results in body swaying. At certain sway phases, the AO and RO may transiently overlap, resulting in minima in the activity of multiple muscles across the body. EMG kinematic patterns of the 3 tasks were recorded and explained based on the RO concept that implies that these patterns emerge due to referent control without being pre-programmed. We also confirmed the predicted occurrence of minima in the activity of multiple muscles at specific body configurations during swaying. Results re-affirm previous rejections of model-based computational theories of motor control. The role of different descending systems in the referent control of posture and movement in the gravitational field is considered. PMID- 29164286 TI - Effect of a cognitive task and light finger touch on standing balance in healthy adults. AB - The purpose of the study was to investigate the individual and combined effects of applying light finger touch and performing a cognitive task on postural sway. Fourteen healthy young individuals stood on the force platform with light finger touch contact applied to an external stable structure and without finger touch. Both tasks were performed with and without a cognitive task (counting backward from a randomly chosen three-digit number). The center of pressure excursion and velocity as well as sway area were calculated. Participants demonstrated significantly smaller postural sway in the presence of a finger touch contact (p < 0.05), while postural sway was increased during the performance of the cognitive task (p < 0.05). When two tasks were performed simultaneously, body sway increased as compared to standing with light touch only (p < 0.05) and decreased when compared to standing and performing the cognitive task only (p < 0.05). This suggests that a positive effect of finger touch on body sway could be diminished by the simultaneous performance of a cognitive task. The outcome provides a foundation for future studies of the individual and combined effects of light finger touch and cognitive tasks on postural control. PMID- 29164288 TI - Correction to: The Kidney, Liver, Index surgery and C reactive protein score is a predictor of treatment response in acute prosthetic joint infection. AB - There is an error in the name of one of the author in the original publication. The correct name is I Rodriguez-Delourme and not Delourne. PMID- 29164290 TI - Correction to: Prokaryotic expression and action mechanism of antimicrobial LsGRP1C recombinant protein containing a fusion partner of small ubiquitin-like modifier. AB - The published online version contains editing mistake in Table 2. See below for the corrected Table. PMID- 29164289 TI - Cell membrane biophysics with optical tweezers. AB - Membrane elastic properties play important roles in regulating cell shape, motility, division and differentiation. Here I review optical tweezer (OT) investigations of membrane surface tension and bending modulus, emphasizing didactic aspects and insights provided for cell biology. OT measurements employ membrane-attached microspheres to extract long cylindrical nanotubes named tethers. The Helfrich-Canham theory yields elastic parameters in terms of tether radius and equilibrium extraction force. It assumes initial point-like microsphere attachment and no cytoskeleton content within tethers. Experimental force-displacement curves reveal violations of those assumptions, and I discuss proposed explanations of such discrepancies, as well as recommended OT protocols. Measurements of elastic parameters for predominant cell types in the central nervous system yield correlations between their values and cell function. Micro rheology OT experiments extend these correlations to viscoelastic parameters. The results agree with a quasi-universal phenomenological scaling law and are interpreted in terms of the soft glass rheology model. Spontaneously-generated cell nanotube protrusions are also briefly reviewed, emphasizing common features with tethers. Filopodia as well as tunneling nanotubes (TNT), which connect distant cells and allow transfers between their cytoplasms, are discussed, including OT tether pulling from TNTs which mediate communication among bacteria, even of different species. Pathogens, including bacteria, viruses and prions, opportunistically exploit TNTs for cell-to-cell transmission of infection, indicating that TNTs have an ancient evolutionary origin. PMID- 29164291 TI - Bacterial Diversity in Traditional Doogh in Comparison to Industrial Doogh. AB - Forty-four samples of traditional Doogh and yoghurt were collected from 13 regions of 4 provinces in west of Iran (13 area) and analyzed using molecular methods including PCR, denaturing gradient gel electrophoresis (DGGE) of 16S rDNA, and sequencing. Moreover, collected samples as well as samples from industrially Doogh were analyzed with quantitative real-time PCR (RT-PCR). Analyzed 16S rRNA gene sequences of Doogh samples could be allocated to the presence of Lactobacillus spp. The typical yoghurt starter culture bacteria included four different Lactobacillus species with possible probiotic properties, L. acidophilus, L. helveticus, L. kefiranofaciens, and L. amylovorus. DGGE of traditional Doogh and yoghurt and RT-PCR of traditional Doogh and yoghurt and also industrial Doogh samples demonstrated that traditional Doogh and yoghurt show a higher abundance of total bacteria and lactobacilli and a higher bacterial diversity, respectively. Considering diversity and higher probiotic bacteria content in traditional Doogh, consumers' healthiness in tribes and villages could be promoted with these indigenous products. PMID- 29164292 TI - Incidence and impact of atrial arrhythmias on thrombotic events in MPNs. AB - Atrial arrhythmias (AA) induce a high rate of thromboses and require vitamin K antagonists (VKA) or direct anticoagulants (DOAC) prescriptions. Essential thrombocythemia (ET) and polycythemia vera (PV) are also pro-thrombotic diseases. The prevention of thromboses is based on the association of cytoreductive drug and low-dose aspirin (LDA). We studied the incidence and complications of AA among patients with ET or PV. We identified 96/713 patients (13.5%) carrying AA. These patients were older (median 72.1 vs. 61.3 years old, p < 0.0001). In a case control analysis, we observed that patients with AA had a higher frequency of cardiovascular risk factors (77/96, 80% vs. 61/96, 61%; p = 0.01). A higher incidence of thromboses before and after myeloproliferative neoplasm (MPN) diagnosis was seen in this group: 26/96, 27.1% vs. 14/96, 14.6% (p = 0.03) and 34/96, 35% vs. 18/96, 18.8% (p = 0.009). Most of the events were arterial (82 vs. 61%, p = 0.09). This translates into a shorter thrombosis-free survival (11.0 vs. 21.6 years, p = 0.01). Continuation of LDA in this situation exposed patients to more thrombotic events (p = 0.04) but VKA did not seem to be good anticoagulant drugs either. The association of AA and MPN is more frequent than expected. AA clearly increased the thrombotic risk of these patients. Anticoagulant drugs should be carefully managed between cardiologists and hematologists. Association of LDA and VKA or the role of DOAC in such population should be rapidly discussed to reduce the thrombotic rate. PMID- 29164293 TI - Evaluating Partnerships to Enhance Disaster Risk Management using Multi-Criteria Analysis: An Application at the Pan-European Level. AB - Disaster risk is increasingly recognized as a major development challenge. Recent calls emphasize the need to proactively engage in disaster risk reduction, as well as to establish new partnerships between private and public sector entities in order to decrease current and future risks. Very often such potential partnerships have to meet different objectives reflecting on the priorities of stakeholders involved. Consequently, potential partnerships need to be assessed on multiple criteria to determine weakest links and greatest threats in collaboration. This paper takes a supranational multi-sector partnership perspective, and considers possible ways to enhance disaster risk management in the European Union by better coordination between the European Union Solidarity Fund, risk reduction efforts, and insurance mechanisms. Based on flood risk estimates we employ a risk-layer approach to determine set of options for new partnerships and test them in a high-level workshop via a novel cardinal ranking based multi-criteria approach. Whilst transformative changes receive good overall scores, we also find that the incorporation of risk into budget planning is an essential condition for successful partnerships. PMID- 29164294 TI - A Novel Technique of Paravertebral Thoracic and Preperitoneal Analgesia Enhances Early Recovery After Oesophagectomy. AB - BACKGROUND: Excellent analgesia following oesophagectomy facilitates patient comfort, early extubation, physiotherapy and mobilisation, reduces post-operative complications and should enhance recovery. Thoracic epidural analgesia (TEA), the gold standard analgesic regimen for this procedure, is often associated with systemic hypotension treated with inotropes or fluid. This may compromise enhanced recovery and be complicated by anastomotic ischaemia or tissue oedema. METHODS: We report a novel analgesic regimen to reduce post-operative inotrope usage. Infusion of ropivicaine via bilateral preperitoneal and right paravertebral catheters was used. Patient-controlled epidural pethidine provided rescue analgesia (WC) (n = 21). A retrospective audit of inotrope requirement, mean pain scores, episodes of respiratory depression and excessive sedation, need for reintubation, reoperation in the first 5 post-operative days, time to mobilisation, time in intensive care, time in hospital and 30-day mortality were measured. These results were compared with those of an earlier patient group who received a thoracic epidural infusion of low-dose local anaesthetic and fentanyl (TEA) (n = 21). RESULTS: Inotrope use was reduced by 29% in the WC group (p = 0.03) and the mean intensive care stay reduced by 2.4 days (p = 0.03), as was reintubation rate (p = 0.01) and early mobilisation (p = 0.03). The pain score was comparable in both groups, and there was no difference in the other outcomes examined. CONCLUSION: The data demonstrated that it was possible to provide excellent post-oesophagectomy analgesia equivalent to thoracic epidural infusions of local anaesthetic with reduction in inotrope requirements, intensive care stay, more rapid mobilisation, facilitating enhanced recovery. PMID- 29164295 TI - The Economic and Social Burden of Traumatic Injuries: Evidence from a Trauma Hospital in Port-au-Prince, Haiti. AB - INTRODUCTION: The cost of traumatic injury is unknown in Haiti. This study aims to examine the burden of traumatic injury of patients treated and evaluated at a trauma hospital in the capital city of Port-au-Prince. METHODS: A retrospective cross-sectional chart review study was conducted at the Hospital Bernard Mevs Project Medishare for all patients evaluated for traumatic injury from December 2015 to January 2016, as described elsewhere (Zuraik and Sampalis in World J Surg, https://doi.org/10.1007/s00268-017-4088-2 , 2017). Direct medical costs were obtained from patient hospital bills. Indirect and intangible costs were calculated using the human capital approach. RESULTS: A total of 410 patients were evaluated for traumatic injury during the study period. Total costs for all patients were $501,706 with a mean cost of $1224. Indirect costs represented 63% of all costs, direct medical costs 19%, and intangible costs 18%. Surgical costs accounted for the majority of direct medical costs (29%). Patients involved in road traffic accidents accounted for the largest number of injuries (41%) and the largest percentage of total costs (51%). Patients with gunshot wounds had the highest total mean costs ($1566). Mean costs by injury severity ranged from $62 for minor injuries, $1269 for serious injuries, to $13,675 for critical injuries. CONCLUSION: Injuries lead to a significant economic burden for individuals treated at a semi-private trauma hospital in the capital city of Port-au-Prince, Haiti. Programs aimed at reducing injuries, particularly road traffic accidents, would likely reduce the economic burden to the nation. PMID- 29164296 TI - Pharmacokinetic and toxicodynamic evaluation of oxaliplatin-induced neuropathy and hematological toxicity in rats. AB - PURPOSE: Oxaliplatin (L-OHP) is a third-generation, platinum-based chemotherapeutic agent and is widely used in gastroenterological cancer regimens. It is important to complete chemotherapy cycles to improve treatment efficacy for cancer patients. However, undesirable side effects, including acute and chronic neuropathies, and myelosuppression, lead to the discontinuation of chemotherapy in some treatment regimens. To predict and prevent the onset of side effects, and to establish appropriate dose adjustment, pharmacokinetic and toxicodynamic studies were performed to investigate the effects of L-OHP in rats. METHODS: Rats were administered intravenous L-OHP, once a week for 4 weeks, at doses of 3, 5, or 8 mg/kg. Pharmacokinetic profiles were observed on Day 1 and Day 22. Acute and chronic neuropathies were evaluated over 4 weeks; cold allodynia was evaluated using an acetone test and mechanical allodynia using the von Frey test. Hematological parameters were also investigated during the same period. RESULTS: The mean AUC0-infinity values for L-OHP were 0.4 +/- 0.2, 2.4 +/- 0.4, and 3.5 +/ 0.9 ng h/mL, increasing dose-dependently on Day 1. The accumulation of L-OHP on Day 22 was observed after repeated administration of L-OHP, as shown by mean AUC0 infinity values of 0.6 +/- 0.2, 4.0 +/- 1.0, and 14.1 +/- 9.8 ng.h/mL, for the three doses. Cold allodynia was observed from Day 3 in the 5 and 8 mg/kg groups, and the extent of this response was dose-dependent. Mechanical allodynia was also observed from Day 10 in the 5 and 8 mg/kg groups. Moreover, the platelet count was the most sensitive among the hematological parameters. CONCLUSION: These results provide useful experimental data for clinical cancer patients undergoing chemotherapy, to establish a pharmacokinetic and toxicodynamic model of L-OHP for adequate dose adjustment. PMID- 29164297 TI - Dose and schedule modification are required for long-term continuation of sunitinib in Japanese patients with advanced pancreatic neuroendocrine tumors. AB - PURPOSE: This study aimed to clarify the efficacy and safety of sunitinib in Japanese patients with pancreatic neuroendocrine tumors (PNET), especially by focusing on dose and schedule modification. METHODS: Sixteen patients with advanced PNET treated with sunitinib were reviewed retrospectively. Efficacy was evaluated by progression-free survival (PFS) and objective tumor response. Toxicity profile was assessed regularly. Correlation between relative dose intensity (RDI) and treatment period was also evaluated. RESULTS: The median PFS was 25.8 months, and the probability of PFS at 1-year was 92%. The objective response rate and clinical benefit rate were 44% and 69%, respectively. The common adverse drug reactions (ADRs) were hand-foot syndrome (88%), neutropenia (75%), leucopenia (75%), and diarrhea (63%). Due to the development of severe ADRs, 81% required dose reduction and 31% discontinued sunitinib treatment, respectively. Prolonged treatment period was significantly correlated with decreased RDI (Spearman r = - 0.57, P = 0.022). The median RDI among 9 patients whom continued sunitinib more than 1 year was 49%. CONCLUSIONS: Sunitinib showed significant clinical benefit in Japanese patients with advanced PNET in the real world clinical setting. Successful management of ADRs with appropriate dose reduction and interruption can enable long-term continuation of sunitinib. PMID- 29164298 TI - Value of 18F-FDG PET/CT for predicting EGFR mutations and positive ALK expression in patients with non-small cell lung cancer: a retrospective analysis of 849 Chinese patients. AB - PURPOSE: Epidermal growth factor receptor (EGFR) mutations and the anaplastic lymphoma kinase (ALK) rearrangement are the two most common druggable targets in non-small cell lung cancer (NSCLC). However, genetic testing is sometimes unavailable. Previous studies regarding the predictive role of 18F-FDG PET/CT for EGFR mutations in NSCLC patients are conflicting. We investigated whether or not 18F-FDG PET could be a valuable noninvasive method to predict EGFR mutations and ALK positivity in NSCLC using the largest patient cohort to date. METHODS: We retrospectively reviewed and included 849 NSCLC patients who were tested for EGFR mutations or ALK status and subjected to 18F-FDG PET/CT prior to treatment. The differences in several clinical characteristics and three parameters based on 18F FDG PET/CT, including the maximal standard uptake value (SUVmax) of the primary tumor (pSUVmax), lymph node (nSUVmax) and distant metastasis (mSUVmax), between the different subgroups were analyzed. Multivariate logistic regression analysis was performed to identify predictors of EGFR mutations and ALK positivity. RESULTS: EGFR mutations were identified in 371 patients (45.9%). EGFR mutations were found more frequently in females, non-smokers, adenocarcinomas and stage I disease. Low pSUVmax, nSUVmax and mSUVmax were significantly associated with EGFR mutations. Multivariate analysis demonstrated that pSUVmax < 7.0, female sex, non smoker status and adenocarcinoma were predictors of EGFR mutations. The receiver operating characteristic (ROC) curve yielded area under the curve (AUC) values of 0.557 and 0.697 for low pSUVmax alone and the combination of the four factors, respectively. ALK-positive patients tended to have a high nSUVmax. Younger age and distant metastasis were the only two independent predictors of ALK positivity. CONCLUSION: We demonstrated that low pSUVmax is associated with mutant EGFR status and could be integrated with other clinical factors to enhance the discriminability on the EGFR mutation status in some NSCLC patients whose EGFR testing is unavailable. PMID- 29164299 TI - Comparison of 18F-FDG PET/MRI and MRI alone for whole-body staging and potential impact on therapeutic management of women with suspected recurrent pelvic cancer: a follow-up study. AB - PURPOSE: To evaluate the diagnostic performance of 18F-FDG PET/MRI for whole-body staging and potential changes in therapeutic management of women with suspected recurrent pelvic cancer in comparison with MRI alone. METHODS: Seventy-one consecutive women (54 +/- 13 years, range: 25-80 years) with suspected recurrence of cervical (32), ovarian (26), endometrial (7), vulvar (4), and vaginal (2) cancer underwent PET/MRI including a diagnostic contrast-enhanced MRI protocol. PET/MRI and MRI datasets were separately evaluated regarding lesion count, localization, categorization (benign/malignant), and diagnostic confidence (3 point scale; 1-3) by two physicians. The reference standard was based on histopathology results and follow-up imaging. Diagnostic accuracy and proportions of malignant and benign lesions rated correctly were retrospectively compared using McNemar's chi2 test. Differences in diagnostic confidence were assessed by Wilcoxon test. RESULTS: Fifty-five patients showed cancer recurrence. PET/MRI correctly identified more patients with cancer recurrence than MRI alone (100% vs. 83.6%, p < 0.01). In contrast to PET/MRI, MRI alone missed 4/15 patients with pelvic recurrence and miscategorized 8/40 patients with distant metastases as having local recurrence only. Based on the reference standard, 241 lesions were detected in the study cohort (181 malignant, 60 benign). While PET/MRI provided correct identification of 181/181 (100%) malignant lesions, MRI alone correctly identified 135/181 (74.6%) malignant lesions, which was significantly less compared to PET/MRI (p < 0.001). PET/MRI offered superior diagnostic accuracy (99.2% vs. 79.3%, p < 0.001) and diagnostic confidence in the categorization of malignant lesions compared with MRI alone (2.7 +/- 0.5 vs. 2.4 +/- 0.7, p < 0.001). CONCLUSION: PET/MRI demonstrates excellent diagnostic performance and outperforms MRI alone for whole-body staging of women with suspected recurrent pelvic cancer, indicating potential changes in therapy management based on evaluation of local recurrence and distant metastatic spread. PMID- 29164300 TI - 177Lu-PSMA-617 radioligand therapy in mCRPC: ready for phase III trial? PMID- 29164301 TI - Changes in multimodality functional imaging parameters early during chemoradiation predict treatment response in patients with locally advanced head and neck cancer. AB - OBJECTIVE: To assess the optimal timing and predictive value of early intra treatment changes in multimodality functional and molecular imaging (FMI) parameters as biomarkers for clinical remission in patients receiving chemoradiation for head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty five patients with stage III-IVb (AJCC 7th edition) HNSCC prospectively underwent 18F-FDG-PET/CT, and diffusion-weighted (DW), dynamic contrast-enhanced (DCE) and susceptibility-weighted MRI at baseline, week 1 and week 2 of chemoradiation. Patients with evidence of persistent or recurrent disease during follow-up were classed as non-responders. Changes in FMI parameters at week 1 and week 2 were compared between responders and non-responders with the Mann-Whitney U test. The significance threshold was set at a p value of <0.05. RESULTS: There were 27 responders and 8 non-responders. Responders showed a greater reduction in PET derived tumor total lesion glycolysis (TLG40%; p = 0.007) and maximum standardized uptake value (SUVmax; p = 0.034) after week 1 than non-responders but these differences were absent by week 2. In contrast, it was not until week 2 that MRI-derived parameters were able to discriminate between the two groups: larger fractional increases in primary tumor apparent diffusion coefficient (ADC; p < 0.001), volume transfer constant (Ktrans; p = 0.012) and interstitial space volume fraction (Ve; p = 0.047) were observed in responders versus non responders. ADC was the most powerful predictor (? >17%, AUC 0.937). CONCLUSION: Early intra-treatment changes in FDG-PET, DW and DCE MRI-derived parameters are predictive of ultimate response to chemoradiation in HNSCC. However, the optimal timing for assessment with FDG-PET parameters (week 1) differed from MRI parameters (week 2). This highlighted the importance of scanning time points for the design of FMI risk-stratified interventional studies. PMID- 29164302 TI - Impact of initial myocardial perfusion imaging versus invasive coronary angiography on outcomes in coronary artery disease: a nationwide cohort study. AB - PURPOSE: In patients with stable coronary artery disease (CAD), two main options exist to guide management: initial invasive coronary angiography (CAG), or selective CAG after risk stratification using myocardial perfusion imaging (MPI). This study compared clinical outcomes between these two strategies in a large, real-world population. METHODS: The initial cohort comprised 1,000,000 randomly selected patients who had been entered in the National Health Insurance Research Database of Taiwan between 2000 and 2011. Patients with acute coronary syndromes, prior myocardial infarction (MI) or coronary revascularization, and prior treadmill testing or stress echocardiography were excluded. The remaining patients with suspected or known CAD were divided into those in whom initial CAG had been performed and those in whom initial MPI had been performed, and were followed until the end of 2011 for all-cause mortality, MI, and revascularization. A Cox proportional hazards model was used to estimate the risk of events after adjusting for covariates. RESULTS: The MPI and CAG groups each comprised 4,495 patients after frequency matching, with a similar Charlson comorbidity index (CCI). The MPI group had a significantly and dramatically lower incidence of revascularization (729 vs. 2,380, p < 0.001), MI (268 vs. 1,044, p < 0.001), and all-cause mortality (522 vs. 784, p < 0.001) than the CAG group. Multivariable analysis adjusting for age, gender, CCI, and comorbidities showed that in the MPI group fewer patients had revascularization (HR 0.24, 95% CI 0.22 0.26) and MI (HR 0.23, 95% CI 0.20-0.26), and the rate of all-cause mortality was lower (HR 0.58, 95% CI 0.52-0.64). CONCLUSIONS: In patients with suspected stable CAD, compared with initial invasive CAG, a selective strategy guided by MPI was associated with lower rates of revascularization and MI and improved survival. PMID- 29164303 TI - Percutaneous nephrolithotomy: position, position, position! AB - Percutaneous nephrolithotomy (PCNL) is the regular surgery for treating large or complex renal stones. Since its first inception, many variations have come in the approach including the modifications of patient position. The prone position is traditionally used, and subsequently, variations in prone and supine technique have been proposed and assessed over time. In an attempt to provide comprehensive information about the strategy applications of patient's position, the present review describes the position-related general basis, and provides a literature review of the pros and cons of various positions from a surgical and anaesthetic point of view. Latest evidence has shown the major advantages of supine PCNL compared with standard prone PCNL to be as follows: optimal cardiovascular and airway control; shorter operation time due to lack of the need for repositioning; opportunity for a combined retrograde approach. However, the prone position provides a broader surface area for percutaneous access; a wider space for manipulating the nephroscope and lithotripters; and opportunity for bilateral simultaneous PCNL. To overcome their respective limitations, various positioning modifications have been proposed. However, most reports are based on case series and/or have not obtained their results in a randomized controlled fashion and/or have not been analysed according to stone complexity and particular body status (e.g. obesity, etc.), thereby limiting the ability to make strong recommendations. One important caveat is that endourology training of supine PCNL would increase supine popularization, and the prone ureteroscopic technique would overcome the difficulty of endoscopic combined intrarenal surgery in the prone position. Thereby, adequate training in the different techniques for PCNL is important for optimizing the indications and treatment outcomes. PMID- 29164304 TI - Preface: Breaking the stone. PMID- 29164305 TI - Nuclear transport of the human aryl hydrocarbon receptor and subsequent gene induction relies on its residue histidine 291. AB - The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor involved in the metabolism of physiological substances and xenobiotics, representing an interesting target in both toxicology and pharmacology. In this study, we investigated the ligand-dependent conjunction of nuclear import of the human AHR in living cells and target gene induction. Our findings strengthen the theory that the AHR triggers a precisely defined and rapid reaction upon binding to endogenous ligands, while the xenobiotic beta-naphthoflavone only induces rather unspecific and slow effects. To better illuminate the ligand-mediated responses of the human AHR, we applied site-directed mutagenesis and identified histidine 291 as key residue for AHR functionality, essential for both nuclear import and target gene induction. Contrary, replacing histidine at position 291 by alanine did not affect nucleo-cytoplasmic shuttling, showing that permanent endogenous import and ligand-induced import of the AHR into the nucleus are two independent and differently regulated processes. Combining these observations with our structural investigations using a homology model of the AHR-PAS B domain, we suggest a dual role of histidine 291: (1) a major role for shaping the ligand binding site including direct interactions with ligands and, (2) an essential role for the conformational dynamics of a PAS B loop, which most likely influences the association of the AHR with the AHR nuclear translocator through interference with their protein-protein interface. PMID- 29164306 TI - A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins. AB - Migration of neural crest cells (NCC) is a fundamental developmental process, and test methods to identify interfering toxicants have been developed. By examining cell function endpoints, as in the 'migration-inhibition of NCC (cMINC)' assay, a large number of toxicity mechanisms and protein targets can be covered. However, the key events that lead to the adverse effects of a given chemical or group of related compounds are hard to elucidate. To address this issue, we explored here, whether the establishment of two overlapping structure-activity relationships (SAR)-linking chemical structure on the one hand to a phenotypic test outcome, and on the other hand to a mechanistic endpoint-was useful as strategy to identify relevant toxicity mechanisms. For this purpose, we chose polychlorinated biphenyls (PCB) as a large group of related, but still toxicologically and physicochemically diverse structures. We obtained concentration-dependent data for 26 PCBs in the cMINC assay. Moreover, the test chemicals were evaluated by a new high-content imaging method for their effect on cellular re-distribution of connexin43 and for their capacity to inhibit gap junctions. Non-planar PCBs inhibited NCC migration. The potency (1-10 uM) correlated with the number of ortho-chlorine substituents; non-ortho-chloro (planar) PCBs were non-toxic. The toxicity to NCC partially correlated with gap junction inhibition, while it fully correlated (p < 0.0004) with connexin43 cellular re-distribution. Thus, our double-SAR strategy revealed a mechanistic step tightly linked to NCC toxicity of PCBs. Connexin43 patterns in NCC may be explored as a new endpoint relevant to developmental toxicity screening. PMID- 29164308 TI - Endovascular Repair of 40 Visceral Artery Aneurysms and Pseudoaneurysms with the Viabahn Stent-Graft: Technical Aspects, Clinical Outcome and Mid-Term Patency. AB - PURPOSE: Endovascular repair of true visceral artery aneurysms (VAAs) and pseudoaneurysms (VAPAs) with stent-grafting (SG) can simultaneously allow aneurysm exclusion and vessel preservation, minimizing the risk of ischemic complications. Our aim was to report a single-center experience on SG of visceral aneurysms, focusing on technical aspects, clinical outcome and mid-term patency. MATERIALS AND METHODS: Consecutive patients affected by VAAs-VAPAs and submitted to endovascular treatment were retrospectively reviewed, and SG cases with the self-expandable peripheral Viabahn stent-graft were analyzed (2003-2017). Aneurysm type, patient number, SG clinical setting, procedural data, peri procedural complications, technical success, 30-day clinical success, 30-day mortality and follow-up period (aneurysm exclusion, stent-graft patency, ischemic complications) were analyzed. RESULTS: SG was performed in 40 patients (24 VAPAs/16 VAAs) and in 44 procedures (25 in emergency, 19 in elective treatments), via transfemoral in 37 cases (transaxillary in 7 cases). One peri-procedural complication was recorded (a splenic artery dissection successfully converted to transcatheter embolization). The overall technical and clinical success rates were, respectively, 96 and 84%, with excellent trend in elective treatments (both 100%). Overall 30-day mortality was 12.5% (septic shock after pancreatic surgery). Stent-graft thrombosis occurred in 2 patients within 3 months, with aneurysm exclusion and without ischemic complications. Stent-graft patency and aneurysm exclusion were confirmed at 6, 12 and 36 months in 18, 12 and 7 patients, respectively. CONCLUSION: SG of VAAs and VAPAs was safe and effective, particularly in elective treatments. The Viabahn stent-graft, flexible and without shape memory, is suitable for endovascular repair of tortuous visceral arteries. PMID- 29164309 TI - Pathologic Diagnosis and Genetic Analysis of a Lung Tumor Needle Biopsy Specimen Obtained Immediately After Radiofrequency Ablation. AB - PURPOSE: To evaluate the possibility of pathologic diagnosis and genetic analysis of percutaneous core-needle biopsy (CNB) lung tumor specimens obtained immediately after radiofrequency ablation (RFA). MATERIALS AND METHODS: Patients who underwent CNB of lung tumors immediately after RFA from May 2013 to May 2016 were analyzed. There were 19 patients (8 men and 11 women; median age, 69 years; range, 52-88 years) and 19 lung tumors measuring 0.5-2.6 cm (median, 1.6 cm). Thirteen tumors were solid, and 6 were predominantly ground-glass opacity (GGO) on computed tomography. All specimens were pathologically examined using hematoxylin and eosin (H&E) staining and additional immunostaining, as necessary. The specimens were analyzed for EGFR and KRAS genetic mutations. The safety and technical success rate of the procedure and the possibility of pathologic diagnosis and genetic mutation analysis were evaluated. RESULTS: Major and minor complication rates were 11% (2/19) and 53% (10/19), respectively. Tumor cells were successfully obtained in 16 cases (84%, 16/19), and technical success rate was significantly lower for GGO-dominant tumors (50%, 3/6) compared with solid lesions (100%, 13/13, p = 0.02). Pathologic diagnosis was possible in 79% (15/19) of cases based on H&E staining alone (n = 12) and with additional immunostaining (n = 3). Although atypical cells were obtained, pathologic diagnosis could not be achieved in 1 case (5%, 1/19). Both EGFR and KRAS mutations could be analyzed in 74% (14/19) of the specimens. CONCLUSION: Pathologic diagnosis and genetic analysis could be performed even for lung tumor specimens obtained immediately after RFA. PMID- 29164307 TI - Cartilage oligomeric protein, matrix metalloproteinase-3, and Coll2-1 as serum biomarkers in knee osteoarthritis: a cross-sectional study. AB - Biochemical markers reflecting joint remodeling in osteoarthritis (OA) are a promising diagnostic tool. The aim of this study was to investigate serum levels of candidate biomarkers in subjects with and without knee OA and assess their correlation with clinical parameters and knee structural damage. 56 patients with primary knee OA and 31 healthy controls participated in this study. Patients were separated into two groups: isolated knee OA and generalized OA. Clinical parameters were obtained by validated self-reported questionnaires and a visual analogue scale. Serum levels of cartilage oligomeric protein (COMP), matrix metalloproteinase-3 (MMP-3), and Coll2-1 were quantified by enzyme-linked immunosorbent assay. Knee structural damage was determined by plain X-ray and 1.5 T magnetic resonance imaging (MRI), using Kellgren-Lawrence (KL) grading scale and Whole-Organ Magnetic Resonance Imaging Score (WORMS), respectively. Compared to controls, patients had significantly higher median serum COMP (985 vs. 625 ng/ml; p < 0.001) and MMP-3 (36.85 vs. 22.10 ng/ml; p = 0.003) levels. Patients with radiographic evidence of KLII/III knee OA had greater median COMP levels than KLI patients (1095 vs. 720 ng/ml; p = 0.001). In the generalized OA group, mean MMP-3 levels were higher than in the isolated knee OA group (30.40 vs. 55.13 ng/ml; p < 0.001). COMP correlated positively with WORMS (r s = 0.454, p < 0.001) and MMP-3 (r s = 0.337, p = 0.003). Cut-off values for serum COMP and MMP-3 were determined. We observed higher serum COMP and MMP-3 levels in knee OA patients compared to controls. COMP may reflect knee structural damage, while MMP-3-OA "generalization". PMID- 29164310 TI - Relevance of TRPA1 and TRPM8 channels as vascular sensors of cold in the cutaneous microvasculature. AB - Cold exposure is directly related to skin conditions, such as frostbite. This is due to the cold exposure inducing a vasoconstriction to reduce cutaneous blood flow and protect against heat loss. However, a long-term constriction will cause ischaemia and potentially irreversible damage. We have developed techniques to elucidate the mechanisms of the vascular cold response. We focused on two ligand gated transient receptor potential (TRP) channels, namely, the established "cold sensors" TRP ankyrin 1 (TRPA1) and TRP melastin (TRPM8). We used the anaesthetised mouse and measured cutaneous blood flow by laser speckle imaging. Two cold treatments were used. A generalised cold treatment was achieved through whole paw water immersion (10 degrees C for 5 min) and a localised cold treatment that will be potentially easier to translate to human studies was carried out on the mouse paw with a copper cold probe (0.85-cm diameter). The results show that TRPA1 and TRPM8 can each act as a vascular cold sensor to mediate the vasoconstrictor component of whole paw cooling as expected from our previous research. However, the local cooling-induced responses were only blocked when the TRPA1 and TRPM8 antagonists were given simultaneously. This suggests that this localised cold probe response requires both functional TRPA1 and TRPM8. PMID- 29164311 TI - Macdonald Critchley (1900-1997). PMID- 29164312 TI - Efficacy and safety of rotigotine in elderly patients with Parkinson's disease in comparison with the non-elderly: a post hoc analysis of randomized, double-blind, placebo-controlled trials. AB - Rotigotine-a non-ergot dopamine agonist-has two advantages; it can stimulate all dopamine receptors (D1-D5) like innate dopamine, and its transdermal administration provides continuous dopaminergic stimulation. The age of the patient impacts the effect and adverse events of anti-parkinsonian treatment. We conducted a post hoc analysis on three randomized, double-blind, placebo controlled trials performed in Japan to clarify the difference of anti parkinsonian treatment in elderly and non-elderly patients. Data from two combination therapy trials (with levodopa) in advanced stage Parkinson's disease patients and one monotherapy trial in early stage patients were pooled and grouped by age (non-elderly aged < 70, elderly aged 70 +). In each age group, efficacy of rotigotine was compared to placebo. In the combination therapy, total Unified Parkinson's Disease Rating Scale Part III scores and some subtotal scores, including those for tremor, akinesia and gait disturbance, significantly improved in both elderly and non-elderly patients. Regarding safety, the incidence of total adverse event tended to be lower in elderly patients than non elderly patients, although it was not significant. No difference was observed in maintenance dosage of rotigotine between the two groups. In conclusion, the improvement in motor symptoms and frequency of adverse events were shown to be similar in elderly and non-elderly patients with rotigotine-levodopa combination therapy. Further, there was no major difference in maintenance dosage of rotigotine between the age groups. These results suggest good tolerability of rotigotine among elderly patients. PMID- 29164313 TI - Genome-wide analysis of a recently active retrotransposon, Au SINE, in wheat: content, distribution within subgenomes and chromosomes, and gene associations. AB - KEY MESSAGE: Here, we show that Au SINE elements have strong associations with protein-coding genes in wheat. Most importantly Au SINE insertion within introns causes allelic variation and might induce intron retention. The impact of transposable elements (TEs) on genome structure and function is intensively studied in eukaryotes, especially in plants where TEs can reach up to 90% of the genome in some cases, such as in wheat. Here, we have performed a genome-wide in silico analysis using the updated publicly available genome draft of bread wheat (T. aestivum), in addition to the updated genome drafts of the diploid donor species, T. urartu and Ae. tauschii, to retrieve and analyze a non-LTR retrotransposon family, termed Au SINE, which was found to be widespread in plant species. Then, we have performed site-specific PCR and realtime RT-PCR analyses to assess the possible impact of Au SINE on gene structure and function. To this end, we retrieved 133, 180 and 1886 intact Au SINE insertions from T. urartu, Ae. tauschii and T. aestivum genome drafts, respectively. The 1886 Au SINE insertions were distributed in the seven homoeologous chromosomes of T. aestivum, while ~ 67% of the insertions were associated with genes. Detailed analysis of 40 genes harboring Au SINE revealed allelic variation of those genes in the Triticum Aegilops genus. In addition, expression analysis revealed that both regular transcripts and alternative Au SINE-containing transcripts were simultaneously amplified in the same tissue, indicating retention of Au SINE-containing introns. Analysis of the wheat transcriptome revealed that hundreds of protein-coding genes harbor Au SINE in at least one of their mature splice variants. Au SINE might play a prominent role in speciation by creating transcriptome variation. PMID- 29164314 TI - Cross-national gender variations of digit ratio (2D:4D) correlate with life expectancy, suicide rate, and other causes of death. AB - The second-to-fourth finger length ratio (2D:4D) is an indication of prenatal sex hormone exposure, and has sex-specifically been associated with several lethal illnesses including ischemic heart disease, diverse cancers, and suicide. Our primary aim was to verify that 2D:4D sex-specifically relates to life expectancy and suicide numbers on a national level (23 countries). We also used a hypothesis free approach to investigate associations with other causes of death [p value adjustment for multiple hypothesis testing using the false discovery rate procedure (FDR)]. All parameters were normalized to the national mean (of males and females) and analyzed across nations. Normalized male 2D:4D correlated positively with normalized male life expectancy (at birth, r = 0.46, p = 0.029; at the age of 60, r = 0.44, p = 0.038) and negatively with normalized male suicide rates (r = - 0.49, p = 0.017). In the exploratory analyses, the normalized male 2D:4D values were negatively associated with the normalized male deaths rates from communicable, maternal, perinatal, and nutritional conditions [r = - 0.65, p(FDR) = 0.011], respiratory infections [r = - 0.69, p(FDR) = 0.008], asthma [r = - 0.65, p(FDR) = 0.011], neurological conditions [r = - 0.56, p(FDR) = 0.046], and Alzheimer's disease and other dementias [r = - 0.59, p(FDR) = 0.036]. The normalized female parameters showed the same cross-national correlations. In line with the previous individual level findings, the results suggest that prenatal sex hormone effects are sex-specifically involved in suicide and neurological conditions. Moreover, we provide novel national level evidence that prenatal sex hormone priming may sex-specifically influence life expectancy and death risk from respiratory diseases. PMID- 29164315 TI - The risk of lung cancer among cooking adults: a meta-analysis of 23 observational studies. AB - PURPOSE: Cooking has been regarded as a potential risk factor for lung cancer. We aim to investigate the evidence of cooking oil fume and risk of lung cancer. METHODS: Medline and Embase were searched for eligible studies. We conducted a meta-analysis to summarize the evidences of case-control or cohort studies, with subgroup analysis for the potential discrepancy. Sensitivity analysis was employed to test the robustness. RESULTS: We included 23 observational studies, involving 9411 lung cancer cases. Our meta-analysis found that, for cooking female, the pooled OR of cooking oil fume exposure was 1.98 (95% CI 1.54, 2.54, I 2 = 79%, n = 15) among non-smoking population and 2.00 (95% CI 1.46, 2.74, I 2 = 75%, n = 10) among partly smoking population. For cooking males, the pooled OR of lung cancer was 1.15 (95% CI 0.71, 1.87; I 2 = 80%, n = 4). When sub grouped by ventilation condition, the pooled OR for poor ventilation was 1.20 (95% CI 1.10, 1.31, I 2 = 2%) compared to good ventilation. For different cooking methods, our results suggested that stir frying (OR = 1.89, 95% CI 1.23, 2.90; I 2 = 66%) was associated with increased risk of lung cancer while not for deep frying (OR = 1.41, 95% CI 0.87, 2.29; I 2 = 5%). Sensitivity analysis suggested our results were stable. CONCLUSION: Cooking oil fume is likely to be a risk factor for lung cancer for female, regardless of smoking status. Poor ventilation may increase the risk of lung cancer. Cooking methods may have different effect on lung cancer that deep frying may be healthier than stir frying. PMID- 29164316 TI - Heavy-ion beam mutagenesis of the ectomycorrhizal agaricomycete Tricholoma matsutake that produces the prized mushroom "matsutake" in conifer forests. AB - Tricholoma matsutake is an ectomycorrhizal agaricomycete that produces the prized mushroom "matsutake" in Pinaceae forests. Currently, there are no available cultivars or cultivation methods that produce fruiting bodies. Heavy-ion beams, which induce mutations through double-stranded DNA breaks, have been used widely for plant breeding. In the present study, we examined whether heavy-ion beams could be useful in isolating T. matsutake mutants. An argon-ion beam gave a suitable lethality curve in relation to irradiation doses, accelerating killing at 100-150 Gy. Argon-ion beam irradiation of the agar plate cultures yielded several transient mutants whose colony morphologies differed from that of the wild-type strain at the first screening, but which did not persist following culture transfer. It also generated a mutant whose phenotype remained stable after repeated culture transfers. The stable pleiotropic mutant not only exhibited a different colony morphology to the wild type, but also showed increased degradation of dye-linked water-insoluble amylose and cellulose substrates. Thus, heavy-ion beams may be useful for isolating mutants of T. matsutake, although precautions may be required to maintain the mutants, without phenotypic reversion, during repetitive culture of their mycelia. PMID- 29164318 TI - Clinical-Pathological Conference Series from the Medical University of Graz : Case No 153: A 55-year-old woman with atypical multiple sclerosis and irritable bowel syndrome. PMID- 29164320 TI - [Target and patient-oriented care using the comprehensive geriatric assessment : Prognosis estimation for clinical decisions with elderly patients]. PMID- 29164319 TI - Cancer incidence in Stockholm firefighters 1958-2012: an updated cohort study. AB - OBJECTIVES: Previous studies on firefighters indicate an increased risk of cancer although findings regarding which cancer sites are in excess have been inconsistent. The aim of this study was to investigate the cancer incidence among Swedish firefighters. METHODS: This updated cohort study included 1080 men who worked at least 1 year as a firefighter in the city of Stockholm, Sweden during 1931-1983. First-time diagnoses of cancer were identified through the Swedish Cancer Registry from 1958 until 2012. Employment as a firefighter was determined from the annual fire station enrolment records. Standardized incidence ratios were calculated using the Stockholm population as reference. RESULTS: Firefighters in Stockholm had a low overall risk of cancer (SIR = 0.81 95% CI 0.71-0.91). However, firefighters were at an increased risk of stomach cancer (SIR = 1.89 95% CI 1.25-2.75). Firefighters had significantly low risks for prostate cancer (SIR = 0.68 95% CI 0.52-0.87) and malignant melanoma of the skin (SIR = 0.30 95% CI 0.06-0.88). There was a statistically significant trend of increasing overall risk of cancer with increasing employment duration, although there was still no excess of cancer overall in any of the categories of employment duration. CONCLUSION: Stockholm firefighters had an increased risk of stomach cancer but a low overall risk of cancer. The trend of increasing overall risk of cancer with increasing employment duration could potentially be related to the carcinogenic exposures at work. PMID- 29164322 TI - Prevalence and characteristics of hearing loss in patients diagnosed with Bell's Palsy. AB - OBJECTIVES: To assess the incidence of hearing loss in patients diagnosed with Bell's palsy (BP) and to characterize its clinical features. DESIGN: Patients with BP who underwent audiometry testing in our institute were included. Bone hearing level differences between the ipsilateral and the contralateral ears to the palsied side were calculated for 6 frequencies: 250, 500, 1000, 2000, 4000 and 8000 Hz. Subjects with interaural differences higher than 5 dB in at least one frequency were considered as having ipsilateral unilateral sensorineural hearing loss (uSNHL). RESULTS: Twenty-four cases of subjects with BP who underwent hearing exams were included. Thirteen were women (54.2%) and the average age was 37.4 years. Nine patients (37.5%) were found to have an ipsilateral uSNHL (group A); a maximal interaural difference of 5dB in all the frequencies was found in 15 subjects (62.5%, group B). The interaural maximal difference was found to be significantly higher between the two groups (p = 0.0295, n = 24). Group A showed a mean of maximal difference of 18.9 +/- 9.3 dB compared to 3 +/- 2.5 dB in group B (p < 0.001). A higher difference was calculated in the higher frequencies (2000, 4000, 8000 Hz) (R-spearman = 0.226, p = 0.003). CONCLUSIONS: We have demonstrated significant ipsilateral uSNHL in our cohort of patients diagnosed with BP. We, therefore, believe that all patients who are diagnosed with BP should undergo an audiometry examination. Further prospective studies with larger cohorts are necessary to support our observations. PMID- 29164321 TI - Canine Leishmania infantum infection: an imported case in UK after staying in the Canary Islands. AB - Leishmaniosis is reported in the Iberian Peninsula and the Balearic Islands, but the Canary Islands are deemed free. In the present communication, we report a clinical leishmaniosis due to Leishmania infantum in a dog that was presumptively infected during its stay on Tenerife. The result of Leishmania serology (whole cell based ELISA with L. infantum antigen) was high positive (test score of 82.2 at a cut-off value of 12.0). This result was further confirmed with quantitative real-time polymerase chain reaction (qPCR) for Leishmania spp. on a blood sample. A medium load of parasites was detected (48 parasites/ml blood). L. infantum was identified by RFLP analysis of the ITS-1 PCR product. Confirmation that leishmaniosis is endemic to the Canary Islands would further require study on local dogs with no travel history as well as reassessment on frequency and distribution of Phlebotomus spp. as well as Leishmania spp. detection in the sand fly vector. However, this case strongly suggests that L. infantum is present on the Canary Islands. Although transmission seems to be still exceptional, preventive measures in dogs travelling to the Canaries should be considered. PMID- 29164323 TI - Safety of intranasal corticosteroid sprays during pregnancy: an updated review. AB - INTRODUCTION: Rhinitis and rhinosinusitis are commonly encountered in pregnant women. Intranasal corticosteroid (INCS) sprays are generally safe and effective in the treatment of these conditions in the general population. However, the use of some of these INCS sprays during pregnancy is still controversial. OBJECTIVE: To review the current literature about the safety of intranasal corticosteroid sprays during pregnancy. METHODOLOGY: Using different search engines, each type of INCS was reviewed separately (triamcinolone, beclomethasone, budesonide, fluticasone propionate, fluticasone furoate, mometasone, and ciclesonide). A total of 51 full-length articles were examined for eligibility. After applying inclusion and exclusion criteria, a total of three articles were reviewed. RESULTS: No significant association with congenital organ malformations has been linked to intranasal use of beclomethasone, budesonide, fluticasone propionate, fluticasone furoate, or mometasone. Intranasal triamcinolone, however, has been found to have a significant association with respiratory tract defects. Data about the safety of intranasal ciclesonide during pregnancy are not available. CONCLUSION: Lacking sufficient clinical trials on the use of intranasal corticosteroid sprays in pregnancy, we suggest that the intranasal use of fluticasone furoate, mometasone, and budesonide is safe if they are used at the recommended therapeutic dose after a proper medical evaluation. Intranasal fluticasone propionate might be a safe option in the absence of other INCS options due to its questionable efficacy during pregnancy. Risk-benefit ratio should always be considered before prescribing any intranasal corticosteroid sprays during pregnancy. PMID- 29164324 TI - Effect of follow-up period on minimal-significant dose in the atomic-bomb survivor studies. AB - It was recently suggested that earlier reports on solid-cancer mortality and incidence in the Life Span Study of atomic-bomb survivors contain still-useful information about low-dose risk that should not be ignored, because longer follow up may lead to attenuated estimates of low-dose risk due to longer time since exposure. Here it is demonstrated, through the use of all follow-up data and risk models stratified on period of follow-up (as opposed to sub-setting the data by follow-up period), that the appearance of risk attenuation over time may be the result of less-precise risk estimation-in particular, imprecise estimation of effect-modification parameters-in the earlier periods. Longer follow-up, in addition to allowing more-precise estimation of risk due to larger numbers of radiation-related cases, provides more-precise adjustment for background mortality or incidence and more-accurate assessment of risk modification by age at exposure and attained age. It is concluded that the latest follow-up data are most appropriate for inferring low-dose risk. Furthermore, if researchers are interested in effects of time since exposure, the most-recent follow-up data should be considered rather than the results of earlier reports. PMID- 29164326 TI - Men with family history of prostate cancer have a higher risk of disease recurrence after radical prostatectomy. AB - PURPOSE: We aimed to determine if family history (FH) of prostate cancer (PC) influenced cancer control after radical prostatectomy (RP). METHODS: Patients were evaluated in a prospectively-collected PC family database: The focus was on hereditary prostate cancer (HPC) defined by Johns Hopkins criteria and sporadic prostate cancer (SPC), rigorously defined by absence of prostate cancer in >= 2 brothers aged >= 60 years. Additionally, patients with first-degree (FPC) and non first-degree PC (non-FPC) were assessed. Endpoints were biochemical recurrence free survival (BRFS) and prostate cancer-specific survival (CSS). Finally, clinico-pathological characteristics were compared and multiple proportional hazards regression was used to identify prognostic factors. RESULTS: In total 11,654 patients were included (807 HPC, 2251 FPC, 8072 non-FPC and 524 SPC). Familial imposition (HPC/FPC) was associated with a younger age at diagnosis. Thus, HPC patients were diagnosed 2.9 years earlier than SPC patients with more locally advanced tumors (>= pT3). With a median follow up of 6.2 years (range 0 31.5) BRFS was significantly different when stratified by FH. In pairwise analyses BRFS differed significantly for HPC compared to SPC (HR = 1.27). Consecutively FH was identified as prognostic factor for BRFS (p = 0.021) together with age, PSA, pathologic characteristics and adjuvant androgen deprivation. Analyses of CSS did not show a difference. CONCLUSION: Patients with FH of PC are likely to be diagnosed earlier and present a higher proportion of locally advanced disease. In addition, men with FH are at higher risk of biochemical recurrence after surgery but reveal similar outcomes regarding prostate cancer-specific survival. PMID- 29164325 TI - Effects of recreational football on women's fitness and health: adaptations and mechanisms. AB - The review describes the fitness and health effects of recreational football in women aged 18-65 years. The review documents that 2 * 1 h of recreational football training for 12-16 weeks causes marked improvements in maximal oxygen uptake (5-15%) and myocardial function in women. Moreover, mean arterial blood pressure was shown to decrease by 2-5 mmHg in normotensive women and 6-8 mmHg in hypertensive women. This review also show that short-term (< 4 months) and medium term (4-16 months) recreational football training has major beneficial impact on metabolic health profile in women, with fat losses of 1-3 kg and improvements in blood lipid profile. Lastly, 2 * 1 h per week of recreational football training for women elevates lower extremity bone mineralisation by 1-5% and whole-body bone mineralization by 1-2% within 4-12-month interventions. These training adaptations are related to the high heart rates, high number of fast runs, and multiple changes of direction and speed occurring during recreational football training for untrained women. In conclusion, regular small-sided football training for women is an intense and versatile type of training that combines elements of high-intensity interval training (HIIT), endurance training and strength training, thereby providing optimal stimuli for cardiovascular, metabolic and musculoskeletal fitness. Recreational football, therefore, seems to be an effective tool for prevention and treatment of lifestyle diseases in young and middle-aged women, including hypertension, type 2 diabetes and osteopenia. Future research should elucidate effects of football training for elderly women, and as treatment and rehabilitation of breast cancer patients and other women patient groups. PMID- 29164327 TI - Macular retinoschisis in eyes with glaucomatous optic neuropathy: Vitrectomy and natural course. AB - PURPOSE: Our purpose was to determine the effectiveness of vitrectomy in resolving the macular retinoschisis in an eye with glaucomatous optic neuropathy and also to determine the natural course of macular retinoschisis. METHODS: This was a retrospective case series of patients who were diagnosed with macular retinoschisis and glaucomatous optic neuropathy. Fourteen eyes of 13 patients were studied. Patients with high myopia, vitreomacular traction syndrome, and the pit macular syndrome were excluded. RESULTS: There were three men and ten women, and 12 had unilateral and one had bilateral macular retinoschisis. Vitrectomy was performed for a serous retinal detachment, macular hole, or severe visual loss in five eyes. The mean follow-up time was 68.8 months in these five eyes, and the macular retinoschisis was resolved and the best-corrected visual acuity (BCVA) at the final visit was significantly improved in all eyes (P = 0.007). However, two of these fiv e eyes developed a macular hole and required a second vitrectomy. Of the nine eyes without treatment with a mean follow-up time of 29.0 months, the BCVA at the final visit remained unchanged from the baseline BCVA in all eyes. The macular retinoschisis was resolved or reduced in three eyes without treatment. CONCLUSIONS: Vitrectomy was effective for the resolution of macular retinoschisis in eyes with glaucomatous optic neuropathy and serous retinal detachment or macular hole or severe reduction of the BCVA. Macular retinoschisis can be resolved without a reduction of the BCVA in some cases without treatment. PMID- 29164328 TI - Metallosis after traumatic loosening of Bryan cervical disc arthroplasty: a case report and literature review. AB - PURPOSE: Cervical disc arthroplasty has been a popular alternative to traditional arthrodesis treatment for maintaining postoperative cervical spine mobility. However, certain adverse reactions to cervical disc arthroplasty have emerged during the last few decades. METHODS: Metallosis or metalloma is a rarely reported complication after spinal fusion or spinal arthroplasty surgery. We report on the first metallosis case occurring in a patient who received Bryan Disc implantation approximately 8 years earlier. She was involved in a traffic accident and sustained a whiplash injury to the cervical spine one and a half years ago. The traumatic Bryan Disc loosening developed after the traffic accident, causing metallosis. RESULTS: To the best of our knowledge, this is the first reported case of spinal metallosis caused by the Bryan Disc. A series of metallosis cases reported in the literature are also reviewed. CONCLUSIONS: Although uncommon, intraspinal metallosis or metalloma should be considered as an infrequent cause of delayed neurological symptoms after spinal surgery involving metallic instrumentation, especially after disc arthroplasty. Once metallosis is suspected, immediate metallic implant removal is mandatory for definite diagnosis and treatment. PMID- 29164330 TI - Posterior only approach to open wedge osteotomy in the thoracolumbar spine. PMID- 29164331 TI - Kairomones from an estuarine fish increase visual sensitivity in brine shrimp (Artemia franciscana) from Great Salt Lake, Utah, USA. AB - Chemical cues from fish, or kairomones, often impact the behavior of zooplankton. These behavioral changes are thought to improve predator avoidance. For example, marine and estuarine crustacean zooplankton become more sensitive to light after kairomone exposure, which likely deepens their vertical distribution into darker waters during the day and thereby reduces their visibility to fish predators. Here, we show that kairomones from an estuarine fish induce similar behavioral responses in adult brine shrimp (Artemia franciscana) from an endorheic, hypersaline lake, Great Salt Lake, Utah, USA. Given downwelling light stimuli, kairomone-exposed A. franciscana induce a descent response upon dimmer light flashes than they do in the absence of kairomones. Using extracellular electroretinogram (ERG) recordings, we also find that kairomones induce physiological changes in the retina that may lead to increased visual sensitivity, suggesting that kairomone-induced changes to photobehavior are mediated at the photoreceptor level. However, kairomones did not induce structural changes within the eye. Although A. franciscana inhabit endorheic environments that are too saline for most fish, kairomones from an estuarine fish amplify photobehavior in these branchiopod crustaceans. The mechanism for this behavioral change has both similarities to and differences from that described in marine malacostracan crustaceans. PMID- 29164333 TI - The ubiquity of pleiotropy in human disease. AB - Pleiotropy has long been thought to be a common phenomenon in the human genome; however, until recently appropriate data was unavailable to test this hypothesis. Prior studies focused on assessing the prevalence of pleiotropy in only small subsets of phenotypes (<= 53 phenotypes), without a truly comprehensive assessment of pleiotropy in the human genome. In this study, we determined the prevalence of pleiotropy, using the entire GWAS catalog (1094 disease phenotypes, 14,459 genes), as well as investigate the relationship between the degree of pleiotropy and the average effect size for each associating gene. The number of associating phenotypes per gene ranged from 1 to 53, with 44% of genes reported in the GWAS catalog associating with more than one phenotype. The proportion of genes shown to be pleiotropic has continued to increase as more studies are added to the catalog. We also found the degree of pleiotropy scales positively with a gene's average effect size (r = 0.04, p value = 0.0003) and negatively with the variance of effect sizes in genes with a given number of associating phenotypes (r = - 0.590, p value = 0.0019). Based on this and prior work, it is becoming evident that pleiotropy is a common, if not ubiquitous, phenomenon. These results have implications in understanding disease etiologies, potentially common biology underlying even disparate diseases, and in elucidating the genotype-phenotype map. PMID- 29164334 TI - Association between fentanyl test results and rescue morphine requirements in children after adenotonsillectomy. AB - PURPOSE: Preoperative sleep study helps to predict post-adenotonsillectomy morphine requirements. However, in some institutions, many suspected children with obstructive sleep apnoea syndrome have an adenotonsillectomy without polysomnography assessments. This study investigated the relationship between the results of a fentanyl test performed before extubation and the postoperative morphine requirements in children after adenotonsillectomy. METHODS: Intravenous fentanyl (1 ug/kg) was given as a test before extubation when spontaneous ventilation was restored in 80 children aged 3-7 years who underwent adenotonsillectomy. The result was considered positive if the patient's respiratory rate decreased >50% after the test. In the recovery room, pain was assessed every 10 min using the Children's Hospital of Eastern Ontario Pain Scale. Rescue morphine (10 ug/kg) was given when the score was >=6. RESULTS: The median [IQR (range)] cumulative morphine consumption rates for children with a positive result (n = 25) and a negative result (n = 52) were 30 (20, 40) and 50 (40, 50) ug/kg, respectively (P = 0.002). Eighty-eight percent of the positive result patients and 48% of the negative-result patients were light consumers of morphine (cumulative dose <50 ug/kg) (P = 0.001). CONCLUSIONS: We conclude that children with a positive result after a fentanyl test require less morphine to achieve comfort than those with a negative result. CLINICALTRIALS. GOV ID: NCT02484222. PMID- 29164332 TI - Individual trajectories of cognitive performance in first episode psychosis: a 2 year follow-up study. AB - Individual changes over time in cognition in patients with psychotic disorders have been studied very little, especially in the case of first episode psychosis (FEP). We aimed to establish whether change in individual trajectories in cognition over 2 years of a sample of 159 FEP patients was reliable and clinically significant, using the reliable change index (RCI) and clinically significant change (CSC) methods. We also studied a sample of 151 matched healthy controls. Patients and controls were assessed with a set of neuropsychological tests, as well as premorbid, clinical and functionality measures. We analysed the course of cognitive measures over time, using analysis of variance, and the individual trajectories in the cognitive measures with the regression-based RCI (RCISRB) and the CSC. The RCISRB showed that between 5.4 and 31.2% of the patients showed deterioration patterns, and between 0.6 and 8.8% showed improvement patterns in these tests over time. Patients showing better cognitive profiles according to RCISRB (worsening in zero to two cognitive measures) showed better premorbid, clinical and functional profiles than patients showing deterioration patterns in more than three tests. When combining RCISRB and CSC values, we found that less than 10% of patients showed improvement or deterioration patterns in executive function and attention measures. These results support the view that cognitive impairments are stable over the first 2 years of illness, but also that the analysis of individual trajectories could help to identify a subgroup of patients with particular phenotypes, who may require specific interventions. PMID- 29164335 TI - Clinical characteristics of acute pancreatitis in pregnancy: experience based on 121 cases. AB - PURPOSE: Acute pancreatitis in pregnancy (APIP) is a rare condition; however, it markedly affects maternal and fetal health. This study aimed to describe the types, clinical characteristics, mortality, and the safety and necessity of gestation termination of acute pancreatitis in pregnancy (APIP). METHODS: We retrospectively reviewed 121 APIP cases in the Gastroenterology Department of The First Affiliated Hospital of Nanchang University. APIP diagnosis were based on 2012 Atlanta Criteria. The correlation between APIP types, severity, biochemical parameters and mortality was analyzed. RESULTS: The most common symptoms for APIP were abdominal pain (86.8%) and vomiting (73.6%). The most common causes for APIP were gallstone (36.4%) and hypertriglyceridemia (32.2%) and hypertriglyceridemic APIP was correlated with a higher rate for local complication (P = 0.012). Serum calcium level was negatively correlated with the severity of APIP (P < 0.01). The overall maternal and fetal mortality rate were 3.3% (4/121) and 11.6% (14/121), respectively. The severity of APIP was significantly correlated with higher risks for maternal and fetal death (P < 0.01). 72.7% of moderate-to-severe APIP patients underwent Cesarean section to terminate gestation safely. CONCLUSION: The most common causes of APIP were gallstone and hypertriglyceridemia. Lower level of serum calcium could be used as an indicator for the severity of the APIP. The severity of APIP was associated with higher risk for neonate asphyxia, and maternal and fetal death. PMID- 29164336 TI - Stimulation of chemokines in human endometrial stromal cells by tumor necrosis factor-alpha and interferon-gamma is similar under apoptotic and non-apoptotic conditions. AB - PURPOSE: Tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma are pro inflammatory cytokines which have been shown to be involved in the pathophysiology of implantation disorders. Both cytokines in combination are able to sensitize primarily resistant human endometrial stromal cells (ESCs) to Fas induced apoptosis. Since CCL (CC-chemokine ligand) 5 and CCL2 are important regulators of the endometrial immune cell population, we examined the impact of TNF-alpha and IFN-gamma on these two chemokines under non-apoptotic and apoptotic conditions. METHODS: ESCs were isolated from hysterectomy specimens, decidualized in vitro and incubated with TNF-alpha, IFN-gamma, an activating anti-Fas antibody and a caspase-inhibitor. CCL5 and CCL2 were measured using ELISA and real-time RT PCR. Apoptosis was determined by flow cytometry, and cellular viability and membrane integrity were measured by fluorescent assays. RESULTS: The secretion of CCL5 and CCL2 was stimulated in undifferentiated and decidualized ESCs by the combination of TNF-alpha and IFN-gamma under non-apoptotic as well as apoptotic (with Fas-stimulation in parallel) conditions. TNF-alpha or IFN-gamma alone did not have this effect. The stimulatory influence of TNF-alpha plus IFN-gamma on CCL5 and CCL2 in ESCs was also seen on the transcriptional level. Inhibition of cell death by a caspase-inhibitor had no influence on the secretion of CCL5 and CCL2 in ESCs under apoptotic stimulation. CONCLUSION: TNF-alpha and IFN-gamma modulate the secretion of chemokines in ESCs independently of Fas-induced apoptosis. These results suggest a constant response pattern on pro-inflammatory cytokines within the population of human ESCs. PMID- 29164337 TI - Changes in the midgut cells in the European cave spider, Meta menardi, during starvation in spring and autumn. AB - During the growth period, in surface habitats, spiders catch enough prey to feed normally. In contrast, in the cave entrance zone, prey may be relatively scarce. Meta menardi inhabits this cave section, resulting in temporary starvation. We studied structural changes in the midgut epithelial cells of M. menardi during a short-term and a medium-term controlled starvation to mimic the occasional starvation in caves, during spring and autumn. Digestive cells, secretory cells and adipocytes were examined before the experimental starvation, in the middle and at the end of starvation. We used light microscopy, transmission electron microscopy and specific histochemical methods for the detection of lipids, polysaccharides and proteins. Detection of lysosomes, autolysosomes and apoptosis was also carried out. The general structures of the cells did not change during the experimental starvation in either season, while some specific differences in the ultrastructure were observed. In both sexes, in both seasons, the amounts of lipids, glycogen and proteins decreased during starvation. Larger amounts of lipids were found in autumn, while there were no significant differences in the amounts of glycogen and proteins. In both sexes, in both seasons, autophagy and apoptosis intensified with starvation in progress, but more intensively in females. Thus, autumn individuals, in contrast to spring ones, compile energy supplying stores to confront the subsequent winter deficiency of prey in caves, while the cellular ultrastructures undergo the same starvation-dependant changes at any time during the growth period. PMID- 29164338 TI - Bias-dependent photoresponsivity of multi-layer MoS2 phototransistors. AB - We studied the variation of photoresponsivity in multi-layer MoS2 phototransistors as the applied bias changes. The photoresponse gain is attained when the photogenerated holes trapped in the MoS2 attract electrons from the source. Thus, the photoresponsivity can be controlled by the gate or drain bias. When the gate bias is below the threshold voltage, a small amount of electrons are diffused into the channel, due to large barrier between MoS2 and source electrode. In this regime, as the gate or drain bias increases, the barrier between the MoS2 channel and the source becomes lower and the number of electrons injected into the channel exponentially increases, resulting in an exponential increase in photoresponsivity. On the other hand, if the gate bias is above the threshold voltage, the photoresponsivity is affected by the carrier velocity rather than the barrier height because the drain current is limited by the carrier drift velocity. Hence, with an increase in drain bias, the carrier velocity increases linearly and becomes saturated due to carrier velocity saturation, and therefore, the photoresponsivity also increases linearly and becomes saturated. PMID- 29164339 TI - Fractional nuclear charge approach to isolated anion densities for Hirshfeld partitioning methods. AB - Atoms in molecules methods that rely on reference promolecular densities typically require that one define, or otherwise determine, the densities of unbound atomic anions. Whereas the isolated atomic polyanions are always physically and computationally unbound, monoanions can be either physically bound but computationally unbound (like the oxygen anion at the Hartree-Fock level of theory), or physically unbound but computationally bound (like the nitrogen anion using many DFT methods with a basis set including diffuse functions). Depending on the level of theory and basis set used, the densities of negatively charged atomic ions can decay very slowly and even be nonmonotonically decreasing. These delocalized anionic densities induce ill-behaved atomic properties for compounds containing highly reduced atoms. To treat the problem of unphysical proatom densities in iterative Hirshfeld methods, we compute the smallest (typically fractional) nuclear charge to bind all electrons, called the effective nuclear charge [Formula: see text] of an atom A. When [Formula: see text] at a given level of theory, the scaled density corresponding to the effective nuclear charge is used as the negatively charged proatom density. This novel approach dramatically improves the computational robustness of the iterative Hirshfeld partitioning scheme. PMID- 29164340 TI - Correlation Filters for Detection of Cellular Nuclei in Histopathology Images. AB - : Nuclei detection in histology images is an essential part of computer aided diagnosis of cancers and tumors. It is a challenging task due to diverse and complicated structures of cells. In this work, we present an automated technique for detection of cellular nuclei in hematoxylin and eosin stained histopathology images. Our proposed approach is based on kernelized correlation filters. Correlation filters have been widely used in object detection and tracking applications but their strength has not been explored in the medical imaging domain up till now. Our experimental results show that the proposed scheme gives state of the art accuracy and can learn complex nuclear morphologies. Like deep learning approaches, the proposed filters do not require engineering of image features as they can operate directly on histopathology images without significant preprocessing. However, unlike deep learning methods, the large margin correlation filters developed in this work are interpretable, computationally efficient and do not require specialized or expensive computing hardware. AVAILABILITY: A cloud based webserver of the proposed method and its python implementation can be accessed at the following URL: http://faculty.pieas.edu.pk/fayyaz/software.html#corehist . PMID- 29164342 TI - Survival pathways in cardiac conditioning: individual data vs. meta-analyses. What do we learn? PMID- 29164341 TI - Mathematical Models of HIV Latency. AB - Viral latency is a major barrier to curing HIV infection with antiretroviral therapy, and consequently, for eliminating the disease globally. The establishment, maintenance, and potential clearance of latent infection are complex dynamic processes and can be best understood and described with the help of mathematical models. Here we review the use of viral dynamics models for HIV, with a focus on applications to the latent reservoir. Such models have been used to explain the multiphasic decay of viral load during antiretroviral therapy, the early seeding of the latent reservoir during acute infection and the limited inflow during treatment, the dynamics of viral blips, and the phenomenon of posttreatment control. In addition, mathematical models have been used to predict the efficacy of potential HIV cure strategies, such as latency-reversing agents, early treatment initiation, or gene therapies, and to provide guidance for designing trials of these novel interventions. PMID- 29164344 TI - Theoretical investigation on the covalence in AgRnX and XAgRn (X = F - I). AB - CCSD(T) calculations were performed to investigate the stabilities and interaction mechanisms of the AgRnX and XAgRn (X = F - I) series. Dissociation energies and frontier orbital properties demonstrate an increased trend of stabilities. Ag spd hybrids and Rn/X sp hybrids come into the sigmaAg-Rn and sigmaAg-X bonding orbital. The nature of Ag-Rn, Ag-X and Rn-X interactions were investigated by atoms in molecules (AIM) theory. The negative energy density and positive Laplacian values, as well as small electron densities at bond critical points (BCPs), characterize the moderate strength with partial covalence of interactions. BCP properties (-G/V and G/rho), electron density deformations and natural resonance theory (NRT) results display increased covalence down the periodic table. PMID- 29164343 TI - Determining the size of a complete disturbance landscape: multi-scale, continental analysis of forest change. AB - The scale of investigation for disturbance-influenced processes plays a critical role in theoretical assumptions about stability, variance, and equilibrium, as well as conservation reserve and long-term monitoring program design. Critical consideration of scale is required for robust planning designs, especially when anticipating future disturbances whose exact locations are unknown. This research quantified disturbance proportion and pattern (as contagion) at multiple scales across North America. This pattern of scale-associated variability can guide selection of study and management extents, for example, to minimize variance (measured as standard deviation) between any landscapes within an ecoregion. We identified the proportion and pattern of forest disturbance (30 m grain size) across multiple landscape extents up to 180 km2. We explored the variance in proportion of disturbed area and the pattern of that disturbance between landscapes (within an ecoregion) as a function of the landscape extent. In many ecoregions, variance between landscapes within an ecoregion was minimal at broad landscape extents (low standard deviation). Gap-dominated regions showed the least variance, while fire-dominated showed the largest. Intensively managed ecoregions displayed unique patterns. A majority of the ecoregions showed low variance between landscapes at some scale, indicating an appropriate extent for incorporating natural regimes and unknown future disturbances was identified. The quantification of the scales of disturbance at the ecoregion level provides guidance for individuals interested in anticipating future disturbances which will occur in unknown spatial locations. Information on the extents required to incorporate disturbance patterns into planning is crucial for that process. PMID- 29164345 TI - Ab initio molecular dynamics of the reactivity of vitamin C toward hydroxyl and HO2/O-2 radicals. AB - Vitamin C is one of the most abundant exogenous antioxidants in the cell, and it is of the utmost importance to elucidate its mechanism of action against radicals. In this study, the reactivity of vitamin C toward OH and [Formula: see text] radicals in aqueous medium was analyzed by ab initio molecular dynamics using CPMD code. The simulations led to results similar to those of static studies or experiments for the pair of [Formula: see text] radicals but bring new insights for the reactivity with hydroxyl radical: the reaction takes place before the formation of an adduct and consists of two steps: first an electron is transferred to hydroxyl radical and then the ascorbyl radical loses a proton. Graphical Abstract Reactivity of vitamin C toward hydroxyl and [Formula: see text] radicals. PMID- 29164347 TI - An EPIC Switch: Preparing for an Electronic Health Record Transition at Vanderbilt University Medical Center. PMID- 29164346 TI - Impact of prior androgen receptor-axis-targeted agents on the clinical activity of subsequent docetaxel in patients with metastatic castration-resistant prostate cancer: comparative assessment between abiraterone acetate and enzalutamide. AB - The objective of this study was to investigate the impact of prior treatment with androgen receptor-axis-targeted (ARAT) agents, abiraterone acetate (AA) and enzalutamide (Enz), on the activity of subsequently introduced docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). This study included a total of 114 mCRPC patients consisting of 54 and 60 who progressed following treatment with AA and Enz, respectively, prior to the introduction of docetaxel, and compared oncological outcomes with docetaxel between these two groups. There were no significant differences in the major clinicopathological characteristics before treatment with docetaxel between the AA and Enz groups. The prostate-specific antigen (PSA) response rates to docetaxel in the AA and Enz groups were 40.7 and 43.3%, respectively, with no significant differences in the rates between these two groups. Following the introduction of docetaxel, the median PSA progression-free survival (PFS) and overall survival (OS) in the 114 patients were 7.2 and 17.5 months, respectively. There was no significant difference in the PSA PFS or OS between the AA and Enz groups. Despite the lack of a significant impact of the type of ARAT agent on PSA PFS or OS by univariate analysis, multivariate analyses identified the following independent prognostic predictors: performance status (PS) for PSA PFS and PS and visceral metastasis for OS. Collectively, these findings suggest that the type of ARAT agent may not have a significant impact on disease control by subsequent docetaxel therapy in mCRPC patients. PMID- 29164348 TI - Delineation of Inheritance Pattern of Aleurone Layer Colour Through Chemical Tests in Rice. AB - BACKGROUND: Rice aleurone layer develops different colours with various chemical tests that may help to develop some rapid tests for identification/grouping of rice varieties. Understanding the colour inheritance pattern could enable to develop chemical clues that may help for genetic purity analysis along with grow out-test. RESULTS: In this study, inheritance pattern of aleurone layer colour was studied in parents, F1 and F2 progenies derived from the crosses IR 36 * Acc. No. 2693 and IR 64 * Acc. No. 2693. The parent IR 36 showed light yellow (NaOH/KOH) and brown (phenol/modified phenol test) colour; whereas, Acc. No. 2693 revealed wine red/dark wine red (NaOH/KOH) and light brown colour/no reaction (phenol/modified phenol test). In contrary, another parent IR 64 exhibited light yellow (KOH/NaOH) and dark brown (phenol, modified phenol) colour. Both the F1 showed an intermediate light wine red colour (NaOH/KOH) and dark brown (phenol and modified phenol) colour, which is dominant over their one of the parents. The colour pattern with standard phenol/modified phenol, NaOH and KOH tests in F2 progenies of both the crosses showed 9:7 (complementary gene interaction) and 11:5 ratios (reciprocal dominance modification of recessive alleles), respectively. CONCLUSIONS: Our findings clearly elucidate the colour inheritance pattern in rice that may facilitate to develop rapid chemical tests to identify/ group the varieties for genetic purity analysis. PMID- 29164349 TI - The influence of solvent on conformational properties of peptides with Aib residue-a DFT study. AB - The conformational propensities of the Aib residue on the example of two model peptides Ac-Aib-NHMe (1) and Ac-Aib-NMe2 (2), were studied by B3LYP and M06-2X functionals, in the gas phase and in the polar solvents. To verify the reliability of selected functionals, we also performed MP2 calculations for the tested molecules in vacuum. Polarizable continuum models (PCM and SMD) were used to estimate the solvent effect. Ramachandran maps were calculated to find all energy minima. Noncovalent intramolecular interactions due to hydrogen-bonds and dipole attractions between carbonyl groups are responsible for the relative stabilities of the conformers. In order to verify the theoretical results, the available conformations of similar X-ray structures from the Cambridge Crystallographic Data Center (CCDC) were analyzed. The results of the calculations show that both derivatives with the Aib residue in the gas phase prefer structures stabilized by intramolecular N-H?O hydrogen bonds, i.e., C5 and C7 conformations, while polar solvent promotes helical conformation with phi, psi values equal to +/-60 degrees , +/-40 degrees . In addition, in the case of molecule 2, the helical conformation is the only one available in the polar environment. This result is fully consistent with the X-ray data. Graphical abstract Effect of solvent on the Ramachandran maps of the model peptides with Aib residue. PMID- 29164350 TI - Predictors of Partial Hospital Readmission for Young Children with Oppositional Defiant Disorder. AB - This study aimed to: (1) examine rates of readmission among young children with oppositional defiant disorder (ODD) following discharge from a psychiatric partial hospital treatment program, and (2) examine child factors (i.e., age, sex, co-occurring diagnoses, suicidality) and family factors (i.e., parental depression, stress) as prospective predictors of readmission. Participants were 261 children (ages 3-7 years) who entered the study at the time of their initial program admission and who met DSM-IV criteria for ODD. Of these 261 children, 61 (23%) were subsequently readmitted, with most readmissions occurring within 1 year. Cox regression survival analyses demonstrated that younger child age, child suicidal thoughts and behavior, and child PTSD diagnosis were associated with decreased time to readmission. Findings suggest that young children with ODD who present with co-occurring suicidality or PTSD are at risk for readmission following partial hospitalization, with implications for treatment and aftercare planning. PMID- 29164351 TI - Latent Class Symptom Profiles of Selective Mutism: Identification and Linkage to Temperamental and Social Constructs. AB - Selective mutism (SM) is a stable, debilitating psychiatric disorder in which a child fails to speak in most public situations. Considerable debate exists as to the typology of this population, with empirically-based studies pointing to possible dimensions of anxiety, oppositionality, and communication problems, among other aspects. Little work has juxtaposed identified symptom profiles with key temperamental and social constructs often implicated in SM. The present study examined a large, diverse, non-clinical, international sample of children aged 6 10 years with SM to empirically identify symptom profiles and to link these profiles to key aspects of temperament (i.e., emotionality, shyness, sociability, activity) and social functioning (i.e., social problems, social competence). Exploratory and confirmatory factor analysis revealed anxiety/distress, oppositionality, and inattention domains. In addition, latent class analysis revealed nuanced profiles labeled as (1) moderately anxious, oppositional, and inattentive, (2) highly anxious, and moderately oppositional and inattentive, and (3) mildly to moderately anxious, and mildly oppositional and inattentive. Class 2 was the most impaired group and was associated with greater emotionality, shyness, and social problems. Class 3 was the least impaired group and was associated with better sociability and social competence and activity. Class 1 was largely between the other classes, demonstrating less shyness and social problems than Class 2. The results help confirm previous findings of anxiety and oppositional profiles among children with SM but that nuanced classes may indicate subtle variations in impairment. The results have implications not only for subtyping this population but also for refining assessment and case conceptualization strategies and pursuing personalized and perhaps less lengthy treatment. PMID- 29164353 TI - Assessing the Theory of Gender and Power: HIV Risk Among Heterosexual Minority Dyads. AB - This study drew on the Theory of Gender and Power (TGP) as a framework to assess power inequalities within heterosexual dyads and their effects on women. Structural equation modeling was used to better understand the relationship between structural and interpersonal power and HIV sexual risk within African American and Latina women's heterosexual dyads. The main outcome variable was women's sexual HIV risk in the dyad and was created using women's reports of condomless sex with their main male partners and partners' reports of their HIV risk behaviors. Theoretical associations developed a priori yielded a well fitting model that explained almost a quarter of the variance in women's sexual HIV risk in main partner dyads. Women's and partner structural power were indirectly associated with women's sexual HIV risk through substance use and interpersonal power. Interpersonal power was directly associated with risk. In addition, this study found that not identifying as heterosexual was directly and indirectly associated with women's heterosexual sex risk. This study provides further support for the utility of the TGP and the relevance of gender-related power dynamics for HIV prevention among heterosexually-active women. PMID- 29164352 TI - Assessment of Methylobacterium oryzae CBMB20 aggregates for salt tolerance and plant growth promoting characteristics for bio-inoculant development. AB - Salinity is one of the major factors contributing to the loss of crop productivity and thereby impacting livelihood of people in more than 100 countries of the world and the area of land affected by salinity is increasing day by day. This will worsen due to various factors such as drought that might result in high soil salinity. Use of plant growth promoting rhizobacteria is one of the promising eco-friendly strategies for salinity stress management as part of sustainable agricultural practices. However, it requires selecting rhizobacteria with good survivability and adaptation to salt stress. In this study we report aggregation of Methylobacterium oryzae CBMB20 cells grown in media containing high C/N ratio (30:1) than in media containing low C/N ratio (7:1). Aggregated Methylobacterium oryzae CBMB20 cells exhibited enhanced tolerance to UV irradiation, heat, desiccation, different temperature regimes, oxidative stress, starvation and supported higher population in media. Poly-beta hydroxybutyrate accumulation, exopolysaccharide production, proline accumulation and biofilm formation were good at 100 mM salt concentration with good microbial cell hydrophobicity at both 50 and 100 mM than other concentrations. Both the aggregated and non-aggregated cells grown under 0-200 mM salt concentrations produced IAA even at 200 mM salt concentration with a peak at 100 mM concentration with aggregated cells producing significantly higher quantities. ACC deaminase activity was observed in all NaCl concentrations studied with gradual and drastic reduction in aggregated and non-aggregated cells over increased salt concentrations. PMID- 29164354 TI - Associations Between Major Depressive Episode, Methamphetamine Use Disorder Severity, and Engagement in Sexual Risk-Taking Among Methamphetamine-Using Men Who Have Sex with Men. AB - Depression and methamphetamine use have been associated with increased sexual risk-taking among men who have sex with men (MSM). This study estimated associations between current major depressive episode and/or methamphetamine use disorder and engagement in condomless anal intercourse (CAI). From March 2014 thru January 2016, 286 methamphetamine-using MSM were enrolled into a RCT to reduce methamphetamine use and sexual risk-taking. Analyses revealed that current major depressive episode was associated with a 92% increase in the rate of engagement in CAI with casual male partners (IRR 1.92; 95% CI 1.12-3.31) and a 76% increase in the rate of engagement in CAI with anonymous male partners (IRR 1.76; 95% CI 1.00-3.09). Additionally, for each unit increase in diagnostic methamphetamine use disorder severity, rates of engagement in CAI with anonymous male partners increased by 44% (IRR 1.44; 95% CI 1.11-1.87) and rates of engagement in CAI with exchange male partners increased by 140% (IRR 2.40; 95% CI 1.39-4.13). Neither diagnosis was associated with CAI with main male partners. Depression and methamphetamine use influence sexual risk-taking in unique ways, and interventions working with MSM should assess participants for both depression and methamphetamine use, and may tailor intervention content based on diagnostic outcomes. PMID- 29164356 TI - Investigating the impacts of treated effluent discharge on coastal water health (Visakhapatnam, SW coast of Bay of Bengal, India). AB - The present study investigated the impacts of treated effluent discharge on physicochemical and biological properties of coastal waters from three pharmaceuticals situated along the coast of Visakhapatnam (SW Bay of Bengal). Seawater samples were collected (during the months of December 2013, March 2014 and April 2014) from different sampling locations (Chippada (CHP), Tikkavanipalem (TKP) and Nakkapalli (NKP)) at 0- and 30-m depths within 2-km radius (0.5 km = inner, 1 km = middle and 2 km = outer sampling circles) from the marine outfall points. Physicochemical and biological parameters, which differed significantly within the stations, were likely to be influenced by strong seasonality rather than local discharge. Dissolved oxygen variability was tightly coupled with both physical and biological processes. Phytoplankton cell density and total chlorophyll (TChla) concentrations were significantly correlated with dissolved inorganic nutrient concentrations. CHP (December) represented a diatom bloom condition where the highest concentrations of diatom cells, total chlorophyll (TChla), dissolved oxygen coupled with lower zooplankton abundance and low nutrient levels were noticed. The centric diatom, Chaetoceros sp. (> 50%) dominated the phytoplankton community. TKP (March) represented a post-diatom bloom phase with the dominance of Pseudo-nitzschia seriata; zooplankton abundance and nutrient concentrations were minimum. Conversely, NKP (April) represented a warm well-stratified heterotrophic period with maximum zooplankton and minimum phytoplankton density. Dinoflagellate abundance increased at this station. Relatively higher water temperature, salinity, inorganic nutrients coupled with very low concentrations of dissolved oxygen, TChla and pH were observed at this station. Copepods dominated the zooplankton communities in all stations and showed their highest abundance in the innermost sampling circles. Treated effluent discharge did not seem to have any significant impact at these discharge points. PMID- 29164355 TI - Plastid Genome of Dictyopteris divaricata (Dictyotales, Phaeophyceae): Understanding the Evolution of Plastid Genomes in Brown Algae. AB - Dictyotophycidae is a subclass of brown algae containing 395 species that are distributed worldwide. A complete plastid (chloroplast) genome (ptDNA or cpDNA) had not previously been sequenced from this group. In this study, the complete plastid genome of Dictyopteris divaricata (Okamura) Okamura (Dictyotales, Phaeophyceae) was characterized and compared to other brown algal ptDNAs. This plastid genome was 126,099 bp in size with two inverted repeats (IRs) of 6026 bp. The D. divaricata IRs contained rpl21, making its IRs larger than representatives from the orders Fucales and Laminariales, but was smaller than that from Ectocarpales. The G + C content of D. divaricata (31.19%) was the highest of the known ptDNAs of brown algae (28.94-31.05%). Two protein-coding genes, rbcR and rpl32, were present in ptDNAs of Laminariales, Ectocarpales (Ectocarpus siliculosus), and Fucales (LEF) but were absent in D. divaricata. Reduced intergenic space (13.11%) and eight pairs of overlapping genes in D. divaricata ptDNA made it the most compact plastid genome in brown algae so far. The architecture of D. divaricata ptDNA showed higher similarity to that of Laminariales compared with Fucales and Ectocarpales. The difference in general features, gene content, and architecture among the ptDNAs of D. divaricata and LEF clade revealed the diversity and evolutionary trends of plastid genomes in brown algae. PMID- 29164357 TI - Reversible inflammatory neuropathy superimposed on Charcot-Marie-Tooth type 1A disease. PMID- 29164358 TI - Medical and neuropsychiatric phenomena depicted in two Spanish medieval texts of Marian miracles. AB - In the history of Christianity, veneration of the Virgin Mary reached its greatest intensity in the XIII century. Her perceived impact on daily life was tremendous and not surprisingly this extended to the spheres of disease and healing. The purpose of this study is to compare the medical and neuropsychiatric findings in two XIII century Spanish texts of Marian miracles, both examples of the popular Catholicism (vs. official catholic doctrine). We analyzed the medical and neuropsychiatric events in the Cantigas de Santa Maria (Canticles of St. Mary, CSM), composed at the court of Alfonso X and the Milagros de Nuestra Senora (The Miracles of Our Lady, MNS), written by Gonzalo de Berceo. Among the 25 miracles reported in the MNS, medically relevant facts were addressed in 19 miracles with a total of 23 recorded events (including resurrection or escape from death in five) and demonic possession in three (one with witchcraft/deicide). The most common medical subjects were ergotism, obstetric gynecological, sudden death, intellectual disability/illiteracy, encephalopathy/alcohol intoxication, suicide (with self-mutilation/castration), infanticide, infections, and absence of body decomposition after death. The 427 canticles in the CSM contain 270 medically relevant facts. Neuropsychiatric conditions were alluded to in 98 songs. Blindness and dystonia/weakness/deformities were the most common phenomena. Illuminations detailed many of the medical facts in the CSM, but not in the MNS. Medically relevant facts were described in both texts, but with more details in the CSM. Neurological conditions were more often described in the CSM, psychiatric conditions in the MNS. PMID- 29164359 TI - Exposure assessment of particulate matter and blood chromium levels in people living near a cement plant. AB - This study evaluates the effect of air pollution caused by cement plants on nearby residential areas and performs an exposure assessment of particulate matter (PM) and total Cr, Cr6+, Pb, and Al. Further, the blood Cr levels of residents exposed to PM released by cement plants are also assessed. Nine buildings (eight residential and one elementary school building) close to cement plants were selected for this study, which were located in Pyeongtaek port, in west of Gyeonggi Province, South Korea. A total of 51 suspended particulate samples were collected at a flow rate of 2.0 L/min. Total Cr was more widely detected in residents' houses and elementary schools. PM levels were higher at distances of 4.1 and 4.8 km than those at closer distances of 2.7 km. This was due to the influence of wind direction. The estimated mean blood level of Cr for the study participants was 3.80 MUg/L, which is higher than levels estimated by other studies on Cr blood levels. Therefore, cement plants could cause an increase in total Cr and blood Cr levels in residential areas, and more continuous monitoring is necessary to better understand their impacts. PMID- 29164360 TI - Risk of osteoporosis after gastrectomy in long-term gastric cancer survivors. AB - INTRODUCTION: Although early detection and successful gastrectomy have improved the survival of patients with gastric cancer, long-term health problems remain troubling. We evaluated the prevalence of osteoporosis and its risk factors in long-term survivors of gastric cancer after gastrectomy. METHODS: We reviewed the medical records of a tertiary hospital between 2007 and 2014 to identify survivors of gastric cancer who had visited our center at around 5 years after gastrectomy. We evaluated their health status, including bone mineral density (BMD). Dual-energy X-ray absorptiometry was used to measure the BMD of the lumbar spine and femur (total and neck area). The prevalence of osteoporosis, defined by a BMD T score <-2.5, was investigated, and clinical variables associated with the presence of osteoporosis were identified. RESULTS: A total of 250 survivors were included. The mean age was 54.6 years old, and the median follow-up was 6.0 years. The prevalence of osteoporosis was 34.0% (27.4% for men and 43.6% for women). Older age [odds ratio (OR) 5.50, 95% CI 2.33-13.00], higher alkaline phosphatase levels before gastrectomy (OR 5.67, 95% CI 1.36-23.64), and marked weight loss (>=20%) after gastrectomy (OR 3.59, 95% CI 1.32-9.77) were independently associated with the presence of osteoporosis. CONCLUSIONS: In our cohort, osteoporosis was commonly observed in long-term survivors of gastric cancer, and several risk factors for it were identified. To reduce the risk of osteoporosis after gastrectomy, maintaining adequate body weight may be necessary. PMID- 29164362 TI - Coping and Sexual Harassment: How Victims Cope across Multiple Settings. AB - The ways sexual harassment occurs both online and in face-to-face settings has become more complicated. Sexual harassment that occurs in cyberspace or online sexual harassment adds complexity to the experiences of victims, current research understandings, and the legal dimensions of this phenomenon. Social networking sites (SNS) are a type of social media that offer unique opportunities to users and sometimes the communication that occurs on SNS can cross the line from flirtation into online sexual harassment. Victims of sexual harassment employ communicative strategies such as coping to make sense of their experiences of sexual harassment. The current study qualitatively examined problem-focused, active emotion-focused, and passive emotion-focused coping strategies employed by sexual harassment victims across multiple settings. We conducted 26 in-depth interviews with victims that had experienced sexual harassment across multiple settings (e.g., face-to-face and SNS). The findings present 16 types of coping strategies-five problem-focused, five active emotion-focused, and six passive emotion-focused. The victims used an average of three types of coping strategies during their experiences. Theoretical implications extend research on passive emotion-focused coping strategies by discussing powerlessness and how victims blame other victims. Furthermore, theoretically the findings reveal that coping is a complex, cyclical process and that victims shift among types of coping strategies over the course of their experience. Practical implications are offered for victims and for SNS sites. PMID- 29164361 TI - Bacteraemia in emergency departments: effective antibiotic reassessment is associated with a better outcome. AB - Patients with bacteraemia constitute an useful population for an audit of antibiotic treatments. Empirical antibiotic therapy (EAT) and its reassessment must take into account clinical data and microbiological results. Our aim was to determine the impact of these sequential steps of the therapy on survival. This was a retrospective multicentre study which included patients admitted to emergency departments (ED) for whom blood cultures were positive over a 4-month period. Microbial results were compiled from the database of the laboratories. The relevant information was extracted from the computerized patient's chart. An efficient EAT was based on antibiotic susceptibility of the bacteria. An effective antibiotic reassessment (AR) was defined as any modification of the EAT. Unfavorable outcome was defined as death of the patient during in-hospital care. Three hospitals and two clinics took part in this study, 169 patients with bacteraemia being included. The diagnosis in ED was undetermined in 21 cases (12%), 35 patients (21%) required intensive care, and 23 died (14%). One hundred and thirty-six patients (80%) received an EAT, the latter being efficient in 107 cases (63%). An effective AR was performed in 116 cases (69%). In multivariate analysis, risks factors for death were: ongoing cancer AOR (adjusted odds ratio) 3.34, undetermined diagnosis in ED: AOR 9.34 and severe sepsis or shock: AOR 6.98. Effective AR was a protective factor: AOR 0.28 [0.09-0.81]. One third of bacteraemic patients in ED did not benefit from AR. Improvement of antimicrobial stewardship should be associated with a higher rate of survival. PMID- 29164363 TI - Can we HIIT cancer if we attack inflammation? AB - Physical exercise offers numerous health-related benefits to individuals with cancer. Epidemiologic research has primarily been concerned with conventional exercise training that aligns with the recommendations of 150 min of moderate to vigorous physical activity per week. These recommendations are safe and effective at improving physical and psychosocial outcomes. Given the extensive evidence for generalized physical activity, researchers have begun to explore novel training regimens that may provide additional health benefits and/or improved adherence. Specifically, exercise at higher intensities may offer more or different benefits than conventional training approaches with potentially profound effects on the tumor microenvironment. This commentary focuses on the physiological effects of high-intensity interval training, also known as "HIIT," and its potential antineoplastic properties. PMID- 29164365 TI - Organ doses and lifetime attributable risk evaluations for scoliosis examinations of adolescent patients with the EOS imaging system. AB - PURPOSE: The goal of this work is to evaluate organ doses and lifetime attributable risk of cancer incidence and mortality in scoliosis examinations of adolescent patients performed with EOS imaging system, in order to optimize patient dose and protocols. METHODS: An anthropomorphic phantom of a normal patient, with thermoluminescent dosimeters in correspondence with the main organs at risk, was imaged with both EOS and computed radiography (CR). For each modality, effective dose was calculated from the measured organ doses. Lifetime attributable risk was computed accordingly to the Committee on the Biological Effects of Ionizing Radiation (BEIR VII) and Public Health England (HPA) publications. RESULTS: Except for testes and eyes, which were excluded from the scan in CR protocol, for all the other organs the doses delivered with CR examination were higher than these delivered by EOS system. The effective dose in EOS examination (0.43 +/- 0.04 mSv) is about two times less than the dose in computed radiography with anti-scatter grid examination (0.87 +/- 0.09 mSv), and, consequently, also the cancer probability is lower (5.4 vs 9.7 number of any cancers induction cases per 100,000 person examined, for a 20-year-old male patient). CONCLUSIONS: The EOS system is efficient in limiting patient dose. The shielding of testes and the exclusion of eyes from the scan could allow to further reduce the dose. PMID- 29164364 TI - Highlights on MRI of the fetal body. AB - Fetal MRI is a level III diagnostic tool performed subsequently a level II prenatal ultrasound (US), in cases of inconclusive ultrasonographic diagnosis or when a further investigation is required to confirm or improve the diagnosis, to plan an appropriate pregnancy management. Fetal MRI plays an increasingly important role in the prenatal diagnosis of fetal neck, chest and abdominal malformations, even if its role has been amply demonstrated, especially, in the field of fetal CNS anomalies. Due to its multiparametricity and multiplanarity, MRI provides a detailed evaluation of the whole fetal respiratory, gastrointestinal and genitourinary systems, especially on T2-weighted (W) images, with a good tissue contrast resolution. In the evaluation of the digestive tract, T1-W sequences are very important in relation to the typical hyperintensity of the large intestine, due to the presence of meconium. The objective of this review is to focus on the application of fetal MRI in neck, chest and abdominal diseases. PMID- 29164366 TI - Contrasting survival and physiological responses of sub-Arctic plant types to extreme winter warming and nitrogen. AB - MAIN CONCLUSION: Evergreen plants are more vulnerable than grasses and birch to snow and temperature variability in the sub-Arctic. Most Arctic climate impact studies focus on single factors, such as summer warming, while ecosystems are exposed to changes in all seasons. Through a combination of field and laboratory manipulations, we compared physiological and growth responses of dominant sub Arctic plant types to midwinter warming events (6 degrees C for 7 days) in combination with freezing, simulated snow thaw and nitrogen additions. We aimed to identify if different plant types showed consistent physiological, cellular, growth and mortality responses to these abiotic stressors. Evergreen dwarf shrubs and tree seedlings showed higher mortality (40-100%) following extreme winter warming events than Betula pubescens tree seedlings and grasses (0-27%). All species had growth reductions following exposure to - 20 degrees C, but not all species suffered from - 10 degrees C irrespective of other treatments. Winter warming followed by - 20 degrees C resulted in the greatest mortality and was strongest among evergreen plants. Snow removal reduced the biomass for most species and this was exacerbated by subsequent freezing. Nitrogen increased the growth of B. pubescens and grasses, but not the evergreens, and interaction effects with the warming, freezing and snow treatments were minor and few. Physiological activity during the winter warming and freezing treatments was inconsistent with growth and mortality rates across the plants types. However, changes in the membrane fatty acids were associated with reduced mortality of grasses. Sub-Arctic plant communities may become dominated by grasses and deciduous plants if winter snowpack diminishes and plants are exposed to greater temperature variability in the near future. PMID- 29164367 TI - Mannans and endo-beta-mannanase transcripts are located in different seed compartments during Brassicaceae germination. AB - MAIN CONCLUSION: Mannans but not endo-beta-mannanases are mainly found in the mucilage layer of two Brassicaceae seeds. Nonetheless, mannanase mobilization from inner to outer seed layers cannot be ruled out. The contribution of endo beta-mannanase (MAN) genes to the germination of the wild-type Sisymbrium officinale and cultivated Brassica rapa (Brassicaceae) species has been explored. In both species, mannans have been localized to the imbibed external seed coat layer (mucilage) by fluorescence immunolocalization and MAN enzymatic activity increases in seeds as imbibition progresses, reaching a peak before 100% germination is achieved. The MAN gene families have been annotated and the expression of their members analyzed in vegetative and reproductive organs. In S. officinale and B. rapa, MAN2, MAN5, MAN6, and MAN7 transcripts accumulate upon seed imbibition. SoMAN7 is the most expressed MAN gene in S. officinale germinating seeds, as occurs with its ortholog in Arabidopsis thaliana, but in B. rapa, the most abundant transcripts are BrMAN2 and BrMAN5. These genes (MAN2, MAN5, MAN6, and MAN7) are localized, by mRNA in situ hybridization, to the micropylar at the endosperm layer and to the radicle in S. officinale, but in B. rapa, these mRNAs are faintly found to the micropylar living seed coat layer and are mainly present at the radicle tip and the vascular bundles. If the domestication process undergone by B. rapa is responsible for these different MAN expression patterns, upon germination remains to be elucidated. Since mannans and MAN genes are not spatially distributed in the same seed tissues, a movement of MAN enzymes that are synthesized with typical signal peptides from the embryo tissues to the mucilage layer (via apoplastic space) is necessary for the mannans to be hydrolyzed. PMID- 29164368 TI - 3D reconstruction of endoplasmic reticulum in a hydrocarbon-secreting green alga, Botryococcus braunii (Race B). AB - MAIN CONCLUSION: Based on 3D sections through cells of Botryococcus braunii, the structure of three domains of endoplasmic reticulum, and their spatial and functional relationships to other organelles are clarified. Oil production by photosynthetic microalgae has attracted attention since these oils can be converted into renewable, carbon-neutral fuels. The green alga B. braunii accumulates large amounts of hydrocarbons, 30-50% of cell dry weight, in extracellular spaces rather than its cytoplasm. To advance the knowledge of hydrocarbon biosynthesis and transport pathways in this alga, we utilized transmission EM combined with rapid freezing and image reconstruction. We constructed detailed 3D maps distinguishing three ER domains: rdER with ribosomes on both sides, rsER with ribosomes on one side, and sER without ribosomes. The rsER and sER domains were especially prominent during the oil body formation and oil secretion stages. The ER contacted the chloroplasts, oil bodies, or plasma membrane via the rsER domains, oriented with the ribosome-free surface facing the organelles. We discuss the following transport pathway for hydrocarbons and their precursors in the cytoplasm: chloroplast -> endoplasmic reticulum (ER) -> oil bodies -> ER -> plasma membrane -> secretion. This study represents the first 3D study of the three-domain classification (rdER, rsER and sER) of the ER network among eukaryotic cells. Finally, we propose the novel features of the ERs in plant cells that are distinct from the latest proposed model for the ERs in mammalian cells. PMID- 29164370 TI - Does enemy damage vary across the range of exotic plant species? Evidence from two coastal dune plant species in eastern Australia. AB - Release from natural enemies is often cited as a key factor for understanding the success of invasive plant species in novel environments. However, with time invasive species will accumulate native enemies in their invaded range, with factors such as spread distance from the site of introduction, climate and leaf level traits potentially affecting enemy acquisition rates. However, the influence of such factors is difficult to assess without examining enemy attack across the entire species' range. We tested the significance of factors associated with range expansion (distance from source population and maximum population density), climatic variables (annual temperature and rainfall) and leaf-level traits [specific leaf area (SLA) and foliar nitrogen concentration] in explaining variation in enemy damage across multiple populations of two coastal invasive plants (Gladiolus gueinzii Kunze and Hydrocotyle bonariensis Lam.) along their entire introduced distribution in eastern Australia. We found that for H. bonariensis, amount of foliar damage increased with distance from source population. In contrast, for G. gueinzii, probability and amount of foliar damage decreased with decreasing temperature and increasing rainfall, respectively. Our results show that patterns of enemy attack across species' ranges are complex and cannot be generalised between species or even range edges. PMID- 29164369 TI - Birth date promotes a tortoise or hare tactic for body mass development of a long lived male ungulate. AB - Maternal and early-life influences may affect life-long individual phenotype, potentially influencing reproductive success. However, some individuals may compensate for a poor start to life, which may improve longevity and reproductive success later in life. We developed four models to assess whether maternal characteristics (age, body mass and previous year cumulative lactation demand) and/or birth date influenced a long-lived mammal's phenotype to maturity. We used a directional separation analysis to assess the relative influence of each maternal characteristic and birth date on captive male white-tailed deer (Odocoileus virginianus) body mass and antler size. We found that birth date was the only characteristic that persistently influenced male body mass. Depending on when offspring were born, they used alternative tactics to increase their body mass. Birth date positively influenced body mass at 1, 2 and 3 years of age indicating males displayed faster growth and compensated for late birth (hare tactic). However, early-, heavy-born males were heavy juveniles, and juvenile body mass positively influenced mature body mass (slow but steady growth; tortoise tactic). Our findings provide a first evidence that a long-lived ungulate can display alternative tactics to achieve heavy body mass; individuals are either born early and heavy and are heavy throughout life (tortoise), or light, late-born individuals compensate for a poor start in life by growing at a faster rate to equal or surpass the body mass of early-born individuals (hare). Either tactic may be viable if it influences reproductive success as body mass positively influences access to mates in ungulates. PMID- 29164371 TI - Effects of multiple mutualists on plants and their associated arthropod communities. AB - Although most studies of mutualisms focus on a single partner at a time, host species often associate with multiple mutualist partners simultaneously. Because of potential interactions between mutualists, only studying a single type of mutualism could lead to a biased perspective of mutualism benefit and how mutualisms may scale-up to affect communities. The legume Chamaecrista fasciculata engages in a resource mutualism with nitrogen-fixing rhizobia and also forms symbiotic interactions with ants by providing nectar in exchange for defense against herbivores. Although they provide very different benefits to the plant, both mutualists receive carbon resources from the plant. As a result, these two mutualists are likely to interact, potentially competing for carbon resources or mutually benefitting each other via their positive effects on plant hosts. In a full-factorial field experiment, we explored how rhizobia and ants influence one another, C. fasciculata fitness, and the associated arthropod community. Ants reduced plant allocation to rhizobia, but ants also increased rhizobia contamination of uninoculated plants, suggesting that ants may disperse rhizobia. In turn, rhizobia increased ant abundances, with ants preferentially tending plants with rhizobia. Chamaecrista fasciculata received substantial fitness benefits from rhizobia; in contrast, associating with ants reduced fitness. Additionally, the mutualists interacted to influence the abundance of other arthropods found on the plants. Rhizobia increased arthropod abundances, likely because more nitrogen-rich leaf tissue was more attractive to arthropod herbivores, but ants negated these increases. As these results illustrate, multiple mutualists may interact, influencing each other's abundance and the abundance of other community members. PMID- 29164372 TI - Hippocampal neurogenesis in the C57BL/6J mice at early adulthood following prenatal alcohol exposure. AB - We examined the effect of chronic prenatal alcohol exposure (PAE) on the process of adult neurogenesis in C57BL/6J mice at early adulthood (PND 56). Pregnant mice, and their in utero litters, were exposed to alcohol, through oral gavage, on gestational days 7-16, with recorded blood alcohol concentrations averaging 184 mg/dL (CA group). Two control groups, sucrose (CAc) and non-treated (NTc) control groups were also examined. The brains of pups at PND 56 from each experimental group were sectioned in a sagittal plane, and stained for Nissl substance with cresyl violet, and immunostained for Ki-67 which labels proliferative cells and doublecortin (DCX) for immature neurons. Morphologically, the neurogenic pattern was identical in all three groups studied. Populations of Ki-67 immunopositive cells in the dentate gyrus were not statistically significantly different between the experimental groups and there were no differences between the sexes. Thus, the PAE in this study does not appear to have a strong effect on the proliferative process in the adult hippocampus. In contrast, the numbers of immature neurons, labeled with DCX, was statistically significantly lower in the prenatal alcohol exposed mice compared with the two control groups. Alcohol significantly lowered the number of DCX hippocampal cells in the male mice, but not in the female mice. This indicates that the PAE appears to lower the rate of conversion of proliferative cells to immature neurons and this effect of alcohol is sexually dimorphic. This lowered number of immature neurons in the hippocampus appears to mirror hippocampal dysfunctions observed in FASD children. PMID- 29164374 TI - Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis. AB - Published literature suggests that a fixed-dose 4-factor prothrombin complex concentrate (4FPCC) may be efficacious in managing warfarin-associated hemorrhage, however the ideal dose is still unclear. The purpose of this evaluation was to determine the efficacy of fixed-dose 4FPCC in reducing the International Normalized Ratio (INR) to <= 1.5 among warfarin patients with need for urgent or emergent anticoagulation reversal. Starting October 2016, our institution changed from standard 4FPCC FDA-labeled dosing based on the patient's presenting INR and weight, to a fixed-dose of 1500 units for all patients requiring urgent or emergent warfarin reversal. We conducted a retrospective evaluation, after implementation, with the primary outcome being the proportion of patients who achieved an INR <= 1.5 with a single fixed-dose of 1500 units of 4FPCC. Secondary outcomes assessed included: medication turnaround times, attainment of target INR <= 2 or clinical hemostasis (as judged by the prescribing provider), use of rescue doses, thrombotic events, and cost savings. A total of 37 patients were included in the analysis. Almost 75% of patients achieved an INR <= 1.5 after a single fixed dose of 1500 units, and 100% of patients achieved an INR <= 2. The median pre- and post-dose INRs were 3.06 and 1.32 respectively. Based on this evaluation, the administration of a fixed dose of 1500 units 4FPCC, was shown to be effective in adequately reversing the INR in the majority of patients with minimal thrombotic risks. PMID- 29164373 TI - The possible factors affecting microglial activation in cases of obesity with cognitive dysfunction. AB - Obesity has reached epidemic proportions in many countries around the world. Several studies have reported that obesity can lead to the development of cognitive decline. There is increasing evidence to demonstrate that microglia play a crucial role in cognitive decline in cases of obesity, Alzheimer's disease and also in the aging process. Although there have been several studies into microglia over the past decades, the mechanistic link between microglia and cognitive decline in obese models is still not fully understood. In this review, the current available evidence from both in vitro and in vivo investigations regarding the association between the alteration in microglial activity in different obese models with respect to cognition are included. The metabolite profiles from obesity, adiposity, dietary and hormone affected microglial activation and its function in the brain are comprehensively summarized. In addition, the possible roles of microglial activation in relation to cognitive dysfunction are also presented and discussed. To ensure a balanced perspective controversial reports regarding these issues are included and discussed. PMID- 29164375 TI - Patient-reported physical activity and the association with health-related quality of life in head and neck cancer survivors. AB - PURPOSE: This study aimed to assess patient-reported levels of physical activity (PA) and its associations with health-related quality of life (HRQoL) adjusted for important demographic, lifestyle-related, and clinical factors, among head and neck (HNC) survivors. METHODS: This cross-sectional study included 116 HNC survivors. PA was assessed with the Physical Activity Scale for the Elderly (PASE) and HRQoL with the EORTC-QLQ-C30 and EORTC-HN35. Associations were studied using univariable and multivariable regression analyses. RESULTS: Median PASE score was 100.3 (interquartile range 65.1;170.8) of which 54% were household, 34% leisure-time, and 12% occupational activities. Younger HNC survivors had higher levels of PA. Higher PA was significantly associated with higher global QoL (p < 0.05). Findings for physical function, role function, social function, fatigue, and pain were in line, but not statistically significant (0.05 <= p < 0.10). CONCLUSIONS: Among HNC survivors, a large proportion of PA consists of household activities. Younger HNC survivors had higher PA levels, and higher PA levels were associated with higher HRQoL. PMID- 29164376 TI - Evaluation of quality of life in caregivers who are providing home care to cancer patients. AB - PURPOSE: The author aimed to evaluate the quality of life and the factors affecting the caregivers of cancer patients receiving home care. METHODS: This cross-sectional descriptive study was performed in 48 cancer patients who were served from home care unit and 48 caregivers between 01 and 28 February 2014. Patients' functional status was evaluated with Katz Index for Activities of Daily Living and the Lawton Scale for Instrumental Activities of Daily Living. The levels of quality of life of caregivers of patients with cancer were determined with Caregiver Quality of Life Index-Cancer (CQOLC). RESULTS: The mean age of forty-eight patients was 69.79 +/- 16.09 years; 62.5% of them were female. The mean duration of home care was 5.99 +/- 5.26 years; 25% of patients were fully dependent on the bed. 83.3% of caregivers were female, mean age of caregivers was 50.75 +/- 14.89 years, and 77.1% of them were family members. The mean CQOLC score was 74.43 +/- 24.45. The highest score was detected in the financial distress and the lowest score was detected in the positive adaptation. The quality of life is increasing as the length of care is reduced and income status increased. CONCLUSION: The quality of life of caregivers is very low. Each characteristic of the caregiver will affect the care he/she gives. From this point of view, it is important to consider the characteristics of caregivers in improving the care given to cancer patients. In this respect, there is a need to support caregivers both materially and spiritually. PMID- 29164377 TI - Systemic and local effects of vaginal dehydroepiandrosterone (DHEA): NCCTG N10C1 (Alliance). AB - BACKGROUND: Dehydroepiandrosterone (DHEA) is helpful for treating vaginal symptoms. This secondary analysis evaluated the impact of vaginal DHEA on hormone concentrations, bone turnover, and vaginal cytology in women with a cancer history. METHODS: Postmenopausal women, diagnosed with breast or gynecologic cancer, were eligible if they reported at least moderate vaginal symptoms. Participants could be on tamoxifen or aromatase inhibitors (AIs). Women were randomized to 3.25 versus 6.5 mg/day of DHEA versus a plain moisturizer (PM) control. Sex steroid hormone levels, biomarkers of bone formation, vaginal pH, and maturation index were collected at baseline and 12 weeks. Analysis included independent t tests and Wilcoxon rank tests, comparing each DHEA arm with the control. RESULTS: Three hundred forty-five women contributed evaluable blood and 46 contributed evaluable cytology and pH values. Circulating DHEA-S and testosterone levels were significantly increased in those on vaginal DHEA in a dose-dependent manner compared to PM. Estradiol was significantly increased in those on 6.5 mg/day DHEA but not in those on 3.25 mg/day DHEA (p < 0.05 and p = 0.05, respectively), and not in those on AIs. Biomarkers of bone formation were unchanged in all arms. Maturation of vaginal cells was 100% (3.25 mg/day), 86% (6.5 mg/day), and 64% (PM); pH decreased more in DHEA arms. CONCLUSION: DHEA resulted in increased hormone concentrations, though still in the lowest half or quartile of the postmenopausal range, and provided more favorable effects on vaginal cytology, compared to PM. Estrogen concentrations in women on AIs were not changed. Further research on the benefit of vaginal DHEA is warranted in hormone-dependent cancers. PMID- 29164378 TI - Discrimination and Sleep Difficulties during Adolescence: The Mediating Roles of Loneliness and Perceived Stress. AB - Irregular and insufficient sleep place youth at risk for adverse psychological and physical health outcomes. Recent research indicates that discrimination constitutes a type of stressor that interferes with adolescent sleep; however, the mechanisms through which discrimination affects sleep are not well understood. This study examined whether ethnic and non-ethnic (i.e., gender, age, and height/weight) discrimination were associated with adolescents' sleep duration, variability, and quality, and whether loneliness and perceived stress mediated these associations. An ethnically-diverse sample (42% Latino, 29% European American, 23% Asian) of adolescents (N = 316; M age = 16.40 years, 57% girls) reported on their experiences of discrimination, perceived stress, and loneliness. Sleep duration and variability were assessed by actigraphy and sleep quality through self-reports. Ethnic discrimination was related to shorter sleep duration and both ethnic and non-ethnic discrimination were associated with worse sleep quality. Loneliness and perceived stress partially mediated the relation between discrimination and sleep quality. Discriminatory experiences can heighten feelings of loneliness and stress, which, in turn, may contribute to diminished sleep quality during adolescence. PMID- 29164379 TI - Identifying as American among Adolescents from Asian Backgrounds. AB - An important aspect of identity development requires adolescents to consider and select the cultural label or labels that best fit with their conception of who they are. Yet, little is known about the longitudinal development of such labeling preferencs and their possible links with adjustment. Using longitudinal data from 180 Asian Americans (60% female; 74% U.S.-born), intra-individual and group-level changes in adolescents' American label use were tracked. Over time, 48% chose an American label as their "best-fitting" label and 42% chose an American label at least once, but did not include an American label during at least one other time point. American label use was not associated with continuous measures of American identity, but the use of American labels was linked with lower levels of ethnic identity. American identity, whether indicated by label use or continuous scale scores, was generally linked with positive psychological and academic adjustment, with some effects of label use moderated by gender and generational status. Developmental implications of American cultural labels as markers of adolescent identity and broader adjustment are discussed. PMID- 29164380 TI - Correlation between the availability of dopamine transporter and olfactory function in healthy subjects. AB - OBJECTIVES: Olfactory dysfunction in Parkinson's disease is usually prodromal to other symptoms. In this study, we aimed to explore the association of olfactory function with the availabilities of striatal dopamine transporter (DAT) in healthy subjects. METHODS: Data used in the preparation of this article were obtained from Parkinson's Progression Markers Initiative database ( www.ppmi info.org/data ). The study population consisted of healthy controls with screening 123I-FP-CIT single photon emission tomography (SPECT). University of Pennsylvania Smell Identification Test (UPSIT) was assessed to evaluate the olfactory function. RESULTS: Totally, 181 healthy subjects (117 male, 64 female) with 123I-FP-CIT SPECT data were included in this study. Specific binding ratios (SBRs) of the caudate nucleus (rho = -0.4217, p < 0.0001), putamen (rho = 0.2292, p = 0.0019), and striatum (rho=-0.3425, p < 0.0001) showed a reduction with ageing. SBRs of the caudate nucleus, putamen, and striatum were positively correlated with UPSIT (rho = 0.3716, p < 0.0001; rho = 0.3655, p < 0.0001; rho = 0.3880, p < 0.0001). After controlling for age by partial correlation, SBRs of the caudate nucleus, putamen, and striatum showed an influence on UPSIT (rho = 0.3288, p < 0.0001; rho = 0.3374, p < 0.0001; rho = 0.3511, p < 0.0001). CONCLUSION: Olfactory function is associated with the availability of striatal DAT independent of age in healthy subjects. KEY POINTS: * Olfactory dysfunction in Parkinson's disease is prodromal to other symptoms. * The availability of dopamine transporter showed a reduction with ageing. * Olfactory function is associated with the availability of dopamine transporter. PMID- 29164381 TI - Assessment of micro-dose biplanar radiography in lower limb measurements in children. AB - OBJECTIVES: To evaluate in children microdose protocol compared with low dose for lower limb alignment (LLA) measurements on biplanar radiography. METHODS: Children 6 years or older were included. Height, weight and hip width were measured prior to imaging. Hip width allowed classifying children into morphotype M1 (width <25 cm), M2 (25-35 cm) or M3 (>35 cm) corresponding to predefined acquisition parameters (kV, mA, tube speed). Micro- and low-dose protocols were used alternately, with simultaneous acquisition of frontal and lateral radiographs. LLA measurements were performed by two independent observers (n = 526). In 15 children per morphotype, a third observer performed measurements twice (n = 180). Intraclass correlation coefficients and the dose (delivered, absorbed) were calculated. RESULTS: 100 girls and 160 boys (mean age = 11.7 years) were investigated: 74 M1 (mean BMI, 15.7kg/m2), 149 M2 (19.8 kg/m2) and 40 M3 (30.2 kg/m2). With microdose, inter- and intra-observer agreement was >0.90 for lengths whatever the morphotype, 0.75-0.90 (M1) and >0.90 (M2, M3) for valgus/varus and flexion/hyperextension deviations. Dose reduction reached a factor of 8.5 and 5.4 for the delivered and absorbed dose respectively. CONCLUSIONS: Microdose could be used for LLA measurements in children and permits a significant dose reduction. KEY POINTS: * Lower limb lengths of children can be evaluated with microdose biplanar radiography. * Valgus/varus deviations also can be evaluated with microdose biplanar radiography. * Microdose biplanar radiography significantly reduces delivered and absorbed dose in children. PMID- 29164382 TI - CT texture features of liver parenchyma for predicting development of metastatic disease and overall survival in patients with colorectal cancer. AB - OBJECTIVES: To determine if identifiable hepatic textural features are present at abdominal CT in patients with colorectal cancer (CRC) prior to the development of CT-detectable hepatic metastases. METHODS: Four filtration-histogram texture features (standard deviation, skewness, entropy and kurtosis) were extracted from the liver parenchyma on portal venous phase CT images at staging and post treatment surveillance. Surveillance scans corresponded to the last scan prior to the development of CT-detectable CRC liver metastases in 29 patients (median time interval, 6 months), and these were compared with interval-matched surveillance scans in 60 CRC patients who did not develop liver metastases. Predictive models of liver metastasis-free survival and overall survival were built using regularised Cox proportional hazards regression. RESULTS: Texture features did not significantly differ between cases and controls. For Cox models using all features as predictors, all coefficients were shrunk to zero, suggesting no association between any CT texture features and outcomes. Prognostic indices derived from entropy features at surveillance CT incorrectly classified patients into risk groups for future liver metastases (p < 0.001). CONCLUSIONS: On surveillance CT scans immediately prior to the development of CRC liver metastases, we found no evidence suggesting that changes in identifiable hepatic texture features were predictive of their development. KEY POINTS: * No correlation between liver texture features and metastasis-free survival was observed. * Liver texture features incorrectly classified patients into risk groups for liver metastases. * Standardised texture analysis workflows need to be developed to improve research reproducibility. PMID- 29164385 TI - ? PMID- 29164383 TI - Image quality and radiation dose of coronary CT angiography performed with whole heart coverage CT scanner with intra-cycle motion correction algorithm in patients with atrial fibrillation. AB - OBJECTIVES: To evaluate image quality, coronary evaluability and radiation exposure of coronary CT angiography (CCTA) performed with whole-heart coverage cardiac-CT in patients with atrial fibrillation (AF). MATERIALS AND METHODS: We prospectively enrolled 164 patients with AF who underwent a clinically indicated CCTA with a 16-cm z-axis coverage scanner. In all patients CCTA was performed using prospective ECG-triggering with targeted RR interval. We evaluated image quality, coronary evaluability and effective dose (ED). Patients were divided in two subgroups based on heart rate (HR) during imaging. Group 1: 64 patients with low HR (<75 bpm), group 2: 100 patients with high HR (>=75 bpm). Written informed consent was obtained from all patients and the institutional ethics committee approved the study protocol. RESULTS: In a segment-based analysis, coronary evaluability was 98.4 % (2,577/2,620 segments) in the whole population, without significant differences between groups (1,013/1,024 (98.9 %) and 1,565/1,596 (98.1 %), for groups 1 and 2, respectively, p=0.15). Mean ED was similar in both groups (3.8+/-1.9 mSv and 3.9+/-2.1 mSv in groups 1 and 2, respectively, p=0.75) CONCLUSIONS: The whole-heart-coverage scanner could evaluate coronary arteries with high image quality and without increase in radiation exposure in AF patients, even in the high HR group. KEY POINTS: * Last-generation CT scanner improves coronary artery assessment in AF patients. * The new CT scanner enables low radiation exposure in AF patients. * Diagnostic ICA maybe avoided in AF patients with suspected CAD. * Whole-heart coverage CT scanner enables low radiation exposure in AF patients. PMID- 29164386 TI - ? PMID- 29164384 TI - Comparison of gradient-recalled echo and spin-echo echo-planar imaging MR elastography in staging liver fibrosis: a meta-analysis. AB - OBJECTIVES: To compare the diagnostic performance of gradient-recalled echo-based magnetic resonance elastography (GRE-MRE) and spin-echo echo-planar imaging-based MRE (SE-EPI-MRE) in liver fibrosis staging. METHODS: A systematic literature search was performed to identify studies involving the performance of MRE for the diagnosis of liver fibrosis. Pooled sensitivity, specificity, positive and negative likelihood ratios, the diagnostic odds ratio, and a summary receiver operating characteristic (ROC) curve were estimated by using a bivariate random effects model. Subgroup analyses were performed between different study characteristics. RESULTS: Twenty-six studies with a total of 3,200 patients were included in the meta-analysis. Pooled sensitivity and specificity of GRE-MRE and SE-EPI-MRE did not differ significantly. The area under the summary ROC curve for stage diagnosis of any (F >= 1), significant (F >= 2), advanced (F >= 3), and cirrhosis (F = 4) on GRE-MRE and SE-EPI-MRE were 0.93 versus 0.94, 0.95 versus 0.94, 0.94 versus 0.95, and 0.92 versus 0.93, respectively. Substantial heterogeneity was detected for both sequences. CONCLUSION: Both GRE and SE-EPI MRE show high sensitivity and specificity for detection of each stage of liver fibrosis, without significant differences. Magnetic resonance elastography (MRE) may be useful for noninvasive evaluation of liver fibrosis in chronic liver disease. KEY POINTS: * Pooled sensitivity and specificity of GRE-MRE and SE-EPI MRE did not differ significantly. * GRE-MRE and SE-EPI-MRE were highly accurate for detecting all stages of fibrosis. * Due to better agreement and repeatability, GRE-MRE should be used first. * In case of failure on GRE-MRE, SE EPI-MRE should be used. PMID- 29164387 TI - Establishment of an efficient transformation system for Pleurotus ostreatus. AB - Pleurotus ostreatus is widely cultivated worldwide, but the lack of an efficient transformation system regarding its use restricts its genetic research. The present study developed an improved and efficient Agrobacterium tumefaciens mediated transformation method in P. ostreatus. Four parameters were optimized to obtain the most efficient transformation method. The strain LBA4404 was the most suitable for the transformation of P. ostreatus. A bacteria-to-protoplast ratio of 100:1, an acetosyringone (AS) concentration of 0.1 mM, and 18 h of co-culture showed the best transformation efficiency. The hygromycin B phosphotransferase gene (HPH) was used as the selective marker, and EGFP was used as the reporter gene in this study. Southern blot analysis combined with EGFP fluorescence assay showed positive results, and mitotic stability assay showed that more than 75% transformants were stable after five generations. These results showed that our transformation method is effective and stable and may facilitate future genetic studies in P. ostreatus. PMID- 29164388 TI - Correction to: Physiological insights of recent clinical diagnostic and therapeutic technologies for cardiovascular diseases. AB - The article Physiological insights of recent clinical diagnostic and therapeutic technologies for cardiovascular diseases, written by Kenji Shigemi, Soichiro Fuke, Dai Une, Keita Saku, Shuji Shimizu, Toru Kawada, Toshiaki Shishido, Kenji Sunagawa and Masaru Sugimachi, was originally published Online First without open access. PMID- 29164389 TI - Early-life stress induces motor coordination dysfunction in adult mice. AB - Although child abuse has become a serious social problem in most countries, the neural mechanisms by which it induces adulthood mental disorders is not yet fully understood. Mice exposed to early-life stresses, such as maternal deprivation (MD) during lactation, are a good model for studying the effects of neglect of humans in early life. Early-life stress induces structural/functional changes of neurons in the hippocampus, prefrontal cortex, and amygdala, and causes mental disorders in adulthood. In this study, we found motor coordination dysfunction in male MD mice. We also found that the expression levels of the aminomethylphosphonic acid receptor subunits GluA1 and GluA3 were high in the cerebellum of male MD mice. The basal activity of the cerebellum detected by field-potential analysis was higher in male MD mice than in male control mice. Caloric stimulation increased the activity of the cerebellum of control mice, but it did not significantly increase the activity of the cerebellum in male MD mice. We concluded that early-life stress induced a functional change in the cerebellum of MD mice and that this change induced motor coordination dysfunctions. PMID- 29164390 TI - Nutrition and mobility predict all-cause mortality in patients 12 months after transcatheter aortic valve implantation. AB - BACKGROUND: The aim of the study was to determine pre-interventional predictors for all-cause mortality in patients after transcatheter aortic valve implantation (TAVI) with a 12-month follow-up. METHODS: From 10/2013 to 07/2015, 344 patients (80.9 +/- 5.0 years, 44.5% male) with an elective TAVI were consecutively enrolled prospectively in a multicentre cohort study. Prior to the intervention, sociodemographic parameters, echocardiographic data and comorbidities were documented. All patients performed a 6-min walk test, Short Form 12 and a Frailty Index (score consisting of activities of daily living, cognition, nutrition and mobility). Peri-interventional complications were documented. Vital status was assessed over telephone 12 months after TAVI. Predictors for all-cause mortality were identified using a multivariate regression model. RESULTS: At discharge, 333 patients were alive (in-hospital mortality 3.2%; n = 11). During a follow-up of 381.0 +/- 41.9 days, 46 patients (13.8%) died. The non-survivors were older (82.3 +/- 5.0 vs. 80.6 +/- 5.1 years; p = 0.035), had a higher number of comorbidities (2.6 +/- 1.3 vs. 2.1 +/- 1.3; p = 0.026) and a lower left ventricular ejection fraction (51.0 +/- 13.6 vs. 54.6 +/- 10.6%; p = 0.048). Additionally, more suffered from diabetes mellitus (60.9 vs. 44.6%; p = 0.040). While the global Frailty Index had no predictive power, its individual components, particularly nutrition (OR 0.83 per 1 pt., CI 0.72-0.95; p = 0.006) and mobility (OR 5.12, CI 1.64-16.01; p = 0.005) had a prognostic impact. Likewise, diabetes mellitus (OR 2.18, CI 1.10-4.32; p = 0.026) and EuroSCORE (OR 1.21 per 5%, CI 1.07-1.36; p = 0.002) were associated with a higher risk of all-cause mortality. CONCLUSIONS: Besides EuroSCORE and diabetes mellitus, nutrition status and mobility of patients scheduled for TAVI offer prognostic information for 1-year all-cause mortality and should be advocated in the creation of contemporary TAVI risk scores. PMID- 29164391 TI - Association between low diastolic blood pressure and subclinical myocardial injury. AB - BACKGROUND: Coronary arteries perfuse cardiac myocytes during diastole. We hypothesized that marked lowering of diastolic blood pressure (DBP) is associated with increased risk of subclinical myocardial injury (SC-MI). METHODS: This analysis included 6107 participants without history of cardiovascular disease (CVD) from the third National Health and Nutrition Examination Survey. SC-MI was determined by a validated electrocardiogram-based scoring system. Logistic regression was used to examine the cross-sectional association between DBP (< 70, 70-80 mmHg (reference group), and > 80 mmHg; and per each 10 mmHg decrease, separately) with SC-MI across levels of systolic blood pressure (SBP) (< 120, 120 139, or > 140 mmHg). RESULTS: In a multivariable model, DBP < 70 mmHg was associated with a higher risk of SC-MI [OR (95% CI) 1.40 (1.02, 1.94)] in participants with SBP > 140 mmHg. This association was consistent in subgroups stratified by age, race, diabetes, hypertension, obesity and smoking, but was stronger in women than in men [OR (95% CI) 1.58 (1.06, 2.37) vs. 1.10 (0.62, 1.94), respectively; interaction p value = 0.006]. Also, among participants with SBP > 140 mmHg, every 10 mmHg decrease in DBP was associated with a 12% increased odds of SC-MI [OR (95% CI) 1.12 (1.01, 1.23)]. No significant associations between DBP and SC-MI were observed in those with SBP < 120 mmHg or 120-139 mmHg, or between DBP > 80 mmHg and SC-MI in any of SBP levels. CONCLUSIONS: Low DBP < 70 mmHg in those with SBP > 140 mmHg carries higher risk of SC-MI, especially in women. Further research is needed to understand the therapeutic implications of these findings. PMID- 29164392 TI - Maturation and cytokine pattern of human dendritic cells in response to different yeasts. AB - Activated dendritic cells (DC) induce and polarize T-cell responses by expression of distinct maturation markers and cytokines. This study systematically investigated the capacity of different biotechnically relevant yeast species and strains including Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces lactis, Pichia pastoris, Hansenula polymorpha, Yarrowia lipolytica, and Candida glabrata to initiate maturation of human DC. As important prerequisite for T-cell activation, all yeasts were shown to effectively induce, though to a different extent, the expression of the activation marker CD83, the co-stimulatory molecules CD80, CD86, CD54, CD58, and CD40, as well as the antigen presenting molecules MHCs I and II. Furthermore, yeast-activated DC secreted various cytokines including inflammatory TNF-alpha, IL-6, IL-8, and IL-1beta or T cell polarizing IL-12, IL-10, IL-23, and IL-27. Variability was observed in the expression of TNF-alpha, IL-6, IL-8, IL-1beta, and IL-10 in response to the tested yeasts, whereas expression levels of IL-12, IL-23, and IL-27 were similar. Interestingly, maturation marker expression and cytokine secretion were not negatively affected after application of yeast mutants with altered cell wall mannoprotein structure (Deltamnn11) or defective in protein N-glycosylation (Deltaost3), indicating that elongated cell wall mannoproteins at the outer yeast cell surface are not a prerequisite for the observed yeast-mediated DC maturation. Thus, our data provide a valuable basic knowledge for the future design of effective yeast-based delivery approaches. PMID- 29164394 TI - Combination of NAD+ and NADPH Offers Greater Neuroprotection in Ischemic Stroke Models by Relieving Metabolic Stress. AB - Both reduced nicotinamide adenine dinucleotide phosphate (NADPH) and beta nicotinamide adenine dinucleotide hydrate (NAD+) have been reported to have potent neuroprotective effects against ischemic neuronal injury. Both NADPH and NAD+ are essential cofactors for anti-oxidation and cellular energy metabolism. We investigated if combined NADPH and NAD+ could offer better neuroprotective effects on cellular and animal models of ischemic stroke. In vitro studies with primary cultured neurons demonstrated that NAD+ was effective in protecting neurons against oxygen-glucose deprivation/reoxygenation (OGD/R) injury when given during the early time period of reoxygenation. In vivo studies in mice also suggested that NAD+ was effective for ameliorating ischemic brain damage when administered within 2 h after reperfusion. The combination of NADPH and NAD+ provided not only greater beneficial effects but also larger therapeutic window in both cellular and animal models of stroke. The combination of NADPH and NAD+ significantly increased the levels of adenosine triphosphate (ATP) and reduced the levels of reactive oxygen species (ROS) and oxidative damage of macromolecules. Furthermore, the combined medication significantly reduced long term mortality, improved the functional recovery, and inhibited signaling pathways involved in apoptosis and necroptosis after ischemic stroke. The present study indicates that the combination of NAD+ and NADPH can produce greater therapeutic effects with smaller dose of NADPH; on the other hand, NADPH can significantly prolong the therapeutic window of NAD+. The current results suggest that the combination of NADPH and NAD+ may provide a novel effective therapy for ischemic stroke. PMID- 29164393 TI - Bordetella Pertussis virulence factors in the continuing evolution of whooping cough vaccines for improved performance. AB - Despite high vaccine coverage, whooping cough caused by Bordetella pertussis remains one of the most common vaccine-preventable diseases worldwide. Introduction of whole-cell pertussis (wP) vaccines in the 1940s and acellular pertussis (aP) vaccines in 1990s reduced the mortality due to pertussis. Despite induction of both antibody and cell-mediated immune (CMI) responses by aP and wP vaccines, there has been resurgence of pertussis in many countries in recent years. Possible reasons hypothesised for resurgence have ranged from incompliance with the recommended vaccination programmes with the currently used aP vaccine to infection with a resurged clinical isolates characterised by mutations in the virulence factors, resulting in antigenic divergence with vaccine strain, and increased production of pertussis toxin, resulting in dampening of immune responses. While use of these vaccines provide varying degrees of protection against whooping cough, protection against infection and transmission appears to be less effective, warranting continuation of efforts in the development of an improved pertussis vaccine formulations capable of achieving this objective. Major approaches currently under evaluation for the development of an improved pertussis vaccine include identification of novel biofilm-associated antigens for incorporation in current aP vaccine formulations, development of live attenuated vaccines and discovery of novel non-toxic adjuvants capable of inducing both antibody and CMI. In this review, the potential roles of different accredited virulence factors, including novel biofilm-associated antigens, of B. pertussis in the evolution, formulation and delivery of improved pertussis vaccines, with potential to block the transmission of whooping cough in the community, are discussed. PMID- 29164396 TI - Crystal structure of the coxsackievirus A16 RNA-dependent RNA polymerase elongation complex reveals novel features in motif A dynamics. AB - The RNA-dependent RNA polymerases (RdRPs) encoded by RNA viruses represent a unique class of nucleic acid polymerases. Unlike other classes of single-subunit polymerases, viral RdRPs have evolved a unique conformational change in their palm domain to close the active site during catalysis. The hallmark of this conformational change is the backbone shift of the polymerase motif A from an "open" state to a "closed" state, allowing two universally conserved aspartic acid residues to orient toward each other for divalent metal binding and catalysis. The "closed" motif A conformation was only observed upon the binding of correct NTP in RdRP catalytic complexes or under rare conditions such as induced by a bound lutetium ion or a bound glutamate molecule. By solving the crystal structure of the catalytic elongation complex of the coxsackievirus RdRP, we in this work observed for the first time the "closed" motif A conformation in the absence of an NTP substrate or other conformational-change-inducing factors. This observation emphasizes the intrinsic dynamic features of viral RdRP motif A, and solidifies the structural basis for how this important structural element participates in catalytic events of the RdRPs. PMID- 29164395 TI - Primary biliary cholangitis: a comprehensive overview. AB - Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by biliary destruction, progressive cholestasis, and potentially liver cirrhosis. Patients develop a well-orchestrated immune reaction, both innate and adaptive, against mitochondrial antigens that specifically targets intrahepatic biliary cells. A puzzling feature of PBC is that the immune attack is predominantly organ specific, although the mitochondrial autoantigens are found in all nucleated cells. The disease results from a combination of genetic and environmental risk factors; however, the exact pathogenesis remains unclear. Serologically, PBC is characterized by presence of antimitochondrial antibodies, which are present in 90-95 % of patients and are often detectable years before clinical signs appear. Like other complex disorders, PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. A significant number of patients develop end-stage liver disease and eventually require liver transplantation. Recent studies from large international cohorts have better identified prognostic factors, suggesting a change in patient management based on risk stratification. Therapeutic options are changing. In this review we discuss data on the autoimmune responses and treatment of the disease. PMID- 29164397 TI - Factors for time to trastuzumab-induced cardiotoxicity in breast cancer patients. AB - Trastuzumab is a drug used for the treatment of metastatic breast cancer patients. Due to blockage of the human epidermal growth factor receptor 2 signaling in cardiac myocytes, cardiotoxicity has been observed. There are many studies that investigated risk factors for trastuzumab-induced cardiotoxicity, but no study has been published for factors on the time to cardiotoxicity. This study aimed to investigate the factors for the time to occur trastuzumab-induced cardiotoxicity. From January 2014 to December 2015, a retrospective study was performed with breast cancer patients who were treated with trastuzumab. Associations between presence of and time to cardiotoxicity and various factors were analyzed. Based on multivariate models, it was found that baseline left ventricular ejection fraction (LVEF) < 62.5% (AHR 5.96, 95% CI 2543-13.95) and anthracycline-based chemotherapy (AHR 7.90, 95% CI 1.05-59.71) were significant factors for time to cardiotoxicity after adjusting other confounding factors. Multivariate analysis also showed that BMI >= 23 kg/m2 and baseline LVEF value < 62.5% increased cardiotoxicity 3.0 and 6.6 times, respectively. Our study showed that BMI >= 23 kg/m2, LVEF < 62.5%, and anthracycline-based chemotherapy were associated with time to trastuzumab-induced cardiotoxicity. Thus, close monitoring of cardiac function is recommended especially for patients using the above risk factors. PMID- 29164398 TI - C-reactive protein levels for early detection of early postoperative complications after proximal femoral fracture surgery. AB - INTRODUCTION: We have studied the early C-reactive protein (CRP) kinetics after proximal femoral fracture (PFF) surgery and defined a chart of CRP threshold values beyond which early postoperative complications are likely. MATERIALS AND METHODS: We have prospectively followed up a 42-patient cohort for surgical treatment by osteosynthesis or hip arthroplasty, and CRP was dosed at admission, on day 1, day 3, day 5 and then twice weekly for 30 days at the same time as a platelet count control of low molecular weight heparins. Then, we identified postoperative complications (medical complications like infections other than the surgical site, thromboembolic complications, death and surgical complications like surgical site infections, dislocation, haematoma) and established the evolutive profile of CRP in a 'complication' group and a 'no complication' group. We developed a threshold value model for complications detection from our results and compared with Chapman's 500/d formula (d being the postoperative day). RESULTS: CRP in the 'complication' group (20 patients) is on average 19 points higher than the 'no complication' group (22 patients) (p = 0.007). Our model, which corresponds to the formula CRP(d) = e(4.71 - 0.06*d), is valid from day 1 to day 30 and has a threshold value of 105 mg/L at day 1. From day 5, the correlation between our chart and the 500/d chart is 0.84 (p < 10-5). Two successive CRP values strictly above our chart at a 48-h interval have a sensitivity of 65% and a specificity of 85% to detect a postoperative complication while only one CRP value above the chart has a sensitivity and a specificity of 48%. DISCUSSION/CONCLUSION: Early postoperative CRP kinetics of PFF surgical patients can be modelled as a threshold value scale valid between day 1 and day 30. This can be an additional tool in the early detection of postoperative complications, if two CRP values are above the threshold values, without replacing the clinical examination, which remains the 'gold standard'. LEVEL OF EVIDENCE: Prospective observational study. PMID- 29164399 TI - Efficacy of a single intra-articular injection of ultra-high molecular weight hyaluronic acid for hip osteoarthritis: a randomized controlled study. AB - BACKGROUND: Viscosupplementation with hyaluronic acid (HA) is increasingly used for the treatment of hip osteoarthritis (OA). The purpose of this study was to compare the efficacy of intra-articular injections of an ultra-high molecular weight viscosupplement (UHMW-HA, Fermathron S) with a medium molecular weight hyaluronan (MMW-HA, Hyalubrix 60) in hip OA. METHODS: Fifty-four patients with hip OA grade 3 on the Kellgren/Lawrence scale were randomized. All infiltrations were performed under ultrasound guidance. Evaluation was performed preoperatively and at 1, 3, 6 and 12 months after infiltration. Patients were clinically evaluated using Lequesne index, VAS and WOMAC score. RESULTS: Fifty patients, including 27 in the MMW-HA group and 23 in the UHMW-HA group, completed the follow-up. No significant difference was found between the two groups in terms of VAS, WOMAC or Lequesne index preoperatively or at 1, 3, 6 and 12 months after viscosupplementation. A stratified analysis was performed to study the development over time of Lequesne index of patients aged <= 55 years, > 55 and, <= 70 years and > 70 years and Lequesne index was different between the three age stratified subgroups only in the MMW-HA group. The subgroup of older patients showed a higher Lequesne index than the subgroups of younger patients (p < 0.05). CONCLUSIONS: UHMW-HA is a safe and effective treatment for hip osteoarthritis. A single dose of UHMW-HA was as effective as two doses of MMW-HA resulting in similar reductions of pain and disability. STUDY DESIGN: Multicenter, independent, prospective, randomized controlled trial with level of evidence 1. PMID- 29164400 TI - Hepatitis C virus infection among illicit drug users in an archipelago of the Amazon. AB - Hepatitis C virus (HCV) infection causes acute and chronic liver disease and may lead to cirrhosis, liver failure or hepatocellular carcinoma. The behavior of illicit drug users (DUs) typically exposes them to risks of viral infection. In the Brazilian Amazon region, a number of studies have identified high rates of drug use among adolescents, and a high prevalence of HBV infection in DUs, disseminated by sexual and parenteral activities. However, the epidemiological scenario of HCV infection in the region is still poorly understood. This study determined the prevalence, genotypes, and risk factors for HCV infection among DUs of the Marajo Archipelago. This cross-sectional study collected samples and epidemiological information from DUs in 11 municipalities. The diagnosis was established by EIA and real-time PCR, and the samples were genotyped by multiplex real time PCR. The data were analyzed by simple and multiple logistical regression. In 466 DUs, 28.3% had anti-HCV antibodies, and 25.5% had HCV-RNA. In 92 injecting drug users, 88.0% had anti-HCV antibodies, and 80.4% had HCV-RNA. Genotypes 1 and 3 were detected, with three cases of mixed infections. The multivariate analysis indicated associations of HCV infection with age (>= 35 years), tattoos, intravenous drug use, shared use of injection equipment, and the daily and long-term (> 3 years) use of illicit drugs. These findings will contribute to the development of effective measures for the prevention of HCV infection among Brazilian DUs, as well as its general population. PMID- 29164401 TI - Isolation and molecular characterization of an H5N1 swine influenza virus in China in 2015. AB - In 2015, an H5N1 influenza virus was isolated from a pig in Zhejiang Province, Eastern China. This strain was characterized by whole-genome sequencing with subsequent phylogenetic analysis. Phylogenetic analysis showed that all segments from this strain belonged to clade 2.3.2 and that it had received its genes from poultry influenza viruses in China. A Glu627Lys mutation associated with pathogenicity was observed in the PB2 protein. This strain was moderately pathogenic in mice and was able to replicate without prior adaptation. These results suggest that active surveillance of swine influenza should be used as an early warning system for influenza outbreaks in mammals. PMID- 29164402 TI - Molecular characterization reveals that squash chlorosis mottling virus and zucchini tigre mosaic virus are the same newly emerging potyvirus. AB - In 2013, we published the first report of a novel potyvirus isolate, which was tentatively named squash chlorosis mottling virus (SqCMV), from an infected squash plant (Cucurbita pepo) collected in the Homestead area of Florida. The purpose of the current work was to further characterize the virus isolate based on molecular properties, and to determine its relationship to other potyviruses. The complete genome sequence of the virus was 10,292 nucleotides (nt), consisting of a 5'-UTR (182 nt), a complete ORF (10,098 nt) encoding a polyprotein of 3,365 amino acids, a motif for the PIPO protein and a 3'-UTR (112 nt), but excluding the poly-(A) tail. Phylogenetic analysis based on the complete genome and amino acid sequences revealed that the virus from Florida clustered with the type isolate of the newly described potyvirus zucchini tigre mosaic virus (ZTMV) sharing 82-90% nucleotide and 83-86% amino acid identities, respectively. Recombination analysis confirmed one major recombination event in the putative P1 coding region of the virus with the putative parental sequences predicted to resemble to ZTMV-Venezuela and France isolates. In addition, genetic diversity analysis indicated that the CP gene was under the highest selection pressure compared to other genes. Together, these results suggest that SqCMV and ZTMV are both representative isolates of the same species, Zucchini tiger mosaic virus. We present the first complete genome sequence of the ZTMV-HFL isolate from the USA. PMID- 29164403 TI - A novel photodynamic therapy-based drug delivery system layered on a stent for treating cholangiocarcinoma. AB - This study aimed to investigate the drug delivery efficacy and bio-effectiveness of a novel photodynamic therapy (PDT)-matrix drug delivery system for cholangiocarcinoma (CCA). Metallic stents were coated with polyurethane (PU) as the first layer. A 2-hydroxyethyl methacrylate (2-HEMA)/ethylene glycol dimethacrylate (EGDMA)/benzoyl peroxide (BPO) layer and a poly(ethylene-co-vinyl acetate) (PEVA)/poly(n-butyl methacrylate) (PBMA)/polyvinylpyrrolidone K30 (K30) layer containing various concentrations of Photofrin were then incorporated onto the stent as the second and third layers. After incubating the layered membranes with cultured CCA cell line, the release of Photofrin, cell viability, the intracellular uptake of Photofrin, reactive oxygen species (ROS) generation, and apoptosis were determined. Using a single-layer diffusion model, the maximum release of Photofrin from the 5 to 10% K30 formulas was 80 and 100%, respectively, after 24 h. When using the multiple-layer diffusion model, the released Photofrin showed an initial burst of the loading dose from the PEVA/PBMA/K30 layer. In the immobilized model, less than 5% of the Photofrin from the 2-HEMA/EGDMA/BPO layer was released over the 24-h period. Cell viability decreased linearly with increasing Photofrin concentrations, and ROS generation and apoptosis were shown to increase significantly with increasing Photofrin concentrations, until the concentration of Photofrin reached a saturation point of 1.5 MUg/ml. This new, multiple-layered, PDT-based stent with dual-release mechanisms is a promising treatment for CCA and cancer-related ductal stenosis. PMID- 29164404 TI - Size selectivity in antibiofilm activity of 3-(diphenylphosphino)propanoic acid coated gold nanomaterials against Gram-positive Staphylococcus aureus and Streptococcus mutans. AB - Biofilm formation by pathogenic bacteria is one of the major threats in hospital related infections, hence inhibiting and eradicating biofilms has become a primary target for developing new anti-infection approaches. The present study was aimed to develop novel antibiofilm agents against two Gram-positive bacteria; Staphylococcus aureus (ATCC 43300) and Streptococcus mutans (ATCC 25175) using gold nanomaterials conjugated with 3-(diphenylphosphino)propionic acid (Au-LPa). Gold nanomaterials with different sizes as 2-3 nm small and 9-90 nm (50 nm average size) large were stabilized by LPa via different chemical synthetic strategies. The nanomaterials were fully characterized using atomic force microscope (AFM), transmission electron microscope, ultraviolet-visible absorption spectroscopy, and Fourier transformation infrared spectroscopy. Antibiofilm activity of Au-LPa nanomaterials was tested using LPa alone, Au-LPa and unprotected gold nanomaterials against the both biofilm-producing bacteria. The results showed that LPa alone did not inhibit biofilm formation to a significant extent below 0.025 mM, while conjugation with gold nanomaterials displayed manifold enhanced antibiofilm potential against both strains. Moreover, it was also observed that the antibiofilm potency of the Au-LPa nanomaterials varies with size variations of nanomaterials. AFM analysis of biofilms further complemented the assay results and provided morphological aspects of the antibiofilm action of Au-LPa nanomaterials. PMID- 29164405 TI - Genetic Variance in Homophobia: Evidence from Self- and Peer Reports. AB - The present twin study combined self- and peer assessments of twins' general homophobia targeting gay men in order to replicate previous behavior genetic findings across different rater perspectives and to disentangle self-rater specific variance from common variance in self- and peer-reported homophobia (i.e., rater-consistent variance). We hypothesized rater-consistent variance in homophobia to be attributable to genetic and nonshared environmental effects, and self-rater-specific variance to be partially accounted for by genetic influences. A sample of 869 twins and 1329 peer raters completed a seven item scale containing cognitive, affective, and discriminatory homophobic tendencies. After correction for age and sex differences, we found most of the genetic contributions (62%) and significant nonshared environmental contributions (16%) to individual differences in self-reports on homophobia to be also reflected in peer-reported homophobia. A significant genetic component, however, was self report-specific (38%), suggesting that self-assessments alone produce inflated heritability estimates to some degree. Different explanations are discussed. PMID- 29164406 TI - Comment on the letter 'Brain abscess due to Nocardia infection in an immunocompetent patient with asymptomatic pulmonary alveolar proteinosis' by de Leon et al. PMID- 29164407 TI - Neurological Complications of HIV Infection. AB - PURPOSE OF REVIEW: HIV-associated neurocognitive disorders (HAND) are common in patients with HIV disease, even during suppressive combination antiretroviral therapy (cART). This review article addresses the pathogenesis of HAND, focusing on important findings from the last 5 years. RECENT FINDINGS: While HIV associated dementia is now rare in settings with cART availability, mild forms of HAND are increasing in prevalence. Biomarkers of cellular injury, such as neurofilament light chain and neopterin, can detect early stages of neuroinflammation associated with HIV infection and are increased even in asymptomatic individuals with chronic HIV infection. Several recent studies form a growing body of evidence that HIV can infect and replicate in monocytes and that blocking monocyte activity can potentially improve neurological outcomes in HIV. Early cART may also prevent HAND. Understanding the multifactorial causes of CNS infection and inflammation is critical to devising treatment and preventive strategies for HAND. PMID- 29164408 TI - Long-Term Clinical Outcome of Early Generation Versus New-Generation Drug-Eluting Stents in 481 Patients Undergoing Rotational Atherectomy: A Retrospective Analysis. AB - INTRODUCTION: New-generation drug-eluting stents (NG-DES) are superior to early generation DES (EG-DES) in the majority of lesion and patient subsets, but comparative data in patients with severely calcified coronary lesions are lacking. This study aims to compare clinical outcomes of EG-DES and NG-DES in patients undergoing rotational atherectomy (RA) in calcified lesions. METHODS: Data of 268 patients (288 lesions) treated with EG-DES and 213 patients (225 lesions) receiving NG-DES after RA were retrospectively analyzed from a single center registry. All major adverse cardiac events (MACE) were assessed at 2 years. RESULTS: Compared to the EG-DES group, patients with NG-DES more commonly had diabetes mellitus (31.9% vs. 40.9%; p = 0.04), left main lesions (7.6% vs. 17.3%; p < 0.001) and chronic total occlusions (3.5% vs. 8.5%; p = 0.016), and had a higher total stent length (30.5, IQR 20-40 mm, vs. 38, IQR 22-53 mm, p < 0.001). The Kaplan-Meier estimated rate of cardiovascular events at 2 years showed a lower incidence of death (13.5% vs. 8.2%, log-rank p = 0.13; adjusted HR after Cox regression analysis 0.49; 95% CI 0.26-0.92; p = 0.03) and a lower MACE rate (31.1% vs. 21.1%, log-rank p = 0.04; adjusted HR 0.65; 95% CI 0.42-0.98; p = 0.04) in the NG-DES group. CONCLUSIONS: Although RA is performed in more complex patients and lesions in the NG-DES era, use of NG-DES is associated with lower rates of death and MACE at 2 years as compared to EG-DES. PMID- 29164409 TI - Sun Exposure and Behavioral Activation for Hypovitaminosis D and Depression: A Controlled Pilot Study. AB - Several independent meta-analytic reviews suggest a relationship between vitamin D (VTD) deficiency and depressive symptoms. Theoretically, behavioural withdrawal (staying home, discontinuing outdoor activities etc.) is likely to exacerbate VTD deficiency. This pilot study assessed the efficacy of a modified form of behavioral therapy designed to simultaneously target VTD deficiency and depressive symptoms. College women (N = 114), all citizens of the United Arab Emirates, were screened for depressive symptoms and VTD deficiency. Those participants who were severely VTD deficient and experiencing clinically significant depressive symptoms, were randomly allocated to either a 12-week program of behavioral activation, emphasizing safe-sun exposure (N = 10), or a waiting list control group (N = 10). At time 2 the sun exposure and behavioral activation (SEBA) group showed a significant increases in 25-hydroxyvitamin D and were, on average, no longer VTD deficient, whereas the control group deteriorated in terms of VTD. Similarly positive results were observed for depressive symptoms. Sun exposure and behavioral activation (SEBA) may be an effective approach to improving VTD status and alleviating depressive symptoms. PMID- 29164411 TI - In Reply: Refining Tumor Resection Techniques for Managing Inferior Pole Breast Malignancies. PMID- 29164410 TI - Increased BATF expression is associated with the severity of liver damage in patients with chronic hepatitis B. AB - T helper (Th) 17 cells have a critical role in the pathogenesis of chronic hepatitis B virus (HBV) infection, and basic leucine zipper transcription factor, ATF-like (BATF) is a newly identified transcriptional factor regulating the differentiation of Th17 cells. However, its precise role in patients with chronic hepatitis B remains unclear. Sixty chronic hepatitis B (CHB) patients, twenty-two acute-on-chronic hepatitis B liver failure (ACHBLF) patients and seventeen healthy controls were included in our study. Both peripheral and intrahepatic expressions of BATF were analyzed by flow cytometry, quantitative real-time polymerase chain reaction and immunohistochemical staining. Peripheral BATF mRNA and protein expression levels were higher in CHB patients than those in healthy controls. Particularly in ACHBLF patients, the BATF mRNA and protein levels were further increased over those in CHB patients. Intrahepatic BATF-positive infiltrating cells were enriched in portal area of CHB patients, and more positive cells were found in patients with higher inflammation grade. Peripheral BATF expression was positively correlated with serum parameters of liver injury and plasma HBV DNA load. Furthermore, a positive correlation was found between the frequency of BATF-positive CD3+ T cells and the increased Th17 response in chronic HBV-infected patients. BATF over-expression might augment Th17 cell response and relate to the disease progression of CHB. PMID- 29164412 TI - Age and Charlson Score: A Reply. PMID- 29164413 TI - Comparison of Recurrence Between Pancreatic and Duodenal Neuroendocrine Neoplasms After Curative Resection: A Single-Institution Analysis. AB - BACKGROUND: The primary site of a neuroendocrine neoplasms (NEN) around the head of the pancreas is sometimes difficult to assess before resection, and the characteristics of the primary site around this region have not been elucidated for recurrence after curative resection. In this study, the clinicopathologic characteristics of pancreatic NEN (PanNEN) and duodenal NEN (DuNEN) were evaluated, and the risk factors as well as the recurrence types after resection were investigated. METHODS: Consecutively diagnosed NEN patients at the authors' hospital from January 2000 to July 2016 were evaluated in this study. For 117 PanNEN patients and 31 non-ampullary DuNEN patients, R0 resection was achieved. The median follow-up period was 8.1 years. RESULTS: In this study, 27 PanNEN patients (23.1%) had recurrences, with a median disease-free survival (DFS) of 133 months, whereas 11 DuNEN patients (35.5%) had recurrences, with a median DFS of 156 months. The PanNEN patients tended to have primary recurrence in the liver (85.2%), followed by lymph nodes (11.1%). The independent risk factors for short DFS were lymph node metastasis at resection (p = 0.001) and microvascular invasion (p = 0.048). In contrast, the DuNEN patients were likely to have lymph node metastasis (81.8%). The independent risk factors for short DFS were lymph node metastasis at resection (p = 0.003) and large diameter (p = 0.013). CONCLUSIONS: Most initial recurrences of PanNEN occurred in the liver, whereas those of DuNEN appeared in lymph nodes, suggesting that proper diagnosis of the primary site and appropriate imaging methods for surveillance after resection are necessary. PMID- 29164414 TI - A Novel T-Stage Classification System for Adrenocortical Carcinoma: Proposal from the US Adrenocortical Carcinoma Study Group. AB - BACKGROUND: The 7th AJCC T-stage system for adrenocortical carcinoma (ACC), based on size and extra-adrenal invasion, does not adequately stratify patients by survival. Lymphovascular invasion (LVI) is a known poor prognostic factor. We propose a novel T-stage system that incorporates LVI to better risk-stratify patients undergoing resection for ACC. METHOD: Patients undergoing curative intent resections for ACC from 1993 to 2014 at 13 institutions comprising the US ACC Group were included. Primary outcome was disease-specific survival (DSS). RESULTS: Of the 265 patients with ACC, 149 were included for analysis. The current T-stage system failed to differentiate patients with T2 versus T3 disease (p = 0.10). Presence of LVI was associated with worse DSS versus no LVI (36 mo vs. 168 mo; p = 0.001). After accounting for the individual components of the current T-stage system (size, extra-adrenal invasion), LVI remained a poor prognostic factor on multivariable analysis (hazard ratio 2.14, 95% confidence interval 1.05-4.38, p = 0.04). LVI positivity further stratified patients with T2 and T3 disease (T2: 37 mo vs. median not reached; T3: 36 mo vs. 96 mo; p = 0.03) but did not influence survival in patients with T1 or T4 disease. By incorporating LVI, a new T-stage classification system was created: [T1: <= 5 cm, (-)local invasion, (+/-)LVI; T2: > 5 cm, (-)local invasion, (-)LVI OR any size, (+)local invasion, (-)LVI; T3: > 5 cm, (-)local invasion, (+)LVI OR any size, (+)local invasion, (+)LVI; T4: any size, (+)adjacent organ invasion, (+/-)LVI]. Each progressive new T-stage group was associated with worse median DSS (T1: 167 mo; T2: 96 mo; T3: 37 mo; T4: 15 mo; p < 0.001). CONCLUSIONS: Compared with the current T-stage system, the proposed T-stage system, which incorporates LVI, better differentiates T2 and T3 disease and accurately stratifies patients by disease-specific survival. If externally validated, this T-stage classification should be considered for future AJCC staging systems. PMID- 29164415 TI - Decrease of insoluble glucan formation in Streptococcus mutans by co-cultivation with Enterococcus faecium T7 and glucanase addition. AB - OBJECTIVES: To develop preventive canine oral health bio-materials consisting of probiotics and glucanase to reduce insoluble glucan and volatile sulfur compound formation. RESULTS: Co-cultivation of Enterococcus faecium T7 with Streptococcus mutans at inoculation ratio of 3:1 (v/v) resulted in 25% reduction in the growth of Streptococcus mutans. Amounts of soluble and insoluble glucans produced by S. mutans were decreased to 70 and 55%, respectively. Insoluble glucan was decreased from 0.6 ug/ml in S. mutans culture to 0.03 ug/ml in S. mutans co-cultivated with E. faecium T7 in the presence of Lipomyces starkeyi glucanase. Volatile sulfur compound, a main component of halitosis produced by Fusobacteria nucleatum, was decreased by co-cultivating F. nucleatum with E. faecium. CONCLUSION: E. faecium and glucanase can be combined as potentially active ingredients of oral care products for pets by reducing plaque-forming bacteria growth and their by products that cause cavity and periodontal disease. PMID- 29164416 TI - High-throughput and direct measurement of androgen levels using turbulent flow chromatography liquid chromatography-triple quadrupole mass spectrometry (TFC-LC TQMS) to discover chemicals that modulate dihydrotestosterone production in human prostate cancer cells. AB - OBJECTIVES: To develop a high-throughput screening system to measure the conversion of testosterone to dihydrotestosterone (DHT) in cultured human prostate cancer cells using turbulent flow chromatography liquid chromatography triple quadrupole mass spectrometry (TFC-LC-TQMS). RESULTS: After optimizing the cell reaction system, this method demonstrated a screening capability of 103 samples, including 78 single compounds and 25 extracts, in less than 12 h without manual sample preparation. Consequently, fucoxanthin, phenethyl caffeate, and Curcuma longa L. extract were validated as bioactive chemicals that inhibited DHT production in cultured DU145 cells. In addition, naringenin boosted DHT production in DU145 cells. CONCLUSION: The method can facilitate the discovery of bioactive chemicals that modulate the DHT production, and four phytochemicals are potential candidates of nutraceuticals to adjust DHT levels in male hormonal dysfunction. PMID- 29164417 TI - Native promoters of Corynebacterium glutamicum and its application in L-lysine production. AB - OBJECTIVE: To identify useful native promoters of Corynebacterium glutamicum for fine-tuning of gene expression in metabolic engineering. RESULTS: Sixteen native promoters of C. glutamicum were characterized. These promoters covered a strength range of 31-fold with small increments and exhibited relatively stable activity during the whole growth phase using beta-galactosidase as the reporter. The mRNA level and enzymatic activity of the lacZ reporter gene exhibited high correlation (R 2 = 0.96) under the control of these promoters. Sequence analysis found that strong promoters had high similarity of the -10 hexamer to the consensus sequence and preference of the AT-rich UP element upstream the -35 region. To test the utility of the promoter library, the characterized native promoters were applied to modulate the sucCD-encoded succinyl-CoA synthetase expression for L-lysine overproduction. CONCLUSIONS: The native promoters with various strengths realize the efficient and precise regulation of gene expression in metabolic engineering of C. glutamicum. PMID- 29164418 TI - Inhibition of epidermal growth factor receptor by ferulic acid and 4 vinylguaiacol in human breast cancer cells. AB - OBJECTIVES: To examine the potential of ferulic acid and 4-vinylguaiacol for inhibiting epidermal growth factor receptor (EGFR) in human breast cancer cells in vitro. RESULTS: Ferulic acid and 4-vinylguaiacol limit the EGF (epidermal growth factor)-induced breast cancer proliferation and new DNA synthesis. Western blot analysis revealed both ferulic acid and 4-vinylguaiacol exhibit sustained inhibition of EGFR activation through down-regulation of Tyr 1068 autophosphorylation. Molecular docking analysis shows ferulic acid forming hydrogen bond interaction with Lys 745 and Met 793 whereas, 4-vinylguaiacol forms two hydrogen bonds with Phe 856 and exhibits stronger hydrophobic interactions with multiple amino acid residues at the EGFR kinase domain. CONCLUSIONS: Ferulic acid and 4-vinylguaiacol could serve as a potential structure for the development of new small molecule therapeutics against EGFR. PMID- 29164419 TI - Rhegmatogenous retinal detachment in uveitis. AB - BACKGROUND: Retinal detachment is more common among uveitis patients than in the general population. Here, we aimed to assess the prevalence of rhegmatogenous retinal detachment (RRD) in a uveitis population. METHODS: We retrospectively studied 851 uveitis patients, recording characteristics such as uveitis duration, anatomical location, and cause; RRD occurrence; proliferative vitreoretinopathy (PVR) at presentation; surgical approach; reattachment rate; and initial and final visual acuity (VA). RESULTS: RRD occurred in 26 patients (3.1%; 29 affected eyes) and was significantly associated with posterior uveitis (p < 0.001), infectious uveitis (p < 0.001), and male gender (p = 0.012). Among cases of infectious uveitis, cytomegalovirus and varicella zoster virus were most commonly associated with RRD development. RRD in non-infectious uveitis was not found to be associated with any specific uveitis entity. The rate of single-operation reattachment was 48%, and the rate of final reattachment was 83%. Mean final VA was 20/125, with 41% of eyes ultimately having a VA of less than 20/200. CONCLUSION: Uveitis is a risk factor for RRD development, which carries a poor prognosis. PMID- 29164420 TI - BRCAsearch: written pre-test information and BRCA1/2 germline mutation testing in unselected patients with newly diagnosed breast cancer. AB - PURPOSE: To evaluate a simplified method of pre-test information and germline BRCA1/2 mutation testing. METHODS: In a prospective, single-arm study, comprehensive BRCA1/2 testing was offered to unselected patients with newly diagnosed breast cancer at three hospitals in south Sweden (BRCAsearch, ClinicalTrials.gov Identifier: NCT02557776). Pre-test information was provided by a standardized invitation letter, but the patients could contact a genetic counselor for telephone genetic counseling if they felt a need for that. Noncarriers were informed about the test result through a letter. Mutation carriers were contacted and offered an appointment for in-person post-test genetic counseling. RESULTS: During the period Feb 2, 2015-Aug 26, 2016, eight hundred and eighteen patients were invited to participate in the study. Through Jan 31, 2017, five hundred and forty-two (66.2%) of them consented to analysis of BRCA1 and BRCA2. Eleven pathogenic mutations were found (BRCA1, n = 2; BRCA2, n = 9), corresponding to a mutation prevalence of 2.0%. Six out of 11 fulfilled the Swedish BRCA testing criteria, and 9 out of 11 fulfilled the NCCN testing criteria. None of the BRCA-associated tumors were of the luminal A-like subtype. Very few patients contacted us for telephone genetic counseling or practical questions, suggesting that a majority felt that the written pre-test information was sufficient for them to make a decision on testing. CONCLUSIONS: Streamlining the process of pre-test information, genetic testing, and delivery of test results was feasible and was associated with an uptake of genetic testing in 2/3 of the breast cancer patients. PMID- 29164421 TI - Ribociclib plus letrozole versus letrozole alone in patients with de novo HR+, HER2- advanced breast cancer in the randomized MONALEESA-2 trial. AB - PURPOSE: Determine the efficacy and safety of first-line ribociclib plus letrozole in patients with de novo advanced breast cancer. METHODS: Postmenopausal women with HR+ , HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021). Patients were randomized to ribociclib (600 mg/day; 3 weeks on/1 week-off) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation. The primary endpoint was investigator-assessed progression-free survival; predefined subgroup analysis evaluated progression-free survival in patients with de novo advanced breast cancer. Secondary endpoints included safety and overall response rate. RESULTS: Six hundred and sixty-eight patients were enrolled, of whom 227 patients (34%; ribociclib plus letrozole vs placebo plus letrozole arm: n = 114 vs. n = 113) presented with de novo advanced breast cancer. Median progression-free survival was not reached in the ribociclib plus letrozole arm versus 16.4 months in the placebo plus letrozole arm in patients with de novo advanced breast cancer (hazard ratio 0.45, 95% confidence interval 0.27-0.75). The most common Grade 3/4 adverse events were neutropenia and leukopenia; incidence rates were similar to those observed in the full MONALEESA 2 population. Ribociclib dose interruptions and reductions in patients with de novo disease occurred at similar frequencies to the overall study population. CONCLUSIONS: Ribociclib plus letrozole improved progression-free survival vs placebo plus letrozole and was well tolerated in postmenopausal women with HR+, HER2- de novo advanced breast cancer. PMID- 29164422 TI - Efficient production and secretion of oxaloacetate from Halomonas sp. KM-1 under aerobic conditions. AB - The alkaliphilic, halophilic bacterium Halomonas sp. KM-1 can utilize glucose for the intracellular storage of the bioplastic poly-(R)-3-hydroxybutyric acid (PHB) and extracellular secretion of pyruvate under aerobic conditions. In this study, we investigated the effects of sodium chloride concentration on PHB accumulation and pyruvate secretion in the KM-1 strain and, unexpectedly, observed that oxaloacetate, an important intermediate chemical in the TCA cycle, glycogenesis, and aspartic acid biosynthesis, was secreted. We then further analyzed oxaloacetate productivity after changing the sodium chloride additive concentration, additive time-shift, and culture temperature. In 42-h batch cultivation experiments, we found that wild-type Halomonas sp. KM-1 secreted 39.0 g/L oxaloacetate at a rate of 0.93 g/(L h). The halophilic bacteria Halomonas has already gained attention for industrial chemical-production processes owing to its unique properties, such as contamination-free culture conditions and a tolerance for high substrate concentrations. Moreover, no commercial scale oxaloacetate production was previously reported to result from bacterial fermentation. Oxaloacetate is an important intermediate chemical in biosynthesis and is used as a health food based on its role in energy synthesis. Thus, these data provided important insights into the production of oxaloacetate and other derivative chemicals using this strain. PMID- 29164423 TI - Successful radical surgical resection of initially unresectable intrahepatic cholangiocarcinoma by downsizing chemotherapy with gemcitabine plus cisplatin: a case report. AB - BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a subtype of biliary tract cancer (BTC). Recently, downsizing chemotherapy has been applied to initially unresectable BTCs, including ICC. CASE PRESENTATION: We report a case of liver resection in a 23-year-old woman who was diagnosed with initially unresectable ICC attached to the inferior vena cava, with portal vein (PV) cavernous transformation. Positron emission tomography (PET) showed fluorodeoxyglucose (FDG) uptake in the para-aortic lymph nodes. Upon using downsizing chemotherapy (the combination of gemcitabine [GEM] and cisplatin [CDDP]), the size of tumor reduced by 55% and FDG uptake in the para-aortic lymph node metastases disappeared. A right hemihepatectomy was performed, along with dissection of lymph nodes, including the para-aortic lymph nodes. The PV cavernous transformation was preserved to maintain collateral flow as much as possible, as it was considered to originate from a congenital anomaly. Pathological examination revealed that R0 resection was performed and that there were no viable neoplastic cells remaining in the para-aortic lymph nodes. The patient is alive at 31 months after initial treatment, with a local recurrence. CONCLUSION: Downsizing chemotherapy with GEM plus CDDP followed by radical surgical resection is an attractive treatment for initially unresectable BTC. PMID- 29164424 TI - Service quality benchmarking via a novel approach based on fuzzy ELECTRE III and IPA: an empirical case involving the Italian public healthcare context. AB - A novel fuzzy-based approach which combines ELECTRE III along with the Importance Performance Analysis (IPA) is proposed in the present work to comparatively evaluate the service quality in the public healthcare context. Specifically, ELECTRE III is firstly considered to compare the service performance of examined hospitals in a noncompensatory manner. Afterwards, IPA is employed to support the service quality management to point out improvement needs and their priorities. The proposed approach also incorporates features of the Fuzzy Set Theory so as to address the possible uncertainty, subjectivity and vagueness of involved experts in evaluating the service quality. The model is applied to five major Sicilian public hospitals, and strengths and criticalities of the delivered service are finally highlighted and discussed. Although several approaches combining multi criteria methods have already been proposed in the literature to evaluate the service performance in the healthcare field, to the best of the authors' knowledge the present work represents the first attempt at comparing service performance of alternatives in a noncompensatory manner in the investigated context. PMID- 29164425 TI - Outflow graft anastomosis site design could be correlated to aortic valve regurgitation under left ventricular assist device support. AB - Aortic valve regurgitation (AR) is a critical complication during circulatory support with a left ventricular assist device (LVAD). The time-course of AR and related factors, including outflow graft anastomosis site design, were investigated. Twenty-three patients who had continuous-flow LVAD implantation and were supported for more than 6 months were investigated. AR grade (none, 0; trivial, 0.5; mild, 1; mild-moderate, 1.5; moderate, 2; moderate-severe, 2.5; severe, 3) and aortic valve opening were evaluated with echocardiography. Computed tomography was performed to all the patients postoperatively. The angle of the outflow graft to the aorta (O-A angle, parallel 0; tangent 90 degrees , 0 180 degrees ), aortic diameter at the anastomosis site, sino-tubular junction (STJ) diameter, distance between the STJ and the anastomosis site, and distance between the anastomosis site and the brachiocephalic artery were measured. The patients' age was 38 +/- 11 years. Support duration was 686 +/- 354 days. Mean AR grade after continuous-flow LVAD implantation was increased to around mild and was maintained thereafter. No patient needed any intervention to the aortic valve. The aortic valves of 82.6% of patients were closed continuously. The O-A angle (83 +/- 14) was positively correlated with maximum AR grade (p = 0.0095). The O-A angle was significantly smaller in patients with maximum AR grade of 1 or less (77 +/- 9 degrees ) than in those with 1.5 or greater (94 +/- 15 degrees , p = 0.021). The other CT measurements had no correlation with AR grade. In conclusion, the O-A angle was correlated with AR grade progression. The O-A angle appears to be one of the important factors related to AR under continuous-flow LVAD support. PMID- 29164427 TI - Virulence traits of avian pathogenic (APEC) and fecal (AFEC) E. coli isolated from broiler chickens in Algeria. AB - Avian pathogenic E. coli (APEC) is the etiologic agent of avian colibacillosis, the most common disease responsible for chicken morbidity in the world. Although multiple virulence-associated factors were identified, their prevalence in Algeria is still poorly known. In the present research, 92 avian pathogenic E. coli (APEC) isolates were recovered from broilers with clinical signs and lesions of colibacillosis. In addition, 32 E. coli isolates collected from feces of healthy birds (AFEC) were included for comparison. All isolates were investigated by PCR for the presence of a total of 11 virulence-associated genes described for avian pathogenic (iroN, ompT, hlyF, iss, iutA, and fimC) and diarrheagenic E. coli (eae, stx, elt/est, ipaH, and aggR). The sensitivity of 39 APEC isolates to 16 antibiotics was also determined using antimicrobial pretreated microplates. Here, we report that 98% of the examined isolates host at least one of the tested virulence factors. The most prevalent genes in APEC were iutA (90.6%), ompT (86.9%), and iss (85.8%); whereas, iutA (78.1%), fimC (78.1%), and iroN (68.7%) were the highest prevalent genes in AFEC. Our data showed that none of the AFEC isolates harbor any of the tested diarrheagenic genes. Moreover, only elt/est (5.4%), stx (2.1%), and ipaH (2.1%) genes were carried by APEC isolates. We further established that ceftazodime, ceftiofur, mequindox, amoxicillin/clavulanic acid, and meropenem were the most efficient antibiotics against the analyzed APEC isolates. Overall, our findings provide more insights about APEC and AFEC virulence potential in Algeria which could participate in the fight against colibacillosis. PMID- 29164426 TI - The Impact of Vascular Disease Treatment on Platelet-Derived Microvesicles. AB - Platelet-derived microvesicles (pMVs) are small, heterogeneous vesicles released from platelet membranes as a result of activation. These microvesicles possess a wide range of properties, including prothrombotic, proatherogenic, proinflammatory, immunomodulatory, and even anticoagulant activity. The elevated release of these microvesicles has been observed in various metabolic, inflammatory, thrombotic, and vascular diseases, including ischemic heart disease, stroke, hypertension, diabetes, and connective tissue disease. Modulation of both pMV generation and the expression of their surface molecules may have beneficial clinical implications and could become a novel therapeutic target. However, mechanisms by which pharmacological agents can modify pMV formation are elusive. The purpose of this review is to discuss the effects of drugs routinely used in primary and secondary prevention of vascular disease on the release of pMV and expression of their surface procoagulant and proinflammatory molecules. PMID- 29164428 TI - The value of high-sensitivity C-reactive protein in hand and knee radiographic osteoarthritis: data from the Dong-gu Study. AB - Due to the inconsistent association between high-sensitivity C-reactive protein (hs-CRP) and osteoarthritis (OA), we evaluated the relationship between hs-CRP and various radiographic findings in older adults with OA. This cross-sectional study recruited 2376 participants from the population-based Dong-gu cohort. The scores of radiographic features in OA on X-rays of the knees and hands were computed using a semi-quantitative grading system. The hs-CRP levels were measured using a particle-enhanced immunonephelometry assay. Correlations showing the relationship between hs-CRP and OA were calculated using multiple linear correlation analysis. The hs-CRP levels were significantly higher in older subjects (p < 0.001), those with a higher body mass index (BMI) (p < 0.001), current smokers (p < 0.001), current alcohol drinkers (p = 0.011), those who were less physically active (p = 0.002), and those with a lower level of education (p = 0.043). After adjusting for BMI and other confounders, the total OA scores (knee, p = 0.022; hand, p = 0.029) and sclerosis score (knee, p = 0.007; hand, p = 0.030) in the knees and hands were all significantly positively correlated with hs-CRP. A significant association was also observed between hs-CRP and hand erosion score (p = 0.045), hand malalignment score (p = 0.015), and tibial attrition score (p = 0.039). In this large cross-sectional study, a higher hs-CRP level was significantly associated with radiographic OA severity. Of the various types of radiographic damage, all of sclerosis, erosion, and malalignment were significantly associated with hs-CRP levels. PMID- 29164429 TI - Red blood cell distribution width as a related factor of pulmonary arterial hypertension in patients with systemic sclerosis. AB - The aim of this study was to investigate the utility of red blood cell distribution width (RDW) as a simple and readily available marker of occurrence of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc). One hundred and forty-five consecutive patients with SSc were recruited to the single-center cross-sectional study. Demographic characteristics, hematological parameters, Modified Rodnan Skin Score, and World Health Organization functional classification were determined. Diagnosis of PAH was based on screening by echocardiography and was confirmed by right heart catheterization. Interstitial lung disease (ILD) was diagnosed based on chest high-resolution computed tomography findings. There were no significant differences in gender, age, or disease duration between limited and diffused SSc groups. PAH was detected in 28 of lcSSc (33.3%) and 14 of dcSSc (23.0%) subjects. Patients with higher RDW values were more likely to be men with high anti-u1RNP titers and PAH. A significant correlation was found between RDW and high sensitivity C-reactive protein (p = 0.375, p < 0.01) and the diffusing capacity of the lungs for carbon monoxide (rho = - 0.396, p < 0.01). The SSc-PAH group had significantly higher RDW values compared to the SSc group without pulmonary disease (15.7 +/- 2.2 and 13.7 +/- 1.0, p < 0.001). The mean RDW in the SSc-PAH ILD group was significantly higher than that in the SSc-ILD group (16.3 +/- 2.2% and 14.0 +/- 1.5%, p < 0.001). Besides the recognized risk factors, high RDW was an independent predictor of PAH in patients with SSc (OR = 3.314 [95%CI 1.038 10.580], p < 0.05). RDW may be a related factor for identifying the pulmonary arterial hypertension in SSc patients. PMID- 29164432 TI - Special Issue Dedicated to Dr. Kazuhiro Ikenaka. PMID- 29164431 TI - Response of the GABAergic System to Axotomy of the Rat Facial Nerve. AB - The responses of inhibitory neurons/synapses to motoneuron injury in the cranial nervous system remain to be elucidated. In this study, we analyzed GABAA receptor (GABAAR) and GABAergic neurons at the protein level in the transected rat facial nucleus. Immunoblotting revealed that the GABAARalpha1 protein levels in the axotomized facial nucleus decreased significantly 5-14 days post-insult, and these levels remained low for 5 weeks. Immunohistochemical analysis indicated that the GABAARalpha1-expressing cells were motoneurons. We next examined the specific components of GABAergic neurons, including glutamate decarboxylase (GAD), vesicular GABA transporter (VGAT) and GABA transporter-1 (GAT-1). Immunoblotting indicated that the protein levels of GAD, VGAT and GAT-1 decreased transiently in the transected facial nucleus from 5 to 14 days post-insult, but returned to the control levels at 5 weeks post-insult. Although GABAARalpha1 protein levels in the transected nucleus did not return to their control levels for 5 weeks post-insult, the administration of glial cell line-derived neurotrophic factor at the cut site significantly ameliorated the reductions. Through these findings, we verified that the injured facial motoneurons suppressed the levels of GABAARalpha1 protein over the 5 weeks post-insult, presumably due to the deprivation of neurotrophic factor. On the other hand, the levels of the GAD, VGAT and GAT-1 proteins in GABAergic neurons were transiently reduced in the axotomized facial nucleus at 5-14 days post-insult, but recovered at 4-5 weeks post-insult. PMID- 29164430 TI - Eclalbasaponin II Ameliorates the Cognitive Impairment Induced by Cholinergic Blockade in Mice. AB - Eclalbasaponin II derived from Eclipta prostrata L. (Asteraceae) has been reported to have anti-fibrotic, anti-bacterial and autophagic activities, but its effect on cognitive function has not been investigated. We studied the effect of eclalbasaponin II on cholinergic blockade-induced memory impairment in mice using the passive avoidance, Y-maze, and Morris water maze tasks. Eclalbasaponin II (10 or 20 mg/kg, p.o.) significantly ameliorated the cognitive dysfunction induced by scopolamine in the passive avoidance, Y-maze, and the Morris water maze tasks. To identify the mechanism of the memory-ameliorating effect of eclalbasaponin II, acetylcholinesterase (AChE) activity assay, Western blot analysis and electrophysiology were conducted. Eclalbasaponin II inhibited the AChE activity in ex vivo study, and the administration of eclalbasaponin II and its metabolite, echinocystic acid, increased the phosphorylation levels of memory-related signaling molecules, including protein kinase B (Akt) and glycogen synthase kinase-3beta (GSK-3beta), in the hippocampus. Although eclalbasaponin II did not affect hippocampal long term potentiation (LTP), echinocystic acid significantly enhanced hippocampal LTP formation (30 MUM). These results suggest that eclalbasaponin II ameliorates cholinergic blockade-induced cognitive impairment via AChE inhibition, LTP formation and the activation of Akt-GSK-3beta signaling, and that eclalbasaponin II may be a useful to treat cognitive impairment derived from cholinergic dysfunction. PMID- 29164433 TI - Distal Lateral Subungual Onychomycosis Owing to Tritirachium oryzae: A Bystander or Invader? AB - The genus Tritirachium is a mitosporic fungus which inhabits in soil and decaying plant material and also a notable insect pathogen. Human infections with Tritirachium species though rare were previously reported to cause corneal ulcers, otomycosis, onychomycosis, and dermatomycosis of the scalp and hence may be considered as a potential pathogen. Here we report a case of distal lateral subungual onychomycosis involving right great toenail in a 22-year-old female, wherein direct potassium hydroxide preparations, fungal cultures, and molecular sequencing of the isolate established Tritirachium oryzae as the etiological agent. Antifungal susceptibility performed by the microbroth technique of CLSI revealed increased MICs to amphotericin B and low MICs to azoles and echinocandins. The case was managed with surgical nail avulsion followed by topical application of 2% ketoconazole cream resulting regrowth of normal nail. To the best of our knowledge, this is the first report of non-dermatophytic mold T. oryzae causing onychomycosis in India. PMID- 29164435 TI - Written Expression in Individuals with Autism Spectrum Disorder: A Meta-Analysis. AB - Although studies exist measuring the effectiveness of writing interventions for students with autism spectrum disorder (ASD), research assessing the writing skills for this group is sparse. The present study identified differences in the written expression of individuals with ASD compared to typically developing (TD) peers, using variables selected from 13 different studies. Using Pearson Product Moment-correlation the relationship between the quality of research studies and the magnitude of the effect sizes was examined. Findings indicate significant differences in the following components of written expression; length, legibility, handwriting size, speed, spelling, and overall structure, highlighting the need for future research to determine if the characteristics of written expression in individuals with ASD are similar to other struggling writers. PMID- 29164434 TI - Isolated Cutaneous Granuloma Caused by Candida glabrata: A Rare Case Report and Literature Review. AB - The incidence of candidiasis due to non-albicans Candida species (especially Candida glabrata) has significantly increased in recent decades. Candida glabrata often invades immunocompromised hosts and causes systemic or mucosal infections, whereas cutaneous infections are rarely reported. We present a rare case of cutaneous infection caused by C. glabrata and review all similar cases available in the PubMed database. A patient was admitted to the hospital with a 2-month history of a plaque on the face. Histopathological examination displayed typical infectious granulomas in the deep dermis, and the pathogen was finally confirmed as C. glabrata using a series of microbial examinations (fungal culture, biochemical test, and PCR-directed sequencing). The patient was completely cured after 4 months of treatment with oral itraconazole combined with topical terbinafine. We reviewed similar reports of cutaneous infection caused by C. glabrata. All the data suggested that an accurate diagnosis of cutaneous candidiasis depends mainly on histological and fungal examinations, especially molecular biological assays. Antifungal agents based on microbial susceptibility tests are the first-line treatment choice for C. glabrata infection, but the prognosis might be more dependent on the basic condition of the host. PMID- 29164436 TI - Priorities for Advancing Research on Youth with Autism Spectrum Disorder and Co occurring Anxiety. AB - Research on anxiety disorders in youth with autism spectrum disorder (ASD) has burgeoned in the past two decades. Yet, critical gaps exist with respect to measuring and treating anxiety in this population. This study used the nominal group technique to identify the most important research priorities on co occurring anxiety in ASD. An international group of researchers and clinicians with experience in ASD and anxiety participated in the process. Topics ranked as most important focused on understanding how ASD symptoms affect treatment response, implementing treatments in real world settings, developing methods to disentangle overlapping symptoms between anxiety and ASD, and developing objective measures to assess anxiety. Collectively, these priorities can lead to collaborative studies to accelerate research in the field. PMID- 29164437 TI - School Discipline, Hospitalization, and Police Contact Overlap Among Individuals with Autism Spectrum Disorder. AB - The objective was to examine the frequency, correlates, and overlap of school disciplinary actions, psychiatric hospitalizations, and police contact among children and adolescents with autism. Survey results from 2525 caregivers of individuals with autism in elementary through high school were examined. Logistic regression was used to examine predictors of each outcome. Youth with autism most frequently experienced school disciplinary action (15.0%), followed by police contact (7.9%) and hospitalization (7.8%). Experiencing any one of the three events increased risk of experiencing either of the other events. Strong associations between traumatic experiences such as police contact and hospitalizations (OR 9.2), need to be explored to determine risk factors for potential intervention. Further research is needed to determine the temporal ordering of these outcomes. PMID- 29164438 TI - Brief Report: Mapping Systems of Support and Psychological Well-Being of Mothers of Adolescents with Autism Spectrum Disorders. AB - Parents of children with autism spectrum disorders are generally known to experience elevated levels of stress and poorer psychological well-being. To provide treatments and resources that most effectively support parent mental health, it is critical to understand how parents' connections with various networks and systems impact their well-being. This study examined the relationship between the psychological well-being of mothers of adolescents with ASD (n = 20) and their systems of support from an ecological systems theoretical framework. Findings indicated that most connections across mothers' ecosystems were strong in nature. However, the presence of strong connections was not significantly related to psychological well-being. In contrast, stressful/weak connections were significantly related to elevated levels of depressive symptoms, perceived stress, and sense of burden. PMID- 29164439 TI - Brief Report: Major Depressive Disorder with Psychotic Features in Williams Syndrome: A Case Series. AB - Descriptions of individuals with Williams syndrome (WS) and co-morbid major depressive disorder (MDD) with psychotic features have not appeared in the literature. In addition to reviewing previous reports of psychotic symptoms in persons with WS, this paper introduces clinical histories and therapeutic management strategies for three previously unreported adults with WS diagnosed with co-morbid MDD with psychotic features. Co-morbid medical disorders common in WS are highlighted with regard to safe and appropriate pharmacological treatment. The importance of assessment for co-morbid MDD with psychotic features in individuals with WS is emphasized. PMID- 29164441 TI - Structure Mapping in Autism Spectrum Disorder: Levels of Information Processing and Relations to Executive Functions. AB - Analogical reasoning was investigated among children with autism spectrum disorders (ASD) without intellectual disabilities and typical development (TD). Children were asked to select one of two targets in two conditions: (1) with and without spatial structure similarity; (2) with and without a perceptual distractor. Results demonstrate that children with ASD were able to select targets based on structural similarity, but this ability decreased to chance level when presented with a perceptual distractor. Everyday executive functions were positively correlated with structural selections among children with ASD. Results suggest that although children with ASD were able to select based on systematicity principle, perceptual distractor decreased their selection so that their cognitive system produced less structure similarities, that negatively affects spatial analogical reasoning. PMID- 29164442 TI - Brief Report: Checklist for Autism Spectrum Disorder: Most Discriminating Items for Diagnosing Autism. AB - The smallest subset of items from the 30-item Checklist for Autism Spectrum Disorder (CASD) that differentiated 607 referred children (3-17 years) with and without autism with 100% accuracy was identified. This 6-item subset (CASD-Short Form) was cross-validated on an independent sample of 397 referred children (1-18 years) with and without autism and on data from 1417 children in the CASD standardization sample and 1052 children in the CASD normative sample, resulting in 98.5, 97.6, and 99.8% diagnostic accuracy, respectively. Diagnostic agreement was high between the CASD-Short Form and the Autism Diagnostic Interview-Revised (96%), and the Child Autism Rating Scale (98%). Diagnostic accuracy for the CASD SF was similar to accuracy for the 30-item CASD full form. PMID- 29164440 TI - Parent and Teacher Concordance of Child Outcomes for Youth with Autism Spectrum Disorder. AB - Cross-informant ratings of are considered gold standard for child behavioral assessment. To date, little work has examined informant ratings of adaptive functioning for youth with autism spectrum disorder (ASD). In a large, diverse sample of youth with ASD, this study evaluated parent-teacher concordance of ratings of adaptive functioning and ASD-specific symptomatology across time. The impact of child clinical characteristics on concordance was also examined. Participants included 246 children, their caregivers and teachers. Parent-teacher concordance was variable but generally consistent across time. Concordance was significantly impacted by autism severity and child cognitive abilities. Findings inform the broader concordance literature and support the need to consider child clinical factors when assessing child functioning in samples of children with ASD. PMID- 29164443 TI - Child Autism Spectrum Disorder Traits and Parenting Stress: The Utility of Using a Physiological Measure of Parental Stress. AB - Caregivers of children with autism spectrum disorder (ASD) report greater stress due to unique parenting demands (e.g.; Estes et al. in Brain Dev 35(2):133-138, 2013). Stress is often studied through self-report and has not been extensively studied using physiological measures. This study compared parenting stress in mothers of children with and without ASD traits. Twenty-seven mother-child dyads participated in an interaction task while measuring mother's heart rate variability (HRV) and mothers self-reported stress levels. Results demonstrated that while self-report and physiological stress measures were not correlated, ASD symptomology did account for HRV change score (i.e., more severe ASD symptoms were positively related to HRV change). This may reflect an atypical coping response. Implications for using physiological indicators for studying parenting stress are explored. PMID- 29164444 TI - A Randomized Controlled Trial of the Social Tools And Rules for Teens (START) Program: An Immersive Socialization Intervention for Adolescents with Autism Spectrum Disorder. AB - Adolescents with ASD face numerous personal and contextual barriers that impede the development of social motivation and core competencies, warranting the need for targeted intervention. A randomized controlled trial was conducted with 40 adolescents to evaluate the merits of a multi-component socialization intervention that places emphasis on experiential learning. This investigation evaluated the impact of the 20-week START program on the social functioning of adolescents with ASD. Significant Group * Time differences between START and waitlist control groups were found across multiple measures. Secondary analyses of the entire program cohort also yielded significant improvement trends across all measures. These findings may be an important step in identifying optimal strategies to target the complex factors limiting optimal social development in ASD. PMID- 29164445 TI - Changes in Depressive Symptoms Among Adolescents with ASD Completing the PEERS(r) Social Skills Intervention. AB - Depression is a common concern among people with autism spectrum disorder (ASD) and is often associated with social skills and relationship challenges. The present data, from a randomized controlled trial, examined the effect of PEERS(r) on self-reported depressive symptoms via the Children's Depression Inventory (CDI) among 49 adolescents with ASD. Findings revealed that many CDI subscale scores declined (p's < 0.05) and were related to direct social contact on the Quality of Socialization Questionnaire at posttest (p's < 0.05). Exploratory analyses uncovered that suicidality was less evident following PEERS(r). Findings support the notion that social functioning and depression may be intimately intertwined in ASD; therefore, bolstering social skills in ASD may positively influence other domains of functioning, including mental health. PMID- 29164446 TI - Automated Detection of Repetitive Motor Behaviors as an Outcome Measurement in Intellectual and Developmental Disabilities. AB - Repetitive sensory motor behaviors are a direct target for clinical treatment and a potential treatment endpoint for individuals with intellectual or developmental disabilities. By removing the burden associated with video annotation or direct observation, automated detection of stereotypy would allow for longer term monitoring in ecologic settings. We report automated detection of common stereotypical motor movements using commercially available accelerometers affixed to the body and a generalizable detection algorithm. The method achieved a sensitivity of 80% for body rocking and 93% for hand flapping without individualized algorithm training or foreknowledge of subject's specific movements. This approach is well-suited for implementation in a continuous monitoring system outside of a clinical setting. PMID- 29164447 TI - Specific Patterns of Emotion Recognition from Faces in Children with ASD: Results of a Cross-Modal Matching Paradigm. AB - Children with ASD show emotion recognition difficulties, as part of their social communication deficits. We examined facial emotion recognition (FER) in intellectually disabled children with ASD and in younger typically developing (TD) controls, matched on mental age. Our emotion-matching paradigm employed three different modalities: facial, vocal and verbal. Results confirmed overall FER deficits in ASD. Compared to the TD group, children with ASD had the poorest performance in recognizing surprise and anger in comparison to happiness and sadness, and struggled with face-face matching, compared to voice-face and word face combinations. Performance in the voice-face cross-modal recognition task was related to adaptive communication. These findings highlight the specific face processing deficit, and the relative merit of cross-modal integration in children with ASD. PMID- 29164448 TI - Measuring Nutrition Literacy in Spanish-Speaking Latinos: An Exploratory Validation Study. AB - Nutrition is important for preventing and treating chronic diseases highly prevalent among Latinos, yet no tool exists for measuring nutrition literacy among Spanish speakers. This study aimed to adapt the validated Nutrition Literacy Assessment Instrument for Spanish-speaking Latinos. This study was developed in two phases: adaptation and validity testing. Adaptation included translation, expert item content review, and interviews with Spanish speakers. For validity testing, 51 participants completed the Short Assessment of Health Literacy-Spanish (SAHL-S), the Nutrition Literacy Assessment Instrument in Spanish (NLit-S), and socio-demographic questionnaire. Validity and reliability statistics were analyzed. Content validity was confirmed with a Scale Content Validity Index of 0.96. Validity testing demonstrated NLit-S scores were strongly correlated with SAHL-S scores (r = 0.52, p < 0.001). Entire reliability was substantial at 0.994 (CI 0.992-0.996) and internal consistency was excellent (Cronbach's alpha = 0.92). The NLit-S demonstrates validity and reliability for measuring nutrition literacy among Spanish-speakers. PMID- 29164449 TI - A Generalized Speed-Accuracy Response Model for Dichotomous Items. AB - We propose a generalization of the speed-accuracy response model (SARM) introduced by Maris and van der Maas (Psychometrika 77:615-633, 2012). In these models, the scores that result from a scoring rule that incorporates both the speed and accuracy of item responses are modeled. Our generalization is similar to that of the one-parameter logistic (or Rasch) model to the two-parameter logistic (or Birnbaum) model in item response theory. An expectation-maximization (EM) algorithm for estimating model parameters and standard errors was developed. Furthermore, methods to assess model fit are provided in the form of generalized residuals for item score functions and saddlepoint approximations to the density of the sum score. The presented methods were evaluated in a small simulation study, the results of which indicated good parameter recovery and reasonable type I error rates for the residuals. Finally, the methods were applied to two real data sets. It was found that the two-parameter SARM showed improved fit compared to the one-parameter SARM in both data sets. PMID- 29164450 TI - Accuracy of early CT findings for predicting disease course in patients with acute pancreatitis. AB - PURPOSE: To investigate whether computed tomography (CT)-based scoring systems obtained within 72 h of symptoms onset can predict disease course in acute pancreatitis. METHODS: Between October 2007 and December 2015, 189 patients (age range 21-93 years) who underwent abdominopelvic CT for the diagnosis of acute pancreatitis were included in the study. Balthazar grade and original and modified versions of CT severity index (CTSI) measurements were carried out for each patient. RESULTS: There were significant associations between each CT based scoring system and development of pancreatic and extrapancreatic complications (p < 0.001). A cutoff value of > 6 for CTSI and > 9 for the modified version of CTSI achieved a specificity of 98.7 and 99.2% for predicting pancreatic and extrapancreatic complications with areas under the curve (AUC) of 0.96 and 0.96, respectively. Balthazar grade of > C yielded a sensitivity of 98.4% for predicting pancreatic and extrapancreatic complications with an AUC of 0.95. The modified version of CTSI had the most significant association with pancreatic and extrapancreatic complications (HR: 3.22; p = 0.002, HR: 2.99, p = 0.003, respectively). Pancreatic necrosis was the only parameter significantly associated with mortality (HR: 5.83, p = 0.045). CONCLUSION: Early CT scan has an important role in prediction of complications and the management of acute pancreatitis. PMID- 29164454 TI - Postsurgical sympathetic ophthalmia: retrospective analysis of a rare entity. AB - PURPOSE: To describe clinical manifestations, management and visual outcome in postsurgical sympathetic ophthalmia (SO). METHODS: Retrospective study. RESULTS: Mean age of the patients was 41.1 years, and males were affected 1.8 times than the female. Vitrectomy and scleral buckling were the most common inciting surgeries followed by cataract surgery. Among 10 eyes with anterior uveitis, mutton-fat keratic precipitate was seen in only two eyes. Mean follow-up duration was 1556.50 +/- 1470.75 days. Vision significantly improved in 11 patients (78.6%; p = 0.005). CONCLUSION: Postsurgical SO is a rare entity, but it is a bilateral blinding disease and SO following surgical intervention can have variable presentations. Rapid, effective management of postsurgical sympathetic ophthalmia can give improved visual outcomes. PMID- 29164452 TI - Identification of suh gene and evidence for involvement of notch signaling pathway on gonadal differentiation of Yellow River carp (Cyprinus carpio). AB - The suh gene is crucial in Notch pathway and regulates mammalian gonad development. In this study, the sequences of suh1 and suh2 genes in Yellow River carp (Cyprinus carpio) were verified. The partial 5'-flanking regions of suh1 and suh2 were analyzed and several potential transcription factor-binding sites were identified. Phylogenetic, gene structure, and chromosome synteny analyses revealed that carp suh1 and suh2 were orthologs and homologous to vertebrate suh. Investigation of the expression profiles of suh1 and suh2 with qPCR showed that these genes were abundant in the brain and gonad of carp, with suh1 exhibiting sexual dimorphism expression pattern in gonad. To study the relationship between gonad differentiation and Notch signaling, primordial gonads were exposed to DAPT, an inhibitor of Notch signaling, in vitro and in vivo. The results revealed a significant downregulation of suh1 and other Notch genes in vitro. In addition, expression of male-biased genes, such as amh, dmrt1, etc., was downregulated, whereas that of female-biased genes, such as foxl2, gdf9, etc., was upregulated. When the primordial gonads were subjected to long-term DAPT exposure, an increased proportion of ovary and delay in testis development were observed. These results suggest that suh gene may have a conservative function between teleosts and mammals. Furthermore, Notch signaling was found to be involved in gonad differentiation in Yellow River carp, and DAPT was noted to inhibit and enhance the expression of male- and female-biased genes, respectively, and induce the increase in number of females. PMID- 29164453 TI - Enhancing the sensitivity of multidimensional NMR experiments by using triply compensated pi pulses. AB - In multidimensional solution NMR experiments, pi pulses are used extensively for inversion and refocusing operations on 1H, 13C and 15N nuclei. Pulse miscalibration, off-resonance effects, and J-coupling evolution during pi pulse execution result in severe signal losses that are exacerbated at high magnetic fields. Here, we report the implementation of a triply-compensated pi pulse (G5) optimized for both inversion and refocusing in widely used 2- and 3-dimensional experiments. By replacing most of the hard pi pulses, adiabatic or composite pulses on the 1H, 13C and 15N channels with G5 pulses, we obtained signal enhancements ranging from 80 to 240%. We anticipate that triply-compensated pulses will be crucial for improving the performance of multidimensional and multinuclear pulse sequences at ultra-high fields. PMID- 29164455 TI - Removal of lead from aqueous solution using polyacrylonitrile/magnetite nanofibers. AB - Lead is known for its toxic and non-biodegradable behavior. The consumption of lead-contaminated water is one of the major threat the world is facing nowadays. In this study, polyacrylonitrile (PAN) and magnetite (Fe3O4) composite nanofiber adsorbent was developed for Pb2+ removal in batch mode. The synthesis was done by a simple and scalable process of electrospinning followed by chemical precipitation of Fe3O4. The nanofibers thus obtained were characterized through FTIR, zeta potential analyzer, and scanning electron microscope (SEM) and were analyzed for their adsorption capability for Pb2+ ions. The amount of metal ion adsorbed was influenced by the initial metal ion concentration, the time the adsorbent was in contact, the amount of nanofiber, and the pH of the solution. The experimental data fitted well with pseudo 2nd-order and Langmuir adsorption isotherm model. The nanofibers showed high adsorption capability and could be recommended for Pb2+ removal successfully. PMID- 29164451 TI - The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression. AB - Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed. PMID- 29164456 TI - The effect of animal grazing on vegetation and soil and element cycling in nature. AB - Appropriate level of bio-components in blood plasma of animals is associated with their concentration in soil and in green fodder. Cycling of elements in nature and their adequate level in animal organisms result in proper functioning of an organism as a whole (Khan et al. 68:279-284, 2007). Therefore, it is important to analyse soil and green fodder for these components. If some deficits are found, it is important to supplement components responsible for e.g. proper growth and development of a young organism, proper reproduction and, consequently, good quality of obtained product, which may affect human health (Minzanova et al. 134:524-533, 2015). The aim of the presented study was to demonstrate the effect of extensive grazing by sheep on vegetation and soil and to analyse the cycling of some elements important for animal health. The effects of vegetation season on the concentration of potassium in soil and differences in the concentration of some elements in soil, green fodder and animal blood were demonstrated. PMID- 29164457 TI - Drying-submergence alternation enhanced crystalline ratio and varied surface properties of iron plaque on rice (Oryza sativa) roots. AB - Iron plaque (IP) is valuable in nutrient management and contaminant tolerance for rice (Oryza sativa) because it can adsorb various nutrients and toxic ions. Crystalline ratio (CR) can be defined as the proportion of crystalline iron (CI) to total IP to describe IP crystallinity. Although the knowledge on IP has abounded, the information on the relationship among its formation condition, surface properties, and CR remains insufficient. In this study, quartz sand-soil cultivation with rice was conducted to explore the effect of drying-submergence alternation (DSA) on CI, amorphous iron (AI), CR, root oxidizing capacity (ROC), and surface properties of IP with different treatment durations and at different stages. Fourteen-day DSA treatment increased CI to 2.20 times of that after continuous submergence (CS) but decreased AI to 72.3% of that after CS. Correspondingly, CR was raised to 6.89% from 4.08%. Remarkably, CR of IP after DSA ending in submergence and ending in drying was 6.89% and 4.23%, respectively. In addition, ROC after 14-day DSA was enhanced to twice of that after CS. Results from scanning electronic microscope suggested that 14-day DSA induced thinner sheets with finer particles in IP compared to that after CS. Results from X-ray diffraction revealed that IP contained higher proportions of goethite, lepidocrocite, magnetite, and hematite after DSA than those after CS. Variable charge and surface area of IP after DSA were only 26.5% and 32.0% of those after CS, respectively. Together, our results indicated that proper strength DSA promoted ROC and transformation from AI to CI, and consequently increased CR of IP, while it changed its surface properties. PMID- 29164458 TI - Phosphorus speciation and release kinetics of swine manure biochar under various pyrolysis temperatures. AB - Converting swine manure to biochar is an effective way to recycle valuable nutrients, but there are few reports on its feasibility as a phosphorus (P) source. The objective of this study was to clarify the unique nature, including P speciation, of manure biochar products under various pyrolysis temperatures. We used solution 31P nuclear magnetic resonance and P K-edge X-ray adsorption near edge spectroscopy (P XANES) to characterize P species in swine manure biochar. For every 100 degrees C increment starting from 300 degrees C, the P content in manure biochar increased by 2.16 to 3.37 g kg-1. However, above 400 degrees C, organic P species did not appear anymore, and only inorganic P, including orthophosphate and pyrophosphate, existed. P K-edge XANES spectra further showed all biochar samples had higher percentages of Ca3 (PO4)2 and NaP2O7, and lower percentages of FePO4, AlPO4, and inositol hexaphosphate compared to manure. Interestingly, percentages of Ca3(PO4)2, FePO4, and AlPO4 in MB400 (indicating manure pyrolysed at 400 degrees C) were comparable with those in MB700 while the percentage of NaP2O7 was higher in MB400. Phosphorus release from MB400 maintained a relatively high level at 0.33 g kg-1 during the whole 300-h observation period. These results suggest that with a suitable pyrolysis temperature, it was feasible for manure biochar to be a P source alternative. Graphical abstract ?. PMID- 29164459 TI - Deposition, acute toxicity, and bioaccumulation of nickel in some freshwater organisms with best-fit functions modeling. AB - Although nickel (Ni) frequently enters into water, documents on speciation of the metal and its toxicity to freshwater organisms are scanty. Laboratory experiments, made in this study, with 1.0-5.0 mg/L of Ni revealed that Ni was not quickly removed from water. Application of cubic regression followed by classical optimization technique showed that maximum reduction time (T) of Ni in water ranged between 60 to 65 h. Ninety-six hours of LC50 value of Ni to crustacean Diaptomus forbesi, fish Cyprinus carpio, and worm Branchiura sowerbyi was respectively 5.43, 14.70, and 19.73 mg/L. Normalizing the lethal values and plotting them against time, it was observed that C. carpio was more sensitive than D. forbesi, which was not reflected in the 96-h LC50 values. However, sensitivity of these organisms to Ni was better explained by power regression equation (M = aNib), which exhibited that mortality (M) of D. forbesi and B. sowerbyi increased slowly between 24 to 72 h, increasing sharply at 96 h, while mortality of C. carpio increased steadily every 24 till 96 h. Experiment with 1.0 mg/L of Ni in outdoor vats showed that crustacean zooplankton and worms accumulated high concentration of Ni, while only gut and liver tissues of fish C. carpio accumulated trace and moderately high concentration of Ni, respectively. It is assumed that toxicity of Ni to fish is mediated primarily through gill. PMID- 29164460 TI - Di-(2-ethylhexyl)-phthalate induces glucose metabolic disorder in adolescent rats. AB - As a plasticizer, di-(2-ethylhexyl)-phthalate (DEHP) is widely added in various commercial products. Some researchers had suggested that DEHP has adverse effects on the glucose metabolism, but the mechanisms remain unclear. Adolescent Wistar rats were divided into four groups and administered DEHP by gavage at 0, 5, 50, and 500 mg kg-1 d-1 for 28 days. ELISA was used to quantify the serum insulin and leptin levels; RT-PCR, immunohistochemistry, and Western blot were used to detect the mRNA and protein expressions of Janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3), leptin receptor (Ob-R), and insulin receptor (IR) in liver and pancreas In comparison to the control group, the DEHP-treated rats showed the following: (1) higher organ coefficient of liver; (2) higher fasting blood glucose levels, higher fasting serum insulin and leptin levels, higher insulin resistance index homeostasis model assessment; (3) lower protein levels of Ob-R and IR in the liver and pancreas; (4) higher protein levels of JAK2 and STAT3 in the liver; and (5) higher protein and mRNA levels of SOCS3 in the liver and pancreas. Exposure to DEHP induced glucose metabolic disorder in the adolescent rats, and the mechanism is that DEHP may interfere with the JAK2/STAT3/SOCS3 pathway, regulated the sensitivity of the insulin receptor and leptin receptor. PMID- 29164461 TI - Seasonal toxicity variation in light-textured soil amended with urban sewage sludge: interaction effect on cadmium, nickel, and phytotoxicity. AB - Sewage sludge is increasingly used as an organic amendment to agricultural soils, especially to soils containing little organic matter. However, little is known on the impact of this biowaste on seasonal changes of nickel and cadmium toxicity in a sandy loam soil. Accordingly, the aim of this field-scale study was to evaluate the seasonal phytotoxicity according to Cd, Ni, and dehydrogenase variation in an agricultural soil during two successive annual amendments with increasing amounts of urban sludge (0, 40, 80, and 120 t ha-1 year-1). Sampling was carried out at the end of dry season (EDS) and at the end of wet season (EWS) during 2 years 2012/2013. Sludge application significantly increased the amount of organic matter and dehydrogenase activity in the soil. In order to explain the seasonal variation of Cd and Ni, pH and electrical conductivity were also monitored in this study. The increased rate of sewage sludge addition slightly reduced the pH but soil remained above neutrality. The electrical conductivity which reflects soil salinity was strongly correlated with Cd and Ni content that increased with sludge dose. Salinity and heavy metals were highest at EDS 2013. In addition, soil phytotoxicity testing was performed by the evaluation of lettuce seed germination for 120 h. Although heavy metal content did not generally exceed Tunisian thresholds (3 and 75 mg kg-1 for Cd and Ni, respectively), the seed germination index decreased with sewage sludge dose at all seasons. In general, we observed a significant effect of seasonal variation for all studied parameters. Sewage sludge reuse could be a feasible way to improve soil organic matter but toxicity risks consistently increased with time. PMID- 29164462 TI - Ameliorative effect of the anticancer agent salinomycin on cadmium-induced hepatotoxicity and renal dysfunction in mice. AB - This study presents experimental data on the effects of the tetraethylammonium salt of salinomycinic acid (Sal) on Cd-induced hepatotoxicity and renal dysfunction in Cd-treated mice compared to those of meso-2,3-dimercaptosuccinic acid (DMSA). Forty 60-day-old male ICR mice were randomized into five groups: control group (untreated mice), Cd group (Cd(II) acetate 20 mg/kg body weight provided orally once per day for 14 days), Cd + DMSA group (exposed to Cd(II) acetate as the Cd-exposed group followed by DMSA 20 mg/kg body weight provided orally once per day for 14 days), and Cd + Sal group (exposed to Cd(II) acetate as the Cd-exposed group followed by Sal 20 mg/kg body weight once per day for 14 days). Cd intoxication of mice induced significant liver and kidney injury and a significant elevation of the concentration of Cd in both organs. Treatment of Cd exposed mice with DMSA or Sal restored the levels of the renal and hepatic functional markers and significantly decreased the concentration of the toxic metal ion in both organs. Administration of Sal improved Cd-induced alterations of the endogenous levels of the essential metal ions. Histological studies revealed that the antibiotic more effectively ameliorated the Cd effect on the liver morphology compared to DMSA. Taken together, the results confirm that the anticancer agent salinomycin is a promising antidote to Cd poisoning. PMID- 29164463 TI - Environmental mineralization of caffeine micro-pollutant by Fe-MFI zeolites. AB - Environmentally emerging micro-pollutant, caffeine, was mineralized (i.e., full degradation) by the isomorphic incorporation of Fe into silicalite-1 (mordenite framework inverted (MFI) structure zeolite) through a microwave synthesis method. The Fe incorporation conferred mesopore formation that facilitated caffeine access and transport to the MFI zeolite structure. Increasing the Fe content favored the formation of Fe(O)4 sites within the MFI structure. The catalytic activity for the degradation of caffeine increased as a function of Fe(O)4 sites via a Fenton-like heterogeneous reaction, otherwise not attainable using Fe-free pure MFI zeolites. Caffeine degradation reached 96% (TOC based) for zeolites containing 2.33% of Fe. PMID- 29164464 TI - Kinetic simulation and prediction of pyrolysis process for non-metallic fraction of waste printed circuit boards by discrete distributed activation energy model compared with isoconversional method. AB - Kinetic studies on the pyrolysis process for non-metallic fraction (NMF) of waste printed circuit boards (WPCBs) were conducted using both the isoconversional SKAS method and the discrete distributed activation energy model (discrete DAEM). The pyrolysis process of the NMF sample could be classified into three stages, and a large mass loss was observed from 98 to 570 degrees C, attributed to thermal degradation of epoxy resins in the NMF sample. The kinetic parameters, including activation energies (E i), pre-exponential factors (A i), and contributed fractions (f i,0), were determined. It indicated that the discrete DAEM could predict the pyrolysis process of the NMF more accurately and completely when compared with the isoconversional SKAS method. In the discrete DAEM, E i and A i values were evaluated at 99 equally spaced intervals of conversion. The E i and A i (in the form of lnA i) transformed with reaction progress, ranging from 80.9 to 240.5 kJ/mol and 19.07 to 39.55 s-1, respectively, with the conversion increased from 0.01 to 0.99. The pyrolysis of the NMF of WPCBs could be accurately characterized as 17 dominating reactions from f i,0 results. Graphical abstract ?. PMID- 29164465 TI - Assessment of pollutions and identification of sources of heavy metals in sediments from west coast of Shenzhen, China. AB - The sediment samples were collected from eight sites located in the Pearl River Estuary and the Shenzhen Bay of the west coast of Shenzhen. The distributions of the seven elements Zn, Cr, Hg, Cu, Cd, Pb and As have been analyzed, and their pollution degrees, corresponding potential ecological risks and source identifications have been studied using geo-accumulation index, potential ecological risk index and integrated multivariate statistical methods, respectively. Based on the calculated geo-accumulation indices, the contamination levels of all elements in the Pearl River Estuary are similar to those in the Shenzhen Bay, reflecting that these elements in the study areas have similar sources because of the adequate seawater exchange. The calculated potential ecological risk indices suggest that Cd and Hg are at considerable and moderate risk, respectively. Multivariate statistical analyses further reveal that Zn, Hg, Cd and Pb originated from industrial wastewater, while Cr and Cu are mainly from both industrial wastewater and agricultural sources, and As is mainly from natural source. These research results provide baseline information for both the coastal environment management and the worldwide heavy metal distribution and assessment. PMID- 29164466 TI - Bioagents and silicon promoting fast early upland rice growth. AB - Upland rice can overcome major challenges through the insertion of silicate fertilization and the presence of plant growth-promoting microorganisms (PGPMs) during its cultivation, as these factors promote an increase in vigor and plant disease resistance. Two consecutive experiments were conducted to evaluate the beneficial effects of silicon fertilization combined with the PGPM, Pseudomonas fluorensces, Burkholderia pyrrocinia, and a pool of Trichoderma asperellum, in upland rice seedlings, cultivar BRS Primavera CL: (a) E1, selecting PGPM type and Si doses for rice growth promotion and leaf blast supression, and (b) E2, evaluating physiological characteristics correlated with mechanisms involved in the higher vegetative growth in highlighted treatments from E1. In E1, 2 Si t ha 1 combined with the application of T. asperellum pool or PGPM mixture increased 54% in root dry matter biomass and 35 and 65% in shoot and root lengths, respectively; it also suppressed 99% of rice blast severity. In E2, shoot and root dry matter biomass and length, photosynthetic rate, water use efficiency, total soluble sugar, and chloroplastidic pigments were superior in BRS Primavera CL seedlings treated with 2 Si t ha-1 and T. asperellum pool or PGPM mixture. Higher salicilic and jasmonic acid levels were found in seedlings treated with Si and T. asperellum pool, individually. These physiological characteristics may explain, in part, the higher vigor of upland rice seedlings promoted by the synergistic effect between silicate fertilization and beneficial microorganisms. PMID- 29164467 TI - Solid fuel use for cooking and its health effects on the elderly in rural China. AB - Indoor air pollution is mainly caused by solid fuel use for cooking in developing countries. Many previous studies focused on its health risks on the children and in specific local area. This paper investigates household energy usage and transition for cooking in rural China and the health effects on the elderly. A national large-scale dataset CHARLS (China Health and Retirement Longitudinal Study) covering 450 villages and communities is employed. Logit regressions were used to quantitatively estimate the effects, after controlling for some factors such as income, demographic, and geographical variables. The results robustly show that compared to non-solid fuels, solid fuel use significantly increases the possibility of chronic lung diseases (30%), exacerbation of chronic lung diseases (95%), seizure of heart disease (1.80 times), and decreases self-evaluated health status of the elderly (1.38 times). Thus, it is urgent to improve clean energy access for cooking in rural China. PMID- 29164468 TI - Assessment of water resource contamination by pesticides in vegetable-producing areas in Burkina Faso. AB - This study proposes a comprehensive approach to investigate water resource contamination by pesticides under the specific climatic and hydrological conditions of the Sudano-Sahelian climate. Samples were collected from traditional wells, boreholes, and a lake in Burkina Faso. A multiresidue analysis was developed for 25 pesticides identified during field surveys. Polar organic chemical integrative samplers (POCIS) were used to confirm trends observed with grab samples. Uptake kinetics of POCIS were assessed by in situ calibration. The proposed use of nonlinear least squares regression proved to be a robust approach for estimating time-weighted average concentration in cases of nonlinear uptake. High sampling rates for triazines in a quasi-stagnant lake were attributed to warm water temperatures (30.8 +/- 1.3 degrees C). The combination of sampling techniques during a 3-year monitoring period allowed for identifying potential interactions between resources, seasonal patterns, and origins of contaminants. Atrazine, azadirachtin, carbofuran, chlorpyrifos, cypermethrin, dieldrin, imidacloprid, and profenofos exceeded 0.1 MUg L-1, indicating a potential risk for the consumers. Ecological risk assessment was performed using the Pesticide Tool Index for fish, cladocerans, and benthic invertebrates. Peak concentrations of cypermethrin and chlorpyrifos were systematically associated with hazard to the studied taxa. PMID- 29164469 TI - Antibiotic anisomycin induces cell cycle arrest and apoptosis through inhibiting mitochondrial biogenesis in osteosarcoma. AB - The anti-cancer activities of antibiotic anisomycin have been demonstrated in kidney, colon and ovarian cancers whereas its underlying mechanisms are not well elucidated. In this work, we investigated whether anisomycin is effective in sensitizes osteosarcoma cell response to chemotherapy. We show that anisomycin inhibits proliferation via inducing osteosarcoma cell arrest at G2/M phase, accompanied by the increased levels of mitotic marker cyclin B and the decreased levels of Rb and E2F-1. Anisomycin also induces apoptosis in a caspase-dependent manner in osteosarcoma cells. Importantly, anisomycin is less effective in normal control NIH3T3 cells compared to osteosarcoma cells. In addition, anisomycin inhibits osteosarcoma growth in xenograft mouse model and enhances the inhibitory effects of doxorubicin in osteosarcoma in vitro and in vivo. Mechanistically, anisomycin targets mitochondrial biogenesis in osteosarcoma as shown by the decreased mitochondrial membrane potential, suppressed mitochondrial respiration via decreasing complex I activity, reduced ATP production. Furthermore, mitochondrial biogenesis stimulator acetyl-L-Carnitine (ALCAR) significantly rescues the inhibitory effects of anisomycin in osteosarcoma cells. Our work demonstrates that anisomycin is active against osteosarcoma cells and the molecular mechanism of its action is the inhibition of mitochondrial biogenesis. PMID- 29164470 TI - Viral Communities Among Sympatric Vampire Bats and Cattle. AB - Vampire bats are the only mammals known to feed exclusively on blood from other animals, often from domestic cattle. We tested the hypothesis that the adaptation of vampire bats to hematophagy would have resulted in shared viral communities among vampire bats and cattle, as a direct result of historic spillover events occurring due to hematophagy. We analyzed the presence of different viruses in sample populations of sympatric bat and prey populations and searched for shared viruses between taxa. A limited number of DNA viral groups were detected within each species. However, there was no evidence for a shared viral community among the vampire bat and cattle populations tested. PMID- 29164471 TI - The Era of Human-Induced Diseases. PMID- 29164472 TI - Rodent-Borne Bartonella Infection Varies According to Host Species Within and Among Cities. AB - It is becoming increasingly likely that rodents will drive future disease epidemics with the continued expansion of cities worldwide. Though transmission risk is a growing concern, relatively little is known about pathogens carried by urban rats. Here, we assess whether the diversity and prevalence of Bartonella bacteria differ according to the (co)occurrence of rat hosts across New Orleans, LA (NO), where both Norway (Rattus norvegicus) and roof rats (Rattus rattus) are found, relative to New York City (NYC) which only harbors Norway rats. We detected human pathogenic Bartonella species in both NYC and New Orleans rodents. We found that Norway rats in New Orleans harbored a more diverse assemblage of Bartonella than Norway rats in NYC and that Norway rats harbored a more diverse and distinct assemblage of Bartonella compared to roof rats in New Orleans. Additionally, Norway rats were more likely to be infected with Bartonella than roof rats in New Orleans. Flea infestation appears to be an important predictor of Bartonella infection in Norway rats across both cities. These findings illustrate that pathogen infections can be heterogeneous in urban rodents and indicate that further study of host species interactions could clarify variation in spillover risk across cities. PMID- 29164473 TI - Clinicopathological and Immunohistochemical Study of Head and Neck Langerhans Cell Histiocytosis from Latin America. AB - Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplastic proliferation with variable clinical behavior caused by the accumulation of CD1a+/CD207+ histiocytes, associated with a variable number of eosinophils, lymphocytes, plasma cells and multinucleated giant cells, most commonly observed in male children. LCH is uncommon in the head and neck region, occurring as ulcerated and reddened plaques or nodules that cause destruction of adjacent soft tissues and bone. The exact etiology of LCH is still unknown and controversial, with possible etiologic role of viruses, including Epstein-Barr virus (EBV). The aim of this study was to describe the clinicopathologic and immunohistochemical features of patients with LCH of the head and neck region. Clinical data from 19 patients with LCH were obtained from the archives of the Federal University of Rio de Janeiro and the Clinical Head and Neck Center of Guatemala. All cases were submitted to morphological, immunohistochemical analysis with CD1a, CD207, CD3, CD20, CD68, S-100 and Ki-67 and in situ hybridization for EBV. Ten cases were female and 9 male, with mean age of 11.5 years. Fourteen cases were located in the oral cavity, three cases in lymph nodes, and two cases in the scalp. In regard to the oral lesions, 13 cases were intra-osseous with six cases in anterior mandible, five cases in posterior mandible, and two cases in posterior maxilla while one case was located exclusively in the gingiva. The inflammatory pattern showed variation in the number of plasma cells, eosinophils and lymphocytes, while tumor cells were positive for CD1a, S-100 and CD68 in all cases, and positive for CD207 in 18 cases. In situ hybridization for EBV were negative in all cases. PMID- 29164474 TI - Microcystic Calcifying Epithelial Odontogenic Tumor. AB - Microcystic variant of calcifying epithelial odontogenic tumor is rare. We herein describe an additional well-documented case of microcystic CEOT. The affected patient is a Guatemalan 42-year-old female with an expansile well-defined mixed radiolucent-radiopaque lesion located in the right posterior mandible. The lesion was associated to an unerupted third molar. Histopathologic examination revealed nests and cords of moderately pleomorphic, eosinophilic polyhedral epithelial cells surrounded by a fibromyxoid stroma. The neoplastic cells showed microcystic pattern made of pseudo-glandular spaces with variable diameter. Occasional amyloid deposits and calcified acellular material were observed. Tumor cells were positive for AE1/AE3, CK14, CK19, p63, CD138, and beta-catenin. Conservative surgical resection was performed with an uneventful immediate post-surgical follow-up. After 1 year follow-up there is no evidence of recurrence. Pathologists should be aware of this unusual microcystic presentation of CEOT, which may pose a diagnostic challenge and potential diagnostic dilemma. PMID- 29164475 TI - Naphthyridines part 4: unprecedented synthesis of polyfunctionally substituted benzo[c][2,7]naphthyridines and benzo[c]pyrimido[4,5,6-ij][2,7]naphthyridines with structural analogy to pyrido[4,3,2-mn]acridines present in the marine tetracyclic pyridoacridine alkaloids. AB - An easy, efficient and one-step synthesis of the versatile, hitherto unreported of polyfunctionally substituted benzo[c][2,7]naphthyridines 4a-c is described. The reaction of 4a-c with sodium azide gives the corresponding tetracyclic ring system 6a-c in near quantitative yield, and with phenyl isothiocyanate it gives the corresponding novel 3-alkyl-2-oxo-6-phenyl-5-thioxo-3,4,5,6-tetrahydro-2H benzo[c]pyrimido[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 8a-c. Refluxing compound 4a, with alkyl amines 9a-d for 2-3 h furnished 3-alkyl-5-alkylamino-4 amino-2-oxo-2,3-dihydrobenzo[c][2,7]naphthyridine-1-carbonitriles 10a-d, as stable crystalline solids. Compounds 10a-d reacted with acetic anhydride and triethyl orthoformate to furnish novel 3,6-dialkyl-2-oxo-3,6-dihydro-2H-benzo[c] pyrimido[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 13a-c and 14a-c, respectively. Lastly, diazotization of 10a-c afforded the novel tetracyclic ring system 3,6-dialkyl-2-oxo-3,6-dihydro-2H-benzo[c][1,2,3]triazino[4,5,6 ij][2,7]naphthyridine-1-carbonitriles 16a-c. PMID- 29164476 TI - Diverticular colitis with progression to ulcerative colitis after sigmoidectomy. AB - Diverticular colitis is chronic inflammation of the colon where diverticula are present. The endoscopic and histopathological findings of this disease are sometimes similar to those of ulcerative colitis, and several reports describe cases of diverticular colitis that progressed to typical ulcerative colitis. A 77 year-old woman with intramesenteric penetration of the sigmoid diverticulum underwent low anterior resection. One month later, the patient experienced anastomotic leakage, and transverse colostomy was performed. Six months after the colostomy, the patient returned to the hospital with complaints of bloody discharge from the rectum and stoma. Colonoscopy revealed newly developed loss of vascular pattern and a granular appearance of the mucosa in the rectum that had not been present at prior examinations. She was diagnosed with ulcerative colitis, which developed after colectomy, and treated with mesalazine and high dose prednisolone, but the clinical and endoscopic response was poor. Finally, the patient underwent total proctocolectomy and ileal pouch anal anastomosis with diverting ileostomy. As a few reports have described, diverticular colitis can progress to typical ulcerative colitis after surgery in some cases, suggesting a possible pathogenic similarity between the two diseases and association between colorectal surgery and disease progression. PMID- 29164478 TI - Excited State and Non-linear Optical Properties of NIR Absorbing beta-Thiophene Fused BF2-Azadipyrromethene Dyes-Computational Investigation. AB - Density functional theory and time-dependent density functional theory computations were used to understand the electronic and photophysical parameters of NIR beta-thiophene-fused BF2-azadipyrromethene dyes. The computed data are in good agreement with those obtained experimentally and they provide insights into the origin of red shifted optical spectra compared to the parent aza-BODIPY, low Stokes shift, non-linear optical responses and quantitative description of the singlet-triplet energy gap. The resultant decrease in the HOMO - LUMO energy gap is responsible for the red shift. The possible use as non-linear optical materials is supported by large enhancement in the non-linear optical properties. On the basis of vertical triplet energies, their possible potential therapeutic use as a photosensitizer in photodynamic therapy is proposed. The singlet-triplet energetic gaps suggest that the beta-thiophene-fused BF2-azadipyrromethene dyes can act as a sensitizer to produce an efficient generation of singlet oxygen. Their optimal use as an efficient singlet fission materials has been proposed on the basis of excitation energies in the ground, lowest singlet and triplet excited states. PMID- 29164477 TI - Genetic Variants Within Molecular Targets of Antipsychotic Treatment: Effects on Treatment Response, Schizophrenia Risk, and Psychopathological Features. AB - Schizophrenia (SCZ) is a common and severe mental disorder. Genetic factors likely play a role in its pathophysiology as well as in treatment response. In the present study, we investigated the effects of several single nucleotide polymorphisms (SNPs) within 9 genes involved with antipsychotic (AP) mechanisms of action. Two independent samples were recruited. The Korean sample included 176 subjects diagnosed with SCZ and 326 healthy controls, while the Italian sample included 83 subjects and 194 controls. AP response as measured by the positive and negative syndrome scale (PANSS) was the primary outcome, while the secondary outcome was the SCZ risk. Exploratory analyses were performed on (1) symptom clusters response (as measured by PANSS subscales); (2) age of onset; (3) family history; and (4) suicide history. Associations evidenced in the primary analyses did not survive to the FDR correction. Concerning SCZ risk, we partially confirmed the associations among COMT and MAPK1 genetic variants and SCZ. Finally, our exploratory analysis suggested that CHRNA7 and HTR2A genes may modulate both positive and negative symptoms responses, while PLA2G4A and SIGMAR1 may modulate respectively positive and negative symptoms responses. Moreover, GSK3B, HTR2A, PLA2G4A, and S100B variants may determine an anticipation of SCZ age of onset. Our results did not support a primary role for the genes investigated in AP response as a whole. However, our exploratory findings suggested that these genes may be involved in symptom clusters response. PMID- 29164481 TI - Excipient Stability: a Critical Aspect in Stability of Pharmaceuticals. PMID- 29164479 TI - Spectro Analytical, Computational and In Vitro Biological Studies of Novel Substituted Quinolone Hydrazone and it's Metal Complexes. AB - Some novel transition metal [Cu (II), Ni (II) and Co (II)] complexes of nalidixic acid hydrazone have been prepared and characterized by employing spectro analytical techniques viz: elemental analysis, 1H-NMR, Mass, UV-Vis, IR, TGA-DTA, SEM-EDX, ESR and Spectrophotometry studies. The HyperChem 7.5 software was used for geometry optimization of title compound in its molecular and ionic forms. Quantum mechanical parameters, contour maps of highest occupied molecular orbitals (HOMO) and lowest unoccupied molecular orbitals (LUMO) and corresponding binding energy values were computed using semi empirical single point PM3 method. The stoichiometric equilibrium studies of metal complexes carried out spectrophotometrically using Job's continuous variation and mole ratio methods inferred formation of 1:2 (ML2) metal complexes in respective systems. The title compound and its metal complexes screened for antibacterial and antifungal properties, exemplified improved activity in metal complexes. The studies of nuclease activity for the cleavage of CT- DNA and MTT assay for in vitro cytotoxic properties involving metal complexes exhibited high activity. In addition, the DNA binding properties of Cu (II), Ni (II) and Co (II) complexes investigated by electronic absorption and fluorescence measurements revealed their good binding ability and commended agreement of Kb values obtained from both the techniques. Molecular docking studies were also performed to find the binding affinity of synthesized compounds with DNA (PDB ID: 1N37) and "Thymidine phosphorylase from E.coli" (PDB ID: 4EAF) protein targets. PMID- 29164480 TI - Dispensing Patterns of Ranibizumab and Aflibercept for the Treatment of Neovascular Age-Related Macular Degeneration: A Retrospective Cohort Study in Australia. AB - INTRODUCTION: Anti-vascular endothelial growth factor therapy is the standard of care for neovascular age-related macular degeneration (nAMD). The dosage of two licensed agents, ranibizumab and aflibercept, was established through clinical trials; however, it is unclear if either agent is administered as recommended in routine clinical practice. Using pharmacy claims data, we investigated if the dispensing patterns of ranibizumab differ from those of aflibercept 6 and 12 months after treatment initiation. METHODS: Prescription data retrieved from the Australian IMS(r) AUS LRx database were used to identify nAMD patients with one or more claims for ranibizumab or aflibercept between December 1, 2012, and March 31, 2015, with follow-up of at least 6 months. The number of ranibizumab and aflibercept units dispensed was adjusted for baseline patient Medication-Based Disease Burden Index (MBDBI) scores. No difference in the number of ranibizumab versus aflibercept units dispensed was concluded if the 95% confidence interval (CI) limits of the adjusted mean difference between the study cohorts were 1.00 unit or less. RESULTS: Baseline patient MBDBI scores were similar for the ranibizumab (N = 1235) and aflibercept (N = 959) cohorts. The adjusted mean (standard deviation) number of units dispensed was 5.3 (1.3) versus 5.1 (1.4) at month 6 and 8.9 (2.2) versus 8.9 (2.3) at month 12. The 95% CI limits of the adjusted mean difference did not exceed 1.00 unit dispensed at either time point: 95% CI of 0.09 to 0.32 for an adjusted mean difference of 0.20 at month 6 and 0.23 to 0.30 for an adjusted mean difference of 0.04 at month 12. Mean (standard deviation) dispensing intervals were comparable for both cohorts: 35.3 (19.2) days versus 36.8 (20.0) days at month 6 (adjusted mean difference -1.59 days; 95% CI -2.51 to -0.67 days) and 41.2 (20.9) days versus 41.6 (20.4) days at month 12 (adjusted mean difference -0.40 days; 95% CI -1.70 to 0.91 days). CONCLUSIONS: Ranibizumab and aflibercept are dispensed in a similar manner by Australian pharmacies during the first year of treatment. FUNDING: Novartis Pharma AG. PMID- 29164482 TI - Molecular imaging in musculoskeletal infections with 99mTc-UBI 29-41 SPECT/CT. AB - OBJECTIVE: To determine the added value of CT over planar and SPECT-only imaging in the diagnosis of musculoskeletal infection using 99mTc-UBI 29-4. MATERIALS AND METHODS: 184 patients with suspected musculoskeletal infection who underwent planar and SPECT/CT imaging with 99mTc-UBI 29-41 were included. Planar, SPECT only and SPECT/CT images were reviewed by two independent analysts for presence of bone or soft tissue infection. Final diagnosis was confirmed with tissue cultures, surgery/histology or clinical follow-up. RESULTS: 99mTc-UBI 29-41 was true positive in 105/184 patients and true negative in 65/184 patients. When differentiating between soft tissue and bone infection, planar + SPECT-only imaging had a sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 95.0, 74.3, 84.8, 91.3 and 86.9%, respectively, versus 99.0, 94.5, 92.5, 98.5 and 94.5% for SPECT/CT. SPECT/CT resulted in a change in reviewers' confidence in the final diagnosis in 91/184 patients. Inter observer agreement was better with SPECT/CT compared with planar + SPECT imaging (kappa 0.87, 95% CI 0.71-0.85 versus kappa 0.81, 95% CI 0.58-0.75). CONCLUSION: Addition of CT to planar and SPECT-only imaging led to an increase in diagnostic performance and an improvement in reviewers' confidence and inter-observer agreement in differentiating bone from soft tissue infection. PMID- 29164483 TI - Dosimetry-based treatment planning for molecular radiotherapy: a summary of the 2017 report from the Internal Dosimetry Task Force. AB - BACKGROUND: The European directive on basic safety standards (Council directive 2013/59 Euratom) mandates dosimetry-based treatment planning for radiopharmaceutical therapies. The directive comes into operation February 2018, and the aim of a report produced by the Internal Dosimetry Task Force of the European Association of Nuclear Medicine is to address this aspect of the directive. A summary of the report is presented. RESULTS: A brief review of five of the most common therapy procedures is included in the current text, focused on the potential to perform patient-specific dosimetry. In the full report, 11 different therapeutic procedures are included, allowing additional considerations of effectiveness, references to specific literature on quantitative imaging and dosimetry, and existing evidence for absorbed dose-effect correlations for each treatment. Individualized treatment planning with tracer diagnostics and verification of the absorbed doses delivered following therapy is found to be scientifically feasible for almost all procedures investigated, using quantitative imaging and/or external monitoring. Translation of this directive into clinical practice will have significant implications for resource requirements. CONCLUSIONS: Molecular radiotherapy is undergoing a significant expansion, and the groundwork for dosimetry-based treatment planning is already in place. The mandated individualization is likely to improve the effectiveness of the treatments, although must be adequately resourced. PMID- 29164484 TI - Association Between Cortisol to DHEA-s Ratio and Sickness Absence in Japanese Male Workers. AB - PURPOSE: This study aimed to investigate the association between serum levels of cortisol and dehydroepiandrosterone sulfate (DHEA-s) and sickness absence over 2 years in Japanese male workers. METHOD: A baseline survey including questions about health behavior, along with blood sampling for cortisol and DHEA-s, was conducted in 2009. In total, 429 men (mean +/- SD age, 52.9 +/- 8.6 years) from whom blood samples were collected at baseline were followed until December 31, 2011. The hazard ratios (HR) and 95% confidence intervals (CI) for sickness absence were calculated using a Cox proportional hazard model, adjusted for potential confounders. RESULTS: Among 35 workers who took sickness absences, 31 had physical illness. A high cortisol to DHEA-s ratio increased the risk of sickness absence (crude HR = 2.68, 95% CI 1.12-6.41; adjusted HR = 3.33, 95% CI 1.35-8.20). The cortisol to DHEA-s ratio was linearly associated with an increased risk of sickness absence (p for trend < .050). Single effects of cortisol and DHEA-s levels were not associated with sickness absences. This trend did not change when limited to absences resulting from physical illness. CONCLUSION: Hormonal conditions related to the hypothalamus-pituitary adrenocortical axis and adrenal function should be considered when predicting sickness absence. The cortisol to DHEA-s ratio may be more informative than single effects of cortisol and DHEA-s levels. PMID- 29164485 TI - Music Listening and Stress in Daily Life-a Matter of Timing. AB - PURPOSE: Despite increasing evidence suggesting that music listening in daily life has stress-reducing effects, studies mostly rely on subjective, retrospective data on music listening. Thus, the temporal dynamics underlying the stress-reducing effect of music listening remain unclear. Therefore, we aimed to examine the temporal dynamics of the associations between stress and music listening by assessing subjective and objective data on music in daily life. DESIGN: An exploratory Ambulatory Assessment study examining a total of 60 participants (37 women), aged 18 to 34 years (M = 22.4 years, SD = 3.5) was conducted. METHODS: For 1 week, participants answered questions on music listening and stress six times per day via an electronic diary device, which additionally objectively sampled the exact time point of music listening and its duration. RESULTS: Self-reports on mere music listening were associated with lower stress reports, whereas objectively assessed data was not. However, concerning duration of music listening, both subjective and objective data on music listening showed associations between a minimum of 20 min of music listening and lower stress reports. Concerning the latency, objective data on music listening revealed that the association between stress reports and music listening occurs in a time-delayed manner. CONCLUSIONS: Although the study design does not allow for causal inferences, substantial associations among subjectively and objectively assessed data on music listening were found to differentially affect the experience of stress after music listening. In particular, when focusing on the temporal dynamics, objectively assessed data allowed for a more fine-grained analysis. In consequence, subjectively and objectively reported data on music listening should be assessed jointly when investigating effects of music listening on health. Experimental research with rigorous methodological control is required in order to corroborate our findings in a laboratory setting. PMID- 29164487 TI - Correction to: Altruistic Behavior among Twins : Willingness to Fight and Self Sacrifice for Their Closest Relatives. AB - The original version of this article unfortunately contained a mistake. The presentation of the article title and subtitle was incorrect. PMID- 29164486 TI - Adaptation and Probiotic Potential of Lactobacilli, Isolated from the Oral Cavity and Intestines of Healthy People. AB - The present study shows that, from 300 Lactobacillus strains isolated from the oral cavity and large intestine of 600 healthy people, only 9 had high antagonistic activity against pathogens and opportunistic pathogens. All antagonistic strains of lactobacilli have been identified by 16S rRNA sequencing and assigned to four species: Lactobacillus fermentum, Lactobacillus rhamnosus, Lactobacillus plantarum, and Lactobacillus casei. In addition, these lactobacilli appeared to be nonpathogenic and had some probiotic potential: the strains produced lactic acid and bacteriocins, showed high sensitivity to broad-spectrum antibiotics, and were capable of forming biofilms in vitro. With the help of PCR and specific primers, the presence of genes for prebacteriocins in L. plantarum (plnEF, plnJ, plnN) and L. rhamnosus (LGG_02380 and LGG_02400) has been revealed. It was found that intestinal strains of lactobacilli were resistant to hydrochloric acid and bile. Lactobacilli isolated from the oral cavity were characterized by a high degree of adhesion, whereas intestinal strains were characterized by average adhesion. Both types of lactobacilli had medium to high rates of auto-aggregation and hydrophobicity and could coaggregate with pathogens and opportunistic pathogens. Additionally, the ability of the lactobacilli strains to produce gasotransmitters, CH4, CO2, C2H6, CO, and NH3, has been revealed. PMID- 29164488 TI - Spontaneous Elimination of Hepatitis C Virus Infection. AB - Hepatitis C virus (HCV) is the etiological agent of chronic hepatitis C and a major cause of liver cirrhosis and hepatocellular carcinoma. Only a minority of infected individuals can clear the virus spontaneously. The knowledge of the determinants of virus clearance would allow the development of effective methods preventing its further spread and optimizing treatment regimens. Viral factors associated with spontaneous virus clearance in the acute phase of infection, such as HCV genotype, virus heterogeneity, and the impact of viral proteins on the immune system have been characterized. Likewise, host genetic markers, such as the interleukin genotypes, HLA alleles, and factors affecting the T lymphocyte response appear to play an important role. Studies have revealed that natural clearance of HCV infection in the chronic phase is rare and its mechanisms are not well understood. In this review, we present the state-of-the art knowledge on the viral and host factors affecting the spontaneous elimination of HCV infection. PMID- 29164489 TI - Antimicrobial Stewardship Opportunities in Critically Ill Patients with Gram Negative Lower Respiratory Tract Infections: A Multicenter Cross-Sectional Analysis. AB - INTRODUCTION: Lower respiratory tract infections (LRTIs) are a major cause of morbidity and death. Because of changes in how LRTIs are defined coupled with the increasing prevalence of drug resistance, there is a gap in knowledge regarding the current burden of antimicrobial use for Centers for Disease Control and Prevention (CDC)-defined LRTIs. We describe the infection characteristics, antibiotic consumption, and clinical and economic outcomes of patients with Gram negative (GN) LRTIs treated in intensive care units (ICUs). METHODS: This was a retrospective, observational, cross-sectional study of adult patients treated in ICUs at two large academic medical centers in metropolitan Detroit, Michigan, from October 2013 to October 2015. To meet the inclusion criteria, patients must have had CDC-defined LRTI caused by a GN pathogen during ICU stay. Microbiological assessment of available Pseudomonas aeruginosa isolates included minimum inhibitory concentrations for key antimicrobial agents. RESULTS: Four hundred and seventy-two patients, primarily from the community (346, 73.3%), were treated in medical ICUs (272, 57.6%). Clinically defined pneumonia was common (264, 55.9%). Six hundred and nineteen GN organisms were identified from index respiratory cultures: P. aeruginosa was common (224, 36.2%), with 21.6% of these isolates being multidrug resistant. Cefepime (213, 45.1%) and piperacillin/tazobactam (174, 36.8%) were the most frequent empiric GN therapies. Empiric GN therapy was inappropriate in 44.6% of cases. Lack of in vitro susceptibility (80.1%) was the most common reason for inappropriateness. Patients with inappropriate empiric GN therapy had longer overall stay, which translated to a median total cost of care of $79,800 (interquartile range $48,775 to $129,600) versus $68,000 (interquartile range $38,400 to $116,175), p = 0.013. Clinical failure (31.5% vs 30.0%, p = 0.912) and in-hospital all-cause mortality (26.4% vs 25.9%, p = 0.814) were not different. CONCLUSION: Drug-resistant pathogens were frequently found and empiric GN therapy was inappropriate in nearly 50% of cases. Inappropriate therapy led to increased lengths of stay and was associated with higher costs of care. PMID- 29164490 TI - Immunotherapy with interferon-alpha-induced dendritic cells for chronic HCV infection (the results of pilot clinical trial). AB - The key role of T cells in hepatitis C virus (HCV) elimination and the ability of dendritic cells (DCs) to induce antiviral T cell responses suggest that DC vaccines could be a promising approach in the treatment of chronic HCV infection. The aim of our study was to evaluate, whether immunotherapy with DCs is safe and elicits anti-HCV T cell responses. Ten patients with HCV (genotype 1) were vaccinated with monocyte-derived DCs, generated in the presence of IFN-alpha (IFN DCs) and pulsed with recombinant HCV Core and NS3 proteins. Treatment schedule included four subcutaneous vaccinations with 1 week interval and six vaccinations with month interval. No serious adverse events or an increase in hepatitis C biochemical activity were registered after vaccination. Using ex vivo assays for the detection of proliferative responses, IFN-gamma production and CD8+ degranulation have shown that immunotherapy elicited antigen-specific responses in all patients although individual heterogeneity existed within their types, magnitude, and timing. Core/NS3-specific proliferative response and CD8+ T cell degranulation have already been registered after the first course of vaccination. Of note, Core-specific responses had higher magnitude. The appearance of antigen specific IFN-gamma responses was registered after the second vaccination course. Vaccination did not cause Th2 response and expansion of the CD4+CD25+CD127- regulatory T cells. Generated immune responses failed to provide virus elimination. Nevertheless, there were inverse correlations between viral load and NS3-specific proliferation (R S = 0.62; p = 0.05) and IFN-gamma secretion (R S = 0.82; p = 0.001) at 6-month post-treatment period. Immunotherapy with IFN-DCs was safe and elicited HCV-specific T cell responses which were insufficient to eliminate viruses but could be implicated in the restriction of viral replication. PMID- 29164491 TI - Gene activation in human cells using CRISPR/Cpf1-p300 and CRISPR/Cpf1-SunTag systems. PMID- 29164492 TI - Advanced Melanoma: Current Treatment Options, Biomarkers, and Future Perspectives. AB - Malignant melanoma accounts for the highest number of deaths from skin cancer, and the prognosis of patients with stage IV disease has historically been poor. Novel insights into both mutations driving tumorigenesis and immune escape mechanisms of these tumors have led to effective treatment options that have revolutionized the treatment of this disease. Targeting the MAPK kinase pathway (with BRAF and MEK inhibitors), as well as targeting checkpoints, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or programmed death 1 (PD 1), have improved overall survival in patients with late-stage melanoma, and biomarker research for personalized therapy is ongoing for each of these treatment modalities. In this review, we will discuss current first-line treatment options, discuss biomarkers supporting treatment decisions, and give an outlook on (combination) therapies we expect to become relevant in the near future. PMID- 29164493 TI - Mapping Quality of Life (EQ-5D) from DAPsA, Clinical DAPsA and HAQ in Psoriatic Arthritis. AB - BACKGROUND: Clinical trials and observational studies lacking measures of health related quality of life (QoL) are often inapplicable when conducting cost effectiveness analyses using quality-adjusted life-years (QALYs). The only solution is to map QoL ex post from additionally collected clinical outcomes and generic QoL instruments. Nonetheless, mapping studies are absent in psoriatic arthritis (PsA). METHODS: In this 2-year, prospective, multicentre, non interventional study of PsA patients, EQ-5D and key clinical parameters such as Disease Activity in PsA (DAPsA), clinical DAPsA (cDAPsA; DAPsA without C-reactive protein [CRP]), and Health Assessment Questionnaire disability index (HAQ) were collected. We employed a linear mixed-effect regression model (ME) of the longitudinal dataset to explore the best predictors of QoL. RESULTS: A total of 228 patients were followed over 873 appointments/observations. DAPsA, cDAPsA and HAQ were stable and highly significant predictors of EQ-5D utilities in both cross-sectional and longitudinal analyses. The best prediction was provided using a linear ME with HAQ and cDAPsA or DAPsA. A HAQ increase of 1 point represented a decrease in EQ-5D by -0.204 or -0.203 (p < 0.0001); a one-point increase in cDAPsA or DAPsA dropped EQ-5D equally by -0.005 (p < 0.0001). The ME revealed steeper and more accurate association compared with cross-sectional regressions or non-linear models/transformations. CONCLUSIONS: This is the first mapping study conducted in PsA and we hope that our study will encourage further mapping studies in PsA. The results showed that in cases where CRP is absent, cDAPsA provides similar results to DAPsA in predicting QoL. PMID- 29164494 TI - Betel Quid Use and Oral Cancer in a High-Risk Refugee Community in the USA: The Effectiveness of an Awareness Initiative. AB - Betel nut (BN) is a psychoactive oral carcinogen that is commonly used among Asian communities. This study aims to investigate BN usage patterns and the effectiveness of a visually guided educational initiative in a high-risk refugee population. All adult patients presenting to a private practice clinic, free community clinic, or health fair in the refugee community of Clarkston, Georgia during days when survey staff were present were approached for the study. Participants were first categorized into a familiar and unfamiliar cohort depending on participant-reported familiarity with BN. Depending on familiarity, subjects were then administered a pre-intervention test surveying health awareness for BN and usage patterns where relevant; subsequently, a visually guided educational brochure was reviewed, and a post-intervention test was administered. Results were statistically analyzed (STATA 12). Forty-eight participants were surveyed for the familiar cohort and 25 for the unfamiliar cohort. Among the familiar cohort, South and Southeast Asians comprised 91% of participants. On frequency of use, 42.8% reported social, 28.6% reported usage during celebrations only, and 28.6% reported daily. The most common reasons for use were for taste (40.9%), enjoyment (38.6%), and addiction (25%). Among the familiar cohort, 75% believed BN was harmful for health compared to 8% among the unfamiliar (p < 0.0001). In the familiar cohort, 52.3% believed BN alone could cause cancer compared to 4% among the unfamiliar (p < 0.0001). Following the educational intervention, 100% of participants believed BN mastication is harmful in both cohorts (p < 0.01), while 87.5% of participants in both cohorts recognized that BN alone could cause cancer (p < 0.0007). This study illustrates gaps in understanding regarding oral cancer and the health consequences of chronic BN mastication, as well as the efficacy of a visually guided educational brochure to improve participant knowledge among a high-risk refugee population. PMID- 29164496 TI - Correction to: Opicapone: A Review in Parkinson's Disease. AB - Parkinson's disease (PD) is the most common chronic, progressive, neurodegenerative disease, with a mean age of onset of 57 years [1, 2]. PMID- 29164495 TI - The clinical trajectory of emerging bipolar disorder among the high-risk offspring of bipolar parents: current understanding and future considerations. AB - BACKGROUND: Relatively little is known about the onset of bipolar disorder, yet the early illness course is already associated with significant morbidity and mortality. Therefore, characterizing the bipolar illness trajectory is key to risk prediction and early intervention advancement. MAIN BODY: In this narrative review, we discuss key findings from prospective longitudinal studies of the high risk offspring of bipolar parents and related meta-analyses that inform us about the clinical trajectory of emerging bipolar disorder. Challenges such as phenotypic and etiologic heterogeneity and the non-specificity of early symptoms and syndromes are highlighted. Implications of the findings for both research and clinical practice are discussed. CONCLUSION: Bipolar disorder in young people at familial risk does not typically onset with a hypomanic or manic episode. Rather the first activated episode is often preceded by years of impairing psychopathological states that vary over development and across emerging bipolar subtype. Taking heterogeneity into account and adopting a more comprehensive approach to diagnosis seems necessary to advance earlier identification and our understanding of the onset of bipolar disorder. PMID- 29164498 TI - Gender and the Stability of Same-Sex and Different-Sex Relationships Among Young Adults. AB - Most research on the stability of adult relationships has focused on coresidential (cohabiting or married) unions and estimates rates of dissolution for the period of coresidence. Studies examining how the stability of coresidential unions differs by sex composition have typically found that same sex female couples have higher rates of dissolution than same-sex male couples and different-sex couples. We argue that the more elevated rates of dissolution for same-sex female couples are a by-product of the focus on coresidential unions. We use data from the National Longitudinal Study of Adolescent to Adult Health to compare rates of dissolution based on the total duration of romantic and sexual relationships for same-sex male couples, same-sex female couples, and different-sex couples. Results from hazard models that track the stability of young adult relationships from the time they are formed demonstrate that male couples have substantially higher dissolution rates than female couples and different-sex couples. Results based on models restricted to the period of coresidence corroborate the counterintuitive finding from earlier studies that female couples have the highest rates of dissolving coresidential unions. This study underlines the importance of comparisons between these couple types for a better understanding of the role that institutions and gender play in the stability of contemporary relationships. PMID- 29164497 TI - Identifying Motives of Midlife Black Triathlete Women Using Survey Transformation to Guide Qualitative Inquiry. AB - Demonstrating health disparities related to race, age, and gender, older Black women (BW) are the most sedentary demographic group in the United States. Increasing PA in mid-life is important, as it improves health as BW age into their later years. Advancing our understanding of the exercise motives of BW triathletes presents a "reverse engineering" opportunity to identify motives that could influence sedentary mid-life BW to increase their activity. The purposes of this study were to: (a) utilize an innovative survey transformation method to adapt a measure developed primarily in Caucasian males, i.e., the Motivations of Marathoners Scale for Triathletes (MOMS-T) into a qualitative interview guide for use with BW triathletes; (b) use this interview guide to identify culturally based motives for triathlon participation among BW not previously addressed by the MOMS-T and; (c) interpret the novel motivational domains of the MOMS-T discovered, in order to gain understanding and influence subsequent interventions. Purposive sampling was used to select 12 interview participants from 121 self-identified Black female US residents aged >=36 years with recent experience completing or training for a triathlon. The interviews identified four culturally based themes, including improving body composition to become "more lean", physical attractiveness, triathlete family, and camaraderie. These novel themes were related to existing MOMS-T scales, but the current MOMS-T questions did not illuminate their culturally distinct aspects. The process of survey transformation provides a viable approach to identify important culturally based characteristics and to adapt surveys to cultural minority populations, particularly when study resources are limited. PMID- 29164500 TI - Three Dimensions of Change in School Segregation: A Grade-Period-Cohort Analysis. AB - This study uses the first age-period-cohort (APC) analysis of segregation to examine changes in U.S. public school segregation from 1999-2000 to 2013-2014. APC analyses disentangle distinct sources of change in segregation, and they account for grade effects that could distort temporal trends if grade distributions change over time. Findings indicate that grade effects are substantial, drastically reducing segregation at the transition to middle school and further at the transition to high school. These grade effects do not substantially distort the analysis of recent trends, however, because grade distributions were sufficiently stable. Black-white segregation was stagnant overall, while Hispanic-white segregation declined modestly. In both cases, declines across periods were offset by increases across cohorts. Further analyses reveal variation in these trends across metropolitan and nonmetropolitan areas, regions, and areas with different histories of desegregation policy. PMID- 29164501 TI - ? PMID- 29164499 TI - Cognitive Disparities: The Impact of the Great Depression and Cumulative Inequality on Later-Life Cognitive Function. AB - Population aging has driven a spate of recent research on later-life cognitive function. Greater longevity increases the lifetime risk of memory diseases that compromise the cognitive abilities vital to well-being. Alzheimer's disease, thought to be the most common underlying pathology for elders' cognitive dysfunction (Willis and Hakim 2013), is already the sixth leading cause of death in the United States (Alzheimer's Association 2016). Understanding social determinants of pathological cognitive decline is key to crafting interventions, but evidence is inconclusive for how social factors interact over the life course to affect cognitive function. I study whether early-life exposure to the Great Depression is directly associated with later-life cognitive function, influences risky behaviors over the life course, and/or accumulates with other life-course disadvantages. Using growth curve models to analyze the Health and Retirement Study, I find that early-life exposure to the Great Depression is associated with fluid cognition, controlling for intervening factors-evidence for a critical period model. I find little support for a social trajectory model. Disadvantage accumulates over the life course to predict worse cognitive function, providing strong evidence for a cumulative inequality model. PMID- 29164503 TI - Developing the field of neurogenetics. PMID- 29164502 TI - Superovulation alters DNA methyltransferase protein expression in mouse oocytes and early embryos. AB - PURPOSE: DNA methylation is an epigenetic mechanism that plays critical roles during mammalian oocyte and preimplantation embryo development. It is achieved by adding a methyl group to the fifth carbon atom of cytosine residues within cytosine-phosphate-guanine (CpG) and non-CpG dinucleotide sites using DNA methyltransferase (DNMT) enzymes for de novo and maintenance methylation processes. DNMT1, DNMT3A, and DNMT3B play important roles in establishing methylation of developmentally related genes in oocytes and early embryos. The purpose of this study is to identify the effect of superovulation on the expression and subcellular localizations of these three DNMT enzymes in the mouse oocytes and early embryos. METHODS: Three groups composed of control, normal dose [5 IU pregnant mare serum gonadotropin (PMSG) and 5 IU human chorionic gonadotropin (hCG)], and high dose [7.5 IU PMSG and 7.5 IU hCG] were created from 4-5-week-old female BALB/c mice. The relative expression and subcellular localizations of the DNMT proteins in the control and experiment groups have been characterized by using immunofluorescence staining subsequently analyzed in detailed. RESULTS: DNMT1, DNMT3A, and DNMT3B protein expression in the germinal vesicle and metaphase II oocytes and in one-cell and two-cell embryos differed significantly when some of the normal- and high-dose groups were compared with the control counterparts. CONCLUSION: This study has demonstrated for the first time that superovulation alters expression levels of the DNMT proteins, a finding that indicates that certain developmental defects in superovulated oocytes and early embryos may result from impaired DNA methylation processes. PMID- 29164504 TI - Basal ganglia cerebral blood flow associates with psychomotor speed in adults with type 1 diabetes. AB - Type 1 diabetes is associated with slower psychomotor speed, but the neural basis of this relationship is not yet understood. The basal ganglia are a set of structures that are vulnerable to small vessel disease, particularly in individuals with type 1 diabetes. Thus, we examined the relationship between psychomotor speed and resting state resting cerebral blood flow in a sample of adults with diabetes onset during childhood (<= 17 years of age). The sample included 77 patients (39 M, 38 F) with a mean age of 47.43 +/- 5.72 years, age of onset at 8.50 +/- 4.26 years, and duration of disease of 38.92 +/- 4.18 years. Resting cerebral blood flow was quantified using arterial spin labeling. After covarying for sex, years of education and normalized gray matter volume, slower psychomotor speed was associated with lower cerebral blood flow in bilateral caudate nucleus-thalamus and a region in the superior frontal gyrus. These results suggest that the basal ganglia and frontal cortex may underlie slower psychomotor speed in individuals with type 1 diabetes. PMID- 29164505 TI - Network-level dysconnectivity in patients with nasopharyngeal carcinoma (NPC) early post-radiotherapy: longitudinal resting state fMRI study. AB - In this study, we seek to longitudinally investigate the network-level functional connectivity (FC) alternations and its association with irradiation dose and cognition changes in the early stage post radiotherapy (RT) in nasopharyngeal carcinoma (NPC) patients. We performed independent component analysis (ICA) of resting state blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) from 39 newly diagnosed NPC patients before receiving treatment (baseline), and 3 months post-RT. the default mode network (DMN), salience network (SN), and executive control network (ECN) were extracted with well validated software (GIFT). Inter-network connectivity was assessed using the functional network connectivity (FNC) toolbox. The inter- and intra-network FC was compared between time points, and the z value of FC alternation was correlated with the RT dose value and cognitive changes. Compared with baseline, the FC of the left anterior cingulate cortex (ACC) within the DMN, and the right insular within the SN, significantly reduced 3 months post-RT, with greater effects at higher doses in the right insular. Bilateral ECN FC was also significantly lower 3 months post-RT compared to the baseline. Chemotherapy was not associated with inter- and intra- network FC change. We found intra- and inter-network FC disruption in NPC patients 3 months post-RT, with the right insular showing a dose-dependent effect. Thus, this network-level FC may serve as a potential biomarker of the RT-induced brain functional impairments, and provide valuable targets for further functional recovery treatment. PMID- 29164506 TI - Enzymatic Production of Glutathione Coupling with an ATP Regeneration System Based on Polyphosphate Kinase. AB - Glutathione (GSH) is an important reducing agent in the living cells. It is synthesized by a two-step reaction and requires two molecules of adenosine triphosphate (ATP) for one molecule GSH. The enzymatic cascade reaction in vitro is a promising approach to achieve a high titer and limit side reactions; although, a cost-effective phosphate donor for ATP regeneration is required. Triphosphate (PolyP(3)), tetraphosphate (PolyP(4)), and hexametaphosphate (PolyP(6)) were investigated in this study. Triphosphate inhibited the bifunctional GSH synthetase (GshF) from Streptococcus agalactiae, while no significant inhibition was observed by adding hexametaphosphate. The polyphosphate kinase from Corynebacterium glutamicum was hence investigated to use hexametaphosphate for regeneration of ATP. Further, the orthogonal experiment, which includes seven factors (buffer concentration, pH value, ADP concentration, GshF dosage, polyphosphate kinase (PPK) dosage, reaction temperature, substrate ratio of amino acid, and reaction times), indicated that the capacity of buffer is the most significant factor of the reaction conditions for enzymatic production of glutathione coupling with a PPK-based ATP regeneration system. After optimizing the Mg2+ concentration, the reaction was scaled up to 250 mL in a stirred reactor with pH feedback control to stabilize the pH value of reaction system and nitrogen protection to avoid the oxidation of product. A yield of 12.32 g/L was achieved. This work provided a potential GshF based enzymatic way coupling the PPK-based ATP regeneration to product GSH in the optimal conditions towards cost-effectiveness at the industrial scale. PMID- 29164507 TI - Enzyme-linked immunosorbent assay for the quantitative/qualitative analysis of plant secondary metabolites. AB - Immunoassays are antibody-based analytical methods for quantitative/qualitative analysis. Since the principle of immunoassays is based on specific antigen antibody reaction, the assays have been utilized worldwide for diagnosis, pharmacokinetic studies by drug monitoring, and the quality control of commercially available products. Berson and Yalow were the first to develop an immunoassay, known as radioimmunoassay (RIA), for detecting endogenous plasma insulin [1], a development for which Yalow was awarded the Nobel Prize in Physiology or Medicine in 1977. Even today, after half a century, immunoassays are widely utilized with some modifications from the originally proposed system, e.g., radioisotopes have been replaced with enzymes because of safety concerns regarding the use of radioactivity, which is referred to as enzyme immunoassay/enzyme-linked immunosorbent assay (ELISA). In addition, progress has been made in ELISA with the recent advances in recombinant DNA technology, leading to increase in the range of antibodies, probes, and even systems. This review article describes ELISA and its applications for the detection of plant secondary metabolites. PMID- 29164508 TI - EUS-Guided Transrectal Evacuation of Organized Pelvic Collection Following Roux en-Y Gastric Bypass After Failure of Radiological and Surgical Approach. AB - INTRODUCTION: Postoperative collections are an important cause of morbidity following obesity surgery. Surgical revision is most often required if general sepsis is present. Conservative treatment consists of broad spectrum antibiotics and percutaneous drainage of any collection. EUS drainage is a new technique that is gaining momentum allowing an easy access to collections close to the GI tract. MATERIALS AND METHODS: We present the case report of a 39-year-old woman who underwent to robotic Roux-en-Y gastric bypass for morbid obesity. She developed a jejuno-jejunal dehiscence treated with revision surgery. Afterward, a pelvic collection/hematoma was highlighted; however, neither percutaneous approach nor surgery succeeded in draining it. RESULTS: EUS-guided deployment of a fully covered lumen-apposing metal stent was performed. Subsequently, two necrosectomies were required to remove necrotic tissue and clots from the perirectal cavity. Finally, three double pigtail stents were deployed to promote healing. The patient spontaneously expelled the stents with the stool, and she is asymptomatic after a follow-up of 3 months. CONCLUSION: EUS transmural rectal drainage may represent a sound option for the treatment of pelvic postoperative collections. FCLAMS deployment guarantees a rapid drainage allowing to perform an endoscopic necrosectomy. PMID- 29164509 TI - Evolution and Standardisation of Techniques in Single-Incision Laparoscopic Bariatric Surgery. AB - Bariatric surgery has proven benefits for morbid obesity and its associated comorbidities. Laparoscopic approach is well established for bariatric surgery. Single-incision laparoscopic surgery (SILS) offers even more minimally invasive approach for the same with the added advantage of better cosmesis. We have developed and standardised the SILS approach at our institute. We share our experience and technical "tips" and modifications which we have learnt over the years. Technical details of performing sleeve gastrectomy and Roux-en-Y gastric bypass with special attention to liver retraction, techniques of dissection in difficult areas, creation of anastomoses and suturing have all been described. In our experience and in experience of others, single-incision bariatric surgery is feasible. Use of conventional laparoscopic instruments makes single-incision approach practical for day-to-day practice. Supervised training is essential to learn these techniques. PMID- 29164511 TI - Effect of Partners' Disgust Responses on Psychological Wellbeing in Cancer Patients. AB - The aim of this study was to explore quantitatively the relationship between disgust responses in cancer patients and their partners, and in turn their relationship to patients' psychological well-being. We recruited 50 participants with heterogeneous cancer diagnoses and their partners from cancer-related groups (e.g., charities). Patients completed questionnaires to determine levels of disgust propensity, disgust sensitivity, self-disgust, and symptoms of anxiety and depression. Disgust propensity and sensitivity were also assessed in their partners. Partners' disgust sensitivity was significantly positively correlated with cancer patients' self-disgust, disgust propensity, and depression. Path analyses suggested that patients' self-disgust plays a role in mediating the effect of partners' disgust sensitivity on patients' psychological well-being. This study provides the first quantitative evidence that psychological well-being in cancer patients is contingent on their partners' sensitivity to disgust, and that patients' self-disgust plays a mediating role. Focusing therapeutically on disgust responses could well be beneficial to people with cancer. PMID- 29164512 TI - Individuals with Type 1 and Type 2 Diabetes Mellitus Trade Increased Hyperglycemia for Decreased Hypoglycemia When Glycemic Variability is not Improved. AB - INTRODUCTION: Glycemic variability refers to oscillations in blood glucose within a day and differences in blood glucose at the same time on different days. Glycemic variability is linked to hypoglycemia and hyperglycemia. The relationship among these three important metrics is examined here, specifically to show how reduction in both hypo- and hyperglycemia risk is dependent on changes in variability. METHODS: To understand the importance of glycemic variability in the simultaneous reduction of hypoglycemia and hyperglycemia risk, we introduce the glycemic risk plot-estimated HbA1c % (eA1c) vs. minutes below 70 mg/dl (MB70) with constant variability contours for predicting post-intervention risks in the absence of a change in glycemic variability. RESULTS: The glycemic risk plot illustrates that individuals who do not reduce glycemic variability improve one of the two metrics (hypoglycemia risk or hyperglycemia risk) at the cost of the other. It is important to reduce variability to improve both risks. These results were confirmed by data collected in a randomized controlled trial consisting of individuals with type 1 and type 2 diabetes on insulin therapy. For type 1, a total of 28 individuals out of 35 (80%) showed improvement in at least one of the risks (hypo and/or hyper) during the 100-day course of the study. Seven individuals (20%) showed improvement in both. Similar data were observed for type 2 where a total of 36 individuals out of 43 (84%) showed improvement in at least one risk and 8 individuals (19%) showed improvement in both. All individuals in the study who showed improvement in both hypoglycemia and hyperglycemia risk also showed a reduction in variability. CONCLUSION: Therapy changes intended to improve an individual's hypoglycemia or hyperglycemia risk often result in the reduction of one risk at the expense of another. It is important to improve glucose variability to reduce both risks or at least maintain one risk while reducing the other. FUNDING: Abbott Diabetes Care. PMID- 29164510 TI - 4-Year Changes in Sex Hormones, Sexual Functioning, and Psychosocial Status in Women Who Underwent Bariatric Surgery. AB - BACKGROUND: Initial weight loss after bariatric surgery has been associated with improvements in reproductive hormones and sexual functioning in women. Few studies have investigated the durability of these changes. OBJECTIVES: The objective of this paper is to investigate changes in sex hormones, sexual functioning, and relevant psychosocial constructs over 4 years in women who underwent bariatric surgery. SETTING: The setting is a prospective cohort of 106 women from the Longitudinal Assessment of Bariatric Surgery consortium. METHODS: Changes in sex hormones were assessed by blood assay. Sexual functioning, quality of life (QOL), body image, depressive symptoms, and marital adjustment were assessed by psychometric measures. RESULTS: Women lost on average (95% confidence interval) 32.3% (30.4%, 34.3%) at postoperative year 3 and 30.6% (28.5%, 32.8%) at postoperative year 4. Compared to baseline, women experienced significant changes at 4 years in all hormones assessed, except estradiol. Women reported significant improvements in sexual functioning (i.e., arousal, desire, and satisfaction) through year 3, but these changes were not maintained through year 4. Changes in relationship quality followed a similar pattern. Improvements in physical aspects of QOL, body image, and depressive symptoms were maintained through 4 years. CONCLUSIONS: Improvements in reproductive hormones and physical aspects of QOL, body image, and depressive symptoms were maintained 4 years after bariatric surgery. Improvements in sexual functioning, relationship satisfaction, and mental components of QOL eroded over time. PMID- 29164513 TI - The Combined Effects of Iron Excess in the Diet and Chromium(III) Supplementation on the Iron and Chromium Status in Female Rats. AB - Inadequate iron supply has significant consequences to health. There are some relations between the metabolism of different trace elements, such as iron, zinc, copper and chromium. However, the direction of these interactions can be antagonistic or synergistic, and it depends on many factors. The aim of the study was to evaluate the combined effects of supplementary of chromium(III) propionate complex (Cr3) with iron excess on the Cr and Fe status in healthy female rats. The 36 healthy female Wistar rats were divided into six experimental groups (six animals in each) with different Fe levels-adequate (45 mg kg-1-100% RDA) and high (excessive-180 mg kg-1-400% RDA). At the same time, they were supplemented with Cr(III) at doses of 1, 50 and 500 mg kg-1 of diet: C1-control (Fe 45 mg kg-1, Cr 1 mg kg-1); C50 (Fe 45 mg kg-1, Cr 50 mg kg-1); C500 (Fe 45 mg kg-1, Cr 500 mg kg 1); H1 (Fe 180 mg kg-1, Cr 1 mg kg-1); H50 (Fe 180 mg kg-1, Cr 50 mg kg-1); H500 (Fe 180 mg kg-1, Cr 500 mg kg-1). The serum iron level and total iron binding capacity (TIBC) were measured with colorimetric methods. The serum ferritin level was measured by means of electrochemiluminescence immunoassay. The serum transferrin level was measured with the ELISA method. Haematological measurements were made with an automated blood analyser. The Cr and Fe tissular levels were measured with the AAS method. The exposure to a high level of Fe(III) alone or in combination with Cr caused Fe accumulation in tissues, especially in the liver and kidneys, but there were no significant changes in the TIBC, transferrin, ferritin concentration in the serum and most haematological parameters. Moreover, the serum, hepatic and renal Cr concentrations decreased. The doses of supplementary Cr(III) given separately or in combination with high level of Fe(III) disturbed the Cr content in the liver and kidneys of healthy female rats. However, they did not change most of the parameters of Fe metabolism, except the Fe kidney concentration. Supplementary Cr3 decreased the renal Fe level in groups with adequate Fe content in the diet. However, the renal Fe levels increased along with a higher Cr level in the diet in groups with high Fe content. The findings proved a relationship between Fe(III) and Cr(III) metabolism in healthy female rats. However, the direction of change varied and depended on relative amounts of these elements in the diet. PMID- 29164514 TI - High Urinary Iodine, Thyroid Autoantibodies, and Thyroid-Stimulating Hormone for Papillary Thyroid Cancer Risk. AB - Thyroid nodules have become a common clinical problem, and the clinical importance of thyroid nodules lies in the determination of thyroid cancer. This study aims to evaluate the risk factors for papillary thyroid cancer (PTC) with regard to urinary iodine concentration (UIC), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TGAb) in comparison to thyroid nodular goiter (NG). Among the 2041 patients, 43.8% of which showed more than adequate (UIC 200-299 MUg/L) and excessive iodine (UIC >= 300.0 MUg/L) status. Compared with adequate iodine intake, iodine deficiency (UIC < 100 MUg/L) was inversely associated with multifocality (OR 0.59, P = 0.040), while more than adequate iodine intake was independently associated with an increased risk of larger tumor size (OR 1.33, P = 0.002) in female PTC patients but not in males. No significant difference in UIC was observed between patients with PTC and NG, suggesting that high iodine intake may be related with the growth of PTC, but not with its oncogenesis. Besides, positive for TPOAb and TGAb were individually associated with papillary thyroid microcarcinoma (PTMC) risk (OR 2.05 and 1.71, respectively, both P < 0.05) in female patients with tumor foci < 1 cm but not in males. Furthermore, younger age (< 46 years), TGAb positivity and small thyroid nodules in both sexes, higher TSH, TPOAb positivity, and multifocality in females could all predict PTC risk (all P < 0.05). These results might have clinical significance for managing patients with thyroid nodules and those with thyroidectomy. PMID- 29164515 TI - Early-Life Exposure to Cadmium Triggers Distinct Zn-Dependent Protein Expression Patterns and Impairs Brain Development. AB - The objective of this study was to determine if the brain development impairment induced by early-life exposure to cadmium (Cd) could result from changes in the expression pattern of distinct zinc (Zn)-dependent proteins. For this purpose, adult female rats receiving either tap water, Cd, Zn, or Cd + Zn in their drinking water during gestation and lactation periods were used. After birth, the male offspring were screened for locomotors and sensorial defects. At postnatal day 21 (PND 21), the male pups were sacrificed and their brains, liver, and plasma were taken for chemical, biochemical, and molecular analyses. Our results show that exposure to Cd significantly increased the metal accumulation and decreased Zn concentrations in the brain of male pups from Cd-treated mothers. Besides, Cd exposure reduced significantly the locomotor activity of the offspring in open-field test, the body weight, and the cranio-caudal length at PND21. Insulin-like growth factor-I (IGF-1) levels in the plasma and liver were also decreased in male pups from Cd-treated mothers. Cd-induced brain development disruption was accompanied by a significant increase of the superoxide dismutase (SOD) activity, induction of the metallothionein (MT) synthesis, and, at the molecular level, by an upregulation of Zrt-,Irt-related protein 6 (ZIP6) gene and a significant downregulation of the expression of the Zn transporter 3 (ZnT3) and brain-derived neurotrophic factor (BDNF) genes in the brain. No significant changes on the expression of genes encoding other Zn-dependent proteins and factors such as ZnT1, ZIP12, NF-kappaB, and Zif268. Interestingly, Zn supplementation provided a total or partial correction of the changes induced by the Cd exposure. These data indicated that changes in expression of ZnT3 and ZIP6 as well as alteration of other transcription factors, such as BDNF, or Zn dependent proteins, such as SOD and MTs, in response to Cd exposure might be an underlying mechanism of Cd-induced brain development impairment. PMID- 29164516 TI - Mineralocorticoid receptor antagonism protects the aorta from vascular smooth muscle cell proliferation and collagen deposition in a rat model of adrenal aldosterone-producing adenoma. AB - The number of patients with adrenal aldosterone-producing adenomas (APAs) has gradually increased. However, even after adenoma resection, some patients still suffer from high systolic blood pressure (SBP), which is possibly due to great arterial remodeling. Moreover, mineralocorticoid receptors (MRs) were found to be expressed in vascular smooth muscle cells (VSMCs). This study aims to determine whether MR antagonism protects the aorta from aldosterone-induced aortic remolding. Male rats were subcutaneously implanted with an osmotic minipumps and randomly divided into four groups: control; aldosterone (1 MUg/h); aldosterone plus a specific MR antagonist, eplerenone (100 mg/kg/day); and aldosterone plus a vasodilator, hydralazine (25 mg/kg/day). After 8 weeks of infusion, aortic smooth muscle cell proliferation and collagen deposition, as well as the MDM2 and TGF beta1 expression levels in the aorta, were examined. Model rats with APAs were successfully constructed. Compared with the control rats, the model rats exhibited (1) marked SBP elevation, (2) no significant alteration in aortic morphology, (3) increased VSMC proliferation and MDM2 expression in the aorta, and (4) enhanced total collagen and collagen III depositions in the aorta, accompanied with up-regulated expression of TGF-beta1. These effects were significantly inhibited by co-administration with eplerenone but not with hydralazine. These findings suggested that specific MR antagonism protects the aorta from aldosterone-induced VSMC proliferation and collagen deposition. PMID- 29164517 TI - The mycoestrogen zearalenone in Portuguese flowing waters and its potential environmental impact. AB - This study provides the first environmental risk assessment (ERA) for zearalenone (ZEN), the only known mycoestrogen, based on a broad-scale investigation on its occurrence in rivers and creeks from Portugal. Water sample filtration and immunoaffinity columns (IAC) clean-up followed by liquid chromatograph with tandem mass spectrometry (LC/MS n ) provided an analytical method with good analytical performance. ZEN levels were determined for seven Portuguese rivers and one creek, during two different seasons, in a total of 38 samples collected upstream wastewater treatment plants (WWTPs). Overall, 23.7% were contaminated with ZEN at levels ranging between 5.6 and 82.6 ng/L. The highest concentration was observed during spring, although no statistically significant differences were observed between spring and autumn sampling campaigns. The potential ecotoxicological risk from ZEN to different trophic levels of aquatic organisms was evaluated by means of risk quotients (RQs) calculation. Although all the RQs obtained were lower than 1, our results confirm that ZEN is a relatively frequent contaminant in flowing waters in Portugal and might contribute to the overall estrogenic activity in the environment. PMID- 29164518 TI - Reducing production of fumonisin mycotoxins in Fusarium verticillioides by RNA interference. AB - The fungus Fusarium verticillioides is a maize pathogen that can produce fumonisin mycotoxins in ears under certain environmental conditions. Because fumonisins pose health risks to humans and livestock, control strategies with minimal risk to the environment are needed to reduce fumonisin contamination. Host-induced gene silencing is a promising technique in which double-stranded RNA expressed in the plant host is absorbed by an invading fungus and down-regulates genes critical for pathogenicity or mycotoxin production in the fungus. A key preliminary step of this technique is identification of DNA segments within the targeted fungal gene that can effectively silence the gene. Here, we used segments of the fumonisin biosynthetic gene FUM1 to generate double-stranded RNA in F. verticillioides. Several of the resulting transformants exhibited reduced FUM1 gene expression and fumonisin production (24- to 3675-fold reduction in fumonisin FB1). Similar reductions in fumonisin production resulted from double stranded RNA constructs with segments of FUM8, another fumonisin biosynthetic gene (3.5- to 2240-fold reduction in fumonisin FB1). FUM1 or FUM8 silencing constructs were transformed into three isolates of F. verticillioides. Whole genome sequence analysis of seven transformants revealed that reductions in fumonisin production were not due to mutation of the fumonisin biosynthetic gene cluster and revealed a complex pattern of plasmid integration. These results suggest the cloned FUM1 or FUM8 gene segments could be expressed in maize for host-induced gene silencing of fumonisin production. PMID- 29164519 TI - Atorvastatin Prevents Early Oxidative Events and Modulates Inflammatory Mediators in the Striatum Following Intranasal 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Administration in Rats. AB - Atorvastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor with cholesterol-lowering, anti-inflammatory, and antioxidant properties. Increasing evidence show atorvastatin acts as a protective agent against insults in the central nervous system (CNS). The regular use of statins has been associated with a reduced risk of Parkinson's disease (PD) development. Here, we evaluated early events involved in the neurotoxicity induced by intranasal (i.n.) infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rats and the potential of atorvastatin to prevent these early toxic events. Male Wistar rats were pretreated orally with atorvastatin (10 mg/kg/day) or vehicle once a day during seven consecutive days. Twenty-four hours after atorvastatin administration, animals received a single bilateral i.n. infusion of MPTP (1 mg/nostril), and 6 h later, the striatum and the hippocampus were collected to evaluate early oxidative stress parameters and inflammatory cytokines. Atorvastatin prevented MPTP-induced increase in reactive species (RS) generation and in glutathione levels in the striatum. Atorvastatin also prevented the reduction in mitochondrial respiratory chain complex I and II activities evoked by MPTP in the striatum. Atorvastatin per se reduced the levels of the cytokines TNF-alpha and IL-1beta, and surprisingly, it reduced IL-10 and nerve growth factor levels in the striatum. However, the anti-inflammatory IL-10 levels increased in the striatum following atorvastatin plus MPTP treatment. These effects were not observed in the hippocampus. Our findings reinforce and extend the notion of the neuroprotective effects of atorvastatin in a PD model and indicate the modulation of oxidative and inflammatory responses as the mechanisms associated with therapeutic action of atorvastatin in PD. PMID- 29164520 TI - Adrenal myelolipoma: a comprehensive review. AB - INTRODUCTION: Adrenal myelolipoma is an invariably benign neoplasm of the adrenal gland that is the second most common primary adrenal incidentaloma following adrenocortical adenomas. It is composed of elements of adipose tissue and extramedullary hematopoiesis. Hypotheses on stem cells and hormonal factors have been formulated regarding its pathogenesis that is still obscure. Despite its benign behavior, adrenal myelolipoma is clinically relevant as it might cause significant difficulties in the differential diagnosis of adrenal tumors. METHODS: We have reviewed 420 cases reported between 1957 and 2017 on adrenal myelolipoma retrieved from PubMed and Scopus databases and also 20 of our case series to provide a comprehensive analysis of their pathology, epidemiological and clinical features. RESULTS AND CONCLUSIONS: The average age for its diagnosis was 51 years, and no gender difference was observed. The average size of tumors was 10.2 cm. Congenital adrenal hyperplasia was associated to 10% of all cases analyzed, while other adrenal hypersecretory disorders (cortisol, aldosterone) were found in 7.5% of cases. Computed tomography and magnetic resonance imaging can be reliably used for its differential diagnosis. If the diagnosis of an adrenal myelolipoma is unambiguous, and no associated symptoms or hormonal activity are established, surgical intervention is usually not necessary. PMID- 29164522 TI - Prioritization to visual objects: Roles of sensory uncertainty. AB - Two hypotheses, attentional prioritization and attentional spreading, have been proposed to account for object-based attention. The attentional-prioritization hypothesis posits that the positional uncertainty of targets is sufficient to resolve the controversy raised by the competing attentional-spreading hypothesis. Here we challenge the sufficiency of this explanation by showing that object based attention is a function of sensory uncertainty in a task with consistent high positional uncertainty of the targets. In Experiment 1, object-based attention was modulated by sensory uncertainty induced by the noise from backward masking, showing an object-based effect under high as compared to low sensory uncertainty. This finding was replicated in Experiment 2 with increased task difficulty, to exclude that as a confounding factor, and in Experiment 3 with a psychophysical method, to obtain converging evidence using perceptual threshold measurement. Additionally, such a finding was not observed when sensory uncertainty was eliminated by replacing the backward-masking stimuli with perceptually dissimilar ones in Experiment 4. These results reveal that object based attention is influenced by sensory uncertainty, even under high positional uncertainty of the targets. Our findings contradict the proposition of attentional spreading, proposing instead an automatic form of object-based attention due to enhancement of the perceptual representation. More importantly, the attentional-prioritization hypothesis based solely on positional uncertainty cannot sufficiently account for object-based attention, but needs to be developed by expanding the concept of uncertainty to include at least sensory uncertainty. PMID- 29164521 TI - Funding source, conflict of interest and positive conclusions in neuro-oncology clinical trials. AB - We aimed to test any association between authors' conclusions and self-reported COI or funding sources in central nervous system (CNS) studies. A review was performed for CNS malignancy clinical trials published in the last 5 years. Two investigators independently classified study conclusions according to authors' endorsement of the experimental therapy. Statistical models were used to test for associations between positive conclusions and trials characteristics. From February 2010 to February 2015, 1256 articles were retrieved; 319 were considered eligible trials. Positive conclusions were reported in 56.8% of trials with industry-only, 55.6% with academia-only, 44.1% with academia and industry, 77.8% with none, and 76.4% with not described funding source (p = 0.011). Positive conclusions were reported in 60.4% of trials with unrelated COI, 60% with related COI, and 60% with no COI reported (p = 0.997). Factors that were significantly associated with the presence of positive conclusion included trials design (phase 1) [OR 11.64 (95 CI 4.66-29.09), p < 0.001], geographic location (outside North America or Europe) [OR 1.96 (95 CI 1.05-3.79), P = 0.025], primary outcomes (non overall or progression free survival) [OR 3.74 (95 CI 2.27-6.18), p < 0.001], and failure to disclose funding source [OR 2.45 (95 CI 1.22-5.22), p = 0.011]. In a multivariable regression model, all these factors remained significantly associated with trial's positive conclusion. Funding source and self-reported COI did not appear to influence the CNS trials conclusion. Funding source information and COI disclosure were under-reported in 14.1 and 17.2% of the CNS trials. Continued efforts are needed to increase rates of both COI and funding source reporting. PMID- 29164523 TI - Identification of Uridine 5'-Diphosphate-Glucuronosyltransferases Responsible for the Glucuronidation of Mirabegron, a Potent and Selective beta3-Adrenoceptor Agonist, in Human Liver Microsomes. AB - BACKGROUND AND OBJECTIVES: Mirabegron is cleared by multiple mechanisms, including drug-metabolizing enzymes. One of the most important clearance pathways is direct glucuronidation. In humans, M11 (O-glucuronide), M13 (carbamoyl glucuronide), and M14 (N-glucuronide) have been identified, of which M11 is one of the major metabolites in human plasma. The objective of this study was to identify the uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) isoform responsible for the direct glucuronidation of mirabegron using human liver microsomes (HLMs) and recombinant human UGTs (rhUGTs). METHODS: Reaction mixtures contained 1-1000 MUM mirabegron, 8 mM MgCl2, alamethicin (25 MUg/mL), 50 mM Tris HCl buffer (pH 7.5), human liver microsome (HLM) or rhUGT (1.0 mg protein/mL), and 2 mM UDP-glucuronic acid in a total volume of 200 MUL for 120 min at 37 degrees C. HLMs from 16 individuals were used for the correlation study, and mefenamic acid and propofol were used for the inhibition study. RESULTS: Regarding M11 formation, rhUGT2B7 showed high activity among the rhUGTs tested (11.3 pmol/min/mg protein). This result was supported by the correlation between M11 formation activity and UGT2B7 marker enzyme activity (3-glucuronidation of morphine, r 2 = 0.330, p = 0.020) in individual HLMs; inhibition by mefenamic acid in pooled HLMs (IC50 = 22.8 MUM); and relatively similar K m values between pooled HLMs and rhUGT2B7 (1260 vs. 486 MUM). Regarding M13 and M14 formation, rhUGT1A3 and rhUGT1A8 showed high activity among the rhUGTs tested, respectively. CONCLUSIONS: UGT2B7 is the main catalyst of M11 formation in HLMs. Regarding M13 and M14 formation, UGT1A3 and UGT1A8 are strong candidates for glucuronidation, respectively. PMID- 29164524 TI - The anchoring effect in metamemory monitoring. AB - Judgments about future memory performance (metamemory judgments) are known to be susceptible to illusions and bias. Here we asked whether metamemory judgments are affected, like many other forms of judgment, by numerical anchors. Experiment 1 confirmed previous research showing an effect of informative anchors (e.g., past peer performance) on metamemory monitoring. In four further experiments, we then explored the effects of uninformative anchors. All of the experiments obtained significant anchoring effects on metamemory monitoring; in contrast, the anchors had no effect on recall itself. We also explored the anchoring effect on metamemory control (restudy choices) in Experiment 4. The results suggested that anchors can affect metamemory monitoring, which in turn affects metamemory control. The present research reveals that informative and, more importantly, uninformative numbers that have no influence on recall itself can bias metamemory judgments. On the basis of the current theoretical understanding of the anchoring effect and metamemory monitoring, these results offer insight into the processes that trigger metacognitive biases. PMID- 29164526 TI - Erratum to: Generation of Induced Pluripotent Stem Cells in Defined Three Dimensional Hydrogels. PMID- 29164525 TI - Heat shock factor 4 regulates the expression of HSP25 and alpha B-crystallin by associating with DEXD/H-box RNA helicase UAP56. AB - Heat shock factor 4 controls the transcription of small heat shock proteins (e.g., HSP25, alpha B-cyrstallin, and r-crystallin), that play important roles in modulating lens proteostasis. However, the molecular mechanism underlying HSF4 mediated transcription is still unclear. Using yeast two hybrid, we found that HSF4 interacts with the ATP-dependent DEXD/H-box RNA helicase UAP56, and their interaction in lens epithelial cell line was further confirmed by GST-pull down assay. UAP56 is a vital regulator of pre-mRNA splicing and mature mRNA nuclear export. The immunofluorescence assay showed that HSF4 and UBA56 co-localize with each other in the nucleus of lens epithelial cells. Ectopic UAP56 upregulated HSF4-controlled HSP25 and alpha B-crystallin proteins expression, while knocking down UAP56 by shRNA reversed it. Moreover, UAP56 interacts with and facilitates the nuclear exportation of HSP25 and alpha B-crystallin mRNA without impacting their total mRNA expression level. In lens tissues, both UAP56 and HSF4 are expressed in the same nucleus of lens fiber cells, and their expression levels are simultaneously reduced with fiber cell maturation. Taken together, these data suggested that UAP56 is a novel regulator of HSF4 and might upregulate HSF4's downstream mRNA maturation and nuclear exportation. PMID- 29164527 TI - Correction to: A primer on nerve agents: what the emergency responder, anesthesiologist, and intensivist needs to know. AB - In the article entitled: "A primer on nerve agents: what the emergency responder, anesthesiologist, and intensivist needs to know" published in the October 2017 issue of the Journal, Can J Anesth 2017; 64: 1059-1070, two doses in Table 3 contained errors and have now been corrected (and highlighted in bold) in the revised table herein. In the table on page 1064, next to "Pralidoxime/Obidoxime/HI-6", the second column should read: "Pralidoxime- Mild cases: 1-2 g iv over 5-10 min or im". Also in the same row, the third column should read: "Individual doses should not exceed 2 g". The publisher apologizes most sincerely for this error. PMID- 29164528 TI - Equivalent analgesic effectiveness between perineural and intravenous dexamethasone as adjuvants for peripheral nerve blockade: a systematic review and meta-analysis. AB - PURPOSE: Dexamethasone is commonly used as an adjuvant to local anesthetics for peripheral nerve blockade; however, uncertainty persists regarding its optimal route of administration and safety. A systematic review and meta-analysis of randomized-controlled trials (RCTs) was conducted to compare the incremental benefits of intravenous (IV) vs perineural (PN) dexamethasone when used as adjuvants for peripheral nerve blockade to improve analgesia. SOURCES: A search strategy was developed to identify eligible articles from the Cochrane and National Library of Medicine databases from inception until June 2017. The National Center for Biotechnology Information Medical Subject Headings browser thesaurus was used to identify search terms and combinations of keywords. Any clinical trial that randomly allocated adult patients (>= 18 yr old) to receive either IV or PN dexamethasone for peripheral nerve blockade was considered for inclusion. PRINCIPAL FINDINGS: After full-text screening of potentially eligible articles, 14 RCTs were included in this review. Overall, the use of PN dexamethasone did not provide a significant incremental benefit to the duration of analgesia [ratio of means (ROM), 1.23; Hartung-Knapp-Sidik-Jonkman (HKSJ) 95% confidence interval (CI), 0.85 to 1.85; P = 0.23] or to motor block duration (ROM, 1.14; HKSJ 95% CI, 0.98 to 1.31; P = 0.07). Also, at 24-hr follow-up, there was no significant difference between the two groups regarding pain scores (standardized mean difference, 0.36; HKSJ 95% CI, -0.08 to 0.80; I2 = 75%; P = 0.09) and cumulative opioid consumption (mean difference, 5.23 mg; HKSJ 95% CI, 4.60 to 15.06; P = 0.15). Lastly, no long-term nerve-related complications were observed with the use of PN dexamethasone. CONCLUSIONS: The results of our meta analysis suggest that PN and IV dexamethasone provide equivalent analgesic benefits and have similar safety profiles, when used as adjuvants, for peripheral nerve blockade. PMID- 29164529 TI - Open season: positive changes for increased transparency in the biomedical literature. PMID- 29164530 TI - Ultrasound-guided lateral-medial transmuscular quadratus lumborum block for analgesia following anterior iliac crest bone graft harvesting: a clinical and anatomical study. AB - BACKGROUND: The anterior iliac crest (AIC) is one of the most common sites for harvesting autologous bone, but the associated postoperative pain can result in significant morbidity. Recently, the transmuscular quadratus lumborum block (TQL) has been described to anesthetize the thoraco-lumbar nerves. This study utilizes a combination of cadaveric models and clinical case studies to evaluate the dermatomal coverage and analgesic utility of TQL for AIC bone graft donor site analgesia. METHODS: Ten ultrasound-guided TQL injections were performed in five cadaver specimens using a lateral-to-medial transmuscular approach. Twenty mL of 0.5% methylcellulose was injected on each side after ultrasound confirmation of the needle tip ventral to the quadratus lumborum muscle (QLM). Cranio-caudal and medial-lateral extent of the dye spread in relation to musculoskeletal anatomy and direct staining of the thoraco-lumbar nerves were recorded. Following the anatomical findings, continuous catheter TQL blocks were performed in four patients undergoing ankle surgery with autologous AIC bone graft. The dermatomal anesthesia and postoperative analgesic consumption were recorded. RESULTS: In the anatomical component of the study, 9/10 specimens showed a lateral spread anterior to the transversalis fascia and medially between the QLM and psoas major muscle. Direct staining of the branches of the T12, L1, and L2 nerves was noted ventral to the QLM, while variable staining of the T9-T11 nerves was seen laterally in the transversus abdominis plane and the transversalis fascia. The vertical spread of injectate anterior to the QLM was T12 to the iliac crest (n = 5/10) and L1 to the iliac crest (n = 4/10). In the four patients who received TQL, the T9-L2 dermatomal anesthesia correlated with the injectate spread seen in the cadavers and provided effective analgesia at the bone graft donor site. CONCLUSION: Ultrasound-guided TQL injections consistently cover the thoraco lumbar innervation relevant to the AIC graft donor site. The injectate spread seen in anatomical dissections correlated with the dermatomal anesthesia clinically. The TQL has the potential to provide reliable analgesia for patients undergoing AIC bone graft harvesting. PMID- 29164531 TI - Biphasic bioresorbable scaffold (TruFit(r)) in knee osteochondral defects: 3-T MRI evaluation of osteointegration in patients with a 5-year minimum follow-up. AB - PURPOSE: The aim of this study is to follow morphological imaging characteristics and osteointegration of TruFit(r) bone graft substitute (BGS) plugs in cases of chondral and osteochondral defects of the articular surface of the knee joint, using high-quality cartilage-sensitive 3-T magnetic resonance imaging (MRI), linked to clinical outcomes. METHODS: The MRI was used to assess osteointegration and biological evolution of the TruFit(r) BGS plugs in cases with minimum 5-year follow-up: The TruFit(r) plug was used in 46 patients for a total of 47 cases with mean age of 57.89 (range 32-80). In this study, we reviewed only the cases with minimum follow-up of 5 years: 5 patients with mean age 64.4 years (minimum 38, maximum 80). The mean follow-up was 71 months (range 63-77). Patients were evaluated clinically, with Lysholm Knee Scoring Scale and MOCART Scale. RESULTS: 3-T MRI, which is preferable to 1.5 T for the better signal-to-noise ratio, contrast and the ability to acquire morphological images at higher spatial resolution, shows a satisfactory integration of bone scaffolds in studied cases for more than 5 years and a satisfactory restoration of the articular cartilage, with the exception of a case of which we still have to consider the factors age, type of lesion and the relationship between the plugs implanted. CONCLUSION: Clinical and radiological results significantly improve in a longer follow-up time. PMID- 29164532 TI - Correction to: Atraumatic femoral neck fracture during bisphosphonate treatment: case report and review of the literature. AB - Correction to: Aging Clin Exp Res https://doi.org/10.1007/s40520-017-0846-0. PMID- 29164534 TI - Correction to: Tanner-Whitehouse Skeletal Ages in Male Youth Soccer Players: TW2 or TW3? AB - An Online First version of this article was made available online at https://link.springer.com/article/10.1007%2Fs40279-017-0799-7 on 29 October 2017. Errors were subsequently identified in the article, and the following corrections should be noted. PMID- 29164533 TI - Lower Serum Zinc Concentration Despite Higher Dietary Zinc Intake in Athletes: A Systematic Review and Meta-analysis. AB - BACKGROUND: Zinc is an essential trace element that has been implicated in numerous biological functions, including immunity, energy metabolism and antioxidative processes. Recent evaluations of the literature have provided evidence of significant acute changes in zinc metabolism following a bout of aerobic exercise. OBJECTIVE: The aim of this study was to determine the zinc status of trained athletes compared with control populations, as described in cross-sectional studies. DESIGN: We conducted a systematic literature search of the PubMed, Scopus, SPORTDiscus and Cochrane Library electronic databases from inception to 28 January 2016 to identify cross-sectional studies that determined the zinc status of athletes compared with a control population. Meta-analysis of the differences in serum zinc concentration and dietary zinc intake between groups were conducted. RESULTS: Twelve studies were included in the systematic review. Of the included studies, nine and eight studies provided sufficient data for the meta-analysis of serum zinc concentration and dietary zinc intake, respectively. Serum zinc concentration was significantly lower in athletes [- 0.93 MUmol/L, 95% confidence interval (CI) - 1.62 to - 0.23] despite significantly higher dietary zinc intake compared with the control population (2.57 mg/day, 95% CI 0.97-4.16). Data on erythrocyte and urinary zinc from the included studies were insufficient for meta-analysis. CONCLUSIONS: Despite higher total dietary zinc intake, athletes generally have lower serum zinc concentration, which suggests that athletes have higher requirement of zinc than those who are physically inactive. Further investigations of zinc metabolism during exercise and dietary zinc requirement in active populations are needed to establish evidence-based recommendations. PMID- 29164535 TI - Multi-criterial evaluation of P-removal optimization in rural wastewater treatment plants for a sub-catchment of the Baltic Sea. AB - Rural wastewater treatment plants (WWTP) are recognized as a significant phosphorous (P)-emission source in the German sub-catchments of the Baltic Sea. But enhancement of P-removal is cost intensive especially for small communities. This study proposes a concept to efficiently reduce P-emissions from WWTP by introducing low-cost non-constructional measures and assessing the resulting change of ambient water quality on a river basin scale. As case study, we choose the Warnow catchment in Mecklenburg-Vorpommern (Germany) where 76 % of WWTP emissions originate from treatment plants without P-discharge limits. For these facilities, we evaluated two modification options: (1) optimization of enhanced biological Phosphorous removal (EBPR) in activated sludge systems (ASS) and/or (2) chemical precipitation (where EBPR is applicable). The total operational optimization potential in the Warnow catchment is about 20 %. Further improvements can only be applied by a chemical precipitation, with the drawback of increasing the wastewater disposal cost up to 6.5 euros CAP-1a-1. To prioritize relevant plants for improved P-removal we proposed two evaluation criteria: combining absolute emission, and impact on ambient water quality and costs. PMID- 29164536 TI - Particle size distribution predicts particulate phosphorus removal. AB - Particulate phosphorus (PP) is often the largest component of the total phosphorus (P) load in stormwater. Fine-resolution measurement of particle sizes allows us to investigate the mechanisms behind the removal of PP in stormwater wetlands, since the diameter of particles influences the settling velocity and the amount of sorbed P on a particle. In this paper, we present a novel method to estimate PP, where we measure and count individual particles in stormwater and use the total surface area as a proxy for PP. Our results show a strong relationship between total particle surface area and PP, which we use to put forth a simple mechanistic model of PP removal via gravitational settling of individual mineral particles, based on a continuous particle size distribution. This information can help improve the design of stormwater Best management practices to reduce PP loading in both urban and agricultural watersheds. PMID- 29164537 TI - Simple technology for recycling phosphate from wastewater to farmland in rural areas. AB - A simple technology for phosphate (P i ) recovery has been developed using a bifunctional adsorption-aggregation agent. The bifunctional agent was prepared by soaking calcium silicates in hydrochloric acid solution. Importantly, recyclable calcium silicates were available almost free of charge from the cement industry and also from the steel industry. The acid treatment was essential not only for enhancing the ability of calcium silicates to remove P i from aqueous solution but also for enabling the high settleability of removed P i . On-site experiments using a mobile plant showed that approximately 80% P i could be recovered from anaerobic sludge digestion liquor at a wastewater treatment plant. This technology has the potential to offer a simple, compact service for recycling P i from wastewater to farmland in rural areas. PMID- 29164538 TI - Particle deposition, resuspension and phosphorus accumulation in small constructed wetlands. AB - To improve understanding of phosphorus (P) retention processes in small constructed wetlands (CWs), we analysed variations in sediment deposition and accumulation in four CWs on clay soils in east-central Sweden. Sediment deposition (in traps) generally exceeded the total suspended solids (TSS) load suggesting that resuspension and wetland base erosion were important. This was confirmed by quantification of particle accumulation (on plates) (1-23 kg m-2 year-1), which amounted to only 13-23% of trap deposition. Spatial mean P concentrations in accumulated sediment on plates (0.09-0.15%) were generally similar to temporal mean P concentrations of particles in water (0.11-0.15%). Deposition/accumulation was minor in one wetland with high hydraulic load (400 m year-1), suggesting that such small wetlands are not efficient as particle sinks. Economic support for CWs are given, but design and landscape position are here demonstrated to be important for effective P retention. PMID- 29164539 TI - Amphibian recovery after a decrease in acidic precipitation. AB - We here report the first sign of amphibian recovery after a strong decline due to acidic precipitation over many decades and peaking around 1980-90. In 2010, the pH level of ponds and small lakes in two heavily acidified areas in southwestern Scandinavia (Aust-Agder and Ostfold in Norway) had risen significantly at an (arithmetic) average of 0.14 since 1988-89. Parallel with the general rise in pH, amphibians (Rana temporaria, R. arvalis, Bufo bufo, Lissotriton vulgaris, and Triturus cristatus) had become significantly more common: the frequency of amphibian localities rose from 33% to 49% (n = 115), and the average number of amphibian species per locality had risen from 0.51 to 0.88. In two other (reference) areas, one with better buffering capacity (Telemark, n = 21) and the other with much less input of acidic precipitation (Nord-Trondelag, n = 106), there were no significant changes in pH or amphibians. PMID- 29164540 TI - Phytoplankton can bypass nutrient reductions in eutrophic coastal water bodies. AB - The EU-water framework directive aims at nutrient reductions, since anthropogenically induced eutrophication is a major threat for coastal waters. However, phytoplankton biomass in southern Baltic Sea coastal water bodies (CWB) remains high and the underlying mechanisms are not well understood. Therefore, a CWB data set was analysed regarding changes in phytoplankton biomass and nutrient concentration of nitrogen (N) and phosphorus (P) from 2000 to 2014. It was expected to find imbalances between produced phytoplankton biomass and total nutrient concentrations. Inner CWB were cyanobacteria-dominated and showed up to five times higher chlorophyll a-concentrations compared to outer CWB with similar total phosphorus-concentrations. Phytoplankton tended to be P-limited during spring and N-limited during summer. Phytoplankton biomass and nutrient concentrations were even higher during very humid years, which indicated a close coupling of the CWB with their catchment areas. This study suggests that re mesotrophication efforts need to consider the importance of changed phytoplankton composition and nutrient availabilities. PMID- 29164541 TI - [The Application of Information and Communication Technology (ICT) in Nursing Education]. AB - With the rapid development of information and communication technologies (ICT) in the 21st century, all walks of life have experienced disruptive changes, including the healthcare profession. Although nurses represent the largest number of professionals in medical institutions, it is doubtful whether nurses possess sufficient capabilities to face challenges in this era of rapid medical informatization. Currently, the courses necessary to cultivate information literacy in nursing students are insufficient in Taiwan, and traditional instruction methods are largely adopted as nursing teaching strategies. Additionally, most teachers hold a passive attitude towards the application of ICT in teaching. On the contrary, ICT have been integrated into nursing education in many countries around the world for nearly 20 years, achieving good levels of teaching efficacy. Reflecting the Taiwan government's promotion of digital learning projects, academic circles in various fields have also started to gradually integrate ICT into teaching. Nursing educators in Taiwan have much to reference and to learn from these disparate integration experiences. Therefore, this article introduces the concepts of integration of ICT into teaching, the current status of the application of ICT in international nursing education, and the issues faced during this application as a reference for nursing education in Taiwan in order to promote the integration of ICT into nursing education. PMID- 29164542 TI - [VR and AR Applications in Medical Practice and Education]. AB - As technology advances, mobile devices have gradually turned into wearable devices. Furthermore, virtual reality (VR), augmented reality (AR), and mixed reality (MR) are being increasingly applied in medical fields such as medical education and training, surgical simulation, neurological rehabilitation, psychotherapy, and telemedicine. Research results demonstrate the ability of VR, AR, and MR to ameliorate the inconveniences that are often associated with traditional medical care, reduce incidents of medical malpractice caused by unskilled operations, and reduce the cost of medical education and training. What is more, the application of these technologies has enhanced the effectiveness of medical education and training, raised the level of diagnosis and treatment, improved the doctor-patient relationship, and boosted the efficiency of medical execution. The present study introduces VR, AR, and MR applications in medical practice and education with the aim of helping health professionals better understand the applications and use these technologies to improve the quality of medical care. PMID- 29164543 TI - [Exploration of Recent Mobile Technologies Applied in Nursing Education]. AB - The development of science and technology has fundamentally changed people's lives and the way that medical systems function. Increasingly, mobile technologies are being introduced and integrated into classroom teaching and clinical applications, resulting in healthcare providers introducing innovative applications into health education. These applications enhance the clinical, education, and research expertise of medical staffs and nurses, while improving quality of care and providing new experiences for patients. In order to understand the current situation and trends in nursing education, the present study adopted literature analysis to explore the influence and effect of mobile technologies that have been introduced into nursing education from the school and clinical environments. The results found that students hold positive attitudes toward introducing these technologies into their curricula. Although these technologies may increase the work efficiency of nurses in the workplace, questions remain user perceptions and professional expression. Therefore, securing patient agreement and healthcare system approval were major turning points in the introduction of mobile technologies into nursing education. In the future, adapting mobile technologies for use in teaching materials and courses may be further developed. Moreover, empirical studies may be used in future research in order to facilitate the increasingly successful integration of relevant technologies into nursing education. PMID- 29164544 TI - [Construction and Application of Innovative Education Technology Strategies in Nursing]. AB - The evolution of information and communication technologies has deeply impacted education reform, promoted the development of digital-learning models, and stimulated the development of diverse nursing education strategies in order to better fulfill needs and expand in new directions. The present paper introduces the intelligent-learning resources that are available for basic medical science education, problem-based learning, nursing scenario-based learning, objective structured clinical examinations, and other similar activities in the Department of Nursing at Chang Gung University of Science and Technology. The program is offered in two parts: specialized classroom facilities and cloud computing / mobile-learning. The latter includes high-fidelity simulation classrooms, online e-books, and virtual interactive simulation and augmented reality mobile-learning materials, which are provided through multimedia technology development, learning management systems, web-certificated examinations, and automated teaching and learning feedback mechanisms. It is expected that the teaching experiences that are shared in this article may be used as a reference for applying professional wisdom teaching models into nursing education. PMID- 29164545 TI - [Sleep Quality, Depression, Anxiety, and Self-Esteem in People Living With HIV/AIDS (PLWHA)]. AB - BACKGROUND: HIV has become a chronic disease. Therefore, the mental health and sleep quality of people living with HIV/AIDS (PLWHA) have become increasingly important issues of concern. PURPOSE: To explore the sleep quality, depression, anxiety, and self-esteem of PLWHA and the correlation between sleep quality and various related mental-health factors. METHODS: A cross-sectional, descriptive, correlational study was conducted at a medical center in southern Taiwan in 2013 2014. Data on the sleep quality, depression, anxiety, and self-esteem of 146 PLWHA cases were collected using a structural questionnaire (the Pittsburgh Sleep Quality Index, the Center for Epidemiologic Studies Depression Scale, Zung's Self Administered Anxiety Scale, and Rosenberg Self-Esteem Scale). RESULTS: Three fifths (60.3%) of the cases had poor sleep quality, 50% were inclined toward depression, and 36.3% were inclined toward anxiety, indicating that sleep quality, depression, and anxiety levels in these cases were worse than the general population. Moreover, significant correlations were identified between poor sleep quality and the variables of depression (r = .40, p < .001) and anxiety (r = .53, p < .001). Multiple variate analysis revealed that older age, subjective feelings that HIV significantly influenced personal life, anxiety, and depression were all significant predictors of sleep quality. No significant correlations were found between CD4 (cluster of differentiation 4) lymphocyte count, HIV viral load, or receiving antiretroviral therapy and the variables of sleep quality, depression, anxiety, or self-esteem. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: About half of the PLWHA cases in the present study exhibited poor sleep quality and tendencies toward depression and anxiety. Moreover, sleep quality and mental health factors were found to be not correlated with CD4 lymphocyte count, HIV viral load, or receiving antiretroviral therapy. Therefore, early evaluation of the sleep quality and mental health of people living with HIV/AIDS is recommended in order to provide holistic care. PMID- 29164547 TI - [The Effectiveness of a Strategy for the Flexible Management of Nursing Human Resources: A Pilot Study]. AB - BACKGROUND: The flexibility of a hospital's nursing-related human resource management policies affects the working willingness and retention of nurses. PURPOSE: To explore the effectiveness of a flexible nursing-related human resource management strategy. METHODS: This quasi-experimental research used a one group pretest-posttest design. Supervisors at participating hospitals attended the "Application of Flexible Nursing Human Resources Management Strategies" workshop, which introduced the related measures and assessed nurses' pretest satisfaction. After these measures were implemented at the participating hospitals, implementation-related problems were investigated and appropriate consultation was provided. The posttest was implemented after the end of the project. Data were collected from nurses at the participating hospitals who had served in their present hospital for more than three months. The participating hospitals were all nationally certified healthcare providers, including 13 medical centers, 17 regional hospitals, and 3 district hospitals. A total of nurses 2,810 nurses took the pretest and 2,437 took the posttest. The research instruments included the "Satisfaction with working conditions and system flexibility" scale and the "Flexible nursing human resource management strategies". The effectiveness of the implemented strategy was assessed using independent samples t-test and variance analysis. RESULTS: The result of implementing the flexible strategies shows that the total mean of pretest satisfaction (Likert 5 scores) was 3.47 (SD = 0.65), and the posttest satisfaction was 3.52 (SD = 0.65), with significant statistical differences in task, numerical, divisional, and leading flexibility. CONCLUSIONS: Due to the good implementation effectiveness, the authors strongly suggest that all of the participating hospitals continue to apply this strategic model to move toward a more flexible nursing system and work. PMID- 29164546 TI - [Testing the Reliability and Validity of the Taiwan Health-Related Quality of Life for Nausea and Vomiting During Pregnancy Scale]. AB - BACKGROUND: Symptom distress related to pregnancy-related nausea and vomiting is known to impact quality of life in pregnant women. However, few reliable and valid assessment tools are available for research use. PURPOSE: To test the reliability and validity of the Taiwan health-related quality of life for nausea and vomiting during pregnancy (NVPQOL) scale. METHODS: A cross-sectional study design was conducted. A convenience sample of 416 pregnant women in their first and second trimesters were recruited from the prenatal clinics of one medical center and one regional teaching hospital in southern Taiwan. Chi-square tests, item analysis, and principal axis factor analysis were used to examine construct validity. Pearson's correlation coefficient was then conducted to compare the concurrent validity of the scale against the Chinese-language version of the World Health Organization Quality of Life Assessment [WHOQOL-BREF (TW)]. RESULTS: Four factors were extracted using factor analysis: "limitations" (10 items), "physical symptoms/aggravating factors" (9 items), "emotions" (6 items), and "fatigue" (4 items), which together accounted for 67.45% of the total variance. The NVPQOL showed good convergent (r = .78 ~ .85, p < .01), discriminate (r = .48 - .68, p < .01), and concurrent validities, with a -0.37 correlation coefficient between the WHOQOL-BREF (TW) and the NVPQOL (p < .01). The Cronbach's alpha of the NVPQOL was .95. The intraclass correlation coefficient for test-retest reliability of two weeks was .92 (n = 37, p < .001). CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The NVPQOL may be used in future research and clinical assessment to measure quality of life in women who experience nausea and vomiting during pregnancy in order to provide appropriate nursing interventions in a timely manner to improve quality of life. PMID- 29164548 TI - [The Establishment and Examination of the Reliability, Validity, Discrimination, and Difficulty of Nursing Objective Structured Clinical Examination (OSCE)]. AB - BACKGROUND: The objective structured clinical examination (OSCE) is one of the evaluation strategies used to examine the clinical competence of nursing students. More attention needs to be paid to establishing an examination that is based on the standardized protocol and on reliability and validity. PURPOSE: The aims of this study were to develop an OSCE that is based on a standardized protocol and to analyze the content validity and predictive validity, inter-rater consistency, internal consistency, item-to-total correlation, and the degree of discrimination and difficulty of this OSCE. METHODS: Based on the blueprint for OSCEs that use an 8-station format, this study used a descriptive, cross sectional design and a sample population of 207 senior students who were preparing for their last-mile practicum at a nursing technology university in northern Taiwan. The study period lasted from September 2015 to October 2016. Furthermore, the validity, reliability, degree of discrimination, and difficulty of the OSCE were examined. RESULTS: An OSCE with an eight-station format was developed. The content validity index (CVI) was .85-1.0, inter-rater reliability was .80-1.0, Cronbach' alpha internal consistency was .53-.82, and item-to-total correlation was .36-.63. In addition, the level of difficulty of the OSCE was easy to moderate and the discrimination of the OSCE ranged from fair to excellent. Meanwhile, the OSCE scores of the participants appeared to be a valid predictor of scores on the last mile practicum. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: According to the standardized protocol of OSCE development, an 8- station nursing OSCE format is reliable and valid, providing fair levels of difficulty and discrimination. The developed OSCE may be applied to evaluate the clinical competence of nursing students prior to beginning their last mile practicum. The results from the present study may provide a reference for nursing educators who are responsible for developing OSCE evaluation strategies. PMID- 29164549 TI - [Improving the Accuracy Rate of Analgesics and Sedatives Administration in an Intensive Care Unit]. AB - BACKGROUND: Patients with respiratory failure needing mechanical ventilation are common in the intensive care unit. These patients often require sedative and analgesic agents to alleviate their discomfort and to avoid causing associated safety issues. However, prolonged post-awakening confusion and changes in perception after withdrawal from sedatives and analgesic agents are common in daily practice. Thus, the optimal use of sedative and analgesic agents remains an important issue in the intensive care unit. PURPOSE: To optimize sedation by raising the rate of accuracy for administering analgesic and sedative agents in the intensive care unit from 30.44% to 60.88%. METHODS: We first analyzed the problem from the current situation of the daily practice and revised the protocol of using analgesic and sedative agents. In order to achieve an optimal outcome, the authors further arranged staff education and bedside training and established an audit system to check and improve protocol adherence. RESULTS: The rate of accuracy for administering sedatives and analgesics improved from 34% to 93%. CONCLUSIONS: With appropriately scaled protocols of sedatives and analgesics administration, intensive care nurses may easily target the consistent and optimal assessment and provide pain relief prior to sedation, which will improve the quality of sedation and patient safety. PMID- 29164550 TI - [Improve the Rate of Bone Collection at Human Tissue Banks]. AB - BACKGROUND: Lack of familiarity with collection and inspection procedures, incorrect bone-packaging procedures, and unclear instructions for bone placement during storage are primary reasons for the resultant low bone collection pass rate of bone banks. Moreover, 8 cases / operations were directly affected by this problem, which caused bone-nail dislocations during the post-operative period that nearly caused medical disputes. PURPOSE: The present project was designed to improve the pass rate of the bone of the human organ to 95%. METHODS: Education and training programs were planned, visual-aid posters depicting standard procedures were produced, the repository was remarked and relabeled, and a regular audit system was established with the medical team. RESULTS: The pass rate for the collection of the bone of the human organ increased from 71.4% pre intervention to 96% post-intervention. CONCLUSIONS: The project reduced patient complaints and raised the accuracy of the bone collection process. PMID- 29164551 TI - [The Code of Ethics for Nurses: The Ethical Norms of "Fidelity", From Novice to Expert]. PMID- 29164552 TI - [The Application of Grief Theories to Bereaved Family Members]. AB - Loss is an inevitable experience for humans for which grief is a natural response. Nurses must have an adequate understanding of grief and bereavement in order to be more sensitive to these painful emotions and to provide appropriate care to families who have lost someone they love deeply. This article introduces four important grief theories: Freud's grief theory, Bowlby's attachment theory, Stroebe and Schuts' dual process model, and Neiyemer's meaning reconstruction model. Freud's grief theory holds that the process of grief adaptation involves a bereaved family adopting alternative ways to connect with the death of a loved one and to restore their self-ego. Attachment theory holds that individuals who undergo grieving that is caused by separation from significant others and that triggers the process of grief adaptation will fail to adapt if they resist change. The dual process model holds that bereaved families undergo grief adaptation not only as a way to face their loss but also to restore normality in their lives. Finally, the meaning reconstruction model holds that the grief adaptation strength of bereaved families comes from their meaning reconstruction in response to encountered events. It is hoped that these theories offer nurses different perspectives on the grieving process and provide a practical framework for grief assessment and interventions. Additionally, specific interventions that are based on these four grief theories are recommended. Furthermore, theories of grief may help nurses gain insight into their own practice-related reactions and healing processes, which is an important part of caring for the grieving. Although the grieving process is time consuming, nurses who better understand grief will be better able to help family members prepare in advance for the death of a loved one and, in doing so, help facilitate their healing, with a view to the future and to finally returning to normal daily life. PMID- 29164553 TI - [Implementing Inter-Professional Education (IPE): Challenges and Strategies]. AB - Inter-professional practice (IPP), necessary in today's healthcare environment, should be guided and practiced through inter-professional education (IPE). Within the context of an effective IPE program, collaborative medical professionals must be cognizant of the demands of patients' integrated care, organize a collaborative inter-professional team, and achieve the objectives of patient centered care. However, the many challenges of IPE include insufficient understanding of inter-professional care, occupational culture-related boundary issues, lack of a college education, and insufficient support from academic and medical institutions. This article suggests adopting effective strategies to promote inter-professional recognition, create a harmonious medical culture, eliminate barriers to education, and enhance support for academic and medical institutions. Inter-professional collaboration between academic and clinical institutions must provide resources and substantive professional training. Effectively implementing IPE and IPP is expected to elicit trust, respect, and efficient communication from team members. PMID- 29164554 TI - [The Experience of Caring for a Child Suffering From Incontinent Dermatitis]. AB - This paper describes the experience of caring for a child with incontinent dermatitis that was caused by improper family care. From March 27, 2015 to April 2, 2015, the authors used Gordon's 11 functional health parameters to collect subjective and objective data on the physical, mental and social conditions of the care recipient. To understand the nursing-related problems, including impaired skin integrity, acute pain, and caregiver anxiety, the data for this case and his mother were conducted by observation, physical assessment, the process of caring, and communication. For the three nursing problems, we established a good relationship with the family by providing individual care, continuously active care, listening, and companionship. In order to reduce the pain during wound dressing, we used game therapy and an attention-transfer technique that was based on the case's preferences. We encouraged family members to participate in treatment in order to ensure that the case continued to receive proper and continuous care after returning home. The authors taught the family members the correct information for treating incontinent dermatitis in order to reduce their concerns and to enhance their confidence and care abilities. We hope that this nursing experience may provide a reference for other nursing staffs when caring for similar cases in order to ensure appropriate quality of care. PMID- 29164555 TI - An insight into the role of cyclooxygenase and lipooxygenase pathway in renal ischemia. AB - OBJECTIVE: Renal ischemia (RI) is a clinical condition that occurs due to marked decrease in renal blood flow. The pathophysiology of RI is interlinked with atherosclerotic renal artery stenosis, infarction, organ transplantation and sepsis. The mechanism of RI injury depends on various factors such as inflammatory response, oxidative stress and apoptosis. In this review, we evaluate the role of cyclooxygenase and lipoxygenase in modulating the process of ischemic renal injury. MATERIALS AND METHODS: This is a literature review of articles published on PubMed and Web of Science in English. RESULTS: RI is characterized by an inflammatory response and oxidative stress, which are further worsened by the metabolites of the arachidonic acid pathway. CONCLUSIONS: RI results from a vigorous process involving inflammation and some mediators in a multifaceted interaction. Indulgence of oxidative stress and lipid peroxidation seems to be major factors which promote the inflammation process during RI. PMID- 29164556 TI - The effect of miR-224 down-regulation on SW80 cell proliferation and apoptosis and weakening of ADM drug resistance. AB - OBJECTIVE: Glycogen synthase kinase-3beta (GSK-3beta) can phosphorylate and degrade beta-catenin, and negatively regulates Wnt/beta-catenin signal pathway. MiR-224 up-regulation is associated with colorectal cancer (CRC). Bioinformatics analysis showed complementary binding sites between miR-224 and GSK-3beta. This study investigated if miR-224 plays a role in mediating GSK-3beta expression, Wnt/beta-catenin pathway activity, CRC cell proliferation, apoptosis as well as drug sensitivity of Adriamycin (ADM). MATERIALS AND METHODS: Dual luciferase gene reporter assay demonstrated the regulatory relationship between miR-224 and GSK 3beta. Expression of miR-224, GSK-3beta, beta-catenin, and Survivin was measured in normal colon epithelium NCM460, CRC cell line SW480, and drug-resistant SW480/ADM cell line. Flow cytometry measured apoptosis under ADM with an IC50 concentration of SW480 cells, followed by CCK-8 analysis of cell proliferation. SW480/ADM cells were treated with miR-224 inhibitor and/or pSicoR-GSK-3beta, followed by analysis of the expressions of GSK-3beta, beta-catenin and Survivin, cell apoptosis, and cell proliferation by EdU staining. RESULTS: MiR-224 targeted and inhibited GSK-3beta expression. In SW480/ADM cells, GSK-3beta expression and cell apoptosis rate were lower than those in SW480 cells, whilst miR-224, beta catenin, and Survivin expression or proliferation were higher than those in SW480 cells. Transfection of miR-224 inhibitor and/or pSicoR-GSK-3beta significantly increased GSK-3beta expression in SW480/ADM cells, and decreased beta-catenin and Survivin expression, leading to reduced proliferation potency, enhanced cell apoptosis and suppressed ADM resistance. CONCLUSIONS: MiR-224 up-regulation is associated with ADM resistance of CRC cells. Suppression of miR-224 expression up regulated GSK-3beta expression, inhibited Wnt/beta-catenin signal pathway activity and Survivin expression, as well as reduced ADM resistance of CRC SW480 cells. PMID- 29164557 TI - Adiponectin attenuates endoplasmic reticulum stress and alveolar epithelial apoptosis in COPD rats. AB - OBJECTIVE: The present study was designed to evaluate the effect of Adiponectin (APN) against alveolar epithelial apoptosis in chronic obstructive pulmonary disease (COPD) rat models. MATERIALS AND METHODS: Thirty-six male Sprague-Dawley (SD) rats were randomly assigned to three groups: Sham group, COPD group, and COPD + APN group (2.5 ug/kg/day). To assess the effect of APN, histopathological evaluations, lung function, and the apoptotic index (AI) of alveolar septal cells, were performed. In addition, the levels of oxidative stress and endoplasmic reticulum stress were measured. RESULTS: HE staining demonstrated that APN inhibited pathological injury in COPD rats. In addition, APN could restore the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in serum. APN also inhibited the levels of endoplasmic reticulum stress pathway including CHOP, phospho-JNK and Caspase-12 in alveolar epithelial cell. Furthermore, APN significantly inhibited the protein levels of Caspase-3 and apoptosis in alveolar epithelial cell of COPD rats. CONCLUSIONS: Our findings suggested that APN might effectively ameliorate the progression of COPD via inhibiting the endoplasmic reticulum stress-induced alveolar epithelial apoptosis in rats. PMID- 29164558 TI - Rapamycin facilitates fracture healing through inducing cell autophagy and suppressing cell apoptosis in bone tissues. AB - OBJECTIVE: To investigate the changes in cell autophagy and the molecular mechanism of rapamycin affecting the fracture healing. MATERIAL AND METHODS: Sprague-Dawley (SD) rats were used to establish the right femoral shaft fracture models, and then underwent immunofluorescence assay to detect the autophagy level in bone tissues. After model establishment, SD rats were divided into two groups, the control group and the rapamycin group (1 mg/kg/d). Respectively, at the 2nd, 4th, and 6th week, rats were randomly selected from each group for X-ray and Micro-computed tomography (Micro-CT) examinations to determine callus growth, immunofluorescence assay to detect the protein expression of light chain 3 II (LC3 II), immunohistochemistry to evaluate the autophagy level through detecting the expression of Beclin1 in rats, Western blotting assay to detect cell apoptosis in tissues, hematoxylin and eosin staining (HE staining) to evaluate the osteoblastic activity through count of osteoblast in bone tissue at the end of fracture, and measure the expression of vascular endothelial growth factors (VEGF). RESULTS: Significant increases were seen in protein expression of cells in bone tissues at the end of fracture. In rapamycin group, callus formation and calcification level in rats were all higher than those in control group; compared with control group, for rats in rapamycin group, cell autophagy was significantly elevated in bone tissues, while cell apoptosis at the end of fracture was reduced with a significant increase in osteoblastic activity. The expression of VEGF in rapamycin group was higher than that in control group. CONCLUSIONS: Rapamycin can facilitate fracture healing through inducing cell apoptosis and suppressing cell apoptosis in bone tissues. PMID- 29164559 TI - Effects of carvedilol on vascular reactivity in human left internal mammary artery. AB - OBJECTIVE: Surgical treatment choice for coronary artery disease is coronary artery bypass grafting (CABG) surgery. Left internal mammary artery (LIMA) is frequently used as an arterial graft in CABG operations. Perioperative spasm of LIMA can result in increased morbidity and mortality. Pharmacological interventions are routinely used for prevention and treatment of LIMA spasm. In this study, we aimed to investigate the effects of carvedilol, an alpha- and beta adrenergic receptor blocker, on responses to endogenous vasoconstrictors which play a role in graft spasm and the possible interaction between carvedilol and diltiazem/papaverine which are vasodilators commonly used in CABG surgery. PATIENTS AND METHODS: Isolated LIMA rings collected from patients undergoing CABG operation were suspended in an organ bath. Concentration-dependent responses to norepinephrine (NE), serotonin (5-HT) and diltiazem were examined before and after carvedilol incubation (10-6 M, 1 hour). Maximum relaxation response to papaverine (10-4 M) was compared in LIMA rings incubated with 0.05% dimethyl sulfoxide (DMSO, placebo) or carvedilol (10-6 M). RESULTS: Carvedilol did not affect the maximal contractile response to NE; however, it significantly reduced the sensitivity of LIMA to NE. Carvedilol increased contractile response and sensitivity to 5-HT. Promisingly, carvedilol increased the vasodilatory effects of diltiazem and papaverine. CONCLUSIONS: Our study suggests that carvedilol may be administered perioperatively in combination with diltiazem or papaverine to prevent or resolve LIMA graft spasm. PMID- 29164560 TI - The expression of transforming growth factor-beta1 in myocardial tissue and concentration of serum B-type natriuretic peptide in myocardial remodeling of Sprague-Dawley rats treated with carvedilol. AB - OBJECTIVE: The objective of this study was to observe the expression of transforming growth factor-beta1 (TGF-beta1) in myocardial tissue and the concentration of serum B-type natriuretic peptide (BNP) in myocardial remodeling of Sprague-Dawley rats induced by isoproterenol (ISO) and the effects of carvedilol intervention. MATERIALS AND METHODS: Thirty rats were divided randomly into three groups: (1) Control group: rats were injected with 5 mL/(kg.d) of saline for 10 days, followed by 10 mL/(kg.d) of saline by gavage for 4 weeks. (2) Model group: rats were injected with 5 mg/(kg.d) ISO for 10 days, followed by 10 mL/(kg.d) of saline by gavage for 4 weeks. (3) Treatment group: rats were injected with 5 mg/(kg.d) ISO for 10 days, followed by 10 mg/(kg.d) carvedilol by gavage for 4 weeks. Following treatments, the Cardiac Weight Index (CWI) was measured. The pathological changes to myocardial tissue were observed by HE staining and Masson's trichrome staining. The mRNA expression of TGF-beta1 was determined by RT-PCR. The protein expression of TGF-beta1 was detected by immunohistochemistry and Western blot. The concentration of serum BNP was measured by ELISA. RESULTS: According to our results, no significant pathological changes were observed in myocardial tissue of the control group. The denaturation, hypertrophy, edema and necrosis of myocardial cells as well as increased collagen fibers in myocardial tissue of the model group, were more pronounced compared to the treatment group. The CWI, level of TGF-beta1 in myocardial tissue, and the concentration of serum BNP of the model group, were significantly higher than that of the treatment group, and those of the treatment group were significantly higher than in the control group. There were significant differences among the three groups. There were also significant differences between any two groups. CONCLUSIONS: The expression of TGF-beta1 in myocardial tissue was upregulated and the concentration of serum BNP was increased in myocardial remodeling of SD rats induced by ISO. Carvedilol intervention can downregulate the expression of TGF-beta1 and decrease the concentration of BNP, inhibiting myocardial remodeling, and improve cardiac function. PMID- 29164561 TI - Study of prevalence and influencing factors of depression in tumor patients and the therapeutic effects of fluoxetine. AB - OBJECTIVE: To observe the depression in patients with malignant tumor and influencing factors of the disease, as well as to investigate the effects of fluoxetine on depressive symptoms in cancer patients and the immune function. PATIENTS AND METHODS: 262 patients with malignant tumors, confirmed by pathological and radiological diagnosis as malignant tumor were randomly divided into 2 groups: the control group with chemotherapy; the treatment group with chemotherapy and 20 mg/d fluoxetine for six weeks. Before and after treatment, the scores of QLQ-C30 scale and changes of immune parameters were observed, including the determination of NK and T cell subsets. RESULTS: The prevalence of depression in cancer patients was not related to the tumor location. But gender, age, tumor stage, the income level of satisfaction and chronic cancer pain were related to the occurrence of depression in cancer patients (p < 0.05). In the fluoxetine treatment groups, by QLQ-C30 scores, in quality of life scores including body, function, social and cognitive function, and single symptoms including nausea, vomiting, constipation, diarrhea, and economic difficulties, the differences were not statistically significant. The QLQ-C30 scores of overall quality of life and emotional function were rising in the fluoxetine treatment group. The QLQ-C30 scores of the pain, shortness of breath, fatigue, loss of appetite, insomnia symptoms were decreased, which had a statistical significance (p < 0.05) compared with the control group. To compare with the control group, the scores of HAMD were decreasing in the fluoxetine treatment group, which had a statistical significance (p < 0.05). Before treatment, the NK cells, CD3+, CD4+, CD4+/CD8+ ratios of tumor patients decreased significantly, while CD8+ increased. After 6 weeks of treatment, NK cells, CD3+, CD4+, CD4+/CD8+ ratios increased significantly and CD8+ decreased. CONCLUSIONS: Sex, age, tumor stage, income satisfaction, and cancer pain were relevant factors in patients with tumor associated depression. If depression can be detected in the early stage, and oral fluoxetine therapy can be conducted, it can improve the depression situation and immune function of patients with malignant tumor. PMID- 29164562 TI - Resveratrol transcriptionally regulates miRNA-18a-5p expression ameliorating diabetic nephropathy via increasing autophagy. AB - OBJECTIVE: To investigate the effects of resveratrol on autophagy in the chronically diabetic nephropathy and to study the effects of the different expression of microRNAs after resveratrol (RSV) treated in db/db mice (diabetic mice). MATERIALS AND METHODS: Db/m (non- diabetic) and db/db mice were randomly divided into intra gastric RSV treatment group or control group. Renal tissues were prepared for HE/PAS staining. In vitro, mouse podocytes cell lines were grown in different mediums with different dose of resveratrol treatment. microRNA (miRNA) gene chips assay was performed for differentially expressed miRNAs screening. Western blot was used to detect protein levels. RESULTS: In vivo, RSV significantly decreased urinary albumin, serum creatinine, mesangial area and glomerular size in db/db mice. After RSV treatment, LC3-II/LC3-I and synaptopodin were increased while cleaved-caspase 3 was decreased in kidney tissues. In vitro, podocytes treated with RSV exhibited significantly increased LC3-II/LC3-I and decreased cleaved caspase 3. Moreover, this effect of RSV can be enhanced by rapamycin (RAPA, an activator of autophagy) but partially reversed by 3-MA (an autophagy inhibitor). Further, we found that miR-18a-5p was significantly upregulated after RSV treatment in db/db mice. Overexpression of miR-18a-5p in podocytes resulted in significant inhibition of cleaved-caspase 3 protein, and increased the ratio of LC3-II/LC3-I. Dual luciferase report assay validated that Atactic telangiectasis mutation (ATM) was a target of miR-18a-5p. In podocytes, downregulation of cleaved caspase 3 and the enhanced ratio of protein LC3-II/LC3 I were detected in cells transfected with ATM siRNA. CONCLUSIONS: Role of miRNA 18a-5p in the regulation of autophagy via targeting ATM may represent a promising therapeutic target for preventing and attenuating diabetic nephropathy. PMID- 29164563 TI - Melatonin regulates traumatic optic neuropathy via targeting autophagy. AB - OBJECTIVE: Traumatic optic neuropathy (TON) usually refers to the indirect damage to the optical nerve, which can cause partial or complete blindness. Melatonin (MT) is a kind of indole hormone, and the retina is one of its natural sites of secretion in the human body. This study aims to explore MT in the retina and optic nerve injuries due to TON. MATERIALS AND METHODS: Sprague-Dawley (SD) rats were used for TON model in the study. After operation, rats were treated with MT or phosphate buffered saline (PBS) for 4, 7, 14, 21, and 28 days before sacrifice. The changes in retinal ganglion cells (RGCs) were observed via hematoxylin-eosin (HE) staining. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining was applied to observe apoptosis. Immunofluorescence staining was applied to detect caspase-3 and Western blot was used to detect LC3, cleaved caspase-3 and glyceraldehyde phosphate dehydrogenase (GAPDH). RESULTS: The number of RGCs in MT group increased compared to the model group. After MT treatment, the increased number of TUNEL positive cells and the increased number of caspase-3 positive cells in the retina of MT group was alleviated. Moreover, Western blot analysis revealed that the LC3-II/LC3-I ratio in the retinal tissue of MT group was further increased, while the increased cleaved caspase-3 protein level in the retina of MT group was alleviated compared to the model group. CONCLUSIONS: The results of this study revealed that MT therapy affects the apoptosis level of RGCs after TON through alleviating the increased caspase-3 protein level. Its mechanism may be that it further up regulates the autophagy level of RGCs after TON, ultimately inhibiting the apoptosis of RGCs after TON and playing a neuroprotective role. PMID- 29164564 TI - Role of silodosin in patients with LUTS/BPE non responding to medical treatment with tamsulosin: a prospective, open-label, pilot study. AB - OBJECTIVE: Lower urinary tract symptoms (LUTS) are frequently experienced in association with benign prostatic enlargement (BPE). Current guidelines state that alpha-blockers should be considered the first-line therapy of LUTS associated with BPE in most patients. However, in clinical practice treatment efficacy differs among individuals and, therefore, intra-class switch from one alpha-blocker to another, is frequently applied. In particular, switching to silodosin in clinical practice appears an intriguing therapeutic strategy due to the peculiar pharmacological properties of this molecule. This study evaluates the efficacy of silodosin in patients with LUTS associated with BPE who were not responders to tamsulosin. PATIENTS AND METHODS: This was a prospective, open label, single-center study. Patients treated with tamsulosin 0.4 mg once daily for BPE/LUTS for at least 12 months and not responding to therapy were switched to silodosin 8 mg once daily. The co-primary endpoints for evaluation of efficacy were the change in IPSS and quality of life (QoL) from the beginning of silodosin therapy to week 8. RESULTS: In total, 96 patients were enrolled. Mean International Prostatic Symptoms Score (IPSS) score at baseline was 20.0 +/- 4.4, and it significantly decreased to 18.6 +/- 4.5 at week 8 (mean change: -1.3 +/- 1.4; 95% CI -1.6 - -1.0; p < 0.03). A decrease was also observed for the two IPSS subscores; in particular, the IPSS subscore for storage symptoms was significantly reduced at week 8, compared with baseline. A significant improvement in QoL was observed after switching to silodosin, as compared with baseline (-0.8 +/- 1.0; 95% CI -1.0 - -0.6; p < 0.001). CONCLUSIONS: Silodosin improves IPSS symptoms score and QoL in patients with LUTS associated with BPE who were not-responders to tamsulosin therapy. PMID- 29164565 TI - A naturally-inspired, curcumin-based lecithin formulation (Meriva(r) formulated as the finished product Algocur(r)) alleviates the osteo-muscular pain conditions in rugby players. AB - OBJECTIVE: Curcumin is one of the most investigated phytochemical products because of its low toxicity and its broad spectrum of bioactivity, including anti inflammatory and analgesic properties. A new delivery form of curcumin, resorting to phosphatidylcholine (Meriva(r), formulated as the finished product Algocur(r)) has been developed to increase its bioavailability. In this study, we tested the efficacy and safety of a Meriva(r)-based product in rugby players suffering by different osteo-muscular pain conditions PATIENTS AND METHODS: In this pilot study, 50 male rugby players with osteo-muscular pain due to traumatic injuries, physical overload or acute episode of chronic pain were recruited and treated with conventional analgesic drugs (n = 25) or Meriva(r)-based product (n = 25) for a maximum of 10 days. The pain perception and the functio laesa were evaluated at baseline and after 1, 3, 6, 10 and 20 days from the initiation of the treatment protocol. Treatment tolerability, compliance, and adverse events were also reported. RESULTS: During the study, the analgesic effect decreased in both treated group compared to baseline, starting from the third day of treatment. Similarly, the impaired physical function evaluated after 3, 6, 10 and 20 days improved in Meriva(r)-based product treated group and in subjects treated with conventional analgesic drugs, compared to the baseline condition. The percentage of excellent adherence to treatment or tolerability was higher in the Meriva(r)-based product treated group. Only 1 (4%) subject treated with Meriva(r) based product experienced adverse events whereas 4 (16%) subjects treated with conventional analgesic drugs reported gastric pain as an adverse event. CONCLUSIONS: Despite the small sample size and the group heterogeneity, this study suggests that the naturally-derived, curcumin-based delivery form, Meriva(r) (formulated as the finished product Algocur(r)), could represent a promising safe, analgesic remedy in painful osteo-muscular conditions associated with intense, high impact, physical activities. PMID- 29164566 TI - Drug-related oral malodour (halitosis): a literature review. AB - Dry mouth (xerostomia), is a fairly common, well-researched condition, which is an indirect cause of oral malodour. This systematic literature review looked into another cause of bad breath: adverse drug reactions in the orofacial region causing halitosis. The study focused on extraoral halitosis, and its subdivisions, particularly blood borne halitosis in which malodourous compounds in the blood stream are carried to the lungs, passively diffused across the pulmonary alveolar membrane to enter the breath. An electronic search was conducted in various databases. Inclusion criteria were: editorials, case control studies, retrospective studies and randomized double-blind studies published in English between 1983 and March 2017. The search identified a total of 23 articles. According to these, drug-related halitosis may be caused by nine medications. Dimethyl sulfoxide, cysteamine and suplatast tosilate are metabolised to dimethyl sulfide, a malodourous compound that is stable in blood and is transported into the breath. Disulfiram is reduced to carbon disulfide, also a stable compound in blood. Nitric oxide reacts with foul-smelling volatile organosulfur compounds. The degradation of penicillamine raises the pH level, favouring the growth of gram-negative bacteria in the oral cavity producing halitosis. Chloral hydrate, phenothiazine, and paraldehyde could not be related to halitosis. The analysis showed that halitosis can be caused by medication but does not correlate to any specific disease or specific form of drug therapy. The pharmacological compounds identified as causes of halitosis are administered to treat a broad spectrum of diseases, or in therapeutic regimes. PMID- 29164567 TI - Role of MLL3 in regulating cardiac stem cells following cardiac cachexia. AB - OBJECTIVE: Cardiac cachexia is a form of serious illness that results with terminal stage of heart failure. It is associated with unreasonable weight loss and muscle loss with poor prognosis. Cardiac stem cells play a major role in repairing, damaged cardiac tissue and they are regulated by different mechanisms. In the present study, we investigated the role of MLL3 in regulating cardiac stem cells following cardiac cachexia. MATERIALS AND METHODS: To effectively study the cardiac cachexia, we established a Dahl rat model that produces symptoms similar to cachexia. Using histology, we analyzed the acute and chronic stage of cardiac cachexia. Immunohistochemistry and Western blotting were used to analyze the expression of MLL3 and Oct-4. RESULTS: The rat develops an acute form of cachexia after 2 months of fed with high-salt (8% NaCl) diet, which is characterized by inflammation and tissue damage that are observed through the histological sectioning. The chronic cardiac cachexia developed after 5 months of high-salt diet and histologically it shows tissue loss. At the molecular level the stem cell marker, Oct-4, shows elevated expression at acute stage, but down regulated latter in the chronic stage of cardiac cachexia. Also, MLL3 shows a similar pattern of upregulated expression in acute stage of cachexia, but significantly down regulated in the chronic stage of cachexia that implies their role in regulating the cardiac stem cell and their proliferation. CONCLUSIONS: Our results show that the cardiac stem cells in association with MLL3 support in maintaining homeostatic after initial pathological stages of cachexia but not in the chronic stage of cachexia. PMID- 29164568 TI - Cystic hygroma of the neck: single center experience and literature review. AB - OBJECTIVE: Malformations of the lymphatic system are recognized as benign congenital tumors that affect infant and children in the perinatal era. In children, these abnormalities usually found in the neck and the axillary region, but they can present in other parts of the body such as mediastinum, pelvis, retroperitoneum as well as in solid organs (e.g., adrenal glands, pancreas, stomach). Our aim is to report our experience on cystic hygromas via two cases and review the literature. MATERIALS AND METHODS: Herein we present two cases of cystic hygroma, the first of female children and the second of a female adult patient respectively. Both of these patients underwent surgical excision of the masses. RESULTS: After the procedure, both patients have recovered well, and no recurrence of the lesion has been noted during the follow-up period. CONCLUSIONS: Surgical treatment remains the gold-standard treatment for these tumors, while other modalities have been used with mixed results. PMID- 29164569 TI - Correlation between intestinal flora and serum inflammatory factors in patients with Crohn's disease. AB - OBJECTIVE: We investigated the correlation between intestinal flora and serum inflammatory factors in patients with Crohn's disease. PATIENTS AND METHODS: From February 2014 to June 2016, 132 patients with Crohn's were enrolled in this study. There were 84 males and 48 females. The age range was from 28 to 72 years. We had 62 patients in active stage (the activity group) and 70 patients in remission stage (the remission group). We also enrolled 71 healthy cases in the control group. The expression levels of serum inflammatory factors including IL 6, IL-17, IL-22, and IL-33 were measured using ELISA. Fresh feces samples were diluted and, after cultivating the bacteria for 48 hours at 37 degrees C, the number of colonies was counted. The number of flora per gram of feces (CFU/g) was determined. RESULTS: The number of Escherichia coli and Enterococcus sp. in feces was significantly higher in the activity group compared to that of the control group and the remission group. The levels IL-1, IL-17, L-22, and IL-33 in the activity group were significantly higher than those of other groups. The number of Escherichia coli and Enterococcus sp. was positively correlated with the levels of IL-6, IL-17, IL-22, and IL-33, while the number of Bifidobacteria and Bacillus lactic acid was negatively correlated with the levels of IL-6, IL-17, IL 22, and IL-33. CONCLUSIONS: The number of conditional pathogenic bacteria in the activity group, was higher than other groups, while the number of probiotics bacteria decreased distinctly. We concluded that monitoring the changes in distribution and composition of intestinal flora as well as the levels of blood inflammatory factors could play a significant role in the treatment process of Crohn's disease. PMID- 29164570 TI - Von Willebrand factor and ADAMTS13 plasma in older patients with high CHA2DS2 VASc Score with and without atrial fibrillation. AB - OBJECTIVE: Ischemic stroke risk rises with the increasing cardiovascular risk factors in patients with and without AF. How atrial fibrillation (AF) incrementally contributes to the risk for ischemic stroke with increasing age and multiple cardiovascular risk factors is unclear. Von Willebrand factor (vWF) is a biomarker of endothelial dysfunction. PATIENTS AND METHODS: We suggested that in older patients with high CHA2DS2-VASc Score, the vWF and ADAMTS13 would be comparable between patients with and without AF. Consecutive 196 old patients (>= 60 years, 45.9% with concomitant AF) with and without non-valve atrial fibrillation were recruited from April 2014 to April 2016. Data on baseline clinical characteristics were recorded at study entry. Plasma ADAMTS13 levels and plasma vWF levels were determined. Statistical analyses were performed using SPSS19.0 statistical software package. RESULTS: There were significant correlations between plasma vWf levels, ADMATS13 and CHA2DS2- VASc Score in older patients with and without AF (with AF: Spearman, r = 0.215, p < 0.05; without AF: Spearman, r = 0.197, p < 0.05). Results of research indices in our older patients were as follows: vWf 180. 79 +/- 28.27 IU/dL in AF and 153.5 +/- 35.54 in non AF with p < 0.001, ADAMTS13 431.5 +/- 160.33 IU/dL in AF and 536.7 +/- 169.96 in non AF with p < 0.05. Results of research indices in our older patients (>= 75 year) were as follows: vWf 181.4 +/- 22.04 in AF and 174.1 +/- 29.45 in non AF, and ADMATS-13 412.9 +/- 130.76 IU/dL in AF and 451.7 +/- 153.18 in non AF. There were no differences (p > 0.05). CHA2DS2-VASc Score can predict stroke risk in old patients without atrial fibrillation. At high CHA2DS2-VASc Score, the levels of vWF and ADAMTS13 have difference in old patients (60-74) with and without AF, but in such older patients, age (>= 75 year), there were no differences. In elderly patients, atrial fibrillation has a limited effect on VWF, and the age is an important factor affecting the endothelial function. CONCLUSIONS: For elderly patients with a high incidence rate of stroke and thrombosis, we should pay more attention to the thrombotic events, and atrial fibrillation can be used as one of the risk factors involved and improving the risk scoring system of stroke. PMID- 29164571 TI - Assessment of mismatch negativity and P300 response in patients with disorders of consciousness. AB - OBJECTIVE: To evaluate changes in mismatch negativity (MMN) and P300 response in vegetative state (VS) and minimally conscious state (MCS) patients before and after treatment, and their value for prediction of prognosis. PATIENTS AND METHODS: Event-related potentials (ERPs), performed on 11 patients classified as VS (n = 6) or MCS (n = 5), and five healthy participants (i.e., control group). We performed a six months telephone follow-up to monitor changes in consciousness recovery. RESULTS: Comparison of the three groups showed significantly higher MMN latency elicited by salient stimuli and P300 elicited by the subject's own name for the VS group, as well as significant difference in amplitudes of MMN elicited by frequent stimuli and P300 elicited by other first names for this group. The source of MMN and P300 responses was the frontal lobe for the control group, and temporal lobe for the VS and MCS groups. CONCLUSIONS: The sudden increase in MMN amplitude and latency shortening may indicate an improvement in the state of consciousness. Neurophysiological evaluations suggest that patients with vegetative state (VS) and minimally conscious state (MCS) may preserve patterns of higher-order cerebral processing similar to those observed in conscious patients. PMID- 29164572 TI - Expression of GLUT-1 in nasopharyngeal carcinoma and its clinical significance. AB - OBJECTIVE: To investigate the relationship between the expression of glucose transporter-1 (GLUT-1) and the clinicopathological features and prognosis of patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Sixty-three patients with NPC (the NPC group) and 24 patients with chronic nasopharyngitis (the control group) who were treated between December 2014 and February 2016 were selected for this study. Pathological nasopharyngeal tissues were collected from patients. The expression of GLUT-1 was detected by immunohistochemistry. The expression of GLUT-1 was correlated with clinicopathological features and survival time. RESULTS: The positive GLUT-1 expression rate in the NPC group was 58.73% (37/63), which was significantly higher than in the control group (29.17%, 7/24) (p<0.01). The positive GLUT-1 expression rate was significantly correlated with clinical stage, lymph node metastasis, and Epstein-Barr (EB) virus infection (p<0.05). The 3-year survival rate of GLUT-1-positive NPC patients was 75.00% and was significantly lower than that of GLUT-1-negative NPC patients (88.89%) (p<0.05). CONCLUSIONS: GLUT-1 was highly expressed in the nasopharyngeal tissues of patients with NPC, and its expression was associated with clinical stage, lymph node metastasis, and EB virus infection. PMID- 29164573 TI - Role of perfusion CT in the evaluation of metastatic nodal tumor response after radiochemotherapy in head and neck cancer: preliminary findings. AB - OBJECTIVE: To assess changes of CT perfusion parameters (DeltaPCTp) of cervical lymph node metastases from head and neck cancer (HNC) before and after radiochemotherapy (RT-CT) and their association with nodal tumor persistence. PATIENTS AND METHODS: Eligibility criteria included HNC (Stage III-IV) candidates for RT-CT. Patients underwent perfusion CT (PCT) at baseline 3 weeks and 3 months after RT-CT. Blood volume (BV), blood flow (BF), mean transit time (MTT) and permeability surface (PS) were calculated. PET/CT examination was also performed at baseline and 3 months after treatment for metabolic assessment. RESULTS: Between July 2012 and May 2016, 27 patients were evaluated. Overall, only 3 patients (11%) experienced tumor persistence in the largest metastatic lymph node. A significant reduction of all PCTp values (p<0.0001), except MTT (from 6.3 to 5.7 s; p=0.089), was observed at 3 weeks post-RT-CT compared to baseline. All PCTp values including MTT were significantly lower at 3-month follow-up compared to baseline (p<0.05). Moreover, a statistically significant association was observed between nodal tumor persistence and high BF values (p=0.045) at 3 months after treatment that did not occur for the other parameters. CONCLUSIONS: Our preliminary findings show that all PCTp except MTT are significantly reduced after RT-CT. High BF values at 3 months post-RT-CT are predictive of nodal tumor persistence. PMID- 29164575 TI - Long non-coding RNA XLOC_010235 correlates with poor prognosis and promotes tumorigenesis of hepatocellular carcinoma. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. Long non-coding RNAs (lncRNAs) are novel proposed non coding RNAs, and play critical roles in tumorigenesis. However, the clinical significance, biological role and molecular mechanism of ncRNAs in HCC still remain largely elusive. The aim of this study was to uncover the clinical value and biological role of XLOC_010235 (XLOC), which has been demonstrated as an oncogene in gastric cancer, in HCC. PATIENTS AND METHODS: Quantitative Real-time polymerase chain reaction (QRT-PCR) was conducted to measure the level of XLOC in HCC tissues and cell lines. The relationship between XLOC expression and clinicopathological features of HCC patients was analyzed. Then loss-of-function assays were conducted to determine the biological effect of XLOC in HCC cells. RESULTS: Our investigations revealed that XLOC was increased in HCC tissues and cell lines, and high level of XLOC was significantly correlated with poor prognosis. Additionally, silenced XLOC significantly inhibited cell proliferation, induced cell apoptosis and facilitated cell migration of HCC in vitro. CONCLUSIONS: Our findings advance our understanding of the role of XLOC as an oncogene in HCC, which may help in the development of new therapeutics. PMID- 29164574 TI - Mechanism of As2O3 induces apoptosis of glioma U87 cells. AB - OBJECTIVE: To investigate the mechanism of arsenic trioxide (As2O3)-induced apoptosis of glioma cells. MATERIALS AND METHODS: U87 cells were treated by different concentrations of As2O3 (8 MUmol/L, 6 MUmol/L, 4 MUmol/L, 2 MUmol/L, 1 MUmol/L and 0.5 MUmol/L) for 24 h, 48 h and 72 h, respectively. Cell viability was detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the appropriate dosage and time were screened. Transferase mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) was used to stain cells, followed by an investigation on the apoptosis of cells. In the study of molecular mechanism, the expression of p53 in the cells was determined by immunofluorescence, and then apoptosis-related factors, Fas, FasL and Bax, were tested using Real-time polymerase chain reaction (RT-PCR). Finally, the effect of As2O3 on apoptosis-related proteins, caspase-3 and caspase-9, was investigated by Western blotting. RESULTS: As2O3 could significantly inhibit proliferation of U87 cells, and the result of TUNEL staining displayed As2O3 had the function of inducing apoptosis. Immunofluorescence results demonstrated that p53 was highly expressed in glioma cells, which was reduced after drug administration. The results of detection of apoptosis factors using RT-PCR revealed that mRNA expressions of Fas, FasL and Bax in the glioma cells were distinctly higher than those in the As2O3 group. The result of Western blotting indicated that caspase-3 and caspase-9 proteins were highly expressed in glioma cells. Analysis of variance showed that the difference between the control group and the As2O3 group was statistically significant (p<0.01). CONCLUSIONS: As2O3 can inhibit proliferation of glioma cells and induce its apoptosis, which may be correlated with down-regulation of expressions of apoptosis-related factors, Fas, FasL and Bax, and apoptosis-related proteins, p53, caspase-3 and caspase-9. PMID- 29164576 TI - Potentiation of treatment efficacy against colon cancer of dopamine via elevating KLF2 expression in tumor vascular endothelial cells. AB - OBJECTIVE: To investigate the anti-tumor effect and potential mechanism of dopamine combined with 5-FU in colon cancer. MATERIALS AND METHODS: Babl/c F1 generation male mice (N = 60) were inoculated with mouse C26 colon cancer cells below the pit to construct colon cancer model. Tumor-bearing mice were then divided into 4 groups (N = 8 each): model control group, dopamine group, 5-FU group and dopamine combined with 5-FU group. Dopamine (100 mg/kg/d) was intraperitoneally injected into mice. The tumor-suppressing rate was calculated. Serum VEGF concentration was gained. Tumor tissues were subjected to HE staining. KLF2 expression was determined by immunohistochemical (IHC) staining. In vitro cultured C26 cells which treated with dopamine and cell apoptosis were analyzed by flow cytometry. RESULTS: Compared with model control group, all treatment groups showed significantly decreased tumor weight and volume (p < 0.01), increased tumor necrosis (p < 0.05), reduced serum VEGF concentration (p < 0.05), and enhanced KLF2 expression in microvessels (p < 0.05). Combined treatment in terms of dopamine combined with 5-FU had the most pronounced effect compared with both dopamine and 5-FU treatment groups individually. Dopamine single t 5-FU and 5-FU groups showed a similar proportion of viable C26 cells (p > 0.05). CONCLUSIONS: Dopamine exerts anti-tumor effects by modulating tumor vascular homeostasis through the KLF2 signaling pathway, and potentiates the treatment efficacy of anti-tumor drug 5-FU. Our study discovered clinical significance concerning the novelty of therapeutic strategy against colon cancer. PMID- 29164577 TI - MiR-150 alleviates EMT and cell invasion of colorectal cancer through targeting Gli1. AB - OBJECTIVE: Epithelial-mesenchymal transition (EMT) is related to colorectal cancer invasion and metastasis. Glioma-associated oncogene homolog 1 (Gli1) abnormal expression is associated with EMT, invasion, and metastasis in various cancers. MiR-150 is found downregulated in colorectal cancer pathogenesis. Bioinformatics analysis shows the complementary targeted relationship between miR 150 and the 3'-UTR of Gli1 mRNA. This study explores the role of miR-150 in regulating Gli1 expression, colorectal cancer cell EMT, and invasion. MATERIALS AND METHODS: Dual luciferase assay confirmed the targeted relationship between miR-150 and Gli1 predicted by bioinformatics analysis. MiR-150 and Gli1 expressions were compared in NCM460, SW480, and SW620 cells. Cell colony formation and invasion were tested in SW480 and SW620 cells. Anip973 and AGYZ83-a cells were treated by 10 ng/mL TGF-beta1 to detect miR-150 and Gli1 expressions. SW620 cells were cultured in vitro and divided into five groups, including miR NC, miR-150 mimic, si-NC, si-Gli1, and miR-150 mimic + si-Gli1 groups. RESULTS: MiR-150 specifically inhibited Gli1 expression. The level of miR-150 was significantly downregulated, while Gli1 was elevated in SW480 and SW620 cells compared with that in NCM460 cells. SW620 exhibited markedly stronger invasive and colony formation abilities than SW480. The level of miR-150 was apparently reduced, whereas Gli1 was increased in SW620 than that in SW480 cells after the treatment of TGFbeta1. MiR-150 mimic and/or si-Gli1 transfection markedly reduced Gli1 and Snail levels, upregulated E-cadherin expression, and attenuated cell colony formation and invasion. CONCLUSIONS: Downregulation of miR-150 and elevation of Gli1 promote the development and invasion of colorectal cancer cell EMT. MiR-150 attenuated the progression of colorectal cancer cell EMT via inhibiting Gli1. PMID- 29164578 TI - miR-590-3p promotes colon cancer cell proliferation via Wnt/beta-catenin signaling pathway by inhibiting WIF1 and DKK1. AB - OBJECTIVE: Colon cancer is one of the most common and deadly types of gastrointestinal tumor. Despite progressive treatments, the patient prognosis has not been improved effectively. MATERIALS AND METHODS: Expression of miRNA and mRNA were tested by Realtime PCR. Cell cycle was detected by flow cytometry. Cell viability was evaluated by MTT assay. Cell spheroid formation was determined by colony assay. Wnt signaling pathway activity was evaluated by TOP/FOP ratio. Protein expression was tested using Western blot. beta-catenin binding ability was detected by ChIP assay. miRNA target gene was confirmed by luciferase assay. RESULTS: miR-590-3p was found to be overexpressed in both glioma tissues and cell lines. miR-590-3p is upregulated in colon cancer cells and tissues compared to non-tumorigenic colon cells and normal colon tissues. miR-590-3p positively regulated cell proliferation, spheroid formation, and cell cycle in LS174T cells. Conversely, inhibition of miR-590-3p reduced these effects. We confirmed that WIF1 and DKK1 are targets of miR-590-3p. Overexpression of miR-590-3p promoted TOP flash luciferase activity, enhanced nuclear beta-catenin levels and increased target genes expression of Wnt signaling pathway. The results indicated that miR 590-3p activates the Wnt/beta-catenin signaling pathway. CONCLUSIONS: We demonstrate that miR-590-3p regulates colon cancer progression via WIF1 and DKK1, which suggests that miR-590-3p may be a promising candidate for therapeutic applications in colon cancer treatment. PMID- 29164579 TI - MiR-181a promotes epithelial to mesenchymal transition of prostate cancer cells by targeting TGIF2. AB - OBJECTIVE: Prostate cancer is the most commonly diagnosed cancer, and metastatic prostate cancer often leads to poor outcomes for patients. During the metastasis processes, cancer cells acquire a migratory and invasive phenotype. Epithelial to mesenchymal transition (EMT) has been implicated in multiple processes of prostate cancer development including migration, chemoresistance, and carcinogenesis. PATIENTS AND METHODS: Expressions of miR-181a in prostate tumor samples and cancer cells were measured by qRT-PCR. Epithelial or mesenchymal markers were detected by Western blot. Nuclear translocation of Smad 2/3 was measured by immunostaining of prostate cancer cells. RESULTS: In this study, we report an oncogenic role of microRNA-181a in prostate cancer cells and patients. MiR-181a is upregulated in metastatic prostate tumor samples compared with primary prostate tumors. Interestingly, we found that overexpression of miR-181a promotes prostate cancer cell migration and invasion. Moreover, we observed that overexpression of miR-181a contributes to an epithelial to mesenchymal transition phenotype in prostate cancer cells: the epithelial marker, E-cadherin was downregulated, and mesenchymal markers, N-cadherin, vimentin, and snail were upregulated. Consistently, the phosphorylation of Smad 2/3 and the nuclear localization of Smad 2/3 were increased by miR-181a expression. We identified that TGIF2 - a repressor of the Smad pathway - is a direct target of miR-181a in prostate cancer cells. Importantly, restoration of TGIF2 in miR-181a overexpressing prostate cancer cells inhibited the Smad pathway and EMT processes. CONCLUSIONS: This research identifies a molecular mechanism for microRNA-mediated cancer metastasis and improvement novel therapeutic avenue for metastatic prostate cancer patient treatments. PMID- 29164580 TI - miR-564 inhibited metastasis and proliferation of prostate cancer by targeting MLLT3. AB - OBJECTIVE: MiR-564 has been discovered to be abnormally expressed in human malignancy. Two recent studies suggested that miR-564 plays a role in tumor inhibition in both lung and breast cancer. However, no evidence reported the mechanism and function of miR-564 in prostate cancer (PCa). PATIENTS AND METHODS: The PCa tissues and their adjacent normal tissues were collected from 50 PCa patients. Expressions of miR-564 in tissues and cells were evaluated with RT qPCR. The MTT [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide] assay, flow cytometry and Western-blot analysis, were applied to detect the proliferation, cell cycle progression and the protein expression of PCa cell lines (PC-3 and DU-145). Migration and invasion of PCa cells were analyzed by Transwell assays. Furthermore, the correlation between miR-564 and MLLT3 was assessed by luciferase reporter assay. Also, the PCa cells were transfected with miR-564 mimics control and inhibitor. RESULTS: In our present research, miR-564 was found dysregulated in PCa cells and to act as a suppressor in PCa cell proliferation, progression of cell cycle, cell invasion and migration. MLLT3 (also known as Af9) is a proto-oncogene, which has first reported in leukemia, and the regulation of its expression remains incompletely elucidated. Also, it is first reported in our study, suggesting that MLLT3 is a direct target of miR-564. The results also showed a significant negative correlation with miR-564 in PCa cells. Furthermore, up-regulation of MLLT3 attenuates the effects of miR-564 on the ability of PCa cells. CONCLUSIONS: Our research demonstrated the suppressor function of miR-564 in PCa, revealing restoration of miR-564 as a potential therapeutic strategy for the treatment of PCa. PMID- 29164581 TI - MicroRNA-30c suppressed giant-cell tumor of bone cell metastasis and growth via targeting HOXA1. AB - OBJECTIVE: To dissect the functioning mode of miR-30c on giant cell tumor of bone cell metastasis and growth and provide therapeutic targets for giant cell tumor of bone. PATIENTS AND METHODS: By quantitative Real-time polymerase chain reaction (qRT-PCR), miR-30c expression level in 62 pairs of giant cell tumor of bone cells tissue samples and five breast cancer-derived cell lines. Using miR 30c mimics and inhibitors, we analyzed the effects of miR-30c over-expression and knockdown on cell proliferation, invasion, and migration. Dual-luciferase activity assay was recruited to examine the potential target gene HOXA1, which predicted by several databases. Protein level was studied using Western blot. RESULTS: MiR-30c expressed significantly lower in giant cell tumor of bone tissue samples and cell lines. Over-expression miR-30c in giant cell tumor of bone cells decreased the cell proliferation, invasion, and migration abilities while down regulation miR-30c in giant cell tumor of bone cells increased these abilities oppositely. Dual-luciferase and Western blot confirmed HOXA1 as a target gene of miR-30c. Furthermore, up-regulation of HOXA1 reserved the suppressive effect of miR-30c over-expression on cell growth and progression. CONCLUSIONS: miR-30c could suppress giant cell tumor of bone cell proliferation and progression via HOXA1, which might provide a new target for giant cell tumor of bone diagnosis and therapy. PMID- 29164582 TI - miR-15a-5p suppresses endometrial cancer cell growth via Wnt/beta-catenin signaling pathway by inhibiting WNT3A. AB - OBJECTIVE: Endometrial cancer is one of the three most common types of gynecologic cancer. The global incidence has increased in recent years. microRNAs (miRNAs) regulate numerous biological processes by binding to the 3'UTR of target mRNA to down-regulate protein synthesis. PATIENTS AND METHODS: Endometrial cancer patients received surgeries in our hospital were enrolled. MiR-15a-5p mimic or miR-15a-5p inhibitor was transfected into HEC-1-A cells by lentivirus. Colony formation assay was applied for detecting cell proliferation. Real-time PCR was performed to test miRNA and mRNA expression. Western blot was used to detect protein level. ChIP was adopted to test transcription activation. TOP/FOP was tested to determine Wnt signaling pathway activity. A dual-luciferase reporter assay was used to confirm miRNA target. RESULTS: miR-15a-5p was decreased in endometrial cancer cells and tissues. miR-15a-5p overexpression restrained HEC-1 A cell proliferation and stemness. miR-15a-5p mimic transfection reduced mRNA and protein levels of the proteins which are related to cell proliferation and Wnt signaling pathway. MiR-15a-5p targeted a putative binding site in the 3'-UTR of Wnt3a gene, thus regulating Wnt signaling pathway. miR-15a-5p overexpression decreased Wnt3a protein expression. Wnt3a presented significant negative correlation with the miR-15a-5p level in endometrial cancer patients. CONCLUSIONS: miR-15a-5p is a regulator of endometrial cancer cell proliferation by directly targeting Wnt3a to block Wnt signaling pathway. PMID- 29164583 TI - Application of dynamic CT to identify lung cancer, pulmonary tuberculosis, and pulmonary inflammatory pseudotumor. AB - OBJECTIVE: To determine the value of dynamic enhanced computed tomography (CT) scanning in diagnosing lung cancer, pulmonary tuberculosis, and pulmonary inflammatory pseudotumor. PATIENTS AND METHODS: We recruited 30 patients with pulmonary tuberculoma, 38 with lung cancer, and 16 with pulmonary inflammatory pseudotumor. All patients received CT scanning, dynamic enhanced CT scanning for 20, 30, 45, 60, 75, 90, and 120 s, and scanning for 3, 5, 8, 12, and 15 min. Then, we compared several parameters to determine which ones help with each diagnosis. RESULTS: The time-density curve for patients with pulmonary tuberculoma was low and flat, and significantly different from lung cancer and inflammatory pseudotumor. The 15 min clearance value and the clearance value for lung cancer and inflammatory pseudotumor were significantly different. The type II time-density curve was common in lung cancer group, whereas the type III time density curve was common in inflammatory pseudotumor. CONCLUSIONS: Dynamic enhanced CT scanning demonstrated the ability to differentiate lung cancer, pulmonary tuberculosis, and pulmonary inflammatory pseudotumor, indicating its diagnostic value. PMID- 29164584 TI - Cardiac magnetic resonance in systemic sclerosis patients with cardiac symptoms. AB - OBJECTIVE: Systemic sclerosis (SSc) is characterized by widespread vascular lesions and skin and internal organs fibrosis, including the heart; all cardiac layers, endocardium, myocardium, and pericardium, may be involved. We report the relevance of cardiac MRI findings in scleroderma patients with cardiac symptoms. PATIENTS AND METHODS: 50 patients, all fulfilling the ACR SSc criteria (19 with limited and 31 with diffused skin involvement) were evaluated using a 1.5T MR scanner. Images were acquired before and after contrast medium administration; the exams were considered positive with one or more of these findings: enlarged volumes, reduced EF, regional kinetic anomalies, edema, DE or pericardial effusion. RESULTS: 40 patients (80%) had one or more cardiac abnormalities: 5 patients had myocardial edema; 2 an increased interventricular septum thickness; 22 dilated ventricles or reduced EF; 12 an abnormal regional ventricular motion (2 of these with akinetic segments); 17 a delayed enhancement with different patterns, all without coronary distribution; 22 a pericardial effusion CONCLUSIONS: Pathologic findings were documented in 80% of the cases confirming a high occurrence of abnormal MR data. Myocardial involvement in systemic sclerosis can be assumed by the presence of multiple pathologic MRI findings. CMR seems to be a valuable tool to identify and assess the presence of cardiac involvement. PMID- 29164585 TI - Expression and clinical significance of miR-181a and miR-203 in systemic lupus erythematosus patients. AB - OBJECTIVE: MiR-181a plays a critical role in modulating T cell and B cell differentiation, as well as immune response. Its abnormal expression probably participates in the pathogenesis of systemic lupus erythematosus (SLE). MiR-203 is involved in regulating Toll-like receptor and inducing immune tolerance. Abnormal expression or function of miR-203 is related to multiple auto-immune diseases but its role in SLE remains unclear. This study, thus, investigated the serum level of miR-181a and miR-203, to analyze their roles in diagnosing and evaluating SLE. PATIENTS AND METHODS: SLE patients were recruited from our hospital, and divided into non-active and active SLE based on disease activity index, along with healthy individuals. qRT-PCR was used to quantify the serum miR 181a and miR-203 expression, and their correlation with clinical features. ROC was used to evaluate the diagnostic value on SLE, while survival curves were compared to show progression-free survival (PFS) between populations with high and low expression. RESULTS: SLE patients had significantly higher serum levels of miR-181a and lower miR-203, both of which were correlated with SLE activity. Expression levels of miR-181a and miR-203 were correlated with erythrocyte sedimentation rate, C reactive protein, anti-dsDNA antibody, complements, and SLEDAI score. Their expression levels had certain values in the differential diagnosis for active SLE (AUC=0.885 and 0.843). PFS in miR-181a high-expression individuals was lower than that in the low-miR-181 group (chi2=7.474, p=0.029). Whilst, miR-203 high-expression SLE patients had higher PFS than low-expression group (chi2=4.367, p=0.037). CONCLUSIONS: SLE patients had higher miR-181a and lower miR-203 expression, which thus may have critical implications in disease diagnosis and evaluation. PMID- 29164586 TI - Functions of microRNAs in osteoporosis. AB - Osteoporosis (OP) is a kind of disease with a 25% incidence, characterized by the bone mass loss, bone microstructure damage, increased bone fragility, and easy fracture. miRNA plays an important regulatory role in the process of bone remodeling, especially in the regulation of differentiation and function of osteoblasts and osteoclasts, and the development and progression of OP and other bone diseases. In the future, it is expected to delay the bone loss and promote the bone remodeling via the overexpression or inhibition of specific miRNAs in specific tissues, thereby treating OP. PMID- 29164587 TI - MiR-214 inhibits human mesenchymal stem cells differentiating into osteoblasts through targeting beta-catenin. AB - OBJECTIVE: Wnt/beta-catenin signaling pathway promotes osteoblasts (OBs) differentiation through up-regulating osteoblast-specific gene runt-related transcription factor 2 (RUNX2) expression. It was showed that microRNA-214 (miR 214) was abnormally increased in bone tissue from osteoporosis patients, suggesting its role in osteogenesis. Bioinformatics analysis revealed the complementary binding site between miR-214 and 3'-UTR of beta-catenin. This study investigated the effects of miR-214 in regulating beta-catenin expression and bone marrow mesenchymal stem cells (BMSCs) differentiating into OB. MATERIALS AND METHODS: BMSCs were induced to differentiate to OB in a specific medium. MiR-214, beta-catenin, and RUNX2 expressions were detected. The regulatory relationship between miR-214 and beta-catenin was confirmed by dual luciferase reporter gene assay. BMSCs were divided into five groups, including agomir-control, miR-214 agomir, pGPU6-normal control group (pGPU6-NC), pGPU6-beta-catenin, and miR-214 agomir + pGPU6-beta-catenin groups. beta-catenin and RUNX2 levels were tested after 21 days' induction. OB differentiation degree was evaluated by alizarin red staining. RESULTS: MiR-214 was down-regulated, while beta-catenin and RUNX2 were enhanced in the process of BMSCs differentiating into OBs. MiR-214 agomir and/or beta-catenin shRNA pGPU6-beta-catenin transfection significantly reduced beta catenin expression, declined RUNX2 level, and attenuated OB differentiation in BMSCs. CONCLUSIONS: Wnt/beta-catenin signaling pathway was enhanced, while the miR-214 level was decreased in the process of BMSCs differentiating into OBs. Up regulation of miR-214 inhibited the OB differentiation of BMSCs through targeted suppressing beta-catenin expression and attenuating Wnt/beta-catenin signaling pathway activity. PMID- 29164588 TI - lncRNA HOXA11-AS is involved in fracture healing through regulating mir-124-3p. AB - OBJECTIVE: Long noncoding RNAs (lncRNAs) have been reported to participate in many diseases. Fracture healing is one of these ordinary diseases. This study aims to identify how lncRNA HOXA11-AS affects the progression of fracture healing. MATERIALS AND METHODS: RT-qPCR was performed to detect the level of HOXA11-AS. Moreover, function assays including cell growth assay and cell apoptosis assay were performed to explore how HOXA11-AS functions in fracture healing. Furthermore, the interaction between HOXA11-AS and mir-124-3p was studied by RT-qPCR, luciferase assay, and RNA immunoprecipitation assay. Rescue experiments were performed to verify the interaction between HOXA11-AS and mir 124-3p in vitro. RESULTS: In the research, function assays revealed that HOXA11 AS overexpression inhibited cell proliferation, while HOXA11-AS knockdown promoted cell proliferation in vitro. Moreover, HOXA11-AS overexpression promoted cell apoptosis, while HOXA11-AS knockdown inhibited cell apoptosis in vitro. Furthermore, mechanism assays demonstrated that HOXA11-AS acts a ceRNA via sponging mir-124-3p. Rescue assay demonstrated that HOXA11-AS suppressed cell proliferation and promoted cell apoptosis via targeting mir-124-3p. CONCLUSIONS: These results indicate that HOXA11-AS could inhibit cell proliferation and promote cell apoptosis of osteoblast via sponging mir-124-3p, which may offer a new vision for interpreting the mechanism of fracture healing. PMID- 29164589 TI - MiR-214 protects MC3T3-E1 osteoblasts against H2O2-induced apoptosis by suppressing oxidative stress and targeting ATF4. AB - OBJECTIVE: Fragility fracture is one of the common complications of osteoporosis. Elevated oxidative stress-induced apoptosis is thought to be one of the unfavorable factors to osteoblastic dysfunction, which increased the risk of bone fracture. However, the molecular mechanisms for oxidative stress-induced osteoblast cells apoptosis still need to be elucidated. This study aims to investigate the protective function of miR-214 in H2O2-induced apoptosis of MC3T3 E1 osteoblasts. MATERIALS AND METHODS: MC3T3-E1 cells were treated with 400 MUM H2O2. Flow cytometry was adopted to detect the apoptosis rate; malondialdehyde (MDA) and glutathione peroxidase (Gpx) levels were used to determine the reactive oxygen species (ROS) level. Reverse transcription-polymerase chain reaction (RT PCR) was employed to test the expression level of miR-214 and ATF4. After transfected MC3T3-E1 cells with miR-214 mimics and inhibitor, RT-PCR was used to detect activating transcription factor 4 (ATF4) expression level. RESULTS: H2O2 treatment increased ROS induced intracellular oxidative injury. Flow cytometry showed that 400 MUM H2O2 induced the apoptosis of MC3T3-E1 cells. Moreover, RT PCR showed decreased expression level of MiR-214. Furthermore, the apoptosis induced by high ROS level was reversed by increased miR-214 expression level. The regulatory ability of MiR-214 to apoptosis is by regulating ATF4 expression. CONCLUSIONS: miR-214 plays a protective role in H2O2 induced MC3T3 osteoblasts apoptosis and its protective effect is proceeded by regulating ROS level and ATF4 expression level. PMID- 29164590 TI - The effect of abdominal obesity in patients with polycystic ovary syndrome on metabolic parameters. AB - OBJECTIVE: Polycystic ovarian syndrome and obesity contribute to the metabolic complications for women of reproductive age. The aim of present study was to analyze the effect of abdominal obesity expressed using waist/hip ratio (WHR) in patients with polycystic ovary syndrome on metabolic parameters. PATIENTS AND METHODS: The study included 659 women with PCOS with WHR <0.8 and >=0.8 aged between 17 and 44 years. Patients were tested for follicular stimulating hormone, luteinizing hormone, 17-beta-estradiol, dehydroepiandrosterone sulfate, androstenedione, sex hormone binding globulin, and total lipid profile during the follicular phase (within 3 and 5 days of their menstrual cycle). Also, fasting glucose and insulin concentrations, and after, oral-glucose glucose administration, were determinate. De Ritis and Castelli index I and II were calculated. RESULTS: Women with WHR >=0.8 had higher concentration of glucose and insulin (both fasting and after 120 min of oral administration of 75 g glucose), as well as HOMA-IR value, than women with WHR value < 0.8. Also, abdominal obesity disorders hormonal parameters. Higher free androgen index and lower concentration of sex hormone binding globulin and dehydroepiandrosterone sulfate were found in female with WHR >= 0.8. Follicular stimulating hormone, luteinizing hormone, androstenedione, and 17-beta-estradiol, were on similar level in both groups. Elevation in triglycerides, total cholesterol, and low-density lipoprotein levels, as well as decrease in high density lipoprotein level in serum of women with WHR value >= 0.8, were found when compared to women with WHR < 0.8. A statistically significant correlation was found between WHR value and glucose, insulin, sex hormone binding globulin, free androgen index and lipid profile parameters. CONCLUSIONS: Abdominal obesity causes additional disorders in metabolic and hormonal parameters in PCOS women, which confirmed changes in analyzed parameters between PCOS women with WHR < 0.8 and WHR >= 0.8 and statistically significant correlations between WHR value and analyzed parameters. PMID- 29164591 TI - Trend of decreasing length of cervical cone excision during the last 20 years. AB - OBJECTIVE: The aim of the present investigation was to evaluate the cervical conizations performed in the last 20 years in a single institution, with a particular interest in analyzing the trend of the length of cone excisions. PATIENTS AND METHODS: A retrospective cohort study of women who underwent a CO2 laser cervical conization between January 1996 and December 2015. Cytological abnormalities on referral pap smear, colposcopic findings and pertinent clinical and socio-demographic characteristics of each woman were collected. In particular, the length of cone specimen was evaluated, taking into account all the factors potentially influencing the length of excision. RESULTS: A total of 1270 women who underwent cervical conization from January 1996 to December 2015 were included in the analysis. A mean cone length of 15.1 +/- 5.7 mm was reported, and we observed a significant decrease in the length of cone excisions over the whole study period. Age (rpartial = 0.1543, p < 0.0001), see & treat procedure (rpartial = -0.1945, p < 0.0001) and grade II colposcopic findings (rpartial = 0.1540, p < 0.0001) were significantly associated with the length of cone excision on multivariate analysis. CONCLUSIONS: In the last 20 years, a significant decrease in the length of cone excision was observed. In our opinion, this can be due to the acquired awareness by the gynecologists of the potential disadvantages of wide cone excision in term of adverse obstetric outcomes in future pregnancies. PMID- 29164592 TI - The moral economy of ready-made food. AB - The aim of this paper is to develop and apply a framework to explore how moralities of consumption are constituted in and through markets. Using the case of ready-made foods, this paper argues moral economies are comprised through interactions between micro-, meso- and macro-level processes in the form of instituted systems of provision, state regulation, collective food customs promoted though media, NGOs and lifestyle practitioners, and the everyday reflections of consumers. Building on a theoretical framework developed to understand the moral economy of work and employment (Bolton and Laaser 2013), this paper explores how markets for ready-made food are incessantly negotiated in the context of moral ideas about cooking, femininity and individual responsibility. It focuses on 'new' market innovations of fresh ready-to-cook meal solutions and explores how these products are both a response to moralizing discourses about cooking 'properly', as well as an intervention into the market that offers opportunities for new moral identities to be performed. Using data gathered from interviews with food manufacturers and consumers, I advocate for a multi-layered perspective that captures the dynamic interplay between consumers, markets and moralities of consumption. PMID- 29164593 TI - Immune correlates of clinical outcome in melanoma. AB - Melanoma has long been recognized as a potentially immunogenic tumour, but only recently has it become clear that the reason for this resides in its many ultraviolet (UV)-induced mutations and expression of multiple autoantigens which can be targeted by the immune system. The first successful applications of immune based treatments included passive immunotherapy using high-dose interleukin (IL) 2 and/or adoptive transfer of natural killer (NK)-cells, as well as active immunotherapy using whole cell-derived or peptide vaccines. In the intervening decades, it has become clear that these approaches can lead to durable responses in stage III/IV melanoma, and even to functional cures - but only in a vanishingly small fraction of patients. With the advent of immune checkpoint blockade first with anti-cytotoxic T-lymphocyte 4 (CTLA-4), then with anti programmed cell death 1 (PD-1) antibodies, and combinations thereof, the small percentage of responding patients may be increased to half, a major accomplishment in this refractory disease. Improved techniques for identifying mutation-derived neoantigens and thus more sophisticated active immunotherapies, probably combined with checkpoint blockade, currently hold great promise for further increasing the fraction of responding patients. As additional immunomodulatory antibodies and therapies become available, it will be increasingly important to develop diagnostic tools to determine which particular therapy is likely to elicit the best response for the individual patient. Practically speaking, therapy selection and efficacy monitoring on the basis of the results of a blood test would be most desirable. The purpose of this review is to consider the feasibility of identifying 'immune signatures' for predicting responses and determining mechanisms responsible for success or failure of these immunotherapies. PMID- 29164594 TI - RNA-sequencing study of peripheral blood mononuclear cells in sporadic Meniere's disease patients: possible contribution of immunologic dysfunction to the development of this disorder. AB - To date, the pathogenesis of Meniere's disease (MD) remains unclear. This study aims to investigate the possible relationship between potential immune system related genes and sporadic MD. The whole RNA-sequencing (RNA-seq) technology was used to analyse the transcriptome of peripheral blood mononuclear cells of three MD patients and three control individuals. Of 366 differentially expressed genes (DEGs), 154 genes were up-regulated and 212 genes were down-regulated (|log2 fold change| > 1 and P < 0.05). Gene ontology (GO) enrichment analysis illustrated that immune relevant factors played a key role in the pathogenesis of MD. Of 366 DEGs, we focused upon analysing the possible immune-related genes, among which the significantly up-regulated genes [glutathione S-transferase mu 1 (GSTM1), transmembrane protein 176 (TMEM176)B, TMEM176A] and down-regulated genes [solute carrier family 4 member (SLC4A)10 and SLC4A1] especially drew our attention. The mRNA expression levels of GSTM1, TMEM176B, TMEM176A, SLC4A1 and SLC4A10 were analysed by quantitative reverse transcription-polymerase chain reaction (qRT PCR). The serum concentration of GSTM1, TMEM176B and SLC4A10 proteins were measured by enzyme-linked immunosorbent assay (ELISA). Considering the results of qRT-PCR and ELISA, it was noteworthy that GSTM1 exhibited the highest fold change between two groups, which was consistent with the deep sequencing results by RNA seq. In conclusion, our study first offers a new perspective in MD development on the basis of RNA expression patterns, suggesting that immune factors might be involved in the MD pathogenesis. Remarkably, GSTM1 might be a possible candidate gene for the diagnostic biomarker of MD and provides the basis for further biological and functional investigations. PMID- 29164595 TI - Frequency of Leaving the House and Mortality from Age 70 to 95. AB - OBJECTIVES: To determine the association between frequency of leaving the house and mortality. DESIGN: Prospective follow-up of an age-homogenous, representative, community-dwelling birth cohort (born 1920-21) from the Jerusalem Longitudinal Study (1990-2015). SETTING: Home. PARTICIPANTS: Individuals aged 70 (n = 593), 78 (n = 973), 85 (n = 1164), and 90 (n = 645), examined in 1990, 1998, 2005, and 2010, respectively. MEASUREMENTS: Frequency of leaving the house, defined as daily (6-7/week), often (2-5/week), and rarely (<=1/week); geriatric assessment; all-cause mortality (2010-15). Kaplan-Meier survival charts and proportional hazards models adjusted for social (sex, marital status, financial status, loneliness), functional (sex, self-rated health, fatigue, depression, physical activity, activity of daily living difficulty), and medical (sex, chronic pain, visual impairment, hearing impairment, diabetes mellitus, hypertension, ischemic heart disease, chronic kidney disease) covariates. RESULTS: At ages 70, 78, 85, and 90, frequency of going out daily was 87.0%, 80.6%, 65.6%, and 48.4%; often was 6.4%, 9.5%, 17.4%, and 11.3%; and rarely was 6.6%, 10.0%, 17.0%, and 40.3% respectively. Decreasing frequency of going out was associated with negative social, functional, and medical characteristics. Survival rates were lowest among those leaving rarely and highest among those going out daily throughout follow-up. Similarly, compared with rarely leaving the house, unadjusted mortality hazard ratios (HRs) were lowest among subjects leaving daily and remained significant after adjustment for social, functional and medical covariates. Among subjects leaving often, unadjusted HRs showed a similar effect of smaller magnitude, with attenuation of significance after adjustment in certain models. Findings were unchanged after excluding subjects dying within 6 months of follow-up. CONCLUSION: In community-dwelling elderly adults aged 70 to 90, leaving the house daily was associated with lower mortality risk, independent of social, functional, or medical status. PMID- 29164597 TI - Maternal body mass index as a predictor for delivery method. AB - INTRODUCTION: High maternal body mass index (BMI) is associated with complications during pregnancy and delivery such as gestational diabetes, hypertensive disorders, perineal injuries and macrosomia. The aim of this study was to assess the association between maternal BMI and delivery method in non breech, singleton deliveries, after 36 weeks of gestation, in women with no more than one previous cesarean section, in Oslo University Hospital, Ulleval. MATERIAL AND METHODS: This retrospective register study used data from the hospital obstetrical database in 2011-2012, forming a cohort of 8821 women. Women were categorized into five different BMI classes and stratified into subgroups according to parity and previous cesarean delivery. Mode of delivery was categorized to spontaneous delivery, instrumental vaginal delivery, planned cesarean section and emergency cesarean section. RESULTS: Incidence of emergency cesarean delivery increased with increasing maternal BMI. Among primiparous women with overweight or obesity, the caesarean delivery rate was doubled (23.2 and 29.1%, respectively), compared with women with underweight or normal weight (12.5 and 13.7%). Also among parous women, maternal BMI >=30 doubled the risk for cesarean delivery. The strongest risk factor for planned or emergency cesarean delivery was previous cesarean section [adjusted odds ratio 16.41 (confidence interval 12.19-22.08) and 8.72 (6.33-12.02), respectively]. Maternal BMI >=30 increased the risk of planned cesarean delivery by 77%, and doubled the risk of emergency cesarean delivery. CONCLUSIONS: Prepregnancy BMI >=30 was an independent risk factor for delivery by emergency cesarean section for both primiparous and parous women. PMID- 29164596 TI - Regulation of T helper cell responses during antigen presentation by norepinephrine-exposed endothelial cells. AB - Dermal blood vessels and regional lymph nodes are innervated by sympathetic nerves and, under stress, sympathetic nerves release norepinephrine (NE). Exposure of primary murine dermal microvascular endothelial cells (pDMECs) to NE followed by co-culture with Langerhans cells (LCs), responsive CD4+ T-cells and antigen resulted in modulation of CD4+ T-cell responses. NE-treatment of pDMECs induced increased production of interleukin (IL)-6 and IL-17A while down regulating interferon (IFN)-gamma and IL-22 release. This effect did not require contact between pDMECs and LCs or T-cells and depended upon pDMEC production of IL-6. The presence of NE-treated pDMECs increased the proportion of CD4+ T-cells expressing intracellular IL-17A and increased IL-17A mRNA while decreasing the proportion of IFN-gamma- or IL-22-expressing CD4+ T-cells and mRNA levels for those cytokines. Retinoic acid receptor-related orphan receptor gamma (ROR gammat) mRNA was significantly increased in CD4+ T-cells while T-box transcription factor (T-bet) mRNA was decreased. Intradermal administration of NE prior to hapten immunization at the injection site produced a similar bias in draining lymph node CD4+ T-cells towards IL-17A and away from IFN-gamma and IL-22 production. Under stress, release of NE may have significant regulatory effects on the outcome of antigen presentation through actions on ECs with enhancement of inflammatory skin disorders involving IL-17/T helper type 17 (Th17) cells. PMID- 29164598 TI - Vitamin C modulates glutamate transport and NMDA receptor function in the retina. AB - Vitamin C (in the reduced form ascorbate or in the oxidized form dehydroascorbate) is implicated in signaling events throughout the central nervous system (CNS). In the retina, a high-affinity transport system for ascorbate has been described and glutamatergic signaling has been reported to control ascorbate release. Here, we investigated the modulatory role played by vitamin C upon glutamate uptake and N-methyl-d-aspartate (NMDA) receptor activation in cultured retinal cells or in intact retinal tissue using biochemical and imaging techniques. We show that both forms of vitamin C, ascorbate or dehydroascorbate, promote an accumulation of extracellular glutamate by a mechanism involving the inhibition of glutamate uptake. This inhibition correlates with the finding that ascorbate promotes a decrease in cell surface levels of the neuronal glutamate transporter excitatory amino acid transporter 3 in retinal neuronal cultures. Interestingly, vitamin C is prone to increase the activity of NMDA receptors but also promotes a decrease in glutamate-stimulated [3 H] MK801 binding and decreases cell membrane content of NMDA receptor glutamate ionotropic receptor subunit 1 (GluN1) subunits. Both compounds were also able to increase cAMP response element-binding protein phosphorylation in neuronal nuclei in a glutamate receptor and calcium/calmodulin kinase-dependent manner. Moreover, the effect of ascorbate is not blocked by sulfinpyrazone and then does not depend on its uptake by retinal cells. Overall, these data indicate a novel molecular and functional target for vitamin C impacting on glutamate signaling in retinal neurons. PMID- 29164600 TI - 18F PET with florbetaben for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). AB - BACKGROUND: 18F-florbetaben uptake by brain tissue, measured by positron emission tomography (PET), is accepted by regulatory agencies like the Food and Drug Administration (FDA) and the European Medicine Agencies (EMA) for assessing amyloid load in people with dementia. Its added value is mainly demonstrated by excluding Alzheimer's pathology in an established dementia diagnosis. However, the National Institute on Aging and Alzheimer's Association (NIA-AA) revised the diagnostic criteria for Alzheimer's disease and confidence in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease may be increased when using some amyloid biomarkers tests like 18F-florbetaben. These tests, added to the MCI core clinical criteria, might increase the diagnostic test accuracy (DTA) of a testing strategy. However, the DTA of 18F-florbetaben to predict the progression from MCI to Alzheimer's disease dementia (ADD) or other dementias has not yet been systematically evaluated. OBJECTIVES: To determine the DTA of the 18F-florbetaben PET scan for detecting people with MCI at time of performing the test who will clinically progress to ADD, other forms of dementia (non-ADD), or any form of dementia at follow-up. SEARCH METHODS: The most recent search for this review was performed in May 2017. We searched MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), BIOSIS Citation Index (Thomson Reuters Web of Science), Web of Science Core Collection, including the Science Citation Index (Thomson Reuters Web of Science) and the Conference Proceedings Citation Index (Thomson Reuters Web of Science), LILACS (BIREME), CINAHL (EBSCOhost), ClinicalTrials.gov (https://clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/search/en/). We also searched ALOIS, the Cochrane Dementia & Cognitive Improvement Group's specialised register of dementia studies (http://www.medicine.ox.ac.uk/alois/). We checked the reference lists of any relevant studies and systematic reviews, and performed citation tracking using the Science Citation Index to identify any additional relevant studies. No language or date restrictions were applied to electronic searches. SELECTION CRITERIA: We included studies that had prospectively defined cohorts with any accepted definition of MCI at time of performing the test and the use of 18F florbetaben scan to evaluate the DTA of the progression from MCI to ADD or other forms of dementia. In addition, we only selected studies that applied a reference standard for Alzheimer's dementia diagnosis, for example, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. DATA COLLECTION AND ANALYSIS: We screened all titles and abstracts identified in electronic-database searches. Two review authors independently selected studies for inclusion and extracted data to create two-by-two tables, showing the binary test results cross classified with the binary reference standard. We used these data to calculate sensitivities, specificities, and their 95% confidence intervals. Two independent assessors performed quality assessment using the QUADAS-2 tool plus some additional items to assess the methodological quality of the included studies. MAIN RESULTS: Progression from MCI to ADD, any other form of dementia, and any form of dementia was evaluated in one study (Ong 2015). It reported data on 45 participants at four years of follow-up; 21 participants met NINCDS-ADRDA criteria for Alzheimer's disease dementia at four years of follow-up, the proportion converting to ADD was 47% of the 45 participants, and 11% of the 45 participants met criteria for other types of dementias (three cases of FrontoTemporal Dementia (FTD), one of Dementia with Lewy body (DLB), and one of Progressive Supranuclear Palsy (PSP)). We considered the study to be at high risk of bias in the domains of the reference standard, flow, and timing (QUADAS-2). MCI to ADD; 18F-florbetaben PET scan analysed visually: the sensitivity was 100% (95% confidence interval (CI) 84% to 100%) and the specificity was 83% (95% CI 63% to 98%) (n = 45, 1 study). Analysed quantitatively: the sensitivity was 100% (95% CI 84% to 100%) and the specificity was 88% (95% CI 68% to 97%) for the diagnosis of ADD at follow-up (n = 45, 1 study). MCI to any other form of dementia (non-ADD); 18F-florbetaben PET scan analysed visually: the sensitivity was 0% (95% CI 0% to 52%) and the specificity was 38% (95% CI 23% to 54%) (n = 45, 1 study). Analysed quantitatively: the sensitivity was 0% (95% CI 0% to 52%) and the specificity was 40% (95% CI 25% to 57%) for the diagnosis of any other form of dementia at follow-up (n = 45, 1 study). MCI to any form of dementia;18F florbetaben PET scan analysed visually: the sensitivity was 81% (95% CI 61% to 93%) and the specificity was 79% (95% CI 54% to 94%) (n = 45, 1 study). Analysed quantitatively: the sensitivity was 81% (95% CI 61% to 93%) and the specificity was 84% (95% CI 60% to 97%) for the diagnosis of any form of dementia at follow up (n = 45, 1 study). AUTHORS' CONCLUSIONS: Although we were able to calculate one estimation of DTA in, especially, the prediction of progression from MCI to ADD at four years follow-up, the small number of participants implies imprecision of sensitivity and specificity estimates. We cannot make any recommendation regarding the routine use of 18F-florbetaben in clinical practice based on one single study with 45 participants. 18F-florbetaben has high financial costs, therefore, clearly demonstrating its DTA and standardising the process of the 18F florbetaben modality are important prior to its wider use. PMID- 29164599 TI - Neurocognition and subjective experience following acute doses of the synthetic cannabinoid JWH-018: a phase 1, placebo-controlled, pilot study. AB - BACKGROUND AND PURPOSE: Synthetic cannabinoids (often sold as Spice or K2) have become a very popular alternative to cannabis due to their easy access and portrayed safety. Controlled studies on the behavioural effects of synthetic cannabinoids are currently lacking, which hampers risk assessments of these compounds. EXPERIMENTAL APPROACH: This is a first attempt to assess the influence of a synthetic cannabinoid, JWH-018, on neurocognition and subjective experience in humans after controlled administration. JWH-018, 2 and 3 mg, was administered to six healthy cannabis-experienced volunteers in a placebo-controlled, cross over study following an escalating dosing schedule. Participants were monitored for 12 h after drug administration, and several neurocognitive measures and subjective questionnaires were taken. KEY RESULTS: Serum concentrations of JWH 018 were highest after the 2 mg dose but generally low after administration of both doses. Both doses of JWH-018 were well tolerated, and no serious side effects were reported. Participants reported feeling more 'high' at 1 and 2 h after administration, particularly after the 2 mg dose. Behavioural impairments also emerged despite the low serum concentrations of JWH-018. The low dose of JWH 018 impaired performance on the tracking, divided attention and stop signal task. CONCLUSION AND IMPLICATIONS: JWH-018 dosing in the present study resulted in drug concentrations that were generally low and not fully representative of common use. Yet initial impairments of neurocognitive function and subjective feelings of high did emerge despite low levels of JWH-018 in serum. Higher doses are needed to obtain a more representative risk profile of JWH-018. PMID- 29164601 TI - Clinical decision analysis in perinatology. AB - Clinical decision-making in perinatology involves trade-offs between two intricately related individuals - mother and fetus. Decision-making in perinatology is challenging due to competing interests of the mother and the fetus. Although decision analytic methods are increasingly used to develop processes for clinical and cost-effectiveness analyses in perinatology, there are no guidelines on the conduct and reporting of decision analysis studies that takes into account the complexities of the mother-fetus dyad. This article describes the basics of decision analysis and highlights areas that require special consideration in the perinatal context. It emphasizes the importance of obtaining patient preferences related to combined maternal-fetal health states, stresses the relevance of both maternal and offspring health outcomes over appropriate time horizons, and explains challenges around the use of quality adjusted life years as an outcome measure in perinatology. It also provides insight into the complexities of dyad status in clinical and cost-effectiveness analyses in perinatology. PMID- 29164602 TI - 18F PET with flutemetamol for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). AB - BACKGROUND: 18F-flutemetamol uptake by brain tissue, measured by positron emission tomography (PET), is accepted by regulatory agencies like the Food and Drug Administration (FDA) and the European Medicine Agencies (EMA) for assessing amyloid load in people with dementia. Its added value is mainly demonstrated by excluding Alzheimer's pathology in an established dementia diagnosis. However, the National Institute on Aging and Alzheimer's Association (NIA-AA) revised the diagnostic criteria for Alzheimer's disease and the confidence in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease may be increased when using some amyloid biomarkers tests like 18F-flutemetamol. These tests, added to the MCI core clinical criteria, might increase the diagnostic test accuracy (DTA) of a testing strategy. However, the DTA of 18F-flutemetamol to predict the progression from MCI to Alzheimer's disease dementia (ADD) or other dementias has not yet been systematically evaluated. OBJECTIVES: To determine the DTA of the 18F-flutemetamol PET scan for detecting people with MCI at time of performing the test who will clinically progress to ADD, other forms of dementia (non-ADD) or any form of dementia at follow-up. SEARCH METHODS: The most recent search for this review was performed in May 2017. We searched MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), BIOSIS Citation Index (Thomson Reuters Web of Science), Web of Science Core Collection, including the Science Citation Index (Thomson Reuters Web of Science) and the Conference Proceedings Citation Index (Thomson Reuters Web of Science), LILACS (BIREME), CINAHL (EBSCOhost), ClinicalTrials.gov (https://clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/search/en/). We also searched ALOIS, the Cochrane Dementia & Cognitive Improvement Group's specialised register of dementia studies (http://www.medicine.ox.ac.uk/alois/). We checked the reference lists of any relevant studies and systematic reviews, and performed citation tracking using the Science Citation Index to identify any additional relevant studies. No language or date restrictions were applied to the electronic searches. SELECTION CRITERIA: We included studies that had prospectively defined cohorts with any accepted definition of MCI at time of performing the test and the use of 18F flutemetamol scan to evaluate the DTA of the progression from MCI to ADD or other forms of dementia. In addition, we only selected studies that applied a reference standard for Alzheimer's dementia diagnosis, for example, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. DATA COLLECTION AND ANALYSIS: We screened all titles and abstracts identified in electronic-database searches. Two review authors independently selected studies for inclusion and extracted data to create two-by-two tables, showing the binary test results cross-classified with the binary reference standard. We used these data to calculate sensitivities, specificities, and their 95% confidence intervals. Two independent assessors performed quality assessment using the QUADAS-2 tool plus some additional items to assess the methodological quality of the included studies. MAIN RESULTS: Progression from MCI to ADD was evaluated in 243 participants from two studies. The studies reported data on 19 participants with two years of follow-up and on 224 participants with three years of follow-up. Nine (47.4%) participants converted at two years follow-up and 81 (36.2%) converted at three years of follow-up.There were concerns about participant selection and sampling in both studies. The index test domain in one study was considered unclear and in the second study it was considered at low risk of bias. For the reference standard domain, one study was considered at low risk and the second study was considered to have an unclear risk of bias. Regarding the domains of flow and timing, both studies were considered at high risk of bias. MCI to ADD;Progression from MCI to ADD at two years of follow-up had a sensitivity of 89% (95% CI 52 to 100) and a specificity of 80% (95% CI 44 to 97) by quantitative assessment by SUVR (n = 19, 1 study).Progression from MCI to ADD at three years of follow-up had a sensitivity of 64% (95% CI 53 to 75) and a specificity of 69% (95% CI 60 to 76) by visual assessment (n = 224, 1 study).There was no information regarding the other two objectives in this systematic review (SR): progression from MCI to other forms of dementia and progression to any form of dementia at follow-up. AUTHORS' CONCLUSIONS: Due to the varying sensitivity and specificity for predicting the progression from MCI to ADD and the limited data available, we cannot recommend routine use of 18F-flutemetamol in clinical practice. 18F flutemetamol has high financial costs; therefore, clearly demonstrating its DTA and standardising the process of the 18F-flutemetamol modality is important prior to its wider use. PMID- 29164603 TI - 18F PET with florbetapir for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). AB - BACKGROUND: 18F-florbetapir uptake by brain tissue measured by positron emission tomography (PET) is accepted by regulatory agencies like the Food and Drug Administration (FDA) and the European Medicine Agencies (EMA) for assessing amyloid load in people with dementia. Its added value is mainly demonstrated by excluding Alzheimer's pathology in an established dementia diagnosis. However, the National Institute on Aging and Alzheimer's Association (NIA-AA) revised the diagnostic criteria for Alzheimer's disease and confidence in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease may be increased when using amyloid biomarkers tests like 18F-florbetapir. These tests, added to the MCI core clinical criteria, might increase the diagnostic test accuracy (DTA) of a testing strategy. However, the DTA of 18F-florbetapir to predict the progression from MCI to Alzheimer's disease dementia (ADD) or other dementias has not yet been systematically evaluated. OBJECTIVES: To determine the DTA of the 18F-florbetapir PET scan for detecting people with MCI at time of performing the test who will clinically progress to ADD, other forms of dementia (non-ADD), or any form of dementia at follow-up. SEARCH METHODS: This review is current to May 2017. We searched MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), BIOSIS Citation Index (Thomson Reuters Web of Science), Web of Science Core Collection, including the Science Citation Index (Thomson Reuters Web of Science) and the Conference Proceedings Citation Index (Thomson Reuters Web of Science), LILACS (BIREME), CINAHL (EBSCOhost), ClinicalTrials.gov (https://clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/search/en/). We also searched ALOIS, the Cochrane Dementia & Cognitive Improvement Group's specialised register of dementia studies (http://www.medicine.ox.ac.uk/alois/). We checked the reference lists of any relevant studies and systematic reviews, and performed citation tracking using the Science Citation Index to identify any additional relevant studies. No language or date restrictions were applied to the electronic searches. SELECTION CRITERIA: We included studies that had prospectively defined cohorts with any accepted definition of MCI at time of performing the test and the use of 18F-florbetapir scan to evaluate the DTA of the progression from MCI to ADD or other forms of dementia. In addition, we only selected studies that applied a reference standard for Alzheimer's dementia diagnosis, for example, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. DATA COLLECTION AND ANALYSIS: We screened all titles and abstracts identified in electronic-database searches. Two review authors independently selected studies for inclusion and extracted data to create two-by-two tables, showing the binary test results cross-classified with the binary reference standard. We used these data to calculate sensitivities, specificities, and their 95% confidence intervals. Two independent assessors performed quality assessment using the QUADAS-2 tool plus some additional items to assess the methodological quality of the included studies. MAIN RESULTS: We included three studies, two of which evaluated the progression from MCI to ADD, and one evaluated the progression from MCI to any form of dementia.Progression from MCI to ADD was evaluated in 448 participants. The studies reported data on 401 participants with 1.6 years of follow-up and in 47 participants with three years of follow-up. Sixty-one (15.2%) participants converted at 1.6 years follow-up; nine (19.1%) participants converted at three years of follow-up.Progression from MCI to any form of dementia was evaluated in five participants with 1.5 years of follow-up, with three (60%) participants converting to any form of dementia.There were concerns regarding applicability in the reference standard in all three studies. Regarding the domain of flow and timing, two studies were considered at high risk of bias. MCI to ADD;Progression from MCI to ADD in those with a follow-up between two to less than four years had a sensitivity of 67% (95% CI 30 to 93) and a specificity of 71% (95% CI 54 to 85) by visual assessment (n = 47, 1 study).Progression from MCI to ADD in those with a follow-up between one to less than two years had a sensitivity of 89% (95% CI 78 to 95) and a specificity of 58% (95% CI 53 to 64) by visual assessment, and a sensitivity of 87% (95% CI 76 to 94) and a specificity of 51% (95% CI 45 to 56) by quantitative assessment by the standardised uptake value ratio (SUVR)(n = 401, 1 study). MCI to any form of dementia;Progression from MCI to any form of dementia in those with a follow-up between one to less than two years had a sensitivity of 67% (95% CI 9 to 99) and a specificity of 50% (95% CI 1 to 99) by visual assessment (n = 5, 1 study). MCI to any other forms of dementia (non-ADD);There was no information regarding the progression from MCI to any other form of dementia (non-ADD). AUTHORS' CONCLUSIONS: Although sensitivity was good in one included study, considering the poor specificity and the limited data available in the literature, we cannot recommend routine use of 18F-florbetapir PET in clinical practice to predict the progression from MCI to ADD.Because of the poor sensitivity and specificity, limited number of included participants, and the limited data available in the literature, we cannot recommend its routine use in clinical practice to predict the progression from MCI to any form of dementia.Because of the high financial costs of 18F-florbetapir, clearly demonstrating the DTA and standardising the process of this modality are important prior to its wider use. PMID- 29164605 TI - Methotrexate-associated lymphoproliferative disorder masquerading as multiple cerebral metastases. PMID- 29164604 TI - Absent fetal nasal bone in the second trimester and risk of abnormal karyotype in a prescreened population of Chinese women. AB - INTRODUCTION: The aim of this study was to evaluate the value of absent fetal nasal bone in the prediction of fetal chromosomal abnormalities, according to whether it was associated with other soft markers or structural abnormalities in a prescreened population of Chinese pregnant women. MATERIAL AND METHODS: In this retrospective cohort study, women whose fetuses had absent nasal bone detected during the second trimester ultrasound scan were followed. Fetal karyotyping was performed and pregnancy outcomes were recorded. The association between absent fetal nasal bone with abnormal karyotype was evaluated according to whether soft markers or structural abnormalities were also observed. RESULTS: Fetal nasal bone was assessed in 56 707 singleton pregnancies. After exclusion of unqualified cases, 71 (71/56 707, 0.13%) fetuses were included in the final analyses, of which 16 (16/71, 22.54%) were detected to have chromosomal abnormalities, including 12 cases of trisomy-21, three of trisomy-18, and one of micro-deletion (in 7q). Among the 42 cases with isolated absence of nasal bone, two had trisomy 21 and one had a micro-deletion. Absence of nasal bone in association with other structural abnormalities had a higher rate of abnormal karyotypes compared with isolated absence of nasal bone [83.33% (10/12) vs. 7.14% (3/42), Fisher's exact test chi2 = 25.620, p < 0.001]. CONCLUSION: Absent fetal nasal bone is a highly specific ultrasonographic soft marker that should be included in the routine second trimester ultrasound scan. PMID- 29164606 TI - Safety and efficacy of pomalidomide, dexamethasone and pegylated liposomal doxorubicin for patients with relapsed or refractory multiple myeloma. AB - Immunomodulatory drugs including thalidomide, lenalidomide (LEN) and pomalidomide (POM), are effective for treating multiple myeloma (MM). POM has shown enhanced efficacy with dexamethasone (DEX). Pegylated liposomal doxorubicin (PLD) with bortezomib is US Food and Drug Administration-approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m2 with the latter two drugs administered on days 1, 4, 8 and 11 on a 28-day cycle for the treatment of relapsed/refractory MM patients. During Phase 1, the maximum tolerated dose of POM was 4 mg, and was used in Phase 2, which also required patients to be refractory to LEN. However, neutropenia >= grade 3 was observed in 10/17 (59%) patients, and the dose was lowered to 3 mg. Median PFS was 5.4 months (range, 0.3-29.0 + months). Overall response rates for patients in Phase 2 were 39% and 31% among subjects receiving POM at 3 mg and 4 mg, respectively, and clinical benefit rates were 51% and 44%, respectively. POM, PLD and DEX is a treatment option for relapsed/refractory MM patients including those who are refractory to LEN. PMID- 29164607 TI - Virtual morality in the helping professions: Simulated action and resilience. AB - Recent advances in virtual technologies have allowed the investigation of simulated moral actions in aversive moral dilemmas. Previous studies have employed diverse populations to explore these actions, with little research considering the significance of occupation on moral decision-making. For the first time, in this study we have investigated simulated moral actions in virtual reality made by professionally trained paramedics and fire service incident commanders who are frequently faced with and must respond to moral dilemmas. We found that specially trained individuals showed distinct empathic and related personality trait scores and that these declined with years of experience working in the profession. Supporting the theory that these professionals develop resilience in moral conflict, reduced emotional arousal was observed during virtual simulations of a distressing dilemma. Furthermore, trained professionals demonstrated less regret following the execution of a moral action in virtual reality when compared to untrained control populations. We showed that, contrary to previous research, trained individuals made the same moral judgements and moral actions as untrained individuals, though showing less arousal and regret. In the face of increasing concerns regarding empathy decline in health care professionals, we suggest that the nature of this decline is complex and likely reflects the development of a necessary emotional resilience to distressing events. PMID- 29164609 TI - Who benefits from adolescent sleep interventions? Moderators of treatment efficacy in a randomized controlled trial of a cognitive-behavioral and mindfulness-based group sleep intervention for at-risk adolescents. AB - BACKGROUND: The aim of this study was to test moderators of therapeutic improvement in an adolescent cognitive-behavioral and mindfulness-based group sleep intervention. Specifically, we examined whether the effects of the program on postintervention sleep outcomes were dependent on participant gender and/or measures of sleep duration, anxiety, depression, and self-efficacy prior to the interventions. METHOD: Secondary analysis of a randomized controlled trial conducted with 123 adolescent participants (female = 59.34%; mean age = 14.48 years, range 12.04-16.31 years) who had elevated levels of sleep problems and anxiety symptoms. Participants were randomized into either a group sleep improvement intervention (n = 63) or group active control 'study skills' intervention (n = 60). The sleep intervention ('Sleep SENSE') was cognitive behavioral in approach, incorporating sleep education, sleep hygiene, stimulus control, and cognitive restructuring, but also had added anxiety-reducing, mindfulness, and motivational interviewing elements. Components of the active control intervention ('Study SENSE') included personal organization, persuasive writing, critical reading, referencing, memorization, and note taking. Participants completed the Pittsburgh Sleep Quality Index (PSQI), Spence Children's Anxiety Scale (SCAS), Center for Epidemiologic Studies Depression Scale (CES-D), and General Self-Efficacy Scale (GSE) and wore an actigraph and completed a sleep diary for five school nights prior to the interventions. Sleep assessments were repeated at postintervention. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612001177842; http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12612001177842&isBasic=T ue). RESULTS: The results showed that compared with the active control intervention, the effect of the sleep intervention on self-reported sleep quality (PSQI global score) at postintervention was statistically significant among adolescents with relatively moderate to high SCAS, CES-D, and GSE prior to the intervention, but not among adolescents with relatively low SCAS, CES-D, and GSE prior to the intervention. The results were consistent across genders. However, the effects of the sleep intervention on actigraphy-measured sleep onset latency and sleep diary-measured sleep efficiency at postintervention were not dependent on actigraphy-measured total sleep time, SCAS, CES-D, or GSE prior to the intervention. CONCLUSIONS: This study provides evidence that some sleep benefits of adolescent cognitive-behavioral sleep interventions are greatest among those with higher levels of anxiety and depressive symptoms, suggesting that this may be an especially propitious group to whom intervention efforts could be targeted. Furthermore, adolescents with lower levels of self-efficacy may need further targeted support (e.g. additional motivational interviewing) to help them reach treatment goals. PMID- 29164608 TI - The absolute percent deviation of IGHV mutation rather than a 98% cut-off predicts survival of chronic lymphocytic leukaemia patients treated with fludarabine, cyclophosphamide and rituximab. AB - The degree of somatic hypermutation, determined as percent deviation of immunoglobulin heavy chain gene variable region sequence from the germline (IGHV%), is an important prognostic factor in chronic lymphocytic leukaemia (CLL). Currently, a cut-off of 2% deviation or 98% sequence identity to germline in IGHV sequence is routinely used to dichotomize CLL patients into mutated and unmutated groups. Because dissimilar IGHV% cut-offs of 1-5% were identified in different studies, we wondered whether no cut-off should be applied and IGHV% treated as a continuous variable. We analysed the significance of IGHV% in 203 CLL patients enrolled on the original frontline fludarabine, cyclophosphamide and rituximab (FCR) trial with a median of 10 years follow-up. Using the Cox Proportional Hazard model, IGHV% was identified as a continuous variable that is significantly associated with progression-free (PFS) and overall survival (OS) (P < 0.001). Furthermore, we validated this finding in 323 patients treated with FCR off-protocol and in the total cohort (n = 535). Multivariate analysis revealed a continuous trend. Higher IGHV% levels were incrementally associated with favorable PFS and OS in both FCR-treated cohorts (P < 0.001, both cohorts). Taken together, our data suggest that IGHV% is a continuous variable in CLL patients treated with FCR. PMID- 29164610 TI - Shared pathological pathways of Alzheimer's disease with specific comorbidities: current perspectives and interventions. AB - Alzheimer's disease (AD) belongs to one of the most multifactorial, complex and heterogeneous morbidity-leading disorders. Despite the extensive research in the field, AD pathogenesis is still at some extend obscure. Mechanisms linking AD with certain comorbidities, namely diabetes mellitus, obesity and dyslipidemia, are increasingly gaining importance, mainly because of their potential role in promoting AD development and exacerbation. Their exact cognitive impairment trajectories, however, remain to be fully elucidated. The current review aims to offer a clear and comprehensive description of the state-of-the-art approaches focused on generating in-depth knowledge regarding the overlapping pathology of AD and its concomitant ailments. Thorough understanding of associated alterations on a number of molecular, metabolic and hormonal pathways, will contribute to the further development of novel and integrated theranostics, as well as targeted interventions that may be beneficial for individuals with age-related cognitive decline. PMID- 29164611 TI - Serial electrophysiology in Guillain-Barre syndrome: A retrospective cohort and case-by-case multicentre analysis. AB - OBJECTIVES: To assess the usefulness of serial electrophysiology in Guillain Barre syndrome (GBS) in a multicenter setting and the reasons for change in electrodiagnostic subtypes with serial studies. METHODS: We retrospectively analysed serial electrophysiology of 51 patients with GBS from 4 European centres. Proportions of subtypes were determined at each timing. Individual case analyses were also performed where diagnostic changes occurred with either criteria, to ascertain if changes were due to disease progression or criteria inadequacy. RESULTS: At first study, comparing old vs new criteria, acute inflammatory demyelinating polyneuropathy (AIDP) was diagnosed in 70.6% vs 51%, axonal GBS in 15.7% vs 39.2%, equivocal forms in 11.8% vs 7.8%. At second study, AIDP was diagnosed in 72.5% vs 52.9%, axonal GBS in 9.8% vs 33.3%, equivocal forms in 15.7% vs 11.7%. Subtype proportions were unchanged, indicating serial studies did not, in the cohort, alter diagnostic rates for each subtype irrespective of criteria used. Individual review of cases where subtype electrodiagnosis changed indicated suboptimal specificity for AIDP/sensitivity for axonal GBS as main cause of diagnostic shifts with old criteria, whereas disease progression explained most changes with new criteria (55.6% vs 81.8%; P = .039). CONCLUSIONS: Serial electrophysiology is unhelpful in GBS. Repeat studies cannot represent the gold standard as electrodiagnosis may alter due to disease progression. Changes in electrodiagnosis relate more often to disease progression with new criteria but are more frequently due to suboptimal sensitivity/specificity with old criteria. A single electrophysiological study using the most accurate available criteria appears sufficient in GBS. PMID- 29164612 TI - Seizures, CSF neurofilament light and tau in patients with subarachnoid haemorrhage. AB - OBJECTIVES: Patients with severe subarachnoid haemorrhage (SAH) often suffer from complications with delayed cerebral ischaemia (DCI) due to vasospasm that is difficult to identify by clinical examination. The purpose of this study was to monitor seizures and to measure cerebrospinal fluid (CSF) concentrations of neurofilament light (NFL) and tau, and to see whether they could be used for predicting preclinical DCI. METHODS: We prospectively studied 19 patients with aneurysmal SAH who underwent treatment with endovascular coiling. The patients were monitored with continuous EEG (cEEG) and received external ventricular drainage (EVD). CSF samples of neurofilament light (NLF) and total tau (T-tau) protein were collected at day 4 and day 10. Cox regression analysis was applied to evaluate whether seizures and protein biomarkers were associated with DCI and poor outcome. RESULTS: Seven patients developed DCI (37%), and 4 patients (21%) died within the first 2 months. Six patients (32%) had clinical seizures, and electrographic seizures were noted in one additional patient (4.5%). Increased tau ratio (proportion tau10/tau4) was significantly associated with DCI and hazard ratio [HR=1.33, 95% confidence interval (CI) 1.055-1.680. P = .016]. CONCLUSION: Acute symptomatic seizures are common in SAH, but their presence is not predictive of DCI. High values of the tau ratio in the CSF may be associated with development of DCI. PMID- 29164613 TI - Calmodulin-like skin protein protects against spatial learning impairment in a mouse model of Alzheimer disease. AB - Humanin and calmodulin-like skin protein (CLSP) inhibits Alzheimer disease (AD) related neuronal cell death via the heterotrimeric humanin receptor in vitro. It has been suggested that CLSP is a central agonist of the heterotrimeric humanin receptor in vivo. To investigate the role of CLSP in the AD pathogenesis in vivo, we generated mouse CLSP-1 transgenic mice, crossed them with the APPswe/PSEN1dE9 mice, a model mouse of AD, and examined the effect of CLSP over-expression on the pathological phenotype of the AD mouse model. We found that over-expression of the mouse CLSP-1 gene attenuated spatial learning impairment, the loss of a presynaptic marker synaptophysin, and the inactivation of STAT3 in the APPswe/PSEN1dE9 mice. On the other hand, CLSP over-expression did not affect levels of Abeta, soluble Abeta oligomers, or gliosis. These results suggest that the CLSP-mediated attenuation of memory impairment and synaptic loss occurs in an Abeta-independent manner. The results of this study may serve as a hint to the better understanding of the AD pathogenesis and the development of AD therapy. PMID- 29164614 TI - Evaluating the utility of a point-of-care glucometer for the diagnosis of gestational diabetes. AB - OBJECTIVE: To investigate the performance of the Roche Accuchek Active glucometer in diagnosing gestational diabetes mellitus (GDM) versus the gold-standard laboratory test. METHODS: In a prospective cohort observational study at a primary healthcare clinic in Johannesburg, South Africa, pregnant women, excluding known diabetics, were recruited between 2013 and 2016. A 75-g 2-hour oral glucose tolerance test (OGTT) was scheduled at 24-28 gestational weeks. Glucose was measured in venous blood (laboratory) and capillary blood (glucometer). GDM was diagnosed via FIGO criteria. Diagnostic accuracy was evaluated by calculating the sensitivity, specificity, and coefficient of variance (CV) of the glucometer test, and by Bland-Altman plots. RESULTS: Data from 529 women were analyzed. Of these, 141 (26.7%) and 79 (14.9%) were diagnosed with GDM by laboratory and glucometer measurements, respectively. The CV of the glucometer ranged from 15% to 17%. Bland-Altman plots showed a positive bias of the glucometer results at 0 hours, but a negative bias at 1 and 2 hours of the OGTT. The sensitivity and specificity of the glucometer for the diagnosis of GDM were 27.0% and 89.4%, respectively. CONCLUSION: Use of the Roche Accuchek Active glucometer for the diagnosis of GDM cannot be recommended. PMID- 29164615 TI - ARHGEF19 interacts with BRAF to activate MAPK signaling during the tumorigenesis of non-small cell lung cancer. AB - Rho guanine nucleotide exchange factors (RhoGEFs) are proteins that activate Rho GTPases in response to extracellular stimuli and regulate various biologic processes. ARHGEF19, one of RhoGEFs, was reported to activate RhoA in the Wnt-PCP pathway controlling convergent extension in Xenopus gastrulation. The goal of our study was to identify the role and molecular mechanisms of ARHGEF19 in the tumorigenesis of non-small cell lung cancer (NSCLC). ARHGEF19 expression was significantly elevated in NSCLC tissues, and ARHGEF19 levels were significantly associated with lymph node status, distant metastasis and TNM stage; Patients with high ARHGEF19 levels had poor overall survival (OS) and progression-free survival (PFS). Our investigations revealed that ARHGEF19 overexpression promoted the cell proliferation, invasion and metastasis of lung cancer cells, whereas knockdown of this gene inhibited these processes. Mechanistically, ARHGEF19 activated the mitogen-activated protein kinase (MAPK) pathway in a RhoA independent manner: ARHGEF19 interacted with BRAF and facilitated the phosphorylation of its downstream kinase MEK1/2; both the Dbl homology (DH) and Pleckstrin homology (PH) domains of ARHGEF19 were indispensable for the phosphorylation of MEK1/2. Furthermore, downregulation of miR-29b was likely responsible for the increased expression of ARHGEF19 in lung cancer tissues and, consequently, the abnormal activation of MAPK signaling. These findings suggest that ARHGEF19 upregulation, due to the low expression of miR-29 in NSCLC tissues, may play a crucial role in NSCLC tumorigenesis by activating MAPK signaling. ARHGEF19 could serve as a negative prognostic marker as well as a therapeutic target for NSCLC patients. PMID- 29164616 TI - Protection against beta-amyloid neurotoxicity by a non-toxic endogenous N terminal beta-amyloid fragment and its active hexapeptide core sequence. AB - High levels (MUM) of beta amyloid (Abeta) oligomers are known to trigger neurotoxic effects, leading to synaptic impairment, behavioral deficits, and apoptotic cell death. The hydrophobic C-terminal domain of Abeta, together with sequences critical for oligomer formation, is essential for this neurotoxicity. However, Abeta at low levels (pM-nM) has been shown to function as a positive neuromodulator and this activity resides in the hydrophilic N-terminal domain of Abeta. An N-terminal Abeta fragment (1-15/16), found in cerebrospinal fluid, was also shown to be a highly active neuromodulator and to reverse Abeta-induced impairments of long-term potentiation. Here, we show the impact of this N terminal Abeta fragment and a shorter hexapeptide core sequence in the Abeta fragment (Abetacore: 10-15) to protect or reverse Abeta-induced neuronal toxicity, fear memory deficits and apoptotic death. The neuroprotective effects of the N-terminal Abeta fragment and Abetacore on Abeta-induced changes in mitochondrial function, oxidative stress, and apoptotic neuronal death were demonstrated via mitochondrial membrane potential, live reactive oxygen species, DNA fragmentation and cell survival assays using a model neuroblastoma cell line (differentiated NG108-15) and mouse hippocampal neuron cultures. The protective action of the N-terminal Abeta fragment and Abetacore against spatial memory processing deficits in amyloid precursor protein/PSEN1 (5XFAD) mice was demonstrated in contextual fear conditioning. Stabilized derivatives of the N terminal Abetacore were also shown to be fully protective against Abeta-triggered oxidative stress. Together, these findings indicate an endogenous neuroprotective role for the N-terminal Abeta fragment, while active stabilized N-terminal Abetacore derivatives offer the potential for therapeutic application. PMID- 29164617 TI - Differential Perturbation of the Protrotropic Equilibrium of a Biological Photosensitizer within Bile Salt Aggregates of Varying Hydrophobicity: A Fluorimetric Investigation. AB - The present work reveals the binding interactions of a credible cancer cell photosensitizer, harmane (HM), with some selected bile salt aggregates of dissimilar hydrophobicity viz. sodium deoxycholate (NaDC), sodium cholate (NaC) and sodium taurocholate (NaTC). The explicit variation of the prototropic equilibrium of the photosensitizer both in the ground and excited state has been utilized to scrutinize the interaction phenomena. Differential modulation in the prototropic equilibrium of HM in the aforesaid aggregates has been explained on the basis of the structural dissimilarities of the bile salt monomers. The contrived hydrophobic surroundings provided by the aggregates have been reflected on the spectroscopic results, especially in the time-resolved fluorescence and the rotational dynamical behavior of the molecule of interest. Slow solvent reorientation time with regard to the lifetime of HM proliferated by the red-edge effect in two specific bile salts namely NaC and NaTC, whereas its absence in NaDC aggregates has also been elucidated on the basis of accessibility of the solvent molecules within the aggregates. PMID- 29164618 TI - Analysis of Erythemal UVB Dose Received Inside a Car in Valencia, Spain. AB - Continuous exposures to ultraviolet radiation can lead to harmful effects on human skin. Professional drivers may spend more than 8 h per day inside a vehicle. This study describes an analysis of the UVER (erythemal ultraviolet radiation) received by a driver and passenger inside a vehicle. A three-door Peugeot 206 was used for the study. VioSpor Blue Line dosimeters (with a response profile close to that of human skin) were used to measure the erythematic dose of UV radiation (able to produce erythema on human skin). Four dosimeters were placed in the driver's position and another four in the passenger's position. Daily irradiance was analyzed for a day in April using PMA radiometers. The measurements were obtained on relatively clear days from February to December 2009 between 9:30 A.M. and 3 P.M. Additionally, a prediction was made of the time required to produce an erythema on the driver's skin. UVER exposure, in some of the driver's positions, exceeds the Exposure Limits given by the International Commission on Non-Ionizing Radiation Protection (ICNIRP). Skin protection measures should be taken into account by professional drivers to prevent the harmful effects of UVER radiation. PMID- 29164619 TI - Nanoflower-like Yttrium-doped ZnO Photocatalyst for the Degradation of Methylene Blue Dye. AB - Pure ZnO and Yttrium-doped (Y-doped) ZnO at various mol% with flower-like nanostructures are synthesized by a microwave-assisted sol-gel method, followed by investigating the morphologies, crystal structures, optical properties and photocatalytic performances. While the phase formations are detected by X-ray diffraction technique, both scanning and transmission electron microscopy images clearly depict the flower-like morphology of ZnO and Y-doped ZnO samples. Formation of flower petals is from the nanoparticles that grew and connected by orientation attachment process. The flower-like architecture is addressed in terms of an Ostwald ripening mechanism. The UV-Vis absorption studies show enhanced absorption for the Y-doped ZnO, whereas the photoluminescence spectra confirm the significance of sample defects in the photocatalytic degradation of organic pollutants. Effects of various experimental parameters such as the amount of photocatalysts, dye concentration and dopant concentration on the dye degradation are also optimized. PMID- 29164620 TI - Repair gene O6 -methylguanine-DNA methyltransferase is controlled by SP1 and up regulated by glucocorticoids, but not by temozolomide and radiation. AB - Therapy of malignant glioma relies on treatment with the O6 -methylating agent temozolomide (TMZ) concomitant with ionizing radiation followed by adjuvant TMZ. For the treatment of recurrences, DNA chloroethylating drugs are also used. The main killing lesion induced by these drugs is O6 -alkylguanine. Since this damage is repaired by O6 -methylguanine-DNA methyltransferase (MGMT), the repair enzyme represents a most important factor of drug resistance, limiting the therapy of malignant high-grade gliomas. Although MGMT has been shown to be transcriptionally up-regulated in rodents following genotoxic stress, it is still unclear whether human MGMT is subject to up-regulation. Here, we addressed the question whether MGMT in glioma cells is enhanced following alkylating drugs or ionizing radiation, using promoter assays. We also checked the response of glioma cell lines to dexamethasone. In a series of experiments, we found no evidence that the human MGMT promoter is significantly up-regulated following treatment with TMZ, the chloroethylating agent nimustine or radiation. It was activated, however, by dexamethasone. Using deletion constructs, we further show that the basal level of MGMT is mainly determined by the transcription factor SP1. The high amount of SP1 sites in the MGMT promoter likely prevents transcriptional up regulation following genotoxic stress by neutralizing inducible signals. The regulation of MGMT by miRNAs plays only a minor role, as shown by DICER knockdown experiments. Since high dose dexamethasone concomitant with temozolomide is frequently used in glioblastoma therapy, induction of the MGMT gene through glucocorticoids in MGMT promoter unmethylated cases might cause further elevation of drug resistance, while radiation and alkylating drugs seem not to induce MGMT at transcriptional level. PMID- 29164621 TI - Determining Candidate Single Nucleotide Polymorphisms in Acquired Laryngotracheal Stenosis. AB - OBJECTIVES/HYPOTHESIS: Despite wide adoption of strategies to prevent injury from prolonged intubation and tracheotomy, acquired laryngotracheal stenosis (ALTS) has not disappeared. ALTS' persistence may be due to patient factors that confer unique susceptibility for some. We sought to identify genetic markers in genes associated with wound healing that could be associated with ALTS. STUDY DESIGN: Case-control study. METHODS: One hundred thirty-eight patients were recruited, 53 patients with ALTS and 85 control patients who underwent intubation or tracheotomy without evidence of ALTS. The patients' DNA was isolated from whole blood. Custom primers were designed, and the TaqMan assay employing allele specific polymerase chain reaction was used to interrogate single nucleotide polymorphisms (SNPs) rs1799750, rs522616, rs2276109, rs2569190, rs1800469, and rs1024611 of candidate wound healing genes MMP1, MMP3, MMP12, CD14, TGFbeta1, and MCP1, respectively. A logistic regression model was used to examine the association of candidate gene polymorphisms with the presence or absence of ALTS. RESULTS: All 138 patients were successfully genotyped. No significant association was found between candidate SNPs and development of ALTS in the overall group. However, subgroup analysis within each ethnicity identified SNPs that are associated with ALTS depending upon the ethnic background. CONCLUSIONS: Patient factors such as variations in wound healing due to functional SNPs may shed light on the development of ALTS. There may be a difference in susceptibility to developing ALTS in different ethnic backgrounds. These preliminary findings need to be corroborated in larger population studies. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:E111-E116, 2018. PMID- 29164623 TI - Pharmacokinetic profiles of the two major active metabolites of metamizole (dipyrone) in cats following three different routes of administration. AB - This study was performed to determine pharmacokinetic profiles of the two active metabolites of the analgesic drug metamizole (dipyrone, MET), 4 methylaminoantipyrine (MAA), and 4-aminoantipyrine (AA), after intravenous (i.v., intramuscular (i.m.), and oral (p.o.) administration in cats. Six healthy mixed breed cats were administered MET (25 mg/kg) by i.v., i.m., or p.o. routes in a crossover design. Adverse clinical signs, namely salivation and vomiting, were detected in all groups (i.v. 67%, i.m. 34%, and p.o. 15%). The mean maximal plasma concentration of MAA for i.v., i.m., and p.o. administrations was 148.63 +/- 106.64, 18.74 +/- 4.97, and 20.59 +/- 15.29 MUg/ml, respectively, with about 7 hr of half-life in all routes. Among the administration routes, the area under the plasma concentration curve (AUC) value was the lowest after i.m. administration and the AUCEV/i.v . ratio was higher in p.o. than the i.m. administration without statistical significance. The plasma concentration of AA was detectable up to 24 hr, and the mean plasma concentrations were smaller than MAA. The present results suggest that MET is converted into the active metabolites in cats as in humans. Further pharmacodynamics and safety studies should be performed before any clinical use. PMID- 29164622 TI - Sino-Nasal outcome test-22 outcomes after sinus surgery: A systematic review and meta-analysis. AB - OBJECTIVES/HYPOTHESIS: The goal of the study was to perform a systematic review with meta-analysis to determine the mean change in the 22-item Sino-Nasal Outcome Test (SNOT-22) across patients who have had endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) in the literature. METHODS: A literature search was performed to identify studies that assessed SNOT-22 scores before and after ESS in adult patients with CRS. A random effects model with inverse variance weighting was used to generate the mean change after surgery, along with the forest plot and 95% confidence interval (CI). The impact of patient-specific factors across studies was assessed using a mixed-effects meta-regression. RESULTS: The final study list included 40 unique patient cohorts published from 2008 to 2016. All studies showed a statistically significant change in mean SNOT 22 scores between baseline and postoperative time points (P < .001), ranging from 12.7 to 44.8, at an average follow-up of 10.6 months. The summary change in mean SNOT-22 across all studies was 24.4 (95% CI: 22.0-26.8). After forward, step-wise multivariate modeling, studies with higher mean preoperative SNOT-22 score and higher asthma prevalence were associated with greater changes in SNOT-22 score after ESS, whereas studies with longer mean follow-up had smaller changes in SNOT 22 score. CONCLUSIONS: Studies evaluating quality-of-life outcomes after sinus surgery using the SNOT-22 instrument universally show significant improvement after ESS. Across the published literature, the magnitude of change is quite variable and appears to be influenced by a number of factors including baseline SNOT-22 score, asthma prevalence, and length of follow-up. Laryngoscope, 128:581 592, 2018. PMID- 29164624 TI - Suppression of Ultraviolet B-mediated Matrix Metalloproteinase Generation by Sorbus commixta Twig Extract in Human Dermal Fibroblasts. AB - Sorbus commixta is a traditional oriental medicinal plant that grows in East Asian countries such as Korea, Japan and China. The twig of S. commixta has been considered valuable for centuries to treat diseases including asthma, cough and other bronchial disorders. However, the effect of S. commixta twig extract on human skin has not been investigated well. The present study aimed at assessing the antiphotoaging effect of S. commixta twig ethanol extract (STE) on ultraviolet B (UVB)-induced matrix metalloproteinase (MMP) levels and its underlying mechanism in human dermal fibroblasts. In this study, we found that STE (12.5-50 MUg mL-1 ) treatment significantly inhibited UVB-induced MMP-1, MMP 2 and MMP-3 expression, concomitant with a downregulation of intracellular ROS generation. These effects might be associated with a STE-induced inhibition of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, STE also downregulated UVB-induced c-Fos expression in a concentration-dependent manner, but had no inhibitory effect on c-Jun phosphorylation. Taken together, these results indicate that STE may be an antiphotoaging agent and that its effect may occur via its inhibition of MMPs expression and MAPK pathway activation. PMID- 29164626 TI - Looking to and nurturing the future of physiology. PMID- 29164627 TI - Locomotor recovery after lumbar spinal cord injury: fact or fancy? PMID- 29164625 TI - Mechanisms and Mitochondrial Redox Signaling in Photobiomodulation. AB - Photobiomodulation (PBM) involves the use of red or near-infrared light at low power densities to produce a beneficial effect on cells or tissues. PBM therapy is used to reduce pain, inflammation, edema, and to regenerate damaged tissues such as wounds, bones, and tendons. The primary site of light absorption in mammalian cells has been identified as the mitochondria and, more specifically, cytochrome c oxidase (CCO). It is hypothesized that inhibitory nitric oxide can be dissociated from CCO, thus restoring electron transport and increasing mitochondrial membrane potential. Another mechanism involves activation of light or heat-gated ion channels. This review will cover the redox signaling that occurs in PBM and examine the difference between healthy and stressed cells, where PBM can have apparently opposite effects. PBM has a marked effect on stem cells, and this is proposed to operate via mitochondrial redox signaling. PBM can act as a preconditioning regimen and can interact with exercise on muscles. PMID- 29164628 TI - Technical Note: Response time evolution of XR-QA2 GafChromicTM film models. AB - PURPOSE: To evaluate the response of the newest XR-QA2 GafChromicTM film model in terms of postexposure signal growth and energy response in comparison with the older XR-QA (Version 2) model. METHODS: Pieces of film were irradiated to air kerma in air values up to 12 cGy with several beam qualities (5.3-8.25 mm Al) commonly used for CT scanning. Film response was scored in terms of net reflectance from scanned film images at various points in time postirradiation ranging from 1 to 7 days and 5 months postexposure. To reconstruct the measurement signal changes with postirradiation delay, we irradiated one film piece and then scanned it at different point times starting from 2" min and up to 3 days postexposure. RESULTS: For all beam qualities and dose range investigated, it appears that the XR-QA2 film signal completely saturated after 15 h. Compared to 15 h postirradiation scanning time, the observed variation in net reflectance were 3%, 2%, and 1% for film scanned 2" min, 20 min, and 3 h after exposure, respectively, which is well within the measurement uncertainty of the XR-QA2 based reference radiochromic film dosimetry system. A comparison between the XR QA (Version 2) and the XR-QA2 film response after several months (relative to their responses after 24 h) show differences in up to 8% and 1% for each film model respectively. CONCLUSIONS: The replacement of cesium bromide in the older XR-QA (Version 2) film model with bismuth oxide in the newer XR-QA2 film, while keeping the same single sensitive layer structure, lead to a significantly more stable postexposure response. PMID- 29164629 TI - Impact of Ultraviolet Radiation on Expression of Transforming Growth Factor beta, Smad2, Metalloproteinases-1, -3, -8, -9, Cathepsin K and Progerin. AB - Ultraviolet radiation (UVR) is one of the most important environmental factors involved in photoaging. Exposure to UVR leads to dysregulation of expression of cell cycle-related proteins which play key role in skin photodegradation that pretends to develop carcinogenesis. This study examines the role of various UVB doses on the expression of transforming growth factor beta (TGF-beta), Smad2, cathepsin K, progerin and matrix metalloproteinases (MMPs)-1,-3,-8,-9. A group consisting of 63 healthy individuals underwent one of the following treatments: (1) whole body exposed to UVB irradiation on each of 10 consecutive days with 0.7 MED, or (2) whole-body irradiation as described followed by a single erythemal UVB dose on a small body area, or (3) irradiated only with a single erythemal UVB dose on small body area, or (4) were not irradiated at all (control group). When we compared all irradiated groups to the control group, there was significantly higher expression of TGF-beta, MMP-1,-3,-9 and cathepsin K proteins evaluated by Western blot method. The results suggest the role of UVB in impairment of proteins expression that is involved in cell cycle's regulation. Changes in the protein expression involved by acute and chronic UVR confirm its essential role in skin photodestruction. Moreover, obtained result indicates the tendency to occurrence of photoadaptation phenomenon. PMID- 29164630 TI - Segmentation and tracking of lung nodules via graph-cuts incorporating shape prior and motion from 4D CT. AB - PURPOSE: We have developed a robust tool for performing volumetric and temporal analysis of nodules from respiratory gated four-dimensional (4D) CT. The method could prove useful in IMRT of lung cancer. METHODS: We modified the conventional graph-cuts method by adding an adaptive shape prior as well as motion information within a signed distance function representation to permit more accurate and automated segmentation and tracking of lung nodules in 4D CT data. Active shape models (ASM) with signed distance function were used to capture the shape prior information, preventing unwanted surrounding tissues from becoming part of the segmented object. The optical flow method was used to estimate the local motion and to extend three-dimensional (3D) segmentation to 4D by warping a prior shape model through time. The algorithm has been applied to segmentation of well circumscribed, vascularized, and juxtapleural lung nodules from respiratory gated CT data. RESULTS: In all cases, 4D segmentation and tracking for five phases of high-resolution CT data took approximately 10 min on a PC workstation with AMD Phenom II and 32 GB of memory. The method was trained based on 500 breath-held 3D CT data from the LIDC data base and was tested on 17 4D lung nodule CT datasets consisting of 85 volumetric frames. The validation tests resulted in an average Dice Similarity Coefficient (DSC) = 0.68 for all test data. An important by product of the method is quantitative volume measurement from 4D CT from end inspiration to end-expiration which will also have important diagnostic value. CONCLUSION: The algorithm performs robust segmentation of lung nodules from 4D CT data. Signed distance ASM provides the shape prior information which based on the iterative graph-cuts framework is adaptively refined to best fit the input data, preventing unwanted surrounding tissue from merging with the segmented object. PMID- 29164631 TI - Effects of selective alpha2 -adrenergic receptor agonists on electrical field stimulated contractions of isolated bronchi in horses. AB - We investigated the effects of different selective alpha2 -adrenergic receptor (AR) agonists (detomidine, medetomidine, xylazine, and brimonidine) on the contractions of horse-isolated bronchi induced by electrical field stimulation (EFS) and by carbachol. No effects were observed on the contraction induced by carbachol, while alpha2 -AR agonists reduced EFS-evoked contractions in a concentration-related fashion. The rank order of potency (pD2 ) was brimonidine (7.40 +/- 0.20) >medetomidine (7.09 +/- 0.24) >detomidine (6.13 +/- 0.55) >xylazine (4.59 +/- 0.16). The maximal effects (Emax ) were -56.3% +/- 6.3%, 40.4% +/- 6.9%, -48.6% +/- 9.9%, and -72.7% +/- 12.7% for brimonidine, medetomidine, detomidine, and xylazine, respectively. Adrenergic block by guanethidine enhanced the potency (8.10 +/- 0.05, 7.30 +/- 0.15, 6.83 +/- 0.41, and 5.40 +/- 0.22) and the efficacy (-95.2% +/- 0.7%, -45.2% +/- 11.7%, -58.5% +/ 9.8%, and -97.9% +/- 0.6%) of brimonidine, medetomidine, detomidine, and xylazine, respectively. Selective alpha2 -AR antagonist, atipamezole, competitively antagonized the inhibition of EFS-evoked contractions induced by all agonists except xylazine. These results suggest the existence of presynaptic alpha2 -ARs on cholinergic neurons, negatively regulating the release of acetylcholine in horse bronchial muscle, and that alpha2 -AR agonists may be beneficial against vagally mediated bronchoconstriction. PMID- 29164632 TI - Characterization of nanoDot optically stimulated luminescence detectors and high sensitivity MCP-N thermoluminescent detectors in the 40-300 kVp energy range. AB - PURPOSE: To investigate empirically the energy dependence of the detector response of two in vivo luminescence detectors, LiF:Mg,Cu,P (MCP-N) high sensitivity TLDs and Al2 O3 :C OSLDs, in the 40-300-kVp energy range in the context of in vivo surface dose measurement. As these detectors become more prevalent in clinical and preclinical in vivo measurements, knowledge of the variation in the empirical dependence of the measured response of these detectors across a wide spectrum of beam qualities is important. METHOD: We characterized a large range of beam qualities of three different kilovoltage x-ray units: an Xstrahl 300 Orthovoltage unit, a Precision x-Ray X-RAD 320ix biological irradiator, and a Varian On-Board Imaging x-ray unit. The dose to water was measured in air according to the AAPM's Task Group 61 protocol. The OSLDs and TLDs were irradiated under reference conditions on the surface of a water phantom to provide full backscatter conditions. To assess the change in sensitivity in the long term, we separated the in vivo dosimeters of each type into an experimental and a reference group. The experimental dosimeters were irradiated using the kilovoltage x-ray units at each beam quality used in this investigation, while the reference group received a constant 10 cGy irradiation at 6 MV from a Varian clinical linear accelerator. The individual calibration of each detector was verified in cycles where both groups received a 10 cGy irradiation at 6 MV. RESULTS: The nanoDot OSLDs were highly reproducible, with +/ 1.5% variation in response following >40 measurement cycles. The TLDs lost ~20% of their signal sensitivity over the course of the study. The relative light output per unit dose to water of the MCP-N TLDs did not vary with beam quality for beam qualities with effective energies <50 keV (~150 kVp/6 mm Al). At higher energies, they showed a reduced (~75-85%) light output per unit dose relative to 6 MV x rays. The nanoDot OSLDs exhibited a very strong (120-408%) dependency of the light output relative to 6 MV x rays. Variations up to 15% between different x-ray units with equivalent effective energies were also observed. CONCLUSIONS: While convenient for clinical use, nanoDot OSLDs exhibit a strong variation in their measured light output per unit dose relative to 6 MV in the 40-300 kV x-ray range. This variability differs unit-to-unit, limiting their effective use for in vivo dosimetry applications in the kilovoltage x-ray energy range. MCP-N TLDs offer a much more stable response, but suffer from variations in sensitivity over time dependent on radiation history, which requires careful experimental handling. PMID- 29164633 TI - Capillarisin blocks prostate-specific antigen expression on activation of androgen receptor in prostate carcinoma cells. AB - BACKGROUND: Capillarisin (Cap), an active ingredient of Artemisia capillaris extracts, has known for its anti-inflammatory, antioxidant, and anticancer properties. Functions of Cap in prostate cancer are not clear. We investigate effects of Cap on downregulation of prostate specific antigen (PSA) via modulation of androgen receptor (AR) in prostate carcinoma cells. METHODS: Cell proliferation was measured by water-soluble tetrazolium-1 (WST-1) cell proliferation assays. The PSA and AR expressions were assessed by immunoblotting and RT-qPCR assays. Effects of Cap on PSA expressions were determined by ELISA, immunoblotting, and reporter assays. Co-immunoprecipitation and immunoblotting assays were used to define the effects of Cap on dissociation of AR-heat shock protein 90 (Hsp90) interaction. RESULTS: Cap inhibited LNCaP cell growth in a dose- and/or time-dependent way without inducing poly ADP-Ribose Polymerase (PARP) cleavage. Cap not only effectively suppressed AR and PSA protein expressions, but also attenuated activations of synthetic androgen (R1881) on PSA promoter activity dose- and time-dependently. The Cap pretreatment abrogated effects of R1881 on AR activity by reducing AR translocation to the nucleus. Immunoblotting assays indicated that Cap promoted a degradation of AR proteins dose-dependently in either cycloheximide pretreated-LNCaP cells or AR-ectopic expressed PC-3 cells. Pretreatment of MG132, a proteasome inhibitor, attenuated effect of Cap on AR degradation. Cap lessened AR stability by dissociation of AR Hsp90 interaction. CONCLUSIONS: Our results indicated that Cap inhibited growth of LNCaP cells. Cap effectively suppressed androgen activation on AR-mediated transactivation, which is AR-dependent through AR degradation and dissociation of AR-Hsp90 in prostate carcinoma cells. PMID- 29164634 TI - Testing the limits of model membrane simulations-bilayer composition and pressure scaling. AB - Studying transfer of bioactive compounds across cell membranes by simulations attracts growing attention. To perform such calculations accurately, it is necessary to verify the validity of computational protocols established for description of unperturbed lipid bilayers also with translocating substances present. The current work reports the results from 1 MUs long atomistic molecular dynamics simulations of two types of model plasma membranes-one built of a single phospholipid (DPPC) and one constructed of four types of phospholipids-in the presence of a drug-peptide complex experimentally known to cross cell membranes. The influence of membrane composition and of applied pressure scaling algorithm on the simulations outcome is analyzed with particular focus on membrane structure and on complex-lipid interactions during the initial penetration stage. It is found that the mixed composition of the membrane is important for correct assessment of the interactions with the complex both from purely structural perspective and because of the uneven charge distribution. The structure of the mixed lipid bilayer is affected more markedly by the pressure scaling algorithm. When the pressure is isotropically scaled, lipids are distributed almost homogeneously along the membrane in liquid ordered state. On semi-isotropic scaling, the lipid tails undergo significant rearrangement and a long-range ordered state is established. This results in "freezing" of the membrane and expulsion of the complex. The statistical analysis of the MD data points to the conclusion that a mixed-lipid membrane model with isotropic pressure scaling would be more suitable for describing the process of complex translocation across neoplastic membranes. (c) 2017 Wiley Periodicals, Inc. PMID- 29164635 TI - Retracted: Influence of genetic variants of IDH1, IDH2, TET2 and DNMT3A on cytarabine cytotoxicity in different populations. AB - 'Influence of genetic variants of IDH1, IDH2, TET2 and DNMT3A on cytarabine cytotoxicity in different populations' by Y. Wang & J. K. Lamba1 The above article from the Journal of Clinical Pharmacy and Therapeutics, published online on 21 November 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted following discussions with the authors, the Journal Editors and John Wiley & Sons Ltd. The Retraction has been agreed as this paper was submitted under the joint names of Yan Wang, Jatinder K. Lamba and a third co-author. After acceptance of the paper, Dr Wang wrote to the EiC asking for the name of the third co-author to be dropped because of insufficient contribution. The EiC asked that the request be signed by all three authors. When this arrived, the paper was published online with only Dr Wang and Dr Lamba. However, Dr Lamba wrote to the EiC after publication indicating that she had not previously seen the manuscript and that there were co-authors missing. As it is clear that Dr Lamba's signature was forged, we cannot rely on the integrity of the report. The retraction is with the agreement of Dr Lamba but not of Dr Wang. REFERENCE 1. Wang Y, Lamba JK. Influence of genetic variants of IDH1, IDH2, TET2 and DNMT3A on cytarabine cytotoxicity in different populations. J Clin Pharm Ther. 2017;00:1-9. https://doi.org/10.1111/jcpt.12653. PMID- 29164636 TI - Development and validation of a simple solid-phase extraction method coupled with liquid chromatography-triple quadrupole tandem mass spectrometry for simultaneous determination of lincomycin, tylosin A and tylosin B in royal jelly. AB - We have developed an analytical method for the determination of lincomycin, tylosin A and tylosin B residues in royal jelly using liquid chromatography triple quadrupole tandem mass spectrometry analysis. For extraction and purification, we employed 1% trifluoroacetic acid and 0.1 m Na2 EDTA solutions along with an Oasis HLB cartridge. The target antibiotics were well separated in a Kinetex EVO C18 reversed-phase analytical column using a combination of 0.1% formate acid in ultrapure water (A) and acetonitrile (B) as the mobile phase. Good linearity was achieved over the tested concentration range (5-50 MUg/kg) in matrix-matched standard calibration. The coefficients of determination (R2 ) were 0.9933, 0.9933 and 0.996, for tylosin A, tylosin B and lincomycin, respectively. Fortified royal jelly spiked with three different concentrations of the tested antibiotics (5, 10 and 20 MUg/kg) yielded recoveries in the range 80.94-109.26% with relative standard deviations <=4%. The proposed method was applied to monitor 11 brand of royal jelly collected from domestic markets and an imported brand from New Zealand; all the samples tested negative for lincomycin, tylosin A and tylosin B residues. In conclusion, 1% trifluoroacetic acid and 0.1 m Na2 EDTA aqueous solvents combined with solid-phase extraction could effectively complete the sample preparation process for royal jelly before analysis. The developed approach can be applied for a routine analysis of lincomycin, tylosin A and tylosin B residues in royal jelly. PMID- 29164637 TI - Internal pilot design for balanced repeated measures. AB - Repeated measures are common in clinical trials and epidemiological studies. Designing studies with repeated measures requires reasonably accurate specifications of the variances and correlations to select an appropriate sample size. Underspecifying the variances leads to a sample size that is inadequate to detect a meaningful scientific difference, while overspecifying the variances results in an unnecessarily large sample size. Both lead to wasting resources and placing study participants in unwarranted risk. An internal pilot design allows sample size recalculation based on estimates of the nuisance parameters in the covariance matrix. We provide the theoretical results that account for the stochastic nature of the final sample size in a common class of linear mixed models. The results are useful for designing studies with repeated measures and balanced design. Simulations examine the impact of misspecification of the covariance matrix and demonstrate the accuracy of the approximations in controlling the type I error rate and achieving the target power. The proposed methods are applied to a longitudinal study assessing early antiretroviral therapy for youth living with HIV. PMID- 29164638 TI - The PIWI-Interacting RNA Molecular Pathway: Insights From Cultured Silkworm Germline Cells. AB - The PIWI-interacting RNA (piRNA) pathway, one of the major eukaryotic small RNA silencing pathways, is a genome surveillance system that silences selfish genes in animal gonads. piRNAs guide PIWI protein to target genes through Watson-Crick RNA-RNA base-parings. Loss of piRNA function causes genome instability, inducing failure in gametogenesis and infertility. Studies using fruit flies and mice as key experimental models have resulted in tremendous progress in understanding the mechanism underlying the piRNA pathway. Recent work using cultured silkworm germline cells has also expanded our knowledge of piRNA biogenesis in particular, since these silkworm cells are the only cells of germline origin that can be cultured. In this review, we describe elucidation of the piRNA pathway using cultured silkworm cells as an experimental model by focusing on recent work in biochemistry and structural biology. Earlier studies that made important contributions to the field are also described. PMID- 29164639 TI - Analytic energy gradients for orbital-optimized MP3 and MP2.5 with the density fitting approximation: An efficient implementation. AB - Efficient implementations of analytic gradients for the orbital-optimized MP3 and MP2.5 and their standard versions with the density-fitting approximation, which are denoted as DF-MP3, DF-MP2.5, DF-OMP3, and DF-OMP2.5, are presented. The DF MP3, DF-MP2.5, DF-OMP3, and DF-OMP2.5 methods are applied to a set of alkanes and noncovalent interaction complexes to compare the computational cost with the conventional MP3, MP2.5, OMP3, and OMP2.5. Our results demonstrate that density fitted perturbation theory (DF-MP) methods considered substantially reduce the computational cost compared to conventional MP methods. The efficiency of our DF MP methods arise from the reduced input/output (I/O) time and the acceleration of gradient related terms, such as computations of particle density and generalized Fock matrices (PDMs and GFM), solution of the Z-vector equation, back transformations of PDMs and GFM, and evaluation of analytic gradients in the atomic orbital basis. Further, application results show that errors introduced by the DF approach are negligible. Mean absolute errors for bond lengths of a molecular set, with the cc-pCVQZ basis set, is 0.0001-0.0002 A. (c) 2017 Wiley Periodicals, Inc. PMID- 29164640 TI - Computer program for finding all possible cycles in graphs. AB - A new approach is presented for identifying all possible cycles in graphs. Input data are the total numbers of vertices and edges, as well as the vertex adjacencies using arbitrary vertex numbering. A homeomorphically reduced graph (HRG) is constructed by ignoring vertices of degree less than three. The algorithm is based on successive generation of possible edge-combinations in the HRG. If a combination yields a cycle, it is either printed or stored and then finally printed in a list of all possible cycles arranged in the order of increasing ring size. A unique numbering of the cycle is used. The computer program is listed and exemplified. Computing times are given. PMID- 29164641 TI - Five criteria for using a surrogate endpoint to predict treatment effect based on data from multiple previous trials. AB - A surrogate endpoint in a randomized clinical trial is an endpoint that occurs after randomization and before the true, clinically meaningful, endpoint that yields conclusions about the effect of treatment on true endpoint. A surrogate endpoint can accelerate the evaluation of new treatments but at the risk of misleading conclusions. Therefore, criteria are needed for deciding whether to use a surrogate endpoint in a new trial. For the meta-analytic setting of multiple previous trials, each with the same pair of surrogate and true endpoints, this article formulates 5 criteria for using a surrogate endpoint in a new trial to predict the effect of treatment on the true endpoint in the new trial. The first 2 criteria, which are easily computed from a zero-intercept linear random effects model, involve statistical considerations: an acceptable sample size multiplier and an acceptable prediction separation score. The remaining 3 criteria involve clinical and biological considerations: similarity of biological mechanisms of treatments between the new trial and previous trials, similarity of secondary treatments following the surrogate endpoint between the new trial and previous trials, and a negligible risk of harmful side effects arising after the observation of the surrogate endpoint in the new trial. These 5 criteria constitute an appropriately high bar for using a surrogate endpoint to make a definitive treatment recommendation. PMID- 29164642 TI - Performance of density functionals for modeling vapor liquid equilibria of CO2 and SO2. AB - Vapor liquid equilibria (VLE) and condensed phase properties of carbon dioxide and sulfur dioxide are calculated using first principles Monte Carlo (FPMC) simulations to assess the performance of several density functionals, notably PBE D3, BLYP-D3, PBE0-D3, M062X-D3, and rVV10. GGA functionals were used to compute complete vapor liquid coexistence curves (VLCCs) to estimate critical properties, while the hybrid and nonlocal van der Waals functionals were used only for computing density at a single state point due to the high computational cost. Our results show that the BLYP-D3 functional performs well in predicting VLE properties for both molecules when compared with other functionals. In the liquid phase, pair correlation functions reveal that there is not a significant difference in the location of the peak for the first solvation shell while the peak heights are different for different functionals. Overall, the BLYP-D3 functional is a good choice for modeling VLE of acidic gases with significant environmental implications such as CO2 and SO2 . (c) 2017 Wiley Periodicals, Inc. PMID- 29164643 TI - Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population. AB - : The metabolic syndrome and alcohol risk use are both associated with a high prevalence of hepatic steatosis, but only a minority develop liver failure or liver cancer. Few general population studies have analyzed metabolic predictors of such severe liver complications. We studied which metabolic factors best predict severe liver complications, stratified by alcohol consumption, in 6732 individuals without baseline liver disease who participated in the Finnish population-based Health 2000 Study (2000-2001), a nationally representative cohort. Follow-up data from national registers until 2013 were analyzed for liver related admissions, mortality, and liver cancer. Baseline alcohol use and metabolic factors were analyzed by backward stepwise Cox regression analysis. Eighty-four subjects experienced a severe liver event during follow-up. In the final multivariate model, factors predictive of liver events were age (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.004-1.04), sex (women: HR, 0.55; 95% CI, 0.34-0.91), alcohol use (HR, 1.002; 95% CI, 1.001-1.002), diabetes (HR, 2.73; 95% CI, 1.55-4.81), low-density lipoprotein (LDL) cholesterol (HR, 0.74; 95% CI, 0.58-0.93), and homeostasis model assessment of insulin resistance (HOMA-IR) (HR, 1.01; 95% CI, 1.004-1.02). Among alcohol risk users (>=210 g/week for men, >= 140 g/week for women), diabetes (HR, 6.79; 95% CI, 3.18-14.5) was the only significant predictor. Among nonrisk drinkers, age, alcohol use, smoking, waist circumference, low LDL cholesterol and HOMA-IR were significant independent predictors. The total-to-LDL cholesterol ratio and waist circumference-to-body mass index ratio emerged as additional independent predictors. CONCLUSION: Multiple components of the metabolic syndrome independently affected the risk for severe liver disease. Alcohol was significant even when average alcohol consumption was within the limits currently defining nonalcoholic fatty liver disease. (Hepatology 2018;67:2141-2149). PMID- 29164644 TI - Should embryos with autosomal monosomy by preimplantation genetic testing for aneuploidy be transferred?: Implications for embryo selection from a systematic literature review of autosomal monosomy survivors. AB - OBJECTIVE: To review the literature for survival and phenotypes of liveborns with autosomal monosomy to inform decisions regarding transfer of in vitro fertilization-derived embryos reported as monosomic on preimplantation genetic testing for aneuploidy (PGT-A). METHOD: Ovid-Medline and EMBASE were systematically searched to identify published case reports of liveborn individuals with autosomal monosomy, full or mosaic, for a whole chromosome. RESULTS: Fifty-three reports describing 56 individuals with autosomal monosomy met the selection criteria: 1 case each of monosomy 14 and 16, 3 each for monosomy 15 and 18, 1 for group "E", 5 for monosomy 20, 24 for monosomy 21, 7 for monosomy 22, and eleven for a "G" group chromosome. There were no reports with monosomy for the larger chromosomes 1 through 13, nor for chromosomes 17 or 19, autosomes with highest gene density. Most reported individuals had severe handicaps and died in infancy with some surviving longer. CONCLUSION: Given potential for survival of handicapped individuals with autosomal monosomy for chromosomes 14, 15, 16, 18, 20, 21, and 22, low priority should be given to transfer of embryos apparently monosomic for these chromosomes. Couples electing transfer of monosomic embryos should consider amniocentesis for ongoing pregnancies but should be informed of its limitations. PMID- 29164646 TI - B-factor profile prediction for RNA flexibility using support vector machines. AB - Determining the flexibility of structured biomolecules is important for understanding their biological functions. One quantitative measurement of flexibility is the atomic Debye-Waller factor or temperature B-factor. Most existing studies are limited to temperature B-factors of proteins and their prediction. Only one method attempted to predict temperature B-factors of ribosomal RNA. Here, we developed and compared machine-learning techniques in prediction of temperature B-factors of RNAs. The best model based on Support Vector Machines yields Pearson's correction coefficient at 0.51 for fivefold cross validation and 0.50 for the independent test. Analysis of the performance indicates that the model has the best performance on rRNAs, tRNAs, and protein bound RNAs, for long chains in particular. The server is available at http://sparks-lab.org/server/RNAflex. (c) 2017 Wiley Periodicals, Inc. PMID- 29164647 TI - Experimental and theoretical electron density of intermediates in palladium phenanthroline catalyzed carbonylation of amines and reductive carbonylation of nitroarenes. AB - The accurate electron density distribution in Pd(Neoc)Cl2 (CO) (Neoc = 2,9 dimethyl-1,10-phenanthroline) was measured and calculated to investigate the chemical bonding features, the electrostatic forces and the polarizable bonds in this complex, which is a prototype of the proposed intermediate in the catalytic carbonylation of amines and nitroarenes. The quantum theory of atoms in molecules enables to investigate the nature of the elusive fifth coordination in the complex, which is approximately intermediate between a bypiramid penta coordination and a square planar tetra-coordination. The analysis of the electrostatic potential and of the distributed atomic polarizabilities enables to address the sites that are more prompt to react, in particular in the context of the catalytic cycle. (c) 2017 Wiley Periodicals, Inc. PMID- 29164645 TI - Current or recent smoking is associated with more variable telomere length in prostate stromal cells and prostate cancer cells. AB - BACKGROUND: Current and recent smoking have been associated with a greater risk of prostate cancer recurrence and mortality, though the underlying mechanism is unknown. METHODS: To determine if telomere shortening, which has been associated with poor outcomes, may be a potential underlying mechanism, we prospectively evaluated the association between smoking status and telomere length in 567 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays (TMA), we measured telomere length in cancer and benign tissue, specifically stromal cells in the same TMA spot using a telomere-specific fluorescence in situ hybridization assay. Smoking status was collected via questionnaire 2-years before diagnosis. Adjusting for age, pathologic stage and grade, the median and standard deviation of the per cell telomere signals were determined for each man for stromal cells and cancer cells by smoking categories. In sub-analyses, we restricted to men without major co-morbidities diagnosed before prostate cancer. RESULTS: Overall, there were no associations between smoking status and telomere length or variability in stromal cells or cancer cells. However, among men without comorbidities, current smokers and former smokers who quit <10 years ago had the most variable telomere length in stromal cells (29.3% more variable than never smokers; P-trend = 0.0005) and in cancer cells (27.7% more variable than never smokers; P-trend = 0.05). Among men without comorbidities, mean telomere length did not differ by smoking status in stromal cells or cancer cells. CONCLUSION: Telomere variability in prostate cells may be one mechanism through which smoking influences poor prostate cancer outcomes. PMID- 29164649 TI - Impact of alcohol and cigarette smoking consumption in male fertility potential: Looks at lipid peroxidation, enzymatic antioxidant activities and sperm DNA damage. AB - Alcohol intake and cigarette smoking are the major lifestyle factors with negative impact on fertility. We were interested to evaluate the negative impact of these factors on oxidative stress (OS), enzymatic antioxidant activity (EAO) of spermatozoa and on its DNA damage. This study included 108 male infertile patients with normal range of sperm conventional parameters but with unexplained infertility in assisted reproductive technologies programme. Firstly, OS was analysed based on lipid peroxidation (MDA) and EAO which included catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR). Secondly, we evaluated DNA fragmentation by TUNEL assay and chromatin decondensation by aniline blue colouration. The whole lot was divided into four groups: control (nonalcoholic and nonsmoker patients), alcohol group, smoking group and alcohol-smoking group. The results showed, in three last groups compared to control an increased CAT, SOD and GR activities with high MDA level especially in smoking and alcohol smoking group. The latter showed the highest values of DNA fragmentation and chromatin decondensation (31% and 39%) to exceed DNA damage normal range. Indeed, smoking and alcohol intake lead to increase EAO due to long-term unbalanced antioxidant/oxidation ratio with high OS which cause consequently sperm DNA damage calling in need by urgency to change the lifestyle behaviour. PMID- 29164648 TI - A state transition framework for patient-level modeling of engagement and retention in HIV care using longitudinal cohort data. AB - The human immunodeficiency virus (HIV) care cascade is a conceptual model used to outline the benchmarks that reflects effectiveness of HIV care in the whole HIV care continuum. The models can be used to identify barriers contributing to poor outcomes along each benchmark in the cascade such as disengagement from care or death. Recently, the HIV care cascade has been widely applied to monitor progress towards HIV prevention and care goals in an attempt to develop strategies to improve health outcomes along the care continuum. Yet, there are challenges in quantifying successes and gaps in HIV care using the cascade models that are partly due to the lack of analytic approaches. The availability of large cohort data presents an opportunity to develop a coherent statistical framework for analysis of the HIV care cascade. Motivated by data from the Academic Model Providing Access to Healthcare, which has provided HIV care to nearly 200,000 individuals in Western Kenya since 2001, we developed a state transition framework that can characterize patient-level movements through the multiple stages of the HIV care cascade. We describe how to transform large observational data into an analyzable format. We then illustrate the state transition framework via multistate modeling to quantify dynamics in retention aspects of care. The proposed modeling approach identifies the transition probabilities of moving through each stage in the care cascade. In addition, this approach allows regression-based estimation to characterize effects of (time-varying) predictors of within and between state transitions such as retention, disengagement, re entry into care, transfer-out, and mortality. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29164650 TI - Market share and costs of biologic therapies for inflammatory bowel disease in the USA. AB - BACKGROUND: Real-world data quantifying the costs of increasing use of biologics in inflammatory bowel disease (IBD) are unknown. AIM: To determine the outpatient IBD drug utilization trends, relative market share, and costs in the USA during a 9-year period. METHODS: The Truven MarketScan(r) Database was analysed for patients with Crohn's disease (CD) and ulcerative colitis (UC) during 2007-2015. National drug codes were used to identify prescription drugs; Healthcare Common Procedure Coding System J-codes were used to capture biologic out-patient infusions. Proportion of drug usage, relative market share and per-member per year (PMPY) costs were analysed for biologics, immunomodulators, 5-ASAs and corticosteroids. RESULTS: In 415 405 patients (188 842 CD; 195 183 UC; 31 380 indeterminate colitis; 54.67% female), utilization trends show a consistent rise in the market share of biologics during the 9-year study period. The proportion of patients using biologics increased from 21.8% to 43.8% for CD and 5.1%-16.2% for UC. This contrasts a small decrease in immunomodulator and 5-ASA use for CD and relative constancy of other classes including corticosteroids-only use as primary IBD medication from 2007 to 2015. The average biologic-taking patient accounted for $25 275 PMPY in 2007 and $36 051 PMPY in 2015. The average paediatric biologic-taking patient accounted for $23 616 PMPY in 2007 and $41 109 PMPY in 2015. In all patients, the share of costs for biologics increased from 72.9% in 2007 to 85.7% in 2015 (81.7% in 2007 to 94.9% in 2015 in paediatrics). CONCLUSION: The vast majority of costs allocated to out-patient IBD medications in the USA is attributed to increasing use of biologic therapies despite the relative minority of biologic-taking patients. PMID- 29164651 TI - Jaw closing movement and sex differences in temporomandibular joint energy densities. AB - Energy densities (ED, mJ/mm3 ) quantify mechanical work imposed on articular cartilages during function. This cross-sectional study examined differences in temporomandibular joint (TMJ) ED during asymmetric versus symmetric jaw closing in healthy females versus males. ED component variables were tested for differences between and within sexes for two types of jaw closing. Seventeen female and 17 male subjects gave informed consent to participate. Diagnostic criteria for temporomandibular disorders and images (magnetic resonance (MR), computed tomography) were used to confirm healthy TMJ status. Numerical modelling predicted TMJ loads (Fnormal ) consequent to unilateral canine biting. Dynamic stereometry combined MR imaging and jaw-tracking data to measure ED component variables during 10 trials of each type of jaw closing in each subject's TMJs. These data were then used to calculate TMJ ED during jaw closing asymmetrically and symmetrically. Paired and Student's t tests assessed ED between jaw closing movements and sexes, respectively. Multivariate data analyses assessed ED component variable differences between jaw closing movements and sexes (alpha = 0.05). Contralateral TMJ ED were 3.6-fold and significantly larger (P < .0001) during asymmetric versus symmetric jaw closing, due to significantly larger (P <= .001) distances of TMJ stress-field translation in asymmetric versus symmetric movement. During asymmetric jaw closing, contralateral TMJ ED were twofold and significantly larger (P = .036) in females versus males, due to 1.5-fold and significantly smaller (P <= .010) TMJ disc cartilage volumes under stress fields in females versus males. These results suggest that in healthy individuals, asymmetric compared to symmetric jaw closure in females compared to males has higher TMJ mechanical fatigue liabilities. PMID- 29164652 TI - Cerium oxide nanoparticle elicits oxidative stress, endocrine imbalance and lowers sperm characteristics in testes of balb/c mice. AB - The toxicity of metallic nanoparticles is a growing concern due to its application in industries and homes. We investigated the toxicity of cerium oxide nanoparticles (CeO2 NPs) on reproductive system in male balb/c mice. Twenty mice were divided into four groups of five animals each and treated thus: normal saline (control), 100, 200 and 300 MUg/kg CeO2 NPs (i.p.,) thrice in a week for five consecutive weeks. Results showed that CeO2 NPs significantly reduced the levels of haemoglobin, PCV and RBC count relative to controls. In addition, luteinising and follicle-stimulating hormones (FSH and LH) and prolactin were significantly reduced in the mice. Specifically, CeO2 NPs at 100 MUg/kg decreased testosterone by 23%, while CeO2 NPs at 200 MUg/kg decreased FSH, LH and prolactin by 25%, 26% and 13%, respectively. Testicular malondialdehyde was increased by 103%, 106% and 135% in mice treated with 100, 200 and 300 MUg/kg CeO2 NPs, respectively. CeO2 NPs caused a significant reduction in activities of antioxidant enzymes and levels of reduced glutathione and total nitric oxide. Moreso, CeO2 NPs decreased sperm motility and count and increased total sperm abnormality in mice. Histology revealed congestion and degeneration of seminiferous tubules. Overall, CeO2 NPs induces testicular dysfunction via disruption of antioxidant/oxidant balance and endocrine suppression. PMID- 29164653 TI - Gradient sperm selection for reproductive techniques in cattle: Is Isolate a suitable replacement for Percoll? AB - In assisted reproductive techniques, it is essential to perform a sperm selection to obtain spermatozoa with high motility and membrane integrity for in vitro fertilisation (IVF) and high-DNA integrity for intracytoplasmic sperm injection (ICSI). In this study, we evaluated whether Isolate(r) was a suitable substitute for Percoll(r) for assisted reproductive techniques. Commercial cryopreserved bovine semen was used after selection in both gradients, and plasma and acrosome membrane integrity, reactive oxygen species (ROS) levels, DNA integrity and mitochondrial membrane potential (DeltaPsim) were assessed by flow cytometry. Motility parameters were also evaluated by CASA system. A similar percentage of spermatozoa with intact plasma membrane, acrosome integrity and high DeltaPsim was observed in both sperm selection methods, but only Percoll(r) showed higher percentage of spermatozoa with intact plasma and acrosome membrane compared to the post-thawing group. No differences were observed in the motility, ROS, DNA fragmentation and on the in vitro embryo production in all experimental groups. In conclusion, the selection of bovine spermatozoa with Isolate(r) generates spermatozoa with similar quality parameters and embryonic development compared to Percoll(r) providing a suitable alternative sperm selection method for assisted reproductive techniques in this species. PMID- 29164654 TI - Exponential decay for binary time-varying covariates in Cox models. AB - Cox models are commonly used in the analysis of time to event data. One advantage of Cox models is the ability to include time-varying covariates, often a binary covariate that codes for the occurrence of an event that affects an individual subject. A common assumption in this case is that the effect of the event on the outcome of interest is constant and permanent for each subject. In this paper, we propose a modification to the Cox model to allow the influence of an event to exponentially decay over time. Methods for generating data using the inverse cumulative density function for the proposed model are developed. Likelihood ratio tests and AIC are investigated as methods for comparing the proposed model to the commonly used permanent exposure model. A simulation study is performed, and 3 different data sets are presented as examples. PMID- 29164655 TI - Role of two 5-aminolevulinic acid biosynthetic pathways in heme and secondary metabolite biosynthesis in Amycolatopsis orientalis. AB - Analysis of the Amycolatopsis orientalis genome revealed that two genes, hemA1 and hemA2, belonging to divergent pathways, were involved in the biosynthesis of 5-aminolevulinic acid. The roles of hemA1 and hemA2 were elucidated via genetic manipulation and metabolite analysis. The disruption of hemA1, encoding the glutamyl-tRNAGlu reductase of the C5 pathway, was essential for cell growth and is used for heme synthesis. Overexpression of hemA1 resulted in elevated vancomycin and ECO-0501 production in Amycolatopsis orientalis, and it was also effective in increasing the production of daptomycin and natamycin in other Streptomycetes. The disruption of hemA2 indicated that it encodes the 5 aminolevulinic acid synthase of the Shemin pathway, serving as a key enzyme for the synthesis of the precursor aminohydroxycyclopentenone unit of ECO-0501. However, hemA2 disruption could not be complemented by the addition of 5 aminolevulinic acid or by the expression of hemA2 outside of the ECO-0501 gene cluster. The synthesis of ECO-0501 was only restored by the insertion of hemA2 at its original locus. The hemA2 gene could partly complement the hemA1 deficiency. Overexpression of hemA1, a key gene from the heme biosynthetic pathway, is proposed here as a new approach to improve the production of secondary metabolites in bacteria, whereas hemA2 plays different roles depending on its pattern of expression. PMID- 29164657 TI - Resveratrol protects Leydig cells from nicotine-induced oxidative damage through enhanced autophagy. AB - Some studies have revealed that nicotine can damage the male reproductive system through various means including oxidative stress, which is a primary factor in the pathogenesis of male infertility. The strong anti-oxidative capacity of resveratrol has been demonstrated previously, but its role in the context of male reproduction remains inconclusive. To explore the biological role of resveratrol in protecting male reproductive function and the potential underlying mechanism, nicotine-induced Leydig cells were used as a cell model of oxidative damage. The data showed that resveratrol treatment increased cell viability, SOD activity and anti-apoptotic activity in nicotine-stressed Leydig cells. This effect was accompanied by the upregulation of autophagy, which was illustrated by MDC LysoTracker red staining. Moreover, pretreating with 3-methyladenine (3-MA), an autophagy inhibitor, attenuated resveratrol-induced Leydig cells autophagy and promoted apoptosis. Apart from this, resveratrol enhanced AMPK phosphorylation but reduced mTOR phosphorylation. Subsequently, upon inhibiting AMPK phosphorylation by AMPK inhibitors, Leydig cell autophagy induced by resveratrol was obviously abolished. In conclusion, resveratrol may exert its cytoprotective role against oxidative injury by the activation of autophagy via AMPK/mTOR pathway. PMID- 29164656 TI - Intergroup LEAP trial (S1612): A randomized phase 2/3 platform trial to test novel therapeutics in medically less fit older adults with acute myeloid leukemia. PMID- 29164658 TI - Successful treatment of Raynaud's phenomenon and digital ulcers in systemic sclerosis patients with botulinum toxin B injection: Assessment of peripheral vascular disorder by angiography and dermoscopic image of nail fold capillary. AB - We recently identified the efficacy and safety of a botulinum toxin (BTX)-A/B in Raynaud's phenomenon (RP) and digital ulcers (DU) in Japanese patients with systemic sclerosis (SSc). Detailed assessments of peripheral vascular disorder using angiography and dermoscopic images of nail fold capillaries have not been performed previously. This study aimed to evaluate the effect of BTX-B on SSc associated peripheral vascular disorder. Two SSc patients who suffered with RP and DU were treated with a BTX-B injection, and thereafter the symptoms of RP were improved and DU healed in both patients. Furthermore, angiography showed an increased blood flow to the palm and fingers, and dermoscopic images of nail fold capillary changes showed improvement. These results suggest that a BTX-B injection may increase peripheral blood flow and improve RP and DU in SSc patients. PMID- 29164659 TI - Spatializing Emotion: No Evidence for a Domain-General Magnitude System. AB - People implicitly associate different emotions with different locations in left right space. Which aspects of emotion do they spatialize, and why? Across many studies people spatialize emotional valence, mapping positive emotions onto their dominant side of space and negative emotions onto their non-dominant side, consistent with theories of metaphorical mental representation. Yet other results suggest a conflicting mapping of emotional intensity (a.k.a., emotional magnitude), according to which people associate more intense emotions with the right and less intense emotions with the left - regardless of their valence; this pattern has been interpreted as support for a domain-general system for representing magnitudes. To resolve the apparent contradiction between these mappings, we first tested whether people implicitly map either valence or intensity onto left-right space, depending on which dimension of emotion they attend to (Experiments 1a, b). When asked to judge emotional valence, participants showed the predicted valence mapping. However, when asked to judge emotional intensity, participants showed no systematic intensity mapping. We then tested an alternative explanation of findings previously interpreted as evidence for an intensity mapping (Experiments 2a, b). These results suggest that previous findings may reflect a left-right mapping of spatial magnitude (i.e., the size of a salient feature of the stimuli) rather than emotion. People implicitly spatialize emotional valence, but, at present, there is no clear evidence for an implicit lateral mapping of emotional intensity. These findings support metaphor theory and challenge the proposal that mental magnitudes are represented by a domain-general metric that extends to the domain of emotion. PMID- 29164660 TI - China: Will the donkey become the next pangolin? PMID- 29164661 TI - Should short-term use of alcohol-containing mouthrinse be avoided for fear of worsening xerostomia? AB - This study aimed to assess the short-term effect of alcohol-containing mouthrinse versus mouthrinse without alcohol on xerostomia scores reported by Xerostomia Inventory (XI) scores and short version of the Xerostomia Inventory (SXI). This study was a two-group parallel-arm randomised controlled trial where participants were randomly allocated to twice a day for 7 days use of either alcohol containing or alcohol-free mouthrinse. Allocation was concealed. The participants, the outcome assessors and the statistician were blinded to the allocation status. A total of 163 participants completed the pre-and post intervention data collection. There were no statistically significant differences between the study groups with respect to demographics or other measured independent variables. After adjusting for age and gender, regression coefficient (95% CI) for XI was 0.02 (-1.72-2.29) and that for SXI was 0.03 (-0.54-0.83). Both adjusted and unadjusted models showed no significant differences in change in XI or SXI. The mean difference in scores between the groups for XI was -0.45 ( 2.45-1.55) and for SXI was 0.05 (-0.65-0.75). There was no significant difference in the change in xerostomia levels as a result of short-term exposure to alcohol containing mouthrinse, when compared to those exposed to alcohol-free mouthrinse. Short-term use of alcohol-containing mouthrinse does not result in worsening xerostomia. PMID- 29164662 TI - Laboratory tests for identification or exclusion of heparin induced thrombocytopenia: HIT or miss? AB - Heparin induced thrombocytopenia (HIT) is a potentially fatal condition that arises subsequent to formation of antibodies against complexes containing heparin, usually platelet-factor 4-heparin ("anti-PF4-heparin"). Assessment for HIT involves both clinical evaluation and, if indicated, laboratory testing for confirmation or exclusion, typically using an initial immunological assay ("screening"), and only if positive, a secondary functional assay for confirmation. Many different immunological and functional assays have been developed. The most common contemporary immunological assays comprise enzyme linked immunosorbent assay [ELISA], chemiluminescence, lateral flow, and particle gel techniques. The most common functional assays measure platelet aggregation or platelet activation events (e.g., serotonin release assay; heparin-induced platelet activation (HIPA); flow cytometry). All assays have some sensitivity and specificity to HIT antibodies, but differ in terms of relative sensitivity and specificity for pathological HIT, as well as false negative and false positive error rate. This brief article overviews the different available laboratory methods, as well as providing a suggested approach to diagnosis or exclusion of HIT. PMID- 29164663 TI - Erythromelanosis follicularis faciei et colli: A clinicoepidemiologic study. AB - We describe 25 cases of erythromelanosis follicularis faciei et colli from India. The male:female ratio was 5.25:1 and the average age of onset was 12.3 years. The cheeks, preauricular area, and submandibular region were the sites most commonly affected. Keratosis pilaris was seen in 22 (88%) of the patients. PMID- 29164664 TI - Can sleep quality and burnout affect the job performance of shift-work nurses? A hospital cross-sectional study. AB - AIM: The aim of this study was to investigate any possible relationship between sleep disorders, burnout and job performance in a shift-work population of nurses. BACKGROUND: Sleep disorders and burnout can affect the job performance of nurses in terms of efficiency, productivity, task execution speed and supervision, which can be compromised when work shifts are organized on a 24-hour schedule and when the shift itself is irregular. DESIGN: A cross-sectional observational study was conducted from August 2014 - January 2015 on a sample of 315 shift-work nurses across 39 wards in seven central Italian hospitals. METHODS: The Pittsburgh Sleep Quality Index was used to detect the presence of sleep disorders, the Copenhagen Burnout Inventory was used to detect the presence of any possible type of burnout and the Job Performance Scale was used to measure job performance. Data analysis was mainly based on a multivariate logistic regression to identify variables significantly associated with investigated outcomes. RESULTS: On shift-work nurses' sleep quality and burnout correlated positively. The female gender and personal burnout were significantly associated with impaired sleep quality, while working in the psychiatric setting, working a long cycle shift pattern and experiencing daytime dysfunction were significantly associated with burnout. A significant negative association between patient related burnout and job performance was observed. CONCLUSION: Specific characteristics of shift-work nurses can directly affect sleep quality and burnout and indirectly job performance. This evidence offers healthcare administrators opportunities to intervene with measures to promote nurse's health, well-being and safety. PMID- 29164665 TI - Comparing safety information of biosimilars with their originators: a cross sectional analysis of European risk management plans. AB - BACKGROUND AND AIMS: Biosimilars have been available in the European Union (EU) since 2006. However, their uptake in routine care is heterogeneous across countries. The aim of the present study was to compare the safety information of biosimilars and their originators based on the information in the European risk management plan (RMP). METHODS: A cross-sectional analysis on publicly available regulatory documents (RMPs and Summaries of Product Characteristics) of biosimilars and corresponding originators up to 1 November 2015 was performed. The safety concerns were extracted and merged into general safety concerns, and clinical relevance was assessed. The frequency of safety concerns and the representation of these safety concerns per general safety concern were assessed by either comparing RMPs of biosimilars and originators (if available for both) or comparing RMPs with the Summary of Product Characteristics of the originator. RESULTS: Nineteen biosimilars and six originators were included. Overall, 55 general safety concerns (12 low, 21 medium and 22 highly clinically relevant) were identified. For all active substances, except for infliximab, no or only one difference was found in the listed general safety concerns. Comparison of regulatory documents for infliximab identified three medium clinically relevant general safety concerns more for infliximab biosimilars and two general safety concerns more for its originator. CONCLUSION: Based on publicly available information filed for regulatory purposes, no substantial differences were observed in the reporting of safety information for biosimilars and related originators. A direct comparison between biosimilars and related originators through formal postmarketing studies is needed to evaluate specific safety issues emerging during the products' life cycle. PMID- 29164666 TI - Expression of DCUN1D1 in laryngeal squamous cell carcinoma and its inhibiting effect on TU-177 cells after interfered by RNA. AB - Expression of DCUN1D1 in laryngeal squamous cell carcinoma (LSCC) and its inhibition by small interfering RNA (siRNA) target in the TU-177 cells was investigated. Immunohistochemistry was used to detect the expression level of DCUN1D1 in LSCC tissue in 140 cases and to analyze its relationship with clinical pathological characteristics. siRNA expression plasmid targeting DCUN1D1 was constructed and transferred into TU-177 cells. The effect of siRNA target DCUN1D1 gene silencing on proliferation, invasion and migration of TU-177 cells were observed by MTS assay and Transwell experiment. The expression levels of focal adhesion kinase (FAK) and matrix metalloproteinase-2(MMP-2) were detected by western blot. Expression level of DCUN1D1 protein increased significantly in T3 + T4, N+, and III + IV stages of LSCC patients (P < .05). After DCUN1D1 was targeted by siRNA, the DCUN1D1 protein level decreased 67% in siRNA-3 group, where average absorbance value was lower than the control and blank group with significant difference(F = 6.076, P < .05) in MTS assay, meantime migration, and invasion cells in each vision were the same (F = 19.851, F = 25.454, P < .01) in the Transwell experiment. The expression level of FAK and MMP-2 was significantly down-regulated in siRNA-3 group (F = 28.896, F = 40.240, P < .01). DCUN1D1 is associated with progression and prognosis of LSCC. After siRNA based target on DCUN1D1, TU-177 cells growth was inhibited and invasion of malignant tumour was diminished by reducing the expression of FAK and MMP-2. DCUN1D1 is could become a potential new target for the treatment of LSCC. PMID- 29164667 TI - Two cases of severe fever with thrombocytopenia syndrome virus infection. PMID- 29164668 TI - Ameliorative effects of riboflavin on acetic acid-induced colonic injury in rats. AB - Riboflavin (RF) has been found to be a promising antioxidant and/or anti inflammatory agent in several studies. However, the effect of RF against acetic acid (AA)-induced colonic injury is currently unknown. This study aimed to investigate the potential antioxidant and protective effects of RF in a rat model of ulcerative colitis. Starting immediately after the colitis induction (AA+RF group) or 1 week before the colitis induction (RF+AA+RF group), the rats were treated with RF (25 mg/kg per day; p.o.) for 3 days. The control and AA groups received saline (1 mL; p.o.) whereas AA+SS group (positive control) received sulfasalazine (100 mg/kg per day; p.o.) for 3 days. Colonic samples were taken for the biochemical and histological assessments on the third day. High damage scores, elevated tissue wet weight index (WI), tissue myeloperoxidase (MPO) activity, 8-hydroxy-2'-deoxyguanosine levels and chemiluminescence values, and a pronounced decrease in antioxidant glutathione (GSH) levels of the AA group were all reversed by RF pretreatment (RF+AA+RF group) and SS treatment (AA+SS group) (P < .05-.001). Tissue WI, MPO activity and GSH levels were not statistically changed in the AA+RF group. Western blot analysis revealed that the decreased protein expressions of tissue collagen (COL) 1A1, COL3A1 and transforming growth factor-beta1 in the AA group were elevated in all the treatment groups (P < .05 .001). In conclusion, RF exerts both the antioxidant and anti-inflammatory effects against AA-induced colonic inflammation by suppressing neutrophil accumulation, inhibiting reactive oxidant generation, preserving endogenous glutathione, improving oxidative DNA damage and regulating inflammatory mediators, suggesting a future potential role in the treatment and prevention of ulcerative colitis. PMID- 29164669 TI - Nasal dermoid sinus cyst in a young girl: A case report. PMID- 29164670 TI - Driver mutations and prognosis in primary myelofibrosis: Mayo-Careggi MPN alliance study of 1,095 patients. AB - The 2013 discovery of calreticulin (CALR) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple-negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2, 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple-negative. Survival was longer with type 1/like CALR, compared to JAK2 (HR 2.6, 95% CI 1.9-3.5), type 2/like CALR (HR 2.5, 95% CI 1.4-4.5), MPL (HR 1.8, 95% CI 1.1-2.9) and triple-negative mutational status (HR 2.4, 95% CI 1.6-3.6), but otherwise similar between the non-type 1/like CALR mutational states (P = .41). In multivariable analysis, the absence of type 1/like CALR (P < .001; HR 2, 95% CI 1.4-2.7), presence of ASXL1/SRSF2 mutations (P < .001; HR 1.9, 95% CI 1.5-2.4) and DIPSS-plus (P < .001) were each predictive of inferior survival. Furthermore, among 210 patients with ASXL1/SRSF2 mutations, survival was significantly longer in the presence vs. absence of type 1/like CALR mutations (median 5.8 vs. 2.9 years; P < .001). Triple-negative status did not disclose additional prognostic information for overall or leukemia free survival. The observations regarding the prognostic distinction between CALR mutation variants were validated in an external cohort of 386 patients from the University of Florence Careggi hospital. We conclude that type 1/like CALR mutations in PMF not only predict superior survival, but also partially amend the detrimental effect of high molecular risk mutations. PMID- 29164671 TI - Characterization of two groups of Spodoptera exigua Hubner (Lepidoptera: Noctuidae) C-type lectins and insights into their role in defense against the densovirus JcDV. AB - Insect innate immunity relies on numerous soluble and membrane-bound receptors, named pattern recognition proteins (PRPs), which enable the insect to recognize pathogen-associated molecular patterns. C-type lectins are among the best-studied PRPs and constitute the most diverse family of animal lectins. Here we have characterized two groups of Spodoptera exigua C-type lectins that differ in their phylogeny, domain architecture, and expression pattern. One group includes C-type lectins with similar characteristics to other lepidopteran lectins, and a second group includes bracoviral-related lectins (bracovirus-like lectins, Se-BLLs) recently acquired by horizontal gene transfer. Subsequently, we have investigated the potential role of some selected lectins in the susceptibility to Junonia coenia densovirus (JcDV). For this purpose, three of the bracoviral-related lectins were expressed, purified, and their effect on the densovirus infection to two different Spodoptera species was assessed. The results showed that Se-BLL3 specifically reduce the mortality of Spodoptera frugiperda larvae caused by JcDV. In contrast, no such effect was observed with S. exigua larvae. In a previous work, we have also shown that Se-BLL2 increased the tolerance of S. exigua larvae to baculovirus infection. Taken together, these results confirm the implication of two different C-type lectins in antiviral response and reflect the biological relevance of the acquisition of bracoviral genes in Spodoptera spp. PMID- 29164672 TI - Resection of an intra-esophageal bronchogenic cyst by endoscopic submucosal dissection. PMID- 29164673 TI - Reviewing and addressing the link between mass media and the increase in obesity among European children: The European Academy of Paediatrics (EAP) and The European Childhood Obesity Group (ECOG) consensus statement. AB - : This study reviewed the link between social media and the growing epidemic of childhood obesity in Europe. A task force from the European Academy of Paediatrics and the European Childhood Obesity Group searched published literature and developed a consensus statement. It found that there was evidence of a strong link between obesity levels across European countries and childhood media exposure and that parents and society needed a better understanding of the influence of social media on dietary habits. CONCLUSION: Health policies in Europe must take account of the range of social media influences that promote the development of childhood obesity. PMID- 29164674 TI - Outcome of chronic lymphocytic leukemia patients who switched from either ibrutinib or idelalisib to alternate kinase inhibitor: A retrospective study of the French innovative leukemia organization (FILO). PMID- 29164675 TI - Significance of day-1 viral response of hepatitis C virus in patients with chronic hepatitis C receiving direct-acting antiviral therapy. AB - BACKGROUND AND AIM: On-treatment response of serum hepatitis C virus (HCV) is reportedly less useful to predict the outcome of anti-HCV therapy with interferon (IFN)-free regimen with direct-acting antivirals than with IFN-based regimens in clinical trials. We evaluated the significance of very early viral response after the start of therapy, which indicates direct HCV response to the drugs, on therapeutic outcome. METHODS: Reductions in serum HCV-RNA levels were measured at 1 day after the start of therapy in 544 patients who underwent IFN-free direct acting antiviral regimens. The association between these reductions and the achievement or failure of sustained virologic response (SVR) was evaluated. RESULTS: Patient characteristics did not influence 1-day reduction in serum HCV RNA except for liver fibrosis. There was no difference in 1-day HCV reduction between SVR and non-SVR patients treated with a 24-week regimen. In contrast, in patients treated with a 12-week regimen, 1-day reduction was significantly greater in SVR than in non-SVR patients (P = 0.0013) and was predictive of SVR versus non-SVR (area under the receiver-operating characteristics curve: 0.80). CONCLUSIONS: Whereas the reduction in serum HCV-RNA levels at 1 day after the start of therapy was not associated with treatment outcomes in patients who underwent a 24-week regimen of IFN-free therapy, there was an association in patients receiving a 12-week regimen, and this reduction was predictive of SVR, thus potentially serving as a factor to identify patients at risk of treatment failure. PMID- 29164676 TI - Association of oxidative stress and dynamic thiol-disulphide homeostasis with atopic dermatitis severity and chronicity in children: a prospective study. AB - BACKGROUND: Oxidative stress (OS) has an important effect on the pathogenesis of atopic dermatitis (AD). Thiols are antioxidants that regulate intracellular redox metabolism and protect keratinocytes against OS damage in the stratum corneum. AIM: To investigate dynamic thiol-disulphide homeostasis (dTDH) as a novel OS parameter in children with AD, and its relationship with disease severity and chronicity. METHODS: Severity of AD was determined by using the instruments SCORing Atopic Dermatitis (SCORAD) and Eczema Area And Severity Index (EASI) upon enrolment in the study (SCORAD1 and EASI1 ) and after 1 year (SCORAD2 and EASI2 ). Native thiol, total thiol and disulphide levels were measured as novel OS parameters, and the ratios of disulphide/native thiol, disulphide/total thiol and native/total thiol were calculated as dTDH. RESULTS: In the AD group, the serum disulphide level and the ratios of disulphide/native thiol and disulphide/total thiol were significantly lower than in healthy controls (P = 0.01, P < 0.01 and P < 0.01, respectively). There was no significant association between OS parameters and disease severity (P > 0.05). SCORAD2 and EASI2 were positively correlated with disulphide/native thiol ratio (r = 0.29, P < 0.03 and r = 0.35, P < 0.01, respectively), whereas they were negatively correlated with the native/total thiol ratio (r = -0.30, P = 0.02 for both). CONCLUSIONS: Both OS and impaired dTDH were found to be related to childhood AD. None of the OS parameters was associated with AD severity. dTDH is a possible diagnostic tool to predict AD chronicity. PMID- 29164677 TI - Perceptions of the effects of childbirth on sexuality among nulliparous individuals. AB - BACKGROUND: Media representations of sexuality after childbirth depict vaginal birth as harmful and cesarean delivery as protective, although research does not support these depictions. The objective of the current study was to investigate perceptions of the effects of mode of delivery on sexuality. METHODS: Nulliparous participants who were able to and interested in giving birth (N = 1428) completed an online survey about their preferences for mode of delivery and their perceptions of childbirth as they specifically relate to sexuality. Participants provided demographic information, rated how influential different sources of information about childbirth were, and completed the Attitudes Toward Women's Genitals Scale. RESULTS: Up to half (16-48%), the participants agreed with different statements about vaginal birth as harmful to, and cesarean delivery as protective of, future sexuality. Participant characteristics that were independently predictive of endorsing these beliefs were: self-identifying as heterosexual, holding negative attitudes toward women's genitals, and reporting that reality media, nonreality media, and online media sources are influential sources of childbirth information. Participants who rated health care professionals as an influential source of information were less likely to endorse these beliefs. CONCLUSION: Given that there is no clear evidence in the empirical literature to support the claim that vaginal births are harmful and cesarean delivery is protective to one's future sexual life, it is important to dispel the existing misconceptions. Various media sources likely play a role in the perpetuation of this misinformation. PMID- 29164678 TI - Speckled acral hypopigmentation in an adolescent. AB - We report a case of speckled acral hypopigmentation in a 12-year-old girl. She presented with asymptomatic hypopigmented macules on the hands and feet. This rare entity is a proposed variant of reticulate acropigmentation and of unknown etiology. PMID- 29164679 TI - Novel antioxidant and anti-inflammatory peptides from the Siamese crocodile (Crocodylus siamensis) hemoglobin hydrolysate. AB - Novel antioxidant and anti-inflammatory peptides were isolated from hydrolysates of Siamese crocodile (Crocodylus siamensis) hemoglobin. C. siamensis hemoglobin hydrolysates (CHHs) were obtained by pepsin digestion at different incubation times (2, 4, 6, and 8 H) at 37 degrees C and subjected to antioxidant and anti inflammatory activity assessment. CHH obtained by 2-H hydrolysis (2H-CHH) showed the highest anti-inflammatory activity with respect to decreasing nitric oxide (NO) production, whereas the strongest antioxidant activity was found for 6-H hydrolysis (6H-CHH) against nitric oxide radicals. To evaluate the anti inflammatory and antioxidant activity of individual peptide components, 2H-CHH and 6H-CHH were purified by semipreparative HPLC. Peptide fraction P57 isolated from 6H-CHH was found to exhibit the highest nitric oxide radical inhibition activity (32.0%). Moreover, purification of 2H-CHH yielded peptide fraction P16, which displayed a high efficacy in decreasing NO production of macrophage RAW 264.7 cells (83.2%) and significantly reduced proinflammatory cytokines and inflammatory mediators interleukin-6 (IL-6), interleukin-1 beta (IL-1beta), and prostaglandin-E2 (PGE2 ) production to about 2.0, 0.3, and 1.9 ng/mL, respectively. Using LTQ orbitrap XL mass spectrometry, active peptide sequences were identified as antioxidant KIYFPHF (KF7), anti-inflammatory SAFNPHEKQ (SQ9), and IIHNEKVQAHGKKVL (IL15). Additionally, CHHs simulated gastric and intestinal in vitro digestion positively contributed to antioxidant and anti-inflammatory activity. Taken collectively, the results of this work demonstrate that CHHs contain several peptides with anti-inflammatory and antioxidant properties, which may prove valuable as treatment or supplement against diseases associated with inflammation and oxidative stress. PMID- 29164680 TI - Effects of tadalafil on storage and voiding function in patients with male lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A urodynamic based study. AB - OBJECTIVE: To investigate the effects of tadalafil on storage and voiding function in treatment-naive patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia, based on a urodynamic study. METHODS: This was an open-labeled, single-center, prospective study. A total of 80 untreated outpatients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia received tadalafil 5 mg/day for 12 weeks. Subjective symptoms and objective findings on voiding and storage function obtained through urodynamic studies, including cystometry and pressure flow study, were evaluated before and after treatment. RESULTS: A total of 71 patients with a mean age of 70.2 years and a mean prostate volume of 45.6 mL were included in the analysis. In the International Prostate Symptom Score and Overactive Bladder Symptom Score, mean total scores significantly improved from 18.2 to 13.4 (P < 0.001) and 6.5 to 4.7 (P < 0.001), respectively, after treatment. Mean maximum bladder capacity significantly increased by approximately 35 mL (P < 0.001). Detrusor overactivity disappeared in 15 (39.5%) of 38 patients with detrusor overactivity at baseline (P < 0.001). Mean maximum flow rate on pressure flow study significantly increased from 7.1 to 9.1 mL/s (P < 0.001) and mean bladder outlet obstruction index significantly decreased from 61.3 to 47.1 (P < 0.001). CONCLUSIONS: Treatment with tadalafil 5 mg once daily effectively relieves lower urinary tract symptoms based on objective improvement of storage and voiding function, such as detrusor overactivity and bladder outlet obstruction, in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. PMID- 29164681 TI - Urticarial vasculitis after meningococcal serogroup B vaccine in a 6-year-old girl. AB - The first vaccine that shows significant potential in providing broad coverage against serogroup B meningococcal disease has recently been approved. Because of its newness, potential adverse events need to be reported. Here we report a case of urticarial vasculitis, a rare disease in children, in probable relationship with the novel vaccine. PMID- 29164682 TI - Reducing amputation in diabetes: work from the West Country provides both evidence and a tool-kit. PMID- 29164683 TI - Is hypertension the fate of aortic coarctation patients treated with Cheatham Platinum (CP) stent? AB - AIM: The aim of this study is to address the presence of hypertension and risk for cardiovascular diseases in patients with Coarctation of the Aorta (CoA) who were treated with endovascular stent placement. METHODS: Twenty patients (mean age: 14.2 +/- 3.9 years) who were treated with stent and 20 age- and sex-matched controls were included to the study. Structure and functions of left ventricle were assessed by echocardiography. Carotid intima media (CIM) thickness was measured by using sonography as a marker for detecting cardiovascular risk. As indirect marker of arterial stiffness, pulse wave velocity, and augmentation index were recorded by ambulatory blood pressure monitorization/arteriography device. RESULTS: By ambulatory blood pressure monitorization, 24 h and daytime systolic and mean arterial pressure values were found to be significantly higher in patient group. Based on percentile values, 15% and 5% of patients were pre hypertensive and hypertensive, respectively. Pulse wave velocity and cardiac output values were found to be significantly higher than control group. CIM thickness was also found to be significantly higher in patient group when compared to controls. CONCLUSIONS: It was shown that hypertension incidence as demonstrated by ambulatory blood pressure monitorization and risk for cardiovascular diseases as indicated by CIM thickness and Pulse wave velocity were higher than those in healthy population even after CoA is corrected. PMID- 29164684 TI - BIBI: Bayesian inference of breed composition. AB - The aim of this paper was to develop statistical models to estimate individual breed composition based on the previously proposed idea of regressing discrete random variables corresponding to counts of reference alleles of biallelic molecular markers located across the genome on the allele frequencies of each marker in the pure (base) breeds. Some of the existing regression-based methods do not guarantee that estimators of breed composition will lie in the appropriate parameter space, and none of them account for uncertainty about allele frequencies in the pure breeds, that is, uncertainty about the design matrix. To overcome these limitations, we proposed two Bayesian generalized linear models. For each individual, both models assume that the counts of the reference allele at each marker locus follow independent Binomial distributions, use the logit link and pose a Dirichlet prior over the vector of regression coefficients (which corresponds to breed composition). This prior guarantees that point estimators of breed composition such as the posterior mean pertain to the appropriate space. The difference between these models is that model termed BIBI does not account for uncertainty about the design matrix, while model termed BIBI2 accounts for such an uncertainty by assigning independent Beta priors to the entries of this matrix. We implemented these models in a data set from the University of Florida's multibreed Angus-Brahman population. Posterior means were used as point estimators of breed composition. In addition, the ordinary least squares estimator proposed by Kuehn et al. () (OLSK) was also computed. BIBI and BIBI2 estimated breed composition more accurately than OLSK, and BIBI2 had a 7.69% improvement in accuracy as compared to BIBI. PMID- 29164685 TI - Vastus intermedius vs vastus lateralis fascicle behaviors during maximal concentric and eccentric contractions. AB - Vastus intermedius (VI) plays a major role in knee extension, but its fascicle behaviors during dynamic contractions are not well understood. This study aimed to compare VI and vastus lateralis (VL) fascicle behaviors during singular maximal concentric and eccentric contractions. Thirteen men (27.1 +/- 3.4 years) performed maximal isokinetic concentric contractions through knee joint angles of 105 degrees to 35 degrees (0 degrees = full extension) and eccentric contractions from 35 degrees to 105 degrees at an angular velocity of 30 degrees /s. Longitudinal VI and VL sonographic images were simultaneously recorded at 30 Hz, and muscle fascicle lengths at the knee joint angles of 40 degrees and 100 degrees were measured to compare the magnitudes of fascicle length change between the muscles. During concentric contractions, VI and VL fascicle lengths at 100 degrees were 108 +/- 12 mm and 104 +/- 12 mm, respectively, and shortened by 36 +/- 12 mm for VI and 28 +/- 13 mm for VL (not statistically different; P = .13) at 40 degrees . During eccentric contractions, VI and VL fascicle lengths at 40 degrees were 72 +/- 7 mm and 75 +/- 8 mm, respectively, but lengthened by 35 +/- 9 mm for VI and 24 +/- 5 mm for VL at 100 degrees , with a significant difference between the muscles (P = .01). These results indicate that VI fascicles are lengthened 1.4 times more than VL fascicles during eccentric contractions, whereas VI and VL fascicles shorten similarly during concentric contractions. This suggests a possibility that a greater mechanical strain is imposed to VI than VL during eccentric contractions. PMID- 29164686 TI - Christmas tree dermatitis caused by colophonium allergy. PMID- 29164688 TI - Polyhexamethylene biguanide and alkyl glucosides: unexpected allergens in an antimicrobial foam dressing. PMID- 29164689 TI - A case of contact dermatitis syndrome caused by Dermabond(r), followed by contact dermatitis caused by false eyelash glue and Aron Alpha(r) glue: possibility of cross-reactions among cyanoacrylates. PMID- 29164690 TI - Severe stomatitis with a deep buccal ulcer associated with an allergic reaction to methyl methacrylate used for dental treatment. PMID- 29164692 TI - Erratum. PMID- 29164691 TI - Allergic contact dermatitis caused by polymethylmethacrylate following intradermal filler injection. PMID- 29164693 TI - Hair colour shampoo dermatitis. PMID- 29164694 TI - Allergic contact dermatitis caused by 2-ethyl cyanoacrylate contained in glucose sensor sets in two diabetic adults. PMID- 29164695 TI - Allergic contact dermatitis caused by acrylic acid used in transcutaneous electrical nervous stimulation. PMID- 29164696 TI - Leukoderma following allergic contact dermatitis caused by the silicone component silprene-30A/B in swimming goggles. PMID- 29164697 TI - Acetophenone azine: a new shoe allergen causing severe foot dermatitis. PMID- 29164699 TI - Re: Protein contact dermatitis caused by lime in a pastry chef (Contact Dermatitis 2015: 73: 54-56). PMID- 29164698 TI - Contact dermatitis caused by Geranium robertianum with erythema multiforme-like reaction. PMID- 29164700 TI - Contact urticaria caused by a silk bed quilt in a young atopic female. PMID- 29164701 TI - Acrylate allergy: time to intervene. PMID- 29164702 TI - Window/door opening-mediated bedroom ventilation and its impact on sleep quality of healthy, young adults. AB - This work examined window/door opening as means of bedroom ventilation and the consequent effect upon occupants' sleep, using data from 17 healthy volunteers. Bedroom CO2 level, temperature, and relative humidity were measured over 5 days, for two cases: open window or door (internal, bedroom door), and closed window and door. Participant filled questionnaires and sleep diary provided subjective measure of sleep quality. Actigraphy objectively monitored the participants during sleep. Additionally, a FlexSensor, placed under pillows of participants, detected movement during sleep. Average CO2 level for the Open conditions was 717 ppm (SD = 197 ppm) and for Closed conditions was 1150 ppm (SD = 463 ppm). Absolute humidity levels were similar for both conditions, while Open conditions were slightly cooler (mean = 19.7 degrees C, SD = 1.8 degrees C) than Closed (mean = 20.1 degrees C, SD = 1.5 degrees C). Results showed significant correlations (P < .001) between actigraphy data and questionnaire responses for: sleep latency (r = .45), sleep length (r = .87), and number of awakenings (r = .28). Of all analyzed sleep parameters, questionnaire-based depth of sleep (P = .002) and actigraphy-based sleep phase (P = .003) were significantly different between Open and Closed conditions. PMID- 29164703 TI - Clinicopathological characteristics of patients with upper urinary tract urothelial cancer with loss of immunohistochemical expression of the DNA mismatch repair proteins in universal screening. AB - OBJECTIVES: To assess the detection rate of putative Lynch syndrome-associated upper urinary tract urothelial cancer among all upper urinary tract urothelial cancers and to examine its clinicopathological characteristics. METHODS: A total of 143 patients with upper urinary tract urothelial cancer who had received total nephroureterectomy were immunohistochemically stained for the expression of mismatch repair proteins MLH1, PMS2, MSH2 and MSH6. For all suspected mismatch repair-deficient cases, MMR genetic testing was recommended and clinicopathological features were examined. RESULTS: Loss of mismatch repair proteins was found in seven patients (5%) who were thus categorized as putative Lynch syndrome-associated upper urinary tract urothelial cancer. Five of these patients showed dual loss of MSH2/MSH6. Two patients were confirmed to be MSH2 germline mutation carriers. Histologically, all seven tumors were low-grade atypical urothelial carcinoma and showed its unique histological features, such as an inverted papilloma-like growth pattern and a villous to papillary structure with mild stratification of tumor cells. Six tumors had no invasion of the muscularis propria. No recurrence or cancer-related deaths were reported in these seven patients. Just three patients met the revised Amsterdam criteria. CONCLUSIONS: This is the first report that universally examined mismatch repair immunohistochemical screening for upper urinary tract urothelial cancers. The prevalence (5%) of putative Lynch syndrome-associated upper urinary tract urothelial cancers is much higher than we had expected. We ascertained that putative Lynch syndrome-associated upper urinary tract urothelial cancers were clinically in the early stage and histologically classified into low-grade malignancy with its characteristic pathological features. The clinicopathological characteristics that we found in the present study could become additional possible markers in the diagnosis of Lynch syndrome-associated upper urinary tract urothelial cancers. PMID- 29164704 TI - Holey Reduced Graphene Oxide Coupled with an Mo2 N-Mo2 C Heterojunction for Efficient Hydrogen Evolution. AB - An in situ catalytic etching strategy is developed to fabricate holey reduced graphene oxide along with simultaneous coupling with a small-sized Mo2 N-Mo2 C heterojunction (Mo2 N-Mo2 C/HGr). The method includes the first immobilization of H3 PMo12 O40 (PMo12 ) clusters on graphite oxide (GO), followed by calcination in air and NH3 to form Mo2 N-Mo2 C/HGr. PMo12 not only acts as the Mo heterojunction source, but also provides the Mo species that can in situ catalyze the decomposition of adjacent reduced GO to form HGr, while the released gas (CO) and introduced NH3 simultaneously react with the Mo species to form an Mo2 N-Mo2 C heterojunction on HGr. The hybrid exhibits superior activity towards the hydrogen evolution reaction with low onset potentials of 11 mV (0.5 m H2 SO4 ) and 18 mV (1 m KOH) as well as remarkable stability. The activity in alkaline media is also superior to Pt/C at large current densities (>88 mA cm-2 ). The good activity of Mo2 N-Mo2 C/HGr is ascribed to its small size, the heterojunction of Mo2 N-Mo2 C, and the good charge/mass-transfer ability of HGr, as supported by a series of experiments and theoretical calculations. PMID- 29164705 TI - Molecular Engineering of MnII Diamine Diketonate Precursors for the Vapor Deposition of Manganese Oxide Nanostructures. AB - Molecular engineering of manganese(II) diamine diketonate precursors is a key issue for their use in the vapor deposition of manganese oxide materials. Herein, two closely related beta-diketonate diamine MnII adducts with different fluorine contents in the diketonate ligands are examined. The target compounds were synthesized by a simple procedure and, for the first time, thoroughly characterized by a joint experimental-theoretical approach, to understand the influence of the ligand on their structures, electronic properties, thermal behavior, and reactivity. The target compounds are monomeric and exhibit a pseudo octahedral coordination of the MnII centers, with differences in their structure and fragmentation processes related to the ligand nature. Both complexes can be readily vaporized without premature side decompositions, a favorable feature for their use as precursors for chemical vapor deposition (CVD) or atomic layer deposition applications. Preliminary CVD experiments at moderate growth temperatures enabled the fabrication of high-purity, single-phase Mn3 O4 nanosystems with tailored morphology, which hold great promise for various technological applications. PMID- 29164706 TI - A Binder-Free and Free-Standing Cobalt Sulfide@Carbon Nanotube Cathode Material for Aluminum-Ion Batteries. AB - Rechargeable aluminum-ion batteries (AIBs) are considered as a new generation of large-scale energy-storage devices due to their attractive features of abundant aluminum source, high specific capacity, and high energy density. However, AIBs suffer from a lack of suitable cathode materials with desirable capacity and long term stability, which severely restricts the practical application of AIBs. Herein, a binder-free and self-standing cobalt sulfide encapsulated in carbon nanotubes is reported as a novel cathode material for AIBs. The resultant new electrode material exhibits not only high discharge capacity (315 mA h g-1 at 100 mA g-1 ) and enhanced rate performance (154 mA h g-1 at 1 A g-1 ), but also extraordinary cycling stability (maintains 87 mA h g-1 after 6000 cycles at 1 A g 1 ). The free-standing feature of the electrode also effectively suppresses the side reactions and material disintegrations in AIBs. The new findings reported here highlight the possibility for designing high-performance cathode materials for scalable and flexible AIBs. PMID- 29164707 TI - Number-Resolved Single-Photon Detection with Ultralow Noise van der Waals Hybrid. AB - Van der Waals hybrids of graphene and transition metal dichalcogenides exhibit an extremely large response to optical excitation, yet counting of photons with single-photon resolution is not achieved. Here, a dual-gated bilayer graphene (BLG) and molybdenum disulphide (MoS2 ) hybrid are demonstrated, where opening a band gap in the BLG allows extremely low channel (receiver) noise and large optical gain (~1010 ) simultaneously. The resulting device is capable of unambiguous determination of the Poissonian emission statistics of an optical source with single-photon resolution at an operating temperature of 80 K, dark count rate 0.07 Hz, and linear dynamic range of ~40 dB. Single-shot number resolved single-photon detection with van der Waals heterostructures may impact multiple technologies, including the linear optical quantum computation. PMID- 29164708 TI - Isolation of Cp*CoIII -Alkenyl Intermediate in Efficient Cobalt-Catalyzed C-H Alkenylation with Alkynes. AB - A general and efficient procedure for C-H alkenylation of arenes with a broad substrate scope catalyzed by Cp*CoIII was demonstrated with alkynes. A highly selective mono-alkenylation and sequential bis-C-H bond functionalization was displayed to exemplify the versatility of the cobalt catalyst. Isolation of cationic Cp*CoIII -alkenyl intermediate was achieved under identical catalytic conditions to further establish the proposed pathway. PMID- 29164709 TI - Identification of pyridoxal phosphate-modified proteins using mass spectrometry. AB - RATIONALE: Pyridoxal 5'-phosphate (PLP) cooperates with a variety of enzymes in all organisms for many important biological processes. The development of mass spectrometry-based methodology for high-throughput modification analyses could provide an alternative way for PLP identification. The present study aims to identify PLP modification. METHODS: More PLP site-determining information was obtained by introducing multistage activation (MSA)-assisted collision-induced dissociation (CID). We then utilized immobilized metal ion affinity chromatography (IMAC) with Ti4+ to enrich the PLP peptides. In addition, alkaline phosphatase (ALP) was used to remove the phosphoryl group and further confirm the PLP modification site. RESULTS: MSA was able to greatly enhance the identification and localization of PLP modification. We applied this strategy to analyze PLP-modified proteins in Escherichia coli samples and accurately determine PLP site K270 in tryptophanase. CONCLUSIONS: MSA-assisted CID was used to provide better identification of PLP-modified peptides. Furthermore, tryptophanase with PLP modification at K270 in E. coli was identified with Ti4+ IMAC enrichment followed by ALP treatment. This method provides a promising alternative for investigating biological functions of PLP-modified proteins. PMID- 29164710 TI - Expression profiles of immunity and reproductive genes during transition period in Holstein cattle. AB - The transition period is a critical time for dairy cows as the animal is subjected to the physiological stress accompanying parturition. Immunosuppression and health status were examined during this period in 80 Holstein cows. Blood samples were taken from each cow 3, 2 and 1 week before and after calving, and at calving (0 day). RNA was extracted and subjected to real-time PCR to determine mRNA levels for the immune-related genes TLR 2, 4, 6, 7 and beta-defensin 5 in addition to the reproduction-related genes prolactin and IGF-I. Results showed significant up-regulation of pro-inflammatory-selected genes, TLR 4, 6 7 and beta defensin 5 at the third-week post-calving; however, earlier periods had lower expression of such genes. In contrast, the immunosuppression biomarker TLR2 gene was up-regulated at calving and 1 week after parturition and then down-regulated again at second and third week. Prolactin and IGF-I genes expression levels were significantly and gradually increased mainly post-partum. This research highlights that the expression patterns of TLRs, BNBD5, PRL and IGF-I could be biomarkers to follow up immune and reproductive status of dairy cow at peri parturient period to predict the most susceptible risk time for disease incidence and to build up management protocol. PMID- 29164711 TI - Vitamin E improves testicular damage in streptozocin-induced diabetic rats, via increasing vascular endothelial growth factor and poly(ADP-ribose) polymerase-1. AB - The precise mechanism by which diabetes impairs spermatogenesis and testicular function is not exactly known. Vascular endothelial growth factor (VEGF) and poly(ADP-ribose) polymerase-1 (PARP-1) are important for germ cell homeostasis and repair of DNA respectively. The aim of this study was to investigate the correlation between diabetes-induced testicular damage and testicular VEGF and PARP-1 expression and the possible protective role of vitamin E supplementation. A total of 45 male Wistar albino rats were randomly divided into three groups: Group I (nondiabetic rats), Group II (streptozocin-induced diabetic rats) and Group III (streptozocin-induced diabetic rats treated orally with 0.4 mg/kg vitamin E). Five weeks later, testicular tissue was used for assessment of MDA concentration by colorimetry, histopathological examination and immunostaining for PARP-1 and VEGFIn diabetic rats, testicular weight, seminiferous tubule diameter and germinal epithelial thickness were decreased, basement membrane was thickened and Johnsen score decreased. Reduced VEGF and PARP-1 immunostaining were associated with decreased Johnsen score in diabetic rats. Vitamin E administration was protective against oxidative stress-associated damage evidenced by lower MDA levels, improved testicular weight, spermatogenesis and higher immunostaining for VEGF and PARP-1. Testicular VEGF and PARP-1 might therefore be helpful biomarkers for diabetic testicular damage. Administration of vitamin E may have a protective role against diabetes-induced testicular damage. PMID- 29164713 TI - Importance of oil overlay for production of porcine embryos in vitro. AB - Technologies to edit the zygote genome have revolutionized biomedical research not only for the creation of animal models for the study of human disease but also for the generation of functional human cells and tissues through interspecies blastocyst complementation technology. The pig is the ideal species for these purposes due to its great similarity in anatomy and physiology to humans. Emerging biotechnologies require the use of oocytes and/or embryos of good quality, which might be obtained using in vitro production (IVP) techniques. However, the current porcine embryo IVP systems are still suboptimal and result in low monospermic fertilization and blastocyst formation rates and poor embryo quality. During recent years, intensive investigations have been performed to evaluate the influence of specific compounds on gametes and embryos and to avoid the use of undefined supplements (serum and serum derivate) in the incubation media. However, little consideration has been given to the use of the mineral oil (MO) to overlay incubation droplets, which, albeit being a routine component of the IVP systems, is a totally undefined and thus problematic product for the safety of gametes and embryos. In this review, we provide an overview on the advantages and disadvantages of using MO to cover the incubation media. We also review one important concern in IVP laboratories: the use of oils containing undetected contamination. Finally, we discuss the effects of different types of oils on the in vitro embryo production outcomes and the transfer of compounds from oil into the culture media. PMID- 29164712 TI - Pristine Metal-Organic Frameworks and their Composites for Energy Storage and Conversion. AB - Metal-organic frameworks (MOFs), a new class of crystalline porous organic inorganic hybrid materials, have recently attracted increasing interest in the field of energy storage and conversion. Herein, recent progress of MOFs and MOF composites for energy storage and conversion applications, including photochemical and electrochemical fuel production (hydrogen production and CO2 reduction), water oxidation, supercapacitors, and Li-based batteries (Li-ion, Li S, and Li-O2 batteries), is summarized. Typical development strategies (e.g., incorporation of active components, design of smart morphologies, and judicious selection of organic linkers and metal nodes) of MOFs and MOF composites for particular energy storage and conversion applications are highlighted. A broad overview of recent progress is provided, which will hopefully promote the future development of MOFs and MOF composites for advanced energy storage and conversion applications. PMID- 29164714 TI - Very Green Photosynthesis of Gold Nanoparticles by a Living Aquatic Plant: Photoreduction of AuIII by the Seaweed Ulva armoricana. AB - Light-assisted in vivo synthesis of gold nanoparticles (NPs) from aqueous solutions of dilute AuIII salts by a living green marine seaweed (Ulva armoricana) is reported for the first time. NPs synthesised using typical procedures have many associated environmental hazards. The reported methods involve green, nontoxic, eco-friendly synthetic procedures. The formation of AuNPs was extremely rapid (~15 min) following illumination of the living U. armoricana, while the rate of NP formation in the dark was very slow (over 2 weeks). The properties of the AuNPs formed were confirmed using a battery of spectroscopic techniques. U. armoricana were found to be very efficient in Au0 uptake, and this, together with the rapid formation of AuNPs under illumination, indicated that the seaweed remained living during NP formation. The TEM images supported this, revealing that the thylakoid membranes and cell structure remained intact. The AuNPs formed on the surface of U. armoricana thallus, along the cell walls and in the chloroplasts. Without further workup, the dried, U. armoricana-supported AuNPs were efficient in the catalytic reduction of 4 nitrophenol, demonstrating the completely green cycle of AuNP formation and catalytic activity. The results mean that an aquatic plant growing in water rich in gold salts could bio-accumulate AuNPs from its aquatic environment, simply with the activation of sunlight. PMID- 29164715 TI - Sleep and its relation to cognition and behaviour in preschool-aged children of the general population: a systematic review. AB - This is the first systematic review of the literature on sleep and its relation to cognition and behaviour in preschool-aged children. In comparison with the literature focused on school-aged children, knowledge involving preschoolers is rather sparse. A total of 26 studies was included in this review, which revealed a high degree of heterogeneity regarding the type and means of measuring sleep variables and behavioural and cognitive variables, as well as the statistical methods employed. Amongst the 13 articles with the largest sample sizes (top 50% of the included studies, 12 different populations), 12 found that a higher quantity or quality of sleep was associated with better behavioural and/or cognitive outcomes. Results point to an association between sleep, behaviour and cognition as early as preschool years, but the strengths of associations reported in the articles were relatively small. Studies with a smaller sample size were less concordant. It is consistent with our findings that the strengths of association are small, and thus require large sample sizes to ensure statistical detection power. Different aspects of sleep were not associated with all cognitive or behavioural features in the same way, which underscores the need for specific measures rather than general ones such as 'sleep problems' or 'behaviour problems' to be able to decipher the relationships. There is also a need for large longitudinal studies using objective measures and accounting for confounding factors. The child's genotype has recently been shown to have a moderating role in the association between sleep and behaviour, and should be further explored. PMID- 29164716 TI - Mechanism matters: the cause of fluctuations in boom-bust populations governs optimal habitat restoration strategy. AB - Many populations exhibit boom-bust dynamics in which abundance fluctuates dramatically over time. Past research has focused on identifying whether the cause of fluctuations is primarily exogenous, e.g., environmental stochasticity coupled with weak density dependence, or endogenous, e.g., over-compensatory density dependence. Far fewer studies have addressed whether the mechanism responsible for boom-bust dynamics matters with respect to at-risk species management. Here, we ask whether the best strategy for restoring habitat across a landscape differs under exogenously vs. endogenously driven boom-bust dynamics. We used spatially explicit individual-based models to assess how butterfly populations governed by the two mechanisms would respond to habitat restoration strategies that varied in the level of resource patchiness, from a single large patch to multiple patches spaced at different distances. Our models showed that the restoration strategy that minimized extinction risk and boom-bust dynamics would be markedly different depending on the governing mechanism. Exogenously governed populations fared best in a single large habitat patch, whereas for endogenously driven populations, boom-bust dynamics were dampened and extinction risk declined when the total restored area was split into multiple patches with low to moderate inter-patch spacing. Adding environmental stochasticity to the endogenous model did not alter this result. Habitat fragmentation lowered extinction risk in the endogenously driven populations by reducing their growth rate, precluding both "boom" phases and, more importantly, "bust" phases. Our findings suggest that (1) successful restoration will depend on understanding the causes of fluctuations in at-risk populations, (2) the level and pattern of spatiotemporal environmental heterogeneity will also affect the ideal management approach, and (3) counterintuitively, for at-risk species with endogenously governed boom-bust dynamics, lowering the intrinsic population growth rate may decrease extinction risk. PMID- 29164717 TI - Antibiotics reduce genetic diversity of core species in the honeybee gut microbiome. AB - The gut microbiome plays a key role in animal health, and perturbing it can have detrimental effects. One major source of perturbation to microbiomes, in humans and human-associated animals, is exposure to antibiotics. Most studies of how antibiotics affect the microbiome have used amplicon sequencing of highly conserved 16S rRNA sequences, as in a recent study showing that antibiotic treatment severely alters the species-level composition of the honeybee gut microbiome. But because the standard 16S rRNA-based methods cannot resolve closely related strains, strain-level changes could not be evaluated. To address this gap, we used amplicon sequencing of protein-coding genes to assess effects of antibiotics on fine-scale genetic diversity of the honeybee gut microbiota. We followed the population dynamics of alleles within two dominant core species of the bee gut community, Gilliamella apicola and Snodgrassella alvi, following antibiotic perturbation. Whereas we observed a large reduction in genetic diversity in G. apicola, S. alvi diversity was mostly unaffected. The reduction in G. apicola diversity accompanied an increase in the frequency of several alleles, suggesting resistance to antibiotic treatment. We find that antibiotic perturbation can cause major shifts in diversity and that the extent of these shifts can vary substantially across species. Thus, antibiotics impact not only species composition, but also allelic diversity within species, potentially affecting hosts if variants with particular functions are reduced or eliminated. Overall, we show that amplicon sequencing of protein-coding genes, without clustering into operational taxonomic units, provides an accurate picture of the fine-scale dynamics of microbial communities over time. PMID- 29164718 TI - Canine prostate specific esterase (CPSE) as an useful biomarker in preventive screening programme of canine prostate: CPSE threshold value assessment and its correlation with ultrasonographic prostatic abnormalities in asymptomatic dogs. AB - Due to the increased attention that pet-owners devote to their animals and to the improved veterinary care, investigations regarding methods to early detect prostatic disorders that might affect canine life quality have been performed. Canine prostate specific esterase (CPSE) concentration was reported to be higher in dogs suffering from prostatic diseases. This study aimed to estimate the CPSE threshold as a biomarker to early identify prostatic diseases in asymptomatic dogs. The ultrasonographic examination of the prostate was performed in 19 dogs (6-40 kg; 1-5 years) with no symptoms of prostatic diseases. Dogs were grouped according to the presence (Group A) or absence (Group B) of prostatic disorders at the ultrasound (altered appearance, the presence of cysts or irregular borders). For each dog, a venous blood sample was collected to measure serum CPSE and the ratio between calculated and normal expected prostatic volume was assessed for each dog. The CPSE data were statistically analysed (t test, p < .05), and the CPSE threshold in blood serum between groups was calculated by ROC. In 11 dogs, ultrasonography showed signs of prostatic abnormalities (Group A, 2-5 years), while no signs were detected in eight dogs (Group B, 1-3 years). The calculated/estimated volume ratio resulted greater than 1.5 in Group A dogs. The CPSE was statistically different between groups (p < .0001): higher in Group A (mean = 184.9, SD = 126 ng/ml) than in Group B (38.9 +/- 22.1 ng/ml). The cut-off CPSE threshold was 52.3 ng/ml (ROC, AUC = 0.974, SE 95.6%, SP 89.2%). This study suggests that CPSE serum concentration higher than 50 ng/ml in asymptomatic dogs is associated with ultrasonographic alterations and increased the prostatic size (volume by 1.5 times greater than the normal size). As the onset of prostatic disorders often remains asymptomatic, the rapid assessment of CPSE could be suitable for selecting preventively those animals that would require further accurate evaluation. PMID- 29164719 TI - Circadian variation of flexor withdrawal and crossed extensor reflexes in patients with restless legs syndrome. AB - An evening state of spinal hyperexcitability has been proposed to be a possible cause of evening increases in restless legs syndrome symptoms. Thus, the objective of the current study was to assess the circadian variation in spinal excitability in patients with restless legs syndrome based on flexor withdrawal reflex and crossed extensor reflex responses. The reflexes were elicited on 12 participants with restless legs syndrome and 12 healthy control participants in the evening (PM) and the morning (AM). Reflex response magnitudes were measured electromyographically and kinematically. Both the reflexes showed a circadian rhythm in participants with restless legs syndrome but not in control participants. Changes in ankle (median flexor withdrawal reflex PM: 16.0 degrees versus AM: 2.8 degrees , P = 0.042; crossed extensor reflex PM: 0.8 degrees versus AM: 0.2 degrees , P = 0.001) angle were significantly larger, and ankle angular velocity (median flexor withdrawal reflex PM: 38.8 degrees s-1 versus AM: 13.9 degrees s-1 , P = 0.049; crossed extensor reflex PM: 2.4 degrees s-1 versus AM: 0.5 degrees s-1 , P = 0.002) was significantly faster in the evening compared with the morning in participants with restless legs syndrome, for both reflexes. For participants with restless legs syndrome, evening change in hallux angle was significantly larger than morning responses (median PM: 5.0 degrees versus AM: 1.3 degrees , P = 0.012). No significant differences for any of the electromyographic or kinematic variables were observed between participants with restless legs syndrome and controls. The flexor withdrawal reflex and the crossed extensor reflex show a circadian rhythm in participants with restless legs syndrome suggesting an evening increase in spinal excitability. We hypothesize the circadian variation in spinal excitability may be due to a possible nocturnal form of afferent circuitry central sensitization in the dorsal horn of the spinal cord in patients with restless legs syndrome. PMID- 29164720 TI - Mechanistic Insights into Growth of Surface-Mounted Metal-Organic Framework Films Resolved by Infrared (Nano-) Spectroscopy. AB - Control over assembly, orientation, and defect-free growth of metal-organic framework (MOF) films is crucial for their future applications. A layer-by-layer approach is considered a suitable method to synthesize highly oriented films of numerous MOF topologies, but the initial stages of the film growth remain poorly understood. Here we use a combination of infrared (IR) reflection absorption spectroscopy and atomic force microscopy (AFM)-IR imaging to investigate the assembly and growth of a surface mounted MOF (SURMOF) film, specifically HKUST-1. IR spectra of the films were measured with monolayer sensitivity and <10 nm spatial resolution. In contrast to the common knowledge of LbL SURMOF synthesis, we find evidence for the surface-hindered growth and large presence of copper acetate precursor species in the produced MOF thin-films. The growth proceeds via a solution-mediated mechanism where the presence of weakly adsorbed copper acetate species leads to the formation of crystalline agglomerates with a size that largely exceeds theoretical growth limits. We report the spectroscopic characterization of physisorbed copper acetate surface species and find evidence for the large presence of unexchanged and mixed copper-paddle-wheels. Based on these insights, we were able to optimize and automatize synthesis methods and produce (100) oriented HKUST-1 thin-films with significantly shorter synthesis times, and additionally use copper nitrate as an effective synthesis precursor. PMID- 29164721 TI - In vitro studies of Norwegian Red bovine semen immobilized and cryopreserved in alginate solid gel network. AB - Development of new semen cryopreservation techniques improving sperm survival and ensuring availability of viable spermatozoa for a prolonged time-period after AI is promising tools to reduce sensitivity of timing of AI and enhance overall fertility. The SpermVital(r) technology utilizes immobilization of bull spermatozoa in a solid network of alginate gel prior to freezing, which will provide a gradual release of spermatozoa after AI. The objective of this study was to compare post-thaw sperm quality and in vitro sperm survival over time of Norwegian Red bull semen processed by the SpermVital(r) (SV) technology, the first commercialized production line of SpermVital(r) (C) and by conventional procedure applying Biladyl(r) extender (B). Post-thaw sperm motility was not significantly different between SV, C and B semen (p > .05). However, sperm viability and acrosome intactness were higher for SV than C and B semen (p < .05). Small differences in DNA quality were observed (p < .05). Sperm viability after storage in uterus ex vivo was higher for SV than for C semen (p < .05). Furthermore, sperm survival in vitro over time at physiological temperature was significantly higher for SV semen than C semen as well as B semen during the incubation period of 48 hr (p < .05). In conclusion, the SpermVital(r) technology is improved and is more efficient in conserving post-thaw sperm quality and results in higher sperm viability over time in vitro for SV than for C and B semen. PMID- 29164722 TI - Experimental manipulation reveals a trade-off between weapons and testes. AB - Theory predicts a trade-off between sexually selected weapons used to secure mates and post-copulatory traits used to maximize fertilization success. However, individuals that have a greater capacity to acquire resources from the environment may invest more in both pre- and post-copulatory traits, and trade offs may not be readily apparent. Here, we manipulate the phenotype of developing individuals to examine allocation trade-offs between weapons and testes in Mictis profana (Hemiptera: Coreidae), a species where the hind legs are sexually selected weapons used in contests over access to females. We experimentally prevented males from developing weapons by inducing them to autotomize their hind legs before the final moult to adulthood. We compared trait expression in this group to males where autotomy was induced in the mid-legs, which are presumably not under sexual selection to the same extent. We found males without weapons invested proportionally more in testes mass than those with their mid-legs removed. Males that developed to adulthood without weapons did not differ from the mid-leg removal group in other traits potentially under precopulatory sexual selection, other post-copulatory traits or naturally selected traits. In addition, a sample of adult males from the same population in the wild revealed a positive correlation between investment in testes and weapons. Our study presents a critical contribution to a growing body of literature suggesting the allocation of resources to pre- and post-copulatory sexual traits is influenced by a resource allocation trade-off and that this trade-off may only be revealed with experimental manipulation. PMID- 29164723 TI - Double-blind placebo-controlled trial of the effect of omalizumab on basophils in chronic urticaria patients. AB - BACKGROUND: Omalizumab has been shown to be effective in treating chronic spontaneous urticaria (CSU). The reduction in FcepsilonRI receptor density on the surface of basophils and mast cells is thought to play a major role in its effectiveness. We conducted a double-blind, randomized, placebo-controlled trial to investigate the mode of action of omalizumab in patients with antihistamine resistant CSU. METHODS: Thirty patients were randomized in a 2:1 ratio to receive either 300 mg omalizumab or placebo. Four monthly applications of omalizumab/placebo were followed up with a visit 2 months after the last injection. The primary endpoint was the FcepsilonRI receptor density change on basophils. RESULTS: Omalizumab led to a significant reduction in FcepsilonRI receptor density on basophils as soon as 1 week after the first injection: baseline omalizumab vs placebo group, 80.31 +/- 47.18 * 103 vs 78.29 +/- 45.09 * 103 receptors/basophil +/- SD; 1 week, 72.89 +/- 47.79 * 103 vs 27.83 +/- 20.87 * 103, P = .001. This effect continued during the treatment phase and persisted for 2 months after the last injection: 93.81 +/- 56.50 * 103 vs 21.09 +/- 15.23 * 103, P = .002. Values for basophil "releasability" and the basophil activation test (CU-BAT) of patient serum using donor basophils were unchanged despite treatment: CU-BAT, CD63 10.75% (7.35) in the placebo group vs 8.35% (15.20) in the omalizumab group, P = .778. CONCLUSION: We demonstrated a rapid reduction of FcepsilonRI receptor density on basophils following treatment with omalizumab. Because CU-BAT using well-characterized, omalizumab-naive donor basophils did not change during the treatment phase, autoreactive serum factors seem to remain unaltered. This points towards a cellular effect of omalizumab on basophils. To predict the omalizumab response time and to monitor disease, FcepsilonRI density and CU-BAT might be promising cellular-based assays. PMID- 29164724 TI - Intraoperative Localization of the Subthalamic Nucleus Using Long-Latency Somatosensory Evoked Potentials. AB - BACKGROUND: Target localization for deep brain stimulation (DBS) is a challenging step that determines not only the correct placement of stimulation electrodes, but also influences the success of the DBS procedure as reflected in the desired clinical outcome of a patient. OBJECTIVE: We report on the feasibility of DBS target localization in the subthalamic nucleus (STN) by long-latency somatosensory evoked potentials (LL-SSEPs) (>40 msec) in Parkinson's disease (PD) patients. METHODS: Micro-macroelectrode recordings were performed intraoperatively on seven PD patients (eight STN hemispheres) who underwent DBS treatment. LL-SSEPs were elicited by ipsi- and contralateral median nerve stimulation to the wrist. RESULTS: Four distinctive LL-SSEP components were elicited ("LL-complex" consisting of P80, N100, P140, and N200). The P80 appeared as the most visible and reliable intraoperative component. Localization of the "LL-complex" within the target was approved with typical microelectrode firing activity patterns, atlas visualization of recording electrodes, and postoperative CT-based visualization of final DBS electrodes. CONCLUSIONS: LL-SSEPs represent a promising approach for DBS target localization in the STN, provided deeper understanding on their anesthesia effect is obtained. This approach is advantageous in that it does not require the patient's participation in an intraoperative setting. PMID- 29164725 TI - A scoping review of environmental health nursing research. AB - OBJECTIVE: The purpose of this scoping review was to determine the extent and focus of published environmental health nursing research. DESIGN AND SAMPLE: The search was limited to peer reviewed, English-language environmental health nursing research with at least one nursing author, published between 1995 and 2015 in a nursing journal, and catalogued in CINAHL. RESULTS: Publication of the 548 identified articles occurred in 118 different nursing journals. Annual number of publications increased from nine articles in 1995 to 50 in 2013 and 2014. Most (63%) of the studies occurred in the Unnited States; the remaining studies took place in 33 other countries. Three primary focus areas were identified: disasters/disaster preparedness, occupational health, and the home environment. Other focus areas included environmental exposures, environmental risk perception, secondhand smoke, and environmental health education. The primary populations studied were nurses/nursing students (40%) and adults (26%). Most common research designs employed were cross-sectional (42%) and qualitative methods (20%). CONCLUSIONS: Findings from this scoping review support a global expansion of published environmental health nursing research addressing a variety of environmental health topics. Additional studies are needed that use more complex research methods and address timely topics such as climate change and sustainability. PMID- 29164726 TI - Functional connectivity changes following interpersonal reactivity. AB - Attachment experiences substantially influence emotional and cognitive development. Narratives comprising attachment-dependent content were proposed to modulate activation of cognitive-emotional schemata in listeners. We studied the effects after listening to prototypical attachment narratives on wellbeing and countertransference-reactions in 149 healthy participants. Neural correlates of these cognitive-emotional schema activations were investigated in a 7 Tesla rest task-rest fMRI-study (23 healthy males) using functional connectivity (FC) analysis of the social approach network (seed regions: left and right Caudate Nucleus, CN). Reduced FC between left CN and bilateral dorsolateral prefrontal cortex (DLPFC) represented a general effect of prior auditory stimulation. After presentation of the insecure-dismissing narrative, FC between left CN and bilateral temporo-parietal junction, and right dorsal posterior Cingulum was reduced, compared to baseline. Post-narrative FC-patterns of insecure-dismissing and insecure-preoccupied narratives differed in strength between left CN and right DLPFC. Neural correlates of the moderating effect of individual attachment anxiety were represented in a reduced CN-DLPFC FC as a function of individual neediness-levels. These findings suggest specific neural processing of prolonged mood-changes and schema activation induced by attachment-specific speech patterns. Individual desire for interpersonal proximity was predicted by attachment anxiety and furthermore modulated FC of the social approach network in those exposed to such narratives. PMID- 29164727 TI - Highly Efficient Synthesis of a Staphylococcus aureus Targeting Payload to Enable the First Antibody-Antibiotic Conjugate. AB - A practical synthesis of the complex payload for an anti-Staphylococcus aureus THIOMABTM antibody-antibiotic conjugate (TAC) is described. The route takes advantage of a delicate oxidative condensation, achieved using a semi-continuous flow procedure. It allows for the generation of kilogram quantities of a key intermediate to enable a mild nucleophilic aromatic substitution to the tertiary amine free drug. The linker component is introduced as a benzylic chloride, which allows formation of the quaternary ammonium salt linker-drug. This chemical process surmounts numerous synthetic challenges and navigates deeply colored and unstable compounds to support clinical studies to counter S. aureus bacterial infections. PMID- 29164728 TI - Management capacity to promote nurse workplace health and safety. AB - PURPOSE: To investigate regarding workplace health and safety factors, and to identify strategies to preserve and promote a healthy nursing workplace. METHODS: Data collected using the Delphi technique with input from 41 key informants across four participant categories drawn from a Chinese university and four hospitals were thematically analysed. RESULTS: Most respondents agreed on the importance of nurses' health and safety, and that nurse managers should act to protect nurses, but not enough on workplace safety. Hospital policies, staff disempowerment, workload and workplace conflicts are major obstacles. CONCLUSION: The reality of Chinese nurses' workplaces is that health and safety risks abound and relate to socio-cultural expectations of women. Self-management of risks is neccessary, gaps exist in understanding of workplace risks among different nursing groups and their perceptions of the professional status, and the value of nurses' contribution to ongoing risks in the hospital workplace. The Chinese hospital system must make these changes to produce a safer working environment for nurses. IMPLICATIONS FOR NURSING MANAGEMENT: This research, based in China, presents an instructive tale for all countries that need support on the types and amounts of management for nurses working at the clinical interface, and on the consequences of management neglect of relevant policies and procedures. PMID- 29164729 TI - Identification and characterization of a histamine-binding lipocalin-like molecule from the relapsing fever tick Ornithodoros turicata. AB - Lipocalins are low molecular weight membrane transporters that are abundantly expressed in the salivary glands and other tissues of ticks. In this study, we identified a lipocalin-like molecule, designated as otlip, from the soft ticks Ornithodoros turicata, the vector for the relapsing fever causing spirochete Borrelia turicatae. We noted that the expression of otlip was developmentally regulated, with adult ticks expressing significantly higher levels in comparison to the larvae or nymphal ticks. Expression of otlip was evident in both fed and unfed O. turicata ticks, with significantly increased expression in the salivary glands in comparison to the midgut or ovary tissues. High conservation of the biogenic amine-binding motif was evident in the deduced primary amino acid sequence of Otlip. Protein modelling of Otlip revealed conservation of most of the residues involved in binding histamine or serotonin ligand. In vitro assays demonstrated binding of recombinant Otlip with histamine. Furthermore, prediction of post-translational modifications revealed that Otlip contained phosphorylation and myristoylation sites. Taken together, our study not only provides evidence for the presence of a lipocalin-like molecule in O. turicata ticks but also suggests a role for this molecule in the salivary glands of this medically important vector. PMID- 29164730 TI - Ups and downs in heart failure: the case of proteomics. PMID- 29164731 TI - Self-management programmes for quality of life in people with stroke. PMID- 29164732 TI - Cobalt Pincer Complexes for Catalytic Reduction of Carboxylic Acid Esters. AB - A selection of cobalt(I) and cobalt(II) pincer type complexes with different substitution patterns was tested in the catalytic reduction of carboxylic acid esters to alcohols. The cobalt pincer type complex 4 is suitable for the hydrogenation of aromatic as well as aliphatic and cyclic esters. Mechanistic investigation indicated a metal ligand cooperated reaction pathway. PMID- 29164733 TI - Regulation of intestinal health by branched-chain amino acids. AB - Besides its primary role in the digestion and absorption of nutrients, the intestine also interacts with a complex external milieu, and is the first defense line against noxious pathogens and antigens. Dysfunction of the intestinal barrier is associated with enhanced intestinal permeability and development of various gastrointestinal diseases. The branched-chain amino acids (BCAAs) are important nutrients, which are the essential substrates for protein biosynthesis. Recently, emerging evidence showed that BCAAs are involved in maintaining intestinal barrier function. It has been reported that dietary supplementation with BCAAs promotes intestinal development, enhances enterocyte proliferation, increases intestinal absorption of amino acids (AA) and glucose, and improves the immune defenses of piglets. The underlying mechanism of these effects is mediated by regulating expression of genes and proteins associate with various signaling pathways. In addition, BCAAs promote the production of beneficial bacteria in the intestine of mice. Compelling evidence supports the notion that BCAAs play important roles in both nutrition and intestinal health. Therefore, as functional amino acids with various physiological effects, BCAAs hold key roles in promoting intestinal development and health in animals and humans. PMID- 29164734 TI - Considering the duration of heart failure: using the past to predict the future. PMID- 29164735 TI - Substituting the Target After Unsatisfactory Outcome of Deep Brain Stimulation in Advanced Parkinson's Disease: Cases From the NSTAPS Trial and Systematic Review of the Literature. AB - BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and the subthalamic nucleus (STN) are established treatment option in Parkinson's disease (PD). If DBS does not provide the desired effect, re operation to the alternative target is a treatment option, but data on the effect of re-operation are scarce. OBJECTIVES: The objective of this study is to evaluate the clinical effect of re-operation the alternative target after failure of initial STN or GPi DBS for Parkinson's disease. MATERIALS AND METHODS: We descriptively analyzed the baseline characteristics, the effect of initial surgery and re-operation of eight NSTAPS (Netherlands SubThalamic and Pallidal Stimulation) patients and six previously published cases that underwent re operation to a different target. RESULTS: In the NSTAPS cohort, two of the eight patients showed more than 30% improvement of off-drug motor symptoms after re operation. The initial DBS leads of these patients were off target. In the cases from the literature, 30% off-drug motor improvement was seen in all three patients re-operated from GPi to STN and none of the three patients re-operated from STN to GPi. Only one of the three cases from the literature where any improvement was seen with the operation had a confirmed on target lead location after the first surgery, while the other two patients did not undergo post operative imaging after the first surgery. CONCLUSIONS: Re-operation to a different target due to lack of effect appears to have a limited chance of leading to objective improvement if the leads were correctly placed during initial surgery. PMID- 29164736 TI - A Technique to Correct Anterior-Posterior Tooth Discrepancy for a Maxillary Immediate Complete Denture. AB - This article describes a chairside technique to correct inappropriate occlusal vertical dimension as well as the inaccurate anterior-posterior tooth set-up of a maxillary immediate complete denture. When fabricating an immediate denture, the inability of a wax-denture trial and the potential for unpredictable complications during surgery, compromised esthetics and function of an immediate complete denture may pose a clinical problem, which needs instant correction. The technique described can provide an alternative method to correct and deliver a definitive immediate complete denture on the day of surgery. PMID- 29164737 TI - Reproducibility of EEG-MEG fusion source analysis of interictal spikes: Relevance in presurgical evaluation of epilepsy. AB - Fusion of electroencephalography (EEG) and magnetoencephalography (MEG) data using maximum entropy on the mean method (MEM-fusion) takes advantage of the complementarities between EEG and MEG to improve localization accuracy. Simulation studies demonstrated MEM-fusion to be robust especially in noisy conditions such as single spike source localizations (SSSL). Our objective was to assess the reliability of SSSL using MEM-fusion on clinical data. We proposed to cluster SSSL results to find the most reliable and consistent source map from the reconstructed sources, the so-called consensus map. Thirty-four types of interictal epileptic discharges (IEDs) were analyzed from 26 patients with well defined epileptogenic focus. SSSLs were performed on EEG, MEG, and fusion data and consensus maps were estimated using hierarchical clustering. Qualitative (spike-to-spike reproducibility rate, SSR) and quantitative (localization error and spatial dispersion) assessments were performed using the epileptogenic focus as clinical reference. Fusion SSSL provided significantly better results than EEG or MEG alone. Fusion found at least one cluster concordant with the clinical reference in all cases. This concordant cluster was always the one involving the highest number of spikes. Fusion yielded highest reproducibility (SSR EEG = 55%, MEG = 71%, fusion = 90%) and lowest localization error. Also, using only few channels from either modality (21EEG + 272MEG or 54EEG + 25MEG) was sufficient to reach accurate fusion. MEM-fusion with consensus map approach provides an objective way of finding the most reliable and concordant generators of IEDs. We, therefore, suggest the pertinence of SSSL using MEM-fusion as a valuable clinical tool for presurgical evaluation of epilepsy. PMID- 29164738 TI - Secondary acute myeloid leukaemia in elderly patients: Patient's fitness criteria and ELN prognostic stratification can be applied to guide treatment decisions. An analysis of 280 patients by the network rete ematologica lombarda (REL). PMID- 29164739 TI - Can specially trained community care workers effectively support patients and their families in the home setting at the end of life? AB - Surveys indicate that many Australians would prefer to die at home, but relatively few do. Recognising that patients and their families may not have the support they need to enable end-of-life care at home, a consortium of care providers developed, and received funding to trial, the Palliative Care Home Support Program (PCHSP) across seven health districts in New South Wales, Australia. The programme aimed to supplement end-of-life care in the home provided by existing multidisciplinary community palliative care teams, with specialist supportive community care workers (CCWs). An evaluation of the service was undertaken, focussing on the self-reported impact of the service on family carers (FCs), with triangulation of findings from community palliative care teams and CCWs. Service evaluation data were obtained through postal surveys and/or qualitative interviews with FCs, community palliative care teams and CCWs. FCs also reported the experience of their loved one based on 10 items drawn from the Quality of Death and Dying Questionnaire (QODD). Thematic analysis of surveys and interviews found that the support provided by CCWs was valued by FCs for: enabling choice (i.e. to realise end-of-life care in the home); providing practical assistance ("hands-on"); and for emotional support and reassurance. This was corroborated by community palliative care teams and CCWs. Responses by FCs on the QODD items indicated that in the last week of life, effective control of symptoms was occurring and quality of life was being maintained. This study suggests that satisfactory outcomes for patients and their families who wish to have end-of-life care in the home can be enabled with the additional support of specially trained CCWs. A notable benefit of the PCHSP model, which provided specific palliative care vocational training to an existing community care workforce, was a relatively rapid increase in the palliative care workforce across the state. PMID- 29164740 TI - Of moral judgments and sexual addictions. PMID- 29164741 TI - Effects of breed proportion and components of heterosis for semen traits in a composite cattle breed. AB - The aim of this study was to estimate the non-additive genetic effects of the dominance component of heterosis as well as epistatic loss on semen traits in admixed Swiss Fleckvieh, a composite of Simmental (SI) and Red Holstein Friesian (RHF) cattle. Heterosis is the additional gain in productivity or fitness of cross-bred progeny over the mid-purebred parental populations. Intralocus gene interaction usually has a positive effect, while epistatic loss generally reduces productivity or fitness due to lack of evolutionarily established interactions of genes from different breeds. Genotypic data on 38,205 SNP of 818 admixed, as well as 148 RHF and 213 SI bulls as the parental breeds were used to predict breed origin of alleles. The genomewide locus-specific breed ancestries of individuals were used to calculate effects of breed difference as well as the dominance component of heterosis, while proxies for two definitions of epistatic loss were derived from 100,000 random pairs of loci. The average Holstein Friesian ancestry in admixed bulls was estimated 0.82. Results of fitting different linear mixed models showed including the dominance component of heterosis considerably improved the model adequacy for three of the four traits. Inclusion of epistatic loss increased the accuracy of the models only for our new definition of the epistatic effect for two traits, while the other definition was so highly correlated with the dominance component that statistical separation was impossible. PMID- 29164742 TI - We need more high-volume myectomy centres in Europe. PMID- 29164743 TI - Patient-initiated recruitment for clinical research: Evaluation of an outpatient letter research statement. AB - BACKGROUND: UK Hospital Trusts are charged with increasing patients' research awareness and willingness to take part in research. This includes implementing strategies to encourage patient-initiated enquiries about participation. OBJECTIVES: To evaluate the impact of a research statement inserted in outpatient letters in one clinical service, and to derive suggestions on potential steps towards increasing patient-initiated recruitment. SETTING: A medical outpatient clinic of a research-active hospital trust, serving an inner-city multi-ethnic population across two boroughs. METHODS: Pre-intervention and post-intervention questionnaires were administered face-to-face to new patients. Questionnaires included closed questions and one open comments section. Data were analysed for frequencies, with thematic coding of open-ended responses. RESULTS: The response rates were 87% for the pre-intervention survey and 92% for the post-intervention survey. In the post-intervention survey, 85% of patients did not notice the research statement in the letter. More than half found the statement "a little unclear," whilst one-third considered it "clear." Three-quarters of respondents perceived the statement to be "a little helpful." Only one person enquired about participating in clinical research having read the statement in the outpatient letter. CONCLUSION: The analysis suggests that simple, single-solution approaches such as including research statements in outpatient letters are unlikely to be sufficient to significantly facilitate patient-initiated recruitment. Recruitment efforts need to take into consideration the diversity of patient constituencies including the reasons they seek health care, and how patients can meaningfully access information (research literacy). PMID- 29164746 TI - It's time to move on from counting co-morbidities to curing them: the case of chronic heart failure-chronic obstructive pulmonary disease co-morbidity. PMID- 29164745 TI - Fully Implantable Peripheral Nerve Stimulation for Hemiplegic Shoulder Pain: A Multi-Site Case Series With Two-Year Follow-Up. AB - OBJECTIVE: To explore the feasibility and safety of a single-lead, fully implantable peripheral nerve stimulation system for the treatment of chronic shoulder pain in stroke survivors. PARTICIPANTS: Participants with moderate to severe shoulder pain not responsive to conservative therapies for six months. METHODS: During the trial phase, which included a blinded sham introductory period, a percutaneous single-lead peripheral nerve stimulation system was implanted to stimulate the axillary nerve of the affected shoulder. After a three week successful trial, participants received an implantable pulse generator with an electrode placed to stimulate the axillary nerve of the affected shoulder. Outcomes included pain, pain interference, pain-free external rotation range of motion, quality of life, and safety. Participants were followed for 24 months. RESULTS: Twenty-eight participants underwent trial stimulation and five participants received an implantable pulse generator. The participants who received the implantable generator experienced an improvement in pain severity (p = 0.0002). All five participants experienced a 50% or greater pain reduction at 6 and 12 months, and four experienced at least a 50% reduction at 24 months. There was an improvement in pain interference (p < 0.0001). There was an improvement in pain-free external ROM (p = 0.003). There were no serious adverse events related to the device or to the procedure. CONCLUSIONS: This case series demonstrates the safety and efficacy of a fully implantable axillary PNS system for chronic HSP. Participants experienced reduction in pain, reduction in pain interference, and improved pain-free external rotation ROM. There were no serious adverse events associated with the system or the procedure. PMID- 29164747 TI - A role for fruit structure in seed survival and germination of Swartzia langsdorffii Raddi beyond dispersal. AB - Diaspore structure has been hypothesised to play a role in seed viability and/or germination of recalcitrant seeds, especially for Swartzia langsdorffii. Thus, this work aims to (i) investigate the in situ contribution of pericarp and aril on seed viability and germination, and (ii) identify morphoanatomical traits of S. langsdorffii diaspores that allow its desiccation-sensitive seeds to remain viable. The role of the pericarp and aril in seed survival and germination was investigated by placing the whole fruit, whole seeds (arillate seed) and bare seeds (without aril) in soil in the forest understorey, assessing germination, emergence, dead, firm and predated seeds, and water content of pericarps, arils and seeds. Correlation analysis was performed between environmental variables and physiological parameters. Histochemical features of diaspores were also investigated. Pericarp water content fell after several months, while the aril maintained its water content. Seeds did not lose water even without the presence of the pericarp and aril. However, presence of the pericarp promoted seed water content, viability and germination long after dispersal. The embryo had a thickened outer periclinal cell wall. Pericarp and aril are not essential to prevent water loss in seeds, but do help to retain seed moisture, favouring viability maintenance and promoting germination during the rainy season. Morphoanatomical features of seeds are suggested as main factors that reduce water loss. Survival of these desiccation-sensitive seeds upon dispersal during the dry season appears to be facilitated by multiple diaspore features that prevent viability loss. PMID- 29164748 TI - Maternal protein malnutrition induced-hypertension: New evidence about the autonomic and respiratory dysfunctions and epigenetic mechanisms. AB - Maternal protein malnutrition during the critical stages of development (pregnancy, lactation and first infancy) can lead to adult hypertension. Studies have shown that renal and cardiovascular dysfunctions can be associated to the development of hypertension in humans and rats exposed to maternal protein malnutrition. The etiology of hypertension, however, includes a complex network involved in central and peripheral blood pressure control. Recently, the hyperactivity of the sympathetic nervous system in protein-restricted rats has been reported. Studies have shown that protein malnutrition during pregnancy and/or lactation alters blood pressure control through mechanisms that include central sympathetic-respiratory dysfunctions and epigenetic modifications, which may contribute to adult hypertension. Thus, this review will discuss the historical context, new evidences of neurogenic disruption in respiratory sympathetic activities and possible epigenetic mechanisms involved in maternal protein malnutrition induced- hypertension. PMID- 29164749 TI - Effects of Neuromuscular Electrical Stimulation on the Frequency of Skeletal Muscle Cramps: A Prospective Controlled Clinical Trial. AB - OBJECTIVES: We investigated if neuromuscular electrical stimulation (NMES) of calf muscles prevents spontaneous calf cramps. MATERIALS AND METHODS: In 19 individuals affected by more than or equal to one calf cramp per week the gastrocnemius of the predominantly affected leg was stimulated twice a week (intervention leg, IL) over six weeks (3 * 6 stimulation trains at 30 Hz above the individual cramp threshold frequency). The other leg served as control (CL). The participants were advised to record all spontaneous muscle cramps from two weeks before the intervention until two weeks after the last NMES session. RESULTS: The number of spontaneous calf cramps in the two weeks after the intervention was 78% lower (2.1 +/- 6.8 cramps) in the stimulated (p < 0.001) and 63% lower (2.0 +/- 6.9 cramps) in the unstimulated calves (p < 0.001), when compared to the two weeks prior to the intervention (IL: 9.6 +/- 12.4 cramps; CL: 5.5 +/- 12.7 cramps). Only in the IL, this improvement was accompanied by an increase in the cramp threshold frequency from 15.5 +/- 8.5 Hz before the NMES intervention to 21.7 +/- 12.4 Hz after the intervention. The severity of the remaining calf cramps tended to be lower in both legs after the intervention. CONCLUSIONS: The applied stimulation protocol seems to provide an effective prevention strategy in individuals affected by regular calf cramps. PMID- 29164750 TI - Association between oropharyngeal dysphagia, oral functionality, and oral sensorimotor alteration. AB - OBJECTIVE: To evaluate whether the oral functionality and the oral sensorimotor alterations are associated with oropharyngeal dysphagia in community-dwelling older persons and long-term care older residents. METHODS: An exploratory study with 265 independent older persons of the southern state of Brazil. The diagnosis of dysphagia, as well as the condition of the oral sensorimotor system, was assessed by a speech-language therapist and the oral health status by a dentist. Poisson Regression with robust variance was used to calculate the crude and adjusted Prevalence Ratios (PR) and their respective confidence intervals of 95%. RESULTS: The mean age was 73.5 (+/-8.9) years, women represented 59.2% of the sample. The frequency of dysphagia in the studied population was 45.3% (n = 120), being more frequent in the long-term care older residents (62.5%; n = 75) than in the community-dwelling older persons (37.5%; n = 45). Individuals with four or more oral sensorimotor alterations (PR = 2.01; 95% CI 1.27-3.18), as well as those who presented a non-functional oral status (PR = 1.61; 95% CI 1.02-2.54) presented a higher frequency of dysphagia. Subgroup analysis indicates the same trend of results, when stratified by community-dwelling older persons and long term older residents. CONCLUSION: A non-functional oral health status and oral sensorimotor alterations are associated with a higher prevalence of oropharyngeal dysphagia. PMID- 29164751 TI - Style polymorphism in Linum (Linaceae): a case of Mediterranean parallel evolution? AB - Heterostyly is a sex polymorphism that has challenged evolutionary biologists ever since Darwin. One of the lineages where heterostyly and related stylar conditions appear more frequently is Linum (Linaceae). This group is particularly suitable for testing competing hypotheses about ancestral and transitional stages on the evolutionary building up of heterostyly. We generated a phylogeny of Linum based on extensive sampling and plastid and nuclear DNA sequences, and used it to trace the evolution of character states of style polymorphism. We also revised available data on pollination, breeding systems, and polyploidy to analyse their associations. Our results supported former phylogenetic hypotheses: the paraphyly of Linum and the non-monophyly of current taxonomic sections. Heterostyly was common in the genus, but appeared concentrated in the Mediterranean Basin and the South African Cape. Ancestral character state reconstruction failed to determine a unique state as the most probable condition for style polymorphism in the genus. In contrast, approach herkogamy was resolved as ancestral state in some clades, giving support to recent hypotheses. Some traits putatively related to heterostyly, such as life history and polyploidy, did show marginal or non significant phylogenetic correlation, respectively. Although pollinator data are limited, we suggest that beeflies are associated with specific cases of heterostyly. The consistent association between style polymorphism and heteromorphic incompatibility points to ecological factors as drivers of the multiple evolution of style polymorphism in Linum. Albeit based on limited evidence, we hypothesised that specialised pollinators and lack of mating opportunities drive evolution of style polymorphism and loss of the polymorphism, respectively. PMID- 29164752 TI - Spinal Cord Stimulation With "Conventional Clinical" and Higher Frequencies on Activity and Responses of Spinal Neurons to Noxious Stimuli: An Animal Study. AB - OBJECTIVES: Spinal cord stimulation (SCS) at both conventional and higher frequencies may effectively reduce pain, but optimal parameters need to be established. This study investigated how SCS at different frequencies and pulse widths acutely modulates nociceptive activity of wide dynamic range (WDR) and high threshold (HT) dorsal horn neurons in rats at a stimulus amplitude that influences both local circuits and dorsal column fibers. MATERIALS AND METHODS: L2 -L3 and L6 -S2 spinal segments were exposed for SCS and spinal neuronal recordings, respectively. Responses to pinch of a hindpaw were recorded before and after SCS (40 or 200 usec pulse width at 50, 500, 1 kHz and 10 kHz, amplitude: 90% of motor threshold) for 5 or 20 min. Pinch responses were tested within 30 s after SCS ceased (first pinch) and at ~4 min intervals until response recovery. RESULTS: 1) SCS for 5 min suppressed averaged first pinch responses, except for 40 usec/50 Hz. 2) Only SCS with 40 us/1 kHz suppressed more spinal neurons than 200 usec/50 Hz. 3) All SCS parameters at 5 min increased pinch responses for a small population of cells, with the incidence being greater for WDR than for HT neurons. 4) SCS at 1 kHz (40 or 200 usec) for 20 min reduced the response to the second pinch as compared with baseline responses. In addition, no neurons exhibited increased pinch responses. CONCLUSIONS: Compared with a typical low frequency SCS (200 us/50 Hz) or high-frequency SCS at 10 kHz, at an amplitude designed to influence both local spinal circuits and dorsal column fiber tracts, 1 kHz SCS suppressed nociceptive responses of more spinal neurons and/or demonstrated longer persisting suppressive effects. SCS at 1 kHz surpassed both low-frequency (50 Hz) and high-frequency (10 kHz) SCS application in this normal animal model. PMID- 29164753 TI - Prevalence of left ventricular systolic dysfunction in pre-dialysis and dialysis patients with preserved left ventricular ejection fraction. AB - AIMS: Patients with chronic kidney disease (CKD) have an excess of cardiovascular morbidity and mortality, with heart failure (HF) being particularly frequent. Reduced left ventricular ejection fraction (LVEF) defines left ventricular (LV) systolic dysfunction and is associated with poor prognosis. However, CKD patients may have HF symptoms with preserved LVEF. In this subgroup of patients, two dimensional speckle tracking echocardiography can detect LV systolic dysfunction by analysing LV myocardial deformation. The present study evaluated the prevalence of impaired LV global longitudinal strain (GLS) in CKD patients with preserved LVEF and its prognostic consequences. METHODS AND RESULTS: Overall, 200 pre-dialysis and dialysis patients (65% men, mean age 60 +/- 14 years) with CKD stage 3b-5 and preserved LVEF (>=50%) were evaluated. Left ventricular systolic dysfunction despite preserved LVEF was defined by LV GLS <=15.2% (cut-off value derived from two standard deviations below the mean value of individuals without structural heart disease). Impaired LV GLS (<=15.2%) despite preserved LVEF was observed in 32% of patients. During a median follow-up of 33 months (interquartile range 17-62 months), 47% of patients underwent renal transplantation, 9% were admitted with HF, and 28% died. Patients with LV GLS <=15.2% showed significantly worse cumulative event-free survival rates of the combined endpoint of HF hospitalization and all-cause mortality compared to patients with LV GLS >15.2% (log-rank P = 0.018). CONCLUSION: The prevalence of impaired LV GLS despite preserved LVEF in pre-dialysis and dialysis patients is relatively high. Patients with preserved LVEF but impaired LV GLS have an increased risk of HF hospitalization and all-cause mortality. PMID- 29164754 TI - Interventions to significantly improve service uptake and retention of HIV positive pregnant women and HIV-exposed infants along the prevention of mother-to child transmission continuum of care: systematic review. AB - OBJECTIVES: Despite the success of Prevention of Mother-to-Child Transmission of HIV (PMTCT) programmes, low uptake of services and poor retention pose a formidable challenge to achieving the elimination of vertical HIV transmission in low- and middle-income countries. This systematic review summarises interventions that demonstrate statistically significant improvements in service uptake and retention of HIV-positive pregnant and breastfeeding women and their infants along the PMTCT cascade. METHODS: Databases were systematically searched for peer reviewed studies. Outcomes of interest included uptake of services, such as antiretroviral therapy (ART) such as initiation, early infant diagnostic testing, and retention of HIV-positive pregnant and breastfeeding women and their infants. Interventions that led to statistically significant outcomes were included and mapped to the PMTCT cascade. An eight-item assessment tool assessed study rigour. PROSPERO ID: CRD42017063816. RESULTS: Of 686 citations reviewed, 11 articles met inclusion criteria. Ten studies detailed maternal outcomes and seven studies detailed infant outcomes in PMTCT programmes. Interventions to increase access to antenatal care (ANC) and ART services (n = 4) and those using lay cadres (n = 3) were most common. Other interventions included quality improvement (n = 2), mHealth (n = 1), and counselling (n = 1). One study described interventions in an Option B+ programme. Limitations included lack of HIV testing and counselling and viral load monitoring outcomes, small sample size, geographical location, and non randomized assignment and selection of participants. CONCLUSIONS: Interventions including ANC/ART integration, family-centred approaches, and the use of lay healthcare providers are demonstrably effective in increasing service uptake and retention of HIV-positive mothers and their infants in PMTCT programmes. Future studies should include control groups and assess whether interventions developed in the context of earlier 'Options' are effective in improving outcomes in Option B+ programmes. PMID- 29164755 TI - Medical and mechanical unloading in advanced heart failure: hope for cardiac recovery? PMID- 29164756 TI - Survey of disability-related content in Australian dietetics programs. AB - AIM: Nutrition and dietetic services are an important component of healthcare for people living with a disability. The introduction of the National Disability Insurance Scheme (NDIS) in Australia is providing more opportunities for individuals to access these services from an Accredited Practising Dietitian (APD). The aim of this research was to identify how students in Australian tertiary dietetics programs are being prepared to provide these services to people with a disability. METHODS: A purpose-built questionnaire with eight open ended questions was developed by the researchers to describe the disability related content of university and professional placement learning opportunities and was distributed to all course conveners (or their nominated representative) of dietetics programs accredited by the Dietitians Association of Australia. The qualitative data were analysed using a descriptive approach. Responses were sorted into response category themes and counted to identify common themes. RESULTS: A representative from 14 of 18 programs (78% response rate) participated in the survey in September and October 2016. Results indicated that although 12 programs incorporate disability-related topics into the curriculum, content was inconsistent and of varying depths. Four programs offered a disability-specific placement opportunity and nine discussed the NDIS to varying degrees. CONCLUSIONS: It is important that graduates are provided with adequate learning opportunities in the area of disability to ensure that they are prepared for entry-level practise in this area. Further research may provide insight into the skills, knowledge and behaviours used by APDs working in disability to identify those that need to be strengthened in dietetics programs. PMID- 29164757 TI - Considerations in fertility preservation in cases of testicular trauma. AB - OBJECTIVE: To perform a review of the literature to assess the options for preserving fertility in patients with fertility threatening testicular injuries and their effectiveness to help guide surgeons who encounter these patients in the future. MATERIALS AND METHODS: Medline, Embase and Cochrane library databases were searched using the keywords 'treatment', 'therapy', 'management', 'scrotal trauma/injury', 'testicular trauma/injury/amputation', 'fertility', and 'fertility preservation'. The inclusion criteria were studies reporting fertility preserving techniques with a history of testicular trauma with loss of one, both, or nearly all testicular parenchymal tissue. RESULTS: Two cases of testicular sperm extraction (TESE), eight cases of testicular replantation, and one case of cryopreservation after injury were identified. Presence of viable sperm after surgery was found in five of 11 patients. Common reasons for failure of replantation were prolonged ischaemic time and extensive crush injury to the vascular supply of the testis. Both cases of TESE and the single cryopreservation case obtained viable sperm. CONCLUSION: Scrotal trauma with threat to fertility is rare. It is important that urologists should consider fertility in any situation where complete or a large amount of testicular tissue loss is at risk of occurring and offer fertility preservation options as locally available. PMID- 29164758 TI - Is GxE a burden or a blessing? Opportunities for genomic selection and big data. PMID- 29164759 TI - It is unlikely that genomic selection will ever be 100% accurate. PMID- 29164760 TI - Can we make genomic selection 100% accurate? PMID- 29164762 TI - Recalibrated MELD and hepatic encephalopathy are prognostic factors in cirrhotic patients with acute variceal bleeding. AB - BACKGROUND & AIMS: Early TIPS placement must be considered in patients with Child Pugh B and active bleeding at endoscopy or in patients with Child-Pugh C 10-13 and variceal bleeding. However, active bleeding at endoscopy is a subjective criterion. Moreover, a previous study has shown that a MELD-based score accurately predicted 6-week mortality and helped to stratify patients. Using a prospective series of patients included in a multicentre study before the era of early TIPS, we aimed (i) to identify factors associated with 6-week mortality, focusing on the prognostic value of active bleeding; and (ii) to assess whether a recalibrated MELD-based score accurately predicted 6-week mortality. METHODS: Ancillary study of the prospective multicentre Baveno IV study, including patients with acute variceal bleeding. RESULTS: Two hundred and nineteen patients were analysed (Child-Pugh A/B/C = 18/45/37%). The overall actuarial likelihood of survival on day 42 was 84%. The variability for the diagnosis of active bleeding at endoscopy was high (range, 41.4% to 84.6% among the centres). Active bleeding at endoscopy was not associated with 6-week mortality in the entire population or in Child-Pugh B patients. In a multivariate analysis, independent factors associated with mortality were liver function, infection, HE and HCC. The recalibrated MELD-based score was accurate in predicting 6-week mortality (AUROC = 0.787). The recalibrated MELD-based score demonstrated better performance compared to the MELD score. CONCLUSION: The recalibrated MELD-based score accurately predicted mortality in our prospective cohort. Active bleeding at endoscopy had no prognostic value in cirrhotic patients presenting with acute variceal bleeding. Standardizing active bleeding assessment at endoscopy is warranted. PMID- 29164763 TI - TMEM207 hinders the tumour suppressor function of WWOX in oral squamous cell carcinoma. AB - The WW domain-containing oxidoreductase (WWOX) functions as a tumour suppressor in oral carcinogenesis. As aberrant TMEM207 expression may lead to tumour progression by hampering the tumour suppressor function of WWOX in various cancers, we explored the expression and pathobiological properties of TMEM207, focusing on the WWOX-mediated regulation of the HIF-1alpha pathway in oral squamous cell carcinoma (OSCC). TMEM207 immunoreactivity was detected in 40 of 90 OSCC samples but not in neighbouring non-tumorous epithelial tissues. Moreover, TMEM207 expression was significantly correlated with lymph node metastasis and poor prognosis. An in situ proximal ligation assay demonstrated the colocalization of TMEM207 and WWOX in invasive OSCC cells, especially glycogen rich ones. Enforced expression of TMEM207 abrogated the binding of WWOX to HIF 1alpha, increased HIF-1alpha and GLUT-1 expression, even under normoxic conditions, and promoted tumour growth in a xenoplant assay using SAS tongue squamous cancer cells. In contrast, TMEM207 knockdown decreased GLUT-1 expression in two OSCC cell lines. As a whole, our findings indicate that the aberrant expression of TMEM207 contributes to tumour progression in OSCC, possibly via promoting aerobic glycolysis. PMID- 29164764 TI - Influence of Levulinic Acid Hydrogenation on Aluminum Coordination in Zeolite Supported Ruthenium Catalysts: A 27 Al 3QMAS Nuclear Magnetic Resonance Study. AB - The influence of a highly oxygenated, polar protic reaction medium, that is, levulinic acid in 2-ethylhexanoic acid, on the dealumination of two zeolite supported ruthenium catalysts, namely Ru/H-beta and Ru/H-ZSM-5, has been investigated by 27 Al triple-quantum magic-angle spinning nuclear magnetic resonance spectroscopy (3QMAS NMR). Upon use of these catalysts in the hydrogenation of levulinic acid, the heterogeneity in aluminum speciation is found to increase for both Ru/H-ZSM-5 and Ru/H-beta. For Ru/H-ZSM-5, the symmetric, tetrahedral framework aluminum species (FAL) were found to be mainly converted into distorted tetrahedral FAL species, with limited loss of aluminum to the solution by leaching. A severe loss of both FAL and extra-framework aluminum (EFAL) species into the liquid phase was observed for Ru/H-beta instead. The large decrease in tetrahedral FAL species, in particular, results in a significant decrease in strong acid sites, as corroborated by Fourier transform infrared spectroscopy (FT-IR). This decrease in acidity, evidence of the inferior stability of the strongly acidic sites in Ru/H-beta relative to Ru/H-ZSM-5 under the applied conditions, is considered as the main reason for differences seen in catalyst performance. PMID- 29164766 TI - Down-regulating Myoferlin inhibits the vasculogenic mimicry of melanoma via decreasing MMP-2 and inducing mesenchymal-to-epithelial transition. AB - Vasculogenic mimicry (VM) constitutes a novel approach for tumour blood supply and contributes to tumour metastasis and poor prognosis in patients with melanoma. Myoferlin (MYOF), a type II membrane protein involved in membrane regeneration and repair, is elevated in several malignant tumours, especially in advanced melanomas. This study aims to investigate the role and mechanism of MYOF in the regulation of VM. VM structures were found in 14 of 52 tested melanoma samples, and high MYOF expression correlated with VM structures. According to Kaplan-Meier survival curves, VM channels and elevated MYOF expression both correlated with poor prognosis in melanoma patients. Down-regulation of MYOF by siRNA severely impaired the capability of A375 cells to form VM structures in vitro. Further studies demonstrated MYOF knockdown inhibited cell migration and invasion, which is required for VM formation, via decreasing MMP-2 expression as evidenced by Western blotting, RT-RCP and ELISA results. SB-3CT, a specific inhibitor of MMP-2, showed similar inhibiting effects with siMYOF, further supporting that MYOF down-regulation inhibits MMP-2 expression to affect VM formation. Moreover, MYOF knockdown suppress VM formation by A375 cells by inducing mesenchymal-to-epithelial transition (MET). After down-regulating MYOF, focal adhesions were enlarged and A375 cells developed into a clear epithelial morphology. Such cells acquired the expression of E-cadherin at adherens junctions along with a loss of mesenchymal markers, such as Vimentin and Twist1. In conclusion, MYOF plays an important role in VM and knockdown of MYOF suppresses VM formation via decreasing MMP-2 and inducing MET in A375 melanoma cells. PMID- 29164765 TI - Maternal pre-pregnancy obesity and child neurodevelopmental outcomes: a meta analysis. AB - This review examined evidence of the association between maternal pre-pregnancy overweight/obesity status and child neurodevelopmental outcomes. PubMed and PsycINFO databases were systematically searched for empirical studies published before April 2017 using keywords related to prenatal obesity and children's neurodevelopment. Of 1483 identified papers, 41 were included in the systematic review, and 32 articles representing 36 cohorts were included in the meta analysis. Findings indicated that compared with children of normal weight mothers, children whose mothers were overweight or obese prior to pregnancy were at increased risk for compromised neurodevelopmental outcomes (overweight: OR = 1.17, 95% CI [1.11, 1.24], I2 = 65.51; obese: OR = 1.51; 95% CI [1.35, 1.69], I2 = 79.63). Pre-pregnancy obesity increased the risk of attention deficit hyperactivity disorder (OR = 1.62; 95% CI [1.23, 2.14], I2 = 70.15), autism spectrum disorder (OR = 1.36; 95% CI [1.08, 1.70], I2 = 60.52), developmental delay (OR = 1.58; 95% CI [1.39, 1.79], I2 = 75.77) and emotional/behavioural problems (OR = 1.42; 95% CI [1.26, 1.59], I2 = 87.74). Given the current obesity prevalence among young adults and women of childbearing age, this association between maternal obesity during pregnancy and atypical child neurodevelopment represents a potentially high public health burden. PMID- 29164767 TI - The association between steatosis and diabetes with hepatocellular carcinoma in non-genotype 3 chronic hepatitis C patients. AB - BACKGROUND & AIMS: Diabetes mellitus (DM) has been found to be strongly associated with an increased risk of hepatocellular carcinoma (HCC) among chronic hepatitis C (CHC) patients. Several studies have also found an association between metabolic steatosis and the risk of HCC in CHC patients, whether this latter association has been accounted for by the known relationship between DM and HCC is still unknown. METHODS: A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC and treated with interferon and ribavirin was studied. Cumulative incidence and HCC risk were analysed using the Kaplan-Meier method and Cox proportional hazard analysis. RESULTS: Hepatocellular carcinoma developed in 140 subjects over a median follow-up period of 97.3 months, while 699 patients achieved sustained virological response (SVR). According to multivariate analyses, age >= 60 years, advanced fibrosis and genotype 1 were identified as independent factors significantly associated with HCC development in SVR patients. Furthermore, using the absence of steatosis and absence of DM as references, the presence of steatosis without DM (HR = 2.09, 95% CI = 1.12-3.9, P = .021), the presence of DM without steatosis (HR = 2.78, 95% CI = 1.3-5.92, P = .008) and the combined presence of steatosis and DM (HR = 3.25, 95% CI = 1.44-7.33, P = .004) were identified as independent factors significantly associated with HCC development in the SVR patients. In contrast, steatosis alone, DM alone and the combined presence of steatosis and DM were not associated with HCC development in non-SVR patients. CONCLUSIONS: Steatosis and DM may be associated with HCC development in non-genotype 3 CHC patients with SVR. PMID- 29164769 TI - Quantum Refinement Does Not Support Dinuclear Copper Sites in Crystal Structures of Particulate Methane Monooxygenase. AB - Particulate methane monooxygenase (pMMO) is one of the few enzymes that can activate methane. The metal content of this enzyme has been highly controversial, with suggestions of a dinuclear Fe site or mono-, di-, or trinuclear Cu sites. Crystal structures have shown a mono- or dinuclear Cu site, but the resolution was low and the geometry of the dinuclear site unusual. We have employed quantum refinement (crystallographic refinement enhanced with quantum-mechanical calculations) to improve the structure of the active site. We compared a number of different mono- and dinuclear geometries, in some cases enhanced with more protein ligands or one or two water molecules, to determine which structure fits two sets of crystallographic raw data best. In all cases, the best results were obtained with mononuclear Cu sites, occasionally with an extra water molecule. Thus, we conclude that there is no crystallographic support for a dinuclear Cu site in pMMO. PMID- 29164768 TI - Rewarming the Primordial Soup: Revisitations and Rediscoveries in Prebiotic Chemistry. AB - A short history of Campbell's primordial soup: In this essay we try to disclose some of the historical connections between the studies that have contributed to our current understanding of the emergence of catalytic RNA molecules and their components from an inanimate matter. PMID- 29164770 TI - Clinical outcomes of patients with coronary artery aneurysm after the first generation drug-eluting stent implantation. AB - OBJECTIVES: We sought to investigate the long-term clinical outcomes of patients with coronary artery aneurysm (CAA) after drug-eluting stent (DES) implantation, compared with patients without CAA. BACKGROUND: CAA developed after DES implantation is a rare but associated with poor clinical outcome. METHODS: We retrospectively compared 78 patients with CAA after DES implantation with 269 patients without CAA who underwent DES implantation for complex lesions (controls). The primary endpoint was defined as major adverse cardiac events (MACE), the composite of all-cause death, nonfatal myocardial infarction (MI), and target lesion revascularization (TLR). RESULTS: Morphologically, CAAs were saccular (32%), fusiform (13%), or microform (55%). The stent types involved were Cypher (n = 56, 71.8%) and Taxus (n = 22, 28.2%). During a median follow-up period of 1164 days, the incidence of MACE was significantly higher in the CAA group (26.9 vs. 2.2%, P < 0.001); the difference was driven mainly by nonfatal MI (11.5 vs. 0%, P < 0.001) and TLR (20.5 vs. 1.9%, P < 0.001). The incidence of stent thrombosis was higher in the CAA group (12.8 vs. 0.74%, P < 0.001), irrespective of the maintenance of dual antiplatelet therapy. In the CAA group, Cox regression analysis showed significantly higher hazard ratios of CAA for MACE during the follow-up period. Further analyses after propensity-score matching of 65 pairs also showed similar results. CONCLUSIONS: The incidence of MACE was higher in patients with CAA compared with patients without CAA after DES implantation. This difference was driven by TLR and nonfatal MI and widened over time. PMID- 29164772 TI - ERRATUM. PMID- 29164771 TI - Functional self-assembled peptide scaffold inhibits tumor necrosis factor-alpha induced inflammation and apoptosis in nucleus pulposus cells by suppressing nuclear factor-kappaB signaling. AB - Although nucleus pulposus (NP) tissue engineering has achieved tremendous success, researches still face the huge obstacles in maintaining cell survival and function. A novel functional self-assembled peptide RADA-KPSS was constructed by conjugating BMP-7 short active fragment (KPSS) to the C-terminus of RADA16-I that displays anti-inflammatory and anti-apoptosis effects. However, whether this functional self-assembled RADA-KPSS peptide can alleviate inflammation and NPC apoptosis induced by tumor necrosis factor-alpha (TNF-alpha) has not been studied. Therefore, we cultured NPCs treated with TNF-alpha for 48 h with the RADA-KPSS peptide, and compared the results to those with RADA16-I peptide. The cell apoptosis rate, inflammatory mediator secretion, expression of matrix degrading enzymes, and extracellular matrix (ECM) protein levels were evaluated. The expression of nuclear factor-kappaB-p65 (NF-kappaB-p65) protein was also tested. TNF-alpha-treated NPCs cultured with the RADA16-I peptide showed up regulated gene expression for matrix-degrading enzymes, such as matrix metalloproteinases-3 (MMP-3), MMP-9, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4), and down-regulated gene expression for ECM proteins such as aggrecan, collagen II, and Sox-9. The RADA-KPSS peptide could attenuate the expression of MMP-3, MMP-9, and ADAMTS-4, promote accumulation of ECM proteins, and increase secretion of glycosaminoglycan as compared with the RADA16-I peptide. Moreover, the TNF-alpha-damaged NPCs was further demonstrated to inhibit NF-kappaB-p65, IL-1, IL-6, and prostaglandin E-2 proteins and decrease cell apoptosis in RADA-KPSS peptide. In conclusion, the functional self-assembled RADA-KPSS peptides have anti-inflammatory and anti-apoptotic effects by promoting anabolic processes and inhibiting catabolic processes in intervertebral disk degeneration. These peptides may be feasible for clinical applications in NP tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1082-1091, 2018. PMID- 29164773 TI - Recent Advances in Flexible/Stretchable Supercapacitors for Wearable Electronics. AB - The popularization of personalized wearable devices has accelerated the development of flexible/stretchable supercapacitors (SCs) that possess remarkable features of miniaturization, high security, and easy integration to build an all in-one integrated system, and realize the functions of comfortable, noninvasive and continuous health monitoring, motion records, and information acquisition, etc. This Review presents a brief phylogeny of flexible/stretchable SCs, represented by planar micro-supercapacitors (MSCs) and 1D fibrous SCs. The latest progress and advantages of different flexible/stretchable/self-healing substrate, solid-state electrolyte and electrode materials for the fabrication of wearable SCs devices are summarized. The various configurations used in planar MSCs and 1D fibrous SCs aiming at the improvement of performance are also discussed. In addition, from the viewpoint of practical value and large-scale production, a survey of integrated systems, from different types of SC powered wearable sensing (gas, pressure, tactile...) systems, wearable all-in-one systems (including energy harvest, storage, and functional groups), to device packaging is presented. Finally, the challenges and future perspectives of wearable SCs are also considered. PMID- 29164775 TI - High-Throughput Phase-Field Design of High-Energy-Density Polymer Nanocomposites. AB - Understanding the dielectric breakdown behavior of polymer nanocomposites is crucial to the design of high-energy-density dielectric materials with reliable performances. It is however challenging to predict the breakdown behavior due to the complicated factors involved in this highly nonequilibrium process. In this work, a comprehensive phase-field model is developed to investigate the breakdown behavior of polymer nanocomposites under electrostatic stimuli. It is found that the breakdown strength and path significantly depend on the microstructure of the nanocomposite. The predicted breakdown strengths for polymer nanocomposites with specific microstructures agree with existing experimental measurements. Using this phase-field model, a high throughput calculation is performed to seek the optimal microstructure. Based on the high-throughput calculation, a sandwich microstructure for PVDF-BaTiO3 nanocomposite is designed, where the upper and lower layers are filled with parallel nanosheets and the middle layer is filled with vertical nanofibers. It has an enhanced energy density of 2.44 times that of the pure PVDF polymer. The present work provides a computational approach for understanding the electrostatic breakdown, and it is expected to stimulate future experimental efforts on synthesizing polymer nanocomposites with novel microstructures to achieve high performances. PMID- 29164776 TI - Nutritional screening and dietitian consultation rates in a geriatric evaluation and management unit. AB - AIM: Nutritional screening may not always lead to intervention. The present study aimed to determine: (i) the rate of nutritional screening in hospitalised older adults; (ii) whether nutritional screening led to dietitian consultation and (iii) factors associated with malnutrition. METHODS: In this prospective study of patients aged >=70 years admitted to a Geriatric Evaluation and Management Unit (GEMU), malnutrition was screened for using the Mini Nutritional Assessment Short Form (MNA-SF) and identified using the Mini Nutritional Assessment (MNA). RESULTS: Of the 172 patients participating in the study, 53 (30.8%) patients were malnourished, and 84 (48.8%) were at risk of malnutrition. Mean (SD) age was 85.2 (6.4 years), with 131 patients (76.2%) female. Nutritional screening was performed for all patients; however, it was incomplete in 59 (34.3%) because of omission of the anthropometric measurement. Overall, 62 (36.0%) of the total number of patients were seen by the dietitian, which included 26 (49%) of malnourished patients, 27 (32%) of at-risk patients and 9 (26%) of the well nourished patients. No patients lost >1% of body weight during GEMU stay. Malnourished patients were more likely to be frail, have poor appetite, depression, and have lower levels of: albumin, cognition, physical function, grip strength and quality of life. CONCLUSIONS: The full benefits of nutritional screening by MNA-SF may not be realised if it does not result in malnourished patients receiving a dietitian consultation. However, it is possible that enrichment of the foodservice with high protein/high-energy options minimised patient weight loss in the GEMU. PMID- 29164774 TI - Task-related changes in degree centrality and local coherence of the posterior cingulate cortex after major cardiac surgery in older adults. AB - OBJECTIVES: Older adults often display postoperative cognitive decline (POCD) after surgery, yet it is unclear to what extent functional connectivity (FC) alterations may underlie these deficits. We examined for postoperative voxel-wise FC changes in response to increased working memory load demands in cardiac surgery patients and nonsurgical controls. EXPERIMENTAL DESIGN: Older cardiac surgery patients (n = 25) completed a verbal N-back working memory task during MRI scanning and cognitive testing before and 6 weeks after surgery; nonsurgical controls with cardiac disease (n = 26) underwent these assessments at identical time intervals. We measured postoperative changes in degree centrality, the number of edges attached to a brain node, and local coherence, the temporal homogeneity of regional functional correlations, using voxel-wise graph theory based FC metrics. Group * time differences were evaluated in these FC metrics associated with increased N-back working memory load (2-back > 1-back), using a two-stage partitioned variance, mixed ANCOVA. PRINCIPAL OBSERVATIONS: Cardiac surgery patients demonstrated postoperative working memory load-related degree centrality increases in the left dorsal posterior cingulate cortex (dPCC; p < .001, cluster p-FWE < .05). The dPCC also showed a postoperative increase in working memory load-associated local coherence (p < .001, cluster p-FWE < .05). dPCC degree centrality and local coherence increases were inversely associated with global cognitive change in surgery patients (p < .01), but not in controls. CONCLUSIONS: Cardiac surgery patients showed postoperative increases in working memory load-associated degree centrality and local coherence of the dPCC that were inversely associated with postoperative global cognitive outcomes and independent of perioperative cerebrovascular damage. PMID- 29164777 TI - Formulation and characterization of poly(propylacrylic acid)/poly(lactic-co glycolic acid) blend microparticles for pH-dependent membrane disruption and cytosolic delivery. AB - Poly(lactic-co-glycolic acid) (PLGA) is widely used as a vehicle for delivery of pharmaceutically relevant payloads. PLGA is readily fabricated as a nano- or microparticle (MP) matrix to load both hydrophobic and hydrophilic small molecular drugs as well as biomacromolecules such as nucleic acids and proteins. However, targeting such payloads to the cell cytosol is often limited by MP entrapment and degradation within acidic endolysosomes. Poly(propylacrylic acid) (PPAA) is a polyelectrolyte polymer with the membrane disruptive capability triggered at low pH. PPAA has been previously formulated in various carrier configurations to enable cytosolic payload delivery, but requires sophisticated carrier design. Taking advantage of PPAA functionality, we have incorporated PPAA into PLGA MPs as a simple polymer mixture to enhance cytosolic delivery of PLGA encapsulated payloads. Rhodamine loaded PLGA and PPAA/PLGA blend MPs were prepared by a modified nanoprecipitation method. Incorporation of PPAA into PLGA MPs had little to no effect on the size, shape, or loading efficiency, and evidenced no toxicity in Chinese hamster ovary epithelial cells. Notably, incorporation of PPAA into PLGA MPs enabled pH-dependent membrane disruption in a hemolysis assay, and a three-fold increased endosomal escape and cytosolic delivery in dendritic cells after 2 h of MP uptake. These results demonstrate that a simple PLGA/PPAA polymer blend is readily fabricated into composite MPs, enabling cytosolic delivery of an encapsulated payload. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1022-1033, 2018. PMID- 29164778 TI - Open-label study assessing the efficacy and tolerability of topical skincare and sun protection products following intense pulsed light treatment. AB - BACKGROUND: The visible signs of photodamage can be improved by intense pulsed light (IPL). Active ingredients in cosmeceuticals also have effects on skin quality and pigmentation, and can camouflage post-treatment side effects. Combination therapies utilizing different treatment modalities have been shown to optimize clinical outcomes for skin rejuvenation and patient satisfaction. AIM: To evaluate the efficacy of a combination of IPL with a daily topical skincare and sunscreen regimen for the treatment of facial photodamage and for the improvement of IPL treatment tolerability. PATIENTS/METHODS: Twenty female subjects with moderate-to-severe facial photodamage, with past history of IPL treatments, received one IPL treatment followed by the use of the topical skincare regimen for 8 weeks. An investigator assessed facial photodamage and hyperpigmentation at baseline, week 4, and week 8, and postprocedure erythema. Subject questionnaires were also administered at each visit. RESULTS: Compared to baseline, there was a significant improvement in photodamage and hyperpigmentation of bare facial skin. The application of the skincare regimen resulted in a significant reduction in post-IPL erythema, stinging/burning, and itching. The majority of patients were very satisfied or satisfied and felt the treatment regimen improved various aspects of skin quality and the tolerability of the procedure. CONCLUSIONS: The addition of a topical skincare regimen after IPL treatment to the face resulted in significant improvements in facial photodamage and pigmentation, decreased post-treatment side effects, and increased tolerability. PMID- 29164779 TI - Characterization of the interaction forces in a drug carrier complex of doxorubicin with a drug-binding peptide. AB - Polypeptide-based materials are used as building blocks for drug delivery systems aimed at toxicity decrease in chemotherapeutics. A molecular-level approach is adopted for investigating the non-covalent interactions between doxorubicin and a recently synthesized drug-binging peptide as a key part of a system for delivery to neoplastic cells. Molecular dynamics simulations in aqueous solution at room and body temperature are applied to investigate the structure and the binding modes within the drug-peptide complex. The tryptophans are outlined as the main chemotherapeutic adsorption sites, and the importance of their placement in the peptide sequence is highlighted. The drug-peptide binging energy is evaluated by density functional theory calculations. Principal component analysis reveals comparable importance of several types of interaction for the binding strength. pi-Stacking is dominant, but other factors are also significant: intercalation, peptide backbone stacking, electrostatics, dispersion, and solvation. Intra- and intermolecular H-bonding also stabilizes the complexes. The influence of solvent molecules on the binding energy is mild. The obtained data characterize the drug to-peptide attachment as a mainly attractive collective process with interactions spanning a broad range of values. These results explain with atomistic detail the experimentally registered doxorubicin-binging ability of the peptide and outline the complex as a prospective carrying unit that can be employed in design of drug delivery systems. PMID- 29164780 TI - Report from 32nd Annual BACCN Conference. PMID- 29164781 TI - Welcome to National Board. PMID- 29164782 TI - What's in this Issue. PMID- 29164783 TI - BACCN Twitter chats. PMID- 29164784 TI - Regional news and events. PMID- 29164785 TI - The need for consistent family-centred support for family and parents of children admitted to paediatric intensive care unit. PMID- 29164786 TI - Four New Acylated Iridoid Glycosides from the Aerial Part of Veronicastrum sibiricum and Their Antioxidant Response Element-Inducing Activity. AB - Four new (1 - 4) and one known (5) acylated iridoid glycosides were isolated from the aerial parts of Veronicastrum sibiricum (L.) Pennell. The chemical structures of the isolated compounds were determined to be 3",4"-dicinnamoyl-6-O rhamnopyranosyl-10-O-bergaptol-5,7-bisdeoxycynanchoside (1), 3",4"-dicinnamoyl-6 O-rhamnopyranosylpaulownioside (2), 2",4"-dicinnamoyl-6-O-rhamnopyranosylcatalpol (3), 3",4"-dicinnamoyl-6-O-rhamnopyranosylaucubin (4), and 3",4"-dicinnamoyl-6-O rhamnopyranosylcatalpol (5) using spectroscopic techniques. Among these compounds, compound 5 increased antioxidant response element (ARE) luciferase activity. PMID- 29164787 TI - Factors related to duration of untreated psychosis of first episode schizophrenia spectrum disorder. AB - AIM: Duration of untreated psychosis (DUP) is associated with outcome and functioning. It is expected that scientists will find factors that modulate DUP, but thus far, research on this topic has shown inconsistent results. Furthermore, similar studies in China are insufficient. This study aims to explore social and clinical factors for DUP in South China and to learn the influence that family plays on DUP through their awareness of psychosis. METHODS: Participants included 216 patients with first episode schizophrenia spectrum disorder. The Nottingham Onset Schedule was used to assess DUP. The relationship between DUP and social and clinical characteristics were then analysed by correlation analysis, survival analysis and Cox regression analysis. The awareness of the patient's family for the cause of psychosis, the reason for treatment and the cause for delay of treatment were investigated using a questionnaire. RESULTS: The median DUP was 64.5 days. Insidious onset and being unemployed were found to be risk factors for a long DUP. The family attributed the main cause of psychosis to stress. The main cause for the delay of treatment was because families misjudged the patients' disease. More family members of long DUP patients compared to short DUP patients thought the causes were due to ideological problems or puberty, rather than to mental health. CONCLUSION: The results of this study indicated that some social or clinical characteristics influence DUP. The family's awareness plays an important role when seeking help. To reduce DUP, the public needs more knowledge of mental illness. PMID- 29164788 TI - Sinus augmentation and concomitant implant placement in low bone-density sites. A retrospective study on an undersized drilling protocol and primary stability. AB - BACKGROUND: Recently, a torque-measuring micromotor has been shown to provide a reliable, quantitative intraoperative evaluation of bone density and implant primary stability. This may be particularly useful for determining bone quality of residual bone and consequently the most appropriate site preparation in the posterior maxilla, where bone often is of low density and quality. PURPOSE: This work aimed to assess the medium-term success of implants placed during 1-stage sinus augmentations using an undersized drilling protocol. In case of low bone density, the relationship between residual bone height (RBH) and primary stability was also investigated. MATERIALS AND METHODS: Clinical records of patients who underwent sinus augmentation and concomitant implant placement following a 12.5% undersized drilling protocol were retrospectively analyzed. In all patients, bone density measured intraoperatively was <= 0.45 g/cm3 . A minimum of 60 months of follow-up was required for inclusion. RESULTS: Records of 106 patients who received 253 implants were reviewed. No significant difference in the implant success rate was found for patients who had less than 4 mm of RBH and those who had more. CONCLUSIONS: Underpreparation of the implant-placement sites enabled achievement of successful implant-supported rehabilitation of the posterior maxilla even when both RBH and bone density were low. PMID- 29164789 TI - Physical effects of habitat-forming species override latitudinal trends in temperature. AB - Latitudinal and elevational temperature gradients (LTG and ETG) play central roles in biogeographical theory, underpinning predictions of large-scale patterns in organismal thermal stress, species' ranges and distributional responses to climate change. Yet an enormous fraction of Earth's taxa live exclusively in habitats where foundation species modify temperatures. We examine little-explored implications of this widespread trend using a classic model system for understanding heat stresses - rocky intertidal shores. Through integrated field measurements and laboratory trials, we demonstrate that thermal buffering by centimetre-thick mussel and seaweed beds eliminates differences in stress inducing high temperatures and associated mortality risk that would otherwise arise over 14 degrees of latitude and ~ 1 m of shore elevation. These results reveal the extent to which physical effects of habitat-formers can overwhelm broad-scale thermal trends, suggesting a need to re-evaluate climate change predictions for many species. Notably, inhabitant populations may exhibit deceptive resilience to warming until refuge-forming taxa become imperiled. PMID- 29164790 TI - Comparative Study of Fatty Acids Profile in Eleven Wild Mushrooms of Boletacea and Russulaceae Families. AB - Eleven species of wild mushrooms which belong to Boletaceae and Russulaceae families were examined by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS) analysis for the presence of fatty acids. As far as we know, the fatty acid profiles of B. purpureus and B. rhodoxanthus were described for the first time. Twenty-six fatty acids were determined. Linoleic (19.5 - 72%), oleic (0.11 - 64%), palmitic (5.9 - 22%) and stearic acids (0.81 - 57%) were present in the highest contents. In all samples, unsaturated fatty acids dominate. Agglomerative hierarchical clustering was used to display the correlation between the fatty acids and their relationships with the mushroom species. Based on the fatty acids profile in the samples, the mushrooms can be divided into two families: Boletaceae and Russulaceae families, using cluster analysis. PMID- 29164791 TI - A matrix for the qualitative evaluation of nursing tasks. AB - AIMS: To formulate a model for patient-nurse interaction; to compile a comprehensive list of nursing tasks on hospital wards; and to construct a nursing tasks demand matrix. BACKGROUND: The physical demands associated with nursing profession are of growing interest among researchers. Yet, it is the complexity of nursing tasks that defines the demands of ward nurses' role. This study explores nursing tasks, based on patient-nurse interaction on hospital wards. METHODS: Extant literature was reviewed to formulate a patient-nurse interaction model. Twenty ward nurses were interviewed to compile a list of nursing tasks. These nursing tasks were mapped against the patient-nurse interaction model. RESULTS: A patient-nurse interaction model was created, consisting of: (1) patient care, (2) patient surveillance and (3) patient support. Twenty-three nursing tasks were identified. The nursing tasks demand matrix was constructed. CONCLUSIONS: Ward managers may use a nursing tasks demand matrix to determine the demands of nursing tasks on ward nurses. IMPLICATIONS FOR NURSING MANAGEMENT: While many studies have explored either the physical or the psychosocial aspects of nursing tasks separately, this study suggests that the physicality of nursing tasks must be evaluated in tandem with their complexity. Ward managers may take a holistic approach to nursing tasks evaluation by using a nursing tasks demand matrix. PMID- 29164792 TI - Validity and correlates of the International Physical Activity Questionnaire in first-episode psychosis. AB - AIM: The International Physical Activity Questionnaire (IPAQ) is a self-report tool commonly used in mental healthcare settings to assess physical activity. However, its validity has not yet been investigated in first-episode psychosis (FEP). The aim of this study was to examine the concurrent validity of the IPAQ compared with an objective real-life measure, the Sensewear Armband (SWA), in assessing moderate and vigorous physical activity (MVPA) in people with FEP. A secondary aim was to explore whether there are differences in correlates of the IPAQ vs SWA scores. METHODS: In total, 19 outpatients with FEP (15 men; 24.4 +/- 5.1 years) wore an SWA for 5 full consecutive days, subsequently completed the IPAQ, performed a maximal cardiorespiratory fitness test and were assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS: There was no significant correlation between time spent in MVPA according to the IPAQ and SWA. In contrast with SWA scores, there were no significant associations between IPAQ scores and cardiorespiratory fitness levels. No correlations with PANSS scores were observed in both measures. CONCLUSIONS: The current results suggest that the IPAQ should be used with caution when assessing levels of MVPA in FEP. More accurate methods of measuring physical activity are needed in this population. PMID- 29164793 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 48/2017. PMID- 29164794 TI - Extending survival by reducing sudden death with implantable cardioverter defibrillators: a challenging clinical issue in non-ischaemic and ischaemic cardiomyopathies. PMID- 29164795 TI - Does Education Level Mitigate the Effect of Poverty on Total Knee Arthroplasty Outcomes? AB - OBJECTIVE: Total knee arthroplasty (TKA) outcomes are worse for patients from poor neighborhoods, but whether education mitigates the effect of poverty is not known. We assessed the interaction between education and poverty on 2-year Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function. METHODS: Patient-level variables from an institutional registry were linked to US Census Bureau data (census tract [CT] level). Statistical models including patient and CT-level variables were constructed within multilevel frameworks. Linear mixed-effects models with separate random intercepts for each CT were used to assess the interaction between education and poverty at the individual and community level on WOMAC scores. RESULTS: Of 3,970 TKA patients, 2,438 (61%) had some college or more. Having no college was associated with worse pain and function at baseline and 2 years (P = 0.0001). Living in a poor neighborhood (>20% below poverty line) was associated with worse 2-year pain (P = 0.02) and function (P = 0.006). There was a strong interaction between individual education and community poverty with WOMAC scores at 2 years. Patients without college living in poor communities had pain scores that were ~10 points worse than those with some college (83.4% versus 75.7%; P < 0.0001); in wealthy communities, college was associated with a 1-point difference in pain. Function was similar. CONCLUSION: In poor communities, those without college attain 2-year WOMAC scores that are 10 points worse than those with some college; education has no impact on TKA outcomes in wealthy communities. How education protects those in impoverished communities warrants further study. PMID- 29164796 TI - The effect of daylight versus darkness on driver sleepiness: a driving simulator study. AB - Driver sleepiness studies are often carried out with alert drivers during daytime and sleep-deprived drivers during night-time. This design results in a mixture of different factors (e.g. circadian effects, homeostatic effects, light conditions) that may confound the results. The aim of this study was to investigate the effect of light conditions on driver sleepiness. Thirty young male drivers (23.6 +/- 1.7 years old) participated in a driving simulator experiment where they drove on a rural road. A 2 * 2 design was used with the conditions daylight versus darkness, and daytime (full sleep) versus night-time (sleep deprived). The results show that light condition had an independent effect on the sleepiness variables. The subjective sleepiness measured by Karolinska Sleepiness Scale was higher, lateral position more left-oriented, speed lower, electroencephalogram alpha and theta higher, and blink durations were longer during darkness. The number of line crossings did not change significantly with light condition. The day/night condition had profound effects on most sleepiness indicators while controlling for light condition. The number of line crossings was higher during night driving, Karolinska Sleepiness Scale was higher, blink durations were longer and speed was lower. There were no significant interactions, indicating that light conditions have an additive effect on sleepiness. In conclusion, Karolinska Sleepiness Scale and blink durations increase primarily with sleep deprivation, but also as an effect of darkness. Line crossings are mainly driven by the need for sleep and the reduced alertness at the circadian nadir. Lane position is, however, more determined by light conditions than by sleepiness. PMID- 29164797 TI - Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study. AB - AIMS: The TITRATION trial investigated two strategies to initiate and up-titrate sacubitril/valsartan (LCZ696) to the same target dose, over a condensed (3-week) or conservative (6-week) period, in patients with heart failure with reduced ejection fraction (HFrEF) and systolic blood pressure (SBP) of >=100 mmHg. This post hoc analysis examined the relationship between baseline SBP at screening and achievement of the target dose of sacubitril/valsartan of 97 mg/103 mg (also termed 'LCZ696 200 mg') twice per day during the study. METHODS AND RESULTS: Patients (n = 498) were categorized in four groups based on SBP at screening: 100 110 mmHg (n = 70); 111-120 mmHg (n = 93); 121-139 mmHg (n = 168) and >=140 mmHg (n = 167). Overall, 72.7%, 76.1%, 85.6% and 82.9%, respectively, of patients in these SBP categories achieved and maintained the target dose of sacubitril/valsartan without down-titration/dose interruption over 12 weeks ('treatment success'). Compared with patients with SBP of 100-110 mmHg, rates of treatment success among patients in the higher SBP groups [111-120 mmHg (P = 0.96); 121-139 mmHg (P = 0.06) and >=140 mmHg (P = 0.25)] did not differ significantly. A higher percentage of patients with lower SBP (100-110 mmHg) achieved treatment success with gradual up-titration (6 weeks) (~80%) than with rapid up-titration (~69%). Similar findings were observed with regard to 'tolerability success' (maintenance of the target dose for at least the final 2 weeks prior to study completion). Hypotension occurred more frequently in patients with lower SBP. CONCLUSIONS: The majority of patients (>80%) with SBP of >=100 mmHg achieved and maintained the target dose of sacubitril/valsartan if the treatment was titrated gradually. These findings suggest that low SBP should not prevent clinicians from considering the initiation of sacubitril/valsartan. PMID- 29164798 TI - Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease. AB - Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimer's disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra-hippocampal white matter structure, in relation to the progression of well-accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid-beta 1-42 (Abeta) and total-tau (tau). We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple sibling familial history of AD. Apolipoprotein (APOE) E4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau, phosphorylated-tau (p-tau) and Abeta. Individuals with a reduction in CSF Abeta levels (an indicator of amyloid accretion into neuritic plaques) as well as evident tau pathology (believed to be linked to neurodegeneration) exhibited lower subiculum volume, lower fornix microstructural integrity, and a trend towards lower cognitive score than individuals who showed only reduction in CSF Abeta. In contrast, persons with normal levels of tau showed an increase in structural MR markers in relation to declining levels of CSF Abeta. These results suggest that hippocampal subfield volume and extra-hippocampal white matter microstructure demonstrate a complex pattern where an initial volume increase is followed by decline among asymptomatic individuals who, in some instances, may be a decade or more away from onset of cognitive or functional impairment. PMID- 29164799 TI - Suicidal ideation in individuals at ultra-high risk for psychosis and its association with suspiciousness independent of depression. AB - AIM: Psychotic experiences, including delusions and hallucinations, and their attenuated forms have been recently suggested as a significant but under recognized marker of suicide risk. However, the relationship between attenuated positive symptoms and suicide has not yet been clearly demonstrated in individuals at ultra-high risk (UHR) for psychosis. Here, we investigated the effect of attenuated positive symptoms on suicidal ideation in UHR individuals. METHODS: Fifty-three healthy controls (HCs) and 74 UHR individuals participated in the present study. All participants were assessed for the intensity of suicidal ideation and depressive symptoms at baseline. The effect of attenuated positive symptoms on suicidal ideation in the UHR group was examined using a multiple linear regression analysis after adjustment for concurrent depressive symptoms. RESULTS: UHR participants were found to have significantly greater suicidal ideation and more severe depressive symptoms compared to those of HCs. The regression model demonstrated that suspiciousness significantly increased suicidal ideation in UHR participants, independent of the severity of depressive symptoms. CONCLUSION: The findings of the present study suggest that suspiciousness may serve as a risk indicator for suicide in clinical practice for UHR individuals. It is crucial to focus on the risk of suicide in the UHR population, as they require sufficient clinical attention and proper management for crises related to their unusual and confusing experiences. PMID- 29164800 TI - The Generation of Human gammadeltaT Cell-Derived Induced Pluripotent Stem Cells from Whole Peripheral Blood Mononuclear Cell Culture. AB - gammadeltaT cells constitute a small proportion of lymphocytes in peripheral blood. Unlike alphabetaT cells, the anti-tumor activities are exerted through several different pathways in a MHC-unrestricted manner. Thus, immunotherapy using gammadeltaT cells is considered to be effective for various types of cancer. Occasionally, however, ex vivo expanded cells are not as effective as expected due to cell exhaustion. To overcome the issue of T-cell exhaustion, researchers have generated induced pluripotent stem cells (iPSCs) that harbor the same T-cell receptor (TCR) genes as their original T-cells, which provide nearly limitless sources for antigen-specific cytotoxic T lymphocytes (CTLs). However, these technologies have focused on alphabetaT cells and require a population of antigen-specific CTLs, which are purified by cell sorting with HLA-peptide multimer, as the origin of iPS cells. In the present study, we aimed to develop an efficient and convenient system for generating iPSCs that harbor rearrangements of the TCRG and TCRD gene regions (gammadeltaT-iPSCs) without cell sorting. We stimulated human whole peripheral blood mononuclear cell (PBMC) culture using Interleukin-2 and Zoledronate to activate gammadeltaT cells. Gene transfer into those cells with the Sendai virus vector resulted in gammadeltaT cell-dominant expression of exogenous genes. The introduction of reprogramming factors into the stimulated PBMC culture allowed us to establish iPSC lines. Around 70% of the established lines carried rearrangements at the TCRG and TCRD gene locus. The gammadeltaT-iPSCs could differentiate into hematopoietic progenitors. Our technology will pave the way for new avenues toward novel immunotherapy that can be applied for various types of cancer. Stem Cells Translational Medicine 2018;7:34-44. PMID- 29164801 TI - Improving the biological function of decellularized heart valves through integration of protein tethering and three-dimensional cell seeding in a bioreactor. AB - Decellularized xenogeneic heart valves (DHVs) are promising products for valve replacement. However, the widespread clinical application of such products is limited due to the risk of immune reaction, progressive degeneration, inflammation, and calcification. Here, we have developed an optimized decellularization protocol for a xenogeneic heart valve. We improved the biological function of DHVs by protein tethering onto DHV and three-dimensional (3D) cell seeding in a bioreactor. Our results showed that heart valves treated with a Triton X-100 and sodium deoxycholate-based protocol were completely cell free, with preserved biochemical and biomechanical properties. The immobilization of stromal derived factor-1alpha (SDF-1alpha) and basic fibroblast growth factor on DHV significantly improved recellularization with endothelial progenitor cells under the 3D culture condition in the bioreactor compared to static culture conditions. Cell phenotype analysis showed higher fibroblast-like cells and less myofibroblast-like cells in both protein-tethered DHVs. However, SDF-DHV significantly enhanced recellularization both in vitro and in vivo compared to basic fibroblast growth factor DHV and demonstrated less inflammatory cell infiltration. SDF-DHV had less calcification and platelet adhesion. Altogether, integration of SDF-1alpha immobilization and 3D cell seeding in a bioreactor might provide a novel, promising approach for production of functional heart valves. PMID- 29164802 TI - Use of Bacillus thuringiensis israelensis in integrated vector control of Aedes sp. in Sri Lanka: a prospective controlled effectiveness study. AB - OBJECTIVES: The annual incidence of dengue has been increasing over the last few years in Sri Lanka with seasonal epidemics. Biological control of the vector has not been part of the integrated vector control implemented by the public health authorities of Sri Lanka so far. This pilot study assessed the effectiveness of using Bacillus thuringiensis israelensis (Bti) spray to control the Aedes mosquito vector population density. METHODS: Prospective controlled effectiveness study in three administrative divisions of Colombo. Study areas were selected from urban, semiurban and rural administrative divisions within the district, and they were compared with two matching controls from the same division. Test areas received three cycles of Bti spraying 1 month apart. Control areas were not sprayed with Bti. Ovitrap and larval indices were calculated at baseline and 2 weeks after each spray cycle. RESULTS: There was a significant improvement in the adult vector population (ovitrap index) in the test areas after three spray cycles, but this effect had disappeared after 8 weeks (no residual effect). There was no consistent positive impact on larval indices (premise, container and Breteau indices) after each spray cycle. CONCLUSION: Bti might have a moderate impact on adult vector populations mediated via transient reductions in larval populations. However, this effect is not sustained probably due to rapid re infestation. Bti spray, if implemented, can only play a supplementary role to other vector control methods. PMID- 29164803 TI - Preclinical Evaluation and Optimization of a Cell Therapy Using Human Cord Blood Derived Endothelial Colony-Forming Cells for Ischemic Retinopathies. AB - Cell therapy using endothelial progenitors holds promise for vascular repair in ischemic retinopathies. Using a well-defined subpopulation of human cord blood derived endothelial progenitors known as endothelial colony-forming cells (ECFCs), we have evaluated essential requirements for further development of this cell therapy targeting the ischemic retina, including dose response, delivery route, and toxicity. First, to evaluate therapeutic efficacy relating to cell dose, ECFCs were injected into the vitreous of mice with oxygen-induced retinopathy. Using angiography and histology, we found that intravitreal delivery of low dose (1 * 103 ) ECFCs was as effective as higher cell doses (1 * 104 , 1 * 105 ) in promoting vascular repair. Second, injection into the common carotid artery was tested as an alternative, systemic delivery route. Intracarotid ECFC delivery conferred therapeutic benefit which was comparable to intravitreal delivery using the same ECFC dose (1 * 105 ), although there were fewer human cells observed in the retinal vasculature following systemic delivery. Third, cell immunogenicity was evaluated by injecting ECFCs into the vitreous of healthy adult mice. Assessment of murine ocular tissues identified injected cells in the vitreous, while demonstrating integrity of the host retina. In addition, ECFCs did not invade into the retina, but remained in the vitreous, where they eventually underwent cell death within 3 days of delivery without evoking an inflammatory response. Human specific Alu sequences were not found in healthy mouse retinas after 3 days of ECFC delivery. These findings provide supportive preclinical evidence for the development of ECFCs as an efficacious cell product for ischemic retinopathies. Stem Cells Translational Medicine 2018;7:59-67. PMID- 29164805 TI - Photobiomodulation in dry age-related macular degeneration. PMID- 29164806 TI - Enhanced cytotoxicity and apoptosis by raloxifene in combination with estrogen and methotrexate in human endometrial stromal cells. AB - Endometrial hyperplasia is a condition that may lead to the development of endometrial carcinoma. Initially, changes of the endometrium are caused by the estrogen's hyperstimulation that may lead to the development of an irregular bleeding and the infertility problems. Therapy of endometrial hyperplasia is limited to medical and surgical approaches. During the past decade, the new types of drugs were developed for the treatment of the endometrial hyperplasia. Here, for the first time, we investigated the cytotoxic effects of the various combinations of estrogen, raloxifene, and methotrexate in human ThESC cell line as a possible potential treatment of the endometrial hyperplasia. Our aim was to investigate and to determine the most efficient combination of investigated drugs in ThESC cells during 24-hr period using MTT assay, FACS analysis, and immunofluorescence staining. Our results demonstrated that the combination of raloxifene with methotrexate efficiently induced both the cytotoxicity and apoptosis in ThESC cells when compared to their single effect, as well as to the effect of combined treatment of raloxifene with estrogen. The application of the low doses of methotrexate combined with raloxifene offers all advantages of a potential beneficial antitumor match in cancer chemoprevention and therapy. PMID- 29164807 TI - ERRATUM. PMID- 29164809 TI - Nonsteroidal anti-inflammatory drugs and anastomotic dehiscence after colorectal surgery: a meta-analysis. AB - BACKGROUND: Enhanced recovery after surgery protocols supports the post-operative use of nonsteroidal anti-inflammatory drugs (NSAIDs) to minimize the use of opioids. However, there is an increasing concern on the impaired wound healing of anastomosis associated with NSAID use, potentially causing a higher risk of anastomotic leakage. The aim was to conduct a meta-analysis to evaluate the association of NSAIDs with anastomotic leakage after colorectal surgery. METHODS: A literature search was conducted using the MEDLINE, PubMed, Cochrane Library and Clinicaltrial.gov. Studies identified were appraised with standard selection criteria. Data points were extracted and meta-analysis was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: Seventeen studies comprising of 26 098 patients were examined. The analysis of all studies showed a significantly lower rate of anastomotic dehiscence in the no NSAID group (pooled odds ratio (OR) = 2.00, 95% confidence interval (CI) = 1.48 2.71, P < 0.00001). The analysis of randomized controlled trials (RCTs) demonstrates similar dehiscence rates between both groups (P = 0.17). In subgroup analysis, non-selective NSAIDs was associated with a higher risk of anastomotic dehiscence (pooled OR = 2.02, 95% CI = 1.62-2.50, P < 0.00001). However, there was no difference in the incidence of anastomotic leakage between no-NSAID group and selective NSAID group (P = 0.05). CONCLUSION: Use of NSAIDs after colorectal surgery may be associated with a higher risk of anastomotic leakage. It is important to balance between the benefits of faster post-operative recovery and potential adverse effects of NSAIDs. Selective NSAIDs may be safer than non selective ones. More RCTs are warranted to further evaluate the relationship between anastomotic leakage and use of NSAIDs, especially selective ones. PMID- 29164808 TI - A Universal Approach to Correct Various HBB Gene Mutations in Human Stem Cells for Gene Therapy of Beta-Thalassemia and Sickle Cell Disease. AB - Beta-thalassemia is one of the most common recessive genetic diseases, caused by mutations in the HBB gene. Over 200 different types of mutations in the HBB gene containing three exons have been identified in patients with beta-thalassemia (beta-thal) whereas a homozygous mutation in exon 1 causes sickle cell disease (SCD). Novel therapeutic strategies to permanently correct the HBB mutation in stem cells that are able to expand and differentiate into erythrocytes producing corrected HBB proteins are highly desirable. Genome editing aided by CRISPR/Cas9 and other site-specific engineered nucleases offers promise to precisely correct a genetic mutation in the native genome without alterations in other parts of the human genome. Although making a sequence-specific nuclease to enhance correction of a specific HBB mutation by homology-directed repair (HDR) is becoming straightforward, targeting various HBB mutations of beta-thal is still challenging because individual guide RNA as well as a donor DNA template for HDR of each type of HBB gene mutation have to be selected and validated. Using human induced pluripotent stem cells (iPSCs) from two beta-thal patients with different HBB gene mutations, we devised and tested a universal strategy to achieve targeted insertion of the HBB cDNA in exon 1 of HBB gene using Cas9 and two validated guide RNAs. We observed that HBB protein production was restored in erythrocytes derived from iPSCs of two patients. This strategy of restoring functional HBB gene expression will be able to correct most types of HBB gene mutations in beta-thal and SCD. Stem Cells Translational Medicine 2018;7:87-97. PMID- 29164810 TI - Anionic Redox Chemistry in Polysulfide Electrode Materials for Rechargeable Batteries. AB - Classical Li-ion battery technology is based on the insertion of lithium ions into cathode materials involving metal (cationic) redox reactions. However, this vision is now being reconsidered, as many new-generation electrode materials with enhanced reversible capacities operate through combined cationic and anionic (non metal) reversible redox processes or even exclusively through anionic redox transformations. Anionic participation in the redox reactions is observed in materials with more pronounced covalency, which is less typical for oxides, but quite common for phosphides or chalcogenides. In this Concept, we would like to draw the reader's attention to this new idea, especially, as it applies to transition-metal polychalcogenides, such as FeS2 , VS4 , TiS3 , NbS3 , TiS4 , MoS3 , etc., in which the key role is played by the (S-S)2- /2 S2- redox reaction. The exploration and better understanding of the anion-driven chemistry is important for designing advanced materials for battery and other energy related applications. PMID- 29164811 TI - Congenital heart defects in IVF/ICSI pregnancy: systematic review and meta analysis. AB - OBJECTIVE: There is no consensus in current practice guidelines on whether conception by in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) techniques is an indication for performing a fetal echocardiogram. The aim of the study was to assess whether congenital heart defects (CHD) occur more often in pregnancies conceived after IVF/ICSI as compared with those conceived spontaneously. METHODS: A systematic search for studies was conducted of PubMed/MEDLINE, EMBASE and Scopus from inception to September 2017. The search included the following medical subject heading (MeSH) terms alone or in different combinations: 'IVF', 'IVF/ICSI', 'ART pregnancy', 'assisted conception', 'birth defect', 'congenital heart defects' and 'congenital malformation or abnormalities'. Studies comparing neonatal incidence of CHD in pregnancies conceived after IVF/ICSI and those conceived spontaneously were included. Studies reporting on other types of assisted reproductive technology (ART) or lacking information concerning termination of pregnancy were excluded. Chromosomal abnormalities were excluded in all analyzed studies. A meta-analysis of selected cohort studies was conducted to estimate the pooled odds ratio (OR) with 95% CI using a random-effects model. Statistical heterogeneity among the studies was evaluated with the I2 statistic and Q-test. RESULTS: Forty-one studies were identified for review including six case-control and 35 cohort studies. Data of eight selected cohort studies were used for meta-analysis. A total of 25 856 children conceived from IVF/ICSI techniques and 287 995 children conceived spontaneously, involving both singleton and multiple gestations, were included in the analysis. Total CHD events were 337/25 856 (1.30%) and 1952/287 995 (0.68%) in the IVF/ICSI and spontaneous conception groups, respectively. The risk of CHD was significantly increased in the IVF/ICSI group as compared with the spontaneous conception group (pooled OR, 1.45; 95% CI, 1.20-1.76; P = 0.0001; I2 = 44%; P = 0.08). In the subgroup of singleton IVF pregnancies, a significant difference was also obtained (OR, 1.55; 95% CI, 1.21-1.99; P = 0.0005; I2 = 36%; P = 0.18) and also multiple confounding factors adjusted ORs showed statistical significance (pooled OR, 1.29; 95% CI, 1.03-1.60; P = 0.02; I2 = 0%; P = 0.43). CONCLUSION: Fetuses conceived with IVF/ICSI methods are at an increased risk of developing CHD compared with those conceived spontaneously. However, this finding deserves further investigation due to heterogeneity of both ART procedures and cardiac defects. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29164804 TI - Biomaterials and Advanced Technologies for Hemostatic Management of Bleeding. AB - Bleeding complications arising from trauma, surgery, and as congenital, disease associated, or drug-induced blood disorders can cause significant morbidities and mortalities in civilian and military populations. Therefore, stoppage of bleeding (hemostasis) is of paramount clinical significance in prophylactic, surgical, and emergency scenarios. For externally accessible injuries, a variety of natural and synthetic biomaterials have undergone robust research, leading to hemostatic technologies including glues, bandages, tamponades, tourniquets, dressings, and procoagulant powders. In contrast, treatment of internal noncompressible hemorrhage still heavily depends on transfusion of whole blood or blood's hemostatic components (platelets, fibrinogen, and coagulation factors). Transfusion of platelets poses significant challenges of limited availability, high cost, contamination risks, short shelf-life, low portability, performance variability, and immunological side effects, while use of fibrinogen or coagulation factors provides only partial mechanisms for hemostasis. With such considerations, significant interdisciplinary research endeavors have been focused on developing materials and technologies that can be manufactured conveniently, sterilized to minimize contamination and enhance shelf-life, and administered intravenously to mimic, leverage, and amplify physiological hemostatic mechanisms. Here, a comprehensive review regarding the various topical, intracavitary, and intravenous hemostatic technologies in terms of materials, mechanisms, and state-of-art is provided, and challenges and opportunities to help advancement of the field are discussed. PMID- 29164812 TI - Inter- and Intraspecific Variability of Nitrogenated Compounds in Gorgonian Corals via Application of a Fast One-Step Analytical Protocol. AB - Gorgonian corals play a structural role in temperate and tropical biogenic reefs, forming animal forests and creating biodiversity hot spots. In the Mediterranean Sea, slow-growing and long-lived gorgonian species are threatened by human disturbances and global environmental changes and concern about their conservation is rising. Alkaloid metabolites have proven to be essential in protecting these species from environmental stressors. Traditional profiling methodologies to detect these metabolites require a large quantity of living tissue. Here, the chemodiversity of gorgonian alkaloids was investigated by applying a fast and effective protocol combining extraction and derivatization using small-scale tissue samples and GC/MS analysis. The method was effective in identifying and quantifying alkaloids and guanine-based compounds. Eight N heterocyclic compounds were found in six Mediterranean gorgonians differing for types and quantity. The metabolomic profile was conservative in species of the Eunicella genus, with three species sharing the same pattern. Conversely, Paramuricea clavata displayed a noticeable spatial pattern of variation among colonies collected in different locations. The analytical approach presented here proved to be effective, allowing rare, endangered, and small-sized species to be screened rapidly for detection of new compounds in order to explore their biological and ecological functions. PMID- 29164813 TI - Chemical Polymorphism of Essential Oils of Artemisia vulgaris Growing Wild in Lithuania. AB - Compositional variability of mugwort (Artemisia vulgaris L.) essential oils has been investigated in the study. Plant material (over ground parts at full flowering stage) was collected from forty-four wild populations in Lithuania. The oils from aerial parts were obtained by hydrodistillation and analyzed by GC(FID) and GC/MS. In total, up to 111 components were determined in the oils. As the major constituents were found: sabinene, 1,8-cineole, artemisia ketone, both thujone isomers, camphor, cis-chrysanthenyl acetate, davanone and davanone B. The compositional data were subjected to statistical analysis. The application of PCA (Principal Component Analysis) and AHC (Agglomerative Hierarchical Clustering) allowed grouping the oils into six clusters. AHC permitted to distinguish an artemisia ketone chemotype, which, to the best of our knowledge, is very scarce. Additionally, two rare cis-chrysanthenyl acetate and sabinene oil types were determined for the plants growing in Lithuania. Besides, davanone was found for the first time as a principal component in mugwort oils. The performed study revealed significant chemical polymorphism of essential oils in mugwort plants native to Lithuania; it has expanded our chemotaxonomic knowledge both of A. vulgaris species and Artemisia genus. PMID- 29164815 TI - Application of kartogenin for musculoskeletal regeneration. AB - Kartogenin (KGN) is a recently characterized small molecule that promotes the selective differentiation of mesenchymal stem cells into chondrocytes, and thus, KGN stimulates cartilage regeneration. KGN also possess chondro-protective effect. Furthermore, because it is a highly stable small molecule, KGN can be stored and transported at room temperature. These obvious superiorities over peptide growth factors make KGN a desirable chondrogenic agent for cartilage regeneration. Since its discovery, KGN has drawn much attention as a new chondrogenic drug for intraarticular (IA) treatment. Although it was originally developed with a focus on OA, it has been used to treat other conditions and to promote disc and bone-tendon junction regeneration. Our group has also developed several formulations for IA delivery of KGN including KGN-conjugated chitosan nano/microparticles, thermo-responsive polymeric nanospheres based on chitosan oligosaccharide conjugated pluronic F127, and hyluronate hydrogels containing polyethylene glycol (PEG/KGN) micelles. This review was undertaken to summarize current research on the action mechanism of KGN and the various formulations described in the literature that induce musculoskeletal regeneration. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1141-1148, 2018. PMID- 29164816 TI - Intravenous fluid therapy in acute pancreatitis: a critical review of the randomized trials. AB - INTRODUCTION: Fluid management is a cornerstone of treatment in acute pancreatitis (AP). METHODS: Identification of existing randomized prospective trials of patients with AP, in which intravenous fluid management was a significant parameter in the experimental design, was undertaken using the PubMed and ENDOBASE databases. RESULTS: Included patients in the seven studies identified were on the whole very unwell with deaths occurring in six trials. Fluid regimens in AP included crystalloid alone, combinations of crystalloid and colloid and in two studies, plasma. In most studies, patients with premorbid major organ failure and advanced age were excluded. Study entry within 6 h of presentation occurred in three trials. Initial fluid administration rates varied from 1 to 2 mL/kg/h to 15 mL/kg/h. Rapid fluid rates were associated with increased morbidity and mortality except in one study in which a high fluid regimen (20 mL/kg bolus within 4 h of presentation followed by 3 mL/kg) led to a better clinical outcome than a more conservative regimen. Use of Ringer's lactate led to improved surrogate outcome markers compared to that of normal saline in one study. Administration of colloid as part of the fluid management was associated with lower morbidity and lower fluid requirements. CONCLUSION: Rapid infusion of crystalloid very early in the course of AP may be beneficial but rapid infusion of fluid later in the course of the illness may be deleterious. Colloid administration and the use of Ringer's lactate solution in preference to normal saline may improve outcome. PMID- 29164814 TI - Detection of Subclinical Arthritis in Mice by a Thrombin Receptor-Derived Imaging Agent. AB - OBJECTIVE: Functional imaging of synovitis could improve both early detection of rheumatoid arthritis (RA) and long-term outcomes. Given the intersection of inflammation with coagulation protease activation, this study was undertaken to examine coagulation protease activities in arthritic mice with a dual fluorescence ratiometric activatable cell-penetrating peptide (RACPP) that has a linker, norleucine (Nle)-TPRSFL, with a cleavage site for thrombin. METHODS: K/BxN-transgenic mice with chronic arthritis and mice with day 1 passive serum transfer arthritis were imaged in vivo for Cy5:Cy7 emission ratiometric fluorescence from proteolytic cleavage and activation of RACPPNleTPRSFL . Joint thickness in mice with serum-transfer arthritis was measured from days 0 to 10. The cleavage-evoked release of Cy5-tagged tissue-adhesive fragments enabled microscopic correlation with immunohistochemistry for inflammatory markers. Thrombin dependence of ratiometric fluorescence was tested by ex vivo application of RACPPNleTPRSFL and argatroban to cryosections obtained from mouse hind paws on day 1 of serum-transfer arthritis. RESULTS: In chronic arthritis, RACPPNleTPRSFL fluorescence ratios of Cy5:Cy7 emission were significantly higher in diseased swollen ankles of K/BxN-transgenic mice than in normal mouse ankles. A high ratio of RACPPNleTPRSFL fluorescence in mouse ankles and toes on day 1 of serum transfer arthritis correlated with subsequent joint swelling. Foci of high ratiometric fluorescence localized to inflammation, as demarcated by immune reactivity for citrullinated histones, macrophages, mast cells, and neutrophils, in soft tissue on day 1 of serum-transfer arthritis. Ex vivo application of RACPPNleTPRSFL to cryosections obtained from mice on day 1 of serum-transfer arthritis produced ratiometric fluorescence that was inhibited by argatroban. CONCLUSION: RACPPNleTPRSFL activation detects established experimental arthritis, and the detection of inflammation by RACPPNleTPRSFL on day 1 of serum-transfer arthritis correlates with disease progression. PMID- 29164817 TI - Regulation of Hedgehog Signaling in Cancer by Natural and Dietary Compounds. AB - The aberrant Hedgehog (Hh) signaling induced by mutations or overexpression of the signaling mediators has been implicated in cancer, associated with processes including inflammation, tumor cell growth, invasion, and metastasis, as well as cancer stemness. Small molecules targeting the regulatory components of the Hh signaling pathway, especially Smoothened (Smo), have been developed for the treatment of cancer. However, acquired resistance to a Smo inhibitor vismodegib observed in clinical trials suggests that other Hh signaling components need to be explored as potential anticancer targets. Natural and dietary compounds provide a resource for the development of potent agents affecting intracellular signaling cascades, and numerous studies have been conducted to evaluate the efficacy of natural products in targeting the Hh signaling pathway. In this review, we summarize the role of Hh signaling in tumorigenesis, discuss results from recent studies investigating the effect of natural products and dietary components on Hh signaling in cancer, and provide insight on novel small molecules as potential Hh signaling inhibitors. PMID- 29164818 TI - Home-Based Transabdominal Interferential Electrical Stimulation for Six Months Improves Paediatric Slow Transit Constipation (STC). AB - BACKGROUND: Transcutaneous electrical stimulation (TES) for one to two months has produced some improvement in treatment-resistant slow-transit constipation (STC) in children. Optimal parameters for treatment are not known. It is possible that more improvement would occur with stimulation for longer. This study examined the effectiveness of stimulation for six months. METHODS: Children with STC confirmed by nuclear transit study (NTS) were enrolled prospectively. All had chronic constipation for greater than two years and had failed medical treatment. TES was performed for one hour/day for six months using the INF 4160 (Fuji Dynamics) portable stimulator and 4 cm * 4 cm electrodes near the belly button and on the back. Families kept bowel diaries and completed PEDSQLCore QOL (4.0) questionnaires before and at end of treatment. RESULTS: Sixty-two children (34 females; seven years, 2-16 year) with STC were studied. Defecation frequency increased in 57/62 (91%, mean +/- SEM pre- 1.49 +/- 0.20 vs. post- 3.25 +/- 0.25 defecation/week, p < 0.0001) with the number with >=3BA increasing from 6 to 37 (10-59%). Soiling frequency decreased from 4.8 to 1.1 days/week (p <0.001). Abdominal pain decreased from 1.7 to 0.3 days/week (<0.0001), and spontaneous urge to defecate improved. Quality of life (p < 0.01), mean transit index and gastric emptying on NTS improved (p < 0.005). CONCLUSION: Treatment-resistant STC responds to TES using interferential current across the abdomen when given daily for many months. Battery operated stimulators allowed stimulation at home for an hour each day. Stimulation for six months produced clinically significant improvement in defecation frequency, soiling, abdominal pain, urge to defecate, and quality of life in half of these chronic patients. PMID- 29164819 TI - Decellularized bovine cotyledons may serve as biological scaffolds with preserved vascular arrangement. AB - Technically produced scaffolds are common to establish transplantable tissues for regenerative medicine, but also biological ones that are closer to the natural condition become of interest. Placentas are promising, because they represented available, complete organs with rich extracellular matrix (ECM) and well developed vasculature that easily could build anastomoses to a host's organ. Only placentas from larger animal models such as the bovine meet the dimensions large enough for most organs but are not adequately described yet. We here studied the nature of the ECM in 27 natural and decellularized bovine cotyledons, that is, the fetal part of the placentomes, by means of histology, immunohistochemistry, and electron microscopy. Successful decellularization was done by perfusion with 0.01%, 0.1%, and 0.5% sodium dodecyl sulfate each and subsequent immersion in 1% Triton X-100, resulting in a removal of cells and DNA, whereas the structure of the allantochorionic surface and villi was preserved. Although some fibres disappeared, also the arrangement of the main ECM proteins was largely similar before and after decellularization: Along the larger vessels, a densely packed network of thick fibres occurred, organized in layers without cells or spaces in between. Collagen IV, fibronectin, and laminin contributed to those areas. In contrast, collagen I and III characterized the meshwork of medium-sized and thin fibres in the mesenchyme, respectively. In conclusion, decellularized bovine cotyledons indeed had characteristics of a biological scaffold and provide an interesting alternative to develop large-scale scaffolds with complex vascular architecture for tissue engineering purposes. PMID- 29164820 TI - Dual PPARalpha/gamma agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common clinico-pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARalpha/gamma agonist, was assessed in models of NAFLD/NASH. METHODS & RESULTS: HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFalpha, IL1beta and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10MUM concentration). Furthermore, these agents reversed PA-mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2-LX2 Coculture studies. In mice with choline-deficient high-fat diet-induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride-induced fibrosis model. CONCLUSIONS: Saroglitazar, a dual PPARalpha/gamma agonist with predominant PPARalpha activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARalpha agonist, fenofibrate and PPARgamma agonist pioglitazone. PMID- 29164821 TI - Cytotoxic Triterpenoids from Roots of Actinidia chinensis. AB - Phytochmical investigation of roots of Actinidia chinensisPlanch. led to the isolation triterpenoids 1 - 16, including a new compound 2alpha,3alpha,23,24 tetrahydroxyursa-12,20(30)-dien-28-oic acid (1). Their structures were identified on the basis of spectroscopic analysis, including 1D- and 2D-NMR, HR-ESI mass spectrometry, and by comparison with the literatures. The cytotoxicities of triterpenoids 1 - 16 against a panel of cultured human cancer cell lines (HepG2, A549, MCF-7, SK-OV-3, and HeLa) were evaluated. The new compound 1 exhibited moderate antitumor activities with IC50 values of 19.62 +/- 0.81, 18.86 +/- 1.56, 45.94 +/- 3.62, 62.41 +/- 2.29, and 28.74 +/- 1.07 MUm, respectively. The experiment data might be available to explain the use of roots of A. chinensis to treat various cancers in traditional Chinese medicine. PMID- 29164822 TI - A transposon mutant library of Bacillus cereus ATCC 10987 reveals novel genes required for biofilm formation and implicates motility as an important factor for pellicle-biofilm formation. AB - Bacillus cereus is one of the most common opportunistic pathogens causing foodborne illness, as well as a common source of contamination in the dairy industry. B. cereus can form robust biofilms on food processing surfaces, resulting in food contamination due to shedding of cells and spores. Despite the medical and industrial relevance of this species, the genetic basis of biofilm formation in B. cereus is not well studied. In order to identify genes required for biofilm formation in this bacterium, we created a library of 5000 + transposon mutants of the biofilm-forming strain B. cereusATCC 10987, using an unbiased mariner transposon approach. The mutant library was screened for the ability to form a pellicle biofilm at the air-media interface, as well as a submerged biofilm at the solid-media interface. A total of 91 genes were identified as essential for biofilm formation. These genes encode functions such as chemotaxis, amino acid metabolism and cellular repair mechanisms, and include numerous genes not previously known to be required for biofilm formation. Although the majority of disrupted genes are not directly responsible for motility, further investigations revealed that the vast majority of the biofilm deficient mutants were also motility impaired. This observation implicates motility as a pivotal factor in the formation of a biofilm by B. cereus. These results expand our knowledge of the fundamental molecular mechanisms of biofilm formation by B. cereus. PMID- 29164824 TI - Pilot study of cognitive remediation and motivational interviewing in youth at risk of serious mental illness. AB - AIM: The aim of this pilot project was to determine the recruitment feasibility for a computerized cognitive remediation treatment (CRT) for youth at-risk of serious mental illness (SMI), and treatment adherence following an adjunct treatment of motivational interviewing (MI). METHODS: Twelve youth at-risk of SMI were randomized to receive either CRT or CRT plus MI. CRT was conducted over 10 wk during which time 5 MI sessions were available for the CRT + MI group. RESULTS: The recruitment rate was 55%. The attrition rate from the study was 25% and on average participants completed 33% of the CRT sessions, with no group differences in the number of CRT sessions completed. CONCLUSIONS: Treatment adherence was low. Participants described the CRT as easy and unchallenging. Future recommendations include engaging youth at-risk into CRT programs based on cognitive deficits, measuring intervention satisfaction and offering access to supportive therapies for concerns other than cognition. PMID- 29164823 TI - Immunoglobulin G; structure and functional implications of different subclass modifications in initiation and resolution of allergy. AB - IgE and not IgG is usually associated with allergy. IgE lodged on mast cells in skin or gut and basophils in the blood allows for the prolonged duration of allergy through the persistent expression of high affinity IgE receptors. However, many allergic reactions are not dependent on IgE and are generated in the absence of allergen specific and even total IgE. Instead, IgG plasma cells are involved in induction of, and for much of the pathogenesis of, allergic diseases. The pattern of IgG producing plasma cells in atopic children and the tendency for direct or further class switching to IgE are the principle factors responsible for long-lasting sensitization of mast cells in allergic children. Indirect class switching from IgG producing plasma cells has been shown to be the predominant pathway for production of IgE while a Th2 microenvironment, genetic predisposition, and the concentration and nature of allergens together act on IgG plasma cells in the atopic tendency to undergo further immunoglobulin gene recombination. The seminal involvement of IgG in allergy is further indicated by the principal role of IgG4 in the natural resolution of allergy and as the favourable immunological response to immunotherapy. This paper will look at allergy through the role of different antibodies than IgE and give current knowledge of the nature and role of IgG antibodies in the start, maintenance and resolution of allergy. PMID- 29164826 TI - Comparative study of buffered 50% glycolic acid (pH 3.0) + 0.5% salicylic acid solution vs Jessner's solution in patients with acne vulgaris. AB - BACKGROUND: Superficial chemical peels are frequently used in acne vulgaris treatment. Although glycolic acid (GA) has been widely used in clinical practice, its pH ranges from 0.08-2.75 and thus should be neutralized after application to avoid burns. OBJECTIVE: To evaluate treatment efficacy and safety of chemical peeling using buffered 50% GA (pH 3.0) + 0.5% salicylic acid (SA) solution that does not need to be neutralized in the treatment of acne vulgaris compared to the conventional peeling using Jessner's solution. METHODS: We performed a prospective, randomized, evaluator-blind, split-face clinical trial. Twenty patients were randomized by assigning one side of each patient's face to receive a 50% GA (pH 3.0) + 0.5% SA peel (GA side) and the other side to receive the Jessner's solution (Jessner's solution side). All patients underwent 2 sessions of treatment spaced 2 weeks apart. Lesion count, acne severity, subjective efficacy assessment, and side effects were evaluated. RESULTS: The total lesion count was significantly reduced for the GA and Jessner's solution sides (P < .001). However, there was no significant difference in the total lesion count, acne severity, or subjective efficacy assessment between the 2 sides (P > .05). The GA side had fewer side effects than the Jessner's solution side. CONCLUSION: The results of this study suggest that chemical peeling using the 50% GA (pH 3.0) + 0.5% SA solution can be as effective and convenient as the conventional peeling using Jessner's solution in the treatment of acne vulgaris and may show fewer adverse events than the conventional peeling. PMID- 29164825 TI - Autism spectrum disorder and birth spacing: Findings from the study to explore early development (SEED). AB - : Previous studies of autism spectrum disorder (ASD) and birth spacing had limitations; few examined phenotypic case subtypes or explored underlying mechanisms for associations and none assessed whether other (non-ASD) developmental disabilities (DDs) were associated with birth spacing. We assessed associations between inter-pregnancy interval (IPI) and both ASD and other DDs using data from the Study to Explore Early Development, a multi-site case-control study with rigorous case-finding and case-classification methods and detailed data collection on maternal reproductive history. Our sample included 356 ASD cases, 627 DD cases, and 524 population (POP) controls born in second or later births. ASD and DD cases were further sub-divided according to whether the child had intellectual disability (ID). ASD cases were also sub-divided by ASD symptom severity, and DD cases were subdivided by presence of some ASD symptoms (indicated on an autism screener). Odds ratios, adjusted for maternal-child sociodemographic factors, (aORs) and 95% confidence intervals were derived from logistic regression models. Among term births, ASD was associated with both IPI <18 months (aOR 1.5 [1.1-2.2]) and >=60 months (1.5 [0.99-2.4]). Both short and long IPI associations were stronger among ASD cases with high severity scores (aORs 2.0 [1.3-3.3] and 1.8 [0.99-3.2], respectively). Associations were unchanged after adding several factors potentially related to the causal pathway to regression models. DD was not associated with either short or long IPI overall, among term births, or in any subgroup examined. These findings extend those from previous studies and further inform recommendations on optimal pregnancy spacing. Autism Res 2018, 11: 81-94. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We investigated whether the amount of time between pregnancies was associated autism spectrum disorder (ASD) or other developmental disabilities (DD) in children. ASD was increased in second and later-born children who were conceived less than 18 months or 60 or more months after the mother's previous birth. Other DDs were not associated with birth spacing. PMID- 29164827 TI - Inhibitors against Fungal Cell Wall Remodeling Enzymes. AB - Fungal beta-1,3-glucan glucanosyltransferases are glucan-remodeling enzymes that play important roles in cell wall integrity, and are essential for the viability of pathogenic fungi and yeasts. As such, they are considered possible drug targets, although inhibitors of this class of enzymes have not yet been reported. Herein we report a multidisciplinary approach based on a structure-guided design using a highly conserved transglycosylase from Sacharomyces cerevisiae, that leads to carbohydrate derivatives with high affinity for Aspergillus fumigatus Gel4. We demonstrate by X-ray crystallography that the compounds bind in the active site of Gas2/Gel4 and interact with the catalytic machinery. The topological analysis of noncovalent interactions demonstrates that the combination of a triazole with positively charged aromatic moieties are important for optimal interactions with Gas2/Gel4 through unusual pyridinium cation-pi and face-to-face pi-pi interactions. The lead compound is capable of inhibiting AfGel4 with an IC50 value of 42 MUm. PMID- 29164828 TI - Attenuated psychosis and basic self-disturbance as risk factors for depression and suicidal ideation/behaviour in community-dwelling adolescents. AB - BACKGROUND AND AIMS: Adolescents at clinical high risk (CHR) for psychosis, as defined by the presence of attenuated psychosis symptoms (APS), exhibit increased levels of suicidal ideation and behaviour. However, no research thus far has examined the link between basic self-disturbances (SDs), an established marker for CHR, and suicidality/self-harm in this population. The goal of this pilot study was to assess the association between SD, depression and suicidal ideation and behaviour among non-help-seeking adolescents from the community. METHOD: A total of 100 community-dwelling adolescents (age range: 13-16) were assessed using the Examination of Anomalous Self-experience, Prodromal Questionnaire, Structured Interview for Prodromal Syndromes, Mood and Anxiety Symptom Questionnaire and the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). The K-SADS was used to derive a binary diagnosis of unipolar depression, as well as to measure suicidal ideation and behaviour and self-harm. RESULTS: In a multiple regression analysis, SD accounted for variance in depressive symptoms and suicidality/self-harm over and above that accounted for by APS. Moreover, SD accounted for variance in suicidality/self-harm over and above that accounted for by depression symptoms. CONCLUSIONS: These pilot results suggest that SD might be a unique dimension of vulnerability to depression and suicidality/self-harm in adolescence. Also, they encourage assessment of SD as part of a suicide risk assessment, particularly in the context of risk for subsequent psychosis. PMID- 29164829 TI - Prevalence of Metabolic Syndrome and Associations with Lipid Profiles in Iranian Men: A Population-Based Screening Program. AB - PURPOSE: Metabolic syndrome (MS) is characterized by a collection of interdependent disorders, including abdominal obesity, dyslipidemia, hyperglycemia, hypertension, and diabetes. The current study aimed to estimate the prevalence of MS in Qom, Iran. MATERIALS AND METHODS: A population-based screening program was conducted in the city of Qom, in 845 urban adult men over 25 years old in 2014. Abdominal obesity, fasting blood glucose (FBG), blood pressure, and the serum lipid profile were measured in subjects after fasting for at least 8 hours. MS was defined according to the Adult Treatment Panel III criteria. Data were analyzed using the chi-square test, t-test, and multiple logistic regression. RESULTS: The overall prevalence of MS was 23.0%, and the most common prevalent metabolic abnormalities associated with MS were low high density lipoprotein cholesterol (<40 mg/dL) in 34.3% of subjects, a waist circumference >102 cm in 33.9%, blood pressure >=130/85 mmHg in 27.6%, fasting triglycerides (TG) >=150 mg/dL in 25%, and FBG >=110 mg/dL in 20.6%. A FBG level >=110 mg/dL (odds ratio [OR]=4.85; 95% confidence interval [CI], 2.14~8.24), dyslipidemia (OR=3.51; 95% CI, 2.10~5.89), and a fasting TG >=150 mg/dL were the most important factors contributing to MS. CONCLUSIONS: The prevalence of MS in men in Qom was higher than has been reported in other countries, but it was lower than the mean values that have been reported elsewhere in Iran. FBG was the most important factor contributing to MS, and all elements of the lipid profile showed important associations with MS. PMID- 29164830 TI - Changes in Erectile Function after Photoselective Vaporization of the Prostate with a 120-W GreenLight High-Performance System Laser: 2-Year Follow-Up. AB - PURPOSE: To evaluate the impact of photoselective vaporization of the prostate (PVP) with a 120-W GreenLight high-performance system on erectile function in a 2 year follow-up study. MATERIALS AND METHODS: One hundred seventy-seven patients who underwent PVP during 2008 to 2012 were analyzed retrospectively. The patients were divided into 5 groups according to their preoperative 5-item International Index of Erectile Function (IIEF-5) scores: Group I (IIEF-5: 5~7, n=28), II (IIEF 5: 8~11, n=47), III (IIEF-5: 12~16, n=43), IV (IIEF-5: 17~21, n=34), and V (IIEF 5: 22~25, n=25). The patients were assessed before surgery and 6, 12, and 24 months after the PVP. Their International Prostate Symptom Score/quality of life, maximum urinary flow rate/post-void residual urine volume, and IIEF-5 scores were measured at each visit. RESULTS: The mean age and presence of hypertension were significantly different among the 5 groups. Perioperative parameters and postoperative complication rates showed no statistical differences. After PVP, voiding parameters were significantly improved in all the groups and sustained during the 2-year follow-up. The postoperative IIEF-5 scores fell slightly overall, while group V showed the largest significant deterioration. In multivariate analysis, body mass index (BMI) was the only independent predictor of decreased erectile function after PVP. CONCLUSIONS: Erectile function declined in all the groups after PVP, with the most extensive deterioration observed in patients with normal erectile function preoperatively. Preoperative BMI was the only independent risk factor for a meaningful decrease in erectile function after PVP. PMID- 29164831 TI - Udenafil, a Phosphodiesterase 5 Inhibitor, Reduces Body Weight in High-Fat-Fed Mice. AB - PURPOSE: High-fat (HF) feeding induces hypothalamic leptin resistance via the activation of toll-like receptor 4 (TLR4). TLR4 deficiency confers resistance to diet-induced obesity. Udenafil, an anti-impotence drug, inhibits TLR4 in airway epithelial cells in vitro. In this study, we evaluated whether udenafil suppressed the hypothalamic expression of TLR4 and reduced body weight. MATERIALS AND METHODS: The hypothalamic expression of TLR4, phosphodiesterase 5 (PDE5), nuclear factor-kappaB (NF-kappaB), and myeloid differentiation primary response gene 88 (Myd88) was analyzed by real-time polymerase chain reaction after treating mice for 2 days with udenafil (0, 12, 120, or 600 MUg/d). Furthermore, the hypothalamic expression of TLR4, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY) was analyzed after 9 days' treatment with udenafil and/or leptin. We also measured body weight and food intake following 9 days of udenafil and/or leptin treatment in control- and HF-fed mice. RESULTS: Udenafil suppressed hypothalamic TLR4 mRNA expression dose-dependently. The changes were associated with decreased PDE5, NF-kappaB, and Myd88 expression. Udenafil treatment for 9 days reduced body weight and caloric intake in HF-fed mice. This may have been associated with the suppression of NPY expression that was elevated by HF feeding. POMC expression was not affected by udenafil. However, udenafil did not augment the effects of leptin on the reduction of body weight and caloric intake in HF-fed mice. CONCLUSIONS: These results suggested that udenafil reduced body weight by suppressing hypothalamic TLR4 mRNA expression in HF-fed mice and the combination effect of udenafil and leptin was additive rather than synergistic. PMID- 29164832 TI - Letter to the Editor regarding the Article: "Anti-Inflammatory and Antimicrobial Effects of a Novel Herbal Formulation (WSY-1075) in a Chronic Bacterial Prostatitis Rat Model" by Park et al. World J Mens Health 2016;34(3):179-185. PMID- 29164833 TI - Efficacy of Holmium Laser Enucleation of the Prostate in Patients with a Small Prostate (<=30 mL). AB - PURPOSE: We investigated the effects of holmium laser enucleation of the prostate (HoLEP) in patients with a small prostate (<=30 mL) in whom medical treatment was ineffective. MATERIALS AND METHODS: Data from 132 patients who underwent HoLEP by a single surgeon between 2012 and 2015 were retrospectively analyzed. All patients received benign prostatic hyperplasia medication for at least 6 months before surgery. The patients were divided into 2 groups according to prostate size: group 1, <=30 mL (n=30); and group 2, >30 mL (n=102). Clinical characteristics and the International Prostate Symptom Score (IPSS), including quality of life (QoL), peak urinary flow rate (Qmax), and postvoid residual urine (PVR), before surgery and 3 months postoperatively, were compared between the 2 groups. RESULTS: In group 1, the IPSS, QoL, and PVR significantly decreased and the Qmax significantly increased 3 months after surgery. The voiding subscore also significantly decreased 3 months after surgery (p<0.001), but the storage subscore was not significantly different (p=0.055). In group 2, hemoglobin, the IPSS, QoL, and PVR significantly decreased and the Qmax significantly increased 3 months after surgery. In these patients, both the storage subscore and voiding subscore significantly decreased after surgery (both p<0.001). There were no significant differences between the groups in hemoglobin, IPSS, QoL, Qmax, and PVR either before or 3 months after surgery. CONCLUSIONS: When other medical treatments are ineffective, HoLEP is an effective intervention for patients with a small prostate. PMID- 29164834 TI - Effects of Next-Generation Low-Energy Extracorporeal Shockwave Therapy on Erectile Dysfunction in an Animal Model of Diabetes. AB - PURPOSE: Gene therapy, stem cell therapy, and low-energy extracorporeal shockwave therapy (ESWT) have been investigated as treatments for refractory erectile dysfunction (ED), but inconclusive evidence has been obtained. We investigated the effect of a next-generation electromagnetic cylinder ESWT device on an animal model of ED. MATERIALS AND METHODS: Diabetes mellitus (DM)-induced rats were divided into 3 groups: group 1, control; group 2, DM; and group 3, DM+ESWT. Rats were treated with ESWT 3 times a week for 2 weeks. After the treatment course, intracavernous pressure was measured and the corpus cavernosum and cavernous nerve were evaluated. RESULTS: In the DM group, all parameters predicted to be significantly lower in the ED model had statistically significantly decreased (p<0.01). As a measurement of erectile function, intracavernous pressure was evaluated. The DM+ESWT group exhibited significantly restored erectile function compared to the DM group (p<0.05). Moreover, ESWT treatment restored smooth muscle content, as assessed by Masson's trichrome staining (p<0.05). Finally, corporal tissue and the dorsal nerve were evaluated by immunohistochemistry, Western blotting, and ELISA. After ESWT treatment, vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), platelet endothelial cell adhesion molecule-1, cyclic guanosine monophosphate, and neuronal nitric oxide synthase (nNOS) expression levels were restored to levels in the DM group (p<0.05). CONCLUSIONS: Electromagnetic cylinder ESWT device resulted in increased VEGF, nNOS, and eNOS expression; reduced smooth muscle atrophy; and increased endothelial cell regeneration in a DM-associated ED model. Our data suggest that safe and effective application could be possible in future clinical studies. PMID- 29164835 TI - Penile Erection Induced by Scoparone from Artemisia capillaris through the Nitric Oxide-Cyclic Guanosine Monophosphate Signaling Pathway. AB - PURPOSE: The objective of this study was to evaluate the relaxant effect of scoparone from Artemisia capillaris on rabbit penile corpus cavernosum smooth muscle (PCCSM) and to elucidate the mechanism of action of scoparone for the treatment of erectile dysfunction (ED). MATERIALS AND METHODS: PCCSM that had been precontracted with phenylephrine was treated with 3 Artemisia herbs (A. princeps, A. capillaris, and A. iwayomogi) and 3 fractions (n-hexane, ethyl acetate, and n-butanol) with different concentrations (0.1, 0.5, 1.0, and 2.0 mg/mL). Four components (esculetin, scopoletin, capillarisin, and scoparone) isolated from A. capillaris were also evaluated. The PCCSM was preincubated with Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME) and 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ). Cyclic nucleotides in the perfusate were measured by a radioimmunoassay. The interactions of scoparone with udenafil and rolipram were also evaluated. RESULTS: A. capillaris extract relaxed PCCSM in a concentration-dependent manner. Scoparone had the highest relaxant effect on PCCSM among the 4 components (esculetin, scopoletin, capillarisin, and scoparone) isolated from the ethyl acetate fraction. The application of scoparone on PCCSM pretreated with L-NAME and ODQ led to significantly less relaxation. Scoparone also increased the cyclic guanosine monophosphate (cGMP) levels in the perfusate in a concentration-dependent manner. Furthermore, scoparone enhanced udenafil- and rolipram-induced relaxation of the PCCSM. CONCLUSIONS: Scoparone relaxed the PCCSM mainly by activating the nitric oxide-cGMP signaling pathway, and it may be a new promising treatment for ED patients who do not completely respond to udenafil. PMID- 29164836 TI - Power-controlled temperature guided retinal laser therapy. AB - Laser photocoagulation has been a treatment method for retinal diseases for decades. Recently, studies have demonstrated therapeutic benefits for subvisible effects. A treatment mode based on an automatic feedback algorithm to reliably generate subvisible and visible irradiations within a constant irradiation time is introduced. The method uses a site-individual adaptation of the laser power by monitoring the retinal temperature rise during the treatment using optoacoustics. This provides feedback to adjust the therapy laser power during the irradiation. The technique was demonstrated on rabbits in vivo using a 532-nm continuous wave Nd:YAG laser. The temperature measurement was performed with 523-nm Q-switched Nd:YLF laser pulses with 75-ns pulse duration at 1-kHz repetition rate. The beam diameter on the fundus was 200 MUm for both lasers, respectively. The aim temperatures ranged from 50 degrees C to 75 degrees C in 11 eyes of 7 rabbits. The results showed ophthalmoscopically invisible effects below 55 degrees C with therapy laser powers over a wide range. The standard deviation for the measured temperatures ranged from 2.1 degrees C for an aim temperature of 50 degrees C to 4.7 degrees C for 75 degrees C. The ED50 temperature value for ophthalmoscopically visible lesions in rabbits was determined as 65.3 degrees C. The introduced method can be used for retinal irradiations with adjustable temperature elevations. PMID- 29164837 TI - Serum surfactant protein D and exhaled nitric oxide as biomarkers of early lung damage in systemic sclerosis. AB - BACKGROUND: Interstitial lung disease (ILD) complicates the course of systemic sclerosis (SSc), representing the main cause of death in these patients. The identification of parameters that can predict the early onset and progression of ILD in SSc represents an unmet need in clinical practice. The study was designed to explore whether the surfactant proteins (SP) A and D may be used as noninvasive tools for the early identification of ILD in SSc. Alveolar exhaled nitric oxide (NO) was investigated as a surrogate marker of distal inflammation. METHODS: Unselected consecutive subjects newly diagnosed with scleroderma and subjects free of respiratory and systemic diseases were recruited. All patients underwent clinical, lung functional, radiological and biological assessments. RESULTS: 15 individuals affected by SSc (M/F: 3/12), and 10 healthy subjects (M/F: 3/7) participated to the study. The serum SP-D values were 115.3+/-81.36 ng/mL in SSc subjects and 32+/-11.9 ng/mL in healthy controls (P=0.004). The concentrations of serum SP-A were not statistically different between groups. Serum SP-D inversely correlated with FEV1% predicted (rs=-0.29; P=0.004), FVC% predicted (rs=-0.20; P=0.02) and DLCO% predicted (rs=-0.36; P=0.001). Alveolar NO concentrations were significantly different between SSc and control subjects (6.5+/-2.9 ppb vs. 2.2+/-1.3 ppb, respectively; P=0.001), and positively associated with the levels of serum SP-D (r=0.60, P=0.03). CONCLUSIONS: These findings suggest that, in patients with scleroderma, SP-D and exhaled alveolar NO could represent novel non-invasive markers of early detection and activity of lung involvement. PMID- 29164838 TI - Supplementation with Robuvit(r) in subjects with burnout associated to high oxidative stress. AB - BACKGROUND: This supplement registry study evaluated the effect of supplementation with Robuvit(r) on the burnout syndrome (BOS) of patients with significant fatigue and high oxidative stress. Robuvit(r) (French oak wood extract) is a standardized supplement, effective in treating chronic fatigue syndrome (CFS), post-traumatic stress disorder (PTSD) and convalescence. METHODS: A group of 108 subjects with BOS, consisting of a subgroup of 42 young surgeons in training and a subgroup of 66 managers, were studied. Subjects followed a standard management (SM); one half of the subjects received 300 mg/day of Robuvit(r) for 4 weeks in addition to SM. RESULTS: Robuvit(r) was (P<0.05) more effective compared to SM in improving parameters evaluated with the aid of Maslach Burnout Inventory: dealing with patients problems, improving the relationship with patients, decreasing emotional drainage and intolerance (P<0.05). The feeling of a positive influence improved. The decrease in strain from interactions at work, the decrease in the lack of care feeling, the improved levels in interest were all positively affected with Robuvit (P<0.05) in comparison with SM. The need for giving up decreased, the level of satisfaction improved and the regrets for being in the profession decreased. BOS symptoms were positively affected by the supplement (P<0.05). Oxidative stress (388;24 Carr Units decreased to 344;22 with Robuvit(r); P<0.05), SM had no influence on oxidative stress. Robuvit(r) was also more effective in professionals with burnout syndrome than the SM only in in decreasing emotional drainage, fatigue and intolerance (P<0.05). Robuvit(r) significantly improved the feeling of having a positive influence (P<0.05). Also, Robuvit(r) significantly decreased the strain resulting from interactions at work and improved the care for colleagues/customers (P<0.05). Interest and enthusiasm were significantly increased in subjects taking Robuvit(r) in comparison with controls with standard management alone (P<0.05). The mean score of the desire to give up was decreased with Robuvit(r) in comparison with SM (P<0.05) and job satisfaction was significantly improved (P<0.05). The feeling of regrets of being in the profession was significantly reduced with the supplement in comparison to SM (P<0.05). Robuvit(r) reduced oxidative stress (P<0.05) from 397;33 to 323;29 Carr Units in comparison with a low decrease with SM (from 396;19 vs. 378;27) at 4 weeks. CONCLUSIONS: In conclusion, in this registry study on BOS, Robuvit(r) by controlling fatigue (the primary symptom) and oxidative stress, relieves the most important 'symptoms' associated with BOS. The effects are comparable in young surgeons not accustomed to stress, as well as in professionals in management positions who are used to control stress. PMID- 29164839 TI - Residual renal and cardiovascular disease risk in conventionally-treated patients with type 2 diabetes: the potential of non-traditional biomarkers. AB - Diabetes is a leading cause of chronic kidney disease (CKD) in the developed world. Promoters of the progression of kidney disease include the traditional profile of cardiovascular risk factors. However, the development of CKD and vulnerability to end-stage renal disease (ESRD) is highly variable. Determinants of the susceptibility to ESRD may include non-traditional risk factors such as gene-environment interactions, socio-geographic factors and/or treatment strategies. We review the conflicting clinical relevance of studies implicating pathways related to oxidative stress. These pathways are strongly implicated in the phenotype of some groups of high-risk patients and could assume importance in clinical care. Recent clinical trial evidence has shown that newer glucose lowering agents also have beneficial effects on reducing the incidence of renal dysfunction and cardiovascular events in high-risk patients. Research is required to identify which patients will benefit most from newer approaches to managing diabetes. Understanding the relationship of non-traditional risk factors to renal and cardiovascular disease could help clinicians targeting new therapeutic approaches in the management of type 2 diabetes. PMID- 29164840 TI - Correlations between anterior wall motion velocity of ascending aorta measured by quantitative tissue velocity image and left ventricular geometry as well as left heart function in hypertension patients. AB - BACKGROUD: This study aimed to analyze the correlations between anterior wall motion velocity of ascending aorta measured by quantitative tissue velocity image (QTVI) technique and left ventricular geometry as well as left heart function to evaluate its value of clinical application. METHODS: One hundred ten hypertension patients and 35 healthy controls were included, divided into left ventricular concentric remodeling group and left ventricular hypertrophy group. The QTVI technique was used to obtain the velocity curve of anterior wall of ascending aorta, the peak systolic velocity (Vs), peak velocity of early diastolic motion (Ve) and peak velocity of late diastolic motion (Va). The single-plane Simpson method was utilized to measure the left ventricular ejection fraction (EF). The QTVI method was used to obtain the index of left ventricular diastolic function (Em/Am). RESULTS: Compared to control group, both Vs and Ve values significantly reduced in hypertension group (P<0.05). Both Vs and Ve values were significantly negatively correlated with LVMI and RWT (P<0.01). The Va value was negatively correlated with LVMI (P<0.05). The Vs value was significantly positively correlated with EF value (P<0.01). The Ve value was significantly positively correlated with both EF and Em/Am (P<0.01). The Va value was positive correlated with Em/Am (P<0.05). CONCLUSIONS: The QTVI anterior wall velocity of ascending aorta could be indicator for the geometric patterns and function of left ventricle, which may provide a simple and comprehensive method for clinical assessment of hypertensive heart disease. PMID- 29164841 TI - Home blood pressure measurement as a systematic tool for clinical practice in CKD patients: a real-world picture. AB - BACKGROUND: Arterial hypertension is very common in chronic kidney disease (CKD) patients and its prevalence increases with lowering estimated glomerular filtration rate (eGFR). Blood pressure (BP) control is a cornerstone in the treatment of CKD patients but still most treatment decisions are based on office BP measurement (OBPM). The aim of this cross-sectional, retrospective study is to investigate the prevalence of hypertension phenotypes in CKD patients and whether different home (HBPM) or OBPM are associated with a different CKD stage and cardiovascular comorbidities. METHODS: We analyzed 560 consecutive patients (359 men, age 70+/-13 years), affected by stage 3-5 CKD, who performed HBPM recording; OBPM during a single visit was also assessed. Uncontrolled hypertension was defined as OBPM values >=140/90 mmHg and HBPM values >=135/85 mmHg, respectively. RESULTS: Systolic and diastolic HBPM values were lower than OBPM values. A white coat effect (systolic BP +18+/-12 mmHg) was detected in 62.5%, while a masked effect (systolic BP -14+/-10 mmHg) was detected in 22.7%. No relationship was found between BP differences and body weight, CKD stage, eGFR or presence of diabetes. Based on OBPM, 18.6% of patients showed controlled systolic and diastolic BP, whereas 37.8% had sustained hypertension. White-coat hypertension was detected in 23.4% and Masked hypertension in 12.1%. The multiple logistic regression model showed that masked uncontrolled hypertensive patients showed a higher probability of having ischemic heart disease (OR=2.54 [1.02-6.36]), while sustained hypertension was associated with an increased prevalence of stroke in comparison to normotensive or true control BP group (OR=4.72 [1.30-17.07]). Age, gender, diabetes or CKD stage, were not different among the four hypertension phenotypes. CONCLUSIONS: We observed a quite high rate of masked uncontrolled hypertension and of white coat hypertension in stage 3-5ND CKD patients. Office BP measurement, as a single tool, is an inadequate diagnostic procedure in the clinical management of CKD patients. HBPM should be routinely implemented for identifying hypertensive phenotypes and then for avoiding misdiagnosis and mistreatment of pre-dialysis CKD patients in a tertiary care setting. PMID- 29164842 TI - Tumor suppressor role of miR-503. AB - MicroRNAs (miRNAs) are non-coding RNAs of around 20-25 nucleotides in length with highly conserved characteristics. They moderate post-transcriptional silencing by precisely combining with 3' untranslated regions (UTRs) of target mRNAs at a complementary site. miR-503, an associate of the "canonical" miRNA-16 family, is expressed in numerous types of tumors such as breast cancer, prostate cancer, lung cancer, colorectal cancer, hepatocellular carcinoma, glioblastoma and several others. There is convincing evidence to show that miR-503 functions as a tumor suppressor gene through its effects on target genes that regulate cell proliferation, migration, and invasion in tumor cells. In this current assessment, we discuss the biology and tumor suppressor role of miR-503 in different cancers and elaborate on its mechanism of action. PMID- 29164843 TI - The Institutionalization and Professionalization of theMedical Library in Puerto Rico: The Conrad F. Asenjo Library's Legacy. AB - The discourse about health in Puerto Rico has been constructed using thephysician and hospital's perspective or a particular disease or epidemic. Thusfar, this approach has not addressed the health library as an object of study. Theorigins and development of the Conrado F. Asenjo Library (CFAL) will be discussed. Before 1912, there were no medical libraries in Puerto Rico, onlyprivate collections. In 1914, the act that created the Institute of Tropical Medicinewas amended to allocate funds for the purchase of books to supportresearch in tropical diseases in Puerto Rico. The history of the CFA Libraryreflects its contribution to issues, concerns, development of research, and to theevolving paradigms in the health field in the Island. Historical documents,such as Bailey K. Ashford's personal papers located at the CFAL and GeorgetownUniversity Archives (GU) were evaluated. Institutional reports fromthe School of Tropical Medicine (STM) and articles published by Puerto Ricanphysicians such as Dr. Pedro Gutierrez Igaravidez and Dr. Isaac GonzalezMartinez, affiliated to the Institute of Tropical Medicine, were also studied.Finally, references and bibliographies in articles published between 1912 and1924 were evaluated and consulted to find additional sources. PMID- 29164845 TI - Current therapeutic options and treatments in development for the management of primary open-angle glaucoma. AB - Primary open angle glaucoma (POAG) is the most common type of glaucoma, and is responsible for approximately 90% of glaucoma cases in North America. POAG is characterized by an asymptomatic onset, where patients do not present with symptoms until significant visual loss occurs in late stages of the disease. Importantly, while glaucoma is associated with several risk factors that contribute to damage and disease progression, intraocular pressure (IOP) is the only proven modifiable risk factor at this time. Treatments for POAG include use of pharmacologic and surgical interventions. As of this writing, available pharmacologic options reduce IOP through reduction of aqueous humor production or by facilitating aqueous humor drainage through the uveoscleral outflow pathway (the unconventional pathway). Although cholinergic agonists (eg, pilocarpine) indirectly targets aqueous humor draining through the trabecular meshwork/Schlemm's canal (the conventional outflow pathway), cholinergic agonists are not frequently used, and as of this writing, no agents are currently available that target both the conventional and unconventional outflow pathways. Therapies in late-stage development include trabodenoson, netardsudil, and latanoprostene bunod. PMID- 29164844 TI - Uncommon cause of dysphagia, shortness of breath and hoarseness: Large subclavian arterypseudoaneurysm. AB - The subclavian artery pseudoaneurysm is a rare entity with only few cases re ported in the literature. Most injuries were related to iatrogenic manipulationwith catheters for canalization of central lines in the hospital setting. In rare cases,this injury has been described secondary to a blunt trauma and motor vehicleaccidents with traumatic injury to the subclavian artery caused by seatbelt use.We report an unusual case presentation of subclavian artery pseudoaneurysm. PMID- 29164846 TI - Anesthetic Challenges and Management in a case of Jarcho-Levin Syndrome with a Neural Tube Defect in a Newborn. AB - Jarcho-Levin syndrome (JLS) is a rare axial skeletal growth disorder characterized by the presence of multi-level costovertebral malformations, a short neck, a short trunk, and kyphoscoliosis at birth. Neural tube defects appear to be common findings in patients with JLS, and chest hypoplasia frequently leads to respiratory insufficiency and death in early childhood. There have been no previous studies in the literature on the anesthetic management of JLS with neural tube defects and hydrocephalus. Therefore, we have reported a case of JLS in a female full-term newborn, who underwent surgery for myelomeningocele repair and ventriculoperitoneal shunting, with the associated anesthetic challenges and their management. PMID- 29164847 TI - Inflammation, Obesity and the Metabolic Syndrome. Implications in Hispanics. AB - We report clinical and molecular mechanisms relating the process ofinflammation involved in the progression of obesity and the metabolic syndrome,emphasizing the cardiovascular problems developed in Hispanic populations.Namely, the incidence, component characteristics and complications of obesityand metabolic syndrome in island Puerto Ricans are described and evidence ispresented supporting the fact that the metabolic syndrome may be milder inPuerto Rico than in the mainland United States because it is characterized byless aggressive coronary artery disease and a relatively normal lipid profile.Moreover, data supports the fact that increased serum cholesterol levels produceless myocardial infarctions in Puerto Rico than in mainland Hispanics andCaucasians. In addition, the incidence of ventricular tachycardia, a complicationcaused by remodeling and ischemia of the heart, may be lower in Puerto Ricothan in the United States, although the prevalence of the metabolic syndrome ishigher in the island. On the other hand, there is evidence of a rising epidemic ofobesity and vascular inflammation in Puerto Rico that suggests that cardiovascularmorbidity and mortality in the island will continue to increase in thefuture decades. PMID- 29164848 TI - Static Capacitive Pressure Sensing Using a Single Graphene Drum. AB - To realize nanomechanical graphene-based pressure sensors, it is beneficial to have a method to electrically readout the static displacement of a suspended graphene membrane. Capacitive readout, typical in micro-electromechanical systems, gets increasingly challenging as one starts shrinking the dimensions of these devices because the expected responsivity of such devices is below 0.1 aF/Pa. To overcome the challenges of detecting small capacitance changes, we design an electrical readout device fabricated on top of an insulating quartz substrate, maximizing the contribution of the suspended membrane to the total capacitance of the device. The capacitance of the drum is further increased by reducing the gap size to 110 nm. Using an external pressure load, we demonstrate the successful detection of capacitance changes of a single graphene drum down to 50 aF, and pressure differences down to 25 mbar. PMID- 29164849 TI - Emulsion Hydrogel Soft Motor Actuated by Thermal Stimulation. AB - An emulsion hydrogel motor (E-H motor), constituted by low-boiling-point oil fuel and a hydrogel matrix, is prepared through a simple yet versatile oil-in-water (O/W) emulsion template method. The E-H motor can be efficiently propelled by the bubbles generated under a thermal stimulus. As thermally induced explosion occurs inside the E-H motor (diameter ~4.0 mm and length ~6.0 mm), the gas bubbles resulting from thermotropic phase transition are violently ejected from one side, leading to a fast speed of 14.78 +/- 4.82 mm s-1 in a 60 degrees C aqueous solution. Additionally, multiple water-insoluble organic solvents can serve as the fuel for self-propulsion, which demonstrates the favorable universality of the E-H motor. The magnetic navigation and near-infrared propulsion can be realized through incorporating hydrophilic iron oxide (Fe3O4) nanoparticles and graphene oxide (GO) into the aqueous phase. Moreover, the synchronous integration of GO and enrofloxacin bactericide can enable intelligent targeted cargo transportation and delivery. The attractive self-propulsion performance, precise locomotion control, and formidable integration ability of the emulsion hydrogel based miniaturized soft motor hold great promise for numerous practical applications. PMID- 29164850 TI - Exploring Highly Reversible 1.5-Electron Reactions (V3+/V4+/V5+) in Na3VCr(PO4)3 Cathode for Sodium-Ion Batteries. AB - The development of highly reversible multielectron reaction per redox center in sodium super ionic conductor-structured cathode materials is desired to improve the energy density of sodium-ion batteries. Here, we investigated more than one electron storage of Na in Na3VCr(PO4)3. Combining a series of advanced characterization techniques such as ex situ 51V solid-state nuclear magnetic resonance, X-ray absorption near-edge structure, and in situ X-ray diffraction, we reveal that V3+/V4+ and V4+/V5+ redox couples in the materials can be accessed, leading to a 1.5-electron reaction. It is also found that a light change on the local electronic and structural states or phase change could be observed after the first cycle, resulting in the fast capacity fade at room temperature. We also showed that the irreversibility of the phase changes could be largely suppressed at low temperature, thus leading to a much improved electrochemical performance. PMID- 29164851 TI - An Integrated Redox Cycling for Electrochemical Enzymatic Signal Enhancement. AB - Highly sensitive analytical methods for the detection of proteins are still an urgent demand in early medical diagnosis and the discovery of biomarkers with ultralow abundance. Here an integrated electrochemical-chemical-enzymatic redox cycling is designed for significant enhancement of electrochemical enzymatic signal in biorecognition. This strategy efficiently utilizes the high specificity of the outersphere to innersphere redox reaction to mediate the enzymatic redox cycling with the nonenzymatic redox cycling. The oxygenation activity of tyrosinase as a label of the biorecognition event ensures low background and generates outersphere-reaction-philic/innersphere-reaction-philic redox couples, which leads to 13 300* amplification of electrochemical signal. The mediation of nonenzymatic redox cycling in the integrated system produces a 14-fold improved ratio of signal to background. The practicality of the proposed approach with clinical samples demonstrates its potential in clinical diagnostic and therapeutic monitoring. This work opens a new avenue to design novel signal amplification strategies for ultrasensitive bioanalysis. PMID- 29164852 TI - Electrochemical Rejuvenation of Anodically Coloring Electrochromic Nickel Oxide Thin Films. AB - Nickel oxide thin films are of major importance as anodically coloring components in electrochromic smart windows with applications in energy-efficient buildings. However, the optical performance of these films degrades upon extended electrochemical cycling, which has hampered their implementation. Here, we use a potentiostatic treatment to rejuvenate degraded nickel oxide thin films immersed in electrolytes of LiClO4 in propylene carbonate. Time-of-flight elastic recoil detection analysis provided unambiguous evidence that both Li+ ions and chlorine based ions participate in the rejuvenation process. Our work provides new perspectives for developing ion-exchange-based devices embodying nickel oxide. PMID- 29164853 TI - Microfluidic Free-Flow Electrophoresis Based Solvent Exchanger for Continuously Operating Lab-on-Chip Applications. AB - For miniaturization and integration of chemical synthesis and analytics on small length scales, the development of complex lab-on-chip (LOC) systems is in the focus of many current research projects. While application specific synthesis and analytic modules and LOC devices are widely described, the combination and integration of different modules is intensively investigated. Problems for in line processes such as solvent incompatibilities, e.g., for a multistep synthesis or the combination of an organic drug synthesis with a cell-based biological activity testing system, require a solvent exchange between serialized modules. Here, we present a continuously operating microfluidic solvent exchanger based on the principle of free-flow electrophoresis for miscible organic/aqueous fluids. We highlight a proof-of-principle and describe the working principle for the model compound fluorescein, where the organic solvent DMSO is exchanged against an aqueous buffer. The DMSO removal performance could be significantly increased to 95% by optimization of the microfluidic layout. Moreover, the optimization of the inlet flow ratio resulted in a minimized dilution factor of 5, and we were able to demonstrate that a reduction of the supporting instrumentation is possible without a significant decrease of the DMSO removal performance. Finally, the compatibility of the developed solvent exchanger for cell based downstream applications was proven. The impedimetric monitoring of HEK293A cells in a continuously operating microfluidic setup revealed no adverse effects of the residual DMSO after the solvent replacement. Our solvent exchanger device demonstrates the power of micro-free-flow electrophoresis not only as a powerful technique for separation and purification of compound mixtures but also for solvent replacement. PMID- 29164854 TI - Nitrogen-Doped Porous Carbon-ZnO Nanopolyhedra Derived from ZIF-8: New Materials for Photoelectrochemical Biosensors. AB - Herein, novel photoactive materials, nitrogen-doped porous carbon-ZnO (NPC-ZnO) nanopolyhedra, were prepared by direct carbonization of zeolitic imidazolate framework (ZIF)-8 nanopolyhedra in a nitrogen atmosphere. The morphology, structure, and photoelectrochemical (PEC) properties were characterized by scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, nitrogen adsorption-desorption method, and PEC methods. The results showed that the obtained NPC-ZnO nanopolyhedra had a rhombic dodecahedron morphology with uniform particle size of about 100 nm and a high surface area of 609.2 m2 g-1. Under visible-light irradiation, the NPC-ZnO nanopolyhedra showed better PEC performance than ZnO nanorod and the ZIF-8 nanopolyhedra in aqueous media with dissolved oxygen and ascorbic acid. Taking alkaline phosphatase (ALP) as a model, a NPC-ZnO nanopolyhedra-based PEC sensor was developed and showed good performance for ALP assay with a wide linear response range from 2 to 1500 U L-1 and a low detection limit of 1.7 U L-1. Moreover, the PEC sensor possessed acceptable selectivity, reproducibility, and stability. The prepared NPC-ZnO nanopolyhedra provide a new photoactive material for the construction of PEC sensors and may have promising applications in PEC assay of heavy metal ions, organic pollutants, and biomolecules. PMID- 29164855 TI - Surface Passivation and Supersaturation: Strategies for Regioselective Deposition in Seeded Syntheses. AB - Crystal growth theory predicts that heterogeneous nucleation will occur preferentially at defect sites, such as the vertices rather than the faces of shape-controlled seeds. Platonic metal solids are generally assumed to have vertices with nearly identical chemical potentials, and also nearly identical faces, leading to the useful generality that heterogeneous nucleation preserves the symmetry of the original seeds in the final product. Herein, we test the limits of this generality in the extreme of low supersaturation, in an effort to expand the methods available for inducing anisotropic overgrowth. We formulate a strategy for favoring localized deposition that differentiates between both different vertices and different edges or faces, i.e., regioselective deposition. Deposition followed a simple kinetic model for nucleation rate, depending on wetting, supersaturation, and temperature. We demonstrate our ability to independently study the effects of varying supersaturation and surface passivation. Regioselective heterogeneous nucleation was achieved at low supersaturation by a kinetic preference for high-energy defect-rich sites over lower-energy sites. This outcome was also achieved by using capping agents to passivate facet sites where deposition was not desired. Collectively, the results presented herein provide a model for breaking the symmetry of seeded growth and for achieving regioselective deposition. PMID- 29164856 TI - Aerosol Cross-Linked Crown Ether Diols Melded with Poly(vinyl alcohol) as Specialized Microfibrous Li+ Adsorbents. AB - Crown ether (CE)-based Li+ adsorbent microfibers (MFs) were successfully fabricated through a combined use of CE diols, electrospinning, and aerosol cross linking. The 14- to 16-membered CEs, with varied ring subunits and cavity dimensions, have two hydroxyl groups for covalent attachments to poly(vinyl alcohol) (PVA) as the chosen matrix. The CE diols were blended with PVA and transformed into microfibers via electrospinning, a highly effective technique in minimizing CE loss during MF fabrication. Subsequent aerosol glutaraldehyde (GA) cross-linking of the electrospun CE/PVA MFs stabilized the adsorbents in water. The aerosol technique is highly effective in cross-linking the MFs at short time (5 h) with minimal volume requirement of GA solution (2.4 mL g-1 MF). GA cross linking alleviated CE leakage from the fibers as the CEs were securely attached with PVA through covalent CE-GA-PVA linkages. Three types of CE/PVA MFs were fabricated and characterized through Fourier transform infrared-attenuated total reflection, 13C cross-polarization magic angle spinning NMR, field emission scanning electron microscope, N2 adsorption/desorption, and universal testing machine. The MFs exhibited pseudo-second-order rate and Langmuir-type Li+ adsorption. At their saturated states, the MFs were able to use 90-99% CEs for 1:1 Li+ complexation, suggesting favorability of their microfibrous structures for CE accessibility to Li+. The MFs were highly Li+-selective in seawater. Neopentyl-bearing CE was most effective in blocking larger monovalents Na+ and K+, whereas the dibenzo CE was best in discriminating divalents Mg2+ and Ca2+. Experimental selectivity trends concur with the reaction enthalpies from density functional theory calculations, confirming the influence of CE structures and cavity dimensions in their "size-match" Li+ selectivity. PMID- 29164857 TI - Modeling Insight into Battery Electrolyte Electrochemical Stability and Interfacial Structure. AB - Electroactive interfaces distinguish electrochemistry from chemistry and enable electrochemical energy devices like batteries, fuel cells, and electric double layer capacitors. In batteries, electrolytes should be either thermodynamically stable at the electrode interfaces or kinetically stable by forming an electronically insulating but ionically conducting interphase. In addition to a traditional optimization of electrolytes by adding cosolvents and sacrificial additives to preferentially reduce or oxidize at the electrode surfaces, knowledge of the local electrolyte composition and structure within the double layer as a function of voltage constitutes the basis of manipulating an interphase and expanding the operating windows of electrochemical devices. In this work, we focus on how the molecular-scale insight into the solvent and ion partitioning in the electrolyte double layer as a function of applied potential could predict changes in electrolyte stability and its initial oxidation and reduction reactions. In molecular dynamics (MD) simulations, highly concentrated lithium aqueous and nonaqueous electrolytes were found to exclude the solvent molecules from directly interacting with the positive electrode surface, which provides an additional mechanism for extending the electrolyte oxidation stability in addition to the well-established simple elimination of "free" solvent at high salt concentrations. We demonstrate that depending on their chemical structures, the anions could be designed to preferentially adsorb or desorb from the positive electrode with increasing electrode potential. This provides additional leverage to dictate the order of anion oxidation and to effectively select a sacrificial anion for decomposition. The opposite electrosorption behaviors of bis(trifluoromethane)sulfonimide (TFSI) and trifluoromethanesulfonate (OTF) as predicted by MD simulation in highly concentrated aqueous electrolytes were confirmed by surface enhanced infrared spectroscopy. The proton transfer (H-transfer) reactions between solvent molecules on the cathode surface coupled with solvent oxidation were found to be ubiquitous for common Li-ion electrolyte components and dependent on the local molecular environment. Quantum chemistry (QC) calculations on the representative clusters showed that the majority of solvents such as carbonates, phosphates, sulfones, and ethers have significantly lower oxidation potential when oxidation is coupled with H-transfer, while without H-transfer their oxidation potentials reside well beyond battery operating potentials. Thus, screening of the solvent oxidation limits without considering H-transfer reactions is unlikely to be relevant, except for solvents containing unsaturated functionalities (such as C?C) that oxidize without H-transfer. On the anode, the F-transfer reaction and LiF formation during anion and fluorinated solvent reduction could be enhanced or diminished depending on salt and solvent partitioning in the double layer, again giving an additional tool to manipulate the order of reductive decompositions and interphase chemistry. Combined with experimental efforts, modeling results highlight the promise of interphasial compositional control by either bringing the desired components closer to the electrode surface to facilitate redox reaction or expelling them so that they are kinetically shielded from the potential of the electrode. PMID- 29164858 TI - Circular Dichroism of CdSe Nanocrystals Bound by Chiral Carboxylic Acids. AB - Chiral semiconductor nanocrystals, or quantum dots (QDs), are promising materials for applications in biological sensing, photonics, and spin-polarized devices. Many of these applications rely on large dissymmetry, or g-factors, the difference in absorbance between left- and right-handed circularly polarized light compared to the unpolarized absorbance. The majority of chiral QDs, specifically CdSe, reported to date have used thiolated amino acid ligands to introduce chirality onto the nanoparticles, but these systems have ultimately reported small g-factors of ~2 * 10-4. In an effort to realize chiral CdSe QDs with higher g-factors and to expand the set of designer chiral semiconductor nanocrystals, we have employed chiral carboxylic acids as a distinct class of ligands for chiral CdSe nanoparticles. Through this family of chiral carboxylic acid ligands, we performed a direct comparison between carboxylate-bound and thiolate-bound chiral CdSe QDs. Spectral analysis revealed that the resulting circular dichroism shifts originate from the splitting of the exciton by the ligand-nanocrystal interaction. Subsequent examination of a series of chiral carboxylic acid ligands revealed a 30-fold range in g-factor through relatively small changes in the structure of the ligand. Finally, we showed that increasing the number of stereocenters on the ligand can further enhance the dissymmetry factors. This versatile and tunable combination of nanocrystals and ligands will inform future designs of chiral nanomaterials and their applications. PMID- 29164859 TI - Supramolecular Cross-Link-Regulated Emission and Related Applications in Polymer Carbon Dots. AB - Involvement of clear photoluminescence (PL) mechanism in specific chemical structure is at the forefront of carbon dots (CDs). Supramolecular interaction exists in plenty of materials, offering an inherent way to administrate the optical and photophysical properties, especially in terms of newly developed polymer carbon dots (PCDs). However, supramolecular-interaction-derived PL regulation is always ignored in the shadow of many kinds of PL factors, and we still have a limited understanding on the distinct chemical structure and mechanism of supramolecular effect in PCDs. Herein, several distinct photoluminescent phenomena of PCDs under aqueous and solid state are reviewed in terms of supramolecular cross-linking, with highly emphasizing the importance of supramolecular cross-link-enhanced emission (SCEE) effects, and the regulated function of supramolecular interaction's intensity and types between PCDs for special PL behaviors of PCDs. In addition, we categorize the photoluminescent phenomena in PCDs into the following aspects: supramolecular cross-link-enhanced dilute-solution-state emission, concentration-controlled multicolor emission, supramolecular regulation for quenching-resistant solid-state fluorescence, as well as supramolecular cross-link-assisted room-temperature- phosphorescence (RTP) under solid states. Furthermore, the applications of PCDs in light-emitting diodes (LED), solar cells, and anticounterfeiting and data encryption, etc., are presented, based on the distinct supramolecular cross-link-regulated photoluminescent phenomena, especially the solid-state emission. Finally, a brief outlook is given, highlighting the currently existing problems and development direction of supramolecular cross-link-regulated emission in PCDs. PMID- 29164860 TI - High-Quality GaN Epilayers Achieved by Facet-Controlled Epitaxial Lateral Overgrowth on Sputtered AlN/PSS Templates. AB - It is widely believed that the lack of high-quality GaN wafers severely hinders the progress in GaN-based devices, especially for defect-sensitive devices. Here, low-cost AlN buffer layers were sputtered on cone-shaped patterned sapphire substrates (PSSs) to obtain high-quality GaN epilayers. Without any mask or regrowth, facet-controlled epitaxial lateral overgrowth was realized by metal organic chemical vapor deposition. The uniform coating of the sputtered AlN buffer layer and the optimized multiple modulation guaranteed high growth selectivity and uniformity of the GaN epilayer. As a result, an extremely smooth surface was achieved with an average roughness of 0.17 nm over 3 * 3 MUm2. It was found that the sputtered AlN buffer layer could significantly suppress dislocations on the cones. Moreover, the optimized three-dimensional growth process could effectively promote dislocation bending. Therefore, the threading dislocation density (TDD) of the GaN epilayer was reduced to 4.6 * 107 cm-2, which is about an order of magnitude lower than the case of two-step GaN on the PSS. In addition, contamination and crack in the light-emitting diode fabricated on the obtained GaN were also effectively suppressed by using the sputtered AlN buffer layer. All of these advantages led to a high output power of 116 mW at 500 mA with an emission wavelength of 375 nm. This simple, yet effective growth technique is believed to have great application prospects in high-performance TDD sensitive optoelectronic and electronic devices. PMID- 29164861 TI - Alcohol-Soluble Isoindigo Derivative IIDTh-NSB as a Novel Modifier of ZnO in Inverted Polymer Solar Cells. AB - Alcohol-soluble isoindigo derivative with thiophene groups and sulfobetaine zwitterions, IIDTh-NSB was applied as a novel modifier of ZnO in inverted polymer solar cells (i-PSCs). When IIDTh-NSB (0.2 mg/mL) was spin-coated on ZnO as an electron transport layer (ETL), power conversion efficiency (PCE) of the PTB7:PC71BM based i-PSCs reached 8.88%, which is a 20% improvement of that of 7.40% for the device with the ZnO-only ETL. If ZnO was doped by IIDTh-NSB of 1.0 wt %, the PCE of 8.50% could be achieved in the i-PSCs. Combined measurements of capacitance-voltage characteristics, carrier mobility, and photocurrent density effective voltage characteristics revealed that incorporating IIDTh-NSB as the modifier of ZnO by coating or doping enhanced the built-in potential, charge carrier density and mobility, exciton dissociation, and charge carrier extraction in the i-PSCs because of the improved interfacial contact between the photoactive layer and ZnO as shown in water contact angle measurements and atomic force microscopy images. Finally, impedance spectroscopy investigation provided strong lines of evidence that incorporating IIDTh-NSB as the modifier of ZnO led to the great enhancement in short-circuit current density and fill factor. Furthermore, all the devices with IIDTh-NSB as a modifier of ZnO presented better stability than the device with ZnO-only. These findings suggest that IIDTh-NSB is an effective and competitive material for modification of ZnO in the i-PSCs. PMID- 29164862 TI - Fabrication of Magnetic Conjugation Clusters via Intermolecular Assembling for Ultrasensitive Surface Plasmon Resonance (SPR) Detection in a Wide Range of Concentrations. AB - Herein, a novel sandwich surface plasmon resonance (SPR) detection assay, which utilizes prion disease-associated isoform (PrPSc) conjugating magnetic nanoparticle clusters (nanoparticle-organic clusters, NOCs) as signal amplification reagents, is constructed for the ultrasensitive detection of PrPSc. Due to the highly specific affinity of aptamer-Fe3O4 nanoparticles (AMNPs) toward PrPSc and the intermolecular assembly behaviors among PrPSc, PrPSc conjugating magnetic nanoparticle clusters were obtained after the incubation of AMNPs and PrPSc and the subsequent concentration processes in an external magnetic field. The conjugation clusters were further injected into the SPR cuvette and captured by the gold sensing film via the Au-S bonding interaction, inducing intense SPR responses. Meanwhile, a traditional sandwich SPR detection format using a gold/PrPSc/AMNPs amplification mode was conducted for the detection of PrPSc as comparison. The results reveal that the synthesized NOCs permitted a 215-fold increase of the SPR signal, while the sandwich format permitted only a 65-fold increase. Moreover, a lower detection limit (1 * 10-4 ng/mL) and a wider quantitation range (1 * 10-4-1 * 105 ng/mL) were demonstrated. The formation of the conjugation clusters and the capture of these clusters were confirmed by high resolution AFM imaging and molecular simulations. This conjugation-cluster induced signal amplification strategy has great potential for the detection of small analytes with similar structural characteristics in trace level concentrations with high selectivity and sensitivity by altering the corresponding aptamer labeled to magnetic particles. PMID- 29164863 TI - Local Acidification of Membrane Surfaces for Potentiometric Sensing of Anions in Environmental Samples. AB - The work dramatically improves the lower detection limit of anion selective membranes at environmental pH by using local acidification to suppress hydroxide interference at the membrane surface. Three separate localized acidification strategies are explored to achieve this, with ionophore-based membrane electrodes selective for nitrite and dihydrogen phosphate as guiding examples. In a first approach, a concentrated acetic acid solution (ca. 1 M) is placed in the inner filling solution of the PVC-based membrane electrode, forcing a significant acid gradient across the membrane. A second strategy achieves the same type of passive acidification by using an external proton source (fast diffusive doped polypropylene membrane) placed in front of a potentiometric solid contact anion selective electrode where the thin layer gap allows one to observe spontaneous acidification at the opposing detection electrode. The third approach shares the same configuration, but protons are here released by electrochemical control from the selective proton source into the thin layer sample. All three protocols improve the limit of detection by more than 2 orders of magnitude at environmental pH. Nitrite and dihydrogen phosphate determinations in artificial and natural samples are demonstrated. PMID- 29164865 TI - Label-Free DNA Assay by Metal Stable Isotope Detection. AB - The interest in label-free bioassays is increasing rapidly because of their simple procedure and direct information on the interaction between the target molecule and the sensing unit. One of the major obstacles in the application of label-free biosensors is the difficulty to produce stable and reproducible optical, electric, electrochemical, or magnetic properties for the sensitive detection of the target molecules. In this work, we demonstrated a label-free DNA assay, by directly measuring the intrinsic 63Cu and 65Cu stable isotopes inside the double-strand DNA-templated Cu nanoparticles. The experimental conditions, including detection of copper by elemental mass spectrometry, the copper nanoparticles formation parameters, the hybrid chain reaction parameters, and analytical performance, were investigated in detail. The 63Cu signal intensity possesses a linear relation with the concentration of target DNA over the range of 20-1000 pM with a detection limit of 4 pM (3sigma). The detection limit of this method is among the most sensitive label-free techniques and also comparable to the lanthanides and Au nanoparticles labeled assays by elemental mass spectrometric detection. The proposed label-free bioassay is simple and sensitive and eliminated the need for optical, electric, electrochemical, or magnetic properties of the sensing unit. To our best knowledge, this is the first report of the label-free bioassay by metal stable isotope detection. PMID- 29164866 TI - Electrochemical Analysis of Enzyme Based on the Self-Assembly of Lipid Bilayer on an Electrode Surface Mediated by Hydrazone Chemistry. AB - In this work, a new strategy for electrochemical analysis of enzyme has been proposed based on a self-assembled lipid bilayer on an electrode surface mediated by hydrazone chemistry. Taking aldolase as an example, the enzyme can catalyze the formation of products containing carbonyl groups. These groups can react with hydrazine groups of the functional lipid derivative, resulting in the self assembly of a lipid bilayer on a guanidinium modified electrode surface. The lipid bilayer will then prevent the movement of hydrophilic electrochemical probes. Consequently, the catalytic reaction of the enzyme may result in the change of the obtained electrochemical peak current. Experimental results reveal that aldolase activity can be analyzed over a widely linear detection range from 5 mU/L to 100 U/L with a low detection limit of 1 mU/L. Meanwhile, the method can exhibit good precision and reproducibility and it can be applied for real sample analysis. What is more, because the lipid bilayer is the universal basis for cell membrane structure, while hydrazone chemistry is popular in nature, this work may also provide a new insight for the development of electrochemical analysis and electrochemical biosensors. PMID- 29164864 TI - Treatment of Aqueous Film-Forming Foam by Heat-Activated Persulfate Under Conditions Representative of In Situ Chemical Oxidation. AB - Poly- and perfluoroalkyl substances (PFASs) have been detected in an increasing number of water supplies. In many instances, the contamination is associated with the use of PFAS-containing aqueous film-forming foams (AFFF) in firefighting activities. To investigate the potential for remediating AFFF contamination in groundwater with heat-activated persulfate, PFAS oxidation and the generation of transformation products was evaluated under well-controlled conditions. Fluorotelomer- and perfluoroalkyl sulfonamide-based polyfluorinated compounds were transformed to perfluorinated carboxylic acids, which underwent further degradation under acidic conditions produced after persulfate decomposed. The presence of aquifer sediments decreased the efficiency of the remedial process but did not alter the transformation pathways. At high concentrations, the presence of organic solvents, such as those present in AFFF formulations, inhibited transformation of a representative perfluorinated compound, perfluorooctanoic acid. Heat-activated persulfate did not transform perfluorooctanesulfonic acid or perfluorohexanesulfonic acid under any conditions. Despite challenges associated with the creation of acidic conditions in the subsurface, the potential for generation of undesirable transformation products, and the release of toxic metals, heat-activated persulfate may be a useful in situ treatment for sites contaminated with polyfluoroalkyl substances and perfluorocarboxylic acids. PMID- 29164867 TI - Is Traffic Still an Important Emitter of Monoaromatic Organic Compounds in European Urban Areas? AB - Trends of long-term observations and emission inventories suggest that traffic emissions will no longer dominate the concentrations of monoaromatic compounds (i.e., TEX - toluene, xylenes, and ethylbenzene) in European urban areas. But the split limit between traffic and other emission sector contributions such as solvent use remains tenuous. Here long-term observations of an extensive set of hydrocarbons, including TEX, at traffic and urban background sites in London, Paris and Strasbourg were combined to estimate the relative importance of traffic emissions on TEX in every city. When analyzing the urban enhancement emission ratios of TEX-to-benzene on a seasonal basis, two potential source signatures other than traffic could be differentiated in all cities (1) summertime evaporation from fuel and/or solvent and (2) wintertime domestic heating. However, traffic emissions still unambiguously dominate the concentration levels of TEX in every city despite the reduction of their emissions at exhaust pipe over the last two decades. Traffic explains between 60% and 96% (at +/-20%) of TEX levels while it is less clear for xylenes at some locations. Our results provide a basis to evaluate regional emission inventories. The method is applicable at any urban area where speciated hydrocarbon monitoring is available. PMID- 29164868 TI - Large-Scale, Lithography-Free Production of Transparent Nanostructured Surface for Dual-Functional Electrochemical and SERS Sensing. AB - In this work, we present a dual-functional sensor that can perform surface enhanced Raman spectroscopy (SERS) based identification and electrochemical (EC) quantification of analytes in liquid samples. A lithography-free reactive ion etching process was utilized to obtain nanostructures of high aspect ratios distributed homogeneously on a 4 in. fused silica wafer. The sensor was made up of three-electrode array, obtained by subsequent e-beam evaporation of Au on nanostructures in selected areas through a shadow mask. The SERS performance was evaluated through surface-averaged enhancement factor (EF), which was ~6.2 * 105, and spatial uniformity of EF, which was ~13% in terms of relative standard deviation. Excellent electrochemical performance and reproducibility were revealed by recording cyclic voltammograms. On nanostructured electrodes, paracetamol (PAR) showed an improved quasi-reversible behavior with decrease in peak potential separation (DeltaEp ~ 90 mV) and higher peak currents (Ipa/Ipc ~ 1), compared to planar electrodes (DeltaEp ~ 560 mV). The oxidation potential of PAR was also lowered by ~80 mV on nanostructured electrodes. To illustrate dual functional sensing, quantitative evaluation of PAR ranging from 30 MUM to 3 mM was realized through EC detection, and the presence of PAR was verified by its SERS fingerprint. PMID- 29164869 TI - Role of Secondary Particle Formation in the Persistence of Silver Nanoparticles in Humic Acid Containing Water under Light Irradiation. AB - The wide use of silver nanoparticles (AgNPs) leads to the increasing release of AgNPs into the environment. Dissolved organic matter (DOM) is a key factor affecting the behaviors and fate of AgNPs in the aquatic environment. However, the mechanisms for the DOM-mediated transformations of AgNPs are still not fully understood. In this study, we investigated the persistence of AgNPs in the aquatic environment in the presence of different concentrations of humic acid (HA) over periods of time up to 14 days. The Ag species were monitored and characterized by absorption spectrometry, transmission electron microscopy (TEM), inductively coupled plasma mass spectrometry (ICP-MS), and multicollector ICP-MS (MC-ICP-MS). Results showed that the long-term persistence of AgNPs in HA containing water was determined by two critical concentrations of HA. When the HA concentration exceeded a lower critical value, AgNPs could be persistent in the solution, and a large number of AgNPs were formed secondarily from the HA-induced reduction of the Ag+ ions released from the primary AgNPs, causing a redistribution of the particle size. With the HA concentration above a higher critical value, AgNPs could persist in the solution without a significant change in particle size. Notably, we used Ag isotope fractionation to investigate the transformation mechanism of AgNPs. The natural isotopic analysis by MC-ICP-MS revealed that the size redistribution of AgNPs caused significant Ag isotope fractionation, which gave additional evidence for the proposed mechanisms. This study provides new insights into the environmental fate of engineered AgNPs and highlights the usefulness of stable isotope fractionation in environmental nanotechnology. PMID- 29164870 TI - Quantitative Visualization of Nanoscale Ion Transport. AB - Understanding ion transport properties at various interfaces, especially at small length scales, is critical in advancing our knowledge of membrane materials and cell biology. Recently, we described potentiometric-scanning ion conductance microscopy (P-SICM) for ion-conductance measurement in polymer membranes and epithelial cell monolayers at discrete points in a sample. Here, we combine hopping mode techniques with P-SICM to allow simultaneous nanometer-scale conductance and topography mapping. First validated with standard synthetic membranes and then demonstrated in living epithelial cell monolayers under physiological conditions, this new method allows direct visualization of heterogeneous ion transport of biological samples for the first time. These advances provide a noncontact local probe, require no labeling, and present a new tool for quantifying intrinsic transport properties of a variety of biological samples. PMID- 29164871 TI - Modeling Transport of Chemotactic Bacteria in Granular Media with Distributed Contaminant Sources. AB - Chemotaxis has the potential to improve bioremediation strategies by enhancing the transport of pollutant-degrading bacteria to the source of contamination, leading to increased pollutant accessibility and biodegradation. This computational study extends work reported previously in the literature to include predictions of chemotactic bacterial migration in response to multiple localized contaminant sources within porous media. An advection-dispersion model, in which chemotaxis was represented explicitly as an additional advection-like term, was employed to simulate the transport of bacteria within a sand-packed column containing a distribution of chemoattractant sources. Simulation results provided insight into attractant and bacterial distributions within the column. In particular, it was found that chemotactic bacteria exhibited a distinct biased migration toward contaminant sources that resulted in a 30% decrease in cell recovery, and concomitantly an enhanced retention within the sand column, compared to the nonchemotactic control. Model results were consistent with experimental observations. Parametric studies were conducted to provide insight into the influence of chemotaxis parameters on bacterial migration and cell percent recovery. The model results provide a better understanding of the effect of chemotaxis on bacterial transport in response to distributed contaminant sources. PMID- 29164872 TI - On Chip Protein Pre-Concentration for Enhancing the Sensitivity of Porous Silicon Biosensors. AB - Porous silicon (PSi) nanomaterials have been widely studied as label-free optical biosensors for protein detection. However, these biosensors' performance, specifically in terms of their sensitivity (which is typically in the micromolar range), is insufficient for many applications. Herein, we present a proof-of concept application of the electrokinetic isotachophoresis (ITP) technique for real-time preconcentration of a target protein on a PSi biosensor. With ITP, a highly concentrated target zone is delivered to the sensing area, where the protein target is captured by immobilized aptamers. The detection of the binding events is conducted in a label-free manner by reflective interferometric Fourier transformation spectroscopy (RIFTS). Up to 1000-fold enhancement in local concentration of the protein target and the biosensor's sensitivity are achieved, with a measured limit of detection of 7.5 nM. Furthermore, the assay is successfully performed in complex media, such as bacteria lysate samples, while the selectivity of the biosensor is retained. The presented assay could be further utilized for other protein targets, and to promote the development of clinically useful PSi biosensors. PMID- 29164873 TI - Plasma Protein Turnover Rates in Rats Using Stable Isotope Labeling, Global Proteomics, and Activity-Based Protein Profiling. AB - Protein turnover is important for general health on cellular and organism scales providing a strategy to replace old, damaged, or dysfunctional proteins. Protein turnover also informs of biomarker kinetics, as a better understanding of synthesis and degradation of proteins increases the clinical utility of biomarkers. Here, turnover rates of plasma proteins in rats were measured in vivo using a pulse-chase stable isotope labeling experiment. During the pulse, rats (n = 5) were fed 13C6-labeled lysine ("heavy") feed for 23 days to label proteins. During the chase, feed was changed to an unlabeled equivalent feed ("light"), and blood was repeatedly sampled from rats over 10 time points for 28 days. Plasma samples were digested with trypsin and analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). MaxQuant was used to identify peptides and proteins and quantify heavy/light lysine ratios. A system of ordinary differential equations was used to calculate protein turnover rates. Using this approach, 273 proteins were identified, and turnover rates were quantified for 157 plasma proteins with half-lives ranging 0.3-103 days. For the ~70 most abundant proteins, variability in turnover rates among rats was low (median coefficient of variation: 0.09). Activity-based protein profiling was applied to pooled plasma samples to enrich serine hydrolases using a fluorophosphonate (FP2) activity based probe. This enrichment resulted in turnover rates for an additional 17 proteins. This study is the first to measure global plasma protein turnover rates in rats in vivo, measure variability of protein turnover rates in any animal model, and utilize activity-based protein profiling for enhancing turnover measurements of targeted, low-abundant proteins, such as those commonly used as biomarkers. Measured protein turnover rates will be important for understanding of the role of protein turnover in cellular and organism health as well as increasing the utility of protein biomarkers through better understanding of processes governing biomarker kinetics. PMID- 29164874 TI - Combined Reflectometric Interference Spectroscopy and Quartz Crystal Microbalance Detect Differential Adsorption of Lipid Vesicles with Different Phase Transition Temperatures on SiO2, TiO2, and Au Surfaces. AB - Quantitative analysis of biomolecular adsorption on a substrate is crucial for understanding biomolecular interactions. A quartz crystal microbalance (QCM) is a highly sensitive device to detect such interactions based on mass. However, the physicochemical analysis by the QCM alone often leads to overestimation of the actual adsorbed mass. Here, a combined reflectometric interference spectroscopy (RIfS) and QCM is developed to simultaneously analyze adsorption of biomolecules. RIfS detects the adsorbed mass based on the reflectance and predicts the adsorbed condition by modeling the reflection spectra using the transfer matrix method. In contrast, the QCM detects physicochemical characteristics of the adsorbed molecules along with the adsorbed mass. The combined RIfS-QCM successfully detected the adsorption of proteins with different surface properties and lipid vesicles with different phase transition temperatures. The initial stage of adsorption revealed distinct individual properties of the adsorbates. Moreover, the RIfS-QCM revealed differential adsorption of the vesicles on silicon dioxide, titania, and gold surfaces, and the differences in adsorption were further interrogated by atomic force microscopy. The results demonstrate that the RIfS QCM serves as a useful tool to quantitatively analyze molecular adsorption on various surfaces. PMID- 29164875 TI - Insights into the Mechanism of Action of the Two-Peptide Lantibiotic Lacticin 3147. AB - Lacticin 3147 is a two peptide lantibiotc (LtnA1 and LtnA2) that displays nanomolar activity against many Gram-positive bacteria. Lacticin 3147 may exert its antimicrobial effect by several mechanisms. Isothermal titration calorimetry experiments show that only LtnA1 binds to the peptidoglycan precursor lipid II, which could inhibit peptidoglycan biosynthesis. An experimentally supported model of the resulting complex suggests that the key binding partners are the C terminus of LtnA1 and pyrophosphate of lipid II. A combination of in vivo and in vitro assays indicates that LtnA1 and LtnA2 can induce rapid membrane lysis without the need for lipid II binding. However, the presence of lipid II substantially increases the activity of lacticin 3147. Furthermore, studies with synthetic LtnA2 analogues containing either desmethyl- or oxa-lanthionine rings confirm that the precise geometry of these rings is essential for this synergistic activity. PMID- 29164876 TI - Live Cell Imaging of Endogenous RNAs Using Pumilio Homology Domain Mutants: Principles and Applications. AB - Recently, dynamic changes in the location of RNA in space and time in living cells have become a target of interest in biology because of their essential roles in controlling physiological phenomena. To visualize RNA, methods for the fluorescent labeling of RNA in living cells have been developed. For RNA labeling, oligonucleotide-based RNA probes have mainly been used because of their high selectivity for target RNAs. By contrast, protein-based RNA probes have not been used widely because of their lack of design flexibility, although they have various potential advantages compared with nucleotide-based probes, such as controllability of intracellular localization, high detectability, and ease of introduction into cells and transgenic organisms in a cell type and tissue specific manner by genetic engineering techniques. This Perspective focuses on a possible approach to the development of protein-based RNA probes using Pumilio homology domain (PUM-HD) mutants. The PUM-HD is a domain of an RNA binding protein that allows custom-made modifications to recognize a given eight-base RNA sequence. PUM-HD-based RNA probes have been applied to visualize various RNAs in living cells. Here, the techniques and RNA imaging results obtained using the PUM HD are introduced. PMID- 29164877 TI - Correction to The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold. PMID- 29164878 TI - Thermal Hetero-Diels-Alder Reaction of Benzocyclobutenones with Isatins To Form 2 Oxindole Spirolactones. AB - Benzocyclobutenones 1a-1g undergo cycloreversion at 150 degrees C in m-xylene solvent to form transient alpha-oxo-ortho-quinodimethanes or "ortho-quinoid ketene methides", which engage in intermolecular [4+2] cycloadditions with isatins 2a-2f to form 2-oxindole spirolactones 3a-3l. This process tolerates an array of different functional groups and substitution patterns, and is applicable to unprotected isatins 2b-2f bearing free NH-functionalities. The superior performance of isatins compared to other carbonyl based dienophiles was demonstrated and rationalized with the aid of quantum chemical calculations. PMID- 29164879 TI - Efficient Singlet Fission and Triplet-Pair Emission in a Family of Zethrene Diradicaloids. AB - Singlet fission offers the potential to overcome thermodynamic limits in solar cells by converting the energy of a single absorbed photon into two distinct triplet excitons. However, progress is limited by the small family of suitable materials, and new chromophore design principles are needed. Here, we experimentally vindicate the design concept of diradical stabilization in a tunable family of functionalized zethrenes. All molecules in the series exhibit rapid formation of a bound, spin-entangled triplet-pair state TT. It can be dissociated by thermally activated triplet hopping and exhibits surprisingly strong emission for an optically "dark" state, further enhanced with increasing diradical character. We find that the TT excited-state absorption spectral shape correlates with the binding energy between constituent triplets, providing a new tool to understand this unusual state. Our results reveal a versatile new family of tunable materials with excellent optical and photochemical properties for exploitation in singlet fission devices. PMID- 29164880 TI - Total Synthesis of (+)-Medicarpin. AB - (+)-Medicarpin has been synthesized asymmetrically for the first time in a linear scalable process with an overall yield of 11%. The two chiral centers were constructed in one step via condensation using a chiral oxazolidinone auxiliary. This method will likely accelerate research on medicarpin as an erythropoietin inducer for erythropoietin-deficient diseases. PMID- 29164881 TI - Monitoring Local Strain Vector in Atomic-Layered MoSe2 by Second-Harmonic Generation. AB - Strain serves as a powerful freedom to effectively, reversibly, and continuously engineer the physical and chemical properties of two-dimensional (2D) materials, such as bandgap, phase diagram, and reaction activity. Although there is a high demand for full characterization of the strain vector at local points, it is still very challenging to measure the local strain amplitude and its direction. Here, we report a novel approach to monitor the local strain vector in 2D molybdenum diselenide (MoSe2) by polarization-dependent optical second-harmonic generation (SHG). The strain amplitude can be evaluated from the SHG intensity in a sensitive way (-49% relative change per 1% strain); while the strain direction can be directly indicated by the evolution of polarization-dependent SHG pattern. In addition, we employ this technique to investigate the interlayer locking effect in 2H MoSe2 bilayers when the bottom layer is under stretching but the top layer is free. Our observation, combined with ab initio calculations, demonstrates that the noncovalent interlayer interaction in 2H MoSe2 bilayers is strong enough to transfer the strain of at least 1.4% between the bottom and top layers to prevent interlayer sliding. Our results establish that SHG is an effective approach for in situ, sensitive, and noninvasive measurement of local strain vector in noncentrosymmetric 2D materials. PMID- 29164882 TI - Synthesis, Anion Recognition, and Transmembrane Anionophoric Activity of Tripodal Diaminocholoyl Conjugates. AB - In this paper, we present the synthesis, anion recognition, and anionophoric activity of 1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene-based tripodal 3alpha hydroxy-7alpha,12alpha-diamino-5beta-cholan-24-oate conjugate 1 and the corresponding tris(2-aminoethyl)amine-based analogue 2 and choloyl analogue 3. Their affinity toward anions was evaluated by means of competitive displacement assay using 5-carboxyfluorescein (5-FAM) as a fluorescent indicator. The results indicate compounds 1 and 2 exhibit strong recognition toward a wide range of biologically important anions, in particular, toward sulfate and phosphate anions. In MeOH-HEPES (4/1, pH 7), the binding constants of compounds 1 and 2 are 416- and 168-fold higher for sulfate than for chloride and 35- and 25-fold higher for phosphate than for chloride, respectively. The anion transport activity was measured by use of pH discharge assay and chloride-ion-selective electrode technique. The results indicate that compounds 1 and 2 function as effective anion-selective transporters in the order of ClO4- > I- > NO3- > Br- > Cl- > SO42 > H2PO4- and exhibit anionophoric activity via a process of major anion exchange and minor anion/cation symport. In addition, some insights into the correlation of the anion binding affinity with the transport efficiency are also briefly discussed. PMID- 29164884 TI - Construction of Sulfonyl Oxabenzo[3.3.1]bicyclic Core via Cyclocondensation of beta-Ketosulfones and o-Formyl Allylbenzenes. AB - NH4OAc mediated domino Knoevenagel/Diels-Alder cyclocondensation of beta ketosulfones 1 and o-formyl allylbenzenes 2 provides sulfonyl oxabenzo[3.3.1]bicyclic core 4 in a cosolvent of toluene and HOAc (v/v = 1/1) at reflux for 3 h. The intermediate 3 contains a chalcone motif. The uses of various ammonium salts and solvent systems are investigated for facile and efficient transformation. The plausible mechanisms have been proposed and the DFT calculations have been included. PMID- 29164883 TI - Raspberry Ketone Reduced Lipid Accumulation in 3T3-L1 Cells and Ovariectomy Induced Obesity in Wistar Rats by Regulating Autophagy Mechanisms. AB - This study aimed to determine the antiobesity effects of raspberry ketone (RK), one of the major aromatic compounds contained in raspberry, and its underlying mechanisms. During adipogenesis of 3T3-L1 cells, RK (300 MUM) significantly reduced lipid accumulation and downregulated the expression of CCAAT/enhancer binding protein alpha (C/EBPalpha), peroxisome proliferation-activated receptor gamma (PPARgamma), fatty acid-binding protein 4 (FABP4), and fatty acid synthase (FAS). RK also reduced the expression of light chain 3B (LC3B), autophagy-related protein 12 (Atg12), sirtuin 1 (SIRT1), and phosphorylated-tuberous sclerosis complex 2 (TSC2), whereas it increased the level of p62 and phosphorylated mammalian target of rapamycin (mTOR). Daily administration of RK decreased the body weight (ovariectomy [Ovx] + RK, 352.6 +/- 5 vs Ovx, 386 +/- 5.8 g; P < 0.05), fat mass (Ovx + RK, 3.2 +/- 0.05 vs Ovx, 5.0 +/- 0.4 g; P < 0.05), and fat cell size (Ovx + RK, 6.4 +/- 0.6 vs Ovx, 11.1 +/- 0.7 * 103 MUm2; P < 0.05) in Ovx-induced obesity in rats. The expression of PPARgamma, C/EBPalpha, FAS, and FABP4 was significantly reduced in the Ovx + RK group compared with that in the Ovx group. Similar patterns were observed in autophagy-related proteins and endoplasmic reticulum stress proteins. These results suggest that RK inhibited lipid accumulation by regulating autophagy in 3T3-L1 cells and Ovx-induced obese rats. PMID- 29164885 TI - Inducing Protein Degradation as a Therapeutic Strategy. PMID- 29164886 TI - Stimuli-Responsive Supramolecular Assemblies between Twisted Cucurbit[14]uril and Hemicyanine Dyes and Their Analysis Application. AB - Two supramolecular assemblies between twisted cucurbit[14]uril and hemicyanine dyes have been successfully constructed on the basis of host-guest recognition. These supramolecular assemblies could be reversibly switched under acidic and neutral conditions. Furthermore, they responded to selected chemical stimuli such as methyl violet, thereby exhibiting potential analysis application. PMID- 29164887 TI - Pterostilbene Enhances TRAIL-Induced Apoptosis through the Induction of Death Receptors and Downregulation of Cell Survival Proteins in TRAIL-Resistance Triple Negative Breast Cancer Cells. AB - Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is nontoxic to normal cells and preferentially cytotoxic to cancer cells. Recent data suggest that malignant breast cancer cells often become resistant to TRAIL. Pterostilbene (PTER), a naturally occurring analogue of resveratrol found in blueberries, is known to induce cancer cells to undergo apoptosis. In the present study, we examined whether PTER affects TRAIL-induced apoptosis and its mechanism in TRAIL resistant triple negative breast cancer (TNBC) cells. Our data indicated that PTER induced apoptosis (14.68 +/- 3.78% for 40 MUM PTER vs 1.98 +/- 0.25% for control, p < 0.01) in TNBC cells and enhanced TRAIL-induced apoptosis in TRAIL resistant TNBC cells (18.45 +/- 4.65% for 40 MUM PTER vs 29.38 +/- 6.35% for combination of 40 MUM PTER and 100 ng/mL TRAIL, p < 0.01). We demonstrated that PTER induced death receptors DR5 and DR4 as well as decreased decoy receptor DcR 1 and DcR-2 expression. PTER also decreased the antiapoptotic proteins c-FLIPS/L, Bcl-Xl, Bcl-2, survivin, and XIAP. PTER induced the cleavage of bid protein and caused proapoptotic Bax accumulation. Moreover, we found that PTER induced the expression of DR4 and DR5 through the reactive oxygen species (ROS)/ endoplasmic reticulum (ER) stress/ERK 1/2 and p38/C/EBP-homologous protein (CHOP) signaling pathways. Overall, our results showed that PTER potentiated TRAIL-induced apoptosis via ROS-mediated CHOP activation leading to the expression of DR4 and DR5. PMID- 29164888 TI - Long-Lived Domain Wall Plasmons in Gapped Bilayer Graphene. AB - Topological domain walls in dual-gated gapped bilayer graphene host edge states that are gate-tunable and valley polarized. Here we predict that plasmonic collective modes can propagate along these topological domain walls even at zero bulk density and possess a markedly different character from that of bulk plasmons. Strikingly, domain wall plasmons are extremely long-lived with plasmon lifetimes that can be orders of magnitude larger than the transport scattering time in the bulk at low temperatures. Importantly, long domain wall plasmon lifetimes persist even at room temperature with values up to a few picoseconds. Domain wall plasmons possess a rich phenomenology including plasmon oscillation over a wide range of frequencies (up to the mid-infrared), tunable subwavelength electromagnetic confinement lengths, as well as a valley polarization for forward/backward propagating modes. Its unusual features render them as a new tool for realizing low-dissipation plasmonics that transcend the restrictions of the bulk. PMID- 29164890 TI - Divergent Access to Functionalized Pyrrolidines and Pyrrolines via Iridium Catalyzed Domino-Ring-Opening Cyclization of Vinyl Aziridines with beta Ketocarbonyls. AB - A useful synthesis of five-membered N-heterocycles has been developed through an iridium-catalyzed domino-ring-opening cyclization of vinylaziridines with beta ketocarbonyls. alpha-Substituted 1,3-dicarbonyls reacted with vinylaziridines to give 2-methylenepyrrolidines bearing two adjacent sp3-carbon centers with moderate to excellent diastereoselectivity, while the reaction of alpha unsubstituted 1,3-dicarbonyls afforded 2-pyrrolines in good yield. PMID- 29164891 TI - Unexpected Solubility Enhancement of Drug Bases in the Presence of a Dimethylaminoethyl Methacrylate Copolymer. AB - The methacrylate copolymer Eudragit EPO (EPO) has previously shown to greatly enhance solubilization of acidic drugs via ionic interactions and by multiple hydrophobic contacts with polymeric side chains. The latter type of interaction could also play a role for solubilization of other compounds than acids. The aim of this study was therefore to investigate the solubility of six poorly soluble bases in presence and absence of EPO by quantitative ultrapressure liquid chromatography with concomitant X-ray powder diffraction analysis of the solid state. For a better mechanistic understanding, spectra and diffusion data were obtained by 1H nuclear magnetic resonance (NMR) spectroscopy. Unexpected high solubility enhancement (up to 360-fold) was evidenced in the presence of EPO despite the fact that bases and polymer were both carrying positive charges. This exceptional and unexpected solubilization was not due to a change in the crystalline solid state. NMR spectra and measured diffusion coefficients indicated both strong drug-polymer interactions in the bulk solution, and diffusion data suggested conformational changes of the polymer in solution. Such conformational changes may have increased the accessibility and extent of hydrophobic contacts thereby leading to increased overall molecular interactions. These initially surprising solubilization results demonstrate that excipient selection should not be based solely on simple considerations of, for example, opposite charges of drug and excipient, but it requires a more refined molecular view. Different solution NMR techniques are especially promising tools to gain such mechanistic insights. PMID- 29164889 TI - Comparison of Quantitative Mass Spectrometry Platforms for Monitoring Kinase ATP Probe Uptake in Lung Cancer. AB - Recent developments in instrumentation and bioinformatics have led to new quantitative mass spectrometry platforms including LC-MS/MS with data-independent acquisition (DIA) and targeted analysis using parallel reaction monitoring mass spectrometry (LC-PRM), which provide alternatives to well-established methods, such as LC-MS/MS with data-dependent acquisition (DDA) and targeted analysis using multiple reaction monitoring mass spectrometry (LC-MRM). These tools have been used to identify signaling perturbations in lung cancers and other malignancies, supporting the development of effective kinase inhibitors and, more recently, providing insights into therapeutic resistance mechanisms and drug repurposing opportunities. However, detection of kinases in biological matrices can be challenging; therefore, activity-based protein profiling enrichment of ATP utilizing proteins was selected as a test case for exploring the limits of detection of low-abundance analytes in complex biological samples. To examine the impact of different MS acquisition platforms, quantification of kinase ATP uptake following kinase inhibitor treatment was analyzed by four different methods: LC MS/MS with DDA and DIA, LC-MRM, and LC-PRM. For discovery data sets, DIA increased the number of identified kinases by 21% and reduced missingness when compared with DDA. In this context, MRM and PRM were most effective at identifying global kinome responses to inhibitor treatment, highlighting the value of a priori target identification and manual evaluation of quantitative proteomics data sets. We compare results for a selected set of desthiobiotinylated peptides from PRM, MRM, and DIA and identify considerations for selecting a quantification method and postprocessing steps that should be used for each data acquisition strategy. PMID- 29164892 TI - Highly Diastereo- and Enantioselective Palladium-Catalyzed [3 + 2] Cycloaddition of Vinyl Epoxides and alpha,beta-Unsaturated Ketones. AB - An asymmetric [3 + 2] cycloaddition reaction of vinyl epoxides with alpha,beta unsaturated ketones, the single activated electron-deficient alkenes, has been achieved under Pd-catalysis in excellent diastereo- and enantioselectivity. The utilities of the protocol are demonstrated by transformation of the products into other useful chiral molecules. Density functional theory calculations rationalize the stereocontrol of the reaction. PMID- 29164893 TI - Highly Enantioselective Synthesis of Chiral Cyclopropyl Nucleosides via Catalytic Asymmetric Intermolecular Cyclopropanation. AB - An efficient route to construct chiral cyclopropyl purine nucleoside analogues has been established via the catalytic asymmetric Michael-initiated ring-closure reactions of alpha-purine acrylates with alpha-bromo-carboxylic esters. Using (DHQD)2AQN as the catalyst, various chiral cyclopropyl purine nucleoside analogues with a chiral quaternary stereocenter were obtained in 72-98% yields, excellent diastereoselectivities, and 93-97% ee. Through simple functional group transformations, diverse chiral cyclopropyl purine nucleosides with hydroxymethyl group or carboxyl group were obtained. PMID- 29164894 TI - Phenanthrene Synthesis via Chromium-Catalyzed Annulation of 2-Biaryl Grignard Reagents and Alkynes. AB - A chromium/2,2'-bipyridine-catalyzed annulation reaction of 2-biarylmagnesium reagents with alkynes is reported. The reaction is applicable to a variety of aryl- and/or alkyl-substituted internal alkynes as well as 2-biaryl and related Grignard reagents, thus affording phenanthrene derivatives in moderate to good yields. The reaction proceeds at the expense of excess alkyne as a hydrogen acceptor and thus does not need an external oxidant. Deuterium-labeling experiments shed light on the reaction mechanism, which likely involves multiple intramolecular C-H activation processes on chromium. PMID- 29164895 TI - Interlayer Coupling and Gate-Tunable Excitons in Transition Metal Dichalcogenide Heterostructures. AB - Bilayer van der Waals (vdW) heterostructures such as MoS2/WS2 and MoSe2/WSe2 have attracted much attention recently, particularly because of their type II band alignments and the formation of interlayer exciton as the lowest-energy excitonic state. In this work, we calculate the electronic and optical properties of such heterostructures with the first-principles GW+Bethe-Salpeter Equation (BSE) method and reveal the important role of interlayer coupling in deciding the excited-state properties, including the band alignment and excitonic properties. Our calculation shows that due to the interlayer coupling, the low energy excitons can be widely tuned by a vertical gate field. In particular, the dipole oscillator strength and radiative lifetime of the lowest energy exciton in these bilayer heterostructures is varied by over an order of magnitude within a practical external gate field. We also build a simple model that captures the essential physics behind this tunability and allows the extension of the ab initio results to a large range of electric fields. Our work clarifies the physical picture of interlayer excitons in bilayer vdW heterostructures and predicts a wide range of gate-tunable excited-state properties of 2D optoelectronic devices. PMID- 29164896 TI - Nuclear Magnetic Shielding of Monoboranes: Calculation and Assessment of 11B NMR Chemical Shifts in Planar BX3 and in Tetrahedral [BX4]- Systems. AB - 11B NMR chemical shifts of tricoordinated BX3 and tetracoordinated BX4- compounds (X = H, CH3, F, Cl, Br, I, OH, SH, NH2, and CH?CH2) were computed, and the shielding tensors were explored not only within the nonrelativistic GIAO approach but also by application of both relativistic ZORA computations including spin orbit coupling as well as scalar nonrelativistic ZORA computations (BP86 level of density functional theory). The contributions of the spin-orbit coupling to the overall shieldings are decisive for X = Br and I in both series. No relationship was found between the 2p orbital occupancies or 1/DeltaE (difference between LUMO and suitably occupied MO that can be coupled with LUMO) with the shielding tensors (or their principal values) in the BX3 series. However, a multidimensional statistical approach known as factor analysis (frequently used in chemometrics) revealed that three factors account for 92% of the cumulative proportion of total variance. The main components of the first factor are occupancies in the 2px and 2py orbitals and 1/DeltaE; the second factor is mainly the occupancy in the 2pz orbital and the inductive substituent parameters by Taft. Finally, the third factor consists exclusively (98.4%) of the electrostatic potential (Vmax), which is directly related to the so-called pi-hole magnitudes. PMID- 29164897 TI - Highly Enantioselective Asymmetric Hydrogenation of Carboxy-Directed alpha,alpha Disubstituted Terminal Olefins via the Ion Pair Noncovalent Interaction. AB - The t-Bu-Wudaphos was successfully applied into Rh-catalyzed asymmetric hydrogenation of alpha,alpha-disubstituted terminal olefins bearing a carboxy directed group with excellent reactivities and enantioselectivities via the ion pair noncovalent interaction (up to >99% conversion, 98% yield, 98% ee) under mild reaction conditions without base. In addition, control experiments were conducted, and the results demonstrated that the ion pair noncovalent interaction between ligand and substrate played an important role in achieving an outstanding performance in this asymmetric hydrogenation. PMID- 29164899 TI - From Physical Mixtures to Co-Crystals: How the Coformers Can Modify Solubility and Biological Activity of Carbamazepine. AB - A combined experimental and computational study on the solubility and biological activity of carbamazepine (CBZ), three co-crystals (COCs), and their parent physical mixtures (MIXs) is carried out to shed light onto the possible modulation of the drug properties. Two of the considered co-crystals, CBZ with vanillic acid (VAN) and CBZ with 4-nitropyridine N-oxide (NPO), are newly synthesized, while the third, CBZ with succinic acid (SUC), is already known. While COC CBZ-VAN and MIX CBZ-NPO did not alter the CBZ dissolution profile, MIX CBZ-SUC and COCs CBZ-SUC and CBZ-NPO inhibit straightaway its solubility. On the other hand, MIX CBZ-VAN induced a remarkable increase of the drug solubility. Analogously, different CBZ permeability values were registered following its dissolution from MIXs and COCs: CBZ and MIXs CBZ-SUC and CBZ-VAN slightly reduce the integrity of intestinal cell monolayers, whereas MIX CBZ-NPO and COCs CBZ SUC, CBZ-VAN, and CBZ-NPO maintain the monolayer integrity. The molecular aggregates formed in solution were found to be the key to interpret these different behaviors, opening new possibilities in the pharmaceutical utilization and definition of drug co-crystals. PMID- 29164900 TI - Theory of Transient Excited State Absorptions in Pentacene and Derivatives: Triplet-Triplet Biexciton versus Free Triplets. AB - Recent experiments in several singlet-fission materials have found that the triplet-triplet biexciton either is the primary product of photoexcitation or has a much longer lifetime than believed until now. It thus becomes essential to determine the difference in the spectroscopic signatures of the bound triplet triplet and free triplets to distinguish between them optically. We report calculations of excited state absorptions (ESAs) from the singlet and triplet excitons and from the triplet-triplet biexciton for a pentacene crystal with the herringbone structure and for nanocrystals of bis(triisopropylsilylethynyl) (TIPS)-pentacene. The triplet-triplet biexciton absorbs in both the visible and the near-infrared (NIR), while the monomer free triplet absorbs only in the visible. The intensity of the NIR absorption depends on the extent of intermolecular coupling, in agreement with observations in TIPS-pentacene nanocrystals. We predict additional weak ESA from the triplet-triplet but not from the triplet, at still lower energy. PMID- 29164901 TI - Co-Amorphous Formation of High-Dose Zwitterionic Compounds with Amino Acids To Improve Solubility and Enable Parenteral Delivery. AB - Solubilization of parenteral drugs is a high unmet need in both preclinical and clinical drug development. Recently, co-amorphous drug formulation has emerged as a new strategy to solubilize orally dosed drugs. The aim of the present study is to explore the feasibility of using the co-amorphous strategy to enable the dosing of parenteral zwitterionic drugs at a high concentration. A new screening procedure was established with solubility as the indicator for co-amorphous co former selection, and lyophilization was established as the method for co amorphous formulation preparation. Various amino acids were screened, and tryptophan was found to be the most powerful in improving the solubility of ofloxacin when lyophilized with ofloxacin at a 1:1 weight ratio, with more than 10 times solubility increase. X-ray powder diffraction showed complete amorphization of both components, and an elevated Tg compared with the theoretical value was observed in differential scanning calorimetry. Fourier transform infrared spectroscopy revealed that hydrogen bonding and pi-pi stacking were possibly involved in the formation of a co-amorphous system in the solid state. Further solution-state characterization revealed the involvement of ionic interactions and pi-pi stacking in maintaining a high concentration of ofloxacin in solution. Furthermore, co-amorphous ofloxacin/tryptophan at 1:1 weight ratio was both physically and chemically stable for at least 2 months at 40 degrees C/75% RH. Lastly, the same screening procedure was validated with two more zwitterionic compounds, showing its promise as a routine screening methodology to solubilize and enable the parenteral delivery of zwitterionic compounds. PMID- 29164898 TI - Ionic Solution: What Goes Right and Wrong with Continuum Solvation Modeling. AB - Solvent-mediated electrostatic interactions were well recognized to be important in the structure and function of molecular systems. Ionic interaction is an important component in electrostatic interactions, especially in highly charged molecules, such as nucleic acids. Here, we focus on the quality of the widely used Poisson-Boltzmann surface area (PBSA) continuum models in modeling ionic interactions by comparing with both explicit solvent simulations and the experiment. In this work, the molality-dependent chemical potentials for sodium chloride (NaCl) electrolyte were first simulated in the SPC/E explicit solvent. Our high-quality simulation agrees well with both the previous study and the experiment. Given the free-energy simulations in SPC/E as the benchmark, we used the same sets of snapshots collected in the SPC/E solvent model for PBSA free energy calculations in the hope to achieve the maximum consistency between the two solvent models. Our comparative analysis shows that the molality-dependent chemical potentials of NaCl were reproduced well with both linear PB and nonlinear PB methods, although nonlinear PB agrees better with SPC/E and the experiment. Our free-energy simulations also show that the presence of salt increases the hydrophobic effect in a nonlinear fashion, in qualitative agreement with previous theoretical studies of Onsager and Samaras. However, the lack of molality-dependency in the nonelectrostatics continuum models dramatically reduces the overall quality of PBSA methods in modeling salt-dependent energetics. These analyses point to further improvements needed for more robust modeling of solvent-mediated interactions by the continuum solvation frameworks. PMID- 29164902 TI - Secondary prevention programme of ischaemic heart disease in the elderly: A randomised clinical trial. AB - Background Elderly patients have been underrepresented in secondary cardiovascular prevention programmes. This study aimed to ascertain the effects of a secondary coronary disease prevention programme in these patients. Design Open randomised intervention study with parallel groups. Methods One hundred and twenty-seven patients aged >=70 years with a recent acute coronary syndrome were randomised to a protocolised clinical intervention plus usual care (intervention group, n = 64) or to usual care alone (control group, n = 63). Patients were assessed at baseline and after 12 months. The main outcome was the percentage of patients with optimal risk factor control after 12 months of follow-up. Secondary outcomes included changes in Mediterranean diet adherence, quality of life and functionality. Mortality was evaluated three years after the end of the intervention. Results One hundred and six patients (83.4%) completed 12 months of follow-up (54 in the intervention group and 52 in the control group). At the end of intervention, 34.2% more patients in the intervention group had achieved optimal risk factor control with a number needed to treat of 3 (relative risk 2.18, 95% confidence interval 1.36 to 3.50). The intervention group improved adherence to the Mediterranean diet ( p = 0.013) and functionality assessed by the Short Physical Performance Battery ( p = 0.047). No differences between groups were found in quality of life (Short-Form 36 Health Survey) or mortality after three years (hazard ratio 1.19, 95% confidence interval 0.41 to 3.45). Conclusions A secondary coronary disease prevention programme in elderly patients with a recent acute coronary syndrome improved risk factor control, Mediterranean diet adherence and functionality. PMID- 29164903 TI - Do mental disorders moderate the association between diabetes status and alcohol consumption? AB - Although heavy alcohol consumption is associated with diabetes-related complications, little is known about patterns of alcohol use among people with diabetes. Moreover, heavy drinking is more common among individuals with major depressive disorder (MDD), bipolar disorder (BD), and generalized anxiety disorder (GAD) than in the general population, and these disorders are often comorbid with diabetes. The present study tested the hypothesis that mental disorders moderate the association between diabetes status and alcohol consumption. A total of 14,302 adult participants aged 40-79 were included from the cross-sectional 2012 Canadian Community Health Survey-Mental Health (1,698 with diabetes). Data were analyzed using hierarchical linear regression models. MDD and BD, but not GAD, significantly moderated the association between diabetes status and alcohol quantity, such that the presence of diabetes was strongly and negatively associated with alcohol quantity if individuals had MDD or BD. There was no interaction between diabetes status and any of the mental disorders and alcohol frequency. This study suggests that among individuals with diabetes, those with comorbid MDD or BD drink less than those without MDD or BD. Further investigation of this association is needed and could help inform future alcohol related interventions among individuals with diabetes. PMID- 29164904 TI - System Validation Experiments for Obtaining Tracer Laser-Induced Fluorescence Data at Elevated Pressure and Temperature. AB - This paper presents a set of system validation experiments that can be used to qualify either static or flow experimental systems for gathering tracer photophysical data or conducting laser diagnostics at high pressure and temperature in order to establish design and operation limits and reduce uncertainty in data interpretation. Tests demonstrated here quantify the effect of tracer absorption at the test cell walls, stratification, photolysis, pyrolysis, adequacy of mixing and seeding, and reabsorption of laser light using acetone as the tracer and 282 nm excitation. Results show that acetone exhibits a 10% decrease in fluorescence signal over 36 000 shots at 127.4 mJ/cm2, and photolysis is negligible below 1000 shots collected. Meanwhile, appropriately chosen gas residence times can mitigate risks due to pyrolysis and inadequate mixing and seeding; for the current work 100 ms residence time ensured <0.5% alteration of tracer number density due to thermal destruction. Experimental results here are compared to theoretical values from the literature. PMID- 29164905 TI - Correction to: Guzmen-Carmeli and Sharabi, Textual healing: tailor-made kabbalistic therapeutics in Jerusalem. PMID- 29164906 TI - Influence of hope, social support, and self-esteem in early stage dementia. AB - Background People in the early stages of dementia adjust to the illness through stages of awareness, coping, and evaluation. Studies have found that hope, social support, and self-esteem facilitate coping, adjustment, and adaptation in chronic illness. Objective The purpose of this descriptive study was to examine the relationships between hope, social support, and self-esteem in individuals with early stage dementia. Methods Data were obtained from 53 individuals with early stage dementia. The scores on the Herth Hope Index, Social Support Questionnaire Short-Form, and the State Self-Esteem Scale were analyzed using linear regression. Results Hope was moderately associated with self-esteem ( r = .49, p < .001). Hope accounted for 25% of the variance in self-esteem and was a key component in predicting self-esteem. No significant relationship was found between social support and self-esteem. Conclusion Findings suggest that hope may be an important factor to help individuals manage potential threats to self esteem in the experience of early stage dementia. Strategies to inspire hope and then enhance self-esteem are promising for individuals living with early stage dementia. PMID- 29164907 TI - Optimisation of dementia care in care homes: Dementia care framework (innovative practice). AB - There are an increasing number of people living with dementia in care home settings. Recent reports suggest that people who deliver care to residents living with dementia in care homes require specialist support to provide optimum care. To address this need Four Seasons Health Care, the largest provider of care homes within the UK today, sought to design a dementia care framework that enhanced the quality of life for people living with dementia in their care homes. The framework was designed using a robust evidence base, engagement with people living with dementia, their care partners, policy-writers, multidisciplinary professionals and people within the organisation. This paper describes the methodology behind the dementia care framework and outcomes data from the first phase (of 20 care homes that included the care of 451 people living with dementia). The main outcome was a significant improvement in the quality of the lives of residents across biological, psychological, social and spiritual needs. PMID- 29164908 TI - Corrigendum to Outpatient low density lipoprotein control - who does it better? PMID- 29164909 TI - Analysis of breathing via optoelectronic systems: comparison of four methods for computing breathing volumes and thoraco-abdominal motion pattern. AB - Breathing parameters can be measured by motion capture systems by placing photo reflective markers on the chest wall. A computational model is mandatory to compute the breathing volume and to calculate temporal and kinematical features by the gathered markers trajectories. Despite different methods based on different geometrical approaches can be adopted to compute volumes, no information about their differences in the respiratory evaluation are available. This study investigated the performances of four methods (conventional, prism based, convex hull with boundary condition, based on Delaunay triangulation) using an optoelectronic motion capture system, on twelve healthy participants during 30 s of breathing. Temporal trends of volume traces, tidal volume values, and breathing durations were compared between methods and spirometry (used as reference instrument). Additionally, thoraco-abdominal motion patterns were compared between methods by analysing the compartmental contributions and their variability. Results shows comparable similarities between the volume traces obtained using spirometry, prism-based and conventional methods. Prism-based and convex hull with boundary condition methods show lower bias in tidal volumes estimation up to 0.06 L, compared to the conventional and Delaunay triangulation methods. Prism-based method shows maximum differences of 30 mL in the comparison of compartmental contributions to the total volume, by resulting in a maximum deviation of 1.6% in the percentage contribution analysis. In conclusion, our finding demonstrated the accuracy of the non-invasive MoCap-based breathing analysis with the prism-based method tested. Data provided in this study will lead researchers and clinicians in the computational method choice for temporal and volumetric breathing analysis. PMID- 29164910 TI - Body fat and metabolic age as indicators of inflammation and cardiovascular risk. PMID- 29164913 TI - Monitoring physical activity after a cardiovascular event: What is 'fit' for purpose? PMID- 29164912 TI - A Community-Based Approach to Assessing the Physical, Emotional, and Health Status of Hispanic Breast Cancer Survivors. AB - INTRODUCTION: Latina breast cancer survivors in the United States face disproportionate risk for poorer quality of life and physical health, as well as greater emotional distress. METHOD: A cross-sectional survey was conducted to describe the physical, emotional, and general health status of 135 Latina breast cancer survivors served by a community-based program. RESULTS: Of the 135 surveys sent, 48 survivors responded. Of those who responded, time since diagnosis ranged from 0 to 24 years ( M = 4.37; SD = 5.54); and 45.9% of the women rated physical health as poor or fair. Fatigue prevalence was high, with 60.5% reporting fatigue as moderate or severe. Nearly 80% reported having pain (score >0); 38.3% reported pain was moderate or severe. The women reported mild levels of anxiety and depression but high levels of stress ( M = 4.14; SD = 3.02). CONCLUSIONS: Latina breast cancer survivors could benefit from interventions focused on commonly shared problems while tailoring specific interventions for subsets with more severe symptoms. PMID- 29164915 TI - Establishment of a Bordetella avium challenge model in turkeys. AB - Despite the importance of Bordetella avium (BA) as a respiratory pathogen of young turkeys, no infection model for the evaluation of BA-vaccine efficacy is available. The objective of this study was to evaluate the influence of route and dose of infection on the establishment of a BA-challenge model. In our first experiment, 28-day-old turkeys were either inoculated oculonasally with 105, 107 or 109 colony forming units (CFU) of BA per bird or exposed to BA by aerosol with 105-108 CFU/m3. The respiratory tract of all inoculated birds was BA-colonized, which was confirmed by choanal swabs and samples of trachea and lung, showing the highest prevalence in the aerosol-inoculated group. BA-specific humoral immune response was detected in the form of IgG in serum from five days post infection (dpi) and IgA in lacrimal fluid from seven dpi. In the second experiment, the model was tested in a vaccination trial. Twenty-one-day-old turkeys were vaccinated with a formalin-inactivated BA vaccine intramuscularly and challenged 21 days post vaccination with 107 CFU per bird oculonasally. BA-specific IgG antibodies were detected in serum and in lacrimal fluid 14 days post vaccination. As in the first experiment, secretory BA-specific antibodies of the IgA isotype were only detected in the inoculated groups from seven dpi. Despite the lack of clinical signs or pathological alterations in both experiments, vaccine efficacy was demonstrated by significant reduction in BA colonization of the trachea (P <= 0.05). In our study, a reliable model for BA infection has been established and has been demonstrated to be suitable for evaluation of vaccine efficacy. PMID- 29164916 TI - Age and gender differences in medical adherence after myocardial infarction: Women do not receive optimal treatment - The Netherlands claims database. AB - Background Following myocardial infarction, medication is, besides lifestyle interventions, the cornerstone treatment to improve survival and minimize the occurrence of new cardiovascular events. Still, data on nationwide medication adherence are scarce. This study assesses medical adherence during one year following myocardial infarction, stratifying per type of infarct, age and gender. Design Retrospective cohort study. Methods In The Netherlands, all inhabitants are by law obliged to have health insurance and all claims data are centrally registered. In 2012 and 2013, all national diagnosis-codings of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) were acquired. Furthermore, information on retrieved medication was extracted from the Dutch Pharmacy Information System. Twelve months after discharge, the retrieved medication at the pharmacy of each pharmacological therapy (aspirin-species, P2Y12-inhibitor, statin, beta-blocker, angiotensin-converting enzyme-/angiotensin 2-inhibitor, vitamin-K antagonists or novel oral anticoagulant) were analysed. Results In total, 59,534 patients (67 +/ 13 years, 39,545 (66%) male, 57% NSTEMI) were included, of whom 52,672 (88%) patients were analysed for one-year medical adherence. STEMI patients more often achieved optimal medical adherence than NSTEMI patients (60% vs. 40%, p <= 0.001). In both STEMI and NSTEMI, use of all five indicated drugs was higher in male patients compared with female (STEMI male 61% vs. female 57%, p <= 0.001; NSTEMI male 43% vs. female 37%, p <= 0.001. With increasing age, a gradual decrease was observed in the use of aspirin, P2Y12-inhibitors and statins. Conclusion Age and gender differences existed in medical adherence after myocardial infarction. Medical adherence was lower in women, young patients and elderly patients, specifically in NSTEMI patients. PMID- 29164917 TI - Efficacy and safety of palbociclib in heavily pretreated patients with HR+/HER2- metastatic breast cancer. AB - AIM: CDK4/6 inhibitors in the first and second treatment line in patients with HR+/HER2- metastatic breast cancer (mBC) in combination with hormonal therapy improve progression-free survival. Role of CDK4/6 inhibitors in further treatment lines remains unclear. METHODS: Retrospective analysis of 24 HR+/HER2- heavily pretreated mBC patients is presented. RESULTS: A total of 58.3% patients achieved stable disease. No objective response was observed. Median progression-free survival was 4.8 months; median overall survival was 11 months. Treatment was well tolerated. CONCLUSION: Favorable toxicity profile and efficacy of palbociclib/aromatase inhibitors combination in heavily pretreated luminal mBC patients in this study emphasize the need for further investigation of such drugs in this population. PMID- 29164920 TI - Cardiac structure and function predicts functional decline in the oldest old. AB - Background This study examined the association between cardiac structure and function and the deterioration in activities of daily living (ADLs) in an age homogenous, community-dwelling population of patients born in 1920-1921 over a five-year follow-up period. Design Longitudinal cohort study. Methods Patients were recruited from the Jerusalem Longitudinal Cohort Study, which has followed an age-homogenous cohort of Jerusalem residents born in 1920-1921. Patients underwent home echocardiography and were followed up for five years. Dependence was defined as needing assistance with one or more basic ADL. Standard echocardiographic assessment of cardiac structure and function, including systolic and diastolic function, was performed. Reassessment of ADLs was performed at the five-year follow-up. Results A total of 459 patients were included in the study. Of these, 362 (79%) showed a deterioration in at least one ADL at follow-up. Patients with functional deterioration had a significantly higher left ventricular mass index and left atrial volume with a lower ejection fraction. There was no significant difference between the diastolic parameters the groups in examined. When the data were examined categorically, a significantly larger percentage of patients with functional decline had an abnormal left ventricular ejection fraction and left ventricular hypertrophy. The association between left ventricular mass index and functional decline remained significant in all multivariate models. Conclusions In this cohort of the oldest old, an elevated left ventricular mass index, higher left atrial volumes and systolic, but not diastolic dysfunction, were predictive of functional disability. PMID- 29164921 TI - Gait speed is not magic, but is prognostically important in older patients. PMID- 29164922 TI - Health Care Access, Utilization, and Cancer Screening Among Low-Income Latina Women. AB - INTRODUCTION: Cancer screening reduces mortality rates for breast, cervical, and colon cancer. Yet cancer screening rates for Latina women are lower than for non Latino Whites, and below Healthy People 2020 goals. Additionally, Latinos face many health care access barriers. This study examined health care access and utilization in relation to cancer screening among low-income Latina women recruited from a high-risk area and enrolled in a navigation-plus-education intervention. METHODS: Latina women considered rarely or never screened for breast, cervical, or colorectal cancer were recruited from community-based organizations and events (N = 691). We gathered self-reported survey data on insurance status, usual source of care, health care utilization, and cancer screening behavior. We conducted multivariable logistic regression models to estimate odds ratios of receipt of at least one cancer screening test. RESULTS: Overall, 28% of women received at least one cancer screening test. Results indicated that women without insurance (odds ratio [OR] = 2.08; confidence interval [CI] = 1.09, 3.98) and without a doctor's visit in the past year (OR = 2.02; CI = 1.28, 3.18), compared with their counterparts, had greater odds of receiving at least one screening test. CONCLUSION: Findings highlight the continued need to explore ways to support uninsured individuals' screening efforts and further investigate barriers among insured women who are not up-to date with screenings. PMID- 29164923 TI - Impact of Traditional Versus Flavored Tongue Depressors on Pediatric Oropharynx Exam. AB - We compared patient-reported discomfort associated with oropharynx examination using traditional (unflavored) versus flavored tongue depressors among pediatric patients presenting to the emergency department in a single-blinded, placebo controlled randomized trial using a convenience sample ages 3 to 12 years. Our primary outcome was patient discomfort. Secondary outcomes included provider perceptions of patient discomfort, provider-reported examination ease, and caregiver perceptions of patient discomfort. Of 96 recruited patients, 92 (95.8%) completed the study. Forty-six (50%) were randomized to a traditional tongue depressor. Mean patient-reported oropharynx examination discomfort scores were 2.3 cm (95% confidence interval = 1.4-3.2 cm) with traditional tongue depressors versus 1.9 cm (95% confidence interval = 1.0-2.8 cm) with flavored tongue depressors ( P = .72). There were similarly no significant differences between the 2 arms with regard to any of the secondary outcomes. We conclude that the use of flavored tongue depressors does not appear to significantly alleviate discomfort associated with examination of the oropharynx in pediatric patients. PMID- 29164925 TI - Mid-Infrared Standoff Spectroscopy Using a Supercontinuum Laser with Compact Fabry-Perot Filter Spectrometers. AB - Mid-infrared (MIR) supercontinuum (SC) lasers are an attractive new option in the field of IR spectroscopy, especially for standoff detection. Supercontinuum radiation unites high brightness, high spatial coherence, and broadband spectral coverage, thereby surpassing thermal IR sources and challenging quantum cascade lasers. The employed SC source operates in the spectral region of 1.2-4.6 um, filling the spectral gap where quantum cascade lasers lack broader availability. In this work, the SC radiation was recorded by compact Fabry-Perot filter spectrometers ideally suited for sensitive standoff detection with real-time capability. The noise performance of the setup and measurements of different substances at standoff distances are presented, e.g., of different paints on a metal surface and an explosive precursor. Furthermore, the real-time capability of the setup is demonstrated by monitoring the evaporation of liquid 2-propanol. PMID- 29164924 TI - Towards enhanced PET quantification in clinical oncology. AB - Positron emission tomography (PET) has, since its inception, established itself as the imaging modality of choice for the in vivo quantitative assessment of molecular targets in a wide range of biochemical processes underlying tumour physiology. PET image quantification enables to ascertain a direct link between the time-varying activity concentration in organs/tissues and the fundamental parameters portraying the biological processes at the cellular level being assessed. However, the quantitative potential of PET may be affected by a number of factors related to physical effects, hardware and software system specifications, tracer kinetics, motion, scan protocol design and limitations in current image-derived PET metrics. Given the relatively large number of PET metrics reported in the literature, the selection of the best metric for fulfilling a specific task in a particular application is still a matter of debate. Quantitative PET has advanced elegantly during the last two decades and is now reaching the maturity required for clinical exploitation, particularly in oncology where it has the capability to open many avenues for clinical diagnosis, assessment of response to treatment and therapy planning. Therefore, the preservation and further enhancement of the quantitative features of PET imaging is crucial to ensure that the full clinical value of PET imaging modality is utilized in clinical oncology. Recent advancements in PET technology and methodology have paved the way for faster PET acquisitions of enhanced sensitivity to support the clinical translation of highly quantitative four dimensional (4D) parametric imaging methods in clinical oncology. In this report, we provide an overview of recent advances and future trends in quantitative PET imaging in the context of clinical oncology. The pros/cons of the various image derived PET metrics will be discussed and the promise of novel methodologies will be highlighted. PMID- 29164926 TI - Serum uric acid level predicts adverse outcomes after myocardial revascularization or cardiac valve surgery. AB - Background High levels of serum uric acid have been associated with adverse outcomes in cardiovascular diseases such as myocardial infarction and heart failure. The aim of the current study was to evaluate the prognostic role of serum uric acid levels in patients undergoing cardiac rehabilitation after myocardial revascularization and/or cardiac valve surgery. Design We performed an observational prospective cohort study. Methods The study included 1440 patients with available serum uric acid levels, prospectively followed for 50 +/- 17 months. Mean age was 67 +/- 11 years; 781 patients (54%) underwent myocardial revascularization, 474 (33%) cardiac valve surgery and 185 (13%) valve-plus coronary artery by-pass graft surgery. The primary endpoints were overall and cardiovascular mortality while secondary end-points were combined major adverse cardiac and cerebrovascular events. Results Serum uric acid level mean values were 286 +/- 95 umol/l and elevated serum uric acid levels (>=360 umol/l or 6 mg/dl) were found in 275 patients (19%). Overall mortality (hazard ratio = 2.1; 95% confidence interval: 1.5-3.0; p < 0.001), cardiovascular mortality (hazard ratio = 2.0; 95% confidence interval: 1.2-3.2; p = 0.004) and major adverse cardiac and cerebrovascular events rate (hazard ratio = 1.5; 95% confidence interval: 1.0-2.0; p = 0.019) were significantly higher in patients with elevated serum uric acid levels, even after adjustment for age, gender, arterial hypertension, diabetes, glomerular filtration rate, atrial fibrillation and medical therapy. Moreover, strong positive correlations between serum uric acid level and probability of overall mortality ( p < 0.001), cardiovascular mortality ( p < 0.001) and major adverse cardiac and cerebrovascular events ( p = 0.003) were found. Conclusions Serum uric acid levels predict mortality and adverse cardiovascular outcome in patients undergoing myocardial revascularization and/or cardiac valve surgery even after the adjustment for age, gender, arterial hypertension, diabetes, glomerular filtration rate and medical therapy. PMID- 29164927 TI - A Case of a Patient with Residual Symptoms of Schizophrenia who Relapsed Following Treatment with the Topical Corticosteroid, Clobetasol: A Review of its Risk of Systemic Absorption and Possibility of Exacerbating Psychosis. AB - Almost fifty percent of patients with schizophrenia experience some type of dermatitis. The standard treatment for dermatitis is a topical corticosteroid. Despite their demonstrated effectiveness, topical corticosteroids are associated with various side effects that may limit their use. These include generalized adverse effects from systemic absorption, such as suppression of the hypothalamic pituitary-adrenal axis. While dose-related, oral corticosteroid-induced psychiatric symptoms, such as psychosis, are well documented, the literature is devoid of cases of topical corticosteroids precipitating psychosis. We present a case of a patient with schizophrenia who developed morphea. She was liberally treated with the potent topical corticosteroid clobetasol, possibly resulting in a "supraphysiologic exposure." Subsequently, our patient developed an exacerbation of activephase symptoms of schizophrenia. After clobetasol administration was reduced, these active phase symptoms dissipated. PMID- 29164928 TI - Clozapine, Diabetes Mellitus, Cardiovascular Risk and Mortality: Results of a 21 year Naturalistic Study in Patients with Schizophrenia and Schizoaffective Disorder. AB - The goal of this 21-year naturalistic study of clozapine treated patients was to examine the cardiovascular risk factors following clozapine initiation and resultant mortality estimates from cardiovascular disease. Data was collected from medical records of clozapine treated patients with schizophrenia or schizoaffective disorder from January 1992 to February 2012. Demographics, clozapine dosage and laboratory results were extracted at 12-month intervals. At clozapine initiation, the mean age of 96 patients was 36.4 years +/-7.6 years; N=27(28%) were women. The mean duration of clozapine use was 13 years. The Kaplan Meier estimate for 21-year cardiovascular events was 29%, while the Kaplan-Meier estimate for 21-year mortality from cardiovascular disease was 10%. The mean cardiovascular risk increased during the first ten years (p<.01), while a slight decrease occurred beyond ten years (p<.01). Patients involved in cardiometabolic research showed a greater decrease in cardiovascular risk factors over 21 years (p = .05). The Kaplan-Meier estimate for 21-year all-cause mortality was 22%. Forty-one patients were diagnosed with diabetes (42.7%), compared to a nationwide prevalence of 13.7% in a similar age group. These results support the hypothesis that clozapine-treated patients are at risk for cardiovascular events and death secondary to an increased risk of medical disorders. Interventions that target weight loss, smoking cessation, and lipid profile improvement may alleviate the increased risk of cardiovascular mortality. PMID- 29164929 TI - Psychosis as a sequelae of paraneoplastic syndrome in Small- Cell Lung Carcinoma: A psycho-neuroendocrine interface. AB - In 2013 more than 150,000 Americans died from all types of lung cancer. Small cell lung cancer (SCLC) represents about 13% of all lung cancers and is notoriously associated with paraneoplastic syndromes (PNS). Here we present an interesting case of psychosis associated with one such PNS-- ectopic Cushing syndrome of SCLC. A 56 year old African-American male with no prior psychiatric history who was diagnosed with SCLC two months prior, presented to the ER for treatment of a right arm laceration he sustained while fighting off attackers, with high concern these individuals may have been part of hallucinatory experiences and well-systematized persecutory delusions regarding his wife. Physical assessment was notable for Cushingoid symptoms. Initial results of serum ACTH and cortisol were 221pg/ml (10-50pg/ml) and 37.1 mcg/dl (10-20mcg/dl) respectively. For psychosis, patient was started on Olanzapine which was titrated from 5 to final dose of 10mg nightly. Since patient was not a surgical candidate, he was treated with metyrapone 250 mg BID and radiation therapy was continued throughout hospitalization. Serum Cortisol level decreased steadily after initiation of metyrapone and psychotic symptoms dramatically reduced on olanzapine, metyrapone, and radiation therapy with apparently resolved persecutory delusions at discharge. This case broadens the available literature and provides data on successful symptomatic treatment with olanzapine while biological treatments of the underlying condition were beginning to take effect. As SCLC remains an important cause of morbidity and mortality in the US, it is imperative that physicians be aware of paraneoplastic syndromes and their psychiatric sequelae. PMID- 29164931 TI - The Clinical Impact of Neuroimaging in First-Episode Psychosis. PMID- 29164930 TI - Relapse Risk Assessment for Schizophrenia Patients (RASP): A New Self-Report Screening Tool. AB - OBJECTIVES: The Relapse Assessment for Schizophrenia Patients (RASP) was developed as a six-question self-report screener that measures indicators of Increased Anxiety and Social Isolation to assess patient stability and predict imminent relapse. This paper describes the development and psychometric characteristics of the RASP. METHODS: The RASP and Positive and Negative Syndrome Scale (PANSS) were administered to patients with schizophrenia (n=166) three separate times. Chart data were collected on a subsample of patients (n=81). Psychometric analyses of RASP included tests of reliability, construct validity, and concurrent validity of items. Factors from RASP were correlated with subscales from PANSS (sensitivity to change and criterion validity [agreement between RASP and evidence of relapse]). RESULTS: Test-retest reliability returned modest to strong agreement at the item level and strong agreement at the questionnaire level. RASP showed good item response curves and internal consistency for the total instrument and within each of the two subscales (Increased Anxiety and Social Isolation). RASP Total Score and subscales showed good concurrent validity when correlated with PANSS Total Score, Positive, Excitement, and Anxiety subscales. RASP correctly predicted relapse in 67% of cases, with good specificity and negative predictive power and acceptable positive predictive power and sensitivity. CONCLUSIONS: The reliability and validity data presented support the use of RASP in settings where addition of a brief self-report assessment of relapse risk among patients with schizophrenia may be of benefit. Ease of use and scoring, and the ability to administer without clinical supervision allows for routine administration and assessment of relapse risk. PMID- 29164932 TI - Development of the Spanish Language Houston Pain Outcome Instrument for Spanish Speakers. AB - PURPOSE: To address reported disparities in pain management among Hispanic patients, this article reports the psychometrics of the newly developed Spanish language Houston Pain Outcome Instrument (HPOI) with postoperative Hispanic patients. METHODS: Findings from qualitative interviews conducted with 35 self identified Hispanics in Phase 1 of the overall project were used to generate items for a new Spanish language instrument, Cuestionario de Houston Sobre el Dolor (HPOI). The second phase tested the psychometric properties with 95 self identified Hispanic postoperative inpatients in three Texas hospitals. RESULTS: HPOI subscale reliabilities ranged from .63 to .91, with similar reliabilities for Spanish and English versions. Concurrent validity was demonstrated by moderate significant correlations with similar items on the Brief Pain Inventory. Participants reported moderate and severe worst pain in the last 24 hours; 38% were undertreated for pain according to the Pain Management Index; and 75% reported nonpharmacologic strategies including family support, prayer, and position change as highly effective in managing pain. CONCLUSIONS: The HPOI is a reliable instrument for addressing disparities in pain management for the rapidly growing Hispanic population in the United States. Subscales for interference with mood and physical function and patient-reported nonpharmacologic strategies facilitate a more comprehensive assessment of the pain experience. PMID- 29164933 TI - The Influence of Acculturation on Traumatic Stress Following Childbirth Among Hispanic Adolescents. AB - INTRODUCTION: Many studies have explored the role of acculturation on health outcomes; however, no studies to date have examined relationships between acculturation and the traumatic stress of childbirth among Hispanic adolescents. METHOD: A convenience sample of 66 Hispanic adolescents 13 to 19 years of age completed the Acculturation Rating Scale for Mexican Americans-II (ARSMA-II), a demographic sheet, birth appraisal scale, and the Impact of Event Scale within 72 hours of birth. RESULTS: Significant associations were found between the ARSMA-II subscales and acculturation proxy variables, excluding language; however, only the Mexican Orientation Subscale and generation proxy variable influenced the birth experience. The study findings showed that Hispanic adolescents reporting a more traumatic childbirth identified closer with the Mexican culture and reported fewer family generations residing in the United States. CONCLUSION: As an overlooked area of research, our findings support the need for additional research related to the traumatic stress of birth among Hispanic adolescents. Using multiple acculturation measurements, including the ARSMA-II, with larger, more diverse samples of adolescents, equally balanced between all categories of acculturation and placement within the five-tier generation matrix, can provide some insightful information and directed health care. PMID- 29164934 TI - ? PMID- 29164935 TI - Hispanic Health Care International Guia de Autores. PMID- 29164936 TI - 42nd Annual NAHN Conference. PMID- 29164937 TI - Opening Remarks During the 42nd Annual NAHN Conference. PMID- 29164938 TI - An Examination of Sociocultural Factors Associated With Mammography Screening Among Latina Immigrants. AB - INTRODUCTION: The study hypothesized that sociocultural factors would be associated with breast cancer screening within the past 2 years among Latina immigrant women. METHOD: This study employed a survey design and included 82 Latina immigrant female participants 40 to 64 years of age for the analysis. Two multivariable binary logistic regression models were estimated, one for the sociocultural deterrents and the other for the symptomatic deterrents from the Cultural Cancer Screening Scale. RESULTS: The results indicated two constructs of the Cultural Cancer Screening Scale, sociocultural deterrents (odds ratio = 2.00; 95% confidence interval = 1.04-3.86) and symptomatic deterrents (odds ratio = 1.65; 95% confidence interval = 1.08-2.54), were associated with screening in the past 2 years, when adjusting for sociodemographic and health-related characteristics. CONCLUSION: These findings provide evidence for the importance of sociocultural factors in Latina immigrant women's timely mammography screening. PMID- 29164939 TI - Using CBPR to Decrease Health Disparities in a Suburban Latino Neighborhood. AB - INTRODUCTION: This project tested the feasibility of using a community-based participatory research (CBPR) approach to deliver health and social resources in two high-risk, suburban neighborhoods. METHOD: An established research network was used to engage stakeholders to design and deliver a neighborhood-based intervention targeting a Latino immigrant population. The intervention provided screenings for hypertension, diabetes, and depression; primary care provider visits; and information about navigating health care delivery systems and related community-based resources. Participants ( N = 216) were consented for participation and their subsequent use of health and social services were measured at baseline and 1 year post intervention. RESULTS: At baseline, 5.1% of participants had health insurance, 16.7% had a primary care provider, and 38.4% had a chronic illness. SF-12 scores showed a majority of participants with low perceived health status (56%) and high risk for clinical depression (33%). Self reported use of primary care services increased from 33.8% at baseline to 48% 1 year after the intervention, and 62% reported use of social services. CONCLUSION: Neighborhood-based interventions informed by a CBPR approach are effective in both identifying community members who lack access to health care-related services and connecting them into needed primary care and social services. PMID- 29164940 TI - Applying Ecological Frameworks in Obesity Intervention Studies in Hispanic/Latino Youth:: A Systematic Review. AB - INTRODUCTION: In the United States, Hispanic children have higher rates of obesity compared with non-Hispanic White children. An ecological framework provides a holistic view of the environment to which Hispanic/Latino children are exposed that can potentially inform prevention and treatment initiatives for this vulnerable population. METHOD: This systematic review examines the existing evidence on the use of an ecological framework in intervention studies targeting overweight and obesity in Hispanic youth from birth to 8 years. Key terms guided the search of PubMed, Google Scholar, CINAHL, and EBSCOhost databases from 1997 to 2016. Results were organized using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) method. RESULTS: Seven studies met the inclusion and exclusion criteria. Significant improvements in body mass index z scores in treatment children were evident in five of the seven studies. Increases in fruit, water, and vegetable consumption and physical activity levels were reported in four of the seven studies. CONCLUSION: Multilevel interventions targeting a child's home and community suggest efficacy in reducing or preventing obesity; increasing fruit, water, and vegetable consumption; and increasing physical activity in overweight/obese young Hispanic children. Future research is needed to explore the sustainability of multilevel obesity prevention interventions in this vulnerable population. PMID- 29164941 TI - Editor's presentation. PMID- 29164942 TI - Why cardiologists should be on social media - the value of online engagement. PMID- 29164943 TI - A Global Perspective on Religious Participation and Suicide. AB - Although sociological research in the Durkheimian tradition has generally accepted that religious involvement protects against suicide, few studies have examined this theoretical proposition outside Western industrialized settings. Using multilevel models to analyze data from the World Health Organization Mortality Database and the World Values Survey (1981-2007) across 42 countries in seven geographical-cultural regions, this study explores whether religious participation is more protective against suicide in some regions than others and, if so, why. Results indicate that while religious participation is protective in Latin America, eastern Europe, northern Europe, and English-speaking countries, it may aggravate the risk of suicide in East Asia, western Europe, and southern Europe. This regional variation is the result of differences in both the degree of integration/regulation of religious communities and suicide underreporting. Overall, the findings support the network perspective of Durkheim's classical theory and suggest that researchers should be more cautious about suicide underreporting in less industrialized settings. PMID- 29164944 TI - Community Context and Child Health: A Human Capital Perspective. AB - Human capital theory suggests that education benefits individuals' and their children's health through the educational skills people acquire in school. This perspective may also be relevant at the community level: the greater presence of adults with educational skills in a community may be a reason why living in a more highly educated setting benefits health. I use Demographic and Health Survey data for 30 sub-Saharan African countries to investigate whether the percentage of literate adults-specifically women-in a community is associated with children's likelihood of survival. I characterize 13,785 African communities according to the prevalence of women who are literate. Multilevel discrete-time hazard models ( N = 536,781 children) confirm that living in a community where more women are literate is positively associated with child survival. The study supports the conceptualization of literacy, and potentially other educational skills, as forms of human capital that can spill over to benefit others. PMID- 29164945 TI - Cardiovascular complications of multiple myeloma in the elderly. AB - INTRODUCTION: Multiple myeloma is a malignant neoplasm characterized by plasma cell proliferation in blood and bone marrow. Approximately two-thirds of the patients with multiple myeloma are >65 years at the time of diagnosis. Patients in this age group often have co-existing cardiovascular diseases. Areas covered: The presence of multiple myeloma adds to the malady by direct deposition of amyloid protein in the heart or via toxicity of chemotherapeutic agents. Cardiac contractile dysfunction, arrhythmias and thromboembolic disorders are the main issues in the management of elderly patients with multiple myeloma. Expert commentary: Assessment of cardiac risk and functional status requires careful evaluation by history, physical examination and imaging studies such as echocardiography and magnetic resonance imaging. The management of cardiovascular disorders in the presence of multiple myeloma is difficult and poses a challenge for the internist, the oncologist, and the cardiologist alike. This review is an overview of the problem of cardiovascular risk in and management of elderly patients with multiple myeloma. PMID- 29164947 TI - Trading Equality for Health? Evaluating the Trade-off and Institutional Hypotheses on Health Inequalities in the Global South. AB - It has been suggested that as medicine advances and mortality declines, socioeconomic disparities in health outcomes will grow. Yet, most research on this topic uses data from affluent Western democracies, where mortality is declining in small increments. We argue that the Global South represents the ideal setting to study this issue in a context of rapid mortality decline. We evaluate two competing hypotheses: (1) there is a trade-off between population health and health inequality such that reductions in under-five mortality are linked to higher levels of social inequality in health; and (2) institutional interventions that improve under-five mortality, like the expansion of educational systems and public health expenditure, are associated with reductions in inequalities. We test these hypotheses using data on 1,369,050 births in 34 low-income countries in the Demographic and Health Surveys from 1995 to 2012. The results show little evidence of a health-for-equality trade-off and instead support the institutional hypothesis. PMID- 29164946 TI - Chronic heart failure management in primary healthcare in Poland: Results of a nationwide cross-sectional study. AB - BACKGROUND: Organizational and educational activities in primary care in Poland have been introduced to improve the chronic heart failure (CHF) management. OBJECTIVES: To assess the use of diagnostic procedures, pharmacotherapy and referrals of CHF in primary care in Poland. METHODS: The cross-sectional survey was conducted in 2013, involving 390 primary care centres randomly selected from a national database. Trained nurses contacted primary care physicians who retrospectively filled out the study questionnaires on the previous year's CHF management in the last five patients who had recently visited their office. The data on diagnostic and treatment procedures were collected. RESULTS: The mean age +/- SD of the 2006 patients was 72 +/- 11 years, 45% were female, and 56% had left ventricular ejection fraction <50%. The percentage of the CHF patients diagnosed based on echocardiography was 67% and significantly increased during the last decade. Echocardiography was still less frequently performed in older patients (>=80 years) than in the younger ones (respectively 50% versus 72%, Rho <0.001) and in women than in men (62% versus 71%, P <0.001). The percentage of the patients treated with beta-blocker alone was 88%, but those with a combination of angiotensin inhibition 71%. The decade before, these percentages were 68% and 57%, respectively. Moreover, an age-related gap observed in the use of the above-mentioned therapy has disappeared. CONCLUSION: The use of echocardiography in CHF diagnostics has significantly improved in primary care in Poland but a noticeable inequality in the geriatric patients and women remains. Most CHF patients received drug classes in accordance with guidelines. PMID- 29164948 TI - Experiences of women living in Hungary seeking a medical abortion online. AB - OBJECTIVE: The aim of the study was to analyse the characteristics and experiences of women living in Hungary who accessed a medical abortion through the telemedical service Women on Web. METHODS: We examined the characteristics and experiences of 136 women who requested a medical abortion from Women on Web between June 2013 and February 2017. The main outcome measures were acceptability and satisfaction with the service. RESULTS: Of the 136 women who completed an online consultation, 118 requested a medical abortion package. Follow-up information was provided by 73 women (61.9%), of whom 49 completed the follow-up survey and 24 provided follow-up information via email. Of the 59 women who went ahead with a medical abortion, five (8.5%) had a surgical intervention afterwards. All women who completed the follow-up survey reported that they found a home medical abortion to be acceptable. CONCLUSION: The lack of availability of medical abortion in the public health sector in Hungary and compulsory biased counselling make medical abortion at home through telemedicine a good alternative for Hungarian women. PMID- 29164950 TI - The Institutional Foundations of Medicalization: A Cross-national Analysis of Mental Health and Unemployment. AB - In this study, we question (1) whether the relationship between unemployment and mental healthcare use, controlling for mental health status, varies across European countries and (2) whether these differences are patterned by a combination of unemployment and healthcare generosity. We hypothesize that medicalization of unemployment is stronger in countries where a low level of unemployment generosity is combined with a high level of healthcare generosity. A subsample of 36,306 working-age respondents from rounds 64.4 (2005-2006) and 73.2 (2010) of the cross-national survey Eurobarometer was used. Country-specific logistic regression and multilevel analyses, controlling for public disability spending, changes in government spending, economic capacity, and unemployment rate, were performed. We find that unemployment is medicalized, at least to some degree, in the majority of the 24 nations surveyed. Moreover, the medicalization of unemployment varies substantially across countries, corresponding to the combination of the level of unemployment and of healthcare generosity. PMID- 29164951 TI - Letter in response to "Acquired methemoglobinemia after hydroxocobalamin administration in a patient with burns and inhalation injury". PMID- 29164949 TI - Local pro-inflammatory cytokine and nitric oxide responses are elevated in patients with pterygium. AB - Pterygium is a common ocular surface disease observed in humans. Chronic ultraviolet (UV) exposure is extensively recognized as an aetiological factor in the pathogenesis of this disease. This hypothesis is sustained by epidemiological and histopathological data in relation to UV injured skin. Although some findings have indicated that genetic factors, anti-apoptotic and immunological mechanisms are involved in the pathogenesis of pterygium, the mechanism by which it develops remains poorly understood. In this study, we analysed the in vivo production of IL-17A, IL-6, IL-10 and nitric oxide (NO) in the tears and sera from Algerian patients. Interestingly, we observed that IL-6, IL-17A and NO production in the tears and sera of all patients was strongly associated with inflammatory infiltration, NOS2, NF-kappaB and Bcl2 expression in pterygia biopsies. Collectively, our results indicate a relationship between local inflammation and anti-apoptotic processes in pterygium disease, leading to both tissue damage and enhanced cellular proliferation. PMID- 29164952 TI - Review of vaccine effectiveness assumptions used in economic evaluations of infant pneumococcal conjugate vaccine. AB - INTRODUCTION: Pneumococcal conjugate vaccines (PCVs) have provided a significant clinical and economic impact globally. The majority of countries which have implemented an infant PCV program have observed a substantial reduction in the burden of invasive pneumococcal disease (IPD), pneumococcal pneumonia, and acute otitis media (AOM) due to vaccine serotypes. After 17 years of use, many countries have evaluated and re-evaluated the value of their vaccine program using cost-effectiveness analyses; however, many of these analyses do not reflect the current body of evidence. Areas covered: This literature review summarizes key assumptions used in cost-effectiveness analyses for PCVs and discusses whether these should be refined. Expert commentary: Many existing models continue to project cost-effectiveness of implementing a PCV program into a naive population, despite sustained PCV use. Furthermore, many assumptions related to program effectiveness are based on evidence from controlled studies or extrapolated from vaccines that are no longer or were never used. Real world effectiveness data published from nearly 10 years of higher-valet vaccine use should be reflected in key assumptions that drive decision makers to choose one vaccine over another. As data continuously emerges, cost-effectiveness of programs should be evaluated in the context of the most current data. PMID- 29164953 TI - Unintended Birth and Children's Long-term Mental Health. AB - Research has examined the proximate effects of unintended birth on infants and young children, but we know relatively little about the longer-term effects. Given that unintended birth is associated with several childhood risk factors, it might set the stage for poor mental health in adulthood. Drawing on rich intergenerational survey data from the National Longitudinal Survey of Youth, 1979 ( N = 3,742), this study used a variety of statistical techniques to examine whether maternal pregnancy intentions are associated with children's depressive symptoms during early adulthood. Results from ordinary least squares regression suggest that children resulting from unintended pregnancies experienced more depressive symptoms in their 20s than children resulting from intended pregnancies, controlling for a host of characteristics. Results from propensity weighted and sibling fixed-effects models suggest that there is little to no causal relationship, however. Much of the initial association between maternal fertility intentions and children's depressive symptoms is attributed to the mother's sociodemographic characteristics. PMID- 29164954 TI - A systematic review of ustekinumab in the treatment of atopic dermatitis. AB - AIM: Ustekinumab, a human monoclonal IgG1 antibody targeting the p40-subunit shared by interleukin (IL)12 and IL-23, represents a potential treatment for atopic dermatitis (AD). We evaluated the efficacy and safety of ustekinumab in the treatment of AD. METHODS: We reviewed the published literature by searching from PubMed, EMBASE, Web of Science and ClinicalTrial.gov then retrieved and analyzed several variables from patients records. RESULTS: Ten studies including eight cases and two RCT, comprising 107 patients, were included in the systematic review. Analysis all studies, a total of 58 patients (54.2%) gained an effective treatment with little adverse events. CONCLUSIONS: Ustekinumab is a well tolerated and safe treatment with no significant difference in effect from placebo in patients with AD. Further, larger randomized controlled trials need to be conducted to identify a suitable regimen for AD and provide more evidence for clinical application. PMID- 29164955 TI - Micellar solubilization of poorly water-soluble drugs: effect of surfactant and solubilizate molecular structure. AB - OBJECTIVE: This study aims to clarify the role of surfactant and drug molecular structures on drug solubility in micellar surfactant solutions. SIGNIFICANCE: (1) Rationale for surfactant selection is provided; (2) the large data set can be used for validation of the drug solubility parameters used in oral absorption models. METHODS: Equilibrium solubility of two hydrophobic drugs and one model hydrophobic steroid in micellar solutions of 19 surfactants was measured by HPLC. The drug solubilization locus in the micelles was assessed by UV spectrometry. RESULTS: Danazol is solubilized much more efficiently than fenofibrate by ionic surfactants due to ion-dipole interactions between the charged surfactant head groups and the polar steroid backbone. Drug solubilization increases linearly with the increase of hydrophobic chain length for all studied surfactant types. Addition of 1-3 ethylene oxide (EO) units in the head group of dodecyl sulfate surfactants reduces significantly the solubilization of both studied drugs and decreases linearly the solubilization locus polarity of fenofibrate. The locus of fenofibrate solubilization is in the hydrophobic core of nonionic surfactant micelles and in the palisade layer of ionic surfactant micelles. CONCLUSIONS: Highest drug solubility can be obtained by using surfactants molecules with long chain length coupled with hydrophilic head group that provides additional drug surfactant interactions (i.e. ion-dipole) in the micelles. PMID- 29164956 TI - Have we successfully implemented CYP2D6 genotyping in psychiatry? PMID- 29164957 TI - Expectations, concerns, and needs of patients who start drugs for chronic conditions. A prospective observational study among community pharmacies in Serbia. AB - BACKGROUND: During the initiation of treatment of a chronic disease, patients may have varying interests, expectations, concerns, and reasons to stop treatment, influencing compliance with prescribed treatment. Thus, healthcare professionals are expected to integrate these needs into medicines management. OBJECTIVES: To determine what information is important to patients; assess predictors of patients' interests, expectations, concerns, reasons to stop therapy; evaluate drug-related problems following initiation of therapy and summarize how pharmacists resolve them during patient-pharmacist counselling. METHODS: In 2014, a four-month study was performed in Serbian community pharmacies, as part of the Pharmaceutical Care Quality Indicators Project led by the European Directorate for the Quality of Medicines & Healthcare. Seventy community pharmacists were asked to participate in the study. Pharmacists recruited adult patients who consented to participate in the study and who initiated treatment, lasting at least six months. Patients completed an open-ended questions form. After two-to four weeks, a patient-pharmacist consultation was performed. RESULTS: Forty-four community pharmacists (response rate 62.9%) sent back the completed forms from 391 patients (response rate 67.1%). The total number of dispensed drugs was 403. In terms of drug safety, 29.4% of patients sought information, 32.5% expressed concerns, and 28.1% of patients cited it as a reason to discontinue treatment. During the first weeks of therapy, 18% of patients experienced practical problems, while 27.3% reported adverse drug reactions. CONCLUSION: Safety issues are a major focus of patients' prescribed new medicines for long-term treatment. PMID- 29164958 TI - Policy Brief. PMID- 29164960 TI - A randomized, open-label study to evaluate an intermittent dosing regimen of fluticasone propionate 0.05% cream in combination with regular emollient skin care in reducing the risk of relapse in pediatric patients with stabilized atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic, relapsing disease that requires maintenance treatment. This study examined the efficacy and safety of extended intermittent fluticasone propionate (FP) 0.05% cream, with emollient, vs emollient alone in children with AD. METHODS: Eligible patients (aged 1-17 years) received FP 0.05% cream twice daily for 4 weeks (acute phase) then randomized (1:1) to FP 0.05% cream once daily, twice per week plus emollient (Group A) or emollient alone (Group B) for up to 20 weeks (maintenance phase). Primary endpoint was time to first AD relapse. Safety was assessed throughout. RESULTS: This study enrolled 123 patients into the acute phase, of whom 107 entered the maintenance phase (Group A: 54; Group B; 53). Three patients (5.6%) in Group A and 30 (56.6%) in Group B experienced relapse (maintenance phase). Due to a low number of relapses, median time to first relapse could not be calculated for Group A; in Group B, it was 142 d (95% CI: 50, 150; p < .0001 vs Group A). FP and emollient were well tolerated. CONCLUSIONS: In pediatric patients with stabilized AD, FP 0.05% cream plus emollient (for AD maintenance treatment) significantly reduced the risk of relapse vs emollient alone. PMID- 29164959 TI - Palmatine attenuates isoproterenol-induced pathological hypertrophy via selectively inhibiting HDAC2 in rats. AB - This study aimed to exploit the potential therapeutic value of palmatine in treatment of cardiac hypertrophy and the underlying molecular mechanism. Rat hypertrophy model was established by intraperitoneal isoproterenol (ISO) injection. The hypertrophy was evaluated with cardiac hypertrophic parameters, hemodynamic parameters, lipid profile, and non-specific cardiac markers. The animals were intraperitoneally administrated with either palmatine or vehicle. The relative expressions of ANP, BNP, HDAC2, HDAC5, KLF4, and INPP5F transcripts were determined by real-time polymerase chain reaction (PCR). The relative protein levels of HDAC2, HDAC5, KLF4, and INPP5F were analyzed by immunoblotting. Palmatine treatment significantly attenuated ISO-induced hypertrophy in rats and elicited remarkable repressions in ANP, BNP, and HDAC2 transcriptions but not HDAC5. The downstream effector genes KLF4 and INPP5F were greatly restored in a dose-dependent manner in response to palmatine treatment. Our data demonstrated that palmatine possessed promising therapeutic potential against hypertrophy, which was mediated by modulation of HDAC2-KLF4/INPP5F pathway. PMID- 29164962 TI - Upholding the human right of children in New Zealand experiencing communication difficulties to voice their needs and dreams. AB - New Zealand Ministry of Education's proposal for an updated service to support children experiencing communication difficulties provides an opportunity to consider the essential criteria required for children to express their opinion, information and ideas as outlined under Article 19 of the Universal Declaration of Human Rights. This commentary begins with a summary of key policies that provide strategic direction for enhancing children's rights to be actively involved in the development of services designed to support them and to communicate and participate in inclusive environments. The authors use a human rights lens to inform the development of speech-language pathology services that facilitate individuals' contribution and engagement and are responsive to their needs. A review of international literature describing the lived experience of children and young people identifies key factors related to accessible information, service coordination, holistic practice, and partnerships that facilitate co-constructed understanding and decision-making. The commentary concludes with suggested recommendations for structuring services, establishing partnership models, and capability building. PMID- 29164961 TI - Disability and Activity-related Emotion in Later Life: Are Effects Buffered by Intimate Relationship Support and Strain? AB - We use daily diary data from the Disability and Use of Time supplement to the 2013 Panel Study of Income Dynamics ( n = 1,162) to evaluate (1) the extent to which marital/partner support and strain moderate the effects of disability on five activity-related emotions (happiness, calm, sadness, frustration, worry) and overall negative and positive emotion among older married, cohabiting, and dating persons and (2) whether such patterns differ significantly by gender. Marital support buffers against negative emotions and increases feelings of calm among severely impaired women. By contrast, support intensifies negative emotions and decreases feelings of calm among severely impaired men. Relationship strain also intensifies the effect of severe impairment on men's frustration, sadness, worry, and negative mood but has negligible effects on the negative emotions of men with low impairment and women. Frequent support and criticism may threaten highly impaired older men's sense of autonomy and emotional well-being. PMID- 29164964 TI - A mouse model of disseminated mantle cell lymphoma highlights a lack of activity of estrogen receptor beta agonists toward tumor burden. PMID- 29164963 TI - Amorphous silica nanoparticles induce malignant transformation and tumorigenesis of human lung epithelial cells via P53 signaling. AB - Rapid development and deployment of engineered nanomaterials, such as amorphous silica nanoparticles (SiNPs) in various commercial and biomedical applications have raised concerns about their potential adverse health effects, especially their chronic effects which have not been well addressed. In this study, human lung epithelial cells, BEAS-2B were continuously exposed to amorphous SiNPs, 5 MUg/mL for 40 passages. We demonstrated here that prolonged exposure of BEAS-2B cells to amorphous SiNPs induced malignant transformation as indicated by enhanced cellular proliferation, anchorage-independent cell growth, and increased cell migration. The transformed cells induced tumorigenesis in nude mice. Furthermore, a comprehensive understanding of genome-wide transcriptional analysis was performed to clarify the molecular mechanisms based on microarray and bioinformatics analysis. Microarray data analysis demonstrated that chronic exposure of SiNPs affected expression of 821 genes, including 5 up-regulated and 816 down-regulated genes. Gene ontology and pathway analysis showed that SiNPs caused significant changes in gene expression patterns related to many important functions and pathways, mainly including response to cellular processes, oxidative stress, DNA damage, and cancer. In addition, Signal-net analysis indicated the most prominent significant role of tumor protein p53 in amorphous SiNPs-induced transformation. Further, data confirmed the inactivated p53 and aberrant p53 signaling under chronic amorphous SiNPs exposure. In summary, our data firstly demonstrated chronically low-dose amorphous SiNPs exposure resulted in malignant transformation of human lung epithelial cell via p53 signaling, which provides new in vitro evidence for the carcinogenicity of amorphous SiNPs. PMID- 29164965 TI - The importance of FLT3 mutational analysis in acute myeloid leukemia. AB - Activating mutations in FMS-like tyrosine kinase 3 (FLT3), including internal tandem duplications (ITDs) and tyrosine kinase domain (TKD) mutations, are common in patients with acute myeloid leukemia (AML). FLT3-ITD is a negative prognostic factor that remains prognostically relevant even after intensive chemotherapy and/or stem cell transplant. FLT3 testing was historically viewed as being purely prognostic; however, with the advent of FLT3 inhibitors, it will likely be seen as both prognostic and predictive. The multikinase inhibitor midostaurin, in combination with chemotherapy, is the first targeted agent to significantly prolong survival in patients with newly diagnosed FLT3-mutated AML and was recently approved by health authorities. Recently, the European LeukemiaNet recommended FLT3 testing (both TKD and ITD) for all patients with AML, with results required within 3 days. The need for optimized, multigene platform testing incorporating FLT3 mutations will increase as knowledge of interactions between FLT3 and other myeloid-relevant mutations grows. PMID- 29164966 TI - Minimal residual disease detected by immunoglobulin sequencing predicts CLL relapse more effectively than flow cytometry. PMID- 29164967 TI - Increased serum midkine levels in autism spectrum disorder patients. AB - BACKGROUND: Midkine (MK) is a heparin binding growth factor and is involved in neurogenesis, neural development and neuroprotection. Additionally, MK may contribute to cancer development and pathogenesis of neurodegenerative disorders and schizophrenia. Considering these effects of MK, this study researched whether MK is involved in autism spectrum disorders (ASD) pathogenesis. METHODS: We evaluated serum MK levels of 38 patients with ASD and 32 healthy control group. MK levels were measured with ELISA, while ASD severity was assessed with Childhood Autism Rating Scale. RESULTS: Our data showed that the serum MK concentration in ASD patients (mean +/- SD, 11.51 +/- 8.53 pg/ml) is significantly higher than healthy controls (mean +/- SD, 6.19 +/- 3.94 pg/ml) (p = 0.007). CONCLUSIONS: According to these results, MK may play a role in ASD pathogenesis. PMID- 29164968 TI - Characterization of basal-like subtype in a Danish consecutive primary breast cancer cohort. AB - BACKGROUND: Transcriptome analysis enables classification of breast tumors into molecular subtypes. BRCA1/2 predisposed patients are more likely to suffer from a basal-like subtype and this group of patients displays a more distinct phenotype and genotype. Hence, in-depth characterization of this separate entity is needed. MATERIAL AND METHODS: Molecular subtyping was performed on a consecutive and unselected series of 1560 tumors from patients with primary breast cancer. Tumors were classified by the 256 gene expression signature (CIT) and associated with basic clinical characteristics and aggregated expression levels in the hallmark gene sets. RESULTS: Of the 1560 samples, 168 were classified basal-like and 120 patients were screened for BRCA1/2 mutations, resulting in 19 BRCA1/2 carriers, 95 non-carriers and six patients carried variants of unknown significance. The BRCA1/2 carriers were significantly younger and there were no carriers above 60 years of age. The tumors showed a loss in DNA-repair profile, as well as an upregulation in proliferative cancer signaling pathways. A robust molecular signature for identification of the BRCA1/2 - carriers was infeasible in the current cohort. Patients with a basal like breast cancer had the lowest median age and the largest median tumor size. They were almost exclusively diagnosed in disease stage III. CONCLUSIONS: Basal-like subtype is indeed a separate entity compared with other molecular breast cancer subtypes and the clinical course for this patient group should reflect the aggressiveness of this cancer. Taken together, patients being diagnosed with a basal-like breast cancer are in the youngest segment of breast cancer patients and are mainly diagnosed in stage III disease. PMID- 29164969 TI - Accuracy of self-reported family history of cancer, mutation status and tumor characteristics in patients with early onset breast cancer. AB - BACKGROUND: The main objectives of this study were to evaluate the concordance between self-reported and registry-reported information regarding family history of breast cancer (BC), ovarian cancer (OvC) and other types of cancer in first degree relatives of patients with early onset BC, and to determine the frequency of mutation carriers and non-mutation carriers. The secondary objective was to describe tumor characteristics for each mutation group. MATERIAL AND METHODS: Between 1993 and 2013, 231 women who were <=35 years old when diagnosed with BC were registered at the Oncogenetic Clinic at Skane University Hospital in Lund, Sweden. Self-reported and registry-reported information regarding first-degree family history of cancer was collected together with information regarding tumor characteristics. RESULTS: Almost perfect agreement was observed between self reported and registry-reported information regarding first-degree family history of BC (kappa = 0.92) and OvC (kappa = 0.86). Lesser agreement was observed between reports regarding family history of other types of cancer (kappa = 0.51). Mutation screening revealed pathogenic germline mutations in 30.4%; 18.8% in BRCA1, 7.1% in BRCA2 and 4.5% in other genes. Compared with other mutation groups, BRCA1 mutation carriers were more likely to be diagnosed with high-grade, ER-, PR- and triple-negative tumors. CONCLUSIONS: Our results demonstrate that physicians and genetic counselors can rely on self-reported information regarding BC and OvC in first-degree relatives. However, self-reported information regarding other types of cancer is not communicated as effectively, and there should be more focus on retrieving the correct information regarding family history of all tumor types. Furthermore, we observed that even though all BC patients fulfilled the criteria for genetic counseling and testing, a large number of patients diagnosed at <=35 years of age did not receive genetic counseling at the Oncogenetic Clinic. This finding merits further elucidation. PMID- 29164970 TI - A feasibility study of trauma-sensitive obstetric care for low-income, ethno racial minority pregnant abuse survivors. AB - PURPOSE: This study evaluated the feasibility and acceptability of an integrated (psychological and obstetric) intervention for pregnant abuse survivors with posttraumatic stress symptoms (PTS) from low-income, ethno-racial minority backgrounds. METHODS: Trauma-sensitive obstetrics to promote control, anxiety reduction and empowerment (TO-CARE) offers cognitive-behavioral therapy (CBT) coping skills delivered over six sessions by therapists, coupled with trauma sensitive obstetric care from specially-trained obstetric physicians. RESULTS: Participants were 21 women who completed at least three sessions of CBT, totaling 51.2% of eligible participants. Participants received approximately one-third (M = 2.29; SD = 2.15) of their prenatal visits with obstetric residents trained in trauma-sensitive care. Nearly all participants (95%) reported that they benefited from the intervention. Although most participants demonstrated improvement in PTS, only four demonstrated reliable improvement, and two demonstrated reliable improvement in depression symptoms. These improvements appeared to be maintained at postpartum follow-up for two of the participants. CONCLUSIONS: Our findings suggest that TO-CARE was acceptable to pregnant abuse survivors and may be a promising intervention to reduce symptoms of distress. Implications of the low retention rate for the CBT (51.2%) are discussed in the context of interventions for low-income minority pregnant women. Limitations regarding feasibility of the integrated intervention are discussed. PMID- 29164971 TI - Allogeneic hematopoietic cell transplantation for lymphoma: baseline and posttransplant prognostic factors. AB - The present study aimed to investigate baseline and posttransplant prognostic factors for allogeneic hematopoietic cell transplantation (HCT) in 61 lymphoma patients. The 5-year probabilities of overall survival (OS), non-relapse mortality (NRM), progression-free survival (PFS), and event-free survival (EFS) were 31.1%, 28.8%, 38.8%, and 23.2%, respectively. Multivariate analysis demonstrated that the International Prognostic Index risk at HCT was a significantly independent prognostic factor for OS, NRM, PFS, and EFS, and chemosensitivity was a prognostic factor for OS, NRM, and EFS. The occurrence of chronic graft-versus-host disease (GVHD) was significantly associated with higher OS, but it was not with PFS or EFS. Various parameters of immune reconstitution at 1 month after transplantation were associated with clinical outcomes in different ways. Our study results might be helpful in selecting appropriate patients or adopting effective posttransplant treatment strategies, eventually leading to an improvement in outcomes after allogeneic HCT for lymphoma. PMID- 29164972 TI - Molecular subtyping of breast cancer improves identification of both high and low risk patients. AB - BACKGROUND: Transcriptome analysis enables classification of breast tumors into molecular subtypes that correlate with prognosis and effect of therapy. We evaluated the clinical benefits of molecular subtyping compared to our current diagnostic practice. MATERIALS AND METHODS: Molecular subtyping was performed on a consecutive and unselected series of 524 tumors from women with primary breast cancer (n = 508). Tumors were classified by the 256 gene expression signature (CIT) and compared to conventional immunohistochemistry (IHC) procedures. RESULTS: More than 99% of tumors were eligible for molecular classification and final reports were available prior to the multidisciplinary conference. Using a prognostic standard mortality rate index (PSMRi) developed by the Danish Breast Cancer Group (DBCG) 39 patients were assigned with an intermediate risk and among these 16 (41%) were furthermore diagnosed by the multi-gene signature assigned with a luminal A tumor and consequently spared adjuvant chemotherapy. There was overall agreement between mRNA derived and IHC hormone receptor status, whereas IHC Ki67 protein proliferative index proved inaccurate, compared to the mRNA derived index. Forty-one patients with basal-like (basL) subtypes were screened for predisposing mutations regardless of clinical predisposition. Of those 17% carried pathogenic mutations. CONCLUSION: Transcriptome based subtyping of breast tumors evidently reduces the need for adjuvant chemotherapy and improves identification of women with predisposing mutations. The results imply that transcriptome profiling should become an integrated part of current breast cancer management. PMID- 29164973 TI - An indirect treatment comparison of the efficacy of insulin degludec/liraglutide (IDegLira) and insulin glargine/lixisenatide (iGlarLixi) in patients with type 2 diabetes uncontrolled on basal insulin. AB - AIMS: To obtain estimates of the relative treatment effects between insulin degludec/liraglutide (IDegLira) and insulin glargine U100/lixisenatide (iGlarLixi) in patients with type 2 diabetes mellitus (T2DM) uncontrolled on basal insulin therapy. MATERIALS AND METHODS: Data from phase 3 trials providing evidence for estimating the relative efficacy and safety of IDegLira vs iGlarLixi in patients uncontrolled on basal insulin-only regimens were used in this analysis. Outcomes of interest were changes in HbA1c, body weight and insulin dose, and rate ratio of hypoglycemia. The indirect comparison of the reported trial findings followed the principles of Bucher et al. RESULTS: IDegLira was estimated to provide a 0.44 [95% CI = 0.17-0.71] %-point reduction in HbA1c compared with iGlarLixi. Body weight was reduced by 1.42 [95% CI = 0.35-2.50] kg with IDegLira compared with iGlarLixi. Insulin dose was comparable between the two interventions. The rate of severe or blood glucose-confirmed (self-measured plasma glucose [SMPG] <= 3.1 mmol/L) hypoglycemia with IDegLira was approximately half that of iGlarLixi (rate ratio = 0.51 [95% CI = 0.29-0.90]). However, using the American Diabetes Association definition of documented symptomatic hypoglycemia (SMPG <=3.9 mmol/L) the rate was comparable between the two treatments (rate ratio = 1.07 [95% CI = 0.90-1.28]). LIMITATIONS: The assumptions made in the indirect comparison and differences between the included trials in baseline HbA1c levels, previous use of sulfonylureas, definitions of hypoglycemia, presence or absence of run-in period, the different duration of the trials, and the cross-over design of one of the trials. CONCLUSIONS: The results of this indirect treatment comparison demonstrate that, among patients with T2DM uncontrolled on basal insulin, treatment with IDegLira results in a greater reduction of HbA1c and a greater reduction in body weight compared with iGlarLixi at similar insulin doses. PMID- 29164974 TI - Clinical and molecular characterization of BRCA-associated breast cancer: results from the DBCG. AB - BACKGROUND: In breast cancer (BC) patients a cancer predisposing BRCA1/2 mutation is associated with adverse tumor characteristics, risk assessment and treatment allocation. We aimed to estimate overall- (OS) and disease-free survival (DFS) according to tumor characteristics and treatment among women who within two years of definitive surgery for primary BC were shown to carry a mutation in BRCA1/2 . MATERIAL AND METHODS: From the clinical database of the Danish Breast Cancer Group we included 141 BRCA1 and 96 BRCA2 BC patients. Estrogen receptor and HER2 status were centrally reviewed on paraffin-embedded tumor tissue. Information on risk reducing surgery was obtained from the Danish Pathology and Patient Registries and included as time-dependent variables in Cox proportional hazard models. RESULTS: Ten-year OS and DFS for BRCA1 BC patients were 78% (95% CI 69 85) and 74% (95% CI 64-81). Ten-year OS and DFS for BRCA2 BC were 88% (95% CI 78 94) and 84% (95% CI 74-91). BRCA1 BC patients as compared to BRCA2 BC patients had a higher risk of BC relapse or non-breast cancer within ten years of follow up, independent of ER status (adjusted HR 2.78 95% CI 1.28-6.05, p = .01), but BRCA mutation was not associated with OS (adjusted HR 1.98, 95% CI 0.87-4.52, p = .10). In multivariate analysis, including both BRCA1 and BRCA2 carriers, no chemotherapy was associated with a higher risk of death (adjusted OS HR 3.58, 95% CI 1.29-9.97, p = .01) and risk reducing contralateral mastectomy (RRCM) was associated with a significantly reduced risk of death (adjusted OS HR 0.42, 95% CI =0.21-0.84, p = .01). CONCLUSION: Difference in OS between BRCA1 and BRCA2 BC patients could be ascribed to tumor-biology. BRCA1 BC patients may have a shorter ten-year DFS than BRCA2 BC patients. Chemotherapy and risk reducing contralateral mastectomy reduce mortality for both BRCA1 and BRCA2 BC patients. PMID- 29164975 TI - Digital clubbing as a first clinical presentation of pulmonary metastases in cutaneous melanoma. AB - Digital clubbing is a paraneoplastic phenomenon usually associated with non-small cell lung cancer. We report the development of clubbing in a 49-year old man diagnosed with cutaneous melanoma which had metastasized to the lungs. We also reviewed the literature to understand the association between metastatic melanoma and clubbing. Previous reports of melanoma associated with hypertrophic osteoarthropathy (HOA) are extremely rare; only 7 cases. In all these patients digital clubbing was the main component of the HOA. However, our patient developed digital clubbing in the absence of other features of HOA. Therefore, to our knowledge, our report is the first in the literature. In conclusion, it should be kept in mind that digital clubbing might be associated with metastatic melanoma to the lung, notwithstanding rarely, and successful treatment of the underlying disease is associated with rapid resolution of the clubbing, as occurs in most patients with paraneoplastic syndromes. PMID- 29164976 TI - Ibrutinib and idelalisib block immunophenotypic changes associated with the adhesion and activation of CLL cells in the tumor microenvironment. AB - The lymph node and bone marrow microenvironments promote the survival and proliferation of CLL cells. Defining the immunophenotype of CLL cells from the tumor microenvironment may help to better understand the mechanisms of action of current therapies and identify novel drug targets. Significant changes in the levels of 25 CD antigens were identified using the DotScanTM antibody microarray following CLL-cell culture with CD40L-expressing fibroblasts. Ibrutinib or idelalisib countered the change in expression of 11 of these antigens (CD23, CD27, CD53, CD58, CD71, CD80, CD84, CD97, CD126, CD150, and FMC7), which have known roles in cell activation and adhesion. The immunophenotypic changes identified may provide further insight into the mechanisms by which CLL cells interact with the tumor microenvironment and better define how ibrutinib and idelalisib release CLL cells from the lymph nodes and bone marrow. PMID- 29164977 TI - A retrospective, matched paired analysis comparing bendamustine containing BeEAM versus BEAM conditioning regimen: results from a single center experience. AB - The combination of carmustine, etoposide, aracytin, and melphalan(BEAM) conditioning regimen in autologous stem-cell transplantation (ASCT) is widely used in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. It is also an option in patients with very-high risk aggressive NHL in first complete remission (CR). Recently, a phase Ib-II feasibility study using bendamustine replacing carmustine (BCNU) was reported. We report herein a safety and efficacy analysis of bendamustine-EAM (BeEAM) with a control BEAM counterpart paired cohort (1/2). One hundred and two patients were analyzed. Overall survival (OS) and progression-free survival (PFS) were not reached and seemed to be comparable between both groups. However, grade III or greater diarrhea was significantly higher in BeEAM patients (44 vs. 15%, p = .002). The median number of days with fever >38 degrees C was significantly higher in BeEAM group (5.5 vs. 2, p < .001). This case-control study suggests that BeEAM followed by ASCT using bendamustine at 100 mg/m2/d is effective but has a different toxicity profile than the BEAM regimen. PMID- 29164978 TI - LenD: a study to establish the safety and efficacy of lenalidomide and dexamethasone in patients with relapsed or refractory chronic lymphocytic leukemia. PMID- 29164979 TI - Primary bone lymphoma presenting as skeletal lesions in a patient recently treated for prostate cancer. PMID- 29164981 TI - Successful treatment of Ph ALL with hematopoietic stem cell transplantation from the same HLA-haploidentical related donor of previous liver transplantation. PMID- 29164980 TI - Role of flunarizine hydrochloride in secondary brain injury following intracerebral hemorrhage in rats. AB - This study aimed to explore the role and mechanism(s) of flunarizine hydrochloride in the intracerebral hemorrhage (ICH) rats. The 32 adult male Sprague Dawley (SD) rats were randomly assigned into four groups: control group, sham group, ICH group, and FLU + ICH group. The effects of flunarizine hydrochloride were assessed on the basis of hematoma volume, blood-brain barrier (BBB) integrity, and brain water content in the ICH rat models. The role of flunarizine hydrochloride in cell recovery was assessed by behavioral scores, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot assay. Involvement of PI3K/AKT pathway in exerting the effect of flunarizine hydrochloride was also determined. Results showed that the hematoma volume, BBB integrity, and brain water content were significantly decreased in the FLU + ICH group. Cell apoptosis significantly increased in the ICH model group, while flunarizine hydrochloride decreased this increase. The expressions of glial cell line-derived neurotrophic factor (GDNF), neuroglobin (NGB), and p-AKT were increased after flunarizine hydrochloride treatment in ICH rats. In conclusion, flunarizine hydrochloride has protective effects against ICH by reducing brain injury, cell apoptosis, and the activation of P13K/AKT pathway. These findings provide a theoretical basis for the treatment of flunarizine hydrochloride in ICH. PMID- 29164982 TI - Spinocerebellar ataxia type 3 presenting with writer's cramp without ataxia. AB - AIM OF THE STUDY: Spinocerebellar ataxia type 3 is the most common cause of autosomal dominant inherited ataxia worldwide. MATERIAL AND METHODS: Clinically, it exhibits wide phenotypic variability. Presentation as isolated dystonia is exceptional. RESULTS: Here, the case of a woman with writers cramp without ataxia is presented as a paucisymptomatic manifestation of this disease. CONCLUSIONS: This association has not been described to date and extends the clinical variability of the disease. PMID- 29164983 TI - A cluster of vitreoretinal lymphoma in New York with possible link to the Chernobyl nuclear disaster. PMID- 29164984 TI - Salvianolic acid A, a novel PI3K/Akt inhibitor, induces cell apoptosis and suppresses tumor growth in acute myeloid leukemia. AB - Salvianolic acid A (SAA), one of the main derivatives of Salvia miltiorrhiza, has been shown to possess anti-inflammatory and anti-thrombotic activities. Its role in inhibiting tumor growth, however, remains elusive. The aim of this study was to investigate the effect of SAA on acute myeloid leukemia (AML). Here, SAA showed a dose-dependent cell viability inhibition and apoptosis induction in AML cells. At the molecular level, SAA increased the expression of Bak and decreased the expression of Bcl-xL, following by PARP cleavage and caspase-3 activation. SAA also markedly attenuated Akt phosphorylation in AML cells. In a xenograft mouse model, SAA significantly suppressed the growth of AML tumors in vivo. Furthermore, SAA exhibited a more profound pro-apoptotic effect on primary AML cells than on bone marrow mononuclear cells from patients with benign diseases. Therefore, the pro-apoptotic and anti-tumor properties of SAA suggested its promising therapeutic value for AML. PMID- 29164985 TI - Bio-soliton model that predicts non-thermal electromagnetic frequency bands, that either stabilize or destabilize living cells. AB - Solitons, as self-reinforcing solitary waves, interact with complex biological phenomena such as cellular self-organization. A soliton model is able to describe a spectrum of electromagnetism modalities that can be applied to understand the physical principles of biological effects in living cells, as caused by endogenous and exogenous electromagnetic fields and is compatible with quantum coherence. A bio-soliton model is proposed, that enables to predict which eigen frequencies of non-thermal electromagnetic waves are life-sustaining and which are, in contrast, detrimental for living cells. The particular effects are exerted by a range of electromagnetic wave eigen-frequencies of one-tenth of a Hertz till Peta Hertz that show a pattern of 12 bands, and can be positioned on an acoustic reference frequency scale. The model was substantiated by a meta analysis of 240 published articles of biological electromagnetic experiments, in which a spectrum of non-thermal electromagnetic waves were exposed to living cells and intact organisms. These data support the concept of coherent quantized electromagnetic states in living organisms and the theories of Frohlich, Davydov and Pang. It is envisioned that a rational control of shape by soliton-waves and related to a morphogenetic field and parametric resonance provides positional information and cues to regulate organism-wide systems properties like anatomy, control of reproduction and repair. PMID- 29164987 TI - Quality of Life for Late Life Patients: Mixed-Methods Evaluation of a Whole Person Approach for Patients With Chronic Illnesses. AB - Quality of life (QOL) for patients with serious illness in late life is important for patients and policy makers and has implications for improved care delivery. This mixed-methods evaluation examined the effectiveness of a new whole-person approach to late life care-the LifeCourse-which provides patients with ongoing, across-setting assistance from lay health care workers, supported by a clinical team. We investigated whether participation in LifeCourse improves QOL for intervention patients, compared with usual care controls. QOL was assessed using baseline and 6 months Functional Assessment of Chronic Illness Therapy-Palliative version tool ( n = 181 patients and 126 controls). LifeCourse had a significant positive effect on overall QOL for patients when compared with controls. Interview data revealed that participants adjusted expectations when assessing QOL and actively sought out ways to maintain QOL with meaningful activities and needed services. LifeCourse offers a promising model for improving QOL for late life patients. PMID- 29164989 TI - Shining a Light: Examining Similarities and Differences in the Work Psychology of Health Support Workers Employed in Long-Term Care and Home and Community Care Settings. AB - Health Support Workers (HSWs) provide up to 80% of care to residents and clients in the long-term care (LTC) and home and community care (HCC) sectors but have received little research attention compared with the regulated professions. The authors explore similarities and differences in the work psychology of HSWs employed in LTC and HCC settings. Data were collected via survey from 276 LTC and 184 HCC HSWs. Descriptive statistics and path analyses were conducted. HSWs in LTC and HCC settings have significant, positive associations between organizational citizenship behaviors directed toward the organization (OCB-Os) and psychological empowerment, as well as intention to stay (ITS) and job satisfaction. For LTC sector HSWs, there are significant relationships between OCB-Os and quality of work life (QWL), ITS and work engagement, and individual performance and both job satisfaction and QWL. For the HCC sector, OCB-Os and ITS are significantly and directly related to organizational commitment. This study has implications for organizations interested in developing targeted interventions to improve the retention of HSWs. PMID- 29164988 TI - Development of Peritoneal Carcinomatosis in Epithelial Ovarian Cancer: A Review. AB - Epithelial ovarian cancer (EOC) metastasizes intra-abdominally with often numerous, superficial, small-sized lesions. This so-called peritoneal carcinomatosis is difficult to treat, and peritoneal recurrences are frequently observed, leading to a poor prognosis. Underlying mechanisms of interactions between EOC and peritoneal cells are incompletely understood. This review summarizes and discusses the development of peritoneal carcinomatosis from a cell biological perspective, focusing on characteristics of EOC and peritoneal cells. We aim to provide insight into how peritoneum facilitates tumor adhesion but limits size of lesions and depth of invasion. The development of peritoneal carcinomatosis is a multistep process that requires adaptations of EOC and peritoneal cells. Mechanisms that enable tumor adhesion and growth involve cadherin restructuring on EOC cells, integrin-mediated adhesion, and mesothelial evasion by mechanical forces driven by integrin-ligand interactions. Clinical trials targeting these mechanisms, however, showed only limited effects. Other factors that inhibit tumor growth and deep invasion are virtually unknown. Future studies are needed to elucidate the exact mechanisms that underlie the development and limited growth of peritoneal carcinomatosis. This review on development of peritoneal carcinomatosis of EOC summarizes the current knowledge and its limitations. Clarification of the stepwise process may inspire future research to investigate new treatment approaches of peritoneal carcinomatosis. PMID- 29164990 TI - Implications of stroke and bleeding risk scores and comorbidities on episode based bundled payments for patients with nonvalvular atrial fibrillation. AB - OBJECTIVES: Due to the high cost of nonvalvular atrial fibrillation (NVAF), this condition may be a suitable candidate for condition-specific bundled payments. This paper evaluates the healthcare cost of NVAF and uses common bleeding and stroke risk scores (HAS-BLED and CHA2DS2-VASc) to explore the risk-based healthcare cost differences among NVAF patients. METHODS: MarketScan claims of NVAF patients (ICD-9-CM code 427.31) were analyzed from January 2010 to April 2015. These claims feature more than 196 million covered lives and more than 300 contributing employers and 25 contributing health plans. A retrospective cohort design was used to assess episodes of care costs among patients with NVAF. Previously and newly diagnosed NVAF patients were selected from adult patients with >=2 diagnoses of NVAF, and without valvular disease. Total all-cause healthcare costs at 1 year were stratified by stroke (CHA2DS2-VASc) and bleeding (HAS-BLED) risk scores. Study data was extracted in the MarketScan Commercial Claims and Encounters Database (Commercial Database) and the MarketScan Medicare Supplemental and Coordination of Benefits Database (Medicare Supplemental Database). RESULTS: Mean all-cause 1 year cost of care based on stroke risk (CHA2DS2-VASc) varied from $15,703 to $59,163 for previously diagnosed and $25,992 to $62,458 for newly diagnosed NVAF. Similarly, mean cost varied base on bleeding risk (HAS-BLED) for previously and newly diagnosed NVAF from $17,950 to $57,029 and $26,356 to $67,104 respectively. CONCLUSION: NVAF patients accrue variable healthcare costs. Stroke and bleeding risk should be taken into account during the creation of NVAF payment bundles. PMID- 29164991 TI - Introduction to thyroid collection issue. PMID- 29164992 TI - Factors associated with recurrence of BTN after ablation. PMID- 29164993 TI - Comparative effects of meditation and exercise on physical and psychosocial health outcomes: a review of randomized controlled trials. AB - No review papers have examined studies that have directly compared non-active forms of meditation with exercise to evaluate effects on physical or psychosocial outcomes, which was the purpose of this paper. Studies were included if they had a randomized controlled trial (RCT) design, included a non-active form of meditation and exercise as intervention arms, and evaluated physical or psychosocial outcomes. The quality of included RCTs was rated using the Cochrane Collaboration's tool for assessing risk of bias in randomized trials. Five RCTs met the inclusion criteria. The total sample size across all studies was N = 325. Of the main outcomes assessed across the five studies, meditation was shown to be more effective than the exercise comparison arm when evaluating the psychosocial outcomes of anxiety, altruism, and life changes. Additionally, meditation was more effective at reducing chronic neck pain at rest and pain-related bothersomeness. Exercise, however, was more effective in improving physical health-related quality of life, HDL and LDL cholesterol, and fasting blood glucose levels. The interventions were found to be comparable when evaluating the outcomes of well-being, ethanol consumption, and perceived stress levels. Four of the evaluated studies were determined to have an overall 'unclear' risk of bias and one study was found to have a 'high' risk of bias. Exercise and non-active meditation may uniquely influence various health-related outcomes. A continued exploration of the effects of exercise and non-active meditation in controlled trials may yield a better understanding of their benefits. PMID- 29164994 TI - STAT3 inhibition as a therapeutic strategy for leukemia. AB - Leukemia is characterized by selective overgrowth of malignant hematopoietic stem cells (HSC's) that interfere with HSC differentiation. Cytoreductive chemotherapy can kill rapidly dividing cancerous cells but cannot eradicate the malignant HSC pool leading to relapses. Leukemic stem cells have several dysregulated pathways and the Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) pathway are prominent among them. STAT3 is an important transcription factor that regulates cell growth, proliferation, and inhibits apoptosis. High STAT3 expression in leukemia has been associated with an increased risk for relapse and decreased overall survival. Multiple strategies for interfering with STAT3 activity in leukemic cells include inhibition of STAT3 phosphorylation, interfering with STAT3 interactions, preventing nuclear transfer, inhibiting transcription and causing interference in STAT: DNA binding. A better understanding of key interactions and upstream mediators of STAT3 activity will help facilitate the development of effective cancer therapies and may result in durable remissions. PMID- 29164995 TI - Novel polyubiquitin imaging system, PolyUb-FC, reveals that K33-linked polyubiquitin is recruited by SQSTM1/p62. AB - Ubiquitin chains are formed with 8 structurally and functionally distinct polymers. However, the functions of each polyubiquitin remain poorly understood. We developed a polyubiquitin-mediated fluorescence complementation (PolyUb-FC) assay using Kusabira Green (KG) as a split fluorescent protein. The PolyUb-FC assay has the advantage that monoubiquitination is nonfluorescent and chain specific polyubiquitination can be directly visualized in living cells without using antibodies. We applied the PolyUb-FC assay to examine K33-linked polyubiquitin. We demonstrated that SQSTM1/p62 puncta colocalized with K33-linked polyubiquitin and this interaction was modulated by the ZRANB1/TRABID-K29 and K33 linkage-specific deubiquitinase (DUB). We further showed that the colocalization of K33-linked polyubiquitin and MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) puncta was impaired by SQSTM1/p62 deficiency. Taken together, these findings provide novel insights into how atypical polyubiquitin is recruited by SQSTM1/p62. Finally, we developed an inducible PolyUb-FC system for visualizing chain-specific polyubiquitin. The PolyUb-FC will be a useful tool for analyzing the dynamics of atypical polyubiquitin chain generation. PMID- 29164997 TI - Where Policy Meets Practice: Employer Perspectives on Scheduling and Hours for Home Care Aides. AB - In a context of growing demand for home-based direct care services, the need to retain direct care workers (DCWs) is clear. The Patient Protection and Affordable Care Act, changes to the Fair Labor Standards Act, and state-level changes in Medicaid support for home-based care together have affected agencies that hire DCWs, with implications for an issue that affects worker satisfaction: scheduling. Many home-based aides employed by agencies cannot count on consistent or sufficient hours. Hours shortfall and instability have been recognized as important issues for retail and restaurant workers, but focused on less for care aides. This study uses semistructured interviews with agency representatives to examine these issues from an employer perspective, with a focus on how the competing influences of health care, labor, and employment policy shape scheduling and a review of how recommendations for changes in policy and practice in other sectors might apply to home care. PMID- 29164998 TI - Chronic and Daily Stressors Along With Negative Affect Interact to Predict Daily Tiredness. AB - The present study examines the within-person relationship of daily stressors and tiredness and whether this depends on daily negative affect and individual differences in chronic stress. One hundred sixteen older adult participants were recruited via Amazon's Mechanical Turk for a 9-day daily diary study. Daily tiredness, daily stressors, and negative affect were measured each day, and chronic stress was measured at baseline. Daily stressors, daily negative affect, and chronic stress interacted to predict daily tiredness. People with high chronic stress who experienced an increase in daily negative affect were the most reactive to daily stressors in terms of experiencing an increase in daily tiredness. We also found that people with low levels of chronic stress were the most reactive to daily stressors when they experienced low levels of daily negative affect. Our results highlight the need for individualized and contextualized approaches to combating daily tiredness in older adults. PMID- 29164996 TI - CPTP: A sphingolipid transfer protein that regulates autophagy and inflammasome activation. AB - The macroautophagy/autophagy and inflammasome pathways are linked through their roles in innate immunity and chronic inflammatory disease. Ceramide-1-phosphate (C1P) is a bioactive sphingolipid that regulates pro-inflammatory eicosanoid production. Whether C1P also regulates autophagy and inflammasome assembly/activation is not known. Here we show that CPTP (a protein that traffics C1P from its site of phosphorylation in the trans-Golgi to target membranes) regulates both autophagy and inflammasome activation. In human epithelial cells, knockdown of CPTP (but not GLTP [glycolipid transfer protein]) or expression of C1P binding-site point mutants, stimulated an 8- to 10-fold increase in autophagosomes and altered endogenous LC3-II and SQSTM1/p62 protein expression levels. CPTP depletion-induced autophagy elevated early markers of autophagosome formation (Golgi-derived ATG9A-vesicles, WIPI1), required key phagophore assembly and elongation factors (ATG5, ATG7, ULK1), and suppressed MTOR phosphorylation and that of its downstream target, RPS6KB1/p70S6K. Wild-type CPTP overexpression exerted a protective effect against starvation-induced autophagy. In THP-1 macrophage-like surveillance cells, CPTP knockdown induced not only autophagy but also elevated CASP1/caspase-1 levels, and strongly increased IL1B/interleukin 1beta and IL18 release via a NLRP3 (but not NLRC4) inflammasome-based mechanism, while only moderately increasing inflammatory (pyroptotic) cell death. Inflammasome assembly and activation stimulated by CPTP depletion were autophagy dependent. Elevation of intracellular C1P by exogenous C1P treatment (instead of CPTP inhibition) also induced autophagy and IL1B release. Our findings identify human CPTP as an endogenous regulator of early-stage autophagosome assembly and inflammasome-driven, pro-inflammatory cytokine generation and release. PMID- 29164999 TI - Collagen type-I A2 gene polymorphisms and susceptibility to intracranial aneurysms: a meta-analysis of genetic association studies. AB - BACKGROUND: The development, evolution and rupture of intracranial aneurysms are in part related to genetic factors. The role of collagen type-I a2 genetic polymorphisms has not been clarified yet. MATERIAL AND METHODS: A meta-analysis was realized by means of a genotype model-fitting process (allele contrast, recessive, dominant, additive and co-dominant), and a model-free approach using the generalized odds ratio. The latter was assessed in association to the degree of dominance (h-index). RESULTS: No statistically significant association was documented between EX28 G>C collagen type-I a2 variant and intracranial aneurysms (generalized odds ratio = 1.23, 95% confidence interval = 0.57, 2.63). Significant associations between INT46 T>G collagen type I a2 variant and intracranial aneurysms were documented in three models, the dominant [0.52 (0.38, 069)], the co-dominant [0.50 (0.32, 0.78)] and the allele contrast models [0.63 (0.49, 0.82)]. The generalized odds ratio was estimated to be as high as 1.94 (1.23, 3.06). The degree of dominance (h-index = -1.54) indicated that the TG genotype was characterized by lower risk of developing intracranial aneurysms compared to the TT genotype. CONCLUSIONS: The available literature data demonstrated that there is no association of collagen type-(2a) and intracranial aneurysms, through EX28 G>C (rs42524) polymorphism according to the model-fitting process and the model-free approach. Regarding the INT46 T>G (rs2621215) polymorphisms, the latter models indicated that there could be a protective effect of the G-allele against the development of intracranial aneurysms. However, the majority of studies are from East Asia, therefore the results are applicable primarily to that patient population. PMID- 29165000 TI - Building Better Caregivers: A Pragmatic 12-Month Trial of a Community-Based Workshop for Caregivers of Cognitively Impaired Adults. AB - Building Better Caregivers (BBC), a community 6-week, peer-led intervention, targets family caregivers of those with cognitive impairments. BBC was implemented in four geographically scattered areas. Self-report data were collected at baseline, 6 months, and 1 year. Primary outcome were caregiver strain and depression. Secondary outcomes included caregiver burden, stress, fatigue, pain, sleep, self-rated health, exercise, self-efficacy, and caregiver and care partner health care utilization. Paired t tests examined 6 month and 1 year improvements. General linear models examined associations between baseline and 6-month changes in self-efficacy and 12-month primary outcomes. Eighty-three participants (75% of eligible) completed 12-month data. Caregiver strain and depression improved significantly (Effect Sizes = .30 and .41). All secondary outcomes except exercise and caregiver health care utilization improved significantly. Baseline and 6-month improvements in self-efficacy were associated with improvements in caregiver strain and depression. In this pilot pragmatic study, BBC appears to assist caregivers while reducing care partner health care utilization. Self-efficacy appears to moderate these outcomes. PMID- 29165001 TI - Beyond "Home-Like" Design: Visitor Responses to an Immersive Creative Space in a Canadian Long-Term Care Facility. AB - This study examined the benefits of expanding upon the "home-like" design by introducing an immersive creative space for residents, staff, and visitors to explore in a long-term care facility in Eastern Ontario, Canada. Data were collected through guestbook comments ( N = 93) and coded for themes according to guidelines for thematic analysis. Selected themes included visitors' enjoyment of the winter aesthetic, expressions of gratitude to the artists, time spent socializing with family and visitors in a creative milieu, and the experience of remembering in an evocative space. The results indicate that residents and visitors benefited from the experience of a creative space that was neither institutional, nor "home-like." Implications for future research are discussed. PMID- 29165002 TI - Adrenal-dependent and -independent stress-induced Per1 mRNA in hypothalamic paraventricular nucleus and prefrontal cortex of male and female rats. AB - Oscillating clock gene expression gives rise to a molecular clock that is present not only in the body's master circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN), but also in extra-SCN brain regions. These extra SCN molecular clocks depend on the SCN for entrainment to a light:dark cycle. The SCN has limited neural efferents, so it may entrain extra-SCN molecular clocks through its well-established circadian control of glucocorticoid hormone secretion. Glucocorticoids can regulate the normal rhythmic expression of clock genes in some extra-SCN tissues. Untimely stress-induced glucocorticoid secretion may compromise extra-SCN molecular clock function. We examined whether acute restraint stress during the rat's inactive phase can rapidly (within 30 min) alter clock gene (Per1, Per2, Bmal1) and cFos mRNA (in situ hybridization) in the SCN, hypothalamic paraventricular nucleus (PVN), and prefrontal cortex (PFC) of male and female rats (6 rats per treatment group). Restraint stress increased Per1 and cFos mRNA in the PVN and PFC of both sexes. Stress also increased cFos mRNA in the SCN of male rats, but not when subsequently tested during their active phase. We also examined in male rats whether endogenous glucocorticoids are necessary for stress-induced Per1 mRNA (6-7 rats per treatment group). Adrenalectomy attenuated stress-induced Per1 mRNA in the PVN and ventral orbital cortex, but not in the medial PFC. These data indicate that increased Per1 mRNA may be a means by which extra-SCN molecular clocks adapt to environmental stimuli (e.g. stress), and in the PFC this effect is largely independent of glucocorticoids. PMID- 29165003 TI - Administrators' Perceptions of Oral Health Care and Cancer Screening in Long-Term Care Nursing Facilities. AB - An estimated 1.7 million adults in the United States more than the age of 65 reside in long-term care nursing facilities (LTCNFs), and only 17% of them receive dental care. More than 83% of LTCNF residents require assistance with oral care. Adequate dental care is a preventative behavior for oral cancer. Adults more than age 65 will account for 60% of oral cancer-related deaths, despite an 80% cure rate for early diagnosis. This study sought to expand knowledge of the perceived benefits, barriers, and ability to perform or provide for oral health care and oral cancer screening as reported by Administrators and Directors of Nursing in LTCNFs. Findings indicate that competing demands for resources make oral health a low priority issue and low knowledge about oral cancer risk among nursing home residents, family members, and staff is a barrier. Potential interventions suggested by participants are discussed. PMID- 29165004 TI - Person-Directed Care Planning in Nursing Homes: Resident, Family, and Staff Perspectives. AB - Empowering individuals to direct their own care is central to person-centered care and health care policy. However, there is limited knowledge of how "person directed care planning" (PDCP) can be achieved in particular settings. This study identifies key structures and processes for operationalizing and implementing PDCP in nursing homes. Using participatory inquiry, we convened "stakeholder engagement sessions" with residents, families, nursing staff, and managers/administrators in two North Carolina nursing homes ( N = 24 sessions; N = 67 unique participants). Stakeholders discussed current care-planning processes and provided feedback on an emergent conceptual framework of PDCP. Three themes emerged through directed-content analysis: strategies included providing formal and informal opportunities to engage in care planning and ensuring effective follow-through; different roles were required among leadership, staff, residents, and families to accomplish PDCP; and limits on achieving PDCP included competing priorities and perceived regulatory and resource constraints. Results are discussed in terms of the specific competencies required for accomplishing PDCP. PMID- 29165005 TI - Models of care in tele-ophthalmology: A scoping review. AB - The objective of this review was to identify and describe telehealth models of care for ophthalmic services. We conducted a scoping review of the literature to identify how ophthalmic care can be delivered by telehealth. We searched the PubMed database to identify relevant articles which were screened based on pre defined inclusion criteria. For included articles, data were extracted, categorised and analysed. Synthesis of findings was performed narratively. The scoping review included 78 articles describing 62 discrete tele-ophthalmic models of care. Tele-ophthalmic models of care can be used for consultative service, screening, triage and remote supervision. The majority of services were for general eye care and triage ( n = 17; 26%) or emergency services ( n = 8; 12%). The most common conditions for disease-specific models of care were diabetic retinopathy ( n = 14; 21%), and glaucoma ( n = 8; 12%). Most models of care involved local clinicians capturing images and transmitting them to an ophthalmologist for assessment. This scoping review demonstrated tele ophthalmology to be feasible for consultation, screening, triage and remote supervision applications across a broad range of ophthalmic conditions. A large number of models of care have been identified and described in this review. Considerable collaboration between patient-end clinicians and substantial infrastructure is typically required for tele-ophthalmology. PMID- 29165006 TI - Effect of non-steroidal anti-inflammatory drugs on postoperative respiratory and heart rate in cats subjected to ovariohysterectomy. AB - Objectives The use of physiological parameters such as respiratory rate and heart rate to assess pain has long been discussed. The aim of the study was to compare postoperative respiratory rate and heart rate in cats subjected to flank ovariohysterectomy treated with a preoperative non-steroidal anti-inflammatory drug (NSAID) or no NSAID, and determine whether these parameters are suitable for postoperative pain assessment in cats. We hypothesised that cats without an NSAID would experience more postoperative pain, which may increase heart rate and respiratory rate. Methods A total of 168 female privately owned cats were studied. All cats were premedicated with medetomidine (0.08 mg/kg) and butorphanol (0.4 mg/kg) subcutaneously and anaesthesia was induced with intramuscular ketamine (5 mg/kg). Cats were divided into subgroups; controls (no NSAID) or cats given an NSAID, carprofen (4 mg/kg) or meloxicam (0.3 mg/kg), at premedication or induction of anaesthesia. Cats were subjected to flank ovariohysterectomy by the same surgeon. Atipamezole was administered 2.5 h after induction of anaesthesia. Respiratory rate and heart rate were measured 3.5 h after the induction of anaesthesia. Data were analysed using one-way ANOVA with mixed procedure and Tukey's adjustment method for multiplicity. Results The postoperative respiratory rate and heart rate per minute for all cats were 34.0 +/- 8.6 and 167.5 +/- 27.4, respectively. Neither respiratory rate nor heart rate differed significantly between the control group and the NSAID groups or between different time points of administration of NSAIDs. Conclusion and relevance Assuming there was less postoperative pain in the group administered NSAIDs, the results of the study presented no support for use of respiratory rate and heart rate as parameters for postoperative pain assessment in individual cats. Study limitations included a lack of pain scoring and baseline data for respiratory rate and heart rate. PMID- 29165007 TI - Genetic Diversity and Virulence of Wheat and Barley Strains of Xanthomonas translucens from the Upper Midwestern United States. AB - Bacterial leaf streak (BLS) of wheat and barley, caused by Xanthomonas translucens pv. undulosa and X. translucens pv. translucens, has been of growing concern in small grains production in the Upper Midwestern United States. To optimize disease resistance breeding, a greater awareness is needed of the pathovars and genetic diversity within the pathogens causing BLS in the region. Multilocus sequencing typing (MLST) and analysis (MLSA) of four common housekeeping genes (rpoD, dnaK, fyuA, and gyrB) was used to evaluate the genetic diversity of 82 strains of X. translucens isolated between 2006 and 2013 from wheat, barley, rye, and intermediate wheatgrass. In addition, in planta disease assays were conducted on 75 strains to measure relative virulence in wheat and barley. All strains were determined by MLSA to be related to X. translucens pv. undulosa and X. translucens pv. translucens. Clustering of strains based on Bayesian, network, and minimum spanning trees correlated with relative virulence levels in inoculated wheat and barley. Thus, phylogeny based on rpoD, dnaK, fyuA, and gyrB correlated with host of isolation and was an effective means for predicting virulence of strains belonging to X. translucens pv. translucens and X. translucens pv. undulosa. PMID- 29165008 TI - Building upon the success of CART19: chimeric antigen receptor T cells for hematologic malignancies. AB - Chimeric antigen receptor T cell (CART) therapy has dramatically changed the therapeutic prospects for B cell malignancies. Over the last decade CD19 redirected CART have demonstrated the ability to induce deep, long-lasting remissions and possibly cure patients with relapsing B cell neoplasms. Such impressive results with CART19 fostered efforts to expand this technology to other incurable malignancies that naturally do not express CD19, such as acute myeloid leukemia (AML), Hodgkin lymphoma (HL) and multiple myeloma (MM). However, to reach this goal, several hurdles have to be overcome, in particular: (i) the apparent lack of suitable targets as effective as CD19; (ii) the immunosuppressive tumor microenvironment; (iii) intra-tumoral heterogeneity and antigen-negative relapses. Therefore, new strategies that allow safer and more potent CART platforms are under development and may provide grounds for new exciting breakthroughs in the field. PMID- 29165009 TI - The Physical-Digital Divide: Exploring the Social Gap Between Digital Natives and Physical Natives. AB - Older adults are the most digitally divided demographic group. The present study explores how older adults perceive the physical use of information and communication technologies (ICTs), particularly across generations and contexts. Data for the present study come from nine focus groups. Seniors acknowledge that ICTs help them connect with geographically distant social ties, but that they lead to feelings of disconnection with geographically close social ties. We label this phenomenon the "physical-digital divide," which exists when a group feels ostracized or offended when those around them engage with ICTs while they themselves are not or cannot engage with ICTs. Younger generations are often referred to as "digital natives" and older generations as "digital immigrants." A more apt label for older adults may be "physical natives," as their preferred method of communication involves physical face-to-face interactions and traditional codes of etiquette. Suggestions are made for reducing the physical digital divide. PMID- 29165010 TI - DNMT3A co-mutation is required for FLT3-ITD as an adverse prognostic indicator in intermediate-risk cytogenetic group AML. AB - This single institution cohort study of 132 AML patients investigated the clinical implications of co-mutations detected with a 42-gene NGS panel. In the intermediate-risk cytogenetic group, FLT3-ITD is an adverse prognostic indicator only in the presence of a DNMT3A co-mutation, regardless of NPM1 mutation status. In the absence of a concomitant DNMT3A mutation, there was no significant difference in overall survival between FLT3-ITD positive and FLT3-ITD negative patients. Furthermore, mutation analysis on post-induction specimens showed that residual FLT3-ITD and/or DNMT3A mutations were associated with a high frequency of therapy resistance or relapse in AML. While FLT3-ITD positive patients are currently considered high risk, incorporation of DNMT3A mutation status may be needed to refine prognostication and guide clinical management in AML. Multi-gene mutation testing is essential to provide novel insights related to diagnostic and prognostic information. PMID- 29165012 TI - Changing Focus: End-of-Life Care in a New York State Managed Long-Term Care Program. AB - In the United States, managed long-term care programs offer a noninstitutional approach to meeting the needs of increasing numbers of frail elders. Providing services that support both quality of life and quality of dying poses unique challenges. Using a qualitative descriptive design, we explored these challenges from the perspectives of care providers. Themes were identified using qualitative content analysis techniques applied to transcripts of 33 semistructured interviews. Professionals comprising an interdisciplinary care team and home health aide direct care providers described cues by which they identified movement into the end-of-life phase, their understandings of how care changed, and their concerns and recommendations for improvement. When the changing care needs could be met, a "good death" ensued, but that was not always possible. Managed long-term care programs are called upon to develop the capacity to integrate the phase of dying into the full story of each life for which they care. PMID- 29165011 TI - Motor imagery of walking and walking while talking: a pilot randomized-controlled trial protocol for older adults. AB - Over a third of community-residing elderly have clinical gait abnormalities, and gait impairment is associated with morbidity, mortality and dementia. Motor imagery - envisioning motor actions without actual execution - has been used to improve gait in Parkinson's disease and poststroke, but the efficacy of motor imagery in healthy elderly is unknown. This single-blind pilot randomized controlled trial aims to establish feasibility and explore the efficacy of a 3 month, telephone-based motor imagery intervention - that involves imagined walking, imagined talking and imagined walking while talking for improving gait in 48 healthy elderly. The primary outcomes will be gait speed during actual walking and walking while talking. Secondary outcomes will include cognitive performance during actual talking and walking while talking, and functional neuroplasticity during imagined walking and walking while talking. This clinical trial has been registered on clinicaltrials.gov (identifier NCT02762604). PMID- 29165013 TI - Efficacy and safety of native versus pegylated Escherichia coli asparaginase for treatment of adults with high-risk, Philadelphia chromosome-negative acute lymphoblastic leukemia. AB - Native or pegylated (PEG) asparaginase (ASP) are commonly used in treatment of acute lymphoblastic leukemia (ALL), but have been scarcely compared in the same trial in adult patients. Native vs. PEG-ASP administered according to availability in each center were prospectively evaluated in adults with high-risk ALL. Ninety-one patients received native ASP and 35 PEG-ASP in induction. No significant differences were observed in complete remission, minimal residual disease levels after induction and after consolidation, disease-free survival, and overall survival. No significant differences in grades 3-4 toxicity were observed in the induction period, although a trend for higher hepatic toxicity was observed in patients receiving PEG-ASP. In this trial the type of ASP did not influence patient response and outcome. PMID- 29165014 TI - Fixation of proximal pole scaphoid nonunion with non-vascularized cancellous autograft. AB - : We present 20 patients with established proximal pole scaphoid nonunions treated with curettage and cancellous autograft from the distal radius and screw fixation. Fractures with significant proximal pole fragmentation were excluded. Patients were treated at a mean of 26 weeks after injury (range 12-72). Union occurred in 18 of 20 patients (90%) based on computed tomographic imaging. The two nonunions that did not heal were treated with repeat curettage and debridement and iliac crest bone grafting without revision of fixation. Union was achieved in both at a mean of 11 weeks after the revision procedures. Our findings suggest that non-vascularized cancellous autograft and antegrade fixation is a useful option for the treatment of proximal pole scaphoid nonunions. LEVEL OF EVIDENCE: IV. PMID- 29165015 TI - Lessons learned from volar plate fixation of scaphoid fracture nonunions. AB - : Treating scaphoid nonunions presents difficulties particularly when there is bone loss, significant humpback deformity or avascular necrosis. We describe a new type of fixation with a volar scaphoid plate that adds to the methods of internal fixation that are available for the treatment of recalcitrant scaphoid nonunions. We will also discuss 'lessons learned' from a cases series. The case series includes 20 consecutive patients treated with volar buttress plating and a pedicled vascularized bone graft from the ipsilateral volar distal radius. There was clinical and radiographic evidence of union in 18 of 20 patients, 13 of which were verified by computed tomographic scan. The range of motion was improved in all patients post-operatively. Four patients with radiographic union experienced intermittent clicking with maximal wrist flexion, believed to be due to the impingement of the plate on the volar aspect of the radioscaphoid articulation and underwent removal at approximately 1 year after the index procedure. Volar scaphoid plating is a useful alternative to headless scaphoid screw fixation in the treatment of unstable scaphoid waist fractures and nonunions. LEVEL OF EVIDENCE: IV. PMID- 29165016 TI - The use of osteochondral flaps in the treatment of carpal disorders. AB - Vascularized osteochondral flaps have been described for use in reconstruction of the wrist, providing the benefits of osteochondral grafts in addition to the benefit of osseous and subchondral perfusion via the microvascular pedicle. Various harvest sites have been described including the medial and lateral femoral trochlea and the proximal third metatarsal. The reconstructed surfaces described include the cartilage surfaces of the scaphoid, lunate, capitate and radius. The ability to transfer analogous osteochondral surfaces poses the possibility for new motion-preserving alternatives for difficult articular problems previously treated with salvage procedures. A description of the procedures and reported outcomes are provided, as well as a discussion of the role of these procedures in the future of wrist surgery. PMID- 29165017 TI - Transportation and Aging: An Updated Research Agenda for Advancing Safe Mobility. AB - This article discusses what is currently known about three important topics related to older driver safety and mobility: screening and evaluation, education and training interventions, and in-vehicle technology. Progress is being made to improve the safe mobility of older adults in these key areas; however, significant research gaps remain. This article advances the state of knowledge by identifying these gaps, and proposing further research topics will improve the lives of older adults. In addition, we discuss several themes that emerged from the review, including the need for multidisciplinary, community-wide solutions; large-scale, longitudinal studies; improved education/training for both older adults themselves and the variety of stakeholders involved in older adult transportation; and programs and interventions that are flexible and responsive to individual needs and differences. PMID- 29165018 TI - Efficacy of an Individually Tailored, Internet-Mediated Physical Activity Intervention in Older Adults: A Randomized Controlled Trial. AB - OBJECTIVE: This study determined the effectiveness of an individually tailored, Internet-mediated physical activity (PA) intervention for increasing walking behavior in inactive older adults. METHOD: This 12-week randomly controlled intervention divided participants ( N = 170) into three groups: control (CON, n = 51), pedometer only (PED, n = 62), and an individually tailored, Internet mediated pedometer (TI-PED, n = 57) group. The PED group was instructed to increase weekly step count by 10% until 10,000 steps per day was achieved. The TI PED group was given the same goal and received tailored feedback via an online platform. Changes in average step count pre-to-post were assessed. RESULTS: Total retention rate at postintervention was 75.3%. PED ( p < .001) and TI-PED ( p < .001) increased step count pre-to-post, which was higher than the CON group at 12 weeks (PED, p < .001; TI-PED, p < .001). The TI-PED group had a higher step count at 12 weeks than the PED group ( p < .001). DISCUSSION: Individually tailored, Internet-mediated PA interventions are an effective way to significantly increase PA in older adults. PMID- 29165019 TI - Care Configurations and Unmet Care Needs in Older Men and Women. AB - Older adults frequently experience adverse consequences as the result of unmet care needs, including not getting dressed and going without food when hungry. Previous studies have noted that characteristics of the caregiver network may be associated with unmet needs. Using National Health and Aging Trends Study data, I modeled the association between care configurations and unmet needs for men and women. In generalized linear models, formal care was not associated with unmet need among women or men. Compared with recipients of spousal care, men receiving care from one nonspousal caregiver, and men and women receiving care from any other configuration, had higher odds of unmet needs. The level of difficulty with daily tasks was strongly associated with unmet needs. These findings support monitoring older adults not receiving spousal care, increasing access to formal care, and regularly assessing level of difficulty with daily tasks in clinical and research settings. PMID- 29165020 TI - Preliminary Outcomes From a Community-Based Elder Abuse Risk and Evaluation Tool. AB - This research addresses the need to develop an assessment tool for case workers working in the aging services field outside of APS. As such, the research discusses the development, implementation, and preliminary outcomes of the Elder Abuse Risk Assessment and Evaluation(c) tool (EARAE). This instrument was developed and pilot tested by the Elder Abuse Prevention Program (EAPP), a program within Lifespan of Greater Rochester Inc. in Rochester, New York. A total of 189 suspected elder mistreatment cases were investigated using the EARAE instrument to track elements at the start and close of each case. Results indicate the tool represents an effective way to capture abuse indicators, track contributing risk factors, measure multiple case outcomes, and track types of interventions utilized. Opportunities and limitations of the tool are also discussed. PMID- 29165021 TI - Two years of tamoxifen or no adjuvant systemic therapy for patients with high risk breast cancer: long-term follow-up of the Copenhagen breast cancer trial. AB - BACKGROUND: The Copenhagen Breast Cancer Trial (CBCT) randomly assigned patients with early breast cancer to two years of tamoxifen or placebo and we evaluated the effect over the following four decades. PATIENT AND METHODS: Between 1975 and 1978, 327 patients with primary breast cancer were randomly assigned to two years of daily placebo or tamoxifen. Survival statistics was collected from the Danish Civil Registration System. RESULTS: The five-year invasive breast cancer recurrence (BCR) rate was 43.2% in the placebo arm and 31.9% in the tamoxifen arm. Compared with the placebo arm the hazard ratio for a BCR event was 0.73 in the tamoxifen arm (p = .07). With an estimated median follow-up on overall survival of 40.9 years, 154 and 145 patients had died in the placebo and tamoxifen arm, respectively. After adjustment for baseline characteristics a significant reduction in mortality was obtained from tamoxifen (HR 0.79; p = .04). CONCLUSION: Two years of adjuvant tamoxifen resulted in a sustained reduction in mortality in pre- and postmenopausal high-risk breast cancer patients with long-term follow-up data. PMID- 29165022 TI - The Behavioral Health Role in Nursing Facility Social Work. AB - Types of compromised resident behaviors licensed nursing facility social workers encounter, the behavioral health role they enact, and effective practices they apply have not been the subject of systematic investigation. Analyses of 20 in depth interviews with Bachelor of Social Work (BSW)/Master of Social Work (MSW) social workers averaging 8.8 years of experience identified frequently occurring resident behaviors: physical and verbal aggression/disruption, passive disruption, socially and sexually inappropriateness. Six functions of the behavioral health role were care management, educating, investigating, preventing, mediating, and advocating. Skills most frequently applied were attention/affirmation/active listening, assessment, behavior management, building relationship, teamwork, and redirection. Narratives revealed role rewards as well as knowledge deficits, organizational barriers, personal maltreatment, and frustrations. Respondents offered perspectives and prescriptions for behavioral health practice in this setting. The findings expand understanding of the behavioral health role and provide an empirical basis for more research in this area. Recommendations, including educational competencies, are offered. PMID- 29165023 TI - Adapting the Elder Abuse Suspicion Index(c) for Use in Long-Term Care: A Mixed Methods Approach. AB - Currently available elder abuse screening and identification tools have limitations for use in long-term care (LTC). This mixed-methods study sought to explore the appropriateness of using the Elder Abuse Suspicion Index(c) (a suspicion tool originally created for use with older adults in the ambulatory setting with Mini-Mental State Examination scores >= 24) with similarly cognitively functioning persons residing in LTC. Results were informed by a literature review, Internet-based consultations with elder abuse experts across Canada ( n = 19), and data obtained from two purposively selected focus groups ( n = 7 local elder abuse experts; n = 7 experienced front-line LTC clinicians). Analyses resulted in the development of a nine-question tool, the EASI-ltc, designed to raise suspicion of EA in cognitively intact older adults residing in LTC (with little or no cognitive impairment). Notable modifications to the original Elder Abuse Suspicion Index PMID- 29165024 TI - Evaluation of separate role of intestine and liver in first pass metabolism of budesonide in rat. AB - 1. Budesonide, a potent topical corticosteroid, reported to have low oral bioavailability in mice, rat, dog and human due to rapid first pass metabolism. However, there is insufficient information available in literature regarding the role of intestine and or liver responsible for the first pass metabolism of budesonide. 2. Current study in rats investigates the role of intestine and liver in first pass metabolism of budesonide using two in vivo models. Additionally, budesonide was also evaluated in in vitro assays such as thermodynamic solubility, permeability in Caco-2 cells and stability in simulated gastric (SGF), intestinal fluids (SIF) to understand the underlaying cause for low oral bioavailability. 3. Budesonide showed low oral, intra-duodenal and high intra portal bioavailability in rat. In a dual vein cannulated rat model, intestinal and hepatic extraction ratios calculated based upon intestinal availability (Fa.Fg) and hepatic availability (Fh), suggests hepatic extraction of budesonide is minimal compared to intestinal. 4. In vitro results suggest, solubility and permeability may not be a barrier for the observed low oral bioavailability in rats. 5. Correlating the in vitro and in vivo data together, it can be concluded that, intestine might be playing major role in first pass metabolism of budesonide. PMID- 29165025 TI - Familiar Face Priming: The Role of Second-Order Configuration and Individual Face Recognition Abilities. AB - The role of second-order configuration-that is, metric distances between individual features-for familiar face recognition has been the subject of debate. Recent reports suggest that better face recognition abilities coincide with a weaker reliance on shape information for face recognition. We examined contributions of second-order configuration to familiar face repetition priming by manipulating metric distances between facial features. S1 comprised familiar face primes as either: unaltered, with increased or decreased interocular distance, with increased or decreased distance between nose and mouth; or a different familiar face (unprimed). Participants performed a familiarity decision task on familiar and unfamiliar S2 targets, and completed a test battery consisting of three face identity processing tests. Accuracies, reaction times, and inverse efficiency scores were assessed for the priming experiment, and potential priming costs in inverse efficiency scores were correlated with test battery scores. Overall, priming was found, and priming effects were reduced only by primes with interocular distance distortions. Correlational data showed that better face recognition skills coincided with a weaker reliance on second-order configurations. Our findings (a) suggest an importance of interocular, but not mouth-to-nose, distances for familiar face recognition and (b) show that good face recognizers are less sensitive to second-order configuration. PMID- 29165026 TI - Comparative evaluation of oral and dento-maxillofacial manifestation of patients with sickle cell diseases and beta thalassemia major. AB - BACKGROUND: Regarding the importance of oral and dental health in patients with hemoglobinopathies and also due to the different results of different studies in this background, in patients with beta thalassemia (BTM) and sickle cell disease (SCD), this study aimed to evaluate and compare the oral and dental manifestations of patients with BTM and SCD. MATERIAL AND METHODS: In this cross sectional study during the years 2014-2017, a total of 175 patients (with documented BTM or SCD attending to Tehran, Mashhad, Isfahan, and Tabriz cities central hospitals) were randomly recruited. Required information was gathered through a thorough physical examination of the oral cavity in a private office and a face-to-face interview by an orthodontist and two dentists. Data were analyzed using SPSS version 22.0. RESULTS: In general, 120 diagnosed patients with BTM (88 males and 32 females) and 55 patients with SCD (25 males and 30 females) attending to Iran largest cities, central hospitals were randomly recruited. We found a significantly higher prevalence (p < .05) of some oral manifestations among the BTM patients (Gingival Index = 2.18 +/- 1.300, 1.64 +/- 0.963; Decayed teeth = 8.31 +/- 3.330, 2.33 +/- 1.221; Missing teeth = 3.51 +/- 2.016, 1.19 +/- 0.820; DMFT = 13.92 +/- 7.001, 2.63 +/- 1.301) than the apparently healthy people. CONCLUSION: Finally, the study gives an insight into the various oral and dento-maxillofacial manifestations of SCD and BTM and also reveals an association that exists between the oral and dento-maxillofacial manifestations and systemic health in these patients, thus stressing the importance of the concise and periodic examination of these individuals to perform appropriate preventive dental and periodontal care, and the facilitation of the management of the disease. PMID- 29165027 TI - Patient-centered decision making in amyotrophic lateral sclerosis: where are we? AB - Developments in amyotrophic lateral sclerosis research and care delivery have created new arenas, and new dilemmas, for patients' decision making. This review explores three aspects of amyotrophic lateral sclerosis patient-centered care and decision making: patient-centered service delivery through the expanding multidisciplinary team; decision making for genetic testing and the implications of undergoing testing; and development of user-designed decision support tools to help patients and families make decisions as their choices become more complex. Until a cure is found, well-timed and effective decision making will rely on patient and family preferences to guide them through an increasingly complicated disease landscape. PMID- 29165028 TI - Super-recognition in development: A case study of an adolescent with extraordinary face recognition skills. AB - Face recognition abilities vary widely. While face recognition deficits have been reported in children, it is unclear whether superior face recognition skills can be encountered during development. This paper presents O.B., a 14-year-old female with extraordinary face recognition skills: a "super-recognizer" (SR). O.B. demonstrated exceptional face-processing skills across multiple tasks, with a level of performance that is comparable to adult SRs. Her superior abilities appear to be specific to face identity: She showed an exaggerated face inversion effect and her superior abilities did not extend to object processing or non identity aspects of face recognition. Finally, an eye-movement task demonstrated that O.B. spent more time than controls examining the nose - a pattern previously reported in adult SRs. O.B. is therefore particularly skilled at extracting and using identity-specific facial cues, indicating that face and object recognition are dissociable during development, and that super recognition can be detected in adolescence. PMID- 29165029 TI - Brief Report: Active Ingredients for Adherence to a Tracker-Based Physical Activity Intervention in Older Adults. AB - OBJECTIVES: To identify factors associated with weekly adherence to a 12-week tracker-based activity intervention in older adults. METHOD: Using generalized linear mixed models in a secondary analysis ( N = 35), we examined factors associated with weekly adherence (defined as wore the Jawbone Up24 tracker for >=5 days and completed weekly calls). Factors examined included individual characteristics, gave and received virtual support, achieved step goals, barrier and task self-efficacy, and self-comment. RESULTS: Participants' ( Mage = 61.7, SDage = 5.7) adherence changed from 86% (Week 1) to 74% (Week 12). Achieved the previous week's goal (beta = 1.13, p = .01) and received virtual support (beta = 0.01, p = .02) significantly increased the odds of weekly adherence. DISCUSSION: Achieved step goals and received virtual support were associated with improved adherence to our tracker-based activity intervention, which has promising potential to be translated into the clinical setting to promote active lifestyles. PMID- 29165031 TI - BST2 inhibits type I IFN (interferon) signaling by accelerating MAVS degradation through CALCOCO2-directed autophagy. AB - Macroautophagy/autophagy is a conserved lysosomal degradation system that breaks down intracellular material through the formation of double-membrane autophagosomes in eukaryotic cells. Cargo receptors have been shown to play essential roles in capturing and delivering specific substrates into phagophores, the precursors to autophagosomes, for degradation. However, the detailed mechanism underlying selective recognition of the substrates for autophagic degradation remains poorly understood. Recently, we have revealed that IFN (interferon)-induced BST2 recruits the E3 ubiquitin ligase MARCH8 to catalyze the K27-linked ubiquitination of MAVS for CALCOCO2-directed autophagic degradation, hence inhibiting DDX58-mediated type I interferon signaling through a negative feedback loop. PMID- 29165032 TI - A new method for evaluating the normal rake angle and inclination angle on medical needles. AB - Hollow needles are the most frequently used medical equipment. The design of a hollow needle that best enables medical procedures requires a better understanding of needle tip geometry. Calculating the cutting angles of a needle for a complex surface topology is difficult. This article proposes a new method based on non-Euclidean geometry for the analysis of biopsy needle tip. The method can be used to calculate the cutting angles on any pipe needle. To verify the validity of this method, the normal rake angle and inclination angle on four types of needles (bias bevel needle, cylinder surface needle, curved surface needle and Cournand-type needle) were investigated. It was found that calculation of the cutting angles was simple and convenient using this method, especially for the curved surface needles. Images of the cutting angles from the Cournand-type needles revealed that the smaller bevel angle [Formula: see text] resulted in a higher normal rake angle [Formula: see text] and inclination angle [Formula: see text]. As [Formula: see text] increased, the range of the normal rake angle [Formula: see text] became larger at first and then became smaller. PMID- 29165030 TI - In mammalian skeletal muscle, phosphorylation of TOMM22 by protein kinase CSNK2/CK2 controls mitophagy. AB - In yeast, Tom22, the central component of the TOMM (translocase of outer mitochondrial membrane) receptor complex, is responsible for the recognition and translocation of synthesized mitochondrial precursor proteins, and its protein kinase CK2-dependent phosphorylation is mandatory for TOMM complex biogenesis and proper mitochondrial protein import. In mammals, the biological function of protein kinase CSNK2/CK2 remains vastly elusive and it is unknown whether CSNK2 dependent phosphorylation of TOMM protein subunits has a similar role as that in yeast. To address this issue, we used a skeletal muscle-specific Csnk2b/Ck2beta conditional knockout (cKO) mouse model. Phenotypically, these skeletal muscle Csnk2b cKO mice showed reduced muscle strength and abnormal metabolic activity of mainly oxidative muscle fibers, which point towards mitochondrial dysfunction. Enzymatically, active muscle lysates from skeletal muscle Csnk2b cKO mice phosphorylate murine TOMM22, the mammalian ortholog of yeast Tom22, to a lower extent than lysates prepared from controls. Mechanistically, CSNK2-mediated phosphorylation of TOMM22 changes its binding affinity for mitochondrial precursor proteins. However, in contrast to yeast, mitochondrial protein import seems not to be affected in vitro using mitochondria isolated from muscles of skeletal muscle Csnk2b cKO mice. PINK1, a mitochondrial health sensor that undergoes constitutive import under physiological conditions, accumulates within skeletal muscle Csnk2b cKO fibers and labels abnormal mitochondria for removal by mitophagy as demonstrated by the appearance of mitochondria-containing autophagosomes through electron microscopy. Mitophagy can be normalized by either introduction of a phosphomimetic TOMM22 mutant in cultured myotubes, or by in vivo electroporation of phosphomimetic Tomm22 into muscles of mice. Importantly, transfection of the phosphomimetic Tomm22 mutant in muscle cells with ablated Csnk2b restored their oxygen consumption rate comparable to wild-type levels. In sum, our data show that mammalian CSNK2-dependent phosphorylation of TOMM22 is a critical switch for mitophagy and reveal CSNK2-dependent physiological implications on metabolism, muscle integrity and behavior. PMID- 29165033 TI - A comparison of various methods of blood sampling in mice and rats: Effects on animal welfare. AB - This study was conducted to investigate the effects of blood sampling on animal welfare in a total of 60 NTac:SD rats and 72 C57BL/6NTac mice of both sexes. Blood was sampled either by sublingual vein puncture, tail vein puncture or by retrobulbar plexus/sinus puncture under light isoflurane anaesthesia and, additionally, by facial vein puncture in mice. Non-punctured animals as well as isoflurane-anaesthetised animals were used as controls. Pre- and post-puncture sucrose intake (1.5% w/w) was measured in rats, and nest building scores were studied in mice for 24 h post-puncture. Post-puncture activity and anxiety levels of rats and mice were measured using an elevated plus maze test and an open field test. Stress levels 24 h post-puncture were assessed by analysing faecal corticosteroid metabolites. Sucrose intake and faecal corticosteroid levels were not affected by the blood sampling procedures. Rats showed reduced activity in the open field test and an increased level of anxiety in the elevated plus maze test following retrobulbar plexus puncture and isoflurane anaesthesia. In mice, nest building activity was affected in all the groups compared with the control group, except for animals subjected to facial vein puncture. Retrobulbar sinus puncture, tail vein puncture and sublingual puncture in mice resulted in reduced activity and increased anxiety. We conclude that, of the tested methods, puncture of the tail vein and the sublingual vein have the least adverse effects in rats, whereas facial vein puncture had the least adverse effects on the welfare parameters in mice. PMID- 29165034 TI - Congenital prosopagnosia without object agnosia? A literature review. AB - A longstanding controversy concerns the functional organization of high-level vision, and the extent to which the recognition of different classes of visual stimuli engages a single system or multiple independent systems. We examine this in the context of congenital prosopagnosia (CP), a neurodevelopmental disorder in which individuals, without a history of brain damage, are impaired at face recognition. This paper reviews all CP cases from 1976 to 2016, and explores the evidence for the association or dissociation of face and object recognition. Of the 238 CP cases with data permitting a satisfactory evaluation, 80.3% evinced an association between impaired face and object recognition whereas 19.7% evinced a dissociation. We evaluate the strength of the evidence and correlate the face and object recognition behaviour. We consider the implications for theories of functional organization of the visual system, and offer suggestions for further adjudication of the relationship between face and object recognition. PMID- 29165035 TI - Selena Gomez, lupus and the impact of celebrity health disclosure on public awareness. PMID- 29165036 TI - A Formative Qualitative Evaluation to Inform Implementation of a Research Participation Enhancement and Advocacy Training Program for Diverse Seniors: The DREAMS Program. AB - This article reports on a formative qualitative evaluation conducted to identify potential barriers and facilitators prior to implementation of a two-part educational intervention designed to increase older adults' participation in clinical research. We conducted focus groups with 35 older adults from diverse racial, ethnic, and socioeconomic backgrounds (Mean age = 74.5 +/- 7.4 years), and six clinical researchers involved in aging research. Two older adult patient stakeholder advisors participated as members of the research team. Findings from thematic analysis showed that common barriers to research participation included older adults' fear and mistrust of researchers and the medical community as well as misperceptions and negative attitudes about clinical research. A commonly held belief was that most clinical research is conducted by "greedy" pharmaceutical companies who are more interested in profits than finding cures for disease. Results provide useful insights regarding enrolling members of hard-to-reach older adult populations in clinical research. PMID- 29165037 TI - Progress and Policy Opportunities in Family Caregiver Assessment: Results From a National Survey. AB - Family caregivers play an essential role in long-term services and supports (LTSS). Despite numerous calls for robust caregiver assessment policies to determine needs and treat them as partners in care planning, there has been limited information about whether or how states assess caregiver needs and strengths, or use caregiver information. Using cross-sectional survey data from the 2015 Process Evaluation of the Older Americans Act National Family Caregiver Support Program (NFCSP), this study analyzes caregiver assessment policies and practices in 54 State Units on Aging, 619 Area Agencies on Aging, and 642 local service providers. It examines whether and for what purposes caregiver assessments are used, what domains are included, and how well current policies conform to recommended practice. It also recommends that policy makers who influence NFCSP and other LTSS programs develop caregiver assessment practices using a multidimensional framework including more caregiver-focused domains and utilizing assessment data to measure program outcomes. PMID- 29165038 TI - "There's Not Enough Knowledge Out There": Examining Older Adults' Perceptions of Digital Technology Use and Digital Inclusion Classes. AB - Older adults' definitions of digital technology, and experiences of digital inclusion sessions, were examined using qualitative approaches. Seventeen older adults (aged between 54 and 85 years) participated in two focus groups that each lasted approximately 90 min to explore how older adults understood technology within their lived experience. Interpretative phenomenological analysis yielded two main themes: thirst for knowledge and a wish list for digital technology sessions. A separate content analysis was performed to identify what technology older adults identified as digital technology. This analysis revealed that the older adults most frequently defined digital technology as computers and telephones. The findings support the conclusions that this group of older adults, some of whom were "successful users," have a wide knowledge of digital technology, are interested in gaining more skills, and desire knowledge acquisition through personalized one-to-one learning sessions. PMID- 29165039 TI - Determination of a tissue-level failure evaluation standard for rat femoral cortical bone utilizing a hybrid computational-experimental method. AB - Macro-level failure in bone structure could be diagnosed by pain or physical examination. However, diagnosing tissue-level failure in a timely manner is challenging due to the difficulty in observing the interior mechanical environment of bone tissue. Because most fractures begin with tissue-level failure in bone tissue caused by continually applied loading, people attempt to monitor the tissue-level failure of bone and provide corresponding measures to prevent fracture. Many tissue-level mechanical parameters of bone could be predicted or measured; however, the value of the parameter may vary among different specimens belonging to a kind of bone structure even at the same age and anatomical site. These variations cause difficulty in representing tissue level bone failure. Therefore, determining an appropriate tissue-level failure evaluation standard is necessary to represent tissue-level bone failure. In this study, the yield and failure processes of rat femoral cortical bones were primarily simulated through a hybrid computational-experimental method. Subsequently, the tissue-level strains and the ratio between tissue-level failure and yield strains in cortical bones were predicted. The results indicated that certain differences existed in tissue-level strains; however, slight variations in the ratio were observed among different cortical bones. Therefore, the ratio between tissue-level failure and yield strains for a kind of bone structure could be determined. This ratio may then be regarded as an appropriate tissue-level failure evaluation standard to represent the mechanical status of bone tissue. PMID- 29165040 TI - A code for transcription elongation speed. AB - The two major steps of gene expression are transcription and translation. While hundreds of studies regarding the effect of sequence features on the translation elongation process have been published, very few connect sequence features to the transcription elongation rate. We suggest, for the first time, that short transcript sub-sequences have a typical effect on RNA polymerase (RNAP) speed: we show that nucleotide 5-mers tend to have typical RNAP speed (or transcription rate), which is consistent along different parts of genes and among different groups of genes with high correlation. We also demonstrate that relative RNAP speed correlates with mRNA levels of endogenous and heterologous genes. Furthermore, we show that the estimated transcription and translation elongation rates correlate in endogenous genes. Finally, we demonstrate that our results are consistent for different high resolution experimental measurements of RNAP densities. These results suggest for the first time that transcription elongation is partly encoded in the transcript, affected by the codon-usage, and optimized by evolution with a significant effect on gene expression and organismal fitness. PMID- 29165042 TI - Suppressed translation as a mechanism of initiation of CASP8 (caspase 8) dependent apoptosis in autophagy-deficient NSCLC cells under nutrient limitation. AB - Macroautophagy/autophagy inhibition under stress conditions is often associated with increased cell death. We found that under nutrient limitation, activation of CASP8/caspase-8 was significantly increased in autophagy-deficient lung cancer cells, which precedes mitochondria outer membrane permeabilization (MOMP), CYCS/cytochrome c release, and activation of CASP9/caspase-9, indicating that under such conditions the activation of CASP8 is a primary event in the initiation of apoptosis as well as essential to reduce clonogenic survival of autophagy-deficient cells. Starvation leads to suppression of CFLAR proteosynthesis and accumulation of CASP8 in SQSTM1 puncta. Overexpression of CFLARs reduces CASP8 activation and apoptosis during starvation, while its silencing promotes efficient activation of CASP8 and apoptosis in autophagy deficient U1810 lung cancer cells even under nutrient-rich conditions. Similar to starvation, inhibition of protein translation leads to efficient activation of CASP8 and cell death in autophagy-deficient lung cancer cells. Thus, here for the first time we report that suppressed translation leads to activation of CASP8 dependent apoptosis in autophagy-deficient NSCLC cells under conditions of nutrient limitation. Our data suggest that targeting translational machinery can be beneficial for elimination of autophagy-deficient cells via the CASP8 dependent apoptotic pathway. PMID- 29165041 TI - AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells. AB - Phosphorylation is a major type of post-translational modification, which can influence the cellular physiological function. ATG4B, a key macroautophagy/autophagy-related protein, has a potential effect on the survival of tumor cells. However, the role of ATG4B phosphorylation in cancers is still unknown. In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells. The phosphorylation of ATG4B at Ser34 had little effect on autophagic flux, but promoted the Warburg effect including the increase of L-lactate production and glucose consumption, and the decrease of oxygen consumption in HCC cells. The Ser34 phosphorylation of ATG4B also contributed to the impairment of mitochondrial activity including the inhibition of F1Fo-ATP synthase activity and the elevation of mitochondrial ROS in HCC cells. Moreover, the phosphorylation of ATG4B at Ser34 enhanced its mitochondrial location and the subsequent colocalization with F1Fo-ATP synthase in HCC cells. Furthermore, recombinant human ATG4B protein suppressed the activity of F1Fo-ATP synthase in MgATP submitochondrial particles from patient-derived HCC tissues in vitro. In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity. Our findings reveal a noncanonical working pattern of ATG4B under pathological conditions, which may provide a scientific basis for developing novel strategies for HCC treatment by targeting ATG4B and its Ser34 phosphorylation. PMID- 29165044 TI - LyP-1-conjugated Fe3O4 nanoparticles suppress tumor growth by magnetic induction hyperthermia. AB - To find a promising drug carrier to suppress tumor using magnetic induction hyperthermia (MIH) and targeted therapy, two superparamagnetic iron oxide nanoparticles (SPIONs) coated with polyethylene glycol (PEG) and LyP-1, respectively, were prepared and compared. The particle size ranges of PEG-SPIONs and LyP-1-SPIONs were 10-15 nm, and 15-20 nm, respectively. In FTIR spectra, PEG SPIONs and LyP-1-SPIONs had strong peaks between 575 and 1630 cm-1. Specifically, the PEG-SPIONs mainly has peaks in 581 and 1630 cm-1. The LyP-1-SPIONs mainly had peaks in 575, 1050 and 1625 cm-1. The contents of Fe3O4 in the PEG-SPIONs and LyP 1-SPIONs were about 94.24 and 89.26%, respectively. The iron contents in the MCF 7 and CT-26 cells were 33.1 +/- 1.8 and 27.9 +/- 0.95 pg, respectively, after co incubation with LyP-1-SPIONs for 8 h. The LyP-1-SPIONs accumulated in the nucleus of MCF-7 cells while PEG-SPIONs in cytoplasma. In vitro, after 30 days we can found the tumor almost stopped to grow in Group LyP-1-SPIONs. LyP-1-SPIONs are promising in treating cancer as they accumulated in the nucleus of MCF-7 cells which expressed p32 and almost stopped tumor growth by combined MIH and targeted therapy. PMID- 29165043 TI - Autophagy balances inflammation in innate immunity. AB - Macroautophagy/autophagy is a homeostatic process with multiple effects on immunity. One of the pivotal contributions of autophagy in immunity is the cell autonomous control of inflammation. This property leads to systemic consequences and thereby influences the development of innate and adaptive immunity, which promotes or suppresses pathology in various disease contexts. In this review we focus on the intersections between autophagy and inflammasome activation, autophagy and interferons, and autophagy and inflammation in association with infection. PMID- 29165045 TI - Determination of the centre of resistance during en masse retraction combined with corticotomy: finite element analysis. AB - OBJECTIVE: To determine the effect of corticotomy on the change in the centre of resistance of the six maxillary anterior teeth Materials and methods: Three dimensional finite element models of the maxillary anterior teeth with and without corticotomy were constructed. Brackets (size 0.022 inch * 0.028 inch) were placed passively on all anterior teeth that were set at the centre of the labial surface in the mesio-distal dimension and 3 mm from the incisal edge to the bracket slot in the vertical direction. The power arm was set mesial of the canine bracket. For the model with corticotomy, the bone density was decreased from initial value at 5% to 25%. The point of force application was varied in order to locate the centre of resistance. The centre of resistance was located by measurement of the difference of the displacement between the apical and incisal edges. The position of force was varied by moving apically parallel to the occlusal plane to simulate tooth movement. RESULTS: As the alveolar bone density decreased from initial value to 25%, the location of the centre of resistance moved apically from the bracket slot from 10.8 mm to 11.2 mm, respectively. CONCLUSIONS: The change of alveolar bone density due to corticotomy was associated with the location of the centre of resistance. The location of the centre of resistance moved apically as the alveolar bone density decreased but it was not clinically noticeable. PMID- 29165046 TI - Phytophthora parasitica Effector PpRxLR2 Suppresses Nicotiana benthamiana Immunity. AB - Phytophthora species secrete several classes of effector proteins during interaction with their hosts. These proteins can have multiple functions including modulation of host physiology and immunity. The RxLR effectors have the ability to enter plant cells using the plant machinery. Some of these effectors have been characterized as immunity suppressors; however, very little is known about their functions in the interaction between Phytophthora parasitica and its hosts. Using a bioinformatics pipeline, we have identified 172 candidate RxLR effectors (CREs) in the isolate IAC 01_95 of P. parasitica. Of these 172 CREs, 93 were found to be also present in eight other genomes of P. parasitica, isolated from different hosts and continents. After transcriptomics and gene expression analysis, we have found five CREs to be up-regulated in in-vitro and in-planta samples. Subsequently, we selected three CREs for functional characterization in the model plant Nicotiana benthamiana. We show that PpRxLR2 is able to completely suppress INF-1-induced cell death, whereas PpRxLR3 and PpRxLR5 moderately suppressed N. benthamiana immunity in a less-extensive manner. Moreover, we confirmed the effector-triggered susceptibility activity of these proteins after transient transformation and infection of N. benthamiana plants. All three CREs enhanced virulence of P. parasitica during the interaction with N. benthamiana. These effectors, in particular PpRxLR2, can be targeted for the development of biotechnology-based control strategies of P. parasitica diseases. PMID- 29165047 TI - Images in Vascular Medicine: Distal radial and ulnar artery thrombosis in a cancer patient with a history of chronic handgun use. PMID- 29165049 TI - Are latent variable models preferable to composite score approaches when assessing risk factors of change? Evaluation of type-I error and statistical power in longitudinal cognitive studies. AB - As with many health constructs, cognition is difficult to measure accurately; it is assessed by multiple psychometric tests. Two approaches are commonly adopted to address this multivariate aspect in longitudinal analyses: the composite score approach summarizes the tests into a single outcome and subsequently analyzes its change; the multivariate approach relates the tests to the underlying cognitive level and simultaneously analyzes its change. We compared the quality of inference of these approaches in a simulation study based on three combinations of tests inspired by two population-based cohorts. In the absence of missing data and with relatively Gaussian psychometric tests, the composite score approach provided similar type-I error rates and statistical power as the multivariate latent process approach. In the more plausible scenario with departures from normality, transformations of each constituent test or of the composite score were required to avoid excess type-I error rates. When missing tests were more likely in cognitively impaired subjects, inference with the composite was not correct. In conclusion, composite scores can be used to assess risk factors for cognitive change provided they are correctly normalized, constituent tests are reliable and the amount of uninformative missing tests remains small. Otherwise, latent variable models are recommended. PMID- 29165048 TI - Psychoradiologic Utility of MR Imaging for Diagnosis of Attention Deficit Hyperactivity Disorder: A Radiomics Analysis. AB - Purpose To identify cerebral radiomic features related to diagnosis and subtyping of attention deficit hyperactivity disorder (ADHD) and to build and evaluate classification models for ADHD diagnosis and subtyping on the basis of the identified features. Materials and Methods A consecutive cohort of 83 age- and sex-matched children with newly diagnosed and never-treated ADHD (mean age 10.83 years +/- 2.30; range, 7-14 years; 71 boys, 40 with ADHD-inattentive [ADHD-I] and 43 with ADHD-combined [ADHD-C, or inattentive and hyperactive]) and 87 healthy control subjects (mean age, 11.21 years +/- 2.51; range, 7-15 years; 72 boys) underwent anatomic and diffusion-tensor magnetic resonance (MR) imaging. Features representing the shape properties of gray matter and diffusion properties of white matter were extracted for each participant. The initial feature set was input into an all-relevant feature selection procedure within cross-validation loops to identify features with significant discriminative power for diagnosis and subtyping. Random forest classifiers were constructed and evaluated on the basis of identified features. Results No overall difference was found between children with ADHD and control subjects in total brain volume (1069830.00 mm3 +/- 90743.36 vs 1079 213.00 mm3 +/- 92742.25, respectively; P = .51) or total gray and white matter volume (611978.10 mm3 +/- 51622.81 vs 616960.20 mm3 +/- 51872.93, respectively; P = .53; 413532.00 mm3 +/- 41 114.33 vs 418173.60 mm3 +/- 42395.48, respectively; P = .47). The mean classification accuracy achieved with classifiers to discriminate patients with ADHD from control subjects was 73.7%. Alteration in cortical shape in the left temporal lobe, bilateral cuneus, and regions around the left central sulcus contributed significantly to group discrimination. The mean classification accuracy with classifiers to discriminate ADHD-I from ADHD-C was 80.1%, with significant discriminating features located in the default mode network and insular cortex. Conclusion The results of this study provide preliminary evidence that cerebral morphometric alterations can allow discrimination between patients with ADHD and control subjects and also between the most common ADHD subtypes. By identifying features relevant for diagnosis and subtyping, these findings may advance the understanding of neurodevelopmental alterations related to ADHD. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29165050 TI - Functional properties of anti-inflammatory substances from quercetin-treated Bifidobacterium adolescentis. AB - The genus Bifidobacterium is well known to have beneficial health effects. We discovered that quercetin and related polyphenols enhanced the secretion of anti inflammatory substances by Bifidobacterium adolescentis. This study investigated characteristics of the anti-inflammatory substances secreted by B. adolescentis. The culture supernatant of B. adolescentis with quercetin reduced the levels of inflammatory mediators in activated macrophages. Spontaneous quercetin degradant failed to increase anti-inflammatory activity, while the enhancement of anti inflammatory activity by quercetin was sustained after washout of quercetin. Physicochemical treatment of the culture supernatant indicated that its bioactive substances may be heat-stable, non-phenolic, and acidic biomolecules with molecular weights less than 3 kDa. Acetate and lactate have little or no effect on nitric oxide production. Taken together, the anti-inflammatory substances secreted by B. adolescentis may be small molecules but not short chain fatty acids. In agreement with these findings, stearic acid was tentatively identified as a bioactive candidate compound. PMID- 29165052 TI - JPEN Journal Club 31. Heterogeneity. PMID- 29165051 TI - A structure-function analysis in patients with prekallikrein deficiency. AB - OBJECTIVE: To investigate the structure-function relation in prekallikrein (PK) deficiency. PK is one of the proteins of the contact phase of blood coagulation which at the present time is the object of a revival of interest. METHODS: All patients with PK deficiency who had been investigated by molecular biology techniques are the object of the present investigation. Details of patients were obtained from personal files and a time-unlimited PubMed search. Only cases with a molecular-biology-based diagnosis were included. RESULTS: Twelve families were included. The total number of missense mutation was 10, together with 3 stop codons and 2 insertions. These mutations involved mainly exons 11 and 14. There were eight proved homozygotes and three compound heterozygotes. In one instance, homozygosity was probable but not proved. In nine cases, the defect was Type I, whereas it was Type II in the remaining three. No bleeding manifestations were present in 11 of the 12 probands. One proband had epistaxis, but she had hypertension. Altogether, four patients had hypertension and one of them had also two myocardial infarctions. CONCLUSIONS: Despite the paucity of cases, it was established that the majority of mutations involved the catalytic domain. It is auspicable that future reports of patients with this disorder should include molecular studies. This would certainly contribute to the understanding of the contact phase of blood coagulation. PMID- 29165053 TI - Pathophysiology of Enteral Feeding Diarrhea: The Intestinal Responses to Enteral Feeding Rather Than Any Role of FODMAPs. PMID- 29165056 TI - Citrinin induces apoptosis in human HCT116 colon cancer cells through endoplasmic reticulum stress. AB - The mycotoxin citrinin (CTN) is a natural contaminant of various human foods that may produce serious adverse health problems. Several studies demonstrated that citrinin exerts cytotoxic and genotoxic effects in both in vivo and in vitro systems. However, the precise mechanisms of action (MOA), particularly in intestinal cells remain unclear. The aim of the present study was to examine the precise MOA of citrinin in vitro. Data demonstrated that CTN significantly decreased the number of viable human intestinal HCT116 cells and induced apoptotic events including (1) decrease in Delta?m indicative of mitochondrial membrane permeabilization, (2) activation of caspase 3, (3) elevated production of reactive oxygen species (ROS) and (4) relative persistence of plasma membrane integrity. Further, the genetic deficiency of the pro-apoptotic protein Bax protected cells against CTN-induced apoptosis, indicating that Bax is required for CTN-mediated toxicity. It was also found that CTN triggered endoplasmic reticulum (ER) stress and activated different arms of the unfolded protein response (UPR) as demonstrated by increase in expression of GRP78 (glucose regulated protein-78), GRP94 (glucose-regulated protein-94), GADD34 (growth arrest and DNA damage-inducible protein-34), the protein disulfide isomerase associated 6 (PDIA6), CHOP (C/EBP-homologous protein) and the splicing of XBP1 (X Box Binding Protein 1). Pretreatment of cells with the chemical chaperone 4 phenylbutyrate (PBA), known to alleviate ER stress, prevented significantly the apoptotic process triggered by CTN. Taken together, these results suggest that CTN exerts its cytotoxic effects in HCT116 cells by inducing apoptosis, at least in part, through induction of ER stress. PMID- 29165058 TI - Erratum. PMID- 29165059 TI - Influence of type of MVC test on electromyography measures of biceps brachii and triceps brachii. AB - OBJECTIVE: This study aimed to investigate the amplitude and frequency measures of the electromyography (EMG) signal in agonistic and antagonistic muscles (biceps brachii, triceps brachii). METHODS: Fifteen males (22.9 +/- 2.1 years old) took three isometric maximum voluntary contraction (MVC) tests. Two tests were typical MVC tests for biceps brachii and triceps brachii. The third was a test often used to obtain MVC for forearm muscles (arm and forearm hanging down). The EMG signal was recorded during three isometric MVC muscle contractions and during a relaxation test. RESULTS: There were no differences in amplitude between relaxation and MVC antagonist in static contraction, with higher values for frequency measures in relaxation. When biceps brachii and triceps brachii act as antagonists in an MVC test, frequency measures present lower values than when the muscles act as agonists. Biceps brachii shows much lower amplitude than during an agonist MVC contraction with similar spectral measures. Triceps brachii presents much higher values of spectral measures than during an agonist MVC test. CONCLUSION: The type of exerted force, i.e., if a muscle acted as an agonist, antagonist or stabilizer, affects the relationship between the time and frequency domain measures. PMID- 29165057 TI - Pulmonary toxicity and global gene expression changes in response to sub-chronic inhalation exposure to crystalline silica in rats. AB - Exposure to crystalline silica results in serious adverse health effects, most notably, silicosis. An understanding of the mechanism(s) underlying silica induced pulmonary toxicity is critical for the intervention and/or prevention of its adverse health effects. Rats were exposed by inhalation to crystalline silica at a concentration of 15 mg/m3, 6 hr/day, 5 days/week for 3, 6 or 12 weeks. Pulmonary toxicity and global gene expression profiles were determined in lungs at the end of each exposure period. Crystalline silica was visible in lungs of rats especially in the 12-week group. Pulmonary toxicity, as evidenced by an increase in lactate dehydrogenase (LDH) activity and albumin content and accumulation of macrophages and neutrophils in the bronchoalveolar lavage (BAL), was seen in animals depending upon silica exposure duration. The most severe histological changes, noted in the 12-week exposure group, consisted of chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis. Microarray analysis of lung gene expression profiles detected significant differential expression of 38, 77, and 99 genes in rats exposed to silica for 3-, 6-, or 12 weeks, respectively, compared to time-matched controls. Among the significantly differentially expressed genes (SDEG), 32 genes were common in all exposure groups. Bioinformatics analysis of the SDEG identified enrichment of functions, networks and canonical pathways related to inflammation, cancer, oxidative stress, fibrosis, and tissue remodeling in response to silica exposure. Collectively, these results provided insights into the molecular mechanisms underlying pulmonary toxicity following sub-chronic inhalation exposure to crystalline silica in rats. PMID- 29165060 TI - Relationship between race and outcome in Asian, Black, and Caucasian patients with spontaneous intracerebral hemorrhage: Data from the Virtual International Stroke Trials Archive and Efficacy of Nitric Oxide in Stroke trial. AB - Background and purpose Although poor prognosis after intracerebral hemorrhage relates to risk factors and hematoma characteristics, there is limited evidence for the effect of race-ethnicity. Methods Data from 1011 patients with intracerebral hemorrhage enrolled into hyperacute trials and randomized to control were obtained from the Virtual International Stroke Trials Archive and Efficacy of Nitric Oxide in Stroke Trial. Clinical characteristics and functional outcome were compared among three racial groups - Asians, Blacks, and Caucasians. Results The majority of patients were Caucasian (78.1%) followed by Asians (14.5%) and Blacks (5.5%). At baseline, Caucasians were older and had larger hematoma volumes; Blacks had lower Glasgow Coma Scale and higher systolic blood pressure (all p < 0.05). Although the primary outcome of modified Rankin Scale did not differ at 90 days (p = 0.14), there were significant differences in mortality (p < 0.0001) and quality of life (EQ-5D p < 0.0001; EQ-VAS p 0.015). In test of multiple comparisons, Caucasians were more likely to die (p = 0.0003) and had worse quality of life (EQ-5D p = 0.003; EQ-VAS p < 0.0001) as compared to Asians. Conclusion Race-ethnicity appears to explain some of the variation in clinical characteristics and outcomes after acute intracerebral hemorrhage. Factors that explain this variation need to be identified. PMID- 29165061 TI - Posterior nutcracker syndrome - a systematic review. AB - Posterior nutcracker syndrome (PNCS) is the entrapment of the left renal vein between the aorta and the vertebral column. Although uncommon, it is still an important diagnosis due to the high morbidity associated with the risk of secondary anaemia from haematuria, from long-term left renal vein hypertension, vascular thrombosis, and even blood clots in the urinary system. A literature search of PubMed and EMBASE databases was performed and 27 publications containing 27 cases were included for the final analysis. The following frequency of clinical signs and symptoms was noted: twenty-five patients had haematuria, 13 patients had flank pain, and two had hypertension. Overall, male-female distribution was balanced and there were more adult than paediatric (age < 18 years) patients. All symptoms of patients with conservative treatment were either well-controlled or under spontaneous resolution. Conservative management instead of surgical treatment should be preferred in most cases. Taken together, despite the low incidence of PNCS, its recognition and management are highly important. This systematic study explores the evidence base for conservative and medical options. PMID- 29165062 TI - Recent Progress of Crosslinking Strategies for Polymeric Micelles with Enhanced Drug Delivery in Cancer Therapy. AB - The drug delivery by versatile types of self-assembled micelles for tumor treatment, which improved the diagnostic and therapeutic effectiveness, is advocated. However, despite the numerous advantages, applications of most micelle system have been retarded by low in vivo bio-stability which led to premature drug release and nonspecific tissue accumulation. To date, a range of chemistries has been introduced in intermolecular non-covalent/covalent crosslinking strategies for these dynamic nanostructures to produce robust functional nanoparticles with enhanced circulation stability and lower non-targeted organ toxicity. In this review, we focused on recent developments in crosslinking polymeric nanoparticles in cancer therapy. Types of chemistries used in the crosslinking strategies of the micelles are outlined and their enhanced drug delivery abilities are discussed. PMID- 29165063 TI - High-Throughput Screening Strategies for the Development of Anti-Virulence Inhibitors Against Staphylococcus Aureus. AB - The increasing threats of antibiotic resistance urge the need for developing new approaches to combat bacterial infections. Unlike conventional antibiotics that aim to kill bacteria or inhibit their growth, targeting bacterial virulence may be a promising alternative approach, which imposes weaker selective pressure for the generation of resistance. Here, we review the pathways related to staphylococcal virulence, summarize the high-throughput screening strategies used to identify novel anti-virulence inhibitors, and discuss the advantages and disadvantages of these strategies. PMID- 29165064 TI - Immunosensors in Early Cancer Diagnostics: From Individual to Multiple Biomarker Assays. AB - Cancer is a widespread disease characterized by high mortality. To improve the survival rate or facilitate effective therapy, accurate and reliable diagnosis at an early stage is needed. For this reason, there is a continuous push to develop sensitive methods which can be used in cancer diagnosis. Current diagnosis relies on the quantification of cancer biomarkers defined as molecules that are measurable in body fluids or tissues and indicate a change in physiological processes with subsequent pathological manifestations. This contribution reviews recent developments in the area of electrochemical immunosensors applicable for the detection of cancer biomarkers that occur in a wide concentration range including extremely low levels, which are typical for the early stage of the disease. A summary of various antibody labels used for biomarker analysis and combined with electrochemical detection is presented. The potential of multiple biomarker analysis, with its indisputable clinical impact for accurate diagnosis, is also highlighted. PMID- 29165065 TI - Electrochemical Nucleic Acid-Based Biosensing of Drugs of Abuse and Pharmaceuticals. AB - BACKGROUND: Studies on the interactions of DNA with small molecular drugs are currently performed both to explore their mechanism of action and to develop new drugs. Electrochemical biosensors offer a very promising alternative to more complex conventional techniques for drug determination due to rapidness, low cost, simplicity, high sensitivity and compatibility with use in different settings. In this review, selected electrochemical nucleic acid-based biosensing methods described so far for the determination of pharmaceuticals and illicit drugs are briefly overviewed, discussing their basics and main features. A section pointing out general conclusions and future directions in this field is also provided. RESULTS: The 42 selected contributions described electrochemical platforms to determine drugs of interest by monitoring their specific interactions with nucleic acids (DNA and aptamers), DNA damage and specific DNA protein interactions. The highlighted approaches reported the use of electrodes unmodified or modified with nanomaterials and/or polymers in which DNA-drug interaction was followed by electrochemical detection of DNA puric bases, active drug or diffusion-free markers, and monitoring changes in the surface layer morphology/permeability and charge transfer resistance using different electrochemical techniques. CONCLUSION: Although electrochemical nucleic acid biosensing approaches constitute an interesting option for drugs determination in terms of cost, simplicity and miniaturized instrumentation, validating exhaustively their performance in real samples against conventional methodologies and implementing them into portable and automatic high throughput devices, together with exploring novel electrode modifications with nanomaterials and polymers and studying in more detail their multiplexing ability for analysis of a large number of analytes, is still needed. PMID- 29165066 TI - Dysregulated Pathway Identification of Alzheimer's Disease Based on Internal Correlation Analysis of Genes and Pathways. AB - Dysregulated pathway identification is an important task which can gain insight into the underlying biological processes of disease. Current pathway identification methods focus on a set of co-expression genes and single pathways and ignore the correlation between genes and pathways. The method proposed in this study, takes into account the internal correlations not only between genes but also pathways to identifying dysregulated pathways related to Alzheimer's disease (AD), the most common form of dementia. In order to find the significantly differential genes for AD, mutual information (MI) is used to measure interdependencies between genes other than expression valves. Then, by integrating the topology information from KEGG, the significant pathways involved in the feature genes are identified. Next, the distance correlation (DC) is applied to measure the pairwise pathway crosstalks since DC has the advantage of detecting nonlinear correlations when compared to Pearson correlation. Finally, the pathway pairs with significantly different correlations between normal and AD samples are known as dysregulated pathways. The molecular biology analysis demonstrated that many dysregulated pathways related to AD pathogenesis have been discovered successfully by the internal correlation detection. Furthermore, the insights of the dysregulated pathways in the development and deterioration of AD will help to find new effective target genes and provide important theoretical guidance for drug design. PMID- 29165067 TI - Optimized Virtual Screening Workflow: Towards Target-Based Polynomial Scoring Functions for HIV-1 Protease. AB - BACKGROUND: One key step in the development of inhibitors for an enzyme is the application of computational methodologies to predict protein-ligand interactions. The abundance of structural and ligand-binding information for HIV 1 protease opens up the possibility to apply computational methods to develop scoring functions targeted to this enzyme. OBJECTIVE: Our goal here is to develop an integrated molecular docking approach to investigateprotein-ligand interactions with a focus on the HIV-1 protease. In addition, with this methodology,we intend to build target-based scoring functions to predict inhibition constant (Ki) for ligandsagainst the HIV-1 protease system. METHODS: Here, we described a computational methodology to build datasets with decoys and actives directly taken from crystallographic structures to be applied in evaluation of docking performance using the program SAnDReS. Furthermore, we built a novel function using as terms MolDock and PLANTS scoring functions to predict binding affinity. To build a scoring function targeted to the HIV-1 protease, we have used machine-learning techniques. RESULTS: The integrated approach reported here has been tested against a dataset comprised of 71 crystallographic structures of HIV protease, to our knowledge the largest HIV-1 protease dataset tested so far. Comparison of our docking simulations with benchmarks indicated that the present approach is able to generate results with improved accuracy. CONCLUSION: We developed a scoring function with performance higher than previously published benchmarks for HIV-1 protease. Taken together, we believe that the approach here described has the potential to improve docking accuracy in drug design projects focused on HIV-1 protease. PMID- 29165068 TI - Identifying Candidates for Breast Cancer Using Interactions of Chemicals and Proteins. AB - Breast cancer is one of the major cause of cancer death in women worldwide. Therefore, it is urgent to discovery novel drugs or design effective treatments for this disease. However, the research and development of drugs by using only experimental methods is always time-consuming and expensive. With the development of computer science, some advanced computational methods can make full use of known knowledge to design candidate drugs, thereby reducing the cost and time of experimental testing. In this study, a computational method was proposed to identify novel candidates for breast cancer. The approved drugs and genes of breast cancer were taken as the input of the method. The chemical-chemical interactions and chemical-protein interactions were adopted to extract possible candidates from large numbers of existing chemicals. The method included three stages, termed searching stage, filtering stage and selecting stage. In the searching stage, chemicals that have associations with approved drugs were extracted. Then, these chemicals were screened in the filtering stage to discard those that have no relationships with breast cancer related genes. Finally, a clustering algorithm, termed as EM clustering algorithm, was employed to identify the potential candidates in the selecting stage. An extensive analysis by retrieving literature indicated that multiple selected candidates, such as gefitinib, canertinib and sirolimus, that have been approved for other diseases were confirmed to have anti-breast cancer activities. Therefore, this method can provide some valuable instructions for drug repositioning. PMID- 29165069 TI - Predicting Hepatotoxicity of Drug Metabolites Via an Ensemble Approach Based on Support Vector Machine AB - OBJECTIVE: Drug-induced liver injury (DILI) is a major cause of drug withdrawal. The chemical properties of the drug, especially drug metabolites, play key roles in DILI. Our goal is to construct a QSAR model to predict drug hepatotoxicity based on drug metabolites. MATERIALS AND METHODS: 64 hepatotoxic drug metabolites and 3,339 non-hepatotoxic drug metabolites were gathered from MDL Metabolite Database. Considering the imbalance of the dataset, we randomly split the negative samples and combined each portion with all the positive samples to construct individually balanced datasets for constructing independent classifiers. Then, we adopted an ensemble approach to make prediction based on the results of all individual classifiers and applied the minimum Redundancy Maximum Relevance (mRMR) feature selection method to select the molecular descriptors. Eventually, for the drugs in the external test set, a Bayesian inference method was used to predict the hepatotoxicity of a drug based on its metabolites. RESULTS: The model showed the average balanced accuracy=78.47%, sensitivity =74.17%, and specificity=82.77%. Five molecular descriptors characterizing molecular polarity, intramolecular bonding strength, and molecular frontier orbital energy were obtained. When predicting the hepatotoxicity of a drug based on all its metabolites, the sensitivity, specificity and balanced accuracy were 60.38%, 70.00%, and 65.19%, respectively, indicating that this method is useful for identifying the hepatotoxicity of drugs. CONCLUSIONS: We developed an in silico model to predict hepatotoxicity of drug metabolites. Moreover, Bayesian inference was applied to predict the hepatotoxicity of a drug based on its metabolites which brought out valuable high sensitivity and specificity. PMID- 29165070 TI - Bortezomib in Kidney Transplant: Current Use and Perspectives. AB - BACKGROUND: Despite major advances in transplant medicine, antibody-mediated rejection (AMR) continues to have severe clinical implications and adversely affect graft survival. Therefore, the search for alternative drugs to treat AMR is widely pursued. The first-in-class proteasome inhibitor bortezomib (BZ) is a selective inhibitor of the 26S proteasome, which was initially approved for the treatment of malignant plasma cell disorders. METHODS: This review encompasses how our understanding of inhibiting proteasome pathway created the basis of BZ research and important milestones accomplished in AMR treatment in the transplant setting. It further discusses at length the results of clinical studies, the tolerability profile, drug-drug interactions and the perspectives of BZ use in desensitization protocols. RESULTS: Proteasome inhibition can downregulate NF kappaB activity; decrease cell proliferation/differentiation; induce apoptosis via cell cycle arrest, endoplasmic reticulum stress and caspase induction due the accumulation of unfolded or misfolded proteins; and downregulate antigen presentation, cell-cell interaction, and cell migration. Proteasome inhibition is more evident in cells with high rate of protein synthesis and secretion, like plasma cells. These cells play a critical role in the production of antibodies during AMR. CONCLUSIONS: There is accumulating evidence that the proteasome inhibitor BZ may substantially affect the function and integrity of alloantibody secreting plasma cells in AMR after organ solid transplant, as well as the activation, proliferation and differentiation of T- and B-lymphocytes. Recent clinical studies have provided evidence that BZ has the capability to downregulate circulating antibodies and treat AMR episodes. Additional randomized controlled studies are required to assess the impact of BZ during short and long follow-ups. PMID- 29165071 TI - Minocycline-loaded In situ Hydrogel for Periodontitis Treatment. AB - BACKGROUND: Periodontitis is a localized inflammatory disorder. If not treated timely, the disease can result in loosening and subsequent loss of teeth. In situ hydrogel prepared with phase separation technique has emerged as an attractive alternative for periodontal pocket injection. OBJECTIVE: Minocycline (MCL)-loaded in situ hydrogel was prepared composed of poly(lactide-coglycolide) (PLGA) and N methylpyrrolidone (NMP) to improve the topical treatment effect of periodontitis. METHOD: A series of reasonable and applicable formulations were optimized by investigating their syringeability, viscosity and in vitro drug release. The rheological profiles, antimicrobial activities and pharmacodynamics were further studied to evaluate its effect on periodontitis treatment. RESULTS: The prepared MCL/PLGA hydrogel exhibited the characteristic of Newton fluid with acceptable syringeability. Drug release could last for more than 48 hours with an acceptable "burst release". It also had obvious antimicrobial activities and pharmacodynamics efficiency similar to the commercial product, Parocline(r). CONCLUSION: MCL/PLGA in situ hydrogel may be a promising clinical formulation for periodontitis treatment. PMID- 29165072 TI - mPEG-PLA Micelle for Delivery of Effective Parts of Andrographis Paniculata. AB - BACKGROUND: Many studies have shown that Andrographis paniculata (Burm. f.) Nees has a good anti-tumor effect, but poor solubility in water and poor bioavailability hinder the modernization of it. METHOD: To formulate the effective parts (mainly diterpene lactones) of Andrographis paniculata (AEP) into targeting drug delivery system, a series of poly(ethylene glycol)-poly(D.L-lactic acid)(mPEG-PLA) with different ratio of hydrophilic and hydrophobic segment was synthetized to encapsulate AEP. AEP micelles were prepared by a simple solvent evaporation method. According to the loading capacity, the best polymer was chosen. mPEG-PLA micelles were characterized in terms of drug entrapping efficiency, loading capacity, size, the crystalline state of AEP, stability and release profile. Meanwhile, the cytotoxicity of micelles on mouse breast cancer 4T-1 was investigated. RESULTS: These micelle (mPEG-PLA-AEP) particles had a size of (92.84+/-5.63) nm and a high entrapping efficiency and loading capacity of (91.00+/-11.53)% and (32.14+/-3.02)%(w/w), respectively. The powder DSC showed that drugs were well encapsulated in the core of micelles. mPEG-PLA-AEP had a good stability against salt dissociation, protein adsorption and anion substitution and the solubility of andrographolide (AG) and 14-deoxy-11,12 didehydroandrographolide(DDAG) in AEP increased 4.51 times and 2.12 times in water, and the solubility of DAG showed no difference. mPEG-PLA-AEP had the same release profile in different dissolution medium. Cytotoxicity testing in vitro demonstrated that mPEG-PLA-AEP exhibited higher cell viability inhibition in mouse breast cancer 4T-1 than free AEP. CONCLUSION: mPEG-PLA micelles offer a promising alternative for TCM therapy with higher solubility and improved antitumor effect. PMID- 29165073 TI - Recent Progress in Delivery of Therapeutic and Imaging Agents Utilizing Organic Inorganic Hybrid Nanoparticles. AB - BACKGROUND: Delivery of conventional small molecule drugs and currently evolving nucleic acid-based therapeutics, such as small interfering RNAs (siRNAs) and genes, and contrast agents for high resolution imaging, to the target site of action is highly demanding to increase the therapeutic and imaging efficacy while minimizing the off-target effects of the delivered molecules, as well as develop novel therapeutic and imaging approaches. METHODS: We have undertaken a structured search for peer-reviewed research and review articles predominantly indexed in PubMed focusing on the organic-inorganic hybrid nanoparticles with evidence of their potent roles in intracellular delivery of therapeutic and imaging agents in different animal models. RESULTS: Organic-inorganic hybrid nanoparticles offer a number of advantages by combining the unique properties of the organic and inorganic counterparts, thus improving the pharmacokinetic behavior and targetability of drugs and contrast agents, and conferring the exclusive optical and magnetic properties for both therapeutic and imaging purposes. Different polymers, lipids, dendrimers, peptides, cell membranes, and small organic molecules are attached via covalent or non-covalent interactions with diverse inorganic nanoparticles of gold, mesoporous silica, magnetic iron oxide, carbon nanotubes and quantum dots for efficient drug delivery and imaging purposes. CONCLUSION: We have thus highlighted here the progress made so far in utilizing different organicinorganic hybrid nanoparticles for in vivo delivery of anti-cancer drugs, siRNA, genes and imaging agents. PMID- 29165074 TI - State of the Art of Dental Adhesive Systems. AB - BACKGROUND: The large dependence on a dental substrate type to bond strength has leveraged the research on materials and techniques that perform different clinical behavior, promoting a stable bonding over time. Bonding to tooth structure has different clinical behaviors and is dependent on several factors. OBJECTIVE: The aim of this paper is to reflect on the state of the art of adhesive systems after the emergence of Buonocore's experiments in current days. METHODS: An electronic search was conducted on PubMed databases and supplemented with a manual study of relevant references. RESULTS: The choice of the ideal adhesive system remains under discussion, housing a range of studies that highlight its potential characteristics, suggesting techniques that enable improvement to boost clinical outcomes. CONCLUSION: It is important to know all different types of adhesive systems, as well as their indications and limitations. An attentive consideration of several factors is crucial to achieve clinical success on the restorative procedures. PMID- 29165075 TI - Preferential Formulation of Second Generation Antipsychotic Asenapine as Inclusion Complex with Sulphobutylether-betaCD (Captisol): In vitro and In vivo Evaluation. AB - BACKGROUND: Asenapine is an anti-psychotic agent approved by the US-FDA for treatment of acute schizophrenia and manic or bipolar I disorder in adults. It is poorly absorbed when administered orally, hence exhibits poor oral bioavailability, which limits its use in clinical practice. OBJECTIVE: Enhancement in solubility of asenapine through complexation with three different cyclodextrins, viz. betaCD, HPbetaCD and sulphobutylether-betaCD (Captisol(r)) was attempted and compared due to its poor bioavailability. METHOD: Kneading method was used for preparation of inclusion complexes which were characterized by FTIR, DSC, and XRD methods. Extent of binding and stability of the 1:1 inclusion complexes were evaluated by molecular modelling and phase solubility studies. Pharmacokinetic studies were also carried out of these inclusion complexes. RESULTS: Captisol(r) complex was the most stable amongst all complexes showing 4.9 times solubility enhancement of asenapine and 96% drug release at the end of 60 min, whereas asenapine maleate (uncomplexed drug) was released completely at the end of 120min. The Cmax and AUC values of Captisol(r) asenapine complex (AS-Captisol complex) were 2.8 and 2.3 times higher than the uncomplexed drug. CONCLUSION: This study thus demonstrated that Captisol(r) inclusion complex is an effective strategy for solubility and bioavailability enhancement of asenapine. PMID- 29165076 TI - PASylation as a Powerful Technology for Improving the Pharmacokinetic Properties of Biopharmaceuticals. AB - : Bckground: One of the major challenges of biopharmaceuticals having short plasma half-life is that daily high dose injections are needed which can lead to economic burden, patient inconvenience and undesirable side effects. Increasing the hydrodynamic volume beyond the pore size of the glomerular basal membrane is a viable approach to increase the size of small biopharmaceuticals with short half-life in blood circulation. OBJECTIVES: PASylation technology is based on the genetic fusion of biopharmaceuticals with a hydrophilic random coil sequence of proline (Pro), alanine (Ala), and serine (Ser) amino acids. METHOD: In this review, we focus on PASylation technology as a novel method to enhance the pharmacokinetic (PK) properties of biopharmaceuticals. RESULTS: PASylated biopharmaceuticals are suitable for the production in Escherichia coli (E.coli) as well as eukaryotic expression systems like yeast, HEK or CHO cells and comprise a homogeneous PAS sequence with exact length.We explain the general concept of PASylation, its development; advantages compared to other PK modifying technologies and describe furthermore the pharmacodynamic (PD) and PK properties of several PAS-fusion proteins in preclinical studies. CONCLUSION: The biodegradable PAS sequence was already used for prolonging plasma half-life of clinical important agents such as antibody fragments, cytokines, enzymes and receptor-binding peptides. PMID- 29165077 TI - Physicochemical and Toxic Properties of Novel Genipin Drug Delivery Systems Prepared by Mechanochemistry. AB - BACKGROUND: Complexes of Genipin and different water-soluble adjuvant polysaccharides, such as arabinogalactane, hydroxyethyl starch, fibergum, and oligosaccharides beta-CD and HP-beta-CD, were synthesized as drug delivery system using mechanochemical technology. METHOD: We have investigated physicochemical properties, stability, and hepatotoxicity of the synthesized complexes in solid state and aqueous solution. The formation of the complexes was evidenced by different physical and spectroscopy assays, and the stability constants of our synthesized Genipin-based complexes were also calculated. RESULTS: The HP-beta-CD inclusion complex showed the highest characteristics. We have found that the molecule of Genipin was completely included in the cyclodextrin cavity of the HP beta-CD. This complex of Genipin has shown a 6.14-fold increase of solubility compared with the original Genipin, and more stable in solvent and solid states. CONCLUSION: The hepatotoxicity assays showed that our investigated complexes of Genipin are much safer than the original Genipin. These results suggest that new Genipin-based preparations can be synthesized with advantageous of higher stability and safety. PMID- 29165078 TI - Pharmaceutical Product Lead Optimization for Better In vivo Bioequivalence Performance: A case study of Diclofenac Sodium Extended Release Matrix Tablets. AB - BACKGROUND: In order to prove the validity of a new formulation, a considerable amount of effort is required to study bioequivalence, which not only increases the burden of carrying out a number of bioequivalence studies but also eventually increases the cost of the optimization process. OBJECTIVE: The aim of the present study was to develop sustained release matrix tablets containing diclofenac sodium using natural polymers and to demonstrate step by step process of product development till the prediction of in vivo marketed product equivalence of the developed product. METHOD: Different batches of tablets were prepared by direct compression. In vitro drug release studies were performed as per USP. The drug release data were assessed using model-dependent, modelindependent and convolution approaches. RESULTS: Drug release profiles showed that extended release action were in the following order: Gum Tragacanth > Sodium Alginate > Gum Acacia. Amongst the different batches prepared, only F1 and F8 passed the USP criteria of drug release. Developed formulas were found to fit Higuchi kinetics model with Fickian (case I) diffusion-mediated release mechanism. Model- independent kinetics confirmed that total of four batches were passed depending on the similarity factors based on the comparison with the marketed Diclofenac. The results of in vivo predictive convolution model indicated that predicted AUC, Cmax and Tmax values for batch F8 were similar to that of marketed product. CONCLUSION: This study provides simple yet effective outline of pharmaceutical product development process that will minimize the formulation development trials and maximize the product success in bioequivalence studies. PMID- 29165079 TI - Comparison of Clobetasol Propionate Generics Using Simplified In vitro Bioequivalence Method for Topical Drug Products. AB - BACKGROUND: The aim of this paper is to evaluate a simple in vitro skin penetration experiment in which the drug is extracted from the whole skin piece as a test valid for formulation screening and optimization during development process, equivalence assessment during quality control or postapproval after changes to the product. METHODS: Twelve clobetasol propionate (CP) formulations (six creams and six ointments, being five generics and one reference from each formulation type) from the local market were used as a model to challenge the evaluated methodology in comparison to in vitro skin penetration following tape stripping for drug extraction. To support the results, physicochemical tests for pH, viscosity, density and assay, as well as in vitro release were performed. RESULTS: Both protocols, extracting the drug from the skin using the tape stripping technique or extracting from the full skin were capable of differentiating CP formulations. Only one formulation did not present statistical difference from the reference drug product in penetration tests and only other two oitments presented equivalent release to the reference. The protocol is straightforward and reproducible. CONCLUSION: Results suggest the bioinequavalence of tested CP formulations reinforcing the necessity of such evaluations. PMID- 29165080 TI - Tuberculosis Treated by Multiple Drugs: An Overview. AB - BACKGROUND: Tuberculosis is an infection and caused by gentle growing bacteria. The Internet provides opportunities for people with tuberculosis (TB) to connect with one another to address these challenges. OBJECTIVE: The aim of this paper is to introduce readers to the platforms on which Tuberculosis participants interact, to discuss reasons for and risks associated with TB-related activity, and to review research related to the potential impact of individual participation on TB outcomes. METHODS: Research and online content related to Tuberculosis online activity is reviewed, however, the difficulty in accurate prescribing and adhering to these protocols and the emergence of M. tuberculosis strains resistant to multiple drugs and drug-drug interactions that interfere with optimal treatment of Tuberculosis and co-infected patients with the different disease has generated a pressing need for improved Tuberculosis therapies. RESULTS: Together with the ominous global burden of Tuberculosis, those shortcomings of current medication have contributed to a renewed interest in the development of improved drugs and protocols for the medication of Tuberculosis. This article features obstacles related with the enhanced utilization of existing drugs and difficulties related with the advancement of enhanced products, concentrating on perspectives characteristic in Tuberculosis drug clinical improvement. The participation includes peer support, advocacy, self-expression, seeking and sharing TB information, improving approaches to Tuberculosis data management, and humour. CONCLUSION: This article highlights hurdles related to the optimised use of existing drugs and challenges related to the development of improved products, focusing on aspects inherent in Tuberculosis drug clinical development. Concluding comments offer processes for more efficient development of Tuberculosis therapies and increase the quality of life. PMID- 29165081 TI - Rheological Characteristics of Novel Meloxicam-Loaded Complex Organogels Based on Fumed Silica and Poloxamer. AB - BACKGROUND: Meloxicam is a non-steroidal anti-inflammatory drug revealing poor solubility in water and good permeability through biological membranes. It is currently administered mostly in forms exerting systemic effects, however, in some conditions topical formulations can be equally useful. OBJECTIVE: The objective of the presented work was to formulate and investigate in detail the rheological behavior of non-aqueous gels containing 0.5% of meloxicam in a non ionic, dissolved form. METHOD: Fumed silica and SynperonicTM PE/L 62 were used as structure forming components. Arlasolve (r), Transcutol(r), ethanol and DMSO were applied as solubilizers and potential skin absorption enhancers. Three formulations were selected for further investigation and compared to placebo samples. The gels were examined in terms of rheological properties, spreadability and loss of volatile components. RESULTS: The investigated samples revealed non Newtonian pseudoplastic behavior with apparent impact of meloxicam on the gel strength. The oscillatory analyses showed an incomplete recovery after structure destruction. Moreover, two yield points were observed, one related to the destruction of fumed silica lattice and the other one to the changes in the spatial arrangement of polymer chains. The tendency to evaporation of volatile components was insignificant. The best spreadability parameter was observed for gels containing Transcutol(r). CONCLUSION: In this study organogels with meloxicam in dissolved form were obtained and characterized. The performed tests showed that the mechanical properties of the investigated samples depended both on the presence of the drug and on the selection of excipients. The presented data are important in terms of semi-solid product manufacturing and further application by patients. PMID- 29165082 TI - Easy Screening for Mild Alzheimer's Disease and Mild Cognitive Impairment from Elderly Speech. AB - OBJECTIVE: This study presents a novel approach for early detection of cognitive impairment in the elderly. The approach incorporates the use of speech sound analysis, multivariate statistics, and data-mining techniques. We have developed a speech prosody-based cognitive impairment rating (SPCIR) that can distinguish between cognitively normal controls and elderly people with mild Alzheimer's disease (mAD) or mild cognitive impairment (MCI) using prosodic signals extracted from elderly speech while administering a questionnaire. Two hundred and seventy three Japanese subjects (73 males and 200 females between the ages of 65 and 96) participated in this study. The authors collected speech sounds from segments of dialogue during a revised Hasegawa's dementia scale (HDS-R) examination and talking about topics related to hometown, childhood, and school. The segments correspond to speech sounds from answers to questions regarding birthdate (T1), the name of the subject's elementary school (T2), time orientation (Q2), and repetition of three-digit numbers backward (Q6). As many prosodic features as possible were extracted from each of the speech sounds, including fundamental frequency, formant, and intensity features and mel-frequency cepstral coefficients. They were refined using principal component analysis and/or feature selection. The authors calculated an SPCIR using multiple linear regression analysis. CONCLUSION: In addition, this study proposes a binary discrimination model of SPCIR using multivariate logistic regression and model selection with receiver operating characteristic curve analysis and reports on the sensitivity and specificity of SPCIR for diagnosis (control vs. MCI/mAD). The study also reports discriminative performances well, thereby suggesting that the proposed approach might be an effective tool for screening the elderly for mAD and MCI. PMID- 29165083 TI - Subjective Spatial Navigation Complaints - A Frequent Symptom Reported by Patients with Subjective Cognitive Decline, Mild Cognitive Impairment and Alzheimer's Disease. AB - BACKGROUND: Great effort has been put into developing simple and feasible tools capable to detect Alzheimer's disease (AD) in its early clinical stage. Spatial navigation impairment occurs very early in AD and is detectable even in the stage of mild cognitive impairment (MCI). OBJECTIVE: The aim was to describe the frequency of self-reported spatial navigation complaints in patients with subjective cognitive decline (SCD), amnestic and non-amnestic MCI (aMCI, naMCI) and AD dementia and to assess whether a simple questionnaire based on these complaints may be used to detect early AD. METHOD: In total 184 subjects: patients with aMCI (n=61), naMCI (n=27), SCD (n=63), dementia due to AD (n=20) and normal controls (n=13) were recruited. The subjects underwent neuropsychological examination and were administered a questionnaire addressing spatial navigation complaints. Responses to the 15 items questionnaire were scaled into four categories (no, minor, moderate and major complaints). RESULTS: 55% of patients with aMCI, 64% with naMCI, 68% with SCD and 72% with AD complained about their spatial navigation. 38-61% of these complaints were moderate or major. Only 33% normal controls expressed complaints and none was ranked as moderate or major. The SCD, aMCI and AD dementia patients were more likely to express complaints than normal controls (p's<0.050) after adjusting for age, education, sex, depressive symptoms (OR for SCD=4.00, aMCI=3.90, AD dementia=7.02) or anxiety (OR for SCD=3.59, aMCI=3.64, AD dementia=6.41). CONCLUSION: Spatial navigation complaints are a frequent symptom not only in AD, but also in SCD and aMCI and can potentially be detected by a simple and inexpensive questionnaire. PMID- 29165084 TI - Advances on Automatic Speech Analysis for Early Detection of Alzheimer Disease: A Non-linear Multi-task Approach. AB - OBJECTIVE: Nowadays proper detection of cognitive impairment has become a challenge for the scientific community. Alzheimer's Disease (AD), the most common cause of dementia, has a high prevalence that is increasing at a fast pace towards epidemic level. In the not-so-distant future this fact could have a dramatic social and economic impact. In this scenario, an early and accurate diagnosis of AD could help to decrease its effects on patients, relatives and society. Over the last decades there have been useful advances not only in classic assessment techniques, but also in novel non-invasive screening methodologies. METHODS: Among these methods, automatic analysis of speech -one of the first damaged skills in AD patients- is a natural and useful low cost tool for diagnosis. RESULTS: In this paper a non-linear multi-task approach based on automatic speech analysis is presented. Three tasks with different language complexity levels are analyzed, and promising results that encourage a deeper assessment are obtained. Automatic classification was carried out by using classic Multilayer Perceptron (MLP) and Deep Learning by means of Convolutional Neural Networks (CNN) (biologically- inspired variants of MLPs) over the tasks with classic linear features, perceptual features, Castiglioni fractal dimension and Multiscale Permutation Entropy. CONCLUSION: Finally, the most relevant features are selected by means of the non-parametric Mann- Whitney U-test. PMID- 29165085 TI - A Speech Recognition-based Solution for the Automatic Detection of Mild Cognitive Impairment from Spontaneous Speech. AB - BACKGROUND: Even today the reliable diagnosis of the prodromal stages of Alzheimer's disease (AD) remains a great challenge. Our research focuses on the earliest detectable indicators of cognitive decline in mild cognitive impairment (MCI). Since the presence of language impairment has been reported even in the mild stage of AD, the aim of this study is to develop a sensitive neuropsychological screening method which is based on the analysis of spontaneous speech production during performing a memory task. In the future, this can form the basis of an Internet-based interactive screening software for the recognition of MCI. METHODS: Participants were 38 healthy controls and 48 clinically diagnosed MCI patients. The provoked spontaneous speech by asking the patients to recall the content of 2 short black and white films (one direct, one delayed), and by answering one question. Acoustic parameters (hesitation ratio, speech tempo, length and number of silent and filled pauses, length of utterance) were extracted from the recorded speech signals, first manually (using the Praat software), and then automatically, with an automatic speech recognition (ASR) based tool. First, the extracted parameters were statistically analyzed. Then we applied machine learning algorithms to see whether the MCI and the control group can be discriminated automatically based on the acoustic features. RESULTS: The statistical analysis showed significant differences for most of the acoustic parameters (speech tempo, articulation rate, silent pause, hesitation ratio, length of utterance, pause-per-utterance ratio). The most significant differences between the two groups were found in the speech tempo in the delayed recall task, and in the number of pauses for the question-answering task. The fully automated version of the analysis process - that is, using the ASR-based features in combination with machine learning - was able to separate the two classes with an F1-score of 78.8%. CONCLUSION: The temporal analysis of spontaneous speech can be exploited in implementing a new, automatic detection-based tool for screening MCI for the community. PMID- 29165086 TI - Association Between LTF Polymorphism and Risk of HIV-1 Transmission Among Zambian Seropositive Mothers. AB - BACKGROUND: Lactoferrin is a member of the innate immune system acting in the first line of defence against pathogens, and it is known for its antibacterial, antifungal and antiviral activity, including HIV-1. Two polymorphisms, T29A and R47K, in the exon 1 region of the LTF gene (encoding for the lactoferrin protein) were previously described as able to influence the lactoferrin antimicrobial function. OBJECTIVES: LTF T29A and R47K genetic variants were analysed in a Zambian population to unravel if these polymorphisms could play a role in HIV-1 mother-to-child HIV-1 transmission. METHODS: LTF T29A and R47K polymorphisms were genotyped, using allelic specific fluorescent probes and real time PCR, in a population comprising 101 HIV-1 positive mothers and 333 children born to seropositive mothers. RESULTS: Maternal LTF T29A A/A and A/G genotypes were found to be associated with decreased risk of HIV-1 MTCT, being more frequent among non transmitter mothers respect to transmitter mothers. CONCLUSION: Our data suggested that maternal LTF genetic background contributes to the susceptibility to HIV-1 transmission from mother to new-borns. PMID- 29165087 TI - Nucleotide Reverse Transcriptase Inhibitors: A Thorough Review, Present Status and Future Perspective as HIV Therapeutics. AB - BACKGROUND: Human immunodeficiency virus type-1 (HIV-1) infection leads to acquired immunodeficiency syndrome (AIDS), a severe viral infection that has claimed approximately 658,507 lives in the US between the years 2010-2014. Antiretroviral (ARV) therapy has proven to inhibit HIV-1, but unlike other viral illness, not cure the infection. OBJECTIVE: Among various Food and Drug Administration (FDA)-approved ARVs, nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) are most effective in limiting HIV-1 infection. This review focuses on NRTIs mechanism of action and metabolism. METHODS: A search of PubMed (1982-2016) was performed to capture relevant articles regarding NRTI pharmacology. RESULTS: The current classical NRTIs pharmacology for HIV-1 prevention and treatment are presented. Finally, various novel strategies are proposed to improve the efficacy of NRTIs, which will increase therapeutic efficiency of present-day HIV-1 prevention/treatment regimen. CONCLUSION: Use of NRTIs will continue to be critical for successful treatment and prevention of HIV 1. PMID- 29165088 TI - Detailed Molecular Surveillance of the HIV-1 Outbreak Among People who Inject Drugs (PWID) in Athens During a Period of Four Years. AB - BACKGROUND: New diagnoses of HIV-1 infection among people who inject drugs (PWID) increased significantly during 2011 in Athens. OBJECTIVE: Our aim was to investigate the patterns of HIV epidemic spread among PWID and to estimate the transmission dynamics for the major local transmission networks (LTNs). METHODS: We analyzed sequences from 2,274 HIV-infected subjects sampled in Greece during 01/01/2011-31/10/2014. Of specimens in our sample, 874 sequences were isolated from HIV-infected PWID. Phylodynamic analysis was performed using birth-death serial skyline models. RESULTS: Phylogenetic analysis revealed that the majority of sequences from PWID (N=746, 85.4%) fell within four LTNs: CRF14_BG (N=456, 58.3%), CRF35_AD (N=149, 19.1%), subtype B (N=118, 15.1%) and A1 (N=59, 7.5%). In addition to PWID, we also found that sequences from 36 non-PWID belonged to the LTNs corresponding to cross-group transmissions. Based on the estimated plots of the effective reproductive number (Re) over time, subtype A1 and CRF35_AD LTNs showed a sharp increase before and during 2011 (maximum value of Re=3.0 and Re=4.6, respectively). For subtype B and CRF14_BG LTNs, the Re was increasing until the end of 2012 (maximum value of Re=3.2 and Re=3.0, respectively). CONCLUSION: HIV transmissions within subtype A1 and CRF35_AD LTNs increased sharply during the early stage of the outbreak, in contrast to subtype B and CRF14_BG. A significant reduction in the number of infections was estimated on all transmission networks from the beginning of 2013 onwards. Prevention measures that took place in the Athens metropolitan area at the end of 2012 including also the ARISTOTLE program may explain this decrease. PMID- 29165089 TI - A Novel Method to Synthesize Phosphocreatine and Phosphocreatine Prodrugs. AB - BACKGROUND: Adenosine triphosphate (ATP) is the energy currency of the body; it takes part in various and indispensable metabolic processes for the maintenance of cell homeostasis, degrading to its hydrolysis product, adenosine diphosphate (ADP). Efficient ways to restore ATP are therefore necessary in the cells. When the cell lacks energy due to ischemic conditions or high ATP demand, phosphocreatine gives its phosphate group to ADP that converts to ATP, in a reaction catalyzed by the enzyme creatine kinase. For this reason, phosphocreatine is utilized as a pharmacological treatment in human diseases that involve a failure of the cellular energy, most notably in coronary artery disease. OBJECTIVE: Commercially available phosphocreatine is currently synthesized using different methods, each of one characterized by a rather low yield of the final product, probably due to the low reactivity of the guanylating reagent. The aim of this work is to overcome the drawbacks of the synthetic methods currently employed, devising a novel synthetic route to obtain phosphocreatine and phosphocreatine prodrugs in higher yields and purity. METHOD: To obtain a higher yield of the final product and a lower number of sub-products, this method utilizes a new guanylating agent characterized by high reactivity, endowed with a protecting group t-Boc on one of the two nitrogen atoms of the guanidinic function and a protected phosphate on the other one; that compound is then conjugated with an opportune secondary amine. The obtained product is cleaved first with acidic conditions to obtain the phosphocreatine prodrug (phosphocreatine ethyl ester) and then with an enzymatic method to obtain the phosphocreatine. RESULT: Have been obtained in good yield and purity as demonstrated by HPLC and mass spectrometry analysis. CONCLUSION: This novel synthetic route permits to obtain the phosphocreatine molecule in higher yield and purity compared to the methods currently employed with a combination of chemical and enzymatic methods. PMID- 29165090 TI - Inhibition of Adipogenesis by Thiourea Derivatives. AB - BACKGROUND: Obesity is one of the major health problems with inherent risk of type 2 diabetes, hypertension, CVDs, etc. Adipogenesis is a major contributor in the process of obesity. Inhibition of adipocytes differentiation is one of the key approaches to treat obesity. OBJECTIVE: To discover the new inhibitors of adipogenesis as the treatment for obesity. METHOD: We describe here, the synthesis, and anti-adipogenic activity of thiourea derivatives 1-14. These derivatives were synthesized by the reactions of phenyl and pentafluorophenyl isothiocyanate with different aromatic amines. Pure compounds 1-14 were evaluated for their in vitro antiadipogenesis activity employing 3T3-L1 cells lines. RESULTS: Compounds 1-3, 5-9, and 11-14 significantly inhibited the pre-adipocyte differentiation into adipocytes, which was measured by staining the cells, and through morphological examination. Compound 10 (1-(4"-Chlorophenyl)-3 (pentafluorophenyl)-thiourea) showed a potent inhibition of adipocyte differentiation with IC50 = 740.00 +/- 2.36 nM, which was more potent than the standards, epigallocatechin gallate (IC50 = 16.73 +/- 1.34 MUM), and curcumin (IC50 = 18.62 +/- 0.74 MUM). All other compounds showed a moderate to weak anti adipogenesis activity. Compounds 1- 14 were also evaluated for their cytotoxicity. Compounds 3, 10, and 14 showed some toxicity to the cancer cell lines, while compounds 2, 3, 10, 12, and 14 showed a moderate to weak cytotoxicity against the normal cell lines. CONCLUSION: All the compounds reported in this paper are known, except compound 11. They have been identified as new inhibitors of Adipogenesis. Adipogenesis is the process of adipocytes differentiation from pre-adipocytes. This extensively studied model of cell diff differentiation. Further synthetic modifications, and optimization of anti adipogenic activity may lead to the development of anti-obesity agents. PMID- 29165091 TI - Antibacterial Assessment of Heteroaryl, Vinyl, Benzyl, and Alkyl Tetrazole Compounds. AB - BACKGROUND: In previous reports, the antibacterial properties of certain tetrazole derivatives have been described. We have previously reported the antibacterial properties of aryl 1Htetrazole compounds. OBJECTIVE: To study the antibacterial activity of 5-substituted heteroaryl, vinyl, benzyl, and alkyl 1H tetrazole derivatives. METHODS: The antibacterial properties of heteroaryl, vinyl, benzylic, and aliphatic tetrazole derivatives were investigated against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The activity was assessed by determining the minimum inhibitory concentration of these tetrazole derivatives and comparing them to the known antibiotics amoxicillin, trimethoprim and sulfamethoxazole. RESULTS: The tetrazole compounds were prepared utilizing cerium(III) chloride heptahydrate catalysis at 160 degrees C for 1-4 h in a microwave reactor using an aqueous solvent mixture. The most active derivatives exhibited minimum inhibitory concentration values between 125-250 ug/mL against Escherichia coli. More importantly, these compounds were considerably more active when used in combination with trimethoprim and a significant synergistic effect was observed (MIC = 0.98-7.81 ug/mL) against E. coli and S. aureus. CONCLUSION: The tetrazole derivatives were synthesized in high yield and short reaction times in water. Several of the tetrazole compounds showed a significant synergistic antibacterial effect when used with trimethoprim. PMID- 29165092 TI - Synthesis, Characterization and Biological Activities of New Symmetric Bis-1,2,3 Triazoles with Click Chemistry. AB - BACKGROUND: 1,2,3-Triazole and its derivatives have important biological activities such as antimicrobial, anti-allergic, analgesic, anti-HIV, antiinflammatory, anticancer, antimalarial and antituberculosis. Other significant triazole derivatives are 1,2,4-triazoles which play a very important role in the medicinal chemistry due to the antiinflammatory, antimicrobial, antimigraine, anticancer, antimicrobial and antimycotic activities. In this study, we aimed to synthesize a new series of bis-1,2,3-triazole derivatives including 1,2,4-triazole to obtain more effective biological activities. METHODS: In this study, a new series of bis-1,2,3-triazole compounds (9,10,11) were synthesized. Antimicrobial Activity: Disc diffusion method was used. Enzyme Inhibition: alpha-Glucosidase Inhibition was investigated. Antioxidant Activities: DPPH Radical Scavenging, Phosphomolybdenum- Reducing Antioxidant Power (PRAP) and Ferrous Ion-Chelating methods were used. RESULTS: Compounds 9a, 9c, 9e, 9f, 10a, 10b, 10d, 11a, 11b and 11f showed significant antibacterial and antifungal activity against all the strains tested. Compound 9g exhibited the highest AChE inhibition. Compounds 10f, 11a and 11g showed remarkable activity against the BuChE enzyme. Compound 10f has the highest antioxidant activities. CONCLUSION: The compounds 9a, 9c, 9e, 9f, 10a, 10b, 10d, 11a, 11b and 11f exhibit the best antimicrobial activity against the bacteria and fungi C.albicans, Y. enterocolitica, E. coli, Candida albicans, Yersinia enterocolitica. Compound 9g exhibit the highest AChE inhibition with 72.67 +/- 3.92% at 100 ug/mL. Compounds 10f, 11a and 11g showed remarkable activity against the BuChE enzyme compared to galantamine. Many of the compounds exhibited significant alpha-glucosidase inhibition activities. Compound 10f has the highest antioxidant activities (DPPH, PRAP, ferrous ionchelating) with 27.71 +/- 0.85%, 0.689 +/- 0.005, 42.07 +/- 2.48 at 100 ug/mL, respectively. PMID- 29165093 TI - A Randomized, Double Blind, Placebo Controlled, Crossover Study to Assess the Safety and Beneficial Effects of Cassia Tora Supplementation in Healthy Adults. AB - OBJECTIVE: The current clinical trial was aimed at evaluating the safety and beneficial effect of Cassia tora (C. tora) supplementation in healthy adults. DESIGN: A randomized, double blind, placebo controlled study with a crossover design was done on 60 healthy normal weight adults (age range: 20-55 yrs). The study consisted of 2 treatment phases of 24 weeks each with a washout period of 4 weeks between the phases. 30 subjects randomly allocated to the 'Placebo first' group and 30 to 'C. tora first' group and assigned to receive a dose of C. tora (330 mg) or matched placebo three times a day. Safety markers were measured at base line and at the end of both the treatment phases. Body mass index, blood pressure, fasting blood sugar, glycated hemoglobin, lipid profile and antioxidants were measured at baseline and at every three months interval. Repeated measures analysis was applied to assess the period and carryover effects of the drug over placebo on biochemistries. RESULTS: C. tora supplementation was well tolerated and no apparent changes were observed in safety markers. The net effect of C. tora in natural units over placebo was 0.83 [0.57, 1.09]- high density lipoprotein cholesterol; 27.63 [24.39, 30.88]- superoxide dismutase; 0.32 [0.28, 0.36]- catalase; 0.68 [0.56, 0.80]- glutathione peroxidase; 0.25 [0.22, 0.29]- glutathione s-transferase; 0.32 [0.29, 0.36]- glutathione and -1.08 [ 1.63, -0.54]- low density lipoprotein cholesterol. CONCLUSION: The findings advocate that C. tora supplementation is safe and beneficial in elevating high density lipoprotein cholesterol and antioxidants and hence advised for consumption. PMID- 29165094 TI - Potential Risks and Mitigation Strategies During the Conduct of a Clinical Trial: An Industry Perspective. AB - BACKGROUND: Every phase of a clinical trial should be designed in compliance with good clinical practices by following all relevant regulatory guidelines. Patient safety, data integrity and ethics are an integral part of a successful clinical trial which must be considered. Therefore, risk monitoring is an essential tool to identify the risks associated with conduct of any trial. This article is a result of extensive research conducted by a reputed pharmaceutical company to identify the potential stages of risks associated with the conduct phase of trial that could impact the overall quality and safety of a trial. METHODS: The skillful and experienced team members of a reputed pharmaceutical company involved in conducting clinical trials underwent brainstorming sessions to assess and categorize the risks associated with each stage of conduct phase of a clinical trial. They also developed a mitigation plan based on their experiences, best practices and applicable guidance documents. RESULTS: During conduct phase, risks are associated with preparation of site master and trial master file, courier of study supply to site(s) including investigational product prior to site initiation visit, patient recruitment, telephonic monitoring, adverse or serious adverse event monitoring, site monitoring visit(s), collected case report form pages forward to data management vendor, data query clarification and site close-out visit. CONCLUSION: A close working relationship with all the persons associated with the clinical trial, timely monitoring and prospective mitigation planning is required for the conduct of a high quality trial. PMID- 29165095 TI - Metabolic Syndrome and Cardiovascular Risk in People Treated with Long-Acting Injectable Antipsychotics. AB - BACKGROUND: People with schizophrenia and other severe mental disorders have an increased mortality mainly attributed to natural causes, specifically cardiovascular disease and cancer. The metabolic syndrome and the Framingham Risk Score are epidemiologic tools related to long-term cardiovascular disease risk and they are increased in people with severe mental disorders. This increase has been attributed both to the disorder itself and to the use of antipsychotic drugs. OBJECTIVE: To quantify the cardiovascular risk in a group of people treated with long-acting injectable antipsychotics. METHODS: This is a cross sectional study developed in an outpatient mental health clinic in which the prevalence of metabolic syndrome was estimated and the cardiovascular risk was measured using the Framingham Risk Score. All the analyses were separated by gender. RESULTS: 130 people (81 men) were recruited. According to the International Diabetes Federation criteria, 60 participants (46,2%) had metabolic syndrome. The individual criterion most often met in both genders was obesity. The mean Framingham Risk Score for the sample was moderate, 7,7 (SD: 6,3). For women, the risk was lower (mean 5,7, SD: 4,9) than for men (mean=9, SD: 6,7). There were no significant differences in the prevalence of metabolic syndrome and Framingham Risk Scores by longacting injectable antipsychotic or years of treatment. CONCLUSION: The prevalence of metabolic syndrome and the cardiovascular risk are high in people with psychosis treated with long acting injectable antipsychotics. To better address this vulnerability, the recommendations involve both behavioral and pharmacological interventions. PMID- 29165096 TI - Depression and Self-Efficacy in Patients with Type 2 Diabetes in Northern Greece. AB - BACKGROUND: Depression represents one of the most common disorders in diabetic patients and frequently complicates the health care of this population. Poor self efficacy has been associated with increased depressive symptoms as well as poor glycemic control. OBJECTIVE: To assess depression and self-efficacy in adults with type 2 diabetes in Northern Greece and to explore the factors which may affect them in this group of population. METHOD: A descriptive study was conducted in a tertiary hospital in the largest city of Northern Greece. The study group included a convenience sample of 170 adults with type 2 diabetes mellitus who completed the General Health Questionnaire-28 (GHQ-28) and the Diabetes Empowerment Scale- short form (DES) questionnaire. RESULTS: The overall rate of diabetic patients showing psychological distress in the present study was 50.6%. Adults with low and moderate income experienced higher levels of depression and anxiety, compared to those with high economical status (p<0,001). Also, adults who graduated elementary education experienced higher levels of depressive and anxiety symptoms than those with a higher educational level (p =0,038). There was a statistically significant difference between age (p<0.001), type of residence (p=0.019), family status (p=0,002), financial status (p<0.001) and self-efficacy. Also, there was a negative correlation between BMI and self efficacy (r=-0.206, p<0.001) and a negative correlation between depression and self-efficacy scale (r=-0.439, p<0.001). CONCLUSION: The results of the present study highlight the importance of well-planned interventions in order to reduce depression and increase self-efficacy in diabetic adults and to help them further improve their quality of life. PMID- 29165097 TI - A Predictive Model of the Prevalence of Delirium in Elderly Subjects Admitted to Nursing Homes. AB - INTRODUCTION: Delirium is common in geriatric patients admitted to nursing homes, with an incidence of 22-79% among long-term residents. AIM: To establish a predictive model of the risk of delirium episodes in a sample of elderly people living in nursing homes. MATERIAL AND METHODS: A retrospective, cross-sectional case-control study covering a period of 12 consecutive months (April 2014 - March 2015) was carried out. The included cases had suffered at least one episode of delirium during the study period. Sociodemographic and clinical variables as well as risk factors predisposing to or triggering episodes of delirium were recorded. RESULTS: A total of 193 cases and 123 controls were recruited. The mean age of the cases was 89.6 years (SD 6.9), and 75.1% were women. The mean age of the controls was 84.7 years (SD 7.42), and 75.6% were women. The prevalence of delirium was 60.7%. The presence of infections (with the exception of urinary tract infections) was the variable offering the best predictive capacity (OR=7.08; 95% CI: 3.30-15.02; p<0.001). Other predictors of delirium were also identified, such as a previous diagnosis of dementia (OR=3.14; 95% CI: 1.81-5.45; p<0.001), the use of anticholinergic drugs (OR=2.98; 95% CI: 1.34-6.60; p=0.007), a diagnosis of depression (OR=1.92; 95% CI: 1.03-3.56; p=0.039), and urinary incontinence (OR=1.73; 95% CI: 0.97-3.08; p=0.065). The area under the curve (AUC) was 0.794 (95% CI: 0.74-0.84; p<0.001). CONCLUSIONS: The prevalence of delirium among elderly subjects admitted to nursing homes was 60.7%. Infections (with the exception of urinary tract infections), dementia, anticholinergic drug use, depression and urinary incontinence were predictive of the presence of delirium. PMID- 29165098 TI - Effects of Olive Oil on TNF-alpha and IL-6 in Humans: Implication in Obesity and Frailty. AB - BACKGROUND AND OBJECTIVE: Tumor necrosis factor-alpha (TNF)-alpha and interleukin (IL)-6 are important mediators of chronic low-grade systemic inflammation. The latter plays a central role in several obesity-related pathologies, such as diabetes, metabolic syndrome and cardiovascular diseases. Besides, these cytokines have been also implicated in geriatric and cancer-induced anorexia, cachexia, sarcopenia and frailty. Potential interventions for both obesity and frailty include dietary advice and nutraceuticals. In this context, the consumption of olive oil (OO) has been associated with the health effects of the Mediterranean diet (Med-diet). This review is aimed to discuss the OO-mediated modulation of TNF- alpha and IL-6 in human studies and the potential implication in obesity and frailty. RESULTS: The reviewed studies suggest that the improvement of postprandial TNF-alpha and IL-6 observed with OO consumption is affected by body mass index (BMI). The effects on TNF-alpha and IL-6 after medium and long-term consumptions involved many factors and the cross-talk between adipose tissue, liver, skeletal muscle and brain. Major anti-inflammatory effects were observed when OO was consumed with Med-diet, which is associated with healthy behaviors. In this context, the role of microbioma- polyphenols, diet gene and exercise-gene interactions in the effects of OO on immune-mediated inflammatory responses involved in obesity and frailty deserves further investigation. CONCLUSION: Further studies are needed to clarify the effect of OO net of possible synergistic effects with other dietary and lifestyle factors of Mediterranean area. PMID- 29165099 TI - Recent Patents and Formulation of Nanopharmaceuticals Using Ultrasonication Technique. AB - BACKGROUND: Ultrasound (US) has the ever-rising role in the delivery of therapeutic agents that includes chemotherapeutic agents, proteins, and genetic material. The microbubbles are the cavitating gas bodies that act as the mediators through which the energy of relatively non-interactive pressure waves is accumulated to produce forces that can permeabilize cell membranes and disrupt the vesicles that carry the therapeutic agent. This shows that the microbubbles greatly enhance the delivery of smaller chemical agents, proteins and genetic material. METHOD: Various databases of online literature and patented reports based on sonication were reviewed. RESULTS AND CONCLUSION: The literature reveals that US-assisted drug delivery is used in the delivery of therapeutic agents into various tissues including vascular, cardiac, tumor, skeletal muscle and fetal tissue. US-assisted delivery of proteins has been studied in the application in transdermal delivery of insulin, hormones and small proteins. Cavitation effect occurring during the sonication reversibly disrupts the stratum corneum structure to allow the transport of the large molecules. Cavitation disrupts the structure of the carrier vesicle and releases the drug. But there still remains a need for better understanding the physics of cavitation of microbubbles and the impact of cavitation on drug-carrying vesicles and cells. Ultrasonic technology has been proven effective at creating encapsulating particles and droplets with specific physical and functional properties. This article provides an overview of the factors influencing ultrasonication and various nanosystems formulated by using this technology. PMID- 29165100 TI - Phytochemicals Formulated As Nanoparticles: Inventions, Recent Patents and Future Prospects. AB - BACKGROUND: The quest to improve the therapeutic effectiveness of herbal drugs has driven the pharmaceutical research towards the development of herbal nanoparticles. OBJECTIVE: Till date, various approaches have been adopted for the design of herbal nanoparticles. METHODS: We carried out an organized search of bibliographic databases consisting of an ample number of published abstracts and research articles using a focused review questionaries and insertion/ omission criteria. The study was systematically structured to review various phytochemicals formulated as nanoparticles, understand its need and prospects. Indeed, research cited has revealed revival of some phytochemicals with therapeutic efficacy fronts. RESULTS: Certain patents (US20170157005A1, US20160228362A1 and US20150050357A1) have evinced entrapment concerns of phytoceuticals into nanoparticles. Amongst various phytochemicals, Curcumin, Quercetin, Silymarin, Paclitaxel etc. seems predominant ones being successfully formulated as nanoparticles. The reason for the availability of their splendid formulations lies in the addresal of poor stability, poor water solubility and consequently poor bioavailability. CONCLUSION: If bioavailability constraint is overcome, diseases like cancer, Alzheimer's, diabetes, liver disorder etc. can be effectively targeted. By doing so, the largely affected society, will breathe the relief. The present article is an attempt to elaborate and conclude on how nanoparticles have been serving as a tool to enhance the effectiveness of phytochemicals, by solubilization, dissolution and consequent bioavailability enhancements, along with in vivo targeting. To further facilitate understanding, the review discusses disease/disorder and phytochemicals with focus on their nanoparticles. PMID- 29165101 TI - Therapeutic Potentials and Cytochrome P450-Mediated Interactions Involving Herbal Products Indicated for Diabetes Mellitus. AB - BACKGROUND: There has been an increase in the use of herbal products to complement conventional drugs in the treatment of various diseases especially in developing countries. This may be attributable to the potential cost effectiveness and ease of accessibility of these products as well as the perception of their safety profiles. However, there are numerous literature reports on herbs altering the pharmacokinetics and pharmacodynamics of other co administered drugs thereby modulating the therapeutic outcomes. The prevalence of diabetes is on a steady increase worldwide and it is now identified as one of the main threats to human health. OBJECTIVE: It is important that knowledge on specific effects of antidiabetic herbs and their products on drug metabolizing enzymes are updated and documented so as to ensure optimization of their therapeutic utility. This review, therefore, aims to highlight herbal products with evidence-based antidiabetic effects, identify their bioactive phyto constituents, and also focus on the important Cytochrome P450 and consequences of their inhibition or induction. METHODS: An extensive literature search was undertaken and the information obtained were critically analyzed and discussed. RESULTS AND CONCLUSION: The literature abounds with reports on the utilization of herbal medications for the treatment of diabetes mellitus since time immemorial, but very few of these herbal products have undergone clinical trials. Also, studies on the herb-drug interactions were limited. Due to the complex phytochemical composition of the herbs, concomitant administration with conventional drugs resulted in alterations of pharmacological effects of some drugs. Evidences of beneficial interactions were identified for medical exploitation. PMID- 29165102 TI - Radio-protective effect and mechanism of 4-Acetamido-2,2,6,6- tetramethylpiperidin-1-oxyl in HUVEC cells. AB - OBJECTIVES: To search for more effective radiation protectors with minimal toxicity, a water-soluble nitroxides Acetamido-Tempol (AA-Tempol) was evaluated for potential radioprotective properties in HUVEC cells (Human Umbilical Vein Endothelial cell line). METHODS: To study the anti-radiation effect of AA-Tempol in cell culture, the viability of irradiated HUVEC cells using a clonogenic survival assay was examined. The anti-apoptosis effects of AA-Tempol using Annexin V/propidium iodide staining in a flow cytometry assay was also evaluated. To elucidate the molecular mechanism of the anti-apoptosis effect of AA-Tempol against X-radiation induced HUVEC cell apoptosis, the expression of Bax, Bcl-2 and p53 and caspase-3 were examined. The changes in the level of malondialdehyde (MDA) and glutathione (GSH) in HUVEC cells after X-radiation were also investigated. RESULTS: Pretreatment of the HUVEC cells colony with AA-Tempol 1 h before X-radiation significantly increased the colony survival (p < 0.05) compared with the cells without pretreatment. This demonstrates that AA-Tempol provides an effective radiation protection in the irradiated HUVEC cells, thus reducing apoptosis from 20.1 +/- 1.3% in 8 Gy X-radiated cells to 12.2 +/- 0.9% (1.0 mmol/L-1 AA-Tempol) in AA-Tempo pretreated HUVEC cells. This implies that 1.0 mM AA-Tempol treatment significantly block the increase of caspase-3 activity in radiated HUVEC cells (P < 0.01), causing down-regulation in expressions of Bax and P53 and up-regulation in the expression of Bcl-2. Pretreatment with AA-Tempol also decreased the MDA activities (P < 0.01) and increase the GSH level (P < 0.05) in HUVEC cells compared to the 8Gy X-radiated cells without pretreatment. CONCLUSIONS: These observations indicate that AA-Tempol is a potential therapeutic agent against the radiation damage. PMID- 29165103 TI - Occupation exposed to road-traffic emissions and respiratory health among Congolese transit workers, particularly bus conductors, in Kinshasa: a cross sectional study. AB - OBJECTIVES: Road-traffic emissions (RTE) induce adverse health effects, notably respiratory symptoms and respiratory diseases, as a result of pollutants deposited into the respiratory tract. The aim of this study was to evaluate the association between occupation groups of Congolese transit workers exposed to RTE, particularly bus conductors and respiratory health, in Kinshasa. METHODS: A cross-sectional study was conducted from 2015 April 20th to May 14th, whose participants were bus conductors (n = 110), bus drivers (n = 107), taxi motorcyclists (n = 102) and high school teachers (control group; n = 106). Subjects had completed the American Thoracic Society respiratory symptom questionnaire. Lung function test was performed by spirometry. Air pollutants levels of PM2.5, NO2 and SO2 were measured between 7:30 and 8:30 and 16:30-17:30 using a portable gas monitor. Multivariate analysis was performed to evaluate the association between occupation exposed to RTE and impaired pulmonary function, after adjustment by plausible confounders. RESULTS: The prevalence of mixed syndrome was 21.9% for bus conductors, 10.9% for bus drivers, 15.4% for taxi motorcyclists and 7.1% for high school teachers with (p < 0.05). The risk of developing a mixed syndrome was seven times higher among bus conductors [OR = 7.64; 95% CI: 1.83-31.67; p < 0.05] than other groups. Additionally, the prevalence of respiratory syndromes increased with the duration of exposure. CONCLUSIONS: Occupation exposed to RTE is associated with impaired pulmonary function and the prevalence of respiratory symptoms among transit workers, especially bus conductors. Furthermore, this association increases with the duration of exposure suggesting the necessity to regulate these categories of occupations and to apply preventives measures. PMID- 29165104 TI - Simple reaction time and obesity in children: whether there is a relationship? AB - OBJECTIVE: Reaction time (RT) testing is one of the oldest diagnostic methods used in modern psychology, and is known as simple and sensitive cognitive test. It has been recently reported that RT is related to obesity in young, adult and elderly individuals. However, most of the studies included small sample of participants, used just body mass index (BMI) as body obesity index, and did not consider some potential confounders such as age, socioeconomic status and physical activity in their studies. Furthermore, there is little and contradictory results for children. Therefore, the present study aimed to examine the relationship between RT and weight status in a sample of children. METHODS: Three hundred and fifty four 9-12 year old schoolboys underwent standard anthropometry, and various simple RT tests. RESULTS: After controlling for potential confounders no significant relationship was observed between audio-RT (RTA) and clinical RT (RTclin) with BMI, %fat, waist circumference (WC) and waist to height ratio (WHtR) (P > 0.05). But, significant relationship (beta = 0.18; P = 0.02) was observed between visual-RT (RTV) and %fat (but not BMI, WC and WHtR). CONCLUSIONS: Among the various simple RT tasks and central and total body obesity indices, just significant relationship was observed between %fat and RTV in the schoolboys. According to the results, it is concluded that RT impairment due to obesity may less be observed, or may not be observed for some types of RT tasks and obesity indices during childhood. PMID- 29165105 TI - A behavioral strategy to minimize air pollution exposure in pregnant women: a randomized controlled trial. AB - BACKGROUND: Pregnant women and their fetus belong to a sensitive group in response to air pollution hazards. The aim of this study was to evaluate the effectiveness of a theory-based educational program to change pollution exposure behavior in pregnant women. METHODS: In this randomized controlled trial, pregnant women attending a prenatal clinic in Tehran, Iran were selected and randomized into the experimental and control groups. The inclusion criteria were age between 18 and 35 years, having a history of pregnancies without adverse outcomes and not suffering from chronic diseases. Data collected at baseline and 2-month follow-up. At baseline face-to-face interviews were conducted using a valid and reliable questionnaire including items on demographic characteristics, stages of change, self-efficacy, decisional balance and practice regarding air pollution preventive behaviors. The intervention composed of three parts: motivational interviewing, a booklet and daily small message service (SMS). The control group received no intervention except receiving usual care. Follow-up data were collected after the intervention. Data were analyzed performing t-test, Mann-Whitney U test, and chi-squared. RESULTS: In all the data for 104 pregnant women (53 in the intervention and 51 in the control group) were analyzed. The mean age of participants was 27.2 (SD = 4.11) years and it was 22.89 (SD = 8.75) weeks for gestational age. At baseline there were no significant statistical differences between intervention and control groups on the study measures while we found significant group differences in terms of stages of change, self efficacy, perceived benefits and practice regarding air pollution preventive behaviors at follow-up assessment (P < 0.05). CONCLUSION: The findings indicated that the TTM-based intervention was effective in increasing air pollution preventive behaviors among pregnant women. This study provided a framework to modify some psychosocial determinants of air pollution preventive behavior other than knowledge using constructs of Transtheoretical model of behavior change, additionally results suggests the importance of education and makes enlightenment of the air pollution risk knowledge accelerate. TRIAL REGISTRATION: IRCT2012091010804N1. PMID- 29165106 TI - The impact of different lenses on visual and musculoskeletal complaints in VDU workers with work-related neck complaints: a randomized controlled trial. AB - OBJECTIVES: The impact of wearing lenses on visual and musculoskeletal complaints in VDU workers is currently unknown. The goal of this study was 1) to evaluate the impact of wearing VDU lenses on visual fatigue and self-reported neck pain and disability, compared to progressive lenses, and 2) to measure the effect of both lenses on head inclination and pressure pain thresholds during the performance of a VDU task. METHODS: Thirty-five eligible subjects were randomly assigned to wear progressive VDU lenses (VDU group) (n = 18) or progressive lenses (P group) (n = 17). They were enquired about visual complaints (VFQ), self perceived pain (NRS) and disability (NDI) at baseline (with old lenses), and 1 week, 3 months and 6 months after wearing their new lenses. In addition, Forward Head Angle (FHA) and PPTs were assessed during and after a VDU task before and 6 months after wearing the new lenses. A short questionnaire concerning the satisfaction about the study lenses was completed at the end of the study. RESULTS: In both groups, visual fatigue and neck pain was decreased at 3 and 6 months follow up, compared to baseline. All PPTs were higher during the second VDU task, independent of the type of lenses. The VDU group reported a significantly higher suitability of the lenses for VDU work. CONCLUSION: It can be concluded that there is little difference in effect of the different lenses on visual and musculoskeletal comfort. Lenses should be adjusted to the task specific needs and habits of the participant. PMID- 29165107 TI - Description of the healthy eating indices-based diet quality in Turkish adults: a cross-sectional study. AB - OBJECTIVES: This study aims to describe the dietary status of Turkish adults using two different versions of the Healthy Eating Index (HEI). METHODS: In this cross sectional study, 494 healthy participants (311 females) with randomly selected and living in Ankara were included between September 2013 and March 2014. A questionnaire was completed and anthropometric measurements (weight and height) were performed. The 24-h dietary recall of individuals was collected. Diet quality was measured through HEI-2005 and HEI-2010 scores. RESULTS: The mean age, body mass index (BMI), HEI-2005 and HEI-2010 scores of individuals were 32.9 +/- 10.8 years; 25.0 +/- 4.8 kg/m2; 56.1 +/- 13.9 and 41.5 +/- 13.7 points, respectively. Significant differences were found between mean HEI-2005 and HEI 2010 scores (p < 0.05). The individual's whose diet quality needs to be improved according to mean HEI-2005 score, had poorer diet based on mean HEI-2010 scores. The highest mean HEI-2005 and HEI-2010 scores were stated in female, in subjects had low education levels, aged 51 years or older and in overweight groups (p <0.05). Both versions of healthy eating indices were correlated positively with BMI and age CONCLUSION: Diet qualities of the individuals are associated with age, gender, education and BMI. Although the components and scores in HEI-2010 version were changed from the version of HEI-2005, the changes may encourage healthy choices of some food group. HEI-2010 gives more attention to food quality than HEI-2005. Thus, in the present study it was concluded that HEI-2010 provided more precise results about diet quality. PMID- 29165108 TI - Medical visits, antihypertensive prescriptions and medication adherence among newly diagnosed hypertensive patients in Korea. AB - OBJECTIVES: The objective of this study was to assess the antihypertensive medication adherence in patients who were newly diagnosed with hypertension in Korea. METHODS: Study subjects were diagnosed with hypertension for the first time by the General Health Screening in 2012 and were 65,919. As indices, visiting rate to medical institution, the antihypertensive prescription rate, medication possession ratio and the rate of appropriate medication adherence were used. The qualification data, the General Health Screening data and the health insurance claims data were used. RESUTLS: Visiting rate to medical institution within one-year was 42.3%. Gender, age, family history of hypertension, smoking status, drinking frequency, insurance type, BMI, hypertension status, blood glucose level and LDL-cholesterol level were significant variables for visiting a medical institution. Of the study subjects who visited a medical institution, the antihypertensive prescription rate was 89.1%. Medication possession ratio was 70.9% and the rate of appropriate medication adherence was 60.6%. Age, family history of hypertension, smoking status, BMI level, hypertension level, blood glucose level, status, and LDL-cholesterol level were significant variables for the antihypertensive prescription and gender, age, family history of hypertension, smoking status, BMI, hypertension status, and the time of the first visit to a medical institution were significant variables for appropriate medication adherence. CONCLUSIONS: This study showed that the antihypertensive medication adherence in patients who were newly diagnosed with hypertension was not relatively high in Korea. National Health Insurance Service should support an environment in which medical institutions and those diagnosed with hypertension can fulfill their roles. PMID- 29165109 TI - Attitude and practice of physical activity and social problem-solving ability among university students. AB - BACKGROUND: Effective social problem-solving abilities can contribute to decreased risk of poor mental health. In addition, physical activity has a favorable effect on mental health. These previous studies suggest that physical activity and social problem-solving ability can interact by helping to sustain mental health. The present study aimed to determine the association between attitude and practice of physical activity and social problem-solving ability among university students. METHODS: Information on physical activity and social problem-solving was collected using a self-administered questionnaire. We analyzed data from 185 students who participated in the questionnaire surveys and psychological tests. Social problem-solving as measured by the Social Problem Solving Inventory-Revised (SPSI-R) (median score 10.85) was the dependent variable. Multiple logistic regression analysis was employed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for higher SPSI-R according to physical activity categories. RESULTS: The multiple logistic regression analysis indicated that the ORs (95% CI) in reference to participants who said they never considered exercising were 2.08 (0.69-6.93), 1.62 (0.55-5.26), 2.78 (0.86-9.77), and 6.23 (1.81-23.97) for participants who did not exercise but intended to start, tried to exercise but did not, exercised but not regularly, and exercised regularly, respectively. This finding suggested that positive linear association between physical activity and social problem-solving ability (p value for linear trend < 0.01). CONCLUSIONS: The present findings suggest that regular physical activity or intention to start physical activity may be an effective strategy to improve social problem-solving ability. PMID- 29165110 TI - Paraben exposure and semen quality of Japanese male partners of subfertile couples. AB - OBJECTIVES: Possible relationship between semen quality (semen volume, sperm concentration and sperm motility) and parabens exposure was investigated in male partners of couples who visited a gynecology clinic in Tokyo for infertility consultation (n = 42, 36.8 +/- 5.4 years). METHODS: Semen parameters were measured according to WHO guideline at the clinic, and urinary methyl- (MP), ethyl- (EP), propyl- (PP) and butyl (BP) paraben concentrations were measured with liquid chromatography-tandem mass spectrometry. RESULTS: Geometric mean urinary concentrations (geometric standard deviation) of the subjects were 48.2 (4.52), 1.88 (4.72), 1.13 (6.75) and 0.184 (11.1) ng/mL for MP, EP, PP and BP, respectively. No significant association was found between semen parameters and urinary paraben concentrations in multiple regression analyses and logistic regression analyses. CONCLUSIONS: Two reasons of the absence of adverse effects on semen quality might be suggested: lower paraben exposure level of the subjects and small sample size. Further investigation of effect of paraben exposure among general male population at environmental levels is warranted. PMID- 29165111 TI - Population profile and residential environment of an urban poor community in Dhaka, Bangladesh. AB - OBJECTIVES: A population survey was conducted in an urban shantytown in Bangladesh, as a baseline study of future epidemiological studies. This paper aims to describe the findings of the study, including the population profile and residential environment of the urban poor. METHODS: We conducted a complete count household survey in an urban poor community in Dhaka. Using a brief structured questionnaire in Bengali language, trained interviewers visited each household and asked questions such as: duration of residence; ownership of house, toilet and kitchen; water supply; number of family members; age, sex, education, occupation, tobacco use, and history of diseases of each family member. RESULTS: We found that there were 8604 households and 34,170 people in the community. Average number of household members was 4.0. Most people had access to safe water, but only 16% lived in the house with a toilet. Based on the proxy indicators of household wealth levels, we identified that about 39% were relatively well-off, while the rest were very poor. Tobacco use was prevalent in men regardless of age and in women aged over 35 years. Prevalence of self reported hypertension and diabetes was slightly higher in women than in men, although over 70% of the respondents didn't know if they had such diseases. Incidences of diarrhea in the last one month were relatively low. CONCLUSIONS: The study showed population profile and sanitation environment in an urban poor community by a complete count survey. We expect the study to serve as a baseline for future epidemiological studies. PMID- 29165112 TI - Influence of a 50bp Ins/Del polymorphism at promoter of the superoxide dismutase 1 on gene expression and risk of heroin dependency. AB - OBJECTIVE: Superoxide dismutase-1 (SOD1, OMIM: 147450) is one of the major antioxidant enzymes, which plays a vital role in clearance of reactive oxygen species. A genetic polymorphism of 50 bp insertion/deletion (Ins/Del) in the promoter region of the SOD1 was reported. The aims of the present study are to evaluate the influence of this polymorphism on the SOD1 mRNA levels in human peripheral blood cells and its association with risk of heroin dependency. METHODS: The present study consisted of 47 healthy students of Shiraz University (south-west Iran) for investigating the association between the Ins/Del polymorphism on expression level of SOD1, also a total of 442 heroin dependent and 799 healthy controls were included in a case-control study investigating the association between the study polymorphism and risk of dependency to heroin. The quantitative SOD1 mRNA expression levels were investigated using quantitative real-time PCR. RESULTS: Statistical analysis revealed a significant difference between the study genotypes (t = 5.17; df = 45; P < 0.001). The Del allele of the study polymorphism decreased approximately 33% of the SOD1 mRNA levels of the gene in the heterozygote individuals. Statistical analysis indicating that in both genders, neither the Ins/Del nor the Del/Del genotypes was associated with the risk of heroin addiction. CONCLUSIONS: The present study indicating that although the Ins/Del polymorphism of SOD1 is associated with the SOD1 expression levels, this polymorphism is not associated with the risk of dependency to heroin. PMID- 29165113 TI - Alteration in plasma free amino acid levels and its association with gout. AB - BACKGROUND: Studies on the association of plasma-free amino acids with gout are very limited and produced conflicting results. Therefore, we sought to explore and characterize the plasma-free amino acid (PFAA) profile in patients with gout and evaluate its association with the latter. METHODS: Data from a total of 819 subjects (including 34 patients with gout) undergoing an annual health examination program in Shimane, Japan were considered for this study. Venous blood samples were collected from the subjects and concentrations of 19 plasma amino acids were determined by high-performance liquid chromatography electrospray ionization-mass spectrometry. Student's t-test was applied for comparison of variables between patient and control groups. The relationships between the presence or absence of gout and individual amino acids were investigated by logistic regression analysis controlling for the effects of potential demographic confounders. RESULTS: Among 19 amino acids, the levels of 10 amino acids (alanine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, tryptophan, valine) differed significantly (P < .001 to .05) between the patient and control groups. Univariate logistic regression analysis revealed that plasma levels of alanine, isoleucine, leucine, phenylalanine, tryptophan and valine had significant positive associations (P < .005 to .05) whereas glycine and serine had significant inverse association (P < .05) with gout. CONCLUSIONS: The observed significant changes in PFAA profiles may have important implications for improving our understanding of pathophysiology, diagnosis and prevention of gout. The findings of this study need further confirmation in future large-scale studies involving a larger number of patients with gout. PMID- 29165114 TI - Prevalence of stroke and associated risk factors among middle-aged and older farmers in western China. AB - OBJECTIVES: China has the world's largest population and the stroke has become the leading cause of death in recent years. The purpose of this study was to explore the associations between hypertension, family history of stroke, diabetes mellitus, obesity and stroke among middle-aged and older farmers of western China. A population-based study was conducted from June 2014 to April 2015 in Shaanxi and Sichuan provinces. METHODS: Twenty thousand five hundred twenty-five Chinese middle-aged and older farmers (>=40 years) were recruited to the Qinling Daba Mountains Region Stroke Study. A structured-questionnaire was used to collect data through face-to-face interviews. Demographic characteristics, risk factors, medical history, and other clinical characteristics were recorded for all participants. The association between hypertension, family history of stroke, diabetes mellitus, obesity and stroke were analyzed by using univariate and multivariate logistic regression analysis. RESULTS: The stoke prevalence rate was 1380/100,000 in middle-aged and older farmers of western China. The difference in hypertension, diabetes mellitus, obesity and family history between different age groups had statistical significance (p < 0.05). The prevalence rate of hypertension and family history of stroke were higher in male population than in the female population. The difference was statistically significant (p < 0.05). Univariate logistic regression analysis demonstrated age, gender, hypertension, obesity and family history of stroke were stroke risk factors (p < 0.05). Multivariate logistic regression analysis revealed that the odds ratios of family history of stroke, obesity and hypertension were 7.177, 4.389 and 3.647 respectively. CONCLUSIONS: Family history is the strongest stroke risk factor in middle-aged and older farmers of western China. PMID- 29165115 TI - Effects of gaps in priorities between ideal and real lives on psychological burnout among academic faculty members at a medical university in Japan: a cross sectional study. AB - BACKGROUND: Accumulating evidence from medical workforce research indicates that poor work/life balance and increased work/home conflict induce psychological distress. In this study we aim to examine the existence of a priority gap between ideal and real lives, and its association with psychological burnout among academic professionals. METHODS: This cross-sectional survey, conducted in 2014, included faculty members (228 men, 102 women) at a single medical university in Tokyo, Japan. The outcome of interest was psychological burnout, measured with a validated inventory. Discordance between ideal- and real-life priorities, based on participants' responses (work, family, individual life, combinations thereof), was defined as a priority gap. RESULTS: The majority (64%) of participants chose "work" as the greatest priority in real life, but only 28% chose "work" as the greatest priority in their conception of an ideal life. Priority gaps were identified in 59.5% of respondents. A stepwise multivariable general linear model demonstrated that burnout scores were associated positively with respondents' current position (P < 0.0018) and the presence of a priority gap (P < 0.0001), and negatively with the presence of social support (P < 0.0001). Among participants reporting priority gaps, burnout scores were significantly lower in those with children than in those with no children (P interaction = 0.011); no such trend was observed in participants with no priority gap. CONCLUSIONS: A gap in priorities between an ideal and real life was associated with an increased risk of burnout, and the presence of children, which is a type of "family" social support, had a mitigating effect on burnout among those reporting priority gaps. PMID- 29165116 TI - Circular RNA profiles in mouse lung tissue induced by radon. AB - BACKGROUND: Radon is a known human lung carcinogen, whose underlying carcinogenic mechanism remains unclear. Recently, circular RNA (circRNA), a class of endogenous non-protein coding RNAs that contain a circular loop, was found to exhibit multiple biological effects. In this study, circRNA profiles in mouse lung tissues between control and radon exposure were analyzed. METHODS: Six mice were exposed to radon at concentration of 100,000 Bq/m3, 12 h/d, for up to cumulative doses of 60 working level months (WLM). H&E staining and immunohistochemistry of caspase-3 were used to detect the damages in lung tissue. The lung tissue of control and exposed group were selected for circRNA microarray study. The circRNA/microRNA interaction was analyzed by starBase prediction software. 5 highest expressing circRNAs were selected by real-time PCR to validate the consistency in mouse lung tissue exposed to radon. RESULTS: Inflammatory reaction was found in mouse lung tissue exposed to radon, and caspase-3 expression was significantly increased. Microarray screening revealed 107 up-regulated and 83 down-regulated circRNAs, among which top 30 circRNAs with the highest fold changes were chosen for further analysis, with 5 microRNAs binding sites listed for each circRNA. Consistency of the top 5 circRNAs with the highest expressions were confirmed in mice exposed with 60WLM of radon. CONCLUSION: Mouse lung tissue was severely injured when exposed to radon through pathological diagnosis and immunohistochemical analysis. A series of differentially expressed circRNAs demonstrated that they may play an important role in pulmonary toxicity induced by radon. PMID- 29165117 TI - Effects of intrauterine exposures to polychlorinated biphenyls, methylmercury, and lead on birth weight in Japanese male and female newborns. AB - BACKGROUND: The effects of prenatal exposures to polychlorinated biphenyls (PCBs), methylmercury, and lead on birth weight remain disputable. The aim of this study was to investigate whether these chemicals affect birth weight of Japanese newborns, with special emphasis on determining whether these effects differ between males and females. METHODS: The subjects from Tohoku Study of Child Development, which was designed to examine the developmental effects of prenatal exposures to such hazardous chemicals, were 489 mother-newborn pairs with complete data including smoking habit during pregnancy. RESULTS: The mean birth weight of all newborns was 3083 (range, 2412-4240) g. The median values of biomarkers in cord blood were 46.0 (5th and 95th percentiles, 18.6-113.8) ng/g lipid for total PCBs, 10.1 (4.3-22.4) ng/g for total mercury (THg), and 1.0 (0.6 1.7) MUg/dL for lead. The birth weight was significantly heavier in the 252 male newborns than in the 237 female ones. A negative association between total PCBs and birth weight was observed in both male and female newborns, even after adjusting for possible confounders. However, a negative association of THg with birth weight was found only in the male newborns. There was no significant relationship between lead and birth weight in both groups. CONCLUSION: Birth weight appears to be affected by prenatal PCB exposure in Japanese male and female newborns, and the effect of methylmercury exposure on male fetal growth may be stronger than that for females. This implication is that the effects on fetal growth should be assessed in males and females separately. PMID- 29165118 TI - Age at first birth and long-term mortality for mothers: the Ohsaki cohort study. AB - BACKGROUND: Although maternal age at first birth has been rising in many developed countries, its long-term effects on the health of the mothers themselves are unclear. In this study, we investigated the relationship between maternal age at first birth and long-term mortality. METHODS: We conducted a cohort study of 20,624 parous Japanese women aged between 40 and 79 years in 1994 and followed up their survival for 14 years. Based on maternal age at first birth, the women were divided into four groups: <=19 years, 20-24 years, 25-29 years, and >=30 years. Using the 20-24 years group as a reference, hazards ratios (HRs) for all-cause and cause-specific mortality were calculated. RESULTS: Multivariate HRs for all-cause mortality were 1.17 in the <=19 years group, 1.09 in the 25-29 years group, and 1.33 in the >=30 years group. A U-shaped relationship was apparent between maternal age at first birth and mortality. This relationship was also observed for mortality attributable to cancer, cardiovascular disease and other diseases. This U-shaped relationship was observed only for women born before 1935 and the birth year of the first child before 1960. CONCLUSION: A U-shaped relationship was apparent between maternal age at first birth and mortality. As maternal age at first birth is rising worldwide, the risk it imposes appears to have significance in the context of public health. PMID- 29165119 TI - Comorbidities according to airflow limitation severity: data from comprehensive health examination in Japan. AB - OBJECTIVES: The present study aimed to investigate the relationship between airflow limitation (AL) severity and comorbidities in comprehensive health examination. METHODS: This cross-sectional study included 6661 men and 6044 women aged 40-89 who underwent a lung function test during medical checkups. AL was defined as forced expiratory volume in 1 s/forced vital capacity of < 0.7. Logistic regression analysis was used to assess the association between AL severity and the presence of comorbidities. RESULTS: When compared with the normal lung function group, subjects with AL had a higher prevalence of lung cancer (odd ratio (OR) 9.88, 95% confidence interval (CI) 3.88-25.14) in men, hypertension (OR 1.63, 95% CI 1.26-2.10) in women, diabetes and hyperglycemia (OR 1.23, 95% CI 1.02-1.49 in men, OR 1.61, 95% CI 1.18-2.20 in women) in men and women after adjusting for potential confounders. In men, lung cancer and MetS (the Joint Interim Statement: JIS) were significantly associated with moderate-to very severe AL after adjustment. In women, hypertension, diabetes and hyperglycemia, MetS (JIS), and MetS (the Japanese Committee of the Criteria for MetS: JCCMS) were significantly associated with mild AL after adjustment. Hypertension was significantly associated with moderate-to-very severe AL after adjustment in women. CONCLUSIONS: Significant relationships were found between AL severity and the presence of comorbid lung cancer in men, hypertension in women, diabetes and hyperglycemia, and MetS in men and women. Knowledge of comorbidities associated with AL should be widely publicized to raise the awareness of chronic obstructive pulmonary disease (COPD). PMID- 29165120 TI - High prevalence of dental fluorosis among adolescents is a growing concern: a school based cross-sectional study from Southern India. AB - BACKGROUND: Fluorosis, caused by ingestion of excessive amount of fluoride through food or water, is a major public health problem in India. This study was undertaken to quantify the dental fluorosis burden among school going adolescents and to find factors associated with dental fluorosis in Kolar taluka, Karnataka, India. METHODS: A total of 1026 high school adolescents (12-17 years) were enrolled from different schools selected by stratified sampling method. Dental examination was done to record Dean's fluorosis index, and socio-demographic, food consumption and oral hygiene data were recorded using a pre-tested structured questionnaire. Fluoride content was measured using Orion apparatus, and Community Fluorosis Index (CFI) was calculated from drinking water samples from various drinking sources. Multivariable analysis with generalized estimating equation (GEE) regression model was used to explore the factors associated with dental fluorosis. RESULT: Among 1026 enrolled students, 64.3% of adolescents were detected with dental fluorosis; more than 50% had either severe or moderate fluorosis according to the Dean's Fluorosis Index and Community Fluorosis Index (CFI). The majority of affected students were from government schools. The significantly associated factors with dental fluorosis were living in study area for more than 5 years and studying in government school. A strong positive correlation between the amount of fluoride content in drinking water sample collected and CFI was observed (rho = 0.570). CONCLUSION: Prevalence of dental fluorosis was considerably high, affecting nearly two-thirds of the students, and mainly in government schools and long-term residents of the area. Health education and community awareness for preventing fluorosis, apart from setting-up defluoridation plants or training for home based defluoridation techniques in study villages, should be considered. PMID- 29165121 TI - Association of Asian Dust with daily medical consultations for pollinosis in Fukuoka City, Japan. AB - BACKGROUND: The objective is to examine the association between AD and the daily number of medical consultations for pollinosis in Fukuoka City. METHODS: We analyzed 65,488 daily medical consultations for pollinosis from 4 clinics in Fukuoka City from February to April, 1989-2012. Time-series analyses were performed to estimate the clinic-specific relative risk (RR) of clinical pollinosis associated with AD, adjusting for airborne pollen, suspended particulate matter (SPM), meteorological and temporal factors. Delayed effects were considered. The association with SPM was also examined given its relationship with AD. The clinic-specific RRs were combined using meta-analytic technique. RESULTS: AD on the same day (lag 0) and the previous 3 to 5 days (lags 3, 4, and 5) was positively associated with the risk of medical consultations for pollinosis. Clinic visits were 21.5% (95% confidence interval 3.1% - 43.1%) higher when there was an AD event (across lags 0-5). The association with SPM showed comparable lag structure, but with smaller effect estimates. When stratified by the occurrence of AD, the estimated risk increases associated with SPM did not differ between the AD-affected and AD-free days. CONCLUSION: AD is associated with an increased risk of medical consultations for pollinosis in spring. More research is needed to elucidate the roles of air particles with different sizes. PMID- 29165122 TI - Decreased blood pressure associated with in-vehicle exposure to carbon monoxide in Korean volunteers. AB - BACKGROUND: Carbon monoxide (CO) is one of the primary components of emissions from light-duty vehicles, and reportedly comprises 77% of all pollutants emitted in terms of concentration. Exposure to CO aggravates cardiovascular disease and causes other health disorders. The study was aimed to assess the negative effects by injecting different amounts of CO concentration directly to human volunteers boarding in the car. METHODS: Human volunteers were exposed to CO concentrations of 0, 33.2, and 72.4 ppm, respectively during the first test and 0, 30.3, and 48.8 ppm respectively during the second test while seated in the car. The volunteers were exposed to each concentration for approximately 45 min. After exposure, blood pressure measurement, blood collection (carboxyhemoglobin [COHb] analysis), medical interview, echocardiography test, and cognitive reaction test were performed. RESULT: In patients who were exposed to a mean concentration of CO for 72.4 +/- 1.4 ppm during the first exposure test and 48.8 +/- 3.7 ppm during the second exposure test, the COHb level exceeded 2%. Moreover, the diastolic blood pressure was decreased while increasing in CO concentration after exposure. The medical interview findings showed that the degree of fatigue was increased and the degree of concentration was reduced when the exposed concentration of CO was increased. CONCLUSION: Although the study had a limited sample size, we found that even a low concentration of CO flowing into a car could have a negative influence on human health, such as change of blood pressure and degree of fatigue. PMID- 29165123 TI - Prevalence and risk factors associated with hypertension and prehypertension in a working population at high altitude in China: a cross-sectional study. AB - BACKGROUND: Little information is available on the epidemiology of hypertension and prehypertension at high altitude in China, the aim of this study was to determine the prevalence of hypertension, prehypertension and their risk factors among Chinese working population at high altitude regions. METHODS: A cross sectional survey was performed in an occupational sample of 4198 employees aged 20-59 years on Qinghai-Tibet Plateau between May to July 2013. Information from a self-administered questionnaire, physical examinations and laboratory measurements were obtained from each participant. Multivariable analysis was performed to determine the association of various risk factors with hypertension and prehypertension. RESULTS: The total crude prevalence of hypertension and prehypertension was 28.1 and 41.5%, respectively; the overall standardized prevalence of hypertension and prehypertension was 26.7 and 41.3%, respectively. Multivariate logistic regression showed that age, sex, ethnicity, job position, overweight or obesity, frequent drinking, family history of hypertension, diabetes and hyperuricemia were risk factors for hypertension, and age, sex, education, job position, overweight or obesity, current smoking and family history of hypertension were risk factors for prehypertension. Among the hypertensives, 36.5% were aware of their condition, 19.4% were being treated and 6.2% had their blood pressure (BP) controlled; among the treated hypertensives, 31.9% had their BP under control. CONCLUSIONS: There is a high prevalence of hypertension and prehypertension in the working population at high altitude in China, but with very low awareness, treatment and control rates. Workplace-based BP screening and intervention programs that aim to modify risk factors such as high BMI, tobacco use, alcohol consumption and inappropriate use of antihypertensive medicine are urgently needed. PMID- 29165124 TI - Changes in the numbers of patients with acute gastroenteritis after voluntary introduction of the rotavirus vaccine in a Japanese children's primary emergency medical center. AB - BACKGROUND: Acute gastroenteritis (AGE) is a major reason for presentation to pediatric primary emergency medical centers. Because rotavirus vaccines were introduced in November 2011 for voluntary vaccination in Japan, we analyzed the changes in the numbers of AGE patients. METHODS: The number and proportion of patients visiting Kobe children's primary emergency medical center from January 2011 to February 2015 due to AGE, out of all visiting children, were investigated retrospectively. The rotavirus and norovirus epidemic periods were defined as the periods from March to June and from November to February, respectively, based on their disease prevalence. RESULTS: In patients <=2 years of age, the numbers and proportions of patients with AGE were significantly decreased from 2464/14098 (17%) in 2011 to 1888/12321 (15%) in 2014 (p < 0.01). In patients <=2 and 3-5 years of age, significant decreases in AGE patients between 2011 and 2014 were observed during the rotavirus season (from 20% [1090/5329] to 14% [642/4482] in patients aged <=2 years and from 23% [704/3047] to 20% [572/2807] in patients aged 3-5 years, p < 0.01 and p < 0.05, respectively), but not during the norovirus season (from 19% [834/4436] to 19% [797/4160] in patients aged <=2 years and from 20% [679/3334] to 25% [710/2852] in patients aged 3-5 years). CONCLUSIONS: The estimated rotavirus vaccine coverage in our area increased from 1% in 2011 to 49% in 2014; this coverage may have resulted in a reduction in AGE patients, both directly and indirectly, in our Japanese children's primary emergency medical center. PMID- 29165125 TI - Nurses' willingness to care for patients infected with HIV or Hepatitis B / C in Vietnam. AB - OBJECTIVES: This study examined the factors associated with nurses' willingness to care for patients infected with human immunodeficiency virus (HIV) or hepatitis B or C virus (HBV/HCV) in Vietnam. METHODS: A cross-section of 400 Vietnamese nurses from two hospitals were selected using stratified random sampling, to whom a self-administered questionnaire was administered which included demographic items, previous experience with patients infected with HIV or HBV/HCV, and their attitudes toward these patients. Data was analyzed using descriptive statistics and multiple logistic regression. RESULTS: The lifetime prevalence of needlestick or sharps injury whilst caring for a patient infected with HIV or HBV/HCV was 9 and 15.8%, respectively. The majority of participants expressed a willingness to care for patients infected with HIV (55.8%) or HBV/HCV (73.3%). Willingness to care for HIV-infected patients was positively associated with being 40-49 years of age and confidence in protecting themselves against infection. Regarding HBV/HCV infection, willingness to care was positively associated with individual confidence in protecting themselves against infection. CONCLUSIONS: This study revealed that Vietnamese nurses were somewhat willing to care for patients infected with HIV or HBV/HCV, and this was associated with individual confidence in protecting themselves against infection and with negative attitudes towards HIV and HBV/HCV. Establishing a positive safety culture and providing appropriate professional education to help reduce the stigma towards infected patients offers an effective way forwards to improve quality of care in Vietnam, as elsewhere. PMID- 29165126 TI - Associations between the duration of active commuting to school and academic achievement in rural Chilean adolescents. AB - BACKGROUND: Habitual active commuting to school may be positively associated with academic achievement. The aim of this study was to examine the relationship between duration of walking or otherwise actively commuting to school and academic achievement. METHODS: This cross-sectional study included 389 adolescents from seven rural schools (12-13 years). Mode and duration of active commuting to school (use of active means such as walking or biking to and from school) and screen time were self-reported. Academic achievement was determined by the outcome in basic grades (language and mathematics). RESULTS: Active commuting to school was not associated with higher scores in any grades after adjustment for potential confounders. No evidence was found of interactions between gender and academic achievement, but there was interaction with duration of walking (<30 min, 30-60 min, and >60 min). Adjusted binary logistic regression analysis suggested that adolescents who spent between 30 and 60 min actively commuting were more likely to obtain high academic achievement (language and mathematics). CONCLUSIONS: Thirty to 60 min of ACS may have a positive influence on academic achievement in adolescents, so, it is necessary to make recommendations for the children to walk from and/or to school. This could help society to recognize the relevance of physical activity to health as well as to academic performance. PMID- 29165127 TI - Perspectives acquired through long-term epidemiological studies on the Great East Japan Earthquake. AB - The Great East Japan Earthquake (GEJE) and subsequent tsunamis that occurred in 2011 caused extensive and severe structural damage and interrupted numerous research activities; however, the majority of such activities have been revived, and further public health researches and activities have started to follow the population affected by the disaster. In this mini-review, we overview our recent activities regarding epidemiologic studies in Miyagi Prefecture, the region most affected by the GEJE. Through our study processes, we were able to identify the particular characteristics of vulnerable populations, and provide ideas that may help save lives and reduce the amount of damage caused by a future disaster. Long term follow-up and care of survivors is essential in affected areas, and health professionals should pay particular attention to various diseases, e.g., cardiovascular complications and mental disorders. Furthermore, building up resilience and social relationships in the community is beneficial to survivors. Ongoing cohort studies conducted before disasters can help minimize biases regarding the survivors' pre-disaster information, and emerging cohort studies after disasters can find potential helpful novel indices. To identify characteristics of vulnerable populations, save lives, and reduce the amount of damage caused by a future disaster, constant research that is consistently improved by new data needs to be performed. PMID- 29165128 TI - Associations between accelerometer-measured physical activity and body fatness in school-aged children. AB - BACKGROUND: The main aim of the study was to examine the cross-sectional associations between objectively measured physical activity (PA) and body fatness in 7-12-year-old children. METHODS: We performed an analysis of 365 children (209 girls). Participant recruitment was performed in eight randomly selected elementary schools in cities and towns with various numbers of inhabitants. The body composition analysis was performed according to a multi-frequency bioelectrical impedance analysis; PA was monitored using an accelerometer. RESULTS: In terms of the overall PA, boys were more active than girls. No significant associations (unadjusted and adjusted models) were found between light PA and all body fatness indicators in either sex. Moderate-to-vigorous PA was significantly negatively associated with all body fatness indicators only in girls. These associations strengthened after adjustment for age, height and sedentary time (beta ranging from -0.49 to -0.36, P <= 0.01). In contrast, vigorous PA was strongly negatively associated with body fatness indicators only in boys. In the fully adjusted model the significant negative associations were found for fat mass percentage (beta = -0.15, P = 0.048) and fat mass index (beta = -0.15, P = 0.040). CONCLUSIONS: The present study suggests that increasing sex specific PA of different intensities may be an appropriate approach for decreasing body fatness in children. Longitudinal studies are needed to verify these associations. PMID- 29165129 TI - Comparative study on three different methods for arm-span measurement: the Japan environment and Children's study pilot. AB - BACKGROUND: Arm span is an important measure for the assessment of growth and hormone deficiency diseases. In an epidemiological survey, with a large number of subjects' indicators, it is especially valuable to establish methods which can measure both quickly and accurately. However, there are various methods, and the length of arm span may vary according to the medical institution. METHODS: The arm span of nine 6-year old subjects was measured using two institutional standard methods, A and B, and a third method C which is an improved method and has been used for the first time in this study. A, No-Wall, with heels together the child stretches the arms out to the sides. B, Wall & No-Line, the child stands against the wall with heels together and spreads the arms against the wall. C, Wall & Line, the method is the same as B except a paper with horizontal lines is placed on the wall. We measured twice by each method. RESULTS: The difference between the 1st and 2nd measurements was marginally significantly smaller by using method of C. CONCLUSION: The method C, which we improved, is the best way to measure arm span. PMID- 29165130 TI - Determinants of polyunsaturated fatty acid concentrations in erythrocytes of pregnant Japanese women from a birth cohort study: study protocol and baseline findings of an adjunct study of the Japan environment & Children's study. AB - BACKGROUND: N-3 polyunsaturated fatty acids (n-3 PUFA) may have multiple beneficial effects on the outcome of pregnancy, maternal health and child development. The present study introduced the protocol of a birth cohort study to examine the beneficial effects of n-3 PUFA status in pregnant Japanese women as an adjunct study of the Japan Environment and Children's Study (JECS). METHODS: The JECS participants in the coastal areas of Miyagi Prefecture were further invited to participate in this adjunct study, and 1,878 pregnant women were enrolled prior to delivery. Their n-3 PUFA status was evaluated with fatty acid profiles in erythrocytes of maternal blood collected from 1,623 mothers at 24-30 weeks of gestation and cord blood from 1,505 deliveries. RESULTS: The baseline results, including comprehensive data on the fatty acid status and determinants affecting the PUFA status, were analyzed. In stepwise multivariate analyses, the cord blood docosahexaenoic acid (DHA) level was found to be significantly influenced by the DHA level in maternal blood, the child's sex, and the gestational period. The maternal DHA level was influenced by fish intake, maternal age, and the prepregnancy body mass index. While cord blood eicosapentaenoic acid (EPA) was influenced by maternal EPA, fish intake, and season at birth, additional factors such as maternal education, household income, and smoking habits affected the maternal EPA content. CONCLUSION: Further studies are warranted to clarify the nutritional impacts of n-3 PUFA in pregnant Japanese women of the cohort study. PMID- 29165131 TI - Classification of indoor-outdoor location using combined global positioning system (GPS) and temperature data for personal exposure assessment. AB - OBJECTIVES: The objectives of this study was to determine the accuracy of indoor outdoor classification based on GPS and temperature data in three different seasons. METHODS: In the present study, a global positioning system (GPS) was used alongside temperature data collected in the field by a technician who visited 53 different indoor locations during summer, autumn and winter. The indoor-outdoor location was determined by GPS data alone, and in combination with temperature data. RESULTS: Determination of location by the GPS signal alone, based on the loss of GPS signal and using the used number of satellites (NSAT) signal factor, simple percentage agreements of 73.6 +/- 2.9%, 72.9 +/- 3.4%, and 72.1 +/- 3.1% were obtained for summer, autumn, and winter, respectively. However, when temperature and GPS data were combined, simple percentage agreements were significantly improved (87.9 +/- 3.3%, 84.1 +/- 2.8%, and 86.3 +/ 3.1%, respectively). A temperature criterion for indoor-outdoor determination of ~ Delta 2 degrees C for 2 min could be applied during all three seasons. CONCLUSION: The results showed that combining GPS and temperature data improved the accuracy of indoor-outdoor determination. PMID- 29165132 TI - Plasma free amino acid profiles evaluate risk of metabolic syndrome, diabetes, dyslipidemia, and hypertension in a large Asian population. AB - BACKGROUND: Recently, the association of plasma free amino acid (PFAA) profile and lifestyle-related diseases has been reported. However, few studies have been reported in large Asian populations, about the usefulness of PFAAs for evaluating disease risks. We examined the ability of PFAA profiles to evaluate lifestyle related diseases in so far the largest Asian population. METHODS: We examined plasma concentrations of 19 amino acids in 8589 Japanese subjects, and determined the association with variables associated with obesity, blood glucose, lipid, and blood pressure. We also evaluated the PFAA indexes that reflect visceral fat obesity and insulin resistance. The contribution of single PFAA level and relevant PFAA indexes was also examined in the risk assessment of lifestyle related diseases. RESULTS: Of the 19 amino acids, branched-chain amino acids and aromatic amino acids showed association with obesity and lipid variables. The PFAA index related to visceral fat obesity showed relatively higher correlation with variables than that of any PFAA. In the evaluation of lifestyle-related disease risks, the odds ratios of the PFAA index related to visceral fat obesity or insulin resistance with the diseases were higher than most of those of individual amino acid levels even after adjusting for potential confounding factors. The association pattern of the indexes and PFAA with each lifestyle related disease was distinct. CONCLUSIONS: We confirmed the usefulness of PFAA profiles and indexes as markers for evaluating the risks of lifestyle-related diseases, including diabetes mellitus, metabolic syndrome, dyslipidemia, and hypertension in a large Asian population. PMID- 29165133 TI - Leisure-time physical activity in youth as a predictor of adult leisure physical activity among Japanese workers: a cross-sectional study. AB - BACKGROUND: Workers in Japan are not sufficiently active; however, it remains unclear how their leisure-time physical activity habits may be developed. This cross-sectional study investigated the relationship of age- and intensity specific leisure-time physical activity in youth to adulthood leisure-time physical activity habits among Japanese workers. METHODS: In 2012, 968 workers (333 males and 635 females) from three companies and six hospitals in the Tokai region of Japan agreed to complete and submit a self-administered questionnaire. Intensity-specific leisure-time physical activity at ages 12 and 20 years was assessed retrospectively, and workers' current participation in regular leisure time physical activity was assessed as an outcome measure. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression analysis. RESULTS: Mean ages for males and females were 40 and 37 years, respectively. Strenuous leisure-time physical activity at age 12 years was significantly positively associated with adulthood participation in leisure-time physical activity among male workers [adjusted OR (95% CI) = 2.29 (1.02, 5.14)]. Additionally, both strenuous and moderate physical activity at age 20 years was significantly positively associated with participation in regular leisure-time physical activity in adulthood among males and females. CONCLUSIONS: Our results suggest that some leisure-time physical activity in youth may predict adult workers' participation in regular leisure-time physical activity in Japan. Encouragement of leisure-time physical activity in youth could therefore be an effective measure to develop adult leisure-time physical activity habits among workers. PMID- 29165134 TI - Level and potential social-ecological factors associated with physical inactivity and sedentary behavior among Moroccan school-age adolescents: a cross-sectional study. AB - BACKGROUND: Creating a successful intervention that supports an active lifestyle and prevents sedentary one requires a better understanding of the factors associated with physical inactivity (PI) and sedentary behavior (SB). However, these factors have not been assessed among Moroccan adolescents. This study aimed to determine prevalence of PI and SB and to explore their potential social ecological associated factors in school-age adolescents. METHODS: In this cross sectional study, 764 students (age range, 14-19 years) were enrolled from six schools in Taza city, Morocco. The Global School-based Student Health Survey was used to collect data about variables. We used bivariate and multivariate analyses to assess relations between dependent and independent variables. RESULTS: Overall, the prevalence of PI was 79.5% and SB was 36.5%. Among girls, these rates were higher (87.0 and 39.1%, respectively) than rates shown in boys (70.9 and 33.6%, respectively). In the multivariate logistic regression analysis, PI was associated with the following variables: illiterate father, hunger, suicidal ideation, inadequate vegetable consumption, and absence from physical education classes. Age, inadequate vegetable consumption, and absenteeism were associated with SB. CONCLUSIONS: The prevalence of PI and SB is high, especially among girls. Thus, there is an urgent need to implement appropriate interventions to reduce PI and SB levels in secondary school-age adolescents and the associated factors identified can be useful. PMID- 29165135 TI - Potential predictors of susceptibility to occupational stress in Japanese novice nurses - a pilot study. AB - BACKGROUND: Occupational stress is a known factor behind employee resignations; thus, early identification of individuals prone to such stress is important. Accordingly, in this pilot study we evaluated potential predictors of susceptibility to occupational stress in Japanese novice nurses. METHODS: Forty two female novice nurses at Kagoshima University Hospital were recruited for the study population. Each underwent physical health and urinary examinations, and completed a lifestyle questionnaire at the time of job entry. Each also completed a Brief Job Stress Questionnaire (BJSQ), related to mental health status, at job entry and 5 months post-entry. Psychological stress, somatic symptoms, and combined BJSQ scores were determined for each time point. RESULTS: All three stress condition scores had significantly decreased at 5 months post-entry, suggesting occupational stress. Systolic blood pressure (r = -0.324, p < 0.05) and urinary sodium (r = -0.313, p < 0.05) were significantly negatively correlated with combined BJSQ score at 5 months post-entry. Post-entry stress condition scores were significantly low in subjects reporting substantial 1-year body weight change (<= +/- 3 kg) and short times between dinner and bedtimes (<=2 h), though baseline stress condition scores were not. Urinary sodium concentration, 1-year body weight change, and pre-sleep evening meals were then targeted for multivariate analysis, and confirmed as independent explanatory variables for post-entry stress condition scores. CONCLUSIONS: One-year body weight change, times between dinner and bedtimes, and urinary sodium concentration are promising potential predictors of susceptibility to occupational stress, and should be further investigated in future research. TRIAL REGISTRATION: ISRCTN ISRCTN17516023. Retrospectively registered 7 December 2016. PMID- 29165136 TI - Genetic analysis of RNF213 p.R4810K variant in non-moyamoya intracranial artery stenosis/occlusion disease in a Chinese population. AB - OBJECTIVES: RNF213 p.R4810K was identified as a susceptibility variant for moyamoya disease in Asia and non-moyamoya intracranial artery stenosis/occlusion disease in Japan and Korea recently. The occurrence of this variant was evaluated in patients with non-moyamoya intracranial artery stenosis/occlusion disease in China. METHODS: Two study populations were used in this study. One was recruited from the Second Hospital of Hebei Medical University from April 2015 to May 2016. The other was the archived DNA samples of intracranial artery stenosis/occlusion patients in XiangYa Hospital collected in 2014. The occurrence of RNF213 p.R4810K was investigated in a total of 715 patients with non-moyamoya intracranial artery stenosis/occlusion disease. The carrier rate of RNF213 p.R4810K in 507 normal individuals was used as control. RESULTS: Six of 715 patients (0.84%) with non moyamoya intracranial artery stenosis/occlusion disease and 2 of the 507 normal controls (0.39%) had RNF213 p.R4810K variant. The carrier rate of RNF213 p.R4810K was higher in non-moyamoya intracranial artery stenosis/occlusion group than that in the normal group. However, no statistically significant association was observed (Odds ratio, 2.14; 95% confidence interval, 0.43-10.63; p = 0.56). CONCLUSIONS: The carrier rate of RNF213 p.R4810K in Chinese non-moyamoya intracranial artery stenosis/occlusion disease patients was significantly lower than that in Korea or Japan. Genetic heterogeneity was highly indicated. Further systematic genetic epidemiology studies with emphasis on Chinese-specific genetic variants and environmental risk factors of intracranial artery stenosis/occlusion disease in larger population are needed. PMID- 29165137 TI - Anorexia nervosa, depression and suicidal thoughts among Chinese adolescents: a national school-based cross-sectional study. AB - BACKGROUND: Although there is much literature on adolescent suicide, combined effects of depression and anorexia nervosa on suicide were rarely investigated. The aims of this study are to examine the association between anorexia nervosa and suicidal thoughts and explore the interaction between anorexia nervosa and depression. METHODS: This is a cross-sectional study, in the study, a sample of 8,746 Chinese adolescents was selected by multistage stratified method in 2012/2013 from 20 middle schools in 7 provinces across China Mainland. Multilevel logistic model was introduced to explore association between anorexia nervosa and suicidal thoughts. And subgroup analyses were conducted on participants with or without depression. RESULTS: Multilevel logistic model revealed that demographic variables, including academic achievement, were not the predictive risk factors of suicidal thoughts. Those who suffered from worse severity of perceived anorexia nervosa were at increased risk of thinking about suicide. The interaction between depression and anorexia nervosa was significant, however, subgroup analyses showed that the associations were significant only among the adolescents without depression. CONCLUSIONS: Our results indicate that all levels of anorexia nervosa serve as predictable indicators of suicidal thoughts in Chinese adolescents, and the effects of anorexia nervosa are modified by depression status. PMID- 29165138 TI - A relationship between a level of hemoglobin after delivery and exclusive breastfeeding initiation at a baby friendly hospital in Japan. AB - BACKGROUND: The recent National Nutrition Survey of 2013 demonstrated that 16.7% of women in childbearing age are underweight, and 5.0-10.0% of these women manifested a Hemoglobin (Hb) level less than 11.0 g/dl. The purpose of this study was to investigate if such maternal nutritional status affects success of exclusive breastfeeding (EBF) practice. METHODS: This cross-sectional study investigated 1532 dyads of mothers and infants with full-term singleton pregnancies delivered during 2011 at a perinatal center in Tokyo. Outcome is EBF initiation defined as the successful practice at discharge and 1 month after discharge. A logistic regression model was applied to investigate the impact of Hb levels (<9.0, 9.0-10.9, and >=11.0 g/dl) measured within 2-3 days after delivery on successful EBF initiation adjusting for covariates including bleeding at delivery. RESULTS: Mean age was 34 years, 23.0% were underweight and 63.0% were nulliparous. The success rate for EBF initiation at discharge and at 1 month after discharge was 72.7 and 63.0% for a Hb level <9.0 g/dl, 81.9 and 68.9% for a Hb level of 9.0-10.9 g/dl, and 85.7 and 75.9% for a Hb level >=11.0 g/dl, respectively. A logistic regression model showed that risk factors of unsuccessful EBF practice at discharge and 1 month after discharge included lower level Hb categories (P < 0.001 and P < 0.001), postpartum hemorrhage > 500 ml (P = 0.089 and P = 0.011), maternal age (P < 0.001 and P < 0.001), nulliparity (P < 0.0001 and P < 0.001), pregnancy-induced hypertension (P = 0.002 and P = 0.012), gestational week (P = 0.006 and P = 0.002), Low Birth Weight (LBW) (P < 0.001 and P < 0.001), and immediate separation (P < 0.001 and P = 0.020). After adjusting for the covariates, compared with a Hb level >=11.0 g/dl, a Hb level <9.0 g/dl was significantly associated with unsuccessful EBF initiation at discharge [odds ratio (OR): 2.15; 95% confidence interval (CI): 1.37-3.39] and at 1 month after discharge (OR: 1.63; 95% CI: 1.10-2.42), and a Hb level of 9.0-10.9 g/dl also was significant at 1 month after discharge (OR: 1.35; 95% CI: 1.04-1.75). Pre pregnancy underweight was not associated with success of EBF practice both at hospital discharge and 1 month after discharge. CONCLUSION: Maternal severe anemia after delivery was associated with the risk of unsuccessful initiation of EBF even after adjusting for bleeding at delivery, suggesting the importance of dietary management especially in the later trimester. PMID- 29165139 TI - Analysis of the evidence-practice gap to facilitate proper medical care for the elderly: investigation, using databases, of utilization measures for National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB). AB - As Japan becomes a super-aging society, presentation of the best ways to provide medical care for the elderly, and the direction of that care, are important national issues. Elderly people have multi-morbidity with numerous medical conditions and use many medical resources for complex treatment patterns. This increases the likelihood of inappropriate medical practices and an evidence practice gap. The present study aimed to: derive findings that are applicable to policy from an elucidation of the actual state of medical care for the elderly; establish a foundation for the utilization of National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), and present measures for the utilization of existing databases in parallel with NDB validation.Cross-sectional and retrospective cohort studies were conducted using the NDB built by the Ministry of Health, Labor and Welfare of Japan, private health insurance claims databases, and the Kyoto University Hospital database (including related hospitals). Medical practices (drug prescription, interventional procedures, testing) related to four issues-potential inappropriate medication, cancer therapy, chronic kidney disease treatment, and end-of-life care-will be described. The relationships between these issues and clinical outcomes (death, initiation of dialysis and other adverse events) will be evaluated, if possible. PMID- 29165140 TI - Comparison between air pollution concentrations measured at the nearest monitoring station to the delivery hospital and those measured at stations nearest the residential postal code regions of pregnant women in Fukuoka. AB - BACKGROUND: Numerous earlier studies examining the association of air pollution with maternal and foetal health estimated maternal exposure to air pollutants based on the women's residential addresses. However, residential addresses, which are personally identifiable information, are not always obtainable. Since a majority of pregnant women reside near their delivery hospitals, the concentrations of air pollutants at the respective delivery hospitals may be surrogate markers of pollutant exposure at home. We compared air pollutant concentrations measured at the nearest monitoring station to Kyushu University Hospital with those measured at the closest monitoring stations to the respective residential postal code regions of pregnant women in Fukuoka. METHODS: Aggregated postal code data for the home addresses of pregnant women who delivered at Kyushu University Hospital in 2014 was obtained from Kyushu University Hospital. For each of the study's 695 women who resided in Fukuoka Prefecture, we assigned pollutant concentrations measured at the nearest monitoring station to Kyushu University Hospital and pollutant concentrations measured at the nearest monitoring station to their respective residential postal code regions. RESULTS: Among the 695 women, 584 (84.0%) resided in the proximity of the nearest monitoring station to hospital or one of the four other stations (as the nearest stations to their respective residential postal code region) in Fukuoka city. Pearson's correlation for daily mean concentrations among the monitoring stations in Fukuoka city was strong for fine particulate matter (PM2.5), suspended particulate matter (SPM), and photochemical oxidants (Ox) (coefficients >=0.9), but moderate for coarse particulate matter (the result of subtracting the PM2.5 from the SPM concentrations), nitrogen dioxide, and sulphur dioxide. Hospital based and residence-based concentrations of PM2.5, SPM, and Ox were comparable. CONCLUSIONS: For PM2.5, SPM, and Ox, exposure estimation based on the delivery hospital is likely to approximate that based on the home of pregnant women. PMID- 29165141 TI - Association between perceived neighborhood environment and health of middle-aged women living in rapidly changing urban Mongolia. AB - BACKGROUND: This study was conducted in rapidly urbanizing Ulaanbaatar, Mongolia, to examine patterns of perceived neighborhood quality by residents and the associations between these patterns and self-reported general and mental health in middle-aged women. METHODS: A questionnaire survey was administered to 960 women aged 40-60 years. Demographic and socio-economic characteristics, subjects' perception of their neighborhood environment, general health status, and mental health as measured using a 12-item General Health Questionnaire (GHQ12) were reported. RESULTS: A total of 830 women completed the questionnaire. Subjects reporting their general health as very good or good accounted for 80.3% and those with a GHQ12 >=16, which reflects psychological distress or severe distress, accounted for 16.1%. A principal component analysis of the perceptions of neighborhood environment by the residents identified six qualities: physical environment, designed environment, neighborhood community, public safety, natural environment, and citizen services. The perception of better-quality citizen services in the neighborhood was associated with better self-reported general health (odds ratio [OR] = 1.330, 95% confidence interval [CI] 1.093-1.618), and the perception of better-quality public safety was associated with less psychological distress (OR = 0.718, 95% CI 0.589-0.876); these associations were independent of education, income, occupation, type of residential area, and number of years living in the current khoroo. CONCLUSIONS: The perception of the quality of a neighborhood environment can affect the self-reported general and mental health of residents, even after accounting for the type of residential area and individual socio-economic status. Developing high-quality neighborhoods is an essential component of good planning to promote population health in urban environments. PMID- 29165142 TI - The effect of exercise intensity on brain derived neurotrophic factor and memory in adolescents. AB - BACKGROUND: Brain derived neurotrophic factor (BDNF) seems to serve as an important regulatory mechanism in the growth and development of neurons in many areas of the brain.Insulin-like growth factor 1 (IGF-1) is related to neurogenesis and regulation of the BDNF gene and is involved in the growth and differentiation of neurons.Cortisol is released in response to stimuli such as psychological oppression, anxiety, and fear. Stress also induces changes in BDNF. The purpose of this study was thus to examine the effects of varying intensities of aerobic exercise on resting serum BDNF, IGF-1 concentrations, cortisol, and memory of adolescents. METHODS: Forty male students with no history of physical illness from the middle school by participated in this study. Participants were randomly assigned to low, moderate, or high intensity treadmill exercise group, or a stretching (control) group. Exercise was performed 4 times per week for 12 weeks. Body composition, brain derived neurotrophic factor levels, insulin-like growth factor 1 levels, cortisol levels, and working memory were assessed. RESULTS: The high intensity exercise group showed a significant increase in brain derived neurotrophic factor at rest, concentration level of insulin-like growth factor 1, cortisol, and working memory. For resting brain derived neurotrophic factor, the high intensity exercise group showed a more significant increase compared to the low intensity aerobic and stretching groups. The change in the working memory significantly increased for the high intensity exercise group compared to the low intensity aerobic group, moderate intensity exercise group, and stretching group. CONCLUSIONS: In adolescents, whose brains are still developing, aerobic exercise of moderate to high intensity levels seems to have a positive effect on levels of serum brain derived neurotrophic factor at rest and on cognitive functioning. TRIAL REGISTRATION: EHPM-D-16-00107R2 . ICMJE. 12 July 2016. PMID- 29165143 TI - Characteristics of stepfamilies and maternal mental health compared with non stepfamilies in Japan. AB - BACKGROUND: Stepfamilies remain poorly understood in Japanese society, and the support needs of stepfamily mothers are unclear. This study aimed to identify characteristics of stepfamilies and maternal mental health as compared with non stepfamilies in Japan to utilize as a primary resource for providing effective support through community-based health care for stepfamilies. METHODS: From December 2011 to July 2012, we conducted this questionnaire survey with mothers at 3- and 4-month checkups for infants. The response rate was 75.1%. The sample for analysis included responses of 2246 mothers, excluding single mothers. RESULTS: Respondents comprised 47 (2.1%) stepfamilies and 2199 (97.9%) non stepfamilies. There were significantly higher rates of parents with not more than a high school education and >=3 children among stepfamilies compared with non stepfamilies. Stepfamily mothers had significantly higher rates of feeling a lack of economic resources, absence of participation in childbirth education classes, smoking during pregnancy, and unplanned pregnancy. Furthermore, they also had significantly higher rates of depression and a lack of confidence in the parent role. Maternal depression was associated with factors such as maternal age, self perceived health, stress level, confidence in breastfeeding, confidence in the parent role, and number of children. CONCLUSIONS: These findings suggest that stepfamilies exhibit many characteristics related to social disadvantage and problems with community-based health care in Japan. Healthcare providers should be aware of stepfamily mothers' support needs and should put in place a support system for stepfamilies. Moreover, compared with non-stepfamily mothers, stepfamily mothers have a significantly higher prevalence of depression. However, stepfamily composition does not necessarily increase the risk of maternal depression. Therefore, healthcare providers should put in place a system for obtaining more thorough information about stepfamilies and conduct an early assessment to identify their support needs. PMID- 29165144 TI - Isolation and identification of Acanthamoeba strains from soil and tap water in Yanji, China. AB - BACKGROUND: Members of the genus Acanthamoeba are widely distributed throughout the world, and some of them are considered pathogenic, as they are capable of causing corneal and central nervous system diseases. In this study, we isolated Acanthamoeba strains from soil and tap water in Yanji, China. METHODS: We identified four strains of Acanthamoeba (CJY/S1, CJY/S2, CJY/S3, and CJY/W1) using mitochondrial DNA restriction fragment length polymorphism (mtDNA RFLP) analysis. Nuclear 18S rDNA sequences were used for phylogenetic analysis and species identification. RESULTS: Genotypic characterization of the isolates showed that they belonged to genotypes T4 (CJY/S1 and CJY/S2), T5 (CJY/S3), and T16 (CJY/W1). Sequence differences between CJY/S1 and Acanthamoeba castellanii Neff, CJY/S2 and Acanthamoeba KA/E7, and CJY/S3 and Acanthamoeba lenticulata 68-2 were 0.31, 0.2, and 0.26%, respectively. 18S ribosomal deoxyribonucleic acid (rDNA) of CJY/W1 had 99% sequence identity to that of Acanthamoeba sp. U/H-C1. Strains CJY/S1 and CJY/S2, isolated from soil, had similar mtDNA RFLP patterns, whereas strain CJY/W1, isolated from tap water, displayed a different pattern. CONCLUSIONS: To the best of our knowledge, this is the first report on the identification of genotypes T4, T5, and T16 from environmental sources in Yanji, China. PMID- 29165146 TI - Association between posttraumatic stress disorder (PTSD) severity and ego structure of the Nanai people. AB - BACKGROUND: A man-made chemical disaster occurred in the Amur River, leading to posttraumatic stress disorder (PTSD) in the Nanai people indigenous to the river's surrounding area. PTSD severity measured by the total scores of Impact of Event Scale-Revised (IES-R) (Total-I) and Clinician-Administered PTSD Scale (CAPS) (Total-C) were not always identical in terms of demographic and ethnocultural characters. It is possible that the results derived using the Total I and Total-C may differ for persons with different backgrounds and/or individual characteristics. In this study, the associations between PTSD severity and personal characteristics were evaluated. METHODS: The study was a field-type survey including 187 randomly selected participants (75 males and 112 females). In addition to Total-I/Total-C, scores for each IES-R/CAPS item, Intrusion, Avoidance, and Hyperarousal, and Ego Structure Test by Ammon (ISTA) score were examined to evaluate their personal characteristics. RESULTS: No specific trends in ISTA score were obvious among four groups defined according to Total-I/Total C. The results of principal component analysis showed that all IES-R/CAPS items contributed positively to the 1st axis but to the 2nd axis in a different manner. ISTA items did not always show correlations to each other, but principal component analysis suggested that Construct contributed positively and Destruct and Deficient (with the exception of Destruct sexuality) contributed negatively. High IES-R scores were associated with Construct Aggression and Deficient Inner demarcation, but high CAPS score was less likely to exhibit Construct Narcissism. CONCLUSION: To avoid the misdiagnosis of PTSD, usage of both IES-R/CAPS may be required. Simultaneous application of personality/ego tests may be helpful, but appropriate numbers of their questions would be important. PMID- 29165145 TI - Organochlorine pesticide level in patients with chronic kidney disease of unknown etiology and its association with renal function. AB - BACKGROUND: Involvement of agrochemicals have been suggested in the development of chronic kidney disease of unknown etiology (CKDu). The association between CKDu and blood level of organochlorine pesticides (OCPs) in CKDu patients has been examined in the present study. METHODS: All the recruited study subjects (n = 300) were divided in three groups, namely, healthy control (n = 100), patients with chronic kidney disease of unknown etiology (n = 100), and patients with chronic kidney disease of known etiology (CKDk) (n = 100). Blood OCP levels of all three study groups were analyzed by gas chromatography. RESULTS: Increased level of OCPs, namely alpha-HCH, aldrin, and beta-endosulfan, were observed in CKDu patients as compared to healthy control and CKD patients of known etiology. The levels of these pesticides significantly correlated negatively with the estimated glomerular filtration rate (eGFR) and positively with urinary albumin of CKD patients. Logistic regression analysis revealed association of gamma-HCH, p, p'-DDE, and beta-endosulfan with CKDu on adjustment of age, sex, BMI, and total lipid content. CONCLUSIONS: Increased blood level of certain organochlorine pesticides is associated with the development of chronic kidney disease of unknown etiology. PMID- 29165147 TI - Enterococcus hirae biofilm formation on hospital material surfaces and effect of new biocides. AB - BACKGROUND: Nowadays, the bacterial contamination in the hospital environment is of particular concern because the hospital-acquired infections (HAIs), also known as nosocomial infections, are responsible for significant morbidity and mortality. This work evaluated the capability of Enterococcus hirae to form biofilm on different surfaces and the action of two biocides on the produced biofilms. METHODS: The biofilm formation of E. hirae ATCC 10541 was studied on polystyrene and stainless steel surfaces through the biomass quantification and the cell viability at 20 and 37 degrees C. The effect of LH IDROXI FAST and LH ENZYCLEAN SPRAY biocides on biomasses was expressed as percentage of biofilm reduction. E. hirae at 20 and 37 degrees C produced more biofilm on the stainless steel in respect to the polystyrene surface. The amount of viable cells was greater at 20 degrees C than with 37 degrees C on the two analyzed surfaces. Biocides revealed a good anti-biofilm activity with the most effect for LH ENZYCLEAN SPRAY on polystyrene and stainless steel at 37 degrees C with a maximum biofilm reduction of 85.72 and 86.37%, respectively. RESULTS: E. hirae is a moderate biofilm producer depending on surface material and temperature, and the analyzed biocides express a remarkable antibiofilm action. CONCLUSION: The capability of E. hirae to form biofilm can be associated with its increasing incidence in hospital-acquired infections, and the adoption of suitable disinfectants is strongly recommended. PMID- 29165148 TI - Japan Environment and Children's Study: backgrounds, activities, and future directions in global perspectives. AB - There is worldwide concern about the effects of environmental factors on children's health and development. The Miami Declaration was signed at the G8 Environment Ministers Meeting in 1997 to promote children's environmental health research. The following ministerial meetings continued to emphasize the need to foster children's research. In response to such a worldwide movement, the Ministry of the Environment, Japan (MOE), launched a nationwide birth cohort study with 100,000 pairs of mothers and children, namely, the Japan Environment and Children's Study (JECS), in 2010. Other countries have also started or planned large-scale studies focusing on children's environmental health issues. The MOE initiated dialogue among those countries and groups to discuss and share the various processes, protocols, knowledge, and techniques for future harmonization and data pooling among such studies. The MOE formed the JECS International Liaison Committee in 2011, which plays a primary role in promoting the international collaboration between JECS and the other children's environmental health research projects and partnership with other countries. This review article aims to present activities that JECS has developed. As one of the committee's activities, a workshop and four international symposia were held between 2011 and 2015 in Japan. In these conferences, international researchers and government officials, including those from the World Health Organization, have made presentations on their own birth cohort studies and health policies. In 2015, the MOE hosted the International Advisory Board meeting and received constructive comments and recommendations from the board. JECS is a founding member of the Environment and Child Health International Birth Cohort Group, and has discussed harmonization of exposure and outcome measurements with member parties, which will make it possible to compare and further combine data from different studies, considering the diversity in the measurements of variables between the studies. JECS is expected to contribute to the international environmental health research community and policy-making. More international collaboration would enhance our understanding of the possible environmental causes of diseases and disabilities. PMID- 29165149 TI - Association of excessive mobile phone use during pregnancy with birth weight: an adjunct study in Kumamoto of Japan Environment and Children's Study. AB - BACKGROUND: Low birth weight has been shown to be closely associated with neonatal mortality and morbidity, inhibited growth, poor cognitive development, and chronic diseases later in life. Some studies have also shown that excessive mobile phone use in the postnatal period may lead to behavioral complications in the children during their growing years; however, the relationship between mobile phone use during pregnancy and neonatal birth weight is not clear. The aim of the present study was to determine the associations of excessive mobile phone use with neonatal birth weight and infant health status. METHODS: A sample of 461 mother and child pairs participated in a survey on maternal characteristics, infant characteristics, and maternal mobile phone usage information during pregnancy. RESULTS: Our results showed that pregnant women tend to excessively use mobile phones in Japan. The mean infant birth weight was lower in the excessive use group than in the ordinary use group, and the frequency of infant emergency transport was significantly higher in the excessive use group than in the ordinary use group. CONCLUSIONS: Excessive mobile phone use during pregnancy may be a risk factor for lower birth weight and a high rate of infant emergency transport. PMID- 29165151 TI - Personal perspective on Environmental Health and Preventive Medicine. PMID- 29165150 TI - Search for biomarkers of asbestos exposure and asbestos-induced cancers in investigations of the immunological effects of asbestos. AB - The immunological effects of asbestos exposure on various lymphocytes such as the regulatory T cell (Treg), responder CD4+ T helper cell (Tresp), CD8+ cytotoxic T lymphocytes (CTL), and natural killer (NK) cells were investigated. Results show that asbestos exposure impairs antitumor immunity through enhancement of regulatory T cell function and volume, reduction of CXCR3 chemokine receptor in responder CD4+ T helper cells, and impairment of the killing activities of CD8+ cytotoxic T lymphocytes (CTL) and NK cells. These findings were used to explore biological markers associated with asbestos exposure and asbestos-induced cancers and suggested the usefulness of serum/plasma IL-10 and TGF-beta, surface CXCR3 expression in Tresp, the secreting potential of IFN-gamma in Tresp, intracellular perforin level in CTL, and surface expression NKp46 in NK cells. Although other unexplored cytokines in serum/plasma and molecules in these immunological cells, including Th17, should be investigated by experimental procedures in addition to a comprehensive analysis of screening methods, biomarkers based on immunological alterations may be helpful in clinical situations to screen the high-risk population exposed to asbestos and susceptible to asbestos-related cancers such as mesothelioma. PMID- 29165152 TI - Detection of antibiotic resistant Acinetobacter baumannii in various hospital environments: potential sources for transmission of Acinetobacter infections. AB - BACKGROUND: Antibiotic resistant Acinetobacter baumannii has emerged as one of the most problematic hospital acquired pathogens around the world. This study was designed to investigate the presence of antibiotic resistant A. baumannii in various hospital environments. METHODS: Air, water and inanimate surface samples were taken in different wards of four hospitals and analyzed for the presence of A. baumannii. Confirmed A. baumannii isolates were analyzed for antimicrobial susceptibility and also screened for the presence of three most common OXA- type carbapenemase-encoding genes. RESULTS: A. baumannii was detected in 11% (7/64) of air samples with the highest recovery in intensive care units (ICUs). A. baumannii was also detected in 17% (7/42) and 2% (1/42) of surface and water samples, respectively. A total of 40 A. baumannii isolates were recovered and analysis of antimicrobial susceptibility showed the highest resistance towards ceftazidime (92.5%, 37/40). 85% (34/40) and 80% (32/40) of the isolates were also resistant to imipenem and gentamicin, respectively. Resistance genes analysis showed that 77.5% (31/40) strains contained OXA-23 and 5% (2/40) strains contained OXA-24, but OXA-58 was not detected in any of the strains. CONCLUSION: Detection of antibiotic resistant A. baumannii in various samples revealed that hospital environments could act as a potential source for transmission of A. baumannii infections especially in ICUs. These results emphasize the importance of early detection and implementation of control measures to prevent the spread of A. baumannii in hospital environments. PMID- 29165153 TI - Impact of single nucleotide polymorphism on short stature and reduced tongue pressure among community-dwelling elderly Japanese participants: a cross sectional study. AB - BACKGROUND: Asian-specific single nucleotide polymorphism (SNPs) (rs3782886) is reported to be associated with myocardial infarction; sarcopenia is reported to be associated with coronary subclinical atherosclerosis. On the other hand, short stature has been revealed as an independent risk factor for cardiovascular disease. However, no studies have reported on the association between sarcopenia and short stature nor on the impact of rs3782886 on this association. METHODS: Since reduced maximum voluntary tongue pressure against the palate (MTP) reflects one aspect of sarcopenia, we conducted a cross-sectional study of 537 community dwelling elderly Japanese participants aged 60-89 years who had participated in a general health checkup in 2015. Short stature was defined as values at or under the 25th percentile, and reduced MTP was defined as the lowest tertile of the study population (<158.0 cm and <26.5 kPa for men, <145.0 cm and <24.1 kPa for women). RESULTS: Independent of classical cardiovascular risk factors, short stature was revealed to be positively associated with reduced MTP. The adjusted odds ratio (OR) and 95% confidence interval (CI) of reduced MTP for short stature was 1.87 (1.19, 2.94). We also found that independent of known cardiovascular risk factors, with the non-minor homo of rs3782886 taken as the reference group, the adjusted OR and 95% CI for short stature and reduced MTP of the minor homo allele were 3.06 (1.23, 7.63) and 3.26 (1.33, 8.03), respectively. CONCLUSION: Short stature is independently associated with reduced MTP, with Asian-specific SNPs possibly playing an important role in this association. PMID- 29165154 TI - Acute effects of air pollutants on pulmonary function among students: a panel study in an isolated island. AB - BACKGROUND: Many epidemiological studies on the health effects of air pollutants have been carried out in regions with major sources such as factories and automobiles. However, the health effects of air pollutants in regions without major sources remain unclear. This study investigated the acute effects of ambient air pollution on pulmonary function among healthy students in an isolated island without major artificial sources of air pollutants. METHODS: A panel study was conducted of 43 healthy subjects who attended a school in an isolated island in the Seto Inland Sea, Japan. We measured the forced expiratory volume in 1 s (FEV1) and peak expiratory flow (PEF) every morning for about 1 month in May 2014. Ambient concentrations of particulate matter <= 2.5 MUm in diameter (PM2.5), particulate matter between 2.5 and 10 MUm in diameter (PM10-2.5), black carbon (BC), ozone (O3), and nitrogen dioxide (NO2) were measured. The associations between the concentrations of air pollutants and pulmonary function were analyzed using mixed-effects models. RESULTS: A decrease in FEV1 was significantly associated with BC concentrations (-27.28 mL [95%confidence interval (CI):-54.10,-0.46] for an interquartile range (IQR) increase of 0.23 MUg/m3). The decrease in PEF was significantly associated with indoor O3 concentrations (-8.03 L/min [95% CI:-13.02,-3.03] for an IQR increase of 11 ppb). Among subjects with a history of allergy, an increase in PM2.5 concentrations was significantly associated with low FEV1. In subjects with a history of asthma, an inverse association between the indoor O3 concentration and pulmonary function was observed. CONCLUSIONS: Our results demonstrate that increases in BC and O3 concentrations have acute effects on the pulmonary function among students in an isolated island without major artificial sources of air pollutants. PMID- 29165155 TI - Association between high and low ambient temperature and out-of-hospital cardiac arrest with cardiac etiology in Japan: a case-crossover study. AB - OBJECTIVE: The objective of the study was to examine the association between high and low temperature and out-of-hospital cardiac arrest (OHCA) with cardiac etiology. METHODS: The study was conducted under a case-crossover design. Subjects were 97,500 patients aged 40 years or older with OHCA having a cardiac etiology in Tokyo, Osaka, and Fukuoka Prefecture from 2005 to 2012. We used national data with an Utstein-style resuscitation registration. Temperature was categorized into five categories with cut points of 5, 10, 24, and 30 degrees C. The reference category was 10-23.9 degrees C. Conditional logistic regression was used with adjustment for daily means of relative humidity, atmospheric pressure, and wind speed and daily amount of precipitation and hours of daylight. RESULTS: Exposure to high temperature (>=30 degrees C) increased the risk of OHCA (OR = 1.11, 95% confidence interval (CI) 1.04-1.18). Further, low temperature (<5 degrees C) and relatively low temperature (5-9.9 degrees C) were also associated with OHCA (OR = 1.20, 95% CI 1.16-1.25; OR = 1.10, 95% CI 1.07-1.13, respectively). The temperature-OHCA association curves were U-shaped or J-shaped, and the association was more prominent among those aged 80 years or older. CONCLUSION: This study shows that the occurrence of OHCA with cardiac etiology is associated with low temperature. In addition, the occurrence is also associated with high temperature in those aged 80 years or older. PMID- 29165156 TI - Total arsenic and speciation analysis of saliva and urine samples from individuals living in a chronic arsenicosis area in China. AB - BACKGROUND: It is generally acknowledged that the determination of harmful chemical compounds excreted into saliva is useful for assessing their exposure levels. The aim of the present study was to compare the total arsenic and its species in saliva and urine samples collected from the people residing in an arsenic-contaminated area of China and to further verify the feasibility of using salivary arsenic as a new biomarker of arsenic exposure. METHODS: Total arsenic and speciation analyses in urine and saliva samples among 70 residents exposed to arsenic from drinking water in Shanxi, China were carried out by high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP/MS). RESULTS: The result showed that, total arsenic concentration in saliva was relatively lower than in urine samples, but it existed a strong positive correlation with total urinary arsenic, drinking water arsenic and different skin lesions. For arsenic metabolism analyses, AsIII, AsV, MMA, and DMA were detected in all of the urine samples with the dominating species of DMA (73.2%). Different with urinary arsenic species, most arsenic species in saliva were not methylated. The major species in saliva was iAs (AsIII + AsV, 76.18%), followed by DMA (13.08%) and MMA (9.13%). And the primary methylation index (PMI), second methylation index (SMI) and proportion of the four different species (AsIII, AsV, MMA, and DMA) in saliva showed no significant positive relationship with that of in urine. CONCLUSIONS: These findings indicated saliva may be used as a useful tool for biological monitoring of total arsenic exposure in the crowd rather than an efficient tool for assessing arsenic metabolism in human body after exposed to arsenic. PMID- 29165158 TI - Comments on "Association of excessive mobile phone use during pregnancy with birth weight: an adjunct study in Kumamoto of Japan Environment and Children's Study". AB - We have read with interest the article by Lu et al. entitled "Association of excessive mobile phone use during pregnancy with birth weight: an adjunct study in Kumamoto of Japan Environment and Children's Study" published recently in the Environmental Health and Preventive Medicine. Although this paper addresses a very challenging issue, it has some shortcomings. Mortazavi et al. have previously studied the effects of ionizing and non-ionizing radiation on birth weight of newborns and found no statistical significant differences between the mean weight of newborns whose mothers had been exposed to electromagnetic fields (EMF) generated by mobile phones and those of non-exposed mothers. The study performed by Lu et al. cannot answer this very key question that whether ordinary use of mobile phone during pregnancy can lead to low birth weight. The origin of the controversy between the findings of these two studies and the shortcomings of the article by Lu et al. are discussed. PMID- 29165157 TI - The Hokkaido Birth Cohort Study on Environment and Children's Health: cohort profile-updated 2017. AB - The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary study goals are (1) to examine the effects of low-level environmental chemical exposures on birth outcomes, including birth defects and growth retardation; (2) to follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders and perform a longitudinal observation of child development; (3) to identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) to identify the additive effects of various chemicals, including tobacco smoking. The purpose of this report is to update the progress of the Hokkaido Study, to summarize the recent results, and to suggest future directions. In particular, this report provides the basic characteristics of the cohort populations, discusses the population remaining in the cohorts and those who were lost to follow-up at birth, and introduces the newly added follow-up studies and case-cohort study design. In the Sapporo cohort of 514 enrolled pregnant women, various specimens, including maternal and cord blood, maternal hair, and breast milk, were collected for the assessment of exposures to dioxins, polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances, phthalates, bisphenol A, and methylmercury. As follow-ups, face-to-face neurobehavioral developmental tests were conducted at several different ages. In the Hokkaido cohort of 20,926 enrolled pregnant women, the prevalence of complicated pregnancies and birth outcomes, such as miscarriage, stillbirth, low birth weight, preterm birth, and small for gestational age were examined. The levels of exposure to environmental chemicals were relatively low in these study populations compared to those reported previously. We also studied environmental chemical exposure in association with health outcomes, including birth size, neonatal hormone levels, neurobehavioral development, asthma, allergies, and infectious diseases. In addition, genetic and epigenetic analyses were conducted. The results of this study demonstrate the effects of environmental chemical exposures on genetically susceptible populations and on DNA methylation. Further study and continuous follow-up are necessary to elucidate the combined effects of chemical exposure on health outcomes. PMID- 29165159 TI - Increase in the prevalence of hypertension among adults exposed to the Great Chinese Famine during early life. AB - OBJECTIVE: This study aimed to assess the association between exposure to the Great Chinese Famine (1959-1961) during early life and hypertension in adulthood. METHODS: From July to September 2009, 1224 eligible adults were recruited in a cross-sectional survey using a multi-stage stratified random sampling method in Chongqing China. A questionnaire was used to collect information of hypertension and sociodemographic factors. Participants were categorized as childhood, fetal, and none exposure to famine based on the date of birth. RESULTS: Of the sample, 12.3% reported having hypertension. The prevalence of hypertension varied by famine status: 11.9% in childhood exposure, 16.1% in fetal exposure, and 10.2% in non-exposure group. After adjusting for sociodemographic and lifestyle factors, compared with non-exposure group, fetal exposure group had an increased likelihood of having hypertension with odds ratio of 1.79 (95%CI 1.13-2.84). Although there was no significant gender and famine interaction, the positive association between famine exposure and hypertension was stronger among women than men. CONCLUSION: Fetal exposure to the Chinese famine may be associated with an increased risk of hypertension in adulthood in women [corrected]. PMID- 29165160 TI - A review of Vietnam's healthcare reform through the Direction of Healthcare Activities (DOHA). AB - OBJECTIVE: This article provides a comprehensive review of the healthcare reform process driven by the Vietnamese Ministry of Health's Direction of Healthcare Activities (DOHA) scheme. METHODS: We reviewed policy documents relating to DOHA, along with historical literature and background information describing its formation. RESULTS: DOHA (Chi dao tuyen in Vietnamese) literally means guidance line or level in English. It requires healthcare facilities at higher government administration levels to support those at lower levels (the four levels being central, provincial, district, and commune), to help lower level hospitals to provide medical services for local communities in primary care settings and reduce the number of patients in higher level (central and provincial) hospitals. Since the 1990s, there have been too many patients attending higher level hospitals, and DOHA has therefore focused on technical skills transfer training to help alleviate this situation. Designated core central hospitals now provide technical skills transfer to provincial hospitals. Professional technical lists for each level of health facility have enabled strong commitment and proactive ownership of the process of training management in both higher and lower level hospitals. CONCLUSION: The DOHA scheme has accelerated the necessary up-skilling of healthcare at lower level public hospitals across Vietnam. These reforms are highly relevant for other countries with limited healthcare resources. PMID- 29165161 TI - Rare variants of RNF213 and moyamoya/non-moyamoya intracranial artery stenosis/occlusion disease risk: a meta-analysis and systematic review. AB - BACKGROUND: The p.R4810K and other rare variants of ring finger protein 213 gene (RNF213) were illustrated as susceptibility variants for moyamoya (MMD) and non moyamoya intracranial artery stenosis/occlusion disease (ICASO) recently. However, the effect sizes of p.R4810K were in great discrepancy even in studies of the same ethnic population and firm conclusions of other rare variants have been elusive given the small sample sizes and lack of replication. Thus, we performed this study to quantitatively evaluate whether or to what extent the rare variants of RNF213 contribute to MMD and ICASO in different populations. METHODS: A systematic search of PubMed, EMBASE, ISI web of science, CNKI, and WANFANG DATA was conducted up to 5 September 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed-effect models based on the between-study heterogeneity. The subgroup analyses were performed by the ethnicity and family history. Sensitivity and publication bias analysis were performed to test the robustness of associations. All the statistical analyses were conduct using STATA 12.0. RESULTS: Twenty studies including 2353 MMD cases and 5488 controls and 11 studies including 1778 ICASO cases and 3140 controls were included in this study. Pooled ORs indicated that RNF213 p.R4810K significantly increased MMD and ICASO risk in East Asians with great effect sizes of discrepancy (dominant model: odds ratios 184.04, 109.77, and 31.53 and 10.07, 28.52, and 5.59 for MMD and ICASO, respectively, in Japan, Korea, and China). It significantly increased familial MMD risk in Japan, Korea, and China with 5 ~ 36 times larger effect sizes than that for sporadic ones in each country (dominant model ORs 1802.44, 512.42, 1109.02 and 134.35, 99.82, and 30.52, respectively, for familial and sporadic cases). The effect sizes of RNF213 p.R4810K to sporadic MMD were 3 ~ 4 times larger in Japan and Korea than those in China. RNF213 p.R4810K also increased the ICASO risk in Japan and Korea with 2 ~ 4 times larger effect sizes than that in China (dominant model ORs 10.71, 28.52, and 5.59, respectively). Another two rare variants- p.E4950D and p.A5021V significantly increased MMD risk in Chinese population (dominant model ORs 9.06 and 5.01, respectively). Various other rare variants in RNF213 were identified in Japanese, Chinese, European, and Hispanic American populations without association evidence available yet. CONCLUSIONS: This meta-analysis shows the critical roles of RNF213 p.R4810K in MMD especially familial MMD and ICASO in Japan, Korea, and China. Except for RNF213 p.R4810K, MMD seems to have more complex determiners in China. Distinct genetic background exists and other environmental or genetic factor(s) may contribute to MMD. Studies focused on delineating the ethnicity-specific factors and pathological role of RNF213 variants in MMD and ICASO are needed. PMID- 29165162 TI - Preventing heat illness in the anticipated hot climate of the Tokyo 2020 Summer Olympic Games. AB - Amid the effects of global warming, Tokyo has become an increasingly hot city, especially during the summertime. To prepare for the upcoming 2020 Summer Olympics and Paralympics in Tokyo, all participants, including the athletes, staff, and spectators, will need to familiarize themselves with Tokyo's hot and humid summer conditions. This paper uses the wet-bulb globe temperature (WBGT) index, which estimates the risk of heat illness, to compare climate conditions of sports events in Tokyo with the conditions of the past three Summer Olympics (held in Rio de Janeiro, London, and Beijing) and to subsequently detail the need for establishing appropriate countermeasures. We compared WBGT results from the past three Summer Olympics with the same time periods in Tokyo during 2016. There was almost no time zone where a low risk of heat illness could be expected during the time frame of the upcoming 2020 Tokyo Olympics. We also found that Tokyo had a higher WBGT than any of those previous host cities and is poorly suited for outdoor sporting events. Combined efforts by the official organizers, government, various related organizations, and the participants will be necessary to deal with these challenging conditions and to allow athletes to perform their best, as well as to prevent heat illnesses among staff and spectators. The sporting committees, as well as the Olympic organizing committee, should consider WBGT measurements in determining the venues and timing of the events to better avoid heat illness and facilitate maximum athletic performance. PMID- 29165163 TI - The potential protective effect of Commelina nudiflora L. against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats, mediated by suppression of oxidative stress and inflammation. AB - BACKGROUND: This study aims to assess the hepatoprotective potential of Commelina nudiflora against CCl4-induced hepatic injury in rats. METHOD: Antioxidant activities were determined. Phytochemical analysis was performed by gas chromatography mass spectrometry (GCMS). In the in vivo study, Sprague Dawley rats were pretreated with C. nudiflora (150, 300, and 450 mg kg body weight (b.wt.)) once daily for 14 days followed by two doses of CCl4 (1 ml/kg b.wt.). After 2 weeks, the rats were sacrificed and hepatoprotective analysis was performed. RESULTS: In vitro studies have shown that the extract possessed strong antioxidant activity and has ability to scavenge 2,2-diphenyl-2-picrylhydrazyl free radicals effectively. GCMS analysis of the C. nudiflora extract revealed the presence of various bioactive compounds. Administration of C. nudiflora significantly reduced the impact of CCl4 toxicity on serum markers of liver damage, serum aspartate transaminase (AST), and alanine transaminase (ALT). C. nudiflora also increased antioxidant levels of hepatic glutathione (GSH) and antioxidant enzymes and ameliorated the elevated hepatic formation of malondialdehyde (MDA) induced by CCl4 in rats. Histopathological examination indicated that C. nudiflora protect the liver from the toxic effect of CCl4 and healed lesions such as necrosis, fatty degeneration, and hepatocyte injury as irregular lamellar organization and dilations in the endoplasmic reticulum. The immunohistochemical studies revealed that pretreatment of C. nudiflora decreased the formation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts and 8-hydroxy 2'-deoxyguanosine (8-OHdG). Furthermore, overexpression of the proinflammatory cytokines TNF-alpha, IL-6, and prostaglandin E2 is also reduced. CONCLUSION: These findings exhibited the potential prospect of C. nudiflora as functional ingredients to prevent ROS-related liver damage. PMID- 29165164 TI - Association between NAT2, CYP1A1, and CYP1A2 genotypes, heterocyclic aromatic amines, and prostate cancer risk: a case control study in Japan. AB - BACKGROUND: Heterocyclic aromatic amines (HAAs) may confer prostate cancer risk; however, the evidence is inconclusive and the activity of HAA-metabolizing enzymes is modulated by gene variants. The purpose of our study was to determine whether there was evidence of an association between HAA intake, polymorphisms in NAT2, CYP1A1, and CYP1A2 and prostate cancer risk in Japanese men. METHODS: Secondary data analysis of an observational case control study was performed. Among 750 patients with prostate cancer and 870 healthy controls, 351 cases and 351 age-matched controls were enrolled for analysis. HAA intake was estimated using a food frequency questionnaire and genotypes were scored by TaqMan real time PCR assay. Logistic regression analysis was conducted according to affected/control status. RESULTS: We found that high HAA intake was significantly associated with an increased risk of prostate cancer (odds ratio (OR), 1.90; 95% confidence interval (95% CI), 1.40-2.59). The increased risk of prostate cancer was observed among individuals with the NAT2 slow acetylator phenotype (OR, 1.65; 95% CI, 1.04-2.61), CYP1A1 GA + GG genotype (OR, 1.27; 95% CI, 1.02-1.59), and CYP1A2 CA + AA genotype (OR, 1.43; 95% CI, 1.03-2.00). In addition, CYP1A1 GA + GG genotypes were associated with increased cancer risk in low (OR, 2.05; 95% CI, 1.19-3.63), moderate (OR, 1.72; 95% CI, 1.07-2.76), and high (OR, 2.86; 95% CI, 1.83-4.47) HAA intake groups. CONCLUSIONS: Our results suggest that high HAA intake is a risk factor of prostate cancer, and genotypes related to HAA metabolic enzymes can modulate the degree of the risk. PMID- 29165166 TI - Correction to: Anthropometric and metabolic indices in assessment of type and severity of dyslipidemia. AB - After the publication of this work [1] an error was noticed in one of the formulas. PMID- 29165165 TI - Perceived effectiveness rating scales applied to insomnia help-seeking messages for middle-aged Japanese people: a validity and reliability study. AB - BACKGROUND: Communicating health messages is an important way to influence people's behaviors towards health issues. Providers need to incorporate audience's perspective to design more persuasive messages. This study aimed to develop rating scales for measuring audience's perception of effectiveness of health messages in Japanese people. METHODS: The comprehensibility scale including five items and the persuasiveness scale including seven items were designed based on literature review. A cross-sectional web-based survey was conducted among Japanese adults aged 35-45 years to assess the reliability and validity of the scales. Participants were asked to rate a text message that encouraged help-seeking intention for insomnia. All scale items were scored on a 1-to-5 point Likert scale, and they were averaged to produce an overall score for each scale. RESULTS: Explanatory factor analysis revealed a two-factor solution that agreed with the comprehensibility and persuasiveness scales, respectively. Correlation coefficients between each set of items ranged between 0.63-0.87 for the comprehensibility scale and 0.37-0.76 for the persuasiveness scale. Cronbach alpha (0.88) indicated satisfactory internal consistency of the set of items. The mean (SD) of the comprehensibility and persuasiveness scores were 3.70 (0.82) and 3.15 (0.61), respectively, without ceiling or floor effects. These scores were significantly associated with intended future use of the message. The proportion of participants who reported a positive help-seeking intention for insomnia was significantly higher in the higher score groups for both scales. Multiple logistic regression analysis showed that the comprehensibility and persuasiveness scores were significantly associated with the help-seeking intention for insomnia. CONCLUSION: The proposed rating scales exhibited adequate reliability and validity for measuring the comprehensibility and persuasiveness of insomnia health-seeking message in middle-aged Japanese people. Further studies are needed to confirm the generalizability of the results, but these scales may be useful for pretesting a health message with audience members to make it more acceptable and persuasive to the intended audience. TRIAL REGISTRATION: Not applicable; this is not a report of intervention trial. PMID- 29165167 TI - The relation between cigarette taxes and older adult smoking in Zhejiang and Gansu: what happened following the 2009 Chinese Tax adjustments? AB - BACKGROUND: In May 2009, the Chinese government raised cigarette excise tax rates and adjusted standards for Grade A cigarettes and Grade B cigarettes. The present study aimed to examine the effects of the tax adjustments in 2009 on smoking behaviors and health outcomes among smokers aged above 45. METHODS: Data from the 2008 and 2012 China Health and Retirement Longitudinal Study of Zhejiang and Gansu provinces were used to estimate the influence of tax increase on the number of cigarettes smoked daily and health capital. The sample included 706 smokers who were 45 years old and older at the time of data collection in 2008. The sample group was surveyed again in 2012. The final sample size was 1366. Logit model was applied. RESULTS: Cigarette tax adjustment in 2009 resulted in the decrease in the likelihood of smoking 0-10 cigarettes per day by 1.06%; the increase in the likelihood of those smoking 11-20 cigarettes per day by 0.44%; and, those smoking 20 cigarettes or more by 0.63%; the decrease in the likelihood of good health by 0.47%; the increase in the prevalence of chronic disease by 1.34%. CONCLUSIONS: The smoke tax adjustment in 2009 worsened individual unhealthy smoking behaviors and health outcomes. The proposed cigarette tax levied at the retail level can reduce the State Tobacco Monopoly Administration's control overall and each price and increase the influence of the market on cigarette consumption in China. PMID- 29165168 TI - Certain personal and environmental factors as predictors of thermal sensation perceived by a population of students in a university setting from Timisoara, Romania: a case study. AB - BACKGROUND: The aim of the performed study was to investigate personal and environmental factors as predictors of thermal sensation perceived by a population of students in a university setting. METHODS: The study consisted of two samples, a winter sample (154 students: 44.2% males and 55.8% females, aged 19-30 years) and a spring sample (147 students: 52.4% males and 47.6% females, aged 19-30 years), randomly selected from the same population of students. The method was an observational inquiry (case study) with a standardized questionnaire (11 items, 3 items for thermal sensation assessing through 3 scales with 3, 5 and 7 steps, alpha Cronbach's index 0.854) applied and establishing 3 microclimate factors (air temperature, relative humidity and wind velocity), with calculation of normal effective temperature. The survey was performed over four successive days, during two seasons (winter-February and spring-May). RESULTS: The performed study demonstrated a tendency of students to perceive the comfortably cold more frequently than comfortably warm throughout the 4 days of the survey during the winter, except Monday. Thermal sensation of discomfort was more frequently perceived as warm than cold throughout the spring time of the survey and winter, except Tuesday. Predictors of thermal sensation perceived by students in the amphitheatre were as follows: nationality (-2loglikelihood change or chi square = 42.12, Sig. 0.000), relative humidity (chi square = 10.65, Sig. 0.005) and gender during the winter, and wind velocity (change in -2loglikelihood = 11.96, Sig. 0.001) and nationality during the spring. CONCLUSIONS: Certain personal and environmental factors were suggested as predictors for thermal sensation perceived by a population of students in a study setting. PMID- 29165169 TI - Cardiovascular effects of linalyl acetate in acute nicotine exposure. AB - BACKGROUD: Smoking is a risk factor for cardiovascular diseases as well as pulmonary dysfunction. In particular, adolescent smoking has been reported to have a higher latent risk for cardiovascular disease. Despite the risk to and vulnerability of adolescents to smoking, the mechanisms underlying the effects of acute nicotine exposure on adolescents remain unknown. This study therefore evaluated the mechanism underlying the effects of linalyl acetate on cardiovascular changes in adolescent rats with acute nicotine exposure. METHODS: Parameters analyzed included heart rate (HR), systolic blood pressure, lactate dehydrogenase (LDH) activity, vascular contractility, and nitric oxide levels. RESULTS: Compared with nicotine alone, those treated with nicotine plus 10 mg/kg (p = 0.036) and 100 mg/kg (p = 0.023) linalyl acetate showed significant reductions in HR. Moreover, the addition of 1 mg/kg (p = 0.011), 10 mg/kg (p = 0.010), and 100 mg/kg (p = 0.011) linalyl acetate to nicotine resulted in significantly lower LDH activity. Nicotine also showed a slight relaxation effect, followed by a sustained recontraction phase, whereas nicotine plus linalyl acetate or nifedipine showed a constant relaxation effect on contraction of mouse aorta (p < 0.001). Furthermore, nicotine-induced increases in nitrite levels were decreased by treatment with linalyl acetate (p < 0.001). CONCLUSIONS: Taken together, our findings suggest that linalyl acetate treatment resulted in recovery of cell damage and cardiovascular changes caused by acute nicotine induced cardiovascular disruption. Our evaluation of the influence of acute nicotine provides potential insights into the effects of environmental tobacco smoke and suggests linalyl acetate as an available mitigating agent. PMID- 29165170 TI - Evaluating prevalence and risk factors of building-related symptoms among office workers: Seasonal characteristics of symptoms and psychosocial and physical environmental factors. AB - BACKGROUND: Psychosocial and environmental factors at the workplace play a significant role in building-related symptoms (BRSs). Environmental factors change during summer cooling and winter heating using air-conditioning systems. Thus, significant risk factors in each season need to be clarified. METHODS: A nationwide cross-sectional study was conducted during summer in Japan and seasonal differences between summer and winter were evaluated. Self-administered questionnaires were distributed to 489 offices. Possible risk factors for BRSs associated with the work environment, indoor air quality, and job stressors were examined by multiple regression analyses. RESULTS: Among people having at least one BRS, the prevalence of BRSs in summer (27.8%) was slightly higher than that in winter (24.9%). High prevalence was observed for eye and nasal symptoms related to dryness and general symptoms related to psychological distress in both seasons. Analyses revealed that dryness of air was an important and significant risk factor associated with BRSs, and job stressors were significantly associated with general symptoms in both seasons. Conversely, humidity was a significant risk factor of general symptoms in summer (odds ratio, 1.20; 95% confidence interval, 1.02-1.43). Carpeting, recently painted walls, and unpleasant chemical odors in summer and noise, dust and dirt, and unpleasant odors such as body or food odors in both seasons were significant risk factors for BRSs. CONCLUSIONS: Improvements in the physical environmental qualities in an office throughout the year are important along with the reduction in psychological distress related to work. PMID- 29165171 TI - Psychosocial factors and colleagues' perceptions of return-to-work opportunities for workers with a psychiatric disorder: a Japanese population-based study. AB - BACKGROUND: This study examined associations between psychosocial factors and the perception that adequate employment opportunities might not be provided for people with limited work capacity due to psychiatric disorders. METHODS: We conducted an online, cross-sectional survey of 3,710 employed individuals aged 20 to 69 years in Japan. Our survey included the Brief Job Stress Questionnaire and investigated participants' perception of opportunities in their workplace for individuals with a psychiatric disorder returning to work (colleagues' negative perception) and psychosocial factors (job demand, job control, and workplace social support). Multiple logistic regression analysis was used to evaluate potential associations between psychosocial factors and colleagues' negative perception. RESULTS: Colleagues' negative perception was associated with low workplace social support (middle tertile: Odds Ratio [OR]: 1.26, 95% Confidence Interval [CI]: 1.12-1.40; low tertile: OR 1.45, 95% CI: 1.32-1.58; p for trend <0.01); low levels of job control (middle tertile: OR 1.22, 95% CI: 1.06-1.38; low tertile: OR 1.64, 95% CI: 1.46-1.81; p for trend <0.01); and no previous experience working with a person with a psychiatric disorder (OR 1.74, 95% CI: 1.60-1.88). CONCLUSIONS: Psychosocial factors may affect colleagues' perceptions of individuals with a psychiatric disorder returning to work in Japan. Greater consideration of psychosocial factors in the workplace may be necessary to facilitate people with a psychiatric disorder successfully returning to work in Japan, as elsewhere. PMID- 29165172 TI - Cross-sectional association between medical expenses and intellectual activity in community-dwelling older adults. AB - BACKGROUND: Little is known concerning the lifestyle habits and health conditions in community-dwelling elderly who do not get medical care. We investigated the cross-sectional association between medical expenses (ME) and intellectual activity (IA) in community-dwelling older Japanese. METHODS: Self-administered questionnaires were mailed to all residents born between 1945 and 1949 and covered by A City's medical insurance system (n = 19,354). Independent variables including health behaviors, oral health, social capital, neighborhood environment, and physical and mental functioning were included in the questionnaires. Medical fee receipts were used to evaluate ME for fiscal 2014, and respondents were classified into no, low, medium, and high ME groups. Higher level functional capacity was evaluated using the Tokyo Metropolitan Institute of Gerontology Index of Competence, which is comprised of three subscales: instrumental activities of daily living, IA, and social role. Poisson regression models were used to examine the association of ME with IA, with the low ME group as reference. RESULTS: Questionnaires were returned by 12,747 individuals (response rate 65.9%). The no ME group had the lowest response rate, the worst lifestyle behaviors, and the lowest social capital, but no problems with neighborhood environment. Higher-level functional capacity, especially IA, was reduced in both the high ME and no ME groups. After adjustments for age, gender, health insurance, accessibility to public facilities in their residential area, family size, body mass index, and physical and mental functioning, the prevalence ratio (PR) for impaired IA lost its significance in the high ME group (PR 0.97, 95% confidence interval 0.90-1.05), but remained significant in the no ME group (1.19, 1.08-1.31). After additional adjustments for health behaviors (i.e., health checks, smoking, fitness, and dietary variety), the PR of the no ME group was attenuated towards the null (1.08, 0.98-1.20). CONCLUSIONS: Community dwelling elderly who did not seek medical treatment were indifferent to health surveys and health-promoting behaviors, and undesirable health behaviors were a possible determinant of their impaired IA. Further longitudinal research is needed to confirm the causal associations. PMID- 29165173 TI - Health and well-being benefits of spending time in forests: systematic review. AB - BACKGROUND: Numerous studies have reported that spending time in nature is associated with the improvement of various health outcomes and well-being. This review evaluated the physical and psychological benefits of a specific type of exposure to nature, forest therapy. METHOD: A literature search was carried out using MEDLINE, PubMed, ScienceDirect, EMBASE, and ProQuest databases and manual searches from inception up to December 2016. Key words: "Forest" or "Shinrin Yoku" or "Forest bath" AND "Health" or "Wellbeing". The methodological quality of each randomized controlled trials (RCTs) was assessed according to the Cochrane risk of bias (ROB) tool. RESULTS: Six RCTs met the inclusion criteria. Participants' ages ranged from 20 to 79 years. Sample size ranged from 18 to 99. Populations studied varied from young healthy university students to elderly people with chronic disease. Studies reported the positive impact of forest therapy on hypertension (n = 2), cardiac and pulmonary function (n = 1), immune function (n = 2), inflammation (n = 3), oxidative stress (n = 1), stress (n = 1), stress hormone (n = 1), anxiety (n = 1), depression (n = 2), and emotional response (n = 3). The quality of all studies included in this review had a high ROB. CONCLUSION: Forest therapy may play an important role in health promotion and disease prevention. However, the lack of high-quality studies limits the strength of results, rendering the evidence insufficient to establish clinical practice guidelines for its use. More robust RCTs are warranted. PMID- 29165174 TI - The joint impact of habitual exercise and glycemic control on the incidence of chronic kidney disease (CKD) in middle-aged and older males. AB - BACKGROUND: This retrospective study evaluated the influence of the joint impact of habitual exercise and glycemic control on the incidence of chronic kidney disease (CKD) during a 6-year follow-up period in middle-aged and older males. METHODS: The study population included 303 males without a history of cardiovascular disease, stroke, renal dysfunction, or dialysis treatment. Their lifestyle behaviors regarding exercise and physical activity were evaluated using a standardized self-administered questionnaire. The participants were divided into four categories according to the performance or non-performance of habitual exercise and the presence or absence of hyperglycemia. RESULTS: After 6 years, 32 subjects (10.6%) developed CKD (estimated glomerular filtration rate < 60 ml/min/1.73 m2 and/or proteinuria). The cumulative incidence of CKD was significantly higher among subjects who did not perform habitual exercise and hyperglycemic subjects (log-rank test: p < 0.05, respectively). According to a Cox proportional hazards model, the hazard ratio (HR) for the incidence of CKD in subjects with a normal glucose tolerance (NGT) who did not perform habitual exercise (HR = 2.82, 95% confidence of interval (CI) = 1.07-7.36, p = 0.034) and that in hyperglycemic subjects who did not perform habitual exercise (HR = 5.89, 95% CI = 1.87-16.63, p = 0.003) were significantly higher in comparison to the subjects with a NGT who performed habitual exercise. CONCLUSIONS: These results suggest that the habitual exercise and good glycemic control and their combination were associated with the incidence of CKD. PMID- 29165175 TI - Triglycerides and blood pressure in relation to circulating CD34-positive cell levels among community-dwelling elderly Japanese men: a cross-sectional study. AB - BACKGROUND: Triglycerides are reported to be positively associated with blood pressure (both systolic and diastolic). However, in a previous study, we reported a significant positive association between triglycerides and circulating CD34 positive cells (endothelial repair) among non-hypertensive, but not hypertensive, participants. Since hypertension and endothelial dysfunction have a bi directional association (vicious cycle), the status of circulating CD34-positive cells may influence the association between triglycerides and hypertension. METHODS: Since antihypertensive medication use may influence results of the present study, we conducted a cross-sectional study of 327 community dwelling elderly (aged 60-69 years) Japanese participants who were not taking anti hypertensive medication and who had participated in a general health check-up in 2013-2015. RESULTS: Participants were classified into two groups based on median values of circulating CD34-positive cells (0.93 cells/MUL). For participants with lower circulating CD34-positive cells (n = 165), a significant positive association was seen between triglycerides and blood pressure, but not for participants with higher circulating CD34-positive cells (n = 162). The multivariable standardized parameter estimates (beta) and p values of systolic blood pressure and diastolic blood pressure were 0.23 (p = 0.007) and 0.18 (p = 0.036) for participants with lower circulating CD34-positive cells and 0.08 (p = 0.409) and 0.03 (p = 0.786) for those with higher circulating CD34-positive cells. CONCLUSION: A significant positive association between triglycerides and blood pressure exists among those with lower, but not higher, circulating CD34 positive cells. The level of circulating CD34-positive cells acts as a determinant factor for the association between triglycerides and blood pressure. PMID- 29165176 TI - The different roles of innate immune receptors in inflammation and carcinogenesis between races. AB - Innate immune factors exert widespread effects on cytokine secretion, cell survival, autophagy, and apoptosis. Nucleotide-binding and oligomerization domain like receptors (NLRs) are members of the innate immune system in the cytosol that sense pathogens, endogenous danger molecules such as uric acid, and pollutants. Nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD1 and NOD2) are components of NLR family, and ligands of these factors are gamma-D glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl dipeptide (MDP), respectively. Upon recognition of ligands, NOD1 and NOD2 induce the production of inflammatory cytokines and transcription factors including interleukin-6 (IL-6) and nuclear factor-kappaB (NF-kappaB). We examined the function of NOD1 and NOD2 in innate immunity, with a focus on their differing roles in disease pathogenesis between Japanese and Caucasian populations. Susceptibility to several immune related diseases, including Crohn's disease, colorectal and breast cancers, and graft-versus-host-disease (GVHD) showed a correlation with genetic variants of NOD2 in Caucasian, but not in Japanese, populations. This difference may be primarily due to the fact that three major NOD2 SNPs (R702W, G908R, L1007insC) prevalent in Caucasians are rare or absent in Japanese populations. Because NLR has diverse effects on immune function, it is possible that many as yet uncharacterized immune-related diseases will also show different susceptibilities between races due to the different ratio of genetic variants in innate immune genes. PMID- 29165177 TI - Level of perception of technical terms regarding the effect of radiation on the human body by residents of Japan. AB - BACKGROUND: This study aimed to examine the level of perception of the technical terms related to the effect of radiation on the human body among residents of the six prefectures of Miyagi, Fukushima, Tokyo, Aichi, Hiroshima, and Nagasaki in Japan. Miyagi and Fukushima were selected as devastated area by Great East Japan Earthquake. Tokyo and Aichi were selected as control. Hiroshima and Nagasaki were selected as the A-bombed area. METHODS: A total of 1030 respondents, 172, 173, 171, 173, 171, and 170, respectively, were surveyed. Differences in the recognition level of technical terms related to the effect of radiation on the human body among residents of the six prefectures were assessed. RESULTS: The highest recognition levels were reported by the respondents from Fukushima (17 items). Those from Miyagi scored the second highest recognition levels (10 out of the 17 terms); the second highest recognition levels for the remaining seven terms were marked by the respondents of Tokyo. Respondents in the Tohoku region had a better recognition for the technical terminology relevant to the effect of radiation on the human body. CONCLUSIONS: Our findings indicate a need for continued, comprehensive risk communication pertaining to health hazards of radiation exposure in Tohoku region. Concerted efforts by central/local governments and other stakeholders are required to allay the anxiety/stress related to radiation exposure among the residents. PMID- 29165180 TI - Overview. PMID- 29165181 TI - Reply. PMID- 29165182 TI - Abstracts from the Eastern Allergy Conference May 31 - June 3, 2012, Palm Beach, Florida. PMID- 29165183 TI - Errata. PMID- 29165184 TI - Errata. PMID- 29165185 TI - Errata. PMID- 29165178 TI - Sasa veitchii extracts suppress acetaminophen-induced hepatotoxicity in mice. AB - BACKGROUND: The aim of this study was to investigate the therapeutic effects of a Sasa veitchii leaf extract (SE) on acetaminophen (APAP)-induced hepatotoxicity. METHODS: Seven-week-old male ddY mice were orally administered SE or saline (0.2 mL) once a day for a week. Twenty-four hours after the last pretreatment, the mice were intraperitoneally injected with 550 mg/kg APAP or saline under fasting conditions. The mice from each group were euthanized and bled for plasma analysis 2, 6, 24, and 72 h after the injection. RESULTS: We found that pretreatment with SE significantly decreased hepatic injury markers (i.e., alanine aminotransferase and aspartate aminotransferase), oxidative stress (malondialdehyde and glutathione level), inflammatory cytokines, histological damage, c-jun N-terminal kinase activation, and receptor-interacting protein-1 activation. Further, SE pretreatment decreased Cyp2e1 expression and increased total antioxidant capacity in the liver. CONCLUSION: Our findings demonstrate that prophylactic SE treatment protects mice from APAP-induced hepatotoxicity through modulation of Cyp2e1 expression and antioxidant capacity. PMID- 29165186 TI - Research abstracts presented at the Eastern Allergy Conference, Palm Beach, Florida, May 6-9, 2010. PMID- 29165187 TI - About the cover. PMID- 29165188 TI - Editorial. PMID- 29165189 TI - Erratum for Khorasani et al., The effect of omeprazole on asthmatic adolescents with gastroesophageal reflux disease. PMID- 29165190 TI - Erratum for Yilmaz-Demirdag et al., Interleukin-2 treatment for persistent cryptococcal meningitis in a child with idiopathic CD4+ T-lymphocytopenia. PMID- 29165192 TI - Letters to the Editor. PMID- 29165191 TI - Research abstracts presented at the 46th annual scientific session of the Western Society of Allergy, Asthma, and Immunology. PMID- 29165194 TI - Letters to the Editor. PMID- 29165193 TI - Letters to the Editor. PMID- 29165195 TI - Research abstracts presented at the Fall Meeting of the New England Society of Allergy, October 23-24, 2010, Woodstock, Vermont. PMID- 29165197 TI - For the Patient. PMID- 29165196 TI - Effects of the tulobuterol patch on the treatment of acute asthma exacerbations in young children. AB - The tulobuterol patch (TP) is a beta2-adrenergic agonist with a favorable pharmacokinetic profile used for asthma management in Japan. Because it contains tulobuterol in a molecular, crystallized form that is gradually absorbed percutaneously, TP exerts a prolonged bronchodilator effect exceeding 24 hours. Although it is a well-established treatment for asthma and wheezing, few studies have investigated whether it can reduce or prevent the symptoms associated with upper respiratory tract infections (URTIs) in young children. This study evaluated the effect of TP on the long-term management of asthma in young children. In this 1-year, randomized, multicenter, double-blind, placebo controlled study, children aged 0.5-3 years old with mild-to-moderate persistent asthma were treated with either TP or placebo patch. The parents/guardians applied the TP or placebo patch to their children after URTI symptoms appeared. Respiratory symptoms were recorded daily during the 1-year observation period. Overall, 86 patients were enrolled and 80 were treated and analyzed in this study. All patients had been treated with anti-inflammatory drugs before enrollment. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p = 0.0457) was significantly lower in the TP group than in the placebo group. In young children with mild-to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores. PMID- 29165198 TI - Abstracts from the Eastern Allergy Conference, Palm Beach, Florida, May 29-June 1, 2014. PMID- 29165199 TI - Erratum. PMID- 29165201 TI - For the Patient. PMID- 29165200 TI - Abstracts from the Eastern Allergy Conference, Palm Beach Florida, May 31-June 2, 2013. PMID- 29165202 TI - New England Society of Allergy (NESA) Fall Meeting Abstracts, October 5-6, 2013, Providence, RI. PMID- 29165203 TI - Ultrashort-specific immunotherapy successfully treats seasonal allergic rhinoconjunctivitis to grass pollen. PMID- 29165204 TI - Erratum. PMID- 29165205 TI - Erratum. PMID- 29165207 TI - Hereditary angioedema: An instructive model of clinical description, molecular discovery, and development of new effective treatments. PMID- 29165209 TI - Erratum. PMID- 29165208 TI - Case Report: First Coinfection Report of Mixed Leishmania infantum/Leishmania major and Human Immunodeficiency Virus-Acquired Immune Deficiency Syndrome: Report of a Case of Disseminated Cutaneous Leishmaniasis in Iran. AB - Visceral leishmaniasis, a neglected tropical disease, is the third most common opportunistic disease in immunosuppressed patients, such as those affected by the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome. Although the reports have been characterized as Leishmania/HIV coinfections, the occurrence of a mixed infection by two Leishmania species in HIV-positive patients is rare. Here, we present an atypical case of disseminated cutaneous leishmaniasis (DCL) in a 26-year-old HIV-positive man. The diagnosis of DCL was established using skin biopsy and histopathology examinations and confirmed by molecular techniques. This is the first case of a Leishmania/HIV coinfection due to a mixed infection of Leishmania infantum/Leishmania major in Iran. PMID- 29165210 TI - Western Society of Allergy, Asthma & Immunology Conference, Kapalua, Hawaii, January 19-23, 2014. PMID- 29165211 TI - Case Report: Myiasis due to Cochliomyia hominivorax and Dermatobia hominis: Clinical and Pathological Differences between Two Species in Northern Peru. AB - Infestations caused by fly larvae (Myiasis) have been observed in patients with risk factors and in tropical zones. The aim of our study was to describe the clinical and epidemiological aspects and the risk factors associated with the occurrence of obligatory myiasis, as well as the therapeutic approach to patients. We identified the cases of myiasis diagnosed in two referral hospitals in northern Peru from January 2012 to December 2015 and included patients in whom larval development and a compatible clinical profile were observed. Epidemiological, clinical, analytical, diagnostic, therapeutic, and follow-up data were collected from clinical files. Nine clinical cases were compatible with a diagnosis of myiasis; of these, two were pediatric patients, one was a middle aged adult, and six were elderly patients. Four of the nine patients were male. The identified species were Dermatobia hominis and Cochliomyia hominivorax. The therapeutic approach included antiparasitic therapy with ivermectin, antibacterial, and in some cases, anti-inflammatory drugs. Dermatobia hominis and C. hominivorax are the predominant species causing myiasis in northern Peru. PMID- 29165212 TI - Newly Arrived African Migrants to Spain: Epidemiology and Burden of Disease. AB - The aim of this study is to describe the epidemiological profile, clinical characteristics, and microbiological findings in African immigrants newly arrived to Spain attended at a specialized reference unit from October 2004 to February 2017. A common protocol for the screening of imported and cosmopolitan diseases was designed to evaluate patients with <= 12 months of stay in Spain. A total of 523 patients were included in the study, 488 (93.3%) of sub-Saharan origin. A high number of helminthic infections were diagnosed in sub-Saharan patients, including geohelminthiasis (hookworms 14.3%; Trichuris trichiura 4.1%; Ascaris lumbricoides 3.1%), schistosomiasis (12.3%), strongyloidiasis (17.2%), and filariasis (8.4%). Thirty-five patients (7.2%) had malaria, most by Plasmodium falciparum. Among communicable diseases, 33.6% of sub-Saharans presented HBsAg positivity compared with 5.7% of North African patients (P = 0.001). Thirteen patients were diagnosed with active tuberculosis. Seventy percent of the sub Saharans and 40% of the North Africans who were tested had a latent tuberculosis infection (LTI). Treatment of LTI was administered in selected cases (14%), achieving end of treatment in 80% of them. In light of these results, effective screening strategies, particularly within the sub-Saharan immigrant population, including potentially communicable diseases and certain potentially serious parasitic diseases (Strongyloides, Schistosoma), should be implemented. It is necessary to facilitate fully and free of charge access to the public health system to newly arrived immigrants, as well as to implement programs and actions aimed at favoring care and follow-up, especially for communicable diseases. Empirical treatment of some parasitic diseases could be a cost-effective action. PMID- 29165213 TI - Use of Antibody Tools to Provide Serologic Evidence of Elimination of Lymphatic Filariasis in The Gambia. AB - A current need in the global effort to eliminate lymphatic filariasis (LF) is the availability of reliable diagnostic tools that can be used to guide programmatic decisions, especially decisions made in the final stages of the program. This study conducted in The Gambia aimed to assess antifilarial antibody levels among populations living in historically highly LF-endemic areas and to evaluate the use of serologic tools to confirm the interruption of LF transmission. A total of 2,612 dried blood spots (DBSs) collected from individuals aged 1 year and above from 15 villages were tested for antibodies to Wb123 by enzyme-linked immunosorbent assay (ELISA). A subset of DBS (N = 599) was also tested for antibodies to Bm14 by ELISA. Overall, the prevalence of Wb123 was low (1.5%, 95% confidence interval [CI] 1.1-2.1%). In 7 of 15 villages (46.7%), there were no Wb123-positive individuals identified. Individuals with positive responses to Wb123 ranged in age from 3 to 100 years. Overall, Bm14 prevalence was also low (1.5%, 95% CI 0.7-2.8%). Bm14 positivity was significantly associated with older age (P < 0.001). The low levels of antibody responses to Wb123 observed in our study strongly suggest that sustainable LF transmission has likely ceased in The Gambia. In addition, our results support the conclusion that serologic tools can have a role in guiding programmatic decision making and supporting surveillance. PMID- 29165215 TI - Erratum. PMID- 29165214 TI - Fecal Contamination on Produce from Wholesale and Retail Food Markets in Dhaka, Bangladesh. AB - Fresh produce items can become contaminated with enteric pathogens along the supply chain at the preharvest (e.g., irrigation water, soil, fertilizer) or postharvest (e.g., vendor handling or consumer handling) stages. This study assesses the concentrations of fecal indicator bacteria Escherichia coli, enterococci (ENT), and Bacteriodales on surfaces of carrots, eggplants, red amaranth leaves, and tomatoes obtained from both a wholesale market (recently harvested) and neighborhood retail markets in Dhaka, Bangladesh. We detected E. coli in 100% of carrot and red amaranth rinses, 92% of eggplant rinses, and 46% of tomato rinses. Using a molecular microbial source tracking assay, we found that 32% of produce samples were positive for ruminant fecal contamination. Fecal indicator bacteria were more likely to be detected on produce collected in retail markets compared with that in the wholesale market; retail market produce were 1.25 times more likely to have E. coli detected (P = 0.03) and 1.24 times more likely to have ENT detected (P = 0.03) as compared with wholesale market produce. Bacteriodales was detected in higher concentrations in retail market produce samples compared with wholesale market produce samples (0.40 log10 gene copies per 100 cm2 higher, P = 0.03). Our results suggest that ruminant and general fecal contamination of produce in markets in Dhaka is common, and suggest that unsanitary conditions in markets are an important source of produce fecal contamination postharvest. PMID- 29165216 TI - Erratum. PMID- 29165217 TI - Abstracts from the New England Society of Allergy Meeting, April 15, 2015, Westford, MA. PMID- 29165218 TI - Molecular Identification of Trichuris suis and Trichuris trichiura Eggs in Human Populations from Thailand, Lao PDR, and Myanmar. AB - Trichuris trichiura is a soil-transmitted helminth infecting human populations globally. Human cases caused by Trichuris suis and Trichuris vulpis have also been reported. Molecular identifications of Trichuris species infecting human populations in Lao PDR and Myanmar are lacking. Here, we explored molecular data obtained from Trichuris eggs recovered from human fecal samples from these countries and compared these with new and existing data from Thailand. Nuclear ribosomal DNA (18S and ITS2) sequences were amplified from Trichuris eggs and sequenced. Forty-one samples showed 99-100% similarity in their 18S sequences to published sequences of T. trichiura and one sample showed 99% similarity to a sequence of T. suis. Similarly, 41 samples showed 92-100% similarity in their ITS2 sequences to published sequences of T. trichiura and one sample showed 94 97% similarity to sequences of T. suis. This study is the first molecular confirmation of human infection with T. suis in northeast Thailand and the first molecular confirmation of the species of Trichuris infecting humans in Lao PDR and Myanmar. PMID- 29165219 TI - Porcine circovirus type 1 was undetected in vaccine but could be cultured in the cell substrate of Lanzhou lamb rotavirus vaccine. AB - In 2010, Rotarix was found to be contaminated with infectious porcine circovirus type 1 (PCV1). In China, the Lanzhou lamb rotavirus (LLR) vaccine is the only vaccine used to prevent rotavirus disease. From 2006 to September 2014, more than 54 million doses of LLR vaccines have been lot released. It is a safety issue whether PCV1 is present in the LLR vaccine. Although the cell substrate of LLR, bovine kidney (BK), is different from that of Rotarix, we have investigated the cell's permissivity for PCV1 by both infectivity and full-length PCR analysis. We have assessed the LLR using a quantitative PCR (qPCR) assay. A total of 171 random batches of LLR final products over a period of 5 years were tested, and no PCV1 was detected (0/171). Infectivity studies showed that two strains of PCV1, the PCV1-prototype, which was derived from PK-15 cells, and the mutant, PCV1-GSK, which was isolated from Rotarix, were capable of replicating in BK cells over a wide m.o.i. ranging from 10 to 0.01. After culture for 6 days, copies of PCV1 prototype DNA were higher than those of PCV1-GSK on average. The genome of the virus was detected at 6 days post-infection. In summary, the LLR vaccine is free of PCV1. Nevertheless, because PCV1 can replicate in the BK cell substrate, manufacturers need to be vigilant in monitoring for this adventitious agent. PMID- 29165220 TI - Epidemiological and Experimental Evidence for Sex-Dependent Differences in the Outcome of Leishmania infantum Infection. AB - Leishmania infantum causes visceral leishmaniasis (VL) in Brazil. We previously observed that VL is more common in males than females living in endemic neighborhoods, despite similar exposure. Using a larger sample, we document that VL is more common in males than females, but only after puberty. BALB/c and C57BL/6 mouse models confirmed that there is a biological basis for male susceptibility to symptomatic VL, showing higher parasite burdens in males than females. Female C57BL/6 mice generated more antigen-induced cytokines associated with curative responses (interferon-gamma, interleukin [IL]-1beta). Males expressed higher levels of IL-10 and tumor necrosis factor, which are linked to exacerbated disease. Different parasite lines entered or survived at a higher rate in macrophages of male- than female-origin. These results suggest that males are inherently more susceptible to L. infantum than females and that mice are a valid model to study this sex-dependent difference. PMID- 29165222 TI - Abstracts presented at the Western Society of Allergy, Asthma and Immunology meeting, January 22-26, 2012, Kauai, Hawaii. PMID- 29165221 TI - Erratum: Assessment of fractionated exhaled nitric oxide as a biomarker for the treatment of eosinophilic esophagitis. PMID- 29165224 TI - Minutes of the RSLAAIS. PMID- 29165223 TI - Health Status of Asylum Seekers, Spain. AB - The rising rate of conflicts and the unsafe situation caused by reasons of ethnicity, religion, gender, sexual orientation, political opinion, or nationality entail an increase in the number of migratory movements. The goal of this article is to describe the health status of asylum seekers visited in an international health center. We conducted a retrospective study of the asylum seekers visited between July 2013 and June 2016. A total of 303 cases were included. The median age was 28.0 years (interquartile range [IQR]: 21-35), and 203 (67.0%) were men. Of the total, 128 cases (42.2%) were from Asia, 82 (27.1%) from Eastern Europe, 42 (13.9%) from sub-Saharan Africa, 34 (11.2%) from America, and 17 (5.6%) from Maghreb. The majority, 287 (94.7%), were asymptomatic. Seventy of the 303 (23.1%) cases were diagnosed with at least one infection, this being more prevalent in men; migrants from sub-Saharan Africa; and in those who took a land-maritime migratory route. Eight of the 303 (2.6%) cases were referred to the transcultural psychiatric department. Two important challenges of the study were the communication barriers and the legal or social situation that condition the psychological symptoms. In 48 of the 303 (15.8%) cases, there was diagnosed a noncommunicable diseases. The process of care was completed by 82.5%; although 21.9% completed the vaccination for hepatitis B. The asylum seekers in this study were in general healthy young men, although special attention was given to infectious diseases with certain geoepidemiological backgrounds. Unstable living arrangements, linguistic, and cultural barriers could account for the failure of the course of care. PMID- 29165225 TI - Prevalence of Asymptomatic Parasitemia and Gametocytemia in HIV-Infected Children on Differing Antiretroviral Therapy. AB - Laboratory data and prior pediatric reports indicate that HIV protease inhibitor (PI)-based antiretroviral therapy (ARV) kills gametocytes and reduces rates of gametocytemia, but not asymptomatic parasitemia, in a high malaria-transmission area. To determine whether ARV regimen impacts these rates in areas with less intense malaria transmission, we compared asymptomatic parasitemia and gametocytemia rates in HIV-infected children by ARV regimen in Lilongwe, Malawi, an area of low-to-moderate transmission intensity. HIV PI lopinavir-ritonavir (LPV-rtv) ARV- or non-nucleoside reverse transcriptase inhibitor nevirapine ARV treated children did not differ in the rates of polymerase chain reaction detected asymptomatic parasitemia (relative risk [RR] 0.43 95% confidence interval [CI] [0.16, 1.18], P value 0.10) or microscopically detected gametocytemia with LPV-rtv ARV during symptomatic malaria (RR 0.48 95% CI [0.22,1.04] P value 0.06). LPV-rtv ARV was not associated with reduced rates of asymptomatic parasitemia, or gametocytemia on days of symptomatic malaria episodes, in HIV-infected children. Larger studies should evaluate whether ARV impacts transmission. PMID- 29165226 TI - Comparability of Inflammation-Adjusted Vitamin A Deficiency Estimates and Variance in Retinol Explained by C-Reactive Protein and alpha1-Acid Glycoprotein during Low and High Malaria Transmission Seasons in Rural Zambian Children. AB - Inflammation-induced hyporetinolemia (IIH), a reduction in serum retinol (SR) during inflammation, may bias population estimates of vitamin A deficiency (VAD). The optimal adjustment for IIH depends on the type and extent of inflammation. In rural Zambian children (4-8 years, N = 886), we compared three models for defining inflammation: alpha-1-acid glycoprotein (AGP) only (inflammation present if > 1 g/L or normal if otherwise), C-reactive protein (CRP) only (moderate inflammation, 5-15 mg/L; high inflammation, > 15 mg/L; or normal if otherwise) and a combined model using both AGP and CRP to delineate stages of infectious episode. Models were compared with respect to 1) the variance in SR explained and 2) comparability of inflammation-adjusted VAD estimated in low and high malaria seasons. Linear regression was used to estimate the variance in SR explained by each model and in estimating the adjustment factors used in generating adjusted VAD (retinol < 0.7 MUmol/L). The variance in SR explained were 2% (AGP-only), 11% (CRP-only), and 11% (AGP-CRP) in the low malaria season; and 2% (AGP-only), 15% (CRP-only), and 12% (AGP-CRP) in the high malaria season. Adjusted VAD estimates in the low and high malaria seasons differed significantly for the AGP (8.2 versus 13.1%) and combined (5.5 versus 9.1%) models but not the CRP-only model (6.1 versus 6.3%). In the multivariate regression, a decline in SR was observed with rising CRP (but not AGP), in both malaria seasons (slope = -0.06; P < 0.001). In this malaria endemic setting, CRP alone, as opposed to CRP and AGP, emerged as the most appropriate model for quantifying IIH. PMID- 29165228 TI - Case Report: Histoplasmosis: First Autochthonous Case from Israel. AB - We present an autochthonous Histoplasma infection in Israel. The patient presented with hoarseness and weight loss. Pathology findings and molecular tests confirmed the diagnosis, and the patient responded to antifungal therapy. Because the patient had an atypical presentation of histoplasmosis, it is likely that other more typical cases have gone unreported. To our knowledge, no other cases have been previously reported from Israel or the Middle East region. PMID- 29165229 TI - Naive T cells are activated by autologous HCMV-infected endothelial cells through NKG2D and can control HCMV transmission in vitro. AB - Apart from classical antigen-presenting cells (APCs) like dendritic cells and macrophages, there are semiprofessional APCs such as endothelial cells (ECs) and Langerhans' cells. Human cytomegalovirus (HCMV) infects a wide range of cell types including the ECs which are involved in the trafficking and homing of T cells. By investigating the interaction of naive T cells obtained from HCMV seronegative umbilical cord blood with autologous HCMV-infected human umbilical vein ECs (HUVECs), we could show that the activation of naive T cells occurred after 1 day of peripheral blood mononuclear cell (PBMC) exposure to HCMV-infected HUVECs. The percentage of activated T cells increased over time and the activation of naive T cells was not induced by either autologous uninfected HUVECs or by autologous HCMV-infected fibroblasts. The activation of T cells occurred also when purified T cells were co-cultured with HCMV-infected HUVECs. In addition, in most of the donors only CD8+ T cells were activated, when the purified T cells were exposed to HCMV-infected HUVECs. The activation of naive T cells was inhibited when the NKG2D receptor was blocked on the surface of T cells and among the different NKG2D ligands, we identified two ligands (ULBP4 and MICA) on HCMV-infected HUVECs which might be the interaction partners of the NKG2D receptor. Using a functional cell culture assay, we could show that these activated naive T cells specifically inhibited HCMV transmission. Altogether, we identified a novel specific activation mechanism of naive T cells from the umbilical cord by HCMV-infected autologous HUVECs through interaction with NKG2D. PMID- 29165227 TI - Reflections on a Community Engagement Strategy for Mass Antimalarial Drug Administration in Cambodia. AB - Mass drug administration (MDA) to interrupt malaria transmission requires the participation of entire communities. As part of a clinical trial in western Cambodia, four villages received MDA in 2015-2016. Before approaching study communities, a collaboration was established with the local health authorities, village leaders, and village malaria workers. Formative research guided the development of engagement strategies. In each village, a team of volunteers was formed to explain MDA to their neighbors and provide support during implementation. Public mobilization events featuring drama and music were used to introduce MDA. Villages comprised groups with different levels of understanding and interests; therefore, multiple tailored engagement strategies were required. The main challenges were explaining malaria transmission, managing perceptions of drug side effects, and reaching mobile populations. It was important that local leaders took a central role in community engagement. Coverage during each round of MDA averaged 84%, which met the target for the trial. PMID- 29165230 TI - ParA-like protein influences the distribution of multi-copy chromosomes in cyanobacterium Synechococcus elongatus PCC 7942. AB - While many bacteria, such as Escherichia coli and Bacillus subtilis, harbour a single-copy chromosome, freshwater cyanobacteria have multiple copies of each chromosome per cell. Although it has been reported that multi-copy chromosomes are evenly distributed along the major axis of the cell in cyanobacterium Synechococcus elongatus PCC 7942, the distribution mechanism of these chromosomes remains unclear. In S. elongatus, the carboxysome, a metabolic microcompartment for carbon fixation that is distributed in a similar manner to the multi-copy chromosomes, is regulated by ParA-like protein (hereafter ParA). To elucidate the role of ParA in the distribution of multi-copy chromosomes, we constructed and analysed ParA disruptant and overexpressing strains of S. elongatus. Our fluorescence in situ hybridization assay revealed that the parA disruptants displayed an aberrant distribution of their multi-copy chromosomes. In the parA disruptant the multiple origin and terminus foci, corresponding to the intracellular position of each chromosomal region, were aggregated, which was compensated by the expression of exogenous ParA from other genomic loci. The parA disruptant is sensitive to UV-C compared to the WT strain. Additionally, giant cells appeared under ParA overexpression at the late stage of growth indicating that excess ParA indirectly inhibits cell division. Screening of the ParA interacting proteins by yeast two-hybrid analysis revealed four candidates that are involved in DNA repair and cell membrane biogenesis. These results suggest that ParA is involved in the pleiotropic cellular functions with these proteins, while parA is dispensable for cell viability in S. elongatus. PMID- 29165231 TI - Sequence Optimized Real-Time Reverse Transcription Polymerase Chain Reaction Assay for Detection of Crimean-Congo Hemorrhagic Fever Virus. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus of the genus Nairovirus within the family Bunyaviridae. Infection can result in general myalgia, fever, and headache with some patients developing hemorrhagic fever with mortality rates ranging from 5% to 30%. CCHFV has a wide geographic range that includes Africa, Asia, the Middle East, and Europe with nucleotide sequence variation approaching 20% across the three negative-sense RNA genome segments. While phylogenetic clustering generally aligns with geographic origin of individual strains, distribution can be wide due to tick/CCHFV dispersion via migrating birds. This sequence diversity negatively impacts existing molecular diagnostic assays, leading to false negative diagnostic results. Here, we updated a previously developed CCHFV real-time reverse transcription polymerase chain reaction (RT-PCR) assay to include strains not detected using that original assay. Deep sequencing of eight different CCHFV strains, including three that were not detectable using the original assay, identified sequence variants within this assay target region. New primers and probe based on the sequencing results and newly deposited sequences in GenBank greatly improved assay sensitivity and inclusivity with the exception of the genetically diverse strain AP92. For example, we observed a four log improvement in IbAr10200 detection with a new limit of detection of 256 PFU/mL. Subsequent comparison of this assay to another commonly used CCHFV real-time RT-PCR assay targeting a different region of the viral genome showed improved detection, and both assays could be used to mitigate CCHFV diversity for diagnostics. Overall, this work demonstrated the importance of continued viral sequencing efforts for robust diagnostic assay development. PMID- 29165232 TI - Functional analysis of the EsaB component of the Staphylococcus aureus Type VII secretion system. AB - Type VII secretion systems (T7SS) are found in many bacteria and secrete proteins involved in virulence and bacterial competition. In Staphylococcus aureus the small ubiquitin-like EsaB protein has been previously implicated as having a regulatory role in the production of the EsxC substrate. Here we show that in the S. aureus RN6390 strain, EsaB does not genetically regulate production of any T7 substrates or components, but is indispensable for secretion activity. Consistent with EsaB being an essential component of the T7SS, loss of either EsaB or EssC are associated with upregulation of a common set of iron acquisition genes. However, a further subset of genes were dysregulated only in the absence of EsaB. Quantitative western blotting indicates that EsaB is present at very low levels in cells. Substitution of a highly conserved threonine for alanine or arginine resulted in a loss of EsaB activity and destabilisation of the protein. Taken together our findings show that EsaB is essential for T7SS activity in RN6390. PMID- 29165234 TI - Blood Meal Analysis of Phlebotomine Sandflies (Diptera: Psychodidae: Phlebotominae) for Leishmania spp. Identification and Vertebrate Blood Origin, Central Tunisia, 2015-2016. AB - During the time periods of June 2015 and from July to August 2016, sandflies were collected among seven collection sites of the three leishmaniasis endemic villages of Sidi Bouzid, Tunisia. A total of 690 sandflies were captured and identified (380 males and 310 females). Four species belonging to genus Phlebotomus (Ph.) and two species belonging to genus Sergentomyia were identified. Leishmania DNA was detected in four out of 310 females (one Ph. sergenti and three Ph. papatasi). The overall sensitivity of the Prepronociceptin gene detection reached 76%. The concurrent presence of Ph. papatasi and Ph. sergenti vectors, the analysis of blood-meals, together with the detection of L. major in Ph. papatasi, confirms the ultimate conditions for the transmission of the disease in center Tunisia. These results expand the known epidemiological area of distrubtion of leishmaniasis and its vectors in this part of Tunisia, highlighting the need for ongoing entomological and parasitological surveillance. PMID- 29165235 TI - Synthesis of N-acetyl-d-quinovosamine in Rhizobium etli CE3 is completed after its 4-keto-precursor is linked to a carrier lipid. AB - Bacterial O-antigens are synthesized on lipid carriers before being transferred to lipopolysaccharide core structures. Rhizobium etli CE3 lipopolysaccharide is a model for understanding O-antigen biological function. CE3 O-antigen structure and genetics are known. However, proposed enzymology for CE3 O-antigen synthesis has been examined very little in vitro, and even the sugar added to begin the synthesis is uncertain. A model based on mutagenesis studies predicts that 2 acetamido-2,6-dideoxy-d-glucose (QuiNAc) is the first O-antigen sugar and that genes wreV, wreQ and wreU direct QuiNAc synthesis and O-antigen initiation. Previously, synthesis of UDP-QuiNAc was shown to occur in vitro with a WreV orthologue (4,6-hexose dehydratase) and WreQ (4-reductase), but the WreQ catalysis in this conventional deoxyhexose-synthesis pathway was very slow. This seeming deficiency was explained in the present study after WreU transferase activity was examined in vitro. Results fit the prediction that WreU transfers sugar-1-phosphate to bactoprenyl phosphate (BpP) to initiate O-antigen synthesis. Interestingly, WreU demonstrated much higher activity using the product of the WreV catalysis [UDP-4-keto-6-deoxy-GlcNAc (UDP-KdgNAc)] as the sugar-phosphate donor than using UDP-QuiNAc. Furthermore, the WreQ catalysis with WreU-generated BpPP-KdgNAc as the substrate was orders of magnitude faster than with UDP-KdgNAc. The inferred product BpPP-QuiNAc reacted as an acceptor substrate in an in vitro assay for addition of the second O-antigen sugar, mannose. These results imply a novel pathway for 6-deoxyhexose synthesis that may be commonly utilized by bacteria when QuiNAc is the first sugar of a polysaccharide or oligosaccharide repeat unit: UDP-GlcNAc -> UDP-KdgNAc -> BpPP-KdgNAc -> BpPP-QuiNAc. PMID- 29165236 TI - For the Patient. PMID- 29165237 TI - Abstracts from the New England Society of Allergy Spring Meeting, April 1, 2016, Westford, MA. PMID- 29165238 TI - Clusters of Human Infection and Human-to-Human Transmission of Avian Influenza A(H7N9) Virus, 2013-2017. AB - To detect changes in human-to-human transmission of influenza A(H7N9) virus, we analyzed characteristics of 40 clusters of case-patients during 5 epidemics in China in 2013-2017. Similarities in number and size of clusters and proportion of clusters with probable human-to-human transmission across all epidemics suggest no change in human-to-human transmission risk. PMID- 29165239 TI - Does smoking affect the outcomes of lumbar decompression surgery? AB - INTRODUCTION: Lumbar decompressions and micro-discectomies are commonly performed non-complex spinal surgeries that do not involve the insertion of metalwork into the spine and are done for symptomatic disc prolapse and lumbar spinal stenosis, whereas complex-spinal surgery does require metalwork [1]. Studies of complex spinal surgeries show that smoking has a significant negative impact on the outcome of the surgery [2] therefore, the cessation of smoking is advised prior to surgery [3]. There are evidences in the literature supportive as well as opposing this statement about continued smoking and poor outcome of decompressive spinal surgeries. METHODS: We retrospectively reviewed 143 consecutive patients who have had either a micro-discectomy or a micro-decompression. RESULTS: We found no statistical difference between smokers and non-smokers in the outcomes of lumbar decompression surgery. Both groups improved equally and significantly in terms of back pain, leg pain and functions. Out of 143 patients, only 2% more non-smokers had improved leg pain compared to smokers, 1% less non-smokers had improved back pain and 2% more non-smokers had an improved Oswestry Disability Index (ODI) score. DISCUSSION: We recommend that it is important to surgically treat both smokers and non-smokers in need of a lumbar spinal decompression. PMID- 29165240 TI - Correction: A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer. PMID- 29165233 TI - The Sec System: Protein Export in Escherichia coli. AB - In Escherichia coli, proteins found in the periplasm or the outer membrane are exported from the cytoplasm by the general secretory, Sec, system before they acquire stably folded structure. This dynamic process involves intricate interactions among cytoplasmic and membrane proteins, both peripheral and integral, as well as lipids. In vivo, both ATP hydrolysis and proton motive force are required. Here, we review the Sec system from the inception of the field through early 2016, including biochemical, genetic, and structural data. PMID- 29165241 TI - Lifting the veil on the dynamics of neuronal activities evoked by transcranial magnetic stimulation. AB - Transcranial magnetic stimulation (TMS) is a widely used non-invasive tool to study and modulate human brain functions. However, TMS-evoked activity of individual neurons has remained largely inaccessible due to the large TMS-induced electromagnetic fields. Here, we present a general method providing direct in vivo electrophysiological access to TMS-evoked neuronal activity 0.8-1 ms after TMS onset. We translated human single-pulse TMS to rodents and unveiled time grained evoked activities of motor cortex layer V neurons that show high frequency spiking within the first 6 ms depending on TMS-induced current orientation and a multiphasic spike-rhythm alternating between excitation and inhibition in the 6-300 ms epoch, all of which can be linked to various human TMS responses recorded at the level of spinal cord and muscles. The advance here facilitates a new level of insight into the TMS-brain interaction that is vital for developing this non-invasive tool to purposefully explore and effectively treat the human brain. PMID- 29165243 TI - The gating cycle of a K+ channel at atomic resolution. AB - C-type inactivation in potassium channels helps fine-tune long-term channel activity through conformational changes at the selectivity filter. Here, through the use of cross-linked constitutively open constructs, we determined the structures of KcsA's mutants that stabilize the selectivity filter in its conductive (E71A, at 2.25 A) and deep C-type inactivated (Y82A at 2.4 A) conformations. These structural snapshots represent KcsA's transient open conductive (O/O) and the stable open deep C-type inactivated states (O/I), respectively. The present structures provide an unprecedented view of the selectivity filter backbone in its collapsed deep C-type inactivated conformation, highlighting the close interactions with structural waters and the local allosteric interactions that couple activation and inactivation gating. Together with the structures associated with the closed-inactivated state (C/I) and in the well-known closed conductive state (C/O), this work recapitulates, at atomic resolution, the key conformational changes of a potassium channel pore domain as it progresses along its gating cycle. PMID- 29165242 TI - Fundamental constraints in synchronous muscle limit superfast motor control in vertebrates. AB - Superfast muscles (SFMs) are extremely fast synchronous muscles capable of contraction rates up to 250 Hz, enabling precise motor execution at the millisecond time scale. SFM phenotypes have been discovered in most major vertebrate lineages, but it remains unknown whether all SFMs share excitation contraction coupling pathway adaptations for speed, and if SFMs arose once, or from independent evolutionary events. Here, we demonstrate that to achieve rapid actomyosin crossbridge kinetics bat and songbird SFM express myosin heavy chain genes that are evolutionarily and ontologically distinct. Furthermore, we show that all known SFMs share multiple functional adaptations that minimize excitation-contraction coupling transduction times. Our results suggest that SFM evolved independently in sound-producing organs in ray-finned fish, birds, and mammals, and that SFM phenotypes operate at a maximum operational speed set by fundamental constraints in synchronous muscle. Consequentially, these constraints set a fundamental limit to the maximum speed of fine motor control. PMID- 29165244 TI - The AAA ATPase Vps4 binds ESCRT-III substrates through a repeating array of dipeptide-binding pockets. AB - The hexameric AAA ATPase Vps4 drives membrane fission by remodeling and disassembling ESCRT-III filaments. Building upon our earlier 4.3 A resolution cryo-EM structure (Monroe et al., 2017), we now report a 3.2 A structure of Vps4 bound to an ESCRT-III peptide substrate. The new structure reveals that the peptide approximates a beta-strand conformation whose helical symmetry matches that of the five Vps4 subunits it contacts directly. Adjacent Vps4 subunits make equivalent interactions with successive substrate dipeptides through two distinct classes of side chain binding pockets formed primarily by Vps4 pore loop 1. These pockets accommodate a wide range of residues, while main chain hydrogen bonds may help dictate substrate-binding orientation. The structure supports a 'conveyor belt' model of translocation in which ATP binding allows a Vps4 subunit to join the growing end of the helix and engage the substrate, while hydrolysis and release promotes helix disassembly and substrate release at the lagging end. PMID- 29165245 TI - Computational modeling of spinal circuits controlling limb coordination and gaits in quadrupeds. AB - Interactions between cervical and lumbar spinal circuits are mediated by long propriospinal neurons (LPNs). Ablation of descending LPNs in mice disturbs left right coordination at high speeds without affecting fore-hind alternation. We developed a computational model of spinal circuits consisting of four rhythm generators coupled by commissural interneurons (CINs), providing left-right interactions, and LPNs, mediating homolateral and diagonal interactions. The proposed CIN and diagonal LPN connections contribute to speed-dependent gait transition from walk, to trot, and then to gallop and bound; the homolateral LPN connections ensure fore-hind alternation in all gaits. The model reproduces speed dependent gait expression in intact and genetically transformed mice and the disruption of hindlimb coordination following ablation of descending LPNs. Inputs to CINs and LPNs can affect interlimb coordination and change gait independent of speed. We suggest that these interneurons represent the main targets for supraspinal and sensory afferent signals adjusting gait. PMID- 29165246 TI - Regulatory coiled-coil domains promote head-to-head assemblies of AAA+ chaperones essential for tunable activity control. AB - Ring-forming AAA+ chaperones exert ATP-fueled substrate unfolding by threading through a central pore. This activity is potentially harmful requiring mechanisms for tight repression and substrate-specific activation. The AAA+ chaperone ClpC with the peptidase ClpP forms a bacterial protease essential to virulence and stress resistance. The adaptor MecA activates ClpC by targeting substrates and stimulating ClpC ATPase activity. We show how ClpC is repressed in its ground state by determining ClpC cryo-EM structures with and without MecA. ClpC forms large two-helical assemblies that associate via head-to-head contacts between coiled-coil middle domains (MDs). MecA converts this resting state to an active planar ring structure by binding to MD interaction sites. Loss of ClpC repression in MD mutants causes constitutive activation and severe cellular toxicity. These findings unravel an unexpected regulatory concept executed by coiled-coil MDs to tightly control AAA+ chaperone activity. PMID- 29165249 TI - Alzheimer's disease: evolution of research diagnostic criteria. PMID- 29165248 TI - Neuromodulatory connectivity defines the structure of a behavioral neural network. AB - Neural networks are typically defined by their synaptic connectivity, yet synaptic wiring diagrams often provide limited insight into network function. This is due partly to the importance of non-synaptic communication by neuromodulators, which can dynamically reconfigure circuit activity to alter its output. Here, we systematically map the patterns of neuromodulatory connectivity in a network that governs a developmentally critical behavioral sequence in Drosophila. This sequence, which mediates pupal ecdysis, is governed by the serial release of several key factors, which act both somatically as hormones and within the brain as neuromodulators. By identifying and characterizing the functions of the neuronal targets of these factors, we find that they define hierarchically organized layers of the network controlling the pupal ecdysis sequence: a modular input layer, an intermediate central pattern generating layer, and a motor output layer. Mapping neuromodulatory connections in this system thus defines the functional architecture of the network. PMID- 29165250 TI - Corrections. PMID- 29165251 TI - Corrections. PMID- 29165252 TI - Corrections. PMID- 29165247 TI - T2N as a new tool for robust electrophysiological modeling demonstrated for mature and adult-born dentate granule cells. AB - Compartmental models are the theoretical tool of choice for understanding single neuron computations. However, many models are incomplete, built ad hoc and require tuning for each novel condition rendering them of limited usability. Here, we present T2N, a powerful interface to control NEURON with Matlab and TREES toolbox, which supports generating models stable over a broad range of reconstructed and synthetic morphologies. We illustrate this for a novel, highly detailed active model of dentate granule cells (GCs) replicating a wide palette of experiments from various labs. By implementing known differences in ion channel composition and morphology, our model reproduces data from mouse or rat, mature or adult-born GCs as well as pharmacological interventions and epileptic conditions. This work sets a new benchmark for detailed compartmental modeling. T2N is suitable for creating robust models useful for large-scale networks that could lead to novel predictions. We discuss possible T2N application in degeneracy studies. PMID- 29165253 TI - Chelated or dechelated gadolinium deposition. PMID- 29165254 TI - Chelated or dechelated gadolinium deposition - Authors' reply. PMID- 29165255 TI - Portrayal of progressive supranuclear palsy in the 16th century. PMID- 29165256 TI - Sonja Scholz. PMID- 29165257 TI - Alcohol and cancer. PMID- 29165258 TI - Does mobile health matter? PMID- 29165259 TI - Food industry must act to safeguard the future of antibiotics. PMID- 29165260 TI - Offline: WHO-a roadmap to renewal? PMID- 29165261 TI - Towards introducing ACOs in the NHS. PMID- 29165262 TI - Picturing health: Rohingya refugees in Bangladesh. PMID- 29165263 TI - Bisphosphonates in osteoporosis: NICE and easy? PMID- 29165264 TI - Charlottesville: blatant racism, not grievances, on display. PMID- 29165265 TI - On evidence-based medicine. PMID- 29165266 TI - On evidence-based medicine. PMID- 29165267 TI - On evidence-based medicine - Authors' reply. PMID- 29165268 TI - On evidence-based medicine. PMID- 29165269 TI - Practical applications of evolutionary biology in public health. PMID- 29165270 TI - 2017 Prince Mahidol Award winners announced. PMID- 29165271 TI - Gastrointestinal Cancers: Timing Is Everything. PMID- 29165272 TI - Are All Head and Neck Squamous Cell Carcinomas Created Equal? PMID- 29165273 TI - The Second Stain: A Viral Whodunnit. PMID- 29165274 TI - More Information Needed, Surgery Provides It. PMID- 29165275 TI - Aggressive Tumor, Aggressive Treatment. PMID- 29165276 TI - Not All Head and Neck Squamous Cell Carcinomas Are Created Equal: Some Are More Aggressive. PMID- 29165277 TI - The Demise of Whole-Brain Radiation Therapy. PMID- 29165278 TI - Reports on the Death of Whole Brain Radiation Therapy Are Greatly Exaggerated. PMID- 29165279 TI - Letter from Puerto Rico: The State of Radiation Oncology After Maria's Landfall. PMID- 29165280 TI - Radiation Oncology Needs to Adopt a Comprehensive Standard for Data Transfer: The Case for HL7 FHIR. PMID- 29165281 TI - Is Advocacy for Active Surveillance Over Definitive Intervention in Low-Risk Prostate Cancer Applicable to African American Patients? PMID- 29165282 TI - A Brief Opinion on Pulling Down Briefs. PMID- 29165284 TI - Cardiac Toxicity: The More We Learn, the Less We Know. PMID- 29165283 TI - Decreased Survival After Combining Thoracic Irradiation and an Anti-PD-1 Antibody Correlated With Increased T-cell Infiltration Into Cardiac and Lung Tissues. PMID- 29165285 TI - Hypofractionated Nodal Radiation Therapy for Breast Cancer Was Not Associated With Increased Patient-Reported Arm or Brachial Plexopathy Symptoms. AB - PURPOSE: To determine whether nodal radiation therapy (RT) for breast cancer using modest hypofractionation (HF) with 2.25 to 2.5 Gy per fraction (fx) was associated with increased patient-reported arm symptoms, compared with conventional fractionation (CF) <=2 Gy/fx. METHODS AND MATERIALS: Two cancer registries were used to identify subjects who received computed tomography planned nodal RT for pT1-3, pN0-2, M0 breast cancer, from 2007 to 2010 at 2 cancer institutions. After ethics approval, patients were mailed an explanatory letter and the Self-reported Arm Symptom Scale, a validated instrument with 8 questions about arm symptoms and 5 related to activities of daily living. Clinicopathologic characteristics and Self-reported Arm Symptom Scale scores were compared between HF/CF cohorts using nonparametric analysis, chi2 analysis, and multivariate ordinal regression. RESULTS: Of 1759 patients, 800 (45.5%) returned a completed survey. A total of 708 eligible cases formed the study cohort. Of these, 406 (57%) received HFRT (40 Gy/16 fx, 45 Gy/20 fx), and 302 (43%) received CFRT (45-50 Gy/25 fx, 50.4 Gy/28 fx). Median time interval after RT was 5.7 years. Forty-three percent and 75% of patients received breast-conserving surgery and chemotherapy, respectively. Twenty-two percent received breast boost RT, independent of fractionation. Median age at diagnosis was 59 years (HF) and 53 years (CF) (P<.001). The mean numbers of excised (n=12) and involved (n=3) nodes were similar between fractionation cohorts (P=.44), as were the mean sums of responses in arm symptoms (P=.17) and activities of daily living (P=.85). Patients receiving HF reported lower rates of shoulder stiffness (P=.04), trouble moving the arm (P=.02), and difficulty reaching overhead (P<.01) compared with the CF cohort. There was no difference in self-reported arm swelling or symptoms related to brachial plexopathy. CONCLUSIONS: Nodal RT with hypofractionation was not associated with increased patient-reported arm symptoms or functional deficits compared with CF. Subjects treated with CF reported more disability in certain aspects of arm/shoulder function. These data support shorter fractionation utilization when regional nodes are within the therapeutic target. PMID- 29165286 TI - Chemoradiation-Induced Alteration of Programmed Death-Ligand 1 and CD8+ Tumor Infiltrating Lymphocytes Identified Patients With Poor Prognosis in Rectal Cancer: A Matched Comparison Analysis. AB - PURPOSE: To evaluate chemoradiotherapy (CRT)-induced changes in the expression levels of programmed death-ligand 1 (PD-L1) and CD8+ tumor-infiltrating lymphocytes (TILs) and prognostic associations in rectal cancer. METHODS AND MATERIALS: We performed a paired analysis using pre-CRT biopsies and the corresponding post-CRT resected tissues of 123 rectal cancer patients undergoing preoperative CRT followed by surgery between 2005 and 2012. Immunohistochemistry of PD-L1 and CD8 was analyzed for the specimens. RESULTS: The expression levels of PD-L1 and density of CD8+ TILs increased after CRT (P<.001 for both). With cutoffs using each median value, sustained higher expression of PD-L1 at pre- and post-CRT (high-to-high) was associated with less increase in the density of CD8+ TILs (P=.020). Patients representing sustained high-to-high PD-L1 expression had poorer overall survival and disease-free interval on univariate Kaplan-Meier analysis (P=.018 and .029, respectively), with inferior disease-free interval in low-to-low density CD8+ TILs (P=.010). On multivariate analysis, 2 subgroups with high baseline PD-L1 expression level, the high-to-low and high-to-high alterations, showed worse overall survival (hazard ratio 8.34, 95% confidence interval 1.85-37.53 and hazard ratio 11.03, 95% confidence interval 2.33-52.29, respectively), with the highest mortality risk observed in the high-to-high group. CONCLUSIONS: This study verified the CRT-induced immunologic shift toward increases in PD-L1 expression and density of CD8+ TILs in rectal cancer patients. The alteration profiles of checkpoint-related molecules identified the patients with poor prognosis, suggesting potential candidates who can benefit from combining CRT and checkpoint inhibitors. PMID- 29165287 TI - Quantitative Evaluation of Head and Neck Cancer Treatment-Related Dysphagia in the Development of a Personalized Treatment Deintensification Paradigm. AB - PURPOSE: To test the hypothesis that quantifying swallow function with multiple patient-reported outcome (PRO) instruments is an important strategy to yield insights in the development of personalized deintensified therapies seeking to reduce the risk of head and neck cancer (HNC) treatment-related dysphagia (HNCTD). METHODS AND MATERIALS: Irradiated HNC subjects seen in follow-up care (April 2015 to December 2015) who prospectively completed the Sydney Swallow Questionnaire (SSQ) and the MD Anderson Dysphagia Inventory (MDADI) concurrently on the web interface to our Oncospace database were evaluated. A correlation matrix quantified the relationship between the SSQ and MDADI. Machine-learning unsupervised cluster analysis using the elbow criterion and CLUSPLOT analysis to establish its validity was performed. RESULTS: We identified 89 subjects. The MDADI and SSQ scores were moderately but significantly correlated (correlation coefficient -0.69). K-means cluster analysis demonstrated that 3 unique statistical cohorts (elbow criterion) could be identified with CLUSPLOT analysis, confirming that 100% of variances were accounted for. Correlation coefficients between the individual items in the SSQ and the MDADI demonstrated weak to moderate negative correlation, except for SSQ17 (quality of life question). CONCLUSIONS: Pilot analysis demonstrates that the MDADI and SSQ are complementary. Three unique clusters of patients can be defined, suggesting that a unique dysphagia signature for HNCTD may be definable. Longitudinal studies relying on only a single PRO, such as MDADI, may be inadequate for classifying HNCTD. PMID- 29165289 TI - In Regard to Kim et al. PMID- 29165290 TI - In Reply to Zoto Mustafayev and Ozyar. PMID- 29165291 TI - In Regard to Amdur. PMID- 29165288 TI - Treatment-Related Noncontiguous Radiologic Changes in Children With Diffuse Intrinsic Pontine Glioma Treated With Expanded Irradiation Fields and Antiangiogenic Therapy. AB - PURPOSE: We previously reported the cases of 3 children with diffuse intrinsic pontine glioma (DIPG) in whom noncontiguous treatment-related abnormalities (NCTRAs) developed in the brain after expanded-field radiation therapy (RT). To investigate the occurrence and putative mechanism of NCTRAs, we reviewed brain magnetic resonance imaging studies of patients with DIPG treated in 2 consecutive phase I clinical trials (trials 1 and 2). METHODS AND MATERIALS: The 55 children included in these trials received small-molecule inhibitors: vandetanib in trial 1 (n=32; mean age 6.4 years) and vandetanib and dasatinib in trial 2 (n=23; mean age 5.8 years). The patients also received conformal 3-dimensional RT (cumulative dose 54 Gy). For patients enrolled in trial 1, the clinical target volume (CTV) was expanded by 1 cm from the gross tumor volume. In trial 2, the expansion to form the CTV was 2 to 3 cm. A review of imaging studies was performed from the initial diagnosis through the end of progression-free survival. The imaging findings were grouped into 5 categories according to the presence, absence, location, extent, and putative mechanism of NCTRAs. Statistical analysis was performed to evaluate the association between covariates and NCTRA, cohort characterization, and survival comparisons. RESULTS: Overall survival was similar in both studies (P=.74). NCTRAs developed in 9 patients (39%) treated in trial 2 but in none treated in trial 1. The NCTRAs included T2-weighted hyperintensities with (n=3; radiation necrosis) or without (n=5) contrast uptake, supratentorial leukoencephalopathy (n=2), and ischemic stroke (n=1). All NCTRAs, except for 1, occurred within the CTV. Compared with nonaffected patients, patients with a NCTRA were younger (P=.003) and had had larger relative brain volumes exposed to doses >20 Gy. CONCLUSIONS: The imaging features of NCTRAs suggest that their development is secondary to synergistic steno-occlusive vascular effects induced by the combination of RT, an expanded CTV, potent antiangiogenic therapy, young age, and, in 1 case, a genetic predisposition. PMID- 29165292 TI - In Regard to Zhong and Chetty. PMID- 29165293 TI - In Regard to Xu et al. PMID- 29165294 TI - In Reply to Hugo et al. PMID- 29165295 TI - In Reply to Song et al. PMID- 29165297 TI - Pulsed dye laser therapy in patients with acquired bilateral telangiectatic macules. PMID- 29165296 TI - Progressive nodular histiocytosis improved by methotrexate. PMID- 29165298 TI - Nail apparatus melanoma in a Japanese population: a comparative study of surgical procedures and prognoses in a large series of 151 cases. AB - Nail apparatus melanoma (NAM) is a rare subtype of malignant melanoma with a prevalence that varies among populations. Conservative surgical approaches for thin to intermediate NAMs have recently been reported, however, their adoption is controversial, and resulting long-term prognoses are unknown. The purpose of this study was to determine the prognosis of NAM in a sample Asian population, and to investigate whether there is a difference in the local control and overall survival (OS) rates according to the extent of resection of the primary tumour. We performed a retrospective study of NAM patients treated at five medical institutions in Japan between 2000 and 2013. Outcomes according to surgery (amputation vs. resection) and tumour thickness were compared. We identified 151 cases of NAM in 83 men and 68 women; the thumb (n = 50; 33.1%) and hallux (n = 55; 36.4%) were the most common sites. No local recurrence was detected following any of the surgical procedures; Kaplan-Meier survival analysis revealed that the surgical procedure type was not significantly associated with disease-free survival (p = 0.786) or OS (p = 0.997). Five-year OS rates according to tumour thickness were 100% for in situ, 94.4% for <=1-mm, 91.7% for 1.01-2.0-mm, 72.7% for 2.01-4.0-mm, and 47.6% for >=4.01-mm tumours. Surgical procedure type does not influence survival as long as total primary tumour resection is accomplished. The prognosis of NAM is comparable to that of other types of melanoma. PMID- 29165299 TI - Herpes simplex virus reactivation: is it common or rare in drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms? PMID- 29165300 TI - FOXI2: a possible gene contributing to ectodermal dysplasia. AB - Cardio-facio-cutaneous syndrome (CFC), Noonan syndrome (NS), and Costello syndrome are a group of diseases that belong to the RASopathies. The syndromes share clinical features making diagnosis a challenge. To investigate the phenotype and genotype of a 10-year-old Iraqi girl with overlapping features of CFC, NS, and Costello syndromes, with additional features of ectodermal dysplasia. DNA was examined by exome sequencing and protein expression by immunohistochemistry. Exome sequencing identified a mutation in the SOS1 gene and a de novo deletion in the FOXI2 gene which was neither present in the international databases, nor in 400 chromosomes from the same population. Based on immunohistochemical staining, FOXI2 was identified in the basal cell layer of the skin and overlapped with the expression of P63, a major player in ectodermal dysplasia. We therefore suggest screening for FOXI2 mutation in the setting of ectodermal features that are not associated with genes known to contribute to ectodermal dysplasia. PMID- 29165301 TI - Early and sustained remission with brentuximab vedotin in a case of disseminated cutaneous relapse from systemic anaplastic large cell lymphoma refractory to chemotherapy. PMID- 29165302 TI - Prominent eye muscle artefact on the EEG of a patient with Hashimoto thyroiditis with primary hypothyroidism. PMID- 29165303 TI - Immunoreactivity to CYP24A1, but not vitamin D receptor, is increased in mast cells of keratinocyte skin cancers. AB - In mouse skin models, mast cells have been shown to express vitamin D receptor (VDR) that can mediate the immunosuppressive effects of ultraviolet B radiation and vitamin D3. However, VDR activation leads to the expression of CYP24A1, a hydroxylase that can inactivate vitamin D3 metabolites. To examine immunoreactivity to VDR and CYP24A1 in mast cells from normal human skin, keratinocyte skin cancers, and disorders of chronic inflammation. Frozen biopsies were collected from the non-lesional and lesional skin of patients with actinic keratosis (AK), Bowen's disease/squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and psoriasis. The expression of VDR and CYP24A1 in tryptase positive mast cells was analysed using double-staining methods. Less than 0.5% of the mast cells were immunoreactive to VDR in both the non-lesional and lesional skin for all disease groups. In non-lesional skin, only 0.5-2.9% of the mast cells were immunopositive for CYP24A1, however, the percentage of mast cells containing CYP24A1 was significantly increased in lesional skin of AK, SCC, and BCC. In contrast to human skin, LAD2 mast cells cultured from a patient with mast cell sarcoma/leukaemia revealed that about 34% and 6.5% of the cells were immunopositive for VDR and CYP24A1, respectively. Whereas a very small proportion of mast cells in human skin express VDR and CYP24A1, the proportion of mast cells expressing CYP24A1 in keratinocyte skin cancers is increased; the mechanism underlying this is unclear. PMID- 29165304 TI - A case of IgA pemphigus foliaceus with high scores on drug-induced lymphocyte stimulation tests secondary to various drugs. PMID- 29165305 TI - Abdominal actinomycetoma with double aetiology due to Nocardia brasiliensis and Actinomadura madurae. PMID- 29165306 TI - Decreased benzothiazole-type pheomelanin in regrown brown hair in alopecia areata. PMID- 29165307 TI - Cutaneous sarcoidosis during rituximab treatment for microscopic polyangiitis: an uncommon adverse effect? PMID- 29165308 TI - Eosinophilic annular erythema localized on the neck. PMID- 29165309 TI - Clinical Characteristics of Patients with Dizziness after Motor Vehicle Accident. AB - OBJECTIVE: The purpose of this study was to identify the clinical characteristics of dizziness occurring after a motor vehicle accident. MATERIALS AND METHODS: We retrospectively analyzed 217 patients who had visited a tertiary medical center complaining of dizziness after a motor vehicle accident between January 2009 and December 2014. Of the 217 patients, we enrolled 54 patients who had undergone a vestibular function test and had no definite evidence of fracture of the temporal bone or intracranial lesions. Patients were divided into two groups: the dizziness group (group A, 29 patients) and the dizziness with audiological symptoms (hearing disturbance, tinnitus, ear fullness) group (group B, 25 patients). RESULTS: The prevalence of benign paroxysmal positional vertigo was higher in group A. Apart from this finding, the clinical features did not differ significantly between the two groups. Group B had a higher number of patients who exhibited asymmetric hearing on pure tone audiometry, but the difference was not statistically significant. CONCLUSION: There were no notable characteristics in patients with dizziness after motor vehicle accidents, although patients without hearing symptoms tended to have benign paroxysmal positional vertigo, whereas other patients tended to have hearing disturbance. This information may be helpful for clinicians in counseling and managing patients with dizziness and audiological symptoms after motor vehicle accidents. PMID- 29165310 TI - Serum Trace Elements and Heavy Metal Levels in Patients Diagnosed with Chronic Otitis Media and Their Association with Surgical Treatment Outcomes. AB - OBJECTIVE: To determine the serum iron (Fe), zinc (Zn), manganese (Mn), copper (Cu), magnesium (Mg), cobalt (Co), and lead (Pb) levels in patients with chronic otitis media (COM) and to evaluate the association of the serum levels of these elements with treatment outcomes. MATERIALS AND METHODS: Thirty-one healthy volunteers and 31 patients with COM were prospectively included in this study. Serum levels of Fe, Zn, Mn, Mg, Cu, Co, and Pb were determined by an atomic absorption UNICAM-929 spectrophotometer. RESULTS: Serum Co, Pb, and Fe levels were significantly increased (p<0.001) and serum Cu, Zn, Mg, and Mn levels were significantly reduced in patients with COM compared with controls (p<0.001). Serum Co and Mn levels were significantly decreased (p<0.001 and p<0.005, respectively) and serum Cu levels were significantly increased after surgery (p<0.005). The other evaluated blood chemicals and heavy metals did not exhibit significant differences (p>0.05). CONCLUSION: Significant alterations in the serum chemical composition of patients with COM were observed. Moreover, with surgical treatment, serum levels of some of these chemicals were significantly altered. Further prospective studies are warranted to elucidate the exact association of these alterations in the etiopathogenesis of COM. PMID- 29165311 TI - Should Nasal Function be Considered Prior to Tympanoplasty? AB - OBJECTIVE: To evaluate the association between nasal airway function and Eustachian tube (ET) functions and their impact on tympanoplasty in patients with chronic suppurative otitis media (CSOM). MATERIALS AND METHODS: The study group (CSOM group) consisted of 33 patients scheduled to undergo tympanoplasty for CSOM. Two control groups were formed: a nasal septal deviation (NSD) group of 25 patients scheduled to undergo nasal surgery for NSD, and a control group of 25 healthy individuals with no otologic or rhinologic symptoms. ET functions were assessed tympanometrically with automatic Williams test (ETF1) and modified pressure equalization inflation-deflation test (ETF2) and nasal functions were analyzed using acoustic rhinometry and rhinomanometry. The patients in the CSOM group underwent tympanoplasty, and tests were repeated at the end of the 3rd postoperative month. RESULTS: Both acoustic rhinometry and rhinomanometry revealed similar nasal function in the CSOM and NSD groups, which was inferior to that of the control group. The CSOM group had the worst ET function. Dysfunctional ETs in the CSOM group improved at 3 months postsurgery, and all groups had a similar outcome regarding ET functions. The outcome of ear surgery was not affected by nasal function, and the graft take rate was 90%. CONCLUSION: Patients with NSD had generally poor ET function; however, this did not affect the outcomes of tympanoplasty. The preoperative ET function results were inconsistent with the results following tympanoplasty; therefore, they were not predictive of need for septoplasty. Thus, we do not universally recommend surgical correction of NSD prior to ear surgery; however, this decision should be made on an individual basis. PMID- 29165312 TI - The Role of High Dose Intratympanic Dexamethasone as Salvage Therapy for Idiopathic Sudden Sensorineural Hearing Loss. AB - OBJECTIVE: The aim of this study was to assess the efficacy of a single high dose intratympanic (IT) dexamethasone (DEX) as salvage therapy for idiopathic sudden sensorineural hearing loss (ISSNHL) after unsuccessful treatment with oral corticosteroid (CS). MATERIALS AND METHODS: This was a prospective open-label study of 59 patients treated with IT DEX after systemic CS therapy has failed. All patients received high dose (24 mg/mL) IT DEX in a single injection through myringotomy. RESULTS: Of the 59 patients, 40.7% showed improvement in their mean pure tone average (PTA) with IT DEX (p=0.005). The difference in the mean PTA after oral CS treatment only from baseline was not statistically significant (p=0.074). The time from onset of hearing loss to the start of therapy was significantly associated with the outcome (p=0.03). CONCLUSION: We determined that high dose IT DEX as salvage therapy was beneficial when the primary treatment with oral CS had failed. An early start of the treatment significantly influenced the improvement of hearing. PMID- 29165313 TI - T-cell differentiation and CD56+ levels in polypoidal choroidal vasculopathy and neovascular age-related macular degeneration. AB - Polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (AMD) are prevalent age-related diseases characterized by exudative changes in the macula. Although they share anatomical and clinical similarities, they are also distinctly characterized by their own features, e.g. vascular abnormalities in PCV and drusen-mediated progression in neovascular AMD. PCV remains etiologically uncharacterized, and ongoing discussion is whether PCV and neovascular AMD share the same etiology or constitute two substantially different diseases. In this study, we investigated T-cell differentiation and aging profile in human patients with PCV, patients with neovascular AMD, and age-matched healthy control individuals. Fresh venous blood was prepared for flow cytometry to investigate CD4+ and CD8+ T-cell differentiation (naive, central memory, effector memory, effector memory CD45ra+), loss of differentiation markers CD27 and CD28, and expression of aging marker CD56. Patients with PCV were similar to the healthy controls in all aspects. In patients with neovascular AMD we found significantly accelerated T-cell differentiation (more CD28-CD27- cells) and aging (more CD56+ cells) in the CD8+ T-cell compartment. These findings suggest that PCV and neovascular AMD are etiologically different in terms of T cell immunity, and that neovascular AMD is associated with T-cell immunosenescence. PMID- 29165315 TI - An expression screen for aged-dependent microRNAs identifies miR-30a as a key regulator of aging features in human epidermis. AB - The mechanisms affecting epidermal homeostasis during aging remain poorly understood. To identify age-related microRNAs, a class of non-coding RNAs known to play a key role in the regulation of epidermal homeostasis, an exhaustive miRNA expression screen was performed in human keratinocytes from young or elderly subjects. Many microRNAs modulated by aging were identified, including miR-30a, in which both strands were overexpressed in aged cells and epidermal tissue. Stable MiR-30a over-expression strongly impaired epidermal differentiation, inducing severe barrier function defects in an organotypic culture model. A significant increase was also observed in the level of apoptotic cells in epidermis over-expressing miR-30a. Several gene targets of miR-30a were identified in keratinocytes, including LOX (encoding lysyl oxidase, a regulator of the proliferation/differentiation balance of keratinocytes), IDH1 (encoding isocitrate dehydrogenase, an enzyme of cellular metabolism) and AVEN (encoding a caspase inhibitor). Direct regulation of LOX, IDH1 and AVEN by miR-30a was confirmed in human keratinocytes. They were, moreover, observed to be repressed in aged skin, suggesting a possible link between miR-30a induction and skin-aging phenotype. This study revealed a new miRNA actor and deciphered new molecular mechanisms to explain certain alterations observed in epidermis during aging and especially those concerning keratinocyte differentiation and apoptosis. PMID- 29165317 TI - The effect of electrospun polycaprolactone scaffold morphology on human kidney epithelial cells. AB - There is a pressing need for further advancement in tissue engineering of functional organs with a view to providing a more clinically relevant model for drug development and reduce the dependence on organ donation. Polymer-based scaffolds, such as polycaprolactone (PCL), have been highlighted as a potential avenue for tissue engineered kidneys, but there is little investigation down this stream. Focus within kidney tissue engineering has been on two-dimensional cell culture and decellularised tissue. Electrospun polymer scaffolds can be created with a variety of fibre diameters and have shown a great potential in many areas. The variation in morphology of tissue engineering scaffold has been shown to effect the way cells behave and integrate. In this study we examined the cellular response to scaffold architecture of novel electrospun scaffold for kidney tissue engineering. Fibre diameters of 1.10 +/- 0.16 MUm and 4.49 +/- 0.47 MUm were used with three distinct scaffold architectures. Traditional random fibres were spun onto a mandrel rotating at 250 rpm, aligned at 1800 rpm with novel cryogenic fibres spun onto a mandrel loaded with dry ice rotating at 250 rpm. Human kidney epithelial cells were grown for 1 and 2 weeks. Fibre morphology had no effect of cell viability in scaffolds with a large fibre diameter but significant differences were seen in smaller fibres. Fibre diameter had a significant effect in aligned and cryogenic scaffold. Imaging detailed the differences in cell attachment due to scaffold differences. These results show that architecture of the scaffold has a profound effect on kidney cells; whether that is effects of fibre diameter on the cell attachment and viability or the effect of fibre arrangement on the distribution of cells and their alignment with fibres. Results demonstrate that PCL scaffolds have the capability to maintain kidney cells life and should be investigated further as a potential scaffold in kidney tissue engineering. PMID- 29165314 TI - Towards natural mimetics of metformin and rapamycin. AB - Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network-based Cellular Signatures (LINCS) dataset to map the gene- and pathway-level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors. PMID- 29165319 TI - Comparison of forward- and back-projection in vivo EPID dosimetry for VMAT treatment of the prostate. AB - In the forward-projection method of portal dosimetry for volumetric modulated arc therapy (VMAT), the integrated signal at the electronic portal imaging device (EPID) is predicted at the time of treatment planning, against which the measured integrated image is compared. In the back-projection method, the measured signal at each gantry angle is back-projected through the patient CT scan to give a measure of total dose to the patient. This study aims to investigate the practical agreement between the two types of EPID dosimetry for prostate radiotherapy. The AutoBeam treatment planning system produced VMAT plans together with corresponding predicted portal images, and a total of 46 sets of gantry resolved portal images were acquired in 13 patients using an iViewGT portal imager. For the forward-projection method, each acquisition of gantry-resolved images was combined into a single integrated image and compared with the predicted image. For the back-projection method, iViewDose was used to calculate the dose distribution in the patient for comparison with the planned dose. A gamma index for 3% and 3 mm was used for both methods. The results were investigated by delivering the same plans to a phantom and repeating some of the deliveries with deliberately introduced errors. The strongest agreement between forward- and back-projection methods is seen in the isocentric intensity/dose difference, with moderate agreement in the mean gamma. The strongest correlation is observed within a given patient, with less correlation between patients, the latter representing the accuracy of prediction of the two methods. The error study shows that each of the two methods has its own distinct sensitivity to errors, but that overall the response is similar. The forward- and back projection EPID dosimetry methods show moderate agreement in this series of prostate VMAT patients, indicating that both methods can contribute to the verification of dose delivered to the patient. PMID- 29165318 TI - Unidirectional BMP2-loaded collagen scaffolds induce chondrogenic differentiation. AB - Microfracture surgery may be improved by the implantation of unidirectional collagen scaffolds that provide a template for mesenchymal stem cells to regenerate cartilage. Incorporation of growth factors in unidirectional scaffolds may further enhance cartilage regeneration. In scaffolds, immobilization of growth factors is required to prolong in vivo activity, to limit diffusion and to reduce the amount of growth factor needed for safe clinical application. We investigated the immobilization of bone morphogenetic protein 2 (BMP2) to unidirectional collagen scaffolds and the effect on in vitro chondrogenesis. C3H10T1/2 cells were seeded on unidirectional collagen scaffolds with and without covalently attached heparin, and with and without incubation with BMP2 (1 and 10 MUg), or with BMP2 present in the culture medium (10-200 ng ml-1). Culturing was for 2 weeks and readout parameters included histology, immunohistochemistry, biochemical analysis and molecular biological analysis. The unidirectional pores facilitated the distribution of C3H10T1/2 cells and matrix formation throughout scaffolds. The effective dose of medium supplementation with BMP2 was 100 ng ml-1 (total exposure 1 MUg BMP2), and similar production of cartilage-specific molecules chondroitin sulfate (CS) and type II collagen was found for scaffolds pre-incubated with 10 MUg BMP2. Pre-incubation with 1 MUg BMP2 resulted in less cartilage matrix formation. The conjugation of heparin to the scaffolds resulted in more CS and less type II collagen deposition compared to scaffolds without heparin. In conclusion, unidirectional collagen scaffolds pre-incubated with 10 MUg BMP2 supported chondrogenesis in vitro and may be suitable for prolonged cartilage matrix synthesis in vivo. PMID- 29165320 TI - Effect of high carbon incorporation in Co substrates on the epitaxy of hexagonal boron nitride/graphene heterostructures. AB - We carried out a systematic study of hexagonal boron nitride/graphene (h-BN/G) heterostructure growth by introducing high incorporation of a carbon (C) source on a heated cobalt (Co) foil substrate followed by boron and nitrogen sources in a molecular beam epitaxy system. With the increase of C incorporation in Co, three distinct regions of h-BN/G heterostructures were observed from region (1) where the C saturation was not attained at the growth temperature (900 degrees C) and G was grown only by precipitation during the cooling process to form a 'G network' underneath the h-BN film; to region (2) where the Co substrate was just saturated by C atoms at the growth temperature and a part of G growth occurs isothermally to form G islands and another part by precipitation, resulting in a non-uniform h-BN/G film; and to region (3) where a continuous layered G structure was formed at the growth temperature and precipitated C atoms added additional G layers to the system, leading to a uniform h-BN/G film. It is also found that in all three h-BN/G heterostructure growth regions, a 3 h h-BN growth at 900 degrees C led to h-BN film with a thickness of 1-2 nm, regardless of the underneath G layers' thickness or morphology. Growth time and growth temperature effects have been also studied. PMID- 29165316 TI - Residual gammaH2AX foci induced by low dose x-ray radiation in bone marrow mesenchymal stem cells do not cause accelerated senescence in the progeny of irradiated cells. AB - Mechanisms underlying the effects of low-dose ionizing radiation (IR) exposure (10-100 mGy) remain unknown. Here we present a comparative study of early (less than 24h) and delayed (up to 11 post-irradiation passages) radiation effects caused by low (80 mGy) vs intermediate (1000 mGy) dose X-ray exposure in cultured human bone marrow mesenchymal stem cells (MSCs). We show that gammaN2AX foci induced by an intermediate dose returned back to the control value by 24 h post irradiation. In contrast, low-dose irradiation resulted in residual gammaN2AX foci still present at 24 h. Notably, these low dose induced residual gammaN2AX foci were not co-localized with rATM foci and were observed predominantly in the proliferating Ki67 positive (Ki67+) cells. The number of gammaN2AX foci and the fraction of nonproliferating (Ki67-) and senescent (SA-beta-gal+) cells measured at passage 11 were increased in cultures exposed to an intermediate dose compared to unirradiated controls. These delayed effects were not seen in the progeny of cells that were irradiated with low-dose X-rays, although such exposure resulted in residual gammaN2AX foci in directly irradiated cells. Taken together, our results support the hypothesis that the low-dose IR induced residual gammaH2AX foci do not play a role in delayed irradiation consequences, associated with cellular senescence in cultured MSCs. PMID- 29165321 TI - Interfacial rheology of model particles at liquid interfaces and its relation to (bicontinuous) Pickering emulsions. AB - Interface-dominated materials are commonly encountered in both science and technology, and typical examples include foams and emulsions. Conventionally stabilised by surfactants, emulsions can also be stabilised by micron-sized particles. These so-called Pickering-Ramsden (PR) emulsions have received substantial interest, as they are model arrested systems, rather ubiquitous in industry and promising templates for advanced materials. The mechanical properties of the particle-laden liquid-liquid interface, probed via interfacial rheology, have been shown to play an important role in the formation and stability of PR emulsions. However, the morphological processes which control the formation of emulsions and foams in mixing devices, such as deformation, break up, and coalescence, are complex and diverse, making it difficult to identify the precise role of the interfacial rheological properties. Interestingly, the role of interfacial rheology in the stability of bicontinuous PR emulsions (bijels) has been virtually unexplored, even though the phase separation process which leads to the formation of these systems is relatively simple and the interfacial deformation processes can be better conceptualised. Hence, the aims of this topical review are twofold. First, we review the existing literature on the interfacial rheology of particle-laden liquid interfaces in rheometrical flows, focussing mainly on model latex suspensions consisting of polystyrene particles carrying sulfate groups, which have been most extensively studied to date. The goal of this part of the review is to identify the generic features of the rheology of such systems. Secondly, we will discuss the relevance of these results to the formation and stability of PR emulsions and bijels. PMID- 29165322 TI - Treatment planning with intensity modulated particle therapy for multiple targets in stage IV non-small cell lung cancer. AB - Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry. PMID- 29165323 TI - Negative differential mobility and trapping in active matter systems. AB - Using simulations, we examine the average velocity as a function of applied drift force for active matter particles moving through a random obstacle array. We find that for low drift force, there is an initial flow regime where the mobility increases linearly with drive, while for higher drift forces a regime of negative differential mobility appears in which the velocity decreases with increasing drive due to the trapping of active particles behind obstacles. A fully clogged regime exists at very high drift forces when all the particles are permanently trapped behind obstacles. We find for increasing activity that the overall mobility is nonmonotonic, with an enhancement of the mobility for small levels of activity and a decrease in mobility for large activity levels. We show how these effects evolve as a function of disk and obstacle density, active run length, drift force, and motor force. PMID- 29165324 TI - In vivo evaluation of modified silk fibroin scaffolds with a mimicked microenvironment of fibronectin/decellularized pulp tissue for maxillofacial surgery. AB - This study aimed to carry out in vivo testing of the formation of new bone by modified silk fibroin scaffolds with a mimicked microenvironment of fibronectin/decellularized pulp in bone defects. Silk fibroin scaffolds were fabricated into three-dimensional scaffolds before being coated with fibronectin/decellularized pulp. The coated scaffolds were implanted into rabbits. Twenty-four bicortical calvarial defects in 12 rabbits were divided randomly into two groups: non-coated and coated silk fibroin scaffolds. The rabbits were sacrificed 2, 4 and 8 weeks after operation for evaluation of new bone formation. The morphology of the scaffolds, new bone formation and histology were evaluated by scanning electron microscopy, micro-CT and hematoxylin and eosin staining, respectively. The results showed that the coated silk fibroin scaffolds had a fibrillar network and crystal particles in the porous structure. The coated silk fibroin scaffolds demonstrated the ability to induce the formation of new bone with low inflammation and high vascularization. The results indicated that the modified silk fibroin scaffolds showed suitable biological performance and promise for bone regeneration in maxillofacial surgery. PMID- 29165325 TI - Collapse in two good solvents, swelling in two poor solvents: defying the laws of polymer solubility? AB - In this work we discuss two mirror but distinct phenomena of polymer paradoxical properties in mixed solvents: co-non-solvency and co-solvency. When a polymer collapses in a mixture of two miscible good solvents the phenomenon is known as co-non-solvency, while co-solvency is a phenomenon that is associated with the swelling of a polymer in poor solvent mixtures. A typical example of co-non solvency is provided by poly(N-isopropylacrylamide) in aqueous alcohol, while poly(methyl methacrylate) in aqueous alcohol shows co-solvency. We discuss these two phenomena to compare their microscopic origins and show that both can be understood within generic universal concepts. A broad range of polymers is therefore expected to exhibit these phenomena where specific chemical details play a lesser role than the appropriate combination of interactions between the trio of molecular components. PMID- 29165326 TI - Aspersymmetide A, a New Centrosymmetric Cyclohexapeptide from the Marine-Derived Fungus Aspergillus versicolor. AB - A new centrosymmetric cyclohexapeptide, aspersymmetide A (1), together with a known peptide, asperphenamate (2), was isolated from the fungus Aspergillus versicolor isolated from a gorgonian coral Carijoa sp., collected from the South China Sea. The chemical structure of 1 was elucidated by analyzing its NMR spectroscopy and MS spectrometry data, and the absolute configurations of the amino acids of 1 were determined by Marfey's method and UPLC-MS analysis of the hydrolysate. Aspersymmetide A (1) represents the first example of marine-derived centrosymmetric cyclohexapeptide. Moreover, 1 exhibited weak cytotoxicity against NCI-H292 and A431 cell lines at the concentration of 10 MUM. PMID- 29165327 TI - Effects of Dl-3-n-butylphthalide on Cerebral Ischemia Infarction in Rat Model by Mass Spectrometry Imaging. AB - Dl-3-n-butylphthalide (NBP) is a drug that is used in the treatment of ischaemic stroke. However, to the best of our knowledge, there are no systematic studies investigating the effects of dl-3-n-butylphtalide on the brain metabolism of small molecules. In this study, we first investigated the effects of dl-3-n butylphthalide on the spatial distribution of small molecules in the brains of rats with permanent middle cerebral artery occlusion (pMCAO) using matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) imaging. After pMCAO modelling or a sham operation, rats were given four mg/kg of dl-3-n-butylphthalide through the caudal vein or saline once a day for nine days. The degree of neurological deficit in rats was evaluated using the modified neurological severity score (mNSS). MALDI-TOF-MS imaging was used to observe the content and distribution of small molecules related to metabolism during focal cerebral ischaemia. Multiple reaction monitoring (MRM) mode with liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to verify the results obtained from MALDI-TOF-MS imaging. These small molecules were found to be involved in glucose metabolism, ATP metabolism, the glutamate-glutamine cycle, malate aspartate shuttle, oxidative stress, and inorganic ion homeostasis. Of the 13 metabolites identified by MALDI-TOF-MS imaging, seven compounds, ATP, ADP, AMP, GMP, N-acetylaspartic acid, ascorbic acid and glutathione, were further validated by LC-MS/MS. Taken together, these results indicate that dl-3-n butylphthalide significantly improved ATP metabolism, level of antioxidants, and sodium-potassium ion balance in a rat model of pMCAO. PMID- 29165328 TI - Transformation of a Thermostable G-Quadruplex Structure into DNA Duplex Driven by Reverse Gyrase. AB - Reverse gyrase is a topoisomerase that can introduce positive supercoils to its substrate DNA. It is demonstrated in our studies that a highly thermal stable G quadruplex structure in a mini-plasmid DNA was transformed into its duplex conformation after a treatment with reverse gyrase. The structural difference of the topoisomers were verified and analyzed by gel electrophoresis, atomic force microscopy examination, and endonuclease digestion assays. All evidence suggested that the overwinding structure of positive supercoil could provide a driven force to disintegrate G-quadruplex and reform duplex. The results of our studies could suggest that hyperthermophiles might use reverse gyrase to manipulate the disintegration of non-B DNA structures and safekeep their genomic information. PMID- 29165329 TI - Four New Glycosides from the Rhizoma of Anemarrhena asphodeloides. AB - Four new compounds, aneglycoside A-C (1-3) and timosaponin U (4), were isolated from the rhizomes of Anemarrhena asphodeloides. Their structures were determined through extensive spectroscopic analysis, chemical characteristics, and high resolution mass spectrometry (HRMS). All the isolations were evaluated for cytotoxicity against HepG2, Hela, and SGC7901 human cancer lines. Compounds 1, 2, and 4 showed weak antiproliferative activities on HepG2, Hela, and SGC7901 cells. PMID- 29165330 TI - Prediction of Mortality in Patients with Isolated Traumatic Subarachnoid Hemorrhage Using a Decision Tree Classifier: A Retrospective Analysis Based on a Trauma Registry System. AB - Background: In contrast to patients with traumatic subarachnoid hemorrhage (tSAH) in the presence of other types of intracranial hemorrhage, the prognosis of patients with isolated tSAH is good. The incidence of mortality in these patients ranges from 0-2.5%. However, few data or predictive models are available for the identification of patients with a high mortality risk. In this study, we aimed to construct a model for mortality prediction using a decision tree (DT) algorithm, along with data obtained from a population-based trauma registry, in a Level 1 trauma center. Methods: Five hundred and forty-five patients with isolated tSAH, including 533 patients who survived and 12 who died, between January 2009 and December 2016, were allocated to training (n = 377) or test (n = 168) sets. Using the data on demographics and injury characteristics, as well as laboratory data of the patients, classification and regression tree (CART) analysis was performed based on the Gini impurity index, using the rpart function in the rpart package in R. Results: In this established DT model, three nodes (head Abbreviated Injury Scale (AIS) score <=4, creatinine (Cr) <1.4 mg/dL, and age <76 years) were identified as important determinative variables in the prediction of mortality. Of the patients with isolated tSAH, 60% of those with a head AIS >4 died, as did the 57% of those with an AIS score <=4, but Cr >=1.4 and age >=76 years. All patients who did not meet the above-mentioned criteria survived. With all the variables in the model, the DT achieved an accuracy of 97.9% (sensitivity of 90.9% and specificity of 98.1%) and 97.7% (sensitivity of 100% and specificity of 97.7%), for the training set and test set, respectively. Conclusions: The study established a DT model with three nodes (head AIS score <=4, Cr <1.4, and age <76 years) to predict fatal outcomes in patients with isolated tSAH. The proposed decision-making algorithm may help identify patients with a high risk of mortality. PMID- 29165331 TI - An Orientation Sensor-Based Head Tracking System for Driver Behaviour Monitoring. AB - Although at present legislation does not allow drivers in a Level 3 autonomous vehicle to engage in a secondary task, there may become a time when it does. Monitoring the behaviour of drivers engaging in various non-driving activities (NDAs) is crucial to decide how well the driver will be able to take over control of the vehicle. One limitation of the commonly used face-based head tracking system, using cameras, is that sufficient features of the face must be visible, which limits the detectable angle of head movement and thereby measurable NDAs, unless multiple cameras are used. This paper proposes a novel orientation sensor based head tracking system that includes twin devices, one of which measures the movement of the vehicle while the other measures the absolute movement of the head. Measurement error in the shaking and nodding axes were less than 0.4 degrees , while error in the rolling axis was less than 2 degrees . Comparison with a camera-based system, through in-house tests and on-road tests, showed that the main advantage of the proposed system is the ability to detect angles larger than 20 degrees in the shaking and nodding axes. Finally, a case study demonstrated that the measurement of the shaking and nodding angles, produced from the proposed system, can effectively characterise the drivers' behaviour while engaged in the NDAs of chatting to a passenger and playing on a smartphone. PMID- 29165332 TI - The Economic Burden of Violence against Children in South Africa. AB - The purpose of this study was to estimate the economic burden of violence against children in South Africa. We assembled summative estimates of lifetime prevalence, calculated the magnitude of associations with negative outcomes, and thereby estimated the economic burden of violence against children. According to our calculations, 2.3 million and 84,287 disability-adjusted life-years (DALYs) lost in South Africa in 2015 were attributable to nonfatal and fatal violence against children, respectively. The estimated economic value of DALYs lost to violence against children (including both fatal and nonfatal) in South Africa in 2015 totalled ZAR173 billion (US $13.5 billion)-or 4.3% of South Africa's gross domestic product (GDP) in 2015. In addition, the reduced earnings attributable to childhood physical violence and emotional violence in South Africa in 2015 were ZAR25.2 billion (US $2.0 billion) and ZAR9.6 billion (US $750 million), respectively. In addition, South Africa spent ZAR1.6 billion (US $124 million) on child care and protection in fiscal year 2015/2016, many of which costs are directly related to violence against children. This study confirms the importance of prioritising violence against children as a key social and economic concern for South Africa's future. PMID- 29165333 TI - Pressure for Pattern-Specific Intertypic Recombination between Sabin Polioviruses: Evolutionary Implications. AB - Complete genomic sequences of a non-redundant set of 70 recombinants between three serotypes of attenuated Sabin polioviruses as well as location (based on partial sequencing) of crossover sites of 28 additional recombinants were determined and compared with the previously published data. It is demonstrated that the genomes of Sabin viruses contain distinct strain-specific segments that are eliminated by recombination. The presumed low fitness of these segments could be linked to mutations acquired upon derivation of the vaccine strains and/or may have been present in wild-type parents of Sabin viruses. These "weak" segments contribute to the propensity of these viruses to recombine with each other and with other enteroviruses as well as determine the choice of crossover sites. The knowledge of location of such segments opens additional possibilities for the design of more genetically stable and/or more attenuated variants, i.e., candidates for new oral polio vaccines. The results also suggest that the genome of wild polioviruses, and, by generalization, of other RNA viruses, may harbor hidden low-fitness segments that can be readily eliminated only by recombination. PMID- 29165334 TI - Development and Validation of an On-Line Water Toxicity Sensor with Immobilized Luminescent Bacteria for On-Line Surface Water Monitoring. AB - Surface water used for drinking water production is frequently monitored in The Netherlands using whole organism biomonitors, with for example Daphnia magna or Dreissena mussels, which respond to changes in the water quality. However, not all human-relevant toxic compounds can be detected by these biomonitors. Therefore, a new on-line biosensor has been developed, containing immobilized genetically modified bacteria, which respond to genotoxicity in the water by emitting luminescence. The performance of this sensor was tested under laboratory conditions, as well as under field conditions at a monitoring station along the river Meuse in The Netherlands. The sensor was robust and easy to clean, with inert materials, temperature control and nutrient feed for the reporter organisms. The bacteria were immobilized in sol-gel on either an optical fiber or a glass slide and then continuously exposed to water. Since the glass slide was more sensitive and robust, only this setup was used in the field. The sensor responded to spikes of genotoxic compounds in the water with a minimal detectable concentration of 0.01 mg/L mitomycin C in the laboratory and 0.1 mg/L mitomycin C in the field. With further optimization, which should include a reduction in daily maintenance, the sensor has the potential to become a useful addition to the currently available biomonitors. PMID- 29165335 TI - Integral Phylogenomic Approach over Ilex L. Species from Southern South America. AB - The use of molecular markers with inadequate variation levels has resulted in poorly resolved phylogenetic relationships within Ilex. Focusing on southern South American and Asian species, we aimed at contributing informative plastid markers. Also, we intended to gain insights into the nature of morphological and physiological characters used to identify species. We obtained the chloroplast genomes of I.paraguariensis and I. dumosa, and combined these with all the congeneric plastomes currently available to accomplish interspecific comparisons and multilocus analyses. We selected seven introns and nine IGSs as variable non coding markers that were used in phylogenomic analyses. Eight extra IGSs were proposed as candidate markers. Southern South American species formed one lineage, except for I. paraguariensis, I. dumosa and I. argentina, which occupied intermediate positions among sampled taxa; Euroasiatic species formed two lineages. Some concordant relationships were retrieved from nuclear sequence data. We also conducted integral analyses, involving a supernetwork of molecular data, and a simultaneous analysis of quantitative and qualitative morphological and phytochemical characters, together with molecular data. The total evidence tree was used to study the evolution of non-molecular data, evidencing fifteen non-ambiguous synapomorphic character states and consolidating the relationships among southern South American species. More South American representatives should be incorporated to elucidate their origin. PMID- 29165336 TI - Comparison of Benchtop Fourier-Transform (FT) and Portable Grating Scanning Spectrometers for Determination of Total Soluble Solid Contents in Single Grape Berry (Vitis vinifera L.) and Calibration Transfer. AB - Near-infrared (NIR) spectroscopy was applied for the determination of total soluble solid contents (SSC) of single Ruby Seedless grape berries using both benchtop Fourier transform (VECTOR 22/N) and portable grating scanning (SupNIR 1500) spectrometers in this study. The results showed that the best SSC prediction was obtained by VECTOR 22/N in the range of 12,000 to 4000 cm-1 (833 2500 nm) for Ruby Seedless with determination coefficient of prediction (Rp2) of 0.918, root mean squares error of prediction (RMSEP) of 0.758% based on least squares support vector machine (LS-SVM). Calibration transfer was conducted on the same spectral range of two instruments (1000-1800 nm) based on the LS-SVM model. By conducting Kennard-Stone (KS) to divide sample sets, selecting the optimal number of standardization samples and applying Passing-Bablok regression to choose the optimal instrument as the master instrument, a modified calibration transfer method between two spectrometers was developed. When 45 samples were selected for the standardization set, the linear interpolation-piecewise direct standardization (linear interpolation-PDS) performed well for calibration transfer with Rp2 of 0.857 and RMSEP of 1.099% in the spectral region of 1000 1800 nm. And it was proved that re-calculating the standardization samples into master model could improve the performance of calibration transfer in this study. This work indicated that NIR could be used as a rapid and non-destructive method for SSC prediction, and provided a feasibility to solve the transfer difficulty between totally different NIR spectrometers. PMID- 29165337 TI - miRNome Profiling in Bicuspid Aortic Valve-Associated Aortopathy by Next Generation Sequencing. AB - The molecular mechanisms underlying thoracic aortic aneurysm (TAA) in patients with bicuspid aortic valve (BAV) are incompletely characterized. MicroRNAs (miRNAs) may play a major role in the different pathogenesis of aortopathy. We sought to employ next-generation sequencing to analyze the entire miRNome in TAA tissue from patients with BAV and tricuspid aortic valve (TAV). In the discovery stage, small RNA sequencing was performed using the Illumina MiSeq platform in 13 TAA tissue samples (seven patients with BAV and six with TAV). Gene ontology (GO) and KEGG pathway analysis were used to identify key pathways and biological functions. Validation analysis was performed by qRT-PCR in an independent cohort of 30 patients with BAV (26 males; 59.5 +/- 12 years) and 30 patients with TAV (16 males; 68.5 +/- 9.5 years). Bioinformatic analysis identified a total of 489 known mature miRNAs and five novel miRNAs. Compared to TAV samples, 12 known miRNAs were found to be differentially expressed in BAV, including two up regulated and 10 down-regulated (FDR-adjusted p-value <= 0.05 and fold change >= 1.5). GO and KEGG pathway enrichment analysis (FDR-adjusted p-value < 0.05) identified different target genes and pathways linked to BAV and aneurysm formation, including Hippo signaling pathway, ErbB signaling, TGF-beta signaling and focal adhesion. Validation analysis of selected miRNAs confirmed the significant down-regulation of miR-424-3p (p = 0.01) and miR-3688-3p (p = 0.03) in BAV patients as compared to TAV patients. Our study provided the first in depth screening of the whole miRNome in TAA specimens and identified specific dysregulated miRNAs in BAV patients. PMID- 29165338 TI - Action of Monomeric/Gemini Surfactants on Free Cells and Biofilm of Asaia lannensis. AB - We investigated the biological activity of surfactants based on quaternary ammonium compounds: gemini surfactant hexamethylene-1,6-bis-(N,N-dimethyl-N dodecylammonium bromide) (C6), synthesized by the reaction of N,N-dimethyl-N dodecylamine with 1,6-dibromohexane, and its monomeric analogue dodecyltrimethylammonium bromide (DTAB). The experiments were performed with bacteria Asaia lannensis, a common spoilage in the beverage industry. The minimal inhibitory concentration (MIC) values were determined using the tube standard two fold dilution method. The growth and adhesive properties of bacterial cells were studied in different culture media, and the cell viability was evaluated using plate count method. Both of the surfactants were effective against the bacterial strain, but the MIC of gemini compound was significantly lower. Both C6 and DTAB exhibited anti-adhesive abilities. Treatment with surfactants at or below MIC value decreased the number of bacterial cells that were able to form biofilm, however, the gemini surfactant was more effective. The used surfactants were also found to be able to eradicate mature biofilms. After 4 h of treatment with C6 surfactant at concentration 10 MIC, the number of bacterial cells was reduced by 91.8%. The results of this study suggest that the antibacterial activity of the gemini compound could make it an effective microbiocide against the spoilage bacteria Asaia sp. in both planktonic and biofilm stages. PMID- 29165339 TI - Chemical Compounds and Bioactivity of Aqueous Extracts of Alibertia spp. in the Control of Plutella xylostella L. (Lepidoptera: Plutellidae). AB - Successive applications of insecticides to control Plutella xylostella L. (Lepidoptera: Plutellidae) have resulted in the emergence of resistant populations of this insect. A novel control measure for this target insect could be the use of botanical insecticides derived from plant tissues. Hence, we experimentally tested aqueous extracts of Alibertia edulis (Rich.), Alibertia intermedia (Mart.), and Alibertia sessilis (Vell.) K. Schum. found in the Brazilian savannah in order to investigate their potential to disrupt the life cycle of P. xylostella. Aqueous extracts of the leaves of A. intermedia and A. sessilis negatively affected the development of P. xylostella in all stages of the life cycle, prolonging the larval stage and causing mortality in the larval or pupal stages. Treatments with A. intermedia and A. sessilis extracts caused the lowest fecundity and the number of hatched larvae. The harmful effects of these aqueous extracts on the life cycle of P. xylostella may be attributable to the flavonoids and other phenolic compounds present in A. intermedia and A. sessilis. These aqueous botanical extracts are low in toxicity when compared to non-aqueous pesticides, and may emerge as an effective approach for control of populations of P. xylostella. PMID- 29165340 TI - Impacts of Low Temperature on the Teleost Immune System. AB - As poikilothermic vertebrates, fish can experience changes in water temperature, and hence body temperature, as a result of seasonal changes, migration, or efflux of large quantities of effluent into a body of water. Temperature shifts outside of the optimal temperature range for an individual fish species can have negative impacts on the physiology of the animal, including the immune system. As a result, acute or chronic exposure to suboptimal temperatures can impair an organisms' ability to defend against pathogens and thus compromise the overall health of the animal. This review focuses on the advances made towards understanding the impacts of suboptimal temperature on the soluble and cellular mediators of the innate and adaptive immune systems of fishes. Although cold stress can result in varying effects in different fish species, acute and chronic suboptimal temperature exposure generally yield suppressive effects, particularly on adaptive immunity. Knowledge of the effects of environmental temperature on fish species is critical for both the optimal management of wild species and the best management practices for aquaculture species. PMID- 29165342 TI - Knee and Ankle Arthroplasty in Hemophilia. AB - Today, major surgical procedures can be safely performed in hemophilic patients with chronic arthropathy, using available factor concentrates. In this setting, total knee replacement is considered the "gold standard", while the use of total ankle replacement is still debated. Indeed, the unsatisfactory results obtained with the previous available design of implants did not raise enthusiasm as knee or hip replacement. Recently, the introduction of new implant designs and better reported outcomes have renewed the interest in total ankle replacement in people with hemophilia. In this review, the role of replacement surgery in the treatment of chronic hemophilic arthropathy will be described. PMID- 29165341 TI - Extracellular Vesicles Released by Oxidatively Injured or Intact C2C12 Myotubes Promote Distinct Responses Converging toward Myogenesis. AB - Myogenic differentiation is triggered, among other situations, in response to muscle damage for regenerative purposes. It has been shown that during myogenic differentiation, myotubes release extracellular vesicles (EVs) which participate in the signalling pattern of the microenvironment. Here we investigated whether EVs released by myotubes exposed or not to mild oxidative stress modulate the behaviour of targeted differentiating myoblasts and macrophages to promote myogenesis. We found that EVs released by oxidatively challenged myotubes (H2O2 EVs) are characterized by an increased loading of nucleic acids, mainly DNA. In addition, incubation of myoblasts with H2O2-EVs resulted in a significant decrease of myotube diameter, myogenin mRNA levels and myosin heavy chain expression along with an upregulation of proliferating cell nuclear antigen: these effects collectively lead to an increase of recipient myoblast proliferation. Notably, the EVs from untreated myotubes induced an opposite trend in myoblasts, that is, a slight pro-differentiation effect. Finally, H2O2-EVs were capable of eliciting an increased interleukin 6 mRNA expression in RAW264.7 macrophages. Notably, this is the first demonstration that myotubes communicate with surrounding macrophages via EV release. Collectively, the data reported herein suggest that myotubes, depending on their conditions, release EVs carrying differential signals which could contribute to finely and coherently orchestrate the muscle regeneration process. PMID- 29165343 TI - Auxeticity of Yukawa Systems with Nanolayers in the (111) Crystallographic Plane. AB - Elastic properties of model crystalline systems, in which the particles interact via the hard potential (infinite when any particles overlap and zero otherwise) and the hard-core repulsive Yukawa interaction, were determined by Monte Carlo simulations. The influence of structural modifications, in the form of periodic nanolayers being perpendicular to the crystallographic axis [111], on auxetic properties of the crystal was investigated. It has been shown that the hard sphere nanolayers introduced into Yukawa crystals allow one to control the elastic properties of the system. It has been also found that the introduction of the Yukawa monolayers to the hard sphere crystal induces auxeticity in the [ 11 1 - ] [ 112 ] -direction, while maintaining the negative Poisson's ratio in the [ 110 ] [ 1 1 - 0 ] -direction, thus expanding the partial auxeticity of the system to an additional important crystallographic direction. PMID- 29165345 TI - Activity In Vitro of Clotrimazole against Canine Methicillin-Resistant and Susceptible Staphylococcus pseudintermedius. AB - Emergence of multidrug-resistance in Staphylococcus pseudintermedius (SP) has increased interest in topical therapy as an alternative to systemic antibiotics in canine pyoderma. The antifungal imidazole, clotrimazole, is contained in numerous licensed canine ear preparations. Its in vitro activity against SP has not been evaluated, although previous studies have shown that the related imidazole, miconazole, has significant anti-staphylococcal efficacy. We therefore determined minimum inhibitory concentrations (MICs) of clotrimazole amongst 50 SP isolates (25 methicillin-resistant [MR]SP and susceptible [MS]SP) collected from dogs in Germany during 2010-2011 using an agar dilution method (CLSI VET01-A4). MICs amongst MRSP and MSSP were comparable (MIC50 and MIC90 = 1mg/L for both groups, p = 0.317); overall, 49 isolates had MIC = 1 mg/L and one had MIC = 0.5 mg/L. The relatively low MICs obtained in this study are likely to be exceeded by topical therapy and thus further clinical evaluation of clotrimazole use in canine superficial pyoderma and otitis externa caused by MRSP and MSSP is now warranted. PMID- 29165344 TI - High-Throughput Identification of Antimicrobial Peptides from Amphibious Mudskippers. AB - Widespread existence of antimicrobial peptides (AMPs) has been reported in various animals with comprehensive biological activities, which is consistent with the important roles of AMPs as the first line of host defense system. However, no big-data-based analysis on AMPs from any fish species is available. In this study, we identified 507 AMP transcripts on the basis of our previously reported genomes and transcriptomes of two representative amphibious mudskippers, Boleophthalmus pectinirostris (BP) and Periophthalmus magnuspinnatus (PM). The former is predominantly aquatic with less time out of water, while the latter is primarily terrestrial with extended periods of time on land. Within these identified AMPs, 449 sequences are novel; 15 were reported in BP previously; 48 are identically overlapped between BP and PM; 94 were validated by mass spectrometry. Moreover, most AMPs presented differential tissue transcription patterns in the two mudskippers. Interestingly, we discovered two AMPs, hemoglobin beta1 and amylin, with high inhibitions on Micrococcus luteus. In conclusion, our high-throughput screening strategy based on genomic and transcriptomic data opens an efficient pathway to discover new antimicrobial peptides for ongoing development of marine drugs. PMID- 29165346 TI - Dielectrophoretic Separation of Live and Dead Monocytes Using 3D Carbon Electrodes. AB - Blood has been the most reliable body fluid commonly used for the diagnosis of diseases. Although there have been promising investigations for the development of novel lab-on-a-chip devices to utilize other body fluids such as urine and sweat samples in diagnosis, their stability remains a problem that limits the reliability and accuracy of readouts. Hence, accurate and quantitative separation and characterization of blood cells are still crucial. The first step in achieving high-resolution characteristics for specific cell subpopulations from the whole blood is the isolation of pure cell populations from a mixture of cell suspensions. Second, live cells need to be purified from dead cells; otherwise, dead cells might introduce biases in the measurements. In addition, the separation and characterization methods being used must preserve the genetic and phenotypic properties of the cells. Among the characterization and separation approaches, dielectrophoresis (DEP) is one of the oldest and most efficient label free quantification methods, which directly purifies and characterizes cells using their intrinsic, physical properties. In this study, we present the dielectrophoretic separation and characterization of live and dead monocytes using 3D carbon-electrodes. Our approach successfully removed the dead monocytes while preserving the viability of the live monocytes. Therefore, when blood analyses and disease diagnosis are performed with enriched, live monocyte populations, this approach will reduce the dead-cell contamination risk and achieve more reliable and accurate test results. PMID- 29165347 TI - A Collaboration-Oriented M2M Messaging Mechanism for the Collaborative Automation between Machines in Future Industrial Networks. AB - Machine-to-machine (M2M) communication is a key enabling technology for industrial internet of things (IIoT)-empowered industrial networks, where machines communicate with one another for collaborative automation and intelligent optimisation. This new industrial computing paradigm features high quality connectivity, ubiquitous messaging, and interoperable interactions between machines. However, manufacturing IIoT applications have specificities that distinguish them from many other internet of things (IoT) scenarios in machine communications. By highlighting the key requirements and the major technical gaps of M2M in industrial applications, this article describes a collaboration-oriented M2M (CoM2M) messaging mechanism focusing on flexible connectivity and discovery, ubiquitous messaging, and semantic interoperability that are well suited for the production line-scale interoperability of manufacturing applications. The designs toward machine collaboration and data interoperability at both the communication and semantic level are presented. Then, the application scenarios of the presented methods are illustrated with a proof-of-concept implementation in the PicknPack food packaging line. Eventually, the advantages and some potential issues are discussed based on the PicknPack practice. PMID- 29165348 TI - Emotion Regulation in Binge Eating Disorder: A Review. AB - The purpose of the present review is to provide a summary of the research findings on emotion regulation in Binge Eating Disorder (BED). Negative emotions and maladaptive emotion regulation strategies play a role in the onset and maintenance of binge eating in BED. Anger and sadness, along with negative emotions related to interpersonal experiences (i.e., disappointment, being hurt or loneliness), seem to be particularly relevant. Individuals with BED have a tendency to suppress and ruminate on their unwanted emotions, which leads to increased psychopathological thoughts and symptoms. Compared to healthy controls, they use adaptive strategies, such as reappraisal, less frequently. Evidence concerning the causal relation between negative affect and binge eating is inconclusive and still very limited. While experimental studies in a laboratory setting lack ecological validity, ecological momentary assessment studies offer more promise at unraveling the causal relationship between emotions and binge eating. Increases in negative affect are found to be antecedents of binge eating in BED. However, there seems to be less support for the possibility that binge eating serves as a means to alleviate negative affect. Finally, BED seems to be related to other forms of maladaptive emotion regulation strategies, such as substance abuse and self-harm. PMID- 29165349 TI - Combating Fusarium Infection Using Bacillus-Based Antimicrobials. AB - Despite efforts to control toxigenic Fusarium species, wilt and head-blight infections are destructive and economically damaging diseases that have global effects. The utilization of biological control agents in disease management programs has provided an effective, safe, and sustainable means to control Fusarium-induced plant diseases. Among the most widely used microbes for biocontrol agents are members of the genus Bacillus. These species influence plant and fungal pathogen interactions by a number of mechanisms such as competing for essential nutrients, antagonizing pathogens by producing fungitoxic metabolites, or inducing systemic resistance in plants. The multivariate interactions among plant-biocontrol agent-pathogen are the subject of this study, in which we survey the advances made regarding the research on the Bacillus Fusarium interaction and focus on the principles and mechanisms of action among plant-growth promoting Bacillus species. In particular, we highlight their use in limiting and controlling Fusarium spread and infestations of economically important crops. This knowledge will be useful to define strategies for exploiting this group of beneficial bacteria for use as inoculants by themselves or in combination with other microbes for enhanced crop protection. PMID- 29165350 TI - Large-Scale Analysis of Antimicrobial Activities in Relation to Amphipathicity and Charge Reveals Novel Characterization of Antimicrobial Peptides. AB - It has been unclear to which antimicrobial activities (e.g., anti-gram-positive bacterial, anti-gram-negative bacterial, antifungal, antiparasitic, and antiviral activities) of antimicrobial peptides (AMPs) a given physiochemical property matters most. This is the first computational study using large-scale AMPs to examine the relationships between antimicrobial activities and two major physiochemical properties of AMPs-amphipathicity and net charge. The results showed that among all kinds of antimicrobial activities, amphipathicity and net charge best differentiated between AMPs with and without anti-gram-negative bacterial activities. In terms of amphipathicity and charge, all the AMPs whose activities were significantly associated with amphipathicity and net charge were alike except those with anti-gram-positive bacterial activities. Furthermore, the higher the amphipathic value, the greater the proportion of AMPs possessing both antibacterial and antifungal activities. This dose-response-like pattern suggests a possible causal relationship-dual antibacterial and antifungal activities of AMPs may be attributable to amphipathicity. These novel findings could be useful for identifying potent AMPs computationally. PMID- 29165351 TI - An Optical Interferometric Triaxial Displacement Sensor for Structural Health Monitoring: Characterization of Sliding and Debonding for a Delamination Process. AB - This paper presents an extrinsic Fabry-Perot interferometer-based optical fiber sensor (EFPI) for measuring three-dimensional (3D) displacements, including interfacial sliding and debonding during delamination. The idea employs three spatially arranged EFPIs as the sensing elements. In our sensor, the three EFPIs are formed by three endfaces of three optical fibers and their corresponding inclined mirrors. Two coincident roof-like metallic structures are used to support the three fibers and the three mirrors, respectively. Our sensor was calibrated and then used to monitor interfacial sliding and debonding between a long square brick of mortar and its support structure (i.e., a steel base plate) during the drying/curing process. This robust and easy-to-manufacture triaxial EFPI-based 3D displacement sensor has great potential in structural health monitoring, the construction industry, oil well monitoring, and geotechnology. PMID- 29165352 TI - Antibody-Based Protective Immunity against Helminth Infections: Antibody Phage Display Derived Antibodies against BmR1 Antigen. AB - Helminth parasite infections are significantly impacting global health, with more than two billion infections worldwide with a high morbidity rate. The complex life cycle of the nematodes has made host immune response studies against these parasites extremely difficult. In this study, we utilized two phage antibody libraries; the immune and naive library were used to identify single chain fragment variable (scFv) clones against a specific filarial antigen (BmR1). The V gene analysis of isolated scFv clones will help shed light on preferential VDJ gene segment usage against the filarial BmR1 antigen in healthy and infected states. The immune library showed the usage of both lambda and kappa light chains. However, the naive library showed preferential use of the lambda family with different amino acid distributions. The binding characteristics of the scFv clones identified from this work were analyzed by immunoassay and immunoaffinity pull down of BmR1. The work highlights the antibody gene usage pattern of a naive and immune antibody library against the same antigen as well as the robust nature of the enriched antibodies for downstream applications. PMID- 29165353 TI - A Cross-Sectional Study on the Association between 24-h Urine Osmolality and Weight Status in Older Adults. AB - Data on the association between hydration and body weight in the elderly are scarce. The objective of this work was to quantify the association between 24-h urine osmolality and weight status in the elderly. A cross-sectional study was conducted within the Nutrition UP 65 study. A quota sampling was implemented to achieve a nationally representative sample of Portuguese older adults (>=65 years) according to age, sex, education and region. From a sample size of 1500 participants, 1315 were eligible for the present analysis, 57.3% were women and 23.5% were aged >=80 years. Participants were grouped using tertiles of 24-h urine osmolality by sex. World Health Organization cutoffs were used to classify participants according to weight status. Multinomial multivariable logistic regression models were conducted to evaluate the association of tertiles of osmolality with weight status, adjusting for confounders. Odds Ratios (OR) and respective 95% Confidence Intervals (95% CI) were calculated. Being in the 3rd urine osmolality tertile (highest) was associated with a higher risk of being obese in men, OR = 1.97, 95% CI = 1.06, 3.66. No such association was found in women. These results highlight the need for implementing studies in order to clarify the association between hydration and weight status in the elderly. PMID- 29165354 TI - The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain. AB - Alzheimer's disease (AD), characterized by the aggregation of amyloid-beta (Abeta) protein and neuroinflammation, is the most common neurodegenerative disease globally. Previous studies have reported that some AD patients show impaired glucose utilization in brain, leading to cognitive decline. Recently, diabetes-induced dementia has been called "type 3 diabetes", based on features in common with those of type 2 diabetes and the progression of AD. Impaired glucose uptake and insulin resistance in the brain are important issues in type 3 diabetes, because these problems ultimately aggravate memory dysfunction in the brain. Glucagon-like peptide 1 (GLP-1) has been known to act as a critical controller of the glucose metabolism. Several studies have demonstrated that GLP 1 alleviates learning and memory dysfunction by enhancing the regulation of glucose in the AD brain. However, the specific actions of GLP-1 in the AD brain are not fully understood. Here, we review evidences related to the role of GLP-1 in type 3 diabetes. PMID- 29165355 TI - Acute Effects of Nitrate-Rich Beetroot Juice on Blood Pressure, Hemostasis and Vascular Inflammation Markers in Healthy Older Adults: A Randomized, Placebo Controlled Crossover Study. AB - Aging is associated with a vasoconstrictive, pro-coagulant, and pro-inflammatory profile of arteries and a decline in the bioavailability of the endothelium derived molecule nitric oxide. Dietary nitrate elicits vasodilatory, anti coagulant and anti-inflammatory effects in younger individuals, but little is known about whether these benefits are evident in older adults. We investigated the effects of 140 mL of nitrate-rich (HI-NI; containing 12.9 mmol nitrate) versus nitrate-depleted beetroot juice (LO-NI; containing <=0.04 mmol nitrate) on blood pressure, blood coagulation, vascular inflammation markers, plasma nitrate and nitrite before, and 3 h and 6 h after ingestion in healthy older adults (five males, seven females, mean age: 64 years, age range: 57-71 years) in a randomized, placebo-controlled, crossover study. Plasma nitrate and nitrite increased 3 and 6 h after HI-NI ingestion (p < 0.05). Systolic, diastolic and mean arterial blood pressure decreased 3 h relative to baseline after HI-NI ingestion only (p < 0.05). The number of blood monocyte-platelet aggregates decreased 3 h after HI-NI intake (p < 0.05), indicating reduced platelet activation. The number of blood CD11b-expressing granulocytes decreased 3 h following HI-NI beetroot juice intake (p < 0.05), suggesting a shift toward an anti-adhesive granulocyte phenotype. Numbers of blood CD14++CD16+ intermediate monocyte subtypes slightly increased 6 h after HI-NI beetroot juice ingestion (p < 0.05), but the clinical implications of this response are currently unclear. These findings provide new evidence for the acute effects of nitrate-rich beetroot juice on circulating immune cells and platelets. Further long-term research is warranted to determine if these effects reduce the risk of developing hypertension and vascular inflammation with aging. PMID- 29165356 TI - Fast Detection of a BRCA2 Large Genomic Duplication by Next Generation Sequencing as a Single Procedure: A Case Report. AB - The aim of this study was to verify the reliability of a next generation sequencing (NGS)-based method as a strategy to detect all possible BRCA mutations, including large genomic rearrangements. Genomic DNA was obtained from a peripheral blood sample provided by a patient from Southern Italy with early onset breast cancer and a family history of diverse cancers. BRCA molecular analysis was performed by NGS, and sequence data were analyzed using two software packages. Comparative genomic hybridization (CGH) array was used as confirmatory method. A novel large duplication, involving exons 4-26, of BRCA2 was directly detected in the patient by NGS workflow including quantitative analysis of copy number variants. The duplication observed was also found by CGH array, thus confirming its extent. Large genomic rearrangements can affect the BRCA1/2 genes, and thus contribute to germline predisposition to familial breast and ovarian cancers. The frequency of these mutations could be underestimated because of technical limitations of several routinely used molecular analysis, while their evaluation should be included also in these molecular testing. The NGS-based strategy described herein is an effective procedure to screen for all kinds of BRCA mutations. PMID- 29165357 TI - New Metabolites of Coumarin Detected in Human Urine Using Ultra Performance Liquid Chromatography/Quadrupole-Time-of-Flight Tandem Mass Spectrometry. AB - Coumarin (1,2-benzopyrone) is a natural compound whose metabolism in humans was established in the 1970s. However, a new metabolite was recently identified in human plasma, indicating that the metabolism of coumarin has not been completely elucidated. To complement the knowledge of its metabolism, a rapid and sensitive method using UPLC-QTOF-MS was developed. A total of 12 metabolites was identified using MetaboLynxTM software, including eight metabolites not previously reported in human urine. The identified biotransformation included hydroxylation, glucuronidation, sulfation, methylation, and conjugation with N-acetylcysteine. The present work demonstrates that the metabolism study of coumarin was incomplete, possibly due to limitations of old techniques. The identification of eight inedited metabolites of such a simple molecule suggests that the information regarding the metabolism of other drugs may also be incomplete, and therefore, new investigations are necessary. PMID- 29165359 TI - Environmentally Friendly Compatibilizers from Soybean Oil for Ternary Blends of Poly(lactic acid)-PLA, Poly(epsilon-caprolactone)-PCL and Poly(3-hydroxybutyrate) PHB. AB - Ternary blends of poly(lactic acid) (PLA), poly(3-hydroxybutyrate) (PHB) and poly(epsilon-caprolactone) (PCL) with a constant weight percentage of 60%, 10% and 30% respectively were compatibilized with soybean oil derivatives epoxidized soybean oil (ESO), maleinized soybean oil (MSO) and acrylated epoxidized soybean oil (AESO). The potential compatibilization effects of the soybean oil derivatives was characterized in terms of mechanical, thermal and thermomechanical properties. The effects on morphology were studied by field emission scanning electron microscopy (FESEM). All three soybean oil-based compatibilizers led to a noticeable increase in toughness with a remarkable improvement in elongation at break. On the other hand, both the tensile modulus and strength decreased, but in a lower extent to a typical plasticization effect. Although phase separation occurred, all three soybean oil derivatives led somewhat to compatibilization through reaction between terminal hydroxyl groups in all three biopolyesters (PLA, PHB and PCL) and the readily reactive groups in the soybean oil derivatives, that is, epoxy, maleic anhydride and acrylic/epoxy functionalities. In particular, the addition of 5 parts per hundred parts of the blend (phr) of ESO gave the maximum elongation at break while the same amount of MSO and AESO gave the maximum toughness, measured through Charpy's impact tests. In general, the herein-developed materials widen the potential of ternary PLA formulations by a cost effective blending method with PHB and PCL and compatibilization with vegetable oil-based additives. PMID- 29165358 TI - Understanding the Molecular Genetics of Basal Cell Carcinoma. AB - Basal cell carcinoma (BCC) is the most common human cancer and represents a growing public health care problem. Several tumor suppressor genes and proto oncogenes have been implicated in BCC pathogenesis, including the key components of the Hedgehog pathway, PTCH1 and SMO, the TP53 tumor suppressor, and members of the RAS proto-oncogene family. Aberrant activation of the Hedgehog pathway represents the molecular driver in basal cell carcinoma pathogenesis, with the majority of BCCs carrying somatic point mutations, mainly ultraviolet (UV) induced, and/or copy-loss of heterozygosis in the PTCH1 gene. Recent advances in sequencing technology allowed genome-scale approaches to mutation discovery, identifying new genes and pathways potentially involved in BCC carcinogenesis. Mutational and functional analysis suggested PTPN14 and LATS1, both effectors of the Hippo-YAP pathway, and MYCN as new BCC-associated genes. In addition, emerging reports identified frequent non-coding mutations within the regulatory promoter sequences of the TERT and DPH3-OXNAD1 genes. Thus, it is clear that a more complex genetic network of cancer-associated genes than previously hypothesized is involved in BCC carcinogenesis, with a potential impact on the development of new molecular targeted therapies. This article reviews established knowledge and new hypotheses regarding the molecular genetics of BCC pathogenesis. PMID- 29165360 TI - Dynamic Docking: A Paradigm Shift in Computational Drug Discovery. AB - Molecular docking is the methodology of choice for studying in silico protein ligand binding and for prioritizing compounds to discover new lead candidates. Traditional docking simulations suffer from major limitations, mostly related to the static or semi-flexible treatment of ligands and targets. They also neglect solvation and entropic effects, which strongly limits their predictive power. During the last decade, methods based on full atomistic molecular dynamics (MD) have emerged as a valid alternative for simulating macromolecular complexes. In principle, compared to traditional docking, MD allows the full exploration of drug-target recognition and binding from both the mechanistic and energetic points of view (dynamic docking). Binding and unbinding kinetic constants can also be determined. While dynamic docking is still too computationally expensive to be routinely used in fast-paced drug discovery programs, the advent of faster computing architectures and advanced simulation methodologies are changing this scenario. It is feasible that dynamic docking will replace static docking approaches in the near future, leading to a major paradigm shift in in silico drug discovery. Against this background, we review the key achievements that have paved the way for this progress. PMID- 29165362 TI - Enhanced Oxygen Reduction Reaction by In Situ Anchoring Fe2N Nanoparticles on Nitrogen-Doped Pomelo Peel-Derived Carbon. AB - The development of effective oxygen electrode catalysts for renewable energy technologies such as metal-air batteries and fuel cells remains challenging. Here, we prepared a novel high-performance oxygen reduction reaction (ORR) catalyst comprised of Fe2N nanoparticles (NPs) in situ decorated over an N-doped porous carbon derived from pomelo peel (i.e., Fe2N/N-PPC). The decorated Fe2N NPs provided large quantities of Fe-N-C bonding catalytic sites. The as-obtained Fe2N/N-PPC showed superior onset and half-wave potentials (0.966 and 0.891 V, respectively) in alkaline media (0.1 M KOH) compared to commercial Pt/C through a direct four-electron reaction pathway. Fe2N/N-PPC also showed better stability and methanol tolerance than commercial Pt/C. The outstanding ORR performance of Fe2N/N-PPC was attributed to its high specific surface area and the synergistic effects of Fe2N NPs. The utilization of agricultural wastes as a precursor makes Fe2N/N-PPC an ideal non-precious metal catalyst for ORR applications. PMID- 29165361 TI - The Obscure World of Integrative and Mobilizable Elements, Highly Widespread Elements that Pirate Bacterial Conjugative Systems. AB - Conjugation is a key mechanism of bacterial evolution that involves mobile genetic elements. Recent findings indicated that the main actors of conjugative transfer are not the well-known conjugative or mobilizable plasmids but are the integrated elements. This paper reviews current knowledge on "integrative and mobilizable elements" (IMEs) that have recently been shown to be highly diverse and highly widespread but are still rarely described. IMEs encode their own excision and integration and use the conjugation machinery of unrelated co resident conjugative element for their own transfer. Recent studies revealed a much more complex and much more diverse lifecycle than initially thought. Besides their main transmission as integrated elements, IMEs probably use plasmid-like strategies to ensure their maintenance after excision. Their interaction with conjugative elements reveals not only harmless hitchhikers but also hunters that use conjugative elements as target for their integration or harmful parasites that subvert the conjugative apparatus of incoming elements to invade cells that harbor them. IMEs carry genes conferring various functions, such as resistance to antibiotics, that can enhance the fitness of their hosts and that contribute to their maintenance in bacterial populations. Taken as a whole, IMEs are probably major contributors to bacterial evolution. PMID- 29165363 TI - Identification and Initial Characterization of the Effectors of an Anther Smut Fungus and Potential Host Target Proteins. AB - (1) Background: Plant pathogenic fungi often display high levels of host specificity and biotrophic fungi; in particular, they must manipulate their hosts to avoid detection and to complete their obligate pathogenic lifecycles. One important strategy of such fungi is the secretion of small proteins that serve as effectors in this process. Microbotryum violaceum is a species complex whose members infect members of the Caryophyllaceae; M. lychnidis-dioicae, a parasite on Silene latifolia, is one of the best studied interactions. We are interested in identifying and characterizing effectors of the fungus and possible corresponding host targets; (2) Methods: In silico analysis of the M. lychnidis dioicae genome and transcriptomes allowed us to predict a pool of small secreted proteins (SSPs) with the hallmarks of effectors, including a lack of conserved protein family (PFAM) domains and also localized regions of disorder. Putative SSPs were tested for secretion using a yeast secretion trap method. We then used yeast two-hybrid analyses for candidate-secreted effectors to probe a cDNA library from a range of growth conditions of the fungus, including infected plants; (3) Results: Roughly 50 SSPs were identified by in silico analysis. Of these, 4 were studied further and shown to be secreted, as well as examined for potential host interactors. One of the putative effectors, MVLG_01732, was found to interact with Arabidopsis thaliana calcium-dependent lipid binding protein (AtCLB) and with cellulose synthase interactive protein 1 orthologues; and (4) Conclusions: The identification of a pool of putative effectors provides a resource for functional characterization of fungal proteins that mediate the delicate interaction between pathogen and host. The candidate targets of effectors, e.g., AtCLB, involved in pollen germination suggest tantalizing insights that could drive future studies. PMID- 29165364 TI - The Rosiglitazone-Like Effects of Vitexilactone, a Constituent from Vitex trifolia L. in 3T3-L1 Preadipocytes. AB - The increased number of patients with type 2 diabetes (T2D) has become a worldwide problem, and insulin sensitizers such as thiazolidinediones (TZDs) are used as therapeutic agents. We found that extracts of Vitex trifolia L. (V. trifolia), a medicinal plant from Myanmar, induced adipogenesis similar to rosiglitazone (ROS), which is a TZD, in 3T3-L1 preadipocytes. In the present study, we attempted to isolate from V. trifolia those compounds that showed ROS like effects. Among the extracts of hexane, ethyl acetate, and methanol obtained from V. trifolia, the ethyl acetate extract with the strongest ROS-like effects was purified by various chromatographic methods to obtain three known compounds: vitexilactone (1), vitexicarpin (2) and oleanolic acid (3). Among the isolated compounds, the ROS-like action of 1 was the strongest. The effects of 1 on 3T3-L1 cells during adipogenesis were compared with those of ROS. Both 1 and ROS increased lipid accumulation, the expression of adiponectin and GLUT4 in the cell membrane and decreased both the size of adipocytes and the phosphorylation of IRS 1, ERK1/2 and JNK in 3T3-L1 cells. In contrast, unlike ROS, the induction of proteins involved in lipogenesis was partial. ROS-like effects of 1 in 3T3-L1 cells were suppressed by the addition of bisphenol A diglycidyl ether (BADGE), one of a peroxisome proliferator-activated receptor gamma (PPARgamma) antagonists, suggesting that the action of 1 on adipocytes is mediated by PPARgamma. From the results of the present study, it can be concluded that 1 is a novel insulin sensitizer candidate. PMID- 29165365 TI - Integrated Evaluation of Coupling Coordination for Land Use Change and Ecological Security: A Case Study in Wuhan City of Hubei Province, China. AB - As land resources and ecosystems provide necessary materials and conditions for human development, land use change and ecological security play increasingly important roles in sustainable development. This study aims to reveal the mutual influence and interaction between land use change and ecological security in Wuhan, based on the coupling coordination degree model. As such, it provides strategies for the achievement of the synchronous and coordinated development of urbanization and ecological security. The results showed that, during the period from 2006 to 2012, the size of built-up area in Wuhan increased to 26.16%, and that all the other types of land use reduced due to the urbanization process, which appeared to be the main driving force of land use change. The ecological security in Wuhan has been improving as a whole although it was somewhat held back from 2006 to 2008 due to the rapid growth of built-up area. The coupling coordination analysis revealed that the relationship between built-up area and ecological security was more coordinated after 2008. The results can provide feasible recommendations for land use management and environmental protection from the viewpoint of coordinated development. To achieve sustainable development from economic and ecological perspective, policy makers should control the rate of urban expansion and exert more effort on intensive land use, clean energy development and emission reduction. PMID- 29165367 TI - Urban Green Space and the Pursuit of Health Equity in Parts of the United States. AB - Research has demonstrated that inequitable access to green space can relate to health disparities or inequalities. This commentary aims to shift the dialogue to initiatives that have integrated green spaces in projects that may promote health equity in the United States. Specifically, we connect this topic to factors such as community revitalization, affordable housing, neighborhood walkability, food security, job creation, and youth engagement. We provide a synopsis of locations and initiatives in different phases of development along with characteristics to support effectiveness and strategies to overcome challenges. The projects cover locations such as Atlanta (GA), Los Angeles (CA), the District of Columbia (Washington D.C.), South Bronx (NY), and Utica (NY). Such insight can develop our understanding of green space projects that support health equity and inform the dialogue on this topic in ways that advance research and advocacy. PMID- 29165366 TI - Nitroxides as Antioxidants and Anticancer Drugs. AB - Nitroxides are stable free radicals that contain a nitroxyl group with an unpaired electron. In this paper, we present the properties and application of nitroxides as antioxidants and anticancer drugs. The mostly used nitroxides in biology and medicine are a group of heterocyclic nitroxide derivatives of piperidine, pyrroline and pyrrolidine. The antioxidant action of nitroxides is associated with their redox cycle. Nitroxides, unlike other antioxidants, are characterized by a catalytic mechanism of action associated with a single electron oxidation and reduction reaction. In biological conditions, they mimic superoxide dismutase (SOD), modulate hemoprotein's catalase-like activity, scavenge reactive free radicals, inhibit the Fenton and Haber-Weiss reactions and suppress the oxidation of biological materials (peptides, proteins, lipids, etc.). The use of nitroxides as antioxidants against oxidative stress induced by anticancer drugs has also been investigated. The application of nitroxides and their derivatives as anticancer drugs is discussed in the contexts of breast, hepatic, lung, ovarian, lymphatic and thyroid cancers under in vivo and in vitro experiments. In this article, we focus on new natural spin-labelled derivatives such as camptothecin, rotenone, combretastatin, podophyllotoxin and others. The applications of nitroxides in the aging process, cardiovascular disease and pathological conditions were also discussed. PMID- 29165368 TI - Human Protoparvoviruses. AB - Next-generation sequencing and metagenomics have revolutionized the discovery of novel viruses. In recent years, three novel protoparvoviruses have been discovered in fecal samples of humans: bufavirus (BuV) in 2012, tusavirus (TuV) in 2014, and cutavirus (CuV) in 2016. BuV has since been studied the most, disclosing three genotypes that also represent serotypes. Besides one nasal sample, BuV DNA has been found exclusively in diarrheal feces, but not in non diarrheal feces, suggesting a causal relationship. According to both geno- and seroprevalences, BuV appears to be the most common of the three novel protoparvoviruses, whereas TuV DNA has been found in only a single fecal sample, with antibody detection being equally rare. Moreover, the TuV sequence is closer to those of non-human protoparvoviruses, and so the evidence of TuV being a human virus is thus far insufficient. Interestingly, besides in feces, CuV has also been detected in skin biopsies of patients with cutaneous T-cell lymphoma and a patient with melanoma, while all other skin samples have tested PCR negative. Even if preliminary disease associations exist, the full etiological roles of these viruses in human disease are yet to be resolved. PMID- 29165369 TI - Metabolic Epilepsies-Commemorative Issue in Honor of Professor Uwe Heinemann. AB - Epilepsy is a very frequent, severe, and disabling neurological disorder with has a considerable disease burden worldwide [...]. PMID- 29165371 TI - Veterinarian Nominated Common Conditions of Rabbits and Guinea Pigs Compared with Published Literature. AB - Rabbits and guinea pigs are increasingly popular pets in the UK, yet little is known about their common ailments, or how these relate to what appears in the published literature. The aim of this study was to characterise the common conditions of rabbits and guinea pigs, and to compare these with the topics found in the published literature. Information about the common conditions seen in rabbits and guinea pigs in clinical practice was obtained from a survey of UK veterinarians. The common conditions seen were compared with results from a structured literature search. Conditions relating to the dental (29.9%), and skin (37.6%) body systems were commonly nominated by veterinarians for rabbits and guinea pigs, respectively. A total of 655 rabbit and 1086 guinea pig citations were examined and there appeared to be a mismatch between the conditions nominated in the veterinary questionnaire, and those found in the literature. This is the first time that the published literature has been compared to the nominated caseload of veterinarians in practice, and there is concern that the literature about rabbits and guinea pigs may not be representative of, or relevant to the caseload seen in clinical practice. This is of importance for clinicians being able to apply an objective, evidence-based approach. The publishing of clinically-relevant, research-based evidence should be prioritised. PMID- 29165370 TI - Vitamin E Bioavailability: Mechanisms of Intestinal Absorption in the Spotlight. AB - Vitamin E is an essential fat-soluble micronutrient whose effects on human health can be attributed to both antioxidant and non-antioxidant properties. A growing number of studies aim to promote vitamin E bioavailability in foods. It is thus of major interest to gain deeper insight into the mechanisms of vitamin E absorption, which remain only partly understood. It was long assumed that vitamin E was absorbed by passive diffusion, but recent data has shown that this process is actually far more complex than previously thought. This review describes the fate of vitamin E in the human gastrointestinal lumen during digestion and focuses on the proteins involved in the intestinal membrane and cellular transport of vitamin E across the enterocyte. Special attention is also given to the factors modulating both vitamin E micellarization and absorption. Although these latest results significantly improve our understanding of vitamin E intestinal absorption, further studies are still needed to decipher the molecular mechanisms driving this multifaceted process. PMID- 29165372 TI - Pedestrian Detection with Semantic Regions of Interest. AB - For many pedestrian detectors, background vs. foreground errors heavily influence the detection quality. Our main contribution is to design semantic regions of interest that extract the foreground target roughly to reduce the background vs. foreground errors of detectors. First, we generate a pedestrian heat map from the input image with a full convolutional neural network trained on the Caltech Pedestrian Dataset. Next, semantic regions of interest are extracted from the heat map by morphological image processing. Finally, the semantic regions of interest divide the whole image into foreground and background to assist the decision-making of detectors. We test our approach on the Caltech Pedestrian Detection Benchmark. With the help of our semantic regions of interest, the effects of the detectors have varying degrees of improvement. The best one exceeds the state-of-the-art. PMID- 29165373 TI - Optimal Pricing and Power Allocation for Collaborative Jamming with Full Channel Knowledge in Wireless Sensor Networks. AB - This paper presents a price-searching model in which a source node (Alice) seeks friendly jammers that prevent eavesdroppers (Eves) from snooping legitimate communications by generating interference or noise. Unlike existing models, the distributed jammers also have data to send to their respective destinations and are allowed to access Alice's channel if it can transmit sufficient jamming power, which is referred to as collaborative jamming in this paper. For the power used to deliver its own signal, the jammer should pay Alice. The price of the jammers' signal power is set by Alice and provides a tradeoff between the signal and the jamming power. This paper presents, in closed-form, an optimal price that maximizes Alice's benefit and the corresponding optimal power allocation from a jammers' perspective by assuming that the network-wide channel knowledge is shared by Alice and jammers. For a multiple-jammer scenario where Alice hardly has the channel knowledge, this paper provides a distributed and interactive price-searching procedure that geometrically converges to an optimal price and shows that Alice by a greedy selection policy achieves certain diversity gain, which increases log-linearly as the number of (potential) jammers grows. Various numerical examples are presented to illustrate the behavior of the proposed model. PMID- 29165374 TI - Connections between Transcription Downstream of Genes and cis-SAGe Chimeric RNA. AB - cis-Splicing between adjacent genes (cis-SAGe) is being recognized as one way to produce chimeric fusion RNAs. However, its detail mechanism is not clear. Recent study revealed induction of transcriptions downstream of genes (DoGs) under osmotic stress. Here, we investigated the influence of osmotic stress on cis-SAGe chimeric RNAs and their connection to DoGs. We found,the absence of induction of at least some cis-SAGe fusions and/or their corresponding DoGs at early time point(s). In fact, these DoGs and their cis-SAGe fusions are inversely correlated. This negative correlation was changed to positive at a later time point. These results suggest a direct competition between the two categories of transcripts when total pool of readthrough transcripts is limited at an early time point. At a later time point, DoGs and corresponding cis-SAGe fusions are both induced, indicating that total readthrough transcripts become more abundant. Finally, we observed overall enhancement of cis-SAGe chimeric RNAs in KCl-treated samples by RNA-Seq analysis. PMID- 29165375 TI - South Asian Children Have Increased Body Fat in Comparison to White Children at the Same Body Mass Index. AB - The ability of body mass index (BMI) to predict excess fat in South Asian children is unknown. This cross-sectional study examines the influence of ethnicity on body fatness in children. Weight status and body fat were determined using BMI, waist circumference (WC), two skinfold sites (SF; triceps and subscapula) and leg-to-leg bioelectrical impedance analysis (BIA; Tanita BF350, Tanita, Tokyo, Japan) in 194 children aged 8.47 +/- 0.50 years from Coventry, United Kingdom. Biological maturity was also determined. Analysis of covariance (ANCOVA) identified significant differences between ethnic (p < 0.001) and gender groups' BMI (p = 0.026), with a significant covariate for skinfold (p < 0.001) and bioelectrical impedance (p < 0.001). For a given body fat value, South Asian children and females had a lower BMI value (-1.12 kg/m2, p < 0.001 and -0.50 kg/m2, p = 0.026, respectively, when adjusted for SF; -1.56 kg/m2, p < 0.001 and 0.31 kg/m2, p = 0.16, respectively, when adjusted for BIA) compared with white children and boys. The prediction model including ethnicity, gender and BIA explained 80.4% of the variance in BMI. Maturation was not found to be a significant covariate (p > 0.05). To conclude, the findings suggest that BMI cut points may need to be lowered in South Asian children, and thus age-by-sex-by ethnicity specific BMI cut-points are needed in children. Further research examining body composition with health parameters in this population is needed. PMID- 29165377 TI - A Novel 3D Pedestrian Navigation Method for a Multiple Sensors-Based Foot-Mounted Inertial System. AB - In this paper, we present a novel method for 3D pedestrian navigation of foot mounted inertial systems by integrating a MEMS-IMU, barometer, and permanent magnet. Zero-velocity update (ZUPT) is a well-known algorithm to eliminate the accumulated error of foot-mounted inertial systems. However, the ZUPT stance phase detector using acceleration and angular rate is threshold-based, which may cause incorrect stance phase estimation in the running gait pattern. A permanent magnet-based ZUPT detector is introduced to solve this problem. Peaks extracted from the magnetic field strength waveform are mid-stances of stance phases. A model of peak-peak information and stance phase duration is developed to have a quantitative calculation method of stance phase duration in different movement patterns. Height estimation using barometer is susceptible to the environment. A height difference information aided barometer (HDIB) algorithm integrating MEMS IMU and barometer is raised to have a better height estimation. The first stage of HDIB is to distinguish level ground/upstairs/downstairs and the second stage is to calculate height using reference atmospheric pressure obtained from the first stage. At last, a ZUPT-based adaptive average window length algorithm (ZUPT AAWL) is proposed to calculate the true total travelled distance to have a more accurate percentage error (TTDE). This proposed method is verified via multiple experiments. Numerical results show that TTDE ranges from 0.32% to 1.04% in both walking and running gait patterns, and the height estimation error is from 0 m to 2.35 m. PMID- 29165376 TI - Preparation of Vitexin Nanoparticles by Combining the Antisolvent Precipitation and High Pressure Homogenization Approaches Followed by Lyophilization for Dissolution Rate Enhancement. AB - Vitexin, a natural flavonoid found in many medicinal plants, is well known for its rich pharmacological activities. However, the poor water solubility of vitexin has limited its therapeutic application. The aim of this study was to prepare the nanoparticles of vitexin by combining the antisolvent precipitation (ASP) and high pressure homogenization (HPH) approaches followed by lyophilization for improving the dissolution rate of this poorly water-soluble drug. The effects of main factors influencing the mean particle size (MPS) of vitexin were investigated and optimized. Under optimum conditions, vitexin nanosuspensions with an MPS of 80.5 nm were obtained and then lyophilized to form nanoparticles. The obtained vitexin nanoparticles were further characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), mass spectrometry (MS), X-ray powder diffraction (XRPD), gas chromatography (GC) and dissolution testing. The results showed that the nanoparticles of vitexin were converted into an amorphous form, with its chemical structure unchanged. Additionally, the residual dimethyl sulfoxide (DMSO) is lower than the International Conference on Harmonization (ICH) limit for class 3 solvents. The dissolution rate of processed vitexin was significantly higher (5.58-fold) than that of raw drug. Overall, the combinative process we developed is an effective way to produce vitexin nanoparticles with markedly enhanced dissolution rate. PMID- 29165378 TI - Effects of Sediment Chemical Properties on Phosphorus Release Rates in the Sediment-Water Interface of the Steppe Wetlands. AB - Rising temperature causes a process of phosphorus release, which can be characterized well using phosphorus release rates (VP). The objective of the present study was to investigate the major factors affecting sediment phosphorus release rates through a wetland habitat simulation experiment. The results showed that the VP of different wetland sediments were different and changed with the order of W-R (river wetland) > W-L (lake wetland) > W-M (grassy marsh wetland) > W-A (reservoir wetland). The main driving factors which influenced sediment phosphorus flux velocity in the sediment-water interface were sediment B-SO42-, B MBN and A-MBP content. Path analysis and determination coefficient analysis indicated the standard multiple regression equation for sediment phosphorus release rates in the sediment-water interface, and each main factor was Y = 0.105 + 0.096X1 + 0.275X2 - 0.010X3 (r = 0.416, p < 0.01, n = 144), where Y is sediment phosphorus release rates; X1 is sediment B-SO42- content; X2 is sediment B-MBN; and X3 is sediment A-MBP content. Sediment B-SO42-, B-MBN and A-MBP content and the interaction between them were the main factors affecting sediment phosphorus release rates in the sediment-water interface. Therefore, these results suggest that soil chemical properties and microbial activities likely play an important role in phosphorus release rates in the sediment-water interface. We hope to provide effective scientific management and control methods for relevant environmental protection departments. PMID- 29165380 TI - Direct Modification of Microcrystalline Cellulose with Ethylenediamine for use as Adsorbent for Removal Amitriptyline Drug from Environment. AB - Cellulose derivatives have been widely used as adsorbents for the removal of micropollutants such as drugs, dyes, and metals, due to their abundance, low cost and non-contaminating nature. In this context, several studies have been performed searching for new adsorbents (cellulose derivatives) efficient at contaminant removal from aqueous solutions. Thus, a new adsorbent was synthesized by chemical modification of cellulose with ethylenediamine in the absence of solvent and applied to the adsorption of amitriptyline (AMI) in aqueous solution. The modification reaction was confirmed by X-ray Diffraction (XRD), elemental analysis, Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetry/Differential Scanning Calorimeter (TG/DSC), solid state Nuclear Magnetic Resonance of 1H and 13C (1H-NMR and 13C-NMR). Moreover, the effectiveness of reaction was confirmed by computational calculations using Density Functional Theory (DFT) at level B3LYP/6-31G(d). This adsorption process was influenced by pH, time, concentration, temperature and did not show significant changes due to the ionic strength variation. Through these experiments, it was observed that the maximum adsorption capacity of AMI by CN polymer at 298 K, 300 min, and pH 7 was 87.66 +/- 0.60 mg.g-1. PMID- 29165381 TI - Factors Associated with the Need for, and the Impact of, Extracorporeal Membrane Oxygenation in Children with Congenital Heart Disease during Admissions for Cardiac Surgery. AB - INTRODUCTION: This study aimed to determine factors associated with the need for extracorporeal membrane oxygenation (ECMO) in children with congenital heart disease (CHD) during admission for cardiac surgery (CS). A secondary aim was to determine how ECMO impacted length, cost, and mortality of the admission. METHODS: Data from the Kids' Inpatient Database (KIDS) were utilized. Admissions with CHD under 18 years of age with cardiac surgery were included. Need for ECMO in these admissions was then identified. Univariate analysis was conducted to compare characteristics between admissions with and without ECMO. Regression analyses were conducted to determine what factors were independently associated with ECMO and whether ECMO independently impacted admission characteristics. RESULTS: A total of 46,176 admissions with CHD and CS were included in the final analysis. Of these, 798 (1.7%) required ECMO. Median age of ECMO admissions was 0.5 years. The following were associated with ECMO: decreased age, heart failure, acute kidney injury, arrhythmia, double outlet right ventricle, atrioventricular septal defect, transposition, Ebstein anomaly, hypoplastic left heart syndrome, common arterial trunk, tetralogy of Fallot, coronary anomaly, valvuloplasty, repair of total anomalous pulmonary venous connection, arterial switch, RV to PA conduit placement, and heart transplant (p < 0.01). ECMO independently increased length of stay by 17.8 days, cost of stay by approximately $415,917, and inpatient mortality 22-fold. CONCLUSION: Only a small proportion of CHD patients undergoing CS require ECMO, although these patients require increased resource utilization and have high mortality. Specific cardiac lesions, cardiac surgeries, and comorbidities are associated with increased need for ECMO. PMID- 29165379 TI - Role of Non-Coding RNAs in the Etiology of Bladder Cancer. AB - According to data of the International Agency for Research on Cancer and the World Health Organization (Cancer Incidence in Five Continents, GLOBOCAN, and the World Health Organization Mortality), bladder is among the top ten body locations of cancer globally, with the highest incidence rates reported in Southern and Western Europe, North America, Northern Africa and Western Asia. Males (M) are more vulnerable to this disease than females (F), despite ample frequency variations in different countries, with a M:F ratio of 4.1:1 for incidence and 3.6:1 for mortality, worldwide. For a long time, bladder cancer was genetically classified through mutations of two genes, fibroblast growth factor receptor 3 (FGFR3, for low-grade, non-invasive papillary tumors) and tumor protein P53 (TP53, for high-grade, muscle-invasive tumors). However, more recently scientists have shown that this disease is far more complex, since genes directly involved are more than 150; so far, it has been described that altered gene expression (up or down-regulation) may be present for up to 500 coding sequences in low-grade and up to 2300 in high-grade tumors. Non-coding RNAs are essential to explain, at least partially, this ample dysregulation. In this review, we summarize the present knowledge about long and short non-coding RNAs that have been linked to bladder cancer etiology. PMID- 29165382 TI - Review of the Functions of Archimedes' Spiral Metallic Nanostructures. AB - Here, we have reviewed some typical plasmonic structures based on Archimedes' spiral (AS) architectures, which can produce polarization-sensitive focusing phenomenon and generate plasmonic vortices (PVs) carrying controllable orbital angular momentum (OAM) because of the relation between the incident polarized states and the chiralities of the spiral structures. These features can be used to analyze different circular polarization states, which has been one of the rapidly developing researching topics in nanophotonics in recent years. Many investigations demonstrate that the multifunctional spiral-based plasmonic structures are excellent choices for chiral selection and generating the transmitted field with well-defined OAM. The circular polarization extinction ratio, as an evaluation criterion for the polarization selectivity of a designed structure, could be effectively improved by properly modulating the parameters of spiral structures. Such functional spiral plasmonic nanostructures are promising for applications in analyzing circular polarization light, full Stokes vector polarimetric sensors, near-field imaging, and so on. PMID- 29165384 TI - Solid Lipid Nanoparticles of Albendazole for Enhancing Cellular Uptake and Cytotoxicity against U-87 MG Glioma Cell Lines. AB - Albendazole (ABZ) is an antihelminthic drug used for the treatment of several parasitic infestations. In addition to this, there are reports on the anticancer activity of ABZ against a wide range of cancer types. However, its effect on glioma has not yet been reported. In the present study, cytotoxicity of ABZ and ABZ loaded solid lipid nanoparticles (ASLNs) was tested in human glioma/astrocytoma cell line (U-87 MG). Using glyceryl trimyristate as lipid carrier and tween 80 as surfactant spherical ASLNs with an average size of 218.4 +/- 5.1 nm were prepared by a combination of high shear homogenization and probe sonication methods. A biphasic in vitro release pattern of ABZ from ASLNs was observed, where 82% of ABZ was released in 24 h. In vitro cell line studies have shown that ABZ in the form of ASLNs was more cytotoxic (IC50 = 4.90 ug/mL) to U 87 MG cells compared to ABZ in the free form (IC50 = 13.30 ug/mL) due to the efficient uptake of the former by these cells. PMID- 29165383 TI - A Mini-Review of the NADPH oxidases in Vascular Dementia: Correlation with NOXs and Risk Factors for VaD. AB - Oxidative stress (OS) is one of the factors that cause dementia conditions such as Alzheimer's disease and vascular dementia (VaD). In the pathogenesis of VaD, OS is associated with risk factors that include increased age, hypertension, and stroke. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are a molecular source of reactive oxygen species (ROS). According to recent studies, inhibition of NOX activity can reduce cognitive impairment in animal models of VaD. In this article, we review the evidence linking cognitive impairment with NOX-dependent OS, including the vascular NOX and non-vascular NOX systems, in VaD. PMID- 29165385 TI - Prevalence of Pre-Diabetes across Ethnicities: A Review of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) for Classification of Dysglycaemia. AB - Prediabetes can be defined by the presence of impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), or glycated haemoglobin (HbA1c) to identify individuals at increased risk of developing type 2 diabetes (T2D). The World Health Organization (WHO, 1999) and the American Diabetes Association (ADA, 2003) utilise different cut-off values for IFG (WHO: 6.1-6.9 mmol/L; ADA: 5.6-6.9 mmol/L) but the same cut-off values for IGT (7.8-11.0 mmol/L). This review investigates whether there are differences in prevalence of IFG, IGT, and combined IFG&IGT between ethnicities, in particular Asian Chinese and European Caucasians. In total, we identified 19 studies using the WHO1999 classification, for which the average proportional prevalence for isolated (i)-IFG, i-IGT, and combined IFG&IGT were 43.9%, 41.0%, and 13.5%, respectively, for Caucasian and 29.2%, 49.4%, and 18.2%, respectively, for Asian. For the 14 studies using ADA2003 classification, the average proportional i-IFG, i-IGT, and combined IFG&IGT prevalences were 58.0%, 20.3%, and 19.8%, respectively, for Caucasian; 48.1%, 27.7%, and 20.5%, respectively, for Asian. Whilst not statistically different, there may be clinically relevant differences in the two populations, with our observations for both classifications indicating that prevalence of i IFG is higher in Caucasian cohorts whilst i-IGT and combined IFG&IGT are both higher in Asian cohorts. PMID- 29165387 TI - Nitric Oxide Mediates Crosstalk between Interleukin 1beta and WNT Signaling in Primary Human Chondrocytes by Reducing DKK1 and FRZB Expression. AB - Interleukin 1 beta (IL1beta) and Wingless-Type MMTV Integration Site Family (WNT) signaling are major players in Osteoarthritis (OA) pathogenesis. Despite having a large functional overlap in OA onset and development, the mechanism of IL1beta and WNT crosstalk has remained largely unknown. In this study, we have used a combination of computational modeling and molecular biology to reveal direct or indirect crosstalk between these pathways. Specifically, we revealed a mechanism by which IL1beta upregulates WNT signaling via downregulating WNT antagonists, DKK1 and FRZB. In human chondrocytes, IL1beta decreased the expression of Dickkopf-1 (DKK1) and Frizzled related protein (FRZB) through upregulation of nitric oxide synthase (iNOS), thereby activating the transcription of WNT target genes. This effect could be reversed by iNOS inhibitor 1400W, which restored DKK1 and FRZB expression and their inhibitory effect on WNT signaling. In addition, 1400W also inhibited both the matrix metalloproteinase (MMP) expression and cytokine-induced apoptosis. We concluded that iNOS/NO play a pivotal role in the inflammatory response of human OA through indirect upregulation of WNT signaling. Blocking NO production may inhibit the loss of the articular phenotype in OA by preventing downregulation of the expression of DKK1 and FRZB. PMID- 29165386 TI - Alterations in Rat Accumbens Endocannabinoid and GABA Content during Fentanyl Treatment: The Role of Ghrelin. AB - The opioid-induced rise of extracellular dopamine, endocannabinoid anandamide and gamma-aminobutyric acid (GABA) concentrations triggered by opioids in the nucleus accumbens shell (NACSh) most likely participate in opioid reward. We have previously demonstrated that systemic administration of ghrelin antagonist (JMV2959) significantly decreased morphine-induced dopamine and anandamide (N arachidonoylethanolamine, AEA) increase in the NACSh. Fentanyl is considered as a u-receptor-selective agonist. The aim of this study was to test whether JMV2959, a growth hormone secretagogue receptor (GHS-R1A) antagonist, can influence the fentanyl-induced effects on anandamide, 2-arachidonoylglycerol (2-AG) and GABA in the NACSh and specify the involvement of GHS-R1A located in the ventral tegmental area (VTA) and nucleus accumbens (NAC). Using in vivo microdialysis in rats, we have found that pre-treatment with JMV2959 reversed dose dependently fentanyl induced anandamide increases in the NACSh, resulting in a significant AEA decrease and intensified fentanyl-induced decreases in accumbens 2-AG levels, with both JMV2959 effects more expressed when administered into the NACSh in comparison to the VTA. JMV2959 pre-treatment significantly decreased the fentanyl evoked accumbens GABA efflux and reduced concurrently monitored fentanyl-induced behavioural stimulation. Our current data encourage further investigation to assess if substances affecting GABA or endocannabinoid concentrations and action, such as GHS-R1A antagonists, can be used to prevent opioid-seeking behaviour. PMID- 29165388 TI - Argan Oil as an Effective Nutri-Therapeutic Agent in Metabolic Syndrome: A Preclinical Study. AB - The present study aims at examining the effects of argan oil on the three main cardiovascular risk factors associated with metabolic syndrome (hypertension, insulin resistance and obesity) and on one of its main complications, neuropathic pain. Male Sprague-Dawley rats had free access to a drinking solution containing 10% d-glucose or tap water for 12 weeks. The effect of argan oil was compared to that of corn oil given daily by gavage during 12 weeks in glucose-fed rats. Glucose-fed rats showed increases in systolic blood pressure, epididymal fat, plasma levels of triglycerides, leptin, glucose and insulin, insulin resistance, tactile and cold allodynia in association with a rise in superoxide anion production and NADPH oxidase activity in the thoracic aorta, epididymal fat and gastrocnemius muscle. Glucose-fed rats also showed rises in B1 receptor protein expression in aorta and gastrocnemius muscle. Argan oil prevented or significantly reduced all those anomalies with an induction in plasma adiponectin levels. In contrast, the same treatment with corn oil had a positive impact only on triglycerides, leptin, adiponectin and insulin resistance. These data are the first to suggest that argan oil is an effective nutri-therapeutic agent to prevent the cardiovascular risk factors and complications associated with metabolic syndrome. PMID- 29165390 TI - Comparison of Anionic, Cationic and Nonionic Surfactants as Dispersing Agents for Graphene Based on the Fluorescence of Riboflavin. AB - Fluorescence quenching is a valuable tool to gain insight about dynamic changes of fluorophores in complex systems. Graphene (G), a single-layered 2D nanomaterial with unique properties, was dispersed in surfactant aqueous solutions of different nature: non-ionic polyoxyethylene-23-lauryl ether (Brij L23), anionic sodium dodecylsulphate (SDS), and cationic hexadecyltrimethylammonium bromide (CTAB) and dodecyltrimethylammonium bromide (DTAB). The influence of the surfactant type, chain length and concentration, G total concentration and G/surfactant weight ratio on the fluorescence intensity of vitamin B2 (riboflavin) was investigated. The quality of the different G dispersions was assessed by scanning and transmission electron microscopies (SEM and TEM). A quenching phenomenon of the fluorescence of riboflavin was found for G dispersions in all the surfactants, which generally becomes stronger with increasing G/surfactant weight ratio. For dispersions in the ionic surfactants, the quenching is more pronounced as the surfactant concentration raises, whilst the non-ionic one remains merely unchanged for the different G/Brij L23 weight ratios. More importantly, results indicate that DTAB solutions are the optimum media for dispersing G sheets, leading to an up to 16-fold drop in the fluorescence intensity. Understanding the mechanism in fluorescence quenching of G dispersions in surfactants could be useful for several optical applications. PMID- 29165389 TI - Proteinase-Activated Receptor 2 May Drive Cancer Progression by Facilitating TGF beta Signaling. AB - The G protein-coupled receptor proteinase-activated receptor 2 (PAR2) has been implicated in various aspects of cellular physiology including inflammation, obesity and cancer. In cancer, it usually acts as a driver of cancer progression in various tumor types by promoting invasion and metastasis in response to activation by serine proteinases. Recently, we discovered another mode through which PAR2 may enhance tumorigenesis: crosstalk with transforming growth factor beta (TGF-beta) signaling to promote TGF-beta1-induced cell migration/invasion and invasion-associated gene expression in ductal pancreatic adenocarcinoma (PDAC) cells. In this chapter, we review what is known about the cellular TGF beta responses and signaling pathways affected by PAR2 expression, the signaling activities of PAR2 required for promoting TGF-beta signaling, and the potential molecular mechanism(s) that underlie(s) the TGF-beta signaling-promoting effect. Since PAR2 is activated through various serine proteinases and biased agonists, it may couple TGF-beta signaling to a diverse range of other physiological processes that may or may not predispose cells to cancer development such as local inflammation, systemic coagulation and pathogen infection. PMID- 29165391 TI - MicroRNAs Associated with Von Hippel-Lindau Pathway in Renal Cell Carcinoma: A Comprehensive Review. AB - Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time. The discovery of microRNAs (miRNAs), a class of small, non-coding, single-stranded RNAs that play a crucial role in post-transcriptional regulation, has added new dimensions to the development of novel diagnostic and treatment tools. Because of an association between Von Hippel-Lindau (VHL) genes with chromosomal loss in 3p25-26 and clear cell RCC, miRNAs have attracted considerable scientific interest over the last years. The loss of VHL function leads to constitutional activation of the hypoxia inducible factor (HIF) pathway and to consequent expression of numerous angiogenic and carcinogenic factors. Since miRNAs represent key players of carcinogenesis, tumor cell invasion, angiogenesis, as well as in development of metastases in RCC, they might serve as potential therapeutic targets. Several miRNAs are already known to be dysregulated in RCC and have been linked to biological processes involved in tumor angiogenesis and response to anti-cancer therapies. This review summarizes the role of different miRNAs in RCC angiogenesis and their association with the VHL gene, highlighting their potential role as novel drug targets. PMID- 29165392 TI - The Tale of Asbestos in Sweden 1972-1986-The Pathway to a Near-Total Ban. AB - This paper provides a narrative of the national intervention strategy in Sweden aimed to restrict the industrial use of asbestos. For many years, asbestos was imported for widespread industrial use, resulting in large amounts throughout Swedish society. In 1972, the whistle was blown in a Communist Party parliamentary motion describing asbestos as a health hazard and requesting action to prohibit its use. Although the motion was rejected, it initiated the extensive charting of asbestos sources on a tripartite basis, involving government agencies, and employer and trade-union organizations. Restrictive asbestos management practices were enforced from July 1982. The year 1985 saw the Government Asbestos Commission review, covering use-determining factors, international regulations, and assessments of cancer risks. The relative risks of chrysotile and amphibole were considered internationally (by the IARC), since chrysotile (a Canadian export) was regarded as unharmful in Canada at that time. Prohibiting asbestos use resulted in its virtual disappearance as an import to Sweden from the early 1980s. However, asbestos has undergone a transition from an occupational to a public-health hazard (although some work-related hazards, such as handling and disposal, remain). The transition reflects the public's exposure to existing stocks, in homes, workplaces, etc. Mesothelioma incidence has come to be regarded as an indicator of prevention effectiveness. PMID- 29165394 TI - WxC-beta-SiC Nanocomposite Catalysts Used in Aqueous Phase Hydrogenation of Furfural. AB - This study investigates the effects of the addition of tungsten on the structure, phase composition, textural properties and activities of beta-SiC-based catalysts in the aqueous phase hydrogenation of furfural. Carbothermal reduction of SiO2 in the presence of WO3 at 1550 degrees C in argon resulted in the formation of WxC beta-SiC nanocomposite powders with significant variations in particle morphology and content of WxC-tipped beta-SiC nano-whiskers, as revealed by TEM and SEM-EDS. The specific surface area (SSA) of the nanocomposite strongly depended on the amount of tungsten and had a notable impact on its catalytic properties for the production of furfuryl alcohol (FA) and tetrahydrofurfuryl alcohol (THFA). Nanocomposite WxC-beta-SiC catalysts with 10 wt % W in the starting mixture had the highest SSA and the smallest WxC crystallites. Some 10 wt % W nanocomposite catalysts demonstrated up to 90% yield of THFA, in particular in the reduction of furfural derived from biomass, although the reproducible performance of such catalysts has yet to be achieved. PMID- 29165395 TI - The Associations among Psychological Distress, Coping Style, and Health Habits in Japanese Nursing Students: A Cross-Sectional Study. AB - Background: Nursing students in many countries have been reported to experience high levels of stress and psychological distress. Health habits could potentially mediate the association between coping styles and psychological status. The purpose of this study was to evaluate the mediation effect of health habits in the relationship between stress coping styles and psychological distress in Japanese nursing students. Methods: A total of 181 nursing students completed anonymous self-reported questionnaires comprised of the General Health Questionnaire-12 (GHQ-12), the Brief Coping Orientation questionnaire, and an additional questionnaire on health behavior. A mediation analysis using path analysis with bootstrapping was used for data analysis. Results: Multivariate linear regression analysis showed that psychological distress was significantly and positively associated with "Avoidance coping" (beta = 0.39, p < 0.001), and was negatively associated with "Active coping" (beta = -0.30, p < 0.001), "exercise habit" (beta = -0.25, p = 0.001), and "sleeping" (beta = -0.24, p = 0.002). In the path model, "Active coping" and "Avoidance coping" had significant or marginally significant associations with "exercise habits" (active: beta = 0.19, p = 0.008, avoidance: beta = -0.12, p = 0.088), and psychological distress (active: beta = -0.25, p < 0.001, avoidance: beta = 0.363, p < 0.001). However, these coping style variables did not have a significant association with "sleep". In general, the size of the correlations was below 0.4. Conclusions: Exercise habits mediated the relationship between coping styles and psychological distress to a greater extent than sleep. The present study suggests the possibility that complex interactions between health habits and coping styles may influence the psychological status of nursing students. PMID- 29165393 TI - The Role of Hypoxia in Glioblastoma Invasion. AB - Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patient's median survival rate ranging from 15 to 17 months. The current treatment for GBM involves tumor resection surgery based on MRI image analysis, followed by radiotherapy and treatment with temozolomide. However, the gradual development of tumor resistance to temozolomide is frequent in GBM patients leading to subsequent tumor regrowth/relapse. For this reason, the development of more effective therapeutic approaches for GBM is of critical importance. Low tumor oxygenation, also known as hypoxia, constitutes a major concern for GBM patients, since it promotes cancer cell spreading (invasion) into the healthy brain tissue in order to evade this adverse microenvironment. Tumor invasion not only constitutes a major obstacle to surgery, radiotherapy, and chemotherapy, but it is also the main cause of death in GBM patients. Understanding how hypoxia triggers the GBM cells to become invasive is paramount to developing novel and more effective therapies against this devastating disease. In this review, we will present a comprehensive examination of the available literature focused on investigating how GBM hypoxia triggers an invasive cancer cell phenotype and the role of these invasive proteins in GBM progression. PMID- 29165396 TI - Markerless Knee Joint Position Measurement Using Depth Data during Stair Walking. AB - Climbing and descending stairs are demanding daily activities, and the monitoring of them may reveal the presence of musculoskeletal diseases at an early stage. A markerless system is needed to monitor such stair walking activity without mentally or physically disturbing the subject. Microsoft Kinect v2 has been used for gait monitoring, as it provides a markerless skeleton tracking function. However, few studies have used this device for stair walking monitoring, and the accuracy of its skeleton tracking function during stair walking has not been evaluated. Moreover, skeleton tracking is not likely to be suitable for estimating body joints during stair walking, as the form of the body is different from what it is when it walks on level surfaces. In this study, a new method of estimating the 3D position of the knee joint was devised that uses the depth data of Kinect v2. The accuracy of this method was compared with that of the skeleton tracking function of Kinect v2 by simultaneously measuring subjects with a 3D motion capture system. The depth data method was found to be more accurate than skeleton tracking. The mean error of the 3D Euclidian distance of the depth data method was 43.2 +/- 27.5 mm, while that of the skeleton tracking was 50.4 +/- 23.9 mm. This method indicates the possibility of stair walking monitoring for the early discovery of musculoskeletal diseases. PMID- 29165397 TI - Low Computational-Cost Footprint Deformities Diagnosis Sensor through Angles, Dimensions Analysis and Image Processing Techniques. AB - Manual measurements of foot anthropometry can lead to errors since this task involves the experience of the specialist who performs them, resulting in different subjective measures from the same footprint. Moreover, some of the diagnoses that are given to classify a footprint deformity are based on a qualitative interpretation by the physician; there is no quantitative interpretation of the footprint. The importance of providing a correct and accurate diagnosis lies in the need to ensure that an appropriate treatment is provided for the improvement of the patient without risking his or her health. Therefore, this article presents a smart sensor that integrates the capture of the footprint, a low computational-cost analysis of the image and the interpretation of the results through a quantitative evaluation. The smart sensor implemented required the use of a camera (Logitech C920) connected to a Raspberry Pi 3, where a graphical interface was made for the capture and processing of the image, and it was adapted to a podoscope conventionally used by specialists such as orthopedist, physiotherapists and podiatrists. The footprint diagnosis smart sensor (FPDSS) has proven to be robust to different types of deformity, precise, sensitive and correlated in 0.99 with the measurements from the digitalized image of the ink mat. PMID- 29165399 TI - Greenhouse Gas Emissions, Energy Consumption and Economic Growth: A Panel Cointegration Analysis for 16 Asian Countries. AB - This research investigates the co-movement and causality relationships between greenhouse gas emissions, energy consumption and economic growth for 16 Asian countries over the period 1990-2012. The empirical findings suggest that in the long run, bidirectional Granger causality between energy consumption, GDP and greenhouse gas emissions and between GDP, greenhouse gas emissions and energy consumption is established. A non-linear, quadratic relationship is revealed between greenhouse gas emissions, energy consumption and economic growth, consistent with the environmental Kuznets curve for these 16 Asian countries and a subsample of the Asian new industrial economy. Short-run relationships are regionally specific across the Asian continent. From the viewpoint of energy policy in Asia, various governments support low-carbon or renewable energy use and are reducing fossil fuel combustion to sustain economic growth, but in some countries, evidence suggests that energy conservation might only be marginal. PMID- 29165398 TI - Synthesis of Spironucleosides: Past and Future Perspectives. AB - Spironucleosides are a type of conformationally restricted nucleoside analogs in which the anomeric carbon belongs simultaneously to the sugar moiety and to the base unit. This locks the nucleic base in a specific orientation around the N glycosidic bond, imposing restrictions on the flexibility of the sugar moiety. Anomeric spiro-functionalized nucleosides have gained considerable importance with the discovery of hydantocidin, a natural spironucleoside isolated from fermentation broths of Streptomyces hygroscopicus which exhibits potent herbicidal activity. The biological activity of hydantocidin has prompted considerable synthetic interest in this nucleoside and also in a variety of analogues, since important pharmaceutical leads can be found among modified nucleoside analogues. We present here an overview of the most important advances in the synthesis of spironucleosides. PMID- 29165400 TI - A New Synthetic Route to Polyhydrogenated Pyrrolo[3,4-b]pyrroles by the Domino Reaction of 3-Bromopyrrole-2,5-Diones with Aminocrotonic Acid Esters. AB - A new synthetic approach to polyfunctional hexahydropyrrolo[3,4-b]pyrroles was developed based on cyclization of N-arylbromomaleimides with aminocrotonic acid esters. A highly chemo- and stereoselective reaction is a Hantzsch-type domino process, involving the steps of initial nucleophilic C-addition or substitution and subsequent intramolecular nucleophilic addition without recyclyzation of imide cycle. PMID- 29165401 TI - Systematic Overview of Bacopa monnieri (L.) Wettst. Dominant Poly-Herbal Formulas in Children and Adolescents. AB - Background: The Ayurvedic medicinal system employs a holistic approach to health, utilising the synergistic properties of organic resources. Research into the Ayurvedic herb Bacopa monnieri (L.) Wettst. (B.monnieri) has reported improvements in cognitive outcomes in child and adult populations. The aim of current review is to systematically assess and critically summarize clinical trials investigating B.monnieri-dominant poly-herbal formulas and their effects on the cognition, memory, learning, and behaviour in children and adolescents. Methods: Key word searches were performed using PubMed, Scopus, Cochrane Library, DHARA, and CINAHL for publications meeting inclusion criteria up to November 2017. There were no restrictions in study design. Effect sizes were calculated for all significant findings to allow for direct comparisons, and each study was evaluated on design quality. Cognitive and behavioural outcomes were grouped into validated constructs for cross-study comparison. Results: Nine trials met inclusion criteria. Five studies reported sufficient data for effect size analysis with most improvements reported in behavioural outcomes. True cognitive abilities and behavioural constructs were reviewed in six studies, with visual perception, impulsivity, and attention demonstrating the greatest improvements. The veracity of the evidence for the formulations reviewed is weakened by inconsistent statistical design and under-reporting of safety and tolerability data (44%). Conclusions: The current review extends research supporting B.monnieri as a cognitive enhancer and provides modest evidence for the use of B.monnieri in poly-herbal preparations for improving cognitive and behavioural outcomes in child and adolescent populations. Greater emphasis on statistical vigour and the reporting of tolerability data are essential for future trials to adequately document poly-herbal treatment efficacy. PMID- 29165402 TI - Quercetin Mitigates Inflammatory Responses Induced by Vascular Endothelial Growth Factor in Mouse Retinal Photoreceptor Cells through Suppression of Nuclear Factor Kappa B. AB - Retinal vascular endothelial growth factor (VEGF) increased by neovascularization is well known as a pathogenic factor in ocular neovascular diseases. However, it is still unclear how retinal neurons are damaged by VEGF. The aims of this study are to demonstrate the inflammatory protein expression regulated by VEGF using mouse photoreceptor-derived cells and the protective effect of quercetin against VEGF-induced inflammatory response. Expression and phosphorylation of protein and expression of mRNA were detected by immunoblot and reverse transcriptase polymerase chain reaction. VEGF-induced degradation of limiting membrane and translocation of nuclear factor kappa B (NF-kappaB) were analyzed by immunocytochemistry. VEGF treatment activated angiogenic signaling pathway in photoreceptor cells. In addition, adhesion molecules and matrix metalloproteinases were increased in VEGF-treated photoreceptor cells. All these events were reversed by quercetin. Zona occludins-1 and beta-catenin decreased by VEGF were recovered by quercetin. NF-kappaB signaling pathway regulated by VEGF through phosphorylations of mitogen-activated protein kinases (MAPK) and protein kinase B (Akt) was suppressed by quercetin. These results suggest that quercetin suppressed VEGF-induced excessive inflammatory response in retinal photoreceptor cells by inactivation of NF-kappaB signals through inhibition of MAPKs and Akt. These data may provide a basic information for development of pharmaceuticals or nutraceuticals for treatment of retinal diseases caused by excessive VEGF. PMID- 29165403 TI - Multicenter (FX)n/NH3 Halogen Bonds (X = Cl, Br and n = 1-5). QTAIM Descriptors of the Strength of the X???N Interaction. AB - In the present work an in depth deep electronic study of multicenter XBs (FX)n/NH3 (X = Cl, Br and n = 1-5) is conducted. The ways in which X???X lateral contacts affect the electrostatic or covalent nature of the X???N interactions are explored at the CCSD(T)/aug-cc-pVTZ level and in the framework of the quantum theory of atoms in molecules (QTAIM). Calculations show that relatively strong XBs have been found with interaction energies lying between -41 and -90 kJ mol-1 for chlorine complexes, and between -56 and -113 kJ mol-1 for bromine complexes. QTAIM parameters reveal that in these complexes: (i) local (kinetics and potential) energy densities measure the ability that the system has to concentrate electron charge density at the intermolecular X???N region; (ii) the delocalization indices [delta(A,B)] and the exchange contribution [VEX(X,N)] of the interacting quantum atoms (IQA) scheme, could constitute a quantitative measure of the covalence of these molecular interactions; (iii) both classical electrostatic and quantum exchange show high values, indicating that strong ionic and covalent contributions are not mutually exclusive. PMID- 29165405 TI - Analysis of the Shear Behavior of Stubby Y-Type Perfobond Rib Shear Connectors for a Composite Frame Structure. AB - Shear connectors are used in steel beam-concrete slabs of composite frame and bridge structures to transfer shear force according to design loads. The existing Y-type perfobond rib shear connectors are designed for girder slabs of composite bridges. Therefore, the rib and transverse rebars of the conventional Y-type perfobond rib shear connectors are extremely large for the composite frames of building structures. Thus, this paper proposes stubby Y-type perfobond rib shear connectors, redefining the existing connectors, for composite frames of building structures; these were used to perform push-out tests. These shear connectors have relatively small ribs compared to the conventional Y-type perfobond rib shear connectors. To confirm the shear resistance of these stubby shear connectors, we performed an experiment by using transverse rebars D13 and D16. The results indicate that these shear connectors have suitable shear strength and ductility for application in composite frame structures. The shear strengths obtained using D13 and D16 were not significantly different. However, the ductility of the shear connectors with D16 was 45.1% higher than that of the shear connectors with D13. PMID- 29165406 TI - [The significance of fibroblasts in experimental modeling of proliferative vitreoretinopathy]. AB - AIM: to investigate the role of heterogeneous fibroblasts in the development of epiretinal membrane in eyes with modeled proliferative vitreoretinopathy. MATERIAL AND METHODS: The material for investigation were 6 eyes of 3 Chinchilla rabbits. Suspended fibroblasts (fibroblasts of the human skin - 200000 cells in 0.1 ml) were injected into the vitreous cavity via the pars plana. The animals were followed up for 1 month and then made out of the experiment. The eyes were enucleated and fixed in 10% neutral buffered formalin for routine histological examination. Microscopy was performed on the Leica system. RESULTS: The main clinical and morphological criteria for a rabbit model of PVR induced by intravitreal injection of heterogenic fibroblasts have been established: epiretinal membrane formation, changes in intraocular structures (the retinal pigment epithelium and retina), and inflammation (due to transplantation immunity). Particularities of the epiretinal membrane development and the role of different intraocular structures have been described. CONCLUSION: The experimental fibroblastic model of PVR reproduces the final, fibrous, stage of PVR, which is significant for efficacy evaluation of antiproliferative drugs. PMID- 29165407 TI - [Uveitis-associated HLA class 1 histocompatibility antigens]. AB - AIM: to evaluate the diagnostic and prognostic significance of HLA class 1 histocompatibility antigens in the development of anterior uveitis. MATERIAL AND METHODS: A total of 137 patients with anterior uveitis followed up at the Research Institute of Eye Diseases in 2009-2016 were tested for HLA antigens (A and B loci). The average patient's age was 29+/-12.4 years. All patients underwent a thorough medical interview with clinical and laboratory assessment. In case of suspected association with systemic disease, the patients were referred for consultation at the V.A. Nasonova Research Institute of Rheumatology. HLA typing was performed using a standard microlymphocytotoxicity test with specific anti-HLA sera (production of Gisans CC, Saint Petersburg). Statistical processing was performed with Statistica 6.0 software by applying methods of descriptive and nonparametric statistics (Mann-Whitney test). RESULTS: The results of HLA class 1 typing indicated a significant positive association between uveitis and the HLA-B27 antigen (p<0.00001). Moreover, there was a trend toward decreased frequencies of V7, B12, and B21 antigens (p=0.1), however, the changes were not statistically significant as compared to the control group. Other HLA class 1 antigens also did not differ significantly in frequency between uveitis patients and the controls. CONCLUSION: The study has confirmed an association between certain histocompatibility antigens and systemic diseases. However, a statistically reliable relationship has been established only for the HLA-B27 antigen. PMID- 29165408 TI - [Mitomycin C after endoscopic endonasal dacryocystorhinostomy]. AB - : Mitomycin-C (MMC) is the most frequently used agent for prevention of excessive scarring at the osteotomy site after endoscopic endonasal dacryocystorhinostomy (EEDCR), which, however, being applied during the final stage of the surgery, shows questionable effectiveness. AIM: to evaluate the effectiveness of a new administration route of mitomycin C in EEDCR. MATERIAL AND METHODS: The study included 86 patients (95 cases) in the age range of 62.3+/-9 years with primary acquired nasolacrimal duct obstruction. All patients underwent P.J. Wormald modification of EEDCR and were further divided into 2 groups. In group 1, MMC was injected into the nasal cavity and lacrimal sac mucosa, while in group 2 it was applied locally according to the standard procedure. To measure tissue concentrations of MMC, mucosal biopsies were taken in patients of Group 1. Systemic absorption of MMC was studied through blood samples in both groups. Clinical efficacy was assessed in 14+/-5 months after surgery. RESULTS: immediately after injection, the average tissue concentration of mitomicyn C in patients of Group 1, was 390+/-10 ug/g and 30 minutes later - 120+/-20 ug/g. No mitomycin C was found in Day 1 tissue samples and in any of the blood samples. Positive clinical results were reported in 97.9% of cases from Group 1 and in 87.2% of cases from Group 2. CONCLUSION: The method of injecting MMC during the final stage of EEDCR has proved clinically effective and safe and can be recommended for use in clinical practice. PMID- 29165409 TI - [Mo-dified scleral buckling for additional fixation of the retina with endovitreal magnetic implant (experimental study)]. AB - Scleral buckling (SB) has been regaining its popularity in the treatment of retinal detachments. On large clinical material, it has been proved to be the technique of choice in phakic patients with retinal detachment of moderate severity. A combined procedure that incorporates features of episcleral as well as intravitreal surgeries has also become widely used. Aim - to investigate the prospects for increasing technical potential of SB, particularly, to investigate the possibility of additional atraumatic mechanical fixation of the retina from within the vitreous cavity. The proposed device consists of an episcleral magnetic buckle and endovitreal magnetic buckles (endobuckles). The episcleral magnetic buckle is made of medical grade silicone and cannot be distinguished from common buckles, except that it contains one or more permanent magnets on the basis of neodymium-iron-boron powders. Endobuckles are small flat elastic elements made of silicone elastomer filled with magnetic particles. Endobuckles are implanted into the vitreous cavity through a small pars plana incision and placed on the retina at the projection of the scleral magnetic buckle. Thus, in experiments with cadaver eyes, the authors have showed the principle feasibility of retinal fixation by the force of magnetic interaction between the magnetic scleral buckle and endobuckles. The described technique of additional mechanical fixation of the retina provides wider surgical opportunities in the management of retinal detachments. PMID- 29165410 TI - [Surgical treatment of purulent corneal ulcers in eyes with neurotrophic keratitis and paralytic lagophthalmos]. AB - AIM: to develop a surgical approach to the treatment of purulent corneal ulcer in eyes with neurotrophic keratitis with lagophthalmos after auditory neuroma removal or stroke. MATERIAL AND METHODS: A total of 12 patients (13 eyes) have been managed. All received combined surgery that included simultaneous keratoplasty, autoconjunctivoplasty, and permanent partial tarsorrhaphy. RESULTS: Ocular integrity was preserved in all cases, and also vision - in half of them. In 29% of cases, visual acuity increased from 0.09+/-0.05 up to 0.21+/-0.13. Lagophthalmos decreased from 5.86+/-1.35 mm down to 3.01+/-0.75 mm. CONCLUSION: Patients with intracranial lesions complicated by neurotrophic keratitis and lagophthalmos often develop progressive purulent ulcers of the cornea. One-step keratoplasty, autoconjunctivoplasty, and permanent partial tarsorrhaphy is an effective treatment that can help preserve visual function in such eyes. PMID- 29165404 TI - Benefits of Nut Consumption on Insulin Resistance and Cardiovascular Risk Factors: Multiple Potential Mechanisms of Actions. AB - Epidemiological and clinical studies have indicated that nut consumption could be a healthy dietary strategy to prevent and treat type 2 diabetes (T2DM) and related cardiovascular disease (CVD). The objective of this review is to examine the potential mechanisms of action of nuts addressing effects on glycemic control, weight management, energy balance, appetite, gut microbiota modification, lipid metabolism, oxidative stress, inflammation, endothelial function and blood pressure with a focus on data from both animal and human studies. The favourable effects of nuts could be explained by the unique nutrient composition and bioactive compounds in nuts. Unsaturated fatty acids (monounsaturated fatty acids and polyunsaturated fatty acids) present in nuts may play a role in glucose control and appetite suppression. Fiber and polyphenols in nuts may also have an anti-diabetic effect by altering gut microbiota. Nuts lower serum cholesterol by reduced cholesterol absorption, inhibition of HMG-CoA reductase and increased bile acid production by stimulation of 7-alpha hydroxylase. Arginine and magnesium improve inflammation, oxidative stress, endothelial function and blood pressure. In conclusion, nuts contain compounds that favourably influence glucose homeostasis, weight control and vascular health. Further investigations are required to identify the most important mechanisms by which nuts decrease the risk of T2DM and CVD. PMID- 29165411 TI - [Peripheral refraction and retinal contour in congenital and acquired high myopia]. AB - AIM: to perform a comparative study of peripheral refraction and retinal contour in patients with congenital versus acquired high myopia. MATERIAL AND METHODS: A total of 30 patients (60 eyes) with high myopia aged 8 to 18 years (11.2+/-0.32 years on average) were examined. The patients were divided into 2 groups. Group 1 consisted of 21 patients (42 eyes) with acquired myopia of -6.0 to -10.25 diopters (-7.55+/-0.17 diopters on average), group 2 - of 9 patients (18 eyes) with congenital myopia of -8.75 to -28.75 diopters (-16.39+/-1.24 diopters on average). Using the Grand Seiko WR-5100K binocular open-field autoref/keratometer (Japan), relative peripheral refraction was assessed with account to relative peripheral eye length measured by the IOL Master partial coherent interferometer ('Carl Zeiss', Germany) at 15 degrees and 30 degrees nasally and temporally from the foveal center along the horizontal meridian. RESULTS: In acquired myopia, relative peripheral refraction and relative peripheral eye length readings evidenced the formation of peripheral hyperopic defocus in all examined zones. Congenital high myopia cases were notable for myopic defocus at 15 degrees of the nasal retina (N15 zone): -0.67+/-0.33 diopters against the eye length change of -0.33+/-0.13 mm. CONCLUSION: The research helped identify retinal contour changes characteristic of congenital myopia and indicative of posterior pole irregularity. PMID- 29165412 TI - [Stabilizing effectiveness of orthokeratology and long-term minute-concentration atropine therapy in myopia (draft report)]. AB - : The rational for the study was the high prevalence of myopia in the world. According to the World Health Organization (WHO), myopia is one of the five leading causes of blindness and low vision. Of recent reports on conservative measures for the stabilization of myopia, two areas of investigation deserve attention: methods of optical correction that affect peripheral refraction, orthokeratology lenses (OKL) in particular, and pharmacotherapy. The aim of the study was to evaluate the effectiveness and safety of myopia control in pediatric patients by combining two methods - OKL wearing and instillation of extra low doses of atropine (0.01%). MATERIAL AND METHODS: Within a prospective cohort study, 31 patients (62 eyes) aged 8 to 14 years with acquired myopia of low 14 (28), medium 11 (22), or high 6 (12) degree, were examined before and 6 months after adding 0.01% atropine instillations to OKL wearing. Refraction (Huvitz MRK 3100P), axial eye length (IOL-Master, 'CarlZeiss', Germany), absolute accommodation (Grand Seiko WRK-5100K), accommodative reserves, and pseudoaccommodation were assessed. RESULTS: The most significant effect on reducing the rate of disease progression was observed in patients with low and moderate myopia (1.5 and 1.7 times, correspondingly, p<0.05). In high myopia no reliable changes were noticed. Obviously, the inhibitory effect of OKL, which is conditioned by optical factors (peripheral myopic defocus in particular), even in combination with atropine, is not able to stop the progression of high myopia, which is based on structural and biomechanical changes of the sclera. CONCLUSION: Judging from these preliminary results, one should not claim 100% effectiveness of prolonged minute-concentration atropine use, however, the positive effect exists and the study continues. PMID- 29165413 TI - [Ophthalmoferon efficacy in the treatment of children with chronic blepharoconjunctivitis]. AB - AIM: To study possibilities of using the medication Ophthalmoferon in the treatment of children with chronic allergic and Demodex blepharoconjunctivitis. MATERIAL AND METHODS: We examined 40 children (80 eyes) aged 3 to 17 years with chronic allergic (group I) and Demodex (group II) blepharoconjunctivitis. Each group was divided into two subgroups ('A' and 'B') respectively based on the treatment regimen used. Subgroup 'A' patients received Ophtalmoferon instillations (four times per day for four weeks) in addition to the standard therapy, whereas subgroup 'B' patients got only basic treatment of blepharoconjunctivitis. The latter included eyelids' ciliary edge massage, eyelids' free edge hygienic treatment, artificial tears instillations and oral intake of the medications, like enterosorbents, probiotics, enzymes and anti allergic remedies. We evaluated the dynamics of subjective and objective blepharoconjunctivitis signs at 1,2,4 and 6 follow-up weeks. The dynamics of eosinophils content in cytograms as well as the dynamics of acarograms were also assessed. RESULTS: From the first treatment week in all patients, regardless of the treatment regimen used, we noted a statistically significant positive change in all subjective and the majority of objective blepharoconjunctivitis clinical manifestations, such as eyelids' edge and conjunctiva hyperemia and eyelid swelling. In patients with allergic and Demodex blepharoconjunctivitis, who received the medication Ophtalmoferon, a significantly more positive result was observed after the first treatment week, by comparing with the control group (p<0,01). The significant difference in the parameters of both comparison subgroups persisted for two weeks. There was a significant difference in the acarogram values, when Ophtalmoferon was used. A further decrease in the cellular infiltration of the conjunctiva by eosinophils was revealed in patients, who additionally used Ophthalmoferon, but without significant differences in parameters. There were no adverse effects in all cases, when the given medication was used. CONCLUSION: Our study results allow us to recommend the medication Ophtalmoferon for a wide clinical use in children with chronic allergic and Demodex blepharoconjunctivitis. PMID- 29165414 TI - [Torpedo macu-lopathy (clinical case)]. AB - The article presents a clinical case of torpedo maculopathy. This congenital disorder is most likely to be caused by changes in the retinal pigment epithelium (RPE) during retinal fissure closure. Visual function is usually unaffected and the condition is revealed at routine ophthalmic examination in children and teens. Optical coherence tomography showed the absence of RPE, photoreceptor damage, and massive thinning of the outer nuclear layer at the diseased site without a significant change in the total retinal thickness. RPE involvement was also evidenced by changes in fundus autofluorescence. PMID- 29165415 TI - [The potential of ectoprosthetics in rehabilitation of patients with orbital pathology]. AB - AIM: rectification of indications and contraindications for ectoprosthetics and exploration of its potential as a modern rehabilitation modality. MATERIAL AND METHODS: Here are summarized the results of 89 cases of facial reconstruction with prosthetic means in trauma patients and those who had had congenital or oncological pathology and in whom other methods of rehabilitation were unable to remedy the defect within the orbital region. RESULTS: The indications and contraindications for facial prosthetics as well as the conditions, under which this type of medical and social rehabilitation can be carried out, were clarified. The authors also explained the process of creating an epiprosthesis and how it should be attached to the orbit to have the maximum effect on the existing defects of both the bone and auxiliary apparatus (including eyelid soft tissues, eyelashes, etc.). Because modern ectoprostheses are made of silicone and held in place with magnets, they provide an optimal cosmetic result, so that, regardless of patient's age, no rough defects can be detected on the affected side at a 2-m distance. CONCLUSION: As the production technology develops, the cosmetic appearance of epiprostheses improves and their use broadens. PMID- 29165416 TI - [A case of progressive glaucoma against the background of chronic constipation]. AB - The authors describe a case of severe glaucoma in the only seeing eye of a patient with venous circulation disturbance resulting from a chronic anal fissure complicated with progressive anal stenosis, severe sphincter spasm, and pain syndrome. The article presents the results of multiple clinical ophthalmological tests and instrumental examinations performed before and after surgical intervention that evidence the importance of venous circulation disturbances for glaucoma development. PMID- 29165417 TI - [Pterygium: etiology, pathogenesis, treatment]. AB - Pterygium is a degenerative condition characterized by fibrovascular outgrowth of conjunctiva over the cornea. Many theories exist that try to explain its pathogenesis. The current belief is that this disease is multifactorial with ultraviolet radiation being the most important trigger. Attention is also paid to such factors as tear film changes, cytokines and growth factors disbalance, immunologic disturbances, genetic mutations, and viral infections. Modern classifications consider the rate of fibrovascular growth, its progressive potential, and histological features. In the beginning pterygium is usually asymptomatic, however, dry eye manifestations may be present, such as burning, itching, and/or tearing. As the lesion grows toward the optical zone, visual acuity gets compromised, and thus, surgical treatment is required. Because of recurrences and repeated surgeries, the growth of the lesion may become more aggressive and cause irregular astigmatism. Comprehensive surgery of pterygium is aimed at not only removing the lesion, but also preventing recurrences. Advisable are modified bare sclera techniques with subsequent transposition of the conjunctival flap, conjunctival autotransplantation, amniotic membrane transplantation, and peripheral lamellar keratoplasty (in cases of significant ingrowth). In some cases, antirecurrent adjuvant therapy may be considered that involves the use of mitomycin C, 5-fluoruracil, and VEGF inhibitors. However, the search for the best treatment for pterygium, i.e. an easy to perform, cosmetically-friendly method associated with minimal risk of recurrences and/or complications, remains an interest of modern ophthalmology. PMID- 29165418 TI - [Corneal transparency: anatomical basis and evaluation methods]. AB - Being just a relatively small part of the fibrous tunic of the eyeball, the cornea is, nevertheless, unique in terms of the variety of its functions. Because the cornea differs significantly from other protective frames in its structure, it provides the possibility of light transmission and strong refraction that largely contributes to the total refraction of the eye. The development of ophthalmology is impossible without improving methods of adequate anatomical and functional assessment of the eye not only as a whole, but also as a collection of interacting structures.In this regard, examination methods of the cornea have undergone significant advances in recent years. So far, the level of corneal transparency has been judged by biomicroscopy findings or indirect characteristics (thickness, structure, etc.). Confocal microscopy of the cornea and wave-based examinations involving one of the available laser interferometers (OCT or HRT) are also used. However, the data obtained with these methods resembles that of layer-specific reflectometry, i.e. the magnitude of directed reflection of the light beam from corneal corpuscles, which does not completely agree with the classical idea of transparency. PMID- 29165419 TI - [Capsule contraction syndrome in pseudophakia]. AB - This is a review of the literature on capsule contraction syndrome (CCS) in pseudophakic patients that involves severe fibrosis along the margin of the anterior capsule's opening and progressive contraction of the capsular bag. Possible causes of CCS and principles of its prevention and treatment have been analyzed. PMID- 29165420 TI - [Clinical features and diagnosis of diabetic polyneuropathy]. AB - Diabetic polyneuropathy (DPN) is a serious complication of diabetes that leads to early disability in patients if late diagnosed. There has been a lot of research into pathophysiological mechanisms of nerve fiber damage and risk factors for neurological complications of diabetes. Early diagnosis of the latter is quite a challenge and, thus, the problem of finding more reliable diagnostic modalities is rather pressing. In this review, an interdisciplinary approach to the said problem, high-end diagnostic methods, and clinical features of DPN are described. PMID- 29165421 TI - [Outcomes of intraocular lens implantation in the absence of capsular support: a review of current literature]. AB - : The prevalence of complications associated with the deficiency or absence of capsular support in cataract patients is 5-15%. Moreover, approximately 20% of patients have an inconspicuous zonular weakness, which is often left undetected preoperatively. AIM: to classify and comparatively analyze the latest published data on the outcomes of various kinds of complicated cataract surgery. MATERIAL AND METHODS: Analysis of available literature on the subject of research published in 2003-2016. RESULTS: The method of sutured scleral fixation of the intraocular lens (IOL) is the most fully covered in the current literature. It has been used long enough and is, therefore, well tested. Its typical complications include sutures degradation, hemorrhage, and inflammation. Sutureless fixation of the IOL, which has become more common in recent years, is free of complications associated with degradation of the sutures. However, studies on the long-term results of this technique are few and most of them were conducted in a small clinical material. CONCLUSION: Basing on the present analysis, one may conclude that at the current level of surgery, sutureless scleral and iridal fixation of the IOL is more preferable in terms of possible postoperative complications. PMID- 29165422 TI - Biomarkers for neonatal therapeutic studies: time for a public-private partnership. PMID- 29165423 TI - Meeting report: a hard look at the state of enamel research. AB - The Encouraging Novel Amelogenesis Models and Ex vivo cell Lines (ENAMEL) Development workshop was held on 23 June 2017 at the Bethesda headquarters of the National Institute of Dental and Craniofacial Research (NIDCR). Discussion topics included model organisms, stem cells/cell lines, and tissues/3D cell culture/organoids. Scientists from a number of disciplines, representing institutions from across the United States, gathered to discuss advances in our understanding of enamel, as well as future directions for the field. PMID- 29165425 TI - RNA metabolism: The short tail that wags the mRNA. PMID- 29165424 TI - Functional 5' UTR mRNA structures in eukaryotic translation regulation and how to find them. AB - RNA molecules can fold into intricate shapes that can provide an additional layer of control of gene expression beyond that of their sequence. In this Review, we discuss the current mechanistic understanding of structures in 5' untranslated regions (UTRs) of eukaryotic mRNAs and the emerging methodologies used to explore them. These structures may regulate cap-dependent translation initiation through helicase-mediated remodelling of RNA structures and higher-order RNA interactions, as well as cap-independent translation initiation through internal ribosome entry sites (IRESs), mRNA modifications and other specialized translation pathways. We discuss known 5' UTR RNA structures and how new structure probing technologies coupled with prospective validation, particularly compensatory mutagenesis, are likely to identify classes of structured RNA elements that shape post-transcriptional control of gene expression and the development of multicellular organisms. PMID- 29165428 TI - Chromosome biology: Spindle asymmetry drives selfish segregation. PMID- 29165426 TI - The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. AB - Mitochondrial function declines during ageing owing to the accumulation of deleterious mitochondrial genomes and damage resulting from the localized generation of reactive oxygen species, both of which are often exacerbated in diseases such as Parkinson disease. Cells have several mechanisms to assess mitochondrial function and activate a transcriptional response known as the mitochondrial unfolded protein response (UPRmt) when mitochondrial integrity and function are impaired. The UPRmt promotes cell survival and the recovery of the mitochondrial network to ensure optimal cellular function. Recent insights into the regulation, mechanisms and functions of the UPRmt have uncovered important and complex links to ageing and ageing-associated diseases. In this Review, we discuss the signal transduction mechanisms that regulate the UPRmt and the physiological consequences of its activation that affect cellular and organismal health during ageing. PMID- 29165429 TI - Air temperature exposure and agricultural occupational injuries in the Autonomous Province of Trento (2000-2013, North-Eastern Italy). AB - OBJECTIVES: The aim of this study was to evaluate the relationship between high air temperatures and occupational injuries (OIs) occurred during the summer seasons 2000-2013 in agricultural workers from the Autonomous Province of Trento (APT), North-Eastern Italy. MATERIAL AND METHODS: Data about OIs for the APT from 2000 to 2013 occurring during the warm season (N = 7325) was provided by the National Institute of Insurance for Occupational Illness and Injury. Daily average and daily maximum temperatures values for the specific geographical site of events were retrieved. Daily temperatures were then assessed in 3 time lags: for the day of the event (lag 0), and for the previous 24 h (lag 1) and 48 h (lag 2). Daily temperatures were then categorized in 3 exposure groups (< 75th, 75 95th and > 95th percentiles). The risk of OIs was assessed as odds ratio (OR) calculated through a Poisson regression model controlled for age, sex, ethnicity and time period, and assuming OI rates for days on which temperature was comprised in < 75th percentile exposure groups as the referent ones. RESULTS: Estimated incidence of OIs during the study period was 3.4+/-2.3 events/day. The peak of work-related accidents occurred on days characterized by severe thermal conditions, and in particular during heat waves (incidence rate ratio = 1.09, 95% confidence interval (CI): 1.02-1.17, p = 0.0165). Days having temperatures higher than 95th percentile, assessed as daily average, both on current days (OR = 1.119, 95% CI: 1.008-1.242) and in lag 1 (OR = 1.125, 95% CI: 1.013-1.249), as well as daily maximum temperatures, were at the highest risk of work-related injuries (OR = 1.144, 95% CI: 1.029-1.272). CONCLUSIONS: In conclusion, presented findings recommend policymakers to develop appropriate warning/alert systems for agricultural workers regarding high environmental temperatures. Int J Occup Med Environ Health 2018;31(3):317-331. PMID- 29165427 TI - Sphingolipids and their metabolism in physiology and disease. AB - Studies of bioactive lipids in general and sphingolipids in particular have intensified over the past several years, revealing an unprecedented and unanticipated complexity of the lipidome and its many functions, which rivals, if not exceeds, that of the genome or proteome. These results highlight critical roles for bioactive sphingolipids in most, if not all, major cell biological responses, including all major cell signalling pathways, and they link sphingolipid metabolism to key human diseases. Nevertheless, the fairly nascent field of bioactive sphingolipids still faces challenges in its biochemical and molecular underpinnings, including defining the molecular mechanisms of pathway and enzyme regulation, the study of lipid-protein interactions and the development of cellular probes, suitable biomarkers and therapeutic approaches. PMID- 29165430 TI - Subcutaneous administration of infliximab-attenuated silica-induced lung fibrosis. AB - OBJECTIVES: To investigate the influence of the anti-tumor necrosis factor-alpha infliximab (IFX) in the case of rats with silicosis. MATERIAL AND METHODS: Forty eight Wistar rats were randomly divided into 3 groups. The study group (N = 16) - silicosis was induced by intratracheal instillation of 50 mg silica on day 1, and IFX was subcutaneously administered at a dose of 15 mg/kg of body weight from day 2 to day 6, the vehicle group (N = 16) - silica used as the study group but without IFX, the sham group (N = 16) - 1 ml of saline was intratracheal-used. Eight rats in each group were euthanized on day 7 and on day 14, respectively. Lung tissue sections were stained with hematoxylin and eosin or Masson's trichromedye. The nuclear factor-kappaB p65 (NF-kappaB p65) positioning in the lung tissues were determined by immunohistochemical staining. Levels of tumor necrosis factor alpha (TNF-alpha) in rat serum and bronchoalveolar lavage fluid were measured with enzyme linked immunosorbent assay. The inducible nitric oxide synthase (iNOS) mRNA in the lung tissues was measured by quantitative real-time polymerase chain reaction, as well as inhibitor protein-kappaB (I-kappaB) and NF kappaB p65 expression were measured quantitatively by western blotting. RESULTS: Silica installation increased the lung tissues inflammation reaction, oxidative stress and pulmonary fibrosis. Infliximab treatment significantly improved silica induced lung pathological changes (inflammatory cells, collagen deposition), decreased the TNF-alpha inhibited NF-kappaB signaling (I-kappaB, NF-kappaB p65) as well as oxidant status (iNOS). CONCLUSIONS: Infliximab may improve silica induced pulmonary inflammation by decreasing the TNF-alpha, inhibiting NF-kappaB signaling (I-kappaB, NF-kappaB p65) as well as oxidant status (iNOS), which suggest that IFX has potential role in the treatment of silica-induced lung damage. Int J Occup Med Environ Health 2018;31(4):503-515. PMID- 29165431 TI - Spinal accessory nerve preservation in modified neck dissections: surgical and functional outcomes. AB - The spinal accessory nerve (SAN) or XI cranial nerve is frequently encountered during neck surgery, and as such is at risk of iatrogenic injury, resulting in "shoulder syndrome". Modified neck dissection (MND) with preservation of the SAN is based on desire to minimise the functional deformity associated with section of the eleventh nerve. The aim of this study was to analyse the intra-operative variations of the spinal accessory nerve pathway and to evaluate shoulder dysfunction postoperatively. The cross-sectional demonstration analysis was created through the medical records retrospectively of 165 consecutive patients who underwent neck dissections at our institution in the past 5 years with attention to ultrasound and MRI preoperative findings, type of neck dissection, type of identification and dissection of SAN, postoperative morbidity and survival rate. The safest identification of SAN is in the posterior neck triangle where it may be recognised exiting from the posterior border of the sternocleidomastoid muscle (SCM) at Erb's point. For exact preoperative planning, ultrasound and MRI are superior to determine the position of the eleventh nerve. The mean distance between the greater auricular point and the SAN was 0.90 cm. Average length of the trunk from Erb's point until the penetration in the trapezius muscle was around 5.1 cm, ranging from 4.8 to 5.4 cm. The diversity in the course from the posterior border of the SCM and posterior neck triangle was confirmed in 9 cases (15%), predominantly at the level of entering the posterior neck triangle. The frequency of postoperative morbidity of SAN was 46.7% for radical neck dissections, 42.5% for selective neck dissections and 25% for MND. For each separate type of dissection, different subtypes were included. Identification of the SAN over established landmarks is unconditionally reliant on the exact preoperative mapping of the nerve with imaging diagnostics. MND has similar regional control rates to more comprehensive operations in appropriately selected patients and significantly reduces the risk of functional disability. PMID- 29165432 TI - Parotid tumours: clinical and oncologic outcomes after microscope-assisted parotidectomy with intraoperative nerve monitoring. AB - Temporary and permanent facial nerve dysfunctions can be observed after parotidectomy for benign and malignant lesions. Intraoperative nerve monitoring is a recognised tool for the preservation of the nerve, while the efficacy of the operative microscope has been rarely stated. The authors report their experience on 198 consecutive parotidectomies performed on 196 patients with the aid of the operative microscope and intraoperative nerve monitoring. 145 parotidectomies were performed for benign lesions and 53 for malignancies. Thirteen patients treated for benign tumours experienced temporary (11 cases) or permanent facial palsy (2 cases, both of House-Brackmann grade II). Ten patients with malignant tumour presented with preoperative facial nerve weakness that did not improve after treatment. Five and 6 patients with malignant lesion without preoperative facial nerve deficit experienced postoperative temporary and permanent weakness respectively (the sacrifice of a branch of the nerve was decided intraoperatively in 2 cases). Long-term facial nerve weakness after parotidectomy for lesions not directly involving or originating from the facial nerve (n = 185) was 2.7%. Patients treated for benign tumours of the extra facial portion of the gland without inflammatory behaviour (n = 91) had 4.4% facial nerve temporary weakness rate and no permanent palsy. The combined use of the operative microscope and intraoperative nerve monitoring seems to guarantee facial nerve preservation during parotidectomy. PMID- 29165433 TI - Management of free flap failure in head and neck surgery. AB - Free flap surgery is overall considered the gold standard in head and neck reconstruction, with a success rate of 95%. The management of a total flap necrosis and which solution, between a pedicled or a second free flap, is safer for a salvage procedure is still controversial. Object of this study is to describe the authors' management of total free flap loss in head and neck reconstruction and compare the choices and results to those reported in the literature. From January 2012 to January 2016, 149 consecutive free flaps were performed at the Maxillo- Facial Operative Unit of the Hospital Casa Sollievo della Sofferenza in San Giovanni Rotondo (Italy) for reconstruction of head and neck defects. Of these, 6 flaps were lost due to a total necrosis. In 5 cases it was decided to harvest a second free flap, and in the remaining patient a temporalis muscle flap was used. All the free salvage flaps were successful, without complications and with a good aesthetic and functional recovery. Analysing the data obtained, and comparing them with those reported in the literature, it can be concluded that a second subsequent free flap can be considered an ideal and safe procedure in salvage surgery. PMID- 29165434 TI - Clinical analysis of Hashimoto thyroiditis coexistent with papillary thyroid cancer in 1392 patients. AB - Papillary thyroid carcinoma (PTC) is the most common malignant tumour of the thyroid. The effect of the concurrent presence of Hashimoto's thyroiditis (HT) and PTC is still under debate. The aim of this study is to investigate the influence of coexistent HT on prognostic outcomes and the association of coexistent HT with clinicopathological features. The demographic and clinicopathological data of 1,392 patients who underwent surgery in our hospital from 2007 to 2016 was collected and analysed. Among 1,392 PTC patients, the rate of HT was 25.6%. There were significant differences in the mean levels of thyroid stimulating hormone (3.27 vs. 2.41 MUIU/L, p < 0.01), thyroperoxidase antibodies (110.31 vs. 131.2 U/ml, p < 0.01) and thyroglobulin antibodies (131.90 vs. 113.53 ng/ml, p < 0.01) between the two groups. PTC patients with HT had the following characteristics compared to patients without HT: smaller tumour size (p < 0.01), female predominance (p < 0.01) and higher rate of multifocality (p = 0.024). In addition, patients with HT had a significantly lower rate of lymph node metastasis (LNM) and advanced TNM stage than patients without HT (all p < 0.01). Multivariate analysis found that both age and multifocality were significantly associated with central LNM in HT patients (p < 0.01, p = 0.019, respectively). Extrathyroidal invasion and TSH level were also significant independent factors for lateral LNM in HT patients (p < 0.008, p = 0.04, respectively). HT is associated with a significantly higher risk of PTC. The coexistence of HT in PTC patients is associated with favourable clinical outcomes compared to PTC without HT. Total thyroidectomy and prophylactic central compartment lymphadenectomy should be a choice for PTC patients with HT. PMID- 29165435 TI - There is no correlation between signs of reflux laryngitis and reflux oesophagitis in patients with gastro-oesophageal reflux disease symptoms. AB - The objective of the present study was to determine if there is correlation between signs of reflux laryngitis (RL) and reflux oesophagitis (RE) in patients with gastro-oesophageal reflux disease (GORD) symptoms. Laryngeal photography obtained from patients during oesophagogastroduodenoscopy were examined by two otolaryngologists experienced in the field of extra-oesophageal reflux regarding the presence and severity of RL. The presence of RE was evaluated by gastroenterologist. Smokers, heavy drinkers and patients with bronchial asthma were excluded from the statistical analysis. A total of 681 patients were analysed. RL was diagnosed in 367 (53.9%) cases, of whom 182 patients had mild, 118 moderate and 67 severe (Reflux Finding Score > 7) RL. RE was diagnosed in 103 (28.1%) patients with RL and in 80 (25.7%) patients without RL. Neither the difference between the overall group of patients with RL and those without (OR 1.141, 95% CI 0.811-1.605, p = 0.448), nor the differences between the respective subgroups of patients with mild, moderate and severe RL and those without RL were statistically significant. The OR and 95% CI for mild, moderate and severe RL were 1.042, 95% CI 0.712-1.526, p = 0.834, 1.182, 95% CI 0.764-1.831, p = 0.453 and 1.0, 95% CI 0.566-1.766, p = 0.999 respectively. It can be concluded that there is no correlation between RL and RE in patients with GORD symptoms. PMID- 29165436 TI - Cochlear implant in prelingually deafened oralist adults: speech perception outcomes, subjective benefits and quality of life improvement. AB - The aim of this study is to report our results in a group of prelingually deafened adults, who followed an oralist rehabilitation programme, and submitted to cochlear implant at our institution. We evaluated 30 prelingually deafened adult patients, 18 males and 12 females, median age 35 years, of a group of 36 prelingually deafened adult patients consecutively submitted to unilateral cochlear implantation at the ENT Unit of the University of Pisa. After implantation, patients achieved significant benefits in terms of speech perception skills, including the ability to have telephone conversations in some cases, quality of life and their own perception of disability. According to literature data, the results herein reported are quite variable but generally satisfactory. Procedures other than traditional speech perception measures should be used to evaluate the benefits of cochlear implant in such patients, to compressively evaluate the global benefits, not only in terms of speech perception, but also in terms of quality of life and daily life. PMID- 29165437 TI - Endolymphatic sac tumour in von Hippel-Lindau disease: management strategies. AB - Endolymphatic sac tumour (ELST) is infrequent, as emerges from small series reported in the literature. It is a slow-growing malignancy with local aggressiveness and a low risk of distant metastases. It is often misdiagnosed because of the late onset of symptoms and difficulty in obtaining a biopsy. Its frequency is higher in von Hippel-Lindau (VHL) disease (a genetic systemic syndrome involving multiple tumours), with a prevalence of around 25%. The diagnosis is based on radiology, with specific patterns on contrast-enhanced MRI and typical petrous bone erosion on bone CT scan. Our experience of ELST in the years between 2012-2015 concerns 7 cases, one of which was bilateral, in patients with VHL disease. Four of the 7 patients underwent 5 surgical procedures at our institution. Each case is described in detail, including clinical symptoms, and the intervals between symptom onset, diagnosis and therapy. Postoperative morbidity was low after early surgery on small tumours, whereas extensive surgery for large tumours was associated with loss of cranial nerve function (especially VII, IX, X). The critical sites coinciding with loss of neurological function were the fallopian canal, jugular foramen, petrous apex and intradural extension into the posterior cranial fossa. Early surgery on small ELST is advocated for patients with VHL disease, in whom screening enables a prompt diagnosis and consequently good prognosis. PMID- 29165439 TI - Proteomic signatures differentiating Bacillus anthracis Sterne sporulation on soil relative to laboratory media. AB - The process of sporulation is vital for the stability and infectious cycle of Bacillus anthracis. The spore is the infectious form of the organism and therefore relevant to biodefense. While the morphological and molecular events occurring during sporulation have been well studied, the influence of growth medium and temperature on the proteins expressed in sporulated cultures is not well understood. Understanding the features of B. anthracis sporulation specific to natural vs. laboratory production will address an important question in microbial forensics. In an effort to bridge this knowledge gap, a system for sporulation on two types of agar-immobilized soils was used for comparison to cultures sporulated on two common types of solid laboratory media, and one liquid sporulation medium. The total number of proteins identified as well as their identity differed between samples generated in each medium and growth temperature, demonstrating that sporulation environment significantly impacts the protein content of the spore. In addition, a subset of proteins common in all of the soil-cultivated samples was distinct from the expression profiles in laboratory medium (and vice versa). These differences included proteins involved in thiamine and phosphate metabolism in the sporulated cultures produced on soils with a notable increase in expression of ATP binding cassette (ABC) transporters annotated to be for phosphate and antimicrobial peptides. A distinct set of ABC transporters for amino acids, sugars and oligopeptides were found in cultures produced on laboratory media as well as increases in carbon and amino acid metabolism-related proteins. These protein expression changes indicate that the sporulation environment impacts the protein profiles in specific ways that are reflected in the metabolic and membrane transporter proteins present in sporulated cultures. PMID- 29165438 TI - Our experience in the surgical management of craniofacial fibrous dysplasia: what has changed in the last 10 years? AB - The mainstay of treatment of craniofacial dysplasia (CFD) remains surgery once clinical observation has been excluded. Nevertheless, disagreement remains about the type of surgical intervention (remodelling versus radical resection). The aim of this paper is to present our experience until 2013 comparing CFD management between 1980 and 2002 and between 2003 and 2013 and to propose our surgical algorithm. From January 2003 to December 2013, 41 new patients (18 males and 23 females) with histologically demonstrated CFD presented to our Department. Data were compared with those of 95 patients observed and/or treated between 1980 and 2002. Considering the last period, we noted that observation (26/41 patients) was the most used method; radical resection was performed in most cases (8/15 patients), but in proportion the numbers of patients undergoing bone shaving has increased (6% between 1980 and 2002 vs 15% between 2003 and 2013), while a decrease in the number of patients undergoing excision was seen (63% between 1980 and 2002 vs. 19% between 2003 and 2013). On this basis, we believe that radical resection is the only technique to obtain resolution of fibrous dysplasia. Wait and-see is indicated in case of stable lesions. Reconstructive techniques allow obtaining adequate aesthetical and functional results; nevertheless, in most cases adjunctive surgical refinements are required and recovery time is higher than with surgical shaving, so that most patients prefer to perform remodelling. Nevertheless, in case of aggressive lesions radical resection is mandatory, except in paediatric patients with residual large defects in which it can be acceptable to try to resolve symptoms via bone shaving, reserving more aggressive treatments in case of relapse or after skeletal maturity. PMID- 29165440 TI - Dynamic characterization of drug resistance and heterogeneity of the gastric cancer cell BGC823 using single-cell Raman spectroscopy. AB - Drug resistance and heterogeneous characteristics of human gastric carcinoma cells (BGC823) under the treatment of paclitaxel (PTX) were investigated using single-cell Raman spectroscopy (RS). RS of normal and drug-resistant BGC823 cells (DR-BGC823) were collected and analyzed using arithmetic, statistic and individual spectrum analysis. The dynamic effects of paclitaxel (PTX) in normal and DR-BGC823 cells were evaluated dynamically. The RS intensity changed with PTX over time and produced distinct different results for the two types of cells. The average RS intensities of the normal BGC823 cells initially decreased and then increased under PTX treatment after 24 hours. In contrast, upon exposure to PTX, the average intensity of the DR-BGC823 cells initially increased within 12 hours and then gradually decreased and approached a steady state. The temporal variation of the typical component in the cells was analyzed by comparing the ratios between Raman bands. More importantly, the heterogeneous characteristics of the BGC823 cells under PTX treatment were quantified and clustered using hierarchical trees combined with RS intensity changes. The 'outlier' cells related to drug resistance were discriminated. The heterogeneity of the normal BGC823 cells under drug treatment gradually appeared over time, and was evaluated with the eigenvalues of principal component analysis (PCA). Our study indicates that single-cell RS may be useful in systematically and dynamically characterizing the drug response of cancer cells at the single-cell level. PMID- 29165441 TI - DNA-crowded enzyme complexes with enhanced activities and stabilities. AB - We present a robust and simple method to prepare DNA-crowded enzyme complexes by directly assembling long DNA duplexes on the enzyme surface. DNA-crowded enzyme complexes show boosted substrate turnover numbers, and increased stabilities against various storage conditions. They could be potentially scaled up for applications in biomaterials and biotechnology. PMID- 29165442 TI - Continuous multi-step synthesis by extrusion - telescoping solvent-free reactions for greater efficiency. AB - Chemical manufacturing typically requires more than one step, involving multiple batch processes, which makes synthesis at scale laborious and wasteful. Herein, we demonstrate that several reactions can be telescoped into a single continuous process and/or be carried out as a continuous multi-component reaction (MCR), by twin screw extrusion (TSE), in the complete absence of solvent. PMID- 29165443 TI - A magnetic nanoparticle-supported N-heterocyclic carbene-palladacycle: an efficient and recyclable solid molecular catalyst for Suzuki-Miyaura cross coupling of 9-chloroacridine. AB - A robust magnetic nanoparticle-supported N-heterocyclic carbene-palladacycle has been readily synthesized by directly anchoring the structural defined acenaphthoimidazolylidene palladacycle with a long tail on magnetic nanoparticles (MNPs), and functioned as a solid molecular catalyst and exhibited extremely high catalytic activity towards the challenging Suzuki-Miyaura cross-coupling reactions between less-studied heterocyclic 9-chloroacridine and diverse boronic acids. Remarkably, the catalyst could be used 5 times without obvious loss of activity highlighting the efficiency of our strategy of immobilization of previledged catalysts. PMID- 29165444 TI - Low-temperature crystallization of solution-derived metal oxide thin films assisted by chemical processes. AB - Over the last few years the efforts devoted to the research on low-temperature processing of metal oxide thin films have increased notably. This has enabled the direct integration of metal oxide layers (amorphous semiconductors) on low melting-point polymeric substrates for flexible electronic systems, which adds to the economic and environmental benefits of the use of these processes with reduced energy consumption. More challenging is the preparation of crystalline complex oxide films at temperatures compatible with their direct integration in flexible devices. However, the usually high crystallization temperatures (>600 degrees C) impede the development of devices that take full advantage of the large variety of oxide functionalities available. This tutorial review analyzes a number of strategies based on wet chemical methods for inducing the crystallization of metal oxide thin films at low temperatures. The key mechanisms are explained in relation to the specific step of the fabrication process reached in an earlier stage: the formation of a defect-free, highly densified amorphous metal-oxygen network or the actual crystallization of the metal oxide. The role of photochemistry, where light can be used as a complementary energy source to induce crystallization, is particularly highlighted. This requires the synthesis of novel photosensitive solutions (modified metal alkoxides, charge-transfer metal complexes or structurally designed molecular compounds) and a precise control over the reactions promoted by UV irradiation (photochemical cleavage, ozonolysis, condensation or photocatalysis). Relevant examples derived from the integration of crystalline metal oxide thin films on flexible substrates (<=350 degrees C) illustrate the most recent achievements in this field. PMID- 29165445 TI - Correction: Calcium carbonate crystallisation at charged graphite surfaces. AB - Correction for 'Calcium carbonate crystallisation at charged graphite surfaces' by E. R. Ravenhill et al., Chem. Commun., 2017, DOI: . PMID- 29165446 TI - Up-conversion luminescence coupled to plasmonic gold nanorods for light harvesting and hydrogen production. AB - The conversion of infrared light to visible-light which allows a larger fraction of sun-light to be used is needed to improve light-harvesting. In this work a tri functional material composed of an up-converter (NaYF4-Yb-Tm), plasmonic gold nanorods and CdS was made photocatalytically active using 980 nm wavelength light for the reduction of H+ to H2. PMID- 29165447 TI - Catalytic substitution/cyclization sequences of O-substituted Isocyanates: synthesis of 1-alkoxybenzimidazolones and 1-alkoxy-3,4-dihydroquinazolin-2(1H) ones. AB - O-Substituted isocyanates (O-isocyanates) have rarely been used in organic synthesis, given their tendency to undergo side reactions (e.g., trimerization). Herein, we show that masked (blocked) O-isocyanate precursors allow one-pot or cascade reaction sequences featuring base-catalyzed substitution with 2 iodoanilines and 2-iodobenzylamines followed by copper-catalyzed cyclization, to form benzimidazolones and 3,4-dihydroquinazolin-2(1H)-ones. This work shows that O-isocyanates can serve as efficient building blocks for the synthesis of hydroxylamine-containing heterocycles. PMID- 29165448 TI - Shedding light on the different behavior of ionic and nonionic surfactants in emulsion polymerization: from atomistic simulations to experimental observations. AB - Although surfactants are known to play a vital role in polymerization reactions carried out in dispersed media, many aspects of their use are poorly understood, perhaps none more so than the vastly different action of ionic and nonionic surfactants in emulsion polymerization. In this work, we combine experimental measurements of emulsion polymerization of styrene with atomistic molecular dynamics simulations to better understand the behavior of surfactants at monomer/polymer-water interfaces. In a batch emulsion polymerization of styrene, the nonionic surfactant Disponil AFX 1080 leads to two nucleation periods, in contrast to the behavior observed for the ionic surfactant SDS. This can be explained by the absorption of the nonionic surfactant into the organic phase at the early stages of the polymerization reaction which is then released as the reaction progresses. Indeed, we find that the partition coefficient of the surfactant between the organic phase and water increases with the amount of monomer in the former, and preferential partitioning is detected to organic phases containing at least 55% styrene. Results from molecular dynamics simulations confirm that spontaneous dissolution of the non-ionic surfactant into a styrene-rich organic phase occurs above a critical concentration of the surfactant adsorbed at the interface. Above this critical concentration, a linear correlation between the amount of surfactant adsorbed at the interface and that absorbed inside the organic phase is observed. To facilitate this absorption into a completely hydrophobic medium, water molecules accompany the intruding surfactants. Similar simulations but with the ionic surfactant instead did not result in any absorption of the surfactant into a neat styrene phase, likely because of its strongly hydrophilic head group. The unusual partitioning behavior of nonionic surfactants explains a number of observable features of emulsion polymerization reactions which use nonionic surfactants and should help with future development of processes for improved control over polymerization. PMID- 29165449 TI - Short two-armed lanthanide-binding tags for paramagnetic NMR spectroscopy based on chiral 1,4,7,10-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane scaffolds. AB - A new pair of enantiomeric two-armed lanthanide-binding tags have been developed for paramagnetic NMR studies of proteins. The tags produce large and significantly different paramagnetic effects to one another when bound to the same tagging site. Additionally, they are less sensitive to sample pH than our previous two-armed tag designs. PMID- 29165450 TI - Phosphine catalysed (5 + 1) annulation of ynone/cinnamates with primary amines. AB - The (5 + 1) annulation of ynone/cinnamates and related substrates with protected primary amines gives rise to isoquinolones, pyrrolidinones and pyrrolopiperazines in good to excellent yields under phosphine catalysis. The reaction is viable with chiral phosphines, although the selectivity is poor. PMID- 29165451 TI - Optical-magnetic bifunctional properties and mechanistic insights on upconversion of NaYF4:Yb,Ho,Tm@NaGdF4 with a tunable nanodumbbell morphology. AB - The energy-upconversion of lanthanide-doped nanoparticles with a core-shell structure can be utilized to enhance and tune optical properties and can generate multifunctionality in a single system. Herein, the core-shell nanoparticles NaYF4:Yb,Ho,Tm@NaGdF4 were prepared by thermally decomposing lanthanide acetylacetonate precursors. Through modifying the molar ratio of the core and shell, nanodumbbell-shaped particles with different sizes and morphologies were precisely synthesized. The formation mechanism and the heterogeneous epitaxial growth process of the nanodumbbell-shaped particles were studied. After coating the shell layer, upconversion luminescence intensities, spectral purity and fluorescence lifetimes were improved. Furthermore, the magnetic performance of the core-shell nanoparticles was characterized. The optical-magnetic bifunctional upconversion core-shell particles with programmable shape and multiple properties provide an ideal platform for the preparation of nanodumbbell-shaped particles and the promotion of upconversion materials for biomedical research. PMID- 29165452 TI - Conformational analysis of spiro-epoxides by principal component analysis of molecular dynamics trajectories. AB - A new procedure for full conformational analyses comprising the statistical analysis of molecular dynamics trajectories was developed and applied. This method included a coordinate space for sampling using molecular dynamics simulations, reduction of dimensionality using tensor decomposition tools, determination of probability distributions in a reduced space, and finally the search for all of the strict extrema points of probability distributions. These extracted extrema points formed an initial guess for geometry optimization and clustering of conformers. A complete conformational space of 1 oxaspiro[2,5]octane and its cis- and trans-4-, 5- and 6-methyl substituted derivatives was also determined. In each case, eight conformers were found with two chair-like conformers predominant at room temperature. It was found that chair-like conformers with an epoxide ring oxygen atom in the pseudo-axial position had less strain, as well as all of their conformers with the methyl substituent in an equatorial position on a cyclohexane moiety. PMID- 29165453 TI - Structural and electronic properties of barbituric acid and melamine-containing ribonucleosides as plausible components of prebiotic RNA: implications for prebiotic self-assembly. AB - The RNA world hypothesis assumes that RNA was the first informational polymer that originated from prebiotic chemical soup. However, since the reaction of d ribose with canonical nucleobases (A, C, G and U) fails to yield ribonucleosides (rNs) in substantial amounts, the spontaneous origin of rNs and the subsequent synthesis of RNA remains an unsolved mystery. To this end, it has been suggested that RNA may have evolved from primitive genetic material (preRNA) composed of simpler prebiotic heterocycles that spontaneously form glycosidic bonds with ribose. As an effort toward evaluating this hypothesis, the present study uses density functional theory (DFT) to assess the suitability of barbituric acid (BA) and melamine (MM) to act as prebiotic nucleobases, both of which have recently been shown to spontaneously form a glycosidic bond with ribose and organize into supramolecular assemblies in solution. The significant strength of hydrogen bonds involving BA and MM indicates that such interactions may have played a crucial role in their preferential selection over competing heterocycles that interact solely through stacking interactions from the primordial soup during the early phase of evolution. However, the greater stability of stacked dimers involving BA or MM and the canonical nucleobases compared to those consisting solely of BA and/or MM points towards the possible evolution of intermediate informational polymers consisting of prebiotic and canonical nucleobases, which could have eventually evolved into RNA. Analysis of the associated rNs reveals an anti conformational preference for the biologically-relevant beta-anomer of both BA and MM rNs, which will allow complementary WC-like hydrogen bonding that can stabilize preRNA polymers. Large calculated deglycosylation barriers suggest BA rNs containing C-C glycosidic bonds are relevant in challenging prebiotic environments such as volcanic geotherms, while lower barriers indicate the MM rNs containing C-N-C glycosidic linkages may have been more likely synthesized from simple precursors such as urea-ice in icy (polar) regions. Together, our quantum chemical data clarifies the physicochemical interactions and stability of potential prebiotically-relevant constituents of BA and MM polymeric assemblies, and complements information from previous experimental studies to bolster the candidature of these heterocycles as prebiotic nucleobases. PMID- 29165454 TI - B12Fn0/- (n = 1-6) series: when do boron double chain nanoribbons become global minima? AB - We present an extensive density-functional and wave function theory study of partially fluorinated B12Fn0/- (n = 1-6) series, which show that the global minima of B12Fn0/- (n = 2-6) are characterized to encompass a central boron double chain (BDC) nanoribbon and form stable BF2 groups at the corresponding BDC corner when n >= 3, but the B12F0/- system maintains the structural feature of the well-known quasi-planar C3v B12. When we put the spotlight on B12F60/- species, our single-point CCSD(T) results unveil that albeit with the 3D icosahedral isomers not being their global minima, C2 B12F6 (6.1, 1A) and C1 B12F6- (12.1, 2A) as typical low-lying isomers are 0.60 and 1.95 eV more stable than their 2D planar counterparts D3h B12F6 (6.7, 1A') and C2v B12F6- (12.7, 2A2), respectively, alike to B12H60/- species in our previous work. Detailed bonding analyses suggest that B12Fn0/- (n = 2-5) possess ribbon aromaticity with sigma plus pi double conjugation along the BDC nanoribbon on account of their total number of sigma and pi delocalized electrons conforming the common electron configuration (pi2(n+1)sigma2n). Furthermore, the simulated PES spectra of the global minima of B12Fn- (n = 1-6) monoanions may facilitate their experimental characterization in the foreseeable future. Our work provides new examples for ribbon aromaticity and powerful support for the F/H/Au/BO analogy. PMID- 29165455 TI - Isomer-specific detection in the UV photodissociation of the propargyl radical by chirped-pulse mm-wave spectroscopy in a pulsed quasi-uniform flow. AB - Isomer-specific detection and product branching fractions in the UV photodissociation of the propargyl radical is achieved through the use of chirped pulse Fourier-transform mm-wave spectroscopy in a pulsed quasi-uniform flow (CPUF). Propargyl radicals are produced in the 193 nm photodissociation of 1,2 butadiene. Absorption of a second photon leads to H atom elimination giving three possible C3H2 isomers: singlets cyclopropenylidene (c-C3H2) and propadienylidene (l-C3H2), and triplet propargylene (3HCCCH). The singlet products and their appearance kinetics in the flow are directly determined by rotational spectroscopy, but due to the negligible dipole moment of propargylene, it is not directly monitored. However, we exploit the time-dependent kinetics of H-atom catalyzed isomerization to infer the branching to propargylene as well. We obtain the overall branching among H loss channels to be 2.9% (+1.1/-0.5) l-C3H2 + H, 16.8% (+3.2/-1.3) c-C3H2 + H, and 80.2 (+1.8/-4.2) 3HCCCH + H. Our findings are qualitatively consistent with earlier RRKM calculations in that the major channel in the photodissociation of the propargyl radical at 193 nm is to 3HCCCH + H; however, a greater contribution to the energetically most favorable isomer, c C3H2 + H is observed in this work. We do not detect the predicted HCCC + H2 channel, but place an upper bound on its yield of 1%. PMID- 29165458 TI - The effect of structural modifications on the thermal stability, melting points and ion interactions for a series of tetraaryl-phosphonium-based mesothermal ionic liquids. AB - A family of mesothermal ionic liquids comprised of tetraarylphosphonium cations and the bis(trifluoromethanesulfonyl)amidate anion are shown to be materials of exceptional thermal stability, enduring (without decomposition) heating in air at 300 degrees C for three months. It is further established that three specific structural elements - phenoxy, phenacyl, and phenyl sulfonyl - can be present in the cation structures without compromising their thermal stability, and that their incorporation has specific impacts on the melting points of the salts. Most importantly, it is shown that the ability of such a structural component to lower a salt melting point is tied to its ability to lower cation-cation repulsions in the material. PMID- 29165460 TI - Variational transition state theory: theoretical framework and recent developments. AB - This article reviews the fundamentals of variational transition state theory (VTST), its recent theoretical development, and some modern applications. The theoretical methods reviewed here include multidimensional quantum mechanical tunneling, multistructural VTST (MS-VTST), multi-path VTST (MP-VTST), both reaction-path VTST (RP-VTST) and variable reaction coordinate VTST (VRC-VTST), system-specific quantum Rice-Ramsperger-Kassel theory (SS-QRRK) for predicting pressure-dependent rate constants, and VTST in the solid phase, liquid phase, and enzymes. We also provide some perspectives regarding the general applicability of VTST. PMID- 29165457 TI - The chemical composition, nutritional value and antimicrobial properties of Abelmoschus esculentus seeds. AB - Okra is a vegetable crop usually used for its immature pods. The harvest stage (fruit size) depends on consumers' preferences and the fruit that does not meet market requirements is being disposed of. Considering the short time interval from the setting of the fruit to the harvest stage, the present study evaluates the nutritional value, chemical composition, and antioxidant and antimicrobial properties of okra seeds from genotypes cultivated under Mediterranean conditions, as an alternative end-use product. For this purpose, seeds from four okra cultivars and local landraces commonly cultivated in the Mediterranean basin, as well as seeds from four commercial cultivars from North America were collected at the maturity stage. A significant variation between the studied okra genotypes was observed for all the evaluated parameters. Okra seeds of cv. "Silver Queen" are a significant source of proteins and minerals, such as Ca, K, Fe and Zn. Seeds of all the genotypes contained significant amounts of gamma tocopherols, liposoluble pigments, and linoleic and palmitic acid. The total phenol content differed between the studied genotypes and correlated with the EC50 values of the Reducing Power assay. Seed extracts exhibited significant antibacterial properties, especially against Listeria monocytogenes, Salmonella enteritidis and S. typhimurium, while fungistatic and fungicidal properties were better than ketoconazole in a genotype dependent manner. The antifungal properties of seeds were noticed towards all tested fungi, where Aspergillus versicolor and Caldosporium cladosporioides were the most sensitive species. Moreover, two of the tested genotypes ("Boyati" and "Clemson Spineless") exhibited higher fungistatic and fungicidal properties than ketoconazole. In conclusion, okra seeds could be considered as innovative okra products and could be proposed for alternative end-uses in the food and pharmaceutical industries, especially for functional foods with antimicrobial and bioactive properties. PMID- 29165461 TI - Synthesis, structures and magnetic properties of two chiral mixed-valence iron(ii,iii) coordination networks. AB - Two rare chiral mixed-valence iron(ii,iii) coordination networks d-and l {[FeIIFeO(BTC)3(DEF)3].0.5H2O}n (d-1 and l-1) (H3BTC = 1,3,5-benzenetricarboxylic acid; DEF = N,N-diethylformamide) have been synthesized without any chiral auxiliary under the solvothermal conditions and structurally characterized by single crystal X-ray crystallography. Structural analysis indicates that these two polymers d-1 and l-1 are enantiomers. The only difference between d-1 and l-1 is that the framework of compound l-1 consists of left-handed double helical chains, while d-1 consists of right-handed double helical chains. Two distinct subunits (SBUs), {(MU3-O)Fe(COO)6(DEF)3} and {FeII(COO)6}, are observed in both structures simultaneously. The integration of two distinct SBUs leads to a trinodal (3,3,6)-connected net with an unusual structural topology. Interestingly, despite the achiral nature of H3BTC, the resulting framework exhibits rare chiral helical channels. The experiments show that dodecatungstosilic acid acts as a catalyst which could increase the conversion of the initial reactant. The magnetic studies indicate antiferromagnetic interactions between Fe3+ ions. Additionally, the luminescence studies revealed that the compound exhibited strong photoluminescence emissions at room temperature with a peak at 457 nm, owing to the strong interactions between organic linkers and metal clusters. PMID- 29165463 TI - Nanoarchitectonics in dielectric/ferroelectric layered perovskites: from bulk 3D systems to 2D nanosheets. AB - We present an overview of recent investigations on the dielectric/ferroelectric properties of Dion-Jacobson-type perovskites, including bulk 3D layered systems and their exfoliated 2D nanosheets. In contrast to the Ruddlesden-Popper and Aurivillius phases, the Dion-Jacobson phases in bulk 3D systems have not been important targets for constructing dielectric/ferroelectric materials. However, recent investigations on Dion-Jacobson phases have provided new impetus to dielectric/ferroelectric materials. Dion-Jacobson perovskites can also facilitate delamination into 2D nanosheets. Layer-by-layer engineering of 2D perovskite nanosheets has a great potential for the rational design of new high-k dielectric/ferroelectric materials and nanodevices. PMID- 29165462 TI - Lithium diffusion study in Li2MnO3 and Li1.17Ni0.17Mn0.67O2: a combined experimental and computational approach. AB - A theoretical and experimental diffusivity study of Li2MnO3 and Li1.17Ni0.17Mn0.67O2 has been carried out to investigate the effect of Mn, Ni and surrounding atoms on Li+ diffusion and to understand how the Li+ diffusion trajectory changes with different charge spheres. It is observed that due to the presence of Ni in Li1.17Ni0.17Mn0.67O2, the activation energy reduces in all the possible diffusion paths, which helps in faster Li+ diffusion. This study brings a new physical insight into Li+ diffusion based on elliptical and straight diffusion trajectories. In Li1.17Ni0.17Mn0.67O2, the Li+ diffusion mechanism in different paths based on 2b, 2c and 4h Wyckoff sites of Li has been discussed. Experimentally, the galvanostatic intermittent titration technique is adopted to identify the diffusion coefficient of Li+. The diffusion coefficient of both the compounds varies in different voltage ranges. For L2MnO3, diffusion varies from 10-11 to 10-13 cm2 s-1, whereas for Li1.17Ni0.17Mn0.67O2, diffusion varies from 10-9 to 10-11 cm2 s-1 in the voltage range of 3.7-4.7 V. PMID- 29165464 TI - Analytical SERS: general discussion. PMID- 29165466 TI - The lone-pair-electron-driven phase transition and order-disorder processes in thermochromic (2-MIm)SbI4 organic-inorganic hybrid. AB - The easy to prepare and stable in air (2-methylimidazolium) tetraiodoantimoniate(iii) single-crystals with optical band gap of 2.17(1) eV at room temperature have been synthesized. The crystal structure features one dimensional [SbI4]-n anionic chains, which are intercepted with stacks of 2MIm+ ions. At 294/295 K, it undergoes a structural phase transition to an incommensurately modulated phase as a result of subtle, lone-pair-electron-driven distortions of the anions. Separately from the anion displacements, the ordering of 2MIm+ countercations takes place over a wide temperature range of the modulated phase. The disorder changes from dynamic to static around 200 K, which affects the crystal structure leading to discontinuities and step-like contraction of the lattice parameters. The material is thermochromic with prominent color changes, from raspberry to yellow at low temperatures. The calculated electronic structures and observed optical properties signify its semiconducting character. PMID- 29165467 TI - Enantiomer surface chemistry: conglomerate versus racemate formation on surfaces. AB - Research on surface chirality is motivated by the need to develop functional chiral surfaces for enantiospecific applications. While molecular chirality in 3D has been the subject of study for almost two centuries, many aspects of 2D chiral surface chemistry have yet to be addressed. In 3D, racemic mixtures of chiral molecules tend to aggregate into racemate (molecularly heterochiral) crystals much more frequently than conglomerate (molecularly homochiral) crystals. Whether chiral adsorbates on surfaces preferentially aggregate into heterochiral rather than homochiral domains (2D crystals or clusters) is not known. In this review, we have made the first attempt to answer the following question based on available data: in 2D racemic mixtures adsorbed on surfaces, is there a clear preference for homochiral or heterochiral aggregation? The current hypothesis is that homochiral packing is preferred on surfaces; in contrast to 3D where heterochiral packing is more common. In this review, we present a simple hierarchical scheme to categorize the chirality of adsorbate-surface systems. We then review the body of work using scanning tunneling microscopy predominantly to study aggregation of racemic adsorbates. Our analysis of the existing literature suggests that there is no clear evidence of any preference for either homochiral or heterochiral aggregation at the molecular level by chiral and prochiral adsorbates on surfaces. PMID- 29165468 TI - Regioisomerism in coordination chemistry: oxidative addition of a bifunctional ligand to palladium, stabilized with 1,2-bis(diphenylphosphino)ethane. AB - A unique phenomenon of regioisomerism in coordination chemistry was discovered: the reaction of a sterically hindered o-quinone annelated with a dithiete ring with Pd2dba3 in the presence of 1,2-bis(diphenylphosphino)ethane (dppe) gave a mixture of two regioisomers: catecholate 3Cat and dithiolate 3Dit. Both isomers were isolated in crystalline form and characterized by NMR, IR and X-ray diffractometry studies. DFT calculations reveal that the 3Dit species is more thermodynamically stable than the isomer 3Cat. Isomerization of 3Cat to 3Dit in solution was observed. PMID- 29165469 TI - Surprisingly high quantum yield of emission in a fluorescent coordination polymer with paramagnetic Mn(ii) ions. AB - A two-dimensional coordination polymer, [Mn3(HEBTC)2(DMSO)6] (1), has been achieved by a solvothermal reaction of Mn2+ with 1,1'-ethynebenzene-3,3',5,5' tetracarboxylic acid (H4EBTC). The layer of a coordination polymer is composed of trinuclear Mn2+ clusters linked by HEBTC3- ligands to form a (3,6)-connected topological net. CP 1 with paramagnetic Mn2+ ions shows dual emissions centered at 397 and 468 nm in the solid state under ambient conditions with respectable quantum yields of 15.3% (397 nm) and 12.3% (468 nm). The dual emissions arise from n <- pi* transition in HEBTC3- and MLCT between HEBTC3- and Mn2+ centers. PMID- 29165470 TI - Microwave-assisted synthesis of hydroxyl-containing isoquinolines by metal-free radical cyclization of vinyl isocyanides with alcohols. AB - A convenient microwave-assisted protocol for the synthesis of hydroxyl-containing isoquinolines from a metal-free radical cyclization reaction of vinyl isonitriles with alcohols was developed with moderate-to-excellent yields. Vinyl isonitriles are coupled with alkyl radicals through direct catalytic functionalization of the alpha sp3 C-H bond of alcohols. The methodology demonstrates a broad substrate scope, shows excellent functional group tolerance, is highly atom-economical and highly efficient, thus enabling the preparation of diverse potentially valuable hydroxyl-containing isoquinolines. PMID- 29165471 TI - Copper-catalyzed ipso-selenation of aromatic carboxylic acids. AB - The copper-catalyzed decarboxylative selenation of aromatic carboxylic acids with diselenide is reported. This transformation tolerated a diverse set of functional groups on the substrates, including pentafluorobenzoic acid and heteroaromatic acids, delivering diaryl and methyl aryl selenides in good to excellent yields. Mechanistic studies indicated that the copper catalyst is essential in the activation of the Se-Se bond and the decarboxylation of aromatic acids. The utility of the products has been demonstrated in the facile synthesis of 10H phenoselenazine and 11-methyldibenzo-(b,f)-1,4-selenazepine. PMID- 29165472 TI - Intracellular delivery of more than one protein with spatio-temporal control. AB - Transient, non-integrative modulation of cell function by intracellular delivery of proteins has high potential in cellular reprogramming, gene editing and therapeutic medicine applications. Unfortunately, the capacity to deliver multiple proteins intracellularly with temporal and spatial control has not been demonstrated. Here, we report a near infrared (NIR) laser-activatable nanomaterial that allows for precise control over the release of two proteins from a single nanomaterial. The nanomaterial is formed by gold nanorods (AuNRs) modified with single stranded DNA (ssDNA) to which complementary DNA-conjugated proteins are hybridized. Using DNA strands with distinct melting temperatures we are able to control independently the release of each protein with a laser using the same wavelength but with different powers. Studies in mammalian cells show that AuNRs conjugated with proteins are internalized by endocytosis and NIR laser irradiation promotes endosomal escape and the release of the proteins from the AuNRs simultaneously. Our results further demonstrate the feasibility of protein release from a carrier that has been accumulated within the cell up to 1 day while maintaining its activity. PMID- 29165473 TI - Large Cu chalcogenone cubic cages with non-interacting counter ions. AB - Two mega size copper(i) cubic cages, [{Cu(Bptp)1.5}8(PF6-)](PF6-)7 (1) and [{Cu(Bpsp)1.5}8(PF6-)](PF6-)7 (2), supported by imidazole-2-chalcogenone ligands (Bptp = 2,6-bis(1-isopropylimidazole-2-thione)pyridine and Bpsp = 2,6-bis(1 isopropylimidazole-2-selone)pyridine) have been synthesized and characterized. The formation of ionic salts 1 and 2 was confirmed by FT-IR, multinuclear (1H, 13C, 31P and 19F) NMR, UV-vis, TGA, CHN analysis, BET analysis, single crystal X ray diffraction and powder X-ray diffraction techniques. To the best of our knowledge, these are the first examples of a octanuclear copper(i) cluster in a perfect cubic architecture with a copper-copper distance of 8.413 A or 8.593 A. Interestingly, these anion-centered Cu cubic arrangements are not supported by cubic centered ions or face centered molecules. The formation of cationic cubic cages was accompanied by the association of twelve ligands (Bptp or Bpsp) with eight trigonal planar [CuSe3] vertices. The cationic charge of cubic cages was satisfied by eight PF6- counter anions, in which one of the PF6- anions occupies the centre of the Cu8 cube without any interaction. The copper(i) cubic cages are found to be highly active catalysts in click chemistry as well as hydroamination reactions. The scope of the catalytic reactions has been investigated with thirty five different combinations of click reactions and six different combinations of the hydroamination of alkynes. PMID- 29165474 TI - Sugar and mineral enriched fraction from olive mill wastewater for promising cosmeceutical application: characterization, in vitro and in vivo studies. AB - Nowadays, agro-food by-products represent a potential low-cost source of biologically active ingredients which have been paid significant attention as nutraceuticals, medicine, food and cosmetics. In a previous study we evaluated the total sugars, metals and polyphenols of olive mill wastewater (OMWW) from a Cerasuola olive cultivar. In the present work we selectively recovered a sugar and mineral enriched fraction (SMEF) from Cerasuola OMWW by a green adsorption/desorption process. The SMEF was mainly found to be composed of monosaccharides and potassium by HPLC-ELSD and ICP-MS. The in vitro cytotoxicity on human fibroblasts, at different concentrations of the fraction, was investigated by MTT and comet assays. In addition, intracellular reactive oxygen species (ROS) production, apoptosis and cell morphological changes were examined. The physical stability of a formulation containing the SMEF (1% w/w) and its in vivo skin effects were also assessed.Our results highlighted that the SMEF showed a toxic effect at higher concentrations (i.e. cell viability reduction, DNA fragmentation and morphological alterations) well correlated with high ROS levels. Conversely, at low concentrations (0.5% and 1% w/w), no significant changes were observed. For the first time, through stability studies and in vivo tests, we also demonstrated that the SMEF formulation is stable and safe for topical application, since skin hydration improvement without negative effects was observed after 7 days of its use. Therefore, the SMEF has great potential to be used for cosmeceutical applications. PMID- 29165476 TI - CTAB-assisted growth of self-supported Zn2GeO4 nanosheet network on a conductive foam as a binder-free electrode for long-life lithium-ion batteries. AB - The Ge-based compounds show great potential as replacements for traditional graphite anode in lithium-ion batteries (LIBs). However, large volume changes and low conductivity of such materials result in a poor electrochemical cycling and rate performance. Herein, we fabricate a self-supported and three-dimensional (3D) sponge-like structure of interlinked Zn2GeO4 ultrathin nanosheets anchored vertically on a nickel foam (ZGO NSs@NF) via a simple hydrothermal process assisted by cetyltrimethyl ammonium bromide (CTAB). Such robust self-supported hybrid structures greatly improve the structural tolerance of the active materials and accommodate the volume variation that occurs during repeated electrochemical cycling. As expected, the self-supported ZGO NSs@NF composites demonstrate an excellent lithium storage with a high discharge capacity, a long cycling life, and a good rate capability when used as binder-free anodes for LIBs. A high reversible discharge capacity of 794 mA h g-1 is maintained after 500 cycles at 200 mA g-1, corresponding to 81% capacity retention of the second cycle. Further evaluation at a higher current density (2 A g-1) also delivers a reversible discharge capacity (537 mA h g-1) for this binder-free anode. This novel 3D structure of the self-supported ultrathin nanosheets on a conductive substrate, with its volume buffer effect and good interfacial contacts, can stimulate the progress of other energy-efficient technologies. PMID- 29165475 TI - Effect of the water fraction isolated from Fructus Ligustri Lucidi extract on bone metabolism via antagonizing a calcium-sensing receptor in experimental type 1 diabetic rats. AB - Our previous studies have demonstrated that the extract of Fructus Ligustri Lucidi (FLL) can maintain in vivo calcium homeostasis in aged and ovariectomized rats. This study was designed to elucidate the action of water fraction isolated from the FLL extract on bone metabolism and a calcium-sensing receptor (CaSR) in parathyroid glands and kidneys of diabetic rats. The streptozotocin-induced diabetic rats were treated with vehicle, FLL extract, and the water fraction (WF) isolated from the FLL extract for 4 weeks. Treatment with WF dramatically increased the serum levels of both calcium and parathyroid hormone and reduced urinary calcium excretion in diabetic rats as well as improved the pathological changes of trabecular bone as shown by the increased BA/TA, BMD/BV, and BV/TV. The mRNA expression of the calcium-binding protein 9k and protein expression of a vitamin D receptor (VDR) and plasma membrane Ca-ATPase in duodenum were significantly increased in diabetic rats after treatment with WF, which reduced the expression of CaSR in parathyroid gland and kidney as well as inhibited the up-regulation of VDR and 25-hydroxyvitamin D-24 hydroxylase expressions in the kidney of diabetic rats. This study reveals that the water fraction may be an active component of the FLL extract that exerts beneficial effects on improving bone metabolism via regulating vitamin D metabolism in kidney and vitamin D dependent calcium transporters in duodenum as well as modulating the expression of CaSR in the parathyroid gland and kidneys. PMID- 29165478 TI - Acid-catalyzed reaction of 2-hydroxycyclobutanone with benzylic alcohols. AB - The acid-promoted syntheses of 2-(benzyloxy)cyclobutanones and bis(benzyloxy)dioxatricyclo decanes were achieved starting from 2 hydroxycyclobutanone and variously functionalized benzyl alcohols. The reaction sequences afforded the desired products in good to high yields and in a solvent dependent chemoselective fashion. PMID- 29165477 TI - Barley beta-glucans varying in molecular mass and oligomer structure affect cecal fermentation and microbial composition but not blood lipid profiles in hypercholesterolemic rats. AB - There is an unmet need for appealing and functional barley beta-glucan (BG) food matrices that can provide sufficient and active BG doses to consumers. We investigated how molecular mass and oligomer structure important for BG food and health properties affected plasma lipids and gut parameters in hypercholesterolemic rats. Following 3 weeks on a high-cholestrol diet, rats were given a high-cholesterol diet supplemented with either cellulose (control) or purified barley BGs with low (100 or 150 kDa; glucagel or lowBG, respectively) or medium (530 kDa; mediumBG) molecular masses varying in cellotriosyl/cellotetraosyl oligomer ratio for 4 weeks. All four diets (control, glucagel, lowBG or mediumBG) reduced plasma triacylglycerol and cholesterols from week 3 to 7. The BG diets increased cecal production of short-chain fatty acids (SCFAs) compared to the control diet. The glucagel and lowBG diets stimulated the number of Bifidobacterium in the cecum, whereas the mediumBG diet reduced numbers of both Bacteroides/Prevotella and Lactobacillus in the cecum compared to the control diet. In conclusion, barley BGs at 6.5-7.5% of the diet independent of molecular mass and oligomer block structure showed no additional effect compared to the control treatment on blood cholesterol and triacylglycerol levels in this hypercholesterolemic rat model. Furthermore, the cecal fermentation pattern and microbial composition did not seem to affect plasma lipid composition. PMID- 29165479 TI - Evaluation of the impact of food matrix change on the in vitro bioaccessibility of carotenoids in pumpkin (Cucurbita moschata) slices during two drying processes. AB - The food matrix is a limiting factor in determining the bioaccessibility of carotenoids. The impact of food matrix change on the bioaccessibility of carotenoids during drying processes is still unknown. The effect of intermittent microwave vacuum-assisted drying (IMVD) and hot air drying (HAD) on the in vitro liberation and micellization of carotenoids in pumpkin slices was studied. This variable depended on the changes of the matrix driven by the drying process. Different changes in the cell morphology and carotenoid distribution of pumpkin slices during the two processing methods were observed. For IMVD, cell wall degradation and complete chromoplast organelle disruption contributed to the improvement in the liberation and micellization of carotenoids. In the HAD-dried sample, large pigment aggregates hindered the liberation of carotenoids. The carotenoid level in the micellar fraction appeared to be lower than that in the aqueous supernatant during the two processes, suggesting that the new obstacles formed during processing and/or digestion hindered the incorporation of carotenoids in mixed micelles. PMID- 29165483 TI - Ion chemistry at elevated ion-molecule interaction energies in a selected ion flow-drift tube: reactions of H3O+, NO+ and O2+ with saturated aliphatic ketones. AB - The reactions of H3O+, NO+ and O2+ ions with a homologous series of six aliphatic ketones, viz. acetone through 2-octanone, have been investigated in a helium buffered selected ion flow-drift tube, SIFDT, in order to reveal their dependencies on ion-molecule interaction energies, Er, and to gain insight into their mechanisms. The ultimate motivation is to allow analysis and absolute quantification of trace amounts of ketones and other volatile organic compounds in air using selected ion flow-drift tube mass spectrometry, SIFDT-MS. The reactions of H3O+ with the ketone molecules, M, proceed via exothermic proton transfer producing MH+ ions, the collisional rate coefficients, kc, for which can be calculated as a function of Er and are seen to reduce by about one third over the Er range from 0.05 eV up to 0.5 eV. The rate coefficients, k, and product ion distributions for the NO+ and O2+ reactions with M had to be obtained experimentally relative to the calculated kc for the H3O+ reactions. The product ions of the NO+/ketones reactions initially proceed via the formation of excited (NO+M)* adduct ions that partially fragment, and the k reduces with Er as much as four times for the acetone reactions but remains close to their respective kc for the higher-order ketones indicating long lifetimes of the (NO+M)* ions with respect to the stabilising collision times with He atoms. The k for the O2+/ketones dissociative charge transfer reactions are observed to be greater than their calculated kc implying that long distance electron transfer occurs. PMID- 29165484 TI - Diffusiophoresis in one-dimensional solute gradients. AB - The diffusiophoretic motion of suspended colloidal particles under one dimensional solute gradients is solved using numerical and analytical techniques. Similarity solutions are developed for the injection and withdrawal dynamics of particles into semi-infinite pores. Furthermore, a method of characteristics formulation of the diffusion-free particle transport model is presented and integrated to realize particle trajectories. Analytical solutions are presented for the limit of small particle diffusiophoretic mobility Gammap relative to the solute diffusivity Ds for particle motions in both semi-infinite and finite domains. Results confirm the build up of local maxima and minima in the propagating particle front dynamics. The method of characteristics is shown to successfully predict particle motions and the position of the particle front, although it fails to accurately predict suspended particle concentrations in the vicinity of sharp gradients, such as at the particle front peak seen in some injection cases, where particle diffusion inevitably plays an important role. Results inform the design of applications in which the use of applied solute gradients can greatly enhance particle injection into and withdrawal from pores. PMID- 29165485 TI - Photo-stimulated triboelectric generation. AB - A new photo-stimulated triboelectric generation occurring between a metal-oxide and polyimide during friction was demonstrated. The output currents of the triboelectric nanogenerator were significantly enhanced, under light illumination, up to approximately 5 times depending on the wavelength of the light, providing a new route for energy harvesting devices as well as self powered selective photodetectors. PMID- 29165486 TI - Optical control of mitochondrial reductive reactions in living cells using an electron donor-acceptor linked molecule. AB - It has been known for decades that intracellular redox reactions control various vital functions in living systems, which include the synthesis of biomolecules, the modulation of protein functions, and cell signaling. Although there have been several reports on the control of such functions using DNA and RNA, the non invasive optical control of biological functions is an important ongoing challenge. In this study, a hybrid of an electron donor-acceptor linked molecule based on a ferrocene(Fc)-porphyrin(ZnP)-fullerene(C60) analogue and an elaborately designed nano-carrier, referred to herein as a MITO-Porter, resulted in a successful photoinduced intermolecular electron transfer reaction via the long-lived intramolecular charge separation, leading to site-specific reductive reactions in the mitochondria of living HeLa cells. A Fc-ZnP-C60 linked molecule, 1-Oct, was designed and prepared for taking advantage of the unique photophysical properties with excellent efficiency (i.e. a long lifetime and a high quantum yield) for photoinduced charge separation. The targeted delivery of 1-Oct to mitochondria was accomplished by using a combination of the Fc-ZnP-C60 molecule and a drug delivery nano-carrier, MITO-Porter, that was recently established by our group for intracellular cargo delivery. The successful delivery of 1-Oct by the MITO-Porter permitted the optically-controlled generation of O2- in the mitochondria of HeLa cells and the following induction of apoptosis as a cell signalling response was observed in confocal laser microscopy experiments. The obtained results indicate the use of an electron donor-acceptor system such as this can be a promising tool for the non-invasive triggering of redox-coupled cellular activities in living systems. PMID- 29165488 TI - Rocket-inspired tubular catalytic microjets with grating-structured walls as guiding empennages. AB - Controllable locomotion in the micro-/nanoscale is challenging and attracts increasing research interest. Tubular microjets self-propelled by microbubbles are intensively investigated due to their high energy conversion efficiency, but the imperfection of the tubular geometry makes it harder to realize linear motion. Inspired by the macro rocket, we designed a tubular microjet with a grating-structured wall which mimics the guiding empennage of the macro rocket, and we found that the fluid can be effectively guided by the grooves. Both theoretical simulation and experimental work have been carried out, and the obtained results demonstrate that the stability margin of the grating-structured microjet can be enhanced. Compared with microjets with smooth walls, the structured microjets show an enhanced ability of moving linearly. In 10% H2O2, only 20% of the smooth microjets demonstrate linear trajectories, while 80% of the grating-structured microjets keep moving straight. The grating-structured microjet can maintain linear motion under external disturbance. We further propose to increase the stability by introducing a helical grating structure. PMID- 29165489 TI - Perylenediimide-based glycoclusters as high affinity ligands of bacterial lectins: synthesis, binding studies and anti-adhesive properties. AB - The synthesis of eight perylenediimide-based glycoclusters was readily performed from hexa- and tetra-propargylated cores through azide-alkyne "click" conjugation. Variations in the carbohydrate epitope (Glc, Gal, Man, Fuc) and the linker arm provided molecular diversity. Interactions with LecA and LecB, two proteins involved in the adhesion of Pseudomonas aeruginosa to host tissues, were evaluated by microcalorimetry (ITC). In both cases high affinities were obtained with Kd values in the nanomolar range. Further evaluation of their anti-adhesive properties using cultured epithelial cells demonstrated their potent anti adhesive activities against Pseudomonas aeruginosa with only 30-40% residual adhesion observed. The fluorescence properties of the PDI core were then investigated by confocal microscopy on cell-bacteria cultures. However, the red fluorescence signal of the PDI-based glycocluster was too weak to provide significant data. The present study provides another type of anti-adhesive glycocluster against bacterial infection with a large aromatic PDI core. PMID- 29165490 TI - Reversibly photo-switchable wettability of stearic acid monolayer modified bismuth-based micro-/nanomaterials. AB - In this work, we demonstrated a general approach to realize superhydrophobic superhydrophilic reversible transition over hydrophilic bismuth-related micro /nanomaterials. Different superhydrophobic bismuth-based micro-/nanomaterials, including BiOCOOH, Bi2O3, (BiO)2CO3 and BiOCl, were obtained by modification with stearic acid, regardless of their morphologies. The reversible wettability of the bismuth-related materials upon alternative UV-vis irradiation and dark storage were investigated via cyclic experiments. The results indicated that the reversible wetting behavior was highly related with the photocatalytic activities of the bismuth-based materials. High photocatalytic activity resulted in less reversible cycles between superhydrophobicity and superhydrophilicity due to the photodegradation of stearic acid. Moreover, with the increase of cycle number, the required minimal time for photo-induced superhydrophilicity decreased and the minimal time for the recovery of superhydrophobicity under dark storage increased. Based on peak deconvolution analysis of XPS and FTIR spectra, a comprehensive understanding of reversible wettability of the bismuth-related micro-/nanomaterials was proposed. This work provides a new strategy to fabricate superhydrophobic-superhydrophilic switchable surfaces for most hydrophilic inorganic materials with different morphologies and photocatalytic activities. PMID- 29165491 TI - Fe3O4-AuNPs anchored 2D metal-organic framework nanosheets with DNA regulated switchable peroxidase-like activity. AB - Two-dimensional (2D) metal-organic framework (MOF) nanosheets emerging as a new member of the 2D family have received significant research interest in recent years. Herein, we have successfully synthesized 2D copper-based MOF nanosheets with bimetallic anchorage using a facile two-step process at room temperature and ambient pressure, denoted as Cu(HBTC)-1/Fe3O4-AuNPs nanosheets. The as synthesized 2D bimetallic MOF nanosheets displayed enhanced peroxidase-like activity with relatively high catalytic velocity and affinity for substrates compared with previously reported peroxidase mimics. Furthermore, their intrinsic peroxidase-like catalytic activity could be flexibly regulated by single-stranded DNA (ssDNA), exhibiting the enhancement of 3,3',5,5'-tetramethylbenzidine (TMB) oxidation or inhibition of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)diammonium salt (ABTS) oxidation due to the adsorption of ssDNA via pi-pi stacking. Accordingly, on the basis of their peroxidase-like activity, our prepared 2D bimetallic immobilized MOF nanosheets achieved ultra-sensitive detection of H2O2 with a linear range of 2.86 to 71.43 nM, and comparable detection performance for glucose with a linear range of 12.86 to 257.14 MUM. By means of their controllable peroxidase-like activity, a versatile colorimetric sensing platform was developed which realized the detection of sulfadimethoxine (SDM) with a linear range of 3.57 to 357.14 MUg L-1 and the limit of detection (LOD) of 1.70 MUg L-1. With the multiplexed performance for detecting various targets, our as-synthesized bimetallic MOF nanosheets hold great promise for applications in environmental monitoring, as well as bioassays by virtue of their good biocompatibility. PMID- 29165492 TI - Controlling the Sn-C bonds content in SnO2@CNTs composite to form in situ pulverized structure for enhanced electrochemical kinetics. AB - The Sn-C bonding content between the SnO2 and CNTs interface was controlled by the hydrothermal method and subsequent heat treatment. Electrochemical analysis found that the SnO2@CNTs with high Sn-C bonding content exhibited much higher capacity contribution from alloying and conversion reaction compared with the low content of Sn-C bonding even after 200 cycles. The high Sn-C bonding content enabled the SnO2 nanoparticles to stabilize on the CNTs surface, realizing an in situ pulverization process of SnO2. The in situ pulverized structure was beneficial to maintain the close electrochemical contact of the working electrode during the long-term cycling and provide ultrafast transfer paths for lithium ions and electrons, which promoted the alloying and conversion reaction kinetics greatly. Therefore, the SnO2@CNTs composite with high Sn-C bonding content displayed highly reversible alloying and conversion reaction. It is believed that the composite could be used as a reference for design chemically bonded metal oxide/carbon composite anode materials in lithium-ion batteries. PMID- 29165495 TI - Electronic structure and dynamics of torsion-locked photoactive yellow protein chromophores. AB - The photocycle of photoactive yellow protein (PYP) begins with small-scale torsional motions of the chromophore leading to large-scale movements of the protein scaffold triggering a biological response. The role of single-bond torsional molecular motions of the chromophore in the initial steps of the PYP photocycle are not fully understood. Here, we employ anion photoelectron spectroscopy measurements and quantum chemistry calculations to investigate the electronic relaxation dynamics following photoexcitation of four model chromophores, para-coumaric acid, its methyl ester, and two analogues with aliphatic bridges hindering torsional motions around the single bonds adjacent to the alkene group. Following direct photoexcitation of S1 at 400 nm, we find that both single bond rotations play a role in steering the PYP chromophore through the S1/S0 conical intersection but that rotation around the single bond between the alkene moiety and the phenoxide group is particularly important. Following photoexcitation of higher lying electronic states in the range 346-310 nm, we find that rotation around the single bond between the alkene and phenoxide groups also plays a key role in the electronic relaxation from higher lying states to the S1 state. These results have potential applications in tuning the photoresponse of photoactive proteins and materials with chromophores based on PYP. PMID- 29165496 TI - Fluorescence quenching-based signal amplification on immunochromatography test strips for dual-mode sensing of two biomarkers of breast cancer. AB - Recently, immunochromatography test strips (ICTS) have been fully developed for point-of-care testing (POCT). However, the intrinsic limitations including non quantitative detection of colloidal gold ICTS and low sensitivity of fluorescence ICTS (FICTS) significantly restrict their further application in clinical diagnosis. Taking advantages of rapid colorimetric qualitative detection and fluorescence quantitation, we designed a kind of sensitive and dual-mode magnetic FICTS (mFICTS) based on PLGA@Fe3O4 super-paramagnetic nanosphere (SPMN) probes quenching multiplex fluorescer on the test line through sandwich immunoreactions. Owing to the large number of Fe3O4 nanoparticles (about 47) encapsulated in one SPMN, about 2680 Cy5 molecules were quenched by one SPMN on the test line such that to significantly improve the analytical sensitivity as well as the detection of whole blood samples via magnetic separation. Moreover, the aggregation of black SPMN on the test line enabled a quick naked-eye screening in 3 min. For high accuracy breast cancer diagnosis, combined determination of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA153) was performed on one mFICTS with the limits of detection of about 0.06 ng mL-1 and 0.09 U mL-1, respectively. Then, more than 50 clinical serum samples were investigated for high-resolution screening by mFICTS, and the results were coincident with those obtained by electrochemiluminescence immunoassay (ECLIA). Thus, the designed mFICTS is suitable for point-of-care diagnostics. PMID- 29165497 TI - Analysis of optimal crosslink density and platelet size insensitivity in graphene based artificial nacres. AB - Exploration of graphene-based artificial nacres with excellent mechanical properties demonstrates the potential to surpass natural nacre. Recent experimental studies report that optimal crosslink density defined as concentration of the surface functional groups is usually observed in these artificial nacres towards superb mechanical performance. A hybrid model integrating a nonlinear shear-lag model and atomistic simulations reveals the emergence of an optimal crosslink density at which the maximum strength and toughness are achieved. The origin is due to the balance among the reduction of in-plane tensile properties of the graphene sheets, the enhancement of the shear strength of the interlayer and the reduction of interface plasticity. In addition, our results also reveal that the size insensitivity of the graphene sheet appears when the shear stress of the interlayer is highly localized, the increase of the crosslink density intensifies the nonuniformity of the shear stress and the optimal mechanical properties of the artificial nacre cannot be further enhanced by tuning the size of the graphene sheets. Three kinds of interface molecular interactions with their optimal crosslink densities are also proposed to simultaneously maximize the strength and toughness of graphene-based artificial nacres. PMID- 29165498 TI - Tomographic magnetic particle imaging of cancer targeted nanoparticles. AB - Magnetic Particle Imaging (MPI) is an emerging, whole body biomedical imaging technique, with sub-millimeter spatial resolution and high sensitivity to a biocompatible contrast agent consisting of an iron oxide nanoparticle core and a biofunctionalized shell. Successful application of MPI for imaging of cancer depends on the nanoparticles (NPs) accumulating at tumors at sufficient levels relative to other sites. NPs' physiochemical properties such as size, crystallographic structure and uniformity, surface coating, stability, blood circulation time and magnetization determine the efficacy of their tumor accumulation and MPI signal generation. Here, we address these criteria by presenting strategies for the synthesis and surface functionalization of efficient MPI tracers, that can target a typical murine brain cancer model and generate three dimensional images of these tumors with very high signal-to-noise ratios (SNR). Our results showed high contrast agent sensitivities that enabled us to detect 1.1 ng of iron (SNR ~ 3.9) and enhance the spatial resolution to about 600 MUm. The biodistribution of these NPs was also studied using near infrared fluorescence (NIRF) and single-photon emission computed tomography (SPECT) imaging. NPs were mainly accumulated in the liver and spleen and did not show any renal clearance. This first pre-clinical study of cancer targeted NPs imaged using a tomographic MPI system in an animal model paves the way to explore new nanomedicine strategies for cancer diagnosis and therapy, using clinically safe magnetic iron oxide nanoparticles and MPI. PMID- 29165500 TI - UV-Vis spectrophotometry of quinone flow battery electrolyte for in situ monitoring and improved electrochemical modeling of potential and quinhydrone formation. AB - Quinone-based aqueous flow batteries provide a potential opportunity for large scale, low-cost energy storage due to their composition from earth abundant elements, high aqueous solubility, reversible redox kinetics and their chemical tunability such as reduction potential. In an operating flow battery utilizing 9,10-anthraquinone-2,7-disulfonic acid, the aggregation of an oxidized quinone and a reduced hydroquinone to form a quinhydrone dimer causes significant variations from ideal solution behavior and of optical absorption from the Beer Lambert law. We utilize in situ UV-Vis spectrophotometry to establish (a), quinone, hydroquinone and quinhydrone molar attenuation profiles and (b), an equilibrium constant for formation of the quinhydrone dimer (KQHQ) ~ 80 M-1. We use the molar optical attenuation profiles to identify the total molecular concentration and state of charge at arbitrary mixtures of quinone and hydroquinone. We report density functional theory calculations to support the quinhydrone UV-Vis measurements and to provide insight into the dimerization conformations. We instrument a quinone-bromine flow battery with a Pd-H reference electrode in order to demonstrate how complexation in both the negative (quinone) and positive (bromine) electrolytes directly impacts measured half-cell and full cell voltages. This work shows how accounting for electrolyte complexation improves the accuracy of electrochemical modeling of flow battery electrolytes. PMID- 29165501 TI - A study of the effectiveness and energy efficiency of ultrasonic emulsification. AB - Three essential experimental parameters in the ultrasonic emulsification process, namely sonication time, acoustic amplitude and processing volume, were individually investigated, theoretically and experimentally, and correlated to the emulsion droplet sizes produced. The results showed that with a decrease in droplet size, two kinetic regions can be separately correlated prior to reaching a steady state droplet size: a fast size reduction region and a steady state transition region. In the fast size reduction region, the power input and sonication time could be correlated to the volume-mean diameter by a power-law relationship, with separate power-law indices of -1.4 and -1.1, respectively. A proportional relationship was found between droplet size and processing volume. The effectiveness and energy efficiency of droplet size reduction was compared between ultrasound and high-pressure homogenisation (HPH) based on both the effective power delivered to the emulsion and the total electric power consumed. Sonication could produce emulsions across a broad range of sizes, while high pressure homogenisation was able to produce emulsions at the smaller end of the range. For ultrasonication, the energy efficiency was higher at increased power inputs due to more effective droplet breakage at high ultrasound intensities. For HPH the consumed energy efficiency was improved by operating at higher pressures for fewer passes. At the laboratory scale, the ultrasound system required less electrical power than HPH to produce an emulsion of comparable droplet size. The energy efficiency of HPH is greatly improved at large scale, which may also be true for larger scale ultrasonic reactors. PMID- 29165504 TI - [Leprosy: we figth the disease not those who suffer from it]. PMID- 29165505 TI - [Evolutionary interactions as a possible mechanism of drug interactions: an approach to the control of antibiotic-resistant bacteria]. AB - In the 21st century, the world is facing a post-antibiotic era, in which the appearance of infections with a minor or no therapeutic alternative is common. In this context, it is essential to implement measures that optimize the available therapeutic tool, thus generating new strategies that strengthen the fight against growing bacterial resistance. The evolutionary interactions suggest that the development of sensitivity or resistance of a microorganism to an antimicrobial will have an inverse effect (collateral sensitivity) or similar (cross resistance) in a second antimicrobial that is involved in this system. The evolutionary interactions are considered as a new mechanism of drug interaction, and additional, it establishes the collateral sensitivity as a therapeutic strategy to combat bacterial resistance, which could be integrated and evaluated in the future as a new strategy in the antimicrobial stewardship programs. PMID- 29165506 TI - [Extremely elevated erythrosedimentation in an adult population in the City of Buenos Aires]. AB - BACKGROUND: An extremely elevated erythrosedimentation rate (ESR), defined as equal or higher than 100 mm/h, has been linked to serious underlying conditions, such as infections, connective tissue and oncologic disease. AIM: To analyze a group of patients in order to determine the underlying diagnosis and the characteristics associated with extremely elevated ESR in our environment. METHODS: Cross-sectional study of adult patients, who presented with at least one ESR equal or higher than 100 mm/h at Hospital Italiano, in Buenos Aires (Buenos Aires, Argentina) between January 2002 and August 2014. RESULTS: During the previously stated period of time, we analyzed the results of 879 patients. All patients were over 18 years of age. The median for the ESR results was 111 mm/h (interquartile range 105-120). The most prevalent etiology of an elevated ESR was infectious (41.64%), followed by malignancies (21.62%) and autoimmune / inflammatory diseases (12.97%). The most frequent individual diagnosis found was pneumonia (11.49%), followed by undetermined causes (5.92%). CONCLUSION: When comparing inpatient versus outpatient populations, the most frequent cause was infectious in the former group, while malignancies were the most frequent diagnosis in the latter. PMID- 29165507 TI - [Infectious or noninfectious phlebitis: lessons from a an interventional programm on phlebitis associated to peripheral venous catheter]. AB - BACKGROUND: There is no consensus definition to distinguish infectious from non infectious phlebitis associated to peripheral venous catheter. AIMS: To evaluate the impact of an intervention program on the rate of infectious (those associated to bacteremia or local purulent discharge) and non-infectious phlebitis (the rest) and identify differential features. METHODS: Interventional study developed in three stages: basal measurement, intervention, and evaluation. RESULTS: Ten infectious and 186 non-infectious phlebitis were registered. Infectious phlebitis diminished after intervention (0.2 to 0.04 events per 1,000 bed-days; p = 0.02) but not the rest (2.3 per 1,000 bed-days before and after). Five of 10 patients with infectious phlebitis had bacteremia, one with infectious endocarditis and valve replacement, and other with septic shock and a fatal outcome. None of the patients in the non-infectious group presented complications. Infectious phlebitis appeared later (mean 4.1 versus 2.4 days; p = 0.007) and were associated to fever (40% vs 5.9%, p = 0.004). Non-infectious phlebitis was associated to irritating compounds (OR 6.1; IC95 1.3-29, p < 0.05). CONCLUSIONS: The intervention program demonstrated a favorable impact only on the rate of infectious phlebitis. Distinction appears to be relevant because those of infectious origin are associated with fever, complications or death, respond to an intervention program, and emerge lately. PMID- 29165508 TI - [Test evaluation and strategy proposal to detect and to characterize carbapenemase-producing gram negative bacilli]. AB - INTRODUCTION: The detection of carbapenemase-producing gram negative bacilli is complicated, because there are available multiple options of test. The confirmation of the enzyme by molecular characterization is not available in all laboratories in our country. OBJECTIVE: To propose a fast, efficient and simple strategy to detect and confirm CPB. MATERIALS AND METHODS: 39 CPB isolates and 8 non-producing were used to evaluate the phenotypic test Carba NP, CarbAcineto NP and Blue-Carba, validating the test Xpert(r) Carba-R, to be used directly with bacterial colonies with conventional PCR. RESULTS: The sensitivity of Carba NP, CarbAcineto NP and Blue-Carba was 79,5; 87,2 y 84,6%, respectively; and specificity was 79.5; 87.2 and 84.6%, respectively. The limit of detection of Xpert(r) Carba-R was different for each carbapenemasa: 40.8 ufc/reaction to KPC and NDM and 30.6 ufc/reaction to VIM. DISCUSSION: On isolates with decreased susceptibility to carbapenems we propose to use as screening the test CarbAcineto NP, follow by Xpert(r)Carba-R to characterize the carbapenemase and adopt specific infection control measures. PMID- 29165509 TI - [Evaluation of Xpert(r) MTB/RIF technique for Mycobacterium tuberculosis complex detection in extra-respiratory specimens]. AB - Extra-pulmonary tuberculosis (TB) represents the 26.2% of total TB cases in Chile. Culture is the gold standard method, but the process is extremely slow. Xpert(r)MTB/RIF technique detects Mycobacterium tuberculosis complex (MTBc) through real time PCR in less than 3 h. However, it has been validated only for respiratory specimens. We aimed to determine the performance of Xpert(r)MTB/RIF test in detecting MTBc in extra-respiratory specimens compared with a combined gold standard consisting in a positive (liquid and solid) mycobacterial culture and/or a positive validated molecular method (q-RPC, Cobas(r)TaqMan(r)-MTB). Fifty extra-respiratory specimens were analyzed, from which 25 were positive and 25 negative for MTBc based on the combined gold standard. The 25 positive specimens had a positive result by Xpert(r)MTB/RIF; from the 25 negative specimens, 24 had a negative result and one had a positive result. We obtained an overall concordance of 98% between Xpert(r)MTB/RIF and the combined gold standard. Xpert(r)MTB/RIF test was able to detect 12 smear-negative specimens and 3 culture-negative specimens, all of them corresponding to extra-pulmonary TB cases. Xpert(r)MTB/RIF showed similar sensitivity to q-RPC in detecting MTBc in extra-respiratory specimens. This procedure allowed a substantial reduction in the time of diagnosis. PMID- 29165510 TI - [The 1,3-beta-d-glucan in critical adult patients as diagnostic tool for invasive Candida spp. infection, performance evaluation]. AB - BACKGROUND: Invasive fungal infections are important causes of morbimortality in critical patients. Most of these infections are caused by Candida spp. which diagnosis has important limitations. AIM: Initial evaluation of the utility of 1,3-beta-D-glucan (BDG) as a diagnostic tool for invasive candida infections in critical patients. PATIENTS AND METHODS: Adult patients over 18 years old, hospitalized in intensive care units for more than five days, with fever > 38 degrees C of unclear origin and two or more risk factors for invasive Candida spp. infection were included. Samples for BDG were obtained on two consecutive days. The results were compared with definitive diagnosis of candidemia/invasive candidiasis (C/IC) confirmed by cultures. RESULTS: Median value of BDG in patients with C/IC was 224.3 +/- 213.7 pg/ml and in patients without C/IC was 63.8 +/- 76.7 pg/ml (p: 0.02). Sensitivity and specificity for the diagnosis of C/IC were 60 and 92%, respectively. Positive predictive value was 60% and negative predictive value was 92%. CONCLUSION: BDG could be considered as a complementary diagnostic tool for the diagnosis of C/IC in critical patients with risk factors. PMID- 29165512 TI - [Antiretroviral treatment adherence for HIV/AIDS in women: a sociocultural perspective]. AB - BACKGROUND: Adequate adherence to HAART has a high impact on survival of AIDA patients. There is little consensus on the causes of low adherence to treatment in women, who are in a situation of inequality in terms of prevention and related care. OBJECTIVES: To explore and describe the socio-cultural aspects related to the adherence of women to antiretroviral treatment for HIV / AIDS. MATERIAL AND METHODS: Qualitative, exploratory-descriptive study. The study population was focused on Chilean women, who are 18 years of age or older, living with HIV/AIDS. The sample size was defined by information saturation. In-depth interviews were conducted with 16 women contacted in seven public care centers for people living with HIV (PLHIV) in 4 regions of the country, and it was take into account the saturation of the information. RESULTS: There are several sociocultural factors that determine the level of adherence that women adopt in relation to HAART. The most relevant ones are the vital satisfaction, the imaginary about HIV, the availability of their networks in front of diagnosis and the availability of information are fundamental. DISCUSSION: It is necessary to enter into specific interventions considering the sociocultural aspects and satisfying the psychosocial needs of women. It is imperative that public policies and health teams consider these aspects to improve adherence to HAART. PMID- 29165511 TI - [Cystoisospora belli infection in HIV patients: Analysis of cases with different clinical evolution]. AB - INTRODUCTION: Cystoisospora belli infection is one of the most important causes of watery diarrhea in patients with HIV and causes high rates of morbidity and mortality. METHODS: A retrospective study was conducted in patients with HIV and diarrhea by C. belli. Clinical and laboratory characteristics were collected by analyzing clinical records. RESULTS: Four had recurrent diarrhea despite receiving secondary prophylaxis with cotrimoxazole and specific treatment, two of which had a good viral and immunological response to highly active antiretroviral therapy (HAART) at the time of diagnosis and antiparasitic treatment. While the remaining three did not receive prophylaxis, neither did HAART (two of them), but they responded well to treatment. CONCLUSIONS: C. belli is an important cause of diarrhea in HIV patients on HAART and prophylaxis, being able to have different clinical evolution. We suggest that persistent infection may be due to drug failure by intrinsic or extrinsic to the parasite causes, or to defects in restoration of the intestinal immune system, or both. PMID- 29165513 TI - [A five-year experience with zoonotic Salmonella at a pediatric reference centre]. AB - BACKGROUND: Salmonella can cause asymptomatic infections, diarrhea, bacteremia and focal infections such as meningitis and osteomyelitis. AIM: To describe clinical and microbiological aspects of infections by Salmonella spp. in children in a pediatric referral hospital: Centro Hospitalario Pereira Rossell, in Montevideo, Uruguay. MATERIALS AND METHODS: Descriptive and retrospective study of 46 patients, from which Salmonella spp was isolated between January 1, 2005 and December 31, 2010. RESULTS: Salmonella spp was isolated in 46 children younger than 15 years old. 18 were below 2 years old and 5 children below three months. 24% of the children had risk factors, such as HIV infection, oncological diseases and malnutrition; low birth weight and pneumonia were associated conditions. No deaths were reported. The serotypes more frequently found were: Typhimurium and Enteritidis. Most of the strains were susceptible to ampicillin and third generation of cephalosporins. DISCUSSION: Diarrhea with blood was the predominant clinical presentation, and there were no outbreaks. Typhimurium and Enteritidis were the most common serotypes. Based on the profiles of susceptibility antimicrobial, we could maintain the same recommendations until the moment suggested. CONCLUSIONS: we must consider the Salmonella infection in febrile children under risk of an invasive bacterial disease, with or without focal infection. PMID- 29165514 TI - [Disseminated histoplasmosis and HIV infection: Case series in a Peruvian hospital]. AB - BACKGROUND: Histoplasmosis is an endemic fungal infection in Peru and HIV coinfection leads to difficult diagnoses and high associated mortality. AIM: To describe clinical, epidemiological and clinical outcomes in patients with HIV infection with diagnosis of disseminated histoplasmosis (DH) at Guillermo Almenara Irigoyen National Hospital, Lima, Peru. METHODS: Retrospective, descriptive study; information was obtained from the computer registry of patients with HIV infection diagnosed with DH, during the period 1996-2014. Clinical, epidemiological, treatment and outcome characteristics were described. RESULTS: We found 27 patients, 25 (92.6%) were male, with a mean age of 36.7 years (+/- 9.4 years) and 22 (81.5%) had an epidemiological history contact. Sixteen patients (59.3%) had DH as an AIDS defining disease. The median CD4 count was 65 cells/mm3 (IQR 15-92). Only 7 (25.9%) received combination antiretroviral therapy at diagnosis. The most common clinical presentation was fever (66.7%), chronic diarrhea (40.7%) and lymphadenopathy (33.3%). The diagnosis was made mainly by histopathology. Six (22.2%) patiens died in the acute stage of the disease. Seven (25.9%) were initially treated empirically as tuberculosis. CONCLUSION: We describe the clinical characteristics of a group of patients who had DH as HIV coinfection and this is still a quasi endemic reality in patients suffering from this pathology. PMID- 29165515 TI - [Statement of the Advisory Committee on Immunizations of Sociedad Chilena de Infectologia about outbreaks of hepatitis A in Chile]. AB - This document represents the position of the Chilean Infectious Diseases Society Advisory Committee on Immunization Practices regarding hepatitis A epidemiological situation in Chile. The recommendations are based on local epidemiological data, the hepatitis A virus infection characteristics and the global experience with the available vaccines. In relation to hepatitis A, Chile is no longer a highly endemic area but actually an intermediate one, currently concentrating cases in individuals over 15 years of age, with frequent outbreaks. In 2017 we have seen an important outbreak of genotype 1A in men who have sex with men (MSM). The current endemic, the presence of regular outbreaks, the frequency of natural disasters in Chile, together with the availability of safe, effective vaccines and local cost-effectiveness studies led us to propose measures for outbreak control for high risk groups protection and mid and long term, including a more definitive solution which is universal vaccination against this disease in small children. PMID- 29165516 TI - [Immigration and impact on infectious diseases of the newborn]. AB - Over the past few years immigration has become an important issue in Chile. Particular attention should be paid in foreign pregnant mothers. Infectious diseases screening in this group greatly reduce the risk of transmission to the fetus with appropriate therapy. PMID- 29165517 TI - ? PMID- 29165518 TI - [On the meaning and usefulness of History of Medicine (1895-1970)]. AB - The knowledge of the history of Medicine does not seem to add "utility" to the activities of a physician. Nevertheless, for a doctor eager to get good intellectual information -or the spiritual perfection called "culture"- the autor gives some reasons on why being acquainted with the history of medicine has some "utility" through the following items: Intellectual dignity: by deliberately and gratefully assuming the best of those who introduced technical devices or methods, as auscultation, or intellectual elaborations, like the etiologic model of Galen. Moral clarity: to perform as if they were his own, great deeds of the personages whose discoveries built the concepts and procedures used nowadays. Intellectual clarity: assuming the reason for being and the sense of what is being done. Intellectual liberty: knowing history in a comprehensive way, frees a doctor from the temptation of considering scientific notions as unmistakably true and definite. A possible option to originality: stimulated by a will of emulation, to search for less insecure or more rewarding knowledge, tending to "complete" what is at present accepted. PMID- 29165519 TI - [Central nervous system infection by Bartonella henselae associated with a choroid plexus papilloma]. AB - Bartonella henselae infection is a prevalent illness in Chile. It presents generally as a cat scratch disease or as a prolonged fever syndrome. There are atypical manifestations, which include central nervous system, bone, cardiac and hepato-esplenic compromised. We present an adolescent case with a history of fever, vomiting and ataxia, whose diagnosis was a central nervous system infection by Bartonella henselae associated with a choroid plexus papilloma. This case corresponds to an unusual presentation, with a challenging diagnosis. It is controversial whether to treat this patient, which antimicrobial is the right choice and how long the treatment should be. PMID- 29165520 TI - [Neisseria subflava bacteremia in newborns: case report and review of the literature]. AB - Neisseria subflava belongs to Neisseriaceae family, is considered a comensal specie, however in certain host, mainly inmunosuppresed patientes and children, the literature has documented invasive infections. We present a case of a bacteriemia due to N. subflava in a newborn, treated with cefotaxime with good outcome. In newborns, the most common Neisseria bacteria to cause invasive infections are N. meningitidis, with highly fatal clinical course and N. gonorrhoeae which compromise the eye, oftalmia neonatorum, with uncommon invasive infections. It's very important the adequate microbiological diagnosis because the biochemical tests may be inconclusive. MALDITOF mass spectrometry technique is a useful tool. PMID- 29165521 TI - [Gastrointestinal tuberculosis as a cause of massive gastrointestinal bleeding in a patient with HIV infection]. AB - Gastrointestinal tuberculosis is a rare and fatal complication in patients with HIV infection. It occurs in 3%-16% of extra pulmonary forms. The main location in 90% of cases is the ileocecal valve and colon. The most unusual presentation of gastrointestinal tuberculosis is massive bleeding with the presence of one or multiple ulcers in the colon. The diagnosis can be confirmed by biopsy and by culture of intestinal tissue. Surgical resection is the treatment of choice. We report a case of a HIV-infected patient, who did not receive antiretrovirals, and who developed disseminated tuberculosis with intestinal perforation, presenting a fatal massive intestinal bleeding. PMID- 29165522 TI - [Lactococcus garvieae endocarditis in a patient undergoing chronic hemodialysis. First case report in Chile and review of the literature]. AB - Reports of Lactococcus garvieae infections in humans are scarce, and only one of them in a patient under-going hemodialysis. We report the first case of Lactococcus garvieae infection in Chile, presenting as an infective endocarditis, ultimately fatal, in a patient with uncomplicated colonic diverticulosis and end stage renal failure undergoing chronic hemodialysis. We review the published cases and discuss the diagnostic and therapeutic challenges associated with this new, increasingly diagnosed pathogen, capable of producing serious infections in susceptible patients. PMID- 29165523 TI - [Chromoblastomycosis: clinical and microbiological characteristics of a neglected disease]. AB - Chromoblastomycosis is a neglected and chronic fungal disease, mainly affects the subcutaneous tissue in limbs of people with occupational risk. Here, we report two cases of adult patients from tropical regions of northern Peru, affected with chronic erythematous scaly lesions and multiple blackheads, pain, itching and scarring in older areas of injury. Direct examination of the dermal scales showed typical of this disease fumagoides cells; Fonsecaea pedrosoi and Fonsecaea sp. were isolated for at first and second case respectively. Patients received antifungal treatment with itraconazole; however, in both cases the final outcome was not observed due to treatment abandonment and medical care. PMID- 29165524 TI - [Bartonella henselae infection, the importance of images for diagnosis and follow up]. AB - Bartonella henselae infection is a frequent zoonosis from the domestic cat. It is presented with regional lymphadenitis in the majority of cases. Searching and characterization of lymph nodes by diagnostic imaging can be useful in the differential diagnosis approach, with a clear advantage, because it is a noninvasive method. Currently, new diagnostic imaging techniques improves the quality of screening and characterization of adenopathies, such is the case of PET/CT, which allows a better evaluation of hypermetabolic lymph nodes, without considering the individual growth of each lymph node. In this article, three cases of cat scratch diseases serology and their respective imaging findings are reviewed. PMID- 29165525 TI - [The colistin MIC determination in Acinetobacter baumannii, Should it be reviewed?] AB - Currently, there is a controversy in how to determine the minimal inhibitory concentration (MIC) of colistin against Acinetobacter baumannii. We compared three methods, concluding that the addition of Tween-80 (0.002%) to Muller-Hinton broth in the microdilution method could improve MIC determination and it could reduce false resistance. PMID- 29165526 TI - [Epidemiological characteristics of HIV infection in Paraguay during 2015]. AB - To characterize the epidemiology of HIV in Paraguay, from january to december, in 2015. The epidemic remains focused in those groups under risk, predominantly male. The characteristics of the study population shows that most of the affected were from the central area and from the capital city, and sexual transmission remains the most common pathway, with delayed diagnosis, which is reflected by the percentage of people presenting a low CD4 cell count. PMID- 29165527 TI - [Viruses that have sexual transmission as an alternative route: reflection on the secondary STIs of the 21st century]. PMID- 29165528 TI - [Leptospirosis after "Coastal Child": A current view of Peruvian north]. PMID- 29165529 TI - [Forgotten prevention: the reemergence of HIV in Chile]. PMID- 29165530 TI - [Control of carbapenemase-producing Enterobacteriaceae outbreaks in acute settings: an evidence review]. PMID- 29165531 TI - Prevention of Frailty in Aging. PMID- 29165532 TI - Relationship of Serum Carnitine Level with Falls and Gait Disturbance in the Elderly. AB - BACKGROUND: Gait disturbance and falls are serious events that can impair activities of daily living (ADL) in the elderly. On the other hand, carnitine plays essential roles in energy production, and carnitine deficiency leads to low activity levels. OBJECTIVES: We examined whether a lower serum carnitine concentration was correlated with falls and gait disturbances in the elderly. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional study. One hundred and ninety-eight elderly patients (male, 83; female, 115; 81 +/- 6 years old) were enrolled in this study. MEASUREMENTS: Physical performance (hand grip strength, leg strength, walking speed, one-leg standing time, and tandem gait steps) and frailty status (The Edmonton Frail Scale: EFS) were evaluated. The serum total, free, and acylated carnitine levels were measured using an enzyme cycling method. We then investigated the associations between the serum carnitine level, history of falls, and the results of these physical examinations. RESULTS: Of the 198 subjects, 56 (28%) had a history of falls within the past one year. The patients with a history of falls had lower serum total carnitine and free carnitine levels than those without a history of falls. Regarding the physical performance results, the patients with a history of falls had higher EFS scores, a weaker hand grip strength, a slower walking speed, a shorter one-leg standing time, and a smaller number of tandem gait steps than those without a history of falls. A logistic regression analysis showed that the low serum total carnitine concentration was identified as an independent factor associated with a history of falls, a slow walking speed after adjustments for age, sex and modified EFS. CONCLUSIONS: A low serum carnitine level is associated with a history of falls and gait disturbances in elderly people. PMID- 29165533 TI - Muscle Quality, Strength, and Lower Extremity Physical Performance in the Baltimore Longitudinal Study of Aging. AB - BACKGROUND: Muscle quality is defined as the force generated by each volumetric unit of muscle tissue. No consensus exists on an optimal measure of muscle quality, impeding comparison across studies and implementation in clinical settings. It is unknown whether muscle quality measures that rely on complex and expensive tests, such as isokinetic dynamometry and computerized tomography correlate with lower extremity performance (LEP) any better than measures derived from simpler and less expensive tests, such as grip strength (Grip) and appendicular lean mass (ALM) assessed by DXA. Additionally, whether muscle quality is more strongly associated with LEP than strength has not been fully tested. OBJECTIVES: This study compares the concurrent validity of alternative measures of muscle quality and characterizes their relationship with LEP. We also whether muscle quality correlates more strongly with LEP than strength alone. DESIGN: Cross-sectional analysis. SETTING: Community. PARTICIPANTS: 365 men and 345 women 65 years of age and older in the Baltimore Longitudinal Study of Aging. MEASURES: Thigh cross-sectional area (TCSA), isokinetic and isometric knee extension strength (ID), BMI adjusted ALM (ALMBMI) from DXA, and Grip. Concurrent validity was assessed as the percent variance of different measures of LEP explained by each muscle quality measure. In addition, we compared LEP relationships between each measure of strength and its correspondent value of muscle quality. Confidence intervals for differences in percent variance were calculated by bootstrapping. RESULTS: Grip/ALMBMI explained as much variance as ID/TCSA across all LEP measures in women and most in men. Across all LEP measures, strength explained as much variance of LEP as muscle quality. CONCLUSIONS: Grip/ALMBMI and ID/TCSA measures had similar correlations with LEP. Muscle quality did not outperform strength. Although evaluating muscle quality may be useful to assess age-related mechanisms of change in muscle strength, measures of strength alone may suffice to understand the relationship between muscle and LEP. PMID- 29165534 TI - Various Diagnostic Measures of Frailty as Predictors for Falls, Weight Change, Quality of Life, and Mortality among Older Finnish Men. AB - BACKGROUND: Frailty predisposes individuals to a variety of complications. However, there is no consensus on the definition of frailty. OBJECTIVES: To examine whether various frailty measures are equivalent in identifying the same individuals as being frail and whether the measures also predict similar outcomes. DESIGN, SETTING AND PARTICIPANTS: The Helsinki Businessmen Study cohort, which is a long-term observational study of men born in 1919-1934, was used as the population. We investigated these men by their postal questionnaire responses in 2000 and 2005. The mean age of the men (N=480) was 73 years at the start of follow-up. MEASUREMENTS: We compared two phenotypic frailty measures, the Helsinki Businessmen Study measure (HBS), the modified Women's Health Initiative Observational Study (WHI-OS), and the Frailty Index (FI) comprising 20 items. All three measurements were applied to Helsinki Businessmen Study cohort data collected via simple postal questionnaire from 480 men. We investigated how effectively these three measures distinguished between the not frail, prefrail, and frail individuals, and predicted mortality, falls, weight change, and health related quality of life (HRQoL, 15D instrument) during a 5-year follow-up. RESULTS: The HBS and the modified WHI-OS identified 35 persons (7.3%) each as frail but their respective sets comprised different groupings of individuals that partly overlapped. The FI identified 86 persons (17.9%) as frail. One-hundred-and two (21.3%) men were classified as frail by at least one of the measures. All three measures significantly predicted higher mortality, higher number of fallers, and lower HRQoL for frail participants. None of the measures showed different results for weight change between the frailty groups or frailty stages. CONCLUSIONS: All three measures identified somewhat different sets of participants as frail. They all predicted increased mortality, falls and reduced HRQoL for the frail groups. PMID- 29165535 TI - The Feasibility of Standardised Geriatric Assessment Tools and Physical Exercises in Frail Older Adults. AB - Geriatric assessment tools are applicable to the general geriatric population; however, their feasibility in frail older adults is yet to be determined. The study aimed to determine the feasibility of standardised geriatric assessment tools and physical exercises in hospitalised frail older adults. Various assessment tools including the FRAIL Screen, the Charlson Comorbidity Index, the SF-36, the Trail Making Test (TMT), the Rapid Cognitive Screen, the Self Mini Nutritional Assessment (MNA-SF) and the Lawton iADL as well as standard physical exercises were assessed using observational protocols. The FRAIL Screen, MNA-SF, Rapid Cognitive Screen, Lawton iADL and the physical exercises were deemed to be feasible with only minor comprehension, execution and safety issues. The TMT was not considered to be feasible and the SF-36 should be replaced by its shorter form, the SF-12. In order to ensure the validity of these findings a study with a larger sample size should be undertaken. PMID- 29165536 TI - Reference Values for Knee Extension Strength Obtained by Hand-Held Dynamometry from Apparently Healthy Older Adults: A Meta-Analysis. AB - Normative reference values for knee extension strength obtained by hand-held dynamometry from adults 60 to 79 years were derived using summary data from 3 studies. The studies, which were identified through PubMed and a hand-search, contributed data from between 3 and 29 individuals for each age, gender, and side stratum. Meta-analysis was employed to consolidate knee extension strength data. Strength, normalized against body weight, ranged 35.6% for the nondominant side of 70 to 79 year old women to 48.8% for the nondominant side of 60 to 69 year old men. These values are more informative than those previously published in individual studies. However, reference values derived from a large population based sample are needed. PMID- 29165537 TI - Frailty Is not Associated with Mistreatment. AB - Muscle Frailty has been previously associated with increased vulnerability for adverse health-related outcomes that could lead to social consequences such as mistreatment. The aim of this cross-sectional study is to determine the association between frailty and mistreatment in 852 community-dwelling persons aged 70 or older. Mistreatment was defined as one positive answer in the Geriatric Mistreatment Scale and frailty was used as a continuum where the greater number of positive criteria according to Fried et al. indicates a higher frailty score. Multivariate logistic regression models were run to establish this association. The mean age of participants was 77.7 years (SD=6.1). Prevalence of frailty phenotype and mistreatment were 13.9% and 20% respectively. Unadjusted analysis showed frailty score was associated with mistreatment (OR = 1.16; 95% CI 1.02 to 1.3, p=0.022). However, after adjustment, the association was no longer present. The results showed that in the presence of other geriatric syndromes such as disability or depression, frailty did not show association with mistreatment in this population. PMID- 29165538 TI - Augmented Reality: Sustaining Autonomous Way-Finding in the Community for Older Persons with Cognitive Impairment. AB - BACKGROUND: Impairment of autonomous way-finding subsequent to a multitude of neurodegenerative and other diseases impedes independence of older persons and their everyday activities. OBJECTIVE: It was the goal to use augmented reality to aid autonomous way-finding in a community setting. DESIGN: A spatial map and directional information were shown via head-up display to guide patients from the start zone on the hospital campus to a bakery in the nearby community. SETTING: Hospital campus and nearby community. PARTICIPANTS: Patients with mild cognitive impairment (age 63 to 89). INTERVENTIONS: A head-up display was used to help patients find their way. MEASUREMENTS: Time needed to reach goal and number of assists needed. RESULTS: With use of augmented reality device, patients preceded along the correct path in 113 out of 120 intersections. Intermittent reassurance was needed for most patients. Patients affirmed willingness to use such an augmented reality device in everyday life if needed or even pay for it. CONCLUSION: Augmented reality guided navigation is a promising means to sustain autonomous way-finding as a prerequisite for autonomy of older persons in everyday activities. Thus, this study lays ground for a field trial in the community using assistive technology for older persons with cognitive impairment. PMID- 29165539 TI - Management of Musculoskeletal Conditions in Rural South Australia: A Randomised Controlled Trial. AB - With age, the prevalence of musculoskeletal conditions increases markedly. This rural-based study determined the benefits of two approaches for managing musculoskeletal conditions: a multiple-component 'Self-management Plus' intervention, and usual care. The intervention combined self-management education with physical activity and health professional support. 6-month outcomes included: Clinical Global Impression-Improvement Scale (CGI-IS) and Quality of Life (QoL). A total of 145 people were recruited; mean (SD) age was 66.1 (11.1) and 63.3 (10.9) years for intervention and control groups respectively. The intervention resulted in greater improvements in global functioning (CGI-IS mean (SD) = 3.2 (1.3)) than usual care (CGI-IS mean (SD) = 4.2 (1.5)). There was no difference in QoL improvement between study groups. A multiple-component 'Self management Plus' intervention had a positive effect on physical functioning for older adults with musculoskeletal conditions. However, recruitment and retention of participants was problematic, which raises questions about the intervention's feasibility in its current form. PMID- 29165540 TI - Mobile Application Removes Societal Barriers to P4 Medicine. AB - The overlap between one innovative paradigm (P4 medicine: predictive, personalized, participatory and preventive) and another (a new definition of "Healthy ageing") is fertile ground for new technologies; a new mobile application (app) that could broaden our scientific knowledge of the ageing process and help us to better analyse the impact of possible interventions in slowing the ageing decline. A novel mobile application is here presented as a game including questions and tests will allow in 10 minutes the assessment of the following domains: robustness, flexibility (lower muscle strength), balance, mental and memory complaints, semantic memory and visual retention. This game is completed by specific measurements, which could allow establishing precise information on functional and cognitive abilities. A global evaluation precedes advice and different types of exercises. The repetition of the tests and measures will allow a long follow up of the individual performances which could be shared (on specific request) with family members and general practitioners. PMID- 29165541 TI - Frailty Exists in Younger Adults Admitted as Surgical Emergency Leading to Adverse Outcomes. AB - BACKGROUND: Frailty is prevalent in the older adult population (>=65 years of age) and results in adverse outcomes in the emergency general surgical population. OBJECTIVE: To determine whether frailty exists in the younger adult emergency surgical population (<65 years) and what influence frailty may have on patient related outcomes. DESIGN: Prospective observational cohort study. SETTING: Emergency general surgical admissions. PARTICIPANTS: All patients >=40 years divided into 2 groups: younger adults (40-64.9 years) and older adult comparative group (>=65). MEASUREMENTS: Over a 6-month time frame the following data was collected: demographics; Scottish Index of Multiple Deprivation (SIMD); blood markers; multi-morbidities, polypharmacy and cognition. Frailty was assessed by completion of the Canadian Study of Health and Ageing (CSHA). Each patient was followed up for 90 days to allow determination of length of stay, re admission and mortality. RESULTS: 82 young adults were included and the prevalence of frailty was 16% (versus older adults 38%; p=0.001) and associated with: multi-morbidity; poly-pharmacy; cognitive impairment; and deprivation. Frailty in older adults was only significantly associated with increasing age. CONCLUSIONS: This novel study has found that frailty exists in 16% of younger adults admitted to emergency general surgical units, potentially leading to adverse short and long-term outcomes. Strategies need to be developed that identify and treat frailty in this vulnerable younger adult population. PMID- 29165542 TI - Measuring Frailty among Older People: Further Evaluation of the Brody Frailty Index. AB - BACKGROUND AND OBJECTIVE: The study aimed to evaluate the predictive validity of the Brody self-report frailty index among older people. Design, setting and measurements: A longitudinal cohort study (2-years) conducted in Sweden, which included 1141 respondents, aged 65-103 years. Data were collected during 2011 2013 through a postal questionnaire with questions about demographic data, living conditions, self-reported health, ADL dependency (ADL-staircase) and frailty (the Brody frailty index). RESULTS: The total sample was comprised of 53 percent women and the mean age was 74.5 years (SD 7.0). The mean frailty index score at baseline was 0.12 and increased with higher age (rs= 0.819) as well as with increased ADL dependency (rs = 0.740). The analyses showed high percentage of correctly classified cases (97.1-98.2), high specificity (98.1-98.4) but low sensitivity (22.2-66.7). CONCLUSION: The self-report frailty index seems to be a valid measure of current frailty, but its predictive validity was found to be non acceptable especially regarding the instrument's sensitivity. Such instrument can be useful to predict frailty and allocate resources in the care of older people. PMID- 29165543 TI - Identification of older adults with frailty in the Emergency Department using a frailty index: results from a multinational study. AB - Objective: frailty is a central concept in geriatric medicine, yet its utility in the Emergency Department (ED) is not well understood nor well utilised. Our objectives were to develop an ED frailty index (FI-ED), using the Rockwood cumulative deficits model and to evaluate its association with adverse outcomes. Method: this was a large multinational prospective cohort study using data from the interRAI Multinational Emergency Department Study. The FI-ED was developed from the Canadian cohort and validated in the multinational cohort. All patients aged >=75 years presenting to an ED were included. The FI-ED was created using 24 variables included in the interRAI ED-Contact Assessment tool. Results: there were 2,153 participants in the Canadian cohort and 1,750 in the multinational cohort. The distribution of the FI-ED was similar to previous frailty indices. The mean FI-ED was 0.26 (Canadian cohort) and 0.32 (multinational cohort) and the 99th percentile was 0.71 and 0.81, respectively. In the Canadian cohort, a 0.1 unit increase in the FI-ED was significantly associated with admission (odds ratio (OR) = 1.43 [95% CI: 1.34-1.52]); death at 28 days (OR = 1.55 [1.38-1.73]); prolonged hospital stay (OR = 1.37 [1.22-1.54]); discharge to long-term care (OR = 1.30 [1.16-1.47]); and need for Comprehensive geriatric Assessment (OR = 1.51 [1.41-1.60]). The multinational cohort showed similar associations. Conclusion: the FI-ED conformed to characteristics previously reported. A FI, developed and validated from a brief geriatric assessment tool could be used to identify ED patients at higher risk of adverse events. PMID- 29165545 TI - Successful in vitro maturation of oocytes: a matter of follicular differentiation. AB - Folliculogenesis is remarkably similar in cattle and humans. In this review, we consider the known differences and provide a possible explanation for the greater success of oocyte in vitro maturation in cattle. Two different parallel processes that are critical for oocyte competence acquisition are examined. The first occurs in the follicle and in turn influences the oocyte, the second occurs within the oocyte itself and involves the gradual cessation of the transcription machinery with additional changes observable in the chromatin structure. We expect this insight to contribute to the improvement of human fertility programs based on in vitro fertilization, and particularly to the development of controlled ovarian stimulation protocols that yield more high-quality oocytes and thereby improve the clinical performance of treatments for infertility. PMID- 29165544 TI - RNA methylation and diseases: experimental results, databases, Web servers and computational models. AB - Ribonucleic acid (RNA) methylation is a type of posttranscriptional modifications occurring in all kingdoms of life. It is strongly related to important biological process, thus making it linked to a number of human diseases. Owing to the development of high-throughput sequencing technology, plenty of achievement had been obtained in RNA methylation research recently. Meanwhile, various computational models have been developed to analyze and mining increasing RNA methylation data. In this review, we first made a brief introduction about eight types of most popular RNA methylation, the biological functions of RNA methylation, the relationship between RNA methylation and disease and five important RNA methylation-related diseases. The research of RNA methylation is based on sequencing data processing, and effective bioinformatics techniques can benefit better understanding of RNA methylation. We further introduced seven publicly available RNA methylation-related databases, and some important publicly available RNA-methylation-related Web servers and software for RNA methylation site identification, differential analysis and so on. Furthermore, we provided detailed analysis of the state-of-the-art computational models used in these Web servers and software. We also analyzed the limitations of these models and discussed the future directions of developing computational models for RNA methylation research. PMID- 29165546 TI - Will liquid biopsies become our fluid transition to personalized immunotherapy? PMID- 29165547 TI - Multiple Imputation for Incomplete Data in Epidemiologic Studies. AB - Epidemiologic studies are frequently susceptible to missing information. Omitting observations with missing variables remains a common strategy in epidemiologic studies, yet this simple approach can often severely bias parameter estimates of interest if the values are not missing completely at random. Even when missingness is completely random, complete-case analysis can reduce the efficiency of estimated parameters, because large amounts of available data are simply tossed out with the incomplete observations. Alternative methods for mitigating the influence of missing information, such as multiple imputation, are becoming an increasing popular strategy in order to retain all available information, reduce potential bias, and improve efficiency in parameter estimation. In this paper, we describe the theoretical underpinnings of multiple imputation, and we illustrate application of this method as part of a collaborative challenge to assess the performance of various techniques for dealing with missing data (Am J Epidemiol. 2018;187(3):568-575). We detail the steps necessary to perform multiple imputation on a subset of data from the Collaborative Perinatal Project (1959-1974), where the goal is to estimate the odds of spontaneous abortion associated with smoking during pregnancy. PMID- 29165548 TI - Affairs of the heart: outcomes in men and women with hypertrophic cardiomyopathy. PMID- 29165549 TI - Prognostic impacts of Rho-kinase activity in circulating leucocytes in patients with vasospastic angina. AB - Aims: Rho-kinase activity in circulating leucocytes is a useful biomarker for diagnosis and disease activity assessment of vasospastic angina (VSA). The present study aimed to examine the long-term prognostic impact of Rho-kinase activity in circulating leucocytes in VSA patients. Methods and results: We prospectively enrolled 174 consecutive patients with VSA and 50 non-VSA patients, in whom we measured Rho-kinase activity in circulating leucocytes, and they were followed for a median of 16 months. The primary endpoint was cardiac events including cardiac death, non-fatal myocardial infarction, and hospitalization for unstable angina. During the follow-up period, cardiac events occurred in 10 VSA patients (5.7%) but in none of the non-VSA patients. When we divided VSA patients into two groups by a median value of their Rho-kinase activity, the Kaplan-Meier survival analysis showed a significantly worse prognosis in VSA patients with high Rho-kinase activity compared with those with low activity or non-VSA patients (log-rank; P < 0.05, respectively). Receiver-operating characteristic curve analysis showed that Rho-kinase activity value of 1.24 was the best cut-off level to predict cardiac events in VSA patients, and multivariable analysis showed that a value above the cut-off point had the largest hazard ratio to predict poor outcome in VSA patients [hazard ratio (95% confidence interval) 11.19 (1.41-88.95); P = 0.022]. Importantly, combination of the Japanese Coronary Spasm Association risk score and Rho-kinase activity significantly improved the prognostic impact in VSA patients as compared with either alone. Conclusion: Rho kinase activity in circulating leucocytes is useful for prognostic stratification of VSA patients. PMID- 29165550 TI - Male breast cancer: pink ribbon blues. PMID- 29165552 TI - What Happened to the IGF Binding Proteins? AB - Insulinlike growth factor (IGF) binding proteins (IGFBPs) 1 to 6 are high affinity regulators of IGF activity. They generally inhibit IGF actions by preventing binding to the IGF-I receptor but can also enhance their actions under some conditions. Posttranslational modifications such as glycosylation and phosphorylation modulate IGFBP properties, and IGFBP proteolysis results in IGF release. IGFBPs have more recently been shown to have IGF-independent actions. A number of mechanisms are involved, including modulation of other growth factor pathways, nuclear localization and transcriptional regulation, interaction with the sphingolipid pathway, and binding to non-IGF biomolecules in the extracellular space and matrix, on the cell surface and intracellularly. IGFBPs modulate important biological processes, including cell proliferation, survival, migration, senescence, autophagy, and angiogenesis. Their actions have been implicated in growth, metabolism, cancer, stem cell maintenance and differentiation, and immune regulation. Recent studies have shown that epigenetic mechanisms are involved in the regulation of IGFBP abundance. A more complete understanding of IGFBP biology is necessary to further define their cellular roles and determine their therapeutic potential. PMID- 29165553 TI - Solvent Transfer-Efficiency of Risk Management Measures. AB - A series of laboratory simulations were conducted in order to determine the airborne protection that might be afforded by different combinations of workplace exposure controls typically encountered when handling volatile solvents (e.g. solvent transfer). These conditions, referred to as risk management measures (RMMs) under the Registration, Evaluation and Authorisation of Chemicals Regulation (REACH), are typically described using standard phrases in safety data sheets [and specifically those of the European Phrase Catalogue (EUPhraC)]. Ethanol was used as a model compound and its emissions were monitored continuously with a portable IR spectrometer at 3000 cm-1. The average emission reduction performance of the investigated RMMs (e.g. containment, extract ventilation, drum pump) exceeded 90%. They present suitable ways to reduce airborne solvent exposure in a workplace and confirmed the initial expectations derived at by the European Solvents Industry Group (ESIG) and the European Centre For Ecotoxicology and toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) model. PMID- 29165551 TI - Evolution and ecology of plant architecture: integrating insights from the fossil record, extant morphology, developmental genetics and phylogenies. AB - Background: In contrast to most animals, plants have an indeterminate body plan, which allows them to add new body parts during their lifetime. A plant's realized modular construction is the result of exogenous constraints and endogenous processes. This review focuses on endogenous processes that shape plant architectures and their evolution. Scope: The phylogenetic distribution of plant growth forms across the phylogeny implies that body architectures have originated and been lost repeatedly, being shaped by a limited set of genetic pathways. We (1) synthesize concepts of plant architecture, so far captured in 23 models; (2) extend them to the fossil record; (3) summarize what is known about their developmental genetics; (4) use a phylogenetic approach in several groups to infer how plant architecture has changed and by which intermediate steps; and (5) discuss which macroecological factors may constrain the geographic and ecological distribution of plant architectures. Conclusions: Dichotomously branching Paleozoic plants already encompassed a considerable diversity of growth forms, here captured in 12 new architectural models. Plotting the frequency of branching types through time based on an analysis of 58 927 land plant fossils revealed a decrease in dichotomous branching throughout the Devonian and Carboniferous, mirrored by an increase in other branching types including axillary branching. We suggest that the evolution of seed plant megaphyllous leaves enabling axillary branching contributed to the demise of dichotomous architectures. The developmental-genetic bases for key architectural traits underlying sympodial vs. monopodial branching, rhythmic vs. continuous growth, and axillary branching and its localization are becoming well understood, while the molecular basis of dichotomous branching and plagiotropy remains elusive. Three phylogenetic case studies of architecture evolution in conifers, Aloe and monocaulous arborescent vascular plants reveal relationships between architectural models and show that some are labile in given groups, whereas others are widely conserved, apparently shaped by ecological factors, such as intercepted sunlight, temperature, humidity and seasonality. PMID- 29165556 TI - Resumption of oral anticoagulation following traumatic injury and risk of stroke and bleeding in patients with atrial fibrillation: a nationwide cohort study. AB - Aims: We examined the risks of all-cause mortality, stroke, major bleeding, and recurrent traumatic injury associated with resumption of vitamin K antagonists (VKAs) and non-VKAs oral anticoagulants (NOACs) following traumatic injury in atrial fibrillation (AF) patients. Methods and results: This was a Danish nationwide registry-based study (2005-16), including 4541 oral anticoagulant (OAC)-treated AF patients experiencing traumatic injury (defined as traumatic brain injury, hip fracture, or traumatic torso or abdominal injury). Within 90 days following discharge from traumatic injury, 60.6% resumed VKA (median age = 80, CHA2DS2-VASc = 4, HAS-BLED = 2), 16.7% resumed NOAC (median age = 81, CHA2DS2 VASc = 4, HAS-BLED = 2), and 22.7% did not resume OAC treatment (median age = 81, CHA2DS2-VASc = 4, HAS-BLED = 3). Switch from VKA to NOAC occurred among 9.5%. Since 2009, the trend in OAC resumption increased (P-value <0.0001), in particular with NOACs (P-value <0.0001). Follow-up started 90 days after discharge, and time-varying multiple Cox regression analyses were used for comparisons. Compared with non-resumption, VKA and NOAC resumption were associated with lower hazard [95% confidence interval (CI)] of all-cause mortality [hazard ratio (HR) 0.48 (0.42-0.53) and HR 0.55 (0.47-0.66), respectively] and ischaemic stroke [HR 0.56 (0.43-0.72) and HR 0.54 (0.35-0.82), respectively], increased major bleeding hazard [HR 1.30 (1.03-1.64) and HR 1.15 (0.81-1.63), respectively], and similar hazard of recurrent traumatic injury [HR 0.93 (0.73-1.18) and HR 0.87 (0.60-1.27), respectively]. Conclusion: AF patients resuming VKA and NOAC treatment following traumatic injury have lower hazard of all-cause mortality and ischaemic stroke, increased hazard of major bleeding but without additional hazards of recurrent traumatic injury. Withholding OAC following a traumatic injury in AF patients may not be warranted. PMID- 29165554 TI - The effect of 1.5 T cardiac magnetic resonance on human circulating leucocytes. AB - Aims: Investigators have proposed that cardiovascular magnetic resonance (CMR) should have restrictions similar to those of ionizing imaging techniques. We aimed to investigate the acute effect of 1.5 T CMR on leucocyte DNA integrity, cell counts, and function in vitro, and in a large cohort of patients in vivo. Methods and results: In vitro study: peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers, and histone H2AX phosphorylation (gamma H2AX) expression, leucocyte counts, and functional parameters were quantified using flow cytometry under the following conditions: (i) immediately following PBMC isolation, (ii) after standing on the benchside as a temperature and time control, (iii) after a standard CMR scan. In vivo study: blood samples were taken from 64 consecutive consenting patients immediately before and after a standard clinical scan. Samples were analysed for gamma-H2AX expression and leucocyte counts. CMR was not associated with a significant change in gamma-H2AX expression in vitro or in vivo, although there were significant inter-patient variations. In vitro cell integrity and function did not change with CMR. There was a significant reduction in circulating T cells in vivo following CMR. Conclusion: 1.5 T CMR was not associated with DNA damage in vitro or in vivo. Histone H2AX phosphorylation expression varied markedly between individuals; therefore, small studies using gamma-H2AX as a marker of DNA damage should be interpreted with caution. Cardiovascular magnetic resonance was not associated with loss of leucocyte viability or function in vitro. Cardiovascular magnetic resonance was associated with a statistically significant reduction in viable leucocytes in vivo. PMID- 29165555 TI - Prenatal exposure to di(2-ethylhexyl) phthalate disrupts ovarian function in a transgenerational manner in female mice. AB - Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer found in polyvinyl chloride products such as vinyl flooring, plastic food containers, medical devices, and children's toys. DEHP is a ubiquitous environmental contaminant and is a known endocrine disrupting chemical. Little is known about the effects of prenatal DEHP exposure on the ovary and whether effects occur in subsequent generations. Thus, we tested the hypothesis that prenatal exposure to DEHP disrupts ovarian functions in the F1, F2, and F3 generations of female mice. To test this hypothesis, pregnant CD-1 mice were orally dosed with corn oil (vehicle control) or DEHP (20 and 200 MUg/kg/day and 200, 500, and 750 mg/kg/day) daily from gestation day 10.5 until birth (7-28 dams/treatment group). F1 females were mated with untreated males to obtain the F2 generation, and F2 females were mated with untreated males to produce the F3 generation. On postnatal days 1, 8, 21, and 60, ovaries were collected and used for histological evaluation of follicle numbers and sera were used to measure progesterone, testosterone, 17beta-estradiol, luteinizing hormone, and follicle stimulating hormone levels. In the F1 generation, prenatal exposure to DEHP disrupted body and organ weights, decreased folliculogenesis, and increased serum 17beta-estradiol levels. In the F2 generation, exposure to DEHP decreased body and organ weights, dysregulated folliculogenesis, and disrupted serum progesterone levels. In the F3 generation, DEHP exposure accelerated folliculogenesis. These data suggest that prenatal exposure to DEHP leads to adverse multigenerational and transgenerational effects on ovarian function. PMID- 29165557 TI - Inverse-Probability-Weighted Estimation for Monotone and Nonmonotone Missing Data. AB - Missing data is a common occurrence in epidemiologic research. In this paper, 3 data sets with induced missing values from the Collaborative Perinatal Project, a multisite US study conducted from 1959 to 1974, are provided as examples of prototypical epidemiologic studies with missing data. Our goal was to estimate the association of maternal smoking behavior with spontaneous abortion while adjusting for numerous confounders. At the same time, we did not necessarily wish to evaluate the joint distribution among potentially unobserved covariates, which is seldom the subject of substantive scientific interest. The inverse probability weighting (IPW) approach preserves the semiparametric structure of the underlying model of substantive interest and clearly separates the model of substantive interest from the model used to account for the missing data. However, IPW often will not result in valid inference if the missing-data pattern is nonmonotone, even if the data are missing at random. We describe a recently proposed approach to modeling nonmonotone missing-data mechanisms under missingness at random to use in constructing the weights in IPW complete-case estimation, and we illustrate the approach using 3 data sets described in a companion article (Am J Epidemiol. 2018;187(3):568-575). PMID- 29165558 TI - "She Had a Smile on Her Face as Wide as the Great Australian Bite": A Qualitative Examination of Family Perceptions of a Therapeutic Robot and a Plush Toy. AB - Background and Objectives: Recent years have seen social robotic pets introduced as a means of treating behavioral and psychological symptoms of dementia, and many show promising potential. In this study, we sought to explore family members' perceptions of the Japanese-developed baby harp seal, Paro (version 9), and a look-alike, nonrobotic Plush Toy, when used by their relative with dementia for 15 min, 3 afternoons per week for 10 weeks. Research Design and Method: The study employed a descriptive qualitative approach, which was nested within a larger cluster randomized controlled trial. A convenience sample of 20 family members (n = 10 each from the Paro and Plush Toy conditions) with relatives in 9 long-term care facilities in Queensland, Australia, completed individual semi structured interviews (telephone or face-to-face). Inductive, data-driven thematic analysis of the data was undertaken with the assistance of the qualitative management software, ATLAS.ti(r). Results: Family members of long term care residents with dementia expressed positive perceptions of the Paro, perceiving that it improved mood, reduced agitation, and provided opportunity for communication for their relative. Negative perceptions of the Plush Toy were given by family members, primarily because of its lack of movement and engagement. Conclusion: Family members were keen for their older relative with dementia to use a social robot that moved and engaged with them, and Plush Toys that were static and unresponsive were perceived as being unimportant in improving quality of life. However, the current cost of Paro was identified by family members as a major limitation to use. PMID- 29165559 TI - Impact of pre-admission oral anticoagulation on ischaemic stroke volume, lesion pattern, and frequency of intracranial arterial occlusion in patients with atrial fibrillation. AB - Aims: Therapeutic oral anticoagulation on hospital admission reduces morbidity and mortality after acute ischaemic stroke in patients with atrial fibrillation (AF). The underlying mechanism is not fully understood. In order to assess the impact of INR-level on admission on stroke volume, lesion pattern and the frequency of intracranial arterial occlusion, we analysed serial MRI measurements in AF patients suffering acute ischaemic stroke. Methods and results: This subgroup analysis of the prospective '1000Plus' study included patients with acute ischaemic stroke and known AF or a first episode of AF in hospital. All patients underwent serial brain magnetic resonance imaging. Stroke patients were categorized as follows: Group1, phenprocoumon intake, international normalized ratio (INR) >=1.7 on admission, no thrombolysis; Group2, INR < 1.7 on admission, thrombolysis; and Group3, INR < 1.7, no thrombolysis. In 98 AF patients {77 +/- 9 years, 60% male; median National Institute of Health Stroke Scale [NIHSS] score on admission 5 (interquartile range [IQR] 2-8)} with known AF before admission, territorial infarction was less often found in Group 1 (n = 20) compared with Group 2 + 3 (20% vs. 47%, P = 0.022). Arterial occlusion rate on admission differed among groups (30%, 75%, and 35%, respectively, P = 0.004) but not between Group 1 vs. Group 2 + 3 (30% vs. 45%, P = 0.31). Median FLAIR volume on Days 5-7 was lower in Group1 compared with Group 2 (n = 20) [3.2 cm3 (IQR 1.1 11.3) vs. 18.6 cm3 (IQR 8.2-49.4); P = 0.009] but not compared with Group 2 + 3 [7.8 cm3 (IQR 1.6-25.9); P = 0.23]. An INR >= 1.7 on admission was not associated with smaller stroke volume in multivariable regression analysis. Adding 57 patients with a first AF episode during the in-hospital stay, similar results were observed in 155 AF patients. Conclusion: In this AF cohort, an INR >= 1.7 at stroke onset affects lesion pattern but does not affect significantly lower stroke volume and the frequency of arterial occlusion on admission. PMID- 29165560 TI - Aging With Long-Term Mobility Impairment: Maintaining Activities of Daily Living via Selection, Optimization, and Compensation. AB - Background and Objectives: There is a growing number of adults with long-term mobility impairment aging into the older adult population. Little is known about the experiences of these individuals in maintaining activities of daily living (ADLs) and instrumental activities of daily living (IADLs) as they face age related changes in addition to a pre-existing mobility impairment. Research Design and Methods: Through in-home interviews with 21 participants (ages 52-86) with long-term mobility impairment, the present study employed a qualitative description design to explore perceptions of how and why select ADL/IADL routines (e.g., bed transfer, toileting) have changed over time. The selection, optimization, and compensation (SOC) model was used as a framework to organize participants' adaptations. Results: Among the ADL/IADL routine changes mentioned, elective selection strategies, in which a person continues to work at maintaining a task, were more frequently endorsed than loss-based selection strategies, in which a person does a task less or gets help from someone. Findings suggest that this population is actively adapting their routines to preserve their involvement in, and frequency of doing, these ADLs/IADLs. Counter to expectation, perceived age-related changes underlying activity routine changes were subtle and generally did not include sensory and cognitive declines. Discussion and Implications: Findings provide insights into the difficulties adults with long-term mobility impairment experience as they age, as well as the adaptations they employ to overcome those challenges. Results highlight the need for customizable, mobility supports (e.g., assistive technologies, home modifications) that can adjust to an individual's changing abilities across the life span. PMID- 29165561 TI - Evaluation of short exposure times of antimicrobial wound solutions against microbial biofilms: from in vitro to in vivo. AB - Objectives: Test the performance of topical antimicrobial wound solutions against microbial biofilms using in vitro, ex vivo and in vivo model systems at clinically relevant exposure times. Methods: Topical antimicrobial wound solutions were tested under three different conditions: (in vitro) 4% w/v Melaleuca oil, polyhexamethylene biguanide, chlorhexidine, povidone iodine and hypochlorous acid were tested at short duration exposure times for 15 min against 3 day mature biofilms of Staphylococcus aureus and Pseudomonas aeruginosa; (ex vivo) hypochlorous acid was tested in a porcine skin explant model with 12 cycles of 10 min exposure, over 24 h, against 3 day mature P. aeruginosa biofilms; and (in vivo) 4% w/v Melaleuca oil was applied for 15 min exposure, daily, for 7 days, in 10 patients with chronic non-healing diabetic foot ulcers complicated by biofilm. Results: In vitro assessment demonstrated variable efficacy in reducing biofilms ranging from 0.5 log10 reductions to full eradication. Repeated instillation of hypochlorous acid in a porcine model achieved <1 log10 reduction (0.77 log10, P = 0.1). Application of 4% w/v Melaleuca oil in vivo resulted in no change to the total microbial load of diabetic foot ulcers complicated by biofilm (median log10 microbial load pre-treatment = 4.9 log10 versus 4.8 log10, P = 0.43). Conclusions: Short durations of exposure to topical antimicrobial wound solutions commonly utilized by clinicians are ineffective against microbial biofilms, particularly when used in vivo. Wound solutions should not be used as a sole therapy and clinicians should consider multifaceted strategies that include sharp debridement as the gold standard. PMID- 29165563 TI - Ceftazidime/avibactam alone or in combination with aztreonam against colistin resistant and carbapenemase-producing Klebsiella pneumoniae. PMID- 29165564 TI - Social networks as a tool for science communication and public engagement: focus on Twitter. AB - Social networks have been used to teach and engage people about the importance of science. The integration of social networks in the daily routines of faculties and scientists is strongly recommended to increase their personal brand, improve their skills, enhance their visibility, share and communicate science to society, promote scientific culture, and even as a tool for teaching and learning. Here we review the use of Twitter in science and comment on our previous experience of using this social network as a platform for a Massive Online Open Course (MOOC) in Spain and Latin America. We propose to extend this strategy to a pan-European Microbiology MOOC in the near future. PMID- 29165562 TI - The Diversity of REcent and Ancient huMan (DREAM): A New Microarray for Genetic Anthropology and Genealogy, Forensics, and Personalized Medicine. AB - The human population displays wide variety in demographic history, ancestry, content of DNA derived from hominins or ancient populations, adaptation, traits, copy number variation, drug response, and more. These polymorphisms are of broad interest to population geneticists, forensics investigators, and medical professionals. Historically, much of that knowledge was gained from population survey projects. Although many commercial arrays exist for genome-wide single nucleotide polymorphism genotyping, their design specifications are limited and they do not allow a full exploration of biodiversity. We thereby aimed to design the Diversity of REcent and Ancient huMan (DREAM)-an all-inclusive microarray that would allow both identification of known associations and exploration of standing questions in genetic anthropology, forensics, and personalized medicine. DREAM includes probes to interrogate ancestry informative markers obtained from over 450 human populations, over 200 ancient genomes, and 10 archaic hominins. DREAM can identify 94% and 61% of all known Y and mitochondrial haplogroups, respectively, and was vetted to avoid interrogation of clinically relevant markers. To demonstrate its capabilities, we compared its FST distributions with those of the 1000 Genomes Project and commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, DREAM's autosomal and X chromosomal distributions had the highest mean FST, attesting to its ability to discern subpopulations. DREAM performances are further illustrated in biogeographical, identical by descent, and copy number variation analyses. In summary, with approximately 800,000 markers spanning nearly 2,000 genes, DREAM is a useful tool for genetic anthropology, forensic, and personalized medicine studies. PMID- 29165565 TI - Cued Reinstatement of Cocaine but Not Sucrose Seeking Is Dependent on Dopamine Signaling in Prelimbic Cortex and Is Associated with Recruitment of Prelimbic Neurons That Project to Contralateral Nucleus Accumbens Core. AB - Background: Drug cues recruit prelimbic cortex neurons that project to ipsilateral nucleus accumbens core. However, it is not known if the same is true for prelimbic cortex projections that decussate to innervate contralateral nucleus accumbens core. Further, a role for prelimbic cortex dopamine signaling in cued reinstatement of cocaine seeking has not been shown. Methods: We assessed Fos expression in prelimbic cortex neurons that project to contralateral nucleus accumbens core following cued reinstatement of cocaine or sucrose seeking. We also tested the effect of intra-prelimbic cortex infusions of the D1/D2 antagonist fluphenazine on cued cocaine and sucrose seeking. Results: Prelimbic cortex-contralateral nucleus accumbens core projections were activated by cocaine cues but not sucrose cues, and this activation correlated with reinstatement behavior. Blockade of prelimbic cortex dopamine signaling prevented cued reinstatement of cocaine- but not sucrose-seeking behavior. Conclusions: Cued cocaine seeking is associated with activation of the prelimbic cortex contralateral nucleus accumbens core pathway. Prelimbic cortex dopamine signaling is necessary for cues to reinstate drug-seeking behavior. PMID- 29165567 TI - Impact of the Pathologist on Prostate Biopsy Diagnosis and Immunohistochemical Stain Usage Within a Single Institution. AB - Objectives: To determine whether pathologists in a tertiary care institution vary in diagnosis and immunohistochemical stain usage in prostate biopsy specimens. Methods: Men who underwent prostate needle biopsies between 2008 and 2013 were included. Results: In total, 1,777 prostate biopsy specimens diagnosed by nine pathologists showed variation in diagnostic reporting (atypical small acinar proliferation, 2.0%-8.0%; high-grade prostatic intraepithelial neoplasia, 2.0% 8.5%; nonneoplastic, 30.2%-48.3%; adenocarcinoma, 46.2%-55.3%; P < .001). Variation in Gleason scoring was observed (P < .001), with the 4 + 3 = 7 category having the greatest variability (6.9%-30.3%). A blinded review from the most outlying pathologist in this category revealed 45% grading discrepancies. The mean number of immunostains performed per case (0.3-1.2) differed between pathologists (P < .001), and one pathologist used immunostains at twice the rate of the remaining cohort. Conclusions: Case pathologist significantly affects prostate biopsy diagnosis and immunohistochemical workup. We recommend evaluation for outlying practice patterns to provide consistent and efficient patient care. PMID- 29165568 TI - Second Harmonic Generation Reveals Subtle Fibrosis Differences in Adult and Pediatric Nonalcoholic Fatty Liver Disease. AB - Objectives: Investigate subtle fibrosis similarities and differences in adult and pediatric nonalcoholic fatty liver disease (NAFLD) using second harmonic generation (SHG). Methods: SHG/two-photon excitation fluorescence imaging quantified 100 collagen parameters and determined qFibrosis values by using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system in 62 adult and 36 pediatric NAFLD liver specimens. Results: Six distinct parameters identified differences among the NASH CRN stages with high accuracy (area under the curve, 0835-0.982 vs 0.885-0.981, adult and pediatric). All portal region parameters showed similar changes across early stages 0, 1C, and 2, in both groups. Parameter values decreased in adults with progression from stage 1A/B to 2 in the central vein region. In children, aggregated collagen parameters decreased, but nearly all distributed collagen parameters increased from stage 1A/B to 2. Conclusions: SHG analysis accurately reproduces NASH CRN staging in NAFLD, as well as reveals differences and similarities between adult and pediatric collagen deposition not captured by currently available quantitative methods. PMID- 29165566 TI - Host Genetic Variation Does Not Determine Spatio-Temporal Patterns of European Bat 1 Lyssavirus. AB - The majority of bat rabies cases in Europe are attributed to European bat 1 lyssavirus (EBLV-1), circulating mainly in serotine bats (Eptesicus serotinus). Two subtypes have been defined (EBLV-1a and EBLV-1b), each associated with a different geographical distribution. In this study, we undertake a comprehensive sequence analysis based on 80 newly obtained EBLV-1 nearly complete genome sequences from nine European countries over a 45-year period to infer selection pressures, rates of nucleotide substitution, and evolutionary time scale of these two subtypes in Europe. Our results suggest that the current lineage of EBLV-1 arose in Europe ~600 years ago and the virus has evolved at an estimated average substitution rate of ~4.19*10-5 subs/site/year, which is among the lowest recorded for RNA viruses. In parallel, we investigate the genetic structure of French serotine bats at both the nuclear and mitochondrial level and find that they constitute a single genetic cluster. Furthermore, Mantel tests based on interindividual distances reveal the absence of correlation between genetic distances estimated between viruses and between host individuals. Taken together, this indicates that the genetic diversity observed in our E. serotinus samples does not account for EBLV-1a and -1b segregation and dispersal in Europe. PMID- 29165569 TI - Preferential Usage of Specific Immunoglobulin Heavy Chain Variable Region Genes With Unmutated Profile and Advanced Stage at Presentation Are Common Features in Patients With Chronic Lymphocytic Leukemia From Senegal. AB - Objectives: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western populations, being rarer in Asian and African people. It has been suggested that patients with CLL from Africa might have a more aggressive disease compared with white patients. In this study, we aimed to identify genetic factors that may account for this difference. Methods: We analyzed immunoglobulin heavy chain (IGH) genes' mutational status by performing next-generation sequencing in 25 Senegalese and 50 Italian patients with CLL. Results: We found that Senegalese patients more frequently had adverse prognostic factors and an unmutated profile. Furthermore, we documented that IGHV1 (IGHV1-69), IGHD3, and IGHJ6 were significantly more frequent in Senegalese patients, whereas IGHV3-30 was common and limited to the Italian cohort. Stereotyped receptors commonly detected in the white population were not recorded in our Senegalese series. Conclusions: The different IGH repertoire we observed in the Senegalese cohort may reflect the diverse genetic and microenvironmental (ie, polymicrobial stimulation) background. PMID- 29165570 TI - Impact of Laboratory Charge Display Within the Electronic Health Record Across an Entire Academic Medical Center: Results of a Randomized Controlled Trial. AB - Objectives: To determine the impact of systemwide charge display on laboratory utilization. Methods: This was a randomized controlled trial with a baseline period and an intervention period. Tests were randomized to a control arm or an active arm. The maximum allowable Medicare reimbursement rate was displayed for tests in the active arm during the intervention period. Total volume of tests in the active arm was compared with those in the control arm. Residents were surveyed before and after the intervention to assess charge awareness. Results: Charge display had no effect on order behavior. This result held for patient type (inpatient vs outpatient) and for insurance category (commercial, government, self-pay). Residents overestimated the charges of tests both before and after the intervention. Many residents failed to notice the charge display in the computerized order entry system. Conclusions: The impact of charge display depends on context. Charge display is not always effective. PMID- 29165571 TI - Reducing Ageism: Education About Aging and Extended Contact With Older Adults. AB - Background and Objectives: Ageism is of increasing concern due to the growing older population worldwide and youth-centered focus of many societies. Research Design and Methods: The current investigation tested the PEACE (Positive Education about Aging and Contact Experiences) model for the first time. Two online experimental studies examined 2 key factors for reducing ageism: education about aging (providing accurate information about aging) and extended contact (knowledge of positive intergenerational contact) as well as their potential combined effect (education plus extended contact). Results and Discussion: In Study 1, 354 undergraduates in all 3 experimental conditions (vs. control participants) reported less negative attitudes toward older adults (delayed post test) and greater aging knowledge (immediate and delayed post-tests), when controlling for pre-study attitudes. In Study 2, 505 national community participants (ages 18-59) in all experimental conditions (vs. control participants) reported less negative attitudes toward older adults (immediate post-test) and greater aging knowledge (immediate and delayed post-tests). In summary, across 2 online studies, education about aging and knowledge of intergenerational extended contact improved attitudes toward older adults and aging knowledge. Implications: Thus, brief, online ageism-reduction strategies can be an effective way to combat ageism. These strategies hold promise to be tested in other settings, with other samples, and to be elaborated into more in depth interventions that aim to reduce ageism in everyday culture. PMID- 29165572 TI - Principled Approaches to Missing Data in Epidemiologic Studies. AB - Principled methods with which to appropriately analyze missing data have long existed; however, broad implementation of these methods remains challenging. In this and 2 companion papers (Am J Epidemiol. 2018;187(3):576-584 and Am J Epidemiol. 2018;187(3):585-591), we discuss issues pertaining to missing data in the epidemiologic literature. We provide details regarding missing-data mechanisms and nomenclature and encourage the conduct of principled analyses through a detailed comparison of multiple imputation and inverse probability weighting. Data from the Collaborative Perinatal Project, a multisite US study conducted from 1959 to 1974, are used to create a masked data-analytical challenge with missing data induced by known mechanisms. We illustrate the deleterious effects of missing data with naive methods and show how principled methods can sometimes mitigate such effects. For example, when data were missing at random, naive methods showed a spurious protective effect of smoking on the risk of spontaneous abortion (odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.19, 0.93), while implementation of principled methods multiple imputation (OR = 1.30, 95% CI: 0.95, 1.77) or augmented inverse probability weighting (OR = 1.40, 95% CI: 1.00, 1.97) provided estimates closer to the "true" full-data effect (OR = 1.31, 95% CI: 1.05, 1.64). We call for greater acknowledgement of and attention to missing data and for the broad use of principled missing-data methods in epidemiologic research. PMID- 29165573 TI - An emerging role for epigenetic factors in relation to executive function. AB - Background: Executive function (EF) includes a range of decision-making and higher-order thinking processes. Although the genetic basis of EF has been studied and reviewed, epigenetic factors that influence EF are an emerging field of interest; here, we summarize the current research. Methods: Work relating to different word combinations of 'Executive Function' and 'Epigenetic' was identified through three academic search directories. Inclusion criteria were human populations, EF testing, epigenetic testing or genotyping related to epigenetic regulation. Results: To date, 14 studies have been reported, which examined epigenetic variation, in particular DNA methylation, in relation to EF assessments conducted in human subjects, with some positive associations found. Study populations included healthy cohorts, as well as psychiatric and neurological patient cohorts. Conclusion: Epigenetics in relation to EF is an emerging area of investigation with relatively few studies to date. Most assay DNA methylation, with some studies suggesting that epigenetic factors can be associated with EF. EF constitutes complex phenotypic and genotypic correlates that differ because of cohort attributes as well as the targeted task examined. Larger studies are required to further elucidate the contribution of epigenetic factors to EF with the identification of epigenetic modifications influencing EF having potential to provide new biomarkers for neuropsychiatric disorders. PMID- 29165574 TI - Histone variants: essential actors in male genome programming. AB - Prior to its transmission to the offspring, the male genome has to be tightly compacted. A genome-scale histone eviction and the subsequent repackaging of DNA by protamines (Prms) direct this essential genome condensation step. The requirement for male germ cells to undergo such a dramatic and unique genome reorganization explains why these cells express the largest number of histone variants, including many testis-specific ones. Indeed, an open chromatin, nucleosome instability and a facilitated process of histone disassembly are direct consequences of the presence of these histone variants in the chromatin of male germ cells. These histone-induced changes in chromatin first control a stage specific gene expression program and then directly mediate the histone-to-Prm transition process. This review aims at summarizing and discussing a series of recent functional studies of male germ cell histone variants with a focus on their impact on the process of histone eviction and male genome compaction. PMID- 29165575 TI - Respiratory Viruses in Babies: Important Insights From Down Under. PMID- 29165576 TI - Timing of First Respiratory Virus Detections in Infants: A Community-Based Birth Cohort Study. AB - Background: Determining timing of first virus detection episodes (fVDEs) for different respiratory viruses in infants identifies risk periods and informs preventive interventions, including vaccination. We describe the ages and nature of fVDEs in an infant birth cohort and explore factors associated with increased odds of symptomatic fVDEs. Methods: The Observational Research in Childhood Infectious Diseases (ORChID) study is a community-based birth cohort describing acute respiratory infections in infants until their second birthday. Parents recorded daily symptoms and collected nose swabs weekly, which were batch-tested using polymerase chain reaction assays for 17 respiratory viruses. Results: One hundred fifty-eight infants participated in ORChID. The median age for fVDEs was 2.9 months for human rhinovirus (HRV) but was >=13.9 months for other respiratory viruses. Overall, 52% of HRV fVDEs were symptomatic, compared with 57%-83% of other fVDEs. Respiratory syncytial virus and human metapneumovirus fVDEs were more severe than HRV fVDEs. Older age and the winter season were associated with symptomatic episodes. Conclusions: Infants do not always experience respiratory symptoms with their fVDE. Predominance of early HRV detections highlights the need for timing any intervention early in life. fVDEs from other respiratory viruses most commonly occur when maternal vaccines may no longer provide protection. PMID- 29165578 TI - Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients. AB - Context: Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. Objective: To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. Methods: Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. Results: We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. Conclusion: Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS. PMID- 29165579 TI - Investigating Mediators of the Poor Pneumonia Outcomes of Human Immunodeficiency Virus-Exposed but Uninfected Children. AB - Background: Human immunodeficiency virus-exposed but uninfected (HIV-EU) children have a higher mortality rate than the children of HIV-negative mothers (HIV unexposed). Causal mediators of the poor health outcomes of HIV-EU children remain poorly defined. Methods: We conducted a hospital-based prospective cohort study of children aged 1 to 23 months with clinically defined pneumonia. The children were recruited at a referral hospital in Gaborone, Botswana, between April 2012 and June 2016. The primary outcome, treatment failure at 48 hours, was assessed by an investigator blinded to the children's HIV-exposure status. We examined associations between HIV exposure and pneumonia outcomes in HIV uninfected children. We next determined whether the effect of HIV exposure on outcomes was mediated by low-birth-weight status, nonbreastfeeding, malnutrition, in utero exposure to combination antiretroviral therapy, or pneumonia severity. Results: A total of 352 HIV-uninfected children were included in these analyses, including 245 (70%) HIV-unexposed and 107 (30%) HIV-EU children. Their median age was 7.4 months, and 57% were male. Treatment failure occurred in 111 (32%) children, and 19 (5.4%) children died. HIV-EU children were more likely to fail treatment (risk ratio [RR], 1.57 [95% confidence interval (CI), 1.19-2.07]; P = .002) and had a higher in-hospital mortality rate (RR, 4.50 [95% CI, 1.86-10.85]; P = .001) than HIV-unexposed children. Nonbreastfeeding mediated 47% of the effect of HIV exposure on the risk of in-hospital death. Conclusions: HIV-EU children have worse pneumonia outcomes than HIV-unexposed children. Nonbreastfeeding mediates nearly half of the effect of HIV exposure on pneumonia mortality. Our findings provide additional evidence for a mortality benefit of breastfeeding by HIV-EU children. PMID- 29165577 TI - Quantitative Brain MRI in Congenital Adrenal Hyperplasia: In Vivo Assessment of the Cognitive and Structural Impact of Steroid Hormones. AB - Context: Brain white matter hyperintensities are seen on routine clinical imaging in 46% of adults with congenital adrenal hyperplasia (CAH). The extent and functional relevance of these abnormalities have not been studied with quantitative magnetic resonance imaging (MRI) analysis. Objective: To examine white matter microstructure, neural volumes, and central nervous system (CNS) metabolites in CAH due to 21-hydroxylase deficiency (21OHD) and to determine whether identified abnormalities are associated with cognition, glucocorticoid, and androgen exposure. Design, Setting, and Participants: A cross-sectional study at a tertiary hospital including 19 women (18 to 50 years) with 21OHD and 19 age matched healthy women. Main Outcome Measure: Recruits underwent cognitive assessment and brain imaging, including diffusion weighted imaging of white matter, T1-weighted volumetry, and magnetic resonance spectroscopy for neural metabolites. We evaluated white matter microstructure by using tract-based spatial statistics. We compared cognitive scores, neural volumes, and metabolites between groups and relationships between glucocorticoid exposure, MRI, and neurologic outcomes. Results: Patients with 21OHD had widespread reductions in white matter structural integrity, reduced volumes of right hippocampus, bilateral thalami, cerebellum, and brainstem, and reduced mesial temporal lobe total choline content. Working memory, processing speed, and digit span and matrix reasoning scores were reduced in patients with 21OHD, despite similar education and intelligence to controls. Patients with 21OHD exposed to higher glucocorticoid doses had greater abnormalities in white matter microstructure and cognitive performance. Conclusion: We demonstrate that 21OHD and current glucocorticoid replacement regimens have a profound impact on brain morphology and function. If reversible, these CNS markers are a potential target for treatment. PMID- 29165580 TI - Role of Anaerobic Blood Cultures in Neonatal Bacteremia. AB - Background: Evaluation for neonatal sepsis routinely includes performing both aerobic and anaerobic blood cultures despite our lack of knowledge of the true incidence of anaerobic bacteremia in this age group and the consequences of not performing these paired cultures. Methods: We performed a retrospective review of all blood cultures performed for neonates in a children's hospital. Clinically significant pathogens were defined as microorganisms that rarely are considered to be contaminants, that were recovered from multiple blood cultures or sites, or were considered significant according to the patient's attending physician. The chart of every patient with positive culture results was reviewed for patient characteristics. Results: A total of 662 culture sets among 403 patients were obtained between November 1, 2013, and April 30, 2015. A clinically significant organism was isolated from 64 (9.7%) culture sets from 25 patients (1.9% contamination rate). A total of 56 organisms were isolated; 35 (62.5%) grew from both the aerobic and anaerobic bottles, 19 (33.9%) grew from the anaerobic bottle alone, and 2 (3.6%) grew from the aerobic bottle alone. One (0.2%) obligate anaerobic bacterium (Clostridium symbiosum) was identified. Conclusions: Although the incidence of anaerobic bacteremia in neonates is rare, anaerobic culture remains important in this population, given the increased yield of both aerobic and facultative anaerobic organisms isolated from anaerobic blood culture bottles. PMID- 29165581 TI - Acquisition, Persistence, and Clearance of Human Papillomavirus Infection Among Male Virgins Residing in Brazil, Mexico, and the United States. AB - Background: Little is known about the natural history of human papillomavirus (HPV) infection in male virgins. This study estimated the incidence and clearance of genital HPV infection and the factors associated with these measures among men who denied at baseline ever having penetrative sex. Methods: A cohort of 4123 men residing in Brazil, Mexico, and the United States were followed every 6 months for up to 10 visits. Genital exfoliated cells were collected and genotyped for 36 HPV types. Eighty-seven men were classified as virgins and included for analysis. Cox proportional hazards models identified factors associated with the incidence and clearance of genital HPV infection. Results: The incidence rates for any HPV infection among virgins who did and those who did not initiate sex during follow up were 26.2 and 14.6 cases/1000 person-months, respectively. After penetrative sex initiation, 45.5% of men acquired HPV within 24 months. Younger age, current smoking, no recent female sex partners, and prevalent HPV infection were associated with high-risk HPV clearance. Conclusion: Virgins who did not initiate sex during follow-up still acquired HPV infection, possibly through nonpenetrative sexual contact. Further prospective cohort studies are needed to better understand factors associated with HPV acquisition and clearance in male virgins and recent nonvirgins. PMID- 29165583 TI - Modelling projections for the risks related with atrial fibrillation in East Asia: a focus on ischaemic stroke and death. AB - Aims: In the Far East, there has generally been low uptake of oral anticoagulants (OACs) using vitamin K antagonists (VKA, e.g. warfarin) for stroke prevention in atrial fibrillation (AF), but OAC use has been increasing more recently, with the introduction of the non-vitamin K antagonist oral anticoagulants (NOACs). To explore the risks of ischaemic stroke (IS) and death related to AF in East Asia using modelling projections. Methods and results: We performed a modelling analysis of possible trends of IS and death rates in AF patients from the time period of only VKA use to current increasing trends of NOAC use projecting until 2050 in East Asia. Data from published articles on the prevalence of AF, IS, and death were used to model estimated event rates. In 2030, the estimated AF population in East Asia will be 608 100, with the use of NOACs leading to a reduction of 82 259 ISs and 16 917 deaths. There was an estimated annual risk reduction of 5484 ISs and 1128 deaths from 2016 to 2030, respectively. The AF population is estimated to reach 861 900 in 2050, with a reduction of 206 315 ISs and 139 353 deaths. Conclusion: This modelling analysis suggests that the transition from VKA to NOACs may greatly help in reducing the burden of IS and death caused by AF in the East Asian region. PMID- 29165582 TI - Predictors, management, and outcome of cardioversion failure early after atrial fibrillation ablation. AB - Aims: Electrical cardioversion (ECV) is frequently required for early atrial fibrillation (AF) recurrence after catheter ablation. However, in some cases, ECV is unsuccessful, and factors associated with long-term rhythm outcomes after failed ECV are unknown. This study aimed to identify possible predictors of ECV failure early after AF ablation and to analyse management and long-term rhythm outcome of these patients. Methods and results: Between 2010 and 2012, 180 consecutive patients (mean age 63.7 +/- 9.4 years, male 53.3%, persistent AF 60%) underwent successful radiofrequency AF ablation but required post-procedural ECV due to early AF recurrence (<= 7 days). Of these, 120 patients were successful (Group A, n = 120, 66.7%) and 60 failed (Group B, n = 60, 33.3%). ECV failure was associated with diabetes [odds ratio (OR) 2.34, 95% confidence interval (CI) 1.154-4.763; P = 0.01] and lack of beta-blocker medication (OR 2.38, 95% CI 1.005 5.635; P = 0.04). In contrast, there were no significant differences in echocardiographic or procedure-related parameters. Atrial fibrillation recurrence was monitored with sequential 7 days of Holter electrocardiogram for 24 months (on average 10.8 +/- 8.8 months) and was documented in 56%, n = 102 in total (Group A: 57%, n = 69 vs. Group B: 55%, n = 33; P = 0.75). Compared with successful ECV, ECV failure shortly after AF ablation had no predictive value on rhythm outcome in the long term (P = 0.98). The necessity of additional linear lesions during catheter ablation [hazard ratio (HR) 2.72, 95% CI 1.47-5.05; P = 0.001], AF duration (HR 1.08, 95% CI 1.04-1.12; P < 0.001), and a prolonged ablation time (HR 3.27, 95% CI 1.53-6.97; P = 0.002) were associated with long term AF recurrence. Conclusion: Patients with diabetes and absence of beta blocker medication are at higher risk for ECV failure. Early post-ablation ECV failure is not associated with long-term rhythm outcome. PMID- 29165584 TI - Carers as System Navigators: Exploring Sources, Processes and Outcomes of Structural Burden. AB - Background and Objectives: Structural features of formal care systems influence the amount, difficulty, and complexity of what carers do as they interface with those systems. In this study, we explored how carers navigate health and social care systems, and their experiences of structural burden related to features such as complexity and fragmentation. Research Design and Methods: This qualitative descriptive inquiry drew on data from in-person interviews with 32 carers of older adults, which were analyzed first using inductive thematic analysis and then using structural burden as a conceptual lens. Results: Participant accounts revealed how navigating formal systems on behalf of older adult family members can exact considerable demands on carers in terms of time investment and emotional energy. In this way, care systems exacerbate the stress and structural burden experienced by carers, even when formal services alleviate other forms of carer burden. Discussion and Implications: Our findings contribute to knowledge of how the structural context of formal services shapes carer experiences and outcomes. To promote equity and prevent burden, system navigation work should be considered as a public, structural issue, rather than an individual-level problem of skills and learning. PMID- 29165585 TI - Lamin A/C mutations in patients with dilated cardiomyopathy. PMID- 29165586 TI - Extent of physician-pharmaceutical industry interactions in low- and middle income countries: a systematic review. AB - Background: Pharmaceutical companies spend large amounts of money promoting their products to physicians. There is evidence that physicians' interactions with pharmaceutical companies negatively affect their prescribing patterns. The objective of this study was to systematically review the extent of the relationship between physicians and pharmaceutical companies in low- and middle income countries (LMICs). Methods: Studies assessing the extent of any type of interaction between practicing physicians and pharmaceutical companies were eligible. We searched MEDLINE and EMBASE databases in July 2016. Reviewers worked in duplicate and independently to complete study selection, data abstraction and assessment of methodological features. We summarized the findings narratively. Results: We included 11 eligible studies (7 quantitative and 4 qualitative). Quantitative studies found that pharmaceutical company representatives visited at least 90% of physicians. Printed material, stationery items and drug samples were the most frequently received gifts. Two of the studies assessing direct payment found percentages of 16 and 5%, respectively. Findings of qualitative studies were consistent with those of quantitative studies. In addition, they revealed an increasing tendency for pharmaceutical companies to provide expensive personal gifts, sponsor social events and offer cash as inducements to physicians based on their demands. They also identified building personal relationships, creating a sense of indebtedness and emotional blackmailing as commonly used techniques to influence physicians. Conclusion: A relatively high percentage of physicians in LMICs interact with pharmaceutical companies. Findings have implications for policy and practice, given the current extent of interaction is likely affecting the prescribing habits and professional behaviour of physicians. PMID- 29165587 TI - Identification of diverse target RNAs that are functionally regulated by human Pumilio proteins. AB - Human Pumilio proteins, PUM1 and PUM2, are sequence specific RNA-binding proteins that regulate protein expression. We used RNA-seq, rigorous statistical testing and an experimentally derived fold change cut-off to identify nearly 1000 target RNAs-including mRNAs and non-coding RNAs-that are functionally regulated by PUMs. Bioinformatic analysis defined a PUM Response Element (PRE) that was significantly enriched in transcripts that increased in abundance and matches the PUM RNA-binding consensus. We created a computational model that incorporates PRE position and frequency within an RNA relative to the magnitude of regulation. The model reveals significant correlation of PUM regulation with PREs in 3' untranslated regions (UTRs), coding sequences and non-coding RNAs, but not 5' UTRs. To define direct, high confidence PUM targets, we cross-referenced PUM regulated RNAs with all PRE-containing RNAs and experimentally defined PUM-bound RNAs. The results define nearly 300 direct targets that include both PUM repressed and, surprisingly, PUM-activated target RNAs. Annotation enrichment analysis reveal that PUMs regulate genes from multiple signaling pathways and developmental and neurological processes. Moreover, PUM target mRNAs impinge on human disease genes linked to cancer, neurological disorders and cardiovascular disease. These discoveries pave the way for determining how the PUM-dependent regulatory network impacts biological functions and disease states. PMID- 29165588 TI - Novel phosphate deficiency-responsive long non-coding RNAs in the legume model plant Medicago truncatula. AB - Emerging evidence indicates that long non-coding RNAs (lncRNAs) play important roles in the regulation of many biological processes. Inhibition of plant growth due to deficiency in soil inorganic phosphate (Pi) occurs widely across natural and agricultural ecosystems; however, we know little about the function of plant lncRNAs in response to Pi deficiency. To address this issue, we first identified 10 785 lncRNAs in the legume model species Medicago truncatula by sequencing eight strand-specific libraries. Out of these lncRNAs, 358 and 224 were responsive to Pi deficiency in the leaves and roots, respectively. We further predicted and classified the putative targets of those lncRNAs and the results revealed that they may be involved in the processes of signal transduction, energy synthesis, detoxification, and Pi transport. Finally, we functionally characterized three Phosphate Deficiency-Induced LncRNAs (PDILs) using their corresponding Tnt1 mutants. The results showed that PDIL1 suppressed degradation of MtPHO2, which encodes a ubiquitin-conjugating E2 enzyme regulated by miR399, while PDIL2 and PDIL3 directly regulated Pi transport at the transcriptional level. These findings demonstrate that PDILs can regulate Pi-deficiency signaling and Pi transport, highlighting the involvement of lncRNAs in the regulation of responses of plants to Pi deficiency. PMID- 29165590 TI - Miltefosine-resistant Leishmania infantum strains with an impaired MT/ROS3 transporter complex retain amphotericin B susceptibility. AB - Objectives: Increasing numbers of miltefosine treatment failures in visceral leishmaniasis therapy and reports of miltefosine resistance in the Indian subcontinent resulted in the recommendation to use liposomal amphotericin B as first-line therapy. Cross-resistance between miltefosine and amphotericin B has recently been documented, suggesting a role of mutations in the miltefosine transporter, a complex encoded by the MT and ROS3 genes. This study aimed to further explore the putative role of MT/ROS3 defects in the molecular basis of amphotericin B cross-resistance. Methods: The susceptibility profiles of different miltefosine-resistant Leishmania infantum strains with well characterized mutations in the transporter complex and the corresponding episomally restored susceptible parasite lines were determined using both the routine extracellular promastigote assay and the intracellular amastigote assay. Results: In vitro amastigote and promastigote susceptibility testing of the two miltefosine-resistant and the episomally reconstituted L. infantum lines revealed full susceptibility to amphotericin B, despite the variable miltefosine susceptibility profile. Conclusions: Mutations present in either the MT and/or ROS3 gene are not sufficient to elicit higher tolerance to amphotericin B. Additional synergistic adaptations may be responsible for the miltefosine/amphotericin B cross-resistance described earlier. PMID- 29165589 TI - NS3 helicase from dengue virus specifically recognizes viral RNA sequence to ensure optimal replication. AB - The protein-RNA interactions within the flavivirus replication complex (RC) are not fully understood. Our structure of dengue virus NS3 adenosine triphosphatase (ATPase)/helicase bound to the conserved 5' genomic RNA 5'-AGUUGUUAGUCU-3' reveals that D290 and R538 make specific interactions with G2 and G5 bases respectively. We show that single-stranded 12-mer RNA stimulates ATPase activity of NS3, however the presence of G2 and G5 leads to significantly higher activation. D290 is adjacent to the DEXH motif found in SF2 helicases like NS3 and interacts with R387, forming a molecular switch that activates the ATPase site upon RNA binding. Our structure guided mutagenesis revealed that disruption of D290-R387 interaction increases basal ATPase activity presumably as a result of higher conformational flexibility of the ATPase active site. Mutational studies also showed R538 plays a critical role in RNA interactions affecting translocation of viral RNA through dynamic interactions with bases at positions 4 and 5 of the ssRNA. Restriction of backbone flexibility around R538 through mutation of G540 to proline abolishes virus replication, indicating conformational flexibility around residue R538 is necessary for RNA translocation. The functionally critical sequence-specific contacts in NS3 RNA binding groove in subdomain III reveals potentially novel allosteric anti-viral drug targets. PMID- 29165591 TI - Translation can affect the antisense activity of RNase H1-dependent oligonucleotides targeting mRNAs. AB - RNase H1-dependent antisense oligonucleotides (ASOs) can degrade complementary RNAs in both the nucleus and the cytoplasm. Since cytoplasmic mRNAs are actively engaged in translation, ASO activity may thus be affected by translating ribosomes that scan the mRNAs. Here we show that mRNAs associated with ribosomes can be cleaved using ASOs and that translation can alter ASO activity. Translation inhibition tends to increase ASO activity when targeting the coding regions of efficiently translated mRNAs, but not nuclear non-coding RNAs or less efficiently translated mRNAs. Increasing the level of RNase H1 protein eliminated the enhancing effects of translation inhibition on ASO activity, suggesting that RNase H1 recruitment to ASO/mRNA heteroduplexes is a rate limiting step and that translating ribosomes can inhibit RNase H1 recruitment. Consistently, ASO activity was not increased by translation inhibition when targeting the 3' UTRs, independent of the translation efficiency of the mRNAs. Contrarily, the activity of 3' UTR-targeting ASOs tended to be reduced upon translation inhibition, likely due to decreased accessibility. These results indicate that ASO activity can be affected by the translation process, and the findings also provide important information toward helping better ASO drug design. PMID- 29165592 TI - Folate deficiency induces mitotic aberrations and chromosomal instability by compromising the spindle assembly checkpoint in cultured human colon cells. AB - Folates comprise the essential B9 vitamin that act as cofactors and cosubstrates in one-carbon metabolism for both biosynthesis and methylation of DNA and RNA. Folate deficiency (FD) has been shown to induce chromosomal instability (CIN), yet the underlying mechanisms are poorly understood. Here, we used human NCM460 colon mucosal cells as a model to investigate the effect of FD on spindle assembly checkpoint (SAC), a cell-cycle regulatory pathway preventing CIN during mitosis. Cells were maintained in medium containing 1.36 (FD) and 2260 nM (control, FC) folate for 21 days. CIN was measured by cytokinesis-block micronucleus assay; mitotic infidelity was determined by aberrant mitosis analysis; SAC activity was assessed by nocodazole-challenge assay, and the expression of core SAC genes was examined by real-time quantitative PCR (RT qPCR). We found that, relative to FC, FD significantly induced CIN in a time dependent way (P < 0.01). Mitotic cells cultured in FD medium had significant higher frequencies of misalignment, misegregation and spindle multipolarity than those cultured in FC medium (P < 0.01). FD-induced SAC impairment and overriding, resulting premature mitotic exit and cell multinucleation (P < 0.05). Moreover, FD deregulated the expression of several key SAC genes (P < 0.01). Overall, these data are the first to demonstrate that FD substantially compromises SAC network which predisposes cells to mitotic aberrations and CIN. These results establish a new link between folate metabolism and SAC signalling, two pathways that are highly relevant for tumorigenesis. PMID- 29165593 TI - FunCoup 4: new species, data, and visualization. AB - This release of the FunCoup database (http://funcoup.sbc.su.se) is the fourth generation of one of the most comprehensive databases for genome-wide functional association networks. These functional associations are inferred via integrating various data types using a naive Bayesian algorithm and orthology based information transfer across different species. This approach provides high coverage of the included genomes as well as high quality of inferred interactions. In this update of FunCoup we introduce four new eukaryotic species: Schizosaccharomyces pombe, Plasmodium falciparum, Bos taurus, Oryza sativa and open the database to the prokaryotic domain by including networks for Escherichia coli and Bacillus subtilis. The latter allows us to also introduce a new class of functional association between genes - co-occurrence in the same operon. We also supplemented the existing classes of functional association: metabolic, signaling, complex and physical protein interaction with up-to-date information. In this release we switched to InParanoid v8 as the source of orthology and base for calculation of phylogenetic profiles. While populating all other evidence types with new data we introduce a new evidence type based on quantitative mass spectrometry data. Finally, the new JavaScript based network viewer provides the user an intuitive and responsive platform to further evaluate the results. PMID- 29165594 TI - Revisiting FIS, FST, Wahlund Effects, and Null Alleles. AB - Null alleles and Wahlund effects are well known causes of heterozygote deficits in empirical population genetics studies as compared to Hardy-Weinberg genotypic expectations. Some authors have theoretically studied the relationship of Wright's FIS computed from subsamples displaying a Wahlund effect and FST before the Wahlund effect, as can occasionally be obtained from populations of long lived organisms. In the 2 subsample case, a positive relationship between these 2 parameters across loci would represent a signature of Wahlund effects. Nevertheless, for most organisms, getting 2 independent subsamples of the same cohort and population, one with a Wahlund effect and the other without, is almost never achieved and most of the time, empirical population geneticists only collect a single sample, with or without a Wahlund effect, or with or without null alleles. Another issue is that null allele increase FIS and FST altogether and thus may also create such correlation. In this article, I show that, for organisms collected in a single sample, which corresponds to the most common situation, Wahlund effects and null alleles affect the values of both FIS and FST though in the opposite direction. I also show that Wahlund effect produces no or weak positive correlation between the 2 F-statistics, while null alleles generate a strong positive correlation between them. Variation of these F-statistics is small and even minimized for FST under Wahlund effects as compared to null alleles. I finally propose a determination key to interpret data with heterozygote deficits. PMID- 29165595 TI - Con: The role of diet for people with advanced Stage 5 CKD. AB - Restriction of dietary protein intake has been used in the management of chronic kidney disease (CKD) for many decades, yet remains controversial, with marked variations in its application in clinical practice. There is extensive literature on the subject, with some expert opinion advocating the use of protein restriction based on the balance of the available evidence. The largest randomized trial of low-protein diets is the Modification of Diet in Renal Disease study. Despite multiple secondary analyses, the essential intention-to treat analysis failed to demonstrate a benefit in the primary outcome of rate of decline of glomerular filtration rate. There are criticisms of many published studies and meta-analyses, including the likelihood of publication bias and unsuitable biochemical endpoints that may be affected by dietary restriction in the absence of effects on kidney function, leading to false positive findings. It is also uncertain whether any benefits observed in these often older studies would be derived in patients undergoing modern standards of CKD management, including blood pressure control and renin-angiotensin blockade. Thus it is unclear whether, even in the strictly controlled environment of a clinical study, low-protein diets significantly slow CKD progression. Important questions exist regarding the applicability of these diets in routine clinical practice. Even in carefully selected study populations with intensive dietetic input, adherence to low-protein diets is poor. It is likely that only a small minority of CKD patients in routine practice could adhere to these diets, and although risks of malnutrition arising from protein restriction are uncertain, they will be greater in less supervised care outside of studies. PMID- 29165596 TI - Molecular relatedness of ESBL/AmpC-producing Escherichia coli from humans, animals, food and the environment: a pooled analysis. AB - Background: In recent years, ESBL/AmpC-producing Escherichia coli (ESBL/AmpC-EC) have been isolated with increasing frequency from animals, food, environmental sources and humans. With incomplete and scattered evidence, the contribution to the human carriage burden from these reservoirs remains unclear. Objectives: To quantify molecular similarities between different reservoirs as a first step towards risk attribution. Methods: Pooled data on ESBL/AmpC-EC isolates were recovered from 35 studies in the Netherlands comprising >27 000 samples, mostly obtained between 2005 and 2015. Frequency distributions of ESBL/AmpC genes from 5808 isolates and replicons of ESBL/AmpC-carrying plasmids from 812 isolates were compared across 22 reservoirs through proportional similarity indices (PSIs) and principal component analyses (PCAs). Results: Predominant ESBL/AmpC genes were identified in each reservoir. PCAs and PSIs revealed close human-animal ESBL/AmpC gene similarity between human farming communities and their animals (broilers and pigs) (PSIs from 0.8 to 0.9). Isolates from people in the general population had higher similarities to those from human clinical settings, surface and sewage water and wild birds (0.7-0.8), while similarities to livestock or food reservoirs were lower (0.3-0.6). Based on rarefaction curves, people in the general population had more diversity in ESBL/AmpC genes and plasmid replicon types than those in other reservoirs. Conclusions: Our 'One Health' approach provides an integrated evaluation of the molecular relatedness of ESBL/AmpC-EC from numerous sources. The analysis showed distinguishable ESBL/AmpC-EC transmission cycles in different hosts and failed to demonstrate a close epidemiological linkage of ESBL/AmpC genes and plasmid replicon types between livestock farms and people in the general population. PMID- 29165597 TI - GSTA1 Expression Is Correlated With Aldosterone Level in KCNJ5-Mutated Adrenal Aldosterone-Producing Adenoma. AB - Context: KCNJ5 mutation is a major cause of aldosterone-producing adenomas (APAs). The development of APA apart from KCNJ5 mutation is less investigated. Objective: To investigate other mechanisms affecting aldosterone secretion apart from KCNJ5. Patients and Methods: Six pairs of KCNJ5-mutated, high and low aldosterone-secreting APAs, five non-KCNJ5-mutated APAs, and four normal adrenal glands were assayed by Affymetrix GeneChip Human Transcriptome Array 2.0. A total of 113 APA samples were investigated to explore the expression of glutathione-S transferase A1 (GSTA1). H295R cells were used to verify the function of GSTA1. Results: GSTA1 was the top gene downregulated in high-aldosterone KCNJ5-mutated APAs. GSTA1 was also downregulated in KCNJ5-mutated APAs compared with wild-type KCNJ5 APAs. Accordingly, mutant KCNJ5 decreased GSTA1 messenger RNA and protein expression levels. GSTA1 overexpression suppressed aldosterone secretion whether in wild-type or mutant KCNJ5 H295R cells. Adding ethacrynic acid or silencing of GSTA1 increased aldosterone secretion by increasing reactive oxygen species (ROS), superoxide, H2O2 levels, and Ca2+ influx. The expression of the transcription factors NR4A1, NR4A2, and CAMK1 and intracellular Ca2+ were significantly upregulated by GSTA1 inhibition. The reduced form of NAD phosphate oxidase inhibitor or H2O2 scavenger or blocking calmodulin or calcium channels could significantly reduce aldosterone secretion in GSTA1-inhibited cells. Conclusions: (1) GSTA1 expression is reversely correlated with aldosterone level in KCNJ5-mutated APAs, (2) GSTA1 regulates aldosterone secretion by ROS and Ca2+ signaling, and (3) KCNJ5 mutation downregulates GSTA1 expression, and overexpression of GSTA1 reverses increased aldosterone in KCNJ5-mutated adrenal cells. PMID- 29165598 TI - Fetal Growth and Birth Anthropometrics in Metformin-Exposed Offspring Born to Mothers With PCOS. AB - Context: Metformin is used in an attempt to reduce pregnancy complications associated with polycystic ovary syndrome (PCOS). Little is known about the effect of metformin on fetal development and growth. Objectives: To compare the effect of metformin versus placebo on fetal growth and birth anthropometrics in PCOS offspring compared with a reference population in relation to maternal body mass index (BMI). Design: Post hoc analysis of a randomized controlled trial. Setting: Double-blind, placebo-controlled, multicenter study. Patients: 258 offspring born to mothers with PCOS. Intervention: 2000 mg metformin (n = 131) or placebo (n = 121) from first trimester to delivery. Main Outcome Measures: Mean abdominal diameter and biparietal diameter (BPD) at gestational weeks 19 and 32. Head circumference (HC), birth length, and weight related to a reference population of healthy offspring, expressed as gestational age- and sex-adjusted z scores. Results: Metformin- versus placebo-exposed offspring had larger heads at gestational week 32 (BPD, 86.1 mm versus 85.2 mm; P = 0.03) and at birth (HC, 35.6 cm versus 35.1 cm; P < 0.01). Analyses stratified by maternal prepregnancy BMI, larger heads were observed only among offspring of overweight/obese mothers. Among normal-weight mothers, the effect of metformin compared with placebo was reduced length (z-score = -0.96 versus -0.42, P = 0.04) and weight (z-score = 0.44 versus 0.02; P = 0.03). Compared with the reference population, offspring born to PCOS mothers (placebo group) had reduced length (z-score = -0.40; 95% confidence interval, -0.60 to -0.40), but similar birth weight and HC. Conclusions: Metformin exposure resulted in larger head size in offspring of overweight mothers, traceable already in utero. Maternal prepregnancy BMI modified the effect of metformin on offspring anthropometrics. Anthropometrics of offspring born to PCOS mothers differed from those of the reference population. PMID- 29165599 TI - Direct axillary cannulation with open Seldinger-guided technique: is it safe? AB - OBJECTIVES: Axillary artery cannulation is commonly used in thoracic aortic surgery, often utilizing a sidearm graft. Although our institutional preference is femoral cannulation, we use axillary cannulation in select cases with a 'dirty' aorta on computed tomography scan or intraoperative transoesophageal echocardiography. Since 2011, we have routinely used an open Seldinger-guided approach for axillary cannulation. Here, we report our experience with open Seldinger-guided technique, evaluating its safety and efficacy. METHODS: A retrospective analysis of our institutional database from 2011 to 2016 was performed to find cases of peripheral arterial cannulation for thoracic aortic surgery. We identified 404 consecutive patients who underwent peripheral arterial cannulation. Of these, 352 were femoral and 52 were axillary cannulations. All axillary cannulations were performed for ascending and/or arch surgery. The technique involves a surgical exposure of the artery which is then cannulated by guidewire inside a purse string without arterial incision. RESULTS: Indications for surgery included aneurysm in 63.5% (33/52), dissection in 30.7% (16/52) and pseudoaneurysm in the remaining 5.8% (3/52). Hospital survival was 98.1% (51/52). There were no instances of axillary arterial injury or intraoperative malperfusion phenomena. No postoperative limb ischaemia or stroke was evident. No wound infections or late pseudoaneurysms were observed. CONCLUSIONS: The open Seldinger-guided technique for axillary artery cannulation is safe and effective. We strongly recommend this technique, given its speed and simplicity. The vessel is not snared, thereby preserving distal arterial flow and minimizing the risk of acute limb ischaemia. Furthermore, the limited manipulation of the artery lowers the risk of local complications. PMID- 29165600 TI - Missed opportunities to identify occupational asthma in acute secondary care. AB - Background: Occupational asthma (OA) accounts for one in six cases of new-onset adult asthma. Despite this it remains under-recognized in the UK. Delayed and missed diagnoses of OA lead to poor health outcomes for workers at significant cost to the UK economy. The burden of occupational aetiology on hospital admissions with asthma is not known. Aims: To measure how frequently medical professionals consider occupational aetiology in patients presenting to secondary care with acute asthma symptoms. Methods: We reviewed electronic records of working-age patients with asthma symptoms, presenting to three sites at a large West Midlands acute hospital NHS trust. We searched emergency department (ED) and acute medical unit (AMU) admission documents, looking specifically at documentation of employment status, job role and work effect on symptoms. We also examined the effect of using a prompt for enquiry about occupation contained within the clerking pro-forma. Results: We searched 100 ED and 100 AMU admission documents. Employment status was established in only 20-31% of patients and none were asked about the effect of their work on current asthma symptoms. The use of a clerking pro-forma, including a prompt for occupation, increased documentation to 63% from 10 to 14% where an enhanced pro-forma was not used. Conclusions: Enquiry into employment status and work effect in working-age patients with asthma symptoms presenting to the ED and the AMU is poor. These may be missed opportunities to identify OA. We propose medical education about high-risk exposures and the use of pro-formas including prompts about occupational exposures. PMID- 29165601 TI - Associations between perceived leadership and presenteeism in an industrial population. AB - Background: Presenteeism has received increasing attention in occupational health research but the evidence for its association with perceived leadership is scant. Aims: To assess the association of perceived leadership and presenteeism among industrial workers. Methods: Survey responses from employees on perceived leadership were linked to the personnel register of a food industry company. The Presenteeism Scale method was used to determine the presenteeism percentage. Perceived leadership was measured as a composite variable of six individual items on motivating and participating leadership. Generalized linear models were used to determine the association of perceived leadership with presenteeism. Results: There were 847 participants. The majority of office workers of both genders reported better perceived leadership than factory workers. We found that perceived poor leadership was associated with a higher likelihood of presenteeism (rate ratio (RR) 1.64, 95% confidence intervals (CIs) 1.51-1.78). However, there was variation amongst and within occupational groups and genders, with a higher risk of presenteeism amongst male factory workers (RR 2.28, 95% CI 2.02-2.52) than female office workers. Conclusions: Leadership was found to be significantly associated with presenteeism, with a greater risk of presenteeism in those reporting poor perceived leadership. The association between levels of perceived leadership and presenteeism was stronger in men than women. Organizations should focus on motivating leadership practices to reduce the risk of presenteeism, especially among men. PMID- 29165602 TI - Deletion of connective tissue growth factor ameliorates peritoneal fibrosis by inhibiting angiogenesis and inflammation. AB - Background: Connective tissue growth factor (CTGF/CCN2) regulates the signalling of other growth factors and promotes fibrosis. CTGF is increased in mice and humans with peritoneal fibrosis. Inhibition of CTGF has not been examined as a potential therapeutic target for peritoneal fibrosis because systemic CTGF knockout mice die at the perinatal stage. Methods: To study the role of CTGF in peritoneal fibrosis of adult mice, we generated CTGF conditional knockout (cKO) mice by crossing CTGF floxed mice with RosaCreERT2 mice. We administered tamoxifen to Rosa-CTGF cKO mice to delete the CTGF gene throughout the body. We induced peritoneal fibrosis by intraperitoneal injection of chlorhexidine gluconate (CG) in wild-type and Rosa-CTGF cKO mice. Results: Induction of peritoneal fibrosis in wild-type mice increased CTGF expression and produced severe thickening of the peritoneum. In contrast, CG-treated Rosa-CTGF cKO mice exhibited reduced thickening of the peritoneum. Peritoneal equilibration test revealed that the excessive peritoneal small-solute transport in CG-treated wild type mice was normalized by CTGF deletion. CG-treated Rosa-CTGF cKO mice exhibited a reduced number of alphaSMA-, Ki67-, CD31- and MAC-2-positive cells in the peritoneum. Analyses of peritoneal mRNA showed that CG-treated Rosa-CTGF cKO mice exhibited reduced expression of Cd68, Acta2 (alphaSMA), Pecam1 (CD31) and Vegfa. Conclusions: These results indicate that a deficiency of CTGF can reduce peritoneal thickening and help to maintain peritoneal function by reducing angiogenesis and inflammation in peritoneal fibrosis. These results suggest that CTGF plays an important role in the progression of peritoneal fibrosis. PMID- 29165603 TI - All roads lead to the vacuole-autophagic transport as part of the endomembrane trafficking network in plants. AB - Plants regulate their development and response to the changing environment by sensing and interpreting environmental signals. Intracellular trafficking pathways including endocytic-, vacuolar-, and autophagic trafficking are important for the various aspects of responses in plants. Studies in the last decade have shown that the autophagic transport pathway uses common key components of endomembrane trafficking as well as specific regulators. A number of factors previously described for their function in endosomal trafficking have been discovered to be involved in the regulation of autophagy in plants. These include conserved endocytic machineries, such as the endosomal sorting complex required for transport (ESCRT), subunits of the HOPS and exocyst complexes, SNAREs, and RAB GTPases as well as plant-specific proteins. Defects in these factors have been shown to cause impairment of autophagosome formation, transport, fusion, and degradation, suggesting crosstalk between autophagy and other intracellular trafficking processes. In this review, we focus mainly on possible functions of endosomal trafficking components in autophagy. PMID- 29165605 TI - Patient-Reported Outcome Measures in Neurosurgery: A Review of the Current Literature. AB - BACKGROUND: Patient-reported outcome measures (PROMs) play an important role in the evaluation of health outcomes, quality of life, and satisfaction, and have been successfully utilized in many areas of clinical medicine and surgical practice. The prevalence of PROMs in neurosurgery is not known. OBJECTIVE: To review the PROMs that have been utilized in the published neurosurgery literature to date. METHODS: Articles were searched in MEDLINE, EMBASE, HMIC Health Management Information Consortium, PsycARTICLES, and PsycINFO using search terms related to neurosurgery and PROMs, published from 1806 to August 2016. A total of 268 articles were identified that were stratified by the inclusion and exclusion criteria leading to a total of 137 articles. Twenty-six PROMs, involving both adult and pediatric populations, were identified. RESULTS: A large number of generic and disease-specific PROMs are used in the neurosurgical literature. Generic PROMs are usually nonspecific measures of health status. Disease-specific PROMs may not address issues relevant to neurosurgical procedures. There are very few neurosurgery-specific PROMs that take into account the impact of a neurosurgical procedure on a specific condition. CONCLUSION: PROMs that currently feature in the neurosurgical literature may not address the specific outcomes relevant to neurosurgical practice. There is an emergent need for generic and disease-specific PROMs to be validated in neurosurgical patients and neurosurgery specific PROMs developed to address unmet needs of patients undergoing neurosurgical procedures. PMID- 29165604 TI - Carbapenemase-Producing Organisms: A Global Scourge. AB - The dramatic increase in the prevalence and clinical impact of infections caused by bacteria producing carbapenemases is a global health concern. Carbapenemase production is especially problematic when encountered in members of the family Enterobacteriaceae. Due to their ability to readily spread and colonize patients in healthcare environments, preventing the transmission of these organisms is a major public health initiative and coordinated international effort are needed. Central to the treatment and control of carbapenemase-producing organisms (CPOs) are phenotypic (growth-/biochemical-dependent) and nucleic acid-based carbapenemase detection tests that identify carbapenemase activity directly or their associated molecular determinants. Importantly, bacterial isolates harboring carbapenemases are often resistant to multiple antibiotic classes, resulting in limited therapy options. Emerging agents, novel antibiotic combinations and treatment regimens offer promise for management of these infections. This review highlights our current understanding of CPOs with emphasis on their epidemiology, detection, treatment, and control. PMID- 29165606 TI - The burden of hip fractures-why aren't we better at prevention? PMID- 29165607 TI - An evidence-based approach to pre-pregnancy counselling for patients with systemic lupus erythematosus. AB - Patients with SLE are often young females of childbearing age and a pregnancy wish in this patient group is common. However, SLE patients are at high risk for adverse pregnancy outcomes that require adequate guidance. It is widely acknowledged that pre-pregnancy counselling is the pivotal first step in the management of SLE patients with a wish to become pregnant. Next, management of these patients is usually multidisciplinary and often requires specific expertise from the different physicians involved. Very recently a EULAR recommendation was published emphasizing the need for adequate preconception counselling and risk stratification. Therefore the present review specifically addresses the issue of pre-pregnancy counselling for SLE patients with an evidence-based approach. The review summarizes data retrieved from recently published, high-quality cohort studies that have contributed to a better understanding and estimation of pregnancy-related risks for SLE patients. The present review categorizes risks from a patient-oriented point of view, that is, the influence of pregnancy on SLE, of SLE on pregnancy, of SLE on the foetus/neonate and of SLE-related medication. Lastly, pre-pregnancy counselling of SLE patients with additional secondary APS is reviewed. Collectively these data can guide clinicians to formulate appropriate preventive strategies and patient-tailored monitoring plans during pre-pregnancy counselling of SLE patients. PMID- 29165608 TI - Improving quality of care through evaluating potentially preventable events and crew resource management implementation. PMID- 29165609 TI - Effects of cognitive loading and force on upper trapezius fatigue. AB - Background: Musculoskeletal disorders (MSDs) are particularly common in the shoulder/neck region for some tasks that involve low force exertions, for example computer work. It has been demonstrated that muscle activity may be stimulated by cognitively demanding tasks. There is a lack of studies on the relationship between qualitative levels of cognitive loading, level of muscle activity, and muscle fatigue. Aims: To investigate the effects of quantitative levels of cognitive loading on conduction velocity changes and isometric endurance times for the upper trapezius. Methods: Participants performed a combination of three levels of a cognitively demanding computer task (0, 1.59 and 3 Bits) while simultaneously performing either of two isometric endurance tests (20 and 40% MVC) for the upper trapezius. Results: Information load had a significant effect (P < 0.05) on normalized conduction velocity slopes for the 40% but not for the 20% maximum voluntary contraction conditions. Information load had a highly significant effect on endurance times for both exertion levels (P < 0.01). Conclusions: This study found that performing a high-difficulty cognitive task while simultaneously performing increasingly higher levels of static isometric shoulder abduction exertions, fatigued the trapezius muscle quicker than performing an equivalent exertion with low cognitive load. This is particularly relevant to workplaces with increasing levels of automation that require high levels of decision making and computer use. PMID- 29165611 TI - A Case of Hodgkin Lymphoma Mimicking Lymphomatoid Granulomatosis Diagnosed at Autopsy. AB - Hodgkin lymphoma and lymphomatoid granulomatosis (LYG) are entities that contain a small number of large, variably Epstein-Barr virus (EBV)-positive neoplastic cells scattered within background non-neoplastic mixed inflammatory infiltrate. The 2 entities can typically be distinguished histologically by the angiocentric and angiodestructive pattern of lymphomatoid granulomatosis (LYG); also, they differ in overall prognosis. Herein, we report a case of Hodgkin lymphoma in a 64 year-old Caucasian woman, diagnosed at autopsy with unusual histologic features and aggressive clinical course that mimicked LYG. PMID- 29165610 TI - Gramene 2018: unifying comparative genomics and pathway resources for plant research. AB - Gramene (http://www.gramene.org) is a knowledgebase for comparative functional analysis in major crops and model plant species. The current release, #54, includes over 1.7 million genes from 44 reference genomes, most of which were organized into 62,367 gene families through orthologous and paralogous gene classification, whole-genome alignments, and synteny. Additional gene annotations include ontology-based protein structure and function; genetic, epigenetic, and phenotypic diversity; and pathway associations. Gramene's Plant Reactome provides a knowledgebase of cellular-level plant pathway networks. Specifically, it uses curated rice reference pathways to derive pathway projections for an additional 66 species based on gene orthology, and facilitates display of gene expression, gene-gene interactions, and user-defined omics data in the context of these pathways. As a community portal, Gramene integrates best-of-class software and infrastructure components including the Ensembl genome browser, Reactome pathway browser, and Expression Atlas widgets, and undergoes periodic data and software upgrades. Via powerful, intuitive search interfaces, users can easily query across various portals and interactively analyze search results by clicking on diverse features such as genomic context, highly augmented gene trees, gene expression anatomograms, associated pathways, and external informatics resources. All data in Gramene are accessible through both visual and programmatic interfaces. PMID- 29165612 TI - Long-Term Outcomes of 107 Cases of Primary Thyroid Mucosa-Associated Lymphoid Tissue Lymphoma at a Single Medical Institution in Japan. AB - Context: Thyroid mucosa-associated lymphoid tissue (MALT) lymphoma is a type of extranodal lymphoma with a favorable prognosis. Objective: To provide information on long-term outcomes that would facilitate establishment of the optimal management strategy for thyroid lymphoma. Design, Setting, and Participants: Medical records of 107 patients (median age 67 years, 20 males, 87 females) who were diagnosed with localized thyroid MALT lymphoma stage IE or IIE at Ito Hospital were retrospectively reviewed. Main Outcome Measure: Overall and event free survival (EFS). Results: Initial treatments included radiation therapy (RT) alone (n = 58), combined modality therapy (CMT) (n = 48), or chemotherapy alone (n = 1). All 107 patients responded to the treatment, six of whom experienced relapse. Only one patient died of lymphoma. The 5-year overall survival (OS) and EFS rates were 94% [95% confidence interval (CI), 87% to 97%] and 92% (95% CI, 85% to 95%), respectively, and the 10-year OS and EFS rates were 91% (95% CI, 83% to 95%) and 84% (95% CI, 74% to 90%), respectively. Of the 106 patients with information available on adverse events, 71 patients (67%) developed hypothyroidism after primary thyroid lymphoma treatment. The CMT group showed additional chemotherapy-induced adverse reactions in the form of neutropenia, neuropathy, constipation, and pneumonia. The 5-year OS rates of patients treated with CMT and RT were 93% (95% CI, 81% to 98%) and 94% (95% CI, 84% to 98%), respectively. Conclusions: Long-term outcomes of localized thyroid MALT lymphoma are favorable with all initial treatment modalities. PMID- 29165613 TI - Exposure to Concentrated Ambient PM2.5 Compromises Spermatogenesis in a Mouse Model: Role of Suppression of Hypothalamus-Pituitary-Gonads Axis. AB - Epidemiological studies link ambient fine particulate matter (PM2.5) pollution to abnormalities in the male reproductive system. However, few toxicological studies have investigated this potentially important adverse effect of PM2.5 pollution. Therefore, in the present study, we analyzed the effects of PM2.5 exposure on spermatogenesis and hypothalamic-pituitary-gonadal (HPG) axis in a murine model. Fourteen male C57BL/6J mice were subjected to a 4-month exposure to filtered air or concentrated ambient PM2.5 (CAP). Their sperm count, testicular histology, spermatogenic parameters, and the major components of HPG axis were assessed. Exposure to CAP significantly reduced sperm count in the epididymis. This was accompanied by Sertoli cell vacuolization, immature germ cell dislocation, and decreases in pachytene spermatocytes and round spermatids of stage VII seminiferous tubules, suggesting a marked impairment of spermatogenesis in these mice. This impairment of spermatogenesis appeared to be attributable to a suppression of HPG axis subsequent to CAP exposure-induced hypothalamic inflammation, as exposure to CAP significantly increased TNFalpha and IL1b mRNA levels and meanwhile decreased gonadotropin-releasing hormone mRNA expression in the hypothalamus. Moreover, CAP exposure significantly reduced circulating testosterone and follicle-stimulating hormone, testicular testosterone and mRNA expression of follicle-stimulating hormone target gene SHBG and luteinizing hormone target genes P450scc, 17betaHSD, and StAR. The present data demonstrate that exposure to ambient PM2.5 impairs spermatogenesis in murine model, raising the concern over effects of ambient PM2.5 pollution on the male reproductive function. PMID- 29165615 TI - Human Herpesvirus 8 in Perinatally HIV-infected Children with Interstitial Lung Disease. AB - Introduction: Human herpesvirus 8 (HHV-8) is associated with the pathogenesis of Kaposi Sarcoma and interstitial pneumonitis in adults. This study aims to evaluate association between HHV-8 and interstitial lung disease in HIV-infected children. Methods: HIV-infected children with interstitial pneumonitis underwent lung biopsies in a tertiary hospital and were investigated for HHV-8, Epstein Barr virus (EBV) and cytomegalovirus (CMV) using polymerase chain reaction (PCR) and immunohistochemistry in lung tissue. Peripheral blood PCR was also performed for HHV-8. Results: From six patients included, PCR for HHV-8 was positive in lung samples in four children and in peripheral blood in one. PCR for EBV and CMV and immunohistochemical study for HHV-8, EBV and CMV in lung were negative in all patients. Conclusion: No previous cases of HHV-8-associated interstitial pneumonitis was described in HIV-infected children. An immunological disorder and an infectious agent might influence development of the lymphoid interstitial pneumonitis. HHV-8 may be this infectious trigger. PMID- 29165616 TI - Work System Assessment to Facilitate the Dissemination of a Quality Improvement Program for Optimizing Blood Culture Use: A Case Study Using a Human Factors Engineering Approach. AB - Background: Work system assessments can facilitate successful implementation of quality improvement programs. Using a human factors engineering approach, we conducted a work system assessment to facilitate the dissemination of a quality improvement program for optimizing blood culture use in pediatric intensive care units at 2 hospitals. Methods: Semistructured face-to-face interviews were conducted with clinicians from Johns Hopkins All Children's Hospital and University of Virginia Medical Center. Interview data were analyzed using qualitative content analysis. Results: Blood culture-ordering practices are influenced by various work system factors, including people, tasks, tools and technologies, the physical environment, organizational conditions, and the external environment. A clinical decision-support tool could facilitate implementation by (1) standardizing blood culture-ordering practices, (2) ensuring that prescribing clinicians review the patient's condition before ordering a blood culture, (3) facilitating critical thinking, and (4) empowering nurses to communicate with physicians and advocate for adherence to blood culture ordering guidelines. Conclusion: The success of interventions for optimizing blood culture use relies heavily on the local context. A work system analysis using a human factors engineering approach can identify key areas to be addressed for the successful dissemination of quality improvement interventions. PMID- 29165614 TI - Long-term health in recipients of transplanted in vitro propagated spermatogonial stem cells. AB - STUDY QUESTION: Is testicular transplantation of in vitro propagated spermatogonial stem cells associated with increased cancer incidence and decreased survival rates in recipient mice? SUMMARY ANSWER: Cancer incidence was not increased and long-term survival rate was not altered after transplantation of in vitro propagated murine spermatogonial stem cells (SSCs) in busulfan treated recipients as compared to non-transplanted busulfan-treated controls. WHAT IS KNOWN ALREADY: Spermatogonial stem cell autotransplantation (SSCT) is a promising experimental reproductive technique currently under development to restore fertility in male childhood cancer survivors. Most preclinical studies have focused on the proof-of-principle of the functionality and efficiency of this technique. The long-term health of recipients of SSCT has not been studied systematically. STUDY DESIGN, SIZE, DURATION: This study was designed as a murine equivalent of a clinical prospective study design. Long-term follow-up was performed for mice who received a busulfan treatment followed by either an intratesticular transplantation of in vitro propagated enhanced green fluorescent protein (eGFP) positive SSCs (cases, n = 34) or no transplantation (control, n = 37). Using a power calculation, we estimated that 36 animals per group would be sufficient to provide an 80% power and with a 5% level of significance to demonstrate a 25% increase in cancer incidence in the transplanted group. The survival rate and cancer incidence was investigated until the age of 18 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: Neonatal male B6D2F1 actin-eGFP transgenic mouse testis were used to initiate eGFP positive germline stem (GS) cell culture, which harbor SSCs. Six-week old male C57BL/6 J mice received a single dose busulfan treatment to deplete the testis from endogenous spermatogenesis. Half of these mice received a testicular transplantation of cultured eGFP positive GS cells, while the remainder of mice served as a control group. Mice were followed up until the age of 18 months (497-517 days post busulfan) or sacrificed earlier due to severe discomfort or illness. Survival data were collected. To evaluate cancer incidence a necropsy was performed and tissues were collected. eGFP signal in transplanted testis and in benign and malignant lesions was assessed by standard PCR. MAIN RESULTS AND THE ROLE OF CHANCE: We found 9% (95% CI: 2-25%) malignancies in the transplanted busulfan treated animals compared to 26% (95% CI: 14-45%) in the busulfan-treated control group, indicating no statistically significant difference in incidence of malignant lesions in transplanted and control mice (OR: 0.3, 95% CI: 0.1-1.1). Furthermore, none of the malignancies that arose in the transplanted animals contained eGFP signal, suggesting that they are not derived from the in vitro propagated transplanted SSCs. Mean survival time after busulfan treatment was found to be equal, with a mean survival time for transplanted animals of 478 days and 437 days for control animals (P = 0.076). LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: Although we attempted to mimic the future clinical application of SSCT in humans as close as possible, the mouse model that we used might not reflect all aspects of the future clinical setting. WIDER IMPLICATIONS OF THE FINDINGS: The absence of an increase in cancer incidence and a decrease in survival of mice that received a testicular transplantation of in vitro propagated SSCs is reassuring in light of the future clinical application of SSCT in humans. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by KiKa (Kika86) and ZonMw (TAS 116003002). The authors report no financial or other conflict of interest relevant to the subject of this article. PMID- 29165617 TI - Selective Activation of Striatal NGF-TrkA/p75NTR/MAPK Intracellular Signaling in Rats That Show Suppression of Methamphetamine Intake 30 Days following Drug Abstinence. AB - Background: The continuing epidemic of methamphetamine addiction has prompted research aimed at understanding striatal dysfunctions potentially associated with long-term methamphetamine use. Methods: Here, we investigated transcriptional and translational alterations in the expression of neurotrophic factors in the rat striatum at 30 days following methamphetamine self-administration and footshock punishment. Male Sprague-Dawley rats were trained to self-administer methamphetamine (0.1 mg/kg/injection, i.v.) or saline during twenty-two 9-hour sessions. Subsequently, rats were subjected to incremental footshocks for 13 additional methamphetamine self-administration sessions. This paradigm led to the identification of rats with shock-resistant and shock-sensitive phenotypes. Thirty days following the last footshock session, the dorsal striatum was dissected and processed for gene expression and protein analyses. Results: PCR arrays revealed significant differences in neurotrophins and their receptors between the 2 phenotypes. Brain-derived neurotrophic factor and nerve growth factor protein levels were increased in the dorsal striatum of both shock resistant and shock-sensitive rats. However, neurotrophic receptor tyrosine kinase 1 phosphorylation and nerve growth factor receptor protein expression were increased only in the shock-sensitive phenotype. Moreover, shock-sensitive rats showed increased abundance of several phosphorylated proteins known to participate in Ras/Raf/MEK/ERK signaling cascade including cRaf, ERK1/2, MSK1, and CREB. Conclusions: These findings support the notion that animals with distinct phenotypes for methamphetamine intake in the presence of adverse consequences also display differential changes in an intracellular signaling cascade activated by nerve growth factor-TrkA/p75NTR interactions. Thus, the development of pharmacological agents that can activate nerve growth factor dependent pathways may be a promising therapeutic approach to combat methamphetamine addiction. PMID- 29165618 TI - Human-Specific Mutations and Positively Selected Sites in MARCO Confer Functional Changes. AB - Macrophage Receptor with COllagenous structure (MARCO) is a class A scavenger receptor that binds, phagocytoses, and modifies inflammatory responses to bacterial pathogens. Multiple candidate gene approach studies have shown that polymorphisms in MARCO are associated with susceptibility or resistance to Mycobacterium tuberculosis infection, but how these variants alter function is not known. To complement candidate gene approach studies, we previously used phylogenetic analyses to identify a residue, glutamine 452 (Q452), within the ligand-binding Scavenger Receptor Cysteine Rich domain as undergoing positive selection in humans. Herein, we show that Q452 is found in Denisovans, Neanderthals, and extant humans, but all other nonprimate, terrestrial, and aquatic mammals possess an aspartic acid (D452) residue. Further analysis of hominoid sequences of MARCO identified an additional human-specific mutation, phenylalanine 282 (F282), within the collagenous domain. We show that residue 282 is polymorphic in humans, but only 17% of individuals (rs6761637) possess the ancestral serine residue at position 282. We show that rs6761637 is in linkage disequilibrium with MARCO polymorphisms that have been previously linked to susceptibility to pulmonary tuberculosis. To assess the functional importance of sites Q452 and F282 in humans, we cloned the ancestral residues and loss-of function mutations and investigated the role of these residues in binding and internalizing polystyrene microspheres and Escherichia coli. Herein, we show that the residues at sites 452 and 282 enhance receptor function. PMID- 29165619 TI - COMPARISON OF RESPONSE OF PASSIVE DOSIMETRY SYSTEMS IN SCANNING PROTON RADIOTHERAPY-A STUDY USING PAEDIATRIC ANTHROPOMORPHIC PHANTOMS. AB - Proton beam therapy has advantages in comparison to conventional photon radiotherapy due to the physical properties of proton beams (e.g. sharp distal fall off, adjustable range and modulation). In proton therapy, there is the possibility of sparing healthy tissue close to the target volume. This is especially important when tumours are located next to critical organs and while treating cancer in paediatric patients. On the other hand, the interactions of protons with matter result in the production of secondary radiation, mostly neutrons and gamma radiation, which deposit their energy at a distance from the target. The aim of this study was to compare the response of different passive dosimetry systems in mixed radiation field induced by proton pencil beam inside anthropomorphic phantoms representing 5 and 10 years old children. Doses were measured in different organs with thermoluminescent (MTS-7, MTS-6 and MCP-N), radiophotoluminescent (GD-352 M and GD-302M), bubble and poly-allyl-diglycol carbonate (PADC) track detectors. Results show that RPL detectors are the less sensitive for neutrons than LiF TLDs and can be applied for in-phantom dosimetry of gamma component. Neutron doses determined using track detectors, bubble detectors and pairs of MTS-7/MTS-6 are consistent within the uncertainty range. This is the first study dealing with measurements on child anthropomorphic phantoms irradiated by a pencil scanning beam technique. PMID- 29165620 TI - Comparative effectiveness of allopurinol, febuxostat and benzbromarone on renal function in chronic kidney disease patients with hyperuricemia: a 13-year inception cohort study. AB - Background: Direct comparisons of the effectiveness of allopurinol with that of other urate-lowering agents in chronic kidney disease (CKD) populations, as well as guideline recommendations for clinical practice, are lacking. Methods: We constructed a pharmacoepidemiology cohort study by including patients from Taiwan's long-term integrated CKD care program to compare the effectiveness among allopurinol, febuxostat and benzbromarone in reducing the risk of progression to dialysis. A total of 874 patients with hyperuricemia who were newly treated with allopurinol, febuxostat or benzbromarone were included. The primary and secondary outcomes were incident end-stage renal disease (ESRD) and the serum uric acid (SUA) changes from baseline, respectively. The results were analyzed using multiple Cox proportional models adjusted for multinomial propensity scores. For subgroup analyses, we further stratified patients according to whether their latest SUA level reached the therapeutic target. Results: Compared with allopurinol, benzbromarone therapy was associated with a reduced risk of progression to dialysis, the adjusted hazard ratio was 0.50 (95% confidence interval, 0.25-0.99). Patients who received allopurinol or febuxostat exhibited a comparable risk of ESRD [adjusted hazard ratio, 0.99 (0.40-2.44)]. Febuxostat was significantly more potent than allopurinol or benzbromarone in lowering SUA levels in the fully adjusted model. Among patients who reached the therapeutic target, those with febuxostat and benzbromarone initiation had a significantly lower risk of ESRD. Conclusions: In conclusion, compared with conventional allopurinol, febuxostat and benzbromarone may be more effective in reducing the risk of progression to dialysis and in lowering SUA levels in CKD populations. PMID- 29165621 TI - Treatment of tuberculosis in complex emergencies in developing countries: a scoping review. AB - Almost 172 million people live in complex emergencies globally resulting from political and/or economic instability. The provision and continuity of health care in complex emergencies remain a significant challenge. Health agencies are often hesitant to implement tuberculosis programmes in particular because its treatment requires a longer commitment than most acute diseases. However, not treating tuberculosis promptly increases mortality and untreated tuberculosis further increases the incidence of tuberculosis. Given that complex emergencies are increasing globally, there is an urgent need to analyse the available evidence to improve our understanding of how best to deliver tuberculosis programmes in such settings. Using a scoping review method, we selected and analysed 15 studies on tuberculosis programmes in complex emergencies. We found that despite the challenges, tuberculosis programmes have been successful in complex emergencies. We identified seven cross-cutting factors that were found to be important: service providers and treatment regime, training and supervision, donor support, adherence, leadership and coordination, monitoring and government and community support. In general, programmes showed greater creativity and flexibility to adapt to the local conditions and at times, it also meant diverting from the WHO guidelines. We identify areas of further research including the need to study the effectiveness of programmes that divert from the WHO guidelines and their implication on drug resistance. PMID- 29165622 TI - Recent Trends in Tobacco Use and New Insights Into Strategies to Reduce Use and Improve Treatment. PMID- 29165623 TI - Effects of Pharmacologic and Nonpharmacologic Interventions on Insomnia Symptoms and Self-reported Sleep Quality in Women With Hot Flashes: A Pooled Analysis of Individual Participant Data From Four MsFLASH Trials. AB - Study Objectives: The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network conducted three randomized clinical trials (RCTs) testing six interventions treating vasomotor symptoms (VMS), and also collected self-reported sleep outcomes. A fourth RCT assessed an intervention for insomnia symptoms among women with VMS. We describe these seven interventions' effects relative to control in women with comparably severe insomnia symptoms and VMS. Methods: We analyzed pooled individual-level data from 546 peri- and postmenopausal women with Insomnia Severity Index (ISI) >= 12, and >=14 bothersome VMS/week across the four RCTs. Interventions included the following: escitalopram 10-20 mg/day; yoga; aerobic exercise; 1.8 g/day omega-3 fatty acids; oral 17-beta-estradiol 0.5 mg/day; venlafaxine XR 75-mg/day; and cognitive behavioral therapy for insomnia (CBT-I). Outcome measures were ISI and Pittsburgh Sleep Quality Index (PSQI) over 8-12 weeks of treatment. Results: CBT-I produced the greatest reduction in ISI from baseline relative to control at -5.2 points (95% CI -7.0 to -3.4). Effects on ISI were similar for exercise at -2.1 and venlafaxine at -2.3 points. Comparably small decreases in ISI were observed with escitalopram, yoga, and estradiol. The largest reduction in PSQI from baseline was with CBT-I at -2.7 points (-3.9 to -1.5), although PSQI decreases of 1.2 to 1.6 points were significantly better than control with escitalopram, exercise, yoga, estradiol, and venlafaxine. Omega-3 supplements did not improve insomnia symptoms. Conclusions: This study's findings support current recommendations for CBT-I as a first line treatment in healthy midlife women with insomnia symptoms and moderately bothersome VMS. PMID- 29165624 TI - Cost and Potential Avoidability of Antibiotic-Associated Adverse Drug Reactions in Children. AB - We identified 375 children who visited the emergency department or urgent care clinic at Children's Mercy Hospitals & Clinics for antibiotic adverse drug reactions over a 1-year period, and the total cost for these visits was $170 893.20. Of these ADRs, 17% were likely avoidable. The potential negative consequences of antibiotics should be considered at the point of prescribing. PMID- 29165625 TI - Evidence of Chikungunya virus circulation in the Terai region of Nepal in 2014 and 2015. AB - Background: Chikungunya virus (CHIKV) infection is an emerging viral disease in Nepal, with the reported by our laboratories in 2013. Because of the similarity in signs and symptoms to dengue virus (DENV) and misdiagnosis, the under reporting of CHIKV infection in DENV-endemic areas of Nepal is very common. The aim of the present study is to identify CHIKV infection among patients with febrile illness during the 2014-2015 outbreaks. Methods: A total of 219 serum samples were tested for CHIKV and DENV by using enzyme-linked immunosorbent assays (ELISAs) to detect immunoglobulin M (IgM) and IgG antibodies, with confirmation by a 50% focal reduction neutralization test (FRNT50). Results: ELISA results demonstrated that for CHIKV and DENV, 20.5% and 14.2% of samples, respectively, were positive for IgG and/or IgM and 9.6% and 5.9% were positive for IgM alone. Further, FRNT50 results confirmed that 7.3% of samples possessed neutralizing anti-CHIKV antibodies. Conclusion: We conclude that CHIKV infection is settling in Nepal as an endemic disease. It is highly recommended to strengthen the surveillance system for CHIKV and DENV to prevent possible outbreaks. PMID- 29165626 TI - The Influence of Physical Activity and Sedentary Behavior on Living to Age 85 Years Without Disease and Disability in Older Women. AB - Background: Whether physical activity (PA) and sedentary behavior influence the odds of women living to age 85 years without chronic disease or disability is not well described. Methods: Participants of the Women's Health Initiative (n = 49,612) were categorized based on health status by age 85 years: (i) lived without developing major chronic disease or mobility disability ("healthy"); (ii) lived and developed mobility disability with or without disease; (iii) lived and developed major chronic disease, but not mobility disability; and (iv) died before their 85th birth year. Multinomial logistic regression models that adjusted for covariates such as age, race/ethnicity, and body size estimated associations of self-reported PA and sitting time on developing major disease or mobility disability or dying before age 85 relative to being healthy. Results: Mean +/- SD baseline age was 70.2 +/- 3.6 years. Distributions were: 22% healthy, 23% had mobility disability, 26% had major disease, and 29% died. Relative to those with high total PA, the adjusted odds ratios (OR) (confidence intervals [CI]) for mobility disability was 1.6 (1.4-1.7), 1.2 (1.1-1.3), and 1.1 (1.0-1.2) for women with no, low, and moderate total PA, respectively (p-trend < .001). The corresponding covariate-adjusted OR (CI) for mortality was 1.7 (1.5-1.8), 1.2 (1.1-1.3), and 1.0 (1.0-1.1) (p-trend < .001). Total PA was not associated with developing chronic disease before age 85 years. Sitting >=10 relative to <5 hours per day increased the odds of mobility disability (1.1, CI: 1.0-1.3) and mortality (1.2, CI: 1.0-1.3) prior to age 85 years (p < .001). Conclusions: Increasing PA to recommended levels and reducing sitting time are modifiable behaviors that may improve healthy aging in older women. PMID- 29165627 TI - Health literacy and patient outcomes in chronic kidney disease: a systematic review. AB - Background: Limited health literacy affects 25% of people with chronic kidney disease (CKD), and may reduce self-management skills resulting in poorer clinical outcomes. By disproportionately affecting people with low socio-economic status and non-white ethnicity, limited health literacy may promote health inequity. Methods: We performed a systematic review of quantitative studies of health literacy and clinical outcomes among adults with CKD. Results: A total of 29 studies (13 articles; 16 conference abstracts) were included. One included non USA patients. Of the 29 studies, 5 were cohort studies and 24 were cross sectional. In all, 18 300 patients were studied: 4367 non-dialysis CKD; 13 202 dialysis; 390 transplant; 341 unspecified. Median study size was 127 [interquartile range (IQR) 92-238)], but 480 (IQR 260-2392) for cohort studies. Median proportion of non-white participants was 48% (IQR 17-70%). Six health literacy measures were used. Outcomes included patient attributes, care processes, clinical/laboratory parameters and 'hard' clinical outcomes. Limited health literacy was significantly, independently associated with hospitalizations, emergency department use, missed dialysis sessions, cardiovascular events and mortality (in cohort studies). Study quality was high (1 study), moderate (3 studies) and poor (25 studies), limited by sampling methods, variable adjustment for confounders and reduced methodological detail given in conference abstracts. Conclusions: There is limited robust evidence of the causal effects of health literacy on patient outcomes in CKD. Available evidence suggests associations with adverse clinical events, increased healthcare use and mortality. Prospective studies are required to determine the causal effects of health literacy on outcomes in CKD patients, and examine the relationships between socio-economic status, comorbidity, health literacy and CKD outcomes. Intervention development and evaluation will determine whether health literacy is a modifiable determinant of poor outcomes in CKD. PMID- 29165628 TI - Sex Differences in 20-Hydroxyecdysone Hormone Levels Control Sexual Dimorphism in Bicyclus anynana Wing Patterns. AB - In contrast to the important role of hormones in the development of sexual traits in vertebrates (Cox RM, Stenquist DS, Calsbeek R. 2009. Testosterone, growth and the evolution of sexual size dimorphism. J Evol Biol. 22(8):1586-1598.), the differentiation of these traits in insects is attributed almost exclusively to cell-autonomous mechanisms controlled by members of the sex determination pathway (Verhulst EC, van de Zande L. 2015. Double nexus - doublesex is the connecting element in sex determination. Brief Funct Genomics 14(6):396-406.), such as doublesex. Although hormones can shape the development of sexual traits in insects, variation in hormone levels are not conclusively known to cause dimorphism in these traits (Prakash A, Monteiro A. 2016. Molecular mechanisms of secondary sexual trait development in insects. Curr Opin Insect Sci. 17:40-48.). Here, we show that butterflies use sex-specific differences in 20-hydroxyecdysone hormone titers to create sexually dimorphic wing ornaments. Females of the dry season (DS) form of Bicyclus anynana display a larger sexual ornament on their wings than males, whereas in the wet season form both sexes have similarly sized ornaments (Prudic KL, Jeon C, Cao H, Monteiro A. 2011. Developmental plasticity in sexual roles of butterfly species drives mutual sexual ornamentation. Science 331(6013):73-75.). High levels of circulating 20-hydroxyecdysone during larval development in DS females and wet season forms cause proliferation of the cells fated to give rise to this wing ornament, and results in sexual dimorphism in the DS forms. This study advances our understanding of how the environment regulates sex-specific patterns of plasticity of sexual ornaments and conclusively shows that hormones can play a role in the development of secondary sexual traits in insects, just like they do in vertebrates. PMID- 29165629 TI - Morbidity, Mortality, and Socioeconomics in Females With 46,XY Disorders of Sex Development: A Nationwide Study. AB - Context: Little is known about long-term health outcomes in phenotypic females with 46,XY disorders of sex development (XY females), and the socioeconomic profile has not been described in detail. Objective: To describe morbidity, mortality, and socioeconomic status in XY females in a comparison to the general population. Design: Nationwide registry study with complete follow-up. Setting: Uniform public health care system. Participants: A total of 123 XY females karyotyped in Denmark during 1960 to 2012 and a randomly selected age-matched control cohort of 12,300 females and 12,300 males from the general population. Main Outcome Measures: Overall mortality and morbidity as well as cause-specific morbidity; medicine use and socioeconomics (education, income, cohabitation, motherhood, and retirement). Results: Compared with female controls, overall morbidity was increased in XY females [hazard ratio (HR), 1.72; 95% confidence interval (CI), 1.43 to 2.08] but not when excluding diagnoses associated with the specific disorder of sex development (DSD) diagnosis or pregnancy and birth (HR, 1.13; CI, 0.93 to 1.37). Mortality was similar to controls (HR, 0.79; CI, 0.35 to 1.77). Cohabitation (HR, 0.44; CI, 0.33 to 0.58) and motherhood (HR, 0.10; CI, 0.05 to 0.18) were reduced in XY females but education (HR, 0.92; CI, 0.61 to 1.37) was similar to controls. Income was higher than among controls in the older years. Conclusions: Morbidity was not increased in XY females when excluding diagnoses associated to the DSD condition per se. Judged on education and income, XY females perform well in the labor market. However, DSD seems to impact on the prospects of family life. PMID- 29165630 TI - An eight-branched aortic graft for reconstruction of visceral and intercostal arteries during extent II thoraco-abdominal aortic surgery. AB - Reconstruction of the visceral and intercostal arteries is the most challenging part in the open repair of thoraco-abdominal aortic aneurysm. For efficient and expeditious reconstruction of these branching vessels, a technique of using a pre handsewn 8-branch aortic graft (octopod technique) has been adopted. The octopod graft was manually constructed using commercially available two 4-branch aortic grafts that were spatially oriented based on the preoperative computed tomographic images and connected each other prior to surgery. This approach was adopted in 12 open repairs of extent II thoraco-abdominal aortic aneurysms from 2015 to 2017, including 8 Marfan patients. Median pump and procedural times were 173 (102-207) min and 437 (343-489) min, respectively. There was no operative mortality or spinal cord injury. The octopod technique for open thoraco-abdominal aortic aneurysm repair showed excellent early results with high procedural efficiency. PMID- 29165631 TI - Instrumental variables estimation under a structural Cox model. AB - Instrumental variable (IV) analysis is an increasingly popular tool for inferring the effect of an exposure on an outcome, as witnessed by the growing number of IV applications in epidemiology, for instance. The majority of IV analyses of time to-event endpoints are, however, dominated by heuristic approaches. More rigorous proposals have either sidestepped the Cox model, or considered it within a restrictive context with dichotomous exposure and instrument, amongst other limitations. The aim of this article is to reconsider IV estimation under a structural Cox model, allowing for arbitrary exposure and instruments. We propose a novel class of estimators and derive their asymptotic properties. The methodology is illustrated using two real data applications, and using simulated data. PMID- 29165632 TI - Relevance of Neonatal Anaerobic Blood Cultures: New Information for an Old Question. PMID- 29165633 TI - Genetic Variation at IFNL4 Influences Extrahepatic Interferon-Stimulated Gene Expression in Chronic HCV Patients. AB - Polymorphisms at IFNL4 strongly influence spontaneous resolution and interferon therapeutic response in hepatitis C virus (HCV) infection. In chronic HCV, unfavorable alleles are associated with elevated interferon (IFN)-stimulated gene (ISG) expression in the liver, but extrahepatic effects are less well characterized. We used RNA sequencing (RNA-Seq) to examine whether IFNL4 genetic variation (rs368234815) modulates ISG expression in peripheral blood mononuclear cells (PBMC) during chronic HCV infection. ISG expression was elevated in unstimulated PBMC homozygous for the unfavorable DeltaG IFNL4 variant; expression following IFN-alpha stimulation was comparable across genotypes. These findings suggest that lambda interferons may have broader systemic effects during HCV infection. PMID- 29165634 TI - The ICRU Proposal for New Operational Quantities for External Radiation. AB - Report Committee 26 of the ICRU proposes a set of operational quantities for radiation protection for external radiation, directly based on effective dose and for an extended range of particles and energies. It is accompanied by quantities for estimating deterministic effects to the eye lens and the local skin. The operational quantities are designed to overcome the conceptual and technical shortcomings of those presently in use. This paper describes the proposed operational quantities, and highlights the improvements with respect to the present, legal monitoring quantities. PMID- 29165636 TI - Reducing Redundant Anaerobic Therapy Through Spaced Education and Antimicrobial Stewardship Interventions. AB - Background: Decreasing the use of redundant anaerobic therapy is a key target for antimicrobial stewardship. Education techniques that optimize knowledge retention could be an important component of reducing these regimens. Methods: We implemented a quality improvement project that incorporated spaced education to reduce the use of redundant anaerobic therapy. The initial interventions (November through December 2015) included education in a hospital-wide newsletter and review of redundant anaerobic regimens by the antimicrobial stewardship program. A spaced education module was then developed with the gastroenterology (GI) service, which had a relatively high rate of redundant anaerobic therapy use. Ten questions with teaching points were delivered to GI physicians at spaced intervals over 2 to 4 weeks (February through March 2016). Knowledge scores were compared at initial and final question presentation using generalized estimating equations. Interrupted time-series analysis was used to compare the rates of redundant-metronidazole-days per 1000 patient-days among patients in the patients admitted to the GI service and those in the non-GI group before and after the intervention. Results: Of 66 GI physicians, 56 (85%) participated in the spaced education activity. After the intervention, their knowledge scores on all the questions improved, and their mean knowledge score increased from 57% to 86% (P < .001). Nearly all (91%) of the participants were very or generally satisfied with the activity. In the GI group, the rate of redundant-metronidazole-days decreased from 26.2 to 13.0 per 1000 patient-days (relative risk [RR], 0.45 [95% confidence interval (CI), 0.27-0.73]; P = .001). This rate in the non-GI group also decreased from 5.47 to 2.18 per 1000 patient-days (RR, 0.47 [95% CI, 0.36-0.60]; P < .001) after our interventions. Conclusions: Spaced education is an effective approach for teaching antimicrobial stewardship topics. Focused provider education was associated with a sustained reduction in the use of redundant anaerobic therapy. PMID- 29165635 TI - Breast Development in Transwomen After 1 Year of Cross-Sex Hormone Therapy: Results of a Prospective Multicenter Study. AB - Context: Breast development is a key feature of feminization and therefore important to transwomen (male-to-female transgender persons). It is not exactly known when breast development starts after initiating cross-sex hormone therapy (CHT) and how much growth may be expected. Objective: To investigate breast development in transwomen during their first year of CHT and whether clinical or laboratory parameters predict breast development. Design: This study was performed as part of the European Network for the Investigation of Gender Incongruence, which is a prospective multicenter cohort study. Setting: Gender clinics in Amsterdam, Ghent, and Florence. Participants: Transwomen who completed the first year of CHT (n = 229). Intervention: CHT. Main Outcome Measures: Breast development in centimeter and cup size. Results: The median age of the included transwomen was 28 years (range, 18 to 69). Mean breast-chest difference increased to 7.9 +/- 3.1 cm after 1 year of CHT, mainly resulting in less than an AAA cup size (48.7%). Main breast development occurred in the first 6 months of therapy. Serum estradiol levels did not predict breast development after 1 year of CHT (first quartile, 3.6 cm [95% confidence interval (CI), 2.7 to 4.5], second quartile, 3.2 cm [95% CI, 2.3 to 4.2], third quartile, 4.4 cm [95% CI, 3.5 to 5.3], and fourth quartile, 3.6 cm [95% CI, 2.7 to 4.5]). Conclusion: This study shows that, after 1 year of CHT, breast development is modest and occurs primarily in the first 6 months. No clinical or laboratory parameters were found that predict breast development. PMID- 29165637 TI - A controlled study of the effects of ferric carboxymaltose on bone and haematinic biomarkers in chronic kidney disease and pregnancy. AB - Background: Intravenous (IV) iron can modulate fibroblast growth factor 23 (FGF23) concentrations and cause transient but significant hypophosphataemia. However, it is unknown what other markers might be involved, especially in different patient groups. This study aimed to determine changes in bone and haematinic biomarkers following IV ferric carboxymaltose (FCM) and to identify risk factors for hypophosphataemia in pregnant subjects and those with chronic kidney disease (CKD). Methods: Changes in bone [serum FGF23, fractional excretion of phosphate urinary fractional excretion of phosphate (FEPi), serum phosphate and serum vitamin D derivatives] and haematinic [plasma hepcidin, serum ferritin and transferrin saturation (TSAT)] biomarkers after 1 g of IV FCM were followed in iron-deficient pregnant and CKD patients and compared with controls (estimated glomerular filtration rate > 60 mL/min/1.73 m2). Data were collected at baseline and up to 42 days after infusion. Risk factors for post-FCM hypophosphataemia were also assessed. Results: Sixty-five subjects completed the study (control, n = 20; pregnant, n = 20; CKD, n = 25). A uniform but variable increase across groups was seen in intact FGF23 (peak Day 2), whereas c-terminal FGF23 varied markedly. Trough serum phosphate timed with the peak FEPi at Day 7, recovering by Day 21 in the pregnant group and Day 42 in other groups. Independent predictors of a low phosphate nadir included baseline phosphate, FEPi and weight-adjusted FCM dose. All groups showed an early and marked increase in plasma hepcidin (peak Day 2), serum ferritin and TSAT (peak Day 7 for both). Conclusions: Changes in bone and haematinic biomarkers differ between patient groups following IV FCM. For patients with lower serum phosphate concentrations, limiting the dose and measuring levels 7 days after administration may mitigate clinically significant hypophosphataemia. PMID- 29165638 TI - Feasibility of real-time molecular profiling for patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation-the NCT Neuro Master Match (N2M2) pilot study. AB - Background: O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is a predictive biomarker in glioblastoma patients. Glioblastoma without hypermethylated MGMT promoter is largely resistant to treatment with temozolomide. These patients are in particular need of new treatment approaches, which are offered by biomarker-driven clinical trials with targeted drugs based on molecular characterization of individual tumors. Methods: In preparation for an upcoming clinical study, a comprehensive molecular profiling approach was undertaken on tissues from 43 glioblastoma patients harboring an unmethylated MGMT promoter at diagnosis. The diagnostic pipeline covered various levels of molecular characteristics, including whole-exome sequencing, low-coverage whole genome sequencing, RNA sequencing, as well as microarray-based gene expression profiling and DNA methylation arrays. Results: Complex multilayer molecular diagnostics were feasible in this setting with a median turnaround time of 4-5 weeks from surgery to the molecular tumor board. In 35% of cases, potentially relevant therapeutic decisions were derived from the data. Alterations were most frequently found in receptor tyrosine kinases, members of the phosphoinositide 3 kinase/Akt/mechanistic target of rapamycin and mitogen-activated protein kinase pathway as well as cell cycle control and p53 regulation cascades. Individual tumors harbored clonal alterations such as oncogenic fusions of tyrosine kinases which constitute promising targets for targeted therapies. A prioritization algorithm is proposed to allocate patients with multiple targets to the potentially best treatment option. Conclusion: With this feasibility study, a comprehensive molecular profiling approach for patients with newly diagnosed glioblastoma harboring an unmethylated MGMT promoter is presented. Analyses in this pilot cohort serve as a basis for trials based on targetable alterations and on the question of allocation of patients to the best treatment arm. PMID- 29165640 TI - Toxicokinetics of Deltamethrin: Dosage Dependency, Vehicle Effects, and Low-Dose Age-Equivalent Dosimetry in Rats. AB - There is increasing concern that infants and children may be at increased risk of neurological effects of pyrethroids, the most widely used class of insecticide. The objectives of this investigation were to (1) characterize the dose-dependent toxicokinetics (TK) of deltamethrin (DLM) for exposures ranging from environmentally relevant to acutely toxic; (2) determine the influence of an aqueous versus oil vehicle on oral absorption and bioavailability; and (3) determine whether DLM exhibits low-dose, age-equivalent internal dosimetry. Serial arterial plasma samples were obtained for 72 h from adult, male Sprague Dawley rats given 0.05-5.0 mg DLM/kg as an oral bolus in corn oil (CO). DLM exhibited linear, absorption rate-limited TK. Increases in maximum plasma concentration (Cmax) and AUC?infinity were directly proportional to the dose. Oral bioavailability was quite limited. The vehicle and its volume had modest effect on the rate and extent of systemic absorption in adult rats. Postnatal day (PND) 15, 21, and 90 (adult) rats received 0.10, 0.25, or 0.50 mg DLM/kg orally in CO and were sacrificed periodically for plasma, brain, and liver collection. Age-dependent differences between PND 15 and 90 plasma Cmax and AUC?24 values progressively diminished as the dose decreased, but there was a lack of low dose age equivalence in these brain and liver dosimeters. Other maturational factors may account for the lack of the low-dose age equivalence in brain and liver. This investigation provides support for the premise that the relatively low metabolic capacity of immature subjects may be adequate to effectively eliminate trace amounts of DLM and other pyrethroids from the plasma. PMID- 29165639 TI - Human cancer tissues exhibit reduced A-to-I editing of miRNAs coupled with elevated editing of their targets. AB - A-to-I RNA editing is an important post-transcriptional modification, known to be altered in tumors. It targets dozens of sites within miRNAs, some of which impact miRNA biogenesis and function, as well as many miRNA recognition sites. However, the full extent of the effect of editing on regulation by miRNAs and its behavior in human cancers is still unknown. Here we systematically characterized miRNA editing in 10 593 human samples across 32 cancer types and normal controls. We find that the majority of previously reported sites show little to no evidence for editing in this dataset, compile a list of 58 reliable miRNA editing sites, and study them across normal and cancer samples. Edited miRNA versions tend to suppress expression of known oncogenes, and, consistently, we observe a clear global tendency for hypo-editing in tumors, in strike contrast to the behavior for mRNA editing, allowing an accurate classification of normal/tumor samples based on their miRNA editing profile. In many cancers this profile correlates with patients' survival. Finally, thousands of miRNA binding sites are differentially edited in cancer. Our study thus establishes the important effect of RNA editing on miRNA-regulation in the tumor cell, with prospects for diagnostic and prognostic applications. PMID- 29165641 TI - How to do (or not to do)... Measuring health worker motivation in surveys in low- and middle-income countries. AB - A health system's ability to deliver quality health care depends on the availability of motivated health workers, which are insufficient in many low income settings. Increasing policy and researcher attention is directed towards understanding what drives health worker motivation and how different policy interventions affect motivation, as motivation is key to performance and quality of care outcomes. As a result, there is growing interest among researchers in measuring motivation within health worker surveys. However, there is currently limited guidance on how to conceptualize and approach measurement and how to validate or analyse motivation data collected from health worker surveys, resulting in inconsistent and sometimes poor quality measures. This paper begins by discussing how motivation can be conceptualized, then sets out the steps in developing questions to measure motivation within health worker surveys and in ensuring data quality through validity and reliability tests. The paper also discusses analysis of the resulting motivation measure/s. This paper aims to promote high quality research that will generate policy relevant and useful evidence. PMID- 29165642 TI - The Corticospinal Reserve Capacity: Reorganization of Motor Area and Excitability As a Novel Pathophysiological Concept in Cervical Myelopathy. AB - BACKGROUND: In degenerative cervical myelopathy (DCM), the dynamics of disease progression and the outcome after surgical decompression vary interindividually and do not necessarily correlate with radiological findings. OBJECTIVE: To improve diagnostic power in DCM by better characterization of the underlying pathophysiology using navigated transcranial magnetic stimulation (nTMS). METHODS: Eighteen patients with DCM due to cervical spinal canal stenosis were examined preoperatively with nTMS. On the basis of the initial Japanese Orthopedic Association (JOA) Score, 2 patient groups were established (JOA <=12/>12). We determined the resting motor threshold, recruitment curve, cortical silent period, and motor area. Accordingly, 8 healthy subjects were examined. RESULTS: Although the resting motor threshold was comparable in both groups (P = .578), the corticospinal excitability estimated by the recruitment curve was reduced in patients (P = .022). In patients with only mild symptoms (JOA > 12), a compensatory higher activation of non-primary motor areas was detected (P < .005). In contrast, patients with severe impairment (JOA <= 12) showed a higher cortical inhibition (P < .05) and reduced cortical motor area (P < .05) revealing a functional restriction on the cortical level. CONCLUSION: Based on these results, we propose a new concept for functional compensation for DCM on the cortical and spinal level, ie corticospinal reserve capacity. nTMS is a useful tool to noninvasively characterize the pattern of functional impairment and compensatory reorganization in patients suffering from DCM. The change in nTMS parameters might serve as a valuable prognostic factor in these patients in the future. PMID- 29165644 TI - 'The money can be a motivator, to me a little, but mostly PBF just helps me to do better in my job.' An exploration of the motivational mechanisms of performance based financing for health workers in Malawi. AB - Performance-based financing (PBF) is assumed to improve health care delivery by motivating health workers to enhance their work performance. However, the exact motivational mechanisms through which PBF is assumed to produce such changes are poorly understood to date. Although PBF is increasingly recognized as a complex health systems intervention, its motivational effect for individual health workers is still often reduced to financial 'carrots and sticks' in the literature and discourse. Aiming to contribute to the development of a more comprehensive understanding of the motivational mechanisms, we explored how PBF impacted health worker motivation in the context of the Malawian Results-based Financing for Maternal and Newborn Health (RBF4MNH) Initiative. We conducted in depth interviews with 41 nurses, medical assistants and clinical officers from primary- and secondary-level health facilities 1 and 2 years after the introduction of RBF4MNH in 2013. Six categories of motivational mechanisms emerged: RBF4MNH motivated health workers to improve their performance (1) by acting as a periodic wake-up call to deficiencies in their day-to-day practice; (2) by providing direction and goals to work towards; (3) by strengthening perceived ability to perform successfully at work and triggering a sense of accomplishment; (4) by instilling feelings of recognition; (5) by altering social dynamics, improving team work towards a common goal, but also introducing social pressure; and (6) by offering a 'nice to have' opportunity to earn extra income. However, respondents also perceived weaknesses of the intervention design, implementation-related challenges and contextual constraints that kept RBF4MNH from developing its full motivating potential. Our results underline PBF's potential to affect health workers' motivation in ways which go far beyond the direct effects of financial rewards to individuals. We strongly recommend considering all motivational mechanisms more explicitly in future PBF design to fully exploit the approach's capacity for enhancing health worker performance. PMID- 29165643 TI - Expanding the repertoire of DNA shape features for genome-scale studies of transcription factor binding. AB - Uncovering the mechanisms that affect the binding specificity of transcription factors (TFs) is critical for understanding the principles of gene regulation. Although sequence-based models have been used successfully to predict TF binding specificities, we found that including DNA shape information in these models improved their accuracy and interpretability. Previously, we developed a method for modeling DNA binding specificities based on DNA shape features extracted from Monte Carlo (MC) simulations. Prediction accuracies of our models, however, have not yet been compared to accuracies of models incorporating DNA shape information extracted from X-ray crystallography (XRC) data or Molecular Dynamics (MD) simulations. Here, we integrated DNA shape information extracted from MC or MD simulations and XRC data into predictive models of TF binding and compared their performance. Models that incorporated structural information consistently showed improved performance over sequence-based models regardless of data source. Furthermore, we derived and validated nine additional DNA shape features beyond our original set of four features. The expanded repertoire of 13 distinct DNA shape features, including six intra-base pair and six inter-base pair parameters and minor groove width, is available in our R/Bioconductor package DNAshapeR and enables a comprehensive structural description of the double helix on a genome wide scale. PMID- 29165645 TI - Down-regulation of miR-378a-3p induces decidual cell apoptosis: a possible mechanism for early pregnancy loss. AB - STUDY QUESTION: Do microRNAs (miRNAs) contribute to human early pregnancy loss (EPL)? SUMMARY ANSWER: miR-378a-3p expression is regulated by progesterone and is down-regulated in ducidua of EPL patients which may contribute to decidual apoptosis through Caspase-3 activation. WHAT IS KNOWN ALREADY: A variety of miRNAs have been demonstrated to be associated with the development of decidualization and placental formation. However, little has been reported on the roles of miRNA in the pathogenesis of EPL. STUDY DESIGN, SIZE, DURATION: Normal and EPL decidual tissues were collected from patients with normal pregnancies undergoing elective termination of gestation, and from patients with EPL, respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: miRNA microarrays were used to identify the differentially expressed miRNAs between normal and EPL decidua, and miRNA expression was confirmed by qRT-PCR, qRT-PCR, western blotting and luciferase reporter assays were employed to validate the downstream targets of miR-378a-3p. The effects of miR-378a-3p were evaluated using miR-378a-3p transfected decidual cells. MAIN RESULTS AND THE ROLE OF CHANCE: Of note, 32 up regulated miRNAs and 38 down-regulated miRNAs were identified by microarray analysis when comparing EPL to normal decidua. MiR-378a-3p was significantly down regulated in the EPL decidua and was found to inversely regulate the expression of Caspase-3 by directly binding to its 3'-UTRs. In decidual cells, transfection of miR-378a-3p mimics resulted in the inhibition of cell apoptosis and in the increase of cell proliferation through Caspase-3 suppression. Moreover, we found that progesterone could induce the expression of miR-378a-3p in decidual cells. LIMITATIONS, REASONS FOR CAUTION: This study focused on the function of miR-378a 3p and its target Caspase-3, however, numerous other targets and miRNAs may also be responsible for the pathogenesis of EPL. Therefore, further studies are required to elucidate the role of miRNAs in EPL. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that miR-378a-3p may contribute to the development of EPL, and that it could serve as a new potential predictive and therapeutic target of progesterone-treatment for EPL. STUDY FUNDING/COMPETING INTEREST: This study was supported by National Basic Research Program of China (No.2012CB944900); National Science Foundation of China (No.31471405 and 81490742, No.81361120246); The National Science and Technology Support Program (No.2012BA132B00). Authors declare no competing interests. PMID- 29165647 TI - LEVELS OF EXTREMELY LOW-FREQUENCY ELECTRIC AND MAGNETIC FIELDS FROM OVERHEAD POWER LINES IN THE OUTDOOR ENVIRONMENT OF RAMALLAH CITY-PALESTINE. AB - In this study, levels of extremely low-frequency electric and magnetic fields originated from overhead power lines were investigated in the outdoor environment in Ramallah city, Palestine. Spot measurements were applied to record fields intensities over 6-min period. The Spectrum Analyzer NF-5035 was used to perform measurements at 1 m above ground level and directly underneath 40 randomly selected power lines distributed fairly within the city. Levels of electric fields varied depending on the line's category (power line, transformer or distributor), a minimum mean electric field of 3.9 V/m was found under a distributor line, and a maximum of 769.4 V/m under a high-voltage power line (66 kV). However, results of electric fields showed a log-normal distribution with the geometric mean and the geometric standard deviation of 35.9 and 2.8 V/m, respectively. Magnetic fields measured at power lines, on contrast, were not log normally distributed; the minimum and maximum mean magnetic fields under power lines were 0.89 and 3.5 MUT, respectively. As a result, none of the measured fields exceeded the ICNIRP's guidelines recommended for general public exposures to extremely low-frequency fields. PMID- 29165646 TI - Development and application of a recombination-based library versus library high- throughput yeast two-hybrid (RLL-Y2H) screening system. AB - Protein-protein interaction (PPI) network maintains proper function of all organisms. Simple high-throughput technologies are desperately needed to delineate the landscape of PPI networks. While recent state-of-the-art yeast two hybrid (Y2H) systems improved screening efficiency, either individual colony isolation, library preparation arrays, gene barcoding or massive sequencing are still required. Here, we developed a recombination-based 'library vs library' Y2H system (RLL-Y2H), by which multi-library screening can be accomplished in a single pool without any individual treatment. This system is based on the phiC31 integrase-mediated integration between bait and prey plasmids. The integrated fragments were digested by MmeI and subjected to deep sequencing to decode the interaction matrix. We applied this system to decipher the trans-kingdom interactome between Mycobacterium tuberculosis and host cells and further identified Rv2427c interfering with the phagosome-lysosome fusion. This concept can also be applied to other systems to screen protein-RNA and protein-DNA interactions and delineate signaling landscape in cells. PMID- 29165649 TI - A COMPREHENSIVE STUDY OF RESIDENTIAL, GEOGENIC AND WATER RADON IN THE NORTH AREA OF MURES COUNTY, ROMANIA. AB - This study presents results of a complex survey about residential, soil and water radon in the North of Mures county (Romania). Indoor radon measurements were performed by using CR-39 track detectors, while radon concentrations in soil and in water were measured by using the LUK3C device and accessories. The indoor radon concentrations of 157 houses ranged from 9 to 414 Bq m-3, with an arithmetic mean of 131 Bq m-3 and a geometric mean of 105 Bq m-3. In ~3.2% of the investigated houses exceed the recommended reference level of 300 Bq m-3. The soil gas radon concentrations in 137 sampling points varied from 5.0 to 88.0 kBq m-3, with a geometric mean of 14.6 kBq m-3. Results of 190 water samples shows radon concentrations from 0.2 to 28.0 Bq L-1, with a geometric mean of 5.0 Bq L 1. Beside these results, indoor, soil and water radon maps were performed, divided into cells of 5 km * 5 km. PMID- 29165648 TI - Structure modeling of RNA using sparse NMR constraints. AB - RNAs fold into distinct molecular conformations that are often essential for their functions. Accurate structure modeling of complex RNA motifs, including ubiquitous non-canonical base pairs and pseudoknots, remains a challenge. Here, we present an NMR-guided all-atom discrete molecular dynamics (DMD) platform, iFoldNMR, for rapid and accurate structure modeling of complex RNAs. We show that sparse distance constraints from imino resonances, which can be readily obtained from routine NMR experiments and easier to compile than laborious assignments of non-solvent-exchangeable protons, are sufficient to direct a DMD search for low energy RNA conformers. Benchmarking on a set of RNAs with complex folds spanning up to 56 nucleotides in length yields structural models that recapitulate experimentally determined structures with all-heavy-atom RMSDs ranging from 2.4 to 6.5 A. This platform represents an efficient approach for high-throughput RNA structure modeling and will facilitate analysis of diverse, newly discovered functional RNAs. PMID- 29165650 TI - Evaluation of 1,25-dihydroxyvitamin D3 pathway in patients with chronic urticaria. AB - Background: Previous studies showed the role of vitamin D (Vit D) on the progression of chronic urticaria. To the best of our knowledge, there are no other results regarding the contribution of single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genes in chronic urticaria (CU). Aim: In the present study, we investigated the Vit pathway and the association between VDR and VDBP gene polymorphisms and CU risk in Iranian population. Methods: All participating individuals in the present study were evaluated for serum Vit D and VDBP concentration VDR rs1544410 and rs2228570 and VDBP rs7041using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The associations of studied analytes and three SNPs with clinical and laboratory outcomes were investigated in CU patients. Results: Patients with CU showed lower Vit D compared to controls (19.26 +/- 1.26 vs. 31.72 +/- 7.14 ng/ml, P-value = 0.006). There was a significant correlation between Vit D levels and urticaria activity score. Serum VDBP was significantly higher in CU patients than controls (1317.3 +/- 183.71 vs. 395.77 +/- 12.96 ug/ml, P-value <0.0001) and had a positive correlation to progression of CU. The A allele of this polymorphism might be a potential risk factor for progression of CU [odds ratio 4.3434, 95% confidence interval (1.7331 10.8852), Z-statistic = 3.133, P-value = 0.0017]. Conclusion: In summary, this study demonstrated that change in Vit D pathway in the level of gene or protein may be a risk factor for progression of CU. PMID- 29165651 TI - Functional Conservation of the AMA1 Host-Cell Invasion Ligand Between P. falciparum and P. vivax: A Novel Platform to Accelerate Vaccine and Drug Development. AB - Plasmodium vivax and P. falciparum malaria species have diverged significantly in receptor-ligand interactions and host-cell invasion. One protein common to both is the merozoite invasion ligand AMA1. While the general structure of AMA1 is similar between species, their sequences are divergent. Surprisingly, it was possible to genetically replace PfAMA1 with PvAMA1 in P. falciparum parasites. PvAMA1 complemented PfAMA1 function and supported invasion of erythrocytes by P. falciparum. Genetically modified P. falciparum expressing PvAMA1 evaded the invasion inhibitory effects of antibodies to PfAMA1, demonstrating species specificity of functional antibodies. We generated antibodies to recombinant PvAMA1 that effectively inhibited invasion, confirming the function of PvAMA1 in genetically modified parasites. Results indicate significant molecular flexibility in AMA1 enabling conserved function despite substantial sequence divergence across species. This provides powerful new tools to quantify the inhibitory activities of antibodies or drugs targeting PvAMA1, opening new opportunities for vaccine and therapeutic development against P. vivax. PMID- 29165652 TI - STUDIES OF COSMIC-RAY MUONS AND NEUTRONS IN A FIVE-STORY CONCRETE BUILDING. AB - This study thoroughly determined the flux and dose rate distributions of cosmic ray muons and neutrons in a five-story concrete building by comparing measurements with Monte Carlo simulations of cosmic-ray showers. An angular energy-dependent surface source comprising secondary muons and neutrons at a height of 200 m above ground level was established and verified, which was used to concatenate the shower development in the upper atmosphere with subsequent simulations of radiation transport down to ground level, including the effect of the terrain and studied building. A Berkeley Lab cosmic-ray detector and a highly sensitive Bonner cylinder were used to perform muon and neutron measurements on each building floor. After careful calibration and correction, the measured responses of the two detectors were discovered to be reasonably consistent with the theoretical predictions, thus confirming the validity of the two-step calculation model employed in this study. The annual effective doses from cosmic ray muons and neutrons on the open roof of the building were estimated to be 115.2 and 35.2 MUSv, respectively. Muons and neutrons were attenuated floor-by floor with different attenuation factors of 0.97 and 0.78, and their resultant dose rates on the first floor of the building were 97.8 and 9.9 MUSv, respectively. PMID- 29165654 TI - Infusions of Nerve Growth Factor Into the Developing Frontal Cortex Leads to Deficits in Behavioral Flexibility and Increased Perseverance. AB - In the pursuit of further establishing a neurodevelopmental animal model to investigate the mechanisms underlying impaired executive function, a core and severely debilitating symptom of schizophrenia, we sought to characterize the deficits in behavioral flexibility in adult rats following neonatal infusions of nerve growth factor (NGF) into the medial part of the developing frontal cortex. Our previous studies using this neonatal frontal cortical lesion model have shown that it leads to adult-onset positive and negative symptom-like features, and several neuropathological abnormalities of schizophrenia. In the present study, we used operant conditioning-based paradigms to investigate set-shifting ability and reversal learning performance in adult rats that received infusions of NGF into the developing frontal cortex on post-natal day 1. NGF-infusion caused apoptosis of cells in the subplate layer. Adult rats that received neonatal infusions of NGF showed decreased grey matter thickness, and decreased levels of parvalbumin in prelimbic and infralimbic areas of the medial prefrontal cortex (mPFC). NGF-treated rats had difficulty completing the set-shifting and reversal learning tasks due to increased perseverance (ie, a failure to disengage from the previously-learned strategy once the rule contingencies were changed) compared to the control group. Collectively, these results identify the crucial role of the frontal cortical subplate layer in the structural and functional development of the mPFC relevant to schizophrenia. Furthermore, the present findings substantially advance the face and construct validity of this putative preclinical model of schizophrenia based on developmental disruption of the frontal cortical subplate. PMID- 29165653 TI - Transgenerational Effects of Bisphenol A on Gene Expression and DNA Methylation of Imprinted Genes in Brain. AB - Bisphenol A (BPA) is a ubiquitous man-made endocrine disrupting compound (EDC). Developmental exposure to BPA changes behavioral and reproductive phenotypes, and these effects can last for generations. We exposed embryos to BPA, producing two lineages: controls and BPA exposed. In the third filial generation (F3), brain tissues containing the preoptic area, the bed nucleus of the stria terminalis, and the anterior hypothalamus were collected. RNA sequencing (RNA-seq) and subsequent data analyses revealed 50 differentially regulated genes in the brains of F3 juveniles from BPA vs control lineages. BPA exposure can lead to loss of imprinting, and one of the two imprinted genes in our data set, maternally expressed gene 3 (Meg3), has been associated with EDCs and neurobehavioral phenotypes. We used quantitative polymerase chain reaction to examine the two imprinted genes in our data set, Meg3 and microRNA-containing gene Mirg (residing in the same loci). Confirming the RNA-seq, Meg3 messenger RNA was higher in F3 brains from the BPA lineage than in control brains. This was true in brains from mice produced with two different BPA paradigms. Next, we used pyrosequencing to probe differentially methylated regions of Meg3. We found transgenerational effects of BPA on imprinted genes in brain. Given these results, and data on Meg3 methylation in humans, we suggest this gene may be a biomarker indicative of early life environmental perturbation. PMID- 29165655 TI - Expression Atlas: gene and protein expression across multiple studies and organisms. AB - Expression Atlas (http://www.ebi.ac.uk/gxa) is an added value database that provides information about gene and protein expression in different species and contexts, such as tissue, developmental stage, disease or cell type. The available public and controlled access data sets from different sources are curated and re-analysed using standardized, open source pipelines and made available for queries, download and visualization. As of August 2017, Expression Atlas holds data from 3,126 studies across 33 different species, including 731 from plants. Data from large-scale RNA sequencing studies including Blueprint, PCAWG, ENCODE, GTEx and HipSci can be visualized next to each other. In Expression Atlas, users can query genes or gene-sets of interest and explore their expression across or within species, tissues, developmental stages in a constitutive or differential context, representing the effects of diseases, conditions or experimental interventions. All processed data matrices are available for direct download in tab-delimited format or as R-data. In addition to the web interface, data sets can now be searched and downloaded through the Expression Atlas R package. Novel features and visualizations include the on-the fly analysis of gene set overlaps and the option to view gene co-expression in experiments investigating constitutive gene expression across tissues or other conditions. PMID- 29165656 TI - Limited Midline Myelotomy for Intractable Visceral Pain: Surgical Techniques and Outcomes. AB - BACKGROUND: Limited midline myelotomy targets the midline nociceptive pathway for intractable visceral pain. Multiple techniques are available for limited midline myelotomy; however, outcome data for each technique are sparse. OBJECTIVE: To review our experience with open and percutaneous approaches for limited midline myelotomy for intractable visceral pain. METHODS: Patients who underwent limited midline myelotomy for intractable visceral pain were reviewed. Myelotomy was performed using 3 techniques: open limited myelotomy, percutaneous radiofrequency myelotomy, and percutaneous mechanical myelotomy. Demographic and perioperative clinical data were recorded. In addition to the visual analog scale and Karnofsy performance score, outcomes were categorized as excellent (no pain), good (considerable reduction in pain, not requiring opioids stronger than codeine), fair (minimal reduction in pain, but no change in opioid medication requirement), and poor (no reduction in pain). RESULTS: Eight patients (median age 56.5 yr, 6 females) underwent limited myelotomy. Four patients underwent open limited thoracic myelotomy with excellent pain outcomes. Three patients underwent percutaneous radiofrequency lesioning with fair (n = 1) and poor outcomes (n = 2). One patient underwent percutaneous mechanical lesioning with a good outcome (n = 1). The median duration of follow-up was 11 wk (2-54 wk). Two patients reported minor sensory complications after the procedure. CONCLUSION: In our preliminary experience, outcomes for open limited thoracic myelotomy were superior to percutaneous approaches. Given the limited utilization of this technique, multicenter registries are needed to further evaluate the best surgical technique for limited midline myelotomy. PMID- 29165657 TI - Rotavirus Vaccination Can Be Performed Without Viral Dissemination in the Neonatal Intensive Care Unit. AB - Background: This study was conducted to assess the transmissibility of rotavirus vaccine strains after rotavirus vaccination in a neonatal intensive care unit (NICU). Methods: Pentavalent (RV5) or monovalent (RV1) rotavirus vaccine was administered to infants admitted to the NICU. Nineteen vaccinated infants and 49 unvaccinated infants whose beds were located in close proximity to the vaccinated infants were enrolled in this study. Dissemination and fecal shedding of vaccine viruses within the NICU were examined using real-time reverse transcription polymerase chain reaction. Results: Shedding of the vaccine strain was detected in all 19 vaccinated infants. RV5 virus shedding started 1 day after the first vaccination and persisted for 8 days after the first vaccination, and viral shedding terminated by day 5 after administration of the second RV5 dose. The kinetics of RV1 virus shedding differed among vaccinated infants. The duration of RV1 virus shedding was longer after the first vaccination than after the second vaccination. In contrast to the vaccinated infants, no vaccine virus genomes were detected in any of the stool samples collected from the 49 unvaccinated infants. Conclusions: This study is direct evidence of no transmission of rotavirus vaccine strains between vaccinated infants and unvaccinated infants in close proximity within a NICU. PMID- 29165658 TI - Thyroid Cancer: Is It All in the Genes? PMID- 29165659 TI - Age Differences in the Influence of Induced Negative Emotion on Decision-Making: The Role of Emotion Regulation. AB - Objectives: In this study, we hypothesized that there is an age difference in the influence of negative emotion on decision-making and that this age difference is related to emotion regulation strategies. Method: We carried out two studies. In the first, the older and younger adults completed the ultimatum game (UG) while in either an induced negative emotional or a neutral context. In the second, both the older and younger adults completed the UG while in an induced negative emotion while using either emotion reappraisal or expressive suppression to regulate their emotions during the task. Results: The first study showed that, unlike younger adults, the older adults made similar choices in the neutral and negative induction groups. In addition, the older adults predominantly used a reappraisal strategy in both the negative and neutral emotional states, whereas the younger adults predominantly used a suppression strategy in the negative emotional state. In the second study, after the emotion regulation strategies were experimentally manipulated so that both age groups used the same strategy, we found no age difference in decision-making. Discussion: Our findings indicated that the influence of negative emotion on decision-making differs between older and younger adults and that this age difference was associated with their different emotion regulation processes. PMID- 29165660 TI - Opponent's comments. PMID- 29165661 TI - Variability and Lack of Prognostic Value Associated With Atypical Pituitary Adenoma Diagnosis: A Systematic Review and Critical Assessment of the Diagnostic Criteria. AB - BACKGROUND: Atypical pituitary adenomas (APAs) are a subset of pituitary adenomas (PAs) characterized by the 2004 World Health Organization (WHO) guidelines to have higher risk histopathological features than typical PAs. In July 2017, the WHO published an update to their classification of pituitary tumors and abandoned the APA terminology. OBJECTIVE: To assess the prevalence and outcomes of patients diagnosed with APA through a literature review. Focus was placed on variation in the application of the previous WHO criteria and on rates of recurrence. METHODS: A systematic review of PubMed (2004-July 2017) was performed to identify studies reporting prevalence and clinical characteristics/outcomes of APA. Eight studies were analyzed for prevalence. Six studies reporting histopathological details were analyzed in depth. RESULTS: Of the 7105 included patients, 373 (5.2%) met criteria for APA (prevalence range: 3%-15%). Only 2 of 8 studies utilized identical grading criteria, demonstrating a lack of standardized application. Most APAs (84%) were macroadenomas, with 52% invasive on magnetic resonance imaging. Nonfunctional PAs were most common (37%), followed by prolactinomas (23%) and Growth Hormone adenomas (21%). Recurrence/progression occurred in 21% of APA patients (follow-up range 37-75 mo). Only 2 of 8 studies reported an association between APA diagnosis and recurrence/progression. CONCLUSION: Based on diagnostic variability and lack of association with clinical outcomes, refinement of criteria for APA was necessary. The WHO update eliminates the ambiguity in APA diagnosis in favor of criteria that emphasize clinical behavior (invasion, recurrence, and resistance to treatment) and molecular markers. Our review supports abandonment of the previous APA designation due to limited prognostic utility. PMID- 29165663 TI - Oral Contraceptives and Cigarette Smoking: A Review of the Literature and Future Directions. AB - Introduction: Evidence continues to mount indicating that endogenous sex hormones (e.g., progesterone and estradiol) play a significant role in smoking-related outcomes. Although approximately 1 out of 4 premenopausal smokers use oral contraceptives (OCs), which significantly alter progesterone and estradiol levels, relatively little is known about how OCs may influence smoking-related outcomes. Thus, the goal of this review paper is to describe the state of the literature and offer recommendations for future directions. Methods: In March 2017, we searched seven databases, with a restriction to articles written in English, using the following keywords: nicotine, smoker(s), smoking, tobacco, cigarettes, abstinence, withdrawal, and craving(s). We did not restrict on the publication date, type or study design. Results: A total of 13 studies were identified. Three studies indicated faster nicotine metabolism in OC users compared to nonusers. Five of six laboratory studies that examined physiological stress response noted heightened response in OC users compared to nonusers. Three studies examined cessation-related symptomatology (e.g., craving) with mixed results. One cross-sectional study observed greater odds of current smoking among OC users, and no studies have explored the relationship between OC use and cessation outcomes. Conclusions: Relatively few studies were identified on the role of OCs in smoking-related outcomes. Future work could explore the relationship between OC use and mood, stress, weight gain and brain function/connectivity, as well as cessation outcomes. Understanding the role of OC use in these areas may lead to the development of novel smoking cessation interventions for premenopausal women. Implications: This is the first review of the relationship between oral contraceptives (OCs) and smoking-related outcomes. The existing literature suggests that the use of OCs is related to increased nicotine metabolism and physiological stress response. However, the relationship between OC use and smoking-related symptoms (e.g., craving) is mixed. Further, no published data were available on OC use and smoking cessation outcomes. Therefore, we recommend additional research be conducted to characterize the relationship between OC use and smoking cessation outcomes, perhaps as a function of the effect of OC use on mood, stress, weight gain and brain function/connectivity. PMID- 29165662 TI - Increased Global DNA Hypomethylation in Distant Metastatic and Dedifferentiated Thyroid Cancer. AB - Context: Global DNA hypomethylation is a major event for the development and progression of cancer, although the significance in thyroid cancer remains unclear. Therefore, we aimed to investigate its role in thyroid cancer progression and its potential as a prognostic marker. Methods: Global hypomethylation of Alu repeats was used as a surrogate marker for DNA global hypomethylation, and was assessed using the Quantification of Unmethylated Alu technique. Mutations in BRAF and RAS were determined by Sanger sequencing. Results: Ninety primary thyroid tumors were included [28 low-risk differentiated thyroid cancer (DTC), 13 pediatric DTC, 33 distant metastatic DTC, 7 poorly differentiated thyroid cancer (PDTC), and 9 anaplastic thyroid cancer (ATC)], as well as 24 distant metastases and 20 normal thyroid tissues. An increasing hypomethylation was found for distant metastatic DTC [median, 4.0; interquartile range (IQR), 3.1 to 6.2] and PDTC/ATC (median, 9.3; IQR, 7.0 to 12.1) as compared with normal thyroid tissue (median, 2.75; IQR, 2.30 to 3.15), whereas low-risk and pediatric DTC were not affected by hypomethylation. Alu hypomethylation was similar between distant metastases and matched primary tumors. Within distant metastatic DTC, Alu hypomethylation was increased in BRAF vs RAS mutated tumors. Kaplan-Meier and Cox regression analyses showed that thyroid cancer-related and all-cause mortality were associated with tumor hypomethylation, but this association was lost after adjustment for thyroid cancer risk category. Conclusion: Distant metastatic DTC, PDTC, and ATC were increasingly affected by global Alu hypomethylation, suggesting that this epigenetic entity may be involved in thyroid cancer progression and dedifferentiation. PMID- 29165664 TI - Analysis of the Huge Immigration of Sogatella furcifera (Hemiptera: Delphacidae) to Southern China in the Spring of 2012. AB - Sogatella furcifera (Horvath) is a migratory rice pest that periodically erupts across Asia, and early immigration is an important cause of its outbreak. The early immigration of S. furcifera into southern China shows evident annual fluctuations. In the spring of 2012, the huge size of the immigrant population and the large number of immigration peaks were at levels rarely seen prior to that year. However, little research has been done on the entire process of round trip migration to clarify the development of the population, the long-distance migration and the final eruption. In this study, the light-trap data for S. furcifera in southern China and Vietnam in 2011-2016 were collected, and the trajectory modeling showed that the early immigrants to southern China came from the northern and central Vietnam, Laos, and northeastern Thailand. Analysis of the development of the population, the migration process and meteorological factors revealed the reasons for the huge size of the early immigration: 1) the expansion of the source area could be seen as a precondition; 2) the large size of the returned population in the last autumn and the warm temperature of southern Vietnam and Laos in the last winter increased the initial populations; 3) the sustained strong southwest winds were conducive to the northward migration of the population during the major immigration period in early May. Therefore, the large-scale immigration of S. furcifera to southern China in the spring of 2012 resulted from the combined effects of several factors involved in the process of round-trip migration. PMID- 29165665 TI - Novel structural features drive DNA binding properties of Cmr, a CRP family protein in TB complex mycobacteria. AB - Mycobacterium tuberculosis (Mtb) encodes two CRP/FNR family transcription factors (TF) that contribute to virulence, Cmr (Rv1675c) and CRPMt (Rv3676). Prior studies identified distinct chromosomal binding profiles for each TF despite their recognizing overlapping DNA motifs. The present study shows that Cmr binding specificity is determined by discriminator nucleotides at motif positions 4 and 13. X-ray crystallography and targeted mutational analyses identified an arginine-rich loop that expands Cmr's DNA interactions beyond the classical helix turn-helix contacts common to all CRP/FNR family members and facilitates binding to imperfect DNA sequences. Cmr binding to DNA results in a pronounced asymmetric bending of the DNA and its high level of cooperativity is consistent with DNA facilitated dimerization. A unique N-terminal extension inserts between the DNA binding and dimerization domains, partially occluding the site where the canonical cAMP binding pocket is found. However, an unstructured region of this N terminus may help modulate Cmr activity in response to cellular signals. Cmr's multiple levels of DNA interaction likely enhance its ability to integrate diverse gene regulatory signals, while its novel structural features establish Cmr as an atypical CRP/FNR family member. PMID- 29165666 TI - Differences in Outcomes Over Time With Exclusive Enteral Nutrition Compared With Steroids in Children With Mild to Moderate Crohn's Disease: Results From the GROWTH CD Study. AB - Background: Exclusive enteral nutrition [EEN] and corticosteroids [CS] induce similar rates of remission in mild to moderate paediatric Crohn's disease [CD], but differ with regard to mucosal healing. Our goal was to evaluate if EEN at diagnosis was superior to CS for improving long-term outcomes. Methods: We prospectively followed newly diagnosed children aged < 17 years, with mild to moderate CD at baseline, for 2 years in the GROWTH CD study. Patients were evaluated at baseline and at 8, 12, 78, and 104 weeks. Remission, relapses, complications [fibrostenotic disease, penetrating disease, and active perianal disease] and growth were recorded throughout the study. A propensity score analysis was performed. Results: A total of 147 children [mean age 12.9 +/- 3.2 years], treated by EEN [n = 60] or CS [n = 87] were included. New complications developed in 13.7% of CS [12/87] versus 11.6% of EEN [7/60], p = 0.29. Remission was achieved in 41/87 [47%] in CS and 38/60 [63%] EEN, p = 0.036. Median time to relapse did not differ [14.4 +/- 1 months with CS, 16.05 +/- 1.1 EEN, p = 0.28]. Mean height Z scores decreased from Week 0 to Week 78 with CS [-0.34 +/- 1.1 to 0.51 +/- 1.2, p = 0.01], but not with EEN [-0.32 +/- 1.1 to -0.22 +/- 0.9, p = 0.56]. In a propensity score analysis, EEN was superior to CS for inducing remission [p = 0.05] and trended to superiority for height Z score [p = 0.055]. Conclusions: Use of EEN was associated with higher remission rates and a trend toward better growth but with similar relapse and complication rates in new-onset mild to moderate paediatric CD. PMID- 29165667 TI - BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment. AB - Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. Methods: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two sided. Results: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. Conclusions: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable. PMID- 29165668 TI - Electrophysiological measures of aging pharynx function in C. elegans reveal enhanced organ functionality in older, long-lived mutants. AB - The function of the pharynx, an organ in the model system Caenorhabditis elegans, has been correlated with lifespan and motility (another measure of health) since 1980. In this study, in order to further understand the relationship between organ function and lifespan, we measured the age-related decline of the pharynx using an electrophysiological approach. We measured and analyzed electropharyngeograms of wild type animals, short-lived hsf-1 mutants, and long lived animals with genetically decreased insulin signaling or increased heat shock pathway signaling; we recorded a total of 2,478 electropharyngeograms from 1,374 individuals. As expected, the long-lived daf-2(e1370) and hsf-1OE(uthIs235) animals maintained pharynx function relatively closer to the youthful state during aging, whereas the hsf-1(sy441) and wild type animals' pharynx function deviated significantly further from the youthful state at advanced age. Measures of the amount of variation in organ function can act as biomarkers of youthful physiology as well. Intriguingly, the long-lived animals had greater variation in the duration of pharynx contraction at older ages. PMID- 29165669 TI - ClinVar: improving access to variant interpretations and supporting evidence. AB - ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) is a freely available, public archive of human genetic variants and interpretations of their significance to disease, maintained at the National Institutes of Health. Interpretations of the clinical significance of variants are submitted by clinical testing laboratories, research laboratories, expert panels and other groups. ClinVar aggregates data by variant-disease pairs, and by variant (or set of variants). Data aggregated by variant are accessible on the website, in an improved set of variant call format files and as a new comprehensive XML report. ClinVar recently started accepting submissions that are focused primarily on providing phenotypic information for individuals who have had genetic testing. Submissions may come from clinical providers providing their own interpretation of the variant ('provider interpretation') or from groups such as patient registries that primarily provide phenotypic information from patients ('phenotyping only'). ClinVar continues to make improvements to its search and retrieval functions. Several new fields are now indexed for more precise searching, and filters allow the user to narrow down a large set of search results. PMID- 29165671 TI - Battling bias. PMID- 29165670 TI - Prevalence of Hypothyroidism and Its Association with Diabetes Mellitus in Patients of an Ambulatory Clinic. AB - Hypothyroidism is the most common thyroid disorder in the adult population.Studies have found a higher prevalence of overt hypothyroidism in type2 diabetic population than in the general population, but the relationshipbetween subclinical hypothyroidism and diabetes mellitus 2 is still controversial.The aim of this study is to estimate the prevalence rate of hypothyroidism inthe adult population receiving services in an ambulatory clinic and to determineif there is an association between hypothyroidism and diabetes mellitus.From the database of all adult patients who attended the outpatient clinic atFamily Medicine Center Policlinica Bella Vista in Mayaguez, P.R. during2014, a random sample of 200 subjects was obtained and the medical recordswere reviewed. The prevalence rate of diabetes mellitus in this group was 22%and the prevalence rate of hypothyroidism was 17%. The prevalence rateof hypothyroidism in diabetic patients was 10/44 (22.7%). The prevalencerate of hypothyroidism in non-diabetic patients was 24/156 (15.4%). The prevalenceratio was 1.48 (95% CI: 0.77, 2.85; X2 = 1.31, p = 0.25). The resultsof this cross sectional study showed a non-statistically significant tendencyfor a higher prevalence of hypothyroidism in diabetic patients, which suggestthat screening for hypothyroidism among patients with diabetes shouldbe considered. More studies with more patients are necessary to investigate theassociation between thyroid dysfunction and diabetic patients. PMID- 29165672 TI - Trans-sylvian Approach to Microvascular Decompression for Trigeminal Neuralgia in Syndromic Cranial Base Settling. AB - BACKGROUND AND IMPORTANCE: The lateral suboccipital approach for microvascular decompression (MVD) of the trigeminal nerve has become a standard-of-care over the past several decades. Syndromic cranial base settling, a rare but known cause for trigeminal neuralgia (TN), poses significant dilemmas in clinical management. In such cases, distorted anatomy may render surgery via the suboccipital approach difficult or even impossible. CLINICAL PRESENTATION: A 34-yr-old male with osteogenesis imperfecta and severe basilar invagination suffered from TN that was refractory to medication and stereotactic radiosurgery. MVD of the fifth nerve root was performed via a pterional trans-sylvian approach after 3-dimensional trajectory modeling suggested the feasibility of this approach. He experienced complete resolution of TN and remains free of both pain and medications after 18 mo of follow-up. CONCLUSION: This microsurgical trajectory, previously undescribed for TN, provides good visualization of the trigeminal root entry zone, thereby offering an excellent surgical option for severe TN in the setting of abnormal posterior fossa anatomy. PMID- 29165673 TI - Molecular identification of Trichophyton benhamiae in Strasbourg, France: a 9 year retrospective study. AB - Trichophyton benhamiae is a zoophilic dermatophyte transmitted to humans mostly from guinea pigs and occasionally other animals. It presents two distinct phenotypes: yellow and white. T. benhamiae was formerly known as Trichophyton species of Arthroderma benhamiae; it was considered part of the T. mentagrophytes species complex, and some authors have incorrectly described the yellow phenotype of T. benhamiae as T. mentagrophytes var. porcellae. Identification of T. benhamiae has been difficult, as it was described under more than three names, two phenotypes, and in several different possible host species. During the past 15 years, human infections due to this dermatophyte have been increasingly reported all over the world. In order to better understand the local epidemiology of T. benhamiae and to compare it to other European countries, we performed a 9 year retrospective study in the Strasbourg University Hospital. We studied 41 dermatophytes (38 isolated from humans and 3 from guinea pigs) identified as T. mentagrophytes var. porcellae or A. benhamiae from January 2008 to December 2016 and verified their identification by ITS (Internal Transcribed Spacer) sequencing. ITS sequencing was performed in 35 of the 41 strains, and they were identified as T. benhamiae (33), T. bullosum (1), and T. eriotrephon (1). The other six remaining strains were identified according to morphology as T. mentagrophytes var. porcellae, name incorrectly used since 2010 for the yellow phenotype of T. benhamiae. ITS sequencing is recommended for accurate identification of this dermatophyte and the culture phenotype (yellow or white) should be specified. PMID- 29165674 TI - How to use bisphosphonates safely and optimally. PMID- 29165675 TI - Work ability, effort-reward imbalance and disability pension claims. AB - Background: Effort-reward imbalance (ERI) and self-rated work ability are known independent correlates and predictors of intended disability pension claims. However, little research has focused on the interrelationship between the three and whether self-rated work ability mediates the relationship between ERI and intended disability pension claims. Aims: To investigate whether self-rated work ability mediates the association between ERI and intended disability pension claims. Methods: Baseline data from participants of the Third German Sociomedical Panel of Employees, a 5-year cohort study that investigates determinants of work ability, rehabilitation utilization and disability pensions in employees who have previously received sickness benefits, were analysed. We tested direct associations between ERI with intended disability pension claims (Model 1) and self-rated work ability (Model 2). Additionally, we tested whether work ability mediates the association between ERI and intended disability pension claims (Model 3). Results: There were 2585 participants. Model 1 indicated a significant association between ERI and intended disability pension claims. Model 2 showed a significant association between ERI and self-rated work ability. The mediation in Model 3 revealed a significant indirect association between ERI and intended disability pension claims via self-rated work ability. There was no significant direct association between ERI and intended disability pension claims. Conclusions: Our results support the adverse health-related impact of ERI on self rated work ability and intended disability pension claims. PMID- 29165677 TI - Being Born Too Small and Too Early May Alter Sleep in Childhood. AB - Study Objectives: Fetal growth restriction (FGR) occurs in up to 10% of pregnancies and is associated with increased risk of prematurity and neurodevelopmental impairment. FGR also alters sleep state distribution in utero and maturation in infancy. Currently, limited data on the long-term associations of FGR and childhood sleep exist. Accordingly, we assessed the associations between preterm birth and FGR and sleep in children aged 5-12 years. Methods: 17 children born preterm and FGR, 15 children born preterm but appropriately grown (AGA) and 20 term AGA children (controls) were studied using overnight polysomnography. Sleep macro-architecture was assessed using standard criteria and sleep micro-architecture was assessed using spectral analysis of the EEG (C4 M1) with Total, Delta (0.5Hz-3.9Hz), Theta (4.0Hz-7.9Hz), Alpha (8.0Hz-11.9Hz), Sigma (12.0Hz-13.9Hz) and Beta Power (14.0Hz-30Hz) calculated. Results: For sleep macro-architecture, preterm FGR children had higher N2% compared to term AGA children (p<0.05). Preterm AGA children had reduced total sleep time, NREM% and sleep efficiency compared to term AGA children (p<0.05 for all). For sleep micro architecture, preterm FGR children had a higher amount of Total, delta and alpha power compared to both groups (p<0.05). Sigma and beta power were lowest in the preterm AGA group compared to both groups (p<0.05 for both). Conclusions: Prematurity and FGR were associated with altered sleep macro- and micro architecture measures indicative of reduced sleep quantity and quality in childhood. As sleep disturbance can impact both behavior and neurodevelopment in children, sleep in FGR and preterm children warrants further investigation. PMID- 29165676 TI - Structure of mycobacterial 3'-to-5' RNA:DNA helicase Lhr bound to a ssDNA tracking strand highlights distinctive features of a novel family of bacterial helicases. AB - Mycobacterial Lhr is a DNA damage-inducible superfamily 2 helicase that uses adenosine triphosphate (ATP) hydrolysis to drive unidirectional 3'-to-5' translocation along single-stranded DNA (ssDNA) and to unwind RNA:DNA duplexes en route. ATPase, translocase and helicase activities are encompassed within the N terminal 856-amino acid segment. The crystal structure of Lhr-(1-856) in complex with AMPPNP*Mg2+ and ssDNA defines a new helicase family. The enzyme comprises two N-terminal RecA-like modules, a winged helix (WH) domain and a unique C terminal domain. The 3' ssDNA end binds in a crescent-shaped groove at the interface between the first RecA domain and the WH domain and tracks 5' into a groove between the second RecA and C domains. A kissing interaction between the second RecA and C domains forms an aperture that demarcates a putative junction between the loading strand tail and the duplex, with the first duplex nucleoside bookended by stacking on Trp597. Intercalation of Ile528 between nucleosides of the loading strand creates another bookend. Coupling of ATP hydrolysis to RNA:DNA unwinding is dependent on Trp597 and Ile528, and on Thr145 and Arg279 that contact phosphates of the loading strand. The structural and functional data suggest a ratchet mechanism of translocation and unwinding coupled to ATP-driven domain movements. PMID- 29165678 TI - The Genealogy of Dementia Praecox I: Signs and Symptoms of Delusional Psychoses From 1880 to 1900. AB - We can trace, with high congruence, the clinical syndromes of depression and mania as described over the 20th century in psychiatric textbooks back to 1880 and to the earliest writing of Kraepelin published in 1883. However, this is not the case for Kraepelin's 2 delusional syndromes central to his overall nosology: Dementia Paranoides (later paranoid schizophrenia) and Paranoia. A detailed examination of 28 textbook descriptions of delusional psychoses from 1880 to 1900 reveals a diverse and partially overlapping set of syndromes with an admixture of symptoms and signs that would later be considered indicative of Dementia Paranoides and Paranoia. A similar pattern in seen in Kraepelin's own description of "Primare Verrucktheit" from the first edition of his textbook (1883). No clear prototypes emerged in these textbooks or in Kraepelin's early writings for the 2 distinct delusional syndromes that would later evolve in his mature writings. Rather, the nosologic approach taken in these writings was symptom based and assumed that a viable diagnostic category could be constituted by including all delusional patients once those suffering from organic or mood disorders were excluded. While Kraepelin used the historical syndromes of mania and depression, with no appreciable change, as building blocks for his category of manic depressive insanity, his nosologic system for the psychotic disorders-the syndromes of Dementia Praecox and Paranoia-was more innovative and without clear precedent in the prior psychiatric literature. PMID- 29165679 TI - A Two-State Model of Tree Evolution and Its Applications to Alu Retrotransposition. AB - Models of tree evolution have mostly focused on capturing the cladogenesis processes behind speciation. Processes that derive the evolution of genomic elements, such as repeats, are not necessarily captured by these existing models. In this article, we design a model of tree evolution that we call the dual-birth model, and we show how it can be useful in studying the evolution of short Alu repeats found in the human genome in abundance. The dual-birth model extends the traditional birth-only model to have two rates of propagation, one for active nodes that propagate often, and another for inactive nodes, that with a lower rate, activate and start propagating. Adjusting the ratio of the rates controls the expected tree balance. We present several theoretical results under the dual birth model, introduce parameter estimation techniques, and study the properties of the model in simulations. We then use the dual-birth model to estimate the number of active Alu elements and their rates of propagation and activation in the human genome based on a large phylogenetic tree that we build from close to one million Alu sequences. PMID- 29165681 TI - Diaphragmatic function in infants and children with congenital diaphragmatic hernia: a cross-sectional study. AB - OBJECTIVES: Few studies have evaluated long-term diaphragmatic function in congenital diaphragmatic hernia (CDH). The aim of our cross-sectional study was to assess diaphragmatic function in infants and young children with CDH after surgical repair. METHODS: All the patients with CDH repair followed in our centre between February 2014 and January 2016 were enrolled. Patients with a postnatal diagnosis after 1 month of life were excluded. Breathing pattern and diaphragmatic function were assessed using esophageal and gastric (Pgas) pressure recording after surgery, or at 1 or 5 years of age. RESULTS: Twenty-eight patients (24 left-sided CDH, 6 with diaphragmatic patch) were included. Twelve patients were assessed before hospital discharge (Y0), 6 around the age of 1 year (Y1) and 10 around the age of 5 years (Y5). Mean antenatal estimated pulmonary volume (VLA) was 42 +/- 10% (n = 23). Diaphragmatic strength, assessed by transdiaphragmatic pressure during crying/sniff, was low at Y0 (47 +/- 18 cmH2O, n = 12) and within normality at Y5 (81 +/- 15 cmH2O, n = 7). Diaphragmatic dysfunction, assessed by Pgas during crying/sniff, was present at Y0 (-58 +/- 22 cmH2O, n = 12) and Y1 (-53 +/- 36 cmH2O, n = 5) and still present at Y5 (3 +/- 9 cmH2O, n = 7) but to a lesser extent. The diaphragmatic tension time index (TTdi), which estimates diaphragmatic endurance, was high at Y0 (0.10 +/- 0.04, n = 11) and within normality at Y5 (0.03 +/- 0.01, n = 6). VLA correlated with neonatal TTdi (r = -0.961, P < 0.001). CONCLUSIONS: Infants with CDH have diaphragmatic dysfunction in the neonatal period, which correlates with VLa and normalizes with age. Future longitudinal studies should assess the role of CDH side, size of diaphragmatic defect and patch repair. PMID- 29165680 TI - A Thermus phage protein inhibits host RNA polymerase by preventing template DNA strand loading during open promoter complex formation. AB - RNA polymerase (RNAP) is a major target of gene regulation. Thermus thermophilus bacteriophage P23-45 encodes two RNAP binding proteins, gp39 and gp76, which shut off host gene transcription while allowing orderly transcription of phage genes. We previously reported the structure of the T. thermophilus RNAP*sigmaA holoenzyme complexed with gp39. Here, we solved the structure of the RNAP*sigmaA holoenzyme bound with both gp39 and gp76, which revealed an unprecedented inhibition mechanism by gp76. The acidic protein gp76 binds within the RNAP cleft and occupies the path of the template DNA strand at positions -11 to -4, relative to the transcription start site at +1. Thus, gp76 obstructs the formation of an open promoter complex and prevents transcription by T. thermophilus RNAP from most host promoters. gp76 is less inhibitory for phage transcription, as tighter RNAP interaction with the phage promoters allows the template DNA to compete with gp76 for the common binding site. gp76 also inhibits Escherichia coli RNAP highlighting the template-DNA binding site as a new target site for developing antibacterial agents. PMID- 29165682 TI - The silencing of political context in health research in Ethiopia: why it should be a concern. AB - In 2004, the Ethiopian government launched what has been called an innovative and groundbreaking solution to the country's public health challenges; the Health Extension Programme (HEP). The positive public health outcomes that have been reported following the implementation of the HEP have led researchers and global health actors to propose it as a model for other countries to emulate. In this systematic review, we point to a potential weakness and methodological bias in the existing research. Despite being implemented within a context of an increasingly authoritarian regime, research conducted following the implementation of HEP reflects a limited discussion of the political context. Following a discussion of why political context is marginalized we provide arguments for why a focus on political context is important: first, political context has an impact on health systems and actualizes questions related to good governance and ethics. While some of the studies we reviewed acknowledge the importance of political factors we contend that the one-sided focus on the positive relationship between political will, political commitment and political leadership on the one hand, and key public health outcomes on the other, reflects a narrow engagement with health system governance frameworks. This leads to a silencing of issues actualized by the authoritarian nature of the Ethiopian regime. Secondly, the political context has methodological implications. More specifically, we contend that the current political situation increases the probability of social desirability bias. In order to balance the overarching positive literature on Ethiopia's health system, research that takes the political context into account is much needed. PMID- 29165683 TI - Systematic Review: Occupational illness in the waste and recycling sector. AB - Background: The waste and recycling sector is a growing part of industry. Whether health surveillance is indicated and how it should be undertaken is unclear. Aims: To undertake a review of the literature to identify hazards to health, biological effects and occupational illnesses for workers in the sector. Methods: A systematic review of the published literature and two UK databases. Results: Rates of fatal, non-fatal injuries and self-reported work-related illness were found to be higher in the waste and recycling sector than in UK industry as a whole. There was an increased prevalence of respiratory, gastro-intestinal and skin complaints in workers exposed to compost relative to controls. They may also be at increased risk of extrinsic allergic alveolitis, allergic bronchopulmonary aspergillosis, occupational asthma and abnormalities of lung function. Workers involved with the recycling of batteries and cables may be at risk of lead poisoning and exposure to other heavy metals. There were case reports of mercury poisoning from the recycling of fluorescent lights. Cases of occupational asthma have been reported in association with wood and paper recycling. The recycling of e-waste may cause exposure to heavy metals and organic pollutants, such as polybrominated diphenyl ethers, dioxins and polyaromatic hydrocarbons, which have been associated with damage to DNA and adverse neonatal outcomes. Conclusions: Ill-health and adverse biological effects have been described in waste and recycling workers, but their true prevalence has probably not been captured. Targeted health surveillance may be required to assess exposure and to identify occupational illness. PMID- 29165685 TI - Corrigendum. PMID- 29165684 TI - Can Biomarkers Advance HIV Research and Care in the Antiretroviral Therapy Era? AB - Despite achieving human immunodeficiency virus type 1 (HIV-1) RNA suppression below levels of detection and, for most, improved CD4+ T-cell counts, those aging with HIV experience excess low-level inflammation, hypercoagulability, and immune dysfunction (chronic inflammation), compared with demographically and behaviorally similar uninfected individuals. A host of biomarkers that are linked to chronic inflammation are also associated with HIV-associated non-AIDS-defining events, including cardiovascular disease, many forms of cancer, liver disease, renal disease, neurocognitive decline, and osteoporosis. Furthermore, chronic HIV infection may interact with long-term treatment toxicity and weight gain after ART initiation. These observations suggest that future biomarker-guided discovery and treatment may require attention to multiple biomarkers and, possibly, weighted indices. We are clinical trialists, epidemiologists, pragmatic trialists, and translational scientists. Together, we offer an operational definition of a biomarker and consider how biomarkers might facilitate progress along the translational pathway from therapeutic discovery to intervention trials and clinical management among people aging with or without HIV infection. PMID- 29165686 TI - Optimal timing for blastomere biopsy of 8-cell embryos for preimplantation genetic diagnosis. AB - STUDY QUESTION: What is the optimal timing for blastomere biopsy during the 8 cell stage, at which embryos will have the best implantation potential? SUMMARY ANSWER: Fast-cleaving embryos that are biopsied during the last quarter (Q4) of the 8-cell stage and are less affected by the biopsy procedure, and their implantation potential is better than that of embryos biopsied earlier during the 8-cell stage (Q1-Q3). WHAT IS KNOWN ALREADY: Blastomer biopsy from cleavage-stage embryos is usually performed on the morning of Day 3 when the embryos are at the 6- to 8-cell stage and is still the preferred biopsy method for preimplantation genetic diagnosis (PGD) for monogentic disorders or chromosomal translocations. Human embryos usually remain at the 8-cell stage for a relatively long 'arrest phase' in which cells grow, duplicate their DNA and synthesize various proteins in preparation for the subsequent division. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study. The study group (195 embryos) included all 8-cell stage embryos that underwent blastomere biopsy for PGD for monogenetic disorders and chromosomal translocations in our unit between 2012-2014 and cultured in the EmbryoScope until transfer. The control group (115 embryos) included all embryos that underwent intracytoplasmic sperm injection without a biopsy during the same period. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 8-cell stage was divided into four quarters: the first 5 h post-t8 (Q1), 5-10 h post-t8 (Q2), 10-15 h post t8 (Q3) and at 15-20 h post-t8 (Q4). Non-biopsied control embryos were divided into four equivalent quarters. Embryos were evaluated for timing of developmental events following biopsy including timing of first cleavge after biopsy, timing of comapction (tM) and start of blastulation (tSB). Timing of these events were compared between PGD and control embryos, as well as with 56 PGD implanted embryos with Known Implantation Data (PGD-KID-positive embryos). MAIN RESULTS AND THE ROLE OF CHANCE: Embryos that were biopsied during Q3 (10-15 h from entry into 8-cell stage) were delayed in all three subsequent developmental events, including first cleavage after biopsy, compaction and start of blastulation. In contrast, these events occurred exactly at the same time as in the control group, in embryos that were biopsied during Q1, Q2 or Q4 of the 8-cell stage. The results show also that embryos that were biopsied during Q1, Q2 or Q3 of the 8 cell stage demonstrated a significant delay from the biopsied implanted embryos already in t8 as well as in tM and tSB. However, embryos that were biopsied during Q4 demonstrated dynamics similar to those of the biopsied implanted embryos in t8 and tM, and a delay was noticed only in the last stage of tSB. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study that is limited to the timing of biopsy that is routinely performed in the IVF lab. A prospective study in which biopsy will be performed at a desired timing is needed in order to differ between the effect of biopsy itself and the cleavage rate of the embryo. WIDER IMPLICATIONS OF THE FINDINGS: Our findings showed that blastomere biopsy can be less harmful to further development if it is carried out during a critical period of embryonic growth, i.e during Q4 of the 8-cell stage. They also demonstrated the added value of time-lapse microscopy for determining the optimal timing for blastomere biopsy. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the routine budget of our IVF unit. TRIAL REGISTRATION NUMBER: N/A. PMID- 29165688 TI - Management of Odontoid Fractures in the Elderly: A Review of the Literature and an Evidence-Based Treatment Algorithm. AB - Odontoid fractures are the most common fracture of the axis and the most common cervical spine fracture in patients over 65. Despite their frequency, there is considerable ambiguity regarding optimal management strategies for these fractures in the elderly. Poor bone health and medical comorbidities contribute to increased surgical risk in this population; however, nonoperative management is associated with a risk of nonunion or fibrous union. We provide a review of the existing literature and discuss the classification and evaluation of odontoid fractures. The merits of operative vs nonoperative management, fibrous union, and the choice of operative approach in elderly patients are discussed. A treatment algorithm is presented based on the available literature. We believe that type I and type III odontoid fractures can be managed in a collar in most cases. Type II fractures with any additonal risk factors for nonunion (displacement, comminution, etc) should be considered for surgical management. However, the risks of surgery in an elderly population must be carefully considered on a case by-case basis. In a frail elderly patient, a fibrous nonunion with close follow up is an acceptable outcome. If operative management is chosen, a posterior approach is should be chosen when fracture- or patient-related factors make an anterior approach challenging. The high levels of morbidity and mortality associated with odontoid fractures should encourage all providers to pursue medical co-management and optimization of bone health following diagnosis. PMID- 29165687 TI - Investigation of the Relationship Between Radiation Dose and Gene Mutations and Fusions in Post-Chernobyl Thyroid Cancer. AB - Background: Exposure to ionizing radiation during childhood is a well-established risk factor for thyroid cancer. However, the genetic mechanisms of radiation associated carcinogenesis remain not fully understood. Methods: In this study, we used targeted next-generation sequencing and RNA-Seq to study 65 papillary thyroid cancers (PTCs) from patients in the Ukrainian-American cohort with measurement-based iodine-131 (I-131) thyroid doses received as a result of the Chernobyl accident. We fitted linear regression models to evaluate differences in distribution of risk factors for PTC according to type of genetic alteration and logistic regression models to evaluate the I-131 dose response. All statistical tests were two-sided. Results: Driver mutations were identified in 96.9% of these thyroid cancers, including point mutations in 26.2% and gene fusions in 70.8% of cases. Novel driver fusions such as POR-BRAF, as well as STRN-ALK fusions that have not been implicated in radiation-associated cancer before, were found. The mean I-131 dose in cases with point mutations was 0.2 Gy (range = 0.013-1.05 Gy), statistically significantly lower than 1.4 Gy (range = 0.009-6.15 Gy) for cases with fusions (P < .001). No driver point mutations were found in tumors from individuals who received more than 1.1 Gy of radiation. Relative to tumors with point mutations, the proportion of tumors with gene fusions increased with radiation dose, reaching 87.8% among individuals exposed to 0.3 Gy or higher. With a limited study sample size, the estimated odds ratio at 1 Gy was 20.01 (95% confidence interval = 2.57 to 653.02, P < .001). In addition, after controlling for I-131 dose, we found higher odds ratios for gene fusion-positive PTCs associated with several specific demographic and geographic features. Conclusions: Our data provide support for a link between I-131 thyroid dose and generation of carcinogenic gene fusions, the predominant mechanism of thyroid cancer associated with radiation exposure from the Chernobyl accident. PMID- 29165689 TI - Oculomotor Disturbances in Patients with Chronic Nonspecific Spinal Pain. AB - Objective: There is increasing evidence that the cerebellum has a role in pain processing. The present study investigates whether chronic pain patients, who are likely to have altered pain processing, exhibit signs of subtle cerebellar dysfunction. We used oculomotor tasks to assess dysfunction of the associated neuronal networks, including the cerebellum. Methods: Thirty patients with chronic nonspecific spinal pain and 30 age- and sex-matched controls were enrolled. Using a head-mounted eye tracker (EyeSeeCam), eye movements were quantified during predictable and unpredictable saccade and smooth pursuit tasks in the horizontal plane. Results: The initial latency and the velocity variability of smooth pursuit were significantly increased in the chronic spinal pain patients compared with controls (initial latency: 198 +/- 20 vs 185 +/- 11 ms, P < 0.01; slow phase velocity standard deviation: 3.31 +/- 1.02 vs 2.70 +/- 0.83 degrees /s, P < 0.05). Moreover, the latency of predictable saccades was prolonged in patients (rightward: 161 +/- 20 vs 152 +/- 12 ms, P < 0.05; leftward: 164 +/- 22 vs 153 +/- 18 ms, P = 0.05). Conclusions: Our results show that chronic spinal pain patients display subtle but significant oculomotor changes as compared with healthy controls. Considering the networks involved in the generation of saccades and smooth pursuit, the results would be consistent with a dysfunction of cerebellar regions, especially parts of the cerebellar hemispheres. Alternatively, they could also point toward a dysfunction in the frontal eye field and/or pontine oculomotor nuclei. PMID- 29165690 TI - The regulatory G4 motif of the Kirsten ras (KRAS) gene is sensitive to guanine oxidation: implications on transcription. AB - KRAS is one of the most mutated genes in human cancer. It is controlled by a G4 motif located upstream of the transcription start site. In this paper, we demonstrate that 8-oxoguanine (8-oxoG), being more abundant in G4 than in non-G4 regions, is a new player in the regulation of this oncogene. We designed oligonucleotides mimicking the KRAS G4-motif and found that 8-oxoG impacts folding and stability of the G-quadruplex. Dimethylsulphate-footprinting showed that the G-run carrying 8-oxoG is excluded from the G-tetrads and replaced by a redundant G-run in the KRAS G4-motif. Chromatin immunoprecipitation revealed that the base-excision repair protein OGG1 is recruited to the KRAS promoter when the level of 8-oxoG in the G4 region is raised by H2O2. Polyacrylamide gel electrophoresis evidenced that OGG1 removes 8-oxoG from the G4-motif in duplex, but when folded it binds to the G-quadruplex in a non-productive way. We also found that 8-oxoG enhances the recruitment to the KRAS promoter of MAZ and hnRNP A1, two nuclear factors essential for transcription. All this suggests that 8 oxoG in the promoter G4 region could have an epigenetic potential for the control of gene expression. PMID- 29165692 TI - Prognostic Value of Clinical vs Pathologic Stage in Rectal Cancer Patients Receiving Neoadjuvant Therapy. AB - Background: Neoadjuvant chemoradiation is currently standard of care in stage II III rectal cancer, resulting in tumor downstaging for patients with treatment responsive disease. However, the prognosis of the downstaged patient remains controversial. This work critically analyzes the relative contribution of pre- and post-therapy staging to the anticipated survival of downstaged patients. Methods: The National Cancer Database (NCDB) was queried for patients with rectal cancer treated with transabdominal resection between 2004 and 2014. Stage II-III patients downstaged with neoadjuvant radiation were compared with stage I patients treated with definitive resection alone. Patients with positive surgical margins were excluded. Overall survival was evaluated using both Kaplan-Meier analyses and Cox proportional hazards models. All statistical tests were two sided. Results: A total of 44 320 patients were eligible for analysis. Survival was equivalent for patients presenting with cT1N0 disease undergoing resection (mean survival = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months) compared with those downstaged to pT1N0 from both cT3N0 (mean survival = 114.9 months, 95% CI = 110.4 to 119.3 months, P = .12) and cT3N1 disease (mean survival = 115.4 months, 95% CI = 110.1 to 120.7 months, P = .22). Survival statistically significantly improved in patients downstaged to pT2N0 from cT3N0 disease (mean survival = 109.0 months, 95% CI = 106.7 to 111.2 months, P < .001) and cT3N1 (mean survival = 112.8 months, 95% CI = 110.0 to 115.7 months, P < .001), compared with cT2N0 patients undergoing resection alone (mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months). Multiple survival analysis confirmed that final pathologic stage dictated long-term outcomes in patients undergoing neoadjuvant radiation (hazard ratio [HR] of pT2 = 1.24, 95% CI = 1.10 to 1.41; HR of pT3 = 1.81, 95% CI = 1.61 to 2.05; HR of pT4 = 2.72, 95% CI = 2.28 to 3.25, all P <= .001 vs pT1; HR of pN1 = 1.50, 95% CI = 1.41 to 1.59; HR of pN2 = 2.17, 95% CI = 2.00 to 2.35, both P < .001 vs pN0); while clinical stage at presentation had little to no predictive value (HR of cT2 = 0.81, 95% CI = 0.69 to 0.95, P = .008; HR of cT3 = 0.83, 95% CI = 0.72 to 0.96, P = .009; HR of cT4 = 1.02, 95% CI = 0.85 to 1.21, P = .87 vs cT1; HR of cN1 = 0.96, 95% CI = 0.91 to 1.02, P = .19; HR of cN2 = 0.96, 95% CI = 0.86 to 1.08, P = .48 vs cN0). Conclusions: Survival in patients with rectal cancer undergoing neoadjuvant radiation is driven by post-therapy pathologic stage, regardless of pretherapy clinical stage. These data will further inform prognostic discussions with patients. PMID- 29165691 TI - Estradiol Protects Proopiomelanocortin Neurons Against Insulin Resistance. AB - Insulin resistance is at the core of the metabolic syndrome, and men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage diminishes sharply when women reach the postmenopausal state. Because 17beta-estradiol (E2) augments the excitability of the anorexigenic proopiomelanocortin (POMC) neurons, we investigated the neuroprotective effects of E2 against insulin resistance in POMC neurons from diet-induced obese (DIO) female and male mice. The efficacy of insulin to activate canonical transient receptor potential 5 (TRPC5) channels and depolarize POMC neurons was significantly reduced in DIO male mice but not in DIO female mice. However, the insulin response in POMC neurons was abrogated in ovariectomized DIO females but restored with E2 replacement. E2 increased T-type calcium channel Cav3.1 messenger RNA (mRNA) expression and whole-cell currents but downregulated stromal interaction molecule 1 mRNA, which rendered POMC neurons more excitable and responsive to insulin-mediated TRPC5 channel activation. Moreover, E2 prevented the increase in suppressor of cytokine signaling-3 mRNA expression with DIO as seen in DIO males. As proof of principle, insulin [intracerebroventricular injection into the third ventricle (ICV)] decreased food intake and increased metabolism in female but not male guinea pigs fed a high-fat diet. The uncoupling of the insulin receptor from its downstream effector system was corroborated by the reduced expression of phosphorylated protein kinase B in the arcuate nucleus of male but not female guinea pigs following insulin. Therefore, E2 protects female POMC neurons from insulin resistance by enhancing POMC neuronal excitability and the coupling of insulin receptor to TRPC5 channel activation. PMID- 29165693 TI - eComment. The importance of definition. PMID- 29165694 TI - eComment. Abiotrofia defectiva - a fastidious bacterial species that warrants optimal co-operation between the clinic and the laboratory. PMID- 29165695 TI - Spotlight on recently published EJCTS articles. PMID- 29165697 TI - Lifting and pregnancy outcomes: feasibility of a randomized controlled trial. AB - Background: The highest incidence of preterm birth (18%) occurs in Africa but the causes are largely unknown. Some studies have reported adverse effects of maternal physical exertion on birth outcomes. A randomized controlled trial (RCT) is proposed to determine the effectiveness of an intervention reducing lifting and carrying in pregnant women in reducing preterm birth and low birthweight. Aims: To test the feasibility and acceptability of the proposed lift-less intervention RCT. Methods: We recruited pregnant women and midwives from antenatal clinics within the Greater Accra Region of Ghana. The midwives were trained to administer the intervention during a 5-week trial. Four intervention trial sessions were organized at weekly intervals. Results: Seven pregnant women and six midwives participated. After piloting, we observed a reduction in participants' self-reported daily exposure to heavy lifting and carrying. The daily average frequency of lifting by a participant within the first seven days of the study was 3.5 (SD 1.7) with an estimated mean total weight of 41.1 kg (SD = 13.3 kg). This had decreased to 2.3 (SD = 1.0) and the amount to 13.4 kg (SD = 10.9) within the last seven days of the study. Conclusions: The findings provide insight into the daily physical exertion experienced by pregnant women in Ghana. The lift-less intervention trial is feasible with modifications and has the potential to reduce excessive physical exertion among pregnant women in Ghana to improve birth outcomes. PMID- 29165696 TI - Which Sleep Health Characteristics Predict All-Cause Mortality in Older Men? An Application of Flexible Multivariable Approaches. AB - Study Objectives: Sleep is multidimensional, with domains including duration, timing, continuity, regularity, rhythmicity, quality, and sleepiness/alertness. Individual sleep characteristics representing these domains are known to predict health outcomes. However, most studies consider sleep characteristics in isolation, resulting in an incomplete understanding of which sleep characteristics are the strongest predictors of health outcomes. We applied three multivariable approaches to robustly determine which sleep characteristics increase mortality risk in the osteoporotic fractures in men sleep study. Methods: In total, 2,887 men (mean 76.3 years) completed relevant assessments and were followed for up to 11 years. One actigraphy or self-reported sleep characteristic was selected to represent each of seven sleep domains. Multivariable Cox models, survival trees, and random survival forests were applied to determine which sleep characteristics increase mortality risk. Results: Rhythmicity (actigraphy pseudo-F statistic) and continuity (actigraphy minutes awake after sleep onset) were the most robust sleep predictors across models. In a multivariable Cox model, lower rhythmicity (hazard ratio, HR [95%CI] =1.12 [1.04, 1.22]) and lower continuity (1.16 [1.08, 1.24]) were the strongest sleep predictors. In the random survival forest, rhythmicity and continuity were the most important individual sleep characteristics (ranked as the sixth and eighth most important among 43 possible sleep and non-sleep predictors); moreover, the predictive importance of all sleep information considered simultaneously followed only age, cognition, and cardiovascular disease. Conclusions: Research within a multidimensional sleep health framework can jumpstart future research on causal pathways linking sleep and health, new interventions that target specific sleep health profiles, and improved sleep screening for adverse health outcomes. PMID- 29165699 TI - Cohort Profile: The National FINRISK Study. PMID- 29165698 TI - Nuclear mRNA degradation tunes the gain of the unfolded protein response in Saccharomyces cerevisiae. AB - Unfolded protein response (UPR) is triggered by the accumulation of unfolded proteins in the endoplasmic reticulum (ER), which is accomplished by a dramatic induction of genes encoding ER chaperones. Activation of these genes involves their rapid transcription by Hac1p, encoded by the HAC1 precursor transcript harboring an intron and a bipartite element (3'-BE) in the 3'-UTR. ER stress facilitates intracellular targeting and recruitment of HAC1 pre-mRNA to Ire1p foci (requiring 3'-BE), leading to its non-spliceosomal splicing mediated by Ire1p/Rlg1p. A critical concentration of the pre-HAC1 harboring a functional 3' BE element is governed by its 3'->5' decay by the nuclear exosome/DRN. In the absence of stress, pre-HAC1 mRNA undergoes a rapid and kinetic 3'->5' decay leading to a precursor pool, the majority of which lack the BE element. Stress, in contrast, causes a diminished decay, thus resulting in the production of a population with an increased abundance of pre-HAC1 mRNA carrying an intact BE, which facilitates its more efficient recruitment to Ire1p foci. This mechanism plays a crucial role in the timely activation of UPR and its prompt attenuation following the accomplishment of homeostasis. Thus, a kinetic mRNA decay provides a novel paradigm for mRNA targeting and regulation of gene expression. PMID- 29165700 TI - Epigenetic Therapy: Novel Translational Implications for Arrest of Environmental Dioxin-Induced Disease in Females. AB - Increased toxicant exposure and resultant environmentally induced diseases are a tradeoff of industrial productivity. Dioxin [2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD)], a ubiquitous byproduct, is associated with a spectrum of diseases including endometriosis, a common, chronic disease in women. TCDD activates cytochrome (CYP) p450 metabolic enzymes that alter organ function to cause disease. In contrast, the transcription factor, Kruppel-like factor (KLF) 11, represses these enzymes via epigenetic mechanisms. In this study, we characterized these opposing mechanisms in vitro and in vivo as well as determining potential translational implications of epigenetic inhibitor therapy. KLF11 antagonized TCDD-mediated activation of CYP3A4 gene expression and function in endometrial cells. The repression was pharmacologically replicated by selective use of an epigenetic histone acetyltransferase inhibitor (HATI). We further showed phenotypic relevance of this mechanism using an animal model for endometriosis. Fibrotic extent in TCDD-exposed wild-type animals was similar to that previously observed in Klf11-/- animals. When TCDD-exposed animals were treated with a HATI, Cyp3 messenger RNA levels and protein expression decreased along with disease progression. Fibrotic progression is ubiquitous in environmentally induced chronic, untreatable diseases; this report shows that relentless disease progression can be arrested through targeted epigenetic modulation of protective mechanisms. PMID- 29165701 TI - The mechano-chemistry of a monomeric reverse transcriptase. AB - Retroviral reverse transcriptase catalyses the synthesis of an integration competent dsDNA molecule, using as a substrate the viral RNA. Using optical tweezers, we follow the Murine Leukemia Virus reverse transcriptase as it performs strand-displacement polymerization on a template under mechanical force. Our results indicate that reverse transcriptase functions as a Brownian ratchet, with dNTP binding as the rectifying reaction of the ratchet. We also found that reverse transcriptase is a relatively passive enzyme, able to polymerize on structured templates by exploiting their thermal breathing. Finally, our results indicate that the enzyme enters the recently characterized backtracking state from the pre-translocation complex. PMID- 29165702 TI - Trend of tuberculosis case notification and treatment outcome in Lagos State, Nigeria: a 5-year retrospective study. AB - Background: This study assessed trends of tuberculosis (TB) case notification rate (CNR) and treatment outcomes between 2011 and 2015 in Lagos State, Nigeria. Methods: A retrospective review of TB notification data to the Lagos State Tuberculosis and Leprosy Control Programme (LSTBLCP) between 1 January 2011 and 31 December 2015 was conducted. Results: A total of 44 516 TB cases were notified during the study period, representing 9.4% of the national figure. The male:female ratio was 1.3:1. About 53%, 44.1% and 2.7% of patients were smear positive, smear negative and extrapulmonary TB cases, respectively. TB notification increased by 12.2% between 2011 and 2013 and subsequently declined by 7.2% in 2015 relative to 2013. The TB CNR declined from 82.9 per 100 000 in 2013 to 72.1 per 100 000 in 2015. However, directly observed treatment short course (DOTS) and microscopy site expansion increased from 0.3 to 0.64 per 25 000 population and from 0.16 to 0.4 per 50 000 population, respectively, from 2011 to 2015. Similarly, there was a slight increase in treatment success rate, from 80.1% in 2011 to 82% in 2015. Conclusion: The CNR declined in Lagos State despite an increasing trend in DOTS and microscopy site expansions between 2013 and 2015. The LSTBLCPs need to re-engineer current strategies of active TB case findings in order to improve case notification in the state. PMID- 29165703 TI - Effects of Neonatal Pain and Temperament on Attention Problems in Toddlers Born Preterm. AB - Objective: To examine the effects of individual characteristics of neonates and neonatal pain-related stress on attention problems and externalizing behavior problems of toddlers born preterm, analyzing the moderating effects of the dispositional traits of temperament. Methods: The sample included 62 toddlers aged 18-36 months and their mothers. The mothers were interviewed using the Child Behavior Checklist 1.5-5 for toddlers' attention and externalizing behavior problems assessment, the Early Childhood Behavior Questionnaire for toddlers' temperament assessment, and the Adult Temperament Questionnaire for their temperament assessment. The Neonatal Infant Stressor Scale analyzed the number of pain-related stress events during neonatal intensive care unit (NICU) hospitalization recorded in the medical charts. Statistical descriptive, correlation, and multiple linear regression analyses were performed. Results: High neonatal pain-related stress total index, associated with toddler's temperament with less Effortful Control, and mother's temperament with high Surgency explained 23% variability of the attention problems. Otherwise, the externalizing behavior problems were explained by temperament, but not by neonatal pain-related stress. Conclusions: The findings support the impact of neonatal pain experiences, and current toddlers' and mothers' temperament characterized by poorer self-regulation on attention problems in toddlers born preterm. Developmental care in the NICU and follow-up programs after discharge are recommended to promote regulated temperament of the mother-child dyads, aiming to prevent attentional problems in toddlers born preterm. PMID- 29165704 TI - Involvement of the def-1 Mutation in the Response of Tomato Plants to Arbuscular Mycorrhizal Symbiosis Under Well-Watered and Drought Conditions. AB - Jasmonic acid (JA) and arbuscular mycorrhizal (AM) symbioses are known to protect plants against abiotic and biotic stresses, but are also involved in the regulation of root hydraulic conductance (L). The objective of this experiment was to elucidate the role of JA in the water relations and hormonal regulation of AM plants under drought by using tomato plants defective in the synthesis of JA (def-1). Our results showed that JA is involved in the uptake and transport of water through its effect on both physiological parameters (stomatal conductance and L) and molecular parameters, mainly by controlling the expression and abundance of aquaporins. We observed that def-1 plants increased the expression of seven plant aquaporin genes under well-watered conditions in the absence of AM fungus, which partly explain the increment of L by this mutation under well watered conditions. In addition, the effects of the AM symbiosis on plants were modified by the def-1 mutation, with the expression of some aquaporins and plant hormone concentration being disturbed. On the other hand, methyl salicylate (MeSA) content was increased in non-mycorrhizal def-1 plants, suggesting that MeSA and JA can act together in the regulation of L. In a complementary experiment, it was found that exogenous MeSA increased L, confirming our hypothesis. Likewise, we confirmed that JA, ABA and SA are hormones involved in plant mechanisms to cope with stressful situations, their concentrations being controlled by the AM symbiosis. In conclusion, under well-watered conditions, the def-1 mutation mimics the effects of AM symbiosis, but under drought conditions the def-1 mutation changed the effects of the AM symbiosis on plants. PMID- 29165705 TI - Preliminary Exploration of the Diagnosis and Treatment of Skull-Based Chondromyxoid Fibromas. AB - BACKGROUND: Chondromyxoid fibromas (CMFs) are benign tumors that occur rarely in the skull base. OBJECTIVE: To conduct a preliminary exploration of the diagnosis and treatment of cranial CMFs. METHODS: A retrospective analysis of 19 cases of CMFs in the base of the skull between 2009 and 2014 in our hospital was conducted. The clinical manifestations, imaging characteristics, pathology, treatment strategies, and outcomes were examined. RESULTS: The study cohort included 7 women (36.8%) and 12 men (63.2%), and symptom duration ranged from 1 mo to 5 yr. Of the 19 intracranial CMF cases examined, 15 (78.9%) conformed with the diagnostic criteria for extracranial CMF. Resection operations yielded subtotal removal of 13 tumors (68.4%) and partial removal of 6 tumors (31.6%). Postoperative pathological analysis demonstrated that the tumors were characterized by spindle-shaped or stellate cells arranged in a myxoid matrix without mitoses or permeation. Follow-up (range 2-7.3 yr; mean, 4.4 +/- 1.7 yr) revealed that symptoms improved postoperatively in 15 cases (78.9%), were maintained in 2 cases (10.5%), and worsened in 2 cases (10.5%). Imaging follow-up revealed that residual tumors were stable in 18 cases (94.7%) and enlarged in 1 case (5.3%). CONCLUSION: An accurate diagnosis should involve comprehensive consideration of clinical, radiological, and pathological features. The treatment strategy for CMFs consists of maximizing tumor removal while protecting adjacent key structures. Postoperative stereotactic radiotherapy is appropriate for residual tumors. PMID- 29165706 TI - Cholera Epidemics of the Past Offer New Insights Into an Old Enemy. AB - Background: Although cholera is considered the quintessential long-cycle waterborne disease, studies have emphasized the existence of short-cycle (food, household) transmission. We investigated singular Danish cholera epidemics (in 1853) to elucidate epidemiological parameters and modes of spread. Methods: Using time series data from cities with different water systems, we estimated the intrinsic transmissibility (R0). Accessing cause-specific mortality data, we studied clinical severity and age-specific impact. From physicians' narratives we established transmission chains and estimated serial intervals. Results: Epidemics were seeded by travelers from cholera-affected cities; initial transmission chains involving household members and caretakers ensued. Cholera killed 3.4%-8.9% of the populations, with highest mortality among seniors (16%) and lowest in children (2.7%). Transmissibility (R0) was 1.7-2.6 and the serial interval was estimated at 3.7 days (95% confidence interval, 2.9-4.7 days). The case fatality ratio (CFR) was high (54%-68%); using R0 we computed an adjusted CFR of 4%-5%. Conclusions: Short-cycle transmission was likely critical to early secondary transmission in historic Danish towns. The outbreaks resembled the contemporary Haiti outbreak with respect to transmissibility, age patterns, and CFR, suggesting a role for broader hygiene/sanitation interventions to control contemporary outbreaks. PMID- 29165707 TI - Inflammation dynamics after praziquantel treatment of Schistosoma haematobium reflected by urinary eosinophil cationic protein. AB - Background: This cohort study assessed urinary eosinophil cationic protein (ECP) as an indicator for urinary tract morbidity and inflammation indication related to single-dose or dual-dose praziquantel (PZQ) treatment. Methods: Urinary ECP was measured at baseline, 24 h and 9 weeks after treatment (baseline 305, follow up 204 participants, ages 2-40 years). Results: ECP was significantly associated with the intensity of infection at baseline (p<0.05). Levels at baseline were 8.31 times higher (p<0.01) in participants with bladder morbidity than in those without. There was no correlation with kidney morbidity and no significant effect of a repeated dose of PZQ 40 mg/kg. Baseline ECP and ECP after 9 weeks were associated with microhaematuria (geometric mean ratio at baseline 7.56 [95% confidence limit {CL} 2.34-24.45]; p<0.01) and macrohaematuria (geometric mean ratio at baseline 6.22 [95% CL 2.71-14.24]; p<0.001). Mean levels of ECP dropped significantly during the first follow-up period and far less so in the second follow-up period (mean ECP at baseline: 70.8 ng/mL; ECP at 24 h: 24.5 ng/mL; ECP at 9 weeks: 14.6 ng/mL). Conclusion: The urine ECP decrease happened immediately after treatment, reflecting the rapid action of PZQ on eggs in the bladder tissue. ECP in urine can be used as an indirect marker of the degree of local inflammatory reaction in the bladder and is not significantly affected by a repeated dose of PZQ. PMID- 29165708 TI - Separase prevents genomic instability by controlling replication fork speed. AB - Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2-7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis. PMID- 29165709 TI - Structural basis for the GTP specificity of the RNA kinase domain of fungal tRNA ligase. AB - Fungal tRNA ligase (Trl1) is an essential enzyme that repairs RNA breaks with 2',3'-cyclic-PO4 and 5'-OH ends inflicted during tRNA splicing and non-canonical mRNA splicing in the fungal unfolded protein response. Trl1 is composed of C terminal cyclic phosphodiesterase and central polynucleotide kinase domains that heal the broken ends to generate the 3'-OH,2'-PO4 and 5'-PO4 termini required for sealing by an N-terminal ligase domain. Trl1 enzymes are found in all human fungal pathogens and are promising targets for antifungal drug discovery because their domain compositions and biochemical mechanisms are unique compared to the mammalian RtcB-type tRNA splicing enzyme. A distinctive feature of Trl1 is its preferential use of GTP as phosphate donor for the RNA kinase reaction. Here we report the 2.2 A crystal structure of the kinase domain of Trl1 from the fungal pathogen Candida albicans with GDP and Mg2+ in the active site. The P-loop phosphotransferase fold of the kinase is embellished by a unique 'G-loop' element that accounts for guanine nucleotide specificity. Mutations of amino acids that contact the guanine nucleobase efface kinase activity in vitro and Trl1 function in vivo. Our findings fortify the case for the Trl1 kinase as an antifungal target. PMID- 29165711 TI - Editorial: Launching a new Reviews section in Poultry Science. PMID- 29165710 TI - Risk of Soft-Tissue Sarcoma Among 69 460 Five-Year Survivors of Childhood Cancer in Europe. AB - Background: Childhood cancer survivors are at risk of subsequent primary soft tissue sarcomas (STS), but the risks of specific STS histological subtypes are unknown. We quantified the risk of STS histological subtypes after specific types of childhood cancer. Methods: We pooled data from 13 European cohorts, yielding a cohort of 69 460 five-year survivors of childhood cancer. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated. Results: Overall, 301 STS developed compared with 19 expected (SIR = 15.7, 95% confidence interval [CI] = 14.0 to 17.6). The highest standardized incidence ratios were for malignant peripheral nerve sheath tumors (MPNST; SIR = 40.6, 95% CI = 29.6 to 54.3), leiomyosarcomas (SIR = 29.9, 95% CI = 23.7 to 37.2), and fibromatous neoplasms (SIR = 12.3, 95% CI = 9.3 to 16.0). SIRs for MPNST were highest following central nervous system tumors (SIR = 80.5, 95% CI = 48.4 to 125.7), Hodgkin lymphoma (SIR = 81.3, 95% CI = 35.1 to 160.1), and Wilms tumor (SIR = 76.0, 95% CI = 27.9 to 165.4). Standardized incidence ratios for leiomyosarcoma were highest following retinoblastoma (SIR = 342.9, 95% CI = 245.0 to 466.9) and Wilms tumor (SIR = 74.2, 95% CI = 37.1 to 132.8). AERs for all STS subtypes were generally low at all years from diagnosis (AER < 1 per 10 000 person-years), except for leiomyosarcoma following retinoblastoma, for which the AER reached 52.7 (95% CI = 20.0 to 85.5) per 10 000 person-years among patients who had survived at least 45 years from diagnosis of retinoblastoma. Conclusions: For the first time, we provide risk estimates of specific STS subtypes following childhood cancers and give evidence that risks of MPNSTs, leiomyosarcomas, and fibromatous neoplasms are particularly increased. While the multiplicative excess risks relative to the general population are substantial, the absolute excess risk of developing any STS subtype is low, except for leiomyosarcoma after retinoblastoma. These results are likely to be informative for both survivors and health care providers. PMID- 29165712 TI - Use of an Articulating Hinge to Facilitate Cervicothoracic Deformity Correction During Vertebral Column Resection. AB - BACKGROUND: Surgical treatment of severe cervicothoracic kyphotic deformity may require the use of 3-column osteotomies such as the pedicle subtraction osteotomy and vertebral column resection (VCR), or VCR with anterior longitudinal ligament resection. Such procedures are extensive and are associated with high intra- and perioperative morbidity, in part, due to the need for risky reduction maneuvers. OBJECTIVE: To describe a novel technique utilizing a laterally placed articulating hinge to facilitate kyphotic deformity correction of the cervicothoracic spine. METHODS: A patient with severe chin-on-chest deformity of the cervicothoracic spine presented for evaluation and a 2-stage VCR with anterior longitudinal ligament resection was planned. To reduce the risk of intraoperative neurological injury and for increased control during reduction maneuvers, lateral instrumentation was placed through the chest wall resection above and below the level of VCR, which was adjoined with an articulating hinge rod apparatus. RESULTS: Satisfactory reduction of the kyphosis was achieved utilizing the hinge rod apparatus for controlled deformity correction. The patient remained neurologically intact following this procedure with improvement in their spinal alignment. CONCLUSION: We present a novel technique utilizing a lateral hinge rod apparatus for efficient, controlled correction of severe kyphotic deformity. PMID- 29165714 TI - Blood lipid genetic scores, the HMGCR gene and cancer risk: a Mendelian randomization study. AB - Background: It is unclear whether there are causal associations between blood lipids, statin use and cancer risks. Under certain assumptions, Mendelian randomization analysis of a genetic marker for an exposure eliminates reverse causation and confounding. Methods: We applied Mendelian randomization analysis to genetic scores, comprising 26-41 single-nucleotide polymorphisms (SNPs), as instrumental variables (IVs) for triglycerides and low- and high-density lipoprotein cholesterol (LDLC, HDLC), using a prospective cohort of 26 904 individuals in which there were 6607 incident cancers. We also investigated cancer risk for a SNP (rs12916) in the gene encoding hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the targeted enzyme in statin treatment. We used logistic regression and SNP pleiotropy-adjusted analyses to estimate the odds ratio per standard deviation (OR). Results: The OR for the triglyceride IV as a predictor of any cancer was 0.91 [95% confidence interval (CI): 0.80-1.03] unadjusted, and 0.87 (95% CI: 0.78-0.95) from the pleiotropy-adjusted analysis. For the HMGCR rs12916 per LDLC-lowering T-allele, the OR was 1.09 (95% CI: 1.01 1.18) for prostate cancer and 0.89 (95% CI: 0.82-0.96) for breast cancer. The LDLC IV was not associated with prostate cancer or breast cancer. There were no associations between IVs and cancers of the lung, colon or bladder. Conclusions: Under the assumptions of Mendelian randomization, there is a causal and negative association between serum triglycerides and risk of any cancer. Further, the HMGCR genetic variant might be associated with risks of prostate and breast cancers but the biological mechanisms behind these findings are unclear, as the LDLC IV was not associated with these cancers. PMID- 29165713 TI - Protein complex scaffolding predicted as a prevalent function of long non-coding RNAs. AB - The human transcriptome contains thousands of long non-coding RNAs (lncRNAs). Characterizing their function is a current challenge. An emerging concept is that lncRNAs serve as protein scaffolds, forming ribonucleoproteins and bringing proteins in proximity. However, only few scaffolding lncRNAs have been characterized and the prevalence of this function is unknown. Here, we propose the first computational approach aimed at predicting scaffolding lncRNAs at large scale. We predicted the largest human lncRNA-protein interaction network to date using the catRAPID omics algorithm. In combination with tissue expression and statistical approaches, we identified 847 lncRNAs (~5% of the long non-coding transcriptome) predicted to scaffold half of the known protein complexes and network modules. Lastly, we show that the association of certain lncRNAs to disease may involve their scaffolding ability. Overall, our results suggest for the first time that RNA-mediated scaffolding of protein complexes and modules may be a common mechanism in human cells. PMID- 29165715 TI - Virus-Induced Silencing of Key Genes Leads to Differential Impact on Withanolide Biosynthesis in the Medicinal Plant, Withania somnifera. AB - Withanolides are a collection of naturally occurring, pharmacologically active, secondary metabolites synthesized in the medicinally important plant, Withania somnifera. These bioactive molecules are C28-steroidal lactone triterpenoids and their synthesis is proposed to take place via the mevalonate (MVA) and 2-C-methyl d-erythritol-4-phosphate (MEP) pathways through the sterol pathway using 24 methylene cholesterol as substrate flux. Although the phytochemical profiles as well as pharmaceutical activities of Withania extracts have been well studied, limited genomic information and difficult genetic transformation have been a major bottleneck towards understanding the participation of specific genes in withanolide biosynthesis. In this study, we used the Tobacco rattle virus (TRV) mediated virus-induced gene silencing (VIGS) approach to study the participation of key genes from MVA, MEP and triterpenoid biosynthesis for their involvement in withanolide biosynthesis. TRV-infected W. somnifera plants displayed unique phenotypic characteristics and differential accumulation of total Chl as well as carotenoid content for each silenced gene suggesting a reduction in overall isoprenoid synthesis. Comprehensive expression analysis of putative genes of withanolide biosynthesis revealed transcriptional modulations conferring the presence of complex regulatory mechanisms leading to withanolide biosynthesis. In addition, silencing of genes exhibited modulated total and specific withanolide accumulation at different levels as compared with control plants. Comparative analysis also suggests a major role for the MVA pathway as compared with the MEP pathway in providing substrate flux for withanolide biosynthesis. These results demonstrate that transcriptional regulation of selected Withania genes of the triterpenoid biosynthetic pathway critically affects withanolide biosynthesis, providing new horizons to explore this process further, in planta. PMID- 29165716 TI - Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition. AB - Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound. Methods: Two CML cell lines with acquired BCR-ABL-independent resistance were generated following culture in ponatinib. RNA sequencing and gene ontology (GO) enrichment were used to detect aberrant transcriptional response in ponatinib-resistant cells. A validated oncogene drug library was used to identify US Food and Drug Administration-approved drugs with activity against TKI resistant cells. Validation was performed using bone marrow (BM)-derived cells from TKI-resistant patients (n = 4) and a human xenograft mouse model (n = 4-6 mice per group). All statistical tests were two-sided. Results: We show that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR. Following transcriptomic analysis and drug screening, we highlight mTOR inhibition as an alternative therapeutic approach in TKI-resistant CML cells. Additionally, we show that catalytic mTOR inhibitors induce autophagy and demonstrate that genetic or pharmacological inhibition of autophagy sensitizes ponatinib-resistant CML cells to death induced by mTOR inhibition in vitro (% number of colonies of control[SD], NVP-BEZ235 vs NVP-BEZ235+HCQ: 45.0[17.9]% vs 24.0[8.4]%, P = .002) and in vivo (median survival of NVP-BEZ235- vs NVP-BEZ235+HCQ-treated mice: 38.5 days vs 47.0 days, P = .04). Conclusion: Combined mTOR and autophagy inhibition may provide an attractive approach to target BCR-ABL-independent mechanism of resistance. PMID- 29165717 TI - Crystal structure of NucB, a biofilm-degrading endonuclease. AB - Bacterial biofilms are a complex architecture of cells that grow on moist interfaces, and are held together by a molecular glue of extracellular proteins, sugars and nucleic acids. Biofilms are particularly problematic in human healthcare as they can coat medical implants and are thus a potential source of disease. The enzymatic dispersal of biofilms is increasingly being developed as a new strategy to treat this problem. Here, we have characterized NucB, a biofilm dispersing nuclease from a marine strain of Bacillus licheniformis, and present its crystal structure together with the biochemistry and a mutational analysis required to confirm its active site. Taken together, these data support the categorization of NucB into a unique subfamily of the betabetaalpha metal dependent non-specific endonucleases. Understanding the structure and function of NucB will facilitate its future development into an anti-biofilm therapeutic agent. PMID- 29165719 TI - How I cannulate the bile duct. PMID- 29165718 TI - A Phi-Class Glutathione S-Transferase Gene for Verticillium Wilt Resistance in Gossypium arboreum Identified in a Genome-Wide Association Study. AB - Verticillium wilt disease is one of the most destructive biotic stresses faced by cotton plants. Here, we performed a genome-wide association study (GWAS) in 215 Chinese Gossypium arboreum accessions inoculated as seedlings with Verticillium dahliae to identify candidate loci involved in wilt resistance. We identified 309 loci that had a significant association with Verticillium wilt resistance and - log(P) values >5.0; the highest signal appeared on Ca3 in a 74 kb haplotype block. Five genes were also located within this haplotype block. One of these genes, CG05, was positioned close to the most significant SNP Ca3_23037225 (14 kb); expression of the gene was induced by V. dahliae or by treatment with salicylic acid (SA). Therefore, we suggest that CG05 may respond to invasion by V. dahliae via an SA-related signaling pathway, and we designated this gene as GaGSTF9. We showed that GaGSTF9 was a positive regulator of Verticillium wilt through the use of virus-induced gene silencing (VIGS) and overexpression in Arabidopsis. In addition, the glutathione S-transferase (GST) mutant gstf9 of Arabidopsis was found to be more susceptible to Verticillium wilt than wild-type plants. The levels of endogenous SA and hydrogen peroxide had a significant effect on Arabidopsis plants that overexpressed GaGSTF9, indicating that GST may regulate reactive oxygen species content via catalytic reduction of the tripeptide glutathione (GSH), and then affect SA content. Our data demonstrated that GaGSTF9 was a key regulator mediating cotton responses to V. dahliae and a potential candidate gene for cotton genetic improvement. PMID- 29165720 TI - [Relationship Strain Parkinson's Disease! Gender-Specific Distress of Partners of Patients with Parkinson's Disease]. AB - A Parkinson's disease is attended by high strain for the patients and an obvious loss of relationship functioning. Partners of patients (N=110) were evaluated via self-assessment in terms of own depression (PHQ-9), own fear of progression (PA-F P-KF), relationship quality (PFB) as well as perceived deficits in everyday life and nonverbal communication. 26% of women and 11% of men showed depression scores, 51% of women and 41% of men dysfunctional fear of progression and about 60% were unsatisfied with their relationship. Gender-specific differences regarding the severity of the symptoms and their distress occurred. The severity of symptoms was estimated highest by spouses of male patients with Parkinson's disease, whereas female spouses showed higher psychological distress than male spouses. Moreover, restrictions of everyday life were associated with depression (r=0.40, p<0.05), fear of progression (r=0.40, p<0.05) und relationship quality (r=-0.52, p<0.05) as well as deficits in nonverbal communication with depression (r=0.37, p<0.05), fear of progression (r=0.27, p<0.05) und relationship quality (r=-0.49, p<0.05). Regression analysis to predict relationship quality explained 46% of the variance. As significant predictors emerged cognitive deficits in everyday life, lacking eye contact, physical mobility and pain. Due to the high association of relationship quality and restrictions through the Parkinson's disease, interventions with couples were discussed. PMID- 29165721 TI - [Psychodynamic Oriented Multimodal Therapy for Inpatients with Borderline Personality Disorder: Effectiveness, Response, and Dropout]. AB - Psychodynamically oriented multimodal therapy approaches are efficacious for outpatients with borderline personality disorder (BPD). Until now, no study has reported the effectiveness, response, and dropout in a psychodynamic oriented multimodal therapy program for inpatients (PDOMT). In this study, we compared the results of 269 individuals seeking a 3-month inpatient treatment with previous studies for BPD inpatients by examining 269 individuals. The Borderline Personality Index (CUT-20-R) was used as the main outcome measure. Therapy outcome was defined in effect size (ES), response, and remission rates. In the pre-post comparison of the CUT-20-R, the ES was 0.74. The response and the remission rates were 34.6% and 2.6%. 50.6% of participants remained unchanged, 6.7% deteriorated, and 27.5% finished treatment prematurely. Male gender and patients with a dependent personality disorder increased the dropout risk. The results suggest that PDOMT might be effective for some, but not all BPD patients. Due to methodological shortcomings of the chosen strategy, future research should examine the effectiveness of PDOMT in a randomized controlled trial. PMID- 29165722 TI - [Healthier after Psychotherapy? Analysis of Claims Data (Lower Saxony, Germany) on Sickness Absence Duration before and after Outpatient Psychotherapy]. AB - INTRODUCTION: In employed populations sickness absence can be used as a good indicator of health status. In the present study, it was examined how periods of sickness absence are developing within one year before and after psychotherapy under comparison of three types of psychotherapy (behavior therapy, psychodynamic psychotherapy, and psychoanalysis), all fully covered by statutory health insurance. METHODS AND DATA: The analyses were performed with pseudonymized claims data from the AOK Niedersachsen, a statutory health insurance (N=2,900,065 insured). Certified sickness absences before and after psychotherapy were examined for 9,916 patients. Parallelized controls were used to build a comparison of the length of sickness absences. Analyses were performed separately for women and for men. RESULTS: Within one year before starting psychotherapy, patients had longer sickness absences than controls on average. There was a reduction in the length of sickness absence of 20 days (median) within one year before to 12 days (median) within one year after the psychotherapy. The obtained differences between types of psychotherapy were considerable. DISCUSSION: Differences in terms of sickness absences may in part be explained by socio demographic differences. Patients who underwent psychoanalysis were younger and had higher educational levels. However, it remains unclear why the differences of sickness absence periods were that high. It has to be discussed whether self selection of patients with better health into psychoanalysis had occurred. CONCLUSIONS: Patients undergoing psychoanalysis differ from patients who underwent other types of psychotherapy in terms of their duration of sickness absence as well as socio-demographic profile. Thus, due to differences in the composition of patients future research in psychotherapy will have to differentiate by type of psychotherapy. PMID- 29165723 TI - The Impact of Hyperosmolarity on Long-Term Outcome in Patients Presenting with Severe Hyperglycemic Crisis: A Population Based Study. AB - AIMS: We compared characteristics of patients with hyperglycemic hyperosmolar state (HHS) and patients with severe hyperglycemia without the signs of hyperosmolarity and ketoacidosis; analyzed long-term all-cause mortality and potential prognostic factors. METHODS: The studied population included 261 749 adults. HHS was diagnosed in patients with plasma glucose >33.0 mmol/L, ketonuria <1+, and serum osmolarity >320 mmol/L. Patients with plasma glucose >33.0 mmol/L, ketonuria <1+ and serum osmolarity <320 mmol/L were considered as controls (nHHS). RESULTS: During the 5-year period, we observed 68 episodes of HHS in 66 patients and 51 patients with nHHS. Patients with HHS were significantly older, had lower BMI, higher serum C-reactive protein and used diuretics and benzodiazepines more frequently. Mortality rates one, three and 12 months after admission were 19.0, 32.1 and 35.7% in the HHS group, and 4.8, 6.3 and 9.4% in the nHHS group (P<0.001). However, after adjustment for patient age, these differences were not statistically significant. In multivariate Cox regression in HHS group, mortality was positively associated with age, male gender, leukocyte count, amylase, presence of dyspnea and altered mental status, and the use of benzodiazepines, ACE inhibitors and sulphonylureas, while it was inversely associated with plasma glucose, bicarbonate, and the use of thiazides and statins. A nomogram derived from these variables had an accuracy of 89% in predicting lethal outcome. CONCLUSIONS: Infection, use of furosemide and benzodiazepines may be important precipitating factors of HHS. Prospective clinical trials are mandatory to analyze the safety of ACE-inhibitors and benzodiazepines in elderly patients with diabetes. PMID- 29165724 TI - Protective Effect and Potential Mechanism of Simvastatin on Myocardial Injury Induced by Diabetes with Hypoglycemia. AB - BACKGROUND: Simvastatin has been reported to reduce cardiovascular related morbidity and mortality in clinical trials which was independent of its cholesterol-lowering effect. This study aims to investigate the protective effect of simvastatin on myocardial injury caused by diabetic hypoglycemia and the possible underlying mechanism. METHODS: We used streptozotocin (STZ) at a dose of 55 mg/kg to induce diabetes mellitus (DM) and over-dose insulin to induce hypoglycemia to establish diabetic hypoglycemia rat models. The cardiac protective effect of simvastatin treatment (at a dose of 40 mg/kg.d) upon diabetic hypoglycemia models was assessed. Ex vivo cardiac function, cardiomyocyte inotropic property and calcium transient were evaluated. The expression levels of microRNA (miRNA) and NF-kappaB in heart tissues were investigated. RESULTS: Both systolic and diastolic functions in diabetic rats were weakened, and further worsened in diabetic hypoglycemia rats, partially restored after administration of simvastatin. The protective effect of simvastatin on cardiac function under diabetic hypoglycermia was associated with decreased intracellular calcium and increased calcium sensitivity. miRNA array showed a differential profile of miRNA expression existed in diabetic hypoglycemia rats compared with diabetic non-hypoglycemia group, and that simvastatin could reverse the altered miRNA expression in diabetic hypoglycemia group. CONCLUSION: Simvastatin has protective effect on myocardial injury caused by diabetes with hypoglycemia, which is associated with increased calcium sensitivity, decreased NF-kappaB expression and altered miRNA expression profile. PMID- 29165725 TI - Somatotrope Pituitary Function in Professional Soccer Players. AB - BACKGROUND AND OBJECTIVE: Soccer is associated with repetitive head trauma, which, as it is known from sports like football and boxing, can result in hypopituitarism. Gonadotropins and GH are the most common pituitary hormones to become deficient. GH deficiency is associated with an increased risk of cardiovascular mortality and has negative influence on body mass index, visceral fat mass, insulin resistance and sensitivity, bone mineral density and inflammatory markers. Therefore the aim of this study was to evaluate the somatotrope pituitary function in professional soccer players. RESEARCH DESIGN AND METHODS: This clinical study included 15 male, professional soccer players with at least 10 years of professional training. Basal hormonal parameters of the pituitary axis were obtained from the participants. To assess GH-IGF-I axis, glucagon stimulation tests were used. Rise in growth hormone during glucagon test was analyzed and the prevalence of newly diagnosed hormone deficiencies was evaluated. RESULTS: Mean age of all participants was 31+/-10 years. None of the 15 soccer players had GH deficiency. Mean rising factor of GH after stimulation with glucagon was 100 in all participants. We did not find signs of ACTH, TSH or LH/FSH deficiency in any player. CONCLUSIONS: In this small collective of soccer players we did not find playing soccer to be a risk factor for the development of GH-deficiency. According to our data screening for somatotrope deficiency is not necessary. Further investigations in larger cohorts are needed. PMID- 29165726 TI - Erratum: Evaluation of Cannabinoid and Terpenoid Content: Cannabis Flower Compared to Supercritical CO2 Concentrate. PMID- 29165727 TI - Erratum: Aucubin Protects against TGFbeta1-Induced Cardiac Fibroblasts Activation by Mediating the AMPKalpha/mTOR Signaling Pathway. PMID- 29165728 TI - Cardioprotective Effect of Hydroxysafflor Yellow A via the Cardiac Permeability Transition Pore. AB - Myocardial ischemia damages cardiac myocytes in part via opening of the mitochondrial permeability transition pore. Preventing this pore's opening is therefore a useful therapeutic goal in treating cardiovascular disease. Hydroxysafflor yellow A has been proposed as a nontoxic alternative to other agents that modulate mitochondrial permeability transition pore opening. In this study, we proposed that hydroxysafflor yellow A prevents mitochondrial permeability transition pore formation in anoxic cardiac myocytes, and thus protects the cell from damage seen during reoxygenation of the cardiac myocytes. Experiments with hydroxysafflor yellow A transport in aerobic myocytes show that roughly 50% of the extracellular dye concentration crosses the cell membrane in a 2-h incubation. In our anoxia/reoxygenation protocol, hydroxysafflor yellow A modulated both the reduction of viability and the loss of rod-shaped cells that attend anoxia and reoxygenation. Hydroxysafflor yellow A's protective effect was similar to that of cyclosporin A, an agent known to inhibit mitochondrial permeability transition pore opening. In additional experiments, plated myocytes were loaded with calcein/MitoTracker Red, then examined for intracellular dye distribution/morphology after anoxia/reoxygenation. Hydroxysafflor yellow A containing cells showed a cardioprotective pattern similar to that of cyclosporin A (an agent known to close the mitochondrial permeability transition pore). We conclude that hydroxysafflor yellow A can enter the cardiac myocyte and is able to modulate anoxia/reoxygenation-induced damage by interacting with the mitochondrial permeability transition pore. PMID- 29165729 TI - Polyphenols from Euphorbia pekinensis Inhibit AGEs Formation In Vitro and Vessel Dilation in Larval Zebrafish In Vivo. AB - To identify active compounds in the roots of Euphorbia pekinensis for treatment of diabetic complications, an active column fraction from a 70% EtOH extract of E. pekinensis root was purified by preparative reversed-phase high-performance liquid chromatography, leading to the isolation of a new ellagic acid derivative, 3,3'-di-O-methylellagic acid 4-O-(6"-O-galloyl)-beta-D-galactopyranoside (1: ), along with three known compounds, geraniin (2: ), 3,3'-di-O-methylellagic acid 4 O-beta-D-xylopyranoside (3: ), and ellagic acid 3,3'-dimethyl ether (4: ). The structure of the new compound was established by extensive spectroscopic studies and chemical evidence. The inhibitory effects of isolated compounds 1: -4: on advanced glycation end-products (AGEs) formation were examined. All compounds exhibited considerable inhibition of AGEs formation and IC50 values of 0.41 - 12.33 uM, compared with those of the positive controls aminoguanidine (IC50 = 1122.34 uM) and quercetin (IC50 = 27.80 uM). In addition, the effects of 2: and 4: on the dilation of hyaloid-retinal vessels induced by high glucose (HG) in larval zebrafish were investigated; both compounds significantly reduced the HG induced dilation of hyaloid-retinal vessels relative to the HG-treated control group. PMID- 29165730 TI - What Else Is in Salviae officinalis folium? Comprehensive Species Identification of Plant Raw Material by DNA Metabarcoding. AB - Quality control of drugs consists of identifying the raw material to avoid unwanted admixtures or exchange of material as well as looking for abiotic and biotic contaminations. So far, identity and microbial contamination are analyzed by separate processes and separate methods. Species identification by their DNA ("DNA barcoding") has the potential to supplement existing methods of identification. The introduction of next-generation sequencing methods offers completely new approaches like the identification of whole communities in one analysis, termed "DNA metabarcoding". Here we present a next-generation sequencing assessment to identify plants and fungi of two commercial sage samples (Salvia officinalis) using the standard DNA barcoding region "internal transcribed spacer" consisting of internal transcribed spacer 1 and internal transcribed spacer 2, respectively. The main species in both samples was identified as S. officinalis. The spectrum of accompanying plant and fungal species, however, was completely different between the samples. Additionally, the composition between internal transcribed spacer 1 and internal transcribed spacer 2 within the samples was different and demonstrated the influence of primer selection and therefore the need for harmonization. This next-generation sequencing approach does not result in quantitative species composition but gives deeper insight into the composition of additional species. Therefore, it would allow for a better knowledge-based risk assessment than any other method available. However, the method is only economically feasible in routine analysis if a high sample throughput can be guaranteed. PMID- 29165731 TI - Effects of the ACTN3 R577X Genotype on the Muscular Strength and Range of Motion Before and After Eccentric Contractions of the Elbow Flexors. AB - The purpose of present study was to examine the association between ACTN3 R577X genotype and functional characteristics of elbow flexors before and after isokinetic eccentric contractions (ECCs). Fifty-two men (age: 20.8+/-3.8 years, height: 172.5+/-5.9 cm, body mass: 64.7+/-6.5 kg, BMI: 21.7+/-1.7) who had not participated in any regular resistance training for at least 1 year prior to this study were recruited. ECCs consisted of five sets of six maximal voluntary isokinetic (30 degrees /s) ECCs of the elbow flexors with a range of motion (ROM) from 90 degrees flexion to 0 degrees (full extension). Measurements of maximal voluntary isometric contraction (MVC) torque, ROM, and muscle soreness were taken before, immediately after, and 1, 2, 3, and 5 days after ECCs. Genotyping results were analyzed for identifying ACTN3 R577X polymorphism (rs1815739) using TaqMan approach. The genotype frequencies of the ACTN3 R577X polymorphism were RR 26.9% (n=14), RX 50.0% (n=26), and XX 23.1% (n=12). There were no significant differences in MVC torque, ROM, and soreness between three genotype groups of ACTN3 R577X. However, MVC at baseline was greater in RR homozygotes than in X allele carriers (combined XX and RX; p<0.05). ROM in RR homozygotes at baseline was lower than that of X-allele carriers. Although a significant decrease in ROM was observed in X-allele carriers until 3 days after ECCs, a significant ROM reduction in RR homozygotes was observed only immediately after ECCs. Our data indicated that ACTN3 RR genotype has higher MVC and lower flexibility than X allele carriers at baseline, but the effect of ACTN3 R577X genotype on these two parameters is limited after ECCs. PMID- 29165732 TI - Effect of Melatonin Supplementation on Antioxidant Status and DNA Damage in High Intensity Trained Athletes. AB - The aim of the study was to evaluate the effect of melatonin supplementation on antioxidant capacity and DNA damage in high intensity interval training (HIIT) athletes. A 2-week randomised, double-blinded, placebo-controlled trial with two groups was conducted. Placebo (PG) and melatonin (MG) (20 mg/d) athletes were monitored over a two-week period of HIIT and strength training. The total antioxidant capacity (TAC) and the glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were analysed in blood samples. DNA damage was measured in isolated lymphocytes by comet assay prior to and immediately after exercise. The supplementation increased plasma melatonin levels in the melatonin treated group (p<0.05) after two weeks of intervention. Analysis of antioxidant status indicated higher (p<0.05) TAC and GPx in MG than PG post-intervention. No differences were found in SOD enzyme activity. DNA damage was diminished in MG (p<0.05) compared to PG in post-training conditions. Antioxidant status was associated with DNA damage (r=-0.679; p=0.047) in the melatonin-treated athletes. The present study suggest that melatonin supplementation improves antioxidant status and may prove to have beneficial effects preventing DNA damage induced by high intensity training. PMID- 29165733 TI - Impact of Type of Sport, Gender and Age on Red Blood Cell Deformability of Elite Athletes. AB - : Our objective was to detect possible differences in red blood cell (RBC) deformability of elite athletes performing different types of sports and being of different age and gender.182 athletes were included in this cross-sectional study. RBC deformability was measured using the laser-assisted optical rotational cell-analyzer. Maximal elongation index (EI max) and shear stress at half-maximum deformation (SS 1/2) were calculated. The ratio SS 1/2 /EI max (EI Ratio) was calculated with low values representing high RBC deformation. Hematocrit (Hct) and mean cellular volume (MCV) were determined in venous blood. Overall RBC deformability did not differ between male and female athletes but, when separated by age of the subjects, RBC deformability increased with age in male but not in female athletes. RBC deformability was lower in Combat sports compared other sport groups. Hct was higher in male compared to female athletes while no difference was observed for MCV. MCV and Hct increased with increasing age. A negative correlation was found between the EI Ratio and MCV and between EI Ratio and Hct. CONCLUSION: RBC deformability is influenced by age and endurance rate of the sport which suggests that the RBC system may adapt to changing conditions such as adolescence with the onset effects of sex hormones or physical exercise. PMID- 29165734 TI - Effects of Age, Joint Angle, and Test Modality on Strength Production and Functional Outcomes. AB - This study investigated the impact of age, knee joint angle, and strength testing modality on lower body maximal and rapid strength production and assessed the transferability of these characteristics to mobility-related function. Twenty young (age=21.9 yrs) and eighteen elderly (71.1 yrs) adults performed single joint and multiple-joint isometric maximal voluntary contractions at three knee angles. Outcome measures included peak torque (PT), rate of torque development (RTD), jump height, power, 10 and 400 m walk, and timed chair stand. Older adults exhibited greater reductions in RTD for the multiple-joint (45%) than for the single-joint mode (18%). The 10 m walk was best predicted by multiple-joint RTD at 90 degrees , the 400 m walk by jump height, and the chair stand by single joint PT at 20 degrees . Single-joint strength tests may underestimate age related rapid strength impairments, likely due to requirements to exert muscular force in excess of one's body mass in an upright position. PMID- 29165735 TI - Thyroid Stimulating Hormone Within the Reference Range is Associated with Visceral Adiposity Index and Lipid Accumulation Product: A Population-Based Study of SPECT-China. AB - Few studies about the relationship of thyroid stimulating hormone (TSH) level with visceral adiposity index (VAI) and lipid accumulation product (LAP) in large Chinese population are available. The aim of this study was to explore whether TSH level within the reference range was associated with these two newer reliable cardiovascular risk factors. The data were obtained from a cross-sectional study (SPECT-China study, 2014-2015), which was based on the population. Participants underwent several checkups, which included anthropometric parameters, blood pressure, TSH levels, and glucose and lipid profiles. VAI and LAP were calculated. A total of 8727 subjects were enrolled in this study. The mean age was 53.00+/-13.05 years. Age, female to male ratio, BMI, systolic pressure, and HOMA-IR increased along with the increasing levels of TSH (p<0.01). Analysis of lipid profile showed significantly higher serum triglycerides and LDL cholesterol levels in the higher TSH quartile (p<0.001 and p=0.028, respectively). The levels of VAI and LAP were all increased along with increasing TSH level (all p<0.001). After full adjustment, TSH levels were positively associated with VAI, LAP, and TG/HDL levels significantly (B=0.041, 0.028 and 0.037, respectively, all p<0.01). Higher TSH concentrations among the reference range were common in older people as well as in women subjects, and they were positively associated with VAI and LAP. This highlighted that even subtle variations of serum TSH within the normal range may be potential risk factors for cardiovascular diseases. PMID- 29165736 TI - The SPARTACUS Trial: Controversies and Unresolved Issues. AB - Adrenal vein sampling (AVS) is considered the gold standard for the differential diagnosis in patients with primary aldosteronism (PA). The distinction between unilateral and bilateral disease dictates the targeted therapeutic approach with surgery for aldosterone producing adenomas and medical therapy for patients with bilateral hyperplasia. Thereby, this diagnostic step is crucial in clinical care. As AVS is an invasive, not well standardized procedure that is restricted to few specialized centers, several attempts have been made to simplify diagnostic algorithms. In this clinical scenario, the recently published SPARTACUS trial aimed at answering the question whether AVS in fact is superior for differential diagnosis in comparison to imaging of the adrenal glands. In this multicenter study, patients were randomized to be treated according to AVS results or based on abdominal imaging only. Clinical outcome in both patient groups after one year was reported as not different. While the study results found broad interest, it also stirred considerable controversies. This review provides an overview on the different views regarding the outline of the SPARTACUS trial and the interpretation of its results. PMID- 29165738 TI - Alloantibodies in von Willebrand Disease. AB - von Willebrand disease (VWD), the most commonly known inherited bleeding disorder, is caused by a partial (type 1) or total (type 3) deficiency or dysfunction (type 2) of von Willebrand factor (VWF). Its management encompasses the prevention or treatment of bleeding by raising endogenous VWF levels using a synthetic agent, such as desmopressin, or providing exogenous VWF concentrates. The development of inhibitory alloantibodies against VWF is a rare but often severe complication encountered during the treatment of type 3 VWD, which is associated with a lack of hemostatic response to infused VWF concentrates and more rarely with allergic, even anaphylactic, reactions. This narrative review will focus on the characteristics of such alloantibodies and their management, which can be very challenging for physicians operating at hemophilia treatment centers. PMID- 29165737 TI - Management of Hemostasis for Pediatric Patients on Ventricular-Assist Devices. AB - Ventricular-assist devices (VADs) have seen increased utilization in the pediatric population. Formerly, this therapeutic modality was limited to only the pulsatile VAD, EXCOR (Berlin Heart GmbH). However, the continuous flow VAD devices, HeartMate II (Abbott Inc.) and HeartWare (Medtronic Inc.), are now increasingly used in this population. Postoperatively, VAD patients are acutely anticoagulated using unfractionated heparin, often beginning 24 to 48 hours after VAD placement. Once the patient is stabilized and ready to transition to a lower acuity or outpatient setting, low-molecular-weight heparin or warfarin therapy may be instituted. Also, because of the risk for thrombotic and thromboembolic complications, antiplatelet strategies are employed using medications such as aspirin, clopidogrel, or dipyridamole. Platelet-rich plasma or whole blood platelet aggregation studies, platelet function analyzer-100 (Siemens), VerifyNow (Accriva Diagnostics), or thromboelastography platelet mapping (Haemonetics) may be used to help monitor antiplatelet effects, though the interpretation of the strength of the antiplatelet effect remains difficult. Care must be taken to monitor the hematologic complications of VAD, including acquired von Willebrand syndrome, which increases the risk for bleeding, and intravascular hemolysis, which increases the risk of thrombosis. Appropriate device placement and anticoagulation management are imperative to help avoid neurological dysfunction and ischemic stroke, the most devastating potential complications of VAD therapy. As our experience grows, we continue to gain an increased understanding of the management of anticoagulation, need for antiplatelet medication, and appropriate monitoring for these critical patients. PMID- 29165739 TI - Inhibitors in Patients with Congenital Bleeding Disorders Other Than Hemophilia. AB - The most worrying complication of replacement therapy for severe hemophilia A and B is currently the occurrence of inhibitory alloantibodies against infused factor VIII and factor IX, respectively. Inhibitors compromise the management of hemorrhage in affected patients, with a considerable increase in complications, disability, and costs. While these alloantibodies have been extensively studied in the past years in hemophilia A and B, those occurring in patients with other inherited bleeding disorders are less well characterized and still poorly understood, mostly due to the rarity of these hemorrhagic conditions. This narrative review will deal with inhibitors arising in patients with inherited bleeding disorders other than "classical" hemophilia, focusing in particular on those developing in patients with congenital deficiency of coagulation factor V, factor VII, factor XI, and factor XIII. PMID- 29165740 TI - Platelets as Modulators of Inflammation. AB - Platelets have classically been considered crucial effector cells in hemostasis, but now are increasingly recognized as players during inflammatory responses in innate and adaptive immunity. Platelets can recognize and kill invading pathogens, and, upon stimulation, also release a wide array of mediators that modify immune and endothelial cell responses. Increased platelet activity can protect the host against infectious insults; however, the excessive activity can lead to inflammation-mediated tissue damage. These critical roles highlight the necessity of balancing the platelet response at the intersection of hemostasis and inflammation. In this review, the authors present the current understanding of the inflammatory role of platelets. They also highlight recent findings on a modulator that links inflammation and deleterious tissue damage in disease pathogenesis. PMID- 29165741 TI - Emerging Roles for von Willebrand Factor in Cancer Cell Biology. AB - von Willebrand factor (VWF) is a complex multimeric plasma glycoprotein that plays critical roles in normal hemostasis. However, additional novel roles for VWF in modulating cancer cell biology, and in particular tumor metastasis, have recently been reported. Markedly elevated plasma VWF levels were associated with advanced tumor stage and metastatic disease. These observations have raised the question of whether VWF may be involved in regulating tumor progression. Interestingly, novel findings indicate that VWF is expressed by a variety of tumor cells of nonendothelial origin. Critically, tumor cells that exhibit de novo acquired VWF expression demonstrate enhanced binding to endothelial cells (EC) and platelets, and increased extravasation through EC barriers. Furthermore, in vitro studies have shown that VWF can bind a variety of different tumor cells mediated by specific receptors expressed on the tumor cell surface. The concept that VWF is important in modulating tumor metastasis is further supported by in vivo experiments demonstrating that antibody-mediated VWF inhibition significantly attenuated murine metastasis. Intriguingly, however, VWF binding to specific human tumor cell lines results in apoptosis. In this study, the authors provide an overview of recent advances supporting a role for VWF in regulating multiple aspects of cancer cell biology. PMID- 29165743 TI - Patellofemoral Cartilage Restoration: Indications, Techniques, and Outcomes. PMID- 29165742 TI - Calculation of HAS-BLED Score Is Useful for Early Identification of Venous Thromboembolism Patients at High Risk for Major Bleeding Events: A Prospective Outpatients Cohort Study. AB - The aim of this study was prospective evaluation of the performance of the HAS BLED score in predicting major bleeding complications in a real-world outpatient cohort, during long-term anticoagulation for venous thromboembolism (VTE), treated with a broad spectrum of anticoagulants. We analyzed 111 outpatients objectively diagnosed with VTE and treated long-term with various anticoagulants. Patients were grouped in three cohorts based on the anticoagulant regimen. Calculation of the HAS-BLED score and documentation of bleeding events were performed every 6 months for 1 year. Patients with a HAS-BLED score >= 3 had an increased risk for major bleeding events (odds ratio [OR]: 13.05, 95% confidence interval [CI]: 0.96-692.58, p = 0.028) and a trend to higher risk for minor bleeding events as well (OR: 2.25, 95% CI: 0.87-5.85, p = 0.091) when compared with patients with a HAS-BLED score < 3.This indicates that a HAS-BLED score >= 3 allows for identification of patients with VTE on long-term anticoagulation at an increased risk for major bleeding events, irrespective of the anticoagulant agent used. PMID- 29165744 TI - Hypothermia Therapy after Traumatic Brain Injury: A Systematic Review and Meta Analysis. AB - : The purpose of this article was mainly focus on in patients with TBI, does or not hypothermia improved mortality and/or chance of good neurologic outcome compared with standard of care alone. We performed a comprehensive search strategy. Articles were eliminated in a stepwise fashion. Data from each study was entered in Review Manager (RevMan) software version 5.0 when reported. 7 studies, including 1331 patients confirmed to all selection criteria and were identified. This meta-analysis got all data of 7 articles together to come to a conclusion, besides that, it also carried on a detailed analysis of different classification, trying to outline the possible mechanism. We included two Chinese articles, tried to find out the effects of hypothermia on Asian race. For the poor outcome of hypothermia on diffuse lesions, we also analyzed the mechanism and gave our speculation. Children with traumatic brain injury were also analyzed the effect of hypothermia treatment and the possible cause of the poor outcome. The results of these clinical trials were heterogeneity. CONCLUSIONS: The hypothermia treatment on TBI seems had good outcomes on focal lesions, adult patients, Asian patients and at a relatively higher temperature (33-36C). PMID- 29165745 TI - Supratentorial embryonal tumors in elderly: diagnostic pitfalls and clinical prognosis. AB - Supratentorial embryonal tumours are very rare malignant tumours of neuroectodermal origin, characterized by an aggressive clinical behavior. They occur prevalently in children. They have been sporadically described in adults and represent an even rarer occurrence in elderly patients, raising many issues on the diagnostic pitfalls and their appropriate management. We present an unusual case of embryonal tumor in a 62-year-old man who presented with speech disorder, left IIIrd and Vth cranial nerves partial deficit secondary to a left temporo-insular embryonal tumour: clinico-radiological features, histopathological insights, therapeutic options and results are discussed along with a review of the most relevant literature, addressing the specific issue of differential diagnosis and the expected results in the elderly population. PMID- 29165746 TI - Computed Tomographic Localization of the Central Sulcus: A Morphometric Study in Adult Patients. AB - AIM: To accurately describe the relations between the anatomical landmarks of the cranial convexity and the main cortical structures. MATERIAL AND METHODS: A retrospective cross-sectional, observational study was performed. Computed tomography scans of 71 adult patients with no pathological imaging were analyzed. The position of the bregma and the central sulcus was determined. The distances from bregma to the pre-central and post-central sulci were calculated. The relationships from the nasion and glabella to cortical structures were also assessed. RESULTS: The mean distances between the bregma and the pre-central, central and post-central sulci were 26.8 +/- 7.2; 47.8 +/- 5.9 and 60.6 +/- 5.7 mm, respectively, without gender discrepancy. The mean distance nasion-bregma and the nasion-related measures showed significant differences among sexes. CONCLUSION: The central sulcus was located accurately, on average 47.8 mm behind the bregma, which should be used instead of nasion in order to avoid gender discrepancy. The data obtained provide useful and reliable information to guide neurosurgical procedures. PMID- 29165747 TI - The Effect of Rosmarinus Officinalis and Chemotherapeutic Etoposide on Glioblastoma (U87 MG) Cell Culture. AB - AIM: To investigate whether high dose toxicities of etoposide can be overcome when used in combination with a natural compound named Rosmarinus Officinalis for glioblastoma (GBM). MATERIAL AND METHODS: The impact of Rosmarinus Officinalis in combination with etoposide on GBM U87 MG cells and Mouse Embryonic Fibroblast (MEF) cells was investigated. Both neutral red and 3-(4, 5-Dimethylthiazol-2-Yl) 2, 5-Diphenyltetrazolium Bromide (MTT) assays were employed to gauge cell viability. RESULTS: We observed that increased quantities of Rosmarinus Officinalis induced MEF cell proliferation while it inhibited the survival of GBM cells. Our results indicate that Rosmarinus Officinalis did not affect the cytotoxicity of etoposide on GBM cell cultures. In contrast, in the MEF cell cultures, Rosmarinus Officinalis induced proliferation and diminished the impact of etoposide. CONCLUSION: Rosmarinus Officinalis offers hope for developing new cancer treatment strategies. However, further studies are needed to verify these results. PMID- 29165748 TI - Orbital arteriovenous fistula around the optic nerve treated by transvenous embolization. AB - (Background) Intraorbital arteriovenous fistula is a very rare disease, therefore an optimal treatment strategy has not yet been established. Here we describe the use of high-resolution cone-beam CT (CBCT) and selective angiography to visualize the detailed anatomy of orbital vessels. The information provided by the intra operative imaging led to a change in treatment strategy and eventually to successful transvenous coil embolization. (Clinical presentation) A 55-year-old man presented with right exophthalmos, chemosis and diplopia 4 months previously. Magnetic resonance (MR) imaging demonstrated a dilated superior orbital vein. Cerebral angiography showed an intraorbital arteriovenous fistula fed by the branch of the ophthalmic artery and drainage to the superior orbital vein (SOV) and inferior orbital vein (IOV). Super-selective angiography and high-resolution CBCT with diluted contrast medium clarified that feeders of the AV fistula came from the first segment of the ophthalmic artery, and the shunt located surrounding an optic nerve sheath. Transvenous embolization via IOV with coils occluded the AV fistula. (Conclusion) Detailed analysis of intraorbital vessels using high-resolution CBCT and selective angiography led to successful treatment by transvenous coil embolization. PMID- 29165749 TI - Analysis of the Factors Affecting Surgical Site Infection and Bone Flap Resorption after Cranioplasty with Autologous Cryopreserved Bone: The Importance of Temporalis Muscle Preservation. AB - AIM: To investigate the outcomes and associated complications after delayed cranioplasty using autologous, cryopreserved bone. MATERIAL AND METHODS: This retrospective study included 57 consecutive patients treated with cranioplasty with autologous cryopreserved bone for various conditions causing increased intracranial pressure due to brain swelling. The incidence and risk factor of surgical site infection (SSI) and bone flap resorption were analyzed. RESULTS: The SSI rate was 12.3% and the bone flap resorption rate was 24.0%. There were statistically significant differences in SSI rate in relation to time from craniectomy to cranioplasty (p=0.002) and previous temporalis muscle resection (p=0.021). These factors were also independently associated with surgical site infection (time from craniectomy to cranioplasty: OR 0.901, 95% CI 0.826?0.982, p=0.018; previous temporalis muscle resection: OR 11.607, 95% CI 1.155?116.590, p=0.037). There was also a statistically significant difference in the bone flap resorption rate in relation to previous temporalis muscle resection (p=0.001). This factor was associated with bone flap resorption (OR 11.667, 95% CI 2.276?59.798, p=0.003). CONCLUSION: The risk of these complications particularly increased after previous temporalis muscle resection. Based on this finding, we believe that preservation of the temporalis muscle may help to decrease postoperative complications after autologous cranioplasty. PMID- 29165750 TI - Our experience in the management of CSF otorrhea: A transmastoid approach with middle ear cavity obliteration and a middle cranial fossa approach. AB - In this report, we present two cases of patients with cerebrospinal fluid (CSF) otorrhea who underwent surgical repair through either a transmastoid or middle cranial fossa approach. In our first case, a 34-year-old male after head trauma with conductive hearing loss and a House-Brackmann grade 2 facial palsy was found to have a soft tissue mass protruding through his right tympanic membrane. Radiological examination revealed a wide tegmen tympani defect. He underwent surgery via a transmastoid approach with repair of the defect and blind sac closure of the external auditory canal after middle ear cavity obliteration. Our second case involved a 50-year-old female who had developed chronic clear otorrhea following tympanostomy tube placement. Radiological evaluation revealed a tegmen tympani defect and CSF fistula. She underwent a middle cranial fossa approach in which a multilayer closure technique was performed. These two cases illustrate that the type of surgical approach for the CSF otorrhea repair depends on the location and size of the defect and hearing status. We recommend a multilayer closure to ensure proper resolution of the defect. PMID- 29165751 TI - The application of critical pathway management to resident doctor's standardized training in pediatrics. AB - OBJECTIVE: To further guide the standardized training work of the resident doctor and apply critical pathway management to resident doctor's standardized training. MATERIALS AND METHODS: The traditional training contents were adjusted. The main research content of evaluating the results of standardized training was designed, and the research method was adopted by the standardized training of the resident doctor. RESULTS: The resident doctors of the group with the new teaching method demonstrated a high participation rate. Because of the constraint of the standardized training, trainers would pay more attention to their training. CONCLUSIONS: The clinical pathway polishes up the ability of resident doctors, further guiding the standardized training work of a resident doctor. PMID- 29165752 TI - The clinical effects of combined use of inhaled nitric oxide at early stage to cure severe respiratory failure in neonates. AB - OBJECTIVE: To observe the clinical effects of combined use of inhaled nitric oxide at the early stage to cure severe respiratory failure in neonates. PATIENTS AND METHODS: 45 cases of neonates with severe respiratory failure, who were admitted to the neonatal intensive care unit (NICU) of XuZhou Children's Hospital from November 2014 to February 2016, were selected as objects of study, namely the iNO treatment group. On the basis of conventional treatment and mechanical ventilation, all of them were treated with the combined use of iNO at the early stage. The arterial blood gas index, respiratory function index and other indexes of those children were observed before iNO treatment and 1 h, 6 h, 12 h and 24 h post-treatment. 31 cases of newborns with severe respiratory failure admitted to the NICU of the same hospital from July 2013 to August 2014 were analyzed and selected as the control group. The cases in this group met the same criteria as those administered the iNO treatment. Comparisons were made between both groups in terms of the duration of ventilator support, complications during treatment, oxygen supply time, hospital stay and other data. RESULTS: When treated after 1 h, 6 h, 12 h and 24 h, the pH value, arterial oxygen and carbon dioxide partial pressure of children in the iNO inhalation group significantly improved compared to those before treatment, and the difference was significant (p<0.05). When treated after 6, 12 and 24 h, the inspired oxygen concentration and oxygenation values of children significantly decreased compared to before treatment (p<0.05). When treated after 6, 12, and 24 h, the mean airway pressure of children was less than that before treatment and the difference was statistically significant (p<0.05). When treated after 1 h, 6, 12, 24 h, the arterial alveolar oxygen partial pressure ratio of children was greater than that before treatment and the difference was significant (p<0.05). When treated after 24 h, the pulmonary artery pressure of children significantly decreased compared to before treatment (p<0.05). Compared to the control group, the complications during the treatment, the respirator use time, oxygen supply time, length of stay and the mortality of children in the iNO treatment group were significantly decreased. CONCLUSIONS: Mechanical ventilation, combined with iNO therapy, can effectively improve the respiratory function and arterial blood gas index of neonates with severe respiratory failure, improve the oxygenation, reduce complications and improve the quality of rescue, which is worthy of promotion. PMID- 29165753 TI - Clinical research on airway intervention before tracheal extubation after general anesthesia on snoring children. AB - OBJECTIVE: To analyze the method and the effect of airway intervention before tracheal extubation in post-anesthesia cure unit (PACU) after anesthesia when removing the tonsil under general anesthesia and adenoidectomy under nasal endoscope on children with snoring. PATIENTS AND METHODS: 46 cases diagnosed as snoring were executively selected in this study. The cases were randomly divided into the control group (n = 22) and the observation group (n = 24). For airway intervention after general anesthesia during the recovery period, the control group was treated with intravenous injection of 0.5 MUg/kg remifentanil, whereas the observation group was treated with atomization inhalation of 15 mg ambroxol hydrochloride and 0.5 mg budesonide suspension. RESULTS: The clinical effects of both methods were compared and analyzed for statistical analysis. The blood pressure, heart rate and blood oxygen saturation at 30 min and 10 min after extubation in the control group was significantly more stable than those in the observation group (p < 0.05). The alertness/sedation (OAA/S) score in the observation group was significantly higher than that in the control group (p < 0.05). The prevalence rate of complications after extubation in the two groups was not statistically significant (p > 0.05). The levels of serum cortisol (Cor) and IL-8 in the control group were significantly lower than those in the observation group (p < 0.05). CONCLUSIONS: Both methods are effective for treatment of airway intervention concerned with snoring children after general anesthesia during the recovery period. The effect of remifentanil on hemodynamics is relatively huge compared with that of atomization inhalation. PMID- 29165754 TI - Current views of pediatric asthma. AB - Childhood asthma is influenced by multiple factors including genetic, socioeconomic, socio demographic and environmental factors. The symptoms of childhood asthma are observed to be variable. Some studies reported that asthma prevalence is disproportionately high among socially disadvantaged children. On the other hand, some reports found weak or no association between social disadvantage and childhood asthma. Recent literature showed that growth of health related quality of life (HRQOL) instruments in the management of childhood asthma. The present review article would discuss the current views and the latest developments in the field of pediatric asthma. PMID- 29165755 TI - Research on the correlation between the fibrinogen beta and attack of pediatric pneumonia. AB - OBJECTIVE: To investigate the correlation of the gene polymorphism of beta-148C/T of fibrinogen with the expression of fibrinogen and the attack of pediatric pneumonia. PATIENTS AND METHODS: We employed polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) to detect the gene polymorphism of beta-fibrinogen gene-148C/T (beta-148C/T). The expression level of fibrinogen in plasma was measured using enzyme-linked immunosorbent assay (ELISA), and the expression level of fibrinogen beta protein was determined using Western-blot method. RESULTS: Compared with the healthy control group, the expression level of fibrinogen beta was significantly higher in patients with pneumonia. Additionally, the frequency of CC genotype, as well as the allele of C, in the pneumonia group were significantly higher than that in the control group. Meanwhile, the frequency of TT genotype and the allele of T were remarkably lower in patients with pneumonia compared to those in the control group. No significant difference was found in comparison with the CT genotype frequency between the two groups. Compared with the patients with TT genotypes, expressions of fibrinogen, IL-6 and CRP were significantly higher in the patients with the CC and CT genotypes. However, the odds ratio (OR) of pediatric pneumonia patients with TT genotype was 0.21, OR of pediatric pneumonia patients with CT genotype was 0.77 and OR of pediatric pneumonia patients with CC genotype was 12.73. The OR of patients with T allele was 1.85 and OR of patients with C allele was 5.15. CONCLUSIONS: We concluded that beta-148C/T gene polymorphism of fibrinogen was correlated with the susceptibility of pediatric pneumonia, suggesting that it may be a genetic risk factor, and fibrinogen beta-148C/T gene may be involved in the onset of pediatric pneumonia through affecting the concentration of fibrinogen beta in plasma. PMID- 29165756 TI - The pathogenic detection for 126 children with diarrhea and drug sensitivity tests. AB - OBJECTIVE: To investigate the cause of infective diarrhea in children, special distribution of the infection and the drug sensitivity. PATIENTS AND METHODS: We carried out pathogenic detection and drug sensitivity tests for one hundred and twenty-six children with diarrhea, including 67 children in infant group (0-<1 year) and 59 children in child group (1-5 years). RESULTS: Fat particles and starch particles were seen in most stool samples under microscope; 42 kinds of pathogenic bacteria were obtained from 126 stool samples, including 10 Diarrheagenic E. coli (8 Enteropathogenic E. coli and Enteroinvasive E. coli); there were found 53 positive samples in the detection of anti-rotavirus antibody in 126 stool samples; in the drug sensitivity tests for major pathogenic bacteria, Staphylococcus aureus, Shigella, Salmonella and Diarrheagenic E. coli were highly sensitive. CONCLUSIONS: The abuse of antimicrobial agents may result in intestinal disorders, leading to aggravation in diarrhea and antimicrobial agents based on drug sensitivity tests may be served as fundamental treatment of diarrhea for children. PMID- 29165758 TI - Therapeutic strategy for multiple VSD combined with MVSD in infants and young children. AB - OBJECTIVE: To investigate the therapeutic strategy for the multiple ventricular septal defects (VSD) combined with a muscular ventricular septal defect (MVSD) in the infants and young children. PATIENTS AND METHODS: We analyzed clinical data of 63 child patients with multiple VSD who received the treatment between January 2009 and April 2013 in our hospital. There were 33 males and 30 females, the patients aged from 6 to 28 (10 +/- 6) months and weighed between 5.5 and 18.0 (7.1 +/- 2.9) kg. Primary repair was performed for all of the patients; the MVSD in 7 patients was not detected during the surgery and no extra treatment was taken. The surgical suture was performed for 36 patients, hybrid repair under the direct vision for 8 patients, and hybrid repair via the right ventricle for 7 patients. After surgery, we followed up the patients regularly to reexamine the X ray image of the chest, EEG, and color Doppler echocardiography to observe the closure of MVSD and the presence of a residual shunt. RESULTS: All of the 63 enrolled patients with multiple VSD survived without perioperative death. Three patients who were undergoing hybrid repair under direct vision received delayed sternal closure. One patient who was undergoing hybrid repair under direct vision had a postoperative cardiac dysfunction. 55 patients were followed up for 1 to 24 months. 28 patients had residual shunt of varying degrees during the follow-up, and most of the MVSD of patients with residual shunt was less than 4 mm, who were receiving further follow-up and observation. CONCLUSIONS: Appropriate surgical strategies can be applied according to the specific surgical condition for the treatment of MVSD in infants with multiple VSD, and the satisfactory clinical outcome can be achieved. PMID- 29165757 TI - Clinical effects of ascending colon patching ileorectal heart-shaped anastomosis on total colonic aganglionosis. AB - OBJECTIVE: We studied the clinical effects of ascending colon patching ileorectal heart-shaped anastomosis in treating total colonic aganglionosis. PATIENTS AND METHODS: From June 2006 to June 2013, 15 children with severe abdominal distension, low small intestine obstruction and intestinal perforation in the neonatal period, were enrolled in this study. In phase I, patients received emergency terminal ileum stoma plus multi-site colonic biopsy and 6 to 12 months later, ascending colon patching ileorectal heart-shaped anastomosis was conducted in phase II. The occurrence of postoperative complications was recorded. Patients' defecation and anal manometry during the follow-up period were monitored and recorded. All operations were successful, and the average hospitalization time was 10.5 days, and the average amount of bleeding was 30 mL. RESULTS: There were 2 cases of enterocolitis, but no intestinal anastomotic leakage, no incision infection, no anal stenosis and no mortality. Postoperative follow-up lasted for 1 to 2 years with an average of 1.2 years. Perianal redness and erosion occurred in an early stage after the operation, but disappeared after 6 months. Postoperative defecation frequency was about 6 to 9 times, but after 2 years this frequency reduced to 2 to 3 times. Feces transformed from watery into soft forms. Normal results were obtained in the detection of serum K+, Na+, Cl-, HCO3-, hemoglobin, albumin and globulin levels in postoperative follow-up. Rectal rest pressure and anal canal rest pressure after a radical operation on megacolon were significantly lower than those of before operation (p < 0.05). CONCLUSIONS: Ascending colon patching ileorectal heart-shaped anastomosis preserved right hemicolon with relatively good absorptive capability and complied with the physiology of colon. Meanwhile, the ileorectal heart-shaped anastomosis was conducted. The anastomotic stoma was in an oblique heart shape, and its aperture was wide and in different planes without stenosis, blind bag and gate syndrome. We concluded that ascending colon patching ileorectal heart-shaped anastomosis was an effective and feasible method for the radical operation on total colonic aganglionosis. PMID- 29165759 TI - Transient receptor potential melastatin 4 cation channel in pediatric heart block. AB - OBJECTIVE: Progressive cardiac conduction disease (PCCD) is a common pediatric heart conduction disorder. It is an autosomal inheritance of rare mutations, which leads to familial cases of PCCD. In these cases, the His-Purkinje system's conductive capacity is progressively deranged, involving either right or left bundle branch block. Also, QRS complexes display widening is an important characteristic that culminates in complete AV block, syncope, and sudden death. Mutations in TRPM4 gene that encodes for transient receptor potential melastatin 4 have recently been reported to cause familial cases of PCCD and heart block. TRPM4 conducts a Ca2+-activated non-selective monovalent cationic current leading to a negative plasma membrane potential. TRPM4 channels let Na+ ion influx, causing membrane depolarization, whereas, at positive membrane potentials, TRPM4 channels repolarize the membrane by facilitating K+ ion efflux from the cell. TRPM4 protein contains many regulatory motifs that confer voltage dependence, ATP/ADP sensitivity, and Ca2+ responsiveness. Mutational studies revealed the significance of the two-calmodulin binding sites at the N-terminus of for Ca2+ dependent activation of this channel. Mutations that reduce deSUMOylation increase the steady-state levels of active TRPM4 channels on the membrane without alteration of its sensitivity to Ca2+ or ATP or its voltage dependence of activation. Increased TRPM4 function interferes with cardiac conduction and eventually contributes to heart block. Both gain and loss of function mutations of TRPM4 are implicated in the cardiac block. Currently, the major therapeutic management of cardiac block due to TRPM4 mutations is implantation of a pacemaker to reinstate normal current propagation through AV node. PMID- 29165760 TI - Factors responsible for mother to child transmission (MTCT) of HIV-1 - a review. AB - Many factors have been identified to influence the risk of mother to child transmission (MTCT) of HIV. Chief amongst these is high maternal VL and advanced disease. High maternal viral load (mVL), measured at delivery, has been described as the strongest risk factor for both in utero (IU) and intrapartum (IP) transmission. Similarly, CD4+ T cell count and clinical stage of infection are also the confirmed significant predictors of transmission. Correspondingly, higher mVL in the genital tract has also been independently associated with a higher risk of MTCT of HIV-1. So, the present review article would put light on various aspects of factors responsible for MTCT of HIV in pediatric patients. PMID- 29165761 TI - Protein metabolism and exercise in children - a review. AB - General nutritional strategies to promote whole body protein retention, particularly with relation to exercise, have been largely based on adult research that does not consider the dynamic process of growth and often ignores scenarios commonly experienced by children (e.g., exercise in the heat). Therefore, the aim of the present review is to highlight the importance of post-exercise protein quantity and timing in active children, specifically with respect to the whole body protein turnover. PMID- 29165762 TI - Recent perspectives of pediatric neurodevelopmental disorders. AB - The assorted circumstances characterized by malfunctioning in cognition, communication or motor skills lead to abnormal development of the central nervous system (CNS) in young infants. These conditions are collectively termed as neurodevelopmental disorders (NDDs) and are usually diagnosed during childhood or infancy. NDDs occur as frequent as 1-3% in the general population and their diagnostic yield is approximately 15-25% with existing available techniques. So, the majority of affected patients are still undiagnosed due to genetic and phenotypic heterogeneity despite the discovery of 450 genes associated with NDDs. Chromosomal rearrangements are known contributors to NDDs, which have been routinely detected by G-banding karyotyping and fluorescence in situ hybridization at extremely low resolution. The present review was focused on the recent perspectives in the diagnosis and management of these neuropathological states in young patients. PMID- 29165763 TI - Neuropsychological intervention of minimal cognitive impairment including language deficits. AB - OBJECTIVE: Mild Cognitive Impairment (MCI) is an early dementia or discrete memory loss. The cognitive deficit in MCI impedes people's daily activities, which influences multiple aspects of thinking and acting including attention, reading, writing, reasoning, language, and judgment. This review aims to assess the outcome of various neuropsychological interventions in treating MCI. MATERIALS AND METHODS: MCI causes memory problems and is characterized by the cognitive damage that is disproportionate about individual education background and age. RESULTS: Post-mortem biopsies performed on 134 patients diagnosed with MCI showed the presence of Alzheimer's disease AD in 54.4% of all the patients, mixed pathologies in 19.4% and gross microscopic infarcts in 39.1% patients. This review was done to assess the outcome of MCI and the various neuropsychological interventions, which are being used in the treatment of MCI. These techniques were studies individually followed by their roles in treating specific cognitive deficits. CONCLUSIONS: The study focused on reviewing the literature for mainly three cognitive rehabilitation strategies: (1) rehearsal-based approaches (2) compensatory techniques (3) mnemonic strategies. In the present review, rehabilitation of language deficits in MCI is also included. PMID- 29165764 TI - Current views of depressive disorders in children - a review. AB - OBJECTIVE: Depression is one of the most debilitating worldwide mental illnesses, which is included in the Diagnostic and Statistical Manual of Mental Disorders. The main risk factors for the development of depression are female gender, early life stress family history of mood disorders, former anxiety disorders, substance abuse and life events. The present review article is focused on the various causative factors like childhood early life stress, cortisol or cortisol awakening response. The review would update readers with regards to the current view of factors responsible for pediatric depression, which in turn helps to plan better therapeutic approaches in the near future. PMID- 29165765 TI - Hypothermia in neonatal hypoxic-ischemic encephalopathy (HIE). AB - Neonatal hypoxic-ischemic encephalopathy (HIE) significantly affects neurodevelopment in infants and is also considered as an important cause of neonatal deaths worldwide. Medical research is being focused worldwide for the development of therapeutic avenues but it is still managed by supportive care. The latest studies in the above field have shown the efficacy of prolonged cooling of neonate's head or whole body at the age of 18 months (approx.) in providing relief from the pathological state of HIE. Moreover, hypothermia is the first reported therapeutic modality that proved beneficial for HIE young patients. Further, it acts by decreasing the cerebral metabolism to mitigate neurological outcomes of the pathological state. The present review article would discuss all-important aspects of hyperthermia therapy in the improvement of young patients affected by HIE. PMID- 29165766 TI - Clinical analysis of 59 children with hand foot and mouth diseases due to enterovirus EV71 and concomitant viral encephalitis. AB - OBJECTIVE: To analyzed the clinical features of children with HFMD and viral encephalitis and to summarize some treatments. PATIENTS AND METHODS: A total of 59 children with HFMD were included in this study. All children underwent complete blood count, blood biochemical test cerebrospinal fluid examination, chest X-ray and brain MRI. RESULTS: One child died 24 hours after admission due to central respiratory failure with myocardial damage. After the treatment, 58 children had normal temperature, resolved rash, normal complete blood count, biochemical blood tests and cerebrospinal fluid test, respiratory and circulatory symptoms and signs, as well as neurological symptoms, disappeared. The hospitalization time was 12-21 days. After follow-up for 1-3 months, all children were recovered, and without any severe sequelae. CONCLUSIONS: HFMD and the complicated viral encephalitis usually occurred in the children < 3 years old. The clinical manifestations were not typical. Monitoring of the child's clinical symptoms, signs and relevant examinations was required. PMID- 29165767 TI - Influence of laryngeal mask airway (LMA) insertion anesthesia on cognitive function after microsurgery in pediatric neurosurgery. AB - OBJECTIVE: To compare the influence of laryngeal mask airway (LMA) insertion anesthesia and endotracheal intubation on cognitive function during anesthesia for neurosurgery microscopy. PATIENTS AND METHODS: A total of 76 pediatric patients who underwent neurosurgery microscopy were selected. They were randomly divided in the LMA insertion group with 35 cases and the endotracheal intubation group with 41 cases. Before the operation, the two groups were injected with 0.02 mg/kg atropine and 2 mg/kg phenobarbital. A combination solution of 2 mg/kg ketamine and 0.1 mg/kg midazolam was then given to induce anesthesia. The inhalation of 4-6% sevoflurane was used to maintain anesthesia. The hemodynamics, complications, cognitive functions, and expression levels of serum NSE and S 100beta protein after anesthesia and extubation were compared. RESULTS: After comparing the average heart rate, average arterial pressure and average oxygen saturation of the LMA insertion group at different times, the difference was not statistically significant (p>0.05). At T2 and T4, compared with the endotracheal intubation group, the average heart rate and arterial pressure of the LMA insertion group were significantly reduced and the average oxygen saturation was significantly increased. The difference was statistically significant (p<0.05). The prevalence of complications from postoperative cognitive dysfunction (POCD) of the LMA insertion group was significantly lower than that of the endotracheal incubation group. The difference was statistically significant (p<0.05). CONCLUSIONS: Compared with the endotracheal intubation group, in the LMA insertion group, the hemodynamics is more stable, the prevalence of postoperative complications and the POCD are lower during pediatric neurosurgery microscopy. The occurrence of POCD is related to the reduction of protein expression levels of NSE and S-100beta during serum anesthesia and the recovery period. PMID- 29165768 TI - Recent perspectives of pediatric leukemia - an update. AB - Leukemia is defined as an aberrant hyper-proliferation of immature blood cells that do not form solid tumor masses (i.e., liquid cancer). Usually, leukemia could be either of the myeloid or lymphoid lineages, and is classified as acute or chronic in nature. Chronic leukemias tend to have more mature cells and are rare in pediatric patients. Acute leukemias, on the other hand, are typically less mature and commonly occur in patients of all ages and are potentially rapidly fatal if not readily treated. The acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Similar to AML, and in some cases, on the same disease spectrum, are the myelodysplastic syndromes (MDS). The present review is focused on the recent perspectives of pediatric leukemia. PMID- 29165769 TI - Current views of chromosomal abnormalities in pediatric acute myeloid leukemia (AML). AB - Chromosomal abnormalities are an attractive avenue for the screening of various disorders especially related to carcinogens like acute myeloid leukemia (AML). The cytogenetic findings like Karyotypic patterns are common in pediatric patients. On the other hand, monosomal karyotype (MK) and complex karyotype (CK) are more common in older patients. Further, recent studies have revealed direct proportion between the number of chromosome abnormalities and mortality rates in both pediatric as well as old patients affected by AML. Moreover, to be specific 5q, 7q and/or 17p loss lead to higher mortality rates in comparison to loss of to MK. The present review article would put light on current views of important chromosomal changes during AML, especially in pediatric patients. PMID- 29165770 TI - Current views of common pediatric cancers - an update. AB - Advancements in pediatric cancers diagnostics clarity and treatments have greatly increased survival rates in the pediatric oncology population. Increased survival rates have turned new attention to studying psychosocial stressors and improvisation of the quality of life of the suffering cancer patients. The cancer treatment experience could be divided into three phases: diagnosis, treatment, and post-treatment/survivorship. The present review article would focus specifically on the three most common pediatric cancer diagnostic categories viz. acute lymphoblastic leukemia (ALL), central nervous system (CNS) tumors, and neuroblastoma. PMID- 29165771 TI - Recent perspectives of ependymomas (childhood brain tumors). AB - Ependymomas are childhood brain tumors that occur throughout the central nervous system, but are most common in the hindbrain, also known as the posterior fossa (PF). Current standard therapy comprises maximal safe surgery, and there is no scope for further increase in survival. Despite the histological similarity, ependymomas from throughout the neuroaxis likely comprise multiple independent entities, each with a distinct molecular pathogenesis. The present review article would discuss both genetics and epigenetics of ependymomas. PMID- 29165772 TI - Pediatric protein metabolism techniques - a review. AB - Some invasive techniques could be safely and ethically applied to estimate protein metabolism in children. Although these methodologies provide valuable information on whole body protein metabolism, a reflection of what is happening to thousands of protein molecules across a variety of different tissues. However, they provide little information regarding the contribution of specific tissues and proteins to the whole-body changes observed (e.g., whether the increase in protein synthesis was a result of the muscle or splanchnic tissues) which might otherwise be determined in more invasive procedures such as those with muscle biopsies. Considering ethical constraints in pediatric research, it is not possible to perform stable isotope methods with concurrent muscle biopsies. The present review article enlightens the techniques in use for measurement of pediatric protein metabolism. PMID- 29165773 TI - Laparoscopic surgery treatment of children with appendiceal abscess. AB - OBJECTIVE: To evaluate the feasibility of treatment for children with appendiceal abscess by laparoscopic surgery and investigate its superiorities to conventional treatments. PATIENTS AND METHODS: 45 children with appendiceal abscess who were treated with laparoscopic surgery from January 2011 to July 2011 were reviewed and analyzed. The age of children ranged from 7 months to 5 years. 37 children received emergency operations, among which 8 children additionally received laparoscopic surgery. 40 children received laparotomy for treatment of appendiceal abscess, and 28 children whose condition was ameliorated after the conservative anti-inflammatory treatment received laparoscopic surgery. RESULTS: Operations of 45 children were successful, and lasted for 35 to 130 minutes with an average time of 75 minutes. There was no obvious difference in comparison of duration of laparotomy between the two groups (p > 0.05). But the laparoscopy resulted in fewer complications than the laparotomy with a statistical significance difference (p < 0.05). Moreover, the operation time for laparoscopy was shorter than that of laparotomy, but the difference in incidence rates of complications after the operation had no statistical significance (p > 0.05). The overall length of stay was apparently prolonged in two groups with a statistically significant difference (p < 0.05). CONCLUSIONS: If the operation and perioperative period are handled properly, treating children with appendiceal abscess by laparoscopic surgery is safe and feasible. PMID- 29165774 TI - Hypospadias in male infants - a review. AB - The external genitalia problems are cumbersome problems for both doctors and parents, as these abnormalities have a consequent impact on future generations. However, the affected young infants are unaware of the consequences due to immature emotional state. Further, the feeling of being different and inferior in affected young patients could give rise to negative emotions including depression, insecurity, anxiety, powerlessness, etc. These all factors collectively could cause a mental imbalance in the affected children. The present review article is focused on the latest updates in the area. PMID- 29165776 TI - Model-driven gas exchange monitoring in the critically ill. AB - Understanding pulmonary gas exchange performance is a dynamic process which, depending on clinical context, exhibits different levels of complexity. Global tools such as tension-based indexes yield clinically crucial information under very specific conditions. Yet, accurate mechanistic insight can only originate in model-based tools. One-parameter models such as shunt or dead space are well established in clinical practice whilst two or three-parameter models have just been advanced and their role is yet to be delineated. Although the latter provide superior accuracy, this comes at the cost of increased complexity and possibly the need for invasive data sets. Modelling gas exchange enables a quantitative and physiologically-driven management of patients with lung failure. Assumptions are inherent to each tool and can clinically mislead if not accounted for. Thorough understanding of their subjacent theoretical construct is a prerequisite for their judicious use. This manuscript aims to describe current gas exchange monitoring tools, with special reference to their mathematical framework and constituent pitfalls. A unifying perspective on their clinical role is proposed. PMID- 29165775 TI - Re-operative abdominal predictive score: a prognostic model combining Acute Re intervention Predictive Index and intra-abdominal pressure. AB - BACKGROUND: The decision to re-operate after abdominal surgery is still difficult, especially in the setting of intraabdominal sepsis. Mathematical models provide a good aid to both diagnosis and decision-making. METHODS: A prospective observational study was conducted with 300 patients consecutively admitted to the intensive care unit of an academic institution affiliated to Calixto Garcia Medical Faculty following abdominal surgery from January 2008 to January 2010. The patients were randomly separated (2:1) into estimation and validation groups. Logistic regression analysis was used in the estimation group to develop three models for decision-making related to re-operation including related factors such as age, ARPI, IAP, type of surgery (elective or emergency), and the duration of surgery. The three models developed were validated on the other group. RESULTS: The acute re-operation predictive index-intra-abdominal pressure (ARPI-IAP) model was the best of the three models, with an excellent calibration, using the Hossmer-Lemeshow goodness-of-fit statistical test (C = 9.976, P = 0.267), as well as discrimination (AUC = 0.989; 95% CI: 0.976-1.000). CONCLUSION: The combination of IAP with ARPI in a mathematical model can add accuracy to the prediction of need for re-operation related to intra-abdominal infectious complications in patients following abdominal surgery. This may be useful in all medical settings, but especially those with limited resources. PMID- 29165777 TI - The use of crystalloids in traumatic brain injury. AB - Fluid therapy is one of the most important treatments in patients with traumatic brain injury (TBI) as both hypo- and hypervolaemia can cause harm. The main goals of fluid therapy for patients with TBI are to optimize cerebral perfusion and to maintain adequate cerebral oxygenation. The avoidance of cerebral oedema is clearly essential. The current weight of evidence in the published literature suggests that albumin therapy is harmful and plasma substitutes have failed to demonstrate superiority over crystalloids solutions. Crystalloids are the most common fluids administered in patients with TBI. However, differences in their composition may affect coagulation and plasma tonicity and acid-base homeostasis. The choice of the ideal crystalloid fluid in TBI should be made based on tonicity, type of buffer used and volume status. Hypotonic fluids buffered with substances altering blood coagulation should be avoided in clinical practice. The prescriber remains faced with choices about the tonicity and pH buffering capability of fluid therapy, which we review here. PMID- 29165778 TI - Cardiac ultrasound: a true haemodynamic monitor? AB - Cardiac ultrasound has been used in the critically ill for more than thirty years. The technology has made enormous progression with respect to image quality and quantity, various Doppler techniques, as well as connectivity, the transfer of data and offline calculations. Some consider cardiac ultrasound as the stethoscope of the Twenty-first century. The potential of eye-balling moving cardiac structures gives undeniable power to this diagnostic and monitoring tool. The main shortcoming is the discontinuous mode of monitoring and the fact that optimal information acquisition can only be obtained when one is well-trained and experienced. Cardiac ultrasound has become an indispensable tool, especially in haemodynamically unstable patients. This review summarizes some important aspects of cardiac ultrasound with use of Doppler monitoring for assessment of the three most important pillars of haemodynamics, namely cardiac preload, afterload and contractile function. PMID- 29165779 TI - Resilience to post-traumatic stress among World Trade Center survivors: A mixed methods study. AB - The purpose of this study was to identify individual characteristics, behaviors, and psychosocial factors associated with symptoms of post-traumatic stress disorder (PTSD) among World Trade Center (WTC) disaster evacuation survivors. The study utilized a mixed-method design. In-depth interviews were conducted using a prepared script. PTSD was assessed using the PTSD checklist-civilian (PCL-C; a score >= 50 indicates probable PTSD). Thematic analysis was conducted to identify factors associated with PTSD. A purposive sample of 29 WTC evacuees was recruited using a multimodal recruitment strategy. Eligibility included: history of evacuation from the WTC (Tower 1 and/or Tower 2) on September 11, 2001, and decisional capacity for informed consent. Five participants had PCL-C scores >= 50. Thematic analysis identified resiliency factors (protective for PTSD), including leadership, taking action based on "gut" feelings (to evacuate), social support (staying in a group), going on "automatic survival" mode, and previous training on emergency response. Risk factors for PTSD included lack of emergency response training, lack of sense of urgency, poor physical condition, lack of communication skills, lack of direction, peri-event physical injury, peri-event traumatic exposure (horror), and moral injury (guilt and remorse). Several modifiable factors that may confer resilience were identified. In particular, the role of emergency response training in preventing disaster-related mental illness should be explored as a possible strategy for enhancing resilience to disaster events. PMID- 29165780 TI - Twitter weather warnings: Communicating risk in 140 characters-the impact of imperative and declarative message style on weather risk perception and behavioral intentions. AB - Understanding how individuals utilize risk messages is important for protecting lives and gaining compliance toward safe behaviors. Recent advances in technology afford users with timeliness when needing to acquire information, and research investigating imperative and declarative message styles suggests utilizing both strategies is most effective. Similarly, the element of time can play a role when an individual engages in certain behaviors. This study employed an experimental design to better understand how imperative and declarative tweets, and time can contribute to risk perceptions and behavioral intentions. Results indicate the most negative affect is experienced after receiving an imperative-only tweet in a short-lead time condition, whereas a tweet utilizing both message styles in a long-lead time condition induces the most fear. Future research should investigate stylistic message elements on new media platforms to better understand how messages can be effectively sent and received by the intended audience within character-limited platforms. PMID- 29165781 TI - Controlling disasters: Local emergency management perceptions about Federal Emergency Management and Homeland Security actions after September 11, 2001. AB - This article examines local emergency manager's beliefs regarding control over tasks during various stages of the hazard cycle since federal policies went into effect following the September 11 attacks. The study considers whether a disparity exists between the actions of local officials during each phase of the "hazard cycle" and the policy expectations of the federal government, which call for greater federal control over activities in emergency management and homeland security. To do so, hypothesis testing investigates the jurisdiction's use of comprehensive emergency management (CEM) practices, the perceived "clarity" of the federal policy demands, and if the local actors feel coerced to comply with federal policy demands so that grant funding is not compromised. Using a model developed from "third-generation" policy implementation research, the results show that the odds of local officials citing federal control over these actions have very limited statistical significance. This signals that the perceived lack of local input into the development of these federal policies and the policies' limited use of traditional CEM measures may not be in concert with what local actors perform in the field. Simply put, the respondents claim to understand the federal policy demands, support the concept of federal control as the policies describe, yet follow their own plans or traditional CEM principles, even if such actions do not support the federal policy demands. These results align with pre existing research in the emergency management field that show issues with efforts to centralize policies under the Department of Homeland Security and Federal Emergency Management Agency. PMID- 29165782 TI - Rescue workers and trauma: Assessing interaction among risk factors after a firework factory explosion. AB - INTRODUCTION: This study investigates which factors had the biggest impact on developing distress in rescue workers who were involved in a firework factory explosion. METHOD: Four hundred sixty-five rescuers were assessed using items investigating demographic factors, organizational variables, social support, personality variables, and distress symptoms. Correlation and regression analyses were performed. RESULTS: Our final model provided 70 percent of the predictive model for post-traumatic stress disorder (PTSD) severity. Waiting time, lack of rest, problems at work, and perceived level of danger seemed to have the highest impact on protective factors. DISCUSSION: In addition to perceived life danger and personality, small organizational factors seem to play an important role in the prediction of PTSD. The importance of such factors needs further investigation in future research, contributing to a better organization in the field of disaster management. PMID- 29165783 TI - After-action review of the 2009-10 H1N1 Influenza Outbreak Response: Ohio's Public Health System's performance. AB - OBJECTIVE: In early 2009, H1N1 influenza was identified within the human population. Centers for Disease Control and Prevention (CDC) officials responded with focused assessment, policy development, and assurances. The response was mobilized through efforts including procurement of adequate vaccine supply, local area span of control, materials acquisition, and facilities and resource identification. METHODS: Qualitative evaluation of the assurance functions specific to the system's ability to assure safe and healthy conditions are reported. The methodology mirrors the Homeland Security Exercise and Evaluation Program used to assess system capability. RESULTS: Findings demonstrate the effectiveness of community responsive disease prevention efforts in partnership with the public health systems mission to unify traditional public sector systems, for-profit systems, and local area systems was accomplished. As a result of this response pharmaceutical industries, healthcare providers, healthcare agencies, police/safety, colleges, and health and human service agencies were united. CONCLUSIONS: Findings demonstrate the effectiveness of community response strategies utilizing feedback from system stakeholders. After-action review processes are critical in all-hazards preparedness. This analysis of local health district response to the H1N1 influenza outbreak informs future public health service delivery. Results provide a synthesis of local health department's emergency response strategies, challenges encountered, and future-focused emergency response strategy implementation. A synthesis is provided as to policy and practice developments which have emerged over the past seven years with regard to lessons learned from the 2009-10 H1N1 influenza outbreak and response. PMID- 29165784 TI - Interventions for managing skeletal muscle spasticity following traumatic brain injury. AB - BACKGROUND: Skeletal muscle spasticity is a major physical complication resulting from traumatic brain injury (TBI), which can lead to muscle contracture, joint stiffness, reduced range of movement, broken skin and pain. Treatments for spasticity include a range of pharmacological and non-pharmacological interventions, often used in combination. Management of spasticity following TBI varies from other clinical populations because of the added complexity of behavioural and cognitive issues associated with TBI. OBJECTIVES: To assess the effects of interventions for managing skeletal muscle spasticity in people with TBI. SEARCH METHODS: In June 2017, we searched key databases including the Cochrane Injuries Group Specialised Register, CENTRAL, MEDLINE (Ovid), Embase (Ovid) and others, in addition to clinical trials registries and the reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross-over RCTs evaluating any intervention for the management of spasticity in TBI. Only studies where at least 50% of participants had a TBI (or for whom separate data for participants with TBI were available) were included. The primary outcomes were spasticity and adverse effects. Secondary outcome measures were classified according to the World Health Organization International Classification of Functioning, Disability and Health including body functions (sensory, pain, neuromusculoskeletal and movement-related functions) and activities and participation (general tasks and demands; mobility; self-care; domestic life; major life areas; community, social and civic life). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Data were synthesised narratively; meta-analysis was precluded due to the paucity and heterogeneity of data. MAIN RESULTS: We included nine studies in this review which involved 134 participants with TBI. Only five studies reported between-group differences, yielding outcome data for 105 participants with TBI. These five studies assessed the effects of a range of pharmacological (baclofen, botulinum toxin A) and non-pharmacological (casting, physiotherapy, splints, tilt table standing and electrical stimulation) interventions, often in combination. The studies which tested the effect of baclofen and tizanidine did not report their results adequately. Where outcome data were available, spasticity and adverse events were reported, in addition to some secondary outcome measures.Of the five studies with results, three were funded by governments, charities or health services and two were funded by a pharmaceutical or medical technology company. The four studies without useable results were funded by pharmaceutical or medical technology companies.It was difficult to draw conclusions about the effectiveness of these interventions due to poor reporting, small study size and the fact that participants with TBI were usually only a proportion of the overall total. Meta-analysis was not feasible due to the paucity of data and heterogeneity of interventions and comparator groups. Some studies concluded that the intervention they tested had beneficial effects on spasticity, and others found no difference between certain treatments. The most common adverse event was minor skin damage in people who received casting. We believe it would be misleading to provide any further description of study results given the quality of the evidence was very low for all outcomes. AUTHORS' CONCLUSIONS: The very low quality and limited amount of evidence about the management of spasticity in people with TBI means that we are uncertain about the effectiveness or harms of these interventions. Well-designed and adequately powered studies using functional outcome measures to test the interventions used in clinical practice are needed. PMID- 29165785 TI - Genomic profiles of nasopharyngeal carcinoma: The importance of histological subtyping and Epstein-Barr virus in situ assays. PMID- 29165786 TI - Square Pegs; Round Holes: Our Healthcare System Is Failing Seriously Ill Older Americans in Their Last Years. PMID- 29165787 TI - Reply to Genomic profiles of nasopharyngeal carcinoma: The importance of histological subtyping and Epstein-Barr virus in situ assays. PMID- 29165788 TI - Factors affecting compliance with confirmatory colonoscopy after a positive fecal immunochemical test in a national colorectal screening program. AB - BACKGROUND: Screening with the fecal immunochemical test (FIT) is effective in reducing deaths from colorectal cancer (CRC). Since 2004, biennial FIT screening has been available to a target population in Taiwan as a national screening program. The objective of the current study was to identify the factors that influence willingness to undergo a confirmatory colonoscopy after a positive FIT, because related references in the published literature were scarce. METHODS: A semistructured questionnaire was based on the Health Belief Model (HBM) and a literature review. A stratified, random sampling method was used to recruit participants who had a positive FIT from all cities/counties in Taiwan. Cross sectional, computer-assisted telephone interviews were conducted in 2012, and the results were analyzed using a logistic regression model that took into account population demographics, core content of the HBM, and HBM-modifying variables. RESULTS: In total, 2807 respondents were included in the analysis. The completion rate was 50%. Multivariate analyses revealed that higher perceived threat (adjusted odds ratio [aOR], 1.62; 95% confidence interval [CI], 1.31-2.01), higher cues for action (aOR, 2.18; 95% CI, 1.68-1.82), lower perceived barriers (aOR, 0.42; 95% CI, 0.34-0.42) and higher health behavior scores (aOR, 1.30; 95% CI, 1.05-1.60) were associated with a greater willingness to participate in confirmatory colonoscopy. Participants who were older (aOR, 0.74; 95% CI, 0.55 0.98) or unmarried (aOR, 0.72; 95% CI, 0.56-0.92) were less likely to participate in verification. CONCLUSIONS: The government could improve the screening rate by training case managers to assist in following patients until they complete colonoscopy, subsidizing sedated colonoscopies, and providing health education not only to the general public but also to physicians. Cancer 2018;124:907-15. (c) 2017 American Cancer Society. PMID- 29165789 TI - Medicaid Cost Savings of a Preventive Home Visit Program for Disabled Older Adults. AB - BACKGROUND/OBJECTIVES: Little is known about cost savings of programs that reduce disability in older adults. The objective was to determine whether the Community Aging in Place, Advancing Better Living for Elders (CAPABLE) program saves Medicaid more money than it costs to provide. DESIGN: Single-arm clinical trial (N = 204) with a comparison group of individuals (N = 2,013) dually eligible for Medicaid and Medicare matched on baseline geographic and demographic characteristics, chronic conditions, and healthcare use. We used finite mixture model regression estimates in a Markov model. SETTING: Baltimore, MD PARTICIPANTS: Individuals aged 65 and older with reported difficulty with at least one activity of daily living. INTERVENTION: CAPABLE is a 5-month program to reduce the health effects of impaired physical function in low-income older adults by addressing individual capacity and the home environment. CAPABLE uses an interprofessional team (occupational therapist, registered nurse, handyman) to help older adults attain self-identified functional goals. MEASUREMENTS: Monthly average Medicaid expenditure and likelihood of high- or low-cost use of eight healthcare service categories. RESULTS: Average Medicaid spending per CAPABLE participant was $867 less per month than that of their matched comparison counterparts (observation period average 17 months, range 1-31 months). The largest differential reduction in expenditures were for inpatient care and long term services and supports. CONCLUSION: CAPABLE is associated with lower likelihood of inpatient and long-term service use and lower overall Medicaid spending. The magnitude of reduced Medicaid spending could pay for CAPABLE delivery and provide further Medicaid program savings due to averted services use. CLINICAL TRIAL REGISTRATION: CAPABLE for Frail dually eligible older adults NCT01743495 https://clinicaltrials.gov/ct2/show/NCT01743495. PMID- 29165791 TI - Targeting Function at Home in Older Adults: How to Promote and Disseminate Promising Models of Care? PMID- 29165792 TI - Cover Image, Volume 115, Number 1, January 2018. AB - Cover Legend: The cover image, by Catherine B. Matthews et al., is based on the Article Development of a general defined medium for Pichia pastoris, DOI 10.1002/bit.26440. PMID- 29165790 TI - Physician interpretation of genomic test results and treatment selection. AB - BACKGROUND: Genomic testing is increasingly performed in oncology, but concerns remain regarding the clinician's ability to interpret results. In the current study, the authors sought to determine the agreement between physicians and genomic annotators from the Precision Oncology Decision Support (PODS) team at The University of Texas MD Anderson Cancer Center in Houston regarding actionability and the clinical use of test results. METHODS: On a prospective protocol, patients underwent clinical genomic testing for hotspot mutations in 46 or 50 genes. Six months after sequencing, physicians received questionnaires for patients who demonstrated a variant in an actionable gene, investigating their perceptions regarding the actionability of alterations and clinical use of these findings. Genomic annotators independently classified these variants as actionable, potentially actionable, unknown, or not actionable. RESULTS: Physicians completed 250 of 288 questionnaires (87% response rate). Physicians considered 168 of 250 patients (67%) as having an actionable alteration; of these, 165 patients (98%) were considered to have an actionable alteration by the PODS team and 3 were of unknown significance. Physicians were aware of genotype matched therapy available for 119 patients (71%) and 48 of these 119 patients (40%) received matched therapy. Approximately 46% of patients in whom physicians regarded alterations as not actionable (36 of 79 patients) were classified as having an actionable/potentially actionable mutation by the PODS team. However, many of these were only theoretically actionable due to limited trials and/or therapies (eg, KRAS). CONCLUSIONS: Physicians are aware of recurrent mutations in actionable genes on "hotspot" panels. As larger genomic panels are used, there may be a growing need for annotation of actionability. Decision support to increase awareness of genomically relevant trials and novel treatment options for recurrent mutations (eg, KRAS) also are needed. Cancer 2018;124:966-72. (c) 2017 American Cancer Society. PMID- 29165793 TI - Risk of preterm birth in women with cervical intraepithelial neoplasia grade one: a population-based cohort study. AB - INTRODUCTION: In this population-based register study our objective was to explore the association of cervical intraepithelial neoplasia, grade 1 and loop electrosurcigal excision procedure with preterm birth. MATERIAL AND METHODS: Our population consisted of 4759 women diagnosed with cervical intraepithelial neoplasia, grade 1 during 1997-2009 and their 3021 subsequent deliveries analyzed by loop electrosurcigal excision procedure and parity. Hospital Discharge Register was used to identify women diagnosed for cervical intraepithelial neoplasia, grade 1 and these data were linked with the Medical Birth Register data. We calculated odds ratios with 95% confidence intervals. RESULTS: Cervical intraepithelial neoplasia, grade 1 patients with loop electrosurcigal excision procedure had 54 (6.7%) subsequent preterm births and the corresponding figure among cervical intraepithelial neoplasia, grade 1 patients without loop electrosurcigal excision procedure was 116 (5.2%). This results in odds ratios 1.31 (95% confidence interval 0.94-1.83). We assessed the risk before and after diagnosis of cervical intraepithelial neoplasia, grade 1 both for patients with loop electrosurcigal excision procedure (odds ratios 1.47, 95% confidence interval 1.05-2.06) and without loop electrosurcigal excision procedure (odds ratios 0.90, 95% confidence interval 0.71-1.13). An increased risk for preterm birth after diagnosis of cervical intraepithelial neoplasia, grade 1 and loop electrosurcigal excision procedure was observed. We also compared both groups to the background population in the Medical Birth Register. For cervical intraepithelial neoplasia, grade 1 patients without loop electrosurcigal excision procedure the risk for preterm birth was not increased (odds ratios 0.95, 95% confidence interval 0.76-1.21) whereas for cervical intraepithelial neoplasia, grade 1 patients treated with loop electrosurcigal excision procedure the risk for preterm birth was increased (odds ratios 1.45, 95% confidence interval 1.02 1.92). CONCLUSIONS: Loop electrosurcigal excision procedure itself increases the risk for preterm birth. Cervical intraepithelial neoplasia, grade 1 as such does not increase the risk for preterm birth. PMID- 29165794 TI - Leptomeningeal metastasis from systemic cancer: Review and update on management. AB - Leptomeningeal metastasis is an uncommon and typically late complication of cancer with a poor prognosis and limited treatment options. Diagnosis is often challenging, with nonspecific presenting symptoms ranging from headache and confusion to focal neurologic deficits, such as cranial nerve palsies. Standard diagnostic evaluation involves a neurologic examination, magnetic resonance imaging of the brain and spine with gadolinium, and cytologic evaluation of the cerebral spinal fluid. Therapy entails a multimodal approach focused on palliation with surgery, radiation, and/or chemotherapy, which may be administered systemically or directly into the cerebral spinal fluid. Limited trial data exist to guide treatment, and current regimens are based primarily on expert opinion. Although newer targeted and immunotherapeutic agents are under investigation and have shown promise, an improved understanding of the biology of leptomeningeal metastasis and treatment resistance as well as additional randomized controlled studies are needed to guide the optimal treatment of this devastating disease. Cancer 2018;124:21-35. (c) 2017 American Cancer Society. PMID- 29165795 TI - Therapeutic potency of mTOR signaling pharmacological inhibitors in the treatment of proinflammatory diseases, current status, and perspectives. AB - Mammalian target of rapamycin (mTOR) signaling pathway controls cell energy metabolism. There is an interplay between mTOR and proinflammatory signaling pathways, supporting the role of the pathway in the pathogenesis of inflammatory diseases. Inhibition of mTOR signaling using specific pharmacological inhibitors could offer therapeutic promise in several inflammatory-associated diseases. In this review, we summarize recent findings on the regulatory effects of mTOR signaling on inflammation and the therapeutic potency of mTOR pharmacological inhibitors in the treatment of inflammatory diseases including cancer, neurodegenerative diseases, atherosclerosis, sepsis, and rheumatoid arthritis for a better understanding and hence a better management of these diseases. PMID- 29165796 TI - International Bullous Diseases Group: consensus on diagnostic criteria for epidermolysis bullosa acquisita. AB - BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a complex autoimmune bullous disease disease with variable clinical presentations and multiple possible diagnostic tests, making an international consensus on the diagnosis of EBA essential. OBJECTIVES: To obtain an international consensus on the clinical and diagnostic criteria for EBA. METHODS: The International Bullous Diseases Group (IBDG) met three times to discuss the clinical and diagnostic criteria for EBA. For the final voting exercise, 22 experts from 14 different countries voted on 50 different items. When > 30% disagreed with a proposal, a discussion was held and re-voting carried out. RESULTS: In total, 48 of 50 proposals achieved consensus after discussion. This included nine diagnostic criteria, which are summarized in a flow chart. The IBDG was unable to determine one procedure that would be applicable worldwide. A limitation of the study is that differential diagnosis of bullous systemic lupus erythematosus has not been addressed. CONCLUSIONS: This first international consensus conference established generally agreed-upon clinical and laboratory criteria defining the clinical classification of and diagnostic testing for EBA. Holding these voting exercises in person with the possibility of discussion prior to voting has advantages in reaching consensus over Delphi exercises with remote voting. PMID- 29165797 TI - The Reply to the letter on the cost-effectiveness of human papillomavirus in Punjab further distorts the scientific record. PMID- 29165799 TI - Congenital unilateral reticulate keratotic papules on the lower extremity. PMID- 29165800 TI - Generic Versions of Narrow Therapeutic Index Drugs: A National Survey of Pharmacists' Substitution Beliefs and Practices. AB - Small changes in bioavailability of narrow therapeutic index (NTI) drugs can alter clinical outcomes, raising concern over generic NTI substitution. We surveyed pharmacists to identify their perceptions of generic NTI drugs, their frequency of performing generic NTI substitution, and predictors of this behavior. Of 710 respondents (33% response rate), 87% perceived generic NTI drugs as effective as their brand-name versions and 94% as safe. Whereas 82% almost always performed generic NTI substitution for initial prescriptions, only 60% did for refills. Pharmacists in non-chain settings (odds ratio (OR) = 2.37; 95% confidence interval (CI) = 1.40-4.02), in practice longer (per year OR = 1.04; 95% CI = 1.02-1.06), in states with affirmative patient consent laws (OR = 1.88; 95% CI = 1.06-3.32), and in states with NTI-specific substitution requirements (OR = 1.95; 95% CI = 1.16-3.26) were more likely not to substitute initial prescriptions. Education of non-chain and veteran pharmacists and elimination of affirmative patient consent and NTI-specific substitution requirements could increase generic NTI substitution. PMID- 29165801 TI - Sex and rank affect how infant rhesus macaques look at faces. AB - We investigated how differences in infant sex and mothers' dominance status affect infant rhesus macaques' (Macaca mulatta) interest in visually exploring emotional facial expressions. Thirty-eight infants were presented with animated avatars of macaque facial expressions during the first month of life. Sons of high-ranking mothers looked more at faces, especially the eye region, than sons of low-ranking mothers, but no difference in looking duration was found for daughters. Males looked significantly more at eyes than females, but this effect was reversed in infants who were reared without mothers in a primate nursery facility. In addition, in mother-infant interactions, mothers of sons were more likely to gaze at their infant's face compared to mothers of daughters. Combined with previous research indicating that rhesus macaque mothers interact differently with infants based on their own rank and infant's sex, these results support the view that social experiences shape early face preferences in rhesus macaques. PMID- 29165802 TI - Treatment of severe drug reactions by hemodialysis. AB - BACKGROUND: Extracorporeal treatments such as hemodialysis and plasma exchange are lifesaving measures in the treatment of drug poisoning. This treatment method generally is not used for severe cutaneous and systemic drug reactions. METHODS: Here, we describe three cases wherein hemodialysis therapy was instrumental in reversing the adverse drug reaction. RESULTS: In the cases of severe cutaneous drug reactions reviewed, patients presented with linear immunoglobulin A bullous dermatosis, acute generalized exanthematous pustulosis, and toxic epidermal necrolysis. Salvage treatment with hemodialysis therapy drastically influenced the course of disease, resulting in remission. CONCLUSIONS: This novel and highly effective treatment option is not considered in current algorithms for adverse drug reactions. Hence, in addition to the rarity of these reactions, the main limitation of the study is the small number of patients. Hemodialysis can substantially alter the prognosis and, in some cases, be a lifesaving treatment for patients with severe adverse cutaneous drug reaction associated with systemic toxicity. PMID- 29165803 TI - Rust-colored patches on the lower extremities: lichen aureus. PMID- 29165798 TI - Weight management and physical activity throughout the cancer care continuum. AB - Mounting evidence suggests that weight management and physical activity (PA) improve overall health and well being, and reduce the risk of morbidity and mortality among cancer survivors. Although many opportunities exist to include weight management and PA in routine cancer care, several barriers remain. This review summarizes key topics addressed in a recent National Academies of Science, Engineering, and Medicine workshop entitled, "Incorporating Weight Management and Physical Activity Throughout the Cancer Care Continuum." Discussions related to body weight and PA among cancer survivors included: 1) current knowledge and gaps related to health outcomes; 2) effective intervention approaches; 3) addressing the needs of diverse populations of cancer survivors; 4) opportunities and challenges of workforce, care coordination, and technologies for program implementation; 5) models of care; and 6) program coverage. While more discoveries are still needed for the provision of optimal weight-management and PA programs for cancer survivors, obesity and inactivity currently jeopardize their overall health and quality of life. Actionable future directions are presented for research; practice and policy changes required to assure the availability of effective, affordable, and feasible weight management; and PA services for all cancer survivors as a part of their routine cancer care. CA Cancer J Clin 2018;68:64-89. (c) 2017 American Cancer Society. PMID- 29165804 TI - Intrahepatic congenital portosystemic shunts in dogs: short- and long-term outcome of suture attenuation. AB - OBJECTIVES: To report the short- and long-term outcomes of one- or two-staged suture attenuation for complete closure of intrahepatic congenital portosystemic shunts in dogs. MATERIALS AND METHODS: Retrospective cohort study of dogs surgically treated for intrahepatic congenital portosystemic shunts between February 2000 and March 2015. Long-term follow-up was conducted by telephone conversations with the referring veterinary surgeon, owner, or both. RESULTS: In total, 55 dogs had suture attenuation of their intrahepatic congenital portosystemic shunt; 10 dogs (18.2%) tolerated complete attenuation, whilst 45 dogs (81.8%) tolerated partial attenuation. Postoperative complications occurred in 24 dogs (43.6%), and six dogs (10.9%) died. Repeat surgery was performed in 33 of 39 dogs (84.6%) that had previously undergone partial attenuation, and 27 of these (84.9%) ultimately achieved complete shunt attenuation. One dog (3.0%) died following second surgery, resulting in an overall postoperative mortality of seven of 55 (12.7%). Detailed follow-up was available for 22 dogs that were still alive at a median of 29 months after surgery (7.4 to 103.1) with a subjectively good quality of life. Of 17 dogs (82.4%), 14 with complete attenuation in one or two surgeries had an excellent outcome compared with one of five dogs (20%) with persistent shunting. CLINICAL SIGNIFICANCE: Staged suture ligation resulted in a high proportion of complete attenuation and reduced persistent shunting compared with a single surgery. Repeat surgery was associated with fewer complications than the first surgery. The proportion of dogs with an excellent outcome was greater for those that had complete attenuation in one or two surgeries compared with those with persistent shunting. PMID- 29165805 TI - Effect of Sorbitol Plasticizer on the Structure and Properties of Melt Processed Polyvinyl Alcohol Films. AB - Poly (vinyl alcohol) (PVA) possesses wide applications as food packaging materials, but is difficult to melt process for its strong inter/intra hydrogen bonding. In this work, flexible PVA films with different content of sorbitol plasticizers were prepared by melt processing with the assistance of water. And the influence of sorbitol plasticizer content on the crystallinity, optical transparency, water-retaining capability, mechanical properties, thermal stability and oxygen and water permeability were investigated. The results indicated that sorbitol dramatically improved the melt processing ability of PVA. Sorbitol could interact with PVA to form strong hydrogen bonding interactions, which would decrease the original hydrogen bonding of the matrix, resulting in the decrease of crystallinity degrees. The glass transition, melting and crystallization peak temperatures decreased with the increase of sorbitol. All the films exhibited fine optical transparency. The water retaining capability were improved with the increase of sorbitol. Especially, an increase in elongation at break and decrease in Young's modulus and tensile strength were observed indicating good plasticizing effect of sorbitol on PVA films. In addition, the PVA films prepared in this work exhibited fine barrier properties against oxygen and water, suggesting wide application potential as packaging materials. PMID- 29165806 TI - Host preference and network properties in biotrophic plant-fungal associations. AB - Analytical methods can offer insights into the structure of biological networks, but mechanisms that determine the structure of these networks remain unclear. We conducted a synthesis based on 111 previously published datasets to assess a range of ecological and evolutionary mechanisms that may influence the plant associated fungal interaction networks. We calculated the relative host effect on fungal community composition and compared nestedness and modularity among different mycorrhizal types and endophytic fungal guilds. We also assessed how plant-fungal network structure was related to host phylogeny, environmental and sampling properties. Orchid mycorrhizal fungal communities responded most strongly to host identity, but the effect of host was similar among all other fungal guilds. Community nestedness, which did not differ among fungal guilds, declined significantly with increasing mean annual precipitation on a global scale. Orchid and ericoid mycorrhizal fungal communities were more modular than ectomycorrhizal and root endophytic communities, with arbuscular mycorrhizal fungi in an intermediate position. Network properties among a broad suite of plant-associated fungi were largely comparable and generally unrelated to phylogenetic distance among hosts. Instead, network metrics were predominantly affected by sampling and matrix properties, indicating the importance of study design in properly inferring ecological patterns. PMID- 29165807 TI - Arabidopsis thaliana plants challenged with uranium reveal new insights into iron and phosphate homeostasis. AB - Uranium (U) is a naturally occurring radionuclide that is toxic to plants. It is known to interfere with phosphate nutrition and to modify the expression of iron (Fe)-responsive genes. The transporters involved in the uptake of U from the environment are unknown. Here, we addressed whether IRT1, a high-affinity Fe2+ transporter, could contribute to U uptake in Arabidopsis thaliana. An irt1 null mutant was grown hydroponically in different conditions of Fe bioavailability and phosphate supply, and challenged with uranyl. Several physiological parameters (fitness, photosynthesis) were measured to evaluate the response to U treatment. We found that IRT1 is not a major route for U uptake in our experimental conditions. However, the analysis of irt1 indicated that uranyl interferes with Fe and phosphate homeostasis at different levels. In phosphate-sufficient conditions, the absence of the cation chelator EDTA in the medium has drastic consequences on the physiology of irt1, with important symptoms of Fe deficiency in chloroplasts. These effects are counterbalanced by U, probably because the radionuclide competes with Fe for complexation with phosphate and thus releases active Fe for metabolic and biogenic processes. Our study reveals that challenging plants with U is useful to decipher the complex interplay between Fe and phosphate. PMID- 29165809 TI - Medical industry at tumor board: Three-years analysis of the open payments database and comparison of oncologic specialties. AB - BACKGROUND AND OBJECTIVES: To analyze and contrast medical industry payments across U.S. oncologic providers, including hematology-oncology (HO), surgical oncology (SO), interventional radiology (IR), and radiation oncology (RO). METHODS: Open-payment-data for each provider including provider specialty, state of practice, industry payor, reason for payment, and amount was compiled for each transaction between 2013 and 2015. Total, mean, and median payment amounts per provider were calculated for each specialty. Tukey's-method was used to identify and remove statistical outliers and Kruskal-Wallis-test with Bonferonni-post-hoc analysis was used to evaluate for differences in total payments received per provider across specialties. The percentage of providers accepting payments within each specialty were compared by Marascuilo's multiple-proportion comparison. RESULTS: Total aggregate payment amount (and number of transactions) for HO, SO, IR, and RO was $164 743 746 (778 007), $7 925 467 (15 031), $49 817 380 (44 939), and $13 643 739 (49 778), respectively. Corrected-median (and corrected-mean) payments-per-specialty were $676 ($1796), $330 ($1209), $487 ($1301), and $242 ($766). A significantly higher proportion of HO providers accepted payments than both RO (97% vs 80%, P < 0.0001) and IR (97% vs 78%, P < 0.0001). The mean total payment received per-provider differed significantly across specialties (P = 0.0001). HO providers, on average, received significantly more payment-per-provider during the study period (P < 0.001) compared to all others while RO and IR received significantly less (P < 0.0001). CONCLUSIONS: Among industry payments made to oncologic providers, HO received the highest median and corrected-mean amounts along with the highest proportion of providers receiving open payments. PMID- 29165808 TI - MdWRKY9 overexpression confers intensive dwarfing in the M26 rootstock of apple by directly inhibiting brassinosteroid synthetase MdDWF4 expression. AB - Dwarfing rootstocks enable high-density planting and are therefore highly desirable in modern apple (Malus domestica) production. M26 is a semi-dwarfing rootstock that is used worldwide, but identifying intensive dwarfing rootstock is a major goal of apple breeding programs. Herein, we show that MdWRKY9 mediates dwarfing by directly inhibiting the transcription of the brassinosteroid (BR) rate-limiting synthetase MdDWF4 and reducing BR production. We found that the transcriptional factor MdWRKY9 is highly expressed in all tested dwarfing rootstocks. Transgenic lines of M26 rootstock overexpressing MdWRKY9 exhibit further dwarfing, which resulted from the reduced BR levels and was reversed via exogenous brassinolide treatment. Both an in vivo chromatin immunoprecipitation (ChIP) analysis and an in vitro electrophoretic mobility shift assay (EMSA) indicated that MdWRKY9 binds to the promoter of MdDWF4. Furthermore, MdWRKY9 repressed MdDWF4 expression in stable transgenic apple plants as determined by quantitative PCR. In addition, RNA-interfered expression of MdWRKY9 in transiently transformed apple calli led to a significant increase of MdDWF4, suggesting MdWRKY9 plays a critical role in regulating the expression of MdDWF4. We report a novel dwarfing mechanism in perennial woody plants that involves WRKY controlled BR production, and present a new dwarfing M26 rootstock for potential applications in apple production. PMID- 29165811 TI - Synovial sarcoma of the shoulder: A series of 14 cases. AB - BACKGROUND AND OBJECTIVES: Synovial sarcoma is a rare soft tissue sarcoma with poor long-term prognosis due to late recurrence and metastasis. Synovial sarcoma arises in less than 6% from the shoulder. As a result, there is limited information in the literature about synovial sarcoma of the shoulder (SSS). METHODS: We included all patients treated for SSS at our institution between 1985 and 2013. Medical charts were retrospectively reviewed to collect demographics, information about the clinical course, and outcome. This subgroup was compared to our institution's entire synovial sarcoma patient cohort and the data in the published literature. RESULTS: SSS Patients presented most commonly with pain and a growing mass; the majority of tumors were grade 2 and measured greater than 5 cm. 43% (7) of SSS patients developed metastatic disease and 36% (5) had died at a median follow-up of 64 months (36-127); SSS 5-year survival (83.3%) was higher in our series than in the general literature (57-75%). CONCLUSIONS: We found better prognosis in patients with synovial sarcoma of the shoulder than expected based on the current literature. The clinical behavior of synovial sarcoma in the shoulder is closer to that of synovial sarcoma in the extremities than the trunk. LEVEL OF EVIDENCE: Level IV, Case Series. PMID- 29165810 TI - Insecticide susceptibility status in Mexican populations of Stegomyia aegypti (= Aedes aegypti): a nationwide assessment. AB - In Mexico, mosquito vector-borne diseases are of public health concern as a result of their impact on human morbidity and mortality. The use of insecticides against adult mosquitoes is one of the most common ways of controlling mosquito population densities. However, the use of these compounds has resulted in the development of insecticide resistance. The aim of this study was to estimate susceptibility to six pyrethroids, two carbamates and two organophosphates in Mexican populations of Stegomyia aegypti (Linnaeus, 1762) (= Aedes aegypti) (Diptera: Culicidae) mosquitoes. Bottle insecticide susceptibility tests, with 1 h exposure, were performed on adult mosquitoes from 75 localities across 28 states. At 30 min of exposure, the proportion of fallen mosquitoes was recorded. After 60 min of exposure, mosquitoes were recovered in non-treated containers and mortality was determined at 24 h after the set-up of the experiment. In general, the carbamate insecticides represented the most effective group in terms of the proportion of mosquitoes fallen at 30 min (72-100%) and 24-h mortality (97-100%). High and widespread resistance to pyrethroids Types I and II and, to a lesser extent, to organophosphates was observed. Insecticide susceptibility among and within states was highly variable. PMID- 29165812 TI - A novel and validated prognostic nomogram based on liver fibrosis and tumor burden for patients with hepatocellular carcinoma after curative resection. AB - BACKGROUND AND OBJECTIVES: Most conventional staging systems were formulated concerning the tumor burden rather than the severity of liver fibrosis, which plays a central role in tumor promotion. The aim of this study was to formulate a prognostic nomogram comprehensively considering these two aspects for HCC after hepatectomy. METHODS: The prognostic significances of the four indicators namely laminin, hyaluronic acid, human procollagen type-III, and collagen type-IV that reflect liver fibrosis were explored in two independent cohorts. A nomogram was established based on the results of multivariate analysis. The predictive accuracy of the nomogram was measured by concordance index (C-index) and calibration. The decision curve analysis (DCA) was used to evaluate the clinical benefit of the nomogram. RESULTS: Preoperative serum laminin level is an independent prognostic factor for overall survival in HCC patients after resection. The C-indices of the nomogram in the training and validation cohorts were 0.779 and 0.719, respectively. The calibration showed optimal agreement between the prediction by nomogram and actual observation. Moreover, the C indices and DCA revealed that the nomogram provided better clinical benefit compared with the BCLC stage, CLIP score, and AJCC 7th edition. CONCLUSIONS: The prognostic nomogram constructed on laminin represents a superior predictive model. PMID- 29165813 TI - Radiation therapy in retroperitoneal sarcoma management. AB - Surgery is potentially curative for primary non-metastatic retroperitoneal soft tissue sarcomas (RPS), although patients remain at risk for local recurrence. To reduce this risk, the addition of radiotherapy to radical surgery may be considered. Nevertheless, level I evidence to support radiotherapy is currently lacking. The results from the EORTC-STBSG 62092-22092 studying this question are awaited. This manuscript addresses issues to consider when radiation-oncologists engage in a multidisciplinary treatment approach for RPS patients, including radiotherapy. PMID- 29165814 TI - Reverse Effect of Opuntia ficus-indica L. Juice and Seeds Aqueous Extract on Gastric Emptying and Small-Bowel Motility in Rat. AB - This study was conducted to compare the effects of juice and seeds on gastric emptying, small-bowel motility and intestinal ion transport. Separate groups of rats were randomized to receive NaCl, increasing doses of juice (5, 10, and 20 mL/kg, b.w.) or seeds aqueous extract (100, 200, and 400 mg/kg, b.w.). Simultaneously, two other groups were received, the reference drugs; clonidine (1 mg/kg) and yohimbine (2 mg/kg). The charcoal meal was used as a suspension for gastrointestinal motility test. The purgative action of juice was confirmed using the loperamide (5 mg/kg, p.o.) induced constipation. To evaluate the antisecretory effect, we were used as a hypersecretion agent, the castor oil at the dose of 5 mL/kg. Compared to the control and standard groups, we were showed that the prickly pear has an opposite effect on small-bowel motility and gastric emptying. Indeed, the juice at various doses has a laxative effect of gastrointestinal transit in healthy and constipated-rats. However, the aqueous extract of the seeds leads to a reduction of motility in normal rats which gives it a remarkable antidiarrhoeal activity, a notable intestinal fluid accumulation decline and electrolyte concentrations reestablishment. Moreover, orally juice administered at different doses accelerated the stomach emptying time in contrast to the seeds aqueous extract. More importantly, a significant variation in the phytochemical constituents levels between juice and seeds was found. These findings confirm the reverse therapeutic effects of this fruit in the treatment of digestive disturbances such as difficulty stool evacuation and massive intestinal secretion, likewise, the gastric emptying process perturbation. PMID- 29165815 TI - Development and validation of a liquid chromatography-tandem mass spectrometry analytical method for the therapeutic drug monitoring of eight novel anticancer drugs. AB - To support therapeutic drug monitoring of patients with cancer, a fast and accurate method for simultaneous quantification of the registered anticancer drugs afatinib, axitinib, ceritinib, crizotinib, dabrafenib, enzalutamide, regorafenib and trametinib in human plasma using liquid chromatography tandem mass spectrometry was developed and validated. Human plasma samples were collected from treated patients and stored at -20 degrees C. Analytes and internal standards (stable isotopically labeled analytes) were extracted with acetonitrile. An equal amount of 10 mm NH4 CO3 was added to the supernatant to yield the final extract. A 2 MUL aliquot of this extract was injected onto a C18 column, gradient elution was applied and triple-quadrupole mass spectrometry in positive-ion mode was used for detection. All results were within the acceptance criteria of the latest US Food and Drug Administration guidance and European Medicines Agency guidelines on method validation, except for the carry-over of ceritinib and crizotinib. These were corrected for by the injection order of samples. Additional stability tests were carried out for axitinib and dabrafenib in relation to their reported photostability. In conclusion, the described method to simultaneously quantify the eight selected anticancer drugs in human plasma was successfully validated and applied for therapeutic drug monitoring in cancer patients treated with these drugs. PMID- 29165817 TI - Development of Mayonnaise with Substitution of Oil or Egg Yolk by the Addition of Chia (Salvia Hispanica L.) Mucilage. AB - : Chia mucilage is formed by the hydration of chia seeds and presents characteristics that potentiate its application as substitute of fat in several foods. In this study, mayonnaises were prepared with different levels of freeze dried chia mucilage instead of oil or egg yolk. The substitution of oil in mayonnaise promoted increased stability and texture parameters, and the mayonnaise substituted by egg yolk presented similar stability and texture parameters as the control mayonnaise. The substitution of oil in mayonnaise was about 50% with 45% oil substitution, whereas for the mayonnaise with 35% of egg yolk replacement it was about 0.94%. Sensorially, an inverse relation was found, the mayonnaises with substitution of the egg yolk that presented a smaller reduction of the lipid content, presented better sensory acceptance than the mayonnaise with substitution of the oil. Therefore, the results indicated that chia mucilage has potential to substitute part of the amount of oil in the mayonnaise formulation. As for the use of the mucilage in the substitution of the egg yolk, it is not possible to promote a significant reduction in the lipid content nor maintain emulsion stability. PRACTICAL APPLICATION: Chia mucilage presents high emulsifying hability and water-holding capacity that potentiabilize its use as a substitute for fat in various foods. Mayonnaises developed with up to 45% oil substitution by chia mucilage, presented a reduction in the lipid content by about 50%, an increasing stability and a good sensorial acceptance. PMID- 29165818 TI - Delivering quality lung cancer care in crisis-wracked Greece. PMID- 29165816 TI - Prospective phase II trial of combination hepatic artery infusion and systemic chemotherapy for unresectable colorectal liver metastases: Long term results and curative potential. AB - BACKGROUND/OBJECTIVES: Combination hepatic artery infusion (HAI) and systemic (SYS) chemotherapy for unresectable CRLM results in high tumor-response rates. This study represents an update of long-term survival and conversion to resectability in patients with unresectable CRLM treated with HAI and SYS chemotherapy in a phase II study. METHOD: The primary endpoint was complete resection. Multivariate and landmark analysis assessed the effect of complete resection on progression-free (PFS) and overall survival (OS). RESULTS: From 2007 to 2012, 64 patients with median of 13 tumors were enrolled; 67% had prior chemotherapy. 33 patients (52%) were converted to resection. Median follow-up among survivors was 81 months. Median PFS and OS were 13 and 38 months, respectively, with 5-year-OS of 36%. Chemotherapy-naive patients had 5-year-OS of 51%. Conversion to resection was the only independent factor prognostic of improved PFS and OS. Nine of 64 patients (14%) are NED (five since initial resection, three after resection of recurrent disease, one from chemotherapy alone) at median follow-up of 86 months from treatment initiation, and 72 months from last operative intervention. CONCLUSION: Combination HAI and SYS is an effective therapy for high-volume unresectable CRLM, resulting in a high rate of resection, long-term survival, and the potential for cure. PMID- 29165819 TI - Metastasectomy following incomplete response to high-dose interleukin-2. AB - OBJECTIVE: To evaluate our experience with metastasectomy following partial response or stable disease after treatment with high-dose interleukin-2 (HD IL 2). METHODS: A total of 305 patients with metastatic renal cell carcinoma or melanoma treated with HD IL-2 over a 12-year period were reviewed. Age, objective response, and overall survival data were evaluated using standard RECIST criteria and Kaplan-Meier estimates. RESULTS: The average age was 55.3 years (range, 15 85) and 245 (80.3%) patients had melanoma and 60 (19.7%) had renal cell carcinoma. The objective response rate to IL-2 for all patients was 13.6% and median survival was 16.8 months. Complete follow-up data were available for 236 patients with 147 (62.3%) progressing after treatment and 8 (3.3%) with a complete response. Incomplete responses were seen in 81 (34.3%) patients, including 57 (24.2%) patients with stable disease and 24 (10.1%) with partial responses. Of these 81 incomplete responders, 15 (18.5%) underwent subsequent metastasectomy. Patients without surgery had overall survival of 38.2 months and median survival has not yet been reached in those who underwent metastasectomy (P = 0.026). CONCLUSION: The data support prospective evaluation of metastasectomy following incomplete therapeutic responses to immunotherapy and defines a new role for surgical resection following IL-2 and perhaps other immunotherapy regimens. PMID- 29165820 TI - Nutrient limitation of terrestrial free-living nitrogen fixation. AB - Nitrogen (N) fixation by free-living bacteria is a primary N input pathway in many ecosystems and sustains global plant productivity. Uncertainty exists over the importance of N, phosphorus (P) and molybdenum (Mo) availability in controlling free-living N fixation rates. Here, we investigate the geographic occurrence and variability of nutrient constraints to free-living N fixation in the terrestrial biosphere. We compiled data from studies measuring free-living N fixation in response to N, P and Mo fertilizers. We used meta-analysis to quantitatively determine the extent to which N, P and Mo stimulate or suppress N fixation, and if environmental variables influence the degree of nutrient limitation of N fixation. Across our compiled dataset, free-living N fixation is suppressed by N fertilization and stimulated by Mo fertilization. Additionally, free-living N fixation is stimulated by P additions in tropical forests. These findings suggest that nutrient limitation is an intrinsic property of the biochemical demands of N fixation, constraining free-living N fixation in the terrestrial biosphere. These findings have implications for understanding the causes and consequences of N limitation in coupled nutrient cycles, as well as modeling and forecasting nutrient controls over carbon-climate feedbacks. PMID- 29165821 TI - Glomeromycotina: what is a species and why should we care? AB - A workshop at the recent International Conference on Mycorrhiza was focused on species recognition in Glomeromycotina and parts of their basic biology that define species. The workshop was motivated by the paradigm-shifting evidence derived from genomic data for sex and for the lack of heterokaryosis, and by published exchanges in Science that were based on different species concepts and have led to differing views of dispersal and endemism in these fungi. Although a lively discussion ensued, there was general agreement that species recognition in the group is in need of more attention, and that many basic assumptions about the biology of these important fungi including sexual or clonal reproduction, similarity or dissimilarity of nuclei within an individual, and species boundaries need to be re-examined and scrutinized with current techniques. PMID- 29165822 TI - Erratum: "iVI: An iterative vector interaction method for large eigenvalue problems" [J. Comput. Chem. 38, 2481 (2017)]. PMID- 29165823 TI - Identification of predisposing factors for osteonecrosis of the jaw after marginal mandibulectomy in the surgical management of oral squamous cell carcinoma. AB - BACKGROUND: The aim of this study is to evaluate osteonecrosis of the jaw (ONJ) with the extent of marginal mandibulectomy. METHODS: Between January 2006 and December 2012, 3087 patients undergoing ablative resection were consecutively enrolled. Among them, 345 cases undergoing marginal mandibulectomy were retrospectively reviewed. RESULTS: The occurrence of ONJ was 5.51% and associated with body mass index, overall stage, diabetes, concomitant mandibulotomy, and radiotherapy (P = 0.023, 0.033, 0.009, 0.016, and 0.006, respectively). As for bone parameters based on radiological measurements after marginal mandibulectomy, resected bone height, remaining bone height to original bone height ratio, and resected bone height to original bone height ratio were associated with ONJ. In multivariate logistic analyses, concomitant mandibulotomy, radiotherapy, diabetes, resected bone height of >14.5 mm, resected bone height to original bone height ratio of >49.5%, and remaining bone height to original bone height ratio of <53.5% indicated higher risks for ONJ (adjusted HR: 4.345, 4.152, 4.079, 3.402, 3.541, and 3.211; P = 0.018, 0.013, 0.009, 0.021, 0.018, and 0.043, respectively). CONCLUSIONS: This study demonstrated the predisposing factors and parameters associated with ONJ with marginal mandibulectomy; more caution is necessitated in performing marginal mandibulectomy in patients with multiple risks to prevent ONJ. PMID- 29165824 TI - Measurement of Social Norms Affecting Modern Contraceptive Use: A Literature Review. AB - As a critical building block to developing social norms interventions to support healthy family planning and other reproductive health behaviors, we conducted a literature review to identify and evaluate social norm measures related to modern contraceptive use. Of 174 articles reviewed in full, only 17 studies met our criteria for inclusion. Across these articles, no single measure of norms was used in more than one study; failure to specify the boundaries of who was engaging in and influencing the behaviors of interest contributed to the variation. Most of the studies relied on cross-sectional data, only included condom use as their contraceptive use outcome, used individual- or interpersonal level behavior change theories rather than social-level theories, and assumed a reference group, all of which limit the quality of the norm measures. We make several recommendations to bring greater consistency and comparability to social norm measures. PMID- 29165825 TI - Understanding the lived experiences of Parkinson's disease and deep brain stimulation (DBS) through occupational changes. AB - BACKGROUND: Deep brain stimulation (DBS), a surgically based treatment for people living with Parkinson's disease (PD), can result in a significant improvement of motor symptoms. However, the broader impact of DBS and the changes it creates are not well understood. Greater understanding of the experiences and needs related to DBS would enable development of relevant outcome measures and supports. OBJECTIVES: To explore the lived experiences of people undergoing DBS for Parkinson's disease. METHODS: A descriptive phenomenological study was undertaken exploring experiences, perspectives and outcomes with key stakeholders. Semi structured, audiotaped interviews were undertaken with people with PD who have had DBS, their family members and health professionals across four states and territories in Australia. RESULTS: Perspectives and experiences of 14 people with PD undergoing DBS, 10 family members and 11 health professionals were analysed. Occupations emerged as a key aspect throughout the DBS experience. Two major themes captured the role of occupation in relation to DBS: Occupations as a barometer, where occupational experiences and performances shaped people's understanding of their condition, the impact of treatments and their overall adjustment; and Shifting occupational identity where the life transition of DBS altered the occupational experiences of relationships, volition, roles and responsibilities of people with PD and their family members. CONCLUSION: Occupational experiences and changes served as an important way for people with PD and their families to understand and communicate their experiences of PD and related treatments. There is an identified need for outcome measures and clinical education and interventions to reflect this. PMID- 29165827 TI - Erratum. PMID- 29165826 TI - Fear of stigma: The lived experiences of Iranian women after suicide attempt. AB - BACKGROUND: Suicide attempt is the most important predictor of completed suicide. The aim of this study was to explore the lived experiences of women after suicide attempts. METHODS: This was an interpretative phenomenological study carried out through in-depth semi-structured interviews with 13 interviews. Data were analyzed using Van Manen method. RESULTS: Women of this study experienced fears of stigma. Their fears were not only related to labels of being "unbelief and mentally illness but also being involved in illicit sexual affairs." On the other hand, they were afraid of labeling "mental illness" and also "doing an unacceptable action." CONCLUSION: The women tried to hide their suicide attempts because they fear of being labeled by others. It is recommended that societies and families progress toward becoming free of stigma of suicide and suicide attempt. PMID- 29165828 TI - Nursing center-Health Intervention Program in Philadelphia: Program evaluation and outcomes. AB - BACKGROUND: The La Salle Neighborhood Nursing Center provided the Health Intervention Program (HIP) for vulnerable children with special needs, and families in Philadelphia challenged by chronic physical, developmental, behavioral, and emotional conditions and low incomes. AIMS: We evaluated the effectiveness of HIP for a 5-year period and the consistency of quarterly and annual reports as a quality improvement initiative. METHODS: Using program evaluation, secondary analysis design, the effect of a city-wide, family support home visiting program was assessed. Consistency of documentation of program outcomes on annual reports was described. Data were obtained from reports, framed by program objectives submitted via the ETO(r) database to the Department of Public Health. Components of the HIP consisted of case management, supportive services, information, and referrals provided by a multidisciplinary healthcare team. RESULTS: Family services, program outcomes, referrals, community meetings, and themes demonstrated program complexity and effectiveness. Reports showed inconsistent documentation on 19 outcomes for program objectives. CONCLUSIONS: Children with special needs and their families shared challenges and barriers to their health. The institution staff should create a table to report outcomes on program objectives to evaluate trends across funding years and establish interrater reliability on quarterly and annual reports. PMID- 29165829 TI - Simultaneous determination and method validation of clethodim and its metabolites clethodim sulfoxide and clethodim sulfone in tobacco by LC-MS/MS. AB - A simple method was developed and validated for the simultaneous determination of clethodim, clethodim sulfoxide, and clethodim sulfone in soil and tobacco by liquid chromatography with tandem mass spectrometry. The three target compounds were extracted from tobacco and soil with acetonitrile, and the extracts were purified using octadecyl silane. The proposed method showed satisfactory linearity (R2 >= 0.9973) for the target compounds. The limits of detection and quantitation of the three analytes in all matrices were 0.024-0.06 and 0.08-0.2 mg/kg, respectively. The recovery was tested in blank soil and tobacco leaf samples and calculated to be 74.8-104.4% with relative standard deviations of 1.9 12.1%. The developed method was successfully applied to the analysis of residues of clethodim, clethodim sulfoxide and clethodim sulfone in real soil and tobacco samples. The results indicated that the developed method can meet the requirements for the analysis of trace amounts of all three analytes in soil and tobacco. PMID- 29165830 TI - Possible protective mechanisms exerted by metformin or metformin and vitamin E in isoproterenol-induced cardiac injury. AB - Several studies have reported that metformin is cardioprotective for diabetic and non-diabetic ischemic hearts through mechanisms that cannot be entirely attributed to its anti-hyperglycemic effect. This study was designed to investigate the cardioprotective effects of metformin with and without vitamin E after induction myocardial infarction (MI) in rats, using isoproterenol. Administration of metformin or vitamin E significantly reduced the cardiac mass index (P < 0.01), ameliorated the changes to cardiac biomarkers, and attenuated oxidative stress levels compared to the isoproterenol group. Interestingly, combination therapy showed a slight synergistic effect. Histopathological analysis suggested that metformin treatment reduced NF-kappaB expression and protected against isoproterenol-induced MI. Our results indicate that metformin mediates a cardioprotective effect against isoproterenol-induced MI via antioxidant activity and modulation of the NF-kappaB signaling pathway. This suggests that metformin would be beneficial in MI treatment. PMID- 29165831 TI - External validation of the ITA.LI.CA prognostic system for patients with hepatocellular carcinoma: A multicenter cohort study. AB - : Several staging systems for hepatocellular carcinoma (HCC) have been developed. The Barcelona Clinic Liver Cancer staging system is considered the best in predicting survival, although limitations have emerged. Recently, the Italian Liver Cancer (ITA.LI.CA) prognostic system, integrating ITA.LI.CA tumor staging (stages 0, A, B1-3, C) with the Child-Turcotte-Pugh score, Eastern Cooperative Oncology Group performance status, and alpha-fetoprotein with a strong ability to predict survival, was proposed. The aim of our study was to provide an external validation of the ITA.LI.CA system in an independent real-life occidental cohort of HCCs. From September 2008 to April 2016, 1,508 patients with cirrhosis and incident HCC were consecutively enrolled in 27 Italian institutions. Clinical, tumor, and treatment-related variables were collected, and patients were stratified according to scores of the Barcelona Clinic Liver Cancer system, ITA.LI.CA prognostic system, Hong Kong Liver Cancer system, Cancer of the Liver Italian Program, Japanese Integrated System, and model to estimate survival in ambulatory patients with hepatocellular carcinoma. Harrell's C-index, Akaike information criterion, and likelihood-ratio test were used to compare the predictive ability of the different systems. A subgroup analysis for treatment category (curative versus palliative) was performed. Median follow-up was 44 months (interquartile range, 23-63 months), and median overall survival was 34 months (interquartile range, 13-82 months). Median age was 71 years, and patients were mainly male individuals and hepatitis C virus carriers. According to ITA.LI.CA tumor staging, 246 patients were in stage 0, 472 were in stage A, 657 were in stages B1/3, and 133 were in stage C. The ITA.LI.CA prognostic system showed the best discriminatory ability (C-index = 0.77) and monotonicity of gradients compared to other systems, and its superiority was also confirmed after stratification for treatment strategy. CONCLUSION: This is the first study that independently validated the ITA.LI.CA prognostic system in a large cohort of Western patients with incident HCCs. The ITA.LI.CA system performed better than other multidimensional prognostic systems, even after stratification by curative or palliative treatment. This new system appears to be particularly useful for predicting individual HCC prognosis in clinical practice. (Hepatology 2018;67:2215-2225). PMID- 29165832 TI - Considerations for Studying Folate Beyond the Typical Range of Exposure. PMID- 29165833 TI - Gestational Age and Child Development at Age Five in a Population-Based Cohort of Australian Aboriginal and Non-Aboriginal Children. AB - BACKGROUND: Preterm birth and developmental vulnerability are more common in Australian Aboriginal compared with non-Aboriginal children. We quantified how gestational age relates to developmental vulnerability in both populations. METHODS: Perinatal datasets were linked to the Australian Early Development Census (AEDC), which collects data on five domains, including physical, social, emotional, language/cognitive, and general knowledge/communication development. We quantified the risk of developmental vulnerability on >=1 domains at age 5, according to gestational age and Aboriginality, for 97 989 children born in New South Wales, Australia, who started school in 2009 or 2012. RESULTS: Seven thousand and seventy-nine children (7%) were Aboriginal. Compared with non Aboriginal children, Aboriginal children were more likely to be preterm (5% vs. 9%), and developmentally vulnerable on >=1 domains (20% vs. 36%). Overall, the proportion of developmentally vulnerable children decreased with increasing gestational age, from 44% at <=27 weeks to 20% at 40 weeks. Aboriginal children had higher risks than non-Aboriginal children across the gestational age range, peaking among early term children (risk difference [RD] 19.0, 95% confidence interval [CI] 16.3, 21.7; relative risk [RR] 1.91, 95% CI 1.77, 2.06). The relation of gestational age to developmental outcomes was the same in Aboriginal and non-Aboriginal children, and adjustment for socio-economic disadvantage attenuated the risk differences and risk ratios across the gestational age range. CONCLUSIONS: Although the relation of gestational age to developmental vulnerability was similar in Aboriginal and non-Aboriginal children, Aboriginal children had a higher risk of developmental vulnerability at all gestational ages, which was largely accounted for by socio-economic disadvantage. PMID- 29165834 TI - Juvenile xanthogranuloma with angiomatous appearance and a peculiar immunophenotype. AB - Juvenile xanthogranuloma is the most common form of non-Langerhans cell histiocytosis in childhood. The clinical differential diagnosis of a solitary juvenile xanthogranuloma includes molluscum contagiosum, Spitz nevus, and melanoma. Lesions larger than 2 cm in diameter may be misdiagnosed as hemangiomas, but this is not typical of smaller juvenile xanthogranuloma. We report a case of solitary juvenile xanthogranuloma in a 10-year-old boy with angiomatous appearance and peculiar immunophenotype. PMID- 29165836 TI - Morbihan disease treated with Tripterygium wilfordii successfully. PMID- 29165835 TI - The function of contactin-2/TAG-1 in oligodendrocytes in health and demyelinating pathology. AB - The oligodendrocyte maturation process and the transition from the pre myelinating to the myelinating state are extremely important during development and in pathology. In the present study, we have investigated the role of the cell adhesion molecule CNTN2/TAG-1 on oligodendrocyte proliferation, differentiation, myelination, and function during development and under pathological conditions. With the combination of in vivo, in vitro, ultrastructural, and electrophysiological methods, we have mapped the expression of CNTN2 protein in the oligodendrocyte lineage during the different stages of myelination and its involvement on oligodendrocyte maturation, branching, myelin-gene expression, myelination, and axonal function. The cuprizone model of central nervous system demyelination was further used to assess CNTN2 in pathology. During development, CNTN2 can transiently affect the expression levels of myelin and myelin regulating genes, while its absence results in reduced oligodendrocyte branching, hypomyelination of fiber tracts and impaired axonal conduction. In pathology, CNTN2 absence does not affect the extent of de- and remyelination. However during remyelination, a novel, CNTN2-independent mechanism is revealed that is able to recluster voltage gated potassium channels (VGKCs) resulting in the improvement of fiber conduction. PMID- 29165837 TI - Pulse duration settings in subthalamic stimulation for Parkinson's disease. AB - BACKGROUND: Stimulation parameters in deep brain stimulation (DBS) of the subthalamic nucleus for Parkinson's disease (PD) are rarely tested in double blind conditions. Evidence-based recommendations on optimal stimulator settings are needed. Results from the CUSTOM-DBS study are reported, comparing 2 pulse durations. METHODS: A total of 15 patients were programmed using a pulse width of 30 us (test) or 60 us (control). Efficacy and side-effect thresholds and unified PD rating scale (UPDRS) III were measured in meds-off (primary outcome). The therapeutic window was the difference between patients' efficacy and side effect thresholds. RESULTS: The therapeutic window was significantly larger at 30 us than 60 us (P = .0009) and the efficacy (UPDRS III score) was noninferior (P = .00008). INTERPRETATION: Subthalamic neurostimulation at 30 us versus 60 us pulse width is equally effective on PD motor signs, is more energy efficient, and has less likelihood of stimulation-related side effects. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 29165839 TI - Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies. AB - A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882. PMID- 29165838 TI - Discordance of pediatric morphea treatment by pediatric dermatologists. AB - BACKGROUND/OBJECTIVES: Studies describing treatment efficacy in pediatric morphea are lacking. Subspecialists have reached no consensus on how to optimally treat pediatric morphea. The objective of the current study was to describe the most common treatment practices of pediatric dermatologists worldwide who care for children with morphea. METHODS: A survey regarding topical treatment practices of pediatric morphea, with representative case-based scenarios, was distributed to pediatric dermatologists and results were tallied. RESULTS: The survey response rate was 13.4%, with 110 respondents in the final analysis. The majority of respondents agreed on red violaceous rim (99%), increased local warmth (75%), raised borders (69%), and dermal thickening (64%) as signs of disease activity. Respondents had less agreement on sclerotic lesions (41%), scaling (43%), dyspigmentation (19%), and atrophy (13%) as signs of disease activity. Ninety-two percent of respondents used primary therapy or monotherapy with topical medications, including 45% in linear morphea of the limbs and 37% in linear morphea of the head or neck. High-potency topical corticosteroids were most commonly used (80%), although respondents did not agree on specific regimens. Sixteen different treatment regimens were selected as first-line therapy for one case scenario of active disease. CONCLUSION: The survey found large variation in how pediatric dermatologists treat pediatric morphea. Consensus treatment guidelines developed by pediatric dermatologists and pediatric rheumatologists are urgently needed regarding the efficacy of therapies for pediatric morphea. Prospective studies of treatment efficacy in pediatric morphea are urgently needed as well. PMID- 29165840 TI - How Important Is Vitamin D for Calcium Homeostasis During Pregnancy and Lactation? PMID- 29165843 TI - Pillar[5]arene-Based Supramolecular Organic Framework with Multi-Guest Detection and Recyclable Separation Properties. AB - The selective detection and separation of target ions or molecules is an intriguing issue. Herein, a novel supramolecular organic framework (SOF-THBP) was constructed by bis-thioacetylhydrazine functionalized pillar[5]arenes. The SOF THBP shows a fluorescent response for Fe3+ , Cr3+ , Hg2+ and Cu2+ ions. The xerogel of SOF-THBP shows excellent recyclable separation properties for these metal ions and the absorption rates were up to 99.29 %. More interestingly, by rationally introducing these metal ions into the SOF-THBP, a series of metal-ion coordinated SOFs (MSOFs) such as MSOF-Fe, MSOF-Hg and MSOF-Cu were constructed. These metal ions coordinated MSOFs could selectively sense F- , Br- , and l-Cys, respectively. The detection limits of these MSOFs for F- , Br- and l-Cys were about 10-8 m. PMID- 29165842 TI - Nitrogen Reduction to Ammonia on a Biomimetic Mononuclear Iron Centre: Insights into the Nitrogenase Enzyme. AB - Nitrogenases catalyse nitrogen fixation to ammonia on a multinuclear Fe-Mo centre, but their mechanism and particularly the order of proton and electron transfer processes that happen during the catalytic cycle is still unresolved. Recently, a unique biomimetic mononuclear iron model was developed using tris(phosphine)borate (TPB) ligands that was shown to convert N2 into NH3 . Herein, we present a computational study on the [(TPB)FeN2 ]- complex and describe its conversion into ammonia through the addition of electrons and protons. In particular, we tested the consecutive proton transfer on only the distal nitrogen atom or alternated protonation of the distal/proximal nitrogen. It is found that the lowest energy pathway is consecutive addition of three protons to the same site, which forms ammonia and an iron-nitrido complex. In addition, the proton transfer step of complexes with the metal in various oxidation and spin states were tested and show that the pKa values of biomimetic mononuclear nitrogenase intermediates vary little with iron oxidation states. As such, the model gives several possible NH3 formation pathways depending on the order of electron/proton transfer, and all should be physically accessible in the natural system. These results may have implications for enzymatic nitrogenases and give insight into the catalytic properties of mononuclear iron centres. PMID- 29165844 TI - Oral microbiomes from hunter-gatherers and traditional farmers reveal shifts in commensal balance and pathogen load linked to diet. AB - Maladaptation to modern diets has been implicated in several chronic disorders. Given the higher prevalence of disease such as dental caries and chronic gum diseases in industrialized societies, we sought to investigate the impact of different subsistence strategies on oral health and physiology, as documented by the oral microbiome. To control for confounding variables such as environment and host genetics, we sampled saliva from three pairs of populations of hunter gatherers and traditional farmers living in close proximity in the Philippines. Deep shotgun sequencing of salivary DNA generated high-coverage microbiomes along with human genomes. Comparing these microbiomes with publicly available data from individuals living on a Western diet revealed that abundance ratios of core species were significantly correlated with subsistence strategy, with hunter gatherers and Westerners occupying either end of a gradient of Neisseria against Haemophilus, and traditional farmers falling in between. Species found preferentially in hunter-gatherers included microbes often considered as oral pathogens, despite their hosts' apparent good oral health. Discriminant analysis of gene functions revealed vitamin B5 autotrophy and urease-mediated pH regulation as candidate adaptations of the microbiome to the hunter-gatherer and Western diets, respectively. These results suggest that major transitions in diet selected for different communities of commensals and likely played a role in the emergence of modern oral pathogens. PMID- 29165845 TI - Wolbachia infection alters the relative abundance of resident bacteria in adult Aedes aegypti mosquitoes, but not larvae. AB - Insect-symbiont interactions are known to play key roles in host functions and fitness. The common insect endosymbiont Wolbachia can reduce the ability of several human pathogens, including arboviruses and the malaria parasite, to replicate in insect hosts. Wolbachia does not naturally infect Aedes aegypti, the primary vector of dengue virus, but transinfected Ae. aegypti have antidengue virus properties and are currently being trialled as a dengue biocontrol strategy. Here, we assess the impact of Wolbachia infection of Ae. aegypti on the microbiome of wild mosquito populations (adults and larvae) collected from release sites in Cairns, Australia, by profiling the 16S rRNA gene using next generation sequencing. Our data indicate that Wolbachia reduces the relative abundance of a large proportion of bacterial taxa in Ae. aegypti adults, that is in accordance with the known pathogen-blocking effects of Wolbachia on a variety of bacteria and viruses. In adults, several of the most abundant bacterial genera were found to undergo significant shifts in relative abundance. However, the genera showing the greatest changes in relative abundance in Wolbachia-infected adults represented a low proportion of the total microbiome. In addition, there was little effect of Wolbachia infection on the relative abundance of bacterial taxa in larvae, or on species diversity (accounting for species richness and evenness together) detected in adults or larvae. These results offer insight into the effects of Wolbachia on the Ae. aegypti microbiome in a native setting, an important consideration for field releases of Wolbachia into the population. PMID- 29165846 TI - Total Synthesis of Disciformycin A and B: Unusually Exigent Targets of Biological Significance. AB - The first total synthesis of the potent antibiotic disciformycin B (2) is described, which is exceptionally isomerization-prone and transforms into disciformycin A (1) even under notably mild conditions. To outweigh this bias, the approach to 2 hinged on the use of a silyl residue at C4 to lock the critical double bond in place and hence insure the integrity of the synthetic intermediates en route to 2. This tactic was instrumental for the preparation of the building blocks and formation of the macrocyclic ring via ring closing alkyne metathesis (RCAM). To make the end game successful, however, it proved necessary to cleave the C-silyl protecting group off; it was at this stage that the exceptional sensitivity of the target became fully apparent. PMID- 29165847 TI - Breast lesion characterization using whole-lesion histogram analysis with stretched-exponential diffusion model. AB - BACKGROUND: Diffusion-weighted imaging (DWI) has been studied in breast imaging and can provide more information about diffusion, perfusion and other physiological interests than standard pulse sequences. The stretched-exponential model has previously been shown to be more reliable than conventional DWI techniques, but different diagnostic sensitivities were found from study to study. PURPOSE: This work investigated the characteristics of whole-lesion histogram parameters derived from the stretched-exponential diffusion model for benign and malignant breast lesions, compared them with conventional apparent diffusion coefficient (ADC), and further determined which histogram metrics can be best used to differentiate malignant from benign lesions. STUDY TYPE: This was a prospective study. POPULATION: Seventy females were included in the study. FIELD STRENGTH/SEQUENCE: Multi-b value DWI was performed on a 1.5T scanner. ASSESSMENT: Histogram parameters of whole lesions for distributed diffusion coefficient (DDC), heterogeneity index (alpha), and ADC were calculated by two radiologists and compared among benign lesions, ductal carcinoma in situ (DCIS), and invasive carcinoma confirmed by pathology. STATISTICAL TESTS: Nonparametric tests were performed for comparisons among invasive carcinoma, DCIS, and benign lesions. Comparisons of receiver operating characteristic (ROC) curves were performed to show the ability to discriminate malignant from benign lesions. RESULTS: The majority of histogram parameters (mean/min/max, skewness/kurtosis, 10-90th percentile values) from DDC, alpha, and ADC were significantly different among invasive carcinoma, DCIS, and benign lesions. DDC10% (area under curve [AUC] = 0.931), ADC10% (AUC = 0.893), and alphamean (AUC = 0.787) were found to be the best metrics in differentiating benign from malignant tumors among all histogram parameters derived from ADC and alpha, respectively. The combination of DDC10% and alphamean , using logistic regression, yielded the highest sensitivity (90.2%) and specificity (95.5%). DATA CONCLUSION: DDC10% and alphamean derived from the stretched-exponential model provides more information and better diagnostic performance in differentiating malignancy from benign lesions than ADC parameters derived from a monoexponential model. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1701-1710. PMID- 29165848 TI - Ecological disturbance influences adaptive divergence despite high gene flow in golden perch (Macquaria ambigua): Implications for management and resilience to climate change. AB - Populations that are adaptively divergent but maintain high gene flow may have greater resilience to environmental change as gene flow allows the spread of alleles that have already been tested elsewhere. In addition, populations naturally subjected to ecological disturbance may already hold resilience to future environmental change. Confirming this necessitates ecological genomic studies of high dispersal, generalist species. Here we perform one such study on golden perch (Macquaria ambigua) in the Murray-Darling Basin (MDB), Australia, using a genome-wide SNP data set. The MDB spans across arid to wet and temperate to subtropical environments, with low to high ecological disturbance in the form of low to high hydrological variability. We found high gene flow across the basin and three populations with low neutral differentiation. Genotype-environment association analyses detected adaptive divergence predominantly linked to an arid region with highly variable riverine flow, and candidate loci included functions related to fat storage, stress and molecular or tissue repair. The high connectivity of golden perch in the MDB will likely allow locally adaptive traits in its most arid and hydrologically variable environment to spread and be selected in localities that are predicted to become arid and hydrologically variable in future climates. High connectivity in golden perch is likely due to their generalist life history and efforts of fisheries management. Our study adds to growing evidence of adaptation in the face of gene flow and highlights the importance of considering ecological disturbance and adaptive divergence in biodiversity management. PMID- 29165849 TI - A novel public health threat - high lead solder in stainless steel rainwater tanks in Tasmania. AB - OBJECTIVE: We identified two water tanks in Tasmania with water lead concentrations exceeding the Australian Drinking Water Guidelines (ADWG) limit; they had been constructed with stainless steel and high-lead solder from a single manufacturer. An investigation was initiated to identify all tanks constructed by this manufacturer and prevent further exposure to contaminated water. METHODS: To identify water tanks we used sales accounts, blood and water lead results from laboratories, and media. We analysed blood and water lead concentration results from laboratories and conducted a nested cohort study of blood lead concentrations in children aged <18 years. RESULTS: We identifed 144 tanks constructed from stainless steel and high lead solder. Median water lead concentrations were significantly higher in the stainless steel tanks (121ug/L) than in the galvanised tanks (1ug/L). Blood lead concentrations ranged from 1 to 26ug/dL (median 5ug/dL); of these, 77% (n=50) were below the then-recommended health-related concentration of 10ug/dL. Concentrations in the 15 people (23%) above this limit ranged from 10-26ug/dL, with a median of 14ug/dL. The median blood lead concentration in the nested cohort of children was initially 8.5ug/dL, dropping to 4.5ug/dL after follow-up. CONCLUSIONS: Lead concentrations in the water tanks constructed from stainless steel and high-lead solder were up to 200 times above the recommended ADWG limits. Implications for public health: This investigation highlights the public health risk posed by use of non-compliant materials in constructing water tanks. PMID- 29165850 TI - The TCP4 transcription factor regulates trichome cell differentiation by directly activating GLABROUS INFLORESCENCE STEMS in Arabidopsis thaliana. AB - Trichomes are the first cell type to be differentiated during the morphogenesis of leaf epidermis and serve as an ideal model to study cellular differentiation. Many genes involved in the patterning and differentiation of trichome cells have been studied over the past decades, and the majority of these genes encode transcription factors that specifically regulate epidermal cell development. However, the upstream regulators of these genes that link early leaf morphogenesis with cell type differentiation are less studied. The TCP proteins are the plant-specific transcription factors involved in regulating diverse aspects of plant development including lateral organ morphogenesis by modulating cell proliferation and differentiation. Here, we show that the miR319-regulated class II TCP proteins, notably TCP4, suppress trichome branching in Arabidopsis leaves and inflorescence stem by direct transcriptional activation of GLABROUS INFLORESCENCE STEMS (GIS), a known negative regulator of trichome branching. The trichome branch number is increased in plants with reduced TCP activity and decreased in the gain-of-function lines of TCP4. Biochemical analyses show that TCP4 binds to the upstream regulatory region of GIS and activates its expression. Detailed genetic analyses show that GIS and TCP4 work in same pathway and GIS function is required for TCP4-mediated regulation of trichome differentiation. Taken together, these results identify a role for the class II TCP genes in trichome differentiation, thus providing a connection between organ morphogenesis and cellular differentiation. PMID- 29165851 TI - Many encephalitis cases still a medical mystery. PMID- 29165852 TI - Capturing and missing the patient's story through outcome measures: A thematic comparison of patient-generated items in PSYCHLOPS with CORE-OM and PHQ-9. AB - BACKGROUND: There is increasing interest in individualized patient-reported outcome measures (I-PROMS), where patients themselves indicate the specific problems they want to address in therapy and these problems are used as items within the outcome measurement tool. OBJECTIVE: This paper examined the extent to which 279 items reported in an I-PROM (PSYCHLOPS) added qualitative information which was not captured by two well-established outcome measures (CORE-OM and PHQ 9). DESIGN: Comparison of items was only conducted for patients scoring above the "caseness" threshold on the standardized measures. SETTING AND PATIENTS: 107 patients were participating in therapy within addiction and general psychiatric clinical settings. MAIN RESULTS: Almost every patient (95%) reported at least one item whose content was not covered by PHQ-9, and 71% reported at least one item not covered by CORE-OM. DISCUSSION: Results demonstrate the relevance of individualized outcome assessment for capturing data describing the issues of greatest concern to patients, as nomothetic measures do not always seem to capture the whole story. PMID- 29165853 TI - Past-year Prescription Drug Monitoring Program Opioid Prescriptions and Self reported Opioid Use in an Emergency Department Population With Opioid Use Disorder. AB - BACKGROUND: Despite increasing reliance on prescription drug monitoring programs (PDMPs) as a response to the opioid epidemic, the relationship between aberrant drug-related behaviors captured by the PDMP and opioid use disorder is incompletely understood. How PDMP data should guide emergency department (ED) assessment has not been studied. OBJECTIVES: The objective was to evaluate a relationship between PDMP opioid prescription records and self-reported nonmedical opioid use of prescription opioids in a cohort of opioid-dependent ED patients enrolled in a treatment trial. METHODS: PDMP opioid prescription records during 1 year prior to study enrollment on 329 adults meeting Diagnostic and Statistical Manual IV criteria for opioid dependence entering a randomized clinical trial in a large, urban ED were cross-tabulated with data on 30-day nonmedical prescription opioid use self-report. The association among these two types of data was assessed by the Goodman and Kruskal's gamma; a logistic regression was used to explore characteristics of participants who had PDMP record of opioid prescriptions. RESULTS: During 1 year prior to study enrollment, 118 of 329 (36%) patients had at least one opioid prescription (range = 1-51) in our states' PDMP. Patients who reported >=15 of 30 days of nonmedical prescription opioid use were more likely to have at least four PDMP opioid prescriptions (20/38; 53%) than patients reporting 1 to 14 days (14/38, 37%) or zero days of nonmedical prescription opioid use (4/38, 11%; p = 0.002). Female sex and having health insurance were significantly more represented in the PDMP (p < 0.05 for both). CONCLUSION: PDMPs may be helpful in identifying patients with certain aberrant drug-related behavior, but are unable to detect many patients with opioid use disorder. The majority of ED patients with opioid use disorder were not captured by the PDMP, highlighting the importance of using additional methods such as screening and clinical history to identify opioid use disorders in ED patients and the limitations of PDMPs to detect opioid use disorders. PMID- 29165854 TI - MMP-3 (-1171 5A/6A; Lys45Glu) variants affect serum levels of matrix metalloproteinase (MMP)-3 and correlate with severity of COPD: A study of MMP-3, MMP-7 and MMP-12 in a Tunisian population. AB - BACKGROUND: The present study aimed to examine the role of matrix metalloproteinase (MMP)-3 [(-1171) 5A/6A; Lys45Glu (A/G)], MMP-7 [(-181) A/G] and MMP-12 [(-82) A/G; Asn357Ser (A/G)] variants in the development and severity of chronic obstructive pulmonary disease (COPD) in Tunisians. METHODS: Plethysmography was performed in all participants to measure forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC parameters. Genotyping of MMP-3, MMP-7 and MMP-12 polymorphisms was carried out in 138 patients with COPD and 216 healthy controls using a polymerase chain reaction restriction fragment length polymorphism. Serum levels of MMPs and cytokines (interleukin-6, tumor necrosis factor-alpha) were determined by an enzyme-linked immunosorbent assay. RESULTS: No significant correlations were observed between genetic variations in MMP-3, MMP-7 and MMP-12 and the risk of development of COPD. Additionally, no impact of MMP-7 (-181) A/G and MMP-12 [(-82) A/G; Asn357Ser (A/G)] polymorphisms was observed on the respective protein levels and clinical parameters of the disease. Interestingly, both MMP-3 (-1171) 5A/6A and Lys45Glu (A/G) variants were associated with respiratory function, as well as with serum levels of MMP-3 in COPD patients. A relationship was found between the (-1171) 6A and 45Glu (G) alleles of the MMP-3 gene and enhanced airflow limitation among COPD patients. Additionally, carriers of the 6A6A and 45 GG genotypes present higher MMP-3 levels than noncarriers. CONCLUSIONS: MMP-3 ( 1171) 5A/6A and Lys45Glu (A/G) polymorphisms were associated with the decline of lung function among COPD patients. These results could be linked to the upregulation of MMP-3 in serum from COPD patients carrying the (-1171) 6A and 45 G homozygous genotypes. PMID- 29165855 TI - Physical activity coaching by Australian Exercise Physiologists is cost effective for patients referred from general practice. AB - OBJECTIVE: Interventions to promote physical activity for sedentary patients seen in general practice may be a way to reduce the burden of chronic disease. Coaching by an exercise physiologist is publicly funded in Australia, but cost effectiveness has not been documented. METHODS: In a three-arm randomised controlled trial, face-to-face coaching and telephone coaching over 12 weeks were compared with a control group using the outcome of step count for one week at baseline, three months and twelve months. Program costs and time-based costs were considered. Quality of life was measured as a secondary outcome. RESULTS: At 12 months, the intervention groups were more active than controls by 1,002 steps per day (95%CI 244, 1,759). This was achieved at a cost of AUD$245 per person. There was no change in reported quality of life or utility values. CONCLUSION: Coaching achieved a modest increase in activity equivalent to 10 minutes walking per day, at a cost of AUD$245 per person. Face-to-face and telephone counselling were both effective. Implication for public health: Persistence of increases nine months after the end of coaching suggests it creates long-term change and is a good value health intervention. PMID- 29165856 TI - Saccharomyces cerevisiae Hog1 MAP kinase pathway is activated in response to honokiol exposure. AB - AIM: The goal of the study was to investigate the cellular tolerance mechanism in response to honokiol exposure. METHODS AND RESULTS: The broth microdilution method was employed to test the sensitivity of different Saccharomyces cerevisiae strains to honokiol. Intracellular levels of reactive oxygen species (ROSs) were determined by DCFH-DA staining. The phosphorylation of Hog1 was evaluated by Western blot analysis. The mRNA expressions of genes involved in the Ras-cyclic AMP (cAMP) pathway were analysed by real-time reverse transcription polymerase chain reaction. We found that the sod1? mutant was hypersensitive to honokiol and produced more ROS compared with wild-type and sod2? cells. Hog1 was phosphorylated in response to honokiol exposure and deletion of HOG1 increased the sensitivity to honokiol. The expressions of genes involved in the Ras-cAMP pathway were down-regulated after honokiol exposure; exogenous cAMP significantly reduced the phosphorylation of Hog1, although the level was higher than the control level. CONCLUSIONS: In addition to SOD1, the Ras-cAMP cascade and Hog1 MAP kinase pathway is essential for protecting against honokiol-induced oxidative stress. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results provide insight into the understanding of the action mechanism of honokiol. PMID- 29165857 TI - Isolation of phage-display library-derived scFv antibody specific to Listeria monocytogenes by a novel immobilized method. AB - AIMS: To select Listeria monocytogenes-specific single-chain fragment variable (scFv) antibodies from a phage-display library by a novel simple and cost effective immobilization method. METHODS AND RESULTS: Light expanded clay aggregate (LECA) was used as biomass support matrix for biopanning of a phage display library to select L. monocytogenes-specific scFv antibody. Four rounds of positive selection against LECA-immobilized L. monocytogenes and an additional subtractive panning against Listeria innocua were performed. The phage clones selected using this panning scheme and LECA-based immobilization method exhibited the ability to bind L. monocytogenes without cross-reactivity toward 10 other non L. monocytogenes bacteria. One of the selected phage clones was able to specifically recognize three major pathogenic serotypes (1/2a, 1/2b and 4b) of L. monocytogenes and 11 tested L. monocytogenes strains isolated from foods. CONCLUSIONS: The LECA-based immobilization method is applicable for isolating species-specific anti-L. monocytogenes scFv antibodies by phage display. SIGNIFICANCE AND IMPACT OF THE STUDY: The isolated scFv antibody has potential use in development of immunoassay-based methods for rapid detection of L. monocytogenes in food and environmental samples. In addition, the LECA immobilization method described here could feasibly be employed to isolate specific monoclonal antibodies against any given species of pathogenic bacteria from phage-display libraries. PMID- 29165858 TI - The rebirthing of the Kevin O' Day animal slides collection. PMID- 29165859 TI - Alkene 1,2-Difunctionalization by Radical Alkenyl Migration. AB - Transition-metal-free radical alpha-perfluoroalkylation with the accompanying vicinal beta-alkenylation of unactivated alkenes is presented. These radical cascades proceed by means of 1,4- or 1,5-alkenyl migration by electron catalysis on readily accessed allylic alcohols. The reactions comprise a regioselective perfluoroalkyl radical addition with subsequent alkenyl migration and concomitant deprotonation to generate a ketyl radical anion that sustains the chain as a single-electron-transfer reducing reagent. PMID- 29165860 TI - Rehabilitation and convalescent hospital stay in New South Wales: an analysis of 3,979 women aged 75. AB - OBJECTIVES: With a rapidly ageing population, it is imperative to examine health service costs and plan appropriately for the future. This paper determines the factors related to extended hospital stay for 'Rehabilitation' or 'Convalescence', as defined by ICD-10 coding, in acute hospital settings for older women in New South Wales, Australia. METHODS: Participants were from the 1921-26 cohort of the Australian Longitudinal Study on Women's Health. For this analysis, self-reported survey data were linked to the NSW Admitted Patient Data Collection and the National Death Index. RESULTS: Of the 3,979 participants, 88% had a hospitalisation in the 13-year observation period, and 37% had either a rehabilitation or convalescence admission in an acute hospital setting. In the multivariate model, living in a regional or remote area was the only variable positively associated with having a rehabilitation or convalescence hospitalisation (AOR=1.58 [1.33, 1.87]). CONCLUSIONS: Area of residence is the determining factor for rehabilitation or convalescence hospital admissions. These long stay admissions are not necessarily inappropriate, but due to a lack of other non-acute care options. Implications for public health: Increased availability of rehabilitation and respite care in non-acute settings will not only improve older patient care, but will also reduce the burden on acute hospitals. PMID- 29165861 TI - Engineered Biomolecular Recognition of RDX by Using a Thermostable Alcohol Dehydrogenase as a Protein Scaffold. AB - There are many biotechnology applications that would benefit from simple, stable proteins with engineered biomolecular recognition. Here, we explored the hypothesis that a thermostable alcohol dehydrogenase (AdhD from Pyrococcus furiosus) could be engineered to bind a small molecule instead of a cofactor or molecules involved in the catalytic transition state. We chose the explosive molecule 1,3,5-trinitro-1,3,5-triazine (royal demolition explosive, RDX) as a proof-of-concept. Its low solubility in water was exploited for immobilization for biopanning by using ribosome display. Docking simulations were used to identify two potential binding sites in AdhD, and a randomized library focused on tyrosine or serine mutations was used to determine that RDX was binding in the substrate binding pocket of the enzyme. A fully randomized binding pocket library was selected, and affinity maturation by error-prone PCR led to the identification of a mutant (EP-16) that gained the ability to bind RDX with an affinity of (73+/-11) MUm. These results underscore the way in which thermostable enzymes can be useful scaffolds for expanding the biomolecular recognition toolbox. PMID- 29165862 TI - An assessment of an Australasian pathway for the introduction of transanal total mesorectal excision (taTME). AB - AIM: To evaluate the use of a pathway for the introduction of transanal total mesorectal excision (taTME) into Australia and New Zealand. METHOD: A pathway for surgeons with an appropriate level of specialist training and baseline skill set was initiated amongst colorectal surgeons; it includes an intensive course, a series of proctored cases and ongoing contribution to audit. Data were collected for patients who had taTME, for benign and malignant conditions, undertaken by the initial adopters of the technique. RESULTS: A total of 133 taTME procedures were performed following the introduction of a training pathway in March 2015. The indication was rectal cancer in 84% of cases. There was one technique specific visceral injury, which occurred prior to that surgeon completing the pathway. There were no cases of postoperative mortality; morbidity occurred in 27.1%. The distal resection margin was clear in all cases of rectal cancer, and the circumferential resection margin was positive in two cases. An intact or nearly intact total mesorectal excision was obtained in more than 98% of cases. CONCLUSION: This study demonstrates the safe and controlled introduction of a new surgical technique in a defined surgeon population with the use of a pathway for training. The authors recommend a similar pathway to facilitate the introduction of taTME to colorectal surgical practice. PMID- 29165863 TI - Paediatric Salzmann's nodular degeneration in Dandy-Walker syndrome variant. PMID- 29165864 TI - An Australian hospital's training program and referral pathway within a multi disciplinary health-justice partnership addressing family violence. AB - OBJECTIVE: An innovative health-justice partnership was established to deliver legal assistance to women experiencing family violence who attended an Australian hospital. This paper reports on a multifaceted response to build capacity and willingness of health professionals to identify signs of family violence and engage with referral pathways to on-site legal assistance. METHODS: A Realistic Evaluation analysed health professionals' knowledge and attitudes towards identification, response and referral for family violence before and after training; and use of referral pathways. RESULTS: Of 123 health professionals participating in training, 67 completed baseline and follow-up surveys. Training improved health professionals' self-reported knowledge of, and confidence in, responding to family violence and understanding of lawyers' roles in hospitals. Belief that patients should be referred to on-site legal services increased. Training did not correspond to actual increased referrals to legal assistance. CONCLUSION: The program built capacity and willingness of health professionals to identify signs of, and respond to, family violence. Increase in referral rates to legal assistance was not shown. Potential improvements include better data capture and greater availability of legal services. Implications for public health: Strong hospital system supports and reliable recording of family violence referrals need to be in place before introducing such partnerships to other hospitals. PMID- 29165865 TI - Mimicking Class I b Mn2 -Ribonucleotide Reductase: A MnII2 Complex and Its Reaction with Superoxide. AB - A fascinating discovery in the chemistry of ribonucleotide reductases (RNRs) has been the identification of a dimanganese (Mn2 ) active site in class I b RNRs that requires superoxide anion (O2.- ), rather than dioxygen (O2 ), to access a high-valent Mn2 oxidant. Complex 1 ([Mn2 (O2 CCH3 )(N-Et-HPTB)](ClO4 )2 , N-Et HPTB=N,N,N',N'-tetrakis(2-(1-ethylbenzimidazolyl))-2-hydroxy-1,3-diaminopropane) was synthesised in high yield (90 %). 1 was reacted with O2.- at -40 degrees C resulting in the formation of a metastable species (2). 2 displayed electronic absorption features (lambdamax =460, 610 nm) typical of a Mn-peroxide species and a 29-line EPR signal typical of a MnII MnIII entity. Mn K-edge X-ray absorption near-edge spectroscopy (XANES) suggested a formal oxidation state change of MnII2 in 1 to MnII MnIII for 2. Electrospray ionisation mass spectrometry (ESI-MS) suggested 2 to be a MnII MnIII -peroxide complex. 2 was capable of oxidizing ferrocene and weak O-H bonds upon activation with proton donors. Our findings provide support for the postulated mechanism of O2.- activation at class I b Mn2 RNRs. PMID- 29165866 TI - Assessing enclosure design and husbandry practices for successful keeping and breeding of the Burmese brow antlered deer (Eld's deer, Rucervus eldii thamin) in European zoos. AB - The endangered Burmese brow antlered deer (Rucervus eldii thamin) is a medium sized tropical cervid kept in a number of European zoos. Studbook data and anecdotal reports have suggested that this species suffers from poor reproductive success and relatively high neonatal mortality in captivity. Questionnaires were sent to 10 European zoos, holding 91 (20.71.0) deer, in order to record information on husbandry practices and enclosure design. Studbook analysis was performed to determine reproductive success and mortality values at each of the zoos participating in the study. Statistical analysis was carried out to identify any links between husbandry or enclosure design and the population parameters calculated from the studbook. From the nine zoos that were analyzed in this study, no significant differences were found for population parameters between male and female deer. Neonatal mortality was negatively correlated to enclosure size (in males) and enclosure cover (in females). Positive correlations were found between enclosure cover, average temperature and group size with life expectancy, and negative correlations between enclosure visibility and visitor distance with female life expectancy. These results may be useful for informing husbandry guidelines, although further research into stress responses in captivity is recommended for this species to improve their welfare. PMID- 29165867 TI - Applying behavior-analytic methodology to the science and practice of environmental enrichment in zoos and aquariums. AB - Environmental enrichment in zoos and aquariums is often evaluated at two overlapping levels: published research and day-to-day institutional record keeping. Several authors have discussed ongoing challenges with small sample sizes in between-groups zoological research and have cautioned against the inappropriate use of inferential statistics (Shepherdson, , International Zoo Yearbook, 38, 118-124; Shepherdson, Lewis, Carlstead, Bauman, & Perrin, Applied Animal Behaviour Science, 147, 298-277; Swaisgood, , Applied Animal Behaviour Science, 102, 139-162; Swaisgood & Shepherdson, , Zoo Biology, 24, 499-518). Multi-institutional studies are the typically-prescribed solution, but these are expensive and difficult to carry out. Kuhar ( Zoo Biology, 25, 339-352) provided a reminder that inferential statistics are only necessary when one wishes to draw general conclusions at the population level. Because welfare is assessed at the level of the individual animal, we argue that evaluations of enrichment efficacy are often instances in which inferential statistics may be neither necessary nor appropriate. In recent years, there have been calls for the application of behavior-analytic techniques to zoo animal behavior management, including environmental enrichment (e.g., Bloomsmith, Marr, & Maple, , Applied Animal Behaviour Science, 102, 205-222; Tarou & Bashaw, , Applied Animal Behaviour Science, 102, 189-204). Single-subject (also called single-case, or small-n) designs provide a means of designing evaluations of enrichment efficacy based on an individual's behavior. We discuss how these designs might apply to research and practice goals at zoos and aquariums, contrast them with standard practices in the field, and give examples of how each could be successfully applied in a zoo or aquarium setting. PMID- 29165868 TI - The effects of intrinsic enrichment on captive felids. AB - Environmental enrichment is a well-known technique, which has been used to enhance the welfare of captive animals. The aim of this study is to investigate how three different forms of intrinsic enrichment, namely, a hay ball without scent, a hay ball with catnip, and a hay ball with cinnamon, influenced the behavior of six cheetah and two Sumatran tigers at Fota Wildlife Park, Ireland. Enrichment-directed behaviors, as well as pacing, locomotion, inactive, and exploratory behaviors were investigated. The results indicated that the three forms of enrichment had similar effects, in terms of enrichment-directed behavior, with cinnamon resulting in the highest levels of enrichment-directed behaviors. The cinnamon treatment resulted in a significant decrease in pacing behavior when compared with baseline observations. No evidence of habituation (i.e., a significant reduction in enrichment-directed behaviors) was observed for any of the three enrichments. This means that these low cost, easy to apply, practical forms of enrichment could be frequently applied for these species as part of an enrichment regime. PMID- 29165869 TI - Canagliflozin stability study and ecofriendly chromatographic determination of its degradation product: A comparative study. AB - Canagliflozin is a newly approved drug for type II diabetes mellitus. A full stability study of canagliflozin was performed following international conference on harmonization strategies. The drug was stable against all conditions except oxidation where only one degradation product was separated and structurally elucidated using mass spectrometry and infrared spectroscopy. A green high performance thin-layer chromatographic densitometric determination was developed and validated for the accurate quantification of canagliflozin and its main oxidative degradation product. Separation was performed on high-performance aluminum plates precoated with silica gel using acetone/ethanol (80:20, v/v) as a developing system and scanning at 290 nm. Retardation factor values were 0.64 and 0.81 and linearity ranges were 0.4-3.6 and 0.2-3.2 MUg/band for the drug and the degradation product, respectively. It was a matter of interest to use green solvents with no harmful effects on the environment. The comparison between the proposed and the reported high-performance liquid chromatography method regarding greenness profile showed that the proposed method was greener and so could be used as an alternative method to the reported one with no environmental harm. Method validity was tested as per international conference on harmonization and method utility was verified by application to Invokana(r) tablets. PMID- 29165870 TI - Evidence-Based Practice: An Ethical Perspective. PMID- 29165871 TI - Shipping living donor kidneys and transplant recipient outcomes. AB - Kidney paired donation (KPD) is an important tool to facilitate living donor kidney transplantation (LDKT). Concerns remain over prolonged cold ischemia times (CIT) associated with shipping kidneys long distances through KPD. We examined the association between CIT and delayed graft function (DGF), allograft survival, and patient survival for 1267 shipped and 205 nonshipped/internal KPD LDKTs facilitated by the National Kidney Registry in the United States from 2008 to 2015, compared to 4800 unrelated, nonshipped, non-KPD LDKTs. Shipped KPD recipients had a median CIT of 9.3 hours (range = 0.25-23.9 hours), compared to 1.0 hour for internal KPD transplants and 0.93 hours for non-KPD LDKTs. Each hour of CIT was associated with a 5% increased odds of DGF (adjusted odds ratio: 1.05, 95% confidence interval [CI], 1.02-1.09, P < .01). However, there was not a significant association between CIT and all-cause graft failure (adjusted hazard ratio [aHR]: 1.01, 95% CI: 0.98-1.04, P = .4), death-censored graft failure ( [aHR]: 1.02, 95% CI, 0.98-1.06, P = .4), or mortality (aHR 1.00, 95% CI, 0.96 1.04, P > .9). This study of KPD-facilitated LDKTs found no evidence that long CIT is a concern for reduced graft or patient survival. Studies with longer follow-up are needed to refine our understanding of the safety of shipping donor kidneys through KPD. PMID- 29165872 TI - Manganese Dioxide Coated WS2 @Fe3 O4 /sSiO2 Nanocomposites for pH-Responsive MR Imaging and Oxygen-Elevated Synergetic Therapy. AB - Recently, the development of multifunctional theranostic nanoplatforms to realize tumor-specific imaging and enhanced cancer therapy via responding or modulating the tumor microenvironment (TME) has attracted tremendous interests in the field of nanomedicine. Herein, tungsten disulfide (WS2 ) nanoflakes with their surface adsorbed with iron oxide nanoparticles (IONPs) via self-assembly are coated with silica and then subsequently with manganese dioxide (MnO2 ), on to which polyethylene glycol (PEG) is attached. The obtained WS2 -IO/S@MO-PEG appears to be highly sensitive to pH, enabling tumor pH-responsive magnetic resonance imaging with IONPs as the pH-inert T2 contrast probe and MnO2 as the pH-sensitive T1 contrast probe. Meanwhile, synergistic combination tumor therapy is realized with such WS2 -IO/S@MO-PEG, by utilizing the strong near-infrared light and X-ray absorbance of WS2 for photothermal therapy (PTT) and enhanced cancer radiotherapy (RT), respectively, as well as the ability of MnO2 to decompose tumor endogenous H2 O2 and relieve tumor hypoxia to further overcome hypoxia-associated radiotherapy resistance. The combination of PTT and RT with WS2 -IO/S@MO-PEG results in a remarkable synergistic effect to destruct tumors. This work highlights the promise of developing multifunction nanocomposites for TME specific imaging and TME modulation, aiming at precision cancer synergistic treatment. PMID- 29165874 TI - AML presenting with a preleukemic episode and acquired heterochromia in a child with macrosomia. PMID- 29165873 TI - Andrographolide inhibits hypoxia-induced hypoxia-inducible factor 1alpha and endothelin 1 expression through the heme oxygenase 1/CO/cGMP/MKP-5 pathways in EA.hy926 cells. AB - Andrographolide is a potent anti-inflammatory agent found in Andrographis paniculata. Endothelin 1 (ET-1) is an endothelium-derived vasoconstrictor with pro-inflammatory properties secreted in response to hypoxia. Mitogen-activated protein kinase phosphatase 5 (MKP-5) is a dual-specificity phosphatase that dephosphorylates threonine and tyrosine residues of MAPKs. We showed previously that hypoxia-induced HIF-1alpha expression and ET-1 secretion are dependent on p38 MAPK in EA.hy926 cells. Here, we investigate what role MKP-5 plays in andrographolide's inhibition of hypoxia-induced expression of HIF-1alpha and ET 1. Hypoxic conditions were created using the hypoxia-mimetic agent CoCl2 . Andrographolide enhanced HO-1 and MKP-5 expression and cellular cGMP content in addition to inhibiting hypoxia-induced ROS generation. Concomitantly, the HO-1 byproduct CO and the cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate (8 Br-cGMP) increased MKP-5 expression, and pretreatment with CO and 8-Br-cGMP inhibited hypoxia-induced HIF-1alpha and ET-1 expression. Transfection of HO-1 siRNA or pretreatment with the HO-1 inhibitor ZnPP-9 or 1H-[1,2,4]oxadiazolo[4,3 a]quinoxalin-1-one, a specific inhibitor of soluble guanylate cyclase, reduced andrographolide-induced MKP-5 expression. Moreover, silencing MKP-5 or treatment with the phosphatase inhibitor vanadate abrogated andrographolide's suppressing hypoxia-induced p38 MAPK activation and HIF-1alpha expression. The inhibition of hypoxia-induced HIF-1alpha and ET-1 expression by andrographolide is likely associated with HO-1/CO/cGMP/MKP-5 pathways, which is involved in inhibiting hypoxia-induced p38 MAPK activation. PMID- 29165876 TI - Effect of Gamma Irradiation on Dynamics of Charge Exchange Processes between Single Trap and Nanowire Channel. AB - In the present study, transport properties and single trap phenomena in silicon nanowire (NW) field-effect transistors (FETs) are reported. The dynamic behavior of drain current in NW FETs studied before and after gamma radiation treatment deviates from the predictions of the Shockley-Read-Hall model and is explained by the concept taking into account an additional energy barrier in the accumulation regime. It is revealed that dynamics of charge exchange processes between single trap and nanowire channel strongly depend on gamma radiation treatment. The results represent potential for utilizing single trap phenomena in a number of advanced devices. PMID- 29165875 TI - 4beta-Hydroxywithanolide E selectively induces oxidative DNA damage for selective killing of oral cancer cells. AB - Reactive oxygen species (ROS) induction had been previously reported in 4beta hydroxywithanolide (4betaHWE)-induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4betaHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (gammaH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8-oxo-2'deoxyguanosine [8-oxodG]) were detected in 4betaHWE-treated oral cancer (Ca9-22) and/or normal (HGF-1) cells. 4betaHWE decreased cell viability, changed cell morphology and induced ROS generation in oral cancer cells rather than oral normal cells, which were recovered by a free radical scavenger N-acetylcysteine (NAC). For immunofluorescence, 4betaHWE also accumulated more of the DSB marker, gammaH2AX foci, in oral cancer cells than in oral normal cells. For western blotting, DSB signaling proteins such as gammaH2AX and MRN complex (MRE11, RAD50, and NBS1) were overexpressed in 4betaHWE-treated oral cancer cells in different concentrations and treatment time. In the formamidopyrimidine-DNA glycolyase (Fpg)-based comet assay and 8-oxodG-based flow cytometry, the 8-oxodG expressions were higher in 4betaHWE-treated oral cancer cells than in oral normal cells. All the 4betaHWE-induced DSB and oxidative DNA damage to oral cancer cells were recovered by NAC pretreatment. Taken together, the 4betaHWE selectively induced DSB and oxidative DNA damage for the ROS-mediated selective killing of oral cancer cells. PMID- 29165877 TI - A familial case of PDE10A-associated childhood-onset chorea with bilateral striatal lesions. PMID- 29165878 TI - Robotic transabdominal intersphincteric resection and coloanal anastomosis with the da Vinci Xi System - a video vignette. PMID- 29165880 TI - Hvidoere Smiley Faces: International diabetes quality of life assessment tool for young children. AB - BACKGROUND: Few diabetes-specific quality of life (QOL) tools are available for young children. OBJECTIVES: To design and evaluate, a new age-specific QOL questionnaire and its associations with treatment regimens and metabolic control. METHODS: Clinical, demographic data and centrally analyzed HbA1c were collected on 1133 children <11 years (girls 48%; mean +/- SD age 8.0 +/- 2.1 years; diabetes duration >=1 year) from 18 centers (Europe, Japan, North America and Australia). Children completed the 10-item Smiley Faces QOL questionnaire constructed for the study, and children >=7 years also completed the KIDSCREEN-10 Index. RESULTS: In total, 1035 children completed the new Smiley Faces questionnaire which was well understood by 993 (70% >=4 years and 96% >=5 years, respectively). Internal consistency and reliability were good (Cronbach's alpha = .73). Inter-item correlation ranged r = 0.047 to 0.451 indicating each item measures separate aspects of children's satisfaction construct. Convergent validity assessed by comparison to the HrQOL KIDSCREEN-10 Index showed moderate correlation coefficient 0.501. Factor analysis revealed 3 factors explaining 51% of the variance. Children reported good QOL with most items positive, mean values between 1 and 2 on a 5-point scale (lower scores indicating greater QOL). Diabetes satisfaction was unrelated to age, diabetes duration, HbA1c, or severe hypoglycemia. Girls were more satisfied than boys. Children on intensive regimens reported better QOL (P < .02). Main dissatisfaction related to insulin injections and blood sugar testing. CONCLUSIONS: The Smiley Faces questionnaire enables QOL assessment in young children and identification of areas of dissatisfaction and other clinically relevant items relating to diabetes management. PMID- 29165881 TI - Nerve injury associated with high-intensity focused ultrasound: A case report. AB - Skin laxity is a common cosmetic concern in middle-aged women. High-intensity focused ultrasound (HIFU) is one of noninvasive modalities that provides safe and effective improvement in skin laxity and tightening with minimal adverse effects. Concerning an extensive use of HIFU for facial rejuvenation, dermatologists should be aware of potential adverse effects of HIFU treatment. We herein present a case of 33-year-old Thai female with facial nerve injury after HIFU treatment for skin laxity. PMID- 29165883 TI - Issue Information - ToC. PMID- 29165882 TI - Single Pixel Black Phosphorus Photodetector for Near-Infrared Imaging. AB - Infrared imaging systems have wide range of military or civil applications and 2D nanomaterials have recently emerged as potential sensing materials that may outperform conventional ones such as HgCdTe, InGaAs, and InSb. As an example, 2D black phosphorus (BP) thin film has a thickness-dependent direct bandgap with low shot noise and noncryogenic operation for visible to mid-infrared photodetection. In this paper, the use of a single-pixel photodetector made with few-layer BP thin film for near-infrared imaging applications is demonstrated. The imaging is achieved by combining the photodetector with a digital micromirror device to encode and subsequently reconstruct the image based on compressive sensing algorithm. Stationary images of a near-infrared laser spot (lambda = 830 nm) with up to 64 * 64 pixels are captured using this single-pixel BP camera with 2000 times of measurements, which is only half of the total number of pixels. The imaging platform demonstrated in this work circumvents the grand challenges of scalable BP material growth for photodetector array fabrication and shows the efficacy of utilizing the outstanding performance of BP photodetector for future high-speed infrared camera applications. PMID- 29165884 TI - Issue Information - Editorial Board. PMID- 29165885 TI - The Association Between the Dosage of SGLT2 Inhibitor and Weight Reduction in Type 2 Diabetes Patients: A Meta-Analysis. AB - OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors may induce urinary glucose excretion via the inhibition of renal glucose reabsorption, improve glycemic control, and lower body weight. The aim of this meta-analysis was to evaluate weight changes in patients who received different dosages of SGLT2 inhibitors. METHODS: Overall, 55 placebo-controlled trials were included. RESULTS: The results indicated that treatment with 2.5 mg, 5 mg, 10 mg, and 20 mg of dapagliflozin led to significant decreases in body weight compared with a placebo (weighted mean difference [WMD], -1.30 kg, -1.51 kg, -1.79 kg, -2.24 kg, respectively; P < 0.001). Treatment with 50 mg, 100 mg, 200 mg, and 300 mg of canagliflozin also led to significant decreases in weight (WMD, -1.20 kg, -1.82 kg, -1.83 kg, -2.37 kg, respectively; P < 0.001). In the treatment with empagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin, body weight also significantly decreased. The decrease in weight was associated with the dosage of dapagliflozin (P < 0.05). CONCLUSIONS: Body weight significantly decreased in patients with type 2 diabetes who received different dosages of SGLT2 inhibitors compared with patients who received a placebo. Moreover, in patients treated with dapagliflozin, there was a statistically significant dosage-dependent trend in body weight reduction. PMID- 29165886 TI - Pre-operative features of non-invasive follicular thyroid neoplasms with papillary-like nuclear features: An analysis of their cytological, Gene Expression Classifier and sonographic findings. AB - OBJECTIVE: To investigate the corresponding cytological diagnoses, Gene Expression Classifier (GEC) results and ultrasound features of thyroid nodules diagnosed as non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), as well as any coexisting pathology. METHODS: We performed a retrospective review of thyroid nodules histologically diagnosed as NIFTP at our institution between 1st April 2016 and 1st April 2017. The following data points were collected: demographics, nodule size, ultrasound features, cytological diagnosis, GEC results, origin of sample (in-house vs outside hospital) and any additional pathology identified in the resection specimen. RESULTS: The case cohort included 87 nodules diagnosed as NIFTP (size range: 1-7 cm, mean: 2.5 cm) from 82 patients (age range: 22-82, mean age: 50.4, M:F-1:4.1). Corresponding FNA results were available for 72 nodules (82.8%) and were categorised as follows: benign (n = 5, 6.9%), atypia of unknown significance/follicular lesion of undetermined significance (n = 29, 40.3%), follicular neoplasm/suspicious for follicular neoplasm/follicular neoplasm with oncocytic features (n = 27, 37.5%), suspicious for papillary thyroid carcinoma (n = 6, 8.3%) and malignant (n = 5, 6.9%). GEC results were available for 32 (44.4%) nodules, with the majority of cases classified as suspicious (81.3%). On ultrasound, most of the nodules were predominantly solid (81.8%), vascular (93.8%), non-calcified (86.5%), and either hypoechoic (44.9%) or isoechoic (38.8%). In addition to NIFTP and other benign findings in the background thyroid, 75 separate malignant tumours were identified in 38 (46.3%) patients, many of which were papillary thyroid microcarcinomas (86.5%) with lymph node metastases present in two cases. CONCLUSIONS: The majority of thyroid nodules histologically diagnosed as NIFTP have indeterminate cytology (77.8%) and are classified as suspicious (81.3%) by GEC testing. Taken together, these findings can guide clinicians toward a more conservative therapeutic approach. PMID- 29165887 TI - This month's Cytopathology. PMID- 29165888 TI - Molecular pathology and thyroid FNA. AB - This review summarises molecular pathological techniques applicable to thyroid FNA. The molecular pathology of thyroid tumours is now fairly well understood. Molecular methods may be used as a rule-in test for diagnosis of malignancy in thyroid nodules, eg BRAF V600E point mutation, use of a seven-gene mutational panel (BRAF V600E, RAS genes, RET/PTC or PAX8/PPARG rearrangement), or as a comprehensive multigene next-generation sequencing panel, eg ThyroSeq v2. Molecular methods can also be applied as rule-out tests for malignancy in thyroid nodules, eg Afirma or ThyroSeq v2 or as markers of prognosis, eg TERT promoter mutation or other gene mutations including BRAF V600E, TP53 and AKT1, and as tests for newly defined tumour entities such as non-invasive follicular thyroid neoplasm with papillary like nuclei, or as a molecular marker(s) for targeted therapies. This review describes practical examples of molecular techniques as applied to thyroid FNA in routine clinical practice and the value of molecular diagnostics in thyroid FNA. It describes the range of molecular abnormalities identified in thyroid nodules and thyroid cancers with some practical applications of molecular methods to diagnosis and prognosis of thyroid nodules and thyroid cancer. PMID- 29165889 TI - Rosettes in papillary carcinoma of thyroid: A rare cytomorphological indicator of aggressive variants. PMID- 29165892 TI - Assays for estimating HIV incidence: updated global market assessment and estimated economic value. AB - INTRODUCTION: Accurate incidence estimates are needed to characterize the HIV epidemic and guide prevention efforts. HIV Incidence assays are cost-effective laboratory assays that provide incidence estimates from cross-sectional surveys. We conducted a global market assessment of HIV incidence assays under three market scenarios and estimated the economic value of improved incidence assays. METHODS: We interviewed 27 stakeholders, and reviewed journal articles, working group proceedings, and manufacturers' sales figures. We determined HIV incidence assay use in 2014, and estimated use in 2015 to 2017 and in 5 to 10-years under three market scenarios, as well as the cost of conducting national and key population surveys using an HIV incidence assay with improved performance. RESULTS: Global 2014 HIV incidence assay use was 308,900 tests, highest in Asia and mostly for case- and population-based surveillance. Estimated 2015 to 2017 use was 94,475 annually, with declines due to China and the United States discontinuing incidence assay use for domestic surveillance. Annual projected 5 to 10 year use under scenario 1 - no change in technology - was 94,475. For scenario 2 - a moderately improved incidence assay - projected annual use was 286,031. Projected annual use for scenario 3 - game-changing technologies with an HIV incidence assay part of (a) standard confirmatory testing, and (b) standard rapid testing, were 500,000 and 180 million, respectively. As HIV incidence assay precision increases, decreased sample sizes required for incidence estimation resulted in $5 to 23 million annual reductions in survey costs and easily offset the approximately $3 million required to develop a new assay. CONCLUSIONS: Improved HIV incidence assays could substantially reduce HIV incidence estimation costs. Continued development of HIV incidence assays with improved performance is required to realize these cost benefits. PMID- 29165893 TI - High rates of hospitalised burn injury in Indigenous children living in remote areas: a population data linkage study. PMID- 29165894 TI - Application of the Milan system for reporting risk stratification in salivary gland cytopathology. PMID- 29165895 TI - Adaptation and validation of the Turkish version of the Nasal Obstruction Symptom Evaluation scale. AB - BACKGROUND: The Nasal Obstruction Symptom Evaluation (NOSE) scale is a questionnaire used to assess the quality of life in patients with nasal obstruction. The aim of this study was to validate the Turkish translation of the NOSE questionnaire. METHODS: The NOSE questionnaire was translated into Turkish and then back to English. Fifty patients with septal deviation leading to nasal obstruction and 50 healthy subjects without any nasal complaints and pathologies were recruited into the study. The Cronbach alpha was used to test internal consistency. The Mann-Whitney U test was used to compare the NOSE scores of the 2 groups. Psychosomatic features (reliability, repeatability, validity, responding) were evaluated by concerning the criteria as test-retest procedure, self consistency, within-score and inter-score correlation and sensitivity of responding between the 2 groups. RESULTS: There was no statistically significant difference between patients and healthy subjects in terms of age, gender, and body mass index. Test-retest results among control subjects also did not demonstrate significant difference and the Cronbach alpha value of the NOSE scale was found to be 0.966. There was a positive correlation among every question of the NOSE scale and it was statistically significantly different from the control group. Total scores of the NOSE scale were significantly higher than the control group. CONCLUSION: The Turkish version of the NOSE scale is a valid tool for assessing patients with septal deviation and measuring the subjective severity of nasal obstruction. PMID- 29165896 TI - Investigation of the abnormal nasal aerodynamics and trigeminal functions among empty nose syndrome patients. AB - BACKGROUND: Abnormal nasal aerodynamics or trigeminal functions have been frequently implicated in the symptomology of empty nose syndrome (ENS), yet with limited evidence. METHODS: Individual computed tomography (CT)-based computational fluid dynamics (CFD) was applied to 27 ENS patients to simulate their nasal aerodynamics and compared with 42 healthy controls. Patients' symptoms were confirmed with Empty Nose Syndrome 6-item Questionnaire (ENS6Q), 22 item Sino-Nasal Outcome Test (SNOT-22), and Nasal Obstruction Symptom Evaluation (NOSE) scores. Nasal trigeminal sensitivity was measured with menthol lateralization detection thresholds (LDTs). RESULTS: ENS patients had significantly lower (~25.7%) nasal resistance and higher (~2.8 times) cross sectional areas compared to healthy controls (both p < 0.001). Despite inferior turbinate reductions, CFD analysis demonstrated that ENS patients had increased airflow concentrated in the middle meatus region (66.5% +/- 18.3%) compared to healthy controls (49.9% +/- 15.1%, p < 0.0001). Significantly less airflow (25.8% +/- 17.6%) and lower peak wall shear stress (WSS) (0.58 +/- 0.24 Pa) were found in the inferior meatus (vs healthy: 36.5% +/- 15.9%; 1.18 +/- 0.81 Pa, both p < 0.05), with the latter significantly correlated with the symptom scores of ENS6Q (r = -0.398, p = 0.003). Item-wise, complaints of "suffocation" and "nose feels too open" were also found to be significantly correlated with peak WSS around the inferior turbinate (r = -0.295, p = 0.031; and r = -0.388, p = 0.004, respectively). These correlations were all negative, indicating that less air mucosal stimulations resulted in worse symptom scores. ENS patients (n = 12) also had impaired menthol LDT when compared to healthy controls (p < 0.0001). CONCLUSION: This is the first CFD examination of nasal aerodynamics in a large cohort of ENS patients. The results indicated that a combination of loss of neural sensitivity and poorer inferior air-mucosal stimulation may potentially lead to ENS symptomology. PMID- 29165897 TI - Lithospermum erythrorhizon Root and its Naphthoquinones Repress SREBP1c and Activate PGC1alpha Through AMPKalpha. AB - OBJECTIVE: To examine specific molecular mechanisms involved in modulating hepatic lipogenesis and mitochondria biogenesis signals by Lithospermum erythrorhizon (gromwell) root extract. METHODS: Stable cell lines with luciferase reporter constructs were generated to examine sterol regulatory element binding protein 1c (SREBP1c) and peroxisome proliferator-activated receptor gamma, coactivator 1 (PGC1) alpha promoter activity and estrogen-related receptor (ERR) alpha response element activity. Gene expression of SREBP1c, stearoyl coenzyme A desaturase 1, and PGC1alpha was measured by using reverse transcription polymerase chain reaction. Lipogenesis was measured in human hepatoma cells with Nile red staining and flow cytometry. Phosphorylation of AMP-activated protein kinase (AMPK) alpha was determined by using ELISA and Western blot. RESULTS: Gromwell root extract and its naphthoquinones dose-dependently repressed high glucose and liver X receptor alpha induction of SREBP1c promoter activity and gene expression. Hepatic lipogenesis was repressed, and PGC1alpha promoter and gene expression and ERRalpha response element activity were increased by gromwell root extract. Gromwell root extract, shikonin, and alpha-methyl-n-butyrylshikonin increased AMPKalpha phosphorylation, and inhibition of AMPK blunted the repression in SREBP1c promoter activity by gromwell root extract and its naphthoquinones. CONCLUSIONS: Data suggest that gromwell root extract and its naphthoquinones repress lipogenesis by increasing the phosphorylated state of AMPKalpha and stimulating mitochondrial biogenesis signals. PMID- 29165898 TI - Thrombocytopenia-associated multi-organ failure secondary to hyperglycemic, hyperosmolar non-ketotic syndrome: A case report. AB - Thrombocytopenia associated multi-organ failure (TAMOF) is a clinical syndrome with features of new onset thrombocytopenia, increased lactate dehydrogenase, and multi-organ failure in critically ill patients. TAMOF can be the initial presentation of an underlying disease process or can develop during the course of illness either during the hospital stay. TAMOF has a high mortality rate if not treated; therefore, early detection is critical. TAMOF has been rarely reported in diabetic ketoacidosis. We are describing the first case of a patient diagnosed with hyperglycemic, hyperosmolar non-ketotic syndrome who developed TAMOF on the third day of his hospital course. In addition to supportive care in the intensive care unit the patient received serial therapeutic plasma exchanges and improved quickly after treatment. Early diagnosis and treatment of TAMOF decreases morbidity and mortality. PMID- 29165899 TI - Quantitative performance evaluation of a back-illuminated sCMOS camera with 95% QE for super-resolution localization microscopy. AB - Scientific Complementary Metal Oxide Semiconductor (sCMOS) cameras were introduced into the market in 2009 and are now becoming a major type of commercial cameras for low-light imaging. sCMOS cameras provide simultaneously low read noise, high readout speed, and large pixel array; however, the relatively low quantum efficiency (QE) of sCMOS cameras has been a major limitation for its application in single molecule imaging, especially super resolution localization microscopy which requires high detection sensitivity. Here we report the imaging performance of a newly released back-illuminated sCMOS camera (called Dhyana 95 from Tucsen) which is claimed to be the world's first 95% QE sCMOS camera. The imaging performance evaluation is based on a new methodology which is designed to provide paired images from two tested cameras under almost identical experimental conditions. We verified that this new 95% QE sCMOS camera is able to provide superior imaging performance over a representative front-illuminated sCMOS camera (Hamamatsu Flash 4.0 V2) and a popular back-illuminated EMCCD camera (Andor iXon 897 Ultra) in a wide signal range. We hope this study will inspire more studies on using sCMOS cameras in super-resolution localization microscopy, or even single molecule imaging. (c) 2017 International Society for Advancement of Cytometry. PMID- 29165900 TI - Development of a precolumn derivatization HPLC method with diode-array detection for the determination of amino sugars in peat and soil humic acids. AB - The work is focused on the development of a high-performance liquid chromatography method with diode-array detection for the separation and quantitation of the three most abundant amino sugars; d-glucosamine, d galactosamine, and d-mannosamine. The high-performance liquid chromatography separation was carried out by reversed-phase chromatography on Chromolith Performance RP-18e monolithic column after acid hydrolysis (5 M HCl) and precolumn derivatization of samples using diethyl ethoxymethylenemalonate. Gradient elution and a mobile phase composed of ammonium formate buffer solution (10 mmol/L, pH 3.60) and methanol with flow rate of 1.0 mL/min were used. The monitoring wavelength was set at 280 nm. The limits of detection and quantitation for analytes ranged from 0.017 to 0.122 mg/L and from 0.057 to 0.407 mg/L, respectively. The proposed method was successfully applied for the determination of amino sugars in samples of humic acids isolated from different soils and peat. PMID- 29165901 TI - Influence of ventral tegmental area input on cortico-subcortical networks underlying action control and decision making. AB - It is argued that the mesolimbic system has a more general function in processing all salient events, including and extending beyond rewards. Saliency was defined as an event that is unexpected due to its frequency of occurrence and elicits an attentional-behavioral switch. Using functional magnetic resonance imaging (fMRI), signals were measured in response to the modulation of salience of rewarding and nonrewarding events during a reward-based decision making task, the so called desire-reason dilemma paradigm (DRD). Replicating previous findings, both frequent and infrequent, and therefore salient, reward stimuli elicited reliable activation of the ventral tegmental area (VTA) and ventral striatum (vStr). When immediate reward desiring contradicted the superordinate task-goal, we found an increased activation of the VTA and vStr when the salient reward stimuli were presented compared to the nonsalient reward stimuli, indicating a boosting of activation in these brain regions. Furthermore, we found a significantly increased functional connectivity between the VTA and vStr, confirming the boosting of vStr activation via VTA input. Moreover, saliency per se without a reward association led to an increased activation of brain regions in the mesolimbic reward system as well as the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG), and anterior cingulate cortex (ACC). Finally, findings uncovered multiple increased functional interactions between cortical saliency-processing brain areas and the VTA and vStr underlying detection and processing of salient events and adaptive decision making. PMID- 29165902 TI - Multicontrast endomyocardial imaging by single-channel high-resolution cross polarization optical coherence tomography. AB - A single-channel high-resolution cross-polarization (CP) optical coherence tomography (OCT) system is presented for multicontrast imaging of human myocardium in one-shot measurement. The intensity and functional contrasts, including the ratio between the cross- and co-polarization channels as well as the cumulative retardation, are reconstructed from the CP-OCT readout. By comparing the CP-OCT results with histological analysis, it is shown that the system can successfully delineate microstructures in the myocardium and differentiate the fibrotic myocardium from normal or ablated myocardium based on the functional contrasts provided by the CP-OCT system. The feasibility of using A-line profiles from the 2 orthogonal polarization channels to identify fibrotic myocardium, normal myocardium and ablated lesion is also discussed. PMID- 29165903 TI - Isomeric Diruthenium Complexes Bridged by Deprotonated Indigo in cis and trans Configuration. AB - The doubly deprotonated form L2- of indigo=H2 L can bind two [Ru(acac)2 ] complex fragments in the cis (1) and trans configuration (2), as evidenced from crystal structure analysis. While the latter type of N,O; N' ,O' coordination has been observed earlier, for example, with [Ru(bpy)2 ]2+ , leading to two equivalent six membered ring chelates, the cis arrangement in 1 is observed here for the first time in a dinuclear complex, producing one five-membered ring chelate with N,N' coordination and one seven-membered chelate with O,O' coordination. The different structures of the isomers result in differing electrochemical and spectroelectrochemical (EPR, UV-Vis-NIR) responses for various accessible charge states 1n and 2n , n=-, 0, +, 2+. The associated electronic structures were analyzed by DFT (structures, spin density) and TD-DFT calculations (electronic transitions), revealing mainly metal-based reduction but largely indigo ligand based oxidation of both neutral precursors. PMID- 29165904 TI - Palladium-Catalyzed Intermolecular Acylation of Aryl Diazoesters with ortho Bromobenzaldehydes. AB - In this work, we describe a palladium-catalyzed intermolecular O acylation of alpha-diazoesters with ortho-bromobenzaldehydes. The C(sp2 )-H bond activation of the aldehyde is enabled by migratory insertion of a palladium carbene intermediate. The diazoesters act as modular three-atom units to build up key seven-membered palladacycles, which are transformed into a variety of isocoumarin derivatives upon reductive elimination. Mechanistic experiments and DFT calculations provide insight into the reaction pathway. PMID- 29165905 TI - Loop-mediated isothermal amplification (LAMP): a versatile technique for detection of micro-organisms. AB - Loop-mediated isothermal amplification (LAMP) amplifies DNA with high specificity, efficiency and rapidity under isothermal conditions by using a DNA polymerase with high displacement strand activity and a set of specifically designed primers to amplify targeted DNA strands. Following its first discovery by Notomi et al. ( Nucleic Acids Res 28: E63), LAMP was further developed over the years which involved the combination of this technique with other molecular approaches, such as reverse transcription and multiplex amplification for the detection of infectious diseases caused by micro-organisms in humans, livestock and plants. In this review, available types of LAMP techniques will be discussed together with their applications in detection of various micro-organisms. Up to date, there are varieties of LAMP detection methods available including colorimetric and fluorescent detection, real-time monitoring using turbidity metre and detection using lateral flow device which will also be highlighted in this review. Apart from that, commercialization of LAMP technique had also been reported such as lyophilized form of LAMP reagents kit and LAMP primer sets for detection of pathogenic micro-organisms. On top of that, advantages and limitations of this molecular detection method are also described together with its future potential as a diagnostic method for infectious disease. PMID- 29165906 TI - Noninvasive, high-speed, near-infrared imaging of the biomolecular distribution and molecular mechanism of embryonic development in fertilized fish eggs. AB - In this study, the distribution of biomaterials and its molecular mechanism of embryonic development in Japanese medaka fish were analyzed nondestructively and noninvasively without staining using near-infrared (NIR) imaging. The microscopic NIR imaging system used in this research was a device capable of ultra-high-speed imaging; using this system, one can acquire microscopic imaging data in a few seconds. Therefore, the medaka eggs remained alive throughout measurements and were successfully monitored in vivo. The distributions of biomolecules were examined by mapping the intensities of NIR bands resulting from lipids, proteins and water in 2 dimensions (2D). The structures of eyes, lipid bilayer membranes, micelles and water-structure differences at the interface of different substances constituting different structures on the egg were visualized. Furthermore, insights on the metabolic mechanisms of lipids and membrane functions were drawn from the biased distribution of lipoproteins and the presence of unsaturated fatty acids in the egg membrane. These results indicated the potential for NIR imaging in evaluating the biological functions and metabolic systems of cells and embryos. PMID- 29165907 TI - Stripping flow cytometry: How many detectors do we need for bacterial identification? AB - Multicolor approaches are challenging for microbial flow cytometry; as flow cytometers are mainly developed for biomedical applications, modern instruments contain more detectors than needed. Some of these additional fluorescence detectors measure biological information due to spectral overlap, yet the extent to which this information is relevant for the identification of bacterial populations is ambiguous. In this paper we characterize the usefulness of these additional detectors. We propose a data-driven detector selection method to select the smallest subset of detectors that will optimally discriminate between bacterial populations. Using a detector elimination strategy, we show that one or more detectors can be removed without loss of resolving power. A number of additional detectors are included in the final subset, which help to improve the identification of bacterial populations. Experimental data were retrieved from two types of modern cytometers with different configurations. The method reveals a clear ordering of detector importances, which depends on the instrument from which the data were retrieved. In addition, we were able to pinpoint unexpected behavior of SYBR Green I in the red spectrum. As the field of microbial flow cytometry is maturing, these results motivate the construction of a different kind of cytometric instruments for microbiologists, for which the number of detectors is reduced, but tailored toward the characteristics of microbial experiments. (c) 2017 International Society for Advancement of Cytometry. PMID- 29165909 TI - Process mapping: A cornerstone of quality improvement. PMID- 29165908 TI - Association between adolescents' consumption of total and different types of sugar-sweetened beverages with oral health impacts and weight status. AB - OBJECTIVE: To examine the associations between adolescents' intake of sugar sweetened beverages (SSBs) with oral health impacts (OHI) and weight status. METHODS: Cross-sectional health survey with anthropometry and self-report OHI (toothache and avoiding some foods because of oral problems) and SSB intake (fruit juice, flavoured water, soft, diet, sports and energy drinks) collected in 2015. RESULTS: A total of 3,671 adolescents participated (50% girls; mean age 13.2 years +/-1.7). Drinking >=1cup/day of SSBs was consistently associated with higher odds of OHI compared with drinking <1cup/day: diet soft drinks (AOR, 5.21 95%CI 2.67, 10.18); sports drinks (AOR 3.60 95%CI 1.93, 6.73); flavoured water (AOR 3.07 95%CI 1.55, 6.06); and energy drinks (AOR 2.14 95%CI 1.44, 3.19). Daily SSB intake was not consistently associated with weight status. The odds of overweight/obesity (AOR 1.27 95%CI 1.01, 1.59) and obesity (AOR 1.61 95%CI 1.01, 2.57) were higher for energy drink consumption, compared with not drinking energy drinks; and the odds of abdominal obesity were twice as high among adolescents who drank >=1cup/day of sports drinks, compared with <1cup/day intake. CONCLUSIONS: Daily consumption of SSBs is prevalent among adolescents and is consistently associated with higher odds of OHI. The most popular SSBs among adolescents were energy drinks. Different types of SSB were differentially associated with OHI and weight status. Implications for public health: Different types of SSBs were differentially associated with OHI and weight status in adolescents. Diet soft drinks and new generation SSBs such as energy and sport drinks and flavoured water had a greater impact on adolescents' OHI compared with soft drinks and fruit juice. PMID- 29165910 TI - Retrospective evaluation of the prognostic utility of plasma lactate concentration, base deficit, pH, and anion gap in canine and feline emergency patients. AB - OBJECTIVE: To determine the association of plasma lactate concentration, pH, base deficit (BD), and anion gap (AG) in dogs and cats on presentation to an emergency room with outcome, and to compare the prognostic significance of hyperlactatemia with a concurrent metabolic acidosis with that of hyperlactatemia and a normal metabolic acid-base balance. DESIGN: Retrospective study. SETTING: University teaching hospital. ANIMALS: Five hundred sixty-six dogs and 185 cats that had venous blood gas analysis performed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records were reviewed for plasma lactate concentrations, electrolyte concentrations, and acid-base parameters obtained on emergency room admission, clinical diagnosis, and in-hospital mortality. The primary outcome measure was all-cause mortality for the hospitalized visit. Median plasma lactate concentration and AG were higher, BD was more negative, and pH was lower, in non survivor dogs and cats. The prevalence of hyperlactatemia was 53% in dogs and 30% in cats. Lactic acidosis was present in 42% and 80% of hyperlactatemic dogs and cats, respectively. Multivariate regression analyses revealed that plasma lactate concentration, BD, and pH, but not AG, were independent predictors of mortality in dogs, and that only plasma lactate concentration was an independent predictor of mortality in cats. Mortality was highest for animals with lactic acidosis, at 59.8% in dogs and 49% in cats. Mortality in dogs with lactic acidosis was significantly higher than dogs with hyperlactatemia and a normal acid-base status (P < 0.0001). CONCLUSIONS: The presence and magnitude of hyperlactatemia on presentation to the emergency room may help identify dogs and cats with high likelihood of in-hospital mortality, and the presence of lactic acidosis specifically may help identify dogs with yet higher risk of in-hospital mortality. PMID- 29165911 TI - Defects and Interfaces on PtPb Nanoplates Boost Fuel Cell Electrocatalysis. AB - Nanostructured Pt is the most efficient single-metal catalyst for fuel cell technology. Great efforts have been devoted to optimizing the Pt-based alloy nanocrystals with desired structure, composition, and shape for boosting the electrocatalytic activity. However, these well-known controls still show the limited ability in maximizing the Pt utilization efficiency for achieving more efficient fuel cell catalysis. Herein, a new strategy for maximizing the fuel cell catalysis by controlling/tuning the defects and interfaces of PtPb nanoplates using ion irradiation technique is reported. The defects and interfaces on PtPb nanoplates, controlled by the fluence of incident C+ ions, make them exhibit the volcano-like electrocatalytic activity for methanol oxidation reaction (MOR), ethanol oxidation reaction (EOR), and oxygen reduction reaction (ORR) as a function of ion irradiation fluence. The optimized PtPb nanoplates with the mixed structure of dislocations, subgrain boundaries, and small amorphous domains are the most active for MOR, EOR, and ORR. They can also maintain high catalytic stability in acid solution. This work highlights the impact and significance of inducing/controlling the defects and interfaces on Pt based nanocrystals toward maximizing the catalytic performance by advanced ion irradiation strategy. PMID- 29165912 TI - Reproducibility of radioactive iodine uptake (RAIU) measurements. AB - BACKGROUND: Measurement of radioactive iodine uptake (RAIU) is an important aspect of the assessment and treatment of patients with hyperthyroidism. Its uncertainty affects how much of a true change in RAIU can be detected as well as appropriateness of the therapy dosage upon which it is based. In this study, a method of estimating the reproducibility and least significant change (LSC) values for RAIU measurements, and the implications of the values observed are discussed, with emphasis on application to quality assurance initiatives. METHODS: We prospectively studied 36 consecutive patients referred for RAIU measurements. Twenty-four hours after oral administration of 370 kBq of 131 I-NaI in capsule form, RAIU measurements were obtained in duplicate using a thyroid probe uptake system. Assessment of reproducibility was performed using root-mean square standard deviation. RESULTS: Average difference between duplicated RAIU measurements in our study cohort was -0.1 +/- 1.6% and ranged from -4.8% to 3.1%. Reproducibility of probe-based RAIU measurement was calculated to be 1.1% and 95% LSC was 3.2%. CONCLUSION: In our clinic, probe-based RAIU is a reproducible and relatively precise measurement. Using the method we have outlined, each institution can perform reproducibility assessment and compute the LSC of RAIU measurements based on its own staff, iodine isotope, equipment, protocols, and patient population. These values are useful in the assessment of serial change in RAIU, and as more experience is accumulated, can serve as benchmarks to be used in quality assurance initiatives. PMID- 29165913 TI - COMP report: CPQR technical quality control guidelines for kilovoltage X ray radiotherapy machines. AB - The Canadian Organization of Medical Physicists (COMP) in close partnership with the Canadian Partnership for Quality Radiotherapy (CPQR) has developed a series of Technical Quality Control (TQC) guidelines for radiation treatment equipment. These guidelines outline the performance objectives that equipment should meet in order to ensure an acceptable level of radiation treatment quality. The TQC guidelines have been rigorously reviewed and field tested at various Canadian radiation treatment facilities. The development process enables rapid review and update to keep the guidelines current with changes in technology (the most updated version of this guideline can be found on the CPQR website). This particular TQC details recommended quality control for kilovoltage X Ray radiotherapy machines. PMID- 29165914 TI - Solution-Processed Wide-Bandgap Organic Semiconductor Nanostructures Arrays for Nonvolatile Organic Field-Effect Transistor Memory. AB - In this paper, the development of organic field-effect transistor (OFET) memory device based on isolated and ordered nanostructures (NSs) arrays of wide-bandgap (WBG) small-molecule organic semiconductor material [2-(9-(4-(octyloxy)phenyl)-9H fluoren-2-yl)thiophene]3 (WG3 ) is reported. The WG3 NSs are prepared from phase separation by spin-coating blend solutions of WG3 /trimethylolpropane (TMP), and then introduced as charge storage elements for nonvolatile OFET memory devices. Compared to the OFET memory device with smooth WG3 film, the device based on WG3 NSs arrays exhibits significant improvements in memory performance including larger memory window (~45 V), faster switching speed (~1 s), stable retention capability (>104 s), and reliable switching properties. A quantitative study of the WG3 NSs morphology reveals that enhanced memory performance is attributed to the improved charge trapping/charge-exciton annihilation efficiency induced by increased contact area between the WG3 NSs and pentacene layer. This versatile solution-processing approach to preparing WG3 NSs arrays as charge trapping sites allows for fabrication of high-performance nonvolatile OFET memory devices, which could be applicable to a wide range of WBG organic semiconductor materials. PMID- 29165915 TI - Development and implementation of a radiation therapy incident learning system compatible with local workflow and a national taxonomy. AB - PURPOSE: Collaborative incident learning initiatives in radiation therapy promise to improve and standardize the quality of care provided by participating institutions. However, the software interfaces provided with such initiatives must accommodate all participants and thus are not optimized for the workflows of individual radiation therapy centers. This article describes the development and implementation of a radiation therapy incident learning system that is optimized for a clinical workflow and uses the taxonomy of the Canadian National System for Incident Reporting - Radiation Treatment (NSIR-RT). METHODS: The described incident learning system is a novel version of an open-source software called the Safety and Incident Learning System (SaILS). A needs assessment was conducted prior to development to ensure SaILS (a) was intuitive and efficient (b) met changing staff needs and (c) accommodated revisions to NSIR-RT. The core functionality of SaILS includes incident reporting, investigations, tracking, and data visualization. Postlaunch modifications of SaILS were informed by discussion and a survey of radiation therapy staff. RESULTS: There were 240 incidents detected and reported using SaILS in 2016 and the number of incidents per month tended to increase throughout the year. An increase in incident reporting occurred after switching to fully online incident reporting from an initial hybrid paper-electronic system. Incident templating functionality and a connection with our center's oncology information system were incorporated into the investigation interface to minimize repetitive data entry. A taskable actions feature was also incorporated to document outcomes of incident reports and has since been utilized for 36% of reported incidents. CONCLUSIONS: Use of SaILS and the NSIR-RT taxonomy has improved the structure of, and staff engagement with, incident learning in our center. Software and workflow modifications informed by staff feedback improved the utility of SaILS and yielded an efficient and transparent solution to categorize incidents with the NSIR-RT taxonomy. PMID- 29165916 TI - Response to Kawada: Sleep habits and non-alcoholic fatty liver disease: Risk assessment by adjusting confounders. PMID- 29165917 TI - A novel multisite confocal system for rapid Ca2+ imaging from submicron structures in brain slices. AB - In brain slices, resolving fast Ca2+ fluorescence signals from submicron structures is typically achieved using 2-photon or confocal scanning microscopy, an approach that limits the number of scanned points. The novel multiplexing confocal system presented here overcomes this limitation. This system is based on a fast spinning disk, a multimode diode laser and a novel high-resolution CMOS camera. The spinning disk, running at 20 000 rpm, has custom-designed spiral pattern that maximises light collection, while rejecting out-of-focus fluorescence to resolve signals from small neuronal compartments. Using a 60* objective, the camera permits acquisitions of tens of thousands of pixels at resolutions of ~250 nm per pixel in the kHz range with 14 bits of digital depth. The system can resolve physiological Ca2+ transients from submicron structures at 20 to 40 MUm below the slice surface, using the low-affinity Ca2+ indicator Oregon Green BAPTA-5N. In particular, signals at 0.25 to 1.25 kHz were resolved in single trials, or through averages of a few recordings, from dendritic spines and small parent dendrites in cerebellar Purkinje neurons. Thanks to an unprecedented combination of temporal and spatial resolution with relatively simple implementation, it is expected that this system will be widely adopted for multisite monitoring of Ca2+ signals. PMID- 29165918 TI - Micelle-Assisted Electrodeposition of Mesoporous Fe-Pt Smooth Thin Films and their Electrocatalytic Activity towards the Hydrogen Evolution Reaction. AB - Mesoporous Fe-Pt thin films are obtained by micelle-assisted electrodeposition onto metallic substrates with dissimilar activity (namely, gold, copper, and aluminum seed layers evaporated on Si/Ti) under constant applied potential (E= 1.1 V vs. Ag/AgCl) and deposition time (600 s). The amphiphilic triblock copolymer Pluronic P-123 is used as a soft template to guide the formation of mesopores. The occurrence of pores (ca. 7 nm in diameter) with narrow size distribution, distributed evenly over the surface, is observed in all cases. Despite the applied conditions being the same, the roughness and the amount of Fe incorporated in the films are influenced by the nature of the substrate. In particular, ultra-smooth films containing a larger amount of Fe (21 wt %) are obtained when deposition takes place on the Au surface. X-ray diffraction analyses reveal that Pt and Fe are alloyed to a certain extent, although some iron oxides/hydroxides also unavoidably form. The resulting films have been tested as electrocatalysts in the hydrogen evolution reaction (HER) in alkaline media. The mesoporous Fe-rich Fe-Pt films on Au show excellent HER activity and cyclability. PMID- 29165919 TI - Identification of two new HLA class I alleles in Italian bone marrow donors: A*31:125 and B*44:269. AB - Two novel alleles, HLA-A*31:125 and HLA-B*44:269, are described in Italian bone marrow donors. PMID- 29165920 TI - Diabetes-related complications: Which research topics matter to diverse patients and caregivers? AB - BACKGROUND: Diabetes is a chronic disease with increasing prevalence worldwide. Although research has improved its treatment and management, little is known about which research topics matter to people living with diabetes, particularly among under-represented groups. OBJECTIVES: To explore the importance of research topics among a diverse range of people living with any type of diabetes or caring for someone living with any type of diabetes. METHODS: We used a convergent mixed method design with quantitative and qualitative aspects. We surveyed a national sample of people living with diabetes and caregivers of people with diabetes, asking them to rate the importance of 10 predetermined important research topics. We also held three focus groups in two major cities to explore research concerns of people who are under-represented in research. RESULTS: 469 adults (57% men, 42% women) in Canada completed the online survey, indicating that all 10 areas of research mattered to them, with the highest ratings accorded to preventing and treating kidney, eye and nerve complications. Fourteen individuals participated in three focus groups and similarly noted the importance of research on those three complications. Additionally, focus group participants also noted the importance of research around daily management. No new topics were identified. CONCLUSIONS: This study confirmed the importance of research topics among a population of people living with or caring for someone with diabetes. Findings from this study were used to inform the vision for Diabetes Action Canada-a pan Canadian Strategy for Patient-Oriented Research (SPOR) Network on diabetes and its complications. PMID- 29165921 TI - Impact of Flue Gas Compounds on Microalgae and Mechanisms for Carbon Assimilation and Utilization. AB - To shift the world to a more sustainable future, it is necessary to phase out the use of fossil fuels and focus on the development of low-carbon alternatives. However, this transition has been slow, so there is still a large dependence on fossil-derived power, and therefore, carbon dioxide is released continuously. Owing to the potential for assimilating and utilizing carbon dioxide to generate carbon-neutral products, such as biodiesel, the application of microalgae technology to capture CO2 from flue gases has gained significant attention over the past decade. Microalgae offer a more sustainable source of biomass, which can be converted into energy, over conventional fuel crops because they grow more quickly and do not adversely affect the food supply. This review focuses on the technical feasibility of combined carbon fixation and microalgae cultivation for carbon reuse. A range of different carbon metabolisms and the impact of flue gas compounds on microalgae are appraised. Fixation of flue gas carbon dioxide is dependent on the selected microalgae strain and on flue gas compounds/concentrations. Additionally, current pilot-scale demonstrations of microalgae technology for carbon dioxide capture are assessed and its future prospects are discussed. Practical implementation of this technology at an industrial scale still requires significant research, which necessitates multidisciplinary research and development to demonstrate its viability for carbon dioxide capture from flue gases at the commercial level. PMID- 29165922 TI - Abortion care as a key women's health service. PMID- 29165925 TI - Erratum. PMID- 29165924 TI - The emancipation of women's fertility. PMID- 29165926 TI - Contraception - of potions, pills and social change. PMID- 29165927 TI - Reproductive rights: perspectives from a retired American obstetrician gynaecologist. PMID- 29165928 TI - How to solve the problem of hypersensitivity to asparaginase? PMID- 29165929 TI - Spatial population genomics of the brown rat (Rattus norvegicus) in New York City. AB - Human commensal species such as rodent pests are often widely distributed across cities and threaten both infrastructure and public health. Spatially explicit population genomic methods provide insights into movements for cryptic pests that drive evolutionary connectivity across multiple spatial scales. We examined spatial patterns of neutral genomewide variation in brown rats (Rattus norvegicus) across Manhattan, New York City (NYC), using 262 samples and 61,401 SNPs to understand (i) relatedness among nearby individuals and the extent of spatial genetic structure in a discrete urban landscape; (ii) the geographic origin of NYC rats, using a large, previously published data set of global rat genotypes; and (iii) heterogeneity in gene flow across the city, particularly deviations from isolation by distance. We found that rats separated by <=200 m exhibit strong spatial autocorrelation (r = .3, p = .001) and the effects of localized genetic drift extend to a range of 1,400 m. Across Manhattan, rats exhibited a homogeneous population origin from rats that likely invaded from Great Britain. While traditional approaches identified a single evolutionary cluster with clinal structure across Manhattan, recently developed methods (e.g., fineSTRUCTURE, sPCA, EEMS) provided evidence of reduced dispersal across the island's less residential Midtown region resulting in fine-scale genetic structuring (FST = 0.01) and two evolutionary clusters (Uptown and Downtown Manhattan). Thus, while some urban populations of human commensals may appear to be continuously distributed, landscape heterogeneity within cities can drive differences in habitat quality and dispersal, with implications for the spatial distribution of genomic variation, population management and the study of widely distributed pests. PMID- 29165930 TI - Reply to Application of the Milan system for reporting risk stratification in salivary gland cytopathology. PMID- 29165931 TI - Remarkable Differences in Spin Couplings for Various Self-Paired Dimers of Ring Expansion-Radicalized Uracil: A Basis for the Design of Magnetically Anisotropic Assemblies. AB - The spin-coupling properties of a series of radicalized uracil (rU) dimer diradicals with different H-bonding modes is examined. Each rU has four double H bonding sites [the amide units: two at the Watson-Crick face (upper site WC1 and lower site WC2 ), a Hoogsteen site (HO), and a minor-groove site (MI)], and ten homogeneous dimers (rU-rU) can self-pair with well-defined diradical characters and comparable stability to the native U dimers. More interestingly, all these dimers exhibit distinctly different spin-coupling characters (ferromagnetic (FM) versus antiferromagnetic (AFM) and large- versus small-magnitude spin couplings), indicative of remarkable magnetic-coupling anisotropy of rU. This observation originates from the fusion of a cyclopentadienyl radical to U, which leads to uneven spin-density distribution. In rU, the fused five-membered radical ring can spin-polarize to the edge in the minor groove, and thus dimerization of rU leads to different H-bonded structures with remarkably different magnetic couplings. The calculated larger magnetic coupling constants J are 1003.7 and 540.2 cm-1 for the WC2 -HO and MI-HO H-bonding modes between rU, which exhibit considerably large FM couplings, the MI-MI, WC1 -WC2 and WC2 -WC2 modes show moderate FM couplings (J=0.4-77 cm-1 ), and the other modes exhibit moderate or weak AFM couplings. These observations indicate that the HO and MI sites are favorable spin-coupling sites. In addition, the H-bond lengths and electronic structures of the H-bonding sites, proton transfer, and extra H-bonding interaction with the surroundings can also affect the magnetic couplings of the base pairs. Clearly, the unique magnetic coupling anisotropy of rU provides a promising application basis for the design and assembly of bio-inspired anisotropically magnetic membranes and even magnetism-tunable building blocks for novel magnetic nanoscale devices. PMID- 29165932 TI - Carbon Necklace Incorporated Electroactive Reservoir Constructing Flexible Papers for Advanced Lithium-Ion Batteries. AB - Metal-organic frameworks (MOFs) and their derivatives with well-defined structures and compositions show great potential for wide applications such as sensors, catalysis, energy storage, and conversion, etc. However, poor electric conductivity and large volume expansion are main obstacles for their utilization in energy storage, e.g., lithium-ion batteries and supercapacitors. Herein, a facile strategy is proposed for embedding the MOFs, e.g., ZIF-67 and MIL-88 into polyacrylonitrile fibers, which is further used as a template to build a 3D interconnected conductive carbon necklace paper. Owing to the unique structure features of good electric conductivity, interconnected frameworks, electroactive reservoir, and dual dopants, the obtained flexible electrodes with no additives exhibit high specific capacities, good rate capability, and prolonged cycling stability. The hollow dodecahedral ZIF-67 derived carbon necklace paper delivers a high specific capacity of 1200 mAh g-1 and superior stability of more than 400 cycles without capacity decay. Moreover, the spindle-like MIL-88 derived carbon necklace paper shows a high reversible capacity of 980 mAh g-1 . Their unique 3D interconnected structure and outstanding electrochemical performance pave the way for extending the MOF-based interweaving materials toward potential applications in portable and wearable electronic devices. PMID- 29165933 TI - Transmission scenarios of major vector-borne diseases in Colombia, 1990-2016. AB - Introduccion. Las enfermedades transmitidas por vectores representan mas de 17 % de todas las enfermedades infecciosas y causan anualmente un millon de defunciones a nivel mundial. En Colombia, la malaria, el dengue, la enfermedad de Chagas y las leishmaniasis son condiciones endemoepidemicas persistentes.Objetivo. Determinar el comportamiento epidemiologico de las enfermedades transmitidas por vectores en zonas urbanas y rurales de Colombia entre 1990 y 2016.Materiales y metodos. Se hizo un estudio descriptivo del comportamiento epidemiologico de las principales enfermedades transmitidas por vectores en zonas urbanas y rurales de Colombia entre 1990 y 2016, con la informacion proveniente de fuentes oficiales secundarias.Resultados. En el periodo estudiado se registraron 5'360.134 casos de enfermedades transmitidas por vectores, de los cuales 54,7 % fueron de malaria y 24,9 % de dengue. Estos casos concentraron el 80 % de la carga acumulada de casos de enfermedades transmitidas por vectores. Las medianas de las tasas de incidencia fueron 1.371 y 188 por 100.00 habitantes para malaria y dengue, respectivamente. Ademas, los casos de chikungunya fueron 774.831 desde su introduccion en el 2014 y, los de Zika, 117.674 desde su aparicion en 2015. En las zonas rurales predominaron las enfermedades parasitarias transmitidas por vectores como la malaria, las leishmaniasis y la enfermedad de Chagas. A nivel urbano, predominaron el dengue, el chikungunya y el Zika.Conclusiones. La transmision en Colombia de estas enfermedades es persistente en las zonas urbanas y en las rurales, y de tipo endemoepidemico en los casos de malaria, dengue, leishmaniasis y enfermedad de Chagas. Dicha transmision se ha dado de manera focalizada y con patrones variables de intensidad. Asimismo, se mantienen las condiciones que han favorecido la transmision emergente de nuevas arbovirosis. PMID- 29165934 TI - First Rapid Assessment of Avoidable Blindness Survey in the Maldives: Prevalence and Causes of Blindness and Cataract Surgery. AB - PURPOSE: A nationwide rapid assessment of avoidable blindness survey was undertaken in the Maldives among people aged 50 years or more to assess the prevalence and causes of blindness and visual impairment, cataract surgical coverage, cataract surgery outcome, and barriers to uptake of cataract surgical services. DESIGN: Prospective population-based study. METHODS: In the cluster sampling probability proportionate to size method, 3100 participants in 62 clusters across all 20 atolls were enrolled through house-to-house visits. They were examined in clusters by an ophthalmologist-led team. Data was recorded in mRAAB version 1.25 software on a smartphone. RESULTS: The age-sex standardized prevalence of blindness was 2.0% [95% confidence interval (CI), 1.5-2.6]. Cataract was the leading cause of blindness (51.4%) and uncorrected refractive error was the leading cause of visual impairment (50.9%). Blindness was more prevalent in higher age groups and women (16.3%). Cataract surgical coverage was 86% in cataract blind eyes and 93.5% in cataract blind persons. Good visual outcome in cataract operated eyes was 67.9% (presenting) and 76.6% (best corrected visual acuity). In this study, 48.1% of people had received cataract surgery in neighboring countries. Important barriers for not using the services were "did not feel the need" (29.7%) and "treatment deferred" (33.3%). CONCLUSIONS: Cataract surgical coverage is good, though nearly half the people received surgery outside the Maldives. Cataract surgery outcomes are below World Health Organization standards. Some barriers could be overcome with additional human resources and training to improve cataract surgical outcomes, which could encourage greater uptake of services within the country. PMID- 29165936 TI - ? PMID- 29165937 TI - [Jobsharing in medical hospital care : the experience of the medical department of Lausanne university hospital]. AB - Job sharing is a promising way of organizing work : it allows physicians wishing to work part-time to access jobs that are usually inaccessible to them, while offering hospitals the possibility to recruit or retain qualified physicians to ensure succession planning. This article describes the advantages and the main challenges of jobsharing in a medical department. It provides concrete guidance to physicians wishing to practice it, to contribute to its dissemination. Jobsharing it is a way of organizing work that is practicable and safe in hospitals, provided that partners have compatible values and vision, respect therapeutic attitudes taken by the partner and optimally coordinate their work. PMID- 29165938 TI - [The electronic patient record - a great opportunity to rethink medical information and its use]. AB - Since the early 2000s, the management of information concerning patient care has fundamentally changed. Previously stored in separate medical and nursing paper medical records, patient data are now gathered in a single electronic health record (EHR) thanks to the digitization of our hospitals, whose development and mastery are a major issue in today's health system. PMID- 29165935 TI - Peripapillary Perfused Capillary Density in Exfoliation Syndrome and Exfoliation Glaucoma versus POAG and Healthy Controls: An OCTA Study. AB - PURPOSE: To compare the peripapillary perfused capillary density (PCD) among eyes with exfoliation syndrome (XFS), exfoliation glaucoma (XFG), primary open-angle glaucoma (POAG), and controls. DESIGN: Observational, cross-sectional study. METHODS: Optical coherence tomography angiography (OCTA) images (4.5*4.5 mm) of the optic nerve head were obtained using a commercial spectral domain OCTA system (AngioVue Avanti RTVue-XR, OptoVue, Fremont, CA). Two concentric circles with 1.95-mm (inner) and 3.45-mm (outer) diameters were placed manually, producing an annulus of width 0.75 mm centered at the optic disc. PCD was calculated as the ratio of pixels associated with capillaries to the pixels in the annulus after large blood vessel removal. Continuous variables were assessed by analysis of variance and Tukey honest significant difference (HSD) test. Multiple linear regression analysis was performed to adjust for confounding factors. RESULTS: Forty-three XFG eyes, 31 POAG eyes matched for visual field mean deviation, 33 XFS eyes, and 45 control eyes were analyzed. PCD demonstrated a progressive decrease from controls to XFS to POAG to XFG. Pairwise comparisons revealed significant differences in PCD between each pair of groups (all P<0.01) except for PCD between XFS and POAG (P = 0.08). A multivariable model adjusting for age and stage showed a more significant decrease in PCD in XFG compared with POAG (P = 0.001). CONCLUSIONS: PCD was more significantly decreased in XFG compared with POAG eyes and in XFS compared with control eyes. OCTA provides the first quantitative evidence of the microvascular disturbance that accompanies XFS. PMID- 29165939 TI - [Importance of handoffs for patient safety]. AB - Handoffs are defined as the transfer of mission specific information and care authority from one healthcare professional to another. Handoffs may create gaps that are especially vulnerable to errors and may have an impact on patient safety. Conceptualising handoffs that are safe gains in importance in medicine with the growing clinical complexity, the reduction of working hours, and a great amount of care fragmentation. Different strategies on the handoff procedure have been identified to improve patient safety. An institutional approach with adaptations to the specific characteristics of each medical discipline is necessary. PMID- 29165940 TI - [Use of clinical practice guidelines in medicine : what's new ?] AB - Clinicians are confronted to an abundance of clinical practice guidelines (CPG). It has been proven for several pathologies that the use of guidelines improves quality of care by reducing mortality, the number of hospitalisations and the length of stay. Despite these proven benefits, adherence to CPGs remains low, mainly due to lack of awareness and familiarity with the guidelines, as well as lack of applicability and flexibility for elderly and comorbid patients. Since adherence to CPGs are influenced by their accessibility and format, informatics will certainly play an important role in the development and implementation of CPGs in the future. An online platform listing swiss CPGs is now available. PMID- 29165941 TI - [Allocation of time in internal medicine]. AB - The hospital internal medicine practice is changing : increasing complexity of patients; implementation of the Electronic Medical Record (EMR); growing volume of medical data and administrative tasks, and limitation of working hours. We quantified the daily tasks of our internal medicine residents. They didn't manage to fulfill their duties in the scheduled time and had to stay after hours ; further, activities indirectly related to patients predominated. Residents spent a daily average of 1.7 hours with patients, 5.2 hours with the computer, and 13 minutes with both. Computer use predominated before 8 am or after 6 pm, while time dedicated to the patient was concentrated in morning during the medical round. Improvements are needed to increase residents' efficiency, and to make them focus on high medical value activities. PMID- 29165942 TI - [Delegation of medico-administrative tasks : what do medical interns and secretaries think?] AB - The hospital activity of physicians in training mainly consists in direct contacts with patients, tasks indirectly linked to patients such as administration, as well as clinical and theoretical training. In our era of digitalization, an important administrative work load without any added medical value fills their daily chores. In parallel activities of medical secretaries are getting more partitioned, with their desks situated far from physicians' and tasks often limited to finalizing discharge letters. Added to multiple overtime, this reduces physicians' and secretaries' work satisfaction. This article describes the context and development of delegating medico-administrative tasks to secretaries in our department of internal medicine. PMID- 29165943 TI - [Abdominal wall pain : the " anterior cutaneous nerve entrapment syndrom "]. AB - Abdominal wall pain is a poorly recognized clinical problem and ofently misdiagnosed. It results in inappropriate diagnostic testing, unsatisfactory treatments and considerable costs. However, chronic abdominal wall pain can be easily diagnosed by a precise physical examination and can be rapidly and efficiently treated. Awareness of knowing criteria of the diagnosis is important but their validity needs to be evaluated in additional studies. PMID- 29165944 TI - ? PMID- 29165945 TI - ? PMID- 29165947 TI - ? PMID- 29165946 TI - ? PMID- 29165948 TI - ? PMID- 29165949 TI - ? PMID- 29165950 TI - Just Culture and Its Impact on a Culture of Safety. PMID- 29165951 TI - Step Up and Start to Engage Professional Power. PMID- 29165952 TI - Identifying and Eliminating the Barriers to Patient Education for Patients in the Early Stages of Chronic Kidney Disease. AB - Patients with chronic kidney disease (CKD) often do not have the knowledge they need to adequately manage their disease and prevent progression. Educating patients with the early stages of CKD is warranted and may assist in delaying progression of disease, improving outcomes, and reducing health expenditures. However, evidence is currently lacking regarding the best methods and approach to educating patients in the early stages of CKD. Multiple patient, provider, and system barriers can interfere with the delivery of patient education in the early stages of CKD. A brief approach, described in this article, is a cost-effective education method that can be easily implemented into a busy clinic setting. PMID- 29165953 TI - An Alternative View of Living Well: Survival Trajectory of Korean Patients with Kidney Failure on Hemodialysis. AB - Patients with kidney failure undergoing hemodialysis rely on a hemodialysis machine for survival. Experiences of patients going through this situation were described using a phenomenological approach. These patients experienced early and late transitions within a dual structure of despair and hope, dependence and independence, and activity and passivity. Early transitions included experiencing shock and a struggle for survival. Late transitions included facing up to the reality and maintaining a hemodialysis-life balance. A traditional Korean belief system constituted a buffering system for the difficulties of their reality. These results may help nurses understand the survival trajectory of patients with kidney failure on hemodialysis and to respond more effectively to the needs of such patients in transition periods. PMID- 29165954 TI - The HIV Organ Policy Equity Act: Offering Hope to Individuals with End Stage Renal Disease and HIV. AB - The HIV Organ Policy Equity Act, or HOPE Act, requires the Secretary of Health and Human Services to develop guidelines for research on the transplantation of kidneys and livers from individuals infected with the human immunodeficiency virus (HIV) into patients with end stage organ failure who are also infected with HIV. Although signed into law in 2013, the guidelines were not finalized until November 2015. Currently, 18 transplant centers that wish to participate in this research have received Institutional Review Board approval. The HOPE Act is expected to expand the donor pool by approximately 500 to 600 per year in the United States and reduce wait times for HIV-infected patients as well as those not infected with the virus. South Africa, a country that began HIV+ to HIV+ transplants several years ago, has demonstrated encouraging patient and graft survival rates. The extent to which these results will be replicated in the United States is unknown. The outcomes experienced by patients and transplant centers that participate in the HOPE Act research will determine if the practice of transplanting HIV-infected organs will one day be considered for more widespread use in the United States. PMID- 29165955 TI - Male Caregivers of Persons with End Stage Renal Disease: A Qualitative Study. AB - This study explored experiences associated with burden, depressive symptoms, and perceived health in six male caregivers of persons with end stage renal disease (ESRD) using qualitative interviews. Analysis employed open coding and analysis to generate codes and categories. Eighty-three percent of the participants reported significant subjective and objective burden. Linkages occurred between sociodemographic characteristics, care recipient attributes, and caregiver-care recipient relationship, and caregivers' experience of burden and depressive symptoms. Findings suggest the need for intervention trials targeting new coping strategies to help improve the well-being of this population. PMID- 29165956 TI - Prophylactic Management of Contrast-Induced Acute Kidney Injury in High-Risk Patients. AB - Contrast-induced acute kidney injury (CI-AKI) has been linked to morbidity and mortality, especially in high-risk patients whose kidney function is compromised. Recently, many studies have been conducted to search for more novel, preventative methods of decreasing CI-AKI. Through a detailed analysis of recent studies, this article discusses recommendations for hydration, N-acetylcysteine, and statin therapy in relation to the prophylactic management of CI-AKI in high-risk patients. PMID- 29165957 TI - Inpatient Dialysis Unit Project Development: Redesigning Acute Hemodialysis Care. AB - Executive leaders of an acute care hospital performed a market and financial analysis, and created a business plan to establish an inpatient hemodialysis unit operated by the hospital to provide safe, high-quality, evidence-based care to the population of individuals experiencing end stage renal disease (ESRD) within the community. The business plan included a SWOT (Strengths - Weaknesses - Opportunities - Threats) analysis to assess advantages of the hospital providing inpatient hemodialysis services versus outsourcing the services with a contracted agency. The results of the project were a newly constructed tandem hemodialysis room and an operational plan with clearly defined key performance indicators, process improvement initiatives, and financial goals. This article provides an overview of essential components of a business plan to guide the establishment of an inpatient hemodialysis unit. PMID- 29165958 TI - Advanced Practice Nurses and End-of-Life Care for Patients with Progressive Chronic Kidney Disease and End Stage Renal Disease. PMID- 29165959 TI - Take Pride in What You Do and Expand Your Horizons. PMID- 29165960 TI - Sentinel Event Alert: The Essential Role of Leadership in Developing a Safety Culture. PMID- 29165962 TI - Caring for Ourselves. PMID- 29165961 TI - Assuring the Next Generation of Nephrology Nurses. PMID- 29165963 TI - Post-Transfer Predictors of Poor Outcomes in Pediatric Renal Transplant Recipients. AB - The aims of this study were twofold: 1) to describe the post-transfer (defined as from pediatric to adult providers) incidence of predictors (medication nonadherence, acute rejection, and change in kidney function), as well as outcomes (graft loss) for adolescent and young adult kidney transplant recipients during a three-year post-transfer follow-up period; and 2) to identify variables to monitor these predictors, in the form of a clinical profile, so providers can promote early intervention for these medically at-risk adolescents. National data were used to describe predictors and outcomes for 250 youth (16 to 25 years old) three years after transfer of care. These predictors were combined with previous literature to develop a preliminary clinical profile. Using an evidence-based clinical profile with predictors for graft loss by a dedicated healthcare professional as a transition coordinator will assist in identifying those at risk for poor outcomes after transfer. PMID- 29165964 TI - Preventing Intradialytic Hypotension: Translating Evidence into Practice. AB - Intradialytic hypotension (IDH) remains the most frequent severe side effect of hemodialysis. This prospective, exploratory study aimed to measure the compliance of an IDH prevention pathway and to identify the effects of pathway use on hypotension incidence. Additionally, the study explored barriers and facilitators to pathway implementation in five hemodialysis centers. Instituting an ultrafiltration pause decreased the odds of hypotensive episodes by 44% (OR = 0.56, 95% CI = 0.20 to 1.56, chi2 1 = 1.25, p = 0.26); however, audits indicated that mean compliance with the pathway (n = 2,711) was only 34%. Focus group interviews revealed nurse concern regarding lack of education prior to pathway implementation and patient apprehension at ultrafiltration pausing without symptoms. This highlights the importance of active translational strategies for clinicians to optimize clinical outcomes in reducing hypotension incidence. PMID- 29165965 TI - Using Teams to Improve Outcomes and Performance. AB - Mastering the use of teams in healthcare organizations can maximize outcomes and optimize the use of resources. Most work in healthcare organizations is done by teams, whether it's the clinical team taking care of patients on a unit, the leadership team accountable for operations of the organization, or a team formed to solve a specific problem, improve quality, or plan an event. Effective teams make organizations successful; ineffective teams can create more problems than they solve. This article describes how to successfully use the power of teams within the healthcare setting, create and develop teams, be a team leader or member, create conditions for team effectiveness and high performance, and provide team training. PMID- 29165966 TI - Merging an Activity Tracker with SystemCHANGETM to Improve Physical Activity in Older Kidney Transplant Recipients. AB - Motivational strategies to increase adherence to a long-term physical activity regimen have been unsuccessful for kidney transplant recipients. We propose a theory-based SystemCHANGETM + Activity Tracker framework. The SystemCHANGETM + Activity Tracker approach combines small, individual-driven experiments for increasing physical activity with visual feedback from the wireless activity tracker, which enables clients to study their progress in increasing physical activity. The SystemCHANGETM + Activity Tracker approach is designed to empower kidney transplant recipients to improve and maintain their physical activity behavior. PMID- 29165967 TI - Measurements of Self-Efficacy in Patients with Chronic Kidney Disease: A Literature Review. AB - This article reviews the literature addressing assessment instruments about various aspects of self-efficacy in patients with chronic kidney disease (CKD). Each scale's structure, reliability, validity, and clinical application are described in detail. When selecting assessment tools to measure the self-efficacy level of patients with CKD, we should take the suitable subjects and application scope into account. With valid and reliable measurement tools, researchers and clinical nurses can assess and stimulate the self-efficacy of patients with CKD more effectively and carry out targeted nursing interventions so as to improve patients' self-efficacy level. This could ultimately enhance the abilities of patients to selfmanage their diseases and improve patient outcomes for people with CKD. PMID- 29165968 TI - Restless Legs Syndrome and Sleep Quality in Patients on Hemodialysis. AB - Restless legs syndrome (RLS) is a common health problem in patients on hemodialysis. This descriptive study was carried out with patients from a hemodialysis unit in the province of Eskisehir, Turkey. Of the 317 patients in the unit, 244 (77.0%) comprised the study group. RLS was assessed by diagnostic criteria defined by the International RLS Working Group, sleep quality by the Pittsburgh Sleep Quality Index, and depression by the Beck Depression Inventory. RLS was found in 15.6% of patients and was associated with depression and sleep quality. Sleep quality is impaired with the increasing severity of RLS. RLS is an important health problem in patients on hemodialysis. PMID- 29165969 TI - All Things Bed Bugs: A Primer for Nephrology Nurses. AB - Bed bug infestation is on the rise, affecting individuals across all demographics and geographics worldwide. Of concern is nursing's lack of knowledge about bed bug transmission, prevention, elimination, and the management of bed bug bites. This article explores the evidence about the lifecycle of the bed bug, its typical presentation, and ways to prevent and eliminate bed bug infestation. Ways that the nephrology nurse can assist in eradication and policy development are discussed, and resources are provided for further information. PMID- 29165970 TI - Primary cutaneous B-cell lymphoblastic lymphoma: A pediatric case report. AB - FPrecursor T- or B-cell non-Hodgkin lymphoblastic lymphomas representonly a small fraction of pediatric cancer cases. Due to its rarity, the diagnosis oflymphoblastic lymphoma (LBL) in a pediatric patient is challenging, particularlyif its manifestation is solely cutaneous. We describe the case of an infant with primary cutaneous B-cell LBL whowas initially diagnosed by a primary care physician with an infectious etiologyand consequently treated with topical and oral antibiotics. Subcutaneous noduleslocated on the head or neck of infants should raise suspicion for lymphomaand biopsy should be performed in order to rule out malignancy. A promptdiagnosis is imperative when considering the aggressive nature of LBLs. Expeditedtherapy has been known to help cease systemic involvement of primarycutaneous B-cell LBLs and encourage a more favorable outcome. PMID- 29165971 TI - Rejection, Recurrence, or Something Else? AB - Since the introduction of liver transplant as treatment for end-stage liver disease,thousands of lives have been saved. To prevent organ rejection, immunosuppressionis given chronically and hence, patients are at increased risk foropportunistic infections related to immunosuppression, especially within thefirst year after the transplant. However, opportunistic infections can occur yearsafter the transplantation. Disseminated nocardiosis is one of these infections,and although the common presentation includes involvement of skin, lungs, andcentral nervous system. We present an uncommon presentation of nocardiosisin which cholestasis and elevated liver enzymes predominate, mimicking organrejection and liver disease recurrence. Infectious etiologies, including opportunisticmicroorganisms, must always be ruled out in patients presenting elevationin liver enzymes and cholestasis after liver transplant as early diagnosis can preventcomplications such as re-transplantation and even death. PMID- 29165972 TI - Right Heart Thrombus in Transit: Unusual Echocardiographic Finding in a patient with Acute Pulmonary Embolism. AB - Eighty year old male patient with heart failure preserved ejection fraction (EF),Obstructive sleep apnea, peripherovascular disease admitted with increasingshortness of breath and found with pulmonary emboli. Baseline 2D-echo cardiogramperformed demonstrated preserved ejection fraction and a rightthrombus in transit. Anticoagulation with weight based-low molecularweight heparin was given for six days. Follow-up echo performed demonstratedcomplete dissolution of right heart thrombi. Since there was complete dis-solution of thrombi seen on right atrium, anticoagulation with Rivaroxabanwas given instead. PMID- 29165973 TI - ST Elevations and Elevated Cardiac Enzymes Not Always a STEMI: Two Case Reports. AB - Chest pain is a common complaint in the emergency department (ED). Besidesa careful history and physical exam; electrocardiogram, laboratorytests and imaging studies are widely available diagnostic tests that are usedfor patient assessment. When ST elevation and elevated cardiac enzymesare present the most likely diagnosis are ST elevation myocardial infarction(STEMI) or myocarditis. In this case report we present two low risk patientsfor major adverse cardiac event with ST elevation and elevated cardiac enzymesand how a careful risk assessment and detailed electrocardiogram evaluationcould help differentiating between these two diagnoses. PMID- 29165974 TI - Epidemiology of pediatric bone fractures across age groups: Analysis of a pediatric population at an outpatient clinic in the Southwest region of Puerto Rico. AB - BACKGROUND: Background: Gender disparities in pediatric fracture events has beenwell-documented however, less is known about racial disparities. The aim of this study is to investigate the epidemiology ofpediatric bone fractures in a Hispanic population. METHODS: This is a retrospective cross-sectional analysis of patient's records from aPediatric Orthopeadic outpatient clinic in the Southwest region of Puerto Ricoduring a 1-year span (August 2014 - August 2015). Differences in sex, BMI,health insurance coverage, parental educational level and employment status,mechanism of fracture, fracture site, and seasonality were investigated amongthree age classes (pre-school children, school children and adolescents). RESULTS: The sample consited of 243 subjects (0-21 y/o) sustaining a fracture ofany extremity within the study period. Boys were at a higher risk of having afracture event and as age increased, the male/female ratio also increased. Themean BMI was 18.0 kg/m2, with the highest in the school children age group(20.3 kg/m2). Slighlty more than half of the subjects (55.7%) benefitted frompublic health insurance coverage. The typical father was a laborer with a highschool diploma, while the mother had a high school diploma but was unemployedThere was a tendency for the children to suffer a bone fracture whileat school (49.4%), followed by fractures at home (34.6%). In both the pre-schooland school children groups, the upper extremity was more frequently involved(66.7% and 63.9%, respectively) in fracture events. Finally, there was very littlevariation in the seasonality of fracture events. CONCLUSION: This study provided valuable epidemiological information aboutpediatric bone fractures within a Hispanic population. It may contribute tothe development and implementation of educational and preventive strategiesappropriate to age and sex differences. PMID- 29165979 TI - Addressing Challenges and Scalability in the Synthesis of Thin Uniform Metal Shells on Large Metal Nanoparticle Cores: Case Study of Ag-Pt Core-Shell Nanocubes. AB - Bimetallic nanoparticles in which a metal is coated with an ultrathin (~1 nm) layer of a second metal are often desired for their unique chemical and physical properties. Current synthesis methods for producing such core-shell nanostructures often require incremental addition of a shell metal precursor which is rapidly reduced onto metal cores. A major shortcoming of this approach is that it necessitates precise concentrations of chemical reagents, making it difficult to perform at large scales. To address this issue, we considered an approach whereby the reduction of the shell metal precursor was controlled through in situ chemical modification of the precursor. We used this approach to develop a highly scalable synthesis for coating atomic layers of Pt onto Ag nanocubes. We show that Ag-Pt core-shell nanostructures are synthesized in high yields and that these structures effectively combine the optical properties of the plasmonic Ag nanocube core with the surface properties of the thin Pt shell. Additionally, we demonstrate the scalability of the synthesis by performing a 10 times scale-up. PMID- 29165980 TI - Controlled Insertion of Planar Defect in Inverse Opals for Anticounterfeiting Applications. AB - Inverse opals have been used for structural coloration and photonic applications owing to their photonic bandgap properties. When the photonic structures contain planar defects, they provide defect modes, which are useful for lasing, sensing, and waveguiding. However, it remains a challenge to insert a planar defect into inverse opals in a reproducible manner. Here, we report a new method for producing planar-defect-inserted inverse opals using sequential capillary wetting of colloidal crystals and creating micropatterns through photolithography. Three cycles of deposition and thermal embedding of colloidal crystals into the underlying film of negative photoresist were performed. In the three cycles, opal, particle monolayer, and opal were sequentially employed, which yielded the monolayer-templated planar defect sandwiched by two inverse opals after particle removal. The planar defect provided a passband whose wavelength can be controlled by adjusting the diameter of particles for the defect layer. Moreover, the defect inserted inverse opals can be micropatterned by photolithography as the negative photoresist is used as a matrix. The resulting micropatterns deliver a unique spectral code featured by a combination of stop band and defect mode and a graphical code dictated by photolithography, being useful for anticounterfeiting applications. PMID- 29165981 TI - Layered Double Hydroxide and Polypeptide Thermogel Nanocomposite System for Chondrogenic Differentiation of Stem Cells. AB - Stem cell therapy for damaged cartilage suffers from low rates of retention, survival, and differentiation into chondrocytes at the target site. To solve these problems, here we propose a two-dimensional/three-dimensional (2D/3D) nanocomposite system. As a new two-dimensional (2D) material, hexagonal layered double hydroxides (LDHs) with a uniform lateral length of 2-3 MUm were prepared by a hydrothermal process. Then, tonsil-derived mesenchymal stem cells (TMSCs), arginylglycylaspartic acid-coated LDHs, and kartogenin (KGN) were incorporated into the gel through the thermal-energy-driven gelation of the system. The cells exhibited a tendency to aggregate in the nanocomposite system. In particular, chondrogenic biomarkers of type II collagen and transcription factor SOX 9 significantly increased at both the mRNA and protein levels in the nanocomposite system, compared to the pure thermogel systems. The inorganic 2D materials increased the rigidity of the matrix, slowed down the release of a soluble factor (KGN), and improved cell-material interactions in the gel. The current 2D/3D nanocomposite system of bioactive LDH/thermogel can be a new platform material overcoming drawbacks of hydrogel-based 3D cell culture systems and is eventually expected to be applied as an injectable stem cell therapy. PMID- 29165982 TI - Phosphor-Assisted Temperature Sensing and Imaging Using Resonant and Nonresonant Photoexcitation Scheme. AB - Phosphor-assisted luminescent thermometry relies on studying, often subtle, temperature-dependent spectral properties, such as luminescence spectra, bands shifts, or luminescence lifetimes. Although this is feasible with high-resolution spectrometers or time-resolved detectors, technical implementation of such temperature mapping or wide-field imaging is complex and cumbersome. Therefore, a new approach for noncontact ratiometric temperature detection has been proposed based on comparison of emission properties of bright Cr3+-doped phosphors at single emission band upon two, resonant and nonresonant, optical excitation bands. The proposed method of temperature readout was examined for three different host materials: YAlO3, Y3Al5O12, and LiLaP4O12 nanocrystals. The highest relative sensitivity in physiological temperature range was found for YAlO3 nanocrystals reaching 0.35%/K, which is related to the highest crystal field found for this phosphor. The proposed methodology and the obtained materials enabled to not only reliably measure temperature in the range of -150 to 300 degrees C but also significantly simplify the technical detection scheme. In consequence, lamp-photoexcited, wide-field, micron-resolution microscopy imaging became possible, which is of special interest for many remote temperature studies in technology and biomedical applications. PMID- 29165983 TI - Incorporating an Electrode Modification Layer with a Vertical Phase Separated Photoactive Layer for Efficient and Stable Inverted Nonfullerene Polymer Solar Cells. AB - For bulk heterojunction polymer solar cells (PSCs), the donors and acceptors featuring specific phase separation and concentration distribution within the electron donor/acceptor blends crucially affect the exciton dissociation and charge transportation. Herein, efficient and stable nonfullerene inverted PSCs incorporating a phase separated photoactive layer and a titanium chelate electrode modification layer are demonstrated. Water contact angle (WCA), scanning kelvin probe microscopy (SKPM), and atomic force microscopy (AFM) techniques are implemented to characterize the morphology of photoactive layers. Compared with the control conventional device, the short-circuit current density (Jsc) is enhanced from 14.74 to 17.45 mAcm-2. The power conversion efficiency (PCE) for the inverted PSCs with a titanium (diisopropoxide)-bis-(2,4 pentanedionate) (TIPD) layer increases from 9.67% to 11.69% benefiting from the declined exciton recombination and fairly enhanced charge transportation. Furthermore, the nonencapsulated inverted device with a TIPD layer demonstrates the best long-term stability, 85% of initial PCE remaining and an almost undecayed open-circuit voltage (Voc) after 1440 h. Our results reveal that the titanium chelate is an excellent electrode modification layer to incorporate with a vertical phase separated photoactive layer for producing high-efficiency and high-stability inverted nonfullerene PSCs. PMID- 29165984 TI - On-Chip Lipid Extraction Using Superabsorbent Polymers for Mass Spectrometry. AB - Pretreatment of samples is one of the most important steps in analytical methods for efficient and accurate results. Typically, an extraction method used for lipid analysis with mass spectrometry is accompanied by complex liquid-liquid extraction. We have devised a simple, rapid, and efficient lipid extraction method using superabsorbent polymers (SAPs) and developed a high-throughput lipid extraction platform based on a microfluidic system. Since SAPs can rapidly absorb an aqueous solution from a raw sample and convert it into the gel, the lipid extraction process can be remarkably simplified. The hydrophobic lipid components were captured into the fibrous SAP gel and then solubilized and eluted directly into the organic solvent without significant interference by this polymer. The small-scale lipid extraction process minimizes the liquid handling and unnecessary centrifugation steps, thereby enabling the implementation of a SAP integrated microfluidic lipid extraction platform. The SAP method successfully induced reproducible extraction and high recovery rates (95-100%) compared to the conventional Folch method in several lipid classes. We also demonstrated the feasibility of the SAP method for the analysis of lipids in complex biological samples, such as the brain and liver, as well as Escherichia coli. This small scale SAP method and its microfluidic platform will open up new possibilities in high-throughput lipidomic research for diagnosing diseases because this new technique saves time, labor, and cost. PMID- 29165985 TI - Nanoscale Dynamics of Amyloid beta-42 Oligomers As Revealed by High-Speed Atomic Force Microscopy. AB - Amyloid beta-protein (Abeta) oligomers are emerging as potent neurotoxic species in Alzheimer's disease pathogenesis. Detailed characterization of oligomer structure and dynamics is necessary to develop oligomer-specific therapeutic agents. However, oligomers exist transiently, which complicates their structural analysis. One approach to mitigate these problems has been photochemical cross linking of native oligomers. In these states, the oligomers can be isolated and purified for physical and chemical studies. Here we characterized the structure of isolated cross-linked Abeta42 trimers, pentamers, and heptamers with atomic force microscopy (AFM) imaging and probed their dynamics in solution using time lapse high-speed AFM. This technique enables visualization of the structural dynamics of the oligomers at nanometer resolution on a millisecond time scale. Results demonstrate that cross-linked pentamers and heptamers are very dynamic fluctuating between a compact single-globular and multiglobular assemblies. Trimers remain in their single-globular geometry that elongates adopting an ellipsoidal shape. Biological significance of oligomers dynamics is discussed. PMID- 29165986 TI - Scalable Low-Band-Gap Sb2Se3 Thin-Film Photocathodes for Efficient Visible-Near Infrared Solar Hydrogen Evolution. AB - A highly efficient low-band-gap (1.2-0.8 eV) photoelectrode is critical for accomplishing efficient conversion of visible-near-infrared sunlight into storable hydrogen. Herein, we report an Sb2Se3 polycrystalline thin-film photocathode having a low band gap (1.2-1.1 eV) for efficient hydrogen evolution for wide solar-spectrum utilization. The photocathode was fabricated by a facile thermal evaporation of a single Sb2Se3 powder source onto the Mo-coated soda-lime glass substrate, followed by annealing under Se vapor and surface modification with an antiphotocorrosive CdS/TiO2 bilayer and Pt catalyst. The fabricated Sb2Se3(Se-annealed)/CdS/TiO2/Pt photocathode achieves a photocurrent density of ca. -8.6 mA cm-2 at 0 VRHE, an onset potential of ca. 0.43 VRHE, a stable photocurrent for over 10 h, and a significant photoresponse up to the near infrared region (ca. 1040 nm) in near-neutral pH buffered solution (pH 6.5) under AM 1.5G simulated sunlight. The obtained photoelectrochemical performance is attributed to the reliable synthesis of a micrometer-sized Sb2Se3 (Se-annealed) thin film as photoabsorber and the successful construction of an appropriate p-n heterojunction at the electrode-liquid interface for effective charge separation. The demonstration of a low-band-gap and high-performance Sb2Se3 photocathode with facile fabrication might facilitate the development of cost-effective PEC devices for wide solar-spectrum utilization. PMID- 29165987 TI - Hierarchical Self-Assembly of a Porphyrin into Chiral Macroscopic Flowers with Superhydrophobic and Enantioselective Property. AB - Supramolecular self-assembly provides an efficient way to fabricate simple units into various hierarchical nano/microstructures, which could mimic the bioself assembly and develop functional materials. Since chiral molecules and chiral nanostructures are widely adopted by biological systems, an introduction of the chiral factor into the self-assembly process will provide better understanding of the biological systems. Here, using a chiral amphiphilic histidine to assist the self-assembly of a porphyrin with four carboxylic acids, we obtained hierarchical chiral nano- to microstructures. We have found that through the hydrogen bonds/electrostatic interactions between the porphyrin and histidine derivatives, the pi-pi stacking between the porphyrins, and hydrophobic interactions between the amphiphilic histidine, the two components could self-assemble into chiral nanohelices and microflowers. The supramolecular chirality of these structures was confirmed by scanning electron microscopy images as well as the circular dichroism spectra, which was found to follow the molecular chirality of the histidine derivative. More interestingly, the microflower structures formed a superhydrophobic and chiral surface, which exhibited macroscopic enantioselective recognition of some l- and d-amino acids via contact angle measurements. PMID- 29165988 TI - Bioconjugate Strategies for the Induction of Antigen-Specific Tolerance in Autoimmune Diseases. AB - Antigen-specific immunotherapy (ASI) holds great promise for the treatment of autoimmune diseases. In mice, administration of major histocompatibility complex (MHC) binding synthetic peptides which modulate T cell receptor (TCR) signaling under subimmunogenic conditions induces selective tolerance without suppressing the global immune responses. However, clinical translation has yielded limited success. It has become apparent that the TCR signaling pathway via synthetic peptide antigen alone is inadequate to induce an effective tolerogenic immunity in autoimmune diseases. Bioconjugate strategies combining additional immunomodulatory functions with TCR signaling can amplify the antigen-specific immune tolerance and possibly lead to the development of new treatments in autoimmune diseases. In this review, we provide a summary of recent advances in the development of bioconjugates to achieve antigen-specific immune tolerance in vivo, with the discussion focused on the underlying design principles and challenges that must be overcome to target these therapies to patients suffering from autoimmune diseases. PMID- 29165989 TI - Bispentafluorophenyl-Containing Additive: Enhancing Efficiency and Morphological Stability of Polymer Solar Cells via Hand-Grabbing-Like Supramolecular Pentafluorophenyl-Fullerene Interactions. AB - A new class of additive materials bis(pentafluorophenyl) diesters (BFEs) where the two pentafluorophenyl (C6F5) moieties are attached at the both ends of a linear aliphatic chain with tunable tether lengths (BF5, BF7, and BF13) were designed and synthesized. In the presence of BF7 to restrict the migration of fullerene by hand-grabbing-like supramolecular interactions induced between the C6F5 groups and the surface of fullerene, the P3HT:PC61BM:BF7 device showed stable device characteristics after thermal heating at 150 degrees C for 25 h. The morphologies of the active layers were systematically investigated by optical microscopy, grazing-incidence small-angle X-ray scattering (GISAXS), and atomic force microscopy. The tether length between the two C6F5 groups plays a pivotal role in controlling the intermolecular attractions. BF13 with a long and flexible tether might form a BF13-fullerene sandwich complex that fails to prevent fullerene's movement and aggregation, while BF5 with too short tether length decreases the possibility of interactions between the C6F5 groups and the fullerenes. BF7 with the optimal tether length has the best ability to stabilize the morphology. In sharp contrast, the nonfluorinated BP7 analogue without C6F5 C60 physical interactions does not have the capability of morphological stabilization, unambiguously revealing the necessity of the C6F5 group. Most importantly, the function of BF7 can be also applied to the high-performance PffBT4BT-2OD:PC71BM system, which exhibited an original PCE of 8.80%. After thermal heating at 85 degrees C for 200 h, the efficiency of the PffBT4BT 2OD:PC71BM:BF7 device only decreased slightly to 7.73%, maintaining 88% of its original efficiency. To the best of our knowledge, this is the first time that the thermal-driven morphological evolution of the high-performance PffBT4BT-2OD polymer has been investigated, and its morphological stability in the inverted device can be successfully preserved by the incorporation of BF7. This research also demonstrates that BF7 is not only effective with PC61BM but also to PC71BM. PMID- 29165990 TI - UiO-66-NH2 Metal-Organic Framework (MOF) Nucleation on TiO2, ZnO, and Al2O3 Atomic Layer Deposition-Treated Polymer Fibers: Role of Metal Oxide on MOF Growth and Catalytic Hydrolysis of Chemical Warfare Agent Simulants. AB - Metal-organic frameworks (MOFs) chemically bound to polymeric microfibrous textiles show promising performance for many future applications. In particular, Zr-based UiO-66-family MOF-textiles have been shown to catalytically degrade highly toxic chemical warfare agents (CWAs), where favorable MOF/polymer bonding and adhesion are attained by placing a nanoscale metal-oxide layer on the polymer fiber preceding MOF growth. To date, however, the nucleation mechanism of Zr based MOFs on different metal oxides and how product performance is affected are not well understood. Herein, we provide new insight into how different inorganic nucleation films (i.e., Al2O3, ZnO, or TiO2) conformally coated on polypropylene (PP) nonwoven textiles via atomic layer deposition (ALD) influence the quality, overall surface area, and the fractional yield of UiO-66-NH2 MOF crystals solvothermally grown on fiber substrates. Of the materials explored, we find that TiO2 ALD layers lead to the most effective overall MOF/fiber adhesion, uniformity, and a rapid catalytic degradation rate for a CWA simulant, dimethyl p nitrophenyl phosphate (DMNP) with t1/2 = 15 min, 580-fold faster than the catalytic performance of untreated PP textiles. Interestingly, compared to ALD TiO2 and Al2O3, ALD ZnO induces a larger MOF yield in solution and mass loading on PP fibrous mats. However, this larger MOF yield is ascribed to chemical instability of the ZnO layer under MOF formation condition, leading to Zn2+ ions that promote further homogeneous MOF growth. Insights presented here improve understanding of compatibility between active MOF materials and substrate surfaces, which we believe will help advanced MOF composite materials for a variety of useful functions. PMID- 29165991 TI - Ultrastretchable Graphene-Based Molecular Barriers for Chemical Protection, Detection, and Actuation. AB - A wide range of technologies requires barrier films to impede molecular transport between the external environment and a desired internal microclimate. Adding stretchability to barrier films would enable the applications in packaging, textiles, and flexible devices, but classical barrier materials utilize dense, ordered molecular architectures that easily fracture under small tensile strain. Here, we show that textured graphene-based coatings can serve as ultrastretchable molecular barriers expandable to 1500% areal strain through programmed unfolding that mimics the elasticity of polymers. These coatings retain barrier function under large deformation and can be conformally applied to planar or curved surfaces, where they are washfast and mechanically robust to cycling. These graphene-polymer bilayer structures also function as sensors or actuators by transducing chemical stimuli into mechanical deformation and electrical resistance change through asymmetric polymer swelling. These results may enable multifunctional fabrics that integrate chemical protection, sensing, and actuation, with further applications as selective barriers, membranes, stretchable electronics, or soft robotics. PMID- 29165992 TI - Quantitative Chemical Analysis at the Nanoscale Using the Photothermal Induced Resonance Technique. AB - Photothermal induced resonance (PTIR), also known as AFM-IR, is a scanning probe technique that provides sample composition information with a lateral resolution down to 20 nm. Interest in PTIR stems from its ability to identify unknown samples at the nanoscale thanks, in first approximation, to the direct comparability of PTIR spectra with far-field infrared databases. The development of rapidly tuning quantum cascade lasers has increased the PTIR throughput considerably, making nanoscale hyperspectral imaging within a reasonable time frame possible. Consequently, a better understanding of PTIR signal generation and of the fine details of PTIR analysis has become of paramount importance for extending complex IR analysis methods developed in the far-field, e.g., for classification and hyperspectral imaging, to nanoscale PTIR spectra. Here we calculate PTIR spectra via thin-film optics, to identify subtle changes (band shifts, deviation from linear approximation, etc.) for common sample parameters in the case of PTIR with total internal reflection illumination. Results show signal intensity linearity and small band shifts as long as the sample is prepared correctly, with band shifts typically smaller than macroscale attenuated total reflection (ATR) spectroscopy. Finally, a generally applicable algorithm to retrieve the pure imaginary component of the refractive index (i.e., the chemically specific information) is provided to overcome the PTIR spectra nonlinearity. PMID- 29165993 TI - Hybrid Structured Illumination Expansion Microscopy Reveals Microbial Cytoskeleton Organization. AB - Recently developed tissue-hydrogel methods for specimen expansion now enable researchers to perform super-resolution microscopy with ~65 nm lateral resolution using ordinary microscopes, standard fluorescent probes, and inexpensive reagents. Here we use the combination of specimen expansion and the optical super resolution microscopy technique structured illumination microscopy (SIM) to extend the spatial resolution to ~30 nm. We apply this hybrid method, which we call ExSIM, to study the cytoskeleton of the important human pathogen Giardia lamblia including the adhesive disc and flagellar axonemes. We determined the localization of two recently identified disc-associated proteins, including DAP86676 , which localizes to disc microribbons, and the functionally unknown DAP16263 , which primarily localizes to dorsal microtubules of the disc overlap zone and the paraflagellar rod of ventral axonemes. Based on its strong performance in revealing known and unknown details of the ultrastructure of Giardia, we find that ExSIM is a simple, rapid, and powerful super-resolution method for the study of fixed specimens, and it should be broadly applicable to other biological systems of interest. PMID- 29165994 TI - From Graphene Oxide to Reduced Graphene Oxide: Impact on the Physiochemical and Mechanical Properties of Graphene-Cement Composites. AB - Graphene materials have been extensively explored and successfully used to improve performances of cement composites. These formulations were mainly optimized based on different dosages of graphene additives, but with lack of understanding of how other parameters such as surface chemistry, size, charge, and defects of graphene structures could impact the physiochemical and mechanical properties of the final material. This paper presents the first experimental study to evaluate the influence of oxygen functional groups of graphene and defectiveness of graphene structures on the axial tension and compression properties of graphene-cement mortar composites. A series of reduced graphene oxide (rGO) samples with different levels of oxygen groups (high, mild, and low) were prepared by the reduction of graphene oxide (GO) using different concentrations of hydrazine (wt %, 0.1, 0.15, 0.2, 0.3, and 0.4%) and different reduction times (5, 10, 15, 30, and 60 min) and were added to cement mortar composites at an optimal dosage of 0.1%. A series of characterization methods including scanning electron microscopy, energy-dispersive X-ray spectroscopy, X ray diffraction, thermogravimetric analysis, and Fourier transform infrared spectroscopy were performed to determine the distribution and mixing of the prepared rGO in the cement matrix and were correlated with the observed mechanical properties of rGO-cement mortar composites. The measurement of the axial tension and compression properties revealed that the oxygen level of rGO additives has a significant influence on the mechanical properties of cement composites. An addition of 0.1% rGO prepared by 15 min reduction and 0.2% (wt %) hydrazine with mild level of oxygen groups resulted in a maximum enhancement of 45.0 and 83.7%, respectively, in the 28-day tensile and compressive strengths in comparison with the plain cement mortar and were higher compared to the composite prepared with GO (37.5 and 77.7%, respectively). These results indicate that there is a strong influence of the level of oxygen groups and crystallinity of graphene structures on the physiochemical and mechanical properties. The influence of these two parameters are interconnected and their careful balancing is required to provide an optimum level of oxygen groups on rGO sheets to ensure that there is sufficient bonding between the calcium silicate hydrate (C-S-H) components in the cement matrix and minimum level of defects and higher crystallinity of graphene structures, which will improve the mechanical properties of the composite. Finding the optimized balance between these two parameters is required to formulate graphene cement composites with the highest performance. PMID- 29165996 TI - iTop-Q: an Intelligent Tool for Top-down Proteomics Quantitation Using DYAMOND Algorithm. AB - Top-down proteomics using liquid chromatogram coupled with mass spectrometry has been increasingly applied for analyzing intact proteins to study genetic variation, alternative splicing, and post-translational modifications (PTMs) of the proteins (proteoforms). However, only a few tools have been developed for charge state deconvolution, monoisotopic/average molecular weight determination and quantitation of proteoforms from LC-MS1 spectra. Though Decon2LS and MASH Suite Pro have been available to provide intraspectrum charge state deconvolution and quantitation, manual processing is still required to quantify proteoforms across multiple MS1 spectra. An automated tool for interspectrum quantitation is a pressing need. Thus, in this paper, we present a user-friendly tool, called iTop-Q (intelligent Top-down Proteomics Quantitation), that automatically performs large-scale proteoform quantitation based on interspectrum abundance in top-down proteomics. Instead of utilizing single spectrum for proteoform quantitation, iTop-Q constructs extracted ion chromatograms (XICs) of possible proteoform peaks across adjacent MS1 spectra to calculate abundances for accurate quantitation. Notably, iTop-Q is implemented with a newly proposed algorithm, called DYAMOND, using dynamic programming for charge state deconvolution. In addition, iTop-Q performs proteoform alignment to support quantitation analysis across replicates/samples. The performance evaluations on an in-house standard data set and a public large-scale yeast lysate data set show that iTop-Q achieves highly accurate quantitation, more consistent quantitation than using intraspectrum quantitation. Furthermore, the DYAMOND algorithm is suitable for high charge state deconvolution and can distinguish shared peaks in coeluting proteoforms. iTop-Q is publicly available for download at http://ms.iis.sinica.edu.tw/COmics/Software_iTop-Q . PMID- 29165997 TI - Materials for the Recovery of Uranium from Seawater. AB - More than 1000* uranium exists in the oceans than exists in terrestrial ores. With nuclear power generation expected to increase over the coming decades, access to this unconventional reserve is a matter of energy security. With origins in the mid-1950s, materials have been developed for the selective recovery of seawater uranium for more than six decades, with a renewed interest in particular since 2010. This review comprehensively surveys materials developed from 2000-2016 for recovery of seawater uranium, in particular including recent developments in inorganic materials; polymer adsorbents and related research pertaining to amidoxime; and nanostructured materials such as metal-organic frameworks, porous-organic polymers, and mesoporous carbons. Challenges of performing reliable and reproducible uranium adsorption studies are also discussed, as well as the standardization of parameters necessary to ensure valid comparisons between different adsorbents. PMID- 29165995 TI - Magnetic Particle Imaging for Highly Sensitive, Quantitative, and Safe in Vivo Gut Bleed Detection in a Murine Model. AB - Gastrointestinal (GI) bleeding causes more than 300 000 hospitalizations per year in the United States. Imaging plays a crucial role in accurately locating the source of the bleed for timely intervention. Magnetic particle imaging (MPI) is an emerging clinically translatable imaging modality that images superparamagnetic iron-oxide (SPIO) tracers with extraordinary contrast and sensitivity. This linearly quantitative modality has zero background tissue signal and zero signal depth attenuation. MPI is also safe: there is zero ionizing radiation exposure to the patient and clinically approved tracers can be used with MPI. In this study, we demonstrate the use of MPI along with long circulating, PEG-stabilized SPIOs for rapid in vivo detection and quantification of GI bleed. A mouse model genetically predisposed to GI polyp development (ApcMin/+) was used for this study, and heparin was used as an anticoagulant to induce acute GI bleeding. We then injected MPI-tailored, long-circulating SPIOs through the tail vein, and tracked the tracer biodistribution over time using our custom-built high resolution field-free line (FFL) MPI scanner. Dynamic MPI projection images captured tracer accumulation in the lower GI tract with excellent contrast. Quantitative analysis of the MPI images show that the mice experienced GI bleed rates between 1 and 5 MUL/min. Although there are currently no human scale MPI systems, and MPI-tailored SPIOs need to undergo further development and evaluation, clinical translation of the technique is achievable. The robust contrast, sensitivity, safety, ability to image anywhere in the body, along with long-circulating SPIOs lends MPI outstanding promise as a clinical diagnostic tool for GI bleeding. PMID- 29165998 TI - Characterization of Natural Organic Substances Potentially Hindering RT-PCR-Based Virus Detection in Large Volumes of Environmental Water. AB - Quantitative detection of pathogenic viruses in the environmental water is essential for the assessment of water safety. It is known that some of natural organic substances interfere with virus detection processes, i.e., nucleic acid extraction and reverse transcription-PCR. Such substances are carried over into a sample after virus concentration. In this study, inhibitory substances in coastal water samples were characterized in view of their effects on efficiency of virus detection and property as organic matters. Among 81 samples tested, 77 (95%) showed low recoveries (<10%) of spiked murine norovirus. These recovery rates were correlated with the levels of organic matter present in virus concentrates as measured by ultraviolet absorbance at 254 nm (r = -0.70 - -0.71, p < 0.01). High-performance gel chromatography and fluorescence excitation-emission matrix spectroscopy revealed that organic fractions in the 10-100 kDa size range, which were not dominant in the original samples, and those possessing humic acid-like fluorescence properties were dominant in virus concentrates. The inhibitory effect was more pronounced during summer. Substances originating from seawater seemed to cause a more pronounced effect than those originating from wastewater. Our data highlight the previously unknown characteristics of natural inhibitory substances and are helpful in establishing an effective sample purification technique. PMID- 29165999 TI - Crystal Growth with Macromolecular Additives. AB - Interactions of macromolecules with growing crystalline surfaces play an important role in biomineralization, determine survival of some organisms at low temperatures, and offer a range of potential industrial applications. The current understanding of crystal growth processes in the presence of macromolecules, including peptides and proteins, is reviewed, with a focus on interactions between macromolecules and surfaces of crystalline materials, macromolecule adsorption on different types of crystal surfaces, crystallization kinetics in the presence of macromolecular additives, macromolecule incorporation, and defect generation. Throughout, special attention is paid to the selectivity of macromolecule adsorption on, and incorporation within, crystal surfaces. The special role played by the size and complexity of macromolecules as compared to other crystallization additives is emphasized. PMID- 29166000 TI - Synthesis and Reactivity of Propargylamines in Organic Chemistry. AB - Propargylamines are a versatile class of compounds which find broad application in many fields of chemistry. This review aims to describe the different strategies developed so far for the synthesis of propargylamines and their derivatives as well as to highlight their reactivity and use as building blocks in the synthesis of chemically relevant organic compounds. In the first part of the review, the different synthetic approaches to synthesize propargylamines, such as A3 couplings and C-H functionalization of alkynes, have been described and organized on the basis of the catalysts employed in the syntheses. Both racemic and enantioselective approaches have been reported. In the second part, an overview of the transformations of propargylamines into heterocyclic compounds such as pyrroles, pyridines, thiazoles, and oxazoles, as well as other relevant organic derivatives, is presented. PMID- 29166002 TI - Structure and Affinity of Cu(I) Bound to Human Serum Albumin. AB - Human serum albumin (HSA) is a major Cu carrier in human blood and in cerebrospinal fluid. A major assumption is that Cu bound to HSA is in the Cu(II) oxidation state; thus, interactions between HSA and Cu(II) have been intensely investigated for over four decades. HSA has been reported previously to support the reduction of Cu(II) to the Cu(I) oxidation state in the presence of the weak reductant, ascorbate; however, the interactions between HSA and Cu(I) have not been explicitly investigated. Here, we characterize both the apparent affinity of HSA for Cu(I) using solution competition experiments and the coordination structure of Cu(I) bound to HSA using X-ray absorption spectroscopy and in silico modeling. We find that HSA binds to Cu(I) at pH 7.4 with an apparent conditional affinity of KCu(I):HSA = 1014.0 using digonal coordination in a structure that is similar to the bis-His coordination modes characterized for amyloid beta (Abeta) and the prion protein. This high affinity and familiar Cu(I) coordination structure suggests that Cu(I) interaction with HSA in human extracellular fluids is unappreciated in the current scientific literature. PMID- 29166001 TI - A Redox Role for the [4Fe4S] Cluster of Yeast DNA Polymerase delta. AB - A [4Fe4S]2+ cluster in the C-terminal domain of the catalytic subunit of the eukaryotic B-family DNA polymerases is essential for the formation of active multi-subunit complexes. Here we use a combination of electrochemical and biochemical methods to assess the redox activity of the [4Fe4S]2+ cluster in Saccharomyces cerevisiae polymerase (Pol) delta, the lagging strand DNA polymerase. We find that Pol delta bound to DNA is indeed redox-active at physiological potentials, generating a DNA-mediated signal electrochemically with a midpoint potential of 113 +/- 5 mV versus NHE. Moreover, biochemical assays following electrochemical oxidation of Pol delta reveal a significant slowing of DNA synthesis that can be fully reversed by reduction of the oxidized form. A similar result is apparent with photooxidation using a DNA-tethered anthraquinone. These results demonstrate that the [4Fe4S] cluster in Pol delta can act as a redox switch for activity, and we propose that this switch can provide a rapid and reversible way to respond to replication stress. PMID- 29166004 TI - Comment on "Molecular Mechanism of Dioxin Formation from Chlorophenol based on Electron Paramagnetic Resonance Spectroscopy". PMID- 29166003 TI - Hydrogenation Properties of Laves Phases LnMg2 (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Ho, Er, Tm, Yb). AB - The hydrogenation properties of Laves phases LnMg2 (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Ho, Er, Tm, Yb) were investigated by thermal analysis, X-ray, synchrotron, and neutron powder diffraction. At 14.0 MPa hydrogen gas pressure and 393 K, PrMg2 and NdMg2 take up hydrogen and form the colorless, ternary hydrides PrMg2H7 (P41212, a = 632.386(6) pm, c = 945.722(11) pm) and NdMg2H7 (P41212, a = 630.354(9) pm, c = 943.018(16) pm). The crystal structures were refined by the Rietveld method from neutron powder diffraction data on the deuterides (PrMg2D7, P41212, a = 630.56(2) pm, c = 943.27(3) pm; NdMg2D7, P41212, a = 628.15(2) pm, c = 940.32(3) pm) and shown to be isotypic to LaMg2D7. The LaMg2D7 type of hydrides decompose at 695 K (La), 684 K (Ce), 684 K (Pr), 672 K (Nd), and 639 K (Sm) to lanthanide hydrides and magnesium. The Laves phase EuMg2 forms a hydride EuMg2Hx of black color. Its crystal structure (P212121, a = 664.887(4) pm, b = 1136.993(7) pm, c = 1069.887(7) pm) is closely related to the hexagonal Laves phase (MgZn2 type) of the hydrogen-free parent intermetallic. GdMg2 and TbMg2 form hydrides GdMg2Hx with orthorhombic unit cells (a = 1282.7(4) pm, b = 572.5(2) pm, c = 881.7(2) pm) and TbMg2Hx (a = 617.8(3) pm, b = 1045.8(8) pm, c = 997.1(5) pm), presumably also with a distorted MgZn2 type of structure. CeMg2H7 and NdMg2H7 are paramagnetic with effective magnetic moments of 2.49(1) MUB and 3.62(1) MUB, respectively, in good agreement with the calculated magnetic moments of the free trivalent rare-earth cations (MUcalc(Ce3+) = 2.54 MUB; MUcalc(Nd3+) = 3.62 MUB). PMID- 29166005 TI - Self-Assembly of Tetrameric and Hexameric Terpyridine-Based Macrocycles Using Cd(II), Zn(II), and Fe(II). AB - The self-assembly behavior of a tritopic 2,2':6',2"-terpyridine (tpy) ligand with Cd(II), Zn(II), and Fe(II) has been exploited herein to generate a series of tetrameric and hexameric macrocycles. The main advantage of using such transition metals with an octahedral coordination geometry is their distinct coordination abilities (e.g., binding strength and reversibility). With the same ligand, this study reveals that the supramolecular structural variation between tetrameric and hexameric macrocycle architectures can be precisely controlled using different metal ions with the same coordination geometry. When Cd(II) was used, a tetrameric macrocycle was the only observed structure in the self-assembly, whereas Zn(II) and Fe(II) assembled a mixture of tetrameric and hexameric macrocycles. Because of the high stability of Fe(II) as the coordination center, we successfully isolated tetrameric and hexameric macrocycles using a regular column. In-depth characterization was carried out to establish the proposed structures, including multinuclear NMR (1H, 19F, and 13C) analysis, electrospray ionization mass spectrometry, and 2D ion-mobility mass spectrometry. PMID- 29166006 TI - COPTEM: A Model to Investigate the Factors Driving Crude Oil Pipeline Transportation Emissions. AB - Previous transportation fuel life cycle assessment studies have not fully accounted for the full variability in the crude oil transport stage, for example, transporting a light crude through a high-diameter pipeline, vs transporting a heavy crude through a small-diameter pipeline. We develop a first-principles, fluid mechanics-based crude oil pipeline transportation emissions model (COPTEM) that calculates the greenhouse gas (GHG) emissions associated with pipeline transport as a function of crude oil parameters, pipeline dimensions, and external factors. Additionally, we estimate the emissions associated with the full life cycle of pipeline construction, maintenance, and disposal. This model is applied to an inventory of 62 major Canadian and U.S. pipelines (capacity greater than 100 000 barrels/day) to estimate the variability of GHG emissions associated with pipeline transportation. We demonstrate that pipeline GHG emissions intensities range from 0.23 to 20.3 g CO2e/(bbl.km), exhibiting considerably greater variability than data reported in other studies. A sensitivity analysis demonstrates that the linear velocity of crude transport and pipeline diameter are the most impactful parameters driving this variability. To illustrate one example of how COPTEM can be used, we develop an energy efficiency gap analysis to investigate the possibilities for more efficient pipeline transport of crude oil. PMID- 29166007 TI - Titanium-Based Hydrides as Heterogeneous Catalysts for Ammonia Synthesis. AB - The problem of activating N2 and its subsequent hydrogenation to form NH3 has been approached from many directions. One of these approaches involves the use of transition metal hydride complexes. Recently, transition metal hydride complexes of Ti and Ta have been shown to activate N2, but without catalytic formation of NH3. Here, we show that at elevated temperatures (400 degrees C, 5 MPa), solid state hydride-containing Ti compounds (TiH2 and BaTiO2.5H0.5) form a nitride hydride surface similar to those observed with titanium clusters, but continuously (~7 days) form NH3 under H2/N2 flow conditions to achieve a catalytic cycle, with activity (up to 2.8 mmol.g.-1.h-1) almost comparable to conventional supported Ru catalysts such as Cs-Ru/MgO or Ru/BaTiO3 that we have tested. As with the homogeneous analogues, the initial presence of hydride within the catalyst is critical. A rare hydrogen-based Mars van Krevelen mechanism may be at play here. Conventional scaling rules of pure metals predict essentially no activity for Ti, making this a previously overlooked element, but our results show that by introducing hydride, the repertoire of heterogeneous catalysts can be expanded to include formerly unexamined compositions without resorting to precious metals. PMID- 29166008 TI - Porous Scaffolds for Electrochemically Controlled Reversible Capture and Release of Ethylene. AB - This Communication describes the use of porous coordination polymers (PCP) with integrated metal bis(dithiolene) units to achieve electrochemically controlled capture and release of ethylene in the solid state. Applying positive potential (+2.0 V) to these PCPs promotes ethylene capture, and subsequent dose of negative potential (-2.0 V) induces the release. These materials are resistant to poisoning by small reactive gases (CO and H2S) that may interact with embedded metallic sites. PMID- 29166009 TI - Formation of Spherical Aromatic Endohedral Metallic Fullerenes. Evaluation of Magnetic Properties of M@C28 (M = Ti, Zr, and Hf) from DFT calculations. AB - The small C28 cage has been shown experimentally to encapsulate titanium, zirconium, and hafnium (M), among other elements. Here, we explore computationally its magnetic response properties accounting for both global and local shielding tensors. Our results exhibit a continuous shielding region for M@C28 for an orientation-averaged applied field thereby differing from that observed for the hollow C28 structure. Moreover, under a specific orientation of the applied field a long-ranged shielding cone is obtained supporting the spherical aromatic behavior expected by the 2(N + 1)2 Hirsch rule for M@C28, standing for its particular abundance. The comparison between the hollow and endohedral C28 fullerenes exhibits a characteristic long-range behavior at the outside region of the structure. The particular shape of the local chemical shift anisotropy tensor at a representative carbon atom exhibits inherent patterns as a consequence of the spherical aromatic behavior. This shows the capabilities from NMR experiments to account for the nonaromatic -> aromatic variation. We envisage that the current approach will be beneficial in comparative studies of aromatic and electronic structure properties, to gain a deeper understanding of the geometrical and electronic structure situation in other endohedral species beyond that available from the information provided by routine NMR measurements. PMID- 29166011 TI - A Cooperative Folding Unit as the Structural Link for Energetic Coupling within a Protein. AB - Previously, we demonstrated that binding of a ligand to Escherichia coli cofactor dependent phosphoglycerate mutase (dPGM), a homodimeric protein, is energetically coupled with dimerization. The equilibrium unfolding of dPGM occurs with a stable, monomeric intermediate. Binding of several nonsubstrate metabolites stabilizes the dimeric native form over the monomeric intermediate, reducing the population of the intermediate. Both the active site and the dimer interface appear to be unfolded in the intermediate. We hypothesized that a loop containing residues 118-152 was responsible for the energetic coupling between the dimer interface and the distal active site and was unfolded in the intermediate. Here, we investigated the structure of the dPGM intermediate by probing side-chain interactions and solvent accessibility of the peptide backbone. By comparing the effect of a mutation on the global stability and the stability of the intermediate, we determine an equilibrium phi value (phieq value), which provides information about whether side-chain interactions are retained or lost in the intermediate. Hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) was used to investigate differences in the solvent accessibility of the peptide backbone in the intermediate and native forms of dPGM. The results of phieq value analysis and HDX-MS reveal the least stable folding unit of dPGM, which is unfolded in the intermediate and links the active site to the dimer interface. The structure of the intermediate reveals how the cooperative network of residues in dPGM gives rise to the observed energetic coupling between dimerization and ligand binding. PMID- 29166012 TI - The Use of Fluoroproline in MUC1 Antigen Enables Efficient Detection of Antibodies in Patients with Prostate Cancer. AB - A structure-based design of a new generation of tumor-associated glycopeptides with improved affinity against two anti-MUC1 antibodies is described. These unique antigens feature a fluorinated proline residue, such as a (4S)-4-fluoro-l proline or 4,4-difluoro-l-proline, at the most immunogenic domain. Binding assays using biolayer interferometry reveal 3-fold to 10-fold affinity improvement with respect to the natural (glyco)peptides. According to X-ray crystallography and MD simulations, the fluorinated residues stabilize the antigen-antibody complex by enhancing key CH/pi interactions. Interestingly, a notable improvement in detection of cancer-associated anti-MUC1 antibodies from serum of patients with prostate cancer is achieved with the non-natural antigens, which proves that these derivatives can be considered better diagnostic tools than the natural antigen for prostate cancer. PMID- 29166010 TI - Conformational Dynamics of Asparagine at Coiled-Coil Interfaces. AB - Coiled coils (CCs) are among the best-understood protein folds. Nonetheless, there are gaps in our knowledge of CCs. Notably, CCs are likely to be structurally more dynamic than often considered. Here, we explore this in an abundant class of CCs, parallel dimers, focusing on polar asparagine (Asn) residues in the hydrophobic interface. It is well documented that such inclusions discriminate between different CC oligomers, which has been rationalized in terms of whether the Asn can make side-chain hydrogen bonds. Analysis of parallel CC dimers in the Protein Data Bank reveals a variety of Asn side-chain conformations, but not all of these make the expected inter-side-chain hydrogen bond. We probe the structure and dynamics of a de novo-designed coiled-coil homodimer, CC-Di, by multidimensional nuclear magnetic resonance spectroscopy, including model-free dynamical analysis and relaxation-dispersion experiments. We find dynamic exchange on the millisecond time scale between Asn conformers with the side chains pointing into and out of the core. We perform molecular dynamics simulations that are consistent with this, revealing that the side chains are highly dynamic, exchanging between hydrogen-bonded-paired conformations in picoseconds to nanoseconds. Combined, our data present a more dynamic view for Asn at CC interfaces. Although inter-side-chain hydrogen bonding states are the most abundant, Asn is not always buried or engaged in such interactions. Because interfacial Asn residues are key design features for modulating CC stability and recognition, these further insights into how they are accommodated within CC structures will aid their predictive modeling, engineering, and design. PMID- 29166013 TI - Slow Magnetic Relaxation in a Dysprosium Ammonia Metallocene Complex. AB - We report the serendipitous discovery and magnetic characterization of a dysprosium bis(ammonia) metallocene complex, [(C5Me5)2Dy(NH3)2](BPh4) (1), isolated in the course of performing a well-established synthesis of the unsolvated cationic complex [(C5Me5)2Dy][(MU-Ph)2BPh2]. While side reactivity studies suggest that this bis(ammonia) species owes its initial incidence to impurities in the DyCl3(H2O)x starting material, we were able to independently prepare 1 and its tetrahydrofuran (THF) derivative, [(C5Me5)2Dy(NH3)(THF)](BPh4) (2), from the reaction of [(C5Me5)2Dy][(MU-Ph)2BPh2] with ammonia in THF. The low symmetry complex 1 exhibits slow magnetic relaxation under zero applied direct current (dc) field to temperatures as high as 46 K and notably exhibits an effective barrier to magnetic relaxation that is more than 150% greater than that previously reported for the [(C5Me5)2Ln][(MU-Ph)2BPh2] precursor. On the basis of fitting of the temperature-dependent relaxation data, magnetic relaxation is found to occur via Orbach, Raman, and quantum-tunneling relaxation processes, and the latter process can be suppressed by the application of a 1400 Oe dc field. Field-cooled and zero-field-cooled dc magnetic susceptibility measurements reveal a divergence at 4 K indicative of magnetic blocking, and magnetic hysteresis was observed up to 5.2 K. These results illustrate the surprises and advantages that the lanthanides continue to offer for synthetic chemists and magnetochemists alike. PMID- 29166014 TI - Probing the Surface of Platinum during the Hydrogen Evolution Reaction in Alkaline Electrolyte. AB - Understanding the surface chemistry of electrocatalysts in operando can bring insight into the reaction mechanism, and ultimately the design of more efficient materials for sustainable energy storage and conversion. Recent progress in synchrotron based X-ray spectroscopies for in operando characterization allows us to probe the solid/liquid interface directly while applying an external potential, applied here to the model system of Pt in alkaline electrolyte for the hydrogen evolution reaction (HER). We employ ambient pressure X-ray photoelectron spectroscopy (AP-XPS) to identify the oxidation and reduction of Pt-oxides and hydroxides on the surface as a function of applied potential, and further assess the potential for hydrogen adsorption and absorption (hydride formation) during and after the HER. This new window into the surface chemistry of Pt in alkaline electrolyte brings insight into the nature of the rate limiting step, the extent of H ad/absorption, and its persistence at more anodic potentials. PMID- 29166015 TI - Structure of ZnCl2 Melt. Part II: Fragile-to-Strong Transition in a Tetrahedral Liquid. AB - The fraction of edge- and corner-sharing tetrahedra in liquid ZnCl2 is quantified as a function of temperature using Raman spectroscopy and ab initio molecular dynamic simulations. Two distinct regimes are found in the temperature dependence of the change in these structural units. This behavior is consistent with the existence of a fragile-to-strong transition in liquid ZnCl2 as suggested by calorimetric and viscosity measurements. The structural origin of this transition is rationalized in terms of a constraint counting formalism. It is suggested that the ratio of edge- to corner-sharing tetrahedra controls the configurational entropy and in turn the viscosity of the melt. The temperature dependence of this ratio above the melting point is also found to be qualitatively consistent with neutron diffraction data. The observation of a similar fragile-to-strong transition in the isostructural GeSe2 melt indicates that it may be a common feature of tetrahedral liquids. PMID- 29166016 TI - Enantioselective Friedel-Crafts Alkylation between Nitroalkenes and Indoles Catalyzed by Charge Activated Thiourea Organocatalysts. AB - A series of methylated and octylated pyridinium and quinolinium containing thiourea salts with a chiral 2-indanol substituent are reported. These organocatalysts are positively charged analogues of privileged bis(3,5 trifluoromethyl)phenyl substituted thioureas, and are found to be much more active catalysts despite the absence of an additional hydrogen bond donor or acceptor site (i.e., the presence of a heteroatom-hydrogen or heteroatom). Friedel-Crafts reactions of trans-beta-nitorostyrenes with indoles are examined, and good yields and enantioselectivities are obtained. Mechanistic studies indicate that this is a second-order transformation under the employed conditions, and is consistent with the dimer of the thiourea being the active catalyst. Charged organocatalysts, consequently, represent an attractive design strategy for catalyst development. PMID- 29166017 TI - Bond Dissociation Energies of Tungsten Molecules: WC, WSi, WS, WSe, and WCl. AB - Resonant two-photon ionization spectroscopy was used to locate predissociation thresholds in WC, WSi, WS, WSe, and WCl, allowing bond dissociation energies to be measured for these species. Because of the high degree of vibronic congestion in the observed spectra, it is thought that the molecules dissociate as soon as the lowest separated atom limit is exceeded. From the observed predissociation thresholds, dissociation energies are assigned as D0(WC) = 5.289(8) eV, D0(WSi) = 3.103(10) eV, D0(WS) = 4.935(3) eV, D0(WSe) = 4.333(6) eV, and D0(WCl) = 3.818(6) eV. These results are combined with other data to obtain the ionization energy IE(WC) = 8.39(9) eV and the anionic bond dissociation energies of D0(W-C-) = 6.181(17) eV, D0(W--C) = 7.363(19) eV, D0(W-Si-) <= 3.44(4) eV, and D0(W--Si) <= 4.01(4) eV. Combination of the D0(WX) values with atomic enthalpies of formation also provides DeltafH0K degrees values for the gaseous WX molecules. Computational results are also provided, which shed some light on the electronic structure of these molecules. PMID- 29166018 TI - Discovery of Small-Molecule Inhibitors of Ubiquitin Specific Protease 7 (USP7) Using Integrated NMR and in Silico Techniques. AB - USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53, and for this reason it has gained increasing attention as a potential oncology target for small molecule inhibitors. Herein we describe the biophysical, biochemical, and computational approaches that led to the identification of 4-(2 aminopyridin-3-yl)phenol compounds described by Kategaya ( Nature 2017 , 550 , 534 - 538 ) as specific inhibitors of USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual screening and re-mining of biochemical high throughput screening (HTS) hits led to the discovery of a series of ligands that bind in the "palm" region of the catalytic domain of USP7 and inhibit its catalytic activity. These ligands were then optimized by structure-based design to yield cell-active molecules with reasonable physical properties. This discovery process not only involved multiple techniques working in concert but also illustrated a unique way in which hits from orthogonal screening approaches complemented each other for lead identification. PMID- 29166019 TI - Femtosecond Raman Microscopy Reveals Structural Dynamics Leading to Triplet Separation in Rubrene Singlet Fission. AB - Singlet fission generates multiple excitons from a single photon, which in theory can result in solar cell efficiencies with values above the Shockley-Queisser limit. Understanding the molecular structural dynamics during singlet fission will help to fabricate efficient organic photovoltaic devices. Here we use femtosecond stimulated Raman spectroscopy to reveal the structural evolution during the triplet separation in rubrene. We observe vibrational signatures of the correlated triplet pair, as well as shifting of the vibrational frequencies of the 1430 and 1542 cm-1 excited state modes, which increase by more than 25 cm 1 in 5 ps. Our results indicate that the correlated pair separation into two individual triplets occurs concurrently with the loss of electron density from the tetracene backbone in rubrene. This study provides new insights into the triplet separation process and proves the utility of structurally sensitive ultrafast vibrational techniques to understand the mechanism of singlet fission. PMID- 29166020 TI - Solid Digestion of Demineralized Bone as a Method To Access Potentially Insoluble Proteins and Post-Translational Modifications. AB - Bone proteomics is an expanding field for understanding protein changes associated with disease as well as characterizing and detecting proteins preserved in fossil bone. Most previous studies have utilized a protocol with demineralization and extraction approach to isolate and characterize proteins from bone. Through near-complete EDTA demineralization, followed by solid digestion of the remaining bone pseudomorph, a total of 92 protein accessions were detected from dog bone. In the EDTA, 14 unique proteins were found, including osteocalcin, an important bone protein. Osteocalcin was not found in the solid digestion samples, demonstrating the importance of examining the demineralization supernatant. The solid-digestion samples were analyzed both with (11 unique accessions) and without (16 unique accessions) alkylation, resulting in a total of 78 protein accessions. In addition to the diversity of proteins detected, various post-translational modifications were observed, including phosphorylation and glycosylation. The solid-digestion approach will allow for characterization of proteins that are insoluble and would otherwise be missed by traditional bone protein extraction alone. All data are available at ftp://massive.ucsd.edu/MSV000081399 . PMID- 29166021 TI - Differences in the Aspect Ratio of Gold Nanorods that Induce Defects in Cell Membrane Models. AB - Understanding the interactions between biomolecules and nanomaterials is of great importance for many areas of nanomedicine and bioapplications. Although studies in this area have been performed, the interactions between cell membranes and nanoparticles are not fully understood. Here, we investigate the interactions that occur between the Langmuir monolayers of dipalmitoylphosphatidyl glycerol (DPPG) and dipalmitoylphosphatidyl choline (DPPC) with gold nanorods (NR)-with three aspect ratios-and gold nanoparticles. Our results showed that the aspect ratio of the NRs influenced the interactions with both monolayers, which suggest that the physical morphology and electrostatic forces govern the interactions in the DPPG-NR system, whereas the van der Waals interactions are predominant in the DPPC-NR systems. Size influences the expansion isotherms in both systems, but the lipid tails remain conformationally ordered upon expansion, which suggests phase separation between the lipids and nanomaterials at the interface. The coexistence of lipid and NP regions affects the elasticity of the monolayer. When there is coexistence between two phases, the elasticity does not reflect the lipid packaging state but depends on the elasticity of the NP islands. Therefore, the results corroborate that nanomaterials influence the packing and the phase behavior of the mimetic cell membranes. For this reason, developing a methodology to understand the membrane-nanomaterial interactions is of great importance. PMID- 29166022 TI - Dynamics of OmpF Trimer Formation in the Bacterial Outer Membrane of Escherichia coli. AB - The self-assembly of outer membrane protein F (OmpF) in the outer membrane of Escherichia coli Gram-negative bacteria was studied using multiscale molecular dynamics simulations. To accommodate the long time scale required for protein assembly, coarse-grained parametrization of E. coli outer membrane lipids was first developed. The OmpF monomers formed stable dimers at specific protein protein interactions sites irrespective of the lipid membrane environment. The dimer intermediate was asymmetric but provided a template to form a symmetric trimer. Superposition analysis of the self-assembled trimer with the X-ray crystal structure of the trimer available in the protein data bank showed excellent agreement with global root-mean-square deviation of less than 2.2 A. The free energy change associated with dimer formation was -26 +/- 1 kcal mol-1, and for a dimer to bind to a monomer and to form a trimer yielded -56 +/- 4 kcal mol-1. Based on thermodynamic data, an alternate path to trimer formation via interaction of two dimers is also presented. PMID- 29166023 TI - Rhodium-Catalyzed Synthesis of Sulfur Ylides via in Situ Generated Iodonium Ylides. AB - A convenient strategy for the synthesis of sulfur ylides via rhodium-catalyzed coupling of in situ generated iodonium ylides with sulfides or sulfoxides has been developed. A wide range of sulfur ylides were obtained in moderate to good yields from inexpensive sulfur compounds and active methylene compounds with a short reaction time (MW, 5-10 min) or 12-16 h at rt. Furthermore, these sulfoxonium ylides were used as novel acceptor/acceptor carbenes for N-H insertion reactions. PMID- 29166024 TI - Correction to Methods for the Synthesis of Substituted Azetines. PMID- 29166025 TI - Copper(II)-Catalyzed Oxidative Coupling of Anilines, Methyl Arenes, and TMSN3 via C(sp3/sp2)-H Functionalization and C-N Bond Formation. AB - Copper(II)-catalyzed cross-coupling of anilines, methyl arenes, and TMSN3 in the presence of tert-butylhydroperoxide at moderate temperature produced 2-aryl benzimidazoles via a tandem C(sp3/sp2)-H functionalization and C-N bond formations. The selectivity and multiple C-H functionalization of the simple substrates are significant practical features. PMID- 29166026 TI - Electrospun Thin-Walled CuCo2O4@C Nanotubes as Bifunctional Oxygen Electrocatalysts for Rechargeable Zn-Air Batteries. AB - Rational design of optimal bifunctional oxygen electrocatalyst with low cost and high activity is greatly desired for realization of rechargeable Zn-air batteries. Herein, we fabricate mesoporous thin-walled CuCo2O4@C with abundant nitrogen-doped nanotubes via coaxial electrospinning technique. Benefiting from high catalytic activity of ultrasmall CuCo2O4 particles, double active specific surface area of mesoporous nanotubes, and strong coupling with N-doped carbon matrix, the obtained CuCo2O4@C exhibits outstanding oxygen electrocatalytic activity and stability, in terms of a positive onset potential (0.951 V) for oxygen reduction reaction (ORR) and a low overpotential (327 mV at 10 mA cm-2) for oxygen evolution reaction (OER). Significantly, when used as cathode catalyst for Zn-air batteries, CuCo2O4@C also displays a low charge-discharge voltage gap (0.79 V at 10 mA cm-2) and a long cycling life (up to 160 cycles for 80 h). With desirable architecture and excellent electrocatalytic properties, the CuCo2O4@C is considered a promising electrocatalyst for Zn-air batteries. PMID- 29166027 TI - Nanoscale Detection of Intermediate Solid Solutions in Equilibrated LixFePO4 Microcrystals. AB - Redox-driven phase transformations in solids determine the performance of lithium ion batteries, crucial in the technological transition from fossil fuels. Couplings between chemistry and strain define reversibility and fatigue of an electrode. The accurate definition of all phases in the transformation, their energetics, and nanoscale location within a particle produces fundamental understanding of these couplings needed to design materials with ultimate performance. Here we demonstrate that scanning X-ray diffraction microscopy (SXDM) extends our ability to image battery processes in single particles. In LiFePO4 crystals equilibrated after delithiation, SXDM revealed the existence of domains of miscibility between LiFePO4 and Li0.6FePO4. These solid solutions are conventionally thought to be metastable, and were previously undetected by spectromicroscopy. The observation provides experimental verification of predictions that the LiFePO4-FePO4 phase diagram can be altered by coherency strain under certain interfacial orientations. It enriches our understanding of the interaction between diffusion, chemistry, and mechanics in solid state transformations. PMID- 29166028 TI - Synthesis of N-Oxyureas by Substitution and Cope-Type Hydroamination Reactions Using O-Isocyanate Precursors. AB - Oxy-carbamate O-isocyanate precursors facilitate access to synthetically valuable N-oxyureas via substitution with amines. This work exploits the reactivity of suitable O-isocyanate precursors, identified by a thorough study highlighting the different reactivity of isocyanate masking groups. This led to bench-stable O isocyanate precursors, offering improved versatility in the synthesis of N oxyureas, and demonstrates the controlled reactivity of masked O-isocyanates. Suitable precursors also enabled the first example of Cope-type hydroamination of unsaturated hydroxyureas. PMID- 29166029 TI - Rh-Catalyzed Conversion of 3-Diazoindolin-2-imines to 5H-Pyrazino[2,3-b]indoles with Photoluminescent Properties. AB - A rhodium-catalyzed reaction between 3-diazoindolin-2-imines and 2H-azirines, followed by treatment with a base, furnishes 5H-pyrazino[2,3-b]indoles in excellent yields. A number of functional groups tolerate the reaction conditions, and the resulting 5H-pyrazino[2,3-b]indoles present strong photoluminecence in solutions, powders, and films. PMID- 29166030 TI - Dissolution and Characterization of Boron Nitride Nanotubes in Superacid. AB - Boron nitride nanotubes (BNNTs) are of interest for their unique combination of high tensile strength, high electrical resistivity, high neutron cross section, and low reactivity. The fastest route to employing these properties in composites and macroscopic articles is through solution processing. However, dispersing BNNTs without functionalization or use of a surfactant is challenging. We show here by cryogenic transmission electron microscopy that BNNTs spontaneously dissolve in chlorosulfonic acid as disentangled individual molecules. Electron energy loss spectroscopy of BNNTs dried from the solution confirms preservation of the sp2 hybridization for boron and nitrogen, eliminating the possibility of BNNT functionalization or damage. The length and diameter of the BNNTs was statistically calculated to be ~4.5 MUm and ~4 nm, respectively. Interestingly, bent or otherwise damaged BNNTs are filled by chlorosulfonic acid. Additionally, nanometer-sized synthesis byproducts, including boron nitride clusters, isolated single and multilayer hexagonal boron nitride, and boron particles, were identified. Dissolution in superacid provides a route for solution processing BNNTs without altering their chemical structure. PMID- 29166031 TI - A Twist of the Twist Mechanism, 2-Iodoxybenzoic Acid (IBX)-Mediated Oxidation of Alcohol Revisited: Theory and Experiment. AB - 2-Iodoxybenzoic acid (IBX) is an important species for the oxidation of alcohols to aldehydes or ketones. An often-cited mechanism involving a hypervalent twist as the rate-determining step (RDS) is inconsistent with kinetic isotope effect (KIE) experiments. The computations with larger basis sets reveal that the reductive elimination involving the C-H bond cleavage is the RDS (rate determining step). Further computational/experimental studies suggest that the reactivity can be improved by adjusting the trans influence with Lewis acids. PMID- 29166032 TI - Combined Cononsolvency and Temperature Effects on Adsorbed PNIPAM Microgels. AB - The present study addresses the multiresponsive behavior of poly(N isopropylacrylamide) (PNIPAM) microgels adsorbed to interfaces. The microgels react to changes in temperature by shrinking in aqueous solution above their volume phase transition temperature (VPTT). Additionally, they shrink in mixtures of water and ethanol, although both individual liquids are good solvents for PNIPAM. The combination of this so-called cononsolvency effect and the temperature response of adsorbed microgels is studied by atomic force microscopy (AFM). Adsorbed microgels are of special interest because they are compressed considerably compared to those in bulk solution. It is shown that the impact of adsorption on swelling depends on the specific surface details, as well as the sample preparation. Thereby, the microgels are deposited on two different kinds of surfaces: on gold surface and on polycation (PAH) coating which show different interactions with the microgels in terms of electrostatic interaction and wettability. In addition, the microgels were deposited from different solvent mixtures. This influences the microgel structure and thereby the swelling properties. Nanorheology studies by dynamic AFM measurements lead to surprising results which are explained by the fact that not only polymer density but a subtle interaction between polymer and solvent might dominate the rheological properties. This work supports the view that preferential adsorption of ethanol at PNIPAM drives cononsolvency, while the shrinking at T > VPTT is caused by general breaking of hydrogen bonds between solvents and PNIPAM. PMID- 29166034 TI - Lewis Acid Mediated "endo-dig" Hydroalkoxylation-Reduction on Internal Alkynols for the Stereoselective Synthesis of Cyclic Ethers and 1,4-Oxazepanes. AB - Lewis acid mediated 5/6/7-endo-dig hydroalkoxylation-reduction cascade on internal alkynols gave an expedient, stereoselective synthesis of cyclic ethers and 1,4-oxazepanes. The strategy has been extended to the first examples of hydroalkoxylation-alkyne Prins-type cyclization cascade of alkyne-tethered alkynols, giving access to oxa-bicyclic scaffolds. This method was used as the key step in the stereoselective total synthesis of calyxolane A-B, as well as (+/ )-centrolobine and its homologue. PMID- 29166033 TI - Mapping Nanoscale Hotspots with Single-Molecule Emitters Assembled into Plasmonic Nanocavities Using DNA Origami. AB - Fabricating nanocavities in which optically active single quantum emitters are precisely positioned is crucial for building nanophotonic devices. Here we show that self-assembly based on robust DNA-origami constructs can precisely position single molecules laterally within sub-5 nm gaps between plasmonic substrates that support intense optical confinement. By placing single-molecules at the center of a nanocavity, we show modification of the plasmon cavity resonance before and after bleaching the chromophore and obtain enhancements of >=4 * 103 with high quantum yield (>=50%). By varying the lateral position of the molecule in the gap, we directly map the spatial profile of the local density of optical states with a resolution of +/-1.5 nm. Our approach introduces a straightforward noninvasive way to measure and quantify confined optical modes on the nanoscale. PMID- 29166035 TI - Direct Visualization and Control of Atomic Mobility at {100} Surfaces of Ceria in the Environmental Transmission Electron Microscope. AB - Ceria is one of the world's most prominent material for applications in heterogeneous catalysis, as catalyst support or catalyst itself. Despite an exhaustive literature on the structure of reactive facets of CeO2 in line with its catalytic mechanisms, the temporal evolution of the atomic surface structure exposed to realistic redox conditions remains elusive. Here, we provide a direct visualization of the atomic mobility of cerium atoms on {100} surfaces of CeO2 nanocubes at room temperature in high vacuum, O2, and CO2 atmospheres in an environmental transmission electron microscope. Through quantification of the cationic mobility, we demonstrate the control of the surface dynamics under exposure to O2 and CO2 atmospheres, providing opportunities for a better understanding of the intimate catalytic mechanisms. PMID- 29166036 TI - Solid-like features in dense vapors near the fluid critical point. AB - The phase diagram (pressure versus temperature) of the pure fluid is typically envisioned as being featureless apart from the presence of the liquid-vapor coexistence curve terminating at the critical point. However, a number of recent authors have proposed that this simple picture misses important features, such as the Widom line, the Fisher-Widom line, and the Frenkel line. In our paper, we discuss another way of augmenting the pure fluid phase diagram, lines of zero thermodynamic curvature R = 0 separating regimes of fluid solid-like behavior (R > 0) from gas-like or liquid-like behavior (R < 0). We systematically evaluate R for the 121 pure fluids in the NIST/REFPROP (version 9.1) fluid database near the saturated vapor line from the triple point to the critical point. Our specific goal was to identify regions of positive R abutting the saturated vapor line ("feature D"). We found the following: (i) 97/121 of the NIST/REFPROP fluids have feature D. (ii) The presence and character of feature D correlates with molecular complexity, taken to be the number of atoms Q per molecule. (iii) The solid-like properties of feature D might be attributable to a mesoscopic model based on correlations among coordinated spinning molecules, a model that might be testable with computer simulations. (iv) There are a number of correlations between thermodynamic quantities, including the acentric factor omega, but we found little explicit correlation between omega and the shape of a molecule. (v) Feature D seriously constrains the size of the asymptotic fluid critical point regime, possibly resolving a long-standing mystery about why these are so small. (vi) Feature D correlates roughly with regimes of anomalous sound propagation. PMID- 29166038 TI - Theory of polyelectrolyte complexation-Complex coacervates are self-coacervates. AB - The complexation of mixtures of cationic and anionic polymers to produce complex coacervate phases is a subject of fundamental importance to colloid and polymer science as well as to applications including drug delivery, sensing technologies, and bio-inspired adhesives. Unfortunately the theoretical underpinnings of complex coacervation are widely misunderstood and conceptual mistakes have propagated in the literature. Here, a simple symmetric polyelectrolyte mixture model in the absence of salt is used to discuss the salient features of the phase diagram, including the location of the critical point, binodals, and spinodals. It is argued that charge compensation by dimerization in the dilute region renders the phase diagram of an oppositely charged polyelectrolyte mixture qualitatively and quantitatively similar to that of a single-component symmetric diblock polyampholyte solution, a system capable of "self-coacervation." The theoretical predictions are verified using fully fluctuating field-theoretic simulations for corresponding polyelectrolyte and diblock polyampholyte models. These represent the first comprehensive, approximation-free phase diagrams for coacervate and self-coacervate systems to appear in the literature. PMID- 29166037 TI - Adenosine triphosphate diffusion through poly(ethylene glycol) diacrylate hydrogels can be tuned by cross-link density as measured by PFG-NMR. AB - The diffusion of small molecules through hydrogels is of great importance for many applications. Especially in biological contexts, the diffusion of nutrients through hydrogel networks defines whether cells can survive inside the hydrogel or not. In this contribution, hydrogels based on poly(ethylene glycol) diacrylate with mesh sizes ranging from xi = 1.1 to 12.9 nm are prepared using polymers with number-average molecular weights between Mn = 700 and 8000 g/mol. Precise measurements of diffusion coefficients D of adenosine triphosphate (ATP), an important energy carrier in biological systems, in these hydrogels are performed by pulsed field gradient nuclear magnetic resonance. Depending on the mesh size, xi, and on the polymer volume fraction of the hydrogel after swelling, phi, it is possible to tune the relative ATP diffusion coefficient D/D0 in the hydrogels to values between 0.14 and 0.77 compared to the ATP diffusion coefficient D0 in water. The diffusion coefficients of ATP in these hydrogels are compared with predictions of various mathematical expressions developed under different model assumptions. The experimental data are found to be in good agreement with the predictions of a modified obstruction model or the free volume theory in combination with the sieving behavior of the polymer chains. No reasonable agreement was found with the pure hydrodynamic model. PMID- 29166039 TI - Segmental dynamics of polyethylene-alt-propylene studied by NMR spin echo techniques. AB - Segmental dynamics of a highly entangled melt of linear polyethylene-alt propylene with a molecular weight of 200 kDa was studied with a novel proton nuclear magnetic resonance (NMR) approach based upon 1H -> 2H isotope dilution as applied to a solid-echo build-up function ISE(t), which is constructed from the NMR spin echo signals arising from the Hahn echo (HE) and two variations of the solid-echo pulse sequence. The isotope dilution enables the separation of inter- and intramolecular contributions to this function and allows one to extract the segmental mean-squared displacements in the millisecond time range, which is hardly accessible by other experimental methods. The proposed technique in combination with time-temperature superposition yields information about segmental translation in polyethylene-alt-propylene over 6 decades in time from 10-6 s up to 1 s. The time dependence of the mean-squared displacement obtained in this time range clearly shows three regimes of power law with exponents, which are in good agreement with the tube-reptation model predictions for the Rouse model, incoherent reptation and coherent reptation regimes. The results at short times coincide with the fast-field cycling relaxometry and neutron spin echo data, yet, significantly extending the probed time range. Furthermore, the obtained data are verified as well by the use of the dipolar-correlation effect on the Hahn echo, which was developed before by the co-authors. At the same time, the amplitude ratio of the intermolecular part of the proton dynamic dipole dipole correlation function over the intramolecular part obtained from the experimental data is not in agreement with the predictions of the tube-reptation model for the regimes of incoherent and coherent reptation. PMID- 29166040 TI - Analytic derivative couplings and first-principles exciton/phonon coupling constants for an ab initio Frenkel-Davydov exciton model: Theory, implementation, and application to compute triplet exciton mobility parameters for crystalline tetracene. AB - Recently, we introduced an ab initio version of the Frenkel-Davydov exciton model for computing excited-state properties of molecular crystals and aggregates. Within this model, supersystem excited states are approximated as linear combinations of excitations localized on molecular sites, and the electronic Hamiltonian is constructed and diagonalized in a direct-product basis of non orthogonal configuration state functions computed for isolated fragments. Here, we derive and implement analytic derivative couplings for this model, including nuclear derivatives of the natural transition orbital and symmetric orthogonalization transformations that are part of the approximation. Nuclear derivatives of the exciton Hamiltonian's matrix elements, required in order to compute the nonadiabatic couplings, are equivalent to the "Holstein" and "Peierls" exciton/phonon couplings that are widely discussed in the context of model Hamiltonians for energy and charge transport in organic photovoltaics. As an example, we compute the couplings that modulate triplet exciton transport in crystalline tetracene, which is relevant in the context of carrier diffusion following singlet exciton fission. PMID- 29166041 TI - Molecular origin of aging of pure Se glass: Growth of inter-chain structural correlations, network compaction, and partial ordering. AB - Glass transition width W of pure Se narrows from 7.1(3) degrees C to 1.5(2) degrees C and the non-reversing enthalpy of relaxation (DeltaHnr) at Tg increases from 0.23(5) cal/g to 0.90(5) cal/g upon room temperature aging for 4 months in the dark as examined in modulated differential scanning colorimetry (MDSC) at low scan rates. In Raman scattering, such aging leads the A1 mode of Sen-chains (near 250 cm-1) to narrow by 26% and its scattering strength to decrease as the strength of modes of correlated chains (near 235 cm-1) and of Se8 rings (near 264 cm-1) systematically grows. These calorimetric and Raman scattering results are consistent with the "molecular" chains of Sen, predominant in the fresh glass, reconstructing with each other to compact and partially order the network. Consequences of the aging induced reconstruction of the long super-flexible and uncorrelated Sen-chains are also manifested upon alloying up to 4 mol. % of Ge as revealed by a qualitative narrowing (by 25%) of the Raman vibrational mode of the corner-sharing GeSe4 tetrahedra and a blue-shift of the said mode by nearly 1 cm 1 in 194 cm-1. But, at higher Ge content (x> 6%), as the length of Sen chain segments across Ge cross-links decreases qualitatively (?n? < 8), these aging induced chain-reconstruction effects are suppressed. The width of Tg increases beyond 15 degrees C in binary GexSe100-x glasses as x> 10% to acquire values observed earlier as alloying concentration approaches 20% and networks become spontaneously rigid. PMID- 29166042 TI - Laplace-transformed multi-reference second-order perturbation theories in the atomic and active molecular orbital basis. AB - In the present article, we show how to formulate the partially contracted n electron valence second-order perturbation theory (NEVPT2) energies in the atomic and active molecular orbital basis by employing the Laplace transformation of orbital-energy denominators (OEDs). As atomic-orbital (AO) basis functions are inherently localized and the number of active orbitals is comparatively small, our formulation is particularly suited for a linearly scaling NEVPT2 implementation. In our formulation, there are two kinds of NEVPT2 energy contributions, which differ in the number of active orbitals in the two-electron integrals involved. Those involving integrals with either no or a single active orbital can be formulated completely in the AO basis as single-reference second order Moller-Plesset perturbation theory and benefit from sparse active pseudo density matrices-particularly if the active molecular orbitals are localized only in parts of a molecule. Conversely, energy contributions involving integrals with either two or three active orbitals can be obtained from Coulomb and exchange matrices generalized for pairs of active orbitals. Moreover, we demonstrate that Laplace-transformed partially contracted NEVPT2 is nothing less than time dependent NEVPT2 [A. Y. Sokolov and G. K.-L. Chan, J. Chem. Phys. 144, 064102 (2016)] iff the all-active intermediates are computed with the internal contraction approximation. Furthermore, we show that for multi-reference perturbation theories it is particularly challenging to find optimal parameters of the numerical Laplace transformation as the fit range may vary among the 8 different OEDs by many orders of magnitude. Selecting the number of quadrature points for each OED separately according to an accuracy-based criterion allows us to control the errors in the NEVPT2 energies reliably. PMID- 29166043 TI - Comment on "Temperature fluctuations and the thermodynamic determination of the cooperativity length in glass forming liquids" [J. Chem. Phys. 146, 104501 (2017)]. PMID- 29166044 TI - Publisher's Note: "The boomerang effect in electron-hydrogen molecule scattering as determined by time-dependent calculations" [J. Chem. Phys. 146, 204303 (2017)]. PMID- 29166045 TI - Controlling relative polymorph stability in soft porous crystals with a barostat. AB - We use Monte Carlo simulations to investigate the thermodynamic behavior of soft porous crystal (SPC) adsorbents under the influence of an external barostat. We consider SPCs that naturally exhibit polymorphism between crystal forms of two distinct pore sizes. In the absence of barostatting, these crystals may be naturally divided into two categories depending on their response to stress applied by the adsorbate fluid: those which macroscopically deform and change the volume of their unit cell ("breathing") and those which instead undergo internal rearrangements that change the adsorbate-accessible volume without modifying the unit cell volume ("gate-opening"). When breathing SPCs have a constant external pressure applied, in addition to the thermodynamic pressure of the adsorbate fluid, we find that the free energy difference between the crystal polymorphs is shifted by a constant amount over the entire course of adsorption. Thus, their relative stability may be easily controlled by the barostat. However, when the crystal is held at a fixed overall pressure, changes to the relative stability of the polymorphs tend to be more complex. We demonstrate a thermodynamic analogy between breathing SPCs held at a fixed pressure and macroscopically rigid gate opening ones which explains this behavior. Furthermore, we illustrate how this implies that external mechanical forces may be employed to tune the effective free energy profile of an empty SPC, which may open new avenues to engineer the thermodynamic properties of these polymorphic adsorbents, such as selectivity. PMID- 29166046 TI - FCC-HCP coexistence in dense thermo-responsive microgel crystals. AB - Analogous to hard-sphere suspensions, monodisperse thermo-responsive poly (N isopropyl acrylamide) (PNIPAM) microgel particles beyond a volume fraction (phi) of 0.5 freeze into face centered cubic (FCC)-hexagonal close packed (HCP) coexistence under as prepared conditions and into an FCC structure upon annealing. We report here FCC-HCP coexistence to be stable in dense PNIPAM microgel crystals (phi > 0.74) with particles in their deswollen state (referred to as osmotically compressed microgel crystals) and the FCC structure with particles in their swollen state by performing annealing studies with different cooling rates. The structure of PNIPAM microgel crystals is characterized using static light scattering technique and UV-Visible spectroscopy and dynamics by dynamic light scattering (DLS). DLS studies reveal that the particle motion is diffusive at short times in crystals with phi < 0.74 and sub-diffusive at short times in PNIPAM crystals with phi > 0.74. The observed sub-diffusive behavior at short times is due to the overlap (interpenetration) of the dangling polymer chains between the shells of neighbouring PNIPAM microgel particles. Overlap is found to disappear upon heating the crystals well above their melting temperature, Tm due to reduction in the particle size. Annealing studies confirm that the overlap of dangling polymer chains between the shells of neighbouring PNIPAM spheres is responsible for the stability of FCC-HCP coexistence observed in osmotically compressed PNIPAM microgel crystals. Results are discussed in the light of recent reports of stabilizing the HCP structure in hard sphere crystals by adding interacting polymer chains. PMID- 29166047 TI - Ortho-para interconversion in cation-water complexes: The case of V+(H2O) and Nb+(H2O) clusters. AB - Vanadium and niobium cation-water complexes, V+(H2O) and Nb+(H2O), are produced by laser vaporization in a pulsed supersonic expansion, mass selected in a time of-flight spectrometer, and studied with infrared photodissociation spectroscopy using rare gas atom (Ar, Ne) complex predissociation. The vibrational bands measured in the O-H stretching region contain K-type rotational sub-band structure, which provides insight into the structures of these complexes. However, rotational sub-bands do not exhibit the simple patterns seen previously for other metal ion-water complexes. The A rotational constants are smaller than expected and the normal 3:1 intensity ratios for K = odd:even levels for independent ortho:para nuclear spin states are missing for some complexes. We relied on highly correlated internally contracted multi-reference configuration interaction and Coupled Cluster [CCSD(T)] electronic structure calculations of those complexes with and without the rare gas atoms to investigate these anomalies. Rare gas atoms were found to bind via asymmetric motifs to the hydrated complexes undergoing large amplitude motions that vibrationally average to the quasi-C2v symmetry with a significant probability off the C2 axis, thus explaining the reduced A values. Both vanadium and niobium cations exhibit unusually strong nuclear spin coupling to the hydrogen atoms of water, the values of which vary with their electronic state. This catalyzes ortho-para interconversion in some complexes and explains the rotational patterns. The rate of ortho-para relaxation in the equilibrated complexes must therefore be greater than the collisional cooling rate in the supersonic expansion (about 106 s-1). PMID- 29166048 TI - Symmetry breaking and spectral considerations of the surprisingly floppy c-C3H radical and the related dipole-bound excited state of c-C3H. AB - The C3H radical is believed to be prevalent throughout the interstellar medium and may be involved in the formation of polycyclic aromatic hydrocarbons. C3H exists as both a linear and a cyclic isomer. The C2v cyclopropenylidenyl radical isomer was detected in the dark molecular cloud TMC-1, and the linear propenylidenyl radical isomer has been observed in various dark molecular clouds. Even though the c-C3H radical has been classified rotationally, the vibrational frequencies of this seemingly important interstellar molecule have never been directly observed. Established, highly accurate quartic force field methodologies are employed here to compute useful geometrical data, spectroscopic constants, and vibrational frequencies. The computed rotational constants are consistent with the experimental results. Consequently, the three a1 (nu1, nu2, and nu3) and one b1 (nu6) anharmonic vibrational frequencies at 3117.7 cm-1, 1564.3 cm-1, 1198.5 cm-1, and 826.7 cm-1, respectively, are reliable predictions for these, as of yet unseen, observables. Unfortunately, the two b2 fundamentals (nu4 and nu5) cannot be treated adequately in the current approach due to a flat and possible double-well potential described in detail herein. The dipole-bound excited state of the anion suffers from the same issues and may not even be bound. However, the trusted fundamental vibrational frequencies described for the neutral radical should not be affected by this deformity and are the first robustly produced for c-C3H. The insights gained here will also be applicable to other structures containing three-membered bare and exposed carbon rings that are surprisingly floppy in nature. PMID- 29166049 TI - Interaction of rigid C3N- with He: Potential energy surface, bound states, and rotational spectrum. AB - A two-dimensional rigid rotor model of the potential energy surface is developed for the collision of C3N- with He. Ab initio calculations are performed at the coupled cluster level with single and double excitations and using a perturbative treatment of triple excitations. An augmented correlation consistent polarized valence quadruple zeta basis set complemented with a set of mid-bond functions is chosen for these calculations. The global T-shaped minimum (De = 62.114 cm-1) is found at the intermolecular distance R = 6.42 a0. A secondary minimum (De = 41.384 cm-1) is obtained for the linear configuration C3N--He and for R = 9.83 a0. Calculations of the rovibrational bound states are carried out by using a discrete variable representation method based on Sturmian functions. The first theoretical prediction of the absorption spectra for the He-C3N- complex in the microwave region is also provided. PMID- 29166050 TI - Plane-wave pseudopotential implementation and performance of SCAN meta-GGA exchange-correlation functional for extended systems. AB - We present the implementation and performance of the strongly constrained and appropriately normed, SCAN, meta-GGA exchange-correlation (XC) approximation in the planewave-pseudopotential (PW-PP) formalism using the Troullier-Martins pseudopotential scheme. We studied its performance by applying the PW-PP implementation to several practical applications of interest in condensed matter sciences: (a) crystalline silicon and germanium, (b) martensitic phase transition energetics of phosphorene, and (c) a single water molecule physisorption on a graphene sheet. Given the much-improved accuracy over the GGA functionals and its relatively low computational cost compared to hybrid XC functionals, the SCAN functional is highly promising for various practical applications of density functional theory calculations for condensed matter systems. At same time, the SCAN meta-GGA functional appears to require more careful attention to numerical details. The meta-GGA functional shows more significant dependence on the fast Fourier transform grid, which is used for evaluating the XC potential in real space in the PW-PP formalism, than other more conventional GGA functionals do. Additionally, using pseudopotentials that are generated at a different/lower level of XC approximation could introduce noticeable errors in calculating some properties such as phase transition energetics. PMID- 29166051 TI - A time-correlation function approach to nuclear dynamical effects in X-ray spectroscopy. AB - Modern X-ray spectroscopy has proven itself as a robust tool for probing the electronic structure of atoms in complex environments. Despite working on energy scales that are much larger than those corresponding to nuclear motions, taking nuclear dynamics and the associated nuclear correlations into account may be of importance for X-ray spectroscopy. Recently, we have developed an efficient protocol to account for nuclear dynamics in X-ray absorption and resonant inelastic X-ray scattering spectra [Karsten et al., J. Phys. Chem. Lett. 8, 992 (2017)], based on ground state molecular dynamics accompanied with state-of-the art calculations of electronic excitation energies and transition dipoles. Here, we present an alternative derivation of the formalism and elaborate on the developed simulation protocol using gas phase and bulk water as examples. The specific spectroscopic features stemming from the nuclear motions are analyzed and traced down to the dynamics of electronic energy gaps and transition dipole correlation functions. The observed tendencies are explained on the basis of a simple harmonic model, and the involved approximations are discussed. The method represents a step forward over the conventional approaches that treat the system in full complexity and provides a reasonable starting point for further improvements. PMID- 29166052 TI - A Jeziorski-Monkhorst fully uncontracted multi-reference perturbative treatment. I. Principles, second-order versions, and tests on ground state potential energy curves. AB - The present paper introduces a new multi-reference perturbation approach developed at second order, based on a Jeziorski-Mokhorst expansion using individual Slater determinants as perturbers. Thanks to this choice of perturbers, an effective Hamiltonian may be built, allowing for the dressing of the Hamiltonian matrix within the reference space, assumed here to be a CAS-CI. Such a formulation accounts then for the coupling between the static and dynamic correlation effects. With our new definition of zeroth-order energies, these two approaches are strictly size-extensive provided that local orbitals are used, as numerically illustrated here and formally demonstrated in the Appendix. Also, the present formalism allows for the factorization of all double excitation operators, just as in internally contracted approaches, strongly reducing the computational cost of these two approaches with respect to other determinant based perturbation theories. The accuracy of these methods has been investigated on ground-state potential curves up to full dissociation limits for a set of six molecules involving single, double, and triple bond breaking together with an excited state calculation. The spectroscopic constants obtained with the present methods are found to be in very good agreement with the full configuration interaction results. As the present formalism does not use any parameter or numerically unstable operation, the curves obtained with the two methods are smooth all along the dissociation path. PMID- 29166053 TI - Towards the Irving-Kirkwood limit of the mechanical stress tensor. AB - The probability density functions (PDFs) of the local measure of pressure as a function of the sampling volume are computed for a model Lennard-Jones (LJ) fluid using the Method of Planes (MOP) and Volume Averaging (VA) techniques. This builds on the study of Heyes, Dini, and Smith [J. Chem. Phys. 145, 104504 (2016)] which only considered the VA method for larger subvolumes. The focus here is typically on much smaller subvolumes than considered previously, which tend to the Irving-Kirkwood limit where the pressure tensor is defined at a point. The PDFs from the MOP and VA routes are compared for cubic subvolumes, V=l3. Using very high grid-resolution and box-counting analysis, we also show that any measurement of pressure in a molecular system will fail to exactly capture the molecular configuration. This suggests that it is impossible to obtain the pressure in the Irving-Kirkwood limit using the commonly employed grid based averaging techniques. More importantly, below l~3 in LJ reduced units, the PDFs depart from Gaussian statistics, and for l=1.0, a double peaked PDF is observed in the MOP but not VA pressure distributions. This departure from a Gaussian shape means that the average pressure is not the most representative or common value to arise. In addition to contributing to our understanding of local pressure formulas, this work shows a clear lower limit on the validity of simply taking the average value when coarse graining pressure from molecular (and colloidal) systems. PMID- 29166054 TI - Modeling super-resolution SERS using a T-matrix method to elucidate molecule nanoparticle coupling and the origins of localization errors. AB - A computational method to model diffraction-limited images from super-resolution surface-enhanced Raman scattering microscopy is introduced. Despite significant experimental progress in plasmon-based super-resolution imaging, theoretical predictions of the diffraction limited images remain a challenge. The method is used to calculate localization errors and image intensities for a single spherical gold nanoparticle-molecule system. The light scattering is calculated using a modification of generalized Mie (T-matrix) theory with a point dipole source and diffraction limited images are calculated using vectorial diffraction theory. The calculation produces the multipole expansion for each emitter and the coherent superposition of all fields. Imaging the constituent fields in addition to the total field provides new insight into the strong coupling between the molecule and the nanoparticle. Regardless of whether the molecular dipole moment is oriented parallel or perpendicular to the nanoparticle surface, the anisotropic excitation distorts the center of the nanoparticle as measured by the point spread function by approximately fifty percent of the particle radius toward to the molecule. Inspection of the nanoparticle multipoles reveals that distortion arises from a weak quadrupole resonance interfering with the dipole field in the nanoparticle. When the nanoparticle-molecule fields are in-phase, the distorted nanoparticle field dominates the observed image. When out-of-phase, the nanoparticle and molecule are of comparable intensity and interference between the two emitters dominates the observed image. The method is also applied to different wavelengths and particle radii. At off-resonant wavelengths, the method predicts images closer to the molecule not because of relative intensities but because of greater distortion in the nanoparticle. The method is a promising approach to improving the understanding of plasmon-enhanced super-resolution experiments. PMID- 29166055 TI - The entropy of a complex molecule. AB - Entropy is a central concept in the theory of coarse-graining. Through Einstein's formula, it provides the equilibrium probability distribution of the coarse grained variables used to describe the system of interest. We study with molecular dynamics simulations the equilibrium probability distribution of thermal blobs representing at a coarse-grained level star polymer molecules in melt. Thermal blobs are characterized by the positions and momenta of the centers of mass, and internal energies of the molecules. We show that the entropy of the level of description of thermal blobs can be very well approximated as the sum of the thermodynamic entropy of each single molecule considered as isolated thermodynamic systems. The entropy of a single molecule depends on the intrinsic energy, involving only contributions from the atoms that make the molecule and not from the interactions with atoms of other molecules. PMID- 29166056 TI - Understanding the effects of electronic polarization and delocalization on charge transport levels in oligoacene systems. AB - Electronic polarization and charge delocalization are important aspects that affect the charge-transport levels in organic materials. Here, using a quantum mechanical/embedded-charge (QM/EC) approach based on a combination of the long range corrected omegaB97X-D exchange-correlation functional (QM) and charge model 5 (CM5) point-charge model (EC), we evaluate the vertical detachment energies and polarization energies of various sizes of crystalline and amorphous anionic oligoacene clusters. Our results indicate that QM/EC calculations yield vertical detachment energies and polarization energies that compare well with the experimental values obtained from ultraviolet photoemission spectroscopy measurements. In order to understand the effect of charge delocalization on the transport levels, we considered crystalline naphthalene systems with QM regions including one or five-molecules. The results for these systems show that the delocalization and polarization effects are additive; therefore, allowing for electron delocalization by increasing the size of the QM region leads to the additional stabilization of the transport levels. PMID- 29166057 TI - A rigorous full-dimensional quantum dynamics study of tunneling splitting of rovibrational states of vinyl radical C2H3. AB - We report a rigorous quantum mechanical study of the rovibrational energy levels of vinyl radical C2H3. The calculations are carried out using a real two component multi-layer Lanczos algorithm in a set of orthogonal polyspherical coordinates based on a recently developed accurate ab initio potential energy surface of C2H3. All well converged 158 vibrational bands up to 3200 cm-1 are determined, together with a comparison to previous calculations and experimental results. Results show a remarkable multi-dimensional tunneling effect on the vibrational spectra of the radical. The vibrational tunneling splitting is substantially different from that of previous reduced dimensional calculations. The rotational constants of the fundamental vibrational bands of C2H3 are also given. It was found that the rovibrational states are strongly coupled, especially among those bending vibrational modes. In addition, the perturbative iteration approach of Gruebele has been extended to assign the rovibrational energy levels of C2H3 without the requirement of explicit wavefunctions. PMID- 29166058 TI - Structural entanglements in protein complexes. AB - We consider multi-chain protein native structures and propose a criterion that determines whether two chains in the system are entangled or not. The criterion is based on the behavior observed by pulling at both termini of each chain simultaneously in the two chains. We have identified about 900 entangled systems in the Protein Data Bank and provided a more detailed analysis for several of them. We argue that entanglement enhances the thermodynamic stability of the system but it may have other functions: burying the hydrophobic residues at the interface and increasing the DNA or RNA binding area. We also study the folding and stretching properties of the knotted dimeric proteins MJ0366, YibK, and bacteriophytochrome. These proteins have been studied theoretically in their monomeric versions so far. The dimers are seen to separate on stretching through the tensile mechanism and the characteristic unraveling force depends on the pulling direction. PMID- 29166060 TI - Origin of OER catalytic activity difference of oxygen-deficient perovskites A2Mn2O5 (A = Ca, Sr): A theoretical study. AB - Mn-based oxygen-deficient perovskite catalysts A2Mn2O5 (A = Ca, Sr) have been experimentally proved high oxygen evolution reaction (OER) activities for replacing Pt in oxygen electrocatalysis. Nevertheless, the correlation between the fundamental electronic structure at room temperature and the corresponding electrocatalysis is not fully accessible. In this paper, we combine the ground state density functional theory (DFT) method and dynamic mean-field theory (DFT+DMFT) at room temperature to investigate the origin of the OER difference for electrocatalysts A2Mn2O5 (A = Ca, Sr). We find that at room temperature the highest occupied Mn dz2 orbital in the square pyramidal crystal field of oxygen deficient perovskites A2Mn2O5 with insulating properties can provide a moderate bonding strength with intermediate hydroxyl OH*, leading to a high OER catalytic activity. According to the electronic structure analysis, we observe that replacing the A-site element Ca by Sr with the larger ionic radii would result in a higher OER activity due to the weakened hybridization between the Mn dz2 orbital and the O psigma orbital of OH*. This insight could provide hints for the screening metal oxide electrocatalysts in the applications of the energy storage and conversion. PMID- 29166059 TI - QM/MM nonadiabatic dynamics simulations on photoinduced Wolff rearrangements of 1,2,3-thiadiazole. AB - The photoinduced rearrangement reaction mechanism of 1,2,3-thiadiazole remains experimentally elusive. Two possible mechanisms have been proposed to date. The first is a stepwise mechanism via a thiocarbene intermediate; the second is an excited-state concerted rearrangement mechanism. Herein we have adopted both the electronic structure calculations and nonadiabatic dynamics simulations to study the photoinduced rearrangement reactions of 1,2,3-thiadiazole in the S2, S1, and S0 states in solution. On the basis of QM(CASPT2)/MM [quantum mechanics(complete active space self-consistent field second-order perturbation theory)/molecular mechanics] calculations, we have found that (1) the thiocarbene intermediate is not stable; thus, the stepwise mechanism should be unfavorable; (2) the excited state decay from the S2 via S1 to S0 state is ultrafast and completed within ca. 200 fs; therefore, both the S2 and S1 states should not have a long enough time for the excited-state rearrangements. Instead, we have computationally proposed a modified photoinduced rearrangement mechanism. Upon irradiation, the S2 state is first populated (114.0 kcal/mol), followed by an ultrafast S2 -> S1 -> S0 excited state decay along the S-N bond fission, which eventually leads to a very "hot" intermediate with the S-N bond broken (18.3 kcal/mol). Then, thermal rearrangements to thioketene, thiirene, and ethynethiol occur in a concerted asynchronous way. This mechanistic scenario has been verified by full-dimensional trajectory-based nonadiabatic dynamics simulations at the QM(CASPT2)/MM level. Finally, our present computational work provides experimentally interesting mechanistic insights into the photoinduced rearrangement reactions of cyclic and acyclic diazo compounds. PMID- 29166061 TI - Modeling hydroxylated nanosilica: Testing the performance of ReaxFF and FFSiOH force fields. AB - We analyze the performance of the FFSiOH force field and two parameterisations of the ReaxFF force field for modeling hydroxylated nanoscale silica (SiO2). Such nanosystems are fundamental in numerous aspects of geochemistry and astrochemistry and also play a key role during the hydrothermal synthesis of technologically important nanoporous silicas (e.g., catalysts, absorbents, and coatings). We consider four aspects: structure, relative energies, vibrational spectra, and hydroxylation energies, and compare the results with those from density functional calculations employing a newly defined dataset (HND: Hydroxylated Nanosilica Dataset). The HND consists of three sets of (SiO2)16(H2O)N nanoparticles (NPs), each with a different degree of hydroxylation and each containing between 23 and 26 distinct isomers and conformers. We also make all HND reference data openly available. We further consider hydroxylated silica NPs of composition (SiO2)M(H2O)N with M = 4, 8, 16, and 24 and infinite surface slabs of amorphous silica, both with variable hydroxylation. For energetics, both ReaxFF and FFSiOH perform well for NPs with an intermediate degree of hydroxylation. For increased hydroxylation, the performance of FFSiOH begins to significantly decline. Conversely, for the lower degree of hydroxylation both parameterisations of ReaxFF do not perform well. For vibrational frequencies, FFSiOH performs particularly well and significantly better than ReaxFF. This feature also opens the door to inexpensively calculating Gibbs free energies of the hydroxylated nanosilica systems in order to efficiently correct density functional theory calculated electronic energies. We also show how some small changes to FFSiOH could improve its performance for higher degrees of hydroxylation. PMID- 29166063 TI - Hard-hard coupling assisted anomalous magnetoresistance effect in amine-ended single-molecule magnetic junction. AB - We proposed a single-molecule magnetic junction (SMMJ), composed of a dissociated amine-ended benzene sandwiched between two Co tip-like nanowires. To better simulate the break junction technique for real SMMJs, the first-principles calculation associated with the hard-hard coupling between a amine-linker and Co tip-atom is carried out for SMMJs with mechanical strain and under an external bias. We predict an anomalous magnetoresistance (MR) effect, including strain induced sign reversal and bias-induced enhancement of the MR value, which is in sharp contrast to the normal MR effect in conventional magnetic tunnel junctions. The underlying mechanism is the interplay between four spin-polarized currents in parallel and anti-parallel magnetic configurations, originated from the pronounced spin-up transmission feature in the parallel case and spiky transmission peaks in other three spin-polarized channels. These intriguing findings may open a new arena in which magnetotransport and hard-hard coupling are closely coupled in SMMJs and can be dually controlled either via mechanical strain or by an external bias. PMID- 29166062 TI - Nonadiabatic photodissociation dynamics of the hydroxymethyl radical via the 22A(3s) Rydberg state: A four-dimensional quantum study. AB - The quantum mechanical nonadiabatic photodissociation dynamics of the hydroxymethyl (CH2OH) radical in its lowest absorption band is investigated for the first time on a set of coupled diabatic potential energy surfaces determined by accurately fitting a large set of ab initio data. In this two-state approximation, only the ground and first excited states of CH2OH, which are coupled by conical intersections, are included. The reduced-dimensional dynamical model includes the CO stretch, the COH bend, the HCOH torsion, and the O-H dissociation coordinate. The experimentally measured hydrogen atom kinetic energy distribution is satisfactorily reproduced. The calculated product state distribution of the H2CO(X) fragment indicates strong vibrational excitation in the CO stretching mode, resulting from the relatively large difference in the C-O bond length between the ground and excited electronic states of CH2OH due to the photo-induced promotion of an electron from the half-occupied pi*CO antibonding orbital to a Rydberg orbital. In addition, the bimodal kinetic energy distribution is confirmed to originate from nonadiabatic transitions near the conical intersection along the O-H dissociation coordinate. PMID- 29166064 TI - Interaction-component analysis of the effects of urea and its alkylated derivatives on the structure of T4-lysozyme. AB - The effects of urea and its alkylated derivatives on the structure of T4-lysozyme were analyzed from the standpoint of energetics. Molecular dynamics simulations were conducted with explicit solvent, and the energy-representation method was employed to compute the free energy of transfer of the protein from pure-water solvent to the mixed solvents of water with urea, methylurea, 1,1-dimethylurea, and isopropylurea. Through the decomposition of the transfer free energy into the cosolvent and water contributions, it was observed that the former is partially cancelled by the latter and governs the total free energy of transfer. To determine the interaction component responsible for the transfer energetics, the correlations of the transfer free energy were also examined against the change in the solute-solvent interaction energy upon transfer and the corresponding changes in the electrostatic, van der Waals, and excluded-volume components. It was then found over the set of protein structures ranging from native to (partially) unfolded ones that the transfer free energy changes in parallel with the van der Waals component even when the cosolvent is alkylated. The electrostatic and excluded-volume components play minor roles in the structure modification of the protein, and the denaturing ability of alkylurea is brought by the van der Waals interaction. PMID- 29166065 TI - Note: On the inclusion of a diagonal Born-Oppenheimer correction in the reduced dimensional treatment of the H2O-para-H2 complex. PMID- 29166066 TI - Manipulation of Pauli spin blockade in double quantum dot systems. AB - Pauli spin blockade (PSB) is a significant physical effect in double quantum dot (DQD) systems. In this paper, we start from the fundamental quantum model of the DQD with the electron-electron interaction being considered and then systematically study the PSB effect in DQD by using a recently developed nonperturbative method, the hierarchical equations of motion approach. By checking the current-voltage and nonequilibrium spectral function features, the physical picture of the PSB is explicitly elucidated. Then, various kinds of manipulation of PSBs are discussed, including gate voltage, exchange interaction, and electron spin resonance. Three main characteristics beyond low-order perturbation theory are demonstrated in detail as follows: (1) the finite leakage current in the strongly correlated limit; (2) the enhancement and lifting of PSB by exchange interaction; and (3) the ON-and-OFF switch of PSB by real-time modulation. PMID- 29166067 TI - Equilibrium configurations of large nanostructures using the embedded saturated fragments stochastic density functional theory. AB - An ab initio Langevin dynamics approach is developed based on stochastic density functional theory (sDFT) within a new embedded saturated fragment formalism, applicable to covalently bonded systems. The forces on the nuclei generated by sDFT contain a random component natural to Langevin dynamics, and its standard deviation is used to estimate the friction term on each atom by satisfying the fluctuation-dissipation relation. The overall approach scales linearly with the system size even if the density matrix is not local and is thus applicable to ordered as well as disordered extended systems. We implement the approach for a series of silicon nanocrystals (NCs) of varying size with a diameter of up to 3 nm corresponding to Ne = 3000 electrons and generate a set of configurations that are distributed canonically at a fixed temperature, ranging from cryogenic to room temperature. We also analyze the structure properties of the NCs and discuss the reconstruction of the surface geometry. PMID- 29166068 TI - Pure-rotational H2 thermometry by ultrabroadband coherent anti-Stokes Raman spectroscopy. AB - Coherent anti-Stokes Raman spectroscopy (CARS) is a sensitive technique for probing highly luminous flames in combustion applications to determine temperatures and species concentrations. CARS thermometry has been demonstrated for the vibrational Q-branch and pure-rotational S-branch of several small molecules. Practical advantages of pure-rotational CARS, such as multi-species detection, reduction of coherent line mixing and collisional narrowing even at high pressures, and the potential for more precise thermometry, have motivated experimental and theoretical advances in S-branch CARS of nitrogen (N2), for example, which is a dominant species in air-fed combustion processes. Although hydrogen (H2) is of interest given its prevalence as a reactant and product in many gas-phase reactions, laser bandwidth limitations have precluded the extension of CARS thermometry to the H2 S-branch. We demonstrate H2 thermometry using hybrid femtosecond/picosecond pure-rotational CARS, in which a broadband pump/Stokes pulse enables simultaneous excitation of the set of H2 S-branch transitions populated at flame temperatures over the spectral region of 0-2200 cm 1. We present a pure-rotational H2 CARS spectral model for data fitting and compare extracted temperatures to those from simultaneously collected N2 spectra in two systems of study: a heated flow and a diffusion flame on a Wolfhard-Parker slot burner. From 300 to 650 K in the heated flow, the H2 and N2 CARS extracted temperatures are, on average, within 2% of the set temperature. For flame measurements, the fitted H2 and N2 temperatures are, on average, within 5% of each other from 300 to 1600 K. Our results confirm the viability of pure rotational H2 CARS thermometry for probing combustion reactions. PMID- 29166069 TI - Revealing the role of thiocyanate anion in layered hybrid halide perovskite (CH3NH3)2Pb(SCN)2I2. AB - The effect of the SCN- ion on the structural, electronic, optical, and mechanical properties of the layered (MA)2Pb(SCN)2I2 (MA=CH3NH3+) perovskite is investigated by using first-principles calculations. Our results suggest that the introduction of SCN- ions at the apical positions gives rise to shorter Pb-S bond lengths, more distorted octahedra, and more hydrogen bonds, which have important effects on the electronic, optical, mechanical, and piezoelectric properties in (MA)2Pb(SCN)2I2. Furthermore, a strong relativistic Rashba splitting is induced due to the breaking of the inversion symmetry, which helps to suppress the carrier recombination and enhance the carrier lifetime. The analysis of mechanical properties reveals that the incorporation of SCN- ions is beneficial to strengthen Young's modulus of the perovskite materials and it enhances the piezoelectric properties. Our investigation suggests that doping SCN- ions into the perovskite materials could be a promising strategy to improve the stability and mechanical properties of organic-inorganic hybrid halide perovskite compounds. PMID- 29166070 TI - Effect of the diradical character on static polarizabilities and two-photon absorption cross sections: A closer look with spin-flip equation-of-motion coupled-cluster singles and doubles method. AB - We present static polarizabilities and two-photon absorption (2PA) cross sections for the low-lying electronic states of prototypical diradicals such as benzynes and analogues of m-xylylene and p-quinodimethane computed with the spin-flip equation-of-motion coupled-cluster singles and doubles (EOM-SF-CCSD) method. The static polarizabilities were calculated as analytic second derivatives of the EOM energies, and the 2PA cross sections were calculated using the expectation-value approach. We explain the trends in the nonlinear responses of the SF target states by constructing few-states models based on truncated sum-over-states expressions for these nonlinear properties. By using a Huckel-type treatment of the frontier molecular orbitals that host the unpaired electrons, we rationalize the trends in the dipole interactions between the SF target states relevant in the few-states models. We demonstrate the correlation between the nonlinear responses of these electronic states and the diradical character. PMID- 29166071 TI - Tunability of the CO adsorption energy on a Ni/Cu surface: Site change and coverage effects. AB - The adsorption energy of carbon monoxide on Ni ad-islands and ultra-thin films grown on the Cu(110) surface can be finely tuned via a complex interplay among diffusion, site change mechanisms, and coverage effects. The observed features of CO desorption can be explained in terms of migration of CO molecules from Cu to Ni islands, competition between bridge and on-top adsorption sites, and repulsive lateral adsorbate-adsorbate interactions. While the CO adsorption energy on clean Cu(110) is of the order of 0.5 eV, Ni-alloying allows for its controlled, continuous tunability in the 0.98-1.15 eV range with Ni coverage. Since CO is a fundamental reactant and intermediate in many heterogeneous catalytic (electro) conversion reactions, insight into these aspects with atomic level detail provides useful information to potentially drive applicative developments. The tunability range of the CO adsorption energy that we measure is compatible with the already observed tuning of conversion rates by Ni doping of Cu single crystal catalysts for methanol synthesis from a CO2, CO, and H2 stream under ambient pressure conditions. PMID- 29166072 TI - Size effect on dynamics and glass transition in metallic liquids and glasses. AB - The relaxation dynamics and glass transition in finite-sized metallic liquid droplets were investigated via molecular dynamic simulations in model monoatomic Ta and binary Cu50Zr50 metallic liquids. We find that the droplet size has a significant impact on liquid dynamics and glass transition. Glass transition temperature and structural relaxation time exhibit strong size dependence and decrease drastically as the droplet is smaller than a certain size. It is revealed that this results from a liquid-like surface layer (~1 nm thick) of droplets, in which the dynamics is much faster than the interior of droplets. A proposed scaling relationship can well describe the size dependent behavior of the glass transition temperature in metallic liquid droplets. These findings provide insight into the dynamics of metallic liquid droplets and plausible understanding of recent novel experimental observations. Apart from temperature and pressure, size may be another important parameter for potentially tuning the properties of metallic liquids and glasses in nanometer scale. PMID- 29166073 TI - Theoretical investigation of rotationally inelastic collisions of CH(X2Pi) with hydrogen atoms. AB - We report calculations of state-to-state cross sections for collision-induced rotational transitions of CH(X2Pi) with atomic hydrogen. These calculations employed the four adiabatic potential energy surfaces correlating CH(X2Pi) + H(2S), computed in this work through the multi-reference configuration interaction method [MRCISD + Q(Davidson)]. Because of the presence of deep wells on three of the potential energy surfaces, the scattering calculations were carried out using the quantum statistical method of Manolopoulos and co-workers [Chem. Phys. Lett. 343, 356 (2001)]. The computed cross sections included contributions from only direct scattering since the CH2 collision complex is expected to decay predominantly to C + H2. Rotationally energy transfer rate constants were computed for this system since these are required for astrophysical modeling. PMID- 29166074 TI - Low-lying vibronic level structure of the ground state of the methoxy radical: Slow electron velocity-map imaging (SEVI) spectra and Koppel-Domcke-Cederbaum (KDC) vibronic Hamiltonian calculations. AB - A joint experimental and theoretical study is reported on the low-lying vibronic level structure of the ground state of the methoxy radical using slow photoelectron velocity-map imaging spectroscopy of cryogenically cooled, mass selected anions (cryo-SEVI) and Koppel-Domcke-Cederbaum (KDC) vibronic Hamiltonian calculations. The KDC vibronic model Hamiltonian in the present study was parametrized using high-level quantum chemistry, allowing the assignment of the cryo-SEVI spectra for vibronic levels of CH3O up to 2000 cm-1 and of CD3O up to 1500 cm-1 above the vibrational origin, using calculated vibronic wave functions. The adiabatic electron affinities of CH3O and CD3O are determined from the cryo-SEVI spectra to be 1.5689 +/- 0.0007 eV and 1.5548 +/- 0.0007 eV, respectively, demonstrating improved precision compared to previous work. Experimental peak splittings of <10 cm-1 are resolved between the e1/2 and e3/2 components of the 61 and 51 vibronic levels. A pair of spin-vibronic levels at 1638 and 1677 cm-1 were predicted in the calculation as the e1/2 and e3/2 components of 62 levels and experimentally resolved for the first time. The strong variation of the spin-orbit splittings with a vibrational quantum number is in excellent agreement between theory and experiment. The observation of signals from nominally forbidden a1 vibronic levels in the cryo-SEVI spectra also provides direct evidence of vibronic coupling between ground and electronically excited states of methoxy. PMID- 29166075 TI - A detailed-balance model for thermionic emission from polyanions: The case of fullerene dianions. AB - A detailed-balance model for thermionic emission from polyanions has been developed and applied to fullerene dianions. The specificity of this delayed decay process is electron tunneling through the repulsive Coulomb barrier (RCB). An analytical expression of the RCB is derived from electrostatic modeling of the fullerene cage. The reverse process, namely, electron attachment to the singly charged anion, is described by a hard sphere cross section weighted by the Wentzel-Kramers-Brillouin tunneling probability. This simple expression leads to a very good agreement with a measured time-resolved kinetic energy distribution of C842-. Electron binding energy is reduced when the fullerene cage size decreases, leading to an almost zero one for C702- and a negative one for C602-. Extension of the model to these systems of interest is discussed, and model outputs are compared with the experimental data from the literature. PMID- 29166076 TI - Note: Smooth torsional potentials for degenerate dihedral angles. AB - A general method is proposed for smoothing torsional potentials when the dihedral angle becomes undefined. PMID- 29166077 TI - Low-energy photoelectron transmission through aerosol overlayers. AB - The transmission of low-energy (<1.8 eV) photoelectrons through the shell of core shell aerosol particles is studied for liquid squalane, squalene, and di-ethyl hexyl-sebacate shells. The photoelectrons are exclusively formed in the core of the particles by two-photon ionization. The total photoelectron yield recorded as a function of shell thicknesses (1-80 nm) shows a bi-exponential attenuation. For all substances, the damping parameter for shell thicknesses below 15 nm lies around 8 to 9 nm and is tentatively assigned to the electron attenuation length at electron kinetic energies of ?1 eV. The significantly larger damping parameters for thick shells (>20 nm) are presumably a consequence of distorted core-shell structures. A first comparison of aerosol and traditional thin film overlayer methods is provided. PMID- 29166079 TI - Strong correlation in incremental full configuration interaction. AB - Incremental Full Configuration Interaction (iFCI) reaches high accuracy electronic energies via a many-body expansion of the correlation energy. In this work, the Perfect Pairing (PP) ansatz replaces the Hartree-Fock reference of the original iFCI method. This substitution captures a large amount of correlation at zero-order, which allows iFCI to recover the remaining correlation energy with low-order increments. The resulting approach, PP-iFCI, is size consistent, size extensive, and systematically improvable with increasing order of incremental expansion. Tests on multiple single bond, multiple double bond, and triple bond dissociations of main group polyatomics using double and triple zeta basis sets demonstrate the power of the method for handling strong correlation. The smooth dissociation profiles that result from PP-iFCI show that FCI-quality ground state computations are now within reach for systems with up to about 10 heavy atoms. PMID- 29166078 TI - Perspective: Theory and simulation of hybrid halide perovskites. AB - Organic-inorganic halide perovskites present a number of challenges for first principles atomistic materials modeling. Such "plastic crystals" feature dynamic processes across multiple length and time scales. These include the following: (i) transport of slow ions and fast electrons; (ii) highly anharmonic lattice dynamics with short phonon lifetimes; (iii) local symmetry breaking of the average crystallographic space group; (iv) strong relativistic (spin-orbit coupling) effects on the electronic band structure; and (v) thermodynamic metastability and rapid chemical breakdown. These issues, which affect the operation of solar cells, are outlined in this perspective. We also discuss general guidelines for performing quantitative and predictive simulations of these materials, which are relevant to metal-organic frameworks and other hybrid semiconducting, dielectric and ferroelectric compounds. PMID- 29166080 TI - Continuum balances from extended Hamiltonian dynamics. AB - The classical procedure devised by Irving and Kirkwood in 1950 and completed slightly later by Noll produces counterparts of the basic balance laws of standard continuum mechanics starting from an ordinary Hamiltonian description of the dynamics of a system of material points. Post-1980 molecular dynamics simulations of the time evolution of such systems use extended Hamiltonians such as those introduced by Andersen, Nose, and Parrinello and Rahman. The additional terms present in these extensions affect the statistical properties of the system so as to capture certain target phenomenologies that would otherwise be beyond reach. We here propose a physically consistent application of the Irving-Kirkwood Noll procedure to the extended Hamiltonian systems of material points. Our procedure produces balance equations at the continuum level featuring non standard terms because the presence of auxiliary degrees of freedom gives rise to additional fluxes and sources that influence the thermodynamic and transport properties of the continuum model. Being aware of the additional contributions may prove crucial when designing multiscale computational schemes in which information is exchanged between the atomistic and continuum levels. PMID- 29166081 TI - Three sources of errors in the Ehrenfest treatment of inelastic scattering and possible ways of resolving them. AB - In order to identify the origin of possible errors in the mixed quantum/classical approach to inelastic scattering [A. Semenov and D. Babikov, J. Chem. Phys. 140, 044306 (2014) and A. Semenov, M.-L. Dubernet, and D. Babikov, J. Chem. Phys. 141, 114304 (2014)], a simplified model is considered that consists of one intermolecular degree of freedom and two intramolecular states, coupled by a simple potential. For this system, analytic derivations are carried out to determine (i) the exact quantum mechanical solution of the inelastic scattering problem, (ii) a simplified version of it with all oscillatory terms neglected, and (iii) the Ehrenfest solution in which the translational motion is described by the mean-field trajectory while the internal molecular motion is treated by the time-dependent Schrodinger equation. It is shown that the appropriate choice of velocity for the mean-field trajectory permits to enforce microscopic reversibility and gives results in excellent agreement with full-quantum results. The average velocity method of Billing is rigorously derived as a limiting case (of this more general approach), when reversibility is enforced locally, at the initial moment of time only. It is demonstrated that errors of state-to-state transition probabilities in the Ehrenfest approach occur at lower values of total energy E if the magnitudes of excitation energy DeltaE, potential energy difference between the two states DeltaV, and coupling of two states V12 are large. Possible ways of applying this concept to rotational transitions in real molecules are explored, using examples from CO + CO inelastic scattering. PMID- 29166082 TI - Ionic versus metallic bonding in AlnNam and AlnMgm (m <= 3, n + m <= 15) clusters. AB - First principles electronic structure studies on the ground state geometries, stability, and the electronic structure of AlnNam and AlnMgm (m <= 3, n + m <= 15) clusters have been carried out to examine the nature of bonding between Na or Mg and Al. Identifying whether the bonding is ionic or metallic in bulk materials is typically straightforward; however, in small clusters where quantum confinement is important, the nature of bonding may become unclear. We have performed a critical analysis of the bonding in these bimetallic clusters using charge analysis, electrical dipole moments, hybridization of the atomic orbitals, the Laplacian of the charge density at the bond critical points, and the change in the bonding energy between neutral and anionic forms of the cluster. For NanAlm clusters, we find that the Na binding is primarily ionic, while the bonding in AlnMgm is primarily metallic. We find that the Mulliken population of the 3p orbital of Na and Mg can provide a rapid assessment of the nature of bonding. We also find that the Hirshfeld charge and dipole moments are effective indicators, when placed in context. We found that the Laplacian of the charge density at the bond critical points can be misleading in identifying whether the bonding is ionic or metallic in small clusters. PMID- 29166083 TI - Water structure around hydrophobic amino acid side chain analogs using different water models. AB - The water structure around hydrophobic groups governs various biochemical processes. There is an ongoing debate on whether water molecules near hydrophobic groups are more ordered with greater participation in water-water hydrogen bonding with respect to water in the pure bulk state. The water structure around six different hydrophobic amino acid side chain analog molecules has been studied in pure water using molecular dynamics simulations. The analysis of water tetrahedral order parameter and the number of hydrogen bonds formed by the individual water molecules in the first hydration shell of the hydrophobic analogs provide evidence that both ordering and hydrogen bonds involving water molecules are to some extent reduced in the hydrophobic hydration shell. It is revealed that the water tetrahedrality in the outer part of the first hydrophobic hydration shell is equivalent to bulk water for all the water models except for the TIP4P-2005 model which shows marginally higher tetrahedrality. However, irrespective of the model employed, water tetrahedrality has always been found to be reduced in the inner part of the first hydration shell, which eventually makes the overall water tetrahedrality in the first hydrophobic hydration shell marginally lower than that observed for pure bulk water. Importantly, it is noticed that the decrease in water structuring exhibits solute size dependencies. Around a small solute like methane, the water tetrahedral ordering or hydrogen bonding propensity is quite similar to that of the bulk state. The effect, reduction in water structuring, is however more pronounced for relatively larger solutes. PMID- 29166084 TI - On the electron density localization in elemental cubic ceramic and FCC transition metals by means of a localized electrons detector. AB - The electron density localization in insulator and semiconductor elemental cubic materials with diamond structure, carbon, silicon, germanium, and tin, and good metallic conductors with face centered cubic structure such as alpha-Co, Ni, Cu, Rh, Pd, Ag, Ir, Pt, and Au, was studied using a localized electrons detector defined in the local moment representation. Our results clearly show an opposite pattern of the electron density localization for the cubic ceramic and transition metal materials. It was found that, for the elemental ceramic materials, the zone of low electron localization is very small and is mainly localized on the atomic basin edges. On the contrary, for the transition metals, there are low-valued localized electrons detector isocontours defining a zone of highly delocalized electrons that extends throughout the material. We have found that the best conductors are those in which the electron density at this low-value zone is the lowest. PMID- 29166085 TI - Confirming the relationship between first hyperpolarizability and the bond length alternation coordinate for merocyanine dyes. AB - We investigated the first electronic hyperpolarizability of a typical merocyanine dye in several solvents in a wide range of dielectric constants. The equilibrium geometry of the molecule was obtained in each solvent by employing an optimization technique allied to atomistic simulations. The results confirm, for the first time with a realistic model of the molecular environment, the relationship between the first electronic hyperpolarizability (beta) and the bond length alternation (BLA) coordinate, with a maximum value of beta for intermediate positive BLA and a vanishing beta when the BLA goes to zero. PMID- 29166086 TI - Focused conformational sampling in proteins. AB - A detailed understanding of the conformational dynamics of biological molecules is difficult to obtain by experimental techniques due to resolution limitations in both time and space. Computer simulations avoid these in theory but are often too short to sample rare events reliably. Here we show that the progress index guided sampling (PIGS) protocol can be used to enhance the sampling of rare events in selected parts of biomolecules without perturbing the remainder of the system. The method is very easy to use as it only requires as essential input a set of several features representing the parts of interest sufficiently. In this feature space, new states are discovered by spontaneous fluctuations alone and in unsupervised fashion. Because there are no energetic biases acting on phase space variables or projections thereof, the trajectories PIGS generates can be analyzed directly in the framework of transition networks. We demonstrate the possibility and usefulness of such focused explorations of biomolecules with two loops that are part of the binding sites of bromodomains, a family of epigenetic "reader" modules. This real-life application uncovers states that are structurally and kinetically far away from the initial crystallographic structures and are also metastable. Representative conformations are intended to be used in future high throughput virtual screening campaigns. PMID- 29166087 TI - DFT/MRCI Hamiltonian for odd and even numbers of electrons. AB - DFT/MRCI is a well-established method of Grimme and Waletzke [J. Chem. Phys. 111, 5645 (1999)] combining density functional theory and multireference configuration interaction. It was later redesigned by Lyskov, Kleinschmidt, and Marian [J. Chem. Phys. 144, 034104 (2016)] to provide a better treatment of bi-chromophores while treating all other systems as well as Grimme's version did by computing individual energy shifts for each state function of a configuration. But all previous operators lack the ability to compute states with an odd number of electrons (doublet and quartet states). Here we present a general Hamiltonian based on Lyskov's redesign which calculates excited singlet, doublet, triplet, and quartet states of systems that have up to one open shell in the parent determinant. The multiplicity-independent correction parameters provide an extra correction for the open shell in the parent determinant. The Hamiltonian in combination with two parameter sets for different selection thresholds has been tested and compared to experimental vertical excitation and ionization energies yielding similar statistics for all multiplicities with a root mean square deviation smaller than 0.2 eV while maintaining the good computational performance of the Hamiltonians of Grimme and Lyskov. PMID- 29166088 TI - Extraction of effective solid-liquid interfacial free energies for full 3D solid crystallites from equilibrium MD simulations. AB - Molecular dynamics simulations of an embedded atom copper system in the isobaric isenthalpic ensemble are used to study the effective solid-liquid interfacial free energy of quasi-spherical solid crystals within a liquid. This is within the larger context of molecular dynamics simulations of this system undergoing solidification, where single individually prepared crystallites of different sizes grow until they reach a thermodynamically stable final state. The resulting equilibrium shapes possess the full structural details expected for solids with weakly anisotropic surface free energies (in these cases, ~5% radial flattening and rounded [111] octahedral faces). The simplifying assumption of sphericity and perfect isotropy leads to an effective interfacial free energy as appearing in the Gibbs-Thomson equation, which we determine to be ~177 erg/cm2, roughly independent of crystal size for radii in the 50-250 A range. This quantity may be used in atomistically informed models of solidification kinetics for this system. PMID- 29166089 TI - Steric effect in CO oxidation on Pt(111). AB - We present experimental evidence showing that the rate of CO oxidation on Pt(111) depends strongly on the geometry of an incident O2 molecule. The O2 sticking probability and the CO2 production rate on CO-covered Pt(111) surfaces during the alignment-controlled O2 beam irradiation were simultaneously monitored at a surface temperature of 330 K. The results indicate that, at the translational energy of 0.1-0.2 eV and at the CO coverage of <0.4 monolayers, both O2 adsorption and CO oxidation proceed exclusively when the O2 molecular axis is nearly parallel to the surface. PMID- 29166090 TI - Analytical expression for the tunnel current through the redox-mediated tunneling contact in the case of the adiabatic electron transfer at one of the working electrodes and any possible type of the electron transfer at the other electrode. AB - We study the tunnel current through a one-level redox molecule immersed into the electrolyte solution for the case when the coupling of the molecule to one of the working electrodes is strong while it is arbitrary to the other electrode. Using the Feynman-Vernon influence functional theory and the perturbation expansion of the effective action of the classical oscillator coupled both to the valence level of the redox molecule and to the thermal bath representing the classical fluctuations of the polarization of the solvent, we obtain, following the canonical way, the Langevin equation for the oscillator. It is found that for the aqueous electrolyte solution, the damping and the stochastic forces which arise due to the tunnel current are much smaller than those due to the thermal bath and therefore can be neglected. We estimate the higher-order corrections to the effective action and show that the Langevin dynamics takes place in this case for arbitrary parameters of the tunneling junction under the condition of the strong coupling of the redox molecule to one of the working electrodes. Then the steady state coordinate distribution function of the oscillator resulting from the corresponding Fokker-Planck equation is the Boltzmann distribution function which is determined by the adiabatic free energy surface arising from the mean current induced force. It enables us to obtain the expression for the tunnel current in the case when the coupling of the redox molecule to one of the working electrodes is strong while it is arbitrary to the other electrode. PMID- 29166091 TI - String-like collective motion and diffusion in the interfacial region of ice. AB - We investigate collective molecular motion and the self-diffusion coefficient Ds of water molecules in the mobile interfacial layer of the secondary prismatic plane (112-0) of hexagonal ice by molecular dynamics simulation based on the TIP4P/2005 water potential and a metrology of collective motion drawn from the field of glass-forming liquids. The width xi of the mobile interfacial layer varies from a monolayer to a few nm as the temperature is increased towards the melting temperature Tm, in accordance with recent simulations and many experimental studies, although different experimental methods have differed in their precise estimates of the thickness of this layer. We also find that the dynamics within this mobile interfacial ice layer is "dynamically heterogeneous" in a fashion that has many features in common with glass-forming liquids and the interfacial dynamics of crystalline Ni over the same reduced temperature range, 2/3 < T/Tm < 1. In addition to exhibiting non-Gaussian diffusive transport, decoupling between mass diffusion and the structural relaxation time, and stretched exponential relaxation, we find string-like collective molecular exchange motion in the interfacial zone within the ice interfacial layer and colored noise fluctuations in the mean square molecular atomic displacement after a "caging time" of 1 ps, i.e., the Debye-Waller factor. However, while the heterogeneous dynamics of ice is clearly similar in many ways to molecular and colloidal glass-forming materials, we find distinct trends between the diffusion coefficient activation energy Ea for diffusion Ds and the interfacial width xi from the scale of collective string-like motion L than those found in glass forming liquids. PMID- 29166092 TI - The influence of mesoscopic confinement on the dynamics of imidazolium-based room temperature ionic liquids in polyether sulfone membranes. AB - The structural dynamics of a series of 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (CnmimNTf2, n = 2, 4, 6, 10: ethyl-Emim; butyl Bmim; hexyl-Hmim; decyl-Dmim) room temperature ionic liquids confined in the pores of polyether sulfone (PES 200) membranes with an average pore size of ~350 nm and in the bulk liquids were studied. Time correlated single photon counting measurements of the fluorescence of the fluorophore coumarin 153 (C153) were used to observe the time-dependent Stokes shift (solvation dynamics). The solvation dynamics of C153 in the ionic liquids are multiexponential decays. The multiexponential functional form of the decays was confirmed as the slowest decay component of each bulk liquid matches the slowest component of the liquid dynamics measured by optical heterodyne-detected optical Kerr effect (OHD-OKE) experiments, which is single exponential. The fact that the slowest component of the Stokes shift matches the OHD-OKE data in all four liquids identifies this component of the solvation dynamics as arising from the complete structural randomization of the liquids. Although the pores in the PES membranes are large, confinement on the mesoscopic length scale results in substantial slowing of the dynamics, a factor of ~4, for EmimNTf2, with the effect decreasing as the chain length increases. By DmimNTf2, the dynamics are virtually indistinguishable from those in the bulk liquid. The rotation relaxation of C153 in the four bulk liquids was also measured and showed strong coupling between the C153 probe and its environment. PMID- 29166093 TI - A study of the dense uniform electron gas with high orders of coupled cluster. AB - We investigate the accuracies of different coupled cluster levels in a finite model solid, the 14 electron spin-non-polarised uniform electron gas. For densities between rs = 0.5 a0 and rs = 5 a0, we calculate ground state correlation energies with stochastic coupled cluster ranging from coupled cluster singles and doubles (CCSD) to coupled cluster including all excitations up to quintuples (CCSDTQ5). We find the need to add triple excitations for an accuracy of 0.01 eV/electron beyond rs = 0.5 a0. Quadruple excitations start being significant past rs = 3 a0. At rs = 5 a0, CCSD gives a correlation energy with a 16% error and coupled cluster singles doubles and triples is in error by 2% compared to the CCSDTQ5 result. CCSDTQ5 gives an energy in agreement with full configuration interaction quantum Monte Carlo results. PMID- 29166094 TI - Structure and electronic states of a graphene double vacancy with an embedded Si dopant. AB - Silicon represents a common intrinsic impurity in graphene, bonding to either three or four carbon neighbors, respectively, in a single or double carbon vacancy. We investigate the effect of the latter defect (Si-C4) on the structural and electronic properties of graphene using density functional theory. Calculations based both on molecular models and with periodic boundary conditions have been performed. The two-carbon vacancy was constructed from pyrene (pyrene 2C) which was then expanded to circumpyrene-2C. The structural characterization of these cases revealed that the ground state is slightly non-planar, with the bonding carbons displaced from the plane by up to +/-0.2 A. This non-planar structure was confirmed by embedding the defect into a 10 * 8 supercell of graphene, resulting in 0.22 eV lower energy than the previously considered planar structure. Natural bond orbital analysis showed sp3 hybridization at the silicon atom for the non-planar structure and sp2d hybridization for the planar structure. Atomically resolved electron energy loss spectroscopy and corresponding spectrum simulations provide a mixed picture: a flat structure provides a slightly better overall spectrum match, but a small observed pre-peak is only present in the corrugated simulation. Considering the small energy barrier between the two equivalent corrugated conformations, both structures could plausibly exist as a superposition over the experimental time scale of seconds. PMID- 29166095 TI - Computer simulations of alkali-acetate solutions: Accuracy of the forcefields in difference concentrations. AB - When proteins are solvated in electrolyte solutions that contain alkali ions, the ions interact mostly with carboxylates on the protein surface. Correctly accounting for alkali-carboxylate interactions is thus important for realistic simulations of proteins. Acetates are the simplest carboxylates that are amphipathic, and experimental data for alkali acetate solutions are available and can be compared with observables obtained from simulations. We carried out molecular dynamics simulations of alkali acetate solutions using polarizable and non-polarizable forcefields and examined the ion-acetate interactions. In particular, activity coefficients and association constants were studied in a range of concentrations (0.03, 0.1, and 1M). In addition, quantum-mechanics (QM) based energy decomposition analysis was performed in order to estimate the contribution of polarization, electrostatics, dispersion, and QM (non-classical) effects on the cation-acetate and cation-water interactions. Simulations of Li acetate solutions in general overestimated the binding of Li+ and acetates. In lower concentrations, the activity coefficients of alkali-acetate solutions were too high, which is suggested to be due to the simulation protocol and not the forcefields. Energy decomposition analysis suggested that improvement of the forcefield parameters to enable accurate simulations of Li-acetate solutions can be achieved but may require the use of a polarizable forcefield. Importantly, simulations with some ion parameters could not reproduce the correct ion-oxygen distances, which calls for caution in the choice of ion parameters when protein simulations are performed in electrolyte solutions. PMID- 29166096 TI - Building better water models using the shape of the charge distribution of a water molecule. AB - The unique properties of liquid water apparently arise from more than just the tetrahedral bond angle between the nuclei of a water molecule since simple three site models of water are poor at mimicking these properties in computer simulations. Four- and five-site models add partial charges on dummy sites and are better at modeling these properties, which suggests that the shape of charge distribution is important. Since a multipole expansion of the electrostatic potential describes a charge distribution in an orthogonal basis set that is exact in the limit of infinite order, multipoles may be an even better way to model the charge distribution. In particular, molecular multipoles up to the octupole centered on the oxygen appear to describe the electrostatic potential from electronic structure calculations better than four- and five-site models, and molecular multipole models give better agreement with the temperature and pressure dependence of many liquid state properties of water while retaining the computational efficiency of three-site models. Here, the influence of the shape of the molecular charge distribution on liquid state properties is examined by correlating multipoles of non-polarizable water models with their liquid state properties in computer simulations. This will aid in the development of accurate water models for classical simulations as well as in determining the accuracy needed in quantum mechanical/molecular mechanical studies and ab initio molecular dynamics simulations of water. More fundamentally, this will lead to a greater understanding of how the charge distribution of a water molecule leads to the unique properties of liquid water. In particular, these studies indicate that p orbital charge out of the molecular plane is important. PMID- 29166097 TI - Volatility of the catalytic hydrogenation products of 1,4 bis(phenylethynyl)benzene. AB - Measurements of equilibrium vapor pressures by effusion thermogravimetry and melting points by differential scanning calorimetry reveal that the melting temperature and equilibrium vapor pressures of 1,4-bis(phenylethynyl)benzene (DEB) do not vary monotonically with the hydrogenation extent. Contrary to intuition which suggests increasing volatility with hydrogenation, results indicate decreasing volatility for the first two hydrogenation steps before a non monotonic upward trend, in which trans-isomers are less volatile. Insights on structural packing and functional groups were obtained from x-ray diffraction and infrared studies to shed light on the observed variation in the volatility of DEB with hydrogenation. Density functional theory calculations were performed to obtain molecular level information and to establish the thermodynamics of DEB hydrogenation reactions. A major factor influencing the observed melting points and volatility of the hydrogenated intermediate species is identified as the local attractive or repulsive carbon-hydrogen (CH) dipole interactions among the getter molecules in their respective crystal structures. Such collective CH dipole interactions can be used to predict the trends in the volatilities of catalytic hydrogenation processes. PMID- 29166098 TI - Pulling force and surface tension drive membrane fusion. AB - Despite catalyzed by fusion proteins of quite different molecular architectures, intracellular, viral, and cell-to-cell fusions are found to have the essential common features and the nearly same nature of transition states. The similarity inspires us to find a more general catalysis mechanism for membrane fusion that minimally depends on the specific structures of fusion proteins. In this work, we built a minimal model for membrane fusion, and by using dissipative particle dynamics simulations, we propose a mechanism that the pulling force generated by fusion proteins initiates the fusion process and the membrane tension regulates the subsequent fusion stages. The model shows different features compared to previous computer simulation studies: the pulling force catalyzes membrane fusion through lipid head overcrowding in the contacting region, leading to an increase in the head-head repulsion and/or the unfavorable head-tail contacts from opposing membranes, both of which destabilize the contacting leaflets and thus promote membrane fusion or vesicle rupture. Our simulations produce a variety of shapes and intermediates, closely resembling cases seen experimentally. Our work strongly supports the view that the tight pulling mechanism is a conserved feature of fusion protein-mediated fusion and that the membrane tension plays an essential role in fusion. PMID- 29166099 TI - Long-range dipolar order and dispersion forces in polar liquids. AB - Complex solvation phenomena, such as specific ion effects, occur in polar liquids. Interpretation of these effects in terms of structure and dispersion forces will lead to a greater understanding of solvation. Herein, using molecular dynamics, we probe the structure of polar liquids through specific dipolar pair correlation functions that contribute to the potential of mean force that is "felt" between thermally rotating dipole moments. It is shown that unique dipolar order exists at separations at least up to 20 A for all liquids studied. When the structural order is compared with a dipolar dispersion force that arises from local co-operative enhancement of dipole moments, a strong agreement is found. Lifshitz theory of dispersion forces was compared with the structural order, where the theory is validated for all liquids that do not have significant local dipole correlations. For liquids that do have significant local dipole correlations, specifically liquid water, Lifshitz theory underestimates the dispersion force by a factor of 5-10, demonstrating that the force that leads to the increased structure in liquid water is missed by Lifshitz theory of van der Waals forces. We apply similar correlation functions to an ionic aqueous system, where long-range order between water's dipole moment and a single chloride ion is found to exist at 20 A of separation, revealing a long-range perturbation of water's structure by an ion. Furthermore, we found that waters within the 1st, 2nd, and 3rd solvation shells of a chloride ion exhibit significantly enhanced dipolar interactions, particularly with waters at larger distances of separation. Our results provide a link between structures, dispersion forces, and specific ion effects, which may lead to a more robust understanding of solvation. PMID- 29166100 TI - Modifying hydrogen-bonded structures by physical vapor deposition: 4-methyl-3 heptanol. AB - We prepared films of 4-methyl-3-heptanol by vapor depositing onto substrates held at temperatures between Tdep = 0.6Tg and Tg, where Tg is the glass transition temperature. Using deposition rates between 0.9 and 6.0 nm/s, we prepared films about 5 MUm thick and measured the dielectric properties via an interdigitated electrode cell onto which films were deposited. Samples prepared at Tdep = Tg display the dielectric behavior of the ordinary supercooled liquid. Films deposited at lower deposition temperatures show a high dielectric loss upon heating toward Tg, which decreases by a factor of about 12 by annealing at Tg = 162 K. This change is consistent with either a drop of the Kirkwood correlation factor, gk, by a factor of about 10, or an increase in the dielectric relaxation times, both being indicative of changes toward ring-like hydrogen-bonded structure characteristic of the ordinary liquid. We rationalize the high dielectric relaxation amplitude in the vapor deposited glass by suggesting that depositions at low temperature provide insufficient time for molecules to form ring-like supramolecular structures for which dipole moments cancel. Surprisingly, above Tg of the ordinary liquid, these vapor deposited films fail to completely recover the dielectric properties of the liquid obtained by supercooling. Instead, the dielectric relaxation remains slower and its amplitude much higher than that of the equilibrium liquid state, indicative of a structure that differs from the equilibrium liquid up to at least Tg + 40 K. PMID- 29166101 TI - Self-consistency of electron-THF cross sections using electron swarm techniques. AB - The drift velocity and first Townsend ionization coefficient of electrons in gaseous tetrahydrofuran are measured over the range of reduced electric fields 4 1000 Td using a pulsed-Townsend technique. The measured drift velocities and Townsend ionization coefficients are subsequently used, in conjunction with a multi-term Boltzmann equation analysis, as a further discriminative assessment on the accuracy and completeness of a recently proposed set of electron-THF vapor cross sections. In addition, the sensitivity of the transport coefficients to uncertainties in the existing cross sections is presented. As a result of that analysis, a refinement of the momentum transfer cross section for electron-THF scattering is presented, along with modifications to the neutral dissociation and dissociative electron attachment cross sections. With these changes to the cross section database, we find relatively good self-consistency between the measured and simulated drift velocities and Townsend coefficients. PMID- 29166102 TI - Testing the limits of the Maxwell distribution of velocities for atoms flying nearly parallel to the walls of a thin cell. AB - For a gas at thermal equilibrium, it is usually assumed that the velocity distribution follows an isotropic 3-dimensional Maxwell-Boltzmann (M-B) law. This assumption classically implies the assumption of a "cos theta" law for the flux of atoms leaving the surface. Actually, such a law has no grounds in surface physics, and experimental tests of this assumption have remained very few. In a variety of recently developed sub-Doppler laser spectroscopy techniques for gases one-dimensionally confined in a thin cell, the specific contribution of atoms moving nearly parallel to the boundary of the vapor container becomes essential. We report here on the implementation of an experiment to probe effectively the distribution of atomic velocities parallel to the windows for a thin (60 MUm) Cs vapor cell. The principle of the setup relies on a spatially separated pump-probe experiment, where the variations of the signal amplitude with the pump-probe separation provide the information on the velocity distribution. The experiment is performed in a sapphire cell on the Cs resonance line, which benefits from a long-lived hyperfine optical pumping. Presently, we can analyze specifically the density of atoms with slow normal velocities ~5-20 m/s, already corresponding to unusual grazing flight-at ~85 degrees -88.5 degrees from the normal to the surface-and no deviation from the M-B law is found within the limits of our elementary setup. Finally we suggest tracks to explore more parallel velocities, when surface details-roughness or structure-and the atom-surface interaction should play a key role to restrict the applicability of an M-B-type distribution. PMID- 29166103 TI - Erratum: "Quasichemical theory and the description of associating fluids relative to a reference: Multiple bonding of a single site solute" [J. Chem. Phys. 147, 124505 (2017)]. PMID- 29166104 TI - Rapid spectro-polarimetry to probe molecular symmetry in multiplex coherent anti Stokes Raman scattering. AB - We present the simultaneous detection of the spectrum and the complete polarization state of a multiplex coherent anti-Stokes Raman scattering signal with a fast division-of-amplitude spectro-polarimeter. The spectro-polarimeter is based on a commercial imaging spectrograph, a birefringent wedge prism, and a segmented polarizer. Compared to the standard rotating-retarder fixed-analyzer spectro-polarimeter, only a single measurement is required and an up to 21-fold reduced acquisition time is shown. The measured Stokes parameters allow us to differentiate between vibrational symmetries and to determine the depolarization ratio rho by data post-processing. PMID- 29166105 TI - Electrode reactions in slowly relaxing media. AB - Standard models of reaction kinetics in condensed materials rely on the Boltzmann Gibbs distribution for the population of reactants at the top of the free energy barrier separating them from the products. While energy dissipation and quantum effects at the barrier top can potentially affect the transmission coefficient entering the rate pre-exponential factor, much stronger dynamical effects on the reaction barrier are caused by the breakdown of ergodicity for populating the reaction barrier (violation of the Boltzmann-Gibbs statistics). When the spectrum of medium modes coupled to the reaction coordinate includes fluctuations slower than the reaction rate, such nuclear motions dynamically freeze on the reaction time scale and do not contribute to the activation barrier. Here we consider the consequences of this scenario for electrode reactions in slowly relaxing media. Changing the electrode overpotential speeds the electrode electron transfer up, potentially cutting through the spectrum of nuclear modes coupled to the reaction coordinate. The reorganization energy of electrochemical electron transfer becomes a function of the electrode overpotential, switching between the thermodynamic value at low rates to the nonergodic limit at higher rates. The sharpness of this transition depends on the relaxation spectrum of the medium. The reorganization energy experiences a sudden drop with increasing overpotential for a medium with a Debye relaxation but becomes a much shallower function of the overpotential for media with stretched exponential dynamics. The latter scenario characterizes the electron transfer in ionic liquids. The analysis of electrode reactions in room-temperature ionic liquids shows that the magnitude of the free energy of nuclear solvation is significantly below its thermodynamic limit. This result applies to reaction times faster than microseconds and is currently limited by the available dielectric relaxation data. PMID- 29166106 TI - Nodeless vibrational amplitudes and quantum nonadiabatic dynamics in the nested funnel for a pseudo Jahn-Teller molecule or homodimer. AB - The nonadiabatic states and dynamics are investigated for a linear vibronic coupling Hamiltonian with a static electronic splitting and weak off-diagonal Jahn-Teller coupling through a single vibration with a vibrational-electronic resonance. With a transformation of the electronic basis, this Hamiltonian is also applicable to the anti-correlated vibration in a symmetric homodimer with marginally strong constant off-diagonal coupling, where the non-adiabatic states and dynamics model electronic excitation energy transfer or self-exchange electron transfer. For parameters modeling a free-base naphthalocyanine, the nonadiabatic couplings are deeply quantum mechanical and depend on wavepacket width; scalar couplings are as important as the derivative couplings that are usually interpreted to depend on vibrational velocity in semiclassical curve crossing or surface hopping theories. A colored visualization scheme that fully characterizes the non-adiabatic states using the exact factorization is developed. The nonadiabatic states in this nested funnel have nodeless vibrational factors with strongly avoided zeroes in their vibrational probability densities. Vibronic dynamics are visualized through the vibrational coordinate dependent density of the time-dependent dipole moment in free induction decay. Vibrational motion is amplified by the nonadiabatic couplings, with asymmetric and anisotropic motions that depend upon the excitation polarization in the molecular frame and can be reversed by a change in polarization. This generates a vibrational quantum beat anisotropy in excess of 2/5. The amplitude of vibrational motion can be larger than that on the uncoupled potentials, and the electronic population transfer is maximized within one vibrational period. Most of these dynamics are missed by the adiabatic approximation, and some electronic and vibrational motions are completely suppressed by the Condon approximation of a coordinate-independent transition dipole between adiabatic states. For all initial conditions investigated, the initial nonadiabatic electronic motion is driven towards the lower adiabatic state, and criteria for this directed motion are discussed. PMID- 29166107 TI - Simulations of water nano-confined between corrugated planes. AB - Water confined to nanoscale widths in two dimensions between ideal planar walls has been the subject of ample study, aiming at understanding the intrinsic response of water to confinement, avoiding the consideration of the chemistry of actual confining materials. In this work, we study the response of such nanoconfined water to the imposition of a periodicity in the confinement by means of computer simulations, both using empirical potentials and from first principles. For that we propose a periodic confining potential emulating the atomistic oscillation of the confining walls, which allows varying the lattice parameter and amplitude of the oscillation. We do it for a triangular lattice, with several values of the lattice parameter: one which is ideal for commensuration with layers of Ih ice and other values that would correspond to more realistic substrates. For the former, the phase diagram shows an overall rise of the melting temperature. The liquid maintains a bi-layer triangular structure, however, despite the fact that it is not favoured by the external periodicity. The first-principles liquid is significantly affected by the modulation in its layering and stacking even at relatively small amplitudes of the confinement modulation. Beyond some critical modulation amplitude, the hexatic phase present in flat confinement is replaced by a trilayer crystalline phase unlike any of the phases encountered for flat confinement. For more realistic lattice parameters, the liquid does not display higher tendency to freeze, but it clearly shows inhomogeneous behaviour as the strength of the rugosity increases. In spite of this expected inhomogeneity, the structural and dynamical response of the liquid is surprisingly insensitive to the external modulation. Although the first-principles calculations give a more triangular liquid than the one observed with empirical potentials (TIP4P/2005), both agree remarkably well for the main conclusions of the study. PMID- 29166108 TI - A simple molecular orbital treatment of current distributions in quantum transport through molecular junctions. AB - A simple molecular orbital treatment of local current distributions inside single molecular junctions is developed in this paper. Using the first-order perturbation theory and nonequilibrium Green's function techniques in the framework of Huckel theory, we show that the leading contributions to local current distributions are directly proportional to the off-diagonal elements of transition density matrices. Under the orbital approximation, the major contributions to local currents come from a few dominant molecular orbital pairs which are mixed by the interactions between the molecule and electrodes. A few simple molecular junctions consisting of single- and multi-ring conjugated systems are used to demonstrate that local current distributions inside molecular junctions can be decomposed by partial sums of a few leading contributing transition density matrices. PMID- 29166109 TI - Temperature and chain length dependence of ultrafast vibrational dynamics of thiocyanate in alkylimidazolium ionic liquids: A random walk on a rugged energy landscape. AB - Ultrafast two-dimensional infrared spectroscopy of a thiocyanate vibrational probe (SCN-) was used to investigate local dynamics in alkylimidazolium bis [trifluoromethylsulfonyl]imide ionic liquids ([Imn,1][Tf2N], n = 2, 4, 6) at temperatures from 5 to 80 degrees C. The rate of frequency fluctuations reported by SCN- increases with increasing temperature and decreasing alkyl chain length. Temperature-dependent correlation times scale proportionally to temperature dependent bulk viscosities of each ionic liquid studied. A multimode Brownian oscillator model demonstrates that very low frequency (<10 cm-1) modes primarily drive the observed spectral diffusion and that these modes broaden and blue shift on average with increasing temperature. An Arrhenius analysis shows activation barriers for local motions around the probe between 5.5 and 6.5 kcal/mol that are very similar to those for translational diffusion of ions. [Im6,1][Tf2N] shows an unexpected decrease in activation energy compared to [Im4,1][Tf2N] that may be related to mesoscopically ordered polar and nonpolar domains. A model of dynamics on a rugged potential energy landscape provides a unifying description of the observed Arrhenius behavior and the Brownian oscillator model of the low frequency modes. PMID- 29166110 TI - Total cross sections for electron scattering by 1-propanol at impact energies in the range 40-500 eV. AB - Absolute total cross section (TCS) measurements for electron scattering from 1 propanol molecules are reported for impact energies from 40 to 500 eV. These measurements were obtained using a new apparatus developed at Juiz de Fora Federal University-Brazil, which is based on the measurement of the attenuation of a collimated electron beam through a gas cell containing the molecules to be studied at a given pressure. Besides these experimental measurements, we have also calculated TCS using the Independent-Atom Model with Screening Corrected Additivity Rule and Interference (IAM-SCAR+I) approach with the level of agreement between them being typically found to be very good. PMID- 29166111 TI - Effective interactions between inclusions in an active bath. AB - We study effective two- and three-body interactions between non-active colloidal inclusions in an active bath of chiral or non-chiral particles, using Brownian dynamics simulations within a standard, two-dimensional model of disk-shaped inclusions and active particles. In a non-chiral active bath, we first corroborate previous findings on effective two-body repulsion mediated between the inclusions by elucidating the detailed non-monotonic features of the two-body force profiles, including a primary maximum and a secondary hump at larger separations that was not previously reported. We then show that these features arise directly from the formation, and sequential overlaps, of circular layers (or "rings") of active particles around the inclusions, as the latter are brought to small surface separations. These rings extend to radial distances of a few active-particle radii from the surface of inclusions, giving the hard-core inclusions relatively thick, soft, repulsive "shoulders," whose multiple overlaps then enable significant (non-pairwise) three-body forces in both non-chiral and chiral active baths. The resulting three-body forces can even exceed the two-body forces in magnitude and display distinct repulsive and attractive regimes at intermediate to large self-propulsion strengths. In a chiral active bath, we show that, while active particles still tend to accumulate at the immediate vicinity of the inclusions, they exhibit strong depletion from the intervening region between the inclusions and partial depletion from relatively thick, circular zones further away from the inclusions. In this case, the effective, predominantly repulsive interactions between the inclusions turn to active, chirality-induced, depletion-type attractions, acting over an extended range of separations. PMID- 29166112 TI - Charge-transfer excited states: Seeking a balanced and efficient wave function ansatz in variational Monte Carlo. AB - We present a simple and efficient wave function ansatz for the treatment of excited charge-transfer states in real-space quantum Monte Carlo methods. Using the recently introduced variation-after-response method [E. Neuscamman, J. Chem. Phys. 145, 081103 (2016)], this ansatz allows a crucial orbital optimization step to be performed beyond a configuration interaction singles expansion, while only requiring calculation of two Slater determinant objects. We demonstrate this ansatz for the illustrative example of the stretched LiF molecule, for a range of excited states of formaldehyde, and finally for the more challenging ethylene tetrafluoroethylene molecule. PMID- 29166113 TI - Statistical mechanics of transport processes in active fluids: Equations of hydrodynamics. AB - The equations of hydrodynamics including mass, linear momentum, angular momentum, and energy are derived by coarse-graining the microscopic equations of motion for systems consisting of rotary dumbbells driven by internal torques. In deriving the balance of linear momentum, we find that the symmetry of the stress tensor is broken due to the presence of non-zero torques on individual particles. The broken symmetry of the stress tensor induces internal spin in the fluid and leads us to consider the balance of internal angular momentum in addition to the usual moment of momentum. In the absence of spin, the moment of momentum is the same as the total angular momentum. In deriving the form of the balance of total angular momentum, we find the microscopic expressions for the couple stress tensor that drives the spin field. We show that the couple stress contains contributions from both intermolecular interactions and the active forces. The presence of spin leads to the idea of balance of moment of inertia due to the constant exchange of particles in a small neighborhood around a macroscopic point. We derive the associated balance of moment of inertia at the macroscale and identify the moment of inertia flux that induces its transport. Finally, we obtain the balances of total and internal energy of the active fluid and identify the sources of heat and heat fluxes in the system. PMID- 29166114 TI - Communication: Recovering the flat-plane condition in electronic structure theory at semi-local DFT cost. AB - The flat-plane condition is the union of two exact constraints in electronic structure theory: (i) energetic piecewise linearity with fractional electron removal or addition and (ii) invariant energetics with change in electron spin in a half filled orbital. Semi-local density functional theory (DFT) fails to recover the flat plane, exhibiting convex fractional charge errors (FCE) and concave fractional spin errors (FSE) that are related to delocalization and static correlation errors. We previously showed that DFT+U eliminates FCE but now demonstrate that, like other widely employed corrections (i.e., Hartree-Fock exchange), it worsens FSE. To find an alternative strategy, we examine the shape of semi-local DFT deviations from the exact flat plane and we find this shape to be remarkably consistent across ions and molecules. We introduce the judiciously modified DFT (jmDFT) approach, wherein corrections are constructed from few parameter, low-order functional forms that fit the shape of semi-local DFT errors. We select one such physically intuitive form and incorporate it self consistently to correct semi-local DFT. We demonstrate on model systems that jmDFT represents the first easy-to-implement, no-overhead approach to recovering the flat plane from semi-local DFT. PMID- 29166115 TI - Resonant electron attachment to mixed hydrogen/oxygen and deuterium/oxygen clusters. AB - Low energy electron attachment to mixed (H2)x/(O2)y clusters and their deuterated analogs has been investigated for the first time. These experiments were carried out using liquid helium nanodroplets to form the clusters, and the effect of the added electron was then monitored via mass spectrometry. There are some important differences between electron attachment to the pure clusters and to the mixed clusters. A particularly notable feature is the formation of HO2- and H2O- ions from an electron-induced chemical reaction between the two dopants. The chemistry leading to these anions appears to be driven by electron resonances associated with H2 rather than O2. The electron resonances for H2 can lead to dissociative electron attachment (DEA), just as for the free H2 molecule. However, there is evidence that the resonance in H2 can also lead to rapid electron transfer to O2, which then induces DEA of the O2. This kind of excitation transfer has not, as far as we are aware, been reported previously. PMID- 29166116 TI - Theoretical study of photodetachment spectroscopy of hydrogenated boron cluster anion H2B7- and its deuterated isotopomer. AB - Photodetachment spectroscopy of H2B7- and its deuterated isotopomer probing the energetically low-lying electronic states of the respective neutral cluster is theoretically investigated in this paper. The theoretical methodology is based on detailed quantum chemistry calculations of electronic state energies, construction of a vibronic coupling model in the diabatic electronic basis, and nuclear dynamics calculations from first principles using time-dependent and time independent quantum mechanical methods. The theoretical model consists of five coupled electronic states and fifteen vibrational modes. Several reduced dimensional calculations are performed to identify the relevant vibrational modes contributing to the vibronic structure of electronic bands and the impact of non adiabatic coupling on them. The low-energy part of the spectrum of both H2B7 and its deuterated analogue is assigned by examining the vibronic wavefunctions and the results are compared with the experimental findings. The nonadiabatic decay dynamics of the electronic excited states of the neutral clusters is examined at length. PMID- 29166117 TI - Adsorption and conformations of lysozyme and alpha-lactalbumin at a water-octane interface. AB - As proteins contain both hydrophobic and hydrophilic amino acids, they will readily adsorb onto interfaces between water and hydrophobic fluids such as oil. This adsorption normally causes changes in the protein structure, which can result in loss of protein function and irreversible adsorption, leading to the formation of protein interfacial films. While this can be advantageous in some applications (e.g., food technology), in most cases it limits our ability to exploit protein functionality at interfaces. To understand and control protein interfacial adsorption and function, it is necessary to understand the microscopic conformation of proteins at liquid interfaces. In this paper, molecular dynamics simulations are used to investigate the adsorption and conformation of two similar proteins, lysozyme and alpha-lactalbumin, at a water octane interface. While they both adsorb onto the interface, alpha-lactalbumin does so in a specific orientation, mediated by two amphipathic helices, while lysozyme adsorbs in a non-specific manner. Using replica exchange simulations, both proteins are found to possess a number of distinct interfacial conformations, with compact states similar to the solution conformation being most common for both proteins. Decomposing the different contributions to the protein energy at oil-water interfaces suggests that conformational change for alpha-lactalbumin, unlike lysozyme, is driven by favourable protein-oil interactions. Revealing these differences between the factors that govern the conformational change at interfaces in otherwise similar proteins can give insight into the control of protein interfacial adsorption, aggregation, and function. PMID- 29166118 TI - Photofragmentation of gas-phase acetic acid and acetamide clusters in the vacuum ultraviolet region. AB - Photofragmentation of gas-phase acetamide and acetic acid clusters produced by a supersonic expansion source has been studied using time-of-flight mass spectrometry and the partial ion yield (PIY) technique combined with tunable vacuum-ultraviolet synchrotron radiation. Appearance energies of the clusters and their fragments were experimentally determined from the PIY measurements. The effect of clusterization conditions on the formation and fragmentation of acetic acid clusters was investigated. Ab initio quantum mechanical calculations were performed on both samples' dimers to find their neutral and ionized geometries as well as proton transfer energy barriers leading to the optimal geometries. In the case of the acetamide dimer, the reaction resulting in the production of ammoniated acetamide was probed, and the geometry of the obtained ion was calculated. PMID- 29166119 TI - Two-phase thermodynamic model for computing entropies of liquids reanalyzed. AB - The two-phase thermodynamic (2PT) model [S.-T. Lin et al., J. Chem. Phys. 119, 11792-11805 (2003)] provides a promising paradigm to efficiently determine the ionic entropies of liquids from molecular dynamics. In this model, the vibrational density of states (VDoS) of a liquid is decomposed into a diffusive gas-like component and a vibrational solid-like component. By treating the diffusive component as hard sphere (HS) gas and the vibrational component as harmonic oscillators, the ionic entropy of the liquid is determined. Here we examine three issues crucial for practical implementations of the 2PT model: (i) the mismatch between the VDoS of the liquid system and that of the HS gas; (ii) the excess entropy of the HS gas; (iii) the partition of the gas-like and solid like components. Some of these issues have not been addressed before, yet they profoundly change the entropy predicted from the model. Based on these findings, a revised 2PT formalism is proposed and successfully tested in systems with Lennard-Jones potentials as well as many-atom potentials of liquid metals. Aside from being capable of performing quick entropy estimations for a wide range of systems, the formalism also supports fine-tuning to accurately determine entropies at specific thermal states. PMID- 29166120 TI - Mechanical response of transient telechelic networks with many-part stickers. AB - A central question in soft matter is understanding how several individual, weak bonds act together to produce collective interactions. Here, gel-forming telechelic polymers with multiple stickers at each chain end are studied through Brownian dynamics simulations to understand how collective interaction of the bonds affects mechanical response of the gels. These polymers are modeled as finitely extensible dumbbells using an explicit tau-leap algorithm and the binding energy of these associations was kept constant regardless of the number of stickers. The addition of multiple bonds to the associating ends of telechelic polymers increases or decreases the network relaxation time depending on the relative kinetics of association but increases both shear stress and extensional viscosity. The relationship between the rate of association and the Rouse time of dangling chains results in two different regimes for the equilibrium stress relaxation of associating physical networks. In case I, a dissociated dangling chain is able to fully relax before re-associating to the network, resulting in two characteristic relaxation times and a non-monotonic terminal relaxation time with increasing number of bonds per polymer endgroup. In case II, the dissociated dangling chain is only able to relax a fraction of the way before it re-attaches to the network, and increasing the number of bonds per endgroup monotonically increases the terminal relaxation time. In flow, increasing the number of stickers increases the steady-state shear and extensional viscosities even though the overall bond kinetics and equilibrium constant remain unchanged. Increased dissipation in the simulations is primarily due to higher average chain extension with increasing bond number. These results indicate that toughness and dissipation in physically associating networks can both be increased by breaking single, strong bonds into smaller components. PMID- 29166121 TI - Photoinduced transformations of indole and 3-formylindole monomers isolated in low-temperature matrices. AB - Photochemical transformations were studied for monomers of indole and 3 formylindole isolated in low-temperature noble-gas matrices. Upon UV (lambda > 270 nm) irradiation of indole trapped in argon and neon matrices, the initial 1H form of the compound converted into the 3H-tautomer. Alongside this photoinduced hydrogen-atom transfer, an indolyl radical was also generated by photodetachment of the hydrogen atom from the N1-H bond. Excitation of 3-formylindole isolated in an argon matrix with UV (lambda > 335 nm) light led to interconversion between the two conformers of the 1H-tautomer, differing from each other in the orientation of the formyl group (cis or trans). Parallel to this conformational phototransformation, the 3H-form of the compound was generated in the 1H -> 3H phototautomeric conversion. The photoproducts emerging upon UV irradiation of indole and 3-formylindole were identified by comparison of their infrared spectra with the spectra calculated for candidate structures. PMID- 29166122 TI - Bulk and interfacial structures of reline deep eutectic solvent: A molecular dynamics study. AB - We apply all-atom molecular dynamics simulations to describe the bulk morphology and interfacial structure of reline, a deep eutectic solvent comprising choline chloride and urea in 1:2 molar ratio, near neutral and charged graphene electrodes. For the bulk phase structural investigation, we analyze the simulated real-space radial distribution functions, X-ray/neutron scattering structure functions, and their partial components. Our study shows that both hydrogen bonding and long-range correlations between different constituents of reline play a crucial role to lay out the bulk structure of reline. Further, we examine the variation of number density profiles, orientational order parameters, and electrostatic potentials near the neutral and charged graphene electrodes with varying electrode charge density. The present study reveals the presence of profound structural layering of not only the ionic components of reline but also urea near the electrodes. In addition, depending on the electrode charge density, the choline ions and urea molecules render different orientations near the electrodes. The simulated number density and electrostatic potential profiles for reline clearly show the presence of multilayer structures up to a distance of 1.2 nm from the respective electrodes. The observation of positive values of the surface potential at zero charge indicates the presence of significant nonelectrostatic attraction between the choline cation and graphene electrode. The computed differential capacitance (Cd) for reline exhibits an asymmetric bell shaped curve, signifying different variation of Cd with positive and negative surface potentials. PMID- 29166123 TI - Tunneling of coupled methyl quantum rotors in 4-methylpyridine: Single rotor potential versus coupling interaction. AB - We study the influence of rotational coupling between a pair of methyl rotators on the tunneling spectrum in condensed phase. Two interacting adjacent methyl groups are simulated within a coupled-pair model composed of static rotational potential created by the chemical environment and the interaction potential between two methyl groups. We solve the two-dimensional time-independent Schrodinger equation analytically by expanding the wave functions on the basis set of two independent free-rotor functions. We investigate three scenarios which differ with respect to the relative strength of single-rotor and coupling potential. For each scenario, we illustrate the dependence of the energy level scheme on the coupling strength. It is found that the main determinant of splitting energy levels tends to be a function of the ratio of strengths of coupling and single-rotor potential. The tunnel splitting caused by coupling is maximized for the coupled rotors in which their total hindering potential is relatively shallow. Such a weakly hindered methyl rotational potential is predicted for 4-methylpyridine at low temperature. The experimental observation of multiple tunneling peaks arising from a single type of methyl group in 4 methylpyridine in the inelastic neutron scattering spectrum is widely attributed to the rotor-rotor coupling. In this regard, using a set of first-principles calculations combined with the nudged elastic band method, we investigate the rotational potential energy surface (PES) of the coaxial pairs of rotors in 4 methylpyridine. A Numerov-type method is used to numerically solve the two dimensional time-independent Schrodinger equation for the calculated 2D-density functional theory profile. Our computed energy levels reproduce the observed tunneling transitions well. Moreover, the calculated density distribution of the three methyl protons resembles the experimental nuclear densities obtained from the Fourier difference method. By mapping the calculated first-principles PES on the model, it is confirmed that the hindering potential in 4-methylpyridine consists of proportionally shallow single-rotor potential to coupling interaction. PMID- 29166124 TI - Some connections between importance sampling and enhanced sampling methods in molecular dynamics. AB - In molecular dynamics, enhanced sampling methods enable the collection of better statistics of rare events from a reference or target distribution. We show that a large class of these methods is based on the idea of importance sampling from mathematical statistics. We illustrate this connection by comparing the Hartmann Schutte method for rare event simulation (J. Stat. Mech. Theor. Exp. 2012, P11004) and the Valsson-Parrinello method of variationally enhanced sampling [Phys. Rev. Lett. 113, 090601 (2014)]. We use this connection in order to discuss how recent results from the Monte Carlo methods literature can guide the development of enhanced sampling methods. PMID- 29166125 TI - Rural-urban differences in unpaid caregivers of adults. AB - INTRODUCTION: Rural–urban differences in the characteristics of unpaid caregivers of adults in the USA were explored. METHODS: Using 'Caregiving in the U.S. 2015', a survey fielded by the National Alliance for Caregiving and AARP, a national examination of rural caregivers (n=1352) is presented. RESULTS: Rural caregivers reported lower socioeconomic status than urban caregivers (measured by income, education, and employment), suggesting greater likelihood of caregiver strain. In multivariable analysis adjusting for age, race, educational attainment, and reported caregiver burden, residence was associated with self-reported health status of the caregiver but not with physical, financial or emotional distress. The odds of rural caregivers reporting poor to fair health were significantly lower than their urban counterparts (adjusted odds ratio 0.57; 95% confidence interval, 0.36­0.91). CONCLUSIONS: These findings may indicate differing cultural values in rural and urban respondents, rather than better health among rural caregivers. Understanding the characteristics of rural caregivers may help policymakers target interventions. . PMID- 29166126 TI - Nutrient-Sensing Biology in Mammals and Birds. AB - Nutrient-sensing mechanisms have emerged as the fringe articulating nutritional needs with dietary choices. Carbohydrate, amino acid, fatty acid, mineral, and water-sensing receptors are highly conserved across mammals and birds, consisting of a repertoire of 22 genes known to date. In contrast, bitter receptors are highly divergent and have a high incidence of polymorphisms within and between mammals and birds and are involved in the adaptation of species to specific environments. In addition, the expression of nutrient-sensing genes outside the oral cavity seems to mediate the required decision-making dialogue between the gut and the brain by translating exogenous chemical stimuli into neuronal inputs, and vice versa, to translate the endogenous signals relevant to the nutritional status into specific appetites and the control of feed intake. The relevance of these sensors in nondigestive systems has uncovered fascinating potential as pharmacological targets relevant to respiratory and cardiovascular diseases. PMID- 29166127 TI - Bat Biology, Genomes, and the Bat1K Project: To Generate Chromosome-Level Genomes for All Living Bat Species. AB - Bats are unique among mammals, possessing some of the rarest mammalian adaptations, including true self-powered flight, laryngeal echolocation, exceptional longevity, unique immunity, contracted genomes, and vocal learning. They provide key ecosystem services, pollinating tropical plants, dispersing seeds, and controlling insect pest populations, thus driving healthy ecosystems. They account for more than 20% of all living mammalian diversity, and their crown group evolutionary history dates back to the Eocene. Despite their great numbers and diversity, many species are threatened and endangered. Here we announce Bat1K, an initiative to sequence the genomes of all living bat species (n~1,300) to chromosome-level assembly. The Bat1K genome consortium unites bat biologists (>148 members as of writing), computational scientists, conservation organizations, genome technologists, and any interested individuals committed to a better understanding of the genetic and evolutionary mechanisms that underlie the unique adaptations of bats. Our aim is to catalog the unique genetic diversity present in all living bats to better understand the molecular basis of their unique adaptations; uncover their evolutionary history; link genotype with phenotype; and ultimately better understand, promote, and conserve bats. Here we review the unique adaptations of bats and highlight how chromosome-level genome assemblies can uncover the molecular basis of these traits. We present a novel sequencing and assembly strategy and review the striking societal and scientific benefits that will result from the Bat1K initiative. PMID- 29166128 TI - The Oxylipin Pathways: Biochemistry and Function. AB - Plant oxylipins form a constantly growing group of signaling molecules that comprise oxygenated fatty acids and metabolites derived therefrom. In the last decade, the understanding of biosynthesis, metabolism, and action of oxylipins, especially jasmonates, has dramatically improved. Additional mechanistic insights into the action of enzymes and insights into signaling pathways have been deepened for jasmonates. For other oxylipins, such as the hydroxy fatty acids, individual signaling properties and cross talk between different oxylipins or even with additional phytohormones have recently been described. This review summarizes recent understanding of the biosynthesis, regulation, and function of oxylipins. PMID- 29166129 TI - Initial clinical observations of intra- and interfractional motion variation in MR-guided lung SBRT. AB - OBJECTIVE: To evaluate variations in intra- and interfractional tumour motion, and the effect on internal target volume (ITV) contour accuracy, using deformable image registration of real-time two-dimensional-sagittal cine-mode MRI acquired during lung stereotactic body radiation therapy (SBRT) treatments. METHODS: Five lung tumour patients underwent free-breathing SBRT treatments on the ViewRay system, with dose prescribed to a planning target volume (defined as a 3-6 mm expansion of the 4DCT-ITV). Sagittal slice cine-MR images (3.5 * 3.5 mm2 pixels) were acquired through the centre of the tumour at 4 frames per second throughout the treatments (3-4 fractions of 21-32 min). Tumour gross tumour volumes (GTVs) were contoured on the first frame of the MR cine and tracked for the first 20 min of each treatment using offline optical-flow based deformable registration implemented on a GPU cluster. A ground truth ITV (MR-ITV20 min) was formed by taking the union of tracked GTV contours. Pseudo-ITVs were generated from unions of the GTV contours tracked over 10 s segments of image data (MR-ITV10 s). RESULTS: Differences were observed in the magnitude of median tumour displacement between days of treatments. MR-ITV10 s areas were as small as 46% of the MR-ITV20 min. CONCLUSION: An ITV offers a "snapshot" of breathing motion for the brief period of time the tumour is imaged on a specific day. Real-time MRI over prolonged periods of time and over multiple treatment fractions shows that ITV size varies. Further work is required to investigate the dosimetric effect of these results. Advances in knowledge: Five lung tumour patients underwent free breathing MRI-guided SBRT treatments, and their tumours tracked using deformable registration of cine-mode MRI. The results indicate that variability of both intra- and interfractional breathing amplitude should be taken into account during planning of lung radiotherapy. PMID- 29166130 TI - The clinical effect of JetpPeel-assisted topical minoxidil in the treatment of androgenetic alopecia: A randomized pilot study. AB - OBJECTIVE: We used JetPeel, combined with topical minoxidil to treat patients with AGA, in order to observe whether the JetPeel can accelerate the recovery of the disease and find a new method for AGA treatment. METHOD: Thirty patients who met the standard were included in the study. The patients were randomly divided into three groups. The first group was treated with JetPeel-assisted topical minoxidil. The second group received topical minoxidil monotherapy. The third group was not given any treatment. We used objective evaluation (amount and diameter of hair, oil secretion level) and subjective evaluation (hair growth score marked by dermatologist and patient) to evaluate the hair growth condition before treatment and every other month. The calculated p values of less than 0.05 were accepted as significant. RESULT: All of the 30 patients finished the study. There was no difference in age, sex, and duration and severity of the disease among groups prior to treatment (p > 0.05). And there was greater improvement in scores of hair growth in the first group compared to the second and third group, which was statistically significant (p < 0.05). CONCLUSION: Compared with topical minoxidil monotherapy, JetPeel-assisted topical minoxidil is more effective during the treatment of androgenetic alopecia. PMID- 29166131 TI - Traditional Chinese Medicine Physicians' Insights into Interprofessional Tensions between Traditional Chinese Medicine and Biomedicine: A Critical Perspective. AB - In Singapore, the institutional preference for biomedicine and the cultural importance of traditional Chinese medicine (TCM) have created tensions between the two medical systems and erected barriers to a more collaborative health-care system. This study foregrounds TCM physicians' voice to reveal ideological struggles and power imbalances that underlie the interprofessional tensions and accompanying marginalization of TCM. Through in-depth interviews with 22 TCM physicians in Singapore, this study reveals the incongruences in ideological underpinnings between biomedicine and TCM, reflected in their different worldviews and epistemological approaches to knowledge formation and evaluation. Power differentials between the two medical systems are manifest in TCM physicians' inferior position in relation to their biomedical peers, the patients' internalization of biomedical standards to question the TCM profession and their own interest in seeking TCM treatments, and the state's limited support for TCM research, subsidies, and service provision in hospital settings. The results suggest that more open dialogue about the dichotomous framings of biomedicine and TCM is key to disrupting the mutual reinforcement of ideology and power, as well as to creating increased mutual understanding between the two medical systems. PMID- 29166132 TI - Imaging of iatrogenic oesophageal injuries using optimized CT oesophageal leak protocol: pearls and pitfalls. AB - Iatrogenic injury to the oesophagus is a serious complication which is increasingly seen in clinical practice secondary to expansion and greater acceptability of surgical and endoscopic oesophageal procedures. Morbidity and mortality following such injury is high. This is mostly due to an inflammatory response to gastric contents in the mediastinum, and the negative intrathoracic pressures that may further draw out oesophageal contents into the mediastinum leading to mediastinitis. Subsequently, pulmonary complications such as pneumonia or abscess may ensue leading to rapid clinical deterioration. Optimized and timely cross-sectional imaging evaluation is necessary for early and aggressive management of these complications. The goal of this review is to make the radiologist aware of the importance of early and accurate identification of postoperative oesophageal injury using optimized CT imaging protocols and use of oral contrast. Specifically, it is critical to differentiate benign post operative findings, such as herniated viscus or redundant anastomosis, from clinically significant postoperative complications as this helps guide appropriate management. Advantages and drawbacks of other diagnostic methods, such as contrast oesophagogram, are also discussed. PMID- 29166133 TI - Dosimetric impact of gastrointestinal air column in radiation treatment of pancreatic cancer. AB - OBJECTIVE: Dosimetric evaluation of air column in gastrointestinal (GI) structures in intensity modulated radiation therapy (IMRT) of pancreatic cancer. METHODS: Nine sequential patients were retrospectively chosen for dosimetric analysis of air column in the GI apparatus in pancreatic cancer using cone beam CT (CBCT). The four-dimensional CT (4DCT) was used for target and organs at risk (OARs) and non-coplanar IMRT was used for treatment. Once a week, these patients underwent CBCT for air filling, isocentre verification and dose calculations retrospectively. RESULTS: Abdominal air column variation was as great as +/-80% between weekly CBCT and 4DCT. Even with such a large air column in the treatment path for pancreatic cancer, changes in anteroposterior dimension were minimal (2.8%). Using IMRT, variations in air column did not correlate dosimetrically with large changes in target volume. An average dosimetric deviation of mere 3.3% and a maximum of -5.5% was observed. CONCLUSION: CBCT revealed large air column in GI structures; however, its impact is minimal for target coverage. Because of the inherent advantage of segmentation in IMRT, where only a small fraction of a given beam passes through the air column, this technique might have an advantage over 3DCRT in treating upper GI malignancies where the daily air column can have significant impact. Advances in knowledge: Radiation treatment of pancreatic cancer has significant challenges due to positioning, imaging of soft tissues and variability of air column in bowels. The dosimetric impact of variable air column is retrospectively studied using CBCT. Even though, the volume of air column changes by +/- 80%, its dosimetric impact in IMRT is minimum. PMID- 29166134 TI - Injection Partners, HCV, and HIV Status among Rural Persons Who Inject Drugs in Puerto Rico. AB - BACKGROUND: The prevalence of hepatitis C (HCV) and HIV among persons who inject drugs (PWID) and the ability of these diseases to spread through injection networks are well documented in urban areas. However, less is known about injection behaviors in rural areas. OBJECTIVES: This study focuses on the association between the number of self-reported injection partners with the PWID's self-reported HCV and HIV status. Injection networks provide paths for infection and information to flow, and are important to consider when developing prevention and intervention strategies. METHODS: Respondent driven sampling was used to conduct 315 interviews with PWID in rural Puerto Rico during 2015. Negative binomial regression was used to test for associations between the number of self-reported injection partners and self-reported HCV and HIV statuses. Multinomial logistic regression was used to test for associations with the participant's self-reported HCV and HIV statuses. RESULTS: Self-reported HCV status is significantly associated with injection risk network size. Injection partner networks of self-reported HCV- respondents are half what is reported by those with a positive or unknown status. Self-reported HIV statuses are not associated with different numbers of injection partners. CONCLUSIONS: Smaller injection networks among those who self-report a HCV- status suggests that those who believe their status to be negative may take protective action by reducing their injection network compared to those have a self-reported HCV+ or an unknown status. Although the cross-sectional design of the study makes it difficult verify, such behavior has implications for prevention programs attempting to prevent HCV transmission. PMID- 29166135 TI - Application of diffusion tensor imaging in quantitatively monitoring chronic constriction injury of rabbit sciatic nerves: correlation with histological and functional changes. AB - OBJECTIVE: To investigate the potential of diffusion tensor imaging (DTI) in quantitatively monitoring chronic constriction injuri (CCI) of sciatic nerves and to analyse the association of DTI parameters with nerve histology and limb function. METHODS: CCI was created on sciatic nerves in the right hind legs of 20 rabbits with the left as control. DTI parameters-fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD) and radial diffusivity (RD)-and limb function were longitudinally evaluated. Pathology analysis was performed on day 3 (d3), week 1 (w1), 2, 4, 6, 8 and 10. RESULTS: FA of the constricted nerves decreased on d3 (0.316 +/- 0.044) and increased from w1 to w10 (0.331 +/- 0.018, 0.354 +/- 0.044, 0.375 +/- 0.015, 0.394 +/- 0.020, 0.42 +/- 0.03 and 0.464 +/- 0.039). ADC increased on d3 until w2 (1.502 +/- 0.126, 1.462 +/- 0.058 and 1.473 +/- 0.124 * 10-3 mm2 s-1) and decreased to normal from w4 to w10 (1.356 +/- 0.129, 1.375 +/- 0.107, 1.290 +/- 0.064 and 1.298 +/- 0.026 * 10-3 mm2 s-1). AD decreased and stayed low from d3 to w10 (2.042 +/- 0.160, 2.005 +/- 0.095, 2.057 +/- 0.124, 1.952 +/- 0.213, 1.988 +/- 0.180, 1.947 +/- 0.106 and 2.097 +/- 0.114). RD increased on d3 (1.233 +/- 0.152) and declined from w1 to w10 (1.19 +/- 0.06, 1.181 +/- 0.14, 1.071 +/- 0.102, 1.068 +/- 0.084, 0.961 +/- 0.063 and 0.923 +/- 0.058). FA, ADC and RD correlated significantly with limb functional scores (all Ps < 0.0001) and their changes were associated with histological changes. CONCLUSION: FA, ADC and RD are promising to monitor CCI. AD may be a stable indicator for injury. Histological changes, oedema, axon loss and demyelination, and fibrosis, accompanied the changes of these parameters. Advances in knowledge: DTI parameters can detect and monitor acute and chronic changes after nerve compression. PMID- 29166136 TI - The gamma-aminobutyric acid-B receptor (GABAB) encephalitis: clinical manifestations and response to immunotherapy. AB - PURPOSE: We report 11 patients diagnosed with GABAB receptor (GABABR) antibodies encephalitis in China and aim to analyze the clinical characteristics, laboratory and imaging findings, therapeutic modalities and outcomes. METHODS: Clinical data from patients diagnosed with anti-GABAB receptor encephalitis in the Second Affiliated Hospital of Hebei Medical University from February 2016 to October 2016 January were retrospectively collected and evaluated. RESULTS: Of the 11 patients, seven were males, and a mean age at presentation of 63 years (range: 47 79 years). The major clinical features include cognitive decline (9/11), epilepsy (10/11), mental and behavioral disorders (6/11), involuntary movement (4/11), sleep disorders (2/11), hearing loss (1/11), disturbance of consciousness (4/11) and fever (3/11). GABA-B receptor antibody was positive in serum and/or cerebrospinal fluid in 11 patients. Small-cell lung cancer was detected in five patients. Electroencephalogram monitoring demonstrated abnormal discharge in 10 cases. Epileptiform activities were found in five patients. Four patients showed abnormality in hippocampal region, parahippocampal gyrus, temporal and occipital lobe on magnetic resonance imaging. Ten patients accepted first-line immune therapy. Five patients with small-cell lung cancer received oncologic treatment. During a median follow-up of 11 months, eight patients showed a good outcome, two patients (cases 8 and 9) with tumors had a poor one and one patient (case 10) died of status epilepticus. CONCLUSION: Anti-GABAB receptor encephalitis is an uncommon autoimmune disease, which has been known to be often associated with cancer. Generally, patients associated with GABABR GABA-B receptor antibody encephalitis respond well to immunotherapy, especially if started early. PMID- 29166137 TI - Primary constrained TIPS for treating refractory ascites or variceal bleeding secondary to hepatic cirrhosis. AB - OBJECTIVE: To report an initial experience using a primary constrained transjugular intrahepatic portosystemic shunt (TIPS) technique for treating cirrhotic patients with refractory ascites or variceal bleeding. METHODS: All patients undergoing primary constrained (n = 9) and conventional (n = 18) TIPS between July 2014 and June 2016 were retrospectively reviewed. Preprocedure demographics, Child-Pugh, model for end-stage liver disease and technical variables were recorded. Outcomes measured included technical and clinical success, complications, 30-day mortality, as well as necessity for TIPS revision. Average (SD) and median follow-up was 237 (190) and 226 days. RESULTS: All constrained and conventional TIPS were technically successful (100%). Clinical success as defined as a reduction or improvement in presenting symptoms was 88.9% (8/9) and 100% (18/18) in the constrained and conventional groups, respectively (p = 1). The average reduction in portosystemic gradient was lower in the constrained group, 6.1 mmHg compared with 10.6 mmHg in the conventional group (p = 0.73). The rate of hepatic encephalopathy following TIPS placement was higher in the conventional group [16.7% (3/18)] compared with 0% in the constrained group (p = 0.52). The percentage of patients requiring TIPS revision was lower in the constrained group, although the results were not significant (11.1 vs 22.2%, p = 0.63). CONCLUSION: Primary constrained TIPS is a feasible modification to conventional TIPS with similar technical and clinical success rates. A trend towards a smaller reduction in the portosystemic gradient and need for revision was observed in the constrained group. Advances in knowledge: Primary constrained TIPS allows for greater stepwise control over shunt diameter and may represent an improved technique for patients at risk for hepatic encephalopathy. PMID- 29166138 TI - Medical Drama Viewing and Healthy Lifestyle Behaviors: Understanding the Role of Health Locus of Control Beliefs and Education Level. AB - The present study advances the understanding of how medical drama viewing influences healthy lifestyle behaviors (e.g., smoking, exercising, and consuming vegetables) by examining the role of the health locus of control (HLOC) beliefs and education level. An analysis of nationally representative data reveals that watching medical dramas is positively associated with chance and powerful others' HLOC beliefs. In addition, healthy lifestyle behaviors are positively associated with the internal HLOC belief and are negatively associated with the chance and powerful others' HLOC beliefs. Research findings demonstrate that there are indirect effects of medical drama viewing on these behaviors via chance and powerful others' HLOC beliefs. The indirect effect through the powerful others' HLOC belief is also contingent on the education level. The implications for the role of HLOC beliefs and education level in terms of the effects of medical dramas on health-promoting behaviors are discussed. PMID- 29166139 TI - Acknoweldgment to Reviewers. PMID- 29166140 TI - Comparison of Short-Term Choroidal Thickness and Retinal Morphological Changes after Intravitreal Anti-VEGF Therapy with Ranibizumab or Aflibercept in Treatment Naive Eyes. AB - PURPOSE: To evaluate choroidal thickness (CT) and retinal morphological changes in eyes with neovascular age-related macular degeneration (nAMD) following ranibizumab or aflibercept intravitreal treatment. MATERIALS AND METHODS: This was a prospective, observational, comparative study where 76 eyes of 76 consecutive patients with treatment-naive nAMD were consecutively enrolled and randomized to ranibizumab 0.5 mg or aflibercept 2 mg injections. Spectral-domain optical coherence tomography images of the choroid were obtained by enhanced depth imaging modality. CT measurements were made of the subfoveal choroid, and at 500 MUm from the center of the fovea in the superior, inferior, temporal, and nasal quadrants. Central subfield retinal thickness, intraretinal fluid, subretinal fluid, and pigment epithelium detachment were evaluated. Patients were followed up for 3 months. RESULTS: Compared with baseline, CT decreased over time in both the ranibizumab and aflibercept group (P = 0.04 and 0.001, respectively). At each location, the decrease in CT was significantly more prominent in aflibercept with respect to ranibizumab-treated eyes (P < 0.05). Among the different choroidal neovascularization subtypes, type 3 lesions showed the greatest CT decrease after anti-vascular endothelial growth factor injections (P = 0.003). Choroidal thinning was significantly greater in type 3 lesions treated with aflibercept compared with ranibizumab (F = 13.6, P = 0.002). Post-treatment incidence of dry macula was higher in aflibercept- versus ranibizumab-treated eyes (50% vs. 76%, P = 0.03). CONCLUSIONS: CT reduction is greater in aflibercept treated eyes, and type 3 lesions show the greatest thickness decrease. The post treatment frequency of dry macula, evaluated by qualitative parameters, is higher in aflibercept-treated eyes, but is not correlated with CT change. PMID- 29166141 TI - Adherence to the WCRF/AICR for Women in Breast Cancer Adjuvant Treatment submitted to Educational Nutritional Intervention. AB - Patients undergoing breast cancer treatment are susceptible to changes in eating behavior and nutrition status, thus making nutrition education relevant. Based on the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guide, with recommendations for cancer prevention released in 2007, the present study aimed to evaluate the effectiveness of educational nutritional intervention for women with breast cancer undergoing treatment while adhering to the 2007 WCRF/AICR guidelines. A nonrandomized clinical trial was conducted with a population composed of female patients, divided in intervention (IG, n = 18) and comparison (CG, n = 68) groups. Data were evaluated at baseline and after treatment/nutritional intervention. The IG participated in the intervention program for 12 mo by biweekly phone calls, personal meetings, and monthly handouts, while targeting the intake of at least 400 g/day of fruits and vegetables, and no more than 500 g/week of red or processed meats. The recommended adherence to physical activity and food intake was evaluated in compliance with the guidelines. The IG improved their adherence to the guidelines and there was a significant decrease in consumption of animal food (-43.9%) and alcoholic drinks (-0.2 g ethanol/d) and increase in plant food intake (+65.4%). Most women in both groups were sedentary and therefore violated the guidelines. The CG presented an increase in body mass index (+1.0 kg/m2) and waist circumference (+1.9 cm), while no change was observed in the IG. These findings are promising as nutritional intervention for women undergoing breast cancer treatment contributed positively to improving their adherence to the WCRF/AICR guidelines. PMID- 29166143 TI - College of American Pathologists Cancer Protocols-Getting It Just Right. PMID- 29166142 TI - Effects of dose-escalated radiotherapy in combination with long-term androgen deprivation on prostate cancer. AB - OBJECTIVE: We aimed to examine the effects of a dose escalation for prostate cancer patients receiving long-term androgen deprivation therapy (ADT). METHODS: A retrospective analysis of 605 patients treated with radiotherapy (RT) and long term ADT (National Comprehensive Cancer Network criteria-defined intermediate risk, minimum 10 months; high-risk and very-high-risk, minimum 20 months) was performed. The median ADT time was 31 months. Cox's proportional hazards models were used to compare biochemical disease-free survival (bDFS), clinical relapse free survival (cRFS) and overall survival (OS) between the >=70, <78 Gy group and 78 Gy group in a univariate analysis and to assess the effects of the dose escalation on bDFS in a multivariate analysis. RESULTS: After a median follow-up of 70 months, 5-year bDFS was significantly better in the 78 Gy group than in the >=70, <78 Gy group [96 vs 83%; hazard ratio 3.6 (95% confidence interval 2.2 6.1); p < 0.001]. 5-year cRFS and OS were similar between the two groups. The multivariate analysis showed that RT dose was still an independent prognostic factor of bDFS (p = 0.005). CONCLUSION: The results of the present study suggest that dose escalations result in significant improvements in bDFS, even when used in combination with long-term ADT. A longer follow-up is needed to clarify the effects of dose escalations on cRFS and OS. Advances in knowledge: It remains unclear whether high-dose RT is necessary for improving the outcomes of patients receiving long-term ADT. The results suggest that dose escalations result in significant improvements in biochemical control. PMID- 29166144 TI - In Reply. PMID- 29166145 TI - Effect of Background Luminance Level on the Assessment of Color Visual Acuity Using Colored Landolt Rings in Young Healthy Subjects. AB - PURPOSE: To evaluate the color visual acuity (CVA) of young healthy subjects using colored Landolt rings and the effect of background luminance level on the CVA. MATERIALS AND METHODS: We measured the CVA of 20 young healthy subjects (age: 23.8 +/- 3.8 years) with different colors using a computer and a liquid crystal display, with 15 Landolt ring colors (30 cd/m2) with a background luminance of 30 cd/m2, and then 100 cd/m2. We then used different background luminance levels (15-50 cd/m2) using four Landolt ring colors (red, green-yellow, green, and blue-green) to evaluate the effect of the background luminance level on CVA. RESULTS: The CVA significantly differed among the colors with a background luminance of 30 cd/m2 (p < 0.0001). Green-yellow and blue-purple had poor CVA (high LogMAR value; 0.808 +/- 0.107 and 0.633 +/- 0.150, respectively) with a background luminance of 30 cd/m2 (same luminance as the Landolt rings). There were no significant differences in the CVAs among the colors with a background luminance of 100 cd/m2 (p = 0.5999). There were no significant difference in the CVA between background luminance 30 cd/m2 and other luminance level ranging from 28 to 32 cd/m2 for colors of red, green-yellow, green, and blue-green. CONCLUSIONS: The results reveal that the background luminance of Landolt rings affects the CVA. Distinctive CVAs for each color are measured by equalizing the luminance between the Landolt ring and the background. We consider that the poor CVAs of these colors reflect the visual function of S-cone, because GY and BP are included in the confusion locus of tritan axis on the chromaticity diagram. We believe that CVA assessment may be useful for individuals who have known or suspected ocular dysfunction or color vision deficiencies. PMID- 29166146 TI - Screening for Lung Cancer: Communicating With Patients. AB - OBJECTIVE: The purposes of this article are to detail the experience of a single center academic institution in applying the patient-centered approach to a lung cancer screening program and to examine how this approach can expand to other aspects of follow-up imaging of lung nodules. CONCLUSION: As the practice of patient-centered radiology gains attention, diagnostic radiologists are findings new ways to become more involved in patient care. A lung cancer screening program is one opportunity for radiologists to consult with and educate patients. PMID- 29166147 TI - Preliminary Results of Lung Cancer Screening in a Socioeconomically Disadvantaged Population. AB - OBJECTIVE: The objective of our study was to describe the preliminary results of our clinical low-dose CT (LDCT) lung cancer screening program targeting a minority, socioeconomically disadvantaged, high-risk population different from that studied in the National Lung Screening Trial (NLST). MATERIALS AND METHODS: Community partner clinics in an underserved region of south Los Angeles County referred interested candidates to our program. All patients met National Comprehensive Cancer Network eligibility criteria for lung cancer screening. RESULTS: From July 21, 2015, through April 3, 2017, 889 individuals were referred to the program. Of the 329 eligible participants, 275 (mean age, 59 years; 52% men) underwent baseline screening LDCT: 84% of patients were black, and 66% had a high school education or less. The median pack-years was 40, and 81% of patients were current smokers. Thirty-one percent of participants reported occupational exposure to one or more known lung carcinogens. Lung CT Screening Reporting and Data System (Lung-RADS) categories were assigned using baseline LDCT examinations: Lung-RADS category 1 or 2 were assigned in 86% of patients, category 3 in 7%, category 4A in 4%, and category 4B or 4X in 3%. Lung cancer has been diagnosed in two of these patients (0.7%) to date: stage IIIB small cell lung carcinoma in one patient and stage IV lung cancer of unknown type in the other patient. Among the 275 patients, 29% had potentially clinically significant incidental findings. CONCLUSION: Lung cancer screening with LDCT in a minority, socioeconomically disadvantaged, high-risk population is feasible but may yield a different lung cancer profile than screening populations in more privileged communities. More follow-up time is required to determine whether the reduction in lung cancer mortality shown in the NLST applies to this underserved population. PMID- 29166148 TI - In Vivo Differentiation of Uric Acid Versus Non-Uric Acid Urinary Calculi With Third-Generation Dual-Source Dual-Energy CT at Reduced Radiation Dose. AB - OBJECTIVE: The objective of our study was to evaluate in vivo urinary calculus characterization with third-generation dual-source dual-energy CT (DECT) at reduced versus standard radiation dose. SUBJECTS AND METHODS: One hundred fifty three patients requiring unenhanced CT for suspected or known urolithiasis were prospectively included in our study. They underwent two acquisitions at reduced dose CT (90 kV and 50 mAsref; Sn150 kV and 31 mAsref, where Sn denotes the interposition of a tin filter in the high-energy beam) and standard-dose CT (90 kV and 50 mAsref; Sn150 kV and 94 mAsref). One radiologist interpreted the reduced-dose examinations before the standard-dose examinations during the same session. Among 103 patients (23 women, 80 men; mean age +/- SD, 50 +/- 15 years; age range, 18-82 years) with urolithiasis, dedicated DECT software measured the maximal diameter and CT numbers, calculated the DECT number ratio, and labeled with a color code each calculus visualized by the radiologist as uric acid (UA) or non-UA. Volume CT dose index (CTDIvol) and dose-length product (DLP) were recorded. RESULTS: The radiologist visualized 279 calculi on standard-dose CT and 262 on reduced-dose CT; 17 calculi were missed on reduced-dose CT, all of which were <= 3 mm. Among the 262 calculi visualized at both doses, the CT number ratio was obtained with the software for 227 calculi and was not different between the doses (p = 0.093). Among these 262 calculi, 197 were labeled at both doses; 194 of the 197 labeled calculi were labeled with the same color code. Among the 65 remaining calculi, 48 and 61 (all <= 5 mm) were not labeled at standard-dose and reduced-dose CT (p = 0.005), respectively. At reduced-dose CT, the mean CTDIvol was 2.67 mGy and the mean DLP was 102.2 mGy * cm. CONCLUSION: With third generation dual-source DECT, a larger proportion of calculi <= 5 mm are not characterized as UA or non-UA at a reduced dose. PMID- 29166149 TI - JOURNAL CLUB: Redefining the Radiology Curriculum in Medical School: Vertical Integration and Global Accessibility. AB - OBJECTIVE: Radiology interconnects medical disciplines given that a working understanding of imaging is essential to clinicians of every specialty. Using online education, we created a globally accessible, web-based undergraduate medical radiology curriculum modeled after the National Medical Student Curriculum in Radiology program of the Alliance of Medical Student Educators in Radiology. SUBJECTS AND METHODS: Seventy-four radiology faculty-mentored video modules were produced, 50 of which were integrated into the 1st-year anatomy course. We administered tests to medical students before and after students saw the videos to assess the effectiveness of the modules. We surveyed students on their interests in pursuing radiology as a career before and after participating in this curriculum. RESULTS: On the preexamination questions, the mean score was 58.0%, which increased to 83.6% on the pair-matched imaging-related questions on the actual examination. Before participating in the new curriculum, 88% of students did not express an interest in radiology, and 9% were undecided about radiology as a future career. There was an increase in students who reported that they would definitely or most likely pursue a career in radiology (7%) after they had viewed the lectures. CONCLUSION: Radiology education is now available to a greater number of multidisciplinary learners worldwide. This project produced a comprehensive, globally accessible radiology curriculum in a self-paced, flexible learning format for new generations of physicians. PMID- 29166150 TI - Exploring the Negative Likelihood Ratio and How It Can Be Used to Minimize False Positives in Breast Imaging. AB - OBJECTIVE: This article describes the definition and proposed utilization of negative likelihood ratios (NLRs) as statistical parameters in breast imaging. Examples with calculations are provided using BI-RADS category 4 subcategories. CONCLUSION: By auditing individual performance early and often against American College of Radiology benchmark positive predictive value ranges for the BI-RADS category 4 subcategories, and by fully understanding NLRs and their application in breast imaging, radiologists can minimize false-positive findings and unnecessary biopsies. PMID- 29166151 TI - Biomarkers and Imaging of Breast Cancer. AB - OBJECTIVE: The goals of this review are to provide background information on the definitions and applications of the general term "biomarker" and to highlight the specific roles of breast imaging biomarkers in research and clinical breast cancer care. A search was conducted of the main electronic biomedical databases (PubMed, Cochrane, Embase, MEDLINE [Ovid], Scopus, and Web of Science). The search was focused on review literature in general radiology and biomedical sciences and on reviews and primary research articles on biomarkers in breast imaging over the 15 years ending in June 2017. The keywords included "biomarker," "trial endpoints," "breast imaging," "breast cancer," "radiomics," and "precision medicine" in the titles and abstracts of the papers. CONCLUSION: Clinical breast care and breast cancer-related research rely on imaging biomarkers for decision support. In the era of precision medicine and big data, the practice of radiology is likely to change. A closer integration of breast imaging with related biomedical fields and the creation of large integrated and shareable databases of clinical, molecular, and imaging biomarkers should allow the field to continue guiding breast cancer care and research. PMID- 29166152 TI - Is Plant Fitness Proportional to Seed Set? An Experiment and a Spatial Model. AB - Individual differences in fecundity often serve as proxies for differences in overall fitness, especially when it is difficult to track the fate of an individual's offspring to reproductive maturity. Using fecundity may be biased, however, if density-dependent interactions between siblings affect survival and reproduction of offspring from high- and low-fecundity parents differently. To test for such density-dependent effects in plants, we sowed seeds of the wildflower Ipomopsis aggregata (scarlet gilia) to mimic partially overlapping seed shadows of pairs of plants, one of which produced twice as many seeds. We tested for differences in offspring success using a genetic marker to track offspring to flowering multiple years later. Without density dependence, the high fecundity parent should produce twice as many surviving offspring. We also developed a model that considered the geometry of seed shadows and assumed limited survivors so that the number of juvenile recruits is proportional to the area. Rather than a ratio of 2?1 offspring success from high- versus low fecundity parents, our model predicted a ratio of 1.42?1, which would translate into weaker selection. Empirical ratios of juvenile offspring and of flowers produced conformed well to the model's prediction. Extending the model shows how spatial relationships of parents and seed dispersal patterns modify inferences about relative fitness based solely on fecundity. PMID- 29166153 TI - Catastrophic Shifts in Semiarid Vegetation-Soil Systems May Unfold Rapidly or Slowly. AB - Under gradual change of a driver, complex systems may switch between contrasting stable states. For many ecosystems it is unknown how rapidly such a critical transition unfolds. Here we explore the rate of change during the degradation of a semiarid ecosystem with a model coupling the vegetation and geomorphological system. Two stable states-vegetated and bare-are identified, and it is shown that the change between these states is a critical transition. Surprisingly, the critical transition between the vegetated and bare state can unfold either rapidly over a few years or gradually over decennia up to millennia, depending on parameter values. An important condition for the phenomenon is the linkage between slow and fast ecosystems components. Our results show that, next to climate change and disturbance rates, the geological and geomorphological setting of a semiarid ecosystem is crucial in predicting its fate. PMID- 29166154 TI - Predator Persistence through Variability of Resource Productivity in Tritrophic Systems. AB - The trophic structure of species communities depends on the energy transfer between trophic levels. Primary productivity varies strongly through time, challenging the persistence of species at higher trophic levels. Yet resource variability has mostly been studied in systems with only one or two trophic levels. We test the effect of variability in resource productivity in a tritrophic model system including a resource, a size-structured consumer, and a size-specific predator. The model complies with fundamental principles of mass conservation and the body-size dependence of individual-level energetics and predator-prey interactions. Surprisingly, we find that resource variability may promote predator persistence. The positive effect of variability on the predator arises through periods with starvation mortality of juvenile prey, which reduces the intraspecific competition in the prey population. With increasing variability in productivity and starvation mortality in the juvenile prey, the prey availability increases in the size range preferred by the predator. The positive effect of prey mortality on the trophic transfer efficiency depends on the biologically realistic consideration of body size-dependent and food-dependent functions for growth and reproduction in our model. Our findings show that variability may promote the trophic transfer efficiency, indicating that environmental variability may sustain species at higher trophic levels in natural ecosystems. PMID- 29166156 TI - Treasurer's Report, 2016: Statement of Activities For the year ending December 31, 2016. PMID- 29166155 TI - Drivers of Diversification in Individual Life Courses. AB - Heterogeneity in life courses among individuals of a population influences the speed of adaptive evolutionary processes, but it is less clear how biotic and abiotic environmental fluctuations influence such heterogeneity. We investigate principal drivers of variability in sequence of stages during an individual's life in a stage-structured population. We quantify heterogeneity by measuring population entropy of a Markov chain, which computes the rate of diversification of individual life courses. Using individual data of a primate population, we show that density regulates the stage composition of the population but that its entropy and the generating moments of heterogeneity are independent of density. This lack of influence of density on heterogeneity is due to neither low year-to year variation in entropy nor differences in survival among stages but is rather due to differences in stage transitions. Our analysis thus shows that well-known classical ecological selective forces, such as density regulation, are not linked to potential selective forces governing heterogeneity through underlying stage dynamics. Despite evolution acting heavily on individual variability in fitness components, our understanding is poor whether observed heterogeneity is adaptive and how it evolves and is maintained. Our analysis illustrates how entropy represents a more integrated measure of diversity compared to the population structural composition, giving us new insights about the underlying drivers of individual heterogeneity within populations and potential evolutionary mechanisms. PMID- 29166157 TI - Rapid Diversification and Time Explain Amphibian Richness at Different Scales in the Tropical Andes, Earth's Most Biodiverse Hotspot. AB - The Tropical Andes make up Earth's most species-rich biodiversity hotspot for both animals and plants. Nevertheless, the ecological and evolutionary processes underlying this extraordinary richness remain uncertain. Here, we examine the processes that generate high richness in the Tropical Andes relative to other regions in South America and across different elevations within the Andes, using frogs as a model system. We combine distributional data, a newly generated time calibrated phylogeny for 2,318 frog species, and phylogenetic comparative methods to test the relative importance of diversification rates and colonization times for explaining Andean diversity at different scales. At larger scales (among regions and families), we find that faster diversification rates in Andean clades most likely explain high Andean richness. In contrast, at smaller temporal and spatial scales (within family-level clades within the Andes), diversification rates rarely explain richness patterns. Instead, we show that colonization times are important for shaping elevational richness patterns within the Andes, with more species found in habitats colonized earlier. We suggest that these scale dependent patterns might apply to many other richness gradients. Recognition of this scale dependence may help to reconcile conflicting results among studies of richness patterns across habitats, regions, and organisms. PMID- 29166158 TI - Secretary's Report, 2017: American Society of Naturalists. PMID- 29166159 TI - Local Regulation of Trail Networks of the Arboreal Turtle Ant, Cephalotes goniodontus. AB - This study examines how an arboreal ant colony maintains, extends, and repairs its network of foraging trails and nests, built on a network of vegetation. Nodes are junctions where a branch forks off from another or where a branch of one plant touching another provides a new edge on which ants could travel. The ants' choice of edge at a node appears to be reinforced by trail pheromone. Ongoing pruning of the network tends to eliminate cycles and minimize the number of nodes and thus decision points, but not the distance traveled. At junctions, trails tend to stay on the same plant. In combination with the long internode lengths of the branches of vines in the tropical dry forest, this facilitates travel to food sources at the canopy edge. Exploration, when ants leave the trail on an edge that is not being used, makes both search and repair possible. The fewer the junctions between a location and the main trail, the more likely the ants are to arrive there. Ruptured trails are rapidly repaired with a new path, apparently using breadth-first search. The regulation of the network promotes its resilience and continuity. PMID- 29166160 TI - Sex-Dependent Phenological Plasticity in an Arctic Hibernator. AB - Hibernation provides a means of escaping the metabolic challenges associated with seasonality, yet the ability of mammals to prolong or reenter seasonal dormancy in response to extreme weather events is unclear. Here, we show that Arctic ground squirrels in northern Alaska exhibited sex-dependent plasticity in the physiology and phenology of hibernation in response to a series of late spring snowstorms in 2013 that resulted in the latest snowmelt on record. Females and nonreproductive males responded to the >1-month delay in snowmelt by extending heterothermy or reentering hibernation after several days of euthermy, leading to a >2-week delay in reproduction compared to surrounding years. In contrast, reproductive males neither extended nor reentered hibernation, likely because seasonal gonadal growth and development and subsequent testosterone release prevents a return to torpor. Our findings reveal intriguing differences in responses of males and females to climatic stressors, which can generate a phenological mismatch between the sexes. PMID- 29166161 TI - Will Invertebrates Require Increasingly Carbon-Rich Food in a Warming World? AB - Elevated temperature causes metabolism and respiration to increase in poikilothermic organisms. We hypothesized that invertebrate consumers will therefore require increasingly carbon-rich diets in a warming environment because the increased energetic demands are primarily met using compounds rich in carbon, that is, carbohydrates and lipids. Here, we test this hypothesis using a new stoichiometric model that has carbon (C) and nitrogen (N) as currencies. Model predictions did not support the hypothesis, indicating instead that the nutritional requirements of invertebrates, at least in terms of food quality expressed as C?N ratio, may change little, if at all, at elevated temperature. Two factors contribute to this conclusion. First, invertebrates facing limitation by nutrient elements such as N have, by default, excess C in their food that can be used to meet the increased demand for energy in a warming environment, without recourse to extra dietary C. Second, increased feeding at elevated temperature compensates for the extra demands of metabolism to the extent that, when metabolism and intake scale equally with temperature (have the same Q10), the relative requirement for dietary C and N remains unaltered. Our analysis demonstrates that future climate-driven increases in the C?N ratios of autotroph biomass will likely exacerbate the stoichiometric mismatch between nutrient limited invertebrate grazers and their food, with important consequences for C sequestration and nutrient cycling in ecosystems. PMID- 29166163 TI - Clarification. PMID- 29166162 TI - Stochastic Evolutionary Demography under a Fluctuating Optimum Phenotype. AB - Many natural populations exhibit temporal fluctuations in abundance that are consistent with external forcing by a randomly changing environment. As fitness emerges from an interaction between the phenotype and the environment, such demographic fluctuations probably include a substantial contribution from fluctuating phenotypic selection. We study the stochastic population dynamics of a population exposed to random (plus possibly directional) changes in the optimum phenotype for a quantitative trait that evolves in response to this moving optimum. We derive simple analytical predictions for the distribution of log population size over time both transiently and at stationarity under Gompertz density regulation. These predictions are well matched by population- and individual-based simulations. The log population size is approximately reverse gamma distributed, with a negative skew causing an excess of low relative to high population sizes, thus increasing extinction risk relative to a symmetric (e.g., normal) distribution with the same mean and variance. Our analysis reveals how the mean and variance of log population size change with the variance and autocorrelation of deviations of the evolving mean phenotype from the optimum. We apply our results to the analysis of evolutionary rescue in a stochastic environment and show that random fluctuations in the optimum can substantially increase extinction risk by both reducing the expected growth rate and increasing the variance of population size by several orders of magnitude. PMID- 29166164 TI - A Physiological Signature of the Cost of Reproduction Associated with Parental Care. AB - Costs of reproduction are an integral and long-standing component of life-history theory, but we still know relatively little about the specific physiological mechanisms underlying these trade-offs. We experimentally manipulated workload during parental care in female European starlings (Sturnus vulgaris) using attachment of radios and/or wing clipping and assessed measures of workload, current breeding productivity, future fecundity, and survival (local return rate) in relation to treatment. Females with wing clipping and radio attachment paid a clear cost of reproduction compared with all other treatment groups: they had lower future fecundity and lower return rates despite having lower current breeding productivity. We then measured 13 physiological traits, including measures of aerobic/metabolic capacity, oxidative stress and muscle damage, intermediary metabolism and energy supply, and immune function. Our results show that the cost of reproduction in females with wing clipping and radio attachment was associated with lower oxygen-carrying capacity (lower hematocrit and hemoglobin levels), lower energy reserves (plasma nonesterified fatty acid and triglyceride levels), decreased immune function (lower haptoglobin levels), and elevated levels of oxidative stress (higher levels of dROMs [reactive oxygen metabolites] and lower levels of the endogenous antioxidant uric acid). Our study provides evidence that costs of reproduction involve a widespread decline in physiological function across multiple physiological systems consistent with long standing ideas of cumulative "wear and tear" and allostatic load. PMID- 29166165 TI - The Rate of Seasonal Changes in Temperature Alters Acclimation of Performance under Climate Change. AB - How the ability to acclimate will impact individual performance and ecological interactions under climate change remains poorly understood. Theory predicts that the benefit an organism can gain from acclimating depends on the rate at which temperatures change relative to the time it takes to induce beneficial acclimation. Here, we present a conceptual model showing how slower seasonal changes under climate change can alter species' relative performance when they differ in acclimation rate and magnitude. To test predictions from theory, we performed a microcosm experiment where we reared a mid- and a high-latitude damselfly species alone or together under the rapid seasonality currently experienced at 62 degrees N and the slower seasonality predicted for this latitude under climate change and measured larval growth and survival. To separate acclimation effects from fixed thermal responses, we simulated growth trajectories based on species' growth rates at constant temperatures and quantified how much and how fast species needed to acclimate to match the observed growth trajectories. Consistent with our predictions, the results showed that the midlatitude species had a greater capacity for acclimation than the high latitude species. Furthermore, since acclimation occurred at a slower rate than seasonal temperature changes, the midlatitude species had a small growth advantage over the high-latitude species under the current seasonality but a greater growth advantage under the slower seasonality predicted for this latitude under climate change. In addition, the two species did not differ in survival under the current seasonality, but the midlatitude species had higher survival under the predicted climate change scenario, possibly because rates of cannibalism were lower when smaller heterospecifics were present. These findings highlight the need to incorporate acclimation rates in ecological models. PMID- 29166166 TI - Coevolution between Mutualists and Parasites in Symbiotic Communities May Lead to the Evolution of Lower Virulence. AB - Most eukaryotes harbor a diverse community of parasitic, mutualistic, and commensal microbial symbionts. Although the diversity of these microbial symbiotic communities has recently drawn considerable attention, theory regarding the evolution of interactions among symbionts and with the host is still in its nascent stages. Here we evaluate the role of interactions among coinfecting symbionts in the evolution of symbiont virulence toward the host. To do so, we place the virulence-transmission trade-off into a community context and model the evolution of symbiont trophic modes along the continuum from parasitism (virulence) to mutualism (negative virulence). We establish a framework for studying multiple infections of a host by the same symbiont species and coinfection by multiple species, using a concept of shared costs, wherein the negative consequences of virulence (or harm) toward the host are shared among symbionts. Our results show that mutualism can be maintained under infection by multiple symbionts when shared costs are sufficiently low, while greater virulence and parasitism toward the host are more likely when shared costs are high. Last, for coinfection by more than one species, we show that if the presence of a mutualist ameliorates some of the costs of pathogen virulence, then the symbiotic community may more often evolve to a more commensal state and maintain mutualisms. PMID- 29166167 TI - Kinship and Incest Avoidance Drive Patterns of Reproductive Skew in Cooperatively Breeding Birds. AB - Social animals vary in how reproduction is divided among group members, ranging from monopolization by a dominant pair (high skew) to equal sharing by cobreeders (low skew). Despite many theoretical models, the ecological and life-history factors that generate this variation are still debated. Here I analyze data from 83 species of cooperatively breeding birds, finding that kinship within the breeding group is a powerful predictor of reproductive sharing across species. Societies composed of nuclear families have significantly higher skew than those that contain unrelated members, a pattern that holds for both multimale and multifemale groups. Within-species studies confirm this, showing that unrelated subordinates of both sexes are more likely to breed than related subordinates are. Crucially, subordinates in cooperative groups are more likely to breed if they are unrelated to the opposite-sex dominant, whereas relatedness to the same sex dominant has no effect. This suggests that incest avoidance, rather than suppression by dominant breeders, may be an important proximate mechanism limiting reproduction by subordinates. Overall, these results support the ultimate evolutionary logic behind concessions models of skew-namely, that related subordinates gain indirect fitness benefits from helping at the nests of kin, so a lower direct reproductive share is required for selection to favor helping over dispersal-but not the proximate mechanism of dominant control assumed by these models. PMID- 29166168 TI - Additional Recommendations for ALK Gene-Rearranged Non-Small-Cell Lung Cancer to the Recently Updated American Society of Clinical Oncology Guideline for Stage IV Non-Small-Cell Lung Cancer. PMID- 29166169 TI - Reply to M.E.H.M. Van Hoef. PMID- 29166170 TI - Highly Accurate Identification of Cystic Precursor Lesions of Pancreatic Cancer Through Targeted Mass Spectrometry: A Phase IIc Diagnostic Study. AB - Purpose Pancreatic cystic lesions are common incidental findings on imaging, but up to half may be forerunners of pancreatic cancer. Therefore, accurate differential diagnosis is crucial for correct patient management. Unfortunately, currently available diagnostic methods cannot robustly identify premalignant and malignant pancreatic cystic lesions. Methods Cyst fluid samples obtained by routine endoscopic ultrasound-guided aspiration were used for the analyses. In a cohort of 24 patients, eight biomarker candidates for malignant potential and high-grade dysplasia/cancer were identified by an explorative proteomic approach. Subsequently, a quantitative analysis, using 30 heavy-labeled peptides from the biomarkers and parallel reaction monitoring mass spectrometry, was devised, tested in a training cohort of 80, and prospectively evaluated in a validation cohort of 68 patients. End points were surgical pathology diagnosis/clinical follow-up. Diagnostic assessments were blinded to mass spectrometry results. Results The optimal set of markers for detecting malignant potential was a panel of peptides from mucin-5AC and mucin-2, which could discriminate premalignant/malignant lesions from benign with an accuracy of 97% (95% CI, 89% to 99%) in the validation cohort. This result compared favorably with the accuracy of standard analyses: cyst fluid carcinoembryonic antigen (61%; 95% CI, 46% to 74%; P < .001) and cytology (84%; 95% CI, 71% to 92%; P = .02). A combination of proteins mucin-5AC and prostate stem-cell antigen could identify high-grade dysplasia/cancer with an accuracy of 96% (95% CI, 90% to 99%), and detected 95% of malignant/severely dysplastic lesions, compared with 35% and 50% for carcinoembryonic antigen and cytology ( P < .001 and P = .003, respectively). Conclusion Targeted mass spectrometry analysis of just three cyst fluid biomarkers provides highly accurate identification and assessment of cystic precursors to pancreatic adenocarcinoma. Additional studies should determine whether the method can facilitate timely cancer diagnosis, successful intervention, and prevention. PMID- 29166171 TI - Decomposition of Economic Inequality in Needle and Syringe Programs Utilization to its Determinants among Men Who Inject Drugs in Tehran using Blinder-Oaxaca Decomposition Method. AB - BACKGROUND: According to latest available data there are more of 300,000 people injects drug users (PWID) in Iran. OBJECTIVES: In this study, we used a Blinder Oaxaca (BO) decomposition to explore the relative contributions of inequality in utilization of NSPs and to decompose it to its determinants in Teheran. METHODS: We used data from a cross-sectional survey using snowball sampling to recruit 500 PWID from June to July 2016 in Tehran. Participants were reported injecting drug use in the past month, were able to speak and comprehend Farsi enough to respond to survey questions, and were able to provide informed consent to complete the interview. We used a BO method to decompose the role of economic inequality on utilization of needle and syringe programs. RESULTS: A total 520 of clients participated in the study of which data was fully complete for 500. The selected predictor variables (age, education level, marital status, homelessness, HIV risk perception, and HIV knowledge) together explain 54% (8.5% out of 16%) of total inequality in utilization of needle and syringe programs and the remaining 46% constitute the unexplained residual. HIV risk perception status contributed about 38% (3.3% out of 8.5%) to the total health inequality, followed by HIV knowledge (26%) and education level were contributed 20% each, respectively. CONCLUSION: The results showed that contribution of economic inequalities in utilization of NSPs was primarily explained by the differential effects of HIV risk perception and HIV knowledge among PWID. Reducing HIV risk perception and increasing HIV knowledge might be essential to efforts to eliminate inequalities in access to NSPs among PWID. PMID- 29166172 TI - Efficacy of LISTEX P100 at Different Concentrations for Reduction of Listeria monocytogenes Inoculated in Sashimi. AB - Sushi restaurants have become quite popular in Europe, with an increase in the consumption of the sashimi speciality. Pathogenic bacteria such as Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus have been reported in this kind of food. Controlling the presence and multiplication of L. monocytogenes is a challenge for food safety management systems owing to its ubiquitous presence and psychrotrophic growth. Bacteriophages have been used as pathogenic biocide agents for decades. The bacteriophage P100, present in LISTEX P100, was used in this study to understand the possibility of implementing a new critical control point for L. monocytogenes in sashimi preparation and sale. Different concentrations of LISTEX P100 were used for reduction of L. monocytogenes in inoculated samples at 3 and 22 degrees C. The reduction in initial counts of 2 log CFU/g was effective in the first 24 h with the 8-log PFU/g inoculation. Promising results were obtained in assays with the 6-log CFU/g initial counts and the 8-log PFU/g inoculation, at 22 degrees C, achieving a maximum reduction of 4.44 log CFU/g, compared with the control group. These results seem to confirm that bacteriophages can be an option in reducing the population of the L. monocytogenes pathogenic bacteria in sashimi, mainly in takeaway sales. PMID- 29166173 TI - Cold Plasma Inactivation of Salmonella in Prepackaged, Mixed Salads Is Influenced by Cross-Contamination Sequence. AB - Customer demand for convenient food products has led to an increased production of prepackaged and ready-to-eat food products. Most of these products rely mainly on surface disinfection and other traditional approaches to ensure shelf life and safety. Novel processing techniques, such as cold plasma, are currently being investigated to enhance the safety and shelf life of prepacked foods. The purpose of this study was to determine the effects of cold plasma corona discharge on the inactivation of Salmonella on prepackaged, tomato-and-lettuce mixed salads. Two different inoculation methods were evaluated to address cross-contamination of Salmonella from cherry tomatoes to lettuce and vice versa. In separate studies, a sample of either cherry tomatoes (55 g) or romaine lettuce (10 g) was inoculated with a Salmonella cocktail (6.93 +/- 0.99 log CFU/mL), placed into a commercial polyethylene terephthalate plastic container, and thoroughly mixed together with its noninoculated counterpart. Mixed salads were allowed to dry in a biosafety cabinet for 1 h. Samples were treated with 35 kV cold plasma corona discharge inside plastic containers for 3 min. Samples were stomached and serially diluted in buffered peptone water and then were plated onto aerobic plate count Petrifilm and incubated for 18 h at 37 degrees C. When lettuce was the inoculated counterpart, log kill of Salmonella was significantly greater on tomatoes (0.75 log CFU/g) compared with lettuce (0.34 log CFU/g) (P = 0.0001). Salmonella was reduced on mixed salad only when lettuce was the inoculated counterpart (0.29 log CFU/g) (P = 0.002). Cold plasma can kill Salmonella in a prepackaged mixed salad, with efficacy dependent on the nature of contamination, direction of transfer, and the surface topography of the contaminated commodity. PMID- 29166174 TI - Low Prevalence of Salmonella and Shiga Toxin-Producing Escherichia coli in Lymph Nodes of Australian Beef Cattle. AB - Salmonella contamination of ground beef has been viewed as originating from the surface of carcasses. Recent studies have identified lymph nodes as a potential source of Salmonella contamination because these tissues play an active role in containment of pathogens in the live animal and because some lymph nodes are unavoidably present in manufacturing beef trimmings or primal cuts that may be incorporated into ground beef. A survey was conducted of the microbiological status of lymph nodes from Australian cattle at the time of slaughter to determine the prevalence of microbiological contamination. Sets of lymph nodes (n = 197), consisting of the superficial cervical (prescapular), prepectoral, axillary, presternal, popliteal, ischiatic, subiliac (precrural), coxalis, and iliofemoralis (deep inguinal), were collected from five geographically separated Australian abattoirs over a period of 14 months. Samples were tested for the presence of Salmonella spp. and Shiga toxin-producing Escherichia coli by BAX PCR assay. Aerobic plate count, E. coli, and coliforms were enumerated with a lower limit of detection of 80 CFU per node. The observed prevalence of Salmonella within peripheral lymph nodes was 0.48% (7 of 1,464). Two of the seven lymph nodes in which Salmonella organisms were detected came from the same animal. Grass-fed, grain-fed, and cull dairy cattle were all found to have detectable Salmonella in lymph nodes. All Salmonella detections occurred during cooler months of the year. No Shiga toxin-producing E. coli were detected. Aerobic microorganisms were detected above the limit of quantification in 3.2% of nodes (median count 2.24 log per node), and E. coli was detected in 0.8% of nodes (median count 3.05 log per node). The low prevalence of Salmonella and low concentration of aerobic microorganisms in Salmonella-positive lymph nodes of Australian cattle at the time of slaughter suggest that the likelihood of lymph nodes contributing significantly to the presence of Salmonella in ground beef is low. PMID- 29166175 TI - Simultaneous Determination of Isopyrazam and Azoxystrobin in Cucumbers by Liquid Chromatography-Tandem Mass Spectrometry. AB - A rapid and sensitive analytical method based on high-performance liquid chromatography-tandem mass spectrometry was developed and validated for the determination of isopyrazam (IZM) and azoxystrobin (AZT) in cucumbers. A modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) method was used as the pretreatment procedure. The samples were extracted with acetonitrile and cleaned up with octadecylsilyl silica (C18) and graphite carbon black. The proposed method resulted in satisfactory recovery of IZM and AZT (91.48 to 114.62%), and relative standard deviations were less than 13.1% at fortification concentrations of 1, 20, and 500 MUg kg-1 (n = 3). The limits of quantification for IZM and AZT were 0.498 and 0.499 MUg kg-1, respectively, which are far below the maximum residue level (0.5 mg kg-1) established for this type of sample. Matrix effects were also evaluated. This study established a sensitive and fast method for the detection of IZM and AZT in cucumber samples. PMID- 29166176 TI - Microbiological Quality Assessment of Game Meats at Retail in Japan. AB - In this study, we examined the prevalence of Shiga toxin-producing Escherichia coli and Salmonella spp. and the distribution of indicator bacteria in 248 samples of game meats (120 venison and 128 wild boar) retailed between November 2015 and March 2016 in Japan. No Salmonella spp. were detected in any of the samples, whereas Shiga toxin-producing Escherichia coli serotype OUT:H25 (stx2d+, eae-) was isolated from one deer meat sample, suggesting a possible source for human infection. Plate count assays indicated greater prevalence of coliforms and E. coli in wild boar meat than in venison, whereas their prevalence in processing facilities showed greater variation than in animal species. The 16S rRNA ion semiconductor sequencing analysis of 24 representative samples revealed that the abundances of Acinetobacter and Arthrobacter spp. significantly correlated with the prevalence of E. coli, and quantitative PCR analyses in combination with selective plate count assay verified these correlations. To our knowledge, this is the first report to characterize the diversity of microorganisms of game meats at retail in Japan, together with identification of dominant microbiota. Our data suggest the necessity of bottom-up hygienic assessment in areas of slaughtering and processing facilities to improve microbiological safety. PMID- 29166177 TI - Kinetic Behavior of Campylobacter jejuni in Beef Tartare at Cold Temperatures and Transcriptomes Related to Its Survival. AB - This study was conducted to examine the kinetic behavior of Campylobacter jejuni in raw beef tartare by using mathematical models and to identify genes related to C. jejuni survival at cold temperatures. C. jejuni was inoculated onto beef tartare samples, stored at 4, 10, 15, 25, and 30 degrees C, plated on modified charcoal-cefoperazone-deoxycholate agar, and enumerated. The survival data was fitted to the Weibull model to calculate delta (delta), which is the time required for the first 1-log reduction of the cells. The Davey model was then fitted to the delta to evaluate the effect of temperature. To evaluate the performance of the developed model, the root mean square error (RMSE) was calculated by comparing the observed data with the predicted data. The mRNA was extracted from samples stored at 4 and 30 degrees C under aerobic and anaerobic conditions, and the expression of oxidative stress response and stress response genes was evaluated. C. jejuni survived in beef tartare longer at 4 degrees C (delta = 657.1 +/- 79.6 min) than at other temperatures (9.7 +/- 11.2 to 465.7 +/ 139.3 degrees C) even under aerobic conditions. The RMSE (0.475) suggested that the developed model was appropriate to describe the kinetic behavior of C. jejuni. Quantitative real-time PCR results revealed that oxidative stress and stress response genes were related to C. jejuni survival at cold temperatures, even under aerobic conditions. These results indicate that the model will be useful for describing the kinetic behavior of C. jejuni in beef tartare and that this pathogen can survive at cold temperatures because of the expression of the sodB, katA, and clpP genes. PMID- 29166178 TI - Changes of Dominant Spoilage Bacteria and Biogenic Amines of Taihu White Prawn (Exopalaemon modestus) during Ice Storage. AB - The microbiological and chemical changes in Taihu white prawn (Exopalaemon modestus) during ice storage were evaluated. For the microbiological changes, total viable counts were obtained. PCR coupled with denatured gradient gel electrophoresis was then performed to investigate the changes in microflora. For the chemical changes, total volatile basic nitrogen was determined and biogenic amines were detected. The initial total viable count was 6.2 log CFU/g, which increased to 7.1 log CFU/g after storage at 0 degrees C for 10 days. Pseudomonas sp., Shewanella, Flavobacterium, and Staphylococcus were the dominant bacteria in fresh white prawn, whereas lactic acid bacteria, Pseudomonas sp., Shewanella, and Flavobacterium were dominant in the spoiled products. The initial total volatile basic nitrogen was 7.2 mg/100 g, a value that significantly increased to 30.5 mg/100 g at the end of storage. Putrescine was the dominant biogenic amine, and its content reached 95.5 mg/kg at the end of storage. PCR coupled with denatured gradient gel electrophoresis showed that Chryseobacterium sp., Acidovorax sp., Pelomonas sp., Kinneretia asaccharophila, and uncultured Curvibacter sp. were the dominant strains during storage, whereas Lactococcus garvieae became dominant at the end of storage. This study facilitated the development of preservation techniques that target these predominant spoilage bacteria. PMID- 29166179 TI - Imbalance between Subpopulations of Regulatory T Cells in Patients with Acute Exacerbation of COPD. AB - Human regulatory T cells (Tregs) have been reported to be not significantly different in the peripheral blood of patients with chronic obstructive pulmonary disease (COPD) and healthy controls. Recent research has identified some new markers for Tregs and indicated that Tregs are composed of distinct subpopulations. The aim of the study was to describe the changing patterns of circulating Treg subpopulations in patients with acute exacerbation of COPD (AECOPD) and healthy controls, and to explore their potential roles in AECOPD pathogenesis. Blood samples were obtained from 30 never-smokers with normal lung function and 30 patients with COPD before and after they had an exacerbation. The proportions of Treg subpopulations were evaluated using flow cytometry. In the peripheral blood, decreased proportions of CD4+CD25+CD127low Tregs, CD4+CD25+CD45RA+ Tregs, and CD4+CD25+CD62L+ Tregs and an increased proportion of CD4+CD25+CD45RO+ Tregs were found in patients with stable COPD compared with non smokers with normal lung function. The patients showed further changes in Treg subpopulations when they had an AECOPD, with an overall decrease in a suppressive subset, indicating that the immune negative regulatory population of Tregs did not play an effective role. Immune homeostasis favored inflammation, and a negative correlation between the circulating tumor necrosis factor-alpha and the proportions of CD4+CD25+CD62L+ cells (r = -0.698, p < 0.05) in patients with AECOPD was found. The imbalance between the suppressive subsets and the proinflammatory subset of Tregs and the decline of Treg subpopulations with immunosuppressive activity may play important roles in AECOPD progression. PMID- 29166180 TI - Measurement of Orbital Biomechanical Properties in Patients with Thyroid Orbitopathy Using the Dynamic Scheimpflug Analyzer (Corvis ST). AB - PURPOSE: To investigate orbital biomechanical properties in patients with thyroid orbitopathy and in age- and gender-matched healthy subjects using the Corvis-ST (CST, Oculus Wetzlar, Germany). METHODS: The CST allows a non-contact tonometry with an ultra-high-speed Scheimpflug device to record the deformation of the cornea during an air pulse. Biomechanical response parameters (intraocular pressure (IOP), whole eye movement length (WEMl) and time (WEMt), deflection amplitude 2 mm ratio max, deflection amplitude max, stiffness parameter, and biomechanically corrected IOP were measured in 39 patients with thyroid orbitopathy (= group I) and in 33 age- and gender-matched healthy subjects (= group II) using the CST. RESULTS: Mean age in group I was 54.3 +/- 11.6 years and in group II 54.2 +/- 12.3 years with no statistical significant difference between the groups (P = 0.98). The gender distribution between the groups was not statistically significantly different (P = 0.51). Mean central corneal thickness was 571 +/- 30 um in group I and 563 +/- 36 um in group II (P = 0.306). There were statistically significant differences (P < 0.001) between groups I and II in mean IOP (19.3 +/- 4.5 vs. 14.8 +/- 2.3 mmHg, mean biomechanically corrected IOP (17.1 +/- 3.4 vs. 13.4 +/- 2.1 mmHg), mean WEMl (207 +/- 57 vs. 322 +/- 50 um), mean WEMt (20.5 +/- 1.0 vs. 21.9 +/- 0.7 ms), mean IOP-adjusted WEMl (213 +/- 56 vs. 314 +/- 62 um), and in mean stiffness parameter (132.5 +/- 29.6 vs. 107.8 +/- 23.3 mmHg/mm), respectively. CONCLUSION: Biomechanical parameters as measured by the CST were significantly reduced in patients with thyroid orbitopathy compared to age- and gender-matched healthy subjects, indicating a reduction in orbital compliance in thyroid orbitopathy. The parameters WEMl and WEMt might be a useful diagnostic tool to evaluate the condition of the eyeball within the orbit. PMID- 29166181 TI - Sensitivity, Specificity, and Accuracy of Kramer Examination of Neonatal Jaundice: Comparison with Total Bilirubin Serum. AB - Neonatal jaundice often occurs in the first week after birth. Early detection of neonatal jaundice can prevent kernicterus as a complication of high levels of bilirubin in neonates. Visual assessment is one of the examinations introduced by Kramer to assess the presence of neonatal jaundice. The purpose of this study was to determine the sensitivity, specificity, and accuracy of Kramer's visual assessment in the examination of neonatal jaundice. This study used cross sectional design to examine 102 infants, with the sample selected by the convenience sampling method. A 2 * 2 table diagnostic test was employed in this study to analyze the data. The results of this study showed that visual assessment of neonatal jaundice obtained a sensitivity value of 76.92%, a specificity value of 89.47%, and an accuracy value of 86.27%. This research can contribute to the development of other non-invasive methods for assessing neonatal jaundice, and thereby contribute to a decrease in neonatal morbidity. PMID- 29166182 TI - Increasing Confidence and Ability in Implementing Kangaroo Mother Care Method Among Young Mothers. AB - Mothers giving birth to low birth weight babies (LBWBs) have low confidence in caring for their babies because they are often still young and may lack the knowledge, experience, and ability to care for the baby. This research aims to determine the effect of education about kangaroo mother care (KMC) on the confidence and ability of young mothers to implement KMC. The research methodology used was a controlled-random experimental approach with pre- and post test equivalent groups of 13 mothers and their LBWBs in the intervention group and 13 mothers and their LBWBs in the control group. Data were collected via an instrument measuring young mothers' confidence, the validity and reliability of which have been tested with a resulting r value of .941, and an observation sheet on KMC implementation. After conducting the education, the confidence score of young mothers and their ability to perform KMC increased meaningfully. The score of confidence of young mothers before education was 37 (p = .1555: and the ability score for KMC Implementation before education was 9 (p = .1555). The median score of confidence of young mothers after education in the intervention group was 87 and in the control group was 50 (p = .001, 95% CI 60.36-75.56), and ability median score for KMC implementation after education in the intervention group was 16 and in the control group was 12 (p = .001, 95% CI 1.50-1.88). KMC education should be conducted gradually, and it is necessary to involve the family, in order for KMC implementation to continue at home. A family visit can be done for LBWBs to evaluate the ability of the young mothers to implement KMC. PMID- 29166183 TI - The Development of an Interactive Health Education Model Based on the Djuwita Application for Adolescent Girls. AB - Alarming incidents of maternal deaths in Indonesia are due to three major causes: bleeding, sepsis, and hypertension, in addition to other non-obstetric causes and unsafe abortions. Adolescent girls contributed to maternal mortality based on early marriage, unwanted pregnancy, and childbirth. Prevention efforts have been taken through government programs and non-governmental organizations, but in practice those were considered ineffective. Thus, a preventative effort in the form of health education should be made, preferably embedded in a popular mobile application that most teenagers would be apt to use. This study aimed to develop an interactive health education model based on adolescent-friendly applications, according to their needs. The design of this research was mixed-method. A quantitative approach was used by conducting a survey of 188 teenagers aged 15-19 years in Bogor, West Java, Indonesia through questionnaires. This research also contained a qualitative component via in-depth interviews with students, parents, and counseling teachers. The quantitative results showed that respondents' knowledge was low about male and female reproductive organs, prevention of pregnancy, and the use of condoms. Respondents' attitudes toward risky behaviors indicate a positive attitude about smoking, drinking, and illegal drugs, as well as premarital sex, while respondents have a negative attitude toward unwanted pregnancies. Respondents' attitudes toward application-based health education shows a high interest. Respondents desired that the application have privacy, up to-date information, interesting features, can be discussed with peer groups and health workers, include a game, animation, and simulation, and can identify reproductive health independently. Qualitative results indicate the need for reliable, accessible, and personal sources of information. The next research recommendation is to develop an interactive health education model based on the application of Djuwita and evaluate its influence on the knowledge, attitudes, and self-efficacy of young women in maintaining their reproductive health. PMID- 29166184 TI - The Quarter Prone Position Increases Oxygen Saturation in Premature Infants Using Continuous Positive Airway Pressure. AB - A primary problem that occurs in premature infants is oxygenation disorders, thus requiring respiratory support, including continuous positive airway pressure (CPAP). The effectiveness of CPAP can be improved by adjusting the body's position, so the aim of this study was to examine the effect of the quarter prone position on the oxygenation status of preterm infants using CPAP. This study used a randomized controlled trial with a crossover design. A group of 15 preterm infants receiving CPAP was selected, and randomization of allocation was done to divide the respondents into the intervention group (quarter prone) or the control group (supine). Oxygenation status was measured using an observation form, and the result showed a significant difference in the oxygen saturation levels of premature infants using CPAP in the quarter prone group compared to that in the supine group (p = .045). The quarter prone position was effective for improving the oxygenation status of premature infants using CPAP. It is recommended that the quarter prone position be applied as part of nursing care in neonatal nursing. PMID- 29166185 TI - Could a Certain Sitting Position Reduce the Pain Experienced by a Child? The Benefits of Parental Holding and an Upright Position. AB - Intravenous injection is the most feared medical procedure and gives rise to an experience of mild to severe pain in children. Unrestrained pain has a negative effect on the child. Pain management in the form of a convenient sitting position is needed by children who undergo intravenous injection procedures. This study aims to determine the effect of parental holding and an upright position on children's pain during intravenous injection procedures. The study used the Randomized Clinical Trial method involving 34 respondents, aged 1-4 years, who were included in the intervention and control group. The result of a Mann-Whitney U test analysis showed a significant difference in the pain score between the intervention and control groups (p value = .000; alpha = .05). The parental holding and upright position can be applied as a nonpharmacological pain management strategy for children who undergo intravenous injection procedures. PMID- 29166186 TI - Medical-Device Related Pressure Injuries to Children in the Intensive Care Unit. AB - Medical devices that are attached to children put pressure on their skin or mucous membranes, and the devices can lead to injuries. The objective of this study was to determine the effectiveness of injury-prevention guidance about children who need to have medical devices attached to their bodies as part of their treatment. The research used a randomized controlled trial method, along with a cross-over design in 50 respondents with age ranges from 1 day to 18 years. The control group was treated in accordance to hospital routine, while the intervention group was given medical treatment based on Kiss and Heiler's guidelines. Skin assessment was conducted for 3 days. Incidence of Grade 1 pressure injuries on the respondent's skin or mucous membranes with a mean score of Neonatal Skin Risk Assessment Scale < 13 and average Braden Q score > 15 were observed. Health devices that caused pressure injuries on respondents were: ETT (13%), OGT (12%), NGT (11%), and SpO2 probe (6%). There were no significant differences between the control group and intervention group in terms of the number of pressure injury incidences. Skin trauma and pressure injuries caused by medical devices were within the low-risk category; therefore, nurses should not be complacent with the NSRAS and Braden Q scores in preventing pressure injuries. Further research is recommended to improve the power of related research and development in risk assessment of pressure injuries caused by medical devices in children. PMID- 29166187 TI - Cognitive Behavioral and Family Psychoeducational Therapies for Adolescent Inmates Experiencing Anxiety in a Narcotics Correctional Facility. AB - Illicit substance use is becoming a major global issue. In Indonesia, inmates imprisoned for illicit substance offences accounted for 40% of the total inmate population. This study aimed to identify the effects of cognitive behavioral and family psychoeducational therapies on inmates' anxiety in the narcotics correctional facility. Quasi-experimental pre-test-post-test with control group was employed in this study. Intervention Group 1 received a general nursing intervention whereas Intervention Group 2 received a combination of general nursing intervention with cognitive behavioral and family psychoeducational therapies. This study involved 31 inmates for each group. Data were collected using the Hamilton Anxiety Rating Scale (HAM-A) and were analyzed using repeated ANOVA and independent t-tests. The study demonstrated that anxiety was significantly lower among those who received the combination of those three therapies compared to those who received general nursing intervention standalone (p < .005). This study suggested the implementation of both general nursing intervention and specialty therapies, particularly cognitive behavioral and family psychoeducational therapies, to address the anxiety problems experienced by adolescent inmates suffering from illicit substance dependence. PMID- 29166188 TI - Enhancement of Pulmonary Tuberculosis Prevention Behavior With Role Play Among Elementary School Students. AB - Tuberculosis as an infectious disease is increasing in both the number of cases and severity of impact, and the number of cases among school-aged children is also increasing. Health promotion campaigns in schools have not been intensive, and there is poor behavior in tuberculosis prevention. Role play-playing roles actively with provided materials-is one health education method that can empower school-aged children to understand tuberculosis prevention. The purpose of this research is to identify the influence of role playing on tuberculosis transmission prevention in school-aged children. Study participants were 100 school-aged children. The study used quasi-experimental types of pre-test and post-test, with a control group. The t test results showed that improvement of tuberculosis prevention behaviors in the intervention group was higher than the control group (p value = .000). The role play method is recommended for health education for at least 6 sessions in school-aged children. PMID- 29166189 TI - The Utilization of Traditional Medicine to Treat Fever in Children in Western Javanese Culture. AB - Fever regularly affects toddlers and may make their parents uneasy. This study aimed to identify common traditional medicines used by parents to treat their children's fever at home. The study was conducted in Karyasari, Leuwiliang, Bogor District. It was descriptive in design, and the instrument used was a questionnaire developed by the authors. A group of 106 respondents was selected through the cluster sampling method. All respondents were female; the youngest was 20 years old, and the oldest was 53 years old. The majority of respondents had graduated from elementary and junior high school (93%), were currently unemployed (95%), and had a household income of less than Bogor's regional minimum wage (RMW) (91%). The majority of mothers (90.6%) identified fever through tactile perception. The most common traditional medicines used by respondents were onion (86.8%) mixed with oil (64.2%) and applied to the body (86.8%). The results of this study suggested the need for health education concerning the use of traditional medicine to treat fever. PMID- 29166190 TI - Comparison of Various Kangaroo Mother Care Carriers on Maternal Comfort: A Pilot Study. AB - Kangaroo mother care (KMC) is an evidence-based approach that has been scientifically proven to have a positive effect on mothers and infants. One of the barriers to performing KMC at home is the absence of a special KMC carrier. The most widely used KMC carriers in Indonesia are kangaroo pouch, thari, wrap and traditional wraps in the form of a long strip of fabric. This study's aim was to compare the level of maternal comfort when performing KMC with three different KMC carriers. The study used crossover design involving 20 mothers with low birth weight (LBW) infants as responders, selected through a consecutive sampling method. Data were collected using a maternal comfort questionnaire, maternal anxiety questionnaire, and KMC observation sheet. The results of repeated analysis of variance (ANOVA) showed that there was no significant difference in maternal comfort when performing KMC with any of three KMC carriers (maternal comfort p = .366, alpha = .05). Therefore, KMC can be implemented using any of the types of carriers including kangaroo pouch, thari wrap, and traditional wrap. PMID- 29166191 TI - The Pediatric Yorkhill Malnutrition Score Is a Reliable Malnutrition Screening Tool. AB - Children often experience malnutrition while they are hospitalized. Therefore, the prevention of malnutrition and nutritional management need to be done properly using malnutrition screening tools. This study aimed to determine the sensitivity and specificity of the Pediatric Yorkhill Malnutrition Score (PYMS) and the Screening Tool for the Risk of Impaired Nutritional Status and Growth (STRONGkids) when compared to the Subjective Global Nutritional Assessment for Children (SGNA). This study involved 81 pediatric patients with ages ranging from 1 to 16 years old. The two screening tools and the SGNA were examined in each subject. The results of this study determined that the sensitivity and specificity of the PYMS were 95.7% and 66.7%, respectively, while in the STRONGkids they were 52.2% and 41.7%, respectively. This indicates that the PYMS is the most appropriate malnutrition screening tool to be used for a malnutrition screening policy. PMID- 29166192 TI - Maternal Self-Efficacy of Pregnant Indonesian Teens: Development and Validation of an Indonesian Version of the Young Adult Maternal Confidence Scale and Measurement of Its Validity and Reliability. AB - Pregnant teens often feel uncertain in the last trimester about their ability to take care of their baby. At this time, maternal confidence in the ability to care for the baby is an important step in the preparation for becoming a mother. The purpose of this study was to examine the validity and reliability of an Indonesian version of the Young Adult Maternal Confidence Scale (YAMCS) as an instrument to measure maternal self-efficacy of pregnant teens in the last trimester. The study consisted of 90 pregnant teens, age of respondents less than 19 years and living in 1 of 3 sub-districts: Cilember, Sukamanah and Megamendung, Bogor Regency. West Java. All the participants completed a questionnaire based on the YAMCS to assess maternal self-efficacy. The YAMCS consists of 3 dimensions (perception of ability, uncertainty, and mothering behaviors) and 10 items. All items of the YAMCS had corrected item-total item correlation more than 0.3 and had 0.859 Cronbach's alpha scores. Based on the findings of this study, this questionnaire is a valid and reliable measure of maternal self-efficacy of pregnant teens in Indonesia. Health workers can use the questionnaire to assess the confidence of pregnant women, especially that of adolescents, in caring for their baby and being a good mother. PMID- 29166193 TI - Traditional Method of Initial Diarrhea Treatment in Children. AB - Diarrhea is the most common cause of death in children. For diarrhea, home treatment should be administered by parents to prevent diarrheal complications. The purpose of this research was to investigate the traditional method of diarrhea treatment in Tegal regency, Central Java, Indonesia. A descriptive study was conducted with the aim of describing the traditional method of home treatment for diarrhea in children. The study sample included families with children who were experiencing or had experienced diarrhea and had received traditional medicine. The participants were randomly selected based on cluster random sampling, and the results showed that traditional diarrheal treatment involved the use of Psidium guajava leaves, curcumic (turmeric), and tea. P. guajava leaves and curcumic were processed by pounding or shredding and then squeezing to obtain the extracts. Some of the respondents also added salt to the mixture. Most traditional medicine could be found in the garden or by purchase, and friends and family were the most common information resources. Most respondents assumed that traditional medicine was effective to treat diarrhea. It is expected that this research can provide information about diarrheal management by traditional method in the community. PMID- 29166194 TI - The Effects of Music Therapy on the Physiological Response of Asthmatic Children Receiving Inhalation Therapy. AB - The clinical manifestation of asthma in children can interfere with their daily activities. Music therapy may become one of the alternative approaches to making children feel comfortable during inhalation therapy. The aim of the study was to identify the effects of music therapy on the physiological response of asthmatic preschool and school-age children receiving inhalation therapy. This study used a quasi-experimental, nonequivalent control group with a pre-test-post-test design. The 44 respondents consisted of preschool and school-age children assigned to intervention and control groups. The results showed a significant difference in average oxygen saturation, heart rate, and respiratory rate between the control and intervention groups before and after intervention (p < alpha; alpha = .05). Music therapy can be used as a nursing intervention to improve the physiological response of children with breathing problems. PMID- 29166195 TI - The Experience of Young Women Living in a Prostitution Area in Maintaining Their Reproductive Health. AB - Young women face a difficult situation when they live in a prostitution area or red light district. A phenomenological approach was applied to explore the experiences in maintaining reproductive health of 10 young women living in the prostitution area in Lampung, one of the provinces in Sumatra. Thematic content analysis found 7 themes including: (1) The participants' perception of prostitution as a place of naughty women and free sexual activity that can transmit STDs and influence adolescent psychology; (2) The ways the participants kept their reproductive organs healthy were through maintaining friendships, maintaining personal hygiene, avoiding free sexual activity, eating healthy food, and having routine medical checkups; (3) Information support was gained from family, health workers, media, and teachers; (4) Emotional support from family and friends; (5) Barriers to maintaining good health were inaccessible health facilities and an underfunded health service; (6) The needs of the participants were reproductive health services and clean environment; (7) The participants hoped for health education and intensive health services with friendly nurses. The results of this research illustrate that there is a need for socializing intensive ways to maintain reproductive health, especially in a risky environment. PMID- 29166196 TI - SETIA Health Education Set Enhances Knowledge, Attitude, and Parenting Self Efficacy Score in Postpartum Adolescent Mothers. AB - The lack of readiness in assuming the role of a mother causes many adolescent mothers to decide not to breastfeed their babies. This study was conducted to assess the effect of the SETIA health education set on adolescent mothers' knowledge, attitude, and parenting self-efficacy score. This quasi-experimental pre-test-post-test with control group study was conducted on 66 adolescent mothers, 33 participants in each group. Data collecting used knowledge and attitude questionnaires and the Parenting Self-Efficacy Scale (PSES). This study revealed that there was a significant difference before and after intervention in knowledge, attitude, and PSE score on postpartum adolescent mothers (p = .045; p = .013; p = .001 respectively). There was an increase in knowledge >= 20%, attitude >=10%, parental self-efficacy >= 10%, and a difference between control and intervention group (p = .001 with 95% CI: 3.587-44.876, p = .001 with 95% CI: 4.954-56.397, p = .001 respectively). Logistic regression analysis found that postpartum adolescent mothers who receive SETIA are 12.687 times more likely to have better knowledge after being controlled for mother's age and education and 0.248 times more likely to have a higher PSES score after being controlled for mother's age, education, and husband's work status than their counterpart. This study recommends the use of the SETIA health education set to provide postpartum education to adolescent mothers. PMID- 29166197 TI - Combining Natural Ingredients and Beliefs: The Dayak Tribe's Experience Caring for Sick Children with Traditional Medicine. AB - Instead of seeking conventional health care, the Dayak tribe in Borneo, Indonesia, treats sick children at home with traditional medicine. The objective of this descriptive, qualitative study was to explore the Dayak tribe's use of traditional medicine to care for sick children. Comprehensive interviews were conducted with 10 caregivers, with collected data analyzed using content analysis. Key recurring themes identified were: 1) traditional medicine as first aid; 2) ease of access and cost-effectiveness; 3) traditional medicine was not always effective; 4) a combination of natural ingredients and beliefs; 5) the importance of "communicating" with plants; and 6) engagement with metaphysical forces. Health professionals should respect familial cultures' beliefs regarding the provision of health care at home. Furthermore, they need to develop competency in performing cultural assessments and providing information to these parents on the risks of not seeking professional emergency care for children with conditions that can't be handled at home with traditional medicine. PMID- 29166198 TI - Heat Loss Prevention Education Aids Nurses' Knowledge in Prevention of Hypothermia in Newborns. AB - Newborns are at risk of developing hypothermia due to the instability of their thermoregulation systems and inability to adjust to changes in ambient temperature. This risk increases during hospitalization. Education is a strategy to improve nurses' understanding of the prevention of hypothermia in newborns in the hospital. This study aimed to analyze the impact of education about preventing heat loss on nurses' knowledge and behavior in preventing hypothermia in newborns. The study design was a quasi-experiment with one group pre-test-post test and a total sample of 21 neonatal nurses who were selected using the consecutive sampling method. The results indicated that there was significant difference in nurses' knowledge and behavior pre- and post-education intervention (p < .001; alpha = .05). This study suggests that education on prevention of heat loss is an effective strategy to promote nurses' knowledge and behavior in preventing hypothermia. PMID- 29166199 TI - Differences in Temperature Changes in Premature Infants During Invasive Procedures in Incubators and Radiant Warmers. AB - Premature infants tend to lose heat quickly. This loss can be aggravated when they have received an invasive procedure involving a venous puncture. This research uses crossover design by conducting 2 intervention tests to compare 2 different treatments on the same sample. This research involved 2 groups with 18 premature infants in each. The process of data analysis used a statistical independent t test. Interventions conducted in an open incubator showed a p value of .001 which statistically related to heat loss in premature infants. In contrast, the radiant warmer p value of .001 statistically referred to a different range of heat gain before and after the venous puncture was given. The radiant warmer saved the premature infant from hypothermia during the invasive procedure. However, it is inadvisable for routine care of newborn infants since it can increase insensible water loss. PMID- 29166200 TI - Effect of Audiovisual Distraction on Distress and Oxygenation Status in Children Receiving Aerosol Therapy. AB - Aerosol therapy, a treatment for children with disorders of the respiratory system, often causes distress, especially in young children. Distress during aerosol therapy can decrease the effectiveness of the treatment. This study aimed to determine the effect of audiovisual distraction on distress levels and oxygenation status (measured by oxygen saturation and respiratory frequency) in children who receive aerosol therapy for disorders of the respiratory system. A quasi-experimental design was employed, specifically a non-equivalent control group, pre-test-post-test design. The study sample consisted of 38 children who were divided into 2 groups (control and intervention), each group consisting of 19 children. The results of this study showed that there were significant differences in distress scores between the control group and the intervention group (p = .0001). There were also significant differences in the mean value changes in oxygenation status before and after intervention between the control and intervention groups. These findings could be used to prevent distress and increase oxygenation status in children who receive aerosol therapy. PMID- 29166201 TI - Warm Water Compress as an Alternative for Decreasing the Degree of Phlebitis. AB - Intravenous fluid therapy is an invasive procedure which may increase the risk of patient complications. One of the most common of these is phlebitis, which may cause discomfort and tissue damage. Therefore, a nursing intervention is needed to effectively treat phlebitis. The purpose of this study was to investigate the effectiveness of applying a warm compression intervention to reduce the degree of phlebitis. A quasi-experimental pre-test and post-test design was used, with a non-equivalent control group. The total sample size was 32 patients with degrees of phlebitis ranging from 1 to 4. The total sample was divided into 2 interventional groups: those patients that were given 0.9% NaCl compresses and those given warm water compresses. The results showed that both compresses were effective in reducing the degree of phlebitis, with similar p values (p = .000). However, there was no difference in the average reduction score between the two groups (p = .18). Therefore, a warm water compress is valuable in the treatment of phlebitis, and could decrease the degree of phlebitis both effectively and inexpensively. PMID- 29166202 TI - The Effectiveness of Distraction (Cartoon-Patterned Clothes and Bubble-Blowing) on Pain and Anxiety in Preschool Children during Venipuncture in the Emergency Department. AB - In preschool children, venipuncture is considered a bodily threat that can cause pain and anxiety, as well as being a traumatic experience. If the pain and anxiety felt by a child during a venipuncture is not addressed properly, it can result in a traumatic experience, and traumatic events in childhood can have long term consequences. Atraumatic treatment in the emergency department has been little explored in previous research; therefore, the present study assessed the effectiveness of using the distractions of cartoon-patterned clothes and bubble blowing on the pain and anxiety of preschool children during venipuncture in the emergency department. This was a quasi-experiment that used a post-test only, control group design approach. The sample consisted of 57 preschool children who were due to undergo venipuncture and who were divided into 3 intervention groups. The results showed that distraction using bubble-blowing is effective in reducing pain and anxiety during venipuncture, while cartoon-patterned clothing is only effective in reducing anxiety. Distractions can refocus the attention of a child away from pain and anxiety during venipuncture. It can inhibit the transmission of pain impulses, such that these impulses are not transmitted to the brain. As a result, the sensation of pain is not experienced. PMID- 29166203 TI - Temporal profile of care following mild traumatic brain injury: predictors of hospital admission, follow-up referral and six-month outcome. AB - OBJECTIVE: To investigate the clinical management and medical follow-up of patients with mild traumatic brain injury (mTBI) presenting to emergency departments (EDs). METHODS: Overall, 168 adult patients with mTBI from the prospective, multicentre Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study with Glasgow Coma Scale (GCS) 13-15, no polytrauma and alive at six months were included. Predictors for hospital admission, three-month follow-up referral and six-month functional disability (Glasgow Outcome Scale Extended (GOSE) <= 6) were analysed using multivariable regression. RESULTS: Overall, 48% were admitted to hospital, 22% received three-month referral and 27% reported six-month functional disability. Intracranial pathology on ED head computed tomography (multivariable odds ratio (OR) = 81.08, 95% confidence interval (CI) [10.28-639.36]) and amnesia (>30-minutes: OR = 5.27 [1.75-15.87]; unknown duration: OR = 4.43 [1.26-15.62]) predicted hospital admission. Older age (per-year OR = 1.03 [1.01-1.05]) predicted three-month referral, while part time/unemployment predicted lack of referral (OR = 0.17 [0.06-0.50]). GCS < 15 (OR = 2.46 [1.05-5.78]) and prior history of seizures (OR = 3.62 [1.21-10.89]) predicted six-month functional disability, while increased education (per-year OR = 0.86 [0.76-0.97]) was protective. CONCLUSIONS: Clinical factors modulate triage to admission, while demographic/socioeconomic elements modulate follow-up care acquisition; six-month functional disability associates with both clinical and demographic/socioeconomic variables. Improving triage to acute and outpatient care requires further investigation to optimize resource allocation and outcome after mTBI. ClinicalTrials.gov registration: NCT01565551. PMID- 29166205 TI - Pregnant women with heart disease: Placental characteristics and their association with fetal adverse events. AB - BACKGROUND: Pregnant women with heart disease (HD) have higher rates of adverse fetal outcomes. We describe placental pathologic characteristics and their association with fetal events. METHODS: In pregnant women, known HD were categorized into: (1) cardiomyopathy (CM) or (2) other HD (congenital, coronary, arrhythmia, or valvular). Outcomes were maternal major adverse cardiac events (MACE), fetal adverse clinical events (FACE), a composite of infant death, prematurity, underweight status, intracranial hemorrhage, and respiratory distress. Only pathologically reported placental analyses were included. RESULTS: We studied 86 pregnancies in women with CM and HD, with pathologic analyses on 35 CM and 52 HD placentas. CM placentas, compared with those with HD, were more likely to have ischemic changes (65.7% vs. 37%, p 0.008), demonstrate immaturity (62.90% vs. 10%, p < 0.001), and have a lower weight (p < 0.001), despite similar gestational age. CM was independently associated with increased risk for MACE (OR 7.38, 95%CI 2.20-24.76). Ischemic placental changes were associated with increased odds of FACE (OR 24.78, 95%CI 2.37-259.03). CONCLUSIONS: Women with CM were more likely to have ischemic placentas, with lower placental and fetal weights, and evidence of immaturity compared with those with other forms of HD, and an increased odds of MACE. PMID- 29166207 TI - Human Vaccines & Immunotherapeutics: News. PMID- 29166208 TI - Letter from the editor. PMID- 29166209 TI - The SexFlex Scale: A Measure of Sexual Script Flexibility When Approaching Sexual Problems in a Relationship. AB - The objective of this paper was to develop a measure of sexual script flexibility when approaching a sexual problem in a relationship. A series of online studies were conducted with individuals in relationships. As one subscale on the two factor model had poor convergent and discriminant validity, a final single factor scale with 6-items was retained. The single factor scale demonstrated good model fit, high internal reliability, adequate convergent and discriminant validity, and moderate test re-test reliability. These results support the SexFlex scale as a reliable and psychometrically sound assessment of an individual.s flexibility in approaching a sexual problem. PMID- 29166210 TI - Improving Spiritual Care in Hospitals in the Netherlands: What Do Health Care Chaplains Involved in an Action-Research Study Report? AB - Health care chaplains participated in a multicenter trial to explore an implementation strategy for the Dutch multidisciplinary guideline for spiritual care. The intervention was concise spiritual care training for hospital staff of departments where patients in curative and palliative trajectories are treated. Data were collected in semistructured interviews with chaplains who acted as trainers, before and after the intervention. Results based on nine preintervention and eleven post-intervention interviews are presented. During preintervention interviews, chaplains describe the baseline situation of palliative care in Dutch hospitals, barriers, and opportunities for improving spiritual care. In the postintervention interviews, characteristics of the training, effects, and critical success factors were identified. Positive effects such as lowering barriers, increasing health care professionals' competences, and increasing health care chaplains' profile are possible. Chaplain-led, multidisciplinary spiritual care training is a feasible method to start implementation of spiritual care in hospitals, as described in the multidisciplinary guideline. PMID- 29166211 TI - Tobacco Use, Medical Illness, and Service Utilization. PMID- 29166212 TI - Hispanic Populations, Veterans, and Symptom Assessment. PMID- 29166213 TI - Relationship of PTSD With impulsivity Dimensions While Controlling the Effect of Anxiety and Depression in a Sample of Inpatients With Alcohol Use Disorder. AB - OBJECTIVE: The aim of the present study was to evaluate the relationship of posttraumatic stress disorder (PTSD) with impulsivity dimensions while controlling the effect of anxiety and depression in a sample of inpatients with alcohol use disorder (AUD). METHODS: Participants were 190 male patients admitted to a specialized center for substance use disorders within a six month period. Participants were evaluated with the State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), the Short Form Barratt Impulsiveness Scale (BIS-11 SF), the Traumatic Experiences Checklist, and PTSD Checklist-Civilian version. RESULTS: Age was lower in the group with PTSD (n = 63, 33.2%) than the group without PTSD (n = 127, 66.8%). Duration of education, marital, and employment status did not differ between the groups. STAI, BDI, and BIS-11-SF scores were higher in the group with PTSD. Trait anxiety, depression, and impulsivity predicted high PTSD risk in a logistic regression model. Same variables predicted the severity of PTSD symptoms in a linear regression. Among dimensions of impulsivity attentional component was the only predictor of PTSD symptoms severity, not motor or nonplanning impulsivity. CONCLUSIONS: These findings suggest that the PTSD may be related to impulsivity, particularly attentional impulsivity, even after controlling anxiety and depression among inpatients with AUD. PMID- 29166214 TI - Gaming out online: Black lesbian identity development and community building in Xbox Live. AB - As gaming culture continues to marginalize women and people of color, other gamers are also highlighting the inequalities they face within digital gaming communities. While heterosexism and homophobia are commonplace within gaming culture, little is known about the actual experiences of "gaymers" and even less about "gaymers" of color. As such, this article seeks to explore lesbians of color and their experiences "gayming" out and online. Exploring identity development, community building, and connectivity via social networking, the women within this study articulate what it means to be lesbian online and how this impacts their physical and digital experiences. The private spaces within gaming culture that many marginalized groups inhabit are the few spaces that value the articulation of marginalized interests and viewpoints. Ethnographic observations reveal how supportive communities can improve resilience by mitigating the effects of stereotyping, microaggressions, and other discriminatory practices in online gaming. PMID- 29166215 TI - Interoception and Awareness of Physiological Sexual Arousal in Women With Sexual Arousal Concerns. AB - Laboratory studies assessing physiological genital arousal have largely failed to find differences between women with and without female sexual arousal disorder (FSAD). Therefore, it is possible that women with FSAD may be unaware of their genital arousal response. The present study examined the extent to which women with FSAD can report their genital arousal response, as well as the role of interoception (body awareness) in this relationship. Additionally, this study examined the influence of interoception on the relationship between subjective and genital arousal. Twenty-six women who met criteria for FSAD (M age = 29.5, SD = 8.1 years) watched an erotic film and completed a series of questionnaires. Physiological (i.e., genital) and perceived genital arousal were measured continuously throughout the film. Results indicated women were able to perceive their level of physiological arousal. Greater levels of interoception were linked with stronger relationships between perceived and physiological arousal, but not between subjective and genital arousal. Methodological and clinical implications are discussed. PMID- 29166216 TI - Mommy markets: Racial differences in lesbians' dating preferences for women with children. AB - Recent work shows that race is a critical factor in shaping sexual identities, partner preference, and family formation, suggesting there may be racial differences in whether lesbians already have children at the time that they look for companions. In this study, we draw on a sample of 1,923 lesbians on Match.com to quantitatively test whether there are racial differences in dating preferences for women with children, underscoring implications for family inequality through racial differences in who has children when looking for a partner. We find that Blacks, Latinas, and Asians are more likely than Whites to not only have children but also be open to dating other women with children. This suggests that race differentially structures lesbians' openness to partners with children, and such preferences may be a possible mechanism for racial stratification. PMID- 29166217 TI - The Radiologist's Primer to Imaging the Noncuff, Nonlabral Postoperative Shoulder. AB - Many radiologists are familiar with the preoperative imaging assessment of patients with labral tears, rotator cuff abnormalities, and end-stage arthritis, as well as the subsequent primary reconstructions and repairs commonly encountered in routine clinical management. However, the second-line surgical procedures and augmentation procedures performed for refractory or recurrent shoulder instability and the extra-articular surgical procedures of the shoulder girdle may challenge even the most experienced musculoskeletal radiologist. Knowledge of the indications, surgical techniques, expected postoperative imaging appearance, and complications of these uncommon shoulder girdle reconstructions and repairs will aid the radiologist in both the pre- and postoperative assessment of the injured shoulder. This article is divided into two parts. In the first part, procedures performed for shoulder instability are addressed, including capsular shift, Bristow-Latarjet coracoid transfer, remplissage, and humeral head allografts. In the second part, the imaging findings of extra articular procedures of the shoulder girdle are reviewed, including biceps tenodesis, os acromiale fixation, and coracoclavicular ligament reconstruction. (c)RSNA, 2017. PMID- 29166218 TI - The effect of stereotype content on intergroup uncertainty and interactions. AB - Drawing on intergroup threat theory and the stereotype content model, we examine intergroup relations in an organizational context. We surveyed 108 Asian immigrants working at a large international organization located in the United Kingdom. We found that perceptions of warmth and competence interact to predict minority group members' willingness to interact with an outgroup majority. Extending previous research, we demonstrate that warmth and competence differentially affect intergroup uncertainty, which mediates the relationship between stereotype content and willingness to interact with the outgroup. Three novel aspects of this research contribute to the existing literature: (1) the focus on stereotype content eliciting intergroup emotions; (2) examining the thoughts and feelings of a minority group (Asian immigrants) toward the majority group (British citizens); (3) the organizational context of the sample presents a real-world situation. PMID- 29166219 TI - To be kind or not to be kind: The moderating role of self-compassion in the relationship between general resourcefulness and academic self-regulation. AB - We investigated whether the relationship between students' general resourcefulness and academic self-regulation changes as a function of self compassion. A predominantly female sample of 196 undergraduates completed inventories assessing these and other measures. The significant moderating effect of self-compassion revealed that the positive relationship between general resourcefulness and academic self-regulation was stronger for participants scoring low in self-compassion than high in self-compassion. For those low in self-compassion, scoring low in general resourcefulness was associated with the lowest academic self-regulation, whereas scoring high in general resourcefulness was associated with the greatest academic self-regulation. The positive relationship between general and academic self-regulation was attenuated for participants high in self-compassion, with predicted scores for academic self regulation falling in between the two values described for the low self compassion function. Implications of the findings are discussed, including the potential value of incorporating self-compassion training alongside programs aimed at increasing general resourcefulness and academic self-regulation. PMID- 29166220 TI - Does the Cognitive Reflection Test actually capture heuristic versus analytic reasoning styles in older adults? AB - : Background/Study Context: This study evaluated adult age differences in the original three-item Cognitive Reflection Test (CRT; Frederick, 2005, The Journal of Economic Perspectives, 19, 25-42) and an expanded seven-item version of that test (Toplak et al., 2013, Thinking and Reasoning, 20, 147-168). The CRT is a numerical problem-solving test thought to capture a disposition towards either rapid, intuition-based problem solving (Type I reasoning) or a more thoughtful, analytical problem-solving approach (Type II reasoning). Test items are designed to induce heuristically guided errors that can be avoided if using an appropriate numerical representation of the test problems. METHODS: We evaluated differences between young adults and old adults in CRT performance and correlates of CRT performance. Older adults (ages 60 to 80) were paid volunteers who participated in experiments assessing age differences in self-regulated learning. Young adults (ages 17 to 35) were students participating for pay as part of a project assessing measures of critical thinking skills or as a young comparison group in the self-regulated learning study. RESULTS: There were age differences in the number of CRT correct responses in two independent samples. Results with the original three-item CRT found older adults to have a greater relative proportion of errors based on providing the intuitive lure. However, younger adults actually had a greater proportion of intuitive errors on the long version of the CRT, relative to older adults. Item analysis indicated a much lower internal consistency of CRT items for older adults. CONCLUSION: These outcomes do not offer full support for the argument that older adults are higher in the use of a "Type I" cognitive style. The evidence was also consistent with an alternative hypothesis that age differences were due to lower levels of numeracy in the older samples. Alternative process-oriented evaluations of how older adults solve CRT items will probably be needed to determine conditions under which older adults manifest an increase in the Type I dispositional tendency to opt for superficial, heuristically guided problem representations in numerical problem-solving tasks. PMID- 29166221 TI - The Relationship Between Perceived Parenting, Negative Core Beliefs, and Dysfunctional Attitudes Among Young Adults. AB - Previous studies have found that perceived parenting is associated with dysfunctional attitudes that predict depression. However, few studies have empirically investigated processes by which perceived parenting is associated with dysfunctional attitudes. To fill this gap, this study tested the hypothesis that perceived low parental care would be associated with negative core beliefs, which, in turn, would be associated with dysfunctional attitudes. To strictly test the hypothesis, this study controlled for current depressive symptoms that could affect the relationships between study variables. The participants were 305 college students (141 females). The results differed by sex: for female students, the hypothesis was supported; for male students, negative core beliefs were associated with dysfunctional attitudes; however, perceived low care was not associated with negative core beliefs. The findings suggest that targeting low parental care and negative core beliefs for females and negative core beliefs for males may help prevent their dysfunctional attitudes and the resultant depression. PMID- 29166223 TI - A Follow-Up Study of a Reminiscence Intervention and Its Effects on Depressed Mood, Life Satisfaction, and Well-Being in the Elderly. AB - The purpose of this study was to investigate the extent to which a reminiscence intervention reduces depressed mood and improves life satisfaction and psychological well-being. 160 healthy elderly people participated in a 10-session intervention. An experimental design with pretest and posttest evaluations was applied, comparing a control group to an intervention group to evaluate the effects of the program. Follow-up measures were also taken to find out whether the intervention's positive effects lasted over time. Mixed Model ANOVAs showed significant increases in the time-group interaction, life satisfaction, and psychological well-being measures, and decreases in depressed mood, after treatment. The effects remained after three months in the case of life satisfaction and some dimensions of psychological well-being, but they were lower on depressed mood. This study provides additional support for the effectiveness of a reminiscence program as a useful intervention to improve the quality of life of older adults. PMID- 29166224 TI - A Reanalysis of Occupation and Suicide: Negative Perceptions of the Workplace Linked to Suicide Attempts. AB - Suicide is the ultimate outcome of poor psychological well-being; however, there is a paucity of research examining the link between occupation and suicide, despite early academic interest and the known importance of work to our everyday lives. We propose that this body of research was abandoned prematurely, and we provide a reanalysis by integrating the Job Characteristics Model and the Conservation of Resources model with extant suicide research. Specifically, we hypothesize that work design characteristics (job autonomy, task variety, physical demands) and threats to personal resources (absence of viewing work-as career, work-family conflict, family-work conflict, job dissatisfaction) are linked to suicide attempts via depression and suicidal ideation. Utilizing three measurement occasions and 2,855 participants from the AddHealth database, our findings indicate that job autonomy, task variety, work-family conflict, family work conflict, and job dissatisfaction all indirectly contribute to employees' suicide attempts via depression and suicidal ideation. Thus, negative employee perceptions of the workplace environment have much more severe consequences than is typically examined. Based on these results, we provide recommendations for developing a theoretically derived nomological net around suicidal behavior in an organizational context, and offer strategies for managers and employees to construct a work environment that is conducive to employee well-being. PMID- 29166225 TI - Big Five Personality Factors and Facets as Predictors of Openness to Diversity. AB - Openness to diversity is a crucial component of cultural competence needed in the increasingly diversified modern society and a necessary condition for benefitting from diversity contacts and interventions (e.g., diversity training, cultural courses). Responding to the recent call for more research on personality and its relation to diversity outcomes, we examined the associations between Big Five personality (i.e., Openness to Experience, Agreeableness, Extraversion, Neuroticism, and Conscientiousness) higher order factors and lower order facets and universal-diverse orientation (i.e., open attitude of appreciating human universality and diversity; Miville et al., 1999 ). In the Study 1 (N = 338) web survey on Big Five factors, Openness to Experience and Agreeableness were associated with universal-diverse orientation significantly. In the Study 2 (N = 176) paper survey on both Big Five factors and facets, Openness to Experience, low Neuroticism, and Conscientiousness, and various lower-order facets of all the Big Five personality were associated with universal-diverse orientation significantly. Practical implications were suggested on how personality facets could be incorporated into current diversity interventions to enhance their effectiveness of promoting openness to diversity. PMID- 29166226 TI - The Origins of Fears of Compassion: Shame and Lack of Safeness Memories, Fears of Compassion and Psychopathology. AB - Empirical and clinical research suggests that some individuals find self generating compassion and receiving compassion from others difficult and aversive. However, it is unclear how these fears of compassion are linked to early experiences and to psychopathological symptoms. This study explores the relationship between shame traumatic memories, centrality of shame memories, early memories of warmth and safeness, fears of compassion, and depression, anxiety and paranoid symptoms. Participants were 302 individuals from the general community population, who completed self-report measures of fears of compassion, shame memories, early affiliative memories, and psychopathology. Shame traumatic and central memories were positively associated with fears of compassion for self, for others and from others, whereas early memories of warmth and safeness were negatively related to such fears. Path analyses revealed that fears of compassion for self and of receiving compassion from others mediated the effects of shame traumatic memory, centrality of shame memory and early memories of warmth and safeness on depressive, anxious and paranoid symptoms. These findings have implications for therapeutic interventions as these fears, as well as the negative shame-based emotional memories fuelling them, may need to be addressed in therapy to assist patients in self-generating and receiving compassion. PMID- 29166227 TI - The Impact of Attachment Style on Sexual Satisfaction and Sexual Desire in a Sexually Diverse Sample. AB - Research has indicated that adult romantic attachment is influential and important to sexual and relationship satisfaction. Sexual desire, although not a direct focus of attachment literature, is highly related to sexual and relationship satisfaction, suggesting it may also be impacted by attachment style in romantic couples. However, the research conducted on sexual desire, sexual satisfaction, and attachment has been largely heterocentric, making it difficult to determine whether the findings documented in the literature thus far are relevant in a sexually diverse group of individuals. The current study aimed to better understand the way that attachment style may impact sexual desire, sexual satisfaction, and relationship satisfaction in a sample of sexually diverse men and women. In total, 955 individuals (63.4% cisgender women, 30.7% cisgender men, 6.0% genderqueer, 54.8% straight, 20.4% bisexual, 18.4% gay) participated in a web-based study examining relationship dynamics. Three multivariate regression models indicated that attachment style significantly predicted relationship satisfaction (29% of variance accounted for), sexual satisfaction (19% of variance accounted for), and sexual desire (4% of variance accounted for). Attachment style appears to be a more important contributing factor to satisfaction than desire among diverse sexual orientations. Clinical implications and future directions are discussed. PMID- 29166229 TI - Case 36-2017. A 30-Year-Old Man with Fatigue, Rash, Anemia, and Thrombocytopenia. PMID- 29166230 TI - Strawberry Gingivitis in Granulomatosis with Polyangiitis. PMID- 29166231 TI - Porphyria. PMID- 29166232 TI - Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. PMID- 29166233 TI - Reduction of Loa loa Microfilaremia with Imatinib - A Case Report. PMID- 29166234 TI - Intensive Blood-Pressure Treatment and Patient-Reported Outcomes. PMID- 29166235 TI - Management of Acute Hip Fracture. PMID- 29166236 TI - Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. PMID- 29166237 TI - A Slick and Stretchable Surgical Adhesive. PMID- 29166238 TI - Shiga Toxin-Producing E. coli Infections Associated with Flour. AB - BACKGROUND: In 2016, a multijurisdictional team investigated an outbreak of Shiga toxin-producing Escherichia coli (STEC) serogroup O121 and O26 infections linked to contaminated flour from a large domestic producer. METHODS: A case was defined as infection with an outbreak strain in which illness onset was between December 21, 2015, and September 5, 2016. To identify exposures associated with the outbreak, outbreak cases were compared with non-STEC enteric illness cases, matched according to age group, sex, and state of residence. Products suspected to be related to the outbreak were collected for STEC testing, and a common point of contamination was sought. Whole-genome sequencing was performed on isolates from clinical and food samples. RESULTS: A total of 56 cases were identified in 24 states. Univariable exact conditional logistic-regression models of 22 matched sets showed that infection was significantly associated with the use of one brand of flour (odds ratio, 21.04; 95% confidence interval [CI], 4.69 to 94.37) and with tasting unbaked homemade dough or batter (odds ratio, 36.02; 95% CI, 4.63 to 280.17). Laboratory testing isolated the outbreak strains from flour samples, and whole-genome sequencing revealed that the isolates from clinical and food samples were closely related to one another genetically. Trace-back investigation identified a common flour-production facility. CONCLUSIONS: This investigation implicated raw flour as the source of an outbreak of STEC infections. Although it is a low-moisture food, raw flour can be a vehicle for foodborne pathogens. PMID- 29166240 TI - More on Anti-CD19 CAR T Cells in CNS Diffuse Large-B-Cell Lymphoma. PMID- 29166239 TI - Molluscum Contagiosum in a Patient with Atopic Dermatitis. PMID- 29166241 TI - Two Classes of Secreted Synaptic Organizers in the Central Nervous System. AB - Research in the last two decades has identified many synaptic organizers in the central nervous system that directly regulate the assembly of pre- and/or postsynaptic molecules, such as synaptic vesicles, active zone proteins, and neurotransmitter receptors. They are classified into secreted factors and cell adhesion molecules, such as neurexins and neuroligins. Certain secreted factors are termed extracellular scaffolding proteins (ESPs) because they are components of the synaptic extracellular matrix and serve as a scaffold at the synaptic cleft. These include Lgi1, Cbln1, neuronal pentraxins, Hevin, thrombospondins, and glypicans. Diffusible secreted factors, such as Wnts, fibroblast growth factors, and semaphorins, tend to act from a distance. In contrast, ESPs remain at the synaptic cleft and often help synaptic adhesion and/or accumulation of postsynaptic receptors. Many fundamental questions remain about when, how, and why various synaptic organizers establish and modify the vast numbers of connections during development and throughout life. PMID- 29166242 TI - Dynamism of an Astrocyte In Vivo: Perspectives on Identity and Function. AB - Astrocytes are an abundant and evolutionarily conserved central nervous system cell type. Despite decades of evidence that astrocytes are integral to neural circuit function, it seems as though astrocytic and neuronal biology continue to advance in parallel to each other, to the detriment of both. Recent advances in molecular biology and optical imaging are being applied to astrocytes in new and exciting ways but without fully considering their unique biology. From this perspective, we explore the reasons that astrocytes remain enigmatic, arguing that their responses to neuronal and environmental cues shape form and function in dynamic ways. Here, we provide a roadmap for future experiments to explore the nature of astrocytes in situ. PMID- 29166244 TI - Precision Medicine from a Public Health Perspective. AB - Over the past decade, precision medicine (PM) approaches have received significant investment to create new therapies, learn more about disease processes, and potentially prevent diseases before they arise. However, in many ways, PM investments may come at the expense of existing public health measures that could have a greater impact on population health. As we tackle burgeoning public health concerns, such as obesity, and chronic diseases, such as cancer, it is not clear whether PM is aligned with public health or in conflict with its goals. We summarize the areas of promise demonstrated by PM, discuss the limitations of each of these areas from a population health perspective, and discuss how we can approach PM in a manner that is congruent with the core aims of public health. PMID- 29166243 TI - Building Capacity for Evidence-Based Public Health: Reconciling the Pulls of Practice and the Push of Research. AB - Timely implementation of principles of evidence-based public health (EBPH) is critical for bridging the gap between discovery of new knowledge and its application. Public health organizations need sufficient capacity (the availability of resources, structures, and workforce to plan, deliver, and evaluate the preventive dose of an evidence-based intervention) to move science to practice. We review principles of EBPH, the importance of capacity building to advance evidence-based approaches, promising approaches for capacity building, and future areas for research and practice. Although there is general agreement among practitioners and scientists on the importance of EBPH, there is less clarity on the definition of evidence, how to find it, and how, when, and where to use it. Capacity for EBPH is needed among both individuals and organizations. Capacity can be strengthened via training, use of tools, technical assistance, assessment and feedback, peer networking, and incentives. Modest investments in EBPH capacity building will foster more effective public health practice. PMID- 29166245 TI - Evidence Supporting LI-RADS Major Features for CT- and MR Imaging-based Diagnosis of Hepatocellular Carcinoma: A Systematic Review. AB - The Liver Imaging Reporting and Data System (LI-RADS) standardizes the interpretation, reporting, and data collection for imaging examinations in patients at risk for hepatocellular carcinoma (HCC). It assigns category codes reflecting relative probability of HCC to imaging-detected liver observations based on major and ancillary imaging features. LI-RADS also includes imaging features suggesting malignancy other than HCC. Supported and endorsed by the American College of Radiology (ACR), the system has been developed by a committee of radiologists, hepatologists, pathologists, surgeons, lexicon experts, and ACR staff, with input from the American Association for the Study of Liver Diseases and the Organ Procurement Transplantation Network/United Network for Organ Sharing. Development of LI-RADS has been based on literature review, expert opinion, rounds of testing and iteration, and feedback from users. This article summarizes and assesses the quality of evidence supporting each LI-RADS major feature for diagnosis of HCC, as well as of the LI-RADS imaging features suggesting malignancy other than HCC. Based on the evidence, recommendations are provided for or against their continued inclusion in LI-RADS. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29166246 TI - Imaging Features of Gadoxetic Acid-enhanced and Diffusion-weighted MR Imaging for Identifying Cytokeratin 19-positive Hepatocellular Carcinoma: A Retrospective Observational Study. AB - Purpose To determine the preoperative magnetic resonance (MR) imaging findings potentially most useful for predicting cytokeratin 19 (CK19)-positive hepatocellular carcinoma (HCC) and to evaluate the prognosis after curative resection in patients with a single HCC lesion positive for CK19 compared with patients with HCC who are negative for CK19. Materials and Methods The institutional review board approved this study and waived the requirement for informed consent. Two hundred four patients with CK19-negative HCC and 38 with CK19-positive HCC who underwent curative resection after gadoxetic acid-enhanced and diffusion-weighted MR imaging were retrospectively evaluated in a single institution. Two radiologists evaluated preoperative findings at MR imaging. Significant findings for differentiating the two groups were identified at univariate and multivariate analyses. By using receiver operating characteristic analysis, the optimal cut-off values for quantitative variables were determined. Recurrence-free survival rates after surgery were also compared between groups. Results At multivariate analysis, irregular tumor margin (P = .024), arterial rim enhancement (P < .001), lower tumor-to-liver signal intensity (SI) ratio on hepatobiliary phase (HBP) images (<=0.522; P = .01), and lower tumor-to-liver apparent diffusion coefficient (ADC) ratio (<=0.820; P < .001) were independent significant factors to predict CK19-positive HCC. When three of these four criteria were combined, 63.2% (24 of 38; 95% confidence interval: 46.0%, 78.2%) of CK19-positive HCCs were identified with a specificity of 90.7% (185 of 204; 95% confidence interval: 46.0%, 78.2%). When all four criteria were satisfied, specificity was 99.5% (203 of 204; 95% confidence interval: 97.3%, 100%). Recurrence-free survival rates were significantly lower in patients with CK19 positive HCCs compared with those with CK19-negative HCCs after curative resection (63.9% vs 90.0% at 1 year, 63.9% vs 79.9% at 2 years, and 54.8% vs 70.2% at 3 years, P = .001 by log-rank test). Conclusion At gadoxetic acid enhanced and diffusion-weighted MR imaging, irregular margin, arterial phase rim enhancement, lower tumor-to-liver ADC ratio, and lower tumor-to-liver SI ratio at HBP imaging may be helpful to predict CK19-positive HCC with early recurrence (<2 years) after curative resection. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29166247 TI - Does Sodium Knowledge Affect Dietary Choices and Health Behaviors? Results From a Survey of Los Angeles County Residents. AB - INTRODUCTION: In 2010, the Los Angeles County Department of Public Health launched a local sodium-reduction initiative to address the rising prevalence of high blood pressure (hypertension) and related cardiovascular conditions in the population. To inform this effort, we evaluated self-reported knowledge and health behaviors related to sodium intake among Los Angeles County residents. METHODS: We administered 3 cross-sectional Internet panel surveys on knowledge about dietary sodium to a sample of Los Angeles County adults, at intervals from December 2014 through August 2016. Multinomial and logistic regression models were constructed to describe associations between sodium knowledge and self reported health behaviors. RESULTS: A total of 7,067 panel subjects clicked into the online survey, and 2,862 completed the survey (adjusted response rate = 40.5%). Only 102 respondents (3.6%) were able to accurately report the recommended milligrams of sodium that an average adult should consume daily (1,500 mg to 2300 mg). Knowing about daily sodium intake recommendations was associated with increased odds of using Nutrition Facts labels to make food purchase decisions (adjusted odds ratio [AOR], 3.48; 95% confidence interval [CI], 1.59-7.60) and with decreased odds of taking measures to prevent hypertension (AOR, 0.38; 95% CI, 0.19-0.74). CONCLUSIONS: Los Angeles County residents had a limited knowledge of recommended daily sodium intake. Efforts to increase understanding of these recommendations may encourage wider engagement in healthy behaviors. Health agencies should integrate sodium reduction messages in their diet and nutrition educational efforts. PMID- 29166248 TI - Neighborhood Disadvantage and Allostatic Load in African American Women at Risk for Obesity-Related Diseases. AB - INTRODUCTION: African American women have higher rates of obesity and related chronic disease than other demographic groups. The poorer health of African American women compared with other groups may be explained by allostatic load, or cumulative physiologic stress, due to chronic socioeconomic disadvantage. The objective of this study was to evaluate neighborhood and individual factors contributing to allostatic load in African American women at risk for obesity related diseases. METHODS: This study evaluated the relationship of allostatic load with neighborhood disadvantage, individual socioeconomic determinants, and synergism between neighborhood and socioeconomic disadvantage, along with health behaviors and other factors as mediators in African American women. Our sample consisted of 220 African American women at risk of obesity-related diseases enrolled in the Better Me Within program (mean [standard deviation] age, 50.1 [11.2] y; mean [standard deviation] body mass index, 36.7 [8.4] kg/m2). Allostatic load score for each participant was calculated by summing the number of biomarkers (of 9 biomarkers) that were determined to be in the high-risk quartile. RESULTS: Poisson regression of neighborhood disadvantage and individual socioeconomic determinants found that neighborhood disadvantage, but not education level or household income, was significantly associated with allostatic load (beta = 0.22, SE, 0.10, P = .04). Tests for mediators showed that household income and alcohol consumption partially mediated the relationship between allostatic load score and neighborhood disadvantage but were not significant. CONCLUSION: More research is necessary to determine the mechanisms by which neighborhoods can exacerbate and attenuate cumulative disadvantage among African American women. Policies and interventions that focus on neighborhood health may improve the outcomes of individual-level health interventions among women who reside in disadvantaged communities. PMID- 29166249 TI - Qualitative Exploration of Cross-Sector Perspectives on the Contributions of Local Health Departments in Land-Use and Transportation Policy. AB - INTRODUCTION: Transportation and land-use policies can affect the physical activity of populations. Local health departments (LHDs) are encouraged to participate in built-environment policy processes, which are outside their traditional expertise. Cross-sector collaborations are needed, yet stakeholders' perceptions of LHD involvement are not well understood. The objective of this study was to describe the perceived value of LHD participation in transportation and land-use decision making and potential contributions to these processes among stakeholders. METHODS: We analyzed qualitative data from 49 semistructured interviews in 2015. Participants were professionals in 13 US states and 4 disciplines: land-use planning (n = 13), transportation/public works (n = 11), public health (n = 19), and other (municipal administration and bike and pedestrian advocacy [n = 6]). Two analysts conducted directed content analysis. RESULTS: All respondents reported that LHDs offer valuable contributions to transportation and land-use policy processes. They identified 7 contributions (interrater agreement 91%): 1) physical activity and health perspective (n = 44), 2) data analysis and assessment (n = 41), 3) partnerships in the community and across sectors (n = 35), 4) public education (n = 27), 5) knowledge of the public health evidence base and best practices (n = 23), 6) resource support (eg, grant writing, technical assistance) (n = 20), and 7) health equity (n = 8). CONCLUSION: LHDs can leverage their strengths to foster cross-sector collaborations that promote physical activity opportunities in communities. Our results will inform development of sustainable capacity-building models for LHD involvement in built-environment decision making. PMID- 29166250 TI - Differences by Sex in Association of Mental Health With Video Gaming or Other Nonacademic Computer Use Among US Adolescents. AB - INTRODUCTION: Although numerous studies have examined the association between playing video games and cognitive skills, aggression, and depression, few studies have examined how these associations differ by sex. The objective of our study was to determine differences by sex in association between video gaming or other nonacademic computer use and depressive symptoms, suicidal behavior, and being bullied among adolescents in the United States. METHODS: We used data from the 2015 Youth Risk Behavior Survey on 15,624 US high school students. Rao-Scott chi2 tests, which were adjusted for the complex sampling design, were conducted to assess differences by sex in the association of mental health with video gaming or other nonacademic computer use. RESULTS: Approximately one-fifth (19.4%) of adolescents spent 5 or more hours daily on video gaming or other nonacademic computer use, and 17.9% did not spend any time in those activities. A greater percentage of female adolescents than male adolescents reported spending no time (22.1% and 14.0%, respectively) or 5 hours or more (21.3% and 17.5%, respectively) in gaming and other nonacademic computer use (P < .001). The association between mental problems and video gaming or other nonacademic computer use differed by sex. Among female adolescents, prevalence of mental problems increased steadily in association with increased time spent, whereas the pattern for male adolescents followed a J-shaped curve, decreasing initially, increasing slowly, and then increasing rapidly beginning at 4 hours or more. CONCLUSION: Female adolescents were more likely to have all 3 mental health problems than male adolescents were. Spending no time or 5 hours or more daily on video gaming or other nonacademic computer use was associated with increased mental problems among both sexes. As suggested by the J-shaped relationship, 1 hour or less spent on video gaming or other nonacademic computer use may reduce depressive symptoms, suicidal behavior, and being bullied compared with no use or excessive use. PMID- 29166251 TI - Risk of Diabetes Mellitus Among Medicaid Beneficiaries in Hawaii. AB - INTRODUCTION: Medicaid is the largest primary health insurance for low-income populations in the United States, and it provides comprehensive benefits to cover treatment and services costs for chronic diseases, including diabetes. The standardized per capita spending on diabetes by Medicare beneficiaries enrolled in the fee-for-service program in Hawaii increased from 2012 to 2015. We examined the difference in odds of diabetes between Medicaid and non-Medicaid populations in major racial/ethnic groups in Hawaii. METHODS: We used data from 2013 through 2015 from the Hawaii Behavioral Risk Factor Surveillance System in this cross sectional study to compare the difference in risk for self-reported diabetes between Medicaid (n = 1,889) and non-Medicaid (n = 17,207) beneficiaries. We used multivariate logistic regression models that could accommodate the complex sampling design to examine the difference in odds of diabetes between the 2 populations. RESULTS: In Hawaii, the Medicaid population was younger, was less educated, had more health impairments, and was more likely to be obese and Native Hawaiian/Other Pacific Islander (NH/OPI) than the non-Medicaid population. The unadjusted prevalence of diabetes in the Medicaid population in Hawaii was higher than that for the non-Medicaid population (10.3% vs 8.9%, P = .02). After adjusting for confounding variables, the odds of diabetes in the Medicaid population was still significantly higher than those in the non-Medicaid population (adjusted odds ratio [AOR] = 1.75; 95% confidence interval [CI], 1.33 2.31). Adjusted analysis stratified by race/ethnicity showed that non-Hispanic Asian (AOR = 2.23; 95% CI, 1.31-3.78) and NH/OPI (AOR = 3.17; 95% CI, 1.05-9.54) Medicaid beneficiaries had significantly higher odds of diabetes than their non Medicaid counterparts. CONCLUSION: The odds of diabetes was significantly higher among the Hawaii Medicaid population than among the non-Medicaid population. Diabetes prevention programs should address the challenges and barriers that the Medicaid population faces. Our findings can be used to promote culturally competent diabetes education programs. PMID- 29166252 TI - Low-intensity Exercise Accelerates Wound Healing in Diabetic Mice. AB - INTRODUCTION: Moderate-intensity aerobic exercise has been noted to improve wound healing rates in mice and people, but different intensities of exercise may have different impacts on healing rates. It is important to determine the most beneficial exercise intensity for improving wound healing in people with type 2 diabetes to help prevent wounds from becoming chronic, greatly reduce pain and immobility, and lower the high cost of health care associated with treatment. OBJECTIVE: The purpose of this study is to determine the impact of low-intensity exercise compared with high-intensity exercise in terms of the rate of wound healing in diabetic mice. MATERIALS AND METHODS: Twenty-one 10-week-old female diabetic mice were randomly assigned to a sedentary control group (CON), low intensity treadmill exercise (LEX) group, or high-intensity treadmill exercise (HEX) group. Mice were exercised for 30 minutes, 5 days per week, for 3 weeks. Mice were wounded on their upper back with a 3.5-mm punch biopsy instrument, and wounds were photographed at the same time every day. RESULTS: In terms of the length of time it took wounds to fully heal, CON mice healed in an average of 14.4 +/- 2.4 days (number of days to decrease to less than 10% of their original size +/- standard deviation) and HEX mice in 14.0 +/- 3.0 days (P = .396). However, LEX mice healed faster than CON in an average of 10.1 +/- 2.3 days (P = .004). CONCLUSIONS: In this preliminary investigation, low-intensity exercise accelerated wound healing rates in diabetic mice but high-intensity exercise did not. Future studies should investigate the mechanisms behind this effect and evaluate different intensities of exercise on wound healing in humans with type 2 diabetes. PMID- 29166253 TI - Hepatitis C Virus: Patients' Risk Factors and Knowledge in an Urban Clinic Providing Wound Care. AB - INTRODUCTION: Affecting about 3.2 million people in the United States, hepatitis C virus (HCV) is the primary cause of chronic liver disease and a global health challenge. Hepatitis C virus can affect the functioning of the liver, the health of the person, and thus wound healing. OBJECTIVE: This quality project explores risk factors of HCV; self-reported screening, occurrence, and treatment; and knowledge of HCV in patients seeking wound care in an urban clinic. MATERIALS AND METHODS: Demographic risk factors, HCV history, and responses to a 22-item true false-don't know HCV Knowledge Test were obtained from 58 patients. Risk factors included age (mean, 61.07 years), male sex (n = 41), non-Hispanic black race/ethnicity (n = 51), and history of injection drugs (n = 38). RESULTS: Thirty nine (67.2%) stated they had been screened for HCV; 31 were told they were infected. Only 14 went to a clinic for HCV care and 11 reported they were treated. The mean number of correct answers on the HCV Knowledge Test was 14.4 (standard deviation, 5.7). CONCLUSIONS: This urban clinic had patients with multiple HCV risk factors; they often lacked HCV screening and/or referral for treatment. Their HCV knowledge was generally low. As a major public health problem that could impact wound healing, wound care practitioners should ask patients about their HCV status, encourage HCV screening and care, and provide HCV information. PMID- 29166254 TI - Proactive and Early Aggressive Wound Management: A Shift in Strategy Developed by a Consensus Panel Examining the Current Science, Prevention, and Management of Acute and Chronic Wounds. AB - Normal wound healing is accomplished through a series of well-coordinated, progressive events with overlapping phases. Chronic wounds are described as not progressing to healing or not being responsive to management in a timely manner. A consensus panel of multidisciplinary wound care professionals was assembled to (1) educate wound care practitioners by identifying key principles of the basic science of chronic wound pathophysiology, highlighting the impact of metalloproteinases and biofilms, as well as the role of the extracellular matrix; and (2) equip practitioners with a systematic strategy for the prevention and healing of acute injuries and chronic wounds based upon scientific evidence and the panel members' expertise. An algorithm is presented that represents a shift in strategy to proactive and early aggressive wound management. With proactive management, adjunct therapies are applied preemptively to acute injuries to reduce wound duration and risk of chronicity. For existing chronic wounds, early aggressive wound management is employed to break the pathophysiology cycle and drive wounds toward healing. Reducing bioburden through debridement and bioburden management and using collagen dressings to balance protease activity prior to the use of advanced modalities may enhance their effectiveness. This early aggressive wound management strategy is recommended for patients at high risk for chronic wound development at a minimum. In their own practices, the panel members apply this systematic strategy for all patients presenting with acute injuries or chronic wounds. PMID- 29166255 TI - Chemical Burns Following Massage With Chopped Pulsatilla koreana. AB - Herbal massage is commonly used for cosmetic and antirheumatic purposes in the Republic of Korea. Cutaneous burns can complicate herbal massages, but this is a very rare occurrence. Pulsatilla koreana, the Korean pasque flower, is a species of the genus Pulsatilla from the Ranunculaceae family. It is a perennial plant native to Korea, where it is used in herbal and folk medicine for its antipyretic, analgesic, anti-inflammatory, astringent, and hemostatic effects. Three cases of burns as a result of herbal massages with Pulsatilla koreana are presented herein to increase public awareness about the adverse effects of products used incorrectly for herbal massage. PMID- 29166256 TI - Infection-free Clinical Response Among Patients With Hidradenitis Suppurativa Who Were Treated With Adalimumab: Results from Two Phase 3 Studies. AB - OBJECTIVE: The objective of this study is to assess the rates of infection-free achievement of hidradenitis suppurativa clinical response (HiSCR) using integrated data from 2 phase 3, placebo-controlled trials, PIONEER I and II. MATERIALS AND METHODS: Analyses from the first 12 weeks of both studies were examined. Patients were randomized to receive adalimumab (ADA) or placebo, and they then were assessed in the clinic at weeks 0, 2, 4, 8, and 12. All reports of an adverse or serious adverse event and infection were classified as treatment emergent adverse events (TEAEs). The HiSCR was evaluated as the primary endpoint; infection-free HiSCR was also evaluated. RESULTS: Treatment-emergent adverse events were observed in 55.4% of the ADA group and 64.4% of the placebo (P < .023). The rates of serious TEAEs and infection-related TEAEs were slightly less in the ADA group compared with the placebo group. A significantly higher percentage of ADA-treated patients achieved HiSCR at week 12 compared with placebo (P < .001). At each visit during the study's 12 weeks, a greater proportion of ADA-treated patients achieved infection-free HiSCR compared with patients treated with placebo (P < .001). Mean durations of HiSCR and infection free HiSCR were significantly longer in ADA-treated patients when compared with placebo-treated patients (P < .001). CONCLUSIONS: Results of this integrated analysis indicate that patients with hidradenitis suppurativa who received a short duration of ADA treatment experienced better combined efficacy and similar safety compared with placebo. Further studies investigating longer ADA treatment may demonstrate further improvements in duration of infection-free clinical response. PMID- 29166257 TI - Raoultella planticola: A Rare Cause of Wound Infection. AB - Raoultella planticola is a gram-negative, aerobic, rod bacterium commonly found in the environment, particularly in water, soil, and fish. This organism has been found to cause a variety of infections, such as necrotizing fasciitis, cystitis, cholecystitis, pancreatitis, hepatic disease, and soft tissue infections. The authors report the case of a 73-year-old-woman who presented with a R planticola wound infection of her left lower extremity after a dog scratch. She was treated successfully with local wound care using dehydrated human amnion/chorion and oral levofloxacin. Her wound healed completely in 4 months but may have been delayed due to her comorbidities. Her chronic proton pump inhibitor use and trial of antibiotics prior to diagnosis of this infection may have selected for this particular organism. Although not commonly reported as a cause of wound infections, practitioners should consider R planticola as a differential diagnosis for a nonhealing wound as prompt identification can allow for timely treatment and decreased morbidity of this serious pathogen. PMID- 29166258 TI - Application of a Skin Adhesive to Maintain Seal in Negative Pressure Wound Therapy: Demonstration of a New Technique. AB - : Optimal wound healing with negative pressure wound therapy (NPWT) relies on a properly sealed vacuum system. Anatomically difficult wounds impair the adhesive dressing, which results in air leaks that disrupt the integrity of the NPWT system and hinder wound healing. OBJECTIVE: The authors demonstrate a new technique using a cyanoacrylate-based tissue adhesive to maintain an airtight, durable seal in NPWT. MATERIALS AND METHODS: A 52-year-old woman with a degloving injury to the right thigh extending into the groin, resulting in massive necrosis, presented to the emergency department. Using a skin closure system, 2 polyester mesh tape strips were placed near the perineal region of the wound to reinforce the adhesive drape of the NPWT system. Skin grafts were applied over the wound after about 3 weeks of NPWT, and the skin closure system was applied in the same fashion to reinforce the adhesive drape. RESULTS: An airtight seal was consistently maintained for several days in between dressing changes. The size of the wound was visibly reduced at each dressing change. An airtight seal was maintained for 5 days after placement of the skin grafts; after 5 days, the dressing was removed without difficulty and skin irritation. The skin grafts appeared healthy with adequate tissue take. CONCLUSIONS: Maintaining an airtight seal in NPWT is crucial to wound healing. Cyanoacrylate tissue adhesives appear to be a safe and viable option for creating a durable seal in NPWT for wounds in anatomically difficult locations. PMID- 29166259 TI - Clinical Outcome of Achilles Tendon Repair Using Viable Intact Cryopreserved Umbilical Tissue Versus Standard of Case. AB - INTRODUCTION: Repair of acute Achilles tendon ruptures is complicated by the severity of the rupture, quality of the tendon, and length of the defect. The adjunct use of biologics (eg, viable umbilical tissue) may provide additional support and reduce postoperative inflammation, adhesions, and fibrosis. OBJECTIVE: The aim of this study is to review the outcomes of Achilles tendon rupture open repairs with viable cryopreserved umbilical tissue (vCUT) compared with patients treated with standard of care only. MATERIALS AND METHODS: Four patients (average age, 59 years; range, 55-65 years; 2 male, 2 female) with acute Achilles tendon injuries treated surgically with vCUT were selected. The repairs were augmented with vCUT sutured over the tendon ends (Wharton's jelly side towards the tendon) with absorbable sutures. RESULTS: Patients remained nonweight bearing after surgery for 4 to 6 weeks followed by a gradual return to ambulation. All patients maintained durable skin closure, had minimal scarring and edema, and were able to return to work in 8 to 10 weeks. All 4 patients returned to their preinjury activity level without pain or loss of function. There were no vCUT-related complications or adverse events. CONCLUSIONS: Clinical outcomes of this study support the use of vCUT for augmentation of Achilles tendon repair. PMID- 29166260 TI - The Development and Content Validation of a Multidisciplinary, Evidence-based Wound Infection Prevention and Treatment Guideline. AB - Acute and chronic wound infections create clinical, economic, and patient centered challenges best met by multidisciplinary wound care teams providing consistent, valid, clinically relevant, safe, evidence-based management across settings. To develop an evidence-based wound infection guideline, PubMed, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature databases were searched from inception through August 1, 2017 using the terms (or synonyms) wound infection and risk factor, significant, diagnosis, prevention, treatment, or surveillance. Studies on parasitic infections, in vitro studies, and non-English publications were excluded. The 19-member International Consolidated Wound Infection Guideline Task Force (ICWIG TF), hosted by the Association for the Advancement of Wound Care (AAWC), reviewed publications/assessed levels of evidence, developed recommendations, and verified representation of all major recommendations from 27 multidisciplinary wound infection documents. Using a web-based survey, practitioners were invited to assess the clinical relevance and strength of each recommendation using standardized scores. Survey responses from 42 practitioners, including registered nurses (RNs), Wound Care Certified and advanced practice RNs, physical therapists, physicians, podiatrists, and scientists from 6 countries were returned to AAWC staff, tabulated in a spreadsheet, and analyzed for content validity. Respondents had a median of >15 years of military or civilian practice and managed an average of 15.9 +/- 23 patients with infected wounds per week. Recommendations supported by strong evidence and/or content validated as relevant by at least 75% of respondents qualified for guideline inclusion. Most (159, 88.8%) of the 179 ICWIG recommendations met these criteria and were summarized as a checklist to harmonize team wound infection management across specialties and settings. Most of the 20 recommendations found not to be valid were related to the use of antibiotics and antiseptics. After final ICWIG TF review of best evidence supporting each recommendation, the guideline will be published on the AAWC website. PMID- 29166261 TI - Pressure Injury Risk Factors in Adult Critical Care Patients: A Review of the Literature. AB - Critically ill patients require complex care in a technologically sophisticated environment where they are highly vulnerable to pressure-related injuries. However, pressure injury (PI) development remains a multifactorial phenomenon in critically ill persons; true risk is both pervasive and elusive. The purpose of this comprehensive review of the empirical literature was to examine the risk factors associated with PIs among adult patients admitted to contemporary intensive care units (ICUs). Inclusion criteria stipulated publications were to be peer-reviewed, quantitative studies with a focus on pressure ulcer (PU) risk factors in adult critical care patients published between 2010 and 2016 in which statistical analysis involved multivariate analysis using PU development as the outcome variable. Studies not available in English, those in which the primary focus was on PU prevention or treatment, and those that focused solely on the use of PU risk assessment scales were excluded. A comprehensive review of the OVID and PubMed computerized databases using the search terms pressure ulcer, critical care, intensive care, and risk factors yielded 540 reports; 358 remained after duplicates were eliminated and 28 after the inclusion/exclusion criteria were applied. Following examination, 16 studies were suitable for inclusion. A total of 43 risk factors emerged. Of those, 7 were identified in 3 or more studies in multivariate regression analysis; these included age, prolonged ICU admission, diabetes mellitus, cardiovascular disease, hypotension, prolonged mechanical ventilation, and vasopressor administration. To facilitate results interpretation, risk factors from multivariate analyses were grouped in 6 broad categories: demographic/patient characteristics, comorbidities, intrinsic factors, iatrogenic/care factors, PI risk assessment scales, and severity of illness/mortality risk. The shared attribute of the 7 risk factors identified was they are all potentially nonmodifiable. Advancing the science regarding the pathogenesis of PI development is imperative when trying to better understand unavoidable pressure-related injuries. The need for large multisite studies and studies using large datasets capable of validating risk factors unique to this population persists. Additionally, the need for enhanced PI risk quantification for adult ICU patients remains. PMID- 29166263 TI - Effects of melatonin implantation on the fertility potentials of Kivircik and Charollais ewes and rams during the non-breeding season. AB - This study examined the effect of melatonin implantation during the non-breeding season on the reproductive performance of ewes and the testicular dimensions of rams. In seasonally anestrus Kivircik and Charollais ewes and rams were subjected to melatonin. Estrus response was significantly higher in treated than control ewes of both breeds (p<0.001). The pregnancy rate was significantly lower (p<0.001) in the control than in the treated animals. The twinning rate was significantly lower in melatonin implanted Kivircik than Charollais ewes (p<0.05). The testicular dimensions after 42 days of melatonin treatment increased in both breeds. Scrotal length (SL) increased in Kivircik and Charollais rams (p<0.01). The increase in scrotal circumference (SC) was more marked in the Charollais (P<0.01) than in the Kivircik rams. There was a large increase in testicular volume (TV) in both Kivircik (p<0.01) and Charollais (p<0.001) rams. This study shows that melatonin implants can be applied to induce estrus in ewes approximately four months earlier than breeding season. Melatonin implantation in the non-breeding season significantly increased testicular dimensions in Kivircik and Charollais rams thus increasing their reproductive potential. PMID- 29166262 TI - Antiphosphatidylserine/prothrombin antibodies (aPS/PT) as potential diagnostic markers and risk predictors of venous thrombosis and obstetric complications in antiphospholipid syndrome. AB - BACKGROUND: The aim of the study was to determine the prevalence and clinical associations of antiphosphatidylserine/prothrombin antibodies (aPS/PT) with thrombosis and pregnancy loss in Chinese patients with antiphospholipid syndrome (APS) and seronegative APS (SNAPS). METHODS: One hundred and eighty six Chinese patients with APS (67 primary, 119 secondary), 48 with SNAPS, 176 disease controls (79 systemic lupus erythematosus [SLE], 29 Sjogren's syndrome [SS], 30 ankylosing spondylitis [AS], 38 rheumatoid arthritis [RA]) and 90 healthy donors were examined. IgG and IgM aPS/PT, IgG/IgM/IgA anticardiolipin (aCL) and IgG/IgM/IgA anti-beta2-glycoprotein I (anti-beta2GPI) antibodies were tested by ELISA. RESULTS: One hundred and sixty (86.0%) of APS patients were positive for at least one aPS/PT isotype. One hundred and thirty five (72.6%) were positive for IgG aPS/PT, 124/186 (66.7%) positive for IgM aPS/PT and 99 (53.2%) positive for both. Approximately half of the SNAPS patients were positive for IgG and/or IgM aPS/PT. Highly significant associations between IgG aPS/PT and venous thrombotic events (odds ratio [OR]=6.72) and IgG/IgM aPS/PT and pregnancy loss (OR=9.44) were found. Levels of IgM aPS/PT were significantly different in APS patients with thrombotic manifestations and those with fetal loss (p=0.014). The association between IgG/IgM aPS/PT and lupus anticoagulant (LAC) was highly significant (p<0.001). When both were positive, the OR for APS was 101.6. Notably, 91.95% (80/87) of LAC-positive specimens were positive for IgG and/or IgM aPS/PT, suggesting aPS/PT is an effective option when LAC testing is not available. CONCLUSIONS: Anti-PS/PT antibody assays demonstrated high diagnostic performance for Chinese patients with APS, detected some APS patients negative for criteria markers and may serve as potential risk predictors for venous thrombosis and obstetric complications. PMID- 29166264 TI - Relationship between pH of ruminal fluid during subacute ruminal acidosis and physiological response of the Polish Holstein-Friesian dairy cows. AB - The aim of the study was to investigate the effect of ruminal fluid pH depression on biochemical indices of blood, urine, feces, and milk, and to determine which of them may be helpful as a marker for the diagnosis of subacute ruminal acidosis (SARA). Ruminal fluid samples were obtained by rumenocentesis from 305 cows representing 13 commercial dairy herds. The herds were selected based on percentages of cows with an assigned value of ruminal fluid pH segregated into three groups as: SARA-positive herd, if at least 25% of the ruminal fluid samples indicated a pH < 5.6; SARA-risk herd, if less than 25% of ruminal fluid samples indicated a pH < 5.6, but at least 33% showed a pH <= 5.8; and SARA-negative herd, if less than 25% of the ruminal fluid samples indicated a pH < 5.6, but less than 33% exhibited a pH = 5.8. Moreover, the dairy cows were divided according to the ruminal fluid pH into three groups as follows: healthy cows (HC, pH>5.80, n = 196), risk cows (RC, pH 5.8 - 5.6, n = 51), and acidotic cows (AC, pH < 5.6, n = 58). Almost 19% (58/305) of the cows were classified as acidotic (pH < 5.6) and 46.2% of the herds as SARA-positive. In the AC group, higher concentrations of insulin-like growth factor-I (IGF-I), non-esterified fatty acids (NEFA), rectal temperature and lower blood pH, compared with those of the HC group, were recorded. Moreover, in the SARA-positive herds, higher concentrations of IGF-I and the lowest blood pH, compared with SARA-negative herds, were observed. The lowering of ruminal fluid pH increased the blood IGF-I and NEFA concentrations and the rectal temperature and decreased the blood pH. These measures are indicators of the physiological changes that occur as part of the pathogenesis of the condition and may be helpful for the diagnosis of the SARA syndrome when serial measurements are conducted. PMID- 29166265 TI - Selection of reference genes for quantitative real-time RT-PCR on gene expression in Golden Pompano (Trachinotus ovatus). AB - Golden pompano (Trachinotus ovatus) is an important economically fish species. In this study, with an aim to identify reliable reference genes for quantitative real-time PCR (qRT-PCR) in golden pompano, we evaluated the expression stability of eight housekeeping genes in the presence and absence of poly I:C stimulation in eight tissues. The PCR data was analyzed by geNorm and NormFinder algorithms. The results showed that the expression of all the examined genes exhibited tissue dependent variations. When under normal physiological condition, geNorm and NormFinder identified B2M and 18S as suitable genes. When studying gene expression under conditions of poly I:C stimulation, the selection of the internal controls should be selected on a tissue basis. At 12 h stimulation, geNorm ranked Actin/UBCE, Actin/B2M, UBCE/B2M, Actin/UBCE, RPL13/B2M, UBCE/GAPDH, B2M/RPL13, and UBCE/B2M, respectively, as the most stably expressed genes in liver, spleen, kidney, gill, intestine, heart, muscle, and brain. Comparable ranking orders were produced by NormFinder. Similar results were obtained at 48 h stimulation. Taken together, these results indicate that B2M and 18S are the most stable gene across tissue types under normal physiological conditions. However, during poly I:C stimulation, no single gene or single pair of genes in the examined set of housekeeping genes can serve as a universal reference across all tissue types. If one gene is preferred, B2M, B2M, UBCE, Actin, B2M/RPL13, B2M, B2M, and RPL13 may be used in spleen, kidney, liver, gill, intestine, brain, muscle, and heart of golden pompano, respectively. PMID- 29166266 TI - Application of loop-mediated isothermal amplification (LAMP) assays for the detection of bovine herpesvirus 1. AB - Bovine herpesvirus-1 (BoHV-1), a causative agent of Infectious Bovine Rhinotracheitis (IBR), is responsible for high economic losses in cattle farming industry. The use of testing methods that allow early detection of BoHV-1 infected animals is a key element of each program of IBR eradication. The aim of the study was to design and evaluate two variants of LAMP isothermal tests with SYBR Green fluorescence probes, specific to the genes encoding gD and gE glycoproteins of BoHV-1. LAMP gE BoHV-1 assay was able to distinguish between gE- and gE+ strains of the virus. Both LAMP gD and gE assays were specific to BoHV-1 and did not react with other related to BoHV-1 alphaherpesviruses. Sensitivity of LAMP gD was 2x104 copies of the viral genome whereas for LAMP gE it was 2x105. Diagnostic sensitivity calculated for LAMP gD was 64.7% whereas for LAMP gE it was 80%. Diagnostic specificity for LAMP gD and LAMP gE was 78.9% and 89.3%, respectively. LAMP assay can be a rapid and simple method of diagnosis of acute BoHV-1 infections and discrimination of gE- strains. However, relatively low diagnostic sensitivity of the method can limit its use in routine diagnostics. PMID- 29166267 TI - Comparison of the Two Types of Stimulating Electrodes in the Study of Motor Nerve Conduction in Dogs. AB - In this research two kinds of stimulation electrodes were compared in motor nerve conduction study: needle electrodes used in human medicine and electrodes made of injection needles connected to the stimulator via alligator-type electrodes. A study was conducted in 22 mixed-breed dogs. The resulting values of the potential amplitudes of the stimulus, the parameters of the complex muscle potentials, and the motor nerve conduction velocity were statistically compared. There was no statistical difference between the parameters obtained with the two types of stimulation electrodes. The results of our research constitute a basis for improving present-day procedures, improving aseptic procedures, reducing tissue trauma during research and lowering research costs due to the introduction of injection-needle electrodes and their benefits into the study of motor nerve conduction in animals. PMID- 29166268 TI - Evaluation of usefulness of a commercial agarose gel electrophoresis kit (QuickGel SP) for bovine serum protein electrophoresis. AB - The aim of this study was to show the usefulness of a commercial agarose gel electrophoresis (AGE) kit (QuickGel SP) for separating bovine serum protein fractions in comparison with conventional cellulose acetate electrophoresis (CAE). Serum protein bands were verified using five reference reagents corresponding to albumin and alpha1-, beta1-, beta2-, and gamma-globulins. AGE clearly revealed six separated fractions of albumin and alpha1-, alpha2-, beta1-, beta2-, and gamma-globulin fractions in 100% and 77.8% in serum samples of dairy cows from the healthy (n=27) and diseased groups (n=27), respectively. The alpha1 and alpha2-globulins were not separated by CAE in 14.8% and 96.3% of the samples from the healthy and diseased groups, respectively, whereas beta2- and gamma globulin were not separated by CAE in 96.3% and 100% of the samples from the healthy and diseased groups, respectively. More than 94% of the points for the alpha-globulin fractions (alpha1- and alpha2-globulins), the beta-gamma-globulin fractions (beta1-, beta2-, and gamma-globulins), and the albumin/globulin ratio between AGE and CAE were within agreement on the Bland-Altman plots. However, the mean biases were not near zero in the albumin and beta-gamma-globulin fractions. These results suggest that the high-resolution commercial AGE kit can be utilized to separate bovine serum protein fractions. PMID- 29166269 TI - Selected steps of swine ICSI method to overcome seasonal effect and achieve acceptable early embryonic development, a preliminary study. AB - Porcine intra cytoplasmic sperm injection's (ICSI) efficacy by selected protocol steps was investigated. Three trials per year's period (hot, medium, cold) were carried out. Only large size follicles (6-8mm) were aspirated, brilliant cresyl blue (BCB) test was performed and only the BCB+ oocytes were in vitro maturated (40h) and involved to ICSI process. The presumptive embryos were in vitro cultured (15h). Raw boar semen and SpermCatch(r) as slowing medium were used. No differences were observed between periods regarding early embryonic development and maturation competence. ICSI achieves acceptable porcine early embryonic development rates under the investigated conditions. PMID- 29166270 TI - Detection of Yersinia Enterocolitica Species in Pig Tonsils and Raw Pork Meat by the Real-Time Pcr and Culture Methods. AB - The aim of the present study was to establish a rapid and accurate real-time PCR method to detect pathogenic Yersinia enterocolitica in pork. Yersinia enterocolitica is considered to be a crucial zoonosis, which can provoke diseases both in humans and animals. The classical culture methods designated to detect Y. enterocolitica species in food matrices are often very time-consuming. The chromosomal locus _tag CH49_3099 gene, that appears in pathogenic Y. enterocolitica strains, was applied as DNA target for the 5' nuclease PCR protocol. The probe was labelled at the 5' end with the fluorescent reporter dye (FAM) and at the 3' end with the quencher dye (TAMRA). The real-time PCR cycling parameters included 41 cycles. A Ct value which reached a value higher than 40 constituted a negative result. The developed for the needs of this study qualitative real-time PCR method appeared to give very specific and reliable results. The detection rate of locus _tag CH49_3099 - positive Y. enterocolitica in 150 pig tonsils was 85 % and 32 % with PCR and culture methods, respectively. Both the Real-time PCR results and culture method results were obtained from material that was enriched during overnight incubation. The subject of the study were also raw pork meat samples. Among 80 samples examined, 7 ones were positive when real-time PCR was applied, and 6 ones were positive when classical culture method was applied. The application of molecular techniques based on the analysis of DNA sequences such as the Real-time PCR enables to detect this pathogenic bacteria very rapidly and with higher specificity, sensitivity and reliability in comparison to classical culture methods. PMID- 29166271 TI - Beta-hydroxybutyrate in milk as screening test for subclinical ketosis in dairy cows. AB - Ketosis is a very frequent metabolic disease in dairy cows, resulting in lower milk production, impaired fertility and increased frequency of other diseases. The course of the disease is often subclinical, so early detection is very important. The aim of the study was to investigate the relation between the concentration of beta-hydroxybutyrate in blood and milk and to determine the cut off value in milk for detection of subclinical ketosis. The study included 94 cows, which were in the first third of lactation. Beta-hydroxybutyrate (BHB) concentrations were measured in blood and milk serum using a biochemical analyser. The average concentration of BHB in the blood serum samples was 1.14 mmol/L while in the milk it was about ten times lower at 0.117 mmol/L. A statistically significant positive correlation between the concentration of BHB in blood and milk (r=0.705, p<0.001) was found. In cows with BHB in blood below 2.0 mmol/L a stronger correlation between blood and milk BHB was established (r=0.658, p<0.001) than in cows with blood BHB above 2.0 mmol/L (r=-0.292, p=0.206). Therefore, BHB in milk is a very suitable indicator in the diagnosis of subclinical ketosis as there is a good correlation between BHB in the blood and milk of cows with subclinical ketosis. The cut-off concentration of BHB in milk set at >=0.080 mmol/L (AUC=0.91+/-0.03; p<0.001) is a significant indicator for subclinical ketosis in dairy cows. The sensitivity of the test was 94% and specificity 74%. Beta-hydroxybutyrate in milk is a good indicator of subclinical ketosis in dairy cows and can be measured accurately with a biochemical analyser. PMID- 29166272 TI - In vitro activity of some essential oils alone and in combination against the fish pathogen Nocardia seriolae. AB - Microplate resazurin assay was applied to investigate the in vitro activity of four essential oils (EOs); cinnamon (Cinnamomum zeylanicum), thyme (Thymus vulgaris), lemongrass (Cymbopogon flexuosus) and tea tree (Melaleuca alternifolia) oils against 80 clinical isolates of the fish pathogen Nocardia seriolae. The checkerboard test was then used to determine the possible synergistic effect of EOs combination against reference type strains of fish nocardiosis. All tested EOs had antibacterial activity against N. seriolae isolates. Among the tested EOs, cinnamon and thyme oils both exhibited the lowest minimum inhibitory concentrations (MICs) with 5-160 and 10-160 MUg/ml, respectively. The activities of lemongrass and tea tree EOs were noted to be less effective with MICs of 20-640 and 160->5120 MUg/ml, respectively. The checkerboard panel of cinnamon-thyme EOs combination against N. seriolae ATCC43993 demonstrated a synergistic effect with a fractional inhibitory concentration (FIC) index of 0.75. For N. salmonicida ATCC27463, the combination panel showed an additive effect with an FIC index of 1.0. For N. asteroides ATCC19247, the combination panel demonstrated an indifference effect with an FIC index of 1.125. These results indicate that thyme and cinnamon oils alone or the combination of them at a given ratio has a promising potent clinical significance in the treatment of fish nocardiosis. Despite the promising results given by our in vitro studies, the clinical benefits of these EOs combinations can only be determined through carefully designed in vivo experimental studies. PMID- 29166273 TI - First report of Feline Calicivirus (FCV) infection in stray cats in northeast China. AB - To improve our understanding of Feline calicivirus (FCV) infection in cats in Northeast China, 1584 serum samples from 974 domestic cats and 610 stray cats were collected between 2012 and 2015. The samples were tested for FCV antibodies using a commercially available ELISA kit. The results revealed an overall seroprevalence of 37.56% (595/1584), a seroprevalence in domestic cats of 32.85% (320/974) and a seroprevalence in stray cats of 45.08% (275/610). Risk factor analysis indicated that species was the only risk factor for the presence of FCV (OR=1.678, 95% CI=1.362-2.066, P<0.001); age, season, region and gender were not risk factors. This is the first report of FCV infection in stray cats in China, and the results of this study can aid in FCV infection control in the felidae family. PMID- 29166274 TI - Detection of Experimental Swine Trichinellosis Using Commercial Elisa Test. AB - The aim of the study carried out on ten young (10-week old) pigs of the native Polish Large White breed experimentally infected with a low dose of 300 invasive muscle larvae (ML) of Trichinella spiralis was intravital detection of trichinellosis using the E-S ELISA test, determination of a variation level of IgG antibodies against excretory-secretory (E-S) antigens of T. spiralis muscle larvae and finally, describing the intensity of T. spiralis larvae infection in selected muscles. The pig sera were collected at 7 and 9 days prior to the experimental infection with T. spiralis and at 9, 14, 20, 23, 25, 27, 30, 33, 37, 41, 46 days post-infection (d.p.i.). The anti-T. spiralis IgG antibodies were detected by a commercial E-S ELISA test (PrioCHECK Trichinella Ab). Average intensity of the T. spiralis infection in the examined muscles of pigs ranged from 1.52 up to 43.09 larvae/g. The studies revealed that the E-S antigen in the ELISA test did not show cross-reaction with the sera of pigs infected with Oesophagostomum spp. The ELISA assay did not recognize trichinellosis in pigs until 27 days after the T. spiralis infection. The anti-T. spiralis IgG antibodies were first detected on day 30 post-infection. A statistically significant increase of IgG antibodies against T. spiralis ML E-S antigens was first observed between days 27-30 (p<0.01) post-infection, and a further significant rise in the antibody level occurred between days 27 and 33 (p<0.01); 30 and 33 (p<0.01); 33 and 37 (p<0.05) following infection. PMID- 29166275 TI - Plasma profile of cimicoxib in sheep after oral administration at two different rates. AB - Sheep are often subjected to painful procedures and thus they need to be treated with analgesics. Nevertheless, knowledges about pharmacokinetic features of these drugs in this species are poor. The aim of this study was to evaluate plasma behaviour of cimicoxib in sheep after a single oral administration at two different dose rates (4 and 6 mg/kg). Maximum plasma concentrations of cimicoxib were equal to 273.78 (median value; range 189.00-567.32) and 565.01 (range 308.27 822.59) ng/mL after treatment with 4 and 6 mg/kg, respectively. The time of maximum concentration (Tmax) was achieved between 4 and 10 hours following treatment at the lower dose, and between 6 and 10 hours after the administration of the higher dose, with one sheep achieving the concentration peak at 0.75 hours. The slow absorption and the great individual variability in plasma concentration, probably due to ruminal effects, suggest that cimicoxib is not suitable for oral treatment in sheep. PMID- 29166276 TI - Comparison of body surface area-based and weight-based dosing format for oral prednisolone administration in small and large-breed dogs. AB - This study compared the pharmacokinetics of Prednisolone (PDS) in small- and large breed dogs with a dosing format based on body surface area (BSA) or body weight (BW). The maximum concentration and area under the curve in large-breed dogs orally administered 2 mg/kg PDS were significantly greater than those in small-breed dogs given 2 mg/kg and in large-breed dogs given 40 mg/m2. The higher blood concentrations that result from BW-based dosing of oral PDS in large-breed dogs can be more than required for effect. Meanwhile, BSA dosing at 40 mg/m may be suboptimal. These findings confirm important differences between standard PDS dosing schemes in dogs while highlighting the need to further optimize PDS dosing in large-breed dogs. PMID- 29166277 TI - The influence of doxazosin on the contractility of the urinary bladder in female pigs with experimentally induced cystitis. AB - The present in vitro study investigated the influence of doxazosin on the contractility of the urinary bladder in female pigs with experimentally induced cystitis. Fifteen juvenile female piglets (18-20 kg body weight) were randomly assigned into three groups (n=5 animals each): i) control (clinically healthy animals, without doxazosin treatment), ii) animals with induced inflammation of the urinary bladder, but without doxazosin treatment (experimental group I) and iii) animals with inflamed bladder, treated orally with doxazosin (0.1 mg/kg body weight for 30 days; experimental group II). Thereafter, the pigs were sacrificed and strips of the bladder trigone were suspended in organ baths. The tension and amplitude of the smooth muscles was measured before and after exposition to 5 hydroxytryptamine (5-HT; 10-6-10-4 M), acetylocholine (ACh; 10-5-10-3 M) and norepinephrine (NE; 10-9-10-7 M). 5-HT caused an increase in the tension of contractions in all the groups and the amplitude in the experimental groups, however, the effect was higher in the experimental group I than in group II as compared to that found in the pre-treatment period. ACh caused an increase in the tension in the control group and a decrease in the amplitude in both experimental groups; these changes significantly differed between the control and doxazosin treated group. NE caused a decrease in the tension in both experimental groups and amplitude in all the groups, however, the effect was most strongly expressed in doxazosine-treated group. The present study has revealed that long-term administration of doxazosin causes a desensitization of the detrusor smooth muscle to in vitro applied mediators in the autonomic nervous system. PMID- 29166278 TI - Interactions between plant-derived oestrogenic substances and the mycoestrogen zearalenone in a bioassay with MCF-7 cells. AB - Human and animal diets may contain several non-steroidal oestrogenic compounds which originate either from plants (phytoestrogens) or from fungi that infect plants (mycoestrogens such as zearalenone (ZEN)). Phytoestrogens may compete with ZEN in binding to the oestrogen receptor beta and thereby may counteract the oestrogenic activity of ZEN. Using a modified version of the E-screen assay, plant-derived oestrogenic substances were tested for their proliferative or anti proliferative effect on oestrogen-dependent MCF-7 cells. The samples were additionally tested for their ability to influence the oestrogenic activity of ZEN (1 MUM). Among the individual substances tested, 8-prenylnaringenin had the strongest effect, as cell proliferation was increased by 78% at the lowest concentration (0.23 MUM), and by 167% at the highest concentration (29.4 MUM). Coumestrol (5.83 MUM) increased cell proliferation by 39%, and genistein (370 MUM) by 61%, respectively. Xanthohumol and enterolactone did not stimulate cell proliferation significantly. In the co-incubation experiments with ZEN, none of the single substances was able to decrease the oestrogenic activity of ZEN. Only for 8-prenylnaringenin (14.7 and 29.4 MUM) was a trend towards an increase in the ZEN-induced cell proliferation up to 72% observed. In conclusion, with the exception of 8-prenylnaringenin, no substantial interaction between phytoestrogens and the mycotoxin ZEN could be detected using a bioassays with MCF 7 cells. PMID- 29166279 TI - Influence of long-term oral application of quinolones on the ECG curve in dogs. AB - The aim of the study was to analyse the influence of enrofloxacin and pradofloxacin administered orally for 14 days on the ECG in dogs. The ECG was performed before and after a 14 day period of quinolone administration. There was an increase in the QTc and the TpTe interval in the group treated with quinolones. QTc was prolonged by 24 ms (p=0.001). The TpTe interval was shortened, on average, by 6.55 ms (p=0.048). In the group treated with enrofloxacin, QTc was prolonged by 16.27 ms (p=0.006) and the TpTe interval was shortened by 9.64 ms (p=0.050), the TpTe/QT index was reduced by 0.034 (p=0.050) on average. In dogs treated with pradofloxacin, QTc was prolonged by 21.55 ms (p=0.012) on average. The results suggest that a prolonged administration of quinolones can increase the risk of arrhythmias. Furthermore, different generations of these drugs increase this risk to various degrees. The study proved that second generation quinolones, such as enrofloxacin, significantly change the phase of depolarization and repolarization of the ventricles, at the same time increasing the risk of ventricular arrythmia. Pradofloxacin does not change the TpTe and TpTe/QT values, so it is safer in use. PMID- 29166280 TI - Differentiation of infectious bronchitis virus vaccine strains Ma5 and 4/91 by TaqMan real-time PCR. AB - The aim of this study was to develop rapid molecular assays for differentiating vaccine strains Ma5 and 4/91 of the infectious bronchitis virus (IBV). Specific primers and probes for S1 and N genes were designed based on the nucleotide sequences of both vaccine strains. Cross-reactivity was not observed. Assay sensitivity was 2.373 * 103 copies of the Ma5 strain, and 3.852 x 103 copies of the 4/91 strain. Samples belonging to a known genotype demonstrated that the designed assays supported rapid and sensitive detection of Ma5 and 4/91 vaccine strains of IBV. PMID- 29166281 TI - Epidemiological Study of Canine Mast Cell Tumours According to the Histological Malignancy Grade. AB - The aim of the study was to identify significant relationships between the tumour malignancy grade and dogs' age, breed, sex, size, and location of mast cell tumours (MCTs). MCTs accounted for 13.27% of all diagnosed canine skin tumours. The highest incidence was recorded among Boxers, Labrador Retrievers, American Staffordshire Terriers, and Golden Retrievers. Statistical analysis revealed significantly higher probability of occurrence of the grade I mast cell tumour in the French Bulldog in the head, neck, torso, and limb regions, the grade-II mast cell tumour in Boxer, Doberman, Dachshund, shepherds, and setters in the scrotal region, and the grade III mast cell tumour in Shar-Pei in the axilla region. In the group of the oldest dogs aged 11-16, there was higher risk of development of MCTs grade II and III. Young dogs (aged 2-3 and 4-6) were found to be more prone to development of MCTs grade I. There was no correlation between MCTs grade and dogs' sex and size. To the authors' knowledge this is the first report on statistical relationships between the degree of mast cell tumour malignancy and dogs' phenotypic traits, age and tumour location. This analysis indicate predilections for development of the particular mast cell tumour malignancy degrees in certain dog breeds, age, and anatomical location. PMID- 29166282 TI - Adenocarcinoma of the posterior segment of the gastrointestinal tract in dogs - clinical, endoscopic, histopathological and immunohistochemical findings. AB - Of all the tumours in dogs, three percent are located in the intestines, and 36 60% of those tumours affect the large intestine. Adenocarcinomas of the intestines account for 20-35% of the gastrointestinal tumours and for almost 60% of the large intestine tumours. The aim of the study was to analyze clinical disorders and endoscopic, histopathological and immunohistochemical changes in colorectal adenocarcinomas in dogs with the use of the E-cadherin, beta-catenin, cytokeratin 20 (CK20), Ki-67 and minichromosome maintenance 3 (MCM-3). The study comprised 11 dogs of both genders and of different breeds diagnosed with adenocarcinoma of the large intestine. They were from 4 to 11 years old. The large intestine adenocarcinoma was diagnosed in all the patients. 72.7% cases were diagnosed with a rectal adenocarcinoma, and 27.3% were found to have a colonic adenocarcinoma. All the studied proteins were expressed at different levels and, together with the histological findings, indicated different levels of malignancy (G). The statistical analysis revealed no statistically significant differences between the expression of E-cadherin and beta-catenin in the studied tissues (p=0.79) and between the expression of Ki-67 andMCM-3 (p=0.39). A strong positive correlation was found between the expression of E-cadherin and beta catenin (r=0.86; p<0.05). The diagnosis of adenocarcinomas of the large intestine may be facilitated by the introduction of immunohistochemical studies using appropriate cell markers. They may also aid in the accurate evaluation of the biological character of the tumours, their origin, the connections between tumour cells and the mitotic index. That, in turn, may help determine the malignancy and the choice of treatment. PMID- 29166283 TI - Cardiac disorders in dogs infected with Babesia canis. AB - The aim of this study was to assess cardiac disorders in dogs infected with B. canis. The study included 50 dogs with babesiosis and 20 healthy control animals. All the animals had haematological tests, ECG, echocardiography and serum troponin I and CK-MB levels checked. The haematology in the group of dogs with babesiosis confirmed thrombocytopaenia in 100% of dogs, decreased haematocrit in 52% and anaemia in 46%. The most common abnormalities in ECG and echocardiography in dogs infected with protozoa included: change in appearance and/or amplitude of the T-wave (34%), increased fractional shortening (24%), an increased sinus rhythm (14%) and heart axis deviation (10%). In 19 of the 50 dogs with babesiosis, the level of serum troponin I was elevated. In 2 dogs that died from babesiosis, the troponin level I was very high. The ECG confirmed sinus tachycardia and interpolated ventricular beat in these animals. In all dogs with babesiosis that were used in the study, the serum CK-MB was high or very high and was within limits of 23.17 U/L - 369.62 U/L. The highest kinase concentration (367.33 U/L and 369.62 U/L) was observed in dogs that died due to the disease. The presented results prove that cardiac changes are common in canine babesiosis, but that most changes are nonspecific and appear to have little clinical significance. Cardiovascular assessment should be based on the assessment of the level of troponin I and CK-MB in the serum of sick animals. High concentrations of these factors might be indicators of poor prognosis. PMID- 29166284 TI - Pulmonary adiaspiromycosis in the Eurasian beaver (Castor fiber) inhabiting Poland. AB - Adiaspiromycosis is a rare fungal infection caused by saprophytic fungi Emmonsia spp. (type Ascomycota) occurring especially in small free-living mammals. The aim of this study was to evaluate the occurrence of histopathological lesions asscociated with adiaspiromycosis in the Eurasian beaver inhabiting Poland. In order to evaluate the presence of natural adiaspiromycosis we systematically investigated beaver populations from north-eastern Poland for adiaspores in the lungs. This study reveals for the first time the presence of pulmonary adiaspiromycosis of Eurasian beaver in Poland. As far as we know, there is no published data regarding pulmonary adiaspiromycosis in human patients in Poland. PMID- 29166285 TI - An evaluation of the usefulness of invasive and non-invasive methods used to diagnose Helicobacter spp. infections in dogs. AB - The aim of this study was to assess the suitability of invasive and non-invasive methods used to diagnose Helicobacter spp. in the stomachs of dogs. The study was carried out on 30 dogs of both sexes and different breeds, between one and 15 years old. A histopathologic examination, a microbiological culture, a rapid urease test, a direct bacteriological preparation and a nested PCR assay were carried out. Gastric Helicobacter spp. was identified in gastric biopsy specimens from 16 (53.3%) dogs using direct bacteriological preparation, in four (13.3%) dogs based on a culture, in 23 (76.6%) dogs using the rapid urease test and in 21 (70,0%) dogs based on a histopathological assessment of the biopsy specimens. The nested PCR of the gastric biopsy specimens revealed gastric Helicobacter spp. in all the dogs (100%). A saliva PCR assay revealed gastric Helicobacter spp. in 23 (76.6%) dogs, while stool PCR revealed the bacterium in seven (23.3%) dogs. We found that invasive methods were more accurate than non-invasive methods in detecting a Helicobacter spp. infection in dogs. In addition, the nested PCR method used to evaluate the gastric mucosal biopsy specimens was the most accurate test for detecting Helicobacter spp. It was further found that the PCR based saliva assay was the best non-invasive method for detecting Helicobacter spp. However, taking into consideration that most of the diagnostic methods used to detect this bacterium have drawbacks, at least two diagnostic methods should be used to detect Helicobacter spp. as is done in human medicine. PMID- 29166286 TI - A trial of doramectin injection and ivermectin spot-on for treatment of rabbits artificially infested with the ear mite "Psoroptes cuniculi". AB - The ear mite "Psoroptes cuniculi" is the main cause of ear mange, a highly contagious parasitic skin disease in rabbits all over the world. In the current work, a preliminary therapeutic trial to study the effect of the broad use acaricides doramectin and ivermectin on P. cuniculi was performed on artificially infested rabbits. Twenty five adult New Zealand white rabbits were used in this study. The rabbits were assigned randomly into five groups/ 5 rabbits in each group. Each rabbit was experimentally infested with 100 mites/ ear. The first group was designated the positive control group and was not treated. The second and third groups were treated with doramectin 200 and 400 MUg/kg bw, respectively. Groups 4 and 5 were treated by dressing with ivermectin in one dose and 2 doses with a 1 week interval. After the therapy, all rabbits were examined microscopically on the 7th, 14th, and 28th day post treatment and the number of live mites (larvae, nymphs, and adults) on each rabbit was counted at the end of the experiment (28th day). The results showed that the rabbits treated subcutaneously with doramectin at a single dose of 200 MUg /kg bw showed a very low effect, although there was significant improvement when the dose was doubled to 400 MUg /kg bw, with the number of mites counted decreasing significantly. Rabbits treated topically with ivermectin spot-on, a single dose or 2 doses, showed great improvement of the lesion: the number of mites was reduced to zero. In conclusion, this work showed that ivermectin spot-on applied locally on infested ears proves to be more effective against P. cuniculi than doramectin injected subcutaneously. Further trials on ear mange therapeutics in rabbits are to be encouraged. PMID- 29166287 TI - Assessment of genomic inbreeding in Polish Konik horses. AB - The aim of this study was to assess the inbreeding coefficient of Polish Konik horses based on runs of homozygosity (ROH). Ninety six horses kept in 6 herds located across Poland were genotyped with the use of EquineSNP60 BeadChip (Illumina). SNP markers with a Minor Allele Frequency lower than 0.01 and SNPs assigned to chromosome X or Y were excluded from the study. A total of 50 708 SNPs were included for statistical analysis (SVS software, Golden Helix). The analysis showed that the population is in genetic equilibrium, with He and Ho estimates both equal to 0.3086. Seven categories of Runs of Homozygozity (ROH) length were defined: >0.5, >1, >2, >4, >8, >16, >25 Mb. The genomic inbreeding coefficient derived from ROH (FROH) calculated for each ROH length ranged from 15.96% based on the shortest ROH (>0,5Mb) to 2.71% for the longest ROH (>25Mb). Among individual horses, the inbreeding coefficient ranged from 5.25% to 22.41% (for ROH >1Mb). Analysis of ROH in Polish Koniks allows for more effective management of their inbreeding in the future. PMID- 29166288 TI - Spirulina Platensis Affects Factors Involved in Spermatogenesis and Increases Ghrelin Receptors in Testis Tissue of Rats Fed a High-Fat Diet. AB - Ghrelin is a peptide hormone which plays important role in maintaining growth hormone release and energy homeostasis in vertebrates. Spirulina platensis (SP) has antioxidant and hypolipidemic effects due to its ingredients. In this study we aimed to investigate the effects of SP on the testicular structure and relation between ghrelin and testosterone in the testis of rats fed a high fat diet (HFD). Sixty four young adult male rats were used and divided to 8 equal groups. Experimental groups received addition of 10% cholesterol (CHL), 43% hydrogenated vegetable oil (HVO) and 3% SP alone or in combination to basal diet while the control group received only basal diet. Serum ghrelin and testosterone levels were measured with ELISA. Receptors for ghrelin and androgen were detected with immunohistochemistry. For histomorphometric investigation, tubulus seminiferus, intertubular area, tubulus seminiferus lumen, Leydig cell nucleus, Sertoli cell nucleus, germ cell nucleus, spermatocyte nucleus and elongated spermatid volume densities were determined stereologically. Serum ghrelin level was increased especially in HVO and CHL combination group compared to the control while serum ghrelin levels were close to control levels in SP-received groups. Ghrelin receptor level was increased in tubulus seminiferus with HVO+CHL administration but this effect was, however, limited in HVO+CHL and SP challenged groups. HVO+CHL administration caused a significant decrease in Leydig cell nucleus volume density, as well as in all SP-received groups, compared to the control. Significantly increased spermatocyte nucleus volume density in cholesterol-receiving groups was decreased to control level with SP alone and its combinations. PMID- 29166289 TI - A statistical method for analysing cospeciation in tritrophic ecology using electrical circuit theory. AB - We introduce a new method to test efficiently for cospeciation in tritrophic systems. Our method utilises an analogy with electrical circuit theory to reduce higher order systems into bitrophic data sets that retain the information of the original system. We use a sophisticated permutation scheme that weights interactions between two trophic layers based on their connection to the third layer in the system. Our method has several advantages compared to the method of Mramba et al. [Mramba, L. K., S. Barber, K. Hommola, L. A. Dyer, J. S. Wilson, M. L. Forister and W. R. Gilks (2013): "Permutation tests for analyzing cospeciation in multiple phylogenies: applications in tri-trophic ecology," Stat. Appl. Genet. Mol. Biol., 12, 679-701.]. We do not require triangular interactions to connect the three phylogenetic trees and an easily interpreted p-value is obtained in one step. Another advantage of our method is the scope for generalisation to higher order systems and phylogenetic networks. The performance of our method is compared to the methods of Hommola et al. [Hommola, K., J. E. Smith, Y. Qiu and W. R. Gilks (2009): "A permutation test of host-parasite cospeciation," Mol. Biol. Evol., 26, 1457-1468.] and Mramba et al. [Mramba, L. K., S. Barber, K. Hommola, L. A. Dyer, J. S. Wilson, M. L. Forister and W. R. Gilks (2013): "Permutation tests for analyzing cospeciation in multiple phylogenies: applications in tri-trophic ecology," Stat. Appl. Genet. Mol. Biol., 12, 679 701.] at the bitrophic and tritrophic level, respectively. This was achieved by evaluating type I error and statistical power. The results show that our method produces unbiased p-values and has comparable power overall at both trophic levels. Our method was successfully applied to a dataset of leaf-mining moths, parasitoid wasps and host plants [Lopez-Vaamonde, C., H. Godfray, S. West, C. Hansson and J. Cook (2005): "The evolution of host use and unusual reproductive strategies in achrysocharoides parasitoid wasps," J. Evol. Biol., 18, 1029 1041.], at both the bitrophic and tritrophic levels. PMID- 29166290 TI - Implementation of a Routine Health Literacy Assessment at an Academic Medical Center. AB - Limited health literacy is a common but often unrecognized problem associated with poor health outcomes. Well-validated screening tools are available to identify and provide the opportunity to intervene for at-risk patients in a resource-efficient manner. This is a multimethod study describing the implementation of a hospital-wide routine health literacy assessment at an academic medical center initiated by nurses in April 2014 and applied to all adult inpatients. Results were documented in the electronic health record, which then generated care plans and alerts for patients who screened positive. A nursing survey showed good ease of use and adequate patient acceptance of the screening process. Six months after hospital-wide implementation, retrospective chart abstraction of 1,455 patients showed that 84% were screened. We conclude that a routine health literacy assessment can be feasibly and successfully implemented into the nursing workflow and electronic health record of a major academic medical center. PMID- 29166291 TI - Job Stress in Young Adults is Associated With a Range of Poorer Health Behaviors in the Childhood Determinants of Adult Health (CDAH) Study. AB - OBJECTIVE: To examine job stress and health behaviors, including their co occurrence, in Australians aged 31 to 41 year assessed in 2009 to 2011. METHODS: Cross-sectional analyses using multivariable regression models of the association between the Effort Reward Imbalance (ERI) scale and health behaviors (smoking, alcohol consumption, diet, physical activity, and body mass index [BMI]) both individually and co-occurring (0 to 3 vs 4 to 5 behaviors) were undertaken. Covariates included sociodemographics, personality, and life events. RESULTS: Greater ERI was associated with a significantly lower prevalence of having co occurring healthy behaviors and poorer diets in both sexes. Higher ERI was also associated greater physical inactivity and sedentary behavior in men and smoking, high alcohol consumption, and more pedometer-measured physical activity in women. CONCLUSION: Job stress at work was associated with a range of unhealthy behaviors, which may explain the higher chronic disease associated with job stress. PMID- 29166292 TI - Concussion in Theater: A Cross-Sectional Survey of Prevalence and Management in Actors and Theater Technicians. AB - OBJECTIVE: Determine the history of occupational head impacts, concussion symptoms, and concussion management in theater personnel. METHODS: Personnel working in theater environments completed a survey about head impacts that occurred in theater activities and how they were managed. RESULTS: Lifetime prevalence of sustaining at least one theater-related head impact was 67%. Thirty nine percent of respondents reported more than five lifetime head impacts; 77% reported three or more. Of those who struck their head, 70% experienced concussion-related symptoms, but continued participating. Nearly half of those did not report the incident. Twenty-eight percent of those diagnosed with a concussion by a healthcare provider were not given recommended care. CONCLUSIONS: Theater personnel are likely to sustain several occupational head impacts. They appear hesitant to report possible concussions and generally do not access definitive, evidence-based healthcare for head injuries. PMID- 29166293 TI - Applicability of the Calcaneal Apophysis Ossification Staging System to the Modern Pediatric Population. AB - BACKGROUND: The calcaneal apophysis ossification staging system is a novel method for assessing skeletal maturity. However, it was created using the same historic patient population that was used to create the Greulich and Pyle atlas of the hand and wrist, predominantly white children. It is unclear if the calcaneal apophysis ossification staging system is still applicable to the modern pediatric population and to children of other races. METHODS: We retrospectively studied 1327 benign lateral foot x-rays from modern white and black children. Calcaneal stage was determined and age, race, and sex were collected for each patient. A 2 tailed Student t test was used to compare between cohorts the differences in age for each calcaneal stage. RESULTS: Mean age was 11.55+/-4.39 years. Modern white females graded as stage 3 and 4 were significantly delayed in their bone age (stage 3 P<0.002; stage 4 P<0.003) when compared with their historic counterparts. Skeletal maturity was consistent between modern and historic white males for stages 1 to 4. Modern black females graded as stage 1 to 4 were significantly advanced in their skeletal age when compared with modern white females (stage 1 P<0.038; stage 2 P<0.005; stage 3 P<0.002; stage 4 P<0.002). Modern black males graded as stages 1, 3, and 4 were also significantly advanced in their bone age when compared with their modern white counterparts (stage 1 P<0.003; stage 3 P<0.012; stage 4 P<0.029). CONCLUSIONS: Modern white females mature more slowly in the later stages when compared with their historic counterparts. No significant difference is seen between modern and historic white males. Modern black females and males were skeletally advanced compared with modern white females and males. We have shown that the calcaneal ossification staging system can be used to assess for skeletal maturity in the modern pediatric population with only mild corrections for white females and more significant adjustments for black females and males. LEVEL OF EVIDENCE: Level III retrospective chart review. PMID- 29166294 TI - Roles and Experiences of Parents in Necrotizing Enterocolitis: An International Survey of Parental Perspectives of Communication in the NICU. AB - BACKGROUND: Although partnering with parents is important to improving neonatal outcomes, no studies have investigated what parents are taught, remember, or experience when their child is afflicted with necrotizing enterocolitis (NEC). PURPOSE: To characterize parental perceptions of communication and support they were given about NEC. METHODS: An online survey was developed, reviewed for face validity, and then administered to parents whose child had experienced NEC. Quantitative data were analyzed using descriptive statistics, and qualitative data were analyzed using a qualitative descriptive approach. FINDINGS: Parents (N = 110) wanted to know the risk factors and warning signs for NEC and wanted to be told as soon as their child was admitted to the neonatal intensive care unit (NICU). Information provided before diagnosis was felt to be poor by the majority of families, with only 32% feeling satisfied or very satisfied. No parent wrote that they were "scared" by information provided to them about NEC; in fact, parents were dissatisfied when they received "sugar-coated" information. Engaged parents were significantly more satisfied than those who were not informed, had their concerns and suggestions dismissed, or who had to advocate for their baby against clinician opposition (eg, activating the chain of command). IMPLICATIONS FOR PRACTICE: Areas for quality improvement include better communication and collaboration with parents through early engagement in NEC prevention using modalities beyond verbal instruction. IMPLICATIONS FOR RESEARCH: More research is needed on how best to engage parents, especially to engage in prevention, and how doing so affects satisfaction and outcomes. PMID- 29166295 TI - Nursing Care of Infants With a Ventriculoperitoneal Shunt. AB - BACKGROUND: Infants with congenital or posthemorrhagic hydrocephalus may require a ventriculoperitoneal (VP) shunt to divert the flow of cerebrospinal fluid, thus preventing increase in intracranial pressure. Knowledge on various aspects of caring for a child with a VP shunt will enable new and experienced nurses to better care for these infants and equip parents for ongoing care at home. PURPOSE: To review the nurses' role in care of infants with hydrocephalus, care after VP shunt placement, prevention of complications, and parental preparation for home care. METHODS/SEARCH STRATEGY: A literature review involving electronic databases, such as CINAHL and MEDLINE, Cochrane Database Systematic Reviews, and resources from the Web sites of the National Hydrocephalus Foundation and Hydrocephalus Association, was performed to gather evidence for current practice information. FINDINGS AND IMPLICATIONS FOR PRACTICE AND RESEARCH: Vigilant care can help with early identification of potential complications. The younger the infant at VP shunt placement, the higher the occurrence of complications. All neonatal intensive care unit nurses must be equipped with knowledge and skills to care for infants with hydrocephalus and those who undergo VP shunt placement. Monitoring for early signs of increased intracranial pressure can facilitate timely diagnosis and prompt surgical intervention. Equipping families will be helpful in early identification and timely management of shunt failure. Research on infants with VP shunt placement is essential to develop appropriate guidelines and explore experiences of families to identify caregiver burden and improve parental preparation. PMID- 29166296 TI - Emergency Intubations in a High-Volume Pediatric Emergency Department. AB - INTRODUCTION: Resuscitation of critically ill children can be chaotic, and emergency airway management is often fraught with difficulties. This study aimed to characterize the Singaporean landscape of tracheal intubation in a pediatric emergency unit, placing emphasis on safety outcomes, procedural process of care, and provider training. METHODS: A retrospective review of all cases presented to the KK Women's and Children's Hospital from January 2009 to December 2013 with intubation carried out within the pediatric emergency unit was done. Medical records were accessed for data collection, and the information was subsequently used for analysis. RESULTS: A total of 207 intubations were carried out in the pediatric emergency unit. The median age was 4 years (interquartile range, 11 months to 8 years). Oral tracheal intubation with the combination of sedation and paralysis was the main approach. Atropine was used for pretreatment in 156 cases (75.4%). Midazolam was the most commonly used induction agent, and succinylcholine was the most commonly used the paralytic agent. Intubation was achieved on the first attempt in 175 cases (84.5%). Postintubation sedation was initiated in 94 cases (45.4%). Postintubation paralysis was initiated in 50 cases (24.2%). Postintubation analgesia was initiated in 13 cases (6.3%). Twenty emergency intubations (9.7%) were associated with at least 1 tracheal intubation adverse event, with 7 cases (3.4%) having severe tracheal intubation adverse events. In 1 case (0.5%), the patient died within the pediatric emergency unit, and 27 patients (13.0%) did not survive to discharge from the hospital. CONCLUSIONS: All tracheal intubations performed were successful. Variance still exists in tracheal intubation practice. Further elucidation of patient, practice, and provider factors will aid development of a bundle quality improvement intervention directed at addressing these factors. PMID- 29166297 TI - Assessing Patients' Perceptions of Safety Culture in the Hospital Setting: Development and Initial Evaluation of the Patients' Perceptions of Safety Culture Scale. AB - OBJECTIVES: Both, patient satisfaction and hospital safety culture have been recognized as key characteristics of healthcare quality and patient safety. Thus, both characteristics are measured widely to support quality and safety improvement efforts. However, because safety culture surveys focus exclusively on the perspective of hospital staff, the complimentary information to be gained from patients' perceptions of safety culture has received little research attention so far. We aimed to develop a measure explicitly focusing on patients' perceptions of safety culture in the hospital setting and perform an initial evaluation of its measurement properties. METHODS: We employed a multistep development approach including (a) literature review of survey instruments for patient experience and safety culture and (b) item categorization and selection. We evaluated the measurement properties of the final item set focusing on factor structure, internal consistency, item difficulty, and discrimination. Data were collected from June to December 2015 via an online patient survey conducted routinely by a health insurer. RESULTS: Overall, 112,814 insured persons participated in the online survey (response rate = 19.7%). The final 11-item set formed a single scale that was named Patients' Perceptions of Safety Culture scale. Its measurement properties were deemed satisfactory based on this initial evaluation. CONCLUSIONS: The Patients' Perceptions of Safety Culture scale contributes to both a more comprehensive view of patients' experience of healthcare and a more balanced approach to safety culture measurement in healthcare. It contributes to an increased recognition of patients' views on safety-relevant aspects of their care that provide important inputs to patient safety improvement.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29166298 TI - Evaluation of a Broad-Spectrum Partially Automated Adverse Event Surveillance System: A Potential Tool for Patient Safety Improvement in Hospitals With Limited Resources. AB - OBJECTIVE: The aim of the study was to evaluate the sensitivity and resource efficiency of a partially automated adverse event (AE) surveillance system for routine patient safety efforts in hospitals with limited resources. METHODS: Twenty-eight automated triggers from the hospital information system's clinical and administrative databases identified cases that were then filtered by exclusion criteria per trigger and then reviewed by an interdisciplinary team. The system, developed and implemented using in-house resources, was applied for 45 days of surveillance, for all hospital inpatient admissions (N = 1107). Each trigger was evaluated for its positive predictive value (PPV). Furthermore, the sensitivity of the surveillance system (overall and by AE category) was estimated relative to incidence ranges in the literature. RESULTS: The surveillance system identified a total of 123 AEs among 283 reviewed medical records, yielding an overall PPV of 52%. The tool showed variable levels of sensitivity across and within AE categories when compared with the literature, with a relatively low overall sensitivity estimated between 21% and 44%. Adverse events were detected in 23 of the 36 AE categories defined by an established harm classification system. Furthermore, none of the detected AEs were voluntarily reported. CONCLUSIONS: The surveillance system showed variable sensitivity levels across a broad range of AE categories with an acceptable PPV, overcoming certain limitations associated with other harm detection methods. The number of cases captured was substantial, and none had been previously detected or voluntarily reported. For hospitals with limited resources, this methodology provides valuable safety information from which interventions for quality improvement can be formulated. PMID- 29166299 TI - Exercise and the Tumor Microenvironment: Potential Therapeutic Implications. AB - An imbalance in oxygen delivery to demand in solid tumors results in local areas of hypoxia leading to poor prognosis for the patient. We hypothesize that aerobic exercise increases tumor blood flow, recruits previously nonperfused tumor blood vessels, and thereby augments blood-tumor O2 transport and diminishes tumor hypoxia. When combined with conventional anticancer treatments, aerobic exercise can significantly improve the outcomes for several types of cancers. PMID- 29166300 TI - Effect of Age on High T1 Signal Intensity of the Dentate Nucleus and Globus Pallidus in a Large Population Exposed to Gadodiamide. AB - OBJECTIVE: The purpose of this study was to assess the effect of age and number of previous injections of gadodiamide on the signal intensity of unenhanced T1 weighted (T1w) images of the dentate nucleus and globus pallidus in a large population. MATERIALS AND METHODS: A large, single-center retrospective population survey was designed and received institutional review board approval. Between January 2014 and December 2014, T1w signal intensity ratios were obtained from a large population of 2500 consecutive enhanced brain magnetic resonance imaging (MRI) scans. Of these, 1906 MRI scans of patients not previously exposed to any gadolinium (Gd)-based contrast agent were used as control group and were compared with 892 MRI scans of patients with documented prior exposure to intravenous gadodiamide. A quantitative study was conducted to assess the T1w signal intensity of dentate nucleus-to-pons (Dn/Po) and globus pallidus-to thalamus (Gp/Th) ratios. Multiple regression analysis was used to test the effect of age, time delay, and number of previous Gd-based contrast agent injections as predictor variables of T1w signal intensity ratios. RESULTS: In the Gd-exposed patients, multivariate regression analysis showed age (beta = -0.285; P < 0.0001) and the number of previous injections of gadodiamide (beta = 0.224; P < 0.0001) to be powerful predictors of Dn/Po ratio. Similarly, age (beta = 0.269; P < 0.0001) and the number of previous injections of gadodiamide (beta = 0.127; P < 0.0001) predicted Gp/Th ratio. CONCLUSIONS: In this study, we confirm that the number of previous gadodiamide injections is a powerful predictor of the signal intensity increase of the Dn/Po and Gp/Th ratios on unenhanced T1w images and demonstrate that aging influences the T1 signal intensity of DN and GP in Gd naive and in Gd-exposed subjects. PMID- 29166301 TI - Can We Train Machine Learning Methods to Outperform the High-dimensional Propensity Score Algorithm? AB - The use of retrospective health care claims datasets is frequently criticized for the lack of complete information on potential confounders. Utilizing patient's health status-related information from claims datasets as surrogates or proxies for mismeasured and unobserved confounders, the high-dimensional propensity score algorithm enables us to reduce bias. Using a previously published cohort study of postmyocardial infarction statin use (1998-2012), we compare the performance of the algorithm with a number of popular machine learning approaches for confounder selection in high-dimensional covariate spaces: random forest, least absolute shrinkage and selection operator, and elastic net. Our results suggest that, when the data analysis is done with epidemiologic principles in mind, machine learning methods perform as well as the high-dimensional propensity score algorithm. Using a plasmode framework that mimicked the empirical data, we also showed that a hybrid of machine learning and high-dimensional propensity score algorithms generally perform slightly better than both in terms of mean squared error, when a bias-based analysis is used. PMID- 29166303 TI - The Next Frontier for Nurses: Improving Quality and Safety in Primary Care. PMID- 29166302 TI - Hierarchical Semi-Bayes Methods for Misclassification in Perinatal Epidemiology. AB - BACKGROUND: Validation data are used to estimate the extent of misclassification in epidemiologic studies. In the Penn MOMS cohort, prepregnancy body mass index is subject to misclassification, and validation data are available to estimate the extent of misclassification. We use these data to estimate the association between maternal prepregnancy body mass index and early preterm (<32 weeks) birth using a semi-Bayes hierarchical model, allowing for more flexible adjustment for misclassification. METHODS: We propose a two-stage model that first fits a Bayesian hierarchical model for the bias parameters in the validation study. This model shrinks bias parameters in different groups toward one another in an effort to gain precision and improve mean squared error. In the second stage, we draw random samples from the posterior distribution of the bias parameters to implement a probabilistic bias analysis adjusting for exposure misclassification in a frequentist outcome model. RESULTS: Bias parameters from the hierarchical model were often more substantively reasonable and often had smaller variance. Adjusting results for misclassification generally attenuated the strength of the unadjusted associations. After adjusting for misclassification, underweight mothers were not at increased risk of early preterm birth relative to normal weight mothers. Severely obese mothers had an increased risk of early preterm birth relative to normal weight mothers. CONCLUSIONS: The two-stage semi-Bayesian hierarchical model borrowed strength between group-specific bias parameters to adjust for exposure misclassification. Model results support evidence of an increased risk of early preterm birth among severely obese mothers, relative to normal weight mothers. PMID- 29166304 TI - Improving Compliance in Obtaining Daily Weights in a Large Academic Children's Hospital. PMID- 29166305 TI - Botulinum Toxin Therapy: Is Syringe Type Related to Cost-Effectiveness? AB - INTRODUCTION: Clostridium botulinum toxin is effective through cleaving presynaptic proteins at the neuromuscular junction, which prevents the release of acetylcholine and inhibits muscle contraction. Several serotypes of botulinum toxin (BT) exist; however, only 2 types have been approved by the US Food and Drug Administration for commercial and medical use, A and B. Both types of BT must be administered intramuscularly with a syringe, but the type of syringe is the injector's preference. Which syringe type is most efficient in minimizing product waste and most cost-effective for the patient and provider? METHODS: We performed a single-center, open-label, analytical study using BT therapy and 2 types of syringes for analytics of cost-effectiveness. OnabotulinumtoxinA was the neuromodulator used in this report. Vials (100 U) of BT A were each reconstituted with 2.5 mL of 0.9% sodium chloride, for a final concentration of 4 U/0.1 mL. High-dead-space syringes are compared with low-dead-space syringes: 1-mL tuberculin (TB) luer slip syringe with detachable 25-gauge needle and 1-mL ultrafine insulin syringe with an attached 31-gauge needle, respectively. After each syringe was evacuated, the TB syringe was noted to contain 0.05 mL of the remaining product in the hub. RESULTS: Providers are discarding approximately 2 U of BT per TB syringe product injection. If the physician uses 30 syringes per day, 3 days a week, for 1 year, it equals to a lost revenue of approximately $155,500 per year. To individualize the cost-effective analysis, average quantity of syringes used per patient and overall patient volume must be considered, with corresponding adjustment of cost and units discarded. DISCUSSION: The American Society of Plastic Surgeons reported that the use of neuromodulators has increased by approximately 797% from 2000 to 2016. During that period, the price of neuromodulators has also increased by approximately 85%. Considering these statistics, the type of syringe used for BT neuromodular injection is a thought provoking concept but surrounded by a paucity of data. Overall, our data suggest that the use of ultrafine insulin syringes for injection of BT reduces product waste and is cost-effective for the patient and the provider. PMID- 29166306 TI - The Surgical Management of Nerve Gaps: Present and Future. AB - Peripheral nerve injuries can result in significant morbidity, including motor and/or sensory loss, which can affect significantly the life of the patient. Nowadays, the gold standard for the treatment of nerve section is end-to-end neurorrhaphy. Unfortunately, in some cases, there is segmental loss of the nerve trunk. Nerve mobilization allows primary repair of the sectioned nerve by end-to end neurorrhaphy if the gap is less than 1 cm. When the nerve gap exceeds 1 cm, autologous nerve grafting is the gold standard of treatment. To overcome the limited availability and the donor site morbidity, other techniques have been used: vascularized nerve grafts, cellular and acellular allografts, nerve conduits, nerve transfers, and end-to-side neurorrhaphy. The purpose of this review is to present an overview of the literature on the applications of these techniques in peripheral nerve repair. Furthermore, preoperative evaluation, timing of repair, and future perspectives are also discussed. PMID- 29166307 TI - Comment: Thoracoacromial Vessels Exposure in Microvascular Breast Reconstruction. PMID- 29166308 TI - An Evaluation of the Choice for Contralateral Prophylactic Mastectomy and Patient Concerns About Recurrence in a Reconstructed Cohort. AB - BACKGROUND: Rising contralateral prophylactic mastectomy rates are a subject of national concern. This study assessed (1) factors critical to patients when deciding on contralateral prophylactic mastectomy and (2) patients' quality of life related to concerns about recurrence after unilateral or bilateral breast reconstruction. METHODS: Patients with stage 0 to III breast cancer who underwent unilateral mastectomy or contralateral prophylactic mastectomy and breast reconstruction at a single institution between 2000 and 2012 were identified. Demographic and clinical data were extracted by chart review. Women's fears about breast cancer recurrence were assessed using the Concerns About Recurrence Scale, and motivational factors for contralateral prophylactic mastectomy were identified using the Decisions for Contralateral Prophylactic Mastectomy Survey. RESULTS: Survey responses were received from 157 patients (59%) who underwent unilateral reconstruction and 109 (41%) who underwent bilateral reconstruction. The top 3 reasons for choosing contralateral prophylactic mastectomy were (1) decreasing the risk of contralateral breast disease (97%), (2) peace of mind (96%), and (3) improved survival (93%). Women who chose contralateral prophylactic mastectomy reported significantly greater overall fear and worry compared with the unilateral group, specifically, greater fears of dying and worries about adequately fulfilling roles of daily life (P < 0.05). CONCLUSIONS: Despite no proven survival benefit, women chose contralateral prophylactic mastectomy primarily to optimize oncologic outcomes. Among breast reconstruction patients, women who underwent contralateral prophylactic mastectomy had greater anxiety and overall fear of breast cancer recurrence compared with those who chose unilateral mastectomy. These findings are important to consider when counseling women contemplating contralateral prophylactic mastectomy. PMID- 29166309 TI - Surgeon Sleep Deprivation, Surgical Complications, and the Ethical Imperatives of Evidence-Based Persuasion. PMID- 29166310 TI - Universal Applicability of the Furlow Palatoplasty: Resident as Primary Surgeon in a Consecutive, Nonselective Series. AB - BACKGROUND: Questions persist regarding the general applicability of the Furlow palatoplasty technique, and thus, widespread adoption of its use has been uneven. This study describes a consecutive, nonselective series of primary Furlow palatoplasties. Highlighted is the unique fact that plastic surgical residents functioned as the primary surgeon for all steps of all procedures throughout the series. METHODS: A retrospective review was undertaken of all primary palatoplasties performed under the direction of the senior surgeon between December 2005 and April 2012. A stringent requirement for speech outcome reporting was patient age at the latest assessment of older than 4.5 years. Other measured parameters included fistula rate, incidence of secondary surgery, and procedure duration. RESULTS: Seventy-five patients were included in this study. Nasal resonance was rated as "normal" in 56.1% of the patients and "mildly hypernasal or better" in 95.1% of the patients. Articulation errors were detected in 14.6% of the patients, and symptoms related to nasal air emission were detected in 4.9% of the patients. Overall fistula rate was 5.3%. The following associations were detected: (1) Veau cleft type and procedure duration, P = 0.001; (2) resident year of training and procedure duration, P = 0.009; (3) developmental delay and resonance score, P = 0.002; (4) patient age at surgery and resonance score, P = 0.025; and (5) presence of syndrome and resonance score, P = 0.036. CONCLUSIONS: This nonselective series of consecutive Furlow palatoplasty procedures demonstrates that plastic surgical residents are able to match best published clinical results performing the entire procedure under the close supervision and guidance of an assisting surgical mentor. PMID- 29166311 TI - The Use and Delivery of Stem Cells in Nerve Regeneration: Preclinical Evidence and Regulatory Considerations. AB - Outcomes following peripheral nerve injury remain poor despite the regenerative capacity displayed by the peripheral nervous system. Current therapies are limited and do not provide satisfactory functional recovery in a multitude of cases. Biomaterials have decreased the need for nerve autograft across small nerve gaps in small-caliber nerves, but the lack of a cellular substrate presents a limiting factor to the effectiveness of this therapy. Schwann cells are the supportive cells in the peripheral nervous system and play an integral role in the physiological response and regeneration following nerve injury. Limitations to autologous Schwann cells include donor site morbidity during harvesting, limited expansion capability, and finite source. Stem cells are multipotent or pluripotent cells with self-renewing capabilities that show promise to improve functional recovery following nerve injury. Differentiation of stem cells into supportive Schwann cells could provide additional trophic support without the disadvantages of autologous Schwann cells, providing an avenue to improve existing therapies. A variety of stem cells have been evaluated in animal models for this clinical application; the current options, along with their clinical feasibility, are summarized in this article. PMID- 29166312 TI - Factors Associated With Late Surgical Cancellations in Pediatric Plastic and Oral Surgery. AB - BACKGROUND: Surgical cancellations that occur within 1 day of the procedure (ie, late cancellations) disrupt the efficiency of the operating room. The aim of the present study was to identify the factors associated with late cancellations in a tertiary pediatric surgical practice. METHODS: We reviewed the medical records of patients treated by plastic and oral surgery services at our institution from 2010 to 2015. We collected data pertaining to the timing and reasons for cancellation. Reasons for cancellation were retrospectively classified by the investigators as either "preventable," "possibly preventable," "unpreventable," or "undocumented." We also measured the frequency of cancellations based on type of surgery. RESULTS: Of 10,730 scheduled operating room cases, 444 (4.1%) were cancelled within 24 hours of the procedure. Sixty-seven percent (297/444 cases) were cancelled on the same day as the planned procedure, and the remaining cases were cancelled the day prior after 1 PM. Forty-two percent of cancellations were deemed preventable, and 45.3% of cases were deemed possibly preventable. The majority of procedures were cancelled because of illness (44%), inadequate fasting (9%), and parental inconvenience (7%). The highest frequency of cancellation was found in skin lesion (36%) followed by dentoalveolar (14%) and cleft lip and palate (12%) cases. CONCLUSIONS: In our study, most late surgical cancellations were preventable or possibly preventable. The timing of the cancellation is important because those that occur near the scheduled procedure time disallow adequate and timely redistribution of operating room resources and personnel. Analyzing and addressing the preventable and possibly preventable causes outlined in this study will significantly improve efficiency and patient access. PMID- 29166313 TI - The Perineal Turnover Perforator Flap: A New and Simple Technique for Perineal Reconstruction After Extralevator Abdominoperineal Excision. AB - BACKGROUND: Extralevator abdominoperineal excision (ELAPE) is increasingly used to treat locally advanced low rectal cancer as it has been related to superior oncological outcomes than traditional abdominoperineal excision.However, ELAPE also has been associated with high perineal wound morbidity rates as it creates a larger perineal cavity than standard abdominoperineal excision. This greater defect, along with the effects of preoperative chemoradiation on wound healing, makes uneventful perineal reconstruction post-ELAPE a real challenge for the plastic surgeon.In this paper, the authors present a new technique for perineal reconstruction post-ELAPE, using a perforator, islanded, turnover, de epithelialized local flap (perineal turnover perforator [PTO] flap). METHODS: The PTO flap is raised based on perforators from internal pudendal artery. The flap is based on the concept that thick gluteal dermis can act as an "autologous dermal vascularized" substitute for the excised pelvic floor muscles, whereas the bulk of its subcutaneous tissue is used to obliterate dead space.Fourteen patients underwent perineal reconstruction using this approach. Patients' demographics, neoadjuvant chemoradiotherapy, histopathology, duration of surgery, follow-up, and complications were analysed retrospectively. RESULTS: Median operating time was 49 minutes. There were no flap, donor site, or major wound complications. One patient had superficial skin dehiscence, and one patient developed perineal hernia. None of the patients developed chronic perineal pain. CONCLUSIONS: The PTO flap is a quick, simple yet safe and reliable option for perineal reconstruction after ELAPE that offers many advantages over the heretofore used reconstructive techniques including primary closure, myocutaneous flaps, and biological meshes. PMID- 29166314 TI - Step Cut Lengthening: A Technique for Treatment of Flexor Pollicis Longus Tendon Rupture. AB - Reconstruction of a tendon defect is a challenging task in hand surgery. Delayed repair of a ruptured flexor pollicis longus (FPL) tendon is often associated with tendon defect. Primary repair of the tendon is often not possible, particularly after debridement of the unhealthy segment of the tendon. As such, various surgical treatments have been described in the literature, including single-stage tendon grafting, 2-stage tendon grafting, flexor digitorum superficialis tendon transfer from ring finger, and interphalangeal joint arthrodesis. We describe step cut lengthening of FPL tendon for the reconstruction of FPL rupture. This is a single-stage reconstruction without the need for tendon grafting or tendon transfer. To our knowledge, no such technique has been previously described. PMID- 29166315 TI - Poly Implants Prosthese Breast Implants: A Case Series and Review of the Literature. AB - BACKGROUND: Silicone breast implants from the French manufacturer Poly Implants Prosthese (PIP) were recalled from the European market after the French regulator has revealed the implants contain non-medical-grade silicone filler. In December 2011, following a large increase in reported rupture rate and a possible cancer risk, the French Ministry of Health recommended consideration of the PIP explantation, regardless of their condition. In 2012, the Israel Ministry of Health recommended to replace the implants only upon suspected implant rupture. OBJECTIVES: The aims of this study were to characterize breast-augmented Israeli patients with PIP implants, compare their outcomes with those of breast-augmented patients with different implant types, and review the current PIP literature. METHODS: Breast-augmented patients who underwent an elective breast implant exchange in Israel between January 2011 and January 2017 were included in the study. Data were collected from electronic and physical medical files. RESULTS: There were 73 breast-augmented female patients with 146 PIP breast implants included in this study. Average implant age was 6.7 +/- 2.79 years. Mean implant size was 342.8 +/- 52.9 mL. Fourteen women (19 implants [16%]) had a high-grade capsular contracture (Baker grade 3-4). During exchange, 28 implants were found to be ruptured (19.2%). CONCLUSIONS: Less than 10 years following breast augmentation, PIP implants demonstrated higher rupture rate compared with other implants. Our data are comparable to overall available rupture rate. Among patients with definitive rupture diagnosis, an elective implant removal should be recommended. In cases of undamaged implants, plastic surgeons should also seriously consider PIP implant explantation. When the patient does not desire to remove the implant, an annual physical examination and breast ultrasound are recommended, beginning a year after augmentation. PMID- 29166316 TI - The Impact of Repetitive Transcranial Magnetic Stimulation on Oxidative Stress in Subjects With Medication-Resistant Depression. AB - OBJECTIVES: Recent studies have shown that oxidative stress is involved in the neurobiology of depression. We investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on a novel oxidative stress marker, thiol-disulfide homeostasis, in subjects with medication-resistant major depression (MRD). METHODS: Twenty-six subjects with MRD underwent 15 rTMS sessions. Sociodemographic and baseline and post-rTMS Montgomery-Asberg Depression Rating Scale (MADRS) data were collected. Serum levels of native thiol, total thiol, and disulfide and their pairwise ratios were measured in baseline and post-rTMS blood samples. RESULTS: Serum levels of native and total thiol were significantly decreased after rTMS treatment (P < 0.05). Serum levels of thiol-disulfide and their ratios did not significantly differ (P > 0.05) between rTMS treatment responders (>50% reduction in MADRS score, n = 11) and rTMS treatment nonresponders (n = 15). The percentage MADRS score changes did not correlate with the changes in the levels of serum thiol-disulfide from baseline to post-rTMS treatment in any subject (P > 0.05). CONCLUSIONS: Our results showed that rTMS treatment was effective in subjects with MRD and was associated with changes in serum thiol levels regardless of improvement in depression severity. Thus, the results did not support a possible therapeutic relationship between rTMS and thiol-disulfide homeostasis in subjects with MRD. PMID- 29166317 TI - Electroconvulsive Therapy in the Czech Republic. AB - OBJECTIVES: Electroconvulsive therapy (ECT) is effective in the treatment of severe psychiatric disorders. Electroconvulsive therapy is applied to almost 1 million patients every year around the world. The aim of this study was to monitor the use of ECT in psychiatric facilities for adults in the Czech Republic (CR) in 2014 and to describe the national practice. METHODS: A 14-item questionnaire was sent to all Czech inpatient psychiatric facilities that provide ECT, with the aim of getting a detailed picture of the use of ECT in the CR. The questionnaire assessed the technical background for using ECT in each center, along with indications for the treatment, the procedure, and the manner of documenting and monitoring adverse effects. The data obtained were supplemented with information about national legal and ethical regulations as well as historical background. RESULTS: Electroconvulsive therapy is used in 26 centers across the CR. More than 1000 patients were treated with ECT in 2014. All centers use instruments delivering brief pulse stimuli, monitoring electroencephalogram and electrocardiogram. All patients have to be indicated for this treatment, which is a decision the patient's psychiatrist makes. All patients have to sign an informed consent form, excluding a situation where the patient's life is endangered. Somatic state is assessed in all patients. Bitemporal electrode placement is the preferred option in all centers. CONCLUSIONS: This article covers detailed information about the use of ECT in the CR. The results will be used to harmonize national practice and reduce the stigma associated with this method in the CR. PMID- 29166318 TI - Neurogenic Pulmonary Edema Complicating ECT. PMID- 29166319 TI - Cardiometabolic Impact of Changing Sitting, Standing, and Stepping in the Workplace. AB - BACKGROUND: According to cross-sectional and acute experimental evidence, reducing sitting time should improve cardiometabolic health risk biomarkers. Furthermore, the improvements obtained may depend on whether sitting is replaced with standing or ambulatory activities. Based on data from the Stand Up Victoria multicomponent workplace intervention, we examined this issue using compositional data analysis-a method that can examine and compare all activity changes simultaneously. METHODS: Participants receiving the intervention (n = 136 >= 0.6 full-time equivalent desk-based workers, 65% women, mean +/- SD age = 44.6 +/- 9.1 yr from seven worksites) were asked to improve whole-of-day activity by standing up, sitting less, and moving more. Their changes in the composition of daily waking hours (activPAL-assessed sitting, standing, and stepping) were quantified then tested for associations with concurrent changes in cardiometabolic risk (CMR) scores and 14 biomarkers concerning body composition, glucose, insulin, and lipid metabolism. Analyses were by mixed models, accounting for clustering (3 months, n = 105-120; 12 months, n = 80-97). RESULTS: Sitting reduction was significantly (P < 0.05) associated only with lower systolic blood pressure at 3 months, and with CMR scores, weight, body fat, waist circumference, diastolic blood pressure, and fasting triglycerides, total/HDL cholesterol, and insulin at 12 months. Significant differences between standing and stepping were only observed for systolic blood pressure and insulin; both favored stepping. However, replacing sitting with standing was significantly associated only with improvements in CMR scores, whereas replacing sitting with stepping was significantly associated with CMR scores and six biomarkers. CONCLUSIONS: Improvements in several cardiometabolic health risk biomarkers were significantly associated with sitting reductions that occurred in a workplace intervention. The greatest degree and/or widest range of cardiometabolic benefits appeared to occur with long-term changes, and when increasing ambulatory activities. TRIAL REGISTRATION: ACTRN1211000742976. PMID- 29166320 TI - Exercise Alters Gut Microbiota Composition and Function in Lean and Obese Humans. AB - PURPOSE: Exercise is associated with altered gut microbial composition, but studies have not investigated whether the gut microbiota and associated metabolites are modulated by exercise training in humans. We explored the impact of 6 wk of endurance exercise on the composition, functional capacity, and metabolic output of the gut microbiota in lean and obese adults with multiple-day dietary controls before outcome variable collection. METHODS: Thirty-two lean (n = 18 [9 female]) and obese (n = 14 [11 female]), previously sedentary subjects participated in 6 wk of supervised, endurance-based exercise training (3 d.wk) that progressed from 30 to 60 min.d and from moderate (60% of HR reserve) to vigorous intensity (75% HR reserve). Subsequently, participants returned to a sedentary lifestyle activity for a 6-wk washout period. Fecal samples were collected before and after 6 wk of exercise, as well as after the sedentary washout period, with 3-d dietary controls in place before each collection. RESULTS: beta-diversity analysis revealed that exercise-induced alterations of the gut microbiota were dependent on obesity status. Exercise increased fecal concentrations of short-chain fatty acids in lean, but not obese, participants. Exercise-induced shifts in metabolic output of the microbiota paralleled changes in bacterial genes and taxa capable of short-chain fatty acid production. Lastly, exercise-induced changes in the microbiota were largely reversed once exercise training ceased. CONCLUSION: These findings suggest that exercise training induces compositional and functional changes in the human gut microbiota that are dependent on obesity status, independent of diet and contingent on the sustainment of exercise. PMID- 29166321 TI - Adipose Lipolysis Unchanged by Preexercise Carbohydrate Regardless of Glycemic Index. AB - PURPOSE: This study aimed to determine the effect of preexercise carbohydrate of different glycemic indices on subcutaneous abdominal adipose tissue (SCAAT) metabolism and running performance. METHODS: Ten trained male runners completed three experimental trials consisting of 30 min at 60% maximal oxygen consumption, 30 min at 75% maximal oxygen consumption, and a 5-km time trial. Thirty minutes before exercise, participants consumed one of three beverages: 1) 75 g low glycemic index modified starch supplement (UCAN), 2) 75 g high glycemic index glucose-based supplement (G), or 3) a flavor-matched noncaloric placebo (PL). SCAAT lipolysis was assessed via microdialysis. RESULTS: Before exercise, blood glucose and insulin were elevated with G versus PL (+53.0 +/- 21.3 mg.dL (mean +/ SD), P < 0.0001; +33.9 +/- 11.0 MUU.mL, P < 0.0001) and G versus UCAN (+36.6 +/- 24.9 mg.dL, P < 0.0001; +25.2 +/- 11.0 MUU.mL, P < 0.0001), respectively. Fat oxidation was attenuated, and carbohydrate oxidation increased before exercise with G versus PL (-0.06 +/- 0.06 g.min, P = 0.005; +0.18 +/- 0.07 g.min, P < 0.0001) and G versus UCAN (-0.06 +/- 0.05 g.min, P = 0.004; +0.18 +/- 0.14 g.min, P < 0.0001). However, there were no differences in SCAAT lipolysis at rest or during running at either exercise intensity. Also, there was no effect of treatment on running performance. CONCLUSIONS: Preexercise carbohydrate lowers fat oxidation and increases carbohydrate oxidation, and these effects are attenuated with low glycemic index carbohydrate. However, these changes are not the result of alterations in SCAAT lipolysis, nor do they affect running performance. PMID- 29166322 TI - Biological/Genetic Regulation of Physical Activity Level: Consensus from GenBioPAC. AB - PURPOSE: Physical activity unquestionably maintains and improves health; however, physical activity levels globally are low and not rising despite all the resources devoted to this goal. Attention in both the research literature and the public policy domain has focused on social-behavioral factors; however, a growing body of literature suggests that biological determinants play a significant role in regulating physical activity levels. For instance, physical activity level, measured in various manners, has a genetic component in both humans and nonhuman animal models. This consensus article, developed as a result of an American College of Sports Medicine-sponsored round table, provides a brief review of the theoretical concepts and existing literature that supports a significant role of genetic and other biological factors in the regulation of physical activity. CONCLUSIONS: Future research on physical activity regulation should incorporate genetics and other biological determinants of physical activity instead of a sole reliance on social and other environmental determinants. PMID- 29166323 TI - Strength, Affect Regulation, and Subcortical Morphology in Military Pilots. AB - INTRODUCTION: Previous studies have shown links of body composition and fitness measures with brain structure, as well as with different aspects of emotional adjustment and well-being. However, the possible role of trait emotion-regulation success in the relationship between fitness/body composition and emotion-related subcortical structures has never been directly addressed. METHODS: Twenty-three elite helicopter pilots were assessed in fat mass percentage, an endurance test to volitional exhaustion, bench-press power output, and negative urgency (trait affect regulation failure). Their brains were scanned using magnetic resonance imaging to estimate the size of the accumbens/amygdala, considered together, and the thalamus. Resulting correlations were used to test the relationship between body composition/fitness measures and brain structures' size, and the role of negative urgency therein, using structural equation modeling. RESULTS: Fat mass percentage was associated with the size of the thalamus and the amygdala/accumbens. In the latter case, negative urgency and bench-press power output predicted structure size (and explained the effect of fat mass percentage away). In other words, bench-press power output and emotion regulation success (but not endurance performance) were associated with a larger amygdala/accumbens size. CONCLUSIONS: Bench-press power output and emotion regulation success are independently associated with a larger amygdala/accumbens size, although present evidence does not allow for determination of causal directionality. PMID- 29166324 TI - Artificial Intelligence for Everyone. PMID- 29166326 TI - 111In-DTPA-Octreotide SPECT (OctreoScan) Uptake in Metastatic Renal Cell Carcinoma to the Pancreas. AB - We report a case of late presentation of metastatic renal cell carcinoma (RCC) demonstrating intense In-DTPA-octreotide uptake in pancreas without recurrence at the primary site. Immunohistochemistry study revealed somatostatin receptor subtype 2 of metastatic RCC preferentially expressed on tumor endothelial cells. The typical hypervascular features of RCC with intense homogeneous contrast enhancement in the arterial phase on CT should raise the possibility of metastatic RCC. This case illustrates that RCC can demonstrate high octreotide uptake in abdominal metastases. PMID- 29166328 TI - 18F-FDG PET/CT Imaging of Hidradenocarcinoma Arising From Preexisting Hidradenoma of the Knee. AB - Malignant tumors of the sweat glands are exceedingly rare and aggressive tumors. We present here a case of a 60-year-old man with a malignant hidradenocarcinoma that developed in a background of preexisting benign hidradenoma on the lateral aspect of the knee that was initially resected, but rapidly recurred with associated inguinal lymphadenopathy. F-FDG PET/CT was performed as part of preoperative staging, which demonstrated abnormal inguinal lymph nodes and metastatic disease to the lungs. FDG PET/CT can play an invaluable role in the initial staging and follow-up of this rare malignancy. PMID- 29166327 TI - 68Ga-Prostate-Specific Membrane Antigen Uptake in Gastrointestinal Stromal Tumor. AB - A 62-year-old man with recently diagnosed prostatic adenocarcinoma was referred for a whole-body Ga-prostate-specific membrane antigen (PSMA) PET/CT scan for staging. Although the scan did not reveal metastatic disease, it did reveal a PSMA-avid lesion in the upper abdomen located between the liver and the stomach. Histopathologic examination demonstrated a gastrointestinal stromal tumor. The lesion demonstrated increased uptake in the margins of the tumor with a central photopenic area, which we consider to be the typical pattern on PSMA images of a gastrointestinal stromal tumor, based on theoretical PSMA distribution in such a tumor and other reported cases. PMID- 29166329 TI - Pseudolesions Impersonating Osseous Tumor Involvement on Both Contrast Enhanced CT and FDG PET/CT. AB - A 27-year-old man with stage IV-B Hodgkin's lymphoma status post autologous peripheral stem cell transplant in 2015 with complete response, presented in 2017 with increasing back pain. Restaging contrast enhanced CT demonstrated left brachiocephalic vein occlusion with peripheral nodular high density areas within C7-T2 vertebral bodies with corresponding radiotracer uptake on same day PET/CT. No matching lesion was seen on noncontrast CT. Findings were consistent with pooling of contrast and radiotracer within vertebral venous plexus collaterals at the cervicothoracic junction secondary to brachiocephalic vein occlusion. Repeat PET/CT with contralateral injection of radiotracer and MRI confirmed absence of osseous lymphomatous involvement. PMID- 29166330 TI - Hepatic Falciform Artery Demonstrating MAA Uptake in the Anterior Abdomen Prior to Embolization. AB - A 58-year-old man was referred for selective internal radiation therapy for locally advanced unresectable hepatocellular carcinoma. Intra-arterial particle perfusion scintigraphy was performed with SPECT/CT following intra-arterial injection of Tc macroaggregated albumin. Angiography demonstrated a hepatic falciform artery, a feeding artery of the ligamentum teres, whereas scintigraphy demonstrated tracer uptake in the mid-anterior abdominal wall. The hepatic falciform artery was subsequently embolized and the repeat angiogram confirmed successful occlusion. Subsequent post-selective internal radiation therapy PET/CT images did not reveal any tracer uptake in the mid-anterior abdominal wall. PMID- 29166331 TI - 223Ra Therapy in Patients With Advanced Castration-Resistant Prostate Cancer With Bone Metastases: Lessons from Daily Practice. AB - PURPOSE: To identify pre-therapeutic variables associated with overall survival (OS) in patients treated with Ra. METHODS: Data from 45 CRPC patients treated with Ra were retrospectively analyzed. All patients who received at least one Ra injection were included in the study. Cox proportional hazard regression models were used to estimate hazard ratio's (HR) and to test for association. RESULTS: Twenty-one patients (47%) received six Ra injections and 24 patients (53%) received one to five Ra injections. Median OS since start of Ra was 13.0 months (95% confidence interval (CI) 8.2-17.8). Patients who completed Ra therapy had a median OS of 19.7 months (95% CI 14.9-24.6), while patients who received one to five Ra injections had a median OS of 5.9 months (95% CI 3.8-8.1; P < 0.001).Univariable analysis showed poor baseline ECOG performance status (PS), baseline opioid use, lowered baseline hemoglobin, and elevated prostate-specific antigen, alkaline phosphatase and lactate dehydrogenase (LD) levels were significantly associated with OS. Multivariable Cox regression analysis demonstrated that poor baseline ECOG PS (HR 10.6) and high LD levels (HR 7.7) were pre-therapeutic variables that predicted poor OS. CONCLUSIONS: In a multivariable Cox regression model, good baseline ECOG PS and low LD levels were significantly associated with longer OS in patients treated with Ra. These variables may be used for stratification of CRPC patients for Ra therapy. Prospective studies to evaluate these variables are warranted, to develop a nomogram to select patients properly. In this retrospective study, predictors of overall survival in 45 metastatic castration-resistant prostate cancer patients treated with Ra therapy were evaluated. Baseline ECOG performance status and lactate dehydrogenase levels turned out to be significant in a multivariable prediction model for overall survival. PMID- 29166332 TI - Testicular Estrogen-Secreting Leydig Cell Tumor in 18F-FDG PET/CT: An Incidental Detection in a Patient Treated by Chemotherapy for Hodgkin Lymphoma. AB - We present images of a 50-year-old man who referred for treatment of a classic Hodgkin lymphoma. While F-FDG PET/CT demonstrated a complete metabolic remission after chemotherapy, an increased F-FDG uptake of a right testicular lesion in F FDG PET/CT and an unexplained bilateral gynecomastia were observed. A benign Leydig cell tumor was histopathologically proved after a right radical orchiectomy. The serum estradiol level was abnormally elevated reflecting the estrogen-secreting profile. This report highlights that a focal F-FDG uptake in the testicular region with unexplained gynecomastia should suggest the diagnosis of an estrogen-secreting Leydig cell tumor on F-FDG PET/CT. PMID- 29166333 TI - High-Energy Collimator Is Preferable to Medium-Energy Collimator for Evaluating 223Ra Uptake in Bone Metastasis at 2 Weeks Postinjection. AB - An 80-year-old man with castration-resistant prostate cancer received Ra injection to treat bone metastases. Two weeks after the injection, the patient underwent static Ra scan of the chest with medium-energy and high-energy collimators for 30 minutes each. Images obtained with the 2 collimators showed that uptake in metastatic lesions was visually clearer and semiquantitatively higher with the high-energy collimator. The use of HE collimator for Ra imaging in the early phase has been reported, and the present case suggests that in the late phase HE collimator would also be preferable to medium-energy collimator in terms of lesion-based evaluation. PMID- 29166334 TI - Gastrointestinal Stromal Tumor of the Prostate: Staging and Evaluation of Response to Therapy With 18F-FDG PET/CT. AB - A 49-year-old man presented for routine general physical examination was found with an enlarged prostate gland without associated symptoms. Ultrasound followed by computed tomography (CT) of abdomen and pelvis confirmed a markedly enlarged heterogeneous prostate gland. Subsequently, a staging flourine-18 fluorodeoxyglucose (F-FDG) positron emission tomography (PET/CT) scan revealed intensely FDG-avid mass involving the prostate, which was biopsied as gastrointestinal stromal tumor (GIST). The patient was treated with imatinib and a follow-up PET/CT scan showed complete metabolic response. F-FDG PET/CT scan is useful in staging and follow-up of this very rare extragastrointestinal stromal tumor (EGIST). PMID- 29166335 TI - Multiple Hypermetabolic Subcutaneous Lesions From Hidradenitis Suppurativa Mimicking Metastases on 18F-FDG PET/CT. AB - Hidradenitis suppurativa is an inflammatory disease associated with subcutaneous nodules/abscesses that occur commonly in the axillary, inguinal, and perineal regions. We describe a case of a 64-year-old man presenting for F-FDG PET/CT for staging of a left vocal cord squamous cell carcinoma. The scan showed uptake in the left vocal cord malignancy and multiple hypermetabolic subcutaneous foci in the right axilla, right buttocks, and scalp in known locations of skin lesions related to hidradenitis suppurativa. This case illustrates an unusual inflammatory cause of F-FDG incidental uptake that should not be mistaken for metastases. PMID- 29166336 TI - Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: Long-term Results After 7 Years of a Randomized Clinical Trial. AB - BACKGROUND: The VIPP study compared valganciclovir prophylaxis with preemptive treatment regarding efficacy, safety, and long-term graft outcome in cytomegalovirus (CMV)-positive (R+) renal transplant recipients. METHODS: Multicenter, open-label, randomized clinical study with a 12-month study phase and a follow-up of up to 84 months. Patients in the prophylaxis group received 2 * 450 mg/d oral valganciclovir for 100 days adjusted to renal function. Preemptive treatment with 2 * 900 mg/d valganciclovir was initiated at a viral load of 400 CMV copies/mL or greater (polymerase chain reaction) and maintained over >=14 days, followed by secondary prophylaxis. Patients were stratified by donor CMV IgG serostatus (donor CMV IgG positive [D+]/R+, donor CMV IgG negative [D-]/R+). RESULTS: The 12-month results were reported previously (Witzke et al Transplantation 2012). The intent-to-treat/safety population comprised 148 patients in the prophylaxis (61.5% D+/R+) and 151 patients in the preemptive group (52.3% D+/R+). Overall, 47% patients completed the follow-up. Significantly fewer patients in the prophylaxis compared with preemptive group experienced a CMV infection or disease up to month 84 (11.5%; 95% confidence interval [95% CI], 6.8-17.8%] vs 39.7%; 95% CI, 31.9-48.0%; P < 0.0001 and 4.7%; 95% CI, 1.9-9.5% vs 15.9%; 95% CI, 10.5-22.7%; P = 0.002). Incidences of graft loss (7.4% vs 8.6%), death (9.5% vs 11.3%), rejection (29.1% vs 28.5%), and renal function (estimated glomerular filtration rate [mean +/- SD]: 58.2 +/- 26.3 vs 59.9 +/- 25.7 mL/min per 1.73 m) were not significantly different between prophylaxis and preemptive treatment. Tolerability was comparable between groups. CONCLUSIONS: Prophylaxis was more effective than the preemptive approach, applying a low-intense surveillance protocol in preventing CMV infection and disease in intermediate risk patients. Both strategies were similarly effective in preventing graft loss and death under the conditions of this long-term trial with a threshold of 400 copies/mL for initiation of anti-CMV treatment. PMID- 29166337 TI - Detection of Hepatitis C Antibodies Without Viral Transmission in Hepatitis C Negative Recipients Receiving Kidneys From Hepatitis C-Positive Donors Treated With Direct-Acting Antiviral Therapy. PMID- 29166339 TI - The "Prepectoral Breast Reconstruction" Supplement. PMID- 29166338 TI - Use of Organs From Hepatitis C Virus-Positive Donors for Uninfected Recipients: A Potential Cost-Effective Approach to Save Lives? AB - BACKGROUND: Organs from hepatitis C virus (HCV) seropositive (HCVpos) individuals are seldom used for transplantation because of the risk of disease transmission. Because transmitted HCV is now amenable to effective treatment, we estimated the potential impact of using HCVpos deceased donor organs for transplantation. METHODS: The Potential Donor Audit of patients (<80 years) dying in UK critical care units and the UK Transplant Registry was searched to identify HCVpos potential and proceeding deceased donors. Donor organ quality was assessed using validated donor organ quality indices. Cost analysis was performed by comparing the cumulative cost of direct-acting antivirals with hemodialysis and renal transplantation. RESULTS: Between 2009 and 2016, 120 patients identified from the Potential Donor Audit were not considered as potential donors because of the presence of HCV. Between 2000 and 2015, 244 HCVpos potential deceased donors were identified from the UK Transplant Registry, and 76 (31%) proceeded to donation, resulting in 63 liver, 27 kidney, and 2 heart transplants. Recipient and graft survival was not adversely impacted by donor HCVpos status. Most (69%) offered organs were declined because of positive virology although their quality was similar to that of other transplanted organs. The additional costs of treating recipients exposed to HCV by receiving a HCVpos kidney was cost-neutral with dialysis 5 years from transplantation. CONCLUSIONS: HCVpos donors represent a potential source of organs for HCV seronegative recipients as many good quality HCVpos donor organs are not currently used for transplantation. This change in practice may increase access to transplantation without having an adverse effect on transplant outcome. PMID- 29166341 TI - Introduction to "Prepectoral Breast Reconstruction". PMID- 29166342 TI - Important Considerations for Performing Prepectoral Breast Reconstruction. AB - Prepectoral breast reconstruction has emerged as an excellent technique for postmastectomy reconstruction, as it allows for full preservation of a patient's pectoralis major muscle and chest wall function. This reduces pain, eliminates animation deformity, and results in high patient satisfaction. Safely performed prepectoral breast reconstruction requires a careful patient selection process before committing to the procedure, taking into account comorbidities, radiation status, and oncologic criteria such as tumor location and breast cancer stage. Furthermore, a thorough intraoperative assessment of mastectomy skin flaps is critical, with careful and precise confirmation that the skin is viable and well perfused, prior to proceeding with prepectoral breast reconstruction. This can be done both clinically and with perfusion assessment devices. The use of acellular dermal matrix (ADM) has enhanced outcomes and aesthetics of prepectoral reconstruction, by providing implant coverage and soft-tissue support. The ADM also adds the benefit of reducing capsular contracture rates and offers full control over the aesthetic definition of the newly reconstructed breast pocket. Aesthetic enhancement of results requires routine use of oversizing implants in the skin envelope, careful selection of full capacity or cohesive gel implants, and autologous fat grafting. In this way, patients in all clinical scenarios can benefit from the full muscle-sparing technique of prepectoral breast reconstruction, including those undergoing immediate reconstruction, delayed reconstruction, and delayed conversion from a subpectoral to prepectoral plane to correct animation deformity. PMID- 29166343 TI - Prepectoral Breast Reconstruction in Challenging Patients. AB - Implant-based reconstructions continue to remain on the forefront of breast reconstruction as the prepectoral approach gains popularity. This article reviews the challenging patients that surgeons face when evaluating their candidacy for prepectoral reconstruction. The prepectoral approach for thin, high body mass index and previously radiated patients will be reviewed. PMID- 29166344 TI - Two-Stage Prosthetic Breast Reconstruction: A Comparison Between Prepectoral and Partial Subpectoral Techniques. AB - BACKGROUND: Prosthetic breast reconstruction with prepectoral placement may confer clinical advantages compared with subpectoral placement. The purpose of this study was to assess and compare clinical outcomes following 2-stage reconstruction following prepectoral and partial subpectoral placement of tissue expanders and implants. METHODS: A retrospective review of 39 (prepectoral) and 50 (partial subpectoral) patients was completed. Acellular dermal matrix was used in all patients. Mean age was 50.4 and 49.2 years, respectively. Body mass index (BMI) > 30 was noted in 15.4% of prepectoral and 18% of partial subpectoral patients. Radiation therapy was delivered to 38.5% of prepectoral patients and to 22% of partial subpectoral patients. Mean follow-up was 8.7 and 13 months for the prepectoral cohort and partial subpectoral cohorts. RESULTS: The percentage of patients having at least 1 adverse event was 20.5% in the prepectoral and 22% in the partial subpectoral cohorts. The incidence of surgical-site infection and seroma was 8.1% and 4.8%, respectively, for the prepectoral cohort and 4.8% and 2.4%, respectively, for the partial subpectoral cohorts. Device explantation was 6.5% for the prepectoral and 7.2% for the partial subpectoral patients. Explantation did not occur in patients who had radiation or who had a BMI > 30. Four patients (6 breasts-7.2%) required conversion from partial subpectoral to prepectoral because of animation deformity. CONCLUSIONS: Prepectoral reconstruction is a viable alternative to partial subpectoral reconstruction. Proper patient selection is an important variable. Prepectoral reconstruction can be safely performed in patients with a BMI < 40 and in patients having postmastectomy radiation therapy. PMID- 29166345 TI - Prepectoral Immediate Direct-to-Implant Breast Reconstruction with Anterior AlloDerm Coverage. AB - BACKGROUND: Staged subpectoral expander-implant breast reconstruction is widely performed. Disruption of the pectoralis major origin and the frequent occurrence of animation deformity and functional discomfort associated with subpectoral reconstruction remain ongoing concerns. Prepectoral single-stage direct-to implant reconstruction resolves many of these issues. In this study, the authors explored the rationale for prepectoral single-stage implant-based breast reconstruction with anterior AlloDerm coverage as an alternative to the staged approach. METHODS: Seventy-three breasts in 50 patients were reconstructed using a single-stage direct-to-implant prepectoral approach with total anterior AlloDerm coverage during a 24-month period. The decision to proceed with single stage reconstruction was predicated upon the adequacy of mastectomy skin flap blood flow based on indocyanine green fluorescence perfusion assessment. The patients were followed up for a maximum of 32 months. RESULTS: Ninety-seven percent of patients achieved complete healing within 8 weeks. There were 2 implant losses (2.7%) due to infection. Major seroma rate requiring repeated aspiration and drain insertion was 1.2%. There were no full-thickness skin losses. Capsular contracture was 0% in nonradiated patients. There were no cases of animation deformity. The authors were unable to establish significant correlation between complications and any of the usually stated risk factors, such as smoking, obesity, and large mastectomy weights, presumably due to the rigorous application of intraoperative skin perfusion assessment. CONCLUSION: Single-stage direct-to-implant reconstruction using a prepectoral approach appears to be a safe and effective means of breast reconstruction in many patients, assuming adequate skin perfusion is present. PMID- 29166346 TI - Options in Acellular Dermal Matrix-Device Assembly. AB - Prepectoral prosthetic breast reconstruction has become increasingly popular during the last several years. Original shortcomings and poor outcomes in the 1970s have been overcome with the use of the bioengineered breast concept-namely, use of improved form stable breast implants, autologous fat grafting, and acellular dermal matrices (ADMs). Careful use of these reconstructive tools combined with improved mastectomy skin flaps has lead to successful early outcomes. Prepectoral breast reconstruction mitigates the animation deformities and muscle tightness previously associated with dual-plane prosthetic breast reconstruction while at the same time producing reproducible and outstanding aesthetic outcomes. The use of ADM is a critical component to performing prepectoral breast reconstruction. There are many techniques utilized to inset the ADM. Various methods of direct in vivo inset have been performed. These techniques are employed following completion of the mastectomy and are performed with both 2-stage as well as single-stage direct-to-implant reconstruction. Various ex vivo techniques have also been used for prepectoral breast reconstruction. Various prefabricated constructs of ADM and implant/tissue expander can be created on the back table while the mastectomy is in progress, which decreases operative time and improves surgical efficiency. This article will describe briefly the history of prepectoral reconstruction as well as describing the various techniques used for creating the ADM-device interphase. PMID- 29166347 TI - Prepectoral Breast Reconstruction: The Breast Surgeon's Perspective. AB - Prepectoral breast reconstruction has been reemerging as a technique for postmastectomy implant-based reconstruction. Due to its advantage in eliminating animation deformity, shortening length of hospital stay and decreasing the amount of narcotics used for pain control, the technique has been embraced by patients and surgeons alike. The authors examined the breast surgeon's perspective regarding prepectoral reconstruction taking into consideration oncologic criteria, breast cancer recurrence, surgical technique, and the team approach to patient care. PMID- 29166348 TI - The Economics of Prepectoral Breast Reconstruction. AB - The world of breast reconstruction over the last several years has seen a dramatic shift in focus to discussion and the application of placing tissue expanders and implants back into the prepectoral space. Although this technique failed during the early advent of breast reconstruction, newer technologies such as advances in fat grafting, improved acellular dermal matrices, better methods of assessing breast flap viability, and enhanced implants appear to have set the stage for the resurgence and positive early results seen with this technique. The main benefits of a switch to prepectoral breast reconstruction clinically appears to be less associated pain, lower incidence of animation deformities, and its associated symptoms as well as presumably better aesthetics. Early data suggest that the results are extremely promising and early adopters have attempted to define the ideal patients for prepectoral breast reconstruction. As with any new operative procedure, an assessment of finances and costs are crucial to its successful implementation. Although current data are minimal, this article attempts to build the fundamentals of an economic model that exhibits and displays potential savings through the use of prepectoral breast reconstruction. PMID- 29166349 TI - Developing End-of-Training Entrustable Professional Activities for Psychiatry: Results and Methodological Lessons. AB - PURPOSE: To develop entrustable professional activities (EPAs) for psychiatry and to demonstrate an innovative, validity-enhancing methodology that may be relevant to other specialties. METHOD: A national task force employed a three-stage process from May 2014 to February 2017 to develop EPAs for psychiatry. In stage 1, the task force used an iterative consensus-driven process to construct proposed EPAs. Each included a title, full description, and relevant competencies. In stage 2, the task force interviewed four nonpsychiatric experts in EPAs and further revised the EPAs. In stage 3, the task force performed a Delphi study of national experts in psychiatric education and assessment. All survey participants completed a brief training program on EPAs. Quantitative and qualitative analysis led to further modifications. Essentialness was measured on a five-point scale. EPAs were included if the content validity index was at least 0.8 and the lower end of the asymmetric confidence interval was not lower than 4.0. RESULTS: Stages 1 and 2 yielded 24 and 14 EPAs, respectively. In stage 3, 31 of the 39 invited experts participated in both rounds of the Delphi study. Round 1 reduced the proposed EPAs to 13. Ten EPAs met the inclusion criteria in Round 2. CONCLUSIONS: The final EPAs provide a strong foundation for competency-based assessment in psychiatry. Methodological features such as critique by nonpsychiatry experts, a national Delphi study with frame-of-reference training, and stringent inclusion criteria strengthen the content validity of the findings and may serve as a model for future efforts in other specialties. PMID- 29166350 TI - Competency Crosswalk: A Multispecialty Review of the Accreditation Council for Graduate Medical Education Milestones Across Four Competency Domains. AB - PURPOSE: To identify common and overlapping themes among the interpersonal and communication skills (ICS), practice-based learning and improvement (PBLI), professionalism (PROF), and systems-based practice (SBP) milestones of the transitional year and 26 specialties. METHOD: In May 2017, milestones were accessed from the Accreditation Council for Graduate Medical Education specialties website. A thematic analysis of the ICS, PBLI, PROF, and SBP milestones was performed to determine unique and common themes across these competencies and across specialties. Keywords from the common program requirements were initially applied as codes to the milestones. Codes were then grouped into common themes. RESULTS: Twenty-two themes were identified: 15 (68%) were unique to a given competency (3 related to ICS, 4 related to PBLI, 5 related to PROF, and 3 related to SBP), and 7 (32%) appeared in the milestones of more than one core competency. Eleven themes (50%) were used by 20 or more specialties, and 6 themes (27%) by 10 or fewer specialties. No theme was present across all specialties. CONCLUSIONS: The ICS, PBLI, PROF, and SBP milestones contain multiple themes with areas of overlap among these four competencies and substantial variability across specialties. This variability may create differential expectations of residents across specialties, complicate faculty development, and make sharing assessment tools difficult. The thematic analysis provides important insights into how individual specialties interpret and operationalize the ICS, PBLI, PROF, and SBP competency domains and can inform future revisions of milestones to enable harmonization and shared understanding of these competencies across specialties where appropriate. PMID- 29166351 TI - Tool for Diagnosing Gaps Within a Competency-Based Assessment System. PMID- 29166352 TI - More Learners, Finite Resources, and the Changing Landscape of Procedural Training at the Bedside. AB - There is growing competition for nonoperative, procedural training in teaching hospitals, due to an increased number of individuals seeking to learn procedures from a finite number of appropriate teaching cases. Procedural training is required by students, postgraduate learners, and practicing providers who must maintain their skills. These learner groups are growing in size as the number of medical schools increases and advance practice providers expand their skills to include complex procedures. These various learner needs occur against a background of advancing therapeutic techniques that improve patient care but also act to reduce the overall numbers of procedures available to learners. This article is a brief review of these and other challenges that are arising for program directors, medical school leaders, and hospital administrators who must act to ensure that all of their providers acquire and maintain competency in a wide array of procedural skills. The authors conclude their review with several recommendations to better address procedural training in this new era of learner competition. These include a call for innovative clinical rotations deliberately designed to improve procedural training, access to training opportunities at new clinical sites acquired in health system expansions, targeted faculty development for those who teach procedures, reporting of competition for bedside procedures by trainees, more frequent review of resident procedure and case logs, and the creation of an institutional oversight committee for procedural training. PMID- 29166353 TI - What Is the Impact of the Underserved Pathway Program on Graduates Entering an Underserved Family Medicine Residency? Five-Year Findings From the University of Washington School of Medicine. AB - PURPOSE: More primary care physicians are needed in underserved areas of the United States. Prior research indicates that medical student experiences in underserved settings increase the likelihood that they will practice in underserved areas; few studies have controlled for selection bias. This study aimed to estimate the effect of the University of Washington School of Medicine's (UWSOM's) longitudinal extracurricular experience, the Underserved Pathway (UP), on graduates' choice in entering a family medicine residency with underserved training opportunities. METHOD: The American Medical College Application Service application that all students submit to apply to UWSOM and a matriculation survey were used to collect demographic information for medical school graduates who subsequently entered family medicine residencies between 2010 and 2015. A given family medicine residency offered underserved training if it had a clinic or rotation at a federally qualified health center or if the admitting hospital was a critical access hospital. Multiple logistic regression was used to estimate the UP program's effect on graduates entering an underserved family medicine residency, adjusting for 26 covariates. RESULTS: Participants were 158 UWSOM graduates; 39 (25%) completed the UP program. UP completion was associated with a 3.58 odds ratio increase to matching to an underserved family medicine residency, compared with non-UP graduates. CONCLUSIONS: Completion of the UP was linked to a significant increase in program graduates matching to an underserved family medicine residency. Longitudinal extracurricular programs similar to the UP could be an important component in the pipeline to meeting the primary care needs of underserved populations. PMID- 29166354 TI - Smoothing the Transition Points in Canadian Medical Education. AB - In 2010, the Association of Faculties of Medicine of Canada, College des medecins du Quebec, College of Family Physicians of Canada, and Royal College of Physicians and Surgeons of Canada launched the Future of Medical Education in Canada Postgraduate (FMEC PG) Project to examine postgraduate medical education (PGME) in Canada and make recommendations for improvement. One recommendation that emerged concerns the transitions learners experience across the undergraduate medical education-PGME-practice continuum. The FMEC PG, using a thorough process, developed projects to address these often-tumultuous transitions for the learner, aiming to provide support, tools, and standards for the learner's educational journey.With leadership by two senior academics and the Transitions Implementation Committee, three working groups helped implement these transitions projects, which addressed (1) the medical-school-to-residency transition, (2) career planning and the residency matching process, and (3) the residency-to-practice transition. Work products include the development of a learner education handover protocol and the establishment of pan-Canadian entrustable professional activities to be used nationally to help define expectations for new graduates entering residencies. A postmatch boot camp tool and a simulated night on-call tool were developed and are available to all medical schools. National standards are being promoted for career services counseling and best practices in residency selection. A practice management curriculum framework, mentorship resources, resiliency training for graduating residents, and the entry-level disciplines of residency are also being explored.Ultimately, with system-wide change and better integration of all players, transitions for Canada's learners will greatly improve. PMID- 29166355 TI - Restoring Faculty Vitality in Academic Medicine When Burnout Threatens. AB - Increasing rates of burnout-with accompanying stress and lack of engagement-among faculty, residents, students, and practicing physicians have caused alarm in academic medicine. Central to the debate among academic medicine's stakeholders are oft-competing issues of social accountability; cost containment; effectiveness of academic medicine's institutions; faculty recruitment, retention, and satisfaction; increasing expectations for faculty; and mission based productivity.The authors propose that understanding and fostering what contributes to faculty and institutional vitality is central to preventing burnout during times of change. They first look at faculty vitality and how it is threatened by burnout, to provide a framework for a greater understanding of faculty well-being. Then they draw on higher education literature to determine how vitality is defined in academic settings and what factors affect faculty vitality within the context of academic medicine. Next, they propose a model to explain and examine faculty vitality in academic medicine, followed by a discussion of the need for a greater understanding of faculty vitality. Finally, the authors offer conclusions and propose future directions to promote faculty vitality.The authors encourage institutional decision makers and other stakeholders to focus particular attention on the evolving expectations for faculty, the risk of extensive faculty burnout, and the opportunity to reduce burnout by improving the vitality and resilience of these talented and crucial contributors. Faculty vitality, as defined by the institution, has a critical role in ensuring future institutional successes and the capacity for faculty to thrive in a complex health care economy. PMID- 29166356 TI - Factors Related to Different Objects of Awareness in Alzheimer Disease. AB - Awareness of deficits is a multidimensional phenomenon described as the ability to acknowledge difficulties and impairments. We investigated whether unawareness affects distinct domains to different degrees and identified the factors related to the awareness impairment in Alzheimer Disease (AD). Using a cross-sectional design, we assessed 89 people with AD (PwAD) and their caregivers. Awareness was evaluated by scoring discrepant responses between PwAD and their caregivers across domains including cognitive functioning and health condition, functional activity impairments, emotional state, social functioning, and interpersonal relationships. The awareness of functional activity impairments domain showed a greater discrepancy compared with the other domains. Multiple regression analysis revealed that lack of awareness of cognitive functioning and health condition was related to PwAD unawareness of functional activity impairments, age, and caregiver burden. The emotional state domain was related to PwAD unawareness of functional activity impairments and depressive symptoms. There was also a relationship between the social functioning and relationships domain and caregiver burden. The functional activity impairments domain was related to deficits in the following domains: cognitive functioning and health condition, emotional state, social and emotional functioning, and PwAD self-reported quality of life. Although we observed that 1 domain can influence another, our results suggest that the factors related to each of the different objects of awareness are varied. PMID- 29166357 TI - Trainee Autonomy and Patient Safety. PMID- 29166358 TI - Comment on: MARS System Effectively Replaces Hepatic Function in Severe Acute Liver Failure. PMID- 29166360 TI - Is Anti-TNF Therapy Associated With an Increased Risk of Postoperative Morbidity After Surgery for Ileocolonic Crohn Disease? PMID- 29166359 TI - Incisional Hernia After Midline Versus Transverse Specimen Extraction Incision: A Randomized Trial in Patients Undergoing Laparoscopic Colectomy. AB - OBJECTIVE: To compare the incidence of incisional hernia (IH) between midline and transverse specimen extraction site in patients undergoing laparoscopic colectomy. BACKGROUND: Midline specimen extraction incision is most commonly used in laparoscopic colectomy, but has high IH risk. IH may be lower for transverse incision. METHODS: A single-center superiority trial was conducted. Eligible patients undergoing laparoscopic colectomy were randomly assigned to midline or transverse specimen extraction. Primary outcome was IH incidence at 1 year. Power calculation required 76 patients per group to detect a reduction in IH from 20% to 5%. Secondary outcomes included perioperative outcomes, pain scores, health related quality of life (SF-36), and cosmesis (Body Image Questionnaire). RESULTS: A total of 165 patients were randomly assigned to transverse (n = 79) or midline (n = 86) specimen extraction site, of which 141 completed 1-year follow up (68 transverse, 73 midline). Patient, tumor, surgical data, and perioperative morbidity were similar. Pain scores were similar on each postoperative day. On intention-to-treat analysis, there was no difference in the incidence of IH at 1 year (transverse 2% vs midline 8%, P = 0.065) or after mean 30.3 month (standard deviation 9.4) follow-up (6% vs 14%, P = 0.121). On per-protocol analysis there were more IH after midline incision with longer follow-up (15% vs 2%, P = 0.013). On intention-to-treat analysis, SF-36 domains body pain and social functioning were improved after transverse incision. Cosmesis was higher after midline incision on per-protocol analysis, but without affecting body image. CONCLUSIONS: Per-protocol analysis of this trial demonstrates that a transverse specimen extraction site has a lower incidence of IH compared to midline with longer follow-up but has worse cosmesis. PMID- 29166361 TI - The Impact of Hepatectomy Time of the Liver Graft on Post-transplant Outcome: A Eurotransplant Cohort Study. AB - OBJECTIVE: Assessing the effect of donor hepatectomy time on outcome after transplantation. SUMMARY OF BACKGROUND DATA: When blood supply in a deceased organ donor stops, ischemic injury starts. Livers are cooled to reduce cellular metabolism and minimize ischemic injury. This cooling is slow and livers are lukewarm during hepatectomy, potentially affecting outcome. METHODS: We used the Eurotransplant Registry to investigate the relationship between donor hepatectomy time and post-transplant outcome in 12,974 recipients of deceased-donor livers (January 1, 2004, to December 31, 2013). Cox regression analyses for patient and graft survival (censored and uncensored for death with a functioning graft) were corrected for donor, preservation, and recipient variables. Donor hepatectomy time was defined as time between start of aortic cold flush and placement of the liver in the ice-bowl. RESULTS: Median donor hepatectomy time was 41 minutes [interquartile range (IQR) 32 to 52]. Livers donated after circulatory death had longer hepatectomy times than those from brain-dead donors [50 minutes (35 to 68) vs 40 minutes (32 to 51), P < 0.001]. Donor hepatectomy time was independently associated with graft loss [adjusted hazard ratio (HR) 1.03 for every 10-minute increase, 95% confidence interval (95% CI) 1.02-1.05; P < 0.001]. The magnitude of this effect was comparable to the effect of each hour of additional cold ischemia time (adjusted HR 1.04, 95% CI 1.02-1.05; P < 0.001). Donor hepatectomy time had a similar effect on death-censored graft survival and patient survival. Livers donated after circulatory death and those with a higher donor risk index were more susceptible to the effect of donor hepatectomy time on death-censored graft survival. CONCLUSION: Donor hepatectomy time impairs liver transplant outcome. Keeping this time short together with efficient cooling during hepatectomy might improve outcome. PMID- 29166362 TI - Neutrophil-to-Lymphocyte Ratio Predicts the Severity of Incarcerated Groin Hernia. AB - BACKGROUND The incarceration of a segment of bowel within a groin hernia can result in intestinal strangulation if hernia treatment is delayed. Once intestinal strangulation occurs, a bowel resection may be required, and there is an overall increased risk for postoperative complications. The aim of this study was to identify biomarkers to predict the severity of an incarcerated groin hernia. MATERIAL AND METHODS We retrospectively evaluated the records of 95 patients with incarcerated groin hernias who underwent emergency surgical correction of the hernias. The need for a bowel resection was regarded as an indicator of severity in incarcerated groin hernia patients. The patients were divided into 2 groups: patients with bowel resection surgery and patients without bowel resection surgery. RESULTS We discovered that leukocyte count (leukocyte count >=10*103/mm3), neutrophil-to-lymphocyte ratio (NLR, NLR >=11.5), presentation of bowel obstruction, and duration of incarceration (duration of incarceration >=26 h) were significantly associated with bowel resection in incarcerated groin hernia patients by using the chi-square test. Factors such as leukocyte count, NLR, presentation of bowel obstruction, and duration of incarceration were analyzed using multivariate logistic regression analysis. We found that NLR, presentation of bowel obstruction, and duration of incarceration were independently and significantly related to bowel resection in incarcerated groin hernia patients. CONCLUSIONS An elevated NLR can serve as a biomarker for the prediction of severity of incarcerated groin hernias. Additionally, incarcerated groin hernia patients who present with bowel obstruction or with duration of intestinal incarceration longer than 26 h have an increased risk for bowel resection. PMID- 29166363 TI - Progress Toward Poliomyelitis Eradication - Pakistan, January 2016-September 2017. AB - In 1988, the World Health Assembly launched the Global Polio Eradication Initiative. Among the three wild poliovirus serotypes, only wild poliovirus (WPV) type 1 (WPV1) has been detected since 2012. Since 2014, Pakistan, Afghanistan, and Nigeria remain the only countries with continuing endemic WPV1 transmission. This report describes activities conducted and progress made toward the eradication of poliovirus in Pakistan during January 2016-July 2017 and provides an update to previous reports (1,2). In 2016, Pakistan reported 20 WPV1 cases, a 63% decrease compared with 54 cases in 2015 (3). As of September 25, 2017, five WPV1 cases have been reported in 2017, representing a 69% decline compared with 16 cases reported during the same period in 2016 (Figure 1). During January September 2017, WPV1 was detected in 72 of 468 (15%) environmental samples collected, compared with 36 of 348 (9%) samples collected during the same period in 2016. WPV1 was detected in environmental samples in areas where no polio cases are being reported, which indicates that WPV1 transmission is continuing in some high-risk areas. Interruption of WPV transmission in Pakistan requires maintaining focus on reaching missed children (particularly among mobile populations), continuing community-based vaccination, implementing the 2017-2018 National Emergency Action Plan (4), and improving routine immunization services. PMID- 29166364 TI - Erratum: Vol. 65, No. 36. PMID- 29166365 TI - CDC Grand Rounds: Improving the Lives of Persons with Sickle Cell Disease. AB - Approximately 100,000 Americans have sickle cell disease (SCD), a group of recessively inherited red blood cell disorders characterized by abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in the red blood cells. Persons with hemoglobin SS or hemoglobin Sbeta0 thalassemia, also known as sickle cell anemia (SCA), have the most severe form of SCD. Hemoglobin SC disease and hemoglobin Sbeta+ thalassemia are other common forms of SCD. Red blood cells that contain sickle hemoglobin are inflexible and can stick to vessel walls, causing a blockage that slows or stops blood flow. When this happens, oxygen cannot reach nearby tissues, leading to attacks of sudden, severe pain, called pain crises, which are the clinical hallmark of SCD. The red cell sickling and poor oxygen delivery can also cause damage to the brain, spleen, eyes, lungs, liver, and multiple other organs and organ systems. These chronic complications can lead to increased morbidity, early mortality, or both. Tremendous strides in treating and preventing the complications of SCD have extended life expectancy. Now, nearly 95% of persons born with SCD in the United States reach age 18 years (1); however, adults with the most severe forms of SCD have a life span that is 20-30 years shorter than that of persons without SCD (2). PMID- 29166366 TI - Abortion Surveillance - United States, 2014. AB - PROBLEM/CONDITION: Since 1969, CDC has conducted abortion surveillance to document the number and characteristics of women obtaining legal induced abortions in the United States. PERIOD COVERED: 2014. DESCRIPTION OF SYSTEM: Each year, CDC requests abortion data from the central health agencies of 52 reporting areas (the 50 states, the District of Columbia, and New York City). The reporting areas provide this information voluntarily. For 2014, data were received from 49 reporting areas. For trend analysis, abortion data were evaluated from 48 areas that reported data every year during 2005-2014. Census and natality data, respectively, were used to calculate abortion rates (number of abortions per 1,000 women aged 15-44 years) and ratios (number of abortions per 1,000 live births). RESULTS: A total of 652,639 abortions were reported to CDC for 2014. Of these abortions, 98.4% were from the 48 reporting areas that provided data every year during 2005-2014. Among these 48 reporting areas, the abortion rate for 2014 was 12.1 abortions per 1,000 women aged 15-44 years, and the abortion ratio was 186 abortions per 1,000 live births. From 2013 to 2014, the total number and rate of reported abortions decreased 2%, and the ratio decreased 7%. From 2005 to 2014, the total number, rate, and ratio of reported abortions decreased 21%, 22%, and 21%, respectively. In 2014, all three measures reached their lowest level for the entire period of analysis (2005-2014). In 2014 and throughout the period of analysis, women in their 20s accounted for the majority of abortions and had the highest abortion rates; women in their 30s and older accounted for a much smaller percentage of abortions and had lower abortion rates. In 2014, women aged 20-24 and 25-29 years accounted for 32.2% and 26.7% of all reported abortions, respectively, and had abortion rates of 21.3 and 18.4 abortions per 1,000 women aged 20-24 and 25-29 years, respectively. In contrast, women aged 30-34, 35-39, and >=40 years accounted for 17.1%, 9.7%, and 3.6% of all reported abortions, respectively, and had abortion rates of 11.9, 7.2, and 2.6 abortions per 1,000 women aged 30-34 years, 35-39 years, and >=40 years, respectively. From 2005 to 2014, the abortion rate decreased among women aged 20-24, 25-29, 30-34, and 35-39 years by 27%, 16%, 12%, and 5%, respectively, but increased 4% among women aged >=40 years. In 2014, adolescents aged <15 and 15-19 years accounted for 0.3% and 10.4% of all reported abortions, respectively, and had abortion rates of 0.5 and 7.5 abortions per 1,000 adolescents aged <15 and 15-19 years, respectively. From 2005 to 2014, the percentage of abortions accounted for by adolescents aged 15-19 years decreased 38%, and their abortion rate decreased 49%. These decreases were greater than the decreases for women in any older age group. In contrast to the percentage distribution of abortions and abortion rates by age, abortion ratios in 2014 and throughout the entire period of analysis were highest among adolescents and lowest among women aged 30-39 years. Abortion ratios decreased from 2005 to 2014 for women in all age groups. In 2014, the majority (67.0%) of abortions were performed at <=8 weeks' gestation, and nearly all (91.5%) were performed at <=13 weeks' gestation. Few abortions were performed between 14 and 20 weeks' gestation (7.2%) or at >=21 weeks' gestation (1.3%). During 2005-2014, the percentage of all abortions performed at <=13 weeks' gestation remained consistently high (>=91.4%). Among abortions performed at <=13 weeks' gestation, there was a shift toward earlier gestational ages, as the percentage performed at <=6 weeks' gestation increased 21%, and the percentage of all other gestational ages at <=13 weeks' gestation decreased 7%-20%. In 2014, among reporting areas that included medical (nonsurgical) abortion on their reporting form, 22.6% of all abortions were performed by early medical abortion (a nonsurgical abortion at <=8 weeks' gestation), 67.4% were performed by surgical abortion at <=13 weeks' gestation, and 8.6% were performed by surgical abortion at >13 weeks' gestation; all other methods were uncommon (<2%). Among abortions performed at <=8 weeks' gestation that were eligible for early medical abortion on the basis of gestational age, 32.2% were completed by this method. In 2014, women with one or more previous live births accounted for 59.5% of abortions, and women with no previous live births accounted for 40.4%. Women with one or more previous induced abortions accounted for 44.9% of abortions, and women with no previous abortion accounted for 55.1%. Women with three or more previous births accounted for 13.8% of abortions, and women with three or more previous abortions accounted for 8.6% of abortions. Deaths of women associated with complications from abortion for 2014 are being assessed as part of CDC's Pregnancy Mortality Surveillance System. In 2013, the most recent year for which data were available, four women were identified to have died as a result of complications from legal induced abortion. INTERPRETATION: Among the 48 areas that reported data every year during 2005 2014, the decreases in the total number, rate, and ratio of reported abortions that occurred during 2010-2013 continued from 2013 to 2014, resulting in historic lows for all three measures of abortion. PUBLIC HEALTH ACTION: The data in this report can help program planners and policymakers identify groups of women with the highest rates of abortion. Unintended pregnancy is the major contributor to induced abortion. Increasing access to and use of effective contraception can reduce unintended pregnancies and further reduce the number of abortions performed in the United States. PMID- 29166367 TI - Smoke-Free Policies in the World's 50 Busiest Airports - August 2017. AB - Exposure to secondhand smoke from burning tobacco products causes premature death and disease, including coronary heart disease, stroke, and lung cancer among nonsmoking adults and sudden infant death syndrome, acute respiratory infections, middle ear disease, exacerbated asthma, respiratory symptoms, and decreased lung function in children (1,2). The U.S. Surgeon General has concluded that there is no risk-free level of exposure to secondhand smoke (1). Previous CDC reports on airport smoke-free policies found that most large-hub airports in the United States prohibit smoking (3); however, the extent of smoke-free policies at airports globally has not been assessed. CDC assessed smoke-free policies at the world's 50 busiest airports (airports with the highest number of passengers traveling through an airport in a year) as of August 2017; approximately 2.7 billion travelers pass through these 50 airports each year (4). Among these airports, 23 (46%) completely prohibit smoking indoors, including five of the 10 busiest airports. The remaining 27 airports continue to allow smoking in designated smoking areas. Designated or ventilated smoking areas can cause involuntary secondhand smoke exposure among nonsmoking travelers and airport employees. Smoke-free policies at the national, city, or airport authority levels can protect employees and travelers from secondhand smoke inside airports. PMID- 29166369 TI - QuickStats: Percentage* of Visits to Office-Based Physicians? by Adults Aged >=18 Years for Diabetes Mellitus,S by Sex and Age - National Ambulatory Medical Care Survey, 2015. AB - In 2015, diabetes was a reason for 4.2% of visits by adults to office-based physicians. Men aged 18-44 years had a higher percentage of visits for diabetes compared with women aged 18-44 years (2.2% versus 0.4%, respectively). Both women and men aged 18-44 years had a lower percentage of visits for diabetes compared with adults aged 45-64 and >=65 years. PMID- 29166370 TI - Erratum: Vol. 66, No. 16. PMID- 29166368 TI - Public Health Economic Burden Associated with Two Single Measles Case Investigations - Colorado, 2016-2017. AB - During July 2016-January 2017, two unrelated measles cases were identified in the Denver, Colorado area after patients traveled to countries with endemic measles transmission. Each case resulted in multiple exposures at health care facilities and public venues, and activated an immediate and complex response by local and state public health agencies, with activities led by the Tri-County Health Department (TCHD), which serves Adams, Arapahoe, and Douglas counties. To track the economic burden associated with investigating and responding to single measles cases, personnel hours and supply costs incurred during each investigation were tracked prospectively. No secondary cases of measles were identified in either investigation. Postexposure prophylaxis (PEP) was administered to 31 contacts involving the first case; no contacts of the second case were eligible for PEP because of a delay in diagnosing measles disease. Public health costs of disease investigation in the first and second case were estimated at $49,769 and $18,423, respectively. Single measles cases prompted coordinated public health action and were costly and resource-intensive for local public health agencies. PMID- 29166371 TI - Effect of iron overload on impaired fertility in male patients with transfusion dependent beta-thalassemia. AB - BackgroundTo investigate the fertility of male patients with transfusion dependent beta-thalassemia, and to use magnetic resonance imaging (MRI) as a novel method to assess the iron overload status of testis in such patients.MethodsTwenty-one male patients with transfusion-dependent beta thalassemia and five normal male controls enrolled in this study. Hormonal profiles, iron levels, MRI testicular dimension, MRI T2 values, parameters for sperm quality, and sperm DNA fragmentation (SDF) of participants were measured.ResultsThe MRI T2 values of the testis were significantly lower in transfusion-dependent beta-thalassemia patients than in normal controls (P=0.027), and they correlated to serum ferritin levels in all enrolled subjects (R2=0.258, P=0.008). There were significantly lower sperm concentrations (P=0.037), a lower percentage of sperm with normal morphology (P=0.001), and a higher percentage of SDF (P=0.009) in transfusion-dependent beta-thalassemia patients without hypogonadotropic hypogonadism and with spontaneous spermatogenesis compared with normal controls. The percentage of SDF was significantly correlated with serum ferritin levels in transfusion-dependent beta thalassemia male patients with spontaneous spermatogenesis (R2=0.48, P=0.009).ConclusionOur study is the first demonstration of iron deposition in the testis of patients with transfusion-dependent beta-thalassemia based on imaging, and such findings might explain the high prevalence of impaired fertility in above patients with normal pituitary function. PMID- 29166372 TI - Placental lipid processing in response to a maternal high-fat diet and diabetes in rats. AB - BackgroundDiabetes and obesity during pregnancy have an impact on the health of both mothers and developing babies. Prevention focuses on glycemic control, but increasing evidence implicates a role for lipids. Using a rat model, we showed that a maternal high-fat (HF) diet increased perinatal morbidity and mortality, but lipid processing across the maternal-placental-fetal triad remained unstudied. We hypothesized that HF diet would disrupt placental lipid processing to exaggerate fuel-mediated consequences of diabetic pregnancy.MethodsWe compared circulating lipid profiles, hormones, and inflammatory markers in dams and rat offspring from normal, diabetes-exposed, HF-diet-exposed, and combination-exposed pregnancies. Placentae were examined for lipid accumulation and expression of fuel transporters.ResultsMaternal HF diet exaggerated hyperlipidemia of pregnancy, with diabetes marked dyslipidemia developed in dams but not in offspring. Placentae demonstrated lipid accumulation and lower expression of fatty acid (FA) transporters. Diet-exposed offspring had a lower fraction of circulating essential FAs. Pregnancy loss was significantly higher in diet exposed but not in diabetes-exposed pregnancies, which could not be explained by differences in hormone production. Although not confirmed, inflammation may play a role.ConclusionMaternal hyperlipidemia contributes to placental lipid droplet accumulation, perinatal mortality, and aberrant FA profiles that may influence the health of the developing offspring. PMID- 29166373 TI - Pilot study of novel lab methodology and testing of platelet function in adolescent women with heavy menstrual bleeding. AB - BackgroundApproximately 40% of adolescent women experience heavy menstrual bleeding (HMB), and 10-62% of them have an underlying bleeding disorder (BD). Diagnosing a BD remains challenging because of limitations of available clinical platelet function assays. The aim of this study was to characterize platelet function in a population of adolescent women with HMB using small-volume whole blood assays.MethodsAnticoagulated whole blood was used to assess platelet GPIIbIIIa activation, alpha-granule secretion, and aggregation in response to multiple agonists. Platelet adhesion on collagen or von Willebrand Factor (VWF) under static and shear flow was also assessed.ResultsFifteen participants with HMB were included in the study, of which eight were diagnosed with a clinically identifiable BD. Platelet activation was blunted in response to calcium ionophore in participants without a BD diagnosis compared with that in all other participants. Impaired GPIIbIIIa activation was observed in response to all GPCR agonists, except adenosine diphosphate (ADP), in participants with qualitative platelet disorders. Our assays detected platelet aggregation in the majority of participants with a BD in response to ADP, collagen-related peptide (CRP), thrombin receptor activator 6 (TRAP-6), or U46619. Platelet adhesion and aggregation on collagen and VWF was decreased for participants with VWD.ConclusionParticipants with and without BD exhibited aberrant platelet function in several assays in response to select agonists. PMID- 29166375 TI - Gastric emptying of different meal volumes of identical composition in preterm infants: a time series analysis. AB - BackgroundPreterm infants' meals typically progress to higher volumes over time. Knowledge of gastric emptying (GE) responses to differing meal volumes may inform enteral feeding management. We examined the effect of meal volume and composition on preterm GE.MethodsForty infants were studied at 33.3+/-1.4 (29.7-35.6) weeks postmenstrual age when fully enteral fed (target 150 ml/kg/day). Intraindividual comparisons of GE were made for paired meals of 100% and 75% prescribed volume and identical composition of mother's own milk (n=21) and pasteurized donor human milk (n=19). Serial stomach ultrasound images were used to calculate gastric residual volumes (GRVs) and remaining meal proportions (% meal).ResultsGE was faster in the early postprandial period and slowed over time (P<0.001). Reduced volume meals had slower GE rates and lower GRV (P<0.001). Serial postprandial % meal was similar between reduced and full volume meals (P=0.41). Higher milk casein concentration was associated with slower GE (P=0.04). Complete gastric emptying (GRV=0 ml) was more common in infants fed at 3 h intervals compared with those fed every 2 h (P=0.002).ConclusionEarly postprandial GE is more rapid for larger meal volumes. Stable preterm infants may tolerate feeding of a 3 h meal volume at shorter intervals. PMID- 29166374 TI - 5-aza-2'-deoxycytidine, a DNA methylation inhibitor, attenuates hyperoxia-induced lung fibrosis via re-expression of P16 in neonatal rats. AB - BackgroundP16 methylation plays an important role in the pathogenesis of hyperoxia-induced lung fibrosis. 5-aza-2'-deoxycytidine (5-aza-CdR) is a major methyltransferase-specific inhibitor. In this study, the effects of 5-aza-CdR on a hyperoxia-induced lung fibrosis in neonatal rats were investigated.MethodsRat pups were exposed to 85% O2 for 21 days of and received intraperitoneal injections of 5-aza-CdR or normal saline (NS) once every other day. Survival rates and lung coefficients were calculated. Hematoxylin-eosin staining was performed to analyze the degree of lung fibrosis. Collagen content and TGF-beta1 levels were determined. A methylation-specific polymerase chain reaction and western blotting were performed to determine P16 methylation status and P16, cyclin D1, and E2F1 protein expression.Results5-aza-CdR treatment during hyperoxia significantly improved the survival rate and weight gain, while it decreases the degree of lung fibrosis and levels of hydroxyproline and TGF-beta1. Hyperoxia induced abnormal P16 methylation and 5-aza-CdR effectively reversed the hypermethylation of P16. Expression of the P16 protein in lung tissues was enhanced, while cyclin D1 and E2F1 protein were reduced by 5-aza-CdR treatment during hyperoxia.ConclusionThese data show that 5-aza-CdR attenuated lung fibrosis in neonatal rats exposed to hyperoxia by lowering hydroxyproline and TGF beta1 expression and via re-expression of P16 in neonatal rats. PMID- 29166376 TI - Predictors of death in infants with probable serious bacterial infection. AB - BackgroundBacterial infections account for a significant proportion of neonatal and infant mortality globally. We aimed to identify predictors of death in infants with probable serious bacterial infection (PSBI) defined as signs/symptoms of possible serious bacterial infection along with baseline C reactive protein (CRP) >=12 mg/l.MethodsWe did a secondary analysis using the data collected from 700 infants with PSBI who participated in a randomized controlled trial in India in which zinc or placebo was given in addition to the standard antibiotics. Logistic regression was used to estimate the associations between relevant variables and death within 21 days.ResultsThose infants who were fed cow's milk or formula before the illness episode had 3.7-fold (95% confidence interval (CI) 1.5-9.3) and 5.3-fold (95% CI 2.0-13.6) higher odds of death, respectively. Lethargy (odds ratio (OR) 2.4, 95% CI 1.1-5.4) and CRP (OR 1.9, 95% CI 1.1-3.3) were also independent predictors of death. In the model including only clinical features, female gender (OR 2.25, 95% CI 1.0-5.0), abdominal distention (3.7, 95% CI 1.1-12.3), and bulging fontanelle (5.8, 95% CI 1.1-30.5) were also independent predictors for death.ConclusionFormula or cow milk feeding prior to the illness, lethargy at the time of presentation, and high serum CRP levels predicted death in infants with PSBI. PMID- 29166377 TI - The effect of body position on esophageal reflexes in cats: a possible mechanism of SIDS? AB - BackgroundIt has been hypothesized that life-threatening events are caused by supraesophageal reflux (SER) of gastric contents that activates laryngeal chemoreflex-stimulated apnea. Placing infants supine decreases the risk of sudden infant death syndrome (SIDS). The aim of this study was to determine whether body position affects esophageal reflexes that control SER.MethodsWe instrumented the pharyngeal and esophageal muscles of decerebrate cats (N=14) to record EMG or manometry, and investigated the effects of body position on the esophago-upper esophageal sphincter (UES) contractile reflex (EUCR), esophago-UES relaxation reflex (EURR), esophagus-stimulated pharyngeal swallow response (EPSR), secondary peristalsis (SP), and pharyngeal swallow (PS). EPSR, EUCR, and SP were activated by balloon distension, EURR by air pulse, and PS by nasopharyngeal water injection. The esophagus was stimulated in the cervical, proximal thoracic, and distal thoracic regions. The threshold stimulus for activation of EUCR, EURR, and PS, and the chance of activation of EPSR and SP were quantified.ResultsWe found that only EPSR was significantly more sensitive in the supine vs. prone position regardless of the stimulus or the position of the stimulus in the esophagus.ConclusionWe hypothesize that the EPSR may contribute to the protection of infants from SIDS by placement in the supine position. PMID- 29166378 TI - Blood pressure variability is independent of systolic pressure in adolescent and young adult patients undergoing hemodialysis. AB - BackgroundPre-dialysis blood pressure variability (BPV) in adolescent and young adult maintenance hemodialysis (MHD) patients remains unknown. This study aimed to show the degree of 44-h BPV and to explore its related risk factors in adolescent and young-adult MHD patients.MethodsOne hundred and fifty-three hemodialysis patients aged from 14 to 29 were selected from 11 medical facilities in Guizhou, China. Variability independent of the mean BP (VIM) obtained by 44-h ambulatory BP monitoring was used to calculate BPV. Baseline characteristics, physical measurement, and laboratory parameters were compared between different groups categorized by quartiles of VIM of systolic BP (VIMSBP).ResultsVIMSBP levels were found to be positively related to interdialytic weigh growth rate (IDWG), serum phosphorus, and serum intact parathyroid hormone (iPTH; Spearman correlation coefficients 0.474, 0.229, and 0.437, respectively; P<0.05 for all) and negatively related to hemoglobin (Hb) and albumin (-0.317, P<0.001, and 0.166, P=0.04, respectively) in all adolescent and young-adult MHD patients. In multiple linear regression analysis, IDWG, Hb, serum phosphorus, and serum iPTH had an independent association with VIMSBP.ConclusionOur analysis revealed an independent association of BPV with IDWG, Hb, serum phosphorus, and serum iPTH among adolescent and young-adult patients undergoing dialysis. This observation warrants further study. PMID- 29166379 TI - BCFA-enriched vernix-monoacylglycerol reduces LPS-induced inflammatory markers in human enterocytes in vitro. AB - BackgroundExcess vernix caseosa produced by the fetal skin appears as particles suspended in the amniotic fluid in late gestation, is swallowed by the fetus, and is found throughout the newborn gastrointestinal tract as the first organisms are arriving to colonize the gut. Lipid-rich vernix contains an unusually high 29% branched chain fatty acids (BCFA). BCFAs reduce the incidence of necrotizing enterocolitis in an animal model, and were recently found predominantly in the sn 2 position of human milk triacylglycerols. Nothing is known about the influence of vernix BCFA on proinflammatory markers in human enterocytes.MethodsWe investigated the effect of vernix-monoacylglycerides (MAGs) (enriched with 30% BCFA) on interleukin (IL)-8 and NF-kappaB production in a human intestinal epithelial cell line (Caco-2). Caco-2 cells were pretreated with vernix-MAG or vernix-free fatty acid (FFA) prior to lipopolysaccharide (LPS) activation.ResultsBoth vernix-MAG and vernix-FFA increased cell BCFA and eliminated an LPS-induced 20% reduction in cell viability. In stimulated Caco-2 cells, vernix-MAG was more effective than vernix-FFA in suppressing IL-8 and NF kappaB. Activated vernix-MAG-treated cells expressed less of the cell-surface Toll-like receptor4 (TLR-4) compared with controls.ConclusionThis is the first study to show the reduction of proinflammatory markers in human cells mediated by BCFA-MAG. PMID- 29166380 TI - Food and nutrient intakes in young adults born preterm. AB - BackgroundAdults born preterm have higher levels of cardiometabolic risk factors than their term-born peers. Studies have suggested that at least those born smallest eat less healthily. We examined the association between early (<34 weeks) and late (34-36 weeks) preterm birth and diet and food preferences in adult age.MethodsParticipants of two cohort studies located in Finland completed a validated food frequency questionnaire (FFQ) at the age of 24 years to assess their usual diet and the adherence to healthy eating guidelines by using a recommended diet index (RDI). Overall, 182 were born early preterm, 352 late preterm, and 631 were term-born controls.ResultsYoung women born early preterm scored 0.77 points (95% confidence interval (CI) 0.03, 1.51) lower in RDI when adjusted for sex, age, parental education, and early-life confounders, indicating a lower quality of diet. There were no differences between young women born late preterm and controls or among men. When food groups were assessed separately, men born early preterm had lower consumption of fruits and berries than controls.ConclusionsYoung women born early preterm have poorer adherence to the healthy eating guidelines than their peers born at term. Differences in diet may contribute to an increased cardiometabolic risk among adults born early preterm. PMID- 29166381 TI - Risk score for the prediction of severe obesity in pediatric craniopharyngiomas: relative to tumor origin. AB - BackgroundWe aimed to develop a risk score to improve the prediction of severe obesity in pediatric craniopharyngiomas (PCs).MethodsOverall, 612 consecutive PCs were prospectively enrolled from six hospitals. Data from 404 participants were analyzed. Participants from three of the six hospitals (n=290) were used to develop a risk score. External validation of the developed risk score was conducted using the participants from the other three hospitals (n=114). Sequential logistic regression was used to develop and validate the risk score. The c statistic and a calibration plot were used to assess the discrimination and calibration of the proposed risk score.ResultsThe overall frequency of severe obesity was 16.1% (65/404). The risk score employed a scale of 0-16 and demonstrated good discriminative power, with an optimism-corrected c statistic of 0.820. Similar results were obtained from external validation, with a c statistic of 0.821. The risk score showed good calibration, with no apparent over- or under prediction observed in the calibration plots.ConclusionsThis novel risk score is a simple tool that can help clinicians assess the risk of severe obesity in PCs, thereby helping to plan and initiate the most appropriate disease management for these patients in time. PMID- 29166382 TI - Human milk H2O2 content: does it benefit preterm infants? AB - BackgroundHuman milk has a high content of the antimicrobial compound hydrogen peroxide (H2O2). As opposed to healthy full-term infants, preterm neonates are fed previously expressed and stored maternal milk. These practices may favor H2O2 decomposition, thus limiting its potential benefit to preterm infants. The goal of this study was to evaluate the factors responsible for H2O2 generation and degradation in breastmilk.MethodsHuman donors' and rats' milk, along with rat mammary tissue were evaluated. The role of oxytocin and xanthine oxidase on H2O2 generation, its pH-dependent stability, as well as its degradation via lactoperoxidase and catalase was measured in milk.ResultsBreast tissue xanthine oxidase is responsible for the H2O2 generation and its milk content is dependent on oxytocin stimulation. Stability of the human milk H2O2 content is pH-dependent and greatest in the acidic range. Complete H2O2 degradation occurs when human milk is maintained, longer than 10 min, at room temperature and this process is suppressed by lactoperoxidase and catalase inhibition.ConclusionFresh breastmilk H2O2 content is labile and quickly degrades at room temperature. Further investigation on breastmilk handling techniques to preserve its H2O2 content, when gavage-fed to preterm infants is warranted. PMID- 29166383 TI - Prematurity disrupts glomeruli development, whereas prematurity and hyperglycemia lead to altered nephron maturation and increased oxidative stress in newborn baboons. AB - BackgroundPremature birth occurs when nephrogenesis is incomplete and has been linked to increased renal pathologies in the adult. Metabolic factors complicating preterm birth may have additional consequences for kidney development. Here, we evaluated the effects of prematurity and hyperglycemia on nephrogenesis in premature baboons when compared with those in term animals.MethodsBaboons were delivered prematurely (67% gestation; n=9) or at term (n=7) and survived for 2-4 weeks. Preterm animals were classified by glucose control during the first 5 days of life: normoglycemic (PtN; serum glucose 50-100 mg/dl, n=6) and hyperglycemic (PtH; serum glucose 150-250 mg/dl, n=3). Kidneys were assessed histologically for glomeruli relative area, maturity, size, and overall morphology. Kidney lysates were evaluated for oxidative damage with 4 hydroxynonenal (4-HNE) antibody.ResultsHistological examination revealed decreased glomeruli relative area (P<0.05), fewer glomerular generations (P<0.01), and increased renal corpuscle area (P<0.001) in preterm compared with those in term animals. Numbers of apoptotic glomeruli were similar between groups. PtH kidneys exhibited reduced nephrogenic zone width (P<0.0001), increased numbers of mature glomeruli (P<0.05), and increased 4-HNE staining compared with those in PtN kidneys.ConclusionPrematurity interrupts normal kidney development, independent of glomerular cell apoptosis. When prematurity is complicated by hyperglycemia; kidney development shifts toward accelerated maturation and increased oxidative stress. PMID- 29166384 TI - Neanderthal hunting strategies inferred from mortality profiles within the Abric Romani sequence. AB - Ungulate mortality profiles are commonly used to study Neanderthal subsistence strategies. To assess the hunting strategies used by Neanderthals, we studied the ages at death of the cervids and equids found in levels E, H, I, Ja, Jb, K, L and M of the Abric Romani sequence. These levels date between 43.2 +/- 1.1 ka BP (14C AMS) and 54.5 +/- 1.7 ka BP (U-series). The degree of eruption and development of the teeth and their wear stages were used to determine the ages of these animals at death, and mortality profiles were constructed using these data. The equids display prime dominated profiles in all of the analyzed levels, whereas the cervids display variable profiles. These results suggest that the Neanderthals of Abric Romani employed both selective and non-selective hunting strategies. The selective strategy focused on the hunting of prime adults and generated prime dominated profiles. On the other hand, non-selective strategies, involved the consumption of animals of variable ages, resulting in catastrophic profiles. It is likely that in the selective hunting events were conducted using selective ambushes in which it was possible to select specific prey animals. On the other hand, encounter hunting or non-selective ambush hunting may have also been used at times, based on the abundances of prey animals and encounter rates. Specific hunting strategies would have been developed accordance with the taxa and the age of the individual to be hunted. The hunting groups most likely employed cooperative hunting techniques, especially in the capture of large animals. Thus, it is not possible to uniquely associate a single mortality profile with the predation tactics of Neanderthals at Abric Romani. PMID- 29166385 TI - Evidence of molting and the function of "rock-nosing" behavior in bowhead whales in the eastern Canadian Arctic. AB - Bowhead whales (Balaena mysticetus) have a nearly circumpolar distribution, and occasionally occupy warmer shallow coastal areas during summertime that may facilitate molting. However, relatively little is known about the occurrence of molting and associated behaviors in bowhead whales. We opportunistically observed whales in Cumberland Sound, Nunavut, Canada with skin irregularities consistent with molting during August 2014, and collected a skin sample from a biopsied whale that revealed loose epidermis and sloughing. During August 2016, we flew a small unmanned aerial system (sUAS) over whales to take video and still images to: 1) determine unique individuals; 2) estimate the proportion of the body of unique individuals that exhibited sloughing skin; 3) determine the presence or absence of superficial lines representative of rock-rubbing behavior; and 4) measure body lengths to infer age-class. The still images revealed that all individuals (n = 81 whales) were sloughing skin, and that nearly 40% of them had mottled skin over more than two-thirds of their bodies. The video images captured bowhead whales rubbing on large rocks in shallow, coastal areas-likely to facilitate molting. Molting and rock rubbing appears to be pervasive during late summer for whales in the eastern Canadian Arctic. PMID- 29166386 TI - You prime what you code: The fAIM model of priming of pop-out. AB - Our visual brain makes use of recent experience to interact with the visual world, and efficiently select relevant information. This is exemplified by speeded search when target- and distractor features repeat across trials versus when they switch, a phenomenon referred to as intertrial priming. Here, we present fAIM, a computational model that demonstrates how priming can be explained by a simple feature-weighting mechanism integrated into an established model of bottom-up vision. In fAIM, such modulations in feature gains are widespread and not just restricted to one or a few features. Consequentially, priming effects result from the overall tuning of visual features to the task at hand. Such tuning allows the model to reproduce priming for different types of stimuli, including for typical stimulus dimensions such as 'color' and for less obvious dimensions such as 'spikiness' of shapes. Moreover, the model explains some puzzling findings from the literature: it shows how priming can be found for target-distractor stimulus relations rather than for their absolute stimulus values per se, without an explicit representation of relations. Similarly, it simulates effects that have been taken to reflect a modulation of priming by an observers' goals-without any representation of goals in the model. We conclude that priming is best considered as a consequence of a general adaptation of the brain to visual input, and not as a peculiarity of visual search. PMID- 29166387 TI - Effects of total sleep deprivation on divided attention performance. AB - Dividing attention across two tasks performed simultaneously usually results in impaired performance on one or both tasks. Most studies have found no difference in the dual-task cost of dividing attention in rested and sleep-deprived states. We hypothesized that, for a divided attention task that is highly cognitively demanding, performance would show greater impairment during exposure to sleep deprivation. A group of 30 healthy males aged 21-30 years was exposed to 40 h of continuous wakefulness in a laboratory setting. Every 2 h, subjects completed a divided attention task comprising 3 blocks in which an auditory Go/No-Go task was 1) performed alone (single task); 2) performed simultaneously with a visual Go/No Go task (dual task); and 3) performed simultaneously with both a visual Go/No-Go task and a visually-guided motor tracking task (triple task). Performance on all tasks showed substantial deterioration during exposure to sleep deprivation. A significant interaction was observed between task load and time since wake on auditory Go/No-Go task performance, with greater impairment in response times and accuracy during extended wakefulness. Our results suggest that the ability to divide attention between multiple tasks is impaired during exposure to sleep deprivation. These findings have potential implications for occupations that require multi-tasking combined with long work hours and exposure to sleep loss. PMID- 29166388 TI - Associations between thyroid dysfunction and developmental status in children with excessive iodine status. AB - BACKGROUND AND OBJECTIVE: Adequate iodine status and normal thyroid hormone synthesis are important for optimal child development. In this study, we explored whether young children's developmental status is associated with thyroid dysfunction in an area of chronic excessive iodine exposure. METHODS: We included 298 children between 18 and 48 months of age residing in Algerian refugee camps. Early child development was measured using the Ages and Stages Questionnaires, third edition (ASQ-3), consisting of five domains: Communication, Gross Motor, Fine Motor, Problem Solving and Personal-Social. Due to poor discriminatory ability in the Gross Motor domain, the total ASQ-3 scores were calculated both including and excluding this domain. Urinary iodine concentration (UIC), thyroid hormones (TSH, FT3 and FT4), thyroid antibodies and serum thyroglobulin (Tg) were measured. RESULTS: The median UIC was 451.6 MUg/L, and approximately 72% of the children had a UIC above 300 MUg/L. Furthermore, 14% had thyroid disturbances, of whom 10% had TSH outside the reference range. Children with thyroid disturbances and TSH outside the reference ranges had lower odds of being among the 66% highest total ASQ scores, with adjusted odds ratios (95% CI) of 0.46 (0.23, 0.93) and 0.42 (0.19, 0.94), respectively. CONCLUSION: We found an association between thyroid dysfunction and poorer developmental status among children with excessive iodine intake. The high iodine intake may have caused the thyroid dysfunction and hence the delayed developmental status; however, other influential factors cannot be excluded. Optimal child development is important for a sustainable future. With iodine excess being an increasing problem globally, this subject should be further explored. PMID- 29166389 TI - Comparisons of management practices and farm design on Australian commercial layer and meat chicken farms: Cage, barn and free range. AB - There are few published studies describing the unique management practices, farm design and housing characteristics of commercial meat chicken and layer farms in Australia. In particular, there has been a large expansion of free range poultry production in Australia in recent years, but limited information about this enterprise exists. This study aimed to describe features of Australian commercial chicken farms, with particular interest in free range farms, by conducting on farm interviews of 25 free range layer farms, nine cage layer farms, nine barn layer farms, six free range meat chicken farms and 15 barn meat chicken farms in the Sydney basin bioregion and South East Queensland. Comparisons between the different enterprises (cage, barn and free range) were explored, including stocking densities, depopulation procedures, environmental control methods and sources of information for farmers. Additional information collected for free range farms include range size, range characteristics and range access. The median number of chickens per shed was greatest in free range meat chicken farms (31,058), followed by barn meat chicken (20,817), free range layer (10,713), barn layer (9,300) and cage layer farms (9,000). Sheds had cooling pads and tunnel ventilation in just over half of both barn and free range meat chicken farms (53%, n = 8) and was least common in free range layer farms (16%, n = 4). Range access in free range meat chicken farms was from sunrise to dark in the majority (93%, n = 14) of free range meat chicken farms. Over half of free range layer farms (56%, n = 14) granted range access at a set time each morning; most commonly between 9:00 to 10.00am (86%, n = 12), and chickens were placed back inside sheds when it was dusk. PMID- 29166390 TI - Criticism by community people and poor workplace communication as risk factors for the mental health of local welfare workers after the Great East Japan Earthquake: A cross-sectional study. AB - After a large-scale natural disaster, demand for social welfare services increases, and the mental health of local social welfare workers becomes a matter of great concern because of their dual role as support providers and disaster survivors. We examined whether work-related social stressors, including criticism by community people and poor workplace communication, were associated with increased risk of post-traumatic stress disorder (PTSD), depression, or psychological distress 20-22 months after the Great East Japan Earthquake (GEJE; March 11, 2011) in local social welfare workers. Demographic characteristics, disaster-related risk factors (near-death experience, dead/missing family members, loss of housing), and work-related social risk factors (criticism, lack of communication) were obtained 20-22 months after the GEJE from 822 local workers. Questionnaires measured PTSD, depression, and psychological stress. Bivariate and multivariate regression analyses were applied. More local social welfare workers suffered from mental health problems than would be expected. Criticism by community people was significantly associated with probable PTSD and high psychological distress (adjusted odds ratio = 2.31 and 2.55, respectively). Furthermore, lack of workplace communication was associated with probable PTSD, depression, and high psychological distress (adjusted odds ratio = 3.97, 4.27, and 4.65, respectively). Almost 2 years after the disaster, local relief workers still suffered from mental health problems. Because post-disaster work-related social stressors constitute risk factors for these mental health problems, measures to improve working conditions and prevent and treat mental disorders should be a priority. PMID- 29166391 TI - Early kinetics of serum Interleukine-17A and infarct size in patients with reperfused acute ST-elevated myocardial infarction. AB - BACKGROUND: Recently, it was shown that interleukin-17A (IL-17A) is involved in the pathophysiology of reperfusion injury and associated with infarct size (IS) in experimental models of myocardial infarction. Our aim was to evaluate whether the IL-17A serum level and the IL-17A active fraction was correlated with IS in humans. METHODS: 101 patients presenting with a ST-elevated Myocardial Infarction (STEMI) referred for primary percutaneous coronary intervention (PPCI) and 10 healthy controls were included. For each participant, blood samples at admission (H0) and 4 hours after admission (H4) were collected. IL-17A serum levels were assessed using ELISA and the active fraction was assessed with a functional test. IS was determined by peak troponin and peak CK levels for every patient and by contrast-enhanced cardiac magnetic resonance (ce-CMR) for 20 patients. RESULTS: The IL-17A serum level was significantly increased in STEMI patients compared to healthy controls, (0.9 pg/mL IQR [0.0-3.2] at H0 and 1.0 pg/mL IQR [0.2-2.8] at H4 versus 0.2 pg/mL IQR [0.0-0.7] for healthy controls; p<0.005). At either time points, IL-17A levels did not correlate with IS as measured by peak troponin, peak CK pr ce-CMR. Also, no correlation was found between the active fraction of IL-17A and IS. CONCLUSION: Serum IL-17A level is significantly increased in patients at the early phase of acute MI compared to healthy controls. However, the level of IL-17A in the early hours after reperfusion does not correlate with IS. PMID- 29166393 TI - Implicit theories concerning the intelligence of individuals with Down syndrome. AB - Studies over the past three decades have shown that learning difficulties are not only determined by neurological disorders, but also by motivational and/or socio cognitive factors Among these factors, implicit theories of intelligence (also referred to as conceptions, mindsets or beliefs about intelligence) are key elements. The belief that intelligence is fixed (entity theory), as opposed to malleable (incremental theory), is generally associated with negative teaching practices and poorer student outcomes, yet beliefs about the intelligence of individuals with intellectual disabilities have not received much attention. We propose the first study on conceptions of intelligence of persons with intellectual disabilities, here people with Down syndrome. Participants were 55 professionally qualified people working with individuals with intellectual disabilities and 81 adults from the community. We compared what both groups of participants believe about intelligence of typical people and what they believe about the intelligence of individuals with Down syndrome. We also investigated implicit theories of intelligence as predictors of explicit judgments about intelligence and implicit attitudes toward people with Down syndrome. Whatever the work experience in the field of intellectual disability, implicit theories of intelligence were found to be less incremental when considering people with Down syndrome than when considering typical people; and the stronger the belief in entity theory, the more negative (and less positive) the judgments expressed explicitly. Implicit theories of intelligence were also found to be predictors of negative implicit attitude but only in adults from the community. These findings offer prospects for improving practices by people working in the field of intellectual disability. They might interest a wide range of people caring for people with intellectual disabilities, such as teachers, but also other professional caregivers, and other scientists focusing on intellectual disabilities or social cognition. PMID- 29166394 TI - Maternity care for trafficked women: Survivor experiences and clinicians' perspectives in the United Kingdom's National Health Service. AB - BACKGROUND: Although trafficked women and adolescents are at risk of unprotected or forced sex, there is little research on maternity care among trafficking survivors. We explored health care needs, service use and challenges among women who became pregnant while in the trafficking situation in the United Kingdom (UK) and clinicians' perspectives of maternity care for trafficked persons. METHODS: Cross-sectional survey and qualitative interviews with trafficking survivors recruited from statutory and voluntary sector organisations in England and qualitative interviews with maternity clinicians and family doctors undertaken to offer further insight into experiences reported by these women. FINDINGS: Twenty eight (29%) of 98 women who took part in a large study of trafficking survivors reported one or more pregnancies while trafficked, whose data are reported here. Twelve (42.8%) of these women reported at least one termination of pregnancy while in the trafficking situation and 25 (89.3%) experienced some form of mental health disorder. Nineteen (67.9%) women experienced pre-trafficking physical abuse and 9 (32.%) sexual abuse. A quarter of women were trafficked for sexual exploitation, six for domestic servitude and two for manual labour. Survivors and clinicians described service challenges, including restrictions placed on women's movements by traffickers, poor knowledge on how to access maternity care, poor understanding of healthcare entitlements and concerns about confidentiality. Maternity care clinicians recognised potential indicators of trafficking, but considered training would help them identify and respond to victims. Main limitations include that findings reflect women who had exited the trafficking situation, however as some had only recently exited the trafficking situation, difficulties with recall were likely to be low. CONCLUSIONS: More than one in four women became pregnant while trafficked, indicating that maternity services offer an important contact point for identification and care. Given the prevalence of sexual exploitation and abuse among trafficking survivors, clinicians should ensure antenatal care and screening for sexually transmitted infections can be readily accessed by women. Clinicians require specialised training alongside designated pathways and protocols with clear referral options to ensure confidential maternity care tailored to each woman's needs. PMID- 29166395 TI - Labour trafficking: Challenges and opportunities from an occupational health perspective. AB - In this essay for the collection on Human Trafficking, Exploitation, and Health, Elena Ronda-Perez and colleague discuss ways occupational health services can detect and address labour trafficking. PMID- 29166392 TI - Intestinal Ralstonia pickettii augments glucose intolerance in obesity. AB - An altered intestinal microbiota composition has been implicated in the pathogenesis of metabolic disease including obesity and type 2 diabetes mellitus (T2DM). Low grade inflammation, potentially initiated by the intestinal microbiota, has been suggested to be a driving force in the development of insulin resistance in obesity. Here, we report that bacterial DNA is present in mesenteric adipose tissue of obese but otherwise healthy human subjects. Pyrosequencing of bacterial 16S rRNA genes revealed that DNA from the Gram negative species Ralstonia was most prevalent. Interestingly, fecal abundance of Ralstonia pickettii was increased in obese subjects with pre-diabetes and T2DM. To assess if R. pickettii was causally involved in development of obesity and T2DM, we performed a proof-of-concept study in diet-induced obese (DIO) mice. Compared to vehicle-treated control mice, R. pickettii-treated DIO mice had reduced glucose tolerance. In addition, circulating levels of endotoxin were increased in R. pickettii-treated mice. In conclusion, this study suggests that intestinal Ralstonia is increased in obese human subjects with T2DM and reciprocally worsens glucose tolerance in DIO mice. PMID- 29166396 TI - Human trafficking and exploitation: A global health concern. AB - In this collection review, Cathy Zimmerman and colleague introduce the PLOS Medicine Collection on Human Trafficking, Exploitation and Health, laying out the magnitude of the global trafficking problem and offering a public health policy framework to guide responses to trafficking. PMID- 29166398 TI - Correction: Perceived Effort for Motor Control and Decision-Making. AB - [This corrects the article DOI: 10.1371/journal.pbio.2002885.]. PMID- 29166397 TI - Extreme exploitation in Southeast Asia waters: Challenges in progressing towards universal health coverage for migrant workers. AB - Rapeepong Suphanchaimat and colleagues present the plight of migrant workers in the fishing industry in Southeast Asia and discuss challenges in providing for their health and safety. PMID- 29166399 TI - Public responses to proposals for a tax on sugar-sweetened beverages: A thematic analysis of online reader comments posted on major UK news websites. AB - BACKGROUND: Regular consumption of sugar sweetened beverages (SSBs) is associated with weight gain, type 2 diabetes, and dental caries. The UK will introduce a levy on the manufacturers of SSBs in 2018. Details will be negotiated over the next two years. How the UK public views SSB taxes is likely to be an important determinant of the content and success of the final policy. We aimed to capture the views, ideas and concerns of commenters on major UK news websites on SSB taxes. METHODS AND FINDINGS: We conducted a qualitative analysis of reader comments to online news coverage of one proposal for an SSB tax in the UK. 1645 comments on four articles were included. Three underpinning themes influenced support or opposition to the tax: the balance between individual responsibility and autonomy, and population need; mistrust of the intention of the proposed tax and those promoting it; and variations in the perceived complexity of unhealthy diets and obesity associated with variations in what are considered appropriate interventions. Arguments under each theme were used to justify both support and opposition in different cases. CONCLUSIONS: As the final form of the UK SSB tax is negotiated, effort should be made to address the concerns we identified. Our results suggest these efforts could usefully focus on emphasising the social and environmental determinants of diet and obesity, reinforcing the benefits of the tax to the NHS, and pitching the tax as playing into a variety of different conceptualisations of obesity. PMID- 29166400 TI - Chronic post-traumatic intramedullary lesions in dogs, a translational model. AB - OBJECTIVES: Post-traumatic intramedullary myelopathies and cavitations are well described lesions following spinal cord injury (SCI) in humans and have been described in histopathological evaluations in dogs. Human intramedullary myelopathies/cavitations are associated with severe initial SCI and deterioration of clinical signs. Canine intervertebral disc extrusions share similarities with SCI in humans. In this descriptive study, magnetic resonance imaging (MRI) findings in spinal cords of dogs suffering from chronic post-traumatic myelopathies, including cavitations, are elucidated. An additional aim of the study was to compare diagnostic imaging and histopathological findings and identify similarities between human and canine chronic post-traumatic spinal cord lesions. METHODS: Thirty-seven dogs with thoracolumbar SCI and one or more 3Tesla MRI investigations more than 3 weeks after SCI were included. Extent of intramedullary lesions and particularly cavitations were evaluated and measured in sagittal and transverse MRI planes. These data were compared with clinical data. RESULTS: A total of 91.9% of study patients developed chronic intramedullary lesions, and 86.5% developed intramedullary cavitations. Paraplegia without deep pain perception at initial examination was significantly associated with longer chronic myelopathies/cavitations (P = 0.002/P = 0.008), and with larger maximal cross-sectional area (mCSA) of the lesions (P = 0.041/0.005). In addition, a non-ambulatory status after decompressive surgery was also associated with the development of longer intramedullary lesions/cavitations (P<0.001) and larger lesion mCSA (P<0.001/P = 0.012). All dogs with negative outcome developed myelopathies/cavitations. In the group of 21 dogs with positive outcome, 3 did not develop any myelopathies, and 5 did not develop cavitations. CONCLUSIONS: Development of chronic intramedullary lesions/cavitations are common findings in canine SCI. Extensive chronic intramedullary lesions/cavitations reflect a severe initial SCI and negative clinical outcome. This supports the hypothesis that chronic spinal cord changes following SCI in humans share similarities with canine chronic spinal cord changes after spontaneous intervertebral disc extrusion. PMID- 29166402 TI - Early Pleistocene archaeological occurrences at the Feiliang site, and the archaeology of human origins in the Nihewan Basin, North China. AB - The Early Pleistocene archaeological evidence from the fluvio-lacustrine sequence of the Nihewan Basin (North China) offers an excellent opportunity to explore early human evolution and behavior in a temperate setting in East Asia, following the earliest 'Out of Africa'. Here we present the first comprehensive study of the Feiliang (FL) site, with emphasis on the archaeological sequence, site integrity, and stone artifact assemblages. Magnetostratigraphic dating results show that early humans occupied the site ca. 1.2 Ma. Archaeological deposits were buried rapidly in primary context within shallow lake margin deposits, with only minor post-depositional disturbance from relatively low energy hydraulic forces. The FL lithic assemblage is characterized by a core and flake, Oldowan-like or Mode 1 technology, with a low degree of standardization, expedient knapping techniques, and casually retouched flakes. The bone assemblage suggests that hominin occupation of the FL site was in an open habitat of temperate grassland with areas of steppe and water. The main features of the FL assemblage are discussed in the context of the early Pleistocene archaeology of Nihewan, for which an assessment of current and future research is also presented. PMID- 29166401 TI - Sexual exploitation of unaccompanied migrant and refugee boys in Greece: Approaches to prevention. AB - In this essay, Julie Freccero and colleagues discuss resources to prevent the sexual exploitation of unaccompanied and separated refugee boys in Greece. PMID- 29166403 TI - Integration of molecular typing results into tuberculosis surveillance in Germany A pilot study. AB - An integrated molecular surveillance for tuberculosis (TB) improves the understanding of ongoing TB transmission by combining molecular typing and epidemiological data. However, the implementation of an integrated molecular surveillance for TB is complex and requires thoughtful consideration of feasibility, demand, public health benefits and legal issues. We aimed to pilot the integration of molecular typing results between 2008 and 2010 in the German Federal State of Baden-Wurttemberg (population 10.88 Million) as preparation for a nationwide implementation. Culture positive TB cases were typed by IS6110 DNA fingerprinting and results were integrated into routine notification data. Demographic and clinical characteristics of cases and clusters were described and new epidemiological links detected after integrating typing data were calculated. Furthermore, a cross-sectional survey was performed among local public health offices to evaluate their perception and experiences. Overall, typing results were available for 83% of notified culture positive TB cases, out of which 25% were clustered. Age <15 years (OR = 4.96, 95% CI: 1.69-14.55) and being born in Germany (OR = 2.01, 95% CI: 1.44-2.80) were associated with clustering. At cluster level, molecular typing information allowed the identification of previously unknown epidemiological links in 11% of the clusters. In 59% of the clusters it was not possible to identify any epidemiological link. Clusters extending over different counties were less likely to have epidemiological links identified among their cases (OR = 11.53, 95% CI: 3.48-98.23). The majority of local public health offices found molecular typing useful for their work. Our study illustrates the feasibility of integrating typing data into the German TB notification system and depicts its added public health value as complementary strategy in TB surveillance, especially to uncover transmission events among geographically separated TB patients. It also emphasizes that special efforts are required to strengthen the communication between local public health offices in different counties to enhance TB control. PMID- 29166404 TI - Species-specific signatures of the microbiome from Camponotus and Colobopsis ants across developmental stages. AB - Symbiotic relationships between hosts and bacteria are common in nature, and these may be responsible for the evolutionary success of various groups of animals. Among ants, these associations have been well studied in some genera of the Camponotini, but several questions remain regarding the generality of the previous findings across all the members of this ant tribe and if bacterial communities change across development in these hosts. This study is the first to characterize the bacterial community associated with a colony of the recently recognized genus Colobopsis and three colonies of Camponotus (two distinct species) and show how different the composition of the bacterial community is when compared across the different genera. Our data reveal that Colobopsis (species: Co. riehlii) and Camponotus (species: Ca. floridanus and Ca. planatus) have distinct microbiota, and we were able to verify that the identity of the species contributes more to the bacterial diversity. We also demonstrated that there were no significant differences between colonies of the same species (Camponotus planatus), and between stages of development from different colonies. We did find that some developmental stages have distinct bacteria, confirming that each stage of development could have a specific microbiota. Our results show species are one of the factors that shape the bacterial community in these Camponotini ants. Additional studies of the intra-colonial microbiome of other hosts and across development may reveal additional clues about the function and importance of bacteria in colony recognition, individual and colony health, and nutritional upgrading. PMID- 29166405 TI - Child sex trafficking in the United States: Challenges for the healthcare provider. AB - V. Jordan Greenbaum discusses ways healthcare providers can identify children trafficked for sex to provide for their physical and mental health and their social and educational needs. PMID- 29166406 TI - Revised geochronology, correlation, and dinosaur stratigraphic ranges of the Santonian-Maastrichtian (Late Cretaceous) formations of the Western Interior of North America. AB - Interbasinal stratigraphic correlation provides the foundation for all consequent continental-scale geological and paleontological analyses. Correlation requires synthesis of lithostratigraphic, biostratigraphic and geochronologic data, and must be periodically updated to accord with advances in dating techniques, changing standards for radiometric dates, new stratigraphic concepts, hypotheses, fossil specimens, and field data. Outdated or incorrect correlation exposes geological and paleontological analyses to potential error. The current work presents a high-resolution stratigraphic chart for terrestrial Late Cretaceous units of North America, combining published chronostratigraphic, lithostratigraphic, and biostratigraphic data. 40Ar / 39Ar radiometric dates are newly recalibrated to both current standard and decay constant pairings. Revisions to the stratigraphic placement of most units are slight, but important changes are made to the proposed correlations of the Aguja and Javelina formations, Texas, and recalibration corrections in particular affect the relative age positions of the Belly River Group, Alberta; Judith River Formation, Montana; Kaiparowits Formation, Utah; and Fruitland and Kirtland formations, New Mexico. The stratigraphic ranges of selected clades of dinosaur species are plotted on the chronostratigraphic framework, with some clades comprising short duration species that do not overlap stratigraphically with preceding or succeeding forms. This is the expected pattern that is produced by an anagenetic mode of evolution, suggesting that true branching (speciation) events were rare and may have geographic significance. The recent hypothesis of intracontinental latitudinal provinciality of dinosaurs is shown to be affected by previous stratigraphic miscorrelation. Rapid stepwise acquisition of display characters in many dinosaur clades, in particular chasmosaurine ceratopsids, suggests that they may be useful for high resolution biostratigraphy. PMID- 29166407 TI - Executive function assessment in New Zealand 2-year olds born at risk of neonatal hypoglycemia. AB - A growing number of babies are born with perinatal risk factors that may impair later development. These children are often assessed at 2 years to help predict outcome and direct support services. Executive function is an important predictor of academic achievement and behavior, but there are limited assessments of executive function in 2-year-olds and few have been tested in at-risk populations. Therefore, we developed a battery of four age-appropriate tasks to assess executive function in 2-year-olds. At 24 months' corrected age 368 children completed tasks assessing attention, inhibition, working memory and cognitive flexibility. Scores on different tasks were weakly correlated, suggesting that they measured separate aspects of executive function, with combined scores for this cohort approximating a normal distribution. Significantly more boys (67%) than girls (57%) were unable to inhibit their behavior on the Snack Delay Task and girls (M = 3.24, SD = 2.4) had higher mean scores than boys (M = 2.7, SD = 2.7) on the Ducks and Buckets Reverse Categorization Task of working memory. Performance was significantly affected by family socioeconomic status. Mean scores were lower on all four individual tasks and on the global score of overall performance in children from a low household income (<$40,000) compared to those from medium ($40,001-$70,000) and high income households (>$70,001). Maternal education was only associated with scores on the working memory task and the global score; and a measure of neighborhood deprivation was only associated with scores on the two inhibitory tasks and the global score. Our findings confirm the feasibility of assessing executive function in 2-year-olds, and its ability to discriminate effects of socioeconomic status, a common confounder in child development research. Further development and standardization of this test battery comparing at-risk children with a normative population would provide a much-needed measure of executive function in early childhood. PMID- 29166409 TI - Post-weaning high-fat diet results in growth cartilage lesions in young male rats. AB - To determine if a high-fat diet (HF) from weaning would result in a pro inflammatory state and affect joint cartilage, we fed male rats either HF or Chow diet post-weaning, and voluntary wheel exercise (EX) or cage only activity (SED) after 9 weeks of age. At 17 weeks body composition, plasma biomarkers and histomorphology scores of femoro-tibial cartilages of HF-SED, HF-EX, Chow-SED and Chow-EX groups were compared. Food intake and activity were not significantly different between groups. HF diet resulted in significantly higher weight gain, %fat, fat:lean ratio, and plasma leptin, insulin and TNFalpha concentrations, with significant interactions between diet and exercise. No abnormal features were detected in the hyaline articular cartilage or in the metaphyseal growth plate in all four groups. However, collagen type X- positive regions of retained epiphyseal growth cartilage (EGC) was present in all HF-fed animals and significantly greater than that observed in Chow-fed sedentary rats. Most lesions were located in the lateral posterior aspect of the tibia and/or femur. The severity of lesions was greater in HF-fed animals. Although exercise had a significantly greater effect in reducing adiposity and associated systemic inflammation in HF-fed rats, it had no effect on lesion incidence or severity. Lesion incidence was also significantly associated with indices of obesity and plasma markers of chronic inflammation. Clinically, EGC lesions induced by HF feeding in rats from very early in life, and possibly by insufficient activity, is typical of osteochondrosis in animals. Such lesions may be the precursor of juvenile osteochondritis dissecans requiring surgery in children/adolescents, conservative management of which could benefit from improved understanding of early changes in cellular and gene expression. PMID- 29166408 TI - Estimating the impact of tuberculosis anatomical classification on treatment outcomes: A patient and surveillance perspective analysis. AB - INTRODUCTION: Tuberculosis anatomical classification is inconsistent in the literature, which limits current tuberculosis knowledge and control. We aimed to evaluate whether tuberculosis classification impacts on treatment outcomes at patient and aggregate level. METHODS: We analyzed adults from Sao Paulo State, Brazil with newly diagnosed tuberculosis from 2010-2013. We used an extended clinical classification of tuberculosis, categorizing cases as pulmonary, pulmonary and extrapulmonary, extrapulmonary and miliary/disseminated. Our primary outcome was unsuccessful outcome of treatment. To investigate the reported treatment outcome at the aggregate level, we sampled 500 different "countries" from the dataset and compared the impact of pulmonary and extrapulmonary classifications on the reported treatment success. RESULTS: Of 62,178 patients, 49,999 (80.4%) were pulmonary, 9,026 (14.5%) extrapulmonary, 1,651 (2.7%) pulmonary-extrapulmonary and 1,502 (2.4%) miliary/disseminated. Pulmonary-extrapulmonary cases had similar unsuccessful outcome of treatment compared with pulmonary (adjusted-OR 1.00, 95%CI, 0.88-1.13, p = 0.941), while extrapulmonary were associated with better (adjusted-OR 0.65, 95%CI, 0.60-0.71, p<0.001) and miliary/disseminated with worse outcomes (adjusted-OR 1.51, 95%CI, 1.33-1.71, p<0.001). We found that 60 (12%) countries would report a difference >=10% in treatment success depending on whether they reported all clinical forms together (current WHO recommendation) or pulmonary forms alone, overestimating the treatment success of pulmonary forms. CONCLUSIONS: The expanded anatomical classification of tuberculosis was strongly associated with treatment outcomes at the patient level. Remarkably, pulmonary with concomitant extrapulmonary forms had similar treatment outcomes compared with pulmonary forms after adjustment for potential confounders. At the aggregate level, reporting treatment success for all clinical forms together might hide differences in progress between pulmonary and extrapulmonary tuberculosis control. PMID- 29166410 TI - Devario in Bangladesh: Species diversity, sibling species, and introgression within danionin cyprinids (Teleostei: Cyprinidae: Danioninae). AB - Four species of Devario are recorded from Bangladesh: D. aequipinnatus, D. anomalus, D. coxi, new species, and D. devario. Devario aequipinnatus has a wide distribution in northern India and Bangladesh. Devario coxi, from southeastern Bangladesh near Cox's Bazar, differs from D. aequipinnatus in mtDNA (COI, p distance 1.8%), colouration, proportional measurements, and meristics. The minor morphological differences and low frequency of overlapping meristics suggest relatively recent separation of D. coxi from other D. aequipinnatus. Devario anomalus occurs only in southeastern Bangladesh and is here reported from localities in addition to the type locality. It differs from the similar D. xyrops in adjacent Myanmar by slender body shape and by 2.3% p-distance in the COI gene. Specimens of D. anomalus from the Sangu River were found to have the mitochondrial genome of D. aequipinnatus from Bangladesh, but agree with other D. anomalus in the nuclear RAG1 gene. Devario devario has a wide distribution on the Indian Peninsula and border regions; in Bangladesh it is restricted in distribution to the Ganga, Brahmaputra, and Meghna drainages. Reports of D. assamensis and D. malabaricus from Bangladesh are misidentifications. Perilampus ostreographus M'Clelland, 1839, is tentatively synonymized with D. aequipinnatus. Phylogenetic analysis of 14 species of striped devarios based on the COI gene results in a polytomy with four unresolved clades. Devario deruptotalea from the Chindwin basin is the sister group of D. aequipinnatus+D. coxi. Devario devario is the sistergroup of D. xyrops+D. anomalus. PMID- 29166411 TI - A machine learning approach to triaging patients with chronic obstructive pulmonary disease. AB - COPD patients are burdened with a daily risk of acute exacerbation and loss of control, which could be mitigated by effective, on-demand decision support tools. In this study, we present a machine learning-based strategy for early detection of exacerbations and subsequent triage. Our application uses physician opinion in a statistically and clinically comprehensive set of patient cases to train a supervised prediction algorithm. The accuracy of the model is assessed against a panel of physicians each triaging identical cases in a representative patient validation set. Our results show that algorithm accuracy and safety indicators surpass all individual pulmonologists in both identifying exacerbations and predicting the consensus triage in a 101 case validation set. The algorithm is also the top performer in sensitivity, specificity, and ppv when predicting a patient's need for emergency care. PMID- 29166412 TI - miR-195 inhibits macrophages pro-inflammatory profile and impacts the crosstalk with smooth muscle cells. AB - Macrophages are a main component of atherosclerotic plaques. Recent studies suggest that pro-inflammatory M1 macrophages are pro-atherogenic while M2 macrophages promote plaque stability. Moreover, toll-like receptor signalling pathways are implicated in atherosclerotic plaque formation, evolution and regression. We propose microRNAs as key regulators of these processes. In this context, our goal is to promote inflammation resolution using miR-195 to reduce M1-like macrophage polarization and to evaluate the molecular mechanisms underlying such effect, as well as to explore the functional consequences for smooth muscle cell recruitment. Human primary macrophages were differentiated from peripheral blood monocytes and stimulated with LPS or IL-10 to promote M1 or M2c polarization, respectively. miR-195 levels were upregulated in M2c macrophages compared with M1 macrophages. In THP-1 macrophages stimulated with LPS and IFN-gamma, results show that TLR2 levels were reduced by miR-195 overexpression compared with scrambled control. In addition, phosphorylated forms of p54 JNK, p46 JNK and p38 MAPK were decreased by miR-195 in macrophages following M1 stimulation. Moreover, miR-195 significantly decreased levels of IL 1beta, IL-6 and TNF-alpha pro-inflammatory cytokines in the supernatants of M1 stimulated macrophage cultures. At the functional level, results from smooth muscle cell recruitment and migration models showed that miR-195 impairs the capacity of M1 macrophages to promote smooth muscle cells migration. In conclusion, miR-195 is involved in macrophage polarization and inhibits TLR2 inflammatory pathway mediators. Moreover, miR-195 impairs the effect of macrophages on smooth muscle cells recruitment capacity and migration profile. Thus, miR-195 might be used as a new potential tool to promote inflammation resolution in cardiovascular research. PMID- 29166413 TI - Comprehensive molecular profiling of 718 Multiple Myelomas reveals significant differences in mutation frequencies between African and European descent cases. AB - Multiple Myeloma (MM) is a plasma cell malignancy with significantly greater incidence and mortality rates among African Americans (AA) compared to Caucasians (CA). The overall goal of this study is to elucidate differences in molecular alterations in MM as a function of self-reported race and genetic ancestry. Our study utilized somatic whole exome, RNA-sequencing, and correlated clinical data from 718 MM patients from the Multiple Myeloma Research Foundation CoMMpass study Interim Analysis 9. Somatic mutational analyses based upon self-reported race corrected for ancestry revealed significant differences in mutation frequency between groups. Of interest, BCL7A, BRWD3, and AUTS2 demonstrate significantly higher mutation frequencies among AA cases. These genes are all involved in translocations in B-cell malignancies. Moreover, we detected a significant difference in mutation frequency of TP53 and IRF4 with frequencies higher among CA cases. Our study provides rationale for interrogating diverse tumor cohorts to best understand tumor genomics across populations. PMID- 29166414 TI - ChrASO, the chromate efflux pump of Shewanella oneidensis, improves chromate survival and reduction. AB - The chromate efflux pump encoding gene chrASO was identified on the chromosome of Shewanella oneidensis MR1. Although chrASO is expressed without chromate, its expression level increases when Cr(VI) is added. When deleted, the resulting mutant DeltachrASO exhibits a chromate sensitive phenotype compared to that of the wild-type strain. Interestingly, heterologous expression of chrASO in E. coli confers resistance to high chromate concentration. Moreover, expression of chrASO in S. oneidensis and E. coli significantly improves Cr(VI) reduction. This effect could result either from extracytoplasmic chromate reduction or from a better cell survival leading to enhanced Cr(VI) reduction. PMID- 29166417 TI - Oral Status and Prosthetic Treatment Needs in Functionally Impaired and Elderly Individuals. AB - PURPOSE: The purpose of this cross-sectional study was to describe the oral status and prosthetic treatment needs of dependent, functionally impaired individuals and dependent elderly individuals in comparison with the general population. METHODS: A total of 355 subjects, sampled from the register of increased financial support for dependent and functionally impaired individuals in the north of Sweden, were examined. The variables were number of teeth, Eichner Index, type and condition of prostheses, and treatment needs. Statistical analyses were carried out using an independent samples t test for means and chi square tests for proportions. Comparisons were made with the results of an earlier study (EPI-Norr) of 908 patients from the general population in the same county. RESULTS: The study group had fewer teeth compared with the general population (20% edentulous in the study group vs 7% in the general population; P < .001), as well as more dentures and fewer tooth- and implant-supported prostheses. A total of 42% of the dentures in the maxilla and 51% of the dentures in the mandible were in poor condition. There was no difference in complications from dental implants between the groups. CONCLUSION: Since the Swedish system for financial support enables dental care to the patient groups in question, the situation is probably better in Sweden than in many other countries. As more accentuated differences can be assumed between these population groups in other countries, these findings are also interesting from an international perspective. PMID- 29166416 TI - Limited Effect of Cement Material on Stress Distribution of a Monolithic Translucent Zirconia Crown: A Three-Dimensional Finite Element Analysis. AB - PURPOSE: The literature shows that the performance of densely sintered zirconia single crowns seems to be unaffected by the cement material. The purpose of this study was to evaluate the effects of various cement materials on the stress distribution in a monolithic translucent zirconia crown. MATERIALS AND METHODS: A crown-cement-dentin complex was modeled. Six cements were evaluated: zinc phosphate, glass-ionomer, resin-modified glass-ionomer, dual-cure resin, calcium aluminate-based, and a theoretical or conceptual cement with mechanical properties close to those of dentin (ie, monoblock cement). RESULTS: While varying stress concentrations were found within the cements, the stress concentrations in the crown and dentin were consistent irrespective of cement material. CONCLUSION: Within the limitations of this study, it can be concluded that cement material had a negligible effect on stress distribution in the monolithic zirconia crown. PMID- 29166415 TI - Prognosis of type 1 autoimmune pancreatitis after corticosteroid therapy-induced remission in terms of relapse and diabetes mellitus. AB - BACKGROUND AND AIM: Relapse and diabetes mellitus (DM) are major problems for the prognosis of autoimmune pancreatitis (AIP). We examined the prognosis of type 1 AIP after corticosteroid therapy (CST)-induced remission in terms of relapse and DM. METHODS: The study enrolled 82 patients diagnosed with type 1 AIP who achieved remission with CST. We retrospectively evaluated the relapse rate in terms of the administration period of CST, clinical factors associated with relapse, and the temporal change in glucose tolerance. RESULTS: During follow-up, 32 patients (39.0%) experienced relapse. There was no significant clinical factor that could predict relapse before beginning CST. AIP patients who ceased CST within 2 or 3 years experienced significantly earlier relapse than those who had the continuance of CST (p = 0.050 or p = 0.020). Of the 37 DM patients, 15 patients (40.5%) had pre-existing DM, 17 (45.9%) showed new-onset DM, and 5 (13.5%) developed CST-induced DM. Patients with new-onset DM were significantly more likely to show improvement (p = 0.008) than those with pre-existing DM. CONCLUSIONS: It was difficult to predict relapse of AIP based on clinical parameters before beginning CST. Relapse was likely to occur within 3 years after the beginning of CST and maintenance of CST for at least 3 years reduced the risk of relapse. The early initiation of CST for AIP with impaired glucose tolerance is desirable because pre-existing DM is refractory to CST. PMID- 29166418 TI - Prosthetic Rehabilitation of a Patient with Rare and Severe Enamel Renal Syndrome. AB - Dental rehabilitation of acute cases of enamel renal syndrome is challenging due to the absence of clinical reports. In the present case history report, examination of an 18-year-old patient revealed a complete lack of permanent teeth, as well as irregular and swollen bone and gingival morphology. Radiographs showed multiple impacted teeth in both arches. Creating a 1.5- to 2-cm interarch space was necessary for setting complete dentures. The ideal occlusal plane was chosen by combining two techniques (cephalometric radiograph and modification of the mandibular occlusal rim according to anatomical guidelines). Extraction of impacted teeth and recontouring of the alveolar process were performed simultaneously. The mandibular denture was connected through Locator abutments to two symphyseal implants. This pioneering clinical report will provide guidance to practitioners in the surgical intervention of patients with FAM20A (family with sequence similarities 20 A) gene mutations. PMID- 29166419 TI - Combined Stereophotogrammetry and Laser-Sintered, Computer-Aided Milling Framework for an Implant-Supported Mandibular Prosthesis: A Case History Report. AB - PURPOSE: This study compared the marginal gaps of computer-aided design/computer aided manufacture (CAD/CAM)-fabricated all-ceramic crowns constructed from scanned impressions and models and with two different occlusal reduction designs. MATERIALS AND METHODS: Two typodont mandibular first molars were prepared to receive CAD/CAM-fabricated all-ceramic crowns. Both molars were prepared to ideal crown reduction, the first with anatomical occlusal reduction (AOR) and the second with completely flat occlusal reduction (FOR). Nine polyvinyl siloxane impressions (PVS) were taken, and nine stone replicas fabricated for each preparation. All impressions and stone models were scanned using a laser scanner (Planmeca Planscan, E4D technologies), and 36 lithium disilicate (IPS e.max CAD) crowns were milled. The marginal gap was measured in four locations using a light stereomicroscope. RESULTS: Crowns constructed from preparations with both occlusal reduction designs demonstrated similar marginal gaps (FOR = 97.98; AOR = 89.12; P = .739). However, all crowns constructed from scanned impressions presented significantly larger marginal gaps than the crowns fabricated from scanned models (impressions = 109.26; models = 77.84; P = .002). CONCLUSION: Scanning stone models produced all-ceramic crowns with significantly smaller marginal gaps than scanning impressions, irrespective of the occlusal reduction design. PMID- 29166420 TI - A Comparison of Marginal Gaps of All-Ceramic Crowns Constructed from Scanned Impressions and Models. AB - PURPOSE: This study compared the marginal gaps of computer-aided design/computer aided manufacture (CAD/CAM)-fabricated all-ceramic crowns constructed from scanned impressions and models and with two different occlusal reduction designs. MATERIALS AND METHODS: Two typodont mandibular first molars were prepared to receive CAD/CAM-fabricated all-ceramic crowns. Both molars were prepared to ideal crown reduction, the first with anatomical occlusal reduction (AOR) and the second with completely flat occlusal reduction (FOR). Nine polyvinyl siloxane impressions (PVS) were taken, and nine stone replicas fabricated for each preparation. All impressions and stone models were scanned using a laser scanner (Planmeca Planscan, E4D technologies), and 36 lithium disilicate (IPS e.max CAD) crowns were milled. The marginal gap was measured in four locations using a light stereomicroscope. RESULTS: Crowns constructed from preparations with both occlusal reduction designs demonstrated similar marginal gaps (FOR = 97.98; AOR = 89.12; P = .739). However, all crowns constructed from scanned impressions presented significantly larger marginal gaps than the crowns fabricated from scanned models (impressions = 109.26; models = 77.84; P = .002). CONCLUSION: Scanning stone models produced all-ceramic crowns with significantly smaller marginal gaps than scanning impressions, irrespective of the occlusal reduction design. PMID- 29166421 TI - Wear and Fracture Strength of New Ceramic Resins for Chairside Milling. AB - PURPOSE: The purpose of this in vitro study was to evaluate wear and fracture strength of chairside-milled new ceramic resins after artificial aging in a chewing simulator. MATERIALS AND METHODS: Two ceramic resins (Lava Ultimate and Vita Enamic) and two conventional ceramics (IPS Empress CAD and Celtra Duo) were tested. For analysis of wear, baseline and follow-up scans of the specimens were made, the scans were superimposed, and the wear was calculated. To determine fracture strength, the specimens were loaded until they fractured. RESULTS: Lava Ultimate showed the highest wear, caused the lowest wear of the opposing dentition, and showed statistically significantly higher fracture strength than conventional ceramics after cyclic loading. CONCLUSION: New ceramic resins for chairside milling are a good alternative to conventional ceramics. PMID- 29166422 TI - Intranasal bevacizumab in the treatment of HHT -related epistaxis: a systematic review. AB - BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) remains a difficult disease for the ENT specialist to manage. Affected patients often report recurrent epistaxis as the most debilitating symptom. The pathogenesis of the disease is due to genetic mutations affecting angiogenesis. For this reason, the anti-angiogenic therapy bevacizumab has gained popularity in the local treatment of epistaxis in patients with HHT. OBJECTIVE: A systematic review of the efficacy of bevacizumab in local treatment of epistaxis in patients with HHT based on epistaxis duration, frequency, severity and impact on quality of life. METHODS: A systematic search was performed using the PubMed, MEDLINE and EMBASE databases. The Preferred Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies that measured the efficacy of intranasal bevacizumab treatment of epistaxis in patients with HHT were included for qualitative analysis. RESULTS: Thirteen studies (four randomised controlled trials, three prospective studies, three retrospective studies, one case series and two case reports) with a total of 357 patients were included. Local administration (either by submucosal injection or topically) did not have a significant impact on epistaxis duration, frequency, severity or quality of life compared to placebo or other local treatments. CONCLUSIONS: The available evidence suggests that intranasal bevacizumab treatment does not have a significant effect on epistaxis in patients with HHT. There are several limitations that require further investigation to confidently rule out local bevacizumab as an effective therapy in HHT related epistaxis. PMID- 29166423 TI - Exhaled and nasal nitric oxide in chronic rhinosinusitis patients with nasal polyps in primary care. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disorder associated with lower airway disease. However, only few studies of CRSwNP from outside secondary/tertiary care centres have been published. We recently reported an asthma frequency of 44% and 65% in primary and secondary care patients respectively. Therefore, we hypothesise that inflammation of the lower airways could be present in all CRSwNP patients, even without asthma. Here, we assessed the degree of lower and upper airway inflammation using exhaled and nasal nitric oxide (NO) in primary care CRSwNP patients with and without asthma. METHODS: Fifty-seven patients who met the EPOS criteria for CRSwNP were prospectively recruited from primary care ear, nose and throat clinics. Nasal endoscopy was performed by an ear, nose and throat specialist upon enrolment. Additionally, 30 healthy controls were enrolled. Expiratory and nasal NO measurements and thorough pulmonary evaluation were performed. Pulmonary disease was diagnosed by a respiratory physician. RESULTS: Fifty-nine percent of CRSwNP patients with asthma showed elevated expiratory NO; the same was seen in 29% of non-asthmatic CRSwNP patients. Compared with controls, a high level of exhaled NO was significantly more prevalent in CRSwNP irrespective of asthma status. Nasal NO was significantly lower in patients with CRSwNP compared with controls. CONCLUSION: Subclinical eosinophilic lower airway inflammation is common in CRSwNP in the primary sector, even in the absence of asthma. PMID- 29166424 TI - The future in Rhinology: from local treatment, to monoclonals and influencing the microbiome. AB - Over the last few decades, rhinology has been one of the most dynamic and progressive areas of ENT. We have not experienced such an intense period of development since the introduction of nasal corticosteroids in the 1970s. PMID- 29166425 TI - Anatomy of the sphenopalatine artery and its implications for transnasal neurosurgery. AB - BACKGROUND: The knowledge of sinonasal vasculature is inevitable in transnasal neurosurgery. We performed an anatomical study on the sphenopalatine artery from the perspective of skull base procedures. METHODOLOGY: To analyse the anatomical landmarks of the sphenopalatine artery, arterial skull corrosion casts (26 head halves) underwent endoscopic transnasal phantom surgery. Furthermore, we performed microsurgical dissection on formaldehyde-fixated cadavers with arterial perfusion (14 head halves) as well as studied Cone Beam CT-scans of anonymised patients and cadavers (115 head sides). RESULTS: In our cadaveric material, the sphenopalatine foramen is located at the transition of the superior and middle nasal meatus (95.0%) or in the superior nasal meatus (5.0%). It is the main entry point of the branches of the sphenopalatine artery into the nasal cavity. In most cadaveric cases (25.0%), at this level there are 2 branches superiorly and 1 vessel inferiorly to the ethmoid crest. An average of 2.4 vessels leave the sphenopalatine foramen superiorly to the ethmoid crest, 97.8% of them belong to the sphenopalatine arterys posterior septal branches. An average of 2.1 branches leave the sphenopalatine foramen inferiorly to the ethmoid crest; all of them belong to the posterior lateral nasal branches. There are no cases with a single artery at the plane of the sphenopalatine foramen. We describe a triangular bony structure bordering the sphenopalatine foramen anteriorly which is built up by the palatine and ethmoid bone as well as the maxilla. According to the radiographic studies, this triangular prominence is surrounded superiorly by a posterior ethmoid cell (57.4%), the sphenoid sinus (41.7%) or the orbit (0.9%) with a varying contribution of the superior nasal meatus; inferolaterally by the maxillary sinus (98.3%) or the pterygopalatine and infratemporal fossa (1.7%) and inferomedially by the middle nasal meatus. The medial vertex of the bony triangle corresponds to the ethmoid crest of the palatine bone. In transnasal endoscopic surgery, the posterior lateral nasal branches of the sphenopalatine artery appear at the triangle's inferomedial edge, the posterior septal branches emerge at its superior edge. CONCLUSIONS: The triangular bony structure is a landmark to find and differentiate the posterior lateral nasal and posterior septal branches of the sphenopalatine artery and to identify the sphenoid sinus. PMID- 29166426 TI - Rhinology Future Debates, an EUFOREA Report. AB - The first Rhinology Future Debates was held in Brussels in December 2016, organized by EUFOREA (European Forum for Research and Education in Allergy and Airways diseases). The purpose of these debates is to bring novel developments in the field of Rhinology to the attention of the medical, paramedical and patient community, in a highly credible and balanced context. For the first time in Rhinology, a peer to peer scientific exchange with key experts in the field of rhinology and key medical colleagues from leading industries let to a brainstorming and discussion event on a number of hot issues in Rhinology. Novel developments are presented by key experts from industry and/or key thought leaders in Rhinology, and then followed by a lively debate on the potential positioning of new developments in care pathways, the strengths and weaknesses of the novel development(s), and comparisons with existing and/or competing products, devices, and/or molecules. As all debates are recorded and distributed on-line with limited editing (www.rhinology-future.com), EUFOREA aims at maximizing the education of the target groups on novel developments, allowing a critical appraisal of the future and a more rapid implementation of promising novel tools, techniques and/or molecules in clinical practise in Europe. The next Rhinology Future debate will be held in Brussels in December 2017. PMID- 29166427 TI - Myxobolus marajoensis sp. n. (Myxosporea: Myxobolidae), parasite of the freshwater catfish Rhamdia quelen from the Brazilian Amazon region. AB - This study provides morphological and molecular data of a new parasite species found in the muscle layer of the intestinal tract of the South American silver catfish, Rhamdia quelen from Marajo Island region (Para State, Brazil), an important fishery resource with recognized potential for fish farming. The morphology of these parasites was reanalyzed and phylogenetic analyses were run on their 18S rDNA gene sequences. The spores were morphologically distinct from those of other Myxobolus species described previously. The obtained partial sequence of the 18S rDNA gene sequences of the new species were compared to those of 24 other Myxobolus and Henneguya species available in GenBank. The results of morphological and molecular analyses indicated clearly the existence of a new species, Myxobolus marajoensis sp. n. PMID- 29166428 TI - A characterization of ecosystem services, drivers and values of two watersheds in Sao Paulo State, Brazil. AB - The evaluation of ecosystem services is a tool to raise awareness about benefits of ecosystem functions for human well-being. In Brazil, few studies and reports assess ecosystem services in a watershed context. The aim of this paper is to fill this gap by assessing ecosystem services of Jacare-Guacu and Jacare-Pepira Watersheds (Sao Paulo State, Brazil) in a temporal scale of 10 years. Land cover and uses' capacity to provide ecosystem services and drivers were assessed as a result of mapping these areas. Economic values were estimated based on literature information. Results showed that cultivated and managed terrestrial areas stands out over other areas and then, regulation and maintenance services are reduced in these areas. Wetlands and natural vegetation, with smaller areas, are important for the supply of regulation and maintenance services of both watersheds and economic values indicate the magnitude of degradation or maintenance/restoration. PMID- 29166429 TI - The life cycle of Neotropical ground beetle, Abaris basistriata (Coleoptera: Carabidae) reared on different substrates. AB - Carabids are recognized worldwide as biological control agents of agricultural pests. The objective was to compare the life cycle of Abaris basistriata Chaudoir (Coleoptera: Carabidae) on three substrates: soil, fine vermiculite, or paper napkins. The biological cycle of A. basistriata presented different durations in soil and paper. The viability of eggs and larvae survival of the first and second instars were similar on all three substrates, while the third instar and pupa in the soil presented higher survival when compared with vermiculite and paper. The soil substrate was more favorable for the longevity of the carabid beetle. Abaris basistriata showed a shorter pre-oviposition period and a higher oviposition and post-oviposition period in the soil. Fecundity and fertility were higher when A. basistriata was reared on soil. The soil was most favorable substrate for rearing of A. basistriata in the laboratory. This information may make this species useful for the biological control. PMID- 29166430 TI - Aquaculture biological waste as culture medium to cultivation of Ankistrodesmus gracilis (Reinsch) Korshikov. AB - Current study investigated the effectiveness of different macrophytes as culture media for Ankistrodesmus gracilis in laboratory conditions. Significant difference (p < 0.05) was reported in cell density with regard to conventional culture medium (CHU12) and macrophytes culture media. Mean cell density in NPK, Eichhornia crassipes and E. azurea media was higher (p < 0.05) than in conventional culture medium. Chlorophyll-a was higher than 1 g.L-1, except in CHU12 (0.7 +/- 0.4 g.L-1) and T. domingensis (0.8 +/- 0.3 g.L-1) media. Nitrate decreased sharply as from the 7th-day of the experiment. Ammonium and total phosphorus were highest in culture media and ranged between 0.4 g.L-1 (P. cordata medium) and 1.7 g.L-1 (CHU12 medium) for ammonium, and between 0.8 g.L-1 (CHU12 medium) and 1.9 g.L-1 (T. domingensis medium) for total phosphorus. Results revealed inorganic fertilizer and macrophytes combined with vitamins may be effective as culture media and strongly supports the growth of Ankistrodesmus gracilis, since cell density and biochemical composition are similar to or higher than conventional culture medium (CHU12). Macrophyte is a tool for aquaculture since biological wastes may be used with nutrients to improve the cultivation of microalgae. PMID- 29166431 TI - Coexistence of morphea and granuloma annulare: a rare case report. AB - CONTEXT: Localized scleroderma (morphea) is characterized by fibrosis of skin and subcutaneous tissue. Granuloma annulare is a relatively common disease that is characterized by dermal papules and arciform plaques. CASE REPORT: Here, we present the case of a 42-year-old woman who developed granuloma annulare on the dorsum of her feet and abdominal region, and morphea on the anterior side of her lower limbs. We also discuss the etiological and pathogenetic processes that may cause the rare coexistence of these two diseases. CONCLUSION: Only a few cases in the literature have described coexistence of morphea and granuloma annulare. PMID- 29166433 TI - Hypoglycemia caused by co-secretion of insulin from lung tumor and cardia cancer: first case report. AB - CONTEXT: Non-islet-cell-tumor-induced hypoglycemia (NICTH) is caused on rare occasions by secretion of insulin from tumor cells that are reported to have a single tissue origin. CASE REPORT: A 67-year-old male patient had cardia adenocarcinoma and concomitant lung adenocarcinoma with extensive metastases and repeated episodes of intractable hypoglycemia. Immunohistochemical staining for insulin showed that lung adenocarcinoma stained positive and gastric cardia adenocarcinoma stained weakly positive. These results indicate that tumor cells of different tissue origins co-secreted insulin. CONCLUSIONS: This is the first report on intractable hypoglycemia due to co-secretion of insulin from two kinds of primary tumor cells in a single patient. PMID- 29166432 TI - Engagement in physical education classes and health among young people: does sports practice matter? A cross-sectional study. AB - CONTEXT AND OBJECTIVE: Physical education classes aim to promote health but it is unknown whether benefits occur independently of sports practice. The purpose of this study was to examine associations between engagement in physical education classes and physical fitness and obesity according to sports practice among Brazilian students. DESIGN AND SETTING: Cross-sectional school-based study involving 737 students aged 10-17 years in southern Brazil. METHODS: Engagement in physical education classes and sports practice were analyzed using a self report questionnaire. The health indicators analyzed were cardiorespiratory fitness, muscle strength, obesity and combinations thereof. The covariates were sex, age, socioeconomic status, physical activity and sedentary behavior. Prevalence ratios (PR) adjusted for confounding variables were estimated using Poisson regression. Analyses were stratified according to sports practice. RESULTS: Engagement in physical education classes was associated with achievement of health-related criteria for cardiorespiratory fitness (PR = 1.52), muscle strength (PR = 1.55), obesity + cardiorespiratory fitness (PR = 1.51), obesity + muscle strength (PR = 1.70), cardiorespiratory fitness + muscle strength (PR = 2.60) and the three outcomes combined (PR = 2.43), only among non-sports practitioners, all P < 0.05. Engagement in physical education classes was not associated with obesity (PR = 1.00, P > 0.05). No associations were found for sports practitioners (P > 0.05). CONCLUSION: Engagement in physical education classes was associated with health among non-sports practitioners. However, to protect students from obesity and promote additional health benefits for sports practitioners, the conventional physical education program offered to the sample studied should be reformulated. PMID- 29166434 TI - Evidence hierarchies relating to hand surgery: current status and improvement. A bibliometric analysis study. AB - BACKGROUND: Hierarchy of evidence is an important measurement for assessing quality of literature. Information regarding quality of evidence within the Brazilian hand surgery setting is sparse, especially regarding whether research has improved in either quality or quantity. This study aimed to identify and classify hand surgery studies published in the two most important Brazilian orthopedics journals based on hierarchy of evidence, with comparisons with previously published data. DESIGN AND SETTING: Bibliometric analysis study performed in a federal university. METHODS: Two independent researchers conducted an electronic database search for hand surgery studies published between 2010 and 2016 in Acta Ortopedica Brasileira and Revista Brasileira de Ortopedia. Eligible studies were subsequently classified according to methodological design, based on the Haynes pyramid model (HP) and the JBJS/AAOS levels of evidence and grades of recommendations (LOR). Qualitative and quantitative data were gathered regarding all studies. Previous data were considered to assess whether the proportion of high-quality studies had improved over time (2000-2009 versus 2010-2016). RESULTS: The final analysis included 123 studies, mostly originating from the southeastern region (78.8%) and private institutions (65%), with self-funding (91.8%). Methodological assessment showed that 15.4% were classified as level I/II using HP and 16.4% using LOR. No significant difference in proportions of high-quality studies was found between the two periods of time assessed (5% versus 12%; P = 0.13). CONCLUSION: Approximately 15% of hand surgery studies published in two major Brazilian journals were likely to be classified as high quality through two different systems. Moreover, no trend towards quality-of evidence improvement was found over the last 15 years. PMID- 29166435 TI - Smoking among adolescents is associated with their own characteristics and with parental smoking: cross-sectional study. AB - BACKGROUND: This study aimed to analyze the association between smoking during adolescence and the characteristics of smoking and alcohol consumption among their parents. DESIGN AND SETTING: Cross-sectional study in Londrina (PR), Brazil. METHODS: The subjects comprised 1,231 adolescents aged 14-17 years. The adolescents and their parents answered a self-report questionnaire that asked for sociodemographic information and data on smoking and alcohol consumption. Multiple logistic regression models were used to analyze associations between smoking among adolescents and their characteristics (age, sex, period of the day for attending school, alcohol consumption and socioeconomic level) and their parents' characteristics (smoking, alcohol consumption, age and education level), adjusted according to the adolescents' characteristics (sex, age and socioeconomic level). RESULTS: The prevalence of smoking among adolescents was 3.4% (95% confidence interval, CI: 2.4-4.4). Adolescents whose mothers or fathers were smokers were 2.0 and 2.5 times more likely to be smokers, respectively. The prevalence of smoking among adolescents with a smoking mother was 7.1% (95% CI: 2.6-10.7) and a smoking father, 5.4% (95% CI: 1.6-8.5). There were significant associations between smoking adolescents and age [5.2% (95% CI: 3.3-6.6)], studying at night [9.6% (95% CI: 4.0-15.5)] and alcohol consumption [69.0% (95% CI: 55.0-83.0)]. It was observed that the number of alcoholic beverage doses consumed was higher among smoking adolescents (P = 0.001). CONCLUSION: Adolescent smoking was associated with smoking by their parents, regardless of the gender of the parents or adolescents. Age, alcohol consumption and studying at night are characteristics of adolescents that can contribute towards smoking. PMID- 29166436 TI - Factors associated with self-reported discrimination against men who have sex with men in Brazil. AB - OBJECTIVE: To estimate self-reported discrimination due to sexual orientation among men who have sex with men (MSM) in Brazil and to analyze associated factors. METHODS: A cross-sectional study of 3,859 MSM recruited in 2008-2009 with respondent driven sampling. Data collection conducted in health centers in 10 Brazilian cities. A face-to-face questionnaire was used and rapid HIV and syphilis tests conducted. Aggregated data were weighted and adjusted odds ratio estimated to measure the association between selected factors and self-reported discrimination due to sexual orientation. RESULTS: The sample was predominantly young, eight plus years of schooling, pardo (brown), single, low-income, and identified themselves as gay or homosexual. The prevalence of self-reported discrimination due to sexual orientation was 27.7% (95%CI 26.2-29.1). Discrimination was independently associated with: age < 30 years, more years of schooling, community involvement and support, history of sexual and physical violence, suicidal thoughts, and unprotected receptive anal intercourse. CONCLUSIONS: The prevalence of self-reported discrimination among MSM in Brazil is high. These results challenge the assumptions that MSM-specific prevention and support programs are not required or that health professionals do not need special training to address MSM needs. PMID- 29166437 TI - Breastfeeding indicators trends in Brazil for three decades. AB - OBJECTIVE: Update breastfeeding indicators trend in Brazil for the last three decades, incorporating more up-to-date information from the National Health Survey. METHODS: We used secondary data from national surveys with information on breastfeeding (1986, 1996, 2006, and 2013) to construct the time series of prevalence for the following indicators: exclusive breastfeeding in children under six months of age (EBF6m), breastfeeding in toddlers under 2 years of age (BF), continued breastfeeding at one year of age (BF1year), and continued breastfeeding at two years of age (BF2years). RESULTS: The prevalence of EBF6m, BF, and BF1year increased until 2006 (rising from 4.7%, 37.4%, and 25.5% in 1986 to 37.1%, 56.3%, and 47.2% in 2006, respectively). For these three indicators, there was relative stabilization between 2006 and 2013 (36.6%, 52.1%, and 45.4%, respectively). The BF2years indicator had a distinct behavior - relatively stable prevalence, around 25% between 1986 and 2006, and a subsequent increase, reaching 31.8% in 2013. CONCLUSIONS: The time series of breastfeeding indicators in Brazil shows an upward trend until 2006, stabilizing from that date onwards on three of the four indicators evaluated. This result, which can be considered as a warning sign, requires evaluation and revision of policies and programs to promote, protect and support breastfeeding, strengthening existing ones and proposing new strategies so that the prevalence of breastfeeding indicators returns to an upwards trend. PMID- 29166438 TI - Prevalence and risk factors of inadequate medicine home storage: a community based study. AB - OBJECTIVE: Assess the extent of inadequate home storage of medicines andidentify important risk factors. METHODS: A cross-sectional survey based on a probability sample in the community, conducted in 267 households in Cuite, State of Paraiba, Northeast Brazil, in 2014. Logistic regression was used to study the risk factors. RESULTS: The prevalence of households with inadequate storage was 76.0%. Problems with storage include direct exposure to sunlight in 10.9% of households, the presence of dust in 23.6%, and storage within reach of children in 76.0%. Medications no longer used are usually disposed of into the environment in 92.1% of households. Inadequate storage is more likely when home organization of medications is the responsibility of a male subject (OR = 1.729) or an older person (OR = 1.029), when out of date medicines are found (OR = 2.963), and in households with no children (OR = 2.088). CONCLUSIONS: Physicians and pharmacists should advise patients on how to adequately store medicines at home, especially when the person in charge of medications is a male or an older adult, and if there are no children in the household. PMID- 29166439 TI - The Geographic Information System applied to study schistosomiasis in Pernambuco. AB - OBJECTIVE: Diagnose risk environments for schistosomiasis in coastal localities of Pernambuco using geoprocessing techniques. METHODS: A coproscopic and malacological survey were carried out in the Forte Orange and Serrambi areas. Environmental variables (temperature, salinity, pH, total dissolved solids and water fecal coliform dosage) were collected from Biomphalaria breeding sites or foci. The spatial analysis was performed using ArcGis 10.1 software, applying the kernel estimator, elevation map, and distance map. RESULTS: In Forte Orange, 4.3% of the population had S. mansoni and were found two B. glabrata and 26 B. straminea breeding sites. The breeding sites had temperatures of 25oC to 41oC, pH of 6.9 to 11.1, total dissolved solids between 148 and 661, and salinity of 1,000 d. In Serrambi, 4.4% of the population had S. mansoni and were found seven B. straminea and seven B. glabrata breeding sites. Breeding sites had temperatures of 24oC to 36oC, pH of 7.1 to 9.8, total dissolved solids between 116 and 855, and salinity of 1,000 d. The kernel estimator shows the clusters of positive patients and foci of Biomphalaria, and the digital elevation map indicates areas of rainwater concentration. The distance map shows the proximity of the snail foci with schools and health facilities. CONCLUSIONS: Geoprocessing techniques prove to be a competent tool for locating and scaling the risk areas for schistosomiasis, and can subsidize the health services control actions. PMID- 29166440 TI - Maternal complications and cesarean section without indication: systematic review and meta-analysis. AB - OBJECTIVE: The objective of this study was to determine the risks of severe acute maternal complications associated with cesarean section without medical indication. METHODS: A systematic review was carried out with meta-analysis. The literature search was performed systematically, in multiple stages, in the PubMed, Lilacs, and Web of Science databases using the following descriptors: (postpartum period) and (cesarean section or natural childbirth) and ((morbidity or mortality) or (postpartum hemorrhage) or (puerperal infection) or (surgical infection) or (puerperal disorders)). The protocol of the study was registered at PROSPERO as CRD42016032933. A total of 1,328 articles were found; after selection, eight publications that met the study objective and inclusion criteria were selected, with information on 1,051,543 individuals. RESULTS: The results obtained in the meta-analyses indicate that women with cesarean section have a higher chance of maternal death (OR = 3.10, 95%CI 1.92-5.00) and postpartum infection (OR = 2.83, 95%CI, 1.585.06), but they have a lower chance of hemorrhage (OR = 0.52, 95%CI 0.48-0.57). For the blood transfusion outcome, the group effect was not associated with the type of delivery (95%CI 0.88-2.81). CONCLUSIONS: The quality of evidence was considered low for hemorrhage and blood transfusion and moderate for postpartum infection and maternal death. Thus, cesarean sections should be performed with caution and safety, especially when its benefits outweigh the risks of a surgical procedure. PMID- 29166441 TI - Transfer of knowledge in international cooperation: the Farmanguinhos - SMM case. AB - OBJECTIVE: To analyze the influence of four mechanisms of knowledge transfer (training, technical visits, expatriation, and standard operating procedures) on the different dimensions (potential and realized) of absorptive capacity in international technical cooperation. METHODS: We examine the case of implementation of the Sociedade Mocambicana de Medicamentos. Data have been collected using semi-structured interviews (applied to 21 professionals of the Sociedade Mocambicana de Medicamentos, Farmanguinhos, FIOCRUZ, and Itamaraty) and official documents. The data of the interviews have been submitted to content analysis, using the software NVivo. RESULTS: Training and technical visits directly influenced the acquisition and, partly, the assimilation of knowledge. Expatriation contributed with the transformation of this knowledge from the development and refinement of operational routines. Finally, the definition of standard operating procedures allowed the Mozambican technicians to be the actors of the transformation of the knowledge previously acquired and assimilated and, at the same time, it laid the foundations for a future exploration of the knowledge. CONCLUSIONS: Training and technical visits mainly influence the potential absorptive capacity, while expatriation and standard operating procedures most directly affect the realized absorptive capacity. PMID- 29166442 TI - Depression and unemployment incidence rate evolution in Portugal, 1995-2013: General Practitioner Sentinel Network data. AB - OBJECTIVE: Quantify, for both genders, the correlation between the depression incidence rate and the unemployment rate in Portugal between 1995 and 2013. METHODS: An ecological study was developed to correlate the evolution of the depression incidence rates estimated by the General Practitioner Sentinel Network and the annual unemployment rates provided by the National Statistical Institute in official publications. RESULTS: There was a positive correlation between the depression incidence rate and the unemployment rate in Portugal, which was significant only for males (R2 = 0.83, p = 0.04). For this gender, an increase of 37 new cases of depression per 100,000 inhabitants was estimated for each 1% increase in the unemployment rate between 1995 and 2013. CONCLUSIONS: Although the study design does not allow the establishment of a causal association between unemployment and depression, the results suggest that the evolution of unemployment in Portugal may have had a significant impact on the level of mental health of the Portuguese, especially among men. PMID- 29166443 TI - EpiFloripa Aging cohort study: methods, operational aspects, and follow-up strategies. AB - OBJECTIVE: To describe the sample plan, operational aspects, and strategies used in the 2009/2010 and 2013/2014 EpiFloripa Aging Study. METHODS: The EpiFloripa Aging is a population-based longitudinal study with 1,705 older adults (60 years or more) living in the municipality of Florianopolis, State of Santa Catarina, Brazil, in 2009/2010 (baseline). The research was conducted with a face-to-face interviews, organized into blocks of identification, socioeconomic, mental health, health and life habits, global functionality, falls, physical activity, morbidities, use of health services, use of medications, food, oral health, and violence, evaluated in the first (2009/2010) and in the second wave (2013/2014). Additionally, in the second wave, we investigated the issue of discrimination and quality of life. RESULTS: The response rate of the first wave was 89.2% (n = 1,705). The baseline sample, with predominance of women (63.9%), was similar to the 2010 Census regarding age for women and slightly different for younger men. In the second wave, 1,197 participants were interviewed (response rate of 70.3%). Follow-up losses were only observed for the variable age group (p = 0.003), and predominantly for those aged 80 years or more. Mortality data linkage and active search for participants were used as a follow-up strategies. CONCLUSIONS: This study used strategies that were able to help locate the participants and maintain adherence, which ensured a good response rate during investigations. PMID- 29166444 TI - Patterns of tobacco consumption among residents of a rural settlement: a cross sectional study. AB - OBJECTIVE: Investigate patterns and factors associated with tobacco consumption among residents of a rural settlement. METHODS: A cross-sectional study conducted between September and November 2014, with 172 residents of a rural settlement in the Midwest region of Brazil. We analyzed as dependent variables tobacco consumption at some point in life; current tobacco consumption; tobacco abuse; and the high risk of nicotine dependence, with sociodemographic variables associated with tobacco use, and we applied the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) and Self-Reporting Questionnaire (SRQ-20). RESULTS: The prevalence of tobacco use in life, current use, tobacco abuse, and high risk of nicotine dependence were 62.2%, 20.9%, 59.8%, and 10.3%, respectively. Advanced age, low education level, evangelical religion, marijuana use, hypnotic or sedative consumption, and male gender were factors associated with smoking patterns in the settlers. CONCLUSIONS: There was a high prevalence of smoking patterns, evidencing the need for public policies on tobacco prevention and control in this population. PMID- 29166445 TI - Regular access and adherence to medications of the specialized component of pharmaceutical services. AB - OBJECTIVE : To investigate the prevalence of the adherence to the medications of the Specialized Component of Pharmaceutical Services and its association with regular access in users of these medications in the municipality of Sao Leopoldo, State of Rio Grande do Sul, Brazil. METHODS : This is a cross-sectional study with adults aged 20 years and over, who are users of medications of the Specialized Component of Pharmaceutical Services. Sampling was carried out consecutively for users who accessed the service of the Specialized Component of Pharmaceutical Services during the period from December 2014 to March 2015. Adherence was measured by the Brief Medication Questionnaire, and adherents were defined as those who did not present barriers to adherence in the three domains. Regular access was defined as getting all medications in the last three months, regardless of how it was obtained (paying or for free). Data analysis was performed using Poisson regression with robust variance. RESULTS : We interviewed 414 subjects, being them mostly women (60.9%), with mean age of 55 years (SD = 13), and using a single medication of the Specialized Component of Pharmaceutical Services (68.1%). The prevalence of adherence to the medications used in the last seven days was 28.3% and the prevalence of free regular access was 46.1%, and 25.7% did not have access to all treatment. After adjusting for the number of medications in the Specialized Component of Pharmaceutical Services and the number of medications of continuous use, users who had free regular access in the last three months were 60% more likely to show adherence. For individuals with paid regular access, no association was found between access and adherence. CONCLUSIONS : The regularity in the free access to the medications of the Specialized Component of Pharmaceutical Services has an impact on the behavior of users, contributing to their commitment to treatment and self-care. The Specialized Component of Pharmaceutical Services needs programming in order to avoid irregular access, which suggests a significant limitation of the drug policies in Brazil. PMID- 29166446 TI - Maternal education and age: inequalities in neonatal death. AB - OBJECTIVE: Evaluate the interaction between maternal age and education level in neonatal mortality, as well as investigate the temporal evolution of neonatal mortality in each stratum formed by the combination of these two risk factors. METHODS: A nonconcurrent cohort study, resulting from a probabilistic relationship between the Mortality Information System and the Live Birth Information System. To investigate the risk of neonatal death we performed a logistic regression, with an odds ratio estimate for the combined variable of maternal education and age, as well as the evaluation of additive and multiplicative interaction. The neonatal mortality rate time series, according to maternal education and age, was estimated by the Joinpoint Regression program. RESULTS: The neonatal mortality rate in the period was 8.090/00 and it was higher in newborns of mothers with low education levels: 12.70/00 (adolescent mothers) and 12.40/00 (mother 35 years old or older). Low level of education, without the age effect, increased the chance of neonatal death by 25% (OR = 1.25, 95%CI 1.14 1.36). The isolated effect of age on neonatal death was higher for adolescent mothers (OR = 1.39, 95%CI 1.33-1.46) than for mothers aged >= 35 years (OR = 1.16, 95%CI 1.09-1.23). In the time-trend analysis, no age group of women with low education levels presented a reduction in the neonatal mortality rate for the period, as opposed to women with intermediate or high levels of education, where the reduction was significant, around 4% annually. CONCLUSIONS: Two more vulnerable groups - adolescents with low levels of education and older women with low levels of education - were identified in relation to the risk of neonatal death and inequality in reducing the mortality rate. PMID- 29166447 TI - Prevalence and clinical profile of chronic pain and its association with mental disorders. AB - OBJECTIVE: To identify the prevalence of 12-month self-reported pain and chronic pain in a general population and to describe their clinical profile to assess if chronic pain is associated with 12-month mental disorders. METHODS: The data used comes from the Sao Paulo Megacity Mental Health Survey, a population-based study assessing adult (>= 18 years) residents of the Sao Paulo metropolitan area, Brazil. We have assessed the respondents (n = 5,037) using the Composite International Diagnostic Interview (CIDI 3.0), with a global response rate of 81.3%. Descriptive analyses have been performed, and crude and adjusted odds ratios (OR) have been calculated with logistic and multinomial regression and presented with respective 95% confidence intervals (95%CI). RESULTS: The prevalence of pain and chronic pain in the past 12 months were 52.6% (95%CI 50.3 54.8) and 31.0% (95%CI 29.2-32.7), respectively. Joints (16.5%, 95%CI 15.4-17.5) and back or neck (15.5%, 95%CI 14.2-16.9) were the most frequently reported anatomical sites of chronic pain. On a 10-point analogue scale, the mean intensity of the worst pain was 7.7 (95%CI 7.4-7.8), and the mean average pain was 5.5 (95%CI 5.2-5.6); the mean treatment response was 6.3 (95%CI 6.0-6.6). Mean pain duration was 16.1 (95%CI 15.6-17.0) days a month and 132 (95%CI 126 144) minutes a day. Chronic pain was associated with 12-month DSM-IV mental disorders (OR = 2.7, 95%CI 2.3-3.3), anxiety disorders (OR = 2.1, 95%CI 1.9-3.0), and mood disorders (OR = 3.3, 95%CI 2.4-4.1). CONCLUSIONS: A high prevalence of chronic pain in multiple sites is observed among the general adult population, and associations between chronic pain and mental disorders are frequent. PMID- 29166448 TI - Meta-evaluation of a participatory process in the strengthening of municipal management. AB - OBJECTIVE: To evaluate, with a focus on participation, an evaluation process developed by municipal managers and administrators of a health region in the state of Sao Paulo, considering the need for theoretical reflection on participatory health practices in the Brazilian context. METHODS: Qualitative research that used the framework developed by Daigneault and Jacob (2009) to analyze the empirical material, encompassing three dimensions of participation: control of the evaluation process, diversity of participants, and extent of their involvement. We highlighted decisions or contextual aspects that deepened or limited the participatory option in the process under study. RESULTS: We identified the presence and important performance of stakeholders who are "not specialists in evaluation", through participation both in the direction of the evaluation process and in its distinct stages. The formed group started from their own annoyances added to the need for information and reflection to define the subject and scope of the evaluation; the use of the process planned by them guided the definition of the data to be collected and the format of result dissemination; the empirical material analysis was undertaken jointly by the participants. Regarding the third dimension, a limitation was identified regarding the diversity of actors involved due to the prioritization of the possibility of in-depth work with a fixed group of managers. CONCLUSIONS: It is stated that there is no "ideal participation model" for evaluations. In certain contexts and structures, real opportunities for participation - even if they seem fragile at first sight - should be leveraged, and that requires flexibility and critical reflection on the part of those responsible for the evaluation processes to undertake the necessary adjustments. PMID- 29166449 TI - Caesarean birth rates in public and privately funded hospitals: a cross-sectional study. AB - OBJECTIVE: To examine maternal and obstetric factors influencing births by cesarean section according to health care funding. METHODS: A cross-sectional study with data from Southeastern Brazil. Caesarean section births from February 2011 to July 2012 were included. Data were obtained from interviews with women whose care was publicly or privately funded, and from their obstetric and neonatal records. Univariate and multivariate analyses were conducted to generate crude and adjusted odds ratios (OR) with 95% confidence intervals (95%CI) for caesarean section births. RESULTS: The overall caesarean section rate was 53% among 9,828 women for whom data were available, with the highest rates among women whose maternity care was privately funded. Reasons for performing a c section were infrequently documented in women's maternity records. The variables that increased the likelihood of c-section regardless of health care funding were the following: paid employment, previous c-section, primiparity, antenatal and labor complications. Older maternal age, university education, and higher socioeconomic status were only associated with c-section in the public system. CONCLUSIONS: Higher maternal socioeconomic status was associated with greater likelihood of a caesarean section birth in publicly funded settings, but not in the private sector, where funding source alone determined the mode of birth rather than maternal or obstetric characteristics. Maternal socioeconomic status and private healthcare funding continue to drive high rates of caesarean section births in Brazil, with women who have a higher socioeconomic status more likely to have a caesarean section birth in all birth settings. PMID- 29166450 TI - Night work and BMI: is it related to on-shift napping? AB - On-shift napping can benefit night workers regarding sleep loss, synchronization of circadian rhythms, and alertness. However, few studies on napping can be found in the literature focused on possible health benefits. This cross-sectional study has investigated the role of on-shift napping on the association between night work and BMI in 409 night-shift nursing professionals. The number of working nights and the years of exposure to night work were significantly associated with increased BMI levels among non-nappers, but not among nappers. Results suggest a benefit of napping for weight gain, thus subsidizing occupational health policies on the regulation of on-shift napping among nursing workers. PMID- 29166451 TI - Factors associated with frailty in a community-dwelling population of older adults. AB - OBJECTIVE: To analyze if demographic and socioeconomic factors and factors related to health and health services are associated with frailty in community dwelling older adults. METHODS: This is a cross-sectional study with 339 older adults (60 years old or more) living in Juiz de Fora, State of Minas Gerais, Brazil, in 2015. A household survey was carried out and frailty was evaluated using the Edmonton Frail Scale. For the analysis of the factors associated with outcome, a theoretical model of determination was constructed with three hierarchical blocks: block 1 with demographic and socioeconomic characteristics, block 2 with the health of the older adult (divided into three sub-levels: 2.1 self-reported health variables, 2.2 self-perceived health variables, and 2.3 geriatric syndromes), and block 3 with characteristics related to health services. The variables were adjusted in relation to each other within each block; those with significance level <= 0.20 were included in the Poisson regression model and adjusted to a higher level, considering a level of significance of 5%. RESULTS: The prevalence of frailty among older adults was 35.7% (95%CI 30.7-40.9). Of the total, 42.2% did not present frailty; 22.1% were apparently vulnerable. Among the frail ones, 52.9% presented mild frailty, 32.2% moderate frailty, and 14.9% severe frailty. Frailty was associated with difficulty walking, need for an auxiliary device to walk, presence of caregiver, depressive disorders, and functional dependence to perform instrumental activities of daily living. CONCLUSIONS: Frailty is frequent among the older population and it is associated with health variables of the three sub-levels that make up block 2 of the theoretical hierarchical model of determination: self reported health variables, self-perceived health variables, and geriatric syndromes. PMID- 29166452 TI - Is the 18F-FDG PET/CT the definite resource to detect the recurrence on high-risk thyroid cancer patients? PMID- 29166453 TI - Biochemical diagnosis of acromegaly without a typical clinical phenotype: what are the concerns? PMID- 29166454 TI - The clinical genetics of phaeochromocytoma and paraganglioma. AB - Phaeochromocytoma and paraganglioma are rare catecholamine-producing tumours, recognised to have one of the richest hereditary backgrounds of all neoplasms, with germline mutations seen in approximately 30% of patients. They can be a part of genetic syndromes such as MEN 2 or Neurofibromatosis type 1, or can be found as apparently sporadic tumours. Germline mutations are almost always found in syndromic patients. Nonetheless, apparently sporadic phaeochromocytoma too show high germline mutation rates. Early detection of a genetic mutation can lead to early diagnosis of further tumours via surveillance, early treatment and better prognosis. Apart from this, the genetic profile has important relevance for tumour location and biochemical profile, and can be a useful predictor of future tumour behaviour. It also enables family screening and surveillance. Moreover, recent studies have demonstrated significant driver somatic mutations in up to 75% of all tumours. Arch Endocrinol Metab. 2017;61(5):490-500. PMID- 29166456 TI - Erratum. AB - [This corrects the article doi: 10.1590/0004-282x20170074]. PMID- 29166455 TI - Progression and Prognosis of Paravalvular Regurgitation After Transcatheter Aortic Valve Implantation. AB - BACKGROUND: The impact of paravalvular regurgitation (PVR) following transcatheter aortic valve implantation (TAVI) remains uncertain. OBJECTIVE: To evaluate the impact of PVR on mortality and hospital readmission one year after TAVI. METHODS: Between January 2009 and June 2015, a total of 251 patients underwent TAVI with three different prostheses at two cardiology centers. Patients were assessed according to PVR severity after the procedure. RESULTS: PVR was classified as absent/trace or mild in 92.0% (n = 242) and moderate/severe in 7.1% (n = 18). The moderate/severe PVR group showed higher levels of aortic calcification (22% vs. 6%, p = 0.03), higher serum creatinine (1.5 +/- 0.7 vs. 1.2 +/- 0.4 mg/dL, p = 0.014), lower aortic valve area (0.6 +/- 0.1 vs. 0.7 +/- 0.2 cm2, p = 0.05), and lower left ventricular ejection fraction (49.2 +/- 14.8% vs. 58.8 +/- 12.1%, p = 0.009). Patients with moderate/severe PVR had more need for post-dilatation (p = 0.025) and use of larger-diameter balloons (p = 0.043). At one year, all-cause mortality was similar in both groups (16.7% vs. 12%, p = 0.08), as well as rehospitalization (11.1% vs. 7.3%, p = 0.915). PVR grade significantly reduced throughout the first year after the procedure (p < 0.01). The presence of moderate/severe PVR was not associated with higher one-year mortality rates (HR: 0.76, 95% CI: 0.27-2.13, p = 0.864), rehospitalization (HR: 1.08, 95% CI: 0.25-4.69, p=0.915), or composite outcome (HR: 0.77, 95% CI: 0.28 2.13, p = 0.613). CONCLUSION: In this sample, moderate/severe PVR was not a predictor of long-term mortality or rehospitalization. (Arq Bras Cardiol. 2017; [online].ahead print, PP.0-0). PMID- 29166457 TI - Anti-MOG syndrome: a road to be paved. PMID- 29166458 TI - MOG-IgG associated optic neuritis is not multiple sclerosis. AB - : Autoantibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with inflammatory central nervous system disorders including isolated optic neuritis (ON). We compared our MOG-IgG ON patients with multiple sclerosis (MS) patients presenting with ON. METHODS AND RESULTS: Among the total of 38 patients with optic neuropathies, six patients with isolated ON were MOG IgG positive and eight patients with ON fulfilled the diagnostic criteria for MS. All MS patients were negative for MOG-IgG using a cell-based assay. When compared with the MS group, the MOG-IgG patients were older (mean 47 years), more frequently male (ratio 2:1) and had a higher frequency of bilateral and/or recurrent ON. The brain magnetic resonance imaging of all MOG-IgG positive patients was normal or had only unspecific white matter T2 lesions. CONCLUSION: These findings suggest that MOG-IgG is a biomarker of an inflammatory demyelinating CNS disease distinct from MS. PMID- 29166459 TI - Could infarct location predict the long-term functional outcome in childhood arterial ischemic stroke? AB - OBJECTIVE: To explore the influence of infarct location on long-term functional outcome following a first-ever arterial ischemic stroke (AIS) in non-neonate children. METHOD: The MRIs of 39 children with AIS (median age 5.38 years; 36% girls; mean follow-up time 5.87 years) were prospectively evaluated. Infarct location was classified as the absence or presence of subcortical involvement. Functional outcome was measured using the modified Rankin scale (mRS) for children after the follow-up assessment. We utilized multivariate logistic regression models to estimate the odds ratios (ORs) for the outcome while adjusting for age, sex, infarct size and middle cerebral artery territory involvement (significance < 0.05). RESULTS: Both infarcts >= 4% of total brain volume (OR 9.92; CI 1.76 - 55.9; p 0.009) and the presence of subcortical involvement (OR 8.36; CI 1.76 - 53.6; p 0.025) independently increased the risk of marked functional impairment (mRS 3 to 5). CONCLUSION: Infarct extension and location can help predict the extent of disability after childhood AIS. PMID- 29166460 TI - Microsurgical treatment of basilar tip aneurysms: is it still acceptable? AB - OBJECTIVE: Basilar tip aneurysms (BTAs) have a complex anatomy, making them difficult to treat. We describe our surgical results for BTAs. METHODS: From 2004 to 2015 (12 years), a total of 25 small BTAs and two giant BTAs were treated in the Hospital do Servidor Publico Estadual de Sao Paulo. RESULTS: In 23 patients harboring aneurysms positioned anteriorly or straight, all aneurysms were clipped (complete exclusion in all on follow-up angiography). In two patients with posteriorly positioned aneurysms, there was residual neck. All patients submitted to surgical treatment of small aneurysms presented with late Glasgow Outcome Scale scores of 4 or 5. Two patients with giant aneurysms died. CONCLUSION: Surgical treatment of these lesions may be accomplished with quite high success rates and low morbidity. PMID- 29166462 TI - Effects of an alternating work shift on air traffic controllers and the relationship with excessive daytime sleepiness and stress. AB - OBJECTIVE: To evaluate symptoms of stress and excessive daytime sleepiness (EDS) in air traffic control (ATC) officers in Brazil. METHODS: Fifty-two ATC officers participated, based at three air traffic control units, identified as A, B and C. Stress symptoms were assessed using the Lipp Inventory of Stress Symptoms for Adults, and EDS by the Epworth Sleepiness Scale. RESULTS: The sample mean age was 37 years, 76.9% of whom were male. Excessive daytime sleepiness was identified in 25% of the ATC officers, with 84.6% of these based at air traffic control unit A, which has greater air traffic flow, operating a 24-hour alternating work shift schedule. A total of 16% of the ATC officers had stress symptoms, and of these, 62% showed a predominance of physical symptoms. CONCLUSION: The high percentage of ATC officers with EDS identified in group A may be related to chronodisruption due to night work and alternating shifts. PMID- 29166461 TI - Presumed Zika virus-related congenital brain malformations: the spectrum of CT and MRI findings in fetuses and newborns. AB - OBJECTIVE: The new epidemic of Zika virus infection raises grave concerns, especially with the increasingly-recognized link between emerging cases of microcephaly and this infectious disease. Besides small cranial dimensions, there are striking morphologic anomalies in the fetal brain. Key anomalies include cortical developmental malformations and a peculiar distribution of pathologic calcifications. These potentially indicate a new pattern of congenital central nervous system infection. METHODS: Eight women underwent fetal MRI. Four infants also underwent postnatal CT. Five of the women underwent amniocentesis. RESULTS: All neonates were born with microcephaly. On fetal MRI, ventriculomegaly, marked reduction of white matter thickness, severe sylvian fissure simplification, abnormal sulcation, and diffuse volumetric loss of cerebellar hemispheres were consistently seen. On postnatal CT, diffuse subcortical and basal ganglia calcifications were observed. The Zika virus was detected in two amniocenteses by polymerase chain reaction assays. CONCLUSION: We hope to assist the medical community in recognizing the spectrum of encephalic changes related to congenital Zika virus infection. PMID- 29166463 TI - Physicians are not well informed about the new guidelines for the treatment of acute stroke. AB - OBJECTIVE: Treatment of cerebrovascular disease has advanced rapidly in the last two decades. Recent data has added challenges to the treatment of ischemic stroke in the acute phase. OBJECTIVE: To evaluate the knowledge of physicians about the treatment of ischemic stroke in the acute phase. METHODS: An online questionnaire was submitted to all physicians enrolled in the Regional Council of Medicine in Brazil. RESULTS: 456 physicians from different specialties answered the questions. Most of them did not know that mechanical endovascular thrombectomy is often considered as the gold standard treatment in cases of ischemic stroke in the acute phase; and 85% of them did not realize that thrombectomy together with intravenous thrombolysis was possible. The maximum time to act in an acute event also presented many divergences, even with regard to the infusion of rtPA. The lack of structure, medication and absence of a neurologist were considered the main barriers to treatment. CONCLUSION: Physicians are not well informed about the new guidelines for the treatment of acute stroke. Most physicians incorrectly answered most of the questions on the questionnaire. PMID- 29166464 TI - Implementing an epilepsy surgery center. Initial experience at a university hospital in Brazil. AB - OBJECTIVE: Epilepsy is a serious neurological condition, often without a full and effective treatment. In some cases, surgery is beneficial, despite being underused. Our aim herein is to describe the implementation of an epilepsy surgery center in a federal university hospital, sharing the initial experience gained, as well as describing the main challenges and first results. METHODS: Experience report of an epilepsy surgery center implementation. Retrospective review of 13 drug-resistant patients who underwent surgical treatment. RESULTS: Thirteen patients underwent surgical epilepsy treatment, five patients categorized as the International League Against Epilepsy class 1, two in class 2, three in class 3, zero in class 4, and two in class 5; with a 30.76% complication rate. CONCLUSION: Despite the challenges, it was possible to implement an epilepsy surgery center with favorable results and acceptable incidence of complications, which were not higher than the incidences found in more experienced centers. PMID- 29166465 TI - Cross-cultural adaptation to Brazilian Portuguese of the Waterloo Footedness Questionnaire-Revised: WFQ-R-Brazil. AB - Post-stroke hemiparesis causes compensated postures, which can modify the footedness established before the impairment. Recently, a paresis severity modulated dominance hypothesis stated that measures to detect footedness become crucial to float new ideas for neurorehabilitation strategies. The Waterloo Footedness Questionnaire-Revised (WFQ-R) represents the most acceptable measure but it had not yet been cross-culturally adapted for Portuguese spoken in Brazil. Our aim was to cross-culturally adapt the WFQ-R to Brazilian Portuguese, verifying its reliability. We completed the essential steps to cross-culturally adapt one version, tested in 12 patients with post-stroke hemiparesis and 12 able bodied individuals, sampled by convenience, to verify reliability. Measurements were taken by two independent raters during the test and by one of them at the one-week retest. No great semantic, linguistic or cultural differences were found, and acceptable reliability was recorded. The WFQ-R-Brazil is reliable and ready for use in the Brazilian able-bodied and post-stroke hemiparesis population. PMID- 29166466 TI - Neurological complications of solid organ transplantation. AB - Solid organ transplantation is a significant development in the treatment of chronic kidney, liver, heart and lung diseases. This therapeutic approach has increased patient survival and improved quality of life. New surgical techniques and immunosuppressive drugs have been developed to achieve better outcomes. However, the variety of neurological complications following solid organ transplantation is broad and carries prognostic significance. Patients may have involvement of the central or peripheral nervous system due to multiple causes that can vary depending on time of onset after the surgical procedure, the transplanted organ, and the intensity and type of immunosuppressive therapy. Neurological manifestations following solid organ transplantation pose a diagnostic challenge to medical specialists despite extensive investigation. This review aimed to provide a practical approach to help neurologists and clinicians assess and manage solid organ transplant patients presenting with acute or chronic neurological manifestations. PMID- 29166467 TI - Paula Coutinho's outstanding contribution to the definition of Machado-Joseph disease. AB - Machado-Joseph disease, also known as spinocerebellar ataxia type 3, is the most common form of autosomal dominant ataxia in the world. Paula Coutinho, a highly regarded Portuguese neurologist worldwide, had a seminal participation in the definition of this disease, more than 40 years ago. PMID- 29166468 TI - Lafora and Tretiakoff: the naming of the inclusion bodies discovered by Lewy. AB - Fritz Heinrich Jakob Lewy described, for the first time, in 1912, novel peculiar inclusions in neurons of certain brain nuclei in patients with Paralysis agitans, and compared his finding to the amyloid bodies described by Lafora one year before. Gonzalo Rodriguez Lafora studied one patient with Paralysis agitans, in 1913, and recognized, described, and depicted structures identical to those previously reported by Lewy. He was the first to acknowledge Lewy's finding, and also the first to name such inclusions after the discoverer - cuerpos intracelulares de Lewy (Lewy bodies). Konstantin Nikolaevich Tretiakoff named the inclusions he found in neurons of the substantia nigra of patients with Parkinson's disease as corps de Lewy (Lewy bodies), in 1919. Tretiakoff has unanimously received the credit for the eponym. However, Lafora's earlier description should make him deserving of the authorship of the eponym. PMID- 29166469 TI - Charles Miller Fisher: the 65th anniversary of the publication of his groundbreaking study "Transient Monocular Blindness Associated with Hemiplegia". AB - Charles Miller Fisher is considered the father of modern vascular neurology and one of the giants of neurology in the 20th century. This historical review emphasizes Prof. Fisher's magnificent contribution to vascular neurology and celebrates the 65th anniversary of the publication of his groundbreaking study, "Transient Monocular Blindness Associated with Hemiplegia." PMID- 29166470 TI - Isolated rhombencephalitis with good clinical recovery. PMID- 29166471 TI - Exercise and sport do not trigger seizures in children and adolescents with epilepsy in school settings. PMID- 29166472 TI - Congenital Zika virus infection in twin pregnancies. PMID- 29166473 TI - [Frequency and variables associated with perceived devaluation-discrimination in victims of the armed conflict in Colombia]. AB - There is no information on frequency of perceived devaluation-discrimination in victims of the armed conflict in Colombia. The aim of this study was thus to determine the frequency of perceived devaluation-discrimination and associated variables among victims of the armed conflict in municipalities in the Department of Magdalena, Colombia. A cross-sectional study was conducted among victims enrolled in the Program for Psychosocial Care and Comprehensive Healthcare for Victims. Depressive symptoms were quantified with four dichotomous items (three or more were classified as high level of depressive symptoms), and perceived devaluation-discrimination was quantified with six dichotomous items (two or more were classified as high perceived devaluation-discrimination). A total of 943 adults participated (M = 47.9; SD = 14.2); 67.4%, women; 109 (11.6%) reported high level of depressive symptoms and 217 (23%) showed high perceived devaluation discrimination. High perceived devaluation-discrimination was associated with high level of depressive symptoms (OR = 6.47; 95%CI: 4.23-9.88). In conclusion, one-fourth of the victims of the armed conflict in Magdalena reported high perceived devaluation-discrimination, which was significantly associated with high level of depressive symptoms. PMID- 29166474 TI - [Disruptive innovations and transformations in public health in the digital age]. PMID- 29166475 TI - Proposal of a trigger tool to assess adverse events in dental care. AB - The aim of this study was to propose a trigger tool for research of adverse events in outpatient dentistry in Brazil. The tool was elaborated in two stages: (i) to build a preliminary set of triggers, a literature review was conducted to identify the composition of trigger tools used in other areas of health and the principal adverse events found in dentistry; (ii) to validate the preliminarily constructed triggers a panel of experts was organized using the modified Delphi method. Fourteen triggers were elaborated in a tool with explicit criteria to identify potential adverse events in dental care, essential for retrospective patient chart reviews. Studies on patient safety in dental care are still incipient when compared to other areas of health care. This study intended to contribute to the research in this field. The contribution by the literature and guidance from the expert panel allowed elaborating a set of triggers to detect adverse events in dental care, but additional studies are needed to test the instrument's validity. PMID- 29166476 TI - [Maternal breastfeeding and associated factors in children under two years: the Brazilian National Health Survey, 2013]. AB - The objective was to assess the prevalence of maternal breastfeeding and associated factors in Brazilian children under two years of age. This was a cross sectional nationwide study in 2013. The outcomes were breastfeeding in children under 24 months and exclusive breastfeeding under six months of age. A hierarchical analysis was performed for associated factors. The analyses were stratified by age (0-5 months and 29 days; 6-11 months and 29 days; 12-23 months and 29 days of age). Prevalence of maternal breastfeeding was 56% for the total sample, and as follows according to age: 80% (0-5 months and 29 days), 62.3% (6 11 months and 29 days), and 40.1% (12-23 months and 29 days). In the adjusted analyses, in all the age brackets, higher prevalence of breastfeeding was associated with consumption of fewer milk products. In children from 6 months to 11 months and 29 days, living in the North of Brazil, black skin color, and the lowest quintile of household assets were associated with higher breastfeeding prevalence. In children from 12 months to 23 months and 29 days of age, higher breastfeeding prevalence was associated with black skin color, consumption of healthy liquids and foods, living in urban areas, head-of-household's higher educational level, and more household assets. Overall prevalence of exclusive breastfeeding was 20.6% and was higher in the South, in families with head-of household's higher educational level, and more household assets. The prevalence rates for breastfeeding and exclusive breastfeeding of Brazilian children under two years can be considered low. Existing policies to increase the prevalence rates of maternal breastfeeding at any age should be reinforced. PMID- 29166477 TI - Regional differences in infection control conditions in a sample of primary health care services in Brazil. AB - International guidelines have pointed out the importance of the physical environment of health care facilities in preventing and controlling infection. We aimed to describe the physical environment of dental care facilities in Brazil in 2014, focusing on characteristics designed to control infections. Exactly 16,202 dental offices in the Brazilian Unified National Health System (SUS) participated in this survey. Trained researchers extracted information about the infection control characteristics of health facilities by using a structured instrument. We used data from 12 dichotomous questions that evaluated the wall, floor, sink and tap conditions, and the presence and condition of sterilization equipment. We calculated a score by summing the number of characteristics handled appropriately for infection control, which could range from 0 to 12. Hierarchical cluster analyses were developed. None of the 12 criteria were met by all the oral health teams. Only 208 (1.3%) dental offices correctly performed all 12-infection control practices. Two clusters, with different frequencies of structure for infection control in dental offices, were identified. South and Southeast regions had the highest frequencies for Cluster 1, with better structure of infection control in dental offices. Dental care facilities of oral health teams were not typically meeting the infection control guidelines regarding clinic design and equipment. Adherence to the guidelines varied among the Brazilian geographic regions. PMID- 29166478 TI - [Right you are... or aren't (if you think so)]. PMID- 29166479 TI - [Challenges and opportunities in digital health]. PMID- 29166480 TI - [Impact of moderate intellectual disability on the dynamics and quality of family life: a qualitative clinical study]. AB - This qualitative clinical study investigated the impact of moderate intellectual disability on family dynamics and quality of life. The data were collected using individual interviews with 15 mothers of children with intellectual disabilities, as a convenience sample, and examined with categorical thematic content analysis. The results were discussed using a comprehensive and interpretative approach. Analysis of the interviews showed that care for children with intellectual disabilities is centered on the mother, contributing to the change in family relations. Religious coping appeared as a common strategy for adjusting. Children with intellectual disabilities had less access to services and support than they needed in the areas of health, education, and leisure. Financial constraints and difficulties in community living had a negative impact on the quality of family life. Emotional and psychological support for all the family members, and practical and social support, including income distribution and access to adequate services, proved essential for the well-being of children with intellectual disabilities and their families. PMID- 29166481 TI - [PrEP Forum: an on-line debate on pre-exposure prophylaxis in Brazil]. AB - This study aimed to identify health-promoting contents focused on HIV/Aids prevention in messages posted in a Facebook group for debates on the use of pre exposure prophylaxis (PrEP). This was a prospective observational study using systematic non-participant observation. From July 2015 to June 2016, all the posts in the group were catalogued and formed a corpus. Everything was processed in IRaMuTeQ and analyzed by descending hierarchical classification. The collected data were grouped in three classes: (1) HIV/Aids prevention: discussing prophylaxis, treatment, target public, and side effects; (2) universal access to PrEP in Brazil: discussing government responsibilities; (3) on-line purchase of truvada: exposing a situation of vulnerability. The findings call attention to a potential public health problem and provide backing for understanding facilitators and barriers to the use of PrEP in Brazil through the identification of health-promoting content linked to individual, social, and institutional markers. PMID- 29166482 TI - Abortion and sex-related conditions in substance-dependent Brazilian patients. AB - Abortion is a very sensitive issue with relevance to public health; however few clinical or population-based studies have examined induced abortion among drug users. The study aims to evaluate the prevalence of induced abortion and sex related conditions in an inpatient drug user sample. A cross-sectional design study was conducted in an inpatient addiction treatment unit in Sao Paulo, Brazil, with a sample of 616 patients, aged 18-75. Sociodemographic data, sexual behavior, and dependence severity were evaluated in relation to induced abortion. Approximately 27% of patients reported having a history of abortion (themselves in the case of women or partners in the case of men). The mean age was 34.6+/ 10.9 years old, 34.9% diagnosed with severe alcohol dependence, 33% were diagnosed with severe levels of dependence on other drugs, 69.6% were diagnosed cocaine users (inhaled and smoked), and alcohol was the drug of choice for 30.4%. Chances of having a history of abortion is greater for women than for men with a odds ratio (OR = 2.9; 95%CI: 1.75-4.76), (OR = 1.7; 95%CI: 1.09-2.75) of no condom use; (OR = 2.0; 95%CI: 1.35-3.23) of history of STI and (OR = 3.2; 95%CI: 1.29-5.73) use of morning-after pill. Drug- and alcohol-dependent patients have high-risk behaviours of sporadic use or no-condom use which contribute to unplanned pregnancy and induced abortion, making this vulnerable population a group which deserves special attention in sexual health prevention programmes and health promotion efforts for the reduction of induced abortion. PMID- 29166483 TI - Processed and ultra-processed food consumption among children aged 13 to 35 months and associated factors. AB - The aim of this study was to evaluate the consumption of processed and ultra processed foods among children aged 13-35 months and its associated factors. We studied 1,185 children within the BRISA cohort in Sao Luis, Maranhao State, Brazil. The food consumption was investigated using a 24-hour recall, and the percentages of daily caloric intake and nutrients were estimated by food groups according to "NOVA" classification. We chose to categorize children belonging to the upper tertile of the distribution as having a high consumption of processed and ultra-processed food products. The Poisson regression model with robust variance estimation using a hierarchical modeling approach was used to calculate the prevalence ratios (PRs) of variables associated with high consumption of processed and ultra-processed food products. The mean energy intake was 1,226Kcal/day. After adjustments, there was a higher proportion of high consumption of processed and ultra-processed food products among children whose mothers had < 12 years of education and among children who were older than 16 months. Mothers with low schooling and children older than 16 months should be the targets of interventions aimed at reducing consumption of these food products and preventing adverse health outcomes in later life. PMID- 29166484 TI - Assessing the role of appropriate primary health care on the use of dental services by Brazilian low-income preschool children. AB - This cross-sectional study aimed to assess the association between the quality of primary health care (PHC) and the use of dental services by preschoolers served by the Family Health Strategy (FHS), controlling for socio-demographic determinants and perceived need. The sample encompassed 438 children aged 3-5 years, enrolled in 19 FHS facilities in Ponta Grossa, Parana State, Brazil. Individual level variables were collected by interviewing parents or caregivers at home. They answered a questionnaire on socioeconomic conditions, oral hygiene habits and use of dental services. Parental perception of child's oral health related quality of life, as perceived need, was assessed by the Brazilian version of Early Childhood Oral Health Impact Scale (ECOHIS). Normative need was assessed by oral examinations, according to guidelines standardized by the World Health Organization. The contextual level factor was defined as the extent of implementation of PHC in the facilities. Managers responded to PCATool-Brazil, a validated questionnaire which measures the extent of PHC. Dentists answered to a version of PCATool, which was adapted and pretested for dental services. Multilevel analysis, based on Andersen's behavioral model, fitted the adjustment of "having ever consulted a dentist" to contextual and individual covariates. We observed high prevalence of dental caries. Almost half of the sample had had dental appointments in life. Social gradients were observed for the use of dental services. Although it was not able to eliminate the impact of adverse social conditions, higher levels of PHC attributes in dental services favored the effective use of such services by low-income children. PMID- 29166485 TI - [Optimistic perspectives for the health of the future]. PMID- 29166486 TI - [Narratives of users of mental health services in an experiment with autonomous management of medication]. AB - Numerous studies have highlighted the tendency to chronicity of treatments centered on the use of medications. This study was conducted in a large Brazilian city with users of Centers for Psychosocial Care (CAPS), with the aim of evaluating the effects of experimenting with the personal Guide for Autonomous Management of Medication (GAM) and the users' relationship to their treatments and participation. The instrument, created in Canada and translated and adapted to Brazil, was tested in intervention groups with users of CAPS with severe mental disorders and a history of political participation in the field of health. Focus groups and in-depth interviews were performed. The transcriptions were transformed into narratives, and four analytical categories were defined: subjects with radical experiences of suffering; experiences with medication; users' rights; and participation and political activism. In testing GAM, users expressed a tension between reproduction of illness-centered identity and the legitimate uniqueness of their personal experiences. They showed greater knowledge of the medications they were taking, began to recognize their own expertise in their use of medications, and some sought adjustments to their treatment. They reported the need for support in claiming their rights and strengthening their participation as mental health activists. In conclusion, the Brazilian version of the GAM guide has the potential to contribute to users' empowerment, thus allowing dialogue between the results in mental health care in Brazil and the international scenario. PMID- 29166488 TI - Income inequality and high blood pressure in Colombia: a multilevel analysis. AB - The objective of this research was to examine the association between income inequality and high blood pressure in Colombia. Using a nationally representative Colombian sample of adults, and data from departments and municipalities, we fit sex-stratified linear and logistic multilevel models with blood pressure as a continuous and binary variable, respectively. In adjusted models, women living in departments with the highest quintile of income inequality in 1997 had higher systolic blood pressure than their counterparts living in the lowest quintile of income inequality (mean difference 4.42mmHg; 95%CI: 1.46, 7.39). Women living in departments that were at the fourth and fifth quintile of income inequality in 1994 were more likely to have hypertension than those living in departments at the first quintile in the same year (OR: 1.56 and 1.48, respectively). For men, no associations of income inequality with either systolic blood pressure or hypertension were observed. Our findings are consistent with the hypothesis that income inequality is associated with increased risk of high blood pressure for women. Future studies to analyze pathways linking income inequality to high blood pressure in Colombia are needed. PMID- 29166487 TI - [Mortality from assault in young men in Brazil, 2010-2014: an ecological study]. AB - The aim was to analyze the association between risk of death from assault in young males and socio-demographic characteristics in Brazilian municipalities. In this ecological study, the units of analysis were the 1,651 municipalities of Brazil with more than 20,000 inhabitants. Data were obtained from the Brazilian Mortality Information System (SIM) and indicators were obtained from the 2010 Population Census and Human Development Atlas. Mortality rate ratios were estimated by a negative binomial regression model. From 2010 to 2014, a total of 127,137 deaths from assault were reported in young males 15 to 29 years of age. Corrected mortality rate was 133.3/100 thousand inhabitants for the set of municipalities (median 71.5/100 thousand inhabitants). The rate increased with the municipalities' population size. In the adjusted model, higher rates ratios were observed in the more urbanized municipalities (1.95; 95%CI: 1.70-2.23), in intermediate categories of income inequality (1.10; 95%CI: 1.01-1.20) and poverty rate (1.69; 95%CI: 1.51-1.89), with lower proportion of youth attending Secondary School (2.05; 95%CI: 1.83-2.30), with higher proportion of unemployed youth 18 to 24 years of age (1.27; 95%CI: 1.16-1.40), and with more women than men (1.28; 95%CI: 1.05-1.58). Mortality from assault was high in young Brazilian men, especially in larger and more urbanized municipalities and those with a higher proportion of youth looking for work and not attending secondary school. The results show the relevance of social policies for dealing with violence against youth. PMID- 29166489 TI - Prevalence of syphilis and HIV infection during pregnancy in incarcerated women and the incidence of congenital syphilis in births in prison in Brazil. AB - This study aimed to estimate the prevalence of syphilis and HIV infection during pregnancy, the mother to child transmission of syphilis and the incidence of congenital syphilis in incarcerated women in Brazil; to compare these rates to those observed in pregnant women outside of jail; and to verify the maternal factors associated with syphilis infection during pregnancy in free and incarcerated women. We used data from two nationwide studies conducted during the period 2011-2014. The Birth in Brazil study included 23,894 free women cared for in 266 hospitals. The Maternal and Infant Health in Prisons study included 495 incarcerated pregnant women or mothers living with their children, according to a census conducted in 33 female prisons. The same case definitions and data collection methods were used in both studies. The chi-square test was used to compare the characteristics of incarcerated and free women with a significance of 0.05. For incarcerated women, the estimated prevalence of syphilis during pregnancy was 8.7% (95%CI: 5.7-13.1) and for HIV infection 3.3% (95%CI: 1.7-6.6); the estimated mother to child transmission of syphilis was 66.7% (95%CI: 44.7 83.2) and the incidence of congenital syphilis was 58.1 per 1,000 living newborns (95%CI: 40.4-82.8). Incarcerated women had a greater prevalence of syphilis and HIV infection during pregnancy, lower quality of antenatal care and higher levels of social vulnerability. Syphilis infection showed to be an indicator of social vulnerability in free women, but not in incarcerated women. Health initiatives in prison are necessary to reduce healthcare inequalities and should include adequate antenatal and birth care. PMID- 29166490 TI - [Guidelines for a line of care for children and adolescents with complex chronic health conditions]. AB - The definition of complex chronic health condition (CCHC) is important for identifying children and adolescents occupying pediatric beds in Brazilian hospitals, where they live out their childhood, requiring complex care by multidisciplinary teams in network format both in-hospital and in home care. The current article addresses guidelines for a line of care for children and adolescents with CCHCs. An expert panel validated 13 guidelines organized in three dimensions. Using the consensus conference technique, experts from different specialties validated the guidelines. We concluded that the process requires planning, professional training, and the production of an inter-sector research agenda involving other definitions, reviewing norms and conventions as to what is expected. Expectations include the ideal professional composition and profile for comprehensive care of these children and adolescents with CCHCs and safeguards for their rights, with access to a wide variety of social equipment, including but not limited to the health sector. PMID- 29166491 TI - 10 th Brazilian Congress of Epidemiology: building our field with solidarity. PMID- 29166492 TI - WAIST-TO-HEIGHT RATIO INDEX OR THE PREDICTION OF OVERWEIGHT IN CHILDREN. AB - OBJECTIVE: To identify a low-cost abdominal adiposity index that has a higher accuracy in predicting excess weight in children aged four to seven years old. METHODS: A cross-sectional study with a sample of 257 children aged 4 to 7 years old. Indicators of abdominal adiposity assessed were: waist circumference (WC), waist-to-height ratio (WHR) and central fat percentage (measured by dual energy X ray absorptiometry - DEXA). Overweight children were classified using body mass index by age (BMI/age). In the analysis, the prevalence ratio (PR) using Poisson regression with a robust variance was estimated, and a receiver operating characteristic (ROC) curve was built, with a statistical significance of p<0.05. RESULTS: The prevalence of overweight children was 24.9% and a higher median of all abdominal adiposity indicators was observed in the overweight group. Children with increased values of WC (PR=4.1; 95%CI 2.86-5.86), WHR (PR=5.76; 95%CI 4.14 8.02) and a central fat percentage (PR=2.48; 95%CI 1.65-3.73) had a higher prevalence of being overweight. Using the ROC curve analysis, the WHR index showed a higher area under the curve, when compared to the WC and to the central fat percentage estimated by DEXA for predicting the classification of being overweight. CONCLUSIONS: Given the results, WHR is suggested for the screening of overweight children. PMID- 29166493 TI - DYSTROPHIC CALCIFICATION OF MAXILLARY SINUS IN PEDIATRIC PATIENTS WITH LIVER TRANSPLANTATION AND PIGMENTATION OF DENTAL ORGAN. AB - OBJECTIVE: To report a case of severe dystrophic calcification in maxillary sinus of a child with liver transplantation and dental organs pigmented by hyperbilirubinemia. CASE DESCRIPTION: female patient, 12 years old, with liver transplantation performed at the age of 7 due to extrahepatic biliary atresia (EHBA). The patient was receiving the immunosuppressant tacrolimus (2 mg daily). Intraoral clinical exam showed tooth green pigmentation by bilirubin. Cone-beam volumetric computed tomography (CT) was performed to verify radiographic density of pigmented dental elements. Hounsfield scale measurement did not show changes in radiographic density of dental structures. However, CT scan showed intense dystrophic calcification in the maxillary sinus region. COMMENTS: CT scan indicated relevant radiographic findings, with radiopacity of the maxillary sinus due to fungal or non-fungal sinusitis. This case report highlights the presence of radiographic image associated with acute infectious processes that could compromise the systemic state of immunosuppressed patients. PMID- 29166495 TI - Photodynamic action of the red laser on Propionibacterium acnes. AB - BACKGROUND: Photodynamic therapy is a therapeutic modality that has consolidated its activity in the photooxidation of organic matter, which arises from the activity of reactive oxygen species. OBJECTIVE: To evaluate the effect of red laser 660nm with the photosensitizer methylene blue on Propionibacterium acnes in vitro. METHOD: The experimental design was distributed into four groups (1 - control group without the application of light and without photosensitizer, 2 - application of light, 3 - methylene blue without light, and 4 - methylene blue with light). Tests were subjected to red laser irradiation 660nm by four cycles of 5 minutes at 3-minute intervals. RESULTS: It was evidenced the prominence of the fourth cycle (20 minutes) groups 2, 3 and 4. STUDY LIMITATIONS: Despite the favorable results, the laser irradiation time photosensitizer associated with methylene blue were not sufficient to to completely inhibit the proliferation of bacteria. CONCLUSION: Further studies in vitro are recommended to enable the clinical application of this photosensitizer in photodynamic therapy. PMID- 29166494 TI - Sporotrichosis: an update on epidemiology, etiopathogenesis, laboratory and clinical therapeutics. AB - In the late 90's there was a change in both the route of transmission and the people at risk for sporotrichosis. This zoonotic cat-man alternative transmission route elicited changes in strategies to control the epidemic. There was a progressive increase in the number of cases involving especially children and the elderly. In addition to becoming hyperendemic, uncommon clinical pictures like immunoreactive clinical presentations or severe systemic cases have emerged. New species were identified and classified through molecular tools using more virulent clinical isolates, like S. brasiliensis, compared to the environmental isolates. Likewise, different species of Sporothrix have been associated with different geographic regions. The serological and molecular techniques are used as an auxiliary tool for the diagnosis and/or for species identification, although the isolation and the identification of Sporothrix spp. in clinical specimen is still the gold standard. Currently sporotrichosis epidemics requires the knowledge of the epidemiological-molecular profile to control the disease and the specific treatment. Itraconazole, potassium iodide, terfinafine, and amphotericin B are the available drugs in Brazil to treat sporotrichosis. The drug of choice, its posology, and treatment duration vary according to the clinical presentation, the Sporothrix species, and host immune status. New treatment choices, including a vaccine, are being developed; nevertheless, more clinical trials are required to confirm its efficacy. PMID- 29166496 TI - Recurrent aphthous stomatitis in 18-year-old adolescents - Prevalence and associated factors: a population-based study. AB - BACKGROUND: Recurrent aphthous stomatitis is a painful disorder of unknown etiology. It is among the most common oral mucosal lesions with high prevalence among young adults. OBJECTIVES: To conduct a population-based study with 18-year old army recruiters to assess its prevalence and associated factors in male adolescents. METHODS: Interview during clinical examination in the army. RESULTS: In this group (2,427 interviewed adolescents) there was a RAS prevalence of 24.9%. Smoking, herpes labialis and socioeconomic status correlated with the outcome. STUDY LIMITATIONS: only male adolescents were interviewed. CONCLUSIONS: Our results showed high prevalence of RAS; association with higher economic level and herpes simplex was found. Protective effect of smoking was confirmed. PMID- 29166497 TI - Epidemiologic analysis of prevalence of the hyperhidrosis. AB - BACKGROUND: The present paper aims to study the prevalence of the various manifestations of hyperhidrosis in patients who sought treatment in a specialized ambulatory in the state of Sao Paulo. OBJECTIVES: Opposite to previous studies, this paper studies the different combinations of sweating sites, not being restricted to the main complaint site of the patients, but taking into consideration secondary complaints patients may present. METHODS: This was a retrospective approach of a database containing more than 1200 patients in which were mapped: combination of sweating sites, age of onset, age spectrum, mean age, body mass index and gender of patients. Patients were categorized into four groups based on their main sweating site - palmar, plantar, axillary and facial. RESULTS: We concluded that hyperhidrosis appears frequently in more than one site, being the main complaint that affects the most patients palmar hyperhidrosis, which appears early in the patients during adolescence. When there are two sites of sweating, the most frequent combination is palmar + plantar, and when there are three sites of sweating the most frequent combinations are palmar + plantar + axillary and axillary + palmar + plantar. STUDY LIMITATIONS: This research has casuistics limited to a single care service for patients with hyperhidrosis. CONCLUSION: It is necessary to keep in mind that the disease manifests itself mainly in more than one location, with different intensities in each of the patients, generating a significant impairment of their quality of life. PMID- 29166498 TI - Evaluation of mean platelet volume in localized scleroderma. AB - BACKGROUND: Localized scleroderma is a chronic inflammatory skin disease characterized by sclerosis of the dermis and subcutaneous tissue. Platelets play an important role in inflammation. Following activation, platelets rapidly release numerous mediators and cytokines, which contribute to inflammation. OBJECTIVES: To evaluate whether there was any relation between localized scleroderma and platelet parameters. METHODS: Forty-one patients with localized scleroderma were enrolled in the study. The control group consisted of 30 healthy subjects. RESULTS: The mean platelet volume level in the patient group was 9.9 +/ 1.3 fl and in the control group was 7.6 +/- 1.1 fl. This difference was statistically significant (p< 0.001). The plateletcrit values are minimally higher in the patient group as compared to the control group. It was statistically significant (p<0.001). There was no significant difference in the platelet counts between the two groups (p= 0.560) In the patient group, there was no significant relation between the mean platelet volume levels and clinical signs of disease (p=0.09). However, plateletcrit values are higher in generalized than localized forms of disease (p=0.01). STUDY LIMITATIONS: The limited number of patients and the retrospective nature of the study were our limitations. CONCLUSIONS: This study suggests that platelets might play a role in the pathogenesis of scleroderma. Platelet parameters may be used as markers for evaluating disease severity and inflammatory processes. Thus, there is a need for more detailed and prospective studies. PMID- 29166499 TI - Skin disorders in renal transplant recipients: a retrospective study. AB - BACKGROUND: Immunosuppressive therapy, which is necessary to avoid graft rejection in renal transplant recipients, presents an increased risk of several pathologies, namely infectious and neoplastic. OBJECTIVES: To identify the most frequent skin diseases and their clinical and demographical risk factors within a population of renal transplant recipients. METHODS: A retrospective study of renal transplant recipients referred to dermatology visit and observed for the first time from January 2008 to December 2014. RESULTS: The study included 197 patients, 120 men (60,9%). Mean age was 50,7 years (+/-13,4). 12 patients (6,1%) had previous skin cancer. Infections were the most frequent reason of referral (93/197; 44%). From the total referred, 18,3% (36/197) presented pre-cancerous lesions. Malignancy was diagnosed in 36 patients (18,3%), with 29 non-melanoma skin cancers (14,7%) and 7 Kaposi sarcomas (3,6%). Ratio of basal cell carcinoma to squamous cell carcinoma was 1,1:1. Non-melanoma skin cancer was significantly associated with older age (p = 0,002), male gender (p = 0,028), history of previous skin cancer (p = 0,002) and higher duration of immunosuppressive therapy (p<0,001). STUDY LIMITATIONS: Retrospective study, with data from the first visit in dermatology. We didn't made classification on skin-types. CONCLUSIONS: The great incidence of cutaneous infections and skin cancer is responsible for a significant morbidity. It is important to assure the regular dermatological follow-up of renal transplant recipients, which will promote the prevention, an early diagnosis and an efficient treatment. PMID- 29166500 TI - Final diagnosis of 86 cases included in differential diagnosis of American tegumentary leishmaniasis in a Brazilian sample: a retrospective cross-sectional study. AB - BACKGROUND: Cutaneous leishmaniasis is distributed worldwide, including Brazil. Its several clinical forms need to be distinguished from other dermatoses. Clinical similarities and lack of a gold standard diagnostic tool make leishmaniasis-like lesions a challenging diagnosis. OBJECTIVES.: To report the final diagnosis of patients primarily suspected of having American tegumentary leishmaniasis (ATL). METHODS.: A retrospective cross-sectional study was conducted on the basis of medical records of 437 patients with clinical suspicion of ATL, registered in electronic hospital system between 1980 and 2013. Demographic, clinical, and laboratory data were compiled. RESULTS.: Analysis of 86 cases (19.7%) registered as ATL in one of the hypothesis revealed a different final diagnosis; 55 (63.9%) and 31 cases (36.1%) had skin and mucosal lesions, respectively. In 58 cases (67.4%), the requested PCR did not identify Leishmania sp. In 28 cases (32.5%), biopsies established the diagnosis and confirmed tumors, mycobacteriosis, and subcutaneous or systemic mycosis. Overall, 27% of the cases had inflammatory etiology, mainly nasal nonspecific inflammatory processes; 27% had infectious etiology, especially paracoccidioidomycosis and leprosy; 20% had neoplastic etiology, mainly basal and squamous cell carcinoma; 15% had miscellaneous etiology, including neuropathic ulcer, traumatic ulcers, idiopathic ulcer; 11% missed the follow-up. STUDY LIMITATIONS: Some cases had no final diagnosis due to loss of follow-up. CONCLUSION.: ATL can be confused with several differential diagnoses, especially inflammatory and infectious granulomatous diseases as well as non-melanoma skin cancers. Clinicians working in tropical areas should be aware of the main differential diagnosis of leishmaniasis-like lesions. PMID- 29166501 TI - Primary cutaneous T-cell lymphoma: experience from the Peruvian National Cancer Institute. AB - BACKGROUND: Primary cutaneous T-cell lymphomas constitute a heterogeneous and rare group of diseases with regional particularities in Latin America. OBJECTIVE: To determine the clinicopathological features, relative frequency and survival among patients from a Peruvian institution. METHODS: Primary cutaneous T-cell lymphomas were defined based on the absence of extracutaneous disease at diagnosis. Classification was performed following the 2008 World Health Organization Classification of Neoplasms of the Hematopoietic and Lymphoid tissues. Risk groups were established according to the 2005 World Health Organization-EORTC classification for cutaneous lymphomas. Data of patients admitted between January 2008 and December 2012 were analyzed. RESULTS: 74 patients were included. Mean age was 49.5 years. In order of frequency, diagnoses were: mycosis fungoides (40.5%), peripheral T-cell lymphoma not otherwise specified (22.95%), adult T-cell lymphoma/leukemia (18.9%), CD30+ lymphoproliferative disorders (6.8%), hydroa vacciniforme-like lymphoma (5.4%), extranodal NK/T-cell lymphoma (4.1%) and Sezary syndrome (1.4%). Predominant clinical patterns were observed across different entities. Mycosis fungoides appeared mainly as plaques (93%). Peripheral T-cell lymphoma not otherwise specified and adult T-cell lymphoma/leukemia presentation was polymorphic. All patients with hydroa vacciniforme-like lymphoma presented with facial edema. All cases of extranodal NK/T-cell lymphoma appeared as ulcerated nodules/tumors. Disseminated cutaneous involvement was found in 71.6% cases. Forty-six percent of patients were alive at 5 years. Five-year overall survival was 76.4% and 19.2%, for indolent and high-risk lymphomas, respectively (p<0.05). High risk group (HR: 4.6 [2.08-10.18]) and increased DHL level (HR: 3.2 [1.57-6.46]) emerged as prognostic factors for survival. STUDY LIMITATIONS: Small series. CONCLUSION: Primary cutaneous T-cell lymphomas other than mycosis fungoides or CD30+ lymphoproliferative disorders are aggressive entities with a poor prognosis. PMID- 29166502 TI - Outcomes of long term treatments of type I hereditary angioedema in a Turkish family. AB - BACKGROUND: Hereditary angioedema is a rare autosomal dominantly inherited immunodeficiency disorder characterized by potentially life-threatening angioedema attacks. OBJECTIVE: We aimed to investigate the clinical and genetic features of a family with angioedema attacks. METHODS: The medical history, clinical features and C1-INH gene mutation of a Turkish family were investigated and outcomes of long-term treatments were described. RESULTS: Five members had experienced recurrent swellings on the face and extremities triggered by trauma. They were all misdiagnosed as familial Mediterranean fever (FMF) depending on frequent abdominal pain and were on colchicine therapy for a long time. They had low C4 and C1-INH protein concentrations and functions. A mutation (c.1247T>A) in C1-INH gene was detected. They were diagnosed as having hereditary angioedema with C1-INH deficiency (C1-INH hereditary angioedema) for the first time. Three of them benefited from danazol treatment without any significant adverse events and one received weekly C1 esterase replacement treatment instead of danazol since she had a medical history of thromboembolic stroke. STUDY LIMITATIONS: Small sample size of participants. CONCLUSION: Patients with C1-INH hereditary angioedema may be misdiagnosed as having familial Mediterranean fever in regions where the disorder is endemic. Medical history, suspicion of hereditary angioedema and laboratory evaluations of patients and their family members lead the correct diagnoses of hereditary angioedema. Danazol and C1 replacement treatments provide significant reduction in hereditary angioedema attacks. PMID- 29166503 TI - Stevens-Johnson syndrome and toxic epidermal necrolysis: epidemiological and clinical outcomes analysis in public hospitals. AB - BACKGROUND: Adverse drug reactions are harmful and involuntary responses to drugs that occur at doses normally used for a given condition. Among them are Stevens Johnson syndrome and toxic epidermal necrolysis, both rare and potentially fatal conditions. OBJECTIVES: To analyze the epidemiological and clinical characteristics related to patients diagnosed with Stevens-Johnson syndrome and toxic epidermal necrolysis in public hospitals in the Federal District - Brazil. METHODS: Retrospective, cross-sectional and descriptive study, in which data were collected referring to patients hospitalized in the public healthcare system of the Federal District from 1999 to 2014. Results: Between 1999 and 2014, 86 cases of hospitalized patients with diagnosis of Stevens-Johnson syndrome and toxic epidermal necrolysis in the Federal District were reported. The majority of patients were women; the most affected age group was 0 to 10 years. Patients older than 60 years (elderly) represent 6.98% of the cases. Most patients admitted to the referral hospital were discharged. However, occurrence of deaths exceeded that of discharge in elderly patients. LIMITATIONS OF THE STUDY: There is fragility in the registry of hospitalization of patients, both in the hospital information system and in the medical records of the reference hospital. CONCLUSION: There is a need for greater production and better dissemination of information on the incidence of adverse drug reactions. PMID- 29166504 TI - Moderate to severe psoriasis treatment challenges through the era of biological drugs. AB - Biological therapy has revolutionized moderate to severe psoriasis treatment. However, despite being more effective than conventional systemic treatments, some patients do not respond or lose response to biotechnological treatments or develop drug-antibodies, interfering with its safety and efficacy. There are also clinical forms of the disease and patient profiles for which is pending further scientific evidence for more sustained therapeutic interventions. The continuous and more detailed knowledge of psoriasis pathophysiology has allowed identifying new therapeutic targets, which is expected to help overcome the challenges of individualized psoriasis treatment. PMID- 29166505 TI - Anogenital warts in pediatric population. AB - The approach to children with anogenital warts in the context of sexual abuse is a challenge in clinical practice. This study aims to review the current knowledge of anogenital warts in children, the forms of transmission, and the association with sexual abuse and to propose a cross-sectional approach involving all medical specialties. A systematic review of the literature was conducted in Portuguese and English from January 2000 to June 2016 using the ISI Web of Knowledge and PubMed databases. Children aged 12 years or younger were included. The ethical and legal aspects were consulted in the Declaration and Convention on the Rights of Children and in the World Health Organization. Non-sexual and sexual transmission events of human papillomavirus in children have been well documented. The possibility of sexual transmission appears to be greater in children older than 4 years. In the case of anogenital warts in children younger than 4 years of age, the possibility of non-sexual transmission should be strongly considered in the absence of another sexually transmitted infection, clinical indicators, or history of sexual abuse. The importance of human papillomavirus genotyping in the evaluation of sexual abuse is controversial. A detailed medical history and physical examination of both the child and caregivers are critical during the course of the investigation. The likelihood of an association between human papillomavirus infection and sexual abuse increases directly with age. A multidisciplinary clinical approach improves the ability to identify sexual abuse in children with anogenital warts. PMID- 29166506 TI - Is Ki-67, keratin 16, involucrin, and filaggrin immunostaining sufficient to diagnose inflammatory linear verrucous epidermal nevus? A report of eight cases and a comparison with psoriasis vulgaris. AB - Inflammatory linear verrucous epidermal nevus and linear psoriasis are sometimes hard to differentiate clinically and pathologically. Although immunohistochemical expression of keratin 10 (K10), K16, Ki-67, and involucrin may be useful for differentiating both entities, these results have been reported in only a few cases. We collected data from 8 patients with inflammatory linear verrucous epidermal nevus, 11 with psoriasis vulgaris, and 8 healthy controls and evaluated immunohistochemical expression of Ki-67, K16, involucrin, and filaggrin among them. Ki-67 and K16 overexpression was similar in inflammatory linear verrucous epidermal nevus and psoriasis vulgaris compared with normal skin. Although staining for involucrin showed discontinuous expression in parakeratotic regions in 4 inflammatory linear verrucous epidermal nevus cases, it was continuous in the other 4 cases and in all psoriasis vulgaris cases. Filaggrin expression was present in hyperkeratotic regions but scarce in parakeratotic areas in both inflammatory linear verrucous epidermal nevus and psoriasis vulgaris. The immunostaining pattern of Ki-67, K16, involucrin, and filaggrin may be insufficient to discriminate inflammatory linear verrucous epidermal nevus from psoriasis vulgaris. PMID- 29166507 TI - Pigmented Bowen's disease associated with high-risk HPV simulating melanoma of the hand. AB - Bowen's disease is an in situ squamous cell carcinoma of the skin with only 2% of pigmented cases reported. It is clinically characterized by papules and plaques of blackened surface that may be caused either by sun damage - usually in photoexposed areas in elderly individuals - or by human papillomavirus infection usually in the anogenital region of young adults. Dermoscopic aspects of Bowen's disease are discussed for over a decade, but with no definitive criteria that would lead to a definitive diagnosis. We present a case of Bowen's disease affecting the finger of a 57-year-old Asian patient. The lesion clinically and dermoscopically simulated a melanoma. Histopathological findings suggested the diagnosis of pigmented Bowen's disease. Pigmented Bowen's disease should be considered a differential diagnosis of melanoma, since its clinical and dermoscopic criteria are unspecific. Histopathological examination remains the gold standard for the diagnosis of the disease. PMID- 29166508 TI - Algorithm for acne treatment: Ibero-Latin American consensus. AB - Acne is a chronic, immune-mediated, inflammatory disease with high prevalence among adolescents. By compromising face, thorax and back, with the risk of permanent scars, it has a negative impact on the quality of life. Effective, safe and early treatment is the key to remission, while decreasing the risk of physical and/or emotional sequelae. The Iberian-Latin American Group of Acne Studies joined professionals with expertise and developed a practical therapeutic algorithm, adapted to the reality of Latin American countries, Spain and Portugal. This article intends to disseminate it with an updated review on a rational, safe and effective acne treatment. PMID- 29166509 TI - Granulomatous slack skin: a rare subtype of mycosis fungoides. AB - We report a case of granulomatous slack skin, a rare and indolent subtype of mycosis fungoides. It affects mainly men between the third and fourth decades. It is characterized by hardened and erithematous plaques that mainly affect flexural areas and become pedunculated after some years. Histological examination shows a dense infiltrate of small atypical lymphocytes involving the dermis (and sometimes the subcutaneous tissue) associated with histiocytic and multinucleated giant cells containing lymphocytes and elastic fibers (lymphophagocytosis and elastophagocytosis, respectively). Patients affected by this entity can develop secondary lymphomas. There are several but little effective therapeutic modalities described. Despite the indolent behavior of granulomatous slack skin, its early recognition and continuous monitoring by a dermatologist becomes essential for its management and prevention of an unfavorable outcome. PMID- 29166510 TI - Ecthyma gangrenosum: a report of eight cases. AB - Ecthyma gangrenosum is a rare skin infection classically associated with Pseudomonas aeruginosa. We performed a retrospective study of all cases diagnosed with ecthyma gangrenosum from 2004-2010 in a university hospital in Mexico (8 cases, 5 female patients and 3 male patients, ages between 4 months and 2 years). The most common risk factor for ecthyma gangrenosum is neutropenia in immunocompromised patients. In previously healthy patients, immunological evaluation is important to rule out underlying immunodeficiency. Ecthyma gangrenosum in healthy patients has a high mortality rate and early diagnosis and aggressive antibiotic treatment is imperative as it can improve patients' prognosis. PMID- 29166511 TI - Primary cutaneous follicle center lymphoma. AB - Cutaneous lymphomas are classified according to their cellular origin into T-cell lymphoma and B-cell lymphoma. The annual incidence rate is 0.3 per 100,000 population. We report a case of a 56-year-old male patient who presented with a two-month history of nodules of varying sizes, some ulcerated, on the face, abdomen, and upper limbs. Histopathological examination and immunohistochemical study confirmed the diagnosis of primary cutaneous centrofollicular lymphoma. Studies have shown an increased incidence of non-Hodgkin lymphomas in the last decade. We report an infrequent case that should be kept as a differential diagnosis of patients with nodules and cutaneous papules. PMID- 29166512 TI - Segmental lichen aureus: an uncommon presentation. AB - Pigmented purpuric dermatoses are chronic vascular inflammatory conditions characterized by the presence of pigmented macules. Among its different presentations, lichen aureus is distinguished by the lichenoid conformation of its plaques and the predilection for lower limb involvement. Its segmented form is rare and difficult to control, especially in cases of symptomatic lesions. We report a rare case of segmental lichen aureus with six years of evolution associated with light itching. We also discuss the main therapeutic approaches to control the disease. PMID- 29166513 TI - Primary cutaneous amelanotic melanoma and gastrointestinal stromal tumor in synchronous evolution. AB - Gastrointestinal stromal tumor is rare digestive tract mesenchymal tumor, most often in the wall of the stomach. It is a benign neoplasm, but it can become malignant if not treated. We report a case of gastrointestinal stromal tumor that was discovered after abdominal ultrasonography during staging of a patient with primary cutaneous amelanotic melanoma. Mutation in the tyrosine kinase receptor could explain the development of two types of tumors in the same patient. PMID- 29166514 TI - Nevus lipomatosus cutaneous superficialis. AB - Nevus lipomatosus cutaneous superficialis is a rare benign hamartomatous skin tumor characterized by dermal deposition of mature adipose tissue. Two clinical forms have been described (classical and solitary types). We describe a case of nevus lipomatosus cutaneous superficialis with a 13-year history of growth in a young woman who had a solitary skin-colored tumoral mass on the right buttock. Histopathological findings were typical and confirmed the diagnosis. In this case, the lesion was a skin-colored isolated mass, as described in the solitary type, but its localization and age of appearance were compatible with the classical type. The combination of simultaneous clinical findings of both types had not been published before. PMID- 29166515 TI - Dyshidrosiform pemphigoid localized on the hands in a child: a rare occurrence. AB - Dyshidrosiform pemphigoid is an acquired autoimmune variant of bullous pemphigoid with persistent vesicobullous eruptions localized on the palms or soles, or both. It generally occurs in the elderly and is rarely reported in childhood. Hereby, we describe the first case of dyshidrosiform pemphigoid in a 12-year-old child, which was limited to the dorsal hands and treated successfully with dapsone (diaminodiphenyl sulfone). Along with this report, we also review the clinical features of various types of dyshidrosiform pemphigoid. PMID- 29166516 TI - Proteus syndrome. AB - Proteus syndrome is a rare syndrome characterized by disproportionate overgrowth of limbs, multiple hamartomas, and vascular malformations. The cerebriform connective tissue nevi, also called cerebriform plantar hyperplasia, are present in most patients, and is the main characteristic of the syndrome. If present, even alone, they can be considered as a pathognomonic sign. This article reports a classic case of Proteus syndrome in a 2-year-old male patient who began to show a discrete asymmetry of the right hemibody in relation to the left one after birth, which increased over the months. He also showed cerebriform plantar hyperplasia and Port-wine stains, among other alterations. PMID- 29166517 TI - Syringocystadenoma papilliferum combined with a tubular apocrine adenoma. AB - Syringocystadenoma papilliferum and tubular apocrine adenoma are rare benign sweat gland tumors. Syringocystadenoma papilliferum occurs alone or in association with other tumors. Although it is rare, the association of tubular apocrine adenoma with syringocystadenoma papilliferum developing in a sebaceous nevus on the scalp is well documented. However, the co-existence of these two tumors without the background of a sebaceous nevus has not been frequently reported. Syringocystadenoma papilliferum and tubular apocrine adenoma may have a histopathological overlap, but a few cases of a syringocystadenoma papilliferum combined with a tubular apocrine adenoma have been reported. Herein we describe an unusual case of syringocystadenoma papilliferum co-existing with a tubular apocrine adenoma located on the back of a 14-year-old patient in the absence of a pre-existing sebaceous nevus. PMID- 29166518 TI - Yellow dots in trichoscopy: relevance, clinical significance and peculiarities. AB - Yellow dots are follicular ostium filled with keratin and/or sebum. Initially, they were exclusively associated with alopecia areata. Currently they have also been described in androgenetic alopecia, chronic cutaneous (discoid) lupus erythematosus, and dissecting cellulitis. Due to the growing importance of trichoscopy and its findings in the evaluation of the scalp, this article describes the main diseases in which yellow dots are a common trichoscopic finding, highlighting its characteristics in each dermatosis. PMID- 29166519 TI - Disseminated tungiasis. AB - The authors report an unusual case of disseminated tungiasis in a 52-year-old patient living in the city of Campo Grande, state of Mato Grosso do Sul, who had crusted-papular-nodular lesions located in feet, hands, and right thigh. Diagnosis was confirmed by dermoscopy and anatomopathological examination. PMID- 29166520 TI - Do you know this syndrome? Ascher's syndrome: clinical findings of little known triad. AB - Ascher's syndrome consists of double lip, blepharochalasis and sometimes non toxic thyroid enlargement. It is a rare, benign, rarely reported, and sometimes misdiagnosed condition that most often affects patients under 20 years old. The etiology remains unknown, although factors such as trauma, hormonal dysfunction and heredity have been suggested. Treatment based on surgical intervention is indicated to improve aesthetics or function. The presented case shows a patient diagnosed with Ascher's syndrome based on clinical findings such as double lip and blepharochalasis. PMID- 29166521 TI - Case for diagnosis. Systemic light chain amyloidosis with cutaneous involvement. AB - Systemic light chain amiloydosis is a rare disease. Due to its typical cutaneous lesions, dermatologists play an essential role in its diagnosis. Clinical manifestations vary according to the affected organ and are often unspecific. Definitive diagnosis is achieved through biopsy. We report a patient with palpebral amyloidosis, typical bilateral ecchymoses and cardiac involvement, without plasma cell dyscrasia or lymphomas. The patient died shortly after the diagnosis. PMID- 29166522 TI - Nickel exposure from keys: a Brazilian issue. AB - Keys are a significant source of exposure to metal allergens and can be a relevant problem for nickel-allergic individuals. This study aimed to perform nickel and cobalt spot testing among the 5 most common Brazilian brands of keys. Among the tested keys, 100% showed positive result to nickel spot test, 83,3% presented strong positive reaction. 50% exhibited cobalt release as well. Nickel release from keys is very common in our country and may cause a negative impact on sensitized individual's quality of life. Study's results highlight the importance of establishing directives to regulate nickel release in Brazil. PMID- 29166523 TI - The pH of the main Brazilian commercial moisturizers and liquid soaps: considerations on the repair of the skin barrier. AB - The pH of the skin is slightly acidic (4.6 to 5.8) which is important for appropriate antibacterial, antifungal, constitution of barrier function, as well as structuring and maturation of the stratum corneum. This study aimed to evaluate the pH of the main commercial moisturizers and liquid soaps in Brazil. Thus, pH of the products was quantified by pH meter in three measurements. A total of 38 moisturizers and six commercial liquid soaps were evaluated. Mean pH of 63% and 50% of the moisturizing and liquid soaps presented results above 5.5, disfavoring repair, function, and synthesis of dermal barrier. PMID- 29166524 TI - Acne arising on a facial Becker nevus following the lines of Blaschko. PMID- 29166525 TI - Tufted angioma. PMID- 29166526 TI - Effectiveness and safety of infliximab for 11 years in a patient with erythrodermic psoriasis and psoriatic arthritis. PMID- 29166527 TI - Phototherapy: experience from a reference service. PMID- 29166528 TI - Rickettsial diseases in Brazil: report of a case with varicella-like skin lesions. PMID- 29166529 TI - Treatment of reaction to red tattoo ink with intralesional triamcinolone. PMID- 29166530 TI - New azhdarchoid pterosaur (Pterosauria, Pterodactyloidea) with an unusual lower jaw from the Portezuelo Formation (Upper Cretaceous), Neuquen Group, Patagonia, Argentina. AB - A new azhdarchoid pterosaur from the Upper Cretaceous of Patagonia is described. The material consists of an incomplete edentulous lower jaw that was collected from the upper portion of the Portezuelo Formation (Turonian-Early Coniacian) at the Futalognko site, northwest of Neuquen city, Argentina. The overall morphology of Argentinadraco barrealensis gen. et sp. nov. indicates that it belongs to the Azhdarchoidea and probable represents an azhdarchid species. The occlusal surface of the anterior portion is laterally compressed and shows blunt lateral margins with a medial sulcus that are followed by two well-developed mandibular ridges, which in turn are bordered laterally by a sulcus. The posterior end of the symphysis is deeper than in any other azhdarchoid. This unique construction of the lower jaw suggests the existence of an elaborate interlocking mechanism with the upper jaw. Furthermore, although speculative, it is advocated here that Argentinadraco barrealensis might have used the lower jaw to obtain its prey by cutting or ploughing through unconsolidated sediment in shallow waters, a feeding behavior not previously proposed for pterosaurs. PMID- 29166531 TI - A polysaccharide fraction extracted from Pleurotus ostreatus mycelial biomass inhibit Sarcoma 180 tumor. AB - Fungi of Pleurotus genus have attracted a great interest due to their medicinal properties such as anti-inflammatory, antimicrobial and antitumor. These properties are attributed mainly to polysaccharides synthesized by Pleurotus. This work aimed to study the mycelial growth of P. ostreatus in submerged culture, evaluating the influence of the initial concentration of substrate (20 and 40 g/L of glucose) and the pH (4 and 6) on kinetic parameters of production of biomass. The effectiveness of different doses (10, 30 and 50 mg/kg) of a mycelium polysaccharide fraction extracted from P. ostreatus in reducing Sarcoma 180 development in mice was also verified. In the range of this study, maximum concentration of mycelial biomass (about 12.8 g/L) was obtained using 40.0 g/L of glucose, at pH 4.0. The total biomass productivity (Px) was not significantly affected by substrate concentration and pH, reaching values of 0.034 g/L.h. Sarcoma 180 tumor weight was reduced in 74.1, 75.5 and 53.7% when 10, 30 and 50 mg/kg were administered, respectively. These results show the high antitumor potential of intracellular polysaccharide fraction of mycelial biomass of P. ostreatus, particularly at lower doses of 10 and 30 mg/kg. PMID- 29166532 TI - Description of fourth instar larva and pupa of Atrichopogon delpontei Cavalieri and Chiossone (Diptera: Ceratopogonidae) from Brazilian Amazonia. AB - The fourth instar larva and pupa of Atrichopogon delpontei Cavalieri and Chiossone are described for the first time. The immatures were collected from stream margins in the northern Brazilian states Rondonia and Piaui, and subsequently reared to adults. Larvae and pupae are illustrated and photomicrographed. Details on the rearing process and feeding behavior in laboratory, bionomics and notes on habitats are also provided. PMID- 29166533 TI - Potential effects of fungicide and algaecide extracts of Annona glabra L. (Annonaceae) on the microalgae Raphidocelis subcapitata and on the oomycete Pythium. AB - Annona glabra L. is a semi-deciduous tree that contains several active substances, including secondary metabolites, with antifungal activity. Phytopathogenic strains of the genus Pythium cause billion dollar losses all over the world on natural and crop species. Searching for eco-friendly algaecides and fungicides, we analyzed the effects of acetone extracts of A. glabra leaves on the algae Rhaphidocelis subcapitata (Korshikov) and on the oomycete Pythium aphanidermatum (Edson). We evaluated ten extract concentrations for each organism - 0 to 400 mg L-1 for algae and 0-1000 ug disc1 for oomycete. The results showed no effect on algae up to 75 mg L-1, but a significant inhibitory effect at 125 mg L-1 and above, which reduced the growth rate and the final biomass of the algae. Extract concentrations above 200 mg L-1 were completely inhibitory. The half maximal inhibitory concentration for 72 and 96 h of exposure to our crude extracts are comparable to those obtained with commercial fungicides and herbicides used in aquatic ecosystems. The P. aphanidermatum inhibition concentrations have effects comparable to fungicides as Cycloheximide and Bifonazole. Some substances isolated from the extracts are described as antifungals, which could explain part of anti-oomycete activity. Our results highlight the importance of searching bioactive compounds from plants. PMID- 29166534 TI - Effect of Syzygium cumini leaves on laying hens performance and egg quality. AB - The aim of this study was to evaluate the effect of Syzygium cumini leaves (SCL) in laying hens diets on productive performance, egg quality and lipid oxidation of yolk. A total of 108 Hysex White laying hens were distributed in a completely randomized design with three treatments and six replicates of six birds each. The treatments consisted of SCL inclusion at dietary levels of 0, 5 and 10 g/kg. There was no significant effect of SCL inclusion on feed intake, laying percentage, weight and egg mass, feed conversion ratio, Haugh units, specific gravity, percentage of yolk, albumen and egg shells and shell thickness. However, the inclusion of SCL significantly influenced the yolk color and yolk lipid oxidation measured by TBARS values. Yolk color increased and TBARS values decreased with the inclusion of SCL. The inclusion of SCL in laying hens diets improves pigmentation and lipid stability of yolk. PMID- 29166535 TI - Genetic parameters in female reproductive traits of Nile tilapia (Oreochromis niloticus). AB - Genetic parameters for reproductive traits in female Nile tilapia were estimated in this study using Bayesian inference method. The data set presented information from 451 Nile tilapia females that were evaluated at two different places in Maringa - Parana - Brazil (hapas of 1 and 10 m3) and at one location in Alfenas - Minas Gerais - Brazil. A spawning examination was conducted once a week from October 2012 to March 2013 for a total of 23 weeks of evaluation. Single-trait analyses for spawning success, multiple spawning, spawning frequency, and volume of eggs/female were performed by using the software MTGSAM Threshold. The heritability estimates were 0.14, 0.16, 0.53, and 0.08 for spawning success, multiple spawning, spawning frequency and volume of eggs/female, respectively, indicating it is possible to achieve a substantial genetic gain using these reproductive traits as selection criteria. PMID- 29166536 TI - Clinical investigation of left ventricular pacing using coronary sinus in patients with mechanical prosthetic tricuspid valve replacement. AB - BACKGROUND: Although transvenous right ventricular (RV) endocardial lead placement is routine practice in clinical pacing, RV inaccessibility in certain clinical situations mandates the search for other sites. HYPOTHESIS: This study is aimed to verify whether left ventricular lead through coronary sinus is safe and efficient. METHODS: Based on a retrospective analysis of a single-center series of 4 patients with inaccessibility for RV pacing, we report on the feasibility and reliability of coronary sinus (CS) pacing via left ventricular (LV) lead, which usually is used in cardiac resynchronization therapy. Four patients with valvular heart disease and bradycardias post-mechanical prosthetic tricuspid valve replacement were studied. The LV leads were implanted into the lateral vein or great cardiac vein of the CS, and all parameters were programmed postprocedure. RESULTS: In all cases procedures yielded favorable parameters, with 1 CS dissection. At long-term follow-up, there was no threshold increase or lead dislocation. CONCLUSIONS: LV lead implantation through the CS appears safe and efficacious in patients with inaccessibility for RV pacing. PMID- 29166537 TI - Database of Absorption and Fluorescence Spectra of >300 Common Compounds for use in PhotochemCAD. AB - The design of new molecules for photochemical studies typically requires knowledge of spectral features of pertinent chromophores beginning with the absorption spectrum (lambdaabs ) and accompanying molar absorption coefficient (epsilon, m-1 cm-1 ) and often extending to the fluorescence spectrum (lambdaem ) and fluorescence quantum yield (Phif ), where the fluorescence properties may be of direct relevance or useful as proxies to gain insight into the nature of the first excited singlet state. PhotochemCAD databases, developed over a period of 30 years, are described here. The previous databases for 150 compounds have been expanded to encompass 339 compounds for which absorption spectra (including epsilon values), fluorescence spectra (including Phif values) and references to the primary literature have been included where available (552 spectra altogether). The compounds exhibit spectra in the ultraviolet, visible and/or near-infrared spectral regions. The compound classes and number of members include acridines (21), aromatic hydrocarbons (41), arylmethane dyes (11), azo dyes (18), biomolecules (18), chlorins/bacteriochlorins (16), coumarins (14), cyanine dyes (19), dipyrrins (7), heterocycles (26), miscellaneous dyes (13), oligophenylenes (13), oligopyrroles (6), perylenes (5), phthalocyanines (11), polycyclic aromatic hydrocarbons (16), polyenes/polyynes (10), porphyrins (34), quinones (24) and xanthenes (15). A database of 31 solar spectra also is included. PMID- 29166538 TI - Antimicrobial Photodynamic Therapy Associated with Conventional Endodontic Treatment: A Clinical and Molecular Microbiological Study. AB - This study evaluated antimicrobial photodynamic therapy (aPDT) as an adjunct to endodontic treatment. Ten uniradicular teeth (control group (CG) = 4 (2 and test group (TG) = 6) with primary endodontic infections, from both genders, between 17 and 65 years old, were analyzed. Microbiological samples were collected before and after chemical-mechanical instrumentation (CMI), after aPDT (for the TG), and after the removal of the temporary restorations (second session). In TG, the aPDT was performed with 100 MUg mL-1 methylene blue and irradiated with low power laser (InGaAIP, 660 nm; 100 mW; 40 s) with a fiber-coupled optical laser. Another irradiation (3 J; 30 s; spot size of 3 mm2 ) was performed in the gingiva close to the apical foramen. The PCR was performed, after previous whole-genome amplification, for Enterococcus faecalis, Candida genus and Bacteria domain. For TG, a positive tooth for Candida spp. before of the CMI presented negative results in subsequent samples. Additionally, E. faecalis species was present in four samples before CMI, two after CMI, in one after the aPDT and was not detected at the second session. aPDT may be an effective adjunct therapy, resulting in a reduction (P = 0.0286) of the incidence of E. faecalis before root canal obturation. PMID- 29166539 TI - An Unusual Cause of Headache and Sudden Death of a Young Sailor-Postmortem Computed Tomography and Histological Findings of a Fatal Retroperitoneal Malignant Mixed Germ Cell Tumor. AB - A 26-year-old Caucasian sailor, with no past medical history aside from headache for the last 1 week, was found dead in his cabin. The body was stored in a refrigerator on board and disembarked for autopsy 3 days later. Autopsy showed a large, nodular, necrotic and hemorrhagic retroperitoneal mass, and smaller hemorrhagic nodules in the brain, lungs, liver, and left kidney, with the brain being markedly edematous. Both testes were descended and normal. Histologically, the retroperitoneal mass showed a malignant mixed germ cell tumor comprising choriocarcinoma, embryonal carcinoma, and teratoma components. Retroperitoneal extragonadal germ cell tumors are uncommon, and this case of a young male who presented with headache and sudden death due to metastases is extremely rare. PMID- 29166540 TI - Statistical optimization of an RP-HPLC method for the determination of selected flavonoids in berry juices and evaluation of their antioxidant activities. AB - An isocratic RP-HPLC method for the separation and identification of selected flavonoids (quercetin, rutin, luteolin-7-O-glucoside, kaempferol and kaempferol-3 O-glucoside) in commercial berry juices (blackcurrant, blueberry, red raspberry and cherry) was developed with the aid of central composite design and response surface methodology. The optimal separation conditions were a mobile phase of 85:15 (% v/v) water-acetonitrile, pH 2.8 (adjusted with formic acid), flow rate 0.5 mL min-1 and column temperature 35 degrees C. The obtained levels of bioflavonoids (mg per 100 mL of juice) were as follows: for quercetin, ca. 0.21 5.12; for kaempferol, ca. 0.05-1.2; for rutin, ca. 0.4-6.5; for luteolin-7-O glucoside, ca. 5.6-10.2; and for kaempferol-3-O-glucoside, ca. 0.02-0.12. These are considerably lower than the values in fresh fruits. Total phenolic, flavonoid and anthocyanin contents were determined spectrophotometrically. Total flavonoid content varied as follows: blackcurrant > blueberry > red raspberry > cherry. The antioxidant activity of juice extracts (DPPH and ABTS methods) expressed as IC50 values varied from 8.56 to 14.05 mg L-1 . These values are ~2.5-3 times lower than quercetin, ascorbic acid and Trolox(r), but compared with rutin and butylhydroxytoluene, berries show similar or better antioxidant activity by both the DPPH and ABTS methods. PMID- 29166541 TI - PhotochemCAD 3: Diverse Modules for Photophysical Calculations with Multiple Spectral Databases. AB - The PhotochemCAD program, developed over 30 years, is described comprehensively with focus on features of the most recent version (PhotochemCAD 3). The program is equipped with a streamlined user interface and provisions for handling multiple spectral databases. Eight modules enable calculations to be performed on the basis of the spectra in the databases. The calculational modules provide results concerning properties of individual compounds (oscillator strength, transition dipole moment, natural radiative lifetime), interactions of multiple compounds (Forster energy transfer, Dexter energy transfer, analysis of energy transfer among an array of chromophores) and composition of mixtures (multicomponent analysis). Synthetic spectra (blackbody radiator, Gaussian and Lorentzian curves, delta functions) also can be generated. For comparison and calculation, synthetic and experimental spectra can be shifted along both coordinate axes and combined by addition, subtraction and use of multiplicative factors. The core databases (described in the companion paper) have been expanded to 339 compounds for which absorption spectra (including molar absorption coefficient, epsilon), fluorescence spectra (including fluorescence quantum yield, Phif ) and references to the primary literature have been included where available (552 spectra altogether). A database of 31 solar spectra also is included. Each calculational module is described along with illustrative examples. PMID- 29166542 TI - Identification of cytochrome P450 isoforms involved in the metabolism of artocarpin and assessment of its drug-drug interaction. AB - Artocarpin isolated from an agricultural plant Artocarpus communis has shows anti inflammation and anticancer activities. In this study, we utilized recombinant human UDP-glucuronosyltransferasesupersomes (UGTs) and human liver microsomes to explore its inhibitory effect on UGTs and cytochrome p450 enzymes (CYPs). Chemical inhibition studies and screening assays with recombinant human CYPs were used to identify if CYP isoform is involved in artocarpin metabolism. Artocarpin showed strong inhibition against UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, CYP2C8 and CYP3A4. In particular, artocarpin exhibited competitive inhibition against CYP3A4 and noncompetitive inhibition against UGT1A3 and UGT1A7. The half inhibition concentration values for CYP3A4, UGT1A3 and UGT1A7 were 4.67, 3.82 and 4.82 MUm, and the inhibition kinetic parameters for them were 0.78, 2.67 and 3.14 MUm, respectively. After artocarpin was incubated in human liver microsomes and determined by HPLC, we observed its main metabolites (M1 and M2). In addition, we proved that CYP2D6 played the key role in the biotransformation of artocarpin in human liver microsomes. The result of molecular docking further confirmed that artocarpin interacted with CYP2D6, CYP2C8 and CYP3A4 through hydrogen bonds. This study provided preliminary results for further research on artocarpin or artocarpin-containing herbs. PMID- 29166543 TI - Transcatheter or surgical aortic valve replacement in patients with advanced kidney disease: A propensity score-matched analysis. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an alternative for surgically inoperable patients with severe aortic stenosis. Advanced kidney disease may significantly affect outcomes in patients treated with TAVR and surgical aortic valve replacement (SAVR). HYPOTHESIS: TAVR is associated with better in-hospital outcomes compared with SAVR in patients with advanced kidney disease. METHODS: We identified our sample from the National Inpatient Sample between 2012 and 2014, using International Classification of Diseases, Ninth Revision, Clinical Modification codes. We included patients with chronic kidney disease stages IV and V and end-stage renal disease as advanced kidney disease patients. We excluded patients with acute kidney injury on admission and patients on dialysis. RESULTS: After propensity matching, 2485 patients were included in each group. The primary outcome of in-hospital mortality (12.9% vs 6.2%; P < 0.01) was higher with SAVR as compared with TAVR. Patients who underwent SAVR reported higher acute kidney injury (50.3% vs 33%; P < 0.01) and dialysis requirements (26.8% vs 20.1%; P < 0.01). Other secondary outcomes including blood transfusion, atrial fibrillation, iatrogenic cardiac complications, pericardial complications, perioperative stroke, perioperative infections, and postoperative shock were more common with SAVR. With SAVR, the length of hospitalization and hospitalization costs were significantly higher; however, permanent pacemaker placement was more common with TAVR compared with SAVR. CONCLUSIONS: In patients with advanced kidney disease, SAVR was associated with higher mortality and higher periprocedural complications, as compared with TAVR. Thus, benefits of TAVR could be extended in patients with advanced kidney disease who cannot undergo surgery. PMID- 29166544 TI - Hours worked and patient visits provided by dentists in Australia. AB - BACKGROUND: The aim was to examine the numbers of hours worked and patient visits provided by age and gender of dentists in Australia, and compare with previous estimates to describe trends. METHODS: Data were collected from a random sample (N = 2961) of Australian dentists. Private sector dentists working in clinical practise were included in the analysis. RESULTS: The response rate was 49% (N = 1345 dentists). Hours per year worked and number of patient visits per year were lower for dentists aged 65 years and older compared with younger dentists, and were higher for male compared with female dentists aged 35-45 to 55-64 years. Hours per year worked were lower in 2013-2014 than reported in 2009-2010, but the number of patient visits in 2013-2014 was similar to the previously reported estimate from 2009-2010. CONCLUSIONS: Hours worked and visits provided were only lower among older dentists aged 65 years or more. Male dentists tend to work more hours per year and provide more patient visits per year than female dentists. Over the last decade, Australian dentists maintained a stable output of visits per year despite a trend towards fewer hours worked per year. PMID- 29166545 TI - Occurrence of primarily noninducible atrioventricular nodal reentry tachycardia after radiofrequency delivery in the slow pathway region during empirical slow pathway modulation. AB - BACKGROUND: The first-line therapy for atrioventricular nodal reentry tachycardia (AVNRT) is catheter-based slow pathway modulation. If AVNRT is not inducible during an electrophysiological study, an empirical slow pathway modulation (ESPM) may be considered in patients with dual atrioventricular nodal physiology and/or a typical electrocardiogram (ECG). METHODS: We screened 149 symptomatic patients who underwent ESPM in our department between 1993 and 2013. All patients fulfilled the following criteria: (1) either dual atrioventricular nodal (AVN) physiology with up to 2 AVN echo beats or characteristic ECG documentation or both, (2) noninducibility of AVNRT by programmed stimulation, and (3) completion of a telephone questionnaire for long-term follow-up. Out of this population we retrospectively investigated 13 patients who were primarily noninducible but in whom an AVNRT occurred during or after radiofrequency (RF) delivery. RESULTS: When AVNRT occurred, the procedure lost its empirical character, and RF delivery was continued until the procedural endpoint of noninducibility of AVNRT. This endpoint was reached in all but one patient (92%). After a follow-up of 73 +/- 15 months, this patient was the only one who reported no benefit from the procedure. CONCLUSIONS: Out of 149 initially noninducible patients, a considerable number (9%) exhibited AVNRT during or after RF delivery. These patients crossed over from empirical to controlled slow pathway modulation resulting in a good clinical outcome. Our observations should encourage electrophysiologists to repeat programmed stimulation even after initial empirical RF delivery to retest for inducibility. PMID- 29166546 TI - Back-to-back colon capsule endoscopy and optical colonoscopy in colorectal cancer screening individuals. AB - AIM: The aim was to determine the polyp detection rate and per-patient sensitivity for polyps > 9 mm of colon capsule endoscopy (CCE) compared with colonoscopy as well as the diagnostic accuracy of CCE. METHOD: Individuals who had a positive immunochemical faecal occult blood test during screening had investigator blinded CCE and colonoscopy. Participants underwent repeat endoscopy if significant lesions detected by CCE were considered to have been missed by colonoscopy. RESULTS: There were 253 participants. The polyp detection rate was significantly higher in CCE compared with colonoscopy (P = 0.02). The per-patient sensitivity for > 9 mm polyps for CCE and colonoscopy was 87% (95% CI: 83-91%) and 88% (95% CI: 84-92%) respectively. In participants with complete CCE and colonoscopy examinations (N = 126), per-patient sensitivity of > 9 mm polyps in CCE (97%; 95% CI: 94-100%) was superior to colonoscopy (89%; 95% CI: 84-94%). A complete capsule endoscopy examination (N = 134) could detect patients with intermediate or greater risk (according to the European guidelines) with an accuracy, sensitivity, specificity and positivity rate of 79%, 93%, 69% and 58% respectively, using a cut-off of at least one polyp > 10 mm or more than two polyps. CONCLUSION: CCE is superior to colonoscopy in polyp detection rate and per-patient sensitivity to > 9 mm polyps, but only in complete CCE examinations. The rate of incomplete CCE examinations must be improved. PMID- 29166547 TI - Chemical metabolome assay by high-resolution Orbitrap mass spectrometry and assessment of associated antitumoral activity of Actinocephalus divaricatus. AB - RATIONALE: Actinocephalus divaricatus (Eriocaulaceae) is an important source of income for rural communities as it is sold as an ornamental plant. To date, no investigation has been conducted concerning the chemical composition and biological studies of the aerial parts of A. divaricatus. METHODS: The methanolic extract of the aerial parts of this species was chemically characterized. We applied an analytical dereplication approach based on Liquid Chromatography coupled to High-Resolution Orbitrap Mass Spectrometry in order to develop, identify and define rapidly the metabolite fingerprint of the aerial parts of A. divaricatus. Biological in vitro antitumor tests were undertaken using breast and lung cell lines of mice and humans. RESULTS: High-Resolution Mass Spectrometry (HRMS) allowed the fast determination of 30 compounds, which comprised three different classes of compounds: naphthopyranones, flavonoids and saponins. Chromatographic fractionation of the crude methanolic extract validated these results, since it led to the isolation of compounds belonging to the aforementioned classes of compounds, including new acyl glycosylated flavonoids (6-hydroxy-7-methoxyquercetin-3-O-(2"-O-acetyl)-beta-D-glucopyranoside and 6 hydroxy-7-methoxyquercetin-3-O-(6"-O-acetyl)-beta-D-glucopyranoside), which were fully characterized by Nuclear Magnetic Resonance and Mass Spectrometry experiments, and a known triterpenic saponin (3-O-beta-D-glucuronopyranosyl-30 norolean-12,20(29)-dien-28-O-beta-D-glucopyranosyl ester). Biological assays indicated that the methanolic extract of the capitula exhibited the best in vitro cytotoxicity against MCF7 cells (human breast cancer). CONCLUSIONS: The HRMS technique enabled us to identify several classes of compounds. In addition, saponins were identified for the first time in plants belonging to the Eriocaulaceae family. Thus, the essential contribution of this work lies in the new elements it brings to the taxonomic discussion which the Actinocephalus genus as a distinct genus of the Paepalanthus. The results obtained show that the methanolic extract of the capitula could be a promising source of bioactive fractions and/or compounds that may contribute towards breast cancer treatment. PMID- 29166548 TI - An exploratory study into therapeutic alliance, defeat, entrapment and suicidality on mental health wards. AB - : WHAT IS KNOWN ON THE SUBJECT?: The strength of a relationship between people with mental health difficulties and professionals has been linked to patients feeling suicidal. A relationship has been found between how defeated and trapped people with mental health difficulties feel and how suicidal they feel. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This study explored the relationship between alliance, suicidality, defeat and entrapment in people admitted to mental health wards as previous research has focused on people in the community. Patient-rated defeat, entrapment and suicidality are related in this sample of people admitted to mental health wards. A relationship was found between how well nurses said they bonded with their named patient and how trapped the patients felt by their environment. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Nurses should consider if patients are feeling defeated or trapped when helping people with mental health difficulties to feel less suicidal. ABSTRACT: Introduction Suicidality is prevalent worldwide, particularly in people who access mental health services. The quality of therapeutic alliance between people with mental health difficulties and staff has been associated with suicidality but only in community settings. Defeat and entrapment are correlated with suicidality and may mediate any relationship between alliance and suicidality. Therefore, this exploratory study explored these relationships in people admitted to mental health wards. Aim To explore defeat, entrapment, suicidality and alliance between nurses and people admitted to mental health wards. Method Fifty inpatient nurse-patient dyads completed questionnaires regarding demographics, defeat, entrapment, suicidality and alliance with their named nurse. Nurses completed questionnaires on demographics, alliance with their patient and the patients' suicidality. Results Defeat, entrapment and suicidality were correlated. A correlation between nurse rated bond and external entrapment was found, but no other correlations between alliance, defeat, entrapment and suicidality were statistically significant. Discussion and clinical implications Ward-based nurses should consider the relationship between defeat, entrapment and suicidality when developing interventions to improve suicidality. Although there was no evidence of a relationship between total alliance and suicidality, developing closer bonds with patients may reduce patients' feelings of being trapped by their environment. PMID- 29166549 TI - Depolymerization of Poly(phosphinoboranes): From Polymers to Lewis Base Stabilized Monomers. AB - We report on depolymerization reactions of poly(phosphinoboranes). The cleavage of the polymers [H2 PBH2 ]n (2 a), [tBuHPBH2 ]n (2 c), [PhHPBH2 ]n (2 e) and the oligomer [Ph2 PBH2 ]n (2 b), with strong Lewis bases (LBs), in particular with NHCs, leads to the corresponding monomeric phosphanylboranes R1 R2 PBH2 LB. It is observed that the depolymerization depends on the strength and stability of the LBs as well as on the substitution pattern of the poly(phosphinoboranes). The solid state structures of the monomeric phosphinoboranes H2 PBH2 NHCMe (NHC=N heterocyclic carbene) (4 a), H2 PBH2 NHCdipp (5 a) and tBuHPBH2 NHCMe (4 c) were determined. DFT calculations support the experimentally observed reaction behavior. PMID- 29166550 TI - Improvement in pancreas transplant evaluation and surgical volume using a multidisciplinary approach. PMID- 29166551 TI - Evaluation of markers out of the steroid profile for the screening of testosterone misuse. Part II: Intramuscular administration. AB - In the fight against doping, the introduction of alternative markers to the steroid profile can be considered as an effective approach to improve the screening capabilities for the detection of testosterone (T) misuse. The aim of this study was to evaluate the potential of several T metabolites (cysteinyl conjugated and glucuronoconjugated resistant to enzymatic hydrolysis) to detect both the transdermal and the intramuscular administration of T. In Part I of the study, we studied the potential of these metabolites for the detection of T transdermal administration. Results revealed that resistant glucuronides can be a suitable complement to the current steroid profile. In this, Part II, dedicated to the intramuscular administration, we studied the potential of cysteinyl conjugated, resistant glucuronoconjugated and 1-cyclopentenoylglycine (1-CPG) for the detection of a single intramuscular injection of T cypionate. Possible differences in the excretion profile of all markers were explored between individuals with low basal (n=6) and medium basal (n=6) values of the testosterone/epitestosterone ratio (T/E). The results showed that all tested markers presented low intra-individual stability in basal conditions. Despite this, all glucuronoconjugated markers and 1-CPG, but not the cysteinyl conjugated markers, provided detection windows that were similar or longer than those obtained by markers currently included in the steroid profile. Based on the results obtained from the 2 parts of this study and from previously reported data, the potential applicability and the limitations of including these markers in the steroid profile are discussed. PMID- 29166552 TI - Vortioxetine versus placebo in major depressive disorder comorbid with social anxiety disorder. AB - BACKGROUND: Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD) are highly comorbid, yet the combined condition has not been subject to any placebo controlled treatment trials. This study reports a trial of vortioxetine, an antidepressant that has also shown benefit in Generalized Anxiety Disorder (GAD), in patients meeting DSM-5 criteria for both MDD and SAD. METHODS: The study was a 12-week double-blind, placebo-controlled comparison of vortioxetine 10-20 mg/day or placebo administered on a 1:1 ratio. The study was designed to include 40 male or female outpatients aged 18-70 years. The primary endpoint was the "composite" Clinical Global Impression of Improvement (CGI-I) responder rate, factoring in improvement in both MDD and SAD features. Major secondary outcome measures were changes on the Montgomery Asberg Depression Rating Scale (MADRS) and Liebowitz Social Anxiety Scale (LSAS). RESULTS: On the composite CGI-I, 10 of 20 (50%) vortioxetine and six of 20 (30%) placebo-treated patients were rated as responders, a non-significant difference. However, vortioxetine-treated patients did show significantly greater improvement than those on placebo on both the MADRS (effect size 0.672) and LSAS (effect size 0.714). Efficacy in depression was seen before improvement in SAD. Adverse effects were similar to those previously reported. CONCLUSIONS: In this preliminary trial vortioxetine appears safe and effective for patients with MDD comorbid with SAD, with robust effect sizes on dimensional measures of both depression and social anxiety, but failure to separate from placebo on the primary outcome measure of composite responder rate. More studies of patients with comorbid conditions are needed, as this mirrors what is often seen in clinical practice. PMID- 29166553 TI - Botulinum toxin injection vs topical nitrates for chronic anal fissure: an updated systematic review and meta-analysis of randomized controlled trials. AB - AIM: Chronic anal fissures (CAFs) are frequently encountered in coloproctology clinics. Chemical sphincterotomy with pharmacological agents is recommended as first-line therapy. Topical nitrates (TN) heal CAF effectively but recurrences are common. An alternative treatment modality is injection of botulinum toxin (BT) into the anal sphincter. We aimed to perform an updated systematic review and meta-analysis to compare the effectiveness of BT and TN in the management of CAF. METHOD: PubMed, EMBASE and Cochrane databases were searched for relevant articles from inception until March 2017. All randomized controlled trials (RCTs) that reported direct comparisons of BT and TN were included. Two independent reviewers performed methodological assessment and data extraction. Random effects models were used to calculate pooled effect size estimates. RESULTS: Six RCTs describing 393 patients (194 BT, 199 TN) were included. There was significant heterogeneity among the trials. On random effects analysis there were no significant differences in incomplete fissure healing (OR = 0.47, 95% CI 0.13 1.68, P = 0.24) or recurrence (OR = 0.70, 95% CI 0.39-1.25, P = 0.22) between BT and TN, respectively. BT was associated with a higher rate of transient anal incontinence (OR = 2.53, 95% CI 0.98-6.57, P = 0.06) but significantly fewer total side effects (OR = 0.12, 95% CI 0.02-0.63, P = 0.01) and headache (OR = 0.10, 95% CI 0.02-0.60, P = 0.01) compared with TN. CONCLUSION: BT is associated with fewer side effects than TN but there is no difference in fissure healing or recurrence. Patients need to be warned regarding the risk of transient anal incontinence associated with BT. PMID- 29166554 TI - Can surgical technology better guide oncological resections in colon cancer? PMID- 29166555 TI - Maximizing the Catalytic Activity of Nanoparticles through Monolayer Assembly on Nitrogen-Doped Graphene. AB - We report a facile method for assembly of a monolayer array of nitrogen-doped graphene (NG) and nanoparticles (NPs) and the subsequent transfer of two layers onto a solid substrate (S). Using 3 nm NiPd NPs as an example, we demonstrate that NiPd-NG-Si (Si=silicon wafer) can function as a catalyst and show maximum NiPd catalysis for the hydrolysis of ammonia borane (H3 NBH3 , AB) with a turnover frequency (TOF) of 4896.8 h-1 and an activation energy (Ea ) of 18.8 kJ mol-1 . The NiPd-NG-S catalyst is also highly active for catalyzing the transfer hydrogenation from AB to nitro compounds, leading to the green synthesis of quinazolines in water. Our assembly method can be extended to other graphene and NP catalyst materials, providing a new 2D NP catalyst platform for catalyzing multiple reactions in one pot with maximum efficiency. PMID- 29166556 TI - Catalytic Three-Component Machinery: Control of Catalytic Activity by Machine Speed. AB - Three supramolecular slider-on-deck systems DS1-DS3 were obtained as two component aggregates from the sliders S1-S3 and deck D with its three zinc porphyrin (ZnPor) binding sites. The binding of the two-footed slider to the deck varies with the donor qualities of and the steric hindrance at the pyridine/pyrimidine (pyr) feet, and was effected by two Npyr ->ZnPor interactions. Accordingly, the sliders move over the three zinc porphyrins in the deck at different speeds, namely with 32.2, 220, and 440 kHz at room temperature. The addition of N-methylpyrrolidine as an organocatalyst to DS1-DS3 generates catalytic three-component machineries. By using a conjugate addition as a probe reaction, we observed a correlation between the operating speed of the slider-on deck systems and the yields of the catalytic reaction. As the thermodynamic binding of the slider decreases, both the frequency of the sliding motion and the yield of the catalytic reaction increase. PMID- 29166557 TI - Impact of Cross-Linker Valency on Gold Nanoparticle Aggregate Formation and Cellular Uptake. AB - Synthesis of spherical, biocompatible nanoparticle aggregates using a small molecular cross-linker is a simple and flexible approach for the controlled assembly of gold nanoparticles. This strategy can be extended to a variety of cross-linkers, making it possible to the test the effect of cross-linker properties on aggregate formation and physicochemical properties. Here, we synthesized aggregates using a series of structurally homologous cross-linkers with differing valencies. These aggregates have the same size, morphology, surface charge, surface coating, and stability in salt, media, and low pH conditions, but they differ in their stability to cyanide etching and uptake by cells. This highlights the fine-tuning of nanoparticle aggregate properties that can be achieved by using small-molecule cross-linkers. PMID- 29166558 TI - Understanding the Cellular Uptake of pH-Responsive Zwitterionic Gold Nanoparticles: A Computer Simulation Study. AB - Surface functionalization of nanoparticles (NPs) with stealth polymers (e.g., hydrophilic and zwitterionic polymers) has become a common strategy to resist nonspecific protein adsorption recently. Understanding the role of surface decoration on NP-biomembrane interactions is of great significance to promote the application of NPs in biomedical fields. Herein, using coarse-grained molecular dynamics (CGMD) simulations, we investigate the interactions between stealth polymer-coated gold nanoparticles (AuNPs) and lipid membranes. The results show that AuNPs grafted with zwitterionic polymers can more easily approach the membrane surface than those coated with hydrophilic poly(ethylene glycol) (PEG), which can be explained by the weak dipole-dipole interaction between them. For zwitterionic AuNPs which can undergo pH-dependent charge conversion, different interaction modes which depend on the polymer protonation degree are found. When the protonation degree is low, the particles just adsorb on the membrane surface; at moderate protonation degrees, the particles can directly translocate across the lipid membrane through a transient hydrophilic pore formed on the membrane surface; the particles are fully wrapped by the curved lipid membrane at high protonation degrees, which may lead to endocytosis. Finally, the effect of polymer chain length on the cellular uptake of zwitterionic polymer-coated AuNPs is considered. The results demonstrate that longer polymer chain length will block the translocation of AuNPs across the lipid membrane when the protonation degree is not high; however, it can improve the transmembrane efficiency of AuNPs at high protonation degrees. We expect that these findings are of immediate interest to the design and synthesis of pH-responsive nanomaterials based on zwitterionic polymers and can prompt their further applications in the field of biomedicine. PMID- 29166560 TI - Analytical Challenges and Recent Advances in Mass Spectrometry Based Lipidomics. PMID- 29166559 TI - Dynamic Nature of Thiolate Monolayer in Au25(SR)18 Nanoclusters. AB - Thiolate monolayer, protecting a gold nanocluster, is responsible for its chemical behavior and interaction with the environment. Understanding the parameters that influence the stability and reactivity of the monolayer will enable its precise and controlled functionalization. Here we present a protocol for the investigation of the monolayer reactivity in Au25(SR)18 based on MALDI mass spectrometry and NMR spectroscopy. Thiol exchange reaction between cluster and thiol molecules has been investigated showing how this reaction is affected by several factors (stability of the thiols in solution, the affinity of the sulfur to the gold cluster, intermolecular interactions within the ligand layer, etc.). Furthermore, intercluster thiol exchange has been clarified to occur during collisions between particles without thiol release to the solution. In this reaction, the stability of the thiols in solution and the affinity of the sulfur to the gold for the two thiols do not affect the equilibrium position because for both thiols one S-Au bond is broken and one is formed within the cycle. Importantly, the rate of direct thiol exchange between clusters is comparable to that of the ligand exchange with free thiols. However, the thermodynamic driving force of the two reactions is different, since only the latter involves free thiol species. PMID- 29166562 TI - LC-HRMS Data Processing Strategy for Reliable Sample Comparison Exemplified by the Assessment of Water Treatment Processes. AB - The behavior of micropollutants in water treatment is an important aspect in terms of water quality. Nontarget screening by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) offers the opportunity to comprehensively assess water treatment processes by comparing the signal heights of all detectable compounds before and after treatment. Without preselection of known target compounds, all accessible information is used to describe changes across processes and thus serves as a measure for the treatment efficiency. In this study, we introduce a novel LC-HRMS data processing strategy for the reliable classification of signals based on the observed fold changes. An approach for filtering detected features was developed and, after parameter adjustment, validated for its recall and precision. As proof of concept, the fate of 411 target compounds in a 0.1 MUg/L standard mix was tracked throughout the data processing stages, where 406 targets were successfully recognized and retained during filtering. Potential pitfalls in signal classification were addressed. We found the recursive peak integration to be a key point for the reliable classification of signal changes across a process. For evaluating the repeatability, a combinatorial approach was conducted to verify the consistency of the final outcome using technical replicates of influent and effluent samples taken from an ozonation process during drinking water treatment. The results showed sufficient repeatability and thus emphasized the applicability of nontarget screening for the assessment of water treatment processes. The developed data processing strategies may be transferred to other research fields where sample comparisons are conducted. PMID- 29166561 TI - Structural Characterization of Native and Modified Encapsulins as Nanoplatforms for in Vitro Catalysis and Cellular Uptake. AB - Recent years have witnessed the emergence of bacterial semiorganelle encapsulins as promising platforms for bio-nanotechnology. To advance the development of encapsulins as nanoplatforms, a functional and structural basis of these assemblies is required. Encapsulin from Brevibacterium linens is known to be a protein-based vessel for an enzyme cargo in its cavity, which could be replaced with a foreign cargo, resulting in a modified encapsulin. Here, we characterize the native structure of B. linens encapsulins with both native and foreign cargo using cryo-electron microscopy (cryo-EM). Furthermore, by harnessing the confined enzyme (i.e., a peroxidase), we demonstrate the functionality of the encapsulin for an in vitro surface-immobilized catalysis in a cascade pathway with an additional enzyme, glucose oxidase. We also demonstrate the in vivo functionality of the encapsulin for cellular uptake using mammalian macrophages. Unraveling both the structure and functionality of the encapsulins allows transforming biological nanocompartments into functional systems. PMID- 29166563 TI - Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Enhancing Cocrystal Yield. AB - Pharmaceutical cocrystals have attracted increasing attention over the past decade as an alternative way to modify the physicochemical properties and hence improve the bioavailability of a drug, without sacrificing thermodynamic stability. Our previous work has demonstrated the viability of in situ formation of ibuprofen/isonicotinamide cocrystal suspensions within a matrix carrier via a single-step hot melt extrusion (HME) process. The key aim of the current work is to establish optimized processing conditions to improve cocrystal yield within extruded matrices. The solubility of each individual cocrystal component in the matrix carrier was estimated using two different methods, calculation of Hansen solubility parameters and Flory-Huggins solution theory using a melting point depression measurement method, respectively. The latter was found to be more relevant to extrusion cocrystallization because of the ability to predict miscibility across a range of temperatures. The predictions obtained from the F-H phase diagrams were verified using ternary extrusion processing. Temperatures that promote solubilization of the parent reagents during processing and precipitation of the newly formed cocrystal were found to be the most suitable in generating high cocrystal yields. The incorporation of intensive mixing/kneading elements to the screw configuration was also shown to significantly improve the cocrystal yield when utilizing a matrix platform. This work has shown that intensive mixing, in combination with appropriate temperature selection, can significantly improve the cocrystal yield within a stable and low viscosity carrier during HME processing. Most importantly, this work reports, for the very first time in the literature, the use of the F-H phase diagrams to guide the most appropriate HME processing window to drive higher cocrystal yield. PMID- 29166566 TI - About Our Knowledge Base: How Knowledge Development Informs Researchers and Readers. PMID- 29166565 TI - Hospital-Based Physicians' Intubation Decisions and Associated Mental Models when Managing a Critically and Terminally Ill Older Patient. AB - BACKGROUND: Variation in the intensity of acute care treatment at the end of life is influenced more strongly by hospital and provider characteristics than patient preferences. OBJECTIVE: We sought to describe physicians' mental models (i.e., thought processes) when encountering a simulated critically and terminally ill older patient, and to compare those models based on whether their treatment plan was patient preference-concordant or preference-discordant. METHODS: Seventy three hospital-based physicians from 3 academic medical centers engaged in a simulated patient encounter and completed a mental model interview while watching the video recording of their encounter. We used an "expert" model to code the interviews. We then used Kruskal-Wallis tests to compare the weighted mental model themes of physicians who provided preference-concordant treatment with those who provided preference-discordant treatment. RESULTS: Sixty-six (90%) physicians provided preference-concordant treatment and 7 (10%) provided preference-discordant treatment (i.e., they intubated the patient). Physicians who intubated the patient were more likely to emphasize the reversible and emergent nature of the patient situation (z = -2.111, P = 0.035), their own comfort (z = -2.764, P = 0.006), and rarely focused on explicit patient preferences (z = 2.380, P = 0.017). LIMITATIONS: Post-decisional interviewing with audio/video prompting may induce hindsight bias. The expert model has not yet been validated and may not be exhaustive. The small sample size limits generalizability and power. CONCLUSIONS: Hospital-based physicians providing preference-discordant used a different mental model for decision making for a critically and terminally ill simulated case. These differences may offer targets for future interventions to promote preference-concordant care for seriously ill patients. PMID- 29166567 TI - Supporting the Most Vulnerable Through Appropriate Infant and Young Child Feeding in Emergencies. PMID- 29166564 TI - Optical Control of Dopamine Receptors Using a Photoswitchable Tethered Inverse Agonist. AB - Family A G protein-coupled receptors (GPCRs) control diverse biological processes and are of great clinical relevance. Their archetype rhodopsin becomes naturally light sensitive by binding covalently to the photoswitchable tethered ligand (PTL) retinal. Other GPCRs, however, neither bind covalently to ligands nor are light sensitive. We sought to impart the logic of rhodopsin to light-insensitive Family A GPCRs in order to enable their remote control in a receptor-specific, cell-type-specific, and spatiotemporally precise manner. Dopamine receptors (DARs) are of particular interest for their roles in motor coordination, appetitive, and aversive behavior, as well as neuropsychiatric disorders such as Parkinson's disease, schizophrenia, mood disorders, and addiction. Using an azobenzene derivative of the well-known DAR ligand 2-(N-phenethyl-N-propyl)amino 5-hydroxytetralin (PPHT), we were able to rapidly, reversibly, and selectively block dopamine D1 and D2 receptors (D1R and D2R) when the PTL was conjugated to an engineered cysteine near the dopamine binding site. Depending on the site of tethering, the ligand behaved as either a photoswitchable tethered neutral antagonist or inverse agonist. Our results indicate that DARs can be chemically engineered for selective remote control by light and provide a template for precision control of Family A GPCRs. PMID- 29166568 TI - Camel whey protein protects lymphocytes from apoptosis via the PI3K-AKT, NF kappaB, ATF-3, and HSP-70 signaling pathways in heat-stressed male mice. AB - Heat stress (HS) is an environmental factor that depresses the immune systems that mediate dysfunctional immune cells. Camel whey protein (CWP) can scavenge free radicals and enhance immunity. This study investigated the impact of dietary supplementation with CWP on immune dysfunction induced by exposure to HS. Male mice (n = 45) were distributed among 3 groups: control group; HS group; and HS mice that were orally administered CWP (HS + CWP group). The HS group exhibited elevated levels of reactive oxygen species (ROS) and pro-inflammatory cytokines (interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha) as well as a significant reduction in the IL-2 and IL-4 levels. Exposure to HS resulted in impaired phosphorylation of AKT and IkappaB-alpha (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha); increased expression of activating transcription factor 3 (ATF-3) and 70 kDa heat shock proteins (HSP70); and aberrant distribution of CD3+ T cells and CD20+ B cells in the thymus and spleen. Interestingly, HS mice treated with CWP presented significantly restored levels of reactive oxygen species and pro-inflammatory cytokines near the levels observed in the control mice. Furthermore, supplementation of HS mice with CWP enhanced the phosphorylation of AKT and IkappaB-alpha; attenuated the expression of ATF-3, HSP70, and HSP90; and improved T and B cell distributions in the thymus and spleen. Our findings reveal a potential immunomodulatory effect of CWP in attenuating immune dysfunction induced by exposure to thermal stress. PMID- 29166569 TI - Breastfeeding Among Women With Physical Disabilities in the United States. AB - BACKGROUND: The benefits of breastfeeding are well established, and breastfeeding is now widely practiced in the United States. Although increasing numbers of women with physical disabilities are having children, little information is available about breastfeeding practices among these women. Nonetheless, the children of women with physical disabilities should benefit from breastfeeding just as children of nondisabled mothers do. Research aim: This study aimed to explore the facilitators and barriers to breastfeeding among women with physical disabilities. METHODS: This study involved semistructured telephone interviews with a convenience sample of women ( N = 25) with diverse physical disabilities from across the United States. All participants had given birth within the past 10 years. Interviews were audio-recorded, professionally transcribed, and analyzed using content analysis. RESULTS: Analyses found four broad themes indicating facilitators to breastfeeding: (a) adaptations and equipment, (b) use of breast pump, (c) physical assistance from others, and (d) peer support. We also found five broad themes suggesting barriers to breastfeeding: (a) lack of supports, (b) disability-related health considerations, (c) limited information, (d) difficulties with milk production, and (e) difficulties latching. CONCLUSION: The need for greater supports for women with physical disabilities who desire to breastfeed as well as information for women and their clinicians about facilitating breastfeeding. PMID- 29166570 TI - Splenectomy after partial hepatectomy accelerates liver regeneration in mice by promoting tight junction formation via polarity protein Par 3-aPKC. AB - AIMS: Several experimental studies have demonstrated that removal of the spleen accelerates liver regeneration after partial hepatectomy. While the mechanism of splenectomy promotes liver regeneration by the improvement of the formation of tight junction and the establishment of hepatocyte polarity is still unknown. MAIN METHODS: We analyzed the cytokines, genes and proteins expression between 70% partial hepatectomy mice (PHx) and simultaneous 70% partial hepatectomy and splenectomy mice (PHs) at predetermined timed points. KEY FINDINGS: Compared with the PHx group mice, splenectomy accelerated hepatocyte proliferation in PHs group. The expression of Zonula occludens-1 (ZO-1) indicated that splenectomy promotes the formation of tight junction during liver regeneration. TNF-alpha, IL 6, HGF, TSP-1 and TGF-beta1 were essential factors for the formation of tight junction and the establishment of hepatocytes polarity in liver regeneration. After splenectomy, Partitioning defective 3 homolog (Par 3) and atypical protein kinase C (aPKC) regulate hepatocyte localization and junctional structures in regeneration liver. SIGNIFICANCE: Our data suggest that the time course expression of TNF-alpha, IL-6, HGF, TSP-1, and TGF-beta1 and the change of platelets take part in liver regeneration. Combination with splenectomy accelerates liver regeneration by improvement of the tight junction formation which may help to establish hepatocyte polarity via Par 3-aPKC. This may provide a clue for us that splenectomy could accelerate liver regeneration after partial hepatectomy of hepatocellular carcinoma and living donor liver transplantation. PMID- 29166572 TI - Territorial aggression in urban and rural Song Sparrows is correlated with corticosterone, but not testosterone. AB - Urban songbirds of several species more vigorously defend their territories in response to conspecific song playback than do their rural counterparts, but the hormonal basis of this behavioral difference is unclear. It is well established in vertebrates that both testosterone and corticosterone affect the intensity of territoriality. Previous studies have found no evidence that initial (i.e., immediately following territorial challenge, but prior to restraint) plasma testosterone accounts for the elevated territorial aggression of urban birds. Determining if testosterone still contributes to urban-rural differences in territoriality requires also assessing males' abilities to transiently increase plasma testosterone (in response to an injection of gonadotropin-releasing hormone). We tested whether these hormones are correlated with the territorial response to conspecific song playback in urban and rural male Song Sparrows (Melospiza melodia) in Montgomery County, Virginia. We found that the elevated territorial aggression of urban sparrows was not related to variation in either initial plasma testosterone or the ability to transiently increase testosterone. In contrast, despite no overall habitat difference in initial corticosterone, levels of this hormone were positively correlated with territoriality in urban and rural sparrows. Furthermore, for a given level of corticosterone, urban sparrows were more territorially aggressive. Our findings suggest that initial corticosterone may either play a role in the regulation of persistent differences in territorial behavior between free-ranging urban and rural male Song Sparrows or be affected by the intensity of behavioral response to territorial challenge. PMID- 29166571 TI - Protective cerebrovascular effects of hydroxysafflor yellow A (HSYA) on ischemic stroke. AB - The purpose of the present work was designed to explore protective cerebrovascular effects of hydroxysafflor yellow A (HSYA), and provide preclinical efficacy and mechanism data for its possible application in patients with cerebral ischemia. The protective effect of HSYA on ischemic stroke was evaluated by infarct sizes and neurological scores in Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO). Cerebrovascular permeability was detected by Evans blue dye leakage in MCAO rats. Cerebral blood flow, as well as blood pressure and heart rate were monitored using flow probes in Beagle dogs. Basilar artery tension isolated from Beagle dogs was evaluated with an MPA 2000 data-acquisition system. Coagulation-related function was also judged, including rabbit platelet aggregation by adenosine diphosphate (ADP) and platelet aggregating factor (PAF), rabbit blood viscosity by a blood viscometer, and thrombus formation by rat arterial-venous shunts. Results showed that HSYA treatment significantly decreased the infarct sizes, neurological scores and cerebrovascular permeability in rats with MCAO. However, cerebral blood flow, blood pressure and heart rate were not affected by HSYA. In vitro, HSYA had a strong effect on cerebrovascular vasodilatation, and significantly decreased platelet aggregation, blood viscosity, and thrombogenesis. Besides well-known anti-coagulation effects, HSYA protects against ischemic stroke by dilating cerebral vessels and improving cerebrovascular permeability. PMID- 29166573 TI - Interaction of Hsp90 with phospholipid model membranes. AB - Heat shock protein 90 (Hsp90) is an essential molecular chaperone with versatile functions in cell homeostatic control under both normal and stress conditions. Hsp90 has been found to be expressed on the cell surface, but the mechanism of Hsp90 association to the membrane remains obscure. In this study, the direct interaction of Hsp90 and phospholipid vesicles was characterized, and the role of Hsp90 on membrane physical state was explored. Using surface plasmon resonance (SPR), we observed a strong interaction between Hsp90 and different compositions of lipid. Hsp90 had a preference to bind with more unsaturated phospholipid species and the affinity was higher with negatively charged lipids than zwitterionic lipids. Increasing the mole fraction of cholesterol in the phospholipid led to a decrease of binding affinity to Hsp90. Circular dichroism (CD) spectroscopy of Hsp90 in PC membranes showed more alpha-helix structure than in aqueous buffer. The differential scanning calorimeter (DSC) and fluorescence polarization results showed Hsp90 could affect the transition temperature and fluidity of the bilayer. We postulate from these results that the association between Hsp90 and membranes may involve both electrostatic and hydrophobic force, and constitute a possible mechanism that modulates membrane lipid order during thermal fluctuations. PMID- 29166574 TI - Altered TNF-alpha response by Aconibal(r) and methotrexate in a lipopolysaccharide-induced setting of inflammatory conditions: Potential on a synergistic combination. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum carmichaelii (AC) is a common herbal medicine used as anti-inflammatory and analgesic agent in Eastern Asia. In Korea, a commercial processed AC (Aconibal(r)) is traditionally used to treat the symptoms of spondylosis deformans and rheumatic pain. AIM OF STUDY: Rheumatoid arthritis (RA) is systemic and autoimmune disease characterized by chronic inflammation. Methotrexate (MTX) is often the first-line therapy for RA. If MTX monotherapy is ineffective or RA is initially severe, adding a tumor necrosis factor alpha (TNF-alpha) inhibitor to the treatment can be beneficial. However, its inhibitory effects on RA when combined with MTX are unknown. Therefore, we investigated the stable modulation of and synergistic to additive effect on TNF alpha using AC combined with MTX (AMC). MATERIALS AND METHODS: An inflammatory response mimicking RA was induced in the mouse macrophage cell line Raw 264.7 using interferon-gamma or lipopolysaccharide (LPS). We predicted that AC and MTX at a 3:1 ratio would have synergistic therapeutic effects and this was determined using the Chou-Talalay method of median effect analysis and CalcuSyn software. We analyzed the profiles of various inflammatory cytokine-related proteins using Search tool for retrieval of interacting genes and Kyoto Encyclopedia of Genes and Genomes. RESULTS: The expression levels of selected inflammatory immune mediators such as interleukin (IL)-6, IL-1alpha, chemokine ligand 5, granulocyte colony stimulating factor, nitric oxide synthase, and cyclooxygenase were reduced via regulation of the mitogen-activated protein kinase signaling pathway. AMC inhibited the levels of matrix metalloproteinases-1 and -3 in the human synovial cell line SW982. CONCLUSIONS: Our data show for the first time the potential beneficial effects of AMC in RA management. PMID- 29166575 TI - Chemical characterization and pharmacological assessment of polysaccharide free, standardized cashew gum extract (Anacardium occidentale L.). AB - ETHNOPHARMACOLOGICAL RELEVANCE: The cashew gum (Anacardium occidentale L.) is used in traditional Brazilian medicine in the treatment of inflammatory conditions, asthma, diabetes, and gastrointestinal disturbances. AIM OF THE STUDY: In the present study, we aimed at forming a chemical characterization and investigation of the antinociceptive and anti-inflammatory activities of the aqueous extract of cashew gum without the presence of polysaccharides in its composition (CGE). MATERIALS AND METHODS: The CGE was obtained after the precipitation and removal of polysaccharides through the use of acetone. After, the acetone was removed by rotaevaporation, and the concentrated extract was lyophilized. The chemical characterization of CGE was performed by liquid chromatography mass spectrometry (LC-MS) and tandem mass spectrometry (MS/MS) analyses. Mice were used for the evaluation of the antinociceptive and anti inflammatory activities. CGE was analyzed via the Irwin test, acetic acid-induced writhing test, formalin-induced pain test, and carrageenan-induced paw edema test. The motor activity or probable sedation was verified through the chimney, open-field, and sodium pentobarbital-induced sleep tests. We investigated if the analgesic and anti-inflammatory effects of CGE depend of reduction in PGE2 levels, were performed the carrageenan or PGE2-induced hyperalgesia tests. RESULTS: The chemical characterization of CGE showed the presence of anacardic acids as the predominant phytoconstituents. The treatment with CGE (75, 150, and 300mg/kg, p.o.) inhibited the number of writhing in a dose-dependent manner. With an intermediate dose, CGE did not cause motor impairment with the chimney test or alterations in either the open-field or sodium pentobarbital-induced sleep. In the formalin-induced pain test, CGE (150mg/kg, p.o.) produced an antinociceptive effect only in the first phase of the test, suggesting anti-inflammatory activity. With the same dosage, CGE also reduced the carrageenan-induced paw edema at all hours of the test, confirming its anti-inflammatory effect. Furthermore, CGE (150mg/kg, p.o.) presented an antihyperalgic effect at all hours of the carrageenan-induced hyperalgesia test. However, this dose of CGE was not able to reduce the hyperalgesia induced by PGE2, suggesting that the anti inflammatory effect of this extract depends on the reduction in the PGE2 levels. CONCLUSION: The anacardic acids are the predominant phytoconstituents identified in the CGE. The action mechanisms of CGE suggest the reduction in the PGE2 levels. These findings support the use of cashew gum in popular medicine and demonstrate that part of its antinociceptive and anti-inflammatory effects should also be attributed to the presence of anacardic acids in its composition, independent of the presence of polysaccharides. PMID- 29166576 TI - The beneficial health aspects of sea buckthorn (Elaeagnus rhamnoides (L.) A.Nelson) oil. AB - ETHNOPHARMACOLOGICAL CONTEXT: Plant oils are known to have biological activity. This review paper summarizes the current knowledge of the composition of sea buckthorn (Elaeagnus rhamnoides (L.) A.Nelson) seed and pulp oil and its beneficial health aspects. MATERIALS AND METHODS: In vitro and in vivo studies on humans and animals have found sea buckthorn oil to have a variety of beneficial properties to human health, and indicate that it may be a valuable component of human and animal nutrition. Various bioactive substances are present in all parts of sea buckthorn, and these are used traditionally as raw material for health foods and as nutritional supplements. The oil, berries, leaves and bark have medicinal properties, and the fruits have a unique taste; these parts can be processed to make oil, juice, jam, jellies and candies, as well as alcoholic and non-alcoholic beverages. RESULTS: Sea buckthorn oil may be extracted from the seed or the pulp. The mature seeds contain 8-20% oil and the dried fruit pulp about 20-25%, while the fruit residue contains about 15-20% oil after juice extraction. These oils have high concentrations of lipophilic constituents, most commonly unsaturated fatty acids (UFAs), phytosterols and vitamins A and E. These components have a multifunctional effect on human health, with the fatty acids playing an important function in modifying cerebrovascular and cardiovascular disorders. The oil also has anti-oxidant, anti-inflammatory and anti-depressive properties. CONCLUSION: Sea buckthorn is a unique plant. Its beneficial properties against cardiovascular disorders have been attributed to its high UFA content and range of phytosterols, especially beta-sitosterol. However, its different action on the human organism remain unclear, and further well controlled, high-quality experiments with human subjects are required to determine the prophylactic and therapeutic doses of sea buckthorn oil for use in clinical studies. Additional studies are also needed to understand the action by which the oil exerts its beneficial properties, i.e. its cardioprotective and anti-cancer activity. PMID- 29166577 TI - Cell cycle-related kinase regulates mammalian eye development through positive and negative regulation of the Hedgehog pathway. AB - Cell cycle-related kinase (CCRK) is a conserved regulator of ciliogenesis whose loss in mice leads to a wide range of developmental defects, including exencephaly, preaxial polydactyly, skeletal abnormalities, and microphthalmia. Here, we investigate the role of CCRK in mouse eye development. Ccrk mutants show dramatic patterning defects, with an expansion of the optic stalk domain into the optic cup, as well as an expansion of the retinal pigment epithelium (RPE) into neural retina (NR) territory. In addition, Ccrk mutants display a shortened optic stalk. These defects are associated with bimodal changes in Hedgehog (Hh) pathway activity within the eye, including the loss of proximal, high level responses but a gain in distal, low level responses. We simultaneously removed the Hh activator GLI2 in Ccrk mutants (Ccrk-/-;Gli2-/-), which resulted in rescue of optic cup patterning and exacerbation of optic stalk length defects. Next, we disrupted the Hh pathway antagonist GLI3 in mutants lacking CCRK (Ccrk-/-;Gli3-/-), which lead to even greater expansion of the RPE markers into the NR domain and a complete loss of NR specification within the optic cup. These results indicate that CCRK functions in eye development by both positively and negatively regulating the Hh pathway, and they reveal distinct requirements for Hh signaling in patterning and morphogenesis of the eyes. PMID- 29166578 TI - Glycans Function as Anchors for Antibodies and Help Drive HIV Broadly Neutralizing Antibody Development. PMID- 29166579 TI - The TCR Takes Some Immune Responsibility. AB - In this issue of Immunity, Van Braeckel-Budimmir et al. (2017) reveal that the pathogenic response of mice to a Plasmodium berghei infection is dominated by a Vbeta8.1 T cell response. Mice lacking Vbeta8.1 T cells fail to mount a pathogenic response, thus showing that the TCR locus can be an Immune response (Ir) gene. PMID- 29166580 TI - A Sweet Solution: Glycolysis-Dependent Treg Cell Migration. AB - mTORC2 is a metabolic regulatory complex activated by PI3K. In this issue of Immunity, Kishore et al. (2017) demonstrate a specialized role for this complex in the migration of regulatory T (Treg) cells to sites of inflammation rather than their differentiation and survival. PMID- 29166581 TI - TGF-beta Gives an Air of Exclusivity to Alveolar Macrophages. AB - Tissue-resident macrophages shape the development and homeostasis of the organs that they colonize. Yu et al. (2017) demonstrate that, unique to the lung, the instructive cytokine TGF-beta collaborates with GM-CSF to induce the master transcription factor PPARgamma to drive alveolar macrophage differentiation and maintenance early in life. PMID- 29166582 TI - The Silent Undertakers: Macrophages Programmed for Efferocytosis. AB - Two recent Immunity papers provide new insight into efferocytosis by tissue resident macrophages. Baratin et al. (2017) identify a resident macrophage population in the T cell zone of lymph nodes responsible for the silent uptake of vast numbers of apoptotic cells. Roberts et al. (2017) find that resident macrophages can be programmed by local tissue signals not to respond to the nucleic acid of apoptotic cells. PMID- 29166583 TI - The Skinny: Pancreatic ILC2s Promote Insulin Secretion. AB - Regulation of pancreatic insulin production is pivotal in the pathophysiology and treatment of diabetes. In this issue of Immunity, Dalmas et al. (2017) describe a type 2 immune circuit where pancreatic interleukin-33 (IL-33) promotes insulin secretion via the activity of islet-associated group 2 innate lymphoid cells (ILC2s). PMID- 29166584 TI - Swell, or Not Too Swell: Cytokines Regulate Arterial Aneurysm Formation. AB - Arterial remodeling participates pivotally in many diseases including arterial aneurysms. In this issue of Immunity, Da Ros et al. (2017) report that, in experimental aortic aneurysm formation, neutralization of interleukin-1beta reduced arterial wall stiffness and hampered aneurysm development. PMID- 29166585 TI - Brain, Immunity, Gut: "BIG" Links between Pregnancy and Autism. AB - Although dysregulation of brain, immune, and gut physiology during pregnancy have each been implicated in neuropsychiatric disorders, whether and how these presumably distinct systems are linked to cause disease is unclear. Kim et al. (2017) and Shin Yim et al. (2017) identify a pathway to explain how these aspects of our physiology are deeply and inextricably connected. PMID- 29166587 TI - Migrating Myeloid Cells Sense Temporal Dynamics of Chemoattractant Concentrations. AB - Chemoattractant-mediated recruitment of hematopoietic cells to sites of pathogen growth or tissue damage is critical to host defense and organ homeostasis. Chemotaxis is typically considered to rely on spatial sensing, with cells following concentration gradients as long as these are present. Utilizing a microfluidic approach, we found that stable gradients of intermediate chemokines (CCL19 and CXCL12) failed to promote persistent directional migration of dendritic cells or neutrophils. Instead, rising chemokine concentrations were needed, implying that temporal sensing mechanisms controlled prolonged responses to these ligands. This behavior was found to depend on G-coupled receptor kinase mediated negative regulation of receptor signaling and contrasted with responses to an end agonist chemoattractant (C5a), for which a stable gradient led to persistent migration. These findings identify temporal sensing as a key requirement for long-range myeloid cell migration to intermediate chemokines and provide insights into the mechanisms controlling immune cell motility in complex tissue environments. PMID- 29166586 TI - The Broad Spectrum of Human Natural Killer Cell Diversity. AB - Natural killer (NK) cells provide protection against infectious pathogens and cancer. For decades it has been appreciated that two major NK cell subsets (CD56bright and CD56dim) exist in humans and have distinct anatomical localization patterns, phenotypes, and functions in immunity. In light of this traditional NK cell dichotomy, it is now clear that the spectrum of human NK cell diversity is much broader than originally appreciated as a result of variegated surface receptor, intracellular signaling molecule, and transcription factor expression; tissue-specific imprinting; and foreign antigen exposure. The recent discoveries of tissue-resident NK cell developmental intermediates, non-NK innate lymphoid cells, and the capacity for NK cells to adapt and differentiate into long-lived memory cells has added further complexity to this field. Here we review our current understanding of the breadth and generation of human NK cell diversity. PMID- 29166588 TI - Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis. AB - Migration of activated regulatory T (Treg) cells to inflamed tissue is crucial for their immune-modulatory function. While metabolic reprogramming during Treg cell differentiation has been extensively studied, the bioenergetics of Treg cell trafficking remains undefined. We have investigated the metabolic demands of migrating Treg cells in vitro and in vivo. We show that glycolysis was instrumental for their migration and was initiated by pro-migratory stimuli via a PI3K-mTORC2-mediated pathway culminating in induction of the enzyme glucokinase (GCK). Subsequently, GCK promoted cytoskeletal rearrangements by associating with actin. Treg cells lacking this pathway were functionally suppressive but failed to migrate to skin allografts and inhibit rejection. Similarly, human carriers of a loss-of-function GCK regulatory protein gene-leading to increased GCK activity had reduced numbers of circulating Treg cells. These cells displayed enhanced migratory activity but similar suppressive function, while conventional T cells were unaffected. Thus, GCK-dependent glycolysis regulates Treg cell migration.